2025-04-17 10:46:55,593 - INFO - --- Starting Ligand Comparison Script ---
2025-04-17 10:46:55,747 - INFO - Generating 8192 unique random pairs...
2025-04-17 10:47:07,711 - INFO - Generated 8192 unique pairs.
2025-04-17 10:47:10,618 - INFO - Saved list to unique_smiles_for_vina_EGFR_2rgp.txt
2025-04-17 10:47:10,639 - INFO - Saved pairs to generated_pairs_EGFR_2rgp.csv
2025-04-17 10:47:10,639 - INFO - --- Intermediate files generated. Run Vina using 'unique_smiles_for_vina_EGFR_2rgp.txt' ---
2025-04-17 10:47:10,639 - INFO - --- Update affinity_map below and set run_llm_processing=True ---
2025-04-17 10:47:10,639 - INFO - --- Starting LLM Processing ---
2025-04-17 10:52:31,157 - 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, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0]
2025-04-17 10:52:31,161 - INFO - Loaded 11290 affinity values.
2025-04-17 10:52:31,269 - INFO - Prepared features for 8192 pairs.
2025-04-17 10:52:31,269 - INFO - Running LLM inference in 512 batches...
2025-04-17 10:52:31,269 - INFO - Processing batch 1/512...
2025-04-17 10:53:14,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.371 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.92) is better than Ligand B (49.41), being below 140, suggesting good absorption. Ligand B is exceptionally low, which could be a concern for potency.

**logP:** Ligand A (1.745) is optimal, while Ligand B (3.355) is slightly higher but still within the acceptable range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, which is good. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.786 and 0.793), indicating good drug-likeness.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (29.779). This is a significant negative for Ligand A.

**BBB:** Ligand A (70.143) has reasonable BBB penetration, while Ligand B (89.298) is even better. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.704 and -4.577), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.011 and -3.527), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.254) has a lower hERG risk than Ligand B (0.677), which is preferable.

**Microsomal Clearance:** Ligand A (10.678) has significantly lower microsomal clearance than Ligand B (26.397), indicating better metabolic stability. This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (17.413) has a longer half-life than Ligand B (-10.409), which is desirable.

**P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux than Ligand B (0.145), which is slightly better.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME liabilities.

**Conclusion:**

Despite Ligand B's superior binding affinity, the combination of significantly lower DILI risk and better metabolic stability (lower Cl_mic and longer t1/2) for Ligand A makes it the more promising candidate. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies. The stronger binding of Ligand B is attractive, but the higher DILI risk is a major red flag.

Output:
0
2025-04-17 10:53:14,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.418 and 349.475 Da) are within the ideal range (200-500 Da).

**TPSA:** Both ligands (64.79 and 65.79) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (2.236 and 2.203) fall within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, well within acceptable limits.

**QED:** Both ligands have good QED scores (0.906 and 0.855), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (22.063 and 21.093 percentile), which is favorable.

**BBB:** Ligand A (93.059) has a significantly higher BBB penetration percentile than Ligand B (63.94). While not a primary concern for a non-CNS target like SRC, it doesn't detract from its profile.

**Caco-2 Permeability:** Ligand A (-4.796) has a slightly worse Caco-2 permeability than Ligand B (-4.866), but both are negative values, indicating relatively poor permeability.

**Aqueous Solubility:** Ligand A (-2.134) has slightly worse aqueous solubility than Ligand B (-1.347), but both are negative values, indicating relatively poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.721 and 0.746 percentile).

**Microsomal Clearance:** Ligand A (9.729 mL/min/kg) has a higher microsomal clearance than Ligand B (0.305 mL/min/kg). This means Ligand B is predicted to have much better metabolic stability.

**In vitro Half-Life:** Ligand A (34.501 hours) has a much longer in vitro half-life than Ligand B (27.795 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.066 and 0.194 percentile).

**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 could outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic) and slightly better solubility and Caco-2 permeability, the significantly stronger binding affinity of Ligand A (-8.7 vs -7.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The longer half-life of Ligand A also contributes to its favorability. The slight differences in solubility and permeability are less critical given the strong potency and acceptable overall profile of Ligand A.

Output:
1
2025-04-17 10:53:14,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (346.471 and 340.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (69.64 and 67.23) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.006 and 1.334) are within the optimal 1-3 range. Ligand B is slightly more hydrophilic.

**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 and 4, respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.591 and 0.826), indicating good drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (36.642) has a lower DILI risk than Ligand B (54.556). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (62.854 and 62.35). Not a major factor for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.61 and -4.844). These values are unusual and suggest poor permeability, but are likely on a log scale where negative values indicate low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.476 and -3.084). These values are also unusual and suggest poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.358 and 0.258).

**12. Microsomal Clearance (Cl_mic):** Ligand B (24.702) has lower microsomal clearance than Ligand A (30.58), suggesting better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (-25.176) has a longer in vitro half-life than Ligand B (-4.32). Again, these values are unusual and likely on a log scale.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.219 and 0.127).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.0 kcal/mol). The difference is less than 0.5 kcal/mol, so it's not a decisive factor.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Comparison:**

*   **Affinity:** Similar.
*   **Metabolic Stability:** Ligand B is better (lower Cl_mic).
*   **Solubility:** Both are poor, but Ligand B is slightly better.
*   **DILI:** Ligand A has a significantly lower DILI risk.
*   **Half-life:** Ligand A has a longer half-life.

Considering the enzyme-specific priorities, the lower DILI risk and longer half-life of Ligand A are more valuable than the slightly better metabolic stability of Ligand B. The poor solubility and permeability of both compounds are concerning, but can be addressed with formulation strategies.

Output:
0
2025-04-17 10:53:14,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (376.475 and 363.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.8) is better than Ligand B (42.68). While both are reasonably low, Ligand B is exceptionally low, which *could* indicate poor binding due to lack of necessary polar interactions.

**logP:** Ligand A (-0.372) is suboptimal, potentially leading to poor permeability. Ligand B (4.22) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is better balanced. Ligand B (0 HBD, 4 HBA) has very few hydrogen bond donors, which could be problematic for binding to the kinase active site.

**QED:** Both ligands have acceptable QED values (0.538 and 0.487), indicating reasonable drug-likeness.

**DILI:** Ligand A (37.301) has a slightly higher DILI risk than Ligand B (27.142), but both are below the concerning threshold of 60.

**BBB:** Both have acceptable BBB penetration, but Ligand B (77.239) is better than Ligand A (67.197). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

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

**hERG:** Ligand A (0.107) has a significantly lower hERG risk than Ligand B (0.741), which is a major advantage.

**Microsomal Clearance:** Ligand A (3.015 mL/min/kg) has much lower microsomal clearance than Ligand B (89.613 mL/min/kg), indicating better metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (10.272 hours) has a much longer half-life than Ligand B (44.325 hours).

**P-gp Efflux:** Ligand A (0.022) has lower P-gp efflux than Ligand B (0.75), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has slightly better binding affinity than Ligand B (-7.6 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand A is the superior candidate. While its logP is slightly low, its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, lower P-gp efflux, and slightly better binding affinity outweigh the concerns about its logP and solubility. Ligand B's high logP and very high clearance are major drawbacks. The unusual negative values for Caco-2 and solubility for both compounds are concerning and would require further investigation, but the other factors strongly favor Ligand A.

Output:
0
2025-04-17 10:53:14,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.332 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.94) is better than Ligand B (43.86) as it is still within the acceptable range for oral absorption (<140), but Ligand B is significantly lower, potentially aiding absorption.

**logP:** Both ligands have good logP values (3.346 and 2.275), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 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 (0.792 and 0.717), indicating good drug-likeness.

**DILI:** Ligand A (74.874) has a higher DILI risk than Ligand B (5.777). This is a significant negative for Ligand A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (70.958) is slightly higher than Ligand B (81), but this difference is less important.

**Caco-2 Permeability:** Ligand A (-5.123) has worse Caco-2 permeability than Ligand B (-4.59). Both are negative, indicating low permeability, but B is better.

**Aqueous Solubility:** Ligand A (-4.085) has worse solubility than Ligand B (-1.752). Solubility is important for bioavailability, making Ligand B preferable.

**hERG:** Both ligands have similar hERG values (0.424 and 0.582), indicating relatively low risk.

**Microsomal Clearance:** Ligand A (19.513) has lower microsomal clearance than Ligand B (23.524), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (45.722) has a significantly longer half-life than Ligand B (22.791), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.387 and 0.052).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.3 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B is superior due to its significantly lower DILI risk, better solubility, and slightly better Caco-2 permeability, despite having a slightly shorter half-life and slightly lower binding affinity. The lower DILI is a critical factor, and the other improvements in ADME properties make it a more promising candidate. While Ligand A has better metabolic stability and half-life, the high DILI risk is a substantial concern.

Output:
1
2025-04-17 10:53:14,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.275 and 363.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.29) is better than Ligand B (95.67). Both are below 140, but A is closer to the preferred threshold for good absorption.

**logP:** Ligand A (2.782) is optimal, while Ligand B (1.58) is a bit low, 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 3 HBA, and Ligand B has 6. Ligand A is preferable here, as higher HBA can sometimes reduce permeability.

**QED:** Both ligands have similar QED values (0.78 and 0.779), indicating good drug-likeness.

**DILI:** Ligand A (79.643) has a higher DILI risk than Ligand B (57.658). This is a significant drawback for Ligand A.

**BBB:** Ligand A (58.007) has a better BBB penetration percentile than Ligand B (36.371), but BBB is not a high priority for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.346 and -5.395), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.874) has slightly better solubility than Ligand B (-1.422), although both are quite poor.

**hERG Inhibition:** Ligand A (0.039) has a very low hERG risk, while Ligand B (0.149) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-8.568) has significantly lower (better) microsomal clearance than Ligand B (-1.099), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.605) has a much longer in vitro half-life than Ligand B (22), suggesting a slower degradation rate and potentially less frequent dosing.

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux than Ligand B (0.062), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk, its superior binding affinity, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better solubility outweigh the concerns. The strong binding affinity is a critical factor for an enzyme inhibitor. While both have poor Caco-2 permeability, the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 10:53:14,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.5 and 348.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (71 and 76.5) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (1.79 and 1.25) 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 5 HBA, also acceptable (<=10).

**6. QED:** Both ligands have high QED scores (0.825 and 0.869), indicating good drug-like properties.

**7. DILI:** Ligand A (28.3%) has a significantly lower DILI risk than Ligand B (39.9%). This is a substantial advantage.

**8. BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B is slightly better (73.8% vs 59.4%).

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the values are similar (-5.13 and -4.38) and likely indicate poor permeability. This is a drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are similar (-2.91 and -2.28).

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.152 and 0.237).

**12. Microsomal Clearance:** Ligand A (30.7 mL/min/kg) has a lower microsomal clearance than Ligand B (52.1 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Both have similar and negative in vitro half-lives (-8.595 and -8.192 hours). This is a concern for both, suggesting rapid metabolism.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.07 and 0.048).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), a 0.4 kcal/mol difference. While affinity is crucial, the difference is not large enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a significantly lower DILI risk and better metabolic stability (lower Cl_mic) than Ligand B. While Ligand B has slightly better binding affinity, the difference is small, and the advantages of Ligand A in safety and metabolic stability are more important for a kinase inhibitor. The poor solubility and permeability are concerns for both, but can be addressed in later stages of optimization.

Output:
0
2025-04-17 10:53:14,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.415 and 371.384 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.41) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (73.2) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.169 and 2.222), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.717 and 0.863), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 90.733, which is high and concerning. Ligand B has a much lower DILI risk of 55.68, which is still not ideal but significantly better.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (81.582) than Ligand A (17.642), but this isn't a major factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.405 and -4.859), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.516 and -3.611), which is also concerning and indicates poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.022) has a very low hERG risk, which is excellent. Ligand B (0.656) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (11.921) has a higher microsomal clearance than Ligand B (4.112), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-20.784) has a very short in vitro half-life, indicating rapid metabolism. Ligand B (-11.308) has a longer half-life, but still relatively short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.026 and 0.107).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.6 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Despite both ligands having good binding affinity, Ligand B is the more promising candidate. The primary driver is the significantly lower DILI risk (55.68 vs 90.733). Although both have poor solubility and permeability, the lower clearance and longer half-life of Ligand B, combined with its better DILI profile, make it a more viable starting point for optimization. The hERG risk is slightly higher for Ligand B, but manageable.

Output:
1
2025-04-17 10:53:14,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.363 Da) is slightly higher than Ligand B (351.447 Da), but both are acceptable.

**TPSA:** Ligand A (66.48) is better than Ligand B (86.79). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.922, Ligand B: 0.723), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for cell permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (Ligand A: 0.482, Ligand B: 0.62), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A has a significantly higher DILI risk (68.476%) than Ligand B (16.053%). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (82.125%) is better than Ligand B (65.064%). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests a potential issue with intestinal absorption. This needs further investigation, but it's not a clear differentiator here.

**Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. Again, further investigation is needed.

**hERG:** Ligand A (0.498) has a slightly higher hERG risk than Ligand B (0.098). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (44.185 mL/min/kg) has a much lower microsomal clearance than Ligand B (16.822 mL/min/kg). This indicates better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (7.869 hours) has a significantly longer half-life than Ligand B (-18.716 hours). This is a major advantage for Ligand A, allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux than Ligand B (0.014), which is favorable.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This 1.9 kcal/mol difference is substantial and can 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), which are crucial for an enzyme target. It also has better BBB penetration and P-gp efflux. However, it has a higher DILI risk and slightly higher hERG risk. Ligand B has a better QED and lower DILI/hERG, but its significantly weaker binding affinity and poorer metabolic stability are major drawbacks.

Given the importance of potency and metabolic stability for kinase inhibitors, and the substantial difference in binding affinity, **Ligand A is the more promising candidate despite its higher DILI risk.** The DILI risk could potentially be mitigated through structural modifications during lead optimization.

Output:
1
2025-04-17 10:53:14,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.451 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly higher than Ligand B (58.64). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (0.037) is quite low, potentially hindering permeability. Ligand B (2.575) 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 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.673 and 0.569), indicating good drug-like properties.

**DILI:** Ligand A (15.083) has a much lower DILI risk than Ligand B (28.461), which is a strong positive for Ligand A.

**BBB:** Ligand B (75.107) has a higher BBB penetration percentile than Ligand A (49.515). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.253) has poor Caco-2 permeability, while Ligand B (-4.805) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.499) has slightly better solubility than Ligand B (-2.421).

**hERG:** Both ligands have low hERG inhibition liability (0.144 and 0.216), which is good.

**Microsomal Clearance:** Ligand A (-57.626) has significantly lower (better) microsomal clearance than Ligand B (35.914), indicating greater metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-27.574) has a more negative value, which translates to a longer half-life, compared to Ligand B (-2.108). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.002 and 0.135).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Overall Assessment:**

Ligand A excels in binding affinity, metabolic stability (low Cl_mic, long t1/2), DILI risk, and has acceptable solubility. Its main drawback is the low logP and poor Caco-2 permeability. However, the strong binding affinity can often compensate for permeability issues, especially for kinase inhibitors where high potency can reduce the required concentration. Ligand B has a better logP and TPSA, but suffers from weaker binding affinity, higher DILI risk, and poorer metabolic stability.

Given the enzyme-specific priorities (potency, metabolic stability, solubility, hERG), and the substantial difference in binding affinity and metabolic stability, Ligand A is the more promising candidate.

Output:
1
2025-04-17 10:53:14,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is well below the 140 threshold for good absorption, while Ligand B (88.1) is still acceptable but less optimal.

**logP:** Ligand A (1.542) is within the optimal 1-3 range. Ligand B (-0.223) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.655 and 0.619), indicating good drug-likeness.

**DILI:** Ligand A (16.402) has a significantly lower DILI risk than Ligand B (25.553), which is a major advantage.

**BBB:** Ligand A (76.813) has a better BBB penetration percentile than Ligand B (29.003), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.699) and Ligand B (-4.661) have similar, and very poor, Caco-2 permeability scores. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.062 and -1.698). This is a significant drawback that would require formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.119 and 0.157).

**Microsomal Clearance:** Ligand A (28.846) has a higher microsomal clearance than Ligand B (-0.067). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-3.08) has a better in vitro half-life than Ligand A (-4.096).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.067).

**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 preferred, this difference is still meaningful.

**Conclusion:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, better t1/2). However, Ligand A has a significantly lower DILI risk, better TPSA, and better BBB penetration. Both have poor solubility and Caco-2 permeability. Given the enzyme-specific priorities, metabolic stability and potency are crucial. The 0.8 kcal/mol difference in binding affinity, coupled with the improved metabolic stability, outweighs the slightly higher DILI risk and poorer TPSA of Ligand B. The solubility issues would need to be addressed with formulation, but the core pharmacodynamic and pharmacokinetic properties of Ligand B are more favorable.

Output:
1
2025-04-17 10:53:14,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.419 and 385.917 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (85.05 and 80.32) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.903) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (2.65) is well within the optimal 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 (6) and Ligand B (5) are both acceptable, below the 10 threshold.

**6. QED:** Ligand A (0.873) has a higher QED score than Ligand B (0.674), indicating better overall drug-likeness.

**7. DILI:** Both ligands have relatively high DILI risk (56.805 and 65.568), but are still below the concerning >60 threshold.

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand A (66.77) is slightly better than Ligand B (50.679). This is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.111 and -5.203). 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 (-2.001 and -3.702). Again, the scale is not specified, making interpretation difficult. Poor solubility is a significant concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.246 and 0.316), which is positive.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (38.62 and 37.898 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (39.647) has a significantly longer in vitro half-life than Ligand A (19.706), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.073 and 0.232).

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 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 more promising candidate. While Ligand A has a better QED score, Ligand B's significantly stronger binding affinity (-8.9 vs -7.6 kcal/mol) and longer half-life are critical advantages for an enzyme inhibitor. Although both have concerning solubility and permeability values, the potency advantage of B is likely to be more impactful in driving *in vivo* efficacy. The slightly better logP of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 10:53:14,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**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 (70.49) and Ligand B (67.43) are both below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (2.489 and 2.703) within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBDs, well within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBAs and Ligand B has 3 HBAs, both are below the acceptable limit of <=10.

**6. QED:** Both ligands have QED scores (0.757 and 0.725) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (8.181) has a significantly lower DILI risk than Ligand B (19.426). This is a major advantage for Ligand A.

**8. BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (79.062) has a higher BBB percentile than Ligand B (63.319).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.345 and -5.064) 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 (-3.167 and -2.87), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.904) has a slightly higher hERG inhibition risk than Ligand B (0.251), but both are relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (7.455) has a significantly lower Cl_mic than Ligand B (33.985), indicating better metabolic stability. This is crucial for an enzyme target.

**13. In vitro Half-Life (t1/2):** Ligand A (-34.235) has a much longer in vitro half-life than Ligand B (28.538). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux liability than Ligand B (0.061), which is favorable.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a 1.3 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B boasts a better binding affinity, Ligand A presents a far superior ADMET profile. The lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux are critical advantages for an enzyme inhibitor. The slightly higher hERG risk for Ligand A is less concerning than the poor metabolic stability of Ligand B. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are paramount.

Output:
0
2025-04-17 10:53:14,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.451 and 347.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is slightly higher than Ligand B (44.81). Both are below the 140 threshold for good oral absorption, but closer to the ideal range.

**logP:** Both ligands have good logP values (3.202 and 2.473), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which is within acceptable limits.

**QED:** Both ligands have good QED scores (0.856 and 0.89), indicating good drug-likeness.

**DILI:** Ligand A (30.748) has a significantly lower DILI risk than Ligand B (10.741). This is a major advantage for Ligand A.

**BBB:** Ligand B (86.196) has a higher BBB penetration percentile than Ligand A (67.468). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.329 and -4.542), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand B (-1.606) has better aqueous solubility than Ligand A (-4.625). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.464) has a lower hERG inhibition liability than Ligand B (0.864), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (-1.244) has a negative clearance, which is highly favorable and suggests excellent metabolic stability. Ligand A (82.633) has a high clearance, indicating poor metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (8.602) has a much longer in vitro half-life than Ligand A (-0.943). This is a significant advantage for Ligand B, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.265 and 0.068).

**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:**

While both ligands have good binding affinity and drug-like properties, Ligand B is the more promising candidate. Its superior metabolic stability (negative Cl_mic), longer half-life, and better solubility outweigh the slightly higher DILI risk and lower BBB penetration (which is not a priority for this target). Ligand A's high microsomal clearance is a significant concern.

Output:
1
2025-04-17 10:53:14,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.515 Da) is slightly better positioned.

**TPSA:** Ligand A (49.41) is excellent, well below the 140 threshold for absorption. Ligand B (113.76) is still reasonable, but less optimal.

**logP:** Ligand A (4.813) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (-0.957) is too low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is excellent. Ligand B (HBD=2, HBA=8) is acceptable, but the higher HBA count could slightly reduce permeability.

**QED:** Both ligands have similar QED values (A: 0.697, B: 0.632), indicating good drug-likeness.

**DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (61.303), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.39) is better than Ligand B (24.544).

**Caco-2 Permeability:** Ligand A (-4.373) is better than Ligand B (-5.248), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.989) is better than Ligand B (-0.874). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.816) has a lower hERG risk than Ligand B (0.086), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (104.052) has higher clearance than Ligand B (-9.284). Ligand B shows negative clearance which is not possible. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (73.984) has a much longer half-life than Ligand B (20.363), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.452) has lower P-gp efflux than Ligand B (0.011), which is favorable for bioavailability.

**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:**

While Ligand B boasts a superior binding affinity, its significantly worse ADME profile, particularly the negative microsomal clearance, high DILI risk, and poor solubility, are major concerns. Ligand A, despite a slightly weaker affinity, presents a much more balanced and favorable profile with acceptable ADME properties, lower toxicity risk, and better metabolic stability. The difference in binding affinity (1.4 kcal/mol) is substantial, but not insurmountable, and can potentially be optimized in subsequent iterations. The ADME issues with Ligand B are much harder to fix.

Output:
0
2025-04-17 10:53:14,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.471 and 374.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (93.53). A TPSA under 140 is good for oral absorption, and both are under, but A is preferable.

**logP:** Ligand A (2.231) is optimal (1-3), while Ligand B (0.916) is slightly 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 3 HBAs, while Ligand B has 6. Both are under the limit of <=10, but A is preferable.

**QED:** Ligand A (0.824) has a better QED score than Ligand B (0.657), indicating a more drug-like profile.

**DILI:** Ligand B (49.826) has a slightly better DILI score than Ligand A (36.022), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (63.358 and 65.374), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.376) has a better Caco-2 permeability than Ligand B (-5.079).

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-1.501 and -1.532).

**hERG Inhibition:** Ligand A (0.724) has a better hERG inhibition profile than Ligand B (0.326), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (54.594) has a better microsomal clearance than Ligand B (58.368), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.857) has a much better in vitro half-life than Ligand A (-0.439). This is a significant advantage.

**P-gp Efflux:** Both ligands have a P-gp efflux of 0, which is good.

**Binding Affinity:** Ligand A (0) has a better binding affinity than Ligand B (0.093).

**Overall Assessment:**

Ligand A generally performs better across most key ADME properties (TPSA, logP, HBA, QED, Caco-2, hERG, Cl_mic) and has a better binding affinity. While Ligand B has a significantly better in vitro half-life, the other advantages of Ligand A, particularly its better potency and lower potential for off-target effects (hERG), make it the more promising candidate. The solubility is a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 10:53:14,855 - INFO - Batch 1 complete. Total preferences: 16
2025-04-17 10:53:14,855 - INFO - Processing batch 2/512...
2025-04-17 10:53:54,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.62) is better than Ligand B (95.74), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.591 and 1.453), 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 acceptable HBD (1 & 2) and HBA (4 & 4) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have similar QED scores (0.732 and 0.729), indicating good drug-likeness.

**DILI:** Ligand B (22.722) has a significantly lower DILI risk than Ligand A (35.595). This is a major advantage for Ligand B.

**BBB:** Ligand B (77.937) shows better BBB penetration than Ligand A (60.566), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.648) has a worse Caco-2 permeability than Ligand B (-5.227), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.773) has slightly better aqueous solubility than Ligand B (-1.869), but both are quite poor.

**hERG:** Both ligands have very low hERG inhibition liability (0.229 and 0.117), which is excellent.

**Microsomal Clearance:** Ligand B (31.708) has lower microsomal clearance than Ligand A (36.555), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-2.033) has a negative half-life, which is not possible. This is likely an error in the data, but it is a significant red flag. Ligand A (1.084) has a short half-life, but it is a plausible value.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.095 and 0.016).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the solubility issues with both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.5 vs -7.6 kcal/mol) and lower DILI risk are major advantages. The lower microsomal clearance also contributes to better metabolic stability. The negative half-life for Ligand B is a concern and needs investigation. However, the substantial affinity difference makes Ligand B the preferred choice.

Output:
1
2025-04-17 10:53:54,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.342 and 366.824 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (46.33) is significantly better than Ligand B (66.71). Lower TPSA generally favors better absorption, and both are acceptable, but A is preferable.

**logP:** Both ligands have good logP values (3.743 and 2.504), falling within the optimal 1-3 range.

**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 limit of 10, but A is slightly better.

**QED:** Both ligands have good QED scores (0.833 and 0.854), indicating good drug-like properties.

**DILI:** Ligand A (17.914) has a much lower DILI risk than Ligand B (67.003). This is a significant advantage for Ligand A.

**BBB:** While not critical for a non-CNS target like SRC, Ligand A (96.2) has a higher BBB percentile than Ligand B (81.815).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating 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:** Ligand A (0.824) has a lower hERG risk than Ligand B (0.376), which is a significant advantage.

**Microsomal Clearance:** Ligand A (3.284) has a much lower microsomal clearance than Ligand B (52.534), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-9.484) has a much longer in vitro half-life than Ligand B (53.133), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux liability than Ligand B (0.171).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are good, the 1.5 kcal/mol difference is a noticeable advantage.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical parameters for an enzyme inhibitor. It has a lower DILI risk, lower hERG risk, significantly 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 ADME/Tox profile of Ligand A is far superior.

Output:
1
2025-04-17 10:53:54,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (386.547 and 385.251 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.41 and 97.11) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration.

**logP:** Ligand A (1.183) is closer to the optimal 1-3 range than Ligand B (2.403), which is still acceptable but edging towards potential solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand B (0.727) has a significantly better QED score than Ligand A (0.402), indicating a more drug-like profile.

**DILI:** Ligand A (39.511) has a much lower DILI risk than Ligand B (69.523). This is a significant advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

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

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a red flag for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.115 and 0.013), which is excellent.

**Microsomal Clearance:** Ligand A (17.623) and Ligand B (16.31) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-22.102) has a significantly longer in vitro half-life than Ligand A (-1.098). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.025).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI) and slightly better binding affinity. However, Ligand B has a significantly better QED score and a much longer in vitro half-life. Both have poor predicted permeability and solubility. Given the enzyme-specific priorities, metabolic stability (half-life) is crucial. The longer half-life of Ligand B is a significant advantage that outweighs the slightly weaker binding and higher DILI risk, especially considering the small difference in binding affinity. The poor permeability and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 10:53:54,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (366.571 and 361.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (81.99). TPSA < 140 is good for oral absorption, and both are within this limit, but lower is generally preferred.

**3. logP:** Both ligands have similar logP values (3.638 and 3.818), falling within the optimal range of 1-3.

**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) for similar reasons as HBD.

**6. QED:** Ligand B (0.723) has a slightly better QED score than Ligand A (0.474), indicating a more drug-like profile.

**7. DILI:** Ligand A (31.601) has a much lower DILI risk than Ligand B (54.323). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand A (66.499) is slightly better than Ligand B (52.423).

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.747 and -4.807), indicating poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-4.336 and -4.908), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Ligand A (0.208) has a significantly lower hERG risk than Ligand B (0.609). This is a major advantage for Ligand A.

**12. Cl_mic:** Ligand B (69.156) has a lower microsomal clearance than Ligand A (82.786), suggesting better metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand B (40.394) has a longer in vitro half-life than Ligand A (22.402), which is desirable. This favors Ligand B.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.156 and 0.136).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This is a positive for Ligand B, and the 0.5 kcal/mol difference is substantial enough to consider.

**Overall Assessment:**

While Ligand B has better affinity, half-life, and metabolic stability, Ligand A has significantly better safety profiles (DILI and hERG) and slightly better permeability characteristics (TPSA, HBD, HBA). Both have poor solubility and Caco-2 permeability. Given the enzyme-specific priorities, the lower hERG risk and DILI risk of Ligand A are crucial. Poor solubility can be addressed with formulation strategies, but mitigating cardiotoxicity and liver injury is far more challenging. The affinity difference is not large enough to outweigh the safety concerns with Ligand B.

Output:
0
2025-04-17 10:53:54,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.427 and 358.781 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is better than Ligand B (70.42), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.604 and 3.275), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but is not a major concern.

**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:** Ligand A (0.91) has a significantly better QED score than Ligand B (0.397), indicating a more drug-like profile.

**DILI:** Ligand A (49.903) has a much lower DILI risk than Ligand B (90.694). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (84.064) is better than Ligand B (63.746).

**Caco-2 Permeability:** Both are negative (-4.456 and -4.508), indicating poor permeability. This is a concern for both, but needs to be balanced against other factors.

**Aqueous Solubility:** Both are negative (-2.6 and -4.055), indicating poor solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.23 and 0.205), which is excellent.

**Microsomal Clearance:** Ligand A (49.493) has significantly lower microsomal clearance than Ligand B (126.773), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (2.949) has a shorter half-life than Ligand B (23.593). This is a disadvantage for Ligand A, but could be mitigated with formulation strategies.

**P-gp Efflux:** Both have low P-gp efflux liability (0.056 and 0.74).

**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, potentially outweighing some of the ADME drawbacks. The difference of 1.6 kcal/mol is quite significant.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic) are key advantages. While its solubility and Caco-2 permeability are poor, these can potentially be addressed through formulation. The QED score is also much higher for Ligand A. Ligand B's longer half-life is a plus, but the significantly weaker binding affinity and higher DILI risk make it less attractive.

Output:
0
2025-04-17 10:53:54,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (375.4 and 344.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.76) is better than Ligand B (49.41). While both are acceptable, lower TPSA generally improves permeability.

**logP:** Ligand A (1.044) is within the optimal range (1-3), while Ligand B (3.42) is towards the higher end but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**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 (0.721 and 0.795, respectively), indicating good drug-likeness.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (13.532). This is a significant negative for Ligand A.

**BBB:** Ligand A (88.174) has better BBB penetration than Ligand B (76.154), but this is less important for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.697) and Ligand B (-4.82) have similar, very negative Caco-2 permeability values. This suggests poor intestinal absorption for both.

**Solubility:** Ligand A (-2.829) has slightly better solubility than Ligand B (-3.86), but both are quite poor.

**hERG:** Both ligands have similar hERG inhibition liability (0.33 and 0.385), indicating low cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (39.431) has significantly lower microsomal clearance than Ligand A (8.583), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-6.632) has a longer in vitro half-life than Ligand A (-13.543), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.147 and 0.098), indicating moderate efflux.

**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 more promising candidate. While Ligand A has slightly better TPSA and BBB penetration (less relevant for SRC), Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The small advantage in binding affinity further supports choosing Ligand B. The poor Caco-2 values for both are a concern, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 10:53:54,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (349.519 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold for good absorption and is favorable. Ligand B (113.44) is still within acceptable limits but less optimal.

**logP:** Ligand A (2.476) is within the optimal 1-3 range. Ligand B (-0.222) is below 1, which could hinder 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 (0.662) has a better QED score than Ligand B (0.421), indicating a more drug-like profile.

**DILI:** Ligand A (7.832) has a significantly lower DILI risk than Ligand B (45.25), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (70.88) has a higher percentile than Ligand B (34.742).

**Caco-2 Permeability:** Both ligands have a negative Caco-2 value (-5.048), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have a negative solubility value (-2.049 and -1.487), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.457) has a lower hERG risk than Ligand B (0.049), which is preferable.

**Microsomal Clearance:** Ligand A (27.006) has a higher (worse) microsomal clearance than Ligand B (-2.964). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-19.626) has a significantly longer in vitro half-life than Ligand A (-6.717), which is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.006).

**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 is still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better overall profile. It has a better QED score, significantly lower DILI risk, lower hERG risk, and slightly better binding affinity. While both ligands have poor solubility and Caco-2 permeability, the lower toxicity and better predicted ADME properties of Ligand A outweigh the slightly better metabolic stability and half-life of Ligand B. The binding affinity difference is not large enough to overcome the ADME advantages of Ligand A.

Output:
1
2025-04-17 10:53:54,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.8) is well below the 140 threshold for oral absorption and even below the 90 threshold for CNS penetration, while Ligand B (104.6) is still within acceptable limits for oral absorption, but less favorable.

**logP:** Ligand A (1.839) is optimal, while Ligand B (0.238) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Ligand A (0.842) has a significantly better QED score than Ligand B (0.699), indicating a more drug-like profile.

**DILI:** Ligand B (67.507) has a higher DILI risk than Ligand A (47.693), though both are reasonably acceptable.

**BBB:** Ligand A (88.755) has a much higher BBB penetration percentile than Ligand B (41.605). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.66) has a worse Caco-2 permeability than Ligand B (-5.561), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.929) has better aqueous solubility than Ligand B (-2.431).

**hERG Inhibition:** Ligand A (0.364) has a lower hERG inhibition liability than Ligand B (0.168), which is a significant advantage.

**Microsomal Clearance:** Ligand A (57.875) has a higher microsomal clearance than Ligand B (0.932), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (29.961) has a longer in vitro half-life than Ligand B (21.971).

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux liability than Ligand B (0.008).

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is only 0.6 kcal/mol, and other factors are more critical.

**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: better QED, lower DILI risk, lower hERG inhibition, better solubility, and a longer half-life. The lower Caco-2 permeability of Ligand A is a concern, but can be addressed through formulation strategies. The superior metabolic stability of Ligand B is a benefit, but the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 10:53:54,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.234 Da) is slightly higher than Ligand B (358.467 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (86.71) is slightly higher than Ligand B (78.09), but both are favorable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.922) is at the higher end, while Ligand B (2.088) is closer to 2. This suggests Ligand A *might* have slight solubility issues, but it's not a major concern.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which is within the acceptable limits for both properties.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand B (0.878) is slightly higher than Ligand A (0.723).

**DILI:** Ligand A (47.732) has a lower DILI risk than Ligand B (58.434), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (50.523) has a slightly higher BBB penetration potential than Ligand A (36.332), but it's not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is unclear, so we can't definitively say how problematic this is.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting poor solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.23 and 0.322 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-10.871) has significantly lower (better) microsomal clearance than Ligand B (14.153). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-24.329) has a longer in vitro half-life than Ligand B (-19.872), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.102 respectively), which is favorable.

**Binding Affinity:** Both ligands have strong binding affinity (-8.0 and -9.1 kcal/mol respectively). Ligand B has a 1.1 kcal/mol advantage in binding affinity, which is substantial.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate overall. Its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and longer t1/2) are crucial advantages for an enzyme target like SRC kinase. The solubility and permeability concerns are present in both, but metabolic stability and safety are paramount. The 1.1 kcal/mol difference in binding can potentially be overcome with further optimization of Ligand A, whereas mitigating the higher DILI and lower metabolic stability of Ligand B would be more challenging.

Output:
0
2025-04-17 10:53:54,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.443 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.84) is better than Ligand B (87.3), being comfortably below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.891 and 1.699), 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 (2 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 3 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.9 and 0.613), indicating good drug-like properties. Ligand A is superior.

**DILI:** Ligand A (43.622) has a lower DILI risk than Ligand B (24.544), indicating a safer profile.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (81.66) is better than Ligand B (59.364).

**Caco-2 Permeability:** Ligand A (-4.641) shows better Caco-2 permeability than Ligand B (-5.462), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.712) has better aqueous solubility than Ligand B (-2.403), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.318 and 0.05), which is excellent.

**Microsomal Clearance:** Ligand B (18.945) has a lower microsomal clearance than Ligand A (24.586), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (21.368) has a longer in vitro half-life than Ligand A (-9.64), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.052).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B demonstrates superior metabolic stability (lower Cl_mic and longer t1/2) which is a key consideration for kinase inhibitors. While Ligand A has advantages in several other areas (TPSA, solubility, QED, DILI), the improved metabolic stability of Ligand B is more critical for an enzyme target. The binding affinities are essentially identical, so the ADME benefits of Ligand B outweigh the slight advantages of Ligand A.

Output:
1
2025-04-17 10:53:54,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.543 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly above the preferred <140, but acceptable. Ligand B (52.65) is well within the range.

**logP:** Both ligands have good logP values (3.015 and 2.408), 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 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.744) has a better QED score than Ligand B (0.487), indicating a more drug-like profile.

**DILI:** Ligand A (32.881) has a significantly lower DILI risk than Ligand B (5.584), which is a major advantage.

**BBB:** Both ligands have moderate BBB penetration (63.048 and 60.876). Since SRC is not a CNS target, this is not a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.922 and -4.888). 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.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.829 and -1.524). Again, these are likely log scales and indicate poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.219) shows a lower hERG inhibition liability than Ligand B (0.6), which is favorable.

**Microsomal Clearance:** Ligand A (71.371) has a higher microsomal clearance than Ligand B (-15.25). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-8.743) has a longer in vitro half-life than Ligand A (-5.97), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.051).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). The difference is 1.0 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity, QED score, and significantly lower DILI risk and hERG liability. However, Ligand B exhibits superior metabolic stability (lower Cl_mic and longer t1/2). The negative Caco-2 and solubility values are concerning for both, but the strong binding affinity of Ligand A, coupled with the lower toxicity profile, makes it the more promising candidate. The slight advantage in binding affinity outweighs the metabolic stability advantage of Ligand B.

Output:
1
2025-04-17 10:53:54,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.379 and 365.411 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (130.68) is slightly above the preferred <140 for good absorption, while Ligand B (110.53) is well within the range.

**logP:** Ligand A (-0.675) is a bit low, potentially hindering permeation. Ligand B (1.17) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.326 and 0.762), with Ligand B being significantly better.

**DILI:** Ligand A (56.727) has a lower DILI risk than Ligand B (77.782), which is a positive.

**BBB:** Both have acceptable BBB penetration, but Ligand A (70.919) is better than Ligand B (60.566). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.538) is slightly better than Ligand B (-4.838).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.333 and -3.727). This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.14 and 0.198).

**Microsomal Clearance:** Ligand A (-13.767) has significantly lower (better) microsomal clearance than Ligand B (42.255), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (27.633) has a better in vitro half-life than Ligand B (-28.566).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.004 and 0.128).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is not substantial enough to outweigh other significant drawbacks.

**Overall Assessment:**

Ligand A has a better DILI score, better metabolic stability (lower Cl_mic and better t1/2), and slightly better Caco-2 permeability. However, its logP is low, and solubility is poor. Ligand B has a better QED score and slightly better binding affinity, but suffers from worse metabolic stability, higher DILI risk, and poor solubility.

The poor solubility of both compounds is a major concern. However, the significantly better metabolic stability of Ligand A, coupled with its lower DILI risk, makes it the more promising candidate despite the slightly weaker binding affinity and lower logP. The difference in binding affinity is not large enough to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 10:53:54,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.407 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.58) is better than Ligand B (62.99), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (-0.376) is a bit low, potentially hindering permeation. Ligand B (2.33) is within the optimal 1-3 range. This favors Ligand B.

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

**H-Bond Acceptors:** Both ligands have 6 and 4 acceptors, respectively, both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.555 and 0.791).

**DILI:** Ligand A (46.801) has a slightly higher DILI risk than Ligand B (22.102), but both are below the concerning threshold of 60.

**BBB:** Ligand A (16.363) has very low BBB penetration, while Ligand B (80.574) has high BBB penetration. Since SRC is not a CNS target, this is less crucial, but still a point for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.576) has poor Caco-2 permeability, which is a concern. Ligand B (-4.276) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.072 and -1.573). This is a potential issue for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.125 and 0.286).

**Microsomal Clearance:** Ligand A (-19.357) has significantly lower (better) microsomal clearance than Ligand B (41.896), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand B (47.08) has a much longer in vitro half-life than Ligand A (4.807). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.004 and 0.101).

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.5), a difference of 0.8 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B has a better logP, BBB penetration, in vitro half-life, and binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic). The difference in binding affinity (0.8 kcal/mol) and half-life (42.28 hours) is significant enough to outweigh the slightly lower metabolic stability of Ligand B. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation.

Output:
1
2025-04-17 10:53:54,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.479 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.47) is better than Ligand B (84.86). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range.

**logP:** Ligand A (1.527) is within the optimal 1-3 range. Ligand B (-0.116) is below 1, which could indicate poor membrane permeability.

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

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also acceptable.

**QED:** Both ligands have similar QED values (0.695 and 0.713), indicating good drug-likeness.

**DILI:** Ligand A (20.434) has a significantly lower DILI risk than Ligand B (42.962). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (64.017 and 64.095). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.974) is slightly better than Ligand B (-4.786), suggesting slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.146) is better than Ligand B (0.125). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.26) has a much lower hERG inhibition liability than Ligand B (0.075). This is a critical advantage for Ligand A, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (13.282) has lower microsomal clearance than Ligand A (23.092), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (12.582) has a longer half-life than Ligand B (-1.347). This is a positive for dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.007 and 0.009).

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.5). This is a 1.5 kcal/mol advantage, which is substantial.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI, lower hERG) and better solubility. The difference in affinity, while significant, might be outweighed by the ADME/Tox advantages of Ligand A, particularly the lower hERG risk. Given the enzyme-specific priorities, metabolic stability (Cl_mic) is also important, and Ligand B has a slight edge here. However, the longer half-life of Ligand A is a positive. Considering the balance, the improved safety profile of Ligand A is more crucial for initial development.

Output:
0
2025-04-17 10:53:54,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (391.274 and 353.375 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.23) is well below the 140 threshold and is favorable. Ligand B (119.76) is still under 140, but less optimal than A.

**3. logP:** Ligand A (1.9) is within the optimal range of 1-3. Ligand B (0.655) is slightly below 1, which could potentially hinder permeation, but not drastically.

**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 (7) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.78 and 0.659), indicating good drug-like properties.

**7. DILI:** Both ligands have high DILI risk (37.728 and 78.402), but Ligand A is significantly lower. This is a major concern for both, but less so for A.

**8. BBB:** Ligand A (78.558) has better BBB penetration potential than Ligand B (68.748), although BBB is not a primary concern for a kinase inhibitor.

**9. Caco-2 Permeability:** Ligand A (-4.739) and Ligand B (-5.043) both have negative values, which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Ligand A (-3.171) and Ligand B (-2.79) both have negative values, indicating very poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.286 and 0.148), which is excellent.

**12. Microsomal Clearance:** Ligand A (50.576) and Ligand B (57.855) have similar microsomal clearance values. These are relatively high, indicating moderate metabolic instability.

**13. In vitro Half-Life:** Ligand A (-39.652) has a much longer in vitro half-life than Ligand B (-1.148). This is a significant advantage for A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.069), which is favorable.

**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 less than 1.5 kcal/mol.

**Enzyme-Specific Considerations:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has slightly better affinity, Ligand A has a significantly longer half-life, lower DILI risk, and better TPSA. The poor solubility and permeability are concerning for both, but the longer half-life and lower DILI of Ligand A are more valuable for an enzyme target.

Output:
0
2025-04-17 10:53:54,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (362.813 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.02) is slightly higher than Ligand B (67.43), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have a logP of approximately 2.97, which is 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 (0.85) has a significantly better QED score than Ligand B (0.662), indicating a more drug-like profile.

**DILI:** Ligand B (54.207) has a lower DILI risk than Ligand A (78.054), which is a significant advantage.

**BBB:** Ligand A (86.351) has a higher BBB penetration percentile than Ligand B (69.407), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.627) has a worse Caco-2 permeability than Ligand B (-5.211). Lower values indicate worse permeability.

**Aqueous Solubility:** Ligand B (-2.707) has better aqueous solubility than Ligand A (-4.549). This is a positive attribute for bioavailability.

**hERG Inhibition:** Ligand A (0.807) has a slightly higher hERG inhibition risk than Ligand B (0.442), which is undesirable.

**Microsomal Clearance:** Ligand A (50.652) has a lower microsomal clearance than Ligand B (65.697), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.805) has a significantly longer in vitro half-life than Ligand A (3.302), which is a major advantage.

**P-gp Efflux:** Ligand A (0.529) has lower P-gp efflux liability than Ligand B (0.248), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and P-gp efflux, Ligand B's superior binding affinity (-7.6 vs -6.9 kcal/mol), lower DILI risk, and significantly longer half-life are more crucial for an enzyme target like SRC. The better solubility of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 10:53:54,391 - INFO - Batch 2 complete. Total preferences: 32
2025-04-17 10:53:54,391 - INFO - Processing batch 3/512...
2025-04-17 10:54:35,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.398 and 353.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (89.35 and 87.74) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.84) is slightly lower than ideal (1-3), potentially impacting permeability. Ligand B (0.991) is also on the lower side but closer to the optimal range.

**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:** Ligand A (0.81) has a better QED score than Ligand B (0.637), indicating a more drug-like profile.

**DILI:** Ligand B (30.826) has a significantly lower DILI risk than Ligand A (55.913), which is a major advantage.

**BBB:** Ligand A (84.141) has better BBB penetration than Ligand B (69.523), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.869 and -4.817), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.511 and -1.039), indicating very poor aqueous solubility, a substantial drawback.

**hERG:** Both ligands have very low hERG inhibition risk (0.096 and 0.085), which is excellent.

**Microsomal Clearance:** Ligand A (35.394) has lower microsomal clearance than Ligand B (43.238), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.138 hours) has a significantly longer half-life than Ligand B (-15.487 hours, which is nonsensical). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.103 and 0.03).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.7 kcal/mol). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -6.7 kcal/mol), better QED, longer half-life, and lower microsomal clearance outweigh the slightly higher DILI risk and lower BBB penetration. The poor solubility and permeability are serious issues that would need to be addressed through formulation or further chemical modification, but the potency and metabolic stability of Ligand A make it a better starting point.

Output:
0
2025-04-17 10:54:35,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.395 and 359.857 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (118.03) is better than Ligand B (54.43). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly lower, potentially improving absorption.

**logP:** Ligand A (0.312) is quite low, potentially hindering permeation. Ligand B (4.191) is at the upper end of the optimal range (1-3), which could lead to solubility issues but is still acceptable.

**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 good QED scores (0.673 and 0.717), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 72.703, which is concerning (high risk). Ligand B has a much lower DILI risk of 22.761, which is favorable.

**BBB:** Both have low BBB penetration (30.787 and 28.81), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.141 and -5.286), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.369 and -3.694), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.13) has a very low hERG risk, which is excellent. Ligand B (0.895) has a moderate hERG risk, which is less ideal.

**Microsomal Clearance:** Ligand A (58.4) and Ligand B (55.584) have similar microsomal clearance values, indicating moderate metabolic stability. Lower is better, but these aren't drastically high.

**In vitro Half-Life:** Ligand A (-26.847) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound's stability. Ligand B (37.483) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.046 and 0.439), which is good.

**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 ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate despite some ADME concerns. The significantly stronger binding affinity (-9.3 vs -8.0 kcal/mol) is a major advantage for an enzyme target like SRC. Furthermore, Ligand B has a much lower DILI risk (22.761 vs 72.703) and a reasonable in vitro half-life. While both have poor solubility and permeability, the superior potency and safety profile of Ligand B make it more promising. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 10:54:35,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.369 Da and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.62) is slightly higher than Ligand B (69.72), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.699) is optimal, while Ligand B (0.831) is a bit low, potentially hindering permeation.

**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 acceptable QED values (0.325 and 0.729), with Ligand B being significantly better.

**DILI:** Ligand A (58.511) has a higher DILI risk than Ligand B (39.434), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.705) has a better BBB score than Ligand B (44.009).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.1) is better than Ligand B (-4.848).

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-3.124) is better than Ligand B (-2.36).

**hERG:** Ligand A (0.866) has a slightly higher hERG risk than Ligand B (0.541), which is preferable.

**Microsomal Clearance:** Ligand B (27.568) has significantly lower microsomal clearance than Ligand A (45.936), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-35.15) has a much longer in vitro half-life than Ligand A (-18.489), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.886) has slightly higher P-gp efflux than Ligand B (0.052), which is preferable.

**Binding Affinity:** Ligand A (-8.4) has a slightly better binding affinity than Ligand B (-7.4), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better binding affinity and BBB penetration, Ligand B excels in key areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG risk. The slightly lower logP of Ligand B is a minor drawback that could potentially be addressed through further optimization, but the metabolic stability advantage is more critical.

Output:
1
2025-04-17 10:54:35,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (98.66) is better than Ligand B (33.2). While both are below 140, the lower TPSA of Ligand B is more favorable for cell permeability.

**logP:** Ligand A (1.889) is within the optimal range (1-3). Ligand B (4.066) is slightly higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.645, B: 0.764), indicating drug-like properties.

**DILI:** Ligand A (48.623) has a moderate DILI risk, while Ligand B (16.906) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (31.834) has low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (94.921) has very high BBB penetration, which is irrelevant here and could even be a negative if off-target CNS effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.268) has poor Caco-2 permeability, while Ligand B (-4.723) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.602) has poor aqueous solubility, while Ligand B (-4.761) is even worse. This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.505) has a slightly higher hERG risk than Ligand B (0.793). Lower is better here, so Ligand B is preferred.

**Microsomal Clearance:** Ligand A (-2.944) has a lower (better) microsomal clearance than Ligand B (56.068), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-15.895) has a longer half-life than Ligand B (18.004), which is desirable.

**P-gp Efflux:** Ligand A (0.045) has very low P-gp efflux, while Ligand B (0.672) has moderate P-gp efflux. This favors Ligand A.

**Binding Affinity:** Both ligands have similar, 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 factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has a lower DILI risk and slightly better Caco-2 permeability, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer half-life) and lower P-gp efflux. The solubility is poor for both, but the metabolic advantages of Ligand A are more critical for an enzyme target like SRC.

Output:
0
2025-04-17 10:54:35,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.298 Da and 353.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.86) is better than Ligand B (73.2), both are below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.606 and 2.325) falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 3 HBA, both are below the 10 threshold.

**QED:** Ligand B (0.843) has a significantly better QED score than Ligand A (0.574), indicating a more drug-like profile.

**DILI:** Ligand A has a high DILI risk (87.01 percentile), while Ligand B has a low DILI risk (28.577 percentile). This is a major advantage for Ligand B.

**BBB:** Ligand B (83.133) has a higher BBB penetration percentile than Ligand A (57.154), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.437) has a slightly better hERG profile than Ligand B (0.548), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (4.187 mL/min/kg) has significantly lower microsomal clearance than Ligand A (95.739 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-10.083 hours) has a better in vitro half-life than Ligand A (-32.667 hours).

**P-gp Efflux:** Ligand A (0.359) has lower P-gp efflux than Ligand B (0.017), which is preferable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly better binding affinity than Ligand A (-10.5 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**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 an enzyme inhibitor: binding affinity, metabolic stability (low Cl_mic and better t1/2), and DILI risk. The higher QED score also supports its drug-likeness. The affinity difference of 3.1 kcal/mol is substantial and likely outweighs the slight disadvantage in P-gp efflux.

Output:
1
2025-04-17 10:54:35,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.571 Da) and Ligand B (348.487 Da) are both acceptable.

**TPSA:** Ligand A (58.2) is better than Ligand B (49.85). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (A: 3.522, B: 2.607), falling within the optimal range of 1-3.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as it provides some hydrogen bonding capability, potentially aiding binding. Both are well within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is good.

**QED:** Both ligands have good QED scores (A: 0.582, B: 0.693), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (21.985) has a significantly lower DILI risk than Ligand B (7.794), which is a major advantage.

**BBB:** Ligand A (67.429) is lower than Ligand B (85.731). Since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and indicates poor permeability. Ligand A (-5) is worse than Ligand B (-4.538).

**Aqueous Solubility:** Ligand A (-4.393) is worse than Ligand B (-2.058). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.406, B: 0.326), which is excellent.

**Microsomal Clearance:** Ligand A (87.391) has a higher microsomal clearance than Ligand B (40.137), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (22.809) has a longer half-life than Ligand B (2.919), which is a positive. However, the low half-life of Ligand B is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.242, B: 0.054), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -8.5 kcal/mol, B: -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is preferable due to its significantly lower DILI risk, better solubility, and lower microsomal clearance (better metabolic stability). While Ligand A has a slightly longer half-life and more H-bond donors, the advantages of Ligand B in terms of safety and metabolic stability outweigh these minor benefits. The poor Caco-2 permeability is a concern for both, but Ligand B is slightly better in this regard.

Output:
1
2025-04-17 10:54:35,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.379 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.79) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (78.09) is excellent, well below 140.

**logP:** Ligand A (-2.268) is a bit low, potentially hindering permeability. Ligand B (2.358) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.484) is below the desired 0.5 threshold, indicating a less drug-like profile. Ligand B (0.823) is excellent, well above 0.5.

**DILI:** Ligand A (41.024) has a moderate DILI risk, but is still acceptable. Ligand B (33.23) has a lower DILI risk, which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (21.985) and Ligand B (68.282) are both relatively low, but this isn't a major drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.284 and -5.098), 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 -2.739), indicating very poor aqueous solubility. This is a major issue for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.104) has a very low hERG risk, which is excellent. Ligand B (0.526) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-13.012) has a very low (negative) microsomal clearance, suggesting excellent metabolic stability. Ligand B (6.672) has a moderate clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (7.32) has a moderate half-life. Ligand B (-28.865) has a negative half-life, which is not physically possible and suggests an issue with the data or the molecule's stability.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable. Ligand B (0.144) has slightly higher P-gp efflux, but still relatively low.

**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 substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME concerns. The significantly improved binding affinity (-9.0 vs -7.7 kcal/mol) is a major advantage for an enzyme target like SRC. While both compounds have poor solubility and permeability, the superior affinity of Ligand B, combined with its better QED and lower DILI risk, makes it more promising. The negative half-life for Ligand B is a red flag, but could be a data error. Ligand A's better metabolic stability is good, but the lower affinity and lower QED are significant drawbacks.

Output:
1
2025-04-17 10:54:35,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (361.427 and 342.378 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.19) is slightly higher than Ligand B (87.75), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (0.468) is quite low, potentially hindering permeability. Ligand B (3.32) 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, still within the limit of 5.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (6) is also good, both under the 10 limit.

**6. QED:** Ligand A (0.835) is excellent, indicating high drug-likeness. Ligand B (0.637) is still acceptable, above the 0.5 threshold.

**7. DILI:** Both ligands have relatively high DILI risk (75.184 and 78.325), which is a concern, but comparable between the two.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (52.966) is lower than Ligand B (34.975).

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

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a potential issue for both.

**11. hERG Inhibition:** Ligand A (0.038) shows very low hERG risk, which is excellent. Ligand B (0.748) has a moderate hERG risk, which is less desirable.

**12. Microsomal Clearance:** Ligand A (-2.258) has a negative clearance, which is highly favorable, indicating excellent metabolic stability. Ligand B (36.944) has a moderate clearance, suggesting moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A (52.17) has a good half-life. Ligand B (4.051) has a short half-life, which is a drawback.

**14. P-gp Efflux:** Ligand A (0.068) has low P-gp efflux, which is good. Ligand B (0.112) also has low P-gp efflux, but slightly higher than A.

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.4), although both are excellent. The 0.2 kcal/mol difference is potentially significant.

**Overall Assessment:**

Ligand A has a superior safety profile (hERG, metabolic stability) and better drug-likeness (QED). However, its low logP is a significant concern for permeability. Ligand B has a better logP and slightly better binding affinity, but its hERG risk and shorter half-life are drawbacks.

Considering the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and potency (affinity) are crucial. While Ligand B has slightly better affinity, Ligand A's significantly better metabolic stability and much lower hERG risk are more important for an enzyme inhibitor. The permeability issues with both are concerning, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 10:54:35,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.5 and 342.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.86) is well below the 140 threshold, while Ligand B (79.13) is still acceptable but higher.

**logP:** Both ligands have good logP values (3.37 and 2.32), falling within the 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 7 HBA, which is acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.744 and 0.662), indicating good drug-likeness.

**DILI:** Ligand A (49.011) has a lower DILI risk than Ligand B (88.872). This is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (77.511) has a slightly better score than Ligand B (69.135).

**Caco-2 Permeability:** Ligand A (-5.369) has a worse Caco-2 permeability than Ligand B (-4.148), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.191) has slightly better aqueous solubility than Ligand B (-4.19).

**hERG:** Both ligands have very low hERG risk (0.261 and 0.218), which is excellent.

**Microsomal Clearance:** Ligand A (47.806) has significantly lower microsomal clearance than Ligand B (109.36), indicating better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-35.073) has a much longer in vitro half-life than Ligand A (-3.77). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.267 and 0.195).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.4 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme targets, Ligand A is more promising. While Ligand B has a better half-life and Caco-2 permeability, Ligand A has a significantly lower DILI risk and lower microsomal clearance, which are crucial for a viable drug candidate. The binding affinity difference is minimal. The lower DILI and better metabolic stability of Ligand A are more important for a kinase inhibitor.

Output:
0
2025-04-17 10:54:35,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.443 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.84) is better than Ligand B (80.32), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Both ligands (2.891 and 2.279) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Ligand A (0.9) is significantly better than Ligand B (0.672), indicating a more drug-like profile.

**DILI:** Ligand A (43.622) has a lower DILI risk than Ligand B (20.706), which is preferable.

**BBB:** Ligand A (81.66) has a higher BBB percentile than Ligand B (66.537), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.641) has worse Caco-2 permeability than Ligand B (-4.756), but both are negative values which are not ideal.

**Aqueous Solubility:** Ligand A (-3.712) has worse aqueous solubility than Ligand B (-1.828). Solubility is important for kinases, and B is better here.

**hERG Inhibition:** Ligand A (0.318) has a lower hERG inhibition liability than Ligand B (0.159), which is a significant advantage.

**Microsomal Clearance:** Ligand A (24.586) has a lower microsomal clearance than Ligand B (37.646), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.64) has a longer in vitro half-life than Ligand B (5.394), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux than Ligand B (0.028), which is preferable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a >1.5 kcal/mol difference, and is a major advantage.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better solubility and Caco-2 permeability, Ligand A excels in the most critical areas for a kinase inhibitor: significantly higher binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, better QED, and lower hERG liability. The stronger binding affinity is likely to outweigh the minor ADME drawbacks.

Output:
1
2025-04-17 10:54:35,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.427 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.43) is better than Ligand B (58.64), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.217 and 2.594), falling within the 1-3 range. Ligand B is slightly higher, potentially improving permeability.

**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 3, both are below the 10 limit.

**QED:** Both ligands have reasonable QED scores (0.735 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A (20.163) has a significantly lower DILI risk than Ligand B (5.894), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand B (78.79) has a higher BBB penetration score than Ligand A (60.799). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.743) has slightly better Caco-2 permeability than Ligand B (-4.608).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.288 and -2.519). This is a significant concern for both, but needs to be addressed during formulation.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.218 and 0.53). Both are relatively low risk.

**Microsomal Clearance:** Ligand A (-7.304) has much lower microsomal clearance than Ligand B (76.154), indicating significantly better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-4.204) has a better in vitro half-life than Ligand B (-11.771).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.082).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Despite similar binding affinities, Ligand A is the more promising candidate. Its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and better t1/2) outweigh the slightly better BBB penetration of Ligand B. The solubility is a concern for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 10:54:35,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.39 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (364.917 Da) is also good.

**TPSA:** Ligand A (67.35) is better than Ligand B (49.41). Both are acceptable, but lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (A: 2.917, B: 3.597), 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 2 HBA. Both are within acceptable limits (<=10).

**QED:** Both ligands have reasonable QED scores (A: 0.875, B: 0.782), indicating good drug-like properties.

**DILI:** Ligand A (50.058) has a higher DILI risk than Ligand B (29.43). This is a significant advantage for Ligand B.

**BBB:** Ligand A (92.943) has better BBB penetration than Ligand B (75.805). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 permeability values, which is unusual and suggests potential issues with absorption prediction. However, the values are similar (-4.12 for A, -4.673 for B).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor predicted solubility. Ligand B (-4.3) is slightly worse than Ligand A (-2.912).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.208, B: 0.44), which is excellent.

**Microsomal Clearance:** Ligand A (44.595) has significantly lower microsomal clearance than Ligand B (71.087), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-10.857) has a negative half-life, which is nonsensical. Ligand B (14.694) has a reasonable half-life. This is a major issue for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.05, B: 0.217).

**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 for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better metabolic stability (lower Cl_mic) and slightly better solubility, Ligand B has a significantly stronger binding affinity (-8.4 vs -6.9 kcal/mol), a much lower DILI risk, and a reasonable in vitro half-life. The negative half-life for Ligand A is a critical flaw. The stronger binding of Ligand B is a major advantage for an enzyme target like SRC kinase.



Output:
1
2025-04-17 10:54:35,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.402 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (65.98), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.483 and 1.066), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Ligand A is preferable here, as lower HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.673 and 0.78), indicating drug-likeness.

**DILI:** Ligand A (40.287) is slightly higher than Ligand B (34.393), but both are below the 40 threshold and considered low risk.

**BBB:** Ligand A (75.921) has better BBB penetration than Ligand B (67.041), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.457) is better than Ligand B (-4.846), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.717) is better than Ligand B (-1.183). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.449) is significantly better than Ligand B (0.165), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (53.748) has higher clearance than Ligand B (3.356). This means Ligand B is more metabolically stable, which is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (8.364) has a longer half-life than Ligand B (3.963).

**P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.11). Lower efflux is preferable.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-8.3). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, lower hERG risk, and better Caco-2 permeability, the significantly stronger binding affinity of Ligand B (-7.3 kcal/mol vs -8.3 kcal/mol) is the most critical factor for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic) of Ligand B is also a significant advantage. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 10:54:35,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.427 and 358.339 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.01) is better than Ligand B (43.18) as it is closer to the upper limit of 140 for good oral absorption. Ligand B is very low, which could indicate issues with solubility.

**logP:** Both ligands (2.201 and 3.023) are within the optimal range of 1-3.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as it strikes a balance between solubility and permeability.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being under the limit of 10.

**QED:** Ligand A (0.845) is better than Ligand B (0.771), indicating a more drug-like profile.

**DILI:** Ligand A (50.33) is slightly higher than Ligand B (32.842), but both are below the 60 threshold, indicating acceptable liver injury risk.

**BBB:** Both ligands have high BBB penetration (92.4 and 90.772), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.289) is worse than Ligand B (-4.61), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.824) is worse than Ligand B (-2.922), indicating lower solubility.

**hERG Inhibition:** Ligand A (0.5) is significantly better than Ligand B (0.781), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (58.172) is worse than Ligand B (18.005), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.959) is better than Ligand B (-20.798), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.526) is better than Ligand B (0.097), suggesting lower P-gp efflux.

**Binding Affinity:** Ligand A (-9.6) has a significantly stronger binding affinity than Ligand B (-8.0). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A having slightly worse Caco-2 permeability and solubility, its significantly stronger binding affinity (-9.6 vs -8.0 kcal/mol) and lower hERG risk outweigh these drawbacks. The better QED and P-gp efflux also contribute to its favorability. Ligand B has better metabolic stability, but the affinity difference is substantial. Given the enzyme-specific priorities, potency is paramount, and Ligand A clearly wins in this regard.

Output:
1
2025-04-17 10:54:35,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 349.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is excellent, well below the 140 threshold for oral absorption. Ligand B (109.04) is still acceptable, but higher and potentially impacting absorption.

**logP:** Ligand A (3.666) is optimal. Ligand B (0.996) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well within the limit of 5.

**H-Bond Acceptors:** Ligand A (2) is good. Ligand B (6) is higher, but still within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.565 and 0.691, respectively), indicating drug-like properties.

**DILI:** Ligand A (23.226) has a very low DILI risk, which is excellent. Ligand B (41.062) is still relatively low, but higher than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.676) is moderate, and Ligand B (42.148) is low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.085 and -4.993), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.006 and -2.208), also unusual and concerning. This suggests poor solubility.

**hERG Inhibition:** Ligand A (0.549) has a very low hERG risk, which is excellent. Ligand B (0.165) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (66.464) has a higher clearance than Ligand B (38.867), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-6.218) has a significantly longer half-life than Ligand A (2.453), suggesting better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.639 and 0.054, respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.6 kcal/mol), with Ligand B being slightly better. The affinity difference is small, and likely less important than the ADME differences.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the ADME profile of Ligand B is superior to Ligand A. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and a lower DILI risk. While Ligand A has a slightly lower hERG risk, the metabolic instability is a significant concern for an enzyme inhibitor. The slightly lower logP of Ligand B is a minor drawback compared to the metabolic issues with Ligand A.

Output:
1
2025-04-17 10:54:35,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (334.335 Da and 358.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.04) is better than Ligand B (136.03). TPSA < 140 is good for oral absorption, both are within this range, but A is closer to the optimal value.

**logP:** Ligand A (3.484) is within the optimal 1-3 range, while Ligand B (0.968) is slightly below, potentially impacting permeability.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 8. Both are within the acceptable limit of 10, but A is preferable.

**QED:** Both ligands have good QED scores (0.532 and 0.597), indicating drug-like properties.

**DILI:** Both have high DILI risk (98.643 and 91.857), which is a concern. However, this is a prediction and needs further investigation.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (32.144) has a slightly better BBB score than Ligand A (23.42), but this is not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.335 and -5.856), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.92 and -2.978), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.764) has a slightly higher hERG risk than Ligand B (0.154). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (69.614) has a higher microsomal clearance than Ligand B (-0.263), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-21.463) has a negative half-life, which is not possible and indicates a potential issue with the data or the molecule. Ligand B (22.515) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.213) has lower P-gp efflux than Ligand B (0.027), which is preferable.

**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, the 0.4 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B is the better candidate despite the high DILI prediction. It has a better binding affinity, significantly better metabolic stability (lower Cl_mic, positive t1/2), lower hERG risk, and a more reasonable half-life. While both have poor solubility and permeability, the metabolic and safety advantages of Ligand B outweigh the slightly better P-gp profile of Ligand A. The negative half-life for Ligand A is a red flag.

Output:
1
2025-04-17 10:54:35,399 - INFO - Batch 3 complete. Total preferences: 48
2025-04-17 10:54:35,399 - INFO - Processing batch 4/512...
2025-04-17 10:55:15,899 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.487 and 381.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.91) is higher than Ligand B (58.48). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (3.437 and 3.778), 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.677 and 0.791), indicating good drug-like properties.

**DILI:** Ligand A (11.322) has a significantly lower DILI risk than Ligand B (31.989). This is a crucial advantage.

**BBB:** Both have similar BBB penetration (62.233 and 66.964). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.476 and -4.871), which is unusual and suggests poor permeability. However, these values are on a log scale and could represent very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.357 and -3.638), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.821 and 0.712), which is positive.

**Microsomal Clearance:** Ligand A (58.417) has lower microsomal clearance than Ligand B (65.586), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (40.524) has a longer in vitro half-life than Ligand B (-18.22). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.871 and 0.703).

**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 less than the 1.5 kcal/mol threshold, it contributes to the overall assessment.

**Conclusion:**

Ligand A 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 both have poor solubility and permeability, the improved safety and pharmacokinetic properties of Ligand A outweigh the small difference in binding affinity.

Output:
0
2025-04-17 10:55:15,900 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.463 and 354.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.99) is slightly above the preferred <140, but acceptable. Ligand B (59.08) is well within the acceptable range.

**logP:** Both ligands have good logP values (3.532 and 2.909), 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 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.655 and 0.639), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 71.656, which is concerning (high risk, >60). Ligand B has a much lower DILI risk of 28.887, which is excellent.

**BBB:** Both ligands have good BBB penetration (72.974 and 77.627). While not a primary concern for a non-CNS target like SRC, it doesn't detract from their potential.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.485), which is very concerning and suggests poor absorption. Ligand B also has a negative value (-4.411), but slightly better than A.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.6 and -2.586), indicating poor aqueous solubility. This is a significant drawback, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.583) has a slightly higher hERG risk than Ligand B (0.637), but both are relatively low.

**Microsomal Clearance:** Ligand A has a Cl_mic of 56.996, which is reasonable. Ligand B has a higher Cl_mic of 67.16, suggesting faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 46.18 hours, which is good. Ligand B has a negative half-life (-5.116), which is highly problematic and suggests rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.441 and 0.231).

**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.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.3 vs -7.4 kcal/mol) is a major advantage for an enzyme inhibitor. Crucially, Ligand B has a much lower DILI risk (28.887 vs 71.656) and a better P-gp efflux profile. While the negative half-life is concerning, it might be addressable through structural modifications. The poor solubility and permeability would require formulation work, but the superior potency and safety profile of Ligand B make it the better choice.

Output:
1
2025-04-17 10:55:15,900 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.47 and 380.482 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is well below the 140 threshold for good absorption, while Ligand B (94.99) is still acceptable but closer to the limit.

**logP:** Ligand A (1.752) is optimal. Ligand B (0.371) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**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 reasonable QED scores (0.603 and 0.553), indicating good drug-like properties.

**DILI:** Ligand A (17.72) has a significantly lower DILI risk than Ligand B (27.414), which is a major advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (82.474) has better BBB penetration than Ligand B (62.311).

**Caco-2 Permeability:** Ligand A (-4.224) has a slightly better Caco-2 permeability than Ligand B (-4.971), although both are negative values, suggesting limited permeability.

**Aqueous Solubility:** Ligand A (-1.681) has slightly better solubility than Ligand B (-0.712).

**hERG Inhibition:** Ligand A (0.845) shows lower hERG inhibition risk compared to Ligand B (0.396), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (61.21) has higher microsomal clearance than Ligand B (-1.69), meaning Ligand B is more metabolically stable. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (7.309) has a significantly longer in vitro half-life than Ligand A (-16.363), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.386) has lower P-gp efflux than Ligand B (0.113), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a crucial factor, and the 2.2 kcal/mol difference is substantial.

**Conclusion:**

While Ligand A has advantages in terms of DILI risk, hERG inhibition, solubility, and P-gp efflux, Ligand B's substantially stronger binding affinity (-9.7 vs -7.5 kcal/mol) and significantly improved metabolic stability (lower Cl_mic, longer t1/2) outweigh these benefits. For an enzyme target like SRC kinase, potency and metabolic stability are paramount. The improved affinity of Ligand B suggests it will be more effective at lower doses, potentially mitigating some of the concerns related to its slightly lower solubility and higher DILI risk.

Output:
1
2025-04-17 10:55:15,900 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.494 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (104.73). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.591) is optimal, while Ligand B (1.138) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) 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 (0.822) has a higher QED score than Ligand B (0.537), indicating a more drug-like profile.

**DILI:** Ligand A (18.534) has a much lower DILI risk than Ligand B (10.392), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.67) is better than Ligand B (60.644), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.721) is better than Ligand B (-4.743), although both are negative, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-3.648) is better than Ligand B (-1.852), indicating better solubility.

**hERG:** Ligand A (0.54) is significantly better than Ligand B (0.101), suggesting a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (28.734 mL/min/kg) has a lower clearance than Ligand B (56.931 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.205 hours) is significantly worse than Ligand B (-31.73 hours). This is a major drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.199) is better than Ligand B (0.014), indicating lower P-gp efflux.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A excels in most ADME properties (DILI, solubility, hERG, metabolic stability, P-gp efflux) and has a good QED score. However, its very short in vitro half-life is a major concern. Ligand B has a better half-life, but is significantly worse in terms of DILI risk, hERG inhibition, solubility, and metabolic stability. The slightly better binding affinity of Ligand B is unlikely to outweigh the significant ADME liabilities. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. While Ligand A's half-life is a problem, it's a property that can potentially be improved through structural modifications. The ADME liabilities of Ligand B are more difficult to address without significantly impacting potency.

Output:
0
2025-04-17 10:55:15,900 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.353 and 348.359 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.95) is excellent, well below the 140 threshold for oral absorption and even favorable for CNS penetration. Ligand B (126.32) is still acceptable, but less optimal.

**logP:** Ligand A (2.342) is within the optimal 1-3 range. Ligand B (0.78) is slightly low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is very good. Ligand B (3 HBD, 6 HBA) is also acceptable, but the higher number of donors/acceptors could slightly impact permeability.

**QED:** Ligand A (0.837) has a very strong drug-like profile. Ligand B (0.635) is still reasonable, but less favorable.

**DILI:** Ligand A (65.723) is a moderate risk, while Ligand B (72.509) is also moderate but slightly higher. Both are acceptable, but lower is preferred.

**BBB:** Ligand A (93.641) shows excellent potential for BBB penetration, though it's less critical for a non-CNS target like SRC. Ligand B (40.597) is low.

**Caco-2 Permeability:** Ligand A (-4.355) is poor, indicating low intestinal absorption. Ligand B (-5.233) is even worse. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.91 and -3.581 respectively). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.243 and 0.225 respectively), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (43.729 and 42.436 mL/min/kg), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (-15.256 hours) has a negative half-life, which is not possible and likely indicates an error in the data. Ligand B (38.19 hours) has a reasonable in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.14 and 0.098 respectively), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.3 and -7.2 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is more promising due to its superior TPSA, QED, and BBB penetration. However, the negative in vitro half-life for Ligand A is a critical flaw. The poor Caco-2 permeability and solubility are significant drawbacks for both. Considering the flawed data for Ligand A, Ligand B is the slightly better candidate, primarily due to its reasonable half-life. Further optimization would be needed to improve solubility and permeability for both.

Output:
1
2025-04-17 10:55:15,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.375 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.87) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (72.88) is well within the ideal range.

**logP:** Ligand A (-0.124) is a bit low, potentially hindering permeation. Ligand B (0.595) is closer to 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 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.556 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A (69.911) has a higher DILI risk than Ligand B (6.282). This is a significant concern.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand B (33.85) has a higher BBB value than Ligand A (21.675).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.981 and -5.096), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.308 and -0.953), indicating poor aqueous solubility. This is a significant issue.

**hERG:** Both ligands have low hERG risk (0.11 and 0.13).

**Microsomal Clearance:** Ligand A (1.76) has a much lower Cl_mic than Ligand B (-9.874). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (3.909) has a shorter half-life than Ligand B (14.784), but both are relatively short.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.013).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.0 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite similar binding affinities, Ligand A is less desirable due to its lower logP, higher DILI risk, and shorter half-life. Ligand B has better logP, a significantly lower DILI risk, and a much longer half-life. While both have poor Caco-2 and solubility, the lower DILI and improved metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 10:55:15,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.351 and 365.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is better than Ligand B (61.38), both are acceptable, but lower is generally preferred for permeability.

**logP:** Both ligands have good logP values (3.699 and 3.462), falling 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=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.414 and 0.752), with Ligand B being significantly better.

**DILI:** Both ligands have low DILI risk (39.511 and 37.922), indicating minimal liver injury potential.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (87.088) is better than Ligand B (63.164). However, BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.356) is better than Ligand B (-5.391), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.261) is better than Ligand B (-3.575), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.891 and 0.91), which is excellent.

**Microsomal Clearance:** Ligand B (30.274) has significantly lower microsomal clearance than Ligand A (60.666), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (109.046) has a much longer in vitro half-life than Ligand A (27.368), further supporting its superior metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.251 and 0.771).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is the most important factor for an enzyme inhibitor, and a difference of 1.1 kcal/mol is substantial.

**Conclusion:**

While Ligand A has slightly better permeability and solubility, Ligand B's significantly stronger binding affinity (-7.9 vs -9.0 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) outweigh these minor advantages. Given the priorities for enzyme inhibitors, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 10:55:15,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.431 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.41) is better than Ligand B (112.92) as it is closer to the 140 threshold for oral absorption.

**logP:** Ligand A (-1.403) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.271) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 8 HBA) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability.

**QED:** Both ligands have similar QED scores (0.677 and 0.576), indicating reasonable drug-likeness.

**DILI:** Ligand A (58.434) has a lower DILI risk than Ligand B (63.862), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (38.193) is slightly higher.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.472 and -5.609), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.059 and -2.726), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.033) has a much lower hERG inhibition liability than Ligand B (0.282), a critical advantage for safety.

**Microsomal Clearance:** Ligand A (-12.228) exhibits significantly lower microsomal clearance than Ligand B (60.053), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (3.575) has a shorter half-life than Ligand B (19.657), which is a disadvantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.021).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.6 kcal/mol), which are excellent.

**Overall Assessment:**

Ligand A is superior despite the shorter half-life. The significantly lower DILI risk, much lower hERG inhibition, and substantially improved metabolic stability (lower Cl_mic) outweigh the slightly lower logP and shorter half-life. The similar binding affinities mean potency is not a differentiating factor. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 10:55:15,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.5 and 350.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (93.45). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (2.767) is optimal (1-3), while Ligand B (0.035) is quite low, potentially hindering permeability. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=0, HBA=7) both have acceptable numbers.

**QED:** Both ligands have reasonable QED scores (0.847 and 0.761), indicating good drug-like properties.

**DILI:** Ligand A (16.712) has a much lower DILI risk than Ligand B (52.617). This is a major advantage for Ligand A.

**BBB:** While not critical for a non-CNS target like SRC, Ligand A (71.384) shows better BBB penetration than Ligand B (59.946).

**Caco-2 Permeability:** Both are negative, indicating poor permeability, but Ligand A (-4.513) is slightly better than Ligand B (-4.781).

**Aqueous Solubility:** Both ligands have negative solubility values (-1.542 and -1.202), indicating poor solubility. This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.492) has a lower hERG risk than Ligand B (0.04). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (34.454) has a higher (worse) microsomal clearance than Ligand B (8.408). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (8.535) has a slightly longer half-life than Ligand B (7.422).

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.023), which is favorable.

**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 concerns.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its significantly stronger binding affinity, lower DILI risk, lower hERG risk, and better logP outweigh its slightly higher microsomal clearance and poorer solubility compared to Ligand B. The low logP of Ligand B is a major concern, likely leading to poor permeability and bioavailability.

Output:
1
2025-04-17 10:55:15,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.415 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.1) is slightly above the preferred <140 for good oral absorption, but still acceptable. Ligand B (67.87) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.4 and 1.891), 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 8 HBAs, acceptable. Ligand B has 4 HBAs, also acceptable.

**QED:** Ligand A (0.855) has a very good QED score, indicating high drug-likeness. Ligand B (0.767) is also good, but slightly lower.

**DILI:** Ligand A has a DILI risk of 86.972, which is high and concerning. Ligand B has a much lower DILI risk of 31.989, a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (68.786) is higher than Ligand A (29.508), but this isn't a major deciding factor.

**Caco-2:** Ligand A (-5.577) and Ligand B (-4.682) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Ligand A (-2.962) and Ligand B (-1.26) both have negative solubility values, indicating poor aqueous solubility. Ligand B is slightly better.

**hERG:** Ligand A (0.004) has a very low hERG risk, which is excellent. Ligand B (0.192) is slightly higher, but still relatively low.

**Cl_mic:** Ligand A (3.154) has a low microsomal clearance, suggesting good metabolic stability. Ligand B (31.256) has a much higher clearance, indicating faster metabolism and a potential issue.

**t1/2:** Ligand A (-6.723) has a negative in vitro half-life, which is not possible and indicates a problem with the data or the molecule. Ligand B (12.691) has a reasonable half-life.

**Pgp:** Both ligands have low Pgp efflux liability (0.049 and 0.036), which is favorable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having slightly worse solubility and Caco-2 permeability, its significantly stronger binding affinity (-8.8 vs -7.2 kcal/mol), much lower DILI risk (31.989 vs 86.972), and better metabolic stability (lower Cl_mic and a reasonable t1/2) make it the more promising candidate. Ligand A's high DILI risk and impossible half-life are major red flags.

Output:
1
2025-04-17 10:55:15,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (352.519 and 352.439 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is well below the 140 threshold for good absorption, and is also favorable. Ligand B (126.23) is still under the threshold, but less favorable than A.

**3. logP:** Ligand A (2.621) is within the optimal 1-3 range. Ligand B (0.24) is below 1, which may impede permeation.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable range (<=10), but A is more favorable.

**6. QED:** Both ligands have similar QED values (0.659 and 0.615), indicating good drug-likeness.

**7. DILI:** Ligand A (17.371) has a much lower DILI risk than Ligand B (57.813). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (44.397) has a lower BBB penetration percentile than Ligand B (62.854). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.595) has a negative value, which is not ideal, but Ligand B (-5.657) is even worse.

**10. Aqueous Solubility:** Ligand A (-2.919) has better solubility than Ligand B (-2.163), both are unfavorable.

**11. hERG Inhibition:** Ligand A (0.23) has a lower hERG risk than Ligand B (0.068). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (41.656) has higher clearance than Ligand B (-0.064). This suggests Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-0.385) has a shorter half-life than Ligand B (3.518). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux liability than Ligand B (0.022).

**15. 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 has a much stronger binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better BBB penetration. However, it has a higher DILI risk, lower solubility, and a lower logP. Ligand A has better solubility, lower DILI and hERG risk, and a more favorable logP.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the stronger binding affinity and metabolic stability of Ligand B are compelling. While the DILI and solubility are concerns, they might be addressed through further optimization. The substantial binding affinity advantage likely outweighs these drawbacks.

Output:
1
2025-04-17 10:55:15,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.415 and 364.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.0) is higher than Ligand B (58.2). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (1.313) is within the optimal 1-3 range. Ligand B (4.288) 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 8 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.703 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (89.57) has a higher DILI risk than Ligand B (37.999). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.015) has a higher BBB value than Ligand A (14.812), but this is not a primary concern here.

**Caco-2 Permeability:** Ligand A (-5.95) has a worse Caco-2 permeability than Ligand B (-4.859), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.976) has better aqueous solubility than Ligand B (-4.343). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.05) has a much lower hERG inhibition liability than Ligand B (0.721), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-23.368) has significantly lower microsomal clearance than Ligand B (87.837), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (29.299) has a shorter half-life than Ligand B (50.977), but both are reasonable.

**P-gp Efflux:** Ligand A (0.012) has lower P-gp efflux liability than Ligand B (0.486), which is favorable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge (0.9 kcal/mol), it's a factor.

**Overall Assessment:**

Ligand B has a better binding affinity and TPSA, but suffers from higher logP, DILI risk, hERG inhibition, and microsomal clearance. Ligand A has better solubility, metabolic stability, lower DILI and hERG risk, and lower P-gp efflux, but slightly weaker binding and worse Caco-2 permeability.

Considering the priorities for an enzyme inhibitor (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. The slightly weaker binding affinity can potentially be optimized in later stages of drug development, while mitigating the higher DILI, hERG, and clearance of Ligand B would be more challenging.

Output:
0
2025-04-17 10:55:15,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.4 and 350.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.15) is higher than Ligand B (58.64). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Ligand A (0.941) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (2.737) is well within the optimal range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Both are under the 10 threshold.

**QED:** Ligand A (0.897) has a better QED score than Ligand B (0.732), indicating better overall drug-likeness.

**DILI:** Ligand B (4.459) has a significantly lower DILI risk than Ligand A (62.815), a major advantage.

**BBB:** Ligand A (73.711) has a good BBB penetration, but it's not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern. Ligand B (81.698) is even better.

**Caco-2:** Ligand A (-5.253) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.684) is also poor, but slightly better.

**Solubility:** Ligand A (-2.618) has poor aqueous solubility, while Ligand B (-2.1) is also poor, but slightly better.

**hERG:** Both ligands have very low hERG inhibition risk (0.104 and 0.511, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (31.811) has lower microsomal clearance than Ligand A (40.719), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.807) has a longer in vitro half-life than Ligand A (4.603), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.303 and 0.067).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -9.1 kcal/mol), with Ligand B being slightly better. The affinity difference is minimal, and doesn't outweigh the other factors.

**Conclusion:**

While Ligand A has a better QED score and slightly better BBB penetration, Ligand B is significantly superior due to its lower DILI risk, better logP, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The poor Caco-2 and solubility of both are concerns, but can potentially be addressed through formulation strategies. The lower DILI risk and improved metabolic stability of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 10:55:15,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.419 Da and 360.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.12) is slightly above the preferred <140, but acceptable. Ligand B (89.27) is excellent, well below 140.

**logP:** Ligand A (-0.831) is a bit low, potentially hindering permeability. Ligand B (0.758) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.601 and 0.818), indicating drug-like properties.

**DILI:** Ligand A (19.698) has a very favorable DILI score, indicating low liver injury risk. Ligand B (67.235) is higher, suggesting a moderate risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.237) is better than Ligand B (43.777).

**Caco-2 Permeability:** Both are negative (-5.401 and -5.357), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative (-0.689 and -2.469), indicating poor solubility. This is a concern for both.

**hERG:** Ligand A (0.172) has a very low hERG risk. Ligand B (0.063) is even lower, indicating very low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-11.173) shows excellent metabolic stability (negative clearance). Ligand B (27.316) has a moderate clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-18.414) has a very long predicted half-life. Ligand B (14.254) has a shorter, but still reasonable, half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.081).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This is a substantial advantage.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B's significantly stronger binding affinity (-9.5 vs -6.1 kcal/mol) and better logP outweigh the moderate DILI risk and slightly higher clearance. The lower hERG risk is also a plus. The superior binding affinity suggests a higher probability of achieving efficacy, even if formulation challenges exist. Ligand A's excellent metabolic stability is attractive, but the weaker binding is a major drawback.

Output:
1
2025-04-17 10:55:15,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.559 Da and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, while Ligand B (74.33) is still acceptable but higher.

**logP:** Both ligands have good logP values (2.784 and 1.994), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 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 similar QED scores (0.586 and 0.52), indicating good drug-likeness.

**DILI:** Ligand A (22.451) has a significantly lower DILI risk than Ligand B (31.563), indicating a better safety profile. Both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (73.711) has a higher BBB percentile than Ligand B (40.675).

**Caco-2 Permeability:** Ligand A (-4.833) has a lower Caco-2 permeability than Ligand B (-5.585), suggesting potentially lower absorption. However, the values are both negative and relatively close, so this is not a major differentiator.

**Aqueous Solubility:** Ligand A (-2.597) has slightly better aqueous solubility than Ligand B (-1.382). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.636) has a much lower hERG inhibition liability than Ligand B (0.149), which is a critical advantage, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (68.102) has a higher microsomal clearance than Ligand B (8.619), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (17.789 hours) has a significantly longer in vitro half-life than Ligand A (10.342 hours), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.38) shows lower P-gp efflux liability than Ligand B (0.025), which could lead to better bioavailability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.1 kcal/mol). This difference of 2.9 kcal/mol is very significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having better solubility and lower DILI/hERG risk, Ligand B's significantly stronger binding affinity (-9.0 vs -6.1 kcal/mol) and longer half-life are decisive advantages for an enzyme inhibitor. While Ligand A's higher clearance is a concern, the potency difference is substantial enough to prioritize Ligand B.

Output:
1
2025-04-17 10:55:15,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (451.68) is closer to the upper limit, while Ligand B (356.41) is more central.

**TPSA:** Ligand A (60.67) is well below the 140 threshold for oral absorption and is favorable. Ligand B (98.58) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.764) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.111) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (3 HBD, 7 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.537, B: 0.665), indicating drug-like properties.

**DILI:** Both ligands have similar, high DILI risk (A: 84.374, B: 84.684). This is a concern for both.

**BBB:** Ligand A (75.727) has a better BBB percentile than Ligand B (34.277), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.398) has poor Caco-2 permeability. Ligand B (-5.683) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-6.253) has extremely poor aqueous solubility, a significant drawback. Ligand B (-3.511) is also poor, but better than Ligand A.

**hERG:** Both ligands have low hERG risk (A: 0.777, B: 0.47).

**Microsomal Clearance:** Ligand A (24.808) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (29.168) has higher clearance.

**In vitro Half-Life:** Ligand A (76.571) has a longer in vitro half-life, which is favorable. Ligand B (-6.781) has a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.752, B: 0.055).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.3 kcal/mol, B: -8.4 kcal/mol). The difference is minimal.

**Conclusion:**

Despite both ligands having good binding affinity, Ligand A is the better candidate. While its logP is slightly high and solubility is very poor, its superior metabolic stability (lower Cl_mic, longer t1/2) and better Caco-2 permeability outweigh these drawbacks, especially given the high DILI risk shared by both compounds. The solubility issue could potentially be addressed with formulation strategies. Ligand B's extremely short half-life is a major concern, making it less likely to be a viable drug candidate.

Output:
0
2025-04-17 10:55:15,903 - INFO - Batch 4 complete. Total preferences: 64
2025-04-17 10:55:15,903 - INFO - Processing batch 5/512...
2025-04-17 10:56:06,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (352.519 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold and favorable for absorption. Ligand B (78.87) is also acceptable, though slightly higher.

**logP:** Ligand A (2.861) is within the optimal 1-3 range. Ligand B (0.79) is a bit low, potentially hindering permeation, but not drastically.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4, both within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.6 (0.706 and 0.635), indicating good drug-like properties.

**DILI:** Ligand A (7.949) has a very low DILI risk. Ligand B (12.369) is also relatively low, but higher than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.37) is higher than Ligand B (46.84).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.649 and -4.783). This is unusual and suggests poor permeability. However, these values are on a log scale, so a more negative value indicates *lower* permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.498 and -1.397), indicating poor aqueous solubility. Again, these are on a log scale, so more negative means lower solubility.

**hERG Inhibition:** Ligand A (0.454) has a lower hERG risk than Ligand B (0.205), which is preferable.

**Microsomal Clearance:** Ligand A (37.674) has a significantly lower microsomal clearance than Ligand B (14.475), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-5.031) has a longer in vitro half-life than Ligand B (12.562). Again, these are on a log scale, so a more negative value indicates a longer half-life.

**P-gp Efflux:** Ligand A (0.184) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial difference (2.3 kcal/mol), and is a major factor.

**Conclusion:**

Despite the poor permeability and solubility for both compounds, the significantly stronger binding affinity of Ligand B (-9.2 kcal/mol vs -6.9 kcal/mol) outweighs the slightly higher DILI risk and lower metabolic stability. The difference in binding affinity is substantial enough to potentially overcome ADME challenges through formulation or structural modifications. Ligand A has better ADME properties, but the potency difference is too large to ignore for an enzyme target.

Output:
1
2025-04-17 10:56:06,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.341 and 366.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (89.27 and 88.93) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.095) is slightly low, potentially hindering permeation. Ligand B (1.678) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (7) are both acceptable, being less than 10.

**QED:** Both ligands have good QED scores (0.753 and 0.688), indicating drug-like properties.

**DILI:** Ligand A (36.603) has a lower DILI risk than Ligand B (54.556), both are good (<40 is preferred, but <60 is acceptable).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.884) and Ligand B (52.074) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.718) is poor, while Ligand B (-5.246) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.815 and -3.031). This is a concern, but can be addressed through formulation.

**hERG Inhibition:** Ligand A (0.115) has a lower hERG risk than Ligand B (0.424), which is preferable.

**Microsomal Clearance:** Ligand A (-23.464) has significantly lower (better) microsomal clearance than Ligand B (63.613), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.58) has a negative value, indicating a very long half-life, while Ligand B (9.989) is acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.013 and 0.143).

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B's substantially better binding affinity (-8.8 vs -7.1 kcal/mol) is the most critical factor, outweighing its slightly higher DILI and hERG risk and lower metabolic stability. While Ligand A has better metabolic stability and lower DILI/hERG, the potency difference is significant. The solubility issues are similar for both and can be addressed during formulation.

Output:
1
2025-04-17 10:56:06,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.63) is better than Ligand B (53.51), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (0.722) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.985) is within the optimal range.

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

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

**QED:** Both ligands have acceptable QED scores (0.872 and 0.78, respectively), indicating good drug-likeness.

**DILI:** Ligand A (47.034) has a slightly higher DILI risk than Ligand B (39.395), but both are below the concerning threshold of 60.

**BBB:** Ligand A (50.95) has a lower BBB penetration percentile than Ligand B (76.735). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.726) has a worse Caco-2 permeability than Ligand B (-4.889). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.376) has better aqueous solubility than Ligand B (-2.572). Solubility is important for bioavailability.

**hERG:** Ligand A (0.256) has a significantly lower hERG inhibition liability than Ligand B (0.483), which is a major advantage.

**Microsomal Clearance:** Ligand A (22.363) has significantly lower microsomal clearance than Ligand B (89.208), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-9.477) has a longer in vitro half-life than Ligand B (8.639), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux liability than Ligand B (0.183), which is favorable for oral bioavailability.

**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.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a better logP and BBB (less relevant here), Ligand A excels in crucial areas for kinase inhibitors: significantly lower hERG risk, much better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. The better solubility of Ligand A also contributes to its favorability. The slightly lower logP of Ligand A is a minor drawback compared to the substantial advantages in safety and PK.

Output:
0
2025-04-17 10:56:06,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (354.353 and 357.479 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (76.66 and 71.09) below 140, suggesting reasonable oral absorption potential.

**3. logP:** Ligand A (2.161) is optimal, while Ligand B (3.056) is towards the higher end of the optimal range. Both are acceptable.

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

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

**6. QED:** Ligand B (0.799) has a significantly better QED score than Ligand A (0.405), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (58.046 and 59.287), both falling within the acceptable range (<60).

**8. BBB:** Ligand A (82.513) has a better BBB penetration percentile than Ligand B (68.554). However, BBB penetration is less critical for a kinase inhibitor unless CNS involvement is specifically targeted.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.719 and -4.968). This is unusual and suggests very poor permeability. This is a major concern for both compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.886 and -4.585). This is also very concerning, indicating extremely poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.56 and 0.626), which is favorable.

**12. Microsomal Clearance:** Ligand A (67.29) has slightly higher microsomal clearance than Ligand B (65.218), suggesting potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (4.817 hours) has a significantly longer in vitro half-life than Ligand A (-9.806 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 (0.25 and 0.251), which is good.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.6 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in binding affinity and has a much better in vitro half-life. While both have poor solubility and permeability, the stronger binding and improved stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 10:56:06,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.4 and 382.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly higher than Ligand B (84.94), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.53) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.561) is closer to the optimal range.

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

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

**QED:** Both ligands have good QED scores (0.629 and 0.696, respectively), indicating drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (41.4 and 42.5, respectively), both below the 60 threshold.

**BBB:** Ligand B (89.96) has a significantly higher BBB penetration percentile than Ligand A (26.48). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.064 and -4.983), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.424 and -2.632), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.044) has a slightly lower hERG inhibition risk than Ligand B (0.56), which is preferable.

**Microsomal Clearance:** Ligand A (-2.291) has a lower (better) microsomal clearance than Ligand B (-8.583), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.015) has a longer in vitro half-life than Ligand B (-14.5), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.088 and 0.04, respectively).

**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.

**Conclusion:**

While both compounds have significant drawbacks (poor solubility and permeability), Ligand A is slightly more favorable. It has better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better permeability. The binding affinity difference is negligible. The poor solubility and permeability are major concerns that would require significant optimization. However, given the choice between these two, Ligand A appears to have a marginally better profile.

Output:
0
2025-04-17 10:56:06,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk, as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.372 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (71.69). Lower TPSA generally correlates with better cell permeability, which is beneficial.

**logP:** Both ligands have good logP values (2.366 and 1.957), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is slightly better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.704 and 0.503), indicating reasonable drug-likeness.

**DILI:** Ligand A (35.789) has a much lower DILI risk than Ligand B (70.686). This is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (89.492) is better than Ligand B (75.998).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.584 and -4.942), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so the negative values indicate very low permeability. Ligand B is slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.424 and -2.13), indicating poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.522) has a lower hERG inhibition liability than Ligand B (0.745), which is a critical advantage for safety.

**Microsomal Clearance:** Ligand A (38.436) has a higher microsomal clearance than Ligand B (28.908), meaning it's metabolized faster and has lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (4.738 hours) has a significantly longer in vitro half-life than Ligand A (-10.099 hours). This is a substantial advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.248).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -7.8 kcal/mol), with Ligand B being slightly better. However, the difference is small and likely not decisive given the other factors.

**Overall Assessment:**

Ligand A excels in DILI risk and hERG inhibition, which are crucial for safety. It also has a better TPSA. However, it has poorer metabolic stability (higher Cl_mic, shorter half-life) and solubility. Ligand B has better metabolic stability and solubility, but a significantly higher DILI risk and hERG liability.

Considering the enzyme-specific priorities, the lower DILI and hERG risk of Ligand A are paramount. While Ligand B has a slightly better half-life and affinity, the safety concerns outweigh these benefits. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 10:56:06,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 A (50.6) is significantly better than Ligand B (84.75). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 1.796, B: 2.26), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) is better. Ligand B has 1 HBD and 7 HBA. Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.852) has a much better QED score than Ligand B (0.587), indicating a more drug-like profile.

**DILI:** Ligand B (64.521) has a higher DILI risk than Ligand A (29.042). Lower DILI is preferred.

**BBB:** Ligand A (86.274) has a higher BBB percentile than Ligand B (41.45). While not a primary concern for a non-CNS target like SRC, higher BBB can indicate better overall permeability.

**Caco-2 Permeability:** Ligand A (-4.541) has a better Caco-2 permeability than Ligand B (-5.684).

**Aqueous Solubility:** Ligand A (-1.739) has better aqueous solubility than Ligand B (-2.68).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (A: 0.92, B: 0.504). This is good.

**Microsomal Clearance:** Ligand A (61.433) has a higher microsomal clearance than Ligand B (38.728). Lower clearance is preferred for better metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (10.56) has a significantly longer in vitro half-life than Ligand A (-6.912). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (A: 0.508, B: 0.03).

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol). This is excellent and removes this as a differentiating factor.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, QED, DILI, solubility, Caco-2 permeability, BBB) and has a better MW. However, Ligand B has a significantly longer half-life and lower microsomal clearance, which are crucial for an enzyme inhibitor. The difference in half-life is substantial. While Ligand A has a better overall ADME profile, the improved metabolic stability of Ligand B is a critical advantage for a kinase inhibitor, potentially allowing for less frequent dosing and sustained target engagement.

Output:
1
2025-04-17 10:56:06,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.389 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (67.23), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.416 and 2.307), 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.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well below the limit of 10.

**QED:** Both ligands have good QED scores (0.775 and 0.804), indicating good drug-likeness.

**DILI:** Ligand A (38.581) has a slightly higher DILI risk than Ligand B (30.826), but both are below the concerning threshold of 60.

**BBB:** Ligand A (72.082) has a lower BBB penetration than Ligand B (83.249). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.755 and -4.718), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.338 and -2.616), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.2) has a lower hERG inhibition risk than Ligand B (0.416), which is favorable.

**Microsomal Clearance:** Ligand A (-21.192) has significantly lower (better) microsomal clearance than Ligand B (43.048), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-33.322) has a longer in vitro half-life than Ligand B (2.626), suggesting a longer duration of action.

**P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.129), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-7.9) 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.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B's significantly superior binding affinity (-7.9 kcal/mol vs 0.0 kcal/mol) is the deciding factor. The improved metabolic stability (lower Cl_mic) and longer half-life of Ligand A are positives, but are outweighed by the substantial difference in potency. The slightly higher DILI and hERG risk of Ligand B are acceptable given the strong binding affinity.

Output:
1
2025-04-17 10:56:06,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.438 Da) is slightly higher than Ligand B (340.387 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (97.38 and 103.87) slightly above the optimal <140 for good oral absorption, but not drastically so.

**logP:** Ligand A (2.193) is within the optimal range (1-3). Ligand B (0.998) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (5) counts, well within the guidelines.

**QED:** Both ligands have similar and good QED scores (0.87 and 0.864), indicating good drug-like properties.

**DILI:** Ligand A (93.059) has a higher DILI risk than Ligand B (64.521). This is a significant concern, as a DILI percentile >60 is considered high risk.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (65.801) and Ligand B (54.013) are both relatively low.

**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 unspecified.

**hERG:** Ligand A (0.574) has a slightly higher hERG risk than Ligand B (0.135), but both are relatively low and acceptable.

**Microsomal Clearance (Cl_mic):** Ligand A (12.329 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (15.217 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life (t1/2):** Ligand A (176.728 hours) has a significantly longer half-life than Ligand B (-10.197 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.514 and 0.027), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.8 kcal/mol), with Ligand B being slightly better. The difference is small, and likely not decisive.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The primary driver is the significantly lower DILI risk associated with Ligand A (93.059 vs 64.521). Additionally, Ligand A has a much longer in vitro half-life (176.728 vs -10.197), and better metabolic stability (lower Cl_mic). While both have issues with Caco-2 and solubility, the DILI and PK advantages of Ligand A outweigh the slightly better binding of Ligand B.

Output:
1
2025-04-17 10:56:06,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (389.323 Da) is still well within the acceptable range.

**TPSA:** Ligand A (85.89) is better than Ligand B (58.64) regarding TPSA. Both are below 140, indicating good oral absorption potential.

**logP:** Ligand A (0.72) is a bit low, potentially hindering permeation. Ligand B (3.149) is within the optimal range (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 3 HBA. Both are acceptable, falling within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.636, B: 0.759), suggesting drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (A: 24.777, B: 27.336), which is favorable.

**BBB:** Both have reasonable BBB penetration (A: 69.678, B: 78.286), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.952), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.616 and -3.393), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.19) has a lower hERG risk than Ligand B (0.405), which is a significant advantage.

**Microsomal Clearance:** Both have similar microsomal clearance values (A: 28.889, B: 27.746), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand B (19.319 hours) has a significantly longer half-life than Ligand A (-0.912 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.018, B: 0.211).

**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 despite its slightly higher logP and hERG risk. Its superior half-life, better QED, and slightly better affinity outweigh the drawbacks. The biggest concern for both is the extremely poor Caco-2 permeability and aqueous solubility. However, these issues might be addressable through formulation strategies. Ligand A's very short half-life is a major disadvantage.

Output:
1
2025-04-17 10:56:06,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.391 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.0) is higher than the preferred <140 for oral absorption, but still reasonable. Ligand B (75.88) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (-0.164) is a bit low, potentially hindering permeation. Ligand B (1.391) 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 have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.695 and 0.823), indicating drug-like properties.

**DILI:** Ligand A (62.233) is moderately risky, while Ligand B (32.067) shows a lower risk of DILI, which is a significant advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (90.074) shows better penetration than Ligand A (32.377).

**Caco-2 Permeability:** Ligand A (-5.537) is poor, suggesting very low intestinal absorption. Ligand B (-4.45) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.349 and -1.069). This could pose formulation challenges, but is not a deal-breaker if other properties are strong.

**hERG Inhibition:** Both ligands show low hERG risk (0.114 and 0.44).

**Microsomal Clearance:** Ligand A (-19.179) shows significantly *lower* (better) microsomal clearance than Ligand B (34.522), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.826) shows a very long half-life, while Ligand B (-17.884) is shorter.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.006 and 0.055).

**Binding Affinity:** Both ligands have similar binding affinities (-8.8 and -8.1 kcal/mol), both of which are excellent. The difference is less than 1.5 kcal/mol, so it doesn't heavily sway the decision.

**Conclusion:**

While Ligand A has a better half-life and lower Cl_mic, the significantly better DILI score, logP, TPSA, and slightly better Caco-2 permeability of Ligand B make it the more promising candidate. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies. The lower DILI risk is a critical advantage for drug development.

Output:
1
2025-04-17 10:56:06,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.419 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.96) is slightly above the preferred <140, but acceptable. Ligand B (89.87) is excellent, well below 140.

**logP:** Ligand A (-0.094) is a bit low, potentially hindering permeability. Ligand B (1.301) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Ligand A (0.372) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.613) is above 0.5, suggesting better drug-likeness.

**DILI:** Ligand A (16.906) has a moderate DILI risk, but is still acceptable. Ligand B (10.702) has a lower DILI risk, which is preferable.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (51.221) is better than Ligand A (30.71).

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

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

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.106 and 0.171), which is excellent.

**Microsomal Clearance:** Ligand A (37.519) has a higher Cl_mic than Ligand B (30.065), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-12.578) has a negative half-life, which is impossible and indicates a problem with the data. Ligand B (-4.193) also has a negative half-life, also indicating a problem with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.013), which is good.

**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.

**Overall Assessment:**

Despite the issues with Caco-2 permeability and solubility, the significantly superior binding affinity of Ligand A (-8.6 kcal/mol vs -7.6 kcal/mol) is a major factor. The difference of 1 kcal/mol is substantial. While Ligand B has better QED and DILI scores, the potency advantage of Ligand A outweighs these benefits, especially for an enzyme target where hitting the target is paramount. The negative half-life values are concerning, but we'll assume this is a data error and focus on the other parameters.

Output:
1
2025-04-17 10:56:06,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.427 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.32 and 88.76) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (2.475 and 1.399). Ligand B is slightly lower, which *could* be a minor drawback, but is still acceptable.

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

**QED:** Both ligands have good QED scores (0.778 and 0.869), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 50.291, while Ligand B has 38.852. Both are below the 60 threshold, but Ligand B is notably lower, suggesting a better safety profile.

**BBB:** Both ligands have relatively low BBB penetration (54.478 and 78.209). This isn't a major concern for a kinase inhibitor, as CNS penetration isn't usually a primary goal.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.057 and -4.926), which is unusual and suggests poor permeability. This is a potential red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.285 and -0.708). This is also a significant concern, as poor solubility can hinder bioavailability. Ligand B is slightly better here.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.503 and 0.396), which is excellent.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (25.352) than Ligand B (0.917). This indicates Ligand A is likely to be cleared more rapidly, reducing its potential duration of action.

**In vitro Half-Life:** Ligand A has a half-life of 79.759 hours, while Ligand B has 12.775 hours. This is a significant difference, with Ligand A having a much longer half-life. However, this must be considered alongside the higher Cl_mic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.079 and 0.015).

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.6 kcal/mol) compared to Ligand B (-8.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A's significantly stronger binding affinity (-9.6 kcal/mol vs -8.0 kcal/mol) and longer half-life (79.759 vs 12.775) are compelling advantages. While its higher Cl_mic is a concern, the potency difference is likely to be more impactful for an enzyme inhibitor. Ligand B has a slightly better DILI score and solubility, but the weaker binding affinity is a major drawback.

Output:
1
2025-04-17 10:56:06,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (366.397 Da) is also good.

**TPSA:** Ligand A (67.35) is significantly better than Ligand B (87.66). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.945) is at the higher end of the optimal range, while Ligand B (2.669) is well within it. Both are acceptable, but Ligand A's higher logP *could* lead to off-target interactions or solubility issues, though not drastically.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5/6 HBA, which are acceptable and balanced for permeability and solubility.

**QED:** Ligand A (0.916) has a significantly better QED score than Ligand B (0.725), indicating a more drug-like profile.

**DILI:** Ligand B (82.435) has a considerably higher DILI risk than Ligand A (61.031). This is a significant concern.

**BBB:** Both have reasonable BBB penetration, but Ligand A (70.803) is slightly better than Ligand B (64.482). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-4.665) shows better Caco-2 permeability than Ligand B (-5.109).

**Aqueous Solubility:** Ligand A (-4.599) has better aqueous solubility than Ligand B (-3.754). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.63 and 0.475 respectively), which is excellent.

**Microsomal Clearance:** Ligand B (42.731) has lower microsomal clearance than Ligand A (51.786), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (11.136 hours) has a significantly longer half-life than Ligand A (2.815 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.201 and 0.256 respectively).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.2 kcal/mol). This 0.8 kcal/mol difference is very significant and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, it has a higher DILI risk. Ligand A has better solubility, permeability, and a better QED score, but weaker binding and poorer metabolic stability.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the stronger binding affinity and improved metabolic stability of Ligand B are compelling. While the higher DILI risk is a concern, it might be mitigated through structural modifications in subsequent optimization rounds. The substantial affinity advantage (-0.8 kcal/mol) is likely to be more impactful than the other differences.

Output:
1
2025-04-17 10:56:06,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.344 and 351.397 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.0) is better than Ligand B (63.13). Both are below the 140 threshold for oral absorption, which is good.

**logP:** Both ligands have acceptable logP values (1.876 and 2.656, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 3 HBA) regarding the number of hydrogen bond donors and acceptors. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.895 and 0.707), indicating good drug-like properties.

**DILI:** Ligand A (38.077) has a significantly lower DILI risk than Ligand B (48.623). This is a major advantage.

**BBB:** Both ligands have high BBB penetration (81.698 and 83.637), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.504 and -4.612). This 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 ligands have negative solubility values (-2.697 and -3.805). This is also unusual and suggests poor aqueous solubility. Again, the scale isn't clear, but both are problematic.

**hERG:** Both ligands show low hERG inhibition liability (0.766 and 0.6), which is excellent.

**Microsomal Clearance:** Ligand A (14.661 mL/min/kg) has significantly lower microsomal clearance than Ligand B (45.25 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (19.552) has a slightly longer in vitro half-life than Ligand A (-7.455). However, the negative value for Ligand A is concerning and likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.325 and 0.326).

**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 noticeable.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate**. It has a lower DILI risk, significantly better metabolic stability (lower Cl_mic), and slightly better binding affinity. While both have problematic solubility and permeability values, the superior safety and pharmacokinetic properties of Ligand A outweigh the minor affinity difference. The negative half-life value for Ligand A is a red flag that needs further investigation, but the other advantages make it the preferred choice.

Output:
0
2025-04-17 10:56:06,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 429.292 Da - Within the ideal range (200-500 Da).
* Ligand B: 353.463 Da - Also within the ideal range.
* *No clear advantage here.*

**2. TPSA:**
* Ligand A: 89.71 - Excellent, below the 140 threshold for good absorption.
* Ligand B: 96.53 - Still good, but slightly higher than Ligand A.
* *Slight advantage to Ligand A.*

**3. logP:**
* Ligand A: 2.009 - Optimal (1-3).
* Ligand B: 0.585 - A bit low. Could potentially hinder permeation.
* *Advantage to Ligand A.*

**4. H-Bond Donors (HBD):**
* Ligand A: 0 - Good, low number.
* Ligand B: 3 - Acceptable, but higher than Ligand A.
* *Advantage to Ligand A.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 6 - Good, within the acceptable range.
* Ligand B: 4 - Good, within the acceptable range.
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.726 - Excellent, strong drug-like profile.
* Ligand B: 0.651 - Good, but slightly lower than Ligand A.
* *Advantage to Ligand A.*

**7. DILI:**
* Ligand A: 84.645 - High risk of DILI. This is a significant concern.
* Ligand B: 25.902 - Low risk of DILI.
* *Significant advantage to Ligand B.*

**8. BBB:**
* Ligand A: 79.915 - Good, but not exceptionally high. Not a primary concern for a kinase inhibitor.
* Ligand B: 39.667 - Low. Not a primary concern for a kinase inhibitor.
* *No clear advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -4.592 - Negative value is unusual and suggests poor permeability.
* Ligand B: -5.369 - Also negative, suggesting poor permeability.
* *Both are poor, but similar.*

**10. Aqueous Solubility:**
* Ligand A: -2.975 - Poor solubility.
* Ligand B: -1.65 - Slightly better than Ligand A, but still poor.
* *Slight advantage to Ligand B.*

**11. hERG Inhibition:**
* Ligand A: 0.395 - Low risk, good.
* Ligand B: 0.129 - Very low risk, excellent.
* *Advantage to Ligand B.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 27.14 mL/min/kg - Relatively high, suggesting faster metabolism.
* Ligand B: 13.721 mL/min/kg - Lower, indicating better metabolic stability.
* *Advantage to Ligand B.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 78.505 hours - Excellent, long half-life.
* Ligand B: 3.064 hours - Very short half-life.
* *Significant advantage to Ligand A.*

**14. P-gp Efflux:**
* Ligand A: 0.105 - Low efflux, good.
* Ligand B: 0.012 - Very low efflux, excellent.
* *Advantage to Ligand B.*

**15. Binding Affinity:**
* Ligand A: -7.5 kcal/mol - Excellent, strong binding.
* Ligand B: -8.3 kcal/mol - Even stronger binding.
* *Advantage to Ligand B.*

**Overall Assessment:**

Ligand B has a significantly better safety profile (DILI, hERG) and metabolic stability (Cl_mic). It also boasts a superior binding affinity. While its solubility and permeability are poor, the strong binding affinity could potentially compensate. Ligand A has a good half-life and decent drug-like properties, but the high DILI risk is a major red flag.

Given the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), **Ligand B is the more promising candidate** despite its permeability and solubility issues. The stronger binding affinity and significantly improved safety profile outweigh the drawbacks, and formulation strategies can be explored to address solubility/permeability.

Output:
1
2025-04-17 10:56:06,509 - INFO - Batch 5 complete. Total preferences: 80
2025-04-17 10:56:06,509 - INFO - Processing batch 6/512...
2025-04-17 10:56:45,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.455 and 367.563 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is higher than Ligand B (54.26). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (1.52) and Ligand B (2.277) are both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are good.

**H-Bond Acceptors:** Both ligands have 6 HBAs, which is acceptable (<=10).

**QED:** Ligand A (0.895) has a significantly better QED score than Ligand B (0.772), indicating a more drug-like profile.

**DILI:** Ligand A (71.113) has a higher DILI risk than Ligand B (33.463). This is a significant negative for Ligand A.

**BBB:** Ligand A (64.676) has a slightly better BBB penetration potential than Ligand B (56.146), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.133) shows poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.895) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.627 and -2.416 respectively). This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.367 and 0.295 respectively). This is positive for both.

**Microsomal Clearance:** Ligand A (35.075) has significantly lower microsomal clearance than Ligand B (57.355), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (35.698) has a longer in vitro half-life than Ligand B (4.875), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.208 and 0.071 respectively).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor. A difference of 8.5 kcal/mol is enormous and likely outweighs most other concerns.

**Conclusion:**

Despite Ligand A's better QED, metabolic stability, and half-life, the overwhelmingly stronger binding affinity of Ligand B (-8.5 kcal/mol vs 0.0 kcal/mol) makes it the far more promising candidate. The poor solubility and Caco-2 permeability are concerns, but these can potentially be addressed through formulation strategies. The lower DILI risk for Ligand B is also a significant advantage.

Output:
1
2025-04-17 10:56:45,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.455 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (119.67). Lower TPSA generally correlates with better cell permeability. Ligand B is approaching a level that might hinder oral absorption.

**logP:** Ligand A (3.377) is optimal, while Ligand B (-0.25) is quite low. A logP below 1 can indicate poor membrane permeability. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=8) both fall within acceptable ranges, but Ligand A is slightly more favorable.

**QED:** Both ligands have reasonable QED values (A: 0.909, B: 0.709), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (17.759) has a much lower DILI risk than Ligand B (63.823). This is a crucial advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (96.627) shows better BBB penetration than Ligand B (83.792).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or prediction method. However, Ligand A (-5.117) is slightly better than Ligand B (-5.045).

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. Ligand A (-3.094) is slightly better than Ligand B (-2.779).

**hERG:** Ligand A (0.854) has a lower hERG risk than Ligand B (0.211), which is a significant advantage.

**Microsomal Clearance:** Ligand A (23.956) has a higher (worse) microsomal clearance than Ligand B (10.658), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-13.565) has a significantly longer in vitro half-life than Ligand A (6.555), which is a major advantage.

**P-gp Efflux:** Ligand A (0.461) has lower P-gp efflux than Ligand B (0.035), which is favorable.

**Binding Affinity:** Ligand A (-9.9 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. The 2.2 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior binding affinity, lower DILI risk, better TPSA, logP, and hERG profile outweigh its slightly higher microsomal clearance. The significantly stronger binding affinity is a key factor for an enzyme inhibitor. While both ligands have questionable solubility and Caco-2 permeability values, Ligand A is still better in those metrics. Ligand B's low logP and high DILI risk are major concerns.

Output:
0
2025-04-17 10:56:45,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (381.259 Da and 348.368 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is slightly higher than Ligand B (41.99). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have a logP around 4.8-4.9, which is slightly high. This could potentially lead to solubility issues or off-target effects, but is not a dealbreaker if other properties are favorable.

**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 range of <=10.

**QED:** Both ligands have good QED scores (0.744 and 0.856), indicating good drug-like properties.

**DILI:** Ligand A (78.17) has a higher DILI risk than Ligand B (59.131). This is a significant concern, as a lower DILI risk is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (86.39) has a higher BBB percentile than Ligand A (69.058), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.551 and -4.517), which is unusual and suggests poor permeability. This is a major drawback for both compounds.

**Aqueous Solubility:** Both have negative solubility values (-5.519 and -5.971), indicating very poor aqueous solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.489) has a slightly lower hERG risk than Ligand B (0.719), which is favorable.

**Microsomal Clearance:** Ligand A (99.727) has a significantly higher microsomal clearance than Ligand B (55.35). This indicates lower metabolic stability for Ligand A, which is undesirable.

**In vitro Half-Life:** Ligand B (26.64) has a longer in vitro half-life than Ligand A (34.153), which is preferable.

**P-gp Efflux:** Ligand A (0.247) has lower P-gp efflux than Ligand B (0.407), which is favorable.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a 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 better binding affinity and lower P-gp efflux, but suffers from higher DILI risk and significantly worse metabolic stability (higher Cl_mic, shorter t1/2). Both compounds have poor solubility and permeability. The difference in binding affinity (-0.5 kcal/mol) is significant. Considering the enzyme-specific priorities, the improved potency of Ligand A is the most important factor. While the ADME properties of both are suboptimal, the stronger binding of Ligand A makes it the more promising candidate, assuming further optimization can address the metabolic stability and solubility issues.

Output:
0
2025-04-17 10:56:45,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.352 and 348.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.66) is better than Ligand B (26.3). While both are below 140, Ligand B is exceptionally low, which *could* indicate poor interactions with the kinase hinge region.

**logP:** Ligand A (0.585) is suboptimal, being slightly below the preferred 1-3 range. Ligand B (4.862) is too high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable, but potentially indicating lower aqueous solubility.

**QED:** Both ligands have good QED scores (0.655 and 0.74), suggesting good drug-like properties.

**DILI:** Ligand A (25.048) has a significantly lower DILI risk than Ligand B (38.852), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (87.127) has a higher BBB score than Ligand A (61.535), but this isn't a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.801) shows poor permeability, while Ligand B (-4.337) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.856) has better solubility than Ligand B (-5.835). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.427) has a much lower hERG risk than Ligand B (0.869). This is a crucial factor for safety.

**Microsomal Clearance:** Ligand A (-6.778) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (67.336). This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (9.8 hours) has a shorter half-life than Ligand B (26.106 hours). While longer is generally preferred, the substantial difference in clearance for Ligand A makes this less critical.

**P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.515), improving bioavailability.

**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 advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite the superior binding affinity of Ligand B, the significant concerns regarding its high logP, higher DILI risk, higher hERG risk, and very high microsomal clearance outweigh this benefit. Ligand A, while having a weaker binding affinity, presents a much more favorable ADME-Tox profile, particularly with its low DILI and hERG risks, and better metabolic stability. The improved solubility and lower P-gp efflux also contribute to its potential for better bioavailability. Therefore, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 10:56:45,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.348 and 375.965 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (117.09) is better than Ligand B (12.47). While both are relatively low, Ligand B is exceptionally low, which *could* indicate poor solubility.

**logP:** Ligand A (1.428) is optimal, while Ligand B (4.971) is high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also acceptable, but very low.

**H-Bond Acceptors:** Ligand A (5) is acceptable, while Ligand B (3) is also acceptable.

**QED:** Both ligands have similar QED values (0.628 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (81.117) has a higher DILI risk than Ligand B (25.436). This is a significant drawback for Ligand A.

**BBB:** Ligand A (52.385) and Ligand B (95.851). BBB is not a primary concern for SRC kinase inhibitors as it is not a CNS target.

**Caco-2 Permeability:** Both have negative values (-5.332 and -5.227), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative values (-3.009 and -4.57), indicating very poor solubility.

**hERG Inhibition:** Ligand A (0.46) has a lower hERG risk than Ligand B (0.956), which is a positive.

**Microsomal Clearance:** Ligand A (25.454) has lower clearance than Ligand B (53.375), suggesting better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (-24.126) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (9.973) is acceptable.

**P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux than Ligand B (0.884), which is favorable.

**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:**

Ligand B has a better binding affinity and a more reasonable half-life. However, its high logP, higher DILI risk, and higher P-gp efflux are concerning. Ligand A has better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. The biggest issue with Ligand A is the very high DILI risk and the impossible half-life value. The solubility of both is extremely poor.

Given the enzyme-specific priorities, metabolic stability and hERG risk are crucial. While Ligand A's DILI is a major concern, its metabolic stability is significantly better. The small difference in binding affinity is unlikely to outweigh the ADME advantages of Ligand A *if* the DILI risk can be addressed through structural modifications. However, the negative half-life is a data quality issue that needs to be resolved.

Output:
0
2025-04-17 10:56:45,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.393 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.12) is well below the 140 threshold and favorable for oral absorption. Ligand B (86.88) is still below 140, but less optimal than A.

**logP:** Ligand A (4.368) is slightly high, potentially causing solubility issues or off-target effects. Ligand B (2.157) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is excellent. Ligand B (3 HBD, 3 HBA) is acceptable.

**QED:** Ligand A (0.865) has a very strong drug-like profile. Ligand B (0.663) is still reasonable, but less favorable.

**DILI:** Ligand A (65.607) has a moderate DILI risk, while Ligand B (35.556) has a low DILI risk, which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (A: 73.129, B: 60.682), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.728) shows poor permeability. Ligand B (-5.303) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-5.198) has very poor solubility, a major concern. Ligand B (-2.305) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.831) has a slightly elevated hERG risk. Ligand B (0.135) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (53.781) has moderate clearance, suggesting moderate metabolic stability. Ligand B (34.289) has lower clearance, indicating better metabolic stability, which is crucial for kinases.

**In vitro Half-Life:** Ligand A (11.177 hours) has a reasonable half-life. Ligand B (-9.948 hours) has a *negative* half-life, which is not physically possible and indicates a severe instability issue.

**P-gp Efflux:** Ligand A (0.6) has moderate P-gp efflux. Ligand B (0.094) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is the better candidate despite the slightly lower binding affinity. Its significantly lower DILI risk, much better metabolic stability (lower Cl_mic), very low hERG risk, and lower P-gp efflux outweigh the slightly weaker binding. Ligand A's poor solubility and permeability, coupled with moderate DILI and hERG risk, make it a less viable option. The negative half-life for Ligand B is a data error, but even ignoring that, the other ADME properties are much better.

Output:
1
2025-04-17 10:56:45,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (447.34 Da) is higher, but still acceptable. Ligand B (386.583 Da) is slightly preferred.

**TPSA:** Ligand A (126.66) is approaching the upper limit for good oral absorption, while Ligand B (83.63) is well below. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 2.663, B: 2.961), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 8 HBA, while Ligand B has 5. Both are acceptable (<=10), but Ligand B is slightly better.

**QED:** Both ligands have good QED scores (A: 0.595, B: 0.706), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A has a high DILI risk (96.549%), which is a significant concern. Ligand B has a much lower DILI risk (36.681%), making it substantially more favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (61.923%) is higher than Ligand A (33.85%), but this is less important.

**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, also unusual and concerning. This suggests poor solubility for both compounds.

**hERG:** Both have low hERG inhibition liability (A: 0.479, B: 0.57), which is good.

**Microsomal Clearance:** Ligand A has lower microsomal clearance (30.76) than Ligand B (50.614), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A has a negative half-life (-1.019), which is nonsensical. Ligand B has a half-life of -8.222, also nonsensical. This is a major red flag for both.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.262, B: 0.393), which is good.

**Binding Affinity:** Ligand B has a better binding affinity (-9.4 kcal/mol) than Ligand A (-8.6 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Despite Ligand A having better metabolic stability, the extremely high DILI risk is a major drawback. The nonsensical half-life values for both compounds are concerning and suggest data quality issues. However, considering the enzyme-specific priorities, Ligand B is the better candidate due to its significantly lower DILI risk, better QED, better TPSA, and superior binding affinity. The slightly better affinity outweighs the slightly worse metabolic stability.

Output:
1
2025-04-17 10:56:45,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (373.503 and 362.352 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (74.25 and 76.46) are below the 140 A^2 threshold for good oral absorption, which is good.

**3. logP:** Ligand A (3.905) is at the upper end of the optimal range (1-3), while Ligand B (1.683) is at the lower end. While Ligand B's logP is acceptable, a slightly higher value is generally preferred for kinases to aid in membrane permeability and target engagement.

**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 (5 each), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.613 and 0.749), indicating drug-like properties.

**7. DILI:** Ligand A (81.66) has a significantly higher DILI risk than Ligand B (39.434). This is a major concern for Ligand A.

**8. BBB:** Both ligands have reasonably high BBB penetration (59.946 and 81.582), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.069 and -5.042). 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 negative solubility values (-4.408 and -1.706). Again, these are on a log scale and suggest poor aqueous solubility. Ligand B is slightly better in this regard.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.64 and 0.433).

**12. Microsomal Clearance (Cl_mic):** Ligand B (-17.484) has significantly lower (better) microsomal clearance than Ligand A (75.376). This indicates better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-10.52) has a longer in vitro half-life than Ligand A (59.899), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.654 and 0.026).

**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 not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic, longer t1/2) are crucial advantages. While both have poor solubility and permeability, the difference in DILI and metabolic stability outweighs the slightly better binding affinity of Ligand A.

Output:
1
2025-04-17 10:56:45,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.511 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.64) is significantly better than Ligand B (74.58), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.539 and 2.725), 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) in terms of hydrogen bonding potential, staying closer to the ideal limits.

**QED:** Both ligands have similar and good QED scores (0.773 and 0.779), indicating good drug-likeness.

**DILI:** Ligand A (7.91) has a much lower DILI risk than Ligand B (51.028), which is a significant advantage. Ligand B's DILI is concerning.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (78.364) is better than Ligand B (58.627).

**Caco-2 Permeability:** 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 (-0.034) is better than Ligand B (-3.03), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.664 and 0.35), which is excellent.

**Microsomal Clearance:** Ligand A (-7.856) has significantly lower (better) microsomal clearance than Ligand B (43.056), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (32.918) has a reasonable half-life, while Ligand B (41.874) is also acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.082).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better ADME properties, specifically lower DILI risk, better solubility, and improved metabolic stability (lower Cl_mic). The lower TPSA is also beneficial. These factors outweigh any minor differences in other parameters.

Output:
0
2025-04-17 10:56:45,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.49 and 352.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (110.26). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Both ligands have acceptable logP values (2.61 and 1.35), 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 it has fewer hydrogen bond forming groups, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.63 and 0.74), indicating drug-like properties.

**DILI:** Ligand A (6.75) has a much lower DILI risk than Ligand B (57.15). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.92) has a higher BBB penetration than Ligand B (70.76), but this is not a major deciding factor.

**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, again suggesting a potential data issue. The values are similar.

**hERG Inhibition:** Ligand A (0.37) has a lower hERG risk than Ligand B (0.25), which is favorable.

**Microsomal Clearance:** Ligand A (53.89) has a lower microsomal clearance than Ligand B (58.04), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.83) has a significantly longer in vitro half-life than Ligand B (8.66). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). While a 1.5 kcal/mol difference is usually significant, the other ADME properties of Ligand A are considerably better.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower TPSA, and lower hERG risk. These factors are particularly important for an enzyme target like SRC kinase, where metabolic stability and safety are critical. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh the slight affinity difference.

Output:
0
2025-04-17 10:56:45,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.423 and 354.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.56) is slightly above the preferred <140, but acceptable. Ligand B (110.59) is well within the acceptable range.

**3. logP:** Ligand A (-1.013) is a bit low, potentially hindering permeability. Ligand B (2.0) is optimal.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 6, B: 6) are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (A: 0.466, B: 0.592), with Ligand B being slightly more drug-like.

**7. DILI:** Ligand A (17.255) has a very low DILI risk, which is excellent. Ligand B (63.513) has a significantly higher DILI risk, which is concerning.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (63.901) than Ligand A (24.389).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand B (-4.741) is slightly better than Ligand A (-5.651).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-0.71) is slightly better than Ligand B (-3.58).

**11. hERG Inhibition:** Ligand A (0.058) has a very low hERG risk, which is excellent. Ligand B (0.452) has a moderate hERG risk.

**12. Microsomal Clearance:** Ligand A (15.373) has lower clearance, suggesting better metabolic stability. Ligand B (31.675) has higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (13.518) has a longer half-life than Ligand B (-2.804).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.006, B: 0.214).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME liabilities of Ligand B.

**Overall Assessment:**

Ligand A is clearly the superior candidate. While its logP is slightly low and Caco-2 permeability is poor, its excellent DILI profile, low hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and acceptable binding affinity outweigh these drawbacks. Ligand B, despite having slightly better binding affinity, suffers from a high DILI risk, moderate hERG risk, and faster metabolism. The DILI risk is a major red flag, making Ligand B a less viable candidate.

Output:
0
2025-04-17 10:56:45,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 374.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.42 and 88.24) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.751 and 2.051) 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 7 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.765 and 0.862), indicating good drug-like properties.

**DILI:** Ligand A (51.687) has a lower DILI risk than Ligand B (75.766). This is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration (54.246 and 84.606), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.72 and -4.887). This 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 (-2.726 and -2.918), indicating very poor solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.173 and 0.305).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (63.265 and 65.918 mL/min/kg), indicating moderate metabolic liability.

**In vitro Half-Life:** Ligand A (-24.571 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (-11.551 hours) also has a negative half-life, also likely an error.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.098 and 0.042).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand A is the more promising candidate due to its significantly stronger binding affinity (-8.9 kcal/mol vs -7.5 kcal/mol) and lower DILI risk (51.687 vs 75.766). The affinity difference is large enough to potentially overcome the solubility/permeability issues through formulation strategies. The negative half-life values are concerning, but could be data errors.

Output:
1
2025-04-17 10:56:45,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.435 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.07) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (78.87) is well within the ideal range.

**logP:** Ligand A (-0.093) is a bit low, potentially hindering permeability. Ligand B (0.968) is closer to 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 within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.765 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (15.51) has a significantly lower DILI risk than Ligand B (34.393), which is a major advantage.

**BBB:** Ligand A (43.001) has a lower BBB penetration than Ligand B (58.007), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.204 and -5.117), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.003 and -2.031). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.208) has a much lower hERG inhibition liability than Ligand B (0.744), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-51.293) has a much lower (better) microsomal clearance than Ligand B (30.639), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (13.257) has a longer half-life than Ligand B (-31.163), which is desirable.

**P-gp Efflux:** Ligand A (0.014) has a much lower P-gp efflux liability than Ligand B (0.132), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.8 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. The difference is >1.5kcal/mol.

**Conclusion:**

While Ligand B has a superior binding affinity, Ligand A demonstrates significantly better ADMET properties, particularly regarding DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and P-gp efflux. The poor solubility and Caco-2 permeability are concerns for both. However, the substantial advantage in safety (DILI and hERG) and metabolic stability for Ligand A, combined with acceptable (though not ideal) binding affinity, makes it the more promising candidate. The stronger binding of Ligand B is tempting, but the higher risk profile is concerning.

Output:
0
2025-04-17 10:56:45,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.417 Da) is slightly higher than Ligand B (338.459 Da), but both are acceptable.

**TPSA:** Ligand A (87.66) is better than Ligand B (66.83). Both are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (1.734) is within the optimal range (1-3). Ligand B (3.429) is at the higher end of the optimal range, potentially increasing off-target effects.

**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:** Ligand B (0.921) has a significantly higher QED score than Ligand A (0.583), indicating a more drug-like profile.

**DILI:** Ligand A (37.263) has a lower DILI risk than Ligand B (56.805), which is preferable.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase. Ligand B (69.794) is slightly better than Ligand A (52.268).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.968) is slightly better than Ligand B (-5.157).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand A (-1.513) is slightly better than Ligand B (-4.3).

**hERG Inhibition:** Ligand A (0.507) has a lower hERG inhibition liability than Ligand B (0.838), which is a significant advantage.

**Microsomal Clearance:** Ligand A (33.677) has a lower microsomal clearance than Ligand B (77.246), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.089) has a negative half-life, which is problematic. Ligand B (-3.288) is also negative, but less so. Both suggest rapid metabolism.

**P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux liability than Ligand B (0.103), which is preferable.

**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 the better candidate despite its lower QED and negative half-life. The significantly stronger binding affinity (-7.6 vs 0.0 kcal/mol) outweighs the other drawbacks, especially for an enzyme target where potency is paramount. The lower DILI and hERG risk are also beneficial. While both ligands have poor solubility and permeability, the superior affinity of Ligand A suggests it's more likely to be effective *in vivo* even with these limitations, and these properties can be addressed through formulation strategies. The better metabolic stability (lower Cl_mic) also favors Ligand A.

Output:
0
2025-04-17 10:56:45,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 360.361 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.67 and 85.69) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.403) is optimal, while Ligand B (0.35) is slightly low, potentially hindering permeation.

**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 (0.839 and 0.791), indicating good drug-likeness.

**DILI:** Ligand A (32.648) has a significantly lower DILI risk than Ligand B (60.062). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (84.141) is better than Ligand A (69.794). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.545 and -4.824), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.697 and -1.263), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.146 and 0.192), which is excellent.

**Microsomal Clearance:** Ligand A (26.598) has a lower microsomal clearance than Ligand B (5.051), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (21.166) has a longer half-life than Ligand A (7.375), which is favorable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.039 and 0.062), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in DILI risk and metabolic stability (lower Cl_mic), and has a good logP. Ligand B has a slightly better binding affinity and half-life, and better BBB penetration. However, the significantly higher DILI risk and worse metabolic stability of Ligand B are major drawbacks. The poor Caco-2 and solubility for both are concerning, but could potentially be addressed with formulation strategies. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial.

Output:
0
2025-04-17 10:56:45,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 340.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.22) is better than Ligand B (101.28) as it is closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.788 and 0.715), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 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 (0.596 and 0.755), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (38.813) has a significantly lower DILI risk than Ligand B (62.776). This is a major advantage for Ligand A.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B is slightly higher (66.227 vs 47.421).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.719) is slightly better than Ligand B (-5.31).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-3.071) is slightly better than Ligand B (-3.029).

**hERG:** Both ligands have very low hERG inhibition risk (0.5 and 0.065). Ligand B is better.

**Microsomal Clearance:** Ligand A (26.833) has lower microsomal clearance than Ligand B (29.586), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.975) has a longer in vitro half-life than Ligand B (-5.994), which is a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.193 and 0.153).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a crucial advantage, as a 1.2 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is the superior candidate. While both ligands have some ADME liabilities (poor Caco-2 and solubility), Ligand A's significantly stronger binding affinity (-8.7 vs -7.5 kcal/mol), lower DILI risk (38.8 vs 62.8), and better metabolic stability (lower Cl_mic and longer t1/2) outweigh its slightly less favorable TPSA and BBB. The potency advantage is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 10:56:45,743 - INFO - Batch 6 complete. Total preferences: 96
2025-04-17 10:56:45,744 - INFO - Processing batch 7/512...
2025-04-17 10:57:26,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (348.349 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.19) is higher than Ligand B (49.85). Both are acceptable, but B is better for permeability.

**logP:** Both ligands have good logP values (3.162 and 2.463, respectively), falling within the 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have acceptable QED scores (0.629 and 0.525, respectively), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (60.915%) compared to Ligand B (13.106%). This is a major concern for Ligand A.

**BBB:** Both have similar BBB penetration (83.637% and 84.025%), which is not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-4.424 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.

**Solubility:** Both have negative solubility values (-2.876 and -1.965), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated through formulation.

**hERG:** Both ligands have low hERG inhibition liability (0.247 and 0.403, respectively), which is positive.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (76.418) than Ligand B (44.385). This suggests lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (7.157 hours) than Ligand A (-11.637 hours). The negative value for A is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both have low P-gp efflux liability (0.747 and 0.307, respectively).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-7.4 kcal/mol) compared to Ligand A (-8.6 kcal/mol). While both are good, the 1.2 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a superior binding affinity. The better binding affinity of Ligand B is a crucial advantage for an enzyme target like SRC. The DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 10:57:26,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.415 and 371.497 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is better than Ligand B (45.23) as it is closer to the threshold for good oral absorption.

**logP:** Both ligands have logP values (2.238 and 3.919) within the optimal 1-3 range, but Ligand B is approaching the upper limit.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have high QED scores (0.904 and 0.873), indicating good drug-like properties.

**DILI:** Ligand B (24.04) has a significantly lower DILI risk than Ligand A (64.793), which is a major advantage.

**BBB:** Ligand B (91.314) has a much higher BBB penetration score than Ligand A (62.156), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar, very negative Caco-2 values (-4.86 and -4.862). This is concerning and suggests poor permeability.

**Aqueous Solubility:** Both ligands have similar, very negative solubility values (-3.516 and -3.721). This is also concerning and suggests poor solubility.

**hERG:** Ligand A (0.185) has a lower hERG risk than Ligand B (0.683), which is favorable.

**Microsomal Clearance:** Ligand A (25.826) has a slightly higher microsomal clearance than Ligand B (23.744), indicating slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.619) has a negative half-life, which is concerning. Ligand A (6.415) has a positive half-life, which is better.

**P-gp Efflux:** Ligand A (0.03) has a much lower P-gp efflux liability than Ligand B (0.449), which is a benefit.

**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 ADME drawbacks.

**Conclusion:**

Despite the solubility and permeability concerns for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.8 vs -7.7 kcal/mol) is a major advantage for an enzyme target. Furthermore, its substantially lower DILI risk (24.04 vs 64.793) is a critical safety factor. While Ligand A has better hERG and P-gp profiles, the potency and safety advantages of Ligand B are more important for initial optimization. The negative half-life of Ligand B is a significant concern that would need to be addressed in further optimization.

Output:
1
2025-04-17 10:57:26,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (382.426 and 359.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.78) is better than Ligand B (29.54) as it is closer to the upper limit for good oral absorption (<=140). Ligand B is quite low, which might suggest good permeability but could also indicate a lack of necessary interactions.

**logP:** Ligand A (2.128) is within the optimal range (1-3). Ligand B (4.264) is slightly above this range, potentially leading to solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, well within the acceptable limits. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.803 and 0.786), indicating good drug-likeness.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (32.842). This is a significant drawback for Ligand A.

**BBB:** Ligand A (49.477) and Ligand B (79.992). BBB is not a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.108) and Ligand B (-4.962) both have negative values, which is unusual and requires investigation. It's difficult to interpret without knowing the scale, but generally, higher values are preferred.

**Aqueous Solubility:** Ligand A (-2.046) and Ligand B (-4.679) both have negative values, which is also unusual and requires investigation. It's difficult to interpret without knowing the scale, but generally, higher values are preferred.

**hERG Inhibition:** Ligand A (0.308) has a lower hERG risk than Ligand B (0.799), which is a positive attribute.

**Microsomal Clearance:** Ligand A (17.043) has significantly lower microsomal clearance than Ligand B (125.886), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (13.494) has a longer in vitro half-life than Ligand B (2.878), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.176) has lower P-gp efflux than Ligand B (0.754), which is beneficial for oral bioavailability.

**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 (0.7 kcal/mol), it's a factor.

**Overall Assessment:**

Ligand B has a better binding affinity and lower DILI risk, but suffers from higher logP, higher P-gp efflux, and significantly worse metabolic stability (higher Cl_mic and shorter t1/2). Ligand A has a better ADME profile overall, with lower DILI, better metabolic stability, lower P-gp efflux and a reasonable logP. The slightly weaker binding affinity of Ligand A can likely be optimized through further medicinal chemistry efforts. Given the enzyme-specific priorities, the improved metabolic stability and reduced efflux of Ligand A are more important than the small difference in binding affinity.

Output:
1
2025-04-17 10:57:26,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.407 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.26) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (68.04) is excellent, well below 140, suggesting good absorption potential.

**logP:** Both ligands (1.572 and 1.813) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.712) has a significantly better QED score than Ligand A (0.312), indicating a more drug-like profile.

**DILI:** Ligand B (21.132) has a much lower DILI risk than Ligand A (34.82), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (90.19) has a higher BBB score than Ligand A (48.391).

**Caco-2 Permeability:** Ligand A (-4.962) and Ligand B (-4.682) both have negative values, which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Ligand A (-1.653) and Ligand B (-0.702) both have negative values, indicating poor solubility. Ligand B is slightly better.

**hERG:** Ligand A (0.075) has a slightly lower hERG risk than Ligand B (0.202), which is preferable.

**Microsomal Clearance:** Ligand A (45.03) has a lower microsomal clearance than Ligand B (63.947), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-16.643) has a significantly longer in vitro half-life than Ligand B (-0.856), which is a major benefit.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.068, respectively).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B has a better QED, lower DILI risk, and better BBB penetration. However, Ligand A exhibits superior metabolic stability (lower Cl_mic) and a longer in vitro half-life, which are crucial for an enzyme inhibitor. The binding affinity difference is relatively small. The solubility is poor for both, but slightly better for Ligand B. Considering the priorities for kinase inhibitors, the improved metabolic stability and half-life of Ligand A outweigh the advantages of Ligand B.

Output:
0
2025-04-17 10:57:26,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (380.411 Da) is also acceptable.

**TPSA:** Ligand A (107.61) is better than Ligand B (72.11). Both are below 140, supporting good oral absorption.

**logP:** Ligand A (-0.465) is a bit low, potentially hindering permeation. Ligand B (3.433) is optimal. This is a significant advantage for Ligand B.

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

**QED:** Both ligands have good QED scores (A: 0.522, B: 0.702), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (20.551) has a much lower DILI risk than Ligand B (39.201). This is a strong advantage for Ligand A.

**BBB:** Ligand A (47.15) has a lower BBB penetration than Ligand B (93.912). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.534) has poor Caco-2 permeability, while Ligand B (-4.621) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.57) has poor solubility, while Ligand B (-4.806) is also poor. This is a concern for both, but potentially more so for Ligand A given its lower logP.

**hERG Inhibition:** Ligand A (0.041) has very low hERG inhibition risk, a significant advantage. Ligand B (0.783) is higher, raising a potential safety concern.

**Microsomal Clearance:** Ligand A (-7.603) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (34.292) has higher clearance, suggesting faster metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-5.355) has a longer half-life than Ligand B (15.006), further supporting its metabolic stability.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, while Ligand B (0.249) has moderate efflux.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. The difference of 8.5 kcal/mol is substantial and likely outweighs many of the ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand A's lower logP and solubility, its *far* superior binding affinity (-8.5 vs 0.0 kcal/mol), excellent metabolic stability (low Cl_mic and long t1/2), low DILI risk, and low hERG risk make it the much more promising candidate. The binding affinity difference is so large that it is likely to overcome the permeability and solubility issues, especially with appropriate formulation strategies. Ligand B has better logP and BBB, but its weak binding affinity and higher DILI/hERG risks are major drawbacks.

Output:
0
2025-04-17 10:57:26,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (351.447 and 366.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (91.4), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Ligand A (0.577) is slightly low, potentially hindering permeation. Ligand B (1.583) 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:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.685 and 0.764), indicating drug-like properties.

**7. DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (37.456). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (67.197 and 66.576), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.144 and -5.176), indicating poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.154 and -3.392), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.184) has a much lower hERG inhibition liability than Ligand B (0.348), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-1.324) has a much lower (better) microsomal clearance than Ligand B (35.017), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.924) has a better in vitro half-life than Ligand B (-11.985).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.028).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.5), although the difference is relatively small.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand A excels in these areas. It has a slightly better affinity, significantly better metabolic stability (lower Cl_mic and better t1/2), lower hERG risk, and a much lower DILI risk. While both have poor Caco-2 and solubility, the superior ADME-Tox profile of Ligand A outweighs the minor affinity difference.

Output:
0
2025-04-17 10:57:26,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.4 and 350.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.7) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (79.3) is well within the range.

**logP:** Both ligands (2.53 and 2.88) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (3) is good.

**QED:** Both ligands have good QED scores (0.667 and 0.889), indicating drug-likeness.

**DILI:** Ligand A (56.8) is preferable to Ligand B (90.5) as it has a lower DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (74.3) is better than Ligand B (57.6).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-4.71) is slightly better than Ligand B (-4.97).

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS-scale values, lower values indicate poorer solubility. Ligand A (-3.23) is slightly better than Ligand B (-3.59).

**hERG:** Both ligands have very low hERG inhibition risk (0.57 and 0.053), which is excellent.

**Microsomal Clearance:** Ligand B (-8.17) has significantly *lower* (better) microsomal clearance than Ligand A (25.46). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-43.53) has a much longer in vitro half-life than Ligand A (21.41), indicating greater stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.21 and 0.023), which is good.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This 0.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better DILI score and BBB penetration, Ligand B excels in key areas for an enzyme inhibitor: significantly improved metabolic stability (lower Cl_mic, longer t1/2), and a substantially stronger binding affinity. The slightly higher DILI risk of Ligand B is likely manageable given the potency advantage and improved stability.

Output:
1
2025-04-17 10:57:26,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.471 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is well below the 140 threshold for good absorption, while Ligand B (95.39) is approaching it but still acceptable.

**logP:** Ligand A (2.946) is optimal (1-3). Ligand B (-1.054) is significantly below this, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**H-Bond Acceptors:** Ligand A (3) is well below the limit of 10. Ligand B (7) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.78 and 0.552), indicating drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (19.155) has a much lower DILI risk than Ligand B (34.161). This is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (78.674) has a higher BBB percentile than Ligand B (52.889).

**Caco-2 Permeability:** Ligand A (-4.617) shows poor permeability, while Ligand B (-5.464) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.362) shows poor solubility, while Ligand B (-0.946) is better, but still poor.

**hERG Inhibition:** Ligand A (0.387) has a very low hERG risk, a crucial advantage. Ligand B (0.148) is also low, but higher than A.

**Microsomal Clearance:** Ligand A (25.49) has a higher microsomal clearance than Ligand B (18.443), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (11.965) has a longer in vitro half-life than Ligand A (-7.938), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.006, respectively).

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in DILI risk and hERG inhibition, which are critical for enzyme inhibitors. However, it suffers from poor Caco-2 permeability and aqueous solubility, and has a higher microsomal clearance. Ligand B has better solubility, half-life, and slightly better binding affinity, but has a significantly higher DILI risk and slightly higher hERG risk. Given the importance of minimizing toxicity (DILI and hERG) for an oncology drug, and the relatively small difference in binding affinity, Ligand A is the more promising candidate, despite its permeability and solubility issues. These issues can potentially be addressed through formulation strategies or further chemical modifications.

Output:
0
2025-04-17 10:57:26,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (364.392 and 362.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (52.89) is well below the 140 threshold and good for oral absorption. Ligand B (67.23) is also below the threshold, but higher than A.

**3. logP:** Ligand A (3.839) is at the upper end of the optimal range (1-3), while Ligand B (1.693) is towards the lower end. While both are acceptable, a logP that is too low can hinder permeation.

**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 HBAs, and Ligand B has 5 HBAs, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.76 and 0.782), indicating good drug-likeness.

**7. DILI:** Ligand A (53.432) has a higher DILI risk than Ligand B (36.254). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (83.443) has a higher BBB penetration percentile than Ligand B (72.625). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.74) has worse Caco-2 permeability than Ligand B (-5.374), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-5.189) has worse aqueous solubility than Ligand B (-2.331). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.941) has a slightly higher hERG inhibition risk than Ligand B (0.593).

**12. Microsomal Clearance (Cl_mic):** Ligand B (39.146) has a lower Cl_mic, suggesting better metabolic stability, than Ligand A (67.573).

**13. In vitro Half-Life (t1/2):** Ligand A (8.678) has a longer half-life than Ligand B (0.752).

**14. P-gp Efflux:** Ligand A (0.343) has lower P-gp efflux than Ligand B (0.126), which is favorable.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 0.3 kcal/mol difference is not substantial enough to overcome the ADME liabilities of Ligand A.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand B excels in metabolic stability (lower Cl_mic) and has better solubility and a lower DILI risk. While Ligand A has slightly better affinity and half-life, the significantly higher DILI risk and lower solubility are major concerns.

Output:
1
2025-04-17 10:57:26,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.5 and 361.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is higher than Ligand B (46.61). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (1.953) is within the optimal 1-3 range. Ligand B (3.345) is at the higher end of the optimal range, potentially leading to solubility issues, but not critically so.

**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 (0.748 and 0.808), indicating good drug-like properties.

**DILI:** Ligand A (37.34) has a slightly higher DILI risk than Ligand B (28.62), but both are below the concerning threshold of 60.

**BBB:** Ligand A (51.997) has a lower BBB penetration percentile than Ligand B (85.847). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.913 and -4.822). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**Aqueous Solubility:** Ligand A (-1.995) has slightly better solubility than Ligand B (-3.244), though both are very poor.

**hERG:** Both ligands have low hERG inhibition liability (0.274 and 0.375), which is excellent.

**Microsomal Clearance:** Ligand A (25.995) has significantly lower microsomal clearance than Ligand B (67.734). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-1.165) has a shorter in vitro half-life than Ligand B (6.948). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.098 and 0.598), which is favorable.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a >3 kcal/mol difference, which is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite Ligand A's better metabolic stability and slightly better solubility, Ligand B's dramatically superior binding affinity (-9.7 vs -6.6 kcal/mol) is the decisive factor. The improved BBB penetration and in vitro half-life also contribute to its favorability. The slightly higher logP and lower solubility of Ligand B are less concerning given the potency advantage.

Output:
1
2025-04-17 10:57:26,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.467 and 359.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (67.59). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.038 and 2.725), falling within the optimal 1-3 range.

**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 permeability.

**QED:** Both ligands have acceptable QED scores (0.848 and 0.775), indicating good drug-likeness.

**DILI:** Ligand A (27.026) has a much lower DILI risk than Ligand B (39.046), which is a significant advantage.

**BBB:** Both have high BBB penetration (90.617 and 87.01), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.56 and -4.6), 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 (-3.318 and -2.028), indicating poor aqueous solubility. This is a concern, but can be addressed through formulation.

**hERG Inhibition:** Ligand A (0.76) has a lower hERG inhibition risk than Ligand B (0.358), which is a positive.

**Microsomal Clearance:** Ligand A (58.493) has a higher microsomal clearance than Ligand B (33.548), meaning it's less metabolically stable. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-15.282) has a significantly longer in vitro half-life than Ligand A (-7.464), which is a substantial advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.463 and 0.089).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.1 and -7.4 kcal/mol). The difference of 0.7 kcal/mol is not enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk and hERG inhibition, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2) is crucial for an enzyme target. The similar binding affinities make the ADME properties the deciding factor. The solubility issues are present in both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 10:57:26,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.587 and 361.368 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.2) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (80.12) is still under 140, but less favorable than A.

**logP:** Ligand A (3.746) is at the upper end of the optimal range (1-3), while Ligand B (1.077) is at the lower end. While both are within range, a higher logP can sometimes improve potency, but also raises concerns about solubility and off-target effects.

**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:** Both ligands have good QED scores (0.652 and 0.822), indicating drug-like properties.

**DILI:** Ligand A (31.33) has a lower DILI risk than Ligand B (43.738), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (74.215) has a higher BBB score than Ligand A (64.482).

**Caco-2 Permeability:** Ligand A (-5.084) has a more negative Caco-2 value, suggesting *lower* permeability compared to Ligand B (-4.917). This is a slight negative for Ligand A.

**Aqueous Solubility:** Ligand A (-4.173) has a more negative solubility value, indicating *lower* solubility compared to Ligand B (-2.158). This is a significant negative for Ligand A.

**hERG:** Both ligands have very low hERG inhibition liability (0.49 and 0.148), which is excellent.

**Microsomal Clearance:** Ligand B (2.753) has significantly lower microsomal clearance than Ligand A (79.106), indicating much better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-18.473) has a much longer in vitro half-life than Ligand A (15.19), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.343 and 0.026), which is good.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.9), although the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better TPSA, Ligand B excels in crucial areas for an enzyme inhibitor: metabolic stability (lower Cl_mic, longer t1/2), solubility, and a marginally better binding affinity. The lower DILI risk of Ligand A is a plus, but the substantial differences in metabolic stability and solubility outweigh this benefit.

Output:
1
2025-04-17 10:57:26,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.53) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (85.57) is excellent, well below 140.

**logP:** Ligand A (0.465) is quite low, potentially hindering permeability. Ligand B (1.561) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands (A: 4, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.508, B: 0.836), indicating drug-likeness. Ligand B is significantly better.

**DILI:** Both ligands have low DILI risk (A: 16.092, B: 15.122), both below the 40 threshold.

**BBB:** Ligand A (25.94) has very low BBB penetration. Ligand B (59.248) is better, but not particularly high. BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.282 and -4.913), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.51 and -1.187), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG risk (A: 0.061, B: 0.151).

**Microsomal Clearance:** Ligand A (12.414) has lower clearance than Ligand B (15.371), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (13.452) has a significantly longer half-life than Ligand A (3.53), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.014, B: 0.015).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B has a significantly better logP, QED, in vitro half-life, and, most importantly, binding affinity. The stronger binding affinity is likely to outweigh the permeability and solubility concerns, as potency is a primary driver for enzyme inhibitors. Ligand A's lower logP and shorter half-life are significant disadvantages.

Output:
1
2025-04-17 10:57:26,535 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (353.423 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.58) is slightly higher than Ligand B (83.56), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (0.669) is a bit low, potentially hindering permeation. Ligand B (1.692) is better positioned 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 (7) is higher than Ligand B (4). Both are within the acceptable limit of 10, but B is better.

**6. QED:** Both ligands have excellent QED scores (0.854 and 0.872), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (49.826 and 46.297), which is positive.

**8. BBB:** Ligand A (66.344) has a better BBB penetration score than Ligand B (56.456), but BBB is not a high priority for a kinase inhibitor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.573 and -4.99), which is unusual and problematic. This suggests poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.944 and -1.482), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.06 and 0.095), which is excellent.

**12. Microsomal Clearance:** Ligand B (-13.028) has significantly lower (better) microsomal clearance than Ligand A (21.871), indicating greater metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (3.238) has a longer half-life than Ligand A (0.334), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.01).

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). This 0.7 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly regarding metabolic stability (lower Cl_mic and longer t1/2). The negative Caco-2 and solubility values are concerning for both, but the improved metabolic profile of Ligand B is crucial for an enzyme inhibitor. The slightly better logP of Ligand B also contributes to its favorability. Given the priorities for kinase inhibitors, the improved metabolic stability of Ligand B outweighs the slightly better binding affinity of Ligand A.

Output:
1
2025-04-17 10:57:26,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 391.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.23) is better than Ligand B (99.56), being comfortably below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have good logP values (1.464 and 1.072), 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) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.835) has a significantly better QED score than Ligand B (0.603), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (41.605 and 36.254), well below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (67.468 and 65.374). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.657) has a worse Caco-2 permeability than Ligand B (-5.69), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.95) has slightly better aqueous solubility than Ligand B (-2.114).

**hERG:** Both ligands have very low hERG inhibition liability (0.119 and 0.304), which is excellent.

**Microsomal Clearance:** Ligand A (26.271) has a higher microsomal clearance than Ligand B (10.575), indicating lower metabolic stability. This is a key disadvantage.

**In vitro Half-Life:** Ligand B (27.8) has a significantly longer in vitro half-life than Ligand A (17.653), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.066 and 0.064).

**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:**

The primary trade-off is between potency (Ligand A) and metabolic stability (Ligand B). Ligand A boasts a much stronger binding affinity, which is crucial for an enzyme inhibitor. However, its higher microsomal clearance and shorter half-life are significant drawbacks. Ligand B, while less potent, exhibits better metabolic stability, which translates to a longer half-life. Given that SRC is an enzyme, metabolic stability is a high priority. The difference in binding affinity (-9.3 vs -7.6) is 1.7 kcal/mol, which is enough to potentially overcome the ADME deficiencies of Ligand A, *especially* if further optimization can improve its metabolic stability.

Output:
1
2025-04-17 10:57:26,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.335 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.04) is higher than Ligand B (41.57). While both are reasonably low, Ligand B's TPSA is significantly better, suggesting better permeability.

**logP:** Both ligands have similar logP values (3.484 and 3.478), 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 3 HBA. Ligand B has a more favorable profile with fewer H-bonds, potentially improving permeability.

**QED:** Ligand B (0.86) has a higher QED score than Ligand A (0.532), indicating a more drug-like profile.

**DILI:** Ligand A has a high DILI risk (98.643 percentile), which is a significant concern. Ligand B has a much lower DILI risk (19.698 percentile), making it far more attractive.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB value (90.927) than Ligand A (23.42), but this is less important in this context.

**Caco-2 Permeability:** Ligand A (-5.335) has a very poor Caco-2 permeability, while Ligand B (-4.498) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-4.92) and Ligand B (-3.813) both have poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.764 and 0.744), which is good.

**Microsomal Clearance:** Ligand A (69.614 mL/min/kg) has lower microsomal clearance than Ligand B (91.297 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.463 hours) has a negative half-life, which is concerning. Ligand B (11.955 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.213 and 0.322).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This is a crucial advantage.

**Conclusion:**

Ligand B is significantly more promising. While both have solubility issues, Ligand B's superior binding affinity, lower DILI risk, better QED, and more favorable TPSA/H-bonding profile outweigh Ligand A's slightly better metabolic stability. The high DILI risk and poor Caco-2 permeability of Ligand A are major red flags. The stronger binding affinity of Ligand B is also a critical factor for an enzyme inhibitor.

Output:
1
2025-04-17 10:57:26,536 - INFO - Batch 7 complete. Total preferences: 112
2025-04-17 10:57:26,536 - INFO - Processing batch 8/512...
2025-04-17 10:58:06,883 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.408 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (78.43 and 71.09) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.305 and 3.146) 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 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.579 and 0.747), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (18.883) has a significantly lower DILI risk than Ligand B (27.336). This is a substantial advantage for Ligand A.

**8. BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (77.239) has a higher BBB percentile than Ligand B (59.287).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.745 and -4.938). This is unusual and suggests poor permeability. However, these values are on a logarithmic scale and likely indicate very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.943 and -2.261). Again, these are likely on a logarithmic scale and indicate poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.362 and 0.237).

**12. Microsomal Clearance:** Ligand B (24.471) has lower microsomal clearance than Ligand A (36.091), suggesting better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (11.87) has a longer in vitro half-life than Ligand A (-24.655). The negative value for Ligand A is concerning and suggests very rapid degradation. This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.11 and 0.055).

**15. 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 notable, but not overwhelming.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk, but suffers from significantly worse metabolic stability (higher Cl_mic, negative t1/2) and poor solubility. Ligand B has better metabolic stability, solubility, and a longer half-life, but a slightly weaker binding affinity and higher DILI risk.

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG), Ligand B is the more promising candidate. The improved metabolic stability and half-life are crucial for *in vivo* efficacy, and the slightly weaker binding affinity can potentially be optimized in later stages of drug development. The DILI risk is moderate but manageable. The solubility issues of both compounds need to be addressed, but Ligand B is slightly better in this regard.

Output:
1
2025-04-17 10:58:06,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 and 350.46 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (102.3), being well below the 140 threshold for good absorption. Ligand B is still acceptable, but less optimal.

**logP:** Both ligands have good logP values (2.657 and 1.052), falling within the 1-3 range. Ligand A is slightly preferred.

**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, well within the guidelines.

**QED:** Both ligands have similar QED scores (0.751 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (18.42) has a slightly higher DILI risk than Ligand B (13.92), but both are below the 40 threshold, indicating low risk.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand A (71.77) is better than Ligand B (62.62). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. Assuming these are logP 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:** Ligand A (0.323) has a much lower hERG inhibition liability than Ligand B (0.089), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (45.79) has a higher microsomal clearance than Ligand B (24.98), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (0.005) has a very short half-life, while Ligand A (7.453) has a longer, more desirable half-life.

**P-gp Efflux:** Ligand A (0.126) has lower P-gp efflux liability than Ligand B (0.002), which is favorable.

**Binding Affinity:** Ligand B (-7.6 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 A has better TPSA, logP, BBB, hERG, P-gp efflux, and in vitro half-life. However, it has worse microsomal clearance and slightly lower binding affinity. Ligand B has better binding affinity, DILI, and microsomal clearance, but worse TPSA, hERG, and BBB.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) is crucial. Ligand B's significantly lower Cl_mic and longer half-life are major advantages. The slightly better binding affinity of Ligand B is also a plus. While Ligand A has a better hERG profile, the metabolic stability issues outweigh this benefit.

Output:
1
2025-04-17 10:58:06,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.507 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (96.53), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (0.857 and 0.649), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is preferable to Ligand B (3 HBD, 4 HBA) as it has fewer HBDs, which can sometimes hinder permeability. Both are within acceptable limits.

**QED:** Ligand A (0.765) has a higher QED score than Ligand B (0.531), indicating a more drug-like profile.

**DILI:** Ligand A (47.15) has a significantly lower DILI risk than Ligand B (21.869). This is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (67.08) is slightly better than Ligand B (54.556).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.403 and -5.473), which is unusual and indicates very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.539 and -1.271), indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.48) has a much lower hERG inhibition liability than Ligand B (0.073), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (-6.955) has a much lower (better) microsomal clearance than Ligand B (-1.471), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.257) has a longer in vitro half-life than Ligand B (3.913), which is desirable.

**P-gp Efflux:** Ligand A (0.257) has lower P-gp efflux liability than Ligand B (0.013), which is preferable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 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 than Ligand B. While both have poor Caco-2 and solubility, Ligand A excels in crucial areas like DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), P-gp efflux, and QED. The slightly better binding affinity of Ligand B is not enough to overcome these substantial advantages of Ligand A. The poor permeability and solubility of both compounds would require significant medicinal chemistry effort to address, but Ligand A provides a much stronger starting point.

Output:
1
2025-04-17 10:58:06,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.387 and 363.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.78) is better than Ligand B (38.77) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (0.04) is quite low, potentially hindering permeation. Ligand B (3.974) is closer to 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.

**QED:** Both ligands have good QED scores (0.539 and 0.701), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (24.467 and 27.181), which is favorable.

**BBB:** Ligand A (54.595) has a low BBB penetration, while Ligand B (88.29) is better, but still not exceptionally high. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.107 and -5.109), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.932 and -3.769), indicating poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.095) has a very low hERG risk, which is excellent. Ligand B (0.687) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-4.795) has a negative clearance, which is not physically possible and likely indicates very high metabolic stability. Ligand B (81.616) has high clearance, suggesting rapid metabolism. This is a major disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (9.394) has a reasonable half-life. Ligand B (30.128) has a longer half-life, which is positive.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is favorable. Ligand B (0.696) has higher efflux, potentially reducing bioavailability.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its significantly higher binding affinity (-10.1 vs -8.3 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand A has a much better metabolic stability profile (negative clearance) and lower P-gp efflux. While Ligand B has a better half-life, the superior potency and metabolic stability of Ligand A are more critical for a kinase inhibitor. The low logP of Ligand A is a concern, but formulation strategies might mitigate this.

Output:
0
2025-04-17 10:58:06,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.487 Da and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (92.78 and 85.25) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.343) is slightly low, potentially hindering permeation. Ligand B (0.855) is better, falling within the optimal 1-3 range.

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

**QED:** Both ligands have good QED scores (0.726 and 0.684), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (32.571 and 39.201), which is favorable.

**BBB:** Ligand A (68.321) has a moderately better BBB penetration score than Ligand B (42.187), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.022) and Ligand B (-4.899) have similar and poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.265 and -1.849). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.099 and 0.049), which is excellent.

**Microsomal Clearance:** Ligand A (-6.708) exhibits significantly lower (better) microsomal clearance than Ligand B (1.285), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (18.202 hours) has a much longer in vitro half-life than Ligand B (-3.993 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.028).

**Binding Affinity:** Both ligands have identical binding affinities (-7.6 kcal/mol), which is excellent.

**Conclusion:**

While both ligands exhibit strong binding affinity and low hERG risk, Ligand A is the superior candidate due to its significantly improved metabolic stability (lower Cl_mic) and longer in vitro half-life. The slightly lower logP and Caco-2 permeability of Ligand A are less concerning given the excellent potency and the fact that these can potentially be addressed through formulation strategies. The better metabolic stability and half-life are more difficult to improve post-discovery.

Output:
1
2025-04-17 10:58:06,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.387 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.77) is slightly higher than Ligand B (76.46), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.598) is a bit low, potentially hindering permeation. Ligand B (2.103) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.83 and 0.777, respectively), indicating drug-like properties.

**DILI:** Ligand A (53.936) has a slightly higher DILI risk than Ligand B (37.456), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (64.676) has a higher BBB score than Ligand A (47.577).

**Caco-2 Permeability:** Ligand A (-5.186) has significantly worse Caco-2 permeability than Ligand B (-4.399), suggesting poorer absorption.

**Aqueous Solubility:** Ligand A (-2.255) has slightly worse solubility than Ligand B (-1.933).

**hERG Inhibition:** Ligand A (0.061) has a lower hERG inhibition risk than Ligand B (0.556), which is a significant advantage.

**Microsomal Clearance:** Ligand A (9.17) has a much lower microsomal clearance than Ligand B (52.203), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.56) has a much longer in vitro half-life than Ligand B (36.226), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux than Ligand B (0.109).

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.1). The difference is 0.3 kcal/mol, which is not a substantial advantage.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has a better logP and Caco-2 permeability, Ligand A demonstrates significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity. The lower logP of Ligand A can potentially be addressed with formulation strategies. The improved metabolic stability and reduced hERG risk are crucial for a viable drug candidate.

Output:
0
2025-04-17 10:58:06,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.5 and 81.67) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.775 and 1.036) are within the optimal 1-3 range. Ligand B is slightly lower, which *could* be a minor drawback, but not a major concern.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 3. Both are acceptable (<=5).

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

**QED:** Both ligands have similar QED values (0.686 and 0.61), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 29.779%, while Ligand B has 4.382%. Ligand B is significantly better regarding DILI risk, a crucial factor.

**BBB:** Both have relatively low BBB penetration (50.679% and 68.127%). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.82 and -5.205). 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 base of the log. We'll need to consider this cautiously.

**Aqueous Solubility:** Both have negative solubility values (-2.938 and -1.923). Again, these are on a log scale and indicate poor solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.234 and 0.34). This is excellent.

**Microsomal Clearance:** Ligand A has a Cl_mic of 67.198 mL/min/kg, while Ligand B has -3.238 mL/min/kg. The negative value for Ligand B is suspect and likely represents a percentile score, indicating *very* low clearance and excellent metabolic stability. Ligand A's clearance is moderate.

**In vitro Half-Life:** Ligand A has a negative half-life (-16.071 hours), which is problematic and likely a percentile score. Ligand B has -15.342 hours, also problematic. These negative values suggest very long half-lives, which could be beneficial, but need further investigation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.178 and 0.008). This is favorable.

**Binding Affinity:** Ligand A has a binding affinity of -8.7 kcal/mol, while Ligand B has -7.6 kcal/mol. Ligand A has a 1.1 kcal/mol advantage in binding affinity, which is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity. However, Ligand B demonstrates a much lower DILI risk and substantially better metabolic stability (indicated by the negative Cl_mic value). The solubility and permeability concerns are shared by both, but the superior potency of Ligand A is a strong advantage. Given the enzyme-specific priorities, the binding affinity difference is significant, and the DILI risk of Ligand B is a major concern.

Output:
0
2025-04-17 10:58:06,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.357 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.71) is significantly better than Ligand B (76.44).  A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Ligand A (4.874) is higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (1.3) is within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.739 and 0.793), indicating good drug-likeness.

**DILI:** Ligand A (82.706) has a higher DILI risk than Ligand B (34.742). This is a significant concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (76.309) is slightly better than Ligand B (63.009). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.424 and -4.678), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Ligand A (-6.506) has worse solubility than Ligand B (-2.863).

**hERG Inhibition:** Ligand A (0.771) has a higher hERG risk than Ligand B (0.553).

**Microsomal Clearance:** Ligand B (-18.552) has significantly lower (better) microsomal clearance than Ligand A (46.279), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (18.413 hours) has a much longer half-life than Ligand A (42.043 hours).

**P-gp Efflux:** Ligand A (0.455) has lower P-gp efflux than Ligand B (0.025), which is favorable.

**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:**

Ligand A has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, worse solubility, higher hERG risk, and significantly worse metabolic stability (higher clearance, shorter half-life). Ligand B has better ADME properties overall, but its binding affinity is considerably weaker.

Despite the ADME concerns with Ligand A, the 2.1 kcal/mol difference in binding affinity is substantial. It's likely that medicinal chemistry efforts could address the DILI, solubility, and metabolic stability issues while retaining the strong binding affinity. The poor Caco-2 values for both are concerning, but might be improved with formulation strategies.

Output:
1
2025-04-17 10:58:06,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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, while Ligand B (360.933 Da) is also good.

**TPSA:** Ligand A (71.34) is better than Ligand B (25.99). Lower TPSA generally favors oral absorption.

**logP:** Ligand A (2.936) is optimal, while Ligand B (4.337) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which is a good balance. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.761 and 0.622), indicating good drug-likeness.

**DILI:** Ligand A (39.899) has a slightly higher DILI risk than Ligand B (12.834), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (69.833 and 66.033), which isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.808 and -4.796). 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 base of the log.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.612 and -4.853). Again, these are on a scale where negative values are not directly interpretable without knowing the scale. This suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.642 and 0.889), which is excellent.

**Microsomal Clearance:** Ligand A (24.834 mL/min/kg) has significantly lower microsomal clearance than Ligand B (40.354 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (38.13 hours) has a shorter half-life than Ligand B (50.821 hours), but both are reasonably good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.352 and 0.458), which is favorable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.4 and -8.4 kcal/mol). Ligand A is slightly better.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have similar affinities, Ligand A has a better logP, TPSA, and significantly better metabolic stability (lower Cl_mic). The slightly better 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 these drawbacks.

Output:
0
2025-04-17 10:58:06,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.33 and 366.487 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 acceptable. Ligand B (59.31) is well within the optimal range.

**3. logP:** Ligand A (3.702) is at the upper end of the optimal range (1-3), potentially raising solubility concerns. Ligand B (0.845) is below the optimal range, which might hinder permeability.

**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 (8) is acceptable, but approaching the upper limit.

**6. QED:** Both ligands (0.635 and 0.646) have good drug-likeness scores.

**7. DILI:** Ligand A (87.049) has a high DILI risk, which is a significant concern. Ligand B (39.55) has a low DILI risk, a major advantage.

**8. BBB:** Both ligands have moderate BBB penetration, but this is less critical for a non-CNS target like SRC.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation, but doesn't immediately disqualify either.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and requires further investigation.

**11. hERG:** Ligand A (0.652) has a slightly elevated hERG risk, while Ligand B (0.881) is also elevated. Both are concerning.

**12. Cl_mic:** Ligand A (55.862) has a moderate clearance, while Ligand B (39.072) has a lower clearance, suggesting better metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand A (26.62) has a longer half-life than Ligand B (13.335), which is a positive for dosing convenience.

**14. Pgp:** Ligand A (0.388) has lower P-gp efflux, which is favorable. Ligand B (0.124) has very low P-gp efflux, even more favorable.

**15. Binding Affinity:** Ligand A (0.0) has slightly better binding affinity than Ligand B (-8.0). This is a significant advantage for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and longer half-life, but suffers from a very high DILI risk and a slightly elevated hERG risk. Ligand B has a lower DILI risk, better metabolic stability, and lower P-gp efflux, but weaker binding affinity.

Given the critical importance of avoiding hepatotoxicity (DILI) in drug development, and the fact that the affinity difference isn't *massive* (0 vs -8 kcal/mol), the lower DILI risk of Ligand B makes it the more promising candidate. While the lower affinity of Ligand B is a drawback, it could potentially be addressed through further optimization. The high DILI risk of Ligand A is a more difficult problem to overcome.

Output:
1
2025-04-17 10:58:06,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.316 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.25) is well below the 140 threshold, while Ligand B (94.22) is approaching it. This favors A for better absorption.

**logP:** Both ligands (2.885 and 2.121) are within the optimal 1-3 range.

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

**QED:** Ligand A (0.913) has a significantly higher QED score than Ligand B (0.58), indicating a more drug-like profile.

**DILI:** Ligand A (74.796) has a higher DILI risk than Ligand B (53.625), which is a negative for A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (93.253) has a higher BBB penetration than Ligand B (49.864).

**Caco-2 Permeability:** Ligand A (-4.291) has a worse Caco-2 permeability than Ligand B (-5.337), suggesting lower intestinal absorption for A.

**Aqueous Solubility:** Ligand A (-4.413) has worse solubility than Ligand B (-3.413). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.346 and 0.457), which is good.

**Microsomal Clearance:** Ligand A (19.919) has significantly lower microsomal clearance than Ligand B (38.421), indicating better metabolic stability. This is a key advantage for A.

**In vitro Half-Life:** Ligand A (-8.789) has a much longer in vitro half-life than Ligand B (27.77), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.116 and 0.095).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 1.1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, QED, metabolic stability (low Cl_mic and long t1/2), and has acceptable logP and H-bond properties. Its weaknesses are higher DILI risk, lower Caco-2 permeability and solubility.

Ligand B has a lower DILI risk and better solubility and permeability, but suffers from lower binding affinity, a lower QED score, and poorer metabolic stability.

Considering the priorities for enzyme inhibitors, the stronger binding affinity and improved metabolic stability of Ligand A are more important than the slightly higher DILI risk and lower solubility. The 1.1 kcal/mol difference in binding is substantial.

Output:
1
2025-04-17 10:58:06,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.929 Da) is slightly higher than Ligand B (367.475 Da), but both are acceptable.

**TPSA:** Ligand A (71.09) is well below the 140 threshold for oral absorption, and is quite favorable. Ligand B (119.23) is still under 140, but less optimal than A.

**logP:** Ligand A (3.392) is within the optimal range (1-3). Ligand B (1.797) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is better balanced than Ligand B (HBD=3, HBA=7). Higher HBA can sometimes reduce permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.821, B: 0.618), indicating good drug-like properties.

**DILI:** Ligand A (49.942) has a much lower DILI risk than Ligand B (88.484). This is a significant advantage for A.

**BBB:** Both ligands have moderate BBB penetration (A: 56.495, B: 63.746). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the negative value for A is slightly less extreme.

**Solubility:** Both ligands have negative solubility values, which is also concerning. Again, A is slightly better (-4.253 vs -3.776).

**hERG:** Ligand A (0.337) shows a much lower hERG inhibition liability than Ligand B (0.774). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (70.406) has significantly higher microsomal clearance than Ligand A (36.87). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand A (25.43) has a longer in vitro half-life than Ligand B (-4.113). This is a positive attribute for A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.362, B: 0.099).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a significant advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher microsomal clearance, shorter half-life, and higher hERG inhibition liability. Ligand A has better ADME properties across the board (DILI, hERG, clearance, half-life, solubility, permeability), but its affinity is weaker.

The difference in binding affinity (1.6 kcal/mol) is substantial. While the ADME profile of Ligand A is more favorable, the potency advantage of Ligand B is likely to be more impactful in driving efficacy. Therefore, Ligand B is the more promising candidate, *assuming* that the ADME liabilities can be addressed through further optimization.

Output:
1
2025-04-17 10:58:06,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.471 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.64) is higher than Ligand B (49.85). Both are below the 140 threshold for oral absorption, but Ligand B is preferable due to the lower value.

**logP:** Both ligands (2.645 and 2.136) 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:** Both ligands have 3 HBAs, well within the acceptable limit of <=10.

**QED:** Ligand A (0.914) has a significantly better QED score than Ligand B (0.737), indicating better overall drug-likeness.

**DILI:** Ligand A (11.322) has a much lower DILI risk than Ligand B (22.722), a significant advantage.

**BBB:** Both ligands have high BBB penetration (94.261 and 85.731), but this is less critical for a kinase inhibitor unless CNS effects are specifically desired.

**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 don't necessarily indicate a complete lack of permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, these are on a scale where negative values are possible.

**hERG Inhibition:** Ligand A (0.791) has a slightly higher hERG risk than Ligand B (0.319), making Ligand B preferable.

**Microsomal Clearance:** Ligand A (8.368) has a much lower microsomal clearance than Ligand B (32.356), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (11.601) has a positive half-life, while Ligand B (-11.731) has a negative half-life, which is highly unfavorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.133 and 0.142).

**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 of Ligand B.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from a higher DILI risk, poorer metabolic stability (higher Cl_mic), and a negative in vitro half-life. Ligand A has a better safety profile (lower DILI), better metabolic stability, a positive half-life, and a higher QED score. The large difference in binding affinity (-8.5 vs 0.0) is very significant. While Ligand A has a better ADME profile, the potency of Ligand B is so much higher that it is likely to be a better starting point for optimization.

Output:
1
2025-04-17 10:58:06,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.837 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**TPSA:** Ligand A (93.9) is slightly higher than Ligand B (75.44). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (Ligand A: 1.489, Ligand B: 2.663), 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 within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (Ligand A: 0.811, Ligand B: 0.853), indicating good drug-like properties.

**DILI:** Ligand A (62.233) has a higher DILI risk than Ligand B (41.877). This is a significant advantage for Ligand B.

**BBB:** Ligand A (58.085) has lower BBB penetration than Ligand B (70.88). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.653) is slightly worse than Ligand B (-4.938).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.789) is slightly better than Ligand B (-2.916).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.142, Ligand B: 0.215).

**Microsomal Clearance:** Ligand A (17.351 mL/min/kg) has significantly lower microsomal clearance than Ligand B (56.299 mL/min/kg). This suggests better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (16.482 hours) has a much longer half-life than Ligand B (-34.614 hours). This is a major advantage for Ligand A, enabling less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.083, Ligand B: 0.141).

**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 of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a clear advantage in metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. While Ligand B has slightly better TPSA and BBB, the superior pharmacokinetic properties of Ligand A are more critical for an enzyme inhibitor. The solubility and Caco-2 values are poor for both, but can potentially be addressed through formulation strategies. The binding affinity difference is minimal.

Output:
0
2025-04-17 10:58:06,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.419 and 349.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.9) is slightly above the preferred <140, but acceptable. Ligand B (61.44) is well within the range, suggesting better absorption potential.

**logP:** Ligand A (0.507) is quite low, potentially hindering membrane permeability. Ligand B (2.474) is within the optimal 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 values (0.658 and 0.662), indicating good drug-likeness.

**DILI:** Ligand A (56.378) has a moderate DILI risk, while Ligand B (11.245) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.415) has a higher BBB percentile, but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.134) shows poor permeability, consistent with its low logP. Ligand B (-4.835) is also not great, but better than A.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.933 and -2.142), indicating poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.124) has a slightly higher hERG risk than Ligand B (0.237), but both are relatively low.

**Microsomal Clearance:** Ligand A (26.147) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (43.976) has higher clearance, meaning it's metabolized faster.

**In vitro Half-Life:** Ligand A (-12.418) has a negative half-life, which is unusual and suggests rapid degradation or a problem with the assay. Ligand B (2.693) has a short half-life, but it's a reasonable value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.041 and 0.1), which is good.

**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 a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity, lower DILI risk, and better logP outweigh the slightly higher microsomal clearance and short half-life. The negative half-life of Ligand A is a major red flag.

Output:
1
2025-04-17 10:58:06,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 357.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.28) is slightly above the preferred <140 for good absorption, while Ligand B (93.46) is well within the range.

**logP:** Ligand A (0.704) is a bit low, potentially hindering permeation. Ligand B (1.657) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.611 and 0.656, respectively), indicating drug-like properties.

**DILI:** Ligand A (62.001) has a higher DILI risk than Ligand B (49.942), though both are moderately risky.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (85.731) has a higher BBB percentile than Ligand A (52.85), but this is less critical here.

**Caco-2 Permeability:** Ligand A (-5.313) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.417) is slightly better, but still indicates limited permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.035 and -2.898, respectively). This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.343) has a slightly higher hERG risk than Ligand B (0.179), but both are relatively low.

**Microsomal Clearance:** Ligand B (34.347) has significantly lower microsomal clearance than Ligand A (48.368), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-10.603) has a longer in vitro half-life than Ligand A (4.738), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.118 and 0.038, respectively).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite both ligands having solubility issues, Ligand B is the more promising candidate. Its superior binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower DILI risk outweigh the slightly lower logP and Caco-2 permeability. The stronger binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 10:58:06,886 - INFO - Batch 8 complete. Total preferences: 128
2025-04-17 10:58:06,887 - INFO - Processing batch 9/512...
2025-04-17 10:58:52,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (388.291 and 358.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is well below the 140 threshold, while Ligand B (75.27) is also acceptable but higher.

**logP:** Both ligands have good logP values (3.783 and 2.726), 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.

**QED:** Ligand A (0.754) has a better QED score than Ligand B (0.59), indicating a more drug-like profile.

**DILI:** Ligand B (35.401) has a significantly lower DILI risk than Ligand A (51.687), which is a major advantage.

**BBB:** Not a primary concern for a general oncology target, but Ligand B (86.002) has a higher BBB percentile than Ligand A (64.366).

**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 also unusual. Assuming these are logS values, both are poor.

**hERG Inhibition:** Ligand A (0.253) has a slightly lower hERG risk than Ligand B (0.402), which is preferable.

**Microsomal Clearance:** Ligand B (9.67 mL/min/kg) has significantly lower microsomal clearance than Ligand A (96.681 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (7.468 hours) has a slightly longer half-life than Ligand A (8.974 hours).

**P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux liability than Ligand B (0.143), which is better.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has a better QED and slightly lower hERG risk, Ligand B demonstrates a much stronger binding affinity (-9.3 vs -7.6 kcal/mol) and significantly improved metabolic stability (lower Cl_mic) and lower DILI risk. The superior binding affinity is the most important factor for an enzyme-kinase target, and the improved metabolic stability and lower DILI risk are highly desirable. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 10:58:52,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.463 and 359.352 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.48) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (96.01) is still acceptable, but less optimal.

**3. logP:** Both ligands have good logP values (1.57 and 1.413), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is excellent. Ligand B (3) is still acceptable, but slightly higher.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**6. QED:** Ligand A (0.807) is excellent, indicating high drug-likeness. Ligand B (0.64) is still acceptable, but lower.

**7. DILI:** Ligand A (38.813) has a very favorable DILI risk, well below the 40% threshold. Ligand B (54.052) is higher, but still within an acceptable range.

**8. BBB:** While not a primary concern for a kinase inhibitor, Ligand B (76.076) has a higher BBB percentile than Ligand A (64.211).

**9. Caco-2 Permeability:** Ligand A (-4.848) has a much better Caco-2 permeability than Ligand B (-5.234).

**10. Aqueous Solubility:** Ligand A (-1.891) has better aqueous solubility than Ligand B (-2.985).

**11. hERG Inhibition:** Ligand A (0.128) has a very low hERG risk. Ligand B (0.275) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (27.521) has significantly lower microsomal clearance than Ligand B (47.194), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.55) has a longer in vitro half-life than Ligand B (-3.336).

**14. P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux than Ligand B (0.028).

**15. Binding Affinity:** Ligand A (-7.6) has significantly better binding affinity than Ligand B (0.0). This is the most critical factor for an enzyme inhibitor. A difference of 7.6 kcal/mol is substantial.

**Overall Assessment:**

Ligand A is superior to Ligand B across most key parameters. It has better solubility, permeability, metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and *significantly* stronger binding affinity. While Ligand B has slightly better BBB penetration, this is less crucial for a kinase inhibitor targeting intracellular signaling. The substantial difference in binding affinity outweighs any minor advantages of Ligand B.

Output:
1
2025-04-17 10:58:52,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.574 Da and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is significantly better than Ligand B (67.87). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (4.287) is a bit high, potentially leading to solubility issues, while Ligand B (1.725) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) and Ligand B (HBD=1, HBA=4) are both acceptable, within the recommended limits.

**QED:** Both ligands have good QED scores (0.793 and 0.837), indicating good drug-like properties.

**DILI:** Ligand A (33.773) has a slightly higher DILI risk than Ligand B (29.818), but both are below the 40 threshold and considered good.

**BBB:** Ligand A (74.176) has better BBB penetration than Ligand B (61.535), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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. This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.757 and 0.282), which is excellent.

**Microsomal Clearance:** Ligand A (39.694) has lower microsomal clearance than Ligand B (44.957), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (30.23) has a significantly longer half-life than Ligand B (2.209), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.311) has lower P-gp efflux than Ligand B (0.127), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.4 kcal/mol and -9.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Despite Ligand B's slightly better logP, Ligand A is the more promising candidate. It demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a better TPSA. While both have issues with solubility and Caco-2 permeability, the metabolic advantages of Ligand A are crucial for an enzyme inhibitor. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 10:58:52,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.451 and 352.341 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.35) is slightly higher than Ligand B (86.94), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-1.92) is a bit low, potentially hindering permeation. Ligand B (0.54) 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) and Ligand B (2 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand B (0.822) has a substantially higher QED score than Ligand A (0.515), indicating a more drug-like profile.

**DILI:** Ligand A (6.863) has a much lower DILI risk than Ligand B (55.991). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (9.965) is lower than Ligand B (42.807).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.477) is slightly worse than Ligand B (-4.896).

**Aqueous Solubility:** Ligand A (-0.32) is slightly better than Ligand B (-1.961), but both are quite poor.

**hERG Inhibition:** Ligand A (0.12) has a much lower hERG risk than Ligand B (0.657). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-8.994) has a much *lower* (better) microsomal clearance than Ligand B (-22.819), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.33 hours) has a significantly longer half-life than Ligand A (2.125 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.002 and 0.012 respectively).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-10.5 kcal/mol). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in potency (affinity), metabolic stability (Cl_mic), DILI risk, and hERG inhibition. However, it suffers from poor solubility and permeability. Ligand B has a better QED score, logP, and significantly longer half-life, but carries a higher DILI and hERG risk.

Given the enzyme-specific priorities, metabolic stability and potency are key. Ligand A's superior metabolic stability and acceptable affinity, coupled with lower toxicity risks (DILI, hERG), outweigh the solubility/permeability concerns, especially as those can be addressed with formulation strategies.

Output:
0
2025-04-17 10:58:52,981 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.447, 78.68, 1.613, 1, 5, 0.875, 21.132, 71.888, -4.857, -1.6, 0.255, -6.545, 4.346, 0.023, -8.3]
**Ligand B:** [383.554, 29.54, 4.344, 0, 4, 0.7, 35.634, 88.445, -4.616, -4.891, 0.745, 123.478, -16.325, 0.597, -8.6]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (348.447) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (78.68) is better than B (29.54). TPSA is good for both, but B is excellent.
3. **logP:** A (1.613) is optimal. B (4.344) is high, potentially leading to solubility issues and off-target effects.
4. **HBD:** A (1) is good. B (0) is also acceptable.
5. **HBA:** A (5) is good. B (4) is good.
6. **QED:** A (0.875) is excellent. B (0.7) is still acceptable, but lower.
7. **DILI:** A (21.132) is very good (low risk). B (35.634) is also acceptable, but higher.
8. **BBB:** A (71.888) is good. B (88.445) is excellent. However, since SRC is not a CNS target, this is less critical.
9. **Caco-2:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. A (-4.857) is worse than B (-4.616), suggesting B has slightly better absorption.
10. **Solubility:** A (-1.6) is poor. B (-4.891) is very poor. This is a significant concern for both, but especially for B given its high logP.
11. **hERG:** Both are very low (0.255 and 0.745), indicating minimal cardiotoxicity risk.
12. **Cl_mic:** A (-6.545) is excellent (low clearance, high metabolic stability). B (123.478) is very high, indicating rapid metabolism and a potential issue.
13. **t1/2:** A (4.346) is reasonable. B (-16.325) is extremely poor, indicating very rapid clearance.
14. **Pgp:** A (0.023) is very low (minimal efflux). B (0.597) is also low.
15. **Affinity:** B (-8.6) is slightly better than A (-8.3), but the difference is small.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B has a slightly better affinity, but the difference is small.
*   **Metabolic Stability:** A is *significantly* better (much lower Cl_mic, better t1/2).
*   **Solubility:** Both are poor, but A is slightly better.
*   **hERG:** Both are good.

**Conclusion:**

Despite B having a slightly better binding affinity, Ligand A is the more promising drug candidate. Its superior metabolic stability (Cl_mic and t1/2), lower DILI risk, and slightly better solubility outweigh the small affinity difference. The high logP and poor solubility of B are significant liabilities that would likely require extensive medicinal chemistry efforts to address.

Output:
0
2025-04-17 10:58:52,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.32) is slightly higher than Ligand B (71.33), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.263 and 1.93), falling within the 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.

**QED:** Both ligands have good QED scores (0.81 and 0.762), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (36.487 and 33.307), which is favorable.

**BBB:** Ligand B (75.107) has a higher BBB penetration score than Ligand A (45.211), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.139) has a worse Caco-2 permeability than Ligand B (-4.676), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.581) has worse aqueous solubility than Ligand B (-2.117). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.15 and 0.134), which is excellent.

**Microsomal Clearance:** Ligand B (40.958) has significantly lower microsomal clearance than Ligand A (7.058), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-3.594) has a longer in vitro half-life than Ligand A (-13.663), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.06).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.5 kcal/mol). Ligand B is slightly better.

**Conclusion:**

While both ligands have good overall profiles, Ligand B is superior due to its significantly improved metabolic stability (lower Cl_mic and longer t1/2) and slightly better binding affinity. The better Caco-2 permeability and solubility are also beneficial. The differences in these parameters outweigh the slightly lower BBB penetration, as SRC is not a CNS target.

Output:
1
2025-04-17 10:58:52,981 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (343.387 Da) is within the ideal range (200-500). Ligand B (378.372 Da) is also within the ideal range. No clear advantage here.
2. **TPSA:** Ligand A (89.35) is excellent, well below the 140 threshold for oral absorption. Ligand B (86.71) is also very good. Again, no clear advantage.
3. **logP:** Ligand A (1.403) is optimal. Ligand B (1.824) is also optimal. Both are within the 1-3 range.
4. **HBD:** Ligand A (1) is good. Ligand B (2) is acceptable, but slightly higher.
5. **HBA:** Ligand A (6) is good. Ligand B (4) is good.
6. **QED:** Ligand A (0.906) is excellent, indicating high drug-likeness. Ligand B (0.837) is also good, but slightly lower.
7. **DILI:** Ligand A (83.986) is concerning, indicating a high risk of drug-induced liver injury. Ligand B (50.64) is much better, falling within the acceptable range (<60). This is a significant advantage for Ligand B.
8. **BBB:** Ligand A (57.929) is not particularly high, suggesting limited brain penetration. Ligand B (66.615) is slightly better, but still not ideal for a CNS target (though SRC is not primarily a CNS target).
9. **Caco-2:** Ligand A (-4.967) is poor, indicating very limited intestinal absorption. Ligand B (-5.113) is also poor, similar to Ligand A.
10. **Solubility:** Ligand A (-2.888) is poor. Ligand B (-3.975) is also poor. Both have solubility issues.
11. **hERG:** Ligand A (0.232) is very low risk. Ligand B (0.794) is a bit higher, but still relatively low risk.
12. **Cl_mic:** Ligand A (38.571) is moderate. Ligand B (21.673) is lower, indicating better metabolic stability. This is a positive for Ligand B.
13. **t1/2:** Ligand A (-13.042) is very poor, suggesting rapid clearance. Ligand B (-22.245) is even worse. Both have very short half-lives.
14. **Pgp:** Ligand A (0.099) is low, indicating minimal P-gp efflux. Ligand B (0.08) is also low, similar to Ligand A.
15. **Affinity:** Ligand A (-8.5 kcal/mol) is excellent. Ligand B (-10.3 kcal/mol) is even better, showing a stronger binding affinity. This is a major advantage for Ligand B.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both compounds have issues with solubility and half-life, Ligand B clearly wins on affinity and has a significantly better DILI profile and lower Cl_mic. The superior binding affinity of Ligand B (-10.3 vs -8.5 kcal/mol) is a substantial advantage that can potentially offset some of the ADME liabilities.

**Conclusion:**

Considering all factors, especially the superior binding affinity and significantly lower DILI risk, **Ligand B** is the more viable drug candidate.

1
2025-04-17 10:58:52,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Ligand B (89.07) is significantly better than Ligand A (114.41). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 1.515, B: 1.134), falling within the optimal range of 1-3.

**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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (A: 0.671, B: 0.8), indicating good drug-like properties.

**DILI:** Ligand B (60.954) is better than Ligand A (97.402). Lower DILI is crucial. Ligand A's DILI is relatively high.

**BBB:** Both ligands have similar BBB penetration (A: 51.997, B: 52.772). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

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

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -3.773, B: -1.643). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.331) is better than Ligand B (0.114), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (0.697) has significantly lower microsomal clearance than Ligand B (11.001). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (14.234) has a longer half-life than Ligand B (10.377), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.031, B: 0.203).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol), but the difference is small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better hERG profile. While both have poor solubility, the metabolic advantages of Ligand A are more critical for an enzyme inhibitor. The small difference in binding affinity is unlikely to outweigh the ADME benefits of Ligand A.

Output:
0
2025-04-17 10:58:52,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.81 Da) is slightly higher than Ligand B (336.355 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption. Ligand B (126.65) is also below the threshold, but higher than A.

**logP:** Both ligands have optimal logP values (A: 2.222, B: 1.071), 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 balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (A: 0.758, B: 0.62), indicating good drug-like properties.

**DILI:** Ligand A (25.436) has a much lower DILI risk than Ligand B (80.147), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.459) has a higher BBB percentile than Ligand B (59.597).

**Caco-2 Permeability:** Ligand A (-4.809) has a worse Caco-2 permeability than Ligand B (-6.065).

**Aqueous Solubility:** Ligand A (-3.35) has a better aqueous solubility than Ligand B (-2.857).

**hERG Inhibition:** Ligand A (0.602) has a lower hERG risk than Ligand B (0.072), which is a major advantage.

**Microsomal Clearance:** Ligand A (15.968) has a higher microsomal clearance than Ligand B (-16.072), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (19.469) has a longer in vitro half-life than Ligand A (2.625), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.142) has lower P-gp efflux than Ligand B (0.095).

**Binding Affinity:** Ligand A (-8.5 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 most of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower hERG and DILI risk. While it has a higher microsomal clearance and lower in vitro half-life and Caco-2 permeability compared to Ligand B, the significantly stronger binding affinity (-8.5 vs 0 kcal/mol) is a critical advantage for an enzyme inhibitor. The lower DILI and hERG risks are also very important. The differences in metabolic stability and permeability can potentially be addressed through further optimization.

Output:
1
2025-04-17 10:58:52,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.37 and 355.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.34) is better than Ligand B (116.76). Both are below 140, but A is closer to the optimal range for oral absorption.

**logP:** Ligand A (3.811) is optimal, while Ligand B (-0.546) is significantly low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (4). Lower HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.494 and 0.414), indicating moderate drug-likeness.

**DILI:** Ligand A (67.43) has a higher DILI risk than Ligand B (17.45), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (60.88) is slightly better than Ligand B (53.55).

**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. The scale is not specified, so it's hard to interpret.

**hERG Inhibition:** Ligand A (0.904) is better than Ligand B (0.056), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (41.33) has a higher clearance than Ligand B (13.47), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (18.20) has a longer half-life than Ligand B (2.14), which is desirable.

**P-gp Efflux:** Ligand A (0.601) is better than Ligand B (0.003), suggesting lower efflux and potentially better bioavailability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly better binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage (over 1.1 kcal/mol difference) and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, it suffers from a very low logP, potentially leading to poor permeability, and a very low P-gp efflux. Ligand A has better ADME properties (logP, HBD, HBA, P-gp, t1/2, hERG), but its DILI risk is concerning and its binding affinity is weaker.

Despite the DILI risk, the superior binding affinity of Ligand B is a critical factor. Optimization efforts could focus on mitigating the DILI risk and improving its logP and permeability.

Output:
1
2025-04-17 10:58:52,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 366.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.23) is better than Ligand B (88.93), both are under the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (0.931 and 1.678, respectively), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are acceptable, under the 10 threshold.

**QED:** Ligand A (0.819) has a significantly better QED score than Ligand B (0.688), indicating a more drug-like profile.

**DILI:** Ligand A (27.608) has a much lower DILI risk than Ligand B (54.556), a significant advantage.

**BBB:** Ligand A (66.886) has a better BBB penetration score than Ligand B (52.074), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.809) has better Caco-2 permeability than Ligand B (-5.246).

**Aqueous Solubility:** Ligand A (-2.543) has better aqueous solubility than Ligand B (-3.031).

**hERG:** Ligand A (0.132) has a much lower hERG inhibition liability than Ligand B (0.424), a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (27.519) has lower microsomal clearance than Ligand B (63.613), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.147) has a slightly lower in vitro half-life than Ligand B (9.989), but this is less concerning given the other advantages of Ligand A.

**P-gp Efflux:** Ligand A (0.029) has much lower P-gp efflux liability than Ligand B (0.143).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference of 0.9 kcal/mol is not substantial enough to outweigh the significantly better ADME properties of Ligand A.

**Conclusion:**

Ligand A demonstrates a superior overall profile. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties like DILI risk, hERG inhibition, metabolic stability (Cl_mic), solubility, and QED score. These factors are particularly important for kinase inhibitors, where long-term safety and bioavailability are critical.

Output:
0
2025-04-17 10:58:52,982 - INFO - Okay, let's analyze these two ligands for their potential as drug candidates targeting SRC, a kinase.

**Step-by-step comparison:**

1. **MW:** Both A (351.491 Da) and B (348.495 Da) fall comfortably within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (81.67) is better than Ligand B (94.99). Both are under the 140 threshold for oral absorption, but A is closer to the preferred <90 for potential CNS penetration (though that's less critical for SRC).

3. **logP:** Ligand A (1.033) is within the optimal 1-3 range. Ligand B (2.87) is also acceptable, but edging towards the higher end.

4. **HBD:** Both A (3) and B (4) are within the acceptable limit of <=5.

5. **HBA:** Ligand A (4) is better than Ligand B (7), being closer to the preferred limit of <=10.

6. **QED:** Both A (0.61) and B (0.545) are above the 0.5 threshold, indicating good drug-like properties. A is slightly better.

7. **DILI:** Ligand A (12.641) has a significantly lower DILI risk than Ligand B (44.475). This is a major advantage for A.

8. **BBB:** Ligand B (69.407) has a better BBB penetration percentile than Ligand A (40.558). However, since SRC is not a CNS target, this is less important.

9. **Caco-2:** Both A (-5.119) and B (-5.007) have similar, very poor Caco-2 permeability. This is a significant concern for both compounds.

10. **Solubility:** Ligand A (-2.305) has better aqueous solubility than Ligand B (-4.456). Solubility is important for kinases.

11. **hERG:** Ligand A (0.152) has a much lower hERG inhibition liability than Ligand B (0.844). This is a crucial advantage for A, minimizing cardiotoxicity risk.

12. **Cl_mic:** Ligand A (33.452) has a lower microsomal clearance than Ligand B (79.326), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

13. **t1/2:** Ligand B (40.822) has a significantly longer in vitro half-life than Ligand A (-1.626). This is a positive for B, but can be offset by other issues.

14. **Pgp:** Ligand A (0.044) has lower P-gp efflux liability than Ligand B (0.163), which is favorable for bioavailability.

15. **Binding Affinity:** Both ligands have very similar binding affinities (-8.9 kcal/mol and -8.6 kcal/mol), with A being slightly better. The difference is not large enough to outweigh other factors.

**Enzyme-Kinase Specific Priorities:**

For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in DILI risk, hERG, Cl_mic, solubility and has slightly better affinity. Ligand B has a longer half-life, but suffers from higher DILI, hERG, and Cl_mic, and lower solubility. The poor Caco-2 values for both are a concern, but can potentially be addressed through formulation strategies.

**Conclusion:**

Considering the balance of properties and the priorities for a kinase inhibitor, **Ligand A** is the more promising drug candidate. Its superior safety profile (lower DILI, hERG), better metabolic stability, and solubility outweigh the slightly shorter half-life and lower BBB penetration (which is not relevant for SRC).

Output:
0
2025-04-17 10:58:52,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.455 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.24) is slightly above the preferred <140 for good oral absorption, but still acceptable. Ligand B (58.64) is excellent, well below 140.

**logP:** Ligand A (-0.235) is a bit low, potentially hindering permeability. Ligand B (2.289) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is good. Ligand B (1 HBD, 3 HBA) is also excellent. Both are within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.595 and 0.437), indicating drug-like properties. Ligand A is slightly better.

**DILI:** Both ligands have low DILI risk (26.444 and 23.459), both well below the 40 threshold.

**BBB:** Ligand A (41.373) has a low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (75.107) has good BBB penetration, but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.82 and -5.058). This 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 poor aqueous solubility (-1.687 and -1.973). This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.07) has very low hERG inhibition risk, which is excellent. Ligand B (0.36) is also low, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-15.012) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (39.88) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-10.892) has a very long in vitro half-life, again indicating excellent stability. Ligand B (0.974) has a short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.139).

**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 significant.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2) and hERG risk, but suffers from low logP and solubility, and lower binding affinity. Ligand B has better logP, solubility, and a slightly better binding affinity, but its metabolic stability is a concern. The binding affinity difference is significant enough to potentially overcome the metabolic stability concern, especially if further optimization can address it. The poor solubility of both is a major concern that would need to be addressed through formulation strategies.

Given the priorities for enzyme inhibitors, the slightly better binding affinity and more favorable logP of Ligand B, combined with acceptable (though not ideal) ADME properties, make it the more promising candidate.

Output:
1
2025-04-17 10:58:52,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.543 and 345.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (64.86), both are below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (2.442 and 2.246), 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 6. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.715 and 0.834), indicating good drug-like properties.

**7. DILI:** Ligand A (32.299) has a lower DILI risk than Ligand B (43.389), both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.91) has a higher BBB percentile than Ligand A (63.784).

**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 negative solubility values, indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.337 and 0.372).

**12. Microsomal Clearance:** Ligand B (32.378) has a lower microsomal clearance than Ligand A (59.722), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.93) has a longer half-life than Ligand A (-11.001). The negative value for Ligand A is concerning.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.232 and 0.377).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This 0.5 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Both compounds have significant issues with solubility and Caco-2 permeability. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and a lower DILI risk. While the solubility and permeability are concerning, the improved potency and metabolic profile of Ligand B make it the more promising candidate, assuming these solubility issues can be addressed through formulation strategies.

Output:
1
2025-04-17 10:58:52,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.56) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (84.5) is well within the range.

**logP:** Ligand A (-1.515) is a bit low, potentially hindering permeability. Ligand B (1.331) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is acceptable. Ligand B (2 HBD, 4 HBA) is also good.

**QED:** Both ligands have reasonable QED scores (0.576 and 0.461), indicating drug-like properties.

**DILI:** Ligand A (46.297) has a moderate DILI risk, but is acceptable. Ligand B (16.712) has a much lower, and preferable, DILI risk.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (54.207) has a higher BBB value than Ligand A (13.261), but this is not a major factor here.

**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:** Ligand A (0.015) has a very low hERG risk, which is excellent. Ligand B (0.105) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-0.196) indicates very low clearance and excellent metabolic stability. Ligand B (7.15) has a significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (22.725 hours) has a good half-life. Ligand B (-1.623 hours) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.005 and 0.074).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is small and may not be significant.

**Overall Assessment:**

Ligand A has a better metabolic stability profile (lower Cl_mic, longer t1/2) and a significantly lower hERG risk, which are crucial for enzyme inhibitors. While its logP is slightly low, the superior ADME properties outweigh this. Ligand B, despite slightly better binding affinity, suffers from a short half-life and higher clearance, making it less likely to be a viable drug candidate. The solubility and permeability concerns are present in both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 10:58:52,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (60.85 and 67.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.425 and 2.364) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2), as lower HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**QED:** Ligand A (0.847) has a significantly better QED score than Ligand B (0.748), indicating a more drug-like profile.

**DILI:** Ligand A (8.104 percentile) has a much lower DILI risk than Ligand B (56.844 percentile). This is a significant advantage.

**BBB:** Both ligands have moderate BBB penetration, but Ligand A (71.733) is slightly better than Ligand B (67.623). Not a major concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.499) is slightly better than Ligand B (-4.67).

**Aqueous Solubility:** Ligand A (-1.699) is better than Ligand B (-3.036), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.492 and 0.317).

**Microsomal Clearance:** Ligand A (48.407 mL/min/kg) has lower microsomal clearance than Ligand B (57.6 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.564 hours) has a longer half-life than Ligand A (-8.522 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.177).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has slightly better binding affinity than Ligand A (-7.1 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior overall. Ligand A demonstrates significantly lower DILI risk, better QED, better solubility, and better metabolic stability (lower Cl_mic). The difference in binding affinity (1.3 kcal/mol) is outweighed by the substantial improvements in ADME-Tox properties. Given the enzyme-specific priorities, the improved safety profile and metabolic stability of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 10:58:52,983 - INFO - Batch 9 complete. Total preferences: 144
2025-04-17 10:58:52,983 - INFO - Processing batch 10/512...
2025-04-17 10:59:33,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.378 Da and 355.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is significantly better than Ligand B (48.42), being below 140 and closer to the desirable range for good absorption.

**logP:** Ligand A (1.358) is optimal (1-3), while Ligand B (4.464) is higher, potentially leading to solubility issues and off-target effects.

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

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Ligand A (0.857) is excellent, indicating a strong drug-like profile. Ligand B (0.587) is acceptable but less favorable.

**DILI:** Ligand A (57.193) has a lower DILI risk than Ligand B (63.086), both are acceptable but A is preferred.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand A (78.79) is better than Ligand B (60.605).

**Caco-2 Permeability:** Ligand A (-4.408) and Ligand B (-4.559) are similar and both are poor.

**Aqueous Solubility:** Ligand A (-3.119) is better than Ligand B (-5.947), indicating better solubility.

**hERG Inhibition:** Ligand A (0.073) has a much lower hERG risk than Ligand B (0.338), a critical advantage.

**Microsomal Clearance:** Ligand A (40.34) has a lower clearance than Ligand B (87.673), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.026) has a longer half-life than Ligand B (-34.141), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux than Ligand B (0.47), indicating better bioavailability.

**Binding Affinity:** Both ligands have similar binding affinities (-8.2 and -8.7 kcal/mol), which are both excellent. The slight advantage of Ligand B is unlikely to outweigh the significant ADME deficiencies.

**Conclusion:**

Ligand A is significantly better overall. It has a more favorable logP, TPSA, QED, solubility, hERG risk, metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While both have good binding affinity, Ligand A's superior ADME properties make it a much more viable drug candidate.

Output:
1
2025-04-17 10:59:33,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.571 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.53) is still under 140, but less optimal than A.

**logP:** Ligand A (3.638) is within the optimal 1-3 range. Ligand B (1.953) is also acceptable, but closer to the lower limit, potentially impacting 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:** Ligand B (0.748) has a better QED score than Ligand A (0.474), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 31.601, Ligand B: 37.34).

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (66.499) is better than Ligand B (51.997), but both are relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.747 and -4.913), which is unusual and suggests poor permeability *in vitro*. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.336 and -1.995), also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.208, Ligand B: 0.274).

**Microsomal Clearance:** Ligand B (25.995) has significantly lower microsomal clearance than Ligand A (82.786), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-1.165) has a negative half-life, which is not possible and likely indicates a very rapid degradation. Ligand A (22.402) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.156, Ligand B: 0.098).

**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 difference (1.5 kcal/mol advantage) and a critical factor.

**Overall Assessment:**

Ligand A's primary advantage is its significantly superior binding affinity. However, it has a higher TPSA, lower QED, and substantially higher microsomal clearance. Ligand B has better metabolic stability (lower Cl_mic) and a higher QED, but its binding affinity is considerably weaker. The negative Caco-2 and solubility values are concerning for both. The negative half-life for ligand B is a showstopper.

Given the enzyme-kinase focus, potency (binding affinity) is paramount. The 1.5 kcal/mol difference in binding affinity is substantial enough to outweigh the ADME drawbacks of Ligand A, *assuming* the solubility and permeability issues can be addressed through formulation or further chemical modification.

Output:
0
2025-04-17 10:59:33,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.463 and 363.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values below 140 (89.95 and 80.24), suggesting good potential for oral absorption.

**3. logP:** Both ligands have logP values within the optimal range (1.549 and 2.741). Ligand B is slightly higher, potentially impacting solubility but not drastically.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable, being less than 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:** Both ligands have good QED scores (0.512 and 0.69), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (25.94) has a significantly lower DILI risk than Ligand B (63.978). This is a major advantage for Ligand A.

**8. BBB:** Both have similar BBB penetration (67.041 and 68.941). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.055 and -4.969), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.713 and -2.332), also unusual and concerning. This suggests poor solubility, which could hinder bioavailability.

**11. hERG Inhibition:** Ligand A (0.206) has a much lower hERG inhibition liability than Ligand B (0.676). This is a crucial advantage for Ligand A, minimizing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (73.273) has a significantly higher microsomal clearance than Ligand A (18.445). This means Ligand A is more metabolically stable, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (18.81) has a longer in vitro half-life than Ligand A (-3.712). However, the negative value for Ligand A is concerning and likely an artifact or error, making this comparison less reliable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.097).

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.6). While a 0.4 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 more promising candidate. While Ligand B has slightly better binding affinity and QED, Ligand A demonstrates significantly better safety profiles (lower DILI and hERG) and metabolic stability (lower Cl_mic). The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh the small binding affinity difference. The negative half-life for Ligand A is a red flag, but the other factors make it the better starting point for optimization.

Output:
0
2025-04-17 10:59:33,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.387 Da and 341.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95) is slightly higher than Ligand B (76.36). Both are acceptable, but B is preferable.

**logP:** Ligand A (0.709) is a bit low, potentially hindering permeation. Ligand B (1.821) is within the optimal range (1-3). This favors B.

**H-Bond Donors:** Both ligands have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.786 and 0.827, respectively), indicating drug-likeness.

**DILI:** Ligand A (65.607) has a higher DILI risk than Ligand B (4.769). This is a significant advantage for B.

**BBB:** Both have relatively low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (71.656) is slightly better than A (49.826).

**Caco-2 Permeability:** Ligand A (-4.633) and Ligand B (-4.959) 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 (-1.842 and -2.431), indicating poor solubility. This is a concern, but can sometimes be overcome with formulation.

**hERG Inhibition:** Ligand A (0.133) has a slightly lower hERG risk than Ligand B (0.692), which is preferable.

**Microsomal Clearance:** Ligand A (-17.822) has a significantly lower (better) microsomal clearance than Ligand B (-7.688), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.037) has a lower half-life than Ligand B (6.999). This favors B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.018), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -7.7 kcal/mol). Ligand B is slightly better (-7.7 kcal/mol).

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in key areas: DILI risk is much lower, it has a better logP, a longer half-life, and slightly better binding affinity. The improved metabolic stability of Ligand A is a positive, but the significantly lower DILI risk of Ligand B outweighs this benefit, especially considering the similar binding affinities.

Output:
1
2025-04-17 10:59:33,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.3) is slightly higher than Ligand B (364.917), but both are acceptable.

**TPSA:** Ligand A (90.98) is better than Ligand B (40.62) as it is closer to the upper limit for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.487) is slightly better than Ligand B (4.087) as it is closer to the optimal range.

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

**QED:** Both ligands have similar QED values (A: 0.814, B: 0.807), indicating good drug-likeness.

**DILI:** Ligand A (66.111) has a higher DILI risk than Ligand B (42.691), which is a negative for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand B (78.868) has a higher BBB value than Ligand A (52.501), but this is less important.

**Caco-2 Permeability:** Ligand A (-5.556) has a lower Caco-2 permeability than Ligand B (-4.648), indicating potentially poorer absorption.

**Aqueous Solubility:** Ligand A (-2.985) has a lower aqueous solubility than Ligand B (-4.526), which is a negative for Ligand A.

**hERG Inhibition:** Ligand A (0.554) has a lower hERG inhibition liability than Ligand B (0.799), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-2.952) has a significantly lower microsomal clearance than Ligand B (59.859), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (6.581) has a lower in vitro half-life than Ligand B (16.849), which is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.085) has a lower P-gp efflux liability than Ligand B (0.517), which is a positive for Ligand A.

**Binding Affinity:** Ligand A (-7.7) has a significantly stronger binding affinity than Ligand B (-6.8). This is a crucial advantage, as a 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and better metabolic stability (lower Cl_mic). While it has some drawbacks in solubility, Caco-2 permeability, and DILI risk, the strong binding affinity and improved metabolic stability are critical for an enzyme inhibitor. The lower hERG and P-gp efflux are also positive. Ligand B has better solubility and lower DILI, but its weaker binding affinity and higher metabolic clearance are significant disadvantages.

Output:
1
2025-04-17 10:59:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (331.339 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 140, indicating good potential for oral absorption (Ligand A: 101.38, Ligand B: 99.1).

**logP:** Ligand A (2.305) is within the optimal range (1-3). Ligand B (-0.393) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=5) both fall within acceptable limits.

**QED:** Ligand A (0.597) has a better QED score than Ligand B (0.385), indicating a more drug-like profile.

**DILI:** Ligand A (97.557) has a high DILI risk, which is a major concern. Ligand B (15.394) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (67.468) has a higher BBB value than Ligand A (18.845), but this isn't a primary factor here.

**Caco-2 Permeability:** Ligand A (-5.702) has poor Caco-2 permeability. Ligand B (-4.913) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.744 and -2.286), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.602) has a slightly higher hERG risk than Ligand B (0.333), but both are relatively low.

**Microsomal Clearance:** Ligand A (-6.587) has significantly lower (better) microsomal clearance than Ligand B (6.898), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (28.67 hours) has a much longer half-life than Ligand B (-38.76 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.034).

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a major drawback with its high DILI risk. However, it boasts a significantly stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). Ligand B has a much lower DILI risk, but suffers from a poor logP, lower binding affinity, and worse metabolic stability.

Considering the enzyme-specific priorities, the strong binding affinity of Ligand A is paramount. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The poor logP of Ligand B is a more fundamental issue that would be harder to address without significantly altering the core structure and potentially losing potency.

Output:
0
2025-04-17 10:59:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.479 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.26 and 75.44) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values (1.857 and 2.625) 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 (0.676 and 0.769), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (22.8 and 21.985 percentiles), which is excellent.

**BBB:** Both ligands have reasonable BBB penetration (79.721 and 71.501 percentiles), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.066 and -4.785), which is unusual and suggests poor permeability. This is a significant drawback.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.711 and -1.501), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.264 and 0.059 percentiles), which is highly desirable.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (25.807 mL/min/kg) than Ligand B (57.997 mL/min/kg), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A has a longer half-life (34.392 hours) than Ligand B (-12.091 hours). The negative value for Ligand B is concerning and likely indicates very rapid degradation. This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.092 percentiles), which is good.

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.3 kcal/mol) than Ligand A (-6.9 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial.

**Conclusion:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The primary reasons are its significantly better metabolic stability (lower Cl_mic, longer half-life) and the problematic negative half-life value for Ligand B. While both have poor solubility and permeability, metabolic stability is crucial for kinase inhibitors. The 1.4 kcal/mol difference in binding affinity can potentially be overcome with further optimization, while fixing the poor metabolic profile of Ligand B would be more challenging.

Output:
0
2025-04-17 10:59:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.405 and 348.334 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is well below the 140 threshold for good absorption, and even below 90, which is good. Ligand B (117.35) is still under 140, but higher than A.

**logP:** Both ligands (1.111 and 1.169) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (3 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar, good QED values (0.718 and 0.721).

**DILI:** Ligand A (30.244) has a significantly lower DILI risk than Ligand B (66.344), placing it in the 'good' category while B is approaching the 'high risk' threshold.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.682) has a better BBB percentile than Ligand B (56.883).

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests issues with the modeling or data. However, Ligand A (-5.012) is slightly better than Ligand B (-4.788).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.166) is slightly better than Ligand B (-3.417).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.176 and 0.075).

**Microsomal Clearance:** Ligand A (4.727) has significantly lower microsomal clearance than Ligand B (27.847), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.674) has a positive half-life, while Ligand B (-18.58) has a negative half-life, which is not physically possible and indicates a significant issue with the modeling.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.013 and 0.022).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a >2.5 kcal/mol difference, which is highly significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is clearly the superior candidate. It has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), and slightly better solubility and permeability predictions. While both have issues with predicted solubility and permeability, the superior potency and safety profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 10:59:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.435 and 357.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.74 and 106.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.645) is within the optimal 1-3 range. Ligand B (-1.484) is slightly below 1, which *could* hinder permeation, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, well within the acceptable limits of <=5 and <=10, respectively.

**QED:** Ligand A (0.785) has a better QED score than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Ligand A (47.266) has a slightly higher DILI risk than Ligand B (35.673), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.18) is higher than Ligand B (35.401), but neither is a major factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.091 and -5.192). This is unusual and suggests poor permeability *in vitro*. However, these values are on a log scale and can be misleading. We'll need to consider other factors.

**Aqueous Solubility:** Both have negative solubility values (-2.111 and -0.978), again suggesting poor solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.322) has a slightly higher hERG risk than Ligand B (0.034), but both are relatively low.

**Microsomal Clearance:** Ligand B (-4.439) has significantly *lower* (better) microsomal clearance than Ligand A (27.004). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (2.299) has a longer half-life than Ligand A (-12.117). Again, this favors Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.051 and 0.007).

**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. A difference of >1.5 kcal/mol can often outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand B has better ADME properties (lower clearance, longer half-life, lower DILI, lower hERG), the significantly stronger binding affinity of Ligand A (-9.1 vs -7.0 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The poor solubility and permeability indicated by the Caco-2 and solubility values are concerns, but could potentially be addressed through formulation strategies. The higher affinity suggests Ligand A might achieve efficacy at lower doses, potentially mitigating some of the ADME issues.

Output:
1
2025-04-17 10:59:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.406 and 357.332 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.32 and 75.44) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands (2.386 and 2.741) are within the optimal 1-3 range.

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

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

**QED:** Both ligands have high QED scores (0.818 and 0.849), indicating good drug-like properties.

**DILI:** Ligand A (41.838) has a lower DILI risk than Ligand B (67.778). This is a significant advantage.

**BBB:** Both ligands have high BBB penetration (83.288 and 89.066), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.303 and -4.558). These values are unusual and suggest poor permeability. However, these are likely reported as log values, and negative values indicate low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.264 and -3.118). This is a major concern.

**hERG:** Both ligands have very low hERG inhibition liability (0.174 and 0.163), which is excellent.

**Microsomal Clearance:** Ligand B (26.915) has significantly lower microsomal clearance than Ligand A (47.906), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-25.256) has a longer in vitro half-life than Ligand A (-18.334), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.033 and 0.072), which is favorable.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 2 kcal/mol difference is substantial 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 (-10.2 vs -8.2 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme target like SRC kinase. The lower DILI risk of ligand A is a positive, but the potency and stability benefits of Ligand B are more impactful.

Output:
1
2025-04-17 10:59:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.531 and 356.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (59.73), both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.887 and 3.011), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides some hydrogen bonding potential.

**H-Bond Acceptors:** Ligand B (7) is better than Ligand A (2).

**QED:** Ligand A (0.838) has a significantly better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Ligand A (14.889) has a much lower DILI risk than Ligand B (49.593), a significant advantage.

**BBB:** Ligand A (93.098) has a much higher BBB penetration potential than Ligand B (62.311), although this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.626) has a worse Caco-2 permeability than Ligand B (-5.627), indicating lower intestinal absorption.

**Solubility:** Ligand A (-4.659) has a worse solubility than Ligand B (-2.659), which is a concern.

**hERG:** Both ligands have similar hERG inhibition liabilities (0.533 and 0.578), posing a moderate risk.

**Microsomal Clearance:** Ligand B (33.099) has lower microsomal clearance than Ligand A (44.74), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (31.626) has a significantly longer in vitro half-life than Ligand A (1.161), a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.233 and 0.208).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.2 kcal/mol), a 1.1 kcal/mol difference. This is a significant advantage and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has a better QED, lower DILI risk, and higher BBB, the significantly stronger binding affinity of Ligand B is the most crucial factor for an enzyme inhibitor. The longer half-life of Ligand B is also a major advantage. The solubility and Caco-2 values of Ligand B are slightly worse, but these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 10:59:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.475 Da and 399.925 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.48) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (71.53) is well within the acceptable range.

**logP:** Ligand A (0.193) is quite low, potentially hindering permeability. Ligand B (3.448) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.571 and 0.774, respectively), indicating good drug-like properties.

**DILI:** Ligand A (60.915) is approaching the higher risk threshold, while Ligand B (83.094) is significantly higher risk. This is a major concern for Ligand B.

**BBB:** Both have moderate BBB penetration (60.023 and 58.123). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.622 and -5.088), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.149 and -4.226). This is a major issue for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.185 and 0.252), which is positive.

**Microsomal Clearance:** Ligand A (18.958) has lower microsomal clearance than Ligand B (51.366), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (20.968) has a longer half-life than Ligand B (13.589), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.317).

**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 a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.1 vs -6.9 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target like SRC kinase. While Ligand B has a better logP and TPSA, its significantly higher DILI risk is a major red flag. The solubility issues would need to be addressed through formulation strategies, but the potency and metabolic stability of Ligand A make it the better starting point for optimization.

Output:
0
2025-04-17 10:59:33,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (383.901 Da) is still well within the acceptable range.

**TPSA:** Ligand A (57.26) is significantly better than Ligand B (80.32). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 3.23, B: 2.567), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a slightly higher HBA count (5 vs 3), but both are below the threshold of 10.

**QED:** Both ligands have reasonable QED values (A: 0.831, B: 0.756), indicating good drug-like properties.

**DILI:** Ligand A (8.104) has a much lower DILI risk than Ligand B (65.568). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (82.668) has a higher BBB percentile than Ligand B (68.941).

**Caco-2 Permeability:** Ligand A (-4.631) has a more negative Caco-2 value, suggesting lower permeability than Ligand B (-5.001). However, both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.745) has better solubility than Ligand B (-4.115), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.512) has a lower hERG inhibition risk than Ligand B (0.306), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (16.199 mL/min/kg) has a lower microsomal clearance than Ligand B (64.436 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (50.895 hours) has a significantly longer half-life than Ligand B (27.783 hours), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.227), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-7.8 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 not substantial enough to outweigh the significant advantages of Ligand A in other key ADME/Tox properties.

**Overall Assessment:**

Ligand A demonstrates a superior profile across most critical parameters. It has a lower DILI risk, better solubility, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a higher BBB percentile. While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A in ADME/Tox properties, particularly the DILI and metabolic stability, make it the more promising drug candidate.

Output:
0
2025-04-17 10:59:33,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.387 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (117.25 and 115.98) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.678) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (0.901) is also on the low side but slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, well within acceptable limits. Ligand B has 4 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.782) has a good drug-likeness score, while Ligand B (0.469) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (56.572) has a moderate DILI risk, while Ligand B (41.877) has a lower, more desirable DILI risk.

**BBB:** Both ligands have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**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 unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.103 and 0.291), which is excellent.

**Microsomal Clearance:** Ligand A (13.191 mL/min/kg) has a lower clearance than Ligand B (29.724 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.399 hours) has a very short half-life, which is a major drawback. Ligand B (-6.372 hours) is also short, but longer than A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.129), which is favorable.

**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, potentially outweighing some of its ADME deficiencies.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly higher binding affinity (-9.1 vs -6.9 kcal/mol) is a major advantage for an enzyme target. While its half-life is very short, this could potentially be addressed through structural modifications. Ligand B's lower QED score and higher clearance further diminish its appeal. The lower DILI risk of Ligand B is a plus, but the potency difference is too significant to ignore.

Output:
0
2025-04-17 10:59:33,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.312 and 358.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (59.81 and 61.88) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.352) is optimal, while Ligand B (4.476) is slightly higher, potentially increasing off-target effects and decreasing 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:** Ligand A (0.737) has a better QED score than Ligand B (0.531), indicating a more drug-like profile.

**7. DILI:** Ligand A (79.953) has a higher DILI risk than Ligand B (53.858). This is a concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.221) is slightly better than Ligand B (64.133).

**9. Caco-2 Permeability:** Ligand A (-4.682) has a worse Caco-2 permeability than Ligand B (-5.173), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.891 and -4.099). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.789 and 0.652).

**12. Microsomal Clearance:** Ligand A (45.304) has a lower microsomal clearance than Ligand B (72.696), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-3.43) has a better in vitro half-life than Ligand B (-19.599). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.342 and 0.56).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). This 0.6 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), better QED, and a more optimal logP. However, it has a higher DILI risk and poorer Caco-2 permeability. Ligand B has a slightly better binding affinity and lower DILI risk, but suffers from poorer metabolic stability and a higher logP.

Given the priorities for an enzyme inhibitor (potency, metabolic stability, solubility, and hERG), the improved metabolic stability and half-life of Ligand A are more critical than the slightly better binding affinity of Ligand B. The solubility is a concern for both, but can be addressed with formulation strategies. The DILI risk for Ligand A is a concern, but may be mitigated through further structural modifications.

Output:
0
2025-04-17 10:59:33,142 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.507 and 380.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (105.31). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have similar logP values (1.544 and 1.546), 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.76 and 0.847), indicating drug-like properties.

**DILI:** Ligand A (17.759) has a much lower DILI risk than Ligand B (84.141). This is a significant advantage for Ligand A.

**BBB:** Ligand A (69.639) has a better BBB penetration score than Ligand B (58.821), although BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.955 and -5.125). 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 (-1.921 and -2.682). Again, the scale is unknown, making interpretation difficult. However, negative values likely indicate poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.225 and 0.194), which is good.

**Microsomal Clearance:** Ligand A (47.814) has a higher (worse) microsomal clearance than Ligand B (-0.058). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (9.835) has a shorter half-life than Ligand B (-0.416). This further supports Ligand B's better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.04).

**Binding Affinity:** Ligand B (-9.9 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 that can outweigh other drawbacks.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-9.9 vs -8.0 kcal/mol) is the most important factor. While Ligand A has better DILI and TPSA, the potency advantage of Ligand B is substantial. Ligand B also exhibits better metabolic stability (lower Cl_mic, longer t1/2). The solubility and permeability concerns are present in both, but the potency difference is likely to be more impactful in early development.

Output:
1
2025-04-17 10:59:33,142 - INFO - Batch 10 complete. Total preferences: 160
2025-04-17 10:59:33,142 - INFO - Processing batch 11/512...
2025-04-17 11:00:14,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (347.459 and 381.885 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is slightly higher than Ligand B (71.53), but both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.077 and 2.253) are within the optimal 1-3 range.

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

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.791 and 0.812), indicating drug-like properties.

**7. DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (61.031). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (62.233) has a lower BBB penetration than Ligand B (79.604). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.002) has worse Caco-2 permeability than Ligand B (-4.964). Both are poor, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-2.584) has slightly better aqueous solubility than Ligand B (-3.473).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.457 and 0.335).

**12. Microsomal Clearance (Cl_mic):** Ligand A (39.901) has a higher microsomal clearance than Ligand B (21.256), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand A (14.214) has a longer half-life than Ligand B (0.271). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux than Ligand B (0.274), which is favorable.

**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 still a factor.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and better metabolic stability (lower Cl_mic). However, Ligand A has a significantly lower DILI risk, better half-life, and lower P-gp efflux. The difference in binding affinity is small (0.2 kcal/mol) and can potentially be optimized in later stages of drug development. The lower DILI risk and better half-life of Ligand A are more critical factors for overall drug viability.

Output:
1
2025-04-17 11:00:14,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.331 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (65.2). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors. Ligand B is quite high and could pose absorption challenges.

**logP:** Both ligands have good logP values (4.318 and 3.198), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) 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 similar and acceptable QED values (0.812 and 0.831).

**DILI:** Ligand A (52.191) has a higher DILI risk than Ligand B (27.104). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (74.758 and 77.239), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.324 and -4.796), which 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 (-5.047 and -4.311), indicating poor aqueous solubility. This is a concern, but formulation strategies can sometimes overcome this.

**hERG Inhibition:** Ligand A (0.768) has a slightly higher hERG risk than Ligand B (0.455), favoring Ligand B.

**Microsomal Clearance:** Ligand B (61.067) has a lower microsomal clearance than Ligand A (65.678), suggesting better metabolic stability, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-22.867) has a significantly longer in vitro half-life than Ligand A (-5.886). 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 (0.208 and 0.169).

**Binding Affinity:** Both ligands have very similar and strong 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:**

Ligand B is the more promising candidate. While both have similar potency, Ligand B demonstrates superior ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. Ligand A has a slightly better TPSA, but the benefits of Ligand B's improved ADME profile outweigh this minor difference. The poor Caco-2 and solubility for both are concerns, but can potentially be addressed with formulation.

Output:
1
2025-04-17 11:00:14,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (340.427 and 346.406 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 67.23, which is acceptable for general absorption but not optimized for CNS penetration. This is less critical for a non-CNS target like SRC.

**3. logP:** Both ligands have logP values around 1.8 (A: 1.827, B: 1.77), which is within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 4. Both are below the limit of 10.

**6. QED:** Ligand A (0.902) has a significantly better QED score than Ligand B (0.792), suggesting a more drug-like profile.

**7. DILI:** Ligand A (61.07) has a slightly higher DILI risk than Ligand B (43.234), but both are still reasonably acceptable (below 60).

**8. BBB:** Both ligands have similar BBB penetration (A: 75.107, B: 74.758), which isn't a primary concern for SRC as it's not a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.983 and -4.826). This is unusual and suggests poor permeability. However, these values might be errors or represent a specific assay artifact. We'll need to consider this cautiously.

**10. Aqueous Solubility:** Ligand A (-3.456) has slightly worse solubility than Ligand B (-2.023). Solubility is important for enzymes.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.592, B: 0.561).

**12. Microsomal Clearance (Cl_mic):** Ligand B (38.549 mL/min/kg) has significantly lower microsomal clearance than Ligand A (48.176 mL/min/kg), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand B (22.434 hours) has a much longer half-life than Ligand A (-6.87 hours). This is a major advantage for dosing convenience and maintaining therapeutic levels.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.211, B: 0.1).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a crucial factor for enzyme inhibitors, and the 1.7 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand A has a better QED score, Ligand B demonstrates superior properties in areas critical for an enzyme inhibitor targeting SRC: significantly stronger binding affinity, better metabolic stability (lower Cl_mic), and a much longer half-life. The slightly higher DILI risk for Ligand A is less concerning than the substantial advantages of Ligand B in potency and PK. The negative Caco-2 values are a red flag for both, but the other favorable properties of Ligand B outweigh this concern, assuming the Caco-2 values are not reliable.

Output:
1
2025-04-17 11:00:14,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.38 and 355.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is higher than Ligand B (52.65). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (1.017 and 1.34), 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 acceptable QED scores (0.736 and 0.635), indicating good drug-likeness.

**DILI:** Ligand A (33.773) has a slightly higher DILI risk than Ligand B (20.589), but both are below the concerning threshold of 40.

**BBB:** Ligand A (68.554) has a lower BBB penetration percentile than Ligand B (88.445). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.861) has a lower Caco-2 permeability than Ligand B (-4.466). Both are negative values, suggesting poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.549 and -1.675). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.404 and 0.462), which is excellent.

**Microsomal Clearance:** Ligand A (-8.53) has a much lower (better) microsomal clearance than Ligand B (-6.673). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-4.705) has a longer in vitro half-life than Ligand B (-1.07). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.025).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a difference of 2.1 kcal/mol, which is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both have solubility issues, Ligand A's dramatically improved metabolic stability (lower Cl_mic, longer t1/2) and significantly stronger binding affinity (-8.9 vs -6.8 kcal/mol) make it a much more promising drug candidate for SRC kinase inhibition. The slightly higher DILI risk is less concerning given the substantial potency advantage.

Output:
1
2025-04-17 11:00:14,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.48) is higher than Ligand B (49.85). While both are reasonably low, Ligand B is significantly better, increasing the chance of good absorption.

**logP:** Ligand A (0.302) is quite low, potentially hindering permeability. Ligand B (2.895) 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 even better, potentially improving permeability.

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

**QED:** Ligand A (0.656) is better than Ligand B (0.475), indicating a more drug-like profile.

**DILI:** Ligand A (49.205) has a slightly higher DILI risk than Ligand B (17.836), but both are below the concerning threshold of 60.

**BBB:** Ligand A (53.509) and Ligand B (92.827). BBB is not a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired. Ligand B is better here.

**Caco-2 Permeability:** Ligand A (-5.107) and Ligand B (-4.684) are both negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.579) and Ligand B (-1.912) are both poor.

**hERG Inhibition:** Ligand A (0.098) and Ligand B (0.678). Ligand A has a lower hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (0.745) has much lower clearance than Ligand B (63.647), suggesting better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (33.013) has a longer half-life than Ligand B (-8.118), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux than Ligand B (0.458), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a better QED, lower hERG risk, and significantly better metabolic stability (lower Cl_mic, longer t1/2, lower Pgp efflux), Ligand B has a superior logP and TPSA, potentially leading to better absorption. However, the metabolic stability advantages of Ligand A are crucial for an enzyme inhibitor. The similar binding affinity means potency is not a differentiating factor. Given the importance of metabolic stability for kinase inhibitors, and the acceptable (though not ideal) ADME profile of Ligand A, it is the more promising candidate.

Output:
0
2025-04-17 11:00:14,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.463 and 341.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.84) is better than Ligand B (71.1), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have good logP values (2.272 and 2.775), 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:** Both ligands have 6 HBA, which is acceptable.

**6. QED:** Ligand A (0.834) has a slightly better QED score than Ligand B (0.719), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.732) has a significantly lower DILI risk than Ligand B (63.668). This is a crucial advantage.

**8. BBB:** Both ligands have acceptable BBB penetration, but Ligand B (88.29) is higher than Ligand A (76.89). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.961) is significantly better than Ligand B (-5.329), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.061) is better than Ligand B (-2.648), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.222 and 0.941).

**12. Microsomal Clearance:** Ligand B (31.233) has lower microsomal clearance than Ligand A (37.409), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (73.891) has a much longer in vitro half-life than Ligand A (-10.723). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.297 and 0.132).

**15. Binding Affinity:** Ligand A (0) has a slightly better binding affinity than Ligand B (0).

**Overall Assessment:**

Ligand A excels in several key areas: DILI risk, Caco-2 permeability, solubility, and QED. Ligand B has a better half-life and lower clearance. However, the significantly lower DILI risk of Ligand A is a major advantage, as liver toxicity is a common issue in drug development. The slightly better solubility and permeability of Ligand A are also beneficial. The affinity is similar. Considering the enzyme-specific priorities, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 11:00:14,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.531 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for good absorption, and even preferable for kinase inhibitors. Ligand B (96.25) is still within the acceptable range, but less optimal.

**logP:** Ligand A (3.89) is at the higher end of the optimal 1-3 range, while Ligand B (1.078) is at the lower end. While both are technically acceptable, a higher logP can sometimes lead to off-target effects, but is less of a concern than poor permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=3, HBA=5) is slightly higher, potentially impacting permeability, but not drastically.

**QED:** Both ligands have similar QED values (0.723 and 0.622), indicating good drug-like properties.

**DILI:** Ligand A (12.679) has a significantly lower DILI risk than Ligand B (23.924). This is a major advantage for Ligand A.

**BBB:** Ligand A (78.015) has better BBB penetration than Ligand B (44.009), though this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.549) shows poor Caco-2 permeability, while Ligand B (-5.414) is even worse. Both are concerning, but Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-4.278) has better solubility than Ligand B (-1.182), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.657) has a lower hERG risk than Ligand B (0.16). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (83.792) has a higher microsomal clearance than Ligand B (2.367), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (17.747) has a longer half-life than Ligand B (13.257), which is a positive.

**P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux than Ligand B (0.013), which is favorable.

**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 relatively small (0.4 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, solubility, and P-gp efflux. However, it suffers from poor Caco-2 permeability and higher microsomal clearance. Ligand B has a slightly better binding affinity and lower clearance, but significantly higher DILI and hERG risk, and lower solubility.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate despite the slightly lower binding affinity and poorer permeability. The lower DILI and hERG risks are critical for drug development. The permeability issue could potentially be addressed through formulation strategies. The metabolic stability issue is less concerning given the relatively good in vitro half-life.

Output:
0
2025-04-17 11:00:14,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.403 and 372.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.65) is better than Ligand B (68.52), being below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (0.716) is within the optimal 1-3 range, while Ligand B (3.591) is at the higher end, potentially raising solubility concerns.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 8 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.717 and 0.686), indicating good drug-like properties.

**DILI:** Ligand A (43.66) has a significantly lower DILI risk than Ligand B (69.058), which is a major advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand B (71.307) is slightly better than Ligand A (50.64), but this is not decisive.

**Caco-2 Permeability:** Ligand A (-4.883) and Ligand B (-5.776) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.558 and -3.526). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.068) has a much lower hERG risk than Ligand B (0.132), which is a crucial safety consideration.

**Microsomal Clearance:** Ligand A (29.611 mL/min/kg) has a lower microsomal clearance than Ligand B (45.407 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (6.788 hours) has a longer half-life than Ligand A (1.183 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.34).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), a 0.3 kcal/mol difference. While a 1.5 kcal/mol advantage is considered significant, this is not the case here.

**Conclusion:**

Despite Ligand B having slightly better binding affinity and a longer half-life, Ligand A is the more promising candidate. The significantly lower DILI risk and hERG inhibition liability of Ligand A are critical advantages. The better TPSA and lower logP also contribute to a more favorable profile. While both have poor solubility and Caco-2 permeability, these are areas that could be addressed through formulation or further chemical modifications. The safety profile of Ligand A makes it the preferred choice.

Output:
0
2025-04-17 11:00:14,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.367 and 351.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.55) is slightly higher than Ligand B (73.91), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.703 and 3.437), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* present a minor solubility issue, but is not a major concern.

**H-Bond Donors & Acceptors:** Both have 2 HBDs, which is acceptable. Ligand A has 6 HBAs and Ligand B has 4 HBAs, both are below the 10 threshold.

**QED:** Both ligands have acceptable QED scores (0.785 and 0.677), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (89.763%) compared to Ligand B (11.322%). This is a major red flag for Ligand A.

**BBB:** Both have similar BBB penetration (61.38% and 62.233%), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.41 and -4.476), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation.

**Aqueous Solubility:** Both have negative solubility values (-4.9 and -3.357), which is also unusual and suggests poor solubility. This is a concern for both, but needs further investigation.

**hERG Inhibition:** Ligand A (0.347) has a slightly lower hERG risk than Ligand B (0.821), which is preferable.

**Microsomal Clearance:** Both have similar microsomal clearance values (58.313 and 58.417 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (40.524 hours) compared to Ligand A (-7.197 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.052) has a lower P-gp efflux liability than Ligand B (0.871), which is preferable.

**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 slightly better affinity, the difference is not substantial enough to outweigh the other significant drawbacks.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** The primary driver for this decision is the significantly lower DILI risk (11.322% vs. 89.763%). The longer half-life of Ligand B is also a significant advantage. While both ligands have concerns regarding Caco-2 permeability and solubility, the DILI risk is a more critical factor in early-stage drug development. The slightly better affinity of Ligand A is overshadowed by its high DILI risk.

Output:
1
2025-04-17 11:00:14,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.483 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is well below the 140 threshold, while Ligand B (78.09) is also acceptable.

**logP:** Both ligands have good logP values (1.581 and 1.268), falling within the optimal 1-3 range.

**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, <=10 HBA).

**QED:** Both ligands have good QED scores (0.795 and 0.846), indicating drug-like properties.

**DILI:** Ligand A (31.756) has a slightly higher DILI risk than Ligand B (27.22), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.464) and Ligand B (49.128) are both relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.973 and -5.198), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.957 and -2.008), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.164 and 0.071). This is excellent.

**Microsomal Clearance:** Ligand A (28.68) has a higher microsomal clearance than Ligand B (-4.857). A negative value for Ligand B suggests very high metabolic stability, which is highly desirable.

**In vitro Half-Life:** Ligand A (-9.149) has a negative half-life, which is not possible. Ligand B (-2.039) also has a negative half-life, which is also not possible. This suggests issues with the data or the compounds themselves.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.028 and 0.047).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has significantly better binding affinity than Ligand A (-7.4 kcal/mol). This 2.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.7 vs -7.4 kcal/mol) is a major advantage for an enzyme target like SRC. Furthermore, its negative microsomal clearance suggests excellent metabolic stability, which is crucial. While both have issues with solubility and permeability, these can potentially be addressed through formulation strategies. The negative half-life values are concerning and should be investigated, but the overall profile of Ligand B is superior.

Output:
1
2025-04-17 11:00:14,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (375.78 and 370.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.39) is slightly higher than Ligand B (50.27). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (3.41 and 3.87), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not drastically.

**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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.558 and 0.764), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 65.72%, which is concerning (high risk). Ligand B has a much lower DILI risk of 39.55%, which is good. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.95%) and Ligand B (93.10%) both have reasonable values.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.798 and -4.202), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.881 and -3.935), indicating very poor aqueous solubility. This is a major drawback for both compounds and could hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.423 and 0.277), which is excellent.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-3.346), indicating very high metabolic stability, which is excellent. Ligand B has a much higher Cl_mic (57.127), suggesting rapid metabolism and a potential issue with dosing frequency.

**In vitro Half-Life:** Ligand A has a half-life of 16.98 hours, which is reasonable. Ligand B has a negative half-life (-16.29), which is not physically meaningful and suggests a significant issue with the experimental setup or the compound's stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.164 and 0.228), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.1 kcal/mol). Ligand A has a slightly better affinity, but the difference (1.1 kcal/mol) isn't large enough to overcome its other significant drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity and metabolic stability, Ligand B is the more promising candidate. The significantly lower DILI risk and better QED score of Ligand B outweigh the small advantage in affinity and stability of Ligand A. The negative half-life for Ligand B is a major red flag, but could be an experimental artifact. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies. The high DILI risk of Ligand A is a more difficult problem to overcome.

Output:
1
2025-04-17 11:00:14,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.4 and 346.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.05) is higher than Ligand B (67.23). While both are reasonably good, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Both ligands have good logP values (2.19 and 2.58), 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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.663 and 0.772), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 93.5%, which is *very* high. Ligand B has a much lower DILI risk of 30.8%, which is excellent. This is a major advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (74.7%) has a higher BBB score than Ligand A (52.2%), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative values, indicating low permeability. Ligand A (-5.39) is worse than Ligand B (-4.45).

**Aqueous Solubility:** Both have negative values, indicating low solubility. Ligand A (-3.54) is worse than Ligand B (-2.76).

**hERG:** Ligand A (0.43) has a slightly higher hERG risk than Ligand B (0.12), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.26) has significantly lower microsomal clearance than Ligand B (69.97). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand A (28.95 hours) has a much longer half-life than Ligand B (8.32 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.08), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a longer half-life and lower P-gp efflux, the *extremely* high DILI risk associated with Ligand A is a major red flag. Ligand B's significantly lower DILI risk, coupled with its better TPSA, solubility, and, crucially, a stronger binding affinity, makes it the more viable drug candidate despite its shorter half-life and higher P-gp efflux. The potency advantage of Ligand B is significant enough to outweigh the ADME drawbacks.

Output:
1
2025-04-17 11:00:14,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.375 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.14) is slightly above the optimal <140 for good oral absorption, while Ligand B (93.43) is well within the range.

**logP:** Ligand A (0.753) is a bit low, potentially hindering permeation. Ligand B (1.893) 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 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.609 and 0.688, respectively), indicating good drug-likeness.

**DILI:** Ligand A (71.307) has a higher DILI risk than Ligand B (8.375). This is a significant concern.

**BBB:** Both have reasonable BBB penetration (40.597 and 70.143), but it's less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.61) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.914) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.58 and -2.225). This is a major drawback.

**hERG Inhibition:** Ligand A (0.143) has a slightly higher hERG risk than Ligand B (0.284), but both are relatively low.

**Microsomal Clearance:** Ligand A (11.883) has a higher microsomal clearance than Ligand B (-10.182), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (-16.28) has a very short half-life, while Ligand B (-14.6) is also short, but better.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.036 and 0.02, respectively).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand B is significantly more promising. While both have solubility issues and less-than-ideal permeability, Ligand B's substantially better binding affinity, lower DILI risk, and improved metabolic stability outweigh the drawbacks. The stronger binding affinity is a key factor for an enzyme target like SRC kinase. Ligand A's high DILI risk and poor metabolic stability are major red flags.

Output:
1
2025-04-17 11:00:14,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.419 and 342.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.84) is slightly higher than Ligand B (67.23). Both are below the 140 A^2 threshold for oral absorption, but Ligand B's lower TPSA is preferable.

**logP:** Ligand A (0.642) is a bit low, potentially hindering permeation. Ligand B (1.691) is better, 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 reasonable QED scores (0.771 and 0.606), indicating good drug-like properties.

**DILI:** Ligand A (48.197) has a higher DILI risk than Ligand B (10.237). This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (73.284) has a higher BBB value than Ligand A (51.803), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.147 and -5.254), 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 very poor aqueous solubility (-1.9 and -1.0). This is a significant drawback for both, but could potentially be addressed with formulation strategies.

**hERG:** Ligand A (0.502) has a slightly higher hERG risk than Ligand B (0.345), though both are relatively low.

**Microsomal Clearance:** Ligand A (20.361) has a higher microsomal clearance than Ligand B (15.999), indicating lower metabolic stability. This is a key disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-11.902) has a significantly longer in vitro half-life than Ligand A (7.979), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.037).

**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.

**Overall Assessment:**

Ligand A has a better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a shorter half-life. Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life), but weaker binding affinity. The difference in binding affinity (1.8 kcal/mol) is significant. Given the importance of potency for enzyme inhibition, and the fact that the ADME issues with Ligand A *might* be addressable through formulation or further optimization, Ligand A is the more promising candidate.

Output:
0
2025-04-17 11:00:14,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.379 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.79) is better than Ligand B (64.41), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-1.555) is a bit low, potentially hindering permeability. Ligand B (2.817) is within the optimal 1-3 range. This favors Ligand B.

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

**H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (3) is also good.

**QED:** Both ligands have similar QED values (0.68 and 0.635), indicating good drug-likeness.

**DILI:** Ligand A (53.781) has a moderate DILI risk, while Ligand B (11.361) has a very low DILI risk. This strongly favors Ligand B.

**BBB:** Ligand A (66.344) and Ligand B (72.237) are both acceptable, but not particularly high. BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.226) is poor, while Ligand B (-4.498) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.441) is poor, while Ligand B (-2.636) is also poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.036) has a very low hERG risk, which is excellent. Ligand B (0.697) has a slightly elevated hERG risk, but still relatively low. This favors Ligand A.

**Microsomal Clearance:** Ligand A (-29.325) has very low microsomal clearance, indicating high metabolic stability. Ligand B (31.973) has moderate clearance. This strongly favors Ligand A.

**In vitro Half-Life:** Ligand A (6.112) has a moderate half-life, while Ligand B (-7.335) has a very short half-life. This favors Ligand A.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is desirable. Ligand B (0.135) has slightly higher efflux. This favors Ligand A.

**Binding Affinity:** Both ligands have similar binding affinities (-9.7 and -7.3 kcal/mol). Ligand A has a significantly better affinity.

**Overall Assessment:**

Ligand A excels in potency (affinity), metabolic stability (Cl_mic, t1/2), P-gp efflux, and hERG risk. While its logP and solubility are suboptimal, the strong affinity and favorable ADME properties outweigh these concerns. Ligand B has a better logP and lower DILI risk, but suffers from poor metabolic stability, short half-life, and weaker binding affinity. Given the enzyme-specific priorities, the superior potency and metabolic stability of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 11:00:14,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.33 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (92.55 and 95.57) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (2.996 and 2.096) within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD, which is acceptable. Ligand A has 4 HBA, and Ligand B has 6 HBA, both are within the acceptable limit of 10.

**QED:** Ligand A (0.681) has a better QED score than Ligand B (0.44), indicating a more drug-like profile.

**DILI:** Ligand A (88.484) has a higher DILI risk than Ligand B (33.346). This is a significant negative for Ligand A.

**BBB:** Both ligands have similar BBB penetration (64.095 and 67.468), which isn't a primary concern for a non-CNS target like SRC.

**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. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.564) has a slightly higher hERG inhibition risk than Ligand B (0.358), but both are relatively low.

**Microsomal Clearance:** Ligand B (100.076) has significantly higher microsomal clearance than Ligand A (45.126). This indicates Ligand A is more metabolically stable, which is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (54.651) has a much longer in vitro half-life than Ligand B (18.263), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.235 and 0.031), which is positive.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.9 and -8.0 kcal/mol). Ligand A has a 1.9 kcal/mol advantage, which is substantial and could outweigh some of its other drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the primary deciding factors here are metabolic stability (Cl_mic and t1/2) and DILI risk. Ligand A has significantly better metabolic stability and a lower DILI risk, and a substantially better binding affinity. While the DILI risk for Ligand A is still relatively high, the superior binding affinity and metabolic profile make it the more promising candidate.

Output:
0
2025-04-17 11:00:14,053 - INFO - Batch 11 complete. Total preferences: 176
2025-04-17 11:00:14,053 - INFO - Processing batch 12/512...
2025-04-17 11:00:55,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.385 and 357.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (55.32) as it is still below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets.

**logP:** Ligand B (3.206) is optimal (1-3), while Ligand A (0.279) is quite low, potentially hindering permeation.

**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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.598 and 0.703, respectively), indicating drug-like properties.

**DILI:** Ligand A (36.758) has a lower DILI risk than Ligand B (47.732), both being acceptable (<60).

**BBB:** Ligand B (85.111) has better BBB penetration than Ligand A (67.197), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can proceed assuming they are both low.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor solubility, a significant drawback.

**hERG Inhibition:** Ligand A (0.189) has a much lower hERG inhibition liability than Ligand B (0.645), which is a major advantage.

**Microsomal Clearance:** Ligand A (-3.979) has significantly better metabolic stability (lower clearance) than Ligand B (65.447). This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-0.898) has a slightly better half-life than Ligand B (-28.159), though both are negative and potentially problematic.

**P-gp Efflux:** Ligand A (0.027) shows lower P-gp efflux liability than Ligand B (0.28).

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand B boasts a much stronger binding affinity, Ligand A has superior ADME properties, particularly regarding metabolic stability (Cl_mic), hERG risk, and P-gp efflux. The poor solubility of both is concerning, but the drastically better metabolic stability and lower hERG risk of Ligand A, coupled with the substantial difference in binding affinity, make Ligand B the more promising candidate. The binding affinity difference is large enough to potentially overcome the solubility issues through formulation strategies.

Output:
1
2025-04-17 11:00:55,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.381 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (102.84). Lower TPSA generally correlates with better cell permeability, crucial for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (2.679) is optimal, while Ligand B (-0.451) is quite low. A logP below 1 can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=6). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Both ligands have similar QED values (A: 0.85, B: 0.701), indicating good drug-likeness.

**DILI:** Ligand A (52.152) has a slightly higher DILI risk than Ligand B (45.25), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (68.166) is better than Ligand B (11.128).

**Caco-2 Permeability:** Ligand A (-4.31) is better than Ligand B (-5.17), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.869) is better than Ligand B (-1.139). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.383) is significantly better than Ligand B (0.041), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (37.8 mL/min/kg) is much better than Ligand B (15.823 mL/min/kg). Lower clearance indicates greater metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (5.2 hours) is better than Ligand B (-27.459 hours). A positive half-life is preferred.

**P-gp Efflux:** Ligand A (0.083) is better than Ligand B (0.026), indicating less efflux and potentially better bioavailability.

**Binding Affinity:** Ligand B (-9.8 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 drawbacks of Ligand B. A difference of >1.5 kcal/mol is significant.

**Overall Assessment:**

While Ligand A has superior ADME properties across the board (better TPSA, logP, solubility, metabolic stability, hERG, etc.), Ligand B's binding affinity is dramatically stronger. For an enzyme target like SRC kinase, potency is paramount. The significant binding advantage of Ligand B is likely to outweigh its less favorable ADME profile, especially as its ADME properties aren't disastrous. Optimization efforts could then focus on improving Ligand B's solubility and metabolic stability.

Output:
1
2025-04-17 11:00:55,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.507 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is slightly higher than Ligand B (56.92), but both are well below the 140 threshold for oral absorption.

**3. logP:** Ligand A (1.497) is optimal, while Ligand B (3.483) 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 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.753 and 0.715), indicating good drug-likeness.

**7. DILI:** Ligand A (5.312) has a significantly lower DILI risk than Ligand B (33.307). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (56.029) is lower than Ligand B (49.554).

**9. Caco-2 Permeability:** Ligand A (-4.848) has a worse Caco-2 permeability than Ligand B (-5.067), but both are quite poor.

**10. Aqueous Solubility:** Ligand A (-1.078) has slightly better solubility than Ligand B (-1.834).

**11. hERG Inhibition:** Ligand A (0.505) has a lower hERG inhibition risk than Ligand B (0.768). This is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand A (0.907) has significantly lower microsomal clearance than Ligand B (9.457), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (6.805) has a lower half-life than Ligand B (54.01). This is a negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.012) has much lower P-gp efflux liability than Ligand B (0.082), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand B (-7.6) has slightly better binding affinity than Ligand A (-7.5), but the difference is minimal (0.1 kcal/mol).

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A demonstrates significantly better ADMET properties, particularly lower DILI risk, lower hERG inhibition, and much lower microsomal clearance (better metabolic stability). The small difference in binding affinity is unlikely to outweigh these substantial improvements in safety and pharmacokinetic properties. SRC kinases are often targets where chronic dosing is anticipated, making metabolic stability and safety paramount.

Output:
0
2025-04-17 11:00:55,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.451 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.7) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.43) is well within the range.

**logP:** Ligand A (0.102) is quite low, potentially hindering permeability. Ligand B (2.586) is optimal.

**H-Bond Donors:** Both ligands have 3 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 good QED scores (0.55 and 0.695 respectively), indicating good drug-like properties.

**DILI:** Ligand A (13.067) has a very low DILI risk, which is excellent. Ligand B (48.313) is higher, but still within an acceptable range (below 60).

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.536) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.938) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.656) has poor aqueous solubility, which could cause formulation issues. Ligand B (-3.927) is even worse.

**hERG Inhibition:** Ligand A (0.046) has very low hERG inhibition risk, which is excellent. Ligand B (0.419) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (20.86) has a lower microsomal clearance than Ligand B (62.868), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.955) has a shorter half-life than Ligand B (42.279).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.272 respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.8 kcal/mol). The difference is minimal.

**Conclusion:**

While both ligands have good binding affinity, Ligand A suffers from poor logP, Caco-2 permeability, and aqueous solubility. Ligand B has better logP and slightly better Caco-2 permeability, but higher DILI and worse solubility. However, the significantly lower microsomal clearance of Ligand A is a major advantage for an enzyme target, suggesting better *in vivo* exposure. The very low hERG risk for Ligand A is also a strong positive. Considering the enzyme-specific priorities, the improved metabolic stability and safety profile of Ligand A outweigh the slightly lower logP and solubility.

Output:
0
2025-04-17 11:00:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.491 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is better than Ligand B (91.76), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands (1.036 and 1.475) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 5 HBA) regarding the balance of solubility and permeability.

**QED:** Both ligands have good QED scores (0.61 and 0.807), indicating drug-like properties.

**DILI:** Ligand A (4.382) has a significantly lower DILI risk than Ligand B (48.158). This is a major advantage.

**BBB:** Ligand A (68.127) has a better BBB penetration score than Ligand B (59.597), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.205) has a worse Caco-2 permeability than Ligand B (-4.927).

**Aqueous Solubility:** Ligand A (-1.923) has better aqueous solubility than Ligand B (-2.842).

**hERG Inhibition:** Ligand A (0.34) has a much lower hERG inhibition liability than Ligand B (0.229), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-3.238) has a much better (lower) microsomal clearance than Ligand B (27.095), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.342) has a better (longer) in vitro half-life than Ligand B (-4.176).

**P-gp Efflux:** Ligand A (0.008) has a lower P-gp efflux liability than Ligand B (0.02).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This is a 1.2 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME-Tox properties. Specifically, the significantly lower DILI risk, hERG inhibition, and microsomal clearance, combined with better solubility and half-life, outweigh the small difference in binding affinity. These factors are critical for developing a safe and effective kinase inhibitor.

Output:
1
2025-04-17 11:00:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.531 and 361.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.77) is better than Ligand B (71.84), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have similar logP values (3.233 and 3.228), falling within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Ligand A is preferable here.

**QED:** Both ligands have good QED scores (0.722 and 0.794), indicating good drug-like properties.

**DILI:** Ligand A (10.585) has a significantly lower DILI risk than Ligand B (55.68). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration (75.107 and 70.88), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.194) and Ligand B (-5.017) both have negative Caco-2 values which is unusual and indicates poor permeability.

**Solubility:** Both ligands have similar poor aqueous solubility (-3.654 and -3.747).

**hERG:** Both ligands have low hERG inhibition risk (0.646 and 0.695).

**Microsomal Clearance:** Ligand B (51.813) has a significantly lower microsomal clearance than Ligand A (83.738), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (15.915) has a longer half-life than Ligand A (7.172). This is another advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.309 and 0.545).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a stronger binding affinity than Ligand B (-6.6 kcal/mol). This 1.0 kcal/mol difference is substantial and a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, which are key priorities for an enzyme inhibitor. While Ligand B has better metabolic stability and half-life, the potency advantage of Ligand A is more critical. The solubility and Caco-2 values are poor for both, but can be addressed through formulation strategies. The lower DILI risk of Ligand A is a significant safety advantage.

Output:
0
2025-04-17 11:00:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (340.423 and 348.359 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (126.32). A TPSA under 140 is good for oral absorption, but Ligand B is approaching a level that could hinder absorption.

**logP:** Ligand A (3.641) is optimal, while Ligand B (0.78) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but lower counts generally favor permeability.

**QED:** Ligand A (0.923) is excellent, indicating high drug-likeness. Ligand B (0.635) is acceptable but lower.

**DILI:** Ligand B (72.509) has a higher DILI risk than Ligand A (56.146), though both are moderately elevated.

**BBB:** Ligand A (76.464) has better BBB penetration than Ligand B (40.597), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.414) has better Caco-2 permeability than Ligand B (-5.233). Both are negative, indicating good permeability.

**Aqueous Solubility:** Ligand A (-4.449) has better aqueous solubility than Ligand B (-3.581). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.925) has a lower hERG risk than Ligand B (0.225), which is a significant advantage.

**Microsomal Clearance:** Ligand B (42.436) has lower microsomal clearance than Ligand A (71.705), suggesting better metabolic stability. This is a key consideration for kinases.

**In vitro Half-Life:** Ligand B (38.19) has a slightly longer half-life than Ligand A (33.399).

**P-gp Efflux:** Ligand A (0.387) has lower P-gp efflux than Ligand B (0.098), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.8 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 minor ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability and slightly longer half-life, Ligand A is the more promising candidate. Its superior binding affinity, better TPSA, logP, solubility, lower hERG risk, and excellent QED outweigh the slightly higher clearance. The stronger binding affinity is particularly important for an enzyme target like SRC.

Output:
1
2025-04-17 11:00:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.547 and 350.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.36) is significantly better than Ligand B (71.78). A TPSA below 140 is desirable for oral absorption, and both meet this, but lower is generally better.

**3. logP:** Ligand A (4.345) is slightly higher than Ligand B (2.939). While both are within the acceptable range (1-3), 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 (2) is lower than Ligand B (4), both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.748 and 0.782, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (23.846) has a significantly lower DILI risk than Ligand B (35.867). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (85.459) has a higher BBB penetration percentile than Ligand B (75.184). While not a primary concern for a kinase inhibitor, higher BBB is never detrimental.

**9. Caco-2 Permeability:** Ligand A (-4.667) has a worse Caco-2 permeability than Ligand B (-4.329). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.363) has worse aqueous solubility than Ligand B (-3.216). This is a concern, especially given Ligand A's higher logP.

**11. hERG Inhibition:** Ligand A (0.67) has a slightly lower hERG inhibition risk than Ligand B (0.754). Lower is better, so this is a minor advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (62.285) has a higher microsomal clearance than Ligand B (34.701). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (24.77) has a longer half-life than Ligand B (12.229). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.195) has a lower P-gp efflux liability than Ligand B (0.391). This is a positive for Ligand A, improving bioavailability.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. A 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor for an enzyme inhibitor. While it has a higher DILI risk and lower metabolic stability than Ligand A, the potency advantage is likely to be decisive. Ligand A has better solubility and lower DILI, but its lower binding affinity is a significant drawback. The longer half-life and lower P-gp efflux of Ligand A are positives, but the potency difference is too large to ignore.

Output:
1
2025-04-17 11:00:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.262 Da) is slightly larger than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (51.1) is slightly higher than Ligand B (49.41), but both are good.

**logP:** Both ligands have logP values between 3 and 4, which is optimal. Ligand A (4.006) is slightly higher than Ligand B (3.273), potentially raising concerns about off-target effects, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of H-bond donors (1) and acceptors (Ligand A: 3, Ligand B: 2), suggesting a good balance between solubility and permeability.

**QED:** Both ligands have QED values above 0.5, indicating a generally drug-like profile. Ligand A (0.806) is slightly better than Ligand B (0.752).

**DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (26.406). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 75.107, Ligand B: 76.192). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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 not uncommon.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both, but could be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.71) has a slightly higher hERG inhibition risk than Ligand B (0.295). Ligand B is preferable here.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (Ligand A: 55.72, Ligand B: 53.173). These are relatively moderate, suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand B (-3.326) has a significantly longer in vitro half-life than Ligand A (65.282). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.573) has a higher P-gp efflux liability than Ligand B (0.36).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a crucial advantage, as potency is a primary consideration for enzyme inhibitors. The 0.7 kcal/mol difference is substantial.

**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, lower DILI risk, longer half-life, and lower P-gp efflux outweigh the slight differences in other properties. The higher affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:00:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.56) is slightly above the preferred <140, but acceptable. Ligand B (49.41) is excellent, well below 140.

**logP:** Ligand A (0.928) is at the lower end of optimal (1-3) and could potentially have permeability issues. Ligand B (4.158) is slightly high, potentially causing solubility or off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is within acceptable limits. Ligand B (1 HBD, 2 HBA) is also good, potentially favoring permeability.

**QED:** Both ligands (0.639 and 0.602) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (31.291) has a very favorable DILI score, indicating low liver injury risk. Ligand B (17.255) is also very good.

**BBB:** Ligand A (55.642) has a moderate BBB penetration score. Ligand B (77.162) is better, but not critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.301) has poor Caco-2 permeability, which is a concern given its already low logP. Ligand B (-4.448) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.885) has poor aqueous solubility, which is a significant drawback. Ligand B (-3.885) is also poor, but worse than A.

**hERG Inhibition:** Ligand A (0.166) has very low hERG inhibition risk, which is excellent. Ligand B (0.757) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-18.2) has very low microsomal clearance, indicating good metabolic stability. Ligand B (82.602) has high clearance, suggesting rapid metabolism and a potential issue for *in vivo* efficacy.

**In vitro Half-Life:** Ligand A (21.779) has a good in vitro half-life. Ligand B (26.809) is also good.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is favorable. Ligand B (0.29) is slightly higher, but still acceptable.

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-9.4 and -8.3 kcal/mol). The difference of 1.1 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have good potency, Ligand A's significantly better metabolic stability (lower Cl_mic), lower hERG risk, and lower DILI risk outweigh its slightly lower logP and poorer Caco-2 permeability. The poor solubility of both is a concern that would need to be addressed in formulation, but the metabolic stability of A is a more critical factor for an enzyme target.

Output:
0
2025-04-17 11:00:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.427 Da) is slightly lower, which could be beneficial for permeability. Ligand B (380.499 Da) is also good.

**TPSA:** Ligand A (70.15) is significantly better than Ligand B (105.31). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.506, B: 1.516), 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 8 HBA. Both are acceptable, but Ligand A's profile is slightly more balanced.

**QED:** Both ligands have similar QED values (A: 0.9, B: 0.862), indicating good drug-likeness.

**DILI:** Both ligands have elevated DILI risk (A: 60.76, B: 63.668), but are still within a manageable range.

**BBB:** Both have good BBB penetration (A: 77.2, B: 82.978), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.78) and Ligand B (-5.24) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.96, B: -3.541). This is a significant drawback, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.718, B: 0.474), which is excellent.

**Microsomal Clearance:** Ligand A (58.412) has a significantly higher microsomal clearance than Ligand B (17.049). This suggests Ligand B is more metabolically stable, a key consideration for enzymes.

**In vitro Half-Life:** Both have similar in vitro half-lives (A: 7.405, B: 6.842).

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.122, B: 0.198), which is favorable.

**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 often outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better TPSA and H-bonding profile, Ligand B's significantly stronger binding affinity (-9.3 vs -8.1 kcal/mol) and much better metabolic stability (lower Cl_mic) make it the more promising candidate. The solubility issues are a concern for both, but the potency advantage of Ligand B is likely to be more impactful in driving forward development, as solubility can be addressed through formulation strategies.

Output:
1
2025-04-17 11:00:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.394 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.14) is better than Ligand B (53.76), both are well below the 140 A^2 threshold for good absorption.

**3. logP:** Ligand A (1.409) is optimal, while Ligand B (3.193) is towards the higher end of the optimal range.

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

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (3).

**6. QED:** Both ligands have acceptable QED scores (0.854 and 0.771), indicating good drug-likeness.

**7. DILI:** Ligand A (52.617) has a moderate DILI risk, while Ligand B (17.798) has a very low DILI risk, a significant advantage.

**8. BBB:** Both ligands have acceptable BBB penetration, but Ligand B (77.2) is better than Ligand A (66.925).

**9. Caco-2:** Both ligands have negative Caco-2 values, suggesting poor permeability.

**10. Solubility:** Ligand A (-1.165) is better than Ligand B (-3.269).

**11. hERG:** Ligand A (0.345) has a lower hERG risk than Ligand B (0.692), which is preferable.

**12. Cl_mic:** Ligand A (4.325) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (62.655).

**13. t1/2:** Ligand B (15.554) has a significantly longer in vitro half-life than Ligand A (-10.177).

**14. Pgp:** Ligand A (0.185) has lower P-gp efflux than Ligand B (0.41).

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.2), but the difference is small.

**Overall Assessment:**

Ligand B has a clear advantage in terms of DILI risk and in vitro half-life. However, Ligand A has better solubility, lower hERG risk, lower Pgp efflux, and better metabolic stability. The binding affinity difference is minimal. Given the enzyme-kinase specific priorities, metabolic stability (Cl_mic and t1/2) and hERG risk are crucial. While Ligand B's half-life is better, Ligand A's lower Cl_mic and hERG risk are more important.

Output:
0
2025-04-17 11:00:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.402 and 355.498 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (62.3 and 61.44) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.697 and 2.256) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands have 3 HBAs, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.632 and 0.736), indicating drug-like properties.

**DILI:** Ligand A (29.159) has a much lower DILI risk than Ligand B (7.135), which is a significant advantage. Both are below the 40 threshold, but A is substantially better.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (87.67) has a higher BBB penetration than Ligand A (67.041).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.634 and -4.919), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.67 and -1.701), which is also concerning. Poor solubility could hinder bioavailability.

**hERG Inhibition:** Ligand A (0.176) has a much lower hERG risk than Ligand B (0.528). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (13.042) has a higher microsomal clearance than Ligand B (-7.624). This means Ligand B is predicted to have better metabolic stability. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand A has a negative half-life (-15.336) which is not possible. Ligand B has a half-life of 3.678 hours. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.032).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.9 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, positive t1/2). However, Ligand A has a significantly lower DILI risk and hERG inhibition liability. The negative solubility and Caco-2 values are concerning for both. Considering the enzyme-specific priorities, metabolic stability and potency are key. The difference in binding affinity (0.9 kcal/mol) is substantial enough to outweigh the slightly higher DILI and hERG risks of Ligand B, especially given that both are still within acceptable ranges.

Output:
1
2025-04-17 11:00:55,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (357.451 and 366.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (97.92 and 93.21) are below the 140 A^2 threshold for good oral absorption, but higher than the 90 A^2 for CNS targets (not a priority here).

**3. logP:** Both ligands (1.394 and 1.318) are 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 (6) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have similar QED values (0.64 and 0.649), indicating good drug-likeness.

**7. DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (42.303). This is a substantial advantage.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (82.009) has a higher BBB percentile than Ligand B (61.613), but this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.636) has a worse Caco-2 permeability than Ligand B (-5.342).

**10. Aqueous Solubility:** Ligand A (-2.076) has a slightly better aqueous solubility than Ligand B (-2.224).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.253 and 0.075).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (29.386 and 28.098 mL/min/kg), indicating comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.738) has a slightly longer in vitro half-life than Ligand B (0.168).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.008).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a 0.2 kcal/mol difference, which is meaningful.

**Overall Assessment:**

Ligand B has a superior binding affinity (-7.2 kcal/mol vs -8.0 kcal/mol), which is a key factor for enzyme inhibitors. While Ligand A has slightly better solubility and half-life, Ligand B's significantly lower DILI risk and comparable ADME properties make it the more promising candidate. The difference in binding affinity is substantial enough to outweigh the minor advantages of Ligand A.

Output:
1
2025-04-17 11:00:55,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (392.537 and 362.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is slightly higher than Ligand B (34.59), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.435 and 3.48), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for off-target effects, but not a major issue.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (0) and Ligand A has 4 HBA and Ligand B has 5 HBA, both under the 10 limit.

**QED:** Both ligands have good QED scores (0.595 and 0.755), indicating good drug-like properties.

**DILI:** Ligand A (31.136) has a slightly higher DILI risk than Ligand B (24.118), but both are below the 40 threshold, indicating low risk.

**BBB:** Both have reasonable BBB penetration, but Ligand B (97.829) is significantly higher than Ligand A (78.558). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.681 and -4.926). 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 very poor aqueous solubility (-2.983 and -2.907). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.514 and 0.866), which is excellent.

**Microsomal Clearance:** Ligand A (40.35) has a lower microsomal clearance than Ligand B (47.21), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-20.646) has a significantly longer in vitro half-life than Ligand B (16.492). This is another strong advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.457).

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

**Conclusion:**

While both ligands have good potency, Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic) and longer half-life. The slightly lower DILI risk is also a bonus. The solubility is a concern for both, but the improved PK properties of Ligand A outweigh this drawback. The Caco-2 permeability is poor for both, but this might be mitigated with formulation strategies.

Output:
0
2025-04-17 11:00:55,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.53 and 346.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is significantly better than Ligand B (95.42). A TPSA under 140 is good for oral absorption, and A is well within this range, while B is approaching the upper limit and could have absorption issues.

**logP:** Ligand A (4.423) is slightly higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (1.751) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (2 HBD, 5 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have similar QED values (0.79 and 0.765), indicating good drug-likeness.

**DILI:** Ligand A (20.32) has a much lower DILI risk than Ligand B (51.69), which is a significant advantage.

**BBB:** Ligand A (92.90) shows good BBB penetration, while Ligand B (54.25) is much lower. While not crucial for all kinase inhibitors, better BBB penetration can be beneficial.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.61 and -4.72), which is unusual and suggests potential issues with intestinal absorption. However, these are relative scales and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.74 and -2.73), indicating poor aqueous solubility. This is a concern for both, but A is slightly better.

**hERG Inhibition:** Ligand A (0.915) has a lower hERG risk than Ligand B (0.173), which is a critical advantage.

**Microsomal Clearance:** Ligand A (69.06) has higher microsomal clearance than Ligand B (63.27), meaning it's metabolized faster and has lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (-24.57) has a significantly longer in vitro half-life than Ligand A (17.04), which is a major advantage.

**P-gp Efflux:** Ligand A (0.808) has slightly higher P-gp efflux than Ligand B (0.098), meaning B is less likely to be pumped out of cells.

**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 has a significantly stronger binding affinity and a longer half-life. While it has a higher TPSA and slightly lower logP, the affinity difference is substantial. Ligand A has better TPSA, DILI, hERG, and BBB, but the weaker binding and faster clearance are major drawbacks. Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity, Ligand B is the more promising candidate despite its slightly less favorable ADME profile.

Output:
1
2025-04-17 11:00:55,780 - INFO - Batch 12 complete. Total preferences: 192
2025-04-17 11:00:55,780 - INFO - Processing batch 13/512...
2025-04-17 11:01:36,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.466 and 379.522 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is better than Ligand B (29.54) as it is still within the acceptable range for oral absorption (<140), while Ligand B is significantly lower, potentially indicating a lack of necessary interactions.

**logP:** Ligand A (2.713) is optimal (1-3). Ligand B (4.247) is slightly higher, potentially leading to solubility issues or off-target effects, but still within a tolerable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, fitting the <5 and <10 rules. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.705 and 0.752), indicating drug-like properties.

**DILI:** Ligand A (24.544) has a much lower DILI risk than Ligand B (41.644), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (95.463) has a higher BBB penetration than Ligand A (81.892).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.683 and -4.881), 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 (-3.844 and -4.933), which is concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.738) has a slightly better hERG profile than Ligand B (0.917), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (53.114) has significantly lower microsomal clearance than Ligand B (111.295), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (22.365) has a longer half-life than Ligand A (2.126), which is desirable.

**P-gp Efflux:** Ligand A (0.113) has lower P-gp efflux than Ligand B (0.822), potentially leading to better bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have similar potency, Ligand A demonstrates a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. The solubility and Caco-2 permeability are concerning for both, but the advantages of Ligand A in safety and PK outweigh these drawbacks.

Output:
0
2025-04-17 11:01:36,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.426 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**TPSA:** Ligand A (83.78) is better than Ligand B (53.51) for oral absorption, but both are well below the 140 threshold.

**logP:** Both ligands have good logP values (A: 2.463, B: 2.969), 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=3) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (A: 0.754, B: 0.682), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (98.992) compared to Ligand B (29.779). This is a major concern for Ligand A.

**BBB:** Ligand A (52.579) has lower BBB penetration than Ligand B (82.125). This isn't a primary concern for a non-CNS target like SRC kinase.

**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 (-4.852 for A, -4.785 for B).

**Aqueous Solubility:** Ligand A (-3.642) has worse solubility than Ligand B (-1.992). Solubility is important for bioavailability, making Ligand B preferable.

**hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (A: 0.425, B: 0.67).

**Microsomal Clearance:** Ligand A (9.307) has significantly lower microsomal clearance than Ligand B (58.685), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (41.546) has a much longer half-life than Ligand B (-13.619). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.288, B: 0.499).

**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 is still a positive for Ligand A.

**Overall Assessment:**

Ligand A has superior binding affinity, metabolic stability (lower Cl_mic), and a longer half-life. However, its significantly higher DILI risk and lower solubility are major drawbacks. Ligand B has a much better safety profile (lower DILI) and better solubility, but weaker binding affinity and poorer metabolic stability.

Given the enzyme-kinase specific priorities, metabolic stability and potency are key. The affinity difference is not large enough to outweigh the significant DILI risk associated with Ligand A. Therefore, Ligand B is the more viable candidate.

Output:
1
2025-04-17 11:01:36,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.422 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (75.44 and 78.95) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (2.139) is optimal, while Ligand B (0.385) is quite low. A logP below 1 can hinder permeation. This is a significant negative 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 QED values (0.852 and 0.794) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (25.785) has a lower DILI risk than Ligand B (30.787), both are acceptable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.531) has a better BBB percentile than Ligand B (65.18).

**9. Caco-2 Permeability:** Ligand A (-4.591) has better Caco-2 permeability than Ligand B (-4.695).

**10. Aqueous Solubility:** Ligand A (-2.449) has better aqueous solubility than Ligand B (-1.302). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.4 and 0.088).

**12. Microsomal Clearance:** Ligand A (23.55) has a slightly higher microsomal clearance than Ligand B (20.555). Lower is better for metabolic stability, so Ligand B is slightly favored here.

**13. In vitro Half-Life:** Ligand B (15.152) has a significantly longer in vitro half-life than Ligand A (8.399). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.097 and 0.024).

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

**Overall Assessment:**

While Ligand B has a longer half-life and slightly better metabolic stability, the significantly lower logP of Ligand B is a major concern. This could lead to poor permeability and bioavailability. Ligand A has a more optimal logP, better solubility, and better Caco-2 permeability. Given the enzyme-specific priorities, the better ADME profile of Ligand A outweighs the slightly shorter half-life of Ligand A.

Output:
1
2025-04-17 11:01:36,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.434 and 343.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is higher than Ligand B (46.61). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Ligand A (1.379) is optimal, while Ligand B (4.287) is approaching the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (0 HBD, 3 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.785) has a better QED score than Ligand B (0.605), indicating a more drug-like profile.

**DILI:** Both ligands have similar, acceptable DILI risk (Ligand A: 54.634, Ligand B: 52.385), both below the 60% threshold.

**BBB:** Both have reasonable BBB penetration (Ligand A: 75.843, Ligand B: 71.656), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.573 and -4.5), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both have negative solubility values (-1.702 and -5.116), which is also concerning. This suggests formulation challenges.

**hERG Inhibition:** Ligand A (0.142) has a much lower hERG risk than Ligand B (0.308), which is a significant advantage.

**Microsomal Clearance:** Ligand A (34.793 mL/min/kg) has a lower microsomal clearance than Ligand B (95.521 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.806 hours) has a longer in vitro half-life than Ligand B (-16.985 hours).

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux than Ligand B (0.411), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), though both are good. The 1.8 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A is the better candidate. While both ligands have concerning solubility and permeability issues (negative Caco-2 and solubility values), Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, lower P-gp efflux, and a slightly better binding affinity. The better QED score also supports its drug-like properties. The higher TPSA of Ligand A is less concerning than the high logP of Ligand B. The binding affinity difference is significant enough to favor Ligand A despite the ADME drawbacks.

Output:
0
2025-04-17 11:01:36,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.36 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.36) is better than Ligand B (65.54), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.536 and 2.255) within the 1-3 range.

**H-Bond Donors:** Both have 1 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 very similar QED values (0.893 and 0.892), indicating good drug-likeness.

**DILI:** Ligand A (32.222) has a lower DILI risk than Ligand B (40.83), which is preferable.

**BBB:** Ligand B (78.402) has a slightly higher BBB penetration than Ligand A (66.072), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.66) is slightly worse than Ligand B (-4.977).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.626) is slightly better than Ligand B (-2.643).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.596 and 0.33), which is good.

**Microsomal Clearance:** Ligand B (42.139) has lower microsomal clearance than Ligand A (68.316), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-3.334) has a longer in vitro half-life than Ligand A (-8.001), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.209 and 0.309).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic and longer t1/2) and slightly lower DILI risk. While Ligand A has slightly better solubility and TPSA, the improved pharmacokinetic properties of Ligand B are more critical for an enzyme target like SRC kinase. The Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:01:36,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.793 and 369.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.06) is slightly above the preferred <140, but acceptable. Ligand B (89.95) is excellent, well below 140.

**logP:** Ligand A (2.725) is optimal (1-3). Ligand B (0.265) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2 respectively, both <=5).

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 each, both <=10).

**QED:** Both ligands have good QED scores (0.659 and 0.748, both >=0.5).

**DILI:** Ligand A has a high DILI risk (98.953 percentile), which is a significant concern. Ligand B has a much lower DILI risk (30.787 percentile), a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (51.725) and Ligand B (30.593) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.006 and -5.6), which is unusual and suggests poor permeability. However, these values are on a log scale, and negative values aren't directly interpretable without knowing the assay specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.073 and -1.156), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Ligand A (0.472) has a slightly higher hERG risk than Ligand B (0.371), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (48.258 mL/min/kg) has moderate clearance. Ligand B has very rapid clearance (-18.504 mL/min/kg, likely a negative value indicating very fast clearance), which is a major drawback.

**In vitro Half-Life:** Ligand A (49.414 hours) has a good half-life. Ligand B has a very short half-life (-3.14 hours, again, likely a negative value indicating very short half-life).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.008).

**Binding Affinity:** Ligand B (-8.9 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 concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity and significantly lower DILI risk, which are critical for an enzyme target. However, it suffers from poor logP, very rapid clearance, and a short half-life. Ligand A has a high DILI risk, which is a major concern, but has better metabolic stability and solubility.

Despite the poor logP, the strong affinity of Ligand B is a significant advantage. The rapid clearance and short half-life *might* be addressable through prodrug strategies or structural modifications, while a high DILI risk is much harder to fix.

Output:
1
2025-04-17 11:01:36,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.373) is slightly higher than Ligand B (348.403), but both are acceptable.

**TPSA:** Ligand A (71.34) is well below the 140 threshold for oral absorption. Ligand B (102.74) is also acceptable, though approaching the upper limit.

**logP:** Ligand A (4.411) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.627) is quite low, which could hinder membrane permeability.

**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 good QED scores (A: 0.703, B: 0.785), indicating generally drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.51), which is a significant concern. Ligand B has a much lower DILI risk (32.842), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB score (71.811) than Ligand A (44.32), but this isn't a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.822 and -4.749), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.108 and -1.952), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.89) has a slightly higher hERG risk than Ligand B (0.16), but both are relatively low.

**Microsomal Clearance:** Ligand B has a significantly *lower* (better) Cl_mic (-43.109) than Ligand A (33.02), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a much longer half-life (-2.376) than Ligand A (125.449), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.461, B: 0.007).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-8.9 kcal/mol) than Ligand A (-0.0 kcal/mol). This is a crucial difference.

**Conclusion:**

Despite both ligands having issues with solubility and permeability, Ligand B is the far superior candidate. Its significantly stronger binding affinity, much lower DILI risk, improved metabolic stability (lower Cl_mic, longer half-life), and lower P-gp efflux outweigh the concerns about its low logP and permeability. Ligand A's extremely high DILI risk is a deal-breaker. While both would require significant medicinal chemistry work to improve solubility and permeability, Ligand B provides a much stronger starting point due to its potency and safety profile.

Output:
1
2025-04-17 11:01:36,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (361.511 and 344.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.25) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is better positioned for good oral absorption (<140).

**3. logP:** Ligand A (4.648) is slightly higher than optimal (1-3), potentially leading to solubility issues. Ligand B (3.232) is within the optimal range.

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

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.736) has a better QED score than Ligand B (0.446), indicating a more drug-like profile.

**7. DILI:** Ligand A (69.756) has a higher DILI risk than Ligand B (13.339). This is a significant concern for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (77.627) is better than Ligand A (64.87). However, BBB is not a primary concern for an oncology target like SRC.

**9. 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.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests potential issues with solubility prediction. However, the values are similar.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liabilities (0.638 and 0.692), indicating a moderate risk.

**12. Microsomal Clearance:** Ligand A (126.566) has a higher microsomal clearance than Ligand B (49.342), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (42.106) has a longer half-life than Ligand B (18.043), which is a positive attribute.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.582 and 0.322).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both have excellent affinity, Ligand A suffers from higher DILI risk and higher microsomal clearance, indicating lower metabolic stability. Ligand B has better solubility, lower DILI risk, and better metabolic stability. The longer half-life of Ligand A is a plus, but the other drawbacks are more concerning.

Output:
1
2025-04-17 11:01:36,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.415 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned for potential CNS penetration if needed.

**logP:** Both ligands have similar logP values (2.249 and 2.283), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.716 and 0.753), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 72.043, which is concerning (high risk). Ligand B has a significantly lower DILI risk of 9.616, which is excellent. This is a major advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 57.425, while Ligand B has 42.769. Neither is particularly high, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.03 and -4.973). This 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 does require further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.267 and -2.964), indicating poor aqueous solubility. This is a significant drawback for both, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.271) has a slightly higher hERG inhibition risk than Ligand B (0.357), but both are relatively low.

**Microsomal Clearance:** Ligand A (58.659) has a higher microsomal clearance than Ligand B (41.748), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (6.286 hours) has a significantly longer in vitro half-life than Ligand A (-38.623 hours, which is effectively very short). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux than Ligand B (0.05), which 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 still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a dramatically lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The DILI risk for Ligand A is a major red flag. The small advantage in P-gp efflux for Ligand A is outweighed by the other factors.

Output:
1
2025-04-17 11:01:36,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.5 and 365.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is significantly better than Ligand B (78.43). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (4.073) is slightly higher than the optimal 1-3 range, while Ligand B (0.918) is a bit 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.

**QED:** Both ligands have good QED scores (0.599 and 0.811), indicating good drug-like properties.

**DILI:** Ligand A (29.24) has a much lower DILI risk than Ligand B (16.17), which is a significant advantage.

**BBB:** Both have similar BBB penetration (64.1 and 67.1), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.612) has a negative Caco-2 value, which is concerning. Ligand B (-5.54) is also poor, but slightly worse.

**Solubility:** Ligand A (-3.72) has poor solubility, while Ligand B (-0.727) is still poor, but better than A.

**hERG:** Ligand A (0.769) has a slightly higher hERG risk than Ligand B (0.127), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (88.92) has higher clearance, indicating lower metabolic stability compared to Ligand B (-21.652), which is a substantial benefit for B.

**In vitro Half-Life:** Ligand A (7.884 hours) has a shorter half-life than Ligand B (1.703 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.852 and 0.025).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol), with Ligand B being slightly better. The affinity difference is small enough that it doesn't overwhelmingly favor one ligand.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is a bit low and Caco-2 is poor, its significantly better DILI score, lower hERG risk, and much improved metabolic stability (lower Cl_mic and longer half-life) outweigh the slightly weaker Caco-2 and logP. The binding affinity is comparable. Ligand A's poor solubility is also a significant drawback.

Output:
1
2025-04-17 11:01:36,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.252 Da) is slightly higher than Ligand B (353.423 Da), but both are acceptable.

**TPSA:** Ligand A (85.25) is well below the 140 threshold for good oral absorption. Ligand B (129.37) is also acceptable, though higher.

**logP:** Ligand A (2.257) is within the optimal range (1-3). Ligand B (-0.78) is below 1, which could indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=4, HBA=7) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.803, Ligand B: 0.509), suggesting good drug-like properties.

**DILI:** Ligand A (77.278) has a higher DILI risk than Ligand B (44.009). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.282) and Ligand B (29.663) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.144 and -5.353), 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 (-3.317 and -1.929), indicating poor aqueous solubility. This is a significant drawback for both, but potentially more problematic for Ligand B given its lower logP.

**hERG Inhibition:** Ligand A (0.562) has a slightly higher hERG risk than Ligand B (0.05), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (13.723) has a higher clearance than Ligand B (3.624), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (30.791 hours) has a significantly longer half-life than Ligand B (-1.842 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.355 and 0.028).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.2 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a much longer half-life, which are critical for an enzyme inhibitor. However, it has a higher DILI risk and lower metabolic stability compared to Ligand B. Ligand B has better DILI and metabolic stability, but its lower logP and significantly weaker binding affinity are major concerns. The poor solubility and permeability are problematic for both, but the superior potency of Ligand A is likely to be more impactful in driving efficacy. Given the enzyme-specific priorities, the stronger binding affinity and longer half-life of Ligand A are more important than the slightly higher DILI risk and lower metabolic stability, especially considering optimization strategies can be employed to address these issues.

Output:
1
2025-04-17 11:01:36,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.455 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.77) is slightly higher than Ligand B (80.32), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.661) is a bit low, potentially hindering permeation. Ligand B (2.38) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) both satisfy the <5 HBD and <10 HBA criteria.

**QED:** Both ligands have reasonable QED scores (0.849 and 0.776), indicating good drug-like properties.

**DILI:** Ligand A (38.503) has a slightly better DILI score than Ligand B (41.411), both are below the concerning threshold of 60.

**BBB:** Ligand A (53.47) has a lower BBB percentile than Ligand B (65.801), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.113) has a significantly worse Caco-2 permeability than Ligand B (-4.474).

**Aqueous Solubility:** Ligand A (-1.667) has a slightly better aqueous solubility than Ligand B (-3.267). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.173 and 0.254), which is excellent.

**Microsomal Clearance:** Ligand A (-18.472) exhibits *much* lower microsomal clearance than Ligand B (76.911), suggesting significantly better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (38.654) has a longer in vitro half-life than Ligand B (-42.067), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.188).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.8 and -8.3 kcal/mol), both being quite good. The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has a slightly better logP and Caco-2 permeability, Ligand A's dramatically improved metabolic stability (lower Cl_mic and longer t1/2) and slightly better DILI score are crucial for an enzyme target like SRC kinase. The comparable binding affinity seals the deal. The lower logP of Ligand A is a minor concern that could potentially be addressed through further optimization.

Output:
0
2025-04-17 11:01:36,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.411 and 359.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.53) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (45.23) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.65) is a bit low, potentially hindering permeation. Ligand B (3.183) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are reasonable. Ligand B has 1 HBD and 4 HBA, also good.

**QED:** Ligand A (0.39) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.847) is excellent.

**DILI:** Ligand A (61.768) has a moderate DILI risk. Ligand B (16.208) has a very low DILI risk, which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (79.566) has a higher value than Ligand A (45.25).

**Caco-2 Permeability:** Ligand A (-5.176) and Ligand B (-5.258) have similar, very poor Caco-2 permeability values.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.841 and -3.487 respectively). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.172) has a slightly higher hERG risk than Ligand B (0.57).

**Microsomal Clearance:** Ligand A (18.358 mL/min/kg) has significantly lower clearance than Ligand B (69.397 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.935 hours) has a slightly longer half-life than Ligand B (9.326 hours).

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is favorable. Ligand B (0.219) has slightly higher efflux.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a lower QED score, slightly higher DILI risk, and lower metabolic stability. Ligand B has superior ADME properties (QED, DILI, metabolic stability, TPSA), but significantly weaker binding affinity. The difference in binding affinity (-9.0 vs -6.4 kcal/mol) is substantial (2.6 kcal/mol), and is likely to be decisive. While the poor solubility and Caco-2 permeability of both are concerning, these can be addressed through formulation. The improved metabolic stability of Ligand A is also a plus.

Output:
0
2025-04-17 11:01:36,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (336.391 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.55) is slightly higher than Ligand B (58.64), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.426 and 3.352), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some 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:** Both ligands have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.79) has a significantly better QED score than Ligand B (0.567), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.913) has a higher DILI risk than Ligand B (21.093). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (53.548) has a lower BBB penetration percentile than Ligand B (70.609). While not critical for a non-CNS target like SRC, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Ligand A (-4.656) has worse Caco-2 permeability than Ligand B (-5.121). Both are negative values, indicating poor permeability, but Ligand A is slightly better.

**10. Aqueous Solubility:** Ligand A (-3.683) has slightly better aqueous solubility than Ligand B (-3.141). Both are negative, indicating poor solubility, but Ligand A is slightly better.

**11. hERG Inhibition:** Ligand A (0.651) has a higher hERG inhibition risk than Ligand B (0.309). This is a significant negative for Ligand A.

**12. Microsomal Clearance:** Ligand A (45.541) has a higher microsomal clearance than Ligand B (40.718). Lower clearance is preferred for better metabolic stability, so Ligand B is slightly better.

**13. In vitro Half-Life:** Ligand A (52.181) has a longer in vitro half-life than Ligand B (-15.79). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.191) has lower P-gp efflux than Ligand B (0.131). Lower efflux is preferred for better bioavailability, so Ligand A is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.0 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a longer half-life and better P-gp efflux, but suffers from higher DILI risk, higher hERG inhibition, and lower Caco-2 permeability. Ligand B has a better safety profile (lower DILI and hERG), better Caco-2 permeability, and slightly better metabolic stability. Considering the enzyme-specific priorities, the safety profile and metabolic stability are more important than the slightly longer half-life of Ligand A. Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 11:01:36,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.463 and 362.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (99.1 and 97.11) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.431) is a bit low, potentially hindering permeation. Ligand B (2.24) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs and 5 HBAs, which are acceptable.

**QED:** Both ligands have good QED scores (0.586 and 0.718), indicating drug-like properties.

**DILI:** Ligand A (15.898) has a significantly lower DILI risk than Ligand B (62.466), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B shows higher BBB penetration (61.923) than Ligand A (33.385), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.885 and -4.989), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.057 and -3.786), indicating poor aqueous solubility. This is a concern, but potentially addressable with formulation strategies.

**hERG:** Ligand A (0.136) has a much lower hERG risk than Ligand B (0.507). This is a critical advantage.

**Microsomal Clearance:** Ligand A (16.664) has a higher microsomal clearance than Ligand B (-0.848), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (22.619 hours) has a significantly longer half-life than Ligand A (9.937 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux liability than Ligand B (0.078), which is favorable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a 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.

**Overall Assessment:**

Ligand B is the better candidate despite its higher DILI and P-gp efflux. The significantly stronger binding affinity (-8.8 vs -7.6 kcal/mol) and longer half-life are crucial for an enzyme inhibitor. While the higher DILI is a concern, it's a risk that can be further investigated and potentially mitigated. Ligand A's lower logP, higher clearance, and lower affinity make it less attractive. The poor Caco-2 and solubility for both are problematic, but formulation work could potentially address these issues. The lower hERG risk for Ligand A is good, but the potency and PK advantages of Ligand B are more important for this target class.

Output:
1
2025-04-17 11:01:36,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (360.53 and 374.52 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.64) is significantly better than Ligand B (69.64). A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (2.72 and 2.13), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD counts 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 reasonable QED values (0.86 and 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A (17.26) has a much lower DILI risk than Ligand B (23.54). This is a significant advantage. Lower DILI is critical.

**8. BBB:** Both ligands have similar BBB penetration (75.81 and 78.87). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.21 and -5.21), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-1.71) is better than Ligand B (-3.05), indicating slightly better solubility. Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.62 and 0.56). This is good.

**12. Microsomal Clearance:** Ligand A (40.37) has a higher microsomal clearance than Ligand B (19.98). This indicates lower metabolic stability for Ligand A, which is a disadvantage.

**13. In vitro Half-Life:** Ligand B (-0.97) has a longer in vitro half-life than Ligand A (-0.69). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.15 and 0.21).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly better 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 has a significantly better binding affinity and lower DILI risk, which are key priorities for an enzyme inhibitor. While it has a higher microsomal clearance and slightly lower solubility than Ligand B, the strong binding affinity is likely to be more impactful. The Caco-2 permeability is concerning for both, but the superior potency of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 11:01:36,427 - INFO - Batch 13 complete. Total preferences: 208
2025-04-17 11:01:36,428 - INFO - Processing batch 14/512...
2025-04-17 11:02:25,533 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [346.391, 116.14 ,  -0.196,   3.   ,   6.   ,   0.67 ,  47.266,   8.143, -5.695,  -1.205,   0.244, -22.296,  -0.586,   0.005,  -8.4  ]
**Ligand B:** [347.459,  82.53 ,   1.629,   2.   ,   4.   ,   0.848,  23.032,  50.795, -4.793,  -2.224,   0.291,  17.745,   5.444,   0.079, -10.2  ]

**Step-by-step comparison:**

1. **MW:** Both ligands (346.391 and 347.459 Da) fall within the ideal range of 200-500 Da. No significant difference.
2. **TPSA:** Ligand A (116.14) is higher than Ligand B (82.53). While both are acceptable, Ligand B is better positioned for oral absorption (closer to the <140 threshold).
3. **logP:** Ligand A (-0.196) is lower than the optimal range (1-3), potentially hindering permeability. Ligand B (1.629) is within the optimal range. This is a significant advantage for Ligand B.
4. **HBD:** Ligand A (3) is slightly higher than Ligand B (2), but both are within the acceptable limit of <=5.
5. **HBA:** 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 (0.67 and 0.848), indicating good drug-like properties. Ligand B is slightly better.
7. **DILI:** Ligand A (47.266) has a higher DILI risk than Ligand B (23.032). This is a substantial advantage for Ligand B.
8. **BBB:** Ligand A (8.143) has very low BBB penetration, while Ligand B (50.795) is moderate. Not a major concern for an oncology target, but a slight edge to B.
9. **Caco-2:** Ligand A (-5.695) has poor Caco-2 permeability, while Ligand B (-4.793) is better, but still not great.
10. **Solubility:** Ligand A (-1.205) has poor solubility, while Ligand B (-2.224) is also poor. Both are problematic.
11. **hERG:** Both ligands have very low hERG inhibition risk (0.244 and 0.291). No significant difference.
12. **Cl_mic:** Ligand A (-22.296) has a much lower (better) microsomal clearance than Ligand B (17.745), indicating greater metabolic stability. This is a significant advantage for Ligand A.
13. **t1/2:** Ligand A (-0.586) has a very short in vitro half-life, while Ligand B (5.444) is much better. This is a significant advantage for Ligand B.
14. **Pgp:** Both ligands have very low Pgp efflux liability (0.005 and 0.079). No significant difference.
15. **Binding Affinity:** Ligand B (-10.2) has a significantly stronger binding affinity than Ligand A (-8.4). This is a major advantage for Ligand B (a 1.8 kcal/mol difference).

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

While Ligand A has better metabolic stability, Ligand B excels in several critical areas: significantly higher binding affinity, a better logP, lower DILI risk, and a much longer half-life. The substantial improvement in binding affinity outweighs the slightly poorer metabolic stability and solubility. The poor solubility of both compounds would need to be addressed in formulation, but the potency and safety profile of Ligand B make it a more promising starting point.

Output:
1
2025-04-17 11:02:25,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is slightly higher than Ligand B (53.35). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.485 and 3.228), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**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 acceptable QED scores (0.782 and 0.691), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (35.052 and 34.277 percentile), which is favorable.

**BBB:** Ligand A (55.913) has a lower BBB penetration score than Ligand B (87.243). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.409 and -4.487), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.296 and -4.478), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.481 and 0.557), which is good.

**Microsomal Clearance:** Ligand A (39.871) has lower microsomal clearance than Ligand B (92.799), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (40.109) has a longer in vitro half-life than Ligand B (-30.645), further supporting better metabolic stability.

**P-gp Efflux:** Ligand A (0.298) has lower P-gp efflux liability than Ligand B (0.678), which is beneficial for oral bioavailability.

**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 not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. While both compounds suffer from poor solubility and permeability, the improved metabolic properties of Ligand A are more critical for an enzyme target like SRC kinase. Addressing the solubility and permeability issues during lead optimization would be the next step, but starting with a metabolically more stable compound is strategically advantageous.

Output:
0
2025-04-17 11:02:25,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.431 and 345.407 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.28) is well below the 140 threshold, suggesting good absorption. Ligand B (117.59) is also below the threshold, but higher than A.

**logP:** Ligand A (1.363) is within the optimal 1-3 range. Ligand B (0.19) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.908 and 0.631, respectively), indicating drug-likeness.

**DILI:** Ligand A (32.105) has a lower DILI risk than Ligand B (54.75), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.45) is higher than Ligand B (43.117).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability. Ligand A (-5.458) is better than Ligand B (-5.715).

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer solubility. Ligand A (-0.551) is better than Ligand B (-1.881).

**hERG Inhibition:** Both ligands have very low hERG risk (0.425 and 0.08, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-14.387) has a *much* lower (better) microsomal clearance than Ligand B (-16.471). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (20.798) has a significantly longer half-life than Ligand B (7.29), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.018, respectively).

**Binding Affinity:** Both ligands have strong binding affinities (-8.3 and -8.9 kcal/mol). Ligand B is slightly better (-8.9 vs -8.3), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is superior due to its better DILI risk, solubility, Caco-2 permeability, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and a reasonably comparable binding affinity. While Ligand B has a slightly better binding affinity, the ADME properties of Ligand A are substantially more favorable, particularly its metabolic stability and solubility. For an enzyme target like SRC kinase, metabolic stability and solubility are critical for *in vivo* efficacy.

Output:
0
2025-04-17 11:02:25,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.427 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (75.44 and 75.19) below 140, suggesting good oral absorption potential.

**logP:** Both ligands have logP values (2.15 and 2.95) 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 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5 HBA, both are acceptable (<=10).

**QED:** Both ligands have QED values (0.831 and 0.755) above 0.5, indicating good drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (31.136 and 37.456 percentile), which is favorable.

**BBB:** Both have moderate BBB penetration (67.235 and 78.79 percentile). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.664 and -4.963). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values can occur. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both have negative solubility values (-3.081 and -3.459). Similar to Caco-2, this is unusual and suggests poor solubility. Again, the scale is unknown.

**hERG Inhibition:** Ligand A (0.093) has a significantly lower hERG inhibition liability than Ligand B (0.465), which is a major advantage.

**Microsomal Clearance:** Ligand A (5.664 mL/min/kg) has a much lower microsomal clearance than Ligand B (57.419 mL/min/kg), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-2.317 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B has a half-life of 8.378 hours, which is reasonable.

**P-gp Efflux:** Ligand A (0.057) has lower P-gp efflux liability than Ligand B (0.499), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). However, the difference is only 0.3 kcal/mol, which is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising drug candidate. It has significantly better metabolic stability (lower Cl_mic), lower hERG risk, lower P-gp efflux, and a more favorable DILI profile. The negative values for Caco-2 and Solubility are concerning for both, but the other advantages of Ligand A make it the better choice. The half-life value for Ligand A is clearly erroneous and would need to be corrected.

Output:
0
2025-04-17 11:02:25,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 354.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (87.66). A TPSA under 140 is desired for oral absorption, and both meet this, but A is much closer to the optimal range for kinase inhibitors.

**logP:** Ligand A (3.30) is optimal, while Ligand B (1.47) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is preferable to Ligand B (HBD=3, HBA=4) as it has fewer hydrogen bonding groups, which generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.628 and 0.554), indicating good drug-like properties.

**DILI:** Ligand A (29.24) has a much lower DILI risk than Ligand B (10.24), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (73.67) shows better BBB penetration than Ligand B (57.74).

**Caco-2 Permeability:** Ligand A (-4.821) is better than Ligand B (-4.716), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.446) is better than Ligand B (-2.06), which is important for formulation and bioavailability.

**hERG:** Both ligands have low hERG risk (0.245 and 0.328), which is good.

**Microsomal Clearance:** Ligand A (47.18) has higher clearance than Ligand B (42.63), suggesting lower metabolic stability. This is a slight disadvantage for A.

**In vitro Half-Life:** Ligand B (4.86) has a significantly longer half-life than Ligand A (-11.26), which is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.131 and 0.086), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While A is better, the difference is small.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, DILI, solubility, Caco-2), and has a good binding affinity. However, its metabolic stability (higher Cl_mic, shorter half-life) is a concern. Ligand B has a slightly better binding affinity and a significantly longer half-life, but suffers from a higher DILI risk, lower logP, and higher TPSA.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the longer half-life of Ligand B is a substantial advantage, potentially outweighing its slightly higher DILI risk and less favorable logP/TPSA. The difference in binding affinity is not large enough to overcome the ADME advantages of ligand B.

Output:
1
2025-04-17 11:02:25,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.414 and 382.81 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is better than Ligand B (58.64) as it is still within the acceptable range for oral absorption (<140), while B is also good.

**logP:** Both ligands have similar logP values (2.384 and 2.222), both 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 (0.648 and 0.758), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 78.286, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 25.436, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Ligand A (46.336) and Ligand B (85.459). BBB is not a high priority for a kinase inhibitor, but B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.833 and -4.809), 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 very poor aqueous solubility (-3.752 and -3.35). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.468) has a slightly better hERG profile than Ligand B (0.602), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (35.906) has a higher microsomal clearance than Ligand B (15.968), meaning it's less metabolically stable. Lower clearance is preferred for kinases.

**In vitro Half-Life:** Ligand A (8.14 hours) has a longer half-life than Ligand B (2.625 hours). Longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux than Ligand B (0.142), which is favorable.

**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. A difference of 2.3 kcal/mol is very significant.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better P-gp efflux, its high DILI risk and higher microsomal clearance are major concerns. Ligand B has a much better safety profile (lower DILI) and improved metabolic stability, but its binding affinity is weaker. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The large difference in binding affinity is a strong point for ligand A, but the DILI risk is too high.

Output:
1
2025-04-17 11:02:25,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (378.332 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.31) is slightly above the optimal <140 for oral absorption, while Ligand B (99.18) is well within the range.

**logP:** Ligand A (0.738) is a bit low, potentially hindering permeation, while Ligand B (-0.5) is even lower and more concerning for permeability.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 6/5 HBA, respectively, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.769 and 0.626), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (90.733 percentile) than Ligand B (20.628 percentile). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (65.413) is better than Ligand B (20.434).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.133 and -5.032), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.268 and -0.322), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.153 and 0.102).

**Microsomal Clearance:** Ligand A (2.69 mL/min/kg) has a higher clearance than Ligand B (-2.305 mL/min/kg). A negative value for clearance is not physically possible, so this is likely an error in the data, but it suggests Ligand B might be more metabolically stable.

**In vitro Half-Life:** Ligand A (4.377 hours) has a longer half-life than Ligand B (-0.586 hours). Again, a negative half-life is impossible, so this is likely an error, but suggests Ligand A is more stable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.093 and 0.019).

**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 has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, its high DILI risk is a major red flag. Both ligands have poor solubility and permeability. Ligand B has a better safety profile (lower DILI) and potentially better metabolic stability, but its significantly weaker binding affinity is a major disadvantage.

Given the critical importance of potency for kinase inhibitors, and assuming the binding affinity data is reliable, the superior binding of Ligand A outweighs its higher DILI risk *provided* that the DILI risk can be mitigated through structural modifications. The poor solubility of both compounds is a concern that would need to be addressed in subsequent optimization.

Output:
1
2025-04-17 11:02:25,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.807 and 356.388 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (49.5), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (4.539 and 3.997), falling within the 1-3 range, though Ligand A is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (1 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.778 and 0.815), indicating drug-likeness.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (13.843). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration (82.629 and 79.411), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.356 and -4.71), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-5.548) has worse solubility than Ligand B (-3.875). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.548) has a lower hERG risk than Ligand B (0.945), which is a positive.

**Microsomal Clearance:** Ligand A (93.849) has higher microsomal clearance than Ligand B (45.179). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (41.155) has a longer in vitro half-life than Ligand A (36.621), which is desirable.

**P-gp Efflux:** Ligand A (0.663) has lower P-gp efflux than Ligand B (0.513), which is a slight advantage.

**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.

**Conclusion:**

Despite Ligand A's slightly better logP and lower P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-8.5 vs -7.3 kcal/mol) is the most important factor for an enzyme inhibitor. Furthermore, Ligand B exhibits much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better solubility. While both have poor Caco-2 permeability, the superior potency and safety profile of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 11:02:25,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (385.819 Da) is slightly better positioned.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (83.36). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (A: 4.854, B: 4.317), slightly above the optimal 1-3 range, but not drastically so.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA is preferable.

**QED:** Ligand A (0.748) has a better QED score than Ligand B (0.516), indicating a more drug-like profile.

**DILI:** Ligand B (67.584) has a higher DILI risk than Ligand A (84.064). Lower DILI is preferred.

**BBB:** Both have reasonably high BBB penetration, but Ligand A (77.472) is better than Ligand B (59.093). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.538) is better than Ligand B (-5.011). Higher Caco-2 permeability is preferred.

**Aqueous Solubility:** Ligand A (-6.128) is better than Ligand B (-3.533). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.37) has a much lower hERG risk than Ligand B (0.902). This is a significant advantage.

**Microsomal Clearance:** Ligand B (45.973) has lower microsomal clearance than Ligand A (85.406), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (74.551) has a significantly longer in vitro half-life than Ligand A (20.323). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.879). Lower efflux is better.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is the most important factor. A difference of 1.9 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

While Ligand A has better overall ADME properties (solubility, hERG, DILI, TPSA, QED, Caco-2, P-gp), the significantly stronger binding affinity of Ligand B (-8.2 vs -10.1 kcal/mol) is a decisive factor for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand B further strengthens its candidacy. The slightly higher DILI risk and lower solubility of Ligand B are concerns, but these can potentially be addressed through further optimization. The potency advantage is substantial enough to prioritize Ligand B.

Output:
1
2025-04-17 11:02:25,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (337.379 and 350.39 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.81) is well below the 140 threshold and favorable for oral absorption. Ligand B (78.87) is still acceptable but less optimal.

**3. logP:** Ligand A (3.598) is at the higher end of the optimal range (1-3), while Ligand B (2.085) is closer to the lower limit.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (0 for A, 2 for B), well below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 for A, 4 for B), below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.728 and 0.871), indicating good drug-like properties.

**7. DILI:** Ligand A (94.959) has a high DILI risk, exceeding the 60% threshold. Ligand B (35.983) has a low DILI risk, well below the 40% threshold. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration (83.831 and 73.75), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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. 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:** Ligand A (0.758) has a slightly higher hERG risk than Ligand B (0.483), but both are relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (65.704) has a higher Cl_mic than Ligand B (16.745), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand A (19.942) has a longer half-life than Ligand B (10.658), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.645) has lower P-gp efflux than Ligand B (0.055), which could translate to better bioavailability.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 kcal/mol and -8.6 kcal/mol). The difference is negligible.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly longer half-life and lower P-gp efflux, its significantly higher DILI risk and higher microsomal clearance are major drawbacks. Ligand B's lower DILI risk and better metabolic stability outweigh the slight disadvantages in half-life and P-gp efflux. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
1
2025-04-17 11:02:25,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.467 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is well below the 140 threshold, while Ligand B (90.12) is approaching it. Both are acceptable, but A is better.

**logP:** Ligand A (3.068) is optimal (1-3). Ligand B (1.105) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.885 and 0.719), indicating good drug-like properties.

**DILI:** Ligand A (77.782) has a higher DILI risk than Ligand B (10.585). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.664) is slightly better than Ligand B (60.644).

**Caco-2 Permeability:** Both have negative values (-5.025 and -5.66), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar.

**Aqueous Solubility:** Both have negative values (-4.518 and -1.489), also unusual and suggesting poor solubility. Again, the absolute values are similar.

**hERG:** Ligand A (0.465) has a slightly better hERG profile than Ligand B (0.238), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (41.028) has a much better microsomal clearance than Ligand B (-21.345). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (74.025) has a significantly longer half-life than Ligand B (-22.519). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.507) has slightly better P-gp efflux liability than Ligand B (0.011).

**Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (0.0). This is the most important factor for an enzyme inhibitor. The difference of >8.1 kcal/mol is substantial.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better hERG and P-gp profiles. While its DILI risk is higher, the substantial advantage in binding affinity and metabolic stability outweighs this concern. Ligand B has a better DILI profile, but its extremely poor metabolic stability and weak binding affinity make it a less promising 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 11:02:25,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.299 and 354.841 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.16) is better than Ligand B (59.81). Both are below the 140 A^2 threshold for oral absorption, but Ligand B is significantly lower, which could be beneficial.

**logP:** Ligand A (1.001) is within the optimal 1-3 range. Ligand B (3.261) is towards the higher end, potentially leading to solubility issues.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4 HBA. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.654 and 0.739, respectively), indicating good drug-like properties.

**DILI:** Ligand A (97.247) has a significantly higher DILI risk than Ligand B (73.09). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (60.644) is lower than Ligand B (49.205).

**Caco-2 Permeability:** Ligand A (-4.708) has better Caco-2 permeability than Ligand B (-5.138).

**Aqueous Solubility:** Ligand A (-5.295) has better aqueous solubility than Ligand B (-4.288).

**hERG:** Both ligands have relatively low hERG inhibition risk (0.418 and 0.527, respectively).

**Microsomal Clearance:** Ligand A (26.959) has significantly lower microsomal clearance than Ligand B (68.926), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (70.832) has a much longer in vitro half-life than Ligand B (17.791), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.285 and 0.35, 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 ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, permeability, metabolic stability, and half-life, the significantly higher DILI risk is a major red flag. Ligand B, despite slightly worse ADME properties, boasts a much stronger binding affinity (-9.0 vs -7.9 kcal/mol) and a considerably lower DILI risk. The potency advantage of Ligand B is substantial enough to overcome its slightly less favorable ADME profile, especially considering we are prioritizing potency and metabolic stability for an enzyme target.

Output:
1
2025-04-17 11:02:25,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.455 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (88.32). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (2.719 and 2.042), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 4 HBA) in terms of balancing solubility and permeability. Lower counts are generally favored.

**QED:** Both ligands have good QED scores (0.649 and 0.828), indicating good drug-like properties.

**DILI:** Ligand A (18.224) has a much lower DILI risk than Ligand B (58.666). This is a significant advantage for A.

**BBB:** Both have reasonable BBB penetration (83.366 and 78.247). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.34) is better than Ligand B (-4.873), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.775) is better than Ligand B (-2.571), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.175 and 0.266).

**Microsomal Clearance:** Ligand A (79.543) has higher microsomal clearance than Ligand B (26.933), indicating lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand B (-21.197) has a significantly longer in vitro half-life than Ligand A (-13.455). This is a major advantage for B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.14).

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-6.8). While a 1.5 kcal/mol advantage is significant, the other ADME properties need to be considered.

**Overall Assessment:**

Ligand A has a better binding affinity, TPSA, Caco-2 permeability, solubility, and a much lower DILI risk. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2). Considering SRC is a kinase, metabolic stability is a crucial factor. While the affinity difference isn't huge, the improved ADME profile of Ligand B, especially the longer half-life and lower clearance, outweighs the slightly weaker binding.

Output:
1
2025-04-17 11:02:25,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.407 and 345.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold for oral absorption, while Ligand B (90.98) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (2.242 and 1.286), 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 within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.8, indicating strong drug-like properties.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (50.446). This is a concern for Ligand A.

**BBB:** Both have similar BBB penetration (74.292 and 72.896), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** 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 very poor aqueous solubility (-4.55 and -2.801). This is a major issue for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.755) shows a slightly higher hERG risk than Ligand B (0.679), but both are relatively low.

**Microsomal Clearance:** Ligand B (-5.994) has significantly lower (better) microsomal clearance than Ligand A (30.593). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-25.231) has a much longer in vitro half-life than Ligand A (67.889), further supporting its superior metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.463 and 0.018).

**Binding Affinity:** Ligand B (-9.8 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 difference threshold.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity, coupled with its superior metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, outweigh the shared issues. The improved affinity is likely to be more impactful for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:02:25,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.447 and 360.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is better than Ligand B (51.02), being closer to the upper limit for good oral absorption (<=140). Lower TPSA generally improves membrane permeability.

**logP:** Ligand A (1.739) is optimal, while Ligand B (3.764) is approaching the higher end of the optimal range. While still acceptable, 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 acceptable QED values (0.869 and 0.755, respectively), indicating good drug-like properties.

**DILI:** Ligand A (54.556) has a slightly higher DILI risk than Ligand B (47.693), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (73.943 and 81.233), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.393) has worse Caco-2 permeability than Ligand B (-4.902), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.395) has slightly better aqueous solubility than Ligand B (-4.244), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.157) has a much lower hERG inhibition liability than Ligand B (0.415), a significant advantage.

**Microsomal Clearance:** Ligand A (19.106 mL/min/kg) has significantly lower microsomal clearance than Ligand B (82.646 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.874 hours) has a much longer in vitro half-life than Ligand B (14.92 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux than Ligand B (0.479), improving bioavailability.

**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, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having better solubility and lower hERG risk, the significantly stronger binding affinity of Ligand B (-8.6 vs -7.1 kcal/mol) and its better metabolic stability (lower Cl_mic and longer t1/2) are decisive. The difference in binding affinity is substantial enough to compensate for the slightly higher logP and P-gp efflux.

Output:
1
2025-04-17 11:02:25,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.5) is slightly higher, but acceptable.

**TPSA:** Both are reasonably low (A: 113.08, B: 121.22), suggesting good potential for cell permeability, though below 90 is preferred for CNS targets (not relevant here).

**logP:** Ligand A (2.161) is optimal. Ligand B (-1.357) is quite low, potentially hindering permeability and absorption.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 7 HBA, which are within acceptable limits.

**QED:** Both have good QED scores (A: 0.552, B: 0.612), indicating drug-like properties.

**DILI:** Ligand A (96.006) has a high DILI risk, which is a significant concern. Ligand B (71.345) is also elevated, but less so.

**BBB:** Not a primary concern for a non-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, again unusual. This suggests poor solubility. Ligand B is slightly better (-1.641 vs -3.48).

**hERG Inhibition:** Ligand A (0.682) has a slightly higher hERG risk than Ligand B (0.071). Lower is better, so B is preferable here.

**Microsomal Clearance:** Ligand B (-20.244) has significantly lower (better) microsomal clearance than Ligand A (72.042), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-33.097) has a longer in vitro half-life than Ligand A (46.401), which is desirable.

**P-gp Efflux:** Ligand A (0.174) has lower P-gp efflux than Ligand B (0.004), which is preferable.

**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 ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, its high DILI risk and higher microsomal clearance are significant drawbacks. Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life, lower hERG), but its binding affinity is considerably weaker and its logP is problematic.

Given the substantial difference in binding affinity, I believe Ligand A is the more promising candidate *despite* the DILI risk. The potency advantage is large enough that further optimization could potentially address the DILI issue. It's easier to modify a molecule to reduce toxicity than to significantly improve its binding affinity.

Output:
1
2025-04-17 11:02:25,536 - INFO - Batch 14 complete. Total preferences: 224
2025-04-17 11:02:25,536 - INFO - Processing batch 15/512...
2025-04-17 11:03:09,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.4 and 376.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.36) is slightly higher than Ligand B (79.42), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.277) is quite low, potentially hindering permeation. Ligand B (3.76) 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, 7 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.703 and 0.755), indicating generally drug-like properties.

**DILI:** Ligand A (43.7) has a lower DILI risk than Ligand B (69.3), which is preferable.

**BBB:** Both ligands have reasonable BBB penetration (77.9% and 71.8%), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, making it difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility 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 (0.387 and 0.351), which is excellent.

**Microsomal Clearance:** Ligand A (4.46) has significantly lower microsomal clearance than Ligand B (59.36), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (2.97) has a shorter half-life than Ligand B (20.04), reinforcing the metabolic stability advantage of Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.512).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 1.2 kcal/mol difference, which is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a much better logP and significantly higher binding affinity. However, it suffers from higher DILI risk, substantially higher microsomal clearance, and a shorter half-life. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, but its logP is concerningly low. The affinity difference is substantial. Given the importance of potency for kinase inhibitors, and the fact that the metabolic liabilities of Ligand B *might* be addressable through structural modifications, Ligand B is the more promising candidate.

Output:
1
2025-04-17 11:03:09,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (392.94 and 346.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.91) is better than Ligand B (76.58), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands have good logP values (4.05 and 2.29), falling within the 1-3 optimal range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand B (0.919) has a significantly higher QED score than Ligand A (0.594), indicating a more drug-like profile.

**DILI:** Ligand B (69.68) has a much lower DILI risk than Ligand A (84.30), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (81.23) is slightly better than Ligand B (75.11).

**Caco-2 Permeability:** Ligand A (-5.477) has a worse Caco-2 permeability than Ligand B (-4.439), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.667) has worse aqueous solubility than Ligand B (-2.933).

**hERG Inhibition:** Ligand B (0.19) has a much lower hERG inhibition liability than Ligand A (0.811), a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (96.82) has higher microsomal clearance than Ligand B (42.67), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-2.41) has a better in vitro half-life than Ligand A (88.99), indicating better stability.

**P-gp Efflux:** Ligand A (0.824) has higher P-gp efflux liability than Ligand B (0.032).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is clearly the superior candidate. It has a significantly better binding affinity, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, better t1/2), better solubility, and a higher QED score. While Ligand A has slightly better BBB penetration, this is not a priority for SRC kinase, and is outweighed by the numerous advantages of Ligand B.

Output:
1
2025-04-17 11:03:09,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.4 and 364.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (66.4) is well within the ideal range.

**logP:** Ligand A (-0.53) is a bit low, potentially hindering permeation. Ligand B (2.673) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

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

**QED:** Both ligands have good QED scores (A: 0.629, B: 0.746), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 41.4, B: 47.9), being below the 60 threshold.

**BBB:** Ligand A (26.5) has a low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (79.1) has good BBB penetration, but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.064 and -4.887), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.424 and -3.125), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.044) has very low hERG risk, which is excellent. Ligand B (0.371) also has low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-2.291) has negative clearance, which is not physically possible and likely indicates a data error or a very stable compound. Ligand B (58.4) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-11.015) has negative half-life, which is not physically possible and likely indicates a data error. Ligand B (4.816) has a short half-life, which is not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.088, B: 0.384), which is favorable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the poor solubility and permeability for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.3 vs -6.3 kcal/mol) is a major advantage for an enzyme inhibitor, and can potentially offset the ADME liabilities. The negative values for clearance and half-life for ligand A are concerning and likely errors, but the binding affinity is so much better that it still appears to be the better option. Ligand B has a higher clearance and shorter half-life, making it less desirable.

Output:
0
2025-04-17 11:03:09,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.435 Da and 338.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.76) is slightly above the optimal <140 for good oral absorption, but still reasonable. Ligand B (70.07) is excellent, well below 140.

**logP:** Ligand A (-0.546) is a bit low, potentially hindering permeability. Ligand B (3.727) is very good, within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) and Ligand B (3) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (5) meet the <=10 criteria.

**QED:** Both ligands have acceptable QED values (0.414 and 0.53), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (56.727), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (80.031) has better BBB penetration, but it's not a primary concern here.

**Caco-2 Permeability:** Both have negative values (-5.482 and -5.051), which is unusual and suggests poor permeability. This is a potential issue for both, but the scale is unclear.

**Aqueous Solubility:** Both have negative values (-1.253 and -4.03), again unusual and suggesting poor solubility. This is a significant concern for both compounds, but Ligand B appears worse.

**hERG Inhibition:** Ligand A (0.056) shows very low hERG inhibition risk, a major advantage. Ligand B (0.919) has a higher, though not alarming, risk.

**Microsomal Clearance:** Ligand A (13.467) has much lower microsomal clearance than Ligand B (69.218), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (34.465) has a significantly longer half-life than Ligand A (2.138). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is favorable. Ligand B (0.409) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9.1) has a substantially stronger binding affinity than Ligand B (-0.0). This is the most important factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand A is the stronger candidate. Despite the concerning negative Caco-2 and solubility values (which need further investigation), its significantly superior binding affinity (-9.1 vs -0.0 kcal/mol) and lower DILI and microsomal clearance outweigh the drawbacks. The low hERG risk is also a significant benefit. Ligand B has a better half-life and logP, but its much weaker binding affinity and higher DILI risk make it less promising. The solubility and permeability issues for both are red flags that would require addressing in further optimization, but the potency of A is a strong starting point.

Output:
0
2025-04-17 11:03:09,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.427 and 354.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (69.64) is well within the ideal range.

**logP:** Both ligands have good logP values (1.957 and 2.965), 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 good QED scores (0.629 and 0.704), indicating good drug-like properties.

**DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (8.647), which is a major advantage.

**BBB:** Both ligands have moderate BBB penetration, with Ligand B (70.686) being slightly better than Ligand A (59.325). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.679 and -4.6), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.679 and -3.13), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.1) has a much lower hERG inhibition liability than Ligand B (0.607), which is a critical advantage.

**Microsomal Clearance:** Ligand B (67.31) has a much higher microsomal clearance than Ligand A (8.57), indicating poorer metabolic stability. This is a significant disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-11.313) has a negative half-life, which is not physically possible and suggests an issue with the data or the model. Ligand B (-5.162) also has a negative half-life. Both are concerning.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.021 and 0.055).

**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 notable, but not overwhelmingly decisive.

**Overall Assessment:**

Ligand A is the better candidate despite the negative Caco-2 and solubility values. Its significantly lower DILI risk and hERG inhibition liability, coupled with much better metabolic stability (lower Cl_mic), outweigh the slightly weaker binding affinity and the questionable half-life value. The negative half-life values for both compounds are concerning and require further investigation, but the other ADME properties of Ligand A are more favorable. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the safety profile of Ligand A is more promising.

Output:
0
2025-04-17 11:03:09,066 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [363.443, 102.05 ,   1.377,   2.   ,   7.   ,   0.721,  71.074,  59.325, -5.334,  -3.474,   0.161,  42.34 , -10.259,   0.118,  -8.1  ]
**Ligand B:** [369.487,  89.95 ,   0.265,   2.   ,   6.   ,   0.748,  30.787,  30.593, -5.6  ,  -1.156,   0.371, -18.504,  -3.14 ,   0.008,  -8.9  ]

**Step-by-step comparison:**

1. **MW:** Both ligands (363.443 & 369.487 Da) fall within the ideal 200-500 Da range.
2. **TPSA:** Ligand A (102.05) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (89.95) is well within the ideal range.
3. **logP:** Both ligands have acceptable logP values (1.377 & 0.265), falling within the 1-3 range. Ligand A is slightly better.
4. **HBD:** Both have 2 HBD, which is good.
5. **HBA:** 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 (0.721 & 0.748), indicating good drug-like properties.
7. **DILI:** Ligand A (71.074) has a higher DILI risk than Ligand B (30.787). This is a significant concern.
8. **BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand A (59.325) is slightly better than Ligand B (30.593).
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 have very low hERG risk (0.161 & 0.371).
12. **Cl_mic:** Ligand B (-18.504) has significantly lower (better) microsomal clearance than Ligand A (42.34). This suggests better metabolic stability for Ligand B.
13. **t1/2:** Ligand B (-3.14) has a longer in vitro half-life than Ligand A (-10.259), which is a positive attribute.
14. **Pgp:** Both have very low Pgp efflux liability (0.118 & 0.008).
15. **Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.1).

**Enzyme-Kinase Specific Considerations:**

For SRC kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the significantly lower DILI risk and improved metabolic profile of Ligand B are more important for an enzyme target.

**Conclusion:**

Considering all factors, especially the lower DILI risk and better metabolic stability, **Ligand B** is the more promising drug candidate.

Output:
1
2025-04-17 11:03:09,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.381 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (379.913 Da) is still well within the acceptable range.

**TPSA:** Ligand A (47.09) is excellent, well below the 140 threshold for good oral absorption. Ligand B (71.09) is higher but still reasonable.

**logP:** Both ligands have good logP values (A: 3.294, B: 4.071), falling within the optimal 1-3 range, though B is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) is better than Ligand B (HBD=2, HBA=4) in terms of these parameters, promoting better permeability.

**QED:** Both ligands have similar, acceptable QED values (A: 0.727, B: 0.711).

**DILI:** Ligand A (43.195) has a significantly lower DILI risk than Ligand B (77.782). This is a major advantage for Ligand A.

**BBB:** Ligand A (97.712) has much better BBB penetration potential than Ligand B (52.656). While SRC is not necessarily a CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.873) shows poor Caco-2 permeability, while Ligand B (-5.062) is also poor. Both are significantly negative, indicating a potential absorption issue.

**Aqueous Solubility:** Ligand A (-2.371) has better solubility than Ligand B (-5.149). Solubility is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.945, B: 0.719), which is excellent.

**Microsomal Clearance:** Ligand A (33.049) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (74.676). This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (-17.005) has a negative half-life, which is concerning and likely an error or outlier. Ligand B (46.382) has a reasonable in vitro half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.698, B: 0.492).

**Binding Affinity:** Ligand B (-7.8 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 A has better ADME properties across the board (DILI, BBB, solubility, metabolic stability, H-bonds) except for the concerning negative half-life. Ligand B has superior binding affinity, which is the most important factor for an enzyme inhibitor. However, its higher DILI risk and poorer metabolic stability are concerning. The negative half-life for Ligand A is a major red flag.

Despite the superior affinity of Ligand B, the combination of lower DILI, better solubility, and metabolic stability of Ligand A, *if the half-life issue can be resolved or is an error*, makes it a more promising starting point for optimization. However, given the negative half-life, and the substantial affinity advantage of Ligand B, I will select Ligand B.

Output:
1
2025-04-17 11:03:09,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (347.503 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.13) is significantly better than Ligand B (74.69). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**3. logP:** Ligand A (3.175) is slightly better than Ligand B (1.89), both are within the optimal range of 1-3. Ligand B is at the lower end, 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 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Ligand A (0.674) has a slightly better QED score than Ligand B (0.527), indicating a more drug-like profile.

**7. DILI:** Ligand A (25.204) has a significantly lower DILI risk than Ligand B (22.683), which is a crucial advantage.

**8. BBB:** Ligand A (70.919) has a better BBB percentile than Ligand B (51.842), although BBB isn't a primary concern for most kinase inhibitors unless CNS penetration is specifically desired.

**9. Caco-2:** Ligand A (-4.758) has a worse Caco-2 permeability than Ligand B (-5.086). Lower values indicate lower permeability, so Ligand B is slightly better here.

**10. Solubility:** Ligand A (-3.218) has better solubility than Ligand B (-1.693), which is a significant advantage for bioavailability.

**11. hERG:** Both ligands have similar hERG inhibition liability (0.696 and 0.673), and are within acceptable ranges.

**12. Cl_mic:** Ligand A (48.947) has slightly better microsomal clearance than Ligand B (46.216), indicating better metabolic stability.

**13. t1/2:** Ligand B (35.355) has a significantly longer in vitro half-life than Ligand A (13.759), which is a major advantage.

**14. Pgp:** Both ligands have similar P-gp efflux liability (0.394 and 0.232).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.7 and -8.5 kcal/mol), which are both excellent. The difference is negligible.

**Overall Assessment:**

Ligand A excels in most key ADME properties (TPSA, logP, DILI, Solubility, Cl_mic) and has a better QED score. While Ligand B has a longer half-life and slightly better Caco-2 permeability, the superior safety profile (lower DILI) and better overall drug-likeness of Ligand A outweigh these benefits. The binding affinity is essentially the same for both. Given the enzyme-kinase target class, metabolic stability and solubility are important, and Ligand A is better in these aspects.

Output:
1
2025-04-17 11:03:09,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk, as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.443 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is better than Ligand B (83.55), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.141 and 1.211), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.819 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (26.755). This is a major advantage.

**BBB:** Both have moderate BBB penetration (66.77 and 61.535), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.626) has a worse Caco-2 permeability than Ligand B (-5.037), both are quite poor.

**Aqueous Solubility:** Ligand A (-1.702) has better aqueous solubility than Ligand B (-2.148).

**hERG:** Both ligands have very low hERG inhibition liability (0.41 and 0.188), which is excellent.

**Microsomal Clearance:** Ligand A (34.818) has higher microsomal clearance than Ligand B (15.003), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (37.591) has a longer in vitro half-life than Ligand B (14.663), which is a positive.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.095 and 0.019).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This difference of 1.4 kcal/mol is substantial and can outweigh some ADME concerns.

**Conclusion:**

While Ligand A has better solubility and a lower DILI risk, Ligand B's significantly stronger binding affinity (-9.4 vs -8.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are more crucial for an enzyme target like SRC kinase. The difference in binding affinity is large enough to compensate for the slightly higher DILI risk.

Output:
1
2025-04-17 11:03:09,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.414 and 351.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.86) is well below the 140 threshold for good absorption, and favorable. Ligand B (117.86) is still within acceptable range, but less optimal.

**logP:** Ligand A (2.122) is within the optimal 1-3 range. Ligand B (-0.65) is below 1, potentially indicating permeability issues.

**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.

**QED:** Both ligands have reasonable QED scores (0.781 and 0.566), indicating good drug-like properties.

**DILI:** Ligand A (63.629) has a slightly higher DILI risk than Ligand B (57.154), but both are still within an acceptable range (<60 is good).

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (31.834) and Ligand B (42.846) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.889 and -4.898), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.509 and -1.283), indicating poor aqueous solubility. This is also a significant concern.

**hERG Inhibition:** Ligand A (0.671) has a slightly higher hERG risk than Ligand B (0.038). This is a favorable point for Ligand B.

**Microsomal Clearance:** Ligand A (54.247) has a higher microsomal clearance than Ligand B (24.663), suggesting lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-4.028) has a shorter in vitro half-life than Ligand B (0.714), reinforcing the metabolic stability advantage of Ligand B.

**P-gp Efflux:** Ligand A (0.56) has slightly higher P-gp efflux liability than Ligand B (0.011), which is better for bioavailability.

**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 drawbacks.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.5 vs -8.2 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. While the logP is suboptimal, the strong binding affinity and improved ADME properties make Ligand B the better choice.

Output:
1
2025-04-17 11:03:09,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.547 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (101.74) is still within acceptable limits, but less optimal than A.

**logP:** Ligand A (4.205) is slightly high, potentially causing solubility issues or off-target effects. Ligand B (1.413) is within the optimal range of 1-3.

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

**QED:** Both ligands have good QED scores (0.58 and 0.745, respectively), indicating drug-like properties.

**DILI:** Ligand A (31.097) has a very favorable DILI score, indicating low liver injury risk. Ligand B (65.491) is higher, suggesting a moderate risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.143) is good, while Ligand B (65.219) is moderate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.66 and -4.737), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.171 and -2.0), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.359) has a very low hERG risk, which is excellent. Ligand B (0.094) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (82.642) has a relatively high microsomal clearance, suggesting faster metabolism and lower metabolic stability. Ligand B (19.894) has a much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.479) has a moderate half-life. Ligand B (-9.749) has a negative half-life, which is not physically possible and indicates a problem with the data or prediction.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.323 and 0.078).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite both ligands having significant solubility and permeability issues (negative Caco-2 and solubility values), Ligand A is the more promising candidate. Its superior binding affinity (-8.6 vs -7.3 kcal/mol) is a major advantage for an enzyme target. It also has a much better DILI score and a lower hERG risk. While its metabolic stability is worse than Ligand B, the strong binding affinity could allow for a lower dose, potentially mitigating the impact of faster metabolism. The negative half-life for Ligand B is a red flag and makes it less reliable.

Output:
0
2025-04-17 11:03:09,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.451 and 344.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is slightly higher than Ligand B (68.84). While both are reasonably low, Ligand B is better positioned for good oral absorption.

**logP:** Ligand A (0.635) is a bit low, potentially hindering permeation. Ligand B (1.934) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are acceptable, but Ligand B's lower HBD count might be slightly favorable for permeability.

**QED:** Both ligands have good QED scores (0.591 and 0.77), indicating good drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (33.501 and 34.238), which is positive.

**BBB:** Ligand B (70.686) has a better BBB percentile than Ligand A (51.415), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.937 and -4.932). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.512 and -0.892). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG risk (0.229 and 0.212), which is excellent.

**Microsomal Clearance:** Ligand A (24.253 mL/min/kg) has a lower microsomal clearance than Ligand B (41.063 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-23.698 hours) has a much longer in vitro half-life than Ligand B (-5.985 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.173).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.0 and -8.2 kcal/mol).

**Conclusion:**

While both ligands have good potency and low toxicity, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic) and longer half-life. The slightly lower logP and higher TPSA of Ligand A are less concerning given the strong binding affinity and the fact that SRC is not a CNS target. The poor Caco-2 and solubility are shared drawbacks that would need to be addressed in further optimization, but the pharmacokinetic advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 11:03:09,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.39 and 353.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.59) is significantly better than Ligand B (88.91). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (1.882 and 1.236), 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.

**QED:** Both ligands have acceptable QED scores (0.747 and 0.699), indicating good drug-likeness.

**DILI:** Ligand A (38.387) has a lower DILI risk than Ligand B (41.411), which is favorable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (88.29) has better BBB penetration than Ligand B (73.633), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.411) has better Caco-2 permeability than Ligand B (-4.982).

**Aqueous Solubility:** Ligand A (-2.79) has better aqueous solubility than Ligand B (-2.402). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.875) has a lower hERG inhibition liability than Ligand B (0.082), which is a significant advantage regarding cardiotoxicity.

**Microsomal Clearance:** Ligand A (98.113) has a *much* higher microsomal clearance than Ligand B (20.429). This means Ligand B is significantly more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (8.202) has a longer half-life than Ligand B (2.837).

**P-gp Efflux:** Ligand A (0.286) has lower P-gp efflux than Ligand B (0.044), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-9) has a slightly better binding affinity than Ligand A (-8). However, the difference is only 1 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all other critical ADME properties. The most significant advantage of Ligand A is its much lower hERG inhibition risk. Ligand B's significantly higher microsomal clearance is a major drawback for a kinase inhibitor, potentially leading to rapid metabolism and reduced efficacy. Ligand A also demonstrates better solubility, permeability, and lower DILI risk. The 1 kcal/mol difference in binding affinity is unlikely to outweigh these substantial ADME advantages.

Output:
0
2025-04-17 11:03:09,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 354.361 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.76) is better than Ligand B (93.01), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.706) is optimal (1-3), while Ligand B (-0.002) is below 1, which could hinder permeation. This is a significant advantage for A.

**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 acceptable (<=10).

**QED:** Both ligands have similar QED values (0.827 and 0.821), indicating good drug-likeness.

**DILI:** Ligand A (49.593) has a lower DILI risk than Ligand B (54.401), both are below the 60 threshold.

**BBB:** Both ligands have high BBB penetration (79.294 and 86.39), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.299) has worse Caco-2 permeability than Ligand B (-5.079), but both are negative values which is not ideal.

**Aqueous Solubility:** Ligand A (-3.043) has worse solubility than Ligand B (-1.823), but both are negative values which is not ideal.

**hERG:** Both ligands have very low hERG risk (0.389 and 0.043).

**Microsomal Clearance:** Ligand A (86.138) has significantly higher microsomal clearance than Ligand B (6.414). This indicates lower metabolic stability for A, a major drawback for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (1.005) has a longer half-life than Ligand A (-30.21), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.029).

**Binding Affinity:** Ligand A (-7.9) has slightly better binding affinity than Ligand B (-7.7). However, the 0.2 kcal/mol difference is unlikely to overcome the significant ADME deficiencies of Ligand A.

**Conclusion:**

Despite slightly better binding affinity, Ligand A has significant drawbacks in logP, microsomal clearance, and in vitro half-life. Ligand B, while having a slightly weaker affinity, possesses a more favorable ADME profile, particularly its significantly improved metabolic stability (lower Cl_mic and longer t1/2). For an enzyme inhibitor, metabolic stability is crucial. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 11:03:09,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.495 and 351.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.03) is higher than Ligand B (52.65). While both are reasonably low, Ligand B is better positioned for good oral absorption.

**logP:** Both ligands have similar logP values (2.657 and 2.653), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is also acceptable (<=10).

**QED:** Ligand A (0.878) has a significantly higher QED score than Ligand B (0.749), suggesting a more drug-like profile.

**DILI:** Ligand A (56.96) has a higher DILI risk than Ligand B (8.298). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (72.237 and 70.531), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.362) has worse Caco-2 permeability than Ligand B (-4.926), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.311) has worse aqueous solubility than Ligand B (-1.079). Solubility is important for bioavailability, favoring Ligand B.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.618 and 0.704), indicating a moderate risk.

**Microsomal Clearance:** Ligand A (55.466) has significantly higher microsomal clearance than Ligand B (18.932). This suggests Ligand B is more metabolically stable, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (-3.516 and -3.661).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.404 and 0.103).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.8 kcal/mol), with a negligible difference.

**Conclusion:**

While Ligand A has a better QED score, Ligand B is superior overall due to its lower DILI risk, better solubility, and significantly improved metabolic stability (lower Cl_mic). The similar binding affinities make the ADME properties the deciding factors. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are paramount.

Output:
1
2025-04-17 11:03:09,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 369.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is better than Ligand B (61.88), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (1.238 and 1.819) are within the optimal 1-3 range.

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

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

**QED:** Ligand A (0.808) has a better QED score than Ligand B (0.742), indicating a more drug-like profile.

**DILI:** Ligand A (13.339) has a significantly lower DILI risk than Ligand B (28.306), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.627) is better than Ligand B (55.176).

**Caco-2 Permeability:** Ligand A (-4.619) is better than Ligand B (-5.167), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (0.156) is better than Ligand B (-1.564). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands (0.623 and 0.266) have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (22.506) has lower microsomal clearance than Ligand B (32.442), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.853) has a longer in vitro half-life than Ligand B (12.237), which is desirable.

**P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux than Ligand B (0.048), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.5 and -8.7 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is superior to Ligand B. While the binding affinities are comparable, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. These factors collectively make Ligand A a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 11:03:09,067 - INFO - Batch 15 complete. Total preferences: 240
2025-04-17 11:03:09,067 - INFO - Processing batch 16/512...
2025-04-17 11:03:50,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (340.427 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.49) is better than Ligand B (104.46). Both are below 140, but A is closer to the optimal for oral absorption.

**3. logP:** Both ligands have good logP values (2.212 and 1.659), 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, while Ligand B has 5. Both are within the acceptable range of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.78 and 0.628), indicating good drug-like properties.

**7. DILI:** Ligand A (52.23) has a slightly higher DILI risk than Ligand B (44.591), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.411) is slightly better than Ligand B (56.999).

**9. Caco-2 Permeability:** Both have negative values (-5.23 and -4.9). 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 relative difference.

**10. Aqueous Solubility:** Both have negative values (-3.138 and -1.569). Similar to Caco-2, these are on a scale where negative values are possible. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.663) has a slightly higher hERG risk than Ligand B (0.177). This is a significant advantage for Ligand B.

**12. Microsomal Clearance:** Ligand A (66.057) has a higher microsomal clearance than Ligand B (35.308), indicating lower metabolic stability. This is a key disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-29.538) has a much longer in vitro half-life than Ligand A (12.157). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.146 and 0.164).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a 0.8 kcal/mol difference, which is substantial and 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 metabolic stability (lower Cl_mic, longer t1/2) and hERG risk. The difference in binding affinity (0.8 kcal/mol) is significant, but the improved pharmacokinetic properties of Ligand B are crucial for a kinase inhibitor, where sustained target engagement is important. The solubility and permeability issues are present in both, but the better metabolic profile of Ligand B makes it more likely to achieve therapeutic concentrations *in vivo*.

Output:
1
2025-04-17 11:03:50,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.343 and 337.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.8) is better than Ligand B (64.84), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.212 and 3.331), falling within the 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 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 good QED scores (0.619 and 0.927), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (84.917) has a higher DILI risk than Ligand B (63.862). This is a significant negative for Ligand A.

**BBB:** Ligand A (46.568) has a lower BBB penetration percentile than Ligand B (91.392). While not crucial for a non-CNS target like SRC, higher BBB is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.801) has worse Caco-2 permeability than Ligand B (-4.872). Both are negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.86 and -4.866). This is a major concern for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.453) has a slightly lower hERG inhibition risk than Ligand B (0.973), which is favorable.

**Microsomal Clearance:** Ligand A (25.107) has a significantly lower microsomal clearance than Ligand B (72.795), indicating better metabolic stability. This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (15.921) has a shorter in vitro half-life than Ligand B (22.693).

**P-gp Efflux:** Ligand A (0.028) has much lower P-gp efflux liability than Ligand B (0.34). This is a positive for Ligand A, suggesting better oral bioavailability.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic) and lower P-gp efflux. However, it has a higher DILI risk, worse Caco-2 permeability, and a shorter half-life. Ligand B has better solubility, QED, and BBB penetration, but weaker binding affinity and poorer metabolic stability.

Given that we are targeting an enzyme (SRC kinase), potency (binding affinity) and metabolic stability are paramount. The 1.4 kcal/mol difference in binding affinity is substantial. While the solubility and DILI of Ligand A are concerning, these can potentially be addressed through formulation strategies or further chemical modifications. The improved metabolic stability is also a key advantage.

Output:
0
2025-04-17 11:03:50,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.53 and 339.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (75.44). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands have a logP around 2 (1.925 and 1.999), which is optimal.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have similar QED scores (0.863 and 0.846), indicating good drug-likeness.

**DILI:** Ligand A (22.84) has a much lower DILI risk than Ligand B (44.05), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (63.16) is better than Ligand B (45.83).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.997 and -5.079), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.093 and -2.534), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Ligand A (0.674) has a slightly higher hERG risk than Ligand B (0.082). This favors Ligand B.

**Microsomal Clearance:** Ligand A (16.06 mL/min/kg) has significantly lower microsomal clearance than Ligand B (42.37 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (10.75 hours) has a much longer half-life than Ligand B (1.74 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.133 and 0.057).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.9 kcal/mol). While both are good, the 0.7 kcal/mol difference is noticeable.

**Overall:**

Ligand A is superior despite the poor solubility and permeability. The significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity outweigh the hERG risk. The poor solubility and permeability would need to be addressed through formulation or structural modifications, but the favorable safety and PK properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 11:03:50,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.387 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.78) is slightly higher than Ligand B (98.32). Both are acceptable, being under 140, but Ligand B is preferable.

**logP:** Ligand A (0.482) is a bit low, potentially hindering permeability. Ligand B (0.61) is also low, but slightly better. Both are below the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10, with Ligand B being slightly better.

**QED:** Ligand B (0.674) has a better QED score than Ligand A (0.442), indicating a more drug-like profile.

**DILI:** Ligand A (37.224) has a significantly lower DILI risk than Ligand B (15.122). This is a major advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration (23.149 and 29.701, respectively), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.217 and -5.467), indicating very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.7 and -1.592), indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.046) has a much lower hERG inhibition risk than Ligand B (0.144), which is a crucial advantage.

**Microsomal Clearance:** Ligand B (-9.633) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand A (2.89) has a positive clearance, indicating faster metabolism. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-21.02) has a very long half-life, while Ligand A (-15.599) has a shorter one. This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.013).

**Binding Affinity:** Ligand B (-8.4 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:**

Ligand A has advantages in DILI and hERG risk, which are important safety parameters. However, Ligand B excels in metabolic stability (Cl_mic, t1/2), QED, and binding affinity, all of which are critical for an enzyme inhibitor. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. Given the strong advantages of Ligand B in potency and metabolic stability, it is the more promising candidate.

Output:
1
2025-04-17 11:03:50,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (371.503 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.32) is slightly above the preferred <140, but acceptable. Ligand B (66.48) is well within the range.

**3. logP:** Ligand A (-0.508) is a bit low, potentially hindering permeability. Ligand B (2.949) is optimal.

**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 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.678 and 0.513, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (26.871) has a significantly lower DILI risk than Ligand B (35.712), which is a strong advantage. Both are below the 40 threshold.

**8. BBB:** Ligand A (41.605) has lower BBB penetration than Ligand B (71.811). However, SRC is not a CNS target, so this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.004) has poor Caco-2 permeability, which is a concern. Ligand B (-4.501) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.275) has poor aqueous solubility. Ligand B (-3.551) is even worse. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.349 and 0.422, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand A (12.463) has a much lower Cl_mic than Ligand B (57.45), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.512) has a longer half-life than Ligand B (-17.768), which is a positive attribute.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.042 and 0.242, respectively).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.5). While both are excellent, the 0.3 kcal/mol difference is notable.

**Enzyme-Specific Priorities:** For SRC kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison & Decision:**

Ligand A has a better binding affinity, significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer half-life), and a slightly better hERG profile. However, it suffers from poor Caco-2 permeability and solubility, and a lower logP. Ligand B has better logP and BBB penetration (irrelevant here), but worse DILI, Cl_mic, half-life, and slightly lower affinity.

The poor solubility and permeability of both compounds are concerning, but the superior metabolic stability and lower DILI risk of Ligand A, combined with its slightly better affinity, outweigh its drawbacks. Optimization efforts could focus on improving the solubility and permeability of Ligand A.

Output:
1
2025-04-17 11:03:50,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is better than Ligand B (65.2), both are acceptable, being under 140.

**3. logP:** Both ligands have good logP values (2.121 and 3.198), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but not drastically.

**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 (2). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED values (0.796 and 0.831), indicating good drug-like properties.

**7. DILI:** Ligand A (12.796) has a significantly lower DILI risk than Ligand B (27.104). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (71.694 and 77.239). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative values (-4.645 and -4.796). These are percentile scores, so lower is worse. Both are poor.

**10. Aqueous Solubility:** Ligand A (-2.094) is better than Ligand B (-4.311). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.395 and 0.455).

**12. Microsomal Clearance:** Ligand A (33.15) has a lower microsomal clearance than Ligand B (61.067), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (-27.349) has a longer in vitro half-life than Ligand B (-22.867). This is another advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.4 and 0.169).

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.7). However, the difference is 0.5 kcal/mol, and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand A is the more promising candidate. It demonstrates a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and fewer H-bonds. While Ligand B has a slightly better binding affinity, the ADME advantages of Ligand A are more critical for an enzyme inhibitor, especially considering the relatively small difference in binding affinity.

Output:
1
2025-04-17 11:03:50,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.354 Da and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.37) is higher than Ligand B (54.34). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (-0.851) is a bit low, potentially hindering membrane permeability. Ligand B (2.232) is 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 acceptable, but Ligand B has a lower count, which is generally favorable for permeability.

**QED:** Both ligands have good QED scores (0.714 and 0.891), indicating good drug-like properties.

**DILI:** Ligand A (66.964) has a higher DILI risk than Ligand B (24.389). This is a significant concern for Ligand A.

**BBB:** Both have reasonable BBB penetration (77.627 and 66.499), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.218 and -4.891), 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 (-1.752 and -2.839), indicating poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.031) has a very low hERG risk, which is excellent. Ligand B (0.307) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-5.514) has a much lower (better) microsomal clearance than Ligand B (16.685), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (38.036) has a longer half-life than Ligand B (11.555), which is desirable.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, while Ligand B (0.112) has slightly higher efflux.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the better candidate despite its slightly higher hERG and P-gp efflux. Its significantly improved binding affinity (-7.4 vs -9.1 kcal/mol) is the most important factor. It also has a lower DILI risk, better logP, and fewer H-bonds. While both have poor solubility and Caco-2 permeability, the superior potency and safety profile of Ligand B make it more likely to succeed. The better metabolic stability of Ligand A is a plus, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 11:03:50,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.901 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is significantly better than Ligand B (106.94).  A TPSA under 140 is desired for oral absorption, both meet this, but A is much more favorable.

**logP:** Ligand A (3.987) is within the optimal 1-3 range, while Ligand B (0.52) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is better than Ligand B (HBD=3, HBA=5) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.778) has a higher QED score than Ligand B (0.56), indicating better overall drug-likeness.

**DILI:** Ligand A (17.642) has a much lower DILI risk than Ligand B (14.928). Both are acceptable, but A is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.833) is better than Ligand B (41.256).

**Caco-2 Permeability:** Ligand A (-4.596) is better than Ligand B (-5.209), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.901) is better than Ligand B (-0.432), which is a significant advantage for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.807) has a much lower hERG risk than Ligand B (0.062). This is a crucial factor, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (-7.539) has a *much* lower (better) microsomal clearance than Ligand A (1.71). This suggests significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-20.448) has a much longer in vitro half-life than Ligand A (20.815), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.441) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). The difference of 1.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2), but suffers from poor logP, solubility, and a concerning hERG risk. Ligand A has a better overall profile with a good balance of properties, a significantly lower hERG risk, better solubility, and a strong binding affinity. The difference in binding affinity is significant enough to overcome the slightly higher Cl_mic of Ligand A. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, hERG), Ligand A is the more promising candidate.

Output:
1
2025-04-17 11:03:50,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 359.539 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is higher than Ligand B (28.6). While both are reasonably low, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have similar logP values (3.911 and 3.945), falling within the optimal range of 1-3.

**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 scores (0.673 and 0.678), indicating good drug-likeness.

**DILI:** Ligand A (39.589) has a slightly higher DILI risk than Ligand B (23.808), but both are below the concerning threshold of 60.

**BBB:** Ligand A (69.446) has a lower BBB penetration percentile than Ligand B (93.331). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.506 and -4.565) which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.256 and -4.339), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.83) has a slightly lower hERG risk than Ligand B (0.934), which is preferable.

**Microsomal Clearance:** Ligand A (87.009) has slightly higher microsomal clearance than Ligand B (84.577), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (19.624) has a slightly longer half-life than Ligand A (17.757).

**P-gp Efflux:** Ligand A (0.354) has lower P-gp efflux than Ligand B (0.835), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having significant solubility and permeability issues, Ligand B is the better candidate. The substantially stronger binding affinity (-7.6 vs -6.9 kcal/mol) is a critical advantage for an enzyme inhibitor. While Ligand A has slightly better hERG and P-gp profiles, the potency difference is more important. The slightly better metabolic stability (lower Cl_mic) and half-life of Ligand B are also positive factors. The poor solubility and permeability would need to be addressed through formulation or further chemical modifications, but the superior potency makes Ligand B the more promising starting point.

Output:
1
2025-04-17 11:03:50,263 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (355.479 and 354.407 Da) fall comfortably within the ideal 200-500 Da range.
2. **TPSA:** Both ligands (101.9 and 100.21) are below the 140 threshold for good oral absorption, which is positive.
3. **logP:** Ligand A (0.005) is very close to 0, which is a slight concern for permeability. Ligand B (-1.221) is also low, but slightly better. Both are below the optimal 1-3 range.
4. **HBD:** Ligand A (4) is at the upper limit of the preferred range, while Ligand B (2) is excellent.
5. **HBA:** Both ligands (5) are within the acceptable limit of 10.
6. **QED:** Both ligands (0.515 and 0.583) are above the 0.5 threshold, indicating good drug-like properties.
7. **DILI:** Ligand A (4.149) has a very low DILI risk, which is excellent. Ligand B (34.858) is higher, but still below the concerning 60 threshold.
8. **BBB:** Both ligands have low BBB penetration. This is not a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.
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, which is also unusual and suggests poor aqueous solubility. This is a significant negative for both.
11. **hERG:** Both ligands (0.1 and 0.11) have very low hERG inhibition risk, which is excellent.
12. **Cl_mic:** Ligand A (-18.136) has a very low (and negative) microsomal clearance, suggesting excellent metabolic stability. Ligand B (-12.803) is also low, but higher than A.
13. **t1/2:** Ligand A (-6.626) has a negative in vitro half-life, which is unusual. Ligand B (6.336) has a positive half-life, which is good.
14. **Pgp:** Both ligands (0.003) have very low P-gp efflux liability, which is positive.
15. **Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.7 kcal/mol). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

Despite the unusual negative values for Caco-2 and solubility, Ligand A is the better candidate. It has a significantly stronger binding affinity (-8.1 vs -9.7 kcal/mol), a much lower (negative) microsomal clearance, and a very low DILI risk. While the negative half-life is concerning, the superior binding and metabolic stability outweigh this drawback. The slightly better HBD count in Ligand B is not enough to compensate for the weaker binding and higher Cl_mic.

Output:
1
2025-04-17 11:03:50,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (377.905 Da) is also good.

**TPSA:** Ligand A (49.85) is excellent, well below the 140 threshold for oral absorption. Ligand B (90.55) is still acceptable, but less optimal.

**logP:** Ligand A (1.912) is within the optimal range (1-3). Ligand B (3.797) is at the higher end, potentially leading to solubility issues or off-target effects, but still within range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable. Ligand B (4 HBD, 7 HBA) is also acceptable, but higher counts could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.662, Ligand B: 0.5), indicating good drug-like properties.

**DILI:** Ligand A (11.283) has a significantly lower DILI risk than Ligand B (76.464), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.162) has a better BBB score than Ligand B (49.011).

**Caco-2 Permeability:** Ligand A (-4.28) has a more negative Caco-2 value, indicating *lower* permeability. Ligand B (-5.395) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-1.631) has better solubility than Ligand B (-4.997).

**hERG Inhibition:** Ligand A (0.304) has a much lower hERG risk than Ligand B (0.695), a critical safety factor.

**Microsomal Clearance:** Ligand A (27.692) has a lower Cl_mic, suggesting better metabolic stability than Ligand B (70.713).

**In vitro Half-Life:** Ligand B (50.981) has a significantly longer half-life than Ligand A (-0.068). This is a substantial advantage for dosing convenience.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (Ligand A: 0.056, Ligand B: 0.193).

**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 likely not enough to overcome its ADME liabilities.

**Overall Assessment:**

Ligand A is superior due to its significantly better safety profile (lower DILI and hERG), better solubility, and improved metabolic stability (lower Cl_mic). While its Caco-2 permeability is poor, the other advantages, particularly the safety profile, outweigh this concern. Ligand B's longer half-life is attractive, but its high DILI and hERG risk are deal-breakers.

Output:
0
2025-04-17 11:03:50,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.515 Da and 358.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.55) is slightly higher than Ligand B (67.87), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.422) is optimal, while Ligand B (1.388) is a bit low, potentially impacting permeability.

**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 ranges.

**QED:** Ligand A (0.82) has a better QED score than Ligand B (0.666), indicating a more drug-like profile.

**DILI:** Ligand B (16.479) has a significantly lower DILI risk than Ligand A (59.015), which is a major advantage.

**BBB:** Ligand A (82.629) has a moderate BBB penetration, while Ligand B (96.2) is very high. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.486 and -4.42), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.8 and -1.872), indicating very poor aqueous solubility, a significant drawback.

**hERG Inhibition:** Ligand A (0.294) has a slightly lower hERG risk than Ligand B (0.672), which is preferable.

**Microsomal Clearance:** Ligand B (15.057 mL/min/kg) has a lower microsomal clearance than Ligand A (19.83 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.156 hours) has a longer in vitro half-life than Ligand A (55.064 hours). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.398) has lower P-gp efflux than Ligand B (0.043), which is preferable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Despite the similar binding affinity, Ligand B is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and higher BBB penetration outweigh the slightly lower logP and QED. The poor solubility and Caco-2 permeability are concerning for both, but can be addressed through formulation strategies. The lower P-gp efflux of Ligand A is a minor advantage, but not enough to overcome the other benefits of Ligand B.

Output:
1
2025-04-17 11:03:50,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.4 and 374.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.5) is well below the 140 threshold, and even preferable for oral absorption. Ligand B (119.4) is still acceptable but higher.

**logP:** Ligand A (3.5) is optimal. Ligand B (-0.7) is significantly below the 1-3 range, which could hinder permeability.

**H-Bond Donors:** Both ligands have 2 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:** Both ligands have QED values above 0.5 (0.709 and 0.521), indicating good drug-likeness.

**DILI:** Ligand A (92.2) has a high DILI risk, which is a significant concern. Ligand B (35.8) has a low DILI risk, which is very favorable.

**BBB:** Both ligands have moderate BBB penetration (44.1 and 47.9), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.9) has poor Caco-2 permeability, likely due to its higher TPSA and lower logP. Ligand B (-5.6) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.8) has poor aqueous solubility. Ligand B (-1.4) has slightly better solubility, but still low.

**hERG Inhibition:** Ligand A (0.6) has a low hERG risk, which is good. Ligand B (0.2) has an even lower hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (73.5) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (11.1) has a much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.8) has a very short half-life, which is undesirable. Ligand B (-10.3) has a longer half-life, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.6 and 0.025), which is favorable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having a better logP and slightly better hERG, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.3 vs -7.3 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). While both have poor Caco-2 permeability and solubility, these can potentially be addressed through formulation strategies. The high DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 11:03:50,264 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (361.467 and 360.841 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.96) is better than Ligand B (51.66), both are below the 140 A^2 threshold for good absorption.

**3. logP:** Both ligands have good logP values (1.729 and 2.983), 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 good QED scores (0.75 and 0.794), indicating good drug-like properties.

**7. DILI:** Ligand A (52.656) has a slightly higher DILI risk than Ligand B (36.409), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (58.24) has a lower BBB penetration than Ligand B (80.535). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.451) has worse Caco-2 permeability than Ligand B (-4.765). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.569) has worse solubility than Ligand B (-3.059). Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.49 and 0.5).

**12. Microsomal Clearance:** Ligand A (36.033) has significantly lower microsomal clearance than Ligand B (63.953), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (51.549) has a significantly longer in vitro half-life than Ligand A (5.062), which is desirable.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.133 and 0.255).

**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 small.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and half-life, Ligand A's significantly lower microsomal clearance (better metabolic stability) and acceptable DILI/hERG profiles outweigh these advantages. Both ligands have poor solubility and permeability, which would need to be addressed during optimization, but metabolic stability is crucial for kinase inhibitors.

Output:
1
2025-04-17 11:03:50,264 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (368.543 and 366.502 Da).

**TPSA:** Ligand A (58.64) is better than Ligand B (49.41) as it is closer to the threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.804 and 3.777), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target effects, but not drastically.

**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 limit of 10.

**QED:** Both ligands have good QED scores (0.728 and 0.862), indicating good drug-like properties.

**DILI:** Ligand A (13.649) has a significantly lower DILI risk than Ligand B (41.411). This is a major advantage for Ligand A.

**BBB:** Ligand B (95.347) has a much higher BBB penetration percentile than Ligand A (76.813). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.879) and Ligand B (-5.084) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.92) and Ligand B (-4.028) both have negative values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.921) has a slightly higher hERG risk than Ligand B (0.778), but both are relatively low.

**Microsomal Clearance:** Ligand A (30.285) has a higher microsomal clearance than Ligand B (24.53). This suggests Ligand B is more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-1.102) has a longer in vitro half-life than Ligand A (-22.6). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux liability than Ligand B (0.543), which is favorable.

**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, potentially outweighing some ADME concerns. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand A has a much better DILI profile and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-10.3 vs -7.3 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are more critical for an enzyme inhibitor like an SRC kinase inhibitor. The slightly higher DILI risk of Ligand B is a concern, but the potency advantage is likely to be more impactful in initial development.

Output:
1
2025-04-17 11:03:50,264 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.483 and 350.346 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.36) is slightly higher than Ligand B (81.75), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.574 and 1.515), 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 within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.825 and 0.784), indicating good drug-like properties.

**DILI:** Ligand A (37.456) has a significantly lower DILI risk than Ligand B (59.907). This is a major advantage for Ligand A.

**BBB:** Ligand B (96.161) has a higher BBB penetration percentile than Ligand A (65.374). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.072) shows poorer Caco-2 permeability than Ligand B (-4.165), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.307 and -2.902). This is a significant concern for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.082) has a lower hERG inhibition liability than Ligand B (0.317), indicating a lower risk of cardiotoxicity. This is a substantial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (8.857) has a lower microsomal clearance than Ligand B (59.404), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-15.882) has a negative half-life, which is not possible. This is a red flag and suggests potential issues with the data or the molecule itself. Ligand A (15.99) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux liability than Ligand B (0.235), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very strong binding affinities (-9.2 and -8.8 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A is the superior candidate. While both have strong binding affinity, Ligand A demonstrates significantly better safety profiles (lower DILI and hERG) and metabolic stability (lower Cl_mic, better t1/2). The slightly poorer Caco-2 permeability of Ligand A is a concern, but potentially manageable. Ligand B's negative half-life is a major issue.

Output:
1
2025-04-17 11:03:50,264 - INFO - Batch 16 complete. Total preferences: 256
2025-04-17 11:03:50,264 - INFO - Processing batch 17/512...
2025-04-17 11:04:28,784 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.449 and 371.84 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.45) is better than Ligand B (65.79). Both are acceptable, but A is closer to the preferred <140 for good absorption.

**logP:** Both ligands have good logP values (2.856 and 1.942), falling within the 1-3 optimal 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 within acceptable limits.

**QED:** Both ligands have good QED scores (0.8 and 0.881), indicating a strong drug-like profile.

**DILI:** Ligand A (40.83) has a slightly higher DILI risk than Ligand B (33.889), but both are below the concerning threshold of 60.

**BBB:** Ligand A (95.89) has significantly better BBB penetration than Ligand B (61.846). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.422) has worse Caco-2 permeability than Ligand B (-4.965). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-3.217) has slightly better aqueous solubility than Ligand B (-2.744). Both are acceptable.

**hERG:** Both ligands have low hERG inhibition liability (0.681 and 0.508), which is good.

**Microsomal Clearance:** This is a critical parameter for enzymes. Ligand A (41.86) has significantly *higher* microsomal clearance than Ligand B (-33.345). This means Ligand B is much more metabolically stable. A negative value for Cl_mic is excellent.

**In vitro Half-Life:** Ligand B (11.107 hours) has a much longer in vitro half-life than Ligand A (-0.011 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.657 and 0.062), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.8 kcal/mol). Ligand A is slightly better (-9.6 kcal/mol), but the difference is relatively small.

**Conclusion:**

While Ligand A has a slightly better binding affinity and BBB penetration, Ligand B is significantly superior in terms of metabolic stability (much lower Cl_mic and longer half-life). Given that SRC is a kinase (enzyme), metabolic stability is a crucial factor. The better solubility of Ligand A is a minor advantage compared to the substantial metabolic benefits of Ligand B. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 11:04:28,785 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 368.587 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (49.41), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (2.511) is within the optimal range of 1-3. Ligand B (3.699) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.751) has a better QED score than Ligand B (0.675), indicating a more drug-like profile.

**DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (24.234). This is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 77.782, Ligand B: 83.249), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**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, indicating poor solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.335) has a lower hERG inhibition liability than Ligand B (0.617), which is a significant advantage regarding cardiotoxicity.

**Microsomal Clearance:** Ligand A (56.839) has a lower microsomal clearance than Ligand B (101.952), suggesting better metabolic stability. This is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-2.373) has a slightly better (less negative) in vitro half-life than Ligand B (-10.27), but both are concerningly low.

**P-gp Efflux:** Ligand A (0.061) has a lower P-gp efflux liability than Ligand B (0.303), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8), but the difference is only 0.3 kcal/mol. Given the other factors, this difference is unlikely to be decisive.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a better QED score, significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), lower P-gp efflux, and a slightly better half-life. While both have poor solubility and permeability, the superior safety and pharmacokinetic properties of Ligand A outweigh the slightly better binding affinity of Ligand B.

Output:
0
2025-04-17 11:04:28,785 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.869 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (75.35 and 75.5) that are acceptable, though pushing the upper limit for optimal oral absorption (<140).

**3. logP:** Both ligands have logP values (2.102 and 2.397) 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 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.74 and 0.773), indicating drug-like properties.

**7. DILI:** Ligand A (32.183) has a significantly lower DILI risk than Ligand B (43.195). This is a major advantage for Ligand A. Both are below the 40 threshold.

**8. BBB:** Ligand A (66.344) has a lower BBB penetration than Ligand B (79.062). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.304) has worse Caco-2 permeability than Ligand B (-4.917), but both are poor.

**10. Aqueous Solubility:** Ligand A (-2.978) has worse aqueous solubility than Ligand B (-3.49). Both are poor, but Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.819) has a slightly higher hERG risk than Ligand B (0.646). Both are reasonably low, but Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (15.968) has significantly lower microsomal clearance than Ligand B (53.535). This indicates better metabolic stability for Ligand A, a crucial factor for enzymes.

**13. In vitro Half-Life:** Ligand A (15.913) has a shorter in vitro half-life than Ligand B (20.508). This is a slight advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.304) has a lower P-gp efflux liability than Ligand B (0.067). Lower efflux is generally better.

**15. Binding Affinity:** Ligand A (-9.3 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 advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. The significantly stronger binding affinity (-9.3 vs -0.0 kcal/mol) is the most important factor. While Ligand A has slightly worse solubility and Caco-2 permeability, the lower DILI risk and significantly better metabolic stability (lower Cl_mic) are also strong positives. The difference in binding affinity is so substantial that it outweighs the minor ADME concerns.

Output:
1
2025-04-17 11:04:28,785 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.386 and 353.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is slightly higher than Ligand B (62.73), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (2.773) is within the optimal 1-3 range. Ligand B (4.751) is higher, potentially leading to solubility issues and off-target effects.

**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 6 HBA. Both are within the acceptable limit of <=10, but Ligand B is approaching the upper end.

**QED:** Both ligands have similar QED values (0.724 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (77.549). This is a negative for Ligand A.

**BBB:** Both ligands have relatively high BBB penetration, but Ligand A (83.404) is better than Ligand B (73.866). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.731) shows better Caco-2 permeability than Ligand B (-5.255).

**Aqueous Solubility:** Ligand A (-4.057) exhibits better aqueous solubility than Ligand B (-4.742).

**hERG:** Ligand A (0.893) has a slightly better hERG profile than Ligand B (0.633), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (54.048) has a significantly lower microsomal clearance than Ligand B (90.875), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (17.087) has a shorter half-life than Ligand B (59.643). This is a negative for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.412 and 0.46).

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

**Conclusion:**

While Ligand A has a shorter half-life and higher DILI risk, it demonstrates superior solubility, permeability, metabolic stability (lower Cl_mic), and a slightly better hERG profile. Ligand B has a longer half-life but suffers from higher logP, potentially impacting solubility and increasing off-target interactions, and a higher Cl_mic, indicating poorer metabolic stability. Given the enzyme-specific priorities, the improved metabolic stability and solubility of Ligand A outweigh its slightly shorter half-life and higher DILI risk, especially considering the similar binding affinities.

Output:
0
2025-04-17 11:04:28,785 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.14) is higher than Ligand B (76.02). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have good logP values (2.573 and 1.813), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.853 and 0.706), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (81.039%) compared to Ligand B (21.908%). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (78.984%) is slightly better than Ligand B (53.276%), but this is not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.714 and -4.791). This is unusual and suggests poor permeability. However, these values are on a log scale and small differences can be significant.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.275 and -3.176). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.088 and 0.057), which is excellent.

**Microsomal Clearance:** Ligand A (69.278) has a higher microsomal clearance than Ligand B (30.013). This indicates lower metabolic stability for Ligand A, which is undesirable.

**In vitro Half-Life:** Ligand B (-16.095) has a longer in vitro half-life than Ligand A (-12.942), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.15 and 0.024).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has slightly better binding affinity than Ligand A (-7.4 kcal/mol), though the difference is small.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both have poor solubility and permeability, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The lower DILI risk and improved metabolic stability are crucial for enzyme targets like SRC kinase.

Output:
1
2025-04-17 11:04:28,786 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.3) is slightly higher than Ligand B (354.491), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (78.53) is slightly higher than Ligand B (70.08), but both are favorable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.788) and Ligand B (1.517) are both good, although Ligand B is a bit lower, which *could* slightly hinder permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within the acceptable limits for good permeability and solubility.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.771, Ligand B: 0.717), indicating good drug-like properties.

**DILI:** Ligand A (54.168) has a moderate DILI risk, while Ligand B (7.794) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 53.276, Ligand B: 53.936). This isn't a primary concern for a non-CNS target like SRC.

**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, again unusual and indicating poor solubility. This is a concern for both, but potentially more so for Ligand A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.422, Ligand B: 0.359). This is good.

**Microsomal Clearance:** Ligand A (66.538) has a higher microsomal clearance than Ligand B (32.231), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (17.42) has a longer in vitro half-life than Ligand A (-18.736). This is a substantial advantage for Ligand B, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.216, Ligand B: 0.088), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.2 kcal/mol, Ligand B: -8.0 kcal/mol). The difference is minimal (0.2 kcal/mol) and doesn't outweigh other factors.

**Conclusion:**

Ligand B is the more promising candidate. While both have similar binding affinity, Ligand B exhibits significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B make it the preferred choice.

Output:
1
2025-04-17 11:04:28,786 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (468.372 Da) is towards the upper end, while Ligand B (354.407 Da) is more favorably positioned.

**TPSA:** Ligand A (106.61) is better than Ligand B (132.7), both are acceptable, but lower is preferred for absorption.

**logP:** Ligand A (2.643) is optimal. Ligand B (-0.008) is quite low, which could hinder membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) is better than Ligand B (HBD=5, HBA=5) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.654) has a better QED score than Ligand B (0.403), indicating a more drug-like profile.

**DILI:** Ligand B (29.624) has a significantly lower DILI risk than Ligand A (98.449), which is a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (61.923) is better than Ligand B (30.787).

**Caco-2 Permeability:** Ligand A (-5.032) is better than Ligand B (-5.602) but both are very low, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.464) is better than Ligand B (-1.093), but both are poor.

**hERG:** Ligand A (0.363) has a much lower hERG risk than Ligand B (0.113), which is a critical advantage.

**Microsomal Clearance:** Ligand A (27.231) has higher clearance than Ligand B (1.888), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (95.428) has a much longer half-life than Ligand B (26.947), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.531) shows lower P-gp efflux than Ligand B (0.013), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a crucial factor, and the 1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A excels in binding affinity, half-life, P-gp efflux, and hERG risk. However, it has poor solubility and permeability. Ligand B has better metabolic stability and a much lower DILI risk, but suffers from poor logP, solubility, permeability, and a weaker binding affinity.

Given the priority for potency (binding affinity) in enzyme inhibition, the significantly stronger binding of Ligand A (-8.5 kcal/mol vs -7.0 kcal/mol) outweighs its ADME drawbacks, *provided* that solubility and permeability can be improved through formulation or further chemical modifications. The hERG risk is also much lower for Ligand A.

Output:
1
2025-04-17 11:04:28,786 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.359 Da and 349.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.71) is better than Ligand B (54.34), being closer to the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (2.888) is optimal (1-3), while Ligand A (0.03) is quite low, potentially hindering permeation.

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

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

**QED:** Both ligands have good QED scores (0.738 and 0.85), indicating drug-likeness.

**DILI:** Ligand B (34.858) has a significantly lower DILI risk than Ligand A (58.511), which is a major advantage.

**BBB:** Ligand B (78.209) has a better BBB penetration score than Ligand A (37.495), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.007) is significantly worse than Ligand B (-4.421) suggesting poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.796) is slightly better than Ligand B (-2.613), but both are quite poor.

**hERG Inhibition:** Ligand A (0.085) has a lower hERG risk than Ligand B (0.3), which is a positive.

**Microsomal Clearance:** Ligand B (31.441) has a much higher microsomal clearance than Ligand A (1.606), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-25.339) has a much longer in vitro half-life than Ligand B (-0.376), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.01) has a lower P-gp efflux liability than Ligand B (0.132), which is favorable.

**Binding Affinity:** Both ligands have comparable binding affinities (-9.4 kcal/mol and -9.2 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite Ligand B having a better logP and lower DILI risk, Ligand A is the more promising candidate. Ligand A's significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better solubility outweigh the lower logP and slightly higher DILI. The binding affinity is comparable. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (like hERG inhibition) are crucial.

Output:
0
2025-04-17 11:04:28,786 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 340.435 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (97.2). A TPSA under 140 is good for oral absorption, and A is well within this, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.99 and 2.124), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.787 and 0.684), indicating good drug-like properties.

**DILI:** Ligand A (25.514) has a much lower DILI risk than Ligand B (64.599). This is a significant advantage for A.

**BBB:** Ligand A (69.794) has a higher BBB penetration percentile than Ligand B (47.46). While not crucial for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.219) has better Caco-2 permeability than Ligand B (-5.908). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.898) has better aqueous solubility than Ligand B (-3.162). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.526) has a lower hERG inhibition liability than Ligand B (0.112). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (27.279) has a significantly lower microsomal clearance than Ligand A (60.802), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-0.046) has a longer in vitro half-life than Ligand A (18.13). This is a positive for B, suggesting less frequent dosing.

**P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux liability than Ligand B (0.156). Lower efflux is generally preferred.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6). While A is still very good, the 1.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. However, Ligand A excels in almost all other ADME properties, particularly DILI risk and hERG inhibition, which are crucial for safety. The significantly lower DILI and hERG risk for Ligand A outweigh the slightly better metabolic stability and affinity of Ligand B.

Output:
0
2025-04-17 11:04:28,786 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.26) is slightly higher than the preferred <140, but acceptable. Ligand B (49.85) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.487 and 2.466), falling within the optimal 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:** Both ligands have reasonable QED scores (0.856 and 0.734), indicating good drug-likeness.

**DILI:** Ligand A (54.634) has a moderate DILI risk, while Ligand B (22.722) has a very low DILI risk, a significant advantage.

**BBB:** Both have acceptable BBB penetration, but Ligand B (78.945) is better than Ligand A (68.282). This isn't a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.055) has poor Caco-2 permeability, which is concerning. Ligand B (-4.458) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.788 and -2.266). This is a potential issue, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.084 and 0.453), which is excellent.

**Microsomal Clearance:** Ligand A (48.946) has lower microsomal clearance than Ligand B (62.825), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-23.603) has a significantly longer in vitro half-life than Ligand B (-9.847), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.057 and 0.397), which is good.

**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, potentially outweighing some of the ADME drawbacks. The difference of 1.6 kcal/mol is quite significant.

**Conclusion:**

While Ligand B has a better safety profile (lower DILI) and slightly better permeability and BBB, Ligand A's significantly superior binding affinity (-8.4 vs -6.8 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme inhibitor. The binding affinity difference is large enough to compensate for the slightly poorer solubility and Caco-2 permeability.

Output:
1
2025-04-17 11:04:28,786 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.474 and 343.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is slightly higher than Ligand B (57.28), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.981) is within the optimal 1-3 range. Ligand B (3.2) is at the higher end of the optimal range, potentially raising concerns about off-target effects, but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.763 and 0.837, respectively), indicating drug-like properties.

**DILI:** Ligand A (26.948) has a significantly lower DILI risk than Ligand B (52.423). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (89.492 and 96.123). While not a primary concern for a kinase inhibitor, it doesn't detract from either.

**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 have negative solubility values, which is also unusual and suggests poor solubility. However, the scale is not defined, so it is difficult to interpret.

**hERG Inhibition:** Ligand A (0.682) has a lower hERG risk than Ligand B (0.948). This is another advantage for Ligand A.

**Microsomal Clearance:** Ligand A (30.286) has a lower microsomal clearance than Ligand B (80.408), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-32.263) has a significantly longer in vitro half-life than Ligand B (29.614). This is a substantial benefit for Ligand A.

**P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.347), indicating better bioavailability.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.0). While both are excellent, the 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have unusual Caco-2 and solubility values, the other advantages of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 11:04:28,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.435 and 363.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (72.08 and 75.44) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.38) is a bit low, potentially hindering permeation. Ligand B (3.194) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent, minimizing potential issues. Ligand B (1) is also acceptable.

**H-Bond Acceptors:** Ligand A (7) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.803 and 0.766), indicating drug-like properties.

**DILI:** Ligand A (34.277) has a much lower DILI risk than Ligand B (56.34), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.815) is lower than Ligand B (37.146).

**Caco-2:** Both ligands have negative Caco-2 values (-5.196 and -5.023), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.709) has slightly better solubility than Ligand B (-3.514). Solubility is important for bioavailability.

**hERG:** Ligand A (0.103) has a much lower hERG risk than Ligand B (0.211), a critical safety parameter.

**Microsomal Clearance:** Ligand A (21.818) has significantly lower microsomal clearance than Ligand B (79.839), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.668) has a shorter half-life than Ligand B (49.031), but still reasonable.

**P-gp efflux:** Both ligands have low P-gp efflux liability (0.019 and 0.066).

**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 a major advantage, potentially outweighing some of the ADME concerns.

**Conclusion:**

Despite the negative Caco-2 values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.3 kcal/mol), lower DILI risk, lower hERG risk, and better metabolic stability (lower Cl_mic) outweigh the slightly lower logP and shorter half-life. The solubility is also slightly better. The Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 11:04:28,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is significantly better than Ligand B (95.5).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.788 and 1.33), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=4). Lower counts are generally preferred for permeability.

**QED:** Ligand A (0.785) has a much better QED score than Ligand B (0.455), indicating a more drug-like profile.

**DILI:** Ligand B (33.307) has a lower DILI risk than Ligand A (13.532), which is a positive. However, both are below the concerning threshold of 60.

**BBB:** Ligand A (89.027) has a significantly higher BBB penetration percentile than Ligand B (43.699). While not a primary concern for a non-CNS target like SRC, it's not a detriment.

**Caco-2 Permeability:** Ligand A (-4.436) has better Caco-2 permeability than Ligand B (-4.937), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.318) has better aqueous solubility than Ligand B (-1.89). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.228 and 0.082).

**Microsomal Clearance:** Ligand B (25.825) has lower microsomal clearance than Ligand A (30.099), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-26.642) has a significantly longer in vitro half-life than Ligand A (-15.413). This is also a crucial advantage for kinase inhibitors, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.047).

**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 and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has superior drug-like properties (QED, TPSA, solubility, permeability) and a good BBB score. However, Ligand B exhibits better metabolic stability (lower Cl_mic, longer t1/2) and a slightly stronger binding affinity. Given that we are targeting a kinase (enzyme), metabolic stability and potency are paramount. The 0.7 kcal/mol difference in binding affinity, coupled with the improved half-life, makes Ligand B the more promising candidate despite its slightly less favorable TPSA and QED.

Output:
1
2025-04-17 11:04:28,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.483 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (47.56 and 46.34) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.858) is optimal, while Ligand B (4.513) is slightly higher, potentially edging towards solubility issues but still acceptable.

**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 (0.603 and 0.585), indicating good drug-likeness.

**DILI:** Ligand A (18.922 percentile) has a significantly lower DILI risk than Ligand B (29.663 percentile). This is a substantial advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (83.288) is better than Ligand B (64.793). While not a primary concern for a kinase inhibitor, it's a slight positive for A.

**Caco-2 Permeability:** Ligand A (-4.344) has better Caco-2 permeability than Ligand B (-5.206).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.063 and -3.909). This could pose formulation challenges, but is not a dealbreaker.

**hERG:** Ligand A (0.605) has a slightly better hERG profile than Ligand B (0.764), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (68.27 mL/min/kg) has significantly lower microsomal clearance than Ligand B (147.567 mL/min/kg). This suggests better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (16.094 hours) has a longer half-life than Ligand A (5.651 hours). This is a positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.193) has lower P-gp efflux than Ligand B (0.744), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand B's superior binding affinity, Ligand A presents a more balanced profile. The lower DILI risk, better metabolic stability (lower Cl_mic), better Caco-2 permeability, and lower P-gp efflux are critical advantages for an enzyme inhibitor. While Ligand B has a longer half-life, the other ADME properties of Ligand A are more favorable, making it a more promising drug candidate.

Output:
0
2025-04-17 11:04:28,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

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

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand A (104.81) is preferable as it's lower.

**logP:** Ligand A (-0.429) is a bit low, potentially hindering permeation. Ligand B (0.469) 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 5 HBA, and Ligand B has 7. Both are within the acceptable limit of 10, but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (A: 0.606, B: 0.644), indicating drug-likeness.

**DILI:** Ligand A (26.444) has a significantly lower DILI risk than Ligand B (57.58), which is a major advantage.

**BBB:** Both have moderate BBB penetration, but it's less critical for a non-CNS target like SRC.

**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, indicating poor solubility. This is a concern, but can sometimes be overcome with formulation.

**hERG Inhibition:** Both have very low hERG inhibition risk (A: 0.044, B: 0.072), which is excellent.

**Microsomal Clearance:** Ligand A (-3.09) has a *much* lower (better) microsomal clearance than Ligand B (-6.287), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-1.522) has a slightly better (less negative) in vitro half-life than Ligand B (-8.055).

**P-gp Efflux:** Both have very low P-gp efflux liability, which is good.

**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 1.4 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a better binding affinity, significantly lower DILI risk, and better metabolic stability (lower Cl_mic and better t1/2). While its logP and solubility are less ideal, the strong binding affinity and favorable safety profile make it a better starting point for optimization. The slight improvements in permeability and solubility could be addressed through structural modifications.

Output:
1
2025-04-17 11:04:28,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.503 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.13) is well below the 140 threshold for oral absorption and favorable. Ligand B (104.19) is still within acceptable range, but less optimal.

**logP:** Ligand A (2.962) is within the optimal 1-3 range. Ligand B (-0.121) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 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 (0.721 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (71.229). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (75.145) has a higher BBB score than Ligand B (27.026), but this is less important.

**Caco-2 Permeability:** Ligand A (-4.582) and Ligand B (-5.119) 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 poor aqueous solubility (-2.914 and -2.64 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.344 and 0.273), which is good.

**Microsomal Clearance:** Ligand B (9.969) has a much lower microsomal clearance than Ligand A (51.721), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-4.173) has a negative half-life, which is not possible. This is a red flag. Ligand A (7.433) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.078 and 0.044), which is favorable.

**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 for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better metabolic stability, but suffers from a potentially problematic negative half-life value. Ligand A has a much lower DILI risk and a reasonable half-life, but its binding affinity is very weak and solubility is poor. The poor solubility of both compounds is a concern. However, the significantly stronger binding affinity of Ligand B is a major advantage for an enzyme target. Given the importance of potency for kinase inhibitors, and assuming the negative half-life for Ligand B is an experimental error, I would choose Ligand B.

Output:
1
2025-04-17 11:04:28,787 - INFO - Batch 17 complete. Total preferences: 272
2025-04-17 11:04:28,787 - INFO - Processing batch 18/512...
2025-04-17 11:05:08,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (409.917 Da) is higher, but still acceptable. Ligand B (347.459 Da) is slightly better.

**TPSA:** Ligand B (71.41) is significantly better than Ligand A (126.64). Lower TPSA generally improves absorption.

**logP:** Ligand B (1.724) is within the optimal range (1-3), while Ligand A (0.288) is quite low, potentially hindering membrane 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.

**QED:** Both ligands have reasonable QED values (A: 0.669, B: 0.575), indicating good drug-like properties.

**DILI:** Ligand B (30.787) has a much lower DILI risk than Ligand A (65.491). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (57.736) is higher than Ligand A (38.813), but not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.653) and Ligand B (-4.81) 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 (-2.814) and Ligand B (-1.202) both have negative values, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.074) has a slightly lower hERG risk than Ligand B (0.355), which is preferable.

**Microsomal Clearance:** Ligand A (-8.661) has a much lower (better) microsomal clearance than Ligand B (50.559), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (13.462 hours) has a significantly longer half-life than Ligand B (-0.154 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux than Ligand B (0.205), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-10.4 kcal/mol and -8.5 kcal/mol respectively). Ligand A is significantly better.

**Overall Assessment:**

Ligand A has a superior binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly lower hERG risk. However, Ligand B exhibits better TPSA, logP, and significantly lower DILI risk. The poor solubility and permeability for both are concerning, but the strong binding affinity of Ligand A, coupled with its improved metabolic properties, outweigh the drawbacks. The difference in binding affinity (1.9 kcal/mol) is substantial enough to consider it a key advantage.

Output:
1
2025-04-17 11:05:08,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.479 and 366.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is significantly better than Ligand B (84.94).  A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**logP:** Ligand A (3.368) is optimal (1-3), while Ligand B (1.104) is at the lower end, 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 good QED scores (0.731 and 0.805), indicating drug-likeness.

**DILI:** Ligand A (67.507) has a higher DILI risk than Ligand B (56.844), but both are reasonably acceptable.

**BBB:**  BBB isn't a primary concern for a non-CNS target like SRC, but Ligand B (64.599) has a better percentile than Ligand A (35.905).

**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, so it's hard to interpret.

**hERG:** Ligand A (0.673) has a lower hERG risk than Ligand B (0.123), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-16.598) has a *much* better (lower) microsomal clearance than Ligand A (81.984), indicating significantly improved metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (60.091) has a considerably longer in vitro half-life than Ligand A (-14.434), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.474) has lower P-gp efflux than Ligand B (0.042), which is favorable.

**Binding Affinity:** Ligand B (-9.2 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.

**Conclusion:**

Despite Ligand A's better hERG and P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.2 vs -7.3 kcal/mol) and *much* improved metabolic stability (lower Cl_mic and longer t1/2) are critical for an enzyme inhibitor. While the logP is lower, the substantial potency advantage and improved PK properties of Ligand B are more important for this target class. The negative Caco-2 and solubility values are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:05:08,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.519 Da and 340.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is better than Ligand B (69.64), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.839 and 2.122, respectively) 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) as it has fewer HBDs, which generally favors permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.731 and 0.712), indicating good drug-likeness.

**DILI:** Ligand A (14.851) has a significantly lower DILI risk than Ligand B (35.673), which is a major advantage. Ligand A is well below the 40 threshold, while ligand B is approaching it.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.347) has a higher BBB percentile than Ligand B (50.523).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.433 and -4.444), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.509 and -3.211), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.605 and 0.606), which is good.

**Microsomal Clearance:** Ligand A (59.694) has a higher microsomal clearance than Ligand B (23.07), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (2.674) has a longer in vitro half-life than Ligand A (1.461), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.182 and 0.129), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), a 0.5 kcal/mol difference. While a 1.5 kcal/mol difference would be more impactful, this difference is still noteworthy.

**Overall Assessment:**

Ligand B has a better binding affinity and longer half-life, but Ligand A has a much lower DILI risk and better Caco-2 permeability. The solubility is poor for both, and the high clearance for Ligand A is concerning. Given the enzyme-specific priorities, the lower DILI risk of Ligand A is a significant advantage, outweighing the slightly weaker binding affinity and higher clearance. However, the poor solubility and permeability are major issues for both. The better binding affinity of Ligand B is a strong point, and the lower clearance is also favorable.

Considering all factors, the slightly better binding affinity and lower clearance of Ligand B, despite the higher DILI risk, make it a marginally better candidate. Further optimization would be needed to address the solubility and permeability issues for both.

Output:
1
2025-04-17 11:05:08,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (381.523 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.57) is better than Ligand B (71.09), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.913 and 3.313) 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 6 HBA, while Ligand B has 3. Both are within the acceptable range (<=10).

**QED:** Both ligands have reasonable QED scores (0.77 and 0.675), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.746, which is moderately high. Ligand B has a much lower DILI risk of 32.067, which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.229) has a higher BBB percentile than Ligand A (52.579).

**Caco-2 Permeability:** Ligand A (-5.299) has poor Caco-2 permeability, while Ligand B (-4.75) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.724) has poor solubility, while Ligand B (-3.204) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.342) has a slightly better hERG profile than Ligand B (0.691). Lower is better here.

**Microsomal Clearance:** Ligand A (54.169) has higher microsomal clearance than Ligand B (43.914). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.515) has a negative half-life, which is not possible, and suggests a very rapid degradation. Ligand A (65.289) has a much better in vitro half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.151 and 0.32).

**Binding Affinity:** Ligand B (-7.3 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 Assessment:**

Ligand B has a substantially better binding affinity, a significantly lower DILI risk, and better metabolic stability (lower Cl_mic). While its Caco-2 permeability and solubility are also slightly better, its half-life is problematic. However, the strong binding affinity of Ligand B is a major advantage for an enzyme target like SRC kinase, and could potentially be optimized with further modifications. Ligand A has a better hERG profile and half-life, but its weak binding affinity makes it a less promising candidate.

Output:
1
2025-04-17 11:05:08,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.47 & 352.32 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.92) is significantly better than Ligand B (80.65). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Ligand A (4.41) is higher than ideal (1-3), while Ligand B (2.851) is within the optimal range. High logP can lead to solubility issues and off-target effects, giving a slight edge to Ligand B.

**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 overall.

**QED:** Both ligands have reasonable QED scores (0.878 and 0.713), indicating good drug-like properties.

**DILI:** Ligand A (29.081) has a much lower DILI risk than Ligand B (80.07), a significant advantage.

**BBB:** Ligand A (73.672) has better BBB penetration than Ligand B (60.527), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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:** Ligand A (0.794) has a lower hERG risk than Ligand B (0.426), which is favorable.

**Microsomal Clearance:** Ligand B (38.119 mL/min/kg) has lower microsomal clearance than Ligand A (52.305 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-33.206 hours) has a significantly longer in vitro half-life than Ligand A (-23.747 hours). This is a substantial benefit for Ligand B.

**P-gp Efflux:** Ligand A (0.475) has lower P-gp efflux than Ligand B (0.237), which is preferable.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is the most important factor, and the 1.9 kcal/mol difference is substantial.

**Conclusion:**

While Ligand A has advantages in DILI, hERG, and P-gp efflux, Ligand B's superior binding affinity (-9.4 vs -7.5 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the drawbacks of its slightly higher logP and worse solubility. The strong binding affinity is critical for an enzyme inhibitor. The solubility issues are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:05:08,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.422 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.16) is slightly higher than Ligand B (62.99). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**3. logP:** Both ligands (2.072 and 2.333) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 0. Lower is generally better for permeability, so Ligand B is favored.

**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 (0.748 and 0.818), indicating good drug-like properties.

**7. DILI:** Ligand A (47.732) has a higher DILI risk than Ligand B (12.485). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have similar BBB penetration (73.866 and 74.447). Not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.743) has slightly better Caco-2 permeability than Ligand B (-4.481), but both are negative values, suggesting poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.486) has slightly better solubility than Ligand B (-1.816), but both are negative values, suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.402 and 0.331).

**12. Microsomal Clearance:** Ligand A (26.736) has higher microsomal clearance than Ligand B (21.75), indicating lower metabolic stability. Ligand B is favored.

**13. In vitro Half-Life:** Ligand A (86.693) has a longer in vitro half-life than Ligand B (30.751). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.091 and 0.071).

**15. Binding Affinity:** Ligand B (-6.8 kcal/mol) has a slightly better binding affinity than Ligand A (-6.4 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). While Ligand A has a longer half-life and slightly better Caco-2 permeability and solubility, the lower DILI and better metabolic stability of Ligand B outweigh these factors, especially for a kinase inhibitor where potency is already good in both cases. The slightly improved binding affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 11:05:08,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (399.347 and 354.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.25) is higher than Ligand B (43.18). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands (3.787 and 3.136) 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:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.821 and 0.827), indicating good drug-likeness.

**DILI:** Ligand A (68.592) has a higher DILI risk than Ligand B (16.712). This is a significant drawback for Ligand A.

**BBB:** Ligand A (65.374) has a lower BBB penetration than Ligand B (96.084). While not a primary concern for a non-CNS target like SRC, higher BBB is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.063) has worse Caco-2 permeability than Ligand B (-4.581). Both are negative, indicating poor permeability, but B is better.

**Aqueous Solubility:** Ligand A (-4.111) has worse aqueous solubility than Ligand B (-2.765). Solubility is important for bioavailability, so B is favored.

**hERG Inhibition:** Ligand A (0.741) has slightly higher hERG inhibition liability than Ligand B (0.841). Lower is better, so B is slightly favored.

**Microsomal Clearance:** Ligand A (23.939) has a higher microsomal clearance than Ligand B (6.613). Lower clearance indicates better metabolic stability, favoring Ligand B.

**In vitro Half-Life:** Ligand A (41.43) has a shorter half-life than Ligand B (-32.665). A longer half-life is generally preferred, strongly favoring Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.552 and 0.511).

**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 for Ligand A. The difference of 2.6 kcal/mol is significant enough to potentially outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand B demonstrates superior ADME properties across the board: lower DILI risk, better BBB penetration, better Caco-2 permeability, better solubility, lower hERG risk, better metabolic stability (lower Cl_mic), and a longer half-life. However, Ligand A has a much stronger binding affinity.

Given the enzyme-kinase target class, potency is paramount. The 2.6 kcal/mol difference in binding affinity is substantial. While Ligand A has some ADME liabilities, these might be addressable through further optimization. The strong binding affinity provides a good starting point.

Output:
1
2025-04-17 11:05:08,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 365.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.57) is higher than Ligand B (47.79). Both are acceptable, but B is better for permeability.

**logP:** Ligand A (2.26) is optimal, while Ligand B (4.621) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable range.

**QED:** Both ligands have similar QED scores (0.821 and 0.803), indicating good drug-likeness.

**DILI:** Ligand A (26.561) has a significantly lower DILI risk than Ligand B (53.354). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (77.898) is higher than Ligand A (66.925). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of the negative value is similar.

**Solubility:** Ligand A (-1.504) has better solubility than Ligand B (-4.525). This is important for bioavailability.

**hERG:** Ligand A (0.286) has a much lower hERG risk than Ligand B (0.91). This is a critical advantage.

**Microsomal Clearance:** Ligand A (33.998) has lower microsomal clearance than Ligand B (43.291), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (90.867) has a significantly longer half-life than Ligand A (26.194). This is a significant advantage for B.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.699), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.7) has a substantially stronger binding affinity than Ligand A (-7.1). This is a 1.6 kcal/mol difference, which is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand B boasts a significantly higher binding affinity and a longer half-life, Ligand A demonstrates a superior safety profile (lower DILI and hERG risk) and better solubility. The high logP of Ligand B is concerning. Given the enzyme-kinase target class, metabolic stability and safety are crucial. The 1.6 kcal/mol difference in binding affinity is substantial, but the combination of lower DILI, hERG, and better solubility makes Ligand A the more promising candidate.

Output:
0
2025-04-17 11:05:08,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.45 and 370.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.42) is slightly higher than Ligand B (84.5). Both are acceptable, being under 140, but B is preferable.

**logP:** Ligand A (0.546) is quite low, potentially hindering permeability. Ligand B (1.416) is better, falling 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 6 HBA, while Ligand B has 4. Both are under the limit of 10, with B being slightly better.

**QED:** Both ligands have similar QED values (0.731 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (47.266). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (68.282 and 68.941). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.096 and -5.22), 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 (-1.734 and -3.766), indicating poor aqueous solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.123) has a much lower hERG inhibition liability than Ligand B (0.432), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (4.245) has a much lower microsomal clearance than Ligand B (53.465), indicating better metabolic stability. This is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-25.554) has a very negative half-life, which is concerning. Ligand B (5.36) is much better.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux liability, while Ligand B (0.067) is slightly higher.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-7.6). This is a 1.5 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG) and metabolic stability (Cl_mic), and P-gp efflux. However, it has a concerningly low in vitro half-life and a low logP. Ligand B has better affinity and a better half-life, but suffers from higher DILI risk, hERG liability, and microsomal clearance.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the better metabolic stability and significantly lower safety liabilities of Ligand A outweigh its slightly weaker binding affinity and solubility concerns. The half-life is a significant concern, but optimization could potentially address this. The low logP of A is also a concern, but may be addressed with prodrug strategies.

Output:
0
2025-04-17 11:05:08,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.463 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.75) is well below the 140 threshold for good absorption, while Ligand B (107.11) is still acceptable but less optimal.

**3. logP:** Ligand A (0.104) is quite low, potentially hindering permeation. Ligand B (1.148) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 4 respectively), below the threshold of 5.

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

**6. QED:** Both ligands have good QED scores (0.666 and 0.593), indicating drug-like properties.

**7. DILI:** Ligand A (10.314) has a very low DILI risk, significantly better than Ligand B (33.579).

**8. BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand A (68.786) is lower than Ligand B (54.052), but this is not a major deciding factor.

**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 aqueous solubility. This is a concern for both.

**11. hERG:** Ligand A (0.189) has a very low hERG risk, much better than Ligand B (0.267).

**12. Cl_mic:** Ligand A (8.547) has a slightly higher microsomal clearance than Ligand B (5.09), suggesting potentially lower metabolic stability. However, both are relatively low.

**13. t1/2:** Ligand B (-27.041) has a significantly longer *in vitro* half-life than Ligand A (-5.93), which is a major advantage for dosing frequency.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.004 and 0.042).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.6 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better DILI and hERG profiles, Ligand B's significantly stronger binding affinity (-8.5 vs -7.9 kcal/mol) and longer half-life are crucial for an enzyme target like SRC kinase. The slightly higher DILI and hERG risks of Ligand B are acceptable given the potency advantage. The poor Caco-2 and solubility for both compounds will need to be addressed during optimization, but the potency and stability advantages of Ligand B make it the better starting point.

Output:
1
2025-04-17 11:05:08,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.55) is slightly higher than Ligand B (82.78), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.719) is a bit low, potentially hindering permeation. Ligand B (2.628) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Ligand B (0.774) has a significantly better QED score than Ligand A (0.41), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A at 51.028 and Ligand B at 41.838 (both <60).

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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, which is also unusual. Again, experimental validation is needed.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.269 and 0.236, respectively).

**Microsomal Clearance (Cl_mic):** Ligand A (-22.881) has a much lower (better) Cl_mic than Ligand B (10.743). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life (t1/2):** Ligand B (21.423 hours) has a substantially longer half-life than Ligand A (-7.838 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.216).

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 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 Ligand A has better metabolic stability (lower Cl_mic), the significantly stronger binding affinity of Ligand B (-10.2 vs -7.9 kcal/mol) is a major advantage for an enzyme inhibitor. The better QED score of Ligand B further supports its selection. The negative Caco-2 and solubility values are concerning for both, but these are properties that can be addressed through formulation or structural modification. The longer half-life of Ligand B is also beneficial.

Output:
1
2025-04-17 11:05:08,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (420.294 Da) is slightly higher than Ligand B (384.479 Da), but both are acceptable.

**TPSA:** Ligand A (47.56) is significantly better than Ligand B (96.89). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target. Ligand B's TPSA is quite high.

**logP:** Ligand A (4.654) is higher than Ligand B (1.413). While Ligand A is approaching the upper limit, it's still within a reasonable range. Ligand B is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=7). Lower counts are generally better for permeability.

**QED:** Both ligands have acceptable QED values (A: 0.467, B: 0.607), indicating reasonable drug-likeness.

**DILI:** Ligand A (20.706) has a much lower DILI risk than Ligand B (56.844). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (89.027) is better than Ligand B (15.743), but not a primary driver in this case.

**Caco-2 Permeability:** Ligand A (-4.485) has a more favorable Caco-2 permeability than Ligand B (-5.592), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.029) is better than Ligand B (-2.351), which is important for formulation and bioavailability.

**hERG:** Ligand A (0.877) has a lower hERG risk than Ligand B (0.217), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand B (29.536) has a significantly lower microsomal clearance than Ligand A (84.629). Lower clearance suggests better metabolic stability, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (10.184) has a longer half-life than Ligand A (46.179). This is a positive attribute for Ligand B.

**P-gp Efflux:** Ligand A (0.374) has lower P-gp efflux than Ligand B (0.061), which suggests better bioavailability.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-6.8). This is the most important factor for an enzyme inhibitor, and the 1.5kcal/mol difference is substantial enough to outweigh many of Ligand A's minor drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability and half-life, Ligand A is the superior candidate. The significantly stronger binding affinity (-9.0 vs -6.8 kcal/mol) is paramount for a kinase inhibitor. Furthermore, Ligand A has better TPSA, solubility, lower DILI risk, and lower hERG risk. The higher logP is manageable, and the higher clearance can be addressed through structural modifications if needed.

Output:
1
2025-04-17 11:05:08,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.28 Da) is slightly higher than Ligand B (353.419 Da), but both are acceptable.

**TPSA:** Ligand A (79.46) is better than Ligand B (96.97). Both are below 140, suggesting reasonable absorption, but lower is generally preferred.

**logP:** Ligand A (3.746) is within the optimal range (1-3). Ligand B (-0.719) is significantly lower, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) and Ligand B (HBD=2, HBA=5) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED values (A: 0.656, B: 0.698), indicating generally drug-like properties.

**DILI:** Ligand A (71.772) has a higher DILI risk than Ligand B (34.432). This is a concern for Ligand A, but not prohibitive at this stage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.821) is higher than Ligand B (27.065).

**Caco-2 Permeability:** Ligand A (-4.997) is better than Ligand B (-5.339), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.762) is better than Ligand B (-0.804), which is a significant advantage for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.694) is better than Ligand B (0.093), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (40.769) has a higher (worse) clearance than Ligand B (-11.378). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (75.308) has a longer half-life than Ligand B (22.676), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.21, B: 0.006).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 kcal/mol and -8.6 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B has a superior metabolic stability profile (lower Cl_mic, longer t1/2) and a significantly lower DILI risk. However, its low logP is a major concern, potentially leading to poor permeability and bioavailability. Ligand A has a better logP, solubility, and hERG profile, and a longer half-life, but its DILI risk is higher and its metabolic clearance is worse. Given the importance of metabolic stability and solubility for kinase inhibitors, and the relatively small difference in binding affinity, Ligand B is slightly favored despite the logP issue. However, the logP of Ligand B is concerning enough that further optimization would be needed.

Output:
1
2025-04-17 11:05:08,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.483 and 337.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (62.3), being closer to the <140 threshold for good absorption.

**logP:** Both ligands (3.285 and 2.754) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are below the threshold of 10.

**QED:** Both ligands have good QED scores (0.737 and 0.933), indicating good drug-like properties.

**DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (49.477). This is a major advantage.

**BBB:** Both have good BBB penetration (72.392 and 78.519), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. We'll assume these are percentile scores and that higher is better, so both are poor.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. We'll assume these are percentile scores and that higher is better, so both are poor.

**hERG:** Both ligands have low hERG inhibition risk (0.659 and 0.555).

**Microsomal Clearance:** Ligand A (79.688) has a higher microsomal clearance than Ligand B (18.337), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-10.516) has a longer in vitro half-life than Ligand A (11.128). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.172 and 0.175).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), although both are excellent. The 0.9 kcal/mol difference is significant.

**Conclusion:**

While Ligand A has a better TPSA and similar logP, the significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity of Ligand B make it the more promising drug candidate. The solubility and permeability are poor for both, but can be addressed with formulation strategies. The DILI and metabolic stability issues with Ligand A are more difficult to overcome.

Output:
1
2025-04-17 11:05:08,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.45 & 357.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.43) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (61.44) is well within the ideal range.

**logP:** Both ligands (1.15 & 1.94) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED scores (0.655 and 0.685), indicating good drug-likeness.

**DILI:** Ligand A (27.88) has a slightly higher DILI risk than Ligand B (24.66), but both are below the concerning threshold of 40.

**BBB:** Ligand A (50.64) has a lower BBB penetration percentile than Ligand B (83.25). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.16) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.96) also has a negative value, but is slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.83 and -2.37), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.074) has a very low hERG inhibition risk, which is excellent. Ligand B (0.539) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (25.33) has a higher microsomal clearance than Ligand B (5.29), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (5.26) has a shorter half-life than Ligand B (-13.17). The negative value for Ligand B is unusual and suggests a very long half-life, which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.038).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While both ligands have some issues with solubility, Ligand B is the superior candidate. Its significantly stronger binding affinity (-8.8 vs -7.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic, longer half-life) and lower DILI risk. The higher BBB value is irrelevant as SRC is not a CNS target. The slightly higher hERG risk is acceptable given the other benefits. The Caco-2 permeability is still a concern for both, but the superior potency and stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 11:05:08,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (351.491 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.51 and 78.43) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (1.979 and 2.517) within the optimal 1-3 range. Ligand B is slightly higher, potentially indicating a slightly better ability to cross cell membranes.

**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 (3) are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.667 and 0.66), indicating good drug-like properties.

**7. DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (24.622). This is a crucial advantage, as minimizing liver toxicity is paramount.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (52.579) and Ligand B (40.558) both have low BBB penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.059 and -4.926), 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 (-2.233 and -3.654), also unusual. Ligand B has slightly lower solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.221 and 0.359).

**12. Microsomal Clearance:** Ligand A (15.47 mL/min/kg) has significantly lower microsomal clearance than Ligand B (26.961 mL/min/kg). This indicates better metabolic stability for Ligand A, which is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (3.879 hours) has a slightly lower half-life than Ligand B (13.641 hours). This is a drawback for Ligand A, but potentially outweighed by its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032 and 0.282).

**15. 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 compensate for minor ADME deficiencies.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. Its significantly stronger binding affinity and lower DILI and microsomal clearance outweigh the slightly shorter half-life and potentially lower solubility. The Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand A suggests it may still achieve sufficient target engagement *in vivo*.

Output:
0
2025-04-17 11:05:08,835 - INFO - Batch 18 complete. Total preferences: 288
2025-04-17 11:05:08,835 - INFO - Processing batch 19/512...
2025-04-17 11:05:49,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.475 and 361.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is better than Ligand B (70.16), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.501 and 1.322), falling within the 1-3 optimal 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, well within the acceptable limit of <=10.

**QED:** Ligand A (0.891) has a significantly better QED score than Ligand B (0.741), indicating a more drug-like profile.

**DILI:** Ligand B (47.305) has a much lower DILI risk than Ligand A (31.059), which is a significant advantage.

**BBB:** Ligand B (84.102) has a higher BBB penetration percentile than Ligand A (68.36), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.603) has a worse Caco-2 permeability than Ligand B (-3.993), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.923) has a worse aqueous solubility than Ligand B (-1.609). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.492 and 0.415), which is excellent.

**Microsomal Clearance:** Ligand B (41.336) has significantly lower microsomal clearance than Ligand A (77.314), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-23.354) has a much longer in vitro half-life than Ligand A (-8.893), reinforcing its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.256 and 0.068).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.2 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Conclusion:**

While both ligands exhibit good binding affinity, Ligand B is the superior candidate. Its significantly lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and better solubility outweigh the slightly lower QED and Caco-2 permeability. The differences in these ADME properties are more critical for an enzyme target like SRC kinase than minor differences in BBB penetration.

Output:
1
2025-04-17 11:05:49,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.515 Da) is slightly higher than Ligand B (349.391 Da), but both are acceptable.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (122.28). Lower TPSA generally improves cell permeability. Ligand B's TPSA is relatively high, potentially hindering absorption.

**logP:** Ligand A (4.512) is higher than Ligand B (0.71). While Ligand A is approaching the upper limit, it's still within a reasonable range. Ligand B is quite low, potentially leading to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better balanced than Ligand B (3 HBD, 7 HBA). Higher HBA counts can sometimes impact permeability.

**QED:** Both ligands have similar QED values (0.641 and 0.645), indicating similar drug-likeness.

**DILI:** Ligand A (87.01) has a higher DILI risk than Ligand B (67.778). This is a concern for Ligand A.

**BBB:** Ligand A (55.099) has a moderate BBB penetration, while Ligand B (20.085) is low. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the model or data. However, the magnitude is more concerning for Ligand B (-5.49 vs -4.336).

**Aqueous Solubility:** Both have negative solubility values, again unusual. Ligand A (-4.336) is slightly better than Ligand B (-1.837).

**hERG Inhibition:** Ligand A (0.832) has a lower hERG risk than Ligand B (0.064), which is a significant advantage.

**Microsomal Clearance:** Ligand A (50.79) has a higher clearance than Ligand B (28.05), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (54.515) has a longer half-life than Ligand B (9.46), which is favorable.

**P-gp Efflux:** Ligand A (0.657) has lower P-gp efflux than Ligand B (0.055), which is better for bioavailability.

**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, potentially outweighing some of the ADME concerns. A 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a longer half-life, and better P-gp efflux. However, it has a higher DILI risk and higher microsomal clearance. Ligand B has better DILI and clearance but a significantly weaker binding affinity and poorer TPSA and logP.

Given the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG), the strong binding affinity of Ligand A is the most critical factor. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. The lower metabolic stability could also be addressed. The weaker affinity of Ligand B makes it a less attractive starting point, even with its better ADME properties.

Output:
1
2025-04-17 11:05:49,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (58.44) is slightly higher than Ligand B (52.65), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.935) and Ligand B (2.357) are both acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both fall within the acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.741, B: 0.751), indicating a generally drug-like profile.

**DILI:** Ligand A (10.818 percentile) has a significantly lower DILI risk than Ligand B (8.298 percentile). This is a major advantage for Ligand A.

**BBB:** Ligand B (85.459 percentile) has better BBB penetration than Ligand A (66.731 percentile). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.843) has a worse Caco-2 permeability than Ligand B (-5.05). Both are poor, but ligand B is slightly better.

**Aqueous Solubility:** Ligand A (-0.913) has slightly better aqueous solubility than Ligand B (-2.032).

**hERG Inhibition:** Ligand A (0.34) has a lower hERG inhibition risk than Ligand B (0.561). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (38.152 mL/min/kg) has a higher microsomal clearance than Ligand B (21.177 mL/min/kg), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (20.217 hours) has a much longer in vitro half-life than Ligand A (-18.013 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.032, B: 0.038).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk and slightly better solubility, Ligand B's significantly stronger binding affinity, longer half-life, and better metabolic stability outweigh these advantages. The difference in affinity is substantial (>0.6 kcal/mol), making it a key factor. The lower DILI risk of Ligand A is good, but can be addressed during further optimization.

Output:
1
2025-04-17 11:05:49,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 345.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.66 and 82.27) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.263 and 0.988), 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 3. Both are below the 10 HBA limit.

**QED:** Both ligands have good QED scores (0.692 and 0.854), indicating good drug-likeness.

**DILI:** Ligand A (42.652) has a slightly higher DILI risk than Ligand B (37.611), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (69.833) shows better penetration than Ligand A (58.434).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.017 and -5.061), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.288 and -2.991), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.389 and 0.268), which is good.

**Microsomal Clearance:** Ligand B (-21.283) has significantly lower (better) microsomal clearance than Ligand A (24.776), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-15.1) has a much longer in vitro half-life than Ligand A (3.169), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.07 and 0.014).

**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 factor.

**Overall Assessment:**

Both ligands have significant drawbacks in terms of Caco-2 permeability and aqueous solubility. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. Given the enzyme-specific priorities, metabolic stability is crucial. While the solubility and permeability issues are concerning, they might be addressed through formulation strategies. The better metabolic profile of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 11:05:49,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.885 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**TPSA:** Ligand A (84.23) is well below the 140 threshold for oral absorption. Ligand B (100.25) is also acceptable, but higher.

**logP:** Ligand A (3.016) is optimal. Ligand B (0.46) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors:** Both ligands are within the acceptable range (<=5). Ligand A has 2, and Ligand B has 1.

**H-Bond Acceptors:** Both ligands are within the acceptable range (<=10). Ligand A has 5, and Ligand B has 6.

**QED:** Both ligands have similar, good QED values (0.77 and 0.782).

**DILI:** Ligand A (63.397) has a moderate DILI risk, while Ligand B (71.345) has a higher DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (52.268) has a higher BBB value than Ligand A (23.187), but it's not a major factor here.

**Caco-2 Permeability:** Both are negative values, indicating poor permeability. Ligand A (-5.29) is better than Ligand B (-4.604).

**Aqueous Solubility:** Both are negative values, indicating poor solubility. Ligand A (-4.023) is better than Ligand B (-3.102).

**hERG Inhibition:** Both ligands show very low hERG risk (0.102 and 0.197).

**Microsomal Clearance:** Ligand A (40.545) has higher clearance than Ligand B (19.18), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-14.391) has a negative half-life, which is concerning. Ligand A (43.056) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.055 and 0.088).

**Binding Affinity:** Both ligands have strong binding affinities (-7.0 and -7.8 kcal/mol). Ligand B is slightly better (-7.8 kcal/mol).

**Conclusion:**

Ligand B has a better binding affinity and significantly better metabolic stability (lower Cl_mic, though the half-life is concerning). While its logP is low, the superior binding and metabolic profile outweigh this drawback. Ligand A has a better solubility and half-life, but its higher clearance is a significant concern for an enzyme target. The slightly higher DILI risk for Ligand B is less concerning than the metabolic instability of Ligand A.

Output:
1
2025-04-17 11:05:49,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.423 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.57) is significantly better than Ligand B (114.62). A TPSA under 90 is preferred, and Ligand A is well within this range, suggesting better permeability. Ligand B is higher, potentially hindering absorption.

**logP:** Ligand A (3.739) is optimal (1-3). Ligand B (-0.453) is quite low, which could lead to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.851 and 0.717), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (44.281 and 43.66).

**BBB:** Ligand A (82.862) has a higher BBB percentile than Ligand B (68.205), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.76) is worse than Ligand B (-5.12), but both are poor.

**Aqueous Solubility:** Ligand A (-4.082) is worse than Ligand B (-2.356), but both are poor.

**hERG:** Ligand A (0.359) has a much lower hERG risk than Ligand B (0.061), which is a significant advantage, as cardiotoxicity is a major concern.

**Microsomal Clearance:** Ligand A (99.48) indicates very high clearance, meaning rapid metabolism and potentially low bioavailability. Ligand B (-4.914) shows a negative value, which is unusual and needs further investigation, but suggests a very low clearance and high metabolic stability.

**In vitro Half-Life:** Ligand A (-12.936) is a negative value, which is unusual and needs further investigation, but suggests a very short half-life. Ligand B (7.316) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.622) is better than Ligand B (0.019), indicating less P-gp efflux and potentially better bioavailability.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-7.8 and -7.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A having a better TPSA, logP, and hERG profile, its extremely high microsomal clearance and short half-life are major drawbacks for an enzyme inhibitor. Ligand B, while having a less ideal logP and TPSA, exhibits significantly better metabolic stability (low Cl_mic, reasonable t1/2), which is a critical factor for kinase inhibitors. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 11:05:49,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.503 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (110.85). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Ligand A (4.289) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (-0.965) is too low, suggesting poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (3 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Ligand A (0.813) has a much better QED score than Ligand B (0.488), indicating a more drug-like profile.

**DILI:** Ligand A (46.801) has a higher DILI risk than Ligand B (29.818), but both are reasonably low.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.784) is better than Ligand B (49.477), but neither is particularly high.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.8) has a slightly higher hERG risk than Ligand B (0.089), but both are relatively low.

**Microsomal Clearance:** Ligand A (117.764) has significantly higher clearance than Ligand B (-18.737). This suggests Ligand B is much more metabolically stable, a critical factor for an enzyme target.

**In vitro Half-Life:** Ligand A (26.868) has a longer half-life than Ligand B (4.558), which is favorable.

**P-gp Efflux:** Ligand A (0.706) shows moderate P-gp efflux, while Ligand B (0.003) is very low, which is desirable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand B has a significantly better metabolic stability profile (lower Cl_mic, longer half-life) and lower P-gp efflux. While its logP is low and TPSA is high, the superior metabolic stability and binding affinity are crucial for an enzyme target like SRC kinase. Ligand A has a better QED and slightly better half-life, but the higher metabolic clearance is a major drawback. The slightly better affinity of Ligand B, combined with its superior metabolic properties, makes it the more promising candidate.

Output:
1
2025-04-17 11:05:49,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.459 Da and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.7) is better than Ligand B (109.39), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.353) is a bit low, potentially hindering permeation. Ligand B (0.75) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent, minimizing potential issues. Ligand B (1) is still acceptable.

**H-Bond Acceptors:** Both ligands have 7 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.74 and 0.815), indicating drug-likeness.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (52.191), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.047) is slightly better than Ligand B (64.017).

**Caco-2:** Both ligands have negative Caco-2 values (-4.508 and -4.981), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have negative solubility values (-1.973 and -1.583), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Ligand A (0.349) has a lower hERG risk than Ligand B (0.087), which is a significant advantage.

**Microsomal Clearance:** Ligand A (3.644) has a much lower microsomal clearance than Ligand B (9.895), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-20.182) has a significantly longer in vitro half-life than Ligand B (2.84), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.01).

**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 could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B's significantly stronger binding affinity (-8.2 vs -7.1 kcal/mol) is a major advantage. The improved DILI risk and lower P-gp efflux are also beneficial. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2) and lower hERG risk, the potency difference is decisive for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:05:49,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.503 and 348.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (89.19) is still under 140, but higher than A, potentially impacting absorption.

**logP:** Both ligands have logP values within the optimal 1-3 range (1.729 and 2.697).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=7) in terms of balancing solubility and permeability. Ligand B has a higher number of HBA, which could slightly hinder permeability.

**QED:** Both ligands have acceptable QED values (0.843 and 0.709), indicating good drug-like properties.

**DILI:** Ligand A (3.994) has a significantly lower DILI risk than Ligand B (39.899), which is a major advantage.

**BBB:** Both ligands have high BBB penetration, but Ligand B (94.455) is slightly higher than Ligand A (82.164). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.898) has a more negative Caco-2 value, suggesting *lower* permeability, while Ligand B (-5.173) is also low. Both are poor.

**Aqueous Solubility:** Ligand A (-1.565) has better solubility than Ligand B (-3.733).

**hERG Inhibition:** Ligand A (0.526) shows a lower hERG inhibition risk than Ligand B (0.797), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (7.562) has significantly lower microsomal clearance than Ligand B (76.376), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.806) has a shorter half-life than Ligand B (14.136), but both are reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.025 and 0.109).

**Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (-0). 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 has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has some ADME liabilities (higher DILI, lower solubility, higher Cl_mic), the potency advantage is substantial. Ligand A has a better safety profile (lower DILI, hERG) and better metabolic stability, but its significantly weaker binding affinity is a major drawback.

Output:
1
2025-04-17 11:05:49,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (367.446 Da) is still well within the range.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (91.32). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Both ligands have good logP values (A: 2.501, B: 1.86), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=5) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability.

**QED:** Ligand A (0.825) has a much higher QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Ligand A (12.524) has a significantly lower DILI risk than Ligand B (52.152), which is a major advantage.

**BBB:** Ligand A (82.745) has a higher BBB penetration percentile than Ligand B (60.411), although BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.897) has a better Caco-2 permeability than Ligand B (-5.258), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.293) has better aqueous solubility than Ligand B (-3.171).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.452, B: 0.374).

**Microsomal Clearance:** Ligand A (47.631) has a higher microsomal clearance than Ligand B (39.898), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-11.27) has a significantly longer in vitro half-life than Ligand A (-4.82), which is a major advantage for dosing frequency.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.378, B: 0.071).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). The difference is 0.6 kcal/mol, which is substantial but not overwhelming.

**Overall Assessment:**

Ligand A excels in most ADME properties (QED, DILI, TPSA, solubility, permeability) and has a slightly better binding affinity. However, its higher microsomal clearance and shorter half-life are concerning. Ligand B has a longer half-life and better metabolic stability, but suffers from a higher TPSA, lower QED, and higher DILI risk.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, hERG), the longer half-life and better metabolic stability of Ligand B are critical advantages that outweigh its slightly lower QED and higher DILI risk. The affinity difference is not large enough to overcome the ADME deficiencies of Ligand A.

Output:
1
2025-04-17 11:05:49,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.423 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.56) is slightly above the optimal <140 for good absorption, but still reasonable. Ligand B (80.48) is excellent, well below 140.

**logP:** Ligand A (-1.013) is a bit low, potentially hindering permeation. Ligand B (2.309) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is good. Ligand B (1 HBD, 7 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.466 and 0.698), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (17.255) has a very low DILI risk, which is excellent. Ligand B (58.511) is higher, indicating a moderate risk, but still not alarming.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**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 less than the trend.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude is important.

**hERG Inhibition:** Ligand A (0.058) has a very low hERG risk, a significant advantage. Ligand B (0.295) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (15.373) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (46.646) has a significantly higher clearance, which is a concern.

**In vitro Half-Life:** Ligand B (23.527) has a longer in vitro half-life than Ligand A (13.518), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Both ligands have very similar 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 factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has a slightly better QED and in vitro half-life, Ligand A's significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and extremely low hERG risk are critical advantages for an oncology drug targeting a kinase. The slightly lower logP of Ligand A is a minor drawback that could potentially be addressed through further optimization, but the safety profile of Ligand A is far superior.

Output:
0
2025-04-17 11:05:49,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.447 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (111.71 and 113.69) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (which requires <90). This is acceptable for an oncology target that doesn't necessarily require brain penetration.

**logP:** Ligand A (0.1) is quite low, potentially hindering permeability. Ligand B (0.548) is better, but still on the lower side of the optimal 1-3 range.

**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 A (0.734) has a better QED score than Ligand B (0.566), indicating a more drug-like profile.

**DILI:** Ligand B (32.299) has a significantly lower DILI risk than Ligand A (84.141). This is a major advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for an oncology drug.

**Caco-2 Permeability:** Ligand A (-4.755) has very poor predicted Caco-2 permeability, while Ligand B (-5.172) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.137) has poor predicted solubility, while Ligand B (-0.779) is better, though still not ideal.

**hERG Inhibition:** Ligand A (0.234) has a lower hERG risk than Ligand B (0.059), which is a positive attribute.

**Microsomal Clearance:** Ligand A (15.131 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (37.938 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-42.707 hours) has a much longer predicted half-life than Ligand B (-7.248 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.009 and 0.031 respectively).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.8 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B's superior binding affinity (-7.5 kcal/mol vs -10.8 kcal/mol) is the most important factor. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED, Ligand B's lower DILI risk and better solubility are also important advantages. The lower logP of Ligand A is a significant concern for permeability. The difference in binding affinity is substantial enough to outweigh the other drawbacks of Ligand B.

Output:
1
2025-04-17 11:05:49,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 355.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 61.88, which is acceptable for oral absorption (<=140).

**logP:** Ligand A (1.171) is slightly higher than Ligand B (0.666), both are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Both have 4 HBA, which is good.

**QED:** Both ligands have good QED scores (0.731 and 0.761, respectively), indicating drug-likeness.

**DILI:** Ligand A (5.584) has a significantly lower DILI risk than Ligand B (6.863). This is a major advantage for Ligand A.

**BBB:** Ligand B (91.663) has a higher BBB penetration percentile than Ligand A (70.997). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.978 and -4.778). These values are unusual and suggest poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-1.147 and -1.253). Again, the scale is not defined, but these suggest poor solubility.

**hERG Inhibition:** Ligand A (0.19) has a lower hERG inhibition liability than Ligand B (0.556), which is favorable.

**Microsomal Clearance:** Ligand B (-7.192) has a significantly lower (better) microsomal clearance than Ligand A (-4.714), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (4.738) has a longer half-life than Ligand B (2.441).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.013 and 0.012).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand B has superior binding affinity and metabolic stability, Ligand A has a much lower DILI risk and a longer half-life. The difference in binding affinity (-1.6 kcal/mol) is significant, but the lower DILI risk of Ligand A is a crucial factor for drug development. Considering the enzyme-specific priorities, the improved safety profile of Ligand A makes it the more viable candidate, despite the slightly weaker binding.

Output:
0
2025-04-17 11:05:49,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.38 Da) is slightly higher than Ligand B (350.463 Da), but both are acceptable.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption. Ligand A (93.53 A^2) and Ligand B (88.33 A^2) are both good.

**logP:** Ligand A (0.515) is a bit low, potentially hindering permeability. Ligand B (2.273) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5-6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.772 and 0.777), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 69.794, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (29.624), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Both have reasonable BBB penetration, with Ligand A slightly higher (81.815) than Ligand B (77.2).

**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 and suggests poor solubility. Again, the scale is not defined.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.337 and 0.209), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (20.353 mL/min/kg) than Ligand B (42.8 mL/min/kg), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a negative half-life (-40.502 hours), which is not physically possible and indicates a problem with the data. Ligand B has a very short half-life (-0.456 hours), also problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.113 and 0.066), which is favorable.

**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 of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, and better metabolic stability. However, it has a higher DILI risk and the negative half-life is a major red flag. Ligand B has a better logP, lower DILI, and slightly better hERG, but weaker binding affinity and worse metabolic stability.

Given the importance of potency for kinase inhibitors, and the significant difference in binding affinity (-9.1 vs -7.8 kcal/mol), I would cautiously favor Ligand A *if* the negative half-life can be explained or corrected (e.g., data error). The DILI risk is concerning but potentially mitigable with further optimization. The negative solubility and permeability values are also concerning and need investigation.

However, the negative half-life is a critical issue. Without clarification, it makes Ligand A a very risky candidate.

Output:
1
2025-04-17 11:05:49,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.427 and 364.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.78) is well below the 140 threshold for good absorption, while Ligand B (93.73) is still acceptable but closer to the limit.

**3. logP:** Both ligands have good logP values (2.469 and 1.392), 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 (6) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.77) has a significantly better QED score than Ligand B (0.227), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, moderately high DILI risk (60.062 and 64.327). This is a concern, but not a deciding factor at this stage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.94) is slightly better than Ligand B (54.517).

**9. Caco-2:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.577) is slightly better than Ligand B (-5.115).

**10. Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.011) is slightly better than Ligand B (-2.559).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.163 and 0.201), which is excellent.

**12. Cl_mic:** Ligand B (21.457) has a lower microsomal clearance than Ligand A (32.072), suggesting better metabolic stability. This is a significant advantage.

**13. t1/2:** Ligand B (-11.276) has a negative in vitro half-life, which is concerning. Ligand A (25.067) has a more reasonable half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.081 and 0.043).

**15. 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 has a better QED score, slightly better Caco-2 and solubility, and a more reasonable in vitro half-life. However, Ligand B exhibits significantly better metabolic stability (lower Cl_mic). Given that we are targeting a kinase (enzyme), metabolic stability is a crucial factor. While both have poor Caco-2 and solubility, these can be addressed through formulation strategies. The slightly better metabolic stability of Ligand B outweighs the advantages of Ligand A.

Output:
1
2025-04-17 11:05:49,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.443 and 367.837 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.44) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (115.98) is still under 140, but less optimal than A.

**logP:** Ligand A (1.363) is within the optimal 1-3 range. Ligand B (0.365) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (4 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (0.792 and 0.504), indicating good drug-like properties.

**DILI:** Ligand A (27.414) has a significantly lower DILI risk than Ligand B (39.822), which is a major advantage. Both are below the 40 threshold.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (62.621) has a slightly better score than Ligand B (54.44).

**Caco-2 Permeability:** Ligand A (-4.386) has a much better Caco-2 permeability score than Ligand B (-5.939).

**Aqueous Solubility:** Ligand A (-1.924) has a better solubility score than Ligand B (-2.518).

**hERG:** Both ligands have very low hERG risk (0.331 and 0.037), which is excellent.

**Microsomal Clearance:** Ligand A (8.58) has a higher microsomal clearance than Ligand B (3.132), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-8.684) has a much better in vitro half-life than Ligand A (13.818), indicating greater stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.01).

**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, potentially outweighing some of the ADME drawbacks. The difference is greater than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A having a higher Cl_mic (lower metabolic stability), its significantly superior binding affinity (-8.8 vs -6.9 kcal/mol) and better overall ADME profile (lower DILI, better solubility, better Caco-2 permeability) make it the more promising drug candidate. The potency advantage is substantial and outweighs the metabolic stability concern, which can be addressed through further optimization.

Output:
1
2025-04-17 11:05:49,532 - INFO - Batch 19 complete. Total preferences: 304
2025-04-17 11:05:49,532 - INFO - Processing batch 20/512...
2025-04-17 11:06:42,383 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision, considering the guidelines and protein class (enzyme - kinase/SRC):

**1. Molecular Weight (MW):**
*   Ligand A: 353.296 Da - Within the ideal range (200-500).
*   Ligand B: 338.415 Da - Within the ideal range (200-500).
*   *Both are good.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 76.23  - Below the 140 threshold for oral absorption.
*   Ligand B: 76.77 - Below the 140 threshold for oral absorption.
*   *Both are good.*

**3. Lipophilicity (logP):**
*   Ligand A: 2.594 - Within the optimal range (1-3).
*   Ligand B: 2.86 - Within the optimal range (1-3).
*   *Both are good.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 1 - Meets the <= 5 criteria.
*   Ligand B: 2 - Meets the <= 5 criteria.
*   *Both are good.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 4 - Meets the <= 10 criteria.
*   Ligand B: 5 - Meets the <= 10 criteria.
*   *Both are good.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.81 - Excellent, well above the 0.5 threshold.
*   Ligand B: 0.695 - Good, above the 0.5 threshold.
*   *Ligand A is better.*

**7. DILI Risk (DILI):**
*   Ligand A: 76.076 - High risk (>60).
*   Ligand B: 61.691 - High risk (>60), but slightly lower than A.
*   *Ligand B is slightly better.*

**8. Blood-Brain Barrier (BBB):**
*   Ligand A: 75.649 - Moderate. Not a primary concern for a non-CNS target.
*   Ligand B: 62.466 - Moderate. Not a primary concern for a non-CNS target.
*   *Similar.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.566 - Negative values are unusual and suggest very poor permeability.
*   Ligand B: -5.07 - Negative values are unusual and suggest very poor permeability.
*   *Both are poor, B is slightly worse.*

**10. Aqueous Solubility:**
*   Ligand A: -4.026 - Very poor solubility.
*   Ligand B: -3.963 - Very poor solubility.
*   *Similar.*

**11. hERG Inhibition:**
*   Ligand A: 0.394 - Low risk.
*   Ligand B: 0.555 - Moderate risk.
*   *Ligand A is better.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 55.527 mL/min/kg - Moderate clearance.
*   Ligand B: 71.686 mL/min/kg - Higher clearance, less desirable.
*   *Ligand A is better.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: -29.913 hours - Negative values are unusual.
*   Ligand B: 14.238 hours - Reasonable half-life.
*   *Ligand B is better.*

**14. P-gp Efflux:**
*   Ligand A: 0.38 - Low efflux, good.
*   Ligand B: 0.164 - Very low efflux, excellent.
*   *Ligand B is better.*

**15. Binding Affinity:**
*   Ligand A: -7.5 kcal/mol - Excellent.
*   Ligand B: -8.5 kcal/mol - Even better, 1 kcal/mol advantage.
*   *Ligand B is significantly better.*

**Overall Assessment:**

For an enzyme target like SRC, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a significantly better binding affinity (-8.5 vs -7.5 kcal/mol), a better half-life (14.238 vs -29.913), and lower P-gp efflux. While both have poor solubility and high DILI risk, the affinity advantage of Ligand B is substantial enough to outweigh these concerns, especially given the potential for optimization of solubility and DILI risk in later stages. Ligand A has a better QED and hERG profile, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 11:06:42,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (357.435 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (80.32 and 78.43) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands (2.615 and 2.857) are 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 scores (0.637 and 0.621), indicating good drug-likeness.

**7. DILI:** Ligand A (90.694) has a significantly higher DILI risk than Ligand B (36.06). This is a major concern for Ligand A.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (60.876) and Ligand B (50.834) are both relatively low.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.005 and -5.064), which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.725 and -3.106), indicating poor aqueous solubility. This is a concern for both, but less so if formulation strategies can be employed.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.334 and 0.342), which is positive.

**12. Microsomal Clearance:** Ligand A (29.624) has a significantly lower microsomal clearance than Ligand B (41.118), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (22.109) has a longer in vitro half-life than Ligand B (6.243), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.3 and 0.259), which is good.

**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.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and improved metabolic stability (lower Cl_mic, longer t1/2). However, its DILI risk is substantially higher than Ligand B. The affinity difference is large (>1.5 kcal/mol), which could potentially outweigh the DILI concern, *if* the DILI risk can be mitigated through structural modifications. Both ligands have poor Caco-2 and solubility, which would need to be addressed. Given the enzyme-kinase focus, the superior potency and metabolic stability of Ligand A make it the more promising starting point, despite the DILI risk.

Output:
1
2025-04-17 11:06:42,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 377.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.22) is better than Ligand B (90.55), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (2.687) is optimal, while Ligand B (3.797) is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is better than Ligand B (HBD=4, HBA=7) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.662) is better than Ligand B (0.5), indicating a more drug-like profile.

**DILI:** Ligand A (41.76) is significantly better than Ligand B (76.464), indicating a lower risk of drug-induced liver injury. This is a crucial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (67.468) is better than Ligand B (49.011).

**Caco-2 Permeability:** Ligand A (-4.695) is better than Ligand B (-5.395), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.794) is better than Ligand B (-4.997), which is important for formulation and bioavailability.

**hERG:** Ligand A (0.338) is better than Ligand B (0.695), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (Ligand A: 69.497, Ligand B: 70.713).

**In vitro Half-Life:** Ligand B (50.981) has a significantly longer half-life than Ligand A (-14.852), which is a positive attribute.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (Ligand A: 0.19, Ligand B: 0.193).

**Binding Affinity:** Both ligands have very similar binding affinities (Ligand A: -9.3 kcal/mol, Ligand B: -8.7 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A is superior due to its significantly better DILI score, solubility, hERG risk, QED, and Caco-2 permeability, while maintaining comparable potency and a good logP. The longer half-life of Ligand B is a benefit, but the other ADME liabilities make it less attractive.

Output:
0
2025-04-17 11:06:42,384 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (363.845 and 353.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (78.95) is also acceptable, but slightly higher.

**3. logP:** Ligand A (2.138) is optimal (1-3). Ligand B (0.492) is a bit low, 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 4. Both are below the 10 limit.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (42.458) has a better DILI score than Ligand B (15.898), indicating a lower risk of liver injury.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.513) has a higher BBB penetration percentile than Ligand B (58.821).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and potentially problematic.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is also concerning.

**11. hERG Inhibition:** Ligand A (0.345) has a much lower hERG inhibition risk than Ligand B (0.107). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (-17.94) has a much lower (better) microsomal clearance than Ligand B (12.165). This suggests greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.761) has a longer half-life than Ligand B (-5.489).

**14. P-gp Efflux:** Ligand A (0.111) has a lower P-gp efflux liability than Ligand B (0.014).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are good, the 1.2 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a more optimal logP, a much lower DILI risk, lower hERG inhibition, superior metabolic stability (lower Cl_mic and 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 A outweigh these concerns, especially given the importance of metabolic stability and safety (hERG, DILI) for kinase inhibitors.

Output:
1
2025-04-17 11:06:42,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.467 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (61.88).  A TPSA under 140 is desired for oral absorption, and both meet this, but lower is generally preferable.

**logP:** Both ligands have acceptable logP values (2.892 and 1.954, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (1 HBD, 5 HBA). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have good QED scores (0.773 and 0.864), indicating good drug-like properties.

**DILI:** Ligand A (17.371) has a much lower DILI risk than Ligand B (30.826). This is a significant advantage.

**BBB:** Ligand A (80.419) has better BBB penetration than Ligand B (55.642), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are percentile scores, Ligand A (-4.609) is slightly better than Ligand B (-4.799), meaning it has slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.656) has better aqueous solubility than Ligand B (-1.044).

**hERG:** Ligand A (0.621) has a lower hERG risk than Ligand B (0.194), which is a crucial advantage for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (50.521) has higher microsomal clearance than Ligand B (12.524), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (18.398) has a significantly longer in vitro half-life than Ligand A (-24.207). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.404) has lower P-gp efflux than Ligand B (0.02), which is beneficial.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor, and the 1.9 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI and hERG risks, which are critical for a kinase inhibitor. It also shows better solubility and P-gp efflux. However, it has higher microsomal clearance and a shorter half-life. Ligand B has a longer half-life and lower clearance, but its binding affinity is very weak, and its DILI and hERG risks are higher.

The substantial difference in binding affinity outweighs the metabolic stability concerns for Ligand A. A weak binder like Ligand B is unlikely to be a viable drug candidate regardless of its other properties.

Output:
1
2025-04-17 11:06:42,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.355 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (389.405 Da) is still well within the acceptable range.

**TPSA:** Both ligands have TPSA values below 140 (A: 94.82, B: 90.41), suggesting good oral absorption potential.

**logP:** Ligand A (0.521) is a bit low, potentially hindering permeation. Ligand B (2.795) is much closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (7/8) counts, balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.814, B: 0.548), indicating drug-like properties.

**DILI:** Ligand A (72.586) has a lower DILI risk than Ligand B (93.059), which is a significant advantage.

**BBB:** Both have moderate BBB penetration (A: 64.056, B: 84.955). Since SRC is not a CNS target, this is less critical.

**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 unknown, making interpretation difficult.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.361, B: 0.321).

**Microsomal Clearance:** Ligand A (55.953) has a lower microsomal clearance than Ligand B (98.647), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-30.065) has a negative half-life, which is impossible. Ligand B (-6.058) also has a negative half-life, indicating an issue with the data.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.14, B: 0.37).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite the questionable solubility and half-life data, the significantly stronger binding affinity of Ligand B (-8.1 kcal/mol vs 0.0 kcal/mol) and its better logP value make it the more promising candidate. The higher DILI risk is a concern, but can be addressed through further optimization. Ligand A's very weak binding affinity is a major drawback. The better metabolic stability of Ligand A is less important given the large difference in binding affinity.

Output:
1
2025-04-17 11:06:42,384 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [404.304, 55.4, 3.843, 1, 3, 0.714, 64.366, 52.734, -4.83, -4.545, 0.707, 86.857, 24.865, 0.283, -8.1]
**Ligand B:** [345.443, 69.72, 0.944, 1, 3, 0.384, 29.081, 54.944, -4.596, -1.773, 0.098, 27.597, -29.763, 0.014, -6.7]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (345.443 Da) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** Ligand A (55.4) is better than Ligand B (69.72), being closer to the <140 threshold for good absorption.
3. **logP:** Ligand A (3.843) is optimal (1-3). Ligand B (0.944) is a bit low, potentially hindering permeation.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** Both have 3 HBA, which is good.
6. **QED:** Ligand A (0.714) is significantly better than Ligand B (0.384), indicating a more drug-like profile.
7. **DILI:** Ligand A (64.366) is higher risk than Ligand B (29.081). This is a significant concern for Ligand A.
8. **BBB:** Both are moderate, but Ligand B (54.944) is slightly better. Not a primary concern for SRC kinase (not a CNS target).
9. **Caco-2:** Both are negative, indicating poor permeability.
10. **Solubility:** Both are negative, indicating poor solubility.
11. **hERG:** Ligand A (0.707) is better than Ligand B (0.098), suggesting lower cardiotoxicity risk.
12. **Cl_mic:** Ligand B (27.597) has significantly lower microsomal clearance than Ligand A (86.857), indicating better metabolic stability.
13. **t1/2:** Ligand B (-29.763) has a negative half-life, which is not possible. This is a major red flag. Ligand A (24.865) is reasonable.
14. **Pgp:** Ligand A (0.283) is better than Ligand B (0.014), suggesting lower P-gp efflux.
15. **Binding Affinity:** Ligand A (-8.1) has a much stronger binding affinity than Ligand B (-6.7), a difference of 1.4 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a much better affinity. However, Ligand B has better metabolic stability and a lower DILI risk. Ligand B's half-life is not possible, which is a major issue.

**Conclusion:**

Despite the DILI risk, Ligand A is the more promising candidate due to its significantly stronger binding affinity (-8.1 vs -6.7 kcal/mol). The 1.4 kcal/mol difference is substantial enough to potentially outweigh the higher DILI risk, *provided* that further modifications can be made to mitigate the DILI liability. Ligand B's negative half-life is a showstopper.

Output:
1
2025-04-17 11:06:42,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.362 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.12 and 87.91) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.899) is slightly better than Ligand B (0.209), as it's closer to the optimal 1-3 range. Ligand B is quite low, potentially hindering permeation.

**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:** Ligand A (0.837) has a better QED score than Ligand B (0.72), indicating a more drug-like profile.

**DILI:** Ligand A (54.517) has a higher DILI risk than Ligand B (15.936). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (57.968 and 56.301), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.893 and -4.867). This is unusual and suggests poor permeability, but could be an artifact of the prediction method.

**Aqueous Solubility:** Both have negative solubility values (-1.74 and -0.389). This is also concerning and suggests poor solubility, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.209) has a lower hERG risk than Ligand B (0.127), which is favorable.

**Microsomal Clearance:** Ligand A (19.291) has a higher microsomal clearance than Ligand B (10.922), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-19.095) has a significantly shorter in vitro half-life than Ligand B (3.831), further indicating lower metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.007).

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand A, its significantly higher DILI risk, higher clearance, and shorter half-life are major concerns. Ligand B, while having a weaker binding affinity, exhibits a much better safety profile (lower DILI) and improved metabolic stability (lower clearance, longer half-life). The solubility and permeability issues are present in both, but can be addressed through formulation strategies. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The substantial affinity difference *could* be overcome with optimization of Ligand B, whereas mitigating the liabilities of Ligand A would be more challenging.

Output:
1
2025-04-17 11:06:42,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 377.941 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.11) is slightly above the preferred <140, but acceptable. Ligand B (36.44) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (1.57) is optimal. Ligand B (3.881) is approaching the upper limit, but still within the acceptable 1-3 range.

**H-Bond Donors:** Ligand A (3) is good. Ligand B (0) is also good, potentially improving permeability.

**H-Bond Acceptors:** Both ligands (A: 5, B: 4) are well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.615, B: 0.766), indicating drug-like properties.

**DILI:** Ligand A (43.738) has a slightly higher DILI risk than Ligand B (29.585), but both are below the concerning threshold of 60.

**BBB:** Both ligands have moderate BBB penetration (A: 62.97, B: 70.919). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.263) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.851) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.359, B: -2.9). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.22) shows a slightly higher hERG risk than Ligand B (0.869), but both are relatively low.

**Microsomal Clearance:** Ligand A (32.927) has lower microsomal clearance than Ligand B (38.874), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.874) has a significantly longer half-life than Ligand A (6.628). This is a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.032) has very low P-gp efflux, which is good. Ligand B (0.503) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B having a slightly higher logP and similar solubility issues, its significantly stronger binding affinity (-8.4 vs -7.4 kcal/mol) and longer half-life are crucial advantages for an enzyme target like SRC kinase. While Ligand A has better P-gp properties, the potency and metabolic stability benefits of Ligand B are more important. The Caco-2 permeability is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:06:42,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.491 and 371.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (101.29) is better than Ligand B (131.44). Both are under the 140 threshold for oral absorption, but A is closer to the desirable range.

**logP:** Ligand A (1.869) is within the optimal range (1-3). Ligand B (-0.615) is below 1, which might hinder permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (4) are both acceptable, being under the limit of 5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (7) are both under the limit of 10.

**QED:** Ligand A (0.56) is slightly better than Ligand B (0.448), both being above the 0.5 threshold.

**DILI:** Ligand B (41.877) has a slightly higher DILI risk than Ligand A (10.702), but both are below the concerning threshold of 60.

**BBB:** Ligand A (75.107) has a significantly higher BBB penetration potential than Ligand B (14.541). While not a primary concern for a non-CNS target like SRC, it's a neutral benefit.

**Caco-2 Permeability:** Ligand A (-5.182) is better than Ligand B (-6.223), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.721) is better than Ligand B (-1.657), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.162 and 0.053 respectively).

**Microsomal Clearance:** Ligand B (-9.408) has a *much* lower (better) microsomal clearance than Ligand A (40.766), suggesting greater metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (-11.524) has a longer in vitro half-life than Ligand A (-15.235), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.01 respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-8.2 and -8.8 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to outweigh other factors.

**Conclusion:**

While Ligand B has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic and longer t1/2), Ligand A has better solubility, permeability, and a much better TPSA. Considering the enzyme-specific priorities, metabolic stability is crucial, but solubility and permeability are also important. The difference in binding affinity is not large enough to overcome the solubility and permeability advantages of Ligand A. Therefore, Ligand A is the more promising candidate.

Output:
1
2025-04-17 11:06:42,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.527 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (67.43) is better than Ligand B (88.16). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 3.051, B: 2.697), 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 6. Ligand A is preferable here.

**QED:** Both ligands have good QED scores (A: 0.706, B: 0.782), indicating good drug-like properties.

**DILI:** Ligand B (73.052) has a higher DILI risk than Ligand A (46.297). This is a significant concern.

**BBB:** Ligand A (68.709) has a better BBB percentile than Ligand B (54.478), but this isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.838) has a much better Caco-2 permeability than Ligand B (-5.339).

**Aqueous Solubility:** Ligand A (-3.669) has better aqueous solubility than Ligand B (-3.296). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.498) has a lower hERG inhibition liability than Ligand B (0.231), which is a crucial advantage.

**Microsomal Clearance:** Ligand B (7.459) has a significantly lower microsomal clearance than Ligand A (63.113), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (29.556) has a slightly longer half-life than Ligand A (26.848).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.354, B: 0.209).

**Binding Affinity:** Ligand B (-7.9 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:**

Ligand B's significantly stronger binding affinity (-7.9 kcal/mol vs 0.0 kcal/mol) is a critical factor. While it has a higher DILI risk and slightly worse solubility and permeability, the potency advantage is substantial. The lower microsomal clearance of Ligand B is also a positive. The hERG risk is lower for Ligand A, but the binding affinity difference is so large that it likely outweighs this concern.

Output:
1
2025-04-17 11:06:42,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 358.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.88) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.67) is well within the ideal range.

**logP:** Ligand A (0.155) is quite low, potentially hindering permeability. Ligand B (0.87) is closer to the optimal 1-3 range.

**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 similar QED values (A: 0.728, B: 0.734), indicating good drug-like properties.

**DILI:** Ligand A (22.218) has a significantly lower DILI risk than Ligand B (37.185), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand A (41.373) has a lower BBB penetration percentile than Ligand B (68.282). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.656) has poor Caco-2 permeability, likely due to its low logP. Ligand B (-4.766) is better, but still not great.

**Aqueous Solubility:** Ligand A (-1.395) has poor aqueous solubility. Ligand B (-0.676) is slightly better, but still not ideal.

**hERG:** Ligand A (0.143) has a very low hERG risk, a significant advantage. Ligand B (0.572) is higher, indicating a moderate risk.

**Microsomal Clearance:** Ligand A (-32.076) has a very low (and therefore good) microsomal clearance, suggesting high metabolic stability. Ligand B (27.497) has a higher clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (13.677) has a longer half-life than Ligand B (-2.984), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.005, B: 0.101).

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand B having slightly better Caco-2 permeability and BBB penetration, Ligand A is the superior candidate. The key advantages of Ligand A are its significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. These factors are crucial for enzyme inhibitors, outweighing the slightly lower Caco-2 permeability and solubility. The equal binding affinity makes the ADME properties the deciding factor.

Output:
0
2025-04-17 11:06:42,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.438 and 346.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.02) is well below the 140 threshold for oral absorption, while Ligand B (102.74) is still acceptable but closer to the limit.

**logP:** Ligand A (1.91) is within the optimal range of 1-3. Ligand B (-0.578) 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 4 HBA, both within acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.752 and 0.737), indicating good drug-likeness.

**DILI:** Ligand A (28.538) has a significantly lower DILI risk than Ligand B (48.275), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.378) shows better potential for BBB penetration than Ligand B (46.064).

**Caco-2 Permeability:** Ligand A (-5.122) has a lower Caco-2 permeability than Ligand B (-4.933). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.182) has slightly better aqueous solubility than Ligand B (-1.802), though both are quite poor.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.393 and 0.114).

**Microsomal Clearance:** Ligand A (11.48) has a much lower microsomal clearance than Ligand B (-17.681), indicating significantly better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (1.548) has a shorter half-life than Ligand B (24.579). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux than Ligand B (0.011).

**Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -8.8 kcal/mol). Ligand B is slightly better (-8.8 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI) and metabolic stability (lower Cl_mic), which are crucial for enzyme inhibitors. While Ligand B has a slightly better binding affinity and a longer half-life, the poor metabolic stability and higher DILI risk are concerning. The slightly lower Caco-2 permeability of Ligand A is a drawback, but can potentially be addressed through formulation strategies. Given the priorities for enzyme targets, the improved safety and metabolic stability of Ligand A outweigh the slightly better affinity and half-life of Ligand B.

Output:
0
2025-04-17 11:06:42,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.434 and 349.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is slightly higher than Ligand B (55.63). Both are below the 140 threshold for oral absorption, which is good.

**logP:** Ligand A (2.71) is within the optimal 1-3 range. Ligand B (4.971) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both ligands 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.

**QED:** Ligand A (0.833) has a higher QED than Ligand B (0.72), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (42.071 and 40.83), which is positive.

**BBB:** Both ligands have high BBB penetration (83.831 and 82.009), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.542) has worse Caco-2 permeability than Ligand B (-5.149).

**Aqueous Solubility:** Ligand A (-3.051) has better aqueous solubility than Ligand B (-4.689).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.477 and 0.498).

**Microsomal Clearance:** Ligand A (55.853) has lower microsomal clearance than Ligand B (56.492), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.934) has a significantly longer in vitro half-life than Ligand B (11.579). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.744).

**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 factor.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability, Ligand A excels in critical areas: significantly higher binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a higher QED score. The higher logP of Ligand B is a concern, and the substantial difference in binding affinity outweighs the minor advantage of Ligand B in Caco-2 permeability.

Output:
1
2025-04-17 11:06:42,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (75.44) is higher than Ligand B (58.12). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.483) is slightly better than Ligand B (3.792), being closer to the middle of the range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, below the 10 threshold.

**QED:** Both ligands have good QED scores (A: 0.769, B: 0.8), indicating good drug-like properties.

**DILI:** Ligand A (13.339) has a significantly lower DILI risk than Ligand B (51.299). This is a major advantage for Ligand A.

**BBB:** Ligand B (87.864) has a higher BBB penetration percentile than Ligand A (74.486). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.931) has a worse Caco-2 permeability than Ligand B (-5.119). Both are quite poor, but similar.

**Aqueous Solubility:** Ligand A (-2.36) has better aqueous solubility than Ligand B (-3.997). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.289) has a much lower hERG inhibition risk than Ligand B (0.628). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (92.872) has a much higher microsomal clearance than Ligand A (25.362). This means Ligand A is more metabolically stable, which is crucial for an enzyme target.

**In vitro Half-Life:** Ligand B (28.644) has a longer in vitro half-life than Ligand A (-2.449). This is a positive for Ligand B, but the negative value for A is concerning.

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux than Ligand B (0.714), which is preferable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better BBB score and in vitro half-life, Ligand A excels in critical areas for an enzyme inhibitor: lower DILI risk, lower hERG risk, significantly better metabolic stability (lower Cl_mic), better solubility, and lower P-gp efflux. The similar binding affinity makes these ADME properties the deciding factors. The negative in vitro half-life for A is a concern, but the other advantages outweigh this.

Output:
0
2025-04-17 11:06:42,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (356.451 and 362.461 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.95) is better than Ligand B (49.85) as it is closer to the upper limit for good oral absorption.

**3. logP:** Both ligands have good logP values (3.457 and 3.797), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0 HBD, which is also acceptable.

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

**6. QED:** Ligand A (0.875) has a significantly better QED score than Ligand B (0.586), indicating a more drug-like profile.

**7. DILI:** Ligand A (72.354) has a higher DILI risk than Ligand B (23.614). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (45.909) has a lower BBB penetration percentile than Ligand B (78.209). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.182) has a worse Caco-2 permeability than Ligand B (-3.991).

**10. Aqueous Solubility:** Ligand A (-4.396) has a worse aqueous solubility than Ligand B (-3.244).

**11. hERG Inhibition:** Ligand A (0.219) has a slightly higher hERG inhibition liability than Ligand B (0.776), but both are relatively low risk.

**12. Microsomal Clearance:** Ligand A (64.468) has a lower microsomal clearance than Ligand B (91.091), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (29.247) has a longer in vitro half-life than Ligand B (7.561), which is desirable.

**14. P-gp Efflux:** Ligand A (0.141) has a lower P-gp efflux liability than Ligand B (0.146), which is slightly better.

**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 crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. Ligand B excels in affinity, while Ligand A has better metabolic stability and half-life. However, the substantial difference in binding affinity (-8.3 vs -6.7 kcal/mol) outweighs the benefits of Ligand A's better metabolic properties. The DILI risk of Ligand A is also a concern.

Output:
1
2025-04-17 11:06:42,386 - INFO - Batch 20 complete. Total preferences: 320
2025-04-17 11:06:42,386 - INFO - Processing batch 21/512...
2025-04-17 11:07:21,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 352.391 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.73) is better than Ligand B (122.55) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (0.59) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (-0.502) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better than Ligand B (3 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (0.562 and 0.569).

**DILI:** Ligand A (10.585) has a significantly lower DILI risk than Ligand B (54.517), which is a major advantage. Ligand B's DILI is concerningly high.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.107) shows better BBB penetration than Ligand B (48.081).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.447 and -5.28), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.437 and -2.107), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.125) has a much lower hERG inhibition liability than Ligand B (0.037), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (0.457) has a lower microsomal clearance than Ligand B (-0.244), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.101) has a worse in vitro half-life than Ligand B (-5.823), indicating faster metabolism.

**P-gp Efflux:** Both ligands have very low P-gp efflux values (0.004 and 0.013).

**Binding Affinity:** Ligand B (-9.5 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.

**Overall Assessment:**

While Ligand B has a much better binding affinity, its significantly higher DILI risk and poorer hERG profile are major concerns. Ligand A has a better safety profile (lower DILI, lower hERG) and better metabolic stability. Both have poor permeability and solubility, which would need to be addressed through formulation or further chemical modification. However, the superior binding affinity of Ligand B is a strong point in its favor. Given the importance of potency for kinase inhibitors, and assuming the permeability/solubility issues can be addressed, Ligand B is the more promising candidate.

Output:
1
2025-04-17 11:07:21,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 354.378 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (92.01). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**logP:** Both ligands have acceptable logP values (0.927 and 1.118), falling within the 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have similar QED scores (0.773 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A (10.508) has a significantly lower DILI risk than Ligand B (33.579). This is a major advantage for Ligand A.

**BBB:** Ligand B (86.817) has a higher BBB penetration percentile than Ligand A (38.232). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.779 and -4.659).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and problematic. Ligand B (-2.892) is slightly better than Ligand A (-1.216), but both are poor.

**hERG:** Ligand A (0.228) has a lower hERG inhibition liability than Ligand B (0.511), indicating a lower risk of cardiotoxicity. This is a significant advantage.

**Microsomal Clearance:** Ligand B (-3.874) has a more negative Cl_mic, indicating *lower* clearance and thus better metabolic stability than Ligand A (-0.658). This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (8.943) has a longer in vitro half-life than Ligand A (23.573). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.027) shows lower P-gp efflux liability than Ligand B (0.056), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This 1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better binding affinity and metabolic stability, Ligand A has a significantly lower DILI risk and hERG liability. The solubility issues are concerning for both, but the DILI and hERG profiles are critical for kinase inhibitors. Given the enzyme-specific priorities, the lower toxicity profile of Ligand A is more important than the slightly better affinity and metabolic stability of Ligand B.

Output:
0
2025-04-17 11:07:21,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.511 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for good oral absorption, but neither is optimized for CNS penetration (below 90).

**logP:** Both ligands have good logP values (3.138 and 2.126), 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 (0.699 and 0.592), suggesting decent drug-likeness.

**DILI:** Ligand A (57.348) has a significantly higher DILI risk than Ligand B (19.426). This is a major concern for Ligand A.

**BBB:** Ligand A (57.968) and Ligand B (73.633). BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.108) has poor Caco-2 permeability, while Ligand B (-4.423) is slightly better, but still suboptimal.

**Aqueous Solubility:** Ligand A (-3.744) has poor aqueous solubility, while Ligand B (-2.655) is better, but still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.253 and 0.37), which is positive.

**Microsomal Clearance:** Ligand A (57.363) has lower microsomal clearance than Ligand B (63.631), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.953) has a negative half-life, which is concerning. Ligand A (7.309) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.472 and 0.12).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.4 kcal/mol). The difference of 0.1 kcal/mol is not significant enough to outweigh other factors.

**Conclusion:**

While Ligand A has slightly better metabolic stability and half-life, its significantly higher DILI risk and poor solubility/permeability are major drawbacks. Ligand B, despite slightly higher clearance and a concerning negative half-life, presents a much better overall profile with a low DILI risk and better solubility. The half-life issue with Ligand B could potentially be addressed through structural modifications, while mitigating the DILI risk of Ligand A would be more challenging.

Output:
1
2025-04-17 11:07:21,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (352.387 and 362.47 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.33) is better than Ligand B (51.22), both are below the 140 threshold for oral absorption.

**3. logP:** Ligand A (-1.216) is suboptimal, being below 1, which might hinder permeation. Ligand B (4.06) is at the upper end of the optimal range, potentially causing solubility issues but 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 (6) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.625 and 0.843, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (50.174) has a lower DILI risk than Ligand B (63.513), both are acceptable.

**8. BBB:** Ligand A (53.703) has a lower BBB penetration than Ligand B (82.396). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have similar, very negative Caco-2 values (-4.847 and -4.765). This is concerning and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have very negative solubility values (-1.916 and -4.278), indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.06) shows a very low risk of hERG inhibition, significantly better than Ligand B (0.686).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-25.421) has a much lower (better) microsomal clearance than Ligand B (36.52). This suggests better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.938) has a shorter half-life than Ligand B (20.39).

**14. P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.813), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much better binding affinity. However, Ligand A has significantly better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. The solubility and permeability are poor for both, but the affinity difference is substantial. The improved metabolic stability and reduced toxicity of Ligand A are valuable, but the significantly better binding affinity of Ligand B likely outweighs these drawbacks, especially considering optimization can address solubility/permeability.

Output:
1
2025-04-17 11:07:21,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.204 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.46) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (75.71) is well below 140, indicating potentially good absorption.

**logP:** Both ligands have logP values within the optimal 1-3 range (1.689 and 2.112).

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 8 HBAs, while Ligand B has 4. Both are below the 10 limit.

**QED:** Both ligands have low QED scores (0.376 and 0.313), indicating suboptimal drug-likeness. This is a concern for both.

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a major red flag. Ligand B has a much lower DILI risk (44.591%), which is acceptable.

**BBB:** Both have reasonable BBB penetration (72.16 and 79.604%), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-4.785), indicating poor permeability. Ligand B has a negative value as well (-4.296), also indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.709 and -2.262), suggesting very poor aqueous solubility, which is a significant issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.378 and 0.488), which is good.

**Microsomal Clearance:** Ligand A has a moderate Cl_mic (80.406), while Ligand B has a higher Cl_mic (84.462). Both are relatively high, suggesting moderate metabolic instability.

**In vitro Half-Life:** Ligand A has a very short half-life (0.16 hours), indicating rapid metabolism. Ligand B has a negative half-life (-19.076 hours), which is nonsensical and suggests a problem with the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.198 and 0.243), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.4 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. The primary reason is the drastically lower DILI risk (44.591% vs 99.147%). While both have poor solubility and permeability, the DILI risk associated with Ligand A is unacceptable. The negative half-life for Ligand B is a data quality issue that would need to be resolved, but the other properties are more favorable.

Output:
1
2025-04-17 11:07:21,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.442 and 344.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.68) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (113.86) is still under 140, but less optimal than A.

**logP:** Ligand A (2.182) is within the optimal 1-3 range. Ligand B (0.609) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (4 HBD, 4 HBA) is acceptable, but the 4 HBDs are less desirable than A's 0.

**QED:** Both ligands have acceptable QED values (0.765 and 0.651, both >0.5).

**DILI:** Ligand A (45.715) has a lower DILI risk than Ligand B (56.456), which is preferable. Both are below the concerning 60 threshold.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (82.009) is significantly better than Ligand B (21.326).

**Caco-2 Permeability:** Ligand A (-4.557) is better than Ligand B (-5.521), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.073) is better than Ligand B (-2.441), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.359) has a much lower hERG risk than Ligand B (0.065), a critical factor for safety.

**Microsomal Clearance:** Ligand A (10.839) has a much better (lower) microsomal clearance than Ligand B (-37.743), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.862) has a longer half-life than Ligand B (-10.838), which is desirable.

**P-gp Efflux:** Ligand A (0.388) has lower P-gp efflux than Ligand B (0.002), which is preferable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 1.1 kcal/mol, which is a good advantage, but not overwhelming considering the ADME profile.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, but Ligand A is superior in almost every ADME property, particularly metabolic stability (Cl_mic and t1/2), solubility, hERG risk, and DILI risk. The better ADME profile of Ligand A is more important for an enzyme target like SRC kinase, as it increases the likelihood of achieving adequate *in vivo* exposure and minimizing potential toxicity.

Output:
0
2025-04-17 11:07:21,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.547 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (49.41 and 49.85) well below the 140 threshold for good absorption.

**logP:** Ligand A (4.28) is slightly above the optimal range (1-3), while Ligand B (2.299) is within the optimal range. This gives a slight edge to Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (0 HBD, 3 HBA) both have acceptable numbers of hydrogen bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have QED values (0.745 and 0.692) above 0.5, indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (21.791 and 22.257 percentiles), which is favorable.

**BBB:** Ligand A (83.288) has a better BBB penetration percentile than Ligand B (65.413). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.7) has slightly better Caco-2 permeability than Ligand B (-4.097).

**Aqueous Solubility:** Ligand A (-4.246) has slightly better aqueous solubility than Ligand B (-2.638).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.62 and 0.41), which is excellent.

**Microsomal Clearance:** Ligand B (56.336 mL/min/kg) has significantly lower microsomal clearance than Ligand A (75.869 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-11.684 hours) has a substantially longer in vitro half-life than Ligand A (-4.847 hours). This is another significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.444 and 0.145). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While this is a positive for Ligand A, the difference is relatively small.

**Overall Assessment:**

Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic) and longer half-life. While Ligand A has a slightly better binding affinity and solubility, the improvements in metabolic stability and half-life for Ligand B are more critical for an enzyme target like SRC kinase. The logP value for Ligand B is also more optimal.

Output:
1
2025-04-17 11:07:21,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.459 Da and 382.961 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.02) is slightly above the preferred <140, but acceptable. Ligand B (51.02) is excellent, well below 140.

**logP:** Ligand A (0.307) is quite low, potentially hindering permeability. Ligand B (4.616) is high, potentially causing solubility/off-target issues, but within a tolerable range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, fitting the guidelines. Ligand B has 0 HBD and 5 HBA, also fitting the guidelines.

**QED:** Both ligands have good QED scores (0.496 and 0.702), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (45.328). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (83.792) is better than Ligand B (66.731). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.942 and -4.852), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.563 and -4.544), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.535) has a slightly higher hERG risk than Ligand B (0.737), though both are relatively low.

**Microsomal Clearance:** Ligand A (79.899) has a higher microsomal clearance than Ligand B (74.005), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (55.584) has a significantly longer in vitro half-life than Ligand A (-64.379), which is a major advantage.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux than Ligand B (0.699), which is favorable.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.7), although the difference is small.

**Overall Assessment:**

Ligand B is the better candidate. While its logP is a bit high and solubility is poor, it has a significantly better in vitro half-life, lower DILI risk, and slightly better binding affinity. Ligand A's low logP and higher DILI risk are significant drawbacks. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, metabolic stability (half-life) and safety (DILI) are crucial, and Ligand B performs better in these areas.

Output:
1
2025-04-17 11:07:21,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.25 and 361.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.39) is slightly higher than Ligand B (64), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.536 and 3.053, respectively), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=7) as it has fewer hydrogen bond acceptors, which can sometimes hinder permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.673 and 0.716), indicating good drug-like properties.

**DILI:** Ligand B (57.968) has a considerably lower DILI risk than Ligand A (83.017). This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (77.007 and 71.035), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.417) has a worse Caco-2 permeability than Ligand B (-5.311), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand B (-3.288) has better aqueous solubility than Ligand A (-5.468). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.621 and 0.779).

**Microsomal Clearance:** Ligand A (58.572) has a lower microsomal clearance than Ligand B (81.799), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (94.356) has a significantly longer in vitro half-life than Ligand A (23.784). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.277 and 0.371).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 1.2 kcal/mol difference is significant, but needs to be weighed against the ADME properties.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates a superior ADME profile. Specifically, the lower DILI risk, better solubility, and *much* longer half-life of Ligand B are critical advantages for a kinase inhibitor. The difference in binding affinity (1.2 kcal/mol) is likely outweighed by the improved pharmacokinetic properties of Ligand B. The lower Caco-2 permeability of Ligand B is a concern, but the longer half-life could compensate for this.

Output:
1
2025-04-17 11:07:21,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.364 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.7) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.12 and 2.891), 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 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.771 and 0.633), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.452, which is higher than Ligand B's 36.603. This is a significant concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (71.035) has a higher BBB percentile than Ligand A (44.009), but this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.099 and -4.612), 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 (-3.778 and -3.807), also unusual, suggesting poor aqueous solubility. This is a concern for both.

**hERG:** Ligand A (0.208) has a slightly higher hERG risk than Ligand B (0.468), but both are relatively low.

**Microsomal Clearance:** Ligand A (19.958 mL/min/kg) has significantly lower microsomal clearance than Ligand B (74.402 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-4.121 hours) has a negative half-life, which is not possible and likely an error in the data. Ligand B (-15.085 hours) also has a negative half-life, indicating a problem with the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.326).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.9 kcal/mol).

**Overall Assessment:**

Despite the questionable half-life and solubility data, Ligand A appears more promising due to its significantly lower microsomal clearance (better metabolic stability) and lower DILI risk. The binding affinity is comparable between the two. The negative solubility and Caco-2 values are concerning for both, but can potentially be addressed through formulation strategies. The lower DILI risk for Ligand B is attractive, but the higher clearance is a significant drawback for an enzyme target.

Output:
1
2025-04-17 11:07:21,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.49) is slightly better being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (71.09). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (2.514) is optimal, while Ligand B (4.124) is pushing the upper limit. High logP can lead to poor solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=4). Lower numbers are generally better for permeability.

**QED:** Ligand B (0.812) has a better QED score than Ligand A (0.375), indicating a more drug-like profile overall. However, QED is a composite score and doesn't outweigh individual problematic properties.

**DILI:** Ligand B (77.007) has a significantly higher DILI risk than Ligand A (19.504). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (68.05) is better than Ligand B (31.989).

**Caco-2 Permeability:** Ligand A (-4.264) is better than Ligand B (-4.915), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.343) is better than Ligand B (-4.25), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.27) has a lower hERG risk than Ligand B (0.466), which is a significant advantage.

**Microsomal Clearance:** Ligand B (33.32) has a significantly lower Cl_mic than Ligand A (61.98), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (78.469) has a much longer half-life than Ligand A (-2.602), which is highly desirable.

**P-gp Efflux:** Ligand A (0.152) has a lower P-gp efflux liability than Ligand B (0.141).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.8 kcal/mol difference is substantial and could potentially overcome some of the ADME liabilities.

**Overall Assessment:**

Ligand A has better physicochemical properties (MW, TPSA, logP, HBD/HBA, solubility, permeability, hERG, and DILI). However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer half-life) and a substantially stronger binding affinity. The DILI risk for Ligand B is a major concern, but the binding affinity advantage is significant. Given that SRC is an intracellular target, metabolic stability and potency are paramount. While the DILI risk is concerning, it might be mitigated through structural modifications in later stages of optimization. The stronger binding affinity of Ligand B is likely to translate to greater efficacy *in vivo*.

Output:
1
2025-04-17 11:07:21,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.487 and 347.371 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.8) is well below the 140 threshold, suggesting good absorption. Ligand B (120.78) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (1.843) is optimal. Ligand B (0.347) is quite low, potentially hindering membrane permeability.

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

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) both fall within the acceptable limit of <=10.

**QED:** Ligand A (0.715) has a better QED score than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Ligand A (10.624) has a significantly lower DILI risk than Ligand B (49.632), which is a substantial advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (51.997) is higher than Ligand B (30.942), but this is less important.

**Caco-2 Permeability:** Ligand A (-4.754) is better than Ligand B (-5.76), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.811) is better than Ligand B (-2.629), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.801) has a lower hERG risk than Ligand B (0.064), a critical advantage.

**Microsomal Clearance:** Ligand A (34.776) has a higher (worse) microsomal clearance than Ligand B (3.148), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (5.842) has a longer half-life than Ligand B (-3.967), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.343) has lower P-gp efflux than Ligand B (0.019), which is beneficial.

**Binding Affinity:** Ligand A (-8.6) has a significantly stronger binding affinity than Ligand B (0.0). This is the most important factor for an enzyme inhibitor. The difference of 8.6 kcal/mol is substantial and likely outweighs most of the ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand A having a higher microsomal clearance, its significantly superior binding affinity (-8.6 vs 0.0 kcal/mol), lower DILI risk, lower hERG risk, better solubility, and better QED make it the more promising drug candidate. The potency advantage is substantial enough to compensate for the slightly reduced metabolic stability.

Output:
1
2025-04-17 11:07:21,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.451 and 367.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.96) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (92.51) is excellent, well below 140.

**logP:** Ligand A (0.19) is quite low, potentially hindering permeability. Ligand B (1.077) is better, within the 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is excellent.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.535, B: 0.728), indicating drug-like properties. Ligand B is better.

**DILI:** Both ligands have low DILI risk (A: 33.307, B: 36.797), below the 40 threshold.

**BBB:** Ligand A (32.532) has a low BBB penetration score. Ligand B (65.452) is significantly better, although not exceptionally high. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.762 and -5.18), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.44 and -2.16), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.194, B: 0.05), which is excellent.

**Microsomal Clearance:** Ligand A (10.783) has a moderate clearance, while Ligand B (6.221) has a lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.987) has a significantly longer half-life than Ligand A (-6.269), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.023, B: 0.067).

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.8 kcal/mol, B: -8.2 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have strong binding affinities and low hERG risk, Ligand B is the more promising candidate. It has a better logP, QED, lower microsomal clearance (better metabolic stability), and a significantly longer in vitro half-life. Although both have poor Caco-2 and solubility, Ligand B's other advantages make it a better starting point for optimization. The lower logP of Ligand A is a significant concern for permeability.

Output:
1
2025-04-17 11:07:21,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.259 Da) is slightly higher than Ligand B (361.511 Da), but both are acceptable.

**TPSA:** Ligand A (83.48) is slightly higher than Ligand B (54.46). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have a logP of approximately 2.78, which is within the optimal range of 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:** Ligand B (0.876) has a significantly higher QED score than Ligand A (0.653), indicating better overall drug-likeness.

**DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (38.775). Ligand B is well below the 40 threshold, while Ligand A is above.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (92.323) has a much higher BBB penetration percentile than Ligand A (46.375).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.946) is slightly worse than Ligand B (-4.873).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.945) is slightly worse than Ligand B (-3.391).

**hERG Inhibition:** Ligand A (0.492) has a slightly higher hERG inhibition risk than Ligand B (0.615). Lower is better here.

**Microsomal Clearance:** Ligand A (31.93) has a significantly lower microsomal clearance than Ligand B (58.647), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.759) has a lower in vitro half-life than Ligand B (4.567).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.194 and 0.362 respectively).

**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.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability (lower Cl_mic) and a slightly better hERG profile, the significantly stronger binding affinity of Ligand B (-7.9 kcal/mol vs 0.0 kcal/mol) outweighs these minor advantages. Furthermore, Ligand B exhibits a better QED score, lower DILI risk, and better BBB penetration. The poor Caco-2 and solubility for both can be addressed with formulation strategies. The substantial difference in binding affinity makes Ligand B the clear choice for further development.

Output:
1
2025-04-17 11:07:21,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.479 and 357.407 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.11) is better than Ligand B (119.41). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**3. logP:** Ligand A (-0.187) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (-2.058) is also on the lower side, raising similar concerns.

**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 QED values above 0.5 (0.533 and 0.46), indicating good drug-like properties.

**7. DILI:** Ligand A (4.769) has a significantly lower DILI risk than Ligand B (16.44). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (43.699) has a lower BBB penetration than Ligand B (17.138), but BBB is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.207 and -5.411), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.05 and -0.962), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.149) has a lower hERG inhibition risk than Ligand B (0.026), which is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand A (-5.728) has a lower (better) microsomal clearance than Ligand B (-2.72). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (8.43) has a shorter half-life than Ligand B (12.294), but the difference isn't huge.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.002).

**15. 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, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a significantly higher DILI risk and worse metabolic stability. Ligand A has better safety (DILI, hERG) and metabolic stability, but its affinity is considerably weaker. Considering the balance, the stronger binding of Ligand B is likely to be more impactful in driving efficacy, and optimization could potentially address the DILI and metabolic stability concerns.

Output:
1
2025-04-17 11:07:21,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.829 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (82.53) is significantly better than Ligand B (104.7). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.137) is optimal, while Ligand B (1.355) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

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

**QED:** Ligand A (0.791) is better than Ligand B (0.615), indicating a more drug-like profile.

**DILI:** Ligand B (43.195) has a significantly lower DILI risk than Ligand A (84.374). This is a major advantage for Ligand B.

**BBB:** Ligand B (65.297) has a higher BBB penetration percentile than Ligand A (38.852), but BBB is less critical for a non-CNS target like SRC.

**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 (0.046) has a much lower hERG inhibition liability than Ligand B (0.277), which is a significant advantage.

**Microsomal Clearance:** Ligand A (18.919) has a much lower microsomal clearance than Ligand B (67.039), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.978) has a positive half-life, while Ligand B (-33.23) has a negative half-life. This is a strong indicator of better stability for Ligand A.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux liability than Ligand B (0.11).

**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 that can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and lower DILI risk. However, it suffers from lower logP, higher P-gp efflux, and significantly worse metabolic stability (higher Cl_mic, negative half-life). Ligand A has better ADME properties overall (logP, TPSA, Cl_mic, t1/2, P-gp, hERG), but its binding affinity is weaker.

Given the enzyme-specific priorities, potency (binding affinity) is crucial. The 1.7 kcal/mol difference in binding affinity is substantial. While Ligand B's ADME profile is concerning, optimization efforts could potentially address the metabolic stability and permeability issues. The lower DILI risk is also a significant benefit. The superior binding affinity of Ligand B is likely to translate to greater efficacy, making it the more promising candidate despite its ADME liabilities.

Output:
1
2025-04-17 11:07:21,674 - INFO - Batch 21 complete. Total preferences: 336
2025-04-17 11:07:21,674 - INFO - Processing batch 22/512...
2025-04-17 11:08:07,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is slightly higher than Ligand B (68.62), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (1.668 and 1.503), falling within the 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 here.

**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 (0.732 and 0.647), indicating good drug-like properties.

**DILI:** Ligand A (31.679) has a significantly lower DILI risk than Ligand B (8.957), indicating a better safety profile. This is a crucial advantage.

**BBB:** Ligand A (40.558) has a lower BBB penetration than Ligand B (82.513). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-5.096) has worse Caco-2 permeability than Ligand B (-4.633), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.196) has worse aqueous solubility than Ligand B (-0.915). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.226) has a lower hERG inhibition risk than Ligand B (0.421), which is a significant advantage regarding cardiotoxicity.

**Microsomal Clearance:** Ligand A (3.692) has significantly lower microsomal clearance than Ligand B (46.934), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (19.562) has a shorter in vitro half-life than Ligand B (34.037), but both are reasonably good.

**P-gp Efflux:** Ligand A (0.033) has lower P-gp efflux than Ligand B (0.012), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability and solubility, Ligand A excels in the most critical areas for an enzyme inhibitor: significantly lower DILI risk, substantially lower microsomal clearance (better metabolic stability), lower hERG risk, and a slightly stronger binding affinity. The differences in permeability and solubility are less critical given the overall profile.

Output:
0
2025-04-17 11:08:07,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.39 and 340.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.48) is slightly higher than Ligand B (58.2). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (1.108) is within the optimal range, while Ligand B (2.38) is also good.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.811) has a better QED score than Ligand B (0.73), indicating a more drug-like profile.

**DILI:** Ligand B (19.7) has a significantly lower DILI risk than Ligand A (42.5). This is a major advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.5) is higher than Ligand B (36.1).

**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 Inhibition:** Ligand A (0.37) has a lower hERG risk than Ligand B (0.145), which is preferable.

**Microsomal Clearance:** Ligand A (-6.76) shows significantly better metabolic stability (lower clearance) than Ligand B (1.329). This is a crucial advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-31.261) has a much longer half-life than Ligand B (6.647), which is highly desirable.

**P-gp Efflux:** Both are very low (0.061 and 0.073), indicating minimal P-gp efflux.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.2). 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 and a much lower DILI risk. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED score. The difference in binding affinity is significant, and the lower DILI risk of Ligand B is a major advantage. While Ligand A's metabolic stability is better, the potency of Ligand B is likely to be more impactful, and metabolic stability can be improved through further optimization. The solubility and permeability issues are similar for both and would need to be addressed regardless.

Output:
1
2025-04-17 11:08:07,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.539 Da) is slightly higher than Ligand B (354.523 Da), but both are acceptable.

**TPSA:** Ligand A (60.25) is higher than Ligand B (41.91). Both are below the 140 threshold for oral absorption, but lower is generally better. Ligand B is preferable here.

**logP:** Both ligands have good logP values (A: 2.766, B: 3.981), 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.

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

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have similar and good QED values (A: 0.739, B: 0.752), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 70.221, while Ligand B has 40.016. Ligand B is significantly better, falling well below the 60 threshold for high risk.

**BBB:** Ligand A (68.592) and Ligand B (81.621) both have acceptable BBB penetration, but Ligand B is better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.099 and -5.421). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value is not necessarily indicative of complete lack of permeability, but rather lower than expected.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.978 and -3.028). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.352) has a lower hERG risk than Ligand B (0.805), which is preferable.

**Microsomal Clearance:** Ligand A (69.438) has a higher clearance than Ligand B (65.521), suggesting lower metabolic stability. Ligand B is slightly better here.

**In vitro Half-Life:** Ligand B (12.168 hours) has a significantly longer half-life than Ligand A (6.279 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.167) has lower P-gp efflux than Ligand B (0.495), which is preferable.

**Binding Affinity:** Ligand A (-6.9 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference, and a >1.5 kcal/mol advantage often outweighs other drawbacks.

**Overall Assessment:**

While both compounds have poor solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-6.9 vs -0.0 kcal/mol) is a decisive advantage for an enzyme inhibitor. The lower DILI risk and P-gp efflux of Ligand A are also beneficial. Although Ligand B has a better half-life, the potency difference is more critical for kinase inhibitors. The slightly higher hERG risk for Ligand B is a concern, but potentially manageable.

Output:
0
2025-04-17 11:08:07,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.443 Da and 362.514 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.25) is higher than the preferred <140, but still acceptable. Ligand B (25.36) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (1.813) is within the optimal 1-3 range. Ligand B (4.827) is slightly high, potentially leading to solubility issues 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 similar QED values (0.657 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (74.68) has a higher DILI risk than Ligand B (30.826). This is a significant concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B (95.231) has high BBB penetration, while Ligand A (27.414) has low penetration, but this is not a major factor here.

**Caco-2 Permeability:** Ligand A (-5.463) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.503) is also low, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-3.711) has poor aqueous solubility. Ligand B (-5.635) is even worse. This is a concern for both, but potentially more so for Ligand B due to its higher logP.

**hERG Inhibition:** Ligand A (0.248) has a very low hERG risk, which is excellent. Ligand B (0.886) has a moderate hERG risk, requiring further investigation.

**Microsomal Clearance:** Ligand A (47.189) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (105.886) has high clearance, indicating poor metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (6.782) has a moderate half-life. Ligand B (3.753) has a short half-life, which is undesirable.

**P-gp Efflux:** Ligand A (0.045) has low P-gp efflux, which is favorable. Ligand B (0.869) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have comparable 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.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While it has a higher DILI risk and lower Caco-2 permeability than Ligand B, it has significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. The binding affinity difference is minimal. The poor solubility of both is a concern, but can be addressed with formulation strategies. The higher DILI risk of Ligand A is a concern, but potentially mitigatable through further structural modifications. The poor metabolic stability of Ligand B is a more difficult issue to resolve.

Output:
0
2025-04-17 11:08:07,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.366 and 370.837 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (116.88 and 104.65) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (0.625 and 0.557) are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 6 HBAs, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.781 and 0.758), indicating drug-like properties.

**DILI:** Ligand A (47.15) has a slightly better DILI score than Ligand B (51.493), indicating a lower risk of liver injury. Both are still reasonably good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.282) has a slightly better BBB score than Ligand B (51.609).

**Caco-2 Permeability:** Both are quite poor (-5.007 and -4.754), suggesting limited intestinal absorption. This is a concern for both.

**Aqueous Solubility:** Both are very poor (-2.148 and -1.801), which is a significant drawback. Poor solubility can limit bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.132 and 0.171). This is excellent.

**Microsomal Clearance:** Ligand A (-11.356) has *much* better microsomal clearance (more negative, indicating lower clearance) than Ligand B (11.551). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-30.635) has a much longer in vitro half-life than Ligand B (4.149), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.017).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). This is a 0.8 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better in terms of metabolic stability (Cl_mic and t1/2) and has a slightly better DILI score. The poor solubility and Caco-2 permeability are concerns for both, but metabolic stability is a critical factor for kinase inhibitors. A compound with poor metabolic stability will likely have a short duration of action and require high doses, potentially leading to toxicity. Given the enzyme-specific priorities, the superior metabolic properties of Ligand A outweigh the slightly weaker binding affinity.

Output:
0
2025-04-17 11:08:07,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (473.14 Da) is within the ideal range, while Ligand B (350.459 Da) is also acceptable, though on the lower end.

**TPSA:** Ligand A (56.15) is good for oral absorption. Ligand B (87.66) is still reasonable, but less optimal.

**logP:** Ligand A (3.948) is at the upper end of the optimal range, potentially leading to solubility issues. Ligand B (0.977) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable.

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

**QED:** Ligand A (0.735) is excellent. Ligand B (0.541) is acceptable, but less drug-like.

**DILI:** Ligand A (76.425) has a high DILI risk. Ligand B (11.4) has a very low DILI risk, a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (89.725) is higher than Ligand B (49.981).

**Caco-2:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, making direct comparison difficult.

**Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unclear.

**hERG:** Ligand A (0.583) is reasonably low risk. Ligand B (0.118) is very low risk, another substantial advantage.

**Microsomal Clearance:** Ligand A (76.617) has high clearance, indicating poor metabolic stability. Ligand B (0.116) has very low clearance, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (24.562) is a moderate half-life. Ligand B (0.615) has a very short half-life, a significant drawback.

**P-gp Efflux:** Ligand A (0.715) is reasonable. Ligand B (0.022) is very low, indicating minimal efflux.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a crucial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate despite its lower half-life. The substantially improved binding affinity (-7.8 vs -9.0 kcal/mol) and significantly lower DILI and hERG risks are major advantages. The excellent metabolic stability (low Cl_mic) is also a key benefit for an enzyme target. While the lower logP and half-life are concerns, these can potentially be addressed through further optimization. Ligand A's high DILI risk and poor metabolic stability are more difficult to overcome.

Output:
1
2025-04-17 11:08:07,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.523 and 360.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (101.8). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA might hinder absorption.

**logP:** Ligand A (3.597) is optimal, while Ligand B (1.144) is on the lower side. A logP between 1-3 is preferred, and Ligand B's value could lead to permeability issues.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 7.  Ligand A is better here, as higher HBA can sometimes reduce permeability.

**QED:** Both ligands have similar QED values (0.762 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (35.789) has a much lower DILI risk than Ligand B (59.519). This is a significant advantage for Ligand A.

**BBB:** Ligand A (65.839) has better BBB penetration than Ligand B (47.15), though neither is exceptionally high. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.114) has better Caco-2 permeability than Ligand B (-5.567).

**Aqueous Solubility:** Ligand A (-4.272) has better aqueous solubility than Ligand B (-2.119). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.306 and 0.207, respectively).

**Microsomal Clearance:** Ligand A (41.158) has higher microsomal clearance than Ligand B (13.481). Ligand B is significantly more metabolically stable, which is a crucial advantage for kinase inhibitors.

**In vitro Half-Life:** Ligand B (13.736) has a significantly longer in vitro half-life than Ligand A (0.716). 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 (0.192 and 0.12, respectively).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a stronger binding affinity than Ligand B (-6.8 kcal/mol). The difference of 1.0 kcal/mol is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better TPSA, logP, solubility, and lower DILI risk. However, Ligand B exhibits significantly better metabolic stability (lower Cl_mic and longer t1/2). Given that we are targeting a kinase, metabolic stability is paramount. While the affinity difference is notable, a kinase inhibitor with poor metabolic stability will likely have limited in vivo efficacy. The improved solubility of Ligand A is also a plus.

Output:
0
2025-04-17 11:08:07,436 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (346.475 Da) is within the ideal range (200-500). Ligand B (368.396 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (64.68) is good, below the 140 threshold for oral absorption. Ligand B (67.87) is also good. No clear advantage.

3. **logP:** Ligand A (1.991) is optimal (1-3). Ligand B (1.593) is also optimal. No clear advantage.

4. **HBD:** Ligand A (2) is within the acceptable limit (<=5). Ligand B (1) is also within the acceptable limit. No clear advantage.

5. **HBA:** Ligand A (3) is within the acceptable limit (<=10). Ligand B (4) is also within the acceptable limit. No clear advantage.

6. **QED:** Ligand A (0.757) is excellent, indicating good drug-likeness. Ligand B (0.636) is also good, but slightly lower. Ligand A has a slight advantage.

7. **DILI:** Ligand A (11.322) has a very low DILI risk. Ligand B (21.869) is higher, but still relatively low. Ligand A has a clear advantage.

8. **BBB:** Ligand A (64.637) has moderate BBB penetration. Ligand B (89.841) has good BBB penetration. Ligand B has a clear advantage. However, SRC is not a CNS target, so this is less important.

9. **Caco-2:** Ligand A (-5.039) and Ligand B (-4.648) both have negative values, which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

10. **Solubility:** Ligand A (-1.037) and Ligand B (-1.684) both have negative values, suggesting poor solubility. This is a concern for both, but Ligand A is slightly better.

11. **hERG:** Ligand A (0.367) has a very low hERG risk. Ligand B (0.534) is slightly higher, but still relatively low. Ligand A has a slight advantage.

12. **Cl_mic:** Ligand A (-11.254) has a very low microsomal clearance, indicating good metabolic stability. Ligand B (32.334) has a higher clearance, suggesting faster metabolism. Ligand A has a significant advantage.

13. **t1/2:** Ligand A (2.476) has a short in vitro half-life. Ligand B (-7.781) has a very long in vitro half-life. Ligand B has a significant advantage.

14. **Pgp:** Ligand A (0.004) has very low P-gp efflux. Ligand B (0.042) also has very low P-gp efflux. No clear advantage.

15. **Binding Affinity:** Ligand A (-7.2 kcal/mol) and Ligand B (-7.6 kcal/mol) both have good binding affinity. Ligand B is slightly better, with a 0.4 kcal/mol advantage.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and a significantly longer half-life. However, Ligand A has a much lower DILI risk, better metabolic stability (lower Cl_mic), and a lower hERG risk. The solubility and Caco-2 values are poor for both, but the metabolic stability and safety profile of Ligand A are more appealing for initial development. The 0.4 kcal/mol difference in binding affinity is not substantial enough to overcome the superior ADME/Tox profile of Ligand A.

**Output:**
0
2025-04-17 11:08:07,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.459 Da) is slightly higher than Ligand B (344.463 Da), but both are acceptable.

**TPSA:** Ligand A (119.74) is better than Ligand B (81.66), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 1.102, B: 2.833), 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 7 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.613, B: 0.714), indicating good drug-like properties.

**DILI:** Ligand B (37.611) has a significantly lower DILI risk than Ligand A (68.476). This is a major advantage for Ligand B.

**BBB:** Ligand B (69.833) has a higher BBB penetration percentile than Ligand A (30.632), but BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**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:** Both ligands show low hERG inhibition liability (A: 0.357, B: 0.173), which is excellent.

**Microsomal Clearance:** Ligand A (32.506) has lower microsomal clearance than Ligand B (42.134), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.44) has a much longer in vitro half-life than Ligand B (-8.086). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.115, B: 0.344).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.1 kcal/mol, B: -9.9 kcal/mol). Ligand B is slightly better (-9.9 vs -9.1).

**Overall Assessment:**

Ligand B has a better binding affinity and significantly lower DILI risk. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2). The slightly better affinity of Ligand B is likely to outweigh the better metabolic stability of Ligand A, especially given the low DILI risk. The negative solubility and Caco-2 values are concerning for both, but the potency is high enough to warrant further investigation.

Output:
1
2025-04-17 11:08:07,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (49.41) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.89) is optimal, while Ligand B (3.204) is slightly higher but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 2 HBA, which is within the acceptable limit of <=10.

**QED:** Ligand B (0.893) has a significantly better QED score than Ligand A (0.571), indicating a more drug-like profile.

**DILI:** Ligand A (19.736) has a much lower DILI risk than Ligand B (26.095), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (77.2) is higher than Ligand A (55.603).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand B (-4.762) is slightly worse than Ligand A (-4.59).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-4.48) is slightly better than Ligand B (-3.334).

**hERG Inhibition:** Ligand A (0.28) has a lower hERG inhibition liability than Ligand B (0.549), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand B (63.719 mL/min/kg) has a higher microsomal clearance than Ligand A (56.386 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (9.175 hours) has a much longer half-life than Ligand B (-18.312 hours), which is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.337 and 0.344 respectively).

**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 some of the ADME drawbacks.

**Conclusion:**

While Ligand B has a superior binding affinity and QED, Ligand A demonstrates a significantly better safety profile (lower DILI, lower hERG) and improved metabolic stability (lower Cl_mic, longer t1/2). Given the enzyme-specific priorities, the improved safety and stability profile of Ligand A, combined with acceptable potency, makes it the more viable drug candidate. The affinity difference, while notable, is not large enough to overcome the ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 11:08:07,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.511 and 343.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.51) is slightly higher than Ligand B (35.5). Both are below the 140 threshold for good absorption, but Ligand B is significantly better.

**logP:** Both ligands (2.887 and 2.943) are within the optimal 1-3 range.

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

**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 good QED scores (0.783 and 0.84), indicating drug-likeness.

**DILI:** Both ligands have similar, low DILI risk (34.277 and 34.703 percentile), which is favorable.

**BBB:** Both have high BBB penetration (90.927 and 87.515 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.035 and -4.995). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.838 and -2.266). This is also concerning, indicating very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.664) has slightly lower hERG inhibition risk than Ligand B (0.944), which is preferable.

**Microsomal Clearance:** Ligand A (48.701 mL/min/kg) has higher clearance than Ligand B (29.536 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (17.617 hours) has a significantly longer half-life than Ligand A (5.932 hours), which is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.327 and 0.355).

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 0.3 kcal/mol difference is not substantial enough to outweigh the ADME concerns of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower hERG risk. Both have poor solubility and permeability, which would require formulation strategies, but the metabolic advantage of Ligand B is more crucial for an enzyme target.

Output:
1
2025-04-17 11:08:07,437 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [356.457, 49.41, 3.355, 1, 2, 0.652, 23.42, 90.617, -4.55, -3.462, 0.763, 38.912, -3.18, 0.277, -8.5]
**Ligand B:** [351.491, 81.67, 0.892, 3, 4, 0.576, 5.971, 50.756, -5.268, -2.181, 0.339, 20.588, 15.063, 0.035, -8]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (356.457) and B (351.491) are very similar.
2. **TPSA:** A (49.41) is excellent, well below the 140 threshold. B (81.67) is higher, but still acceptable for many kinase inhibitors.
3. **logP:** A (3.355) is optimal. B (0.892) is a bit low, potentially hindering permeability.
4. **HBD:** A (1) is good. B (3) is acceptable, but higher HBD can sometimes lead to issues.
5. **HBA:** A (2) is good. B (4) is acceptable.
6. **QED:** A (0.652) is good, indicating a drug-like profile. B (0.576) is acceptable, but slightly lower.
7. **DILI:** A (23.42) is very good, indicating low liver injury risk. B (5.971) is also very good.
8. **BBB:** A (90.617) is excellent, suggesting good potential for brain penetration if desired. B (50.756) is lower, suggesting limited brain penetration.
9. **Caco-2:** A (-4.55) is a negative value, which is unusual and likely indicates very poor permeability. B (-5.268) is also very poor.
10. **Solubility:** A (-3.462) is very poor. B (-2.181) is also poor.
11. **hERG:** A (0.763) is good, low risk of cardiotoxicity. B (0.339) is also good.
12. **Cl_mic:** A (38.912) is moderate. B (20.588) is lower, indicating better metabolic stability.
13. **t1/2:** A (-3.18) is a negative value, indicating a very short half-life. B (15.063) is good.
14. **Pgp:** A (0.277) is good, suggesting low efflux. B (0.035) is excellent, suggesting very low efflux.
15. **Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 kcal/mol and -8 kcal/mol respectively). The difference is negligible.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both have excellent affinity and hERG profiles, Ligand B significantly outperforms Ligand A in metabolic stability (lower Cl_mic, longer t1/2). Both have poor solubility and permeability, which are significant drawbacks.

**Conclusion:**

Despite the similar affinities, **Ligand B** is the more promising candidate due to its superior metabolic stability and lower Pgp efflux. The better half-life and reduced efflux are critical for maintaining therapeutic concentrations *in vivo*. The poor solubility and permeability are concerning for both, but can potentially be addressed through formulation strategies. The poor Caco-2 and solubility of Ligand A, combined with its very short half-life, make it a less attractive starting point.

Output:
1
2025-04-17 11:08:07,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.442 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.12) is well below the 140 threshold, suggesting good absorption. Ligand B (96.11) is still within acceptable limits, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (4.513) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.139) is closer to the optimal range of 1-3.

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

**QED:** Both ligands have good QED scores (0.805 and 0.877), indicating generally drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (55.68 and 51.725), below the 60 threshold.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (80.962) shows better BBB penetration than Ligand B (63.862).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.745 and -4.86), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.754 and -1.804), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.837) has a slightly higher hERG risk than Ligand B (0.233), which is preferable.

**Microsomal Clearance:** Ligand B (29.474) has significantly lower microsomal clearance than Ligand A (70.326), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-20.877) has a negative half-life, which is not physically possible and indicates a very short half-life or instability. Ligand A (25.659) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux than Ligand B (0.143), which is favorable for bioavailability.

**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 and can outweigh some ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.5 vs -7.1 kcal/mol) is a major advantage for an enzyme target. While Ligand B has better metabolic stability, the substantial difference in binding affinity outweighs this benefit. The poor solubility and permeability will need to be addressed through formulation or further chemical modifications, but the strong binding affinity provides a better starting point for optimization.

Output:
0
2025-04-17 11:08:07,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 349.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.41) is slightly higher than Ligand B (74.49). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (1.518) and Ligand B (0.783) are both within the optimal 1-3 range. Ligand A is slightly preferable.

**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 (0.627 and 0.751), indicating drug-like properties.

**DILI:** Ligand B (8.569) has a significantly lower DILI risk than Ligand A (41.877), which is a major advantage.

**BBB:** Both have similar BBB penetration (52.656 and 53.238). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.661 and -4.862), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.947 and -0.174), indicating poor aqueous solubility. Ligand B is slightly better.

**hERG:** Both ligands have very low hERG inhibition liability (0.141), which is excellent.

**Microsomal Clearance:** Ligand A (24.963) has a higher microsomal clearance than Ligand B (5.321), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand B (17.33) has a much longer in vitro half-life than Ligand A (-49.667), indicating better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.044 and 0.037).

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

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 an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and substantially stronger binding affinity. The difference in binding affinity (-9.8 vs -7.1 kcal/mol) is a significant advantage that outweighs the slightly higher TPSA and lower logP of Ligand B.

Output:
1
2025-04-17 11:08:07,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.434 Da and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.07) is excellent, well below the 140 threshold for oral absorption. Ligand B (119.21) is still acceptable, but less optimal.

**logP:** Ligand A (1.858) is within the optimal 1-3 range. Ligand B (-1.831) is below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both meet the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED scores (0.81 and 0.537), indicating good drug-like properties.

**DILI:** Ligand A (72.586) has a moderate DILI risk, but is still acceptable. Ligand B (16.208) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.821) has a better BBB percentile than Ligand B (30.089).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, we should consider the other parameters.

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

**hERG:** Ligand A (0.514) has a low hERG risk, which is excellent. Ligand B (0.132) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (11.542) has a moderate microsomal clearance. Ligand B (-18.06) has a *negative* clearance, which is impossible and likely indicates an experimental error. This is a major red flag.

**In vitro Half-Life:** Ligand A (-0.718) has a negative half-life, which is also impossible and indicates an experimental error. Ligand B (-9.754) also has a negative half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.21 and 0.001).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), although both are excellent.

**Conclusion:**

Despite the unusual negative values for Caco-2, solubility, and half-life, the most significant issue is the negative microsomal clearance and half-life for Ligand B. These values are physically impossible and strongly suggest a problem with the data for Ligand B. While Ligand B has a better DILI score and similar P-gp efflux, the unreliable ADME data makes it a much riskier candidate. Ligand A, while also having questionable solubility and permeability data, at least has plausible values for clearance and half-life. The slightly better binding affinity of Ligand A further supports its selection.

Output:
0
2025-04-17 11:08:07,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (376.909 Da and 358.31 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.43) is slightly higher than Ligand B (41.99). Both are acceptable, but B is better for permeability.

**3. logP:** Both ligands have logP values around 4 (4.087 and 4.599). This is slightly high, potentially leading to solubility issues, but not a deal-breaker given the potency.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**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 (0.855) has a significantly higher QED than Ligand B (0.627), indicating a more drug-like profile.

**7. DILI:** Both have similar DILI risk (64.056 and 65.491), placing them in a moderate risk category.

**8. BBB:** Ligand B (84.917) has a higher BBB penetration percentile than Ligand A (70.531). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.512 and -4.601), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.287 and -5.276). This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.58) has a lower hERG inhibition risk than Ligand B (0.761), which is favorable.

**12. Microsomal Clearance:** Ligand A (52.517) has lower microsomal clearance than Ligand B (67.028), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (34.418) has a longer in vitro half-life than Ligand B (-5.468). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.692) has lower P-gp efflux than Ligand B (0.151), which is better for bioavailability.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have significant ADME liabilities (poor solubility and permeability), Ligand A is the more promising candidate. Its superior binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and higher QED outweigh the slightly higher TPSA. The stronger binding affinity is particularly important for an enzyme target like SRC kinase. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modifications, but the core potency and stability profile of Ligand A is more favorable.

Output:
0
2025-04-17 11:08:07,438 - INFO - Batch 22 complete. Total preferences: 352
2025-04-17 11:08:07,439 - INFO - Processing batch 23/512...
2025-04-17 11:08:48,248 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.3) is better than Ligand B (77.52) as it is closer to the 90 A^2 threshold, but both are acceptable.

**logP:** Ligand A (1.103) is optimal, while Ligand B (3.593) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is also good.

**QED:** Both ligands have similar QED values (0.809 and 0.841), indicating good drug-likeness.

**DILI:** Ligand A (39.162) has a lower DILI risk than Ligand B (46.413), which is preferable.

**BBB:** Ligand B (82.939) shows better BBB penetration than Ligand A (70.182), but this is less critical for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.905) has slightly better Caco-2 permeability than Ligand B (-4.051).

**Aqueous Solubility:** Ligand A (-1.784) has better aqueous solubility than Ligand B (-4.767), which is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.145 and 0.186).

**Microsomal Clearance:** Ligand A (14.148) has significantly lower microsomal clearance than Ligand B (119.696), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-8.357) has a better in vitro half-life than Ligand B (-4.732).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.033).

**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 less than the 1.5 kcal/mol threshold, it contributes to the overall preference for Ligand A.

**Overall:**

Ligand A is the better candidate. It has a lower DILI risk, better solubility, significantly better metabolic stability (lower Cl_mic and better half-life), and slightly better binding affinity. While Ligand B has better BBB penetration, this is less important for a kinase inhibitor targeting SRC. The improved pharmacokinetic properties of Ligand A outweigh the small advantage of Ligand B in BBB penetration.

Output:
0
2025-04-17 11:08:48,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.366 and 343.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (108.73 and 100.35) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (-0.227) is slightly low, potentially hindering permeation. Ligand B (0.527) is better, 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:** Both ligands have good QED scores (0.737 and 0.67), indicating good drug-like properties.

**7. DILI:** Ligand A (44.63) has a slightly higher DILI risk than Ligand B (22.722), but both are below the concerning threshold of 60.

**8. BBB:** Both have similar BBB penetration (64.637 and 67.584), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.045 and -5.56), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have negative solubility values (-2.8 and -1.712), also unusual and concerning, indicating very poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.345 and 0.324), which is excellent.

**12. Microsomal Clearance:** Ligand A (-12.726) has significantly lower (better) microsomal clearance than Ligand B (-5.83), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.496) has a longer in vitro half-life than Ligand B (5.872), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.004), which is favorable.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This difference of 0.8 kcal/mol is significant, and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is slightly favored due to its better logP, and significantly better binding affinity. The improved binding affinity (-8.1 vs -7.3 kcal/mol) is a substantial advantage for an enzyme target like SRC kinase. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), but the affinity difference is more critical. The poor solubility and permeability will need to be addressed in further optimization, but a stronger starting point with better affinity is preferred.

Output:
1
2025-04-17 11:08:48,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.335 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is well below the 140 threshold and quite favorable. Ligand B (87.3) is higher, but still within a reasonable range for oral absorption, though less optimal.

**logP:** Both ligands have good logP values (2.573 and 1.412), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is excellent. Ligand B (HBD=3, HBA=3) is also acceptable.

**QED:** Ligand A (0.649) has a better QED score than Ligand B (0.501), indicating better overall drug-likeness.

**DILI:** Ligand A (52.423) has a slightly higher DILI risk than Ligand B (35.634), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.149) has a higher BBB score than Ligand B (52.617).

**Caco-2 Permeability:** Ligand A (-4.45) has a worse Caco-2 permeability than Ligand B (-5.221), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.198) has a worse solubility score than Ligand B (-2.76), which is a concern.

**hERG:** Both ligands have very low hERG risk (0.605 and 0.095, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (5.862) has a significantly lower Cl_mic than Ligand B (24.034), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (10.637) has a slightly longer half-life than Ligand B (7.832).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.115 and 0.109).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.7 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better QED and metabolic stability, the significantly stronger binding affinity of Ligand B (-8.8 vs -7.1 kcal/mol) is the most important factor for an enzyme inhibitor. The slightly lower solubility and higher DILI risk of Ligand B are less concerning given the potency advantage. The difference in potency is substantial enough to make Ligand B the more promising candidate.

Output:
1
2025-04-17 11:08:48,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.279 Da and 344.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (84.08 and 82.78) are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (3.223 and 2.172) 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 acceptable.

**6. QED:** Both ligands have QED scores above 0.5 (0.651 and 0.806), indicating good drug-likeness.

**7. DILI:** Ligand A (91.237) has a significantly higher DILI risk than Ligand B (34.781). This is a major concern.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (74.292) is slightly higher than Ligand B (56.572), but this is not decisive.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.681 and -4.692), 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.

**10. Aqueous Solubility:** Ligand A (-5.033) has worse solubility than Ligand B (-2.412). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.679) has a slightly higher hERG risk than Ligand B (0.346), but both are reasonably low.

**12. Microsomal Clearance:** Ligand A (63.527) has a higher microsomal clearance than Ligand B (26.376), indicating faster metabolism and lower metabolic stability. This is a significant drawback.

**13. In vitro Half-Life:** Ligand B (72.462) has a much longer in vitro half-life than Ligand A (17.673), which is a strong positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.402 and 0.042).

**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 large enough to outweigh the ADME differences.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is significantly more promising. While both have good potency, Ligand B exhibits a much lower DILI risk, better solubility, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The slightly lower binding affinity of Ligand B is unlikely to be a major issue given its superior ADME profile.

Output:
1
2025-04-17 11:08:48,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.399 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (367.921 Da) is also good.

**TPSA:** Ligand A (93.73) is slightly above the preferred <140 for oral absorption but still reasonable. Ligand B (47.36) is excellent, suggesting good absorption.

**logP:** Ligand A (0.157) is quite low, potentially hindering membrane permeability. Ligand B (3.573) 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 acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.388) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.772) is well above 0.5, suggesting a more favorable drug-like profile.

**DILI:** Ligand A (54.556) has a moderate DILI risk. Ligand B (29.973) has a low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.587) and Ligand B (88.29) are both reasonable, with B being better.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is concerning, but less so for a kinase inhibitor where other administration routes might be considered.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a significant drawback for both compounds and could impact bioavailability.

**hERG Inhibition:** Ligand A (0.12) shows very low hERG inhibition risk. Ligand B (0.523) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (41.398) has moderate clearance. Ligand B (76.465) has higher clearance, suggesting lower metabolic stability. This is a disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-35.13) has a very short half-life. Ligand B (29.408) has a longer half-life, which is a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.7 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:**

Ligand B is the stronger candidate. While it has higher microsomal clearance, its superior binding affinity, better logP, lower DILI risk, and better QED score outweigh this drawback. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies. Ligand A's very low QED and short half-life are more problematic.



Output:
1
2025-04-17 11:08:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.491 and 343.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (84.81), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.706 and 2.505), falling within the 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.695 and 0.757), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (32.92 and 38.62), well below the 40 threshold.

**BBB:** Ligand B (76.347) has a higher BBB penetration score than Ligand A (54.75), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.566) has a better Caco-2 permeability than Ligand B (-4.814).

**Aqueous Solubility:** Ligand A (-2.431) has a better aqueous solubility than Ligand B (-3.625).

**hERG Inhibition:** Ligand A (0.241) has a lower hERG inhibition liability than Ligand B (0.868), which is a significant advantage.

**Microsomal Clearance:** Ligand B (26.39 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (44.882 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (16.231 hours) has a longer in vitro half-life than Ligand A (-17.807 hours), a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.14).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), but the difference is small (0.2 kcal/mol) and may not be decisive.

**Overall Assessment:**

Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and better BBB penetration. Ligand A has a slight advantage in binding affinity and solubility, and a significantly lower hERG risk. However, the improvements in metabolic stability and half-life offered by Ligand B are crucial for an enzyme target like SRC kinase. The slightly lower hERG risk of Ligand A is valuable, but the difference in binding affinity is small enough to be potentially overcome with further optimization.

Output:
1
2025-04-17 11:08:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.852 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is well below the 140 threshold for oral absorption, and even below the 90 for CNS penetration. Ligand B (87.23) is still under 140, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (2.728) is within the optimal 1-3 range. Ligand B (-0.482) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, both well within acceptable limits. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.832) has a very strong drug-like profile. Ligand B (0.626) is still good, but less optimal.

**DILI:** Both ligands have low DILI risk (33.501 and 32.067, respectively), which is positive.

**BBB:** Both have good BBB penetration (86.041 and 79.217), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.135 and -5.008), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-3.297 and -1.862), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG risk (0.316 and 0.058), which is excellent.

**Microsomal Clearance:** Ligand A (8.243) has lower microsomal clearance than Ligand B (11.307), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-4.321) has a longer in vitro half-life than Ligand B (4.618), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.074 and 0.011), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -9.5 kcal/mol), with Ligand B being slightly better. However, the affinity difference is small and may not outweigh other factors.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2), better QED score, and slightly better TPSA profile outweigh the minor affinity advantage of Ligand B. The poor solubility and permeability of both are concerning and would require significant medicinal chemistry efforts to address, but Ligand A's other properties make it a better starting point for optimization.

Output:
0
2025-04-17 11:08:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly preferred due to being lower in MW.

**TPSA:** Ligand A (85.69) is well below the 140 threshold for oral absorption. Ligand B (130.23) is still acceptable but less optimal.

**logP:** Ligand A (-0.012) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (1.442) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (4 HBD, 6 HBA) both fall within acceptable limits.

**QED:** Ligand A (0.76) has a better QED score than Ligand B (0.515), indicating a more drug-like profile.

**DILI:** Ligand B (72.896) has a higher DILI risk than Ligand A (63.086), which is undesirable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.578) is slightly better than Ligand B (56.96).

**Caco-2 Permeability:** Ligand A (-4.779) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.526) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.83) has poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-4.215) is even worse.

**hERG Inhibition:** Ligand A (0.043) has a very low hERG risk, a major advantage. Ligand B (0.416) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (Ligand A: 30.019, Ligand B: 29.753), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (23.747 hours) has a significantly longer half-life than Ligand B (-7.429 hours), which is a substantial benefit.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.021, Ligand B: 0.046).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a considerably stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a very important factor, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount for an enzyme inhibitor. While it has some ADME liabilities (higher DILI, lower solubility, and shorter half-life), the substantial improvement in potency is likely to be the deciding factor. Ligand A has better solubility and a longer half-life, but its weaker binding affinity is a major disadvantage. The slightly higher DILI risk of Ligand B can be investigated further through structural modifications.

Output:
1
2025-04-17 11:08:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**
*   **MW:** 339.395 Da - Good (within 200-500 range)
*   **TPSA:** 65.79 - Good (<=140)
*   **logP:** 2.363 - Good (1-3)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.932 - Excellent (>=0.5)
*   **DILI:** 61.07 - Moderate risk (slightly above 60, but not drastically)
*   **BBB:** 84.917 - Good (high percentile, potentially useful if CNS effects are desired, but not critical for SRC)
*   **Caco-2:** -4.84 - Very poor permeability. A significant negative value is concerning.
*   **Solubility:** -3.03 - Very poor solubility. A significant negative value is concerning.
*   **hERG:** 0.729 - Low risk.
*   **Cl_mic:** 44.937 - Moderate clearance.
*   **t1/2:** 22.779 - Good half-life.
*   **Pgp:** 0.425 - Low efflux.
*   **Affinity:** -8.8 kcal/mol - Excellent.

**Ligand B:**
*   **MW:** 351.451 Da - Good (within 200-500 range)
*   **TPSA:** 120 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 0.923 - Acceptable, but on the lower side.
*   **HBD:** 4 - Good (<=5)
*   **HBA:** 5 - Good (<=10)
*   **QED:** 0.607 - Good (>=0.5)
*   **DILI:** 56.146 - Good (below 60)
*   **BBB:** 36.371 - Low (not a priority for SRC)
*   **Caco-2:** -5.396 - Very poor permeability. A significant negative value is concerning.
*   **Solubility:** -2.667 - Poor solubility. A significant negative value is concerning.
*   **hERG:** 0.06 - Very low risk.
*   **Cl_mic:** 16.629 - Low clearance (good metabolic stability).
*   **t1/2:** -15.387 - Very short half-life (major concern).
*   **Pgp:** 0.037 - Very low efflux.
*   **Affinity:** -7.1 kcal/mol - Good.

**Comparison and Decision:**

Both ligands have very poor Caco-2 permeability and aqueous solubility. However, Ligand A has a significantly better binding affinity (-8.8 kcal/mol vs -7.1 kcal/mol). This 1.7 kcal/mol difference is substantial and could outweigh the permeability and solubility concerns *if* formulation strategies can be developed to address them. Ligand B has a very short in vitro half-life, which is a major drawback for a kinase inhibitor. While Ligand B has slightly better DILI and hERG profiles, the significant difference in binding affinity and half-life makes Ligand A the more promising candidate. The poor permeability and solubility of Ligand A would need to be addressed through formulation or prodrug strategies, but the strong binding affinity provides a better starting point for optimization.

Output:
1
2025-04-17 11:08:48,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.339 and 343.329 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly higher than Ligand B (59.32). Both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (2.472) is within the optimal 1-3 range. Ligand B (3.834) is pushing the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Ligand B (0.792) has a better QED score than Ligand A (0.403), suggesting a more drug-like profile.

**DILI:** Ligand A (54.285) has a lower DILI risk than Ligand B (65.529), which is preferable.

**BBB:** Both ligands have high BBB penetration (Ligand A: 83.715, Ligand B: 84.374), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.789) is slightly better than Ligand B (-3.846), but both are concerning.

**Aqueous Solubility:** Ligand A (-2.81) has better aqueous solubility than Ligand B (-5.293). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.438) has a lower hERG inhibition liability than Ligand B (0.71), which is a significant advantage.

**Microsomal Clearance:** Ligand A (34.322) has a significantly lower microsomal clearance than Ligand B (83.581), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (12.758 hours) has a much longer half-life than Ligand A (0.346 hours). This is a strong positive for Ligand B.

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux than Ligand B (0.321), which is preferable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). The difference is 0.4 kcal/mol, which is not a huge advantage, but still relevant.

**Overall Assessment:**

Ligand B has a better QED score, longer half-life, and slightly better binding affinity. However, it suffers from higher DILI risk, higher logP, worse solubility, and significantly higher microsomal clearance. Ligand A has better solubility, lower DILI and hERG risk, lower P-gp efflux, and much better metabolic stability. Given the importance of metabolic stability and safety (DILI, hERG) for kinase inhibitors, and the relatively small difference in binding affinity, Ligand A appears to be the more promising candidate. The poor Caco-2 values for both are a concern that would need to be addressed through formulation or further structural modification.

Output:
0
2025-04-17 11:08:48,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.832 Da) is slightly higher than Ligand B (355.395 Da), but both are acceptable.

**TPSA:** Ligand A (84.23) is well below the 140 threshold for oral absorption. Ligand B (138.6) is approaching the limit, but still acceptable.

**logP:** Ligand A (3.319) is within the optimal range (1-3). Ligand B (-1.07) is significantly below this range, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is well within the acceptable limits. Ligand B (HBD=4, HBA=8) is also within limits, but closer to the upper bounds.

**QED:** Both ligands have reasonable QED scores (A: 0.638, B: 0.504), indicating good drug-like properties.

**DILI:** Ligand A (97.867) has a very high DILI risk, which is a major concern. Ligand B (68.05) has a moderate DILI risk, which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (60.876) and Ligand B (26.483) are both low, which is not detrimental in this case.

**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, which is also unusual. It suggests very low solubility.

**hERG:** Ligand A (0.779) has a slightly elevated hERG risk, but Ligand B (0.032) has a very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (94.892) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-8.118) has negative clearance, which is also unusual but suggests very good metabolic stability.

**In vitro Half-Life:** Ligand A (54.214) has a moderate half-life. Ligand B (34.762) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.551, B: 0.006), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.3 kcal/mol, B: -8.7 kcal/mol), with Ligand B being slightly more potent. The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A's extremely high DILI risk and poor metabolic stability are major drawbacks. Ligand B, while having a lower logP and solubility, exhibits a significantly lower DILI risk, excellent metabolic stability, and a very low hERG risk. These factors are crucial for kinase inhibitors. Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 11:08:48,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.463 Da and 347.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (56.79) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (89.35) is still under 140, but higher than A, potentially impacting absorption.

**logP:** Ligand A (3.635) is within the optimal range (1-3). Ligand B (0.71) is slightly below 1, which could hinder permeation.

**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 (0.693 and 0.866), indicating drug-like properties.

**DILI:** Ligand A (53.742) has a slightly higher DILI risk than Ligand B (47.926), but both are below the concerning threshold of 60.

**BBB:** Both have reasonable BBB penetration (79.721 and 73.517), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.586) has a more favorable Caco-2 permeability than Ligand B (-5.076), indicating better intestinal absorption. Note that negative values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.358) has better aqueous solubility than Ligand B (-1.681). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.75) has a lower hERG risk than Ligand B (0.099). This is a significant advantage.

**Microsomal Clearance:** Ligand A (75.004) has higher microsomal clearance than Ligand B (30.776), meaning it's less metabolically stable. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (8.564) has a longer half-life than Ligand B (5.379), which is generally desirable.

**P-gp Efflux:** Ligand A (0.671) has lower P-gp efflux than Ligand B (0.032), which is better for bioavailability.

**Binding Affinity:** Ligand B (-8.6 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 some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, permeability, and a lower hERG risk, Ligand B's significantly stronger binding affinity (-8.6 vs -7.0 kcal/mol) is the most crucial factor for an enzyme inhibitor. The improved binding is likely to translate to greater efficacy. While Ligand B has a lower logP and slightly higher DILI, these are less critical concerns compared to potency. The lower metabolic stability of Ligand B could be addressed through structural modifications in future optimization.

Output:
1
2025-04-17 11:08:48,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 355.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.1) is higher than Ligand B (63.91). While both are reasonably low, Ligand B is significantly better, increasing the chance of good oral absorption.

**logP:** Ligand A (-0.224) is quite low, potentially hindering permeability. Ligand B (2.757) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (0) is even better, potentially improving permeability.

**H-Bond Acceptors:** Both ligands (A: 5, B: 6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.545, B: 0.611), indicating generally drug-like properties.

**DILI:** Ligand A (22.024) has a much lower DILI risk than Ligand B (59.48). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (10.392) has very low BBB penetration, while Ligand B (75.107) is quite high. Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.372 and -5.38). This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.785 and -1.772). This could pose formulation challenges.

**hERG:** Ligand A (0.101) has a lower hERG risk than Ligand B (0.363), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-13.162) has much lower (better) microsomal clearance than Ligand B (39.747), indicating better metabolic stability. This is a crucial advantage for Ligand A as we prioritize metabolic stability for enzyme targets.

**In vitro Half-Life:** Ligand A (20.571) has a longer half-life than Ligand B (6.293), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.02) has lower P-gp efflux than Ligand B (0.184), which is favorable.

**Binding Affinity:** Both ligands have similar, strong binding affinities (A: -9.1 kcal/mol, B: -10.5 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), DILI risk, and P-gp efflux. While its logP is suboptimal and Caco-2 permeability is poor, its superior metabolic profile and safety (DILI, hERG) are critical for an enzyme target like SRC. Ligand B has better TPSA, logP, and BBB penetration, but suffers from higher DILI risk and significantly worse metabolic stability. The slightly better binding affinity of Ligand B is unlikely to compensate for these drawbacks.

Output:
0
2025-04-17 11:08:48,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (399.288 and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.5) is excellent, well below the 140 threshold for oral absorption. Ligand B (86.71) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.505) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.493) is quite low, which could hinder membrane permeability.

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

**QED:** Ligand A (0.612) is good, indicating drug-likeness. Ligand B (0.39) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (58.705) has a moderate DILI risk. Ligand B (19.116) has a very low DILI risk, which is a significant advantage.

**BBB:** Both have acceptable BBB penetration, but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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:** Both ligands show low hERG inhibition risk (0.922 and 0.234 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (97.189) has high microsomal clearance, indicating poor metabolic stability. Ligand B (1.95) has very low clearance, suggesting good metabolic stability, a key factor for kinases.

**In vitro Half-Life:** Ligand A (-32.821) has a very short half-life. Ligand B (-31.864) also has a short half-life, but slightly better than A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.792 and 0.043 respectively), which is favorable.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.5 and -8.6 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands bind strongly, Ligand B is the more promising candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme inhibitor. Although its logP is low and QED is suboptimal, the strong binding affinity and favorable safety profile outweigh these concerns. The poor Caco-2 and solubility are concerning for both, and would require further investigation/optimization.

Output:
1
2025-04-17 11:08:48,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.411 and 386.298 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is excellent, well below the 140 threshold for oral absorption. Ligand B (37.61) is also very good.

**logP:** Ligand A (2.604) is optimal (1-3). Ligand B (4.529) is slightly higher, potentially leading to solubility issues or off-target effects, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both within acceptable limits. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Ligand A (0.837) has a very strong drug-like profile. Ligand B (0.559) is acceptable, but less ideal.

**DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (32.493), which is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (89.841) has better penetration than Ligand A (54.44).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.026 and -4.781), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.708 and -5.212), which is also a significant issue. Poor solubility will hinder bioavailability.

**hERG Inhibition:** Ligand A (0.117) has a very low hERG risk, which is excellent. Ligand B (0.845) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (29.496) has lower clearance and therefore better metabolic stability than Ligand B (80.818).

**In vitro Half-Life:** Ligand B (38.11) has a longer half-life than Ligand A (30.636), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.228 and 0.618).

**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 could outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A emerges as the more promising candidate. The significantly stronger binding affinity (-9.3 vs -8.1 kcal/mol) is a major advantage for an enzyme target. While Ligand A has a higher DILI risk, the excellent hERG profile and better metabolic stability (lower Cl_mic) are also favorable. The solubility and permeability issues would need to be addressed through formulation strategies, but the potency advantage of Ligand A is compelling.

Output:
0
2025-04-17 11:08:48,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.423 Da) is slightly better positioned.

**TPSA:** Ligand A (60.45) is significantly better than Ligand B (101.98). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.352) is optimal, while Ligand B (-0.913) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=6) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.783, B: 0.508), indicating drug-likeness.

**DILI:** Ligand A (37.185) has a slightly higher DILI risk than Ligand B (21.908), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (71.966) is better than Ligand B (10.779).

**Caco-2 Permeability:** Ligand A (-4.391) is better than Ligand B (-5.686), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.177) is better than Ligand B (-1.105), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.504, B: 0.034). This is excellent.

**Microsomal Clearance:** Ligand A (104.857) has higher clearance than Ligand B (22.155), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-9.959) has a longer half-life than Ligand A (-27.932), which is a clear advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.181, B: 0.007).

**Binding Affinity:** Both ligands have comparable binding affinities (A: -9.6 kcal/mol, B: -8.3 kcal/mol). Ligand A is slightly better, but the difference is not substantial enough to overcome its ADME liabilities.

**Overall Assessment:**

Ligand B, despite its lower logP, presents a more favorable overall profile. Its superior solubility, metabolic stability (lower Cl_mic, longer t1/2), and acceptable DILI risk outweigh the slightly lower binding affinity and TPSA. The low logP is a concern, but might be mitigated through formulation strategies. Ligand A's higher clearance is a major concern for an enzyme inhibitor, potentially leading to rapid drug elimination and reduced efficacy.

Output:
1
2025-04-17 11:08:48,252 - INFO - Batch 23 complete. Total preferences: 368
2025-04-17 11:08:48,252 - INFO - Processing batch 24/512...
2025-04-17 11:09:35,245 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [410.287, 67.01, 3.109, 2, 3, 0.769, 43.622, 68.127, -5.272, -3.01, 0.843, 35.031, 13.374, 0.428, -9.9]
**Ligand B:** [354.491, 59.08, 2.066, 0, 4, 0.758, 32.648, 71.501, -4.375, -1.748, 0.448, 46.132, 15.4, 0.079, 0]

**Step-by-step comparison:**

1. **MW:** Ligand A (410.287 Da) is within the ideal range (200-500 Da). Ligand B (354.491 Da) is also within range. No clear advantage here.
2. **TPSA:** Ligand A (67.01) is slightly higher than Ligand B (59.08), but both are acceptable for oral absorption (<140).
3. **logP:** Both ligands have good logP values (A: 3.109, B: 2.066), falling within the 1-3 range.
4. **HBD:** Ligand A (2) is slightly better than Ligand B (0). Having some HBD can aid solubility.
5. **HBA:** Ligand B (4) is slightly better than Ligand A (3).
6. **QED:** Both ligands have similar QED values (A: 0.769, B: 0.758), indicating good drug-likeness.
7. **DILI:** Ligand A (43.622) has a slightly higher DILI risk than Ligand B (32.648), but both are below the concerning threshold of 60.
8. **BBB:** Ligand B (71.501) has a better BBB penetration percentile than Ligand A (68.127). While not a primary concern for a kinase inhibitor, it's a slight positive.
9. **Caco-2:** Ligand A (-5.272) has a significantly *better* Caco-2 permeability than Ligand B (-4.375). This suggests better intestinal absorption for Ligand A.
10. **Solubility:** Ligand B (-1.748) has better aqueous solubility than Ligand A (-3.01).
11. **hERG:** Ligand A (0.843) has a slightly higher hERG risk than Ligand B (0.448).
12. **Cl_mic:** Ligand A (35.031) has a *lower* microsomal clearance than Ligand B (46.132), indicating better metabolic stability. This is crucial for kinase inhibitors.
13. **t1/2:** Ligand B (15.4) has a longer in vitro half-life than Ligand A (13.374).
14. **Pgp:** Ligand B (0.079) has lower P-gp efflux liability than Ligand A (0.428), suggesting better bioavailability.
15. **Binding Affinity:** Ligand A (-9.9 kcal/mol) has a *significantly* stronger binding affinity than Ligand B (0 kcal/mol). This is the most important factor for an enzyme inhibitor. A difference of 9.9 kcal/mol is substantial.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in binding affinity and has better metabolic stability. Ligand B has better solubility and a slightly lower hERG risk. However, the *massive* difference in binding affinity outweighs the minor advantages of Ligand B.

**Conclusion:**

Ligand A is the more promising drug candidate due to its significantly superior binding affinity. The better metabolic stability is also a major plus. While Ligand B has some advantages in solubility and Pgp efflux, the potency difference is too large to ignore.

Output:
1
2025-04-17 11:09:35,246 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.303 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.68) is well below the 140 threshold and favorable. Ligand B (72.88) is still under the threshold but less optimal than A.

**logP:** Ligand A (4.525) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.256) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.714 and 0.644, respectively), indicating good drug-like properties.

**DILI:** Ligand A (62.35) has a moderate DILI risk, while Ligand B (5.235) has a very low DILI risk, a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (92.439) has better BBB penetration than Ligand B (33.036).

**Caco-2 Permeability:** Ligand A (-3.903) shows poor permeability, while Ligand B (-4.887) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.877) has very poor solubility, which is a major concern. Ligand B (-0.367) has better, though still suboptimal, solubility.

**hERG Inhibition:** Ligand A (0.544) has a slightly elevated hERG risk, while Ligand B (0.189) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (59.504) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (12.261) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.141 hours) has a reasonable half-life. Ligand B (3.284 hours) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.215 and 0.015, respectively).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A's superior binding affinity, its poor solubility, higher DILI risk, and higher microsomal clearance are major concerns. Ligand B, while having weaker binding, exhibits a much more favorable ADME profile, particularly regarding DILI, hERG, and metabolic stability. Considering the enzyme-specific priorities, the improved safety and metabolic stability of Ligand B make it the more promising candidate, even with the slightly lower potency.

Output:
1
2025-04-17 11:09:35,246 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.308 Da and 360.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.53) is higher than Ligand B (76.15). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (1.097) is within the optimal range, while Ligand B (0.591) is slightly below, potentially impacting permeability.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable, with Ligand B potentially having better membrane permeability due to fewer H-bonds.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit.

**QED:** Both ligands have QED values above 0.5 (0.788 and 0.648), indicating good drug-like properties.

**DILI:** Ligand A (54.052) has a higher DILI risk than Ligand B (37.263). This is a significant advantage for Ligand B.

**BBB:** Ligand A (63.629) and Ligand B (89.608). Since SRC is not a CNS target, this is less critical, but Ligand B is better.

**Caco-2:** Ligand A (-5.451) and Ligand B (-4.267). Both are negative, indicating poor permeability.

**Solubility:** Ligand A (-2.371) and Ligand B (-1.393). Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.024) and Ligand B (0.27). Both are very low, indicating minimal hERG inhibition risk.

**Cl_mic:** Ligand A (-13.067) has a significantly *lower* (better) microsomal clearance than Ligand B (27.117). This suggests better metabolic stability for Ligand A.

**t1/2:** Ligand A (-25.667) has a *longer* (better) in vitro half-life than Ligand B (-8.719). This further supports better metabolic stability for Ligand A.

**Pgp:** Ligand A (0.006) has a much lower Pgp efflux liability than Ligand B (0.051), suggesting better oral bioavailability and potentially better tissue distribution.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly *stronger* binding affinity than Ligand B (-6.3 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand B has advantages in DILI, TPSA, and BBB, Ligand A's significantly stronger binding affinity (-10.2 vs -6.3 kcal/mol), better metabolic stability (lower Cl_mic and longer t1/2), and lower Pgp efflux liability are more critical for an enzyme target like SRC kinase. The stronger binding is likely to overcome the slightly higher DILI risk and lower solubility.

Output:
1
2025-04-17 11:09:35,246 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.407 and 334.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.77) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (65.96) is excellent, well below 140.

**logP:** Ligand A (1.031) is at the lower end of optimal (1-3), potentially impacting permeability. Ligand B (3.574) is excellent, within the optimal range.

**H-Bond Donors & Acceptors:** Ligand A (3 HBD, 7 HBA) is good. Ligand B (1 HBD, 5 HBA) is also good, potentially slightly better due to lower counts.

**QED:** Both ligands have good QED scores (0.564 and 0.741), indicating drug-likeness.

**DILI:** Both ligands have similar DILI risk (59.519 and 62.001), both are acceptable but not ideal.

**BBB:** Ligand A (44.746) and Ligand B (77.394). BBB is not a high priority for a kinase inhibitor, but Ligand B is better.

**Caco-2 Permeability:** Ligand A (-4.981) and Ligand B (-5.059). Both are poor, indicating low intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.373) and Ligand B (-3.561). Both are poor, indicating low aqueous solubility.

**hERG Inhibition:** Ligand A (0.261) is very low, indicating minimal risk of cardiotoxicity. Ligand B (0.863) is higher, suggesting a moderate risk. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (51.308) and Ligand B (32.692). Ligand B has lower clearance, indicating better metabolic stability, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-11.36) and Ligand B (-26.301). Ligand B has a significantly longer half-life, indicating better stability. This is a strong advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.07) and Ligand B (0.767). Ligand A shows very low P-gp efflux, which is favorable for bioavailability. Ligand B has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.5) and Ligand B (-8.5). Ligand B has a significantly stronger binding affinity (1.0 kcal/mol advantage), which is a major driver for selection.

**Overall Assessment:**

Ligand B has a stronger binding affinity, better metabolic stability (lower Cl_mic and longer t1/2), and better BBB penetration. However, it has a higher hERG risk and moderate P-gp efflux. Ligand A has a much lower hERG risk and lower P-gp efflux, but weaker binding affinity, poorer metabolic stability, and lower BBB penetration.

The binding affinity difference is substantial (1.0 kcal/mol). For a kinase inhibitor, potency is paramount. While the hERG risk for Ligand B is a concern, it's manageable with further optimization. The metabolic stability and potency gains of Ligand B outweigh the drawbacks, particularly given the potential for further optimization to address the hERG risk.

Output:
1
2025-04-17 11:09:35,247 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (345.374 and 366.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is slightly higher than Ligand B (60.25), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (1.896) is within the optimal 1-3 range. Ligand B (3.082) 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 (4) is good. Ligand B (6) is acceptable, but higher.

**6. QED:** Both ligands have reasonable QED scores (0.898 and 0.788), indicating good drug-like properties.

**7. DILI:** Ligand A (41.062) has a slightly better DILI score than Ligand B (55.409), both are still acceptable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (80.38) has a higher BBB score than Ligand A (62.233), but this isn't a major deciding factor here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.775 and -4.816), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.352 and -3.829), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.426) has a lower hERG risk than Ligand B (0.292), which is favorable.

**12. Microsomal Clearance:** Ligand A (12.641) has a significantly lower microsomal clearance than Ligand B (56.616), suggesting better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (2.566) has a shorter half-life than Ligand B (8.496). This is a drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.033) has a much lower P-gp efflux liability than Ligand B (0.137), which is favorable.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol), by a margin of 1 kcal/mol. This is a substantial advantage for Ligand B.

**Overall Assessment:**

While both ligands have significant issues with solubility and permeability, Ligand B's substantially stronger binding affinity (-8.9 vs -7.9 kcal/mol) is a critical advantage for an enzyme target. The improved metabolic stability of Ligand A is attractive, but the 1 kcal/mol difference in binding is likely to outweigh this benefit, especially considering the poor permeability and solubility of both compounds. Further optimization would be needed to address the ADME properties of either compound.

Output:
1
2025-04-17 11:09:35,247 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 Da and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is higher than Ligand B (42.01). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**logP:** Both ligands have good logP values (2.689 and 2.356), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable, being less than 5.

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

**QED:** Both ligands have good QED scores (0.55 and 0.64), indicating good drug-like properties.

**DILI:** Ligand A (26.871) has a slightly higher DILI risk than Ligand B (13.3), but both are below the concerning threshold of 40, suggesting low liver injury risk.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (89.376) has a higher BBB percentile than Ligand A (75.533), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.731 and -4.725). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.828 and -2.222). This is also unusual and indicates poor aqueous solubility. Again, the values are very similar.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.254 and 0.722), which is excellent.

**Microsomal Clearance:** Ligand A (66.333) has a higher microsomal clearance than Ligand B (61.509). Lower clearance is preferred for metabolic stability, giving a slight edge to Ligand B.

**In vitro Half-Life:** Ligand B (23.144 hours) has a significantly longer half-life than Ligand A (3.371 hours). 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 (0.335 and 0.369), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent and well below the -7.0 kcal/mol threshold.

**Conclusion:**

While both ligands have excellent binding affinity and acceptable safety profiles, Ligand B is superior due to its lower TPSA, longer half-life, and lower DILI risk. The similar Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 11:09:35,247 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 Da and 349.475 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.99) is slightly higher than Ligand B (63.57), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.533 and 1.975), 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 (0.782 and 0.884), indicating drug-like properties.

**DILI:** Ligand A (20.008) has a significantly lower DILI risk than Ligand B (34.238). This is a major advantage.

**BBB:** Ligand B (65.413) has a higher BBB penetration percentile than Ligand A (47.615), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.587 and -4.538). This is unusual and suggests poor permeability. However, these values are on a log scale and could be misinterpreted.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.569 and -1.899), which is also concerning. Similar to Caco-2, these values may be on a log scale and require careful interpretation.

**hERG Inhibition:** Ligand A (0.648) has a slightly higher hERG inhibition risk than Ligand B (0.371), but both are relatively low.

**Microsomal Clearance:** Ligand A (36.25) has a lower microsomal clearance than Ligand B (59.942), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (40.513) has a longer in vitro half-life than Ligand B (18.137), further supporting its superior metabolic stability.

**P-gp Efflux:** Ligand A (0.359) has lower P-gp efflux liability than Ligand B (0.156), which is favorable for bioavailability.

**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 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 presents a much more favorable ADME profile, particularly regarding DILI risk and metabolic stability (lower Cl_mic and longer t1/2). The negative Caco-2 and solubility values are concerning for both, but the difference in binding affinity is substantial. Given the importance of metabolic stability for kinase inhibitors and the lower DILI risk, the stronger binding affinity of Ligand B is likely to outweigh the ADME concerns.

Output:
1
2025-04-17 11:09:35,247 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (348.353 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.42) is slightly above the preferred <90 for kinases, but still reasonable. Ligand B (67.23) is well within the acceptable range.

**3. logP:** Both ligands have good logP values (2.783 and 2.391), falling within the optimal 1-3 range.

**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:** Ligand A (0.719) has a better QED score than Ligand B (0.551), indicating a more drug-like profile.

**7. DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (24.506). This is a significant drawback for Ligand A.

**8. BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (76.58) has a better BBB score than Ligand A (67.468).

**9. Caco-2 Permeability:** Ligand A (-5.016) has poor Caco-2 permeability, whereas Ligand B (-4.648) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-4.147) has poor aqueous solubility, whereas Ligand B (-2.156) is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.795 and 0.125 respectively). Ligand B is significantly better.

**12. Microsomal Clearance (Cl_mic):** Ligand A (10.125) has a much lower (better) microsomal clearance than Ligand B (44.741), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.122) has a significantly longer in vitro half-life than Ligand A (1.254).

**14. P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux than Ligand B (0.073), which is preferable.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.2 kcal/mol), with Ligand B being slightly better. The difference is small and likely not decisive.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has a slightly better QED and lower P-gp efflux, its significantly higher DILI risk, poor solubility, poor Caco-2 permeability, and shorter half-life outweigh these benefits. Ligand B exhibits a much more favorable safety profile (lower DILI, lower hERG), better solubility, and a longer half-life, making it a more viable drug candidate despite slightly higher P-gp efflux.

Output:
1
2025-04-17 11:09:35,248 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.415 and 345.422 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.23) is slightly higher than Ligand B (73.91). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.592 and 2.467), falling within the optimal 1-3 range.

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

**QED:** Ligand A (0.832) has a better QED score than Ligand B (0.756), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (36.099 and 39.667), well below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (66.382) has a higher BBB percentile than Ligand A (50.058).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.348) is slightly better than Ligand B (-2.838).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.041 and 0.736), which is excellent.

**Microsomal Clearance:** Ligand A (11.923 mL/min/kg) has significantly lower microsomal clearance than Ligand B (18.659 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.634 hours) has a longer in vitro half-life than Ligand B (-12.543 hours), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.065).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.0 and -7.9 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both ligands have good potency and low toxicity risks, Ligand A exhibits superior metabolic stability (lower Cl_mic) and a longer half-life, which are crucial for an enzyme target. It also has a slightly better QED score and solubility. The slightly higher TPSA of Ligand A is not a significant concern given its other advantages.

Output:
1
2025-04-17 11:09:35,248 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is better than Ligand B (87.74). Both are below 140, suggesting reasonable absorption.

**logP:** Ligand A (1.831) is optimal, while Ligand B (0.683) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**QED:** Ligand A (0.766) has a higher QED score than Ligand B (0.659), indicating better overall drug-likeness.

**DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (10.702), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.094) has a higher BBB percentile than Ligand B (64.25).

**Caco-2 Permeability:** Ligand A (-4.522) is better than Ligand B (-4.843), suggesting slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.312) is better than Ligand B (-1.427), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.268 and 0.2 respectively).

**Microsomal Clearance:** Ligand B (-3.423) has a *much* lower (better) microsomal clearance than Ligand A (51.327), suggesting significantly improved metabolic stability.

**In vitro Half-Life:** Ligand B (-16.652) has a longer in vitro half-life than Ligand A (-21.522), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.012).

**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.

**Overall Assessment:**

Ligand A excels in most areas: QED, DILI, solubility, and binding affinity. However, Ligand B has a *much* better metabolic stability profile (lower Cl_mic and longer half-life). The difference in Cl_mic is substantial. While the affinity difference is notable, the improved metabolic stability of Ligand B is crucial for an enzyme target. A compound with poor metabolic stability will likely have a short duration of action and require high doses, potentially leading to toxicity. The slightly lower logP of Ligand B is a minor drawback that could be addressed with further optimization.

Output:
1
2025-04-17 11:09:35,248 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (334.423 Da) is within the ideal range (200-500 Da). Ligand B (525.657 Da) is slightly above, but still acceptable.

**TPSA:** Ligand A (69.02) is excellent, well below the 140 threshold for oral absorption. Ligand B (87.55) is still reasonable, but less optimal.

**logP:** Ligand A (2.589) is optimal (1-3). Ligand B (5.308) is high, potentially leading to solubility issues and off-target effects.

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

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (8) is approaching the upper limit, but still within bounds.

**QED:** Ligand A (0.933) is excellent, indicating high drug-likeness. Ligand B (0.257) is poor, suggesting potential issues.

**DILI:** Ligand A (47.964) has a low DILI risk. Ligand B (85.537) has a significantly higher DILI risk.

**BBB:** Both ligands have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both 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 have negative solubility values, which is also unusual. Again, we'll assume these represent poor solubility.

**hERG:** Ligand A (0.789) has a low hERG risk. Ligand B (0.939) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (51.124 mL/min/kg) is moderate. Ligand B (98.313 mL/min/kg) is high, indicating faster metabolism and lower systemic exposure.

**In vitro Half-Life:** Ligand A (6.391 hours) is reasonable. Ligand B (52.087 hours) is very good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Conclusion:**

Ligand A is the superior candidate. While both have issues with predicted solubility and permeability, Ligand A's significantly better binding affinity (-8.4 vs -6.9 kcal/mol), excellent QED, lower DILI risk, and acceptable metabolic stability outweigh the concerns. Ligand B's high logP, poor QED, and high DILI risk make it a less attractive candidate despite its longer half-life. The potency difference is large enough to likely overcome the solubility/permeability issues with further optimization.

Output:
0
2025-04-17 11:09:35,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.418 and 344.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.64) is better than Ligand B (40.62), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.018 and 3.227), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some formulation challenges, but not a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 2 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 reasonable QED scores (0.855 and 0.735), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (29.973 and 31.524 percentile), which is favorable.

**BBB:** Both ligands have good BBB penetration (80.574 and 78.868 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.581 and -4.74), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.204 and -3.906), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.661 and 0.382 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (-13.298 mL/min/kg) has *much* better metabolic stability than Ligand B (72.263 mL/min/kg). This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (7.71 hours) has a better half-life than Ligand B (24.26 hours), though both are reasonable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.121 and 0.505 percentile), which is good.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). The difference is 1.3 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability for both compounds, Ligand A is the better candidate. Its significantly improved metabolic stability (lower Cl_mic, better half-life) and slightly better binding affinity are crucial for an enzyme target like SRC kinase. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies. Ligand B's high microsomal clearance is a major disadvantage.

Output:
0
2025-04-17 11:09:35,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.391 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.36) is slightly above the preferred <140 for good absorption, while Ligand B (89.27) is well within the range.

**logP:** Ligand A (0.217) is quite low, potentially hindering permeability. Ligand B (1.921) is much 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 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have identical QED scores of 0.724, indicating good drug-likeness.

**DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (45.638), though both are moderately risky.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (56.378) and Ligand B (14.153) have low BBB penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.21 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 (-3.17 and -2.465), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.04) has a very low hERG risk, which is excellent. Ligand B (0.121) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-14.955) has significantly lower (better) microsomal clearance than Ligand B (37.248), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (30.961) has a longer half-life than Ligand B (-4.639), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.004 and 0.055).

**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 threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -8.0 kcal/mol) outweighs the slightly higher DILI and lower metabolic stability compared to Ligand A. The better logP of Ligand B also suggests improved permeability compared to Ligand A. The lower hERG risk for Ligand A is a positive, but the potency difference is more critical for an enzyme target.



Output:
1
2025-04-17 11:09:35,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.264 Da) is slightly higher, but acceptable. Ligand B (377.438 Da) is also good.

**TPSA:** Ligand A (71.25) is well below the 140 threshold for oral absorption. Ligand B (98.23) is also acceptable, though approaching the upper limit.

**logP:** Ligand A (2.665) is within the optimal range (1-3). Ligand B (-1.644) is below 1, which could indicate permeability issues.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.69 and 0.633), indicating good drug-likeness.

**DILI:** Ligand A (65.607) has a higher DILI risk than Ligand B (30.942). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (54.362) shows better BBB penetration than Ligand A (36.952), but it's not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.036 and -4.727), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without knowing the original units.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.714 and -0.271), which is also concerning. Again, the scale isn't specified, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.84 and 0.115). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (33.111) has a higher microsomal clearance than Ligand B (-0.151), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-30.56) has a much longer in vitro half-life than Ligand A (11.403). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.284) has lower P-gp efflux than Ligand B (0.014), which is preferable.

**Binding Affinity:** Both ligands have strong binding affinities (-8.8 and -8.1 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol and is unlikely to outweigh other significant drawbacks.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have issues with Caco-2 and solubility, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and a slightly better hERG profile. The slightly lower logP of Ligand B is a concern, but the superior ADME properties outweigh this. The small difference in binding affinity is not enough to favor Ligand A given its metabolic liabilities and higher DILI risk.

Output:
1
2025-04-17 11:09:35,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.849 and 365.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.22) is better than Ligand B (100.35), being closer to the 90 A^2 threshold for potential CNS penetration (though not a primary concern for SRC).

**logP:** Ligand A (2.213) is optimal, while Ligand B (0.786) is slightly low, potentially impacting permeability.

**H-Bond Donors & Acceptors:** Ligand A (3 HBD, 3 HBA) is slightly better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.594 and 0.785), indicating drug-likeness.

**DILI:** Ligand A (57.425) has a lower DILI risk than Ligand B (64.133), which is preferable.

**BBB:** Ligand A (42.769) has a slightly better BBB score than Ligand B (22.412), though this isn't a primary concern for SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.338 and -5.419), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.049 and -2.456), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.573) has a lower hERG risk than Ligand B (0.277), which is a significant advantage.

**Microsomal Clearance:** Ligand A (39.77 mL/min/kg) has a higher (worse) microsomal clearance than Ligand B (21.628 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (64.769 hours) has a significantly longer half-life than Ligand B (-0.714 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.197) has lower P-gp efflux than Ligand B (0.03), which is preferable.

**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 notable.

**Overall Assessment:**

Ligand A is the better candidate despite the poor Caco-2 and solubility values. The stronger binding affinity, lower hERG risk, longer half-life, and lower DILI risk outweigh the higher microsomal clearance. The poor permeability and solubility are significant drawbacks that would need to be addressed through formulation or further chemical modifications, but the core potency and safety profile of Ligand A is superior. Ligand B's very short half-life is a major concern.

Output:
1
2025-04-17 11:09:35,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.343 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.17) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (87.46) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (1.51) is within the optimal 1-3 range. Ligand B (0.645) is a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, both within acceptable limits. Ligand B has 2 HBD and 5 HBA, also good.

**QED:** Both ligands have good QED scores (0.534 and 0.675), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (94.765 percentile), which is a significant concern. Ligand B has a very low DILI risk (19.969 percentile), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (44.591) and Ligand B (37.456) are both low, as expected.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.468 and -5.103), which is unusual and suggests poor permeability *in vitro*. This needs further investigation, but is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.011 and -1.227), also unusual. This suggests very poor aqueous solubility, which could hinder bioavailability.

**hERG Inhibition:** Ligand A (0.126) has a slightly higher hERG risk than Ligand B (0.195), but both are relatively low.

**Microsomal Clearance:** Ligand A (0.554) has a very low microsomal clearance, indicating high metabolic stability, which is excellent. Ligand B (9.176) has a much higher clearance, suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (68.84) has a good in vitro half-life. Ligand B (-4.216) has a negative half-life, which is not physically meaningful and suggests a problem with the data or assay.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.049), which is favorable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol) - a difference of 1.0 kcal/mol. This is a substantial advantage, and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand A has excellent metabolic stability and a good half-life, but its extremely high DILI risk is a major red flag. Its solubility and permeability are also questionable based on the negative values.

Ligand B has a superior binding affinity, a much lower DILI risk, and better TPSA. While its logP is a bit low and its clearance is higher, the significantly improved potency and safety profile outweigh these drawbacks. The negative half-life is a data quality concern, but the strong binding affinity is a compelling factor.

Output:
1
2025-04-17 11:09:35,250 - INFO - Batch 24 complete. Total preferences: 384
2025-04-17 11:09:35,250 - INFO - Processing batch 25/512...
2025-04-17 11:10:16,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.349 and 354.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, while Ligand B (93.22) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.121) is optimal, while Ligand B (0.198) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable, below the threshold of 10.

**QED:** Ligand A (0.843) has a significantly better QED score than Ligand B (0.517), indicating a more drug-like profile.

**DILI:** Ligand B (42.536) has a lower DILI risk than Ligand A (81.427), which is a positive for Ligand B.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (73.362) is slightly better than Ligand B (39.511).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, this is likely a scale issue and doesn't provide much comparative information.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. However, this is likely a scale issue and doesn't provide much comparative information.

**hERG Inhibition:** Ligand A (0.625) has a lower hERG risk than Ligand B (0.052), which is a significant advantage.

**Microsomal Clearance:** Ligand B (20.029) has significantly lower microsomal clearance than Ligand A (45.19), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.103) has a longer in vitro half-life than Ligand A (8.644), which is a positive.

**P-gp Efflux:** Ligand A (0.181) has lower P-gp efflux than Ligand B (0.033), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.8 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 of Ligand A.

**Overall Assessment:**

Ligand A has a superior binding affinity, better QED, and lower hERG risk. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI. However, the substantial difference in binding affinity (-8.8 vs -6.6 kcal/mol) is a critical factor for an enzyme target. The improved potency of Ligand A is likely to be more impactful than the slightly better ADME profile of Ligand B, especially considering optimization can address ADME properties later. The low logP of Ligand B is a significant concern.

Output:
1
2025-04-17 11:10:16,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (374.94 and 355.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.13) is significantly better than Ligand B (108.41). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (4.044) is a bit high, potentially leading to solubility issues, but still within a reasonable range. Ligand B (-0.892) is too low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 6. Ligand A is preferable here.

**QED:** Ligand A (0.847) has a better QED score than Ligand B (0.619), indicating better overall drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (35.60 and 39.98, respectively), both below the 40 threshold.

**BBB:** Ligand A (80.38) has a better BBB penetration score than Ligand B (44.79), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.21) and Ligand B (-5.018) both have negative values, which is unusual. Assuming these are log scale values, lower numbers indicate lower permeability. Both are poor, but similar.

**Aqueous Solubility:** Ligand A (-4.466) is better than Ligand B (-0.41), indicating better solubility.

**hERG:** Both ligands have very low hERG risk (0.719 and 0.047, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (68.803) has a higher microsomal clearance than Ligand B (1.724), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-11.606) has a much longer in vitro half-life than Ligand A (37.055), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.567 and 0.008, respectively), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.1 and -9.5 kcal/mol), with Ligand B being slightly better. The difference is less than 1.5 kcal/mol, so this is not decisive.

**Conclusion:**

While Ligand A has better TPSA, QED, and solubility, Ligand B demonstrates superior metabolic stability (much lower Cl_mic and a longer half-life) and a slightly better binding affinity. Given the enzyme-specific priorities, metabolic stability and potency are paramount. Ligand B's significantly better half-life and slightly better affinity outweigh the drawbacks of its higher TPSA and lower logP.

Output:
1
2025-04-17 11:10:16,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.379 and 364.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.39) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (60.85) is excellent, well below 140.

**logP:** Ligand A (-0.144) is a bit low, potentially hindering permeation. Ligand B (1.899) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is within acceptable limits. Ligand B (1 HBD, 3 HBA) is also good.

**QED:** Both ligands have acceptable QED values (0.361 and 0.783, respectively), with Ligand B being significantly better.

**DILI:** Ligand A (46.452) has a moderate DILI risk, while Ligand B (23.846) has a very low risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.335) and Ligand B (91.47) are both reasonable, with B being better.

**Caco-2 Permeability:** Ligand A (-5.152) shows poor permeability. Ligand B (-4.496) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor solubility (-1.896 and -2.878). This is a major concern for both.

**hERG Inhibition:** Ligand A (0.121) has a very low hERG risk, which is excellent. Ligand B (0.584) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (23.808) has lower clearance, suggesting better metabolic stability. Ligand B (45.83) has higher clearance.

**In vitro Half-Life:** Ligand A (2.077) has a short half-life. Ligand B (-8.299) has a very long half-life, a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.023 and 0.21).

**Binding Affinity:** Ligand A (-9.5 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 much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability and a shorter half-life. Ligand B has better ADME properties (lower DILI, better logP, longer half-life) but significantly weaker binding affinity. The difference in binding affinity (-9.5 vs -6.2 kcal/mol) is a 3.3 kcal/mol difference, which is substantial and likely outweighs the ADME drawbacks of Ligand A, *especially* if formulation strategies can be employed to address the solubility and permeability issues.

Output:
0
2025-04-17 11:10:16,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.419 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (369.487 Da) is still well within acceptable limits.

**TPSA:** Ligand A (55.56) is significantly better than Ligand B (80.76). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (4.366) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.934) is optimal.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (6) compared to Ligand A (2), but both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.681, B: 0.794), indicating good drug-like properties.

**DILI:** Ligand A (72.858) has a higher DILI risk than Ligand B (53.742), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.047) has a better BBB score than Ligand B (48.585), but this isn't a major factor here.

**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 concerning. Ligand B (-2.272) is slightly better than Ligand A (-5.047).

**hERG Inhibition:** Ligand A (0.906) has a slightly higher hERG risk than Ligand B (0.298), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (24.963) has significantly lower microsomal clearance than Ligand A (78.429), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (17.309 hours) has a much longer half-life than Ligand A (-3.593 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.724) has a slightly higher P-gp efflux liability than Ligand B (0.127), which is preferable for Ligand B.

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol, making it a key consideration.

**Overall Assessment:**

While Ligand B has superior ADME properties (lower DILI, better metabolic stability, longer half-life, lower hERG, lower P-gp efflux), Ligand A boasts a considerably stronger binding affinity. For an enzyme target like SRC kinase, potency is paramount. The 1.4 kcal/mol difference in binding is substantial and likely to be more impactful than the ADME liabilities of Ligand A, especially if those liabilities can be addressed through further optimization. The solubility and permeability issues are concerning, but can be potentially mitigated through formulation strategies or further chemical modifications.

Output:
0
2025-04-17 11:10:16,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.372 Da and 353.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (72.18 and 73.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.394 and 3.199) within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA. Both are below the 10 threshold.

**QED:** Both ligands have QED values (0.765 and 0.728) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 91.082, which is high. Ligand B has a DILI risk of 18.651, which is very good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (72.741 and 89.919). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.836 and -4.273), 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 (-4.117 and -3.564), indicating poor solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A has a hERG risk of 0.383, which is acceptable. Ligand B has a hERG risk of 0.872, which is slightly higher but still within a manageable range.

**Microsomal Clearance:** Ligand A has a Cl_mic of 34.889, and Ligand B has a Cl_mic of 68.843. Ligand A has better metabolic stability (lower clearance).

**In vitro Half-Life:** Ligand A has a t1/2 of 20.74 hours, while Ligand B has a t1/2 of -12.596 hours. The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation. Ligand A has a significantly better half-life.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.444, and Ligand B has a Pgp efflux liability of 0.083. Ligand B shows lower P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A has a binding affinity of -7.8 kcal/mol, while Ligand B has a binding affinity of 0.0 kcal/mol. Ligand A has a substantially stronger binding affinity.

**Conclusion:**

Ligand A has a significantly stronger binding affinity and better metabolic stability and half-life. However, its high DILI risk is a major concern. Ligand B has a much lower DILI risk and lower P-gp efflux, but its binding affinity is very weak and its half-life is problematic.

Given the priorities for enzyme inhibitors, strong binding affinity is crucial. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications. The extremely weak binding of Ligand B is a more fundamental issue that is less likely to be overcome. Therefore, I would initially favor Ligand A, but with a strong caveat to address the DILI risk.

Output:
0
2025-04-17 11:10:16,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.51 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is better than Ligand B (61.88). Both are below the 140 threshold for oral absorption, but lower TPSA is generally preferred.

**logP:** Ligand A (4.332) is higher than Ligand B (1.251). While Ligand A is at the upper end of the optimal range, it's still acceptable. Ligand B is quite 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 (3) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.746 and 0.782), indicating drug-like properties.

**DILI:** Ligand A (10.702) has a significantly lower DILI risk than Ligand B (6.359), which is a crucial advantage.

**BBB:** Both ligands have good BBB penetration, but Ligand A (82.513) is slightly better than Ligand B (77.976). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.458) is slightly better than Ligand B (-4.769), but both are problematic.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.364 and -1.466). Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.849) has a slightly higher hERG risk than Ligand B (0.289). This is a concern for Ligand A, but not prohibitive.

**Microsomal Clearance:** Ligand A (49.476) has significantly higher microsomal clearance than Ligand B (18.405), meaning it's less metabolically stable. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (10.33) has a longer half-life than Ligand A (5.679), which is favorable.

**P-gp Efflux:** Ligand A (0.39) has lower P-gp efflux than Ligand B (0.01), which is better.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better BBB score and P-gp efflux, Ligand B excels in crucial areas for kinase inhibitors: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. The lower logP of Ligand B is a minor concern, but the significant improvements in safety and pharmacokinetic properties outweigh this drawback. The similar binding affinities make these differences decisive.

Output:
1
2025-04-17 11:10:16,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.435 and 364.515 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.18) is slightly higher than Ligand B (67.23). Both are below 140, suggesting reasonable absorption, but Ligand B is significantly better.

**logP:** Ligand A (0.343) is quite low, potentially hindering permeability. Ligand B (1.603) 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) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (5) are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.654 and 0.833 respectively), indicating good drug-like properties.

**DILI:** Ligand A (18.418) has a much lower DILI risk than Ligand B (28.228), which is a positive for A. Both are below 40, indicating low risk.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (51.493) is slightly higher.

**Caco-2 Permeability:** Ligand A (-4.941) has poor Caco-2 permeability, while Ligand B (-5.416) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.806) has slightly better solubility than Ligand B (-2.087).

**hERG:** Both ligands have very low hERG risk (0.155 and 0.112), which is excellent.

**Microsomal Clearance:** Ligand A (-6.779) has significantly lower (better) microsomal clearance than Ligand B (28.094), indicating much better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.834) has a much longer half-life than Ligand B (1.48), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.005 and 0.057).

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

**Conclusion:**

While both ligands have good binding affinity and low hERG risk, Ligand A is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk outweigh the slightly lower solubility and Caco-2 permeability, and the lower logP. The low logP of Ligand A is a concern, but could potentially be addressed with prodrug strategies. Ligand B's higher logP is good, but its poor metabolic stability is a significant drawback for an enzyme inhibitor.

Output:
0
2025-04-17 11:10:16,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.451 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (67.43) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.451 and 3.308) within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.76 and 0.743), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (39.434 and 38.852), below the 40 threshold.

**BBB:** Ligand A (80.264) has a better BBB percentile than Ligand B (68.67), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.479) has a much worse Caco-2 permeability than Ligand B (-4.638). This is a significant drawback for Ligand A.

**Aqueous Solubility:** Ligand A (-2.561) has a slightly better solubility than Ligand B (-4.125).

**hERG:** Ligand A (0.696) has a lower hERG risk than Ligand B (0.463), which is favorable.

**Microsomal Clearance:** Ligand A (-8.936) has significantly better microsomal clearance (lower value = more stable) than Ligand B (77.172). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (44.834) has a longer half-life than Ligand B (20.643), which is desirable.

**P-gp Efflux:** Ligand A (0.5) has lower P-gp efflux than Ligand B (0.145), which is favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is not substantial enough to outweigh the ADME advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly improved metabolic stability (Cl_mic and t1/2), better P-gp efflux, and a lower hERG risk. The Caco-2 permeability is a concern for Ligand A, but the other advantages, particularly the metabolic stability, are more critical for an enzyme target.

Output:
0
2025-04-17 11:10:16,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (349.406 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.74) is slightly higher than Ligand B (61.44). Both are below the 140 threshold for good absorption, but closer to the 90 threshold for CNS targets (not relevant here).

**logP:** Ligand A (1.446) is within the optimal 1-3 range. Ligand B (2.728) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 limit.

**QED:** Ligand A (0.877) has a better QED score than Ligand B (0.745), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (A: 34.548, B: 34.393), both well below the concerning threshold of 60.

**BBB:** Ligand A (71.966) has a slightly better BBB penetration percentile than Ligand B (64.948), but this isn't a primary concern for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-4.46) shows better Caco-2 permeability than Ligand B (-5.297). Higher values are better.

**Aqueous Solubility:** Ligand A (-1.393) has better aqueous solubility than Ligand B (-2.193). Higher values are better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.496, B: 0.664).

**Microsomal Clearance:** Ligand A (-10.969) has significantly lower (better) microsomal clearance than Ligand B (21.558), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.817) has a shorter half-life than Ligand B (26.038). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.116, B: 0.183).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.5 kcal/mol, B: -9.3 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Ligand A is favored due to its superior QED, Caco-2 permeability, aqueous solubility, and significantly better metabolic stability (lower Cl_mic). While Ligand B has a longer half-life, the improved ADME properties of Ligand A, coupled with comparable binding affinity, make it the more promising drug candidate.

Output:
0
2025-04-17 11:10:16,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.403 and 357.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.66) is better than Ligand B (64.41), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.033 and 2.875), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 3 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 (0.726 and 0.814), indicating drug-like properties.

**DILI:** Ligand A (46.219) has a slightly higher DILI risk than Ligand B (25.165), but both are below the concerning threshold of 60.

**BBB:** Ligand A (57.231) has a lower BBB penetration than Ligand B (82.629). This is not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-5.28) has a worse Caco-2 permeability than Ligand B (-4.922).

**Aqueous Solubility:** Ligand A (-3.084) has a worse aqueous solubility than Ligand B (-4.058).

**hERG Inhibition:** Ligand A (0.089) has a lower hERG inhibition risk than Ligand B (0.783), which is a significant advantage.

**Microsomal Clearance:** Ligand A (22.465) has a lower microsomal clearance than Ligand B (39.141), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.612) has a much longer in vitro half-life than Ligand B (3.969), a substantial benefit.

**P-gp Efflux:** Ligand A (0.023) has a lower P-gp efflux liability than Ligand B (0.296).

**Binding Affinity:** Ligand B (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage.

**Conclusion:**

Despite Ligand A's better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk, the substantially stronger binding affinity of Ligand B (-10.4 vs -7.9 kcal/mol) outweighs these advantages. The difference in binding affinity is significant enough to overcome the slightly higher DILI and P-gp efflux liabilities of Ligand B. Solubility and permeability are similar enough that they don't drive the decision.

Output:
1
2025-04-17 11:10:16,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.399 & 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.06) is slightly higher than the preferred <140, but acceptable. Ligand B (40.62) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.678) is a bit low, potentially hindering permeation. Ligand B (3.171) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are within acceptable limits. Ligand B has 0 HBD and 2 HBA, also good.

**QED:** Both ligands have reasonable QED scores (0.699 and 0.57), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 57.736, which is moderately high. Ligand B has a much lower DILI risk of 12.02, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (70.997) has a higher BBB score than Ligand A (41.218), but this is less critical here.

**Caco-2 Permeability:** Ligand A (-5.115) has poor Caco-2 permeability. Ligand B (-4.279) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.479 and -3.909). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.429) has a slightly elevated hERG risk, while Ligand B (0.74) is higher. This is a concern for both, but more so for Ligand B.

**Microsomal Clearance:** Ligand A (-43.725) has significantly lower microsomal clearance, indicating better metabolic stability. Ligand B (77.828) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (4.782) has a shorter half-life than Ligand B (14.994), but both are acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.136), which is favorable.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-9.1 and -8.1 kcal/mol). The difference of 1 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is favored due to its significantly better metabolic stability (lower Cl_mic) and lower DILI risk, despite its lower logP and Caco-2 permeability. The binding affinity difference is not large enough to outweigh these ADME advantages. The slightly higher hERG risk for Ligand B is also a concern.

Output:
0
2025-04-17 11:10:16,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.386 and 361.433 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (79.46) is still under 140, but less favorable than A.

**logP:** Ligand A (4.091) is at the higher end of the optimal range (1-3), potentially raising solubility concerns. Ligand B (3.168) is comfortably within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.779 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A (89.415) has a higher DILI risk than Ligand B (32.726). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 61.846, Ligand B: 81.233), but this is less critical for a non-CNS target like SRC.

**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 making interpretation difficult without knowing the scale.

**hERG:** Ligand A (0.711) has a slightly higher hERG risk than Ligand B (0.468), but both are reasonably low.

**Microsomal Clearance:** Ligand A (58.633) has lower microsomal clearance than Ligand B (64.371), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (58.877) has a significantly longer in vitro half-life than Ligand B (-18.822). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.513) has lower P-gp efflux than Ligand B (0.058), suggesting better bioavailability.

**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 less than the 1.5 kcal/mol threshold, it's still a factor.

**Overall Assessment:**

Ligand A has a significant advantage in metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux. However, it has a concerningly high DILI risk. Ligand B has a better DILI profile and slightly better binding affinity, but suffers from poorer metabolic stability and higher P-gp efflux. Given the importance of metabolic stability for kinase inhibitors and the relatively small difference in binding affinity, the longer half-life and lower P-gp efflux of Ligand A are compelling. The DILI risk is a concern, but could potentially be mitigated through structural modifications.

Output:
1
2025-04-17 11:10:16,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (357.405 and 351.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (80.12 and 81.67) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.873 and 1.033), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (3 HBDs), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5 HBA) is slightly better than Ligand B (4 HBA), both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.872) has a significantly higher QED score than Ligand B (0.61), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.732) has a much lower DILI risk than Ligand B (12.641), indicating a better safety profile. Both are below the 60 threshold.

**8. BBB:** Ligand A (81.97) has a better BBB penetration score than Ligand B (40.558), although BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.547) has a worse Caco-2 permeability than Ligand B (-5.119). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-2.826) has a better aqueous solubility than Ligand B (-2.305). Higher values are more desirable.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.317 and 0.152), which is excellent.

**12. Microsomal Clearance:** Ligand A (21.044) has a lower microsomal clearance than Ligand B (33.452), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.883) has a much longer in vitro half-life than Ligand B (-1.626), indicating better persistence.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.073 and 0.044).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-9.4 and -8.9 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. While Ligand B has slightly better Caco-2 permeability, the other advantages of Ligand A, particularly the safety profile and metabolic stability, outweigh this minor difference. The binding affinities are comparable. Given the enzyme-specific priorities, Ligand A is the more promising drug candidate.

Output:
1
2025-04-17 11:10:16,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.447 and 376.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is well below the 140 threshold, while Ligand B (129.88) is still acceptable but higher.

**logP:** Ligand A (3.38) is optimal. Ligand B (-0.683) is significantly below the optimal range and could indicate poor permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.85) is excellent, indicating high drug-likeness. Ligand B (0.608) is still reasonable, but lower.

**DILI:** Ligand B (31.02) has a much lower DILI risk than Ligand A (89.957), a significant advantage.

**BBB:** Both have acceptable BBB penetration, but Ligand A is better (71.035 vs 63.086). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.492) is poor, while Ligand B (-5.542) is even worse. Both are concerning, but Ligand B is worse.

**Aqueous Solubility:** Ligand A (-4.833) is poor, while Ligand B (-1.467) is better.

**hERG:** Ligand A (0.528) has a slightly higher hERG risk than Ligand B (0.094), which is a significant advantage for B.

**Microsomal Clearance:** Ligand B (-7.1) has significantly lower (better) microsomal clearance than Ligand A (69.704), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (13.976) has a longer half-life than Ligand A (35.964), a positive attribute.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.008), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.2 kcal/mol). This difference of 1.9 kcal/mol is very significant and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME concerns. The significantly improved binding affinity (-9.1 vs -7.2 kcal/mol) and much lower DILI risk are major advantages. The better metabolic stability (lower Cl_mic and longer t1/2) and lower hERG risk also contribute to its favorability. While the logP and Caco-2 permeability are suboptimal, the strong binding affinity suggests that potency might be less sensitive to these parameters, and formulation strategies could potentially address solubility and permeability issues.

Output:
1
2025-04-17 11:10:16,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (378.376 and 338.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.42) is better than Ligand B (41.05) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (1.494) is optimal, while Ligand B (4.405) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both are within the acceptable range.

**QED:** Both ligands have good QED scores (0.858 and 0.897), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (46.53 and 47.538), both are good (low risk).

**BBB:** Both ligands have high BBB penetration (89.027 and 81.582), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar.

**Solubility:** Ligand A (-2.947) is better than Ligand B (-5.457), indicating higher aqueous solubility.

**hERG:** Ligand A (0.204) has a much lower hERG inhibition liability than Ligand B (0.927), which is a significant advantage.

**Microsomal Clearance:** Ligand A (15.614 mL/min/kg) has a lower clearance than Ligand B (107.355 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.121 hours) has a negative half-life, which is unusual. Ligand B (58.148 hours) has a much longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux liability than Ligand B (0.539), which is preferable.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.2 and -8.0 kcal/mol).

**Overall:**

Ligand A is superior due to its better logP, solubility, lower hERG risk, and lower microsomal clearance. While Ligand B has a longer half-life, the other ADME properties of Ligand A are more favorable, especially the lower hERG risk and better solubility. The similar binding affinities mean the ADME properties become the deciding factors.

Output:
0
2025-04-17 11:10:16,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (78.95 and 78.51) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.433) is slightly low, potentially hindering permeation. Ligand B (1.2) is 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 B (0.784) has a significantly better QED score than Ligand A (0.455), indicating a more drug-like profile.

**DILI:** Ligand A (20.163) has a higher DILI risk than Ligand B (11.283), though both are below the concerning threshold of 40.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (74.06) is slightly higher than Ligand B (64.599). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-4.794 and -5.065).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates very poor solubility. Ligand A (-0.799) is slightly better than Ligand B (-1.741).

**hERG Inhibition:** Ligand A (0.33) shows a lower hERG inhibition liability than Ligand B (0.116), which is favorable.

**Microsomal Clearance:** Ligand B (-2.237) has a *much* lower (better) microsomal clearance than Ligand A (30.689). This suggests significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (8.046 hours) has a substantially longer in vitro half-life than Ligand A (-22.836 hours - a negative value is concerning).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.013), which is good.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-6.5 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold that would strongly favor one ligand, it is still a positive factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. Its superior QED, significantly lower microsomal clearance, longer half-life, and slightly better binding affinity outweigh the slightly lower BBB and solubility compared to Ligand A. The lower DILI risk is also a benefit. While both have poor Caco-2 and solubility, the metabolic stability and potency advantages of Ligand B are more critical for an enzyme target.

Output:
1
2025-04-17 11:10:16,485 - INFO - Batch 25 complete. Total preferences: 400
2025-04-17 11:10:16,485 - INFO - Processing batch 26/512...
2025-04-17 11:11:08,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.559 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (95.33). Lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (A: 2.593, B: 1.715), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both have reasonable H-bond characteristics, well within the suggested limits.

**QED:** Both ligands have high QED scores (A: 0.781, B: 0.91), indicating good drug-like properties.

**DILI:** Ligand A (22.8) has a much lower DILI risk than Ligand B (63.746). This is a significant advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (57.619) is lower than Ligand B (43.001), but this isn't a major deciding factor.

**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 negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is undefined.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.358, B: 0.432), which is good.

**Microsomal Clearance:** Ligand A (65.216) has a higher microsomal clearance than Ligand B (27.326), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-49.582) has a significantly longer in vitro half-life than Ligand A (21.176), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.041, B: 0.088).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), although both are strong binders. The difference is 0.6 kcal/mol, which is not a huge advantage.

**Overall Assessment:**

Ligand A has a significant advantage in terms of DILI risk and TPSA. However, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has slightly better binding affinity. Given that we are targeting a kinase (enzyme), metabolic stability is crucial. While the solubility and permeability data are concerning for both, the superior metabolic profile of Ligand B, coupled with its slightly better affinity, makes it the more promising candidate.

Output:
1
2025-04-17 11:11:08,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:**
* Ligand A: 456.309 Da - Within the ideal range (200-500 Da).
* Ligand B: 349.519 Da - Also within the ideal range.
* *Advantage: Neither is significantly outside the preferred range.*

**2. TPSA:**
* Ligand A: 53.51 A^2 - Good for oral absorption (<=140).
* Ligand B: 52.65 A^2 - Also good for oral absorption.
* *Advantage: Similar, both are good.*

**3. logP:**
* Ligand A: 3.493 - Optimal (1-3).
* Ligand B: 2.26 - Optimal (1-3).
* *Advantage: Both are good, A is slightly higher.*

**4. H-Bond Donors:**
* Ligand A: 0 - Acceptable (<=5).
* Ligand B: 1 - Acceptable (<=5).
* *Advantage: A is slightly better, fewer HBDs generally improve permeability.*

**5. H-Bond Acceptors:**
* Ligand A: 5 - Acceptable (<=10).
* Ligand B: 3 - Acceptable (<=10).
* *Advantage: B is slightly better, fewer HBAs generally improve permeability.*

**6. QED:**
* Ligand A: 0.707 - Excellent (>0.5).
* Ligand B: 0.695 - Excellent (>0.5).
* *Advantage: Very similar, both are good.*

**7. DILI:**
* Ligand A: 83.249 - High risk (>60).
* Ligand B: 7.794 - Low risk (<40).
* *Advantage: B is significantly better, a major concern for A.*

**8. BBB:**
* Ligand A: 85.459 - High, but not a primary concern for a non-CNS target like SRC.
* Ligand B: 78.054 - Good, but not a primary concern.
* *Advantage: Not a major factor in this case.*

**9. Caco-2 Permeability:**
* Ligand A: -4.789 - Poor permeability.
* Ligand B: -4.848 - Poor permeability.
* *Advantage: Similar, both are poor.*

**10. Aqueous Solubility:**
* Ligand A: -5.207 - Poor solubility.
* Ligand B: -2.552 - Poor solubility, but better than A.
* *Advantage: B is slightly better.*

**11. hERG Inhibition:**
* Ligand A: 0.869 - Acceptable risk.
* Ligand B: 0.477 - Lower risk, preferred.
* *Advantage: B is better.*

**12. Microsomal Clearance:**
* Ligand A: 45.548 - Moderate clearance.
* Ligand B: 53.12 - Moderate clearance.
* *Advantage: A is slightly better, lower clearance is preferred.*

**13. In vitro Half-Life:**
* Ligand A: -9.121 - Long half-life.
* Ligand B: -5.899 - Moderate half-life.
* *Advantage: A is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.531 - Moderate efflux.
* Ligand B: 0.066 - Low efflux, preferred.
* *Advantage: B is better.*

**15. Binding Affinity:**
* Ligand A: -7.5 kcal/mol - Excellent.
* Ligand B: 0.0 kcal/mol - Very weak binding.
* *Advantage: A is *significantly* better, a >1.5 kcal/mol advantage.*

**Overall Assessment:**

Ligand A has a significantly better binding affinity (-7.5 kcal/mol vs 0.0 kcal/mol) and a longer in vitro half-life. However, it suffers from a high DILI risk, poor solubility, and poor Caco-2 permeability. Ligand B has a much lower DILI risk, better solubility, and lower P-gp efflux, but its binding affinity is extremely weak.

Given the enzyme-specific priorities, potency (binding affinity) is paramount. The substantial difference in binding affinity between A and B outweighs the ADME concerns with Ligand A *provided* that the DILI risk can be mitigated through structural modifications. The poor solubility and permeability of A are also addressable through prodrug strategies or formulation approaches. Ligand B's lack of potency makes it a non-starter.

Output:
1
2025-04-17 11:11:08,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.467 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (91.24). Lower TPSA generally correlates with better cell permeability.

**logP:** Both are within the optimal range (1-3), with Ligand A (3.841) being slightly higher. This isn't a major concern, but could potentially lead to off-target effects if it's significantly higher than other compounds in the series.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is preferable to Ligand B (HBD=1, HBA=5). While both are acceptable, lower HBA counts can improve permeability.

**QED:** Both ligands have similar QED values (A: 0.741, B: 0.666), indicating good drug-like properties.

**DILI:** Ligand A (39.667) has a much lower DILI risk than Ligand B (89.841). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (79.217) has better BBB penetration than Ligand B (51.105).

**Caco-2 Permeability:** Ligand A (-4.31) shows better Caco-2 permeability than Ligand B (-4.748), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.578 and -5.287 respectively). This is a concern for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.669) has a lower hERG risk than Ligand B (0.315), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (64.14) has a higher microsomal clearance than Ligand B (24.823). This means Ligand B is more metabolically stable, a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (1.178) has a slightly longer half-life than Ligand A (0.817), but the difference isn't substantial.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.242 and 0.222 respectively).

**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 positive for Ligand B.

**Overall Assessment:**

Ligand A has superior ADME properties (lower DILI, better TPSA, better Caco-2, lower hERG) and comparable binding affinity. Ligand B has better metabolic stability (lower Cl_mic) and a slightly better binding affinity. However, the significantly higher DILI risk for Ligand B is a major concern. Given the enzyme-specific priorities, metabolic stability is important, but a high DILI risk is a significant hurdle. The small advantage in binding affinity of Ligand B does not outweigh the substantial ADME benefits of Ligand A.

Output:
0
2025-04-17 11:11:08,190 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [362.459, 103.91 ,   0.488,   1.   ,   7.   ,   0.739,  51.028,  49.787, -5.43 ,  -2.753,   0.099,  10.983,   7.164,   0.068,  -7.5  ]
**Ligand B:** [354.407, 126.46 ,  -0.007,   3.   ,   7.   ,   0.507,  54.634,  30.167, -5.396,  -1.281,   0.049,  28.316,   0.051,   0.08 ,  -9.3  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (362.459) and B (354.407) are comparable.
2. **TPSA:** A (103.91) is better than B (126.46), falling comfortably under the 140 A^2 threshold for oral absorption. B is still acceptable, but less optimal.
3. **logP:** A (0.488) is slightly better than B (-0.007). Both are relatively low, potentially impacting permeability, but not drastically.
4. **HBD:** A (1) is preferable to B (3). Lower HBD generally improves permeability.
5. **HBA:** Both A (7) and B (7) are within the acceptable range (<=10).
6. **QED:** Both A (0.739) and B (0.507) are above the 0.5 threshold, indicating good drug-like properties. A is slightly better.
7. **DILI:** Both are acceptable, but A (51.028) is better than B (54.634). Lower DILI is always preferred.
8. **BBB:** A (49.787) is better than B (30.167), but BBB isn't a high priority for a kinase inhibitor.
9. **Caco-2:** Both are very poor (-5.43 and -5.396). This is a significant concern for oral bioavailability.
10. **Solubility:** Both are very poor (-2.753 and -1.281). This is a major issue for formulation and bioavailability.
11. **hERG:** Both are very low (0.099 and 0.049), indicating low cardiotoxicity risk.
12. **Cl_mic:** A (10.983) is *much* better than B (28.316). Lower clearance indicates better metabolic stability, a key factor for kinase inhibitors.
13. **t1/2:** A (7.164) is better than B (0.051). A longer half-life is desirable.
14. **Pgp:** Both are low (0.068 and 0.08), suggesting minimal efflux issues.
15. **Binding Affinity:** B (-9.3) is significantly better than A (-7.5). A difference of 1.8 kcal/mol is substantial and can often outweigh other drawbacks.

**Enzyme-Kinase Specific Priorities:**

Given that SRC is a kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are the most important factors. B has a much stronger binding affinity. While A has better metabolic stability and half-life, the large difference in binding affinity is likely to be more impactful. The poor solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

**Conclusion:**

Despite the better ADME properties of Ligand A, the significantly superior binding affinity of Ligand B (-9.3 kcal/mol vs -7.5 kcal/mol) makes it the more promising drug candidate. The potency advantage is likely to outweigh the solubility and permeability concerns, which can be addressed through formulation.

1
2025-04-17 11:11:08,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.777 and 376.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.7) is slightly higher than Ligand B (92.78). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is closer to the 90 A^2 threshold for CNS penetration (though that's not a priority here).

**logP:** Ligand A (1.548) and Ligand B (0.837) are both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is higher than Ligand B (1), but both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.528 and 0.677, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 91.974, 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.

**BBB:** This is not a primary concern for a kinase inhibitor, but Ligand B (66.188) has a higher BBB percentile than Ligand A (10.314).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.683 and -5.046). This is unusual and suggests poor permeability. However, these values are on a log scale and the absolute values are similar, so the difference isn't critical.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.837 and -1.487). Again, this is unusual and suggests poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.169 and 0.322), which is good.

**Microsomal Clearance:** Ligand A (14.073 mL/min/kg) has lower microsomal clearance than Ligand B (24.3 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (69.659 hours) has a significantly longer half-life than Ligand B (11.901 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.015), which is favorable.

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

**Overall Assessment:**

Ligand B is clearly superior due to its significantly lower DILI risk. While Ligand A has a longer half-life and better metabolic stability, the high DILI risk is a major concern. A high DILI risk often leads to attrition during drug development. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 11:11:08,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.455 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is higher than Ligand B (75.44). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Both ligands have similar logP values (2.23 and 2.157), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Ligand B is slightly better here, with fewer HBDs, potentially improving permeability.

**QED:** Both ligands have good QED scores (0.612 and 0.815), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 75.533, which is concerning (high risk). Ligand B has a much lower DILI risk of 41.954, which is good. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.319) has better BBB penetration than Ligand A (26.483), but this isn't a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.418) is slightly worse than Ligand B (-4.568).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.676) is slightly worse than Ligand B (-2.777).

**hERG Inhibition:** Ligand A (0.203) has a slightly lower hERG risk than Ligand B (0.429), which is preferable.

**Microsomal Clearance:** Ligand A (-10.552) has significantly lower (better) microsomal clearance than Ligand B (39.656), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.852) has a slightly longer half-life than Ligand B (-5.127).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.078 and 0.161).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better metabolic stability and a slightly lower hERG risk, Ligand B's significantly lower DILI risk is a major advantage. The slightly better binding affinity of Ligand B, combined with its better QED, TPSA, and Caco-2 permeability, further support its selection. The solubility issues are a concern for both, but can be addressed with formulation strategies. The DILI risk for Ligand A is a serious red flag.

Output:
1
2025-04-17 11:11:08,190 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (375.487 and 369.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (89.98 and 87.74) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have similar logP values (1.366 and 1.351), falling within the optimal range of 1-3.

**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 6 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Ligand B (0.759) has a better QED score than Ligand A (0.47), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk, with Ligand A at 40.83 and Ligand B at 49.632, both under the 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (73.323 and 75.727), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.837 and -4.934). 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 (-2.212 and -2.122). Again, the scale is undefined, making interpretation difficult. However, negative values likely indicate poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.389 and 0.39), which is excellent.

**12. Microsomal Clearance:** Ligand B (7.378) has significantly lower microsomal clearance than Ligand A (69.278), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-38.698) has a longer in vitro half-life than Ligand A (-44.082). Again, the scale is undefined, but a less negative value suggests a longer half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.14 and 0.056).

**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 0.4 kcal/mol difference, which is notable but not overwhelming.

**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 a longer in vitro half-life. The better QED score also favors Ligand B. Given the enzyme-kinase target class priority, metabolic stability and half-life are crucial. The slight difference in binding affinity can potentially be optimized in later stages of drug development. The poor solubility and permeability indicated by the negative values are concerning for both, but could be addressed with formulation strategies.

Output:
1
2025-04-17 11:11:08,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (345.443 and 362.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.74) is slightly higher than Ligand B (69.68), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.234) is optimal, while Ligand B (3.703) is approaching the upper limit of the preferred range. This could potentially lead to solubility issues for Ligand B.

**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 below the 10 threshold.

**QED:** Both ligands have a QED of approximately 0.87, indicating good drug-likeness.

**DILI:** Ligand A (19.426) has a significantly lower DILI risk than Ligand B (85.227). This is a major advantage for Ligand A.

**BBB:** Both ligands have moderate BBB penetration, with Ligand B (67.468) being slightly higher than Ligand A (55.487). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.803 and -4.644), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference is small.

**Aqueous Solubility:** Ligand A (-0.991) has better predicted solubility than Ligand B (-4.018). This is important for bioavailability.

**hERG Inhibition:** Ligand A (0.225) has a much lower hERG inhibition risk than Ligand B (0.347). This is a critical safety parameter.

**Microsomal Clearance:** Ligand A (13.321 mL/min/kg) has significantly lower microsomal clearance than Ligand B (49.816 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.098 hours) has a longer predicted half-life than Ligand B (-14.932 hours).

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.186), suggesting better oral bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 1.5 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better across several crucial ADMET properties. Specifically, the much lower DILI risk, better solubility, lower hERG inhibition, improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux make Ligand A a far more promising drug candidate. The slight difference in binding affinity is likely surmountable with further optimization, whereas mitigating the significant ADMET liabilities of Ligand B would be much more challenging.

Output:
0
2025-04-17 11:11:08,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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.

**TPSA:** Both are acceptable (Ligand A: 111.15, Ligand B: 104.7), being under the 140 threshold for oral absorption.

**logP:** Ligand A (-0.318) is a bit low, potentially hindering permeation. Ligand B (1.041) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (A: 7, B: 7) are within the acceptable range of 10.

**QED:** Both have good QED scores (A: 0.77, B: 0.869), indicating drug-likeness.

**DILI:** Ligand A (63.823) is better than Ligand B (75.184) in terms of DILI risk, being further from the high-risk threshold of 60.

**BBB:** Both have low BBB penetration (A: 34.548, B: 32.299), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.76) is slightly better than Ligand B (-4.735).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.632) is slightly better than Ligand B (-2.528).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.02, B: 0.028), which is excellent.

**Microsomal Clearance:** Ligand A (-20.177) has significantly lower (better) microsomal clearance than Ligand B (50.871), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (28.365) has a better in vitro half-life than Ligand B (-13.185).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.009, B: 0.065).

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is not substantial enough to outweigh the ADME advantages of Ligand A.

**Overall:**

Ligand A has several advantages: better metabolic stability (lower Cl_mic, longer t1/2), slightly better solubility and Caco-2 permeability, and a lower DILI risk. While Ligand B has a slightly better affinity and logP, the ADME profile of Ligand A is more favorable for development as an enzyme inhibitor. The affinity difference is not large enough to overcome the metabolic liability of Ligand B.

Output:
0
2025-04-17 11:11:08,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.451 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Both are acceptable, but Ligand B (72.01) is significantly better than Ligand A (97.35), being well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (0.89) is a bit low, potentially hindering permeation. Ligand B (2.141) is within the optimal range (1-3).

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.852) has a better QED score than Ligand B (0.738), indicating a more drug-like profile.

**DILI:** Ligand A (35.13) has a much lower DILI risk than Ligand B (15.394), which is a significant advantage.

**BBB:** Both have good BBB penetration, but Ligand B (79.721) is slightly better than Ligand A (70.997). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-5.226) is slightly better than Ligand B (-5.744).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.674) is slightly better than Ligand B (-2.252).

**hERG:** Ligand A (0.117) has a much lower hERG risk than Ligand B (0.397), a crucial factor for kinase inhibitors.

**Microsomal Clearance:** Ligand B (-1.024) has a negative clearance, which is impossible and likely an error. Ligand A (10.674) has a moderate clearance. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand B (24.758) has a much longer half-life than Ligand A (-11.881). However, the negative value for Ligand A is suspect.

**P-gp Efflux:** Both have low P-gp efflux liability, with Ligand A (0.044) being slightly lower than Ligand B (0.066).

**Binding Affinity:** Ligand A (-7.9 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 the stronger candidate. While Ligand B has slightly better BBB penetration and in vitro half-life, the significant advantages of Ligand A in terms of DILI risk, hERG inhibition, binding affinity, and a more reasonable microsomal clearance outweigh these factors. The negative values for Caco-2, solubility and half-life for Ligand A are concerning, but the values for Ligand B are even more problematic (negative clearance and affinity). The superior binding affinity of Ligand A is particularly important for an enzyme target like SRC kinase.

Output:
0
2025-04-17 11:11:08,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (448.308 Da) is closer to the upper limit, while Ligand B (347.379 Da) is closer to the lower limit. This isn't a major differentiating factor.

**TPSA:** Ligand A (51.02) is well below the 140 threshold for good oral absorption. Ligand B (126.45) is also below the threshold, but higher than A.

**logP:** Ligand A (4.115) is slightly above the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-1.455) is significantly below the optimal range, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 6 HBA) both fall within acceptable ranges (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.565, B: 0.691), indicating drug-like properties.

**DILI:** Ligand A (59.17) has a higher DILI risk than Ligand B (44.63), but both are reasonably acceptable.

**BBB:** Both ligands have similar BBB penetration (A: 79.217, B: 77.433). This isn't a major factor for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.889) has poor Caco-2 permeability, while Ligand B (-5.295) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.085) has poor aqueous solubility, while Ligand B (-2.206) has slightly better aqueous solubility.

**hERG Inhibition:** Ligand A (0.847) has a slightly higher hERG risk than Ligand B (0.072). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (98.355) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-12.497) has excellent metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (103.49) has a reasonable in vitro half-life, while Ligand B (6.382) has a very short half-life.

**P-gp Efflux:** Ligand A (0.571) has moderate P-gp efflux, while Ligand B (0.004) has very low P-gp efflux. This is an advantage for Ligand B.

**Binding Affinity:** Ligand A (-9.4 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. The difference of 1.3 kcal/mol is significant.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability, poor aqueous solubility, high microsomal clearance, and moderate P-gp efflux. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower hERG, lower P-gp efflux, slightly better solubility), but its binding affinity is considerably weaker.

Given the substantial difference in binding affinity (1.3 kcal/mol), I believe Ligand A is the more promising candidate, despite its ADME liabilities. Optimization efforts could focus on improving its solubility, permeability, and metabolic stability while retaining its high potency.

Output:
0
2025-04-17 11:11:08,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.343 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.14) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (85.77) is excellent, well below 140.

**logP:** Ligand A (3.15) is at the high end of the optimal 1-3 range. Ligand B (0.533) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both within acceptable limits. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.671 and 0.679), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (95.89%), which is a significant concern. Ligand B has a very low DILI risk (19.659%), a major advantage.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

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

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A has a slightly higher hERG risk (0.545) than Ligand B (0.264), but both are relatively low.

**Microsomal Clearance:** Both have similar microsomal clearance values (41.622 and 40.879 mL/min/kg), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (86.983 hours) than Ligand B (24.858 hours), which is preferable.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**Binding Affinity:** Ligand B has a significantly better binding affinity (-7.8 kcal/mol) compared to Ligand A (0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand B is the stronger candidate despite its low logP and solubility. The significantly superior binding affinity (-7.8 kcal/mol vs 0 kcal/mol) outweighs the potential permeability issues. The dramatically lower DILI risk (19.659% vs 95.89%) is also a critical factor. While both have poor Caco-2 and solubility, these can be addressed with formulation strategies. The longer half-life of Ligand A is a plus, but not enough to overcome the DILI and affinity concerns.

Output:
1
2025-04-17 11:11:08,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (362.348 Da and 367.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (97.3) is still within acceptable limits, but less favorable than A.

**3. logP:** Ligand A (3.566) is at the upper end of the optimal range (1-3), while Ligand B (0.727) is slightly below, potentially impacting 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 (4) and Ligand B (6) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.803 and 0.846), indicating drug-like properties.

**7. DILI:** Ligand A (62.001) has a slightly higher DILI risk than Ligand B (55.642), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (70.027) shows better BBB penetration potential than Ligand B (55.797), though BBB isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.596 and -4.791), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.287 and -0.789), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.641) has a lower hERG risk than Ligand B (0.147), which is a significant advantage.

**12. Microsomal Clearance:** Ligand B (-20.19) exhibits significantly lower microsomal clearance than Ligand A (70.267), indicating much better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (-0.33) has a slightly longer in vitro half-life than Ligand A (2.392), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.141) shows slightly lower P-gp efflux than Ligand B (0.03), which is a minor advantage.

**15. Binding Affinity:** Ligand A (-9.0) has a substantially stronger binding affinity than Ligand B (0.0). This is a major advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While both ligands have significant ADME liabilities (poor solubility and permeability), Ligand A's dramatically superior binding affinity (-9.0 kcal/mol vs. 0.0 kcal/mol) is a decisive factor. The difference in affinity is so large that it's likely to overcome the solubility/permeability issues, especially with formulation strategies. Ligand B's better metabolic stability is attractive, but the lack of significant binding affinity makes it unlikely to be a viable candidate.

Output:
1
2025-04-17 11:11:08,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.415 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.41) is slightly higher than Ligand B (69.72), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.669 and 1.398), 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 (0.762 and 0.834), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 43.971, while Ligand B has a much lower risk of 11.632. This is a significant advantage for Ligand B.

**BBB:** Ligand A (46.336) has a lower BBB penetration percentile than Ligand B (76.347). While BBB isn't a primary concern for a non-CNS target like SRC, higher BBB is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.574) has worse Caco-2 permeability than Ligand B (-4.793). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.112) has slightly better aqueous solubility than Ligand B (-1.845). Both are negative, indicating poor solubility, but A is slightly better.

**hERG Inhibition:** Ligand A (0.639) has a higher hERG inhibition risk than Ligand B (0.268). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (-44.717) has much lower microsomal clearance (better metabolic stability) than Ligand B (11.784). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (6.575) has a shorter in vitro half-life than Ligand B (-11.669). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux than Ligand B (0.013). Lower efflux is better, so A is slightly better.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a significant advantage in binding affinity and metabolic stability. However, Ligand B excels in DILI risk, hERG inhibition, BBB penetration, and in vitro half-life. The difference in binding affinity is significant, and for an enzyme target like SRC kinase, potency is paramount. While Ligand B's ADME profile is better, the substantial binding affinity advantage of Ligand A makes it the more promising candidate, assuming further optimization can address its slightly less favorable metabolic stability and solubility.

Output:
0
2025-04-17 11:11:08,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.4 and 344.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.3) is higher than Ligand B (40.6). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Both ligands have good logP values (2.46 and 3.23), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting solubility but not dramatically.

**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). Ligand B is preferable here as fewer hydrogen bonds can improve membrane permeability.

**QED:** Both ligands have similar QED values (0.778 and 0.738), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 87.6%, which is high. Ligand B has a much lower DILI risk of 16.1%, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (78.6%) has a higher BBB value than Ligand A (63.1%), but this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.73 and -4.69). These values are unusual and suggest 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 (-4.72 and -3.23). Again, these are unusual and suggest poor solubility. Ligand B is slightly better, but both are concerning.

**hERG:** Ligand A (0.65) has a higher hERG risk than Ligand B (0.433), making Ligand B preferable.

**Microsomal Clearance:** Ligand A (44.54) has a lower microsomal clearance than Ligand B (78.873), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-28.7) has a much longer half-life than Ligand B (-5.86). This is a substantial benefit for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux values (0.141 and 0.231), which is good.

**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, potentially outweighing some of the ADME drawbacks of Ligand A. The difference of 1.9 kcal/mol is substantial.

**Overall Assessment:**

Ligand B has a much better safety profile (lower DILI, lower hERG) and superior binding affinity. While Ligand A has better metabolic stability and half-life, the strong binding affinity of Ligand B is a critical factor for an enzyme inhibitor. The lower DILI risk of Ligand B is also a major advantage. The solubility and permeability concerns are present in both, but the potency advantage of Ligand B is likely to be more impactful in early development.

Output:
1
2025-04-17 11:11:08,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.427 and 351.334 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is significantly better than Ligand B (124.69). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Both ligands have acceptable logP values (1.479 and 1.256), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 6 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.846) has a much better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Ligand A (38.93) has a lower DILI risk than Ligand B (56.844), which is a significant advantage. Both are below the 60 threshold, but lower is always better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.617) has a higher BBB penetration than Ligand B (19.542).

**Caco-2 Permeability:** Ligand A (-4.59) shows better Caco-2 permeability than Ligand B (-5.498).

**Aqueous Solubility:** Ligand A (-0.746) has better aqueous solubility than Ligand B (-2.467). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.653 and 0.422), which is good.

**Microsomal Clearance:** Ligand A (47.385) has a higher microsomal clearance than Ligand B (15.118), meaning Ligand B is more metabolically stable. This is a key consideration for kinases.

**In vitro Half-Life:** Ligand B (-4.395) has a better in vitro half-life than Ligand A (-17.159), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.235 and 0.046).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.1 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2), Ligand A excels in almost all other crucial ADME properties (TPSA, QED, DILI, Solubility, Caco-2 permeability). The binding affinity is nearly identical. Given the enzyme-specific priorities, the better ADME profile of Ligand A, particularly the lower DILI risk and better solubility, outweigh the slight advantage in metabolic stability offered by Ligand B.

Output:
1
2025-04-17 11:11:08,192 - INFO - Batch 26 complete. Total preferences: 416
2025-04-17 11:11:08,192 - INFO - Processing batch 27/512...
2025-04-17 11:11:56,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.471 and 343.303 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is excellent, below 140 and even approaching the threshold for CNS penetration. Ligand B (132.21) is still acceptable but less favorable.

**logP:** Ligand A (-0.546) is a bit low, potentially hindering permeability. Ligand B (0.941) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is good. Ligand B (1 HBD, 9 HBA) is also acceptable, though slightly higher HBA could be a minor concern.

**QED:** Ligand A (0.69) is good, indicating strong drug-likeness. Ligand B (0.414) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (27.569) has a very favorable DILI risk, well below 40. Ligand B (91.663) has a high DILI risk, significantly above 60. This is a major red flag.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (71.966) is slightly better than Ligand A (61.846). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.963 and -5.079), which is unusual and suggests poor permeability. This needs further investigation, but is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.638 and -2.891), indicating very poor aqueous solubility. This is a significant issue for both compounds.

**hERG:** Both ligands have low hERG inhibition risk (0.265 and 0.09), which is excellent.

**Microsomal Clearance:** Ligand A (18.458 mL/min/kg) is better than Ligand B (33.289 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.588 hours) is better than Ligand B (-8.779 hours), suggesting a longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.159), which is favorable.

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

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand A is significantly more promising due to its much lower DILI risk (27.569 vs 91.663), better metabolic stability (lower Cl_mic), and longer half-life. While both have poor solubility and permeability, the DILI risk for Ligand B is a major concern that outweighs its slightly better BBB penetration and logP. The better QED score for Ligand A also contributes to its favorability.

Output:
0
2025-04-17 11:11:56,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.411 and 373.806 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is well below the 140 threshold, while Ligand B (35.58) is even better, suggesting good absorption potential for both.

**logP:** Ligand A (1.575) is within the optimal 1-3 range. Ligand B (3.044) is also acceptable, being at the higher end of the optimal range.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 4 HBA, both within the recommended limits. Ligand B has 1 HBD and 2 HBA, also well within limits.

**QED:** Both ligands have good QED scores (0.726 and 0.821), indicating drug-like properties.

**DILI:** Ligand A (49.399) has a slightly higher DILI risk than Ligand B (27.181), but both are below the concerning threshold of 60.

**BBB:** Ligand A (57.154) has a lower BBB penetration percentile than Ligand B (92.555). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.963 and -4.864), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.665 and -3.953), which is also concerning and suggests poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.48) has a lower hERG inhibition risk than Ligand B (0.882), which is favorable.

**Microsomal Clearance:** Ligand A (32.017 mL/min/kg) has a higher microsomal clearance than Ligand B (17.023 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** The in vitro half-lives are similar for both ligands (11.21 and 11.198 hours).

**P-gp Efflux:** Ligand A (0.066) has a lower P-gp efflux liability than Ligand B (0.235), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 1.6 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.4 vs -6.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has a lower DILI risk, better BBB penetration (though not crucial here), and lower P-gp efflux. While its hERG risk is slightly higher and clearance slightly lower than Ligand A, the potency difference is the dominant factor. The poor permeability and solubility would need to be addressed through formulation or further chemical modifications, but the strong binding provides a solid foundation for optimization.

Output:
1
2025-04-17 11:11:56,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.423 and 357.841 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is better than Ligand B (62.3). Both are below the 140 A^2 threshold for oral absorption, but Ligand B is significantly lower, potentially indicating better absorption.

**logP:** Ligand B (1.862) is optimal (1-3), while Ligand A (-0.496) is slightly below 1, which might hinder permeation.

**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, <=10 HBA).

**QED:** Both ligands have good QED scores (0.515 and 0.663, respectively), indicating drug-like properties.

**DILI:** Ligand B (60.682) has a slightly higher DILI risk than Ligand A (48.468), but both are still within a reasonable range (<60 is good).

**BBB:** Ligand A (58.085) has a lower BBB penetration than Ligand B (46.026). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.319) has a worse Caco-2 permeability than Ligand B (-4.733).

**Aqueous Solubility:** Ligand A (-1.033) has a worse aqueous solubility than Ligand B (-3.507). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.048) has a very low hERG inhibition risk, which is excellent. Ligand B (0.212) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (18.911) has a higher microsomal clearance than Ligand B (14.366), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.703) has a much longer in vitro half-life than Ligand A (3.385), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.01) has a lower P-gp efflux than Ligand B (0.032), which is favorable.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.9). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having a slightly higher DILI risk, its significantly stronger binding affinity (-9.0 vs -7.9 kcal/mol), better solubility, and dramatically improved in vitro half-life make it the more promising drug candidate. The slightly lower BBB penetration is not a concern for a non-CNS target like SRC. The better logP and TPSA of Ligand B also contribute to its favorability.

Output:
1
2025-04-17 11:11:56,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.435 and 361.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.24) is slightly above the preferred <100 for optimal absorption, but still reasonable. Ligand B (91.32) is excellent, well below 140 and closer to the ideal for good absorption.

**logP:** Ligand A (0.79) is a bit low, potentially hindering permeation. Ligand B (2.609) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.729) has a better QED score than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand B (75.456) has a higher DILI risk than Ligand A (36.797). This is a significant concern.

**BBB:** Ligand A (85.537) shows better BBB penetration than Ligand B (43.583), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.528 and -5.399), which is unusual and suggests poor permeability. This is a major red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.495 and -4.116), indicating very poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.299) has a much lower hERG inhibition liability than Ligand B (0.435), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (16.115 mL/min/kg) has significantly lower microsomal clearance than Ligand B (34.802 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.664 hours) has a much longer in vitro half-life than Ligand B (-7.14 hours). The negative value for B is concerning and likely indicates rapid degradation.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux liability, while Ligand B (0.149) is slightly higher.

**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 the other significant differences.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. It has a better QED score, significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While both have poor Caco-2 permeability and solubility, the other advantages of Ligand A make it a better starting point for optimization. Addressing the solubility and permeability issues would be the next step.

Output:
0
2025-04-17 11:11:56,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.45) is higher than Ligand B (66.4). While both are reasonably acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Both ligands have good logP values (1.224 and 2.532), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors:** Ligand A has 4 HBD, while Ligand B has 0. Lower is generally better for permeability, making Ligand B favorable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Ligand B (0.794) has a significantly better QED score than Ligand A (0.339), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (31.524 and 34.277), which is good.

**BBB:** Ligand B (90.578) has a higher BBB percentile than Ligand A (54.091). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.19) has a worse Caco-2 permeability than Ligand B (-4.653).

**Aqueous Solubility:** Ligand A (-2.438) has a worse aqueous solubility than Ligand B (-1.916). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.829 and 0.612), which is excellent.

**Microsomal Clearance:** Ligand A (28.012) has a significantly lower microsomal clearance than Ligand B (61.623), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-14.177) has a longer half-life than Ligand A (-11.27), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.182 and 0.316).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.7 and -8.6 kcal/mol). Ligand A has a 1.1 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic). However, Ligand B excels in most other ADME properties: better TPSA, logP, QED, Caco-2 permeability, solubility, and BBB. The difference in binding affinity (1.1 kcal/mol) is substantial enough to potentially overcome the ADME drawbacks of Ligand A, especially considering the importance of potency for kinase inhibitors. The improved metabolic stability of Ligand A is also a critical factor.

Output:
0
2025-04-17 11:11:56,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.407 Da) is slightly higher than Ligand B (349.391 Da), but both are acceptable.

**TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (122.14) is still reasonable but less favorable.

**logP:** Ligand A (3.573) is optimal. Ligand B (1.249) is a bit low, potentially hindering permeability.

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

**QED:** Ligand A (0.768) is very good, indicating high drug-likeness. Ligand B (0.555) is acceptable, but lower.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A at 51.377 and Ligand B at 58.24. Both are below the 60 threshold.

**BBB:** Ligand A (81.621) shows good BBB penetration, while Ligand B (31.214) is low. This is less critical for a non-CNS target like SRC, but a bonus for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.737) is very poor, while Ligand B (-5.769) is also poor. This is a concern for both, but worse for B.

**Aqueous Solubility:** Ligand A (-4.287) is poor, while Ligand B (-1.832) is better. Solubility is important for bioavailability, so B has an advantage here.

**hERG Inhibition:** Ligand A (0.492) has a low risk of hERG inhibition, which is excellent. Ligand B (0.035) has a very low risk, which is even better.

**Microsomal Clearance:** Ligand A (40.88) is moderate, while Ligand B (-1.666) is very low, suggesting much better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (0.584) has a very short half-life, which is unfavorable. Ligand B (11.691) has a much longer half-life, which is a major advantage.

**P-gp Efflux:** Ligand A (0.137) has low P-gp efflux, which is good. Ligand B (0.017) has very low P-gp efflux, which is even better.

**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 Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and good drug-like properties (QED, DILI, hERG, P-gp). However, its poor Caco-2 permeability, low solubility, and short half-life are significant concerns.

Ligand B has better solubility, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. However, its lower binding affinity and lower logP are drawbacks.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is a major factor. While its ADME properties are less ideal, the potency advantage could be addressed through further optimization. The improved metabolic stability and longer half-life of Ligand B are attractive, but the weaker binding affinity is a substantial disadvantage.

Output:
1
2025-04-17 11:11:56,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (346.383 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly higher than Ligand B (84.71), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.272) is optimal, while Ligand B (3.004) is also within the optimal range, but closer to the upper limit.

**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 scores (0.756 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (65.374) has a higher DILI risk than Ligand B (42.032). This is a significant negative for Ligand A.

**BBB:** Ligand A (56.611) has a lower BBB penetration than Ligand B (82.823). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.07) has worse Caco-2 permeability than Ligand B (-4.577), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-3.572 and -3.577). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.154) has a slightly lower hERG inhibition risk than Ligand B (0.571), which is favorable.

**Microsomal Clearance:** Ligand A (-11.455) has significantly lower microsomal clearance than Ligand B (24.15). This suggests much better metabolic stability for Ligand A, a crucial factor for kinases.

**In vitro Half-Life:** Ligand A (11.104 hours) has a longer half-life than Ligand B (6.599 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.061) shows lower P-gp efflux than Ligand B (0.106), which could lead to better bioavailability.

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk and slightly worse Caco-2 permeability, its *significantly* superior binding affinity, much better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux make it the more promising drug candidate. The strong binding affinity is particularly important for an enzyme target like SRC, and the improved metabolic stability will likely translate to better *in vivo* exposure. The DILI risk, while higher, is not prohibitive and could be addressed through further optimization.

Output:
1
2025-04-17 11:11:56,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.419 Da and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.33) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.43) is still under 140, but less favorable than A.

**logP:** Ligand A (4.371) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.13) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (3 HBD, 3 HBA) is acceptable.

**QED:** Both ligands have similar QED values (0.77 and 0.688), indicating good drug-likeness.

**DILI:** Ligand A (75.107) has a higher DILI risk than Ligand B (6.514). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.407) and B (35.595) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.845 and -4.929), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Ligand A (-6.165) and B (-2.952) both have negative solubility values, indicating very poor aqueous solubility. This is a major issue.

**hERG:** Ligand A (0.796) has a slightly higher hERG risk than Ligand B (0.241).

**Microsomal Clearance:** Ligand A (57.796) has a higher microsomal clearance than Ligand B (21.747), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (23.464) has a longer half-life than Ligand B (10.33), which is favorable.

**P-gp Efflux:** Ligand A (0.695) has lower P-gp efflux than Ligand B (0.019), which is favorable.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate despite its slightly less optimal logP and TPSA. The significantly stronger binding affinity (-9.0 vs -8.1 kcal/mol) is a major advantage for an enzyme target. While both ligands have poor solubility and permeability, the lower DILI risk and better metabolic stability (lower Cl_mic, though half-life is lower) of Ligand B are crucial. The higher P-gp efflux for ligand B is a concern, but less so than the DILI risk of Ligand A.

Output:
1
2025-04-17 11:11:56,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.431 and 369.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.89) is better than Ligand B (100.35), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.538) is slightly better than Ligand B (0.173), both are a bit low, potentially impacting permeability. However, for a kinase inhibitor, this isn't a critical issue.

**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 7. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.771 and 0.753), indicating good drug-like properties.

**DILI:** Ligand A (56.844) has a lower DILI risk than Ligand B (65.491), which is preferable. Both are acceptable, but A is better.

**BBB:** Ligand A (57.193) has a better BBB penetration than Ligand B (36.758). While not a primary concern for a non-CNS target, it's a slight advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.137 and -5.471), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.653 and -2.72). This is a major red flag, indicating very poor solubility, which will hinder bioavailability.

**hERG Inhibition:** Ligand A (0.134) has a significantly lower hERG risk than Ligand B (0.506), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (15.596) has a lower microsomal clearance than Ligand B (26.902), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (21.44) has a positive half-life, while Ligand B (-21.703) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.028) has a lower P-gp efflux liability than Ligand B (0.087), which is preferable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-9.0 kcal/mol). While both are excellent, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have poor solubility and permeability, Ligand A demonstrates superior metabolic stability (lower Cl_mic, positive t1/2), lower DILI risk, lower hERG risk, and slightly better binding affinity. These factors are crucial for an enzyme inhibitor targeting oncology. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the other properties of Ligand A make it a more promising starting point.

Output:
0
2025-04-17 11:11:56,139 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [372.531, 92.34, 1.648, 2, 4, 0.61, 34.626, 63.28, -5.123, -2.209, 0.319, 37.39, 5.234, 0.147, -6.7]
**Ligand B:** [382.913, 58.64, 3.082, 1, 4, 0.851, 50.601, 79.488, -4.736, -4.23, 0.432, 30.796, 8.585, 0.57, -9]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (372.531) is slightly lower, which is generally favorable for permeability.
2. **TPSA:** A (92.34) is higher than B (58.64). Both are below 140, but B is significantly better for oral absorption.
3. **logP:** A (1.648) is good, within the optimal range. B (3.082) is also good, leaning towards the upper end, potentially increasing off-target interactions.
4. **HBD:** A (2) and B (1) are both acceptable, below the threshold of 5. B is slightly better.
5. **HBA:** Both A (4) and B (4) are within the acceptable range of <=10.
6. **QED:** Both A (0.61) and B (0.851) are good, indicating drug-like properties. B is better.
7. **DILI:** A (34.626) is better than B (50.601), indicating lower liver injury risk.
8. **BBB:** A (63.28) is lower than B (79.488). While not a primary concern for a kinase inhibitor, B has better potential for CNS penetration if needed.
9. **Caco-2:** A (-5.123) is very poor, indicating very low intestinal absorption. B (-4.736) is also poor, but slightly better than A.
10. **Solubility:** A (-2.209) is poor, while B (-4.23) is even worse. Both have solubility issues.
11. **hERG:** A (0.319) is lower and thus better than B (0.432), indicating a lower risk of cardiotoxicity.
12. **Cl_mic:** A (37.39) is higher than B (30.796), suggesting faster metabolism and lower metabolic stability. B is better.
13. **t1/2:** A (5.234) is lower than B (8.585), indicating a shorter half-life. B is better.
14. **Pgp:** A (0.147) is lower than B (0.57), suggesting less P-gp efflux and potentially better bioavailability. A is better.
15. **Binding Affinity:** B (-9) is significantly better than A (-6.7), a difference of 2.3 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme (kinase) target, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B has a much stronger binding affinity.
*   **Metabolic Stability:** B has lower Cl_mic and longer t1/2, indicating better metabolic stability.
*   **Solubility:** Both are poor, but B is worse. This is a concern for both.
*   **hERG:** A has a slightly better hERG profile.
*   **Absorption:** Both have poor Caco-2 permeability.

**Conclusion:**

Despite the solubility concerns for both compounds, **Ligand B** is the more promising candidate due to its significantly superior binding affinity and improved metabolic stability. The 2.3 kcal/mol difference in binding affinity is substantial and outweighs the slightly worse solubility and Pgp efflux. The better metabolic stability (lower Cl_mic, longer t1/2) is also a critical advantage for an enzyme inhibitor.

Output:
1
2025-04-17 11:11:56,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.515 and 358.498 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (58.64), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.522 and 2.788), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.748) has a better QED score than Ligand B (0.653), indicating a more drug-like profile.

**DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (12.33), which is a major advantage.

**BBB:** Ligand A (73.129) has a good BBB percentile, while Ligand B (94.261) is even better. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.856) and Ligand B (-4.289) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.733) has slightly better solubility than Ligand B (-2.789), but both are poor.

**hERG Inhibition:** Ligand A (0.406) has a lower hERG inhibition liability than Ligand B (0.834), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (75.675) has a higher microsomal clearance than Ligand B (36.756), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.337) has a very poor in vitro half-life, while Ligand B (-0.13) is slightly better but still poor.

**P-gp Efflux:** Ligand A (0.278) has lower P-gp efflux liability than Ligand B (0.201), which is a slight advantage.

**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 1.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a better QED, significantly lower DILI risk, and lower hERG inhibition. Its binding affinity is also slightly better. However, it suffers from higher microsomal clearance and a very poor in vitro half-life. Ligand B has better BBB penetration and lower clearance, but its DILI and hERG risks are higher.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate despite its metabolic instability. The lower DILI and hERG risks are critical advantages, and the slightly better binding affinity can help compensate for the potential metabolic issues. Solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 11:11:56,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.353 Da) is slightly lower, which could be beneficial for permeability. Ligand B (376.435 Da) is also acceptable.

**TPSA:** Ligand A (73.48) is well below the 140 threshold for good oral absorption. Ligand B (133.91) is still under the threshold but closer to it. This favors Ligand A.

**logP:** Ligand A (1.146) is within the optimal range. Ligand B (-1.899) 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) is excellent. Ligand B (HBD=3, HBA=6) is acceptable but less ideal.

**QED:** Ligand A (0.809) has a very good drug-likeness score. Ligand B (0.366) is considerably lower, indicating a less favorable overall drug-like profile.

**DILI:** Ligand A (39.667) has a low DILI risk. Ligand B (47.926) is slightly higher, but still within an acceptable range.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.151) is higher than Ligand B (44.707).

**Caco-2 Permeability:** Ligand A (-4.723) is very poor. Ligand B (-5.632) is also poor.

**Aqueous Solubility:** Ligand A (-2.326) is poor. Ligand B (-1.896) is also poor.

**hERG Inhibition:** Both ligands have very low hERG risk (0.249 and 0.049 respectively).

**Microsomal Clearance:** Ligand A (-12.574) has a much lower (better) microsomal clearance than Ligand B (-1.266), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-37.445) has a longer half-life than Ligand B (-30.289).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.029 and 0.004 respectively).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.1 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is significantly better overall. While both have poor Caco-2 and solubility, Ligand A excels in key areas for an enzyme inhibitor: better logP, QED, metabolic stability (lower Cl_mic, longer t1/2), and a lower TPSA. The slightly better DILI profile is also a plus. The similar binding affinity makes the ADME advantages of Ligand A decisive.

Output:
1
2025-04-17 11:11:56,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.289 and 362.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.41) is slightly above the optimal <140, but acceptable. Ligand B (78.87) is excellent, well below 140.

**logP:** Ligand A (2.562) is within the optimal 1-3 range. Ligand B (1.172) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.674 and 0.713), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 89.957, which is high and concerning. Ligand B has a very low DILI risk of 16.402, a significant advantage.

**BBB:** Both have reasonable BBB penetration, but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired. Ligand B (87.67) is better than Ligand A (58.976).

**Caco-2 Permeability:** Ligand A (-4.311) shows poor permeability, which is a major drawback. Ligand B (-4.754) also shows poor permeability.

**Aqueous Solubility:** Ligand A (-5.683) has poor solubility. Ligand B (-1.768) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.718) has a moderate hERG risk. Ligand B (0.469) has a lower hERG risk, which is favorable.

**Microsomal Clearance:** Ligand A (67.794) has moderate clearance. Ligand B (-8.685) has *negative* clearance, which is extremely favorable and indicates very high metabolic stability. This is a huge advantage.

**In vitro Half-Life:** Ligand A (34.787 hours) has a reasonable half-life. Ligand B (-24.64 hours) has a negative half-life, which is not physically possible, but indicates extremely high stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.184 and 0.027), which is good.

**Binding Affinity:** Ligand B (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage, as a >1.5 kcal/mol difference is considered impactful.

**Conclusion:**

Despite both ligands having acceptable MW, QED, and P-gp efflux, Ligand B is clearly superior. Its significantly stronger binding affinity, dramatically lower DILI risk, and exceptionally high metabolic stability (indicated by negative clearance and half-life) outweigh the slightly lower logP and permeability. Ligand A's high DILI risk and poor permeability are major red flags.



Output:
1
2025-04-17 11:11:56,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.371 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.12 and 104.61) are slightly above the optimal <140 for oral absorption, but acceptable.

**logP:** Ligand A (1.179) is within the optimal 1-3 range. Ligand B (-1.022) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 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 (0.795 and 0.749) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Both ligands have relatively high DILI risk (67.197 and 69.252), but are not excessively high.

**BBB:** Ligand A (61.846) has a moderate BBB penetration score, while Ligand B (43.117) is lower. BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.16 and -4.92) which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.196 and -1.298). This is a major drawback.

**hERG:** Both ligands have very low hERG inhibition liability (0.064 and 0.063), which is excellent.

**Microsomal Clearance:** Both ligands have relatively low microsomal clearance (18.287 and 16.98), indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (-7.636) has a significantly longer in vitro half-life than Ligand B (7.452). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.024).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). The difference is 1.1 kcal/mol, which is significant.

**Conclusion:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A is superior. It has a better binding affinity, a significantly longer half-life, and a slightly better BBB score. The slightly better logP of Ligand A is also favorable. The DILI risk is comparable for both. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), Ligand A is the more promising candidate despite the shared solubility issues. Further optimization would be needed to address the solubility and permeability, but the stronger binding and better half-life provide a better starting point.

Output:
0
2025-04-17 11:11:56,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.459 and 343.366 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.32) is better than Ligand B (93.54), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.128 and 1.491), 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 7. Ligand A is preferable here, as fewer HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.876 and 0.729), indicating good drug-like properties.

**7. DILI:** Ligand A (26.871) has a significantly lower DILI risk than Ligand B (78.364). This is a major advantage for Ligand A.

**8. BBB:** Both have high BBB penetration (89.221 and 83.172), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**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 solubility. This is a significant drawback for both compounds.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.501 and 0.391), which is good.

**12. Microsomal Clearance:** Ligand A (2.444) has a much lower microsomal clearance than Ligand B (20.874). This indicates better metabolic stability for Ligand A, which is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-18.286) has a negative half-life, which is concerning. Ligand B (-6.329) also has a negative half-life, but is less negative. Again, the scale is not specified.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.012 and 0.198).

**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 substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a much better binding affinity, Ligand A is superior in terms of safety (DILI), metabolic stability (Cl_mic), and has fewer HBA. The poor solubility and permeability are concerning for both, but the difference in binding affinity is substantial. Given that SRC kinases are intracellular targets, metabolic stability and safety are critical. However, potency is paramount for kinases. The large difference in binding affinity is likely to outweigh the other drawbacks.

Output:
1
2025-04-17 11:11:56,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.483 Da and 352.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.53) is well below the 140 threshold, while Ligand B (87.46) is still acceptable but higher.

**logP:** Ligand A (3.216) is optimal, while Ligand B (1.031) is slightly low, potentially hindering permeability.

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

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

**QED:** Both ligands (0.788 and 0.767) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (67.313) has a higher DILI risk than Ligand B (21.908). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.623) is slightly better than Ligand B (30.167).

**Caco-2 Permeability:** Ligand A (-4.832) is better than Ligand B (-5.14), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.305) is better than Ligand B (-0.753), which is a significant advantage for bioavailability.

**hERG Inhibition:** Ligand A (0.535) has a lower hERG risk than Ligand B (0.155), a crucial safety parameter.

**Microsomal Clearance:** Ligand A (77.022) has higher clearance than Ligand B (31.822), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Both ligands (12.816 and 12.875) have similar half-lives.

**P-gp Efflux:** Ligand A (0.446) has lower P-gp efflux than Ligand B (0.043), which is favorable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having better solubility and lower hERG risk, Ligand B's substantially stronger binding affinity (-9.5 vs -7.6 kcal/mol) and significantly lower DILI risk make it the more promising candidate. The lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization, but the potency and safety advantages are more critical for an enzyme target like SRC.

Output:
1
2025-04-17 11:11:56,140 - INFO - Batch 27 complete. Total preferences: 432
2025-04-17 11:11:56,140 - INFO - Processing batch 28/512...
2025-04-17 11:12:41,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.389 and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.53) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (78.95) is excellent, well below 140.

**logP:** Ligand A (-0.352) is a bit low, potentially hindering permeation. Ligand B (0.777) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.35 and 0.652), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (33.773) has a low DILI risk, which is excellent. Ligand B (6.049) is even better, indicating very low liver injury potential.

**BBB:** Ligand A (40.326) has low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (71.772) has good BBB penetration, but again, less critical here.

**Caco-2:** Both ligands have negative Caco-2 values (-4.966 and -4.991), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have negative solubility values (-2.069 and -0.705), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Ligand A (0.587) has a slightly elevated hERG risk, but still relatively low. Ligand B (0.234) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (13.18 mL/min/kg) has moderate clearance. Ligand B (6.126 mL/min/kg) has lower clearance, suggesting better metabolic stability, which is a priority for enzymes.

**In vitro Half-Life:** Ligand A (-16.12 hours) has a negative half-life, which is impossible and likely an error in the data. Ligand B (-22.249 hours) also has a negative half-life, also likely an error. This is a major concern for both.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.006).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has significantly better binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the issues with Caco-2, solubility, and half-life, the significantly superior binding affinity of Ligand A (-8.2 vs -6.9 kcal/mol) is a major deciding factor. A 1.3 kcal/mol difference is substantial and can often outweigh other ADME concerns, especially if optimization efforts can address the solubility and permeability issues. Ligand B has better ADME properties overall (lower DILI, better logP, lower clearance, lower hERG), but the weaker binding affinity makes it less likely to be a viable candidate. The negative half-life values are concerning and need to be investigated, but the binding affinity difference is the most important factor in this comparison.

Output:
0
2025-04-17 11:12:41,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.4 and 351.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.5) is slightly higher than Ligand B (95.7), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.52 and 1.89), 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 5. Both are acceptable, being under the 10 limit.

**QED:** Both ligands have good QED scores (0.723 and 0.816), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (94.6%), which is a significant concern. Ligand B has a much lower DILI risk (36.1%), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (57.2%) and Ligand B (66.8%) are both relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified and these values could be percentiles, in which case higher is better. Assuming they are percentiles, Ligand B ( -4.459) is slightly better than Ligand A (-5.389).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming they are percentiles, Ligand B (-2.729) is slightly better than Ligand A (-3.842).

**hERG:** Both ligands have low hERG inhibition liability (0.121 and 0.227), which is good.

**Microsomal Clearance:** Ligand A has a much lower Cl_mic (10.1 mL/min/kg) compared to Ligand B (63.1 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a very long in vitro half-life (99.953 hours), while Ligand B has a very short half-life (1.6 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.069 and 0.146).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-7.9 kcal/mol) than Ligand A (-9.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is a stronger binder, which is the most important factor for an enzyme target. However, Ligand A has significantly better metabolic stability (lower Cl_mic, longer half-life) and a much lower DILI risk. The negative solubility and Caco-2 values are concerning for both, but the difference in binding affinity is substantial. Given the importance of potency for kinase inhibitors, and the relatively manageable ADME issues, Ligand B is the more promising candidate.

Output:
1
2025-04-17 11:12:41,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.804 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is well below the 140 threshold for oral absorption, and even better for kinase inhibitors. Ligand B (78.87) is still acceptable, but less optimal.

**logP:** Ligand A (3.227) is within the optimal 1-3 range. Ligand B (1.165) is a bit low, potentially impacting permeability.

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

**QED:** Both ligands have good QED scores (0.605 and 0.775), indicating drug-like properties.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (20.24), which is a significant concern.

**BBB:** Both ligands have high BBB penetration (70.531 and 82.823), which isn't crucial for a non-CNS target like SRC, but isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.612 and -4.626). This is unusual and suggests a potential issue with the data or a predicted poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.71 and -1.35). This is also unusual and suggests a potential issue with the data or a predicted poor solubility.

**hERG Inhibition:** Ligand A (0.281) has a very low hERG risk, which is excellent. Ligand B (0.427) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (92.061) has a higher microsomal clearance, indicating faster metabolism and potentially lower *in vivo* exposure. Ligand B (-6.176) has a *negative* clearance, which is impossible and suggests a data error.

**In vitro Half-Life:** Ligand A (8.081) has a reasonable half-life. Ligand B (13.231) has a longer half-life, which is generally desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.103 and 0.04), which is favorable.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). The 0.8 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the slightly better affinity of Ligand A, the significantly higher DILI risk and higher microsomal clearance are major drawbacks. The negative values for Caco-2 and solubility are concerning and suggest potential data issues. Ligand B, while having a slightly weaker affinity, exhibits a much lower DILI risk, a longer half-life, and lower P-gp efflux. The negative clearance value is a data error, but the other parameters are more favorable. Considering the enzyme-specific priorities, Ligand B is the more promising candidate, assuming the negative clearance value is a data error.

Output:
1
2025-04-17 11:12:41,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is better than Ligand B (49.85), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.581) is a bit low, potentially hindering permeability. Ligand B (1.782) is within the optimal 1-3 range.

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

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

**QED:** Both ligands have acceptable QED scores (0.792 and 0.551, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (49.321) has a slightly higher DILI risk than Ligand B (23.381), but both are below the concerning threshold of 60.

**BBB:** Ligand A (60.76) and Ligand B (77.705) both have acceptable BBB penetration, but it's not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.012) shows poor permeability, while Ligand B (-4.852) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.342 and -2.623 respectively). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.166) has a lower hERG risk than Ligand B (0.366), which is preferable.

**Microsomal Clearance:** Ligand A (10.98) has significantly lower microsomal clearance than Ligand B (52.283), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.918) has a longer in vitro half-life than Ligand B (-17.038), which is a major advantage.

**P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux than Ligand B (0.108), suggesting better bioavailability.

**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 substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand A is the more promising candidate. It has a better binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a lower hERG risk. While Ligand B has a slightly better logP, the advantages of Ligand A in potency and ADME properties are more critical for an enzyme target like SRC kinase. The solubility issue would need to be addressed through formulation strategies, but the overall profile of Ligand A is superior.

Output:
1
2025-04-17 11:12:41,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.387 Da) is slightly lower, which could be beneficial for permeability. Ligand B (372.575 Da) is also good.

**TPSA:** Ligand A (94.05) is better than Ligand B (53.01) as it is still within the acceptable range for oral absorption, while Ligand B is significantly lower, potentially increasing permeability.

**logP:** Ligand A (-0.665) is a bit low, potentially hindering permeation. Ligand B (2.086) is within the optimal range (1-3). 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 good QED scores (A: 0.717, B: 0.672), indicating good drug-like properties.

**DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (9.965). Ligand B is much better in this aspect.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (65.413) has a higher BBB score, but it's not a major factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.594 and -4.698), 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 (-0.88 and -2.552), indicating poor aqueous solubility. Ligand B is worse in this regard.

**hERG:** Ligand A (0.068) has a very low hERG risk, which is excellent. Ligand B (0.792) has a moderate hERG risk, which is concerning.

**Microsomal Clearance:** Ligand A (-6.581) has a much lower (better) microsomal clearance than Ligand B (54.324), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (A: 17.46, B: 18.755).

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.016, B: 0.563), which is good.

**Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-7.1). While the difference is small (0.4 kcal/mol), it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, and significantly better metabolic stability (lower Cl_mic). Its hERG risk is also much lower. However, its logP is suboptimal, and its solubility is poor.

Ligand B has a better logP, but suffers from a higher DILI risk, significantly worse metabolic stability, and a moderate hERG risk. Its solubility is also poor.

Considering the priorities for enzyme inhibitors, metabolic stability (Cl_mic) and safety (DILI, hERG) are crucial. Ligand A's superior metabolic stability and lower hERG risk outweigh its slightly lower logP and solubility. The small advantage in binding affinity also tips the balance.

Output:
0
2025-04-17 11:12:41,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.869 and 382.854 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.56) is slightly higher than Ligand B (49.41), but both are well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have good logP values (3.852 and 3.337), 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.713 and 0.654), indicating good drug-like properties.

**DILI:** Ligand A (47.034) has a higher DILI risk than Ligand B (19.426). This is a significant concern.

**BBB:** Ligand B (92.749) has a much higher BBB penetration percentile than Ligand A (33.424). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.799 and -4.487), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.488 and -4.601), indicating very poor aqueous solubility, a major issue for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.783 and 0.749), which is good.

**Microsomal Clearance:** Ligand B (84.894) has a higher microsomal clearance than Ligand A (66.733), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (30.447 hours) has a significantly longer in vitro half-life than Ligand B (-8.269 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.837 and 0.064), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 and -8.1 kcal/mol). The difference of 0.9 kcal/mol is not enough to overcome other significant ADME issues.

**Conclusion:**

Despite the slightly better half-life of Ligand A, the significantly lower DILI risk and better BBB penetration of Ligand B are more compelling. The poor Caco-2 and solubility for both are concerning, but the DILI risk for Ligand A is a major drawback. Given the enzyme-kinase focus, metabolic stability (Cl_mic, t1/2) and solubility are important, but a lower toxicity profile is paramount.

Output:
1
2025-04-17 11:12:41,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (351.447 and 381.489 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (72.88), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.512) is optimal, while Ligand B (0.652) is slightly low, potentially hindering permeation.

**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 acceptable QED values (Ligand A: 0.626, Ligand B: 0.574), indicating good drug-like properties.

**7. DILI:** Ligand A (41.411) has a better DILI percentile than Ligand B (13.61), indicating a lower risk of liver injury.

**8. BBB:** Both ligands have reasonable BBB penetration (Ligand A: 71.229, Ligand B: 63.862). Since SRC is not a CNS target, this is less crucial.

**9. Caco-2 Permeability:** Ligand A (-4.772) is significantly better than Ligand B (-5.323). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.599) is better than Ligand B (-1.443). Higher values are preferred.

**11. hERG Inhibition:** Ligand A (0.408) has a lower hERG inhibition liability than Ligand B (0.675), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand B (-16.623) has a significantly lower (better) Cl_mic than Ligand A (82.125), indicating greater metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (-20.775) has a much longer half-life than Ligand A (-6.876), which is desirable.

**14. P-gp Efflux:** Ligand A (0.27) is better than Ligand B (0.089). Lower efflux is preferred.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). The difference is 1.8 kcal/mol, which is significant.

**Enzyme-Specific Priorities:** For kinases like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Overall Assessment:**

Ligand A has a better binding affinity, solubility, Caco-2 permeability, hERG risk, and DILI risk. However, Ligand B has significantly better metabolic stability (lower Cl_mic and longer half-life). The 1.8 kcal/mol difference in binding affinity is substantial, and the better ADME properties of Ligand A (solubility, permeability, safety) are also important. While metabolic stability is crucial, the superior binding affinity and ADME profile of Ligand A outweigh the metabolic advantages of Ligand B.

Output:
1
2025-04-17 11:12:41,987 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [373.909, 50.8, 4.853, 1, 4, 0.601, 69.833, 27.259, -5.398, -5.725, 0.501, 63.866, 5.738, 0.77, -7.7]
**Ligand B:** [340.467, 41.57, 3.981, 1, 3, 0.905, 31.718, 89.957, -4.603, -3.982, 0.789, 58.581, 26.104, 0.407, -7.3]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (340.467) is slightly lower, which could be beneficial for permeability, but both are acceptable.
2. **TPSA:** Both are below the 140 A<sup>2</sup> threshold for good oral absorption. Ligand B (41.57) is better than Ligand A (50.8).
3. **logP:** Ligand A (4.853) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.981) is within the optimal range (1-3).
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** Ligand A has 4 HBA, and Ligand B has 3. Both are acceptable (<=10).
6. **QED:** Both have good QED scores (>0.5), indicating drug-likeness. Ligand B (0.905) is better than Ligand A (0.601).
7. **DILI:** Ligand A (69.833) has a higher DILI risk than Ligand B (31.718). This is a significant concern.
8. **BBB:** Ligand B (89.957) has a much higher BBB penetration potential than Ligand A (27.259). While not critical for SRC (an intracellular kinase), it's a positive attribute.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method.
10. **Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Similar to Caco-2, these values should be interpreted with caution.
11. **hERG:** Ligand A (0.501) has a slightly higher hERG risk than Ligand B (0.789), but both are relatively low.
12. **Cl_mic:** Ligand B (58.581) has lower microsomal clearance than Ligand A (63.866), indicating better metabolic stability.
13. **t1/2:** Ligand B (26.104) has a significantly longer in vitro half-life than Ligand A (5.738). This is a major advantage.
14. **Pgp:** Ligand A (0.77) has slightly higher P-gp efflux liability than Ligand B (0.407).
15. **Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This is a 1.5 kcal/mol difference, which is significant.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand A has slightly better affinity, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility. The difference in affinity is not large enough to outweigh these significant ADME advantages.

**Conclusion:**

Considering the balance of properties and the priorities for an enzyme target, **Ligand B** is the more promising drug candidate.

1
2025-04-17 11:12:41,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.361 and 345.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (106.73) is still acceptable, but higher, potentially impacting permeability.

**logP:** Ligand A (3.154) is optimal. Ligand B (0.862) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 7 HBA) is also acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands (0.855 and 0.774) have good drug-likeness scores.

**DILI:** Ligand A (55.37) has a slightly better DILI score than Ligand B (64.521), indicating lower potential for liver injury. Both are acceptable, but lower is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.492) is better than Ligand B (49.748), but not a deciding factor.

**Caco-2:** Ligand A (-4.322) is better than Ligand B (-5.196), suggesting better intestinal absorption.

**Solubility:** Ligand A (-4.365) is better than Ligand B (-2.763), which is crucial for bioavailability.

**hERG:** Ligand A (0.291) has a significantly lower hERG risk than Ligand B (0.068), a major advantage.

**Microsomal Clearance:** Ligand A (25.272) has a better (lower) microsomal clearance than Ligand B (8.461), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands (-0.91 and -0.82) are comparable.

**P-gp Efflux:** Ligand A (0.329) has better P-gp efflux profile than Ligand B (0.055), which is good for bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This is a 0.7 kcal/mol difference, which is significant, but needs to be weighed against the other factors.

**Overall:**

Ligand A demonstrates superior ADME properties across the board (solubility, permeability, metabolic stability, hERG risk, DILI, P-gp efflux) while maintaining a very good binding affinity. Ligand B has a slightly better binding affinity, but suffers from poorer solubility, permeability, and a higher hERG risk. Given the enzyme-specific priorities, the improved ADME profile of Ligand A outweighs the small difference in binding affinity.

Output:
1
2025-04-17 11:12:41,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 358.341 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (103.01) is still under 140, but less favorable than A.

**logP:** Ligand A (2.732) is optimal (1-3). Ligand B (0.225) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable.

**QED:** Both ligands (0.723 and 0.654) have good drug-likeness scores (>0.5).

**DILI:** Ligand A (35.13) has a lower DILI risk than Ligand B (56.883), which is better. Both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.623) is higher than Ligand B (31.834).

**Caco-2:** Both are negative, indicating poor permeability. However, the scale is not specified, so it is hard to interpret.

**Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified.

**hERG:** Both ligands (0.489 and 0.334) show low hERG inhibition risk, which is favorable.

**Microsomal Clearance:** Ligand A (61.363) has higher clearance than Ligand B (5.916), indicating lower metabolic stability. Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand B (-11.589) has a significantly longer half-life than Ligand A (-4.89). This is a major advantage.

**P-gp Efflux:** Both ligands (0.398 and 0.051) show low P-gp efflux, which is good.

**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 not huge but still relevant.

**Conclusion:**

While Ligand A has a slightly better binding affinity and TPSA, Ligand B demonstrates superior ADME properties crucial for an enzyme inhibitor. Specifically, its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and better logP are highly desirable. The lower DILI risk is also a plus. The slightly weaker binding of Ligand B can potentially be optimized in subsequent iterations, while improving ADME properties is often more challenging.

Output:
1
2025-04-17 11:12:41,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 372.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.8) is slightly higher than the preferred <140, but acceptable. Ligand B (67.87) is excellent, well below 140.

**logP:** Ligand A (0.769) is a bit low, potentially impacting permeability. Ligand B (0.91) is also on the lower side, but slightly better. Both are below the optimal 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 (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have identical QED scores (0.795), indicating good drug-likeness.

**DILI:** Ligand A (42.148) has a lower DILI risk than Ligand B (49.942), both are acceptable (<60).

**BBB:** Ligand A (33.23) has a very low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (83.637) has a higher BBB penetration, but it's not critical here.

**Caco-2 Permeability:** Ligand A (-4.927) has poor Caco-2 permeability, while Ligand B (-5.067) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.234) has better solubility than Ligand B (-3.355). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.168) has a lower hERG risk than Ligand B (0.214), which is a significant advantage.

**Microsomal Clearance:** Ligand A (8.562) has significantly lower microsomal clearance than Ligand B (45.43), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (34.195) has a much longer half-life than Ligand B (-14.196), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.041, B: 0.055).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 1.8 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, lower hERG risk, and significantly better metabolic stability (lower Cl_mic and longer t1/2), the substantially stronger binding affinity of Ligand B (-9.3 vs -7.5 kcal/mol) is a decisive factor. For an enzyme target like SRC kinase, potency is paramount. The slightly worse ADME properties of Ligand B are less concerning given its superior binding.

Output:
1
2025-04-17 11:12:41,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.459 Da and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.09) is slightly above the preferred <140, while Ligand B (78.51) is well within. This favors Ligand B for better absorption.

**logP:** Both ligands have good logP values (1.523 and 1.152), falling within the optimal 1-3 range.

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

**QED:** Both ligands have reasonable QED scores (0.866 and 0.784), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 56.689, which is moderate but acceptable. Ligand B has a significantly lower DILI risk (16.867), which is a strong advantage.

**BBB:** Both ligands have moderate BBB penetration (75.107 and 57.774). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.472) and Ligand B (-5.116) both have negative Caco-2 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 (-2.718 and -3.131). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.47) and Ligand B (0.089) both have low hERG inhibition risk, which is good. Ligand B is significantly better here.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (35.461 and 36.44 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (11.508 hours) has a better in vitro half-life than Ligand B (-14.517 hours). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.055 and 0.033), 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 within the range where it can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility and Caco-2 permeability issues, Ligand B demonstrates a significantly lower DILI risk and a slightly better binding affinity, coupled with a better hERG profile. The slightly better TPSA also contributes to its favorability. The half-life is worse for B, but the affinity difference and lower toxicity are more important for an enzyme target.

Output:
1
2025-04-17 11:12:41,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.515 and 380.579 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have similar TPSA values (58.36 and 58.2), well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (2.674) is within the optimal 1-3 range, while Ligand B (3.948) is approaching the upper limit. This could potentially lead to solubility issues for B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3-4 HBA, satisfying the <5 HBD and <10 HBA criteria.

**QED:** Ligand A (0.864) has a significantly higher QED score than Ligand B (0.53), indicating better overall drug-likeness.

**DILI:** Ligand A (2.21) has a much lower DILI risk than Ligand B (55.991), which is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (82.202) shows better penetration than Ligand B (64.87).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-5.248) is slightly better than Ligand B (-5.261).

**Aqueous Solubility:** Ligand A (-1.271) has better solubility than Ligand B (-4.093).

**hERG:** Ligand A (0.804) has a lower hERG risk than Ligand B (0.515), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (-32.655) exhibits significantly lower microsomal clearance than Ligand B (75.205), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-9.56) has a shorter half-life than Ligand B (10.608). However, the negative value for A is concerning and likely an error. We will proceed assuming B is better here.

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux than Ligand B (0.439), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is only 0.8 kcal/mol, and the other ADME properties of A are superior.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising drug candidate. Its superior QED, significantly lower DILI risk, better solubility, lower hERG risk, and dramatically improved metabolic stability (lower Cl_mic) outweigh the minor difference in binding affinity. The negative half-life value for A is concerning, but the other benefits are substantial.

Output:
0
2025-04-17 11:12:41,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.21) is better than Ligand B (113), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (0.039) is quite low, potentially hindering permeability. Ligand B (-1.357) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3), as lower HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (6).

**QED:** Ligand A (0.802) has a significantly better QED score than Ligand B (0.558), indicating a more drug-like profile.

**DILI:** Ligand A (41.024) has a much lower DILI risk than Ligand B (12.33), which is a significant advantage.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (45.095) is slightly better than Ligand B (10.624).

**Caco-2 Permeability:** Both are negative (-5.192 and -5.704), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.55) is better than Ligand B (0.018), though both are poor. Solubility is a concern for both.

**hERG:** Both ligands have very low hERG risk (0.048 and 0.067), which is excellent.

**Microsomal Clearance:** Ligand B (-18.379) has a much lower (better) microsomal clearance than Ligand A (19.178), indicating better metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (-17.583) has a much longer half-life than Ligand A (-1.916), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.003).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-9.2 and -8.9 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Conclusion:**

Ligand A has better QED, DILI, solubility and TPSA. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer half-life) and slightly better Caco-2 permeability. Given the enzyme-specific priorities, metabolic stability is crucial. The slightly better solubility of A is outweighed by the significant metabolic advantage of B.

Output:
1
2025-04-17 11:12:41,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.491 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is better than Ligand B (88.76), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.221 and 1.318), 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, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.61 and 0.867), indicating good drug-likeness.

**DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (47.654), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (81.388) is slightly better than Ligand A (72.625). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we will proceed assuming these represent permeability.

**Solubility:** Both have negative solubility values, which is also unusual and requires further investigation.

**hERG:** Ligand A (0.332) has a much lower hERG risk than Ligand B (0.606), which is a significant advantage.

**Microsomal Clearance:** Ligand A (93.86) has a higher microsomal clearance than Ligand B (29.016), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-20.421) has a much longer in vitro half-life than Ligand A (-5.898), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.047).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol), although the difference is less than the 1.5 kcal/mol threshold that would strongly favor one over the other.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly lower DILI and hERG risks. However, Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2). Considering SRC is a kinase, metabolic stability is crucial. The difference in binding affinity is not substantial enough to outweigh the metabolic advantages of Ligand B. The negative solubility and Caco-2 values are concerning for both, but the metabolic profile of Ligand B is more favorable.

Output:
1
2025-04-17 11:12:41,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.447 Da and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (119.67 and 114.87) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.25) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.292) is closer to the optimal range.

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

**H-Bond Acceptors:** Ligand A has 8 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.709) has a better QED score than Ligand B (0.465), indicating a more drug-like profile.

**DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (29.081). This is a significant concern.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (83.792) is higher than Ligand B (72.16). This is less critical for a non-CNS target like SRC.

**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 risk (0.211 and 0.118), which is excellent.

**Microsomal Clearance:** Ligand A (10.658) has significantly lower microsomal clearance than Ligand B (17.832), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.565) has a negative half-life, which is impossible and indicates an issue with the data. Ligand B (6.935) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.035 and 0.025).

**Binding Affinity:** Ligand B (-9.5 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.

**Conclusion:**

Despite Ligand A's better QED and lower Cl_mic, the significantly higher DILI risk and impossible half-life are major red flags. Ligand B, while having a lower QED and higher Cl_mic, exhibits a much stronger binding affinity, lower DILI risk, and a reasonable half-life. The superior binding affinity of Ligand B is a critical factor for an enzyme inhibitor, and the lower DILI risk is a significant advantage.

Output:
1
2025-04-17 11:12:41,990 - INFO - Batch 28 complete. Total preferences: 448
2025-04-17 11:12:41,990 - INFO - Processing batch 29/512...
2025-04-17 11:13:22,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.445 and 352.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold, suggesting good absorption. Ligand B (109.66) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (2.182) is optimal (1-3). Ligand B (-1.266) is below 1, which could hinder permeation.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 7 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.627 and 0.684, respectively), indicating drug-likeness.

**DILI:** Ligand A (11.632) has a significantly lower DILI risk than Ligand B (64.366). This is a major advantage for Ligand A.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (78.635) has a higher percentile than Ligand B (49.128).

**Caco-2 Permeability:** Ligand A (-4.585) and Ligand B (-4.952) both have negative values, which is unusual and requires careful interpretation. Lower (more negative) values suggest poorer permeability.

**Aqueous Solubility:** Ligand A (-2.282) and Ligand B (-0.527) both have negative values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.337 and 0.059).

**Microsomal Clearance:** Ligand A (37.203) has higher microsomal clearance than Ligand B (11.585), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (2.13) has a slightly longer half-life than Ligand A (-8.857), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.063 and 0.014).

**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 relatively small.

**Overall Assessment:**

Ligand A is preferable due to its significantly lower DILI risk, better logP, and lower TPSA. While its microsomal clearance is higher, the substantial advantage in safety (DILI) and absorption/permeation properties outweighs this drawback. Ligand B's slightly better binding affinity is not enough to compensate for its higher DILI risk and lower logP.

Output:
0
2025-04-17 11:13:22,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.32) is slightly higher than Ligand B (71.33). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.073 and 1.482), falling within the optimal 1-3 range.

**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:** Both ligands have similar and good QED scores (0.71 and 0.775), indicating good drug-like properties.

**DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (33.075), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.035) has a higher BBB percentile than Ligand A (32.144), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-5.191) has worse Caco-2 permeability than Ligand B (-4.674), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.271) has worse aqueous solubility than Ligand B (-1.554). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.118 and 0.277), which is excellent.

**Microsomal Clearance:** Ligand A (-5.666) has *much* lower microsomal clearance than Ligand B (36.838). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-17.805) has a much longer in vitro half-life than Ligand B (-7.276). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.081).

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial difference (2.2 kcal/mol), and is a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand B has slightly better TPSA, Caco-2 permeability, and solubility, Ligand A's significantly stronger binding affinity (-9.8 vs -7.6 kcal/mol), much better metabolic stability (lower Cl_mic, longer t1/2), and acceptable ADME properties make it the more promising drug candidate. The difference in binding affinity is substantial enough to compensate for the slightly lower solubility and permeability.

Output:
1
2025-04-17 11:13:22,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.39 and 372.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (123.66 and 112.81) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.386) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (-0.35) is even lower, raising more concerns about permeability.

**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 (0.685 and 0.705), indicating generally drug-like properties.

**DILI:** Ligand A (42.46) has a slightly higher DILI risk than Ligand B (28.62), but both are below the concerning threshold of 60.

**BBB:** Both ligands have relatively low BBB penetration (59.79 and 54.25), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.75 and -5.274), which is unusual and suggests very poor permeability. This is a significant red flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.554 and -1.72), indicating very poor aqueous solubility. This is a major drawback for oral bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.022 and 0.06), which is excellent.

**Microsomal Clearance:** Ligand A (-0.033) has a slightly better (lower) microsomal clearance than Ligand B (-2.335), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (17.36) has a significantly longer in vitro half-life than Ligand B (2.441), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005).

**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 some ADME drawbacks.

**Conclusion:**

Despite the poor permeability and solubility of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.3 vs -7.2 kcal/mol) is a crucial advantage for an enzyme inhibitor. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic) and a longer half-life. While both have poor solubility and permeability, these can potentially be addressed through formulation strategies. The superior potency and pharmacokinetic properties of Ligand A make it the better choice for further optimization.

Output:
1
2025-04-17 11:13:22,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.41 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is slightly higher than Ligand B (58.64), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (4.147) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.043) is 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, under the 10 limit.

**QED:** Both ligands have good QED scores (0.72 and 0.794), indicating good drug-like properties.

**DILI:** Ligand A (88.251) has a significantly higher DILI risk than Ligand B (26.25). This is a major concern.

**BBB:** Both have reasonable BBB penetration (64.831 and 84.025), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and are less important than other factors.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern, but Ligand B (-2.98) is slightly better than Ligand A (-5.148).

**hERG Inhibition:** Ligand A (0.623) has a higher hERG risk than Ligand B (0.353), though both are relatively low.

**Microsomal Clearance:** Ligand A (70.519) has higher microsomal clearance than Ligand B (39.236), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (14.809 hours) has a significantly longer half-life than Ligand A (-24.598 hours - a negative value is concerning).

**P-gp Efflux:** Both have low P-gp efflux liability (0.519 and 0.168).

**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 not a huge difference, it's a positive factor.

**Conclusion:**

Considering all factors, **Ligand B is the more promising candidate.** While both have solubility issues and negative Caco-2 values, Ligand B excels in the critical areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly improved binding affinity. Ligand A's high DILI risk is a major red flag, and its poorer metabolic stability further diminishes its potential. The slightly higher logP of Ligand A is also a concern.



Output:
1
2025-04-17 11:13:22,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.442 and 364.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.47) is well below the 140 threshold for good absorption, while Ligand B (104.45) is still acceptable but less optimal.

**logP:** Ligand A (1.275) is within the optimal 1-3 range. Ligand B (-0.01) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 8. Both are acceptable, but Ligand A is preferable.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (30.748) has a much lower DILI risk than Ligand B (69.872), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (88.988) has a higher BBB percentile than Ligand B (41.838).

**Caco-2 Permeability:** Ligand A (-4.763) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.49) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.262) has poor solubility, while Ligand B (-1.388) is slightly better, but still not ideal.

**hERG Inhibition:** Both ligands have very low hERG risk (0.247 and 0.02).

**Microsomal Clearance:** Ligand A (17.03) has a lower Cl_mic than Ligand B (6.266), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.393) has a negative half-life, which is impossible and indicates a data error or an extremely unstable compound. Ligand B (34.945) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.052).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand A has several concerning properties: poor Caco-2 permeability, poor solubility, and an impossible half-life value. While it has a lower DILI risk and better metabolic stability, these advantages are overshadowed by the significant absorption and stability issues. Ligand B, despite a higher DILI risk and slightly lower affinity, presents a more viable profile with a reasonable half-life and better (though still not great) permeability and solubility. The slightly better binding affinity of Ligand B is a bonus.

Output:
1
2025-04-17 11:13:22,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (356.413 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (399.837 Da) is still well within the acceptable range.

**TPSA:** Ligand A (60.85) is higher than Ligand B (29.54). Lower TPSA generally favors better cell permeability. Ligand B is significantly better here.

**logP:** Ligand A (1.644) is within the optimal range (1-3), while Ligand B (4.281) is slightly above, 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 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.833) has a higher QED score than Ligand B (0.611), indicating a more drug-like profile.

**DILI:** Ligand B (43.583) has a higher DILI risk than Ligand A (13.804). This is a significant advantage for Ligand A.

**BBB:** Ligand B (93.021) shows better BBB penetration than Ligand A (75.107). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.572) and Ligand B (-4.329) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.164) has slightly better solubility than Ligand B (-5.617). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.509) has a lower hERG inhibition risk than Ligand B (0.67). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand B (96.686) has a much higher microsomal clearance than Ligand A (22.967), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-2.029) has a longer in vitro half-life than Ligand B (0.07). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.015) has lower P-gp efflux than Ligand B (0.436), which is favorable for bioavailability.

**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 for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, poorer metabolic stability (high Cl_mic, low t1/2), and higher P-gp efflux. Ligand A has a better overall ADME profile (lower DILI, better metabolic stability, solubility, and P-gp efflux) but a weaker binding affinity. The difference in binding affinity (-7.6 vs -9.5) is substantial (1.9 kcal/mol), and for an enzyme target, this difference is likely to be decisive.

Output:
1
2025-04-17 11:13:22,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.471 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.53) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have acceptable logP values (1.44 and 2.127, respectively), falling within the 1-3 optimal range.

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

**QED:** Ligand B (0.822) has a higher QED score than Ligand A (0.576), suggesting a more drug-like profile.

**DILI:** Both ligands have low DILI risk (42.924 and 37.767, respectively), both below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (55.797) and Ligand B (45.56) both have relatively low BBB penetration.

**Caco-2 Permeability:** Ligand A (-5.346) shows poor Caco-2 permeability, which is a concern. Ligand B (-4.603) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.98 and -2.468, respectively). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.325 and 0.559, respectively).

**Microsomal Clearance:** Ligand A (17.603) has lower microsomal clearance than Ligand B (31.461), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.821) has a longer in vitro half-life than Ligand B (5.119), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.122 and 0.171, respectively).

**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.

**Conclusion:**

While both ligands have good potency, Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic, longer t1/2). Although Ligand B has a better QED and slightly better Caco-2 permeability, the improved metabolic profile of Ligand A is more crucial for an enzyme target like SRC kinase. The poor solubility of both is a concern that would need to be addressed in further optimization.

Output:
1
2025-04-17 11:13:22,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.383 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (97.64) is higher than Ligand B (51.66). While both are below 140, the lower TPSA of Ligand B is more favorable for oral absorption.

**logP:** Ligand A (1.91) and Ligand B (3.268) are both 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:** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5. Ligand B having zero HBD is slightly preferable as it generally improves membrane permeability.

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

**QED:** Both ligands have good QED scores (Ligand A: 0.589, Ligand B: 0.743). Ligand B has a slightly better score, indicating a more drug-like profile.

**DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (29.042). This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (88.057) is higher than Ligand A (76.658). While not a primary concern for a kinase inhibitor, higher BBB is generally a positive.

**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. This suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.638, Ligand B: 0.44), which is good.

**Microsomal Clearance:** Ligand A (51.476) has lower microsomal clearance than Ligand B (70.301), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (67.506) has a longer half-life than Ligand B (-1.19). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.489, Ligand B: 0.336).

**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 ADME drawbacks.

**Overall Assessment:**

Ligand B has a better overall ADME profile (lower DILI, better QED, better BBB, lower P-gp efflux) and a significantly stronger binding affinity. While Ligand A has better metabolic stability and half-life, the potency advantage of Ligand B is substantial. The negative solubility and permeability values are concerning for both, but the potency difference is likely to be more impactful in early stages of drug development.

Output:
1
2025-04-17 11:13:22,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.443 and 390.937 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.62) is better than Ligand B (84.3), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.56 and 1.458), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**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 6. Both are below the 10 threshold.

**QED:** Both ligands have high QED scores (0.801 and 0.841), indicating good drug-like properties.

**DILI:** Ligand A (42.071) has a lower DILI risk than Ligand B (56.34), both are acceptable (<60 is good).

**BBB:** Both have low BBB penetration (52.579 and 55.642), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.59) has slightly better Caco-2 permeability than Ligand B (-5.066).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.899 and -2.667). This is a potential issue that would need to be addressed during formulation.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.163 and 0.124), which is excellent.

**Microsomal Clearance:** Ligand B (24.11) has significantly lower microsomal clearance than Ligand A (40.171), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (31.767) has a significantly longer in vitro half-life than Ligand A (4.463), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.157 and 0.078).

**Binding Affinity:** Both ligands have identical and excellent binding affinity (-7.7 kcal/mol).

**Conclusion:**

While both ligands exhibit excellent binding affinity and acceptable drug-like properties, Ligand B is the superior candidate due to its significantly improved metabolic stability (lower Cl_mic and longer t1/2). The slightly lower solubility is a concern, but can potentially be addressed through formulation strategies. The better metabolic stability is more critical for an enzyme target like SRC kinase, as it translates to potentially longer duration of action and reduced dosing frequency.

Output:
1
2025-04-17 11:13:22,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.391 and 359.398 Da) fall within the ideal 200-500 Da range.
**TPSA:** Ligand A (131.76) is slightly above the preferred <140, but acceptable. Ligand B (96.97) is excellent, well below 140.
**logP:** Both ligands (-0.928 and -0.628) are a bit low. While not immediately disqualifying, lower logP can sometimes hinder cell permeability.
**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (2) is even better, both being <=5.
**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both within the acceptable range of <=10.
**QED:** Both ligands have good QED scores (0.542 and 0.631), indicating drug-like properties.
**DILI:** Ligand A (32.959) has a lower DILI risk than Ligand B (35.634), both are good (<40 is preferred).
**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.519) has a higher BBB percentile than Ligand A (26.599), but this isn't a primary concern here.
**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.784 and -5.077). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values don't necessarily mean zero permeability, but it's a flag.
**Aqueous Solubility:** Both ligands have negative solubility values (-1.899 and -1.597), which is also a concern. Poor solubility can hinder bioavailability.
**hERG Inhibition:** Ligand A (0.108) has a lower hERG risk than Ligand B (0.206), which is preferable.
**Microsomal Clearance:** Ligand A (-8.261) has a significantly *lower* (better) microsomal clearance than Ligand B (-14.419). This indicates better metabolic stability.
**In vitro Half-Life:** Ligand A (0.65) has a shorter half-life than Ligand B (4.337), which is less desirable.
**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.015).
**Binding Affinity:** Both ligands have very similar and good binding affinities (-8.5 and -8.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is slightly favored. While both have similar binding affinities, Ligand A exhibits significantly better metabolic stability (lower Cl_mic) and a lower hERG risk. Although both have poor predicted solubility and permeability, the improved metabolic stability of Ligand A is more critical for *in vivo* efficacy.

Output:
0
2025-04-17 11:13:22,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.35 and 102.06) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.014) is quite low, potentially hindering permeation. Ligand B (-1.547) is also low, but slightly better than A. Both are below 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 6 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**QED:** Both have acceptable QED scores (0.754 and 0.605, both >=0.5).

**DILI:** Ligand A (41.334) has a slightly higher DILI risk than Ligand B (29.042), but both are below the concerning threshold of 60.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (56.572) is better than Ligand A (43.001).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.184 and -5.099), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.208 and -1.246), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG:** Both have very low hERG inhibition risk (0.024 and 0.085), which is excellent.

**Microsomal Clearance:** Ligand B (-9.761) has significantly *lower* (better) microsomal clearance than Ligand A (3.986), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (5.721) has a slightly longer half-life than Ligand A (8.491), which is favorable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.013 and 0.001), which is good.

**Binding Affinity:** Ligand B (-6.7 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. The difference is >1.5 kcal/mol.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-6.7 vs -10.6 kcal/mol) and improved metabolic stability (lower Cl_mic and longer half-life) are critical advantages for an enzyme inhibitor. The slightly lower DILI risk is also a plus. The lower logP is a concern, but the strong binding may compensate.

Output:
1
2025-04-17 11:13:22,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.431 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.28) is slightly higher than Ligand B (71.53), but both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.817 and 2.396), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic.

**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 A (0.887) has a significantly better QED score than Ligand B (0.733), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (37.922 and 39.899), both well below the 40 threshold.

**BBB:** Ligand A (78.364) has a better BBB penetration score than Ligand B (69.678), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.776 and -4.509). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference isn't huge, and could be experimental error.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.065 and -2.617) which indicates poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.268 and 0.499), which is excellent.

**Microsomal Clearance:** Ligand A (5.896) has a significantly lower microsomal clearance than Ligand B (37.834), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (13.257 hours) has a longer in vitro half-life than Ligand B (5.55 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.103 and 0.229), which is favorable.

**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 minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have issues with solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity, better metabolic stability (lower Cl_mic and longer t1/2), and higher QED score make it more likely to be a viable drug candidate. The difference in binding affinity is a key factor, as it provides a larger margin for optimizing the ADME properties.

Output:
1
2025-04-17 11:13:22,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (337.423 and 347.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is better than Ligand B (97.81). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range.

**logP:** Ligand A (2.894) is better than Ligand B (1.464). Both are within the 1-3 range, but B is closer to the lower limit, which could affect permeation.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**H-Bond Acceptors:** Ligand B (6) is higher than Ligand A (3). Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.783 and 0.899, respectively), indicating drug-like properties.

**DILI:** Ligand A (38.116) is significantly better than Ligand B (74.99). A lower DILI percentile is highly desirable.

**BBB:** Both ligands have similar BBB penetration (62.389 and 62.931), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.484 and -4.584). This is unusual and suggests poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Ligand A (-4.31) is better than Ligand B (-2.367). Higher solubility is preferable.

**hERG Inhibition:** Ligand A (0.389) is significantly better than Ligand B (0.18). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (22.193) and Ligand B (23.809) are similar. Both are relatively low, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (22.928) is better than Ligand B (-8.901). A longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.076 and 0.08).

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.5). This is a 0.5 kcal/mol difference, which is significant.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A is superior overall. Ligand A demonstrates significantly lower DILI risk and hERG inhibition, better solubility, and a more favorable in vitro half-life. The slightly weaker binding affinity of Ligand A can potentially be optimized through further medicinal chemistry efforts, while mitigating the higher risks associated with Ligand B would be more challenging. Given the enzyme-specific priorities, the improved safety profile of Ligand A outweighs the small difference in binding affinity.

Output:
0
2025-04-17 11:13:22,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (377.794 Da) is also well within the range.

**TPSA:** Both ligands have TPSA values (58.56 and 61.44) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 2.649 and Ligand B at 3.712. Ligand B is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but is still acceptable.

**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 the acceptable limits (<=10).

**QED:** Both ligands have similar QED values (0.88 and 0.825), indicating good drug-like properties.

**DILI:** Ligand A (30.865) has a significantly lower DILI risk than Ligand B (53.432). This is a major advantage for Ligand A.

**BBB:** Ligand B (83.715) shows better BBB penetration than Ligand A (40.946). However, since SRC is not a CNS target, this is less critical.

**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 scale is not clear, so it's hard to assess the impact.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. Again, the scale is unclear, but suggests poor solubility for both.

**hERG Inhibition:** Ligand A (0.3) has a much lower hERG inhibition liability than Ligand B (0.487), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (20.846) has a higher microsomal clearance than Ligand B (12.475). This suggests Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-22.427) has a negative half-life, which is impossible. This is a major red flag and suggests a significant issue with the data for Ligand B. Ligand A (44.591) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux liability than Ligand B (0.076), suggesting better oral bioavailability.

**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 for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the negative half-life is a critical flaw. The DILI risk for Ligand B is also higher, and its hERG inhibition is more concerning. Ligand A, while having weaker binding, presents a much more favorable ADME profile with lower DILI and hERG risk, and a reasonable half-life. The unusual negative values for Caco-2 and solubility for both ligands are concerning and would require further investigation, but the overall profile of Ligand A is more promising for development as a drug candidate.

Output:
0
2025-04-17 11:13:22,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.5 and 345.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is slightly higher than Ligand B (84.22), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.736 and 2.554), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.63 and 0.732), indicating a drug-like profile.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (67.856). While both are above the preferred <40, Ligand B is closer.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (76.037) has a higher BBB percentile than Ligand A (28.189), but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.055 and -5.031), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.453 and -3.747), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.286) has a lower hERG inhibition liability than Ligand B (0.678), which is favorable.

**Microsomal Clearance:** Ligand B (10.079) has significantly lower microsomal clearance than Ligand A (79.72), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (25.48 and 26.147 hours).

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.172), which is slightly better.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.3 vs -8.5 kcal/mol) and lower microsomal clearance (10.079 vs 79.72) are critical advantages for an enzyme target like SRC kinase. While Ligand A has a slightly better hERG profile, the potency and metabolic stability benefits of Ligand B are more important. The DILI risk is also slightly lower for Ligand B.

Output:
1
2025-04-17 11:13:22,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.407 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (100.43) is better than Ligand B (65.79), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.552) is slightly low, potentially hindering permeation. Ligand B (2.451) is within the optimal 1-3 range. This favors Ligand 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 below the 10 threshold.

**QED:** Both ligands have similar QED values (0.739 and 0.694), indicating good drug-likeness.

**DILI:** Ligand A (43.117) has a moderate DILI risk, while Ligand B (14.618) has a significantly lower risk. This is a strong advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.101) and Ligand B (53.664) are both relatively low.

**Caco-2:** Ligand A (-5.1) and Ligand B (-4.768) are both negative, which is unusual and suggests poor permeability.

**Solubility:** Ligand A (-1.331) and Ligand B (-0.94) are both poor, but Ligand B is slightly better.

**hERG:** Ligand A (0.025) has a very low hERG risk, which is excellent. Ligand B (0.782) is higher, indicating a moderate risk. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (5.911) has a much lower Cl_mic, indicating better metabolic stability, which is crucial for an enzyme target. Ligand B (27.123) is considerably higher.

**In vitro Half-Life:** Ligand A (6.299) has a shorter half-life than Ligand B (41.33). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is favorable. Ligand B (0.125) is slightly higher.

**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 for Ligand B, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a more favorable logP. It also has a much lower DILI risk. However, it has higher microsomal clearance and a slightly higher hERG risk. Ligand A has a better hERG profile and lower clearance, but suffers from a lower logP and significantly weaker binding affinity.

Given the importance of potency for enzyme inhibition, the substantial difference in binding affinity (-9.5 vs -7.1 kcal/mol) is the deciding factor. A 2.4 kcal/mol difference is substantial and likely to translate to a significant difference in *in vivo* efficacy. While Ligand A has better metabolic stability and a lower hERG risk, these can be potentially addressed through further optimization. The weaker binding of Ligand A is a more fundamental limitation.

Output:
1
2025-04-17 11:13:22,849 - INFO - Batch 29 complete. Total preferences: 464
2025-04-17 11:13:22,849 - INFO - Processing batch 30/512...
2025-04-17 11:14:04,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.38 and 350.35 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.95) is significantly better than Ligand B (109.42). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand A is much more favorable.

**logP:** Ligand A (3.141) is optimal (1-3), while Ligand B (-0.894) is below 1, potentially hindering permeation. This is a significant advantage for Ligand A.

**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:** Ligand A (0.89) is excellent, indicating high drug-likeness. Ligand B (0.32) is below the 0.5 threshold, raising concerns about its developability.

**DILI:** Ligand A (54.52) is better than Ligand B (44.13), both are fairly low risk.

**BBB:** Both ligands have high BBB penetration, but Ligand A (91.31) is better than Ligand B (83.87). While not a primary concern for a kinase inhibitor, it's a slight advantage for A.

**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 (0.904) is better than Ligand B (0.198), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-1.911) has lower clearance (better metabolic stability) than Ligand B (-1.077). This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (12.585) has a significantly longer half-life than Ligand B (-8.999). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.282) has lower P-gp efflux than Ligand B (0.006), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by the other ADME properties.

**Overall Assessment:**

Ligand A is significantly superior. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: logP, TPSA, QED, metabolic stability (Cl_mic and t1/2), and P-gp efflux. The poor solubility and permeability are concerns for both, but the superior overall profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 11:14:04,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.45 Da) is slightly higher than Ligand B (340.515 Da), but both are acceptable.

**TPSA:** Ligand A (96.44) is better than Ligand B (41.05). Lower TPSA generally favors better absorption.

**logP:** Ligand A (1.012) is within the optimal range, while Ligand B (4.546) is high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 4 respectively). This is good for balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.697 and 0.873), indicating drug-likeness.

**DILI:** Ligand A (58.976) has a higher DILI risk than Ligand B (37.805), but both are below the concerning threshold of 60.

**BBB:** Ligand A (77.821) and Ligand B (94.184) both have good BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.677) has poor Caco-2 permeability, while Ligand B (-5.069) is also poor. Both are negative values which indicate poor permeability.

**Aqueous Solubility:** Ligand A (-2.03) has better aqueous solubility than Ligand B (-4.77). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.288) has a much lower hERG inhibition risk than Ligand B (0.909). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (33.101) has lower microsomal clearance than Ligand B (75.865), indicating better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand B (36.733) has a longer in vitro half-life than Ligand A (9.978). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux than Ligand B (0.312), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-10.4 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. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand B's higher logP and P-gp efflux, its significantly superior binding affinity (-10.4 vs -7.6 kcal/mol) is the most critical factor for an enzyme inhibitor. The stronger binding is likely to overcome some of the ADME liabilities. Ligand A has better solubility and lower hERG risk, but the potency difference is too large to ignore.

Output:
1
2025-04-17 11:14:04,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.37 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.08) is slightly higher than Ligand B (88.1). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (1.911) is optimal, while Ligand B (0.413) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.725) has a better QED score than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand A (99.031) has a very high DILI risk, a major concern. Ligand B (10.508) has a very low DILI risk, which is excellent.

**BBB:** Both have relatively low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.114) shows poor permeability, while Ligand B (-4.887) is slightly better, but still low.

**Aqueous Solubility:** Ligand A (-3.583) has poor solubility, while Ligand B (-1.401) is better, but still not ideal.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.318 and 0.502 respectively), which is positive.

**Microsomal Clearance:** Ligand A (11.657) has lower clearance than Ligand B (34.783), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (35.467 hours) has a significantly longer half-life than Ligand B (21.566 hours), a clear advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.173 and 0.05 respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-9.0 and -8.3 kcal/mol), both are excellent. The difference is not significant enough to outweigh other factors.

**Conclusion:**

Despite Ligand A's slightly better QED and longer half-life, the extremely high DILI risk is a deal-breaker. Ligand B, while having a slightly lower QED and half-life, possesses a significantly lower DILI risk and better solubility, making it the more promising candidate. The similar binding affinities mean that the ADMET properties are the deciding factors.

Output:
1
2025-04-17 11:14:04,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.427 Da and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (105.56 and 95.66) below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have logP values (2.085 and 1.549) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 5 HBA, which is acceptable.

**QED:** Both ligands have QED scores above 0.5 (0.695 and 0.738), indicating good drug-likeness.

**DILI:** Ligand B (23.187) has a significantly lower DILI risk than Ligand A (29.042), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.699) has a higher BBB percentile than Ligand A (42.924).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.672 and -5.789), which is unusual and suggests poor permeability. However, these values are on a log scale and require careful interpretation.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.689 and -2.938), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.658) has a slightly higher hERG inhibition liability than Ligand B (0.241), which is preferable for Ligand B.

**Microsomal Clearance:** Ligand B (8.338) has significantly lower microsomal clearance than Ligand A (42.427), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (4.563) has a slightly longer in vitro half-life than Ligand A (4.049).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.124 and 0.071).

**Binding Affinity:** Ligand B (-8.2 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 factor.

**Overall Assessment:**

Ligand B is the stronger candidate. It exhibits a lower DILI risk, significantly better metabolic stability (lower Cl_mic), slightly better binding affinity, and lower hERG inhibition. While both ligands have poor predicted solubility and permeability, the improved safety and pharmacokinetic properties of Ligand B outweigh the small difference in binding affinity. The enzyme-specific priorities (potency, metabolic stability, solubility, and hERG) strongly favor Ligand B.

Output:
1
2025-04-17 11:14:04,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.825 and 396.925 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.19) is slightly above the preferred <140, but acceptable. Ligand B (70.4) is excellent, well below 140.

**logP:** Ligand A (2.161) is within the optimal 1-3 range. Ligand B (3.78) is a bit higher, potentially edging towards solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, fitting the <5 and <10 guidelines. Ligand B has 2 HBD and 5 HBA, also within acceptable limits.

**QED:** Both ligands have good QED scores (0.747 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (91.237) has a concerningly high DILI risk (above 60). Ligand B (82.396) is better, but still above the preferred <40, though not as high as A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (46.336) and Ligand B (57.193) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.208 and -4.943), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.051 and -4.863). This is a major concern for bioavailability.

**hERG:** Ligand A (0.16) has a very low hERG risk, which is excellent. Ligand B (0.477) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (6.781) has a lower microsomal clearance than Ligand B (55.335), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-27.674) has a negative half-life, which is not physically possible and indicates a data error or a very rapidly metabolized compound. Ligand B (55.096) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux than Ligand B (0.73), which is favorable.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-7.7). This 1.5 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a very concerning DILI risk and a nonsensical half-life. While it has better metabolic stability and lower P-gp efflux, the DILI and half-life issues are major red flags. Ligand B, despite having slightly higher logP and P-gp efflux, has a much better safety profile (lower DILI) and a reasonable half-life. Crucially, its binding affinity is significantly stronger. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. Given the enzyme-specific priorities, the superior binding affinity and better safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 11:14:04,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.389 Da and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.05) is well below the 140 threshold and favorable for oral absorption. Ligand B (69.64) is still acceptable but less ideal.

**logP:** Ligand A (4.248) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.473) is 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 guidelines.

**QED:** Ligand A (0.883) has a very good QED score, indicating high drug-likeness. Ligand B (0.741) is still good, but less so than A.

**DILI:** Ligand A (29.081) has a very low DILI risk, which is excellent. Ligand B (4.459) also has a low DILI risk.

**BBB:** Ligand A (75.107) has good BBB penetration, though not critical for a non-CNS target like SRC. Ligand B (46.336) has lower BBB penetration.

**Caco-2:** Both ligands have negative Caco-2 values (-4.375 and -4.626), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have negative solubility values (-4.75 and -2.294), indicating very poor aqueous solubility. This is a major drawback.

**hERG:** Ligand A (0.91) has a slightly elevated hERG risk, but still relatively low. Ligand B (0.217) has a very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (50.928) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (45.716) has slightly better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.174) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (9.458) has a good in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.302 and 0.032), which is favorable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol), a difference of 1.1 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand A has a substantially better binding affinity and a very low DILI risk, and a good QED score. However, it has a higher logP, a slightly higher hERG risk, and a problematic negative in vitro half-life value. Ligand B has better solubility, lower hERG, and a reasonable half-life, but its binding affinity is weaker, and its QED is slightly lower. The negative Caco-2 and solubility values are concerning for both.

Despite the issues with solubility and permeability for both, the significantly stronger binding affinity of Ligand A is a critical factor for an enzyme inhibitor. The negative half-life for Ligand A is a data quality issue that needs investigation, but the binding advantage is substantial enough to prioritize it *if* the half-life can be clarified.

Output:
0
2025-04-17 11:14:04,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.447 and 342.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.94) is well below the 140 threshold for good absorption, while Ligand B (112.66) is still acceptable, but higher.

**logP:** Both ligands have good logP values (1.825 and 1.033), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.921) has a significantly higher QED score than Ligand B (0.726), indicating better overall drug-likeness.

**DILI:** Ligand A (61.264) has a higher DILI risk than Ligand B (46.219), but both are acceptable.

**BBB:** Both ligands have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.882) has a worse Caco-2 permeability than Ligand B (-5.28). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.698) has a worse aqueous solubility than Ligand B (-3.084). Higher values indicate better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.577 and 0.089), which is excellent.

**Microsomal Clearance:** Ligand A (53.281) has a higher microsomal clearance than Ligand B (22.465), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-22.612) has a significantly longer in vitro half-life than Ligand A (21.124), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.023).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-9.7 kcal/mol). While both are strong binders, the 1.8 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A's better QED and slightly better TPSA, Ligand B is the more promising candidate. The key factors driving this decision are:

1. **Stronger Binding Affinity:** The 1.8 kcal/mol difference in binding affinity is significant for an enzyme target.
2. **Better Metabolic Stability:** Ligand B has a much lower microsomal clearance and a longer half-life, which is crucial for maintaining therapeutic concentrations.
3. **Better Solubility:** Ligand B has better aqueous solubility.

Ligand A's higher DILI risk and lower metabolic stability are concerning.

Output:
1
2025-04-17 11:14:04,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.454 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.027) is at the lower end of the optimal range (1-3), while Ligand B (2.339) is well within it. Ligand B's logP is more favorable for permeability and reducing off-target effects.

**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.

**QED:** Both ligands have good QED scores (0.574 and 0.751), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (12.214) has a significantly lower DILI risk than Ligand B (34.277). This is a major advantage for Ligand A.

**BBB:** Ligand A (72.819) has better BBB penetration than Ligand B (53.625), but this is less critical for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-4.83) has worse Caco-2 permeability than Ligand B (-4.517).

**Aqueous Solubility:** Ligand A (-3.064) has worse solubility than Ligand B (-1.697). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.318) has a lower hERG inhibition risk than Ligand B (0.538). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (47.415) has higher microsomal clearance than Ligand B (24.744), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (-16.102) has a shorter half-life than Ligand B (23.768). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.015) has lower P-gp efflux than Ligand B (0.133). This is a slight advantage for Ligand A.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.4). This 1.5kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI/hERG risk, but suffers from lower solubility, permeability, metabolic stability, and shorter half-life. Ligand B has better ADME properties (logP, solubility, permeability, metabolic stability, half-life) but slightly weaker binding affinity and higher DILI/hERG risk.

Given the enzyme-specific priorities, the binding affinity difference is crucial. The 1.5 kcal/mol advantage of Ligand A is substantial. While the ADME properties of Ligand A are not ideal, they are not drastically outside acceptable ranges, and optimization could potentially address these issues. The lower DILI and hERG risks are also very important.

Output:
0
2025-04-17 11:14:04,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (465.193 Da) is towards the higher end, while Ligand B (349.406 Da) is more favorably positioned.

**TPSA:** Ligand A (36.67) is excellent, indicating good potential for absorption. Ligand B (76.64) is higher, but still acceptable, though potentially slightly impacting absorption.

**logP:** Ligand A (4.138) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.522) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is good. Ligand B has 2 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (A: 0.583, B: 0.869), suggesting drug-like properties. Ligand B is better here.

**DILI:** Ligand A (67.003) has a moderate DILI risk, while Ligand B (36.254) has a low DILI risk. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (93.563) shows good BBB penetration, and Ligand B (78.48) is also reasonable.

**Caco-2 Permeability:** Ligand A (-5.038) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.769) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.859 and -2.721 respectively). This is a concern for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.977) has a slightly elevated hERG risk, while Ligand B (0.544) is lower and more favorable.

**Microsomal Clearance:** Ligand A (55.605) has moderate clearance, while Ligand B (5.875) has very low clearance, indicating excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (18.672) has a moderate half-life, while Ligand B (-12.101) has a very short half-life. This is a significant drawback for Ligand B.

**P-gp Efflux:** Ligand A (0.888) shows moderate P-gp efflux, while Ligand B (0.037) shows very low efflux. This is a benefit for Ligand B.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a huge advantage for Ligand A, and likely outweighs many of its other drawbacks.

**Overall Assessment:**

Ligand A's primary strength is its exceptional binding affinity. However, it suffers from poor Caco-2 permeability, moderate DILI risk, slightly elevated hERG risk, and moderate metabolic clearance. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux), but its binding affinity is essentially non-existent.

Given that we are targeting a kinase (enzyme class), potency (binding affinity) is paramount. The substantial difference in binding affinity (-9.5 vs 0.0 kcal/mol) is likely to be the deciding factor. While Ligand A's ADME properties are not ideal, they are potentially addressable through formulation or further chemical modifications. Ligand B, with its extremely weak binding, is unlikely to be a viable starting point, regardless of its ADME profile.

Output:
1
2025-04-17 11:14:04,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is better than Ligand B (65.54), both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.403 and 2.255), falling within the 1-3 range. Ligand B is slightly higher, potentially aiding 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 (0.839 and 0.892), indicating good drug-like properties.

**DILI:** Ligand A (32.648) has a significantly lower DILI risk than Ligand B (40.83). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration (69.794 and 78.402), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.545) and Ligand B (-4.977) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.697) has better solubility than Ligand B (-2.643), which is a positive.

**hERG Inhibition:** Ligand A (0.146) has a lower hERG risk than Ligand B (0.33), which is preferable.

**Microsomal Clearance:** Ligand A (26.598) has significantly lower microsomal clearance than Ligand B (42.139), suggesting better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (7.375) has a longer half-life than Ligand B (-3.334), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.309), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.6) has a slightly better binding affinity than Ligand B (-8.1). While the difference is small, it's still a positive.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, lower hERG risk, lower P-gp efflux, and slightly better binding affinity. While both have poor Caco-2 permeability, the superior ADME properties of Ligand A outweigh this drawback, especially given the importance of metabolic stability and safety for an enzyme inhibitor.

Output:
0
2025-04-17 11:14:04,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.49 and 371.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (121.4), being well below the 140 threshold for good absorption. Ligand B is approaching a level that could hinder oral absorption.

**logP:** Both ligands have good logP values (2.49 and 1.64), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (0 HBD, 8 HBA). While both are within acceptable limits, fewer hydrogen bond donors and acceptors generally improve permeability.

**QED:** Ligand A (0.802) has a substantially higher QED score than Ligand B (0.438), indicating a more drug-like profile.

**DILI:** Ligand B (73.98) has a higher DILI risk than Ligand A (25.90), making A safer from a liver toxicity perspective.

**BBB:** Both have similar BBB penetration (78.52 and 76.74), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.76 and -5.11), which is unusual and could indicate issues with the calculation or the compounds themselves. However, the values are very close.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.89 and -2.88). This is a significant drawback and would require formulation strategies to overcome.

**hERG Inhibition:** Ligand A (0.361) has a much lower hERG risk than Ligand B (0.129), which is a critical advantage.

**Microsomal Clearance:** Ligand A (40.97) has higher microsomal clearance than Ligand B (9.96), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (16.71) has a longer in vitro half-life than Ligand A (20.84), which is a positive for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.301 and 0.234).

**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 for Ligand B, potentially outweighing some of its ADME drawbacks. The difference of 1.3 kcal/mol is significant.

**Overall Assessment:**

Despite Ligand A's better QED, lower DILI risk, and lower hERG risk, the significantly stronger binding affinity of Ligand B (-9.3 vs -8.0 kcal/mol) is the most critical factor for an enzyme inhibitor. While Ligand B has a higher DILI risk and lower metabolic stability, these can potentially be addressed through structural modifications in subsequent optimization rounds. The potency advantage of Ligand B is substantial enough to prioritize it as the more promising candidate.

Output:
1
2025-04-17 11:14:04,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.378 and 378.485 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (99.1) is slightly higher than the preferred <140, but acceptable. Ligand B (66.48) is well within the range.

**logP:** Both ligands have good logP values (2.798 and 2.402), 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 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.769 and 0.66), indicating good drug-like properties.

**DILI:** Ligand A (47.693) has a higher DILI risk than Ligand B (18.922). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (87.553) has a substantially higher score than Ligand A (50.679).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but we can assume they are percentile scores. Ligand A (-5.113) is worse than Ligand B (-4.901).

**Aqueous Solubility:** Both ligands have negative solubility values, again assuming percentile scores. Ligand A (-3.457) is slightly worse than Ligand B (-3.082).

**hERG:** Ligand A (0.111) has a slightly higher hERG risk than Ligand B (0.645), though both are relatively low.

**Microsomal Clearance:** Ligand B (18.094) has significantly lower microsomal clearance than Ligand A (25.407), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-40.73) has a much longer in vitro half-life than Ligand A (-2.334), further supporting its superior metabolic stability.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, slightly better than Ligand B (0.081).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 1.5 kcal/mol difference is significant and could potentially outweigh some of the ADME drawbacks of Ligand A. However, the substantial advantages of Ligand B in metabolic stability and DILI risk are compelling.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising drug candidate. The significantly lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and better BBB penetration make it a much safer and more likely to succeed in development. The difference in binding affinity, while notable, is less critical than these ADME-Tox properties for an enzyme inhibitor.

Output:
1
2025-04-17 11:14:04,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.764 and 346.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.55) is better than Ligand B (59.07), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.861) is optimal, while Ligand B (4.334) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.605 and 0.652), indicating generally drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (95.386 percentile) compared to Ligand B (24.932 percentile). This is a major concern for Ligand A.

**BBB:** Ligand B (84.141) has better BBB penetration than Ligand A (54.595), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and indicates poor permeability. Ligand A (-4.59) is slightly better than Ligand B (-4.845).

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and indicates poor solubility. Ligand A (-4.754) is slightly better than Ligand B (-4.483).

**hERG:** Ligand A (0.346) has a slightly better hERG profile than Ligand B (0.911).

**Microsomal Clearance:** Ligand B (86.611 mL/min/kg) has higher clearance than Ligand A (80.03 mL/min/kg), suggesting Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (43.439 hours) has a longer half-life than Ligand B (36.197 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux than Ligand B (0.298), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.9 kcal/mol). Ligand A is slightly better (-9.4 kcal/mol).

**Conclusion:**

Despite Ligand A having slightly better affinity, half-life, P-gp efflux, and clearance, the extremely high DILI risk (95.386 percentile) is a significant red flag. The slightly higher logP of Ligand B is a concern, but its much lower DILI risk (24.932 percentile) makes it the more viable candidate. The similar affinities mean the slightly better binding of Ligand A doesn't outweigh the substantial toxicity concern.

Output:
1
2025-04-17 11:14:04,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.5 and 349.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (88.91). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands have good logP values (2.49 and 1.59), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (5 & 5) counts.

**QED:** Both ligands have similar, good QED scores (0.737 and 0.708), indicating good drug-like properties.

**DILI:** Ligand A (35.79) has a lower DILI risk than Ligand B (28.00), which is favorable.

**BBB:** Both have moderate BBB penetration, but Ligand B (70.57) is better than Ligand A (61.77). However, BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.06) has a worse Caco-2 permeability than Ligand B (-4.97).

**Aqueous Solubility:** Both have poor aqueous solubility (-2.35 and -2.01). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.776) has a slightly higher hERG risk than Ligand B (0.048). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (17.95) has a significantly lower (better) microsomal clearance than Ligand B (34.64), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.41) has a longer in vitro half-life than Ligand A (5.27). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.432) has lower P-gp efflux than Ligand B (0.025), which is favorable.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better DILI and P-gp efflux, Ligand B's superior binding affinity (-9.4 vs -8.4 kcal/mol), longer half-life, and significantly lower hERG risk make it the more promising candidate. The solubility is a concern for both, but the potency and safety profile of Ligand B are more compelling for an oncology target like SRC kinase.

Output:
1
2025-04-17 11:14:04,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.331 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (127.49) is borderline for good oral absorption (<=140), while Ligand B (83.89) is well within the acceptable range. This favors Ligand B.

**logP:** Ligand A (0.353) is quite low, potentially hindering membrane permeability. Ligand B (1.514) 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 is acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (Ligand A: 0.541, Ligand B: 0.858), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A has a DILI risk of 85.576, which is high. Ligand B has a much lower DILI risk of 35.401, which is good. This is a major advantage for Ligand B.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (65.374) and Ligand B (47.111) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.191 and -5.19), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.914 and -1.303), indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.051) has a very low hERG risk, which is excellent. Ligand B (0.118) is slightly higher, but still relatively low. Ligand A has an advantage here.

**Microsomal Clearance:** Ligand A (28.872) has moderate clearance, while Ligand B (-0.379) has *very* low clearance, suggesting excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (70.138 hours) has a good half-life. Ligand B (8.29 hours) has a shorter half-life, which is a drawback. Ligand A has an advantage here.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.029).

**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 not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and permeability, Ligand B excels in key areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, though the half-life is a bit shorter), and a slightly better binding affinity. Ligand A has a better hERG profile and half-life, but the high DILI risk is a major concern. The improved metabolic stability of Ligand B is particularly important for kinases, as they are often susceptible to rapid metabolism.



Output:
1
2025-04-17 11:14:04,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447 Da) is slightly lower, which could be advantageous for permeability, while Ligand B (399.969 Da) is still acceptable.

**TPSA:** Ligand A (102.76) is better than Ligand B (62.3). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.88) is a bit low, potentially hindering permeation. Ligand B (3.193) is within the optimal range (1-3).

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

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

**QED:** Ligand B (0.825) has a significantly higher QED score than Ligand A (0.581), indicating a more drug-like profile.

**DILI:** Ligand A (17.255) has a much lower DILI risk than Ligand B (56.689), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase. Ligand B (61.264) is slightly higher than Ligand A (26.018).

**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 aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.259) has a much lower hERG inhibition liability than Ligand B (0.41), which is a critical advantage for safety.

**Microsomal Clearance:** Ligand A (8.668) has a significantly lower microsomal clearance than Ligand B (32.039), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (21.801) has a longer in vitro half-life than Ligand B (0.033), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.027) has a much lower P-gp efflux liability than Ligand B (0.271), potentially improving bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is only 0.6 kcal/mol, which may not be enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better affinity, Ligand A excels in crucial ADME-Tox properties: lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and 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 A make it the more promising candidate.

Output:
0
2025-04-17 11:14:04,997 - INFO - Batch 30 complete. Total preferences: 480
2025-04-17 11:14:04,997 - INFO - Processing batch 31/512...
2025-04-17 11:14:56,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.5 and 367.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.64) is significantly better than Ligand B (82.96). TPSA < 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Ligand A (0.38) is a bit low, potentially hindering permeation. Ligand B (3.598) is within the optimal 1-3 range. This favors B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.806 and 0.694), indicating good drug-like properties.

**DILI:** Ligand A (8.65) has a much lower DILI risk than Ligand B (82.24). This is a significant advantage for A.

**BBB:** Ligand A (76.46) has a better BBB penetration score than Ligand B (63.75), although this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.125) has poor Caco-2 permeability, while Ligand B (-4.996) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (0.071) has very poor solubility, while Ligand B (-4.933) is also very poor. This is a major concern for both.

**hERG:** Ligand A (0.781) has a lower hERG risk than Ligand B (0.73), which is favorable.

**Microsomal Clearance:** Ligand A (-20.117) has significantly better metabolic stability (lower clearance) than Ligand B (34.083). This is a crucial advantage for A.

**In vitro Half-Life:** Ligand A (30.76 hours) has a better half-life than Ligand B (59.877 hours).

**P-gp Efflux:** Ligand A (0.035) has lower P-gp efflux than Ligand B (0.497), which is beneficial.

**Binding Affinity:** Ligand A (-6.7 kcal/mol) has a significantly better binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand A is clearly superior despite some drawbacks. Its significantly stronger binding affinity (-6.7 vs 0 kcal/mol) is a decisive advantage. It also has much lower DILI risk, better metabolic stability (lower Cl_mic and better half-life), and lower P-gp efflux. While its logP is low and solubility is poor, the strong binding and favorable safety/ADME properties outweigh these concerns. Ligand B has a better logP, but is significantly weaker in binding affinity, has a much higher DILI risk, and poorer metabolic stability.

Output:
0
2025-04-17 11:14:56,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.305 and 350.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.58) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (59.39) is well within the ideal range.

**logP:** Both ligands have logP values (2.804 and 3.005) 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 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED scores (0.838 and 0.821), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 64.211, which is moderately high. Ligand B has a much lower DILI risk of 34.083, which is preferable.

**BBB:** Ligand A has a BBB penetration of 57.619, while Ligand B has 84.374. BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.71 and -4.486), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.352 and -3.221), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.768 and 0.727), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (46.259) than Ligand B (71.739), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (28.681 hours) than Ligand A (-1.416 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.344 and 0.211), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-8.6 kcal/mol). This difference of 1.4 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While both ligands have significant issues with solubility and permeability, Ligand B is the more promising candidate. Its substantially better binding affinity (-7.2 vs -8.6 kcal/mol), lower DILI risk (34.083 vs 64.211), and significantly longer half-life (28.681 vs -1.416) outweigh the slightly higher microsomal clearance. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modification, but the improved potency and PK properties make Ligand B the better starting point.

Output:
1
2025-04-17 11:14:56,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.5) is slightly higher than Ligand B (344.5).

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand B (69.3) is better than Ligand A (82.53).

**logP:** Both are within the optimal 1-3 range. Ligand A (1.961) and Ligand B (2.137) are comparable.

**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 have good QED scores (A: 0.851, B: 0.91), indicating drug-like properties.

**DILI:** Ligand B (32.842) has a significantly lower DILI risk than Ligand A (58.976). This is a major advantage for Ligand B.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (74.292) has a better BBB score than Ligand A (28.189).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand B (-3.043) is slightly better than Ligand A (-2.127).

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.382, B: 0.526).

**Microsomal Clearance (Cl_mic):** Ligand A (6.065) has a significantly lower Cl_mic than Ligand B (54.053), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life (t1/2):** Ligand B (-28.81) has a much longer half-life than Ligand A (-8.694). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.146, B: 0.275).

**Binding Affinity:** Both have excellent binding affinities (A: -8.8 kcal/mol, B: -8.1 kcal/mol). Ligand A is slightly better (-8.8 vs -8.1).

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and significantly better metabolic stability (lower Cl_mic). However, Ligand B exhibits a much lower DILI risk and a significantly longer half-life, both crucial for drug development. The solubility is better for Ligand B. Given the importance of metabolic stability and DILI risk for enzyme inhibitors, and the relatively small difference in binding affinity (1.5 kcal/mol is not exceeded), Ligand B is the more promising candidate.

Output:
1
2025-04-17 11:14:56,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (360.527 and 376.408 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.26) is significantly better than Ligand B (97.03).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**3. logP:** Ligand A (4.157) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (2.029) is within the optimal range. Higher logP can sometimes be tolerated if offset by other favorable properties.

**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 7. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.842 and 0.83), indicating good drug-likeness.

**7. DILI:** Ligand A (55.021) has a slightly higher DILI risk than Ligand B (61.807), but both are acceptable (below 60 is good).

**8. BBB:** Ligand A (93.757) has a much higher BBB penetration potential than Ligand B (78.945). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**9. Caco-2 Permeability:** Ligand A (-4.778) has significantly better Caco-2 permeability than Ligand B (-5.406). Higher values indicate better absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.778 and -3.79). This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.955) has a slightly higher hERG risk than Ligand B (0.328). This is a crucial factor, and Ligand B is significantly better here.

**12. Microsomal Clearance:** Ligand A (29.098) has a higher microsomal clearance than Ligand B (16.046), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (76.204) has a longer in vitro half-life than Ligand B (-13.967). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.694) has lower P-gp efflux than Ligand B (0.008), which is preferable.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a substantially better binding affinity and a longer half-life, which are critical for an enzyme inhibitor. It also has better Caco-2 permeability and P-gp efflux. However, it has a slightly higher DILI risk and a higher hERG risk. Ligand B has better hERG and metabolic stability, but its binding affinity is considerably weaker, and its half-life is very short.

Given the importance of potency and metabolic stability for kinase inhibitors, the superior binding affinity of Ligand A is the deciding factor, despite its slightly higher hERG and DILI risks. The poor solubility of both is a concern that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 11:14:56,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.841 Da and 355.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.47) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (52.65) is excellent, well below the threshold.

**logP:** Both ligands (1.802 and 1.34) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.547 and 0.635, respectively), indicating drug-like properties.

**DILI:** Ligand A (68.166) has a moderate DILI risk, while Ligand B (20.589) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (88.445) is significantly higher than Ligand A (71.656). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**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 ligands have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG:** Both ligands have very low hERG inhibition risk (0.183 and 0.462). This is excellent.

**Microsomal Clearance:** Ligand A (17.933) has a moderate clearance, while Ligand B (-6.673) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-4.383) has a negative half-life, which is also unusual. Ligand B (-1.07) also has a negative half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.025).

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-6.8), but the difference is less than 1.5 kcal/mol.

**Conclusion:**

While Ligand A has slightly better binding affinity, Ligand B is significantly better overall. The key advantages of Ligand B are its much lower DILI risk and exceptionally high metabolic stability (negative Cl_mic). The negative values for Caco-2 and half-life are concerning but could be due to modeling artifacts. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. The small difference in binding affinity is outweighed by the superior ADME-Tox profile of Ligand B.

Output:
1
2025-04-17 11:14:56,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (370.519 Da and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.01) is better than Ligand B (70.08), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.066) is within the optimal 1-3 range, while Ligand B (1.414) is on the lower side, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.569 and 0.812 respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (34.471) has a better DILI score than Ligand B (20.861), both are well below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.456) is better than Ligand B (51.764).

**9. Caco-2 Permeability:** Ligand A (-5.082) and Ligand B (-4.465) are both negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.13) and Ligand B (-1.777) are both negative, indicating poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.342 and 0.477 respectively).

**12. Microsomal Clearance:** Ligand A (83.653) has a higher clearance than Ligand B (20.249), suggesting lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand B (24.676) has a significantly longer half-life than Ligand A (-29.773), indicating better stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.294 and 0.152 respectively).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This difference of 1.2 kcal/mol is substantial and a key driver in the decision.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B excels in binding affinity and metabolic stability (lower Cl_mic and higher t1/2). While both have poor solubility and permeability, the significantly stronger binding and better metabolic profile of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 11:14:56,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.837 and 382.81 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.7) is higher than Ligand B (58.64). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (3.311 and 2.222), 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, but lower HBA is generally preferred.

**QED:** Both ligands have acceptable QED scores (0.803 and 0.758), indicating good drug-like properties.

**DILI:** Ligand A (85.925) has a significantly higher DILI risk than Ligand B (25.436). This is a major concern for Ligand A.

**BBB:** Both have high BBB penetration (53.587 and 85.459). This isn't a primary concern for a kinase inhibitor, but higher is not detrimental.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.817 and -4.809), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both have negative solubility values (-4.946 and -3.35), indicating very poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.272) has a slightly higher hERG risk than Ligand B (0.602), but both are relatively low.

**Microsomal Clearance:** Ligand B (15.968) has a lower microsomal clearance than Ligand A (29.837), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (2.625) has a longer half-life than Ligand A (8.068), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.472) has lower P-gp efflux than Ligand B (0.142), which could lead to better bioavailability.

**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 outweighs many of the other minor differences.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the superior candidate. Its significantly stronger binding affinity (-8.5 vs -7.7 kcal/mol), much lower DILI risk (25.436 vs 85.925), and improved metabolic stability (lower Cl_mic and longer t1/2) make it a more promising starting point for further optimization. The lower P-gp efflux of ligand A is a minor advantage that is overshadowed by the other factors.

Output:
1
2025-04-17 11:14:56,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.34 and 348.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.08) is significantly better than Ligand B (67.43). A TPSA under 140 is desirable for oral absorption, and both are within this range, but A is much closer to the optimal for good permeability.

**logP:** Ligand A (4.843) is higher than Ligand B (2.847). While both are above 1, A is pushing the upper limit and could present solubility challenges. B is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 3 HBA). Both are within acceptable limits.

**QED:** Ligand A (0.718) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand B (21.52) has a significantly lower DILI risk than Ligand A (64.172). This is a major advantage for Ligand B.

**BBB:** Ligand A (62.233) has a slightly better BBB penetration than Ligand B (57.193), but this is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.701) has a worse Caco-2 permeability than Ligand B (-5.152) - lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.914) has worse aqueous solubility than Ligand B (-2.602). This is a concern given Ligand A's higher logP.

**hERG Inhibition:** Ligand A (0.951) has a slightly higher hERG inhibition risk than Ligand B (0.356). Lower is better, so B is preferable.

**Microsomal Clearance:** Ligand A (24.021) has a significantly lower microsomal clearance than Ligand B (40.323), suggesting better metabolic stability. This is a key advantage for A.

**In vitro Half-Life:** Ligand A (-22.844) has a much longer in vitro half-life than Ligand B (-12.134). This is a significant benefit for A.

**P-gp Efflux:** Ligand A (0.839) has slightly lower P-gp efflux than Ligand B (0.169). Lower is better, so A is preferable.

**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, and likely outweighs some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**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 poorer solubility, higher DILI risk, and a higher logP. Ligand B has better solubility, lower DILI, and lower hERG risk. The significantly stronger binding affinity of Ligand A (-9.7 vs -7.6 kcal/mol) is a crucial factor for an enzyme inhibitor. The improved metabolic stability and half-life also contribute to its potential. While the solubility and DILI are concerns, these can potentially be addressed through formulation strategies or further chemical modifications.

Output:
1
2025-04-17 11:14:56,797 - INFO - Here's a step-by-step reasoning for selecting the better drug candidate between Ligand A and Ligand B, targeting the SRC kinase:

**1. Molecular Weight (MW):**
*   Ligand A: 347.371 Da - Within the ideal range (200-500 Da).
*   Ligand B: 412.324 Da - Still within the ideal range, but approaching the upper limit.
*   *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 99.18  - Good for oral absorption (<=140).
*   Ligand B: 48 - Excellent for oral absorption.
*   *Ligand B is better.*

**3. Lipophilicity (logP):**
*   Ligand A: 0.811 - Slightly low, potentially hindering permeation.
*   Ligand B: 3.774 - Optimal range (1-3).
*   *Ligand B is better.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 2 - Within the ideal range (<=5).
*   Ligand B: 0 - Within the ideal range (<=5).
*   *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 5 - Within the ideal range (<=10).
*   Ligand B: 4 - Within the ideal range (<=10).
*   *No clear advantage.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.789 - Good drug-like properties.
*   Ligand B: 0.64 - Acceptable, but slightly lower than Ligand A.
*   *Ligand A is better.*

**7. DILI Risk (DILI):**
*   Ligand A: 74.99 - Moderate risk.
*   Ligand B: 30.671 - Low risk.
*   *Ligand B is significantly better.*

**8. Blood-Brain Barrier Penetration (BBB):**
*   Ligand A: 66.382 - Not particularly high, not a major concern for a non-CNS target.
*   Ligand B: 86.274 - Higher, but not crucial for SRC kinase.
*   *Ligand B is better.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.579 - Poor permeability.
*   Ligand B: -4.728 - Poor permeability.
*   *No clear advantage.*

**10. Aqueous Solubility:**
*   Ligand A: -3.048 - Poor solubility.
*   Ligand B: -3.49 - Poor solubility.
*   *No clear advantage.*

**11. hERG Inhibition:**
*   Ligand A: 0.122 - Low risk.
*   Ligand B: 0.67 - Moderate risk.
*   *Ligand A is better.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: -12.283 - Low clearance, good metabolic stability.
*   Ligand B: 92.13 - High clearance, poor metabolic stability.
*   *Ligand A is significantly better.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: 36.364 - Moderate half-life.
*   Ligand B: -5.541 - Short half-life.
*   *Ligand A is better.*

**14. P-gp Efflux:**
*   Ligand A: 0.014 - Low efflux, good.
*   Ligand B: 0.522 - Moderate efflux.
*   *Ligand A is better.*

**15. Binding Affinity:**
*   Ligand A: -8.5 kcal/mol - Excellent binding.
*   Ligand B: -9.2 kcal/mol - Very strong binding, 0.7 kcal/mol advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior metabolic stability (Cl_mic, t1/2), lower DILI risk, better hERG profile, and lower P-gp efflux. The solubility and permeability are poor for both, but the metabolic stability and safety profile of Ligand A are more critical for kinase inhibitors.

**Conclusion:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising drug candidate due to its significantly better ADME-Tox properties, particularly its metabolic stability, lower DILI risk, and better hERG profile. These factors are crucial for kinase inhibitors, where long-term efficacy and safety are paramount.

1
2025-04-17 11:14:56,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.373 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.36) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (76.46) is still under 140, but less optimal than A.

**logP:** Ligand A (4.279) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.152) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.709 and 0.679), indicating good drug-likeness.

**DILI:** Ligand A (81.117) has a significantly higher DILI risk than Ligand B (38.736). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (70.648 and 77.084), but this is less critical for a non-CNS target like SRC.

**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 them relatively.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.43) is slightly better than Ligand A (-4.783).

**hERG Inhibition:** Ligand A (0.691) has a slightly higher hERG risk than Ligand B (0.317), but both are reasonably low.

**Microsomal Clearance:** Ligand A (53.651) has a higher microsomal clearance than Ligand B (38.962), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.662) has a longer in vitro half-life than Ligand A (22.719), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.68 and 0.127).

**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 B** is the more promising drug candidate. While both have similar potency, Ligand B exhibits a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. The higher logP of Ligand A is a concern, and its higher DILI risk is a major drawback. The small difference in binding affinity is unlikely to outweigh these ADME/Tox advantages.

Output:
1
2025-04-17 11:14:56,797 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [339.439, 54.46, 3.106, 1, 4, 0.93, 63.164, 81.698, -4.698, -4.082, 0.859, 66.277, -12.656, 0.48, -8]
**Ligand B:** [351.451, 116.19, 2.293, 2, 4, 0.272, 23.963, 59.519, -5.127, -1.75, 0.333, 36.511, -22.321, 0.031, -7.7]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (339.439) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (54.46) is excellent, well below the 140 threshold. B (116.19) is higher, but still acceptable, though less favorable for oral absorption.
3. **logP:** Both are within the optimal range (1-3). A (3.106) is slightly higher, which could be a minor concern for off-target effects, but B (2.293) is good.
4. **HBD:** A (1) is ideal. B (2) is acceptable.
5. **HBA:** Both have 4 HBA, which is within the acceptable limit of 10.
6. **QED:** A (0.93) is excellent, indicating high drug-likeness. B (0.272) is poor, suggesting significant issues with its overall drug-like properties.
7. **DILI:** A (63.164) is moderately high risk. B (23.963) is very good, indicating low liver injury risk.
8. **BBB:** A (81.698) is good, suggesting reasonable brain penetration if needed. B (59.519) is lower, indicating less likely CNS penetration.  However, SRC is not typically a CNS target, so this is less critical.
9. **Caco-2:** A (-4.698) is very poor. B (-5.127) is also very poor. Both ligands have very low Caco-2 permeability.
10. **Solubility:** A (-4.082) is poor. B (-1.75) is also poor. Both ligands have low solubility.
11. **hERG:** A (0.859) is good, indicating low cardiotoxicity risk. B (0.333) is very good.
12. **Cl_mic:** A (66.277) is moderate. B (36.511) is better, suggesting improved metabolic stability.
13. **t1/2:** A (-12.656) is poor, indicating rapid clearance. B (-22.321) is even worse. Both have very short half-lives.
14. **Pgp:** A (0.48) is good. B (0.031) is excellent, indicating low P-gp efflux.
15. **Affinity:** A (-8) is excellent, significantly stronger than B (-7.7). A 0.3 kcal/mol difference is substantial.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

Despite the higher DILI risk, **Ligand A is the more promising candidate.** The significantly stronger binding affinity (-8 vs -7.7 kcal/mol) is a major advantage for an enzyme target. While both have poor solubility and permeability, the binding advantage of A is likely to outweigh these issues, especially with potential formulation strategies. The better Pgp profile of B is not enough to overcome the substantial affinity difference. The metabolic stability of B is better, but not enough to offset the lower affinity. The poor half-life of both compounds is a concern that would need to be addressed through structural modifications.

Output:
1
2025-04-17 11:14:56,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (378.885 Da) is still well within the acceptable range.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (75.19) is lower than Ligand A (88.85), which is slightly preferable.

**logP:** Ligand A (0.968) is a bit low, potentially hindering permeation. Ligand B (3.16) is within the optimal range (1-3). This gives Ligand B an advantage.

**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:** Ligand A (0.859) has a better QED score than Ligand B (0.565), indicating a more drug-like profile overall.

**DILI:** Ligand B (68.205) has a slightly higher DILI risk than Ligand A (57.154), but both are still below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.803) has a better BBB score than Ligand B (56.029), but this is not a major factor in this case.

**Caco-2 Permeability:** Ligand A (-4.756) has a more negative Caco-2 value, indicating lower permeability, while Ligand B (-5.16) is slightly worse.

**Aqueous Solubility:** Ligand A (-2.329) has better solubility than Ligand B (-3.49). Solubility is important for bioavailability, giving Ligand A an edge.

**hERG Inhibition:** Ligand A (0.839) has a slightly higher hERG risk than Ligand B (0.497), which is preferable.

**Microsomal Clearance:** Ligand A (0.271) has significantly lower microsomal clearance than Ligand B (75.892), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (12.255 hours) has a much longer half-life than Ligand B (27.089 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.174) has lower P-gp efflux than Ligand B (0.479), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 kcal/mol and -8.1 kcal/mol, respectively). Ligand A is slightly better (-8.9 kcal/mol). The difference of 0.8 kcal/mol is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A demonstrates a superior profile overall, particularly regarding metabolic stability (Cl_mic, t1/2), solubility, P-gp efflux, and a slightly better binding affinity. While Ligand B has a better logP, Ligand A's advantages in key pharmacokinetic parameters and its slightly stronger binding outweigh this.

Output:
0
2025-04-17 11:14:56,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.427 and 357.357 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (92.49) is slightly above the preferred <90 for optimal absorption, while Ligand B (80.76) is well within the range.

**3. logP:** Both ligands have good logP values (1.354 and 1.183), 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 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.688 and 0.756), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 74.99%, which is concerning (high risk). Ligand B has a much lower DILI risk of 39.201% (good). This is a significant advantage for Ligand B.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.48) has a higher BBB score than Ligand A (55.603), but it's not a deciding factor here.

**9. Caco-2 Permeability:** Ligand A (-5.754) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.696) is also negative, but less so.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.976 and -1.684). This is a potential issue, but formulation strategies can sometimes mitigate this.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.224 and 0.29). This is positive.

**12. Microsomal Clearance:** Ligand A (55.048) has a higher microsomal clearance than Ligand B (16.754), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-17.563) has a negative half-life, which is unusual and concerning. Ligand A (22.735) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.016).

**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 for Ligand A.

**Overall Assessment:**

While Ligand A has a much better binding affinity, its high DILI risk, poor Caco-2 permeability, and higher microsomal clearance are major concerns. Ligand B has a better safety profile (lower DILI), better permeability, and improved metabolic stability, despite having a weaker binding affinity. The difference in binding affinity (-1.7 kcal/mol) is significant, but the ADME/Tox profile of Ligand A is too problematic. Considering the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 11:14:56,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 357.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.87) is better than Ligand B (20.31) as it is closer to the threshold of 140 for good oral absorption. Ligand B is very low, which could indicate issues with solubility.

**logP:** Ligand A (1.419) is optimal, while Ligand B (4.929) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both within acceptable limits. Ligand B has 0 HBD and 1 HBA, which is also acceptable, but might contribute to poor aqueous solubility.

**QED:** Ligand A (0.691) has a good drug-likeness score, while Ligand B (0.28) is quite low, indicating a less favorable drug-like profile.

**DILI:** Ligand A (16.402) has a much lower DILI risk than Ligand B (28.655), which is a significant advantage.

**BBB:** Ligand A (58.782) has a lower BBB penetration than Ligand B (95.735). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.739) has poor Caco-2 permeability, while Ligand B (-4.296) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.271) has poor solubility, while Ligand B (-4.693) is even worse.

**hERG Inhibition:** Ligand A (0.249) has a lower hERG risk than Ligand B (0.936), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (34.1) has a lower microsomal clearance than Ligand B (50.156), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.991) has a shorter half-life than Ligand B (30.609), which is a disadvantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.832, respectively).

**Binding Affinity:** Ligand B (-7.2) has a significantly stronger binding affinity than Ligand A (0.0). 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 much stronger binding affinity, which is the primary driver for enzyme inhibitors. While it has poorer solubility, a higher logP, and a lower QED, the substantial improvement in binding affinity (-7.2 vs 0.0 kcal/mol) is likely to be decisive. The DILI risk is also higher for Ligand B, but the potency advantage may allow for lower dosing, potentially mitigating this risk. Ligand A has better safety parameters, but its lack of binding affinity makes it an unlikely candidate.

Output:
1
2025-04-17 11:14:56,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.403 Da) is slightly lower, which is generally favorable for permeability. Ligand B (368.543 Da) is also good.

**TPSA:** Ligand A (111.06) is better than Ligand B (51.66). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.915) is within the optimal range (1-3). Ligand B (3.637) is at the higher end of the optimal range, potentially increasing off-target effects and decreasing solubility.

**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.

**QED:** Ligand B (0.668) has a better QED score than Ligand A (0.353), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (Ligand A: 36.06, Ligand B: 31.834), which is good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.449) has a higher BBB percentile than Ligand A (64.444).

**Caco-2 Permeability:** Ligand A (-5.131) has a worse Caco-2 permeability than Ligand B (-4.817), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.086) has better aqueous solubility than Ligand B (-3.994). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.339) has a lower hERG inhibition liability than Ligand B (0.781), which is a significant advantage.

**Microsomal Clearance:** Ligand A (1.11 mL/min/kg) has significantly lower microsomal clearance than Ligand B (80.597 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.193 hours) has a much longer in vitro half-life than Ligand B (57.788 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux liability than Ligand B (0.765), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This 0.5 kcal/mol difference is notable, but not overwhelming given the other ADME properties.

**Overall Assessment:**

Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (Cl_mic, t1/2), solubility, and hERG risk. While Ligand B has slightly better binding affinity and QED, the substantial differences in metabolic stability and safety (hERG) outweigh this advantage. The lower Caco-2 permeability of Ligand A is a concern, but potentially mitigable with formulation strategies. Given the enzyme-kinase specific priorities, the improved metabolic stability and reduced toxicity risk of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 11:14:56,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.392 and 363.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.47) is better than Ligand B (41.93). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.895) is optimal, while Ligand B (4.588) is pushing the upper limit, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both have 1 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:** Ligand A (0.905) has a significantly better QED score than Ligand B (0.708), indicating a more drug-like profile.

**DILI:** Ligand A (32.803) has a much lower DILI risk than Ligand B (12.059), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (86.39) is better than Ligand B (74.37).

**Caco-2 Permeability:** Ligand A (-4.714) is better than Ligand B (-5.103). Both are negative, indicating good permeability.

**Aqueous Solubility:** Ligand A (-3.537) is better than Ligand B (-4.314). Both are negative, indicating good solubility.

**hERG Inhibition:** Ligand A (0.82) has a lower hERG risk than Ligand B (0.947), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (10.333 mL/min/kg) has significantly better metabolic stability than Ligand B (118.825 mL/min/kg). This is a major advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-9.896 hours) has a much longer half-life than Ligand B (31.267 hours). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux than Ligand B (0.578), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). The difference is 1.3 kcal/mol, which is significant enough to outweigh some minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It exhibits a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, lower P-gp efflux, and slightly better binding affinity. While Ligand B has a slightly better logP, the other advantages of Ligand A make it a much more promising drug candidate for SRC kinase inhibition.

Output:
0
2025-04-17 11:14:56,798 - INFO - Batch 31 complete. Total preferences: 496
2025-04-17 11:14:56,798 - INFO - Processing batch 32/512...
2025-04-17 11:15:35,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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. Ligand B (359.535 Da) is also good.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (29.54). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (2.584) is within the optimal range (1-3). Ligand B (4.878) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable.

**H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is within the acceptable range.

**QED:** Ligand A (0.863) has a better QED score than Ligand B (0.678), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (Ligand A: 20.706, Ligand B: 22.024), which is good.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 74.176, Ligand B: 73.866). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Ligand A (-1.723) is better than Ligand B (-5.433). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.39, Ligand B: 0.582), which is favorable.

**Microsomal Clearance:** Ligand A (18.796) has significantly lower microsomal clearance than Ligand B (126.031). Lower clearance indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-16.736) has a negative half-life, which is not possible. This is a concerning data point. Ligand B (10.96) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.093, Ligand B: 0.792).

**Binding Affinity:** Both ligands have very similar binding affinities (Ligand A: -6.9 kcal/mol, Ligand B: -6.7 kcal/mol). The difference is not substantial enough to override other ADME concerns.

**Overall Assessment:**

Ligand A has several advantages: better TPSA, logP, QED, solubility, and significantly better metabolic stability (lower Cl_mic). However, the negative in vitro half-life is a major red flag, suggesting a data error or a very unstable compound. Ligand B has a reasonable half-life but suffers from a higher logP and significantly worse metabolic stability.

Despite the concerning half-life of Ligand A, its other properties are superior. Assuming the half-life is a data error, Ligand A is the more promising candidate.

Output:
1
2025-04-17 11:15:35,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is slightly higher than Ligand B (65.54), but both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (2.637) is optimal, while Ligand B (1.095) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (5) both meet the <=10 criteria.

**QED:** Both ligands have good QED scores (0.628 and 0.799, respectively), indicating drug-likeness.

**DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (30.012), which is a substantial advantage. Both are below the 40 threshold.

**BBB:** Ligand A (65.529) has better BBB penetration than Ligand B (50.058), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.66) shows poorer Caco-2 permeability than Ligand B (-5.064). Both are negative, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-3.253) has better aqueous solubility than Ligand B (-1.782).

**hERG Inhibition:** Ligand A (0.338) has a lower hERG inhibition liability than Ligand B (0.257), which is a positive. Both are very low risk.

**Microsomal Clearance:** Ligand A (62.565) has a higher microsomal clearance than Ligand B (-4.071), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-29.73) has a much shorter in vitro half-life than Ligand B (-2.249), further confirming the metabolic instability of Ligand A.

**P-gp Efflux:** Ligand A (0.488) has slightly higher P-gp efflux than Ligand B (0.031).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 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 better solubility and a slightly better affinity, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The slightly lower logP of Ligand B is a minor concern, but the superior metabolic profile and safety outweigh this. The difference in binding affinity is small enough that it doesn't negate the other advantages of Ligand B.

Output:
1
2025-04-17 11:15:35,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.503 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (84.23). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (4.289 and 3.265, respectively), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=4), as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.813) has a better QED score than Ligand B (0.677), indicating a more drug-like profile.

**DILI:** Ligand B (35.867) has a significantly lower DILI risk than Ligand A (46.801), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (63.784 and 64.676), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Ligand A (-5.267) has slightly better solubility than Ligand B (-2.776), although both are poor.

**hERG:** Ligand A (0.8) has a slightly higher hERG risk than Ligand B (0.289), which is preferable.

**Microsomal Clearance:** Ligand B (70.312) has a lower microsomal clearance than Ligand A (117.764), suggesting better metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (8.027 hours) has a significantly longer half-life than Ligand A (26.868 hours). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.706) has higher P-gp efflux than Ligand B (0.218), which is less desirable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). This 0.6 kcal/mol difference is notable, but can be outweighed by ADME properties.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life. The lower P-gp efflux of Ligand B is also beneficial. The solubility of both is poor, but Ligand A is slightly better. Considering the enzyme-specific priorities, the improved metabolic stability and lower toxicity profile of Ligand B outweigh the small difference in binding affinity.

Output:
1
2025-04-17 11:15:35,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.423 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.79) is slightly above the preferred <140 for good absorption, while Ligand B (81.08) is well within the range.

**logP:** Ligand A (-1.288) is a bit low, potentially hindering permeation. Ligand B (1.314) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 5 HBA. Ligand B has 2 HBD and 4 HBA. Both are acceptable, but Ligand B is slightly more favorable.

**QED:** Both ligands have reasonable QED scores (0.405 and 0.707), with Ligand B being significantly better.

**DILI:** Ligand A (26.134) has a lower DILI risk than Ligand B (19.698), which is good.

**BBB:** Ligand A (46.375) has a lower BBB penetration than Ligand B (65.839). This is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.61) has poor Caco-2 permeability, while Ligand B (-4.639) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.597) has poor aqueous solubility, while Ligand B (-1.464) is also poor. This is a concern for both.

**hERG Inhibition:** Ligand A (0.093) has a very low hERG risk, which is excellent. Ligand B (0.322) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-10.514) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (8.009) has a moderate clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (12.443) has a longer half-life than Ligand B (4.843).

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is favorable. Ligand B (0.131) has slightly higher efflux.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.3). However, the difference is only 0.4 kcal/mol, which is not huge.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG, lower P-gp efflux) and superior metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from poor solubility, poor permeability, and a lower logP. Ligand B has better solubility and permeability, a slightly better logP, and slightly better binding affinity, but has a higher DILI risk, higher hERG risk, and faster metabolism.

Given the enzyme-specific priorities, metabolic stability and safety (hERG) are crucial. The slightly better affinity of Ligand B doesn't outweigh the significantly better metabolic stability and safety profile of Ligand A. While solubility and permeability are concerns for Ligand A, these can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 11:15:35,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.447 and 370.425 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (86.88), both are below the 140 threshold for oral absorption.

**3. logP:** Ligand A (1.378) is within the optimal 1-3 range, while Ligand B (2.932) is approaching the upper limit.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3), as fewer donors generally improve permeability.

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

**6. QED:** Ligand A (0.818) has a significantly better QED score than Ligand B (0.668), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.71) has a much lower DILI risk than Ligand B (67.817). This is a significant advantage.

**8. BBB:**  BBB is less critical for a non-CNS target like SRC, but Ligand A (76.774) is better than Ligand B (61.923).

**9. Caco-2 Permeability:** Ligand A (-4.997) is better than Ligand B (-5.468).

**10. Aqueous Solubility:** Ligand A (-2.96) is better than Ligand B (-3.077).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.061 and 0.592, respectively), which is excellent.

**12. Microsomal Clearance:** Ligand B (36.755) has a lower microsomal clearance than Ligand A (49.256), suggesting better metabolic stability. This is a positive for Ligand B.

**13. In vitro Half-Life:** Ligand B (-3.662) has a longer in vitro half-life than Ligand A (-16.662), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.153, respectively).

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -8.5 kcal/mol), which are both excellent and well below the -7.0 kcal/mol threshold. The difference is negligible.

**Overall Assessment:**

Ligand A excels in most ADME properties (QED, DILI, solubility, permeability) and has a slightly better logP and TPSA. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2). However, the significantly lower DILI risk and higher QED of Ligand A outweigh the slightly better metabolic stability of Ligand B. The binding affinity is comparable. Given the enzyme-specific priorities, the superior ADME profile of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 11:15:35,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.46 & 348.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good absorption, while Ligand B (99.77) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (1.66 & 1.13), 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 HBA, both are acceptable.

**QED:** Both ligands have good QED scores (0.659 & 0.875), indicating good drug-like properties.

**DILI:** Ligand A (33.81) has a lower DILI risk than Ligand B (46.22), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (82.24) has slightly better BBB penetration than Ligand B (72.94).

**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, we can still compare them. Ligand A (-4.95) is slightly better than Ligand B (-4.83).

**Aqueous Solubility:** Both have negative solubility values, which is concerning. Ligand A (-2.41) is slightly better than Ligand B (-2.17).

**hERG:** Both ligands have very low hERG inhibition risk (0.35 & 0.08), which is excellent.

**Microsomal Clearance:** Ligand A (8.18) has a higher Cl_mic than Ligand B (6.87), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (2.18 hours) has a slightly better half-life than Ligand A (-19.40 hours), although the negative value for ligand A is concerning and likely an artifact of the prediction.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.03 & 0.07), which is good.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has a slightly lower DILI risk and marginally better Caco-2 and solubility, Ligand B's significantly stronger binding affinity (-9.9 vs -8.0 kcal/mol) and better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme inhibitor. The slightly higher DILI risk of Ligand B is acceptable given the potency and stability benefits.

Output:
1
2025-04-17 11:15:35,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.402 and 355.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.01) is slightly higher than the preferred <140, but acceptable. Ligand B (47.36) is excellent, well below 140.

**logP:** Ligand A (1.456) is within the optimal 1-3 range. Ligand B (2.926) is also good, near the upper end of the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, potentially aiding permeability.

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

**QED:** Both ligands have good QED scores (0.659 and 0.756), indicating drug-like properties.

**DILI:** Ligand A (71.539) has a higher DILI risk than Ligand B (35.285). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (97.751) has a higher BBB score, but it's not a primary concern here. Ligand A (56.65) is lower.

**Caco-2 Permeability:** Ligand A (-5.103) has poor Caco-2 permeability. Ligand B (-4.58) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.682) has poor aqueous solubility. Ligand B (-2.705) is better, but still not ideal.

**hERG:** Both ligands have low hERG risk (0.713 and 0.669), which is good.

**Microsomal Clearance:** Ligand A (13.553) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (35.896) has a significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (19.918) has a longer half-life than Ligand B (6.95), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.122 and 0.18).

**Binding Affinity:** Ligand B (-9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability and half-life, Ligand B is superior overall. The significantly stronger binding affinity (-9 vs -8 kcal/mol) of Ligand B is a major advantage for an enzyme target. Additionally, Ligand B has a much lower DILI risk and better Caco-2 permeability and solubility. The slightly higher metabolic clearance of Ligand B is a concern, but the potency advantage is likely to be more impactful.

Output:
1
2025-04-17 11:15:35,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.463 and 366.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.96) is well below the 140 threshold for good absorption, and favorable for kinase inhibitors. Ligand B (132) is still within acceptable range, but less optimal.

**logP:** Ligand A (-0.086) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.336) is also on the lower side, but better than A.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.704 and 0.62), indicating drug-like properties.

**DILI:** Ligand A (21.714) has a much lower DILI risk than Ligand B (77.123), a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (65.413) is better than Ligand B (46.413).

**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 problematic. Again, the scale is unspecified.

**hERG:** Ligand A (0.177) has a much lower hERG risk than Ligand B (0.215), a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (20.911) has a higher (worse) microsomal clearance than Ligand B (3.208), indicating lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand A (-7.389) has a much longer half-life than Ligand B (16.527), a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.007 and 0.058).

**Binding Affinity:** Both ligands have identical binding affinities (-7.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, and in vitro half-life. However, it suffers from lower logP, higher microsomal clearance, and unusual solubility/permeability values. Ligand B has better logP and metabolic stability, but significantly higher DILI and hERG risk.

Given the priorities for enzyme inhibitors, the lower DILI and hERG risk of Ligand A are paramount. The slightly lower logP and higher clearance could potentially be addressed through further optimization, but mitigating high toxicity risks is more challenging. The similar binding affinity makes these ADME properties the deciding factor.

Output:
1
2025-04-17 11:15:35,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.491 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is well below the 140 threshold for good absorption, and suitable for kinase inhibitors. Ligand B (108.46) is still acceptable, but less optimal.

**logP:** Ligand A (1.706) is within the optimal 1-3 range. Ligand B (0.588) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**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 6 HBA, both are within the acceptable limit of <=10.

**QED:** Ligand A (0.661) has a good drug-likeness score, exceeding 0.5. Ligand B (0.36) is significantly lower, indicating a less drug-like profile.

**DILI:** Ligand A (13.61) has a very low DILI risk. Ligand B (35.285) is moderate, but still acceptable.

**BBB:** Both ligands have moderate BBB penetration (60.566 and 64.482 respectively). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.779) and Ligand B (-5.381) both have negative values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are common and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.47 and -2.749). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.337) has a very low hERG risk. Ligand B (0.556) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (43.765) has moderate clearance. Ligand B (-4.218) has *negative* clearance, which is impossible and likely an error in the data. This is a major red flag.

**In vitro Half-Life:** Ligand A (7.59 hours) is reasonable. Ligand B (-21.26 hours) is also impossible and a further indication of data quality issues.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.195 and 0.026), which is favorable.

**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.

**Conclusion:**

Despite the stronger binding affinity of Ligand B, the negative values for microsomal clearance and in vitro half-life are highly suspect and indicate a serious problem with the data or the compound's stability. These values are physically impossible. Ligand A, while having a weaker binding affinity, has more reasonable and plausible ADME properties, including a low DILI risk and low hERG inhibition. The solubility is a concern for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 11:15:35,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.419 Da) is slightly lower, which could be advantageous for permeability. Ligand B (352.475 Da) is also acceptable.

**TPSA:** Ligand A (54.12) is better than Ligand B (59.08), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.853) is optimal, while Ligand B (1.701) is on the lower side. Lower logP can sometimes indicate poor membrane permeability.

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

**QED:** Ligand A (0.719) has a better QED score than Ligand B (0.444), indicating a more drug-like profile.

**DILI:** Ligand B (9.461) has a significantly lower DILI risk than Ligand A (69.678), which is a major advantage.

**BBB:** Ligand B (81.582) has a higher BBB penetration score than Ligand A (40.481). While SRC isn't a CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.967) has better Caco-2 permeability than Ligand B (-4.158), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-6.207) has better aqueous solubility than Ligand B (-0.667). Solubility is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.805) has a slightly higher hERG inhibition risk than Ligand B (0.394), but both are reasonably low.

**Microsomal Clearance:** Ligand A (69.351) and Ligand B (67.076) have similar microsomal clearance values, indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (-29.618) has a significantly longer in vitro half-life than Ligand B (-11.604), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.617) has lower P-gp efflux than Ligand B (0.069), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.9 kcal/mol and -8.5 kcal/mol, respectively). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A has advantages in solubility, Caco-2 permeability, in vitro half-life, and P-gp efflux. However, Ligand B has a much lower DILI risk, a better QED score, and better BBB penetration. Given the enzyme-specific priorities, the lower DILI risk of Ligand B is a significant advantage. While Ligand A's solubility and half-life are attractive, the potential for liver toxicity with Ligand A is concerning.

Output:
1
2025-04-17 11:15:35,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.383 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (83.4) is better than Ligand B (102.76). Both are below 140, suggesting reasonable oral absorption, but A is closer to the preferred <90 for CNS targets (though not a priority here).

**logP:** Ligand A (1.717) is within the optimal range (1-3). Ligand B (0.431) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=3, HBA=6) are both acceptable, well within the limits of 5 and 10, respectively.

**QED:** Both ligands have similar QED values (A: 0.733, B: 0.663), indicating good drug-like properties.

**DILI:** Ligand A (72.199) has a higher DILI risk than Ligand B (61.07), but both are acceptable.

**BBB:** Both have similar low BBB penetration (A: 43.389, B: 41.838), which isn't a major concern for a non-CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.082 and -5.325), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.881 and -2.662). This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.801 and 0.138), which is excellent.

**Microsomal Clearance:** Ligand A (30.047) has a significantly better microsomal clearance than Ligand B (-19.571). This indicates better metabolic stability for Ligand A, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (5.198) has a better in vitro half-life than Ligand B (-26.208), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.018 and 0.015), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A is the more promising candidate. The primary drivers are its better logP, significantly improved metabolic stability (lower Cl_mic and higher t1/2), and slightly better TPSA. While both have excellent binding affinity and low hERG risk, metabolic stability is crucial for kinase inhibitors, making Ligand A the preferred choice. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the core pharmacokinetic properties of A are superior.

Output:
0
2025-04-17 11:15:35,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 347.499 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.56) is better than Ligand B (47.56), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.718) is within the optimal 1-3 range, while Ligand B (3.149) is at the higher end, potentially raising concerns about off-target effects and solubility.

**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 (0.524 and 0.776 respectively), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (35.479) has a slightly higher DILI risk than Ligand B (7.135), but both are below the concerning threshold of 60. Ligand B is significantly better here.

**BBB:** Ligand A (71.501) has better BBB penetration than Ligand B (64.637), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.75 and -4.641). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar.

**Aqueous Solubility:** Ligand A (-1.811) has better aqueous solubility than Ligand B (-3.161). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG risk (0.544 and 0.612), which is good.

**Microsomal Clearance:** Ligand A (34.661) has lower microsomal clearance than Ligand B (40.716), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-14.774) has a negative half-life, which is not physically possible. This is a major red flag. Ligand B (16.304) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.044 and 0.127).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly better binding affinity than Ligand A (-8.7 kcal/mol). This is a substantial advantage, potentially outweighing some minor ADME concerns.

**Conclusion:**

Despite Ligand A having slightly better solubility and BBB penetration, the significantly better binding affinity of Ligand B, coupled with its superior DILI score, and a *realistic* half-life, makes it the more promising drug candidate. The negative half-life of Ligand A is a critical flaw. While both have poor Caco-2 permeability, the potency advantage of Ligand B is likely to be more impactful in driving forward development.

Output:
1
2025-04-17 11:15:35,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (363.845 and 360.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.59) is better than Ligand B (75.19). Both are acceptable, but lower TPSA generally favors better absorption.

**3. logP:** Both ligands have similar logP values (2.364 and 2.377), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBDs generally improve 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 (0.905) has a significantly higher QED score than Ligand B (0.624), indicating a more drug-like profile.

**7. DILI:** Ligand A (70.686) has a slightly higher DILI risk than Ligand B (67.429), but both are reasonably acceptable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (53.276) has a higher BBB value than Ligand A (36.758), but it's not a deciding factor here.

**9. Caco-2 Permeability:** Ligand A (-4.568) shows better Caco-2 permeability than Ligand B (-5.239). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.327) has better solubility than Ligand B (-3.191). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.535) has a slightly higher hERG inhibition risk than Ligand B (0.35), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (35.219) has a significantly lower microsomal clearance than Ligand A (12.431), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (25.165) has a longer in vitro half-life than Ligand A (12.027), further supporting its improved metabolic stability.

**14. P-gp Efflux:** Ligand A (0.418) has lower P-gp efflux than Ligand B (0.139), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a crucial advantage, especially for enzymes. The 0.5 kcal/mol difference is substantial enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, solubility, Caco-2 permeability, and P-gp efflux, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a significantly stronger binding affinity. Given the enzyme-specific priorities for SRC kinase inhibitors, the improved potency and metabolic stability of Ligand B are more important. The slightly higher DILI risk is acceptable considering the other benefits.

Output:
1
2025-04-17 11:15:35,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.39 and 352.494 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.43) is better than Ligand B (49.41), both are below the 140 threshold for oral absorption.

**3. logP:** Ligand A (1.792) is optimal, while Ligand B (3.308) is approaching the upper limit of the optimal 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 2, both are within the acceptable range of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.815 and 0.715, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (48.623) has a slightly higher DILI risk than Ligand B (19.155), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have high BBB penetration (85.653 and 83.443), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.731) has slightly better Caco-2 permeability than Ligand B (-4.427).

**10. Aqueous Solubility:** Ligand A (-3.064) has slightly better aqueous solubility than Ligand B (-3.703).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.615 and 0.694).

**12. Microsomal Clearance:** Ligand A (1.348) has significantly lower microsomal clearance than Ligand B (24.287), suggesting better metabolic stability. This is a crucial factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (24.382) has a much longer in vitro half-life than Ligand B (-12.917), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.101 and 0.181).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.1 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Conclusion:**

Ligand A is the more promising candidate. While both ligands have good potency and acceptable ADME properties, Ligand A exhibits significantly better metabolic stability (lower Cl_mic and longer t1/2) and slightly better solubility and permeability. These factors are particularly important for an enzyme inhibitor like an SRC kinase inhibitor, as they contribute to a more favorable pharmacokinetic profile and potentially less frequent dosing. The slight advantage in binding affinity further supports this conclusion.

Output:
0
2025-04-17 11:15:35,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.781 and 349.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.5 and 96.25) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (1.861) is within the optimal 1-3 range. Ligand B (0.996) is slightly below, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are both acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.727 and 0.794), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 78.829, which is concerning (high risk). Ligand B has a significantly lower DILI risk of 56.65, placing it in a more acceptable range. This is a significant advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration (36.758 and 80.341). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.965 and -4.595), 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 (-4.587 and -1.848). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.249 and 0.225), which is good.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-9.773), which is *excellent* - indicating very high metabolic stability. Ligand B has a Cl_mic of 2.392, which is less favorable. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a long half-life (81.674 hours), which is desirable. Ligand B has a very short half-life (0.264 hours), which is a major drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.183 and 0.022).

**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 override other factors.

**Conclusion:**

While Ligand A has superior metabolic stability (Cl_mic and t1/2) and comparable binding affinity, its high DILI risk is a major concern. Ligand B, despite having a shorter half-life and slightly lower metabolic stability, has a much lower DILI risk. For an enzyme target like SRC kinase, a manageable toxicity profile is crucial. The solubility issues are a concern for both, but can be addressed through formulation strategies. Given the enzyme-specific priorities, the lower DILI risk of Ligand B outweighs the advantages of Ligand A.

Output:
1
2025-04-17 11:15:35,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.475 and 338.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.86) is better than Ligand B (71.18), both are below the 140 A^2 threshold for good absorption.

**3. logP:** Ligand A (4.237) is slightly higher than the optimal range (1-3), while Ligand B (2.483) is within the optimal range. This favors Ligand B initially.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0), as having at least one HBD can improve solubility.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (7) are both acceptable, below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.654 and 0.655), indicating good drug-likeness.

**7. DILI:** Ligand A (56.921) has a slightly higher DILI risk than Ligand B (59.907), but both are acceptable.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (66.731) is slightly better than Ligand B (57.968).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.076 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 (-4.169 and -2.125), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.547 and 0.581), which is good.

**12. Microsomal Clearance:** Ligand B (41.145) has significantly lower microsomal clearance than Ligand A (63.748), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (54.014) has a much longer in vitro half-life than Ligand A (17.643), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.626 and 0.024), which is favorable.

**15. Binding Affinity:** Ligand B (-8.4 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 factor.

**Overall Assessment:**

Despite both ligands having poor permeability and solubility, Ligand B is the more promising candidate. Its superior metabolic stability (lower Cl_mic and longer t1/2), slightly better binding affinity, and acceptable logP outweigh the minor drawbacks. The poor permeability and solubility would need to be addressed through formulation strategies or further chemical modifications, but the foundational pharmacokinetic properties are better with Ligand B.

Output:
1
2025-04-17 11:15:35,903 - INFO - Batch 32 complete. Total preferences: 512
2025-04-17 11:15:35,903 - INFO - Processing batch 33/512...
2025-04-17 11:16:22,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.312 Da) is slightly higher than Ligand B (348.491 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (83.6) is higher than Ligand B (68.09), but both are well within the acceptable range.

**3. logP:** Both ligands have logP values between 1-3 (Ligand A: 3.268, Ligand B: 3.007), indicating good partitioning properties.

**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 5 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (Ligand A: 0.685, Ligand B: 0.724), indicating a good drug-like profile.

**7. DILI:** Ligand A has a DILI risk of 57.697%, which is approaching the higher risk threshold (>60%). Ligand B has a significantly lower DILI risk of 33.23%, which is well within the acceptable range (<40 is good). This is a significant advantage for Ligand B.

**8. BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (50.717%) and Ligand B (71.19%) are both relatively low, which is fine.

**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 negative values are likely indicating very low permeability. Ligand A (-5.283) is worse than Ligand B (-4.846).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.937) is worse than Ligand B (-2.378).

**11. hERG Inhibition:** Ligand A (0.713) shows a slightly higher hERG inhibition risk than Ligand B (0.146). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (47.949) has a moderate clearance, while Ligand B (42.836) has a slightly lower clearance. Lower is better for metabolic stability, giving a slight edge to Ligand B.

**13. In vitro Half-Life:** Ligand B (-9.439) has a significantly longer in vitro half-life than Ligand A (43.677). This is a major advantage for Ligand B, as it suggests less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.517) has a lower P-gp efflux liability than Ligand B (0.317). Lower is better, so Ligand A is preferable.

**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 substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. A difference of 1.7 kcal/mol is significant.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile. Specifically, its lower DILI risk, longer half-life, and lower hERG inhibition are critical advantages. The poor solubility and permeability of both are concerning, but the significantly better affinity of Ligand A might allow for a lower dose to achieve therapeutic effect, potentially mitigating some of these issues. However, the DILI risk of Ligand A is a significant concern.

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, hERG), and the substantial difference in DILI risk, I would select **Ligand B** as the more viable drug candidate. The stronger binding affinity of Ligand A is attractive, but the higher DILI risk and shorter half-life are major drawbacks that would require extensive optimization.

Output:
1
2025-04-17 11:16:22,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.483 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (108.62) is still acceptable but higher, potentially impacting absorption slightly.

**logP:** Ligand A (3.494) is optimal (1-3). Ligand B (0.762) is a bit low, potentially hindering permeation.

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

**QED:** Both ligands have good QED scores (0.581 and 0.653), indicating drug-likeness.

**DILI:** Ligand A (37.999) has a lower DILI risk than Ligand B (50.174), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.878) is higher than Ligand B (53.587).

**Caco-2 Permeability:** Ligand A (-4.613) is better than Ligand B (-5.244), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.532) is better than Ligand B (-2.524). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG risk (0.478 and 0.257), which is excellent.

**Microsomal Clearance:** Ligand B (42.621) has significantly lower microsomal clearance than Ligand A (80.136), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (11.846 hours) has a longer half-life than Ligand A (26.609 hours). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.285 and 0.032), which is good.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better solubility and a lower DILI risk, Ligand B's substantially stronger binding affinity (-7.5 vs -6.5 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization, but the potency and metabolic stability benefits are more impactful.

Output:
1
2025-04-17 11:16:22,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.415 and 378.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (75.27) is well within the ideal range.

**logP:** Ligand A (-0.426) is a bit low, potentially hindering permeability. Ligand B (2.567) 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 (0.639 and 0.772), indicating drug-likeness.

**DILI:** Ligand A (16.596) has a significantly lower DILI risk than Ligand B (56.572). This is a major advantage for Ligand A.

**BBB:** BBB is less crucial for a non-CNS target like SRC, but Ligand B (71.384) has a higher percentile than Ligand A (28.073).

**Caco-2 Permeability:** Both ligands have the same Caco-2 permeability (-4.961), suggesting similar intestinal absorption potential.

**Aqueous Solubility:** Both ligands have the same aqueous solubility (-1.58), suggesting similar formulation characteristics.

**hERG Inhibition:** Ligand A (0.143) has a much lower hERG inhibition liability than Ligand B (0.53). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand B (27.299) has a lower microsomal clearance than Ligand A (13.715), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.757) has a longer in vitro half-life than Ligand A (4.683), which is desirable.

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.214), suggesting better bioavailability.

**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 of Ligand A. The 1.3 kcal/mol difference is significant.

**Conclusion:**

Despite Ligand B's better logP and metabolic stability, Ligand A is the more promising candidate. The significantly stronger binding affinity (-10.1 vs -8.8 kcal/mol), lower DILI risk, lower hERG inhibition, and lower P-gp efflux outweigh the slightly lower logP and higher clearance. The potency advantage is substantial, and the safety profiles (DILI, hERG) are considerably better for Ligand A.

Output:
0
2025-04-17 11:16:22,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.471 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is slightly higher than Ligand B (49.85), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.564 and 2.629) 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.863) has a significantly better QED score than Ligand B (0.665), indicating a more drug-like profile.

**DILI:** Ligand B (34.781) has a much lower DILI risk than Ligand A (17.836), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (74.758 and 79.721), but this is less crucial for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and indicates poor permeability. Ligand A (-4.894) is slightly worse than Ligand B (-4.103).

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and indicates poor solubility. Ligand A (-3.482) is slightly worse than Ligand B (-2.809).

**hERG:** Ligand A (0.309) has a slightly lower hERG risk than Ligand B (0.513), which is favorable.

**Microsomal Clearance:** Ligand B (86.241) has a significantly higher microsomal clearance than Ligand A (42.071), suggesting lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (16.065) has a longer half-life than Ligand A (-2.735), which is a positive. However, the negative half-life for Ligand A is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.157 and 0.285).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This 0.6 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand B has a better binding affinity and longer half-life. However, Ligand A has a much better QED score, lower microsomal clearance (better metabolic stability), and slightly lower hERG risk. The DILI risk for Ligand B is considerably lower, which is a significant advantage. Both have poor Caco-2 and solubility values. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the better metabolic stability of Ligand A, combined with its better QED and acceptable hERG, makes it the more promising candidate despite the slightly weaker binding affinity. The DILI risk of Ligand B is attractive, but the poor metabolic stability is a major concern.

Output:
0
2025-04-17 11:16:22,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 363.805 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.32) is better than Ligand B (98.14), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.532) is optimal, while Ligand B (0.704) is slightly low, potentially hindering permeation.

**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), both are within the acceptable limit of <=10.

**QED:** Ligand B (0.833) has a significantly better QED score than Ligand A (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (34.742) has a much lower DILI risk than Ligand B (83.792). This is a significant advantage for Ligand A.

**BBB:** Ligand A (55.37) has a better BBB percentile than Ligand B (39.434), but BBB isn't a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.223) is slightly better than Ligand B (-5.371).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.024) is slightly better than Ligand B (-3.185).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.549 and 0.143 respectively). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (16.229) has a higher (worse) microsomal clearance than Ligand B (-3.687). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (25.44) has a significantly longer in vitro half-life than Ligand A (-12.56). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.202 and 0.07 respectively). Ligand B is slightly better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a better QED score, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better P-gp efflux. However, Ligand A has a significantly lower DILI risk, slightly better TPSA, logP, Caco-2 permeability, and aqueous solubility. The binding affinities are essentially the same. Given the enzyme-specific priorities, metabolic stability and half-life are crucial. The lower DILI risk of Ligand A is valuable, but the superior metabolic profile of Ligand B outweighs this benefit.

Output:
1
2025-04-17 11:16:22,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.491 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.43) is slightly above the preferred <140 for good absorption, while Ligand B (78.53) is well within the range.

**logP:** Both ligands have good logP values (1.014 and 0.756), 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 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.636 and 0.773), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (38.465 and 40.287), below the 60 threshold.

**BBB:** Both ligands have low BBB penetration (51.377 and 43.117), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.221 and -5.064), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.229 and -1.502). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.093 and 0.225), which is good.

**Microsomal Clearance:** Ligand B has a negative Cl_mic (-8.207), indicating *very* high metabolic stability, which is a significant advantage. Ligand A has a Cl_mic of 25.988, which is moderate and less desirable.

**In vitro Half-Life:** Ligand B has a negative half-life (-4.961), which is also unusual and suggests extremely high stability. Ligand A has a half-life of 8.628, which is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.013 and 0.027), which is favorable.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-9.3 kcal/mol) than Ligand B (-7.3 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-9.3 vs -7.3 kcal/mol) is a major advantage. The improved affinity could potentially overcome the solubility and permeability issues through formulation strategies or structural modifications. Ligand B's extremely high metabolic stability is attractive, but the weaker binding affinity is a critical disadvantage for an enzyme inhibitor. Given the priorities for enzyme inhibitors (affinity, stability, solubility, hERG), Ligand A is the more promising candidate despite its lower metabolic stability.

Output:
1
2025-04-17 11:16:22,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.398 Da) is slightly lower, potentially aiding permeability, while Ligand B (398.985 Da) is still acceptable.

**TPSA:** Ligand A (85.2) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (66.91) is excellent, suggesting better absorption.

**logP:** Ligand A (2.958) is within the optimal 1-3 range. Ligand B (4.826) is a bit high, potentially leading to solubility issues and off-target effects.

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

**QED:** Both ligands have similar QED values (A: 0.68, B: 0.655), indicating good drug-like properties.

**DILI:** Ligand A (89.415) has a higher DILI risk than Ligand B (72.354), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.57) is slightly better than Ligand A (66.305).

**Caco-2 Permeability:** Ligand A (-4.642) shows poor permeability, which is a significant drawback. Ligand B (-5.124) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.719) has poor aqueous solubility. Ligand B (-5.781) is even worse. This is a concern for both, but more so for B.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.351, B: 0.438), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 85.639, B: 85.286), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (70.052) has a significantly longer in vitro half-life than Ligand A (-11.136), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.304, B: 0.375), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.3 kcal/mol, B: -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't heavily favor one over the other.

**Overall Assessment:**

Ligand B is preferable despite its higher logP and lower solubility. The significantly longer in vitro half-life is a crucial advantage for an enzyme inhibitor, potentially allowing for less frequent dosing. While Ligand A has a slightly better DILI score and TPSA, the poor Caco-2 permeability and very short half-life are major drawbacks. The binding affinity difference is negligible.

Output:
1
2025-04-17 11:16:22,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.809 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is well below the 140 threshold, suggesting good absorption. Ligand B (96.45) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.729) is at the higher end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (-0.248) is significantly below the optimal range and could have permeability problems.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (2 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (0.652 and 0.597), indicating drug-like properties.

**DILI:** Ligand A (93.525) has a high DILI risk, which is a major concern. Ligand B (35.673) has a much lower, and acceptable, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (56.534) and Ligand B (62.156) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.692) has poor predicted permeability. Ligand B (-5.49) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.358) has poor predicted solubility. Ligand B (-0.217) is also poor, but slightly better.

**hERG:** Ligand A (0.161) has a very low hERG risk, which is excellent. Ligand B (0.102) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (40.397) has moderate clearance, suggesting moderate metabolic stability. Ligand B (-5.72) has negative clearance, which is not physically possible and likely indicates a modeling error or outlier. This is a significant red flag.

**In vitro Half-Life:** Ligand A (18.712 hours) has a reasonable half-life. Ligand B (-1.299 hours) has a negative half-life, which is not physically possible and further supports the concern about its data quality.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.222 and 0.002), which is favorable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly better binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower DILI risk, and lower P-gp efflux. However, its negative clearance and half-life values are extremely concerning and suggest issues with the data. Ligand A, while having a high DILI risk and poor solubility/permeability, has more plausible ADME properties. Given the importance of metabolic stability for an enzyme inhibitor, and the implausibility of negative clearance/half-life, I would cautiously favor Ligand A despite its drawbacks, with the understanding that further investigation into the DILI risk is crucial. The data for Ligand B is suspect.

Output:
0
2025-04-17 11:16:22,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (360.376 and 354.466 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (49.85). Both are below the 140 A^2 threshold for good absorption, but Ligand B is better.

**3. logP:** Both ligands have good logP values (2.67 and 2.104), 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 have 3 HBA, well within the acceptable range.

**6. QED:** Both ligands have good QED scores (0.701 and 0.76), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 54.556, while Ligand B has a much lower risk of 10.392. This is a significant advantage for Ligand B.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (97.635) is significantly higher than Ligand A (77.627). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.4 and -4.438), which is unusual and suggests poor permeability. This is a potential concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.18 and -2.319), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.477) has a slightly higher hERG risk than Ligand B (0.73). Lower is better, so Ligand B is preferred.

**12. Microsomal Clearance:** Ligand A (62.015) has higher microsomal clearance than Ligand B (49.466), indicating lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand B (-11.901) has a significantly longer in vitro half-life than Ligand A (3.322). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.171 and 0.144).

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.6). However, the difference is only 0.4 kcal/mol, which is not substantial enough to outweigh the other significant advantages of Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility and permeability, Ligand B demonstrates significantly better ADME properties: lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and better hERG profile. The slightly weaker binding affinity of Ligand B is unlikely to be a critical issue given the other improvements.

Output:
1
2025-04-17 11:16:22,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (379.404 and 359.901 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.55) is higher than Ligand B (47.34). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have acceptable logP values (2.126 and 3.87), falling within the 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but it's not a major issue.

**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:** Ligand A (0.848) has a significantly higher QED score than Ligand B (0.694), indicating a more drug-like profile.

**DILI:** Ligand A (43.195) has a slightly higher DILI risk than Ligand B (13.61), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (88.794 and 78.092), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.591 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 (-3.441 and -3.684), indicating very poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Ligand A (0.146) shows slightly lower hERG inhibition liability than Ligand B (0.834), which is favorable.

**Microsomal Clearance:** Ligand A (26.961) has lower microsomal clearance than Ligand B (37.903), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (8.994 and 9.941 hours).

**P-gp Efflux:** Ligand A (0.143) has lower P-gp efflux liability than Ligand B (0.335), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-9.2 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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -7.7 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also exhibits better metabolic stability (lower Cl_mic), lower P-gp efflux, and lower hERG inhibition. While Ligand A has a slightly higher DILI risk, it's still within an acceptable range. The higher QED score also supports its drug-likeness. The solubility and permeability issues would need to be addressed through formulation strategies or further chemical modifications, but the potency advantage of Ligand A makes it the better starting point.

Output:
0
2025-04-17 11:16:22,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.495 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (57.69 and 58.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (1.615 and 2.406) within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 0 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have QED values (0.818 and 0.795) indicating strong drug-like profiles.

**DILI:** Ligand A has a DILI percentile of 39.473, while Ligand B has 18.418. Ligand B is significantly better regarding liver injury risk.

**BBB:** Both have reasonable BBB penetration, but Ligand A (82.164) is slightly better than Ligand B (76.735). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.43 and -4.844), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.782 and -3.35), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.3 and 0.26). This is good.

**Microsomal Clearance:** Ligand A has a Cl_mic of 53.92, while Ligand B has 15.904. Ligand B exhibits significantly better metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 24.138 hours, while Ligand B has 18.799 hours. Ligand A has a slightly longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.267 and 0.095).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While both compounds suffer from poor solubility and permeability, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a stronger binding affinity. The improved binding affinity is a key advantage for an enzyme inhibitor. The slightly shorter half-life of Ligand B is a minor drawback compared to the benefits. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modifications, but the superior potency and safety profile of Ligand B make it the more promising starting point.

Output:
1
2025-04-17 11:16:22,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.367 and 346.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.7) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (60.25) is well within the optimal range.

**logP:** Ligand A (3.619) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.527) is ideal.

**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 within limits.

**QED:** Ligand B (0.822) has a significantly better QED score than Ligand A (0.489), indicating a more drug-like profile.

**DILI:** Ligand A (83.404) has a high DILI risk, exceeding the 60% threshold. Ligand B (32.571) has a low DILI risk, well below the 40% threshold. This is a major advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 50.446, Ligand B: 83.831). BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.916), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.884 and -2.735), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.692 and 0.242).

**Microsomal Clearance:** Ligand A (106.084) has higher microsomal clearance than Ligand B (67.887), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-9.123) has a longer in vitro half-life than Ligand A (-18.618), suggesting better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.361 and 0.336).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity, Ligand B is significantly better overall. It has a much lower DILI risk, a better QED score, better metabolic stability (lower Cl_mic, longer t1/2), and a more optimal logP value. The poor Caco-2 and solubility values are a concern for both, but the superior ADME-Tox profile of Ligand B outweighs this drawback.

Output:
1
2025-04-17 11:16:22,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.442 and 367.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (55.84) is significantly better than Ligand B (71.53). A TPSA under 90 is generally preferred, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands (2.813 and 2.916) are 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 maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.64) has a better QED score than Ligand B (0.51), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (48.313 and 43.505), both below the 60 threshold.

**BBB:** Ligand A (81.97) has a much higher BBB percentile than Ligand B (42.769). While not a primary concern for a non-CNS target like SRC, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Ligand A (-4.301) has a more negative Caco-2 value, indicating lower permeability than Ligand B (-5.176). This is a negative for Ligand A.

**Aqueous Solubility:** Ligand A (-4.015) has a more negative solubility value, indicating lower solubility than Ligand B (-2.227). This is a significant negative for Ligand A.

**hERG:** Ligand A (0.931) has a lower hERG risk than Ligand B (0.236), which is a positive.

**Microsomal Clearance:** Ligand A (102.928) has a higher microsomal clearance than Ligand B (91.915), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-64.355) has a significantly more negative in vitro half-life than Ligand B (2.367), meaning it has a much shorter half-life and is less stable. This is a major negative for Ligand A.

**P-gp Efflux:** Ligand A (0.513) has a lower P-gp efflux liability than Ligand B (0.192), which is a positive.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage for Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has advantages in TPSA, hERG, and P-gp efflux, these are outweighed by its significantly poorer solubility, metabolic stability (higher clearance, shorter half-life), and, most importantly, weaker binding affinity. The stronger binding affinity of Ligand B (-7.1 kcal/mol) is a substantial advantage for an enzyme target, and can compensate for some of the less favorable ADME properties. The solubility of Ligand B is also better than Ligand A.



Output:
1
2025-04-17 11:16:22,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.371 and 358.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.34 and 99.1) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (though that's not a priority here).

**logP:** Both ligands (0.934 and 0.821) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.811) has a significantly higher QED score than Ligand B (0.626), indicating better overall drug-likeness.

**DILI:** Ligand A (88.833) has a higher DILI risk than Ligand B (12.524). This is a significant negative for Ligand A.

**BBB:** This is less important for a non-CNS target. Ligand A (65.413) and Ligand B (59.131) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.143) has worse Caco-2 permeability than Ligand B (-4.767), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.204) has worse aqueous solubility than Ligand B (-0.811). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.097) has a lower hERG inhibition risk than Ligand B (0.249), which is a positive.

**Microsomal Clearance:** Ligand B (-5.481) has significantly *lower* (better) microsomal clearance than Ligand A (28.488), indicating greater metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-13.504) has a longer in vitro half-life than Ligand A (6.845), further supporting its superior metabolic stability.

**P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux than Ligand B (0.008), which is a slight advantage.

**Binding Affinity:** Both ligands have very similar binding affinities (-10.0 and -8.1 kcal/mol). Ligand A has a slightly better affinity, but the difference is unlikely to outweigh the other factors.

**Conclusion:**

While Ligand A has a slightly better binding affinity and lower hERG risk, Ligand B is the more promising candidate. The significantly lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and better solubility of Ligand B outweigh the minor advantage in binding affinity of Ligand A. The better QED score also supports Ligand B.

Output:
1
2025-04-17 11:16:22,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.515 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is excellent, well below the 140 threshold for oral absorption. Ligand B (117.59) is still acceptable, but less optimal.

**logP:** Ligand A (0.712) is a bit low, potentially impacting permeability. Ligand B (0.533) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is well within acceptable limits. Ligand B (3 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.72 and 0.634), indicating good drug-like properties.

**DILI:** Ligand A (14.424) has a significantly lower DILI risk than Ligand B (65.491), which is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (43.117) is better than Ligand B (36.371).

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

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

**hERG:** Ligand A (0.299) has a very low hERG risk, which is excellent. Ligand B (0.035) is even lower, and also excellent.

**Microsomal Clearance:** Ligand A (33.75) has a higher clearance than Ligand B (-3.415). A negative clearance is not physically possible, so this value is suspect, but it indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (-4.576) has a negative half-life, which is not possible. Ligand B (11.932) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.031).

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

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the most significant difference lies in the DILI and metabolic stability. Ligand A has a much lower DILI risk, and while its clearance is higher than ligand B, ligand B has an impossible negative clearance value. Given the enzyme-specific priorities, the lower DILI risk of Ligand A makes it the more promising candidate, even with the slightly lower logP.

Output:
0
2025-04-17 11:16:22,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (379.287 and 355.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.78) is significantly better than Ligand B (60.15), being well below the 140 threshold for good absorption.

**logP:** Both ligands have logP values (3.837 and 4.234) within the optimal 1-3 range, but Ligand B is slightly higher, potentially increasing off-target effects.

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

**QED:** Both ligands have good QED scores (0.878 and 0.719), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (57.348 and 56.727), both falling in the acceptable range (<60).

**BBB:** Ligand B (75.107) has a higher BBB penetration percentile than Ligand A (68.205), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.803 and -4.921), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.286 and -4.533), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands exhibit low hERG inhibition risk (0.896 and 0.906), which is excellent.

**Microsomal Clearance:** Ligand A (24.197) has significantly lower microsomal clearance than Ligand B (91.376), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (54.361) has a longer in vitro half-life than Ligand B (34.242), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.731 and 0.584), suggesting moderate efflux.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While both ligands have significant drawbacks in solubility and permeability, Ligand B's much stronger binding affinity (-9.1 vs -7.9 kcal/mol) is a decisive factor. The improved affinity is likely to outweigh the solubility/permeability concerns, especially given that formulation strategies can sometimes mitigate these issues. Ligand A's better metabolic stability is appealing, but the difference in binding affinity is too large to ignore.

Output:
1
2025-04-17 11:16:22,737 - INFO - Batch 33 complete. Total preferences: 528
2025-04-17 11:16:22,737 - INFO - Processing batch 34/512...
2025-04-17 11:17:01,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.526 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (16.13) is excellent, well below the 140 threshold, suggesting good absorption. Ligand B (80.56) is higher but still acceptable, though potentially slightly impacting absorption.

**logP:** Ligand A (4.961) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.676) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (0 HBD, 6 HBA) is also reasonable, though the higher HBA count might slightly affect permeability.

**QED:** Both ligands have similar QED values (0.771 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (29.159) has a significantly lower DILI risk than Ligand B (42.575). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.012) has better BBB penetration than Ligand B (78.364), but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.887) is better than Ligand B (-4.939), suggesting slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.458) is better than Ligand B (-0.931), which is a significant advantage for *in vivo* performance.

**hERG Inhibition:** Ligand A (0.916) has a lower hERG risk than Ligand B (0.08), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (42.556) and Ligand B (41.12) are comparable, suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand A (6.622) has a longer half-life than Ligand B (-4.548), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.849) has slightly better P-gp efflux properties than Ligand B (0.075).

**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 minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While its logP is slightly elevated, its significantly better binding affinity, lower DILI risk, better solubility, lower hERG risk, and longer half-life outweigh this minor drawback. Ligand B's low logP is a significant concern for permeability, and its higher DILI and hERG risks are unacceptable.

Output:
0
2025-04-17 11:17:01,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.431 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (96.11 and 91.22) below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (1.095) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.144) is within the optimal 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 (4) are well below the 10 threshold.

**6. QED:** Both ligands have reasonable QED scores (0.718 and 0.632), indicating good drug-like properties.

**7. DILI:** Ligand A (31.369) has a significantly lower DILI risk than Ligand B (6.282), which is a major advantage.

**8. BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (68.941) is slightly higher than A (58.24).

**9. Caco-2 Permeability:** Ligand A (-5.512) has poorer Caco-2 permeability than Ligand B (-4.665), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.152) has slightly better aqueous solubility than Ligand B (-1.845).

**11. hERG Inhibition:** Ligand A (0.129) shows a much lower hERG inhibition liability than Ligand B (0.371), a critical safety parameter.

**12. Microsomal Clearance:** Ligand A (0.24) has significantly lower microsomal clearance than Ligand B (19.944), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.155) has a shorter half-life than Ligand B (10.966), but both are reasonable.

**14. P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.01 and 0.007).

**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 Ligand B has slightly better Caco-2 permeability and half-life, Ligand A boasts a significantly stronger binding affinity, lower DILI risk, lower hERG inhibition, and better metabolic stability (lower Cl_mic). The strong binding affinity of Ligand A is a major driver, and the improved safety profile (DILI and hERG) is crucial. The slightly lower Caco-2 permeability of A is a manageable concern, especially given the potency advantage.

Output:
1
2025-04-17 11:17:01,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.411 and 353.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is slightly higher than Ligand B (61.36). Both are below the 140 A^2 threshold for good absorption, but B is better.

**logP:** Both ligands (1.911 and 2.094) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands (0.905 and 0.878) have excellent drug-likeness scores.

**DILI:** Ligand A (35.634) has a lower DILI risk than Ligand B (42.264), which is preferable. Both are below the 40 threshold.

**BBB:** Ligand A (63.164) has a lower BBB penetration than Ligand B (91.392). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.484) has worse Caco-2 permeability than Ligand B (-4.768). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.541) has better aqueous solubility than Ligand B (-3.071). Solubility is important for enzymes.

**hERG Inhibition:** Ligand A (0.153) has a much lower hERG inhibition risk than Ligand B (0.757). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (6.252) has lower microsomal clearance than Ligand B (47.344), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (52.311) has a longer in vitro half-life than Ligand B (-20.186). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.207). This is slightly better for A.

**Binding Affinity:** Ligand B (-9.3) has a slightly better binding affinity than Ligand A (-8.6). However, the difference is only 0.7 kcal/mol, and can be overcome by better ADME properties.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, better solubility, and lower DILI risk. These are crucial properties for an enzyme inhibitor like an SRC kinase inhibitor. The small difference in binding affinity is outweighed by the substantial advantages in ADME and safety.

Output:
0
2025-04-17 11:17:01,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (376.435 Da) is still well within the acceptable range.

**TPSA:** Ligand A (88.91) is excellent, well below the 140 threshold for oral absorption. Ligand B (133.91) is still reasonable, but approaching the upper limit.

**logP:** Ligand A (1.467) is optimal. Ligand B (-1.899) is a bit low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=6) both fall within acceptable limits.

**QED:** Ligand A (0.817) has a very strong drug-like profile. Ligand B (0.366) is significantly lower, indicating a less favorable overall drug-likeness.

**DILI:** Ligand B (47.926) has a slightly higher DILI risk than Ligand A (32.067), but both are below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with the assay or the compounds themselves. However, we'll proceed with the other parameters.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual. This is a significant concern, as poor solubility can severely limit bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.078 and 0.049 respectively).

**Microsomal Clearance:** Ligand B (-1.266) has a *negative* microsomal clearance, which is physically impossible and suggests a data error. Ligand A (11.63) is reasonable, indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand B (-30.289) has a negative half-life, also indicating a data error. Ligand A (12.312) is a good half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.011 and 0.004 respectively).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the superior candidate. While both have excellent binding affinity, Ligand A has a much better QED score, more reasonable (though still concerning) solubility and clearance data, and avoids the impossible negative values seen for Ligand B's clearance and half-life. The slightly lower logP of Ligand B is a concern, and the negative solubility values for both are problematic, but the data issues with Ligand B are more severe.

Output:
0
2025-04-17 11:17:01,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.46 and 353.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (75.44) as it's closer to the <140 threshold for good absorption.

**3. logP:** Both ligands (2.19 and 2.35) 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 similar QED scores (0.83 and 0.82), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (34.59 and 35.94 percentile), which is good.

**8. BBB:** Ligand B (86.66) shows better BBB penetration than Ligand A (67.70), but this is not a high priority for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.76) has a slightly better Caco-2 permeability than Ligand B (-4.36), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.98) has better aqueous solubility than Ligand B (-2.64). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.11) has a significantly lower hERG inhibition liability than Ligand B (0.42), which is a crucial advantage for safety.

**12. Microsomal Clearance:** Ligand A (24.82) has a much lower microsomal clearance than Ligand B (65.06), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.66) has a positive in vitro half-life, while Ligand B (-28.29) has a negative in vitro half-life, indicating poor stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.12).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.7 kcal/mol), which are both excellent. The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have excellent binding affinity, Ligand A demonstrates superior ADME properties, specifically better solubility, significantly lower hERG risk, and much better metabolic stability (lower Cl_mic and positive half-life). These factors are critical for kinase inhibitors, outweighing the slightly better BBB penetration of Ligand B.

Output:
0
2025-04-17 11:17:01,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 358.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.37) is better than Ligand B (104.03), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (though that isn't a priority here).

**logP:** Both ligands have good logP values (2.622 and 1.077), 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 5 HBA, while Ligand B has 8. Ligand A is preferable here.

**QED:** Both ligands have good QED scores (0.654 and 0.872), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (35.867) has a significantly lower DILI risk than Ligand B (81.776). This is a major advantage for Ligand A.

**BBB:** Not a primary concern for a non-CNS target. Ligand A (76.696) is better than Ligand B (53.083).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.975) is slightly better than Ligand B (-5.221).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.239) is slightly better than Ligand B (-3.318).

**hERG:** Both have low hERG inhibition liability (0.65 and 0.364), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (-32.814) has much lower (better) microsomal clearance than Ligand B (24.362), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (13.424) has a longer half-life than Ligand B (9.499), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.279 and 0.121), which is good. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage for Ligand A, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better QED and P-gp efflux, Ligand A excels in the most critical areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and substantially stronger binding affinity. The slightly better solubility and TPSA of Ligand A are also beneficial. The negative Caco-2 and solubility values are concerning for both, but the potency and metabolic advantages of Ligand A outweigh these drawbacks.

Output:
0
2025-04-17 11:17:01,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.375 and 351.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (111.79 and 114.79) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (-1.786 and -1.127) are slightly on the lower side of the optimal 1-3 range. This *could* be a concern for permeability, but is not a major issue.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 7 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both have good QED scores (0.623 and 0.71), indicating good drug-like properties.

**DILI:** Ligand A (46.452) has a significantly lower DILI risk than Ligand B (79.837). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (54.052) has a higher BBB value than Ligand A (16.479), but this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.14 and -5.036), which is unusual and indicates poor permeability. This is a significant drawback for both compounds.

**Aqueous Solubility:** Both have negative solubility values (-1.218 and -1.93), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.017 and 0.06), which is excellent.

**Microsomal Clearance:** Ligand A (-18.907) has significantly lower (better) microsomal clearance than Ligand B (-14.665), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.044) has a slightly better in vitro half-life than Ligand B (-10.098).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.009 and 0.008).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.5 and -8.7 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is the better candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A demonstrates a significantly lower DILI risk and better metabolic stability (lower Cl_mic, better t1/2). Given the enzyme-specific priorities, metabolic stability and safety (DILI) are paramount. The comparable binding affinity further solidifies this choice.

Output:
0
2025-04-17 11:17:01,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.341 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is better than Ligand B (83.56), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.337 and 1.677, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5/4 HBA, which are acceptable.

**QED:** Ligand A (0.854) has a significantly better QED score than Ligand B (0.662), indicating a more drug-like profile.

**DILI:** Ligand A (84.374) has a higher DILI risk than Ligand B (41.915). This is a significant negative for Ligand A.

**BBB:** Both ligands have high BBB penetration (64.017 and 85.072), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.056) has a worse Caco-2 permeability than Ligand B (-4.347).

**Aqueous Solubility:** Ligand A (-3.594) has worse aqueous solubility than Ligand B (-2.273).

**hERG Inhibition:** Ligand A (0.469) has a slightly higher hERG risk than Ligand B (0.291), but both are relatively low.

**Microsomal Clearance:** Ligand A (3.827) has significantly better microsomal clearance (lower value = better stability) than Ligand B (51.601).

**In vitro Half-Life:** Ligand A (-9.079) has a much longer in vitro half-life than Ligand B (-14.961).

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.035).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has slightly better binding affinity than Ligand B (-7.9 kcal/mol). The difference is 0.8 kcal/mol, which is a reasonable advantage.

**Overall Assessment:**

Ligand A has superior QED, microsomal clearance, and in vitro half-life, and slightly better binding affinity. However, it has significantly higher DILI risk and worse solubility and Caco-2 permeability. Ligand B has a much better safety profile (lower DILI) and better solubility/permeability, but suffers from poorer metabolic stability and a slightly weaker binding affinity.

Given the enzyme-kinase target class, metabolic stability (Cl_mic and t1/2) and safety (DILI, hERG) are crucial. While Ligand A has a slightly better affinity, the significantly higher DILI risk and poorer solubility/permeability are concerning. Ligand B's better safety profile and reasonable ADME properties make it the more promising candidate, despite the slightly lower affinity. The 0.8 kcal/mol difference in affinity can potentially be optimized in later stages of drug development.

Output:
1
2025-04-17 11:17:01,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (393.148 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is well below the 140 threshold, and Ligand B (78.95) is also acceptable.

**logP:** Ligand A (4.446) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.736) is a bit 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 similar QED values (0.783 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (90.461 percentile) than Ligand B (29.391 percentile). This is a major concern for Ligand A.

**BBB:** Both have similar BBB penetration (68.67 and 65.723 percentile). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.536 and -4.3). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close, so the difference isn't huge.

**Aqueous Solubility:** Both have negative solubility values (-5.706 and -2.308). Again, these are on a log scale, and the absolute values are close, but Ligand B is better.

**hERG Inhibition:** Ligand A (0.499) has a slightly higher hERG risk than Ligand B (0.106), but both are relatively low.

**Microsomal Clearance:** Ligand A (77.857 mL/min/kg) has a higher clearance than Ligand B (16.027 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-22.023 hours) has a negative half-life, which is not possible. This is a significant red flag. Ligand A (46.206 hours) is acceptable.

**P-gp Efflux:** Ligand A (0.445) has lower P-gp efflux than Ligand B (0.011), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 1.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the better metabolic stability and P-gp efflux of Ligand A, the significantly higher DILI risk and lower binding affinity make it less attractive. The negative half-life for Ligand B is a major issue, but the superior binding affinity (-8.3 kcal/mol) is a strong advantage. The DILI risk for Ligand B is also much lower. While both have solubility and permeability concerns, Ligand B's potency is compelling enough to warrant further investigation, potentially with formulation strategies to address solubility.

Output:
1
2025-04-17 11:17:01,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.415 and 345.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.12) is significantly better than Ligand B (112.91). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (0.855 and 1.363, respectively), 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:** Ligand A (0.845) has a substantially better QED score than Ligand B (0.594), indicating a more drug-like profile.

**DILI:** Ligand A (25.514) has a much lower DILI risk than Ligand B (60.915). This is a significant advantage for A.

**BBB:**  BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (42.962) is slightly better than Ligand B (39.55).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is lower for Ligand A (-5.408) than for Ligand B (-5.85), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-0.924) is slightly better than Ligand B (-2.576).

**hERG:** Both ligands have very low hERG inhibition liability (0.179 and 0.208), which is excellent.

**Microsomal Clearance:** Ligand A (-7.47) has *much* lower microsomal clearance than Ligand B (33.543). This indicates significantly better metabolic stability for Ligand A, a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand A (-13.706) has a much longer in vitro half-life than Ligand B (4.062), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.083).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity and low hERG risk, Ligand A is significantly superior due to its better QED, much lower DILI risk, substantially improved metabolic stability (lower Cl_mic and longer t1/2), slightly better TPSA and solubility, and a marginally better Caco-2 permeability. These factors are critical for developing a viable drug candidate targeting an enzyme like SRC.

Output:
0
2025-04-17 11:17:01,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.451 Da) is slightly better as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (52.57) is significantly better than Ligand B (91.22). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is higher, potentially hindering absorption.

**logP:** Both ligands have acceptable logP values (A: 2.166, B: 3.257), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 5. Both are acceptable (<=10), but A is slightly preferred.

**QED:** Both have reasonable QED scores (A: 0.831, B: 0.628), indicating good drug-like properties. Ligand A is superior.

**DILI:** Ligand A (35.479) has a much lower DILI risk than Ligand B (57.697). This is a significant advantage for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (71.811) has a higher BBB score, but this isn't crucial here.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both, but the lower TPSA of Ligand A may mitigate this somewhat.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a significant drawback for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.702) has a lower hERG risk than Ligand B (0.751), which is preferable.

**Microsomal Clearance:** Ligand A (-19.942) has a *much* lower (better) microsomal clearance than Ligand B (45.377). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (35.929) has a longer half-life than Ligand A (10.152). This is a positive for Ligand B, but the metabolic stability advantage of Ligand A is more important.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.463, B: 0.197).

**Binding Affinity:** Ligand B (-7.8) 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. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, Ligand A has a superior ADME profile, particularly regarding DILI risk and metabolic stability (Cl_mic). The poor solubility and Caco-2 permeability are concerns for both, but the metabolic advantage of A is critical for an enzyme target. The strong binding of B is tempting, but the higher DILI and clearance suggest it might be quickly eliminated and potentially toxic. Given the enzyme-specific priorities, I favor the compound with better metabolic stability and lower toxicity, even with a weaker binding affinity.

Output:
0
2025-04-17 11:17:01,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.364 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold, while Ligand B (82.97) is also acceptable, though slightly higher.

**logP:** Ligand A (2.081) is optimal (1-3). Ligand B (0.38) is a bit low, potentially hindering permeation.

**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 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.762 and 0.855, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (40.054 and 39.201 percentiles), which is favorable.

**BBB:** Ligand A has a high BBB penetration percentile (91.508), while Ligand B is significantly lower (46.336). While not a primary concern for a kinase inhibitor, higher BBB is generally a plus.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.608 and -4.602). This 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 (-3.042 and -0.984). Again, these are on a log scale and indicate poor solubility. This is a significant concern for enzyme inhibitors, as adequate solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.449) has a very low hERG risk, while Ligand B (0.125) is even lower, both are excellent.

**Microsomal Clearance:** Ligand A (38.396 mL/min/kg) is higher than Ligand B (0.779 mL/min/kg). Lower clearance indicates better metabolic stability, making Ligand B significantly more favorable.

**In vitro Half-Life:** Ligand B (12.778 hours) has a much longer half-life than Ligand A (-2.94 hours). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux than Ligand B (0.027), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity, much improved metabolic stability (lower Cl_mic), and longer half-life are critical advantages for an enzyme inhibitor. While Ligand A has better P-gp efflux and BBB, these are less crucial for a kinase inhibitor compared to potency and metabolic stability. The lower logP of Ligand B is a potential concern, but the superior binding affinity may compensate for this.

Output:
1
2025-04-17 11:17:01,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (377.897 and 354.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is slightly higher than Ligand B (44.81), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (3.12) is within the optimal range (1-3). Ligand B (4.519) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**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 reasonable QED scores (0.889 and 0.758), indicating good drug-like properties.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (34.471). This is a significant concern for Ligand A.

**BBB:** Both have good BBB penetration, but Ligand B (80.031) is slightly better than Ligand A (75.107). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.011) is worse than Ligand B (-4.932).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.635) is slightly worse than Ligand B (-4.189).

**hERG Inhibition:** Ligand A (0.531) has a slightly higher hERG risk than Ligand B (0.948), but both are relatively low.

**Microsomal Clearance:** Ligand B (25.453) has significantly lower microsomal clearance than Ligand A (73.388), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (12.777) has a longer half-life than Ligand A (47.512), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.594) has slightly lower P-gp efflux than Ligand B (0.319), which is a minor advantage.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have some ADME issues (poor Caco-2 and solubility), Ligand B's significantly stronger binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2) make it a much more promising drug candidate for SRC kinase inhibition. The slightly higher logP of Ligand B is a minor concern compared to the substantial advantages it offers.

Output:
1
2025-04-17 11:17:01,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (336.435 and 342.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (66.4), being well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (3.064 and 2.181, respectively) within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is slightly better than Ligand B (0 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and good QED scores (0.852 and 0.844).

**DILI:** Ligand A (56.921) has a slightly higher DILI risk than Ligand B (38.542), but both are acceptable (<60).

**BBB:** Ligand B (86.933) has a much higher BBB penetration percentile than Ligand A (60.333). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of the negative value is similar.

**Aqueous Solubility:** Ligand A (-4.359) has slightly better solubility than Ligand B (-2.633), although both are poor.

**hERG:** Both ligands have very low hERG inhibition liability (0.301 and 0.257).

**Microsomal Clearance:** Ligand A (37.461) has a lower microsomal clearance than Ligand B (44.163), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.723 hours) has a better in vitro half-life than Ligand B (-19.249 hours - a negative value is concerning).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.17 and 0.264).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol) - a difference of 2.0 kcal/mol, which is substantial.

**Conclusion:**

Despite Ligand A having slightly better TPSA, solubility and metabolic stability, the significantly stronger binding affinity of Ligand B (-8.2 vs -6.2 kcal/mol) outweighs these minor ADME differences. The improved binding affinity is crucial for an enzyme target like SRC kinase. While Ligand B's negative half-life is concerning, the potency advantage is substantial enough to prioritize further investigation into that specific issue.

Output:
1
2025-04-17 11:17:01,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.415 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.14 and 71.53) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.084 and 1.782) 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 within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.836 and 0.883), indicating a drug-like profile.

**DILI:** Ligand A (50.33) has a slightly higher DILI risk than Ligand B (44.048), but both are below the concerning threshold of 60.

**BBB:** Both ligands have relatively low BBB penetration (63.901 and 70.609). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.556 and -4.644). These values are unusual and suggest very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.772 and -1.497). This is also a significant drawback, indicating very poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.414 and 0.249). This is positive.

**Microsomal Clearance:** Ligand A (7.391) has significantly lower microsomal clearance than Ligand B (21.832). Lower clearance implies better metabolic stability, which is a high priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-6.123) has a longer in vitro half-life than Ligand B (-13.856). This is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.043). This is favorable.

**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, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, the significantly superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2) of Ligand A make it the more promising candidate. The 1.9 kcal/mol difference in binding affinity is substantial and could potentially be addressed with formulation strategies to mitigate the solubility issues. Ligand B's weaker binding and higher clearance are less desirable.

Output:
0
2025-04-17 11:17:01,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (60.77) is better than Ligand B (67.23).

**logP:** Ligand A (3.247) is optimal, while Ligand B (1.696) is a bit low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have acceptable QED scores (A: 0.902, B: 0.724), indicating good drug-like properties.

**DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (17.759), which is a major advantage.

**BBB:** Ligand B (68.321) shows better BBB penetration than Ligand A (47.111), but this isn't a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-4.895) has a worse Caco-2 permeability score than Ligand B (-5.024).

**Aqueous Solubility:** Ligand A (-3.651) has a better solubility score than Ligand B (-2.265).

**hERG Inhibition:** Ligand A (0.822) has a slightly higher hERG risk than Ligand B (0.061), which is a concern.

**Microsomal Clearance:** Ligand A (24.987) has a significantly lower (better) microsomal clearance than Ligand B (58.357), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-21.7) has a much longer in vitro half-life than Ligand B (14.783), which is highly desirable.

**P-gp Efflux:** Ligand A (0.56) has a lower P-gp efflux liability than Ligand B (0.019), which is favorable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 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 it has a slightly higher hERG risk and lower Caco-2 permeability, its superior binding affinity, significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux outweigh these drawbacks. The strong binding affinity is particularly important for an enzyme inhibitor. Ligand B's lower logP and higher DILI are significant concerns.

Output:
1
2025-04-17 11:17:01,345 - INFO - Batch 34 complete. Total preferences: 544
2025-04-17 11:17:01,345 - INFO - Processing batch 35/512...
2025-04-17 11:17:41,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.391 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.12) is higher than Ligand B (75.71). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Ligand A (0.177) is quite low, potentially hindering permeability. Ligand B (2.117) 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, while Ligand B has 4. Both are within the acceptable limit of 10, but Ligand B is preferable.

**QED:** Ligand A (0.804) has a better QED score than Ligand B (0.645), indicating a more drug-like profile.

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (16.092). This is a substantial advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (70.919 and 70.027), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.962 and -4.565), which is unusual and indicates poor permeability. This is a concern for both, but less so for Ligand B given its better logP.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.096 and -2.032), which is also unusual and indicates poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.207) has a slightly lower hERG risk than Ligand B (0.352), which is preferable.

**Microsomal Clearance:** Ligand A (29.632) has a lower microsomal clearance than Ligand B (72.227), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (41.295) has a longer half-life than Ligand B (-8.162), which is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.099 and 0.056).

**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 for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). While its logP is suboptimal and solubility is poor, the significantly improved potency is a major factor for an enzyme target. Ligand B has better logP, lower DILI risk, and fewer HBA, but its weaker binding affinity is a critical disadvantage. Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity, Ligand A is the more promising candidate despite its ADME liabilities.

Output:
0
2025-04-17 11:17:41,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.5 and 352.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (112.7), being well below the 140 threshold for good absorption.

**logP:** Ligand A (0.968) is slightly better than Ligand B (0.183), both are a bit low, but still acceptable.

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

**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 (0.715 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (34.393) has a significantly lower DILI risk than Ligand B (55.68), which is a major advantage.

**BBB:** Ligand B (70.066) has a better BBB penetration than Ligand A (58.007), but this is less critical for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.117 and -5.152), 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 (-2.031 and -2.661), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.744) has a slightly better hERG profile than Ligand B (0.126), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (30.639) has a significantly better microsomal clearance than Ligand B (0.425), suggesting much better metabolic stability.

**In vitro Half-Life:** Ligand A (-31.163) has a much longer in vitro half-life than Ligand B (-16.137), which is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.132) has lower P-gp efflux than Ligand B (0.011), which is beneficial for bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-9.8 and -9.0 kcal/mol), which are both excellent. The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have similar affinity, Ligand A demonstrates significantly better ADME properties, particularly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slightly better hERG profile is also a plus. The poor Caco-2 and solubility are concerns for both, but are addressable through formulation.

Output:
1
2025-04-17 11:17:41,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (378.881 and 356.394 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.29) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (107.89) is still within acceptable limits, but less favorable than A.

**3. logP:** Ligand A (2.869) is optimal (1-3). Ligand B (0.801) 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:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.715) is excellent, indicating good drug-likeness. Ligand B (0.464) is lower, suggesting a less ideal drug-like profile.

**7. DILI:** Ligand A (70.221) is moderately high, representing a potential concern. Ligand B (23.924) is very good, indicating low liver injury risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (42.924) and B (23.11) are both low.

**9. Caco-2:** Ligand A (-4.926) and B (-5.311) are both negative, indicating poor permeability. This is a significant drawback for both.

**10. Solubility:** Ligand A (-3.937) and B (-1.979) are both negative, indicating poor solubility. This is a significant drawback for both.

**11. hERG:** Ligand A (0.373) is very low risk. Ligand B (0.544) is slightly higher, but still acceptable.

**12. Cl_mic:** Ligand A (91.309) has a higher clearance, suggesting lower metabolic stability. Ligand B (9.328) has much lower clearance, indicating better metabolic stability.

**13. t1/2:** Ligand A (-0.803) has a negative half-life, which is not ideal. Ligand B (-0.511) is also negative, but slightly better.

**14. Pgp:** Both ligands (A: 0.135, B: 0.068) have low P-gp efflux, which is favorable.

**15. Binding Affinity:** Both ligands have excellent 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 better candidate. While both have poor Caco-2 and solubility, Ligand B's significantly lower DILI risk and much better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme target. Ligand A has a better QED and lower hERG risk, but the DILI and metabolic stability concerns are more significant. The slightly better logP of Ligand A is not enough to offset these concerns.

Output:
1
2025-04-17 11:17:41,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.443 and 343.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.69) is significantly better than Ligand B (93.46). A TPSA below 140 is good for oral absorption, and both are within this range, but A is preferable.

**3. logP:** Both ligands have good logP values (1.74 and 1.434), 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 H-bond acceptors (5), which is acceptable (<=10).

**6. QED:** Ligand A (0.901) has a substantially higher QED score than Ligand B (0.756), indicating a more drug-like profile.

**7. DILI:** Ligand A (10.237) has a much lower DILI risk than Ligand B (52.385). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (76.696 and 74.292). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.73 and -4.891). These values are unusual and suggest poor permeability. However, the values are very close, so this isn't a major differentiator.

**10. Aqueous Solubility:** Ligand A (-0.927) is better than Ligand B (-2.815), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.316) has a lower hERG inhibition liability than Ligand B (0.168), which is favorable.

**12. Microsomal Clearance:** Ligand A (4.762) has a significantly lower microsomal clearance than Ligand B (28.624), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (3.385) has a shorter half-life than Ligand B (-3.393). This is a negative for Ligand A, but the difference isn't huge.

**14. P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.123), which is favorable.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a superior QED score, much lower DILI risk, better solubility, lower hERG risk, and significantly better metabolic stability (lower Cl_mic). While Ligand B has a slightly better in vitro half-life, the other advantages of Ligand A outweigh this single benefit. Both have similar binding affinity and acceptable logP/TPSA values. Given the enzyme-specific priorities, the improved metabolic stability and reduced toxicity of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 11:17:41,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.423 and 381.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.05) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (88.91) is excellent, well below 140.

**logP:** Ligand A (-0.868) is a bit low, potentially hindering permeability. Ligand B (2.321) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is good.

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

**QED:** Ligand A (0.475) is marginally below the desirable 0.5 threshold, while Ligand B (0.831) is excellent.

**DILI:** Ligand A (39.511) has a low DILI risk, which is favorable. Ligand B (78.945) has a significantly higher DILI risk, a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (50.446) has a better score than Ligand A (33.656).

**Caco-2:** Both ligands show poor Caco-2 permeability (-5.248 and -5.168). This is a concern for oral bioavailability.

**Solubility:** Both ligands have poor aqueous solubility (-1.135 and -3.684). This could pose formulation challenges.

**hERG:** Ligand A (0.062) shows very low hERG inhibition risk, which is excellent. Ligand B (0.25) also shows low risk, but higher than Ligand A.

**Microsomal Clearance:** Ligand A (2.461) has a lower Cl_mic, suggesting better metabolic stability. Ligand B (6.65) has a higher Cl_mic, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-10.074) has a very long in vitro half-life, which is highly desirable. Ligand B (31.103) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.008) shows very low P-gp efflux, which is favorable. Ligand B (0.213) has a slightly higher P-gp efflux.

**Binding Affinity:** Ligand B (0.0) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from a significantly higher DILI risk, poorer QED, and faster metabolism. Ligand A has a better safety profile (lower DILI, hERG), better metabolic stability, and a longer half-life, but its affinity is much weaker and logP is suboptimal.

Despite the affinity advantage of Ligand B, the high DILI risk is a major red flag. DILI is a common reason for drug development failure. The combination of better safety, metabolic stability, and half-life makes Ligand A the more promising starting point, even with its weaker binding. Optimization efforts can focus on improving its affinity while maintaining the favorable ADME/Tox properties.

Output:
0
2025-04-17 11:17:41,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (352.366 Da) is also good.

**TPSA:** Ligand A (66.71) is significantly better than Ligand B (118.53). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.713) is optimal, while Ligand B (0.012) is very low. A logP close to zero can lead to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.844) has a much higher QED score than Ligand B (0.67), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 50.136, Ligand B: 46.258).

**BBB:** Ligand A (53.354) and Ligand B (77.821) are both relatively low, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.466) is significantly worse than Ligand B (-5.336), indicating lower intestinal absorption. However, this is a relative scale and both are quite poor.

**Aqueous Solubility:** Ligand A (-3.525) is slightly better than Ligand B (-2.038), but both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.215, Ligand B: 0.179).

**Microsomal Clearance:** Ligand A (14.882) has a higher (worse) microsomal clearance than Ligand B (-0.769), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-12.542) has a negative half-life, which is concerning. Ligand B (2.592) is better, but still relatively short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.05, Ligand B: 0.028).

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial difference (2.9 kcal/mol) and is a major advantage.

**Conclusion:**

Despite Ligand A having better TPSA, logP, QED, and solubility, Ligand B's substantially stronger binding affinity (-10.2 vs -7.3 kcal/mol) and better metabolic stability (lower Cl_mic) are critical for an enzyme target like SRC kinase. The improved affinity is likely to outweigh the drawbacks of its higher TPSA and lower logP. The poor Caco-2 and solubility of both compounds are concerns that would need to be addressed in further optimization, but the potency and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 11:17:41,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is slightly higher than the ideal <140, but acceptable. Ligand B (66.92) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.875) is a bit low, potentially hindering permeation. Ligand B (1.916) is within the optimal 1-3 range.

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

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

**QED:** Both ligands have similar QED values (0.796 and 0.706), indicating good drug-likeness.

**DILI:** Ligand A (30.322) has a slightly higher DILI risk than Ligand B (24.622), but both are below the 40 threshold and considered low risk.

**BBB:** Ligand A (49.826) has a lower BBB penetration score, while Ligand B (92.168) is very high. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.16) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.118) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.35 and -1.837). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.141) has a slightly higher hERG risk than Ligand B (0.223), but both are relatively low.

**Microsomal Clearance:** Ligand A (-4.176) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (50.452) has a high clearance, indicating rapid metabolism. This is a major disadvantage.

**In vitro Half-Life:** Ligand A (21.4) has a reasonable half-life. Ligand B (-9.628) has a negative half-life, which is not possible and indicates a significant issue with the data or the compound.

**P-gp Efflux:** Ligand A (0.043) has low P-gp efflux, which is good. Ligand B (0.062) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.3) has significantly better binding affinity than Ligand B (0). A difference of >1.5 kcal/mol is substantial and can outweigh other drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the more promising candidate due to its significantly higher binding affinity (-8.3 kcal/mol vs -0 kcal/mol) and exceptionally high metabolic stability (negative clearance). The lower logP of Ligand A is a concern, but the strong binding affinity can compensate. Ligand B's extremely high clearance and negative half-life are dealbreakers.

Output:
0
2025-04-17 11:17:41,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (368.88 Da) is also good.

**TPSA:** Ligand A (87.04) is better than Ligand B (40.62). Lower TPSA generally improves cell permeability.

**logP:** Both ligands have good logP values (A: 3.762, B: 3.417), falling within the optimal range of 1-3.

**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: 0.753, B: 0.713), indicating good drug-like properties.

**DILI:** Ligand A (69.911) has a higher DILI risk than Ligand B (40.132). This is a significant concern, as a lower DILI risk is highly desirable.

**BBB:** Ligand B (96.355) has a much higher BBB penetration potential than Ligand A (51.415). While SRC is not a CNS target, higher BBB is generally not a negative.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.827 and -4.682). These values are unusual and suggest poor permeability. However, these are likely experimental artifacts or indicate the assay is not suitable for these compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.59 and -4.183). Similar to Caco-2, these are likely problematic assay results.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.728, B: 0.672), which is excellent.

**Microsomal Clearance:** Ligand B (49.804) has significantly lower microsomal clearance than Ligand A (95.637). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (36.882) has a longer in vitro half-life than Ligand B (-14.118). A longer half-life is generally preferred. However, the negative value for Ligand B is suspect.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.411, B: 0.387).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.4 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B is the better candidate. While both have excellent binding affinity, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The negative solubility and Caco-2 values are concerning for both, but may be experimental artifacts. The longer half-life of Ligand A is a plus, but is outweighed by the higher DILI risk and poorer metabolic stability.

Output:
1
2025-04-17 11:17:41,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (332.363 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.68) is better than Ligand B (101.8), both are acceptable but A is preferable.

**logP:** Ligand A (2.657) is optimal (1-3), while Ligand B (0.403) is below 1, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors:** Both have 2 HBD, within the acceptable limit of 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 slightly better.

**QED:** Both ligands have similar QED values (0.769 and 0.676), indicating good drug-likeness.

**DILI:** Ligand A (85.227) has a higher DILI risk than Ligand B (57.387). This is a negative for Ligand A.

**BBB:** Both have low BBB penetration, which is not a major concern for a kinase inhibitor not specifically targeting the CNS. Ligand B (43.777) is slightly better than A (35.983).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.67) has a lower hERG risk than Ligand B (0.057), which is a significant advantage.

**Microsomal Clearance:** Ligand A (14.178) has a lower Cl_mic than Ligand B (28.936), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (33.788) has a longer half-life than Ligand B (-1.768), suggesting slower metabolism and potentially less frequent dosing. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.263) has lower P-gp efflux than Ligand B (0.016), which is preferable.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While it has a higher DILI risk, its significantly superior binding affinity, metabolic stability (lower Cl_mic, longer half-life), lower hERG risk, and better logP outweigh this concern. Ligand B's very low logP is a major drawback, likely leading to poor absorption. Both have poor solubility and permeability, but these can be addressed with formulation strategies. The potency advantage of Ligand A is crucial for an enzyme inhibitor.

Output:
1
2025-04-17 11:17:41,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.383 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.53) is slightly above the preferred <140, but acceptable. Ligand B (79.31) is excellent, well below 140.

**logP:** Ligand A (0.684) is a bit low, potentially hindering permeability. Ligand B (-0.374) is even lower, raising concerns about absorption.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is good. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.476 and 0.54), indicating moderate drug-likeness.

**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 of 25.087, which is excellent.

**BBB:** Both have similar BBB penetration (59.054 and 55.099), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.29 and -4.511), suggesting absorption issues.

**Aqueous Solubility:** Both have negative solubility values (-2.44 and -1.721), indicating very poor aqueous solubility, a significant drawback.

**hERG Inhibition:** Ligand A (0.051) has a very low hERG risk, which is excellent. Ligand B (0.294) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-4.415) and Ligand B (-5.286) both have negative values, which is unusual and likely indicates very slow clearance (high metabolic stability). This is a positive.

**In vitro Half-Life:** Ligand A (10.828) has a reasonable half-life. Ligand B (-5.189) has a negative half-life, which is not physically possible and suggests an issue with the data.

**P-gp Efflux:** Both have very low P-gp efflux (0.008 and 0.075).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly better binding affinity than Ligand B (-8.5 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some ADME liabilities.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.1 vs -8.5 kcal/mol) is a major advantage for an enzyme target like SRC. While Ligand A's DILI risk is higher than Ligand B, it's still within a manageable range. Ligand B's negative in vitro half-life is a red flag suggesting data quality issues or an unstable compound. The better hERG profile of Ligand A is also a plus.

Output:
0
2025-04-17 11:17:41,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.415 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.91 and 72.28) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.193) is optimal, while Ligand B (0.744) is slightly below the ideal range of 1-3. This could potentially impact permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, well within the limits. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.804 and 0.797), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 58.511, considered moderate. Ligand B has a significantly lower DILI risk of 24.855, which is a major advantage.

**BBB:** Ligand A (59.325) and Ligand B (70.997). BBB isn't a primary concern for a non-CNS target like SRC, but higher is generally better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.983 and -4.964). This is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.381 and -1.572), indicating poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.505) has a slightly higher hERG risk than Ligand B (0.137), which is preferable.

**Microsomal Clearance:** Ligand A (29.577 mL/min/kg) has a higher clearance than Ligand B (1.537 mL/min/kg). Lower clearance is better for metabolic stability, giving Ligand B a clear advantage.

**In vitro Half-Life:** Ligand A (-9.15 hours) has a negative half-life, which is not possible. Ligand B (4.126 hours) is a reasonable half-life. The negative value for Ligand A is a red flag.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.088 and 0.027).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). However, the difference is not substantial enough to outweigh other significant drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, Ligand B is the more promising candidate. Ligand B has a significantly lower DILI risk, much better metabolic stability (lower Cl_mic, positive t1/2), lower hERG risk, and a better BBB score. While both have poor solubility and permeability, the metabolic and toxicity profiles of Ligand B are far superior. The negative half-life for Ligand A is a critical issue.

Output:
1
2025-04-17 11:17:41,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.461 and 355.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (66.32). Both are below the 140 threshold for good oral absorption, but not optimized for CNS penetration (which requires <90).

**logP:** Ligand A (2.64) is within the optimal 1-3 range. Ligand B (3.886) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**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 (0.636 and 0.768), indicating drug-like properties.

**DILI:** Ligand A (30.399) has a lower DILI risk than Ligand B (38.503), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand B (90.772) shows better BBB penetration than Ligand A (57.736), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.838 and -4.356). This is unusual and suggests poor permeability. It's likely an artifact of the prediction method or a structural feature causing issues.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.256 and -4.684), indicating very poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.523) has a slightly lower hERG risk than Ligand B (0.677), which is favorable. Both are relatively low, but A is better.

**Microsomal Clearance:** Ligand A (57.704) has lower microsomal clearance than Ligand B (72.594), suggesting better metabolic stability. This is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-23.198) has a significantly *longer* in vitro half-life than Ligand B (-15.456). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux liability than Ligand B (0.263), which is beneficial for oral bioavailability.

**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 some ADME drawbacks.

**Conclusion:**

Despite both ligands having issues with predicted permeability and solubility, Ligand A is the more promising candidate. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux outweigh the slightly less favorable BBB and TPSA values. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the potency and pharmacokinetic advantages of Ligand A make it the better starting point for further optimization.

Output:
0
2025-04-17 11:17:41,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.475 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.96) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (89.35) is still under 140, but less optimal than A.

**logP:** Ligand A (4.08) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-0.543) is significantly below the optimal range, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 6 HBA) is acceptable, but A is better.

**QED:** Both ligands have reasonable QED scores (0.709 and 0.575), indicating good drug-like properties.

**DILI:** Ligand A (80.923) has a higher DILI risk than Ligand B (44.242). This is a significant drawback for A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.566) and Ligand B (46.219) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.829 and -4.714), which is unusual and suggests poor permeability. This is a concerning sign for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.162 and -1.588), indicating very poor aqueous solubility. This is a major issue for both.

**hERG:** Ligand A (0.479) has a lower hERG risk than Ligand B (0.047), which is a positive for A.

**Microsomal Clearance:** Ligand A (27.207) has lower clearance than Ligand B (31.09), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (59.679) has a significantly longer half-life than Ligand B (-22.69), which is a major advantage for A.

**P-gp Efflux:** Ligand A (0.59) has lower P-gp efflux than Ligand B (0.024), which is favorable.

**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).

**Overall Assessment:**

Despite Ligand A's higher DILI risk, it has several advantages: better TPSA, better H-bonding characteristics, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slightly better affinity of Ligand B is unlikely to outweigh the significant drawbacks of its poor metabolic stability, poor permeability, and lower P-gp profile. Both compounds have poor solubility and permeability, which are major hurdles. However, the metabolic stability and half-life of Ligand A are considerably better.

Output:
0
2025-04-17 11:17:41,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (378.885 Da) is also acceptable.

**2. TPSA:** Ligand A (107.4) is better than Ligand B (75.19). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is closer to the 90 A^2 threshold for CNS penetration, although that is not a priority here.

**3. logP:** Both ligands have good logP values (A: 2.92, B: 2.532), 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 within the acceptable limit of <=10.

**6. QED:** Ligand B (0.867) has a significantly better QED score than Ligand A (0.516), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (A: 59.519, B: 60.101), and are both acceptable as they are below 60.

**8. BBB:** Ligand A (72.276) has a better BBB penetration percentile than Ligand B (51.532), but this is not a high priority for a kinase inhibitor.

**9. Caco-2 Permeability:** Ligand A (-4.726) has a worse Caco-2 permeability than Ligand B (-5.093). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.642) has better aqueous solubility than Ligand B (-3.312). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.28, B: 0.156), which is excellent.

**12. Microsomal Clearance:** Ligand B (28.961) has lower microsomal clearance than Ligand A (15.27), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.549) has a longer in vitro half-life than Ligand A (32.526). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.055, B: 0.065).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better QED, solubility, metabolic stability (lower Cl_mic, longer t1/2), and Caco-2 permeability, the significantly stronger binding affinity of Ligand A (-8.2 kcal/mol vs -6.5 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. The slight drawbacks of Ligand A in terms of QED and metabolic stability can be addressed through further optimization, but a strong initial binding affinity is harder to achieve.

Output:
0
2025-04-17 11:17:41,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.362 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (98.74) is better than Ligand B (34.59). While both are acceptable, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.511) is optimal, while Ligand B (4.931) is high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which is good. Ligand B has 0 HBD and 5 HBA, also acceptable, but the lack of HBD might slightly hinder solubility.

**QED:** Ligand A (0.702) has a better QED score than Ligand B (0.583), indicating a more drug-like profile.

**DILI:** Ligand B (35.44) has a significantly lower DILI risk than Ligand A (67.313), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 76.464, Ligand B: 77.705). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also a red flag. Ligand A (-3.194) is slightly better than Ligand B (-5.098).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.215, Ligand B: 0.853). Ligand B is better here.

**Microsomal Clearance:** Ligand A (1.857 mL/min/kg) has much lower microsomal clearance than Ligand B (102.322 mL/min/kg). This indicates better metabolic stability for Ligand A, which is crucial for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (28.771 hours) has a significantly longer half-life than Ligand B (46.66 hours). This is a positive for Ligand A, allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.022, Ligand B: 0.608). Ligand A is better here.

**Binding Affinity:** Both ligands have very strong binding affinities (Ligand A: -9.4 kcal/mol, Ligand B: -8.6 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is significant and can outweigh some of the ADME drawbacks of Ligand B.

**Overall:**

Ligand A has a better overall profile, particularly regarding metabolic stability (Cl_mic, t1/2), QED, and binding affinity. While Ligand B has a lower DILI risk, the significantly higher clearance and lower QED are concerning. The strong binding affinity of Ligand A (-9.4 kcal/mol) is a substantial advantage, and the slightly better solubility and permeability predictions (despite both being poor) further support its selection.

Output:
1
2025-04-17 11:17:41,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.34 and 69.72) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.265) is optimal, while Ligand B (0.752) is slightly below the preferred range, potentially hindering permeation.

**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 (3), well below the limit of 10.

**QED:** Both ligands have good QED scores (0.832 and 0.823), indicating a drug-like profile.

**DILI:** Ligand A (33.695) has a significantly lower DILI risk than Ligand B (70.182), which is a substantial concern.

**BBB:** Both ligands have similar BBB penetration (55.099 and 59.403), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.807) and Ligand B (-4.47) both have negative Caco-2 permeability values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-4.009) and Ligand B (-2.901) both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.355 and 0.252).

**Microsomal Clearance:** Ligand A (49.639) has a higher microsomal clearance than Ligand B (14.55), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-35.801) has a significantly longer in vitro half-life than Ligand A (44.461), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.302 and 0.059).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a 1.8 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk, the significantly stronger binding affinity of Ligand A (-9.3 vs -7.5 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The difference in affinity is large enough to potentially overcome the moderate metabolic liability of Ligand A. The DILI risk for Ligand A is still acceptable. The permeability and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:17:41,726 - INFO - Batch 35 complete. Total preferences: 560
2025-04-17 11:17:41,726 - INFO - Processing batch 36/512...
2025-04-17 11:18:24,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.422 and 340.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.24) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (69.73) is well within the ideal range.

**logP:** Ligand A (2.283) is optimal (1-3). Ligand B (3.464) is slightly higher but still within an acceptable range.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also good, both are <=5.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also good, both are <=10.

**QED:** Ligand B (0.761) has a better QED score than Ligand A (0.487), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (Ligand A: 63.513, Ligand B: 71.113). This is a concern, but we'll consider it in the context of other properties.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (76.735) shows higher BBB penetration than Ligand A (51.105).

**Caco-2 Permeability:** Both show negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.831) is slightly better than Ligand B (-5.165).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (Ligand A: -2.669, Ligand B: -4.223). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.347) has a lower hERG risk than Ligand B (0.918), which is a positive.

**Microsomal Clearance:** Ligand B (46.817) has significantly lower microsomal clearance than Ligand A (6.751), indicating better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (35.769) has a much longer in vitro half-life than Ligand A (-8.736), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux than Ligand B (0.236), which is favorable.

**Binding Affinity:** Ligand B (-9.3 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 both have concerning DILI and solubility issues, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2) and substantially higher binding affinity are critical advantages for an enzyme inhibitor. The better QED score also contributes to its favorability. The slightly higher hERG risk is a concern, but the potency advantage of Ligand B is likely to be more impactful in initial optimization efforts.

Output:
1
2025-04-17 11:18:24,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.45 and 348.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.6) is slightly higher than Ligand B (76.46). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets. This isn't a major concern for a non-CNS target like SRC.

**logP:** Ligand A (0.739) is a bit low, potentially hindering permeation. Ligand B (1.68) is better, falling comfortably within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.73 and 0.849), indicating drug-like properties.

**DILI:** Ligand A (35.79) has a significantly lower DILI risk than Ligand B (46.45), which is a substantial advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (72.63) is slightly higher. This isn't a major factor for SRC.

**Caco-2 Permeability:** Ligand A (-5.255) has a negative Caco-2 value, which is concerning. Ligand B (-4.699) is also negative, but less so. Both suggest poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.817) has slightly better solubility than Ligand B (-2.684).

**hERG:** Ligand A (0.104) has a much lower hERG risk than Ligand B (0.554), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-14.475) has *much* lower microsomal clearance, indicating significantly better metabolic stability than Ligand B (67.643). This is a major positive.

**In vitro Half-Life:** Ligand A (4.915) has a shorter half-life than Ligand B (-22.044), but the negative value for B is suspect and likely indicates a very long half-life.

**P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux than Ligand B (0.192), which is favorable.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-7.9), a difference of 0.6 kcal/mol. While this is a positive for Ligand B, the other ADME properties are more concerning.

**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 for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. The Caco-2 permeability is a concern for both, but the other advantages of Ligand A outweigh this drawback. The slightly lower logP of Ligand A is less concerning than the poor metabolic stability and higher toxicity risks associated with Ligand B.

Output:
0
2025-04-17 11:18:24,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.547 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (103.93). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (4.205) is higher than the optimal 1-3 range, potentially causing solubility issues or off-target effects. Ligand B (0.917) is below the optimal range, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is better balanced. Ligand B has 1 HBD and 8 HBA, which is less ideal.

**QED:** Ligand A (0.58) is better than Ligand B (0.453), indicating a more drug-like profile.

**DILI:** Ligand B (59.907) has a higher DILI risk than Ligand A (31.097), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.143) is better than Ligand B (40.791).

**Caco-2 Permeability:** Ligand A (-4.66) and Ligand B (-5.013) are both poor.

**Aqueous Solubility:** Ligand A (-5.171) is better than Ligand B (-1.373), which is a significant advantage for an enzyme inhibitor.

**hERG:** Ligand A (0.359) is much better than Ligand B (0.114), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (57.793) has lower clearance than Ligand A (82.642), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.479) has a longer half-life than Ligand B (-17.314), which is desirable.

**P-gp Efflux:** Ligand A (0.323) has lower P-gp efflux than Ligand B (0.087), improving bioavailability.

**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 significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A has a more balanced profile overall, with better solubility, lower DILI risk, lower hERG risk, better QED, and a longer half-life. While Ligand B has a slightly better binding affinity, the other ADME properties of Ligand A are significantly more favorable for drug development. The higher logP of Ligand A is a concern, but the other advantages likely outweigh this drawback.

Output:
1
2025-04-17 11:18:24,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.447 and 363.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.19) is excellent, well below the 140 threshold for oral absorption. Ligand B (38.77) is also very good.

**logP:** Ligand A (2.237) is optimal (1-3). Ligand B (3.791) is slightly higher, but still acceptable.

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

**H-Bond Acceptors:** Ligand A (7) is good. Ligand B (4) is also good.

**QED:** Ligand A (0.861) is excellent, indicating high drug-likeness. Ligand B (0.627) is still acceptable, but lower.

**DILI:** Ligand A (47.499) has a moderate DILI risk, but is still preferable. Ligand B (26.018) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (84.141) is higher than Ligand A (57.619).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. This needs further investigation, but 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, a potential formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.68 and 0.677), which is excellent.

**Microsomal Clearance:** Ligand A (26.175) has lower microsomal clearance, indicating better metabolic stability. Ligand B (74.412) has significantly higher clearance, a major drawback.

**In vitro Half-Life:** Ligand A (11.548) has a shorter half-life than Ligand B (24.655), but is still acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.736).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and metabolic stability (lower Cl_mic). However, Ligand B has a much lower DILI risk and a longer half-life. The negative Caco-2 and solubility values for both are concerning and would require experimental validation. Considering the enzyme-specific priorities, metabolic stability and low toxicity are crucial. While Ligand A has slightly better affinity, the significantly lower DILI risk of Ligand B, coupled with its acceptable half-life, makes it the more promising candidate.

Output:
1
2025-04-17 11:18:24,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.441 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold and good for oral absorption. Ligand B (75.88) is still within acceptable limits but higher, potentially impacting absorption slightly.

**logP:** Ligand A (2.919) is optimal (1-3). Ligand B (1.178) is on the lower side, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.782 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (13.804) has a significantly lower DILI risk than Ligand B (35.091). This is a major advantage for Ligand A.

**BBB:** Ligand A (93.563) has a much higher BBB penetration percentile than Ligand B (61.846). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.483 and -4.478), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.484) and Ligand B (-1.304) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.674) has a lower hERG inhibition risk than Ligand B (0.089). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (46.117) has a higher microsomal clearance than Ligand B (20.481), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-23.86) has a negative half-life, which is not physically possible and indicates a data error or unusual behavior. Ligand B (-8.517) also has a negative half-life, indicating a similar issue.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.193 and 0.029).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a crucial advantage, as a 2 kcal/mol difference is substantial.

**Conclusion:**

Despite the shared issues with Caco-2 permeability and solubility, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -7.4 kcal/mol) outweighs the higher microsomal clearance. Furthermore, Ligand A demonstrates a much lower DILI risk and a better hERG profile. The negative half-life values are concerning and would require further investigation, but the potency and safety advantages of Ligand A make it the preferred choice for further development.

Output:
1
2025-04-17 11:18:24,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.333 and 367.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.33) is higher than Ligand B (61.68). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Ligand A (-0.284) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.696) is within the optimal range.

**H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, which is also good.

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

**QED:** Both ligands have similar QED values (0.675 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (47.732) has a slightly higher DILI risk than Ligand B (35.789), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (70.027 and 68.554), but this is less critical for a non-CNS target like SRC.

**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 (0.269) has a slightly higher hERG risk than Ligand B (0.54), but both are relatively low.

**Microsomal Clearance:** Ligand A (0.588) has significantly lower microsomal clearance than Ligand B (28.672), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-40.583) has a much longer in vitro half-life than Ligand B (-3.634). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.099).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a considerably stronger binding affinity than Ligand B (-9.4 kcal/mol). This is a substantial advantage and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly lower logP and higher TPSA, its significantly superior binding affinity (-8.4 vs -9.4 kcal/mol), much lower microsomal clearance, and longer half-life make it the more promising drug candidate. The improved metabolic stability and potency are critical for an enzyme target like SRC kinase. The slightly higher DILI risk is less concerning than the potential for rapid metabolism and lower target engagement with Ligand B.

Output:
1
2025-04-17 11:18:24,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.41 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is slightly higher than Ligand B (78.68). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (0.946 and 1.434), falling within the optimal 1-3 range. Ligand B is slightly better.

**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 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.795 and 0.841), indicating good drug-like properties.

**DILI:** Ligand A (26.871) has a slightly higher DILI risk than Ligand B (23.769), but both are well below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (71.19 and 76.58), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.791) has worse Caco-2 permeability than Ligand B (-4.897). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.394) has slightly better aqueous solubility than Ligand B (-1.907). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.462) has a lower hERG inhibition liability than Ligand B (0.387), which is preferable.

**Microsomal Clearance:** Ligand A (-14.217) has significantly *lower* (better) microsomal clearance than Ligand B (31.548). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-13.059) has a significantly *longer* (better) in vitro half-life than Ligand B (9.158).

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux than Ligand B (0.076), which is preferable.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is small (0.4 kcal/mol), and the affinities are both excellent.

**Conclusion:**

While Ligand B has a slightly better binding affinity and logP, Ligand A is superior due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk. These factors are crucial for an enzyme target like SRC kinase. The slightly lower Caco-2 and solubility of Ligand A are less concerning given the overall profile and the fact that these can be addressed with formulation strategies.

Output:
1
2025-04-17 11:18:24,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (362.308 Da and 380.457 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (104.65 and 98.66) below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (0.504 and 0.66) which are a bit low. Ideally, we want values between 1-3 for optimal permeability. This could be a potential issue for both, but not a dealbreaker if other properties are favorable.

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

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

**6. QED:** Both ligands have reasonable QED scores (0.791 and 0.543), indicating drug-like properties. Ligand A is slightly better.

**7. DILI:** Ligand A (62.737) has a higher DILI risk than Ligand B (47.034). This is a concern for Ligand A.

**8. BBB:** This isn't a high priority for an enzyme target like SRC. Ligand A (63.901) and Ligand B (52.191) are both relatively low.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.937 and -5.546). This is unusual and indicates very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.101 and -2.364), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.135 and 0.236), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-2.638) has a *negative* microsomal clearance, which is impossible. This is a red flag and suggests an issue with the data or the molecule's predicted metabolism. Ligand B (16.883) has a higher clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (-23.314) has a negative half-life, which is impossible. This is another major red flag. Ligand B (-19.616) also has a negative half-life, also a major red flag.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.038), which is favorable.

**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 substantial advantage for Ligand A.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Conclusion:**

Despite the strong binding affinity of Ligand A, the impossible values for Cl_mic and t1/2 are dealbreakers. These indicate a serious problem with the molecule or its predicted properties. Ligand B also has impossible values for Cl_mic and t1/2. Both ligands have poor permeability and solubility. However, Ligand B has a lower DILI risk. Given the impossible values for both, and the slightly lower DILI risk for B, I would cautiously select Ligand B for further investigation, *assuming the negative values are data errors*. The strong affinity of A is tempting, but the negative metabolic parameters are too concerning.

Output:
1
2025-04-17 11:18:24,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (55.89) is significantly better than Ligand B (82.94). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have acceptable logP values (A: 0.526, B: 1.3), falling within the 1-3 range. Ligand B is slightly better here.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have high QED scores (A: 0.805, B: 0.81), indicating good drug-likeness.

**DILI:** Ligand A (5.894) has a much lower DILI risk than Ligand B (54.323). This is a significant advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (70.609) has better BBB penetration than Ligand B (48.158).

**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 (-1.161 vs -2.02), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. The absolute value is smaller for Ligand A (-1.161 vs -2.02), suggesting slightly better solubility.

**hERG Inhibition:** Ligand A (0.281) has a much lower hERG risk than Ligand B (0.124). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (2.955) has a lower Cl_mic than Ligand B (1.415), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (17.87) has a significantly longer half-life than Ligand A (5.006). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.008, B: 0.092).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a major advantage for Ligand B. The 2.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are critical for an enzyme inhibitor. However, it suffers from higher DILI risk, higher TPSA, and a higher hERG risk. Ligand A has better ADME properties across the board (DILI, hERG, TPSA, solubility, permeability, metabolic stability), but its binding affinity is considerably weaker.

Given the importance of potency for kinase inhibitors, the substantial binding affinity advantage of Ligand B is likely to outweigh its ADME liabilities, *provided* those liabilities can be addressed through further optimization. The difference in binding affinity is large enough to make Ligand B the more promising starting point, despite its drawbacks.

Output:
1
2025-04-17 11:18:24,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.4 & 344.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.37) is significantly better than Ligand B (66.48).  A TPSA under 140 is desired for oral absorption, and both meet this, but A is preferable.

**logP:** Both ligands have good logP values (2.368 & 1.899), 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 acceptable QED scores (0.855 & 0.795), indicating good drug-like properties.

**DILI:** Ligand A (54.44) has a higher DILI risk than Ligand B (27.336). This is a significant negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (86.7 & 76.89), but this is less critical for a non-CNS target like SRC.

**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 ligands have negative solubility values, which is also unusual and problematic.  Again, we proceed with caution.

**hERG:** Ligand A (0.545) has a slightly higher hERG risk than Ligand B (0.173). Lower is better here.

**Microsomal Clearance:** Ligand B (12.047) has significantly lower microsomal clearance than Ligand A (44.126), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-11.523) has a negative half-life, which is impossible and indicates a data issue. Ligand A (6.873) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.315) has lower P-gp efflux than Ligand B (0.125), which is favorable.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Despite the questionable solubility and Caco-2 values, Ligand B is the stronger candidate. Its significantly better binding affinity (-10.1 vs -8.5 kcal/mol) and lower microsomal clearance (12.05 vs 44.13) are crucial for an enzyme target. While Ligand A has a better half-life, the affinity difference is substantial. The lower DILI risk for Ligand B is also a positive. The negative half-life for Ligand B is a major concern, but the binding affinity is so much stronger that it may be worth investigating further.

Output:
1
2025-04-17 11:18:24,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.46 and 369.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is significantly better than Ligand B (100.55). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands have good logP values (1.96 and 1.42), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=6). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.866) has a significantly higher QED score than Ligand B (0.651), indicating a more drug-like profile.

**DILI:** Ligand A (31.06) has a much lower DILI risk than Ligand B (69.72). This is a major advantage for Ligand A.

**BBB:** Ligand A (76.15) has a better BBB penetration score than Ligand B (29.39). While not critical for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.664) has a better Caco-2 permeability than Ligand B (-5.02), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.82) has a better aqueous solubility than Ligand B (-3.555).

**hERG Inhibition:** Ligand A (0.369) has a lower hERG inhibition liability than Ligand B (0.406), which is preferable.

**Microsomal Clearance:** Ligand A (24.82) has a significantly lower microsomal clearance than Ligand B (48.62), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.61) has a longer in vitro half-life than Ligand B (13.27), which is desirable.

**P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux liability than Ligand B (0.141).

**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, and the substantial advantages of Ligand A in ADME properties likely outweigh this.

**Conclusion:**

Ligand A is significantly superior to Ligand B. It has better predicted ADME properties across the board (lower DILI, better solubility, permeability, metabolic stability, and lower efflux) and a comparable binding affinity. While Ligand B has slightly better affinity, the overall profile of Ligand A makes it a much more promising drug candidate.

Output:
0
2025-04-17 11:18:24,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.5 and 368.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is better than Ligand B (61.36), being comfortably below the 140 threshold for good absorption.

**logP:** Both have acceptable logP values (2.046 and 3.949), within the 1-3 range. Ligand B is approaching the upper limit, potentially raising concerns about off-target effects, but not critically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 3 HBA). Lower HBDs generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.788 and 0.765), indicating good drug-likeness.

**DILI:** Ligand A (16.751) has a significantly lower DILI risk than Ligand B (46.801). This is a major advantage for Ligand A.

**BBB:** Both have high BBB penetration (88.29 and 83.637), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.772 and -4.793). This is unusual and suggests a potential issue with permeability prediction. Further investigation would be needed.

**Aqueous Solubility:** Ligand A (-1.343) is better than Ligand B (-3.776), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.66 and 0.705), which is good.

**Microsomal Clearance:** Ligand A (23.919) has a significantly lower microsomal clearance than Ligand B (46.82). This suggests better metabolic stability for Ligand A, a crucial factor for enzymes.

**In vitro Half-Life:** Ligand B (30.801) has a longer in vitro half-life than Ligand A (5.504). This is a positive for Ligand B, but the difference might be offset by its higher clearance.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.244 and 0.446).

**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 can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a lower DILI risk, better solubility, and significantly lower microsomal clearance, all critical for an enzyme inhibitor. Its slightly better binding affinity further strengthens its position. While Ligand B has a longer half-life, the superior ADME profile and potency of Ligand A make it the preferred choice. The negative Caco-2 values for both are a concern that needs further investigation, but the other factors strongly favor Ligand A.

Output:
0
2025-04-17 11:18:24,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.411 and 369.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.07) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (97.83) is still acceptable, but less optimal.

**logP:** Ligand A (2.447) is within the optimal 1-3 range. Ligand B (0.369) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**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.

**QED:** Ligand A (0.885) has a significantly better QED score than Ligand B (0.665), indicating a more drug-like profile.

**DILI:** Ligand B (72.082) has a higher DILI risk than Ligand A (41.179). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.535) and Ligand B (23.187) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.578) and Ligand B (-5.061) both have negative values, indicating poor permeability. However, this is a scale and the absolute values are not directly comparable without knowing the scale's range.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.993 and -1.232 respectively). This is a potential issue, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.012 and 0.024), which is excellent.

**Microsomal Clearance:** Ligand A (13.997) has a lower microsomal clearance than Ligand B (9.186), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.436) has a much longer in vitro half-life than Ligand B (4.911), which is a major advantage.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.012 and 0.021).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 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 significantly more favorable overall. Ligand A has a better QED score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable logP. The solubility is a concern for both, but can be addressed. The slightly weaker binding affinity of Ligand A is outweighed by its superior ADME properties and safety profile.

Output:
1
2025-04-17 11:18:24,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.852 Da) is slightly lower, which could be advantageous for permeability. Ligand B (388.515 Da) is also good.

**TPSA:** Ligand A (62.3) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.67) is still acceptable but higher, potentially impacting absorption.

**logP:** Ligand A (2.728) is optimal. Ligand B (-0.02) is concerningly low, potentially leading to poor membrane permeability and bioavailability.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 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.

**QED:** Both ligands have reasonable QED scores (A: 0.832, B: 0.705), indicating good drug-like properties.

**DILI:** Ligand A (33.501) has a significantly lower DILI risk than Ligand B (49.67), which is a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (86.041) has better BBB penetration than Ligand B (56.572).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-5.135) is worse than Ligand B (-5.562), but both are problematic.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.297) is slightly better than Ligand B (-1.657).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.316, B: 0.066). This is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 8.243, B: 8.074). These values are relatively low, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (-4.321) has a significantly longer in vitro half-life than Ligand B (-20.222), which is a substantial advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.074, B: 0.025).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.3 kcal/mol, B: -8.5 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A is significantly better overall. While both have good binding affinity and low hERG risk, Ligand A excels in crucial ADME properties: lower DILI risk, better solubility, and a much longer in vitro half-life. The logP of Ligand B is a major concern, and its Caco-2 permeability is also poor. Ligand A's slightly better TPSA and BBB penetration are additional benefits. The slightly better binding affinity of Ligand A further strengthens its position.

Output:
1
2025-04-17 11:18:24,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.386 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (83.56) is still under 140, but less optimal than A.

**logP:** Ligand A (2.438) is within the optimal 1-3 range. Ligand B (0.743) is slightly below 1, which *could* indicate permeability issues, although not severely.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 5 HBAs. Both are acceptable, but lower is generally preferred.

**QED:** Ligand A (0.848) has a very strong drug-like profile. Ligand B (0.611) is still acceptable, but less desirable.

**DILI:** Ligand A (50.058) has a moderate DILI risk, which is acceptable. Ligand B (27.065) has a lower, and thus better, DILI risk.

**BBB:** Ligand A (83.249) shows reasonable BBB penetration, while Ligand B (47.926) is lower. This is less critical for a non-CNS target like SRC, but still a consideration.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.698 and -4.902), which is unusual and concerning. These values likely indicate poor permeability *in vitro*.

**Aqueous Solubility:** Both have negative solubility values (-3.675 and -1.355), also concerning. These suggest very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.257) has a very low hERG risk, which is excellent. Ligand B (0.195) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (37.217) has a moderate clearance, while Ligand B (1.433) has a *very* low clearance, indicating excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-20.1) has a negative half-life, which is nonsensical. Ligand B (24.782) has a good half-life.

**P-gp Efflux:** Ligand A (0.108) has low P-gp efflux, which is good. Ligand B (0.009) has even lower P-gp efflux, which is excellent.

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and better TPSA, but suffers from a nonsensical half-life and moderate clearance. Its solubility and permeability are also questionable. Ligand B has excellent metabolic stability (very low clearance, good half-life), low P-gp efflux, and a lower DILI risk. However, its binding affinity is weaker, and its logP is a bit low.

Given the enzyme-kinase target class, potency and metabolic stability are paramount. The substantial difference in binding affinity (-8.9 vs -7.8 kcal/mol) is a major factor. While Ligand A's ADME properties are concerning, the strong binding could potentially be optimized with further modifications. The poor solubility and permeability are significant hurdles, but not insurmountable. Ligand B's ADME profile is better, but the weaker binding makes it less likely to be a successful drug candidate without substantial potency improvements.

Output:
1
2025-04-17 11:18:24,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.53 and 372.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (75.71). A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.89 and 2.17), 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, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have reasonable QED scores (0.80 and 0.73), indicating good drug-like properties.

**DILI:** Ligand A (26.48) has a much lower DILI risk than Ligand B (12.64). This is a significant advantage for Ligand A.

**BBB:** Ligand A (78.95) has better BBB penetration than Ligand B (57.23), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.73) has better Caco-2 permeability than Ligand B (-4.82).

**Aqueous Solubility:** Ligand A (-3.22) has better aqueous solubility than Ligand B (-1.37). Solubility is important for bioavailability.

**hERG:** Ligand A (0.92) has a slightly better hERG profile than Ligand B (0.23), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (58.57) has significantly higher microsomal clearance than Ligand B (0.85). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-58.74) has a much shorter in vitro half-life than Ligand B (-3.31). This is a major drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.37) has lower P-gp efflux than Ligand B (0.04).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has advantages in solubility, DILI risk, and BBB, the poor metabolic stability and short half-life are critical drawbacks for an enzyme inhibitor. A longer half-life translates to less frequent dosing and potentially better efficacy. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 11:18:24,866 - INFO - Batch 36 complete. Total preferences: 576
2025-04-17 11:18:24,866 - INFO - Processing batch 37/512...
2025-04-17 11:19:11,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.823 Da) is slightly higher than Ligand B (348.403 Da), but both are acceptable.

**TPSA:** Ligand A (63.99) is significantly better than Ligand B (113.18). Lower TPSA generally improves oral absorption, which is beneficial.

**logP:** Ligand A (3.026) is optimal, while Ligand B (0.82) is a bit low, potentially hindering permeation.

**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 similar QED values (A: 0.734, B: 0.602), indicating reasonable drug-likeness.

**DILI:** Ligand A (82.59) has a higher DILI risk than Ligand B (53.858). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.227) and B (48.313) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.748) is better than Ligand B (-5.308), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.237) is better than Ligand B (-2.04), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.753) has a lower hERG risk than Ligand B (0.095). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (48.896) has higher clearance than Ligand B (33.102), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-22.019) has a significantly longer half-life than Ligand A (43.783), which is a major advantage.

**P-gp Efflux:** Ligand A (0.605) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 kcal/mol and -8.5 kcal/mol, respectively). The difference is negligible.

**Conclusion:**

While Ligand A has better TPSA, logP, solubility, Caco-2 permeability, and P-gp efflux, it suffers from higher DILI risk and lower metabolic stability (higher clearance, shorter half-life). Ligand B, despite having a slightly lower logP and higher TPSA, exhibits a much better safety profile (lower DILI) and significantly improved metabolic stability (longer half-life). Given the enzyme-specific priorities, the longer half-life and lower DILI risk of Ligand B are more important than the slight advantages of Ligand A in other parameters, especially considering the comparable binding affinities.

Output:
1
2025-04-17 11:19:11,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (400.28 and 391.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.53) is significantly better than Ligand B (110.53).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Ligand A (3.338) is optimal, while Ligand B (1.243) is on the lower side. While not a hard cutoff, lower logP can sometimes indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=2, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.714 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A (72.392) is better than Ligand B (86.933) in terms of DILI risk, indicating a lower potential for liver injury. Both are acceptable, but A is preferred.

**BBB:** Ligand A (88.639) has a better BBB percentile than Ligand B (55.913). While SRC isn't a CNS target, higher BBB is generally a positive indicator of reduced off-target effects.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.984 and -5.195), which is unusual and suggests a potential issue with permeability prediction. This needs further investigation, but it's a flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.524 and -3.438), which is also unusual and suggests a potential issue with solubility prediction. This needs further investigation, but it's a flag for both.

**hERG:** Ligand A (0.746) is better than Ligand B (0.224), indicating a lower risk of hERG inhibition and cardiotoxicity. This is a critical factor.

**Microsomal Clearance:** Ligand A (54.207) has a higher (worse) microsomal clearance than Ligand B (41.477), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-16.471) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand A (52.211) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.397 and 0.207).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.6 kcal/mol). The difference is minimal and unlikely to be decisive.

**Overall Assessment:**

Ligand A is generally superior. It has better TPSA, logP, DILI, BBB, and hERG inhibition profiles. While its microsomal clearance is worse than Ligand B, the other advantages, particularly the lower hERG risk, outweigh this drawback. The negative Caco-2 and solubility values are concerning for both, but the other parameters favor A. The negative half-life for Ligand B is a major red flag.

Output:
0
2025-04-17 11:19:11,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.478 and 350.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for good absorption, and is favorable. Ligand B (87.66) is still under 140, but less optimal.

**logP:** Ligand A (3.285) is within the optimal range of 1-3. Ligand B (1.26) is on the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is excellent. Ligand B (HBD=3, HBA=4) is acceptable, but higher than A.

**QED:** Both ligands have similar QED values (0.799 and 0.615), indicating good drug-likeness.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (21.946), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (96.045) is much higher than Ligand B (44.203).

**Caco-2 Permeability:** Ligand A (-4.572) is better than Ligand B (-5.375), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.877) is better than Ligand B (-2.426).

**hERG:** Ligand A (0.604) has a lower hERG risk than Ligand B (0.222), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (43.834) has higher metabolic stability (lower clearance) than Ligand B (4.911).

**In vitro Half-Life:** Ligand A (-2.493) has a longer half-life than Ligand B (31.323).

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.058).

**Binding Affinity:** Ligand B (-10.0) has a substantially stronger binding affinity than Ligand A (-6.8). This is a very significant advantage, potentially outweighing some of the ADME drawbacks of Ligand B. A difference of 3.2 kcal/mol is substantial.

**Overall Assessment:**

While Ligand A has superior ADME properties across the board (solubility, permeability, metabolic stability, safety), Ligand B's binding affinity is significantly stronger. For an enzyme target like SRC kinase, potency is paramount. The 3.2 kcal/mol difference in binding affinity is substantial enough to favor Ligand B, even with its less ideal ADME profile. Optimization of Ligand B could address the ADME concerns while retaining its strong potency.

Output:
1
2025-04-17 11:19:11,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.809 Da and 345.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.88) is better than Ligand B (121.3), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (0.787) is slightly better than Ligand A (0.273), as it's closer to the optimal 1-3 range. Ligand A is quite low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 8 HBA) is preferable to Ligand B (2 HBD, 7 HBA) as it has fewer hydrogen bond donors. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.68 and 0.711), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (70.182 and 72.47), which is moderately high. This is a concern for both, but not a deciding factor at this stage.

**BBB:** Ligand A (68.748) has a better BBB percentile than Ligand B (48.119). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.82) has a worse Caco-2 permeability than Ligand B (-5.092). Both are poor.

**Aqueous Solubility:** Ligand A (-2.651) has better solubility than Ligand B (-3.386). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.103 and 0.054). This is excellent.

**Microsomal Clearance:** Ligand B (51.453) has significantly lower microsomal clearance than Ligand A (67.119), suggesting better metabolic stability. This is a significant advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-16.56) has a negative half-life, which is not possible. This is a major red flag and indicates a problem with the data or the compound itself. Ligand A (12.689) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.015 and 0.066).

**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, potentially outweighing some ADME concerns.

**Conclusion:**

Despite Ligand B's better metabolic stability, the negative in vitro half-life is a critical flaw. It suggests either a data error or a rapidly degrading compound. Ligand A, while having a lower logP and slightly higher DILI, possesses a significantly stronger binding affinity and a reasonable half-life. For an enzyme target like SRC kinase, potency is paramount. The solubility of Ligand A is also better.

Output:
1
2025-04-17 11:19:11,117 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (399.705 and 369.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.78) is significantly better than Ligand B (84.86).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (4.31) is slightly higher than the optimal range (1-3), while Ligand B (2.599) is within the ideal range. High logP can lead to solubility issues and off-target effects, but is less critical than affinity.

**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 similar QED values (0.782 and 0.735), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (54.634 and 57.929), and are within an acceptable range (<60 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.815) is better than Ligand B (44.591).

**Caco-2 Permeability:** Ligand A (-4.961) and Ligand B (-5.497) both have negative values, suggesting poor permeability. This is a concern for oral bioavailability.

**Aqueous Solubility:** Ligand A (-4.632) and Ligand B (-2.167) both have negative values, indicating poor solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.94) is better than Ligand B (0.028), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (49.04) has a higher clearance than Ligand B (-7.306). Lower clearance is preferred for better metabolic stability, making Ligand B more favorable.

**In vitro Half-Life:** Ligand A (-10.484) has a shorter half-life than Ligand B (12.286). Longer half-life is desirable, favoring Ligand B.

**P-gp Efflux:** Ligand A (0.597) is better than Ligand B (0.012), indicating lower P-gp efflux.

**Binding Affinity:** Ligand A (-11.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns. A difference of >1.5 kcal/mol is considered significant.

**Conclusion:**

Despite Ligand A having a higher logP and poorer solubility and permeability, its significantly stronger binding affinity (-11.2 vs -9.3 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The improved metabolic stability (lower Cl_mic, longer half-life) and lower P-gp efflux of Ligand B are beneficial, but the substantial difference in binding affinity makes Ligand A the more promising candidate. Further optimization could focus on improving the solubility and permeability of Ligand A while maintaining its potent binding.

Output:
1
2025-04-17 11:19:11,117 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.434 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.53) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (63.57) is well within the ideal range.

**logP:** Both ligands have good logP values (0.974 and 1.439), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED scores (0.733 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 68.205, which is moderately high. Ligand B has a significantly lower DILI risk (19.504), a major advantage.

**BBB:** Ligand A has a BBB penetration of 48.275, while Ligand B has 85.343. While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.525 and -4.735). 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 base of the log.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.34 and -1.987), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.453 and 0.423), which is excellent.

**Microsomal Clearance:** Ligand A has a very low (and good) microsomal clearance (-20.862), indicating high metabolic stability. Ligand B has a clearance of 8.055, which is moderate and less favorable than Ligand A.

**In vitro Half-Life:** Ligand A has a half-life of 25.804 hours, which is good. Ligand B has a shorter half-life of 8.897 hours.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.048 and 0.124), which is favorable.

**Binding Affinity:** Ligand A has a stronger binding affinity (-8.8 kcal/mol) compared to Ligand B (-7.5 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.8 vs -7.5 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target like SRC kinase. The lower DILI risk of Ligand B is attractive, but the substantial affinity advantage of Ligand A is more important. Further optimization would be needed to improve solubility and permeability for either compound.

Output:
0
2025-04-17 11:19:11,117 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [362.451, 76.66, 3.175, 2, 5, 0.827, 71.384, 55.642, -4.9, -3.387, 0.406, 81.62, -23.564, 0.108, -8.2]
**Ligand B:** [345.403, 80.03, 0.648, 0, 6, 0.805, 47.77, 65.956, -4.617, -1.75, 0.158, 22.389, 1.016, 0.039, -8.6]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (362.451) is slightly higher than B (345.403), but both are acceptable.
2. **TPSA:** A (76.66) is better than B (80.03), both are still acceptable for an enzyme target.
3. **logP:** A (3.175) is optimal, while B (0.648) is quite low, potentially hindering permeability. This is a significant drawback for B.
4. **HBD:** A (2) is good, B (0) is also acceptable.
5. **HBA:** A (5) is good, B (6) is also acceptable.
6. **QED:** Both A (0.827) and B (0.805) have excellent drug-likeness scores.
7. **DILI:** A (71.384) is higher than B (47.77), indicating a slightly increased risk of liver injury, but still within a reasonable range. B is preferable here.
8. **BBB:** Not a primary concern for a non-CNS target like SRC, but B (65.956) is slightly better than A (55.642).
9. **Caco-2:** Both are negative, indicating poor permeability. This is a concern for both.
10. **Solubility:** A (-3.387) is worse than B (-1.75), indicating lower solubility. This is a drawback for A.
11. **hERG:** A (0.406) is better than B (0.158), indicating lower hERG inhibition risk. This is a significant advantage for A.
12. **Cl_mic:** A (81.62) is significantly higher than B (22.389), meaning A has much faster metabolic clearance and lower metabolic stability. This is a major drawback for A.
13. **t1/2:** A (-23.564) is much worse than B (1.016), indicating a very short half-life for A. This is a critical disadvantage for A.
14. **Pgp:** A (0.108) is better than B (0.039), indicating lower P-gp efflux.
15. **Affinity:** B (-8.6) is slightly better than A (-8.2), but the difference is relatively small.

**Enzyme-Kinase Specific Priorities:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

*   **Affinity:** B has a slightly better affinity, but it's not a huge difference.
*   **Metabolic Stability:** B is *significantly* better (lower Cl_mic, longer t1/2).
*   **Solubility:** B is better.
*   **hERG:** A is better.

**Conclusion:**

Despite A having a slightly better hERG profile and Pgp efflux, the significantly worse metabolic stability (high Cl_mic, short t1/2) and lower solubility of A are major drawbacks. The low logP of B is concerning, but the superior metabolic stability and solubility are more critical for an enzyme inhibitor. The slightly better affinity of B further supports its selection.

Therefore, **Ligand B** is the more viable drug candidate.

1
2025-04-17 11:19:11,117 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (71.09), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.398) is within the optimal 1-3 range, while Ligand B (3.301) is at the higher end, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.834) has a significantly better QED score than Ligand B (0.696), indicating a more drug-like profile.

**DILI:** Ligand A (16.673) has a much lower DILI risk than Ligand B (34.393), which is a significant advantage.

**BBB:** Ligand A (70.027) shows better BBB penetration than Ligand B (53.897), although SRC is not a CNS target, this isn't a major negative.

**Caco-2 Permeability:** Ligand A (-4.733) is better than Ligand B (-5.093), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.73) is better than Ligand B (-3.392). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.102) has a much lower hERG inhibition risk than Ligand B (0.411), a critical safety parameter.

**Microsomal Clearance:** Ligand A (28.865) has a lower microsomal clearance than Ligand B (51.874), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.22) has a better in vitro half-life than Ligand B (8.105).

**P-gp Efflux:** Ligand A (0.01) has a lower P-gp efflux liability than Ligand B (0.341), improving bioavailability.

**Binding Affinity:** Ligand B (-7.5 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 numerous ADME advantages of Ligand A.

**Overall:** Ligand A consistently outperforms Ligand B across most critical ADME properties (DILI, solubility, hERG, metabolic stability, permeability, QED) while maintaining a very competitive binding affinity. The slightly weaker binding affinity of Ligand A is likely surmountable with further optimization, whereas addressing the ADME liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 11:19:11,118 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.487 Da and 374.819 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.4) is slightly above the preferred <140 for good absorption, while Ligand B (76.02) is well within the range.

**logP:** Ligand A (0.873) is a bit low, potentially hindering permeation. Ligand B (2.056) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, which are acceptable.

**QED:** Ligand A (0.749) has a better QED score than Ligand B (0.513), suggesting a more drug-like profile.

**DILI:** Ligand B (48.468) has a higher DILI risk than Ligand A (35.556), but both are below the concerning threshold of 60.

**BBB:** Ligand B (83.443) has significantly better BBB penetration potential than Ligand A (40.52), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.244) has poor Caco-2 permeability, while Ligand B (-4.916) is also poor but slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-3.188) is slightly better than Ligand A (-1.292).

**hERG Inhibition:** Ligand A (0.095) has a very low hERG risk, which is excellent. Ligand B (0.26) is also low, but slightly higher.

**Microsomal Clearance:** Ligand B (32.541) has a significantly better microsomal clearance profile (lower clearance = better stability) than Ligand A (0.587).

**In vitro Half-Life:** Ligand B (4.079) has a longer in vitro half-life than Ligand A (8.338).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.123 respectively).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A's better QED and lower hERG risk, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.7 kcal/mol vs 0.0 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, Ligand B demonstrates better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility. While both have poor Caco-2 permeability, the potency advantage of Ligand B is likely to be more impactful in driving overall efficacy.

Output:
1
2025-04-17 11:19:11,118 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.387 and 366.849 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand B (85.77) is significantly better than Ligand A (116.4), being well below the 140 threshold for oral absorption.

**logP:** Ligand B (0.378) is within the optimal 1-3 range, while Ligand A (-0.13) is slightly below 1, potentially hindering permeation.

**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:** Ligand B (0.786) has a much better QED score than Ligand A (0.396), indicating a more drug-like profile.

**DILI:** Ligand B (28.461) has a significantly lower DILI risk than Ligand A (55.758), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.862) and Ligand B (30.787) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.507 and -5.025), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.6 and -1.618), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand B (0.113) has a much lower hERG inhibition liability than Ligand A (0.029), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-43.083) has a much lower (better) microsomal clearance than Ligand A (-10.971), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (23.785 hours) has a longer half-life than Ligand A (13.21 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.012).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is significantly better across most crucial ADME-Tox properties. It has a better QED score, lower DILI risk, lower hERG inhibition, significantly lower microsomal clearance, and a longer half-life. While both have poor Caco-2 and solubility, the other advantages of Ligand B outweigh this concern, especially given the slightly better binding affinity. Ligand A's lower logP and higher DILI risk are significant drawbacks.

Output:
1
2025-04-17 11:19:11,118 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (360.523 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is well below the 140 threshold and favorable for oral absorption. Ligand B (83.36) is still within acceptable limits, but less optimal.

**3. logP:** Both ligands have good logP values (2.353 and 1.377), falling within the 1-3 range.

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

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable range of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.74 and 0.63), indicating good drug-likeness.

**7. DILI:** Ligand A (31.33) has a significantly lower DILI risk than Ligand B (12.059), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.846) is lower than Ligand B (38.891).

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.377) is slightly better than Ligand B (-5.001).

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.323) is slightly better than Ligand B (-1.103).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.156 and 0.154).

**12. Microsomal Clearance:** Ligand A (39.158) has higher microsomal clearance than Ligand B (7.837), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (26.095) has a much longer in vitro half-life than Ligand A (6.529), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.081).

**15. Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.4), but the difference is small (0.3 kcal/mol).

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better DILI score and slightly better Caco-2/Solubility, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2) is crucial for an enzyme target like SRC kinase. The small difference in binding affinity is outweighed by the substantial difference in metabolic stability. The slightly higher TPSA of Ligand B is not a major concern.

Output:
1
2025-04-17 11:19:11,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.869 and 354.441 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (58.56 and 58.2) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (4.771) is slightly higher than Ligand B (3.323). While both are above the optimal range of 1-3, Ligand A's value is approaching a level where solubility issues might arise.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBDs, which is acceptable. Ligand A has 3 HBAs, and Ligand B has 2. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.698 and 0.689), indicating good drug-likeness.

**DILI:** Ligand A (53.936) has a higher DILI risk than Ligand B (32.067). This is a significant concern, as lower DILI is preferred.

**BBB:** Ligand A (17.798) has a very low BBB penetration, while Ligand B (84.064) has a high BBB penetration. Since SRC is not a CNS target, BBB is not a primary concern, but higher BBB can sometimes correlate with off-target effects.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.962 and -4.7), which is unusual and suggests poor permeability. This is a major red flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.13 and -4.064), also very concerning, indicating very poor solubility.

**hERG Inhibition:** Ligand A (0.778) has a slightly higher hERG inhibition risk than Ligand B (0.582), but both are reasonably low.

**Microsomal Clearance:** Ligand B (37.39 mL/min/kg) has significantly lower microsomal clearance than Ligand A (93.587 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-10.103 hours) has a negative half-life, which is impossible. This is a data error and a major concern. Ligand A has a half-life of 27.16 hours.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.637 and 0.163).

**Binding Affinity:** Both ligands have very similar binding affinities (-9.0 and -8.5 kcal/mol), which are both excellent and strong.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is a critical data issue that needs to be resolved, but assuming it is a data error, the other ADME properties favor Ligand B. The poor Caco-2 and solubility for both are concerning and would require significant optimization, but the metabolic stability and safety profile of Ligand B are more favorable.

Output:
1
2025-04-17 11:19:11,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.431 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (116.42 and 113.44) are below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.023) is very close to 0, which is a slight concern for permeability. Ligand B (-0.102) is also low, but marginally better.

**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 6. Both are within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED scores (0.689 and 0.565, both >=0.5).

**DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (56.689). While both are above the ideal <40, Ligand B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (52.85) and Ligand B (45.56) are both low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.346 and -5.457), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.523 and -1.638), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.139 and 0.111). This is excellent.

**Microsomal Clearance:** Ligand A (-5.935) has a *much* lower (better) microsomal clearance than Ligand B (2.569). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-49.152) has a much longer in vitro half-life than Ligand B (15.332), further supporting its superior metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.019).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the poor Caco-2 and solubility predictions for both, Ligand A is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic and longer t1/2) outweighs the slightly higher DILI risk and marginally lower logP. The binding affinity is essentially the same. The poor permeability and solubility are concerning and would require further investigation (e.g., salt formation, formulation strategies), but the metabolic advantage of Ligand A is crucial for an enzyme inhibitor.

Output:
1
2025-04-17 11:19:11,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.415 and 339.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.29) is slightly higher than Ligand B (56.15). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**3. logP:** Ligand A (0.89) is within the optimal 1-3 range. Ligand B (3.55) is at the higher end, potentially leading to solubility issues and off-target interactions, 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 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.799) has a better QED score than Ligand B (0.646), indicating a more drug-like profile.

**7. DILI:** Ligand A (54.323) has a slightly higher DILI risk than Ligand B (36.642), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 72.005, Ligand B: 71.229), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.817) has slightly better Caco-2 permeability than Ligand B (-4.773).

**10. Aqueous Solubility:** Ligand A (-1.547) has better aqueous solubility than Ligand B (-3.933). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.176) has a much lower hERG inhibition risk than Ligand B (0.696). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (48.769) has lower microsomal clearance than Ligand B (70.074), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.613) has a longer in vitro half-life than Ligand B (-11.425). This is a major advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux than Ligand B (0.607), leading to better bioavailability.

**15. Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-0.0). This is a very significant advantage.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better TPSA, Ligand A excels in almost every other critical parameter, especially binding affinity, metabolic stability (lower Cl_mic, longer t1/2), solubility, hERG risk, and P-gp efflux. The substantial difference in binding affinity (-7.1 vs -0.0 kcal/mol) is a decisive factor, outweighing any minor drawbacks. The improved ADME properties of Ligand A further solidify its potential as a viable drug candidate.

Output:
1
2025-04-17 11:19:11,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.32 Da) is slightly higher than Ligand B (346.515 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, indicating good potential for oral absorption. Ligand A (47.56) is higher than Ligand B (40.62).

**logP:** Both ligands have logP values between 3 and 4, which is good. Ligand A (4.103) is slightly higher than Ligand B (3.739).

**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 QED values above 0.5, indicating good drug-likeness. Ligand A (0.753) is slightly better than Ligand B (0.704).

**DILI:** Ligand B (15.083) has a significantly lower DILI risk than Ligand A (45.25). This is a major advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (91.392) has higher BBB penetration than Ligand A (55.021), but this is less critical.

**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 misleading. We'll consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Similar to Caco-2, these values need to be interpreted cautiously.

**hERG Inhibition:** Ligand A (0.849) has a higher hERG inhibition risk than Ligand B (0.575). This is a concern for Ligand A.

**Microsomal Clearance:** Ligand B (80.527 mL/min/kg) has a lower microsomal clearance than Ligand A (102.452 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (1.205 hours) has a slightly longer half-life than Ligand A (23.287 hours). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.418) has lower P-gp efflux than Ligand B (0.333), which is slightly better.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a crucial advantage for Ligand B, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. It has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG inhibition. While both have issues with Caco-2 and solubility, the substantial improvement in potency and safety profile of Ligand B makes it the more promising drug candidate.

Output:
1
2025-04-17 11:19:11,120 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.445 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.27) is better than Ligand B (96.89). Lower TPSA generally improves absorption. Ligand A is well below the 140 threshold.

**logP:** Ligand A (2.971) is optimal, while Ligand B (0.598) is quite low. A logP below 1 can hinder permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3 respectively), below the threshold of 5.

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

**QED:** Both ligands have the same QED score (0.621), indicating good drug-likeness.

**DILI:** Ligand A (45.25) has a slightly higher DILI risk than Ligand B (27.181), but both are below the concerning threshold of 60.

**BBB:** Ligand A (87.631) shows better BBB penetration than Ligand B (41.838), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.543) is better than Ligand B (-5.119), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.188) is better than Ligand B (-2.139), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.36 and 0.272 respectively).

**Microsomal Clearance:** Ligand A (27.778) has lower microsomal clearance than Ligand B (31.882), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.197) has a much longer in vitro half-life than Ligand B (10.369), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.035 respectively).

**Binding 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 needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a slightly better binding affinity. However, Ligand A has substantially better logP, solubility, metabolic stability (lower Cl_mic and longer t1/2), and Caco-2 permeability. The lower logP of Ligand B is a significant concern for oral bioavailability. The improved metabolic stability and solubility of Ligand A are crucial for a kinase inhibitor. The difference in binding affinity (0.8 kcal/mol) is not large enough to outweigh the substantial ADME advantages of Ligand A.

Output:
1
2025-04-17 11:19:11,120 - INFO - Batch 37 complete. Total preferences: 592
2025-04-17 11:19:11,120 - INFO - Processing batch 38/512...
2025-04-17 11:19:53,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.363 Da) is slightly higher than Ligand B (352.41 Da), but both are acceptable.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold for oral absorption. Ligand B (84.42) is higher, but still reasonable.

**logP:** Ligand A (4.875) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.935) 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: 0.537, B: 0.811), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (12.796) has a very low DILI risk, significantly better than Ligand B (29.779).

**BBB:** Both have reasonable BBB penetration, but Ligand B (92.323) is higher than Ligand A (83.986). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.426 and -2.76 respectively).

**hERG Inhibition:** Ligand A (0.892) has a slightly higher hERG risk than Ligand B (0.207), which is preferable.

**Microsomal Clearance:** Ligand A (102.043) has a higher microsomal clearance, suggesting lower metabolic stability, compared to Ligand B (63.06).

**In vitro Half-Life:** Ligand B (-26.421) has a significantly longer in vitro half-life than Ligand A (28.044). This is a major advantage.

**P-gp Efflux:** Ligand A (0.683) has lower P-gp efflux liability than Ligand B (0.012), which is better.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has a better DILI score and lower P-gp efflux, Ligand B is superior overall. The significantly stronger binding affinity (-8.3 vs -6.6 kcal/mol) and longer half-life are crucial for an enzyme inhibitor. Although Ligand B has a slightly higher logP and lower solubility, the potency advantage is likely to be more impactful, and formulation strategies can be employed to address solubility issues.

Output:
1
2025-04-17 11:19:53,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.447 and 373.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.87) is higher than Ligand B (71.53). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.029) is quite low, potentially hindering permeability. Ligand B (1.812) 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 5 HBA. Both are acceptable, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.706 and 0.826), indicating good drug-like properties.

**DILI:** Ligand A (65.103) has a higher DILI risk than Ligand B (43.622). This is a concern for Ligand A.

**BBB:** Ligand A (52.191) and Ligand B (85.498). Since SRC is not a CNS target, this is less crucial, but Ligand B is better.

**Caco-2 Permeability:** Ligand A (-5.142) has poor Caco-2 permeability, while Ligand B (-4.8) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.983) and Ligand B (-2.322) both have poor aqueous solubility.

**hERG:** Ligand A (0.05) has a very low hERG risk, which is excellent. Ligand B (0.165) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (29.569) has a higher microsomal clearance than Ligand B (-3.967). This suggests Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-2.355) has a shorter in vitro half-life than Ligand B (-1.731). Again, favoring Ligand B.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, while Ligand B (0.042) is slightly higher.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.1). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a more favorable logP, and, most importantly, a much stronger binding affinity. The slightly higher DILI and hERG risks are less concerning than the poor permeability and metabolic profile of Ligand A. The stronger binding affinity of Ligand B is a critical advantage for an enzyme inhibitor.

Output:
1
2025-04-17 11:19:53,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (338.411 and 342.439 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.12) is better than Ligand B (49.85) as it is closer to the threshold of 140 for good oral absorption.

**3. logP:** Both ligands have good logP values (2.603 and 2.481), falling within the optimal range of 1-3.

**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 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.783 and 0.773), indicating good drug-likeness.

**7. DILI:** Ligand A (59.325) has a higher DILI risk than Ligand B (21.055). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (65.801) has a lower BBB penetration than Ligand B (97.751). While not a primary concern for a kinase inhibitor, higher BBB is generally preferable.

**9. Caco-2 Permeability:** Ligand A (-4.914) has worse Caco-2 permeability than Ligand B (-4.272).

**10. Aqueous Solubility:** Ligand A (-3.941) has worse aqueous solubility than Ligand B (-2.456). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.354) has a slightly higher hERG inhibition risk than Ligand B (0.556).

**12. Microsomal Clearance:** Ligand A (15.646) has a lower microsomal clearance than Ligand B (46.5). This suggests better metabolic stability for Ligand A, which is a key priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (51.506) has a longer in vitro half-life than Ligand B (-6.632). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.019) has much lower P-gp efflux than Ligand B (0.124), indicating better bioavailability.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.5). This is a 1.5 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better metabolic stability and half-life, the superior binding affinity of Ligand B, combined with its lower DILI risk and better solubility, makes it the more promising candidate. The difference in binding affinity is large enough to compensate for the slightly higher P-gp efflux and microsomal clearance.

Output:
1
2025-04-17 11:19:53,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.33 and 352.385 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.7) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (78.35) is well within the range.

**logP:** Ligand A (3.702) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.663) is well within the optimal range.

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

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

**QED:** Both ligands have good QED scores (0.635 and 0.843, respectively), indicating drug-likeness.

**DILI:** Ligand A (87.049) has a significantly higher DILI risk than Ligand B (49.166). This is a major concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (80.69) is better than Ligand A (61.535). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.325) shows poor permeability, while Ligand B (-4.907) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.446) has very poor aqueous solubility, which is a significant drawback. Ligand B (-2.963) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.652) has a slightly elevated hERG risk, but it's not alarming. Ligand B (0.385) has a lower hERG risk.

**Microsomal Clearance:** Ligand A (55.862) has moderate clearance, indicating moderate metabolic stability. Ligand B (0.512) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (26.62) has a moderate half-life. Ligand B (18.747) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.388) has low P-gp efflux. Ligand B (0.036) has very low P-gp efflux.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage.

**Conclusion:**

Ligand B is the superior candidate. While both have poor Caco-2 permeability and solubility, Ligand B's significantly stronger binding affinity, much lower DILI risk, and excellent metabolic stability outweigh its slightly shorter half-life. Ligand A's poor solubility, high DILI risk, and weak binding affinity make it a less desirable candidate despite its acceptable MW, TPSA, and logP.

Output:
1
2025-04-17 11:19:53,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.334 and 354.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.34) is slightly higher than the preferred <140, but acceptable. Ligand B (68.31) is excellent, well below 140.

**logP:** Ligand A (0.661) is a bit low, potentially hindering permeation. Ligand B (0.831) is also on the lower side, but slightly better.

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

**H-Bond Acceptors:** Ligand A (7) is good. Ligand B (5) is also good.

**QED:** Both ligands have acceptable QED values (0.771 and 0.661, respectively), indicating good drug-like properties.

**DILI:** Ligand A (86.002) has a higher DILI risk than Ligand B (46.064). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (80.962) is higher than Ligand B (58.782).

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. However, the scale is not specified, so it is hard to interpret.

**hERG:** Both ligands have very low hERG inhibition liability (0.127 and 0.132), which is excellent.

**Microsomal Clearance:** Ligand B (31.117) has significantly lower microsomal clearance than Ligand A (46.465), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (1.058) has a slightly better in vitro half-life than Ligand A (-5.477).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.14).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While both are excellent, the difference is notable.

**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 and better metabolic stability (lower Cl_mic, better t1/2), which are critical for enzyme inhibitors. The slightly better binding affinity also contributes to its favorability. The slightly lower TPSA is also a plus. The lower logP of both is a concern, but can potentially be addressed through further optimization.

Output:
1
2025-04-17 11:19:53,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.406 and 365.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (50.6 and 52.65) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.343) is optimal, while Ligand B (2.296) is also within the preferred 1-3 range.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (1) are both acceptable, being less than 5.

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

**6. QED:** Both ligands have reasonable QED scores (0.82 and 0.683), indicating good drug-like properties.

**7. DILI:** Ligand A (47.77) has a much lower DILI risk than Ligand B (10.857), which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.072) has better BBB penetration than Ligand B (63.086), but it's not a primary concern here.

**9. Caco-2 Permeability:** Ligand A (-4.423) has a worse Caco-2 permeability than Ligand B (-5.249).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.088 and -1.059). This is a potential issue, but formulation strategies could be employed.

**11. hERG Inhibition:** Ligand A (0.562) has a lower hERG risk than Ligand B (0.701), which is a positive.

**12. Microsomal Clearance:** Ligand A (3.721) has significantly lower microsomal clearance than Ligand B (24.562), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (0.039) has a very short half-life, while Ligand B (8.77) has a much longer half-life. This is a major drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux than Ligand B (0.212), which is favorable.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand B has a better binding affinity and in vitro half-life, but Ligand A has a significantly better safety profile (lower DILI and hERG) and metabolic stability (lower Cl_mic). The improved metabolic stability and safety of Ligand A are more important for an enzyme target like SRC kinase. While the half-life is a concern for Ligand A, it could potentially be addressed through structural modifications. The lower DILI risk is a significant advantage, as liver toxicity is a common issue in kinase inhibitors.

Output:
0
2025-04-17 11:19:53,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand B (80.23) is significantly better than Ligand A (104.45), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.753 and 1.854), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand B (1 HBD, 5 HBA) is preferable to Ligand A (4 HBD, 4 HBA) as it has fewer HBDs, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.589 and 0.676), indicating drug-like properties.

**DILI:** Ligand B (8.104 percentile) is *much* better than Ligand A (26.444 percentile) regarding potential liver injury risk. This is a significant advantage.

**BBB:** Both have moderate BBB penetration, but Ligand B (65.258) is higher than Ligand A (57.193). This isn't a primary concern for a kinase inhibitor, but is still a positive.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.126 and -4.931), 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 (-2.358 and -1.064), also unusual. Ligand B is slightly better.

**hERG:** Both ligands show low hERG inhibition liability (0.409 and 0.289), which is excellent.

**Microsomal Clearance:** Ligand B (-13.873 mL/min/kg) has a lower (better) microsomal clearance than Ligand A (14.748 mL/min/kg), indicating improved metabolic stability.

**In vitro Half-Life:** Ligand B (-1.178 hours) has a slightly better (less negative) in vitro half-life than Ligand A (-13.294 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.033).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand B is the superior candidate. While both have comparable binding affinity, Ligand B demonstrates significantly better DILI risk, lower microsomal clearance, and slightly improved TPSA, solubility, and half-life. These factors collectively make Ligand B a more promising starting point for further optimization as an SRC kinase inhibitor.

Output:
1
2025-04-17 11:19:53,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.366 and 361.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.0) is slightly above the optimal <140 for oral absorption, while Ligand B (91.32) is well within the range.

**logP:** Both ligands have logP values (1.605 and 2.609) within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD (4 and 3) and HBA (5) counts, satisfying the <5 and <10 guidelines respectively.

**QED:** Both ligands have similar QED scores (0.591 and 0.577), indicating good drug-likeness.

**DILI:** Ligand A (67.429) has a moderate DILI risk, while Ligand B (75.456) has a higher DILI risk. Both are above the preferred <40, but Ligand A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (43.583) has a higher BBB percentile than Ligand A (30.748), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.418 and -5.399), which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.247 and -4.116), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.198) has a lower hERG inhibition liability than Ligand B (0.435), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (33.114 and 34.802 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-47.84) has a significantly longer in vitro half-life than Ligand B (-7.14). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.052 and 0.149), which is favorable.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.2). This is a 0.8 kcal/mol difference, which is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B's substantially stronger binding affinity (-9.0 kcal/mol vs -8.2 kcal/mol) is a significant advantage for an enzyme target like SRC kinase. The longer half-life of Ligand A is attractive, but the potency difference is more important. The slightly higher DILI risk and hERG liability of Ligand B are concerns, but may be manageable with further optimization.

Output:
1
2025-04-17 11:19:53,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.429 Da and 367.921 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is well below the 140 threshold, and even better, under 90, suggesting good permeability. Ligand B (73.99) is still under 140 but less optimal than A.

**logP:** Both ligands (3.129 and 3.898) are within the optimal 1-3 range, though B is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (3 HBD, 2 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.909) has a significantly higher QED score than Ligand B (0.738), indicating a more drug-like profile.

**DILI:** Ligand A (25.94) has a much lower DILI risk than Ligand B (41.877), which is a significant advantage. Both are below the concerning 60 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.012) has better BBB penetration than Ligand B (68.592), but this isn't a primary concern.

**Caco-2 Permeability:** Ligand A (-4.495) shows better Caco-2 permeability than Ligand B (-4.956).

**Aqueous Solubility:** Ligand A (-2.984) has better aqueous solubility than Ligand B (-4.697). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.872) has a lower hERG inhibition liability than Ligand B (0.506), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (-2.479) has significantly lower microsomal clearance than Ligand B (40.196), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (10.418 hours) has a longer half-life than Ligand B (6.672 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.197) has lower P-gp efflux than Ligand B (0.224), which is a slight advantage.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 kcal/mol and -8.4 kcal/mol). The 0.5 kcal/mol difference is not enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is significantly better than Ligand B. It has a superior drug-like profile (QED), lower DILI risk, better solubility, lower hERG inhibition, and significantly improved metabolic stability (lower Cl_mic and longer t1/2). While both have good binding affinity, the ADME properties of Ligand A make it a much more viable drug candidate.

Output:
0
2025-04-17 11:19:53,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.502 and 349.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is significantly better than Ligand B (109.14). A TPSA under 90 is preferable, and Ligand A is much closer to that threshold, suggesting better permeability.

**logP:** Both ligands have acceptable logP values (0.97 and 1.081), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.737 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (16.014) has a much lower DILI risk than Ligand B (66.964). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.827) is better than Ligand B (36.293), but it's not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of the negative value is similar (-4.882 vs -4.929).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-2.786) is slightly worse than Ligand A (-0.846).

**hERG Inhibition:** Ligand A (0.673) has a lower hERG risk than Ligand B (0.116), which is a significant advantage.

**Microsomal Clearance:** Ligand A (16.456) has a lower microsomal clearance than Ligand B (45.114), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (2.106 hours) has a positive half-life, while Ligand B (-28.602 hours) has a negative half-life, which is nonsensical. This suggests Ligand B is rapidly degraded.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.027).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), lower hERG risk, and a more favorable TPSA. While both have issues with Caco-2 and solubility, Ligand A is better in both regards. The binding affinity is essentially the same. The enzyme-specific priorities heavily favor Ligand A due to its superior ADME properties.

Output:
1
2025-04-17 11:19:53,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.391 and 363.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (129.88) is better than Ligand B (137.08), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.002) is quite low, potentially hindering permeation. Ligand B (1.699) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

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

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

**QED:** Ligand A (0.639) is better than Ligand B (0.467), indicating a more drug-like profile.

**DILI:** Ligand A (36.293) has a much lower DILI risk than Ligand B (68.437). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (57.193 and 67.623), and this isn't a primary concern for a non-CNS target like SRC.

**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 difference isn't as drastic as it appears.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the difference isn't huge, but Ligand A (-2.379) is slightly better than Ligand B (-3.424).

**hERG Inhibition:** Ligand A (0.138) has a lower hERG risk than Ligand B (0.394), which is favorable.

**Microsomal Clearance:** Ligand A (10.483) has slightly higher microsomal clearance than Ligand B (9.975), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.257) has a longer in vitro half-life than Ligand A (-6.483), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.037 and 0.054).

**Binding Affinity:** Ligand B (-9.2 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 of the ADME drawbacks.

**Conclusion:**

While Ligand A has better QED, DILI, solubility, and hERG, Ligand B's superior binding affinity (-9.2 vs -7.7 kcal/mol) and better logP are crucial for an enzyme target. The longer half-life of Ligand B is also beneficial. The slightly higher DILI risk of Ligand B is a concern, but the substantial improvement in potency makes it the more promising candidate.

Output:
1
2025-04-17 11:19:53,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (373.837 and 365.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.9) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (78.51) is well within the acceptable range.

**3. logP:** Both ligands have good logP values (1.489 and 0.929), 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 (6) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.811 and 0.687), indicating good drug-like properties.

**7. DILI:** Ligand A (62.233) has a higher DILI risk than Ligand B (17.836). This is a significant concern.

**8. BBB:** Both ligands have similar BBB penetration (58.085 and 57.929), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.653) has worse Caco-2 permeability than Ligand B (-5.45). Lower values indicate poorer absorption.

**10. Aqueous Solubility:** Ligand A (-2.789) has worse aqueous solubility than Ligand B (-2.467).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.142 and 0.086).

**12. Microsomal Clearance:** Ligand A (17.351) has higher microsomal clearance than Ligand B (12.697), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.697) has a *longer* in vitro half-life than Ligand A (16.482). This is a significant advantage. Note the negative values indicate a longer half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.083 and 0.018).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand B is significantly more favorable due to its superior ADME properties. Specifically, it has a much lower DILI risk, better solubility, better Caco-2 permeability, and a longer in vitro half-life. Ligand A's higher DILI risk and lower metabolic stability are major drawbacks. Since we are targeting an enzyme, metabolic stability and minimizing toxicity (DILI) are crucial.

Output:
1
2025-04-17 11:19:53,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.463 and 344.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (80.23 and 81.66) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.854) is optimal, while Ligand B (2.833) is also within the optimal range, but closer to 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 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.676 and 0.714), indicating drug-like properties.

**7. DILI:** Ligand A (8.104 percentile) has a significantly lower DILI risk than Ligand B (37.611 percentile). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (65.258 and 69.833 percentile), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**9. Caco-2 Permeability:** Ligand A (-4.931) has worse Caco-2 permeability than Ligand B (-5.59).

**10. Aqueous Solubility:** Ligand A (-1.064) has better aqueous solubility than Ligand B (-2.623). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.289 and 0.173), which is good.

**12. Microsomal Clearance:** Ligand A (-13.873 mL/min/kg) has much lower microsomal clearance than Ligand B (42.134 mL/min/kg), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (-1.178 hours) has a worse in vitro half-life than Ligand B (-8.086 hours).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.033 and 0.344).

**15. Binding Affinity:** Ligand B (-9.9 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:**

Ligand B has a significantly better binding affinity (-9.9 vs -7.7 kcal/mol). However, Ligand A demonstrates superior ADMET properties, particularly a much lower DILI risk and significantly improved metabolic stability (lower Cl_mic). While Ligand B's longer half-life is beneficial, the DILI and metabolic stability concerns are more critical for an enzyme inhibitor. The difference in binding affinity is significant (2.2 kcal/mol), but not insurmountable, and could potentially be optimized in future iterations of Ligand A. Given the priorities for kinase inhibitors, the improved safety and metabolic stability of Ligand A are more valuable than the stronger binding of Ligand B.

Output:
0
2025-04-17 11:19:53,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (384.93 and 345.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (91.16). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.96 and 1.99), 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 8. While both are under the 10 limit, A is preferable.

**QED:** Both ligands have good QED scores (0.605 and 0.767), indicating drug-like properties.

**DILI:** Ligand B (78.40) has a higher DILI risk than Ligand A (54.75). Lower is better, and A is preferable.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Both are reasonably high (62.16 and 75.11).

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

**Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG:** Ligand A (0.567) has a slightly better hERG profile than Ligand B (0.139), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Both have similar microsomal clearance values (82.04 and 83.88), indicating similar metabolic stability. These are relatively high, suggesting moderate metabolic liability.

**In vitro Half-Life:** Ligand A (28.36) has a significantly longer half-life than Ligand B (2.06). This is a major advantage for A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.568 and 0.241).

**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:**

Ligand A is the better candidate. While both compounds suffer from poor solubility and Caco-2 permeability, Ligand A demonstrates advantages in TPSA, DILI risk, in vitro half-life, and binding affinity. The slightly better hERG profile is also a plus. The longer half-life and stronger binding of Ligand A could outweigh the solubility issues with appropriate formulation strategies.

Output:
1
2025-04-17 11:19:53,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.383 and 357.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.54) is slightly above the preferred <140 for good absorption, but not drastically. Ligand B (37.61) is excellent, well below 140.

**logP:** Both ligands (3.521 and 3.966) are 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:** Ligand A has 5 HBA, within the acceptable limit. Ligand B has 4, also good.

**QED:** Ligand A (0.289) is below the 0.5 threshold, indicating a less drug-like profile. Ligand B (0.671) is above the threshold and more drug-like.

**DILI:** Ligand A (72.974) has a higher DILI risk than Ligand B (32.493). Ligand B is well below the 40% threshold for low risk.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (65.297) and Ligand B (89.57) are both reasonable.

**Caco-2 Permeability:** Ligand A (-4.401) has poor Caco-2 permeability. Ligand B (-5.091) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.268) has poor aqueous solubility. Ligand B (-4.04) also has poor aqueous solubility.

**hERG:** Ligand A (0.486) has a slightly higher hERG risk than Ligand B (0.94), but both are acceptable.

**Microsomal Clearance:** Ligand A (98.771) has a high microsomal clearance, suggesting poor metabolic stability. Ligand B (100.738) also has high microsomal clearance.

**In vitro Half-Life:** Ligand A (7.771 hours) has a shorter half-life than Ligand B (13.519 hours).

**P-gp Efflux:** Ligand A (0.347) has lower P-gp efflux than Ligand B (0.855).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While both are good, the 1.9 kcal/mol difference is significant.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand B is the better candidate. While both have poor Caco-2 and solubility, Ligand B demonstrates superior drug-likeness (QED), lower DILI risk, a longer half-life, and a better binding affinity. The slightly better affinity of Ligand B can outweigh the minor ADME drawbacks.

Output:
1
2025-04-17 11:19:53,868 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (415.288 Da) is within the ideal range, while Ligand B (352.475 Da) is also good. No clear advantage here.
2. **TPSA:** Ligand A (96.74) is acceptable, below 140, but higher than ideal for CNS penetration. Ligand B (70.08) is excellent, well below 90.
3. **logP:** Both ligands have good logP values (A: 2.837, B: 1.435) falling within the 1-3 range.
4. **HBD:** Both ligands have acceptable HBD counts (A: 2, B: 1).
5. **HBA:** Both ligands have acceptable HBA counts (A: 5, B: 4).
6. **QED:** Both ligands have good QED scores (A: 0.527, B: 0.785), indicating drug-like properties. Ligand B is slightly better.
7. **DILI:** Both ligands have low DILI risk (A: 39.434, B: 30.981), both below the 40 threshold. Ligand B is slightly better.
8. **BBB:** Ligand A (84.025) has a better BBB score than Ligand B (53.974). However, since SRC is not a CNS target, this is less critical.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, lower is worse. Ligand A (-5.031) is worse than Ligand B (-4.279).
10. **Solubility:** Both have negative solubility values, which is also unusual. Assuming these are percentile scores, lower is worse. Ligand A (-3.023) is worse than Ligand B (-1.735).
11. **hERG:** Both ligands have low hERG risk (A: 0.816, B: 0.474), which is good. Ligand B is better.
12. **Cl_mic:** Ligand A (-19.54) has a *much* lower (better) microsomal clearance than Ligand B (37.055). This suggests significantly better metabolic stability for Ligand A.
13. **t1/2:** Both have similar in vitro half-lives (A: 23.371, B: 23.12).
14. **Pgp:** Both ligands have low Pgp efflux liability (A: 0.076, B: 0.147). Ligand A is slightly better.
15. **Binding Affinity:** Both ligands have excellent binding affinity (A: -7.7 kcal/mol, B: -7.0 kcal/mol). Ligand A is slightly better.

**Prioritization for Enzyme (Kinase) Targets:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand A has a slightly better affinity (-7.7 vs -7.0).
*   **Metabolic Stability:** Ligand A has a significantly better Cl_mic (-19.54 vs 37.055).
*   **Solubility:** Ligand B is better.
*   **hERG:** Ligand B is better.
*   **Caco-2 and Solubility:** Both are poor, but Ligand B is better.

**Conclusion:**

Despite the slightly better solubility and hERG profile of Ligand B, the significantly improved metabolic stability (lower Cl_mic) and slightly better affinity of Ligand A outweigh these advantages. The lower Cl_mic suggests a longer duration of action and potentially lower dosing requirements, which are critical for kinase inhibitors. The affinity difference, while small, is also a benefit.

Output:
1
2025-04-17 11:19:53,868 - INFO - Batch 38 complete. Total preferences: 608
2025-04-17 11:19:53,868 - INFO - Processing batch 39/512...
2025-04-17 11:20:43,679 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.43 & 341.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.09) is higher than Ligand B (54.26). While both are reasonably low, Ligand B is significantly better, suggesting better permeability.

**logP:** Ligand A (0.839) is slightly lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (2.226) is well within the optimal range.

**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, and potentially favoring permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.639 and 0.837), indicating drug-like properties.

**DILI:** Ligand A (72.08%) has a higher DILI risk than Ligand B (25.82%), which is a significant concern.

**BBB:** Both have low BBB penetration, which is not critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.788) has poor Caco-2 permeability, while Ligand B (-4.649) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.864) has poor aqueous solubility, while Ligand B (-1.024) is better, but still low.

**hERG:** Ligand A (0.125) has a slightly higher hERG risk than Ligand B (0.399), although both are relatively low.

**Microsomal Clearance:** Ligand A (37.79) has significantly higher microsomal clearance than Ligand B (0.489), indicating poorer metabolic stability.

**In vitro Half-Life:** Ligand A (-23.16) has a very short half-life, while Ligand B (17.62) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.076).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is significantly better overall. While both have acceptable MW, QED, and P-gp efflux, Ligand B excels in key areas for an enzyme inhibitor: lower DILI risk, better logP, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. Ligand A's poor solubility, permeability, and high DILI risk are major drawbacks. The slightly better affinity of Ligand B, combined with the improved ADME properties, makes it the more promising candidate.

Output:
1
2025-04-17 11:20:43,679 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.383 and 345.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.92) is better than Ligand B (109.85), being comfortably below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.88 and 1.175), falling 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 have 6 H-bond acceptors, which is within the acceptable range (<=10).

**QED:** Ligand A (0.862) has a significantly better QED score than Ligand B (0.624), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (62.815 and 64.327), which is moderately high, but not alarming.

**BBB:** Ligand B (77.821) has a higher BBB penetration percentile than Ligand A (55.176). However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-4.845) and Ligand B (-5.025) have similar, very poor Caco-2 permeability. This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.246 and -3.552). This could present formulation challenges.

**hERG Inhibition:** Ligand A (0.498) has a lower hERG inhibition risk than Ligand B (0.195), which is a positive attribute.

**Microsomal Clearance:** Ligand A (6.406) has a much lower microsomal clearance than Ligand B (34.078), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-13.704) has a significantly longer in vitro half-life than Ligand B (3.222). This is another major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.055).

**Binding Affinity:** Ligand B (-7.8 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 advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a better QED score, and a lower hERG risk. Both have poor solubility and Caco-2 permeability, which would need to be addressed during optimization, but the ADME profile of Ligand A is more favorable overall.

Output:
0
2025-04-17 11:20:43,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.25 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.39) is better than Ligand B (75.44), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.536) is slightly higher than Ligand B (2.04). Both are within the optimal 1-3 range, but Ligand A is approaching the upper limit.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.673 and 0.835), indicating good drug-like properties.

**DILI:** Ligand A (83.017) has a significantly higher DILI risk than Ligand B (60.566). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration (77.007 and 74.254), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both, but the value for Ligand A (-4.417) is worse than that of Ligand B (-4.746).

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-3.627) is slightly better than Ligand A (-5.468).

**hERG:** Ligand A (0.621) has a higher hERG risk than Ligand B (0.241). This is a concern for Ligand A.

**Microsomal Clearance:** Ligand B (19.499) has a significantly lower microsomal clearance than Ligand A (58.572), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-3.363) has a negative half-life, which is unusual. Ligand A (23.784) has a reasonable half-life.

**P-gp:** Both have low P-gp efflux liability (0.277 and 0.37).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a substantial advantage for Ligand B. The 1.1 kcal/mol difference is enough to outweigh some of the ADME concerns.

**Conclusion:**

Despite the unusual Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly better binding affinity, lower DILI risk, and lower microsomal clearance outweigh the slightly worse TPSA and solubility. Ligand A's higher DILI and hERG risk are significant liabilities.

Output:
1
2025-04-17 11:20:43,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.841 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.97) is well below the 140 threshold for good absorption, while Ligand B (82.53) is still acceptable but less optimal.

**logP:** Ligand A (4.672) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.772) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is good. Ligand B (HBD=2, HBA=4) is also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.723, B: 0.822), indicating drug-likeness.

**DILI:** Ligand A (68.166) has a higher DILI risk than Ligand B (33.734), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.733) is slightly better than Ligand B (32.726).

**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 undefined.

**hERG:** Ligand A (0.552) has a slightly higher hERG risk than Ligand B (0.289), but both are reasonably low.

**Microsomal Clearance:** Ligand B (15.188) has significantly lower microsomal clearance than Ligand A (55.482), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (2.957) has a slightly longer half-life than Ligand A (31.758), which is a positive.

**P-gp Efflux:** Ligand A (0.776) has slightly higher P-gp efflux than Ligand B (0.069). Lower is better.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly better binding affinity than Ligand A (-9.5 kcal/mol). The difference of 1.4 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the overall profile of Ligand B is superior. Its significantly better binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic, longer t1/2) make it the more promising drug candidate for SRC kinase inhibition. Ligand A's higher logP and DILI risk are concerning.

Output:
1
2025-04-17 11:20:43,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.941 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, while Ligand B (75.88) is still acceptable but higher.

**logP:** Ligand A (4.237) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.854) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, both within acceptable limits. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.849) has a very good drug-likeness score, while Ligand B (0.502) is acceptable but lower.

**DILI:** Ligand A (38.62) has a low DILI risk, while Ligand B (17.255) is even lower and preferable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (81.233) is better than Ligand A (74.641). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.034 and -4.901), which is unusual and indicates poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.681 and -0.307), indicating very poor aqueous solubility. This is a major concern for *in vivo* efficacy.

**hERG Inhibition:** Ligand A (0.678) has a slightly higher hERG risk than Ligand B (0.278), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (32.307 and 31.404 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-19.42) has a significantly longer half-life than Ligand A (-5.47), which is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.34 and 0.047), which is good.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a major advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity, a better QED score, and a lower DILI risk. However, it has a higher logP, potentially leading to solubility issues, and a shorter half-life. Ligand B has better solubility, a longer half-life, and lower hERG risk. Both have poor Caco-2 permeability and aqueous solubility.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is a critical factor. While the solubility and logP are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The significantly better affinity (-9.9 vs -7.2 kcal/mol) is a substantial advantage that likely outweighs the ADME drawbacks, *especially* if the goal is to achieve potent target inhibition.

Output:
1
2025-04-17 11:20:43,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (373.787 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is slightly higher than Ligand B (59.08). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have similar logP values (1.663 and 1.677), 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 (0.608 and 0.699), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 54.75, while Ligand B has a much lower risk of 12.369. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (77.937 and 75.107), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.148) has poor Caco-2 permeability, while Ligand B (-4.163) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-3.531) has very poor aqueous solubility, a major concern. Ligand B (-1.026) is better, but still not great.

**hERG Inhibition:** Ligand A (0.692) has a higher hERG inhibition risk than Ligand B (0.306), which is preferable.

**Microsomal Clearance:** Ligand A (17.569) has lower microsomal clearance than Ligand B (56.262), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (23.384) has a longer in vitro half-life than Ligand B (-1.907), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.085), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.2 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 metabolic stability (lower Cl_mic, longer t1/2, lower P-gp efflux). However, it suffers from very poor aqueous solubility and poor Caco-2 permeability. Ligand B has a significantly lower DILI risk and slightly better solubility and permeability, but weaker binding affinity.

Given the priority for potency in enzyme inhibitors, the superior binding affinity of Ligand A is a critical advantage. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The lower DILI risk of Ligand B is attractive, but the substantial difference in binding affinity outweighs this benefit.

Output:
1
2025-04-17 11:20:43,681 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [342.355, 120.16 ,  -1.085,   4.   ,   4.   ,   0.388,  47.887,  29.12 ,
  -5.495,  -2.779,   0.031, -22.606, -19.905,   0.009,  -7.6  ]
**Ligand B:** [377.432,  45.55 ,   1.919,   0.   ,   5.   ,   0.76 ,  22.218,  87.088,
  -4.766,  -1.851,   0.67 ,   7.901, -26.107,   0.095,  -9.9  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (342.355) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (120.16) is better than B (45.55). Both are below the 140 cutoff for oral absorption, but B is significantly lower, which is good.
3. **logP:** A (-1.085) is a bit low, potentially hindering permeation. B (1.919) is within the optimal range (1-3). B is better here.
4. **HBD:** A (4) is acceptable. B (0) is excellent, minimizing potential off-target interactions. B is better.
5. **HBA:** Both A (4) and B (5) are within the acceptable limit of 10.
6. **QED:** Both A (0.388) and B (0.76) are reasonably drug-like, but B is significantly better.
7. **DILI:** A (47.887) is better than B (22.218) - lower risk is always preferred.
8. **BBB:** A (29.12) is low, while B (87.088) is high. Since SRC is not a CNS target, this is less critical, but B is still better.
9. **Caco-2:** A (-5.495) is very poor, indicating very low intestinal absorption. B (-4.766) is also poor, but slightly better.
10. **Solubility:** A (-2.779) is poor. B (-1.851) is also poor, but slightly better.
11. **hERG:** A (0.031) is very low risk. B (0.67) is slightly higher, but still acceptable. A is better.
12. **Cl_mic:** A (-22.606) is excellent (low clearance, high metabolic stability). B (7.901) is moderate. A is significantly better.
13. **t1/2:** A (-19.905) is excellent (long half-life). B (-26.107) is also excellent.
14. **Pgp:** A (0.009) is very low efflux, which is good. B (0.095) is also low.
15. **Binding Affinity:** B (-9.9) is significantly stronger than A (-7.6) - a difference of 2.3 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B is much better.
*   **Metabolic Stability:** A is significantly better (lower Cl_mic).
*   **Solubility:** Both are poor, but B is slightly better.
*   **hERG:** A is better.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, hERG, and metabolic stability, the *substantial* improvement in binding affinity for Ligand B (-9.9 kcal/mol vs -7.6 kcal/mol) outweighs these drawbacks. The difference in affinity is large enough to potentially overcome the slightly higher DILI risk and moderate Cl_mic. The better logP and QED of ligand B also contribute to its overall drug-likeness. The poor Caco-2 and solubility of both compounds would need to be addressed in further optimization, but the stronger binding of B makes it a more promising starting point.

Output:
1
2025-04-17 11:20:43,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.47 and 342.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.37) is better than Ligand B (115.11). TPSA <140 is good for oral absorption, and both are within this limit, but A is closer to the optimal range.

**logP:** Ligand A (2.216) is optimal (1-3), while Ligand B (0.739) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

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

**QED:** Both ligands have similar QED values (0.747 and 0.73), indicating good drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (39.36 and 41.84), both below the 40 threshold.

**BBB:** Ligand A (80.96) is significantly better than Ligand B (45.13). While not a primary concern for a non-CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.04 and -5.07), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.81 and -2.77), also unusual and concerning. Poor solubility can hinder formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.274) has a much lower hERG risk than Ligand B (0.157), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-7.699) has a significantly *lower* (better) microsomal clearance than Ligand B (-20.828), indicating greater metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (14.23) has a longer half-life than Ligand B (5.85), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.016).

**Binding Affinity:** Ligand A (-6.6 kcal/mol) has a slightly weaker binding affinity than Ligand B (-7.5 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be overcome by the superior ADME properties of Ligand A.

**Conclusion:**

Despite the slightly weaker binding affinity, Ligand A is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better BBB penetration outweigh the minor difference in binding affinity. Both ligands have concerning solubility and permeability issues, but these might be addressed through formulation strategies. The superior ADME profile of Ligand A makes it a more viable starting point for optimization.

Output:
0
2025-04-17 11:20:43,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.259 Da) is slightly higher than Ligand B (337.339 Da), but both are acceptable.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (95.33). Lower TPSA generally improves cell permeability.

**logP:** Ligand A (4.201) is higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (1.149) is a bit 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 limits (HBD <=5, HBA <=10).

**QED:** Both ligands have good QED scores (Ligand A: 0.602, Ligand B: 0.757), indicating drug-like properties.

**DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (63.668). Both are acceptable, but B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (49.244) and Ligand B (28.344) are both low.

**Caco-2 Permeability:** Ligand A (-4.438) is worse than Ligand B (-5.283), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.909) is significantly worse than Ligand B (-3.262). Solubility is a crucial factor for bioavailability.

**hERG Inhibition:** Ligand A (0.58) is better than Ligand B (0.472), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (75.988) has higher clearance than Ligand B (14.541), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (27.336) has a shorter half-life than Ligand B (22.267), which is undesirable.

**P-gp Efflux:** Ligand A (0.111) is better than Ligand B (0.005), indicating lower P-gp efflux.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially better binding affinity than Ligand A (-9.2 kcal/mol). This is a major advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is a bit low, its superior binding affinity (-7.8 vs -9.2 kcal/mol), significantly better solubility, lower microsomal clearance, and lower DILI risk outweigh the slightly lower Caco-2 permeability and BBB. The improved metabolic stability and potency are particularly important for an enzyme target like SRC kinase. Ligand A's high logP and poor solubility are concerning, and its higher clearance and shorter half-life are significant drawbacks.

Output:
1
2025-04-17 11:20:43,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.483 and 351.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (43.78) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (87.74) is still under 140, but less optimal than A.

**logP:** Ligand A (2.827) is within the optimal 1-3 range. Ligand B (0.433) is slightly low, potentially hindering permeation.

**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 similar and acceptable QED values (0.775 and 0.752, respectively).

**DILI:** Ligand A (10.585) has a significantly lower DILI risk than Ligand B (19.349). This is a substantial advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (84.141) has a higher percentile than Ligand B (52.695).

**Caco-2 Permeability:** Ligand A (-4.723) is better than Ligand B (-5.162), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.385) is better than Ligand B (-2.08), suggesting better formulation potential.

**hERG:** Ligand A (0.921) has a lower hERG risk than Ligand B (0.164), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (31.614) has a higher (worse) microsomal clearance than Ligand B (-10.628), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (29.229) has a longer half-life than Ligand B (7.134). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.723) has lower P-gp efflux than Ligand B (0.013), suggesting better bioavailability.

**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 and likely not decisive.

**Overall Assessment:**

Ligand A has several advantages: better TPSA, logP, DILI risk, solubility, hERG risk, Caco-2 permeability, and P-gp efflux. While Ligand A has a higher microsomal clearance, its longer half-life partially compensates for this. The superior ADME profile of Ligand A, coupled with comparable binding affinity, makes it the more promising drug candidate.

Output:
1
2025-04-17 11:20:43,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.82 and 376.513 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.15) is slightly higher than Ligand B (49.41). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have good logP values (3.883 and 3.166), 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 3. Both are within the acceptable limit of 10, but Ligand B is preferable.

**QED:** Both ligands have similar and good QED scores (0.728 and 0.742), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.604 percentile), which is a major concern. Ligand B has a much lower DILI risk (22.838 percentile), making it significantly safer.

**BBB:** Both ligands have high BBB penetration (89.531 and 96.355 percentile). While not a primary concern for a kinase inhibitor, it doesn't hurt.

**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 (0.48) has a slightly better hERG profile than Ligand B (0.772), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (36.675 mL/min/kg) has lower clearance than Ligand B (42.801 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.049 hours) has a significantly longer half-life than Ligand B (-5.165 hours). This is a substantial advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.376) has lower P-gp efflux than Ligand B (0.162), suggesting better oral bioavailability and potentially better CNS exposure.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Despite Ligand A's slightly better affinity and half-life, the extremely high DILI risk is a deal-breaker. Ligand B, while having a slightly lower affinity and shorter half-life, presents a much more favorable safety profile (DILI) and comparable drug-like properties. The lower TPSA and HBA of Ligand B are also advantageous for permeability. Given the enzyme-specific priorities, the lower DILI risk of Ligand B is the most critical factor.

Output:
1
2025-04-17 11:20:43,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.5 and 358.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.8) is slightly above the preferred <140, but acceptable. Ligand B (85.35) is well within the acceptable range.

**logP:** Ligand A (0.719) is a bit low, potentially impacting permeability. Ligand B (-1.16) is even lower, raising more concerns about permeability.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 8 HBA, acceptable. Ligand B has 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.654 and 0.541), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 86.041, which is high and a significant concern. Ligand B has a very low DILI risk of 5.312, a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (33.075) is lower than Ligand B (22.838).

**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.

**Solubility:** Both have negative solubility values, also unusual. Again, difficult to interpret without knowing the scale.

**hERG:** Ligand A (0.147) has a slightly higher hERG risk than Ligand B (0.217), but both are relatively low.

**Microsomal Clearance:** Ligand A (32.316) and Ligand B (30.271) have similar, relatively low, microsomal clearance values, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (12.245 hours) has a better in vitro half-life than Ligand B (-11.341 hours - which is not possible and likely an error). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a better in vitro half-life. However, its high DILI risk is a major red flag. Ligand B has a much lower DILI risk, but significantly weaker binding affinity and a questionable half-life value. Given the importance of potency for kinase inhibitors, and the severity of DILI, the stronger binding affinity of Ligand A is a compelling factor, *provided* the DILI risk can be mitigated through structural modifications. However, the negative solubility and Caco-2 values for both are concerning and need further investigation.

Despite the DILI risk, I lean towards Ligand A as the more promising starting point due to the substantial difference in binding affinity.

Output:
1
2025-04-17 11:20:43,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.43 and 362.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is better than Ligand B (125.8), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.27 and 1.12) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 8 HBA). While both are acceptable, fewer HBA generally favors permeability.

**QED:** Both ligands have acceptable QED scores (0.559 and 0.595), indicating good drug-likeness.

**DILI:** Ligand A (14.54) has a significantly lower DILI risk than Ligand B (98.06), which is a major advantage. Ligand B's DILI is very high.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (49.01) has a higher value than Ligand A (21.91), which is not relevant here.

**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 ligands have negative solubility values, which is also unusual and indicates poor solubility. This is a concern for both, but the values are similar.

**hERG Inhibition:** Ligand A (0.126) has a much lower hERG inhibition liability than Ligand B (0.527), a significant safety advantage.

**Microsomal Clearance:** Ligand A (36.53) has a lower microsomal clearance than Ligand B (39.57), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.45) has a significantly longer in vitro half-life than Ligand B (24.07).

**P-gp Efflux:** Ligand A (0.017) has a lower P-gp efflux liability than Ligand B (0.026), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-7.7) has a substantially better binding affinity than Ligand A (0.0). This is a very large difference and a major factor.

**Overall Assessment:**

While Ligand B has a much stronger binding affinity, the significant drawbacks in DILI risk, hERG inhibition, and metabolic stability make it a less desirable candidate. Ligand A, despite its weaker binding affinity, presents a much more favorable ADMET profile, with lower DILI, hERG, and P-gp efflux, and better metabolic stability and half-life. The difference in binding affinity is substantial, but a well-optimized Ligand A scaffold could potentially achieve comparable potency. Given the enzyme-specific priorities, the ADMET advantages of Ligand A outweigh the potency difference at this stage.

Output:
0
2025-04-17 11:20:43,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.503 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is significantly better than Ligand B (40.62). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target. Ligand A is well below the 140 threshold, while B is approaching it.

**logP:** Ligand A (4.414) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (2.237) is well within the optimal range. Higher logP can sometimes lead to off-target effects, but the difference isn't drastic here.

**H-Bond Donors/Acceptors:** Both have low HBD (0) and acceptable HBA (2 for A, 3 for B).

**QED:** Both ligands have similar and good QED values (0.719 and 0.725), indicating good drug-like properties.

**DILI:** Ligand A (37.689) has a lower DILI risk than Ligand B (47.77), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (79.411 and 79.139). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.717 and -4.925). This 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 (-4.993 and -3.61). This is also concerning and suggests poor aqueous solubility. Formulation challenges are likely.

**hERG Inhibition:** Ligand A (0.944) has a slightly higher hERG risk than Ligand B (0.564), but both are relatively low.

**Microsomal Clearance:** Ligand A (100.737) has significantly higher microsomal clearance than Ligand B (50.461). This means Ligand A will be metabolized faster, leading to a shorter half-life and potentially lower bioavailability. This is a major drawback.

**In vitro Half-Life:** Ligand A (28.544 hours) has a longer half-life than Ligand B (-9.016 hours). However, the negative value for B is problematic and likely indicates a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.481 and 0.352).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A having a slightly better TPSA and DILI score, Ligand B is the more promising candidate. The primary reason is the significantly lower microsomal clearance and better binding affinity. The longer half-life of Ligand A is negated by its rapid metabolism. While both have solubility issues, this can be addressed through formulation strategies. The slightly better affinity of Ligand B is a crucial advantage for a kinase inhibitor.

Output:
1
2025-04-17 11:20:43,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (397.89 and 356.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.54) is significantly better than Ligand B (76.14). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (4.166) is slightly higher than the optimal range (1-3), while Ligand B (2.863) is within the optimal range. High logP can cause issues, but the binding affinity difference will be considered.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.75 and 0.674), indicating good drug-likeness.

**DILI:** Ligand A (33.7) has a lower DILI risk than Ligand B (41.9), which is desirable. Both are below the 60 threshold, but A is better.

**BBB:** Both ligands have high BBB penetration (70.4 and 89.0), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method. We'll have to rely on other parameters for permeability assessment.

**Aqueous Solubility:** Both have negative solubility values, again suggesting issues with the prediction method.

**hERG:** Both ligands have a low hERG risk (0.828 and 0.481), which is excellent.

**Microsomal Clearance:** Ligand A (80.5 mL/min/kg) has higher clearance than Ligand B (79.4 mL/min/kg), indicating lower metabolic stability. This is a slight negative for Ligand A.

**In vitro Half-Life:** Ligand B (-33.05 hours) has a significantly longer half-life than Ligand A (6.08 hours). This is a major advantage for Ligand B, as it suggests less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.564 and 0.078).

**Binding Affinity:** Ligand A (-8.0 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 has a superior binding affinity, lower DILI risk, and better TPSA. However, Ligand B has a significantly longer half-life and a more optimal logP. The difference in binding affinity is substantial (0.9 kcal/mol), and for an enzyme target like SRC kinase, potency is paramount. While Ligand A's higher clearance is a concern, the strong binding affinity suggests it may still have sufficient *in vivo* efficacy. The solubility and Caco-2 values are suspect due to the negative values.

Output:
1
2025-04-17 11:20:43,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.531 and 351.466 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (56.67), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.887) is slightly higher than Ligand B (2.169), both are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A (2) is better than Ligand B (4), both are below the 10 threshold.

**QED:** Both ligands have similar, good QED values (0.838 and 0.818).

**DILI:** Ligand A (14.889) has a significantly lower DILI risk than Ligand B (4.459), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (93.098 and 92.749), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.626 and -4.658). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**Aqueous Solubility:** Ligand A (-4.659) is slightly better than Ligand B (-0.997), both are quite poor.

**hERG Inhibition:** Ligand A (0.533) has a lower hERG risk than Ligand B (0.841), which is favorable.

**Microsomal Clearance:** Ligand A (44.74) has significantly better metabolic stability (lower clearance) than Ligand B (10.669). This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (1.161) has a slightly better half-life than Ligand B (-22.834), but both are poor.

**P-gp Efflux:** Ligand A (0.233) has lower P-gp efflux than Ligand B (0.265), which is slightly better.

**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 (1.7 kcal/mol difference).

**Conclusion:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much better safety profile (lower DILI, lower hERG) and improved metabolic stability (lower Cl_mic). The difference in affinity is significant, but the ADME/Tox profile of Ligand A is substantially more promising. Considering the importance of metabolic stability and safety for kinase inhibitors, and the fact that the affinity difference *could* potentially be overcome with further optimization, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 11:20:43,683 - INFO - Batch 39 complete. Total preferences: 624
2025-04-17 11:20:43,683 - INFO - Processing batch 40/512...
2025-04-17 11:21:23,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 Da and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.64) is slightly higher than Ligand B (75.71), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.538) is within the optimal 1-3 range. Ligand B (2.221) is also within range, but slightly higher.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are acceptable values.

**QED:** Ligand A (0.79) has a better QED score than Ligand B (0.61), indicating a more drug-like profile.

**DILI:** Ligand A (7.135) has a significantly lower DILI risk than Ligand B (24.622), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration (68.67 and 72.625, respectively), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.767) and Ligand B (-4.301) both have negative values, indicating poor permeability. However, the absolute value is slightly lower for Ligand A, suggesting marginally better permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.303 and -2.493). Ligand B has worse solubility.

**hERG Inhibition:** Ligand A (0.474) has a lower hERG inhibition liability than Ligand B (0.332), which is favorable.

**Microsomal Clearance:** Ligand A (-11.659) has significantly lower microsomal clearance than Ligand B (93.86), indicating much better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (2.889) has a shorter half-life than Ligand B (-5.898). However, the negative value for Ligand B is unusual and might indicate an issue with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.039).

**Binding Affinity:** Ligand B (-7.6) has a significantly better binding affinity than Ligand A (0.0). This is a substantial advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, Ligand A presents a significantly better safety profile (lower DILI, lower hERG) and improved metabolic stability (lower Cl_mic). The solubility and permeability are poor for both, but the metabolic stability and safety advantages of Ligand A are more critical for an enzyme target like SRC. The substantial difference in binding affinity is a concern, but the other factors make Ligand A a more promising starting point for optimization.

Output:
0
2025-04-17 11:21:23,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 Da and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is well below the 140 threshold for oral absorption, and even favorable. Ligand B (107.53) is still within acceptable limits, but less optimal.

**logP:** Ligand A (1.175) is within the optimal 1-3 range. Ligand B (-0.747) is slightly below 1, potentially hindering permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is excellent. Ligand B (HBD=4, HBA=5) is acceptable, but slightly higher, potentially impacting permeability.

**QED:** Ligand A (0.643) is good, indicating strong drug-likeness. Ligand B (0.257) is significantly lower, suggesting a less favorable overall drug-like profile.

**DILI:** Ligand A (8.298) has a very low DILI risk. Ligand B (18.418) is higher, but still below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.384) is reasonable, while Ligand B (39.046) is lower.

**Caco-2 Permeability:** Ligand A (-4.66) and Ligand B (-5.514) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-2.287) and Ligand B (-1.659) both have negative solubility values, which is also a significant concern.

**hERG Inhibition:** Ligand A (0.599) has a low hERG risk. Ligand B (0.079) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (32.563) has moderate clearance. Ligand B (-2.421) has *negative* clearance, which is not physically possible and indicates a potential data error or unusual behavior. However, even if we interpret this as very low clearance, it's a positive.

**In vitro Half-Life:** Ligand A (-6.061) has a negative half-life, which is not physically possible and indicates a potential data error. Ligand B (-11.308) also has a negative half-life, indicating a potential data error.

**P-gp Efflux:** Ligand A (0.102) has low P-gp efflux. Ligand B (0.006) has very low P-gp efflux.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 kcal/mol and -8.9 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite the issues with Caco-2 and Solubility, Ligand A is the better candidate. The primary reason is its significantly better QED score (0.643 vs 0.257), indicating a more generally drug-like profile. The DILI risk is also lower for Ligand A. The negative values for half-life and Caco-2 permeability for both are concerning and would require further investigation, but the overall profile of Ligand A is more promising.

Output:
0
2025-04-17 11:21:23,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.845 and 348.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.6) is slightly higher than Ligand B (59.39), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.754) is at the upper end of the optimal range (1-3), while Ligand B (2.267) is comfortably within it. Ligand A's higher logP *could* lead to solubility issues or off-target interactions, but it's not extreme.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are acceptable values.

**QED:** Both ligands have similar QED values (0.876 and 0.857), indicating good drug-likeness.

**DILI:** Ligand A (72.043) has a significantly higher DILI risk than Ligand B (13.532). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (77.007 and 74.292), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.664 and -4.81), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-4.711) has worse solubility than Ligand B (-1.375), which is consistent with its higher logP.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.608 and 0.473).

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (46.795 and 44.11 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (10.936 hours) has a longer half-life than Ligand B (-8.309 hours - this negative value is suspect and likely an error, but we'll proceed assuming it's very short).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.504 and 0.06).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol), but the difference is not substantial enough to overcome other issues.

**Conclusion:**

Ligand B is the more promising candidate. While both have poor Caco-2 permeability, Ligand B has a significantly lower DILI risk and a better solubility profile. The slightly better binding affinity of Ligand B is a bonus. The negative half-life for Ligand B is concerning, and would need to be experimentally verified, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 11:21:23,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.415 and 352.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.11) is slightly higher than Ligand B (70.08). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**3. logP:** Ligand A (1.614) is within the optimal range (1-3). Ligand B (0.054) is quite low, potentially hindering permeation. This is a significant disadvantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) 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: 0.711, B: 0.686), indicating good drug-likeness.

**7. DILI:** Ligand A (56.805) has a higher DILI risk than Ligand B (16.13). This favors Ligand B.

**8. BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand B (74.06) is higher, but this isn't decisive.

**9. Caco-2 Permeability:** Ligand A (-5.367) has poor Caco-2 permeability, while Ligand B (-4.467) is slightly better, but both are quite poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.687, B: -2.332).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.459, B: 0.255), which is excellent.

**12. Microsomal Clearance:** Ligand A (1.758) has significantly lower microsomal clearance than Ligand B (6.713), indicating better metabolic stability. This is a major advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (14.813 hours) has a much longer half-life than Ligand B (3.783 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.04, B: 0.044).

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.5 kcal/mol). This difference of 3.3 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher DILI risk and poorer Caco-2 permeability, its significantly superior binding affinity (-9.8 vs -6.5 kcal/mol) and much better metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target like SRC kinase. The lower logP of Ligand B is a significant concern, potentially hindering its ability to reach the target.



Output:
1
2025-04-17 11:21:23,561 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (348.443 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.65) is slightly higher than Ligand B (82.53). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable due to the lower TPSA.

**3. logP:** Both ligands have acceptable logP values (1.299 and 2.223), falling within the 1-3 range. Ligand B's logP is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors:** Ligand A has 3 HBDs, and Ligand B has 2. Both are 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:** Both ligands have good QED scores (0.645 and 0.716), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 9.112%, while Ligand B has 23.187%. Ligand A is significantly better here, indicating a lower risk of liver injury.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (55.913%) is higher than Ligand B (40.364%).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.81 and -4.73). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.468 and -1.809). This is also unusual and indicates very poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Ligand A (0.243) has a slightly lower hERG inhibition risk than Ligand B (0.415), which is favorable.

**12. Microsomal Clearance:** Ligand A (32.83) has a higher microsomal clearance than Ligand B (29.634), indicating lower metabolic stability. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand A (-11.923) has a significantly lower in vitro half-life than Ligand B (25.555). This is a major drawback for Ligand A, as a longer half-life is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.081 and 0.062).

**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 enough to be considered, especially given the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B demonstrates better metabolic stability (lower Cl_mic, higher t1/2), a slightly better binding affinity, and a lower DILI risk. Ligand A's significantly shorter half-life is a major concern. The slightly better hERG profile of Ligand A is outweighed by the other factors.

Output:
1
2025-04-17 11:21:23,561 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.459 Da and 386.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.84) is slightly above the preferred <140 for good absorption, while Ligand B (66.48) is well within the range.

**logP:** Ligand A (0.498) is a bit low, potentially hindering permeation. Ligand B (3.264) is optimal.

**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 (0.757 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 62.001, which is moderately high. Ligand B has a lower DILI risk of 35.983, which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (55.254) and Ligand B (70.182) are both reasonable.

**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 solubility. Again, the scale is unspecified, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.153) has a very low hERG risk, which is excellent. Ligand B (0.824) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (26.821) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (48.594).

**In vitro Half-Life:** Ligand A (-19.307) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (-21.345) also has a negative half-life, indicating a data quality issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.421).

**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:**

Despite the questionable solubility and permeability data, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.6 vs -6.3 kcal/mol) is a major advantage for an enzyme target. It also has a lower DILI risk and a better logP value. The hERG risk is slightly higher, but acceptable. The negative half-life values are concerning and would require further investigation, but the binding affinity difference is compelling.

Output:
1
2025-04-17 11:21:23,561 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (393.286 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold, suggesting good absorption. Ligand B (121.6) is also below the threshold, but higher than A.

**logP:** Ligand A (2.097) is optimal (1-3). Ligand B (0.014) is very low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.568 and 0.653), indicating drug-likeness.

**DILI:** Ligand A (37.767) has a lower DILI risk than Ligand B (47.887), both are acceptable.

**BBB:** Ligand A (72.005) has better BBB penetration than Ligand B (60.993), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.052) and Ligand B (-5.856) have negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-2.985) and Ligand B (-2.283) have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.42) has a much lower hERG risk than Ligand B (0.147). This is a significant advantage.

**Microsomal Clearance:** Ligand A (9.141) has a lower (better) microsomal clearance than Ligand B (-30.18). This suggests better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.897) has a longer half-life than Ligand B (-15.558).

**P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux than Ligand B (0.014), which is favorable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.8 and -8.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand A is the superior candidate. While both have good affinity, Ligand A demonstrates significantly better ADME properties: lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. Although both have poor solubility and permeability, the ADME advantages of Ligand A outweigh the slight difference in binding affinity. The low logP of Ligand B is a major concern.

Output:
1
2025-04-17 11:21:23,561 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.447 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Ligand A (126.65) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (95.32) is well within the acceptable range.

**logP:** Ligand A (0.637) is a bit low, potentially hindering permeation. Ligand B (1.771) is better, 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 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.605, B: 0.812), indicating good drug-likeness.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (43.66), which is preferable.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which 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 have negative solubility values, which is also unusual. Again, the scale is unknown.

**hERG:** Ligand A (0.301) has a slightly better hERG profile than Ligand B (0.402), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (13.081) has significantly lower microsomal clearance than Ligand B (49.368), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-11.135) has a negative half-life, which is not possible. This is a red flag. Ligand B (-3.048) also has a negative half-life, which is also concerning.

**P-gp Efflux:** Ligand A (0.072) has very low P-gp efflux, while Ligand B (0.034) is even lower. Both are good.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially 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 concerns. The significantly superior binding affinity (-9.2 kcal/mol vs 0.0 kcal/mol) is a critical advantage for an enzyme inhibitor. While Ligand A has better metabolic stability (lower Cl_mic) and slightly better hERG, the negative half-life is a major issue. Both ligands have issues with solubility and Caco-2 permeability, but the binding affinity difference is the most important factor. The DILI risk is also lower for Ligand B.

Output:
1
2025-04-17 11:21:23,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.446 and 353.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (100.55). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is relatively high, potentially hindering absorption.

**logP:** Ligand A (2.703) is optimal (1-3), while Ligand B (0.692) is slightly low, potentially impacting permeability.

**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:** Ligand A (0.915) has a much better QED score than Ligand B (0.67), indicating a more drug-like profile.

**DILI:** Ligand A (33.346) has a lower DILI risk than Ligand B (55.68), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.731) is higher than Ligand B (58.317).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so this is difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.476 and -1.462), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.488) has a lower hERG risk than Ligand B (0.165), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (25.909) has a higher (worse) microsomal clearance than Ligand B (0.832), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-8.597) has a much longer half-life than Ligand B (6.995), which is a positive.

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux liability than Ligand B (0.016), which is favorable.

**Binding Affinity:** Ligand B (-9.2) has a slightly better binding affinity than Ligand A (-8.6), but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has several advantages: better QED, lower DILI, lower hERG risk, and longer half-life. However, its higher microsomal clearance is a significant concern. Ligand B has better metabolic stability, but suffers from higher TPSA, lower QED, higher DILI, and a higher hERG risk.

Given the priorities for enzyme inhibitors, the metabolic stability of Ligand B is attractive. However, the significantly better overall drug-likeness (QED, DILI, hERG) of Ligand A, combined with a still-reasonable binding affinity, makes it the more promising candidate, assuming the metabolic stability issues can be addressed through further optimization.

Output:
1
2025-04-17 11:21:23,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.881 and 363.933 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.47) is better than Ligand B (48.99), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.217) is optimal, while Ligand B (4.717) is approaching the upper limit and could potentially cause solubility issues.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the 5 threshold.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 2 respectively), well below the 10 threshold.

**QED:** Both ligands have good QED scores (0.695 and 0.795), indicating good drug-like properties.

**DILI:** Ligand A (38.038) has a slightly higher DILI risk than Ligand B (22.8), but both are below the 40 threshold, indicating low risk.

**BBB:** Both ligands have good BBB penetration (70.609 and 78.868), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. This could indicate issues with the prediction method or potential problems with intestinal absorption. However, since both are similarly affected, it doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests potential formulation challenges. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.246) has a much lower hERG inhibition risk than Ligand B (0.697), which is a significant advantage.

**Microsomal Clearance:** Ligand A (43.519) has significantly lower microsomal clearance than Ligand B (81.486), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (77.441) has a longer in vitro half-life than Ligand B (20.738), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.779), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.2 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 demonstrates better ADMET properties (lower hERG, lower clearance, longer half-life, lower P-gp efflux), Ligand B's significantly superior binding affinity (-9.2 vs -7.1 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The potency advantage outweighs the ADME concerns, especially since Ligand B's ADME profile is still reasonably acceptable. The negative solubility and Caco-2 values are concerning for both, but can be addressed during formulation development.

Output:
1
2025-04-17 11:21:23,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 and 344.46 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (67.43).  A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have good logP values (2.59 and 3.07), 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:** Both ligands have similar, good QED values (0.788 and 0.747), indicating good drug-like properties.

**DILI:** Ligand A (26.10) has a much lower DILI risk than Ligand B (45.44), which is a significant advantage.  A value under 40 is desirable, and A is closer to that.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.61) has a higher BBB penetration than Ligand B (54.60), but this isn't a major factor in this case.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.30 and -4.39), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.57) is slightly better than Ligand B (-4.05), but both are very poor, indicating potential formulation challenges.

**hERG Inhibition:** Ligand A (0.54) has a lower hERG risk than Ligand B (0.31), which is a positive. Lower values are preferred.

**Microsomal Clearance:** Ligand A (58.91) has a lower microsomal clearance than Ligand B (69.14), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (7.41 hours) has a significantly longer half-life than Ligand B (-17.55 hours). The negative value for B is concerning and suggests very rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.24 and 0.21), which is good.

**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 noticeable.

**Overall Assessment:**

Ligand A is clearly superior. It demonstrates a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better solubility, lower hERG risk, and a slightly stronger binding affinity. While both have poor Caco-2 permeability, the other advantages of Ligand A outweigh this drawback. The longer half-life and improved safety profile of Ligand A make it a more promising drug candidate.

Output:
1
2025-04-17 11:21:23,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.479 Da and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is higher than Ligand B (54.46). While both are reasonably good, Ligand B is significantly better, being well below the 140 threshold for oral absorption.

**logP:** Ligand A (0.989) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (3.229) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are acceptable, but Ligand B has a more favorable balance.

**QED:** Both ligands have good QED scores (0.541 and 0.806), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (6.747) has a very low DILI risk, significantly better than Ligand B (19.426).

**BBB:** Both have reasonable BBB penetration, but Ligand B (78.519) is better than Ligand A (67.429). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.794 and -4.811). This is unusual and suggests poor permeability *in vitro*. It's difficult to interpret without further context, but it's a negative for both.

**Aqueous Solubility:** Both have negative solubility values (-1.189 and -3.42). Again, this is unusual and suggests poor solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.167) has a much lower hERG risk than Ligand B (0.751), which is a significant advantage.

**Microsomal Clearance:** Ligand A (27.959) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (70.604).

**In vitro Half-Life:** Ligand A (-22.76) has a negative half-life, which is not physically possible. This is a major red flag. Ligand B (4.046) has a short half-life, but it's a realistic value.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.218).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-7.5 kcal/mol and -7.3 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a major issue with its reported negative in vitro half-life, which is not physically plausible and suggests a data error. It also has a slightly lower logP and a worse Caco-2 permeability. While it has a better DILI score and hERG risk, the half-life issue is critical. Ligand B, despite having a slightly higher DILI risk and lower solubility, presents a more realistic and potentially developable profile.

Output:
1
2025-04-17 11:21:23,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.503 and 348.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is slightly higher than Ligand B (59.81), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.495) is optimal, while Ligand B (4.282) is approaching the upper limit of the preferred range. Higher logP can sometimes lead to off-target effects and solubility issues.

**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 (0.749 and 0.781), indicating good drug-like properties.

**DILI:** Ligand A (10.585) has a significantly lower DILI risk than Ligand B (24.661). This is a major advantage for Ligand A.

**BBB:** Ligand A (66.809) has a lower BBB penetration than Ligand B (74.952). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.589 and -4.702), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.014 and -4.998), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.385) has a slightly higher hERG risk than Ligand B (0.162), but both are relatively low.

**Microsomal Clearance:** Ligand A (38.602) has a lower microsomal clearance than Ligand B (71.116), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-4.935) has a longer in vitro half-life than Ligand B (0.388). This further supports its better metabolic stability.

**P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux liability than Ligand B (0.242), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a 1.0 kcal/mol difference is noticeable, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. The poor solubility and permeability are concerns for both, but the superior safety and pharmacokinetic profile of Ligand A outweigh the minor affinity difference.

Output:
0
2025-04-17 11:21:23,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.451 and 386.949 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.14) is slightly above the preferred <140, but acceptable. Ligand B (74.33) is excellent, well below 140.

**logP:** Ligand A (0.936) is a bit low, potentially hindering permeability. Ligand B (2.545) is optimal.

**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:** Ligand A (0.823) has a very good QED score, indicating high drug-likeness. Ligand B (0.684) is still acceptable, but lower.

**DILI:** Ligand A (38.62) has a slightly higher DILI risk than Ligand B (32.532), but both are below the concerning threshold of 60.

**BBB:** Both ligands have moderate BBB penetration (67.197 and 64.482), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.461 and -5.209), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.433 and -2.159), also unusual and concerning for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.069 and 0.492), which is excellent.

**Microsomal Clearance:** Ligand A (8.875) has significantly lower microsomal clearance than Ligand B (20.234), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (-16.436) has a negative half-life, which is not possible and indicates a data error or a very rapidly metabolized compound. Ligand B (32.539) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.1), which is favorable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.6 and -8.4 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the similar binding affinities, Ligand A is problematic due to the negative and unrealistic in vitro half-life. While Ligand A has a better QED and lower Cl_mic, the negative half-life is a showstopper. Ligand B, while having a slightly lower QED and higher Cl_mic, has a reasonable half-life and acceptable values for other ADME properties. The negative Caco-2 and solubility values for both are concerning, but the metabolic stability advantage of Ligand B, coupled with its realistic half-life, makes it the more viable candidate.

Output:
1
2025-04-17 11:21:23,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.407 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.42) is better than Ligand B (113.44), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have low logP values (0.268 and 0.115). While not ideal (optimal is 1-3), they aren't excessively low. This might be acceptable if other properties are strong.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is better than Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.737 and 0.671), indicating good drug-like properties.

**DILI:** Ligand A (56.727) has a slightly higher DILI risk than Ligand B (49.011), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.87) is slightly better than Ligand B (43.66).

**Caco-2 Permeability:** Ligand A (-4.945) is significantly better than Ligand B (-5.249), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.761) is slightly better than Ligand B (-1.391). Both are negative, suggesting poor solubility, which is a concern.

**hERG Inhibition:** Ligand A (0.095) has a lower hERG risk than Ligand B (0.158), which is favorable.

**Microsomal Clearance:** Ligand B (-4.236) has a significantly lower (better) microsomal clearance than Ligand A (23.337), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (26.75) has a much longer half-life than Ligand A (-6.287), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.016), which is good.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better TPSA, solubility, and hERG, Ligand B's significantly stronger binding affinity, much improved metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability make it the more promising drug candidate. The lower affinity of Ligand A, combined with its higher clearance, is a significant drawback. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:21:23,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.861 Da and 369.29 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.34) is well below the 140 threshold, suggesting good absorption. Ligand B (84.22) is still within acceptable limits but less favorable.

**logP:** Ligand A (4.478) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.456) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable H-bonding characteristics.

**QED:** Both ligands have good QED scores (0.667 and 0.781), indicating drug-like properties.

**DILI:** Ligand A (88.057) has a higher DILI risk than Ligand B (63.862), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (73.672) has a slightly better score than Ligand B (67.623).

**Caco-2 Permeability:** Ligand A (-4.968) shows poor permeability, which is a significant drawback. Ligand B (-5.095) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.418 and -2.817 respectively). This is a major concern for both.

**hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.057), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (89.001) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-5.151) 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 (9.255 hours) has a reasonable half-life. Ligand B (-22.346 hours) also has a negative value, which is not possible and suggests a very long half-life.

**P-gp Efflux:** Ligand A (0.673) has moderate P-gp efflux. Ligand B (0.007) has very low P-gp efflux, which is favorable.

**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 for Ligand B.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand B is the more promising candidate. It has a significantly lower DILI risk, much lower hERG inhibition, and lower P-gp efflux. The negative values for clearance and half-life are concerning and likely data errors, but even without those, the other ADME properties are more favorable. The slightly better binding affinity of Ligand B further supports this conclusion. The high logP of Ligand A is also a concern.

Output:
1
2025-04-17 11:21:23,563 - INFO - Batch 40 complete. Total preferences: 640
2025-04-17 11:21:23,563 - INFO - Processing batch 41/512...
2025-04-17 11:22:02,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (348.355 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.49) is slightly above the preferred <140, but acceptable. Ligand B (70.67) is excellent, well below 140.

**logP:** Both ligands have good logP values (2.398 and 1.642), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which is acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.604 and 0.552), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 88.057, which is high and concerning. Ligand B has a much lower DILI risk of 35.479, which is good.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (77.123) has a higher score than Ligand A (57.736).

**Caco-2 Permeability:** Ligand A (-4.653) shows poor permeability. Ligand B (-5.027) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.245) has poor solubility. Ligand B (-1.794) has better solubility.

**hERG:** Ligand A (0.099) has a very low hERG risk, which is excellent. Ligand B (0.552) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (106.579) has relatively high microsomal clearance, indicating lower metabolic stability. Ligand B (-1.397) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-41.377) has a negative half-life, which is concerning. Ligand B (17.461) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.174 and 0.105).

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A's excellent hERG profile, its high DILI risk, poor solubility, poor permeability, and lower binding affinity make it a less desirable candidate. Ligand B excels in key areas: significantly higher binding affinity, excellent metabolic stability (low Cl_mic, good t1/2), lower DILI risk, and better solubility. While Caco-2 permeability is poor for both, the superior potency and ADME profile of Ligand B outweigh this concern.

Output:
1
2025-04-17 11:22:02,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 356.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.9) is better than Ligand B (70.67), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.176) is quite low, potentially hindering permeability. Ligand B (3.469) 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 (2) is also acceptable.

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (0.765 and 0.832, respectively), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (48.197 and 47.77).

**BBB:** Both ligands have moderate BBB penetration (56.572 and 61.38). Not a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.529) is quite poor, suggesting very limited intestinal absorption. Ligand B (-5.22) is also poor, but slightly better than A.

**Solubility:** Ligand A (-1.056) is poor. Ligand B (-4.057) is also poor, but again, slightly better.

**hERG:** Ligand A (0.137) is very low risk, excellent. Ligand B (0.539) is slightly higher, but still relatively low risk.

**Microsomal Clearance:** Ligand A (24.381) is better than Ligand B (33.802), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.641) is positive, but Ligand B (-14.953) is negative, suggesting very poor stability. This is a critical drawback for Ligand B.

**P-gp:** Both ligands have low P-gp efflux liability (0.153 and 0.21).

**Binding Affinity:** Both ligands have identical and excellent binding affinity (-7.9 kcal/mol).

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B has a significantly better logP value, which is crucial for permeability. However, its extremely poor *in vitro* half-life is a major concern. Ligand A has a poor logP and Caco-2 permeability, but its better metabolic stability (lower Cl_mic and positive half-life) and excellent hERG profile make it the more promising candidate. The poor permeability of Ligand A could potentially be addressed through formulation strategies, but the poor stability of Ligand B is a more fundamental issue.

Output:
0
2025-04-17 11:22:02,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.434 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.53) is well below the 140 threshold for good absorption. Ligand B (139.97) is close to the limit, but still acceptable.

**logP:** Ligand A (0.974) is at the lower end of the optimal range (1-3), potentially impacting permeability. Ligand B (-0.089) is slightly below 1, raising concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) and Ligand B (HBD=5, HBA=5) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Ligand A (0.733) has a better QED score than Ligand B (0.444), indicating a more drug-like profile.

**DILI:** Ligand A (68.205) has a slightly higher DILI risk than Ligand B (54.478), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (48.275) and Ligand B (30.748) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.525 and -5.436), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.34 and -2.245), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.453) exhibits a lower hERG inhibition liability than Ligand B (0.121), which is favorable.

**Microsomal Clearance:** Ligand A (-20.862) has significantly lower (better) microsomal clearance than Ligand B (-5.129), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.804) has a longer in vitro half-life than Ligand B (-10.27), which is desirable.

**P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux liability than Ligand B (0.012), which is favorable.

**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.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its superior binding affinity (-8.8 vs -7.8 kcal/mol), better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and better QED score outweigh the slightly higher DILI risk. The strong affinity suggests a higher likelihood of achieving efficacy, and the improved metabolic stability and reduced toxicity potential are crucial for drug development. The permeability and solubility issues would need to be addressed through formulation or further chemical modifications, but the core potency and safety profile of Ligand A is more favorable.

Output:
0
2025-04-17 11:22:02,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (369.491 and 356.438 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (111.21) is slightly above the preferred <140, but acceptable. Ligand B (76.66) is well within the acceptable range.

**3. logP:** Ligand A (0.126) is quite low, potentially hindering permeability. Ligand B (1.846) is within 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 (4) is also acceptable.

**6. QED:** Both ligands have reasonable QED scores (0.506 and 0.463), suggesting decent drug-likeness.

**7. DILI:** Ligand A (26.095) has a much lower DILI risk than Ligand B (39.201), which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (81.698) has a higher BBB score, but this isn't a major factor here.

**9. Caco-2 Permeability:** Ligand A (-6.079) shows poor permeability, consistent with its low logP. Ligand B (-4.715) is better, but still not great.

**10. Aqueous Solubility:** Ligand A (-0.996) has poor solubility, while Ligand B (-1.76) is even worse. Both are concerning.

**11. hERG Inhibition:** Ligand A (0.155) has a very low hERG risk, a major advantage. Ligand B (0.458) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-14.797) indicates very *low* clearance and excellent metabolic stability, a huge positive. Ligand B (29.36) has significantly higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (4.979) has a reasonable half-life. Ligand B (-0.008) has a very short half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.115).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). The difference is 0.8 kcal/mol, which is not a huge advantage.

**Overall Assessment:**

Ligand A is significantly better despite the slightly weaker binding affinity. Its superior metabolic stability (very low Cl_mic, longer half-life), lower DILI risk, and very low hERG risk outweigh the slightly weaker binding. While both have solubility concerns, the metabolic advantages of Ligand A are critical for an enzyme target. The low logP of Ligand A is a drawback, but can potentially be addressed through formulation strategies. Ligand B's higher clearance and shorter half-life are substantial liabilities.

Output:
0
2025-04-17 11:22:02,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 351.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.89) is better than Ligand B (53.51) as it is still within the acceptable range for oral absorption (<140), while Ligand B is even more favorable.

**logP:** Both ligands have good logP values (1.03 and 2.362), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.837) has a significantly higher QED score than Ligand A (0.452), indicating a more drug-like profile.

**DILI:** Ligand B (21.481) has a much lower DILI risk than Ligand A (34.781), which is a significant advantage.

**BBB:** Ligand B (95.192) has a much higher BBB penetration score than Ligand A (75.145). While not a primary concern for a kinase inhibitor, higher BBB is never a detriment.

**Caco-2 Permeability:** Ligand A (-5.469) has a lower Caco-2 permeability than Ligand B (-4.184), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.101 and -2.325). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.428) has a slightly higher hERG inhibition risk than Ligand B (0.279), although both are relatively low.

**Microsomal Clearance:** Ligand B (21.36) has a lower microsomal clearance than Ligand A (26.58), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.314) has a significantly longer in vitro half-life than Ligand A (10.692), which is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.072 and 0.063).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This 1.1 kcal/mol difference is significant, and can outweigh some of the ADME drawbacks.

**Overall:**

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), slightly better binding affinity, and higher BBB penetration. While both have poor solubility, the other advantages of Ligand B outweigh this concern. The improved ADME profile and binding affinity make Ligand B a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 11:22:02,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.308 Da) is slightly higher than Ligand B (363.447 Da), but both are acceptable.

**TPSA:** Ligand A (74.25) is well below the 140 threshold for oral absorption. Ligand B (129.89) is also acceptable, but closer to the limit.

**logP:** Ligand A (4.06) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.786) is quite low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 7. Ligand B's higher HBA count could slightly impact permeability.

**QED:** Ligand A (0.722) has a better QED score than Ligand B (0.467), indicating a more drug-like profile.

**DILI:** Ligand B (61.419) has a slightly higher DILI risk than Ligand A (55.487), but both are moderately risky.

**BBB:** Ligand A (73.711) shows better BBB penetration potential than Ligand B (59.248), although this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.762) has a significantly worse Caco-2 permeability than Ligand B (-6.154). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-5.036) has worse aqueous solubility than Ligand B (-2.985).

**hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.689 and 0.691), which is acceptable.

**Microsomal Clearance:** Ligand B (33.935) has a lower microsomal clearance than Ligand A (41.758), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (93.912) has a significantly longer in vitro half-life than Ligand B (-13.892), which is highly desirable.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.416 and 0.075).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a crucial advantage, potentially outweighing some of its ADME drawbacks. The difference of 1.2 kcal/mol is significant.

**Conclusion:**

Despite Ligand A's higher logP and lower solubility/permeability, its significantly superior binding affinity (-9.2 vs -8.0 kcal/mol) and longer half-life are compelling advantages, especially for an enzyme target like SRC kinase. The improved QED score also favors Ligand A. While Ligand B has better metabolic stability, the potency difference is substantial enough to prioritize Ligand A.

Output:
1
2025-04-17 11:22:02,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.394 and 360.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (99.1) is higher than Ligand B (66.4). While both are reasonably good, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (-0.933) is a bit low, potentially hindering permeation. Ligand B (1.745) is within the optimal range of 1-3. This favors Ligand B.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is even better, potentially improving permeability.

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

**QED:** Both ligands have good QED scores (0.591 and 0.821), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (14.618) has a significantly lower DILI risk than Ligand B (49.011). This is a major advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (56.611) is slightly higher.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.23 and -4.95), 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 (-1.088 and -2.98), indicating poor aqueous solubility. Ligand A is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.282 and 0.211), which is good.

**Microsomal Clearance:** Ligand A (-9.604) has a much lower (better) microsomal clearance than Ligand B (52.619), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.215) has a better in vitro half-life than Ligand B (-4.095).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.114).

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-6.7). While both are good, the 1.1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and higher t1/2), and slightly better solubility. Ligand B has a more favorable logP and TPSA, but its higher DILI risk and significantly worse metabolic stability are major drawbacks. For an enzyme target like SRC kinase, metabolic stability and potency are crucial. The superior binding affinity of Ligand A, coupled with its better safety profile (lower DILI) and metabolic stability, make it the more promising candidate, despite its slightly lower logP.

Output:
0
2025-04-17 11:22:02,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.46 and 373.84 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (66.4 and 62.31) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.14 and 2.094) are within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 6 HBA) in terms of balancing solubility and permeability, although both are acceptable.

**QED:** Both ligands have reasonable QED scores (0.842 and 0.745), indicating good drug-likeness.

**DILI:** Ligand A (46.30) has a slightly better DILI score than Ligand B (57.46), suggesting a lower risk of liver injury. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand B (88.25) has a higher BBB percentile than Ligand A (73.83).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.697 and -4.844). This is unusual and suggests potential issues with intestinal absorption. However, these values are on a log scale and are difficult to interpret without knowing the base.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.06 and -3.684). Similar to Caco-2, these values are on a log scale and are difficult to interpret.

**hERG Inhibition:** Ligand A (0.451) has a significantly lower hERG inhibition liability than Ligand B (0.845), which is a major advantage.

**Microsomal Clearance:** Ligand A (46.79) has a higher microsomal clearance than Ligand B (19.04), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (58.14) has a much longer in vitro half-life than Ligand A (0.401), which is a major advantage.

**P-gp Efflux:** Ligand A (0.181) has lower P-gp efflux liability than Ligand B (0.047), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better hERG and P-gp profiles, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.6 vs -7.5 kcal/mol) and substantially longer in vitro half-life (58.14 vs 0.401) outweigh the slightly higher DILI risk and P-gp efflux. The metabolic stability (lower Cl_mic) is also better for Ligand B. The negative Caco-2 and solubility values are concerning for both, but the superior potency and PK profile of Ligand B make it the better choice.

Output:
1
2025-04-17 11:22:02,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.403 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.78) is slightly higher than Ligand B (72.12), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.803) is within the optimal 1-3 range, while Ligand B (4.01) is at the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it balances solubility and permeability.

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

**QED:** Both ligands have good QED scores (0.629 and 0.709), indicating drug-like properties.

**DILI:** Ligand A (50.368) has a slightly higher DILI risk than Ligand B (37.03), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.552) has a lower BBB penetration than Ligand B (86.855). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.39) shows poor Caco-2 permeability, which is a concern for oral absorption. Ligand B (-4.987) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.555) has very poor aqueous solubility, which is a significant drawback. Ligand B (-4.728) also has poor solubility, but is better than Ligand A.

**hERG Inhibition:** Ligand A (0.087) has a very low hERG inhibition risk, which is excellent. Ligand B (0.668) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (21.722) has significantly lower microsomal clearance than Ligand B (80.166), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (25.044) has a shorter half-life than Ligand B (31.905), but both are reasonable.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is favorable. Ligand B (0.652) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.4 and -7.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While its Caco-2 permeability and solubility are poor, its significantly better metabolic stability (lower Cl_mic) and very low hERG risk outweigh these drawbacks, especially for an enzyme target like SRC kinase. The slightly better P-gp efflux is also a plus. The binding affinity is comparable between the two. The higher logP of Ligand B is a concern.

Output:
0
2025-04-17 11:22:02,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (100.45) is better than Ligand B (49.41). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.051) is within the optimal range (1-3), while Ligand B (3.382) is approaching the upper limit. While not a major concern, Ligand A's logP is more favorable.

**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 A (0.723) has a better QED score than Ligand B (0.493), indicating a more drug-like profile.

**DILI:** Ligand A (47.693) has a significantly lower DILI risk than Ligand B (18.108), which is a substantial advantage.

**BBB:** Ligand B (85.111) has a higher BBB penetration score than Ligand A (50.679). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.154) is slightly better than Ligand B (-5.008).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.129) is slightly better than Ligand B (-4.184).

**hERG Inhibition:** Ligand A (0.189) has a much lower hERG inhibition liability than Ligand B (0.696), which is a critical advantage for safety.

**Microsomal Clearance:** Ligand B (53.736) has a higher microsomal clearance than Ligand A (3.063), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (16.205) has a longer in vitro half-life than Ligand B (-3.78), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.024) has a lower P-gp efflux liability than Ligand B (0.269), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (0.0). This is the most important factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the significant drawbacks in metabolic stability (high Cl_mic, short t1/2), DILI risk, hERG inhibition, and solubility are concerning. Ligand A, while having weaker binding affinity, presents a much more balanced profile with lower toxicity risks, better metabolic stability, and improved drug-like properties. For an enzyme target like SRC kinase, metabolic stability and safety are crucial. The substantial difference in binding affinity *might* be overcome with further optimization of Ligand A, whereas fixing the ADME issues of Ligand B would likely require more extensive structural modifications.

Output:
0
2025-04-17 11:22:02,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.459 and 338.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.4) is higher than the preferred <140, but acceptable. Ligand B (58.12) is excellent, well below 140.

**3. logP:** Ligand A (0.916) is slightly low, potentially impacting permeability. Ligand B (4.576) is high and could lead to solubility issues or off-target interactions.

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

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (3) is also good.

**6. QED:** Both ligands have high QED scores (0.546 and 0.888), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (49.632 and 51.221), both are acceptable.

**8. BBB:** Ligand A (65.452) and Ligand B (86.274) are both acceptable, but not particularly high, which isn't critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.349) is very poor, indicating very low intestinal absorption. Ligand B (-4.373) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-2.752) is poor. Ligand B (-4.932) is even worse.

**11. hERG Inhibition:** Ligand A (0.242) is very low risk. Ligand B (0.777) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (30.971) is relatively low, suggesting better metabolic stability. Ligand B (65.504) is higher, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (-16.329) is very poor, indicating rapid degradation. Ligand B (26.696) is better, but not ideal.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.01 and 0.216), which is good.

**15. 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 A has a better metabolic stability profile (lower Cl_mic, better half-life) and a significantly lower hERG risk. However, its Caco-2 permeability and aqueous solubility are very poor, and its logP is on the low side. Ligand B has better permeability (though still not great) and a slightly better BBB score, but suffers from higher metabolic clearance and a worse half-life.

Given the enzyme-specific priorities, metabolic stability and low hERG risk are crucial. While both have solubility issues, Ligand A's superior metabolic stability and lower hERG risk make it the more promising candidate, despite the permeability concerns. Solubility and permeability can be addressed with formulation strategies.

Output:
0
2025-04-17 11:22:02,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.559 Da and 348.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (70.95) is still under 140, but less optimal than A.

**logP:** Ligand A (2.686) is within the optimal 1-3 range. Ligand B (1.071) is on the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 7 HBA. Both are acceptable, but A is slightly preferred.

**QED:** Both ligands have good QED scores (0.678 and 0.873), indicating drug-like properties.

**DILI:** Ligand A (31.291) has a lower DILI risk than Ligand B (47.77), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (71.772) is slightly better than Ligand A (68.205). However, BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both, but the less negative value for A (-5.007) is slightly better than B (-4.852).

**Solubility:** Both have negative solubility values, indicating poor aqueous solubility. A (-3.169) is slightly better than B (-1.799). This is a concern, but can be addressed with formulation strategies.

**hERG:** Ligand A (0.458) has a lower hERG risk than Ligand B (0.711), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand B (40.533) has lower microsomal clearance than Ligand A (48.851), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (21.258) has a significantly longer half-life than Ligand A (3.295), which is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.286) has lower P-gp efflux than Ligand B (0.032), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage and can potentially outweigh some of the ADME drawbacks. The difference of >1.5 kcal/mol is very important.

**Overall Assessment:**

While Ligand A has better solubility, lower DILI risk, and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-9.8 vs -7.7 kcal/mol) and longer half-life are compelling advantages for an enzyme inhibitor. The lower clearance of B is also beneficial. The slightly higher DILI and hERG risks of B are manageable, and the poor Caco-2 and solubility can be addressed with formulation. The affinity difference is the most important factor here.

Output:
1
2025-04-17 11:22:02,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (360.385 Da) is also good.

**TPSA:** Ligand A (93.97) is better than Ligand B (52.08). Lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (1.177) is optimal, while Ligand B (4.325) is high. High logP can lead to solubility issues and off-target interactions.

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

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable range.

**QED:** Ligand A (0.832) has a significantly better QED score than Ligand B (0.502), indicating a more drug-like profile.

**DILI:** Ligand A (22.683) has a much lower DILI risk than Ligand B (80.729), which is a significant advantage.

**BBB:**  BBB isn't a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired. Ligand B (65.529) has a higher BBB score than Ligand A (29.973), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar, so it doesn't strongly favor either.

**Aqueous Solubility:** Ligand A (-0.855) has better solubility than Ligand B (-5.407). Solubility is crucial for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.205 and 0.28, respectively).

**Microsomal Clearance:** Ligand A (13.888) has significantly lower microsomal clearance than Ligand B (101.592), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.188) has a longer in vitro half-life than Ligand B (-3.547).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.182, respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-7.7 and -7.5 kcal/mol). The difference is minimal.

**Conclusion:**

Ligand A is significantly better overall. It has a better QED score, much lower DILI risk, better solubility, lower microsomal clearance, and a longer half-life. While Ligand B has a slightly higher BBB score, this is not a critical factor for an SRC kinase inhibitor. The similar binding affinities mean that the superior ADME properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 11:22:02,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.45 & 371.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (103.86), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (not a priority here).

**logP:** Ligand A (1.252) is within the optimal 1-3 range. Ligand B (-0.685) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have similar QED values (0.663 and 0.623), indicating good drug-likeness.

**DILI:** Ligand A (26.173) has a significantly lower DILI risk than Ligand B (47.77), which is a major advantage.

**BBB:** Not a primary concern for a non-CNS target. Ligand B (50.911) is slightly higher than Ligand A (42.303).

**Caco-2 Permeability:** Ligand A (-4.996) is better than Ligand B (-5.403), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.265) is better than Ligand B (-1.388), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.18 and 0.03), which is excellent.

**Microsomal Clearance:** Ligand B (-8.366) has a *negative* Cl_mic, suggesting very high metabolic stability, while Ligand A (11.746) is higher, indicating faster clearance. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (12.175 hours) has a significantly longer half-life than Ligand A (-0.042 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.016).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has advantages in TPSA, solubility, and DILI risk, Ligand B's significantly stronger binding affinity (-9.3 vs -8.2 kcal/mol) and dramatically improved metabolic stability (negative Cl_mic and longer half-life) are crucial for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed with further optimization, but the potency and metabolic stability benefits are more important.

Output:
1
2025-04-17 11:22:02,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.357 Da and 367.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is higher than Ligand B (29.54). While both are reasonably low, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have logP values around 4.2-4.7, which is slightly high. This could lead to solubility issues or off-target effects, but is not a dealbreaker if other properties are favorable.

**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 ranges.

**QED:** Ligand A (0.704) has a better QED score than Ligand B (0.567), suggesting a more drug-like profile overall.

**DILI:** Both ligands have very high DILI risk (96.937 and 96.549), which is a significant concern.

**BBB:** Both have reasonable BBB penetration, but Ligand A is better (80.264 vs 73.711). This is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**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 (-5.57 and -6.489). This is a major drawback.

**hERG Inhibition:** Ligand A (0.621) has a slightly higher hERG risk than Ligand B (0.527), but both are relatively low.

**Microsomal Clearance:** Both have high microsomal clearance (93.358 and 90.188), indicating poor metabolic stability.

**In vitro Half-Life:** Both have relatively short in vitro half-lives (53.814 and 49.332 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.435 and 0.877).

**Binding Affinity:** Ligand B (-10 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.

**Conclusion:**

Despite the high DILI risk and poor solubility/permeability for both compounds, Ligand B's substantially superior binding affinity (-10 kcal/mol vs -6.9 kcal/mol) makes it the more promising candidate. The >3 kcal/mol difference in affinity is a significant advantage for an enzyme inhibitor, and could be addressed through further medicinal chemistry optimization focused on improving solubility and reducing DILI risk. Ligand A's slightly better QED and BBB are not enough to offset the weaker binding.

Output:
1
2025-04-17 11:22:02,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.467 and 362.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.7) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**3. logP:** Ligand A (1.883) is within the optimal range (1-3). Ligand B (4.16) is slightly above this, 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 5 HBAs, while Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.71 and 0.8), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (49.244 and 41.062), below the concerning threshold of 60.

**8. BBB:** Both ligands have moderate BBB penetration (67.546 and 76.347). Since SRC is not a CNS target, this is not a major deciding factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.885 and -4.914). This is unusual and suggests poor permeability *in vitro*. However, these values are close enough to each other that they don't significantly differentiate the two.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.35 and -4.085). This is a significant concern for both, but slightly worse for Ligand B.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.393 and 0.547), which is excellent.

**12. Microsomal Clearance:** Ligand A (70.712) has higher microsomal clearance than Ligand B (61.785). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (12.694) has a much longer in vitro half-life than Ligand A (-35.551). This is a substantial advantage for Ligand B, indicating a slower rate of degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.489).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.3 kcal/mol), which is excellent and removes this as a differentiating factor.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its lower logP, significantly lower microsomal clearance, and substantially longer in vitro half-life outweigh the slightly lower solubility and higher TPSA. The improved metabolic stability and longer half-life are particularly important for an enzyme target like SRC kinase, as they suggest a potentially more durable effect *in vivo*.

Output:
1
2025-04-17 11:22:02,774 - INFO - Batch 41 complete. Total preferences: 656
2025-04-17 11:22:02,774 - INFO - Processing batch 42/512...
2025-04-17 11:22:44,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 and 362.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, and favorable for oral absorption. Ligand B (78.87) is still under the threshold, but less optimal than A.

**logP:** Ligand A (2.974) is within the optimal 1-3 range. Ligand B (1.133) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 4 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.766 and 0.603), indicating drug-likeness.

**DILI:** Ligand A (21.869) has a significantly lower DILI risk than Ligand B (16.402), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (86.739) is better than Ligand B (68.282). While not a primary concern for a kinase inhibitor, it's a slight positive for A.

**Caco-2 Permeability:** Ligand A (-4.261) shows better Caco-2 permeability than Ligand B (-4.517).

**Aqueous Solubility:** Ligand A (-3.052) has better aqueous solubility than Ligand B (-1.496), which is crucial for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.549 and 0.484), which is excellent.

**Microsomal Clearance:** Ligand A (50.534) has a higher microsomal clearance than Ligand B (19.97), indicating lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (-20.486) has a longer in vitro half-life than Ligand A (-19.864).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.547 and 0.037).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -7.9 kcal/mol). The difference is negligible.

**Conclusion:**

Despite Ligand A having better TPSA, logP, solubility, and DILI, Ligand B's significantly better metabolic stability (lower Cl_mic and longer half-life) is a critical advantage for an enzyme inhibitor. While Ligand A has a slightly better solubility profile, the increased metabolic clearance is a substantial concern. The binding affinities are comparable, so the ADME properties become the deciding factor.

Output:
1
2025-04-17 11:22:44,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.435 and 350.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.63 and 78.09) are below 140, suggesting reasonable absorption potential.

**logP:** Ligand A (3.893) is slightly higher than optimal (1-3), potentially leading to off-target effects, while Ligand B (2.354) is within the ideal range.

**H-Bond Donors:** Both ligands have 2 HBDs, well within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are below the limit of 10.

**QED:** Ligand B (0.856) has a significantly better QED score than Ligand A (0.492), indicating a more drug-like profile.

**DILI:** Ligand A (85.227) has a high DILI risk, exceeding the 60% threshold, which is a major concern. Ligand B (50.097) has a much lower, and acceptable, DILI risk.

**BBB:** Both ligands have reasonable BBB penetration (67.468 and 70.997), but this is less critical for a non-CNS target like SRC.

**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 (0.753) has a slightly higher hERG risk than Ligand B (0.438), but both are relatively low.

**Microsomal Clearance:** Ligand B (29.792) has significantly lower microsomal clearance than Ligand A (81.316), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-31.544) has a much longer in vitro half-life than Ligand A (-14.567). This is a significant benefit, allowing for potentially less frequent dosing.

**P-gp Efflux:** Ligand A (0.591) has a slightly higher P-gp efflux liability than Ligand B (0.091).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor, and the difference of 7.8 kcal/mol is very significant.

**Conclusion:**

Ligand B is clearly the superior candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly better binding affinity, lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), better QED score, and lower P-gp efflux outweigh the slightly higher logP. The substantial difference in binding affinity is particularly crucial for an enzyme target like SRC. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 11:22:44,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.359 and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.57) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (87.74) is excellent, well below 140 and suggesting good absorption.

**logP:** Ligand A (-1.437) is a bit low, potentially hindering permeability. Ligand B (1.44) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 6 HBA, acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.443) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.826) is excellent, well above 0.5.

**DILI:** Ligand A (49.05) is good, below the 60 threshold. Ligand B (69.678) is approaching a higher risk level, but not critically high.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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 unusual and suggests poor solubility. This is a significant concern for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.173 and 0.197), which is excellent.

**Microsomal Clearance:** Ligand A (-23.544) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (-15.687) also has a negative clearance, also suggesting an issue with the data.

**In vitro Half-Life:** Ligand A (26.59 hours) is reasonable. Ligand B (12.965 hours) is acceptable, but less desirable than A.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.004 and 0.045), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol) - a difference of 1.5 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B is the more promising candidate despite the issues with the Caco-2, solubility, and clearance data. Its superior binding affinity (-7.9 vs -6.4 kcal/mol) is a major advantage for an enzyme target like SRC. The QED score is also significantly better for Ligand B. While the DILI score is higher for B, it's not alarming. The negative values for Caco-2, solubility, and clearance are concerning and need investigation, but the strong affinity makes Ligand B worth further investigation. Ligand A's QED score is below the desired threshold, and its affinity is weaker. The negative clearance value is also problematic.

Output:
1
2025-04-17 11:22:44,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (356.486 and 364.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.68) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (84.42) is still under 140, but less favorable than A.

**3. logP:** Both ligands have logP values within the optimal 1-3 range (0.773 and 1.109).

**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 6 respectively), below the limit of 10.

**6. QED:** Both ligands have QED values above 0.5 (0.674 and 0.576), indicating good drug-likeness.

**7. DILI:** Ligand A (5.7) has a significantly lower DILI risk than Ligand B (57.193). This is a major advantage for Ligand A.

**8. BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (75.145) shows better BBB penetration potential than Ligand B (57.231).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.297 and -5.2), which is unusual. These values likely represent a logP-scaled permeability, where negative values indicate poor permeability. However, the values are very similar, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.886 and -1.689), indicating poor aqueous solubility. This is a potential issue for both, but Ligand A is slightly better.

**11. hERG Inhibition:** Ligand A (0.627) has a lower hERG inhibition risk than Ligand B (0.057), which is a significant advantage.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-38.455) has a much lower (better) microsomal clearance than Ligand B (32.825), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.352) has a longer in vitro half-life than Ligand B (-26.374), further supporting its improved metabolic stability.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.009 and 0.014).

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.3). While a 0.5 kcal/mol difference is noticeable, the other ADME properties of Ligand A are far superior.

**Enzyme-Specific Considerations:** For a kinase inhibitor, metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand A excels in these areas, with significantly lower DILI, hERG, and Cl_mic, and a longer half-life. While Ligand B has slightly better binding affinity, the substantial improvements in ADME properties for Ligand A outweigh this small difference in potency.

Output:
0
2025-04-17 11:22:44,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.5 and 363.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (117.7) is still under 140, but less optimal than A.

**logP:** Both ligands (2.036 and 2.201) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED scores (0.748 and 0.728), indicating good drug-likeness.

**DILI:** Ligand A (11.83) has a significantly lower DILI risk than Ligand B (85.62), which is a major concern.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (74.49) is better than Ligand B (48.66).

**Caco-2 Permeability:** Ligand A (-4.909) shows better Caco-2 permeability than Ligand B (-5.248).

**Aqueous Solubility:** Ligand A (-2.263) has better aqueous solubility than Ligand B (-3.249).

**hERG Inhibition:** Ligand A (0.369) has a lower hERG inhibition liability than Ligand B (0.133), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (37.55) has higher microsomal clearance than Ligand B (13.27), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (23.17) has a longer in vitro half-life than Ligand A (17.31), which is favorable.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.153), which is favorable for bioavailability.

**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.

**Conclusion:**

Despite Ligand A having a higher microsomal clearance, its significantly superior binding affinity (-8.4 vs -7.4 kcal/mol), lower DILI risk, better solubility, lower hERG risk, and better permeability make it the more promising drug candidate. The difference in affinity is large enough to compensate for the slightly reduced metabolic stability.

Output:
1
2025-04-17 11:22:44,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.515 and 360.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.45 and 75.94) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (3.428) is slightly higher than Ligand B (2.69), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (1), as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (7), keeping within the desired range.

**QED:** Both ligands have good QED scores (0.625 and 0.768), indicating good drug-like properties.

**DILI:** Ligand A (28.461) has a significantly lower DILI risk than Ligand B (67.313). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (66.072 and 70.415), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand B (-5.319) shows better Caco-2 permeability than Ligand A (-4.471), suggesting better absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.1 and -3.095). This is a significant drawback for both, but could potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.548) has a slightly higher hERG risk than Ligand B (0.454), but both are relatively low.

**Microsomal Clearance:** Ligand B (40.046) has significantly lower microsomal clearance than Ligand A (82.617), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (10.878) has a much shorter half-life than Ligand A (30.569). Ligand A is preferable here.

**P-gp Efflux:** Ligand A (0.228) has lower P-gp efflux than Ligand B (0.117), which is a slight advantage.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic). While its solubility is also poor, its DILI risk is considerably higher than Ligand A. However, the substantial difference in binding affinity (-9.2 vs -8.5 kcal/mol) is a significant factor, and the better metabolic stability is also important for kinase inhibitors. The higher DILI risk of Ligand B is concerning, but potentially mitigatable with further optimization. The better Caco-2 permeability of Ligand B is also a plus.

Output:
1
2025-04-17 11:22:44,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.356 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.13) is well below the 140 threshold and favorable for absorption. Ligand B (87.74) is still under 140, but less optimal than A.

**logP:** Ligand A (4.456) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.988) is quite low, which may 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, staying within the guidelines.

**QED:** Ligand A (0.865) has a higher QED score than Ligand B (0.67), indicating a more drug-like profile.

**DILI:** Ligand A (62.001) has a higher DILI risk than Ligand B (18.612). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (88.406) has better BBB penetration than Ligand B (54.866), but this is less important here.

**Caco-2 Permeability:** Ligand A (-4.387) has poor Caco-2 permeability, while Ligand B (-5.344) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.024) has poor aqueous solubility, consistent with its higher logP. Ligand B (-2.159) has better solubility, which is a positive.

**hERG Inhibition:** Ligand A (0.426) has a slightly higher hERG risk than Ligand B (0.097), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (56.515) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (0.115) has *very* low clearance, suggesting excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-33.136) has a negative half-life (which is unusual and likely an error in the data, but indicates very rapid metabolism). Ligand B (-0.728) has a very short half-life, but is significantly better than A.

**P-gp Efflux:** Ligand A (0.225) has lower P-gp efflux than Ligand B (0.009), which is slightly favorable.

**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 could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a much better binding affinity, and a better QED score. However, it suffers from poor solubility, poor permeability, higher DILI risk, and significantly lower metabolic stability. Ligand B has better solubility, metabolic stability (very low Cl_mic), and lower DILI risk, but weaker binding affinity and lower QED.

Given the enzyme-specific priorities, metabolic stability is crucial. The extremely low clearance and better solubility of Ligand B are very attractive. While the affinity difference is significant, it may be possible to optimize Ligand B's affinity through further medicinal chemistry efforts, while mitigating the issues with Ligand A would be more challenging.

Output:
1
2025-04-17 11:22:44,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.403 and 354.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (89.78 and 86.34) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.908) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.978) is within the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (8) are both below the 10 limit.

**6. QED:** Ligand A (0.841) has a better QED score than Ligand B (0.741), suggesting a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (61.07 and 60.915), both falling into the acceptable range (<60 is preferred, but these are close enough to not be a major differentiator).

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (84.451) is better than Ligand A (77.705). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.962) is slightly better than Ligand B (-5.135).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests very poor solubility. Ligand A (-1.793) is slightly better than Ligand B (-3.349).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.274 and 0.151), which is excellent.

**12. Microsomal Clearance:** Ligand A (6.316) has a lower microsomal clearance than Ligand B (6.886), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.975) has a significantly longer half-life than Ligand B (-3.8). This is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.159).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial difference (0.8 kcal/mol), which can often outweigh minor ADME concerns.

**Overall Assessment:**

While Ligand A has better QED, solubility, metabolic stability, and half-life, the significantly stronger binding affinity of Ligand B (-8.3 vs -7.5 kcal/mol) is the most critical factor for an enzyme inhibitor. The difference in binding affinity is likely to have a greater impact on efficacy than the slightly less favorable ADME properties of Ligand B. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:22:44,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.515 and 365.478 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.53 and 71.96) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.766) is optimal, while Ligand B (3.12) is slightly higher but still acceptable.

**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.

**QED:** Both ligands have acceptable QED scores (0.767 and 0.662), indicating good drug-like properties.

**DILI:** Ligand A (46.801) has a significantly lower DILI risk than Ligand B (82.513), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (87.088) has a higher score than Ligand A (59.325).

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern.

**hERG Inhibition:** Ligand A (0.461) shows a lower hERG inhibition liability than Ligand B (0.892), which is preferable.

**Microsomal Clearance:** Ligand A (66.195) has a slightly lower microsomal clearance than Ligand B (70.331), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (51.711) has a significantly longer half-life than Ligand A (10.986), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux liability than Ligand B (0.421), potentially leading to better bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better safety (DILI, hERG) and metabolic stability (Cl_mic, Pgp), Ligand B's significantly stronger binding affinity (-8.2 vs -7.1 kcal/mol) is a crucial advantage for an enzyme inhibitor. The longer half-life of Ligand B is also beneficial. The poor solubility and Caco-2 permeability are concerns for both, but the potency difference is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 11:22:44,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 348.495 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (78.68 and 73.39) below 140, suggesting good oral absorption potential.

**logP:** Both ligands have logP values (1.197 and 1.644) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.865) has a better QED score than Ligand B (0.661), indicating a more drug-like profile.

**DILI:** Ligand A (18.651) has a significantly lower DILI risk than Ligand B (22.8), which is a substantial advantage. Both are below the 40 threshold.

**BBB:** Ligand A (62.97) has a lower BBB penetration percentile than Ligand B (79.217). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.228 and -5.286), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.021 and -1.376), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.108) has a much lower hERG inhibition liability than Ligand B (0.775), a major advantage.

**Microsomal Clearance:** Ligand A (-0.586) has a lower (better) microsomal clearance than Ligand B (18.288), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.658) has a significantly longer in vitro half-life than Ligand B (3.047), which is desirable.

**P-gp Efflux:** Ligand A (0.033) has lower P-gp efflux liability than Ligand B (0.029), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). The difference is 0.9 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better across multiple crucial ADMET properties. Specifically, Ligand A exhibits much lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, longer t1/2), and a superior QED score. The solubility and Caco-2 permeability are poor for both, but the other advantages of Ligand A outweigh the small binding affinity difference. Given the enzyme-kinase target class, prioritizing metabolic stability, solubility, and safety (hERG, DILI) is crucial.

Output:
0
2025-04-17 11:22:44,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (382.873 Da) is also good.

**TPSA:** Ligand A (79.7) is excellent, well below the 140 threshold for oral absorption. Ligand B (96.25) is still acceptable, but less optimal.

**logP:** Ligand A (0.6) is a bit low, potentially hindering permeation. Ligand B (1.364) is 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 fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.444, Ligand B: 0.63), with Ligand B being more drug-like.

**DILI:** Ligand A (49.864) has a better DILI score than Ligand B (67.584), indicating a lower risk of liver injury.

**BBB:** Ligand A (68.282) has a moderate BBB penetration, while Ligand B (29.042) has very low BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.159) has poor Caco-2 permeability, which is a significant concern. Ligand B (-5.335) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -1.219, Ligand B: -2.612). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.514) has a slightly higher hERG risk than Ligand B (0.217), but both are reasonably low.

**Microsomal Clearance:** Ligand A (14.569) has significantly lower microsomal clearance than Ligand B (27.631), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-6.48) has a longer in vitro half-life than Ligand B (25.213), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.036, Ligand B: 0.116).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme target. While it has a higher DILI risk and lower BBB penetration, the strong binding affinity is a significant advantage. Ligand A has better metabolic stability and lower DILI, but its poor Caco-2 permeability and weaker binding affinity are major drawbacks. The difference in binding affinity is substantial enough to favor Ligand B despite its other shortcomings.

Output:
1
2025-04-17 11:22:44,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 356.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (107.11). A TPSA under 140 is good for oral absorption, but lower is preferable. Ligand B's TPSA is quite high, potentially hindering absorption.

**logP:** Ligand A (2.923) is optimal (1-3), while Ligand B (1.106) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (4 HBD, 4 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have acceptable QED values (0.739 and 0.612, both > 0.5).

**DILI:** Ligand A (18.534) has a much lower DILI risk than Ligand B (55.68). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (81.7) is better than Ligand B (62.0).

**Caco-2 Permeability:** Ligand A (-4.534) shows poor permeability, while Ligand B (-5.262) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.553) is better than Ligand B (-3.141), though both are poor.

**hERG Inhibition:** Ligand A (0.463) has a lower hERG risk than Ligand B (0.327), which is favorable.

**Microsomal Clearance:** Ligand A (51.707) has a higher clearance than Ligand B (0.568), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-11.078) has a longer half-life than Ligand A (-18.147).

**P-gp Efflux:** Ligand A (0.188) has lower P-gp efflux than Ligand B (0.042), which is good.

**Binding Affinity:** Ligand B (-9.3 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 liabilities. The difference of 1.7 kcal/mol is significant.

**Conclusion:**

While Ligand A has better DILI, TPSA, logP, and hERG profiles, Ligand B's substantially stronger binding affinity (-9.3 vs -7.6 kcal/mol) and longer half-life are critical for an enzyme target like SRC kinase. The improved metabolic stability (lower Cl_mic) of Ligand B is also a major benefit. Although Ligand B has a higher TPSA and lower solubility, the potency advantage is likely to be decisive, and these ADME properties could be addressed through further optimization.

Output:
1
2025-04-17 11:22:44,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.423 and 358.454 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (127.63) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (78.87) is well within the acceptable range and even favorable.

**3. logP:** Both ligands (1.114 and 1.267) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBDs, 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 B (0.641) has a better QED score than Ligand A (0.385), indicating a more drug-like profile.

**7. DILI:** Ligand A (24.04) has a significantly lower DILI risk than Ligand B (5.777), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.872) has higher BBB penetration than Ligand A (47.421), but this isn't a primary concern.

**9. Caco-2 Permeability:** Ligand A (-5.297) has worse Caco-2 permeability than Ligand B (-4.716), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.353) has slightly better aqueous solubility than Ligand B (-1.151).

**11. hERG Inhibition:** Ligand A (0.13) has a lower hERG inhibition risk than Ligand B (0.608), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (-1.995) has a lower (better) microsomal clearance than Ligand B (-2.541), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.413) has a longer half-life than Ligand B (-5.908), which is desirable.

**14. P-gp Efflux:** Ligand A (0.011) has a lower P-gp efflux liability than Ligand B (0.143), suggesting better bioavailability.

**15. Binding Affinity:** Both ligands have similar binding affinities (-7.7 and -7.4 kcal/mol), which are both good. 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 lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has a better QED and slightly better Caco-2 permeability, the safety and pharmacokinetic advantages of Ligand A outweigh these benefits.

Output:
0
2025-04-17 11:22:44,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.41 and 353.344 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is higher than Ligand B (57.01). Both are below the 140 threshold for oral absorption, but Ligand B is preferable due to lower TPSA.

**logP:** Ligand A (2.254) is within the optimal 1-3 range. Ligand B (3.698) is slightly higher, but still acceptable.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

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

**QED:** Ligand A (0.847) has a better QED score than Ligand B (0.769), indicating a more drug-like profile.

**DILI:** Ligand B (72.043) has a slightly better DILI score than Ligand A (65.064), indicating a lower risk of liver injury. Both are acceptable (<60 is good, and both are below 70).

**BBB:** Ligand A (91.392) has a higher BBB penetration percentile than Ligand B (87.864). While BBB isn't a primary concern for a kinase inhibitor, higher is generally better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.363 and -4.435), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-3.582) has better aqueous solubility than Ligand B (-5.106). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.15) has a much lower hERG inhibition liability than Ligand B (0.236), which is a significant advantage. Lower hERG risk is crucial.

**Microsomal Clearance:** Ligand A (73.688) has lower microsomal clearance than Ligand B (75.258), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.359 hours) has a shorter half-life than Ligand B (-22.319 hours). The negative value for Ligand B is concerning and likely an error. Ligand A is preferable.

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux liability than Ligand B (0.241), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.8 kcal/mol and -8.5 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. It has a better QED score, significantly lower hERG risk, better solubility, lower P-gp efflux, and better metabolic stability (lower Cl_mic). While Ligand B has a slightly better DILI score and lower TPSA, the advantages of Ligand A in key areas like hERG and metabolic stability are more critical for an enzyme inhibitor. The negative half-life value of Ligand B is also a red flag.

Output:
0
2025-04-17 11:22:44,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.439 Da) is slightly lower, which could be beneficial for permeability. Ligand B (366.38 Da) is also good.

**TPSA:** Ligand A (96.25) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (78.87) is well within the acceptable range.

**logP:** Ligand A (-0.571) is a bit low, potentially hindering membrane permeability. Ligand B (1.941) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is good. Ligand B (2 HBD, 4 HBA) is also good. Both are within the recommended limits.

**QED:** Ligand A (0.782) has a strong drug-like profile. Ligand B (0.391) is significantly lower, indicating a less ideal overall drug-like profile.

**DILI:** Ligand A (30.942) has a low DILI risk. Ligand B (21.869) also has a low DILI risk, and is slightly better.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (77.317) is better than Ligand A (50.795).

**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 (0.05) has very low hERG risk, excellent. Ligand B (0.513) has slightly higher hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-3.857) has a negative clearance, which is not physically possible and indicates an issue with the data or model. Ligand B (7.062) has a moderate clearance, which is less ideal but not a complete dealbreaker.

**In vitro Half-Life:** Ligand A (13.329 hours) has a reasonable half-life. Ligand B (-27.609 hours) has a negative half-life, which is not physically possible and indicates an issue with the data or model.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand B (-8.5 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 much stronger binding affinity, a better logP, and a slightly better DILI score. However, it has a significantly lower QED and problematic negative values for half-life and Caco-2 permeability. Ligand A has a better QED and hERG profile, but a lower logP and binding affinity. The negative values for clearance and half-life for Ligand A and B are concerning and likely indicate data issues.

Despite the issues with the data, the significantly stronger binding affinity of Ligand B is a major advantage for an enzyme target like SRC kinase. If the negative values for half-life and Caco-2 permeability are corrected, Ligand B would be the preferred candidate. Given the data as presented, the binding affinity advantage is strong enough to favor Ligand B, assuming the negative values are errors.

Output:
1
2025-04-17 11:22:44,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (97.19). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is relatively high, potentially hindering absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.267, Ligand B: 0.87), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors & Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 8. Ligand A is better here as higher HBA can sometimes reduce permeability.

**QED:** Both ligands have good QED scores (A: 0.777, B: 0.823), indicating good drug-like properties.

**DILI:** Ligand A (23.187) has a much lower DILI risk than Ligand B (58.434). This is a significant advantage for Ligand A.

**BBB:** Ligand A (69.213) has better BBB penetration than Ligand B (46.026), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.681) is better than Ligand B (-5.491), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.872) is better than Ligand B (-1.665), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.132, B: 0.188).

**Microsomal Clearance:** Ligand A (65.299) has a higher microsomal clearance than Ligand B (-19.583). This means Ligand B is more metabolically stable, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (6.134) has a shorter half-life than Ligand B (-0.511), further supporting Ligand B's better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.065, B: 0.077).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, HBA, DILI, solubility, Caco-2 permeability) and has comparable binding affinity. However, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer half-life). For a kinase inhibitor, metabolic stability is paramount. While Ligand A has a better overall ADME profile, the substantial improvement in metabolic stability offered by Ligand B outweighs the slight advantages of Ligand A.

Output:
1
2025-04-17 11:22:44,595 - INFO - Batch 42 complete. Total preferences: 672
2025-04-17 11:22:44,595 - INFO - Processing batch 43/512...
2025-04-17 11:23:23,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.451 and 353.857 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.34) is slightly above the preferred <140, but acceptable. Ligand B (62.73) is well within the optimal range.

**logP:** Ligand A (-0.788) is a bit low, potentially hindering permeability. Ligand B (4.366) is high, potentially causing solubility issues and off-target effects.

**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 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.648 and 0.689), indicating good drug-like properties.

**DILI:** Ligand A (13.416) has a very low DILI risk, which is excellent. Ligand B (67.39) has a significantly higher DILI risk, which is a major concern.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (27.608) is lower than Ligand B (40.597).

**Caco-2 Permeability:** Both have negative values (-5.083 and -5.248), 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 (0.295) has very poor solubility, which is a significant drawback. Ligand B (-4.771) also has poor solubility, but slightly better than A.

**hERG Inhibition:** Ligand A (0.045) has a very low hERG risk, which is excellent. Ligand B (0.669) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (-7.646) has very low (negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (72.619) has high clearance, suggesting rapid metabolism and potentially low bioavailability.

**In vitro Half-Life:** Ligand A (-9.996) has a very long half-life, which is highly desirable. Ligand B (90.184) has a long half-life, but not as exceptionally long as Ligand A.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is favorable. Ligand B (0.233) has slightly higher P-gp efflux.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.0 and -7.7 kcal/mol), which is excellent. The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite both ligands having good binding affinity, Ligand A is the stronger candidate. Its significantly lower DILI risk, exceptionally low microsomal clearance (leading to a very long half-life), and very low hERG risk are major advantages. While its solubility and logP are not ideal, the benefits in safety and PK outweigh these drawbacks, especially given the comparable binding affinity. Ligand B's high DILI risk and high clearance are significant liabilities.

Output:
0
2025-04-17 11:23:23,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.415 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than Ligand B (80.57), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have excellent logP values (2.644 and 2.504), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (5 and 4 respectively), fulfilling the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.769 and 0.707), indicating good drug-like properties.

**DILI:** Ligand B (44.048) has a significantly lower DILI risk than Ligand A (64.366). This is a major advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (74.758 and 62.078), but this isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.738 and -4.796), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.836 and -2.781), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.555 and 0.471), which is good.

**Microsomal Clearance:** Ligand B (40.739) has significantly lower microsomal clearance than Ligand A (84.739), suggesting better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (34.562) has a longer in vitro half-life than Ligand A (-26.423), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.214 and 0.236).

**Binding Affinity:** Ligand B (-8.6 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 be considered.

**Overall Assessment:**

Ligand B is the superior 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 lower DILI risk. The slightly improved binding affinity is a bonus. The poor solubility and permeability would need to be addressed in further optimization, but the ADME profile of Ligand B is more favorable.

Output:
1
2025-04-17 11:23:23,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.455 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (65.63 and 67.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (3.05 and 2.396).

**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.

**QED:** Both ligands have QED values above 0.5 (0.526 and 0.47), indicating good drug-likeness.

**DILI:** Ligand A (32.067) has a slightly higher DILI risk than Ligand B (28.228), but both are below the concerning threshold of 60.

**BBB:** Ligand B (63.358) has a higher BBB penetration percentile than Ligand A (33.23). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.77) shows significantly *better* Caco-2 permeability than Ligand B (-4.851). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-1.961) has better aqueous solubility than Ligand B (-3.247). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.909) has a slightly higher hERG inhibition liability than Ligand B (0.3). Lower is better here.

**Microsomal Clearance:** Ligand A (-3.437) exhibits *much* lower microsomal clearance than Ligand B (30.947). This suggests greater metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (7.186) has a slightly lower in vitro half-life than Ligand B (8.784).

**P-gp Efflux:** Ligand A (0.296) has lower P-gp efflux liability than Ligand B (0.152), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.4 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other ADME considerations.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better BBB penetration (irrelevant here) and in vitro half-life, Ligand A demonstrates significantly better Caco-2 permeability, aqueous solubility, and *much* improved metabolic stability (lower Cl_mic). The slightly higher hERG risk for Ligand A is a minor concern compared to the substantial metabolic advantage. The binding affinities are comparable. Therefore, the improved ADME profile of Ligand A makes it a better choice for further development.

Output:
0
2025-04-17 11:23:23,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.379 and 344.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is better than Ligand B (50.16) as it is closer to the optimal range for oral absorption.

**logP:** Both ligands have logP values (2.686 and 4.127) within the acceptable range (1-3), but Ligand A is more optimal. Ligand B is approaching the upper limit and could potentially have solubility issues.

**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 (0.747 and 0.907), indicating good drug-like properties.

**DILI:** Both ligands have DILI risk around the 50-60 percentile, which is acceptable, but lower is better. Ligand A (60.527) is slightly higher than Ligand B (56.805).

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (81.388) has a higher BBB penetration than Ligand A (33.928).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.174) is slightly better than Ligand B (-4.715).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.859) is slightly better than Ligand B (-4.233).

**hERG Inhibition:** Ligand A (0.461) has a lower hERG risk than Ligand B (0.66). This is a significant advantage.

**Microsomal Clearance:** Ligand A (-17.402) has a significantly lower (better) microsomal clearance than Ligand B (44.104), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-22.067) has a longer in vitro half-life than Ligand B (23.638), which is desirable.

**P-gp Efflux:** Ligand A (0.042) has lower P-gp efflux than Ligand B (0.41), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial factor, and the 1.5 kcal/mol advantage threshold is far exceeded.

**Overall Assessment:**

While Ligand A has better ADME properties (solubility, permeability, metabolic stability, hERG, P-gp efflux), Ligand B's significantly higher binding affinity (-8.1 vs 0.0 kcal/mol) is a decisive factor. The potency advantage outweighs the ADME drawbacks, especially considering the ADME properties are not drastically poor. Improvements can be made to Ligand B's ADME profile through further optimization, but it's difficult to significantly improve a weak binder.

Output:
1
2025-04-17 11:23:23,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.365 and 350.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.32) is slightly higher than Ligand B (76.46). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (4.409) is higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.431) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Ligand B (0.8) has a significantly better QED score than Ligand A (0.323), indicating a more drug-like profile.

**DILI:** Ligand A (77.705) has a higher DILI risk than Ligand B (17.681). This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration, but Ligand B (81.233) is better than Ligand A (67.197). While not a primary concern for a kinase inhibitor, it's a slight benefit.

**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:** Ligand A (0.761) has a higher hERG risk than Ligand B (0.494), which is preferable.

**Microsomal Clearance:** Ligand B (30.337) has lower microsomal clearance than Ligand A (43.901), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-14.031) has a negative half-life, which is not possible. This is a major red flag. Ligand A (44.939) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.534) has lower P-gp efflux than Ligand B (0.109), which is preferable.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.4). This is the most important factor, and the 0.6 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and Solubility, the most important factor is binding affinity. Ligand B has a significantly stronger binding affinity (-9.0 kcal/mol vs -8.4 kcal/mol). It also has better QED, lower DILI risk, and better metabolic stability. The negative half-life for Ligand B is concerning, but the substantial affinity advantage outweighs this issue.

Output:
1
2025-04-17 11:23:23,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (386.43 and 344.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.59) is slightly higher than Ligand B (65.86), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.89) is at the upper end of the optimal range (1-3), while Ligand B (0.38) is below it. Low logP can hinder permeation, which is a concern for B.

**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:** Both ligands have good QED scores (0.689 and 0.779), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 91.24%, which is high. Ligand B has a much lower DILI risk of 42.58%, which is preferable.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (73.63%) has a higher value than Ligand B (62.20%).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting potential issues with the prediction method.

**hERG Inhibition:** Ligand A (0.747) has a slightly higher hERG risk than Ligand B (0.206), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (30.98 and 30.62), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-18.72), which is problematic. Ligand B has a very short half-life (-1.99), which is also concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.485 and 0.066).

**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.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the most significant factor is the binding affinity. Ligand B has a 1.5 kcal/mol stronger binding affinity, which outweighs the slightly lower logP. Furthermore, Ligand B has a much lower DILI risk, which is a critical consideration. While both have concerning half-life predictions, the superior affinity and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 11:23:23,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 347.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is well below the 140 threshold and favorable for oral absorption. Ligand B (112.78) is still within acceptable limits but less optimal.

**logP:** Ligand A (2.132) is within the optimal 1-3 range. Ligand B (0.944) is slightly below 1, which *could* indicate permeability issues, though not drastically.

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

**QED:** Ligand A (0.758) has a better QED score than Ligand B (0.587), indicating a more drug-like profile.

**DILI:** Ligand A (33.501) has a significantly lower DILI risk than Ligand B (41.024), which is a substantial advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand A (71.501) is slightly better than Ligand B (62.233).

**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 ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is undefined.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.304 and 0.327), which is excellent.

**Microsomal Clearance:** Ligand B (-7.118) has a *negative* microsomal clearance, which is impossible. This is likely an error in the data. Ligand A (54.718) has a reasonable clearance. This alone is a major issue for Ligand B.

**In vitro Half-Life:** Ligand A (18.623 hours) has a better in vitro half-life than Ligand B (4.977 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.104).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). This is a 0.5 kcal/mol difference, which is significant, but not overwhelming.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, the negative microsomal clearance is a critical flaw. A negative clearance is physically impossible and indicates a major data error or a fundamental issue with the compound's metabolism. Ligand A, while having slightly weaker binding, has a much more favorable ADME profile (better QED, lower DILI, reasonable clearance, better half-life) and acceptable hERG risk. Therefore, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 11:23:23,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.515 Da and 381.973 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is better than Ligand B (30.29). While both are acceptable, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.656) is optimal, while Ligand B (4.616) is high. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (0 HBD, 5 HBA). The counts for both are within acceptable limits, but a balance is generally desired.

**QED:** Ligand A (0.817) has a significantly better QED score than Ligand B (0.6), indicating a more drug-like profile.

**DILI:** Ligand A (12.834) has a much lower DILI risk than Ligand B (33.501), a crucial factor for drug development.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (70.415) is better than Ligand B (48.895).

**Caco-2 Permeability:** Ligand A (-4.933) is better than Ligand B (-5.061), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.603) is better than Ligand B (-4.536), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.468) has a lower hERG inhibition risk than Ligand B (0.919), a significant safety advantage.

**Microsomal Clearance:** Ligand A (21.645) has a lower microsomal clearance than Ligand B (88.65), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.786) has a longer in vitro half-life than Ligand B (49.809), which is favorable for dosing frequency.

**P-gp Efflux:** Ligand A (0.024) has significantly lower P-gp efflux than Ligand B (0.792), improving bioavailability.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-9.1). However, the difference is not substantial enough to outweigh the numerous ADME/Tox advantages of Ligand A. A 1.4 kcal/mol difference is not enough to overcome the significant liabilities of ligand B.

**Conclusion:**

Ligand A demonstrates a superior overall profile, particularly regarding safety (DILI, hERG), ADME properties (solubility, permeability, metabolic stability, P-gp efflux), and drug-likeness (QED). While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A in other critical areas make it the more promising drug candidate.

Output:
0
2025-04-17 11:23:23,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.399 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (93.71) is slightly higher than Ligand B (79.81). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (A: 2.113, B: 1.856), 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 within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.762) has a significantly better QED score than Ligand B (0.464), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (A: 53.936, B: 52.423), and are both acceptable (<60).

**BBB:** Ligand A (48.352) has a lower BBB penetration percentile than Ligand B (58.821). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.854 and -4.761). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development.

**Aqueous Solubility:** Ligand A (-2.731) has worse solubility than Ligand B (-1.03). Solubility is important for enzymes, and B is better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.319, B: 0.179), which is excellent.

**Microsomal Clearance:** Ligand B (99.672) has a much higher microsomal clearance than Ligand A (52.941). This means Ligand A is more metabolically stable, a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (28.92 hours) has a significantly longer half-life than Ligand B (-1.204 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.137, B: 0.107).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.4 kcal/mol). This is a >1.5 kcal/mol advantage, which is significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better QED, metabolic stability (lower Cl_mic), and a longer half-life, the significantly stronger binding affinity of Ligand B (-8.1 vs -6.4 kcal/mol) is the deciding factor. The potency advantage is substantial enough to overcome the slightly lower QED and worse metabolic stability. The solubility difference is also not large enough to be a major concern.

Output:
1
2025-04-17 11:23:23,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.843 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (107.55). A TPSA under 90 is preferred, and A is comfortably within that, while B is pushing the limit for oral absorption.

**logP:** Ligand A (3.687) is optimal, while Ligand B (0.569) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is more favorable than Ligand B (HBD=3, HBA=5), staying well within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.877 and 0.695), indicating good drug-like properties.

**DILI:** Ligand A (33.773) has a much lower DILI risk than Ligand B (58.395). Both are below 60, but A is significantly better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.151) is better than Ligand B (32.299).

**Caco-2 Permeability:** Ligand A (-4.839) is better than Ligand B (-5.248), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.054) is better than Ligand B (-2.604), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.392 and 0.272).

**Microsomal Clearance:** Ligand A (25.072) has a slightly higher clearance than Ligand B (20.258), suggesting potentially lower metabolic stability, but both are reasonably low.

**In vitro Half-Life:** Ligand B (11.756) has a significantly longer half-life than Ligand A (-0.616), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.117 and 0.038).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 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 A is superior in most key ADME properties (TPSA, logP, solubility, DILI) and has slightly better binding affinity. While Ligand B has a longer half-life, the significant drawbacks in permeability (low logP) and solubility, combined with higher DILI risk, make it less attractive. For an enzyme target like SRC kinase, metabolic stability is important, but can be addressed through structural modifications. The better overall profile of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 11:23:23,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.23) is slightly above the optimal <140, but acceptable. Ligand B (99.49) is excellent.

**logP:** Ligand A (0.736) is a bit low, potentially impacting permeability. Ligand B (-0.714) is even lower and more concerning for permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 & 3) and HBA (6 & 6) counts.

**QED:** Both ligands have reasonable QED scores (0.754 and 0.602), indicating good drug-like properties.

**DILI:** Ligand A (48.972) has a much lower DILI risk than Ligand B (8.957), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (13.455) is very low, while Ligand A (52.23) is moderate.

**Caco-2:** Both have negative Caco-2 values (-5.083 and -5.582), which is unusual and suggests poor permeability. This is a red flag for both.

**Solubility:** Both have negative solubility values (-2.168 and -0.915), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Both ligands show very low hERG inhibition liability (0.05), which is excellent.

**Microsomal Clearance:** Ligand A (17.852) has a higher Cl_mic than Ligand B (-8.51).  A negative value for Ligand B is unusual and likely indicates *very* high metabolic stability, which is a major advantage.

**In vitro Half-Life:** Ligand A (-7.948) has a negative half-life, which is unusual and suggests a very long half-life. Ligand B (9.924) is a reasonable half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.05 and 0.001), which is favorable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand A has a better binding affinity and a significantly lower DILI risk. However, both ligands suffer from poor predicted permeability (Caco-2) and solubility. Ligand B has a remarkably low (and potentially unrealistic) microsomal clearance, suggesting exceptional metabolic stability, but its binding affinity is very weak. Given the enzyme-specific priorities, binding affinity is paramount. While the permeability and solubility issues are concerning for both, the substantially stronger binding affinity of Ligand A, coupled with the lower DILI risk, makes it the more promising candidate. The negative half-life for Ligand A is also a positive sign.

Output:
1
2025-04-17 11:23:23,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.324 and 345.407 Da) are within the ideal 200-500 Da range.

**TPSA:** Both ligands (97.55 and 97.94) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (0.759) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (-0.013) is even lower, raising more concern for permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 7 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.775 and 0.822), suggesting good overall drug-likeness.

**DILI:** Ligand A (56.34) has a better DILI score than Ligand B (62.931), indicating lower potential for liver injury. Both are acceptable, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.037) has a higher BBB score than Ligand B (46.646).

**Caco-2 Permeability:** Ligand A (-4.437) and Ligand B (-5.208) both have negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative values (-2.543 and -2.015), indicating poor aqueous solubility, which is a significant concern.

**hERG:** Both ligands have very low hERG risk (0.172 and 0.11), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand B (17.231) has significantly lower microsomal clearance than Ligand A (37.357), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life (t1/2):** Ligand B (-6.969) has a longer half-life than Ligand A (-23.536), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.117 and 0.014), which is favorable.

**Binding Affinity:** Ligand B (-9.5 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 of the ADME drawbacks.

**Conclusion:**

While both ligands have issues with solubility and permeability, Ligand B's superior binding affinity (-9.5 kcal/mol vs -7.7 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer t1/2) make it the more promising candidate. The stronger binding is a key advantage for an enzyme target like SRC kinase. The slightly higher DILI risk is a minor concern compared to the substantial improvement in potency and metabolic stability.

Output:
1
2025-04-17 11:23:23,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.471 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (58.2). Both are below 140, suggesting good absorption potential.

**logP:** Ligand A (-0.392) is suboptimal, being slightly below the preferred 1-3 range. Ligand B (4.183) is also slightly high, potentially leading to solubility issues.

**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 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.51 and 0.655, respectively), indicating drug-like properties.

**DILI:** Ligand A (25.63) has a significantly lower DILI risk than Ligand B (30.05), both are good.

**BBB:** Ligand A (56.65) has a lower BBB penetration than Ligand B (71.927). This is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.249) has worse Caco-2 permeability than Ligand B (-4.675).

**Aqueous Solubility:** Ligand A (-2.461) has better aqueous solubility than Ligand B (-4.535).

**hERG Inhibition:** Ligand A (0.16) has a much lower hERG inhibition liability than Ligand B (0.523), which is a significant advantage.

**Microsomal Clearance:** Ligand A (23.39) has a lower microsomal clearance than Ligand B (67.042), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.669) has a worse in vitro half-life than Ligand B (13.073).

**P-gp Efflux:** Ligand A (0.015) has lower P-gp efflux liability than Ligand B (0.424).

**Binding Affinity:** Both ligands have similar binding affinities (-8.6 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is preferable. While its logP is slightly low and Caco-2 permeability is worse, it has significantly better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. The better solubility also helps. The binding affinity difference is minimal. For an enzyme target like SRC kinase, metabolic stability and safety (hERG) are critical, making Ligand A the more promising candidate.

Output:
0
2025-04-17 11:23:23,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.439 Da) is slightly better positioned.

**TPSA:** Ligand A (64.63) is excellent, well below the 140 threshold for oral absorption. Ligand B (104.81) is still acceptable but less favorable.

**logP:** Ligand A (3.253) is optimal. Ligand B (-0.257) is significantly lower, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is well within the preferred ranges. Ligand B (HBD=2, HBA=6) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (A: 0.851, B: 0.596), indicating good drug-like properties. Ligand A is superior.

**DILI:** Both ligands have low DILI risk (A: 47.15, B: 43.544), which is positive.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (78.868) has a better BBB percentile than Ligand B (41.528).

**Caco-2 Permeability:** Ligand A (-4.185) is better than Ligand B (-5.84), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.829) is better than Ligand B (-1.335), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.47) shows a lower hERG risk than Ligand B (0.077), a significant advantage.

**Microsomal Clearance:** Ligand A (83.295) has higher clearance than Ligand B (-13.115). This means Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-8.388) has a longer half-life than Ligand A (-6.516), which is desirable.

**P-gp Efflux:** Ligand A (0.284) has lower P-gp efflux than Ligand B (0.009), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.9 kcal/mol and -7.0 kcal/mol respectively). Ligand A has a 0.9 kcal/mol advantage.

**Overall Assessment:**

Ligand A excels in most ADME properties (logP, TPSA, solubility, hERG, P-gp efflux) and has slightly better binding affinity. While Ligand B has better metabolic stability and half-life, the significantly poorer logP and solubility of Ligand B are major drawbacks. The better overall profile of Ligand A, particularly its favorable solubility and hERG risk, makes it the more promising candidate despite slightly higher clearance. The 0.9 kcal/mol affinity difference is not enough to overcome the ADME issues of Ligand B.

Output:
1
2025-04-17 11:23:23,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (356.304 and 369.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.25) is better than Ligand B (92.51), both are below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands (2.507 and 2.081) are within the optimal range of 1-3.

**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:** Both ligands (5) are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.88) has a significantly higher QED score than Ligand A (0.651), indicating a more drug-like profile.

**7. DILI:** Ligand B (37.805) has a much lower DILI risk than Ligand A (86.778). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (74.758 and 80.264), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.443) is slightly better than Ligand B (-4.617).

**10. Aqueous Solubility:** Ligand A (-4.064) is slightly better than Ligand B (-2.65), both are negative values, suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.273 and 0.129).

**12. Microsomal Clearance:** Ligand B (16.343) has significantly lower microsomal clearance than Ligand A (69.395), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (12.158) has a longer in vitro half-life than Ligand A (65.091), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.153 and 0.038).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand B is the superior candidate due to its significantly better DILI score, lower microsomal clearance, longer half-life, and higher QED. Although both have poor Caco-2 and solubility values, the ADME profile of Ligand B is much more favorable, making it more likely to succeed as a drug candidate.

Output:
1
2025-04-17 11:23:23,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.447 Da) is slightly higher than Ligand B (352.431 Da), but both are acceptable.

**TPSA:** Ligand A (115.21) is slightly above the preferred <140 for oral absorption, while Ligand B (95.94) is well within the range.

**logP:** Ligand A (-0.244) is a bit low, potentially hindering permeation. Ligand B (0.596) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 8 HBAs, while Ligand B has 5. Both are within acceptable limits (<=10).

**QED:** Both ligands have reasonable QED scores (A: 0.48, B: 0.706). Ligand B's score is significantly better, suggesting a more drug-like profile.

**DILI:** Ligand A (74.176) has a higher DILI risk than Ligand B (34.781). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (46.607) has a higher BBB value than Ligand A (26.134), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.424) is worse than Ligand B (-4.793).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.454) is slightly worse than Ligand B (-1.983).

**hERG:** Both ligands have very low hERG risk (0.048 and 0.063), which is excellent.

**Microsomal Clearance:** Ligand A (51.835) has a moderate clearance, while Ligand B (-17.618) has a *negative* clearance, which is highly unusual and suggests excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (1.188 hours) has a short half-life, while Ligand B (0.961 hours) is similar. Neither is ideal, but the metabolic stability of Ligand B may translate to a longer *in vivo* half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.06).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.4 kcal/mol difference is substantial and outweighs many of the minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have issues with permeability and solubility, Ligand B possesses a significantly stronger binding affinity, much lower DILI risk, and remarkably high metabolic stability (indicated by negative Cl_mic). The higher QED score also favors Ligand B. The slightly better logP and TPSA values further support its selection.

Output:
1
2025-04-17 11:23:23,641 - INFO - Batch 43 complete. Total preferences: 688
2025-04-17 11:23:23,641 - INFO - Processing batch 44/512...
2025-04-17 11:24:03,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.434 and 406.372 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.66) is better than Ligand B (38.88) as it is closer to the 140 A^2 threshold.

**logP:** Both ligands have good logP values (2.934 and 3.837), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but is not a major concern.

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

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

**QED:** Both ligands have similar QED values (0.759 and 0.702), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (26.948 and 20.822), which is excellent.

**BBB:** Both ligands have high BBB penetration (85.149 and 85.498), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.604 and -5.152), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.823 and -2.529). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.607 and 0.904), which is excellent.

**Microsomal Clearance:** Both ligands have moderate microsomal clearance (41.249 and 44.026 mL/min/kg). Lower is preferred, but these aren't exceptionally high.

**In vitro Half-Life:** Both have reasonable in vitro half-lives (19.95 and 22.931 hours).

**P-gp Efflux:** Both ligands exhibit low P-gp efflux (0.157 and 0.695), which is favorable.

**Binding Affinity:** Ligand A (-11 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the better candidate due to its *substantially* higher binding affinity (-11 vs -8 kcal/mol). The strong binding is likely to outweigh the ADME liabilities, especially given the low DILI and hERG risks. While solubility and permeability are concerns, these can be addressed through formulation strategies or further chemical modifications guided by the structure-activity relationship.

Output:
0
2025-04-17 11:24:03,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (61.36), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.387) is a bit low, potentially hindering permeation. Ligand B (2.692) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.741 and 0.889), indicating drug-like properties.

**DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (50.33). This is a major advantage for Ligand A.

**BBB:** Ligand A (32.648) has a low BBB penetration, while Ligand B (89.027) has high BBB penetration. Since SRC is not a CNS target, this is less important, but favors B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.677 and -4.848) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.691 and -2.587) which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.091) has a much lower hERG inhibition liability than Ligand B (0.639). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (23.716) has lower microsomal clearance than Ligand B (71.977), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (11.159) has a longer half-life than Ligand B (-1.038). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.009) has lower P-gp efflux than Ligand B (0.294), suggesting better bioavailability.

**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's a positive for Ligand A.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. While Ligand B has a better logP and BBB penetration (which are less important for a non-CNS target like SRC), the ADME-Tox profile of Ligand A is much more favorable. The negative Caco-2 and solubility values are concerning for both, but the other advantages of A outweigh this.

Output:
0
2025-04-17 11:24:03,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.4 and 343.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.71) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (74.43) is excellent, well below 140.

**logP:** Ligand A (-2.463) is a bit low, potentially hindering permeation. Ligand B (1.553) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 9 HBA, acceptable. Ligand B has 3 HBA, which is excellent.

**QED:** Both ligands have good QED scores (0.575 and 0.797), indicating drug-likeness.

**DILI:** Ligand A (56.689) has a moderate DILI risk, while Ligand B (39.628) has a lower, more favorable risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (53.781) has a higher BBB value than Ligand A (32.028).

**Caco-2:** Both have negative Caco-2 values (-5.265 and -5.069), which is unusual and suggests poor permeability. However, these values are on a log scale and require careful interpretation.

**Solubility:** Ligand A (0.111) has very poor solubility, a significant drawback. Ligand B (-2.588) also has poor solubility, but is better than Ligand A.

**hERG:** Ligand A (0.014) has a very low hERG risk, which is excellent. Ligand B (0.5) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-0.253) indicates very low clearance and excellent metabolic stability. Ligand B (7.945) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (9.06) has a good half-life. Ligand B (-4.093) has a negative half-life, which is not physically possible and indicates a problem with the data or model.

**P-gp Efflux:** Ligand A (0.019) has low P-gp efflux, which is favorable. Ligand B (0.106) also has 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 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's excellent metabolic stability and low hERG risk, its very poor solubility and lower binding affinity are major concerns. Ligand B, while having slightly higher DILI and clearance, exhibits a significantly stronger binding affinity and better TPSA and logP values. The negative half-life for Ligand B is a data quality issue that needs to be addressed, but the other properties are more favorable. Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 11:24:03,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 352.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (78.87). Lower TPSA generally correlates with better cell permeability, which is beneficial.

**logP:** Both ligands have good logP values (2.589 and 1.629), falling within the optimal 1-3 range. Ligand A is slightly higher, which *could* be a minor advantage for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is 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 (0.775 and 0.651), indicating reasonable drug-likeness.

**DILI:** Ligand A (11.361) has a significantly lower DILI risk than Ligand B (8.453), which is a major advantage. Lower DILI is crucial for drug development.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated. Ligand B (65.607) is slightly better than Ligand A (45.638).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.536) is slightly better than Ligand B (-4.724).

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. Ligand B (-1.639) is slightly better than Ligand A (-2.116).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.343 and 0.286), which is excellent.

**Microsomal Clearance:** Ligand A (34.454) has a higher microsomal clearance than Ligand B (11.369), meaning Ligand B is more metabolically stable. This is a significant advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-4.318) has a much longer in vitro half-life than Ligand A (11.446), which is a major positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.136 and 0.056).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While both are good, the 1.0 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, Ligand B's superior binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility outweigh the higher DILI risk. The binding affinity difference is particularly important for an enzyme inhibitor. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:24:03,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.471 and 357.841 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.58) is higher than Ligand B (59.23). While both are reasonably low, Ligand B is better positioned for oral absorption due to its lower TPSA.

**3. logP:** Ligand A (0.78) is lower than the optimal range (1-3), potentially hindering permeability. Ligand B (3.783) is closer to the upper end of the optimal range, which is good for binding but could present solubility challenges.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while 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 similar QED values (0.7 and 0.764), indicating good drug-likeness.

**7. DILI:** Ligand A (44.436) has a slightly higher DILI risk than Ligand B (26.871), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand B (76.658) is significantly better than Ligand A (68.127). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-5.446) shows poor Caco-2 permeability, while Ligand B (-4.347) is slightly better, but still low.

**10. Aqueous Solubility:** Ligand A (-3.12) has very poor aqueous solubility, a significant drawback. Ligand B (-5.093) is also poor, but less so than Ligand A.

**11. hERG Inhibition:** Ligand A (0.046) has a very low hERG risk, which is excellent. Ligand B (0.524) has a slightly elevated hERG risk, but still relatively low.

**12. Microsomal Clearance:** Ligand A (18.715 mL/min/kg) has lower microsomal clearance than Ligand B (44.394 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.217 hours) has a shorter half-life than Ligand B (13.256 hours), which is less desirable.

**14. P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, which is favorable. Ligand B (0.222) has slightly higher P-gp efflux, but still acceptable.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of its ADME deficiencies.

**Overall Assessment:**

Ligand A's significantly superior binding affinity (-9.2 kcal/mol vs -0.0 kcal/mol) is the most important factor. While it has issues with solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. Its lower clearance and P-gp efflux are also positives. Ligand B has better solubility and permeability, but its binding affinity is extremely weak, making it unlikely to be effective.

Output:
1
2025-04-17 11:24:03,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.836 and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is well below the 140 threshold, while Ligand B (67.87) is still acceptable but higher.

**logP:** Ligand A (3.441) is optimal, while Ligand B (1.358) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.852) has a significantly better QED score than Ligand B (0.696), indicating better overall drug-likeness.

**DILI:** Ligand B (43.622) has a much lower DILI risk than Ligand A (69.833), which is a significant advantage.

**BBB:** Ligand B (90.617) shows good BBB penetration, while Ligand A (58.782) is lower. However, BBB is less critical for a non-CNS target like SRC.

**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 aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.575) has a slightly higher hERG risk than Ligand B (0.376), though both are relatively low.

**Microsomal Clearance:** Ligand B (28.121) has significantly lower microsomal clearance than Ligand A (121.202), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-24.973) has a negative half-life, which is not possible and indicates a problem with the data or the compound's stability. Ligand A (30.714) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.499) has a lower P-gp efflux liability than Ligand B (0.059), which is favorable.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from higher DILI risk, lower metabolic stability (higher Cl_mic), and lower P-gp efflux. Ligand B has better ADME properties (lower DILI, better metabolic stability, better BBB), but its binding affinity is weaker, and its solubility and permeability are also problematic. The negative half-life for Ligand B is a major red flag.

Despite the solubility and permeability concerns for both, the substantial difference in binding affinity makes Ligand A the more promising candidate. Optimization efforts would need to focus on improving its metabolic stability and reducing DILI risk, but the strong initial binding provides a solid foundation.

Output:
1
2025-04-17 11:24:03,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.359 Da and 358.869 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.57) is good, under the 140 threshold, while Ligand B (56.33) is excellent.

**logP:** Ligand A (-1.437) is a bit low, potentially hindering permeation. Ligand B (3.979) is near the upper limit but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 6 HBA, acceptable. Ligand B has 2 HBD and 2 HBA, also acceptable and potentially beneficial for permeability.

**QED:** Ligand A (0.443) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.81) is excellent, suggesting good drug-likeness.

**DILI:** Ligand A (49.05) is good, below the 60 threshold. Ligand B (39.667) is even better.

**BBB:** Both are low priority for a non-CNS target like SRC kinase. Ligand B (67.352) is higher, but this isn't crucial here.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.173) is very low risk, excellent. Ligand B (0.811) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (-23.544) is excellent, indicating high metabolic stability. Ligand B (4.097) is less favorable, suggesting faster metabolism.

**In vitro Half-Life:** Both are around 30 hours, which is good.

**P-gp Efflux:** Ligand A (0.004) is very low, suggesting minimal efflux. Ligand B (0.369) is higher, potentially leading to lower bioavailability.

**Binding Affinity:** Ligand A (-6.4 kcal/mol) is better than Ligand B (0.0 kcal/mol). This is a significant difference.

**Overall Assessment:**

Ligand A has a superior binding affinity and excellent metabolic stability and low hERG risk. However, it suffers from low logP, poor Caco-2 permeability, poor solubility and a lower QED score. Ligand B has better TPSA, QED, DILI, and P-gp efflux, but significantly weaker binding affinity and worse metabolic stability.

Given that we are targeting a kinase (enzyme), potency (binding affinity) and metabolic stability are paramount. The substantial difference in binding affinity (-6.4 vs 0.0 kcal/mol) outweighs the ADME drawbacks of Ligand A, especially considering the potential for optimization of its logP and solubility.

Output:
1
2025-04-17 11:24:03,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.531 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (75.19). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (3.601 and 2.128), falling 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), but A is slightly better.

**QED:** Both ligands have good QED scores (0.797 and 0.927), indicating good drug-like properties.

**DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (49.399). This is a significant advantage for Ligand A.

**BBB:**  BBB isn't a primary concern for a non-CNS target like SRC kinase, but Ligand A (77.86) has a better BBB percentile than Ligand B (57.774).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, the absolute value for Ligand A (-4.772) is less negative than Ligand B (-4.892), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.601) is slightly better than Ligand B (-2.684).

**hERG:** Both ligands have low hERG inhibition liability (0.534 and 0.357), which is excellent.

**Microsomal Clearance:** Ligand B (15.426) has significantly lower microsomal clearance than Ligand A (60.274). This indicates better metabolic stability for Ligand B, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (6.942) has a longer in vitro half-life than Ligand A (4.41). This further supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.239 and 0.03), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.4 kcal/mol). Ligand B is slightly better (-8.4 kcal/mol).

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic and longer t1/2) and slightly better binding affinity. However, Ligand A has a significantly lower DILI risk and slightly better TPSA, solubility and Caco-2 permeability. Given that SRC kinases are intracellular targets, metabolic stability is paramount. The slightly better affinity of Ligand B, combined with its superior metabolic profile, outweighs the slightly higher DILI risk compared to Ligand A.

Output:
1
2025-04-17 11:24:03,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (427.32 Da) is slightly higher, but acceptable. Ligand B (381.845 Da) is also good.

**TPSA:** Ligand A (77.85) is better than Ligand B (112.13). Lower TPSA generally correlates with better cell permeability. Ligand B is approaching the upper limit for good oral absorption (140).

**logP:** Both ligands have good logP values (A: 3.557, B: 2.114), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 7 HBA). Lower numbers are generally better for permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.632, B: 0.676), indicating good drug-like properties.

**DILI:** Ligand A (80.031) has a higher DILI risk than Ligand B (99.186). This is a significant concern for Ligand A.

**BBB:** This isn't a primary concern for a kinase inhibitor, but Ligand A (63.862) has better BBB penetration than Ligand B (38.077).

**Caco-2 Permeability:** Ligand A (-4.711) shows better Caco-2 permeability than Ligand B (-5.181), suggesting better absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.82 and -4.082 respectively). This could pose formulation challenges, but is not a dealbreaker.

**hERG Inhibition:** Ligand A (0.463) has a lower hERG inhibition risk than Ligand B (0.35), which is favorable.

**Microsomal Clearance:** Ligand A (58.566) has significantly higher microsomal clearance than Ligand B (14.205). This suggests Ligand B is more metabolically stable, a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (75.791) has a much longer in vitro half-life than Ligand A (28.803), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.355, B: 0.057). Ligand B is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.6 kcal/mol and -7.0 kcal/mol respectively). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have good potency, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Although its TPSA is slightly higher, the benefits in metabolic stability and safety outweigh this drawback. The solubility is a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 11:24:03,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.404 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is significantly better than Ligand B (67.43). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (2.251 and 2.979, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=4) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.842) has a substantially higher QED score than Ligand B (0.662), indicating a more drug-like profile.

**DILI:** Ligand A (23.653) has a much lower DILI risk than Ligand B (54.207), which is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (90.074) shows better BBB penetration than Ligand B (69.407).

**Caco-2 Permeability:** Ligand A (-4.418) is better than Ligand B (-5.211), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.647) is better than Ligand B (-2.707), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.943) has a lower hERG inhibition liability than Ligand B (0.442), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-31.537) has a significantly lower (better) microsomal clearance than Ligand B (65.697), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.805) has a much longer in vitro half-life than Ligand A (-4.895). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.173) has lower P-gp efflux liability than Ligand B (0.248).

**Binding Affinity:** Ligand B (-7.6) 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 ADME drawbacks.

**Overall Assessment:**

Ligand A excels in almost all ADME properties (DILI, solubility, permeability, metabolic stability, hERG, QED) and has a reasonable binding affinity. However, Ligand B's significantly stronger binding affinity (-7.6 vs -10.2 kcal/mol) is a substantial advantage. The difference of 2.6 kcal/mol is significant enough to potentially overcome the ADME liabilities of Ligand B. While Ligand B has higher DILI risk and lower metabolic stability, these can potentially be addressed through further optimization. The strong binding affinity is more difficult to improve post-hoc.

Output:
1
2025-04-17 11:24:03,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.742 Da) is slightly higher, but acceptable. Ligand B (349.399 Da) is also good.

**TPSA:** Ligand A (72.36) is well below the 140 threshold for oral absorption. Ligand B (123.72) is also below the threshold, but closer.

**logP:** Ligand A (3.614) is within the optimal range (1-3). Ligand B (-0.902) is below 1, which could impede permeation.

**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 9 HBAs. Both are within the acceptable limit of <=10, but Ligand B is closer to the upper bound.

**QED:** Ligand A (0.792) has a better QED score than Ligand B (0.589), indicating better overall drug-likeness.

**DILI:** Ligand A (33.773) has a significantly lower DILI risk than Ligand B (60.14), placing it in the good risk category while Ligand B is in the high-risk category.

**BBB:** Ligand A (80.884) has a higher BBB penetration percentile than Ligand B (39.783). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.267 and -5.805), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.703 and -0.615), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.807) has a lower hERG inhibition risk than Ligand B (0.03), which is a significant advantage.

**Microsomal Clearance:** Ligand A (14.06 mL/min/kg) has a lower microsomal clearance than Ligand B (34.429 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.449 hours) has a longer half-life than Ligand B (15.809 hours).

**P-gp Efflux:** Ligand A (0.638) has lower P-gp efflux liability than Ligand B (0.027).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). The difference is 1.5 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, but it is significantly hampered by its poor solubility, high DILI risk, and low P-gp efflux. Ligand A, while having a slightly weaker affinity, demonstrates a much more favorable ADME profile, with lower DILI risk, better metabolic stability, and lower hERG risk. The poor Caco-2 and solubility are concerns for both, but the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 11:24:03,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal 200-500 Da range (A: 426.292, B: 364.471).

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption (A: 88.4, B: 87.47).

**logP:** Both are within the optimal 1-3 range (A: 2.079, B: 1.984).

**H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are acceptable (<=5).

**H-Bond Acceptors:** Both have 6 HBA, which is acceptable (<=10).

**QED:** Both have good QED scores (A: 0.691, B: 0.748), indicating drug-likeness.

**DILI:** Ligand A has a high DILI risk (87.786), while Ligand B has a low DILI risk (34.548). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (67.352) is slightly better than Ligand B (50.523).

**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 (-4.973) is slightly better than Ligand B (-5.568).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-4.201) is slightly better than Ligand B (-1.636).

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.431, B: 0.618).

**Microsomal Clearance:** Ligand A has a higher Cl_mic (66.367) than Ligand B (12.128), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B has a much longer half-life (56.754) than Ligand A (-5.576), indicating better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.764, B: 0.111). Ligand B is significantly better.

**Binding Affinity:** Ligand B has a better binding affinity (-7.4 kcal/mol) than Ligand A (-8.8 kcal/mol). While A is better, the difference is not substantial enough to overcome the ADME issues.

**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 a much lower DILI risk, lower microsomal clearance, longer half-life, and lower P-gp efflux. These factors are crucial for developing a viable drug candidate, especially for an enzyme target where metabolic stability and safety are paramount. The slightly lower binding affinity of Ligand B can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 11:24:03,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (362.47 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is slightly higher than Ligand B (49.85). Both are acceptable, being below 140, but B is preferable.

**logP:** Ligand A (4.145) is higher than the optimal range (1-3), potentially causing solubility issues or off-target effects. Ligand B (1.666) is within the optimal range. This is a significant advantage for B.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.811 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (65.529) has a higher DILI risk than Ligand B (39.511). B is significantly better here.

**BBB:** Both ligands have good BBB penetration (69.252 and 74.292), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these are on a log scale, so the absolute values are important. -4.465 for B is better than -4.702 for A.

**Aqueous Solubility:** Ligand A (-4.431) and Ligand B (-2.815) both have poor solubility, but B is better.

**hERG Inhibition:** Ligand A (0.756) has a higher risk of hERG inhibition than Ligand B (0.39). B is preferable.

**Microsomal Clearance:** Ligand A (75.866) has a higher microsomal clearance than Ligand B (40.836), indicating lower metabolic stability. B is significantly better.

**In vitro Half-Life:** Ligand A (56.79) has a longer half-life than Ligand B (-1.257). This is a positive for A, but the negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.457) has lower P-gp efflux than Ligand B (0.272), which is preferable.

**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, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B demonstrates superior ADME properties across several key parameters (logP, DILI, hERG, Cl_mic). However, Ligand A has a substantially better binding affinity (-9.9 vs -8.4 kcal/mol). Given that we are targeting an enzyme (kinase), potency is paramount. While Ligand A has some concerning ADME properties, the significantly improved binding affinity is likely to be the dominant factor in its success as a drug candidate, and optimization could address the ADME issues.

Output:
0
2025-04-17 11:24:03,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (432.34 Da) is slightly higher than Ligand B (355.356 Da), but both are acceptable.

**TPSA:** Ligand A (95.58) is higher than Ligand B (57.61). Both are below 140, supporting oral absorption, but Ligand B's lower TPSA is preferable.

**logP:** Ligand A (1.626) is within the optimal range (1-3). Ligand B (4.009) is slightly above, potentially raising concerns about solubility and off-target effects.

**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.

**QED:** Both ligands have good QED scores (A: 0.707, B: 0.785), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 59.48, B: 50.33), both being acceptable.

**BBB:** Both ligands have good BBB penetration (A: 74.176, B: 71.927), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.979 and -4.796). 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 base of the logarithm.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.689 and -3.299). Similar to Caco-2, these values are on a log scale and indicate poor solubility.

**hERG Inhibition:** Ligand A (0.468) has a slightly higher hERG risk than Ligand B (0.284), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 24.221, B: 24.431).

**In vitro Half-Life:** Ligand B (-5.963) has a significantly better (longer) in vitro half-life than Ligand A (-44.66). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.077, B: 0.17).

**Binding Affinity:** Ligand B (-9.3 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.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand B is the more promising candidate. Its superior binding affinity, significantly improved metabolic stability (half-life), and slightly better safety profile (lower hERG, lower logP) outweigh the slightly higher TPSA. The substantial difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 11:24:03,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.219 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (71.53) is significantly lower than Ligand A (106.1), which is favorable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.949) and Ligand B (2.04) are very similar.

**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: 0.555, Ligand B: 0.784), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A has a DILI risk of 81.776, which is concerning (high risk, >60). Ligand B has a much lower DILI risk of 52.191 (still not ideal, but significantly better). This is a major advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 69.678, Ligand B: 67.274). This isn't a primary concern for a kinase inhibitor, but higher is generally 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 hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.059 for A, -2.3 for B). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.095) has a very low hERG risk, which is excellent. Ligand B (0.449) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (82.006) has a higher microsomal clearance than Ligand B (55.772), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 26.51, Ligand B: 27.547).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.022, Ligand B: 0.111), which is favorable.

**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 enough to be considered, especially given the other factors.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both have solubility issues, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), a slightly better binding affinity, and a higher QED score. The slightly lower TPSA is also a benefit. The hERG risk is acceptable for both. The difference in binding affinity, while not enormous, adds to the advantage of Ligand B.

Output:
1
2025-04-17 11:24:03,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.356 Da and 383.945 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.22) is better than Ligand B (58.36), both are acceptable but A is closer to the ideal <140 for oral absorption.

**logP:** Both ligands (3.887 and 3.769) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<10).

**QED:** Ligand A (0.802) has a slightly better QED score than Ligand B (0.754), indicating better overall drug-likeness.

**DILI:** Ligand A (52.772) has a higher DILI risk than Ligand B (35.789). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (73.672) is better than Ligand B (60.644). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.68) is slightly better than Ligand B (-4.952), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-4.064) is slightly better than Ligand B (-3.409). This is a significant issue for both.

**hERG:** Ligand A (0.689) has a lower hERG risk than Ligand B (0.848), which is favorable.

**Microsomal Clearance:** Ligand B (53.227) has lower microsomal clearance than Ligand A (84.995), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (26.53) has a longer half-life than Ligand A (10.939), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux than Ligand B (0.824), which is favorable.

**Binding Affinity:** Ligand A (-9.7) has a significantly better binding affinity than Ligand B (-8.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower P-gp efflux, but suffers from higher DILI risk, poorer metabolic stability (higher Cl_mic, shorter t1/2), and poorer solubility. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better solubility, but weaker binding affinity.

The difference in binding affinity (-9.7 vs -8.0) is substantial (1.7 kcal/mol), and this can often outweigh minor ADME drawbacks, *especially* for an enzyme target like a kinase. However, the DILI risk for Ligand A is concerning. Given the importance of metabolic stability for kinases, and the relatively small difference in solubility, the better binding affinity of Ligand A is likely to be more impactful.

Output:
0
2025-04-17 11:24:03,847 - INFO - Batch 44 complete. Total preferences: 704
2025-04-17 11:24:03,847 - INFO - Processing batch 45/512...
2025-04-17 11:24:53,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (335.451 and 345.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (41.29) is well below the 140 threshold, while Ligand B (108.88) is still acceptable but higher.

**logP:** Ligand A (3.995) is at the upper end of the optimal range (1-3), while Ligand B (0.595) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 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 (0.71 and 0.651), indicating good drug-likeness.

**DILI:** Ligand A (54.478) has a lower DILI risk than Ligand B (60.295), both are acceptable but A is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (55.332) and Ligand B (32.765) are not particularly high, which is fine.

**Caco-2 Permeability:** Ligand A (-4.686) is better than Ligand B (-5.586), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.117) is better than Ligand B (-2.316), indicating better solubility.

**hERG Inhibition:** Ligand A (0.973) has a lower hERG risk than Ligand B (0.152), which is a significant advantage.

**Microsomal Clearance:** Ligand A (52.122) has higher clearance than Ligand B (10.905), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-19.397) has a negative half-life, which is concerning and likely an error. Ligand A (26.658) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.906) has lower P-gp efflux than Ligand B (0.025), which is preferable.

**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 concerns.

**Conclusion:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability, Ligand A's superior binding affinity, better solubility, lower hERG risk, and more reasonable half-life outweigh the slightly higher clearance. The negative half-life reported for Ligand B is a major red flag.

Output:
1
2025-04-17 11:24:53,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.296 Da) is slightly higher than Ligand B (345.447 Da), but both are acceptable.

**TPSA:** Ligand A (57.7) is better than Ligand B (82.23). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.595) is optimal, while Ligand B (1.68) is on the lower side. A logP below 1 can hinder permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are low, having at least one HBD can improve solubility.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA is generally preferred for permeability.

**QED:** Both ligands have similar QED values (0.848 and 0.813), indicating good drug-likeness.

**DILI:** Ligand A (77.472) has a higher DILI risk than Ligand B (42.924). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 63.164, Ligand B: 69.484), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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:** Ligand A (-3.943) has worse solubility than Ligand B (-2.274). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.744) has a slightly higher hERG risk than Ligand B (0.251). Lower hERG is preferred.

**Microsomal Clearance:** Ligand A (43.078) has a higher microsomal clearance than Ligand B (25.827), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (15.509) has a longer half-life than Ligand B (1.588). This is a positive attribute for Ligand A.

**P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux than Ligand B (0.154), which is favorable.

**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. The difference of 1.6 kcal/mol is large enough to potentially offset some of the ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, a longer half-life, and lower P-gp efflux. However, it has a higher DILI risk, worse solubility, and higher microsomal clearance. Ligand B has better solubility, lower DILI and hERG risk, and better metabolic stability but a weaker binding affinity.

Given the priority for potency in kinase inhibitors, the substantial binding affinity advantage of Ligand A (-9.6 kcal/mol vs -8.0 kcal/mol) is the most important factor. While the DILI risk is a concern, it can be investigated further through structural modifications. The solubility and metabolic stability issues are also addressable through medicinal chemistry efforts.

Output:
1
2025-04-17 11:24:53,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (332.411 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.63 and 76.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.219 and 2.265) within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBD and acceptable HBA counts (5 and 3 respectively), satisfying the <5 and <10 rules.

**QED:** Both ligands have good QED scores (0.77 and 0.793), indicating drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (77.627%) compared to Ligand B (28.655%). This is a major concern.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (64.87%) shows slightly better penetration than Ligand B (53.238%).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.167 and -4.816), 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 (-4.84 and -2.109), which is also concerning. Again, the scale is important, but both appear to have poor solubility.

**hERG:** Ligand A (0.94) has a slightly higher hERG risk than Ligand B (0.418), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand B has a significantly lower microsomal clearance (6.203 mL/min/kg) than Ligand A (41.369 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (3.874 hours) than Ligand A (34.752 hours). This is a discrepancy, as lower Cl_mic should correlate with longer t1/2. This could be a data error, but we'll proceed assuming the Cl_mic data is more reliable.

**P-gp Efflux:** Ligand A (0.513) shows lower P-gp efflux than Ligand B (0.156), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This difference of 1.8 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the unusual Caco-2 and solubility values, Ligand B is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic), and substantially improved binding affinity outweigh the slightly lower BBB penetration and higher P-gp efflux. The higher binding affinity is particularly important for an enzyme inhibitor. The discrepancy in half-life is a concern, but the Cl_mic data is more reliable.

Output:
1
2025-04-17 11:24:53,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.415 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.02) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (59.08) is well within the optimal range.

**logP:** Both ligands (1.411 and 1.185) are 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:** Ligand A has 5 HBA, within the limit. Ligand B has 4, also within the limit.

**QED:** Both ligands have reasonable QED scores (0.876 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A (36.06) has a slightly higher DILI risk than Ligand B (18.069), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.047) has a higher BBB score than Ligand A (54.052), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.137 and -4.596), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.895 and -1.599), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.259 and 0.319), which is excellent.

**Microsomal Clearance:** Ligand A (-14.625) has significantly lower (better) microsomal clearance than Ligand B (33.167), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.769) has a shorter half-life than Ligand B (14.746), which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.062), which is good.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.3). While both are strong binders, the 0.6 kcal/mol difference is notable.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is slightly more promising. Its superior binding affinity (-7.9 vs -7.3 kcal/mol) and significantly better metabolic stability (lower Cl_mic and longer half-life) outweigh the slightly higher DILI risk and lower BBB penetration. The difference in binding affinity is substantial enough to potentially overcome the ADME liabilities with appropriate formulation strategies.

Output:
0
2025-04-17 11:24:53,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.455 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (55.84) is significantly better than Ligand B (99.85). Lower TPSA generally correlates with better cell permeability, crucial for kinase inhibitors to reach their intracellular target. Ligand B's TPSA is approaching a level that could hinder oral absorption.

**logP:** Ligand A (3.728) is optimal, while Ligand B (1.018) is a bit low. A logP below 1 can sometimes indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Fewer hydrogen bonds generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.601, B: 0.772), indicating generally drug-like properties.

**DILI:** Ligand A (28.577) has a significantly lower DILI risk than Ligand B (52.772). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.411) has a better BBB score than Ligand B (55.138).

**Caco-2 Permeability:** Ligand A (-4.309) is better than Ligand B (-5.048), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.32) is better than Ligand B (-3.05), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.776) has a slightly better hERG profile than Ligand B (0.64), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (97.637) has a much higher microsomal clearance than Ligand B (37.376). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-2.225) has a better in vitro half-life than Ligand A (-17.644). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.555) has a better P-gp efflux profile than Ligand B (0.107), meaning less efflux and potentially better bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 0.3 kcal/mol difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, DILI, solubility, hERG, P-gp efflux, Caco-2) and has a slightly better binding affinity. However, Ligand B has significantly better metabolic stability (lower Cl_mic) and a longer in vitro half-life. Given that SRC kinases are intracellular targets, metabolic stability is crucial. While Ligand A's better ADME profile is attractive, the improved half-life of Ligand B is a significant advantage for an enzyme target.

Output:
1
2025-04-17 11:24:53,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.49 and 354.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.43 and 68.84) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands (2.559 and 2.118) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as having some HBD can improve solubility.

**H-Bond Acceptors:** Ligand B (6) is preferable to Ligand A (3) as having some HBA can improve solubility.

**QED:** Both ligands (0.725 and 0.613) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (18.42) has a significantly lower DILI risk than Ligand B (54.36), which is a major advantage.

**BBB:** Ligand B (90.11) has a much higher BBB penetration than Ligand A (51.80). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.682 and -4.93), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.685 and -1.813), which is also a concern.

**hERG Inhibition:** Ligand A (0.211) has a lower hERG inhibition liability than Ligand B (0.544), which is a positive.

**Microsomal Clearance:** Ligand A (29.09 mL/min/kg) has a lower microsomal clearance than Ligand B (38.94 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (20.59 hours) has a longer in vitro half-life than Ligand A (13.95 hours), which is a slight advantage.

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux liability than Ligand B (0.27), which is a positive.

**Binding Affinity:** Both ligands have very similar 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 preferable due to its significantly lower DILI risk, lower hERG inhibition, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While Ligand B has a slightly longer half-life and better BBB penetration (irrelevant here), the safety and ADME advantages of Ligand A outweigh these benefits. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 11:24:53,292 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.494, 58.2, 3.352, 2, 2, 0.738, 23.032, 83.094, -4.717, -3.578, 0.644, 33.54, -2.588, 0.365, -7.8]
**Ligand B:** [347.419, 106.82, 0.008, 2, 6, 0.365, 13.416, 64.676, -5.401, -1.748, 0.678, -21.161, 13.903, 0.013, 0]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (352.494) and B (347.419) are comparable.
2. **TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (106.82) is higher, but still acceptable, though less optimal.
3. **logP:** Ligand A (3.352) is within the optimal range (1-3). Ligand B (0.008) is *very* low, potentially hindering permeability. This is a significant drawback.
4. **HBD:** Both ligands have 2 HBD, which is good.
5. **HBA:** Ligand A (2) is good. Ligand B (6) is higher, potentially impacting permeability.
6. **QED:** Ligand A (0.738) is excellent, indicating strong drug-likeness. Ligand B (0.365) is below the desirable threshold of 0.5, suggesting a less favorable drug-like profile.
7. **DILI:** Ligand A (23.032) has a very low DILI risk. Ligand B (13.416) is also relatively low, but higher than A.
8. **BBB:** Ligand A (83.094) shows good potential for BBB penetration, though not critical for a non-CNS target like SRC. Ligand B (64.676) is lower.
9. **Caco-2:** Ligand A (-4.717) is good, indicating good intestinal absorption. Ligand B (-5.401) is also good.
10. **Solubility:** Ligand A (-3.578) is good. Ligand B (-1.748) is also good.
11. **hERG:** Both ligands have low hERG risk (0.644 and 0.678).
12. **Cl_mic:** Ligand A (33.54) has moderate clearance. Ligand B (-21.161) has *negative* clearance, which is not physically possible and likely an error in the data. Assuming it is a positive value, it suggests much better metabolic stability. However, a negative value is a major red flag.
13. **t1/2:** Ligand A (-2.588) is negative, which is not possible. Ligand B (13.903) has a good in vitro half-life. Again, the negative value for A is a major issue.
14. **Pgp:** Ligand A (0.365) has low P-gp efflux. Ligand B (0.013) has very low P-gp efflux.
15. **Affinity:** Ligand A (-7.8) has a significantly stronger binding affinity than Ligand B (0). This is a crucial advantage.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite the issues with the negative values for Cl_mic and t1/2 for Ligand A, the significantly stronger binding affinity (-7.8 kcal/mol vs 0 kcal/mol) of Ligand A, combined with its better QED and lower DILI risk, makes it the more promising candidate. The extremely low logP of Ligand B is a major concern, likely leading to poor permeability. The negative values for Ligand A are concerning and would require further investigation to confirm the accuracy of the data. However, assuming these are errors, Ligand A is still the better choice due to its superior affinity.

Output:
1
2025-04-17 11:24:53,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.447 and 357.401 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (81.59 and 80.32) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.954) is slightly below the optimal 1-3 range, while Ligand B (2.191) is well within. This favors Ligand B slightly for permeability.

**H-Bond Donors & Acceptors:** Both have 2 HBD and either 5 or 4 HBA, which are acceptable.

**QED:** Ligand A (0.853) has a significantly better QED score than Ligand B (0.629), indicating a more drug-like profile.

**DILI:** Ligand A (8.647 percentile) has a much lower DILI risk than Ligand B (46.219 percentile). This is a significant advantage for Ligand A.

**BBB:** Both have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (81.621) is slightly better.

**Caco-2 Permeability:** Ligand A (-5.05) has a lower Caco-2 permeability than Ligand B (-4.35), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.813) has better aqueous solubility than Ligand B (-2.532). This is a positive for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.343) has a lower hERG inhibition liability than Ligand B (0.613), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (-35.351 mL/min/kg) has significantly lower microsomal clearance than Ligand B (57.186 mL/min/kg), indicating much better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.787 hours) has a lower in vitro half-life than Ligand B (26.948 hours). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.004) has a much lower P-gp efflux liability than Ligand B (0.115), suggesting better oral bioavailability.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in potency (binding affinity), metabolic stability (Cl_mic), DILI risk, hERG inhibition, and P-gp efflux. While its Caco-2 permeability is lower and half-life is shorter, the significantly better binding affinity and safety profile (DILI, hERG) are critical for an enzyme target like SRC. Ligand B has better logP and half-life, but its higher DILI risk, hERG liability, and lower binding affinity are significant drawbacks.

Output:
0
2025-04-17 11:24:53,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.515 and 364.452 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have a TPSA of 49.41, well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.524) is within the optimal range (1-3), while Ligand B (4.041) is slightly above, potentially hinting at solubility issues.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD and 2 HBA, satisfying the criteria of <=5 and <=10 respectively.

**QED:** Both ligands have acceptable QED scores (0.513 and 0.693), indicating good drug-like properties.

**DILI:** Ligand A (11.128) has a significantly lower DILI risk than Ligand B (35.75). This is a crucial advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (89.841) is better than Ligand A (76.309). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is a concern for both, but needs to be balanced against other factors.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.63 and 0.5), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (68.215 and 67.516), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (15.77) has a much longer half-life than Ligand A (-15.275). 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 (0.405 and 0.203).

**Binding Affinity:** Both ligands exhibit strong binding affinity (-8.0 and -8.9 kcal/mol). Ligand B has a slightly better affinity, but the difference (0.9 kcal/mol) isn't huge enough to outweigh other concerns.

**Conclusion:**

While Ligand B has a slightly better binding affinity and half-life, Ligand A is significantly better regarding DILI risk, a critical factor for drug development. Both have poor solubility and permeability, but the lower DILI risk of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 11:24:53,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.463 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (49.85), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.705) is slightly lower than optimal (1-3), but still acceptable. Ligand B (1.832) is within the optimal range.

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

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also good.

**QED:** Both ligands have similar QED values (0.598 and 0.565), indicating good drug-likeness.

**DILI:** Both ligands have very similar, low DILI risk (18.651 and 18.147 percentile), which is excellent.

**BBB:** Both ligands have moderate BBB penetration (60.45 and 63.784 percentile). Not a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.013) is significantly worse than Ligand B (-4.445), indicating poorer intestinal absorption.

**Solubility:** Ligand A (-0.739) is slightly better than Ligand B (-2.246), but both are poor.

**hERG:** Both ligands have very low hERG risk (0.197 and 0.193 percentile), which is excellent.

**Microsomal Clearance:** Ligand B (34.559) has slightly higher microsomal clearance than Ligand A (31.228), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.799) has a significantly worse in vitro half-life than Ligand A (-0.635), suggesting faster metabolism.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.018 and 0.155 percentile).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has slightly better binding affinity than Ligand B (-6.7 kcal/mol). This 0.8 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and slightly better solubility. However, Ligand B has better Caco-2 permeability and a slightly better metabolic stability profile. The difference in binding affinity (0.8 kcal/mol) is substantial, and given that we are targeting an enzyme, potency is a high priority. The slightly poorer Caco-2 of Ligand A is a concern, but could potentially be addressed with formulation strategies. The better half-life of Ligand A is also a positive.

Output:
1
2025-04-17 11:24:53,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.49 and 343.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (74.59). Lower TPSA generally correlates with better permeability, which is important for oral bioavailability.

**logP:** Both ligands have good logP values (2.04 and 1.81), 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 acceptable, but lower is generally preferred.

**QED:** Both ligands have good QED scores (0.716 and 0.779), indicating good drug-like properties.

**DILI:** Ligand A (12.37) has a much lower DILI risk than Ligand B (33.62), which is a significant advantage.

**BBB:** Ligand A (54.44) has a slightly better BBB score than Ligand B (46.06), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.54 and -4.74), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.17 and -1.97), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Both ligands have low hERG risk (0.47 and 0.45). This is good.

**Microsomal Clearance:** Ligand A (36.13) has significantly lower microsomal clearance than Ligand B (53.82), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-6.90) has a much longer in vitro half-life than Ligand B (32.13), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.27 and 0.05).

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.4). While both are good, the 0.3 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is the better candidate. While both have poor solubility and permeability, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity. These factors are particularly important for an enzyme target like SRC kinase. The solubility/permeability issues would need to be addressed through formulation or further chemical modifications, but the more favorable ADME and toxicity profile of Ligand A makes it the more promising starting point.

Output:
1
2025-04-17 11:24:53,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.417 and 345.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is well below the 140 threshold and good for oral absorption. Ligand B (120.33) is also acceptable, but less optimal.

**logP:** Ligand A (1.734) is within the optimal 1-3 range. Ligand B (-0.308) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5. Both are acceptable, below the 10 limit.

**QED:** Both ligands have good QED scores (0.583 and 0.636), indicating good drug-like properties.

**DILI:** Ligand A (37.263) has a lower DILI risk than Ligand B (52.772), which is a significant advantage. Both are below the concerning 60 threshold, but lower is better.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (52.268) is lower than Ligand B (15.975).

**Caco-2 Permeability:** Ligand A (-4.968) shows poor permeability, while Ligand B (-5.905) is even worse. This is a concern for both, but more so for B.

**Aqueous Solubility:** Ligand A (-1.513) has slightly better solubility than Ligand B (-2.117), but both are quite poor.

**hERG:** Both ligands have very low hERG risk (0.507 and 0.141), which is excellent.

**Microsomal Clearance:** Ligand A (33.677) has a better (lower) microsomal clearance than Ligand B (-32.946 - note the negative value, indicating very rapid clearance). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-12.089) has a negative half-life, which is not possible and likely an error in the data. Ligand B (-3.469) is also negative, indicating very rapid degradation. Both are problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.15 and 0.004), which is favorable.

**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 not a huge advantage, but still noteworthy.

**Overall Assessment:**

Ligand A is preferable despite the negative half-life value. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better solubility. While both have poor Caco-2 permeability, the other advantages of A outweigh this. The negative half-life values are concerning, but could be an artifact of the data. The slightly better binding affinity of Ligand B is not enough to overcome the higher DILI risk and worse metabolic stability.

Output:
0
2025-04-17 11:24:53,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. 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 (390.615 Da) is also acceptable.

**2. TPSA:** Ligand A (119.66) is better than Ligand B (75.27), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand B (3.198) is optimal, while Ligand A (0.516) is quite low, potentially hindering membrane permeability and absorption.

**4. H-Bond Donors:** Both ligands are acceptable (Ligand A: 3, Ligand B: 2), being less than 5.

**5. H-Bond Acceptors:** Both ligands are acceptable (Ligand A: 5, Ligand B: 4), being less than 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.66, Ligand B: 0.7), indicating drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (Ligand A: 56.689, Ligand B: 54.246), below the concerning threshold of 60.

**8. BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (45.095) is slightly better than Ligand A (35.828).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the magnitude suggests poor permeability for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.44, Ligand B: 0.344), which is excellent.

**12. Microsomal Clearance:** Ligand A (-10.632) has significantly lower (better) microsomal clearance than Ligand B (66.935), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-20.701) has a much longer in vitro half-life than Ligand B (-37.166), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.068, Ligand B: 0.235).

**15. 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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity (-7.9 vs -9.1 kcal/mol). While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2) and slightly better TPSA, Ligand B's superior potency is a critical factor for an enzyme inhibitor. The lower logP of Ligand A is a significant concern, potentially leading to poor absorption. The negative Caco-2 and solubility values for both are concerning and would require further investigation, but the potency advantage of Ligand B is likely to be more readily addressed through formulation or structural modifications.

Output:
1
2025-04-17 11:24:53,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.341 and 355.479 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the preferred <140, while Ligand B (84.32) is well within. This favors Ligand B slightly for absorption.

**logP:** Ligand A (1.744) is optimal, while Ligand B (-0.089) is slightly below 1, potentially hindering permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.8) is better than Ligand B (0.696), indicating a more drug-like profile.

**DILI:** Ligand A (80.109) has a significantly higher DILI risk than Ligand B (5.157). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand B (15.432) is much lower than Ligand A (48.042).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.976 and -4.953), which is unusual and suggests poor permeability. However, these values are on the same scale, so don't differentiate the two.

**Aqueous Solubility:** Ligand B (0.017) has slightly better solubility than Ligand A (-2.451).

**hERG:** Ligand A (0.056) has a much lower hERG risk than Ligand B (0.171), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-21.566) has a much lower (better) microsomal clearance than Ligand B (-18.331), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-30.524) has a much longer half-life than Ligand B (9.737), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.002) has almost no P-gp efflux liability, while Ligand B (0.01) has slightly more.

**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 has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. It also has a much lower DILI risk and slightly better solubility. However, it has a lower logP, potentially impacting permeability, and a shorter half-life. Ligand A has better logP, QED, metabolic stability, and half-life, but suffers from a high DILI risk.

Given the substantial difference in binding affinity (-8.3 vs 0.0 kcal/mol), the benefits of Ligand B outweigh its drawbacks. The lower DILI risk is also a major advantage. While the logP is suboptimal, this can potentially be addressed through further medicinal chemistry optimization.

Output:
1
2025-04-17 11:24:53,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (352.475 and 362.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is better than Ligand B (34.59). Both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have acceptable logP values (2.119 and 3.48), falling within the 1-3 range. Ligand B is slightly higher, potentially posing a minor solubility concern, but not a major one.

**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 good QED scores (0.587 and 0.755), indicating good drug-like properties.

**7. DILI:** Ligand A (12.136) has a significantly lower DILI risk than Ligand B (24.118). This is a substantial advantage.

**8. BBB:** Ligand A (78.092) has a lower BBB penetration than Ligand B (97.829). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.497 and -4.926). 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 (-2.524 and -2.907). These are also unusual and suggest very low solubility.

**11. hERG Inhibition:** Ligand A (0.394) has a lower hERG inhibition risk than Ligand B (0.866). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (53.758) has a higher microsomal clearance than Ligand B (47.21). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-14.178) has a significantly shorter in vitro half-life than Ligand B (16.492). This is a major drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.457). This is a slight advantage.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 1.5 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand B has a better binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and better BBB penetration. However, Ligand A has a significantly lower DILI risk and hERG inhibition liability, and lower P-gp efflux. The poor Caco-2 and solubility for both ligands are concerning. Considering the enzyme-kinase specific priorities, metabolic stability and potency are key. The affinity difference between B and A is significant, and the improved metabolic stability of B outweighs the slightly higher DILI and hERG risks.

Output:
1
2025-04-17 11:24:53,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.407 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of around 80, well below the 140 threshold for oral absorption.

**logP:** Both ligands have logP values within the optimal 1-3 range (1.361 and 1.997).

**H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are acceptable (<=5).

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

**QED:** Both ligands have high QED scores (0.824 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 82.784, which is high. Ligand B has a DILI risk of 49.477, which is much better (below 60). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration scores (64.444 and 63.784). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.343 and -4.872), 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 (-4.117 and -2.388), indicating poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.389 and 0.258).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (59.785) than Ligand B (39.526), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-2.687 hours) compared to Ligand A (-12.785 hours), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.246 and 0.172).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-7.9 kcal/mol) than Ligand A (-8.4 kcal/mol). While the difference isn't huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic and longer t1/2). The slightly improved binding affinity further supports its selection. The high DILI risk associated with Ligand A is a major concern that outweighs its slightly better binding affinity.

Output:
1
2025-04-17 11:24:53,294 - INFO - Batch 45 complete. Total preferences: 720
2025-04-17 11:24:53,294 - INFO - Processing batch 46/512...
2025-04-17 11:25:40,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.4 and 361.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.22) is slightly higher than Ligand B (70.67), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.012 and 1.155), falling within the 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 (0.881) has a significantly better QED score than Ligand B (0.714), indicating a more drug-like profile.

**DILI:** Ligand B (19.04) has a much lower DILI risk than Ligand A (41.88), which is a significant advantage.

**BBB:** Ligand B (83.48) has a much higher BBB penetration percentile than Ligand A (35.32). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.511 and -4.84), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.073 and -1.486), which is also concerning and suggests poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.121) has a slightly lower hERG inhibition liability than Ligand B (0.4), which is preferable.

**Microsomal Clearance:** Ligand A (7.511) has a higher microsomal clearance than Ligand B (3.07), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-9.035) has a longer in vitro half-life than Ligand A (25.914), which is a major advantage.

**P-gp Efflux:** Ligand B (0.014) has a much lower P-gp efflux liability than Ligand A (0.047), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B demonstrates significantly better ADME properties: lower DILI risk, higher BBB, longer half-life, lower P-gp efflux, and slightly better binding affinity. The better binding affinity, combined with the improved ADME profile, outweighs the slightly lower QED score. Ligand A's higher clearance is a significant concern for an enzyme target.

Output:
1
2025-04-17 11:25:40,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (357.426 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is slightly higher than Ligand B (67.87), but both are well below the 140 threshold for good absorption.

**3. logP:** Ligand A (0.337) is a bit low, potentially hindering permeation. Ligand B (1.501) 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:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the threshold of 10.

**6. QED:** Both ligands have a QED of 0.73, indicating good drug-likeness.

**7. DILI:** Ligand A (28.306) has a slightly higher DILI risk than Ligand B (21.636), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (79.217) shows better BBB penetration than Ligand B (65.801). However, as SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.43 and -4.662), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.363 and -1.925), also concerning, indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.51) has a slightly higher hERG risk than Ligand B (0.129). This favors Ligand B.

**12. Microsomal Clearance:** Ligand A (43.995) and Ligand B (45.253) have similar microsomal clearance values, suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.288 hours) has a significantly longer half-life than Ligand A (-8.688 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.03).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This is a 0.6 kcal/mol difference, which is notable but not overwhelming.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior in several key ADME properties crucial for an enzyme inhibitor. Specifically, Ligand B has a better logP, lower hERG risk, and a significantly longer in vitro half-life. The poor Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh the slightly weaker binding.

Output:
1
2025-04-17 11:25:40,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 353.507 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.73) is slightly above the preferred <140, but acceptable. Ligand B (87.3) is excellent, well below 140.

**logP:** Ligand A (0.224) is quite 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 5 HBA, which are acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.752) has a better QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand A (58.434) has a higher DILI risk than Ligand B (16.324). This is a significant concern for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (64.211) is slightly better than Ligand A (46.026).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.551 and -4.864), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.289 and -2.705), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.182 and 0.189), which is positive.

**Microsomal Clearance:** Ligand A (5.431) has significantly lower microsomal clearance than Ligand B (45.518), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.384) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (-3.174) also has a negative half-life, also suggesting data issues.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.022).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.3 kcal/mol difference is substantial and outweighs many of the other drawbacks.

**Conclusion:**

Despite the unusual Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.6 vs -7.3 kcal/mol) is a major advantage for an enzyme target. It also has a much lower DILI risk and better logP. While Ligand A has a better QED and lower microsomal clearance, the superior affinity and safety profile of Ligand B make it the better choice. The negative half-life values are concerning and would require further investigation, but the affinity difference is substantial enough to prioritize Ligand B for further optimization.

Output:
1
2025-04-17 11:25:40,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.391 and 362.436 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (62.55 and 58.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.426 and 3.414) are within the optimal 1-3 range. 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 1 HBD and 3 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values (0.79 and 0.682) above the 0.5 threshold, indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 55.913, while Ligand B has 40.054. Both are acceptable, but Ligand B is noticeably better, falling comfortably below the 60 threshold.

**BBB:** Both ligands have similar BBB penetration (53.548 and 57.852). BBB is not a high priority for a kinase inhibitor unless CNS targets are specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.656 and -4.696). These values are unusual and suggest poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.683 and -4.296). Again, these are unusual and indicate very poor aqueous solubility, a major concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.651 and 0.461), which is excellent.

**Microsomal Clearance:** Ligand A has a Cl_mic of 45.541, while Ligand B has 53.858. Lower is better, so Ligand A is slightly favored in terms of metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 52.181 hours, while Ligand B has only 3.083 hours. This is a *major* advantage for Ligand A. A longer half-life translates to less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.191 and 0.082), which is favorable.

**Binding Affinity:** Ligand A has a binding affinity of -8.2 kcal/mol, while Ligand B has -7.8 kcal/mol. Ligand A is significantly more potent, with a 0.4 kcal/mol advantage. This difference in affinity is substantial enough to potentially outweigh some of the ADME concerns.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly higher binding affinity (-8.2 vs -7.8 kcal/mol) and substantially longer half-life (52.181 vs 3.083 hours) are critical advantages for an enzyme inhibitor. The slightly better DILI score for Ligand B is not enough to offset these benefits. The poor solubility and permeability would need to be addressed through formulation strategies, but the potency and metabolic stability of Ligand A make it a better starting point for optimization.

Output:
0
2025-04-17 11:25:40,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.451 and 347.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (89.35 and 91.46) are below the 140 A^2 threshold for good oral absorption, and acceptable for kinase inhibitors.

**3. logP:** Ligand A (0.528) is slightly low, potentially hindering permeation. Ligand B (0.781) is also on the lower side, but better than A.

**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 6 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.701 and 0.785), indicating good drug-like properties.

**7. DILI:** Ligand A (39.899) has a slightly better DILI risk profile than Ligand B (46.917), both being below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (66.305) has a slightly higher BBB penetration than Ligand A (55.642).

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. Ligand A (-5.068) is slightly better than Ligand B (-4.461), but both are concerning.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.073 and -1.658). This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.069) has a much lower hERG risk than Ligand B (0.637). This is a major advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (16.505) has lower microsomal clearance than Ligand B (21.731), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (9.177 and 8.251 hours).

**14. P-gp Efflux:** Ligand A (0.027) has much lower P-gp efflux than Ligand B (0.209), indicating better bioavailability.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most crucial factor for an enzyme inhibitor. However, it suffers from higher hERG risk, higher P-gp efflux, and higher microsomal clearance compared to Ligand A. Both compounds have poor solubility and Caco-2 permeability. The improved binding affinity of Ligand B likely outweighs the ADME drawbacks, especially considering the relatively low hERG and P-gp values.

Output:
1
2025-04-17 11:25:40,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.39 and 367.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.69) is better than Ligand B (69.22), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.184) is quite low, potentially hindering permeability. Ligand B (3.426) 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 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.675 and 0.751), indicating drug-likeness.

**DILI:** Ligand A (67.313) has a higher DILI risk than Ligand B (36.681). This is a concern for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (50.523) is slightly better than Ligand A (41.218).

**Caco-2 Permeability:** Ligand A (-5.161) has poor Caco-2 permeability, while Ligand B (-4.882) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.982) has poor aqueous solubility, while Ligand B (-3.72) is even worse. Both are problematic.

**hERG:** Ligand A (0.104) has a very low hERG risk, which is excellent. Ligand B (0.88) has a moderate hERG risk. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (14.284) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (44.34). This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-0.317) has a slightly negative half-life, which is concerning. Ligand B (44.309) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is favorable. Ligand B (0.62) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is not substantial enough to outweigh the other ADME concerns.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, very low hERG, low P-gp efflux) and better metabolic stability (lower Cl_mic). However, it suffers from poor solubility, permeability, and a concerning half-life. Ligand B has better logP and a good half-life but has higher DILI risk, moderate hERG risk, and higher P-gp efflux.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the slightly better candidate. The better metabolic stability and safety profile are more important than the slightly better affinity of Ligand B, especially given the solubility issues with both. Further optimization of Ligand A to improve solubility and permeability would be a logical next step.

Output:
0
2025-04-17 11:25:40,808 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [376.312, 105.59 ,   2.393,   2.   ,   6.   ,   0.794,  84.257,  24.389, -5.185,  -4.038,   0.32 ,  23.297,  -2.834,   0.127,   0.   ]
**Ligand B:** [342.443,  67.23 ,   1.725,   1.   ,   4.   ,   0.847,  31.097,  73.362, -4.848,  -2.403,   0.219,  18.302, -13.706,   0.052,  -7.5  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (342.443) is slightly lower, which could be beneficial for permeability, but both are acceptable.
2. **TPSA:** Ligand A (105.59) is higher than Ligand B (67.23).  Both are below the 140 threshold for oral absorption, but B is significantly better, potentially indicating better cell permeability.
3. **logP:** Both are within the optimal range (1-3). Ligand A (2.393) is slightly higher, which could lead to some off-target effects, but is still reasonable. Ligand B (1.725) is slightly lower, potentially affecting permeability.
4. **HBD:** Both are acceptable (<=5). Ligand A has 2, Ligand B has 1.
5. **HBA:** Both are acceptable (<=10). Ligand A has 6, Ligand B has 4.
6. **QED:** Both are good (>0.5). Ligand A (0.794) and Ligand B (0.847) are both highly drug-like.
7. **DILI:** Ligand A (84.257) has a significantly higher DILI risk than Ligand B (31.097). This is a major concern for Ligand A.
8. **BBB:** Ligand B (73.362) has a much higher BBB penetration potential than Ligand A (24.389). While not a primary concern for a kinase inhibitor, it's a positive attribute.
9. **Caco-2:** Ligand A (-5.185) has a negative Caco-2 value, which is concerning and suggests poor permeability. Ligand B (-4.848) is also negative, but less so.
10. **Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.403) is slightly better than Ligand A (-4.038).
11. **hERG:** Both have low hERG risk (0.32 and 0.219 respectively).
12. **Cl_mic:** Ligand B (18.302) has a lower microsomal clearance than Ligand A (23.297), suggesting better metabolic stability.
13. **t1/2:** Ligand B (-13.706) has a much longer *in vitro* half-life than Ligand A (-2.834). This is a significant advantage.
14. **Pgp:** Both have very low Pgp efflux liability (0.127 and 0.052 respectively).
15. **Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a decisive advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme target like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in all these areas. The substantially better binding affinity and metabolic stability of Ligand B are critical. The lower DILI risk is also a major factor.

**Conclusion:**

Ligand B is significantly more likely to be a viable drug candidate than Ligand A. Its superior binding affinity, metabolic stability, lower DILI risk, and better permeability profile outweigh any minor drawbacks.

1
2025-04-17 11:25:40,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (355.331 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.33) is significantly better than Ligand B (78.87).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**3. logP:** Ligand A (4.318) is higher than Ligand B (1.482). While Ligand A is pushing the upper limit, it's still within a reasonable range. Ligand B is quite low, potentially hindering 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), well below the threshold of 10.

**6. QED:** Ligand A (0.812) has a better QED score than Ligand B (0.649), indicating a more drug-like profile.

**7. DILI:** Ligand B (16.673) has a much lower DILI risk than Ligand A (52.191), a significant advantage.

**8. BBB:** Ligand A (74.758) has a better BBB penetration score than Ligand B (44.94), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value for Ligand A (-4.324) is slightly less negative than Ligand B (-4.464), potentially indicating marginally better absorption.

**10. Aqueous Solubility:** Ligand B (-1.888) is better than Ligand A (-5.047), which is a crucial advantage for bioavailability.

**11. hERG Inhibition:** Ligand A (0.768) has a lower hERG risk than Ligand B (0.239), a significant advantage.

**12. Microsomal Clearance:** Ligand B (35.619) has a significantly lower microsomal clearance than Ligand A (65.678), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.166) has a slightly better in vitro half-life than Ligand A (-5.886).

**14. P-gp Efflux:** Ligand B (0.08) has a lower P-gp efflux liability than Ligand A (0.208), which is beneficial for bioavailability.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A's primary strength is its significantly superior binding affinity. This is the most important factor for an enzyme inhibitor. While Ligand B has better ADME properties (lower DILI, better solubility, lower clearance, lower P-gp efflux), the difference in binding affinity is substantial. The slightly higher logP of Ligand A is acceptable, and its hERG risk is lower. The negative Caco-2 values are concerning for both, but the affinity difference is likely to be more impactful in initial optimization.

Output:
1
2025-04-17 11:25:40,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (363.571 Da) is also good.

**TPSA:** Ligand A (106.96) is better than Ligand B (48.99). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.224) is within the optimal range (1-3). Ligand B (4.584) is slightly 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 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.698) has a significantly better QED score than Ligand A (0.22), indicating a more drug-like profile.

**DILI:** Ligand A (19.659) has a much lower DILI risk than Ligand B (21.636), which is a significant advantage.

**BBB:** Ligand B (78.635) shows better BBB penetration than Ligand A (54.634), but this is less critical for a kinase inhibitor unless CNS involvement is specifically targeted.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.04) has slightly better permeability than Ligand B (-5.13), but both are very poor.

**Aqueous Solubility:** Ligand A (-2.05) has better solubility than Ligand B (-4.541).

**hERG Inhibition:** Ligand A (0.313) has a lower hERG risk than Ligand B (0.563), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand B (88.683) has a much higher microsomal clearance than Ligand A (15.219), indicating poorer metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (4.533) has a better in vitro half-life than Ligand B (-5.073).

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux than Ligand B (0.332), which is favorable for bioavailability.

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, a higher QED score, and better BBB penetration. However, it suffers from higher logP, higher DILI risk, significantly higher microsomal clearance (lower metabolic stability), and higher P-gp efflux.

Ligand A has better solubility, lower hERG risk, lower DILI, lower clearance, and lower P-gp efflux. Its major weakness is the very poor binding affinity.

Given the enzyme-specific priorities, metabolic stability (Cl_mic) and potency (affinity) are paramount. While Ligand B's affinity is significantly better, its poor metabolic stability is a major concern. The difference in affinity is substantial (>1.5 kcal/mol), but the metabolic instability of Ligand B is a significant hurdle. Ligand A, while having a very weak binding affinity, has a much more favorable ADME profile.

Output:
0
2025-04-17 11:25:40,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.419 and 369.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.56) is slightly higher than Ligand B (64.43), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.223) is quite low, potentially hindering permeability. Ligand B (2.835) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

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

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have reasonable QED scores (0.765 and 0.628), indicating good drug-like properties.

**DILI:** Ligand A (40.752) has a slightly higher DILI risk than Ligand B (14.23), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (83.094) has a higher BBB score than Ligand A (62.195).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.687 and -4.451), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.415 and -1.827), also unusual and indicating poor solubility. This is another significant drawback for both.

**hERG Inhibition:** Ligand A (0.205) has a slightly lower hERG risk than Ligand B (0.445), which is preferable.

**Microsomal Clearance:** Ligand A (30.954) has a lower microsomal clearance than Ligand B (64.97), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (4.129) has a shorter half-life than Ligand B (13.649). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.218), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.9 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 concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic) and P-gp efflux. However, Ligand B has a more favorable logP and slightly lower DILI risk. Both have concerningly low/negative Caco-2 and solubility values. The stronger binding affinity of Ligand A is a critical factor for an enzyme inhibitor, and its better metabolic stability is also highly desirable. While the low logP of Ligand A is a concern, the substantial affinity advantage likely outweighs this drawback, *assuming* formulation strategies can address the solubility/permeability issues.

Output:
0
2025-04-17 11:25:40,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 350.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (125.35) is still acceptable, but less favorable.

**logP:** Ligand A (2.092) is optimal (1-3). Ligand B (-1.994) is slightly low, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is acceptable.

**QED:** Both ligands (0.716 and 0.633) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (21.675) has a much lower DILI risk than Ligand B (48.468), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (68.282) is better than Ligand B (48.158).

**Caco-2:** Ligand A (-4.471) and Ligand B (-5.236) are both negative, indicating poor permeability. This is a concern for both.

**Solubility:** Ligand A (-2.258) is better than Ligand B (-1.055), although both are poor.

**hERG:** Ligand A (0.271) has a lower hERG risk than Ligand B (0.01), which is a significant advantage.

**Microsomal Clearance:** Ligand A (25.386) has higher clearance than Ligand B (-7.183), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (26.801) has a longer half-life than Ligand A (-7.719), indicating better stability.

**P-gp Efflux:** Both ligands (0.017 and 0.002) show low P-gp efflux, which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.2 kcal/mol). The difference is not substantial enough to override other ADME considerations.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, DILI risk, hERG risk, and solubility. However, Ligand B has better metabolic stability (lower Cl_mic, longer half-life). Given the enzyme-specific priorities, metabolic stability is crucial. While Ligand A has a better safety profile (DILI, hERG), the significantly better metabolic stability of Ligand B is more important for an enzyme inhibitor. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 11:25:40,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.427 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.3) is better than Ligand B (114.69). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal for oral bioavailability.

**logP:** Ligand A (0.727) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.935) is also slightly low, but closer to the ideal range.

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

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable.

**QED:** Ligand A (0.846) has a significantly better QED score than Ligand B (0.644), indicating a more drug-like profile.

**DILI:** Ligand A (55.642) has a higher DILI risk than Ligand B (25.436). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (55.797) is slightly better than Ligand B (40.132).

**Caco-2:** Ligand A (-4.791) has a worse Caco-2 permeability than Ligand B (-5.573). Lower values indicate poorer permeability.

**Solubility:** Ligand A (-0.789) has better solubility than Ligand B (-3.09). Solubility is important for bioavailability.

**hERG:** Ligand A (0.147) has a much lower hERG risk than Ligand B (0.514). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-20.19) has significantly lower (better) microsomal clearance than Ligand B (32.761), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.33) has a slightly better half-life than Ligand B (4.758).

**P-gp:** Ligand A (0.03) has lower P-gp efflux than Ligand B (0.015).

**Binding Affinity:** Ligand B (-7.6) 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 significantly better binding affinity (-7.6 kcal/mol vs. 0 kcal/mol). While it has some ADME liabilities (higher DILI, worse solubility, higher Cl_mic, and P-gp efflux), the substantial improvement in potency is a key factor for an enzyme target like SRC kinase. The difference in binding affinity is >1.5 kcal/mol, making it a critical advantage. Ligand A has better solubility and hERG, but its very weak binding affinity is a major concern.

Output:
1
2025-04-17 11:25:40,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 Da and 358.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is better than Ligand B (33.2). While both are acceptable, lower TPSA generally improves cell permeability.

**logP:** Ligand A (2.949) is optimal (1-3), while Ligand B (4.442) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as some H-bond donors can aid solubility. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.513 and 0.78), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (35.712) has a slightly higher DILI risk than Ligand B (21.171), but both are below the concerning threshold of 60.

**BBB:** Ligand A (71.811) and Ligand B (87.515) both have good BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.501) is worse than Ligand B (-5.281). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.551 and -3.766). This is a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.422 and 0.669).

**Microsomal Clearance:** Ligand A (57.45) has lower microsomal clearance than Ligand B (93.514), suggesting better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-17.768) has a much longer in vitro half-life than Ligand B (-5.862). This is highly desirable.

**P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux than Ligand B (0.628), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (-7.5). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the solubility concerns for both, Ligand B is the more promising candidate. The significantly improved binding affinity (-8.3 vs -7.5 kcal/mol) is a major advantage for an enzyme target like SRC kinase. While Ligand A has better metabolic stability and half-life, the potency difference is more critical. The slightly higher logP of Ligand B is manageable, and its other ADME properties are reasonable.

Output:
1
2025-04-17 11:25:40,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as guidelines for enzyme targets suggest.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.323 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand A (83.99 A^2) is better than Ligand B (88.61 A^2).

**logP:** Ligand A (-0.464) is suboptimal, potentially hindering permeation. Ligand B (4.392) is high and could cause solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both are reasonably drug-like, but Ligand A (0.484) is better than Ligand B (0.343).

**DILI:** Ligand B (87.515) has a significantly higher DILI risk than Ligand A (56.921). This is a major concern.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (72.974) is better than Ligand B (49.515).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.622) is slightly better than Ligand B (-4.843).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.714) is slightly better than Ligand B (-4.175).

**hERG:** Ligand A (0.172) has a much lower hERG risk than Ligand B (0.915). This is a critical advantage.

**Microsomal Clearance:** Ligand A (-7.291) has a much lower (better) microsomal clearance than Ligand B (52.576), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.188) has a much longer half-life than Ligand B (66.864), which is desirable.

**P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux than Ligand B (0.82).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly better binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor.

**Overall:**

Ligand A is significantly better than Ligand B. It has a superior binding affinity, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better QED. While its logP and solubility are suboptimal, the strong binding affinity and favorable safety/ADME profile outweigh these drawbacks. Ligand B has a very high DILI risk and poor binding affinity, making it a poor candidate.

Output:
0
2025-04-17 11:25:40,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (340.47 & 355.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (45.48) is significantly better than Ligand B (71.84).  A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**3. logP:** Both ligands have logP values (3.81 & 4.03) within the optimal 1-3 range, suggesting good permeability. Ligand B is slightly higher, potentially increasing 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 better than Ligand B (6). Lower HBA also aids permeability.

**6. QED:** Ligand A (0.9) is significantly better than Ligand B (0.741), indicating a more drug-like profile.

**7. DILI:** Ligand A (14.85) has a much lower DILI risk than Ligand B (83.25). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (89.53) has better BBB penetration than Ligand B (61.61), although this is less critical for a non-CNS target like SRC.

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

**10. Solubility:** Ligand A (-2.332) is better than Ligand B (-4.085). Better solubility is crucial for bioavailability.

**11. hERG:** Ligand A (0.929) has a lower hERG risk than Ligand B (0.626). This is a significant advantage for Ligand A.

**12. Cl_mic:** Ligand A (29.20) has lower microsomal clearance than Ligand B (39.77), suggesting better metabolic stability.

**13. t1/2:** Ligand A (69.29) has a longer in vitro half-life than Ligand B (80.97). This is a positive attribute.

**14. Pgp:** Ligand A (0.4) has lower P-gp efflux than Ligand B (0.689), which is favorable for oral bioavailability.

**15. Binding Affinity:** Ligand B (-9.6) has a slightly better binding affinity than Ligand A (-8.9). While a 1.5 kcal/mol difference is significant, the other ADME properties of Ligand A are far superior.

**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, including DILI risk, solubility, metabolic stability, and QED. The lower DILI and hERG risks are particularly important. The negative Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh this drawback.

Output:
0
2025-04-17 11:25:40,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.411 and 350.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.44) is better than Ligand B (60.85). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.327 and 2.567), falling within the optimal range of 1-3.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, well within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.868 and 0.833), indicating good drug-likeness.

**DILI:** Ligand A (44.048) has a slightly higher DILI risk than Ligand B (15.743), but both are below the concerning threshold of 60.

**BBB:** Ligand A (73.827) has a higher BBB penetration percentile than Ligand B (64.87), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.901) has worse Caco-2 permeability than Ligand B (-4.489).

**Aqueous Solubility:** Ligand A (-3.141) has worse aqueous solubility than Ligand B (-2.13).

**hERG Inhibition:** Ligand A (0.757) has a slightly higher hERG inhibition risk than Ligand B (0.306), but both are relatively low.

**Microsomal Clearance:** Ligand A (14.8) has lower microsomal clearance than Ligand B (20.389), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-24.866) has a significantly longer in vitro half-life than Ligand B (0.967), which is a major advantage.

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux than Ligand B (0.132), implying better bioavailability.

**Binding Affinity:** Ligand B (-7.9) has a significantly better binding affinity than Ligand A (-9.4). The affinity difference is >1.5 kcal/mol, making this a critical factor.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better DILI and BBB scores, the significantly stronger binding affinity of Ligand B (-7.9 kcal/mol vs -9.4 kcal/mol) outweighs these advantages. The improved affinity is likely to translate to greater efficacy. Solubility is slightly better for B, and P-gp efflux is lower.

Output:
1
2025-04-17 11:25:40,810 - INFO - Batch 46 complete. Total preferences: 736
2025-04-17 11:25:40,811 - INFO - Processing batch 47/512...
2025-04-17 11:26:22,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.394 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (26.71) is significantly lower than Ligand B (87.74). Lower TPSA generally favors better cell permeability. Ligand B's TPSA is relatively high, potentially hindering oral absorption.

**logP:** Ligand A (4.69) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.683) is quite low, which could impede permeation.

**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, acceptable QED values (A: 0.753, B: 0.705).

**DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (7.445). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (76.154) is higher than Ligand A (66.344). This is less critical for a non-CNS target like SRC.

**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 (0.959) has a slightly higher hERG risk than Ligand B (0.163). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (92.685) has a significantly higher microsomal clearance than Ligand B (11.121). This indicates lower metabolic stability for Ligand A, a major drawback for an enzyme target.

**In vitro Half-Life:** Ligand A (-28.383) has a very short in vitro half-life, while Ligand B (-13.069) is also short but better. Both are concerning.

**P-gp Efflux:** Ligand A (0.767) has a higher P-gp efflux liability than Ligand B (0.012). Lower efflux is preferred.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered significant, and here it's a massive difference.

**Conclusion:**

Despite Ligand A's lower TPSA and acceptable QED, its significantly higher DILI risk, higher microsomal clearance, shorter half-life, higher P-gp efflux, and *much* weaker binding affinity make it a far less desirable candidate than Ligand B. Ligand B, while having a higher TPSA and lower logP, exhibits a substantially better binding affinity and superior metabolic stability, which are paramount for an enzyme inhibitor. The lower DILI and hERG risks are also beneficial.

Output:
1
2025-04-17 11:26:22,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.483 and 345.399 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is well below the 140 threshold and favorable for oral absorption. Ligand B (84.67) is still below 140, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (4.34) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.163) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have similar QED values (0.884 and 0.81), indicating good drug-likeness.

**DILI:** Ligand A (24.312) has a significantly lower DILI risk than Ligand B (54.634). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.072) has better BBB penetration than Ligand B (57.425), but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.575 and -4.646), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.761 and -2.124), indicating poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.782) has a slightly higher hERG risk than Ligand B (0.052). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (73.301) has higher microsomal clearance than Ligand B (11.524), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-9.596) has a longer in vitro half-life than Ligand A (7.662), suggesting better metabolic stability.

**P-gp Efflux:** Ligand A (0.517) has lower P-gp efflux than Ligand B (0.024), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands show strong binding affinity, Ligand B is the more promising candidate. Its lower hERG risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and better solubility outweigh the slightly higher TPSA and lower P-gp efflux. Ligand A has a better DILI score, but the metabolic stability issues are more concerning for an enzyme target. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:26:22,030 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and priorities for enzymes.

**Step-by-step comparison:**

1. **MW:** Ligand A (344.5) is well within the ideal range (200-500). Ligand B (393.2) is also acceptable, though approaching the upper limit.
2. **TPSA:** Ligand A (59.8) is excellent, well below the 140 threshold for oral absorption. Ligand B (84.4) is still reasonable, but higher and potentially slightly less favorable for absorption.
3. **logP:** Ligand A (3.6) is optimal. Ligand B (1.7) is a bit low, potentially impacting permeability.
4. **HBD:** Both ligands have 1 HBD, which is within the ideal range.
5. **HBA:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both acceptable.
6. **QED:** Both ligands have similar QED scores (A: 0.733, B: 0.714), indicating good drug-likeness.
7. **DILI:** Ligand A (27.2) has a much lower DILI risk than Ligand B (59.1), which is a significant advantage.
8. **BBB:**  BBB isn't a primary concern for a non-CNS target like SRC, but Ligand B (83.2) has a higher percentile than Ligand A (69.8). This is not a major factor in this decision.
9. **Caco-2:** Both have negative values, indicating permeability. The absolute value for A (-4.912) is more negative than B (-4.455), suggesting potentially better permeability.
10. **Solubility:** Both have negative values, indicating solubility. The absolute value for A (-4.259) is more negative than B (-3.231), suggesting potentially better solubility.
11. **hERG:** Both ligands have very low hERG inhibition risk (A: 0.224, B: 0.133), which is excellent.
12. **Cl_mic:** Ligand B (56.0) has lower microsomal clearance than Ligand A (71.7), indicating better metabolic stability. This is a key consideration for enzymes.
13. **t1/2:** Ligand B (-26.2) has a significantly longer in vitro half-life than Ligand A (-6.55), which is a major advantage.
14. **Pgp:** Both have very low Pgp efflux liability (A: 0.388, B: 0.044), which is good.
15. **Binding Affinity:** Both ligands have similar and excellent binding affinities (A: -8.6, B: -8.7). The difference is negligible.

**Enzyme-Specific Priorities:**

For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

*   **Affinity:** Both are excellent.
*   **Metabolic Stability:** Ligand B is superior due to lower Cl_mic and a much longer t1/2.
*   **Solubility:** Ligand A is slightly better.
*   **hERG:** Both are excellent.
*   **DILI:** Ligand A is significantly better.

**Conclusion:**

While Ligand A has a slightly better solubility profile and lower DILI risk, Ligand B's significantly improved metabolic stability (lower Cl_mic and longer t1/2) is a more critical factor for an enzyme target like SRC. The similar binding affinities mean this difference in ADME properties is decisive.

Output:
1
2025-04-17 11:26:22,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.37 and 362.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.19) is better than Ligand B (51.02), being closer to the 140 threshold. Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.54) is optimal, while Ligand B (4.066) is approaching the upper limit of preference. High logP can lead 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.768) has a better QED score than Ligand B (0.676), indicating a more drug-like profile.

**DILI:** Ligand B (32.842) has a significantly lower DILI risk than Ligand A (80.109), which is a major advantage.

**BBB:** Ligand B (77.549) shows better BBB penetration than Ligand A (56.34), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.123 and -4.996). This is unusual and suggests poor permeability. However, these values are on a log scale and the absolute values are close, so the difference isn't substantial.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.723 and -3.745). This is concerning and suggests poor aqueous solubility, potentially hindering bioavailability. Again, the difference is minimal.

**hERG Inhibition:** Ligand A (0.425) has a slightly lower hERG inhibition risk than Ligand B (0.624), which is preferable.

**Microsomal Clearance:** Ligand A (33.62) has a much lower microsomal clearance than Ligand B (106.209). This indicates better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (14.393) has a slightly longer half-life than Ligand B (16.976).

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.504), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.7). However, the difference is only 0.2 kcal/mol, which is not substantial enough to outweigh other significant drawbacks.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic), better P-gp efflux, and a better QED score. The most significant advantage for Ligand A is the much lower DILI risk. Both ligands have poor solubility and permeability, which would need to be addressed through formulation or further chemical modifications, but the ADME profile of Ligand A is generally more favorable.

Output:
0
2025-04-17 11:26:22,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.877 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is better than Ligand B (88.69) as it is closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.717) is optimal (1-3), while Ligand B (0.237) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 3 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.

**QED:** Ligand A (0.748) has a better QED score than Ligand B (0.594), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 34.471, Ligand B: 32.067), both under the 40 threshold.

**BBB:** Ligand A (60.915) has a moderate BBB penetration, while Ligand B (23.42) is very low. BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.78) is better than Ligand B (-5.6), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.663) is better than Ligand B (-0.789), indicating better solubility.

**hERG Inhibition:** Ligand A (0.452) has a lower hERG risk than Ligand B (0.083), which is preferable.

**Microsomal Clearance:** Ligand A (-11.91) has a lower (better) microsomal clearance than Ligand B (-13.63), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (32.85) has a significantly longer half-life than Ligand B (3.918), which is a major advantage.

**P-gp Efflux:** Ligand A (0.059) has lower P-gp efflux than Ligand B (0.013), indicating better bioavailability.

**Binding Affinity:** Ligand B (0.0) has a much better binding affinity than Ligand A (-7.4). This is a significant advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.4 kcal/mol vs 0.0 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks. However, Ligand B has a very low logP, poor solubility, and a very short half-life. Ligand A has a more balanced profile with better ADME properties across the board, even though its affinity is considerably weaker.

Given the enzyme-specific priorities, the binding affinity is paramount. While Ligand A is more drug-like, the large difference in binding affinity of Ligand B makes it the more promising candidate, assuming further optimization can address its ADME deficiencies.

Output:
1
2025-04-17 11:26:22,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.503 and 346.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 78.43, which is acceptable for oral absorption (<=140).

**3. logP:** Both ligands have logP values within the optimal range (2.517 and 2.169).

**4. H-Bond Donors:** Both ligands have 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 above 0.5 (0.66 and 0.708), indicating good drug-like properties.

**7. DILI:** Ligand A (27.414) has a lower DILI risk than Ligand B (20.008), which is favorable.

**8. BBB:** Both ligands have relatively low BBB penetration (39.162 and 30.438), which is not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.896 and -4.742). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon. It's difficult to interpret without knowing the scale, but it suggests both compounds may have absorption challenges.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.653 and -2.437). Similar to Caco-2, this is on a scale where negative values are possible, and interpretation is difficult without knowing the scale. It suggests both compounds may have solubility issues.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.243 and 0.258), which is excellent.

**12. Microsomal Clearance:** Ligand A (37.876) has higher microsomal clearance than Ligand B (27.126), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (5.762) has a longer half-life than Ligand B (4.097), which is favorable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.316 and 0.098), which is good.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This 0.7 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and lower DILI risk, but it has higher microsomal clearance and a shorter half-life compared to Ligand B. Ligand B has a better half-life and lower clearance, but a slightly higher DILI risk and weaker binding affinity. Given the importance of potency for kinase inhibitors, the 0.7 kcal/mol advantage of Ligand A is significant. The slightly higher clearance of Ligand A could potentially be addressed through structural modifications during lead optimization. The DILI risk for both is low enough to not be a major concern at this stage. The negative Caco-2 and solubility values are concerning for both, but could be improved with prodrug strategies or salt formation.

Output:
1
2025-04-17 11:26:22,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is better than Ligand B (96.33) as it's closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.71 and 1.338), 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) as it has fewer H-bond donors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand B (0.808) has a significantly higher QED score than Ligand A (0.548), indicating a more drug-like profile overall.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 35.169, Ligand B: 39.977), well below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (Ligand A: 58.821, Ligand B: 59.131). BBB is less critical for a non-CNS target like SRC.

**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 (-5.205 and -4.988).

**Aqueous Solubility:** Ligand A (-0.936) has slightly better solubility than Ligand B (-2.755), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.293) has a much lower hERG inhibition liability than Ligand B (0.103), which is a significant advantage. Lower hERG risk is crucial.

**Microsomal Clearance:** Ligand A (5.654) has significantly lower microsomal clearance than Ligand B (47.476), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-11.247) has a much longer in vitro half-life than Ligand B (23.624). This is a major advantage, suggesting less frequent dosing.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux than Ligand B (0.012), which is preferable.

**Binding Affinity:** Ligand B (0.0 kcal/mol) has a significantly better binding affinity than Ligand A (-8.8 kcal/mol). This is the most important factor, and the 8.8 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (lower Cl_mic, longer t1/2), hERG risk, and solubility, the dramatically superior binding affinity of Ligand B (-0.0 kcal/mol vs -8.8 kcal/mol) outweighs these benefits. A difference of 8.8 kcal/mol is a large advantage in binding and suggests a much more potent inhibitor. The higher QED of Ligand B also contributes to its favorability. The 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 11:26:22,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (354.422 Da) is within the ideal range (200-500 Da). Ligand B (463.3 Da) is at the upper end, but still acceptable.

**TPSA:** Ligand A (86.71) is excellent, well below the 140 threshold for good absorption. Ligand B (55.63) is also good.

**logP:** Ligand A (0.962) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (4.649) is high, raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is well within acceptable limits. Ligand B (1 HBD, 6 HBA) is also acceptable.

**QED:** Ligand A (0.696) is good, indicating drug-like properties. Ligand B (0.355) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (29.081) has a very low DILI risk. Ligand B (91.043) has a high DILI risk, a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.307) is reasonable. Ligand B (56.378) is lower.

**Caco-2 Permeability:** Ligand A (-5.044) is poor, suggesting low intestinal absorption. Ligand B (-4.665) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.862) is poor. Ligand B (-5.789) is very poor.

**hERG Inhibition:** Ligand A (0.166) has a low hERG risk. Ligand B (0.788) has a higher, but still moderate, hERG risk.

**Microsomal Clearance:** Ligand A (2.399 mL/min/kg) is low, indicating good metabolic stability. Ligand B (105.279 mL/min/kg) is very high, suggesting rapid metabolism and potentially low bioavailability.

**In vitro Half-Life:** Ligand A (-2.896 hours) is poor, indicating rapid degradation. Ligand B (32.043 hours) is excellent, suggesting a long half-life.

**P-gp Efflux:** Ligand A (0.049) has low P-gp efflux, which is good. Ligand B (0.796) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). The 1.1 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A has a superior safety profile (low DILI, low hERG) and a much better binding affinity. While its solubility and Caco-2 permeability are poor, the strong binding affinity may compensate for these issues. Ligand B has a high DILI risk, poor solubility, and high metabolic clearance, despite a longer half-life and slightly better Caco-2 permeability. The high logP also raises concerns. The superior binding affinity of Ligand A, combined with its better safety profile, makes it the more promising candidate, even with its permeability challenges.

Output:
0
2025-04-17 11:26:22,032 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.415 and 386.945 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.12 and 78.43) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.748) is slightly low, potentially hindering permeation, while Ligand B (2.989) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is good, while Ligand B (3) is acceptable but approaching the upper limit.

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

**QED:** Ligand A (0.802) has a better QED score than Ligand B (0.642), indicating a more drug-like profile.

**DILI:** Ligand A (36.293) has a significantly lower DILI risk than Ligand B (44.63), both being acceptable but A is preferred.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (62.389) is slightly better than Ligand B (54.478).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.141 and -4.916), which is unusual and concerning. This suggests poor permeability. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.943 and -3.929), also concerning. Again, these are on a log scale and indicate poor solubility.

**hERG Inhibition:** Ligand A (0.112) has a much lower hERG risk than Ligand B (0.471), a significant advantage.

**Microsomal Clearance:** Ligand A (2.503 mL/min/kg) has significantly lower microsomal clearance than Ligand B (57.558 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.039 hours) has a negative half-life, which is not physically possible and indicates an issue with the data or model. Ligand B (23.601 hours) has a good half-life.

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux than Ligand B (0.564), which is favorable.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it has concerningly high microsomal clearance, a moderate DILI risk, and a higher hERG risk compared to Ligand A. Ligand A has better ADME properties (lower DILI, hERG, P-gp, and Cl_mic, better QED), but its binding affinity is weaker. The negative Caco-2 and solubility values for both are concerning and need further investigation.

Despite the ADME advantages of Ligand A, the substantial difference in binding affinity (-9.0 vs -8.4 kcal/mol) makes Ligand B the more promising candidate. A 1.5 kcal/mol difference is often enough to prioritize a compound even with some ADME liabilities, as these can often be improved through further optimization.

Output:
1
2025-04-17 11:26:22,032 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 Da and 361.829 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is better than Ligand B (75.29), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.239 and 2.438) are within the optimal 1-3 range.

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

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

**QED:** Ligand B (0.768) has a higher QED score than Ligand A (0.471), indicating a more drug-like profile.

**DILI:** Ligand A (19.504) has a significantly lower DILI risk than Ligand B (53.548). This is a major advantage for Ligand A.

**BBB:** Ligand A (75.107) has a better BBB penetration percentile than Ligand B (62.117), but this is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.293 and -4.645), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.982) has better aqueous solubility than Ligand B (-4.148).

**hERG Inhibition:** Ligand A (0.328) has a lower hERG inhibition liability than Ligand B (0.435), which is preferable.

**Microsomal Clearance:** Ligand A (85.586) has a higher microsomal clearance than Ligand B (46.44). This suggests Ligand B is more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-41.041) has a much longer in vitro half-life than Ligand A (-15.672), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.077).

**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 ADME concerns.

**Conclusion:**

While Ligand A has better solubility, lower DILI risk, and slightly better BBB penetration, Ligand B's significantly stronger binding affinity (-9.4 vs -7.0 kcal/mol) and longer half-life are critical advantages for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic, longer t1/2) is also very important. The Caco-2 permeability is a concern for both, but the potency advantage of Ligand B is likely to be more impactful in driving forward development.

Output:
1
2025-04-17 11:26:22,032 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as drug candidates targeting SRC, a kinase.

**Step-by-step comparison:**

1. **MW:** Both A (366.795 Da) and B (361.873 Da) are within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (48.15) is better than Ligand B (51.27), both are under the 140 threshold for oral absorption.

3. **logP:** Both A (4.324) and B (4.364) are slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects. B is marginally higher.

4. **HBD:** Both A (0) and B (0) have zero H-bond donors, which is acceptable, though a single donor can sometimes improve solubility.

5. **HBA:** Both A (4) and B (4) have 4 H-bond acceptors, well within the acceptable limit of 10.

6. **QED:** Ligand A (0.811) has a better QED score than Ligand B (0.718), indicating a more drug-like profile.

7. **DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (36.099). This is a significant negative for Ligand A.

8. **BBB:** Ligand A (92.439) has a higher BBB penetration percentile than Ligand B (67.197). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

9. **Caco-2:** Ligand A (-4.463) and Ligand B (-4.885) both have negative Caco-2 values, which is unusual and suggests poor permeability. B is slightly worse.

10. **Solubility:** Ligand A (-5.86) has slightly better solubility than Ligand B (-3.545), but both are very poor.

11. **hERG:** Both A (0.336) and B (0.746) have low hERG inhibition liability, which is good. A is better.

12. **Cl_mic:** Ligand A (31.637) has significantly lower microsomal clearance than Ligand B (82.303), indicating better metabolic stability. This is a major advantage for A.

13. **t1/2:** Ligand A (23.157) has a shorter in vitro half-life than Ligand B (37.967). B is better.

14. **Pgp:** Both A (0.362) and B (0.732) have low P-gp efflux liability, which is good. A is better.

15. **Binding Affinity:** Both A (-9.5) and B (-9.4) have excellent binding affinity, very close to each other.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Decision:**

Despite the similar binding affinities, **Ligand A** is the more promising candidate. It has a significantly better QED score, lower microsomal clearance (better metabolic stability), and lower Pgp efflux. While its DILI risk is higher, the substantial advantage in metabolic stability and the better hERG profile outweigh this concern. The solubility is poor for both, but A is slightly better. The Caco-2 values are concerning for both, but the other advantages of A make it the preferred choice.

Output:
0
2025-04-17 11:26:22,032 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (405.336 and 387.933 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.73) is well below the 140 threshold and favorable. Ligand B (73.74) is still under 140, but less optimal than A.

**logP:** Ligand A (4.403) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.513) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is good. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.774 and 0.861), indicating drug-like properties.

**DILI:** Ligand A (35.673) has a lower DILI risk than Ligand B (46.336), which is preferable. Both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.639) is higher than Ligand B (53.044), but neither is particularly high.

**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. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.918) shows lower hERG inhibition risk than Ligand B (0.432), which is a significant advantage.

**Microsomal Clearance:** Ligand B (32.035) has a lower microsomal clearance than Ligand A (36.964), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (25.547 hours) has a longer half-life than Ligand A (19.043 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.432) has lower P-gp efflux than Ligand B (0.573), which is favorable.

**Binding Affinity:** Ligand B (-8.7 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:**

While Ligand A has advantages in DILI and hERG, Ligand B's significantly stronger binding affinity (-8.7 vs -6.8 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are more critical for an enzyme target like SRC kinase. The slightly higher logP of Ligand A is a concern, but the substantial affinity difference of Ligand B makes it the more promising candidate. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:26:22,033 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.406 and 360.204 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is well below the 140 threshold for good absorption, and even better for potential CNS penetration. Ligand B (137.46) is still within acceptable limits but less favorable than A.

**logP:** Both ligands (1.869 and 1.689) are 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:** Ligand A (3) is good. Ligand B (8) is higher, but still within the acceptable range of 10.

**QED:** Ligand A (0.852) has a significantly better QED score than Ligand B (0.376), indicating a more drug-like profile.

**DILI:** Ligand A (24.622) has a much lower DILI risk than Ligand B (99.147), which is a major concern.

**BBB:** Both ligands have reasonable BBB penetration (74.176 and 72.16), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.965) has a more negative Caco-2 value, suggesting lower permeability. Ligand B (-4.785) is slightly better, but both are poor.

**Aqueous Solubility:** Ligand A (-2.724) has a more negative solubility value, suggesting lower solubility. Ligand B (-4.709) is even worse. Both are problematic.

**hERG:** Both ligands have low hERG risk (0.325 and 0.378).

**Microsomal Clearance:** Ligand A (24.715) has significantly lower microsomal clearance than Ligand B (80.406), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.7) has a more negative half-life, indicating a longer half-life. Ligand B (0.16) is very short.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.022 and 0.198).

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-7.8), a difference of 0.7 kcal/mol.

**Overall Assessment:**

Despite Ligand B having a slightly better binding affinity, Ligand A is the superior candidate. The significant advantages of Ligand A in QED, DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and solubility outweigh the small difference in binding affinity. The high DILI risk associated with Ligand B is a major red flag. While both have poor Caco-2 and solubility, these can potentially be addressed with formulation strategies. The improved ADME profile of Ligand A makes it more likely to succeed as a drug candidate.

Output:
0
2025-04-17 11:26:22,033 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.53 and 346.34 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is well below the 140 threshold for oral absorption, while Ligand B (117.57) is still acceptable but less optimal.

**logP:** Ligand A (2.974) is within the optimal 1-3 range. Ligand B (0.315) is quite 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 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**QED:** Ligand A (0.816) has a significantly better QED score than Ligand B (0.333), indicating a more drug-like profile.

**DILI:** Ligand A (40.25) has a low DILI risk, while Ligand B (65.76) has a higher, concerning DILI risk.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, suggesting poor permeability. This is a concern.

**Solubility:** Both ligands have negative solubility values, suggesting poor solubility. This is a concern.

**hERG:** Both ligands have low hERG inhibition risk (0.157 and 0.18), which is excellent.

**Microsomal Clearance:** Ligand A (17.43 mL/min/kg) has a better (lower) microsomal clearance than Ligand B (-0.571 mL/min/kg), suggesting better metabolic stability. Note that negative clearance is not physically possible, and likely indicates the model is predicting very rapid clearance.

**In vitro Half-Life:** Ligand A (0.243 hours) has a very short half-life, while Ligand B (-18.992 hours) is also problematic (negative half-life is not realistic). Both are poor.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.233 and 0.066).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Ligand A is the superior candidate. While both have issues with Caco-2 permeability, solubility, and half-life, Ligand A has a significantly better binding affinity, QED, and DILI profile, and better metabolic stability. The stronger binding affinity is the most important factor, and it outweighs the ADME concerns, which can be addressed through further optimization. Ligand B's high DILI risk and lower affinity make it a less attractive starting point.

Output:
1
2025-04-17 11:26:22,033 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.349 and 353.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is better than Ligand B (82.11). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral absorption.

**logP:** Ligand A (2.444) is optimal (1-3). Ligand B (-0.025) is slightly below 1, which could hinder permeation. This is a significant negative for B.

**H-Bond Donors:** Both have acceptable HBD counts (1 and 2 respectively), well below the threshold of 5.

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

**QED:** Ligand A (0.846) has a superior QED score compared to Ligand B (0.672), indicating a more drug-like profile.

**DILI:** Ligand A (53.005) has a higher DILI risk than Ligand B (12.834). This is a significant advantage for B.

**BBB:** Both have high BBB penetration, but Ligand A (90.112) is slightly better than Ligand B (66.925). However, BBB is not a primary concern for a kinase inhibitor unless CNS effects are specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the value for Ligand A (-4.228) is less negative than Ligand B (-4.726), indicating slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.372) is slightly better than Ligand B (-0.87).

**hERG Inhibition:** Both have low hERG inhibition risk (0.154 and 0.228 respectively), which is good.

**Microsomal Clearance:** Ligand A (54.854) has a higher microsomal clearance than Ligand B (13.115), suggesting lower metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (23.779) has a longer in vitro half-life than Ligand A (19.923), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.081 and 0.038 respectively).

**Binding Affinity:** Both have excellent binding affinities (-9.2 and -8.2 kcal/mol respectively). Ligand A is 1 kcal/mol better, which is a substantial advantage.

**Overall Assessment:**

Ligand A has a better binding affinity and QED score, and slightly better TPSA, Caco-2 and solubility. However, Ligand B has a significantly better DILI score, lower microsomal clearance (better metabolic stability), and a longer half-life. The logP of Ligand B is concerning, but the substantial affinity advantage of Ligand A might overcome this. Given the enzyme-specific priorities, the improved metabolic stability and lower toxicity of Ligand B are very important. The 1 kcal/mol difference in binding affinity, while significant, may be addressable through further optimization, while fixing the logP issues might be more challenging.

Output:
1
2025-04-17 11:26:22,033 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.463 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is slightly higher than Ligand B (63.05), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.308 and 3.082), 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 here.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.756 and 0.896), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (56.805) has a moderate DILI risk, while Ligand B (26.522) has a low DILI risk. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (89.608) has a higher BBB penetration than Ligand A (48.74), but this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.582 and -4.814). These values are unusual and suggest poor permeability. It's important to note that negative values in this context are not meaningful and likely represent a data issue. However, we can compare them relatively, and they are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.14 and -2.521). Similar to Caco-2, these are unusual and likely represent a data issue. Again, they are relatively similar.

**hERG Inhibition:** Ligand A (0.636) has a slightly higher hERG risk than Ligand B (0.18). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (74.787) has a higher microsomal clearance than Ligand B (11.553), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-45.312) has a negative half-life, which is not possible. Ligand B (27.038) has a reasonable half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.43) has lower P-gp efflux than Ligand B (0.137), which is slightly better.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 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. It demonstrates a significantly stronger binding affinity, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, better t1/2), and a better QED score. While both ligands have issues with Caco-2 and solubility data, the other advantages of Ligand B outweigh these concerns.

Output:
1
2025-04-17 11:26:22,034 - INFO - Batch 47 complete. Total preferences: 752
2025-04-17 11:26:22,034 - INFO - Processing batch 48/512...
2025-04-17 11:27:04,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (360.394 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (50.8). Both are below the 140 threshold for good oral absorption, but Ligand B is closer to the preferred <90 for CNS targets (though CNS penetration isn't a primary concern for SRC).

**3. logP:** Both ligands have similar logP values (3.914 and 3.885), 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 (0.736 and 0.878), indicating good drug-like properties.

**7. DILI:** Ligand B (26.406) has a significantly lower DILI risk than Ligand A (71.035). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (91.237) has a higher BBB penetration percentile than Ligand A (58.899). While not critical for SRC, it's a slight positive.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.769 and -4.261). These values are unusual and suggest poor permeability. It's difficult to interpret these without knowing the scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.801 and -3.793). Again, these values are unusual and suggest poor solubility. It's difficult to interpret these without knowing the scale.

**11. hERG Inhibition:** Ligand A (0.603) has a slightly lower hERG inhibition risk than Ligand B (0.842), which is preferable.

**12. Microsomal Clearance:** Ligand B (61.143) has a higher microsomal clearance than Ligand A (58.34). This suggests Ligand A is more metabolically stable, which is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-6.622) has a negative half-life, which is not possible. This is a significant red flag. Ligand A (16.787) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.307 and 0.314).

**15. Binding Affinity:** Ligand B (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Despite the negative Caco-2 and solubility values, the significantly stronger binding affinity of Ligand B (-10.6 vs -7.0 kcal/mol) is a major driver. The lower DILI risk of Ligand B is also a significant advantage. The negative half-life for Ligand B is a critical flaw. Ligand A has better metabolic stability and a plausible half-life, but the weaker binding affinity is a substantial drawback.

Given the enzyme-specific priorities (potency, metabolic stability, solubility, hERG), and the magnitude of the affinity difference, Ligand B is the more promising candidate *despite* the questionable half-life value. The half-life issue needs investigation, but the potency advantage is substantial.

Output:
1
2025-04-17 11:27:04,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.427 and 358.829 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (82.27 and 78.09) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.293 and 2.118) are within the optimal range of 1-3.

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

**QED:** Both ligands have good QED scores (0.636 and 0.822), indicating drug-like properties.

**DILI:** Ligand A (49.166) has a lower DILI risk than Ligand B (59.403), which is favorable. Both are below the concerning threshold of 60.

**BBB:** Both have relatively low BBB penetration (54.478 and 63.474), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.116 and -5.341), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-3.424 and -3.847), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.184) has a lower hERG inhibition liability than Ligand B (0.416), which is preferable.

**Microsomal Clearance:** Ligand A (10.9 mL/min/kg) has a lower microsomal clearance than Ligand B (15.076 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.324 hours) has a significantly longer in vitro half-life than Ligand B (-1.966 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.114 and 0.134).

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial difference (1.7 kcal/mol), which could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, Ligand A has superior ADME properties, particularly regarding metabolic stability (lower Cl_mic) and half-life. The poor solubility and permeability are concerning for both, but the longer half-life of Ligand A could compensate for lower absorption. The lower DILI and hERG risk for Ligand A are also beneficial. Given the enzyme-specific priorities, the improved metabolic stability and reduced toxicity risks of Ligand A are more important than the slightly stronger binding of Ligand B, especially considering the potential for optimization of binding affinity.

Output:
0
2025-04-17 11:27:04,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.35 and 352.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is better than Ligand B (15.27) as it is still within the acceptable range for oral absorption, while ligand B is very low and may indicate poor potency.

**logP:** Ligand A (2.804) is optimal, while Ligand B (4.776) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 2. Both are within the acceptable limit of 10.

**QED:** Both ligands have acceptable QED values (0.802 and 0.724 respectively), indicating good drug-like properties.

**DILI:** Ligand A (12.563) has a much lower DILI risk than Ligand B (6.592), which is a significant advantage.

**BBB:** Ligand A (77.472) has a good BBB penetration, while Ligand B (95.269) has excellent BBB penetration. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.016) has poor Caco-2 permeability, while Ligand B (-4.672) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.311) has poor aqueous solubility, while Ligand B (-3.319) is even worse. This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.633) has a lower hERG inhibition risk than Ligand B (0.99), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-10.024) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (5.083). This is a major advantage.

**In vitro Half-Life:** Ligand A (-5.62) has a longer in vitro half-life than Ligand B (33.901).

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux than Ligand B (0.552), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a better binding affinity than Ligand A (-6.7 kcal/mol). The difference is 0.8 kcal/mol, which is significant, but can be outweighed by other factors.

**Overall Assessment:**

Ligand B has superior binding affinity. However, Ligand A demonstrates a much more favorable safety profile (lower DILI and hERG) and better metabolic stability (lower Cl_mic, longer t1/2). While both have solubility concerns, Ligand A's solubility is slightly better. Considering the enzyme-specific priorities, the improved ADME/Tox profile of Ligand A, particularly the lower DILI and hERG risk, outweighs the slightly weaker binding affinity.

Output:
0
2025-04-17 11:27:04,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (436.703 Da) is slightly higher, but acceptable. Ligand B (370.837 Da) is also good.

**TPSA:** Ligand A (28.16) is excellent, suggesting good permeability. Ligand B (113.33) is higher, potentially hindering absorption, but not a complete deal-breaker.

**logP:** Ligand A (4.765) is slightly high, potentially leading to solubility issues and off-target effects. Ligand B (1.259) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, though slightly higher.

**QED:** Ligand A (0.751) is excellent, indicating good drug-likeness. Ligand B (0.566) is acceptable, but less optimal.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 42.73, Ligand B: 45.25), below the 60 threshold.

**BBB:** Ligand A (95.153) shows excellent BBB penetration, while Ligand B (61.729) is lower. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.82) is poor, suggesting low intestinal absorption. Ligand B (-5.454) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-5.033) is poor, which is concerning given its already high logP. Ligand B (-2.402) is better, though still not ideal.

**hERG Inhibition:** Ligand A (0.948) shows low hERG inhibition risk, which is excellent. Ligand B (0.2) is very low, also excellent.

**Microsomal Clearance:** Ligand A (-3.074) indicates very low clearance and excellent metabolic stability. Ligand B (5.754) suggests faster clearance and lower metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (70.297 hours) is excellent. Ligand B (30.341 hours) is good, but not as favorable.

**P-gp Efflux:** Ligand A (0.62) suggests moderate P-gp efflux, while Ligand B (0.093) suggests very low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -9.1 kcal/mol, Ligand B: -8.7 kcal/mol). Ligand A has a 0.4 kcal/mol advantage, which is substantial and can outweigh some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher logP and poorer Caco-2/Solubility, its significantly better metabolic stability (lower Cl_mic, longer t1/2), excellent QED, and slightly better binding affinity make it the more promising candidate. The SRC kinase is not a CNS target, so the higher BBB penetration of Ligand A is not a major advantage. The lower hERG risk for both is positive. The binding affinity difference is significant enough to overcome the solubility concerns, which can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:27:04,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.447 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.94) is better than Ligand B (87.22) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.825 and 0.75), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=2, HBA=5) as it has fewer HBDs, which can sometimes improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.921) has a significantly better QED score than Ligand B (0.794), indicating a more drug-like profile.

**DILI:** Ligand B (31.95) has a much lower DILI risk than Ligand A (61.264). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (67.313 and 67.041). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.882) is slightly better than Ligand B (-5.297).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-1.604) is slightly better than Ligand A (-2.698).

**hERG Inhibition:** Ligand A (0.577) has a slightly higher hERG risk than Ligand B (0.245), which is preferable.

**Microsomal Clearance:** Ligand B (17.633) has a significantly lower microsomal clearance than Ligand A (53.281), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (21.124 and 23.184 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.077 and 0.013).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage for Ligand A. The difference of 1.5 kcal/mol is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a better QED score, but suffers from higher DILI risk and higher microsomal clearance. Ligand B has a much better safety profile (lower DILI) and improved metabolic stability (lower Cl_mic), but its binding affinity is weaker.

Given the enzyme-specific priorities, metabolic stability and safety are crucial. While the affinity difference is significant, the improved ADME profile of Ligand B, particularly the lower DILI and Cl_mic, makes it the more promising candidate. The slightly better solubility of Ligand B is also a plus.

Output:
1
2025-04-17 11:27:04,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.434 and 348.462 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is slightly higher than Ligand B (49.41), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.451 and 2.838 respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 2 HBA, which is excellent and balances solubility and permeability.

**QED:** Ligand A (0.891) has a significantly better QED score than Ligand B (0.627), indicating a more drug-like profile.

**DILI:** Ligand B (29.701) has a much lower DILI risk than Ligand A (47.538), which is a significant advantage.

**BBB:** Ligand A (83.831) shows better BBB penetration than Ligand B (74.913), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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, so it's hard to interpret.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.491 and 0.355), which is excellent.

**Microsomal Clearance:** Ligand B (32.526) has a slightly lower microsomal clearance than Ligand A (36.606), suggesting potentially better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.32) has a much longer in vitro half-life than Ligand A (-1.605), which is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.131 and 0.23), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.5 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has a better QED and slightly better BBB penetration, Ligand B is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic), and substantially longer in vitro half-life. The similar binding affinities make the ADME properties the deciding factors. For an enzyme target like SRC kinase, metabolic stability and safety (DILI) are crucial.

Output:
1
2025-04-17 11:27:04,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (439.14 and 425.71 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (37.61) is significantly better than Ligand B (50.8), being well below the 140 threshold for good absorption.

**3. logP:** Both ligands have similar logP values (4.888 and 4.928), slightly above the optimal 1-3 range, but not drastically so. This could potentially lead to some solubility issues, but is not a major concern.

**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 (4) is preferable to Ligand B (3) as fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.542 and 0.756), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have similar DILI risk (75.378 and 77.123), indicating moderate risk. This isn't a major differentiating factor.

**8. BBB:** Both ligands have high BBB penetration (82.978 and 85.925), which isn't critical for a non-CNS target like SRC, but doesn't hurt.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.637 and -4.735), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.23 and -6.433). This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.72 and 0.844), which is good.

**12. Microsomal Clearance:** Ligand A (52.936) has significantly lower microsomal clearance than Ligand B (89.595), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (99.249) has a slightly longer in vitro half-life than Ligand A (95.303), which is a minor advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.798 and 0.716), which is favorable.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, HBD/HBA counts, and metabolic stability, Ligand B's significantly stronger binding affinity (-7.9 vs -10.2 kcal/mol) is a critical advantage for an enzyme inhibitor. The poor solubility and Caco-2 permeability are concerns for both, but a potent inhibitor can sometimes overcome these issues with formulation strategies. The slightly longer half-life of Ligand B is also a minor benefit.

Output:
1
2025-04-17 11:27:04,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (352.381 and 341.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.5) is well below the 140 threshold for good absorption and is favorable. Ligand B (107.77) is still within range, but less optimal.

**3. logP:** Ligand A (2.621) is within the optimal 1-3 range. Ligand B (1.136) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern at this stage.

**4. H-Bond Donors:** Ligand A (0) is excellent. 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 QED values (0.785 and 0.689), indicating good drug-like properties.

**7. DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (42.846), both being reasonably low.

**8. BBB:** Ligand A (97.945) shows excellent BBB penetration, while Ligand B (57.193) is significantly lower. While SRC isn't a CNS target, good BBB penetration generally correlates with better overall drug distribution.

**9. Caco-2 Permeability:** Ligand A (-4.024) shows poor permeability, while Ligand B (-5.249) is even worse. This is a significant concern for both.

**10. Aqueous Solubility:** Ligand A (-3.431) and Ligand B (-2.429) both have poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.454) has a very low hERG risk, which is excellent. Ligand B (0.098) is also very low, and comparable to Ligand A.

**12. Microsomal Clearance:** Ligand A (77.29) has higher clearance than Ligand B (0.366), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-17.611) has a very short half-life, while Ligand B (-4.806) is also short, but less so. This is a major concern for both, but more so for Ligand A.

**14. P-gp Efflux:** Ligand A (0.191) has lower P-gp efflux than Ligand B (0.011), which is favorable.

**15. Binding Affinity:** Ligand B (-9.5 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.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much better binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). While both have poor solubility and permeability, the superior potency and metabolic stability of Ligand B are more critical for an enzyme target.

Output:
1
2025-04-17 11:27:04,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (399.607 and 373.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (93.46). TPSA < 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have good logP values (2.869 and 1.333), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands have 6 H-bond acceptors, which is within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.843 and 0.714), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (69.174 and 65.568), which is acceptable (below 60 is good, these are moderately risky).

**BBB:** Ligand A (43.583) and Ligand B (71.501). BBB is less important for a non-CNS target like SRC, but B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.074 and -5.266). 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.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.833 and -3.119). Similar to Caco-2, this is unusual and requires understanding the scale. Negative values suggest very poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.296 and 0.29), which is excellent.

**Microsomal Clearance:** Ligand A (47.5) and Ligand B (46.625) have similar microsomal clearance values. Lower is better, indicating greater metabolic stability, and both are reasonable.

**In vitro Half-Life:** Ligand A (3.367) and Ligand B (5.027) have different half-lives. B has a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.296 and 0.075), which is good.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While the difference is small, it's within the range where it can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a better TPSA, and slightly better binding affinity. Ligand B has a better BBB and *in vitro* half-life. The solubility and Caco-2 values are concerning for both, but are difficult to interpret without knowing the scale. Given the enzyme-specific priorities, the slightly better binding affinity of Ligand A, combined with its superior TPSA, makes it the more promising candidate. The small difference in binding affinity is likely more important than the slightly better half-life of Ligand B.

Output:
0
2025-04-17 11:27:04,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.435 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.48) is slightly above the preferred <140, while Ligand B (86.12) is well within.

**logP:** Ligand A (0.759) is a bit low, potentially hindering permeability. Ligand B (2.183) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, within the limit. Ligand B has 8 HBA, still acceptable but approaching the upper limit.

**QED:** Ligand A (0.781) has a better QED score than Ligand B (0.672), indicating better overall drug-likeness.

**DILI:** Ligand A (24.816) has a significantly lower DILI risk than Ligand B (62.195), which is a major advantage.

**BBB:** Both have high BBB penetration (83.366 and 86.196), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.898) has a poor Caco-2 permeability, while Ligand B (-5.004) is also poor.

**Solubility:** Ligand A (-2.258) has better solubility than Ligand B (-3.104).

**hERG:** Ligand A (0.408) has a much lower hERG risk than Ligand B (0.898), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (-8.425) exhibits significantly lower microsomal clearance, indicating better metabolic stability, a key factor for kinases. Ligand B (62.951) has high clearance.

**In vitro Half-Life:** Ligand A (12.464 hours) has a better in vitro half-life than Ligand B (51.106 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.028 and 0.241).

**Binding Affinity:** Ligand B (-7.3 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 primary strength is its significantly higher binding affinity. However, it suffers from higher DILI risk, higher hERG risk, and significantly higher microsomal clearance. Ligand A has better ADME properties (lower DILI, hERG, and Cl_mic, better solubility, and half-life) but a very weak binding affinity.

Given the importance of potency for kinase inhibitors, the substantial binding affinity advantage of Ligand B is likely to outweigh its ADME liabilities *provided* those liabilities can be addressed through further optimization. The difference in binding affinity (>7 kcal/mol) is considerable.

Output:
1
2025-04-17 11:27:04,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.542 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.22) is slightly higher than Ligand B (71.09). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (0.253) is quite low, potentially hindering permeability. Ligand B (3.787) is within the optimal 1-3 range. This is a significant advantage 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 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.704 and 0.805), indicating good drug-like properties.

**DILI:** Ligand A (43.622) has a lower DILI risk than Ligand B (51.997), which is preferable.

**BBB:** Ligand A (34.161) has a lower BBB penetration than Ligand B (78.209). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.479) has poor Caco-2 permeability, while Ligand B (-4.749) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-2.148) has better solubility than Ligand B (-5.867). This is a positive for Ligand A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.097 and 0.545).

**Microsomal Clearance:** Ligand A (24.834) has significantly lower microsomal clearance than Ligand B (78.878), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.667) has a much longer in vitro half-life than Ligand B (-1.881). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, while Ligand B (0.247) is slightly higher. This favors Ligand A.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.1 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a better logP and slightly better DILI, but Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2), solubility, P-gp efflux, and Caco-2 permeability (although both are poor). Given the enzyme-specific priorities, metabolic stability and solubility are paramount. The significantly better metabolic stability and half-life of Ligand A outweigh the slightly better logP of Ligand B. The comparable binding affinity makes these factors decisive.

Output:
0
2025-04-17 11:27:04,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.37) is significantly better than Ligand B (117.7), being well below the 140 threshold for good absorption. Ligand B is higher, potentially impacting absorption.

**logP:** Both ligands (1.205 and 2.201) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 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 (0.78 and 0.728), indicating good drug-likeness.

**DILI:** Ligand A (10.702) has a much lower DILI risk than Ligand B (85.615). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (59.131) is lower than Ligand B (48.662).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.409) is slightly better than Ligand B (-5.248).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-0.761) is slightly better than Ligand B (-3.249).

**hERG Inhibition:** Ligand A (0.219) shows a lower hERG inhibition liability than Ligand B (0.133), which is favorable.

**Microsomal Clearance:** Ligand A (-12.011) has a much lower (better) microsomal clearance than Ligand B (13.265), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.963) has a lower half-life than Ligand B (23.172). This is a drawback for Ligand A, but can be overcome with structural modifications.

**P-gp Efflux:** Ligand A (0.033) has lower P-gp efflux than Ligand B (0.153), which is favorable.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.4). While the difference is small (0.3 kcal/mol), it's still a positive factor.

**Overall:**

Ligand A is clearly superior. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), better solubility, and lower P-gp efflux. While its half-life is shorter, the other advantages, especially the lower DILI and better metabolic stability, outweigh this drawback. The binding affinity difference is small but favors Ligand A. Ligand B's high DILI risk and poor metabolic stability are major concerns.

Output:
0
2025-04-17 11:27:04,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (336.351 and 360.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.3) is slightly higher than Ligand B (84.94), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.068) is optimal, while Ligand B (0.496) 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 6 HBA, and Ligand B has 5, both are below the 10 limit.

**QED:** Ligand A (0.786) has a significantly better QED score than Ligand B (0.387), indicating a more drug-like profile.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (37.379). This is a concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 71.733, Ligand B: 75.107). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.994 and -4.842), which is unusual and suggests poor permeability. However, these values are on a scale where negative values can occur and don't necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values (-4.74 and -1.503). This is also unusual, and suggests poor solubility.

**hERG:** Ligand A (0.892) has a slightly higher hERG risk than Ligand B (0.336), but both are relatively low.

**Microsomal Clearance:** Ligand B (-5.896) has a *much* lower (better) microsomal clearance than Ligand A (48.562), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand B (-4.887) has a longer in vitro half-life than Ligand A (33.063).

**P-gp Efflux:** Ligand A (0.438) has lower P-gp efflux than Ligand B (0.015).

**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 small, it's still a factor.

**Overall Assessment:**

Ligand B is the stronger candidate. Despite its lower logP and solubility, its significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and comparable binding affinity outweigh the drawbacks. The low logP and solubility are potential issues, but formulation strategies could be employed to address them. Ligand A's high DILI risk and higher metabolic clearance are significant concerns. The slightly better affinity of Ligand A isn't enough to overcome these issues.

Output:
1
2025-04-17 11:27:04,436 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [380.901, 86.88, 3.363, 3, 4, 0.743, 73.672, 48.468, -5.23, -4.527, 0.305, 34.91, 13.791, 0.293, -7.1]
**Ligand B:** [392.905, 95.94, 0.579, 2, 5, 0.689, 41.877, 45.987, -5, -2.15, 0.35, 12.91, -5.741, 0.047, -7.3]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (380.9) is slightly better.
2. **TPSA:** A (86.88) is better than B (95.94), both are acceptable for oral absorption (<140).
3. **logP:** A (3.363) is optimal. B (0.579) is quite low, potentially hindering permeability.
4. **HBD:** A (3) and B (2) are both good, within the acceptable limit of 5.
5. **HBA:** A (4) and B (5) are both acceptable, below the limit of 10.
6. **QED:** Both are reasonably good (A: 0.743, B: 0.689), indicating drug-like properties.
7. **DILI:** A (73.672) is higher than B (41.877), suggesting a greater potential for liver injury. This is a significant concern for A.
8. **BBB:** Both are relatively low, which is fine since SRC is not a CNS target. B (45.987) is slightly better than A (48.468).
9. **Caco-2:** Both are negative, indicating very poor permeability. This is a major issue for both.
10. **Solubility:** Both are negative, indicating very poor solubility. This is a major issue for both.
11. **hERG:** A (0.305) is better than B (0.35), indicating lower cardiotoxicity risk.
12. **Cl_mic:** A (34.91) is better than B (12.91), suggesting better metabolic stability.
13. **t1/2:** A (13.791) is better than B (-5.741), indicating a longer half-life.
14. **Pgp:** A (0.293) is better than B (0.047), suggesting lower P-gp efflux.
15. **Binding Affinity:** B (-7.3) is slightly better than A (-7.1), but the difference is small.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

While Ligand B has a slightly better binding affinity, Ligand A is preferable. Ligand B's very low logP is a major concern, likely leading to poor absorption. The DILI risk associated with Ligand A is concerning but potentially manageable with further structural modifications. Ligand A has better metabolic stability (Cl_mic and t1/2) and Pgp efflux. The solubility and Caco-2 permeability are poor for both, but these are areas that can be addressed through formulation or prodrug strategies. The slightly better affinity of B is not enough to overcome the significant permeability issues.

Output:
1
2025-04-17 11:27:04,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.427 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (90.01 and 88.91) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (2.201 and 1.467).

**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 good QED scores (0.845 and 0.817), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 50.33, while Ligand B has 32.067. Ligand B is significantly better regarding DILI risk.

**BBB:** Ligand A has a BBB penetration of 92.4, while Ligand B has 50.097. While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.289 and -5.396). This is unusual and suggests very poor permeability. However, these values are on a log scale, and negative values are possible.

**Aqueous Solubility:** Both have negative solubility values (-3.824 and -2.012). This is also concerning, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.5, while Ligand B has 0.078. Ligand B is substantially better in terms of hERG risk.

**Microsomal Clearance:** Ligand A has a Cl_mic of 58.172 mL/min/kg, and Ligand B has 11.63 mL/min/kg. Ligand B exhibits significantly better metabolic stability (lower clearance).

**In vitro Half-Life:** Ligand A has a t1/2 of 10.959 hours, while Ligand B has 12.312 hours. Ligand B has a slightly longer half-life.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.526, while Ligand B has 0.011. Ligand B is much less susceptible to P-gp efflux.

**Binding Affinity:** Ligand A has a binding affinity of -9.6 kcal/mol, while Ligand B has -8.6 kcal/mol. Ligand A has a 1 kcal/mol stronger binding affinity.

**Overall Assessment:**

Ligand A has a better binding affinity (-9.6 kcal/mol vs -8.6 kcal/mol). However, Ligand B demonstrates superior ADMET properties: significantly lower DILI risk, much lower hERG inhibition, substantially better metabolic stability (lower Cl_mic and slightly longer t1/2), and lower P-gp efflux. Both have poor solubility and permeability. The difference in binding affinity (1 kcal/mol) is not large enough to overcome the substantial ADMET advantages of Ligand B, especially considering the importance of metabolic stability and safety (DILI, hERG) for an oncology drug.

Output:
1
2025-04-17 11:27:04,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 346.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.25) is better than Ligand B (70.07), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.596) is suboptimal, being below the ideal 1-3 range, potentially hindering permeation. Ligand B (3.671) is within the optimal range.

**H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

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

**QED:** Both ligands have QED values above 0.5 (0.727 and 0.68), indicating good drug-likeness.

**DILI:** Ligand A (38.62) has a significantly lower DILI risk than Ligand B (71.152). This is a major advantage for Ligand A.

**BBB:** Ligand B (77.588) has a higher BBB penetration percentile than Ligand A (33.501). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.038) has a very poor Caco-2 permeability, while Ligand B (-4.794) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.199) has better aqueous solubility than Ligand B (-4.1).

**hERG Inhibition:** Ligand A (0.289) has a much lower hERG inhibition liability than Ligand B (0.879). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (6.09) has a lower microsomal clearance than Ligand B (51.302), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (97.71) has a much longer in vitro half-life than Ligand A (9.4).

**P-gp Efflux:** Ligand A (0.025) has much lower P-gp efflux liability than Ligand B (0.478).

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.1). While a 1.5 kcal/mol advantage is usually significant, the other factors are more important here.

**Overall Assessment:**

Ligand A demonstrates a superior safety profile with significantly lower DILI and hERG risk, and better solubility. It also has lower P-gp efflux and microsomal clearance. While its Caco-2 permeability and BBB are lower, and logP is suboptimal, the benefits in safety and metabolic stability outweigh these drawbacks, especially considering SRC is not a CNS target. Ligand B's main advantage is its slightly better binding affinity and longer half-life, but the higher DILI, hERG, and P-gp efflux liabilities are concerning.

Output:
0
2025-04-17 11:27:04,437 - INFO - Batch 48 complete. Total preferences: 768
2025-04-17 11:27:04,437 - INFO - Processing batch 49/512...
2025-04-17 11:27:44,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.515 Da) and Ligand B (344.411 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (75.19) and Ligand B (66.9) are both good.

**logP:** Both ligands have logP values between 1 and 3, which is optimal. Ligand A (1.906) and Ligand B (2.816) are both good.

**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:** Both ligands have good QED scores (Ligand A: 0.724, Ligand B: 0.808), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 39.977, which is good (low risk). Ligand B has a DILI risk of 24.157, even better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (49.36) and Ligand B (77.976) are both acceptable, but B is better.

**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 solubility values, which is also unusual. Again, the values are similar, so this isn't a major differentiator.

**hERG Inhibition:** Ligand A (0.248) and Ligand B (0.614) both have relatively low hERG inhibition liability, which is good. Ligand A is better.

**Microsomal Clearance:** Ligand A (42.803 mL/min/kg) has a higher clearance than Ligand B (21.641 mL/min/kg). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (3.836 hours) has a longer half-life than Ligand A (0.98 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.025, Ligand B: 0.286), which is good. Ligand A is better.

**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 better candidate. While Ligand A has slightly better hERG and P-gp profiles, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. For a kinase inhibitor, metabolic stability and potency are paramount. The lower DILI risk is also a plus.

Output:
1
2025-04-17 11:27:44,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (62.99) is slightly higher than Ligand B (56.67).

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.33, Ligand B: 2.527), which is optimal.

**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.

**QED:** Both ligands have good QED scores (Ligand A: 0.791, Ligand B: 0.83), indicating a drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 22.102, Ligand B: 23.032), which is positive.

**BBB:** Both ligands have high BBB penetration (Ligand A: 80.574, Ligand B: 83.831), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.276 and -4.703), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.573 and -1.631), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.286, Ligand B: 0.762), which is favorable.

**Microsomal Clearance:** Ligand B (20.507 mL/min/kg) has significantly lower microsomal clearance than Ligand A (41.896 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.179 hours) has a negative half-life, which is not possible. This is a data error and a major red flag. Ligand A (47.08 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.101, Ligand B: 0.452), which is good.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), a difference of 0.6 kcal/mol.

**Conclusion:**

Despite the slightly better affinity of Ligand B, the negative and unrealistic in vitro half-life is a critical flaw. The poor solubility and permeability of both compounds are also major concerns. However, considering the priorities for enzyme inhibitors, metabolic stability is crucial. Ligand B has significantly better metabolic stability (lower Cl_mic). Given the choice between the two, and acknowledging the data error with Ligand B's half-life, Ligand B is marginally preferred *if* the half-life data can be corrected. The affinity difference is not large enough to overcome the metabolic stability advantage.

Output:
1
2025-04-17 11:27:44,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.515 and 353.344 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.36) is better than Ligand B (62.61), both are below the 140 threshold for good absorption.

**logP:** Both ligands (2.674 and 2.167) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.864 and 0.836), indicating good drug-like properties.

**DILI:** Ligand A (2.21) has a significantly lower DILI risk than Ligand B (60.682). This is a major advantage for Ligand A.

**BBB:** Ligand B (87.088) has a higher BBB penetration than Ligand A (82.202), but BBB isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-5.248) has worse Caco-2 permeability than Ligand B (-4.687), but both are negative values which is not ideal.

**Aqueous Solubility:** Ligand A (-1.271) has better aqueous solubility than Ligand B (-3.348). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.804) has a slightly better hERG profile than Ligand B (0.451), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-32.655) has *much* lower microsomal clearance than Ligand B (11.311). This indicates significantly better metabolic stability for Ligand A, a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand A (-9.56) has a slightly longer in vitro half-life than Ligand B (-2.971).

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux than Ligand B (0.031).

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.7). However, the difference is only 0.6 kcal/mol, and can be overcome by superior ADME properties.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. Its significantly lower DILI risk and dramatically improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly weaker binding affinity. Solubility is also better for Ligand A. While Ligand B has slightly better Caco-2 and binding affinity, the ADME profile of Ligand A is far superior and more likely to translate into a viable drug candidate.

Output:
0
2025-04-17 11:27:44,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.351 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.27) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (76.66) is well within the ideal range.

**logP:** Ligand A (0.167) is quite low, potentially hindering permeation. Ligand B (1.836) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 9 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.731) has a good drug-likeness score. Ligand B (0.379) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (85.576) has a higher DILI risk (above 60), which is concerning. Ligand B (22.218) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.06) and Ligand B (56.223) are both moderate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.04 and -5.044). This is unusual and suggests poor permeability *in vitro*. However, these values are on a log scale and could be interpreted as very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.631 and -2.819). Again, these are likely on a log scale and indicate poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.047) has a very low hERG risk, a major plus. Ligand B (0.273) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (34.954) has a moderate clearance, while Ligand B (4.776) has a very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.201) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (4.535) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.009 and 0.049).

**Binding Affinity:** Ligand B (-7.5 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 the more promising candidate. While its QED is lower, its significantly lower DILI risk, much better metabolic stability (lower Cl_mic, positive t1/2), and slightly better binding affinity outweigh the lower QED score. Ligand A has a concerningly high DILI risk and a nonsensical half-life. The poor solubility and permeability of both ligands need to be addressed through further optimization, but Ligand B provides a better starting point.

Output:
1
2025-04-17 11:27:44,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.291 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is well below the 140 threshold for good absorption, while Ligand B (95.67) is approaching the upper limit, but still acceptable.

**logP:** Ligand A (3.693) is within the optimal 1-3 range. Ligand B (1.643) 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 reasonable H-bond counts, well within the suggested limits.

**QED:** Both ligands have good QED scores (0.732 and 0.761), indicating good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (91.314), while Ligand B has a very low risk (31.059). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (85.498) and Ligand B (24.622) are less relevant here.

**Caco-2 Permeability:** Ligand A (-4.636) shows poor permeability, while Ligand B (-5.228) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.818) indicates poor solubility, while Ligand B (-1.11) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.751) has a moderate hERG risk, while Ligand B (0.077) has a very low risk. This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (68.571) has moderate clearance, while Ligand B (8.612) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (43.791) has a moderate half-life, while Ligand B (-11.417) has a very short half-life.

**P-gp Efflux:** Ligand A (0.434) has low P-gp efflux, while Ligand B (0.056) has very low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.6 kcal/mol), which is comparable and strong enough to be considered excellent. The slight difference is not a major deciding factor.

**Conclusion:**

Despite comparable binding affinities, Ligand B is the superior candidate. Its significantly lower DILI risk, lower hERG inhibition, and much better metabolic stability (lower Cl_mic) outweigh the slightly shorter half-life and lower Caco-2 permeability. Ligand A's high DILI risk and poor solubility are major drawbacks.

Output:
1
2025-04-17 11:27:44,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is slightly higher than Ligand B (77.1), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.53) is better than Ligand B (0.493). A logP between 1-3 is optimal, and Ligand B is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

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

**QED:** Ligand A (0.867) has a better QED score than Ligand B (0.746), indicating a more drug-like profile.

**DILI:** Ligand B (43.66) has a significantly lower DILI risk than Ligand A (29.818), which is a major advantage. Lower DILI is highly desirable.

**BBB:** Both ligands have similar BBB penetration (61.535 and 63.94), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.867 and -4.719), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.513 and -1.612), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.113 and 0.162), which is excellent.

**Microsomal Clearance:** Ligand B (12.795) has significantly lower microsomal clearance than Ligand A (30.713), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-7.33) has a slightly longer in vitro half-life than Ligand A (-9.311), which is favorable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.027 and 0.031).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 1.5 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Conclusion:**

While both ligands have issues with predicted permeability and solubility, Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), a slightly longer half-life, and a superior binding affinity. The improved binding affinity is a key factor, and the better ADME properties (lower DILI, lower Cl_mic) further support its selection.

Output:
1
2025-04-17 11:27:44,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.535 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (84.67). Lower TPSA generally improves permeability.

**logP:** Both ligands have acceptable logP values (3.373 and 2.396, respectively), 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 5. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have good QED scores (0.612 and 0.764), indicating good drug-like properties.

**DILI:** Ligand A (16.247) has a much lower DILI risk than Ligand B (49.399). This is a significant advantage.

**BBB:** Both have reasonable BBB penetration (74.641 and 71.966), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.501 and -4.343). This is unusual and suggests poor permeability, but the scale isn't clearly defined.

**Aqueous Solubility:** Both have negative solubility values (-3.116 and -3.158). Again, the scale is unclear, but this suggests poor solubility.

**hERG:** Ligand A (0.797) has a slightly higher hERG risk than Ligand B (0.232), which is a concern.

**Microsomal Clearance:** Ligand A (74.255) has a higher microsomal clearance than Ligand B (67.626), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-26.715) has a significantly longer in vitro half-life than Ligand A (-8.803). This is a major advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.568) has lower P-gp efflux than Ligand B (0.147), which is preferable.

**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 potentially overcome some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk, but suffers from higher microsomal clearance and a slightly higher hERG risk. Ligand B has a significantly longer half-life and lower hERG risk, but has a higher DILI risk and slightly weaker binding affinity. Given the enzyme-specific priorities, the longer half-life of Ligand B is a substantial advantage, especially considering the relatively modest difference in binding affinity. The lower DILI risk of Ligand A is attractive, but the improved metabolic stability of Ligand B is more critical for an enzyme target.

Output:
1
2025-04-17 11:27:44,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.63) is slightly above the optimal <140, while Ligand B (86.63) is well within. This suggests potentially better absorption for Ligand B.

**logP:** Both ligands have good logP values (2.717 and 1.257), falling within the 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5-6 HBA, satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.699 and 0.801), indicating good drug-like properties.

**DILI:** Ligand A (55.176) has a higher DILI risk than Ligand B (39.201). This is a significant advantage for Ligand B.

**BBB:** Both have acceptable BBB penetration (70.492 and 65.529), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.628 and -4.762). These values are unusual and likely represent a scale where lower numbers indicate *lower* permeability. Both have poor predicted permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.105 and -1.96). Again, lower values indicate *lower* solubility. This is a concern for both, but potentially less so for Ligand B.

**hERG Inhibition:** Ligand A (0.567) has a slightly higher hERG risk than Ligand B (0.353), which is preferable for Ligand B.

**Microsomal Clearance:** Ligand B (46.693 mL/min/kg) has lower microsomal clearance than Ligand A (64.614 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-9.512 hours) has a significantly longer in vitro half-life than Ligand A (30.298 hours). This is a major advantage for Ligand B, potentially allowing for less frequent dosing. Note the negative value for Ligand B is likely an artifact of the scale.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.313).

**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 notable, but may not outweigh the ADME advantages of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. The solubility and permeability are poor for both, but the improved metabolic stability and safety profile of Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 11:27:44,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.415 and 344.342 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (76.71 and 76.66) below 140, suggesting reasonable absorption potential.

**logP:** Both ligands have logP values (2.16 and 2.869) 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 3 HBD and 3 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Ligand B (0.836) has a significantly higher QED score than Ligand A (0.582), indicating a more drug-like profile.

**DILI:** Ligand A (52.074) has a lower DILI risk than Ligand B (88.639), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (68.592 and 74.254), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.748 and -4.619), which is unusual and suggests poor permeability. This is a concerning aspect for both compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.335 and -4.862), indicating very poor aqueous solubility. This is a major drawback for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.368) shows a lower hERG inhibition liability than Ligand B (0.58), which is preferable.

**Microsomal Clearance:** Ligand A (-39.89 mL/min/kg) has a much lower microsomal clearance than Ligand B (79.761 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (20.573 hours) has a longer in vitro half-life than Ligand B (29.024 hours).

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.247), indicating better absorption.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 1.9 kcal/mol is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better QED score. However, it suffers from higher DILI risk, higher P-gp efflux, and significantly higher microsomal clearance, indicating poorer metabolic stability. Ligand A has a better safety profile (lower DILI, hERG, and P-gp), better metabolic stability, and a longer half-life. The poor solubility and Caco-2 permeability are concerning for both, but the stronger binding affinity of Ligand B is a significant advantage. Given the importance of potency for enzyme inhibitors, and the substantial difference in binding affinity, Ligand B is the more promising candidate, *provided* solubility and permeability can be addressed through formulation or structural modifications.

Output:
1
2025-04-17 11:27:44,192 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (355.507 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (35.58) is significantly better than Ligand B (58.64).  A TPSA under 140 is good for oral absorption, and both are well below this.

**3. logP:** Both ligands have good logP values (3.138 and 2.593), 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, Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.808) has a significantly better QED score than Ligand B (0.695), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.034) has a slightly higher DILI risk than Ligand B (9.306), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have similar BBB penetration (74.292 and 73.827), which is good but not critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.824) has worse Caco-2 permeability compared to Ligand B (-4.55), but both are negative values which is not ideal.

**10. Aqueous Solubility:** Ligand A (-4.043) has worse aqueous solubility than Ligand B (-2.179). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.881) has a higher hERG risk than Ligand B (0.418).  Lower hERG is preferred.

**12. Microsomal Clearance:** Ligand B (67) has a lower microsomal clearance than Ligand A (77.03), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (15.302) has a significantly longer half-life than Ligand B (-6.519). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.579) has lower P-gp efflux than Ligand B (0.102), which is favorable for bioavailability.

**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 and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, and half-life. However, Ligand B has better solubility, lower hERG risk, and lower microsomal clearance. The affinity difference is significant, and the longer half-life of Ligand A is a substantial benefit for a kinase inhibitor. While Ligand B has better ADME properties in some areas, the improved potency and PK profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 11:27:44,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.471 and 349.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.33) is better than Ligand B (117.62), both being under the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.9) is optimal, while Ligand B (0.752) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (5) is at the upper limit, while Ligand B (3) is good.

**5. H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (6) is acceptable.

**6. QED:** Both ligands have acceptable QED values (0.408 and 0.653, respectively), with Ligand B being better.

**7. DILI:** Both ligands have similar, moderately high DILI risk (69.484 and 70.88). This is a concern for both, but not a deciding factor between them.

**8. BBB:** Ligand A (62.931) is better than Ligand B (20.783), but BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.022 and -5.256), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.274 and -2.604), indicating poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.417) has a slightly higher hERG risk than Ligand B (0.063). Ligand B is significantly better here.

**12. Microsomal Clearance:** Ligand B (-3.554) has a *much* lower (better) microsomal clearance than Ligand A (19.26). This suggests significantly better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-18.327) has a much longer half-life than Ligand A (67.523).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.033).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. The poor solubility and permeability are concerning for both, but the substantial difference in metabolic stability and hERG risk makes Ligand B more promising. The 1.5kcal/mol advantage in binding affinity is not enough to overcome the ADME liabilities of Ligand A.

Output:
1
2025-04-17 11:27:44,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.519 and 344.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (2.787 and 2.609), falling within the optimal 1-3 range.

**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 here.

**H-Bond Acceptors:** Both ligands have 3 HBA, well below the limit of 10.

**QED:** Both ligands have good QED scores (0.588 and 0.749), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (24.506 and 29.236), both well below the 40 threshold.

**BBB:** Ligand A (53.858) and Ligand B (83.443). BBB is not a primary concern for a kinase inhibitor, but higher is generally better. Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.4). This is unusual and suggests very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.365 and -3.337). This is also unusual and indicates very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.415 and 0.524).

**Microsomal Clearance:** Ligand A (57.453) has lower clearance than Ligand B (81.503), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (17.374) has a shorter half-life than Ligand B (-23.683). The negative value for Ligand B is concerning and likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.256 and 0.33).

**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 outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A appears slightly more promising. While both have excellent binding affinity and acceptable safety profiles, Ligand A has significantly lower microsomal clearance, suggesting better metabolic stability. The negative Caco-2 and solubility values are concerning for both, but the metabolic stability advantage of Ligand A is more critical for an enzyme inhibitor.

Output:
0
2025-04-17 11:27:44,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.833 and 372.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.19) is slightly higher than Ligand B (67.35), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.682) is within the optimal 1-3 range. Ligand B (2.86) is also within range, but 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 6 HBA, both are acceptable (<=10).

**QED:** Ligand A (0.898) has a significantly better QED score than Ligand B (0.533), suggesting a more drug-like profile.

**DILI:** Ligand B (44.552) has a lower DILI risk than Ligand A (56.883), which is favorable.

**BBB:** Ligand B (96.045) has a much higher BBB penetration percentile than Ligand A (32.765). While SRC is not a CNS target, higher BBB is generally not detrimental.

**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 indicates poor solubility.

**hERG:** Ligand A (0.382) has a lower hERG inhibition liability than Ligand B (0.602), which is a significant advantage.

**Microsomal Clearance:** Ligand B (32.202) has a much higher microsomal clearance than Ligand A (0.05), indicating poorer metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (6.655) has a longer in vitro half-life than Ligand A (-22.221). However, the negative value for Ligand A is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.174), which is favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-22.221 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite Ligand B's superior binding affinity, the significantly higher microsomal clearance and negative in vitro half-life are major concerns. The lower DILI risk is good, but the poor solubility and permeability are also problematic. Ligand A has a better QED score, lower hERG risk, and much better metabolic stability. The binding affinity is significantly weaker, but could potentially be improved through further optimization. Considering the enzyme-specific priorities, metabolic stability is crucial. Therefore, I would choose Ligand A as the more viable drug candidate, as its ADME properties are more favorable and can be optimized, while the poor metabolic stability of Ligand B is a more difficult issue to address.

Output:
0
2025-04-17 11:27:44,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (386.901 and 386.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is significantly better than Ligand B (86.63). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (2.83 and 1.3), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could aid membrane permeability, but Ligand B is still reasonable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (1 HBD, 7 HBA). Fewer hydrogen bond donors and acceptors generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.483 and 0.678), indicating acceptable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (59.442) has a higher DILI risk than Ligand B (47.034), which is a negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.158) is slightly better than Ligand B (43.311).

**Caco-2 Permeability:** Ligand A (-4.454) shows better Caco-2 permeability than Ligand B (-5.437).

**Aqueous Solubility:** Ligand A (-2.463) has better aqueous solubility than Ligand B (-1.515). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands exhibit very low hERG inhibition risk (0.29 and 0.147), which is excellent.

**Microsomal Clearance:** Ligand B (28.614) has significantly lower microsomal clearance than Ligand A (104.253), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-3.062) has a negative half-life, which is concerning. Ligand A (37.298) has a positive half-life, indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.194 and 0.176).

**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 factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better solubility and Caco-2 permeability, Ligand B's significantly improved metabolic stability (lower Cl_mic) and slightly better binding affinity outweigh those advantages. The lower DILI risk for Ligand B is also a positive factor. The negative half-life of Ligand B is concerning, but the lower clearance suggests it might be an artifact of the assay.

Output:
1
2025-04-17 11:27:44,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.435 and 356.373 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.77) is better than Ligand B (104.21), both are under the 140 threshold for oral absorption.

**logP:** Ligand A (-1.144) is slightly low, potentially hindering permeation, while Ligand B (0.945) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.558 and 0.675), indicating drug-likeness.

**DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (36.642). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (68.36) has a higher BBB penetration than Ligand A (34.354).

**Caco-2 Permeability:** Both have negative values (-5.44 and -5.179), which are unusual and likely indicate poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values (-0.934 and -2.404), again, the scale is not specified. Ligand A appears slightly better.

**hERG:** Both ligands have very low hERG inhibition liability (0.059 and 0.045), which is excellent.

**Microsomal Clearance:** Ligand A (-34.765) has *much* lower (better) microsomal clearance than Ligand B (5.294). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (7.877) has a better in vitro half-life than Ligand B (-21.4).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.007).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.8 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't heavily sway the decision.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has a slightly better logP, Ligand A excels in crucial areas: significantly lower DILI risk, dramatically improved metabolic stability (lower Cl_mic and higher t1/2), and slightly better solubility. The binding affinity difference is minimal. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this.

Output:
0
2025-04-17 11:27:44,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.42) is better than Ligand B (113.93). Both are reasonably good, but A is closer to the <140 threshold for oral absorption.

**logP:** Ligand A (0.981) is better than Ligand B (0.474). Both are a little low, potentially impacting permeability, but A is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.803) is significantly better than Ligand B (0.642), indicating a more drug-like profile.

**DILI:** Ligand B (61.807) has a slightly higher DILI risk than Ligand A (56.844), but both are acceptable (<60 is good).

**BBB:** Ligand A (64.87) has better BBB penetration than Ligand B (36.758), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.398 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 (-2.323 and -2.888), which is also unusual and concerning. Poor solubility can severely limit bioavailability.

**hERG Inhibition:** Ligand A (0.05) has a much lower hERG risk than Ligand B (0.184), a crucial advantage.

**Microsomal Clearance:** Ligand A (1.799 mL/min/kg) has significantly lower microsomal clearance than Ligand B (16.001 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.459 hours) has a much longer half-life than Ligand B (26.087 hours). A negative value is strange, but the magnitude suggests a longer half-life for A relative to B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.05), which is good.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.2 kcal/mol). This is a 1.0 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 every other critical ADME property. Specifically, Ligand A has a better QED score, lower DILI risk, lower hERG risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. The negative Caco-2 and solubility values are concerning for both, but the other advantages of A outweigh the small affinity difference. Given the enzyme-specific priorities, metabolic stability and safety (hERG) are crucial, making Ligand A the more promising candidate.

Output:
0
2025-04-17 11:27:44,193 - INFO - Batch 49 complete. Total preferences: 784
2025-04-17 11:27:44,193 - INFO - Processing batch 50/512...
2025-04-17 11:28:25,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.881 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.12) is better than Ligand B (104.53). Both are acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.42) is within the optimal 1-3 range. Ligand B (-0.562) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers, within the suggested limits.

**QED:** Both ligands have similar QED values (0.734 and 0.711), indicating good drug-likeness.

**DILI:** Ligand A (29.314) has a significantly lower DILI risk than Ligand B (52.191). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (64.172) is better than Ligand B (51.105).

**Caco-2 Permeability:** Ligand A (-5.549) and Ligand B (-5.167) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-2.716) is slightly better than Ligand B (-1.888), but both are poor. Solubility is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.491) has a lower hERG risk than Ligand B (0.17). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-23.302) exhibits much lower (better) microsomal clearance than Ligand B (-5.877), indicating greater metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-14.451) has a longer half-life than Ligand B (12.055), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.035), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While both are good, the 1.4 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical parameters for an enzyme inhibitor. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better solubility, lower hERG risk, and superior binding affinity. While both have poor Caco-2 permeability and solubility, the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 11:28:25,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.483 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**TPSA:** Ligand A (103.6) is higher than Ligand B (45.55). While both are reasonably low, Ligand B's lower TPSA is more favorable for absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.003, Ligand B: 2.524), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have low HBD counts (0). Ligand A has 7 HBA, while Ligand B has 3. Both are within acceptable limits (<=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.713, Ligand B: 0.847), indicating drug-like properties.

**DILI:** Ligand A (74.176) has a higher DILI risk than Ligand B (35.518). This is a significant concern, as lower DILI is preferred.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (69.988) has a slightly higher BBB penetration than Ligand A (46.375).

**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 low hERG inhibition liability (Ligand A: 0.413, Ligand B: 0.493), which is good.

**Microsomal Clearance:** Ligand A (81.662) has a higher microsomal clearance than Ligand B (69.738), indicating lower metabolic stability. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand B (1.467) has a longer in vitro half-life than Ligand A (-0.228), which is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (Ligand A: 0.084, Ligand B: 0.582).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage and can outweigh some ADME drawbacks.

**Conclusion:**

Despite some questionable solubility/permeability values (due to negative scales), Ligand B is the more promising candidate. Its significantly higher binding affinity, lower DILI risk, and longer half-life outweigh the slightly higher TPSA and potentially lower solubility/permeability. The stronger binding affinity is a crucial factor for an enzyme inhibitor.

Output:
1
2025-04-17 11:28:25,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.362 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is slightly above the preferred <140 for good absorption, while Ligand B (91.64) is well within the range.

**logP:** Ligand A (2.479) is optimal, while Ligand B (0.89) is a bit low, potentially hindering permeation.

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

**QED:** Both ligands have good QED scores (0.456 and 0.775, respectively), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A (75.572) has a higher DILI risk than Ligand B (55.758). Lower is better, so Ligand B is preferable.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (43.311) and Ligand B (32.92) are both low.

**Caco-2 Permeability:** Ligand A (-5.387) has poor predicted permeability. Ligand B (-4.858) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.844) and Ligand B (-2.046) both have poor predicted aqueous solubility.

**hERG Inhibition:** Ligand A (0.421) has a slightly higher hERG risk than Ligand B (0.118). Lower is better, favoring Ligand B.

**Microsomal Clearance:** Ligand A (60.377) has higher clearance, indicating lower metabolic stability, while Ligand B (-5.767) has negative clearance, which is excellent (more stable).

**In vitro Half-Life:** Ligand A (-44.03) has a very long half-life, which is positive. Ligand B (-2.277) has a shorter half-life, but still reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.145 and 0.037, respectively).

**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.

**Overall Assessment:**

Ligand B is generally better across several key ADME properties: lower DILI risk, better metabolic stability (negative Cl_mic), and lower hERG risk. While Ligand A has a slightly better binding affinity, the ADME profile of Ligand B is more favorable for development. The solubility and permeability are poor for both, but can be addressed with formulation strategies. The superior metabolic stability and safety profile of Ligand B outweigh the small difference in binding affinity.

Output:
1
2025-04-17 11:28:25,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.535 Da and 350.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.73) is slightly above the preferred <60 for optimal permeability, but still reasonable. Ligand B (58.2) is excellent.

**logP:** Ligand A (1.205) is within the optimal 1-3 range. Ligand B (3.227) is at the higher end of optimal, but still acceptable.

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

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 2 HBA. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.604 and 0.823, respectively), indicating good drug-like properties.

**DILI:** Ligand A (35.169) has a lower DILI risk than Ligand B (52.152), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (78.209 and 86.002), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and likely indicates poor permeability.

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

**hERG Inhibition:** Ligand A (0.913) has a slightly higher hERG risk than Ligand B (0.519), which is less desirable.

**Microsomal Clearance:** Ligand A (14.96) has significantly lower microsomal clearance than Ligand B (45.587), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (29.019) has a longer in vitro half-life than Ligand B (15.156), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux than Ligand B (0.335), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-8.1 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 of Ligand B. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand A having better DILI, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.1 vs -6.8 kcal/mol) is the deciding factor. For an enzyme inhibitor, potency is paramount. While the Caco-2 and solubility values are concerning for both, the superior affinity of Ligand B makes it the more promising candidate, assuming these issues can be addressed through formulation or further optimization.

Output:
1
2025-04-17 11:28:25,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.41 and 373.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.16) is better than Ligand B (107.97), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (1.838) is optimal (1-3), while Ligand B (-1.03) is below 1, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.698 and 0.527), indicating good drug-like properties.

**DILI:** Ligand A (60.489) has a higher DILI risk than Ligand B (29.236). This is a significant negative for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (54.13) is slightly better than Ligand B (27.026).

**Caco-2 Permeability:** Ligand A (-5.009) is better than Ligand B (-5.686), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.949) is better than Ligand B (-1.443), which is important for formulation and bioavailability.

**hERG:** Both ligands have very low hERG risk (0.075 and 0.089), which is excellent.

**Microsomal Clearance:** Ligand B (-14.878) has significantly lower (better) microsomal clearance than Ligand A (32.464), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have similar and negative in vitro half-lives (-6.193 and -6.861), suggesting rapid metabolism. However, Ligand B is slightly better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.005), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B is superior in several crucial areas: significantly lower DILI risk, substantially better metabolic stability (lower Cl_mic), and a slightly better in vitro half-life. The logP value of Ligand A is optimal, but the difference isn't enough to overcome the other advantages of Ligand B. Given the enzyme-kinase specific priorities, metabolic stability and safety (DILI) are paramount.

Output:
1
2025-04-17 11:28:25,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.447 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (53.09), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (0.98) is slightly better than Ligand A (0.45), both are within the optimal 1-3 range, but A is quite low and may have permeability issues.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (0), both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (5) is slightly worse than Ligand B (4), both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.693 and 0.713), indicating good drug-likeness.

**DILI:** Ligand B (20.938) has a significantly lower DILI risk than Ligand A (13.571), making it more favorable.

**BBB:** Ligand B (69.911) has a higher BBB penetration than Ligand A (50.058), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.814) is worse than Ligand B (-4.128), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.791 and -0.961). This is a significant concern.

**hERG Inhibition:** Ligand A (0.151) has a lower hERG inhibition risk than Ligand B (0.415), which is a positive.

**Microsomal Clearance:** Ligand A (9.23) has a much lower microsomal clearance than Ligand B (48.282), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (23.383) has a better in vitro half-life than Ligand B (-26.807), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.073), indicating better bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a crucial difference, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having better metabolic stability, half-life, and P-gp efflux, the significantly stronger binding affinity of Ligand B (-9.5 vs -7.6 kcal/mol) is a decisive factor. While both have poor solubility, the improved DILI risk and better Caco-2 permeability of Ligand B make it the more promising candidate. The potency advantage outweighs the solubility concerns, and formulation strategies can be explored to address solubility issues.

Output:
1
2025-04-17 11:28:25,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (375.255 Da and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.35) is higher than Ligand B (58.64). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (4.192) is slightly high, potentially leading to solubility issues and off-target effects. Ligand B (2.173) is within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (3 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable counts.

**QED:** Both ligands have similar QED values (0.599 and 0.54), indicating good drug-likeness.

**DILI:** Ligand A (75.339) has a significantly higher DILI risk than Ligand B (24.855). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.58) and Ligand B (33.579) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.844 and -4.727), which is unusual and suggests poor permeability. This needs further investigation, but it's a shared weakness.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.745 and -2.955), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.885) shows slightly higher hERG inhibition risk than Ligand B (0.443), but both are relatively low.

**Microsomal Clearance:** Ligand A (20.496 mL/min/kg) has a much lower microsomal clearance than Ligand B (63.784 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (97.124 hours) has a significantly longer half-life than Ligand B (-16.091 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.615) has lower P-gp efflux liability than Ligand B (0.107), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 kcal/mol and -8.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, its significantly higher DILI risk and higher logP are major red flags. The poor solubility and permeability are also concerning for both. However, the DILI risk for Ligand A is substantially higher. Considering the enzyme-specific priorities, the lower DILI risk of Ligand B makes it the more promising candidate, despite its poorer metabolic stability. Further optimization would be needed to improve solubility and permeability for both, but starting with the lower toxicity profile is preferable.

Output:
1
2025-04-17 11:28:25,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.793) and Ligand B (344.499) are both acceptable.

**TPSA:** Ligand A (71.09) is slightly higher than Ligand B (49.41). Both are well below the 140 A^2 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (A: 3.723, B: 3.588), 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, <=10 HBA). Ligand B is slightly better due to fewer potential off-target interactions.

**QED:** Both ligands have good QED scores (A: 0.543, B: 0.775), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A has a high DILI risk (96.82%), while Ligand B has a much lower risk (32.92%). This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (76.735) has a higher BBB score than Ligand A (55.487).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.864 and -4.743). 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 (-5.877 and -3.753). Again, this is unusual and suggests poor solubility. Ligand B is better.

**hERG Inhibition:** Ligand A (0.279) has a slightly lower hERG risk than Ligand B (0.474), which is favorable.

**Microsomal Clearance:** Ligand A (34.48) has lower microsomal clearance than Ligand B (93.166), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (101.147) has a much longer in vitro half-life than Ligand B (-12.579). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.289) has lower P-gp efflux than Ligand B (0.579), which is preferable.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.7). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, metabolic stability, half-life, and P-gp efflux. However, it has a very high DILI risk. Ligand B has a much better safety profile (lower DILI), better solubility, and a slightly better QED score, but its binding affinity is considerably weaker and has poor metabolic stability.

Given the priorities for enzyme inhibitors, the strong binding affinity of Ligand A is crucial. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The poor solubility and permeability of both compounds are also areas for improvement, but these are often addressed later in the drug discovery process. The significantly better affinity of Ligand A makes it the more promising starting point, despite the DILI concern.

Output:
1
2025-04-17 11:28:25,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.43 and 363.93 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.43) is better than Ligand B (36.44) as it is still within acceptable range for oral absorption, while ligand B is significantly lower.

**logP:** Ligand A (1.947) is optimal, while Ligand B (3.986) is approaching the upper limit, potentially raising solubility concerns.

**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 (0.921) has a significantly higher QED score than Ligand B (0.7), indicating better overall drug-likeness.

**DILI:** Ligand B (12.641) has a much lower DILI risk than Ligand A (58.395), which is a significant advantage.

**BBB:** Both have good BBB penetration, with Ligand A at 79.682 and Ligand B at 88.29. This isn't a primary concern for a kinase inhibitor.

**Caco-2 Permeability:** Both have negative Caco-2 values, suggesting poor permeability.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.726) has a slightly higher hERG risk than Ligand B (0.822), but both are reasonably low.

**Microsomal Clearance:** Ligand B (71.002) has a lower microsomal clearance than Ligand A (57.664), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.841) has a slightly longer half-life than Ligand A (13.981).

**P-gp Efflux:** Ligand B (0.528) has lower P-gp efflux liability than Ligand A (0.593), which is favorable.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is the most critical factor for an enzyme inhibitor. The 8 kcal/mol difference is substantial and likely outweighs many of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux). However, the massive difference in binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) for Ligand A is a decisive factor. A strong binding affinity is paramount for kinase inhibitors, and the difference is large enough to overcome the ADME liabilities. While Ligand A's solubility and permeability are poor, these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:28:25,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.387 and 361.32 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.47) is better than Ligand B (105.64), both are under the 140 threshold for oral absorption.

**logP:** Both ligands have similar logP values (1.272 and 1.298), 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, Ligand B has 4. Both are under the 10 threshold.

**QED:** Both ligands have similar QED values (0.839 and 0.824), indicating good drug-likeness.

**DILI:** Ligand A (48.623) has a slightly better DILI percentile than Ligand B (52.695), both are acceptable (<60).

**BBB:** Ligand B (77.705) has a higher BBB percentile than Ligand A (57.154). However, BBB is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.792) has slightly better Caco-2 permeability than Ligand B (-5.102).

**Aqueous Solubility:** Ligand A (-2.974) has better aqueous solubility than Ligand B (-3.516). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.533) has a slightly better hERG inhibition profile than Ligand B (0.369), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-22.954) has significantly better microsomal clearance than Ligand B (-10.368). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (39.523) has a significantly longer in vitro half-life than Ligand B (-9.964). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.01) has much lower P-gp efflux liability than Ligand B (0.041).

**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 less significant than the substantial ADME advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior metabolic stability (Cl_mic, t1/2), solubility, lower P-gp efflux, and a better safety profile (hERG, DILI). These factors are crucial for developing a viable drug candidate, and the small difference in binding affinity is outweighed by the significant ADME advantages of Ligand A.

Output:
0
2025-04-17 11:28:25,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.559 Da and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (119.46) is still under 140, but higher than A, potentially impacting absorption.

**logP:** Both ligands have good logP values (2.441 and 1.074), 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 A is slightly better.

**QED:** Both ligands have similar QED values (0.777 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A (11.206) has a significantly lower DILI risk than Ligand B (54.944). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (64.87) is better than Ligand B (27.957).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and concerning. Again, values are similar.

**hERG Inhibition:** Ligand A (0.838) has a slightly better hERG profile than Ligand B (0.276), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (7.686) has a better (lower) microsomal clearance than Ligand B (-4.782). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-27.46) has a significantly longer in vitro half-life than Ligand B (12.699). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux than Ligand B (0.072), which is favorable.

**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 outweigh the significant ADME advantages of Ligand A.

**Overall:**

Ligand A demonstrates superior ADME properties, particularly regarding DILI risk, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While Ligand B has a slightly better binding affinity, the difference is not large enough to overcome the substantial advantages of Ligand A in terms of safety and pharmacokinetic properties. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (DILI, hERG) are crucial.

Output:
1
2025-04-17 11:28:25,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.29) is slightly higher than Ligand B (82.61), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.266) is within the optimal 1-3 range, while Ligand B (0.475) is slightly below, potentially impacting permeability.

**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 4 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.658 and 0.77), indicating drug-like properties.

**DILI:** Ligand A (55.758) has a higher DILI risk than Ligand B (30.942). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (50.523) is slightly better than Ligand B (33.346).

**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, suggesting poor aqueous solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.161 and 0.081), which is excellent.

**Microsomal Clearance:** Ligand B (-6.818) has significantly lower (better) microsomal clearance than Ligand A (11.048), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (7.713) has a longer in vitro half-life than Ligand A (-16.644), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.055 and 0.004).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.7 kcal/mol difference is substantial and outweighs minor ADME concerns.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have issues with Caco-2 and solubility, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and, crucially, a much stronger binding affinity. The stronger binding affinity is a key advantage for an enzyme inhibitor and outweighs the slightly lower logP.

Output:
1
2025-04-17 11:28:25,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.43 and 363.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.49 and 71.53) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.21 and 1.98) are 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 acceptable, staying within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.78 and 0.75), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (52.23 and 56.26), below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.23 and -5.06), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.14 and -2.13), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.66 and 0.16), which is favorable.

**Microsomal Clearance:** Ligand B (31.76 mL/min/kg) has significantly lower microsomal clearance than Ligand A (66.06 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (17.34 hours) has a longer in vitro half-life than Ligand A (12.16 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.15 and 0.12), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While both are strong binders, the 0.7 kcal/mol difference is notable.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. It exhibits significantly better metabolic stability (lower Cl_mic and longer t1/2) and slightly better binding affinity. These factors are prioritized for enzyme inhibitors. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the improved pharmacokinetic profile of Ligand B makes it the better starting point.

Output:
1
2025-04-17 11:28:25,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 348.531 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.35) is well below the 140 threshold for good absorption and is favorable. Ligand B (49.41) is also excellent.

**logP:** Ligand A (1.673) is within the optimal 1-3 range. Ligand B (4.033) is at the higher end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 6 HBA, within the acceptable limit of 10. Ligand B has only 2 HBA, also good.

**QED:** Both ligands have similar QED values (0.685 and 0.684), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 66.693, which is moderately high. Ligand B has a much lower DILI risk of 12.214, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both have high BBB penetration, but Ligand B (90.772) is slightly better than Ligand A (79.488). While not a primary concern for a kinase inhibitor, it's a minor positive for 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, which is also unusual and suggests poor solubility. Again, the scale is unspecified.

**hERG Inhibition:** Ligand A (0.325) has a very low hERG risk, which is excellent. Ligand B (0.667) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (40.526) has a moderate microsomal clearance. Ligand B (51.662) has a higher clearance, suggesting lower metabolic stability. This is a negative for Ligand B.

**In vitro Half-Life:** Ligand A (2.455 hours) has a short half-life. Ligand B (-16.875 hours) has a negative half-life, which is not physically possible and suggests an issue with the data or model.

**P-gp Efflux:** Ligand A (0.093) has low P-gp efflux, which is favorable. Ligand B (0.384) has slightly higher efflux, but still relatively low.

**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 factors.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While it has a slightly higher logP and clearance, its significantly lower DILI risk and slightly better BBB penetration are crucial advantages. The negative half-life for ligand B is a major red flag, however, and would need to be investigated further. The similar binding affinities make the ADMET properties the deciding factor.

Output:
1
2025-04-17 11:28:25,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.47 and 365.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (104.36). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is higher and could indicate poorer absorption.

**logP:** Both ligands have acceptable logP values (2.75 and 1.63), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=6). Lower HBA is generally preferred for better permeability.

**QED:** Ligand A (0.916) is significantly better than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Ligand A (13.53) has a much lower DILI risk than Ligand B (49.13). This is a major advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (76.27) has a better BBB percentile than Ligand B (36.45).

**Caco-2 Permeability:** Ligand A (-4.814) is better than Ligand B (-5.06), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.949) is better than Ligand B (-3.422), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.384) shows lower hERG inhibition liability than Ligand B (0.568), reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (42.90) has a lower microsomal clearance than Ligand B (57.16), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.00) has a negative half-life, which is unusual and potentially problematic. Ligand B (22.29) is a more reasonable value. However, negative values can sometimes be artifacts of the prediction method.

**P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux liability than Ligand B (0.099), potentially improving bioavailability.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-10.2). While a 1.5 kcal/mol advantage can sometimes outweigh other issues, the difference here is substantial (3 kcal/mol). However, the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

Ligand A is significantly better overall. It has a superior drug-likeness score (QED), much lower DILI risk, better solubility, permeability, and metabolic stability. The only significant drawback is the negative in vitro half-life, which needs further investigation, but the overall profile is much more promising. Ligand B, while having a slightly better binding affinity, suffers from a higher TPSA, HBA, DILI risk, and poorer ADME properties. The substantial difference in binding affinity is unlikely to overcome the multiple ADME liabilities of Ligand B.

Output:
0
2025-04-17 11:28:25,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.349 and 347.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (124.47) is better than Ligand B (64.86) as it is closer to the 140 threshold.

**logP:** Both ligands have acceptable logP values (1.094 and 2.895), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 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:** Ligand B (0.783) has a significantly better QED score than Ligand A (0.217), indicating a more drug-like profile.

**DILI:** Ligand B (21.753) has a much lower DILI risk than Ligand A (35.091), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (78.054 and 79.256), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.714) has a worse Caco-2 permeability than Ligand B (-5.09), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.052) has slightly better aqueous solubility than Ligand B (-2.386).

**hERG Inhibition:** Ligand A (0.237) has a slightly lower hERG inhibition risk than Ligand B (0.452), which is preferable.

**Microsomal Clearance:** Ligand B (34.02) has lower microsomal clearance than Ligand A (46.917), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (13.987) has a significantly longer in vitro half-life than Ligand A (-28.417), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.267).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.1 and -8.0 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better solubility and hERG risk, Ligand B is superior overall. It has a much better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and comparable binding affinity. These factors are more critical for an enzyme inhibitor like an SRC kinase inhibitor than slight differences in solubility and hERG.

Output:
1
2025-04-17 11:28:25,405 - INFO - Batch 50 complete. Total preferences: 800
2025-04-17 11:28:25,405 - INFO - Processing batch 51/512...
2025-04-17 11:29:07,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (354.376 and 349.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.95) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.51) is still within acceptable limits (<140) but less optimal than A.

**3. logP:** Ligand A (3.141) is within the optimal 1-3 range. Ligand B (1.917) is slightly lower, but still acceptable.

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

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3, both within the ideal limit of <=10.

**6. QED:** Ligand A (0.89) has a higher QED score than Ligand B (0.704), indicating a more drug-like profile.

**7. DILI:** Ligand A (54.517) has a slightly higher DILI risk than Ligand B (38.813), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (91.314) has better BBB penetration than Ligand B (76.658).

**9. Caco-2 Permeability:** Ligand A (-5.08) has lower Caco-2 permeability than Ligand B (-4.903). Both are negative values, which is unusual and requires careful interpretation. Lower (more negative) values typically indicate *lower* permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.084 and -3.034 respectively). This is a significant concern.

**11. hERG Inhibition:** Ligand A (0.904) has a slightly higher hERG risk than Ligand B (0.508), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-1.911) has *lower* (better) microsomal clearance than Ligand B (15.391), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (12.585) has a longer in vitro half-life than Ligand B (24.734). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.282) has lower P-gp efflux than Ligand B (0.078), suggesting better bioavailability.

**15. Binding Affinity:** Both ligands have identical binding affinities (-7.2 kcal/mol), which is excellent.

**Overall Assessment:**

Despite both ligands having excellent binding affinity, Ligand A is the more promising candidate. It has a better QED score, better metabolic stability (lower Cl_mic), a longer half-life, and lower P-gp efflux. While its solubility and Caco-2 permeability are poor (similar to Ligand B), the improved metabolic properties are critical for an enzyme target like SRC kinase. The slightly higher DILI and hERG risks are less concerning given the overall profile.

Output:
0
2025-04-17 11:29:07,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 & 345.45 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is excellent, well below the 140 threshold for oral absorption. Ligand B (90.98) is still acceptable, but higher, potentially impacting absorption.

**logP:** Both ligands (0.963 & 1.834) fall within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands (4) are well below the 10 threshold.

**QED:** Ligand A (0.712) is stronger, indicating better drug-likeness than Ligand B (0.555).

**DILI:** Ligand A (24.234) has a significantly lower DILI risk than Ligand B (36.758). This is a major advantage.

**BBB:** Both ligands have high BBB penetration (71.733 & 70.609), which isn't a primary concern for a non-CNS target like SRC kinase, but isn't detrimental.

**Caco-2:** Ligand A (-4.138) is better than Ligand B (-5.079), indicating better intestinal absorption.

**Solubility:** Ligand A (-1.609) is better than Ligand B (-2.774), which is crucial for bioavailability.

**hERG:** Ligand A (0.072) has a much lower hERG inhibition liability than Ligand B (0.218), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (16.518) has significantly lower microsomal clearance than Ligand B (41.051), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.827) has a positive half-life, while Ligand B (-18.082) has a negative half-life, which is concerning.

**P-gp efflux:** Ligand A (0.021) has lower P-gp efflux than Ligand B (0.211), which is favorable.

**Binding Affinity:** Ligand B (-8.1) 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 clearly superior. While Ligand B has a slightly better binding affinity, Ligand A excels in almost all ADMET properties: lower DILI risk, better solubility, lower hERG inhibition, significantly better metabolic stability (lower Cl_mic and positive half-life), and lower P-gp efflux. These factors are crucial for developing a viable drug candidate, especially for an enzyme target where metabolic stability and minimizing off-target effects are paramount. The small difference in binding affinity is easily outweighed by the significant advantages in ADMET properties.

Output:
0
2025-04-17 11:29:07,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.397 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.26) is excellent, well below the 140 threshold for oral absorption. Ligand B (107.55) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.826) is optimal. Ligand B (-0.069) is significantly low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, but higher.

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

**QED:** Both ligands have good QED scores (0.81 and 0.569), indicating drug-likeness.

**DILI:** Ligand A (56.727) has a moderate DILI risk, while Ligand B (39.046) has a lower, more favorable DILI risk.

**BBB:** Ligand A (77.2) shows reasonable BBB penetration, while Ligand B (21.171) is very low. This isn't a primary concern for a non-CNS target like SRC, but it's a data point.

**Caco-2 Permeability:** Ligand A (-4.415) is poor, indicating low intestinal absorption. Ligand B (-5.522) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.499) is poor, while Ligand B (-1.507) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.579) has a low risk of hERG inhibition, which is excellent. Ligand B (0.076) also has a low risk.

**Microsomal Clearance:** Ligand A (43.13) has moderate clearance, indicating moderate metabolic stability. Ligand B (1.75) has very low clearance, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-20.866) has a very short half-life, which is a significant drawback. Ligand B (-7.591) has a longer half-life, though still not ideal.

**P-gp Efflux:** Ligand A (0.278) has low P-gp efflux, which is favorable. Ligand B (0.02) also has low P-gp efflux.

**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 concerns.

**Conclusion:**

Despite Ligand A's poor Caco-2 permeability and solubility, and moderate clearance, its *significantly* stronger binding affinity (-8.5 vs -7.3 kcal/mol) makes it the more promising candidate. The potency advantage is likely to be crucial for efficacy, and the other issues might be addressable through formulation or structural modifications. Ligand B's better ADME profile is offset by its weaker binding.

Output:
1
2025-04-17 11:29:07,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.483 and 383.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.56) is better than Ligand B (80.32), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands have a logP around 2.1, which is optimal (1-3).

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2), keeping in mind the preference for <=5.

**H-Bond Acceptors:** Both ligands have 6 H-bond acceptors, which is within the acceptable range of <=10.

**QED:** Both ligands have similar QED values (0.889 and 0.814), indicating good drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (60.062 and 65.258), which is a concern. However, this is not a dealbreaker if other properties are favorable.

**BBB:** Both ligands have similar BBB penetration (64.986 and 66.382). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.889) is better than Ligand B (-5.332), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.621) is better than Ligand B (-3.442), indicating better solubility.

**hERG Inhibition:** Ligand A (0.507) is better than Ligand B (0.263), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (32.137) has significantly lower microsomal clearance than Ligand A (58.386), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (23.589) has a longer half-life than Ligand A (10.314), which is also desirable.

**P-gp Efflux:** Ligand A (0.333) is better than Ligand B (0.21), indicating lower P-gp efflux.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, permeability, and hERG risk, Ligand B's substantially stronger binding affinity (-7.5 vs -10 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme target like SRC kinase. The DILI risk is a concern for both, but the potency and metabolic properties of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 11:29:07,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (358.395 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.07) is slightly above the preferred <140 for good oral absorption, but still acceptable. Ligand B (76.36) is excellent, well below 140.

**logP:** Ligand A (-1.828) is a bit low, potentially hindering permeation. Ligand B (1.821) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.238) is quite low, indicating a less drug-like profile. Ligand B (0.827) is excellent, suggesting good drug-likeness.

**DILI:** Ligand A (35.595) has a moderate DILI risk, but below the concerning threshold of 60. Ligand B (4.769) has a very low DILI risk, which is highly favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (54.207) and Ligand B (71.656) are both reasonable.

**Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-4.959) is worse than Ligand A (-5.279), suggesting lower intestinal absorption. However, the negative values are concerning and may indicate issues with the data.

**Solubility:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-2.431) is worse than Ligand A (-1.407), suggesting lower solubility. However, the negative values are concerning and may indicate issues with the data.

**hERG:** Ligand A (0.14) has a very low hERG risk, which is excellent. Ligand B (0.692) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (21.402) has moderate clearance. Ligand B (-7.688) has *negative* clearance, which is impossible and indicates a data error. This is a major red flag.

**In vitro Half-Life:** Ligand A (-31.456) has a negative half-life, which is impossible and indicates a data error. Ligand B (6.999) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is good. Ligand B (0.018) also has very low P-gp efflux.

**Binding Affinity:** Ligand A (-8.9) has significantly better binding affinity than Ligand B (-7.7). This 1.2 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, the negative values for half-life and the low QED are major concerns. The negative clearance for Ligand B is a critical data error, making it immediately unsuitable. However, even ignoring that error, Ligand B has a much better overall ADME profile (higher QED, lower DILI, better logP) and a reasonable half-life. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. Given the data issues with Ligand A, and the generally better profile of Ligand B, I would choose Ligand B as the more viable candidate, *assuming the negative clearance value is corrected*.

Output:
1
2025-04-17 11:29:07,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.475 and 372.575 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (68.18 and 67.43) well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (4.19) is slightly higher than the optimal 1-3 range, potentially raising solubility concerns. Ligand B (3.124) is within the optimal 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 HBA, both within the acceptable limit of 10.

**6. QED:** Ligand A (0.823) has a better QED score than Ligand B (0.652), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.846) has a slightly higher DILI risk than Ligand B (29.081), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.698) has a higher BBB percentile than Ligand B (67.197).

**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:** Ligand A (0.922) has a slightly higher hERG risk than Ligand B (0.391). Lower is better, so Ligand B is preferable here.

**12. Microsomal Clearance:** Ligand A (93.74) has a significantly higher microsomal clearance than Ligand B (70.15), suggesting lower metabolic stability. This is a major disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (8.609 hours) has a much longer in vitro half-life than Ligand A (46.237 percentile, which is not a raw time value, but suggests a shorter half-life). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.328 and 0.079).

**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:**

While Ligand A has a slightly better QED score and BBB penetration, Ligand B is significantly better in terms of metabolic stability (lower Cl_mic, longer half-life), hERG risk, and DILI risk. The poor solubility and Caco-2 permeability are concerns for both, but the ADME profile of Ligand B is superior. The affinity difference is minimal. Given the enzyme-kinase focus, metabolic stability and safety (hERG, DILI) are crucial.

Output:
1
2025-04-17 11:29:07,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.419 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.38) is better than Ligand B (58.64), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (2.215) is slightly better than Ligand A (1.031), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (1), lower is preferred.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (3), both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.684 and 0.772), indicating drug-likeness.

**DILI:** Ligand B (18.418) is significantly better than Ligand A (31.563), indicating a lower risk of drug-induced liver injury. This is a crucial advantage.

**BBB:** Ligand A (93.68) is better than Ligand B (87.476), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-3.965) is better than Ligand B (-4.628), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.658) is better than Ligand B (-3.116), indicating better solubility.

**hERG Inhibition:** Ligand A (0.124) is better than Ligand B (0.395), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (36.53) is better than Ligand A (51.428), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (2.305) is better than Ligand A (-16.294), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.038) is better than Ligand B (0.034), indicating lower P-gp efflux.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) is significantly better than Ligand A (-6.3 kcal/mol). This 1.5+ kcal/mol difference in binding affinity is a major advantage, and can outweigh some ADME concerns.

**Conclusion:**

While Ligand A has advantages in solubility, Caco-2 permeability, and BBB, Ligand B demonstrates a substantially stronger binding affinity (-8.4 vs -6.3 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic and higher t1/2). The superior binding affinity and reduced toxicity profile of Ligand B make it the more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 11:29:07,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.91) is slightly higher than Ligand B (87.46). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets, which isn't a primary concern here.

**logP:** Ligand A (-0.753) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (1.315) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5-6 HBA, which are acceptable.

**QED:** Both ligands have similar, good QED values (0.726 and 0.74).

**DILI:** Ligand A (18.845) has a significantly lower DILI risk than Ligand B (32.183). This is a strong advantage for Ligand A.

**BBB:** Ligand B (63.048) has a higher BBB penetration percentile than Ligand A (26.638), but BBB isn't a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.526 and -4.878), which is unusual and suggests poor permeability. However, these values are on a scale where negative values can occur and don't necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values (-0.551 and -2.021), indicating poor solubility. Ligand B is worse.

**hERG:** Both ligands have low hERG inhibition liability (0.121 and 0.211), which is excellent.

**Microsomal Clearance:** Ligand A (-5.275) has much lower (better) microsomal clearance than Ligand B (47.027), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (7.03 hours) has a positive half-life, while Ligand B (-6.263 hours) has a negative half-life, suggesting faster degradation. This favors Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.011 and 0.133).

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Ligand A is the better candidate. While it has slightly higher TPSA and lower logP, its significantly stronger binding affinity (-10.1 vs -6.9 kcal/mol), lower DILI risk, and much better metabolic stability (lower Cl_mic and longer t1/2) outweigh these minor drawbacks. The improved binding affinity is a critical factor for an enzyme inhibitor.

Output:
1
2025-04-17 11:29:07,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 Da and 344.371 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.87) is better than Ligand B (85.17), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have similar logP values (1.071 and 1.027), falling 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:** Ligand B (6) is higher than Ligand A (4), both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.798 and 0.876), indicating good drug-like properties.

**DILI:** Ligand A (12.214) has a significantly lower DILI risk than Ligand B (75.184). This is a major advantage for Ligand A.

**BBB:** Ligand B (77.084) has a higher BBB penetration than Ligand A (56.34), but BBB is less critical for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-4.751) is worse than Ligand B (-5.005), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.851) is better than Ligand B (-2.792), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.174 and 0.166).

**Microsomal Clearance:** Ligand A (-5.574) has significantly lower microsomal clearance than Ligand B (5.916), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (20.412) has a shorter half-life than Ligand B (35.222), but still reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.012).

**Binding Affinity:** Ligand B (-9.4) has a significantly stronger binding affinity than Ligand A (-8.0). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, its significantly higher DILI risk and higher microsomal clearance are major concerns. Ligand A has a much better safety profile (DILI) and metabolic stability (Cl_mic), and acceptable binding affinity. The difference in binding affinity (-1.4 kcal/mol) is substantial, but the improved safety and metabolic stability of Ligand A may outweigh this difference. Considering the balance of properties, and prioritizing metabolic stability and safety for an enzyme inhibitor, Ligand A is the more viable candidate.

Output:
0
2025-04-17 11:29:07,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.429 Da and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold and favorable for absorption. Ligand B (72.53) is also acceptable, though slightly higher.

**logP:** Both ligands have good logP values (2.344 and 1.79), 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 6 HBA. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.793 and 0.863), indicating good drug-like properties.

**DILI:** Ligand A (22.761) has a significantly lower DILI risk than Ligand B (35.595). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (86.817) has better BBB penetration than Ligand B (57.115).

**Caco-2 Permeability:** Ligand A (-4.584) shows better Caco-2 permeability than Ligand B (-5.049).

**Aqueous Solubility:** Ligand A (-2.367) has better aqueous solubility than Ligand B (-1.627).

**hERG:** Both ligands have very low hERG inhibition liability (0.428 and 0.143), which is excellent.

**Microsomal Clearance:** Ligand A (8.975) has a significantly lower microsomal clearance than Ligand B (20.99), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (54.82) has a much longer in vitro half-life than Ligand A (6.432). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.026).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a very significant advantage, potentially outweighing some of the ADME drawbacks. The difference of 1.9 kcal/mol is substantial.

**Overall Assessment:**

Ligand A has better ADME properties (lower DILI, better solubility, better permeability, lower clearance) but significantly weaker binding affinity. Ligand B has a much stronger binding affinity, but at the cost of higher DILI risk, lower solubility, lower permeability, and higher clearance.

Given the priority for potency in enzyme inhibitors, the 1.9 kcal/mol difference in binding affinity is a major factor. While the ADME profile of Ligand A is more favorable, the stronger binding of Ligand B is likely to translate to greater efficacy *in vivo*. Further optimization of Ligand B to improve its ADME properties would be a reasonable next step, capitalizing on its strong potency.

Output:
1
2025-04-17 11:29:07,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (68.6) is significantly better than Ligand B (75.19). Lower TPSA generally improves oral absorption.

**logP:** Both are within the optimal range (1-3), with Ligand A (2.207) being slightly preferred.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4, and Ligand B has 5. Both are acceptable, but Ligand A is slightly better.

**QED:** Ligand A (0.911) has a much better QED score than Ligand B (0.749), indicating a more drug-like profile.

**DILI:** Ligand A (41.877) has a lower DILI risk than Ligand B (54.75), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (84.064) is better than Ligand B (39.822).

**Caco-2 Permeability:** Ligand A (-4.67) is better than Ligand B (-5.012) indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.772) is better than Ligand B (-2.38), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.845) has a lower hERG risk than Ligand B (0.064), a crucial safety parameter.

**Microsomal Clearance:** Ligand A (26.086) has a lower Cl_mic than Ligand B (44.021), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (26.071) has a slightly better half-life than Ligand A (38.756), but the difference is not substantial.

**P-gp Efflux:** Ligand A (0.152) has a lower Pgp efflux liability than Ligand B (0.042), which is favorable.

**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, potentially outweighing some of the ADME drawbacks of Ligand B. However, the difference is 1.5kcal/mol, which is on the edge of being enough to overcome other issues.

**Overall Assessment:**

Ligand A has a superior ADME profile across almost all parameters (QED, DILI, solubility, hERG, metabolic stability, Pgp efflux). Ligand B's primary advantage is its significantly stronger binding affinity. Given that SRC kinases are enzymes, metabolic stability, solubility, and safety (hERG, DILI) are critical. While the affinity difference is notable, the more favorable ADME properties of Ligand A, especially the lower DILI and hERG risks, make it the more promising candidate.

Output:
0
2025-04-17 11:29:07,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 363.477 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (21.06) as it is closer to the threshold for good oral absorption (<140). Ligand B is very low, which might suggest good permeability but could also indicate a lack of necessary interactions.

**logP:** Ligand A (2.683) is within the optimal 1-3 range. Ligand B (4.865) is slightly higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 3 HBA, both within acceptable limits. Ligand B has 0 HBD and 4 HBA, also acceptable, but the lack of HBDs might affect solubility.

**QED:** Both ligands have similar QED values (0.645 and 0.57), indicating reasonable drug-likeness.

**DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (46.064), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (57.542) has a lower BBB penetration than Ligand B (92.71). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-4.691) and Ligand B (-5.039) both have negative Caco-2 values, which is unusual. These values likely represent a logP scale and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-2.487) and Ligand B (-4.026) both have negative solubility values, which is also unusual and indicates poor solubility.

**hERG Inhibition:** Ligand A (0.137) has a lower hERG inhibition risk than Ligand B (0.976), which is a significant advantage.

**Microsomal Clearance:** Ligand A (23.826) has a lower microsomal clearance than Ligand B (54.019), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.827) has a negative half-life, which is unusual. Ligand B (65.435) has a much longer in vitro half-life, indicating better stability.

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.909), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have similar binding affinities (-9.1 and -8.8 kcal/mol), both being strong binders. The difference of 0.3 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, hERG risk), Ligand A is the better candidate. While both have good binding affinity, Ligand A has a significantly lower DILI risk, lower hERG inhibition, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. Although both have poor solubility and permeability, the other advantages of Ligand A outweigh these drawbacks.

Output:
0
2025-04-17 11:29:07,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (397.232 and 367.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (70.63 and 70.16) are reasonably low, suggesting good potential for cell permeability, though not optimal for CNS penetration.

**3. logP:** Ligand A (3.003) is optimal, while Ligand B (0.495) is quite low, potentially hindering membrane permeability and absorption.

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

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

**6. QED:** Both ligands have good QED scores (0.633 and 0.726), indicating drug-like properties.

**7. DILI:** Ligand A (83.637) has a higher DILI risk than Ligand B (39.201). This is a concern for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B is slightly better (71.85 vs 59.791).

**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 show low hERG inhibition liability (0.858 and 0.314), which is positive.

**12. Microsomal Clearance (Cl_mic):** Ligand B (57.682 mL/min/kg) has lower clearance than Ligand A (80.85 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (-19.505 hours) has a negative half-life, which is unusual. Ligand A (11.163 hours) is more reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.693 and 0.038).

**15. Binding Affinity:** Both ligands have strong binding affinities (-9.9 and -8.8 kcal/mol). Ligand A has a 1.1 kcal/mol advantage.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. While Ligand A has a slightly better affinity, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic) and a much lower DILI risk. The negative solubility and half-life for Ligand B are concerning, but the lower DILI and better metabolic stability are more important for an enzyme target. The low logP of Ligand B is a significant drawback.

Considering the balance of these factors, Ligand A's superior binding affinity, despite its higher DILI risk, makes it the more promising candidate, assuming the DILI risk can be mitigated through structural modifications.

Output:
1
2025-04-17 11:29:07,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 363.477 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.03) is better than Ligand B (21.06) as it is still within the acceptable range for oral absorption (<140), while ligand B is very low.

**logP:** Ligand A (2.42) is optimal (1-3). Ligand B (4.865) is slightly high, potentially leading to solubility issues and off-target effects.

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

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**QED:** Ligand A (0.767) is significantly better than Ligand B (0.57), indicating a more drug-like profile.

**DILI:** Ligand A (23.497) has a much lower DILI risk than Ligand B (46.064). Both are below the concerning threshold of 60, but A is preferable.

**BBB:** Both ligands have good BBB penetration, but Ligand B (92.71) is slightly higher than Ligand A (84.141). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.354) is worse than Ligand B (-5.039), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.651) is better than Ligand B (-4.026), suggesting better formulation potential.

**hERG:** Both ligands have similar hERG inhibition liability (0.823 and 0.976), and are acceptable.

**Microsomal Clearance:** Ligand A (59.886) has a slightly better (lower) microsomal clearance than Ligand B (54.019), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (65.435) has a significantly longer half-life than Ligand A (1.725), which is a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.153 and 0.909).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), though the difference is not huge.

**Overall Assessment:**

Ligand A has better physicochemical properties (MW, TPSA, logP, QED, DILI, solubility) and metabolic stability. However, Ligand B has a much longer half-life and slightly better binding affinity. Given the enzyme-specific priorities, the longer half-life of Ligand B is a significant advantage, potentially outweighing the slightly less favorable physicochemical properties. The binding affinity difference is not large enough to favor Ligand A.

Output:
1
2025-04-17 11:29:07,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.401 and 360.523 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.47) is higher than Ligand B (49.41). While both are acceptable, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have good logP values (1.442 and 3.84), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially raise concerns about off-target effects, but is still within an acceptable 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 (0.7 and 0.867), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (53.509 and 53.781), which is acceptable (below 60).

**BBB:** Ligand B (78.945) has a better BBB percentile than Ligand A (62.466), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.081) has a worse Caco-2 permeability than Ligand B (-4.977), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.578) has a worse aqueous solubility than Ligand B (-4.467). Solubility is important for bioavailability, making Ligand B preferable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.652 and 0.532), which is good.

**Microsomal Clearance:** Ligand A has a significantly better microsomal clearance (-4.962) than Ligand B (90.025). This suggests that Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (-16.409) than Ligand B (-6.217). This is a significant advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.05) has a much lower P-gp efflux liability than Ligand B (0.649), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better metabolic stability, half-life, and P-gp efflux, the substantial difference in binding affinity (-9.3 vs -7.1 kcal/mol) outweighs these advantages. Ligand B also has better solubility and Caco-2 permeability.

Output:
1
2025-04-17 11:29:07,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (386.5 and 355.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.97) is higher than the preferred <140, while Ligand B (28.16) is excellent.

**logP:** Ligand A (2.641) is optimal (1-3). Ligand B (4.366) is slightly high, potentially leading to solubility issues and off-target effects.

**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 (0.823 and 0.747), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 76.1%, which is high. Ligand B has a much lower DILI risk of 6.6%, which is excellent.

**BBB:** Both have reasonable BBB penetration (50.7% and 76.5%). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.774) and Ligand B (-5.539) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Solubility:** Both ligands have very poor aqueous solubility (-3.285 and -3.063). This is a significant concern.

**hERG:** Ligand A (0.508) has a slightly elevated hERG risk, while Ligand B (0.957) is higher. Both are concerning, but Ligand B is more problematic.

**Microsomal Clearance:** Ligand A (27.2 mL/min/kg) and Ligand B (26.3 mL/min/kg) have similar, moderate clearance rates.

**In vitro Half-Life:** Ligand A (86.0 hours) has a significantly longer half-life than Ligand B (9.3 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.174) has lower P-gp efflux than Ligand B (0.321), which is preferable.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a crucial factor, as a 1.6 kcal/mol difference is significant.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.3 vs -7.7 kcal/mol) and longer half-life (86 vs 9.3 hours) outweigh the higher DILI risk and slightly higher hERG risk. The improved P-gp efflux is also a benefit. While solubility needs to be addressed through formulation strategies, the potency and PK advantages of Ligand A make it the better starting point for optimization.

Output:
0
2025-04-17 11:29:07,371 - INFO - Batch 51 complete. Total preferences: 816
2025-04-17 11:29:07,371 - INFO - Processing batch 52/512...
2025-04-17 11:29:48,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.411 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.3) is better than Ligand B (53.76) as it is closer to the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.346 and 3.596, respectively), falling within the 1-3 range. Ligand B is slightly higher, potentially indicating a minor risk of off-target effects, but not 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:** Ligand A (0.855) has a significantly higher QED score than Ligand B (0.592), indicating better overall drug-likeness.

**DILI:** Ligand A (59.636) has a higher DILI risk than Ligand B (35.944). This is a significant negative for Ligand A.

**BBB:** Ligand A (48.662) and Ligand B (67.933). BBB is not a primary concern for SRC kinase inhibitors, but higher is generally better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.058 and -4.96). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.497 and -2.627). This is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.493) has a lower hERG inhibition liability than Ligand B (0.886), which is favorable.

**Microsomal Clearance:** Ligand A (29.601) has a much lower microsomal clearance than Ligand B (92.805). This indicates better metabolic stability for Ligand A, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-12.613) has a negative half-life, which is not possible. Ligand B (76.541) has a very long half-life, which is a significant advantage.

**P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux liability than Ligand B (0.62), which is favorable.

**Binding Affinity:** Ligand A (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8 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 (lower Cl_mic) and P-gp efflux. However, it has a higher DILI risk and a problematic negative in vitro half-life. Ligand B has a better DILI profile, a long half-life, and acceptable BBB, but its binding affinity is weaker.

Given the enzyme-specific priorities, binding affinity and metabolic stability are paramount. The substantial difference in binding affinity (-10.6 vs -8 kcal/mol) is a significant factor. While the DILI risk for Ligand A is a concern, it might be mitigated through structural modifications. The negative half-life is a major red flag.

Considering all factors, **Ligand B** is the more viable drug candidate due to its better safety profile (lower DILI), longer half-life, and acceptable binding affinity.

Output:
1
2025-04-17 11:29:48,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 367.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.8) is well below the 140 threshold for good absorption, and even better for potential CNS penetration. Ligand B (126.2) is still acceptable, but less optimal.

**logP:** Ligand A (1.58) is within the optimal 1-3 range. Ligand B (0.63) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is excellent. Ligand B (4 HBD, 5 HBA) is acceptable, but the 4 HBDs are approaching the upper limit.

**QED:** Both ligands have reasonable QED scores (0.83 and 0.503), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (37.0 and 36.8), which is positive.

**BBB:** Ligand A (78.9) has better BBB penetration potential than Ligand B (70.4), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.26) shows poor permeability, while Ligand B (-5.7) is even worse. This is a significant concern.

**Aqueous Solubility:** Ligand A (-2.07) has slightly better solubility than Ligand B (-1.37), but both are quite poor.

**hERG Inhibition:** Ligand A (0.52) has a much lower hERG risk than Ligand B (0.13), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-0.13) shows excellent metabolic stability (low clearance), while Ligand B (12.29) suggests faster metabolism.

**In vitro Half-Life:** Ligand A (34.2 hr) has a significantly longer half-life than Ligand B (2.43 hr), which is highly desirable.

**P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux liability than Ligand B (0.03), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Conclusion:**

Despite Ligand B having a slightly better binding affinity, Ligand A is the more promising candidate. Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. While both have poor Caco-2 permeability and solubility, Ligand A's superior ADME profile, particularly the hERG and metabolic stability, makes it a more viable starting point for optimization. The binding affinity difference is small enough that it can likely be addressed through further medicinal chemistry efforts, while fixing the poor permeability and solubility of Ligand B would be more challenging.

Output:
0
2025-04-17 11:29:48,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.451 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.86) is better than Ligand B (59.08), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.635) is slightly low, potentially hindering permeation. Ligand B (2.932) is optimal.

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

**H-Bond Acceptors:** Ligand A (7) is good. Ligand B (4) is good.

**QED:** Ligand A (0.751) is excellent, indicating strong drug-likeness. Ligand B (0.447) is acceptable, but less ideal.

**DILI:** Ligand A (23.497) has a significantly lower DILI risk than Ligand B (16.673), both are good.

**BBB:** Ligand A (31.02) is lower than Ligand B (89.027). BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.213) is poor, indicating low intestinal absorption. Ligand B (-4.054) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (0.264) is very poor. Ligand B (-2.169) is also poor. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.201) has a very low hERG risk. Ligand B (0.798) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-44.356) indicates very slow clearance and excellent metabolic stability. Ligand B (94.584) indicates rapid clearance and poor metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (23.212) has a good half-life. Ligand B (-9.268) has a very short half-life.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux. Ligand B (0.227) has slightly higher efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.1 and -7.3 kcal/mol). Ligand B is slightly better, but the difference is small.

**Conclusion:**

Despite Ligand B having a better logP and BBB, Ligand A is the more promising candidate. The significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and very low P-gp efflux outweigh the slightly lower logP and Caco-2 permeability. The solubility is a concern for both, but can be addressed with formulation strategies. The similar binding affinities mean that ADME properties become the deciding factor.

Output:
0
2025-04-17 11:29:48,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.364 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is better than Ligand B (75.27), both are below the 140 threshold for oral absorption, but lower is preferable.

**3. logP:** Both ligands have good logP values (2.081 and 2.113), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is preferable to balance solubility and permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (3). Lower is preferable to balance solubility and permeability.

**6. QED:** Both ligands have good QED scores (0.762 and 0.802), indicating good drug-like properties.

**7. DILI:** Ligand A (40.054) is slightly higher than Ligand B (25.785), but both are below the 60 threshold, indicating low risk. Ligand B is preferable here.

**8. BBB:** Ligand A (91.508) has significantly better BBB penetration than Ligand B (55.176). However, BBB is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.608 and -4.864). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.042 and -2.718). This is also unusual and suggests poor solubility. The values are similar.

**11. hERG Inhibition:** Ligand A (0.449) is slightly higher than Ligand B (0.076), indicating a slightly higher risk of hERG inhibition. Ligand B is preferable here.

**12. Microsomal Clearance:** Ligand A (38.396) has higher microsomal clearance than Ligand B (23.512), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (-2.94 and -2.797).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.083 and 0.06).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a crucial advantage for an enzyme inhibitor, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better BBB penetration (irrelevant for a non-CNS target) and slightly better TPSA, Ligand B exhibits superior metabolic stability (lower Cl_mic), lower hERG risk, and, most importantly, significantly higher binding affinity. The similar poor Caco-2 and solubility values are concerning for both, but the substantial difference in binding affinity makes Ligand B the more promising starting point for optimization.

Output:
1
2025-04-17 11:29:48,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.471 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.55) is slightly higher than Ligand B (74.59). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand B (1.814) is within the optimal 1-3 range, while Ligand A (0.689) is slightly below, potentially impacting permeability.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**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 (0.658 and 0.779, respectively), indicating drug-like properties.

**DILI:** Ligand B (33.618) has a significantly lower DILI risk than Ligand A (54.323), making it more favorable.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (46.064) is slightly better than Ligand A (41.024).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.74) is slightly better than Ligand A (-5.36).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-1.971) is slightly better than Ligand A (-1.048).

**hERG Inhibition:** Ligand A (0.059) has a lower hERG inhibition liability than Ligand B (0.448), which is a significant advantage.

**Microsomal Clearance:** Ligand B (53.815) has a higher microsomal clearance than Ligand A (9.56), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (32.132 hours) has a longer half-life than Ligand A (24.223 hours), which is preferable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.016 and 0.047, respectively).

**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.

**Conclusion:**

Despite Ligand B having better DILI and half-life, Ligand A's significantly superior binding affinity (-8.5 vs -7.4 kcal/mol) and lower hERG risk outweigh its slightly lower solubility and higher DILI. The lower microsomal clearance of Ligand A also suggests better metabolic stability. Given the enzyme-kinase target class, potency and safety (hERG) are paramount.

Output:
1
2025-04-17 11:29:48,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.47 and 368.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.68) is higher than Ligand B (58.64). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Both ligands have good logP values (3.315 and 2.442), 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.

**QED:** Both ligands have good QED scores (0.665 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (64.87) has a higher DILI risk than Ligand B (32.30). This is a significant negative for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand B (63.78) is slightly better than Ligand A (45.72). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand B (-5.051) shows better Caco-2 permeability than Ligand A (-4.772).

**Aqueous Solubility:** Ligand B (-3.184) has better aqueous solubility than Ligand A (-3.802).

**hERG:** Both ligands have low hERG inhibition liability (0.398 and 0.337), which is positive.

**Microsomal Clearance:** Ligand B (59.72) has a lower microsomal clearance than Ligand A (88.87), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-11.001) has a significantly longer in vitro half-life than Ligand A (-4.423). This is another major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.502 and 0.232).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has 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:** Ligand B is superior to Ligand A. It exhibits lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and slightly better binding affinity. While Ligand A has a slightly better binding affinity, the ADME properties of Ligand B are significantly more favorable, making it a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 11:29:48,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (362.495 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (79.03 and 76.02) are below the 140 A^2 threshold for good oral absorption, which is good.

**3. logP:** Both ligands (2.657 and 2.181) are 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 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 (0.878 and 0.829), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 56.96, while Ligand B has a significantly lower risk of 21.714. This is a substantial advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration (72.237 and 68.399), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.362 and -4.855). 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 negative solubility values (-3.311 and -2.816), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.618 and 0.353), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand A has a higher Cl_mic (55.466) than Ligand B (41.734). Higher clearance means faster metabolism and potentially lower exposure, making Ligand B preferable.

**13. In vitro Half-Life (t1/2):** Ligand B has a slightly better in vitro half-life (-0.599 hours) than Ligand A (-3.516 hours). While both are negative, a less negative value indicates a longer half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.404 and 0.062), which is good.

**15. Binding Affinity:** Ligand B has a slightly stronger binding affinity (-9.1 kcal/mol) than Ligand A (-8.7 kcal/mol). This 0.4 kcal/mol difference is significant, potentially outweighing some of the ADME drawbacks.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B demonstrates advantages in DILI risk, Cl_mic, t1/2, and binding affinity. While both have poor solubility and permeability, the superior binding affinity and improved ADME properties of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 11:29:48,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.5 and 353.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (107.97). A TPSA under 140 is good for oral absorption, but A is much closer to the ideal for better permeability.

**logP:** Ligand A (3.23) is optimal (1-3). Ligand B (-0.983) is below 1, which might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.719) has a higher QED score than Ligand B (0.494), indicating better overall drug-likeness.

**DILI:** Both ligands have similar DILI risk (11.361 vs 11.594), and are both low risk (<40).

**BBB:** Ligand A (93.563) has a much higher BBB penetration percentile than Ligand B (40.675). While not a primary concern for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.618) is significantly better than Ligand B (-5.292). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.571) is better than Ligand B (-0.833). Higher solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.641) has a lower hERG inhibition liability than Ligand B (0.05), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (92.52) has a higher microsomal clearance than Ligand B (11.231), meaning it is less metabolically stable. This is a drawback for A.

**In vitro Half-Life:** Ligand B (18.675) has a longer in vitro half-life than Ligand A (-6.563), which is a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.325) has lower P-gp efflux liability than Ligand B (0.006), which is preferable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.7 kcal/mol and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold to override other ADME issues.

**Overall Assessment:**

Ligand A has significant advantages in terms of TPSA, logP, QED, solubility, and hERG risk. While its microsomal clearance is higher and half-life is shorter, the superior ADME profile and comparable binding affinity make it the more promising candidate. Ligand B's lower logP and higher clearance are concerning.

Output:
0
2025-04-17 11:29:48,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (405.252 Da and 380.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is slightly higher than Ligand B (73.66), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.257) is optimal, while Ligand B (3.802) is approaching the upper limit.

**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 (0.803 and 0.774), indicating good drug-likeness.

**DILI:** Ligand A (77.278) has a higher DILI risk than Ligand B (51.028). This is a significant drawback for Ligand A.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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, indicating poor aqueous solubility. This is a concern, but similar for both.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.562 and 0.411).

**Microsomal Clearance:** Ligand A (13.723) has significantly lower microsomal clearance than Ligand B (45.084), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (30.791) has a longer half-life than Ligand B (26.632).

**P-gp Efflux:** Both have low P-gp efflux liability (0.355 and 0.559).

**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 outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. While Ligand A has slightly better metabolic stability and half-life, Ligand B has a significantly lower DILI risk. DILI is a major concern in drug development, and a lower risk profile is highly desirable. The binding affinities are comparable, and both have issues with solubility and permeability. Therefore, the lower DILI risk of Ligand B makes it the more viable drug candidate.

Output:
1
2025-04-17 11:29:48,256 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.511 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (95.5). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is preferable.

**logP:** Ligand A (2.785) is optimal (1-3), while Ligand B (-0.293) is below 1, potentially hindering permeation. This is a significant drawback for Ligand B.

**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 (0.792 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (64.754). Both are acceptable (<60 is good), but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.292) is better than Ligand B (53.276).

**Caco-2 Permeability:** Ligand A (-5.445) is better than Ligand B (-4.503), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.216) is better than Ligand B (-1.317), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.78) has a lower hERG risk than Ligand B (0.139). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (55.302) is better than Ligand B (57.778), suggesting better metabolic stability. Lower is better.

**In vitro Half-Life:** Ligand A (5.098) has a positive half-life, while Ligand B (-39.491) has a negative half-life, which is a major concern.

**P-gp Efflux:** Ligand A (0.192) has lower P-gp efflux than Ligand B (0.024), indicating better bioavailability.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.3), a 0.4 kcal/mol difference. While affinity is a priority, the other significant drawbacks of Ligand B likely outweigh this small advantage.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, including logP, solubility, hERG risk, and metabolic stability (half-life and clearance). The negative logP and half-life of Ligand B are major red flags.

Output:
1
2025-04-17 11:29:48,256 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.382 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.33) is slightly above the optimal <140, but acceptable. Ligand B (58.64) is well within the ideal range.

**logP:** Ligand A (-0.246) is a bit low, potentially hindering permeability. Ligand B (2.893) is excellent, 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.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.763 and 0.65), indicating drug-like properties.

**DILI:** Ligand A (72.741) has a higher DILI risk than Ligand B (31.059). Ligand B is preferable here.

**BBB:** Both ligands have reasonable BBB penetration (75.262 and 78.868), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.055 and -4.628). This 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 (-2.944 and -3.157). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.349 and 0.494), which is favorable.

**Microsomal Clearance:** Ligand A (-1.532) has a significantly *lower* (better) microsomal clearance than Ligand B (81.987). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (6.95) has a shorter half-life than Ligand B (17.545). Ligand B is preferable here.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.288).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This 1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic). However, it has a lower logP and a higher DILI risk. Ligand B has a better logP, lower DILI, and a longer half-life. The poor solubility and permeability for both are concerning, but the affinity difference is substantial. Given the enzyme-specific priority on potency, and the fact that the affinity difference is >1.5 kcal/mol, Ligand A is the more promising candidate, despite its drawbacks. Further optimization would focus on improving its logP and reducing DILI risk, while maintaining the strong binding affinity.

Output:
0
2025-04-17 11:29:48,256 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (54.43), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.668 and 3.551), 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 (2) is better than Ligand B (6), both are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.746 and 0.635), indicating good drug-like properties.

**DILI:** Ligand A (19.426) has a significantly lower DILI risk than Ligand B (27.414). This is a major advantage.

**BBB:** Ligand A (77.084) has a better BBB penetration score than Ligand B (54.013), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.796) is better than Ligand B (-5.507), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.764) is better than Ligand B (-2.609), indicating better aqueous solubility.

**hERG Inhibition:** Ligand A (0.602) has a lower hERG inhibition liability than Ligand B (0.892), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (80.058) has a higher microsomal clearance than Ligand B (30.666), meaning it is less metabolically stable. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (86.801) has a much longer in vitro half-life than Ligand A (-15.979), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux liability than Ligand B (0.692), which is a slight advantage.

**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 has advantages in DILI risk, solubility, hERG, Caco-2 permeability, and P-gp efflux. However, Ligand B has a significantly better in vitro half-life and lower microsomal clearance, making it more metabolically stable. The binding affinities are essentially the same. Given the enzyme-specific priorities (metabolic stability, solubility, hERG), and the substantial difference in half-life, Ligand B is the more promising candidate despite the slightly higher DILI and hERG risks. The improved metabolic stability is likely to be more impactful on overall drug development success.

Output:
1
2025-04-17 11:29:48,256 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.296 Da) is slightly higher than Ligand B (356.482 Da), but both are acceptable.

**TPSA:** Ligand A (80.32) is higher than Ligand B (49.85). While both are reasonably low, Ligand B is preferable as lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 3.954, B: 2.637) within the optimal range of 1-3.

**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 (A: 0.71, B: 0.628), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (76.464) than Ligand B (11.439). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B has a higher BBB score (90.617) than Ligand A (77.2), but this is not a primary deciding factor.

**Caco-2 Permeability:** Both ligands exhibit negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are on a similar scale, so this doesn't strongly favor one over the other.

**Aqueous Solubility:** Ligand A (-5.036) has very poor aqueous solubility, while Ligand B (-1.722) is better, though still not ideal. Solubility is important for bioavailability, making Ligand B preferable.

**hERG Inhibition:** Ligand A (0.583) has a slightly higher hERG risk than Ligand B (0.811), but both are reasonably low.

**Microsomal Clearance:** Ligand A (110.817) has a higher microsomal clearance than Ligand B (48.086), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (113.985) has a longer in vitro half-life than Ligand B (9.105), which is a positive. However, this benefit is likely outweighed by the poor metabolic stability indicated by the high Cl_mic.

**P-gp Efflux:** Ligand A (0.179) has lower P-gp efflux than Ligand B (0.307), which is slightly favorable.

**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 (1.5 kcal/mol difference).

**Conclusion:**

Despite the superior binding affinity of Ligand A, its significantly higher DILI risk, poor aqueous solubility, and higher microsomal clearance make it a less desirable candidate. Ligand B, while having a slightly weaker binding affinity, exhibits a much better safety profile (lower DILI), better solubility, and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and safety are crucial. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 11:29:48,257 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.356 and 378.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is better than Ligand B (60.44), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.767 and 3.989), 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 similar QED values (0.791 and 0.755), indicating good drug-likeness.

**DILI:** Ligand A (54.323) has a significantly lower DILI risk than Ligand B (84.917). This is a major advantage for Ligand A.

**BBB:** Ligand A (95.386) has a much higher BBB penetration potential than Ligand B (61.962). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.182) has better Caco-2 permeability than Ligand B (-4.74).

**Aqueous Solubility:** Ligand A (-4.958) has better aqueous solubility than Ligand B (-5.065).

**hERG Inhibition:** Ligand A (0.651) shows lower hERG inhibition liability than Ligand B (0.351), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (49.217) has lower microsomal clearance than Ligand A (75.321), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (14.111) has a significantly longer in vitro half-life than Ligand A (-2.906). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.174) has lower P-gp efflux liability than Ligand B (0.353).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a 1.3 kcal/mol difference, which is a significant advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand B has superior binding affinity and metabolic stability (lower Cl_mic and longer t1/2), Ligand A demonstrates a much better safety profile (lower DILI and hERG) and better solubility and permeability. The difference in binding affinity is significant, but the substantial improvements in safety and ADME properties for Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 11:29:48,257 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 370.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is better than Ligand B (75.71). Both are below 140, suggesting good oral absorption potential.

**logP:** Both ligands have good logP values (1.843 and 2.233, respectively), falling within the 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 have 4 H-bond acceptors, well within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.715 and 0.753), indicating good drug-likeness.

**DILI:** Ligand A (10.624) has a significantly lower DILI risk than Ligand B (23.226). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (51.997 and 56.029), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.754 and -4.967), which is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.811 and -1.113), indicating poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.801) shows a slightly better hERG profile than Ligand B (0.124), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (34.776 mL/min/kg) has a higher (worse) microsomal clearance than Ligand B (7.208 mL/min/kg), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (5.842 hours) has a longer half-life than Ligand B (3.155 hours), which is preferable.

**P-gp Efflux:** Ligand A (0.343) has lower P-gp efflux liability than Ligand B (0.045), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.6 vs -7.4 kcal/mol) and much lower DILI risk are major advantages. The longer half-life and lower P-gp efflux also contribute to its favorability. While Ligand B has better metabolic stability (lower Cl_mic), the difference in binding affinity is more critical for an enzyme target like SRC kinase.

Output:
0
2025-04-17 11:29:48,257 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.5 and 361.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.26) is significantly better than Ligand B (67.6), being well below the 140 threshold for good absorption.

**logP:** Both ligands (2.66 and 2.48) are 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), both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.645 and 0.817), indicating drug-like properties.

**DILI:** Ligand A (13.53) has a much lower DILI risk than Ligand B (52.42), which is a significant advantage.

**BBB:** Ligand A (83.83) has a higher BBB penetration percentile than Ligand B (49.94), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.974 and -5.096), which is unusual and suggests poor permeability. However, these values are on a log scale, so the negative values are expected.

**Aqueous Solubility:** Ligand A (-0.914) is better than Ligand B (-4.151), indicating better solubility. Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.414 and 0.42), which is excellent.

**Microsomal Clearance:** Ligand A (31.49) has significantly lower microsomal clearance than Ligand B (61.54), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.66) has a slightly shorter half-life than Ligand B (9.163), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.318 and 0.192).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better solubility, and lower microsomal clearance (better metabolic stability). While Ligand B has slightly better binding affinity, the ADME advantages of Ligand A outweigh this minor difference, especially considering we're targeting a kinase. The lower DILI and better metabolic stability are crucial for a viable drug candidate.

Output:
0
2025-04-17 11:29:48,257 - INFO - Batch 52 complete. Total preferences: 832
2025-04-17 11:29:48,257 - INFO - Processing batch 53/512...
2025-04-17 11:30:36,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (360.42 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.43) is still under 140, but less favorable than A.

**3. logP:** Both ligands have good logP values (2.815 and 1.983), 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 (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have reasonable QED values (0.81 and 0.711), indicating good drug-like properties.

**7. DILI:** Ligand A (30.826) has a significantly lower DILI risk than Ligand B (16.247). This is a major advantage for Ligand A.

**8. BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (91.896) shows better BBB penetration potential than Ligand B (62.156).

**9. Caco-2 Permeability:** Ligand A (-4.585) has a slightly better Caco-2 permeability than Ligand B (-4.744), although both are negative values which is not ideal.

**10. Aqueous Solubility:** Ligand A (-4.424) shows better aqueous solubility than Ligand B (-2.974).

**11. hERG Inhibition:** Ligand A (0.547) has a lower hERG inhibition liability than Ligand B (0.135), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (26.426) has a higher microsomal clearance than Ligand B (20.138), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (3.138) has a slightly longer half-life than Ligand A (5.504).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.03).

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B's superior binding affinity (-9.6 kcal/mol vs -7.9 kcal/mol) is a major driver. While Ligand A has advantages in DILI risk, solubility, hERG, and TPSA, the potency difference is substantial enough to outweigh these factors for an enzyme target like SRC kinase. The slightly better metabolic stability (lower Cl_mic) and half-life of Ligand B are also positive.

Output:
1
2025-04-17 11:30:36,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.401 and 357.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (95.13). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have acceptable logP values (1.795 and 2.994), 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=5) in terms of maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.877 and 0.86).

**DILI:** Ligand A (40.636) has a better DILI percentile than Ligand B (70.105), indicating a lower risk of drug-induced liver injury. This is a significant advantage.

**BBB:** Ligand A (79.682) has a better BBB percentile than Ligand B (42.536), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.7 and -4.854), which is unusual and indicates very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.303 and -4.835), which is also a significant concern. Poor solubility will hinder bioavailability.

**hERG Inhibition:** Ligand A (0.356) has a much lower hERG inhibition risk than Ligand B (0.45). This is a critical advantage.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (43.934 and 42.313 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (62.148) has a significantly longer in vitro half-life than Ligand A (-3.416). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.044) has a much lower P-gp efflux liability than Ligand B (0.279), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly better binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, and a better half-life. However, Ligand A has significantly better DILI and hERG profiles, and lower P-gp efflux. Both have poor Caco-2 and solubility. The affinity difference is substantial (>1.5 kcal/mol), and given that we are targeting an enzyme, potency is paramount. The poor solubility and permeability are shared issues that would need to be addressed in further optimization, but the strong binding of Ligand B makes it the more promising starting point.

Output:
1
2025-04-17 11:30:36,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (361.467 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.22) is higher than Ligand B (58.44). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**3. logP:** Both ligands (2.649 and 2.0) have optimal logP values between 1 and 3.

**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 (6) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.606 and 0.819), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (30.826). This is a significant advantage for Ligand B.

**8. BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand B (74.176) is higher than Ligand A (59.093).

**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 similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both, but the value for Ligand A (-3.583) is worse than Ligand B (-1.703).

**11. hERG Inhibition:** Ligand A (0.36) has a slightly higher hERG risk than Ligand B (0.202), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (133.729) has a significantly higher microsomal clearance than Ligand B (40.563), indicating lower metabolic stability. This is a major drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (8.153) has a much longer in vitro half-life than Ligand A (-27.471), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.363 and 0.112).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). Although A is better, the difference is not substantial enough to overcome the ADME deficiencies.

**Overall Assessment:**

Ligand B is the more promising candidate. It exhibits a significantly lower DILI risk, better metabolic stability (lower Cl_mic and higher t1/2), better solubility, and comparable binding affinity to Ligand A. While both have issues with Caco-2 and solubility, Ligand B's superior ADME profile makes it the preferred choice for further development as an SRC kinase inhibitor.

Output:
1
2025-04-17 11:30:36,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.519 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (104.39). A TPSA under 90 is preferable, and Ligand A is comfortably within this range, suggesting better permeability. Ligand B is pushing the upper limit for good oral absorption.

**logP:** Ligand A (2.691) is optimal (1-3), while Ligand B (0.331) is a bit low, potentially hindering 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 improve permeability.

**QED:** Both ligands have similar QED values (0.719 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (11.671) has a much lower DILI risk than Ligand B (54.634). This is a significant advantage for Ligand A.

**BBB:** Ligand A (77.084) has better BBB penetration than Ligand B (62.854), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.957) is better than Ligand B (-4.766), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-2.46 and -2.654). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.554) has a lower hERG risk than Ligand B (0.216), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (48.983) has higher microsomal clearance than Ligand B (33.358), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-19.751) has a significantly longer in vitro half-life than Ligand A (0.559). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.116) has lower P-gp efflux than Ligand B (0.035), which is favorable.

**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 excels in TPSA, logP, DILI risk, hERG risk, Caco-2 permeability, and P-gp efflux. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a longer half-life and lower clearance, but its higher TPSA, lower logP, and significantly higher DILI and hERG risks are concerning.

Given the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), the lower DILI and hERG risks of Ligand A are more critical than the slightly better metabolic stability of Ligand B. While the half-life of Ligand A is a concern, it could potentially be addressed through prodrug strategies or formulation approaches. The solubility is similar for both, and the binding affinity is nearly identical.

Output:
0
2025-04-17 11:30:36,439 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [344.459, 83.98, 2.167, 2, 4, 0.673, 39.24, 59.984, -5.217, -1.645, 0.184, 37.958, 8.382, 0.032, -8.6]
**Ligand B:** [358.467, 67.23, 2.777, 1, 5, 0.914, 67.623, 64.87, -5.238, -3.728, 0.522, 24.986, 17.03, 0.218, -7.4]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (344.459) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** Both are good, below 140. Ligand B (67.23) is better, suggesting improved permeability.
3. **logP:** Both are within the optimal range (1-3). Ligand B (2.777) is slightly higher, which could be a minor concern for solubility but isn't critical.
4. **HBD:** Ligand A (2) is better than Ligand B (1). Lower is generally preferred for permeability.
5. **HBA:** Ligand A (4) is better than Ligand B (5). Lower is generally preferred for permeability.
6. **QED:** Ligand B (0.914) is significantly better than Ligand A (0.673), indicating a more drug-like profile.
7. **DILI:** Ligand A (39.24) is much better than Ligand B (67.623). This is a significant advantage for Ligand A.
8. **BBB:** Both are relatively low, not a major factor here as SRC is not a CNS target. Ligand B (64.87) is slightly higher.
9. **Caco-2:** Both are negative, indicating poor permeability. Ligand A (-5.217) is slightly worse than Ligand B (-5.238).
10. **Solubility:** Both are negative, indicating poor solubility. Ligand B (-3.728) is slightly better than Ligand A (-1.645).
11. **hERG:** Ligand A (0.184) is much better than Ligand B (0.522). This is a critical advantage for Ligand A, reducing cardiotoxicity risk.
12. **Cl_mic:** Ligand B (24.986) has significantly lower microsomal clearance than Ligand A (37.958), indicating better metabolic stability.
13. **t1/2:** Ligand B (17.03) has a significantly longer in vitro half-life than Ligand A (8.382), which is desirable.
14. **Pgp:** Ligand B (0.218) has lower P-gp efflux than Ligand A (0.032), suggesting better bioavailability.
15. **Binding Affinity:** Ligand A (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a >1.2 kcal/mol difference, which is a major advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a much stronger binding affinity and significantly lower hERG risk. However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility. The poor Caco-2 and solubility for both compounds are concerning, but the significantly better affinity of Ligand A is likely to outweigh these issues, especially as solubility can be improved through formulation strategies. The DILI risk for Ligand A is also much lower.

**Conclusion:**

Despite the better QED, metabolic stability, and Pgp profile of Ligand B, the significantly superior binding affinity and lower hERG/DILI risk of Ligand A make it the more promising drug candidate. The potency advantage is substantial and can potentially compensate for the ADME liabilities.

Output:
1
2025-04-17 11:30:36,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.455 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.79) is significantly better than Ligand B (87.22). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.322) is optimal, while Ligand B (1.436) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA) regarding the balance between solubility and permeability.

**QED:** Both ligands (0.858 and 0.762) have good drug-likeness scores.

**DILI:** Ligand A (54.75) has a slightly higher DILI risk than Ligand B (31.601), but both are acceptable (<60).

**BBB:** Ligand A (44.397) has a lower BBB penetration than Ligand B (74.796). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-4.802) has a worse Caco-2 permeability than Ligand B (-5.179), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.678) has worse solubility than Ligand B (-1.565). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.431) has a slightly higher hERG risk than Ligand B (0.326), but both are relatively low.

**Microsomal Clearance:** Ligand A (23.902) has a significantly higher microsomal clearance than Ligand B (12.811), indicating lower metabolic stability. This is a critical drawback for an enzyme target.

**In vitro Half-Life:** Ligand A (30.646) has a longer half-life than Ligand B (5.116). However, the higher clearance of A negates this benefit.

**P-gp Efflux:** Ligand A (0.235) has lower P-gp efflux than Ligand B (0.01), which is favorable.

**Binding Affinity:** Ligand B (-9.0) has a substantially stronger binding affinity than Ligand A (0.0). This is the most important factor for an enzyme target. A difference of >1.5 kcal/mol is significant.

**Conclusion:**

Despite Ligand A having slightly better TPSA and P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.0 kcal/mol vs. 0.0 kcal/mol) of Ligand B outweighs the minor drawbacks in logP and Caco-2 permeability. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic) and solubility, which are crucial for an enzyme inhibitor.

Output:
1
2025-04-17 11:30:36,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 356.511 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (78.87 and 73.91) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.363) is optimal, while Ligand B (0.45) 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 4 HBA, and Ligand B has 5, both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.5 (0.681 and 0.556), indicating good drug-like properties.

**DILI:** Ligand A (17.798) has a significantly lower DILI risk than Ligand B (9.461), which is a major advantage.

**BBB:** Both ligands have low BBB penetration (47.15 and 40.52), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.755) has poor Caco-2 permeability, while Ligand B (-5.268) is also poor.

**Aqueous Solubility:** Ligand A (-1.621) has better aqueous solubility than Ligand B (-0.309).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.191 and 0.356).

**Microsomal Clearance:** Ligand A (27.779) has higher microsomal clearance than Ligand B (14.657), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (10.168) has a significantly longer in vitro half-life than Ligand A (-1.946), a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.008).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.1 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. While Ligand A has slightly better logP and solubility, Ligand B has a significantly lower DILI risk, a substantially longer half-life, and comparable binding affinity. The longer half-life is particularly important for an enzyme target, as it suggests less frequent dosing. The lower DILI risk is also a critical factor for safety.

Output:
1
2025-04-17 11:30:36,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (366.483 Da) is also good.

**TPSA:** Ligand A (52.65) is well below the 140 threshold for oral absorption and is favorable. Ligand B (86.71) is still acceptable, but less ideal than A.

**logP:** Ligand A (2.736) is within the optimal 1-3 range. Ligand B (0.493) is quite low, potentially hindering permeation and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is excellent. Ligand B (HBD=2, HBA=4) is also acceptable, but slightly higher.

**QED:** Ligand A (0.916) is very high, indicating excellent drug-likeness. Ligand B (0.39) is significantly lower, raising concerns about its overall drug-like properties.

**DILI:** Ligand A (22.838) has a low DILI risk, which is very favorable. Ligand B (19.116) also has a low DILI risk, comparable to A.

**BBB:** Ligand A (92.09) shows good BBB penetration, though SRC isn't necessarily a CNS target. Ligand B (60.023) is lower, less favorable.

**Caco-2 Permeability:** Ligand A (-4.764) is a negative value, indicating poor permeability. Ligand B (-5.126) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.259 and -2.347 respectively). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.798) has a low hERG risk, which is excellent. Ligand B (0.234) also shows a low hERG risk.

**Microsomal Clearance:** Ligand A (0.949) has a low microsomal clearance, indicating good metabolic stability. Ligand B (1.95) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (52.876) has a good in vitro half-life. Ligand B (-31.864) has a very short half-life, a major concern.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.043 respectively).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the superior candidate. It has a significantly better binding affinity, a much higher QED score, better metabolic stability (lower Cl_mic), a longer half-life, and better BBB penetration. While solubility is a concern, the strong binding affinity and favorable ADME properties (excluding solubility) make Ligand A the more promising drug candidate.

Output:
0
2025-04-17 11:30:36,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.825 and 375.881 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is slightly higher than Ligand B (55.2). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.746 and 2.955) within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are 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 (0.916) has a significantly higher QED score than Ligand B (0.755), indicating better overall drug-likeness.

**DILI:** Ligand A (73.362) has a higher DILI risk than Ligand B (42.924). This is a significant concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (79.488 and 75.301). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.051) is worse than Ligand B (-4.493).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.999) is worse than Ligand B (-3.82).

**hERG Inhibition:** Ligand A (0.299) has a slightly higher hERG inhibition risk than Ligand B (0.073), but both are relatively low.

**Microsomal Clearance:** Ligand A (39.973) has lower microsomal clearance than Ligand B (42.446), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.515) has a shorter half-life than Ligand B (10.94), which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.149 and 0.144).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While Ligand 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 both have issues with Caco-2 and solubility, Ligand B has a significantly lower DILI risk, a longer half-life, and a slightly better binding affinity. Ligand A's higher DILI risk is a major red flag. The slightly better metabolic stability of Ligand A is not enough to compensate for the DILI concern and the shorter half-life.

Output:
1
2025-04-17 11:30:36,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.415 and 356.438 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (117.43) is slightly above the preferred <140 for good absorption but still reasonable. Ligand B (67.87) is excellent, well below 140.

**logP:** Ligand A (0.541) is a bit low, potentially hindering permeation. Ligand B (1.426) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also good.

**QED:** Both ligands have good QED scores (0.767 and 0.809), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 85.576, which is high and concerning. Ligand B has a much lower DILI risk of 40.054, which is good.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (62.854) and Ligand B (78.868) are both reasonable.

**Caco-2 Permeability:** Ligand A (-5.306) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.598) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.376 and -2.018 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.315 and 0.401), which is positive.

**Microsomal Clearance:** Ligand A (41.777) has moderate clearance, while Ligand B (5.876) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (29.625) has a moderate half-life, while Ligand B (1.354) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.05), which is favorable.

**Binding Affinity:** Crucially, both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Conclusion:**

Despite the equal binding affinity, Ligand B is the more promising candidate. While its half-life is very short, its significantly lower DILI risk, better logP, lower TPSA, and *much* better metabolic stability (lower Cl_mic) outweigh the drawbacks of the short half-life and poor solubility. The short half-life could potentially be addressed through prodrug strategies or formulation approaches. The high DILI risk associated with Ligand A is a major red flag that is difficult to overcome.

Output:
1
2025-04-17 11:30:36,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (344.455 and 370.559 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (62.66), both are below the 140 threshold for oral absorption.

**3. logP:** Ligand A (1.9) is optimal, while Ligand B (3.517) is approaching the upper limit.

**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 below the limit of <=10.

**6. QED:** Ligand A (0.793) has a better QED score than Ligand B (0.684), indicating better overall drug-likeness.

**7. DILI:** Ligand A (15.743) has a significantly lower DILI risk than Ligand B (11.128), which is a crucial advantage.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 75.572, Ligand B: 78.48), but this is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.592) is slightly better than Ligand B (-4.528).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.033) is slightly better than Ligand B (-2.681).

**11. hERG Inhibition:** Ligand A (0.151) has a much lower hERG inhibition risk than Ligand B (0.645), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (55.158) has lower microsomal clearance than Ligand B (83.809), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.271) has a longer in vitro half-life than Ligand A (10.305), which is a positive.

**14. P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux than Ligand B (0.175), which is favorable.

**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 is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A demonstrates significantly better safety profiles (lower DILI and hERG risk), better drug-likeness (QED), and improved metabolic stability (lower Cl_mic). The slight improvements in solubility and permeability are also beneficial. The affinity difference is not substantial enough to overcome the ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 11:30:36,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.483 and 372.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (78.52), being well below the 140 threshold for good absorption. Ligand B is higher, potentially impacting absorption.

**logP:** Both ligands have good logP values (3.836 and 3.689), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (3 HBD, 6 HBA) as it has fewer hydrogen bond donors and acceptors, which generally improves permeability.

**QED:** Both ligands have reasonable QED scores (0.837 and 0.718), indicating good drug-like properties.

**DILI:** Ligand A (39.201) has a much lower DILI risk than Ligand B (78.209). This is a significant advantage.

**BBB:**  BBB is less critical for a non-CNS target like SRC kinase. Ligand A (94.494) has a higher BBB percentile than Ligand B (54.13).

**Caco-2 Permeability:** Ligand A (-4.452) has a lower Caco-2 permeability than Ligand B (-5.251), but both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.938) has better aqueous solubility than Ligand B (-4.44).

**hERG:** Both ligands have similar hERG inhibition liability (0.558 and 0.649), which is acceptable.

**Microsomal Clearance:** Ligand A (65.327) has a higher microsomal clearance than Ligand B (47.962), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (20.108 hours) has a significantly longer in vitro half-life than Ligand A (6.991 hours), a major advantage for dosing frequency.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.572 and 0.304).

**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 A excels in properties related to absorption (TPSA, solubility, H-bonds) and safety (DILI). However, it suffers from lower metabolic stability (higher Cl_mic, shorter half-life) and lower Caco-2 permeability. Ligand B has a slightly better binding affinity and significantly better metabolic stability and half-life, but has a higher DILI risk and worse absorption characteristics.

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, hERG), the improved metabolic stability and half-life of Ligand B outweigh the slightly lower solubility and higher DILI risk, especially given the relatively modest difference in binding affinity. The DILI risk for Ligand B is still within an acceptable range.

Output:
1
2025-04-17 11:30:36,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 350.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.3) is better than Ligand B (96.89). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred value.

**logP:** Ligand A (2.461) is optimal (1-3), while Ligand B (0.263) is quite low, potentially hindering permeation. This is a significant drawback for B.

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

**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.

**QED:** Both ligands have similar QED values (0.601 and 0.555), indicating good drug-likeness.

**DILI:** Ligand A (51.338) has a slightly higher DILI risk than Ligand B (34.238), but both are below the concerning threshold of 60.

**BBB:** Ligand A (76.774) has better BBB penetration than Ligand B (36.836). While not a primary concern for a non-CNS target like SRC, it isn't detrimental.

**Caco-2 Permeability:** Ligand A (-4.793) has better Caco-2 permeability than Ligand B (-5.145).

**Aqueous Solubility:** Ligand A (-4.059) has better aqueous solubility than Ligand B (-1.376). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.561) has a slightly higher hERG risk than Ligand B (0.334), but both are relatively low.

**Microsomal Clearance:** Ligand B (15.418) has significantly lower microsomal clearance than Ligand A (31.011), indicating better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand B (12.45) has a slightly longer half-life than Ligand A (14.264).

**P-gp Efflux:** Ligand A (0.104) has lower P-gp efflux than Ligand B (0.064), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.8 kcal/mol), with Ligand B being slightly better. However, the affinity difference is small and likely less important than the ADME differences.

**Conclusion:**

While Ligand B has a slightly better binding affinity and metabolic stability, Ligand A is superior overall. The significantly lower logP of Ligand B is a major concern, potentially leading to poor absorption. Ligand A has better solubility, permeability, and a more balanced profile across most ADME properties. The small difference in affinity is outweighed by the more favorable ADME profile of Ligand A.

Output:
1
2025-04-17 11:30:36,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.284 Da) is slightly higher than Ligand B (356.463 Da), but both are acceptable.

**TPSA:** Ligand A (82.11) is better than Ligand B (99.1). TPSA is good for both, but lower is generally preferred for better absorption.

**logP:** Ligand A (1.91) is optimal, while Ligand B (0.147) is quite low. Low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.795, B: 0.484), suggesting drug-like properties, but A is significantly better.

**DILI:** Ligand A (56.689) has a higher DILI risk than Ligand B (5.777). This is a significant drawback for Ligand A.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (56.805) and Ligand B (44.94) are both relatively low.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.648) is slightly better than Ligand B (-4.99).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.863) is slightly better than Ligand B (-0.368).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.439, B: 0.331), which is good.

**Microsomal Clearance:** Ligand A (-18.534) has significantly lower (better) microsomal clearance than Ligand B (-5.929), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.97) has a much longer half-life than Ligand B (1.822), which is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.028, B: 0.02).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.8 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk, its significantly stronger binding affinity (-9.3 vs -5.8 kcal/mol), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better permeability/solubility make it the more promising candidate. The potency advantage is substantial and likely to be critical for kinase inhibition. While the DILI risk is a concern, it could potentially be mitigated through structural modifications in further optimization.

Output:
1
2025-04-17 11:30:36,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.419 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.56) is well below the 140 threshold for good absorption, while Ligand B (107.53) is still acceptable but less optimal.

**logP:** Ligand A (3.146) is within the optimal 1-3 range. Ligand B (0.161) is significantly below this, potentially hindering permeation.

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

**QED:** Ligand A (0.581) is good, indicating drug-likeness. Ligand B (0.37) is below the 0.5 threshold, suggesting a less desirable drug-like profile.

**DILI:** Ligand A (69.639) has a moderate DILI risk, but is acceptable. Ligand B (25.165) has a very low DILI risk, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.466) is higher than Ligand B (37.379).

**Caco-2 Permeability:** Ligand A (-4.546) is poor, while Ligand B (-5.336) is also poor. Both are negative values, which is concerning.

**Aqueous Solubility:** Ligand A (-4.146) is poor, while Ligand B (-1.767) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.149) has a very low hERG risk, which is excellent. Ligand B (0.062) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (90.724) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (14.702) has a much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.322) has a short in vitro half-life. Ligand B (-10.267) has an even shorter half-life. Both are negative values, which is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.131 and 0.017 respectively).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.7 and -8.3 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other ADME concerns.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower microsomal clearance (better metabolic stability) and lower DILI risk outweigh the slightly lower QED and logP values. While both have poor Caco-2 permeability and solubility, the metabolic stability is a crucial factor for kinase inhibitors, and Ligand B is superior in this regard.

Output:
1
2025-04-17 11:30:36,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Ligand A (464.117 Da) is within the ideal range, while Ligand B (343.383 Da) is towards the lower end but still acceptable.

**TPSA:** Ligand A (71.42) is good for oral absorption. Ligand B (93.45) is approaching the upper limit for good absorption, but not critically high.

**logP:** Ligand A (4.602) is high, potentially causing solubility issues and off-target effects. Ligand B (1.683) is optimal.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Ligand B (0.832) has a significantly better QED score than Ligand A (0.466), indicating a more drug-like profile.

**DILI:** Ligand A (96.82) has a very high DILI risk, a major concern. Ligand B (63.513) has an elevated DILI risk, but significantly lower than Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**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, which is also unusual. This suggests poor solubility.

**hERG Inhibition:** Ligand A (0.898) has a moderate hERG risk. Ligand B (0.032) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand B (-4.202) has a negative clearance, which is not physically possible and likely indicates very high metabolic stability. Ligand A (45.254) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-4.606) has a negative half-life, which is not physically possible and suggests extremely long half-life. Ligand A (63.127) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.867) has moderate P-gp efflux. Ligand B (0.016) has very low P-gp efflux.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly better binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a strong binding affinity, but suffers from high DILI risk, high logP, and moderate hERG risk. Ligand B has a better drug-like profile (QED, hERG, Pgp) and exceptional metabolic stability (negative clearance/half-life, which is likely an artifact of the model), but its binding affinity is very weak.

The difference in binding affinity (-7.6 vs 0.0 kcal/mol) is substantial. While Ligand B has better ADME properties, the lack of potency makes it unlikely to be a viable drug candidate. Ligand A's issues could potentially be addressed through medicinal chemistry optimization, but the high DILI risk is a major hurdle. However, given the importance of potency for kinase inhibitors, and the potential to mitigate the ADME liabilities through further optimization, Ligand A is the more promising starting point.

Output:
1
2025-04-17 11:30:36,440 - INFO - Batch 53 complete. Total preferences: 848
2025-04-17 11:30:36,440 - INFO - Processing batch 54/512...
2025-04-17 11:31:15,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.447 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.67 and 61.88) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.104 and 1.498) are 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.799 and 0.718), indicating drug-like properties.

**DILI:** Ligand A (28.306) has a significantly lower DILI risk than Ligand B (10.198). This is a substantial advantage.

**BBB:** Both ligands have moderate BBB penetration (59.364 and 70.531). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.621 and -4.586), 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 (-1.128 and -0.969), also unusual and indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.161 and 0.344). This is excellent.

**Microsomal Clearance:** Ligand A (20.619 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (55.526 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.792 hours) has a longer half-life than Ligand B (-0.661 hours). The negative value for ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.013).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a 1.3 kcal/mol difference, which is a substantial advantage and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and comparable drug-like properties to Ligand B. While both have poor predicted permeability and solubility, the strong binding affinity of Ligand A makes it more likely to be a viable starting point for optimization, as potency is a key driver in enzyme inhibitor development.

Output:
1
2025-04-17 11:31:15,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.889 Da and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.36) is better than Ligand B (57.69), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (4.725) is slightly high, potentially leading to solubility issues, while Ligand B (2.551) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have low HBD (0) and acceptable HBA (4 and 3 respectively).

**QED:** Both ligands have acceptable QED scores (0.725 and 0.581, both > 0.5).

**DILI:** Ligand A (51.26) has a slightly higher DILI risk than Ligand B (44.009), but both are acceptable (<60).

**BBB:** Both have good BBB penetration, but Ligand B (81.776) is slightly better than Ligand A (76.774). This isn't a primary concern for a kinase inhibitor.

**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 significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.512 and 0.305).

**Microsomal Clearance:** Ligand A (74.325) has higher microsomal clearance than Ligand B (53.092), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-14.829) has a negative half-life, which is not possible and indicates a major issue. Ligand A (31.275) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.317 and 0.329).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.2 and -7.0 kcal/mol). The difference is minimal.

**Conclusion:**

While both compounds have excellent binding affinity, Ligand B appears more promising due to its better logP, lower microsomal clearance, and a more reasonable (though still problematic) half-life. The negative Caco-2 and solubility values are concerning for both, but a negative half-life is a showstopper. Ligand A's higher clearance is also a negative. Therefore, despite the issues, Ligand B is the better candidate for further optimization.

Output:
1
2025-04-17 11:31:15,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.387 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.46) is slightly higher than Ligand B (72.36). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.492 and 1.712), 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 QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (76.386) has a higher DILI risk than Ligand B (39.201). Ligand B is significantly better here, falling well below the 40% threshold.

**BBB:** Ligand A (27.957) has poor BBB penetration, while Ligand B (69.794) is better, although not exceptional. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.072 and -5.013), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.864 and -2.517), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.248) has a lower hERG inhibition risk than Ligand B (0.34), which is preferable.

**Microsomal Clearance:** Ligand A (6.225) has significantly lower microsomal clearance than Ligand B (53.761), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (10.075) has a longer in vitro half-life than Ligand B (0.944), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux than Ligand B (0.181), which is favorable.

**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 factor.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand A is the more promising candidate. Its significantly lower DILI risk, lower microsomal clearance, longer half-life, lower P-gp efflux, and slightly better binding affinity outweigh the slightly higher TPSA and lower BBB penetration. The metabolic stability advantages are particularly important for an enzyme target like SRC kinase. The solubility issues would need to be addressed through formulation strategies.

Output:
0
2025-04-17 11:31:15,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.433 and 364.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is slightly higher than Ligand B (60.25). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better positioned.

**3. logP:** Both ligands have good logP values (1.418 and 2.119), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as having some HBDs can improve solubility.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (7). Higher HBA can sometimes negatively impact permeability.

**6. QED:** Both ligands have acceptable QED values (0.649 and 0.578), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (11.361) has a significantly lower DILI risk than Ligand B (63.203). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (65.878) has a lower BBB penetration than Ligand B (82.319). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.823) has worse Caco-2 permeability than Ligand B (-4.493).

**10. Aqueous Solubility:** Ligand A (-1.356) has better aqueous solubility than Ligand B (-2.954). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.489 and 0.442).

**12. Microsomal Clearance:** Ligand A (24.631) has significantly lower microsomal clearance than Ligand B (79.667), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-6.011) has a much longer in vitro half-life than Ligand B (-29.882). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.234).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a 1.8 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity. However, Ligand A demonstrates significantly better ADMET properties, particularly in terms of DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and solubility. The difference in binding affinity, while significant, can potentially be overcome with further optimization of Ligand A. The lower DILI and improved metabolic stability of Ligand A are crucial for developing a safe and effective drug. Given the enzyme-specific priorities, the improved ADMET profile of Ligand A outweighs the binding affinity advantage of Ligand B.

Output:
0
2025-04-17 11:31:15,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (424.339 Da) is higher than Ligand B (338.451 Da), but both are acceptable.

**TPSA:** Ligand A (46.92) is significantly better than Ligand B (61.36). Lower TPSA generally favors better absorption, which is important for oral bioavailability.

**logP:** Both ligands have acceptable logP values (A: 4.136, B: 3.249), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=2) as it has fewer HBDs, which can sometimes hinder permeability.

**QED:** Both ligands have similar QED values (A: 0.647, B: 0.615), indicating good drug-likeness.

**DILI:** Ligand A (55.487) has a higher DILI risk than Ligand B (35.169). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (88.91) has a higher BBB percentile than Ligand B (57.619).

**Caco-2 Permeability:** Ligand A (-5.3) has a much worse Caco-2 permeability than Ligand B (-4.648). Lower values indicate poorer permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.03, B: -3.645). Solubility is a concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.916, B: 0.843), which is good.

**Microsomal Clearance:** Ligand A (82.477) has a higher microsomal clearance than Ligand B (43.19). This suggests Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (17.723) has a longer in vitro half-life than Ligand A (61.066). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.947, B: 0.533). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 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 solubility issues, Ligand B excels in key areas for an enzyme inhibitor: significantly better binding affinity, lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and better Caco-2 permeability. The slightly better logP and P-gp efflux also contribute to its favorability. Ligand A's higher DILI risk and poorer permeability are major drawbacks.

Output:
1
2025-04-17 11:31:15,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.411 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.09) is better than Ligand B (54.46) as it is closer to the threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.03 and 3.229), 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 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.851 and 0.806), indicating good drug-likeness.

**DILI:** Ligand A (53.548) has a significantly lower DILI risk than Ligand B (19.426), which is a major advantage.

**BBB:** Ligand B (78.519) has a better BBB penetration than Ligand A (64.133), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.871 and -4.811), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.692 and -3.42), indicating very poor aqueous solubility, which is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.571 and 0.751), which is good.

**Microsomal Clearance:** Ligand A (15.764) has a much lower microsomal clearance than Ligand B (70.604), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-15.501) has a negative half-life, which is not possible. Ligand B (4.046) has a short half-life. Both are concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.091 and 0.218), which is favorable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is not substantial enough to outweigh the other significant drawbacks of Ligand B.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. Ligand A has a significantly lower DILI risk and much better metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the lower DILI and better metabolic stability of Ligand A are more critical for an enzyme inhibitor. The negative half-life for Ligand A is a data error, but the other properties make it the better choice.

Output:
0
2025-04-17 11:31:15,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (362.813 Da and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is significantly better than Ligand B (122.55). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the upper limit.

**logP:** Ligand A (2.302) is optimal (1-3). Ligand B (0.181) is quite low, potentially hindering permeability.

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

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

**QED:** Ligand A (0.595) is better than Ligand B (0.442), indicating a more drug-like profile.

**DILI:** Ligand A (64.754) has a higher DILI risk than Ligand B (31.33). This is a negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (96.161) has a better BBB score than Ligand B (78.519).

**Caco-2 Permeability:** Ligand A (-4.711) is significantly worse than Ligand B (-5.286), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.91) is slightly better than Ligand B (-2.573), but both are poor.

**hERG Inhibition:** Ligand A (0.258) is much better than Ligand B (0.076), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (55.767) has higher clearance than Ligand B (30.313), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-14.048) has a negative half-life, which is very bad. Ligand B (7.808) is acceptable.

**P-gp Efflux:** Ligand A (0.17) is better than Ligand B (0.019), indicating less efflux.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly better binding affinity than Ligand B (-7.8 kcal/mol). The 1.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better physicochemical properties (TPSA, logP, HBD, QED, hERG, P-gp) despite having a higher DILI risk and worse Caco-2 permeability. The significantly improved potency and metabolic stability of Ligand B are attractive, but the poor logP and overall lower affinity are concerning. The negative half-life for Ligand A is a significant drawback. However, the substantial binding affinity advantage of Ligand A is likely to be more important for an enzyme target like SRC kinase.

Output:
0
2025-04-17 11:31:15,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.825 Da and 364.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.41) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (93.01) is well within the acceptable range.

**logP:** Both ligands have good logP values (0.907 and 1.311), falling within the 1-3 optimal 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 (0.613 and 0.762), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (52.152 and 54.207), both falling in the acceptable range (<60).

**BBB:** Ligand A (71.268) has a better BBB percentile than Ligand B (55.176), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.458 and -5.336). This 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 (-3.261 and -1.486), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.523) has a slightly higher hERG risk than Ligand B (0.177), which is preferable.

**Microsomal Clearance:** Ligand A (-9.476) has significantly *lower* (better) microsomal clearance than Ligand B (48.854). This indicates better metabolic stability, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-20.936) has a much longer in vitro half-life than Ligand B (28.734), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.066).

**Binding Affinity:** Ligand A (-9.3 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.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.3 vs -6.5 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher hERG risk and similar DILI risk. The binding affinity difference is substantial and would likely translate to greater efficacy *in vivo*. Addressing the solubility issues through formulation strategies would be a priority in further development.

Output:
0
2025-04-17 11:31:15,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.418 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is well below the 140 threshold for good absorption and is favorable. Ligand B (103.79) is still within range, but less optimal.

**logP:** Ligand A (2.335) is within the optimal 1-3 range. Ligand B (0.444) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is excellent. Ligand B (HBD=3, HBA=7) is acceptable but slightly higher, potentially impacting permeability.

**QED:** Both ligands have acceptable QED values (0.887 and 0.713, both > 0.5).

**DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (71.694). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (88.057) shows better penetration than Ligand B (36.487).

**Caco-2 Permeability:** Ligand A (-4.47) is better than Ligand B (-5.146), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-1.879 and -1.851). This could pose formulation challenges for both.

**hERG Inhibition:** Ligand A (0.634) has a lower hERG risk than Ligand B (0.224), which is a significant advantage.

**Microsomal Clearance:** Ligand A (41.786) has higher microsomal clearance than Ligand B (-13.794), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (17.557) has a much longer in vitro half-life than Ligand A (1.431), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.021), which is favorable.

**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 noteworthy.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, lower hERG) and better permeability (Caco-2, Pgp). Its binding affinity is slightly better. However, Ligand B has a much longer half-life and better metabolic stability (lower Cl_mic). Considering the priorities for enzyme inhibitors, the improved safety and permeability of Ligand A, coupled with its slightly better affinity, outweigh the metabolic stability concerns. The metabolic stability of Ligand A could potentially be addressed through structural modifications in later optimization stages.

Output:
1
2025-04-17 11:31:15,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (350.503 and 384.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is well below the 140 threshold and excellent for oral absorption. Ligand B (92.26) is still acceptable, but less optimal.

**3. logP:** Both ligands have good logP values (2.759 and 1.584), 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 HBAs, and Ligand B has 6 HBAs, both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.685 and 0.752), indicating good drug-likeness.

**7. DILI:** Ligand A (17.255) has a lower DILI risk than Ligand B (56.883). This is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (75.921 and 73.401). This isn't a primary concern for a kinase inhibitor, but it's not detrimental.

**9. Caco-2 Permeability:** Ligand A (-4.37) has worse Caco-2 permeability than Ligand B (-5.055), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.798) has worse solubility than Ligand B (-3.63). Solubility is important for kinases.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.445 and 0.242).

**12. Microsomal Clearance (Cl_mic):** Ligand A (76.671) has higher microsomal clearance than Ligand B (66.441), suggesting lower metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (-38.786) has a significantly longer half-life than Ligand A (3.863). This is a crucial advantage for kinases.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.119 and 0.229).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While both ligands have excellent affinity and low hERG risk, Ligand B demonstrates superior metabolic stability (longer half-life) and better solubility, despite slightly worse TPSA. The lower DILI risk for Ligand A is a positive, but the substantial improvement in half-life for Ligand B outweighs this benefit. The Caco-2 permeability is less important than metabolic stability for a kinase inhibitor.

Output:
1
2025-04-17 11:31:15,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.447 and 359.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is excellent, well below the 140 threshold for oral absorption. Ligand B (29.54) is also very good.

**logP:** Ligand A (-0.016) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (4.666) is above the optimal range, raising concerns about solubility and off-target effects.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, within the limit of 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.682 and 0.663), indicating good drug-like properties.

**DILI:** Ligand A (22.024) has a much lower DILI risk than Ligand B (32.299), which is a significant advantage. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (61.38) shows higher BBB penetration than Ligand A (29.275).

**Caco-2 Permeability:** Ligand A (-4.698) has a negative Caco-2 value, which is concerning. Ligand B (-5.093) is also negative, but similar.

**Aqueous Solubility:** Ligand A (-0.959) has slightly better solubility than Ligand B (-4.867).

**hERG Inhibition:** Ligand A (0.121) has a significantly lower hERG risk than Ligand B (0.689), which is a crucial safety consideration.

**Microsomal Clearance:** Ligand A (10.175) has a much lower microsomal clearance than Ligand B (114.106), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.722) has a much longer in vitro half-life than Ligand B (-5.326), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.009) has a very low P-gp efflux liability, while Ligand B (0.7) is higher.

**Binding Affinity:** Ligand B (-9.5 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. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding metabolic stability (Cl_mic, t1/2), DILI risk, and hERG inhibition. Ligand B's high logP and clearance are significant concerns. The substantial difference in binding affinity (-9.5 vs -6.9 kcal/mol) is a strong point for Ligand B. However, given the enzyme target class, metabolic stability and safety (DILI, hERG) are paramount. The significantly better ADME properties of Ligand A, combined with a reasonable binding affinity, make it the more promising candidate.

Output:
0
2025-04-17 11:31:15,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.43) is better than Ligand B (84.86), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (1.718) is optimal, while Ligand B (0.669) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is favorable. Ligand B (0 HBD, 6 HBA) is also acceptable, though the lack of HBDs might slightly hinder solubility.

**QED:** Both ligands have reasonable QED scores (0.872 and 0.703), indicating good drug-like properties.

**DILI:** Ligand A (28.306) has a significantly lower DILI risk than Ligand B (63.629). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (71.85 and 72.354), which is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.818) is slightly better than Ligand B (-4.344), suggesting slightly better absorption.

**Aqueous Solubility:** Ligand A (-2.969) is better than Ligand B (-0.967), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.431) has a lower hERG risk than Ligand B (0.087), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (34.664) has a slightly lower microsomal clearance, suggesting better metabolic stability than Ligand A (35.555). However, the difference is minimal.

**In vitro Half-Life:** Ligand B (-26.475) has a significantly longer in vitro half-life than Ligand A (-10.142), which is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.103 and 0.011), indicating minimal efflux issues.

**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 advantages of Ligand A.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. It has a significantly lower DILI risk and hERG inhibition liability, better solubility, and a slightly better Caco-2 permeability. While Ligand B has a longer half-life, the safety and ADME advantages of Ligand A are more critical for an enzyme inhibitor. The affinity difference is minor.

Output:
1
2025-04-17 11:31:15,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.845 Da and 351.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.02) is better than Ligand B (73.89), both are acceptable, but lower TPSA generally favors absorption.

**logP:** Both ligands have good logP values (2.781 and 1.366, respectively), 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=0, HBA=8). Both are within acceptable limits, but fewer H-bonds can improve permeability.

**QED:** Both ligands have similar, good QED scores (0.749 and 0.75).

**DILI:** Ligand A (58.627) has a slightly higher DILI risk than Ligand B (47.421), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (83.482 and 89.531), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**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 (0.573 and 0.344).

**Microsomal Clearance:** Ligand B (18.183 mL/min/kg) has significantly lower microsomal clearance than Ligand A (30.717 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (8.797 hours) has a much longer half-life than Ligand A (61.197 hours - this seems like an error and should be 6.197 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.241 and 0.188).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). The 0.8 kcal/mol difference is substantial and outweighs minor ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand B is the more promising candidate. Its superior binding affinity, significantly better metabolic stability (lower Cl_mic), and longer half-life are crucial for an enzyme inhibitor. While Ligand A has a slightly better TPSA and logP, the potency and pharmacokinetic advantages of Ligand B are more important.

Output:
1
2025-04-17 11:31:15,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (337.383 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.19) is better than Ligand B (97.11). Both are below 140, but A is closer to the desirable threshold for good absorption.

**3. logP:** Both ligands have good logP values (2.735 and 2.384), 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). Both are within the acceptable range.

**6. QED:** Ligand A (0.75) has a better QED score than Ligand B (0.598), indicating a more drug-like profile.

**7. DILI:** Ligand A (75.339) has a significantly higher DILI risk than Ligand B (41.76). This is a major concern for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (64.948 and 68.166). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.953) is better than Ligand B (-5.18). Both are negative, indicating poor permeability, but A is slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.287 and -3.208). This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.356) has a lower hERG inhibition liability than Ligand B (0.673), which is favorable.

**12. Microsomal Clearance:** Ligand A (29.688) has a lower microsomal clearance than Ligand B (44.852), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (32.979) has a longer in vitro half-life than Ligand B (5.162), which is desirable.

**14. P-gp Efflux:** Ligand A (0.029) has a lower P-gp efflux liability than Ligand B (0.033), which is favorable.

**15. Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-9.1). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has better properties in terms of TPSA, H-bond donors/acceptors, QED, metabolic stability, half-life, and P-gp efflux, the significantly higher DILI risk is a major red flag. Ligand B, despite having poorer ADME properties overall, boasts a substantially stronger binding affinity (-7.8 vs -9.1 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. The improved binding affinity of Ligand B is likely to outweigh its ADME liabilities, especially if further optimization can address the solubility and permeability issues.

Output:
1
2025-04-17 11:31:15,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.52) is better than Ligand B (116.42). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal for oral bioavailability.

**logP:** Ligand A (1.256) is within the optimal 1-3 range. Ligand B (0.207) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable, being less than 10.

**QED:** Ligand A (0.819) is significantly better than Ligand B (0.619), indicating a more drug-like profile.

**DILI:** Ligand B (76.503) has a higher DILI risk than Ligand A (57.425), although both are above the ideal <40.

**BBB:** Ligand A (78.868) has a better BBB penetration percentile than Ligand B (39.511). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2:** Ligand A (-4.996) shows better Caco-2 permeability than Ligand B (-5.631), suggesting better intestinal absorption.

**Solubility:** Ligand A (-1.586) has better aqueous solubility than Ligand B (-2.782). Solubility is crucial for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.521 and 0.105 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (2.483) has significantly lower microsomal clearance than Ligand B (23.909), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-3.302) has a much longer in vitro half-life than Ligand B (16.552).

**P-gp:** Both ligands have very low P-gp efflux liability (0.01 and 0.014 respectively), which is good.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is only 0.7 kcal/mol, and the other advantages of Ligand A likely outweigh this.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, including higher QED, lower DILI risk, better solubility, and *much* better metabolic stability (lower Cl_mic and longer t1/2). These factors are critical for a successful enzyme inhibitor drug candidate.

Output:
1
2025-04-17 11:31:15,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.424 and 376.875 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.33) is slightly higher than Ligand B (43.78), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (4.22) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.334) is 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.

**QED:** Ligand A (0.766) has a better QED score than Ligand B (0.693), indicating a more drug-like profile.

**DILI:** Ligand B (8.569) has a significantly lower DILI risk than Ligand A (46.297), which is a major advantage.

**BBB:** Ligand B (83.404) has a higher BBB penetration potential than Ligand A (57.619), though this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.026) has worse Caco-2 permeability than Ligand B (-4.488), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand B (-2.293) has better aqueous solubility than Ligand A (-4.173).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.737 and 0.723 respectively).

**Microsomal Clearance:** Ligand B (8.668) has significantly lower microsomal clearance than Ligand A (69.735), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (25.253) has a longer in vitro half-life than Ligand A (19.648).

**P-gp Efflux:** Ligand A (0.774) has slightly higher P-gp efflux than Ligand B (0.154), which could reduce bioavailability.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a substantially better binding affinity than Ligand B (-7.3 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks. The difference of 2.3 kcal/mol is substantial.

**Conclusion:**

Despite Ligand A's superior binding affinity, Ligand B presents a much more favorable ADME profile, particularly regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and solubility. While the affinity difference is significant, the improved drug-like properties of Ligand B make it a more promising starting point for further optimization. The high affinity of A could be difficult to maintain while addressing its ADME liabilities.

Output:
1
2025-04-17 11:31:15,601 - INFO - Batch 54 complete. Total preferences: 864
2025-04-17 11:31:15,601 - INFO - Processing batch 55/512...
2025-04-17 11:32:05,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.36 Da) is slightly higher than Ligand B (366.483 Da), but both are acceptable.

**TPSA:** Ligand A (76.14) is better than Ligand B (86.71). Both are below 140, suggesting reasonable absorption, but lower is generally preferred.

**logP:** Ligand A (4.351) is higher than Ligand B (0.707). Ligand A is pushing the upper limit, potentially leading to solubility issues, while Ligand B is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.768, B: 0.801), indicating good drug-like properties.

**DILI:** Ligand A (37.728) has a lower DILI risk than Ligand B (9.616), which is a significant advantage.

**BBB:** Ligand A (86.002) has a better BBB percentile than Ligand B (54.478). While not a primary concern for a kinase inhibitor, it's a slight positive for A.

**Caco-2 Permeability:** Ligand A (-4.67) has a much worse Caco-2 permeability than Ligand B (-5.383). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-4.385) has worse solubility than Ligand B (-1.675). Solubility is a key factor for kinases, and B is significantly better.

**hERG Inhibition:** Ligand A (0.426) has a lower hERG risk than Ligand B (0.28), which is a positive.

**Microsomal Clearance:** Ligand A (72.735) has a higher microsomal clearance than Ligand B (-9.849). This means Ligand B is more metabolically stable, a crucial factor for kinases.

**In vitro Half-Life:** Ligand A (31.706) has a longer half-life than Ligand B (6.539), which is a positive.

**P-gp Efflux:** Ligand A (0.148) has lower P-gp efflux than Ligand B (0.056), which is a positive.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly better binding affinity than Ligand A (-7.1 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 Ligand A has better DILI and BBB, Ligand B's superior binding affinity (-8.9 vs -7.1 kcal/mol) and metabolic stability (negative Cl_mic) are critical for a kinase inhibitor. The better solubility of Ligand B is also a significant advantage. The slightly lower logP of Ligand B is a minor drawback, but the strong affinity and metabolic stability are more important.

Output:
1
2025-04-17 11:32:05,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (365.5 and 352.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.74) is better than Ligand B (118.55).  A TPSA under 140 is good for oral absorption, both are, but A is significantly better.

**3. logP:** Ligand A (2.067) is optimal (1-3). Ligand B (0.127) is quite low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) 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 (0.89) is excellent, indicating high drug-likeness. Ligand B (0.6) is still acceptable, but less optimal.

**7. DILI:** Both ligands have low DILI risk (38.08 and 36.60, respectively), both are good.

**8. BBB:** This is less critical for an oncology target, but Ligand A (50.68) is better than Ligand B (36.76).

**9. Caco-2 Permeability:** Ligand A (-4.909) is better than Ligand B (-5.39), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.043) is better than Ligand B (-1.875). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.469 and 0.289, respectively).

**12. Microsomal Clearance:** Ligand B (-25.446) has significantly lower (better) microsomal clearance than Ligand A (26.563), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (14.128) has a longer half-life than Ligand B (1.365). This is desirable for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.35) has lower P-gp efflux than Ligand B (0.045), which is preferable.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic). However, it suffers from a low logP, which could limit permeability. Ligand A has better overall ADME properties (TPSA, logP, solubility, half-life, P-gp efflux) and good binding affinity. The difference in binding affinity (-9.6 vs -8.8) is 0.8 kcal/mol, which is a good advantage, but the ADME profile of Ligand A is more balanced and favorable for oral bioavailability and metabolic stability. Given the enzyme target class, metabolic stability and a good ADME profile are crucial.

Output:
1
2025-04-17 11:32:05,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (364.324 Da and 362.499 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.55) is higher than Ligand B (65.54). While both are below 140, the lower TPSA of Ligand B is preferable for better absorption.

**3. logP:** Ligand A (0.759) is slightly lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (1.881) is within the optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.775 and 0.892, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI Risk:** Ligand A (56.34) has a slightly higher DILI risk than Ligand B (48.895), but both are below the concerning threshold of 60.

**8. BBB Penetration:** This isn't a primary concern for a non-CNS target like SRC kinase. Ligand A (76.037) is slightly higher than Ligand B (69.407).

**9. Caco-2 Permeability:** Ligand A (-4.437) has worse Caco-2 permeability than Ligand B (-5.019). Lower values are less favorable.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-2.543 and -2.811). This is a significant drawback for both, but needs to be balanced against other properties.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.172 and 0.442, respectively).

**12. Microsomal Clearance:** Ligand B (22.834) has significantly lower microsomal clearance than Ligand A (37.357), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (35.906) has a longer in vitro half-life than Ligand A (-23.536). This is also a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.117 and 0.108, respectively).

**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:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While both have poor solubility, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), a slightly better logP, and a lower DILI risk. The binding affinities are essentially the same, so the ADME properties become the deciding factors.

Output:
1
2025-04-17 11:32:05,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.354 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.19) is slightly higher than Ligand B (67.43), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.941) is at the upper end of the optimal range (1-3), while Ligand B (2.924) is well within it. Ligand A's higher logP *could* lead to off-target effects, but isn't a dealbreaker.

**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 reasonable QED scores (0.808 and 0.707), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (87.049%) compared to Ligand B (25.242%). This is a major concern for Ligand A.

**BBB:** Ligand A (48.042%) has a lower BBB penetration than Ligand B (74.796%). While not critical for a non-CNS target like SRC, higher BBB is generally preferable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.384 and -4.534), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-6.079 and -3.31), indicating very poor aqueous solubility. This is a major issue for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.592) has a slightly higher hERG risk than Ligand B (0.314), but both are relatively low.

**Microsomal Clearance:** Ligand A (58.887) has a higher microsomal clearance than Ligand B (32.379). This means Ligand A is likely to be metabolized more quickly, leading to a shorter duration of action.

**In vitro Half-Life:** Ligand A (57.555) has a longer half-life than Ligand B (18.556). However, this advantage is overshadowed by the higher clearance.

**P-gp Efflux:** Ligand A (0.571) has a lower P-gp efflux liability than Ligand B (0.061). Lower efflux is generally better.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). While both are excellent, the difference is important.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. The primary reason is the dramatically lower DILI risk (25.242% vs 87.049%). While both compounds have poor solubility and permeability, the lower DILI risk and better metabolic stability (lower Cl_mic, longer half-life) of Ligand B make it a more viable starting point for optimization. The slightly better BBB penetration is a minor additional benefit.

Output:
1
2025-04-17 11:32:05,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.387 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.35 and 98.74) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (0.655 and 0.561) are a bit low, potentially hindering permeation, but not drastically.

**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.

**QED:** Both ligands have good QED scores (0.83 and 0.623), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 40.946, which is good (below 40 is preferred). Ligand B has a significantly higher DILI risk of 14.114, which is still acceptable but less desirable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (40.403) and Ligand B (28.189) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.474 and -5.291), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.617 and -1.153), also unusual and indicating poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.07 and 0.079), which is excellent.

**Microsomal Clearance:** Ligand A has a slightly better (less negative) microsomal clearance (-2.155 mL/min/kg) than Ligand B (-6.167 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (-12.517 hours) than Ligand B (3.822 hours), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.026 and 0.011).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-7.3 kcal/mol) than Ligand A (-7.1 kcal/mol). While the difference is small (0.2 kcal/mol), 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, Ligand A has a better DILI score, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a slightly lower hERG risk. The slightly better binding affinity of Ligand B is not enough to overcome these ADME deficiencies. Given the enzyme-specific priorities, metabolic stability is crucial, and Ligand A demonstrates a clear advantage in this area.

Output:
0
2025-04-17 11:32:05,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.53) is slightly higher than Ligand B (59.08), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (1.782 and 1.677), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable range (<=10).

**QED:** Ligand A (0.903) has a significantly higher QED score than Ligand B (0.633), indicating better overall drug-likeness.

**DILI:** Ligand B (15.898) has a much lower DILI risk than Ligand A (37.999), which is a significant advantage.

**BBB:** Ligand B (77.782) has a higher BBB penetration score than Ligand A (58.627), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.551 and -4.523), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.373 and -1.221), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.267) has a slightly lower hERG inhibition liability than Ligand B (0.404), which is preferable.

**Microsomal Clearance:** Ligand B (27.554) has a lower microsomal clearance than Ligand A (31.396), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (12.733 hours) has a significantly longer in vitro half-life than Ligand A (-5.948 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.053) has a lower P-gp efflux liability than Ligand B (0.161), which is preferable.

**Binding Affinity:** Ligand A (-10.7 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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A's significantly superior binding affinity (-10.7 vs -8.7 kcal/mol) is a major driver. The difference of 2 kcal/mol is substantial and likely to be critical for efficacy. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, the potency advantage of Ligand A is more important for an enzyme target like SRC kinase. The slightly better hERG profile of Ligand A is also a plus. The solubility/permeability issues would need to be addressed through formulation or further structural modifications, but starting with the more potent compound is the better strategy.

Output:
1
2025-04-17 11:32:05,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.5 and 344.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.53 and 69.64) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (1.998 and 1.801) 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, although both are acceptable.

**QED:** Ligand A (0.802) has a significantly higher QED score than Ligand B (0.454), indicating a more drug-like profile.

**DILI:** Ligand A (37.999) has a much lower DILI risk than Ligand B (14.696), which is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration (63.629 and 58.86), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.195 and -5.091) which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.216 and -2.257) which is also unusual and suggests poor solubility. This is a concern for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.158 and 0.166), which is excellent.

**Microsomal Clearance:** Ligand A (12.451) has a much lower microsomal clearance than Ligand B (39.77), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.404) has a longer in vitro half-life than Ligand B (-31.12), though the negative value for B is concerning and likely an artifact or error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.091).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.8 kcal/mol). The difference is minimal.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is significantly more promising. It has a much better QED score, lower DILI risk, and significantly better metabolic stability (lower Cl_mic and longer t1/2). While both have issues with Caco-2 and solubility, the superior ADME profile of Ligand A outweighs the slightly better binding affinity of Ligand B.

Output:
1
2025-04-17 11:32:05,755 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.511 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (82.43) is still under 140, but less optimal than A.

**logP:** Ligand A (3.951) is at the upper end of the optimal range (1-3), while Ligand B (1.885) is at the lower end. While both are acceptable, higher logP can sometimes lead to off-target effects, but is less of a concern than poor solubility.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4-5 HBA, which are within the acceptable limits.

**QED:** Both ligands have similar QED values (0.896 and 0.885), indicating good drug-likeness.

**DILI:** Ligand A (38.697) has a lower DILI risk than Ligand B (54.556), which is a significant advantage.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (74.796) has a slightly higher BBB percentile than Ligand B (64.87).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is more important, and A (-4.703) is slightly better than B (-4.617).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. A (-3.084) is slightly better than B (-3.172).

**hERG:** Ligand A (0.789) has a slightly better hERG profile than Ligand B (0.568), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (36.802) has a lower microsomal clearance than Ligand A (43.498), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (6.525) has a significantly longer half-life than Ligand A (17.845). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.586) has lower P-gp efflux than Ligand B (0.147), which is better for bioavailability.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic and longer t1/2). These are critical for an enzyme inhibitor. While Ligand A has slightly better TPSA, solubility, and lower DILI, the potency and metabolic stability advantages of Ligand B are more important. The slightly lower P-gp efflux of Ligand A is a minor benefit, but doesn't outweigh the other factors.

Output:
1
2025-04-17 11:32:05,755 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [347.419, 86.28, 2.889, 0, 7, 0.845, 60.682, 92.4, -4.151, -3.98, 0.174, 57.951, -21.214, 0.179, -9.1]
**Ligand B:** [369.487, 91.76, 0.826, 2, 6, 0.708, 37.03, 31.912, -5.007, -1.297, 0.096, 3.031, 8.158, 0.043, 0]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (347.419) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** Both are acceptable (<=140), A (86.28) is better than B (91.76) for oral absorption.
3. **logP:** A (2.889) is optimal. B (0.826) is a bit low and might hinder permeation.
4. **HBD:** A (0) is excellent. B (2) is acceptable.
5. **HBA:** A (7) is good. B (6) is also good.
6. **QED:** A (0.845) is excellent, indicating high drug-likeness. B (0.708) is still good, but less so.
7. **DILI:** A (60.682) is moderately risky. B (37.03) is much better, indicating a lower risk of liver injury. This is a significant advantage for B.
8. **BBB:** A (92.4) is excellent, suggesting good brain penetration. B (31.912) is poor. However, SRC is not a CNS target, so this is less critical.
9. **Caco-2:** A (-4.151) is very poor. B (-5.007) is also poor. Both have issues with intestinal absorption.
10. **Solubility:** A (-3.98) is poor. B (-1.297) is also poor, but better than A. Solubility is important for enzymes.
11. **hERG:** A (0.174) is very low risk. B (0.096) is even lower, a slight advantage for B.
12. **Cl_mic:** A (57.951) is moderate. B (3.031) is *very* low, indicating excellent metabolic stability. This is a major advantage for B, crucial for an enzyme target.
13. **t1/2:** A (-21.214) is very short, suggesting rapid clearance. B (8.158) is better, but still not ideal.
14. **Pgp:** A (0.179) is low efflux, good. B (0.043) is even lower, excellent.
15. **Affinity:** A (-9.1) is *significantly* better than B (0). A has a much stronger binding affinity. This is the most important factor for an enzyme target.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A wins decisively.
*   **Metabolic Stability:** B wins decisively (much lower Cl_mic).
*   **Solubility:** B is slightly better.
*   **hERG:** B is slightly better.
*   **DILI:** B is significantly better.

**Conclusion:**

While Ligand B has superior ADME properties (especially metabolic stability and lower DILI risk), the *massive* difference in binding affinity (-9.1 kcal/mol vs. 0 kcal/mol) for Ligand A is a game-changer. A >1.5 kcal/mol advantage is considered significant, and here we have a 9.1 kcal/mol difference. This suggests A is far more likely to be potent enough to be effective, even if its ADME properties require further optimization. The poor Caco-2 and solubility of A are concerning, but can be addressed with formulation strategies or further chemical modifications. The metabolic stability of B is excellent, but without sufficient potency, it won't be effective.

Therefore, I recommend prioritizing **Ligand A**.

1
2025-04-17 11:32:05,755 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.451 and 345.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (109.61 and 110.75) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Both ligands (2.076 and 1.951) are within the optimal 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 adhering to the <5 HBD and <10 HBA guidelines.

**QED:** Ligand B (0.568) has a slightly better QED score than Ligand A (0.43), indicating a more drug-like profile.

**DILI:** Ligand A (20.589) has a significantly lower DILI risk than Ligand B (55.758). This is a major advantage for Ligand A.

**BBB:** Ligand B (89.298) has a higher BBB penetration percentile than Ligand A (22.257). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand B (-5.438) has better Caco-2 permeability than Ligand A (-4.858), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.184) has better aqueous solubility than Ligand B (-2.809). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.178) has a much lower hERG inhibition liability than Ligand B (0.745). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (18.578 mL/min/kg) has significantly lower microsomal clearance than Ligand B (66.013 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (15.725 and 15.099 hours).

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.259), which is favorable for bioavailability.

**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, potentially outweighing some of the ADME drawbacks of Ligand B. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI, significantly lower hERG inhibition) and better metabolic stability (lower Cl_mic). The improved solubility and P-gp efflux also contribute to better potential bioavailability. Given the enzyme-specific priorities, the improved safety and metabolic properties of Ligand A, combined with a still-respectable binding affinity, make it the more viable drug candidate.

Output:
0
2025-04-17 11:32:05,755 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.849 and 348.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.55) is better than Ligand B (104.53), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.447) is optimal (1-3), while Ligand B (0.771) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=3) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (0.783 and 0.685), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (47.77 and 49.864), both are good (low risk).

**BBB:** Both ligands have good BBB penetration (70.609 and 75.533), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.842) is better than Ligand B (-5.234), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.024) is better than Ligand B (-2.428), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.318 and 0.127).

**Microsomal Clearance:** Ligand A (13.274) has a significantly lower (better) microsomal clearance compared to Ligand B (-14.878). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-7.704) has a significantly longer half-life than Ligand B (3.147). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.013).

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Conclusion:**

While both ligands exhibit excellent binding affinity and acceptable safety profiles, Ligand A is superior due to its better logP, Caco-2 permeability, aqueous solubility, significantly lower microsomal clearance, and longer half-life. These factors are crucial for enzyme inhibitors, ensuring good bioavailability, metabolic stability, and potentially less frequent dosing.

Output:
1
2025-04-17 11:32:05,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.527 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.23) is well below the 140 threshold, while Ligand B (93.46) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.756) is at the upper end of the optimal range (1-3), while Ligand B (1.294) is slightly below. Ligand B's lower logP *could* indicate potential permeability issues.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, both within acceptable limits. Ligand B has 2 HBD and 5 HBA, also acceptable, but slightly higher HBA could affect permeability.

**QED:** Both ligands have similar QED values (0.659 and 0.621), indicating good drug-likeness.

**DILI:** Ligand A (38.309) has a slightly higher DILI risk than Ligand B (14.541). This is a point in favor of Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.347) has a better BBB score than Ligand B (51.609), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.8 and -4.796), 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 (-4.513 and -1.983), indicating poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.562) has a slightly higher hERG risk than Ligand B (0.071). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (69.414) has a higher microsomal clearance than Ligand B (27.208), indicating lower metabolic stability. This is a clear advantage for Ligand B.

**In vitro Half-Life:** Ligand A (38.605) has a longer half-life than Ligand B (-3.052). This is a benefit for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.106 and 0.007), which is favorable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. However, it has a higher DILI risk, higher microsomal clearance (lower metabolic stability), and a slightly higher hERG risk. Ligand B has better ADME properties (lower DILI, lower clearance, lower hERG), but its binding affinity is considerably weaker.

Given the importance of potency for enzyme inhibition, the 1.2 kcal/mol advantage of Ligand A is likely to be decisive. While the ADME properties of Ligand A are not ideal, they are not catastrophic, and further optimization could address these issues. The weaker binding of Ligand B would likely necessitate a much higher dose to achieve therapeutic effect, potentially exacerbating any ADME-related toxicity.

Output:
1
2025-04-17 11:32:05,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (384.707 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (34.15) is excellent, well below the 140 threshold for oral absorption. Ligand B (58.64) is still reasonable, but higher.

**logP:** Ligand A (4.784) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.431) is optimal.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.728 and 0.687), indicating drug-likeness.

**DILI:** Ligand A (53.548) has a moderate DILI risk, while Ligand B (9.926) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration (79.488 and 82.396), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.564 and -4.818), which is unusual and suggests poor permeability. This is a potential concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.94 and -2.545), indicating poor aqueous solubility. This is a significant drawback for both, but less severe for Ligand B.

**hERG Inhibition:** Ligand A (0.796) has a slightly elevated hERG risk, while Ligand B (0.312) is very low. This favors Ligand B.

**Microsomal Clearance:** Ligand A (43.342) has a higher clearance than Ligand B (26.772), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (23.075) has a longer half-life than Ligand B (-0.524). This favors Ligand A.

**P-gp Efflux:** Ligand A (0.553) has lower P-gp efflux than Ligand B (0.058), which is preferable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While A is stronger, the difference is not substantial enough to overcome the ADME issues.

**Overall:**

Ligand B demonstrates a superior ADME profile, with lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), and a more optimal logP. While Ligand A has a slightly better binding affinity and half-life, the ADME liabilities of Ligand A, particularly the higher DILI and hERG risk, are concerning. The slightly better binding affinity of Ligand A is not enough to overcome these significant drawbacks.

Output:
1
2025-04-17 11:32:05,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.43 and 345.40 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is better than Ligand B (72.91), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**3. logP:** Both ligands have acceptable logP values (0.725 and 1.96), falling within the 1-3 range. Ligand B is slightly better.

**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 good QED scores (0.602 and 0.763), indicating good drug-like properties. Ligand B is better.

**7. DILI Risk:** Ligand A (55.14%) has a higher DILI risk than Ligand B (39.78%). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (57.97%) has lower BBB penetration than Ligand B (88.91%). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.6 and -4.182), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.576 and -3.325), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.274) has a lower hERG inhibition risk than Ligand B (0.576). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (23.85 mL/min/kg) has a lower microsomal clearance than Ligand B (75.95 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-5.084 hours) has a negative half-life, which is not possible. Ligand B (6.406 hours) has a reasonable half-life. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux than Ligand B (0.298), which is favorable.

**15. 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 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) and P-gp efflux. However, it has a higher DILI risk and a nonsensical half-life. Ligand B has better solubility, lower DILI, and a reasonable half-life, but weaker binding affinity and poorer metabolic stability.

Given the enzyme-specific priorities, binding affinity is paramount. The 2 kcal/mol difference in binding affinity is substantial. While the negative half-life for Ligand A is concerning, it could be an experimental error. The poor solubility and permeability of both compounds are significant issues that would need to be addressed through formulation or further chemical modification. However, the potency advantage of Ligand A is likely to be more impactful in initial lead optimization.

Output:
0
2025-04-17 11:32:05,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (87.32). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.714) is slightly higher than the optimal 1-3 range, but acceptable. Ligand B (1.748) is on the lower side, 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 2 HBA, while Ligand B has 4. Both are below the limit of <=10.

**QED:** Both ligands have good QED values (0.69 and 0.784), indicating good drug-like properties.

**DILI:** Ligand A (22.334) has a much lower DILI risk than Ligand B (40.636). Both are below the 40 threshold, but A is preferable.

**BBB:** Both have reasonable BBB penetration (65.374 and 61.38), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.773 and -4.854), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.397 and -2.854), indicating poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.453 and 0.474), which is excellent.

**Microsomal Clearance:** Ligand A (65.04) has a higher microsomal clearance than Ligand B (20.856). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-8.771) has a significantly longer in vitro half-life than Ligand A (4.044). This is a substantial advantage for B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.435 and 0.089).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A's significantly superior binding affinity (-9.4 vs -7.6 kcal/mol) is a decisive factor. While Ligand B has better metabolic stability and half-life, the potency advantage of A is crucial for a kinase inhibitor. The lower DILI risk of A is also a positive. The poor permeability and solubility would need to be addressed in further optimization, but the strong binding provides a solid starting point.

Output:
1
2025-04-17 11:32:05,757 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.718 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.52) is well below the 140 threshold and favorable for oral absorption. Ligand B (92.58) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.842) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-0.276) is significantly below the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are both acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.76 and 0.689), indicating good drug-likeness.

**DILI:** Ligand A (96.51) has a very high DILI risk, which is a major concern. Ligand B (45.638) has a much lower and acceptable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (86.351) has better BBB penetration than Ligand A (65.374), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.627) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.017) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.101) has very poor solubility, which could hinder formulation and bioavailability. Ligand B (-1.244) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.598) has a slightly elevated hERG risk, while Ligand B (0.282) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (54.366) has moderate clearance, while Ligand B (2.542) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.438) has a very short half-life, suggesting rapid metabolism. Ligand B (9.214) has a much longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.537) has moderate P-gp efflux, while Ligand B (0.058) has very low P-gp efflux, improving bioavailability.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.9 kcal/mol). While both are good, the difference is significant.

**Conclusion:**

Despite Ligand B having lower logP and Caco-2 permeability, its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG risk, and slightly better binding affinity outweigh the drawbacks. Ligand A's very high DILI risk and poor solubility are major red flags. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 11:32:05,757 - INFO - Batch 55 complete. Total preferences: 880
2025-04-17 11:32:05,757 - INFO - Processing batch 56/512...
2025-04-17 11:32:44,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.427 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.93) is higher than Ligand B (52.65). While both are reasonably acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (0.399) is quite low, potentially hindering permeation. Ligand B (2.426) 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. Ligand B's lower HBA count is slightly better.

**QED:** Both ligands have similar QED values (0.763 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A (66.111) has a higher DILI risk than Ligand B (8.414). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Both have moderate values.

**Caco-2 Permeability:** Ligand A (-5.205) has poor Caco-2 permeability, while Ligand B (-4.64) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.411) has very poor aqueous solubility, while Ligand B (-1.654) is better, but still low.

**hERG:** Both ligands have low hERG inhibition risk (0.238 and 0.314).

**Microsomal Clearance:** Ligand A (67.283) has higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (34.918).

**In vitro Half-Life:** Ligand A (33.342) has a shorter half-life than Ligand B (4.01).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.05).

**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's a positive for Ligand B.

**Overall:**

Ligand B is significantly better due to its superior logP, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. Ligand A suffers from poor solubility, permeability, and a higher risk of liver injury. While Ligand B's solubility and Caco-2 permeability are not ideal, they are less critical than the significant liabilities of Ligand A.

Output:
1
2025-04-17 11:32:44,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.431 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.167) is quite low, potentially hindering membrane permeability. Ligand B (3.866) 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 0 HBD and 2 HBA. Both are within acceptable limits, but Ligand B's lower count might contribute to better permeability.

**QED:** Both ligands have good QED scores (0.606 and 0.655), indicating generally drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (24.622 and 24.273 percentile).

**BBB:** Ligand A (52.268) has a lower BBB penetration percentile than Ligand B (78.907). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Ligand A (-4.939) has poor Caco-2 permeability, while Ligand B (-4.511) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.617) has slightly better aqueous solubility than Ligand B (-3.5). Solubility is important for formulation and bioavailability, giving a slight edge to Ligand A.

**hERG Inhibition:** Ligand A (0.206) has a lower hERG inhibition risk than Ligand B (0.789), which is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (15.454 mL/min/kg) has significantly lower microsomal clearance than Ligand B (83.041 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-7.108 hours) has a much longer in vitro half-life than Ligand B (4.063 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux liability, while Ligand B (0.68) is higher. This favors Ligand A.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). This difference of 1.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, better binding affinity, and lower hERG risk. While Ligand B has a better logP and TPSA, the significantly better potency and ADME properties of Ligand A make it the more promising candidate. The low logP of Ligand A is a concern, but the strong binding affinity might compensate for it.

Output:
0
2025-04-17 11:32:44,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.463 and 342.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.96) is significantly better than Ligand B (112.66). A TPSA under 90 is preferred, and A is closer to this threshold, suggesting better absorption.

**3. logP:** Ligand B (1.227) is slightly better than Ligand A (0.056), falling comfortably within the 1-3 range. Ligand A is quite 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 B (5) is preferable to Ligand A (4). Both are within the acceptable range.

**6. QED:** Both ligands have good QED scores (0.735 and 0.756), indicating drug-like properties.

**7. DILI:** Ligand B (59.519) has a lower DILI risk than Ligand A (13.687), which is a significant advantage.

**8. BBB:** Ligand A (63.862) has better BBB penetration than Ligand B (41.218), but BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.964) has better Caco-2 permeability than Ligand B (-5.372), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.162) has better aqueous solubility than Ligand B (-3.334), which is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.207) has a lower hERG inhibition risk than Ligand B (0.178), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand B (-5.734) has better metabolic stability (lower clearance) than Ligand A (7.172). This is a key advantage for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (2.118) has a longer half-life than Ligand A (-4.765), which is desirable.

**14. P-gp Efflux:** Ligand A (0.009) has lower P-gp efflux than Ligand B (0.046), which is favorable.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility, permeability, and lower P-gp efflux, Ligand B's superior binding affinity (-8.3 vs -7.3 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer half-life) are more critical for an enzyme target like SRC kinase. The lower DILI risk for Ligand B is also a major benefit. The slightly higher logP of Ligand B is acceptable, and the TPSA is not ideal but not prohibitive given the strong binding.

Output:
1
2025-04-17 11:32:44,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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, while Ligand B (379.551 Da) is still well within the range.

**TPSA:** Ligand B (62.3) is significantly better than Ligand A (85.05). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (3.78) is higher than Ligand A (0.411). While 3.78 is approaching the upper limit, it's still acceptable. Ligand A's 0.411 is quite low and could lead to poor membrane permeability.

**H-Bond Donors/Acceptors:** Both 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 (0.851 and 0.804), indicating good drug-likeness.

**DILI:** Both have similar DILI risk (56.689 and 53.625), indicating moderate risk.

**BBB:** Both have low BBB penetration, which isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** 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:** Both have negative solubility values, which is also unusual. This suggests poor solubility, which could hinder bioavailability.

**hERG Inhibition:** Ligand A (0.253) has a slightly lower hERG risk than Ligand B (0.392), which is preferable.

**Microsomal Clearance:** Ligand A (30.756) has a lower microsomal clearance than Ligand B (58.984), indicating better metabolic stability. This is a significant advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (30.139) has a significantly longer in vitro half-life than Ligand A (8.193). This is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1 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). However, Ligand B has a better TPSA, logP, and in vitro half-life. The poor solubility and permeability (indicated by negative Caco-2 and solubility values) are concerning for both. However, the significantly stronger binding affinity of Ligand A (-8.4 kcal/mol vs -7.4 kcal/mol) is a critical advantage for an enzyme inhibitor. The improved metabolic stability also contributes to its viability. While the solubility/permeability issues need to be addressed through formulation or further chemical modification, the potency and stability profile of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 11:32:44,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.411 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.86) is well below the 140 threshold for oral absorption, and even better for kinase inhibitors. Ligand B (93.87) is still acceptable but less optimal.

**logP:** Ligand A (2.757) is within the optimal 1-3 range. Ligand B (0.916) is a bit low, potentially hindering permeability, but not drastically.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (32.377), but both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (77.976) has better BBB penetration than Ligand B (62.389).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-4.343 vs -4.383).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-1.753) is slightly better than Ligand A (-4.08).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.375 and 0.304).

**Microsomal Clearance:** Ligand A (83.762) has significantly higher microsomal clearance than Ligand B (21.57), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-15.736) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound itself. Ligand B (-11.983) also has a negative half-life, but slightly less negative.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.171 and 0.144).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This 1.6 kcal/mol difference is substantial and outweighs many of the minor ADME drawbacks.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the superior candidate. Its significantly stronger binding affinity (-7.8 vs -6.2 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, Ligand B exhibits much better metabolic stability (lower Cl_mic) and a less problematic (though still negative) in vitro half-life compared to Ligand A. The slightly lower DILI risk is also a positive. The negative half-life values are concerning for both compounds and would require further investigation, but the difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 11:32:44,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.41 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (101.21) is better than Ligand B (49.25) as it is lower and more likely to have good oral absorption.

**logP:** Ligand A (1.164) is optimal, while Ligand B (4.278) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=6) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.803, B: 0.669), indicating good drug-like properties.

**DILI:** Ligand A (51.609) has a slightly higher DILI risk than Ligand B (38.309), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.513) has a better BBB score than Ligand B (65.801).

**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. This is a significant concern.

**hERG Inhibition:** Ligand A (0.404) has a much lower hERG inhibition risk than Ligand B (0.734), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (4.074) has significantly lower microsomal clearance than Ligand B (60.911), indicating better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-13.403) has a negative half-life, which is not realistic. Ligand B (19.295) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, while Ligand B (0.781) has moderate efflux. Lower efflux is generally preferred.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is less than 1.5 kcal/mol, and other factors are more important.

**Overall:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While its half-life is unrealistic, its superior metabolic stability (lower Cl_mic), lower hERG risk, lower P-gp efflux, and optimal logP outweigh the slightly lower binding affinity and higher DILI risk. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 11:32:44,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.429 and 368.493 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (33.2). While both are acceptable, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (2.416) is optimal (1-3). Ligand B (4.541) is slightly higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (2) is within the ideal range (<=5). Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (3) are within the ideal range (<=10).

**QED:** Both ligands have similar QED values (0.622 and 0.6), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (26.755 and 24.544), which is excellent.

**BBB:** Both ligands have high BBB penetration (90.074 and 84.917), but SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.862 and -4.734). This is unusual and suggests poor permeability. However, these values might be errors or indicate a specific transport mechanism.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.529 and -4.611), which is concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.313) has a lower hERG risk than Ligand B (0.889), which is a significant advantage.

**Microsomal Clearance:** Ligand A (29.284) has a lower microsomal clearance than Ligand B (80.226), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-6.298) has a longer in vitro half-life than Ligand B (-4.787), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux than Ligand B (0.412), which is favorable for oral bioavailability.

**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 meaningful.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. It has a better logP, lower hERG risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have issues with Caco-2 and solubility, the ADME properties of Ligand A are superior, making it more likely to succeed as a drug candidate for SRC kinase.

Output:
0
2025-04-17 11:32:44,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.424 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold for oral absorption. Ligand B (104.46) is still acceptable but less favorable.

**logP:** Both ligands have good logP values (2.909 and 1.585), 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 balancing solubility and permeability.

**QED:** Both ligands have similar QED scores (0.639 and 0.628), indicating good drug-likeness.

**DILI:** Ligand A (26.871) has a significantly lower DILI risk than Ligand B (42.575), which is a major advantage. Both are below the 60 threshold, but A is much safer.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (88.174) shows better potential for BBB penetration than Ligand B (58.821).

**Caco-2 Permeability:** Ligand A (-4.525) and Ligand B (-4.797) have similar Caco-2 permeability.

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-3.009 and -3.234). This might require formulation strategies.

**hERG Inhibition:** Ligand A (0.704) has a lower hERG risk than Ligand B (0.166), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (56.103) has a higher microsomal clearance than Ligand B (44.35), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-9.9) has a significantly longer in vitro half-life than Ligand A (4.017), which is a substantial benefit.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.12).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 1.2 kcal/mol is significant and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, and a better in vitro half-life. However, Ligand A has a much better safety profile (lower DILI and hERG risk) and better TPSA. The difference in binding affinity is substantial enough to overcome the slightly higher clearance and lower BBB of Ligand B.

Output:
1
2025-04-17 11:32:44,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.42 Da) and Ligand B (353.369 Da) are both acceptable.

**TPSA:** Ligand A (97.11) is slightly higher than ideal (<140), but still reasonable. Ligand B (60.5) is excellent, well below the 140 threshold.

**logP:** Both ligands have good logP values (A: 2.956, B: 3.243), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which is good. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.735) has a better QED score than Ligand B (0.513), indicating a more drug-like profile.

**DILI:** Ligand A (59.829) has a higher DILI risk than Ligand B (41.024), but both are still within acceptable limits (<60 is good).

**BBB:** Both ligands have high BBB penetration (A: 81.698, B: 84.451), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.97 and -4.739). 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 (-3.835 and -2.082), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.087) has a lower hERG risk than Ligand B (0.627), which is a major advantage.

**Microsomal Clearance:** Ligand A (25.96 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (71.501 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.619 hours) has a lower in vitro half-life than Ligand B (16.016 hours), which is a disadvantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.084, B: 0.396).

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.6 vs -8.1 kcal/mol) is a major advantage for an enzyme target. Furthermore, it exhibits lower hERG risk and better metabolic stability (lower Cl_mic) than Ligand B. While the shorter half-life is a concern, the potency advantage is likely to be more impactful in early-stage development. The lower DILI risk is also a plus.

Output:
1
2025-04-17 11:32:44,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.364 and 365.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (123.13 and 123.95) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.715) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (2.231) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) and Ligand B (1 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, suggesting a good balance between solubility and permeability.

**QED:** Ligand A (0.679) has a better QED score than Ligand B (0.431), indicating a more drug-like profile.

**DILI:** Ligand A (65.723) has a higher DILI risk than Ligand B (60.45), but both are acceptable.

**BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

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

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.328 and 0.453), which is positive.

**Microsomal Clearance:** Ligand A (0.073) has significantly lower microsomal clearance than Ligand B (30.859), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.592) has a shorter half-life than Ligand B (11.165), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.11), which is favorable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better QED and lower Cl_mic, the significantly stronger binding affinity of Ligand B (-9.5 vs -8.7 kcal/mol) is the deciding factor. The affinity difference is large enough to compensate for the slightly less favorable logP and QED. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. The improved metabolic stability of Ligand A is a plus, but the potency advantage of Ligand B is more critical for an enzyme inhibitor.

Output:
1
2025-04-17 11:32:44,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.467 and 348.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (114.2).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Both ligands have good logP values (1.637 and 2.106), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 5 HBA) is better than Ligand B (3 HBD, 8 HBA). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Ligand A (0.815) has a much better QED score than Ligand B (0.59), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (68.437 and 64.676), below the concerning threshold of 60.

**BBB:** Ligand A (48.313) and Ligand B (73.517). BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.337 and -5.061). This is unusual and suggests very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.393 and -3.277). This is also a major concern, suggesting poor solubility and potential bioavailability issues.

**hERG Inhibition:** Ligand A (0.044) has a significantly lower hERG risk than Ligand B (0.516), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (28.855) has a much lower microsomal clearance than Ligand B (74.647), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (28.779) has a longer in vitro half-life than Ligand B (-1.666), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.035), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.9), but the difference is only 0.1 kcal/mol. Given the significant ADME advantages of Ligand A, this small difference in affinity is unlikely to be decisive.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising drug candidate. It has superior QED, lower hERG risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While both have poor Caco-2 and solubility, the other advantages of Ligand A make it a better starting point for optimization. Addressing the solubility and permeability issues will be crucial for either compound, but Ligand A's other properties are more favorable.

Output:
0
2025-04-17 11:32:44,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.435 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.07) is slightly higher than Ligand B (66.24), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.224) is within the optimal 1-3 range. Ligand B (2.968) is also within range, but closer to the upper limit.

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

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6. Both are below the 10 threshold.

**QED:** Ligand A (0.786) has a significantly better QED score than Ligand B (0.419), indicating a more drug-like profile.

**DILI:** Ligand A (37.301) has a much lower DILI risk than Ligand B (64.637). Both are below 60, but A is preferable.

**BBB:** Ligand A (59.364) has a lower BBB penetration than Ligand B (70.648). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.032) has worse Caco-2 permeability than Ligand B (-4.515), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.453) has slightly better solubility than Ligand B (-3.699). Both are poor, but A is better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.191 and 0.105, respectively).

**Microsomal Clearance:** Ligand A (27.077) has significantly lower microsomal clearance than Ligand B (56.164), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.341) has a positive half-life, while Ligand B (-14.602) has a negative half-life, indicating faster degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.482, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Conclusion:**

Despite similar binding affinities, Ligand A is the more promising candidate. It has a significantly better QED score, lower DILI risk, better metabolic stability (lower Cl_mic and positive t1/2), and slightly better solubility. While Caco-2 permeability is poor for both, the other advantages of Ligand A outweigh this drawback, especially given that SRC is not a CNS target.

Output:
1
2025-04-17 11:32:44,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (383.47 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.28) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (94.05) is well within the range.

**logP:** Both ligands have good logP values (2.403 and 3.696), 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 (0.542 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (86.972) has a higher DILI risk than Ligand B (72.043). This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (72.082) has a slightly better score than Ligand A (50.64).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-5.32) is slightly worse than Ligand B (-4.907).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.285) is slightly worse than Ligand B (-4.293).

**hERG:** Both ligands have low hERG inhibition liability (0.472 and 0.49), which is good.

**Microsomal Clearance:** Ligand A (32.963) has significantly lower microsomal clearance than Ligand B (86.181), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (30.244) has a lower in vitro half-life than Ligand B (44.644), but both are acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.34 and 0.423), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -9.5 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A has a significant advantage in microsomal clearance (better metabolic stability) and a comparable binding affinity. However, it has a higher DILI risk and slightly worse Caco-2 permeability and solubility. Ligand B has a lower DILI risk and slightly better solubility and permeability, but significantly higher microsomal clearance. Given the importance of metabolic stability for kinase inhibitors (to maintain therapeutic concentrations), and the relatively small difference in binding affinity, Ligand A is the more promising candidate, despite the higher DILI risk. The DILI risk can be further investigated and potentially mitigated through structural modifications.

Output:
0
2025-04-17 11:32:44,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 353.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is higher than Ligand B (53.09). While both are reasonable, Ligand B's lower TPSA is preferable for potential cell permeability.

**logP:** Both ligands have similar logP values (1.519 and 1.593), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 0. Lower HBD is generally preferred for permeability, giving a slight edge to Ligand B.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Ligand A (0.768) has a slightly higher QED than Ligand B (0.632), indicating a more drug-like profile.

**DILI:** Ligand B (14.66) has a significantly lower DILI risk than Ligand A (60.14). This is a major advantage for Ligand B.

**BBB:** Ligand B (72.82) has a better BBB penetration percentile than Ligand A (53.59), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.759) has a much worse Caco-2 permeability than Ligand B (-4.617). This suggests Ligand B will have better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2) has worse solubility than Ligand B (0.165). Solubility is important for formulation and bioavailability, favoring Ligand B.

**hERG Inhibition:** Ligand A (0.098) has a slightly lower hERG inhibition risk than Ligand B (0.639), which is a slight advantage.

**Microsomal Clearance:** Ligand B (8.222) has a significantly lower microsomal clearance than Ligand A (-17.548). Lower clearance indicates better metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-0.67) has a negative half-life, which is concerning, but Ligand A (14.86) is also not particularly long. This is a potential area for improvement for both, but Ligand B is worse.

**P-gp Efflux:** Ligand A (0.008) has lower P-gp efflux than Ligand B (0.051), which is a slight advantage.

**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 for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has superior ADME properties (lower DILI, better solubility, better Caco-2 permeability, better metabolic stability). However, Ligand A boasts a significantly higher binding affinity (-9.1 vs -7.7 kcal/mol). For an enzyme like SRC kinase, potency is paramount. The 1.4 kcal/mol difference in binding is substantial and likely to translate to greater efficacy *in vivo*. While Ligand B's ADME profile is better, the potency difference of Ligand A is likely to be more impactful, and ADME issues can be addressed through further optimization.

Output:
0
2025-04-17 11:32:44,751 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.571 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, while Ligand B (70.67) is still acceptable but higher.

**logP:** Ligand A (3.657) is at the upper end of the optimal 1-3 range, while Ligand B (1.642) is towards the lower end.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, both within acceptable limits. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.748) has a better QED score than Ligand B (0.552), indicating a more drug-like profile.

**DILI:** Ligand A (41.373) and Ligand B (35.479) both have low DILI risk, below the 40 threshold.

**BBB:** Both ligands have good BBB penetration (72.005 and 77.123), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with absorption prediction. However, the scale is not clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with solubility prediction. However, the scale is not clearly defined, so it's hard to interpret.

**hERG Inhibition:** Ligand A (0.604) has a slightly higher hERG risk than Ligand B (0.552), but both are relatively low.

**Microsomal Clearance:** Ligand A (107.135) has a higher microsomal clearance than Ligand B (-1.397). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (17.461) has a significantly longer in vitro half-life than Ligand A (8.763), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.624) has slightly higher P-gp efflux than Ligand B (0.105).

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a *much* stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a difference of 2.6 kcal/mol, which is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better QED score, Ligand B is significantly better in terms of metabolic stability (lower Cl_mic, longer t1/2) and, crucially, *much* higher binding affinity. The binding affinity difference is the most important factor here, given that we are targeting an enzyme. The slightly lower logP of Ligand B is not a major concern, and its other ADME properties are acceptable.

Output:
1
2025-04-17 11:32:44,751 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.333 Da) is slightly higher than Ligand B (345.418 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for oral absorption. Ligand B (62.3) is also acceptable, but higher.

**logP:** Both ligands have good logP values (A: 3.439, B: 2.167) 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 (A: 0.79, B: 0.91), indicating good drug-likeness.

**DILI:** Ligand A (46.491) has a slightly higher DILI risk than Ligand B (30.748). This is a point in favor of Ligand B.

**BBB:** Both ligands have high BBB penetration (A: 89.066, B: 84.878), but this is less crucial for a kinase inhibitor not specifically targeting the CNS.

**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 (A: 0.514, B: 0.511), which is excellent.

**Microsomal Clearance:** Ligand A (9.965) has a lower microsomal clearance than Ligand B (10.076), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-2.04 hours) has a negative half-life, which is not possible. Ligand B (-10.916 hours) 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: 0.16, B: 0.043), which is favorable.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite the questionable solubility and permeability data, the most important factor for an enzyme inhibitor is binding affinity. Ligand B has a much stronger binding affinity (-8.3 kcal/mol) compared to Ligand A (0.0 kcal/mol). The slightly lower DILI risk for Ligand B is also a positive. While Ligand A has better metabolic stability, the difference isn't substantial enough to overcome the large difference in binding affinity. The negative half-life values for both compounds are concerning and should be investigated, but the affinity difference is the dominant factor in this comparison.

Output:
1
2025-04-17 11:32:44,751 - INFO - Batch 56 complete. Total preferences: 896
2025-04-17 11:32:44,751 - INFO - Processing batch 57/512...
2025-04-17 11:33:25,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (346.431 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (87.47 and 88.58) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (1.09) is at the lower end of the optimal 1-3 range, while Ligand B (2.318) is more centrally located. Ligand B's logP is slightly preferable.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the limit of 5. Ligand B is slightly better here.

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

**6. QED:** Both ligands have high QED scores (0.805 and 0.898), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (44.591), which is a significant advantage.

**8. BBB:** Both ligands have similar BBB penetration (69.833 and 69.95), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.925 and -5.104), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.095 and -2.584), also unusual and concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.241 and 0.222), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (4.055) has significantly lower microsomal clearance than Ligand B (10.953), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (19.882) has a longer in vitro half-life than Ligand B (16.643), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.124).

**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 strong binders, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a slightly better binding affinity, significantly lower microsomal clearance and longer half-life, and a lower DILI risk. While both have poor predicted solubility and permeability, the metabolic advantages of Ligand A outweigh the slightly better logP of Ligand B. The binding affinity difference is also a factor.

Output:
0
2025-04-17 11:33:25,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.386 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.59) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (89.95) is still acceptable but closer to the upper limit.

**3. logP:** Ligand A (2.511) is optimal (1-3). Ligand B (0.291) is quite low, potentially hindering membrane permeability and absorption.

**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 reasonable QED scores (0.845 and 0.673), indicating good drug-like properties.

**7. DILI:** Ligand A (62.001) has a higher DILI risk than Ligand B (20.24). This is a concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.968) has a better BBB score than Ligand B (38.775), but this isn't a primary driver here.

**9. Caco-2 Permeability:** Ligand A (-4.879) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.072) is also poor, but similar to A.

**10. Aqueous Solubility:** Ligand A (-3.445) and Ligand B (-1.587) both have negative solubility values, which is concerning.

**11. hERG Inhibition:** Ligand A (0.675) has a slightly higher hERG risk than Ligand B (0.135), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-1.729) has a negative clearance, which is excellent, indicating very high metabolic stability. Ligand A (23.855) has a moderate clearance.

**13. In vitro Half-Life:** Ligand B (6.334) has a short half-life, but it is still better than Ligand A (36.573).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.172 and 0.021).

**15. Binding Affinity:** Ligand B (0.0) has a significantly better binding affinity than Ligand A (-10.7). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B's significantly superior binding affinity (-10.7 kcal/mol vs 0.0 kcal/mol) and excellent metabolic stability (negative Cl_mic) outweigh the slightly higher DILI risk and lower logP. The low logP of Ligand B is a concern, but the strong binding affinity suggests it can still be effective. Ligand A's poor Caco-2 permeability is a major drawback.

Output:
1
2025-04-17 11:33:25,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.791 and 360.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.12) is slightly higher than Ligand B (88.12), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (4.79) is significantly higher than Ligand B (1.135). While a logP between 1-3 is optimal, Ligand A's value is quite high and could lead to solubility issues and off-target interactions. Ligand B is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are acceptable. Ligand B has 0 HBD and 9 HBA, also acceptable, although the higher number of acceptors might slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (0.408 and 0.514), indicating moderate drug-likeness. Ligand B is slightly better.

**DILI:** Ligand B (87.088) has a higher DILI risk than Ligand A (59.403), but both are above the preferred <40. This is a concern for both, but more so for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (78.868 and 69.756), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.55 and -4.505), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.159 and -3.334). This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.691) has a slightly higher hERG risk than Ligand B (0.542), but both are relatively low.

**Microsomal Clearance:** Ligand B (64.886) has a lower microsomal clearance than Ligand A (40.583), indicating better metabolic stability, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand B (12.715) has a significantly longer in vitro half-life than Ligand A (30.546). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.229) has a slightly higher P-gp efflux liability than Ligand B (0.691), but both are relatively low.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered significant, and here it's a massive 7.5 kcal/mol difference.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the far superior candidate due to its dramatically stronger binding affinity, better metabolic stability (lower Cl_mic), and longer half-life. The higher DILI risk is a concern, but the potency advantage is likely to outweigh this drawback in initial optimization efforts.

Output:
1
2025-04-17 11:33:25,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.4 and 344.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.6 and 107.7 A^2) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.32) is within the optimal 1-3 range. Ligand B (-0.45) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3 and 4) and HBA (5 and 5) counts, staying within the recommended limits.

**QED:** Ligand A (0.68) has a better QED score than Ligand B (0.427), indicating a more drug-like profile.

**DILI:** Ligand A (68.4) has a higher DILI risk than Ligand B (51.2), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (45.7) is lower than Ligand B (14.5).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.741) has a lower hERG inhibition liability than Ligand B (0.278), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-16.9) has a much lower (better) microsomal clearance than Ligand B (-30.4), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (28.9) has a significantly longer half-life than Ligand B (-14.5).

**P-gp Efflux:** Ligand A (0.132) has lower P-gp efflux liability than Ligand B (0.008).

**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.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor logP, solubility, permeability, and a higher hERG risk. Ligand A has better ADME properties (logP, hERG, clearance, half-life, P-gp) and a better QED score, but its binding affinity is very weak.

Given the significant difference in binding affinity, the potency advantage of Ligand B likely outweighs its ADME liabilities, *provided* those liabilities can be addressed through further optimization. The weak binding of Ligand A is a more fundamental issue that would be harder to overcome.

Output:
1
2025-04-17 11:33:25,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.559 Da) and Ligand B (354.447 Da) are both acceptable.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption. Ligand B (99.1) is still under 140, but getting closer to the limit, potentially impacting absorption slightly.

**logP:** Ligand A (2.686) is optimal (1-3). Ligand B (0.042) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but slightly higher.

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

**QED:** Both ligands have similar QED values (A: 0.678, B: 0.648), indicating good drug-like properties.

**DILI:** Ligand A (31.291) has a lower DILI risk than Ligand B (25.165), which is preferable.

**BBB:** Ligand A (68.205) has better BBB penetration than Ligand B (34.044), but BBB isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both have negative values (-5.007 and -4.978), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is significant.

**Aqueous Solubility:** Both have negative values (-3.169 and -1.226), indicating poor aqueous solubility. Ligand B is slightly better than A.

**hERG Inhibition:** Ligand A (0.458) has a lower hERG risk than Ligand B (0.098), which is a significant advantage.

**Microsomal Clearance:** Ligand A (48.851) has higher microsomal clearance than Ligand B (4.738), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 3.295, B: 3.138).

**P-gp Efflux:** Ligand A (0.286) has lower P-gp efflux than Ligand B (0.018), which is favorable.

**Binding Affinity:** Ligand B (-9.8 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. The difference of 2.1 kcal/mol is quite large.

**Conclusion:**

Despite Ligand A having better DILI and hERG profiles, Ligand B's significantly superior binding affinity (-9.8 vs -7.7 kcal/mol) is the most critical factor for an enzyme inhibitor. While Ligand B has a lower logP and higher DILI, the potency advantage is likely to be more impactful in driving efficacy. The lower metabolic stability of Ligand A is also a concern.

Output:
1
2025-04-17 11:33:25,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.419 and 368.869 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.8) is slightly above the preferred <140 for good absorption, while Ligand B (96.12) is well within this range.

**logP:** Ligand A (0.682) is a bit low, potentially hindering permeability. Ligand B (3.162) is optimal.

**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 relatively low QED scores (0.464 and 0.38), indicating they are not particularly drug-like, but this isn't a dealbreaker if other properties are strong.

**DILI:** Ligand A (46.219) has a slightly higher DILI risk than Ligand B (37.999), but both are reasonably low.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (72.237) has a higher BBB percentile than Ligand A (27.491), but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.191) has poor Caco-2 permeability, which is a significant concern. Ligand B (-4.571) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.921 and -3.132 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.071) has a very low hERG risk, which is excellent. Ligand B (0.404) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (18.581) has much lower microsomal clearance than Ligand B (58.679), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-2.51) has a negative half-life, which is concerning and likely indicates rapid degradation. Ligand B (12.01) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.128), which is good.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.2 kcal/mol). While both are good, the 0.4 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B has a better logP, better Caco-2 permeability, and a significantly better in vitro half-life. Its binding affinity is also slightly higher. However, Ligand A has a much lower microsomal clearance and a significantly lower hERG risk. The poor Caco-2 permeability and negative half-life of Ligand A are major drawbacks. While the lower clearance and hERG risk of Ligand A are attractive, the superior ADME profile and slightly better affinity of Ligand B outweigh these advantages.

Output:
1
2025-04-17 11:33:25,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.463 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.63) is higher than Ligand B (59.39). Both are below the 140 threshold for oral absorption, but B is better.

**3. logP:** Both ligands (2.33 and 1.943) 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 6 HBA, and Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Ligand B (0.82) has a significantly better QED score than Ligand A (0.53), indicating a more drug-like profile.

**7. DILI:** Ligand B (13.532) has a much lower DILI risk than Ligand A (31.718), a significant advantage.

**8. BBB:** Ligand B (81.349) has better BBB penetration than Ligand A (45.211), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-5.385) is slightly worse than Ligand B (-5.091).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.37) is slightly worse than Ligand B (-1.112).

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.297 and 0.655).

**12. Microsomal Clearance:** Ligand B (47.985) has lower microsomal clearance than Ligand A (33.118), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.477) has a significantly longer in vitro half-life than Ligand A (-2.915), which is a major advantage.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.106 and 0.068).

**15. 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 not huge.

**Overall Assessment:**

Ligand B is clearly superior. It has a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), slightly better binding affinity, and better BBB penetration. While both have poor Caco-2 and solubility, the other advantages of Ligand B outweigh these drawbacks. The improved metabolic stability and reduced toxicity risk are particularly important for kinase inhibitors.

Output:
1
2025-04-17 11:33:25,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.379 and 354.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.66) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (85.89) is excellent, well below 140.

**logP:** Ligand A (-0.795) is a bit low, potentially hindering permeation. Ligand B (1.331) is 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 7 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.627 and 0.736, respectively), indicating drug-like properties.

**DILI:** Ligand A (48.623) has a slightly better DILI score than Ligand B (54.75), both are acceptable (<60).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (72.78) has a higher BBB score than Ligand A (57.193), but it's not a major deciding factor here.

**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 ligands have negative solubility values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.024) has a very low hERG risk, significantly better than Ligand B (0.375). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (11.731) has significantly lower microsomal clearance than Ligand B (21.723), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.45) has a slightly longer half-life than Ligand B (9.295).

**P-gp Efflux:** Both have low P-gp efflux liability (0.006 and 0.04, respectively).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage (1.6 kcal/mol difference).

**Conclusion:**

While Ligand B boasts a superior binding affinity, Ligand A presents a much better safety profile regarding hERG inhibition and demonstrates improved metabolic stability (lower Cl_mic) and half-life. The slightly lower logP and TPSA of Ligand A are less concerning than the hERG risk associated with Ligand B. Given the enzyme-specific priorities, the improved safety and metabolic stability of Ligand A, combined with acceptable potency, make it the more promising drug candidate.

Output:
0
2025-04-17 11:33:25,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.391 and 360.523 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.3) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (49.41) is well within the optimal range.

**logP:** Ligand A (0.817) is a bit low, potentially hindering permeation. Ligand B (3.783) is excellent, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.644 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (61.07) has a moderate DILI risk, while Ligand B (37.999) has a lower, more favorable risk.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (77.084) has a higher BBB percentile than Ligand A (52.423), but this is less critical 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, which is also unusual. Again, we'll assume this indicates poor solubility. Ligand A (-2.181) is slightly better than Ligand B (-4.318).

**hERG Inhibition:** Ligand A (0.152) has a very low hERG risk, which is excellent. Ligand B (0.504) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (26.108) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (51.527) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (19.901) has a longer half-life than Ligand B (-9.378), which is a significant advantage. The negative half-life for Ligand B is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.07 and 0.38), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (0.0 kcal/mol).

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, much lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. Ligand B has a better logP and TPSA, but its negative half-life is a major red flag. While both have issues with Caco-2 and solubility, the metabolic stability and safety profile of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 11:33:25,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (359.348 Da) is also good.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (69.04) is slightly higher than Ligand B (63.69), but both are acceptable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.484) is at the higher end, potentially increasing off-target effects, while Ligand B (3.026) is closer to the ideal.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.724 and 0.882), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a higher DILI risk (82.939%) than Ligand B (43.66%), which is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (70.027%) and Ligand B (96.937%) are both reasonable, with Ligand B being better.

**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, which indicates poor solubility.

**hERG:** Ligand A (0.772) has a slightly higher hERG risk than Ligand B (0.583), but both are reasonably low.

**Microsomal Clearance:** Ligand B has significantly lower microsomal clearance (13.469 mL/min/kg) than Ligand A (67.288 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B has a negative in vitro half-life (-2.011 hours), which is concerning. Ligand A has a half-life of 39.224 hours, which is much better.

**P-gp Efflux:** Ligand A (0.594) has lower P-gp efflux than Ligand B (0.248), which could lead to better oral bioavailability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This 2.8 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand B's negative in vitro half-life, its significantly superior binding affinity (-9.1 vs -6.3 kcal/mol) and much better metabolic stability (lower Cl_mic) are decisive advantages. The lower DILI risk of Ligand B is also a major positive. While both have solubility issues, the potency and metabolic stability benefits of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 11:33:25,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight (MW):** Both ligands (347.415 and 356.329 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.76) is well below the 140 threshold for good oral absorption, and even below the 90 threshold for CNS penetration. Ligand B (117.34) is still within the acceptable range for oral absorption but higher than A.

**3. logP:** Ligand A (0.916) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (0.12) is quite low, raising concerns about membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands (A: 1, B: 3) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (A: 5, B: 6) are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.827) has a strong drug-like profile, exceeding the 0.5 threshold. Ligand B (0.69) also exceeds the threshold but is lower than A.

**7. DILI:** Ligand A (37.611) has a low DILI risk, well below the 40 threshold. Ligand B (60.876) is approaching the higher risk threshold of 60.

**8. BBB:** Both ligands have similar BBB penetration (A: 57.425, B: 59.597), and are not particularly high, but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.861) and Ligand B (-5.487) both have negative Caco-2 values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.105) and Ligand B (-2.003) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.181, B: 0.013).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-3.626) has a negative clearance, indicating very good metabolic stability. Ligand B (-36.002) has a high negative clearance, indicating very rapid metabolism.

**13. In vitro Half-Life:** Ligand A (15.753) has a reasonable half-life. Ligand B (-5.469) has a very short half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.013, B: 0.004).

**15. Binding Affinity:** Both ligands have comparable binding affinities (A: -8.6, B: -8.8). The difference is minimal.

**Enzyme-Kinase Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Comparison & Conclusion:**

Ligand A is superior to Ligand B. While both have good affinity, Ligand A demonstrates significantly better metabolic stability (Cl_mic and t1/2), lower DILI risk, and a better QED score. Although both have poor Caco-2 and solubility, the metabolic advantages of Ligand A are more critical for an enzyme target, as it suggests a longer duration of action and reduced potential for drug-drug interactions. The slightly better TPSA and QED also contribute to its favorability.

Output:
1
2025-04-17 11:33:25,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.896 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (35.58) is significantly better than Ligand B (53.16). A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally better.

**logP:** Both ligands have logP values (3.887 and 4.785) within the optimal range (1-3), but Ligand B is pushing the upper limit. Higher logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=3, HBA=2). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.707) has a much better QED score than Ligand B (0.393), indicating a more drug-like profile.

**DILI:** Ligand B (89.841) has a significantly higher DILI risk than Ligand A (11.128). This is a major concern.

**BBB:** Ligand A (92.594) has better BBB penetration than Ligand B (69.833), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the experimental setup or the compounds themselves. It's hard to draw conclusions from these values.

**Aqueous Solubility:** Ligand A (-3.27) has better solubility than Ligand B (-6.296). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.958 and 0.866), which is good.

**Microsomal Clearance:** Ligand A (15.28 mL/min/kg) has a much lower microsomal clearance than Ligand B (51.604 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.513 hours) has a better in vitro half-life than Ligand B (62.948 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.397 and 0.341).

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial difference and likely outweighs minor ADME drawbacks.

**Conclusion:**

Ligand A is significantly better than Ligand B. It has superior potency (binding affinity), a better drug-like profile (QED), lower DILI risk, improved solubility, and better metabolic stability (lower Cl_mic and longer t1/2). While both have acceptable hERG and P-gp profiles, the overall profile of Ligand A is far more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 11:33:25,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.427 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (88.83) is slightly higher than Ligand B (76.46), but both are below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.232 and 1.371), 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 7 HBAs, and Ligand B has 5. Both are below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.761 and 0.755), indicating good drug-likeness.

**7. DILI:** Ligand A (73.439) has a higher DILI risk than Ligand B (30.865). This is a significant negative for Ligand A.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (74.99) is slightly better than Ligand A (56.495). BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.072) has poor Caco-2 permeability, while Ligand B (-4.801) is also poor but slightly better.

**10. Aqueous Solubility:** Ligand A (-2.768) has poor aqueous solubility, while Ligand B (-1.144) is also poor, but better than Ligand A. Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.399) has a slightly higher hERG risk than Ligand B (0.549). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand B (14.377) has significantly lower microsomal clearance than Ligand A (37.116), indicating better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-5.745) has a longer in vitro half-life than Ligand A (2.057). This is another important advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.2) has lower P-gp efflux than Ligand B (0.076), which is slightly better.

**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 advantage for Ligand A. The difference of 2.6 kcal/mol is significant.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its significantly higher DILI risk, poor solubility, poor Caco-2 permeability, and higher microsomal clearance are major drawbacks. Ligand B, while having a weaker binding affinity, presents a much more favorable ADME-Tox profile with lower DILI, better solubility, better permeability, and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and a favorable safety profile are crucial. The affinity difference, while substantial, could potentially be addressed through further optimization of Ligand B.

Output:
1
2025-04-17 11:33:25,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (347.459 Da and 367.559 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.74) is slightly above the preferred <140, but acceptable. Ligand B (69.22) is well within the acceptable range.

**3. logP:** Ligand A (1.931) is optimal. Ligand B (3.167) is also within the optimal range, but approaching the upper limit.

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

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the ideal range.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (12.951) has a much lower DILI risk than Ligand B (18.418), which is a significant advantage.

**8. BBB:** Both ligands have similar BBB penetration, around 60-65%, which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.362) has poor Caco-2 permeability. Ligand B (-5.298) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-1.33) has poor aqueous solubility. Ligand B (-2.809) has even poorer aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.426) has a lower hERG inhibition risk than Ligand B (0.739).

**12. Microsomal Clearance:** Ligand A (52.234) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (60.568).

**13. In vitro Half-Life:** Ligand B (-29.069) has a significantly longer in vitro half-life than Ligand A (-5.086). This is a major advantage.

**14. P-gp Efflux:** Both ligands show minimal P-gp efflux liability.

**15. Binding Affinity:** Ligand B (-6.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a very important factor.

**Enzyme-Specific Considerations:** For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in binding affinity and has a much longer half-life. While its solubility is poor, the significantly improved potency and half-life likely outweigh this drawback. Ligand A has a better safety profile (lower DILI and hERG), but its extremely weak binding affinity makes it unlikely to be effective.

Output:
1
2025-04-17 11:33:25,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.5) is slightly higher than Ligand B (348.4).

**TPSA:** Ligand A (57.7) is well below the 140 threshold and suitable for oral absorption. Ligand B (123.4) is still acceptable but higher, potentially impacting absorption slightly.

**logP:** Ligand A (2.8) is optimal. Ligand B (0.044) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is acceptable but higher, potentially affecting permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.682, B: 0.642).

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (34.3), which is a substantial advantage.

**BBB:** Ligand A (78.9) shows good BBB penetration, while Ligand B (61.3) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the assay or the compounds themselves. However, the magnitude is different, with Ligand A (-5.0) being more negative than Ligand B (-5.6).

**Aqueous Solubility:** Both have negative solubility values, also unusual. Ligand A (-2.3) is slightly better than Ligand B (-2.1).

**hERG Inhibition:** Ligand A (0.354) has a much lower hERG risk than Ligand B (0.019). This is a critical advantage.

**Microsomal Clearance:** Ligand A (36.8) has a higher (worse) microsomal clearance than Ligand B (4.9), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-7.8) has a longer half-life than Ligand B (3.9).

**P-gp Efflux:** Ligand A (0.105) shows lower P-gp efflux than Ligand B (0.003), which is favorable.

**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 favorable properties of A.

**Overall:**

Ligand A is significantly better due to its lower DILI risk, lower hERG inhibition, better logP, and slightly better binding affinity. While Ligand A has higher microsomal clearance, its longer half-life and superior safety profile outweigh this drawback. Ligand B's low logP is a significant concern, potentially hindering absorption.

Output:
0
2025-04-17 11:33:25,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.371 and 346.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.55) is better than Ligand B (114.18), both are acceptable but closer to the upper limit for good oral absorption (<=140).

**logP:** Ligand A (-0.099) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (0.924) is closer to the ideal range.

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

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

**QED:** Both ligands have acceptable QED scores (0.718 and 0.649, both >=0.5).

**DILI:** Ligand A (68.282) has a higher DILI risk than Ligand B (31.989). This is a significant negative for Ligand A.

**BBB:** Ligand A (17.216) has very poor BBB penetration, while Ligand B (62.233) is better, but still not ideal. BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.314 and -5.385). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.567 and -2.832). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.184 and 0.062). This is positive for both.

**Microsomal Clearance:** Ligand A (-18.799) has significantly lower microsomal clearance than Ligand B (24.349), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (21.237) has a longer half-life than Ligand B (-0.309), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.014).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand A having a slightly lower logP and TPSA, the significantly lower DILI risk and much better metabolic stability (lower Cl_mic and longer t1/2) outweigh those minor drawbacks. While both have poor solubility and permeability, metabolic stability is a critical factor for kinase inhibitors, as they often require sustained exposure. The similar binding affinity means potency isn't a differentiating factor.

Output:
1
2025-04-17 11:33:25,960 - INFO - Batch 57 complete. Total preferences: 912
2025-04-17 11:33:25,960 - INFO - Processing batch 58/512...
2025-04-17 11:34:06,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (398.94 and 341.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is higher than Ligand B (45.23). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands (3.86 and 4.64) are within the optimal 1-3 range, though B is slightly higher.

**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 acceptable (<=10).

**QED:** Both ligands have similar QED values (0.719 and 0.676), indicating good drug-likeness.

**DILI:** Ligand A (78.21) has a higher DILI risk than Ligand B (55.76). This is a significant concern.

**BBB:** Ligand A (52.58) has a lower BBB penetration than Ligand B (92.67). Not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.78 and -4.69).

**Solubility:** Both have negative solubility values, also unusual. Again, the values are similar (-4.87 and -4.08).

**hERG:** Ligand A (0.693) has a lower hERG risk than Ligand B (0.978). This is a positive for A.

**Microsomal Clearance:** Ligand A (38.95) has significantly lower microsomal clearance than Ligand B (108.86). This indicates better metabolic stability for A, a key factor for kinases.

**In vitro Half-Life:** Ligand A (-6.94) has a negative half-life, which is not possible. Ligand B (105.77) has a very long half-life, which is excellent. The negative value for A is a major red flag.

**P-gp Efflux:** Ligand A (0.337) has lower P-gp efflux than Ligand B (0.91). This is a slight advantage for A.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.5). While both are good, the 1.5 kcal/mol difference is noticeable.

**Conclusion:**

Despite the similar binding affinities, Ligand A has a negative in vitro half-life, which is impossible and indicates a significant issue with the data or the molecule itself. Ligand B has a very long half-life and lower DILI risk. While both have unusual solubility and Caco-2 values, the metabolic stability and safety profile of Ligand B are more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 11:34:06,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.463 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is better than Ligand B (110.44).  A TPSA under 140 is good for oral absorption, both are, but A is preferable.

**logP:** Both ligands (0.727 and 0.985) are within the optimal 1-3 range.

**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:** Both ligands have similar QED values (0.762 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A (18.379) has a significantly lower DILI risk than Ligand B (46.336). This is a major advantage for Ligand A.

**BBB:** Ligand B (83.986) has a higher BBB penetration than Ligand A (67.352). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.243) has a worse Caco-2 permeability than Ligand B (-4.884).

**Aqueous Solubility:** Ligand A (-1.918) has a worse aqueous solubility than Ligand B (-2.418).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.493 and 0.303).

**Microsomal Clearance:** Ligand A (16.254) has significantly lower microsomal clearance than Ligand B (37.259). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (18.05) has a better in vitro half-life than Ligand B (-13.994).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.026).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a better binding affinity than Ligand B (-7.5 kcal/mol). The 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the better candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a superior binding affinity. While Ligand B has slightly better Caco-2 permeability and solubility, the advantages of Ligand A in terms of safety (DILI) and efficacy (affinity, stability) are more important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.378 and 378.807 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is better than Ligand B (107.11), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (2.798) is optimal, while Ligand B (1.486) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) is slightly better than Ligand B (HBD=4, HBA=4) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.769) has a better QED score than Ligand B (0.576), indicating a more drug-like profile.

**DILI:** Ligand A (47.693) has a significantly lower DILI risk than Ligand B (61.691), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 50.679, Ligand B: 48.972), which isn't a primary concern for a non-CNS target like SRC.

**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 (0.111) has a much lower hERG risk than Ligand B (0.322), a critical factor for safety.

**Microsomal Clearance:** Ligand A (25.407) has a higher (worse) microsomal clearance than Ligand B (-16.106), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (4.318) has a longer in vitro half-life than Ligand A (-2.334), which is preferable.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 kcal/mol and -8.1 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite Ligand A having a better QED, lower DILI, and lower hERG risk, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2) is more critical for an enzyme target like SRC. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies. The slight reduction in logP for Ligand B is less concerning than the metabolic lability of Ligand A.

Output:
1
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Ligand A (88.91) is significantly better than Ligand B (33.2). While both are acceptable, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.442) is optimal, while Ligand B (4.704) is high. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is preferable to Ligand B (0 HBD, 3 HBA). A balance is good, and Ligand A has a more balanced profile.

**QED:** Both ligands have good QED scores (A: 0.66, B: 0.716), indicating drug-like properties.

**DILI:** Ligand A (32.183) has a much lower DILI risk than Ligand B (65.491), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.872) has a higher BBB score, but it's not a major factor here.

**Caco-2 Permeability:** Ligand A (-5.314) shows poor permeability, while Ligand B (-4.693) is better, but still not great.

**Aqueous Solubility:** Ligand A (-1.305) has slightly better solubility than Ligand B (-4.728).

**hERG:** Ligand A (0.215) has a much lower hERG risk than Ligand B (0.628), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (26.232) has a lower clearance than Ligand B (31.039), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.525) has a longer half-life than Ligand B (-3.611), which is desirable.

**P-gp Efflux:** Ligand A (0.043) shows lower P-gp efflux liability than Ligand B (0.684), which is favorable.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is less than 1.5 kcal/mol, it adds to the overall advantage of Ligand A.

**Overall:** Ligand A is significantly better. It has a lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly better binding affinity. While its Caco-2 permeability is poor, the other advantages outweigh this drawback, especially considering SRC is not a CNS target. Ligand B's high logP and DILI risk are major concerns.

Output:
0
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.435 and 345.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is well below the 140 threshold and good for oral absorption. Ligand B (121.45) is still within acceptable limits but less optimal.

**logP:** Ligand A (1.835) is within the optimal 1-3 range. Ligand B (0.205) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7 HBA, both within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (73.013) has a higher DILI risk than Ligand B (61.031), but both are still reasonably low.

**BBB:** Ligand A (60.411) has a moderate BBB penetration, while Ligand B (27.142) has very low BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.981) has a negative Caco-2 value, which is concerning. Ligand B (-5.152) also has a negative Caco-2 value, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.797) has poor aqueous solubility, and Ligand B (-1.866) is also poor. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.355) has a very low hERG risk, which is excellent. Ligand B (0.104) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (9.423) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (23.645) has a significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (54.626) has a longer half-life than Ligand B (-17.54), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux, which is favorable. Ligand B (0.016) has even lower efflux, slightly better.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.2 kcal/mol). Ligand A is slightly better (-8.7 kcal/mol).

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have good potency, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. Although its solubility and Caco-2 permeability are poor, the strong binding affinity and metabolic stability are more critical for an enzyme target like SRC kinase. The slightly higher DILI risk is acceptable given the other favorable properties. Ligand B's lower logP and higher clearance are significant drawbacks.

Output:
1
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.47) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (38.56) is better than Ligand B (56.59), falling well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (A: 4.057, B: 3.456), within the optimal range of 1-3. Ligand A is slightly higher, potentially raising concerns about off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) 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:** Both ligands have acceptable QED values (A: 0.599, B: 0.749), indicating good drug-like properties.

**DILI:** Ligand A (17.45) has a significantly lower DILI risk than Ligand B (13.84), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration (A: 68.55, B: 76.08), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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, which is also unusual and suggests poor solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.977, B: 0.856), which is excellent.

**Microsomal Clearance:** Ligand A (26.64) has a lower microsomal clearance than Ligand B (52.56), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (29.77) has a significantly longer half-life than Ligand B (2.01), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.717, B: 0.589).

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.6, B: -8.1). The difference is 0.5 kcal/mol, which isn't enough to overcome the ADME deficiencies of Ligand B.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have good potency, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and slightly better TPSA and H-bonding characteristics. The solubility and permeability issues are shared, but the other advantages of Ligand A outweigh the minor affinity difference.

Output:
0
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.371 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.93) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands (1.287 and 2.104) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 4. Both are below the threshold of 10.

**QED:** Both ligands have good QED scores (0.705 and 0.862), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 82.396, which is high. Ligand B has a much lower DILI risk of 24.661, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Ligand A (26.638) has poor BBB penetration, while Ligand B (72.78) has good BBB penetration. Since SRC is not a CNS target, this is less critical, but still a positive for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.471) has very poor Caco-2 permeability, while Ligand B (-4.888) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-3.23) and Ligand B (-2.577) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.242) has a slightly higher hERG risk than Ligand B (0.449), but both are relatively low.

**Microsomal Clearance:** Ligand A (-3.52) has a negative clearance, indicating high metabolic stability, which is excellent. Ligand B (26.662) has a high clearance, indicating poor metabolic stability, which is a major drawback.

**In vitro Half-Life:** Ligand A (2.39) has a short half-life, while Ligand B (15.268) has a much longer half-life.

**P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux, while Ligand B (0.119) has slightly higher efflux. Both are good.

**Binding Affinity:** Both ligands have excellent binding affinities (-10.0 and -9.3 kcal/mol), with Ligand A being slightly better. However, the 1.5 kcal/mol advantage is likely outweighed by the other factors.

**Conclusion:**

Despite Ligand A having slightly better binding affinity and metabolic stability, Ligand B is the more promising candidate. The significantly lower DILI risk and longer half-life of Ligand B are crucial advantages for an oncology drug. While both have poor solubility and Caco-2 permeability, these can be addressed with formulation strategies. The higher BBB penetration of Ligand B is a bonus, even though SRC is not a CNS target. The difference in metabolic stability is substantial and favors Ligand A, but the DILI risk of Ligand A is too high to ignore.

Output:
1
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (373.322 and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.5) is slightly higher than Ligand B (62.13). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Ligand A (1.337) is within the optimal 1-3 range. Ligand B (3.556) is at the higher end but still acceptable.

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

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

**QED:** Ligand B (0.762) has a better QED score than Ligand A (0.497), indicating better overall drug-likeness.

**DILI:** Ligand B (23.885) has a significantly lower DILI risk than Ligand A (36.138), which is a major advantage.

**BBB:** Ligand A (76.541) shows better BBB penetration than Ligand B (53.354), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.357) has a worse Caco-2 permeability than Ligand B (-5.027).

**Aqueous Solubility:** Ligand A (-2.249) has better aqueous solubility than Ligand B (-3.52).

**hERG:** Ligand A (0.455) has a lower hERG inhibition liability than Ligand B (0.657), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-15.886) has a much lower (better) microsomal clearance than Ligand B (81.612), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.057) has a slightly better in vitro half-life than Ligand B (-0.045).

**P-gp Efflux:** Ligand A (0.029) has a lower P-gp efflux liability than Ligand B (0.275), which is favorable.

**Binding Affinity:** Ligand B (-8.2) has a significantly stronger binding affinity than Ligand A (-10.7). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.2 vs -10.7 kcal/mol) and a much lower DILI risk (23.885 vs 36.138). While Ligand A has better hERG and P-gp efflux, the superior potency and safety profile of Ligand B are more important for an enzyme target like SRC kinase. The metabolic stability of Ligand A is better, but the difference isn't drastic enough to overcome the potency advantage of Ligand B.

Output:
1
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.427 and 357.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is slightly higher than Ligand B (55.32), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.763 and 3.206), 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 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.91) has a significantly higher QED score than Ligand B (0.703), indicating better overall drug-likeness.

**DILI:** Both ligands have similar DILI risk (47.344 and 47.732), and are below the concerning threshold of 60.

**BBB:** Ligand B (85.111) has a higher BBB penetration percentile than Ligand A (75.107), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.345 and -4.201). This is unusual and suggests potential issues with permeability prediction, but doesn't immediately disqualify either.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.105 and -3.393), which is also unusual and suggests poor predicted solubility.

**hERG:** Ligand A (0.213) has a much lower hERG inhibition liability than Ligand B (0.645), which is a significant advantage.

**Microsomal Clearance:** Ligand A (46.15) has a lower microsomal clearance than Ligand B (65.447), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (34.532) has a better in vitro half-life than Ligand B (-28.159). The negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.28), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). The difference is 1.1 kcal/mol, which is a notable advantage, but not overwhelming.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, but Ligand A demonstrates superior ADME properties across the board. Specifically, Ligand A has a much better QED score, lower hERG risk, lower microsomal clearance (better metabolic stability), a longer in vitro half-life, and lower P-gp efflux. The solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh the small affinity difference. Given the enzyme-specific priorities, the improved metabolic stability and reduced toxicity risk of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (380.275 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is better than Ligand B (71.53), both are acceptable but lower is better for permeability.

**3. logP:** Ligand A (4.379) is higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (1.848) is within the optimal range.

**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 4, respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.809 and 0.847), indicating drug-like properties.

**7. DILI:** Ligand A (73.401) has a higher DILI risk than Ligand B (30.942). This is a significant concern.

**8. BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**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 (0.746) has a higher hERG risk than Ligand B (0.261). This is a significant concern.

**12. Microsomal Clearance:** Ligand A (30.982) has a higher microsomal clearance than Ligand B (13.831), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand A (100.592) has a significantly longer half-life than Ligand B (15.517). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.318) has lower P-gp efflux than Ligand B (0.076), which is better.

**15. Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference and could outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and longer half-life, which are crucial for an enzyme inhibitor. However, it suffers from higher logP, DILI risk, hERG risk, and microsomal clearance. Ligand B has better ADME properties (lower logP, DILI, hERG, and clearance) but a very poor binding affinity.

Given the importance of potency for kinase inhibitors, the superior binding affinity of Ligand A is a strong advantage. While the ADME properties are concerning, they might be addressable through further optimization. The extremely poor affinity of Ligand B makes it a less promising starting point, even with its better ADME profile.

Output:
1
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.435 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.39) is slightly higher than Ligand B (76.46), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.256 and 1.25), 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, 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 high QED scores (0.822 and 0.869), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.203, placing it in the moderate risk category. Ligand B has a significantly lower DILI risk (39.899), which is a strong advantage.

**BBB:** Ligand A (61.807) and Ligand B (73.788) both have acceptable BBB penetration, but Ligand B is better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.833 and -4.381), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.305 and -2.283), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.5) has a slightly higher hERG risk than Ligand B (0.237), which is preferable.

**Microsomal Clearance:** Ligand A (48.762) has lower microsomal clearance than Ligand B (52.149), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.192) has a significantly longer in vitro half-life than Ligand A (59.952). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.048).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 0.6 kcal/mol difference is significant, but must be weighed against other factors.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is the more promising candidate. The key advantages of Ligand B are its significantly lower DILI risk, longer in vitro half-life, and slightly better BBB penetration. Both compounds suffer from poor predicted solubility and permeability, which are major liabilities. However, the improved safety profile and metabolic stability of Ligand B outweigh the minor potency difference.

Output:
1
2025-04-17 11:34:06,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.479 and 355.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.11) is significantly better than Ligand B (92.79).  A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (0.628) is a bit low, potentially hindering permeability. Ligand B (3.375) is 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) regarding the number of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar and good QED scores (0.725 and 0.732, respectively).

**DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (92.982), which is a significant concern.

**BBB:** Ligand A (65.723) has better BBB penetration than Ligand B (50.523), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.161) and Ligand B (-5.073) have similar, and very poor, Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-0.233) has better solubility than Ligand B (-4.734). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.192) has a much lower hERG inhibition risk than Ligand B (0.318). This is a critical safety parameter.

**Microsomal Clearance:** Ligand A (-3.411) has significantly lower (better) microsomal clearance than Ligand B (40.624), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.086) has a better in vitro half-life than Ligand B (-2.392).

**P-gp Efflux:** Ligand A (0.005) has lower P-gp efflux than Ligand B (0.241), which is favorable.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While the difference is less than 1.5 kcal/mol, it's still a positive factor.

**Overall:**

Ligand A is significantly better than Ligand B. It has a much lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, lower P-gp efflux, and slightly better binding affinity. While its logP is a bit low, the substantial advantages in safety and ADME properties outweigh this minor drawback. Ligand B's high DILI and hERG risk are major red flags.

Output:
0
2025-04-17 11:34:06,142 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.458 and 348.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.49) is well below the 140 threshold, suggesting good absorption. Ligand B (113.44) is still within acceptable limits but less favorable than A.

**logP:** Ligand A (3.735) is optimal. Ligand B (0.128) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 5 HBA) is better balanced than Ligand B (3 HBD, 6 HBA), both are within acceptable limits.

**QED:** Ligand A (0.882) has a significantly better QED score than Ligand B (0.615), indicating a more drug-like profile.

**DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (38.038), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.77) is slightly better than Ligand B (54.052).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.667) is slightly better than Ligand B (-4.844).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.731) is slightly better than Ligand B (-2.226).

**hERG Inhibition:** Ligand A (0.939) has a lower hERG risk than Ligand B (0.083), which is a significant advantage.

**Microsomal Clearance:** Ligand A (32.554) has a higher clearance than Ligand B (24.281), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (85.146) has a longer half-life than Ligand B (-35.159), which is a major advantage.

**P-gp Efflux:** Ligand A (0.505) has lower P-gp efflux liability than Ligand B (0.007), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly higher DILI risk and higher microsomal clearance, its superior binding affinity, QED, hERG inhibition profile, half-life, and P-gp efflux characteristics make it the more promising drug candidate. The significantly stronger binding affinity is a key factor for an enzyme target like SRC kinase. The lower logP of Ligand B is a major concern, likely leading to poor absorption.

Output:
1
2025-04-17 11:34:06,142 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.825 and 351.447 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.14) is well below the 140 threshold, and even below the 90 for CNS targets. Ligand B (96.53) is still within the acceptable range for oral absorption (<140), but higher than A.

**logP:** Ligand A (3.247) is optimal (1-3). Ligand B (0.481) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable, though slightly higher in HBD count.

**QED:** Both ligands have good QED scores (0.733 and 0.671), indicating good drug-like properties.

**DILI:** Ligand A (79.333) has a higher DILI risk than Ligand B (25.514). This is a significant concern for Ligand A.

**BBB:** Both have moderate BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.998) has poor Caco-2 permeability, which is concerning. Ligand B (-5.297) is similarly poor.

**Aqueous Solubility:** Ligand A (-4.039) has poor aqueous solubility. Ligand B (-1.784) is also poor, but better than A.

**hERG:** Ligand A (0.704) has a relatively low hERG risk. Ligand B (0.057) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (57.044) has moderate clearance. Ligand B (10.098) has very low clearance, indicating good metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (65.031) has a reasonable half-life. Ligand B (20.089) has a shorter half-life, but could be improved with structural modifications.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.665 and 0.011), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has *significantly* stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor, as a >1.5 kcal/mol advantage often outweighs other drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better TPSA and hERG profile, Ligand B is the far superior candidate. The dramatically stronger binding affinity (-8.4 vs 0.0 kcal/mol) is decisive. Furthermore, Ligand B exhibits much lower DILI risk and significantly better metabolic stability (lower Cl_mic). While solubility and Caco-2 permeability are poor for both, these can be addressed through formulation or structural modifications. The weak binding of Ligand A makes it unlikely to be a viable drug candidate regardless of other properties.

Output:
1
2025-04-17 11:34:06,142 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.363 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.04) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (84.94) is excellent, well below 140.

**logP:** Ligand A (-0.136) is quite low, potentially hindering permeability. Ligand B (1.518) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.453 and 0.553), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (94.649) has a high DILI risk, which is a significant concern. Ligand B (45.366) has a much lower, and acceptable, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (73.827) has a higher BBB value than Ligand A (40.791), but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.483 and -4.744). 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 (-3.703 and -2.397). Again, the scale is not specified, so it is hard to interpret.

**hERG Inhibition:** Ligand A (0.098) has a very low hERG risk, which is excellent. Ligand B (0.224) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (10.662) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (51.189) has a much higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (48.581) has a longer half-life than Ligand B (-27.409), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.034).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. However, it suffers from a very high DILI risk and a low logP, which could impact permeability and bioavailability. Ligand B has a better TPSA, logP, and DILI risk, but its binding affinity is considerably weaker and it has poorer metabolic stability.

Given the enzyme-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 low logP is also a concern, but again, could be addressed with chemical modifications. The weaker binding of Ligand B is a more difficult issue to overcome.

Output:
1
2025-04-17 11:34:06,142 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.49 and 379.55 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is better than Ligand B (61.44), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (3.23 and 2.11, respectively), falling within the 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:** Ligand B (0.679) has a better QED score than Ligand A (0.446), indicating a more drug-like profile.

**DILI:** Ligand A (12.60) has a significantly lower DILI risk than Ligand B (44.59), which is a major advantage.

**BBB:** Ligand A (81.70) has a higher BBB penetration percentile than Ligand B (68.83), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.96) has better Caco-2 permeability than Ligand B (-5.43).

**Aqueous Solubility:** Ligand A (-3.15) has better aqueous solubility than Ligand B (-2.88).

**hERG:** Both ligands have very low hERG inhibition liability (0.64 and 0.46, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (70.75) has higher microsomal clearance than Ligand B (54.24), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (16.86) has a much longer in vitro half-life than Ligand A (-2.31), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.45 and 0.18, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has a better QED and longer half-life, Ligand A exhibits a much lower DILI risk and better solubility and permeability. Given the enzyme-kinase focus, metabolic stability (Ligand B) and DILI risk (Ligand A) are crucial. The significantly lower DILI risk of Ligand A outweighs the slightly better metabolic stability of Ligand B, especially as both have excellent binding affinity.

Output:
0
2025-04-17 11:34:06,142 - INFO - Batch 58 complete. Total preferences: 928
2025-04-17 11:34:06,142 - INFO - Processing batch 59/512...
2025-04-17 11:34:53,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.312 and 371.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.68) is well below the 140 threshold for oral absorption, and is favorable. Ligand B (104.9) is still under 140, but less optimal than A.

**logP:** Ligand A (2.225) is within the optimal 1-3 range. Ligand B (0.063) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (2 HBD, 7 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED scores (0.763 and 0.666), indicating good drug-like properties.

**DILI:** Ligand A (63.358) has a higher DILI risk than Ligand B (54.285), but both are reasonably acceptable.

**BBB:** Ligand A (98.41) shows excellent BBB penetration, while Ligand B (22.606) is very low. While not a primary concern for a non-CNS target like SRC, it's a positive attribute for A.

**Caco-2 Permeability:** Ligand A (-4.115) has poor Caco-2 permeability, which is concerning. Ligand B (-5.43) is even worse.

**Aqueous Solubility:** Ligand A (-3.412) has poor aqueous solubility. Ligand B (-2.04) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.586) has a low hERG risk, which is excellent. Ligand B (0.085) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (35.543) has a moderate microsomal clearance. Ligand B (16.268) has a lower clearance, suggesting better metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand A (-1.7) has a short half-life, which is undesirable. Ligand B (-0.828) is also short, but slightly better than A.

**P-gp Efflux:** Ligand A (0.339) has low P-gp efflux, which is good. Ligand B (0.02) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.7 kcal/mol), making this parameter essentially neutral in the comparison.

**Overall Assessment:**

Ligand B is preferable despite its lower logP and Caco-2 permeability. The primary driver is its significantly better metabolic stability (lower Cl_mic) and slightly better solubility. While Ligand A has better BBB penetration and Caco-2 permeability, these are less critical for an SRC kinase inhibitor. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
1
2025-04-17 11:34:53,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.41 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.1) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (99.5) is still under 140, but less favorable than A.

**3. logP:** Ligand A (0.415) is a bit low, potentially hindering permeation. Ligand B (0.844) 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:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (49.011) has a slightly higher DILI risk than Ligand B (30.71), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.404) is better than Ligand B (59.364).

**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 interpret this.

**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 (0.249 and 0.364 respectively).

**12. Microsomal Clearance:** Ligand A (2.057) has significantly lower microsomal clearance than Ligand B (29.684), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (0.469) has a lower in vitro half-life than Ligand B (2.485), but both are quite low.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.05 respectively).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), a 0.4 kcal/mol difference. While a difference of >1.5 kcal/mol would be very significant, this is not the case here.

**Overall Assessment:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic) and slightly better TPSA. While Ligand B has a slightly better binding affinity and logP, the improved metabolic stability of Ligand A is more crucial for an enzyme target like SRC kinase. The poor solubility and permeability indicated by the negative values are concerning for both, but metabolic stability is a more critical factor to optimize early in the drug discovery process.

Output:
0
2025-04-17 11:34:53,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly better being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (91.76). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have acceptable logP values (A: 2.948, B: 1.798) falling within the 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 hydrogen bond donors and acceptors, potentially improving permeability.

**QED:** Both ligands have similar QED values (A: 0.663, B: 0.593), indicating reasonably good drug-likeness.

**DILI:** Ligand A (17.371) has a much lower DILI risk than Ligand B (43.273), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.927) is better than Ligand B (28.655).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.923) is slightly better than Ligand B (-4.807).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.015) is slightly better than Ligand B (-1.591).

**hERG Inhibition:** Ligand A (0.54) has a slightly better hERG profile than Ligand B (0.342), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (50.436) has a higher microsomal clearance than Ligand B (32.597), meaning it's less metabolically stable. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (44.66) has a significantly longer in vitro half-life than Ligand A (-18.123), a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.402, B: 0.25).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better properties in terms of TPSA, DILI, hERG, and slightly better solubility and permeability, Ligand B's significantly stronger binding affinity (-7.8 vs -8.5 kcal/mol) and longer half-life are critical advantages for an enzyme inhibitor. The improved metabolic stability (longer half-life) is particularly important. Although Ligand B has a higher DILI risk, the potency difference is substantial enough to potentially mitigate this risk through structural modifications during lead optimization.

Output:
1
2025-04-17 11:34:53,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 353.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.46 and 87.74) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.027) is slightly higher than Ligand B (0.591), both are within the optimal 1-3 range. Ligand B is closer to the lower limit, which *could* indicate potential permeability issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Ligand A (0.852) has a higher QED score than Ligand B (0.684), indicating a more drug-like profile.

**DILI:** Ligand A (26.173) has a significantly lower DILI risk than Ligand B (42.846), which is a substantial advantage.

**BBB:** Both ligands have moderate BBB penetration (67.895 and 77.898). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.123) has a worse Caco-2 permeability than Ligand B (-4.606).

**Aqueous Solubility:** Ligand A (-2.514) has a worse aqueous solubility than Ligand B (-2.14).

**hERG:** Both ligands have very low hERG inhibition liability (0.143 and 0.227), which is excellent.

**Microsomal Clearance:** Ligand A (38.598) has a higher microsomal clearance than Ligand B (22.117), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-38.071) has a much longer in vitro half-life than Ligand A (-20.83), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.03).

**Binding Affinity:** Both ligands have similar binding affinity (-8.6 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so this is not a deciding factor.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has a slightly better QED score, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better aqueous solubility. These factors are crucial for an enzyme target like SRC kinase. The slightly lower Caco-2 permeability of Ligand B is a minor concern compared to the metabolic liabilities of Ligand A. The similar binding affinities further solidify this decision.

Output:
1
2025-04-17 11:34:53,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.371 Da) is slightly lower, which could be advantageous for permeability. Ligand B (367.515 Da) is also good.

**TPSA:** Ligand A (99.93) is slightly higher than Ligand B (78.51). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (A: 1.287, B: 0.804), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (A: 6, B: 5) counts.

**QED:** Both ligands have good QED scores (A: 0.705, B: 0.664), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (82.396) compared to Ligand B (13.649). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (46.064) has a better score than Ligand A (26.638).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.471) is slightly worse than Ligand B (-5.749).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.23) is slightly better than Ligand B (-1.271).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.242, B: 0.104).

**Microsomal Clearance:** Both ligands have negative microsomal clearance values, which is unusual. Ligand A (-3.52) is slightly worse than Ligand B (-3.098).

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-9.101) than Ligand A (2.39). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.028, B: 0.014).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-10 kcal/mol). This is a crucial advantage.

**Conclusion:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and solubility, Ligand B's significantly better binding affinity, lower DILI risk, and longer half-life outweigh the slight disadvantages in TPSA and solubility. Ligand A's high DILI risk is a major red flag. The improved potency of Ligand B also provides a buffer to overcome potential ADME challenges.

Output:
1
2025-04-17 11:34:53,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.439 Da and 342.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.53) is higher than Ligand B (32.34). While both are reasonably low, Ligand B is significantly better, suggesting better potential for cell permeability.

**logP:** Ligand A (2.59) is within the optimal 1-3 range. Ligand B (4.089) is slightly above, potentially leading to solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.704 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 71.152, which is concerning (high risk). Ligand B has a much lower DILI risk of 16.053 (good). This is a significant advantage for Ligand B.

**BBB:** Ligand A (73.905) has moderate BBB penetration. Ligand B (96.278) has excellent BBB penetration. While SRC is not a CNS target, better BBB penetration generally correlates with better overall permeability.

**Caco-2 Permeability:** Ligand A (-5.012) has poor Caco-2 permeability, while Ligand B (-4.784) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.295) has poor aqueous solubility, while Ligand B (-4.533) is even worse. This is a significant drawback for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.335) has a low hERG risk, which is excellent. Ligand B (0.787) has a slightly elevated hERG risk, but still acceptable.

**Microsomal Clearance:** Ligand A (41.054) has moderate clearance, while Ligand B (51.331) has higher clearance. Lower clearance is preferred for metabolic stability, giving Ligand A a slight edge.

**In vitro Half-Life:** Ligand A (-15.633) has a negative half-life (which is not physically possible and likely an error in the data), indicating very rapid metabolism. Ligand B (6.813) has a reasonable half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.303 and 0.217), which is good.

**Binding Affinity:** Ligand B (-7.4) has significantly better binding affinity than Ligand A (0). A difference of >1.5 kcal/mol is considered substantial, and this difference could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has slightly higher logP and worse solubility than Ligand A, its significantly better binding affinity, much lower DILI risk, and superior half-life outweigh these drawbacks. Ligand A's extremely poor predicted half-life and high DILI risk are major concerns. The slightly better Caco-2 permeability of Ligand B is also a plus.

Output:
1
2025-04-17 11:34:53,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.491 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.51) is slightly higher than Ligand B (76.02), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.584) is a bit low, potentially hindering permeation. Ligand B (2.774) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have QED values above 0.5 (0.731 and 0.683), indicating good drug-likeness.

**DILI:** Ligand A (40.946) has a slightly higher DILI risk than Ligand B (19.038), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (60.876) has a higher BBB value than Ligand A (52.617).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.325 and -5.04), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.285 and -2.471), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.253) has a slightly lower hERG risk than Ligand B (0.268), which is preferable.

**Microsomal Clearance:** Ligand A (-15.361) has significantly lower (better) microsomal clearance than Ligand B (59.724), indicating better metabolic stability. This is a crucial advantage.

**In vitro Half-Life:** Ligand A (32.459) has a longer half-life than Ligand B (-12.579), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.014 and 0.239).

**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 ADME concerns.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.2 kcal/mol vs -10.2 kcal/mol) is a major advantage for an enzyme target like SRC kinase. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), the difference in binding affinity is more impactful. The slightly lower DILI and hERG risk with Ligand A are positive, but the potency advantage of Ligand B is more critical. Addressing the solubility and permeability issues through formulation or structural modifications would be the next steps for Ligand B.

Output:
1
2025-04-17 11:34:53,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (365.5 and 352.4 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (107.69). A TPSA under 90 is preferred, and Ligand A is comfortably within that range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.57 and 0.74), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 3 respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (5 and 6 respectively), being less than 10.

**6. QED:** Both ligands have similar, good QED scores (0.80 and 0.67), indicating good drug-like properties.

**7. DILI:** Ligand A (35.7) has a slightly higher DILI risk than Ligand B (29.4), but both are well below the concerning threshold of 60.

**8. BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (67.7) is better than Ligand B (31.2), but neither is particularly high.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. This 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 very low hERG inhibition liability (0.40 and 0.15), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (21.19) has significantly lower microsomal clearance than Ligand B (37.64), indicating better metabolic stability. This is a high priority for kinase inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand A (16.66) has a positive half-life, while Ligand B (-27.01) has a negative half-life, which is not possible. This suggests a significant issue with Ligand B's stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.12 and 0.02), which is good.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.1 and -8.9 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand A is the superior candidate. While both have excellent binding affinity and low hERG risk, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, positive t1/2) and a more favorable TPSA. The negative values for Caco-2 and Solubility are concerning for both, but the superior metabolic profile of Ligand A outweighs these concerns. The negative half-life for Ligand B is a major red flag.

Output:
0
2025-04-17 11:34:53,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.804 and 382.501 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.95) is higher than Ligand B (41.99). While both are reasonably low, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Ligand A (3.608) is within the optimal 1-3 range. Ligand B (4.873) 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 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 (0.714 and 0.75), indicating generally drug-like properties.

**DILI:** Ligand A (76.076) has a higher DILI risk than Ligand B (59.442), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (89.415) has a higher percentile than Ligand A (65.374).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.569 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 (-5.817 and -5.22), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.62) has a slightly higher hERG risk than Ligand B (0.555), making Ligand B slightly more favorable.

**Microsomal Clearance:** Ligand A (4.519 mL/min/kg) has a lower microsomal clearance than Ligand B (55.979 mL/min/kg), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (56.781 hours) has a much longer in vitro half-life than Ligand B (38.61 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.585), indicating better bioavailability.

**Binding Affinity:** Ligand B (-9.1 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. The difference of 2.7 kcal/mol is quite large.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most crucial factor for an enzyme inhibitor. While it has some ADME liabilities (higher logP, higher P-gp efflux, lower solubility, and higher clearance), the strong binding affinity is a significant advantage. Ligand A has better ADME properties (lower clearance, longer half-life, lower P-gp efflux, lower DILI), but its significantly weaker binding affinity is a major drawback. Given the importance of potency for kinase inhibitors, the superior binding affinity of Ligand B outweighs its ADME concerns, assuming these can be addressed through further optimization.

Output:
1
2025-04-17 11:34:53,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.366 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (96.25 and 96.53) below the 140 threshold for good oral absorption, but higher than the 90 threshold for CNS targets (not relevant here).

**3. logP:** Ligand A (0.996) is closer to the optimal 1-3 range than Ligand B (0.259), which is a bit low and might cause permeability issues.

**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 acceptable QED values (0.794 and 0.641), indicating good drug-like properties.

**7. DILI:** Ligand A (56.65) has a higher DILI risk than Ligand B (25.94), which is a significant concern.

**8. BBB:** This is less important for a non-CNS target. Ligand A (80.341) has a higher BBB value than Ligand B (43.699).

**9. Caco-2 Permeability:** Ligand A (-4.595) has better Caco-2 permeability than Ligand B (-5.32).

**10. Aqueous Solubility:** Ligand A (-1.848) has better aqueous solubility than Ligand B (-1.667). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.225 and 0.099).

**12. Microsomal Clearance:** Ligand A (2.392) has a significantly *lower* (better) microsomal clearance than Ligand B (-5.441). This indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.264) has a shorter half-life than Ligand B (10.074). This is a disadvantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.013).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -7.0 kcal/mol). The difference of 1 kcal/mol is substantial, and Ligand A has the better affinity.

**Overall Assessment:**

Despite the higher DILI risk for Ligand A, its superior binding affinity, better metabolic stability (lower Cl_mic), better solubility, and better Caco-2 permeability outweigh the DILI concern. The affinity difference is significant. Ligand B has a better DILI profile and half-life, but its lower affinity and worse ADME properties make it less attractive.

Output:
0
2025-04-17 11:34:53,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (353.463 and 357.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (108.41). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (0.776) is within the optimal 1-3 range, while Ligand B (-1.797) is below 1, which might hinder permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 6 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits, but A is slightly more favorable.

**QED:** Ligand A (0.699) is better than Ligand B (0.543), indicating a more drug-like profile.

**DILI:** Ligand B (34.432) has a lower DILI risk than Ligand A (24.195), which is a positive for B.

**BBB:** Ligand A (56.417) has better BBB penetration than Ligand B (18.147), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.773) is better than Ligand B (-5.035), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.107) is better than Ligand B (-0.772), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.112 and 0.096, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (-0.365) has a *much* lower (better) microsomal clearance than Ligand A (13.76). This indicates significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-14.641) has a *much* longer in vitro half-life than Ligand A (3.741), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.011, respectively).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in logP, TPSA, solubility, and QED, Ligand B's superior binding affinity and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are critical for an enzyme target like SRC kinase. The stronger binding is likely to translate to greater efficacy, and the improved metabolic stability will lead to a more favorable pharmacokinetic profile. The slightly higher DILI risk for A is less concerning than the metabolic liabilities of A.

Output:
1
2025-04-17 11:34:53,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 361.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (38.25) as it is closer to the ideal range of <=140 for good oral absorption.

**logP:** Ligand A (3.0) is within the optimal 1-3 range, while Ligand B (4.445) is slightly higher, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (0 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.769 and 0.696), indicating good drug-likeness.

**DILI:** Ligand A (25.126) has a significantly lower DILI risk than Ligand B (21.946), which is a major advantage.

**BBB:** Ligand B (85.459) has better BBB penetration than Ligand A (74.641), but this is less critical for a kinase inhibitor unless CNS activity is desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.733 and -4.965), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.136 and -3.534), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.42) has a lower hERG inhibition liability than Ligand B (0.85), which is a positive.

**Microsomal Clearance:** Ligand A (44.198) has a lower microsomal clearance than Ligand B (49.209), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.509) has a better in vitro half-life than Ligand B (33.342).

**P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux liability than Ligand B (0.653), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While the difference is not huge, it's enough to potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), lower hERG inhibition, lower P-gp efflux, and slightly better binding affinity. While both have poor solubility and permeability, the improvements in safety and metabolic stability make Ligand A more promising.

Output:
0
2025-04-17 11:34:53,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.415 Da) is slightly lower, which can be beneficial for permeability. Ligand B (350.394 Da) is also good.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (90.12) is better than Ligand B (95.42).

**logP:** Ligand A (3.161) is optimal, while Ligand B (1.622) is on the lower side, potentially impacting permeability.

**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 QED values above 0.5 (A: 0.798, B: 0.86), indicating good drug-like properties.

**DILI:** Ligand A (79.449) has a higher DILI risk than Ligand B (57.193), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.164) has a higher BBB value than Ligand A (54.634), but this is not a major factor here.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.086) is worse than Ligand B (-4.775), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are percentile scores, Ligand A (-4.388) is worse than Ligand B (-3.094), suggesting lower solubility.

**hERG Inhibition:** Ligand A (0.474) has a lower hERG risk than Ligand B (0.281), which is favorable.

**Microsomal Clearance:** Ligand A (-6.53) has significantly lower microsomal clearance than Ligand B (17.475), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (27.652) has a longer half-life than Ligand B (-20.054), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.042, B: 0.072).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). The difference is 1.2 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B has a better binding affinity and lower DILI risk, but suffers from lower metabolic stability (higher Cl_mic, shorter half-life) and lower logP. Ligand A has a better ADME profile with much better metabolic stability, but a higher DILI risk and slightly weaker binding.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the improved metabolic stability of Ligand A is a significant advantage. While the DILI risk is concerning, it might be mitigated through structural modifications. The binding affinity difference, while notable, might be overcome with further optimization of Ligand A.

Output:
1
2025-04-17 11:34:53,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.414 and 373.509 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.36) is better than Ligand B (29.54) as it is closer to the threshold of 140 for good oral absorption. Ligand B is very low, which could indicate good permeability but might compromise solubility.

**logP:** Ligand A (1.584) is within the optimal range (1-3). Ligand B (4.476) is slightly high, potentially leading to solubility issues and off-target interactions.

**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 reasonable QED values (0.809 and 0.617), indicating good drug-like properties.

**DILI:** Ligand A (75.029) has a higher DILI risk than Ligand B (11.245). This is a significant drawback for Ligand A.

**BBB:** Ligand A (82.164) has moderate BBB penetration, while Ligand B (95.308) has high BBB penetration. While SRC is not a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.624 and -4.625). This is unusual and suggests a potential issue with the data or the model used to predict this value. It's difficult to interpret without further information.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.071 and -4.913). Similar to Caco-2, this is concerning and requires further investigation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.629 and 0.734), which is good.

**Microsomal Clearance:** Ligand A (35.862) has significantly lower microsomal clearance than Ligand B (89.184), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (28.533) has a longer half-life than Ligand B (-6.118). This is another advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.144 and 0.561).

**Binding Affinity:** Ligand B (-7.1 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:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and has a reasonable QED. However, its higher DILI risk and weaker binding affinity are significant concerns. Ligand B has a much stronger binding affinity, lower DILI risk, and better BBB penetration. While its logP is slightly high, and solubility/Caco-2 values are problematic, the potency advantage is substantial. Given the enzyme-specific priorities, binding affinity is paramount. The solubility and permeability concerns with Ligand B could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:34:53,596 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [368.474, 59.5, 3.036, 0, 5, 0.66, 41.915, 86.041, -4.65, -3.194, 0.598, 86.966, -1.299, 0.207, -8.2]
**Ligand B:** [348.487, 54.71, 3.517, 1, 4, 0.781, 8.375, 78.79, -4.844, -2.516, 0.505, 50.548, 59.319, 0.098, -8.8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (368.474) is slightly higher than B (348.487), but both are acceptable.
2. **TPSA:** Both are below the 140 A<sup>2</sup> threshold for good oral absorption. A (59.5) is slightly higher than B (54.71), but both are good.
3. **logP:** Both are within the optimal range (1-3). A (3.036) is slightly lower than B (3.517).
4. **HBD:** A (0) is preferable to B (1). Lower HBD generally improves permeability.
5. **HBA:** A (5) is preferable to B (4). Both are acceptable, but lower is generally better.
6. **QED:** Both are above 0.5, indicating good drug-like properties. B (0.781) is slightly better than A (0.66).
7. **DILI:** A (41.915) is significantly better than B (8.375). Lower DILI risk is crucial.
8. **BBB:** A (86.041) is better than B (78.79), but BBB is less critical for a non-CNS target like SRC.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.65) is slightly worse than B (-4.844).
10. **Solubility:** Both are negative, indicating poor solubility. A (-3.194) is slightly better than B (-2.516).
11. **hERG:** Both are very low, indicating low risk of cardiotoxicity. A (0.598) is slightly higher than B (0.505).
12. **Cl_mic:** A (86.966) is significantly higher than B (50.548), meaning B has better metabolic stability. Lower Cl_mic is preferred.
13. **t1/2:** B (59.319) is significantly better than A (-1.299), indicating a much longer in vitro half-life. This is a major advantage.
14. **Pgp:** A (0.207) is better than B (0.098). Lower Pgp efflux is preferred.
15. **Affinity:** B (-8.8 kcal/mol) is slightly better than A (-8.2 kcal/mol). A difference of 0.6 kcal/mol is meaningful, but not overwhelming.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B has a slightly better affinity.
*   **Metabolic Stability:** B has *much* better metabolic stability (lower Cl_mic, longer t1/2). This is a significant advantage.
*   **Solubility:** A has slightly better solubility.
*   **hERG:** Both are good.
*   **DILI:** A has a much better DILI profile.

**Conclusion:**

While ligand A has a better DILI profile and slightly better solubility, ligand B's significantly improved metabolic stability (lower Cl_mic and much longer half-life) and slightly better binding affinity outweigh these advantages. The poor Caco-2 and solubility for both compounds would need to be addressed in further optimization, but the metabolic stability is a critical factor for kinase inhibitors.

1
2025-04-17 11:34:53,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.415 and 342.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (68.62 and 67.35) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (3.024 and 2.166). Ligand B is slightly better here.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Both ligands have high QED scores (0.874 and 0.894), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 47.421, while Ligand B has 29.546. Ligand B is significantly better regarding liver injury risk.

**BBB:** Both have reasonable BBB penetration, but Ligand B (90.229) is higher than Ligand A (75.029). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.73) is slightly better than Ligand A (-4.396), but both are problematic.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand B (-1.818) is slightly better than Ligand A (-2.965).

**hERG Inhibition:** Both have very low hERG inhibition risk (0.437 and 0.192). Ligand B is better here.

**Microsomal Clearance:** Ligand B (13.731 mL/min/kg) has significantly lower microsomal clearance than Ligand A (37.367 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (25.693 hours) has a longer half-life than Ligand A (11.067 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.051).

**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 is superior to Ligand A. While both have good potency and drug-likeness, Ligand B demonstrates significantly better ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), slightly better solubility, and lower hERG risk. The Caco-2 permeability is concerning for both, but the improvements in metabolic stability and safety for Ligand B outweigh this drawback.

Output:
1
2025-04-17 11:34:53,597 - INFO - Batch 59 complete. Total preferences: 944
2025-04-17 11:34:53,597 - INFO - Processing batch 60/512...
2025-04-17 11:35:35,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.431 and 348.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (96.11 and 95.75) are below 140, suggesting reasonable oral absorption potential.

**3. logP:** Ligand A (1.261) is optimal, while Ligand B (0.572) is slightly low, potentially hindering permeation.

**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, acceptable. Ligand B has 5 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.648 and 0.839), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 60.14%, which is borderline high. Ligand B has a significantly lower DILI risk of 35.014%, which is good. This is a substantial advantage for Ligand B.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.637) and Ligand B (48.158) are both relatively low.

**9. Caco-2:** Both have negative Caco-2 values (-5.569 and -5.016), 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 (-2.526 and -1.719), also unusual and suggesting poor solubility. Similar to Caco-2, direct comparison is difficult.

**11. hERG:** Ligand A (0.633) has a slightly higher hERG risk than Ligand B (0.116). Ligand B is much better here.

**12. Cl_mic:** Ligand A (45.688) has a higher microsomal clearance than Ligand B (9.51), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**13. t1/2:** Ligand B (12.427) has a significantly longer in vitro half-life than Ligand A (5.684), which is highly desirable.

**14. Pgp:** Ligand A (0.291) has a slightly higher Pgp efflux liability than Ligand B (0.01), meaning Ligand B is less likely to be pumped out by P-glycoprotein.

**15. Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is the most critical factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is clearly superior. It has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and lower Pgp efflux. While both have questionable Caco-2 and solubility values, the substantial advantage in binding affinity and the improved ADME properties of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 11:35:35,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (356.463 and 348.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.31) is better than Ligand B (104.45). Both are below 140, but A is closer to the desirable threshold for oral absorption.

**3. logP:** Ligand A (0.674) is slightly better than Ligand B (-0.829). Both are a bit low, potentially impacting permeability, but A 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 5 HBA, while Ligand B has 7. Both are below the 10 limit, but A is preferable.

**6. QED:** Both ligands have similar QED values (0.647 and 0.673), indicating good drug-likeness.

**7. DILI:** Ligand B (39.279) has a lower DILI risk than Ligand A (20.512), which is a significant advantage. Lower DILI is always preferred.

**8. BBB:** Ligand A (53.548) has a better BBB penetration percentile than Ligand B (27.646). However, as SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.45) has better Caco-2 permeability than Ligand B (-4.968), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.594) has slightly better aqueous solubility than Ligand B (-0.686). Both are negative, which is not ideal, but A is better.

**11. hERG Inhibition:** Ligand A (0.26) has a much lower hERG inhibition liability than Ligand B (0.03), which is a crucial advantage for safety.

**12. Microsomal Clearance:** Ligand B (9.534) has significantly lower microsomal clearance than Ligand A (45.649), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-17.125) has a longer in vitro half-life than Ligand A (15.83), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.02), which is good.

**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:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, Ligand A has a significantly better binding affinity and better hERG profile. Given that SRC is a kinase, potency and safety (hERG) are paramount. The 0.8 kcal/mol difference in binding affinity is substantial. The slightly lower metabolic stability of Ligand A can potentially be addressed through structural modifications during lead optimization. The better hERG profile of A is a significant advantage.

Output:
1
2025-04-17 11:35:35,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (383.47 and 372.881 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.28) is higher than Ligand B (72.78). While both are reasonably acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Both ligands have logP values within the optimal range (2.403 and 3.922). Ligand B is slightly higher, which *could* present solubility challenges, 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 within acceptable limits, but Ligand B's lower HBD count is slightly advantageous for permeability.

**QED:** Both ligands have good QED scores (0.542 and 0.711), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (86.972) has a higher DILI risk than Ligand B (73.982). This is a significant concern, as lower DILI is highly desirable.

**BBB:** This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (61.38) is slightly better than Ligand A (50.64).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.472) has a slightly lower hERG inhibition risk than Ligand B (0.899), which is preferable.

**Microsomal Clearance:** Ligand A (32.963) has a lower microsomal clearance than Ligand B (41.964), suggesting better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (30.244) has a shorter half-life than Ligand B (41.298). Ligand B is preferable.

**P-gp Efflux:** Ligand A (0.34) has lower P-gp efflux liability than Ligand B (0.606), which is preferable.

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.3 vs -9.3 kcal/mol). While it has some ADME liabilities (slightly higher logP, higher P-gp efflux, lower solubility and permeability), the strong binding advantage, coupled with a lower DILI risk, makes it the more promising candidate. The improved half-life is also a benefit. Ligand A has better metabolic stability and lower hERG risk, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 11:35:35,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 351.447 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is slightly higher than Ligand B (78.95), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.884) is optimal, while Ligand B (0.531) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable, below the limit of 5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well within the acceptable limit of 10.

**QED:** Ligand B (0.801) has a significantly better QED score than Ligand A (0.556), indicating a more drug-like profile.

**DILI:** Ligand A (10.896) has a much lower DILI risk than Ligand B (18.728), which is a significant advantage.

**BBB:** Ligand B (80.031) has a higher BBB penetration percentile than Ligand A (69.678), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.551 and -4.824). This is unusual and suggests poor permeability, but the scale is not specified, so the absolute impact is unclear.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.761 and -0.885). Again, the scale is unspecified, but these suggest poor solubility.

**hERG Inhibition:** Ligand A (0.636) has a slightly higher hERG risk than Ligand B (0.079), which is a concern. Ligand B is much better here.

**Microsomal Clearance:** Ligand A (56.999) has a significantly higher microsomal clearance than Ligand B (1.913), meaning it's less metabolically stable. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (6.975) has a longer in vitro half-life than Ligand A (13.767).

**P-gp Efflux:** Ligand A (0.229) has a higher P-gp efflux liability than Ligand B (0.009), which could reduce bioavailability.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a significantly better binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage that could outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher metabolic clearance, P-gp efflux, and hERG risk, and lower QED. Ligand B has better ADME properties (QED, DILI, hERG, Cl_mic, t1/2, Pgp), but its binding affinity is essentially non-existent.

Given the significant difference in binding affinity, and the fact that SRC is not a CNS target, I believe Ligand A is the more promising candidate *despite* its ADME liabilities. The potency advantage is likely to be more easily addressed through further optimization than trying to significantly improve the affinity of Ligand B.

Output:
0
2025-04-17 11:35:35,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.18) is better than Ligand B (107.5), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (though that isn't a priority here).

**logP:** Ligand A (2.557) is optimal (1-3), while Ligand B (0.889) is slightly low, potentially impacting permeability.

**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 good QED scores (0.439 and 0.769, respectively), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (59.364) has a higher DILI risk than Ligand B (17.449). This is a significant advantage for Ligand B.

**BBB:** Both have similar BBB penetration (51.066 and 60.566), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.116 and -5.069), which is unusual and suggests poor permeability. This is a drawback for both, but doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-2.702 and -1.881), indicating poor solubility. Again, a drawback for both, but doesn't differentiate them.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.213 and 0.299), which is good.

**Microsomal Clearance:** Ligand A (57.584) has a higher microsomal clearance than Ligand B (4.42), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-3.214) has a negative half-life, which is not possible. Ligand B (-4.704) also has a negative half-life, which is not possible. This is a major drawback for both, but doesn't differentiate them.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.214 and 0.006).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good binding affinity, Ligand B is significantly better overall. It has a much lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly better QED score. The slightly lower logP of Ligand B is a minor concern, but outweighed by its advantages in safety and metabolism. The negative half-life and Caco-2 permeability are concerning for both, but don't differentiate them.

Output:
1
2025-04-17 11:35:35,405 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.442 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (369.491 Da) is also good.

**TPSA:** Ligand A (49.33) is excellent, well below the 140 threshold for oral absorption. Ligand B (91.42) is higher, but still acceptable, though potentially slightly impacting absorption.

**logP:** Ligand A (4.023) is at the upper end of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (1.017) is a bit low, potentially hindering membrane permeability.

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

**QED:** Both ligands have reasonable QED scores (A: 0.832, B: 0.722), indicating good drug-like properties.

**DILI:** Ligand A (30.399) has a significantly lower DILI risk than Ligand B (67.235), which is a major advantage.

**BBB:** Ligand A (68.515) has better BBB penetration than Ligand B (42.342), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.684) has a very poor Caco-2 permeability score, indicating poor absorption. Ligand B (-5.378) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.547) has poor solubility, which is concerning. Ligand B (-2.336) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.907) has a lower hERG risk than Ligand B (0.233), which is a significant advantage.

**Microsomal Clearance:** Ligand A (50.154) has a moderate microsomal clearance, while Ligand B (45.079) is slightly better, suggesting slightly improved metabolic stability.

**In vitro Half-Life:** Ligand A (32.606) has a reasonable half-life. Ligand B (-20.345) has a *negative* half-life, which is impossible and indicates a significant issue with the data or the molecule's stability.

**P-gp Efflux:** Ligand A (0.721) has moderate P-gp efflux, while Ligand B (0.087) has very low efflux, which is beneficial.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite Ligand A's poor Caco-2 permeability and solubility, its *much* stronger binding affinity (-8.9 vs -7.0 kcal/mol) and significantly lower DILI and hERG risk make it the more promising candidate. The strong binding is a critical factor for an enzyme inhibitor, and the lower toxicity risks are highly desirable. Ligand B's negative in vitro half-life is a showstopper.

Output:
0
2025-04-17 11:35:35,405 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (379.287 and 367.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is well below the 140 threshold and is favorable. Ligand B (80.32) is still acceptable but less optimal.

**3. logP:** Ligand A (4.816) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.676) 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:** Ligand A has 2 HBA, well within the limit. Ligand B has 5 HBA, still acceptable but higher.

**6. QED:** Both ligands have a QED of 0.749 and 0.74, respectively, indicating good drug-like properties.

**7. DILI:** Ligand A (77.356) has a higher DILI risk than Ligand B (52.966). This is a significant concern.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (63.435) and B (49.244) are both relatively low.

**9. Caco-2:** Both have negative Caco-2 values (-4.524 and -4.851), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-6.53) has very poor aqueous solubility, which is a major drawback. Ligand B (-2.761) is also poor, but better than A.

**11. hERG:** Both ligands have low hERG inhibition liability (0.51 and 0.173), which is good.

**12. Cl_mic:** Ligand A (70.127) has a higher microsomal clearance than Ligand B (30.656), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. t1/2:** Ligand A (82.795) has a longer in vitro half-life than Ligand B (20.222), which is a positive.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.18 and 0.124), which is favorable.

**15. Binding Affinity:** Both ligands have the same strong binding affinity (-7.9 kcal/mol).

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand B is the more promising candidate. Ligand A suffers from poor solubility, higher DILI risk, and higher metabolic clearance. The longer half-life of Ligand A is a positive, but it's outweighed by the significant ADME liabilities. Ligand B, while also having poor Caco-2 permeability and solubility, is better overall due to its lower DILI risk and improved metabolic stability. Addressing the permeability and solubility issues of Ligand B through structural modifications would be a more viable strategy than attempting to mitigate the multiple liabilities of Ligand A.

Output:
1
2025-04-17 11:35:35,405 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.861 Da and 377.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.42) is better than Ligand B (62.3). While both are reasonably low, Ligand B is significantly lower, potentially aiding absorption.

**logP:** Both ligands have good logP values (3.964 and 3.379), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBDs, while Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBAs, which is within the acceptable range (<=10).

**QED:** Ligand B (0.888) has a substantially better QED score than Ligand A (0.416), indicating a more drug-like profile.

**DILI:** Ligand A (41.024) has a lower DILI risk than Ligand B (63.125), which is preferable.

**BBB:** Both have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (78.209) is higher than Ligand A (59.325).

**Caco-2 Permeability:** Ligand A (-4.936) and Ligand B (-5.255) both have negative Caco-2 values, indicating poor permeability. Ligand B is slightly worse.

**Aqueous Solubility:** Ligand A (-5.03) and Ligand B (-4.647) both have poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.626) has a lower hERG risk than Ligand B (0.555), which is preferable.

**Microsomal Clearance:** Ligand A (24.332) has a significantly lower microsomal clearance than Ligand B (47.44), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.024) has a longer in vitro half-life than Ligand B (13.087), which is desirable.

**P-gp Efflux:** Ligand A (0.241) has lower P-gp efflux than Ligand B (0.53), which is preferable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1 kcal/mol difference is a major advantage.

**Conclusion:**

While Ligand A has advantages in DILI, metabolic stability (Cl_mic and t1/2), P-gp efflux, and hERG, the substantially stronger binding affinity of Ligand B (-8.8 vs -7.8 kcal/mol) outweighs these drawbacks. The improved QED score 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 11:35:35,405 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.419 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.57) is better than Ligand B (96.97), both are acceptable but closer to the upper limit for optimal absorption.

**logP:** Ligand A (2.841) is optimal (1-3), while Ligand B (-0.719) is below 1, which could hinder permeation. This is a significant negative for Ligand B.

**H-Bond Donors:** Both have acceptable HBD counts (3 and 2 respectively), below the threshold of 5.

**H-Bond Acceptors:** Both have acceptable HBA counts (5), below the threshold of 10.

**QED:** Both ligands have good QED scores (0.654 and 0.698), indicating good drug-likeness.

**DILI:** Ligand A (81.504) has a higher DILI risk than Ligand B (34.432). This favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.044) and Ligand B (27.065) are both low.

**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 and suggests poor solubility. The scale isn't specified, so it's difficult to interpret.

**hERG:** Both ligands have very low hERG inhibition risk (0.675 and 0.093), which is excellent.

**Microsomal Clearance:** Ligand A (52.378) has a higher clearance than Ligand B (-11.378). The negative value for Ligand B is unusual, but suggests very good metabolic stability. This is a strong advantage for Ligand B.

**In vitro Half-Life:** Ligand A (104.781) has a longer half-life than Ligand B (22.676). This favors Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.585 and 0.006), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand B is the better candidate. While Ligand A has a slightly longer half-life, Ligand B has significantly better logP, DILI risk, and microsomal clearance. The negative logP of Ligand A is a major concern as it can severely impact absorption. The lower DILI and significantly improved metabolic stability (indicated by the negative Cl_mic) of Ligand B outweigh the slightly shorter half-life of Ligand B.

Output:
1
2025-04-17 11:35:35,405 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 Da and 358.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.44) is slightly higher than Ligand B (99.1), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.115) is quite low, potentially hindering permeation. Ligand B (-0.393) is also low, but slightly better. Both are below the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.671) has a better QED score than Ligand B (0.385), indicating a more drug-like profile.

**DILI:** Ligand B (15.394) has a significantly lower DILI risk than Ligand A (49.011), which is a major advantage.

**BBB:** Ligand B (67.468) has a higher BBB penetration percentile than Ligand A (43.66), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.249) has a very poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.913) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.391) has poor aqueous solubility, while Ligand B (-2.286) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.158) has a lower hERG inhibition liability than Ligand B (0.333), which is a positive.

**Microsomal Clearance:** Ligand A (-4.236) has a much lower (better) microsomal clearance than Ligand B (6.898), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (26.75 hours) has a significantly longer half-life than Ligand B (-38.76 hours - which is essentially zero/very rapid clearance). This is a major advantage.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, while Ligand B (0.034) is slightly higher. Both are good.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage and could potentially offset some of the ADME liabilities.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) than Ligand B. Its QED score is also higher. However, Ligand B has a much lower DILI risk. Both have poor solubility and Caco-2 permeability, and low logP values. The strong binding affinity of Ligand A and its improved metabolic stability are crucial for an enzyme target. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The DILI risk of Ligand A is a concern, but the potency advantage is substantial.

Output:
1
2025-04-17 11:35:35,405 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.797 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.88) is well below the 140 threshold, while Ligand B (87.66) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.504) is optimal, while Ligand B (0.977) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, well within acceptable limits. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.732 and 0.541), indicating good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (82.319 percentile), while Ligand B has a very low risk (11.4 percentile). This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (62.233) is better than Ligand B (49.981).

**Caco-2 Permeability:** Ligand A (-4.108) shows poor permeability, while Ligand B (-4.632) is also poor but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.654 and -1.6). This is a concern for both, but Ligand B is slightly better.

**hERG:** Ligand A (0.243) has a slightly elevated hERG risk, while Ligand B (0.118) is lower.

**Microsomal Clearance:** Ligand A has high microsomal clearance (95.702), indicating poor metabolic stability. Ligand B has very low clearance (0.116), suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A has a very short half-life (-15.449), while Ligand B has a very short half-life (0.615). Both are poor.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.081 and 0.022).

**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 can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity, excellent metabolic stability (low Cl_mic), and very low DILI risk outweigh the slightly lower logP and BBB. The poor solubility would need to be addressed through formulation strategies, but the other properties position Ligand B as a better starting point for optimization.

Output:
1
2025-04-17 11:35:35,406 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.873 and 348.531 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is higher than Ligand B (41.57). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (3.159 and 3.663), 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.

**QED:** Ligand B (0.771) has a slightly better QED score than Ligand A (0.522), indicating better overall drug-likeness.

**DILI:** Ligand A (24.893) has a higher DILI risk than Ligand B (13.804), which is preferable.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand B (89.608) has a higher BBB percentile than Ligand A (69.523).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.704 and -4.729), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.718 and -3.5), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.728 and 0.702), which is good.

**Microsomal Clearance:** Ligand B (75.842) has a significantly higher microsomal clearance than Ligand A (33.535). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (54.722) has a longer in vitro half-life than Ligand B (7.055), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand B (0.458) has slightly higher P-gp efflux than Ligand A (0.243), which is less desirable.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a significantly weaker binding affinity than Ligand A (-8.5 kcal/mol). This is the most critical factor. A difference of 8.5 kcal/mol is substantial and likely outweighs the other drawbacks of Ligand A.

**Conclusion:**

Despite the poor Caco-2 and solubility for both compounds, Ligand A is the much stronger candidate due to its significantly superior binding affinity (-8.5 kcal/mol vs -0.0 kcal/mol). The better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk further support choosing Ligand A. While solubility and permeability are major hurdles, these can be addressed with formulation strategies. A compound with negligible binding affinity is unlikely to be a viable drug candidate, regardless of its ADME properties.

Output:
1
2025-04-17 11:35:35,406 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as drug candidates targeting SRC, a kinase.

**Step-by-step comparison:**

1. **MW:** Ligand A (345.403 Da) is within the ideal range (200-500). Ligand B (361.515 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (95.33) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (70.15) is excellent, well below the 140 threshold, suggesting better absorption potential.

3. **logP:** Both ligands (A: 1.715, B: 1.989) are within the optimal 1-3 range. No significant difference.

4. **HBD:** Ligand A (1) is good. Ligand B (2) is also acceptable, both are below the 5 threshold.

5. **HBA:** Ligand A (5) is good. Ligand B (6) is also acceptable, both are below the 10 threshold.

6. **QED:** Ligand A (0.91) is excellent, indicating a highly drug-like profile. Ligand B (0.617) is still acceptable, above the 0.5 threshold, but less ideal than A.

7. **DILI:** Ligand A (63.746) is moderately high risk. Ligand B (34.277) is much lower risk, a significant advantage.

8. **BBB:** Ligand A (43.001) is low, not a major concern for a non-CNS target like SRC. Ligand B (62.04) is also low, and not a major concern.

9. **Caco-2:** Ligand A (-4.987) is very poor. Ligand B (-5.488) is also very poor. Both are problematic, indicating poor intestinal absorption.

10. **Solubility:** Ligand A (-1.725) is poor. Ligand B (-2.108) is even worse. Both are concerning for formulation and bioavailability.

11. **hERG:** Both ligands (A: 0.432, B: 0.279) have low hERG inhibition liability, which is good. Ligand B is slightly better.

12. **Cl_mic:** Ligand A (27.326) is moderate. Ligand B (16.064) is lower, indicating better metabolic stability, a key consideration for kinases.

13. **t1/2:** Ligand A (-49.582) is very poor. Ligand B (4.766) is poor, but significantly better than A. Longer half-life is desirable.

14. **Pgp:** Both ligands (A: 0.088, B: 0.017) have low P-gp efflux, which is good. Ligand B is slightly better.

15. **Binding Affinity:** Ligand B (-8.9 kcal/mol) is slightly better than Ligand A (-8.4 kcal/mol), but the difference is relatively small.

**Enzyme-Kinase Specific Priorities:**

For kinases like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While both ligands have acceptable binding affinities, Ligand B clearly outperforms Ligand A in metabolic stability (lower Cl_mic, better t1/2) and DILI risk. The solubility is poor for both, but similar.

**Conclusion:**

Considering the enzyme-specific priorities, **Ligand B** is the more promising drug candidate. Its lower DILI risk, better metabolic stability, and slightly improved binding affinity outweigh the slightly lower QED score. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:35:35,406 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 343.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.09) is better than Ligand B (71.76), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.001) is optimal, while Ligand B (2.223) is still within the acceptable 1-3 range, but less ideal.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 7. Ligand A is preferable here, being closer to the <10 threshold.

**QED:** Both ligands have good QED scores (0.769 and 0.867), indicating drug-likeness.

**DILI:** Ligand A (5.894) has a significantly lower DILI risk than Ligand B (52.423), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (62.621 and 63.901), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.773) and Ligand B (-5.232) both have negative Caco-2 values, which is unusual and suggests very poor permeability. This is a significant drawback for both.

**Solubility:** Ligand A (-0.496) is better than Ligand B (-2.295), indicating better aqueous solubility.

**hERG:** Ligand A (0.125) has a much lower hERG inhibition liability than Ligand B (0.404), which is a critical safety advantage.

**Microsomal Clearance:** Ligand A (6.02) has a much lower Cl_mic than Ligand B (17.906), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.644) has a better in vitro half-life than Ligand B (33.74).

**P-gp:** Both ligands have very low P-gp efflux liability (0.022 and 0.058).

**Binding Affinity:** Both ligands have the same excellent binding affinity (-8 kcal/mol).

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is significantly better across multiple crucial ADMET properties. It has a much lower DILI risk, lower hERG liability, better solubility, and better metabolic stability (lower Cl_mic and longer t1/2). The Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh this drawback. Ligand B's higher logP and HBA count, coupled with its significantly worse DILI and hERG profiles, make it a less desirable candidate.

Output:
0
2025-04-17 11:35:35,406 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (98.74), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.175) is optimal, while Ligand B (0.417) is slightly low, potentially hindering permeation.

**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.

**QED:** Ligand A (0.808) has a significantly better QED score than Ligand B (0.589), indicating a more drug-like profile.

**DILI:** Ligand A (41.218) has a slightly higher DILI risk than Ligand B (13.106), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (56.65) is better than Ligand B (29.081).

**Caco-2 Permeability:** Ligand A (-4.819) is better than Ligand B (-5.039), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.805) is better than Ligand B (-1.718), which is important for formulation and bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.162 and 0.042 respectively).

**Microsomal Clearance:** Ligand A (39.465) has a lower microsomal clearance than Ligand B (43.879), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.182) has a positive half-life, while Ligand B (-13.483) has a negative half-life, indicating that Ligand A is more stable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.013 respectively).

**Binding Affinity:** Ligand B (-9.0 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 advantage that can outweigh other drawbacks.

**Overall Assessment:**

Ligand A demonstrates a superior overall profile. It has a better QED score, better solubility, better permeability, better metabolic stability (lower Cl_mic and positive t1/2), and a reasonable DILI risk. While Ligand B has slightly better binding affinity, the other advantages of Ligand A, particularly its improved ADME properties, make it the more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 11:35:35,406 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (361.364 and 359.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.58) is significantly better than Ligand B (108.92).  A TPSA under 90 is preferred, and A is much closer to that target.

**3. logP:** Both ligands have good logP values (1.79 and 1.069), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (8). Lower HBA is generally preferred for better permeability.

**6. QED:** Both ligands have similar, good QED values (0.726 and 0.717), indicating good drug-likeness.

**7. DILI:** Ligand A (11.516) has a much lower DILI risk than Ligand B (88.057). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (86.08) has a better BBB percentile than Ligand B (36.836), but BBB is less critical for a non-CNS target like SRC.

**9. Caco-2:** Ligand A (-4.988) and Ligand B (-5.393) both have negative values, which is not ideal. Higher values are better, indicating better absorption.

**10. Solubility:** Ligand A (-2.37) is slightly better than Ligand B (-3.189), but both are poor. Solubility is a key consideration for kinases.

**11. hERG:** Both ligands have low hERG risk (0.88 and 0.727).

**12. Cl_mic:** Ligand A (-30.614) has a much lower (better) microsomal clearance than Ligand B (10.463). This indicates better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (1.49) has a slightly better in vitro half-life than Ligand B (-6.756).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.08 and 0.045).

**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 DILI score, lower TPSA, lower microsomal clearance, and slightly better solubility and half-life. While both have good binding affinity, the ADME properties of Ligand A are substantially more favorable, making it a more promising drug candidate for SRC kinase inhibition.

Output:
0
2025-04-17 11:35:35,406 - INFO - Batch 60 complete. Total preferences: 960
2025-04-17 11:35:35,406 - INFO - Processing batch 61/512...
2025-04-17 11:36:13,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.386 and 361.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is better than Ligand B (40.54) as it is still within the acceptable range for oral absorption (<140), while B is significantly lower.

**logP:** Both ligands have logP values (3.494 and 4.481) within the optimal 1-3 range, although B is slightly higher.

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

**H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.646 and 0.79), indicating drug-like properties.

**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 (31.291), making it more favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.957) has a higher BBB penetration than Ligand B (56.146).

**Caco-2 Permeability:** Ligand A (-4.76) and Ligand B (-5.026) 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 negative solubility values (-4.262 and -4.491), indicating poor solubility.

**hERG Inhibition:** Ligand A (0.545) has a slightly lower hERG inhibition risk than Ligand B (0.934), which is preferable.

**Microsomal Clearance:** Ligand A (67.287) has a significantly lower microsomal clearance than Ligand B (113.262), suggesting better metabolic stability. This is a crucial factor for enzymes.

**In vitro Half-Life:** Ligand A (32.162) has a longer half-life than Ligand B (-3.46), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.52) has lower P-gp efflux than Ligand B (0.617), which is favorable.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a >3 kcal/mol difference, which is a very significant advantage and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's slightly elevated DILI risk, its significantly superior binding affinity (-9.6 vs -6.5 kcal/mol), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux outweigh the concerns. The strong binding affinity is the most important factor for an enzyme inhibitor. While both have solubility issues, the potency of A is likely to compensate.

Output:
1
2025-04-17 11:36:13,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (385.869 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.88) is slightly higher than Ligand B (65.2). Both are acceptable, being below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (3.38 and 2.903), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.862) has a significantly higher QED score than Ligand A (0.526), indicating a more drug-like profile.

**DILI:** Ligand B (54.634) has a lower DILI risk than Ligand A (71.423), which is a significant advantage. Both are below the concerning threshold of 60, but lower is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (57.736) is slightly higher than Ligand A (46.375).

**Caco-2 Permeability:** Ligand A (-4.7) shows better Caco-2 permeability than Ligand B (-5.388). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.962) has slightly better aqueous solubility than Ligand B (-3.575).

**hERG:** Ligand A (0.307) has a lower hERG risk than Ligand B (0.6), a crucial factor for safety.

**Microsomal Clearance:** Ligand B (40.653) exhibits significantly lower microsomal clearance than Ligand A (65.629), suggesting better metabolic stability. Lower clearance is preferred.

**In vitro Half-Life:** Ligand B (-9.693) has a longer in vitro half-life than Ligand A (50.75). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.579) has lower P-gp efflux than Ligand B (0.354), indicating potentially better bioavailability.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This difference of 1.7 kcal/mol is a major advantage and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having slightly better Caco-2 permeability and lower P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.2 vs -7.5 kcal/mol), much better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and higher QED score outweigh the minor drawbacks in permeability and efflux. For an enzyme target like SRC kinase, potency and metabolic stability are paramount.

Output:
1
2025-04-17 11:36:13,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (368.463 Da) is also good.

**TPSA:** Ligand A (96.11) is better than Ligand B (114.42), being closer to the desirable threshold of <=140 for oral absorption.

**logP:** Ligand A (1.535) is within the optimal range (1-3). Ligand B (-0.635) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is better balanced than Ligand B (HBD=1, HBA=7). While both are within acceptable limits, a higher number of HBA in Ligand B might affect permeability.

**QED:** Both ligands have good QED scores (A: 0.591, B: 0.62), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (A: 39.201, B: 43.622), below the 60 threshold.

**BBB:** Both have moderate BBB penetration (A: 59.325, B: 56.572). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.344 and -5.498), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.343 and -1.223), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both have very low hERG risk (A: 0.125, B: 0.059), which is excellent.

**Microsomal Clearance:** Ligand A (27.937) has a higher clearance than Ligand B (15.161). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (-16.015) has a slightly longer half-life than Ligand A (-18.402), which is a positive.

**P-gp Efflux:** Both have very low P-gp efflux (A: 0.075, B: 0.012), which is favorable.

**Binding Affinity:** Both have very similar and strong binding affinities (A: -7.7 kcal/mol, B: -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is slightly more promising. While both have issues with Caco-2 permeability and solubility, Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life. The logP value for Ligand A is better, but the difference isn't substantial enough to outweigh the metabolic advantages of Ligand B. The binding affinity is essentially the same.

Output:
1
2025-04-17 11:36:13,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.268 Da) is slightly higher than Ligand B (356.463 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (80.55 and 88.1) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (2.76) is optimal, while Ligand B (0.408) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 5 HBAs, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.594 and 0.658), indicating drug-like properties.

**DILI:** Ligand A (66.344) has a higher DILI risk than Ligand B (10.896). This is a significant concern for Ligand A.

**BBB:** Both have similar BBB penetration (67.739 and 66.77), which isn't a primary concern for a non-CNS target like SRC.

**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 have negative solubility values, indicating poor aqueous solubility. Ligand B (-1.142) is slightly better than Ligand A (-2.696), but both are problematic.

**hERG Inhibition:** Ligand A (0.684) has a slightly higher hERG risk than Ligand B (0.326), but both are relatively low.

**Microsomal Clearance:** Ligand B (0.047) has significantly lower microsomal clearance than Ligand A (61.16), indicating much better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-5.887) has a much longer in vitro half-life than Ligand A (10.457), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.12) has slightly higher P-gp efflux than Ligand B (0.015), which is not ideal.

**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 for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk and substantially worse metabolic stability (higher Cl_mic, shorter t1/2) are major drawbacks. Ligand B, despite a slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly regarding metabolic stability and liver toxicity. Given the enzyme-kinase focus, metabolic stability and minimizing off-target effects (like DILI) are crucial. The 1.7 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, whereas mitigating the DILI risk associated with Ligand A would be far more challenging.

Output:
1
2025-04-17 11:36:13,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.487 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.84) is well below the 140 threshold for good absorption, and favorable for kinase inhibitors. Ligand B (91.56) is higher, but still within an acceptable range, though less optimal.

**logP:** Ligand A (3.691) is within the optimal 1-3 range. Ligand B (0.157) is quite low, potentially hindering membrane permeability and absorption.

**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 identical QED scores (0.837), indicating good drug-likeness.

**DILI:** Ligand A (46.297) has a lower DILI risk than Ligand B (53.044), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.553) has a higher BBB penetration than Ligand B (47.964).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.882 and -4.808), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.83 and -1.2), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.86) has a lower hERG risk than Ligand B (0.232), which is a major advantage.

**Microsomal Clearance:** Ligand A (65.449) has a higher microsomal clearance than Ligand B (28.528), meaning Ligand B is more metabolically stable. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (6.077 hours) has a longer half-life than Ligand B (-4.857 hours). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Ligand A (0.577) has lower P-gp efflux than Ligand B (0.063), which is preferable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol) - a difference of 0.9 kcal/mol. This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B is the more promising candidate due to its significantly stronger binding affinity (-8.4 vs -7.5 kcal/mol) and better metabolic stability (lower Cl_mic). The lower hERG risk of Ligand A is a positive, but the substantial affinity advantage of Ligand B is more critical for an enzyme target like SRC. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modifications, but the potency and metabolic stability of Ligand B provide a better starting point.

Output:
1
2025-04-17 11:36:13,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.471 and 348.334 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (117.35). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Both ligands have acceptable logP values (2.174 and 1.169), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=3, HBA=6). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar QED scores (0.76 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (15.394) has a much lower DILI risk than Ligand B (66.344). This is a significant advantage for Ligand A.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (69.794) is slightly better than Ligand B (56.883).

**Caco-2 Permeability:** Ligand A (-5.011) is better than Ligand B (-4.788), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.544) is better than Ligand B (-3.417). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.611) has a lower hERG risk than Ligand B (0.075). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (2.708) has significantly lower microsomal clearance than Ligand B (27.847). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (2.483) has a positive half-life, while Ligand B (-18.58) has a negative half-life, indicating faster degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.022).

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand A is clearly the superior candidate. It has a better safety profile (lower DILI, lower hERG), better ADME properties (better solubility, permeability, metabolic stability, and half-life), and, most importantly, a significantly stronger binding affinity for the target. While both ligands meet the basic drug-likeness criteria, Ligand A's advantages across multiple parameters make it the more viable drug candidate.

Output:
1
2025-04-17 11:36:13,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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.

**TPSA:** Ligand A (88.85) is better than Ligand B (56.92) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (0.968) is within the optimal range, while Ligand B (4.253) is high. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=3, HBA=2) both fall within acceptable ranges.

**QED:** Ligand A (0.859) has a significantly better QED score than Ligand B (0.509), indicating a more drug-like profile.

**DILI:** Ligand B (42.962) has a lower DILI risk than Ligand A (57.154), which is favorable.

**BBB:** Ligand B (91.392) has a much higher BBB penetration percentile than Ligand A (70.803). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.756) has a worse Caco-2 permeability than Ligand B (-5.071).

**Aqueous Solubility:** Ligand A (-2.329) has a better aqueous solubility than Ligand B (-4.351).

**hERG:** Ligand A (0.839) has a lower hERG risk than Ligand B (0.921), which is a significant advantage.

**Microsomal Clearance:** Ligand A (0.271) has much lower microsomal clearance than Ligand B (59.059), suggesting better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (12.255 hours) has a shorter half-life than Ligand B (45.203 hours).

**P-gp Efflux:** Ligand A (0.174) has lower P-gp efflux than Ligand B (0.757), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.9 kcal/mol and -8.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has lower DILI and a longer half-life, Ligand A excels in key areas for an enzyme inhibitor: better QED, lower logP (reducing potential for off-target effects and solubility issues), significantly lower microsomal clearance (better metabolic stability), lower hERG risk, and lower P-gp efflux. The slight difference in binding affinity is not enough to overcome these advantages.

Output:
0
2025-04-17 11:36:13,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.491 and 353.369 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (60.5). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.788) is optimal, while Ligand B (3.243) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides some hydrogen bonding capability.

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

**QED:** Ligand A (0.785) has a significantly better QED score than Ligand B (0.513), indicating a more drug-like profile.

**DILI:** Ligand A (13.532) has a much lower DILI risk than Ligand B (41.024). This is a significant advantage.

**BBB:** Both ligands have high BBB penetration (Ligand A: 89.027, Ligand B: 84.451), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.436) is slightly better than Ligand B (-4.739).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.318) is slightly better than Ligand B (-2.082).

**hERG:** Ligand A (0.228) has a much lower hERG risk than Ligand B (0.627), a critical factor for safety.

**Microsomal Clearance:** Ligand A (30.099) has a significantly lower microsomal clearance than Ligand B (71.501), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.413) has a negative half-life, which is unusual. Ligand B (16.016) has a positive half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.02) has a much lower P-gp efflux liability than Ligand B (0.396), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.1) has a stronger binding affinity than Ligand A (-7.0), a difference of 1.1 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a significantly better safety profile (lower DILI and hERG), better metabolic stability (lower Cl_mic), and better predicted bioavailability (lower P-gp efflux). The QED score is also much higher for Ligand A. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh the affinity difference, especially considering SRC is an enzyme target where metabolic stability and safety are paramount.

Output:
0
2025-04-17 11:36:13,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (345.443 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.53) is slightly higher than Ligand B (70.39), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have acceptable logP values (1.582 and 2.616), 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:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.631 and 0.772), indicating good drug-like properties.

**7. DILI:** Ligand B (22.334) has a significantly lower DILI risk than Ligand A (48.197). This is a major advantage for Ligand B.

**8. BBB:** Both have low BBB penetration (28.848 and 27.646), which is not a primary concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Ligand A (-4.539) has worse Caco-2 permeability than Ligand B (-5.15). Both are quite poor, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-3.468) has slightly better aqueous solubility than Ligand B (-3.154).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.461 and 0.179).

**12. Microsomal Clearance:** Ligand B (75.227) has a higher microsomal clearance than Ligand A (55.066), indicating lower metabolic stability. This is a drawback for Ligand B.

**13. In vitro Half-Life:** Ligand B (13.262) has a significantly longer in vitro half-life than Ligand A (3.51). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.191 and 0.032).

**15. Binding Affinity:** Ligand A (-8.0) has a better binding affinity than Ligand B (-6.6). This is a substantial advantage for Ligand A (1.4 kcal/mol difference).

**Overall Assessment:**

Ligand A has a stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand B exhibits a much better safety profile (lower DILI) and a longer half-life, which are crucial for *in vivo* efficacy. The difference in binding affinity (1.4 kcal/mol) is significant, but not insurmountable, and could potentially be addressed with further optimization. The lower DILI and longer half-life of Ligand B are more difficult to improve later in development. Considering the balance of properties, and prioritizing metabolic stability and safety for an enzyme target, Ligand B is the more promising candidate.

Output:
1
2025-04-17 11:36:13,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 Da and 364.511 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 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.979) is slightly lower than optimal (1-3), but acceptable. Ligand B (1.665) is within the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, both are below the limit of 5.

**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: 0.623, B: 0.698), indicating good drug-like properties.

**DILI:** Ligand A (21.83) has a significantly lower DILI risk than Ligand B (18.108), which is preferable.

**BBB:** Ligand B (56.534) has a higher BBB penetration than Ligand A (32.183), but BBB is not a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-4.987) has a much better Caco-2 permeability than Ligand B (-5.006).

**Aqueous Solubility:** Ligand A (-1.867) has better aqueous solubility than Ligand B (-3.447).

**hERG Inhibition:** Ligand A (0.102) has a slightly lower hERG inhibition risk than Ligand B (0.265), which is favorable.

**Microsomal Clearance:** Ligand B (19.705) has a significantly higher microsomal clearance than Ligand A (3.816), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (1.642) has a better in vitro half-life than Ligand B (-1.789).

**P-gp Efflux:** Ligand A (0.022) has a lower P-gp efflux liability than Ligand B (0.102), which is preferable.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive advantage.

**Conclusion:**

Ligand A is the superior candidate. It has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, lower hERG risk, and lower P-gp efflux. While Ligand B has a slightly better logP and BBB, the substantial advantages of Ligand A in potency and ADME properties outweigh these minor differences.

Output:
0
2025-04-17 11:36:13,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.435 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.32 and 88.18) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.615) is optimal (1-3). Ligand B (0.218) is quite low, potentially hindering permeation.

**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 (0.637 and 0.69) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (90.694) has a high DILI risk, while Ligand B (37.185) is much lower and acceptable. This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.309) is higher than Ligand A (60.876).

**Caco-2 Permeability:** Ligand A (-5.005) has poor Caco-2 permeability, while Ligand B (-4.615) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.725 and -2.065).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.334 and 0.367).

**Microsomal Clearance:** Ligand A (29.624) has higher clearance than Ligand B (-5.672), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-13.785) has a more negative value, indicating a longer half-life than Ligand A (22.109).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.3 and 0.041).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage for Ligand A. The difference of 2.3 kcal/mol is significant.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand A, its high DILI risk, poor Caco-2 permeability, and higher microsomal clearance are major concerns. Ligand B, while having a weaker binding affinity, exhibits a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better permeability. The improved ADME properties of Ligand B outweigh the affinity difference, making it the more promising drug candidate.

Output:
1
2025-04-17 11:36:13,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.394 and 369.893 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.77) is slightly higher than Ligand B (80.32). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.944 and 2.731) falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

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

**QED:** Both have similar QED values (0.7 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (72.392) has a higher DILI risk than Ligand B (34.471). Ligand B is significantly better here, falling well below the 40% threshold.

**BBB:** Both ligands have similar BBB penetration (65.839 and 65.103). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.159 and -5.04). This is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values (-3.678 and -3.012), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.134) has slightly lower hERG inhibition risk than Ligand B (0.502), which is preferable.

**Microsomal Clearance:** Ligand A (20.725 mL/min/kg) has significantly lower microsomal clearance than Ligand B (53.571 mL/min/kg). Lower clearance indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (16.96 hours) has a shorter half-life than Ligand B (42.976 hours). Ligand B is better here.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.138 and 0.179).

**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 small, it's enough to be considered, especially given the other factors.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both have issues with solubility and Caco-2 permeability, Ligand B demonstrates a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly improved binding affinity. These factors are particularly important for an enzyme target like SRC kinase. The slightly higher hERG risk for Ligand B is a minor concern compared to the other advantages.

Output:
1
2025-04-17 11:36:13,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (336.355 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.8) is slightly above the preferred <140, while Ligand B (69.64) is well within the range.

**logP:** Both ligands (2.088 and 2.712) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are below the threshold of 10.

**QED:** Both ligands have good QED scores (0.759 and 0.881), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 90.733, which is high. Ligand B has a much lower DILI risk of 25.863, which is excellent. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (66.227) has a higher BBB score than Ligand A (40.403), but it's not a primary concern here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.205 and -5.12), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.401 and -2.876), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.349) has a slightly higher hERG risk than Ligand B (0.189), but both are relatively low.

**Microsomal Clearance:** Ligand B (-2.238) has significantly lower (better) microsomal clearance than Ligand A (16.743). This indicates better metabolic stability for Ligand B, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-7.996) has a negative half-life, which is unusual. Ligand A (32.863) has a more reasonable half-life. However, the negative value for B is likely an artifact of the model and doesn't necessarily mean it's immediately disqualifying, especially given its other strong points.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.022).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the superior candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic), and substantially stronger binding affinity outweigh the concerns. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 11:36:13,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.515 Da and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.87 and 75.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.15 and 1.954) 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 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.742 and 0.853), indicating drug-like properties.

**DILI:** Ligand A (16.751) has a significantly lower DILI risk than Ligand B (41.218). This is a major advantage for Ligand A.

**BBB:** Both ligands have the same BBB penetration (63.086), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar, very negative Caco-2 values (-4.791 and -4.781). This suggests poor permeability, which could be a problem, but is not a deciding factor given the other data.

**Aqueous Solubility:** Both ligands have similar, very negative solubility values (-2.788 and -2.796). This suggests poor solubility, which could be a problem, but is not a deciding factor given the other data.

**hERG:** Both ligands have low hERG inhibition liability (0.428 and 0.307).

**Microsomal Clearance:** Ligand B (22.269) has a lower microsomal clearance than Ligand A (39.105), suggesting better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (4.204) has a longer in vitro half-life than Ligand A (-0.39). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.078 and 0.276).

**Binding Affinity:** Ligand B (-9.1 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 the ADME concerns. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand A has a much better DILI profile, the significantly stronger binding affinity of Ligand B (-9.1 vs -8.4 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. The improved metabolic stability (lower Cl_mic) and longer half-life of Ligand B further support its selection. The solubility and permeability issues are concerning for both, but can potentially be addressed through formulation strategies. The lower DILI risk of Ligand A is attractive, but the potency advantage of Ligand B is more important in this case.

Output:
1
2025-04-17 11:36:13,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 Da and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is slightly higher than Ligand B (71.54), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.84 and 1.839), 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.524 and 0.659), indicating good drug-likeness.

**DILI:** Ligand A (16.092) has a significantly lower DILI risk than Ligand B (26.095), which is a major advantage. Both are below the 40 threshold.

**BBB:** Both have similar BBB penetration (61.846 and 68.399), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.795) shows poorer Caco-2 permeability than Ligand B (-5.104), but both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-2.16) has slightly poorer solubility than Ligand B (-1.905), but both are negative values, indicating low solubility.

**hERG Inhibition:** Ligand A (0.146) has a lower hERG inhibition risk than Ligand B (0.905), which is a significant advantage.

**Microsomal Clearance:** Ligand A (49.702) has a higher microsomal clearance than Ligand B (34.4), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand B (24.734) has a significantly longer in vitro half-life than Ligand A (-14.621), which is a major advantage.

**P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux liability than Ligand B (0.017), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.3). Although the difference is small, it is still a positive factor for Ligand B.

**Overall Assessment:**

Ligand A has advantages in DILI risk and P-gp efflux, but suffers from poorer Caco-2 permeability, solubility, metabolic stability (higher Cl_mic and shorter half-life), and a slightly weaker binding affinity. Ligand B excels in metabolic stability (lower Cl_mic and longer half-life), has a slightly better binding affinity, and a lower hERG risk. The lower DILI and hERG risk of Ligand B are crucial for an oncology drug. While solubility and permeability are concerns for both, the metabolic stability and safety profile of Ligand B outweigh the small advantage of Ligand A in those areas.

Output:
1
2025-04-17 11:36:13,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.435 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.93) is better than Ligand B (122.56), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.952) is within the optimal 1-3 range, while Ligand B (-0.619) is slightly below 1, which *could* indicate potential permeability issues.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 3 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.634) has a better QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Ligand B (41.024) has a significantly better DILI score than Ligand A (16.867), suggesting a lower risk of liver injury. This is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (63.862) has a slightly better BBB percentile than Ligand B (57.968).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.662 and -5.374), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.084 and -1.324), indicating poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.363) has a much lower hERG inhibition risk than Ligand B (0.044), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-4.654) has a *much* better (lower) microsomal clearance than Ligand B (24.203), indicating significantly better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.209) has a better in vitro half-life than Ligand B (-3.302).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.011).

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.7). While both are good, the 1.3 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior binding affinity, significantly better metabolic stability (lower Cl_mic and higher t1/2), lower hERG risk, and better QED outweigh the slightly higher DILI risk. Both ligands suffer from poor predicted solubility and permeability, but these issues can potentially be addressed through formulation strategies. The substantial difference in metabolic stability and hERG risk makes Ligand A the more promising starting point for optimization.

Output:
1
2025-04-17 11:36:13,795 - INFO - Batch 61 complete. Total preferences: 976
2025-04-17 11:36:13,795 - INFO - Processing batch 62/512...
2025-04-17 11:36:54,204 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.4 and 344.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the preferred <140, but acceptable. Ligand B (49.85) is excellent, well below 140.

**logP:** Both ligands have good logP values (0.933 and 1.808), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.85 and 0.731), indicating good drug-like properties.

**DILI:** Ligand A (41.88) has a slightly higher DILI risk than Ligand B (13.3), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (70.03) has a higher BBB score than Ligand A (54.63), but this is less relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale and can be interpreted relative to each other. Ligand A (-4.875) has a slightly better (less negative) Caco-2 value than Ligand B (-4.291).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-1.865) is slightly better than Ligand A (-2.579).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.131 and 0.257), which is excellent.

**Microsomal Clearance:** Ligand A (7.476) has a significantly lower microsomal clearance than Ligand B (20.022). This suggests better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-14.252) has a longer in vitro half-life than Ligand B (-10.424), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.116).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.1 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other considerations.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a slightly better TPSA and solubility, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better Caco-2 permeability. Given the enzyme-specific priorities, metabolic stability is paramount, and the small advantage in binding affinity is not enough to favor Ligand B.

Output:
0
2025-04-17 11:36:54,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (332.37 and 348.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (88.49 and 87.32) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.00 and 1.26), falling within the 1-3 range. Ligand B is slightly more hydrophilic.

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

**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 good QED scores (0.585 and 0.81), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 80.65, which is considered high risk (>60). Ligand B has a significantly lower DILI risk of 36.49, which is good (<40). This is a major advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration (41.22 and 45.21), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.64 and -5.14), 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 (-3.42 and -2.58), again 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 (0.47 and 0.15). This is excellent.

**Microsomal Clearance:** Ligand A has a Cl_mic of 37.33, while Ligand B has a Cl_mic of 7.06. Ligand B has significantly lower clearance, indicating better metabolic stability, which is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A has a negative half-life (-8.33), and Ligand B has a negative half-life (-13.66). These negative values are concerning and suggest rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.15 and 0.02).

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent and meets the criteria of < -7.0 kcal/mol.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is significantly better overall. The major advantages of Ligand B are its much lower DILI risk (36.5 vs 80.7) and significantly improved metabolic stability (lower Cl_mic, 7.06 vs 37.33). Although both have poor predicted solubility and permeability, the metabolic stability and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 11:36:54,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.328 Da) is slightly lower, which could be advantageous for permeability, while Ligand B (367.519 Da) is also good.

**TPSA:** Ligand A (65.46) is better than Ligand B (70.47), both are acceptable for oral absorption (<140).

**logP:** Ligand A (3.827) is optimal, while Ligand B (1.201) is on the lower side. A logP below 1 can sometimes hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=1, HBA=6). Both are within acceptable limits, but Ligand A's profile is more balanced.

**QED:** Both ligands have similar QED values (A: 0.864, B: 0.792), indicating good drug-likeness.

**DILI:** Ligand A (52.966) has a higher DILI risk than Ligand B (29.857). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.625) is better than Ligand B (49.011).

**Caco-2 Permeability:** Both have negative values, which is unusual and requires further investigation. However, we can assume lower values are worse. Ligand A (-5.078) is slightly better than Ligand B (-5.189).

**Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-4.414) is slightly better than Ligand B (-1.669).

**hERG Inhibition:** Ligand A (0.627) has a slightly higher hERG risk than Ligand B (0.135). This is a concern for Ligand A.

**Microsomal Clearance:** Ligand B (4.145) has significantly lower microsomal clearance than Ligand A (32.94). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand B (27.096) has a much longer in vitro half-life than Ligand A (-14.097). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.146) has lower P-gp efflux than Ligand B (0.036), which is favorable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better TPSA, Caco-2, solubility, and P-gp efflux, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better binding affinity, much lower microsomal clearance, and a longer in vitro half-life. Furthermore, Ligand B has a lower DILI risk and hERG inhibition liability. The lower logP of Ligand B is a minor concern, but the superior binding affinity and metabolic stability are more important.

Output:
1
2025-04-17 11:36:54,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.358 Da and 342.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.72) is slightly above the preferred <140, but still reasonable. Ligand B (67.98) is excellent, well below 140.

**logP:** Both ligands (1.574 and 2.792) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Both have good QED scores (0.793 and 0.912), indicating drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (94.804 percentile). Ligand B has a much lower and acceptable DILI risk (44.591 percentile). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration (83.87 and 92.012 percentile). Not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we can still compare them.

**Solubility:** Both have negative solubility values, also unusual.

**hERG:** Both have low hERG risk (0.133 and 0.54 percentile).

**Microsomal Clearance:** Ligand A has a much lower (better) microsomal clearance (-8.459 mL/min/kg) than Ligand B (22.661 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a significantly longer half-life (21.887 hours) than Ligand B (2.397 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux (0.104 and 0.157 percentile).

**Binding Affinity:** Both have very similar and excellent binding affinities (-8.6 kcal/mol and -8.3 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Conclusion:**

Despite Ligand A's superior metabolic stability and half-life, its extremely high DILI risk is a major red flag. The DILI risk for Ligand B is much more acceptable. The binding affinities are comparable. Therefore, Ligand B is the more promising candidate due to the lower predicted toxicity.

Output:
1
2025-04-17 11:36:54,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.383 and 345.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.58 and 75.44) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.712) is optimal, while Ligand B (1.896) is slightly lower but still acceptable.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.634 and 0.898), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 75.184, which is concerning (high risk). Ligand B has a much lower DILI risk of 41.062, which is good. This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (89.957) is higher than Ligand B (62.233).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.396 and -4.775), which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are common. The absolute values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.72 and -2.352), indicating poor aqueous solubility. Again, these are on a log scale, and the absolute values are similar.

**hERG:** Ligand A (0.538) has a slightly higher hERG risk than Ligand B (0.426), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (83.888) has a higher microsomal clearance, suggesting lower metabolic stability, while Ligand B (12.641) has a much lower clearance, indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (2.218) has a shorter half-life than Ligand B (2.566), consistent with the higher clearance.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.408 and 0.033).

**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 minor ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is the superior candidate due to its significantly lower DILI risk and improved metabolic stability (lower Cl_mic, longer t1/2). The stronger binding affinity of Ligand B is also a significant benefit. The solubility and permeability issues are similar for both, and the hERG risk is acceptable for both. Given the enzyme-specific priorities, the improved safety and metabolic stability of Ligand B make it the more viable drug candidate.

Output:
1
2025-04-17 11:36:54,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.377 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 A (42.68) is slightly higher than Ligand B (37.61), but both are good.

**logP:** Both ligands have logP values around 4.4, which is slightly high. This could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 3 HBA, which is within the acceptable range and promotes good permeability.

**QED:** Ligand A (0.815) has a better QED score than Ligand B (0.641), indicating a more drug-like profile.

**DILI:** Both ligands have DILI risk above 50, indicating moderate risk. Ligand A (56.572) is slightly lower than Ligand B (60.644), suggesting a marginally lower potential for liver injury.

**BBB:** Both ligands have high BBB penetration (Ligand A: 86.429, Ligand B: 89.763), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates poor permeability. Ligand B (-5.028) is worse than Ligand A (-4.337).

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-4.384) is slightly better than Ligand B (-4.048).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.8 and 0.876), which is excellent.

**Microsomal Clearance:** Ligand B (87.818) has significantly higher microsomal clearance than Ligand A (65.884), indicating lower metabolic stability. This is a critical drawback.

**In vitro Half-Life:** Ligand A (50.728 hours) has a much longer in vitro half-life than Ligand B (4.393 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.7 and 0.843), which is favorable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference of 1.6 kcal/mol is significant.

**Conclusion:**

Despite the slightly better QED, solubility, and metabolic stability of Ligand A, the significantly stronger binding affinity of Ligand B (-8.7 vs -7.1 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. While Ligand B has higher clearance and lower half-life, these issues can potentially be addressed through structural modifications in subsequent optimization rounds. The strong binding affinity provides a better starting point for further development.

Output:
1
2025-04-17 11:36:54,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (349.431 and 389.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (89.43 and 88.6) are below the 140 A^2 threshold for good oral absorption, and well below the 90 A^2 threshold for CNS targets (not relevant here).

**3. logP:** Both ligands (1.2 and 1.784) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (1) as it is closer to the ideal range of <=5.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 6) are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (A: 0.808, B: 0.732), indicating good drug-like properties.

**7. DILI:** Ligand A (39.24) has a significantly lower DILI risk than Ligand B (61.807). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (78.558) is higher than Ligand B (63.862).

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand B (-5.263) is worse than Ligand A (-4.636).

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand B (-3.124) is worse than Ligand A (-2.043).

**11. hERG Inhibition:** Both ligands have low hERG risk (A: 0.194, B: 0.41).

**12. Microsomal Clearance:** Ligand A (22.616 mL/min/kg) has a much lower microsomal clearance than Ligand B (54.411 mL/min/kg), suggesting better metabolic stability. This is a key consideration for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (11.476 hours) has a significantly longer half-life than Ligand B (2.146 hours), which is desirable for less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.029, B: 0.113).

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is not substantial enough to outweigh the significant advantages of Ligand A in other crucial ADME properties.

**Overall Assessment:**

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility and permeability. These factors are critical for *in vivo* efficacy and safety.

Output:
0
2025-04-17 11:36:54,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.515 and 370.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is slightly higher than Ligand B (58.2). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better permeability.

**logP:** Both ligands (2.256 and 3.021) are 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA). Ligand B is slightly more favorable due to fewer potential off-target interactions.

**QED:** Both ligands have similar QED values (0.762 and 0.731), indicating good drug-likeness.

**DILI:** Ligand A (55.021) has a higher DILI risk than Ligand B (34.471). This is a significant advantage for Ligand B.

**BBB:** Ligand A (70.803) and Ligand B (88.29) both have acceptable BBB penetration, but Ligand B is better. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.973) has worse Caco-2 permeability than Ligand B (-4.66). Both are negative, but B is less negative, suggesting better absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.537 and -3.478). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.51 and 0.535), which is moderate.

**Microsomal Clearance:** Ligand A (26.111) has higher microsomal clearance than Ligand B (23.899), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-19.156) has a much longer in vitro half-life than Ligand A (-9.879), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.115 and 0.026).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to outweigh other factors, it contributes to the overall favorability of Ligand B.

**Overall:** Ligand B is superior due to its lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), 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 11:36:54,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.33 and 355.331 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.4) is better than Ligand B (38.33), being under the 140 threshold for good oral absorption.

**logP:** Ligand A (2.228) is optimal (1-3), while Ligand B (4.204) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

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

**QED:** Ligand A (0.837) has a higher QED score than Ligand B (0.756), indicating better overall drug-likeness.

**DILI:** Ligand B (68.205) has a lower DILI risk than Ligand A (98.565), which is a significant advantage.

**BBB:** Ligand B (73.827) has a better BBB penetration percentile than Ligand A (68.748), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.748 and -4.58), which is unusual and suggests poor permeability. However, these values are on a log scale and need careful interpretation.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.414 and -5.391), indicating poor aqueous solubility. This is a concern for both, but Ligand B appears slightly worse.

**hERG Inhibition:** Ligand A (0.161) has a significantly lower hERG inhibition risk than Ligand B (0.831). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-6.473) has much lower microsomal clearance than Ligand B (59.72), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (33.881 hours) has a significantly longer half-life than Ligand B (0.094 hours). This is a substantial advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux liability than Ligand B (0.334), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a 1.6 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, poor metabolic stability (high Cl_mic, low t1/2), higher hERG risk, and higher P-gp efflux. Ligand A, while having a weaker binding affinity, demonstrates much better ADME properties, particularly in terms of metabolic stability, hERG risk, and half-life. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand A. Given the importance of avoiding toxicity and ensuring reasonable drug exposure, I would initially favor Ligand A as the more promising starting point for further development.

Output:
0
2025-04-17 11:36:54,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.388 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (93.36) is better than Ligand B (107.53), falling comfortably under the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.2) is within the optimal range (1-3). Ligand B (-0.007) is very close to 1, but acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (4 HBD, 4 HBA). Both are within acceptable limits.

**QED:** Ligand A (0.836) is significantly better than Ligand B (0.541), indicating a more drug-like profile.

**DILI:** Ligand B (22.8) has a much lower DILI risk than Ligand A (62.737), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (93.37) is higher than Ligand B (28.461).

**Caco-2 Permeability:** Ligand A (-4.928) is better than Ligand B (-5.275). Both are negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-2.957) is better than Ligand B (-2.107). Both are negative, indicating low solubility.

**hERG Inhibition:** Ligand A (0.69) is better than Ligand B (0.039), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-10.748) is significantly better than Ligand B (15.697), indicating much greater metabolic stability.

**In vitro Half-Life:** Ligand A (5.114) is better than Ligand B (-2.462), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.12) is better than Ligand B (0.013), indicating lower P-gp efflux.

**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 small.

**Overall Assessment:**

Ligand A excels in most ADME properties (QED, metabolic stability, half-life, P-gp efflux, hERG) and has a slightly better binding affinity. However, Ligand B has a much lower DILI risk, which is a crucial factor. While Ligand A's better metabolic stability is attractive, the lower DILI risk of Ligand B is a significant advantage, especially early in development. The binding affinity difference is not large enough to outweigh the DILI concern.

Output:
1
2025-04-17 11:36:54,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (369.443 and 373.406 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (117.36) is slightly above the preferred <140 for good oral absorption, while Ligand B (101.78) is well within the range.

**3. logP:** Ligand A (0.793) is a bit low, potentially hindering permeation. Ligand B (1.752) is better positioned within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

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

**6. QED:** Both ligands have similar QED values (0.524 and 0.552), indicating good drug-like properties.

**7. DILI:** Ligand A (77.472) has a higher DILI risk than Ligand B (57.348). Both are acceptable, but B is preferable.

**8. BBB:**  BBB is less critical for a non-CNS target like SRC kinase. Ligand B (86.274) has a higher BBB percentile than Ligand A (35.246), but this isn't a major factor here.

**9. Caco-2 Permeability:** Ligand A (-5.206) and B (-4.816) both have negative values which is not ideal, but not a deal breaker.

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.113 and -3.092). This is a significant concern.

**11. hERG Inhibition:** Ligand A (0.089) has a slightly lower hERG risk than Ligand B (0.484), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (21.935) has a lower Cl_mic, suggesting better metabolic stability than Ligand B (33.787). This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand A (-6.497) has a longer half-life than Ligand B (-2.239), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.119), which is good.

**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 a positive for Ligand B.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B emerges as the slightly better candidate. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk, Ligand B has a better logP, TPSA, and binding affinity. The solubility is poor for both, which would require formulation strategies. The slightly better binding affinity of B, combined with its more favorable logP and TPSA, outweighs the small differences in metabolic stability and hERG risk.

Output:
1
2025-04-17 11:36:54,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.495 and 363.359 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.15) is better than Ligand B (63.17), both are below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (3.122 and 2.579), 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 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.805 and 0.717), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (52.346 and 51.493), well below the concerning threshold of 60.

**8. BBB:** Ligand A (70.686) has a better BBB percentile than Ligand B (94.649), but BBB is not a primary concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Ligand A (-5.121) and Ligand B (-4.778) have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.492 and -4.082). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.686 and 0.694), which is good.

**12. Microsomal Clearance:** Ligand B (42.402) has significantly lower microsomal clearance than Ligand A (95.753), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-2.012) has a slightly better (less negative) in vitro half-life than Ligand A (-24.728), suggesting a longer half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.663).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -8.5 kcal/mol). Ligand A is slightly better (-9.5 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and BBB penetration, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic) and a better in vitro half-life. Given that SRC kinase is an enzyme, metabolic stability is a critical factor. The poor solubility of both compounds is a concern, but can potentially be addressed through formulation strategies. The slightly better affinity of Ligand A is outweighed by the superior metabolic profile of Ligand B.

Output:
1
2025-04-17 11:36:54,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.435 and 358.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.25) is slightly higher than Ligand B (105.17), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have very low logP values (0.074 and 0.08), which is suboptimal. Values between 1-3 are preferred. This could indicate poor membrane permeability.

**H-Bond Donors:** Ligand A has 4 HBD, while Ligand B has 2. 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:** Ligand B (0.596) has a better QED score than Ligand A (0.397), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A at 35.285 and Ligand B at 40.287, both below the 60 threshold.

**BBB:** Both ligands have low BBB penetration (23.11 and 32.726), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.305 and -4.922), which is unusual and suggests very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.958 and -0.979), which is also unusual and indicates very poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.153 and 0.154), which is good.

**Microsomal Clearance:** Ligand A (-2.577) has a significantly *lower* (better) microsomal clearance than Ligand B (52.687). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (13.561) has a longer half-life than Ligand B (-2.503), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.063 and 0.057).

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.0). While both are strong binders, the 0.6 kcal/mol difference is notable.

**Conclusion:**

Despite both ligands having issues with logP and solubility, Ligand A is the more promising candidate. It exhibits a slightly better binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a better QED score. The poor logP and solubility are significant drawbacks for both, but can potentially be addressed through prodrug strategies or formulation techniques. The improved metabolic stability of Ligand A is crucial for an enzyme inhibitor, as it will likely lead to higher *in vivo* exposure.

Output:
0
2025-04-17 11:36:54,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (344.411 and 362.392 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.8) is slightly higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but B is better.

**3. logP:** Both ligands have good logP values (3.109 and 2.275), 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 acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.84 and 0.764), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (17.449 and 16.673 percentiles), which is favorable.

**8. BBB:** Both ligands have good BBB penetration (83.172 and 81.466 percentiles), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.992) and Ligand B (-4.688) both have negative values, which is unusual. Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-4.024) and Ligand B (-2.201) both have negative values, suggesting poor solubility. Ligand B is better.

**11. hERG Inhibition:** Ligand A (0.812) and Ligand B (0.46) both have low hERG inhibition risk, which is good. Ligand B is better.

**12. Microsomal Clearance:** Ligand A (91.086) has a higher microsomal clearance than Ligand B (-2.34). Higher clearance means faster metabolism and lower metabolic stability, which is undesirable. Ligand B is much better.

**13. In vitro Half-Life:** Ligand A (-29.431) has a negative in vitro half-life, which is not possible and indicates a very short half-life. Ligand B (-7.047) is also negative, but less so.

**14. P-gp Efflux:** Ligand A (0.499) and Ligand B (0.042) both have low P-gp efflux, which is favorable. Ligand B is better.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, its extremely poor in vitro half-life is a major red flag. Ligand B has better ADME properties (lower clearance, better solubility, better hERG, lower P-gp efflux), but its binding affinity is weaker. Considering the enzyme-specific priorities, the strong binding affinity of Ligand A is very attractive. While the poor half-life is concerning, it might be addressable through structural modifications during lead optimization. The ADME profile of Ligand B, while better, might not be sufficient to overcome the affinity gap.

Output:
1
2025-04-17 11:36:54,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (393.883 and 391.94 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.73) is slightly higher than Ligand B (47.36), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (4.261 and 3.456), falling within the optimal 1-3 range. Ligand A is slightly higher, which *could* present a minor solubility issue, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have 0 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 5. Both are under the 10 limit.

**QED:** Ligand A (0.695) has a better QED score than Ligand B (0.477), indicating a more drug-like profile.

**DILI:** Ligand B (35.75) has a significantly lower DILI risk than Ligand A (42.691), which is a significant advantage.

**BBB:** Both have high BBB penetration (96.123 and 92.555), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.375 and -4.365), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-4.355 and -4.768). This is a major drawback for both compounds.

**hERG Inhibition:** Both have low hERG inhibition liability (0.664 and 0.472), which is excellent.

**Microsomal Clearance:** Ligand B (97.103) has a much higher microsomal clearance than Ligand A (41.235), indicating lower metabolic stability. This is a significant disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (20.66) has a longer in vitro half-life than Ligand B (10.239), which is preferable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.473 and 0.489).

**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 could outweigh some of the ADME concerns.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, the significantly stronger binding affinity of Ligand B (-8.2 kcal/mol vs -7.1 kcal/mol) and its lower DILI risk are compelling advantages. While Ligand B has higher microsomal clearance, the potency difference is large enough to prioritize it for further optimization, focusing on improving its metabolic stability and solubility. Ligand A's slightly better QED and half-life aren't enough to overcome the affinity gap.

Output:
1
2025-04-17 11:36:54,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.5 and 344.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is higher than Ligand B (24.5). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**logP:** Both ligands have logP values (2.665 and 3.929) within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some 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 3. Both are within the acceptable limit of 10, but Ligand B is preferable due to fewer potential off-target interactions.

**QED:** Both ligands have similar, high QED scores (0.871 and 0.876), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 55.1%, which is moderate. Ligand B has a much lower DILI risk of 9.965%, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration (79.1% and 85.3%), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.868 and -4.745). This is unusual and suggests poor permeability. However, the absolute values are similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values (-2.845 and -2.652). This is also unusual and suggests poor solubility. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.188) has a slightly lower hERG risk than Ligand B (0.907), which is preferable.

**Microsomal Clearance:** Ligand A (32.927) has a higher microsomal clearance than Ligand B (18.427), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (14.45 hours) has a longer half-life than Ligand B (6.087 hours). This is a positive for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both have low P-gp efflux liability (0.166 and 0.266), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent and a major driver of potency.

**Overall Assessment:**

Ligand B is superior. While Ligand A has a slightly longer half-life and lower hERG risk, Ligand B significantly outperforms it in DILI risk and has better metabolic stability (lower Cl_mic) and fewer HBA. The similar binding affinity means potency is not a differentiating factor. The lower TPSA of Ligand B is also beneficial for permeability. The unusual negative values for Caco-2 and solubility are concerning for both, but not enough to outweigh the other advantages of Ligand B.

Output:
1
2025-04-17 11:36:54,206 - INFO - Batch 62 complete. Total preferences: 992
2025-04-17 11:36:54,206 - INFO - Processing batch 63/512...
2025-04-17 11:37:37,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.53 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (76.66). Both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.55 and 2.06), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which is acceptable.

**QED:** Both ligands have similar QED scores (0.785 and 0.769), indicating good drug-likeness.

**DILI:** Ligand B (27.92) has a significantly lower DILI risk than Ligand A (47.15), which is a major advantage.

**BBB:** Ligand A (68.75) has a higher BBB penetration score than Ligand B (50.52), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.17 and -5.03).

**Aqueous Solubility:** Ligand B (-1.96) is better than Ligand A (-3.64), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.178 and 0.202).

**Microsomal Clearance:** Ligand B (47.54) has a slightly lower microsomal clearance than Ligand A (63.3), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.05) has a significantly longer half-life than Ligand B (5.31). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.107 and 0.041).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand B is preferable. While Ligand A has a longer half-life, Ligand B has a substantially lower DILI risk, better solubility, and slightly better binding affinity and metabolic stability. The lower DILI risk is a critical factor, as liver toxicity is a major concern in drug development. The slight advantage in binding affinity further supports choosing Ligand B. The similar Caco-2 values are a concern for both, but can be addressed in later optimization stages.

Output:
1
2025-04-17 11:37:37,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.354 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (111.54 and 118.37) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (-0.557) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.14) is closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 7 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.659 and 0.625), indicating good drug-likeness.

**DILI:** Both ligands have DILI risk above 50, indicating a moderate risk. Ligand A (56.572) is slightly lower than Ligand B (61.303), suggesting a marginally better safety profile.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.619) has a higher BBB percentile than Ligand B (34.393).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.113 and -5.422), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.81 and -1.636), indicating poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.19 and 0.066), which is excellent.

**Microsomal Clearance:** Ligand A (-7.195) has significantly lower (better) microsomal clearance than Ligand B (-4.721), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.121) has a much longer in vitro half-life than Ligand B (64.155), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.008).

**Binding Affinity:** Ligand A (-0.0) has a significantly stronger binding affinity (-0.0 kcal/mol) than Ligand B (-6.7 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A is the more promising candidate. Its substantially stronger binding affinity (-0.0 kcal/mol vs -6.7 kcal/mol) outweighs the slightly less favorable logP and DILI scores. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic) and a longer half-life, crucial for an enzyme inhibitor. The poor solubility and permeability would need to be addressed through formulation strategies, but the potency and PK advantages of Ligand A make it the better starting point for optimization.

Output:
0
2025-04-17 11:37:37,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.487 and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is better than Ligand B (67.87), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.004 and 1.19), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both have acceptable HBD counts (2 and 1 respectively), well below the limit of 5.

**H-Bond Acceptors:** Both ligands are within the acceptable range (3 and 4 respectively, below 10).

**QED:** Both ligands have good QED scores (0.694 and 0.8), indicating good drug-like properties.

**DILI:** Ligand A (10.275) has a significantly lower DILI risk than Ligand B (28.344), which is a major advantage.

**BBB:** Ligand B (89.957) has a better BBB penetration score than Ligand A (71.307), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values (-4.979 and -4.575), indicating poor permeability. This is a concern for both, but not a deciding factor.

**Aqueous Solubility:** Both have negative values (-2.061 and -2.215), indicating poor solubility. This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.264 and 0.28), which is good.

**Microsomal Clearance:** Ligand A (18.181) has a higher microsomal clearance than Ligand B (14.75). This suggests Ligand B is more metabolically stable, which is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-6.073) has a longer in vitro half-life than Ligand A (10.435), which is also a positive for metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.019).

**Binding Affinity:** Both ligands have identical and excellent binding affinity (-7.9 kcal/mol).

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and BBB penetration, the significantly lower DILI risk for Ligand A is a crucial advantage. Given the enzyme-specific priorities, minimizing toxicity is paramount. The similar binding affinities mean that the ADME differences are the deciding factors. The lower DILI risk of Ligand A outweighs the slightly better metabolic stability of Ligand B.

Output:
0
2025-04-17 11:37:37,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**

*   **MW:** 335.323 Da - Good, within the ideal range.
*   **TPSA:** 124.07 - Acceptable, but approaching the upper limit for good oral absorption.
*   **logP:** 2.379 - Optimal.
*   **HBD:** 3 - Good.
*   **HBA:** 7 - Good.
*   **QED:** 0.625 - Excellent, highly drug-like.
*   **DILI:** 97.596 - Very high risk of liver injury. This is a major concern.
*   **BBB:** 20.318 - Low, not a concern for a non-CNS target like SRC.
*   **Caco-2:** -4.92 - Very poor permeability. A significant issue.
*   **Solubility:** -5.15 - Very poor solubility. A significant issue.
*   **hERG:** 0.505 - Low risk, good.
*   **Cl_mic:** 34.599 - Moderate clearance, not ideal but not terrible.
*   **t1/2:** -2.571 - Very short half-life. A major drawback.
*   **Pgp:** 0.069 - Low efflux, good.
*   **Affinity:** -8.3 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 361.389 Da - Good, within the ideal range.
*   **TPSA:** 78.95 - Excellent, favorable for absorption.
*   **logP:** 0.101 - Low, potentially hindering permeation.
*   **HBD:** 1 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.441 - Below the preferred threshold, less drug-like.
*   **DILI:** 23.808 - Low risk of liver injury, excellent.
*   **BBB:** 66.072 - Low, not a concern for a non-CNS target like SRC.
*   **Caco-2:** -4.859 - Very poor permeability. A significant issue.
*   **Solubility:** -0.817 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.253 - Low risk, good.
*   **Cl_mic:** 27.502 - Low clearance, indicating good metabolic stability.
*   **t1/2:** -27.274 - Extremely short half-life. A major drawback, even worse than Ligand A.
*   **Pgp:** 0.009 - Very low efflux, good.
*   **Affinity:** -7.4 kcal/mol - Good binding affinity, though not as strong as Ligand A.

**Comparison and Decision:**

Both ligands have significant issues with permeability and solubility. Both also have very short half-lives. However, Ligand A has a significantly better binding affinity (-8.3 vs -7.4 kcal/mol) and a better QED score. The biggest concern with Ligand A is the extremely high DILI risk. Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic).

Despite the superior affinity of Ligand A, the extremely high DILI risk and poor solubility/permeability make it a less viable candidate. While Ligand B's affinity is slightly lower, its significantly better safety profile (DILI) and metabolic stability make it the more promising starting point for optimization. Improving solubility and permeability would be the primary focus for Ligand B.

Output:
1
2025-04-17 11:37:37,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 346.395 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.42) is excellent, well below the 140 threshold for good absorption. Ligand B (120.83) is still acceptable, but less optimal.

**logP:** Ligand A (1.649) is within the optimal 1-3 range. Ligand B (-0.37) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is excellent. Ligand B (3 HBD, 7 HBA) is still reasonable, but more polar.

**QED:** Both ligands have acceptable QED scores (0.81 and 0.656, respectively), indicating good drug-like properties.

**DILI:** Ligand B (63.552) has a higher DILI risk than Ligand A (50.291), though both are within a moderate range.

**BBB:** Ligand A (62.233) has a better BBB penetration score than Ligand B (36.099), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.834) has a more negative Caco-2 value, indicating *lower* permeability compared to Ligand B (-5.711). This is a slight negative for Ligand A.

**Aqueous Solubility:** Ligand A (-2.519) has slightly better solubility than Ligand B (-1.975).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.201 and 0.318 respectively).

**Microsomal Clearance:** Ligand B (15.42 mL/min/kg) has significantly lower microsomal clearance than Ligand A (40.041 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (14.726 hours) has a longer half-life than Ligand B (8.683 hours), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.015 respectively).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability and slightly better solubility, the significantly stronger binding affinity of Ligand A (-8.5 vs -6.9 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. While Ligand A has a higher Cl_mic, the substantial binding advantage is likely to translate to sufficient *in vivo* efficacy, and metabolic liabilities can be addressed through further optimization.

Output:
1
2025-04-17 11:37:37,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Ligand A:**

*   **MW:** 356.491 Da - Within the ideal range (200-500).
*   **TPSA:** 40.62 - Good for oral absorption (<140).
*   **logP:** 2.892 - Optimal (1-3).
*   **HBD:** 0 - Acceptable, though some H-donors can aid solubility.
*   **HBA:** 3 - Acceptable (<10).
*   **QED:** 0.782 - Excellent drug-likeness (>0.5).
*   **DILI:** 42.846 - Good, low risk (<40 is preferred, but <60 is acceptable).
*   **BBB:** 83.249 - High, suggesting potential CNS penetration, but not a primary concern for a non-CNS target like SRC.
*   **Caco-2:** -4.742 - Poor permeability. This is a significant drawback.
*   **Solubility:** -3.994 - Poor solubility. This is also a significant drawback.
*   **hERG:** 0.373 - Low risk.
*   **Cl_mic:** 98.744 - High, indicating poor metabolic stability.
*   **t1/2:** -17.867 - Very short half-life.
*   **Pgp:** 0.367 - Low efflux, good.
*   **Affinity:** -7.6 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 352.366 Da - Within the ideal range (200-500).
*   **TPSA:** 104.97 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 0.147 - Low, potentially hindering permeation.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.448 - Moderate drug-likeness, below the ideal threshold.
*   **DILI:** 68.98 - Moderate risk, but still within an acceptable range.
*   **BBB:** 49.787 - Low, not a major concern.
*   **Caco-2:** -5.044 - Very poor permeability.
*   **Solubility:** -2.366 - Poor solubility.
*   **hERG:** 0.353 - Low risk.
*   **Cl_mic:** -5.673 - Very low, indicating excellent metabolic stability.
*   **t1/2:** -28.149 - Very long half-life.
*   **Pgp:** 0.012 - Very low efflux, excellent.
*   **Affinity:** -6.4 kcal/mol - Good binding affinity, but 1.2 kcal/mol weaker than Ligand A.

**Comparison and Decision:**

Both ligands have significant issues with Caco-2 permeability and solubility. However, Ligand A has a substantially better binding affinity (-7.6 vs -6.4 kcal/mol). While Ligand B boasts superior metabolic stability and half-life, the difference in binding affinity is substantial enough to outweigh these benefits, especially for a kinase inhibitor where potency is crucial. The poor permeability and solubility of both compounds are serious concerns that would need to be addressed through formulation or further chemical modifications, but starting with the more potent compound (Ligand A) is a more rational approach.

Output:
1
2025-04-17 11:37:37,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 352.345 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is well below the 140 threshold for good absorption, while Ligand B (116.08) is still acceptable but less optimal.

**logP:** Both ligands (2.625 and 2.054) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is excellent, while Ligand B (4) is acceptable but higher.

**H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (8) is higher, potentially impacting permeability.

**QED:** Ligand A (0.769) is better than Ligand B (0.624), indicating a more drug-like profile.

**DILI:** Ligand A (21.985) has a significantly lower DILI risk than Ligand B (67.468), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (71.501) is better than Ligand B (55.603).

**Caco-2 Permeability:** Ligand A (-4.785) is better than Ligand B (-5.357), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.501) is better than Ligand B (-3.605), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.059) has a very low hERG risk, while Ligand B (0.259) is slightly higher.

**Microsomal Clearance:** Ligand A (57.997) has higher metabolic stability (lower clearance) than Ligand B (13.348).

**In vitro Half-Life:** Ligand A (-12.091) has a longer half-life than Ligand B (-14.126).

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux than Ligand B (0.011), which is favorable.

**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 to outweigh other issues, it contributes to the overall assessment.

**Overall:** Ligand A is superior to Ligand B across most critical parameters. It has a lower DILI risk, better solubility, better permeability, lower hERG risk, higher metabolic stability, longer half-life, lower P-gp efflux, and a slightly better binding affinity. While Ligand B is within acceptable ranges for many properties, Ligand A presents a significantly more favorable profile for drug development targeting SRC kinase.

Output:
0
2025-04-17 11:37:37,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.4 and 345.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.62) is slightly higher than Ligand B (62.3). Both are well below the 140 threshold for oral absorption, and acceptable for a kinase inhibitor.

**3. logP:** Ligand A (1.56) is optimal, while Ligand B (3.191) is towards the higher end 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:** Ligand A has 5 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.895) has a better QED score than Ligand B (0.787), indicating better overall drug-likeness.

**7. DILI:** Ligand B (30.593) has a significantly lower DILI risk than Ligand A (51.493). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand A (90.035) shows better BBB penetration than Ligand B (70.919), but BBB penetration isn't a primary concern for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.532 and -4.698), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-2.674 and -2.871), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition risk (0.449 and 0.513), which is good.

**12. Cl_mic:** Ligand A (49.932) has lower microsomal clearance than Ligand B (56.327), suggesting better metabolic stability. This is a positive for Ligand A.

**13. t1/2:** Ligand A (10.831) has a longer in vitro half-life than Ligand B (-3.54). This is a substantial advantage for Ligand A.

**14. Pgp:** Ligand A (0.027) has much lower P-gp efflux liability than Ligand B (0.235), suggesting better oral bioavailability and potentially better tissue distribution.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This 0.5 kcal/mol difference is significant, and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity and lower DILI risk, Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2), better P-gp efflux profile, and a better QED score. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the importance of metabolic stability for kinase inhibitors, and the substantial difference in half-life, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 11:37:37,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.793 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.53) is still acceptable but less optimal.

**logP:** Both ligands have good logP values (3.369 and 2.397), 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 4 HBA, both acceptable (<=10).

**QED:** Both ligands have acceptable QED scores (0.684 and 0.55), indicating reasonable drug-likeness.

**DILI:** Ligand A has a DILI risk of 87.631, which is high and concerning. Ligand B has a much lower DILI risk of 18.651, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (76.735) has a higher percentile than Ligand B (57.968).

**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 still compare them relatively. Ligand A (-4.682) is slightly better than Ligand B (-4.736).

**Aqueous Solubility:** Ligand A (-5.489) has worse solubility than Ligand B (-1.533). Solubility is important for bioavailability.

**hERG:** Ligand A (0.49) has a slightly higher hERG risk than Ligand B (0.13), indicating a potentially greater risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (45.29) has a lower microsomal clearance than Ligand B (48.237), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (54.125) has a significantly longer half-life than Ligand B (14.743), which is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.319 and 0.032), which is good.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 0.7 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). However, it has a very high DILI risk and lower solubility, and a slightly higher hERG risk. Ligand B has a much better safety profile (lower DILI, lower hERG) and better solubility, but weaker binding affinity and poorer metabolic stability.

Given the priorities for enzyme inhibitors, the binding 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 solubility issue is also addressable. The much stronger binding of Ligand A makes it a more promising starting point, despite the liabilities.

Output:
1
2025-04-17 11:37:37,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for kinase inhibitors (affinity, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (390.977 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (75.02), being well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.661 and 3.399), 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 HBA, both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.647 and 0.852), indicating drug-like properties.

**DILI:** Ligand A (14.036) has a much lower DILI risk than Ligand B (68.476), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (71.268) is better than Ligand B (53.587).

**Caco-2 Permeability:** Ligand A (-4.797) is better than Ligand B (-5.431), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.866) is better than Ligand B (-4.069), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.542 and 0.435).

**Microsomal Clearance:** Ligand A (72.138) has significantly lower microsomal clearance than Ligand B (105.282), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.102 hours) has a shorter half-life than Ligand B (-31.985 hours). However, the negative value for Ligand B is concerning and likely indicates a very long half-life, potentially due to poor solubility or other issues.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.218).

**Binding Affinity:** Both ligands have the same excellent binding affinity (-8.8 kcal/mol).

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have excellent binding affinity, Ligand A demonstrates superior ADME properties, particularly lower DILI risk, lower microsomal clearance (better metabolic stability), and better solubility. Ligand B's very long in vitro half-life (indicated by the negative value) is also a red flag. The combination of these factors makes Ligand A the stronger candidate for further development as an SRC kinase inhibitor.

Output:
0
2025-04-17 11:37:37,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (391.827 and 369.437 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.06) is slightly above the optimal <140, while Ligand B (62.3) is well within. This favors B for absorption.

**logP:** Both ligands have good logP values (3.54 and 2.227), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4-5 HBA, which are acceptable.

**QED:** Both ligands have high QED scores (0.864 and 0.885), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (91.431 percentile) compared to Ligand B (47.732 percentile). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB score (88.949) than A (47.538), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both, but the values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.304 and 0.294).

**Microsomal Clearance:** Ligand A has a higher Cl_mic (37.543 mL/min/kg) than Ligand B (13.276 mL/min/kg). Lower is better for metabolic stability, favoring B.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (-6.91 hours) than Ligand A (90.035 hours). This is a positive for B.

**P-gp Efflux:** Ligand A has a higher P-gp efflux liability (0.155) than Ligand B (0.116), favoring B.

**Binding Affinity:** Ligand A has a slightly better binding affinity (-7.1 kcal/mol) than Ligand B (-0.0 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME liabilities of Ligand A.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer half-life), lower DILI risk, and lower P-gp efflux. The slightly weaker binding affinity of Ligand B is outweighed by its superior ADME properties, which are crucial for *in vivo* efficacy. The high DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 11:37:37,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.483 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.06) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (62.55) is still under 140, but less optimal than A.

**logP:** Ligand A (4.218) is slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects. Ligand B (3.591) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 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 (0.729 and 0.797), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (27.918 and 31.989), which is excellent.

**BBB:** Ligand A (96.782) shows very good BBB penetration, while Ligand B (78.713) is still reasonable but less favorable. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.675 and -4.566), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.031 and -3.962), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.902 and 0.769), which is positive.

**Microsomal Clearance:** Ligand A (48.357) has lower microsomal clearance than Ligand B (82.825), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (82.116) has a significantly longer in vitro half-life than Ligand A (45.691), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.692 and 0.202), which is good.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), but the difference is minimal.

**Conclusion:**

Despite the slightly higher logP of Ligand A, its superior metabolic stability (lower Cl_mic) and slightly better binding affinity are attractive. However, the *major* issue for both compounds is the very poor predicted solubility and permeability (negative Caco-2 values). Ligand B has a significantly longer half-life, which is a substantial benefit. Given the critical importance of solubility and permeability for oral bioavailability, and the longer half-life of B, I would cautiously favor Ligand B, hoping that the negative predictions can be overcome with formulation strategies. However, both compounds require significant medicinal chemistry efforts to address the solubility/permeability issues.

Output:
1
2025-04-17 11:37:37,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (345.443 and 347.415 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (75.44 and 75.88) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (3.052) is optimal, while Ligand B (1.178) is slightly low, potentially impacting permeability.

**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 reasonable QED scores (0.832 and 0.748), indicating good drug-like properties.

**7. DILI:** Ligand A (42.536) has a slightly higher DILI risk than Ligand B (35.091), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.031) has better BBB penetration than Ligand B (61.846), but it's not a major deciding factor here.

**9. Caco-2 Permeability:** Both have negative values (-4.824 and -4.478), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.406 and -1.304), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.218) has a lower hERG risk than Ligand B (0.089), which is preferable.

**12. Microsomal Clearance:** Ligand A (67.817) has a higher microsomal clearance than Ligand B (20.481), indicating lower metabolic stability. This is a significant negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (-8.517) has a longer in vitro half-life than Ligand A (-24.543), which is a positive.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.139 and 0.029).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-6.5 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B exhibits superior binding affinity, a longer half-life, and lower microsomal clearance. The lower hERG risk of Ligand A is a benefit, but the stronger binding of Ligand B is more critical for an enzyme target like SRC kinase. The difference in binding affinity is significant enough to prioritize Ligand B despite its slightly lower solubility and permeability. Further optimization would focus on improving solubility and permeability, but the core potency and stability profile of Ligand B is more favorable.

Output:
1
2025-04-17 11:37:37,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (477.324 Da) is towards the higher end, while Ligand B (348.531 Da) is more optimal.

**TPSA:** Ligand A (89.43) is good, under the 140 threshold. Ligand B (40.62) is excellent.

**logP:** Ligand A (1.519) is within the optimal range. Ligand B (3.841) is approaching the upper limit, but still acceptable.

**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: 0.592, B: 0.732), indicating good drug-like properties.

**DILI:** Ligand A (77.898) has a higher DILI risk than Ligand B (26.173). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (35.401) and Ligand B (92.71) are not particularly relevant here.

**Caco-2 Permeability:** Ligand A (-5.245) has poor Caco-2 permeability, indicating potential absorption issues. Ligand B (-4.641) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.428 and -4.011 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.474 and 0.524 respectively), which is good.

**Microsomal Clearance:** Ligand A (51.37 mL/min/kg) has a moderate clearance, while Ligand B (88.465 mL/min/kg) has a high clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.155 hours) has a better half-life than Ligand B (28.073 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.371 and 0.469 respectively), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This 1.9 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's significantly higher binding affinity (-7.6 vs -9.5 kcal/mol) is a major advantage for an enzyme target like SRC. It also has a much lower DILI risk (26.173 vs 77.898). Although it has a higher microsomal clearance, the potency advantage of Ligand B is likely to be more impactful. Ligand A's poor Caco-2 permeability is also a concern.

Output:
1
2025-04-17 11:37:37,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.471 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.37 and 84.22) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.617) is optimal, while Ligand B (1.115) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Both ligands (0.752 and 0.719) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (58.123) has a higher DILI risk than Ligand B (33.23), but both are below the concerning threshold of 60.

**BBB:** Ligand A (49.205) has lower BBB penetration than Ligand B (73.943). This is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand B (-5.005) shows better Caco-2 permeability than Ligand A (-4.761), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.162) has slightly better aqueous solubility than Ligand A (-2.006).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.227 and 0.062).

**Microsomal Clearance:** Ligand B (22.992) has lower microsomal clearance than Ligand A (24.034), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.324) has a significantly longer in vitro half-life than Ligand A (31.757), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.026 and 0.039).

**Binding Affinity:** Ligand A (-7.0 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol), but 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 more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly in metabolic stability (lower Cl_mic, longer t1/2) and permeability (better Caco-2). The lower DILI risk is also a positive factor. The slightly lower logP of Ligand B is a minor concern outweighed by its other advantages. For an enzyme target like SRC kinase, metabolic stability and solubility are critical, making Ligand B the preferred choice.

Output:
1
2025-04-17 11:37:37,795 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [343.471, 61.44, 2.186, 2, 3, 0.798, 21.869, 62.233, -4.825, -2.31, 0.49, 17.456, 7.995, 0.089, 0]
**Ligand B:** [352.475, 59.08, 1.844, 0, 4, 0.469, 18.379, 73.517, -4.447, -1.399, 0.556, 41.334, 9.373, 0.084, -6.8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (343.471) is slightly lower, which is generally favorable for permeability.
2. **TPSA:** Both are below the 140 A<sup>2</sup> threshold for good oral absorption. A (61.44) is slightly higher than B (59.08), but both are acceptable.
3. **logP:** Both are within the optimal range (1-3). B (1.844) is slightly lower, which *could* be a minor drawback, but both are acceptable.
4. **HBD:** A (2) is good. B (0) is also good, and potentially better as it minimizes potential off-target interactions.
5. **HBA:** A (3) is good. B (4) is still within the acceptable range (<=10).
6. **QED:** A (0.798) is significantly better than B (0.469), indicating a more drug-like profile.
7. **DILI:** A (21.869) is much better than B (18.379), suggesting a lower risk of liver injury.
8. **BBB:** B (73.517) is better than A (62.233), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.
9. **Caco-2:** Both have negative values, indicating poor permeability. This is a significant concern for both compounds.
10. **Solubility:** Both have negative values, indicating poor solubility. This is a significant concern for both compounds.
11. **hERG:** Both are very low, indicating minimal hERG inhibition risk. This is excellent for both.
12. **Cl_mic:** A (17.456) is much lower than B (41.334), indicating better metabolic stability. This is a significant advantage for A.
13. **t1/2:** B (9.373) has a slightly longer half-life than A (7.995), which is preferable.
14. **Pgp:** Both are very low, indicating minimal P-gp efflux. This is good for both.
15. **Binding Affinity:** B (-6.8 kcal/mol) has a significantly stronger binding affinity than A (0 kcal/mol). This is a *major* advantage for B. A binding difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

Despite A's better QED, DILI, and Cl_mic, the *substantial* difference in binding affinity (-6.8 kcal/mol vs 0 kcal/mol) overwhelmingly favors **Ligand B**. The stronger binding is likely to translate to greater efficacy, and can potentially compensate for the slightly lower QED and higher DILI risk. The solubility and Caco-2 permeability are problematic for both, but can be addressed through formulation strategies.

Output:
1

2025-04-17 11:37:37,795 - INFO - Batch 63 complete. Total preferences: 1008
2025-04-17 11:37:37,795 - INFO - Processing batch 64/512...
2025-04-17 11:38:26,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (349.391 and 378.845 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (121.23) is slightly above the preferred <140, but acceptable. Ligand B (110.17) is well within the range.

**3. logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 1.329 and Ligand B at 2.63.

**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 8 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.593 and 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (93.68). This is a significant negative for Ligand A.

**8. BBB:** Both have similar BBB penetration (65.18 and 68.864). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**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:** Ligand A (0.208) has a lower hERG risk than Ligand B (0.618), which is preferable.

**12. Microsomal Clearance:** Ligand A (11.571) has significantly lower microsomal clearance than Ligand B (21.526), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-5.106) has a negative half-life, which is not possible. Ligand B (16.828) has a reasonable half-life. This is a major issue for Ligand A.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.099 and 0.147).

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This 1.2 kcal/mol difference is substantial and outweighs many other concerns.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand B excels in affinity, while Ligand A has a problematic half-life and DILI risk. Ligand A's lower clearance is good, but the negative half-life is a deal-breaker.

Output:
1
2025-04-17 11:38:26,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (356.375 and 352.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.45) is slightly above the optimal <140, but acceptable. Ligand B (75.71) is well within the ideal range.

**3. logP:** Ligand A (-0.671) is a bit low, potentially hindering permeability. Ligand B (1.038) 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 (7) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.602 and 0.767, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (57.425) is moderately risky, but acceptable. Ligand B (33.579) has a much lower DILI risk, which is a significant advantage.

**8. BBB:** BBB is not a primary concern for an oncology target unless CNS penetration is specifically desired. Ligand A (58.434) and Ligand B (83.715) are both reasonable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.538 and -4.701), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.549 and -2.296), indicating poor aqueous solubility, which is a major drawback.

**11. hERG Inhibition:** Ligand A (0.027) shows very low hERG inhibition risk, which is excellent. Ligand B (0.318) is also relatively low risk.

**12. Microsomal Clearance:** Ligand A (10.635) has a lower clearance than Ligand B (21.48), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (-8.143) has a longer half-life than Ligand B (-3.197), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.064).

**15. Binding Affinity:** Ligand A (-8.2) has a slightly better binding affinity than Ligand B (-7.7), but the difference is not substantial enough to overcome other weaknesses.

**Overall Assessment:**

Ligand B has a significantly better safety profile (lower DILI) and better logP, which are important for an enzyme target. While both have poor solubility and permeability, Ligand B's lower DILI risk and better logP make it more promising. Ligand A has better metabolic stability and half-life, but the higher DILI risk is a significant concern. Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more viable candidate.

Output:
1
2025-04-17 11:38:26,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.36) is better than Ligand B (49.85) as it is still within the acceptable range for oral absorption (<140), but the lower TPSA of ligand B is advantageous.

**logP:** Both ligands have good logP values (1.548 and 2.687), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 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 (0.666 and 0.74), indicating drug-like properties.

**DILI:** Ligand A (11.361) has a significantly lower DILI risk than Ligand B (16.247), which is a major advantage.

**BBB:** Ligand B (88.29) has a higher BBB penetration score than Ligand A (43.699). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.922) has a lower Caco-2 permeability than Ligand B (-4.345), suggesting slightly poorer intestinal absorption.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-1.672 and -1.838). This is a concern for both, but could be mitigated with formulation strategies.

**hERG:** Ligand A (0.077) has a much lower hERG inhibition liability than Ligand B (0.428), a critical advantage for safety.

**Microsomal Clearance:** Ligand A (21.998) has a significantly lower microsomal clearance than Ligand B (58.52), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (11.003) has a longer in vitro half-life than Ligand B (-7.705), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.009) has a much lower P-gp efflux liability than Ligand B (0.267), which is beneficial for oral bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference of 0.1 kcal/mol is not substantial enough to outweigh the other significant advantages of Ligand A.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have good potency, Ligand A excels in crucial ADME-Tox properties: lower DILI risk, significantly lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The slightly lower Caco-2 permeability is a minor drawback compared to these substantial benefits.

Output:
0
2025-04-17 11:38:26,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.372 and 363.424 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.13) is slightly higher than Ligand B (52.65), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (3.484) is optimal, while Ligand B (1.673) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.907 and 0.809), indicating drug-likeness.

**DILI:** Ligand A (38.736) has a slightly higher DILI risk than Ligand B (17.371), but both are below the concerning threshold of 60.

**BBB:** Ligand A (94.067) has significantly better BBB penetration than Ligand B (84.141), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Solubility:** Ligand A (-4.46) has worse solubility than Ligand B (-1.855), which is a concern.

**hERG:** Ligand A (0.803) has a slightly higher hERG risk than Ligand B (0.456), but both are relatively low.

**Microsomal Clearance:** Ligand B (-5.305) has *much* lower microsomal clearance than Ligand A (19.203), indicating significantly better metabolic stability. This is a major advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-22.035) has a substantially longer in vitro half-life than Ligand A (-0.984), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.228) has lower P-gp efflux than Ligand B (0.019), which is favorable.

**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 only 0.9 kcal/mol, and the other ADME properties are more concerning for Ligand A.

**Conclusion:**

While Ligand A has slightly better binding affinity and P-gp efflux, Ligand B is the more promising candidate due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2), better solubility, and lower DILI risk. These factors are crucial for an enzyme inhibitor, outweighing the small difference in binding affinity.

Output:
1
2025-04-17 11:38:26,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.535 and 353.329 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption and is favorable. Ligand B (93.37) is still under 140, but getting closer to the upper limit, potentially hinting at slightly reduced absorption.

**logP:** Ligand A (3.227) is within the optimal 1-3 range. Ligand B (1.242) is at the lower end, potentially causing permeability issues.

**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 B is higher, potentially affecting permeability.

**QED:** Both ligands have good QED scores (0.728 and 0.84), indicating good drug-like properties.

**DILI:** Ligand A (20.279) has a significantly lower DILI risk than Ligand B (69.135). This is a major advantage for Ligand A.

**BBB:** Both have similar BBB penetration (71.307 and 70.609), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.328 and -4.621), 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 (-3.463 and -2.413), indicating poor aqueous solubility. This is a concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.564) has a lower hERG risk than Ligand B (0.121), which is a significant advantage.

**Microsomal Clearance:** Ligand A (78.478) has a higher microsomal clearance than Ligand B (-0.718). This means Ligand B is likely to have better metabolic stability, which is crucial for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (6.342) has a shorter half-life than Ligand B (-28.978). Again, this favors Ligand B.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.024), which is favorable.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and improved metabolic stability (lower Cl_mic, longer t1/2). However, it has a higher DILI risk, higher HBA count, lower logP, and worse hERG inhibition. Ligand A has better safety profiles (DILI, hERG) and permeability (lower TPSA), but weaker binding and poorer metabolic stability.

Given the importance of potency for enzyme inhibitors, the significantly stronger binding affinity of Ligand B is the most critical factor. While the ADME properties of Ligand B are less ideal, these can potentially be improved through further optimization. The large affinity difference is likely to be more impactful than the moderate ADME concerns.

Output:
1
2025-04-17 11:38:26,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.391 and 348.422 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.35) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (88.32) is excellent, well below 140.

**logP:** Ligand A (-0.486) is a bit low, potentially hindering permeation. Ligand B (1.96) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, fitting well within the guidelines. Ligand B has 2 HBD and 4 HBA, also good.

**QED:** Both ligands have good QED scores (0.787 and 0.851), indicating drug-like properties.

**DILI:** Ligand A (56.727) has a moderate DILI risk, while Ligand B (41.877) has a lower, more favorable risk.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (89.027) than Ligand A (26.444), but this is less critical here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.859 and -4.939). These values are unusual and likely indicate poor permeability *in vitro*. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.705 and -2.679). This is also a major concern, suggesting poor aqueous solubility.

**hERG:** Ligand A (0.132) has a slightly higher hERG risk than Ligand B (0.493), but both are relatively low.

**Microsomal Clearance:** Ligand A (3.647) has a lower microsomal clearance than Ligand B (4.295), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have very short in vitro half-lives (-11.733 and -16.744 hours). This is a significant drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Both ligands suffer from poor predicted permeability and solubility. However, Ligand B is superior due to its better logP, lower DILI risk, and significantly better TPSA. While Ligand A has slightly better metabolic stability, the other advantages of Ligand B outweigh this. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 11:38:26,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.503 and 357.296 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (97.54), being comfortably below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.483) is slightly better than Ligand B (0.277). Both are a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 8. Ligand A is preferable here, staying closer to the ideal of <=10.

**QED:** Both ligands have good QED scores (0.704 and 0.785), indicating good drug-like properties.

**DILI:** Ligand A (36.293) has a significantly lower DILI risk than Ligand B (71.694). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (88.174) has a higher BBB percentile than Ligand A (43.117).

**Caco-2 Permeability:** Ligand A (-5.294) has a worse Caco-2 permeability than Ligand B (-4.809), but both are very poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.158 and -2.625). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.099) has a much lower hERG inhibition risk than Ligand B (0.135), which is a significant advantage.

**Microsomal Clearance:** Ligand A (28.723) has lower microsomal clearance than Ligand B (41.72), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.56) has a positive half-life, while Ligand B (-17.587) has a negative half-life. This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.07).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most crucial factor, and the 8.3 kcal/mol difference is substantial.

**Overall:**

Ligand A is significantly better than Ligand B. It has a much stronger binding affinity, lower DILI risk, lower hERG risk, better metabolic stability, and a better half-life. While both have poor solubility and permeability, the superior potency and safety profile of Ligand A outweigh these drawbacks.

Output:
1
2025-04-17 11:38:26,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (363.53 and 364.56 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is slightly higher than Ligand B (49.41), but both are well below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (3.21 and 4.25), within the optimal 1-3 range, although Ligand B is pushing 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 3. Both are below the 10 threshold.

**6. QED:** Both ligands have reasonable QED scores (0.835 and 0.712), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 66.62%, which is moderately high. Ligand B has a significantly lower DILI risk (34.78%), which is a strong advantage.

**8. BBB:** Both ligands have acceptable BBB penetration, but Ligand B (73.71%) is better than Ligand A (67.62%). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.83 and -4.78), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.91 and -4.00), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.537) has a slightly higher hERG risk than Ligand B (0.676), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (58.68) has a lower microsomal clearance than Ligand B (78.34), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (54.76) has a slightly lower half-life than Ligand B (50.17), but the difference is minor.

**14. P-gp Efflux:** Ligand A (0.188) has lower P-gp efflux than Ligand B (0.468), which is a positive.

**15. Binding Affinity:** Ligand B (-7.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 1.6 kcal/mol difference is substantial and likely outweighs the other drawbacks.

**Overall Assessment:**

While both ligands have significant issues with solubility and Caco-2 permeability, Ligand B's superior binding affinity (-7.0 vs -6.4 kcal/mol) and lower DILI risk are decisive. The improved BBB penetration is a bonus. The higher metabolic clearance of Ligand B is a concern, but can potentially be addressed through structural modifications. The poor solubility and permeability would require formulation strategies (e.g., salt formation, co-crystallization, or lipid-based formulations) to overcome.

Output:
1
2025-04-17 11:38:26,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (368.543 and 384.929 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (58.64 and 55.57) well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.442) is within the optimal 1-3 range. Ligand B (4.332) is slightly above this range, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good. 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 (0.715) has a better QED score than Ligand B (0.572), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk, with Ligand A at 32.299% and Ligand B at 36.293%. Both are below the 40% threshold.

**8. BBB:** This is less critical for an oncology target, but Ligand B (74.874%) has a slightly higher BBB penetration than Ligand A (63.784%).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.051 and -5.09). This is unusual and suggests very poor permeability. However, these values are on a log scale and may not be directly comparable without knowing the units.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.184 and -2.882). This is also concerning, indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.337 and 0.671), which is favorable.

**12. Microsomal Clearance:** Ligand A (59.722 mL/min/kg) has significantly lower microsomal clearance than Ligand B (111.11 mL/min/kg), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-11.001 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (34.879 hours) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.232 and 0.864).

**15. Binding Affinity:** Ligand B (-8.4 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:**

Despite the concerning negative values for Caco-2 and solubility, the significantly stronger binding affinity of Ligand B (-8.4 kcal/mol vs -7.3 kcal/mol) and its better in vitro half-life (34.879 hours) make it the more promising candidate. While Ligand A has a better QED and lower microsomal clearance, the potency advantage of Ligand B is crucial for an enzyme target. The negative values for Caco-2 and solubility would need to be investigated further, but can potentially be addressed through formulation strategies. The error in Ligand A's half-life is also a significant concern.

Output:
1
2025-04-17 11:38:26,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.483 and 350.478 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.66) is higher than Ligand B (49.41). Both are below 140, but B is better for absorption.

**logP:** Both ligands have good logP values (2.443 and 3.367), 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.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 2 HBA. Ligand B is preferable here, as fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar and good QED values (0.787 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A (46.297) has a higher DILI risk than Ligand B (22.644). This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (94.223) has a much higher percentile than Ligand A (57.619).

**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 have negative solubility values, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.443) has a slightly lower hERG inhibition risk than Ligand B (0.532), which is preferable.

**Microsomal Clearance:** Ligand A (-10.522) has significantly *lower* (better) microsomal clearance than Ligand B (43.758). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (37.163) has a longer half-life than Ligand B (0.633), which is highly desirable.

**P-gp Efflux:** Ligand A (0.235) has lower P-gp efflux than Ligand B (0.156), which is better for bioavailability.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This is a crucial factor, and the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, a lower DILI risk, and better BBB penetration. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer half-life) and lower P-gp efflux. The difference in binding affinity is significant enough to outweigh the ADME advantages of Ligand A. While Ligand A's metabolic stability is attractive, the potency of Ligand B is more critical for an enzyme target.

Output:
1
2025-04-17 11:38:26,300 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (360.38 Da) is also good.

**TPSA:** Ligand A (101.21) is slightly higher than Ligand B (76.02). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (A: 1.75, B: 2.116), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (A: 5, B: 4) counts, suggesting a reasonable balance between solubility and permeability.

**QED:** Both ligands have QED values above 0.5 (A: 0.827, B: 0.782), indicating good drug-like properties.

**DILI:** Ligand A (85.964) has a significantly higher DILI risk than Ligand B (41.605). This is a major concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (A: 62.233, B: 83.327). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.106) has very poor Caco-2 permeability, while Ligand B (-4.634) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.159, B: -3.311). This could pose formulation challenges, but is not a dealbreaker if other properties are favorable.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.399, B: 0.452).

**Microsomal Clearance:** Ligand A (2.076) has much lower microsomal clearance than Ligand B (30.239), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-17.79) has a much longer in vitro half-life than Ligand B (-28.548), which is a strong positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.013, B: 0.069).

**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 drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) than Ligand B. However, it has a much higher DILI risk and poor Caco-2 permeability. Ligand B has a lower DILI risk and slightly better Caco-2 permeability, but weaker binding affinity and poorer metabolic stability.

Given the enzyme-specific priorities, strong binding affinity and metabolic stability are paramount. The 1.3 kcal/mol difference in binding affinity is substantial. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications in later stages of optimization. The poor Caco-2 permeability is also a concern, but could be addressed through formulation strategies. The better metabolic stability of Ligand A is a significant advantage for an enzyme target.

Output:
0
2025-04-17 11:38:26,300 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.4 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.81) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (71.53) is excellent, well below 140.

**logP:** Ligand A (0.384) is a bit low, potentially hindering permeation. Ligand B (1.782) is within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 8 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have high QED scores (0.804 and 0.883), indicating good drug-likeness.

**DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (44.05), though both are reasonably acceptable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (70.61) has a better score than Ligand A (48.2).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.507 and -4.644), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.687 and -1.497), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.078) has a slightly lower hERG risk than Ligand B (0.249), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (20.612 and 21.832 mL/min/kg), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand B (-13.856) has a significantly better (longer) in vitro half-life than Ligand A (-25.742). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.043), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. It has a better logP, lower DILI risk, significantly improved in vitro half-life, and a more favorable TPSA. While both have poor Caco-2 permeability and aqueous solubility, these are areas that could potentially be addressed through formulation strategies. Ligand A's lower logP and higher DILI risk make it less attractive.

Output:
1
2025-04-17 11:38:26,300 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.395 Da) and Ligand B (339.443 Da) are both acceptable.

**TPSA:** Ligand A (111.73) is better than Ligand B (64.86) as it is still within the acceptable range for oral absorption (<140), while Ligand B is significantly lower, which could potentially impact binding.

**logP:** Ligand A (-1.489) is a bit low, potentially hindering permeation. Ligand B (3.244) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Ligand B (0.926) has a significantly higher QED score than Ligand A (0.599), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 65.568, Ligand B: 48.313), though Ligand B is slightly better.

**BBB:** Ligand B (82.513) has a better BBB percentile than Ligand A (49.593), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.418) has very poor Caco-2 permeability, which is a significant concern. Ligand B (-4.851) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.899) has poor solubility, while Ligand B (-4.233) is also poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.027) has a very low hERG risk, which is excellent. Ligand B (0.361) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-11.905) has significantly lower (better) microsomal clearance than Ligand B (52.256), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.917) has a very long in vitro half-life, which is highly desirable. Ligand B (-7.68) is less favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.004, Ligand B: 0.397).

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -7.9 kcal/mol, Ligand B: -8.8 kcal/mol), with Ligand B being slightly better.

**Overall Assessment:**

Ligand B has a better logP, QED, and binding affinity. However, Ligand A has a superior metabolic stability profile (lower Cl_mic, longer t1/2) and a much lower hERG risk. The poor Caco-2 permeability and solubility of both are concerning, but the significantly better metabolic stability and hERG profile of Ligand A, combined with its comparable binding affinity, make it the more promising candidate. The slightly better binding affinity of Ligand B is unlikely to outweigh the metabolic and safety advantages of Ligand A.

Output:
0
2025-04-17 11:38:26,300 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 438.631 Da - Within the ideal range (200-500 Da).
* Ligand B: 379.888 Da - Also within the ideal range.
* *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 46.5  - Good for oral absorption (<140).
* Ligand B: 49.15 - Good for oral absorption (<140).
* *No clear advantage.*

**3. Lipophilicity (logP):**
* Ligand A: 4.85 - Slightly high, potentially leading to solubility issues or off-target effects.
* Ligand B: 4.64 - Also slightly high, similar concerns as Ligand A.
* *No clear advantage.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Meets the criteria (<=5).
* Ligand B: 0 - Meets the criteria (<=5).
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 3 - Meets the criteria (<=10).
* Ligand B: 5 - Meets the criteria (<=10).
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.729 - Excellent drug-likeness.
* Ligand B: 0.703 - Good drug-likeness.
* *Ligand A slightly better.*

**7. DILI:**
* Ligand A: 78.945 - High DILI risk (>60). This is a significant concern.
* Ligand B: 31.601 - Low DILI risk (<40). This is a major advantage for Ligand B.

**8. BBB:**
* Ligand A: 79.139 - Good BBB penetration, but not crucial for a non-CNS target like SRC.
* Ligand B: 76.464 - Good BBB penetration, but not crucial.
* *No clear advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -4.653 - Poor permeability.
* Ligand B: -4.359 - Poor permeability.
* *No clear advantage.*

**10. Aqueous Solubility:**
* Ligand A: -5.723 - Very poor solubility.
* Ligand B: -5.542 - Very poor solubility.
* *No clear advantage.*

**11. hERG Inhibition:**
* Ligand A: 0.545 - Relatively low risk.
* Ligand B: 0.867 - Higher risk.
* *Ligand A slightly better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 58.923 - Moderate clearance.
* Ligand B: 76.525 - Higher clearance, suggesting lower metabolic stability.
* *Ligand A better.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 24.751 - Good half-life.
* Ligand B: 7.11 - Short half-life.
* *Ligand A significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.595 - Low efflux.
* Ligand B: 0.587 - Low efflux.
* *No clear advantage.*

**15. Binding Affinity:**
* Ligand A: -9.3 kcal/mol - Excellent affinity.
* Ligand B: -8.6 kcal/mol - Very good affinity, but less potent than A.
* *Ligand A significantly better.*

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a longer half-life, coupled with better metabolic stability. However, it has a very high DILI risk and poor solubility. Ligand B has a much lower DILI risk, but weaker affinity and poorer metabolic stability.

Despite the superior binding affinity of Ligand A, the high DILI risk and poor solubility are major drawbacks that would likely hinder its development. While solubility and DILI can be addressed through formulation or chemical modification, starting with a molecule with inherently lower risk is preferable.

Output:
1
2025-04-17 11:38:26,301 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is better than Ligand B (69.64) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.883 and 1.801), 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:** Ligand A (0.909) has a significantly higher QED score than Ligand B (0.454), indicating a much more drug-like profile.

**DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (14.696), which is a significant advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand A (71.539) is better than Ligand B (58.86).

**Caco-2 Permeability:** Ligand A (-4.717) is better than Ligand B (-5.091), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.216) is better than Ligand B (-2.257), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.228) has a lower hERG inhibition risk than Ligand B (0.166), a critical safety parameter.

**Microsomal Clearance:** Ligand A (46.94) has a better (lower) microsomal clearance than Ligand B (39.77), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-31.12) has a significantly longer in vitro half-life than Ligand A (-3.203), a major advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.091, respectively).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme target. While Ligand A excels in many ADME properties (QED, DILI, solubility, hERG, clearance), the difference in binding affinity is substantial (>1.5 kcal/mol). The longer half-life of Ligand B is also a significant benefit. The slightly higher DILI risk and lower solubility of Ligand B are concerns, but the potency advantage is likely to be more impactful in early-stage drug development.

Output:
1
2025-04-17 11:38:26,301 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.446 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.39) is significantly better than Ligand B (56.15).  A TPSA under 140 is preferred for oral absorption, and both are well below this, but lower is generally better.

**logP:** Ligand A (4.689) is slightly higher than Ligand B (3.425). Ligand A is approaching the upper limit of the optimal range (1-3), while Ligand B is comfortably within it. This could potentially lead to solubility issues for A.

**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 good QED scores (0.826 and 0.859), indicating good drug-like properties.

**DILI:** Ligand A (32.144) has a much lower DILI risk than Ligand B (52.307). This is a significant advantage for Ligand A.

**BBB:** Both have high BBB penetration (95.89 and 82.086). While not a primary concern for a kinase inhibitor, it's not detrimental.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.211 and -4.6), which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.298 and -4.309), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.876) has a slightly higher hERG risk than Ligand B (0.52). This is a negative for Ligand A.

**Microsomal Clearance:** Ligand A (77.325) has a higher microsomal clearance than Ligand B (68.818), meaning it's less metabolically stable. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (39.806) has a longer in vitro half-life than Ligand A (26.993), indicating better metabolic stability. This is a positive for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.379 and 0.622).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. The significantly stronger binding affinity (-7.8 vs -6.6 kcal/mol) is a major advantage for an enzyme inhibitor. Additionally, Ligand A has a much lower DILI risk. While Ligand A has higher hERG risk and lower metabolic stability, the potency advantage and reduced toxicity risk are more critical for an oncology target. Further work would be needed to address the solubility and permeability issues, but the starting point is better with Ligand A.

Output:
0
2025-04-17 11:38:26,301 - INFO - Batch 64 complete. Total preferences: 1024
2025-04-17 11:38:26,301 - INFO - Processing batch 65/512...
2025-04-17 11:39:15,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.77 and 352.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is better than Ligand B (42.43), both are below the 140 threshold for good absorption.

**logP:** Ligand A (4.844) is slightly higher than Ligand B (3.938). While both are within the 1-3 range, Ligand A is approaching the upper limit where solubility issues could arise.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.818) has a better QED score than Ligand B (0.632), indicating a more drug-like profile.

**DILI:** Ligand B (15.975) has a significantly lower DILI risk than Ligand A (62.931). This is a major advantage for Ligand B.

**BBB:** Ligand A (77.898) has a moderate BBB penetration, while Ligand B (94.067) has a high BBB penetration. While SRC is not a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.327) has worse Caco-2 permeability than Ligand B (-3.763). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-5.352) has worse aqueous solubility than Ligand B (-3.54). Lower (more negative) values indicate lower solubility.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.633 and 0.713), and are within acceptable limits.

**Microsomal Clearance:** Ligand A (53.317) has a lower microsomal clearance than Ligand B (83.91), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.999) has a slightly longer half-life than Ligand B (-2.234).

**P-gp Efflux:** Ligand A (0.312) has lower P-gp efflux than Ligand B (0.425), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.5 and -9.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Conclusion:**

Ligand B is the better candidate. While Ligand A has slightly better metabolic stability and P-gp efflux, Ligand B's significantly lower DILI risk and better solubility and Caco-2 permeability are more crucial for an enzyme target like SRC kinase. The binding affinities are comparable, so the ADME properties become the deciding factors.

Output:
1
2025-04-17 11:39:15,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (366.418 and 385.961 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.25) is better than Ligand B (52.65) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally correlates with better cell permeability.

**3. logP:** Ligand A (1.244) is optimal, while Ligand B (3.243) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

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

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have similar QED values (0.806 and 0.783), indicating good drug-likeness.

**7. DILI:** Ligand A (76.464) has a significantly higher DILI risk than Ligand B (19.969). This is a major concern for Ligand A.

**8. BBB:** Both have acceptable BBB penetration, but Ligand B (74.758) is slightly better than Ligand A (66.576). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.057 and -5.053), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.442 and -2.989), indicating very poor aqueous solubility. This is a major issue for both compounds.

**11. hERG Inhibition:** Ligand A (0.183) has a slightly lower hERG risk than Ligand B (0.644), which is preferable.

**12. Microsomal Clearance:** Ligand A (16.832) has higher microsomal clearance than Ligand B (8.218), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (34.374) has a longer in vitro half-life than Ligand A (45.104), which is desirable.

**14. P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux than Ligand B (0.107), which is preferable.

**15. Binding Affinity:** Ligand A (-10.3 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 concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity, but suffers from higher DILI risk, higher clearance, and lower P-gp efflux. Ligand B has better ADME properties (lower DILI, better half-life, better P-gp efflux), but significantly weaker binding affinity.

Given that we are targeting a kinase (enzyme), potency is paramount. The 2.1 kcal/mol difference in binding affinity is substantial. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications during lead optimization. The poor solubility and permeability are shared issues that would need to be addressed regardless of which lead is chosen.

Output:
0
2025-04-17 11:39:15,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.873 and 385.848 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent, well below the 140 threshold for oral absorption. Ligand B (82.53) is still acceptable, but less optimal.

**logP:** Ligand A (2.778) is within the optimal 1-3 range. Ligand B (1.096) is at the lower end, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also good, within the acceptable limits.

**QED:** Both ligands have similar QED values (0.896 and 0.811), indicating good drug-likeness.

**DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (65.568), which is a significant advantage.

**BBB:** Ligand A (77.976) has better BBB penetration than Ligand B (43.001), although this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.047) and Ligand B (-4.996) have similar, and very poor, Caco-2 permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-3.918) and Ligand B (-2.651) have poor solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.259) has a very low hERG risk, which is excellent. Ligand B (0.327) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (49.543) has moderate clearance, while Ligand B (-0.307) has *negative* clearance, which is highly unusual and suggests excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-2.436) has a negative half-life, which is impossible. This is likely an error in the data. Ligand B (-7.763) also has a negative half-life, also likely an error.

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

**Binding Affinity:** Both ligands have very strong binding affinities (-9.1 and -8.8 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite the questionable half-life data, Ligand B is the more promising candidate. The significantly lower DILI risk and *extremely* favorable microsomal clearance (negative value indicates exceptional stability) outweigh the slightly lower logP and BBB. The binding affinities are comparable. The poor Caco-2 permeability and solubility are concerns for both, but can be addressed during formulation. The negative half-life values are concerning and would need to be experimentally verified, but the other factors favor Ligand B.

Output:
1
2025-04-17 11:39:15,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.479 and 372.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (97.11), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (not a priority here).

**logP:** Ligand A (0.8) is slightly lower than optimal (1-3), while Ligand B (2.1) is within the ideal range. This favors B slightly.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=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: 0.636, B: 0.712), indicating good drug-like properties.

**DILI:** Ligand A (28.616) has a significantly lower DILI risk than Ligand B (59.403). This is a major advantage for A.

**BBB:** Ligand A (39.511) has a lower BBB penetration than Ligand B (77.821), but BBB is not a priority for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-4.582) has worse Caco-2 permeability than Ligand B (-5.143), both are very poor.

**Aqueous Solubility:** Ligand A (-0.916) has better aqueous solubility than Ligand B (-3.306). This is a significant advantage for A.

**hERG Inhibition:** Ligand A (0.353) has a lower hERG inhibition risk than Ligand B (0.271). Lower is better, so A is preferable.

**Microsomal Clearance:** Ligand A (34.844) has higher microsomal clearance than Ligand B (8.921), indicating lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand A (-5.771) has a shorter in vitro half-life than Ligand B (12.075), indicating lower stability. This favors B.

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux than Ligand B (0.099), which is beneficial.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage for B, potentially outweighing some ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, it has a higher DILI risk and lower aqueous solubility. Ligand A has better solubility, lower DILI, and lower hERG risk, but weaker binding and poorer metabolic stability. Given the importance of potency for kinase inhibitors, the 1.6 kcal/mol difference in binding affinity is substantial. While the DILI risk of Ligand B is a concern, it's not excessively high, and could potentially be mitigated with further optimization. The solubility of B is a concern, but not as critical as potency.

Output:
1
2025-04-17 11:39:15,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight (MW):**
* Ligand A: 357.455 Da - Within the ideal range (200-500 Da).
* Ligand B: 343.471 Da - Also within the ideal range.
* *No clear advantage.*

**2. TPSA:**
* Ligand A: 105.22  - Acceptable, but approaching the upper limit for good oral absorption.
* Ligand B: 54.34 - Excellent, well below the 140 threshold.
* *Ligand B has a significant advantage here, suggesting better absorption.*

**3. logP:**
* Ligand A: -2.309 -  Too low. May have permeability issues.
* Ligand B: 2.564 - Optimal, within the 1-3 range.
* *Ligand B is clearly superior in terms of lipophilicity.*

**4. H-Bond Donors (HBD):**
* Ligand A: 3 - Acceptable.
* Ligand B: 1 - Acceptable.
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 6 - Acceptable.
* Ligand B: 3 - Acceptable.
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.401 - Below the desirable threshold of 0.5.
* Ligand B: 0.863 - Excellent, indicating a strong drug-like profile.
* *Ligand B is significantly better in terms of predicted drug-likeness.*

**7. DILI:**
* Ligand A: 5.777 - Low risk, good.
* Ligand B: 17.836 - Still relatively low risk, but higher than Ligand A.
* *Ligand A has a slight advantage.*

**8. BBB:**
* Ligand A: 3.218 - Not relevant for a non-CNS target.
* Ligand B: 74.758 - Not relevant for a non-CNS target.
* *Not a deciding factor.*

**9. Caco-2 Permeability:**
* Ligand A: -5.86 - Very poor permeability.
* Ligand B: -4.894 - Poor permeability, but better than Ligand A.
* *Ligand B is slightly better.*

**10. Aqueous Solubility:**
* Ligand A: 0.601 - Low solubility, potentially problematic.
* Ligand B: -3.482 - Very low solubility, a significant concern.
* *Ligand A has a slight advantage.*

**11. hERG Inhibition:**
* Ligand A: 0.037 - Very low risk, excellent.
* Ligand B: 0.309 - Low risk, but higher than Ligand A.
* *Ligand A is better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: -28.17 - Negative value suggests very low clearance, excellent metabolic stability.
* Ligand B: 42.071 - Moderate clearance.
* *Ligand A is significantly better in terms of metabolic stability.*

**13. In vitro Half-Life:**
* Ligand A: -11.598 - Negative value suggests very long half-life, excellent.
* Ligand B: -2.735 - Moderate half-life.
* *Ligand A is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.001 - Very low efflux, excellent.
* Ligand B: 0.157 - Low efflux, but higher than Ligand A.
* *Ligand A is better.*

**15. Binding Affinity:**
* Ligand A: -9.8 kcal/mol - Excellent, very strong binding.
* Ligand B: -8.2 kcal/mol - Good, strong binding.
* *Ligand A has a substantial advantage in potency.*

**Overall Assessment:**

Ligand A has a significantly better binding affinity, metabolic stability (Cl_mic, t1/2), P-gp efflux, hERG risk, and DILI risk. While its logP is suboptimal and solubility is low, the strong binding affinity (-9.8 kcal/mol) can potentially compensate for these ADME drawbacks, especially given the enzyme target class. Ligand B has better TPSA and QED, but its lower affinity and poorer metabolic stability are major concerns. The solubility issues with both are problematic, but potentially addressable through formulation.

Output:
1
2025-04-17 11:39:15,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.451 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is slightly higher than Ligand B (71.11), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.578) is optimal, while Ligand B (-0.044) is slightly below the preferred range of 1-3. This could potentially hinder permeation for Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

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

**QED:** Ligand A (0.86) has a significantly better QED score than Ligand B (0.465), indicating a more drug-like profile.

**DILI:** Ligand A (42.536) has a lower DILI risk than Ligand B (16.44), suggesting better hepatotoxicity potential.

**BBB:** Both ligands have relatively low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (51.183) is higher than Ligand A (31.756).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.3) is slightly better than Ligand B (-4.805).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-2.853) is slightly better than Ligand B (-0.984).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.28 and 0.186 respectively).

**Microsomal Clearance:** Ligand A (-9.574) has a significantly *lower* (better) microsomal clearance than Ligand B (18.743), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-0.334) has a slightly better (less negative) in vitro half-life than Ligand B (-2.081).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.01 respectively).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). While both are good, the 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better QED score, lower DILI risk, better metabolic stability (lower Cl_mic and better t1/2), and a slightly stronger binding affinity. While both have issues with Caco-2 and solubility, Ligand A is better in both regards. The slightly better logP of Ligand A also supports its potential for better absorption. The affinity difference, combined with the ADME advantages, makes Ligand A the more promising candidate.

Output:
1
2025-04-17 11:39:15,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.406 and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.43) is better than Ligand B (49.41), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.734 and 3.16), 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.708 and 0.798), indicating good drug-likeness.

**DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (24.506), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.28) has a lower BBB penetration than Ligand B (97.286). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.239) has worse Caco-2 permeability than Ligand B (-4.595). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.909) has slightly better aqueous solubility than Ligand B (-3.805), but both are quite poor.

**hERG Inhibition:** Ligand A (0.412) has a lower hERG inhibition risk than Ligand B (0.762), which is a significant advantage.

**Microsomal Clearance:** Ligand A (10.887 mL/min/kg) has significantly lower microsomal clearance than Ligand B (37.89 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.051 hours) has a very short half-life, while Ligand B (-16.024 hours) has a negative half-life, which is not possible. This suggests a data error for Ligand B.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux than Ligand B (0.46), which is favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the slightly better affinity of Ligand B, the negative half-life is a critical flaw, likely indicating a data error. Ligand A, while having a slightly weaker affinity, exhibits a much more favorable ADME profile, particularly in terms of metabolic stability (lower Cl_mic) and hERG risk. The solubility and Caco-2 permeability are suboptimal for both, but these can be addressed through formulation strategies. Given the enzyme-specific priorities, the improved metabolic stability and reduced hERG risk of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 11:39:15,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (344.39 and 342.439 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.25 and 69.64) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.818) is optimal, while Ligand B (1.109) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3 HBA, well within the acceptable limits of 5 and 10, respectively.

**QED:** Ligand A (0.876) has a significantly better QED score than Ligand B (0.459), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (38.658 and 33.307 percentile), below the 40 threshold.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, this is a relative scale and the absolute values are not directly comparable without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is unknown, but suggests poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.538 and 0.54 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (-14.616 mL/min/kg) has *much* lower (better) microsomal clearance than Ligand B (56.043 mL/min/kg), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (-16.516 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (2.97 hours) is reasonable, but not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.119 and 0.267 percentile), which is good.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.3 and -8.1 kcal/mol), both well below the -7.0 kcal/mol threshold.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the key differentiating factors are QED and microsomal clearance. Ligand A has a much higher QED score (0.876 vs 0.459) and significantly better metabolic stability (lower Cl_mic). The binding affinity is comparable. While the negative half-life for Ligand A is concerning and suggests a data error, the other factors strongly favor Ligand A.

Output:
1
2025-04-17 11:39:15,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.403 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.17) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.67) is still under 140, but less optimal than A.

**logP:** Ligand A (3.666) is within the optimal 1-3 range. Ligand B (1.361) is at the lower end, potentially hindering permeation, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (0 HBD, 5 HBA) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.796 and 0.824), indicating drug-like properties.

**DILI:** Ligand A (46.84) has a slightly higher DILI risk than Ligand B (35.75), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (88.29 and 85.459), which isn't a primary concern for a non-CNS target like SRC kinase, but isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.678 and -4.477). This is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, given that it's a relative comparison, we'll consider the values in context.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.984 and -1.6). This is a significant concern for bioavailability.

**hERG:** Ligand A (0.78) has a slightly higher hERG risk than Ligand B (0.209), but both are relatively low.

**Microsomal Clearance:** Ligand A (19.511) has a lower microsomal clearance than Ligand B (28.31), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-19.456) has a negative in vitro half-life, which is not physically possible and likely indicates an experimental error or a very rapid degradation. Ligand B (1.571) has a short half-life, but it's a realistic value.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.202 and 0.079), which is favorable.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the poor solubility and questionable Caco-2 values for both, Ligand A is the stronger candidate due to its significantly higher binding affinity (-10.3 vs -8.2 kcal/mol) and better metabolic stability (lower Cl_mic). The negative half-life for Ligand A is a red flag, but the large affinity difference outweighs this concern, assuming the half-life is an error. The slightly higher DILI risk for A is acceptable given the other benefits.

Output:
1
2025-04-17 11:39:15,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.559 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**TPSA:** Ligand A (83.47) is better than Ligand B (98.17) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 2.566, B: 3.01), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is slightly better than Ligand B (HBD=1, HBA=3) as it is closer to the ideal range.

**QED:** Both ligands have acceptable QED values (A: 0.633, B: 0.454), with Ligand A being slightly more drug-like.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (15.587). This is a significant negative for Ligand A.

**BBB:** Ligand B (77.162) has a better BBB penetration score than Ligand A (46.219), but BBB isn't a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.6) is slightly better than Ligand B (-4.881).

**Aqueous Solubility:** Both ligands have negative solubility values, which is concerning. Ligand A (-2.83) is slightly better than Ligand B (-3.192).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.465, B: 0.356), which is positive.

**Microsomal Clearance:** Ligand A (28.382) has a lower microsomal clearance than Ligand B (37.625), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.014) has a longer in vitro half-life than Ligand B (-9.925), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.465, B: 0.039).

**Binding Affinity:** Both ligands have similar strong binding affinities (A: -6.3 kcal/mol, B: -6.5 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a significantly lower DILI risk and a slightly better binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED score. The negative solubility and Caco-2 values are concerning for both. Considering the enzyme-specific priorities, metabolic stability and affinity are crucial. While the affinity difference is small, the substantial difference in DILI risk makes Ligand B the more promising candidate.

Output:
1
2025-04-17 11:39:15,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.307 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (91.32). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B is approaching a level that could hinder absorption.

**logP:** Both ligands have acceptable logP values (1.846 and 2.26), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (3 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.479 and 0.69), suggesting acceptable drug-likeness, with Ligand B being slightly better.

**DILI:** Both ligands have low DILI risk (47.693 and 42.885), both under the 60 threshold.

**BBB:** Ligand A (47.809) and Ligand B (57.619) are both low, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.599 and -4.96). This is unusual and suggests poor permeability. However, these values are on a logarithmic scale and can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.391 and -3.481), indicating poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.426) is significantly better than Ligand B (0.09), indicating a lower risk of cardiotoxicity. This is a crucial advantage.

**Microsomal Clearance:** Ligand A (42.244) is better than Ligand B (45.626), suggesting better metabolic stability. Lower clearance is preferred.

**In vitro Half-Life:** Ligand B (-43.288) has a significantly longer half-life than Ligand A (-7.979). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.077) is better than Ligand B (0.041), suggesting lower P-gp efflux and potentially better bioavailability.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a significantly better binding affinity than Ligand A (-7.6 kcal/mol). This is the most critical factor for an enzyme inhibitor. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity (-0.0 kcal/mol vs -7.6 kcal/mol). While it has some drawbacks (higher TPSA, more H-bonds, poorer hERG, and lower P-gp), the significantly improved potency is likely to outweigh these concerns, especially for an enzyme target where binding affinity is paramount. The longer half-life of Ligand B is also a significant advantage. The poor solubility and permeability of both compounds are concerning, but these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:39:15,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.451 and 357.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.47) is slightly above the preferred <90 for CNS targets, but acceptable for a non-CNS target like SRC. Ligand B (64.34) is well within the ideal range.

**logP:** Ligand A (-0.039) is slightly low, potentially hindering permeability. Ligand B (3.876) is approaching the upper limit but still within the acceptable 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 7 HBA) both have reasonable numbers of H-bond donors and acceptors, balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.669 and 0.751), indicating drug-like properties.

**DILI:** Ligand A (9.965) has a very low DILI risk, significantly better than Ligand B (84.335), which is quite high. This is a major concern for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (69.252) has a higher BBB percentile than Ligand A (32.299), but this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.883 and -4.928), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.648 and -3.806), indicating poor aqueous solubility. This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.104) has a very low hERG risk, while Ligand B (0.759) has a moderate risk.

**Microsomal Clearance:** Ligand A (-4.62) has a negative clearance, which is excellent, indicating very high metabolic stability. Ligand B (48.176) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (11.244 hours) has a good half-life. Ligand B (20.024 hours) has a longer half-life, which is positive.

**P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, while Ligand B (0.701) has moderate efflux.

**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 not substantial enough to overcome the significant ADME liabilities of Ligand B.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. Ligand B has a high DILI risk, poor solubility, moderate P-gp efflux, and high microsomal clearance. Ligand A has excellent metabolic stability (negative clearance), low DILI and hERG risk, and low P-gp efflux. While both have poor Caco-2 and solubility, the superior safety profile and metabolic stability of Ligand A make it the better choice for further development.

Output:
0
2025-04-17 11:39:15,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.46) is higher than Ligand B (76.46). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have good logP values (1.486 and 0.965), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable, but fewer HBDs (Ligand B) generally improve permeability.

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

**QED:** Both ligands have good QED scores (0.692 and 0.779), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (48.623 and 45.173), below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (63.474 and 65.374). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.971) and Ligand B (-5.082) have similar Caco-2 permeability values, suggesting similar intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.348) has worse solubility than Ligand B (-1.186). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.239 and 0.166), which is excellent.

**Microsomal Clearance:** Ligand B (2.928) has significantly lower microsomal clearance than Ligand A (64.84). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (6.32) has a much longer in vitro half-life than Ligand A (-23.494). 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 (0.191 and 0.03).

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.0). While the difference is not huge, it is still a positive factor.

**Overall:**

Ligand B is superior to Ligand A. It has better solubility, significantly better metabolic stability (lower Cl_mic and longer t1/2), a slightly better binding affinity, and fewer H-bond donors. While Ligand A has a slightly lower TPSA, the advantages of Ligand B in metabolic stability and solubility outweigh this minor difference.

Output:
1
2025-04-17 11:39:15,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 Da and 359.348 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (92.5 and 91.32) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (1.497 and 2.144) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 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 (0.596 and 0.751), indicating good drug-likeness.

**DILI:** Ligand A (18.108) has a significantly lower DILI risk than Ligand B (41.489). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (65.103 and 71.656), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values (-5.078 and -4.952), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.206 and -3.146), which is also unusual and indicates very poor aqueous solubility. This is a major issue.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.173 and 0.233), which is excellent.

**Microsomal Clearance:** Ligand A (41.2 mL/min/kg) has a higher microsomal clearance than Ligand B (10.128 mL/min/kg). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-29.123 hours) has a significantly longer in vitro half-life than Ligand A (-12.079 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.031).

**Binding Affinity:** Both ligands have strong binding affinities (-9.9 kcal/mol and -8.8 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While both ligands have strong binding affinities, Ligand A is preferable due to its significantly lower DILI risk. The poor solubility and permeability are concerning for both, but can potentially be addressed through formulation strategies. Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), but the higher DILI risk is a significant concern. Given the enzyme-specific priorities, the lower DILI risk of Ligand A outweighs the slightly better metabolic stability of Ligand B.

Output:
0
2025-04-17 11:39:15,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (374.419 Da and 391.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (119.83) is better than Ligand B (74.73), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (-1.201) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (3.159) 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:** Ligand A has 8 HBAs, while Ligand B has 7. Both are below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.664 and 0.673), indicating good drug-likeness.

**7. DILI:** Ligand A (76.192) has a lower DILI risk than Ligand B (93.059). This is a positive for Ligand A, but both are reasonably acceptable.

**8. BBB:** Both ligands have similar low BBB penetration (48.197 and 46.413). BBB is not a high priority for an oncology target.

**9. Caco-2 Permeability:** Ligand A (-5.142) has worse Caco-2 permeability than Ligand B (-4.743).

**10. Aqueous Solubility:** Ligand A (-1.297) has slightly better solubility than Ligand B (-4.478).

**11. hERG Inhibition:** Ligand A (0.015) has a very low hERG risk, significantly better than Ligand B (0.737). This is a crucial advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (-14.158) has much lower (better) microsomal clearance than Ligand B (11.077), indicating greater metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-1.141) has a shorter in vitro half-life than Ligand B (25.326). This is a disadvantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.017) has lower P-gp efflux than Ligand B (0.434), which is favorable.

**15. Binding Affinity:** Ligand B (-9.5) has a significantly stronger binding affinity than Ligand A (-7.0). This is a substantial advantage for Ligand B, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and significantly better binding affinity. Ligand A has better hERG inhibition, lower DILI risk, lower microsomal clearance, and lower P-gp efflux. The difference in binding affinity is substantial (-9.5 vs -7.0 kcal/mol). For a kinase target, potency is paramount. While Ligand A has a better safety profile (hERG, DILI, Cl_mic), the superior binding affinity of Ligand B is likely to be more critical for efficacy. The slightly worse ADME properties of Ligand B can be addressed through further optimization.

Output:
1
2025-04-17 11:39:15,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.519 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (88.91). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.291) is optimal, while Ligand B (1.868) is slightly lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 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 (0.614 and 0.749), indicating drug-likeness.

**DILI:** Ligand A (11.322) has a much lower DILI risk than Ligand B (70.725). This is a significant advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (77.2) has a better BBB percentile than Ligand B (65.374).

**Caco-2 Permeability:** Ligand A (-4.491) has a better Caco-2 permeability than Ligand B (-5.475).

**Aqueous Solubility:** Ligand A (-3.089) has a better aqueous solubility than Ligand B (-3.682).

**hERG Inhibition:** Ligand A (0.657) has a lower hERG inhibition risk than Ligand B (0.314), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (36.711) has a lower microsomal clearance than Ligand B (53.485), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (53.003) has a significantly longer in vitro half-life than Ligand A (2.993). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.165) has lower P-gp efflux than Ligand B (0.149).

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.2). While a 1.5 kcal/mol advantage is significant, the other factors weigh heavily in favor of Ligand A.

**Overall:** Considering all factors, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better solubility, better permeability, lower hERG risk, and better metabolic stability. While Ligand B has a slightly better binding affinity and longer half-life, the advantages of Ligand A in ADME-Tox properties are more critical for overall drug development success, especially for an enzyme target where metabolic stability and safety are paramount.

Output:
0
2025-04-17 11:39:15,694 - INFO - Batch 65 complete. Total preferences: 1040
2025-04-17 11:39:15,694 - INFO - Processing batch 66/512...
2025-04-17 11:40:01,059 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (341.411 and 345.531 Da) fall well within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is better than Ligand B (35.58) as it is still within a reasonable range for oral absorption.

**3. logP:** Both ligands have a logP around 3.4, which is optimal.

**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 scores (0.797 and 0.784), indicating good drug-likeness.

**7. DILI:** Ligand B (5.428) is significantly better than Ligand A (49.283) regarding DILI risk, indicating a much lower potential for liver injury. This is a major advantage for Ligand B.

**8. BBB:** Both have good BBB penetration (86.778 and 80.729), but this is less crucial for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.458) is better than Ligand B (-5.007).

**10. Aqueous Solubility:** Ligand B (-1.695) is better than Ligand A (-4.199).

**11. hERG Inhibition:** Ligand A (0.651) is better than Ligand B (0.957), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (-20.725) has a much lower (better) microsomal clearance than Ligand A (33.483), suggesting significantly improved metabolic stability. This is a critical advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (11.766) has a slightly better in vitro half-life than Ligand A (14.788).

**14. P-gp Efflux:** Ligand A (0.106) is better than Ligand B (0.085).

**15. Binding Affinity:** Ligand B (-8.0) has slightly better binding affinity than Ligand A (-7.8). While the difference is small, it's still a positive.

**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 an enzyme inhibitor: significantly lower DILI risk and much improved metabolic stability (lower Cl_mic and better half-life). The slightly better binding affinity of Ligand B further supports its selection. The better solubility of Ligand B is also a plus.

Output:
1
2025-04-17 11:40:01,059 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (363.483 Da) is also good.

**TPSA:** Ligand A (117.09) is better than Ligand B (64.02) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Both ligands have acceptable logP values (A: 1.139, B: 3.166), falling within the optimal range of 1-3.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (A: 0.752, B: 0.698), indicating good drug-like properties.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (51.57), which is preferable.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (65.064) is slightly better than Ligand A (27.608).

**Caco-2 Permeability:** Ligand A (-5.395) has worse Caco-2 permeability than Ligand B (-4.301).

**Aqueous Solubility:** Ligand A (-2.988) has worse aqueous solubility than Ligand B (-3.977).

**hERG Inhibition:** Ligand A (0.065) has a much lower hERG inhibition liability than Ligand B (0.249), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-12.441) has significantly lower microsomal clearance than Ligand B (63.459), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (2.824) has a significantly shorter in vitro half-life than Ligand B (-11.529).

**P-gp Efflux:** Ligand A (0.011) has lower P-gp efflux than Ligand B (0.301), which is a positive.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). The difference is 1.1kcal/mol, which is significant.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better solubility and BBB, Ligand A excels in the most critical areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic), lower hERG risk, lower P-gp efflux, and a slightly improved binding affinity. The better binding affinity outweighs the slightly worse solubility and Caco-2 permeability. The DILI risk is higher for Ligand A, but still within an acceptable range.

Output:
0
2025-04-17 11:40:01,059 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.423 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is better than Ligand B (49.85) as it is still within the acceptable range for oral absorption (<140), while Ligand B is excellent.

**logP:** Ligand A (-0.496) is slightly low, potentially hindering permeation. Ligand B (2.143) is 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 (7) is acceptable, and Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.515 and 0.762, respectively), indicating drug-like properties.

**DILI:** Ligand A (48.468) has a slightly higher DILI risk than Ligand B (19.271), but both are below the concerning threshold of 60.

**BBB:** Ligand A (58.085) has a lower BBB penetration than Ligand B (97.751). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.319) has poor Caco-2 permeability, while Ligand B (-4.34) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.033) has poor aqueous solubility, while Ligand B (-2.969) is also poor.

**hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, which is excellent. Ligand B (0.576) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (18.911) has a higher microsomal clearance than Ligand B (16.27), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (3.385) has a shorter in vitro half-life than Ligand B (16.462), further indicating lower metabolic stability.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is favorable. Ligand B (0.087) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.2). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has better solubility, permeability, metabolic stability, and a lower DILI risk, Ligand A boasts a significantly stronger binding affinity (-7.9 vs -7.2 kcal/mol). Given that we are targeting an enzyme (SRC kinase), potency is paramount. The slightly lower metabolic stability and solubility of Ligand A are potentially addressable through further optimization, but the stronger binding is a substantial advantage.

Output:
1
2025-04-17 11:40:01,059 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.909 Da and 363.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (61.36 and 62.3) are reasonably low, suggesting good potential for cell permeability, although not optimal for CNS penetration.

**3. logP:** Ligand A (2.536) is within the optimal 1-3 range. Ligand B (3.441) 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 5 HBAs, and Ligand B has 4. Both are below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.785 and 0.769), indicating good drug-likeness.

**7. DILI:** Ligand A (22.838) has a significantly lower DILI risk than Ligand B (43.505). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.943) has a higher BBB score than Ligand B (67.701), but it's not a deciding 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 ligands have negative solubility values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.577) has a slightly higher hERG risk than Ligand B (0.359), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (11.407) has a much lower microsomal clearance than Ligand B (71.019). This suggests better metabolic stability for Ligand A, a crucial factor for an enzyme target.

**13. In vitro Half-Life:** Ligand A (26.538) has a longer in vitro half-life than Ligand B (16.121), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.034) has much lower P-gp efflux than Ligand B (0.287), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-9.6 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 boasts a much superior binding affinity, Ligand A demonstrates significantly better ADME properties. Specifically, its lower DILI risk, lower microsomal clearance, longer half-life, and lower P-gp efflux are all highly desirable characteristics for a drug candidate, especially targeting an enzyme like SRC. The poor solubility and permeability are concerns for both, but the metabolic advantages of Ligand A, coupled with its acceptable safety profile, outweigh the affinity difference. The binding affinity of Ligand A is also not terrible, and optimization could potentially improve it.

Output:
1
2025-04-17 11:40:01,059 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.354 and 369.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.79) is better than Ligand B (91.76), both are below the 140 threshold for oral absorption, but A is closer to the ideal for enzyme inhibitors.

**3. logP:** Ligand A (2.329) is within the optimal 1-3 range. Ligand B (0.826) is slightly below 1, which *could* indicate permeability issues, but is not a major concern.

**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 (0.641 and 0.708), indicating good drug-like properties.

**7. DILI:** Ligand A (44.63) 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 low BBB penetration (29.12 and 31.912), which is not a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.31 and -5.007), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.913 and -1.297), indicating very poor aqueous solubility. This is a major issue for *in vivo* bioavailability.

**11. hERG Inhibition:** Ligand A (0.408) shows a lower hERG inhibition risk than Ligand B (0.096), which is desirable.

**12. Microsomal Clearance:** Ligand A (8.688) has a higher microsomal clearance than Ligand B (3.031), meaning it's less metabolically stable. This is a significant negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (8.158) has a significantly longer in vitro half-life than Ligand A (-5.493), indicating better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.068) has slightly higher P-gp efflux than Ligand B (0.043), but both are low.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher microsomal clearance and lower in vitro half-life. Ligand B has better metabolic stability and solubility, but its binding affinity is extremely weak. The poor Caco-2 and solubility for both are concerning.

Despite the metabolic stability advantages of Ligand B, the *massive* difference in binding affinity (-7.8 vs 0.0 kcal/mol) makes Ligand A far more likely to be a viable starting point for optimization. A medicinal chemist could focus on improving the metabolic stability of Ligand A while retaining its strong binding. The solubility and permeability issues would also need to be addressed, but a strong starting affinity is crucial.

Output:
1
2025-04-17 11:40:01,059 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.446 and 353.413 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (65.38) is slightly above the preferred <140, but acceptable. Ligand B (54.34) is well within the range.

**logP:** Both ligands (2.948 and 2.52) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.738 and 0.854), indicating good drug-like properties.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (34.82), but both are below the concerning threshold of 60.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand B (93.059) has a higher percentile than Ligand A (76.154).

**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 significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.705 and 0.559).

**Microsomal Clearance:** Ligand A (62.397) has a higher microsomal clearance than Ligand B (17.81). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-8.8) has a significantly longer in vitro half-life than Ligand A (50.587). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.502 and 0.093).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good potency, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better BBB penetration. The negative Caco-2 and solubility values are concerning for both, but the ADME advantages of Ligand B outweigh these concerns.

Output:
1
2025-04-17 11:40:01,059 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.55 and 351.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is well below the 140 threshold for oral absorption, while Ligand B (121.71) is still acceptable but less optimal.

**logP:** Ligand A (1.595) is within the optimal 1-3 range. Ligand B (-0.114) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.74 and 0.73), indicating good drug-likeness.

**DILI:** Both ligands have similar, relatively low DILI risk (8.53 and 69.06), suggesting a low risk of liver injury.

**BBB:** Ligand A (69.37) has a moderate BBB penetration, while Ligand B (19.81) has very low BBB penetration. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.81) has poor Caco-2 permeability, while Ligand B (-5.06) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.25) has poor solubility, while Ligand B (-2.12) has even poorer solubility. This is a significant concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.48 and 0.05).

**Microsomal Clearance:** Ligand A (5.06) has a moderate clearance, while Ligand B (-15.55) has a much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.48) has a very long half-life, while Ligand B (-34.44) has an even longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.02).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

The key differences lie in solubility, Caco-2 permeability, and metabolic stability. Ligand B has significantly better metabolic stability (lower Cl_mic, longer half-life) despite having lower solubility and Caco-2 permeability. However, the binding affinity is identical. The poor solubility of both compounds is a major drawback, but the improved metabolic stability of Ligand B is a significant advantage for an enzyme target. While Ligand A has slightly better TPSA and BBB penetration, these are less critical for SRC.

Output:
1
2025-04-17 11:40:01,059 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [347.415, 93.46, 1.104, 2, 5, 0.804, 45.328, 55.603, -5.559, -0.792, 0.115, 7.537, 6.191, 0.024, -8.6]
**Ligand B:** [342.403, 103.87, 0.951, 2, 5, 0.861, 64.676, 27.918, -5.476, -2.094, 0.246, -7.498, -11.076, 0.012, -7.9]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (347.415) and B (342.403) are very close.
2. **TPSA:** Both are acceptable for oral absorption (<140), A (93.46) is better than B (103.87).
3. **logP:** Both are within the optimal range (1-3). A (1.104) and B (0.951) are similar.
4. **HBD:** Both have 2 HBD, which is good.
5. **HBA:** Both have 5 HBA, which is good.
6. **QED:** Both have good QED scores (A: 0.804, B: 0.861), indicating drug-likeness. B is slightly better.
7. **DILI:** A (45.328) has a lower DILI risk than B (64.676). This is a significant advantage for A.
8. **BBB:** A (55.603) has better BBB penetration than B (27.918), but this is less critical for a non-CNS target like SRC.
9. **Caco-2:** Both have negative values, which is unusual and suggests poor permeability. A (-5.559) is slightly better than B (-5.476).
10. **Solubility:** Both have negative values, indicating poor solubility. A (-0.792) is slightly better than B (-2.094).
11. **hERG:** Both have very low hERG risk (A: 0.115, B: 0.246).
12. **Cl_mic:** A (7.537) has a higher microsomal clearance than B (-7.498). B is significantly more metabolically stable.
13. **t1/2:** A (6.191) has a longer in vitro half-life than B (-11.076). A is significantly more stable.
14. **Pgp:** Both have very low Pgp efflux liability (A: 0.024, B: 0.012).
15. **Binding Affinity:** A (-8.6 kcal/mol) has a slightly better binding affinity than B (-7.9 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A is slightly better (-8.6 vs -7.9).
*   **Metabolic Stability:** B is *much* better (negative Cl_mic indicates metabolic stability, and a positive t1/2 is better).
*   **Solubility:** A is slightly better.
*   **hERG:** Both are good.
*   **DILI:** A is significantly better.

**Conclusion:**

While ligand B has superior metabolic stability, ligand A has a better binding affinity, better DILI profile, and slightly better solubility. The difference in binding affinity, coupled with the lower DILI risk, outweighs the metabolic stability advantage of ligand B, especially considering the in vitro half-life of A is also favorable.

Output:
1
2025-04-17 11:40:01,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (351.397 and 341.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (54.26) is well below the 140 threshold and is favorable. Ligand B (72.16) is also below 140, but higher than A.

**3. logP:** Ligand A (3.826) is at the upper end of the optimal range (1-3), while Ligand B (1.292) is slightly below. Ligand A's higher logP *could* lead to solubility issues, but is not immediately disqualifying.

**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):** Both ligands have acceptable HBA counts (4 for A, 5 for B), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.81 and 0.609), indicating drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (56.727 and 54.207), both are acceptable (below 60).

**8. BBB:** Ligand A (77.2) has a better BBB percentile than Ligand B (38.852). While not a primary concern for a kinase inhibitor, it's a slight advantage for A.

**9. Caco-2 Permeability:** Ligand A (-4.415) has worse Caco-2 permeability than Ligand B (-5.233). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-3.499) has worse aqueous solubility than Ligand B (-1.602). Solubility is important for kinases.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.579 and 0.559).

**12. Microsomal Clearance (Cl_mic):** Ligand B (35.443) has a lower Cl_mic than Ligand A (43.13), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-2.57) has a significantly longer in vitro half-life than Ligand A (-20.866). This is a major advantage for B.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.278 and 0.151).

**15. Binding Affinity:** Both ligands have comparable binding affinity (-8.5 and -7.5 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is more promising. While Ligand A has slightly better binding affinity and BBB penetration, Ligand B exhibits significantly improved metabolic stability (lower Cl_mic, longer half-life) and better aqueous solubility. These factors are crucial for *in vivo* efficacy and reducing dosing frequency. The slightly lower affinity of Ligand B is outweighed by its superior ADME properties.

Output:
1
2025-04-17 11:40:01,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (391.383 and 364.461 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (33.2). Both are well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have logP values (4.044 and 4.893) that are slightly above the optimal 1-3 range, but still acceptable. Ligand B is a bit higher, which *could* lead to solubility issues.

**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 similar QED values (0.614 and 0.655), indicating good drug-likeness.

**DILI:** Ligand A (27.53) has a significantly lower DILI risk than Ligand B (36.758). This is a major advantage for Ligand A.

**BBB:** Ligand A (66.615) and Ligand B (84.529) both have acceptable BBB penetration, but Ligand B is better. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.859 and -4.568). These values are unusual and suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.158 and -4.341), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.489) has a lower hERG inhibition risk than Ligand B (0.841). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (72.395) has a slightly lower microsomal clearance than Ligand B (79.299), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (34.256) has a significantly longer in vitro half-life than Ligand A (-6.293). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.259) has lower P-gp efflux than Ligand B (0.773), which is favorable.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-8.0). This is a major advantage for Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.3 kcal/mol vs -8.0 kcal/mol) and a longer half-life (34.256 vs -6.293). These are critical for an enzyme inhibitor. While Ligand A has better DILI and hERG profiles, the potency and metabolic stability advantages of Ligand B outweigh these concerns. Both ligands have poor solubility and permeability, which would need to be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 11:40:01,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.511 and 354.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.76) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (72.8) is still under 140 but less optimal than A.

**logP:** Ligand A (3.501) is at the higher end of the optimal range (1-3), while Ligand B (2.163) is closer to the lower bound. Both are acceptable, but A's higher logP *could* lead to off-target effects, which needs consideration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both have reasonable numbers of H-bonds, within the guidelines.

**QED:** Ligand A (0.751) has a better QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand A (48.623) has a much lower DILI risk than Ligand B (9.771), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (77.045 and 73.711), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.827 and -4.858), which is unusual and suggests poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.8 and -2.566), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.578) has a slightly higher hERG risk than Ligand B (0.777), but both are relatively low.

**Microsomal Clearance:** Ligand A (75.97) has significantly higher microsomal clearance than Ligand B (40.048), meaning it's less metabolically stable. This is a major disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-5.263) has a longer in vitro half-life than Ligand A (12.783).

**P-gp Efflux:** Ligand A (0.644) has lower P-gp efflux than Ligand B (0.45), which is favorable.

**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, while not huge, is a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, and lower DILI risk, and P-gp efflux. However, it suffers from significantly higher microsomal clearance and poorer solubility. Ligand B has better metabolic stability and solubility, but weaker binding affinity and higher DILI risk. The poor Caco-2 and solubility for both are concerning.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and solubility are crucial. While Ligand A has a slightly better affinity, the significantly higher clearance and poor solubility of Ligand A are major drawbacks. Ligand B, despite its slightly weaker affinity, presents a more favorable ADME profile with better metabolic stability and solubility.

Output:
1
2025-04-17 11:40:01,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.383 and 359.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.53 and 73.32) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.122) is optimal (1-3), while Ligand B (-0.125) is below 1, potentially hindering permeation.

**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 5, both within the acceptable limit of <=10.

**QED:** Ligand A (0.865) has a significantly better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Ligand A (74.292) has a higher DILI risk than Ligand B (17.371). This is a concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (69.756 and 77.084), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.966 and -4.753), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.642 and -0.608), indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.215 and 0.214). This is positive for both.

**Microsomal Clearance:** Ligand A (29.977) has a higher microsomal clearance than Ligand B (23.209), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (5.246) has a significantly longer in vitro half-life than Ligand A (-18.658), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.091 and 0.011).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -8.0 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is the better candidate. It has a better binding affinity, a significantly longer half-life, lower DILI risk, and a slightly better BBB score. Ligand A's higher DILI risk and lower half-life are significant drawbacks. The poor solubility and permeability would need to be addressed through formulation strategies, but the superior ADME properties of Ligand B make it the more promising starting point.

Output:
1
2025-04-17 11:40:01,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (365.415 Da) is also well within range.

**TPSA:** Ligand A (138.28) is close to the upper limit for good oral absorption (<=140), while Ligand B (116.57) is well below, suggesting potentially better absorption.

**logP:** Ligand A (0.24) is quite low, potentially hindering permeation. Ligand B (0.901) is better, falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 10 HBA. Ligand B has 3 HBD and 6 HBA. Both are within acceptable limits, but Ligand B's values are more balanced.

**QED:** Ligand A (0.425) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.725) is above 0.5, suggesting a more favorable drug-like profile.

**DILI:** Ligand A (96.51) has a high DILI risk, which is concerning. Ligand B (87.98) has a lower, though still elevated, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.047) and Ligand B (31.214) are not particularly relevant here.

**Caco-2 Permeability:** Ligand A (-4.44) has very poor Caco-2 permeability, while Ligand B (-5.194) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.912 and -3.291 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.177 and 0.202 respectively), which is good.

**Microsomal Clearance:** Ligand A (101.797) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (23.026) has significantly lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.837) has a negative half-life, which is not possible and likely indicates a very rapid degradation. Ligand B (5.274) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.255 and 0.022 respectively), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.4 kcal/mol). The difference is minor, and not a deciding factor.

**Conclusion:**

Ligand B is significantly more promising. While both have poor solubility, Ligand B exhibits a better QED score, lower microsomal clearance (better metabolic stability), a reasonable half-life, and a more favorable logP. Ligand A has a high DILI risk, poor Caco-2 permeability, and a nonsensical half-life value. The slightly better binding affinity of Ligand B is a bonus, but the ADME properties are the key differentiators.

Output:
1
2025-04-17 11:40:01,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.352 Da) is higher, but still acceptable. Ligand B (362.396 Da) is slightly preferred.

**TPSA:** Ligand A (88.32) is better than Ligand B (59.39) as it is closer to the threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 2.881, B: 2.115), falling within the optimal 1-3 range.

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

**QED:** Both ligands have good QED scores (A: 0.787, B: 0.895), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (76.968) has a higher DILI risk than Ligand B (38.348). This is a significant concern, as a lower DILI percentile is preferred.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (84.413) has a higher BBB percentile than Ligand A (52.889).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.419) is worse than Ligand B (-4.54).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.956) is worse than Ligand B (-1.657).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.611, B: 0.238), which is good. Ligand B is better.

**Microsomal Clearance:** Ligand A (27.121 mL/min/kg) has higher microsomal clearance than Ligand B (17.361 mL/min/kg), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-8.478 hours) has a negative half-life, which is concerning. Ligand A (24.642 hours) has a positive half-life, which is much better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.207, B: 0.105). Ligand B is slightly better.

**Binding Affinity:** Both ligands have the same binding affinity (-8.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is significantly better due to its lower DILI risk, better solubility, lower clearance, and better P-gp efflux. While Ligand A has a better in vitro half-life, the DILI risk associated with Ligand A is a major concern. The similar binding affinities mean that the ADME properties are the deciding factor.

Output:
1
2025-04-17 11:40:01,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.34 and 346.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.76) is slightly above the preferred <140 for good oral absorption, while Ligand B (104.7) is well within the range.

**logP:** Ligand A (-1.335) is a bit low, potentially hindering permeation. Ligand B (0.888) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 5 HBA, acceptable. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.38 and 0.594), with Ligand B being slightly more drug-like.

**DILI:** Both ligands have relatively low DILI risk (33.346 and 38.193), both below the 40 threshold.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (59.364) and Ligand B (32.493) are both low.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.495 and -5.775), indicating potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.679 and -1.583). This is a significant concern.

**hERG Inhibition:** Both ligands have very low hERG risk (0.075 and 0.547), which is excellent.

**Microsomal Clearance:** Ligand A (10.882) has lower microsomal clearance than Ligand B (15.189), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.135) has a significantly longer in vitro half-life than Ligand B (2.131), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.008 and 0.01).

**Binding Affinity:** Ligand A (-7.6) has a stronger binding affinity than Ligand B (-6.3) by 1.3 kcal/mol. This difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-7.6 vs -6.3 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target like SRC kinase. While the logP is suboptimal, the strong binding may compensate. The solubility issue would need to be addressed through formulation strategies.

Output:
1
2025-04-17 11:40:01,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.3 and 359.86 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.68) is better than Ligand B (67.59), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.667 and 3.204) 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 4. Both are within the acceptable range (<=10).

**QED:** Both ligands have high QED scores (0.832 and 0.879), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (66.421 and 67.468), placing them in a moderate risk category. This isn't ideal, but not a dealbreaker.

**BBB:** Both ligands have similar BBB penetration (71.229 and 66.421). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.733) has better Caco-2 permeability than Ligand B (-4.951).

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-4.148 and -4.115). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.55 and 0.586), which is moderate and requires attention.

**Microsomal Clearance:** Ligand A (23.34 mL/min/kg) has significantly *lower* microsomal clearance than Ligand B (-5.585 mL/min/kg). This suggests better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-3.426 hours) has a longer in vitro half-life than Ligand B (39.893 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.304 and 0.184).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands exhibit good binding affinity and drug-like properties, Ligand A is the more promising candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2) and better Caco-2 permeability outweigh the slight differences in other parameters. The similar DILI and hERG risks require further investigation, but the improved pharmacokinetic profile of Ligand A makes it the better choice for development as an SRC kinase inhibitor.

Output:
0
2025-04-17 11:40:01,061 - INFO - Batch 66 complete. Total preferences: 1056
2025-04-17 11:40:01,061 - INFO - Processing batch 67/512...
2025-04-17 11:40:43,096 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.463 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 140 threshold for absorption. Ligand B (109.58) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.681) is optimal (1-3). Ligand B (-0.523) is significantly below 1, which is a concern for permeability.

**H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well within the limit of 5.

**H-Bond Acceptors:** Ligand A (2) is good. Ligand B (7) is higher, but still within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.929 and 0.713), indicating good drug-like properties.

**DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (61.497), which is approaching a higher risk category.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.121) is higher than Ligand B (39.395).

**Caco-2 Permeability:** Both have negative values (-4.788 and -4.92), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-4.246 and -1.332), indicating very poor solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.922) has a slightly higher hERG risk than Ligand B (0.106), but both are relatively low.

**Microsomal Clearance:** Ligand A (45.81) has higher clearance than Ligand B (25.544), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.872) has a slightly better (longer) half-life than Ligand A (-7.953).

**P-gp Efflux:** Both have low P-gp efflux liability (0.686 and 0.019).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.4 kcal/mol), with a negligible difference.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand A is the more promising candidate. While its clearance is higher, its logP is within the optimal range, and its DILI risk is significantly lower. The biggest concern for both is the poor Caco-2 permeability and solubility. However, Ligand B's very negative logP is a more substantial drawback, likely leading to even worse absorption than Ligand A. The solubility issues could potentially be addressed through formulation strategies.

Output:
0
2025-04-17 11:40:43,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.551 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold and favorable for oral absorption. Ligand B (115.39) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.447) is within the optimal 1-3 range. Ligand B (-0.709) is significantly below 1, which could hinder permeability.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=3) is excellent. Ligand B (HBD=3, HBA=5) is acceptable, but slightly higher values could potentially affect permeability.

**QED:** Both ligands have reasonable QED scores (0.691 and 0.588), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (38.503 and 35.595), which is positive.

**BBB:** Ligand A (55.797) has a moderate BBB penetration, while Ligand B (16.324) has very low BBB penetration. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.778) has poor Caco-2 permeability, while Ligand B (-5.394) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.362 and -2.462). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG risk (0.693 and 0.11).

**Microsomal Clearance:** Ligand A (51.616) has moderate clearance, while Ligand B (4.302) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (39.203) has a reasonable half-life, while Ligand B (-12.806) has a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.26 and 0.007).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -9.0 kcal/mol).

**Overall Assessment:**

Ligand B stands out due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2). While its logP is a concern, the strong binding affinity (-9.0 kcal/mol) could potentially compensate for this. The poor solubility and Caco-2 permeability are drawbacks for both, but formulation strategies could be explored. Ligand A's Caco-2 permeability is worse than Ligand B.

Output:
1
2025-04-17 11:40:43,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.332 Da) is slightly higher than Ligand B (373.507 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (72.01 and 72.7) below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.141) is within the optimal range (1-3). Ligand B (3.64) is slightly higher, but still acceptable.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD and 7 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5 (0.738 and 0.642), indicating good drug-likeness.

**DILI:** Ligand A (15.394) has a significantly lower DILI risk than Ligand B (69.484). This is a major advantage for Ligand A.

**BBB:** Ligand A (79.721) has a better BBB penetration score than Ligand B (37.805), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.744) has a worse Caco-2 permeability than Ligand B (-5.32).

**Aqueous Solubility:** Ligand A (-2.252) has a worse aqueous solubility than Ligand B (-2.749).

**hERG:** Both ligands have low hERG inhibition liability (0.397 and 0.581), which is good.

**Microsomal Clearance:** Ligand A (-1.024) has a much lower (better) microsomal clearance than Ligand B (47.02). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (24.758) has a longer half-life than Ligand B (8.621). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.066 and 0.626).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly better 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 stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A has significantly better safety profiles (DILI) and metabolic stability (Cl_mic, t1/2). While Ligand B's affinity is compelling, the poor DILI score and rapid clearance are major concerns. The difference in affinity is large (>1.5 kcal/mol), but the DILI risk of Ligand B is very high.

Output:
1
2025-04-17 11:40:43,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.308 Da and 346.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.53) is higher than Ligand B (54.19). While both are reasonably low, Ligand B is significantly better, suggesting better permeability.

**logP:** Ligand A (1.097) is within the optimal range, while Ligand B (3.506) is approaching the upper limit. This could potentially lead to solubility issues for Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is acceptable.

**QED:** Both ligands have good QED scores (0.788 and 0.884), indicating drug-like properties.

**DILI:** Ligand A (54.052) has a higher DILI risk than Ligand B (9.965). This is a significant concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (92.012) has a higher BBB value than Ligand A (63.629), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.451 and -5.455), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both have negative solubility values (-2.371 and -1.921), which is also concerning.

**hERG:** Ligand A (0.024) has a much lower hERG risk than Ligand B (0.889), which is a major advantage.

**Microsomal Clearance:** Ligand A (-13.067) has a much lower (better) microsomal clearance than Ligand B (-2.345), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-25.667) has a more negative (better) in vitro half-life than Ligand B (23.973), suggesting a longer half-life.

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.231), indicating better bioavailability.

**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.

**Conclusion:**

Despite the concerning Caco-2 and solubility values for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-10.2 vs -8.5 kcal/mol) is a major advantage for an enzyme target. Furthermore, it exhibits much better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a significantly lower hERG risk. While Ligand A has a higher DILI risk, the strong binding affinity and favorable metabolic/toxicity profiles make it the preferred choice for further optimization. The solubility and permeability issues would need to be addressed through structural modifications.

Output:
0
2025-04-17 11:40:43,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.389 and 372.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is significantly better than Ligand B (119.39). A TPSA under 140 is good for oral absorption, and A is well within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.318) is optimal, while Ligand B (-0.833) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=2, HBA=7) regarding the balance between solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (0.629 and 0.644).

**DILI:** Ligand A (87.01) has a higher DILI risk than Ligand B (62.233), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.154) is higher than Ligand B (48.895).

**Caco-2 Permeability:** Ligand A (-4.404) is better than Ligand B (-5.342). Higher is better.

**Aqueous Solubility:** Ligand A (-4.409) is better than Ligand B (-1.765). Higher is better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.223 and 0.117).

**Microsomal Clearance:** Ligand A (110.09) has significantly higher microsomal clearance than Ligand B (6.787), indicating lower metabolic stability. This is a major drawback for A.

**In vitro Half-Life:** Ligand B (45.599) has a much longer half-life than Ligand A (0.018). This is a significant advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.251 and 0.014).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.2 kcal/mol). This difference of 1.4 kcal/mol is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having better TPSA, logP, solubility, and Caco-2 permeability, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.6 vs -7.2 kcal/mol) and substantially improved metabolic stability (lower Cl_mic and longer half-life) are crucial for an enzyme target like SRC kinase. While Ligand A has a lower DILI risk, the difference isn't substantial enough to offset the major advantages of Ligand B.

Output:
1
2025-04-17 11:40:43,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.471 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.8) is better than Ligand B (80.37), both are acceptable for oral absorption (<140).

**logP:** Ligand A (3.143) is slightly higher than Ligand B (1.774), 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:** Ligand A (7) is slightly higher than Ligand B (5), both are acceptable (<10).

**QED:** Both ligands have similar and good QED scores (0.7 and 0.793, respectively).

**DILI:** Ligand B (48.313) has a significantly lower DILI risk than Ligand A (77.472). This is a major advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (61.535 and 68.554). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.269) has worse Caco-2 permeability than Ligand B (-4.94).

**Aqueous Solubility:** Ligand A (-3.146) has worse aqueous solubility than Ligand B (-2.229). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.296 and 0.151).

**Microsomal Clearance:** Ligand B (40.928) has lower microsomal clearance than Ligand A (71.179), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.893) has a longer in vitro half-life than Ligand A (32.409). This is a significant advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.446 and 0.096).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is superior due to its lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility and Caco-2 permeability. Ligand A's higher DILI risk and poorer metabolic stability are significant drawbacks. The small advantage in binding affinity of Ligand B is a bonus.

Output:
1
2025-04-17 11:40:43,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.22 Da) is slightly higher than Ligand B (367.873 Da), but both are acceptable.

**2. TPSA:** Ligand A (38.77) is well below the 140 threshold and even below 90, suggesting good permeability. Ligand B (51.91) is still acceptable, but less optimal than A.

**3. logP:** Both ligands have logP values around 3-4, which is within the optimal range (1-3). Ligand A (4.0) is slightly higher, potentially increasing off-target effects, but not drastically. Ligand B (3.617) is slightly better.

**4. H-Bond Donors:** Both ligands have a low number of HBDs (0 for B and 0 for A), which is favorable for permeability.

**5. H-Bond Acceptors:** Both ligands have a reasonable number of HBAs (3 for A and 4 for B), within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.508 for A and 0.797 for B), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A has a DILI risk of 53.044, which is acceptable (below 60). Ligand B has a much lower DILI risk (25.902), which is a significant advantage.

**8. BBB:** Both ligands have high BBB penetration (89.066 for A and 84.102 for B), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.684 for A and -4.667 for B). This is unusual and suggests poor permeability. It's likely an error in the data, or these compounds are actively effluxed.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.536 for A and -3.413 for B). This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.815 for A and 0.65 for B), which is good.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (47.951) than Ligand B (55.384), indicating better metabolic stability, which is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (59.285) than Ligand A (2.992), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.426 for A and 0.419 for B), which is favorable.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-7.9 kcal/mol) than Ligand B (-7.7 kcal/mol). This 0.2 kcal/mol difference is potentially significant, but needs to be weighed against other factors.

**Overall Assessment:**

Despite the slightly better affinity of Ligand A, Ligand B is the more promising candidate. The significantly lower DILI risk, substantially longer half-life, and better QED score outweigh the minor affinity difference and slightly higher logP. Both compounds suffer from poor solubility and potentially poor permeability (based on the Caco-2 data), but these issues might be addressed through formulation strategies. The improved metabolic stability of Ligand A is a plus, but the other advantages of Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 11:40:43,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.391 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.17) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (70.67) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (-0.585) is a bit low, potentially hindering permeability. Ligand B (1.829) is 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 6 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.62 and 0.698 respectively), indicating drug-like properties.

**DILI:** Ligand A (55.68) has a moderate DILI risk, while Ligand B (11.09) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have similar BBB penetration (55.138 and 54.789), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.107 and -5.093). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.306 and -1.168). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.111 and 0.212).

**Microsomal Clearance:** Ligand A (23.548) has a higher microsomal clearance than Ligand B (2.303), indicating lower metabolic stability. This is a key disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (18.179) has a significantly longer in vitro half-life than Ligand A (-7.518), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.012 and 0.013).

**Binding Affinity:** Ligand A (-7.1) 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 more promising candidate. While both have poor solubility and permeability, 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 outweighed by these critical ADME/Tox advantages of Ligand B.

Output:
1
2025-04-17 11:40:43,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.411 and 345.393 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.2) is better than Ligand B (36.44). Both are well below the 140 threshold for oral absorption, but Ligand B is significantly lower, potentially aiding absorption.

**logP:** Both ligands have good logP values (2.671 and 3.016), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also good.

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

**QED:** Both ligands have good QED scores (0.644 and 0.858), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (53.742) has a higher DILI risk than Ligand B (35.479). This is a significant advantage for Ligand B.

**BBB:** Ligand A (52.423) has lower BBB penetration than Ligand B (96.937). Since SRC is not a CNS target, this is less critical, but higher BBB is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.12) has worse Caco-2 permeability than Ligand B (-4.544). Both are negative, suggesting poor permeability, but B is better.

**Aqueous Solubility:** Ligand A (-3.064) has worse solubility than Ligand B (-2.533). Solubility is important for bioavailability, so Ligand B is favored.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.683 and 0.945). Both are relatively low risk.

**Microsomal Clearance:** Ligand A (2.531) has significantly lower microsomal clearance than Ligand B (55.621). Lower clearance indicates better metabolic stability, a key factor for enzymes. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (35.093) has a much longer in vitro half-life than Ligand B (-15.918). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux than Ligand B (0.635). Lower efflux is preferable for oral bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, while Ligand B shows better solubility, DILI risk, and Caco-2 permeability. The binding affinity is the same for both. Given the enzyme-specific priorities, the improved metabolic stability and longer half-life of Ligand A are crucial. While Ligand B's solubility and DILI are better, these can potentially be addressed through formulation or minor structural modifications. The better metabolic profile of Ligand A is more difficult to improve post-hoc.

Output:
0
2025-04-17 11:40:43,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 Da and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is slightly higher than Ligand B (70.47), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.458) is optimal, while Ligand B (0.41) is a bit low, potentially hindering permeation.

**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 (0.727 and 0.809, respectively), indicating drug-like properties.

**DILI:** Ligand A (8.414) has a significantly lower DILI risk than Ligand B (11.322), which is a crucial advantage.

**BBB:** Both ligands have moderate BBB penetration (60.838 and 52.385), which is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.65) shows poor permeability, while Ligand B (-5.24) is even worse. This is a concern for both, but more so for B.

**Aqueous Solubility:** Ligand A (-2.089) has slightly better solubility than Ligand B (-0.057). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.24) has a much lower hERG risk than Ligand B (0.371), a significant safety advantage.

**Microsomal Clearance:** Ligand A (7.892) has higher microsomal clearance than Ligand B (-1.957), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-1.021) has a shorter half-life than Ligand B (-4.719), further indicating lower metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.078 and 0.02), which is favorable.

**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 ADME drawbacks.

**Conclusion:**

Despite Ligand A's poorer metabolic stability (higher Cl_mic and shorter t1/2) and permeability, its significantly superior binding affinity (-8.9 vs -7.5 kcal/mol), much lower DILI risk, and lower hERG risk make it the more promising candidate. The strong binding affinity is a key driver for kinase inhibitors, and the safety profile is crucial. While permeability is a concern, it might be addressable through formulation strategies. The metabolic stability issues could potentially be mitigated through structural modifications in later optimization stages.

Output:
1
2025-04-17 11:40:43,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.375 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (378.969 Da) is still well within acceptable limits.

**TPSA:** Ligand A (129.75) is better than Ligand B (33.2). A TPSA under 140 is good for oral absorption, and both meet this criteria.

**logP:** Ligand A (-1.224) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (4.93) is higher than optimal, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 6 HBA) is acceptable. Ligand B (0 HBD, 3 HBA) is also acceptable, with fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (Ligand A: 0.433, Ligand B: 0.728), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (54.323) has a moderate DILI risk, while Ligand B (22.722) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (18.185) has very low BBB penetration, while Ligand B (87.127) has high BBB penetration. Since SRC is not a CNS target, this is less important, but still a slight advantage for B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.624 and -5.185), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.744 and -4.684), which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.087) has a very low hERG risk, which is excellent. Ligand B (0.765) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-19.626) has a negative clearance, which is not possible, indicating a potential data error. Ligand B (88.877) has high microsomal clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (1.872) has a short half-life, while Ligand B (3.088) has a slightly longer half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is favorable. Ligand B (0.497) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This difference is significant (0.4 kcal/mol) and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While it has a higher logP and higher microsomal clearance, its significantly stronger binding affinity (-8.2 vs -7.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has a lower DILI risk and better QED score. The negative values for Caco-2 and solubility are concerning for both, but can be addressed through formulation strategies. The negative clearance for Ligand A is a data quality issue.

Output:
1
2025-04-17 11:40:43,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (373.494 and 362.857 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is slightly higher than Ligand B (62.4), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.942 and 3.51), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to minor solubility concerns.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable (<=5).

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

**QED:** Both ligands have similar QED values (0.621 and 0.576), indicating good drug-likeness.

**DILI:** Ligand A (60.876) has a slightly higher DILI risk than Ligand B (57.697), but both are reasonably acceptable.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.904 and -4.684), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.461 and -3.672). This is a major concern for *in vivo* bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.646 and 0.482), which is positive.

**Microsomal Clearance:** Ligand A (37.333) has significantly lower microsomal clearance than Ligand B (88.09), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (46.642) has a slightly shorter half-life than Ligand B (51.401), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.183 and 0.456), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.9 and -7.8 kcal/mol). The difference of 0.1 kcal/mol is negligible.

**Conclusion:**

While both ligands have good potency, the significantly lower microsomal clearance of Ligand A (37.333 vs 88.09) makes it the more promising candidate. Metabolic stability is critical for kinase inhibitors. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies. The slightly higher DILI risk for Ligand A is less concerning than the higher clearance of Ligand B.

Output:
0
2025-04-17 11:40:43,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.463 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is slightly higher than Ligand B (78.95), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.097) is slightly higher than Ligand B (0.387), both 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 similar QED scores (0.771 and 0.795), indicating good drug-likeness.

**DILI:** Ligand A (31.175) has a slightly higher DILI risk than Ligand B (19.426), but both are below the concerning threshold of 40.

**BBB:** Ligand A (29.236) has a lower BBB penetration percentile than Ligand B (57.852). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.264) has a lower Caco-2 permeability than Ligand B (-4.867). Both are negative, which is unusual and requires further investigation, but the difference isn't huge.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.474 and -1.409). This is a significant concern and would require formulation strategies.

**hERG Inhibition:** Ligand A (0.215) has a slightly higher hERG inhibition liability than Ligand B (0.119), but both are low and acceptable.

**Microsomal Clearance:** Ligand B (-3.143) has significantly lower microsomal clearance (better metabolic stability) than Ligand A (8.786). This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-2.019) has a longer in vitro half-life than Ligand A (13.247). This is another significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.059) has slightly higher P-gp efflux liability than Ligand B (0.015).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.1 kcal/mol difference is substantial and outweighs the minor drawbacks of Ligand B.

**Conclusion:**

Ligand B is the more promising candidate. It has a significantly better binding affinity, improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While both have poor solubility, the superior potency and pharmacokinetic properties of Ligand B make it the preferred choice for further development.

Output:
1
2025-04-17 11:40:43,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.435 and 354.466 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.91) is better than Ligand B (55.57), being closer to the upper limit of 140 for good oral absorption, but both are acceptable.

**logP:** Ligand A (1.935) is optimal, while Ligand B (3.872) is approaching the upper limit of 4. This could potentially lead to solubility issues 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 (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.833) has a significantly better QED score than Ligand B (0.675), indicating a more drug-like profile.

**DILI:** Ligand A (52.423) has a higher DILI risk than Ligand B (18.534). This is a significant advantage for Ligand B.

**BBB:** Ligand A (76.464) has a reasonable BBB penetration, while Ligand B (96.355) has very high BBB penetration. Since SRC is not a CNS target, this is less important, but still slightly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-4.445) and Ligand B (-3.965) both have negative values, which is unusual and indicates poor permeability. However, the scale is not specified, so it is hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.643 and -3.964). This is a major concern for both, but Ligand B is worse.

**hERG Inhibition:** Ligand A (0.343) has a lower hERG risk than Ligand B (0.878), which is a significant advantage.

**Microsomal Clearance:** Ligand A (78.851) has a lower microsomal clearance than Ligand B (96.226), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have very short in vitro half-lives (-12.297 and -12.299 hours). This is a significant drawback for both.

**P-gp Efflux:** Ligand A (0.036) has much lower P-gp efflux liability than Ligand B (0.768), which is favorable.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly better binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand B's lower DILI risk, Ligand A is the better candidate. The significantly stronger binding affinity (-9.1 vs -7.9 kcal/mol) is the most important factor for an enzyme target like SRC kinase. While Ligand A has a higher DILI risk and poorer solubility, these can be addressed through further optimization. The better QED, lower P-gp efflux, and lower hERG risk also contribute to its favorability. The similar poor half-lives and permeability are issues for both and would need to be addressed in later stages of development.

Output:
1
2025-04-17 11:40:43,099 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 343.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (71.53). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is much closer to the ideal for good permeability.

**logP:** Both ligands have good logP values (3.23 and 2.04, respectively), falling 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 HBD/HBA generally improves permeability.

**QED:** Both ligands have similar, good QED scores (0.735 and 0.784).

**DILI:** Ligand A (20.124) has a much lower DILI risk than Ligand B (52.191). This is a significant advantage for A.

**BBB:** Ligand A (89.88) has a better BBB percentile than Ligand B (67.274), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.68) is slightly better than Ligand B (-4.753), but both are concerning.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.602 and -2.3, respectively). This is a drawback for both.

**hERG:** Both ligands have low hERG risk (0.53 and 0.449).

**Microsomal Clearance:** Ligand A (60.229) has a slightly higher microsomal clearance than Ligand B (55.772), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (27.547) has a significantly longer in vitro half-life than Ligand A (1.871). This is a major advantage for B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.467 and 0.111).

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.9). While both are excellent, the 0.2 kcal/mol difference is not substantial enough to overcome other issues.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. Its significantly lower DILI risk and better TPSA are crucial advantages. While Ligand B has a better half-life and slightly better affinity, the DILI risk is a major concern. The poor solubility and Caco-2 permeability are drawbacks for both, but can potentially be addressed with formulation strategies. The slightly lower metabolic stability of A is less concerning than the higher DILI risk of B.

Output:
0
2025-04-17 11:40:43,099 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 356.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.51) is better than Ligand B (116.93). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (1.331) is better than Ligand B (0.482). Both are within the 1-3 range, but B is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Both are acceptable, but lower is generally preferred.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (7). Both are acceptable, but A is closer to the optimal.

**QED:** Ligand A (0.79) is significantly better than Ligand B (0.412). A higher QED indicates a more drug-like profile.

**DILI:** Ligand B (35.285) is significantly better than Ligand A (54.517). Lower DILI is crucial, and B has a much lower risk.

**BBB:** Ligand A (51.377) is better than Ligand B (24.622), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.441) is better than Ligand B (-5.6). Higher is better, indicating better absorption.

**Aqueous Solubility:** Ligand A (-2.288) is better than Ligand B (-1.03). Higher solubility is important for bioavailability.

**hERG Inhibition:** Both ligands (0.125 and 0.159) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand B (-0.652) is *much* better than Ligand A (12.593). A negative clearance suggests very high metabolic stability, a major advantage.

**In vitro Half-Life:** Ligand B (18.76) is significantly better than Ligand A (-18.309). A longer half-life is desirable.

**P-gp Efflux:** Both ligands (0.026 and 0.019) have very low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) is slightly better than Ligand A (-7.9 kcal/mol). While both are good, B has a 0.6 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand B has a clear advantage in key areas: DILI risk, metabolic stability (Cl_mic and t1/2), and binding affinity. While Ligand A has better TPSA, logP, solubility and Caco-2 permeability, the improvements in metabolic stability and safety (DILI) offered by Ligand B are more critical for an enzyme target. The slightly better affinity of B further strengthens its position.

Output:
1
2025-04-17 11:40:43,099 - INFO - Batch 67 complete. Total preferences: 1072
2025-04-17 11:40:43,099 - INFO - Processing batch 68/512...
2025-04-17 11:41:26,223 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.511 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (89.69). A TPSA under 140 is good for oral absorption, and both are under, but A is much closer to the preferred value for kinases.

**logP:** Both ligands have acceptable logP values (A: 3.095, B: 2.126), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (0) and HBA (A: 4, B: 10) counts. Ligand A is preferable due to the lower HBA count.

**QED:** Both ligands have acceptable QED scores (A: 0.813, B: 0.613), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand B (90.112) has a considerably higher DILI risk than Ligand A (45.56). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.743) is better than Ligand B (51.221).

**Caco-2 Permeability:** Ligand A (-4.719) is better than Ligand B (-5.598), indicating better intestinal absorption.

**Aqueous Solubility:** Both have poor solubility (-3.086 and -3.071 respectively). This is a potential issue for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.525) has a lower hERG inhibition liability than Ligand B (0.067), which is a major advantage.

**Microsomal Clearance:** Ligand B (69.106) has slightly higher microsomal clearance than Ligand A (66.378), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand A (-12.121) has a significantly longer in vitro half-life than Ligand B (-27.002), which is a strong positive.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.308, B: 0.375).

**Binding Affinity:** Ligand A (-8.8 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.

**Conclusion:**

Ligand A is clearly the superior candidate. It has a better binding affinity, lower DILI risk, lower hERG inhibition, longer half-life, better TPSA and Caco-2 permeability, and a higher QED score. While both have poor solubility, the other advantages of Ligand A outweigh this concern. The significantly stronger binding affinity of Ligand A is a key factor, and its improved ADME properties further solidify its potential as a viable drug candidate.

Output:
1
2025-04-17 11:41:26,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.403 and 340.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.39) is higher than Ligand B (86.88). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**3. logP:** Both ligands have good logP values (1.318 and 1.618), 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, while Ligand B has 3.  Ligand B is preferable here, as fewer HBA generally correlate with better permeability.

**6. QED:** Both ligands have similar QED values (0.561 and 0.562), indicating good drug-likeness.

**7. DILI:** Ligand A (52.617) has a slightly higher DILI risk than Ligand B (47.15), but both are within an acceptable range (<60).

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (48.391) has a higher BBB value than Ligand A (13.377), but this isn't a major factor in this comparison.

**9. Caco-2:** Ligand A (-5.519) has a worse Caco-2 permeability than Ligand B (-4.883).

**10. Solubility:** Ligand A (-2.114) has a worse solubility than Ligand B (-4.01). Solubility is important for bioavailability, making Ligand B more favorable.

**11. hERG:** Both ligands have low hERG inhibition liability (0.353 and 0.155), which is excellent.

**12. Cl_mic:** Ligand A (14.769) has a higher microsomal clearance than Ligand B (8.584), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. t1/2:** Ligand B (-15.774) has a much longer in vitro half-life than Ligand A (81.496). This is a major advantage for Ligand B, as it suggests less frequent dosing.

**14. Pgp:** Both have low Pgp efflux liability (0.181 and 0.075).

**15. Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). While the difference is not huge, it's enough to be considered, especially given the other advantages of Ligand B.

**Overall:**

Ligand B is the more promising candidate. It has better predicted permeability (lower TPSA, better Caco-2), better solubility, significantly improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While Ligand A has a slightly lower DILI risk, the other advantages of Ligand B outweigh this minor difference.

Output:
1
2025-04-17 11:41:26,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.435 Da and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (99.5) is well within the optimal range.

**logP:** Ligand A (-0.336) is a bit low, potentially hindering permeability. Ligand B (1.036) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is good. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.526 and 0.812), indicating drug-like properties.

**DILI:** Ligand A (21.132) has a significantly lower DILI risk than Ligand B (68.166), which is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (57.464) and Ligand B (48.895) are both relatively low.

**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 factors.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also concerning. Again, these values can be unreliable.

**hERG:** Ligand A (0.041) has a very low hERG risk, while Ligand B (0.578) is somewhat higher. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (2.587 mL/min/kg) has a much lower microsomal clearance than Ligand B (36.938 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.424 hours) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (-7.991 hours) also has a negative half-life. These values are unreliable.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, while Ligand B (0.07) is slightly higher.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.4 kcal/mol and -8.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. It has a significantly lower DILI risk, lower microsomal clearance (better metabolic stability), lower hERG risk, and lower P-gp efflux. While its logP is slightly low, the other advantages, particularly the safety profile and metabolic stability, outweigh this drawback. The negative half-life values are concerning, but likely data errors.

Output:
0
2025-04-17 11:41:26,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 349.406 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (86.63 and 82.53) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.257 and 0.972) are 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 acceptable, staying within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.801 and 0.83), indicating a strong drug-like profile.

**DILI:** Both ligands have low DILI risk (39.201 and 32.726), both below the 40 threshold.

**BBB:** Both ligands have moderate BBB penetration (65.529 and 63.164). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.762 and -4.752). 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 very poor aqueous solubility (-1.96 and -1.821). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.353 and 0.185), which is excellent.

**Microsomal Clearance:** Ligand A has a moderate Cl_mic (46.693), while Ligand B has a very low (and negative) Cl_mic (-0.162). This is a *major* advantage for Ligand B, indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-9.512), which is not physically possible. Ligand B has a very short half-life (-23.759), also not physically possible. These values are problematic and suggest issues with the experimental setup or data reporting.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.313 and 0.025).

**Binding Affinity:** Ligand A has a slightly better binding affinity (-7.7 kcal/mol) compared to Ligand B (-7.4 kcal/mol). While the difference is not huge, it's within the range where it could be a deciding factor.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising candidate. The significantly lower microsomal clearance (higher metabolic stability) of Ligand B is a critical advantage for an enzyme target. The solubility of both is poor, but metabolic stability is more crucial for kinase inhibitors. The negative half-life values are concerning for both, but the negative Cl_mic for Ligand B is a stronger indicator of favorable metabolism.

Output:
1
2025-04-17 11:41:26,224 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [360.384, 86.8, 2.043, 2, 5, 0.861, 50.33, 88.445, -5.124, -3.556, 0.279, 8.911, -24.407, 0.039, -7.9]
**Ligand B:** [379.917, 70.84, 4.135, 1, 6, 0.421, 69.833, 60.644, -5.961, -3.443, 0.88, 65.612, 135.866, 0.602, -7.2]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (360.384) is slightly preferred.
2. **TPSA:** Both are below the 140 A<sup>2</sup> threshold for good oral absorption. B (70.84) is better than A (86.8).
3. **logP:** A (2.043) is optimal. B (4.135) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.
4. **HBD:** Both are acceptable (A: 2, B: 1). B is slightly better.
5. **HBA:** Both are acceptable (A: 5, B: 6). A is slightly better.
6. **QED:** A (0.861) is excellent, indicating strong drug-like properties. B (0.421) is considerably lower and less desirable.
7. **DILI:** A (50.33) is good, indicating low liver injury risk. B (69.833) is higher, suggesting a moderate risk.
8. **BBB:** A (88.445) is very good, suggesting reasonable brain penetration if needed. B (60.644) is lower. While SRC isn't necessarily a CNS target, higher BBB is generally a positive.
9. **Caco-2:** Both are negative, indicating poor permeability. This is a significant concern for both.
10. **Solubility:** Both are negative, indicating poor solubility. This is a significant concern for both.
11. **hERG:** Both are very low, indicating minimal hERG inhibition risk. This is excellent for both.
12. **Cl_mic:** A (8.911) is much lower than B (65.612), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.
13. **t1/2:** A (-24.407) is much longer than B (135.866), indicating a longer half-life and potentially less frequent dosing.
14. **Pgp:** Both are very low, indicating minimal P-gp efflux. This is good for both.
15. **Binding Affinity:** B (-7.2) is slightly better than A (-7.9), but the difference is relatively small (0.3 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While B has a slightly better binding affinity, A significantly outperforms it in metabolic stability (Cl_mic and t1/2), DILI risk, QED, and BBB. The poor Caco-2 and solubility are concerns for both, but these can be addressed with formulation strategies. The slight advantage in binding affinity of B is unlikely to overcome the substantial ADME advantages of A.

**Conclusion:**

Considering the enzyme-specific priorities and the overall profile, **Ligand A** is the more viable drug candidate.

Output:
0
2025-04-17 11:41:26,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.321 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.47) is slightly above the preferred <90 for CNS, but acceptable. Ligand B (88.17) is good.

**logP:** Both ligands (2.308 and 2.093) are within the optimal 1-3 range.

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

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

**QED:** Both ligands (0.592 and 0.667) have good drug-likeness scores, exceeding 0.5.

**DILI:** Ligand A (54.556) has a higher DILI risk than Ligand B (39.201), but both are still reasonably low.

**BBB:** Ligand A (52.579) has a lower BBB penetration score than Ligand B (74.641). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.738) has a significantly *lower* Caco-2 permeability than Ligand B (-5.241). Both are negative, indicating poor permeability, but A is slightly better.

**Aqueous Solubility:** Ligand A (-3.398) has slightly lower solubility than Ligand B (-2.026). Both are poor, but B is better.

**hERG Inhibition:** Ligand A (0.662) has a slightly higher hERG risk than Ligand B (0.344), but both are relatively low.

**Microsomal Clearance:** Ligand A (37.009) has a higher microsomal clearance than Ligand B (31.215), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (25.845) has a longer in vitro half-life than Ligand A (18.56), which is preferable.

**P-gp Efflux:** Ligand A (0.297) has a slightly higher P-gp efflux liability than Ligand B (0.019).

**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, potentially outweighing some ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have some ADME concerns (particularly solubility and Caco-2 permeability), Ligand B's dramatically improved binding affinity (-8.6 vs 0 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower DILI risk further support its selection.

Output:
1
2025-04-17 11:41:26,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.398) is slightly higher than Ligand B (369.355), but both are acceptable.

**TPSA:** Ligand A (102.87) is better than Ligand B (138.13). TPSA is acceptable for both, but lower is generally preferred for oral absorption.

**logP:** Ligand A (2.686) is optimal, while Ligand B (0.288) is quite low. Low logP can hinder membrane permeability.

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

**H-Bond Acceptors:** Ligand A (8) is preferable to Ligand B (6). Both are within the acceptable range.

**QED:** Ligand B (0.594) has a slightly better QED score than Ligand A (0.401), indicating a more drug-like profile.

**DILI:** Ligand A (62.156) has a lower DILI risk than Ligand B (93.37), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.105) is better than Ligand B (25.475), but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.596) is better than Ligand B (-5.066), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.587) is better than Ligand B (-3.752), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.106 and 0.036, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (109.965) has higher microsomal clearance than Ligand B (21.361), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-20.575) has a longer in vitro half-life than Ligand A (-18.984), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.225 and 0.04, respectively).

**Binding Affinity:** Both ligands have comparable binding affinity (-8.2 and -8.7 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better TPSA and solubility, Ligand B excels in crucial areas: logP, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and a slightly better binding affinity. The low logP of Ligand A is a significant concern, potentially limiting its permeability. The higher DILI risk and lower metabolic stability of Ligand A are also major drawbacks.

Output:
1
2025-04-17 11:41:26,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (334.43 and 342.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.21) is significantly better than Ligand B (115.11). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (2.268) is optimal, while Ligand B (0.739) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED scores (0.796 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (79.68%) has a higher DILI risk than Ligand B (41.84%). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.41%) is slightly better than Ligand B (45.13%).

**Caco-2 Permeability:** Ligand A (-4.882) is better than Ligand B (-5.066), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.261) is better than Ligand B (-2.766), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.937) has a lower hERG risk than Ligand B (0.157), a crucial advantage.

**Microsomal Clearance:** Ligand A (1.196 mL/min/kg) has significantly lower clearance than Ligand B (-20.828 mL/min/kg), indicating much better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.503 hours) has a much longer half-life than Ligand B (5.848 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.194) has lower P-gp efflux than Ligand B (0.016), improving bioavailability.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.9 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the higher DILI risk, Ligand A is the superior candidate. The significantly improved metabolic stability (lower Cl_mic, longer t1/2), better solubility, lower hERG risk, and *much* stronger binding affinity outweigh the DILI concern. The DILI risk could be further investigated and potentially mitigated through structural modifications, but the potency and pharmacokinetic advantages of Ligand A are too significant to ignore.

Output:
1
2025-04-17 11:41:26,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (368.396 and 369.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is significantly better than Ligand B (100.29). TPSA < 140 is good for oral absorption, and A is closer to the optimal range.

**3. logP:** Both ligands (1.217 and 1.178) are 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.

**6. QED:** Both ligands have similar QED values (0.621 and 0.672), indicating good drug-likeness.

**7. DILI:** Ligand A (21.132) has a much lower DILI risk than Ligand B (58.511). This is a significant advantage for A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.2) is better than Ligand B (54.246), but this isn't a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-4.306) is better than Ligand B (-5.315), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.439) is better than Ligand B (-3.092). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.67) is better than Ligand B (0.389), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (19.772) has lower clearance than Ligand B (26.133), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-31.083) has a longer half-life than Ligand A (-20.965). This is a positive for B, but the difference is not huge.

**14. P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.053), which is favorable.

**15. Binding Affinity:** Ligand B (0.0) has a better binding affinity than Ligand A (-8.1). This is a significant advantage for B. A difference of 8.1 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has significantly better binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding DILI risk, solubility, and metabolic stability. The superior binding affinity of Ligand B is compelling, however, the lower DILI and better solubility of Ligand A are critical for a viable drug candidate. Considering the enzyme-specific priorities, and the substantial difference in DILI risk, I believe Ligand A is the more promising candidate.

Output:
0
2025-04-17 11:41:26,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.395 Da) is slightly lower, which can be advantageous for permeability. Ligand B (352.366 Da) is also good.

**TPSA:** Ligand A (78.25) is well below the 140 threshold for good oral absorption. Ligand B (118.53) is still acceptable, but less optimal.

**logP:** Ligand A (2.952) is within the optimal range (1-3). Ligand B (0.012) is very low, potentially hindering permeation and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is excellent. Ligand B (HBD=2, HBA=5) is also good, but slightly higher.

**QED:** Ligand A (0.846) has a very strong drug-like profile. Ligand B (0.67) is still acceptable, but less favorable.

**DILI:** Ligand A (75.184) has a moderate DILI risk. Ligand B (46.258) has a lower and more desirable DILI risk.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (77.821) is slightly better. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.57) has poor Caco-2 permeability. Ligand B (-5.336) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.378) has poor aqueous solubility. Ligand B (-2.038) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.756) has a low hERG risk, which is excellent. Ligand B (0.179) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (103.016) has moderate microsomal clearance. Ligand B (-0.769) has negative clearance, which is highly favorable, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (26.246 hours) has a reasonable half-life. Ligand B (2.592 hours) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.328) has low P-gp efflux, which is good. Ligand B (0.028) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, excellent metabolic stability (negative Cl_mic), and low P-gp efflux. While its logP and solubility are suboptimal, the strong binding and metabolic stability are crucial for an enzyme target like SRC kinase. Ligand A has better solubility and permeability predictions, but its weaker binding affinity and moderate clearance are less desirable. The significantly stronger binding of Ligand B is the deciding factor.

Output:
1
2025-04-17 11:41:26,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (415.154 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (114.41) is slightly above the optimal <140 for oral absorption, while Ligand B (73.64) is well within the range. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 1.963, B: 1.577), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 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: 0.659, B: 0.725), indicating good drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.225%), which is a major concern. Ligand B has a much lower, and acceptable, DILI risk (29.43%). This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B (75.572%) has a higher BBB score than Ligand A (46.724%), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the absolute value is smaller for Ligand B (-4.276) compared to Ligand A (-5.681), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. The absolute value is smaller for Ligand B (-2.32) compared to Ligand A (-3.118), suggesting slightly better solubility.

**hERG Inhibition:** Ligand A (0.042) has a very low hERG risk, which is excellent. Ligand B (0.301) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-0.491), which is unusual and suggests very high metabolic stability. Ligand B has a higher Cl_mic (33.789), indicating faster metabolism. This favors Ligand A.

**In vitro Half-Life:** Ligand A has a positive half-life (26.883), while Ligand B has a negative half-life (-17.963), which is unusual. This favors Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.02, B: 0.096).

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.3 kcal/mol) than Ligand B (-7.6 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's extremely high DILI risk, its significantly superior binding affinity (-9.3 vs -7.6 kcal/mol) and better metabolic stability (negative Cl_mic) are compelling. The difference in binding affinity is substantial (>1.5 kcal/mol advantage). While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. Ligand B has a better safety profile (lower DILI), but its weaker binding affinity makes it less likely to be a successful drug candidate.

Output:
1
2025-04-17 11:41:26,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.551 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (95.42). A TPSA under 140 is good for oral absorption, and Ligand A is well within that, while Ligand B is approaching a concerning level.

**logP:** Ligand A (4.579) is a bit high, potentially leading to solubility issues, but still within a manageable range. Ligand B (1.509) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=6). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Both ligands have similar QED values (0.631 and 0.691), indicating good drug-likeness.

**DILI:** Ligand A (21.055) has a much lower DILI risk than Ligand B (37.611), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (70.027) has a better BBB score than Ligand B (56.495).

**Caco-2 Permeability:** Both are negative, suggesting poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.711 and -2.86), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.953) has a slightly higher hERG risk than Ligand B (0.167), which is a negative.

**Microsomal Clearance:** Ligand A (78.901) has a higher microsomal clearance than Ligand B (40.044), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-5.687) has a negative half-life, which is concerning. Ligand A (49.547) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.785) has a lower P-gp efflux liability than Ligand B (0.36), which is preferable.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is small and may not be significant.

**Overall Assessment:**

Ligand A has several advantages: lower DILI risk, better BBB penetration, and lower P-gp efflux. However, it suffers from higher microsomal clearance and a slightly higher hERG risk. Ligand B has better metabolic stability and lower hERG risk, but its TPSA is high, logP is low, and DILI risk is elevated. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the slightly better binding affinity of Ligand B is not enough to overcome its significant drawbacks in TPSA and DILI. The poor solubility of both is a concern, but formulation strategies could potentially address this. The metabolic stability of Ligand B is better, but the overall profile of Ligand A is more favorable.

Output:
0
2025-04-17 11:41:26,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.247 Da) is slightly higher than Ligand B (368.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 100, which is acceptable for oral absorption but not ideal for CNS penetration (not a priority here).

**logP:** Ligand A (2.801) is optimal, while Ligand B (0.632) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) and Ligand B (2 HBD, 7 HBA) are both within acceptable limits.

**QED:** Both ligands have similar QED values (0.71 and 0.616), indicating good drug-likeness.

**DILI:** Ligand A (66.731) has a lower DILI risk than Ligand B (80.186), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (83.831) is higher than Ligand B (46.879), but this is less important.

**Caco-2 Permeability:** Ligand A (-4.998) has better predicted Caco-2 permeability than Ligand B (-5.445), though both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.725) has slightly better predicted solubility than Ligand B (-3.018), though both are negative values, indicating low solubility.

**hERG Inhibition:** Ligand A (0.451) has a lower hERG risk than Ligand B (0.32), which is a positive attribute.

**Microsomal Clearance:** Ligand A (-5.855) has significantly lower microsomal clearance than Ligand B (41.575), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (29.336 hours) has a much longer half-life than Ligand B (-31.068 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.033), which is good.

**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 1.5 kcal/mol, it contributes to the overall preference for Ligand A.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, Ligand A is the more promising drug candidate. It exhibits lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), slightly better solubility and permeability, and a slightly stronger binding affinity. While Ligand B has a slightly lower molecular weight and acceptable QED, the superior ADME properties of Ligand A outweigh these minor differences.

Output:
1
2025-04-17 11:41:26,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (347.415 and 354.357 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (82.85 and 84.42) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.363) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (0.645) is also on the lower side but better than A.

**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 high QED scores (0.834 and 0.811), indicating good drug-like properties.

**7. DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (38.038), making it more favorable from a safety perspective.

**8. BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (87.864) has a higher BBB value than Ligand A (64.715), but this is not a major deciding factor here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.626 and -4.636). These values are unusual and suggest poor permeability. However, the absolute values are similar.

**10. Aqueous Solubility:** Ligand A (-0.901) has slightly better aqueous solubility than Ligand B (-2.09), which is beneficial for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.064) has a much lower hERG inhibition liability than Ligand B (0.192), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-5.179) has significantly lower microsomal clearance than Ligand B (7.866), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-0.088) has a slightly better in vitro half-life than Ligand B (-7.321).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.004).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This is a 0.4 kcal/mol difference, which is not huge, but still noticeable.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, lower hERG inhibition, and better solubility. These factors are more critical for a successful kinase inhibitor than a small difference in binding affinity. The similar Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 11:41:26,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.391 and 361.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (114.3) is better than Ligand B (69.72), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands (1.177 and 0.876) 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 5 HBA, and Ligand B has 4, both are below the 10 threshold.

**6. QED:** Ligand B (0.813) has a significantly better QED score than Ligand A (0.491), indicating a more drug-like profile.

**7. DILI:** Ligand B (32.299) has a much lower DILI risk than Ligand A (57.348). This is a significant advantage.

**8. BBB:** Ligand B (72.043) has a better BBB penetration score than Ligand A (59.093), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.939) is better than Ligand B (-5.204), however, both are negative values, which is not ideal.

**10. Aqueous Solubility:** Ligand A (-2.018) is better than Ligand B (-2.209), both are negative values, which is not ideal.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.145 and 0.184).

**12. Microsomal Clearance:** Ligand A (-4.135) has a much lower (better) microsomal clearance than Ligand B (10.879), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.818) has a better in vitro half-life than Ligand B (6.508).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.038).

**15. Binding Affinity:** Ligand B (0.0) has a significantly better binding affinity than Ligand A (-9.8). This is a crucial difference.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B excels in several key areas: significantly better binding affinity, a much lower DILI risk, and a higher QED score. The superior binding affinity of Ligand B (-9.8 kcal/mol vs -0.0 kcal/mol) is a major advantage that can potentially compensate for the slightly higher clearance. The lower DILI risk is also very important.

Output:
1
2025-04-17 11:41:26,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.491 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is well below the 140 threshold, and good for oral absorption. Ligand B (124.14) is still within acceptable limits, but less favorable.

**logP:** Ligand A (2.652) is optimal (1-3). Ligand B (-0.314) is below 1, which could hinder permeation.

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

**H-Bond Acceptors:** Ligand A (4) and Ligand B (7) are both acceptable (<=10).

**QED:** Both ligands have good QED scores (0.483 and 0.696, respectively), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (18.108) has a much lower DILI risk than Ligand B (32.183), which is a significant advantage. Both are below the 40 threshold.

**BBB:** Ligand A (77.162) has a better BBB penetration percentile than Ligand B (25.746), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.379) and Ligand B (-5.476) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.597) and Ligand B (-1.453) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.459) has a lower hERG risk than Ligand B (0.085), which is a significant advantage.

**Microsomal Clearance:** Ligand A (92.362) has a higher microsomal clearance than Ligand B (-13.115), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-17.64) has a negative half-life, which is not possible. This suggests an issue with the data or the molecule's stability. Ligand B (3.256) has a short half-life, but it is at least a positive value.

**P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux than Ligand B (0.025), which is a slight advantage.

**Binding Affinity:** Both ligands have comparable binding affinities (-7.8 and -7.9 kcal/mol), which are both excellent.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG inhibition, and P-gp efflux. However, it suffers from higher microsomal clearance and a nonsensical negative in vitro half-life. Ligand B has a better QED score and a more reasonable (though still short) half-life, but has a higher DILI risk, a lower logP, and a higher hERG risk.

Given the importance of metabolic stability and a reasonable half-life for an enzyme inhibitor, and the concerning negative half-life for Ligand A, **Ligand B is the more promising candidate despite its drawbacks.** The binding affinity is comparable, and the ADME properties, while not ideal, are less problematic than the instability suggested by Ligand A's data.

Output:
1
2025-04-17 11:41:26,226 - INFO - Batch 68 complete. Total preferences: 1088
2025-04-17 11:41:26,226 - INFO - Processing batch 69/512...
2025-04-17 11:42:13,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.344 and 362.543 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.85) is better than Ligand B (51.02), both are acceptable but lower is generally preferred for absorption.

**logP:** Ligand A (2.687) is optimal (1-3), while Ligand B (4.066) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

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

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5), both are within the acceptable range of <=10.

**QED:** Ligand A (0.783) is better than Ligand B (0.676), indicating a more drug-like profile.

**DILI:** Ligand A (68.437) has a higher DILI risk than Ligand B (32.842). This is a significant drawback for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (93.563) is higher than Ligand B (77.549).

**Caco-2:** Both have negative values, indicating poor permeability. Ligand A (-4.126) is slightly better than Ligand B (-4.996).

**Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.007) is slightly better than Ligand B (-3.745).

**hERG:** Both ligands have low hERG inhibition risk (0.491 and 0.624).

**Microsomal Clearance:** Ligand A (56.311) has significantly lower clearance than Ligand B (106.209), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-4.049) has a significantly longer half-life than Ligand B (16.976), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.257 and 0.504).

**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 has a better QED, lower clearance, longer half-life, slightly better affinity, and slightly better Caco-2 and solubility. However, it has a significantly higher DILI risk. Ligand B has a much lower DILI risk, but suffers from poorer metabolic stability (higher clearance, shorter half-life) and slightly worse drug-like properties.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) is crucial. The substantial advantage of Ligand A in these parameters, coupled with a small affinity advantage, outweighs the higher DILI risk, *provided* the DILI risk can be mitigated through further structural modifications. The DILI risk is concerning, but the other factors heavily favor Ligand A.

Output:
1
2025-04-17 11:42:13,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.471 and 389.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.55 and 105.98) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (0.689 and 0.622) are a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.658 and 0.641), indicating good drug-likeness.

**DILI:** Ligand A (54.323) has a lower DILI risk than Ligand B (66.615), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration (41.024 and 37.844), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.36 and -5.688), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.048 and -2.402), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.059 and 0.057). This is excellent.

**Microsomal Clearance:** Ligand A (9.56 mL/min/kg) has significantly lower microsomal clearance than Ligand B (48.769 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (24.223 hours) has a much longer half-life than Ligand B (-41.076 hours - a negative value is concerning and likely indicates very rapid degradation). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.058).

**Binding Affinity:** Both ligands have strong binding affinities (-8.5 and -8.8 kcal/mol), with Ligand B being slightly better. However, the difference is small.

**Conclusion:**

While Ligand B has slightly better binding affinity, Ligand A is the superior candidate due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility (less negative value). The poor Caco-2 and solubility are concerning for both, but the metabolic advantages of Ligand A are more critical for an enzyme target like SRC.

Output:
0
2025-04-17 11:42:13,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.5 and 340.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is well below the 140 threshold and excellent for oral absorption. Ligand B (115.8) is still within acceptable limits but less ideal.

**logP:** Both ligands have good logP values (2.62 and 1.69), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 8 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.838) has a significantly higher QED score than Ligand B (0.631), indicating a more drug-like profile.

**DILI:** Ligand A (21.9) has a much lower DILI risk than Ligand B (55.3), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (86.4) is better than Ligand B (54.0).

**Caco-2 Permeability:** Ligand A (-4.638) is better than Ligand B (-5.464), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.892) is better than Ligand B (-3.24), indicating better solubility.

**hERG:** Both ligands have relatively low hERG risk (0.489 and 0.815), which is good.

**Microsomal Clearance:** Ligand A (20.5) has lower microsomal clearance than Ligand B (30.6), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (57.2) has a significantly longer in vitro half-life than Ligand A (8.96). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.094 and 0.01), which is good.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.4), a difference of 0.5 kcal/mol. While affinity is paramount, the other factors must be considered.

**Overall Assessment:**

Ligand A demonstrates a superior overall profile, particularly regarding safety (DILI), drug-likeness (QED), solubility, and metabolic stability (Cl_mic). While Ligand B has a slightly better binding affinity and half-life, the substantial advantages of Ligand A in other critical ADME-Tox properties outweigh this difference. The lower DILI risk alone is a significant factor favoring Ligand A.

Output:
1
2025-04-17 11:42:13,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.471 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.58) is slightly higher than Ligand B (84.23), both are acceptable for oral absorption (<140).

**logP:** Ligand A (0.78) is a bit low, potentially hindering permeation. Ligand B (2.612) is within the optimal range (1-3).

**H-Bond Donors:** Both ligands have 2 HBD, which is good.

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

**QED:** Ligand A (0.7) is better than Ligand B (0.503), indicating a more drug-like profile.

**DILI:** Ligand A (44.436) has a lower DILI risk than Ligand B (18.224), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (68.127 vs 67.468), not a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.446) has a worse Caco-2 permeability than Ligand B (-4.969).

**Solubility:** Ligand A (-3.12) has worse solubility than Ligand B (-1.844).

**hERG:** Ligand A (0.046) has a very low hERG risk, much better than Ligand B (0.14).

**Microsomal Clearance:** Ligand A (18.715) has significantly lower microsomal clearance than Ligand B (59.619), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.217) has a shorter half-life than Ligand B (-18.614), which is a negative.

**P-gp:** Both ligands have low P-gp efflux liability (0.03 and 0.027).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is superior despite some drawbacks. The significantly stronger binding affinity (-9.2 vs -6.0 kcal/mol) and lower DILI risk are major advantages. The better hERG profile and lower Cl_mic also contribute positively. While Ligand A has slightly lower solubility and Caco-2 permeability, the substantial gain in potency and safety outweighs these concerns. The shorter half-life is a potential issue, but can be addressed through structural modifications during lead optimization.

Output:
1
2025-04-17 11:42:13,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Ligand A:**

*   **MW:** 353.463 Da - Within the ideal range (200-500).
*   **TPSA:** 98.74 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 0.581 - Low, potentially hindering permeation.
*   **HBD:** 3 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.583 - Good drug-like properties.
*   **DILI:** 13.3 - Excellent, very low risk.
*   **BBB:** 12.912 - Low, not a concern for a non-CNS target like SRC.
*   **Caco-2:** -5.273 - Very poor permeability.
*   **Solubility:** -1.083 - Poor solubility.
*   **hERG:** 0.076 - Excellent, very low risk.
*   **Cl_mic:** 7.13 mL/min/kg - Relatively low, suggesting reasonable metabolic stability.
*   **t1/2:** -8.05 hours - Excellent in vitro half-life.
*   **Pgp:** 0.017 - Low efflux, favorable.
*   **Affinity:** -7.2 kcal/mol - Very good binding affinity.

**Ligand B:**

*   **MW:** 364.559 Da - Within the ideal range (200-500).
*   **TPSA:** 58.12 - Excellent, promotes good absorption.
*   **logP:** 3.39 - Optimal.
*   **HBD:** 1 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.806 - Excellent drug-like properties.
*   **DILI:** 25.359 - Good, low risk.
*   **BBB:** 74.99 - High, not a primary concern for SRC.
*   **Caco-2:** -4.988 - Poor permeability.
*   **Solubility:** -3.201 - Very poor solubility.
*   **hERG:** 0.142 - Excellent, very low risk.
*   **Cl_mic:** 52.754 mL/min/kg - High, suggesting poor metabolic stability.
*   **t1/2:** 32.333 hours - Excellent in vitro half-life.
*   **Pgp:** 0.201 - Low efflux, favorable.
*   **Affinity:** -9.3 kcal/mol - Excellent binding affinity, significantly better than Ligand A.

**Comparison and Decision:**

Both ligands have poor Caco-2 permeability and solubility. However, Ligand B has a significantly stronger binding affinity (-9.3 vs -7.2 kcal/mol), which is a crucial factor for an enzyme inhibitor. While Ligand B has higher microsomal clearance, its superior binding affinity could potentially compensate for this, especially if further optimization can improve its metabolic stability. Ligand A's low logP is a significant drawback, potentially limiting its absorption. Both have acceptable safety profiles (DILI, hERG).

Given the priority for potency in enzyme inhibitors, and the substantial affinity advantage of Ligand B, it is the more promising candidate despite its higher Cl_mic.

Output:
1
2025-04-17 11:42:13,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.845 Da) is slightly higher than Ligand B (339.435 Da), but both are acceptable.

**TPSA:** Ligand A (99.52) is higher than Ligand B (57.61). While both are below 140, the lower TPSA of Ligand B is preferable for oral absorption.

**logP:** Ligand A (1.755) and Ligand B (3.287) are both within the optimal range of 1-3. Ligand B is slightly higher, potentially leading to some solubility issues, but not critically.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 2. Ligand B is better here, as lower HBA generally improves permeability.

**QED:** Both ligands have good QED scores (A: 0.726, B: 0.857), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (92.865) compared to Ligand B (36.758). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (65.956) and Ligand B (45.599) are both relatively low, which is fine.

**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, making interpretation difficult.

**hERG:** Ligand A (0.432) has a slightly higher hERG risk than Ligand B (0.051). Ligand B is much better here.

**Microsomal Clearance:** Ligand B (6.965) has a much lower microsomal clearance than Ligand A (20.235), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-7.292) has a negative half-life, which is problematic. Ligand A (74.574) has a good half-life. However, the negative value for B is suspect and may indicate an error in the data.

**P-gp Efflux:** Ligand A (0.381) has lower P-gp efflux than Ligand B (0.046), which is preferable.

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

**Overall Assessment:**

Ligand B is significantly better due to its much lower DILI risk, lower microsomal clearance (better metabolic stability), and lower hERG risk. While the negative Caco-2 and solubility values are concerning, the substantial advantage in safety and metabolic stability outweighs these concerns, especially given the similar binding affinities. The negative half-life for Ligand B is a red flag, but could be an error in the data.

Output:
1
2025-04-17 11:42:13,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.815 Da) is slightly higher than Ligand B (356.451 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (88.33) is a bit higher than Ligand B (75.5), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.004) is at the upper end, while Ligand B (2.561) is more centered.

**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 QED values above 0.5, indicating good drug-likeness (Ligand A: 0.697, Ligand B: 0.738).

**DILI:** Both ligands have relatively high DILI risk, but Ligand B (73.013) is slightly lower than Ligand A (77.2). This is a concern for both, but less so for B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.078) has a higher BBB percentile than Ligand B (41.218).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.848) is slightly better than Ligand B (-5.315).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.685) is slightly better than Ligand B (-3.501).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.595, Ligand B: 0.726), which is favorable.

**Microsomal Clearance:** Ligand B (46.228 mL/min/kg) has a lower microsomal clearance than Ligand A (59.301 mL/min/kg), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (35.98 hours) has a longer in vitro half-life than Ligand A (23.512 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.369, Ligand B: 0.47).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While both ligands have some concerning ADME properties (poor solubility and permeability, moderate DILI risk), Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -8.5 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2) are crucial advantages for an enzyme target like SRC kinase. The slightly lower DILI risk is also a plus. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the superior potency and stability of Ligand B make it the better starting point for drug development.

Output:
1
2025-04-17 11:42:13,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.406 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (77.25) is higher than Ligand B (57). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (2.929 and 1.991), 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.

**QED:** Both ligands have good QED scores (0.667 and 0.836), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 60.062, which is borderline high. Ligand B has a much lower DILI risk of 20.9, a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration (89.686 and 59.131). This isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.889 and -4.609). This 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 (-2.702 and -0.64). Again, these values are on a log scale and suggest poor solubility. Ligand B is better than Ligand A.

**hERG Inhibition:** Ligand A (0.668) has a slightly higher hERG risk than Ligand B (0.415), but both are relatively low.

**Microsomal Clearance:** Ligand B (8.452 mL/min/kg) has significantly lower microsomal clearance than Ligand A (55.088 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (43.096 hours) has a much longer in vitro half-life than Ligand A (22.074 hours), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.558 and 0.13). Ligand B is better.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.5 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the superior 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 (lower Cl_mic and longer t1/2), better solubility, and lower P-gp efflux. The lower DILI risk and improved metabolic stability are particularly important for an enzyme target like SRC kinase. The slightly lower affinity of Ligand B is outweighed by its superior ADME profile.

Output:
1
2025-04-17 11:42:13,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.419 and 366.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.54) is well below the 140 threshold, while Ligand B (91.84) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.464) is optimal, while Ligand B (0.351) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, well within acceptable limits. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.454 and 0.784), with Ligand B being better.

**DILI:** Ligand A (79.682) has a higher DILI risk than Ligand B (61.07), which is preferable.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (73.711) is slightly better than Ligand B (54.75).

**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 (0.501) has a slightly higher hERG risk than Ligand B (0.118), which is better.

**Microsomal Clearance:** Ligand B (38.267) has significantly lower microsomal clearance than Ligand A (112.831), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (6.491) has a longer half-life than Ligand A (-29.256), which is highly desirable.

**P-gp Efflux:** Ligand A (0.64) has higher P-gp efflux than Ligand B (0.023), which is unfavorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having a better TPSA and logP, Ligand B is the superior candidate. The significantly stronger binding affinity (-8.6 vs -7.5 kcal/mol), coupled with its lower microsomal clearance, longer half-life, and lower P-gp efflux, make it a more promising drug candidate for SRC kinase inhibition. The lower DILI and hERG risk are also beneficial. While solubility and permeability are questionable for both, the potency and metabolic stability advantages of Ligand B are more critical for an enzyme target.

Output:
1
2025-04-17 11:42:13,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (97.19 and 92.94) are below 140, suggesting reasonable absorption potential.

**logP:** Both ligands have logP values (0.592 and 0.476) that are a bit low. While not ideal, they aren't excessively low.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable, being under the 10 limit.

**QED:** Both ligands have good QED scores (0.758 and 0.72), indicating generally drug-like properties.

**DILI:** Ligand A has a DILI risk of 52.385, while Ligand B has 25.436. Ligand B is significantly better here, falling well below the 40 threshold for low risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (64.133) has a higher BBB percentile than Ligand A (43.699).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.033 and -4.928), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.748 and -1.799). This is a major drawback.

**hERG Inhibition:** Ligand A (0.011) has a very low hERG risk, while Ligand B (0.172) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (15.417 mL/min/kg) has a much lower microsomal clearance than Ligand B (36.523 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.894 hours) has a negative half-life, which is impossible. This is a major red flag. Ligand B (-6.65 hours) is also negative, but less so. These values likely indicate an issue with the data or the assay.

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, while Ligand B (0.023) is also low.

**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.

**Overall Assessment:**

Ligand A has a better binding affinity and lower clearance, but its negative half-life is a critical flaw. Ligand B has a much better safety profile (DILI) and slightly better BBB penetration, but significantly weaker binding. The negative half-life values for both are concerning and suggest data quality issues. However, given the enzyme-specific priorities, binding affinity is paramount. The substantial difference in affinity (-7.1 vs -0.0) is likely to outweigh the other drawbacks *if* the half-life data for Ligand A can be clarified or corrected.

Output:
1
2025-04-17 11:42:13,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.435 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is well below the 140 threshold, and quite favorable. Ligand B (119.67) is still under 140, but less optimal than A.

**logP:** Ligand A (1.609) is within the optimal 1-3 range. Ligand B (-0.394) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (2 HBD, 7 HBA) is acceptable, but slightly higher counts could potentially affect permeability.

**QED:** Both ligands have reasonable QED scores (0.845 and 0.643), indicating good drug-like properties.

**DILI:** Ligand A (65.568) has a slightly elevated DILI risk, but still within a manageable range. Ligand B (72.043) is higher, indicating a more concerning potential for liver injury.

**BBB:** Both ligands have similar BBB penetration (68.127 and 63.901), which isn't a primary concern for a non-CNS target like SRC.

**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 unusual and suggests poor solubility. This is a significant concern for both.

**hERG:** Both ligands have very low hERG risk (0.43 and 0.106), which is excellent.

**Microsomal Clearance:** Ligand A (45.061) has moderate clearance, while Ligand B (8.064) has very low clearance. This is a significant advantage for Ligand B, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (42.421) has a reasonable half-life, while Ligand B (5.556) has a very short half-life. This favors Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.147 and 0.004), which is favorable.

**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 substantial enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and much better metabolic stability (lower Cl_mic). However, it has a higher DILI risk and a shorter half-life. Both have problematic permeability and solubility. The improved potency and metabolic stability of Ligand B are crucial for an enzyme target like SRC kinase. While the permeability and solubility are concerns, they might be addressable through formulation strategies. The DILI risk is moderate and could be investigated further. Ligand A's slightly better half-life is offset by its weaker binding and higher clearance.

Output:
1
2025-04-17 11:42:13,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.861 Da and 358.429 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (67.35 and 69.64) are below the 140 A^2 threshold for good oral absorption, but relatively high.

**3. logP:** Ligand A (3.82) is optimal, while Ligand B (2.078) is slightly lower but still 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 (4) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.848 and 0.764), indicating good drug-like properties.

**7. DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (21.055). This is a significant concern.

**8. BBB:** Ligand A (43.815) has a lower BBB penetration than Ligand B (89.802). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.717 and -4.747), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.676 and -3.337), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.2) has a lower hERG risk than Ligand B (0.662), which is favorable.

**12. Microsomal Clearance:** Ligand A (63.904) has a higher microsomal clearance than Ligand B (10.989), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (24.048) has a longer half-life than Ligand B (2.428), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.064), which is favorable.

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.8 kcal/mol).

**Overall Assessment:**

While both compounds have excellent binding affinity, Ligand B appears to be the more promising candidate. The primary reason is the significantly lower DILI risk (21.055 vs 57.348) and much better metabolic stability (lower Cl_mic and higher t1/2). Although both have poor predicted solubility and permeability, the lower DILI and better metabolic stability of Ligand B are more critical for an enzyme target like SRC kinase. The slightly better BBB penetration of Ligand B is a minor advantage, but not crucial.

Output:
1
2025-04-17 11:42:13,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (341.415 and 345.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.17) is slightly above the preferred <90 for CNS targets, but acceptable for a non-CNS target like SRC. Ligand B (64.41) is well within the ideal range.

**3. logP:** Both ligands (3.729 and 3.266) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have a reasonable number of HBDs (1 and 0, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have 3 HBAs, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.513 and 0.567), indicating drug-like properties.

**7. DILI:** Ligand A (47.848) has a slightly higher DILI risk than Ligand B (28.965), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (78.79 and 76.037), but this isn't a primary concern for a non-CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.785 and -4.473), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.809 and -2.165), indicating poor aqueous solubility. This is also a significant concern.

**11. hERG Inhibition:** Ligand A (0.49) has a slightly lower hERG risk than Ligand B (0.794), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-14.933) has a *much* lower (better) microsomal clearance than Ligand B (46.067), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.809) has a negative half-life, which is not possible. This is a major red flag. Ligand B (-22.087) is also negative, and equally concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.506).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both ligands have issues with solubility and permeability, Ligand B's significantly stronger binding affinity and lower DILI risk are compelling. However, the negative half-life values for both are extremely concerning and suggest issues with the data or the compounds themselves. The significantly better Cl_mic for Ligand A is also a positive.

Despite the negative half-life, the superior affinity of Ligand B is a strong driver. The poor solubility and permeability are serious drawbacks, but potentially addressable through formulation or prodrug strategies. The negative half-life is a bigger issue, but if it's a data error, Ligand B has a clear advantage.

Output:
1
2025-04-17 11:42:13,836 - INFO - Okay, let's analyze these two ligands for their potential as drug candidates targeting SRC kinase, following the provided guidelines.

**Ligand A:** [356.308, 96.18, 2.405, 2, 6, 0.873, 73.245, 71.229, -4.979, -3.825, 0.164, 21.802, 15.877, 0.025, -9.2]
**Ligand B:** [358.551, 33.2, 4.512, 0, 3, 0.726, 17.371, 74.641, -4.663, -5.228, 0.517, 62.544, 17.811, 0.605, -7.9]

**Step-by-step comparison:**

1. **MW:** Both ligands (356.3 and 358.6 Da) fall within the ideal 200-500 Da range.
2. **TPSA:** Ligand A (96.18) is higher than Ligand B (33.2).  While both are under 140, the lower TPSA of Ligand B is significantly better for absorption.
3. **logP:** Ligand A (2.405) is within the optimal 1-3 range. Ligand B (4.512) is slightly higher, potentially leading to solubility issues and off-target interactions, but still acceptable.
4. **HBD:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.
5. **HBA:** Ligand A (6) and Ligand B (3) are both acceptable, being less than 10.
6. **QED:** Ligand A (0.873) has a better QED score than Ligand B (0.726), indicating a more drug-like profile.
7. **DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (17.371). Ligand B is well below the 40% threshold, indicating low liver injury risk.
8. **BBB:** Both ligands have good BBB penetration (A: 71.229, B: 74.641). Not a primary concern for SRC kinase, but a positive attribute.
9. **Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.
10. **Solubility:** Ligand A (-3.825) has worse solubility than Ligand B (-5.228). Both are poor, but B is slightly better.
11. **hERG:** Ligand A (0.164) has a lower hERG risk than Ligand B (0.517). This is a significant advantage for Ligand A.
12. **Cl_mic:** Ligand A (21.802) has a lower microsomal clearance than Ligand B (62.544), suggesting better metabolic stability.
13. **t1/2:** Ligand A (15.877) has a shorter in vitro half-life than Ligand B (17.811).
14. **Pgp:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.605), which is favorable for bioavailability.
15. **Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a >1.3 kcal/mol advantage, which is substantial.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in affinity and metabolic stability. While solubility is poor for both, Ligand B is slightly better. Ligand A has a lower hERG risk. The substantial affinity difference of Ligand A outweighs the slightly higher DILI risk and shorter half-life.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, the significantly stronger binding affinity, lower Cl_mic, lower Pgp efflux, and lower hERG risk of **Ligand A** make it the more promising drug candidate.

Output:
1
2025-04-17 11:42:13,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.539 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.24) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (81.67) is still under 140, but less optimal than A.

**logP:** Ligand A (3.811) is at the higher end of the optimal range (1-3), while Ligand B (1.534) is at the lower end. While both are within range, a higher logP can sometimes be tolerated if other properties are favorable.

**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:** Both ligands have good QED scores (A: 0.686, B: 0.757), indicating drug-like properties.

**DILI:** Ligand A (37.456) has a slightly higher DILI risk than Ligand B (25.204), but both are below the concerning threshold of 60.

**BBB:** Ligand A (78.092) shows better BBB penetration than Ligand B (58.278), though this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.849 and -4.811), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.948 and -1.4), indicating very poor aqueous solubility, which is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.607) has a slightly higher hERG risk than Ligand B (0.354), but both are relatively low.

**Microsomal Clearance:** Ligand B (-17.061) has significantly lower (better) microsomal clearance than Ligand A (62.147), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (30.521) has a longer in vitro half-life than Ligand A (18.627), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.526) has lower P-gp efflux than Ligand B (0.027), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having poor Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.6 vs -7.5 kcal/mol) and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher DILI risk and lower BBB penetration. The better affinity suggests a lower dose could be effective, potentially mitigating some solubility issues.

Output:
1
2025-04-17 11:42:13,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.384 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.2 and 75.27) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.222 and 2.751) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the limits of 5 and 10 respectively.

**QED:** Ligand A (0.863) has a significantly better QED score than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (12.524). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (81.582) has better BBB penetration than Ligand B (67.933).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual, but we can assume that a less negative value is better. Ligand A (-4.859) is slightly better than Ligand B (-4.756).

**Aqueous Solubility:** Both ligands have negative solubility values. Again, we can assume that a less negative value is better. Ligand A (-3.611) is slightly better than Ligand B (-3.069).

**hERG:** Ligand A (0.656) has a lower hERG inhibition liability than Ligand B (0.111), which is favorable.

**Microsomal Clearance:** Ligand A (4.112 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (55.525 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.308 hours) has a longer in vitro half-life than Ligand B (-23.427 hours).

**P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux liability than Ligand B (0.017).

**Binding Affinity:** Ligand B (-8.4 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's not a decisive factor.

**Overall Assessment:**

Ligand A has a superior QED score, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG risk. While its DILI risk is higher, the improvements in metabolic stability and safety parameters are more critical for an enzyme target like SRC. Ligand B's only significant advantage is slightly better binding affinity, which isn't substantial enough to overcome the ADME liabilities.

Output:
1
2025-04-17 11:42:13,837 - INFO - Batch 69 complete. Total preferences: 1104
2025-04-17 11:42:13,837 - INFO - Processing batch 70/512...
2025-04-17 11:43:00,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.463 and 360.893 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.2) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (59.73) is well within the ideal range.

**logP:** Both ligands have logP values (2.445 and 3.802) within the optimal 1-3 range. Ligand B is closer to the upper limit, which *could* raise concerns about off-target effects, but isn't a major issue.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are both acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.601 and 0.776), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (53.354 and 52.385 percentile), both being acceptable (below 60).

**BBB:** Ligand A (45.832) and Ligand B (78.868). BBB is less critical for a non-CNS target like SRC, but higher is generally better. Ligand B has a significantly better BBB score.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.028 and -5.379), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.199 and -3.77). This is a major red flag, indicating very poor aqueous solubility, which will hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG risk (0.296), which is excellent.

**Microsomal Clearance:** Ligand A (44.635 mL/min/kg) has a higher clearance than Ligand B (35.066 mL/min/kg). Lower clearance is preferred for better metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (-7.381 hours) has a longer half-life than Ligand A (-18.195 hours). A longer half-life is generally desirable.

**P-gp Efflux:** Both ligands have similar low P-gp efflux liability (0.108 and 0.396).

**Binding Affinity:** Ligand B (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Both ligands have serious issues with Caco-2 permeability and aqueous solubility. However, Ligand B has a significantly better binding affinity, longer half-life, lower microsomal clearance, and better BBB penetration. The superior binding affinity of Ligand B is a major advantage for an enzyme inhibitor. While the solubility and permeability are concerning, these can potentially be addressed through formulation strategies. The stronger binding is harder to improve post-hoc.

Output:
1
2025-04-17 11:43:00,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.378 and 368.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.87) is better than Ligand B (69.64), both are within the acceptable range for oral absorption (<140).

**logP:** Ligand B (1.793) is optimal (1-3), while Ligand A (0.013) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.655 and 0.673, respectively), indicating drug-likeness.

**DILI:** Ligand A (44.126) has a slightly higher DILI risk than Ligand B (14.889), but both are below the concerning threshold of 60.

**BBB:** Ligand A (64.482) has a lower BBB penetration score than Ligand B (82.047). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.679) has poor Caco-2 permeability, while Ligand B (-4.715) is better, but still low.

**Aqueous Solubility:** Ligand A (-0.798) has poor solubility, while Ligand B (-1.962) is also poor.

**hERG:** Ligand A (0.018) has a very low hERG risk, which is excellent. Ligand B (0.647) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand B (-4.131) has significantly lower (better) microsomal clearance than Ligand A (12.578), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-43.183) has a much longer in vitro half-life than Ligand A (17.441), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 and 0.037).

**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.

**Conclusion:**

Ligand B is the superior candidate. While both have acceptable MW, QED, and P-gp efflux, Ligand B excels in the crucial areas for an enzyme inhibitor: significantly stronger binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), and a lower DILI risk. Although both have poor solubility and Caco-2 permeability, the potency and metabolic stability advantages of Ligand B outweigh these drawbacks. The lower logP of Ligand A is a significant concern for permeability.

Output:
1
2025-04-17 11:43:00,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.379 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (60.25) is significantly better than Ligand B (92.7). Lower TPSA generally improves absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.203, Ligand B: 3.079), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 6 HBA) as it has fewer hydrogen bond donors, potentially improving membrane permeability. Both are within acceptable limits.

**QED:** Ligand A (0.684) has a better QED score than Ligand B (0.449), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 74.021, Ligand B: 72.043), and are at a moderate risk.

**BBB:** Ligand A (68.166) has a better BBB percentile than Ligand B (39.511), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.735) has a better Caco-2 permeability than Ligand B (-5.265).

**Aqueous Solubility:** Ligand A (-2.269) has better aqueous solubility than Ligand B (-4.246). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.425) has a lower hERG inhibition liability than Ligand B (0.177), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (48.064) has a lower microsomal clearance than Ligand B (83.017), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (30.509 hours) has a significantly longer half-life than Ligand B (-5.013 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.145) has lower P-gp efflux liability than Ligand B (0.373), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). However, the difference is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Overall:** Considering all factors, Ligand A is the more promising drug candidate. It has better predicted ADME properties (solubility, permeability, metabolic stability, hERG risk, P-gp efflux) and a good QED score, despite a slightly weaker binding affinity. The longer half-life is also a significant benefit.

Output:
0
2025-04-17 11:43:00,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.406 and 348.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.03) is better than Ligand B (99.23), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (though that's not a priority here).

**logP:** Both ligands (1.707 and 1.805) 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=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.773 and 0.875), indicating good drug-like properties.

**DILI:** Ligand A (24.855) has a significantly lower DILI risk than Ligand B (52.889). This is a major advantage.

**BBB:** Ligand B (87.088) has a higher BBB penetration score than Ligand A (68.903), but this isn't a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale. However, A (-4.889) is slightly better than B (-4.554).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. A (-2.152) is slightly better than B (-3.515).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.443 and 0.394).

**Microsomal Clearance:** Ligand A (-21.106) has a much lower (better) microsomal clearance than Ligand B (29.873), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (29.183) has a better in vitro half-life than Ligand B (-38.491).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.043 and 0.099).

**Binding Affinity:** Both ligands have comparable binding affinities (-9.5 and -8.4 kcal/mol). Ligand A has a slightly better affinity.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and better t1/2), slightly better solubility and Caco-2 permeability, and a slightly better binding affinity. While Ligand B has a higher BBB score, this is less important for an SRC kinase inhibitor. The combination of improved safety (DILI) and pharmacokinetics (Cl_mic, t1/2) makes Ligand A the preferred choice.

Output:
1
2025-04-17 11:43:00,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (345.4 and 367.4 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 acceptable. Ligand B (79.8) is well within the ideal range.

**3. logP:** Both ligands have logP values within the optimal 1-3 range (1.006 and 2.77).

**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 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.751 and 0.736), indicating good drug-likeness.

**7. DILI:** Ligand A (49.5) has a better DILI score than Ligand B (70.9), indicating a lower risk of liver injury. This is a significant advantage.

**8. BBB:** Ligand B (89.5) shows better BBB penetration than Ligand A (54.6), but this is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.178 and -4.877), indicating poor permeability. This is a major concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.104 and -4.177), indicating poor aqueous solubility. This is also a significant concern.

**11. hERG Inhibition:** Ligand A (0.036) has a much lower hERG inhibition liability than Ligand B (0.559), which is a crucial safety advantage.

**12. Microsomal Clearance:** Ligand A (2.467) has a significantly lower microsomal clearance than Ligand B (65.813), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (9.277) has a longer half-life than Ligand A (-5.732). However, the negative value for A is concerning and may indicate rapid degradation.

**14. P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux liability than Ligand B (0.246), which is beneficial for bioavailability.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.7 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol, so it's not decisive.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in metabolic stability (lower Cl_mic), hERG risk (much lower), and DILI risk. While both have poor solubility and permeability, the superior safety and metabolic profile of Ligand A outweigh the slightly better half-life of Ligand B.

Output:
0
2025-04-17 11:43:00,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.455 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.77) is slightly higher than Ligand B (62.55), but both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.311) is within the optimal 1-3 range. Ligand B (3.553) is at the higher end of the optimal range, potentially raising concerns about off-target effects or solubility, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.874) has a better QED score than Ligand B (0.781), indicating a more drug-like profile.

**DILI:** Ligand B (29.818) has a significantly lower DILI risk than Ligand A (67.39), which is a major advantage.

**BBB:** Ligand B (73.827) has a higher BBB penetration score than Ligand A (63.397). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.775 and -4.333), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.108 and -3.16). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.132) has a slightly lower hERG inhibition risk than Ligand B (0.532), which is preferable.

**Microsomal Clearance:** Ligand B (75.151) has a much higher microsomal clearance than Ligand A (19.113), indicating lower metabolic stability. This is a significant disadvantage for Ligand B.

**In vitro Half-Life:** Ligand B (67.544) has a longer in vitro half-life than Ligand A (30.902), which is a positive.

**P-gp Efflux:** Ligand A (0.028) has a lower P-gp efflux liability than Ligand B (0.298), which is a slight advantage.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.9 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks. The difference of 1.2 kcal/mol is substantial.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-10.1 vs -8.9 kcal/mol) is a critical advantage for an enzyme inhibitor. While Ligand B has a better DILI score and longer half-life, the substantial difference in potency and lower P-gp efflux of Ligand A are more important considerations. The higher metabolic clearance of Ligand B is also a concern. Addressing the solubility and permeability issues will be crucial for either compound, but starting with the more potent ligand is the better strategy.

Output:
0
2025-04-17 11:43:00,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.435 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.72) is slightly higher than Ligand B (85.69). Both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets (not relevant here).

**logP:** Ligand A (1.528) is within the optimal 1-3 range. Ligand B (0.243) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria.

**H-Bond Acceptors:** Both ligands (6) meet the HBA <=10 criteria.

**QED:** Both ligands have similar, good QED values (0.826 and 0.824).

**DILI:** Ligand A (55.525) has a higher DILI risk than Ligand B (37.146), but both are below the concerning 60 threshold.

**BBB:** This is less important for a non-CNS target. Ligand B (83.327) has a higher BBB percentile than Ligand A (38.348), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.391) has worse Caco-2 permeability than Ligand B (-4.743), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.654) has worse aqueous solubility than Ligand B (-1.251). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.213 and 0.289).

**Microsomal Clearance:** Ligand A (-13.603) has *much* lower microsomal clearance than Ligand B (7.377), indicating significantly better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (18.899) has a longer in vitro half-life than Ligand B (-3.182). This is another significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.015).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -8.2 kcal/mol). Ligand A is slightly better (-9.2 vs -8.2), but the difference is less than the 1.5 kcal/mol threshold that would make it definitively superior.

**Conclusion:**

While Ligand A has slightly better binding affinity, Ligand B is superior overall. The significantly better metabolic stability (lower Cl_mic, longer t1/2) and solubility of Ligand A are critical advantages for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor drawback compared to the substantial benefits of improved metabolic stability.

Output:
1
2025-04-17 11:43:00,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.531 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 (84.74). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (4.033) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (0.397) is quite low, potentially hindering membrane permeability and absorption.

**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, Ligand A's profile suggests a better balance between solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.684, B: 0.767), indicating generally drug-like properties.

**DILI:** Ligand A (12.214) has a much lower DILI risk than Ligand B (68.786). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (90.772) has a higher BBB percentile than Ligand B (58.085).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. Ligand A (-4.86) is slightly better than Ligand B (-4.991).

**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 (-2.794) is slightly better than Ligand A (-3.893).

**hERG Inhibition:** Ligand A (0.667) has a slightly higher hERG risk than Ligand B (0.452), but both are relatively low.

**Microsomal Clearance:** Ligand A (51.662) has a higher microsomal clearance than Ligand B (20.604), indicating faster metabolism and potentially lower *in vivo* exposure. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (3.239) has a longer half-life than Ligand A (-16.875). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.384, B: 0.082), which is favorable. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-9.7 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 and can outweigh some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA and DILI risk, Ligand B's significantly superior binding affinity (-9.7 vs -7.6 kcal/mol) and longer half-life are crucial for an enzyme inhibitor. The lower logP of Ligand B is a concern, but the strong binding affinity suggests it can still effectively engage the target. The higher DILI risk of Ligand B is a concern but may be mitigated with further optimization.

Output:
1
2025-04-17 11:43:00,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.503 and 388.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.29 and 75.71) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.776 and 2.559) 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 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.715 and 0.776, both > 0.5).

**DILI:** Ligand A has a DILI risk of 81.466, which is high (>60). Ligand B has a DILI risk of 58.938, which is still concerning but better than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.796) and Ligand B (62.466) are both moderate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.881 and -4.785), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.131 and -3.164), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.748) has a slightly higher hERG risk than Ligand B (0.262). Lower is better here.

**Microsomal Clearance:** Ligand A (13.645) has a lower (better) microsomal clearance than Ligand B (45.513), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.502) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (-5.16) also has a negative half-life, but is less extreme.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.324 and 0.197).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly better binding affinity than Ligand B (-7.7 kcal/mol). This is a >1.5 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a very high DILI risk and an impossible half-life. Ligand B has a better safety profile (lower DILI, lower hERG) and a less problematic (though still negative) half-life, but its binding affinity is significantly weaker.

The negative Caco-2 and solubility values for both are major red flags. However, given the significant potency advantage of Ligand A, and the fact that solubility and permeability can sometimes be improved through formulation or structural modifications, I would initially favor Ligand A. The DILI risk is a serious concern, but could potentially be mitigated with further structural modifications. The negative half-life, however, is a showstopper and suggests a fundamental issue with the molecule or the data.

Considering the negative half-life of Ligand A, and the overall better ADME profile of Ligand B, I will select Ligand B.

Output:
1
2025-04-17 11:43:00,183 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [397.232, 70.63, 3.003, 0, 5, 0.633, 83.637, 59.791, -4.716, -4.828, 0.858, 80.85, 11.163, 0.693, -9.9]
**Ligand B:** [357.841, 53.51, 2.211, 0, 3, 0.762, 68.244, 72.664, -4.683, -3.455, 0.35, 50.163, -46.135, 0.282, -7.1]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (357.841 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.
2. **TPSA:** Ligand A (70.63) is higher than Ligand B (53.51). Both are below the 140 threshold for oral absorption, but Ligand B is better.
3. **logP:** Both are within the optimal range (1-3). Ligand A (3.003) is at the higher end, while Ligand B (2.211) is more central.
4. **HBD:** Both have 0 HBD, which is good.
5. **HBA:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of 10. Ligand B is preferable.
6. **QED:** Both have acceptable QED values (A: 0.633, B: 0.762), indicating good drug-like properties. Ligand B is slightly better.
7. **DILI:** Ligand A (83.637) has a significantly higher DILI risk than Ligand B (68.244). This is a major concern for Ligand A.
8. **BBB:** Ligand A (59.791) and Ligand B (72.664) are both not particularly high, but Ligand B is better. Not a primary concern for an oncology target.
9. **Caco-2:** Both have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both.
10. **Solubility:** Both have negative solubility values, indicating poor solubility. This is a significant drawback for both.
11. **hERG:** Ligand A (0.858) has a higher hERG risk than Ligand B (0.35). This is a concern for Ligand A.
12. **Cl_mic:** Ligand A (80.85) has a higher microsomal clearance than Ligand B (50.163), suggesting lower metabolic stability. This is a negative for Ligand A.
13. **t1/2:** Ligand B (-46.135) has a much longer in vitro half-life than Ligand A (11.163). This is a significant advantage for Ligand B.
14. **Pgp:** Ligand A (0.693) has a higher Pgp efflux liability than Ligand B (0.282). This is a negative for Ligand A.
15. **Binding Affinity:** Ligand B (-7.1) has a stronger binding affinity than Ligand A (-9.9). This is a significant advantage for Ligand B.

**Enzyme-Kinase Specific Priorities:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in these areas. While both have poor Caco-2 and solubility, the superior affinity, metabolic stability, lower DILI/hERG risk, and better Pgp profile of Ligand B outweigh the slightly less optimal TPSA and logP. The significantly better binding affinity (-7.1 vs -9.9) is also a major factor.

**Conclusion:**

Ligand B is the more viable drug candidate.

1
2025-04-17 11:43:00,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 346.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (113.24). Both are acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.781) is optimal (1-3). Ligand B (0.191) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 3 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 (0.634) has a slightly better QED score than Ligand A (0.47), suggesting a more drug-like profile. However, this is less critical than other factors.

**DILI:** Ligand A (46.452) has a slightly higher DILI risk than Ligand B (36.758), but both are below the concerning threshold of 60.

**BBB:** Ligand A (27.181) has a much lower BBB penetration percentile than Ligand B (68.67). Since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.997) has a very poor Caco-2 permeability, while Ligand B (-5.709) is also poor. Both are problematic, but A is slightly better.

**Aqueous Solubility:** Ligand A (-2.422) has slightly better solubility than Ligand B (-1.655), although both are poor.

**hERG Inhibition:** Ligand A (0.379) has a lower hERG inhibition liability than Ligand B (0.431), which is preferable.

**Microsomal Clearance:** Ligand B (-38.393) has significantly lower (better) microsomal clearance than Ligand A (24.49). This indicates greater metabolic stability for Ligand B, a key priority for enzymes.

**In vitro Half-Life:** Ligand B (-10.409) has a longer in vitro half-life than Ligand A (-28.577), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux than Ligand B (0.005), which is preferable.

**Binding Affinity:** Ligand A (-7.1) has a significantly stronger binding affinity than Ligand B (-0.0). This is the most important factor for an enzyme inhibitor. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite Ligand B having better metabolic stability (Cl_mic and t1/2) and a slightly better QED, Ligand A's *much* stronger binding affinity (-7.1 kcal/mol vs -0.0 kcal/mol) is the decisive factor. The potency advantage is substantial. While Ligand A has some ADME concerns (Caco-2, solubility), these can potentially be addressed through further optimization. The strong binding affinity provides a solid foundation for a viable drug candidate.

Output:
1
2025-04-17 11:43:00,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.419 Da) is slightly better positioned.

**TPSA:** Both are below the 140 A^2 threshold for good absorption, but Ligand A (72.91) is significantly lower than Ligand B (88.41), which is favorable.

**logP:** Both ligands have good logP values (between 1-3), with Ligand A (3.268) being slightly higher than Ligand B (2.586).

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 6 HBA) is better than Ligand B (2 HBD, 4 HBA) regarding the number of H-bonds, which is beneficial for permeability.

**QED:** Both ligands have similar, acceptable QED values (A: 0.77, B: 0.736).

**DILI:** Both ligands have relatively high DILI risk, but Ligand B (80.031) is slightly higher than Ligand A (77.627).

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (86.739) shows slightly better BBB penetration than Ligand B (71.772).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.494) is slightly better than Ligand B (-4.851).

**Aqueous Solubility:** Both have negative solubility values, which is concerning. Ligand A (-4.65) is slightly better than Ligand B (-3.747).

**hERG Inhibition:** Ligand A (0.224) has a much lower hERG risk than Ligand B (0.533), a crucial advantage.

**Microsomal Clearance:** Ligand B (42.881) has significantly lower microsomal clearance than Ligand A (106.636), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (76.365) has a much longer half-life than Ligand A (-17.961), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.604) has slightly lower P-gp efflux than Ligand B (0.35).

**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 that can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity and significantly improved metabolic stability and half-life. While it has a slightly higher DILI risk and P-gp efflux, the stronger binding and improved PK properties are more critical for an enzyme target like SRC. The negative solubility and Caco-2 values are concerning for both, but the potency advantage of Ligand B is substantial. The lower hERG risk of Ligand A is a positive, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 11:43:00,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.515 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (91.32) is slightly higher than Ligand B (84.23).

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 1.741, Ligand B: 2.608), which is optimal.

**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 similar QED values (Ligand A: 0.653, Ligand B: 0.674), indicating good drug-like properties.

**DILI:** Ligand A (33.812) has a significantly lower DILI risk than Ligand B (43.117), which is a major advantage. Both are below the 40 threshold, but A is preferable.

**BBB:** Ligand A (30.981) has a lower BBB penetration percentile than Ligand B (77.821). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.177) is slightly worse than Ligand B (-4.822). This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand A (-1.94) is slightly better than Ligand B (-3.967), but both are problematic.

**hERG Inhibition:** Ligand A (0.079) has a much lower hERG inhibition liability than Ligand B (0.345), which is a significant advantage.

**Microsomal Clearance:** Ligand A (17.895) has a much lower microsomal clearance than Ligand B (69.899), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (9.961) has a better in vitro half-life than Ligand B (0.433).

**P-gp Efflux:** Ligand A (0.028) has a much lower P-gp efflux liability than Ligand B (0.388), suggesting better oral bioavailability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is significantly better in terms of safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and efflux (Pgp). The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The superior ADME profile of Ligand A, coupled with acceptable potency, outweighs the slightly weaker binding affinity. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (hERG, DILI) are critical.

Output:
0
2025-04-17 11:43:00,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.483 and 352.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is higher than Ligand B (46.34). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Ligand A (1.865) is within the optimal 1-3 range. Ligand B (4.183) 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.84 and 0.798), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (31.601 and 32.842 percentile), which is favorable.

**BBB:** Ligand A (71.501) has moderate BBB penetration, while Ligand B (94.727) has high BBB penetration. Since SRC is not a CNS target, this is less critical, but a slight edge to B.

**Caco-2 Permeability:** Ligand A (-5.14) has poor Caco-2 permeability, while Ligand B (-4.461) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-2.527) has poor aqueous solubility, and Ligand B (-4.644) is even worse. This is a concern for both, but more so for B.

**hERG Inhibition:** Ligand A (0.163) has very low hERG risk, which is excellent. Ligand B (0.601) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (49.791 mL/min/kg) has lower clearance than Ligand B (78.076 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (5.384 hours) has a positive half-life, while Ligand B (-0.952 hours) has a negative half-life, indicating very poor stability.

**P-gp Efflux:** Ligand A (0.162) has low P-gp efflux, while Ligand B (0.556) has moderate P-gp efflux. Lower is better.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 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 the most important factor for an enzyme inhibitor. While it has some ADME liabilities (higher logP, poor solubility, higher clearance, moderate P-gp efflux), the potency advantage is significant. Ligand A has better metabolic stability and lower hERG risk, but its weaker binding affinity is a major drawback. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:43:00,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.353 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (74.69 and 78.87) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.054) is optimal, while Ligand B (1.018) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, satisfying the <5 and <10 rules respectively.

**QED:** Both ligands have acceptable QED scores (0.839 and 0.771), indicating good drug-likeness.

**DILI:** Ligand A (60.527) has a moderate DILI risk, while Ligand B (21.598) has a very low risk, which is a significant advantage.

**BBB:** Both have reasonable BBB penetration (76.154 and 62.97), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.629 and -4.817), which is unusual and suggests poor permeability. This is a potential red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-3.538 and -1.239), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.494 and 0.28).

**Microsomal Clearance:** Ligand A (43.951) has moderate clearance, while Ligand B (-15.197) has *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**In vitro Half-Life:** Ligand B (14.875 hours) has a significantly longer half-life than Ligand A (5.663 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.076 and 0.043).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), though the difference is not huge.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly lower DILI risk, exceptional metabolic stability (negative Cl_mic), longer half-life, and slightly better binding affinity outweigh Ligand A's marginally better logP. The negative Caco-2 and solubility values are concerning for both, but these can potentially be addressed through formulation strategies. The DILI and metabolic stability are harder to fix chemically.

Output:
1
2025-04-17 11:43:00,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.856 Da and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.3) is slightly higher than Ligand B (52.65). Both are below the 140 threshold for good absorption, but lower is generally better.

**logP:** Both ligands have good logP values (2.369 and 2.262), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both have reasonably high QED scores (0.888 and 0.767), indicating good drug-likeness.

**DILI:** Ligand A (43.35) has a slightly higher DILI risk than Ligand B (7.057). This is a significant difference; lower DILI is strongly preferred.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (74.292) and Ligand B (82.9) are both reasonably high, but this isn't a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.842 and -4.797), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.601 and -2.442), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG:** Both ligands have low hERG inhibition liability (0.669 and 0.675), which is good.

**Microsomal Clearance:** Ligand A (16.605) has a lower microsomal clearance than Ligand B (44.33). Lower clearance indicates better metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand A (-18.188) has a significantly longer in vitro half-life than Ligand B (-14.955). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.186 and 0.086), which is favorable.

**Binding Affinity:** Ligand B (-9.6) has a slightly better binding affinity than Ligand A (-8.1). This is a 1.5 kcal/mol difference, which is substantial and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate. The significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and comparable permeability and solubility issues make it a more favorable starting point. The affinity difference, while notable, is not enough to overcome the superior safety and pharmacokinetic profile of Ligand A. The poor solubility and permeability are concerns for both, but can be addressed through formulation strategies or further chemical modifications.

Output:
1
2025-04-17 11:43:00,184 - INFO - Batch 70 complete. Total preferences: 1120
2025-04-17 11:43:00,184 - INFO - Processing batch 71/512...
2025-04-17 11:43:40,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.415 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.32) is significantly better than Ligand B (96.11). TPSA < 140 is good for oral absorption, and both are within this limit, but A is preferable.

**3. logP:** Both ligands have acceptable logP values (0.641 and 1.16), falling within the 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:** Ligand A (6) is better than Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have reasonable QED values (0.809 and 0.699), indicating good drug-like properties.

**7. DILI:** Ligand A (22.722) has a much lower DILI risk than Ligand B (56.185). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (64.327 and 61.613), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.877) is better than Ligand B (-5.385). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.474) is better than Ligand B (-3.519). Better solubility is crucial for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.586 and 0.256), which is excellent.

**12. Microsomal Clearance:** Ligand A (11.705) has higher microsomal clearance than Ligand B (6.974), meaning it's less metabolically stable. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (15.789) has a much longer in vitro half-life than Ligand A (2.7). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.07).

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.3 and -8.1 kcal/mol), which are both excellent. The difference is negligible.

**Overall Assessment:**

Ligand A excels in properties related to absorption and safety (TPSA, HBD, HBA, DILI, Solubility, Caco-2). However, Ligand B demonstrates better metabolic stability (lower Cl_mic and longer t1/2). Given the enzyme-specific priorities, metabolic stability is crucial. While Ligand A has a lower DILI risk, the difference in half-life is substantial. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 11:43:40,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.359 Da and 343.398 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (102.24) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (58.56) is excellent, well below 140.

**logP:** Ligand A (0.274) is quite low, potentially hindering permeation. Ligand B (3.741) is near the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, both within acceptable limits. Ligand B has 2 HBD and 3 HBA, also within acceptable limits.

**QED:** Both ligands have high QED scores (0.859 and 0.868), indicating good drug-like properties.

**DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (61.031), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.254) is slightly better than Ligand B (45.56).

**Caco-2 Permeability:** Ligand A (-5.172) shows poor permeability. Ligand B (-4.888) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.289) has very poor solubility. Ligand B (-4.345) also has poor solubility, but is better than A.

**hERG Inhibition:** Ligand A (0.099) shows very low hERG inhibition risk, which is excellent. Ligand B (0.495) has a slightly higher risk, but still acceptable.

**Microsomal Clearance:** Ligand A (15.342) has lower clearance, suggesting better metabolic stability. Ligand B (22.026) has higher clearance.

**In vitro Half-Life:** Ligand A (36.801) has a shorter half-life than Ligand B (20.328).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.186).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and lower clearance, indicating better potency and metabolic stability. However, its extremely low logP and poor solubility are major drawbacks, likely leading to poor absorption and bioavailability. Ligand B has a more favorable logP and slightly better solubility, despite having a slightly lower affinity and higher clearance.

Given the enzyme-specific priorities, metabolic stability and solubility are crucial. While Ligand A's affinity is marginally better, the significant solubility and permeability issues outweigh this benefit. Ligand B, with its more balanced profile, is more likely to be a viable drug candidate.

Output:
1
2025-04-17 11:43:40,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (382.848 and 383.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.26) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (4.596) is higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.962) is within the optimal range.

**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.

**QED:** Both ligands have good QED scores (0.583 and 0.701), indicating drug-like properties.

**DILI:** Ligand A (88.639) has a significantly higher DILI risk than Ligand B (33.424). This is a major concern.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (61.729) is slightly better.

**Caco-2 Permeability:** Ligand A (-4.743) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.37) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.7) has very poor aqueous solubility, likely due to its high logP. Ligand B (-2.418) has better solubility.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.555 and 0.578).

**Microsomal Clearance:** Ligand A (34.767) has lower microsomal clearance than Ligand B (51.729), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (95.978) has a significantly longer in vitro half-life than Ligand B (-0.673). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.22 and 0.169).

**Binding Affinity:** Both ligands have the same strong binding affinity (-8.7 kcal/mol).

**Conclusion:**

While Ligand A has a longer half-life, its significantly higher DILI risk and poor solubility are major drawbacks. The higher logP contributes to these issues. Ligand B, despite slightly higher clearance, presents a much more favorable ADME profile with lower DILI risk and better solubility. The binding affinity is identical for both. Given the enzyme-specific priorities, metabolic stability and solubility are crucial, and Ligand B excels in these areas.

Output:
1
2025-04-17 11:43:40,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.375 Da) is slightly lower, which could be beneficial for permeability. Ligand B (405.933 Da) is also good.

**TPSA:** Ligand A (81.67) is well below the 140 threshold for oral absorption and is also favorable. Ligand B (97.19) is still acceptable but less optimal.

**logP:** Ligand A (0.602) is a bit low, potentially impacting permeability. Ligand B (1.684) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are both within acceptable limits. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.492, B: 0.755), with Ligand B being significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (18.457) has a much lower DILI risk than Ligand B (86.855), a significant advantage.

**BBB:** Ligand A (71.074) shows reasonable BBB penetration, while Ligand B (39.24) is lower, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.963) has poor Caco-2 permeability, which is a concern. Ligand B (-5.24) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-0.658) has very poor aqueous solubility, a major drawback. Ligand B (-3.139) is also poor, but worse than A.

**hERG Inhibition:** Ligand A (0.437) has a low hERG risk, which is excellent. Ligand B (0.216) is even lower, also very good.

**Microsomal Clearance:** Ligand A (-6.504) has a negative value, indicating very low clearance and excellent metabolic stability. Ligand B (54.731) has high clearance, suggesting poor metabolic stability. This is a critical difference.

**In vitro Half-Life:** Ligand A (-10.242) has a negative value, suggesting a very long half-life, which is highly desirable. Ligand B (-13.099) is also long, but not as good as A.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.005, B: 0.106), which is favorable.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (A: -8.1 kcal/mol, B: -8.9 kcal/mol). Ligand B is slightly better, but the difference is likely not enough to overcome its other weaknesses.

**Conclusion:**

Despite Ligand B having a slightly better binding affinity and QED, Ligand A is the more promising candidate. The significantly lower DILI risk, superior metabolic stability (indicated by negative Cl_mic and half-life), and lower hERG risk outweigh the slightly lower logP and Caco-2 permeability. The poor solubility of both is a concern, but formulation strategies can often address this. The poor permeability is also a concern, but the strong binding affinity might compensate for that. The metabolic stability of Ligand A is a major advantage for an enzyme target.

Output:
0
2025-04-17 11:43:40,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.5 & 362.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands (2.168 & 1.701) are within the optimal 1-3 range. Ligand B is slightly lower, which could potentially impact permeability, but is still acceptable.

**H-Bond Donors:** Both have 2 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 10 limit.

**QED:** Both ligands have similar QED values (0.776 & 0.782), indicating good drug-likeness.

**DILI:** Ligand A (43.622) has a higher DILI risk than Ligand B (12.33). This is a significant advantage for Ligand B.

**BBB:** Ligand A (53.974) has lower BBB penetration than Ligand B (74.254). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.818 and -4.824). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.682 and -2.622). This is also unusual and suggests poor solubility. Again, the values are very similar.

**hERG Inhibition:** Ligand A (0.159) has a slightly lower hERG inhibition risk than Ligand B (0.417), which is preferable.

**Microsomal Clearance:** Ligand A (30.491) has a higher microsomal clearance than Ligand B (7.515). This means Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-18.889) has a significantly longer in vitro half-life than Ligand A (23.411). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.068) has slightly lower P-gp efflux than Ligand B (0.088), which is preferable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand B is the better candidate. While both have similar binding affinities and some concerning permeability/solubility issues, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. These are critical factors for kinase inhibitors. The slightly better BBB and lower HBA also contribute to its advantage.

Output:
1
2025-04-17 11:43:40,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.45 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (90.98 and 98.61) are below the 140 A^2 threshold for good oral absorption, but acceptable.

**logP:** Both ligands have logP values (1.164 and 2.34) 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 (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.558) has a better QED score than Ligand B (0.417), indicating a more drug-like profile.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (26.561). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (78.558 and 71.733). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.85) has worse Caco-2 permeability than Ligand B (-4.642). Lower values indicate poorer absorption.

**Aqueous Solubility:** Ligand A (-3.077) has worse aqueous solubility than Ligand B (-2.313). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.386) has a slightly higher hERG inhibition risk than Ligand B (0.292), but both are relatively low.

**Microsomal Clearance:** Ligand A (20.47 mL/min/kg) has significantly lower microsomal clearance than Ligand B (39.62 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.678 hours) has a much longer in vitro half-life than Ligand B (-15.788 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.137) has lower P-gp efflux than Ligand B (0.064), which is favorable for bioavailability.

**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 factor.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, and has a better QED score. However, it suffers from higher DILI risk and lower solubility/permeability. Ligand B has a slightly better binding affinity and lower DILI, but poorer metabolic stability and lower QED.

Given the priorities for kinase inhibitors, metabolic stability and a reasonable half-life are crucial. The difference in binding affinity is relatively small (0.5 kcal/mol), and can potentially be optimized in later stages. The DILI risk for Ligand A is concerning, but could be mitigated with structural modifications. The solubility/permeability issues of Ligand A are also addressable through prodrug strategies or formulation techniques.

Therefore, I believe Ligand A is the more promising candidate.

Output:
1
2025-04-17 11:43:40,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.402 and 354.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is better than Ligand B (51.02), both being well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.153 and 3.313), 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 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:** Both ligands have good QED scores (0.589 and 0.661), indicating good drug-like properties.

**DILI:** Ligand A (43.583) has a better DILI score than Ligand B (60.062). Ligand B is approaching the higher risk threshold (>60).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.419) is slightly better than Ligand B (73.827).

**Caco-2 Permeability:** Ligand A (-4.863) is significantly better than Ligand B (-5.112), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.41) is better than Ligand B (-2.543), indicating better solubility.

**hERG Inhibition:** Ligand A (0.434) has a much lower hERG inhibition liability than Ligand B (0.675), which is a significant advantage.

**Microsomal Clearance:** Ligand A (19.975) has significantly lower microsomal clearance than Ligand B (51.876), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.49) has a much shorter half-life than Ligand B (-19.841). This is a significant drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux liability than Ligand B (0.705), which is favorable.

**Binding Affinity:** Ligand B (-9.5 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 significantly superior binding affinity (-9.5 vs -7.8 kcal/mol) is the most important factor. While it has a slightly higher logP and a concerning DILI score, the strong binding is likely to be crucial for efficacy. The metabolic stability of Ligand A is better, but the much shorter half-life is a major disadvantage. The hERG risk is also lower for Ligand A, but the affinity difference is substantial. Considering the enzyme-specific priorities, the binding affinity is paramount.

Output:
1
2025-04-17 11:43:40,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.45 and 349.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is higher than Ligand B (64.86). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**logP:** Ligand A (1.148) is within the optimal range (1-3), while Ligand B (3.499) is towards the higher end. This could potentially lead to solubility issues for Ligand B, but isn't a major concern yet.

**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 (0.816) has a higher QED score than Ligand A (0.593), indicating a more drug-like profile overall.

**DILI:** Ligand B (22.8) has a much lower DILI risk than Ligand A (33.58). This is a significant advantage.

**BBB:** Ligand B (82.396) shows better BBB penetration than Ligand A (54.052), although this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.267) has a slightly lower hERG risk than Ligand B (0.407), which is preferable.

**Microsomal Clearance:** Ligand A (5.09 mL/min/kg) has a lower microsomal clearance than Ligand B (28.078 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-27.041 hours) has a negative half-life, which is impossible. Ligand B (-0.726 hours) also has a negative half-life, which is impossible. These values are likely errors or indicate very rapid degradation.

**P-gp Efflux:** Ligand A (0.042) has lower P-gp efflux than Ligand B (0.189), which is favorable.

**Binding Affinity:** Both ligands have a binding affinity of -8.5 and -8.0 kcal/mol, respectively. Ligand A has a slightly better affinity, but 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 candidate. While Ligand A has slightly better affinity and metabolic stability, Ligand B has a significantly lower DILI risk, a higher QED score, and better TPSA. The negative half-life values for both are concerning and need further investigation, but the overall profile of Ligand B is more favorable for development as an enzyme inhibitor.

Output:
1
2025-04-17 11:43:40,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.37 and 360.571 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.75) is better than Ligand B (33.95) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (3.268) is within the optimal range (1-3), while Ligand B (4.968) is slightly above, potentially leading to solubility issues.

**H-Bond Donors & Acceptors:** Both ligands have 0 HBD and 5 HBA, which are acceptable values.

**QED:** Both ligands have similar QED values (0.615 and 0.666), indicating good drug-likeness.

**DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (15.626), but both are below the concerning threshold of 60.

**BBB:** Ligand A (96.316) shows better BBB penetration than Ligand B (79.062), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.367) has worse Caco-2 permeability than Ligand B (-5.148).

**Aqueous Solubility:** Ligand A (-3.799) has slightly better aqueous solubility than Ligand B (-3.656).

**hERG:** Both ligands have similar hERG inhibition liability (0.832 and 0.854), which is acceptable.

**Microsomal Clearance:** Ligand B (46.406) has lower microsomal clearance than Ligand A (62.856), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (9.777) has a longer in vitro half-life than Ligand B (3.785), which is desirable.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.711 and 0.621).

**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 some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B having better metabolic stability, the significantly stronger binding affinity of Ligand A (-8.6 vs -7.6 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. While Ligand B's lower clearance is beneficial, the difference isn't large enough to overcome the substantial affinity advantage of Ligand A. Ligand A also has acceptable ADME properties overall.

Output:
1
2025-04-17 11:43:40,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.364 and 336.326 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.48) is better than Ligand B (76.97), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.73) is optimal, while Ligand B (3.493) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable, while Ligand B (6) is also good.

**QED:** Both ligands have similar QED values (0.691 and 0.617), indicating good drug-likeness.

**DILI:** Ligand A (14.851) has a significantly lower DILI risk than Ligand B (91.857). This is a major advantage for Ligand A.

**BBB:** Ligand A (77.937) has a better BBB penetration score than Ligand B (33.579), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.723) is better than Ligand B (-5.001), both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.002) is better than Ligand B (-4.089), both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.337) has a much lower hERG inhibition liability than Ligand B (0.527). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-9.116) has a much lower (better) microsomal clearance than Ligand B (77.077), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (16.78) has a much longer half-life than Ligand B (-60.697). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.028) has a much lower P-gp efflux liability than Ligand B (0.304).

**Binding Affinity:** Ligand A (-6.0) has a slightly better binding affinity than Ligand B (0.0).

**Overall:**

Ligand A is significantly better than Ligand B across most critical ADME-Tox properties. It has a much lower DILI risk, lower hERG inhibition, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While both have poor solubility and permeability, the superior safety and pharmacokinetic profile of Ligand A outweigh these drawbacks, especially given its slightly better binding affinity.

Output:
1
2025-04-17 11:43:40,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.393 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is excellent, well below the 140 threshold for absorption. Ligand B (115.55) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (3.016) is optimal. Ligand B (0.071) is quite low, which is a significant concern for permeability and could limit oral absorption.

**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:** Both ligands have good QED scores (0.858 and 0.722), indicating generally drug-like properties.

**DILI:** Ligand A (35.479) has a lower DILI risk than Ligand B (52.191), which is a positive. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (96.937) has a much higher BBB percentile than Ligand B (19.465).

**Caco-2 Permeability:** Ligand A (-4.544) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.951) is also negative, but similar.

**Aqueous Solubility:** Ligand A (-2.533) and Ligand B (-1.501) both have negative solubility values, indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.945) has a lower hERG risk than Ligand B (0.245), which is a significant advantage.

**Microsomal Clearance:** Ligand A (55.621) has a higher microsomal clearance than Ligand B (-28.634). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-15.918) has a negative half-life, which is not possible and indicates a major issue. Ligand B (26.904) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.635) has lower P-gp efflux than Ligand B (0.02), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 kcal/mol and -9.5 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a significantly better metabolic stability profile (lower Cl_mic, positive t1/2) and a slightly better binding affinity. However, Ligand A has a better logP, lower DILI risk, and lower hERG risk. The negative Caco-2 and solubility values for both are concerning, but the negative half-life for Ligand A is a deal-breaker. The low logP of Ligand B is also a major drawback. Considering the enzyme-specific priorities, metabolic stability and potency are key. While Ligand A has a better safety profile, the negative half-life is a fatal flaw.

Output:
1
2025-04-17 11:43:40,590 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [364.339, 58.64, 1.826, 1, 3, 0.775, 41.179, 87.476, -4.649, -3.749, 0.42, 35.102, -10.01, 0.12, -7.8]
**Ligand B:** [358.385, 84.5, 1.408, 2, 4, 0.371, 39.434, 89.686, -4.628, -2.93, 0.256, 56.8, -15.5, 0.078, -7.7]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (364.339) and B (358.385) are very similar.
2. **TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold. Ligand B (84.5) is still reasonable, but higher.
3. **logP:** Both are within the optimal range (1-3), A (1.826) is slightly higher than B (1.408).
4. **HBD:** A (1) is preferable to B (2), keeping hydrogen bonding potential low for better permeability.
5. **HBA:** A (3) is preferable to B (4) for the same reason as HBD.
6. **QED:** A (0.775) is significantly better than B (0.371), indicating a more drug-like profile.
7. **DILI:** Both are good, with A (41.179) and B (39.434) both under the 40 threshold.
8. **BBB:** Both have good BBB penetration, A (87.476) and B (89.686) are both high.
9. **Caco-2:** Both are negative, indicating poor permeability.
10. **Solubility:** Both are negative, indicating poor solubility.
11. **hERG:** Both are very low, indicating low risk of cardiotoxicity. A (0.42) is slightly higher than B (0.256).
12. **Cl_mic:** A (35.102) is significantly better than B (56.8), indicating better metabolic stability.
13. **t1/2:** A (-10.01) is better than B (-15.5), indicating a longer half-life.
14. **Pgp:** A (0.12) is significantly better than B (0.078), indicating lower P-gp efflux.
15. **Binding Affinity:** Both are excellent (-7.8 and -7.7 kcal/mol). The difference is minimal.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Both ligands have excellent binding affinity. However, Ligand A clearly wins on metabolic stability (lower Cl_mic, better t1/2), P-gp efflux, and has a better QED score. While both have poor solubility and Caco-2 permeability, the improved metabolic profile of Ligand A is more critical for an enzyme target.

**Conclusion:**

Ligand A is the more promising drug candidate.

Output:
1
2025-04-17 11:43:40,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.208 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Ligand A (110.64) is slightly higher than Ligand B (95.42). Both are below the 140 threshold for oral absorption, which is good.

**logP:** Ligand A (1.741) and Ligand B (0.913) are both within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is acceptable. Ligand A has 7 HBAs, and Ligand B has 5 HBAs, both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (A: 0.742, B: 0.826), indicating good drug-like properties.

**DILI:** Ligand A (90.927) has a significantly higher DILI risk than Ligand B (46.258). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Both have moderate BBB penetration (A: 53.393, B: 51.842).

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, these values should be interpreted cautiously.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.113, B: 0.101), which is excellent.

**Microsomal Clearance:** Ligand B (18.374) has a much lower microsomal clearance than Ligand A (60.205), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-19.986) has a negative half-life, which is not physically possible and indicates a potential data error. Ligand A (13.287) has a reasonable half-life. However, the negative value for B is a red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.098, B: 0.022), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are strong binders, the 1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B 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 values for Caco-2 and solubility are concerning for both, but the DILI and metabolic stability advantages of Ligand B outweigh the slightly better affinity of Ligand A. The negative in vitro half-life for Ligand B is a major data quality concern, but assuming it's an error, the rest of its profile is superior.

Output:
1
2025-04-17 11:43:40,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.479 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.17) is well below the 140 threshold, while Ligand B (86.09) is still acceptable but closer to the limit.

**logP:** Ligand A (3.13) is optimal, while Ligand B (1.908) is slightly lower but still within the acceptable range.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within the recommended limits.

**QED:** Both ligands have very similar QED values (0.911 and 0.907), indicating excellent drug-likeness.

**DILI:** Ligand A (74.021) has a higher DILI risk than Ligand B (39.085). This is a significant negative for Ligand A.

**BBB:** Both ligands have high BBB penetration (76.27 and 78.907), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating 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 (0.386) has a slightly lower hERG inhibition risk than Ligand B (0.547), which is favorable.

**Microsomal Clearance:** Ligand B (23.258) has lower microsomal clearance than Ligand A (29.061), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-15.783) has a significantly longer in vitro half-life than Ligand A (-8.43), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux scores (0.454 and 0.04), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-10.6 and -8.3 kcal/mol). Ligand A has a 2.3 kcal/mol advantage, which is substantial and could outweigh some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2) are major concerns. Ligand B, despite slightly lower affinity, exhibits a significantly better safety profile (lower DILI) and improved metabolic stability. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The 2.3 kcal/mol difference in binding affinity, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 11:43:40,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.349 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (82.11), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (2.311) is optimal (1-3), while Ligand B (-0.025) is slightly below 1, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well within the limit of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5), both are within the limit of 10.

**QED:** Both ligands have similar QED values (0.776 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (68.515) has a higher DILI risk than Ligand B (7.988). This is a significant drawback for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern. Ligand A (55.913) is slightly better than Ligand B (44.591).

**Caco-2 Permeability:** Ligand A (-4.786) is worse than Ligand B (-5.129), indicating lower intestinal absorption for both.

**Aqueous Solubility:** Ligand A (-3.599) is worse than Ligand B (-1.232), indicating lower solubility for Ligand A.

**hERG Inhibition:** Ligand A (0.621) has a slightly higher hERG risk than Ligand B (0.356), but both are relatively low.

**Microsomal Clearance:** Ligand B (-21.591) has significantly lower (better) microsomal clearance than Ligand A (31.668), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (28.566) has a slightly longer half-life than Ligand A (26.344).

**P-gp Efflux:** Ligand A (0.204) has lower P-gp efflux than Ligand B (0.01), indicating better bioavailability.

**Binding Affinity:** Ligand A (-9.7 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 much better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, lower solubility, and higher metabolic clearance. Ligand B has better ADME properties (lower DILI, better solubility, and metabolic stability) but weaker binding affinity. The difference in binding affinity (2.3 kcal/mol) is large enough to potentially overcome the ADME liabilities of Ligand A, especially if further optimization can address the DILI and solubility issues.

Output:
1
2025-04-17 11:43:40,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.475 and 345.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (89.87 and 81.93) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.221) is within the optimal 1-3 range, while Ligand B (3.278) is towards the higher end, potentially raising concerns about off-target effects, but still acceptable.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (7) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have similar QED values (0.544 and 0.526), indicating good drug-like properties.

**7. DILI:** Ligand A (12.214) has a significantly lower DILI risk than Ligand B (58.511). This is a major advantage for Ligand A.

**8. BBB:**  BBB is less critical for a non-CNS target like SRC, but Ligand B (81.194) shows higher penetration than Ligand A (46.026).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.648) is slightly better than Ligand B (-4.935).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.927) is slightly better than Ligand B (-3.75).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.123 and 0.39).

**12. Microsomal Clearance:** Ligand B (109.499) has a significantly higher microsomal clearance than Ligand A (55.653), suggesting lower metabolic stability. This is a critical disadvantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (-14.366) has a longer in vitro half-life than Ligand B (-10.317).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.044 and 0.495).

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -8.3 kcal/mol), indicating comparable potency.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have similar potency, Ligand A exhibits a significantly lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). Solubility is slightly better for Ligand A. These factors are crucial for enzyme inhibitors. The slightly better BBB penetration of Ligand B is not a significant advantage given the target.

Output:
0
2025-04-17 11:43:40,590 - INFO - Batch 71 complete. Total preferences: 1136
2025-04-17 11:43:40,590 - INFO - Processing batch 72/512...
2025-04-17 11:44:21,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (394.509 and 347.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is higher than Ligand B (52.65). Both are acceptable, but B is slightly better for absorption.

**3. logP:** Both ligands have good logP values (2.736 and 1.729), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is ideal.

**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 (0.773 and 0.843), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 53.354, while Ligand B has a significantly lower risk of 3.994. This is a major advantage for Ligand B.

**8. BBB:** Both have reasonable BBB penetration (88.329 and 82.164). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.875 and -4.898), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Ligand A (-3.538) and Ligand B (-1.565) both have negative solubility values, indicating poor aqueous solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.643) has a slightly higher hERG risk than Ligand B (0.526), though both are acceptable.

**12. Microsomal Clearance:** Ligand A (38.441) has a significantly higher microsomal clearance than Ligand B (7.562), indicating lower metabolic stability. This is a major drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-14.754) has a negative half-life, which is not possible and suggests a very rapid degradation. Ligand B has a half-life of 5.806 hours, which is better, but still not ideal.

**14. P-gp Efflux:** Ligand A (0.212) has slightly higher P-gp efflux than Ligand B (0.025).

**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 for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor metabolic stability (high Cl_mic, negative t1/2), a higher DILI risk, and slightly higher P-gp efflux. Ligand B has a much better safety profile (lower DILI) and metabolic stability, but its binding affinity is very weak.

Despite the superior affinity of Ligand A, the poor metabolic stability and DILI risk are major concerns. While affinity is paramount, a compound that is rapidly cleared and potentially hepatotoxic is unlikely to be a viable drug candidate. Ligand B, while weak in affinity, offers a much better starting point for optimization, as improving its binding affinity is more feasible than fixing severe ADME/Tox liabilities.

Output:
1
2025-04-17 11:44:21,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 358.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (53.43). Both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets, which isn't a priority here.

**logP:** Ligand A (1.929) is within the optimal 1-3 range. Ligand B (4.26) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.688 and 0.717), indicating drug-likeness.

**DILI:** Ligand A (17.642) has a significantly lower DILI risk than Ligand B (31.563). This is a major advantage for Ligand A.

**BBB:** This is less crucial for a non-CNS target. Ligand A (83.986) is higher than Ligand B (56.65), but this difference isn't a primary concern.

**Caco-2 Permeability:** Ligand A (-4.938) has a more negative Caco-2 value, indicating *better* permeability than Ligand B (-5.003).

**Aqueous Solubility:** Ligand A (-1.786) has a better solubility score than Ligand B (-3.541). This is important for bioavailability.

**hERG Inhibition:** Ligand A (0.367) has a lower hERG risk than Ligand B (0.598), which is highly desirable.

**Microsomal Clearance:** Ligand A (55.356) has lower microsomal clearance than Ligand B (88.07), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.224) has a shorter half-life than Ligand B (25.674), but both are reasonable.

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux than Ligand B (0.667), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.2), a 0.5 kcal/mol difference. While affinity is a priority, the other ADME properties of Ligand A are significantly better.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A exhibits superior ADME properties: lower DILI risk, better solubility, lower hERG risk, better permeability, lower microsomal clearance, and lower P-gp efflux. These factors collectively outweigh the small difference in binding affinity, making Ligand A a more viable drug candidate for SRC kinase inhibition.

Output:
0
2025-04-17 11:44:21,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 346.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (86.88) is better than Ligand B (92.15), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.545) is optimal, while Ligand B (0.303) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.626 and 0.8), indicating drug-like properties.

**DILI:** Ligand A (37.999) has a significantly lower DILI risk than Ligand B (51.842), which is preferable. Both are below the 60 threshold.

**BBB:** Ligand A (39.162) has a lower BBB penetration than Ligand B (63.474). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.225 and -5.279), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.362 and -1.565), which is also a concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.117 and 0.2). This is excellent.

**Microsomal Clearance:** Ligand A (-8.103) has a much lower (better) microsomal clearance than Ligand B (13.537), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.537) has a better in vitro half-life than Ligand B (23.265).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.011).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). While both are good, the 1.2 kcal/mol difference is significant.

**Conclusion:**

Considering all factors, Ligand A is the more promising candidate. It has a better logP, lower DILI risk, significantly better metabolic stability (lower Cl_mic and better t1/2), and a slightly better binding affinity. While both have issues with Caco-2 and solubility, the superior ADME profile of Ligand A, particularly its metabolic stability, makes it the preferred choice for further development as an SRC kinase inhibitor.

Output:
0
2025-04-17 11:44:21,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.415 and 358.345 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.42) is well below the 140 threshold for good absorption, and favorable. Ligand B (113.33) is still within range, but less optimal.

**logP:** Ligand A (0.475) is a bit low, potentially impacting permeability. Ligand B (0.244) is even lower, raising more concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.693) has a better QED score than Ligand B (0.432), indicating a more drug-like profile.

**DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (50.33), which is a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (83.288) has higher BBB penetration, but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.747 and -4.881) which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without more context.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.943 and -2.947), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.062) has a much lower hERG risk than Ligand B (0.3), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-3.097) has a much lower (better) microsomal clearance than Ligand B (20.409), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.547) has a longer half-life than Ligand B (-1.385), which is also favorable.

**P-gp Efflux:** Ligand A (0.007) has a lower P-gp efflux liability than Ligand B (0.048), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-10.4 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 concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme target. However, it suffers from poorer ADME properties across the board: higher DILI risk, higher hERG risk, higher microsomal clearance, shorter half-life, and higher P-gp efflux. Ligand A has a more favorable ADME profile, but its binding affinity is considerably weaker.

Given the substantial affinity difference, the potential for optimization of Ligand B's ADME properties makes it the more promising candidate. While the solubility and permeability are concerning, these can often be addressed through formulation strategies or further chemical modifications. The stronger binding provides a better starting point for optimization.

Output:
1
2025-04-17 11:44:21,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 354.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (84.65). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Ligand A (3.276) is optimal (1-3), while Ligand B (1.056) is at the lower end. While not terrible, lower logP can sometimes indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 7. Ligand A is preferable here, as excessive HBA can hinder permeability.

**QED:** Both ligands have similar QED values (0.799 and 0.763), indicating good drug-likeness.

**DILI:** Ligand A (18.1) has a much lower DILI risk than Ligand B (61.2). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (93.1) is higher than Ligand A (82.4). However, BBB is less critical for a non-CNS target like SRC kinase.

**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 unknown, making interpretation difficult.

**hERG:** Ligand A (0.409) has a slightly better hERG profile than Ligand B (0.31), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (46.774) has a lower microsomal clearance than Ligand B (48.168), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.222) has a significantly longer in vitro half-life than Ligand B (14.032). This is a major advantage for Ligand A, as it suggests less frequent dosing.

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux than Ligand B (0.031), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-11.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a crucial factor, as a 4.4 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A is clearly superior. It has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and more favorable HBA count. While both have issues with Caco-2 and solubility (scale unknown), the superior potency and safety profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 11:44:21,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.519 Da) is slightly better, being closer to the lower end which can aid permeability. Ligand B (462.46 Da) is still acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (58.64) is preferable to Ligand B (62.3) due to the lower value.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.125) and Ligand B (3.887) are both acceptable, but Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 3, Ligand B: 6) counts.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.827) is better than Ligand B (0.706).

**DILI:** Ligand A (18.147) has a significantly lower DILI risk than Ligand B (82.823). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (90.539) is better than Ligand B (68.282).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability. Ligand A (-4.54) is better than Ligand B (-5.355).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Assuming these are percentile scores, lower values indicate poorer solubility. Ligand A (-3.797) is better than Ligand B (-4.854).

**hERG Inhibition:** Ligand A (0.441) has a lower hERG inhibition liability than Ligand B (0.795), which is favorable.

**Microsomal Clearance:** Ligand A (65.37 mL/min/kg) has a higher microsomal clearance than Ligand B (61.913 mL/min/kg), indicating lower metabolic stability. This is a slight disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (31.928 hours) has a significantly longer in vitro half-life than Ligand A (2.567 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.116) has lower P-gp efflux liability than Ligand B (0.567), which is favorable.

**Binding Affinity:** Ligand B (-7.6 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 has several advantages: lower MW, lower TPSA, better QED, significantly lower DILI risk, lower hERG inhibition, and lower P-gp efflux. Ligand B has a longer half-life and slightly better binding affinity. However, the DILI risk for Ligand B is a major concern. The longer half-life of Ligand B is attractive, but the superior ADME profile of Ligand A, particularly the low DILI risk, makes it the more promising candidate.

Output:
0
2025-04-17 11:44:21,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.459 Da and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.87) is slightly higher than Ligand B (87.47). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (0.964 and 1.3), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have acceptable QED scores (0.797 and 0.683), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.915, which is borderline high. Ligand B has a much lower DILI risk of 28.81, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (50.795) is higher than Ligand A (33.501), but this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.585 and -5.572), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.681 and -2.337), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.417 and 0.331), which is good.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (11.749) than Ligand B (25.769), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (37.683 hours) than Ligand A (-12.903 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.071 and 0.05), which is favorable.

**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 for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B's significantly lower DILI risk, longer half-life, and slightly better binding affinity outweigh the advantages of Ligand A's better metabolic stability. The longer half-life is particularly important for an enzyme target, potentially allowing for less frequent dosing. The DILI risk of Ligand A is concerning.

Output:
1
2025-04-17 11:44:21,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.76 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.24) is well below the 140 threshold, while Ligand B (87.46) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.425) is optimal, while Ligand B (1.097) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.514 and 0.771), indicating drug-like properties.

**DILI:** Ligand A (86.817) has a significantly higher DILI risk than Ligand B (31.175). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (71.539) has a better BBB score than Ligand B (29.236).

**Caco-2 Permeability:** Ligand A (-4.154) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.264) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.208) has very poor solubility, while Ligand B (-1.474) is better, although still not ideal.

**hERG:** Both ligands show low hERG inhibition liability (0.421 and 0.215), which is good.

**Microsomal Clearance:** Ligand A (120.251) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (8.786).

**In vitro Half-Life:** Ligand A (-14.482) has a very short half-life, while Ligand B (13.247) has a longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.291 and 0.059).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Ligand A has a better binding affinity and TPSA, but suffers from very poor solubility, permeability, metabolic stability, and a high DILI risk. Ligand B, while having a slightly lower affinity, presents a much more favorable ADME profile, with lower DILI risk, better solubility, permeability, and metabolic stability. Given the enzyme-specific priorities, metabolic stability and lower toxicity (DILI) are critical. The slightly better binding affinity of Ligand A is not enough to overcome its significant ADME liabilities.

Output:
1
2025-04-17 11:44:21,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.503 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.46 and 79.62) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (1.29) is optimal, while Ligand B (2.56) is also within the acceptable range (1-3).

**H-Bond Donors:** Both ligands have 1 HBD, which is within the ideal range of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.734 and 0.801), indicating good drug-likeness.

**DILI:** Ligand A (35.285) has a slightly better DILI percentile than Ligand B (42.071), both are acceptable (<40 is good).

**BBB:** Both have similar BBB penetration (56.65 and 52.579), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.107) has a worse Caco-2 permeability than Ligand B (-4.59).

**Aqueous Solubility:** Ligand A (-1.392) has slightly better solubility than Ligand B (-2.899).

**hERG:** Both ligands have very low hERG inhibition liability (0.158 and 0.163), which is excellent.

**Microsomal Clearance:** Ligand A (55.223) has higher microsomal clearance than Ligand B (40.171), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (4.463) has a significantly longer in vitro half-life than Ligand A (-3.446), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.094 and 0.157).

**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.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While Ligand A has slightly better solubility and a marginally better binding affinity, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. The difference in metabolic stability is a key factor, as it directly impacts the potential for achieving therapeutic concentrations *in vivo*.

Output:
1
2025-04-17 11:44:21,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.451 and 353.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.7) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (79.72) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.387 and 2.638), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both within acceptable limits. Ligand B has 1 HBD and 8 HBA, also within limits.

**QED:** Both ligands have similar and good QED scores (0.7 and 0.755).

**DILI:** Ligand A (36.022) has a much lower DILI risk than Ligand B (81.621). This is a significant advantage for Ligand A.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**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 (0.106) has a much lower hERG inhibition liability than Ligand B (0.498), a crucial advantage.

**Microsomal Clearance:** Ligand A (27.216) has a significantly lower microsomal clearance than Ligand B (55.557), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.446) has a longer half-life than Ligand B (1.212), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**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 significantly better binding affinity. However, Ligand A demonstrates a much more favorable safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic, longer t1/2). Both have poor solubility and permeability. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The affinity difference, while substantial, might be overcome with further optimization of Ligand A. The poor solubility and permeability are serious issues for both, but could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 11:44:21,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.467 and 350.459 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (50.36) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (76.66) is still under 140, but less optimal than A.

**logP:** Ligand A (4.405) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.385) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is acceptable. Ligand A has 2 HBAs, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.847) has a significantly higher QED score than Ligand B (0.512), indicating a more drug-like profile.

**DILI:** Ligand A (47.383) has a moderate DILI risk, while Ligand B (18.651) has a very low DILI risk, a significant advantage.

**BBB:** Not a primary concern for a kinase inhibitor, but Ligand A (89.066) has better BBB penetration than Ligand B (50.872).

**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, indicating poor aqueous solubility. Ligand B (-2.259) is slightly better than Ligand A (-4.368).

**hERG Inhibition:** Ligand A (0.88) has a higher hERG risk than Ligand B (0.23), which is a crucial consideration.

**Microsomal Clearance:** Ligand A (36.339) has a higher microsomal clearance than Ligand B (13.303), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (47.782) has a longer half-life than Ligand B (9.407), which is preferable.

**P-gp Efflux:** Ligand A (0.474) has lower P-gp efflux than Ligand B (0.04), suggesting better bioavailability.

**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.

**Conclusion:**

Despite Ligand A's higher logP and slightly higher DILI risk, its significantly superior binding affinity (-8.7 vs -7.5 kcal/mol), better QED, longer half-life, and lower P-gp efflux outweigh the drawbacks. The strong binding affinity is particularly important for an enzyme inhibitor. Ligand B has a better safety profile (lower DILI, lower hERG), but the weaker binding makes it less likely to be effective.

Output:
1
2025-04-17 11:44:21,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (362.47 and 377.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is well below the 140 threshold, and excellent for oral absorption. Ligand B (127.59) is still within acceptable limits, but less favorable than A.

**3. logP:** Ligand A (3.295) is optimal. Ligand B (0.268) is quite low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 3 respectively), well below the limit of 5.

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

**6. QED:** Both ligands have good QED scores (0.893 and 0.559), indicating drug-like properties. Ligand A is significantly better.

**7. DILI:** Both ligands have low DILI risk (43.389 and 36.603), both below the 40 threshold.

**8. BBB:** Ligand A (86.894) has a better BBB penetration percentile than Ligand B (56.495), but BBB isn't a high priority for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Ligand A (-4.913) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.479) is similarly poor.

**10. Aqueous Solubility:** Ligand A (-4.211) and Ligand B (-1.72) both have negative solubility values, suggesting very poor solubility.

**11. hERG Inhibition:** Ligand A (0.575) has a low hERG risk. Ligand B (0.189) has an even lower hERG risk, which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (49.803) has a higher clearance than Ligand B (31.223). Lower clearance is preferred for metabolic stability, giving an advantage to Ligand B.

**13. In vitro Half-Life:** Ligand A (0.034) has a very short half-life. Ligand B (-35.912) has a negative half-life, which is not physically possible and indicates a problem with the data.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.22 and 0.016 respectively), which is favorable.

**15. 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 potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A is the better candidate. The significantly stronger binding affinity (-8.2 vs 0.0 kcal/mol) outweighs the slightly higher Cl_mic and the poor permeability/solubility. The negative half-life for Ligand B is a major red flag, suggesting a data error or a highly unstable compound. While Ligand B has a slightly better hERG profile and lower Cl_mic, the lack of binding affinity makes it unlikely to be a viable drug candidate. The poor permeability and solubility of Ligand A could be addressed through formulation strategies or further chemical modifications, but the binding affinity is harder to improve.

Output:
1
2025-04-17 11:44:21,767 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 355.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.01) is better than Ligand B (98.25), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.536 and 2.388), 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 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.805 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A (57.348) has a significantly lower DILI risk than Ligand B (98.992). This is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (54.207) has a higher BBB percentile than Ligand B (39.007).

**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 ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, direct comparison is difficult without knowing the scale.

**hERG Inhibition:** Ligand A (0.404) has a much lower hERG inhibition liability than Ligand B (0.066). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (37.426) has higher microsomal clearance than Ligand B (-0.676). This suggests that Ligand B is more metabolically stable, which is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (18.862) has a significantly longer in vitro half-life than Ligand A (7.987). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.165) has slightly higher P-gp efflux than Ligand B (0.061). Lower P-gp efflux is preferred.

**Binding Affinity:** Ligand B (-10.4 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive factor. The >1.5 kcal/mol advantage easily outweighs the ADME drawbacks.

**Conclusion:**

Despite Ligand A's better DILI and hERG profiles, the significantly stronger binding affinity of Ligand B (-10.4 vs 0.0 kcal/mol) makes it the more promising candidate. The improved metabolic stability (negative Cl_mic) and longer half-life of Ligand B further support this conclusion. While the solubility and permeability are concerning for both, the potency advantage of Ligand B is likely to be more impactful in initial optimization efforts.

Output:
1
2025-04-17 11:44:21,767 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.415 and 358.454 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (67.87), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.24 and 1.531, respectively), 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 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.866) has a significantly better QED score than Ligand B (0.643), indicating a more drug-like profile.

**7. DILI:** Ligand A (37.611) has a slightly higher DILI risk than Ligand B (23.187), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (93.912) has a higher BBB penetration percentile than Ligand A (78.868). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.804) has a lower Caco-2 permeability than Ligand B (-4.585). Both are negative, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.183) has worse solubility than Ligand B (-1.33). Solubility is important for enzyme inhibitors.

**11. hERG Inhibition:** Ligand A (0.243) has a lower hERG inhibition risk than Ligand B (0.564), which is favorable.

**12. Microsomal Clearance:** Ligand A (30.13) has a higher microsomal clearance than Ligand B (21.099), indicating lower metabolic stability. This is a significant drawback.

**13. In vitro Half-Life:** Ligand B (-2.628) has a longer in vitro half-life than Ligand A (6.745), which is desirable.

**14. P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.138), which is slightly better.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a crucial advantage, as a 0.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, a better QED score, and lower hERG risk. However, it suffers from higher microsomal clearance (lower metabolic stability) and lower solubility compared to Ligand B. The substantial affinity difference (-8.2 vs -7.7 kcal/mol) is the most important factor for an enzyme inhibitor. While the metabolic stability and solubility of Ligand A are concerns, these can potentially be addressed through further optimization. The improved affinity is likely to have a greater impact on *in vivo* efficacy.

Output:
0
2025-04-17 11:44:21,767 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (431.302 Da) is slightly higher than Ligand B (352.519 Da), but both are acceptable.

**TPSA:** Ligand A (41.57) is better than Ligand B (49.85) as it is closer to the ideal threshold of <=140 for oral absorption.

**logP:** Both ligands have good logP values (A: 4.164, B: 3.076), falling within the optimal range of 1-3. Ligand A is slightly higher, which *could* present solubility issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A has 1 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 (A: 0.79, B: 0.641), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 61.07, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (13.532), a significant advantage.

**BBB:** Both have good BBB penetration (A: 82.474, B: 86.623), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and need experimental validation.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, these values require experimental validation.

**hERG Inhibition:** Ligand A (0.656) has a slightly higher hERG risk than Ligand B (0.483), but both are relatively low.

**Microsomal Clearance:** Ligand B (73.163) has a lower microsomal clearance than Ligand A (62.936), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (5.65 hours) has a significantly longer half-life than Ligand A (41.696 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.543, B: 0.141), which is good.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). 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 a slightly better binding affinity, Ligand B demonstrates significantly better ADME properties, particularly lower DILI risk and improved metabolic stability (lower Cl_mic and longer t1/2). The lower DILI risk is a crucial advantage, and the improved metabolic stability suggests a potentially longer duration of action. The slightly better affinity of Ligand B is a bonus. The unusual Caco-2 and solubility values for both compounds warrant further investigation, but the ADME profile of Ligand B is superior.

Output:
1
2025-04-17 11:44:21,767 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.295 and 345.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.63) is better than Ligand B (73.91), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.278 and 2.467), 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) as it has fewer HBDs, which can be beneficial for permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.668 and 0.756), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (36.758 and 39.667), well below the concerning threshold of 60.

**BBB:** Ligand A (70.997) has a better BBB percentile than Ligand B (66.382), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.428 and -5.346), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.678 and -2.838), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.714 and 0.736), which is excellent.

**Microsomal Clearance:** Ligand A (11.37 mL/min/kg) has significantly lower microsomal clearance than Ligand B (18.659 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.819 hours) has a much longer half-life than Ligand B (-12.543 hours). 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 (0.231 and 0.065), which is favorable.

**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, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the superior candidate. Its significantly stronger binding affinity (-9.5 vs -7.9 kcal/mol) is a major advantage that can potentially offset the poor solubility and permeability. Furthermore, Ligand A demonstrates better metabolic stability (lower Cl_mic and longer t1/2) and a slightly better BBB profile. While both ligands have problematic solubility and permeability, the much stronger binding affinity of Ligand A makes it the more promising starting point for further optimization.

Output:
0
2025-04-17 11:44:21,767 - INFO - Batch 72 complete. Total preferences: 1152
2025-04-17 11:44:21,767 - INFO - Processing batch 73/512...
2025-04-17 11:45:10,714 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (133.56) is borderline acceptable for oral absorption, while Ligand B (54.46) is excellent.

**logP:** Ligand A (-0.62) is a bit low, potentially hindering permeation. Ligand B (2.8) is optimal.

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

**H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (A: 0.54, B: 0.867), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (41.45) has a moderate DILI risk, while Ligand B (27.336) has a low DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.566) is lower, and Ligand B (91.896) is high.

**Caco-2 Permeability:** Ligand A (-5.453) is poor, and Ligand B (-4.493) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.204 and -2.895 respectively).

**hERG Inhibition:** Ligand A (0.056) has very low hERG risk, which is excellent. Ligand B (0.561) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-9.104) indicates very low clearance and excellent metabolic stability. Ligand B (33.643) has a much higher clearance, suggesting poorer metabolic stability.

**In vitro Half-Life:** Ligand A (-10.572) indicates a very long half-life, which is excellent. Ligand B (33.644) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is good. Ligand B (0.265) has a slightly higher P-gp efflux.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). The difference of 0.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has superior metabolic stability and lower hERG risk, the significantly stronger binding affinity of Ligand B (-7.8 vs -8.7 kcal/mol) is a major advantage for an enzyme target like SRC. Ligand B also has a better logP, QED, and DILI score. The slightly higher clearance of Ligand B could be addressed through structural modifications during lead optimization. The poor Caco-2 and solubility of both compounds would need to be addressed.

Output:
1
2025-04-17 11:45:10,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (357.303 and 342.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (42.68) is well below the 140 threshold and excellent for oral absorption. Ligand B (59.07) is still acceptable, but less optimal.

**3. logP:** Both ligands (4.525 and 4.315) are slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects. However, this isn't a deal-breaker, especially if potency is high.

**4. H-Bond Donors:** Ligand A (0) is excellent, minimizing potential permeability issues. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands (0.714 and 0.748) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (62.35) has a moderate DILI risk, while Ligand B (41.334) has a lower risk. This favors Ligand B.

**8. BBB:** Both have high BBB penetration (92.439 and 95.89), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-3.903) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.58) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.877 and -5.614). This is a major concern for both compounds, potentially hindering bioavailability.

**11. hERG Inhibition:** Ligand A (0.544) has a slightly higher hERG risk than Ligand B (0.944), favoring Ligand B.

**12. Microsomal Clearance:** Ligand A (59.504) has a better microsomal clearance than Ligand B (96.768), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (53.786) has a significantly longer in vitro half-life than Ligand A (31.141), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.215 and 0.284), which is good.

**15. 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 many ADME drawbacks.

**Overall Assessment:**

Ligand A's superior binding affinity (-8.6 kcal/mol) and better metabolic stability (lower Cl_mic) are major advantages. However, its poor Caco-2 permeability and moderate DILI risk are concerning. Ligand B has a better safety profile (lower DILI, hERG) and longer half-life, but its weaker binding affinity is a significant disadvantage.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is the most critical factor. While the solubility and permeability issues need to be addressed through formulation or further chemical modifications, the potency advantage is likely to be more impactful in the initial stages of drug development.

Output:
1
2025-04-17 11:45:10,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (334.423 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (58.43 and 58.64) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.892 and 2.738) 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 QED scores (0.758 and 0.616) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.203, which is moderately high. Ligand B has a significantly lower DILI risk of 11.128, which is excellent. This is a major advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (54.866 and 61.884). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.312) has poor Caco-2 permeability, while Ligand B (-4.588) is slightly better, but still poor. Both are concerning.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.272 and -2.595). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.846) has a slightly higher hERG inhibition risk than Ligand B (0.46), though both are relatively low.

**Microsomal Clearance:** Ligand A has a significantly lower (better) microsomal clearance (-7.385) compared to Ligand B (31.333). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (75.818 hours) than Ligand B (17.328 hours). This is a strong advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.537) has lower P-gp efflux than Ligand B (0.087), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.7 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability, half-life, and P-gp efflux, the significantly lower DILI risk of Ligand B is a crucial advantage. The stronger binding affinity of Ligand B (-8.4 vs -7.7 kcal/mol) further tips the balance. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. Given the enzyme-kinase target class, prioritizing potency and minimizing toxicity (DILI) is key.

Output:
1
2025-04-17 11:45:10,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.547 and 361.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is well below the 140 threshold, and favorable for absorption. Ligand B (113.08) is still under 140, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (4.774) is slightly high, potentially leading to solubility issues or off-target effects, but not drastically so. Ligand B (-0.33) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (4 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Ligand A (0.725) has a better QED score than Ligand B (0.537), indicating a more drug-like profile.

**DILI:** Ligand B (65.452) has a significantly higher DILI risk than Ligand A (11.361). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.743) shows better BBB penetration than Ligand B (24.738), but it's not a primary factor here.

**Caco-2 Permeability:** Ligand A (-4.549) has poor Caco-2 permeability. Ligand B (-5.818) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.871) has slightly better solubility than Ligand B (-2.293), but both are quite poor.

**hERG Inhibition:** Ligand A (0.771) has a much lower hERG risk than Ligand B (0.166). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (66.366) has higher clearance than Ligand B (-1.929). Ligand B exhibits negative clearance, which is not physically possible and indicates an issue with the data or model. Assuming the negative value is an error, it suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (3.744 hours) has a shorter half-life than Ligand B (44.552 hours). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.188) has lower P-gp efflux than Ligand B (0.009), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-11.3 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.

**Conclusion:**

Despite Ligand B's superior binding affinity, its very low logP, poor solubility, high DILI risk, and the questionable negative clearance are major red flags. While the strong binding is attractive, the poor ADME profile makes it a less viable candidate. Ligand A has issues with solubility and permeability, and a shorter half-life, but its lower DILI risk, better hERG profile, and more reasonable ADME properties make it the more promising candidate, even with the weaker binding affinity. The negative clearance for Ligand B is also a data quality concern.

Output:
0
2025-04-17 11:45:10,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.438 and 356.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.02) is well below the 140 threshold for good oral absorption, and even favorable for potential CNS penetration. Ligand B (90.98) is still within acceptable limits, but less optimal than A.

**3. logP:** Ligand A (1.91) is within the optimal 1-3 range. Ligand B (0.138) is quite low, potentially hindering 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 5 HBA, both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.752) has a significantly better QED score than Ligand B (0.429), indicating a more drug-like profile.

**7. DILI:** Ligand A (28.538) has a much lower DILI risk than Ligand B (18.651), indicating better predicted liver safety.

**8. BBB:** Ligand A (75.378) shows good BBB penetration potential, while Ligand B (63.862) is lower. Though not a primary concern for a kinase inhibitor, it's a positive attribute for A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.122 and -5.173), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.182 and -0.851), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.393) has a lower hERG risk than Ligand B (0.13), which is preferable.

**12. Microsomal Clearance:** Ligand A (11.48) has a lower microsomal clearance than Ligand B (22.737), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.548) has a shorter half-life than Ligand B (-4.905), but the negative value for B is suspect.

**14. P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux than Ligand B (0.002), suggesting better bioavailability.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.2). While both are good, the 1.8 kcal/mol difference is significant.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the superior candidate. It has a better QED score, lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, slightly better binding affinity, and a more favorable hERG profile. The lower logP of Ligand B is a significant concern, potentially leading to poor absorption. The negative solubility and Caco-2 values for both compounds indicate that significant formulation work would be needed to improve their drug-like properties. However, given the priorities for kinase inhibitors, the better ADME/Tox profile and slightly improved potency of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 11:45:10,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.471 and 385.936 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.55) is excellent, well below the 140 threshold for oral absorption. Ligand B (38.13) is also good.

**logP:** Ligand A (1.677) is optimal. Ligand B (4.545) is slightly high, potentially leading to solubility issues and off-target effects, but still within a manageable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, fitting the guidelines. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.614 and 0.563), indicating good drug-like properties.

**DILI:** Ligand A (58.55) has a moderate DILI risk, while Ligand B (34.703) has a lower, more favorable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (89.88) has a higher BBB score than Ligand A (61.846), but this is not a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.638) and Ligand B (-4.987) 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 (-2.715 and -4.017), indicating poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.16) has a very low hERG risk, which is excellent. Ligand B (0.819) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (54.015) has a moderate clearance, while Ligand B (83.788) has a higher clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-33.224) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (44.98) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.191) has low P-gp efflux liability, which is good. Ligand B (0.834) has a slightly higher P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and questionable Caco-2 values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.8 vs -7.1 kcal/mol) is a major advantage for an enzyme target like SRC kinase. While Ligand B has a higher logP and clearance, the lower DILI risk and acceptable hERG inhibition make it preferable. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 11:45:10,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.354 and 361.829 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.19) is better than Ligand B (84.22), both are under the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.941 and 3.372), falling within the 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

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

**QED:** Both ligands have high QED scores (0.808 and 0.826), indicating good drug-likeness.

**DILI:** Both ligands have high DILI risk (87.049 and 84.917), which is a concern. However, this is a predictive value and needs further investigation.

**BBB:** Ligand A (48.042) has a slightly better BBB penetration percentile than Ligand B (18.147), but neither is particularly high, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.384) has a worse Caco-2 permeability score than Ligand B (-4.96).

**Aqueous Solubility:** Ligand A (-6.079) has a worse solubility score than Ligand B (-4.05).

**hERG Inhibition:** Ligand A (0.592) has a lower hERG inhibition risk than Ligand B (0.01), which is a significant advantage.

**Microsomal Clearance:** Ligand A (58.887) has a higher microsomal clearance than Ligand B (23.757), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (57.555) has a longer in vitro half-life than Ligand B (-1.301), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.571) has lower P-gp efflux liability than Ligand B (0.03), which is favorable.

**Binding Affinity:** Ligand B (-7.3) has a stronger binding affinity than Ligand A (-8.0). While A is more negative, the difference is small and B has better ADME properties.

**Overall Assessment:**

Ligand B demonstrates a better balance of properties. While both have high DILI risk, Ligand B has better solubility, Caco-2 permeability, and a significantly better microsomal clearance, suggesting improved metabolic stability. The slightly stronger binding affinity of Ligand B is a bonus. Ligand A has a better hERG profile and P-gp efflux, but the poorer metabolic stability is a major concern for an enzyme inhibitor.

Output:
1
2025-04-17 11:45:10,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.65) is higher than Ligand B (49.85). Both are acceptable, but Ligand B is better, potentially indicating improved cell permeability.

**logP:** Ligand A (0.265) is quite low, potentially hindering membrane permeability. Ligand B (1.782) 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 (5) is good. Ligand B (4) is also good.

**QED:** Both ligands have acceptable QED values (0.613 and 0.551, respectively), suggesting reasonable drug-likeness.

**DILI:** Ligand A (32.959) has a slightly higher DILI risk than Ligand B (23.381), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.705) has a higher BBB percentile than Ligand A (58.782), but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.913 and -4.852). This is unusual and suggests a potential issue with the experimental setup or the compounds themselves. It's hard to interpret without further information, but it doesn't strongly favor either.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.01 and -2.623). Similar to Caco-2, this is concerning and requires further investigation. Ligand B appears slightly worse in this regard.

**hERG Inhibition:** Ligand A (0.071) has a very low hERG risk, a significant advantage. Ligand B (0.366) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (10.736) has lower microsomal clearance than Ligand B (52.283), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-12.362) has a longer in vitro half-life than Ligand B (-17.038), which is another positive point for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.017 and 0.108, respectively), which is good.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is small (0.6 kcal/mol) and may not be enough to overcome other deficiencies.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and hERG risk, which are critical for enzyme inhibitors. However, its low logP is a significant concern for permeability. Ligand B has a better logP and TPSA, but suffers from higher metabolic clearance and a slightly lower binding affinity. Given the importance of metabolic stability for an enzyme target like SRC kinase, and the relatively small difference in binding affinity, Ligand A appears to be the more promising candidate, *assuming* the solubility and permeability issues can be addressed through formulation or further chemical modifications.

Output:
0
2025-04-17 11:45:10,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (352.475 and 354.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is slightly above the optimal <140 for good oral absorption, but still reasonable. Ligand B (56.33) is well within the acceptable range.

**3. logP:** Ligand A (1.749) is within the optimal 1-3 range. Ligand B (-0.177) 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 (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 scores (0.507 and 0.575, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (19.504) has a very low DILI risk, which is excellent. Ligand B (5.739) also has a low DILI risk.

**8. BBB:** Both ligands have reasonable BBB penetration (78.868 and 65.839), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a major concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.374 and -4.735), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.075 and -0.01), which is also unusual and suggests poor solubility. This is a significant concern.

**11. hERG Inhibition:** Ligand A (0.244) has a very low hERG risk, which is excellent. Ligand B (0.499) also has a low hERG risk.

**12. Microsomal Clearance:** Ligand A (65.353) has moderate clearance. Ligand B (20.089) has low clearance, indicating better metabolic stability, which is a priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (0.226) has a very short half-life. Ligand B (-12.742) has a negative half-life, which is impossible and indicates a data issue.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.003).

**15. 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.

**Overall Assessment:**

Both ligands have significant issues with predicted permeability and solubility. However, Ligand B has a much stronger binding affinity, significantly lower microsomal clearance (better metabolic stability), and a lower P-gp efflux. While the negative half-life for Ligand B is a data quality concern, the substantial affinity advantage makes it more promising *if* the half-life data can be corrected or further investigated. The low DILI and hERG risks for both are positive. Given the priority for potency in kinase inhibitors, and the substantial difference in affinity, I would choose Ligand B.

Output:
1
2025-04-17 11:45:10,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.447 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.23) is slightly above the preferred <90 for CNS, but acceptable. Ligand B (80.48) is well within the range.

**logP:** Both ligands (1.057 and 1.57) are 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:** Ligand A (5) and Ligand B (6) are both acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.792 and 0.807), indicating drug-likeness.

**DILI:** Ligand A (24.351) has a significantly lower DILI risk than Ligand B (38.813), which is a major advantage. Both are below the concerning threshold of 60.

**BBB:** Ligand A (36.487) has a lower BBB penetration score than Ligand B (64.211). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.682 and -4.848), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.652 and -1.891), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.179 and 0.128), which is excellent.

**Microsomal Clearance:** Ligand A (7.495) has a significantly lower microsomal clearance than Ligand B (27.521), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (13.489) has a longer half-life than Ligand B (-9.55), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.154), which is favorable.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The slightly weaker binding affinity of Ligand A is outweighed by these more critical ADME/Tox advantages for an enzyme target like SRC kinase. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the starting point is better with Ligand A.

Output:
0
2025-04-17 11:45:10,717 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [382.408, 87.46, 0.543, 2, 6, 0.577, 29.159, 57.425, -5.381, -1.553, 0.338, 12.042, -14.605, 0.023, -8.2]
**Ligand B:** [429.424, 49.41, 4.86, 1, 3, 0.727, 54.75, 83.482, -5.021, -6.075, 0.862, 95.829, 11.337, 0.585, -9]

**Step-by-step comparison:**

1. **MW:** Ligand A (382.408 Da) is within the ideal range (200-500). Ligand B (429.424 Da) is also acceptable, but closer to the upper limit.
2. **TPSA:** Ligand A (87.46) is good, under the 140 threshold for oral absorption. Ligand B (49.41) is excellent, well below 140.
3. **logP:** Ligand A (0.543) is a bit low, potentially hindering permeability. Ligand B (4.86) is high and could cause solubility or off-target issues.
4. **HBD:** Ligand A (2) is good. Ligand B (1) is also good.
5. **HBA:** Ligand A (6) is good. Ligand B (3) is also good.
6. **QED:** Ligand A (0.577) is acceptable. Ligand B (0.727) is better, indicating a more drug-like profile.
7. **DILI:** Ligand A (29.159) is very good, low risk. Ligand B (54.75) is moderate, slightly higher risk.
8. **BBB:** Ligand A (57.425) is moderate. Ligand B (83.482) is good, but SRC is not a CNS target, so this is less important.
9. **Caco-2:** Both ligands have negative Caco-2 values (-5.381 and -5.021). This is unusual and suggests poor permeability *in vitro*. However, these values are on a log scale and can be misleading.
10. **Solubility:** Both ligands have negative solubility values (-1.553 and -6.075). Again, this is unusual and suggests poor aqueous solubility.
11. **hERG:** Ligand A (0.338) is very good, low risk. Ligand B (0.862) is moderate, slightly higher risk.
12. **Cl_mic:** Ligand A (12.042) is relatively low, suggesting good metabolic stability. Ligand B (95.829) is very high, indicating rapid metabolism.
13. **t1/2:** Ligand A (-14.605) is very negative, indicating very short half-life. Ligand B (11.337) is positive, indicating a longer half-life.
14. **Pgp:** Ligand A (0.023) is very low, suggesting minimal efflux. Ligand B (0.585) is moderate.
15. **Affinity:** Ligand A (-8.2) is significantly better than Ligand B (-9). This is a substantial difference in binding potency.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, we prioritize potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Conclusion:**

Despite the unusual negative Caco-2 and solubility values, **Ligand A** is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -9 kcal/mol) is a major advantage, and it has a much better DILI score and hERG risk profile. While Ligand A has a shorter half-life and lower metabolic stability than Ligand B, the potency difference is substantial enough to outweigh these drawbacks, especially considering optimization can address metabolic stability. The poor solubility and permeability indicated by the negative values are concerning, but could be addressed through formulation strategies or further structural modifications. Ligand B's high metabolic clearance is a significant negative.

1
2025-04-17 11:45:10,718 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (380.46 and 348.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is higher than Ligand B (58.2). Both are acceptable, but Ligand B is better for oral absorption.

**logP:** Ligand A (0.878) is slightly low, potentially hindering permeation. Ligand B (3.982) is near the upper limit but still acceptable.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the ideal range.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 2. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.654 and 0.652), indicating good drug-likeness.

**DILI:** Ligand A (34.55) has a slightly higher DILI risk than Ligand B (19.70), but both are below the concerning threshold of 60.

**BBB:** Ligand A (53.66) has a lower BBB penetration percentile than Ligand B (69.41). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.086) has a negative Caco-2 value, which is concerning. Ligand B (-4.549) is also negative, but less so. Both indicate poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.12) has better aqueous solubility than Ligand B (-4.309). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.435 and 0.403), which is good.

**Microsomal Clearance:** Ligand A (6.01) has significantly lower microsomal clearance than Ligand B (65.54). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-1.91) has a negative half-life, which is concerning. Ligand B (12.50) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.116 and 0.114).

**Binding Affinity:** Ligand A (-9.1) has a significantly stronger binding affinity than Ligand B (-8.5). This difference of 0.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's negative Caco-2 and half-life values, its significantly superior binding affinity (-9.1 vs -8.5 kcal/mol) and lower microsomal clearance are compelling advantages for an enzyme target like SRC kinase. The improved solubility also helps. While the Caco-2 and half-life are concerning, these could potentially be addressed through formulation strategies or further chemical modifications. Ligand B, while having better Caco-2 and half-life, doesn't have the same potency advantage.

Output:
1
2025-04-17 11:45:10,718 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (360.483 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.53) is better than Ligand B (98.32). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred threshold for oral absorption.

**3. logP:** Both ligands have good logP values (1.478 and 1.028), 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). Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.88) is significantly better than Ligand B (0.641), indicating a more drug-like profile.

**7. DILI:** Ligand A (57.27) has a higher DILI risk than Ligand B (34.82). This is a concern for Ligand A, but not prohibitive.

**8. BBB:** Both ligands have moderate BBB penetration, with Ligand A (73.129) being slightly better than Ligand B (64.676). BBB is not a primary concern for SRC kinase inhibitors unless CNS off-target effects are a worry.

**9. Caco-2 Permeability:** Ligand A (-5.242) is significantly better than Ligand B (-4.935). Higher Caco-2 permeability suggests better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.838) is better than Ligand B (-2.491). Better solubility is preferred for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.278 and 0.427). This is excellent.

**12. Microsomal Clearance:** Ligand A (8.574) has significantly lower microsomal clearance than Ligand B (21.187). This indicates better metabolic stability for Ligand A, a key factor for enzymes.

**13. In vitro Half-Life:** Ligand A (-10.219) has a much longer in vitro half-life than Ligand B (24.038). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.041 and 0.182).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.6 kcal/mol). Ligand B is slightly more potent. However, the difference is small and can be potentially overcome by the better ADME properties of Ligand A.

**Overall Assessment:**

While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic), longer half-life, better solubility, and a more favorable QED score. The DILI risk is slightly higher for Ligand A, but the other advantages outweigh this concern. Given the enzyme-kinase focus, metabolic stability and half-life are crucial, making Ligand A the more promising candidate.

Output:
0
2025-04-17 11:45:10,718 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.776 Da) is slightly higher than Ligand B (354.466 Da), but both are acceptable.

**TPSA:** Ligand A (85.46) is slightly higher than Ligand B (58.64). Both are below 140, suitable for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (A: 3.418, B: 2.439), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 5, B: 3) counts, satisfying the <5 and <10 rules respectively.

**QED:** Both ligands have good QED scores (A: 0.756, B: 0.764), indicating good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (85.537%), placing it well above the 60% threshold. Ligand B has a very low DILI risk (8.453%), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (92.012%) is higher than Ligand A (74.564%).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.435 and -4.479), which is unusual and suggests poor permeability. This is a drawback for both, but needs further investigation (negative values can sometimes be artifacts of the prediction method).

**Aqueous Solubility:** Both have negative solubility values (-4.447 and -2.182), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.291) has a slightly higher hERG risk than Ligand B (0.578), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand B (25.983) has significantly lower microsomal clearance than Ligand A (82.919), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-2.849) has a negative half-life, which is not physically possible and suggests a prediction error. Ligand A (57.615) has a reasonable half-life. However, the negative value for B is a major red flag.

**P-gp Efflux:** Ligand A (0.551) has slightly lower P-gp efflux than Ligand B (0.047), which is favorable.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), but the difference is relatively small (0.3 kcal/mol) and may not be decisive.

**Conclusion:**

Despite Ligand A having slightly better binding affinity and P-gp efflux, Ligand B is the far superior candidate. The extremely high DILI risk associated with Ligand A is a major concern, and its higher microsomal clearance suggests poorer metabolic stability. The negative half-life prediction for Ligand B is concerning, but the other favorable properties, particularly the low DILI risk and low Cl_mic, outweigh this issue. The solubility and Caco-2 permeability issues are present in both and would need to be addressed through formulation or structural modification, but the ADME profile of Ligand B is significantly more promising.

Output:
1
2025-04-17 11:45:10,719 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.427 and 356.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (120.91 and 129.56) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration.

**logP:** Ligand A (0.832) is within the optimal 1-3 range. Ligand B (-2.151) is below 1, which might impede permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3, respectively), below the threshold of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (7 each), below the threshold of 10.

**QED:** Ligand A (0.749) has a better QED score than Ligand B (0.455), indicating a more drug-like profile.

**DILI:** Both ligands have DILI risk around 60-67%, which is moderately high.

**BBB:** Ligand A (48%) has a slightly better BBB penetration score than Ligand B (14%), but neither are particularly high, which isn't critical for a non-CNS target like SRC.

**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, making interpretation difficult.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.475 and 0.133, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (15.127 mL/min/kg) has a higher microsomal clearance than Ligand B (1.517 mL/min/kg). This suggests Ligand B has better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.308 hours) has a slightly better in vitro half-life than Ligand A (-10.011 hours), but both are negative, which is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.008, respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-9 and -8 kcal/mol respectively), with Ligand A being slightly better. The 1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a better QED score, slightly better binding affinity, and a better BBB score, but worse metabolic stability (higher Cl_mic) and in vitro half-life. Ligand B has better metabolic stability and half-life, but a lower QED score and a logP that could hinder permeability. Given the importance of potency and metabolic stability for kinase inhibitors, and the fact that the binding affinity difference is substantial, Ligand A is the more promising candidate despite its slightly lower metabolic stability. The negative solubility and Caco-2 values are concerning for both, and would need further investigation.

Output:
1
2025-04-17 11:45:10,719 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.334 and 355.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (70.67), falling well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.757 and 1.931), 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 it has fewer hydrogen bond forming groups, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.723 and 0.663), indicating good drug-likeness.

**DILI:** Ligand A (35.285) has a much lower DILI risk than Ligand B (5.312), a significant advantage.

**BBB:** While not critical for a non-CNS target like SRC, Ligand A (92.943) shows better BBB penetration than Ligand B (73.129).

**Caco-2 Permeability:** Ligand A (-4.583) has a slightly better (less negative) Caco-2 value than Ligand B (-4.826), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.761 and -2.198). This is a concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.614 and 0.563), which is good.

**Microsomal Clearance:** Ligand A (1.833) has a significantly lower microsomal clearance than Ligand B (27.454), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-17.974) has a much longer in vitro half-life than Ligand B (-6.669), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.087 and 0.028).

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-8.3). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**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: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. The poor solubility is a concern for both, but can be addressed through formulation strategies. Given the enzyme-kinase target class, metabolic stability and safety (DILI) are paramount, making Ligand A the preferred choice.

Output:
0
2025-04-17 11:45:10,719 - INFO - Batch 73 complete. Total preferences: 1168
2025-04-17 11:45:10,719 - INFO - Processing batch 74/512...
2025-04-17 11:45:52,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 and 384.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (96.17) is still under 140, but less optimal than A.

**logP:** Both ligands (0.999 and 1.391) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 9 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands (0.783 and 0.752) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (30.63) has a significantly lower DILI risk than Ligand B (69.14), which is approaching a concerning level.

**BBB:** Both have similar BBB penetration (76.19 and 71.89), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.821) has a better (more negative) Caco-2 value than Ligand B (-5.761), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.322) has better aqueous solubility than Ligand B (-2.7).

**hERG Inhibition:** Ligand A (0.752) has a lower hERG risk than Ligand B (0.056), which is a significant advantage.

**Microsomal Clearance:** Ligand A (33.92) has a higher (worse) microsomal clearance than Ligand B (23.01). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (5.467) has a slightly longer half-life than Ligand B (6.626).

**P-gp Efflux:** Ligand A (0.146) has lower P-gp efflux than Ligand B (0.091), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.3 kcal/mol difference, which is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better solubility, lower hERG inhibition, and better Caco-2 permeability. While Ligand B has slightly better metabolic stability and binding affinity, the improvements in ADME-Tox properties with Ligand A are more critical for a viable drug candidate, especially considering the enzyme class. The small difference in binding affinity (0.3 kcal/mol) can likely be optimized in subsequent iterations of drug design.

Output:
0
2025-04-17 11:45:52,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.435 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.45) is well below the 140 threshold and favorable for oral absorption. Ligand B (100.35) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.718) is within the optimal 1-3 range. Ligand B (0.349) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is excellent. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Ligand A (0.85) has a very strong drug-like profile. Ligand B (0.469) is below the desirable 0.5 threshold, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (68.903) has a moderate DILI risk, but still acceptable. Ligand B (37.844) has a significantly lower DILI risk, which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (74.758) is higher than Ligand B (34.742), but this is less critical.

**Caco-2 Permeability:** Ligand A (-4.443) is poor. Ligand B (-5.376) is even worse, suggesting poor intestinal absorption for both.

**Aqueous Solubility:** Ligand A (-4.556) is poor. Ligand B (-1.285) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.699) has a low hERG risk, which is very favorable. Ligand B (0.091) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (56.094) is moderate. Ligand B (13.271) is very low, indicating excellent metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-11.222) suggests a very short half-life. Ligand B (-6.383) is better, but still relatively short.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.187 and 0.017 respectively).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is not substantial enough to outweigh the other significant ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has a superior QED score, better TPSA, and a slightly better binding affinity. While its solubility and permeability are poor, its metabolic stability is moderate and hERG risk is low. Ligand B has better metabolic stability and lower DILI, but suffers from a significantly lower QED, poor permeability, and a low logP which can hinder absorption. Given the priority on potency, metabolic stability, solubility, and hERG risk for kinase inhibitors, and considering the relatively small difference in binding affinity, Ligand A is the more promising candidate. The poor permeability and solubility of both compounds would need to be addressed in further optimization, but Ligand A's overall profile is more favorable as a starting point.

Output:
0
2025-04-17 11:45:52,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.5 and 351.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is well below the 140 threshold for good absorption, while Ligand B (137.39) is approaching the limit, but still acceptable.

**logP:** Ligand A (1.399) is within the optimal 1-3 range. Ligand B (-0.428) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Both have 4 HBA and a reasonable number of HBDs (2 for A, 4 for B), staying within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.708 and 0.505, respectively), indicating good drug-like properties.

**DILI:** Ligand A (13.571) has a significantly lower DILI risk than Ligand B (36.099), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (56.65) shows slightly better BBB penetration than Ligand A (40.675).

**Caco-2 Permeability:** Ligand A (-4.771) has a negative Caco-2 value, which is concerning. Ligand B (-5.787) is also negative, but slightly worse. This suggests poor intestinal absorption for both, but A is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.02 and -1.891). This is a significant drawback that would require formulation strategies.

**hERG Inhibition:** Ligand A (0.279) has a much lower hERG risk than Ligand B (0.109), which is a critical safety parameter.

**Microsomal Clearance:** Ligand A (38.208) has higher microsomal clearance than Ligand B (-6.908), meaning Ligand B is more metabolically stable. This is a key advantage for B.

**In vitro Half-Life:** Ligand B (5.811) has a longer half-life than Ligand A (2.942), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.013), which is good.

**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 other issues.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI and hERG risk. However, its poor Caco-2 permeability and higher metabolic clearance are significant drawbacks. Ligand B, while having slightly weaker affinity, exhibits superior metabolic stability (lower Cl_mic, longer t1/2), and a lower DILI score. The solubility is poor for both, but can be addressed with formulation. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 11:45:52,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.76 and 360.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.48) is higher than Ligand B (58.64). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have similar logP values (2.51 and 2.45), 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. Ligand B is preferable here, as fewer HBA generally improves permeability.

**QED:** Both ligands have acceptable QED scores (0.61 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (99.81%), which is a major red flag. Ligand B has a much lower, and acceptable, DILI risk (35.75%).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (90.07) than Ligand A (50.52), but this is not a deciding factor.

**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, Ligand B (-4.29) is slightly better than Ligand A (-5.07).

**Aqueous Solubility:** Both have negative solubility values, indicating poor predicted solubility. Ligand B (-2.98) is slightly better than Ligand A (-4.69).

**hERG:** Both ligands have low hERG inhibition risk (0.54 and 0.61), which is good.

**Microsomal Clearance:** Ligand A (58.43) has higher microsomal clearance than Ligand B (37.26), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life ( -23.00 hours) than Ligand A (31.62 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.15 and 0.11).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a crucial advantage, as a 1.3 kcal/mol difference can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have some ADME concerns (negative Caco-2 and solubility), Ligand B demonstrates a much better safety profile (significantly lower DILI risk), better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a substantially stronger binding affinity. The high DILI risk associated with Ligand A is a major disqualifier.

Output:
1
2025-04-17 11:45:52,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.467 and 355.395 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.98) is better than Ligand B (118.81). TPSA < 140 is good for oral absorption, and both are within this range, but A is closer to the ideal for good permeability.

**logP:** Both ligands (-0.413 and -0.758) are slightly below the optimal 1-3 range, which could potentially impact permeability. However, they aren't drastically low.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 8. Both are within the acceptable limit of <=10, but A is preferable.

**QED:** Both ligands have good QED scores (0.586 and 0.617), indicating good drug-like properties.

**DILI:** Ligand B (63.358) has a significantly higher DILI risk than Ligand A (13.3). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.466) is better than Ligand B (40.52).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.217 and -5.169), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.688 and -1.422), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.094 and 0.046), which is excellent.

**Microsomal Clearance:** Ligand A (1.599) has significantly lower microsomal clearance than Ligand B (15.323). This indicates better metabolic stability for Ligand A, a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand A (-13.351) has a much longer in vitro half-life than Ligand B (-3.839), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.004 and 0.031).

**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 enough to outweigh other significant differences.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have issues with Caco-2 permeability and solubility, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. These are critical advantages for an enzyme inhibitor. The slightly better TPSA and HBA count also contribute to its favorability.



Output:
0
2025-04-17 11:45:52,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.447 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands (2.624 and 2.735) are within the optimal 1-3 range.

**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.

**QED:** Both ligands have good QED scores (0.907 and 0.848), indicating good drug-like properties.

**DILI:** Ligand A (32.997) has a slightly higher DILI risk than Ligand B (19.426), but both are below the concerning threshold of 60.

**BBB:** Both have high BBB penetration (86.661 and 84.141), which isn't critical for a non-CNS target like SRC, but doesn't hurt.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.45 and -4.562), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-2.127 and -3.833), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both have low hERG inhibition risk (0.253 and 0.386).

**Microsomal Clearance:** Ligand B (59.636) has higher microsomal clearance than Ligand A (43.798), suggesting lower metabolic stability. This is a negative for Ligand B.

**In vitro Half-Life:** Ligand A (-8.466) has a slightly longer in vitro half-life than Ligand B (-5.829).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.045 and 0.092).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -8.9 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Both compounds have significant solubility and permeability issues (negative Caco-2 and solubility values). However, their binding affinities are excellent. Considering the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) is crucial. Ligand A has better metabolic stability (lower Cl_mic and longer t1/2) and slightly better binding affinity, despite its slightly higher DILI risk. The solubility issues are a major concern for both, but can potentially be addressed through formulation strategies. Given the superior metabolic stability and affinity, Ligand A is the slightly more promising candidate.

Output:
0
2025-04-17 11:45:52,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.447 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (119.39 and 104.7) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.833) is slightly low, potentially hindering permeation. Ligand B (1.162) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (7) and Ligand B (5) are both below the 10 limit.

**QED:** Both ligands have good QED scores (0.644 and 0.701), indicating drug-likeness.

**DILI:** Ligand A (62.233) has a slightly higher DILI risk than Ligand B (51.144), but both are acceptable (<60 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (48.895) and Ligand B (36.72) are both low.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.342 and -5.607).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.765 and -1.917). This is a significant concern.

**hERG Inhibition:** Ligand A (0.117) has a slightly lower hERG risk than Ligand B (0.454), which is preferred.

**Microsomal Clearance:** Ligand B (-7.928) has significantly lower (better) microsomal clearance than Ligand A (6.787), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.662) has a much longer in vitro half-life than Ligand A (45.599), a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.014 and 0.036).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.6 and -8.4 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to be a deciding factor.

**Conclusion:**

While both compounds have good binding affinity and acceptable QED, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better logP. Although both have poor solubility and Caco-2 permeability, the improved pharmacokinetic properties of Ligand B outweigh the slightly higher DILI and hERG risk.

Output:
1
2025-04-17 11:45:52,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (384.234 and 372.774 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (47.56) is better than Ligand B (55.17), both are acceptable but A is closer to the <140 threshold for good oral absorption.

**3. logP:** Both ligands have similar logP values (4.785 and 4.988), slightly above the optimal range of 1-3, but not drastically so. 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:** Both have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.825) has a significantly better QED score than Ligand B (0.574), indicating a more drug-like profile.

**7. DILI:** Ligand A (80.535) has a higher DILI risk than Ligand B (47.15). This is a significant drawback for Ligand A.

**8. BBB:** Both have good BBB penetration (75.107 and 65.374), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.384 and -4.939) which is unusual and indicates very poor permeability.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-5.798 and -5.018). This is a major concern for both compounds.

**11. hERG Inhibition:** Ligand A (0.624) has a slightly better hERG profile than Ligand B (0.941), meaning lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (14.308) has significantly lower microsomal clearance than Ligand A (54.846), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (47.033) has a better in vitro half-life than Ligand A (66.34).

**14. P-gp Efflux:** Ligand A (0.612) has lower P-gp efflux than Ligand B (0.499), which is favorable.

**15. 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 small and may not outweigh other factors.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B appears to be the more promising candidate. While both have poor solubility and permeability, Ligand B's significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk are critical advantages. The slightly better binding affinity of Ligand B is also a positive factor. Ligand A's higher DILI risk is a major concern.

Output:
1
2025-04-17 11:45:52,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.407 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is better than Ligand B (40.62) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (-0.534) is below the optimal 1-3 range and could indicate permeability issues. Ligand B (3.537) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.589 and 0.735), indicating drug-like properties.

**DILI:** Ligand A (43.311) has a slightly higher DILI risk than Ligand B (12.175), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (93.253) has a higher BBB score than Ligand A (53.432).

**Caco-2 Permeability:** Ligand A (-5.311) has poor Caco-2 permeability, while Ligand B (-4.587) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.837) has poor solubility, while Ligand B (-3.572) has even worse solubility.

**hERG:** Ligand A (0.124) has a very low hERG risk, which is excellent. Ligand B (0.333) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-11.806) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (53.647). This is a major advantage.

**In vitro Half-Life:** Ligand A (8.525) has a shorter half-life than Ligand B (-11.218).

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.238) has slightly higher P-gp efflux.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 1.4 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a better binding affinity and logP, which are important. However, Ligand A exhibits significantly better metabolic stability (lower Cl_mic) and lower P-gp efflux, and a much lower hERG risk. The poor solubility and permeability of both are concerning, but the superior metabolic stability and safety profile of Ligand A, combined with a reasonably good binding affinity, make it the more promising candidate. The difference in binding affinity is not large enough to overcome the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 11:45:52,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 371.591 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (112.14) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (52.65) is excellent, well below 140.

**logP:** Both ligands (2.573 and 2.603) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 8 HBAs, which is acceptable (<=10). Ligand B has 4 HBAs, also acceptable.

**QED:** Ligand A (0.853) has a higher QED score than Ligand B (0.677), indicating a more drug-like profile.

**DILI:** Ligand A (81.039) has a significantly higher DILI risk than Ligand B (19.349). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (78.984) is slightly better than Ligand B (65.064). However, BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.714) and Ligand B (-5.054) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.275 and -3.005). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.088) has a very low hERG risk, which is excellent. Ligand B (0.476) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (69.278) has lower microsomal clearance than Ligand B (80.216), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.942) has a negative half-life, which is not physically possible and indicates an issue with the data or the molecule's stability. Ligand B (20.337) has a reasonable in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.15 and 0.072), which is 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 enough to consider.

**Overall Assessment:**

Ligand A has a better QED, slightly better BBB, lower clearance, and significantly lower hERG risk. However, it has a *very* high DILI risk and an impossible in vitro half-life. The negative half-life is a critical flaw. The poor solubility is also a significant concern.

Ligand B has a lower DILI risk, a reasonable half-life, and a slightly better binding affinity. Its TPSA is excellent, and its P-gp efflux is low. The solubility is also poor, but not as problematic as the DILI and half-life issues with Ligand A.

Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. Ligand B is the better candidate due to the unacceptable DILI risk and impossible half-life of Ligand A.

Output:
1
2025-04-17 11:45:52,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.312 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.59 and 78.43) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (3.567 and 3.7) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and a reasonable number of HBA (4 and 3 respectively), satisfying the <5 and <10 rules.

**QED:** Ligand A (0.739) has a much better QED score than Ligand B (0.262), indicating a more drug-like profile.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (39.046), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.492) is slightly better than Ligand B (52.966).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.168 and -5.159). This is unusual and suggests poor permeability. However, these values are on a log scale, so even small differences can be significant. They are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.675 and -4.255). Again, these are on a log scale and indicate poor solubility. Ligand B is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.842 and 0.498), which is excellent.

**Microsomal Clearance:** Ligand B (90.827 mL/min/kg) has significantly higher microsomal clearance than Ligand A (40.6 mL/min/kg), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (-18.225 hours) has a negative half-life, which is not possible. This is a significant red flag and suggests a very short half-life or an issue with the assay. Ligand A (13.235 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.475 and 0.403).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't heavily sway the decision.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While both have poor solubility and permeability, Ligand A has a significantly better QED score, a more reasonable half-life, and lower microsomal clearance (better metabolic stability). The slightly higher DILI risk for Ligand A is less concerning than the very high clearance and impossible half-life of Ligand B.

Output:
0
2025-04-17 11:45:52,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.929 Da and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.33) is excellent, well below the 140 threshold for oral absorption. Ligand B (93.37) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.66) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.667) is low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is optimal. Ligand B (1 HBD, 6 HBA) is also reasonable.

**QED:** Both ligands have similar QED values (0.772 and 0.602), indicating good drug-likeness.

**DILI:** Ligand A (22.257) has a significantly lower DILI risk than Ligand B (46.801), which is a major advantage.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can still compare them relatively.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Ligand B (-1.027) is slightly better than Ligand A (-4.931).

**hERG Inhibition:** Ligand A (0.653) has a slightly higher hERG risk than Ligand B (0.226), which is preferable.

**Microsomal Clearance:** Ligand A (68.24) has higher clearance than Ligand B (9.806). This means Ligand B is likely more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (15.025) has a longer half-life than Ligand A (16.75), which is beneficial.

**P-gp Efflux:** Ligand A (0.707) has higher P-gp efflux liability than Ligand B (0.051), meaning Ligand B will have better oral bioavailability.

**Binding Affinity:** Ligand A (-9.0 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 concerns. The difference of 2.5 kcal/mol is significant.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is paramount for an enzyme inhibitor. While its logP is higher and solubility lower, the substantial affinity advantage (-9.0 vs -6.5) and lower DILI risk make it the more promising candidate. Ligand B has better metabolic stability and P-gp efflux, but the weaker binding is a critical drawback.

Output:
1
2025-04-17 11:45:52,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.857 Da) and Ligand B (349.391 Da) are both acceptable.

**TPSA:** Ligand A (62.4) is well below the 140 threshold for oral absorption, and excellent. Ligand B (121.62) is still within acceptable range, but less optimal.

**logP:** Ligand A (3.51) is within the optimal range (1-3). Ligand B (-0.226) is below 1, which could indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (A: 0.576, B: 0.735), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 57.697, B: 50.291), below the 60 threshold.

**BBB:** Both ligands have similar BBB penetration (A: 54.013, B: 54.905). BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.684) is very poor, while Ligand B (-5.46) is also poor. This suggests both compounds will have limited intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.672) is poor, while Ligand B (-2.211) is also poor, but slightly better.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.482, B: 0.182).

**Microsomal Clearance:** Ligand A (88.09) is relatively high, indicating faster metabolism. Ligand B (-0.442) is excellent, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (51.401) is acceptable, while Ligand B (7.808) is very short, which is a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.456, B: 0.061), which is favorable.

**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 of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility of both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.5 vs -7.8 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, its excellent metabolic stability (very low Cl_mic) and low P-gp efflux are highly desirable. While its in vitro half-life is short, this can potentially be addressed through structural modifications. Ligand A's higher microsomal clearance is a concern.

Output:
1
2025-04-17 11:45:52,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.531 and 335.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (73.2), being well below the 140 threshold for good absorption. Ligand B is still acceptable, but less optimal.

**logP:** Both ligands have good logP values (3.626 and 2.079), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.745 and 0.919), indicating good drug-like properties.

**DILI:** Ligand A (14.424) has a much lower DILI risk than Ligand B (35.789). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.537) is higher than Ligand B (68.282).

**Caco-2 Permeability:** 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:** Both have negative solubility values, which is also unusual. Again, the scale is unknown, making interpretation difficult.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.638 and 0.641), which is good.

**Microsomal Clearance:** Ligand A (97.263) has a higher microsomal clearance than Ligand B (3.501), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-9.698) has a significantly longer in vitro half-life than Ligand A (-13.379). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.314 and 0.048).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a very important factor, as a >1.5 kcal/mol advantage can outweigh other issues.

**Conclusion:**

While Ligand A has a lower DILI risk and slightly better TPSA, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), and a lower P-gp efflux. The affinity difference is substantial enough to offset the slightly higher DILI risk and less favorable TPSA. The unusual negative values for Caco-2 and Solubility are concerning but difficult to assess without knowing the scale.

Output:
1
2025-04-17 11:45:52,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.41 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is well below the 140 threshold for oral absorption, and good for kinase inhibitors. Ligand B (104.08) is still acceptable, but less optimal.

**logP:** Ligand A (0.81) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (-0.138) is even lower, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and are within acceptable limits (<=5 HBD, <=10 HBA). Ligand B has 6 HBA, slightly higher than A's 5.

**QED:** Both ligands have good QED scores (0.681 and 0.747), indicating drug-like properties.

**DILI:** Ligand A (31.214) has a much lower DILI risk than Ligand B (61.38), which is approaching a concerning level.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.482) has better BBB penetration than Ligand B (38.426), but it's not a primary concern.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.298 and 0.108), which is excellent.

**Microsomal Clearance:** Ligand A (3.553) has a higher microsomal clearance than Ligand B (-2.545). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B has a half-life of 0 hours, which is extremely poor. Ligand A has a half-life of -16.828 hours, which is also very poor.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.031 and 0.018).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). However, the difference is only 0.4 kcal/mol, which isn't substantial enough to overcome other significant drawbacks.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is the better candidate. While both have poor solubility and permeability, Ligand A has a significantly lower DILI risk and a more reasonable (though still poor) in vitro half-life compared to Ligand B's zero half-life. The slightly better affinity of Ligand B doesn't outweigh the severe metabolic instability and higher DILI risk.

Output:
0
2025-04-17 11:45:52,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.373 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.34) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Ligand A (4.411) is slightly higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (3.539) is within the optimal range.

**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 and potentially favoring permeability.

**QED:** Both ligands have similar QED scores (0.703 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (96.51 percentile) than Ligand B (13.843 percentile). This is a major concern for Ligand A.

**BBB:** Ligand A (44.32) and Ligand B (76.464) are both relatively low, which isn't critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-4.822) is very poor, indicating poor intestinal absorption. Ligand B (-4.774) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.108 and -3.504), which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.89) has a higher hERG risk than Ligand B (0.315).

**Microsomal Clearance:** Ligand A (33.02 mL/min/kg) has lower clearance than Ligand B (52.904 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (125.449 hours) has a significantly longer half-life than Ligand B (-8.986 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.461) has slightly higher P-gp efflux than Ligand B (0.264).

**Binding Affinity:** Ligand B (-7.3 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 stronger candidate. While both have solubility issues and poor Caco-2 permeability, Ligand B's significantly superior binding affinity (-7.3 vs 0 kcal/mol) outweighs the slightly higher clearance. The much lower DILI risk and hERG inhibition liability of Ligand B are also major advantages. Ligand A's long half-life is attractive, but its very weak binding affinity and high DILI risk make it a less viable candidate.

Output:
1
2025-04-17 11:45:52,276 - INFO - Batch 74 complete. Total preferences: 1184
2025-04-17 11:45:52,277 - INFO - Processing batch 75/512...
2025-04-17 11:46:40,918 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (386.43 and 346.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.38) is higher than Ligand B (58.2). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands (2.68 and 3.30) are 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 2 HBA. Both are acceptable, but Ligand B is slightly more favorable due to lower HBD/HBA counts.

**QED:** Both ligands have good QED scores (0.58 and 0.74), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 86.66%, which is high. Ligand B has a much lower DILI risk of 21.75%, a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (81.04) than Ligand A (63.09), but this is not a major deciding factor.

**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 for both compounds.

**hERG:** Ligand A (0.341) has a slightly lower hERG risk than Ligand B (0.568), which is preferable.

**Microsomal Clearance:** Ligand A (13.28 mL/min/kg) has significantly lower microsomal clearance than Ligand B (40.40 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.11 hours) has a much longer half-life than Ligand B (4.47 hours), a significant advantage.

**P-gp Efflux:** Ligand A (0.395) has lower P-gp efflux than Ligand B (0.147), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is relatively small (0.5 kcal/mol) and may not outweigh other factors.

**Overall Assessment:**

Ligand B has a significantly lower DILI risk and better binding affinity. However, Ligand A exhibits superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly lower hERG risk. The high DILI risk of Ligand A is a major concern. Considering the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. While Ligand B's affinity is slightly better, the substantial DILI risk outweighs this benefit.

Output:
1
2025-04-17 11:46:40,918 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.323 Da and 376.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, while Ligand B (131.78) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.132) is optimal (1-3). Ligand B (-1.673) is significantly lower, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better balanced than Ligand B (HBD=3, HBA=8). High HBA can sometimes reduce permeability.

**QED:** Ligand A (0.791) has a much better QED score than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Ligand B (77.007) has a higher DILI risk than Ligand A (63.086), though both are above the ideal <40.

**BBB:** Ligand A (75.107) has a better BBB percentile than Ligand B (21.404), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.837) has a worse Caco-2 permeability score than Ligand B (-5.655), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.453) has a slightly better solubility score than Ligand B (-1.655), although both are negative, indicating poor solubility.

**hERG:** Ligand A (0.385) has a lower hERG risk than Ligand B (0.115), which is favorable.

**Microsomal Clearance:** Ligand A (20.424) has a higher microsomal clearance than Ligand B (10.028), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-1.495) has a longer in vitro half-life than Ligand A (-8.381), which is a major advantage.

**P-gp Efflux:** Ligand A (0.146) has lower P-gp efflux than Ligand B (0.012), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 kcal/mol and -8.0 kcal/mol respectively), with Ligand A being slightly better. The affinity difference is not large enough to overcome the other ADME issues.

**Overall Assessment:**

Ligand A has better TPSA, logP, QED, hERG, and P-gp efflux. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Given that we are targeting a kinase (enzyme), metabolic stability and minimizing toxicity are paramount. The slightly better affinity of Ligand A is not enough to offset its poorer metabolic profile.

Output:
1
2025-04-17 11:46:40,918 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.372 and 341.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.13) is significantly better than Ligand B (107.18). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is higher, potentially hindering absorption.

**logP:** Ligand A (3.334) is optimal, while Ligand B (0.967) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is better balanced than Ligand B (1 HBD, 8 HBA). High HBA can sometimes cause issues.

**QED:** Both ligands have good QED scores (0.774 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (53.044) has a moderate DILI risk, while Ligand B (66.615) has a higher risk. Lower DILI is preferred.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (88.29) has better BBB penetration than Ligand B (57.929).

**Caco-2 Permeability:** Ligand A (-4.748) shows poor permeability, while Ligand B (-5.067) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.487) is better than Ligand B (-2.303), but both are quite poor. Solubility is a significant concern for both.

**hERG Inhibition:** Ligand A (0.913) has a lower hERG risk than Ligand B (0.036), which is a major advantage.

**Microsomal Clearance:** Ligand A (-15.836) has much lower microsomal clearance (better metabolic stability) than Ligand B (12.599). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (13.285 hours) has a better in vitro half-life than Ligand B (-13.049 hours).

**P-gp Efflux:** Ligand A (0.252) has lower P-gp efflux than Ligand B (0.028), which is favorable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.7 and -8.5 kcal/mol). The difference isn't large enough to override other significant ADME differences.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have poor Caco-2 permeability and solubility, Ligand A excels in crucial areas for an enzyme target: significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and a more favorable DILI profile. Its TPSA and logP are also more optimal. The slightly better BBB penetration is a bonus, even though SRC isn't a CNS target. The similar binding affinities mean that the superior ADME properties of Ligand A outweigh any minor differences in potency.

Output:
1
2025-04-17 11:46:40,919 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.233 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Ligand A (67.77) is well below the 140 threshold for oral absorption. Ligand B (85.25) is also below, but closer to the limit.

**logP:** Ligand A (4.885) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.157) is within the optimal range (1-3).

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

**QED:** Both ligands have good QED scores (A: 0.715, B: 0.757), indicating good drug-like properties.

**DILI:** Ligand A has a higher DILI risk (84.219) than Ligand B (59.636). This is a significant concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A is slightly better (72.431 vs 68.088). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

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

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a red flag for both.

**hERG Inhibition:** Ligand A (0.486) has a slightly higher hERG risk than Ligand B (0.091). Ligand B is much preferred here.

**Microsomal Clearance:** Ligand B (23.237) has significantly lower microsomal clearance than Ligand A (63.54), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (13.982) has a longer half-life than Ligand A (88.654). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.399) has lower P-gp efflux than Ligand B (0.026), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 kcal/mol and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate**. While both have issues with Caco-2 and solubility, Ligand B demonstrates significantly better ADME properties, specifically lower DILI risk, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The slightly lower logP and hERG risk are also beneficial. The binding affinity is comparable between the two. The higher DILI risk for Ligand A is a major concern that outweighs its slightly better BBB penetration and lower P-gp efflux.

Output:
1
2025-04-17 11:46:40,919 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (88.1 and 82.53) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.45) is a bit low, potentially hindering permeation. Ligand B (2.224) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBDs, which is acceptable.

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

**QED:** Both ligands have good QED scores (0.693 and 0.754), indicating good drug-likeness.

**DILI:** Both have low DILI risk (28.228 and 32.377 percentiles), which is favorable.

**BBB:** Both have moderate BBB penetration (55.215 and 50.679 percentiles). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.954 and -4.622), which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted cautiously.

**Aqueous Solubility:** Both have negative solubility values (-0.992 and -2.56), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.134 and 0.663 percentiles), which is excellent.

**Microsomal Clearance:** Ligand A has very low clearance (-0.287 mL/min/kg), suggesting excellent metabolic stability. Ligand B has a higher clearance (79.297 mL/min/kg), indicating faster metabolism.

**In vitro Half-Life:** Ligand A has a short half-life (33.552 hours), while Ligand B has a longer half-life (17.666 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.028 and 0.097 percentiles), which is favorable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability predictions for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.3 vs -7.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, its superior metabolic stability (lower Cl_mic) is crucial. While the solubility is a concern, it might be addressable through formulation strategies. The slightly lower logP of Ligand A is less concerning than the faster metabolism of Ligand B.

Output:
0
2025-04-17 11:46:40,919 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.77) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (96.25) is excellent, well below 140.

**logP:** Ligand A (-0.422) is a bit low, potentially hindering permeation. Ligand B (0.306) is better, within the optimal 1-3 range, but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is good. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.657 and 0.531), indicating good drug-like properties.

**DILI:** Ligand A (54.207) has a moderate DILI risk, but is acceptable. Ligand B (29.74) has a significantly lower DILI risk, which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.04) and Ligand B (39.667) are both relatively low.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.041 and -5.089). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.584 and -2.469). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.166 and 0.111), which is excellent.

**Microsomal Clearance:** Ligand A (4.106 mL/min/kg) has a much lower microsomal clearance than Ligand B (26.937 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (9.039 hours) has a significantly longer half-life than Ligand B (-7.824 hours). This is another strong point for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.032).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -7.7 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other ADME considerations.

**Conclusion:**

While both ligands bind well, Ligand A is the more promising candidate. It has significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Although its logP and solubility are slightly worse than Ligand B, the improved metabolic profile and lower toxicity risk are more important for an enzyme target like SRC. The Caco-2 permeability is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 11:46:40,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.209 Da) is slightly higher than Ligand B (354.491 Da), but both are acceptable.

**TPSA:** Ligand A (47.04) is well below the 140 threshold for oral absorption. Ligand B (67.87) is also below, but closer to the limit.

**logP:** Ligand A (4.787) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.341) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.633) has a better QED score than Ligand B (0.483), indicating a more drug-like profile.

**DILI:** Ligand B (33.695) has a significantly lower DILI risk than Ligand A (93.835). This is a major advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (81.698) is higher than Ligand B (66.305). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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. Ligand B (-2.008) is slightly better than Ligand A (-5.547).

**hERG Inhibition:** Ligand A (0.847) has a slightly higher hERG risk than Ligand B (0.307).

**Microsomal Clearance:** Ligand B (34.603 mL/min/kg) has significantly lower microsomal clearance than Ligand A (82.185 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (7.019 hours) has a longer half-life than Ligand A (63.056 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.552) has lower P-gp efflux than Ligand B (0.032), which is favorable.

**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 is the more promising candidate. While Ligand A has a slightly better QED and BBB, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and lower hERG risk. The slightly higher logP of Ligand A is a concern, and its poor solubility is a drawback. The difference in binding affinity, while not massive, adds to the advantage of Ligand B.

Output:
1
2025-04-17 11:46:40,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 351.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.12) is well below the 140 threshold for oral absorption, and suitable. Ligand B (102.18) is also acceptable, but less optimal.

**logP:** Ligand A (2.247) is within the optimal 1-3 range. Ligand B (0.208) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A has 3 HBDs, which is acceptable. Ligand B has 0, which is also fine.

**H-Bond Acceptors:** Ligand A has 4 HBAs, within the limit. Ligand B has 7, which is still acceptable but approaching the upper limit.

**QED:** Both ligands have good QED scores (0.664 and 0.714), indicating good drug-like properties.

**DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (62.001), which is preferable. Both are below the concerning 60 threshold.

**BBB:** BBB is not a high priority for a non-CNS target like SRC. Both are around 62-65%.

**Caco-2 Permeability:** Ligand A (-5.054) and Ligand B (-4.665) both have negative values, which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Ligand A (-2.919) and Ligand B (-1.644) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.492) has a slightly higher hERG risk than Ligand B (0.031), but both are relatively low.

**Microsomal Clearance:** Ligand A (12.01) has a higher microsomal clearance than Ligand B (-7.071). The negative value for Ligand B is unusual and suggests very high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (8.214) has a reasonable half-life. Ligand B (-5.54) has a negative half-life, which is also unusual and suggests extremely high stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.056).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Conclusion:**

While Ligand B exhibits exceptional metabolic stability and very low P-gp efflux, its extremely low logP, poor solubility and *very* weak binding affinity are major drawbacks. Ligand A, despite having slightly higher DILI and hERG risk, possesses a significantly stronger binding affinity (-8.3 kcal/mol vs 0.0 kcal/mol) which is the most important factor for an enzyme inhibitor. The affinity difference is substantial enough to outweigh the minor ADME concerns with Ligand A.

Output:
1
2025-04-17 11:46:40,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.431 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.83) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (101.29) is still under 140, but less optimal than A.

**logP:** Ligand A (3.163) is within the optimal 1-3 range. Ligand B (1.869) is at the lower end of the range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is favorable. Ligand B has 3 HBD and 3 HBA, also acceptable, but slightly higher donor count.

**QED:** Ligand A (0.767) has a better QED score than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand A (58.705) has a moderate DILI risk, but acceptable. Ligand B (10.702) has a very low DILI risk, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.443) is higher than Ligand B (75.107).

**Caco-2 Permeability:** Ligand A (-4.08) has a better Caco-2 permeability score than Ligand B (-5.182).

**Aqueous Solubility:** Ligand A (-4.242) has a better solubility score than Ligand B (-2.721).

**hERG Inhibition:** Ligand A (0.428) has a lower hERG risk than Ligand B (0.162), which is preferable.

**Microsomal Clearance:** Ligand A (27.461) has a lower microsomal clearance than Ligand B (40.766), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (48.731) has a significantly longer half-life than Ligand B (-15.235), which is a major advantage.

**P-gp Efflux:** Ligand A (0.335) has lower P-gp efflux than Ligand B (0.015), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A having better overall ADME properties (solubility, permeability, metabolic stability, half-life, P-gp efflux, and lower DILI), the significantly stronger binding affinity of Ligand B (-8.2 vs -6.7 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The potency advantage outweighs the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 11:46:40,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 460.32 Da - Within the ideal range (200-500 Da).
* Ligand B: 353.423 Da - Also within the ideal range.
* *Advantage: Neither is problematic.*

**2. TPSA:**
* Ligand A: 73.71 A^2 - Good for oral absorption (<=140).
* Ligand B: 121.23 A^2 - Still acceptable for oral absorption, but approaching the upper limit.
* *Advantage: Ligand A*

**3. logP:**
* Ligand A: 1.275 - Optimal (1-3).
* Ligand B: 1.887 - Optimal (1-3).
* *Advantage: Neither is problematic.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Meets the criteria (<=5).
* Ligand B: 2 - Meets the criteria (<=5).
* *Advantage: Neither is problematic.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 4 - Meets the criteria (<=10).
* Ligand B: 5 - Meets the criteria (<=10).
* *Advantage: Neither is problematic.*

**6. QED:**
* Ligand A: 0.673 - Good drug-like profile (>=0.5).
* Ligand B: 0.518 - Acceptable drug-like profile (>=0.5).
* *Advantage: Ligand A*

**7. DILI:**
* Ligand A: 41.45 - Low risk (<40 is good).
* Ligand B: 62.233 - Moderate risk, but not excessively high.
* *Advantage: Ligand A*

**8. BBB:**
* Ligand A: 62.97 - Not a priority for an oncology target.
* Ligand B: 66.925 - Not a priority for an oncology target.
* *Advantage: Neither is problematic.*

**9. Caco-2 Permeability:**
* Ligand A: -4.781 - Indicates poor permeability.
* Ligand B: -4.939 - Indicates poor permeability.
* *Disadvantage: Both are poor, but B is slightly worse.*

**10. Aqueous Solubility:**
* Ligand A: -2.101 - Indicates poor solubility.
* Ligand B: -3.136 - Indicates poorer solubility than A.
* *Advantage: Ligand A*

**11. hERG Inhibition:**
* Ligand A: 0.615 - Low risk.
* Ligand B: 0.562 - Low risk.
* *Advantage: Neither is problematic.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 36.547 mL/min/kg - Moderate clearance.
* Ligand B: 37.279 mL/min/kg - Moderate clearance.
* *Advantage: Neither is problematic.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -4.929 hours - Very short half-life.
* Ligand B: 19.572 hours - Good half-life.
* *Advantage: Ligand B*

**14. P-gp Efflux:**
* Ligand A: 0.111 - Low efflux.
* Ligand B: 0.202 - Moderate efflux.
* *Advantage: Ligand A*

**15. Binding Affinity:**
* Ligand A: -8.7 kcal/mol - Excellent binding.
* Ligand B: -8.9 kcal/mol - Excellent binding, slightly better than A.
* *Advantage: Ligand B*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a significantly better in vitro half-life, and slightly better binding affinity, which are crucial for kinase inhibitors. While Ligand A has better solubility and DILI risk, the poor half-life is a major drawback. The slight difference in binding affinity can be outweighed by the significant improvement in half-life. Both have poor Caco-2 permeability, which is less critical for an intravenously administered oncology drug.

Output:
1
2025-04-17 11:46:40,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.45 & 352.35 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.88) is significantly better than Ligand B (116.08). A TPSA under 140 is good for oral absorption, but lower is generally preferred.

**logP:** Ligand B (2.054) is optimal (1-3), while Ligand A (0.381) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is better than Ligand B (4 HBD, 8 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.822) has a much better QED score than Ligand B (0.624), indicating a more drug-like profile.

**DILI:** Ligand A (19.23) has a significantly lower DILI risk than Ligand B (67.47), a crucial advantage.

**BBB:** This is less important for a non-CNS target like SRC, but Ligand B (55.60) is slightly better than Ligand A (38.12).

**Caco-2 Permeability:** Both are negative (-5.33 and -5.36), indicating poor permeability. This is a concern for both, but the negative values are on a scale, and the difference is minimal.

**Aqueous Solubility:** Both are negative (-1.69 and -3.61), indicating poor solubility. Ligand B is worse.

**hERG:** Ligand A (0.463) has a much lower hERG risk than Ligand B (0.259), a significant safety advantage.

**Microsomal Clearance:** Ligand A (3.83) has significantly lower microsomal clearance than Ligand B (13.35), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.083) has a much longer in vitro half-life than Ligand B (-14.13), a substantial advantage.

**P-gp Efflux:** Both are very low (0.005 and 0.011), indicating minimal P-gp efflux.

**Binding Affinity:** Ligand A (-8.2) has a slightly better binding affinity than Ligand B (-7.8), although the difference is relatively small (0.4 kcal/mol).

**Overall:**

Ligand A is significantly superior to Ligand B. It has a better QED, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have poor Caco-2 permeability and solubility, the other advantages of Ligand A outweigh these drawbacks, especially considering the importance of metabolic stability and safety (DILI, hERG) for an enzyme target. The slightly lower logP of Ligand A is a minor concern, but the overall profile is much more promising.

Output:
1
2025-04-17 11:46:40,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.813 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (81.43) is better than Ligand B (99.93). Both are below 140, but lower TPSA generally favors absorption.

**logP:** Ligand A (3.542) is higher than Ligand B (1.787). Ligand B is closer to the optimal range of 1-3, while Ligand A is at the upper end, potentially leading to solubility issues.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.601, B: 0.747), indicating good drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (80.496) has a higher DILI risk than Ligand B (52.617). This is a significant negative for Ligand A.

**BBB:** Both have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**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 have very low hERG inhibition risk (A: 0.224, B: 0.181), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand B (24.079) has significantly lower microsomal clearance than Ligand A (110.965). This suggests better metabolic stability for Ligand B, a crucial factor for enzymes.

**In vitro Half-Life (t1/2):** Ligand B (20.442) has a longer half-life than Ligand A (13.975), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent and meets the criteria for a good starting point.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its lower DILI risk, significantly improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better QED score outweigh the slightly higher logP. While both have poor solubility and permeability, metabolic stability is a critical factor for kinase inhibitors, as they need to maintain therapeutic concentrations for a sufficient duration.

Output:
1
2025-04-17 11:46:40,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (342.439 & 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (73.29), both are below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have acceptable logP values (1.109 & 2.162), falling within the 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While low HBD can sometimes indicate poor solubility, it can also improve permeability.

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

**6. QED:** Ligand B (0.712) has a better QED score than Ligand A (0.459), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (33.307 & 31.563), both below the 40 threshold.

**8. BBB:** Ligand B (63.862) has a higher BBB percentile than Ligand A (35.052). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.752 & -4.89). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.626 & -1.962). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.54 & 0.314).

**12. Microsomal Clearance:** Ligand B (43.842) has lower microsomal clearance than Ligand A (56.043), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (2.97) has a better in vitro half-life than Ligand B (-17.22). A negative half-life is not possible, so this is a clear outlier and likely an error in the data.

**14. P-gp Efflux:** Ligand B (0.092) has lower P-gp efflux than Ligand A (0.267), suggesting better bioavailability.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial factor for enzyme inhibitors. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the superior binding affinity of Ligand A (-8.1 kcal/mol vs 0.0 kcal/mol) is the most important factor. The better half-life of Ligand A is also a plus. While Ligand B has better QED and metabolic stability, the potency difference is too large to ignore. The negative solubility and permeability values for both compounds are concerning and would need further investigation, but the strong binding of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 11:46:40,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.395 and 367.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.43) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (62.83) is well within the optimal range.

**logP:** Both ligands (2.952 and 2.37) are within the optimal 1-3 range.

**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 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.871 and 0.808), indicating good drug-likeness.

**DILI:** Ligand A (72.819) has a higher DILI risk than Ligand B (32.765). This is a significant negative for Ligand A.

**BBB:** Ligand A (44.591) has a lower BBB penetration percentile than Ligand B (82.396). While not a primary concern for a non-CNS target like SRC, higher BBB is generally preferable.

**Caco-2 Permeability:** Both ligands have very negative Caco-2 values (-4.931 and -4.919). This is unusual and suggests a potential issue with permeability prediction or a problem with the model. It's difficult to interpret without further investigation, but it raises a flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.159 and -2.791). Similar to Caco-2, this is concerning and suggests potential formulation challenges.

**hERG Inhibition:** Ligand A (0.015) has a slightly lower hERG inhibition risk than Ligand B (0.819). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand B (-13.099) has a significantly lower (better) microsomal clearance than Ligand A (12.439), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (28.633) has a much longer in vitro half-life than Ligand A (-29.38). This is another significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux values (0.014 and 0.073).

**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 still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand B outweighs the slightly better hERG profile of Ligand A. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity (DILI) are paramount.

Output:
1
2025-04-17 11:46:40,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.438 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.02 and 78.68) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values (1.84 and 1.434) 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 limits of 5 HBD and 10 HBA.

**QED:** Both ligands have good QED scores (0.703 and 0.841), indicating good drug-like properties.

**DILI:** Ligand A (32.687) has a slightly higher DILI risk than Ligand B (23.769), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (76.696 and 76.58), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.951 and -4.897). This is unusual and suggests poor permeability. However, these values may be experimental artifacts or indicate a specific transport mechanism.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.986 and -1.907), which is also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.229 and 0.387), which is excellent.

**Microsomal Clearance:** Ligand B (31.548 mL/min/kg) has a higher microsomal clearance than Ligand A (20.768 mL/min/kg), suggesting that Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-11.339 hours) has a negative in vitro half-life, which is not possible. Ligand B (9.158 hours) has a reasonable half-life. The negative value for Ligand A is a significant red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.076), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While both are excellent, the difference is minimal.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand A is slightly favored. The primary reason is its significantly better metabolic stability (lower Cl_mic and a *possible* half-life, assuming the negative value is an error) and lower DILI risk. The binding affinity difference is minimal. The negative half-life for Ligand A is a major concern and should be investigated, but assuming it's an error, the other factors make it the more promising candidate.

Output:
0
2025-04-17 11:46:40,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (395.591 and 369.843 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.7) is better than Ligand B (37.61). While both are reasonably low, A is closer to the upper limit for good oral absorption.

**logP:** Ligand A (1.355) is optimal, while Ligand B (4.239) is approaching the higher end, potentially causing solubility issues.

**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 (0.615 and 0.714), indicating drug-likeness.

**DILI:** Ligand A (43.195) has a slightly higher DILI risk than Ligand B (31.601), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (96.782) has a higher BBB penetration than Ligand A (65.297), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-5.136) has a negative Caco-2 value, which is concerning. Ligand B (-4.44) is also negative but less so.

**Aqueous Solubility:** Ligand A (-2.841) has better solubility than Ligand B (-4.217).

**hERG Inhibition:** Ligand A (0.277) has a lower hERG inhibition risk than Ligand B (0.848), which is a significant advantage.

**Microsomal Clearance:** Ligand B (51.714) has a lower microsomal clearance than Ligand A (67.039), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (4.421) has a longer half-life than Ligand A (-33.23), which is a strong positive.

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux than Ligand B (0.589), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.9 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has advantages in metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower DILI risk. However, Ligand A has better solubility and a significantly lower hERG risk. The negative Caco-2 values for both are concerning, but Ligand B is less negative. Considering the enzyme-specific priorities, the lower hERG risk of Ligand A is crucial, and its better solubility is also beneficial. The similar binding affinities make the ADMET properties the deciding factor.

Output:
0
2025-04-17 11:46:40,923 - INFO - Batch 75 complete. Total preferences: 1200
2025-04-17 11:46:40,923 - INFO - Processing batch 76/512...
2025-04-17 11:47:33,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 340.467 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.23) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.494 and 3.676), falling within the 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 2 HBD and 3 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.881 and 0.909), indicating good drug-like properties.

**DILI:** Ligand A (32.105) has a lower DILI risk than Ligand B (42.691), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (53.083) has a lower BBB penetration than Ligand B (83.482). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.711 and -4.752). This 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 negative solubility values (-3.382 and -4.063). Again, these are on a log scale and suggest poor solubility. This is a concern for bioavailability.

**hERG:** Ligand A (0.407) has a lower hERG risk than Ligand B (0.616), which is a significant advantage.

**Microsomal Clearance:** Ligand A (0.022) has significantly lower microsomal clearance than Ligand B (51.304), indicating much better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (18.938) has a shorter half-life than Ligand B (23.185), but both are reasonable.

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux than Ligand B (0.465), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial difference (1.4 kcal/mol) and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has better ADME properties (lower DILI, lower hERG, much lower Cl_mic, lower P-gp efflux) and better solubility and TPSA. However, Ligand B has a significantly stronger binding affinity. Given that we are targeting an enzyme, potency is paramount. The 1.4 kcal/mol difference in binding affinity is substantial. While Ligand B's higher Cl_mic is a concern, it might be mitigated through formulation strategies or structural modifications. The slightly higher DILI and hERG risks are also manageable.

Output:
1
2025-04-17 11:47:33,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.4 and 355.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.4 and 72.9 A^2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.944) is optimal, while Ligand B (1.479) is a bit low, potentially impacting 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 4 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.603 and 0.692), indicating good drug-like properties.

**DILI:** Ligand A (47.15) has a moderate DILI risk, while Ligand B (6.282) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (86.002) has better BBB penetration than Ligand B (55.487), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.828 and -4.811) which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.632 and -1.075), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.706) has a slightly higher hERG risk than Ligand B (0.544), but both are relatively low.

**Microsomal Clearance:** Ligand B (-9.653) has a significantly *lower* (better) microsomal clearance than Ligand A (15.912), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-4.964) has a longer in vitro half-life than Ligand A (-27.696), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.028), which is favorable.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 1.5 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has a better binding affinity, Ligand B has a significantly better safety profile (lower DILI) and much improved metabolic stability (lower Cl_mic, longer t1/2). The poor solubility and permeability are concerns for both, but the superior ADME properties of Ligand B, particularly the lower DILI risk, make it the more promising candidate. The affinity difference, while notable, is not large enough to overcome the substantial ADME advantages of Ligand B for an enzyme target.

Output:
1
2025-04-17 11:47:33,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.479 and 357.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.31) is better than Ligand B (55.32), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.752) is within the optimal 1-3 range, while Ligand B (3.535) is at the higher end, potentially raising solubility concerns.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as some H-bond donors can aid solubility.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand B (0.84) has a better QED score than Ligand A (0.623), indicating a more drug-like profile.

**DILI:** Ligand A (15.355) has a significantly lower DILI risk than Ligand B (61.07), a critical advantage.

**BBB:** Ligand B (78.519) shows better BBB penetration than Ligand A (50.446), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.319) has a better Caco-2 permeability than Ligand B (-4.523).

**Aqueous Solubility:** Ligand A (-0.661) has better aqueous solubility than Ligand B (-4.068).

**hERG Inhibition:** Ligand A (0.252) exhibits a much lower hERG inhibition liability than Ligand B (0.428), a major safety advantage.

**Microsomal Clearance:** Ligand A (53.051) has lower microsomal clearance than Ligand B (85.163), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.78) has a shorter half-life than Ligand B (-41.276), which is a disadvantage.

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux liability than Ligand B (0.401), improving bioavailability.

**Binding Affinity:** Ligand B (-8.1) 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 demonstrates a significantly better safety profile (lower DILI, lower hERG) and better ADME properties (solubility, permeability, metabolic stability, P-gp efflux). While Ligand B has a slightly higher binding affinity and a better QED score, the advantages of Ligand A in critical ADME/Tox parameters outweigh this difference, especially considering we are dealing with a kinase inhibitor where metabolic stability and off-target effects are key concerns. The improved solubility of Ligand A is also a significant benefit for formulation.

Output:
0
2025-04-17 11:47:33,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.383 and 346.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.54) is better than Ligand B (53.76), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.58 and 2.49), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 0 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 have acceptable QED scores (0.844 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (49.632) has a slightly higher DILI risk than Ligand B (38.116), but both are below the concerning 60 threshold.

**BBB:** Ligand A (83.986) has a lower BBB penetration than Ligand B (94.804), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the absolute value of Ligand B (-4.743) is worse than Ligand A (-4.937).

**Aqueous Solubility:** Both have negative values, which is also unusual and suggests poor solubility. Ligand A (-1.668) is slightly better than Ligand B (-2.652).

**hERG:** Both ligands have very low hERG inhibition risk (0.348 and 0.475), which is excellent.

**Microsomal Clearance:** Ligand B (26.066) has significantly lower microsomal clearance than Ligand A (44.115), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (15.069 hours) has a much longer half-life than Ligand A (3.718 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.139), which is favorable.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference in binding is a major advantage and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better solubility and Caco-2 permeability, Ligand B clearly outperforms it in the most critical areas for an enzyme inhibitor: binding affinity, metabolic stability (lower Cl_mic and longer t1/2), and lower DILI risk. The substantial difference in binding affinity (-9.8 vs -7.2 kcal/mol) is a decisive factor.

Output:
1
2025-04-17 11:47:33,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.3 and 83.56) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.96) is slightly below the optimal 1-3 range, while Ligand B (1.846) is within the optimal range. This gives a slight edge to Ligand B.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

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

**QED:** Both ligands have good QED scores (0.692 and 0.833), indicating drug-like properties.

**DILI:** Ligand A (16.557) has a significantly lower DILI risk than Ligand B (65.917). This is a major advantage for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration (50.446 and 57.425). Since SRC is not a CNS target, this is not a critical factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.536 and -4.964). This is unusual and suggests poor permeability, but the scale is not specified.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.466 and -2.839). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.126) has a much lower hERG inhibition liability than Ligand B (0.44). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-14.818) has significantly lower (better) microsomal clearance than Ligand B (35.095), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.902) has a shorter half-life than Ligand B (10.618), but both are reasonable.

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.225), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.2) has a significantly stronger binding affinity than Ligand A (0). This is a substantial advantage for Ligand B, and likely outweighs many of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better ADME properties (lower DILI, hERG, Cl_mic, and Pgp efflux), the difference in binding affinity is substantial. The negative solubility and Caco-2 values are concerning for both, but the potency advantage of Ligand B is likely to be more easily addressed through formulation or further optimization.

Output:
1
2025-04-17 11:47:33,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.38 Da) is slightly higher, but acceptable. Ligand B (349.431 Da) is also good.

**TPSA:** Ligand A (66.48) is good, being below 140. Ligand B (93.46) is also acceptable, but closer to the upper limit.

**logP:** Both ligands have good logP values (A: 3.161, B: 1.294), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is excellent. Ligand B (HBD=2, HBA=5) is also acceptable, though slightly higher in HBA.

**QED:** Both ligands have reasonable QED scores (A: 0.756, B: 0.621), indicating good drug-like properties.

**DILI:** Ligand A (42.148) has a moderate DILI risk, which is acceptable. Ligand B (14.541) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.702) has better BBB penetration than Ligand B (51.609).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.795 and -4.796), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.115 and -1.983). This is a major drawback for both and would likely require formulation strategies.

**hERG Inhibition:** Ligand A (0.706) has a slightly higher hERG risk than Ligand B (0.071). Ligand B is significantly better in terms of hERG liability.

**Microsomal Clearance:** Ligand A (33.498) has a higher microsomal clearance than Ligand B (27.208), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-3.052) has a negative half-life, which is not physically possible and indicates a very short half-life or a problem with the assay. Ligand A (6.379) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.547) has moderate P-gp efflux, while Ligand B (0.007) has very low P-gp efflux, which is favorable.

**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 difference.

**Overall Assessment:**

Ligand B is the better candidate despite the poor Caco-2 and solubility. The significantly stronger binding affinity (-6.5 vs 0 kcal/mol) outweighs the other drawbacks, especially for a kinase inhibitor where potency is paramount. The lower DILI and hERG risks are also significant advantages. The negative half-life for Ligand B is a major red flag that needs investigation, but the binding affinity is so much better that it still appears superior. The poor solubility of both compounds will need to be addressed through formulation.

Output:
1
2025-04-17 11:47:33,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.304 Da) is slightly higher than Ligand B (357.574 Da), but both are acceptable.

**TPSA:** Ligand A (37.61) is better than Ligand B (44.37). Both are below 140, supporting good oral absorption.

**logP:** Both ligands have similar logP values (A: 4.425, B: 4.287). While slightly high, they are not dramatically outside the optimal 1-3 range and could be acceptable if other properties are favorable.

**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. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.641, B: 0.793), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (60.644) than Ligand B (33.773). This is a major concern for Ligand A.

**BBB:** Ligand A (89.763) has better BBB penetration than Ligand B (74.176), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.028 and -4.843), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.048 and -4.876). This is a major issue for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.876, B: 0.757), which is positive.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (87.818) than Ligand B (39.694), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (30.23 hours) compared to Ligand A (4.393 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.843, B: 0.311), which is favorable.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.4 kcal/mol) than Ligand A (-8.7 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B has a significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a much stronger binding affinity. The higher affinity of Ligand B could potentially compensate for the solubility/permeability issues, whereas the higher DILI risk and lower metabolic stability of Ligand A are more difficult to overcome.

Output:
1
2025-04-17 11:47:33,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.913 Da) is slightly higher than Ligand B (350.419 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (105.6). A TPSA under 140 is good for oral absorption, and A is well within that range, while B is approaching the upper limit.

**logP:** Ligand A (2.957) is optimal, while Ligand B (0.26) is quite low. Low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=7). Both are within acceptable limits, but A has a more favorable balance.

**QED:** Both ligands have similar QED values (A: 0.773, B: 0.676), indicating good drug-likeness.

**DILI:** Ligand A (47.15) has a slightly higher DILI risk than Ligand B (35.479), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (66.886) is better than Ligand B (50.679).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-5.014 for A, -5.319 for B).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-1.126) is slightly better than Ligand A (-3.817).

**hERG Inhibition:** Ligand A (0.342) has a significantly lower hERG risk than Ligand B (0.189), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (4.502) has lower clearance than Ligand B (5.691), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (29.053 hours) has a much longer half-life than Ligand A (3.064 hours). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.373) has lower P-gp efflux than Ligand B (0.004), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.5kcal/mol advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity and a significantly longer half-life, Ligand A is superior in most other critical ADME properties. Specifically, Ligand A has a much better logP, TPSA, and a significantly lower hERG risk. The lower hERG risk is a major advantage, as cardiotoxicity is a common concern with kinase inhibitors. The better logP and TPSA of Ligand A suggest better permeability. The longer half-life of B is appealing, but can potentially be addressed with formulation strategies. The affinity difference is only 0.4kcal/mol, which is less important than the ADME profile.

Output:
0
2025-04-17 11:47:33,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.515 and 363.571 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.12) is better than Ligand B (41.29). While both are reasonably low, Ligand B is significantly lower, potentially improving cell permeability.

**logP:** Ligand A (2.28) is optimal, while Ligand B (4.381) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.659 and 0.757, respectively), indicating drug-likeness.

**DILI:** Ligand B (8.414) has a much lower DILI risk than Ligand A (46.375), a significant advantage.

**BBB:** Ligand B (72.315) has a higher BBB penetration percentile than Ligand A (63.629). While not crucial for a non-CNS target like SRC, it's a minor positive.

**Caco-2 Permeability:** Ligand A (-5.347) and Ligand B (-5.057) 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.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.245 and -3.48 respectively). This is a significant concern for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.449) has a slightly lower hERG risk than Ligand B (0.913), which is favorable.

**Microsomal Clearance:** Ligand A (33.69) has a lower microsomal clearance than Ligand B (41.857), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (30.923) has a significantly longer in vitro half-life than Ligand B (11.645), which is a major advantage.

**P-gp Efflux:** Ligand A (0.047) has a much lower P-gp efflux liability than Ligand B (0.572), suggesting better oral bioavailability.

**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 reasonable advantage.

**Overall Assessment:**

Ligand B has a better binding affinity and lower DILI risk. However, Ligand A exhibits superior metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, which are critical for kinase inhibitors. Both have poor solubility and permeability. The difference in binding affinity (0.7 kcal/mol) is not substantial enough to outweigh the advantages of Ligand A's improved pharmacokinetic properties, particularly its metabolic stability and reduced efflux.

Output:
0
2025-04-17 11:47:33,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (375.969 Da and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (19.37) is excellent, well below the 140 threshold, suggesting good absorption. Ligand B (91.23) is higher, but still within a reasonable range, though potentially impacting absorption slightly.

**logP:** Ligand A (4.77) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.592) is optimal.

**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 (0.77 and 0.832), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (41.877 and 36.099 percentiles), below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.051) shows better BBB penetration than Ligand B (50.058).

**Caco-2 Permeability:** Ligand A (-4.876) is poor, indicating low intestinal absorption. Ligand B (-5.368) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.411) is poor, consistent with its higher logP. Ligand B (-1.348) is better, but still not ideal.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.939 and 0.041), which is excellent.

**Microsomal Clearance:** Ligand A (24.134 mL/min/kg) is higher than Ligand B (11.923 mL/min/kg), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-20.634 hours) has a negative half-life, which is not possible. This is a data error, and makes it difficult to assess. Ligand A (16.207 hours) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.593 and 0.035), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol), with Ligand A being slightly better. However, the difference is less than the 1.5 kcal/mol threshold that could outweigh other issues.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While its Caco-2 and solubility are not ideal, they are better than Ligand A. The significantly lower microsomal clearance of Ligand B is a major advantage, suggesting better metabolic stability and potentially a longer duration of action. The error in Ligand B's half-life is concerning, but the other factors outweigh this. Ligand A's high logP, poor Caco-2 permeability, and higher clearance are significant drawbacks. The slight affinity advantage of Ligand A does not compensate for these issues.

Output:
1
2025-04-17 11:47:33,690 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision, considering the provided guidelines and the target class (enzyme - kinase in oncology):

**1. Molecular Weight (MW):**
*   Ligand A: 350.438 Da - Within the ideal range (200-500 Da).
*   Ligand B: 339.439 Da - Within the ideal range (200-500 Da).
*   *Both are good.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 64.68  -  Excellent, well below the 140 threshold for oral absorption.
*   Ligand B: 81.99 - Still good, below 140, but higher than A.
*   *Ligand A is slightly better.*

**3. Lipophilicity (logP):**
*   Ligand A: 1.488 - Optimal (1-3).
*   Ligand B: 3.446 - Towards the higher end of optimal, but still acceptable.
*   *Ligand A is better.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 2 - Meets the criteria (<=5).
*   Ligand B: 2 - Meets the criteria (<=5).
*   *Both are good.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 4 - Meets the criteria (<=10).
*   Ligand B: 3 - Meets the criteria (<=10).
*   *Both are good.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.816 - Excellent, well above 0.5.
*   Ligand B: 0.779 - Very good, above 0.5.
*   *Ligand A is slightly better.*

**7. DILI Risk (DILI):**
*   Ligand A: 37.146 - Low risk (below 40).
*   Ligand B: 48.895 - Still relatively low risk, but higher than A.
*   *Ligand A is better.*

**8. Blood-Brain Barrier Penetration (BBB):**
*   Ligand A: 89.686 - Good, but not crucial for an oncology target.
*   Ligand B: 77.007 - Lower than A, not crucial for an oncology target.
*   *Ligand A is better.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.858 - Negative values are unusual and suggest poor permeability.
*   Ligand B: -4.479 - Negative values are unusual and suggest poor permeability.
*   *Both are poor, but B is slightly better.*

**10. Aqueous Solubility:**
*   Ligand A: -2.254 - Poor solubility.
*   Ligand B: -5.064 - Very poor solubility.
*   *Ligand A is better.*

**11. hERG Inhibition:**
*   Ligand A: 0.803 - Low risk.
*   Ligand B: 0.561 - Low risk.
*   *Both are good.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 23.78 - Moderate clearance.
*   Ligand B: 50.606 - High clearance.
*   *Ligand A is significantly better (more metabolically stable).*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: -2.024 - Negative values are unusual.
*   Ligand B: 10.128 - Good half-life.
*   *Ligand B is significantly better.*

**14. P-gp Efflux:**
*   Ligand A: 0.023 - Low efflux, good.
*   Ligand B: 0.239 - Higher efflux than A.
*   *Ligand A is better.*

**15. Binding Affinity:**
*   Ligand A: -7.5 kcal/mol - Excellent.
*   Ligand B: -8.7 kcal/mol - Even better, 1.2 kcal/mol stronger.
*   *Ligand B is significantly better.*

**Overall Assessment:**

For an enzyme (kinase) target in oncology, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a significantly better binding affinity (-8.7 vs -7.5 kcal/mol), and a much better in vitro half-life (10.128 vs -2.024). While Ligand A has better DILI risk and some other ADME properties, the superior binding affinity and metabolic stability of Ligand B outweigh these advantages. The solubility and Caco-2 values are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:47:33,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.443 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109) is slightly above the preferred <140 for good absorption, while Ligand B (99.33) is well within.

**logP:** Both ligands have acceptable logP values (0.952 and 1.285), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 4 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.679) has a better QED score than Ligand B (0.477), indicating a more drug-like profile.

**DILI:** Ligand B (28.887) has a significantly lower DILI risk than Ligand A (63.086), which is a major advantage.

**BBB:** Ligand B (70.919) shows better BBB penetration than Ligand A (34.161), but this isn't a primary concern for a non-CNS target like SRC.

**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 ligands have negative solubility values, indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.025 and 0.139), which is excellent.

**Microsomal Clearance:** Ligand A (-5.492) has a *negative* microsomal clearance, which is impossible and likely indicates an error in the data. Ligand B (32.984) has a higher clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (22.632 hours) has a longer half-life than Ligand B (-4.395 hours), but the negative value for B is also suspect.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.028).

**Binding Affinity:** Ligand A (-10.6 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 concerns.

**Conclusion:**

Despite the questionable solubility and Caco-2 values for both, Ligand A's significantly superior binding affinity (-10.6 vs -6.5 kcal/mol) is the most important factor for an enzyme target like SRC. While Ligand B has a better DILI score and slightly better BBB penetration, the large difference in binding affinity makes Ligand A the more promising candidate. The negative microsomal clearance and half-life for Ligand B are also concerning data quality issues. The negative clearance for Ligand A is also suspect, but the strong binding makes it still the better candidate.

Output:
1
2025-04-17 11:47:33,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.371 and 345.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (110.53) is better than Ligand B (120.24), both are acceptable but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.927) is within the optimal range (1-3). Ligand B (-0.463) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED values (0.784 and 0.621, both >0.5).

**DILI:** Ligand A (67.507) has a higher DILI risk than Ligand B (49.826), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (52.889) is slightly better than Ligand A (43.001).

**Caco-2 Permeability:** Both have negative values (-5.064 and -5.861), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative values (-3.027 and -2.469), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.078) has a much lower hERG risk than Ligand B (0.469), which is a major advantage.

**Microsomal Clearance:** Ligand A (1.004) has significantly lower microsomal clearance than Ligand B (3.997), indicating better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (19.346 hours) has a much longer half-life than Ligand B (-18.311 hours), which is a substantial benefit.

**P-gp Efflux:** Ligand A (0.023) has significantly lower P-gp efflux than Ligand B (0.006), meaning better bioavailability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a 1.4 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is superior in almost all other critical ADME-Tox properties. Specifically, Ligand A has a much better safety profile (lower hERG, lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and better bioavailability (lower P-gp efflux). The solubility and permeability issues are concerning for both, but the substantial improvements in safety and PK for Ligand A outweigh the affinity difference. The affinity of Ligand A is still quite good (-7.0 kcal/mol).

Output:
0
2025-04-17 11:47:33,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.86 and 351.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.0) is excellent, well below the 140 threshold for oral absorption. Ligand B (88.93) is still acceptable but higher, potentially impacting absorption slightly.

**logP:** Ligand A (3.215) is optimal (1-3). Ligand B (-0.086) is quite low, which could hinder membrane permeability and bioavailability.

**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 similar QED values (0.807 and 0.763), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (50.95 and 49.94).

**BBB:** Ligand A (89.07) shows better BBB penetration potential than Ligand B (76.04), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.614 and -4.6), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.607 and -1.109), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.408 and 0.174), which is excellent.

**Microsomal Clearance:** Ligand A (52.005) has higher microsomal clearance than Ligand B (32.478), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (23.5 hours) has a significantly longer half-life than Ligand A (43.727 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.45 and 0.007), which is favorable.

**Binding Affinity:** Both ligands have comparable binding affinities (-9.4 and -8.7 kcal/mol), both being excellent. The difference of 0.7 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both compounds have excellent binding affinity and low hERG risk, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better P-gp efflux profile outweigh the slight disadvantage in TPSA and the comparable DILI risk. The biggest concern for both is the very poor predicted solubility and permeability. However, these properties can sometimes be improved through formulation strategies. The low logP of Ligand A is a significant disadvantage.

Output:
1
2025-04-17 11:47:33,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 347.423 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (93.7), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.681) is within the optimal range (1-3), while Ligand B (-0.109) is slightly below, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**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 good QED scores (0.595 and 0.772), indicating drug-like properties.

**DILI:** Ligand A (20.744) has a significantly lower DILI risk than Ligand B (56.65). This is a major advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 ligands have negative solubility values, which is also unusual. This suggests poor solubility.

**hERG:** Ligand A (0.156) has a lower hERG risk than Ligand B (0.288).

**Microsomal Clearance:** Ligand A (-4.372) has significantly lower (better) microsomal clearance than Ligand B (17.661), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.717) has a longer in vitro half-life than Ligand B (9.418), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.2), a difference of 0.8 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better in terms of safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and has a more favorable logP. The difference in binding affinity (0.8 kcal/mol) is not substantial enough to outweigh the significant advantages of Ligand A, especially considering the importance of ADME properties for an enzyme target. The negative solubility and Caco-2 values are concerning for both, but these could be addressed with formulation strategies.

Output:
1
2025-04-17 11:47:33,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.419 and 345.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.7) is slightly above the preferred <140, but acceptable. Ligand B (35.58) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (3.079) is optimal. Ligand B (4.513) is a bit 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 1 HBD and 2 HBA, also good.

**QED:** Ligand B (0.704) has a significantly better QED score than Ligand A (0.449), indicating a more drug-like profile.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (21.753), which is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand B (96.084) has a much higher value than Ligand A (39.511).

**Caco-2 Permeability:** Ligand A (-5.265) has poor Caco-2 permeability. Ligand B (-4.304) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.246 and -4.39 respectively). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.177) has a slightly lower hERG inhibition risk than Ligand B (0.938), which is preferable.

**Microsomal Clearance:** Ligand A (83.017) has lower microsomal clearance than Ligand B (91.112), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (36.356) has a much longer in vitro half-life than Ligand A (-5.013), a significant advantage.

**P-gp Efflux:** Ligand A (0.373) has lower P-gp efflux than Ligand B (0.636), which is better.

**Binding Affinity:** Ligand B (-7.7) has a significantly better binding affinity than Ligand A (-8.0). While both are good, the 1.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate despite its higher logP and P-gp efflux. The significantly improved QED, lower DILI risk, much longer half-life, and superior binding affinity outweigh the concerns regarding logP and solubility. Ligand A's poor Caco-2 permeability and higher DILI risk are major liabilities. While both have poor solubility, the other advantages of Ligand B make it more promising for further optimization.

Output:
1
2025-04-17 11:47:33,691 - INFO - Batch 76 complete. Total preferences: 1216
2025-04-17 11:47:33,691 - INFO - Processing batch 77/512...
2025-04-17 11:48:14,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.431 and 347.371 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.67) is well below the 140 threshold for good absorption, and is preferable to Ligand B (117.51).

**logP:** Ligand A (2.049) is optimal, while Ligand B (0.385) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is excellent, while Ligand B (3) is acceptable but less ideal.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.776 and 0.666, respectively), indicating drug-like properties.

**DILI:** Ligand A (32.92) has a significantly lower DILI risk than Ligand B (63.978), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (73.245) is better than Ligand B (41.218).

**Caco-2 Permeability:** Ligand A (-4.734) is better than Ligand B (-5.413), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.491 and -2.602). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition liability (0.242 and 0.035), which is excellent.

**Microsomal Clearance:** Ligand A (30.543) has higher (worse) microsomal clearance than Ligand B (-2.684), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (5.849) has a longer half-life than Ligand A (-18.299), which is highly desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.161 and 0.025).

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.3), but the difference is less than 1.5 kcal/mol, so it doesn't fully compensate for other weaknesses.

**Overall:** While Ligand A has better TPSA, logP, DILI, Caco-2 permeability, and slightly better binding affinity, Ligand B has significantly better metabolic stability (lower Cl_mic, longer half-life). Given the enzyme-specific priorities, metabolic stability is crucial. The solubility is a concern for both, but the superior metabolic profile of Ligand B outweighs the minor advantages of Ligand A.

Output:
1
2025-04-17 11:48:14,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (352.435 and 344.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (119.52) is slightly above the optimal <140, but still acceptable. Ligand B (96.11) is well within the ideal range.

**3. logP:** Both ligands have good logP values (1.303 and 1.16), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both within the acceptable range of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.431 and 0.699), with Ligand B being better.

**7. DILI:** Ligand A (21.171) has a much lower DILI risk than Ligand B (56.185). This is a significant advantage for Ligand A.

**8. BBB:** Both have similar BBB penetration (62.466 and 61.613). Not a major factor for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.473 and -5.385). These values are unusual and suggest poor permeability. However, they are similar for both compounds.

**10. Aqueous Solubility:** Both have negative solubility values (-1.956 and -3.519). These values are also unusual and suggest poor solubility. Ligand B has worse solubility.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.586 and 0.256).

**12. Microsomal Clearance:** Ligand A (3.163) has lower microsomal clearance, indicating better metabolic stability than Ligand B (6.974).

**13. In vitro Half-Life:** Ligand A (18.36) has a longer in vitro half-life than Ligand B (15.789).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.026 and 0.07).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >1 kcal/mol advantage, which is substantial.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much better binding affinity. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, but worse solubility. The difference in affinity is substantial enough to outweigh the slightly better ADME properties of Ligand A. The poor solubility and permeability of both compounds are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:48:14,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.409 Da) is slightly higher than Ligand B (345.495 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (73.34) is slightly higher than Ligand B (69.21), but both are good.

**logP:** Ligand A (3.637) is at the higher end of the optimal range (1-3), while Ligand B (2.188) is well within the optimal range. The higher logP of Ligand A could potentially lead to off-target effects or solubility issues, but it's not a severe concern at this level.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.508, Ligand B: 0.848). Ligand B has a significantly better QED, indicating a more drug-like profile.

**DILI:** Ligand A has a DILI risk of 79.915%, which is considered high. Ligand B has a much lower DILI risk of 52.423%, which is good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 70.531%, Ligand B: 83.288%). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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. This suggests poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.519) has a slightly higher hERG risk than Ligand B (0.85), but both are relatively low.

**Microsomal Clearance:** Ligand A (108.793 mL/min/kg) has a higher microsomal clearance than Ligand B (36.803 mL/min/kg), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (5.579 hours) has a significantly longer in vitro half-life than Ligand A (0.655 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.378) has lower P-gp efflux liability than Ligand B (0.022), which is favorable.

**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 can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both ligands have some issues with solubility and Caco-2 permeability, Ligand B demonstrates superior drug-like properties (higher QED), significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a much stronger binding affinity. The higher P-gp efflux of Ligand B is a minor concern compared to the significant advantages it offers.

Output:
1
2025-04-17 11:48:14,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 371.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.19 and 79.37) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.719 and 1.981) 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 scores (0.859 and 0.795) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (25.048) has a significantly lower DILI risk than Ligand B (49.399). This is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (72.082) has a slightly better BBB score than Ligand B (62.117).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.871 and -4.91), which 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 (-1.848 and -2.867), which is also unusual and suggests poor solubility. Again, the difference is small.

**hERG Inhibition:** Ligand A (0.205) has a lower hERG inhibition risk than Ligand B (0.443), which is favorable.

**Microsomal Clearance:** Ligand A (14.453) has significantly lower microsomal clearance than Ligand B (29.813), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-0.791) has a better (longer) in vitro half-life than Ligand B (-10.338). This further supports its better metabolic stability.

**P-gp Efflux:** Ligand A (0.015) has a lower P-gp efflux liability than Ligand B (0.174), which is beneficial for oral bioavailability.

**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 contributes to the overall preference for Ligand A.

**Conclusion:**

Ligand A is the more promising candidate. It demonstrates superior ADME properties, specifically lower DILI risk, lower microsomal clearance, longer half-life, lower P-gp efflux, and slightly better binding affinity. While both ligands have issues with Caco-2 permeability and solubility, Ligand A's advantages in metabolic stability and safety outweigh these concerns.

Output:
0
2025-04-17 11:48:14,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (377.271 Da and 361.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.56) is significantly better than Ligand B (100.35). TPSA < 140 is good for oral absorption, and both are within this limit, but A is preferable.

**3. logP:** Ligand A (3.109) is within the optimal range (1-3). Ligand B (0.6) is below 1, which could impede permeation. This is a significant drawback for Ligand B.

**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 7. Both are within the acceptable range (<=10), but A is better.

**6. QED:** Both ligands have similar QED values (0.805 and 0.812), indicating good drug-likeness.

**7. DILI:** Ligand A (53.742) has a lower DILI risk than Ligand B (62.389). Both are acceptable (<60 is good), but A is preferable.

**8. BBB:** Ligand A (37.456) has a slightly better BBB penetration percentile than Ligand B (21.791), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.595) has better Caco-2 permeability than Ligand B (-5.094).

**10. Aqueous Solubility:** Ligand A (-3.636) has better aqueous solubility than Ligand B (-2.464). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.732) has a lower hERG inhibition liability than Ligand B (0.127). This is a crucial advantage for Ligand A, reducing the risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (9.478) has higher microsomal clearance than Ligand B (4.56). Lower clearance is better for metabolic stability, so Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand A (26.551) has a longer in vitro half-life than Ligand B (-7.126). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.503) has lower P-gp efflux liability than Ligand B (0.027). Lower efflux is better for bioavailability.

**15. Binding Affinity:** Ligand B (-9.6) has a significantly stronger binding affinity than Ligand A (-8). This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from a low logP, which could severely limit its permeability and bioavailability. Ligand A has a more balanced profile with better solubility, lower hERG risk, better metabolic stability (longer half-life), and acceptable permeability. The difference in binding affinity is 1.6 kcal/mol, which is significant but not insurmountable, and can potentially be optimized in subsequent rounds of drug design. Given the overall profile, I believe Ligand A is the more viable drug candidate due to its better ADME properties and acceptable potency.

Output:
0
2025-04-17 11:48:14,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.394 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.52) is slightly above the preferred <140 for good absorption, while Ligand B (85.25) is well within the range.

**logP:** Both ligands have acceptable logP values (1.348 and 0.648), falling within the optimal 1-3 range. Ligand A is slightly more lipophilic.

**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 and <=10 HBA).

**QED:** Both ligands have similar QED values (0.613 and 0.608), indicating good drug-likeness.

**DILI:** Ligand A (43.66) has a moderate DILI risk, while Ligand B (17.72) has a much lower, and preferable, DILI risk.

**BBB:** Both ligands have reasonable BBB penetration (75.572 and 64.793), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.091 and -5.202), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.629 and -0.583), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.662) has a slightly higher hERG inhibition risk than Ligand B (0.307), but both are relatively low.

**Microsomal Clearance:** Ligand A (51.216) has a higher microsomal clearance than Ligand B (32.873), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (0.203) has a very short in vitro half-life, which is a major concern. Ligand A (-24.258) also has a negative half-life, which is also concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.114 and 0.042), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

While both ligands have strong binding affinities, Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a lower hERG risk. The negative Caco-2 and solubility values are concerning for both, but these issues might be addressable through formulation strategies. Ligand A's higher DILI and clearance are less desirable.

Output:
1
2025-04-17 11:48:14,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.431 and 345.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.42) is better than Ligand B (93.46), both are below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands (2.842 and 2.667) are within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1) is preferred over 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 (0.89) has a better QED score than Ligand B (0.767), indicating a more drug-like profile.

**7. DILI:** Ligand A (39.434) has a significantly lower DILI risk than Ligand B (65.917). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (80.419) is slightly better than Ligand B (74.06). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are log values, both are poor.

**10. Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**11. hERG:** Both ligands have low hERG risk (0.36 and 0.492).

**12. Cl_mic:** Ligand A (44.523) has lower microsomal clearance than Ligand B (91.545), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. t1/2:** Ligand B (-6.928) has a longer in vitro half-life than Ligand A (-5.422). This is a positive for Ligand B, but the difference is not huge.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.014 and 0.183).

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This is a 0.7 kcal/mol difference, which is significant, but must be weighed against the other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and in vitro half-life, Ligand A excels in critical ADME properties: significantly lower DILI risk, better QED, and lower microsomal clearance (better metabolic stability). The differences in these properties are more impactful for overall drug development success than the small difference in binding affinity. Both have poor solubility and Caco-2 permeability, which would need to be addressed during optimization, but Ligand A starts from a better position regarding safety and metabolic stability.

Output:
0
2025-04-17 11:48:14,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.776 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.04) is better than Ligand B (126.21). TPSA <140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.602) is optimal (1-3), while Ligand B (0.822) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=4, HBA=5) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED values (0.693 and 0.507, both >=0.5).

**DILI:** Ligand A (97.984) has a high DILI risk, while Ligand B (44.591) has a low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Both have moderate BBB penetration (65.684 and 61.225). Not a major concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.856) has a very poor Caco-2 permeability, while Ligand B (-5.637) is also poor, but slightly better.

**Solubility:** Ligand A (-4.698) has poor solubility, while Ligand B (-1.937) is better, but still poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.441 and 0.059).

**Microsomal Clearance:** Ligand A (36.34 mL/min/kg) has a moderate clearance, while Ligand B (12.198 mL/min/kg) has a much lower clearance, indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (52.453 hours) has a good half-life, while Ligand B (4.618 hours) has a very short half-life. This is a key advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.176 and 0.02).

**Binding Affinity:** Ligand B (-9.5 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 B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The poor solubility and Caco-2 permeability of both are concerns, but can potentially be addressed through formulation strategies. The high DILI risk of Ligand A is a major red flag that outweighs its longer half-life.

Output:
1
2025-04-17 11:48:14,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.495 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.53) is higher than Ligand B (59.08). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Both ligands have good logP values (1.613 and 1.148), 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 and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.647 and 0.646), indicating good drug-likeness.

**DILI:** Ligand A (16.208) has a lower DILI risk than Ligand B (19.193), which is favorable.

**BBB:** Both ligands have good BBB penetration (74.564 and 79.721). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.032) has worse Caco-2 permeability than Ligand B (-4.423).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.349 and -2.168). This is a potential issue that may require formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.184 and 0.2).

**Microsomal Clearance:** Ligand A (40.634) has a higher microsomal clearance than Ligand B (23.362), suggesting lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (6.05) has a significantly longer in vitro half-life than Ligand A (1.483). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.005 and 0.176).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a substantially better binding affinity than Ligand A (-6.9 kcal/mol). This ~1.6 kcal/mol difference is a significant advantage and can outweigh some of the ADME drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. The significantly improved binding affinity (-8.5 vs -6.9 kcal/mol) and longer half-life (6.05 vs 1.483 hours) are major advantages. While Ligand A has a slightly lower DILI risk, the superior potency and metabolic stability of Ligand B are more critical for a kinase inhibitor. The slightly lower TPSA and Caco-2 permeability of Ligand B are also beneficial. The solubility is a concern for both, but can be addressed through formulation.

Output:
1
2025-04-17 11:48:14,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.402 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (62.21), both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.212 and 1.74), 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 (0.861) has a better QED score than Ligand B (0.775), indicating a more drug-like profile.

**DILI:** Ligand A (68.282) has a higher DILI risk than Ligand B (18.224). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.6) has a higher BBB percentile than Ligand A (68.67).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. Assuming these are negative log values, both have good permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are negative log values, both have good solubility.

**hERG:** Ligand A (0.23) has a slightly better hERG profile than Ligand B (0.386), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (12.116 mL/min/kg) has a much lower microsomal clearance than Ligand A (52.239 mL/min/kg), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-8.143 hours) has a longer half-life than Ligand A (2.033 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.16) has lower P-gp efflux liability than Ligand B (0.047), which is slightly better.

**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 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 QED and hERG profile, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The lower DILI risk is particularly important.

Output:
1
2025-04-17 11:48:14,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.531 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.76) is well below the 140 threshold for oral absorption, and is favorable. Ligand B (99.1) is still within acceptable range, but less optimal.

**logP:** Ligand A (1.554) is within the optimal 1-3 range. Ligand B (0.042) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have similar QED values (0.68 and 0.648), indicating good drug-likeness.

**DILI:** Ligand A (21.636) has a significantly lower DILI risk than Ligand B (25.165), which is a major advantage. Both are below the 40 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.084) is higher than Ligand B (34.044).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.678 and -4.978), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is not huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.074 and -1.226), which is also concerning. Again, the difference isn't massive, but both need improvement.

**hERG Inhibition:** Ligand A (0.352) has a much lower hERG risk than Ligand B (0.098), a critical factor for safety.

**Microsomal Clearance:** Ligand A (40.378) has a higher microsomal clearance than Ligand B (4.738), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (3.138 hours) has a slightly longer half-life than Ligand A (-4.454 hours), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.079 and 0.018), which is good.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 1.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While its logP is low and solubility is poor, the significantly improved potency is likely to be more impactful. Ligand A has better DILI and hERG profiles, but the weaker binding affinity is a major drawback. The higher metabolic clearance of Ligand A is also a concern.

Output:
1
2025-04-17 11:48:14,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.447 and 362.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.47) is well below the 140 threshold, suggesting good absorption. Ligand B (96.25) is still within acceptable limits but higher, potentially slightly hindering absorption.

**logP:** Ligand A (3.38) is optimal. Ligand B (1.474) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Ligand A (0.85) has a strong drug-like profile. Ligand B (0.678) is still reasonable, but less ideal.

**DILI:** Ligand A (89.957) has a concerningly high DILI risk. Ligand B (66.576) is still elevated, but significantly better than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.035) and Ligand B (59.093) are both moderate.

**Caco-2 Permeability:** Ligand A (-4.492) is poor. Ligand B (-5.232) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.833) is poor. Ligand B (-2.678) is also poor, but better than Ligand A.

**hERG:** Ligand A (0.528) has a low hERG risk, which is excellent. Ligand B (0.344) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (69.704) is moderate. Ligand B (8.387) is very low, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (35.964) is moderate. Ligand B (45.304) is better.

**P-gp Efflux:** Both ligands (0.328 and 0.202) show low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This difference of 3.4 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having a slightly less optimal logP and Caco-2 permeability, its significantly superior binding affinity (-10.6 vs -7.2 kcal/mol) and substantially better metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target. The lower DILI risk for Ligand B is also a significant advantage, mitigating the major concern with Ligand A. While both have poor solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. The strong binding affinity of Ligand B suggests it is more likely to be a viable drug candidate.

Output:
1
2025-04-17 11:48:14,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.37 and 369.57) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.01) is significantly better than Ligand B (38.77), being well below the 140 threshold for oral absorption.

**logP:** Both ligands (3.428 and 3.733) are 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 acceptable.

**QED:** Both ligands have good QED scores (0.534 and 0.588), indicating drug-likeness.

**DILI:** Ligand A has a concerningly high DILI risk (86.933), while Ligand B has a low DILI risk (21.869). This is a major drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration (71.772 and 80.613), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.144 and -5.102), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation (negative values are often artifacts of the prediction method).

**Aqueous Solubility:** Both have negative solubility values (-4.466 and -3.83), also concerning, and requiring further investigation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.884 and 0.731), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (33.859) than Ligand B (79.7), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-6.446), which is impossible and indicates a prediction issue. Ligand B has a half-life of 18.824, which is reasonable.

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.503) while Ligand B has moderate efflux (0.685).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-10.2 kcal/mol) compared to Ligand A (0.0 kcal/mol). This is a decisive advantage.

**Conclusion:**

Despite Ligand A's better metabolic stability and P-gp efflux, its extremely high DILI risk, impossible half-life, and significantly weaker binding affinity make it a poor candidate. Ligand B, while having a higher Cl_mic and moderate P-gp efflux, possesses a much stronger binding affinity, low DILI risk, and a reasonable half-life. The negative Caco-2 and solubility values for both are concerning, but the substantial binding affinity advantage of Ligand B outweighs these concerns, especially given that these values may be prediction artifacts.

Output:
1
2025-04-17 11:48:14,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.43 and 352.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is well below the 140 threshold for good absorption, while Ligand B (113.62) is still acceptable but less optimal.

**logP:** Ligand A (1.672) is within the optimal 1-3 range. Ligand B (-0.456) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.765 and 0.582, both >= 0.5).

**DILI:** Ligand A (24.78) has a significantly lower DILI risk than Ligand B (48.62), indicating a safer profile.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.997) has a better BBB score than Ligand B (52.501), but it's not a primary concern here.

**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 (0.14) has a much lower hERG risk than Ligand B (0.318), a crucial factor for kinase inhibitors.

**Microsomal Clearance:** Ligand A (29.063) has a higher microsomal clearance than Ligand B (11.226), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-19.313) has a longer in vitro half-life than Ligand A (-25.953), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.016).

**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 (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is preferable despite its higher Cl_mic. Its significantly lower DILI and hERG risk are major advantages for a kinase inhibitor. The slightly lower affinity is less concerning than potential toxicity or rapid metabolism. Ligand B's lower logP and higher DILI risk are significant drawbacks.

Output:
0
2025-04-17 11:48:14,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.865 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is slightly higher than Ligand B (81.75). Both are below the 140 threshold for good absorption, but closer to the 90 threshold for CNS targets (not relevant here).

**logP:** Both ligands have similar logP values (0.386 and 0.349), which are a bit low. While not ideal, they aren't excessively low and shouldn't severely hinder permeation.

**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 (0.598 and 0.676), indicating good drug-like properties.

**DILI:** Ligand A (21.636) has a significantly lower DILI risk than Ligand B (11.283). This is a substantial advantage.

**BBB:** Both ligands have similar BBB penetration (54.13 and 52.889), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.124 and -4.914), which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.538 and -1.24), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.207 and 0.122). This is positive.

**Microsomal Clearance:** Ligand A (0.049) has significantly lower microsomal clearance than Ligand B (0.455), suggesting better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (7.757) has a much longer in vitro half-life than Ligand B (1.541). This is another significant advantage, reducing dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.002).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.4 kcal/mol). While the difference is not huge (0.4 kcal/mol), it is still a positive factor.

**Overall Assessment:**

Ligand A is the more promising candidate. It demonstrates a significantly lower DILI risk, better metabolic stability (lower Cl_mic), a longer half-life, and slightly better binding affinity. While both ligands suffer from poor predicted solubility and permeability, the improvements in safety and PK for Ligand A outweigh the small difference in binding affinity. The poor solubility and permeability would need to be addressed through formulation or further chemical modifications, but Ligand A provides a better starting point.

Output:
1
2025-04-17 11:48:14,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (360.845 Da) is also good.

**TPSA:** Both are acceptable, being below 140. Ligand A (73.2) is better than Ligand B (76.02) for oral absorption.

**logP:** Both ligands have good logP values (Ligand A: 3.496, Ligand B: 2.17), 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=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.682, Ligand B: 0.794), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (Ligand A: 10.469, Ligand B: 59.442). Ligand A is significantly better, with a much lower risk of liver injury.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (77.239) is better than Ligand B (66.382).

**Caco-2 Permeability:** Ligand A (-4.414) is significantly worse than Ligand B (-5.194). Lower values indicate poorer permeability.

**Aqueous Solubility:** Both have poor solubility (-2.941 and -3.199). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.729) is better than Ligand B (0.135), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (22.462) has a significantly lower Cl_mic than Ligand A (60.039), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (14.543) has a much longer half-life than Ligand A (0.911), which is highly desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (Ligand A: 0.083, Ligand B: 0.069).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a crucial advantage, outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME liabilities. The significantly better binding affinity (-7.6 vs -9.0 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B has better metabolic stability (lower Cl_mic, longer half-life). While solubility is poor for both, the superior potency and stability of Ligand B make it more likely to succeed, as these can be addressed through formulation. Ligand A has a better DILI score and hERG, but the weaker binding and poorer metabolic stability are significant drawbacks.

Output:
1
2025-04-17 11:48:14,616 - INFO - Batch 77 complete. Total preferences: 1232
2025-04-17 11:48:14,616 - INFO - Processing batch 78/512...
2025-04-17 11:49:00,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 354.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.5) is better than Ligand B (111.21), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.995) is within the optimal 1-3 range. Ligand B (-1.629) is below 1, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3, respectively), below the threshold of 5.

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

**QED:** Ligand A (0.751) has a better QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand B (21.83) has a significantly lower DILI risk than Ligand A (54.75), which is a major advantage.

**BBB:** Both ligands show low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (46.336) is slightly better than Ligand A (38.852).

**Caco-2 Permeability:** Ligand A (-4.873) has better Caco-2 permeability than Ligand B (-5.041), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-2.082) has better aqueous solubility than Ligand B (-0.446).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.124 and 0.107, respectively).

**Microsomal Clearance:** Ligand A (-11.934) has significantly lower microsomal clearance than Ligand B (-23.024), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.404) has a much longer in vitro half-life than Ligand B (1.054), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.001, respectively).

**Binding Affinity:** Ligand B (-11.0) has a significantly stronger binding affinity than Ligand A (-8.7). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has better solubility, permeability, and metabolic stability, the significantly stronger binding affinity of Ligand B (-11.0 vs -8.7 kcal/mol) is a decisive factor. The improved binding is likely to outweigh the slightly higher DILI risk and lower metabolic stability of Ligand B. The lower logP of Ligand B is a concern, but could be addressed with further optimization.

Output:
1
2025-04-17 11:49:00,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.539 Da and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (76.02) is still under 140, but less favorable than A.

**logP:** Ligand A (2.912) is optimal (1-3). Ligand B (1.861) is also within range, but slightly lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 4 HBA) is also good, but slightly higher counts.

**QED:** Both ligands have good QED scores (0.758 and 0.854), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (32.105 and 30.593), which is favorable.

**BBB:** Ligand A (71.501) has a better BBB percentile than Ligand B (61.962), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.044) and Ligand B (-4.985) 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 (-3.31 and -2.31). This is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.295 and 0.088), which is excellent.

**Microsomal Clearance:** Ligand A (49.318) has higher microsomal clearance than Ligand B (15.242). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (10.825 hours) has a significantly longer half-life than Ligand A (3.701 hours), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.25 and 0.036), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

While both compounds have excellent binding affinity and low hERG risk, Ligand B is the more promising candidate. Its significantly improved metabolic stability (lower Cl_mic, longer t1/2) outweighs the slightly lower logP and TPSA. The poor solubility and Caco-2 permeability are concerning for both, but can be addressed with formulation strategies. Ligand A's higher clearance and shorter half-life are less desirable.

Output:
1
2025-04-17 11:49:00,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.447 and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.52) is slightly above the preferred <100 for optimal absorption, but still reasonable. Ligand B (95.58) is well within the acceptable range.

**logP:** Ligand A (0.492) is quite low, potentially hindering membrane permeability. Ligand B (0.794) is also low, but 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 acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.415) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.807) is excellent, suggesting good drug-like properties.

**DILI:** Ligand A (15.51) has a very favorable DILI risk, significantly lower than Ligand B (69.678), which is approaching a higher risk category.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (65.801) shows slightly better penetration but it is not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.57 and -5.042), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.447 and -3.196), also unusual and indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.149) has a very low hERG risk, which is excellent. Ligand B (0.33) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (13.231) has a higher microsomal clearance than Ligand B (11.679), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-13.517) has a very short in vitro half-life, indicating rapid metabolism. Ligand B (-9.93) is better, but still relatively short.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.024).

**Binding Affinity:** Both ligands have comparable and good binding affinities (-7.4 and -7.5 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. It has a significantly better QED score, indicating a more drug-like profile. While both have poor solubility and permeability, Ligand B has a better metabolic stability profile (lower Cl_mic, longer t1/2) and a lower DILI risk. Ligand A's very low logP and extremely short half-life are significant liabilities. The slightly better solubility and DILI profile of Ligand B outweigh the slightly higher hERG risk.

Output:
1
2025-04-17 11:49:00,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.378 and 368.949 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.01) is better than Ligand B (33.73) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (1.525) is optimal, while Ligand B (4.492) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range (<=10).

**QED:** Both ligands (A: 0.663, B: 0.617) have good drug-likeness scores (>0.5).

**DILI:** Ligand A (69.601) has a higher DILI risk than Ligand B (9.112), which is a significant concern.

**BBB:** Both ligands have reasonable BBB penetration, with Ligand B (80.031) being slightly better than Ligand A (70.609). However, BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.191) has poor Caco-2 permeability, while Ligand B (-4.777) is also poor but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.177, B: -2.727).

**hERG Inhibition:** Ligand A (0.488) has a lower hERG risk than Ligand B (0.945), which is a positive attribute.

**Microsomal Clearance:** Ligand A (20.981) has significantly lower microsomal clearance than Ligand B (51.263), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (41.16) has a longer in vitro half-life than Ligand A (23.052), which is desirable.

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux than Ligand B (0.433), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk and poorer Caco-2 permeability, its significantly superior binding affinity (-8.9 vs -7.4 kcal/mol) and lower microsomal clearance make it the more promising candidate. The strong binding affinity is a critical factor for kinase inhibitors, and the improved metabolic stability is highly desirable. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization.

Output:
1
2025-04-17 11:49:00,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.483 and 378.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (97.75) is still under 140, but less favorable than A.

**logP:** Ligand A (1.441) is within the optimal 1-3 range. Ligand B (4.233) is slightly above this, 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 reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.81) has a very good QED score, indicating high drug-likeness. Ligand B (0.443) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (46.103) has a lower DILI risk than Ligand B (58.666), both are acceptable but A is preferable.

**BBB:** Both have reasonable BBB penetration, but Ligand A (70.803) is better than Ligand B (61.535). While SRC isn't a CNS target, better BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.662) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.515) is also poor, but slightly worse than A.

**Aqueous Solubility:** Ligand A (-2.272) and Ligand B (-3.14) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.246) has a very low hERG risk, which is excellent. Ligand B (0.553) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (27.29) has a lower microsomal clearance than Ligand B (38.673), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (33.509) has a significantly longer in vitro half-life than Ligand A (7.25), which is a major advantage.

**P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux than Ligand B (0.401), suggesting better absorption and bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better QED, lower DILI, lower hERG, lower Cl_mic, and lower P-gp efflux. However, it has poor Caco-2 permeability and aqueous solubility. Ligand B has a longer half-life, but its binding affinity is very weak, and it has a lower QED, higher DILI, and higher Cl_mic.

The significantly superior binding affinity of Ligand A (-8.1 vs -0.0 kcal/mol) is the deciding factor. While the permeability and solubility are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The weak binding of Ligand B is a much more difficult challenge to overcome.

Output:
1
2025-04-17 11:49:00,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (353.463 and 354.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.66) is slightly above the preferred <140, but acceptable. Ligand B (78.43) is well within the ideal range.

**3. logP:** Both ligands (1.065 and 2.077) are 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 (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have reasonable QED scores (0.743 and 0.655), indicating good drug-like properties.

**7. DILI:** Ligand A (35.479) has a lower DILI risk than Ligand B (22.761), which is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.821) shows better BBB penetration, but it's not a primary concern here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.824 and -4.789), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.249 and -2.699), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.309 and 0.521), which is good.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance rates (24.066 and 24.959 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (26.055) has a longer in vitro half-life than Ligand A (-21.325), which is a positive attribute.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.067 and 0.078).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 0.5 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Both compounds have significant issues with solubility and permeability. However, Ligand B has a better binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. The slightly lower DILI risk of Ligand A is a minor advantage, but the improved potency and stability of Ligand B are more important. The negative Caco-2 and solubility values are concerning and would require significant medicinal chemistry efforts to improve, but the higher affinity of Ligand B makes it the more promising starting point.

Output:
1
2025-04-17 11:49:00,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (347.503 and 363.38 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (84.23). A TPSA under 140 is good for oral absorption, and both are within this limit, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (2.084 and 2.696), 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 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.693 and 0.744), indicating good drug-like properties.

**7. DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (58.511). This is a significant advantage for Ligand A.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (74.06) is slightly better than Ligand A (68.282). However, BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.868) is slightly better than Ligand B (-4.775), but both are problematic.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.157) is slightly better than Ligand B (-3.047).

**11. hERG Inhibition:** Ligand A (0.235) has a much lower hERG inhibition liability than Ligand B (0.452). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (42.922) has lower microsomal clearance than Ligand B (52.705), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.508) has a negative half-life, which is impossible and suggests a data error or a very rapidly metabolized compound. Ligand A (2.132) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux than Ligand B (0.157), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 1.5 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly superior in terms of safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and P-gp efflux. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. The negative half-life for Ligand B is a major red flag. Given the enzyme-kinase prioritization, the safety and metabolic stability advantages of Ligand A outweigh the slightly better affinity of Ligand B.

Output:
0
2025-04-17 11:49:00,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (41.05). Lower TPSA generally improves oral absorption.

**logP:** Ligand A (2.122) is optimal, while Ligand B (4.649) is pushing the upper limit and could lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=6) both fall within acceptable ranges.

**QED:** Both ligands have similar and acceptable QED values (A: 0.67, B: 0.697).

**DILI:** Ligand A (32.726) has a much lower DILI risk than Ligand B (89.686), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B is slightly higher (77.898 vs 87.088). However, BBB is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.703) has better Caco-2 permeability than Ligand B (-5.002).

**Aqueous Solubility:** Ligand A (-2.091) has better aqueous solubility than Ligand B (-5.442). This is crucial for bioavailability.

**hERG:** Ligand A (0.609) has a lower hERG risk than Ligand B (0.84). This is a critical safety parameter.

**Microsomal Clearance:** Ligand A (18.874) has significantly lower microsomal clearance than Ligand B (101.011), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.734) has a shorter half-life than Ligand B (27.585), but the difference isn't drastic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.066, B: 0.695), which is good.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While a 0.5 kcal/mol difference is good, it's not enough to overcome the significant ADME/Tox advantages of Ligand A.

**Overall:** Ligand A is the superior candidate. It has better solubility, lower DILI risk, lower hERG risk, and significantly better metabolic stability. While Ligand B has slightly better binding affinity, the ADME/Tox profile of Ligand A is far more favorable for drug development, especially considering the enzyme target class.

Output:
0
2025-04-17 11:49:00,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.511 Da and 350.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (66.92), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.545) is optimal, while Ligand B (1.238) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0), 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:** Both ligands have similar QED values (0.645 and 0.694), indicating good drug-likeness.

**DILI:** Ligand B (33.812) has a significantly lower DILI risk than Ligand A (42.536), making it more favorable.

**BBB:** Both ligands have high BBB penetration (89.996 and 87.166), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.754) is better than Ligand B (-4.229), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.708) is better than Ligand B (-1.64), indicating better solubility.

**hERG Inhibition:** Ligand A (0.86) is better than Ligand B (0.432), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (44.184) has lower microsomal clearance than Ligand A (108.082), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (42.949) has a longer half-life than Ligand B (-1.441), which is desirable.

**P-gp Efflux:** Ligand A (0.66) is better than Ligand B (0.055), indicating lower P-gp efflux.

**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 significant.

**Overall Assessment:**

Ligand A has a better binding affinity, solubility, Caco-2 permeability, half-life, and P-gp efflux. However, Ligand B exhibits a much lower DILI risk and better metabolic stability (lower Cl_mic). The difference in binding affinity (0.5 kcal/mol) is a substantial advantage for Ligand A, and can outweigh some of the ADME drawbacks. Considering SRC is a kinase, metabolic stability and solubility are important, but potency is paramount. The improved potency of Ligand A, combined with acceptable ADME properties, makes it the more promising candidate.

Output:
1
2025-04-17 11:49:00,441 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.431, 107.89 ,   0.56 ,   4.   ,   5.   ,   0.427,  28.306,  20.512, -5.625,  -2.268,   0.081, -17.092,  17.733,   0.012,  -9.3  ]
**Ligand B:** [356.901,  47.71 ,   4.896,   2.   ,   2.   ,   0.603,  28.81 ,  55.603, -5.444,  -4.332,   0.931,  47.804,  65.569,   0.59 ,  -8.2  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A: 352.431, B: 356.901. No significant difference.
2. **TPSA:** A (107.89) is higher than B (47.71).  For an enzyme, TPSA is less critical than for CNS targets, but lower is generally preferred for permeability. B is significantly better.
3. **logP:** A (0.56) is lower than B (4.896). A is below the optimal range (1-3), potentially hindering permeation. B is at the upper end but still acceptable.
4. **HBD:** A (4) is higher than B (2).  Both are within the acceptable limit of 5.
5. **HBA:** A (5) is higher than B (2). Both are within the acceptable limit of 10.
6. **QED:** B (0.603) is better than A (0.427). B has a more drug-like profile.
7. **DILI:** Both are very similar and acceptable (A: 28.306, B: 28.81).
8. **BBB:** A (20.512) is much lower than B (55.603). Not a major concern for a non-CNS target like SRC.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-5.625) is slightly worse than B (-5.444).
10. **Solubility:** A (-2.268) is better than B (-4.332). Solubility is important for enzymes.
11. **hERG:** A (0.081) is much lower than B (0.931). This is a significant advantage for A, indicating lower cardiotoxicity risk.
12. **Cl_mic:** A (-17.092) is *much* lower (better) than B (47.804). A demonstrates significantly better metabolic stability.
13. **t1/2:** B (65.569) is much longer than A (17.733). Longer half-life is generally desirable.
14. **Pgp:** A (0.012) is much lower than B (0.59). Lower P-gp efflux is preferred.
15. **Affinity:** A (-9.3) is better than B (-8.2). A has a stronger binding affinity. The difference is >1.5 kcal/mol, which is significant.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Conclusion:**

While Ligand B has better QED and a longer half-life, Ligand A excels in the most critical areas for an enzyme inhibitor: significantly better binding affinity, much lower microsomal clearance (better metabolic stability), lower hERG risk, and lower Pgp efflux. The solubility of A is also better. The lower TPSA of B is a plus, but the substantial improvements in affinity and metabolic stability with A outweigh this benefit.

Therefore, I predict **Ligand A** is the more viable drug candidate.

1
2025-04-17 11:49:00,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.291 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.84) is better than Ligand B (62.55), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.087 and 2.679), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.915) has a significantly higher QED score than Ligand A (0.568), indicating a more drug-like profile.

**DILI:** Ligand B (30.826) has a much lower DILI risk than Ligand A (72.392). This is a substantial advantage.

**BBB:** Ligand A (92.672) has a higher BBB penetration percentile than Ligand B (62.97). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.48) has a better Caco-2 permeability than Ligand B (-5.078).

**Aqueous Solubility:** Ligand A (-3.294) has better solubility than Ligand B (-2.994).

**hERG:** Both ligands have very low hERG inhibition liability (0.521 and 0.204), which is excellent.

**Microsomal Clearance:** Ligand B (19.815 mL/min/kg) has a lower microsomal clearance than Ligand A (24.212 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (38.197 hours) has a significantly longer in vitro half-life than Ligand A (8.115 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.259 and 0.2), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.2 and -9.1 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B is superior overall. Its significantly lower DILI risk, higher QED, lower microsomal clearance, and longer half-life outweigh the minor differences in permeability and solubility. The binding affinity is essentially the same. Given the enzyme-kinase focus, metabolic stability and safety (DILI, hERG) are paramount, making Ligand B the more promising candidate.

Output:
1
2025-04-17 11:49:00,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.397 and 374.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.76) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (88.24) is still acceptable, but less optimal.

**logP:** Both ligands (2.707 and 2.051) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 7 HBA) both have reasonable H-bond characteristics, well within the suggested limits.

**QED:** Both ligands have good QED scores (0.757 and 0.862), indicating generally drug-like properties.

**DILI:** Ligand A (17.72) has a significantly lower DILI risk than Ligand B (75.766). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (83.211 and 84.606). While not a primary concern for a kinase inhibitor, it doesn't hurt.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.691 and -4.887). This is unusual and suggests poor permeability. However, kinase inhibitors are often not reliant on high passive absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.287 and -2.918), indicating poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.518 and 0.305). This is good.

**Microsomal Clearance:** Ligand A (15.261) has a significantly lower microsomal clearance than Ligand B (65.918), suggesting better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (16.167) has a longer in vitro half-life than Ligand B (-11.551). This further supports its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.072 and 0.042).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.9 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both have issues with Caco-2 and solubility, Ligand A boasts a significantly better binding affinity, lower DILI risk, and considerably improved metabolic stability (lower Cl_mic and longer t1/2). The stronger binding affinity is particularly important for an enzyme inhibitor, and the improved ADME properties increase the likelihood of achieving adequate exposure *in vivo*.

Output:
1
2025-04-17 11:49:00,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (338.455 and 368.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.95) is significantly better than Ligand B (76.02). Lower TPSA generally correlates with better cell permeability, crucial for kinase inhibitors to reach their intracellular target.

**3. logP:** Both ligands have acceptable logP values (1.988 and 2.268), 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 are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.847 and 0.821), indicating good drug-likeness.

**7. DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (57.619). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (77.007 and 79.721), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.533 and -5.166), indicating poor permeability. This is a concern for both, but less so for a kinase inhibitor that may rely more on active transport or intracellular accumulation.

**10. Aqueous Solubility:** Ligand A (-1.185) is better than Ligand B (-3.416), though both are poor. Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.686) has a lower hERG risk than Ligand B (0.305). This is a crucial safety parameter.

**12. Microsomal Clearance:** Ligand A (3.597) has lower microsomal clearance than Ligand B (6.775), suggesting better metabolic stability. This is a key advantage for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-1.544) has a longer in vitro half-life than Ligand B (-3.394), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.224) has lower P-gp efflux than Ligand B (0.083), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand A (-11.3) has a significantly stronger binding affinity than Ligand B (-9.2). A 2.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It demonstrates significantly better binding affinity, lower DILI risk, lower hERG inhibition, improved metabolic stability (lower Cl_mic and longer t1/2), and better solubility. While both ligands have poor Caco-2 permeability, the strong binding affinity and favorable ADME properties of Ligand A make it a more promising starting point for further optimization.

Output:
1
2025-04-17 11:49:00,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.47 and 348.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (128.53) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (3.071) is optimal (1-3). Ligand B (0.546) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is acceptable but less ideal.

**QED:** Both ligands have reasonable QED scores (0.776 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (35.48) has a lower DILI risk than Ligand B (50.14), which is preferable. Both are below the concerning 60 threshold.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (64.95) is better than Ligand B (19.54).

**Caco-2 Permeability:** Ligand A (-4.547) is better than Ligand B (-5.503), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.902) is better than Ligand B (-1.623), which is crucial for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.575 and 0.133), which is excellent.

**Microsomal Clearance:** Ligand A (21.553) is better than Ligand B (-0.505). A positive value for B suggests very rapid clearance, a significant drawback.

**In vitro Half-Life:** Ligand A (10.549 hours) is much better than Ligand B (-34.157 hours). A negative value for B suggests a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.165 and 0.032).

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

**Conclusion:**

Ligand A is clearly superior. While both have excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better predicted ADME properties: higher solubility, better permeability, lower DILI risk, and, crucially, much better metabolic stability (lower clearance, longer half-life). Ligand B's low logP and extremely rapid clearance are major red flags.

Output:
1
2025-04-17 11:49:00,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.34 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.56) is significantly better than Ligand B (75.19).  A TPSA under 140 is good for oral absorption, and both are within that range, but lower is preferable.

**logP:** Ligand A (4.683) is higher than Ligand B (1.975). While 1-3 is optimal, Ligand A is pushing the upper limit and could have solubility issues. Ligand B is well within the optimal 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 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.839 and 0.742), indicating good drug-like properties.

**DILI:** Ligand A (74.021) has a higher DILI risk than Ligand B (68.282). Both are acceptable, but lower is better.

**BBB:** Ligand A (48.003) has a slightly better BBB penetration than Ligand B (36.836), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a major concern.

**Caco-2 Permeability:** Ligand A (-4.708) has better Caco-2 permeability than Ligand B (-5.135). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-5.593) has significantly better aqueous solubility than Ligand B (-2.094). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.791) has a slightly higher hERG risk than Ligand B (0.238). Lower is much better here.

**Microsomal Clearance:** Ligand B (30.516) has significantly lower microsomal clearance than Ligand A (63.537), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (44.367) has a significantly longer in vitro half-life than Ligand A (18.118), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux than Ligand B (0.046), which is generally favorable.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.9). While both are excellent, the 0.2 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better solubility and slightly better Caco-2 permeability, Ligand B excels in the critical areas of metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and a slightly better binding affinity. The logP for Ligand B is also more optimal. The differences in metabolic stability and hERG risk are particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:49:00,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.515 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.35) is significantly better than Ligand B (93.26). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (4.117) is a bit high, potentially leading to solubility issues, but still within a manageable range. Ligand B (1.439) is on the lower side, which could hinder permeability. Optimal is 1-3, and A is slightly outside.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better balanced than Ligand B (1 HBD, 6 HBA). Excessive HBA can sometimes reduce permeability.

**QED:** Both ligands have similar and acceptable QED values (0.862 and 0.848).

**DILI:** Ligand A (31.524) has a much lower DILI risk than Ligand B (58.511). This is a significant advantage for A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (81.698) is better than Ligand B (68.941). This isn't a primary concern for a kinase inhibitor, but it's a slight plus for A.

**Caco-2 Permeability:** Ligand A (-4.597) is better than Ligand B (-5.131), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.5) is better than Ligand B (-2.552), indicating better solubility.

**hERG Inhibition:** Ligand A (0.843) has a lower hERG risk than Ligand B (0.159). This is a crucial advantage for A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (68.881) has higher clearance than Ligand B (30.541), indicating lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand B (-21.478) has a significantly longer half-life than Ligand A (30.176). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.435) has lower P-gp efflux than Ligand B (0.054), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.6 kcal/mol), with Ligand B being slightly better. However, the difference is small and likely not enough to outweigh the other factors.

**Overall Assessment:**

Ligand A has several advantages: better TPSA, lower DILI risk, better BBB, better Caco-2 permeability, better solubility, and lower hERG risk. Ligand B has a longer half-life, but suffers from higher DILI risk, lower solubility, and higher hERG risk. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A appears to be the more promising candidate despite its slightly higher clearance. The lower DILI and hERG risks are particularly important.

Output:
0
2025-04-17 11:49:00,441 - INFO - Batch 78 complete. Total preferences: 1248
2025-04-17 11:49:00,441 - INFO - Processing batch 79/512...
2025-04-17 11:49:43,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.415 and 355.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.89) is higher than Ligand B (75.88). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.518) 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:** Ligand A (4) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.619 and 0.781), indicating drug-like properties.

**DILI:** Ligand A (35.712) has a better DILI score than Ligand B (41.915), suggesting lower liver injury risk.

**BBB:** Ligand A (65.839) has a lower BBB penetration percentile than Ligand B (92.71). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Ligand A (-4.974) has worse Caco-2 permeability than Ligand B (-4.041).

**Aqueous Solubility:** Ligand A (-1.683) has worse solubility than Ligand B (-2.473). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.449) has a slightly better hERG profile than Ligand B (0.365), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (34.877) has lower microsomal clearance than Ligand B (39.027), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-2.137) has a significantly better in vitro half-life than Ligand B (-28.382), suggesting a longer duration of action. This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.145), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a 1.6 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a clear advantage in binding affinity and logP, and better Caco-2 permeability. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), better solubility, and lower P-gp efflux. The difference in binding affinity is significant, but the improved pharmacokinetic properties of Ligand A are crucial for an enzyme target like SRC kinase. The lower logP of Ligand A is a concern, but the strong affinity and favorable metabolic profile could compensate for this.

Output:
1
2025-04-17 11:49:43,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.415 and 348.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (96.11 and 93.01) below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands exhibit optimal logP values (1.614 and 1.334), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3 HBD) is preferable to Ligand B (1 HBD) as it balances solubility and permeability.

**5. H-Bond Acceptors:** Ligand A (4 HBA) and Ligand B (6 HBA) are both acceptable, but Ligand B is slightly higher.

**6. QED:** Both ligands have similar QED values (0.711 and 0.716), indicating good drug-like properties.

**7. DILI:** Ligand A (56.805) has a significantly lower DILI risk than Ligand B (64.288). This is a crucial advantage.

**8. BBB:** Both ligands have similar, moderate BBB penetration (51.415 and 56.999). This isn't a primary concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.367 and -5.21), which is unusual and suggests poor permeability. However, these values are on a log scale and might not be directly comparable without knowing the units.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.687 and -2.041), indicating poor aqueous solubility. This is a concern, but can be addressed through formulation strategies.

**11. hERG Inhibition:** Ligand A (0.459) has a lower hERG inhibition liability than Ligand B (0.075), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (1.758 mL/min/kg) has a much lower microsomal clearance than Ligand B (40.744 mL/min/kg). This indicates significantly better metabolic stability for Ligand A, a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (14.813 hours) has a longer in vitro half-life than Ligand B (-6.54 hours). This is a substantial advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux liability than Ligand B (0.091), which is favorable for oral bioavailability.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). This difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a lower DILI risk, lower hERG inhibition, much better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have poor solubility and permeability, the superior safety and pharmacokinetic properties of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 11:49:43,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (373.513 and 366.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (87.66).  A TPSA under 140 is good for oral absorption, and both are under this limit, but A is much closer to the optimal range.

**logP:** Ligand A (4.306) is a bit high, potentially leading to solubility issues, while Ligand B (1.27) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (3 HBD, 4 HBA) as it has fewer potential issues with both solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.836 and 0.661, respectively), indicating good drug-like properties.

**DILI:** Ligand A (37.03) has a slightly higher DILI risk than Ligand B (26.987), but both are below the concerning threshold of 60.

**BBB:** Both have good BBB penetration, but Ligand A (88.6) is better than Ligand B (71.966). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 the relative values. Ligand A (-4.525) is slightly better than Ligand B (-4.645).

**Aqueous Solubility:** Ligand A (-4.252) is better than Ligand B (-1.79), indicating better solubility.

**hERG:** Ligand A (0.686) has a lower hERG risk than Ligand B (0.356), which is a significant advantage.

**Microsomal Clearance:** Ligand A (66.548) has a higher clearance than Ligand B (8.265). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-19.493) has a much longer in vitro half-life than Ligand A (-3.078), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.234) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 kcal/mol and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic and much longer t1/2), despite its higher TPSA and slightly lower solubility. The similar binding affinity makes the ADME properties the deciding factor. While Ligand A has a better hERG profile, the metabolic stability of Ligand B is more critical for a kinase inhibitor, as it impacts drug exposure and duration of action.

Output:
1
2025-04-17 11:49:43,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.423 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (62.4) is slightly higher than Ligand B (60.77), but both are good.

**logP:** Both ligands have logP values between 3 and 4, which is optimal. Ligand B (3.854) is slightly higher than Ligand A (3.376), but both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both fall within the acceptable ranges (HBD <=5, HBA <=10).

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.871) is higher than Ligand B (0.7), suggesting a slightly better overall drug-likeness.

**DILI:** Ligand A (59.984) has a higher DILI risk than Ligand B (35.789). This is a significant concern, as lower DILI is preferred.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (75.107) has a higher BBB percentile than Ligand B (61.962).

**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 ligands have negative solubility values, which is also unusual and problematic. It suggests poor solubility.

**hERG Inhibition:** Ligand A (0.738) has a slightly higher hERG risk than Ligand B (0.67), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand B (54.964) has a lower microsomal clearance than Ligand A (78.001), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (30.859 hours) has a significantly longer half-life than Ligand A (-32.378 hours). The negative value for Ligand A is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have relatively low P-gp efflux liability (Ligand A: 0.482, Ligand B: 0.808).

**Binding Affinity:** Ligand B (-9.1 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. The difference of 1.7 kcal/mol is significant.

**Conclusion:**

Despite Ligand A having a slightly better QED and BBB, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.1 vs -7.4 kcal/mol) and better metabolic stability (lower Cl_mic, significantly longer t1/2) are crucial for an enzyme inhibitor. While Ligand A's DILI risk is a concern, the superior potency and stability of Ligand B make it the better choice. The negative solubility and Caco-2 values are concerning for both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 11:49:43,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.531 and 356.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have similar TPSA values (49.41 and 49.33), which are acceptable for oral absorption (<=140).

**3. logP:** Ligand A (4.055) is slightly higher than Ligand B (2.964). While both are within the optimal range of 1-3, Ligand A is approaching the upper limit and could potentially have solubility issues.

**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 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.639 and 0.848), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (13.571) has a significantly lower DILI risk than Ligand B (41.993). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (78.868 and 77.821). This isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.809 and -4.78), which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.148 and -2.085), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.484) has a lower hERG inhibition risk than Ligand B (0.794), which is preferable.

**12. Microsomal Clearance:** Ligand A (57.072) has a higher microsomal clearance than Ligand B (42.009), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (-11.924) has a shorter in vitro half-life than Ligand B (-11.096), indicating faster degradation. This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.449) has a higher P-gp efflux liability than Ligand B (0.371), which could reduce bioavailability. This favors Ligand B.

**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 for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a much lower DILI risk, which are key advantages for an enzyme inhibitor. However, it suffers from higher microsomal clearance, shorter half-life, and higher P-gp efflux. Ligand B has better metabolic stability and efflux properties, but its DILI risk is considerably higher and its binding affinity is significantly weaker.

Given the importance of potency and safety (DILI) for kinase inhibitors, and the substantial difference in binding affinity (-7.5 vs 0.0 kcal/mol), I would prioritize Ligand A. While the ADME properties of Ligand A are not ideal, the strong binding affinity suggests it might still be a viable starting point for optimization, and the DILI risk is acceptable. The poor solubility and permeability of both compounds would need to be addressed through formulation or structural modifications.

Output:
0
2025-04-17 11:49:43,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.55 and 362.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (94.51) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (3.257) is optimal (1-3). Ligand B (1.68) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (0 HBD, 9 HBA) both meet the criteria (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.746 and 0.742), indicating good drug-likeness.

**DILI:** Ligand A (12.679) has a significantly lower DILI risk than Ligand B (82.784). This is a major advantage for A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (87.088) has a slightly better score than Ligand B (78.945).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.88 and -4.734), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.42 and -3.671), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.668) has a lower hERG risk than Ligand B (0.238), which is preferable.

**Microsomal Clearance:** Ligand A (58.82) has lower microsomal clearance than Ligand B (80.829), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.107) has a significantly longer in vitro half-life than Ligand B (-3.211), which is a major advantage.

**P-gp Efflux:** Ligand A (0.132) has lower P-gp efflux than Ligand B (0.098), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial difference (1.9 kcal/mol), and could potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, Ligand A is the more promising candidate. The significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and better P-gp efflux profile of Ligand A are crucial for a kinase inhibitor. While both have poor solubility and permeability, the ADME profile of Ligand A is substantially better. The 1.9 kcal/mol difference in binding affinity might be overcome with further optimization of Ligand A, while mitigating the ADME issues of Ligand B would be more challenging.

Output:
0
2025-04-17 11:49:43,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.447 and 367.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.29) is slightly higher than Ligand B (68.78), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.921) is optimal, while Ligand B (0.747) 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 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.71 and 0.734), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 78.635, which is concerningly high. Ligand B has a much lower DILI risk of 27.801, a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand B (64.482) has a higher value than Ligand A (46.84).

**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 concerning.

**hERG Inhibition:** Ligand A (0.752) shows a slightly higher hERG risk than Ligand B (0.558), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.563) has a higher clearance than Ligand B (22.571), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (111.766 hours) has a significantly longer half-life than Ligand B (15.043 hours), a major advantage.

**P-gp Efflux:** Ligand A (0.527) shows slightly less P-gp efflux than Ligand B (0.007).

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

**Overall Assessment:**

While Ligand A has a longer half-life, its high DILI risk and weaker binding affinity are major drawbacks. Ligand B, despite its lower half-life and slightly lower logP, exhibits a much better safety profile (DILI) and significantly stronger binding affinity. The potency advantage of Ligand B outweighs the concerns about its half-life, as this can be addressed through structural modifications. The solubility issues for both compounds need to be investigated and addressed.

Output:
1
2025-04-17 11:49:43,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.427 and 342.374 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.51 and 79.04) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.617) is optimal, while Ligand B (3.465) is approaching the upper limit.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2/3) and HBA (3/3) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.583 and 0.6), indicating drug-like properties.

**DILI:** Ligand A (21.52) has a significantly lower DILI risk than Ligand B (91.819). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (60.876) and Ligand B (57.154) are comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.852 and -4.846). This is unusual and suggests poor permeability, but the values are very similar.

**Aqueous Solubility:** Ligand A (-2.851) has better solubility than Ligand B (-4.947). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.386) has a lower hERG risk than Ligand B (0.758), which is a significant advantage.

**Microsomal Clearance:** Ligand A (12.148 mL/min/kg) has a much lower microsomal clearance than Ligand B (68.448 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.649 hours) has a shorter half-life than Ligand B (21.971 hours). This is a drawback for Ligand A, but can be mitigated through formulation strategies.

**P-gp Efflux:** Ligand A (0.032) has lower P-gp efflux than Ligand B (0.166), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.4 kcal/mol), which is comparable.

**Overall Assessment:**

Ligand A is significantly better due to its much lower DILI risk, better solubility, lower hERG risk, and improved metabolic stability (lower Cl_mic). While its half-life is shorter, this is less critical than avoiding potential toxicity and ensuring adequate exposure. The similar binding affinity makes the ADME/Tox differences decisive.

Output:
0
2025-04-17 11:49:43,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.286 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption (A: 111.16, B: 110.8). This is good.

**logP:** Ligand A (2.6) is optimal, while Ligand B (-0.372) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (6 & 6) counts.

**QED:** Both have reasonable QED scores (A: 0.433, B: 0.538), with B being slightly better.

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a major concern. Ligand B has a much lower and acceptable DILI risk (37.301%).

**BBB:** Both have similar BBB penetration (A: 66.576, B: 67.197). Not critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but we can assume this means low permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Ligand A (0.421) has a slightly higher hERG risk than Ligand B (0.107), but both are relatively low.

**Microsomal Clearance:** Ligand B has significantly lower microsomal clearance (3.015 mL/min/kg) compared to Ligand A (62.435 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (10.272 hours) than Ligand A (69.034 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.327, B: 0.022).

**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.

**Conclusion:**

Despite Ligand A having slightly better binding affinity, the extremely high DILI risk is a deal-breaker. Ligand B has a much more favorable safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and acceptable physicochemical properties. The slightly lower logP of Ligand B is a concern, but the superior ADME-Tox profile outweighs this drawback.

Output:
1
2025-04-17 11:49:43,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.312 and 390.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (92.78), being comfortably below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (2.281) is optimal, while Ligand B (0.603) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is better balanced than Ligand B (1 HBD, 6 HBA).

**QED:** Both ligands have similar QED values (0.739 and 0.61), indicating good drug-likeness.

**DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (33.501), but both are acceptable.

**BBB:** Ligand B (59.636) has a better BBB percentile than Ligand A (38.736), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.755) has a much better Caco-2 permeability than Ligand B (-5.051).

**Aqueous Solubility:** Ligand A (-3.72) has better aqueous solubility than Ligand B (-2.81).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.519 and 0.212).

**Microsomal Clearance:** Ligand A (11.67 mL/min/kg) has significantly lower microsomal clearance than Ligand B (63.004 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (32.034 hours) has a much longer in vitro half-life than Ligand B (-56.416 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 (0.143 and 0.017).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). The difference is 0.8 kcal/mol, which is not large enough to overcome the ADME deficiencies of Ligand B.

**Overall:**

Ligand A is superior. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: better logP, solubility, Caco-2 permeability, significantly lower microsomal clearance, and a much longer half-life. These factors are critical for kinase inhibitors, where metabolic stability and adequate exposure are essential. The higher DILI risk for Ligand A is a concern, but manageable.

Output:
0
2025-04-17 11:49:43,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.36 and 344.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.05) is slightly higher than Ligand B (58.44). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (2.75 and 2.01), 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.

**QED:** Ligand A (0.882) has a significantly higher QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand B (25.51) has a much lower DILI risk than Ligand A (52.11), which is a significant advantage.

**BBB:** Ligand A (92.94) has better BBB penetration than Ligand B (77.71), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.44) is slightly better than Ligand B (-4.79).

**Aqueous Solubility:** Ligand B (-1.00) has better aqueous solubility than Ligand A (-3.05).

**hERG Inhibition:** Ligand A (0.46) has a slightly lower hERG risk than Ligand B (0.20), which is preferable.

**Microsomal Clearance:** Ligand A (-10.55) has significantly lower microsomal clearance than Ligand B (48.68), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-29.54) has a longer in vitro half-life than Ligand B (-14.27), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.10) has lower P-gp efflux than Ligand B (0.17), which is favorable.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This 2.3 kcal/mol difference is substantial and outweighs many of the ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand B's better DILI and solubility, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.6 vs -7.3 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme inhibitor. The higher QED score also supports its drug-likeness. While the Caco-2 permeability is poor for both, the potency and metabolic stability advantages of Ligand A are more critical for initial development.

Output:
1
2025-04-17 11:49:43,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.411 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.7) is slightly higher than Ligand B (75.51). Both are below the 140 threshold for good oral absorption, which is favorable.

**3. logP:** Ligand A (3.09) is within the optimal range (1-3). Ligand B (1.605) is at the lower end, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is preferred over Ligand B (0) as a single donor can aid solubility without significantly impacting permeability.

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

**6. QED:** Ligand A (0.828) has a significantly better QED score than Ligand B (0.366), indicating a more drug-like profile.

**7. DILI:** Ligand B (46.297) has a much lower DILI risk than Ligand A (72.043). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (83.986) has better BBB penetration than Ligand B (56.301), but this is less crucial for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.036 and -4.508), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Ligand A (-4.5) has slightly better solubility than Ligand B (-1.627), but both are poor.

**11. hERG Inhibition:** Ligand B (0.089) has a much lower hERG risk than Ligand A (0.305). This is a critical advantage.

**12. Microsomal Clearance:** Ligand A (104.545) has higher microsomal clearance than Ligand B (60.476), indicating lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand B (15.44) has a significantly longer half-life than Ligand A (-9.486). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.164) has lower P-gp efflux than Ligand B (0.099), which is slightly favorable.

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-8.4). While A is better, the difference is not substantial enough to overcome the ADME liabilities.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor Caco-2 permeability and solubility, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG risk. These factors are crucial for an enzyme inhibitor. The slightly better binding affinity of Ligand A is outweighed by its poorer ADME profile.

Output:
1
2025-04-17 11:49:43,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.431 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (50.36 and 49.41) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (4.196 and 3.89) are slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects, but not drastically.

**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 (0.661 and 0.838), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 11.128, while Ligand B has 7.057. Both are low and desirable.

**BBB:** Both have high BBB penetration (89.298 and 83.288), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.325 and -4.668). This is unusual and suggests poor permeability, but the scale is not defined and could be relative to a standard.

**Aqueous Solubility:** Both have negative solubility values (-4.063 and -3.748). Similar to Caco-2, the scale is unclear, but negative values suggest poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.86 and 0.643), which is excellent.

**Microsomal Clearance:** Ligand A has a Cl_mic of 61.971, while Ligand B has 57.215. Lower is better, but both are reasonably acceptable.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (-17.566) compared to Ligand A (0.685). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.069 and 0.085).

**Binding Affinity:** Ligand A has an affinity of -9.0 kcal/mol, while Ligand B has -8.4 kcal/mol. Ligand A has a 0.6 kcal/mol advantage in binding affinity.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates significantly improved metabolic stability (longer half-life) and slightly better DILI risk. Given the enzyme-specific priorities, metabolic stability is crucial. The solubility and permeability concerns are present in both, but the superior half-life of Ligand B outweighs the small affinity difference.

Output:
1
2025-04-17 11:49:43,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 369.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good absorption. Ligand B (91.42) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (1.891 and 1.017), 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 HBAs, and Ligand B has 6. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.767 and 0.722), indicating good drug-likeness.

**DILI:** Ligand A (31.989) has a significantly lower DILI risk than Ligand B (67.235). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.786) is better than Ligand B (42.342), but neither is particularly high.

**Caco-2 Permeability:** Ligand A (-4.682) has a worse Caco-2 permeability than Ligand B (-5.378). Both are negative, suggesting poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.26) has better aqueous solubility than Ligand B (-2.336). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.192 and 0.233), which is excellent.

**Microsomal Clearance:** Ligand A (31.256) has significantly lower microsomal clearance than Ligand B (45.079), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (12.691 hours) has a positive half-life, while Ligand B (-20.345 hours) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.087).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This difference of 1.8 kcal/mol is a significant advantage.

**Overall Assessment:**

Ligand A is substantially better. While Ligand B has slightly better Caco-2 permeability, Ligand A excels in nearly all other critical parameters: significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and positive t1/2), and better aqueous solubility. The strong binding affinity of Ligand A can likely compensate for the slightly lower Caco-2 permeability. Given the enzyme-specific priorities, the superior potency and ADME profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 11:49:43,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (107.35 & 108.29) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (0.51) is quite low, potentially hindering permeation. Ligand B (3.045) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

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

**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 (0.612 and 0.683), indicating drug-like properties.

**DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (72.741), but both are above the 60 threshold and therefore concerning.

**BBB:** BBB is not a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired. Ligand B (52.734) has a higher BBB percentile than Ligand A (32.726).

**Caco-2:** Both ligands have negative Caco-2 values (-5.092 and -4.947), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Solubility:** Both ligands have negative solubility values (-2.581 and -4.345), also unusual and indicating very poor aqueous solubility. This is a major concern for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.256 and 0.192), which is excellent.

**Microsomal Clearance:** Ligand A (-19.225) has a much lower (better) microsomal clearance than Ligand B (52.661), indicating significantly better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-8.417) has a negative half-life, which is not possible. Ligand B (25.801) has a reasonable half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.034), which is good.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-9.2 and -9.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has better logP and in vitro half-life. However, Ligand A exhibits significantly better metabolic stability (lower Cl_mic). Both have poor solubility and permeability (negative Caco-2 and solubility values). The DILI risk is high for both. Considering the enzyme-specific priorities, metabolic stability is crucial. While the solubility and permeability are problematic for both, these can potentially be addressed with formulation strategies. The slight advantage in affinity is negligible.

Output:
0
2025-04-17 11:49:43,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.871 Da) is slightly higher than Ligand B (344.323 Da), but both are acceptable.

**TPSA:** Ligand A (64.63) is better than Ligand B (106.87). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (3.389) is within the optimal range (1-3), while Ligand B (1.266) is at the lower end. A slightly higher logP can be beneficial for membrane permeability, but needs to be balanced with solubility.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) has a more favorable profile than Ligand B (HBD=2, HBA=6). Lower numbers are generally preferred for better permeability.

**QED:** Both ligands have similar QED values (A: 0.73, B: 0.604), indicating good drug-likeness.

**DILI:** Ligand B (90.074) has a significantly higher DILI risk than Ligand A (55.836). This is a major concern, as liver toxicity is a common reason for drug failure.

**BBB:** Both have reasonable BBB penetration, but Ligand A (77.705) is better than Ligand B (61.846). While not a primary concern for a kinase inhibitor, better BBB penetration could be advantageous.

**Caco-2 Permeability:** Ligand A (-4.64) is better than Ligand B (-5.052). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.234) is better than Ligand B (-3.376). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.598) has a lower hERG risk than Ligand B (0.223). Lower hERG risk is critical to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand B (-20.461) exhibits significantly lower microsomal clearance than Ligand A (60.758). This suggests better metabolic stability for Ligand B, which is highly desirable for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-4.608) has a longer in vitro half-life than Ligand A (-31.235). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux than Ligand B (0.085). Lower efflux is generally preferred.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). A 1.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and better overall ADME properties, especially regarding DILI and hERG risk. While Ligand B has better metabolic stability and half-life, the high DILI risk is a major red flag. The stronger binding affinity of Ligand A is a significant advantage for an enzyme inhibitor, and the differences in metabolic stability, while present, might be addressable through further optimization.

Output:
1
2025-04-17 11:49:43,169 - INFO - Batch 79 complete. Total preferences: 1264
2025-04-17 11:49:43,169 - INFO - Processing batch 80/512...
2025-04-17 11:50:34,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 346.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.7) is higher than Ligand B (58.6). While both are reasonably good, Ligand B is better positioned for oral absorption being closer to the <140 threshold.

**logP:** Ligand A (1.15) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (2.75) is well within the optimal 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, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.777 and 0.833), indicating good drug-like properties.

**DILI:** Ligand A (51.7) has a higher DILI risk than Ligand B (11.1), which is a significant advantage for B.

**BBB:** Both have high BBB penetration (91.2 and 88.1), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values which is unusual. Assuming these are percentile scores, both are poor.

**Solubility:** Both have negative solubility values which is unusual. Assuming these are percentile scores, both are poor.

**hERG:** Ligand A (0.33) has a lower hERG risk than Ligand B (0.85), which is a positive for A.

**Microsomal Clearance:** Ligand A (68.9) has higher microsomal clearance than Ligand B (45.1), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-15.6) has a much longer in vitro half-life than Ligand A (-3.6), indicating better metabolic stability. This is a major advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.2 and 0.09), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference isn't huge, it's still a positive for B.

**Overall:**

Ligand B is the better candidate. It has a lower DILI risk, better logP, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While Ligand A has a lower hERG risk, the benefits of Ligand B's improved ADME properties and potency outweigh this. The poor Caco-2 and solubility scores for both are concerning and would require further investigation, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 11:50:34,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.427 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.39 and 78.09) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (4.17) is slightly higher than optimal (1-3), potentially leading to solubility issues. Ligand B (2.702) is within the ideal range.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.789 and 0.779), indicating good drug-likeness.

**DILI:** Ligand A (61.419) has a higher DILI risk than Ligand B (40.403). Ligand B is preferable here.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (74.952) is slightly better than Ligand B (67.119). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.595 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 (-5.277 and -3.9), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.329 and 0.168), which is excellent.

**Microsomal Clearance:** Ligand A (96.954) has higher microsomal clearance than Ligand B (59.786), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (-28.73) has a significantly longer in vitro half-life than Ligand A (8.913), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.386 and 0.103), which is favorable.

**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 B is the more promising candidate. While both have poor solubility and permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic and longer t1/2) and a lower DILI risk. The binding affinity is comparable. The slightly better logP of Ligand B is also a benefit. The poor solubility and permeability are serious issues that would need to be addressed through formulation or further chemical modification, but Ligand B's superior ADME properties give it a clear advantage.

Output:
1
2025-04-17 11:50:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.487 and 381.973 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is better than Ligand B (30.29) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (2.751) is optimal (1-3), while Ligand B (4.616) is slightly high, potentially leading to solubility issues and off-target effects.

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

**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 (0.501 and 0.6), indicating drug-like properties.

**DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (33.501), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (89.88) has a better BBB percentile than Ligand B (48.895).

**Caco-2 Permeability:** Ligand A (-4.655) has a worse Caco-2 permeability than Ligand B (-5.061).

**Aqueous Solubility:** Ligand A (-2.481) has better aqueous solubility than Ligand B (-4.536).

**hERG Inhibition:** Ligand A (0.602) has a lower hERG risk than Ligand B (0.919), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (66.685) has lower microsomal clearance than Ligand B (88.65), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.544) has a longer in vitro half-life than Ligand B (49.809), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.296) has lower P-gp efflux than Ligand B (0.792), which improves bioavailability.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.0), but the difference is less than 1.5 kcal/mol and can be outweighed by other factors.

**Overall:** Considering all factors, Ligand A is the more promising candidate. It has a lower DILI risk, better solubility, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a good QED score. While Ligand B has slightly better binding affinity, the other ADME properties of Ligand A make it a more viable drug candidate.

Output:
0
2025-04-17 11:50:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.403 and 362.857 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.69) is slightly higher than Ligand B (64.35). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (0.171) is quite low, potentially hindering permeability. Ligand B (3.389) 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 6 HBA, while Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have high QED scores (0.838 and 0.8), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (55.719 and 51.493), below the concerning threshold of 60.

**BBB:** Both have reasonable BBB penetration (74.913 and 65.374), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.589 and -4.56), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both have negative solubility values (-1.982 and -3.273), which is also concerning and suggests poor solubility. Ligand B is slightly worse.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.136 and 0.235), which is excellent.

**Microsomal Clearance:** Ligand A (16.543) has significantly lower microsomal clearance than Ligand B (43.497), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (64.516) has a longer in vitro half-life than Ligand B (14.514), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.014 and 0.46).

**Binding Affinity:** Ligand B (-9.6 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 difference threshold.

**Overall Assessment:**

Ligand B's superior binding affinity (-9.6 vs -7.6 kcal/mol) is a major advantage that likely outweighs its slightly lower solubility and higher logP. While both have concerning Caco-2 and solubility values, the potency difference is significant. Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), but the binding affinity is considerably weaker. Given the enzyme-kinase focus, potency is paramount, and the difference in affinity is substantial.

Output:
1
2025-04-17 11:50:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.379 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.14) is excellent, well below the 140 threshold for oral absorption. Ligand B (107.55) is still reasonable, but less optimal.

**logP:** Ligand A (2.609) is within the optimal 1-3 range. Ligand B (-0.099) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is well within acceptable limits. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.901 and 0.718), indicating drug-likeness.

**DILI:** Both ligands have similar DILI risk (67.429 and 68.282), placing them in a moderate risk category. This isn't a major differentiator.

**BBB:** Ligand A (68.282) shows moderate BBB penetration, while Ligand B (17.216) is very low. Since SRC is not a CNS target, this is less crucial, but a slight advantage to A.

**Caco-2 Permeability:** Ligand A (-4.827) has poor Caco-2 permeability, a significant concern. Ligand B (-5.314) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-5.145) has poor aqueous solubility, a major drawback. Ligand B (-2.567) has better, but still poor solubility.

**hERG Inhibition:** Ligand A (0.81) has a low hERG risk, which is excellent. Ligand B (0.184) also has low hERG risk.

**Microsomal Clearance:** Ligand A (14.576) has reasonable microsomal clearance, suggesting moderate metabolic stability. Ligand B (-18.799) has *very* high clearance, indicating poor metabolic stability, a major concern for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (40.147 hours) has a good in vitro half-life. Ligand B (21.237 hours) has a shorter half-life, consistent with its higher clearance.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.291 and 0.004), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol), a difference of 0.7 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its major weakness is its very high microsomal clearance and consequently shorter half-life. This would likely necessitate a high dose and frequent administration. Ligand A has poor solubility and Caco-2 permeability, but its metabolic stability is better, and its hERG risk is very low. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, hERG), the better metabolic stability of Ligand A, combined with its low hERG risk, makes it the more promising candidate *despite* its solubility and permeability issues. Solubility and permeability can be addressed through formulation strategies, but poor metabolic stability is much harder to fix.

Output:
0
2025-04-17 11:50:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.415 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.41) is better than Ligand B (43.86), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.169 and 1.576), falling within the 1-3 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, <=10 HBA).

**QED:** Both ligands have good QED scores (0.717 and 0.763), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (90.733 percentile) compared to Ligand B (6.282 percentile). This is a major concern for Ligand A.

**BBB:** Ligand A (17.642 percentile) has poor BBB penetration, while Ligand B (72.741 percentile) has good BBB penetration. However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.405) has poor Caco-2 permeability, while Ligand B (-4.692) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-3.516) has poor aqueous solubility, while Ligand B (-2.579) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.022) has very low hERG inhibition risk, which is excellent. Ligand B (0.477) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (11.921 mL/min/kg) has lower microsomal clearance than Ligand B (33.835 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.784 hours) has a negative half-life, which is impossible and likely an error in the data. Ligand B (14.901 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.026) has very low P-gp efflux liability, while Ligand B (0.013) is slightly lower. Both are good.

**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 substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand A's better TPSA and lower clearance, the significantly higher DILI risk, poor solubility, poor Caco-2 permeability, and impossible half-life make it a less desirable candidate. Ligand B, while having slightly worse TPSA and solubility, exhibits a much better safety profile (DILI), a significantly stronger binding affinity, and a reasonable half-life. The stronger binding affinity is a critical advantage for an enzyme inhibitor.

Output:
1
2025-04-17 11:50:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.384 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (390.843 Da) is also good.

**TPSA:** Ligand B (71.25) is significantly better than Ligand A (102.04). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 1.571, B: 3.058), falling 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 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.669, B: 0.737), indicating good drug-like properties.

**DILI:** Ligand A (36.293) has a significantly lower DILI risk than Ligand B (62.893). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (85.343) has a higher BBB percentile than Ligand B (74.758).

**Caco-2 Permeability:** Ligand A (-5.268) has a worse Caco-2 permeability than Ligand B (-4.584), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.12 for A, -3.738 for B). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.222, B: 0.242). This is excellent.

**Microsomal Clearance:** Ligand B (8.374) has significantly lower microsomal clearance than Ligand A (40.461), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (15.011 hours) has a much longer in vitro half-life than Ligand A (-5.97 hours). This is a major advantage for Ligand B, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.042, B: 0.109).

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 2.5 kcal/mol is significant and can outweigh many ADME drawbacks.

**Overall Assessment:**

While Ligand A has a lower DILI risk and better BBB penetration, Ligand B's superior binding affinity, metabolic stability (lower Cl_mic), and longer half-life are crucial for an enzyme target like SRC. The stronger binding affinity is a key driver, and the improved pharmacokinetic properties are highly desirable. The slightly higher DILI risk of Ligand B is a concern, but potentially mitigable with further optimization. The solubility is poor for both, but that is a formulation challenge.

Output:
1
2025-04-17 11:50:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.427 and 347.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.92) is slightly higher than Ligand B (79.6). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.401 and 1.444), falling within the optimal 1-3 range. Ligand B is slightly lower, potentially improving solubility.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.689 and 0.908), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (21.869) has a significantly lower DILI risk than Ligand B (65.917). This is a major advantage for Ligand A.

**BBB:** Ligand A (52.074) has a lower BBB penetration percentile than Ligand B (90.655). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.512 and -4.779). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.33 and -3.329), indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.629 and 0.517).

**Microsomal Clearance:** Ligand A (69.769) has higher microsomal clearance than Ligand B (14.204). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (7.086) has a longer half-life than Ligand B (-3.719).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.06 and 0.179).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While Ligand A has a better DILI score, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, though negative half-life is concerning), a higher QED score, and better BBB penetration (though not crucial here). The binding affinities are comparable. The poor Caco-2 and solubility values are a concern for both, but metabolic stability is a higher priority for kinase inhibitors.

Output:
1
2025-04-17 11:50:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.439 and 372.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.59) is slightly higher than Ligand B (75.71), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.319 and 1.76), falling within the 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 within the acceptable limit of 10.

**QED:** Ligand A (0.825) has a significantly better QED score than Ligand B (0.626), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (51.648 and 45.095 percentile), below the 60 threshold. Ligand B is slightly better.

**BBB:** Both have similar BBB penetration (62.97 and 65.103 percentile). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.571 and -4.321) which is unusual and problematic. It suggests very poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.624 and -3.351), which is also problematic and suggests very poor solubility.

**hERG Inhibition:** Ligand A (0.191) has a much lower hERG inhibition liability than Ligand B (0.522), which is a significant advantage.

**Microsomal Clearance:** Ligand A (40.673 mL/min/kg) has a lower microsomal clearance than Ligand B (69.66 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.926 hours) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (-62.767 hours) also has a negative half-life, indicating a data issue.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.027 and 0.08).

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Conclusion:**

Despite the problematic negative values for Caco-2 and solubility, Ligand A is the slightly better candidate. It has a significantly better QED score, lower hERG risk, and lower microsomal clearance (better metabolic stability). The negative half-life values for both are concerning and would need further investigation, but given the other factors, Ligand A is preferable.

Output:
0
2025-04-17 11:50:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 344.405 Da - Within the ideal range (200-500).
* Ligand B: 374.551 Da - Also within the ideal range.
* *No clear advantage.*

**2. TPSA:**
* Ligand A: 32.34 A<sup>2</sup> - Excellent, well below the 140 A<sup>2</sup> threshold for oral absorption.
* Ligand B: 64.17 A<sup>2</sup> - Still good, below 140 A<sup>2</sup>, but higher than Ligand A.
* *Ligand A is better.*

**3. logP:**
* Ligand A: 3.911 -  Slightly high, approaching the upper limit of the optimal range (1-3).
* Ligand B: 0.636 -  Low, potentially hindering permeation.
* *Ligand A is better.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 -  Good, within the recommended limit of <=5.
* Ligand B: 0 - Good, within the recommended limit of <=5.
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 2 - Good, within the recommended limit of <=10.
* Ligand B: 5 - Good, within the recommended limit of <=10.
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.862 - Excellent, indicating a highly drug-like profile.
* Ligand B: 0.554 - Acceptable, but lower than Ligand A.
* *Ligand A is better.*

**7. DILI:**
* Ligand A: 55.487 - Acceptable, below the 60% high-risk threshold.
* Ligand B: 36.642 - Very good, low DILI risk.
* *Ligand B is better.*

**8. BBB:**
* Ligand A: 86.002 - Good, but not exceptionally high.
* Ligand B: 74.254 - Good, but lower than Ligand A.
* *Ligand A is better.* (Although SRC is not a CNS target, higher BBB is generally favorable).

**9. Caco-2 Permeability:**
* Ligand A: -4.792 - Poor permeability.
* Ligand B: -4.523 - Poor permeability, but slightly better than Ligand A.
* *Ligand B is better.*

**10. Aqueous Solubility:**
* Ligand A: -4.827 - Poor solubility.
* Ligand B: -1.736 - Poor solubility, but better than Ligand A.
* *Ligand B is better.*

**11. hERG Inhibition:**
* Ligand A: 0.973 - Relatively low risk.
* Ligand B: 0.846 - Relatively low risk, slightly better than Ligand A.
* *Ligand B is better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 67.089 mL/min/kg - High clearance, suggesting poor metabolic stability.
* Ligand B: 46.066 mL/min/kg - Lower clearance, better metabolic stability.
* *Ligand B is better.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 5.794 hours - Moderate half-life.
* Ligand B: -25.093 hours - Very long half-life, a significant advantage.
* *Ligand B is better.*

**14. P-gp Efflux:**
* Ligand A: 0.681 - Moderate efflux.
* Ligand B: 0.234 - Low efflux, better bioavailability.
* *Ligand B is better.*

**15. Binding Affinity:**
* Ligand A: -10.9 kcal/mol - Excellent, very strong binding.
* Ligand B: -7.7 kcal/mol - Good binding, but significantly weaker than Ligand A.
* *Ligand A is significantly better.*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (binding affinity) and metabolic stability are paramount. Ligand A has a *much* stronger binding affinity (-10.9 vs -7.7 kcal/mol). While Ligand B excels in ADME properties (DILI, Cl_mic, t1/2, P-gp, solubility), the substantial difference in binding affinity outweighs these advantages. The poor permeability and solubility of both compounds are concerns, but these can be addressed through formulation or further chemical modifications. The strong binding of Ligand A provides a better starting point for optimization.

Output:
1
2025-04-17 11:50:34,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.482 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is well below the 140 threshold for good absorption, and favorable for kinase inhibitors. Ligand B (90.56) is still acceptable, but less optimal.

**logP:** Ligand A (2.514) is within the optimal 1-3 range. Ligand B (-0.006) is slightly below 1, which *could* indicate permeability issues, but is not a major concern.

**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 (0.762 and 0.8), indicating generally drug-like properties.

**DILI:** Ligand A (19.232) has a significantly lower DILI risk than Ligand B (23.73), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.904) has a higher BBB penetration score than Ligand B (48.934), but this isn't a key factor here.

**Caco-2 Permeability:** Ligand A (-4.286) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.412) is also negative, and similarly concerning.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.369 and -2.04), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.552) has a lower hERG risk than Ligand B (0.328), which is preferable.

**Microsomal Clearance:** Ligand A (29.505) has a higher microsomal clearance than Ligand B (-34.313). A negative value for Ligand B suggests *very* high metabolic stability, a major advantage.

**In vitro Half-Life:** Ligand A (-12.435) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (6.373) has a short half-life, which is less ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.164 and 0.016), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -9.4 kcal/mol). Ligand B is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand B has a significant advantage in metabolic stability (negative Cl_mic) and slightly better binding affinity. However, Ligand A has a much lower DILI risk and a better hERG profile. The negative Caco-2 and solubility values are concerning for both, but the metabolic stability of Ligand B is a major plus for an enzyme target. The negative half-life for Ligand A is a data quality issue and a serious red flag. Given the importance of metabolic stability for kinase inhibitors, and the questionable half-life of A, I would favor Ligand B despite its slightly higher DILI risk.

Output:
1
2025-04-17 11:50:34,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 347.507 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (81.1), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (0.387) is significantly lower than Ligand B (4.179). Ligand B is pushing the upper limit and could have solubility 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.

**QED:** Ligand A (0.795) has a much better QED score than Ligand B (0.294), indicating better overall drug-likeness.

**DILI:** Ligand A (19.426) has a significantly lower DILI risk than Ligand B (14.541), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (77.705) is better than Ligand A (57.852). This is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-4.867) is better than Ligand B (-5.103), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.409) is better than Ligand B (-3.661), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.119) has a much lower hERG risk than Ligand B (0.789), a critical safety parameter.

**Microsomal Clearance:** Ligand A (-3.143) has significantly lower (better) microsomal clearance than Ligand B (40.004), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.019) has a better in vitro half-life than Ligand B (13.934).

**P-gp Efflux:** Ligand A (0.015) has a lower P-gp efflux liability than Ligand B (0.042).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering all factors, Ligand A is significantly more promising. While both have good binding affinity, Ligand A excels in ADME-Tox properties: better QED, much lower DILI and hERG risk, better solubility, and significantly improved metabolic stability (lower Cl_mic and longer t1/2). Ligand B's high logP and DILI risk are concerning. The slightly better BBB penetration of Ligand B is not enough to offset these significant drawbacks for a non-CNS-targeted kinase inhibitor.

Output:
0
2025-04-17 11:50:34,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.841 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.4) is well below the 140 threshold, while Ligand B (78.87) is still acceptable but higher.

**logP:** Ligand A (3.355) is optimal, while Ligand B (0.461) is quite low, potentially hindering permeability.

**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:** Ligand A (0.893) has a significantly higher QED score than Ligand B (0.573), indicating better overall drug-likeness.

**DILI:** Ligand B (29.857) has a much lower DILI risk than Ligand A (65.413), which is a significant advantage.

**BBB:** Ligand A (74.564) has a better BBB penetration score than Ligand B (47.809), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.742 and -4.737), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.283 and -2.121), indicating poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Ligand A (0.617) has a slightly higher hERG risk than Ligand B (0.103), which is favorable for Ligand B.

**Microsomal Clearance:** Ligand B (0.185) has significantly lower microsomal clearance than Ligand A (19.057), indicating much better metabolic stability.

**In vitro Half-Life:** Ligand B (8.679) has a longer in vitro half-life than Ligand A (34.694), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.259) has lower P-gp efflux than Ligand B (0.033), which is better.

**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 the more promising candidate. While both have poor solubility and permeability, Ligand B excels in key areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better binding affinity. Ligand A has a better QED and P-gp efflux, but these are outweighed by the superior safety and pharmacokinetic properties of Ligand B. The low logP of Ligand B is a concern, but the slightly better binding affinity might compensate.

Output:
1
2025-04-17 11:50:34,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.57) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (97.12) is excellent, well below 140.

**logP:** Ligand A (0.342) is quite low, potentially hindering permeation. Ligand B (2.501) is optimal within the 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also good.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.582 and 0.823), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (53.276) has a moderate DILI risk, but is still acceptable (<60). Ligand B (65.103) is also acceptable, but approaching a higher risk level.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.401) is better than Ligand B (54.478).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.376 and -5.117), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.087 and -3.905), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.288 and 0.22), which is excellent.

**Microsomal Clearance:** Ligand A (-2.726) has a negative clearance, which is highly favorable, indicating excellent metabolic stability. Ligand B (30.98) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (0.474) has a very short half-life, while Ligand B (35.233) has a much longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.23).

**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 substantial.

**Overall Assessment:**

Ligand A has a better metabolic stability profile (negative Cl_mic) and a slightly better BBB score, but suffers from very low logP and solubility, and a short half-life. Ligand B has a better logP, QED, and half-life, but has a higher DILI risk and significantly worse metabolic stability. The poor solubility and Caco-2 permeability are concerning for both. However, the superior metabolic stability of Ligand A, coupled with its acceptable DILI risk, makes it slightly more promising, *assuming* the solubility issues can be addressed through formulation strategies. The rapid clearance of Ligand B is a major disadvantage for an enzyme inhibitor.

Output:
0
2025-04-17 11:50:34,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (340.427 and 348.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (88.99 and 86.88) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.414 and 2.812) are 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:** Both ligands (3) are below the 10 threshold.

**6. QED:** Ligand A (0.862) has a better QED score than Ligand B (0.739), indicating a more drug-like profile.

**7. DILI:** Ligand B (43.66) has a significantly lower DILI risk than Ligand A (56.689), which is a substantial advantage.

**8. BBB:** Both ligands have similar BBB penetration (53.044 and 55.913), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.78 and -4.923), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.003 and -4.133), indicating extremely poor aqueous solubility. This is a major issue for bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.331 and 0.174).

**12. Microsomal Clearance:** Ligand A (23.235) has lower microsomal clearance than Ligand B (39.769), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.867) has a longer half-life than Ligand B (-4.482), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.063 and 0.088).

**15. 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 notable, but not overwhelming.

**Overall Assessment:**

Both compounds have significant issues with solubility and permeability. However, Ligand B has a better binding affinity and a much lower DILI risk. Ligand A has better metabolic stability and half-life, and a slightly better QED score. Given the importance of minimizing toxicity (DILI) and maximizing potency for an oncology target, Ligand B is the slightly more promising candidate despite its higher clearance. The binding affinity difference is enough to outweigh the slightly worse metabolic properties.

Output:
1
2025-04-17 11:50:34,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.767 Da and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.95) is excellent, well below the 140 threshold for absorption. Ligand B (107.61) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (4.126) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.465) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is optimal. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.733 and 0.522, respectively), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.859), a significant concern. Ligand B has a very low DILI risk (20.551), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (66.305) is better than Ligand B (47.15).

**Caco-2 Permeability:** Ligand A (-4.472) is poor, indicating low intestinal absorption. Ligand B (-5.534) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.844) is very poor, consistent with its high logP. Ligand B (-1.57) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.424) has a slightly elevated hERG risk, while Ligand B (0.041) has very low risk.

**Microsomal Clearance:** Ligand A (44.482) has moderate clearance, while Ligand B (-7.603) has negative clearance, which is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (78.026) has a good half-life. Ligand B (-5.355) has a very short half-life, a significant drawback.

**P-gp Efflux:** Ligand A (0.197) has low P-gp efflux, which is good. Ligand B (0.005) has very low P-gp efflux, even better.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 kcal/mol and -8.5 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other significant ADME issues.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and superior metabolic stability (negative Cl_mic) are crucial advantages for an enzyme target. While its solubility and permeability are poor, these can potentially be addressed through formulation strategies. Ligand A's high DILI risk is a major red flag that is difficult to overcome. The slightly better half-life of Ligand A is not enough to compensate for the other issues.

Output:
1
2025-04-17 11:50:34,988 - INFO - Batch 80 complete. Total preferences: 1280
2025-04-17 11:50:34,988 - INFO - Processing batch 81/512...
2025-04-17 11:51:23,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (373.965 Da) is also good.

**TPSA:** Ligand A (99.25) is better than Ligand B (38.77). Lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (2.657) is within the optimal range (1-3). Ligand B (4.304) is slightly higher, potentially leading to solubility issues and off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.912) has a significantly better QED score than Ligand B (0.446), indicating a more drug-like profile.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (12.059). This is a significant drawback for Ligand A.

**BBB:** Ligand A (65.568) has lower BBB penetration than Ligand B (89.88). Since SRC is not a CNS target, this is less critical, but still a point in favor of B.

**Caco-2 Permeability:** Ligand A (-4.427) has worse Caco-2 permeability than Ligand B (-4.259).

**Aqueous Solubility:** Ligand A (-3.381) has better aqueous solubility than Ligand B (-4.45). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.293) has a lower hERG inhibition risk than Ligand B (0.723). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (56.082) has lower microsomal clearance than Ligand B (103.196), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-31.005) has a much longer in vitro half-life than Ligand B (18.712). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.659), which is favorable for bioavailability.

**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 has a significantly better binding affinity, QED, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk. While its DILI risk is higher, the strong binding affinity and favorable ADME properties (especially metabolic stability and half-life) make it a more promising candidate. Ligand B has better solubility and lower DILI, but its weaker binding affinity and poorer metabolic stability are significant concerns.

Output:
0
2025-04-17 11:51:23,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.463 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is higher than Ligand B (68.31). While both are reasonably good, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands (1.297 and 2.023) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 4 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 5, respectively).

**QED:** Both ligands have reasonable QED scores (0.477 and 0.654), with Ligand B being slightly more drug-like.

**DILI:** Both ligands have low DILI risk (28.887 and 36.293 percentiles), which is good.

**BBB:** Ligand A (13.61) has very low BBB penetration, while Ligand B (82.086) has high BBB penetration. Since SRC is not a CNS target, this is less critical, but a lower value is preferred.

**Caco-2 Permeability:** Ligand A (-5.708) has poor Caco-2 permeability, while Ligand B (-4.32) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.726) has poor aqueous solubility, while Ligand B (-1.093) is better. Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.111 and 0.644), which is favorable.

**Microsomal Clearance:** Ligand A (4.289 mL/min/kg) has significantly lower microsomal clearance than Ligand B (59.086 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-15.202 hours) has a negative half-life, which is concerning. Ligand B (-11.335 hours) is also negative, but less so. These values are likely errors or represent very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.151).

**Binding Affinity:** Both ligands have identical binding affinities (-8.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has a major drawback in its poor solubility and Caco-2 permeability, and a negative in vitro half-life. While its metabolic stability is better, the solubility and permeability issues are significant. Ligand B has better solubility and permeability, but its metabolic stability is much worse. Given that SRC is an enzyme, metabolic stability is a high priority. However, the negative half-life values for both are concerning and suggest potential instability issues that need further investigation.

Despite the metabolic stability advantage of Ligand A, the poor solubility and permeability are critical liabilities. Ligand B, while having worse metabolic stability, is more likely to be absorbed and reach the target.

Output:
1
2025-04-17 11:51:23,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.857 Da) is slightly higher than Ligand B (375.485 Da), but both are acceptable.

**TPSA:** Ligand A (116.07) is higher than Ligand B (56.67). While both are under 140, Ligand B's lower TPSA is more favorable for oral absorption.

**logP:** Both ligands have good logP values (A: 1.974, B: 2.527), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 9 HBA, while Ligand B has 5. Both are within the acceptable limit of 10, but Ligand B is better.

**QED:** Both have good QED scores (A: 0.664, B: 0.83), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A has a very high DILI risk (99.806%), which is a major red flag. Ligand B has a much lower DILI risk (23.032%), making it significantly safer.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (83.831%) has better BBB penetration than Ligand A (46.026%).

**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.

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

**hERG:** Both have low hERG inhibition liability (A: 0.265, B: 0.762), which is good.

**Microsomal Clearance:** Ligand A (45.321) has higher microsomal clearance than Ligand B (20.507), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-17.179) has a negative half-life, which is impossible and suggests an issue with the data. Ligand A (110.316) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.433, B: 0.452).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol), but the difference is not substantial enough to overcome other significant drawbacks.

**Conclusion:**

Despite the questionable solubility and Caco-2 values, Ligand B is the far more promising candidate. The extremely high DILI risk associated with Ligand A is a deal-breaker. While Ligand B has a strange negative half-life, its lower TPSA, better QED, significantly lower DILI, and slightly better binding affinity make it the preferred choice. The negative half-life needs investigation, but is less concerning than the high DILI risk of Ligand A.

Output:
1
2025-04-17 11:51:23,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (343.471 and 356.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (44.81) is well below the 140 threshold and good for oral absorption. Ligand B (133.55) is still within acceptable limits but closer to the upper bound.

**3. logP:** Ligand A (2.642) is optimal (1-3). Ligand B (0.387) is quite low, potentially hindering permeability.

**4. H-Bond Donors (HBD):** Ligand A (1) is within the ideal range (<=5). Ligand B (5) is at the upper limit, potentially affecting permeability.

**5. H-Bond Acceptors (HBA):** Ligand A (3) is within the ideal range (<=10). Ligand B (4) is also acceptable.

**6. QED:** Ligand A (0.918) is excellent, indicating high drug-likeness. Ligand B (0.382) is significantly lower, suggesting a less drug-like profile.

**7. DILI:** Ligand A (13.804) has a low DILI risk. Ligand B (10.818) is also relatively low risk, but slightly higher than A.

**8. BBB:** Ligand A (90.617) shows good BBB penetration, while Ligand B (58.666) is lower. Since SRC is not necessarily a CNS target, this is less critical, but a bonus for A.

**9. Caco-2 Permeability:** Ligand A (-4.325) is poor, suggesting low intestinal absorption. Ligand B (-5.497) is even worse.

**10. Aqueous Solubility:** Ligand A (-2.251) is poor. Ligand B (-1.573) is also poor, but slightly better than A.

**11. hERG Inhibition:** Ligand A (0.81) has a low risk of hERG inhibition. Ligand B (0.191) also shows low risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (0.659) indicates good metabolic stability. Ligand B (-2.684) suggests rapid metabolism, which is unfavorable.

**13. In vitro Half-Life (t1/2):** Ligand A (4.962) has a reasonable half-life. Ligand B (-6.087) has a very short half-life, which is a significant drawback.

**14. P-gp Efflux:** Ligand A (0.16) has low P-gp efflux. Ligand B (0.013) also has low P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.5) has a strong binding affinity. Ligand B (0.0) has very weak binding affinity.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in affinity and has good metabolic stability and low hERG risk. While both have poor solubility and Caco-2 permeability, the significantly better affinity, QED, and metabolic stability of Ligand A outweigh these drawbacks. Ligand B's extremely weak binding affinity and very short half-life make it a poor candidate despite its slightly better solubility.

Output:
1
2025-04-17 11:51:23,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.471 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.3) is slightly above the preferred <140, but acceptable. Ligand B (71.25) is well within the range.

**3. logP:** Both ligands have good logP values (1.359 and 2.506), 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:** Both ligands have 5 H-bond acceptors, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.727 and 0.746), indicating good drug-likeness.

**7. DILI:** Ligand A (52.772) has a slightly higher DILI risk than Ligand B (23.885). Both are below the concerning threshold of 60, but lower is better.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.699) has a higher BBB penetration than Ligand A (34.199), but it's not a major factor here.

**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 compounds.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.402 and 0.181), which is excellent.

**12. Microsomal Clearance:** Ligand A (29.767) has lower microsomal clearance than Ligand B (36.473), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (45.053) has a significantly longer in vitro half-life than Ligand B (2.786). This is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.125 and 0.213), which is favorable.

**15. 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:**

Both compounds have significant issues with solubility and permeability. However, Ligand A is preferable due to its better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The lower DILI risk of Ligand B is a positive, but the substantial difference in half-life outweighs this benefit for an enzyme target where maintaining therapeutic concentrations is crucial.

Output:
0
2025-04-17 11:51:23,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.421 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.49) is significantly better than Ligand B (86.88). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's higher TPSA could hinder cell permeability.

**logP:** Ligand A (4.33) is higher than the optimal range (1-3), potentially causing solubility issues or off-target effects. Ligand B (1.545) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable counts, staying within the guidelines.

**QED:** Both ligands have similar QED values (0.782 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (21.055) has a much lower DILI risk than Ligand B (44.591), which is a significant advantage.

**BBB:** Ligand A (89.686) has better BBB penetration than Ligand B (60.644), though this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the absolute value is more important, and Ligand A (-4.37) is slightly better than Ligand B (-4.434).

**Aqueous Solubility:** Ligand A (-4.933) has slightly better solubility than Ligand B (-1.404).

**hERG Inhibition:** Ligand A (0.971) has a lower hERG risk than Ligand B (0.135), which is a crucial advantage.

**Microsomal Clearance:** Ligand B (38.794) has a lower microsomal clearance than Ligand A (32.034), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-30.852) has a significantly longer in vitro half-life than Ligand A (34.173), which is a major positive.

**P-gp Efflux:** Ligand A (0.651) has lower P-gp efflux than Ligand B (0.194), improving bioavailability.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.5 kcal/mol). This difference of 1.7 kcal/mol is significant and can outweigh some of the ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand A's higher logP, the significantly better binding affinity (-8.2 vs -6.5 kcal/mol), lower DILI risk, lower hERG risk, and better P-gp efflux outweigh its drawbacks. Ligand B has better metabolic stability and half-life, but the potency difference is too large to ignore for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:51:23,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.367 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.71) is well below the 140 threshold for oral absorption, and even below 90, suggesting good potential for cell permeability. Ligand B (91.65) is still acceptable, but closer to the upper limit.

**logP:** Ligand A (3.202) is optimal. Ligand B (1.473) is a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable values, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.524 and 0.576), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (84.8%) compared to Ligand B (40.713%). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (71.966) is higher than Ligand B (55.487), but this is less critical here.

**Caco-2 Permeability:** Ligand A (-4.693) is substantially worse than Ligand B (-5.151). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-5.605) is significantly better than Ligand B (-1.793). Solubility is important for bioavailability.

**hERG:** Ligand A (0.793) has a slightly higher hERG risk than Ligand B (0.35), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (92.964) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (9.932). This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (18.005) has a longer half-life than Ligand B (14.924), which is generally desirable.

**P-gp Efflux:** Ligand A (0.439) has lower P-gp efflux than Ligand B (0.109), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a 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 concerns.

**Conclusion:**

Despite the superior binding affinity of Ligand A, its significantly higher DILI risk and higher microsomal clearance are major red flags. The lower Caco-2 permeability is also a concern. Ligand B, while having a slightly weaker affinity, presents a much more favorable ADME profile, particularly regarding safety (DILI) and metabolic stability. For an enzyme target like SRC kinase, metabolic stability and avoiding toxicity are crucial. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 11:51:23,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 353.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.01) is excellent, well below the 140 threshold for oral absorption. Ligand B (49.77) is also very good.

**logP:** Ligand A (1.373) is optimal. Ligand B (3.865) is approaching the upper limit but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the ideal range.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA, both are within the ideal range.

**QED:** Both ligands have similar QED scores (0.712 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (2.326) has a significantly lower DILI risk than Ligand B (7.871), which is a major advantage.

**BBB:** Ligand A (73.672) has moderate BBB penetration, while Ligand B (87.476) has higher penetration. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.135) has poor Caco-2 permeability, while Ligand B (-4.442) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-0.446) has slightly better solubility than Ligand B (-3.388).

**hERG Inhibition:** Ligand A (0.551) has a lower hERG risk than Ligand B (0.788), which is a positive attribute.

**Microsomal Clearance:** Ligand A (-9.948) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (91.777). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (0.095) has a very short half-life, while Ligand B (3.35) has a longer half-life.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is favorable. Ligand B (0.659) has higher efflux.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its significantly better DILI score, lower microsomal clearance (better metabolic stability), stronger binding affinity, and lower P-gp efflux are major advantages. While its Caco-2 permeability and half-life are less ideal, the superior potency and safety profile outweigh these concerns. Ligand B has a better half-life and Caco-2 permeability, but its higher DILI risk and significantly higher clearance are problematic for an enzyme inhibitor.

Output:
0
2025-04-17 11:51:23,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.379 and 348.418 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (137.87) is borderline acceptable, while Ligand B (58.64) is excellent, well below the 140 threshold for good absorption.

**logP:** Both ligands (2.145 and 2.363) fall within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which is acceptable. Ligand B has 1 HBD and 3 HBA, which is also good.

**QED:** Ligand B (0.823) has a significantly higher QED score than Ligand A (0.483), indicating better overall drug-likeness.

**DILI:** Ligand A (86.39) has a high DILI risk, while Ligand B (20.938) has a very low DILI risk. This is a major advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B (94.261) has excellent BBB penetration, while Ligand A (48.236) is moderate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the values are comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.75) is slightly better than Ligand A (-4.172).

**hERG Inhibition:** Ligand A (0.18) has a slightly lower hERG risk than Ligand B (0.614), which is preferable.

**Microsomal Clearance:** Ligand A (17.951) has a lower microsomal clearance than Ligand B (28.406), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.957) has a longer in vitro half-life than Ligand B (6.249), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability, with Ligand B (0.08) being slightly lower than Ligand A (0.032).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.5 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better metabolic stability and half-life, Ligand B is significantly better in terms of QED, DILI risk, and solubility. The high DILI risk associated with Ligand A is a major concern. Given the enzyme-specific priorities, the lower DILI risk of Ligand B outweighs the slightly better metabolic properties of Ligand A.

Output:
1
2025-04-17 11:51:23,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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, while Ligand B (387.33 Da) is still well within the acceptable range.

**TPSA:** Ligand A (111.45) is better than Ligand B (79.37) as it is closer to the threshold for good oral absorption.

**logP:** Ligand B (1.714) is optimal, while Ligand A (0.194) is quite low, 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 (A: 0.584, B: 0.781), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (33.85) has a much lower DILI risk than Ligand B (56.844), which is a significant advantage.

**BBB:** Ligand B (67.158) has a higher BBB penetration potential than Ligand A (14.153), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.918 and -4.938). This is a major concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.543 and -2.52).

**hERG Inhibition:** Ligand A (0.27) shows a lower hERG inhibition liability than Ligand B (0.627), which is a crucial safety factor.

**Microsomal Clearance:** Ligand B (-22.204) has significantly lower (better) microsomal clearance than Ligand A (4.707), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-30.813) has a much longer in vitro half-life than Ligand A (-8.417), which is highly desirable.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.036 and 0.034).

**Binding Affinity:** Ligand B (-10.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This difference in affinity is significant (3.3 kcal/mol), and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite the higher DILI risk. The significantly improved binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and acceptable QED outweigh the slightly higher DILI and lower BBB. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. Ligand A's low logP is a major drawback, potentially limiting its ability to reach the target.

Output:
1
2025-04-17 11:51:23,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.463 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.9) is close to the upper limit for good oral absorption (<=140), while Ligand B (59.65) is well below, suggesting potentially better absorption.

**logP:** Ligand A (-0.212) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (1.504) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 3 HBA, also acceptable and potentially favoring permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.523 and 0.824), indicating drug-like properties.

**DILI:** Ligand A (26.793) has a lower DILI risk than Ligand B (12.485), which is favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (66.925) has a higher BBB percentile than Ligand A (37.301), but this is less critical.

**Caco-2 Permeability:** Ligand A (-5.624) has poor predicted Caco-2 permeability, while Ligand B (-4.9) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-1.313 and -1.413). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.289 and 0.407), which is excellent.

**Microsomal Clearance:** Ligand A (-27.698) has significantly lower (better) microsomal clearance than Ligand B (-7.234), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.899) has a longer half-life than Ligand B (-10.066), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.032).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.9 and -6.8 kcal/mol). Ligand A has a substantially better binding affinity. The 2.1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite solubility concerns for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.9 vs -6.8 kcal/mol) is a major advantage for an enzyme target. Furthermore, it exhibits better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. While Ligand B has slightly better Caco-2 permeability and logP, the potency and metabolic stability advantages of Ligand A are more critical for an enzyme inhibitor. The poor solubility of Ligand A would need to be addressed through formulation strategies, but the core pharmacodynamic and pharmacokinetic properties are more favorable.

Output:
1
2025-04-17 11:51:23,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):**
* Ligand A: 366.527 Da - Within the ideal range (200-500 Da).
* Ligand B: 345.443 Da - Also within the ideal range.
* *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 61.8  - Good for oral absorption (<=140).
* Ligand B: 78.51 - Still acceptable for oral absorption, but higher than A.
* *Ligand A is slightly better.*

**3. Lipophilicity (logP):**
* Ligand A: 3.37 - Optimal (1-3).
* Ligand B: 1.712 - Towards the lower end of optimal, but still acceptable.
* *Ligand A is better.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Meets the criteria (<=5).
* Ligand B: 2 - Meets the criteria (<=5).
* *Equal.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 4 - Meets the criteria (<=10).
* Ligand B: 3 - Meets the criteria (<=10).
* *Equal.*

**6. QED:**
* Ligand A: 0.727 - Excellent drug-like profile (>=0.5).
* Ligand B: 0.753 - Excellent drug-like profile (>=0.5).
* *Ligand B is slightly better.*

**7. DILI:**
* Ligand A: 35.867 - Low risk (<40).
* Ligand B: 42.497 - Low risk (<40).
* *Both are acceptable, A is slightly better.*

**8. BBB:**
* Ligand A: 60.372 - Not a primary concern for a kinase inhibitor (unless CNS off-target effects are a concern).
* Ligand B: 59.946 - Not a primary concern.
* *Equal.*

**9. Caco-2 Permeability:**
* Ligand A: -4.68 - Poor permeability.
* Ligand B: -5.003 - Very poor permeability.
* *Ligand A is slightly better.*

**10. Aqueous Solubility:**
* Ligand A: -3.428 - Poor solubility.
* Ligand B: -2.602 - Better solubility than A, but still poor.
* *Ligand B is better.*

**11. hERG Inhibition:**
* Ligand A: 0.756 - Acceptable risk.
* Ligand B: 0.207 - Very low risk.
* *Ligand B is significantly better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 61.731 - High clearance, indicating lower metabolic stability.
* Ligand B: -4.434 - Negative clearance is unusual and suggests very high stability.
* *Ligand B is significantly better.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 9.585 - Moderate half-life.
* Ligand B: 7.588 - Shorter half-life.
* *Ligand A is better.*

**14. P-gp Efflux:**
* Ligand A: 0.55 - Moderate efflux.
* Ligand B: 0.038 - Low efflux.
* *Ligand B is better.*

**15. Binding Affinity:**
* Ligand A: -6.8 kcal/mol - Good binding affinity.
* Ligand B: -8.1 kcal/mol - Excellent binding affinity (1.3 kcal/mol advantage).

**Overall Assessment:**

For an enzyme (kinase) target, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a significantly better binding affinity (-8.1 vs -6.8 kcal/mol) and *much* better metabolic stability (Cl_mic of -4.434 vs 61.731). It also has a lower hERG risk. While Ligand A has slightly better Caco-2 permeability and half-life, the advantages of Ligand B in the critical areas of potency and metabolic stability outweigh these minor drawbacks. Solubility is poor for both, but B is better.

Output:
1
2025-04-17 11:51:23,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.378 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.01) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (58.64) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands (1.525 and 2.577) 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 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.663 and 0.796), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 69.601, which is concerning as it's above the threshold of 60. Ligand B has a much lower DILI risk of 21.171, which is favorable.

**BBB:** Both have good BBB penetration (70.609 and 76.658), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.191) has poor Caco-2 permeability. Ligand B (-4.695) is also poor, but slightly better than A.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.177 and -2.548). This is a potential issue for formulation and bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.488 and 0.258), which is excellent.

**Microsomal Clearance:** Ligand A (20.981) has lower microsomal clearance than Ligand B (48.191), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (23.052 and 20.646 hours), which is good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.07).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.8 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good potency, Ligand B is significantly better due to its much lower DILI risk (21.171 vs 69.601) and better TPSA (58.64 vs 96.01). Although Ligand A has slightly better metabolic stability, the DILI risk associated with Ligand A is a major concern. The slight improvement in Caco-2 permeability for Ligand B is also a plus.

Output:
1
2025-04-17 11:51:23,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.427 Da and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.01) is slightly higher than Ligand B (78.43), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.201 and 1.846), falling within the optimal 1-3 range.

**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 (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.845) has a significantly higher QED score than Ligand B (0.557), indicating better overall drug-likeness.

**DILI:** Ligand A (50.33) has a moderate DILI risk, while Ligand B (7.445) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (92.4) shows good BBB penetration, while Ligand B (49.981) is lower. However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-5.289) has poorer Caco-2 permeability than Ligand B (-4.648), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.824 and -3.111). This is a concern for both, requiring formulation strategies.

**hERG Inhibition:** Ligand A (0.5) has a lower hERG inhibition risk than Ligand B (0.144), which is a positive attribute.

**Microsomal Clearance:** Ligand A (58.172) has a higher microsomal clearance than Ligand B (36.446), indicating lower metabolic stability. This is a key disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (10.959) has a positive half-life, but Ligand B (-5.097) has a negative half-life, which is concerning.

**P-gp Efflux:** Ligand A (0.526) has lower P-gp efflux than Ligand B (0.023), suggesting better bioavailability.

**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 advantage for Ligand A, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a better QED score, and lower P-gp efflux. However, it suffers from higher microsomal clearance, poorer Caco-2 permeability, and a moderate DILI risk. Ligand B has a much lower DILI risk, better metabolic stability, and slightly better Caco-2 permeability, but its binding affinity is considerably weaker.

Given that we are targeting a kinase (SRC), potency (binding affinity) and metabolic stability are paramount. The 2.6 kcal/mol difference in binding affinity is substantial and likely outweighs the drawbacks of Ligand A, *provided* the solubility and clearance issues can be addressed through formulation or further chemical modification. The DILI risk of Ligand A is manageable.

Output:
1
2025-04-17 11:51:23,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (454.312 Da) is higher, but still reasonable. Ligand B (360.523 Da) is preferable.

**TPSA:** Ligand A (71.94) is higher than Ligand B (49.41). Both are below 140, suggesting good absorption potential. Ligand B is better.

**logP:** Both ligands have similar logP values (A: 2.905, B: 3.082), falling within the optimal 1-3 range. No significant difference 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). Ligand B is slightly better due to fewer H-bonds.

**QED:** Both ligands have good QED scores (A: 0.699, B: 0.847), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 53.199%, while Ligand B has 19.465%. Ligand B is significantly better, indicating a lower risk of liver injury.

**BBB:** Ligand A (57.658%) has a lower BBB penetration than Ligand B (77.433%). Since SRC is not a CNS target, this is less critical, but higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.594 and -5.146), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.186 and -2.999), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Both ligands have similar, low hERG inhibition liability (A: 0.465, B: 0.508), which is good.

**Microsomal Clearance:** Ligand A (22.426 mL/min/kg) has lower clearance than Ligand B (55.623 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (26.876 hours) has a longer half-life than Ligand B (-7.166 hours). This is a significant advantage for Ligand A, as it suggests less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.28, B: 0.29).

**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 a notable advantage.

**Overall Assessment:**

Ligand B has a better binding affinity, lower DILI risk, better QED, and better BBB penetration. However, Ligand A has significantly better metabolic stability (lower Cl_mic) and a much longer half-life. Both have poor solubility and permeability. Given the enzyme-specific priorities, metabolic stability and half-life are crucial for kinase inhibitors. The 0.6 kcal/mol difference in binding affinity is unlikely to outweigh the substantial improvements in pharmacokinetic properties offered by Ligand A.

Output:
1
2025-04-17 11:51:23,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.44) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.43) is well within the optimal range.

**logP:** Ligand A (0.348) is a bit low, potentially hindering permeation. Ligand B (2.787) is near the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are reasonable. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have decent QED scores (0.701 and 0.558), indicating good drug-like properties.

**DILI:** Ligand A (49.632) has a moderate DILI risk, but acceptable. Ligand B (13.377) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (58.821) and Ligand B (41.838) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.302) has poor Caco-2 permeability, which is a major concern. Ligand B (-4.638) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.901) has poor aqueous solubility, which could hinder bioavailability. Ligand B (-2.912) also has poor solubility, but is worse than A.

**hERG Inhibition:** Ligand A (0.053) has very low hERG inhibition risk, a strong positive. Ligand B (0.186) also has low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (8.152) has lower microsomal clearance, indicating better metabolic stability. Ligand B (51.246) has significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (10.519) has a longer in vitro half-life, further supporting its better metabolic stability. Ligand B (8.543) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.079).

**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 ADME drawbacks.

**Conclusion:**

While Ligand A has better hERG and metabolic stability, Ligand B's significantly superior binding affinity (-8.7 vs -7.4 kcal/mol) is the most critical factor for an enzyme inhibitor. The lower DILI risk of Ligand B is also a major benefit. Although both have poor solubility and Caco-2 permeability, the potency advantage of B is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 11:51:23,675 - INFO - Batch 81 complete. Total preferences: 1296
2025-04-17 11:51:23,675 - INFO - Processing batch 82/512...
2025-04-17 11:52:11,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (340.339 and 362.861 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.3) is higher than the preferred <140 for oral absorption, but still acceptable. Ligand B (70.25) is excellent, well below 140.

**3. logP:** Ligand A (-0.123) is quite low, potentially hindering permeability. Ligand B (3.155) is optimal, within the 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (3 and 2, respectively), below the threshold of 5.

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

**6. QED:** Both ligands have good QED scores (0.677 and 0.877), indicating drug-like properties.

**7. DILI:** Ligand A (93.951) has a high DILI risk, exceeding the 60% threshold. Ligand B (64.172) is still elevated but less concerning.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (43.893) and Ligand B (68.67) are both relatively low.

**9. Caco-2 Permeability:** Ligand A (-5.121) is very poor, indicating poor intestinal absorption. Ligand B (-4.797) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.158 and -4.227). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.023) has very low hERG inhibition risk. Ligand B (0.685) is slightly higher but still relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-19.799) has very low clearance, suggesting excellent metabolic stability. Ligand B (31.134) has higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (7.499) has a shorter half-life than Ligand B (24.632), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.026 and 0.233).

**15. Binding Affinity:** Both ligands have strong binding affinities (-9.0 and -6.3 kcal/mol). Ligand A is significantly more potent, with a 2.7 kcal/mol advantage.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison & Decision:**

Ligand A has a *much* stronger binding affinity, and excellent metabolic stability. However, its low logP and poor Caco-2 permeability are significant drawbacks. The high DILI risk is also concerning. Ligand B has a more balanced profile with better logP, acceptable DILI, and a longer half-life, although its affinity is lower and its metabolic clearance is higher.

The substantial affinity advantage of Ligand A (2.7 kcal/mol) is a major factor. While the ADME properties are suboptimal, medicinal chemistry efforts could potentially address the logP and permeability issues without sacrificing potency. The DILI risk is more challenging, but not insurmountable. Ligand B, while more balanced, lacks the potency needed to be a strong candidate.

Output:
1
2025-04-17 11:52:11,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.315 and 359.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.51) is borderline, but acceptable for oral absorption. Ligand B (61.44) is excellent, well below the 140 threshold.

**logP:** Both ligands have good logP values (0.703 and 1.431), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 1 HBD and 9 HBA, well within the limits. Ligand B has 2 HBD and 3 HBA, also within acceptable ranges.

**QED:** Both ligands have good QED scores (0.775 and 0.798), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 87.476, which is high. Ligand B has a significantly lower DILI risk of 22.179, which is excellent. This is a major advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (80.613) than Ligand A (48.972), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with solubility prediction. However, the values are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.091 and 0.376), which is excellent.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (92.166), suggesting poor metabolic stability. Ligand B has a negative clearance (-16.475), which is highly favorable, indicating excellent metabolic stability. This is a critical advantage for Ligand B.

**In vitro Half-Life:** Ligand A has a negative half-life (-13.115), which is unusual. Ligand B has a negative half-life (-3.7), also unusual.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.036), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent and meets the criteria.

**Conclusion:**

While both ligands have comparable binding affinity, Ligand B is significantly better due to its much lower DILI risk and significantly improved metabolic stability (negative Cl_mic). The unusual negative values for Caco-2 and solubility are concerning, but the large differences in DILI and Cl_mic outweigh these concerns.

Output:
1
2025-04-17 11:52:11,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.447 and 371.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is well below the 140 threshold, suggesting good absorption. Ligand B (106.62) is still within acceptable limits, but less favorable.

**logP:** Ligand A (3.84) is at the upper end of the optimal range (1-3), while Ligand B (1.599) is slightly below. Both are acceptable, but Ligand A's higher logP could potentially lead to off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 7 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.78) has a strong drug-like profile, while Ligand B (0.368) is considerably lower, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (90.733) has a high DILI risk, which is a significant concern. Ligand B (52.346) has a moderate DILI risk, which is much better.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (73.827) shows better penetration than Ligand B (51.881).

**Caco-2 Permeability:** Ligand A (-4.895) and Ligand B (-5.384) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-4.901) and Ligand B (-2.014) both have negative values, indicating poor solubility. Ligand B is better than Ligand A in this regard.

**hERG Inhibition:** Ligand A (0.758) has a moderate hERG risk, while Ligand B (0.34) has a lower risk, which is preferable.

**Microsomal Clearance:** Ligand A (93.79) has high microsomal clearance, suggesting poor metabolic stability. Ligand B (51.165) has lower clearance and thus better metabolic stability.

**In vitro Half-Life:** Ligand A (75.587) has a reasonable half-life, while Ligand B (-5.993) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.9) has moderate P-gp efflux, while Ligand B (0.068) has very low efflux, which is favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has better QED and BBB penetration, but suffers from high DILI risk, poor metabolic stability (high Cl_mic), and poor solubility. Ligand B has a significantly better binding affinity, lower DILI and hERG risk, better metabolic stability, and lower P-gp efflux. The major drawback for Ligand B is its very short in vitro half-life and poor solubility. However, the strong binding affinity is a major advantage for an enzyme target, and the other issues might be addressable through further optimization. The high DILI risk of Ligand A is a significant red flag.

Output:
1
2025-04-17 11:52:11,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.467 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is higher than Ligand B (58.2). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (2.088) is within the optimal 1-3 range. Ligand B (4.27) is slightly higher, potentially leading to solubility issues or off-target interactions, though not drastically so.

**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 2. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.878) has a significantly higher QED score than Ligand B (0.508), indicating a more drug-like profile.

**DILI:** Ligand A (58.434) has a higher DILI risk than Ligand B (20.861). This is a significant drawback for Ligand A.

**BBB:** Ligand A (50.523) and Ligand B (72.78) both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.306) has poor Caco-2 permeability, while Ligand B (-4.702) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-3.228) has poor aqueous solubility, while Ligand B (-4.283) is even worse. This is a concern for both, but more so for B.

**hERG Inhibition:** Ligand A (0.322) has a lower hERG risk than Ligand B (0.619), which is favorable.

**Microsomal Clearance:** Ligand A (14.153) has a significantly lower microsomal clearance than Ligand B (66.252), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-19.872) has a much longer in vitro half-life than Ligand B (7.264), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux than Ligand B (0.353), which is favorable.

**Binding Affinity:** Both ligands have comparable binding affinities (-9.1 and -10.3 kcal/mol). Ligand B has a slightly better affinity, but the difference is unlikely to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a better QED score, lower P-gp efflux, and lower hERG risk. While its solubility and Caco-2 permeability are poor, the improved metabolic profile and safety are more critical for an enzyme target like SRC. Ligand B has a slightly better affinity, but suffers from significantly higher DILI risk, poorer metabolic stability, and higher P-gp efflux.

Output:
0
2025-04-17 11:52:11,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (363.395 Da) is also good.

**TPSA:** Ligand A (63.05) is well below the 140 threshold for oral absorption. Ligand B (125.2) is still acceptable, but higher, potentially indicating lower permeability.

**logP:** Ligand A (3.609) is optimal. Ligand B (0.16) is quite low, which is a significant concern for membrane permeability and could hinder oral absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is excellent. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (A: 0.778, B: 0.656), indicating reasonable drug-likeness.

**DILI:** Ligand A (65.723) has a moderate DILI risk, while Ligand B (91.043) has a high DILI risk. This is a significant negative for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.047) is better than Ligand B (52.268).

**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 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, so we cannot interpret these values accurately.

**hERG:** Ligand A (0.629) has a very low hERG risk, which is excellent. Ligand B (0.165) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (30.312) has moderate clearance, while Ligand B (-12.543) has negative clearance, which is impossible and suggests an error in the data. Assuming the negative value is a data error, we can still say that Ligand A has better metabolic stability.

**In vitro Half-Life:** Ligand A (26.353 hours) has a reasonable half-life. Ligand B (50.369 hours) has a better half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.125, B: 0.03), which is good.

**Binding Affinity:** Both ligands have very good binding affinity (-9.9 kcal/mol and -9.0 kcal/mol). The difference is 0.9 kcal/mol, which isn't substantial enough to overcome the ADME concerns of Ligand B.

**Conclusion:**

Ligand A is the more promising candidate. While both have excellent binding affinity, Ligand A has a significantly better logP, lower DILI risk, and a more reasonable (and positive) microsomal clearance. The negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand A. Ligand B's very low logP and high DILI risk are major drawbacks.

Output:
0
2025-04-17 11:52:11,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 348.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.88) is better than Ligand B (89.27), being comfortably below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands (1.132 and 1.512) are 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 3. Both are acceptable (<=10).

**QED:** Both ligands have high QED scores (0.858 and 0.868), indicating good drug-likeness.

**DILI:** Ligand A (42.536) has a lower DILI risk than Ligand B (56.689), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.898) is better than Ligand B (51.415).

**Caco-2 Permeability:** Both have negative values (-4.664 and -4.846). This is unusual and suggests poor permeability, but the scale isn't specified. We'll need to consider this cautiously.

**Aqueous Solubility:** Both have negative values (-1.974 and -2.524). Similar to Caco-2, this is concerning and suggests poor solubility.

**hERG:** Both ligands have very low hERG risk (0.475 and 0.415). This is excellent.

**Microsomal Clearance:** Ligand A (26.623) has a slightly lower microsomal clearance than Ligand B (27.339), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.308) has a significantly longer in vitro half-life than Ligand B (-25.571). This is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.063 and 0.14).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a 1.1 kcal/mol difference, which is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better ADME properties (lower DILI, better BBB, lower Cl_mic, longer t1/2), Ligand B boasts a significantly stronger binding affinity. Given that we are targeting an enzyme (SRC kinase), potency is paramount. The 1.1 kcal/mol difference in binding affinity is substantial enough to favor Ligand B, despite its slightly worse ADME profile. The negative solubility and Caco-2 values are concerning for both, but these could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:52:11,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (387.53 and 377.58 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.6) is higher than the preferred <140, while Ligand B (30.29) is excellent.

**logP:** Ligand A (1.098) is within the optimal 1-3 range. Ligand B (3.588) is slightly higher, but still acceptable.

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

**H-Bond Acceptors:** Both ligands (6) are within the ideal range of <=10.

**QED:** Both ligands have good QED scores (0.512 and 0.736, respectively), indicating drug-likeness.

**DILI:** Ligand A (67.5) has a higher DILI risk than Ligand B (36.6), though both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (73.9) is higher, but it's not a major factor here.

**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 concerning.

**hERG:** Ligand A (0.293) has a lower hERG risk than Ligand B (0.856), which is a significant advantage.

**Microsomal Clearance:** Ligand A (32.7) has lower clearance than Ligand B (92.3), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-26.2) has a much longer in vitro half-life than Ligand B (8.12), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux than Ligand B (0.727), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a 1.9 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 important factor for an enzyme target. While it has some ADME liabilities (higher logP, higher hERG, higher clearance, lower half-life, negative Caco-2 and solubility), the potency advantage is substantial. Ligand A has better ADME properties (lower clearance, longer half-life, lower hERG), but its binding affinity is considerably weaker. Given the importance of potency for kinase inhibitors, the stronger binding of Ligand B is likely to be more impactful in driving efficacy, and optimization efforts could focus on improving its ADME profile.

Output:
1
2025-04-17 11:52:11,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.4 and 337.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (91.32), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have similar logP values (2.626 and 2.622), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3), as lower HBD generally improves permeability.

**H-Bond Acceptors:** Both have the same HBA count (4), well below the 10 threshold.

**QED:** Ligand B (0.578) has a slightly better QED score than Ligand A (0.488), indicating a more drug-like profile.

**DILI:** Ligand B (51.842) has a significantly lower DILI risk than Ligand A (63.358), which is a major advantage.

**BBB:** Ligand A (88.174) has a better BBB penetration score than Ligand B (54.478), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-4.791) has a better Caco-2 permeability than Ligand B (-5.152), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.827) has better aqueous solubility than Ligand B (-4.317).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.249 and 0.202), which is excellent.

**Microsomal Clearance:** Ligand B (31.72) has a lower microsomal clearance than Ligand A (26.367), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-21.984) has a significantly longer in vitro half-life than Ligand A (24.941), which is a substantial benefit for dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.044).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and the most important factor.

**Conclusion:**

While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B demonstrates superior ADME properties. Specifically, the significantly lower DILI risk and longer half-life of Ligand B are crucial advantages for a kinase inhibitor. The slightly better QED score also contributes to its favorability. Given the equal binding affinity, the improved ADME profile of Ligand B makes it the more promising drug candidate.

Output:
1
2025-04-17 11:52:11,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 351.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.93) is better than Ligand B (120.58). TPSA < 140 is good for oral absorption, and both are within this range, but A is closer to the optimal value.

**logP:** Ligand A (1.316) is within the optimal 1-3 range. Ligand B (-0.819) is slightly below 1, which *could* indicate permeability issues, though not drastically.

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

**QED:** Both ligands have reasonable QED scores (0.765 and 0.637), indicating good drug-like properties.

**DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (45.25). This is a negative for Ligand A.

**BBB:** Ligand A (76.309) has a better BBB penetration score than Ligand B (18.961). However, BBB isn't a primary concern for a kinase inhibitor unless CNS effects are specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.135 and -5.484), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.392 and -0.707). This is also concerning, indicating poor aqueous solubility, which can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.368) has a much lower hERG inhibition risk than Ligand B (0.01). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (3.538) has a lower microsomal clearance than Ligand B (-16.135). Lower clearance is better for metabolic stability, making Ligand A preferable.

**In vitro Half-Life:** Ligand A (43.365) has a significantly longer in vitro half-life than Ligand B (10.384). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.009).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-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 better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better TPSA and HBA values. However, Ligand B has a significantly better binding affinity. Both have poor Caco-2 permeability and solubility. The improved affinity of Ligand B is a significant advantage for an enzyme inhibitor, and could be optimized with further medicinal chemistry. The DILI risk is also lower for Ligand B.

Output:
1
2025-04-17 11:52:11,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.482 and 386.298 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (41.29) as it is closer to the 140 threshold.

**logP:** Ligand A (2.683) is optimal (1-3), while Ligand B (4.491) is slightly higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (3 & 4) counts, well within the limits of 5 and 10, respectively.

**QED:** Both ligands have similar and good QED scores (0.763 and 0.762).

**DILI:** Ligand A (21.753) has a significantly lower DILI risk than Ligand B (18.379), which is a major advantage.

**BBB:** Ligand A (88.29) has a better BBB penetration score than Ligand B (73.827), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.539) is slightly better than Ligand B (-4.871).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.145) is slightly better than Ligand B (-4.692).

**hERG:** Ligand A (0.67) has a lower hERG inhibition liability than Ligand B (0.902), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (29.241) has a lower Cl_mic, indicating better metabolic stability, than Ligand B (69.744).

**In vitro Half-Life:** Ligand A (0.225) has a shorter half-life than Ligand B (-2.827), which is a disadvantage.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.687), which is beneficial for bioavailability.

**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 a meaningful advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better in terms of safety (DILI, hERG) and metabolic stability (Cl_mic). The solubility and permeability issues are concerning for both, but Ligand A is slightly better in these aspects as well. For an enzyme target like SRC kinase, metabolic stability and safety are crucial. The 0.7 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand A, while the safety and metabolic advantages are harder to achieve through later-stage modifications.

Output:
0
2025-04-17 11:52:11,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (379.511 and 387.33 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 (79.37) is well within the desired range.

**logP:** Both ligands (1.758 and 1.714) are 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:** Ligand A (6) and Ligand B (4) are both within the acceptable limit of <=10. Ligand B is better.

**QED:** Both ligands have good QED scores (0.682 and 0.781), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (63.513) is at the higher end of acceptable risk, while Ligand B (56.844) is better, indicating a lower risk of drug-induced liver injury.

**BBB:** Ligand A (35.324) has a low BBB penetration percentile, while Ligand B (67.158) is significantly better. Since SRC is not a CNS target, this is less critical, but still a positive for B.

**Caco-2 Permeability:** Ligand A (-5.674) and Ligand B (-4.938) both have negative values, which is unusual. Lower values indicate poorer permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.116 and -2.52). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.211) has a slightly higher hERG inhibition liability than Ligand B (0.627), which is preferable.

**Microsomal Clearance:** Ligand A (15.973) has a higher microsomal clearance than Ligand B (-22.204). The negative value for B indicates very good metabolic stability, which is a major advantage.

**In vitro Half-Life:** Ligand A (-26.801) has a longer in vitro half-life than Ligand B (-30.813). Both are negative, which is unusual.

**P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux liability than Ligand B (0.034), which is slightly better.

**Binding Affinity:** Ligand B (-10.4 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.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility, Ligand B has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer half-life), and better BBB penetration. The slightly better H-bond donor/acceptor profile and QED also contribute. The superior binding affinity is the most crucial factor for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:52:11,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (363.487 and 369.868 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.07) is slightly higher than Ligand B (54.46). Both are below the 140 A^2 threshold for oral absorption, but Ligand B is significantly better positioned for potential CNS penetration, though that's not a primary concern for a typical oncology kinase inhibitor.

**3. logP:** Both ligands have good logP values (3.301 and 2.8), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Lower is generally preferred, giving a slight edge to Ligand B.

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (4), again favoring Ligand B.

**6. QED:** Both ligands have good QED scores (0.629 and 0.867), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A has a significantly higher DILI risk (80.109%) compared to Ligand B (27.336%). This is a major concern for Ligand A.

**8. BBB:** Ligand A (52.423%) and Ligand B (91.896%). BBB is not a priority for an oncology target, but Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-5.121) and Ligand B (-4.493). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.231) and Ligand B (-2.895). Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.18) and Ligand B (0.561). Ligand A has a lower hERG risk, which is a positive.

**12. Microsomal Clearance:** Ligand A (52.159) and Ligand B (33.643). Ligand B has lower microsomal clearance, suggesting better metabolic stability, which is crucial for an enzyme target.

**13. In vitro Half-Life:** Ligand A (52.598) and Ligand B (33.644). Ligand A has a longer half-life.

**14. P-gp Efflux:** Ligand A (0.277) and Ligand B (0.265). Both are similar.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and in vitro half-life, the significantly higher DILI risk is a major red flag. Ligand B demonstrates a superior safety profile (lower DILI, better hERG), better metabolic stability (lower Cl_mic), and a good QED score. The difference in binding affinity (0.4 kcal/mol) is not substantial enough to overcome the safety and metabolic concerns associated with Ligand A. For an enzyme target like SRC kinase, metabolic stability and safety are paramount.

Output:
1
2025-04-17 11:52:11,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (335.37 and 350.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (51.66), both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.03 and 3.13), falling within the 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:** 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 ligands have good QED scores (0.721 and 0.85), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 81.89, which is concerning (high risk). Ligand B has a lower DILI risk of 56.81, which is still moderately high but better than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (96.39) than Ligand A (62.62), but this is not a primary factor in this case.

**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:** Ligand A has a very low hERG inhibition liability (0.463), which is excellent. Ligand B has a slightly higher hERG risk (0.841), but still relatively low.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (26.66) than Ligand B (43.35), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A has a longer half-life (28.45 hours) than Ligand B (-12.597 hours). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A has very low P-gp efflux liability (0.033), while Ligand B has a moderate efflux liability (0.426).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-6.6 kcal/mol) than Ligand A (0 kcal/mol). This is a crucial difference, 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 an enzyme inhibitor. While it has a slightly higher logP and a moderately high DILI risk, the significantly improved potency and better metabolic stability (despite the negative half-life value, which is suspect) outweigh these concerns. Ligand A's low affinity makes it a less attractive candidate, despite its better hERG profile and lower P-gp efflux. The negative solubility and Caco-2 values for both are concerning and need further investigation, but the binding affinity difference is decisive.

Output:
1
2025-04-17 11:52:11,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.219 Da) is slightly higher than Ligand B (366.483 Da), but both are acceptable.

**TPSA:** Ligand A (106.1) is higher than Ligand B (60.89). While both are reasonably low, Ligand B is significantly better for absorption.

**logP:** Both ligands have good logP values (A: 1.949, B: 2.365), falling within the optimal range of 1-3.

**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 6 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (A: 0.555, B: 0.707), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 81.776, which is high. Ligand B has a much lower DILI risk of 36.487, which is good. This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration (A: 69.678, B: 75.107), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.944 and -4.775), 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 (-3.059 and -1.809), indicating poor aqueous solubility. This is a significant drawback for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.095) has a slightly lower hERG risk than Ligand B (0.439), which is preferable.

**Microsomal Clearance:** Ligand A (82.006) has higher microsomal clearance than Ligand B (43.41). Lower clearance is better for metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand A (26.51) has a shorter half-life than Ligand B (22.746). This is a slight advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.022) has lower P-gp efflux than Ligand B (0.094), which is preferable.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This is a significant advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B has a significantly better safety profile (lower DILI) and better metabolic stability (lower Cl_mic). Both have poor solubility and permeability, which would need to be addressed through formulation or further chemical modification. However, the lower DILI risk for Ligand B is a critical advantage, especially for an oncology target where chronic administration is possible. The slightly better affinity of A is not enough to overcome the high DILI risk.

Output:
1
2025-04-17 11:52:11,480 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.813 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for good oral absorption, but neither are optimized for CNS penetration (below 90).

**logP:** Both ligands have good logP values (3.337 and 3.191), 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.818 and 0.787), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (85.537 percentile) compared to Ligand B (30.593 percentile). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (82.009 and 70.919), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.703 and -4.698), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-4.788) has worse solubility than Ligand B (-2.871). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.443 and 0.513), which is good.

**Microsomal Clearance:** Ligand A (57.81) and Ligand B (56.327) have similar microsomal clearance values. Lower is better, but these aren't excessively high.

**In vitro Half-Life:** Ligand B (-3.54) has a negative half-life, which is impossible. This is a major red flag. Ligand A (54.204) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.171 and 0.235), which is favorable.

**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 is above the 1.5 kcal/mol threshold that can outweigh other drawbacks.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Ligand A has a high DILI risk and poor solubility. Ligand B has a better DILI profile, better solubility, and while its half-life is nonsensical, it is still preferable to the other issues with Ligand A. The negative Caco-2 values are concerning for both, but the other ADME properties of Ligand B are more favorable.

Output:
1
2025-04-17 11:52:11,480 - INFO - Okay, let's analyze these two ligands for their potential as drug candidates targeting SRC kinase, following the provided guidelines.

**Ligand A: [354.378, 104.73 ,   1.955,   3.   ,   5.   ,   0.376,  39.395,  58.24 , -5.16 ,  -3.21 ,   0.559,  63.268, -26.85 ,   0.065,  -8.6  ]**
**Ligand B: [373.45 ,  83.72 ,   1.635,   0.   ,   5.   ,   0.692,  51.26 ,  94.223, -4.636,  -2.346,   0.597,  46.333, -55.172,   0.141,   0.   ]**

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (354.378) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (104.73) is higher than B (83.72). B is better here, being comfortably under 140 and closer to the preferred <90 for potential CNS penetration (though not a primary concern for SRC).
3. **logP:** Both are within the optimal range (1-3). B (1.635) is slightly lower, which *could* indicate better solubility, but both are acceptable.
4. **HBD:** A (3) is acceptable, B (0) is excellent. Fewer HBDs generally improve permeability.
5. **HBA:** Both have 5 HBA, which is acceptable.
6. **QED:** B (0.692) is better than A (0.376), indicating a more drug-like profile.
7. **DILI:** A (39.395) is better than B (51.26), indicating lower liver injury risk.
8. **BBB:** B (94.223) is significantly better than A (58.24). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.
9. **Caco-2:** A (-5.16) is significantly worse than B (-4.636), indicating poorer intestinal absorption.
10. **Solubility:** B (-2.346) is better than A (-3.21). Better solubility is crucial for bioavailability.
11. **hERG:** Both are similar (0.559 and 0.597), and represent a low risk.
12. **Cl_mic:** B (46.333) is significantly better than A (63.268), indicating improved metabolic stability.
13. **t1/2:** B (-55.172) is significantly better than A (-26.85), indicating a longer half-life.
14. **Pgp:** B (0.141) is better than A (0.065), indicating lower P-gp efflux.
15. **Binding Affinity:** A (-8.6) is *much* better than B (0). This is a >1.5 kcal/mol advantage, which is a significant driver.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand A has a substantially stronger binding affinity. This is the most important factor.
*   **Metabolic Stability:** Ligand B is better.
*   **Solubility:** Ligand B is better.
*   **hERG:** Both are acceptable.

**Conclusion:**

Despite Ligand B having better ADME properties across the board (QED, DILI, BBB, Caco-2, Solubility, Cl_mic, t1/2, Pgp), the *dramatic* difference in binding affinity (-8.6 kcal/mol vs. 0 kcal/mol) for Ligand A is decisive. A 8.6 kcal/mol difference is a huge advantage and likely outweighs the ADME drawbacks. While optimization of Ligand A's ADME profile would be necessary, the strong initial binding makes it the more promising starting point.

Output:
1
2025-04-17 11:52:11,480 - INFO - Batch 82 complete. Total preferences: 1312
2025-04-17 11:52:11,480 - INFO - Processing batch 83/512...
2025-04-17 11:52:51,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 367.965 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is better than Ligand B (38.13) as it is closer to the ideal range for oral absorption (<=140).

**logP:** Ligand A (3.455) is within the optimal range (1-3), while Ligand B (4.767) is slightly higher, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being <=5.

**H-Bond Acceptors:** Both ligands (A: 3, B: 3) are well within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (A: 0.707, B: 0.663), indicating good drug-like properties.

**DILI:** Ligand A (32.183) has a slightly higher DILI risk than Ligand B (21.908), but both are below the concerning threshold of 60.

**BBB:** Ligand B (87.321) has a significantly higher BBB penetration percentile than Ligand A (51.105). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.492 and -4.726), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.544 and -4.31), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.737, B: 0.693).

**Microsomal Clearance:** Ligand B (96.364) has a significantly higher microsomal clearance than Ligand A (64.125), indicating lower metabolic stability. This is a critical disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-11.32) has a negative half-life, which is not possible. Ligand B (20.147) has a reasonable half-life, suggesting better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.267, B: 0.787).

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.9 kcal/mol, B: -8.1 kcal/mol). Ligand A has a slightly better affinity.

**Conclusion:**

Despite the poor permeability and solubility for both compounds, Ligand A is slightly favored. It has a better binding affinity, lower microsomal clearance (better metabolic stability), and a lower logP, which might help with solubility compared to Ligand B. The negative half-life for Ligand A is a major concern and needs to be investigated further. However, considering the enzyme-specific priorities, metabolic stability and potency are key.

Output:
0
2025-04-17 11:52:51,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.479 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.45) is slightly higher than the ideal <140, but acceptable. Ligand B (72.53) is well within the range.

**logP:** Ligand A (-0.633) is a bit low, potentially hindering permeability. Ligand B (1.79) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), below the threshold of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (7 and 6, respectively), below the threshold of 10.

**QED:** Both ligands have good QED scores (0.558 and 0.863), indicating drug-like properties.

**DILI:** Ligand A (47.15) and Ligand B (35.595) both have low DILI risk, below the 40 threshold.

**BBB:** Both ligands have moderate BBB penetration, but this is less critical for a non-CNS target like SRC. Ligand B (57.115) is slightly better.

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

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.476 and 0.143, respectively).

**Microsomal Clearance:** Ligand A (22.765) has lower microsomal clearance than Ligand B (20.99), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (54.82) has a significantly longer in vitro half-life than Ligand A (-15.773). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.026, respectively).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While both ligands have some issues with permeability and solubility, Ligand B is the stronger candidate. Its superior binding affinity (-9.2 vs -7.7 kcal/mol) and significantly longer half-life (54.82 vs -15.773) outweigh the slightly better metabolic stability of Ligand A. The logP of Ligand B is also more favorable. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 11:52:51,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.379 and 362.55 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.91) is better than Ligand B (66.4). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (2.362) is optimal (1-3), while Ligand A (0.468) is slightly low, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**QED:** Ligand B (0.771) has a significantly better QED score than Ligand A (0.226), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 46.413, Ligand B: 37.999), both below the 40 threshold.

**BBB:** Both have reasonable BBB penetration (Ligand A: 70.105, Ligand B: 68.864), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.477 and -4.481), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-0.463 and -2.95), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.133, Ligand B: 0.223).

**Microsomal Clearance:** Ligand A (18.79 mL/min/kg) has significantly lower microsomal clearance than Ligand B (67.178 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.487 hours) has a negative half-life, which is not possible. Ligand B (7.68 hours) is reasonable.

**P-gp Efflux:** Both have low P-gp efflux liability (Ligand A: 0.035, Ligand B: 0.062).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), though both are good.

**Overall Assessment:**

Ligand B has a better QED score, optimal logP, and slightly better binding affinity. However, Ligand A has significantly better metabolic stability (lower Cl_mic) and a more reasonable (though still problematic) half-life. Both have concerningly poor predicted solubility and permeability. Given the importance of metabolic stability for kinase inhibitors, and the slight advantage in binding affinity, Ligand B is marginally preferred. The poor solubility and permeability would need to be addressed through formulation or further chemical modifications.

Output:
1
2025-04-17 11:52:51,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 and 367.56 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (38.77) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (2.321) is optimal, while Ligand B (4.755) is a bit high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of 10.

**QED:** Both ligands (0.632 and 0.599) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (22.024), but both are below the concerning threshold of 60.

**BBB:** Ligand A (60.682) is lower than Ligand B (89.957). However, as SRC is not a CNS target, BBB is not a primary concern.

**Caco-2:** Both ligands have negative Caco-2 values (-5.023 and -4.924), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have negative solubility values (-2.776 and -4.0), also unusual and concerning.

**hERG:** Ligand A (0.338) has a significantly lower hERG risk than Ligand B (0.821), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (34.158) has a lower Cl_mic, indicating better metabolic stability, which is a key priority for enzyme inhibitors. Ligand B (104.662) has high clearance.

**In vitro Half-Life:** Ligand B (35.305) has a slightly longer half-life than Ligand A (25.943), but the difference is not substantial.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux than Ligand B (0.888), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.3 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 Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a better logP, lower hERG risk, lower microsomal clearance (better metabolic stability), and slightly better binding affinity. While both ligands have concerning Caco-2 and solubility values, the other advantages of Ligand A outweigh these drawbacks.

Output:
0
2025-04-17 11:52:51,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.312 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.59) is well below the 140 threshold for oral absorption, while Ligand B (95.39) is closer to the limit but still acceptable.

**logP:** Ligand A (3.567) is optimal (1-3). Ligand B (-1.054) is significantly below this, 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, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.739 and 0.552), indicating good drug-like properties.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (34.161). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.492) is slightly better than Ligand B (52.889).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.168) is slightly better than Ligand B (-5.464).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.675) is slightly better than Ligand B (-0.946).

**hERG Inhibition:** Ligand A (0.842) has a lower hERG risk than Ligand B (0.148), which is a significant advantage.

**Microsomal Clearance:** Ligand A (40.6 mL/min/kg) has a higher clearance than Ligand B (18.443 mL/min/kg), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (11.965 hours) has a longer half-life than Ligand A (13.235 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.475 and 0.006).

**Binding Affinity:** Both have excellent binding affinities (-8.6 and -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have good binding affinity, Ligand B is preferable due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic), and longer half-life. Ligand A's higher logP is a plus, but the higher DILI risk and clearance are concerning. The slightly better solubility and permeability of Ligand A are not enough to offset these drawbacks.

Output:
1
2025-04-17 11:52:51,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.279 Da) is slightly higher than Ligand B (345.407 Da), but both are acceptable.

**TPSA:** Ligand A (75.71) is better than Ligand B (89.15). Lower TPSA generally favors better absorption.

**logP:** Ligand A (2.168) is optimal, while Ligand B (-0.053) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=0, HBA=7). Both are within acceptable limits, but Ligand A's profile is slightly more balanced.

**QED:** Both ligands have good QED scores (Ligand A: 0.578, Ligand B: 0.758), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (38.62) has a lower DILI risk than Ligand B (54.285), which is preferable.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (71.307) is better than Ligand B (52.423).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.709) is slightly better than Ligand B (-4.982).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.033) is slightly better than Ligand B (-0.196).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.16, Ligand B: 0.115).

**Microsomal Clearance:** Ligand B (-1.964) exhibits significantly lower (better) microsomal clearance than Ligand A (60.327), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (10.059) has a much longer half-life than Ligand A (-11.484), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.094, Ligand B: 0.012). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 0.9 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B has superior ADME properties (lower Cl_mic, longer t1/2, better solubility, lower DILI) but slightly weaker binding affinity. Ligand A has a better binding affinity but poorer ADME properties, particularly concerning metabolic stability and solubility. Given the enzyme-specific priorities, metabolic stability and solubility are critical. The 0.9 kcal/mol difference in binding affinity is not substantial enough to overcome the significant ADME liabilities of Ligand A.

Output:
1
2025-04-17 11:52:51,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.877 and 359.491 Da) are within the ideal 200-500 Da range.

**TPSA:** Both ligands (51.22 and 49.77) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.633) is slightly higher than optimal (1-3), potentially causing solubility issues. Ligand B (3.76) is within the optimal range.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.71 and 0.694), indicating good drug-likeness.

**DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (44.436). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (73.129) has a higher BBB value than Ligand A (29.275), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.942 and -4.697), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.382 and -4.348). This is a major issue for bioavailability.

**hERG Inhibition:** Ligand A (0.443) has a slightly lower hERG risk than Ligand B (0.794), which is preferable.

**Microsomal Clearance:** Ligand B (107.153 mL/min/kg) has significantly higher microsomal clearance than Ligand A (59.653 mL/min/kg), indicating lower metabolic stability. This is a major disadvantage for Ligand B.

**In vitro Half-Life:** Ligand B (67.744 hours) has a much longer half-life than Ligand A (-0.034 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have relatively low P-gp efflux liability (0.455 and 0.832).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.2 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite the similar binding affinities, Ligand A appears to be the better candidate. While it has a slightly higher logP and a somewhat higher DILI risk, its significantly lower microsomal clearance and better hERG profile are crucial advantages for an enzyme inhibitor. The extremely poor solubility and Caco-2 permeability are concerning for both, but metabolic stability is often easier to improve through structural modifications than solubility. The longer half-life of Ligand B is attractive, but the higher clearance is a more pressing issue.

Output:
0
2025-04-17 11:52:51,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.373 and 368.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is excellent, well below the 140 threshold for oral absorption. Ligand B (123.22) is still acceptable, but less favorable.

**logP:** Ligand A (0.21) is quite low, potentially hindering permeability. Ligand B (0.006) is even lower, raising significant concerns about absorption.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is within acceptable limits. Ligand B (1 HBD, 9 HBA) is also within limits, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.503 and 0.725), indicating drug-like properties.

**DILI:** Ligand A (37.185) has a low DILI risk, which is excellent. Ligand B (78.247) has a significantly higher DILI risk, which is concerning.

**BBB:** Ligand A (77.898) has reasonable BBB penetration, while Ligand B (51.415) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a slight advantage for A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.056 and -5.185), which is unusual and suggests very poor permeability. This is a major red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.925 and -2.312), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG risk (0.22 and 0.012), which is excellent.

**Microsomal Clearance:** Ligand A (-19.293) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (6.841) has a much higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-9.587) has a very long half-life (negative value), which is excellent. Ligand B (7.005) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.031), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

While both ligands have issues with permeability and solubility, Ligand A is clearly superior. Its significantly stronger binding affinity, much lower DILI risk, and excellent metabolic stability (low Cl_mic and long t1/2) outweigh its slightly lower logP. Ligand B's very poor affinity and higher DILI risk make it a less attractive candidate. The negative Caco-2 and solubility values for both are concerning and would require significant medicinal chemistry efforts to address, but the starting point with Ligand A is much more promising due to its potency.

Output:
0
2025-04-17 11:52:51,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.895 Da) is slightly higher than Ligand B (351.397 Da), but both are acceptable.

**TPSA:** Ligand A (51.02) is well below the 140 threshold for oral absorption. Ligand B (62.3) is also acceptable, though slightly higher.

**logP:** Both ligands have good logP values (A: 3.222, B: 2.402), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the suggested limits.

**QED:** Both ligands have good QED scores (A: 0.663, B: 0.886), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (77.666) has a higher DILI risk than Ligand B (39.667). This is a significant concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (A: 88.29, B: 89.919), but this is less crucial for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.933 and -4.578), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.136 and -2.798), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.297, B: 0.478), which is positive.

**Microsomal Clearance:** Ligand B (24.675 mL/min/kg) has significantly lower microsomal clearance than Ligand A (48.072 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-31.728 hours) has a longer in vitro half-life than Ligand A (-27.432 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.523, B: 0.081). Ligand B is significantly better here.

**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 for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, it has a significantly higher DILI risk and higher microsomal clearance, indicating poorer metabolic stability. Both ligands have poor solubility and permeability. Ligand B has better ADME properties overall (lower DILI, better metabolic stability, lower P-gp efflux), but its binding affinity is weaker.

Given the importance of potency for kinase inhibitors, the stronger binding 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 are shared issues that would need to be addressed regardless of which lead is chosen.

Output:
1
2025-04-17 11:52:51,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (348.399 and 348.487 Da) fall comfortably 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 threshold for good oral absorption (<140).

**3. logP:** Ligand A (0.984) is slightly lower than optimal (1-3), but acceptable. Ligand B (2.487) 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 5 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.775 and 0.802), indicating good drug-like properties.

**7. DILI:** Ligand A (50.136) has a slightly higher DILI risk than Ligand B (25.902). Ligand B is preferable here.

**8. BBB:** Ligand A (59.442) has a lower BBB penetration than Ligand B (78.519). This isn't a primary concern for a non-CNS target like SRC, but it's a slight advantage for B.

**9. Caco-2 Permeability:** Ligand A (-4.662) has a worse Caco-2 permeability than Ligand B (-4.763).

**10. Aqueous Solubility:** Ligand A (-1.824) has better aqueous solubility than Ligand B (-2.89). This is a positive for Ligand A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.206 and 0.361), which is good.

**12. Microsomal Clearance:** Ligand A (32.506) has lower microsomal clearance than Ligand B (40.973), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-11.668) has a much worse in vitro half-life than Ligand B (20.835). This is a significant drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.301).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 and -8.0 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. While both have good affinity and hERG profiles, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a lower DILI risk. Ligand A has better solubility, but the significantly worse half-life is a major concern.

Output:
1
2025-04-17 11:52:51,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.26 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (91.22) is preferable to Ligand A (104.18) due to being lower.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 1.399, Ligand B: 1.888), which is optimal.

**H-Bond Donors & Acceptors:** Both have 3 HBDs, which is good. Ligand A has 6 HBAs, while Ligand B has 3. Ligand B is preferable here.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.664, Ligand B: 0.762), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a significantly higher DILI risk (85.537%) than Ligand B (30.826%). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but not a primary concern for a non-CNS target like SRC. Ligand A (67.197%) is slightly higher than Ligand B (64.754%).

**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 indicate very low permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.174) has a slightly lower hERG inhibition risk than Ligand B (0.598), which is favorable.

**Microsomal Clearance (Cl_mic):** Ligand B (-2.864 mL/min/kg) has a much lower (better) microsomal clearance than Ligand A (-17.5 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life (t1/2):** Ligand B (-6.542 hours) has a longer half-life than Ligand A (59.711 hours). This is a positive attribute for Ligand B.

**P-gp Efflux:** Ligand A (0.016) has a lower P-gp efflux liability than Ligand B (0.072), which is preferable.

**Binding Affinity:** Both ligands have strong binding affinities (Ligand A: -8.4 kcal/mol, Ligand B: -6.8 kcal/mol). Ligand A has a 1.6 kcal/mol advantage, which is substantial and could outweigh some of its ADME drawbacks.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its significantly higher DILI risk and higher microsomal clearance are major drawbacks. The poor solubility and permeability of both are concerning, but the DILI risk is a dealbreaker. Ligand B, while having a slightly weaker affinity, presents a much more favorable ADME profile, particularly its lower DILI risk and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and safety (DILI) are critical.

Output:
1
2025-04-17 11:52:51,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.407 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is slightly higher than Ligand B (67.67), but both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.423) is within the optimal 1-3 range. Ligand B (0.539) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) both meet the <=10 criteria.

**QED:** Both ligands have similar QED values (0.791 and 0.749), indicating good drug-likeness.

**DILI:** Ligand A (62.233) has a higher DILI risk than Ligand B (33.23). This is a significant negative for Ligand A.

**BBB:** Ligand A (36.526) has a lower BBB penetration percentile than Ligand B (91.702). While not a primary concern for a non-CNS target like SRC, higher BBB is generally preferable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.586 and -4.573), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.141 and -0.848), indicating poor aqueous solubility. This is a significant drawback for both, potentially impacting bioavailability. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.653) has a higher hERG inhibition risk than Ligand B (0.135). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (82.151) has a higher microsomal clearance than Ligand B (4.893), indicating lower metabolic stability. This is a major negative for Ligand A.

**In vitro Half-Life:** Ligand A (-27.44) has a negative half-life, which is not possible. Ligand B (-0.803) is also negative, but less so. Both are problematic.

**P-gp Efflux:** Ligand A (0.379) has lower P-gp efflux than Ligand B (0.038), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.0 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh the ADME differences.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B exhibits significantly lower DILI and hERG risk, and much better metabolic stability (lower Cl_mic). The slightly lower logP of Ligand B is a minor concern compared to the substantial advantages in safety and metabolic stability.

Output:
1
2025-04-17 11:52:51,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (106.32), being comfortably below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.237 and 1.695), falling within the 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have similar QED scores (0.799 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (31.02). This is a major advantage.

**BBB:** Ligand A (44.591) has a lower BBB penetration than Ligand B (56.65). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.681) has better Caco-2 permeability than Ligand B (-4.733), but both are quite poor.

**Aqueous Solubility:** Ligand A (-1.759) has better aqueous solubility than Ligand B (-3.208). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.236 and 0.296).

**Microsomal Clearance:** Ligand A (29.709) has significantly lower microsomal clearance than Ligand B (36.832), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.347 hours) has a positive half-life, while Ligand B (-13.918 hours) has a negative half-life. This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.013).

**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 and can be overcome by other favorable properties.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic and positive t1/2), better solubility, and acceptable binding affinity. While Ligand B has slightly better affinity, the ADME profile of Ligand A is far more favorable for drug development.

Output:
0
2025-04-17 11:52:51,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (340.427 and 340.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (86.88 and 89.87) below 140, suggesting reasonable oral absorption potential.

**3. logP:** Both ligands have logP values (2.111 and 2.686) within the optimal range of 1-3.

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

**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 scores (0.779 and 0.747), indicating good drug-likeness.

**7. DILI:** Ligand A (52.307) has a lower DILI risk than Ligand B (60.527). Both are acceptable, but A is preferred.

**8. BBB:** Ligand A (74.254) has a significantly higher BBB penetration potential than Ligand B (33.928). While not critical for a non-CNS target like SRC, it's a slight advantage.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.266 and -5.174). 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 (-3.349 and -3.859). Again, the scale is undefined, but suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.751) has a lower hERG inhibition liability than Ligand B (0.461), which is a significant advantage. Lower hERG is crucial to avoid cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (59.173) has a higher (worse) microsomal clearance than Ligand B (-17.402). This indicates lower metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-4.121) has a shorter in vitro half-life than Ligand B (-22.067). This further supports the lower metabolic stability of Ligand A.

**14. P-gp Efflux:** Ligand A (0.415) has higher P-gp efflux liability than Ligand B (0.042). This means Ligand B is less likely to be pumped out by P-gp, improving bioavailability.

**15. Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference and a major factor favoring Ligand A.

**Overall Assessment:**

Despite the concerning permeability and solubility values (which need further investigation with defined scales), Ligand A is the more promising candidate. The significantly stronger binding affinity (-7.2 vs -0.0 kcal/mol) outweighs the drawbacks of slightly higher clearance and P-gp efflux. The lower hERG risk and DILI are also important advantages. Ligand B's extremely poor binding affinity makes it unlikely to be a viable candidate, even with better metabolic stability and lower efflux.

Output:
1
2025-04-17 11:52:51,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (95.91), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.302) is within the optimal 1-3 range, while Ligand B (0.527) is slightly below 1, potentially hindering permeation.

**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 range (<=10).

**QED:** Both ligands have similar QED values (0.759 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A (10.392) has a significantly lower DILI risk than Ligand B (49.942). This is a major advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (70.997) is better than Ligand B (38.465).

**Caco-2 Permeability:** Both are negative (-5.062 and -5.597), which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Both are negative (-1.961 and -1.642), also unusual. Again, similar values.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.138 and 0.195).

**Microsomal Clearance:** Ligand A (-6.955) shows better metabolic stability (lower clearance) than Ligand B (-7.487).

**In vitro Half-Life:** Ligand A (-14.742) has a longer half-life than Ligand B (-2.759), which is highly desirable.

**P-gp Efflux:** Ligand A (0.013) has a slightly lower P-gp efflux liability than Ligand B (0.014).

**Binding Affinity:** Ligand B (-7.487) has a slightly better binding affinity than Ligand A (-6.955). The difference is 0.532 kcal/mol, which is not a huge difference but is noticeable.

**Conclusion:**

Despite Ligand B having slightly better binding affinity, Ligand A is the superior candidate. The significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better BBB penetration outweigh the small difference in binding affinity. The solubility and Caco-2 permeability are similar and concerning for both, but the ADME profile of Ligand A is substantially more promising.

Output:
1
2025-04-17 11:52:51,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.01) is significantly better than Ligand B (58.64), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.796 and 3.047), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 3 HBA) as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.786) has a higher QED score than Ligand B (0.616), indicating better overall drug-likeness.

**DILI:** Ligand A (25.94) has a much lower DILI risk than Ligand B (11.361), a significant advantage.

**BBB:** Both ligands have high BBB penetration (83.831 and 80.574), but this isn't a primary concern for a non-CNS target like SRC.

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

**Aqueous Solubility:** Ligand A (-1.545) is slightly better than Ligand B (-2.104), though both are poor. Solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.829) has a lower hERG risk than Ligand B (0.361), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (2.678) has significantly lower microsomal clearance than Ligand B (70.666), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (9.486) has a longer in vitro half-life than Ligand B (17.409), which is also favorable.

**P-gp Efflux:** Ligand A (0.403) has lower P-gp efflux than Ligand B (0.036), which is good.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference and outweighs some of the ADME concerns.

**Overall:** Ligand A is significantly better than Ligand B. It has a superior safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), better drug-likeness (higher QED), and comparable binding affinity. While both have solubility issues, the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 11:52:51,486 - INFO - Batch 83 complete. Total preferences: 1328
2025-04-17 11:52:51,486 - INFO - Processing batch 84/512...
2025-04-17 11:53:35,309 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 336.4, B: 346.4) fall within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (60.25) is well below the 140 threshold for good absorption, and even better for potential CNS penetration. Ligand B (98.32) is still under 140, but higher, potentially impacting absorption slightly.

3. **logP:** Both ligands (A: 1.911, B: 1.239) are 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. **HBD:** Ligand A (0) is ideal, minimizing potential for off-target interactions and maximizing permeability. Ligand B (3) is acceptable, but less optimal.

5. **HBA:** Ligand A (5) is good. Ligand B (4) is also good.

6. **QED:** Both ligands (A: 0.786, B: 0.714) have good drug-like scores, exceeding the 0.5 threshold.

7. **DILI:** Both ligands have similar, acceptable DILI risk (A: 41.8, B: 42.8), both below the 60 threshold.

8. **BBB:** Ligand A (81.8) shows better potential for BBB penetration than Ligand B (43.9). However, since SRC is not a CNS target, this is a lower priority.

9. **Caco-2:** Ligand A (-4.634) has a more negative Caco-2 value, which is unusual and suggests *poor* permeability. Ligand B (-5.315) is also negative, but slightly worse. This is a concerning sign for both, but worse for B.

10. **Solubility:** Ligand A (-3.748) has a more negative solubility value, indicating poor aqueous solubility. Ligand B (-1.874) is better, suggesting improved solubility.

11. **hERG:** Both ligands have similar, low hERG risk (A: 0.43, B: 0.468).

12. **Cl_mic:** Ligand A (47.282) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (-18.543) has a *negative* clearance, which is not physically possible and likely an error in the data, but *indicates* very high metabolic stability. This is a significant advantage for Ligand B.

13. **t1/2:** Ligand A (0.001) has a very short in vitro half-life. Ligand B (-27.17) also has a negative value, which is not physically possible, but *indicates* a very long half-life.

14. **Pgp:** Both ligands have similar, low P-gp efflux liability (A: 0.505, B: 0.074). Ligand B is slightly better.

15. **Binding Affinity:** Ligand A (-8.2) has a slightly better binding affinity than Ligand B (-7.3). This is a 0.9 kcal/mol difference, which is significant.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

Despite the slightly better affinity of Ligand A, Ligand B is the more promising candidate. The negative values for Cl_mic and t1/2 are likely data errors, but strongly suggest significantly improved metabolic stability and a longer half-life, which are crucial for kinase inhibitors. Ligand B also has better solubility. While both have concerning Caco-2 values, the metabolic advantages of Ligand B outweigh the slightly weaker binding affinity. The better solubility of Ligand B also helps mitigate potential issues arising from the Caco-2 values.

Output:
1
2025-04-17 11:53:35,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.515 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.36) is better than Ligand B (71.53). Both are below the 140 threshold for oral absorption, but lower TPSA is generally preferred.

**3. logP:** Both ligands have good logP values (2.926 and 1.928), 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 (3) is higher than Ligand B (1). While both are acceptable (<=5), lower HBD is generally preferred for better permeability.

**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 (0.742 and 0.855), indicating good drug-like properties.

**7. DILI:** Ligand B (23.032) has a significantly lower DILI risk than Ligand A (15.161). This is a major advantage for Ligand B.

**8. BBB:** Both ligands have similar BBB penetration (63.94 and 64.211). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.707 and -4.701). This is unusual and suggests poor permeability. It's difficult to interpret without knowing the scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.927 and -2.002). Again, this is unusual and suggests poor solubility. It's difficult to interpret without knowing the scale.

**11. hERG Inhibition:** Ligand A (0.59) has a slightly higher hERG risk than Ligand B (0.312), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (28.89) has significantly lower microsomal clearance than Ligand A (57.857), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (4.869) has a slightly longer half-life than Ligand B (-4.119). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**14. P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux than Ligand B (0.038), suggesting better oral bioavailability.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, Ligand B is the more promising candidate. The significantly lower DILI risk and much better metabolic stability (lower Cl_mic, although the half-life value is concerning) outweigh the affinity difference. The negative Caco-2 and solubility values are a concern for both, but can be addressed with formulation strategies. The stronger binding of Ligand A might be overcome with optimization, whereas mitigating the higher DILI and poor metabolic stability of Ligand A would be more challenging.

Output:
1
2025-04-17 11:53:35,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 Da and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.48) is better than Ligand B (113.33), both are below the 140 A^2 threshold for good oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (1.366) is slightly better than Ligand B (0.666), both are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 3 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 QED values above 0.5 (0.744 and 0.699 respectively), indicating good drug-like properties.

**DILI:** Ligand A (52.734) has a better DILI score than Ligand B (62.854). Both are acceptable, but A is preferable.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (53.587) and Ligand B (63.784) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.633) is better than Ligand B (-5.456), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.411) is better than Ligand B (-2.262), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.068 and 0.058 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (11.583) has significantly lower microsomal clearance than Ligand B (19.889), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.127) has a much longer in vitro half-life than Ligand B (-8.914), indicating slower metabolism and potentially less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.069 respectively).

**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. The difference of 1.5 kcal/mol is significant enough to potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has better ADME properties (lower DILI, better solubility, lower clearance, longer half-life, better Caco-2 permeability). However, Ligand B exhibits a substantially stronger binding affinity (-10.1 vs -8.6 kcal/mol). Given that we are targeting an enzyme (kinase), potency is paramount. The 1.5 kcal/mol difference in binding affinity is a significant advantage that likely outweighs the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 11:53:35,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (350.419 and 358.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (85.69 and 88.32) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.37) is slightly low, potentially hindering permeation. Ligand B (2.042) is within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands (1 and 2) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (6 and 4) are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.796 and 0.828) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (46.297) has a lower DILI risk than Ligand B (58.666), both are acceptable (<60).

**8. BBB:** Both ligands have similar BBB penetration (76.231 and 78.247), which is not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.816 and -4.873). 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 negative solubility values (-1.276 and -2.571). This also suggests poor solubility. Again, the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.07) has a much lower hERG inhibition liability than Ligand B (0.266), which is a significant advantage.

**12. Microsomal Clearance (Cl_mic):** Ligand A (0.897) has significantly lower microsomal clearance than Ligand B (26.933), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.908 hours) has a much longer in vitro half-life than Ligand B (-21.197 hours). The negative value for B is concerning and likely indicates rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.028 and 0.14).

**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 crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Ligand A is the superior candidate. Its significantly stronger binding affinity (-10.4 vs -6.8 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP and the negative solubility/permeability values. The much lower hERG risk is also a major advantage. While both ligands have issues with solubility and permeability, the superior potency and safety profile of Ligand A make it more likely to be a viable drug candidate.

Output:
1
2025-04-17 11:53:35,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (343.427 Da and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (82.43 and 86.88) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (1.885) is optimal, while Ligand B (2.937) is also within the optimal range, though approaching the upper limit.

**4. H-Bond Donors:** Ligand A (1) is good, while Ligand B (3) is acceptable but slightly higher.

**5. H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (3) is also good.

**6. QED:** Ligand A (0.885) has a significantly better QED score than Ligand B (0.663), indicating a more drug-like profile.

**7. DILI:** Ligand A (54.556) has a slightly higher DILI risk than Ligand B (48.817), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have moderate BBB penetration (64.87 and 56.883). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.617 and -4.99), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.172 and -3.737), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.568) has a lower hERG risk than Ligand B (0.359), which is preferable.

**12. Microsomal Clearance:** Ligand A (36.802) has a higher microsomal clearance than Ligand B (33.812), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.728) has a longer in vitro half-life than Ligand A (6.525), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.147) has lower P-gp efflux than Ligand B (0.204), which is favorable.

**15. Binding Affinity:** Ligand B (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This difference of 1.2 kcal/mol is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have significant issues with solubility and permeability, Ligand B's substantially stronger binding affinity (-10.5 vs -9.3 kcal/mol) and longer half-life are compelling advantages. The slightly better QED and hERG profile of Ligand A are not enough to offset these differences. The poor solubility and permeability would require formulation strategies (e.g., salt formation, amorphous solid dispersions) to address.

Output:
1
2025-04-17 11:53:35,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.473 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (72.8), being well below the 140 threshold for good absorption. Ligand B is higher, potentially impacting absorption.

**logP:** Ligand A (3.696) is optimal, while Ligand B (1.835) is on the lower side. A logP below 1 can sometimes hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Lower counts generally improve permeability.

**QED:** Ligand A (0.769) has a much better QED score than Ligand B (0.461), indicating a more drug-like profile.

**DILI:** Ligand B (3.18%) has a significantly lower DILI risk than Ligand A (16.208%), which is a substantial advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 97.402%, Ligand B: 74.098%), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.294) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.027) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.915) has slightly better solubility than Ligand B (-2.642), but both are quite poor.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.679, Ligand B: 0.622), which is good.

**Microsomal Clearance:** Ligand B (28.781 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (47.149 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (0.642 hours) has a very short half-life, while Ligand A (-21.973 hours) has a negative value which is not physically possible. This indicates a significant issue with the experimental setup or the ligand itself.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.058, Ligand B: 0.066).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). While both are excellent, the 1.2 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the better candidate despite the slightly lower binding affinity. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic, though the half-life is very short) are major advantages. Ligand A has a better QED, but its extremely poor Caco-2 permeability and nonsensical half-life are dealbreakers. The solubility of both is poor, but can be addressed with formulation strategies.



Output:
1
2025-04-17 11:53:35,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 368.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.11) is slightly higher than Ligand B (78.87), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.535) and Ligand B (0.941) are both within the optimal range of 1-3. Ligand B is a bit lower, potentially impacting permeability, but still acceptable.

**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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.591 and 0.722 respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (39.201 and 36.293 respectively), which is favorable.

**BBB:** Ligand A (59.325) has a moderate BBB penetration, while Ligand B (17.914) has very low BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.344) and Ligand B (-4.965) have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.343 and -2.559 respectively). This is a significant drawback, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.125 and 0.162 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (27.937) has a lower microsomal clearance than Ligand B (31.599), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.402) has a significantly longer in vitro half-life than Ligand B (-2.148), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.142 respectively).

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.5), although the difference is small (0.2 kcal/mol).

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is more promising. While both have poor solubility and permeability, Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The difference in half-life is substantial and could translate to a more favorable dosing regimen. The slightly better metabolic stability and affinity outweigh the slightly higher TPSA and lower BBB penetration.

Output:
0
2025-04-17 11:53:35,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.336 Da) is slightly higher than Ligand B (384.801 Da), but both are acceptable.

**TPSA:** Ligand A (60.77) is significantly better than Ligand B (116.36). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.665, B: 2.335), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD: 0, HBA: 6) is preferable to Ligand B (HBD: 1, HBA: 7) as lower counts generally improve permeability.

**QED:** Both ligands have acceptable QED values (A: 0.648, B: 0.48), indicating reasonable drug-likeness. Ligand A is better.

**DILI:** Ligand B (99.147) has a very high DILI risk, exceeding the 60% threshold, which is a major concern. Ligand A (44.591) is well below the 40% threshold, indicating low risk.

**BBB:** Ligand A (68.748) has a better BBB percentile than Ligand B (45.095), though BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**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 (-4.778 for A, -4.909 for B).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-2.583 for A, -4.123 for B).

**hERG:** Ligand A (0.557) has a lower hERG risk than Ligand B (0.262), which is preferable.

**Microsomal Clearance:** Ligand B (21.634) has significantly lower microsomal clearance than Ligand A (96.582), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 30.009, B: 29.022).

**P-gp Efflux:** Ligand A (0.59) has lower P-gp efflux than Ligand B (0.256), which is favorable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This difference of 2 kcal/mol is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability. However, its extremely high DILI risk is a major red flag. Ligand A has a much better safety profile (lower DILI and hERG), better TPSA and QED, and acceptable metabolic stability. The stronger binding affinity of Ligand B is attractive, but the DILI risk is too high to ignore.

Output:
0
2025-04-17 11:53:35,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.415 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.13) is slightly higher than Ligand B (87.3). Both are below the 140 threshold for good oral absorption, but Ligand B is closer to the 90 threshold for CNS penetration (though that's not a priority here).

**logP:** Ligand A (-0.652) is a bit low, potentially hindering permeability. Ligand B (1.059) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (8) and Ligand B (4) are both acceptable (<=10).

**QED:** Ligand A (0.65) is better than Ligand B (0.398), indicating a more drug-like profile.

**DILI:** Ligand A (53.315) has a higher DILI risk than Ligand B (22.722), which is a significant concern.

**BBB:** Not a primary concern for a non-CNS target. Ligand B (42.691) is higher than Ligand A (32.183).

**Caco-2 Permeability:** Both are negative (-5.383 and -5.533), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative (-2.36 and -2.85), indicating poor solubility. This is a concern for both.

**hERG:** Ligand A (0.037) has a slightly better hERG profile than Ligand B (0.191), which is preferable.

**Microsomal Clearance:** Ligand A (26.059) has a higher clearance than Ligand B (6.281), meaning Ligand B is more metabolically stable. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (10.55) has a significantly longer half-life than Ligand A (2.355), further supporting its better metabolic stability.

**P-gp Efflux:** Both are very low (0.011 and 0.032), suggesting minimal P-gp efflux.

**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 be considered, especially given the other favorable properties of Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. It has a more favorable logP, significantly better metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and slightly better binding affinity. While Ligand A has a better QED and hERG profile, the metabolic stability and DILI concerns with Ligand A are more critical drawbacks for an enzyme target like SRC kinase. The poor Caco-2 and solubility for both are concerns that would need to be addressed in further optimization, but are less critical than the metabolic and toxicity profiles at this stage.

Output:
1
2025-04-17 11:53:35,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (351.491 and 347.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (83.71 and 84.23) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (1.774 and 1.881) are 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 permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4). Lower HBA is generally preferred for permeability.

**6. QED:** Both ligands (0.759 and 0.77) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (7.251) is significantly better than Ligand B (44.591). Ligand A is well below the 40% threshold, indicating low liver injury risk, while Ligand B is moderately elevated.

**8. BBB:** Ligand A (87.398) is better than Ligand B (75.107), but BBB is not a high priority for an oncology target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.066) is better than Ligand B (-4.544). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.196) is better than Ligand B (-3.521). Higher solubility is desirable.

**11. hERG Inhibition:** Both ligands (0.341 and 0.153) show low hERG inhibition risk, which is excellent.

**12. Microsomal Clearance:** Ligand A (32.834) is higher than Ligand B (10.077). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**13. In vitro Half-Life:** Ligand A (-24.583) is better than Ligand B (-18.859). A more negative value indicates a longer half-life.

**14. P-gp Efflux:** Both ligands (0.021 and 0.038) show low P-gp efflux liability.

**15. Binding Affinity:** Ligand B (-9.6) is significantly better than Ligand A (-8.3). This is a 1.3 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better DILI, solubility, and half-life, the significantly stronger binding affinity of Ligand B (-9.6 kcal/mol vs -8.3 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. The difference in binding affinity is large enough to compensate for the slightly higher DILI risk and lower metabolic stability. For an oncology target, potency is paramount.

Output:
1
2025-04-17 11:53:35,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.383 and 352.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (107.87 and 101.38) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.01 and 1.365), falling 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5 (0.68 and 0.833), indicating good drug-likeness.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (55.176), but both are reasonably acceptable.

**BBB:** Both ligands have low BBB penetration (59.984 and 54.634), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.558 and -4.996). This 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 ligands have negative solubility values (-3.828 and -1.926), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.491) has a slightly higher hERG risk than Ligand B (0.115), but both are relatively low.

**Microsomal Clearance:** Ligand A has a significantly *lower* (better) microsomal clearance (-14.092 mL/min/kg) than Ligand B (6.679 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (13.78 hours) than Ligand B (-3.144 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.061 and 0.007).

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a *much* stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a difference of 3 kcal/mol, which is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand A is the superior candidate. Its significantly stronger binding affinity (-9.8 vs -6.8 kcal/mol) and substantially better metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target like SRC kinase. The slightly higher DILI risk and hERG inhibition are less concerning given the potency and metabolic advantages.

Output:
1
2025-04-17 11:53:35,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (366.845 and 348.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.82) is slightly above the preferred <60 for optimal permeability, but still reasonable. Ligand B (58.2) is better, falling comfortably under 60.

**3. logP:** Ligand A (0.944) is a bit low, potentially hindering permeation. Ligand B (3.674) 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:** Ligand A has 5 HBA, and Ligand B has 2 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.83) has a better QED score than Ligand B (0.625), indicating a more drug-like profile.

**7. DILI:** Ligand A (49.632) has a moderate DILI risk, but is still acceptable. Ligand B (13.61) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (67.623) is better than Ligand A (52.656). While not a primary concern for a kinase inhibitor, it's a slight positive for B.

**9. Caco-2 Permeability:** Ligand A (-5.278) shows poor Caco-2 permeability. Ligand B (-4.666) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-2.82) has poor aqueous solubility. Ligand B (-4.01) also has poor aqueous solubility, but is slightly better than A.

**11. hERG Inhibition:** Ligand A (0.286) has a very low hERG inhibition risk, which is excellent. Ligand B (0.469) also has a low hERG risk, but slightly higher than A.

**12. Microsomal Clearance:** Ligand A (-3.481) indicates good metabolic stability (lower is better). Ligand B (68.839) has high microsomal clearance, suggesting rapid metabolism and a potential issue with maintaining therapeutic concentrations.

**13. In vitro Half-Life:** Ligand A (44.183) has a reasonable in vitro half-life. Ligand B (-7.184) has a very short in vitro half-life, a significant drawback.

**14. P-gp Efflux:** Ligand A (0.056) shows low P-gp efflux, which is favorable. Ligand B (0.271) has slightly higher P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly better binding affinity than Ligand B (-7.7 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand B having better logP and DILI, Ligand A's superior binding affinity (-8.9 vs -7.7 kcal/mol) and significantly better metabolic stability (lower Cl_mic, longer t1/2) are critical for an enzyme inhibitor. The slightly lower solubility and permeability of Ligand A can potentially be addressed through formulation strategies. The excellent hERG profile of Ligand A is also a strong positive. Therefore, Ligand A is the more promising drug candidate.

Output:
1
2025-04-17 11:53:35,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.344 and 381.395 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.63) is slightly above the preferred <90 for kinases, but still reasonable. Ligand B (62.3) is well within the range.

**3. logP:** Both ligands have similar logP values (2.199 and 2.187), 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 (0.825) has a higher QED than Ligand B (0.702), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.846) has a slightly higher DILI risk than Ligand B (38.62), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.633) has better BBB penetration than Ligand B (71.229).

**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:** Ligand A (0.79) has a higher hERG risk than Ligand B (0.367). This is a significant concern.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (13.287 and 13.183), suggesting similar metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.438) has a longer half-life than Ligand B (-4.816). The negative value for Ligand B is concerning and likely indicates very rapid metabolism.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.214 and 0.077).

**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 >1.5 kcal/mol difference, which is a major advantage.

**Overall Assessment:**

While Ligand A has a better QED and slightly longer half-life, Ligand B's significantly stronger binding affinity (-9.4 vs -7.7 kcal/mol) is the most critical factor for an enzyme inhibitor. The lower hERG risk for Ligand B is also a significant advantage. The unusual negative values for Caco-2 and solubility are concerning for both, but the potency difference outweighs these concerns. The negative half-life for Ligand B is a red flag, but could be addressed with structural modifications.

Output:
1
2025-04-17 11:53:35,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.362 and 365.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.58) is better than Ligand B (82.53), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have good logP values (2.29 and 1.682), falling 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 have 5 HBA, which is acceptable.

**6. QED:** Ligand A (0.919) has a significantly better QED score than Ligand B (0.732), indicating a more drug-like profile.

**7. DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (35.673). This is a significant drawback for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.107) is better than Ligand B (40.558).

**9. Caco-2 Permeability:** Ligand A (-4.439) is better than Ligand B (-5.074), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.933) is better than Ligand B (-2.64), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.19 and 0.151).

**12. Microsomal Clearance:** Ligand B (28.589) has lower microsomal clearance than Ligand A (42.668), suggesting better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (32.385) has a longer in vitro half-life than Ligand A (-2.408), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.032 and 0.046).

**15. Binding Affinity:** Ligand B (-7.5) has a significantly better binding affinity than Ligand A (-9). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and solubility, Ligand B's superior binding affinity (-7.5 vs -9 kcal/mol), lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) are more critical for an enzyme target like SRC kinase. The better affinity is a significant advantage.

Output:
1
2025-04-17 11:53:35,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.371 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.88) is slightly above the preferred <140, while Ligand B (110.1) is well within.

**logP:** Both ligands (-0.185 and -0.22) are a bit low, potentially hindering permeation. However, for kinases, this isn't a critical issue as much as for CNS targets.

**H-Bond Donors/Acceptors:** Both have 4 HBD and a reasonable number of HBA (4 and 5 respectively), satisfying the criteria.

**QED:** Both ligands have acceptable QED scores (0.405 and 0.482), indicating reasonable drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (61.846%) compared to Ligand B (14.308%). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a slightly higher BBB value (23.187 vs 19.038).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.48 and -5.214), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both have negative solubility values (-3.038 and -1.165), indicating poor aqueous solubility. This is a concern for both, but less so for Ligand B.

**hERG:** Both ligands have very low hERG risk (0.148 and 0.183), which is excellent.

**Microsomal Clearance:** Ligand A (-13.314) has a much lower (better) microsomal clearance than Ligand B (0.606), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (13.065 and 13.569 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.037 and 0.008).

**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 and could outweigh some ADME drawbacks.

**Conclusion:**

While both ligands have some issues (low logP, negative Caco-2 and solubility), Ligand B is the more promising candidate. Its significantly lower DILI risk and substantially stronger binding affinity outweigh the slightly higher TPSA and similar metabolic stability. The improved binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:53:35,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.463 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than Ligand B (70.47). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have acceptable logP values (1.546 and 0.791, respectively), falling within the 1-3 range. Ligand B is slightly lower, potentially impacting permeability.

**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 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.611 and 0.792), indicating good drug-like properties.

**DILI:** Ligand A (25.087) has a significantly lower DILI risk than Ligand B (19.271), which is a substantial advantage.

**BBB:** Ligand B (77.898) has a higher BBB penetration percentile than Ligand A (45.095). However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.023 and -5.095). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.582 and -1.162). This is also concerning, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.18) has a lower hERG inhibition liability than Ligand B (0.459), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (3.215) has much lower microsomal clearance than Ligand A (42.028), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (8.535) has a significantly longer in vitro half-life than Ligand A (-3.877), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.013), which is a slight advantage.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.4 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2) and slightly better permeability characteristics, Ligand A has a significantly lower DILI risk and lower hERG inhibition. Given the enzyme-specific priorities, metabolic stability is important, but safety (DILI and hERG) is paramount. The very similar binding affinities mean that the ADME/Tox differences become the deciding factor. The lower DILI and hERG risk of Ligand A outweigh the slightly better metabolic stability of Ligand B.

Output:
0
2025-04-17 11:53:35,312 - INFO - Batch 84 complete. Total preferences: 1344
2025-04-17 11:53:35,312 - INFO - Processing batch 85/512...
2025-04-17 11:54:15,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 337.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (64.45) as it is closer to the 140 threshold.

**logP:** Ligand B (3.106) is optimal (1-3), while Ligand A (0.141) is quite low, potentially hindering permeability.

**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 7. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**QED:** Ligand A (0.769) has a better QED score than Ligand B (0.608), indicating better overall drug-likeness.

**DILI:** Ligand A (32.067) has a significantly lower DILI risk than Ligand B (73.245), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (64.87) is slightly better than Ligand B (57.852).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, Ligand A (-4.842) is worse than Ligand B (-4.917).

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, Ligand A (-1.173) is better than Ligand B (-3.558).

**hERG Inhibition:** Ligand A (0.158) has a much lower hERG risk than Ligand B (0.867), a crucial safety factor.

**Microsomal Clearance:** Ligand A (-1.79) has a lower (better) microsomal clearance than Ligand B (40.188), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.851) has a longer half-life than Ligand B (40.74), which is desirable.

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux than Ligand B (0.706), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-9.9). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has a superior ADMET profile (lower DILI, hERG, Cl_mic, better QED, solubility, and P-gp efflux). However, Ligand B has a much better binding affinity (-7.8 vs -9.9 kcal/mol). The difference in binding affinity is substantial (over 2 kcal/mol), and for an enzyme target like SRC kinase, potency is paramount. While Ligand B has some ADME concerns, these could potentially be addressed through further optimization without sacrificing the strong binding affinity.

Output:
1
2025-04-17 11:54:15,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.405 and 369.437 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.93) is slightly higher than Ligand B (73.2), but both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.901 and 2.44), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic.

**H-Bond Donors:** Both have 1 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 similar QED scores (0.87 and 0.802), indicating good drug-likeness.

**DILI:** Ligand A (55.913) has a higher DILI risk than Ligand B (37.65), which is a significant concern.

**BBB:** Both have high BBB penetration (92.4 and 83.4), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-4.854 and -4.889), which is unusual and suggests poor permeability. This is a red flag for both.

**Solubility:** Both have negative solubility values (-2.625 and -2.749), indicating very poor aqueous solubility, a major issue for bioavailability.

**hERG:** Ligand A (0.225) has a slightly better hERG profile than Ligand B (0.794).

**Microsomal Clearance:** Both have similar, relatively low microsomal clearance (18.657 and 17.759 mL/min/kg), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (9.562) has a longer half-life than Ligand B (-2.176), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.147), which is favorable.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial difference. A >1.5 kcal/mol advantage can outweigh other drawbacks, and here the difference is 9 kcal/mol.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the superior candidate due to its dramatically stronger binding affinity (-9.0 kcal/mol vs -0.0 kcal/mol). The lower DILI risk is also a significant advantage. While the solubility and permeability issues need to be addressed through formulation or further chemical modifications, the potency difference is substantial enough to prioritize Ligand B for further development.

Output:
1
2025-04-17 11:54:15,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.406 and 345.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is significantly better than Ligand B (106.73).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.869 and 0.862), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is acceptable. Ligand A has 3 HBAs, while Ligand B has 7.  Lower HBA counts are generally preferred for better permeability.

**QED:** Both ligands have reasonable QED scores (0.852 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (24.622) has a much lower DILI risk than Ligand B (64.521). This is a significant advantage for Ligand A.

**BBB:**  BBB is less critical for a non-CNS target like SRC, but Ligand A (74.176) is better than Ligand B (49.748).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.965 and -5.196). This is unusual and suggests poor permeability. However, the values are similar, so it doesn't strongly differentiate the two.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.724 and -2.763). This is also unusual and suggests poor solubility. Again, the values are similar.

**hERG:** Both ligands have very low hERG risk (0.325 and 0.068), which is excellent.

**Microsomal Clearance:** Ligand A (24.715) has significantly lower microsomal clearance than Ligand B (8.461). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-4.7) has a better (longer) in vitro half-life than Ligand B (-0.82).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.022 and 0.055).

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-7.8). However, the difference is only 0.7 kcal/mol, which isn't a huge advantage given the other factors.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, better TPSA, lower microsomal clearance, and a longer half-life. These factors are more important for an enzyme inhibitor than a small improvement in binding affinity. The similar solubility and permeability issues are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 11:54:15,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 358.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (67.87) as it is still within the acceptable range for oral absorption.

**logP:** Both ligands have acceptable logP values (0.96 and 1.531, respectively), 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 4 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.692 and 0.643), indicating good drug-likeness.

**DILI:** Ligand A (16.557) has a significantly lower DILI risk than Ligand B (26.444), which is a major advantage.

**BBB:** Ligand B (97.325) has a much higher BBB penetration percentile than Ligand A (50.446). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-5.536) has a lower Caco-2 permeability than Ligand B (-4.543), which is less favorable.

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.466 and -2.456). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.126) has a significantly lower hERG inhibition liability than Ligand B (0.69), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-14.818) has a much lower (better) microsomal clearance than Ligand B (52.333), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.902) has a lower in vitro half-life than Ligand B (11.259), which is less desirable.

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.087), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.2) 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, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher hERG inhibition, and higher microsomal clearance. Ligand A has a better safety profile (lower DILI and hERG) and better metabolic stability, but its binding affinity is very weak.

Despite the significant affinity advantage of Ligand B, the safety concerns (DILI and hERG) and metabolic liability are significant drawbacks. The weak binding of Ligand A is a major issue, but it may be possible to improve it through further optimization without drastically worsening the ADME properties. Given the enzyme class, prioritizing metabolic stability and safety is crucial.

Output:
0
2025-04-17 11:54:15,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.535 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (72.38). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally better.

**logP:** Both ligands have good logP values (A: 4.878, B: 4.249), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) is better than Ligand B (HBD=3, HBA=4). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar QED values (A: 0.678, B: 0.64), both above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (22.024) has a significantly lower DILI risk than Ligand B (28.616), which is a crucial advantage.

**BBB:** Ligand A (73.866) has a much higher BBB penetration percentile than Ligand B (20.938). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.74) shows better Caco-2 permeability than Ligand B (-5.363).

**Aqueous Solubility:** Ligand A (-5.433) has slightly better solubility than Ligand B (-4.669).

**hERG Inhibition:** Ligand A (0.582) has a lower hERG inhibition liability than Ligand B (0.826), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (54.331) has significantly lower microsomal clearance than Ligand A (126.031), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (18.525) has a longer in vitro half-life than Ligand A (10.96), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.792) has slightly lower P-gp efflux than Ligand B (0.364).

**Binding Affinity:** Ligand B (-7.5 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 of Ligand B. The difference of 0.8 kcal/mol is considerable.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). These are the most important factors for an enzyme inhibitor. While Ligand A has advantages in DILI, hERG, and BBB, the potency and metabolic stability of Ligand B are more critical for SRC kinase inhibition. The improved affinity of Ligand B is likely to translate to greater efficacy, and its metabolic stability will contribute to a more favorable pharmacokinetic profile.

Output:
1
2025-04-17 11:54:15,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.543 and 351.405 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is better than Ligand B (81.76). Both are below 140, but A is closer to the desirable range for oral absorption.

**logP:** Both ligands have good logP values (2.49 and 2.044), 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. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.75 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (21.132) has a significantly lower DILI risk than Ligand B (50.485). This is a major advantage.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (59.791) is slightly higher than Ligand A (54.827).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.212 and -5.432). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.029 and -3.056). This is also concerning, indicating very poor solubility.

**hERG Inhibition:** Ligand A (0.235) has a much lower hERG risk than Ligand B (0.872). This is a significant advantage.

**Microsomal Clearance:** Ligand A (36.282) has a higher microsomal clearance than Ligand B (15.755), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-15.907) has a longer in vitro half-life than Ligand A (-19.318), suggesting better stability.

**P-gp Efflux:** Ligand A (0.134) has lower P-gp efflux liability than Ligand B (0.031), which is favorable.

**Binding Affinity:** Ligand B (-7.9) has a substantially better binding affinity than Ligand A (-10.6). This is a crucial factor, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.9 vs -10.6 kcal/mol). While Ligand A has advantages in DILI and hERG risk, the substantial difference in binding affinity of Ligand B is the most critical factor for an enzyme inhibitor. Although both have poor solubility and permeability, the potency advantage of Ligand B is likely to be more readily addressable through formulation or structural modifications. The longer half-life of Ligand B is also a positive.

Output:
1
2025-04-17 11:54:15,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (373.787 and 343.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is well below the 140 threshold for good absorption, and favorable. Ligand B (118.6) is still under 140, but less optimal than A.

**logP:** Both ligands have acceptable logP values (1.663 and 0.696), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 10 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have QED values above 0.5 (0.608 and 0.511), indicating good drug-likeness.

**DILI:** Ligand A (54.75) has a lower DILI risk than Ligand B (77.782), which is preferable. Both are below the concerning threshold of 60, but A is better.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (77.937) has a higher BBB penetration than Ligand B (46.413).

**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 (-5.148) is slightly better than Ligand B (-5.684).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.531) is slightly better than Ligand B (-1.681).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.692 and 0.608).

**Microsomal Clearance:** Both have similar microsomal clearance values (17.569 and 17.949 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (26.848 hours) has a slightly longer half-life than Ligand A (23.384 hours), which is a minor advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.123 and 0.028).

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

**Conclusion:**

Given the equal binding affinity, the decision hinges on ADME properties. Ligand A is superior due to its lower DILI risk, better TPSA, slightly better Caco-2 permeability, and slightly better solubility. While the differences in solubility and permeability are small given the unusual negative values, the lower DILI risk is a significant advantage.

Output:
0
2025-04-17 11:54:15,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.37 and 342.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (20.31) is excellent, well below the 140 threshold, suggesting good absorption. Ligand B (84.73) is higher, but still acceptable, though potentially slightly impacting absorption.

**logP:** Ligand A (4.778) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (3.203) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 1 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.69 and 0.757), indicating drug-like properties.

**DILI:** Ligand A (17.449) has a very low DILI risk, which is excellent. Ligand B (56.146) has a moderate DILI risk, but is still within acceptable limits.

**BBB:** Ligand A (97.247) shows excellent BBB penetration, though this is less crucial for a non-CNS target like SRC. Ligand B (77.937) is also reasonable.

**Caco-2 Permeability:** Ligand A (-4.585) and Ligand B (-4.929) 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 (-4.711 and -4.167). This is a major drawback.

**hERG Inhibition:** Ligand A (0.952) has a low hERG risk, which is good. Ligand B (0.341) has an even lower risk, which is excellent.

**Microsomal Clearance:** Ligand A (37.337) has a moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (71.321) has a higher clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-16.784) has a very short in vitro half-life, which is a significant concern. Ligand B (7.155) has a short half-life, but better than Ligand A.

**P-gp Efflux:** Ligand A (0.592) has moderate P-gp efflux. Ligand B (0.158) has low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 2.4 kcal/mol difference is substantial and can outweigh many ADME concerns.

**Overall Assessment:**

Despite both ligands having poor solubility and permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-10.5 vs -8.1 kcal/mol) is a major advantage for an enzyme target like SRC. It also exhibits a lower hERG risk and P-gp efflux. While its metabolic stability is lower than Ligand A, the potency difference is likely to be more impactful. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modifications, but the superior potency makes Ligand B the better starting point.

Output:
1
2025-04-17 11:54:15,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.53 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold and is favorable. Ligand B (87.46) is higher, but still within a reasonable range for oral absorption, though less optimal than A.

**logP:** Ligand A (2.944) is optimal (1-3). Ligand B (1.539) is on the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, which is excellent. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.64 and 0.619), indicating good drug-likeness.

**DILI:** Ligand A (34.28) has a slightly higher DILI risk than Ligand B (24.51), but both are below the concerning threshold of 60.

**BBB:** Ligand A (85.58) shows better BBB penetration than Ligand B (67.70), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.361) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.297) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.789) has poor aqueous solubility, while Ligand B (-1.97) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.308) has a lower hERG risk than Ligand B (0.7), which is favorable.

**Microsomal Clearance:** Ligand A (87.331) has higher microsomal clearance (less stable) than Ligand B (11.295), which is a major concern.

**In vitro Half-Life:** Ligand A (37.605) has a longer half-life than Ligand B (-1.286), which is positive. However, the negative value for B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.234) has lower P-gp efflux than Ligand B (0.015), which is preferable.

**Binding Affinity:** Both ligands have identical binding affinities (-7.2 kcal/mol), which is excellent.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B has significantly better metabolic stability (lower Cl_mic) and a more reasonable half-life. Ligand A's high microsomal clearance is a major red flag for an enzyme inhibitor, as it suggests rapid metabolism and potentially low *in vivo* exposure. The slightly better hERG and BBB for Ligand A are outweighed by the metabolic stability issues.

Output:
1
2025-04-17 11:54:15,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.407 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.22) is well below the 140 threshold for oral absorption and even below 90 for potential CNS penetration, while Ligand B (133.21) is still acceptable but closer to the upper limit.

**logP:** Ligand A (1.181) is within the optimal 1-3 range. Ligand B (-0.249) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, both within acceptable limits. Ligand B has 4 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.647 and 0.541), indicating good drug-like properties.

**DILI:** Ligand A (67.468) has a higher DILI risk than Ligand B (39.667), which is a significant concern.

**BBB:** Both have high BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.746) has very poor Caco-2 permeability, indicating poor absorption. Ligand B (-5.571) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.317) has poor solubility, while Ligand B (-2.644) is even worse. This is a concern for both, but more so for B.

**hERG:** Ligand A (0.646) has a slightly elevated hERG risk, but is acceptable. Ligand B (0.111) has very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (63.978) has moderate clearance, while Ligand B (-3.278) has *negative* clearance, which is highly unusual and suggests excellent metabolic stability.

**In vitro Half-Life:** Ligand A (50.608) has a reasonable half-life. Ligand B (0.753) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite Ligand B's poor solubility and short half-life, its *significantly* superior binding affinity (-8.1 vs 0 kcal/mol) and excellent metabolic stability (negative Cl_mic) make it the more promising candidate. The lower DILI and hERG risk are also beneficial. While the solubility and half-life are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. Ligand A's poor Caco-2 permeability is a major hurdle.

Output:
1
2025-04-17 11:54:15,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.463 and 350.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is better than Ligand B (87.47), both are below the 140 threshold for good absorption.

**logP:** Ligand B (1.491) is better than Ligand A (0.407). Ligand A is a bit low, potentially hindering permeation. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.749 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A (10.896) has a slightly higher DILI risk than Ligand B (9.965), but both are well below the concerning threshold of 60.

**BBB:** Both are low, which is expected for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-5.596 vs -5.223).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-0.864) is slightly better than Ligand A (-0.114).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.163 and 0.085), which is excellent.

**Microsomal Clearance:** Ligand A (-18.317) has significantly *lower* (better) microsomal clearance than Ligand B (17.549). This indicates greater metabolic stability for Ligand A.

**In vitro Half-Life:** Both have similar in vitro half-lives (11.843 and 11.267 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.005).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This 0.5 kcal/mol difference is significant, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic) and slightly lower DILI risk. However, Ligand B has better logP and a more favorable binding affinity. The binding affinity difference is substantial enough to make Ligand B the more promising candidate, despite its slightly worse logP and Cl_mic. The solubility and permeability issues are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 11:54:15,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.451 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.43) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (93.21) is still within the acceptable range for oral absorption (<140), but less optimal than A.

**logP:** Ligand A (3.564) is at the higher end of the optimal range (1-3), while Ligand B (1.61) is at the lower end. While both are acceptable, a higher logP can sometimes lead to off-target effects, but is less of a concern than poor solubility.

**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:** Both ligands have similar QED values (0.911 and 0.815), indicating good drug-likeness.

**DILI:** Ligand A (25.281) has a significantly lower DILI risk than Ligand B (52.423), which is a strong advantage.

**BBB:** Ligand A (84.529) has better BBB penetration than Ligand B (41.218), but this isn't a major concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-4.542) has a more negative Caco-2 value, which is unusual and suggests *lower* permeability. Ligand B (-5.234) is similarly low. This is a potential concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.606 and -2.28), indicating poor aqueous solubility. This is a significant drawback for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.823) has a slightly higher hERG risk than Ligand B (0.068). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (32.909) has a higher microsomal clearance than Ligand B (28.302), meaning it's likely to be metabolized faster. Lower clearance is preferred for kinases.

**In vitro Half-Life:** Ligand A (24.616) has a longer half-life than Ligand B (3.093), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.482) has lower P-gp efflux than Ligand B (0.01), which is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -9.0 kcal/mol), with Ligand A being slightly better. The affinity difference is small enough that it doesn't outweigh other considerations.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have poor solubility, Ligand A has a significantly lower DILI risk, better BBB penetration, lower P-gp efflux, and a slightly better binding affinity. The longer half-life of Ligand A also contributes to its favorability. The Caco-2 values are concerning for both, but can be addressed during formulation. The hERG risk is lower for Ligand B, but the other advantages of Ligand A outweigh this concern.

Output:
0
2025-04-17 11:54:15,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.39 and 363.76 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (138.59) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (106.85) is well within the range.

**logP:** Ligand A (0.658) is a bit low, potentially hindering permeability. Ligand B (1.066) is better, falling within the optimal 1-3 range.

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

**QED:** Both ligands have good QED scores (0.511 and 0.829), indicating drug-like properties.

**DILI:** Ligand A (52.15) has a lower DILI risk than Ligand B (76.89), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (50.87) is better than Ligand B (14.27).

**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 can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.053) has a much lower hERG risk than Ligand B (0.131), a crucial factor for kinase inhibitors.

**Microsomal Clearance:** Ligand A (8.53) has a higher (worse) microsomal clearance than Ligand B (0.283), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-13.39) has a very short in vitro half-life, which is a major concern. Ligand B (-48.28) also has a short half-life, but is better than Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.4 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:**

Ligand B is the better candidate. While both have solubility and permeability concerns, Ligand B has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic), and a more favorable DILI profile. The stronger binding affinity is the most important factor here, given that we are targeting an enzyme. Although Ligand A has a lower hERG risk, the difference isn't substantial enough to overcome the other deficiencies.

Output:
1
2025-04-17 11:54:15,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.463 and 356.354 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is significantly better than Ligand B (117.57). A TPSA under 140 is good for oral absorption, but A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.577) is good, while Ligand B (1.571) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are acceptable.

**QED:** Ligand A (0.83) is superior to Ligand B (0.613), indicating a more drug-like profile.

**DILI:** Ligand B (62.35) has a slightly higher DILI risk than Ligand A (74.603), but both are acceptable.

**BBB:** Both ligands have good BBB penetration (A: 63.086, B: 72.276), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.489) is significantly worse than Ligand B (-5.079) - both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.945) is better than Ligand B (-2.902), indicating better solubility.

**hERG Inhibition:** Ligand A (0.181) is much better than Ligand B (0.425), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (-14.23) has a much lower (better) microsomal clearance than Ligand A (86.254), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.841) has a longer half-life than Ligand A (-18.455), which is desirable.

**P-gp Efflux:** Ligand A (0.266) is better than Ligand B (0.018), suggesting lower efflux.

**Binding Affinity:** Both ligands have comparable binding affinity (-8.3 and -8.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability. However, Ligand A has better TPSA, logP, solubility, hERG risk, QED, and P-gp efflux. Given the importance of metabolic stability for kinase inhibitors, and the comparable binding affinities, Ligand B appears slightly more promising. However, the significantly better TPSA and solubility of Ligand A, coupled with the lower hERG risk, make it a strong contender. The difference in binding affinity is minimal.

Considering all factors, I lean towards **Ligand B** due to its improved metabolic stability and half-life, which are crucial for an enzyme target.

Output:
1
2025-04-17 11:54:15,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (352.475 and 343.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (66.92 and 64.86) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.868) is optimal, while Ligand B (4.237) is approaching the upper limit and could potentially cause solubility issues or off-target interactions.

**4. H-Bond Donors:** Both ligands are acceptable (0 and 1, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands are acceptable (4 and 6, respectively), well below the 10 threshold.

**6. QED:** Both ligands have similar and good QED values (0.656 and 0.654), indicating good drug-like properties.

**7. DILI:** Ligand A (29.624) has a significantly lower DILI risk than Ligand B (56.921). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (68.786 and 66.731). Since SRC is not a CNS target, this is not a primary concern.

**9. Caco-2 Permeability:** Ligand A (-4.137) has a more favorable Caco-2 permeability than Ligand B (-5.076).

**10. Aqueous Solubility:** Ligand A (-2.071) has a better aqueous solubility than Ligand B (-4.169). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.314 and 0.547).

**12. Microsomal Clearance:** Ligand A (53.269) has a lower microsomal clearance than Ligand B (63.748), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.643) has a significantly longer in vitro half-life than Ligand A (-12.074). This is a positive attribute for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.07 and 0.626).

**15. Binding Affinity:** Ligand B (-8.2) has a significantly stronger binding affinity than Ligand A (-6.9). This is a 1.3 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 important factor for an enzyme inhibitor. However, it has a higher logP, higher DILI risk, lower solubility, and higher microsomal clearance. Ligand A has better ADME properties overall, but weaker binding. The difference in binding affinity is substantial enough to favor Ligand B, despite its ADME liabilities. While the DILI risk is higher for Ligand B, it's not excessively high (56.921), and further optimization could potentially mitigate this. The improved metabolic stability of Ligand A is a plus, but the potency advantage of Ligand B is more critical.

Output:
1
2025-04-17 11:54:15,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.418 and 345.403 Da) fall well within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (51.66) is significantly better than Ligand B (91.56). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.545 and 1.03), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands 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), both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.788 and 0.844), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (30.826 and 37.922), well below the concerning threshold of 60.

**8. BBB:** Ligand A (97.635) has a much higher BBB penetration percentile than Ligand B (32.765). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

**9. Caco-2 Permeability:** Ligand A (-4.366) has a higher (less negative) Caco-2 value than Ligand B (-5.109), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.294) has better solubility than Ligand B (-1.105). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.35 and 0.201).

**12. Microsomal Clearance:** Ligand A (41.262) has a higher microsomal clearance than Ligand B (36.76). Lower is better for metabolic stability, so Ligand B is slightly favored here.

**13. In vitro Half-Life:** Ligand A (-15.48) has a shorter half-life than Ligand B (-12.39). Longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.166 and 0.018).

**15. 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 substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly stronger binding affinity is the most important factor, given the enzyme target class. While Ligand B has slightly better metabolic stability, the difference isn't large enough to overcome the substantial affinity advantage of Ligand A. Ligand A also exhibits better TPSA, logP, Caco-2 permeability, and solubility, all important factors for drug development.

Output:
1
2025-04-17 11:54:15,130 - INFO - Batch 85 complete. Total preferences: 1360
2025-04-17 11:54:15,130 - INFO - Processing batch 86/512...
2025-04-17 11:54:57,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.5 and 341.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.53 and 68.39) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.855) is optimal, while Ligand B (3.673) is approaching the upper limit of the optimal range.

**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 4. Both are below the acceptable limit of <=10.

**QED:** Both ligands have high QED scores (0.835 and 0.865), indicating good drug-likeness.

**DILI:** Ligand A (38.542) has a lower DILI risk than Ligand B (57.154), both are acceptable (<60).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.386) has a higher BBB penetration than Ligand A (59.984).

**Caco-2 Permeability:** Both ligands 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:** Ligand A (-1.65) has better solubility than Ligand B (-4.567). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.192) has a significantly lower hERG risk than Ligand B (0.625). This is a crucial factor for safety.

**Microsomal Clearance:** Ligand A (31.561) has a lower microsomal clearance than Ligand B (80.62), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.222) has a longer half-life than Ligand B (0.289). This is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux than Ligand B (0.383), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a 0.9 kcal/mol difference, which is significant.

**Conclusion:**

While Ligand B has a better binding affinity, Ligand A demonstrates a superior ADMET profile, particularly regarding metabolic stability (lower Cl_mic, longer t1/2), solubility, and, critically, a much lower hERG risk. The 0.9 kcal/mol difference in binding affinity, while noticeable, can potentially be overcome with further optimization of Ligand A. The lower hERG risk and better metabolic stability of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 11:54:57,836 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.367 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.48) is excellent, well below the 140 threshold for oral absorption. Ligand B (100.46) is still acceptable, but less optimal.

**logP:** Ligand A (3.063) is optimal. Ligand B (-0.343) is significantly low, potentially hindering permeability and absorption.

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

**H-Bond Acceptors:** Both ligands (6) are within the acceptable range (<=10).

**QED:** Both ligands (0.711 and 0.706) are very good, indicating strong drug-like properties.

**DILI:** Ligand A (89.647) has a higher DILI risk, but is still below the concerning 60 threshold. Ligand B (27.608) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (70.027) is acceptable, but not highly brain-penetrant. Ligand B (54.246) is lower, suggesting limited BBB penetration. This isn't a primary concern for a non-CNS target like SRC.

**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 often less predictive than logP and TPSA.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.714) has a slightly higher hERG risk than Ligand B (0.169), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (79.318) has moderate clearance, while Ligand B (-5.389) has *negative* clearance, which is impossible and likely indicates a data error or an extremely stable compound. This is a huge advantage for Ligand B.

**In vitro Half-Life:** Ligand A (14.904 hours) is reasonable. Ligand B (27.718 hours) is better, indicating greater metabolic stability.

**P-gp Efflux:** Ligand A (0.278) has low P-gp efflux, which is good. Ligand B (0.018) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 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 issues with Caco-2 and solubility, Ligand B's superior binding affinity, significantly lower logP (potentially improving permeability despite the Caco-2 value), very low DILI and P-gp efflux, and exceptionally low (and likely erroneous) microsomal clearance and long half-life make it a more promising starting point. The negative clearance is a red flag that needs investigation, but even if it's a data error, the other properties strongly favor Ligand B. Ligand A's higher DILI and weaker binding affinity are less desirable.

Output:
1
2025-04-17 11:54:57,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.375 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand B (88.1) is significantly better than Ligand A (125.02), being well below the 140 threshold for good absorption.

**logP:** Ligand A (0.505) is a bit low, potentially hindering permeation. Ligand B (-0.082) is also low, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** 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 (0.753 and 0.698), indicating good drug-like properties.

**DILI:** Ligand B (14.424) has a much lower DILI risk than Ligand A (56.572), which is a significant advantage.

**BBB:** Ligand A (71.733) has better BBB penetration than Ligand B (48.468), but BBB is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.453) has a worse Caco-2 permeability than Ligand B (-4.886), indicating poorer intestinal absorption.

**Solubility:** Ligand A (-1.069) has slightly better aqueous solubility than Ligand B (-1.406), but both are quite poor.

**hERG:** Ligand A (0.04) has a lower hERG inhibition liability than Ligand B (0.195), which is preferable.

**Microsomal Clearance:** Ligand B (2.343) has significantly lower microsomal clearance than Ligand A (15.839), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (29.095) has a much longer in vitro half-life than Ligand A (-10.586), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux than Ligand B (0.012), which is slightly better.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity and hERG, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. The slightly lower affinity of Ligand B is likely addressable through further optimization, while improving the ADME profile of Ligand A would be more challenging.

Output:
1
2025-04-17 11:54:57,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.785 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (108.49 and 106.15) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (1.913) is within the optimal 1-3 range. Ligand B (0.595) is slightly below 1, which *could* indicate permeability issues, but isn't a severe concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, both well within acceptable limits. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.725 and 0.849), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.841, which is high. Ligand B has a DILI risk of 67.429, still elevated, but significantly lower than Ligand A. This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (26.638) and Ligand B (66.499) are not particularly relevant here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.549 and -5.148), which is unusual and suggests poor permeability. This needs further investigation, but is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.232 and -2.454), which is also unusual and indicates very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.033) has a very low hERG risk, which is excellent. Ligand B (0.104) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-24.739) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (16.139) has a moderate clearance, suggesting moderate metabolic stability. This is a strong point for Ligand A.

**In vitro Half-Life:** Ligand A (-17.296) has a negative half-life, which is not physically possible and indicates a data error or unusual behavior. Ligand B (0.433) has a very short half-life, which is undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.043 and 0.032), which is good.

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

**Conclusion:**

Despite Ligand A's excellent metabolic stability and low hERG risk, its *very high* DILI risk and nonsensical half-life are major red flags. The negative solubility and Caco-2 values are also concerning. Ligand B, while having a shorter half-life and slightly higher DILI, has a significantly better binding affinity and a more reasonable DILI profile. The lower binding affinity of ligand A is unlikely to be overcome by its slightly better metabolic stability and hERG profile.

Output:
1
2025-04-17 11:54:57,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.395 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand B (95.07) is significantly better than Ligand A (125.2), being closer to the <140 threshold for good absorption.

**logP:** Ligand B (2.419) is optimal (1-3), while Ligand A (0.16) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better.

**H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (9) is still within the reasonable limit of 10.

**QED:** Ligand A (0.656) is better than Ligand B (0.505), indicating a more drug-like profile.

**DILI:** Ligand B (77.588) has a lower DILI risk than Ligand A (91.043), which is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 B (0.044) has a much lower hERG risk than Ligand A (0.165), a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-12.543) has a *negative* microsomal clearance, which is impossible. This is a major red flag and suggests an issue with the data or the prediction method. Ligand B (97.357) has high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (50.369) has a better half-life than Ligand B (23.029).

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux than Ligand B (0.252), which is favorable.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-6.9). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, the negative microsomal clearance is a critical flaw. It indicates a fundamental problem with the prediction or the molecule itself. Ligand B, while having weaker binding, has a much better safety profile (lower DILI, lower hERG) and, while not ideal, a plausible (though high) clearance. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies. Given the importance of metabolic stability and safety for an enzyme inhibitor, and the highly suspect negative clearance for Ligand A, Ligand B is the more viable candidate.

Output:
1
2025-04-17 11:54:57,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.419 and 369.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.56) is better than Ligand B (100.35), both are acceptable but A is preferable.

**logP:** Ligand A (-0.23) is slightly lower than optimal (1-3), while Ligand B (0.173) is also a bit low. Both could potentially have permeability issues, but ligand B is slightly better.

**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 7. Both are within the acceptable limit of <=10, but A is preferable.

**QED:** Both ligands have a QED around 0.75-0.79, indicating good drug-likeness.

**DILI:** Ligand A (35.285) has a significantly lower DILI risk than Ligand B (65.491). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (45.444) is slightly better than Ligand B (36.758).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.132 and -5.471), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.939 and -2.72), indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.273) has a lower hERG risk than Ligand B (0.506). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-12.688) has a much lower (better) microsomal clearance than Ligand B (26.902), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.198) has a longer half-life than Ligand B (-21.703), indicating better stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.012 and 0.087).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -9.0 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand A is significantly better due to its lower DILI risk, lower hERG inhibition, and much better metabolic stability (lower Cl_mic and longer half-life). While both have issues with permeability and solubility, the ADME-Tox profile of Ligand A is far superior. The binding affinity difference is negligible.

Output:
0
2025-04-17 11:54:57,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.36 and 350.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is better than Ligand B (107.69), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold if CNS penetration were desired.

**logP:** Ligand A (1.902) is optimal, while Ligand B (-0.483) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 6 HBA), both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.761 and 0.642), indicating good drug-like properties.

**DILI:** Ligand A (54.36) has a higher DILI risk than Ligand B (36.29), but both are below the concerning 60 threshold.

**BBB:** Ligand A (89.73) has better BBB penetration potential than Ligand B (27.76), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.668) shows poor permeability, while Ligand B (-5.449) is even worse. Both are concerning.

**Aqueous Solubility:** Ligand A (-2.541) has slightly better solubility than Ligand B (-1.197), but both are quite poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.104 and 0.033).

**Microsomal Clearance:** Ligand B (-11.569) has significantly lower (better) microsomal clearance than Ligand A (21.546), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (13.562 hours) has a longer half-life than Ligand A (7.179 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.006).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial ADME properties for an enzyme target. Specifically, its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk are major advantages. The slightly lower logP and Caco-2 permeability of Ligand B are drawbacks, but the superior metabolic profile outweighs these concerns. The solubility of both is poor and would require formulation work.

Output:
1
2025-04-17 11:54:57,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 366.296 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.53) is excellent, under the 140 and even the 90 threshold. Ligand B (137.36) is still acceptable but closer to the upper limit for good absorption.

**logP:** Both ligands (0.729 and 0.861) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better than Ligand B (4 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.839) has a significantly better QED score than Ligand B (0.399), indicating a more drug-like profile.

**DILI:** Ligand A (27.104) has a much lower DILI risk than Ligand B (67.003). This is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (54.246) is better than Ligand B (35.828).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.141) is slightly better than Ligand B (-5.429).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-1.335) is slightly better than Ligand B (-2.682).

**hERG:** Ligand A (0.129) has a much lower hERG risk than Ligand B (0.466). This is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-13.447) has a *much* better (lower) microsomal clearance than Ligand B (0.26), suggesting significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (-19.075) has a longer in vitro half-life than Ligand B (-16.769).

**P-gp Efflux:** Ligand A (0.019) has a lower P-gp efflux liability than Ligand B (0.053).

**Binding Affinity:** Ligand B (0.0) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is not substantial enough to outweigh the many advantages of Ligand A.

**Overall:** Ligand A is significantly better across most critical ADME-Tox properties (DILI, hERG, Cl_mic, QED) and has a slightly better profile for permeability and solubility. While Ligand B has a marginally better binding affinity, the substantial improvements in safety and pharmacokinetic properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 11:54:57,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.439 and 339.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is well below the 140 threshold for good absorption, and even favorable for potential CNS penetration (though not a priority here). Ligand B (101.38) is still under 140, but less optimal than A.

**logP:** Both ligands have good logP values (3.068 and 2.039), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 6 HBA) in terms of balancing solubility and permeability.

**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 (80.923), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (72.315) is better than Ligand B (37.767).

**Caco-2 Permeability:** Ligand A (-4.491) shows better Caco-2 permeability than Ligand B (-5.621).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.501 and -3.152). This is a concern, but can be addressed through formulation.

**hERG:** Both ligands have low hERG inhibition risk (0.319 and 0.284).

**Microsomal Clearance:** Ligand A (55.99) has higher microsomal clearance than Ligand B (5.575), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (2.472) has a slightly better in vitro half-life than Ligand A (47.881), but both are relatively low.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.219 and 0.187).

**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 less than 1.5 kcal/mol, it's still a positive factor.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better QED score, better Caco-2 permeability, and slightly better binding affinity. While Ligand A has higher microsomal clearance (lower metabolic stability) than Ligand B, the other advantages outweigh this drawback. Both have poor solubility, which is a formulation challenge, but not a deal-breaker.

Output:
1
2025-04-17 11:54:57,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.352 and 354.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is well below the 140 threshold for oral absorption, while Ligand B (137.32) is closer to the limit. A is better here.

**logP:** Ligand A (2.272) is optimal (1-3). Ligand B (-0.142) is below 1, which may impede permeation. A is significantly better.

**H-Bond Donors:** Ligand A (2) is within the ideal range (<=5). Ligand B (4) is also acceptable, but less optimal.

**H-Bond Acceptors:** Ligand A (5) is within the ideal range (<=10). Ligand B (6) is also acceptable.

**QED:** Both ligands have reasonable QED values (0.784 and 0.513), indicating good drug-like properties.

**DILI:** Both ligands have DILI risk around the 50-60 percentile, suggesting moderate risk. This isn't a major differentiator.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.519) is higher than Ligand B (28.383).

**Caco-2 Permeability:** Ligand A (-4.783) is poor, while Ligand B (-5.608) is also poor. Both are suboptimal.

**Aqueous Solubility:** Ligand A (-2.985) is poor, while Ligand B (-1.944) is also poor. Both are suboptimal.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.251 and 0.024). This is excellent for both.

**Microsomal Clearance:** Ligand A (49.473) is moderate, while Ligand B (-5.446) is excellent (negative value suggests very low clearance/high stability). B is much better here.

**In vitro Half-Life:** Ligand A (-1.14) is poor, while Ligand B (-9.54) is excellent. B is much better here.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.017). This is excellent for both.

**Binding Affinity:** Ligand A (-7.3) is slightly better than Ligand B (-7.7), but the difference is small.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and a better logP value. While Ligand A has a slightly better binding affinity, the ADME properties of Ligand B are more favorable for development as an enzyme inhibitor. The poor Caco-2 and solubility of both are concerns, but can potentially be addressed with formulation strategies. The improved metabolic stability of B is more critical for kinase inhibitors.

Output:
1
2025-04-17 11:54:57,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.81) is slightly above the preferred <140 for good absorption, while Ligand B (86.88) is well within the range.

**logP:** Ligand A (-1.131) is a bit low, potentially hindering permeation. Ligand B (2.814) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 7 HBA, acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable and potentially better for permeability.

**QED:** Both ligands have reasonable QED scores (0.419 and 0.646), with Ligand B being better.

**DILI:** Ligand A (62.466) has a higher DILI risk than Ligand B (54.285), though both are reasonably acceptable.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**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 negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.154) shows slightly better hERG profile than Ligand B (0.463).

**Microsomal Clearance:** Ligand A (-13.906) has *much* lower (better) microsomal clearance than Ligand B (23.437), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (7.88 hours) has a better in vitro half-life than Ligand B (22.511 hours), although both are reasonable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), a difference of 0.9 kcal/mol.

**Overall Assessment:**

Ligand B has a better logP, QED, and binding affinity. However, Ligand A has significantly better metabolic stability (lower Cl_mic) and a slightly better hERG profile. Both have poor solubility and permeability, which are major concerns. The difference in binding affinity (0.9 kcal/mol) isn't substantial enough to overcome the metabolic stability advantage of Ligand A, especially for a kinase inhibitor where prolonged exposure is often beneficial. The poor solubility and permeability will likely require significant medicinal chemistry effort to address for either compound. However, the better metabolic stability of Ligand A makes it a slightly more promising starting point.

Output:
1
2025-04-17 11:54:57,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 352.414 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is better than Ligand B (78.07), both are below the 140 threshold for oral absorption, but closer to the 90 threshold is preferable.

**logP:** Both ligands have acceptable logP values (1.07 and 1.452), falling within the 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, Ligand B has 7. Both are acceptable, but A is slightly better.

**QED:** Both ligands have good QED scores (0.821 and 0.719), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (42.575 and 41.411 percentile), which is favorable.

**BBB:** Ligand A (84.8) has a better BBB penetration score than Ligand B (74.564). While not a primary concern for a non-CNS target, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.615) has a slightly better Caco-2 permeability than Ligand B (-4.533).

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-0.911 and -0.91). This is a potential issue that may require formulation strategies.

**hERG Inhibition:** Ligand A (0.161) has a significantly lower hERG inhibition liability than Ligand B (0.228), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (42.63) has a lower microsomal clearance than Ligand B (48.389), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.798) has a better in vitro half-life than Ligand B (5.27).

**P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux liability than Ligand B (0.133).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a significant advantage, as potency is a primary concern for enzyme inhibitors.

**Overall:** Ligand A is superior to Ligand B. It has better binding affinity, lower hERG risk, better metabolic stability (lower Cl_mic and higher t1/2), lower P-gp efflux, and slightly better Caco-2 permeability. While both have poor solubility, the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 11:54:57,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk, as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.435 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.77) is better than Ligand B (87.66), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.44 and 1.506) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3) as lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4) as lower HBA generally improves permeability.

**QED:** Ligand A (0.775) has a better QED score than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand A (25.785) has a significantly lower DILI risk than Ligand B (16.44), which is a major advantage.

**BBB:** Ligand A (36.371) has a higher BBB percentile than Ligand B (25.94), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.55) has a better Caco-2 permeability than Ligand B (-4.901).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.622 and -1.702). This is a significant concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.134 and 0.151), which is excellent.

**Microsomal Clearance:** Ligand A (-19.507) has a much lower (better) microsomal clearance than Ligand B (10.518), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.969) has a shorter half-life than Ligand B (11.617). However, the difference isn't substantial, and the lower clearance of Ligand A suggests it might have a better *in vivo* half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.024).

**Binding Affinity:** Both ligands have similar binding affinities (-9.1 and -8.9 kcal/mol). The difference is less than the 1.5 kcal/mol threshold where minor ADME drawbacks can be overlooked.

**Conclusion:**

Ligand A is the superior candidate. While both have poor solubility, Ligand A demonstrates a significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic), a better QED score, and slightly better permeability. The binding affinity is comparable, so the improved ADME properties of Ligand A outweigh any minor differences in half-life.

Output:
1
2025-04-17 11:54:57,838 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.398 Da) is slightly higher than Ligand B (342.439 Da), but both are acceptable.
2. **TPSA:** Ligand A (102.87) is higher than Ligand B (71.34). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better positioned, especially considering SRC is not a CNS target.
3. **logP:** Both ligands have good logP values (A: 2.686, B: 3.492), 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.
4. **HBD:** Ligand A has 0 HBD, while Ligand B has 2.  Both are within the acceptable limit of 5.
5. **HBA:** Ligand A has 8 HBA, and Ligand B has 3. Both are below the 10 limit.
6. **QED:** Ligand B (0.874) has a significantly higher QED score than Ligand A (0.401), indicating a more drug-like profile.
7. **DILI:** Ligand A (62.156) has a higher DILI risk than Ligand B (49.787). Both are acceptable (<60 is good), but B is preferable.
8. **BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.105) is slightly better than Ligand B (61.225).
9. **Caco-2:** Both have negative values, which is unusual. Assuming these are logP values, both are very poor.
10. **Solubility:** Ligand A (-2.587) has worse solubility than Ligand B (-4.072). Solubility is important for kinases, and B is better.
11. **hERG:** Both have low hERG inhibition liability (A: 0.106, B: 0.373). Both are good.
12. **Cl_mic:** Ligand B (29.376) has significantly lower microsomal clearance than Ligand A (109.965), suggesting better metabolic stability. This is a key factor for kinase inhibitors.
13. **t1/2:** Ligand B (82.956) has a much longer in vitro half-life than Ligand A (-18.984). This is a significant advantage for dosing convenience.
14. **Pgp:** Both have low Pgp efflux liability (A: 0.225, B: 0.109). Both are good.
15. **Binding Affinity:** Ligand A (-8.2 kcal/mol) has a better binding affinity than Ligand B (0.0 kcal/mol). This is a substantial difference and a major positive for Ligand A.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. While Ligand A has a significantly better binding affinity, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2), solubility, and has a better QED and DILI profile. The large difference in binding affinity is a significant advantage for Ligand A, but the ADME properties of Ligand B are much more favorable.

**Conclusion:**

Despite the superior binding affinity of Ligand A, the significantly better ADME properties of Ligand B, particularly its metabolic stability and solubility, make it the more promising drug candidate. A strong binding affinity is important, but it's useless if the compound is rapidly metabolized or poorly absorbed. Ligand B's profile suggests it has a higher probability of achieving adequate *in vivo* exposure and efficacy.

Output:
1
2025-04-17 11:54:57,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.5 & 363.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is higher than Ligand B (56.59). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**3. logP:** Both ligands have similar logP values (2.537 and 2.581), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable, staying within the guideline of <=5.

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

**6. QED:** Ligand B (0.685) has a slightly better QED score than Ligand A (0.538), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.973) has a significantly lower DILI risk than Ligand B (50.136). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (65.413 and 67.197). BBB is not a primary concern for SRC kinase inhibitors unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-5.443) shows poorer Caco-2 permeability than Ligand B (-4.691), suggesting potentially lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.987) has better aqueous solubility than Ligand B (-3.256). This is a positive attribute for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.273) has a much lower hERG inhibition liability than Ligand B (0.507). This is a critical advantage, minimizing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (98.623) has significantly higher microsomal clearance than Ligand A (51.29), indicating lower metabolic stability. This is a major drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (-20.246) has a much longer in vitro half-life than Ligand B (8.078). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux liability than Ligand B (0.321), which is favorable for oral bioavailability.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.5 kcal/mol). While a 0.2 kcal/mol difference isn't huge, it's a positive for Ligand B.

**Overall Assessment:**

Despite Ligand B's slightly better affinity and Caco-2 permeability, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly lower DILI risk, lower hERG inhibition, longer half-life, and lower P-gp efflux. These factors are crucial for a viable drug candidate, especially considering the enzyme class. The slightly weaker binding affinity of Ligand A can potentially be optimized in subsequent iterations, while mitigating the significant ADME/Tox liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 11:54:57,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.881 and 339.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (59.81 and 56.9) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.386) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.566) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.675 and 0.717), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 78.945, which is concerning (high risk). Ligand B has a much lower DILI risk of 39.667, which is good.

**BBB:** Both have moderate BBB penetration (64.87 and 75.572). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.933 and -5.311), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.694 and -2.694), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.301) has a slightly higher hERG risk than Ligand B (0.894), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.293) has lower microsomal clearance than Ligand B (69.372), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (33.456 and 31.867 hours).

**P-gp Efflux:** Ligand A (0.658) has lower P-gp efflux than Ligand B (0.38), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Despite both compounds having excellent binding affinity, Ligand B is the more promising candidate. While both have poor Caco-2 and solubility, Ligand B has a significantly lower DILI risk and a more favorable logP value. The lower DILI risk is a crucial advantage for an oncology drug. Although Ligand A has slightly better metabolic stability and lower P-gp efflux, the high DILI risk outweighs these benefits.

Output:
1
2025-04-17 11:54:57,838 - INFO - Batch 86 complete. Total preferences: 1376
2025-04-17 11:54:57,838 - INFO - Processing batch 87/512...
2025-04-17 11:55:39,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.364 Da and 352.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.87) is excellent, well below the 140 threshold for oral absorption. Ligand B (107.89) is still acceptable, but less optimal.

**logP:** Ligand A (0.568) is a bit low, potentially hindering permeability. Ligand B (-0.3) is even lower, raising concerns about absorption.

**H-Bond Donors/Acceptors:** Both have 4 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5 (0.68 and 0.52), indicating good drug-likeness.

**DILI:** Ligand A (21.946) has a significantly lower DILI risk than Ligand B (47.344), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (64.637) has a better score than Ligand B (29.546).

**Caco-2 Permeability:** Ligand A (-4.925) and Ligand B (-5.099) both have negative values, which are unusual and suggest very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.657 and -1.256), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.444) shows a lower hERG inhibition liability than Ligand B (0.111), which is preferable.

**Microsomal Clearance:** Ligand A (-20.225) has a much lower (better) microsomal clearance than Ligand B (-0.474), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-11.647) has a longer in vitro half-life than Ligand B (-8.92), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.039), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.6 and -8.0 kcal/mol). Ligand A is slightly better, but both are well below the -7.0 kcal/mol threshold.

**Conclusion:**

Despite the poor permeability and solubility of both compounds, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG inhibition, and slightly better binding affinity. The poor solubility and permeability are serious issues that would need to be addressed through formulation or further structural modifications, but the superior ADME-Tox profile of Ligand A makes it the better starting point.

Output:
0
2025-04-17 11:55:39,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.515 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (69.72).  A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**3. logP:** Ligand A (3.524) is slightly higher than Ligand B (1.566). Both are within the optimal 1-3 range, but Ligand B is closer to the lower bound, which *could* indicate permeability 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 2 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.513 and 0.56), indicating good drug-like properties.

**7. DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (31.563). This is a significant advantage for Ligand A.

**8. BBB:** Both have reasonable BBB penetration (76.309 and 68.321). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.966) has better Caco-2 permeability than Ligand B (-4.724), suggesting better absorption.

**10. Aqueous Solubility:** Ligand A (-3.418) has better aqueous solubility than Ligand B (-2.07). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.63 and 0.469).

**12. Microsomal Clearance:** Ligand A (68.215) has higher microsomal clearance than Ligand B (53.744). This means Ligand B is more metabolically stable, which is a key priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand B (-24.636) has a significantly longer in vitro half-life than Ligand A (-15.275). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.405 and 0.252).

**15. Binding Affinity:** Ligand B (-7.8) 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 solubility, permeability, and has a much lower DILI risk. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. For an enzyme target like SRC kinase, metabolic stability and potency are paramount. The slightly better affinity of Ligand B, combined with its significantly improved half-life, outweighs the advantages of Ligand A's better solubility and lower DILI. The DILI risk for Ligand A is still acceptable.

Output:
1
2025-04-17 11:55:39,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.422 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (95.66) is slightly higher than Ligand B (58.64). While both are below 140, the lower TPSA of Ligand B is preferable for oral absorption.

**logP:** Both ligands have good logP values (A: 1.536, B: 3.216), falling within the optimal 1-3 range. Ligand B is closer to the upper end, which *could* raise solubility concerns, but isn't a major issue.

**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 good QED scores (A: 0.678, B: 0.819), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (36.797) has a slightly higher DILI risk than Ligand B (30.516), but both are below the 40 threshold and considered low risk.

**BBB:** Ligand A (61.768) has a lower BBB penetration percentile than Ligand B (75.572). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Ligand A (-4.961) has a negative Caco-2 value, indicating poor permeability. Ligand B (-5.076) also has a negative Caco-2 value, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (A: -2.073, B: -3.165), indicating poor solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.525, B: 0.443). This is excellent.

**Microsomal Clearance:** Ligand A (-2.614) has a lower (better) microsomal clearance than Ligand B (28.371). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (17.871) has a shorter half-life than Ligand B (32.549). The longer half-life of Ligand B is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.039, B: 0.216).

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

**Overall Assessment:**

Ligand B is slightly better overall. While both have poor solubility and permeability, Ligand B has a significantly lower TPSA, a better QED score, and a longer half-life. The improved metabolic stability of Ligand A is a benefit, but the other advantages of Ligand B outweigh this. The equal binding affinity means potency isn't a differentiating factor.

Output:
1
2025-04-17 11:55:39,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.371 and 354.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.34 and 97.33) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (which requires <90). This is acceptable for an oncology target that doesn't necessarily require brain penetration.

**logP:** Ligand A (0.934) is slightly better than Ligand B (-0.719), falling comfortably within the 1-3 range. Ligand B is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is slightly better than Ligand B (2 HBD, 6 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.811) has a better QED score than Ligand B (0.676), indicating a more drug-like profile.

**DILI:** Ligand B (38.852) has a significantly lower DILI risk than Ligand A (88.833). This is a major advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for an oncology target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both, but the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a significant drawback for both, but the values are similar.

**hERG Inhibition:** Ligand A (0.097) has a lower hERG inhibition liability than Ligand B (0.171), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (25.714 mL/min/kg) has a lower microsomal clearance than Ligand A (28.488 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (17.522 hours) has a significantly longer half-life than Ligand A (6.845 hours), which is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-10.0 kcal/mol) has a slightly better binding affinity than Ligand B (-8.9 kcal/mol). This 1.1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and lower hERG risk, but suffers from higher DILI risk, shorter half-life, and lower QED. Ligand B has a much better safety profile (lower DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and a better QED score. The difference in binding affinity (1.1 kcal/mol) is substantial, but the ADME advantages of Ligand B are compelling, especially the lower DILI and longer half-life. For an oncology target, metabolic stability and safety are crucial.

Output:
1
2025-04-17 11:55:39,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.279 Da) is slightly higher than Ligand B (341.455 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (67.87) is higher than Ligand B (58.37), but both are well within the acceptable range.

**logP:** Both ligands have logP values between 1-3 (Ligand A: 3.499, Ligand B: 3.005), which is optimal for permeability and avoiding off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.691, Ligand B: 0.908), indicating a drug-like profile. Ligand B is better here.

**DILI:** Ligand A has a DILI risk of 62.544%, which is considered high risk. Ligand B has a much lower DILI risk of 14.424%, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both have good BBB penetration (Ligand A: 71.307%, Ligand B: 72.354%), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.778) is slightly worse than Ligand B (-5.094).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.776) is slightly better than Ligand B (-2.477).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.655, Ligand B: 0.67), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (Ligand A: 28.339, Ligand B: 29.452), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (14.755 hours) has a slightly longer half-life than Ligand B (10.481 hours), which is a minor advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.397, Ligand B: 0.31), which is good.

**Binding Affinity:** Ligand B (-9.7 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 for Ligand B and can outweigh minor ADME drawbacks.

**Conclusion:**

While both ligands have some issues with Caco-2 and solubility, Ligand B is clearly superior. It has a much lower DILI risk, a significantly stronger binding affinity, and a better QED score. The slightly longer half-life of Ligand A is not enough to offset these advantages.

Output:
1
2025-04-17 11:55:39,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (61.88), but both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have optimal logP values (1.716 and 1.169), 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:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.72) has a better QED score than Ligand B (0.501), indicating a more drug-like profile.

**7. DILI:** Ligand A (4.343) has a significantly lower DILI risk than Ligand B (18.418). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (55.603 and 55.758), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.908 and -4.966) which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.539 and -1.907), which is also unusual and suggests poor solubility. This is a potential issue for both.

**11. hERG Inhibition:** Ligand A (0.218) has a lower hERG inhibition liability than Ligand B (0.439), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (5.921) has a significantly lower microsomal clearance than Ligand B (37.499), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (4.688) has a shorter in vitro half-life than Ligand B (9.839), but both are relatively low.

**14. P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.093), suggesting better bioavailability.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While both have similar affinities, Ligand A demonstrates significantly better ADME properties: lower DILI risk, lower microsomal clearance (better metabolic stability), lower hERG inhibition, and lower P-gp efflux. Although both have poor predicted solubility and permeability, the superior safety and PK profile of Ligand A outweigh this concern.

Output:
0
2025-04-17 11:55:39,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.384 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.11 and 75.94) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.249) is quite low, potentially hindering permeation. Ligand B (2.034) 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 good QED scores (0.621 and 0.78), indicating good drug-like properties.

**DILI:** Ligand A (19.116) has a much lower DILI risk than Ligand B (51.609). This is a positive for Ligand A.

**BBB:** Both ligands have similar BBB penetration (77.627 and 74.292), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.974 and -4.834), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation.

**Aqueous Solubility:** Both have negative solubility values (-0.979 and -2.658), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.339 and 0.306).

**Microsomal Clearance:** Ligand A (-4.817) has significantly lower (better) microsomal clearance than Ligand B (31.474), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-36.77) has a negative half-life, which is not possible. Ligand B (33.404) has a reasonable half-life. The negative value for Ligand A is a red flag.

**P-gp Efflux:** Both ligands have negligible P-gp efflux (0.009 and 0.066).

**Binding Affinity:** Both ligands have similar binding affinity (0.0 and 0.0).

**Overall Assessment:**

Ligand B has a better logP, which is crucial for permeability. However, Ligand A has a significantly better DILI score and, crucially, much better metabolic stability (lower Cl_mic). The negative half-life for Ligand A is a major concern and suggests a data error or a rapidly degrading compound. The poor solubility and Caco-2 values are concerning for both, but can potentially be addressed with formulation strategies. Given the importance of metabolic stability for kinase inhibitors, and the problematic half-life of Ligand A, Ligand B is the more viable candidate *despite* the higher DILI risk.

Output:
1
2025-04-17 11:55:39,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.435 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.23) is better than Ligand B (78.43) as it is still within the acceptable range for oral absorption (<140), but Ligand B is significantly lower and could indicate better permeability.

**logP:** Both ligands have good logP values (1.534 and 2.375), falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.742 and 0.66), indicating good drug-like properties.

**DILI:** Ligand A (37.728) has a lower DILI risk than Ligand B (16.751), which is a significant advantage.

**BBB:** Ligand A (85.266) has a higher BBB penetration percentile than Ligand B (46.026). While not a primary concern for a kinase inhibitor, it's a slight positive for A.

**Caco-2 Permeability:** Ligand A (-5.057) has worse Caco-2 permeability than Ligand B (-4.754). This suggests Ligand B might have better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.593) has slightly better aqueous solubility than Ligand B (-3.081). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.125) has a lower hERG inhibition liability than Ligand B (0.306), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (42.242) and Ligand B (46.489) have similar microsomal clearance values. Neither is particularly favorable, indicating moderate metabolic liability.

**In vitro Half-Life:** Ligand A (-21.295) has a worse in vitro half-life than Ligand B (-6.272). This indicates Ligand B is more metabolically stable.

**P-gp Efflux:** Ligand A (0.003) has a much lower P-gp efflux liability than Ligand B (0.244), which is a positive for bioavailability.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.3). However, the difference is small (0.7 kcal/mol) and may not outweigh other factors.

**Overall Assessment:**

Ligand A is preferable due to its significantly lower DILI risk (37.7 vs 16.8) and lower hERG risk (0.125 vs 0.306). While Ligand B has slightly better Caco-2 permeability and in vitro half-life, the safety profiles of Ligand A are more desirable for a kinase inhibitor. The affinity difference is minimal.

Output:
0
2025-04-17 11:55:39,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.445 and 369.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is well below the 140 threshold for good absorption, and is quite favorable. Ligand B (89.55) is still under 140, but less optimal than A.

**logP:** Both ligands have logP values within the optimal range (Ligand A: 2.155, Ligand B: 1.761).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent, minimizing potential permeability issues. Ligand B (2 HBD, 6 HBA) is acceptable, but slightly higher counts could potentially impact permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.494, Ligand B: 0.614), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (25.553) has a much lower DILI risk than Ligand B (54.75), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (90.074) has a higher percentile than Ligand B (53.819).

**Caco-2 Permeability:** Ligand A (-4.557) has a negative Caco-2 value, which is concerning. Ligand B (-5.332) is also negative, but slightly worse. This suggests poor intestinal absorption for both.

**Aqueous Solubility:** Ligand A (-0.637) has slightly better solubility than Ligand B (-1.48), which is a positive.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.73, Ligand B: 0.225), which is good.

**Microsomal Clearance:** Ligand A (34.766) has a higher microsomal clearance than Ligand B (15.812), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (29.737) has a much longer in vitro half-life than Ligand A (-0.266), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.084, Ligand B: 0.051), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (Ligand A: -7.8 kcal/mol, Ligand B: -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have good potency and acceptable physicochemical properties, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The Caco-2 values are concerning for both, but the other advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 11:55:39,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.385 and 352.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (44.81). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.189) is optimal, while Ligand B (4.865) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**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 within the acceptable limit of 10.

**QED:** Ligand A (0.848) has a superior QED score compared to Ligand B (0.589), indicating better overall drug-likeness.

**DILI:** Ligand A (34.82) has a much lower DILI risk than Ligand B (47.15), which is approaching a moderate risk level.

**BBB:** Both are not particularly relevant for a non-CNS target like SRC kinase. Ligand B (77.433) is higher than Ligand A (64.754), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-4.769) is better than Ligand B (-5.315), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.423) is better than Ligand B (-4.123), which is a critical advantage for *in vivo* efficacy.

**hERG Inhibition:** Ligand A (0.359) shows a significantly lower risk of hERG inhibition compared to Ligand B (0.917). This is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (-6.325) has a much lower (better) microsomal clearance than Ligand B (40.196), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-29.231) has a much longer half-life than Ligand B (17.793).

**P-gp Efflux:** Ligand A (0.019) has a lower P-gp efflux liability than Ligand B (0.68), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are good, the 1.3 kcal/mol difference is significant and can outweigh some minor ADME drawbacks.

**Overall:** Ligand A is clearly superior. It has better solubility, lower toxicity (DILI, hERG), better metabolic stability (Cl_mic, t1/2), lower P-gp efflux, a better QED score, and slightly improved binding affinity. Ligand B has a higher logP which could lead to issues, and its ADME profile is significantly worse than Ligand A.

Output:
0
2025-04-17 11:55:39,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.332 and 360.37 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.82) is better than Ligand B (97.11). Both are below 140, suggesting reasonable absorption, but A is preferable.

**logP:** Both ligands have good logP values (2.133 and 2.412, respectively), 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.696 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A (47.693) has a significantly lower DILI risk than Ligand B (93.874). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.868) is better than Ligand B (35.556).

**Caco-2 Permeability:** Ligand A (-4.963) is better than Ligand B (-5.197), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.881 and -2.905). This is a concern for both, but needs to be balanced against other properties.

**hERG Inhibition:** Ligand A (0.594) has a slightly higher hERG risk than Ligand B (0.071). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (11.104) has higher microsomal clearance than Ligand B (-6.496). This indicates lower metabolic stability for Ligand A, which is a disadvantage.

**In vitro Half-Life:** Ligand B (-15.442) has a significantly longer in vitro half-life than Ligand A (15.567), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.022).

**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 substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk, and better Caco-2 permeability. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower hERG risk. The solubility is poor for both. Given the enzyme-specific priorities, metabolic stability and minimizing off-target effects (hERG) are crucial. While the affinity difference is notable, the improved ADME profile of Ligand B, particularly the lower hERG risk and better metabolic stability, makes it the more promising candidate.

Output:
1
2025-04-17 11:55:39,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (350.375 Da) is within the ideal range (200-500 Da). Ligand B (601.873 Da) is significantly above this range, which could hinder permeability and potentially increase off-target effects.

**TPSA:** Ligand A (113.77) is good for oral absorption (<140). Ligand B (140.76) is at the upper limit, potentially impacting absorption.

**logP:** Ligand A (-0.534) is a bit low, potentially impacting membrane permeability. Ligand B (4.597) is high, raising concerns about solubility and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (6/9) counts, falling within the guidelines.

**QED:** Ligand A (0.667) has a good drug-likeness score. Ligand B (0.123) is quite poor, indicating a less drug-like profile.

**DILI:** Both ligands have elevated DILI risk (52.191 and 64.521), but Ligand A is slightly better. This needs further investigation, but isn't a dealbreaker at this stage.

**BBB:** Ligand A (65.839) has moderate BBB penetration, while Ligand B (27.646) is low. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the experimental setup or prediction method. However, assuming these values are relative, we can infer that both have poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility, which is a concern for bioavailability. Ligand A (-1.161) is slightly better than Ligand B (-3.467).

**hERG Inhibition:** Ligand A (0.076) has a very low hERG risk, which is excellent. Ligand B (0.857) has a moderate risk, requiring further investigation.

**Microsomal Clearance:** Ligand A (9.029) has a lower clearance, suggesting better metabolic stability. Ligand B (71.86) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-36.321) has a negative half-life, which is impossible. This is likely an error in the data. Ligand B (110.257) has a good half-life.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.829) has moderate efflux.

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-7.6 and -7.7 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better overall. While its logP is slightly low and solubility is poor, it has a much better molecular weight, QED, hERG risk, and P-gp efflux. Its metabolic stability (lower Cl_mic) is also preferable. The negative half-life for Ligand A is a data error that needs to be addressed, but the other factors strongly favor it. Ligand B's high molecular weight, poor QED, high logP, and high clearance are significant drawbacks. The comparable binding affinity isn't enough to overcome these issues.

Output:
0
2025-04-17 11:55:39,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.531 and 372.437 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.54) is higher than Ligand B (49.85). Both are below 140, supporting reasonable absorption.

**logP:** Both ligands have good logP values (1.771 and 2.622), 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.

**QED:** Both ligands have good QED scores (0.761 and 0.816), indicating drug-like properties.

**DILI:** Ligand B (43.932) has a significantly lower DILI risk than Ligand A (14.696), which is a major advantage.

**BBB:** Ligand B (92.051) has a higher BBB penetration score than Ligand A (49.981). While not critical for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-5.048) has a worse Caco-2 permeability than Ligand B (-4.636), indicating potentially poorer absorption.

**Aqueous Solubility:** Ligand A (-0.894) has slightly better solubility than Ligand B (-2.694). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.272 and 0.442), which is excellent.

**Microsomal Clearance:** Ligand A (-1.181) has a significantly lower (better) microsomal clearance than Ligand B (31.599), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (10.883) has a longer half-life than Ligand B (-7.817). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.214), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better solubility, half-life, and P-gp efflux, Ligand B shines in its significantly lower DILI risk and better Caco-2 permeability. The metabolic stability of Ligand A is also good, but the DILI risk of Ligand B is a crucial factor. Given the enzyme-specific priorities, a lower DILI risk is highly desirable. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 11:55:39,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.438 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.87 and 75.19) are below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have logP values within the optimal range (1.018 and 2.55). Ligand B is slightly higher, which could potentially lead to some off-target effects, but is not a major concern.

**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 (0.771 and 0.787), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 21.598%, which is excellent (low risk). Ligand B has a significantly higher DILI risk of 47.732%, which is approaching a moderate risk. This is a key difference.

**BBB:** Both have similar BBB penetration (62.97% and 61.807%), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.817 and -5.162), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both have negative solubility values (-1.239 and -2.675), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.28 and 0.126), which is excellent.

**Microsomal Clearance:** Ligand A has a negative microsomal clearance (-15.197), which is excellent (high metabolic stability). Ligand B has a much higher clearance (50.078), indicating lower metabolic stability. This is a critical difference.

**In vitro Half-Life:** Ligand A has a longer half-life (14.875 hours) compared to Ligand B (-1.99 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.043 and 0.283), which is favorable.

**Binding Affinity:** Both have excellent binding affinities (-8.2 and -8.0 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the superior candidate. While both have poor solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The binding affinity difference is minimal. These factors make Ligand A more likely to be a viable drug candidate despite the solubility/permeability concerns, which could potentially be addressed with formulation strategies.

Output:
0
2025-04-17 11:55:39,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (454.308 Da) is higher, but still acceptable. Ligand B (346.471 Da) is slightly better.

**TPSA:** Ligand A (68.29) is higher than Ligand B (53.76). Both are below the 140 A^2 threshold for oral absorption, but lower is generally preferred. Ligand B has a slight advantage.

**logP:** Both ligands have good logP values (A: 3.793, B: 3.868), falling within the optimal 1-3 range. No significant difference here.

**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). Ligand B is slightly more favorable due to fewer potential off-target interactions from H-bonds.

**QED:** Both ligands have similar QED values (A: 0.552, B: 0.556), indicating good drug-likeness.

**DILI:** Ligand A (61.768) has a higher DILI risk than Ligand B (49.981). This is a significant concern, as we want to minimize liver toxicity. Ligand B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (65.374) is slightly higher than Ligand A (51.803).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.754 and -4.654). This is unusual and suggests poor permeability. However, these values might be experimental artifacts or indicate a specific transport mechanism. It's a flag for further investigation, but doesn't immediately disqualify either compound.

**Aqueous Solubility:** Ligand A (-5.149) has worse solubility than Ligand B (-2.992). Solubility is important for bioavailability, so Ligand B is favored.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.76, B: 0.608). This is good.

**Microsomal Clearance:** Ligand A (93.746) has higher microsomal clearance than Ligand B (74.754), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (20.815 hours) has a significantly longer half-life than Ligand A (55.387 hours). 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 (A: 0.328, B: 0.726).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.9 kcal/mol, B: -8.0 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.9 kcal/mol) is unlikely to outweigh the ADME concerns.

**Overall:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates significantly better ADME properties: lower DILI risk, better solubility, lower microsomal clearance, and a longer half-life. These factors are crucial for developing a viable drug candidate, especially for an enzyme target where metabolic stability and bioavailability are key. The Caco-2 values are concerning for both, but the other advantages of Ligand B outweigh this issue.

Output:
1
2025-04-17 11:55:39,032 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.795 Da) is slightly higher than Ligand B (365.47 Da), but both are acceptable.

**2. TPSA:** Ligand A (88.52) is better than Ligand B (38.77) as it is still below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (A: 3.607, B: 3.263), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0) as it is within the acceptable range.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (A: 5, B: 4).

**6. QED:** Both ligands have similar, good QED values (A: 0.786, B: 0.776), indicating good drug-like properties.

**7. DILI:** Ligand B (39.395) has a significantly lower DILI risk than Ligand A (93.525). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (85.033) has a better BBB penetration score than Ligand A (36.293), but BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.086 for A, -4.6 for B).

**10. Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility, but are similar (-3.701 for A, -3.833 for B).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.053, B: 0.911), which is excellent.

**12. Microsomal Clearance:** Ligand A (0.719) has significantly lower microsomal clearance than Ligand B (88.813), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-23.968) has a much longer in vitro half-life than Ligand B (-1.951), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.159, B: 0.532).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -9.9 kcal/mol, B: -9.2 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has a lower DILI risk, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic and longer t1/2) and comparable binding affinity. The solubility and permeability issues are similar for both, and the hERG risk is low for both. The improved metabolic stability of Ligand A is crucial for achieving adequate exposure and efficacy *in vivo*.

Output:
0
2025-04-17 11:55:39,032 - INFO - Batch 87 complete. Total preferences: 1392
2025-04-17 11:55:39,032 - INFO - Processing batch 88/512...
2025-04-17 11:56:19,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (78.43), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.78 and 2.083), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is slightly better than Ligand B (HBD=3, HBA=4) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.724) has a significantly better QED score than Ligand B (0.516), indicating a more drug-like profile.

**DILI:** Ligand A (32.067) has a much lower DILI risk than Ligand B (11.128), a significant advantage.

**BBB:** Both ligands have similar BBB penetration (50.446 and 50.756), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.623) has better Caco-2 permeability than Ligand B (-5.563), suggesting better absorption.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-2.725 and -2.723). This is a potential issue for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.251) has a much lower hERG inhibition liability than Ligand B (0.423), a crucial advantage for safety.

**Microsomal Clearance:** Ligand B (40.612) has slightly lower microsomal clearance than Ligand A (44.304), suggesting better metabolic stability, but the difference isn't huge.

**In vitro Half-Life:** Ligand A (7.486) has a significantly longer in vitro half-life than Ligand B (-4.172), a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.065), which is slightly better.

**Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (0.0), a critical advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall:**

Ligand A is superior to Ligand B across most critical parameters. It has a better QED score, significantly lower DILI and hERG risk, better Caco-2 permeability, a longer half-life, and, most importantly, a much stronger binding affinity. While both have poor solubility, the superior profile of Ligand A outweighs this concern.

Output:
1
2025-04-17 11:56:19,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (384.933 Da) is still well within the range.

**TPSA:** Ligand A (67.43) is higher than Ligand B (52.29). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (A: 3.038, B: 2.844), 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 (HBD <=5, HBA <=10).

**QED:** Ligand A (0.832) has a significantly higher QED score than Ligand B (0.591), indicating a more drug-like profile.

**DILI:** Both have low DILI risk (A: 30.903, B: 34.587), well below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (A: 68.282, B: 68.166). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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 unusual and suggesting poor solubility.

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.437, B: 0.56), which is excellent.

**Microsomal Clearance:** Ligand A (56.195) has a significantly lower Cl_mic than Ligand B (75.019). This suggests better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (39.386) has a much longer half-life than Ligand A (6.846). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.052, B: 0.352).

**Binding Affinity:** Both have excellent binding affinities (A: -8.1, B: -8.2). Ligand B is slightly better, but the difference is small (0.1 kcal/mol).

**Conclusion:**

While Ligand B has a longer half-life and slightly better binding affinity, Ligand A is the stronger candidate overall. Its superior QED score, significantly lower microsomal clearance (indicating better metabolic stability), and acceptable values for other key parameters outweigh the slight advantage of Ligand B's half-life and affinity. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies. Given the enzyme-specific priorities, metabolic stability is crucial, and Ligand A excels in this area.

Output:
0
2025-04-17 11:56:19,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**

*   **MW:** 348.462 Da - Good, within the ideal range.
*   **TPSA:** 40.62 - Good, well below the 140 threshold.
*   **logP:** 2.503 - Excellent, within the optimal 1-3 range.
*   **HBD:** 0 - Acceptable, low.
*   **HBA:** 2 - Acceptable, low.
*   **QED:** 0.474 - Marginal, slightly below the preferred 0.5.
*   **DILI:** 16.324 - Excellent, very low risk.
*   **BBB:** 91.237 - Excellent, high potential for CNS penetration (though less relevant for a general oncology target).
*   **Caco-2:** -4.344 - Very poor, suggests very low intestinal absorption. This is a significant concern.
*   **Solubility:** -3.271 - Very poor, likely to have formulation challenges.
*   **hERG:** 0.721 - Good, low risk of cardiotoxicity.
*   **Cl_mic:** 34.098 - Moderate, could be better for metabolic stability.
*   **t1/2:** -10.346 - Very poor, extremely short half-life.
*   **Pgp:** 0.23 - Good, low efflux.
*   **Affinity:** -7.0 kcal/mol - Excellent, strong binding.

**Ligand B:**

*   **MW:** 368.459 Da - Good, within the ideal range.
*   **TPSA:** 108.47 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 0.267 - Poor, likely to have poor membrane permeability.
*   **HBD:** 2 - Acceptable, low.
*   **HBA:** 6 - Acceptable, within the limit.
*   **QED:** 0.715 - Good, strong drug-like profile.
*   **DILI:** 50.33 - Moderate, acceptable but higher than Ligand A.
*   **BBB:** 43.505 - Poor, low potential for CNS penetration.
*   **Caco-2:** -5.511 - Very poor, suggests very low intestinal absorption.
*   **Solubility:** -1.863 - Poor, likely to have formulation challenges.
*   **hERG:** 0.054 - Excellent, very low risk of cardiotoxicity.
*   **Cl_mic:** -27.935 - Excellent, very high metabolic stability.
*   **t1/2:** 17.232 - Good, reasonable half-life.
*   **Pgp:** 0.014 - Excellent, low efflux.
*   **Affinity:** -8.3 kcal/mol - Excellent, very strong binding (1.3 kcal/mol better than Ligand A).

**Comparison & Decision:**

Both compounds have significant absorption and solubility issues (negative Caco-2 and solubility values). However, Ligand B has a substantially better binding affinity (-8.3 vs -7.0 kcal/mol), excellent metabolic stability (very negative Cl_mic), and a good half-life. While Ligand A has a slightly lower DILI risk, the superior potency and pharmacokinetic properties of Ligand B outweigh this advantage. The difference in binding affinity is significant enough to potentially overcome the absorption/solubility issues through formulation strategies. Ligand A's extremely poor Caco-2 and half-life are major drawbacks.

Output:
1
2025-04-17 11:56:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.419 and 349.431 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (96.53), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (though not a primary concern here).

**logP:** Ligand A (0.615) is slightly better than Ligand B (0.259). Both are a bit low, potentially impacting permeability, but A is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Lower HBD/HBA generally improves permeability. Both are within acceptable limits.

**QED:** Ligand A (0.843) has a significantly better QED score than Ligand B (0.641), indicating a more drug-like profile.

**DILI:** Ligand B (25.94) has a much lower DILI risk than Ligand A (59.752), which is a significant advantage.

**BBB:** Ligand A (70.803) has better BBB penetration than Ligand B (43.699), but this isn't a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-4.864) has better Caco-2 permeability than Ligand B (-5.32), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.181) has better aqueous solubility than Ligand B (-1.667). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.113 and 0.099 respectively).

**Microsomal Clearance:** Ligand B (-5.441) has significantly lower microsomal clearance than Ligand A (14.227), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (10.074) has a longer in vitro half-life than Ligand A (-3.095), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.013 respectively).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). While a 0.6 kcal/mol difference is noticeable, the ADME properties are more concerning.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and Caco-2 permeability, but Ligand B excels in crucial areas for kinase inhibitors: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and a better QED score. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed with further optimization, but the metabolic stability and safety profile are more critical.

Output:
1
2025-04-17 11:56:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.255 Da and 378.904 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.13) is significantly better than Ligand B (53.6). A TPSA under 140 is good for oral absorption, and both are well below that, but lower is generally preferred.

**logP:** Both ligands have similar logP values (4.771 and 4.967), both slightly above the optimal 1-3 range. This could potentially lead to solubility issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 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 (0.65 and 0.659), indicating good drug-likeness.

**DILI:** Ligand A (76.464) has a slightly higher DILI risk than Ligand B (70.221), but both are below the concerning threshold of 60.

**BBB:** Ligand A (75.107) has better BBB penetration than Ligand B (43.001). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.394) has better Caco-2 permeability than Ligand B (-4.914). Higher values are better, so A is preferable.

**Aqueous Solubility:** Ligand A (-5.248) has better aqueous solubility than Ligand B (-5.183). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.896) has a slightly higher hERG inhibition risk than Ligand B (0.658). Lower is better, making B preferable.

**Microsomal Clearance:** Ligand B (36.812) has a lower microsomal clearance than Ligand A (50.812), indicating better metabolic stability. This is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (39.47) has a slightly longer in vitro half-life than Ligand A (43.663). Longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.734) has lower P-gp efflux than Ligand B (0.483), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 kcal/mol and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is slightly more favorable. It has better metabolic stability (lower Cl_mic) and a longer half-life, and a lower hERG risk. While Ligand A has better solubility and Caco-2 permeability, the metabolic stability and safety profile of Ligand B are more important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:56:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.47 and 348.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (76.46). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (3.98) is at the upper end of the optimal range (1-3), while Ligand B (1.37) is at the lower end. While both are acceptable, a higher logP can sometimes improve membrane permeability.

**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 reasonable QED scores (0.905 and 0.755), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (31.72 and 30.87), which is excellent.

**BBB:** Ligand A (89.96) has a better BBB percentile than Ligand B (75.00). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.603) has a worse Caco-2 permeability than Ligand B (-4.801). Lower values indicate lower permeability, so B is slightly better here.

**Aqueous Solubility:** Ligand A (-3.982) has better aqueous solubility than Ligand B (-1.144). Solubility is crucial for bioavailability, making A preferable.

**hERG Inhibition:** Ligand A (0.789) has a lower hERG inhibition risk than Ligand B (0.549), which is a significant advantage. Avoiding cardiotoxicity is paramount.

**Microsomal Clearance:** Ligand A (58.58) has a higher microsomal clearance than Ligand B (14.38). Lower clearance is preferred for metabolic stability, so Ligand B is significantly better.

**In vitro Half-Life:** Ligand A (26.10) has a longer half-life than Ligand B (-5.75). This is a substantial advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.407) has lower P-gp efflux than Ligand B (0.076). Lower efflux is generally preferred.

**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 ADME considerations.

**Overall Assessment:**

Ligand A excels in solubility, hERG risk, half-life, and P-gp efflux. Ligand B is better in metabolic stability (Cl_mic) and Caco-2 permeability. However, the superior hERG profile and longer half-life of Ligand A are more critical for an enzyme target like SRC kinase, as they directly address potential toxicity and dosing concerns. The slight advantage in solubility also supports better bioavailability.

Output:
1
2025-04-17 11:56:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.47 and 368.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is significantly better than Ligand B (78.43). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.76 and 3.26), 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) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.763) has a higher QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand A (18.19) has a much lower DILI risk than Ligand B (38.39), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.25) has a higher BBB percentile than Ligand B (39.16).

**Caco-2 Permeability:** Ligand A (-4.48) has a more negative Caco-2 value than Ligand B (-5.05), indicating poorer permeability.

**Aqueous Solubility:** Ligand A (-3.80) has slightly better solubility than Ligand B (-3.02).

**hERG:** Both ligands have low hERG inhibition liability (0.91 and 0.69 respectively), which is good.

**Microsomal Clearance:** Ligand A (91.76) has a higher microsomal clearance than Ligand B (54.79), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (49.75) has a significantly longer in vitro half-life than Ligand A (-15.66), which is a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.56 and 0.66).

**Binding Affinity:** Ligand B (-7.5 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 A has advantages in TPSA, QED, DILI, solubility, and BBB. However, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has slightly better binding affinity. Given that we are targeting a kinase (enzyme), metabolic stability and potency are paramount. The significantly better metabolic stability and half-life of Ligand B, coupled with its slightly better affinity, outweigh the advantages of Ligand A.

Output:
1
2025-04-17 11:56:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.415 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (82.11 and 80.12) below 140, suggesting reasonable absorption potential.

**logP:** Ligand A (-0.233) is slightly low, potentially hindering permeation. Ligand B (1.725) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (5) are below the threshold of 10.

**QED:** Both ligands have good QED scores (0.743 and 0.752), indicating drug-like properties.

**DILI:** Ligand A (27.453) has a significantly lower DILI risk than Ligand B (43.66). This is a substantial advantage for Ligand A.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, suggesting poor permeability. However, the absolute value is slightly less negative for Ligand A (-4.897 vs -5.301), indicating potentially slightly better permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.124 and -1.343). This is a concern for both, but needs to be balanced against other properties.

**hERG Inhibition:** Ligand A (0.18) has a much lower hERG risk than Ligand B (0.369). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (9.773) has a lower microsomal clearance than Ligand B (29.224), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-15.387) has a negative half-life, which is unusual and suggests very rapid metabolism. Ligand B (20.951) has a positive half-life, indicating better stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.048 and 0.036).

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.7). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall:**

Ligand A excels in safety parameters (DILI, hERG) and metabolic stability (Cl_mic). While its solubility and half-life are concerning, its superior safety profile and metabolic stability, combined with a very strong binding affinity, make it the more promising candidate. Ligand B has a better half-life and logP, but suffers from higher DILI and hERG risk, and higher clearance.

Output:
0
2025-04-17 11:56:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 and 368.46 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (90.65 and 95.00) are acceptable, being under 140, but higher than the ideal <90 for CNS penetration (not a primary concern here).

**logP:** Ligand A (1.269) is optimal, while Ligand B (0.417) is a bit low, potentially impacting permeability.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.5 (0.757 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (29.24%) has a significantly lower DILI risk than Ligand B (45.10%). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target. Ligand A (59.33%) is higher than Ligand B (41.37%).

**Caco-2:** Both have negative values, which is unusual and hard to interpret without knowing the scale. However, the absolute value for Ligand A (-4.761) is less negative than Ligand B (-4.945), suggesting potentially better absorption.

**Solubility:** Both have negative values, which is unusual and hard to interpret without knowing the scale. However, the absolute value for Ligand A (-2.637) is less negative than Ligand B (-2.255), suggesting potentially better solubility.

**hERG:** Both ligands have low hERG risk (0.365 and 0.155).

**Microsomal Clearance:** Ligand A (46.94 mL/min/kg) has a higher clearance than Ligand B (-4.107 mL/min/kg). This suggests Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-25.016 hours) has a negative half-life, which is impossible. Ligand B (6.532 hours) is a more reasonable value. The negative value for Ligand A is a significant red flag.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.058 and 0.013).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly lower DILI risk. However, the negative in vitro half-life is a critical flaw. Ligand B, while having a slightly weaker binding affinity and higher DILI risk, has a reasonable half-life and better metabolic stability. Given the enzyme-specific priorities, metabolic stability (reflected in Cl_mic and t1/2) is crucial. The negative half-life of Ligand A is a showstopper.

Output:
1
2025-04-17 11:56:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.342 and 357.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.86 and 87.74) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.056) is optimal, while Ligand B (0.385) is quite low, potentially hindering permeation.

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

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

**QED:** Both ligands have good QED scores (0.592 and 0.69), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 58.589, which is acceptable (below 60). Ligand B has a much lower DILI risk of 28.616, which is excellent.

**BBB:** Both ligands have moderate BBB penetration (57.852 and 79.217). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.841 and -4.912), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.594 and -1.456), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.694) has a slightly higher hERG risk than Ligand B (0.197), but both are relatively low.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (89.331) than Ligand B (5.076), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-4.882 hours) than Ligand A (-25.566 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.271) has lower P-gp efflux than Ligand B (0.009), which is slightly favorable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.5 kcal/mol difference is substantial and outweighs many of the other drawbacks of Ligand B.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, longer half-life), lower DILI risk, and, most importantly, stronger binding affinity outweigh the slightly lower logP and P-gp efflux. The affinity difference is large enough to potentially overcome formulation challenges related to solubility and permeability.

Output:
1
2025-04-17 11:56:19,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (393.77 and 384.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is better than Ligand B (84.42). Both are acceptable, but lower TPSA generally favors better absorption.

**logP:** Ligand B (1.229) is significantly better than Ligand A (4.867). Ligand A's high logP raises concerns about solubility and potential off-target effects.

**H-Bond Donors:** Both ligands are acceptable (2 and 1 respectively), falling under the threshold of 5.

**H-Bond Acceptors:** Both ligands are acceptable (4 and 6 respectively), falling under the threshold of 10.

**QED:** Both ligands have good QED scores (0.777 and 0.843), indicating good drug-like properties.

**DILI:** Ligand B (84.219) is better than Ligand A (93.525), indicating a lower risk of drug-induced liver injury. Both are reasonably acceptable, but lower is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (40.675) is slightly better than Ligand A (30.128), but not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.71) is better than Ligand B (-5.116). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.012) is better than Ligand B (-3.229). Higher solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.19 and 0.203), which is excellent.

**Microsomal Clearance:** Ligand A (17.697) is significantly better than Ligand B (32.543). Lower clearance indicates better metabolic stability, a key factor for kinases.

**In vitro Half-Life:** Ligand A (22.048) is significantly better than Ligand B (2.278). A longer half-life is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.079).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) is *significantly* better than Ligand B (0.0 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other ADME concerns.

**Conclusion:**

Despite Ligand B's better logP and DILI scores, Ligand A's *substantially* superior binding affinity (-8.7 vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are decisive. The high logP of Ligand A is a concern, but can potentially be addressed through further optimization without sacrificing potency. The difference in binding affinity is so large that it outweighs the drawbacks of Ligand A.

Output:
1
2025-04-17 11:56:19,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (366.487 Da) is also good.

**TPSA:** Ligand A (114.41) is slightly above the preferred <140, but acceptable. Ligand B (83.56) is excellent, well below 140, suggesting good absorption.

**logP:** Both ligands have good logP values (A: 1.515, B: 1.261), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, fitting the guidelines. Ligand B has 2 HBD and 6 HBA, also fitting the guidelines.

**QED:** Both ligands have good QED scores (A: 0.671, B: 0.759), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (97.402), which is a significant concern. Ligand B has a much lower DILI risk (31.291), making it considerably safer.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (51.997) and Ligand B (60.023) are both relatively low.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (A: -5.865, B: -5.113). This suggests potential absorption issues, but is less critical given the kinase target.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -3.773, B: -1.843). This is a significant drawback, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.331, B: 0.212). This is positive.

**Microsomal Clearance:** Ligand A has a very low microsomal clearance (0.697), indicating high metabolic stability. Ligand B has a significantly higher clearance (-13.349), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A has a longer half-life (14.234 hours) than Ligand B (11.153 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.031, B: 0.034), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.4 kcal/mol, B: -8.7 kcal/mol). Ligand B is slightly better, but the difference is small.

**Conclusion:**

While Ligand B has slightly better binding affinity and TPSA, the extremely high DILI risk associated with Ligand A is a deal-breaker. The significantly lower DILI risk of Ligand B, coupled with acceptable metabolic stability and affinity, makes it the more viable drug candidate despite its slightly poorer solubility and metabolic stability.

Output:
1
2025-04-17 11:56:19,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (344.46 and 345.36 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.54) is well below the 140 threshold for good oral absorption, and favorable for kinase inhibitors. Ligand B (130.24) is still within acceptable limits, but higher than A.

**3. logP:** Ligand A (1.662) is optimal (1-3). Ligand B (0.074) is a bit low, potentially hindering permeation, but not drastically.

**4. H-Bond Donors (HBD):** Ligand A (1) is good. Ligand B (3) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is good. Ligand B (7) is also acceptable, but higher.

**6. QED:** Ligand A (0.902) is excellent, indicating high drug-likeness. Ligand B (0.675) is still acceptable, but lower than A.

**7. DILI:** Ligand A (20.4) has a significantly lower DILI risk than Ligand B (61.3). This is a major advantage for Ligand A.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (62.6) is lower than Ligand B (46.3).

**9. Caco-2 Permeability:** Ligand A (-4.735) is lower than Ligand B (-5.24), indicating slightly lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.739) is better than Ligand B (-2.106), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.231 and 0.108, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand A (3.918) has higher clearance than Ligand B (-1.051), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (21.418) has a much longer half-life than Ligand A (5.172), a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.013, respectively).

**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, potentially outweighing some of the ADME drawbacks.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and half-life, while Ligand A has better solubility and lower DILI risk. However, the substantial difference in binding affinity (-9.2 vs -7.6) is a major factor. The longer half-life of Ligand B also contributes to a more favorable profile.

Output:
1
2025-04-17 11:56:19,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.439 and 369.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is better than Ligand B (61.88), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.15 and 1.819), 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 5 HBA, both acceptable (<=10).

**QED:** Ligand A (0.88) has a better QED score than Ligand B (0.742), indicating a more drug-like profile.

**DILI:** Ligand B (28.306) has a significantly lower DILI risk than Ligand A (66.615), which is a major advantage.

**BBB:** Ligand A (76.309) has a better BBB penetration score than Ligand B (55.176), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.905) has better Caco-2 permeability than Ligand B (-5.167), suggesting better absorption.

**Aqueous Solubility:** Ligand B (-1.564) has better aqueous solubility than Ligand A (-3.46), which is important for formulation and bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.3 and 0.266), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance values (33.549 and 32.442 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (13.83 and 12.237 hours), indicating comparable duration of action.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.116 and 0.048), which is favorable.

**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 outweighs many of the minor ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better QED and BBB penetration, Ligand B has a much lower DILI risk and, crucially, significantly higher binding affinity. For an enzyme target like SRC kinase, potency is paramount. The lower DILI risk is also a significant advantage. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 11:56:19,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.336 and 353.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.69) is better than Ligand B (61.44) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally indicates better cell permeability.

**logP:** Ligand B (3.087) is slightly higher than Ligand A (1.94), placing it closer to the optimal range of 1-3. Ligand A 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:** Ligand A (0.883) has a significantly higher QED score than Ligand B (0.669), suggesting a more drug-like profile.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (10.585). This is a significant drawback for Ligand A.

**BBB:** Both ligands have relatively high BBB penetration (Ligand A: 88.872, Ligand B: 66.033), but this is less critical for a kinase inhibitor that isn't specifically targeting the CNS.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.388) is slightly worse than Ligand B (-4.85).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.71) is slightly better than Ligand B (-2.506).

**hERG Inhibition:** Ligand A (0.211) has a slightly lower hERG inhibition risk than Ligand B (0.404), which is favorable.

**Microsomal Clearance:** Ligand A (19.081) and Ligand B (20.478) have similar microsomal clearance values. Lower is better, but these are not alarming.

**In vitro Half-Life:** Ligand A (-22.602) has a significantly *longer* in vitro half-life than Ligand B (12.211). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.041, Ligand B: 0.028).

**Binding Affinity:** Ligand A (-8.9 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 concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. While its DILI risk is higher, the superior potency and metabolic stability are likely to be more impactful. Both ligands have poor solubility and permeability, which would need to be addressed during optimization. Ligand B has a better DILI profile, but its weaker binding and shorter half-life are significant disadvantages.

Output:
1
2025-04-17 11:56:19,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.773 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.0) is higher than Ligand B (75.44). While both are acceptable, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have good logP values (1.962 and 2.409) falling within the 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:** Ligand A (0.72) has a better QED score than Ligand B (0.519), indicating a more drug-like profile.

**DILI:** Ligand B (39.744) has a significantly lower DILI risk than Ligand A (96.782). This is a major advantage for Ligand B.

**BBB:** Ligand B (76.735) shows better BBB penetration than Ligand A (33.579), but BBB isn't a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.686) has a worse Caco-2 permeability than Ligand B (-4.956), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.032) has a worse aqueous solubility than Ligand B (-2.158). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.033) has a slightly lower hERG inhibition risk than Ligand B (0.411), which is preferable.

**Microsomal Clearance:** Ligand A (-4.19) has a much lower microsomal clearance than Ligand B (53.024), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.077) has a better in vitro half-life than Ligand B (-20.261).

**P-gp Efflux:** Ligand A (0.043) has a lower P-gp efflux liability than Ligand B (0.436), which is desirable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. The difference of 8.5 kcal/mol is substantial and likely outweighs many of the ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand B's advantages in DILI, solubility, and Caco-2 permeability, Ligand A's significantly superior binding affinity (-8.5 vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic and higher t1/2) make it the more promising drug candidate. The strong binding affinity is likely to drive efficacy, and the improved metabolic stability will contribute to a more favorable pharmacokinetic profile. While the higher DILI risk of Ligand A is a concern, it can be further investigated and potentially mitigated during lead optimization.

Output:
1
2025-04-17 11:56:19,994 - INFO - Batch 88 complete. Total preferences: 1408
2025-04-17 11:56:19,994 - INFO - Processing batch 89/512...
2025-04-17 11:56:59,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 357.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is better than Ligand B (90.55). Both are under 140, but A is closer to the optimal for oral absorption.

**logP:** Both ligands have similar logP values (2.709 and 2.682), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (4) as lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (7), again favoring permeability.

**QED:** Ligand A (0.893) has a significantly higher QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand B (77.394) has a higher DILI risk than Ligand A (54.75), which is undesirable.

**BBB:** Ligand A (77.705) has a better BBB penetration percentile than Ligand B (54.905), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.848) has a better Caco-2 permeability than Ligand B (-5.828).

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-2.532 and -2.67). This is a potential concern for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.407) has a lower hERG inhibition risk than Ligand B (0.789), which is a significant advantage.

**Microsomal Clearance:** Ligand A (42.426) has a significantly lower microsomal clearance than Ligand B (14.843). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-5.3) has a longer in vitro half-life than Ligand B (-2.661), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.049), which is favorable.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-6.8), a difference of 0.9 kcal/mol. While affinity is crucial, the other ADME properties of Ligand A are significantly better.

**Conclusion:**

Despite the slightly weaker binding affinity, Ligand A is the more promising drug candidate. Its superior QED, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better permeability profiles outweigh the small difference in binding affinity. The combination of these factors makes Ligand A more likely to succeed as a drug candidate targeting SRC kinase.

Output:
0
2025-04-17 11:56:59,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.395 Da) is slightly lower, which could be beneficial for permeability. Ligand B (370.431 Da) is also good.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption. Ligand B (101.81 A^2) is better than Ligand A (121.69 A^2).

**logP:** Both ligands have acceptable logP values (between 1 and 3). Ligand A (-0.238) is a bit low, potentially hindering permeation, while Ligand B (-0.711) is also on the lower side but slightly better.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, which is also acceptable.

**H-Bond Acceptors:** Both ligands have 7 HBA, which is within the acceptable range (<=10).

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness (0.771 for A and 0.678 for B).

**DILI:** Ligand A (72.47) has a higher DILI risk than Ligand B (63.552), but both are reasonably acceptable.

**BBB:** Both ligands have similar BBB penetration (54.634 for A and 59.829 for B). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.434) is slightly better than Ligand A (-5.632).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand B (-1.798) is slightly better than Ligand A (-2.43).

**hERG Inhibition:** Ligand A (0.038) has a very low hERG risk, which is excellent. Ligand B (0.108) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-5.385) has a lower (better) microsomal clearance than Ligand B (8.637), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.909) has a better in vitro half-life than Ligand B (-2.947).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 for A and 0.072 for B).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.0 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.2 kcal/mol vs -6.0 kcal/mol) outweighs the slightly higher DILI risk and lower logP. Furthermore, Ligand A demonstrates better metabolic stability (lower Cl_mic) and a longer in vitro half-life. The excellent hERG profile of Ligand A is also a significant advantage. While solubility and permeability are concerns for both, these can be addressed through formulation strategies. The potency advantage of Ligand A is crucial for an enzyme target like SRC kinase.

Output:
0
2025-04-17 11:56:59,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.451 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (70.67), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (0.981 and 1.23), 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.

**QED:** Ligand A (0.791) has a higher QED score than Ligand B (0.536), indicating better overall drug-likeness.

**DILI:** Ligand B (18.185) has a significantly lower DILI risk than Ligand A (61.109), which is a major advantage.

**BBB:** Ligand B (71.307) has a better BBB penetration score than Ligand A (53.238), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.221) has a worse Caco-2 permeability than Ligand B (-4.793).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.475 and -1.579). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.118) has a lower hERG inhibition risk than Ligand B (0.286), which is a positive.

**Microsomal Clearance:** Ligand A (14.188) has a lower microsomal clearance than Ligand B (22.042), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.186) has a much longer in vitro half-life than Ligand A (0.634), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.034) has a lower P-gp efflux liability than Ligand B (0.008), which is a positive.

**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 of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better QED, lower hERG risk, and lower P-gp efflux, Ligand B's superior binding affinity (-7.8 vs -6.6 kcal/mol), lower DILI risk, and longer half-life are more critical for an enzyme inhibitor. The solubility is a concern for both, but the potency and metabolic stability advantages of Ligand B are more important.

Output:
1
2025-04-17 11:56:59,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.286 and 358.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.16) is better than Ligand B (67.87) as it is still within the acceptable range for oral absorption (<140), while Ligand B is excellent.

**logP:** Both ligands have good logP values (2.6 and 1.112), 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 acceptable (<10).

**QED:** Ligand B (0.772) has a significantly better QED score than Ligand A (0.433), indicating a more drug-like profile.

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a major concern. Ligand B has a much lower, and acceptable, DILI risk (43.932%).

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (88.872%) has a higher BBB penetration than Ligand A (66.576%), but this isn't a primary driver here.

**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 thus can be difficult to interpret directly.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not clear, but both seem to have poor solubility.

**hERG:** Ligand A (0.421) shows a slightly higher hERG risk than Ligand B (0.358), but both are relatively low.

**Microsomal Clearance:** Ligand B (3.347 mL/min/kg) has significantly lower microsomal clearance than Ligand A (62.435 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.527 hours) has a negative half-life, which is not possible. This is a red flag. Ligand A (69.034 hours) has a good in vitro half-life.

**P-gp Efflux:** Ligand B (0.048) exhibits very low P-gp efflux, which is favorable. Ligand A (0.327) has a moderate 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 substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is crucial for an enzyme inhibitor. However, its extremely high DILI risk and relatively high metabolic clearance are major drawbacks. Ligand B has a better QED, lower DILI, and better metabolic stability and P-gp efflux. However, its binding affinity is essentially non-existent, and its in vitro half-life is impossible. Given the importance of potency for enzyme inhibition, and the severity of the DILI risk for Ligand A, I would still lean towards Ligand B as a starting point for optimization, despite the affinity issue. The affinity can be improved through medicinal chemistry efforts, but mitigating a high DILI risk is often much more challenging. The negative half-life for Ligand B is a data error that needs to be resolved.

Output:
1
2025-04-17 11:56:59,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 140, suggesting good oral absorption potential. Ligand A (70.49) is higher than Ligand B (58.64), but both are well within the acceptable range.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.489, Ligand B: 1.705), indicating good lipophilicity.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (Ligand A: 2, Ligand B: 1) and HBA (both: 5) counts, balancing solubility and permeability.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.757, Ligand B: 0.774), indicating good drug-like properties.

**DILI:** Ligand A (8.181) has a significantly lower DILI risk than Ligand B (37.069). This is a major advantage for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration (Ligand A: 79.062, Ligand B: 81.349), but this isn't a primary concern for a non-CNS target like SRC.

**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.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.167 and -3.136). This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.904, Ligand B: 0.388). Ligand B is slightly better here, but both are acceptable.

**Microsomal Clearance:** Ligand A (7.455) has significantly lower microsomal clearance than Ligand B (33.397), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-34.235) has a much longer in vitro half-life than Ligand B (-3.687). This is a significant benefit, suggesting less frequent dosing could be possible.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.079, Ligand B: 0.074).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). The difference is 1.4 kcal/mol, which is significant, but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate due to its significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. The solubility is a concern for both, but the ADME advantages of Ligand A outweigh the minor potency difference, especially for an enzyme target where metabolic stability is crucial.

Output:
0
2025-04-17 11:56:59,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 345.407 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is well below the 140 threshold and favorable for oral absorption. Ligand B (108.8) is still within acceptable limits but less optimal.

**logP:** Ligand A (1.682) is within the optimal 1-3 range. Ligand B (0.199) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, both within acceptable limits. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.812 and 0.804), indicating good drug-likeness.

**DILI:** Ligand A (29.934) has a much lower DILI risk than Ligand B (56.223), which is a significant advantage.

**BBB:** Ligand A (85.111) shows better BBB penetration than Ligand B (35.169), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.336) has better Caco-2 permeability than Ligand B (-5.489), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-1.701) has better aqueous solubility than Ligand B (-2.36), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.199 and 0.084), which is excellent.

**Microsomal Clearance:** Ligand A (35.739) has higher microsomal clearance than Ligand B (-6.978), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-9.772) has a longer in vitro half-life than Ligand A (-11.694), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.099 and 0.037).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge (1.1 kcal/mol), it's enough to consider.

**Overall Assessment:**

Ligand B has a better binding affinity and a longer half-life, which are key for an enzyme inhibitor. However, it suffers from a low logP, which could limit its permeability, and a higher DILI risk. Ligand A has better solubility, permeability, and a significantly lower DILI risk, but its metabolic stability is a concern.

Considering the balance, the slightly better affinity of Ligand B, combined with its longer half-life, outweighs the lower logP and higher DILI. The lower logP might be addressed with prodrug strategies. The DILI risk, while higher, is still moderate.

Output:
1
2025-04-17 11:56:59,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.291 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.84) is better than Ligand B (61.36), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.087 and 2.918) 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:** Ligand A (4) is preferable to Ligand B (5).

**QED:** Both ligands have good QED scores (0.568 and 0.77), indicating drug-likeness.

**DILI:** Ligand B (37.224) has a significantly lower DILI risk than Ligand A (72.392). This is a major advantage for Ligand B.

**BBB:** Both ligands have high BBB penetration (92.672 and 90.229), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.48 and -4.931), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.294 and -2.916), suggesting very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.521) has a lower hERG risk than Ligand B (0.902), which is favorable.

**Microsomal Clearance:** Ligand A (24.212) has significantly lower microsomal clearance than Ligand B (62.809), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (8.115) has a better in vitro half-life than Ligand B (-0.058).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.259 and 0.268).

**Binding Affinity:** Ligand B (-8.5 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:**

Ligand A has advantages in metabolic stability (lower Cl_mic, better t1/2), hERG risk, and fewer H-bonds. However, Ligand B has a much lower DILI risk and slightly better binding affinity. Both have concerningly poor solubility and permeability. Given the enzyme-specific priorities, metabolic stability and potency are crucial. The slightly better affinity of Ligand B, coupled with the substantially lower DILI risk, outweighs the advantages of Ligand A. The poor solubility and permeability are significant issues for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:56:59,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.375 and 352.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.21) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.09) is excellent, well below 140.

**logP:** Ligand A (0.472) is quite low, potentially hindering permeability. Ligand B (2.048) is within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 5 HBD and 5 HBA, acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable and potentially better for permeability.

**QED:** Ligand A (0.366) is below the desirable 0.5 threshold, suggesting a less drug-like profile. Ligand B (0.871) is excellent, indicating a strong drug-like profile.

**DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (54.75). Both are acceptable, but B is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (77.2) is higher, but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.993) has very poor predicted permeability. Ligand B (-4.984) is better, but still not great.

**Aqueous Solubility:** Ligand A (-2.985) and Ligand B (-3.302) both have poor predicted solubility, which is a concern.

**hERG Inhibition:** Ligand A (0.233) has a slightly higher hERG risk than Ligand B (0.479), but both are relatively low.

**Microsomal Clearance:** Ligand A (7.121) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (4.88).

**In vitro Half-Life:** Ligand A (21.105 hours) has a reasonable half-life. Ligand B (-42.239 hours) is a negative value, which is not physically meaningful and suggests a potential issue with the prediction.

**P-gp Efflux:** Ligand A (0.037) has very low P-gp efflux, which is good. Ligand B (0.09) is slightly higher, but still low.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B has a superior binding affinity, better logP, better QED, lower DILI risk, and better metabolic stability. The negative half-life for Ligand B is concerning and needs investigation, but the substantial affinity advantage makes it the better choice for further optimization.

Output:
1
2025-04-17 11:56:59,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.47 and 361.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.91) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for oral absorption, which is good.

**logP:** Ligand A (2.269) is within the optimal 1-3 range, while Ligand B (3.173) is at the higher end of the optimal range.

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

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.771 and 0.876), indicating drug-likeness.

**DILI:** Ligand A (49.399) has a lower DILI risk than Ligand B (57.813), which is favorable.

**BBB:** Ligand A (84.141) has better BBB penetration than Ligand B (62.233), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.439 and -4.862). 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 (-3.101 and -3.583). Again, the scale is unclear, but negative values likely indicate poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.346 and 0.386), which is excellent.

**Microsomal Clearance:** Ligand A (65.187) has a slightly higher microsomal clearance than Ligand B (59.756). Lower is better for metabolic stability, so Ligand B is preferable.

**In vitro Half-Life:** Ligand B (7.796 hours) has a shorter half-life than Ligand A (13.078 hours). Longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.251 and 0.268), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, DILI risk, and half-life, the significantly stronger binding affinity of Ligand B (-7.9 vs -9.2 kcal/mol) is the most critical factor for an enzyme inhibitor. The difference of 1.3 kcal/mol is substantial. Although Ligand B has slightly higher DILI and lower half-life, these can potentially be addressed through further optimization. The improved potency is likely to have a greater impact on efficacy.

Output:
1
2025-04-17 11:56:59,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.471 and 367.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is better than Ligand B (102.22). Both are acceptable, but A is closer to the preferred <140 for oral absorption.

**logP:** Both ligands have good logP values (2.355 and 2.044), 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=5). Both are within acceptable limits.

**QED:** Ligand A (0.874) has a significantly better QED score than Ligand B (0.653), indicating a more drug-like profile.

**DILI:** Ligand A (64.676) has a higher DILI risk than Ligand B (45.444), but both are below the concerning threshold of 60.

**BBB:** Both ligands have the same BBB penetration (31.136), which is low, but not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.332 and -5.074), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.887 and -3.382), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.163) has a much lower hERG inhibition liability than Ligand B (0.568), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-7.115) has a much lower (better) microsomal clearance than Ligand B (40.157), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.912) has a longer in vitro half-life than Ligand B (35.003), which is desirable.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.075), which is favorable.

**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 outweigh the other significant differences.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, **Ligand A** is the more promising drug candidate. While both have poor solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, better QED, and lower P-gp efflux. The slightly weaker binding affinity of Ligand A is less concerning than the ADME liabilities of Ligand B.

Output:
0
2025-04-17 11:56:59,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.519 and 342.483 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is slightly higher than Ligand B (49.41). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (2.476 and 3.494), 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.

**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 reasonable QED values (0.662 and 0.581), indicating good drug-like properties.

**DILI:** Ligand A (7.832) has a significantly lower DILI risk than Ligand B (37.999). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (70.88) is higher than Ligand B (65.878). While not a primary concern for a kinase inhibitor, it's a slight positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-5.048) has worse Caco-2 permeability than Ligand B (-4.613), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.049) has better aqueous solubility than Ligand B (-3.532). This is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.457 and 0.478).

**Microsomal Clearance:** Ligand A (27.006) has significantly lower microsomal clearance than Ligand B (80.136), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-6.717) has a much longer in vitro half-life than Ligand B (26.609). This is another significant advantage for Ligand A, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032 and 0.285).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). A difference of 1.2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better Caco-2 permeability and logP, Ligand A excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and slightly better binding affinity. The improved binding affinity further solidifies its position. The slightly lower Caco-2 permeability of Ligand A is a minor concern that could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 11:56:59,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.378 and 345.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.09) is higher than the preferred <140 for oral absorption, but still reasonable. Ligand B (43.86) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.303) is quite low, potentially hindering permeability. Ligand B (0.837) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of 10.

**QED:** Ligand A (0.629) has a better QED score than Ligand B (0.431), indicating a more drug-like profile.

**DILI:** Ligand A (60.644) has a higher DILI risk than Ligand B (21.055). This is a significant concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (78.79) shows better penetration than Ligand A (51.221).

**Caco-2 Permeability:** Ligand A (-5.44) shows poor permeability. Ligand B (-4.681) is better, but still not great.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.921 and -2.102), indicating poor aqueous solubility, which is a drawback.

**hERG Inhibition:** Ligand A (0.235) has a slightly higher hERG risk than Ligand B (0.393), but both are reasonably low.

**Microsomal Clearance:** Ligand A (-19.358) shows significantly *lower* (better) microsomal clearance than Ligand B (9.639), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (21.338 hours) has a much longer half-life than Ligand B (-30.593 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.086).

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a >1.5 kcal/mol difference, and a major factor.

**Conclusion:**

Despite Ligand A's higher DILI risk and lower logP/Caco-2 permeability, its *significantly* superior binding affinity (-9.8 vs -7.4 kcal/mol) and much better metabolic stability (lower Cl_mic, longer t1/2) outweigh these drawbacks. The strong binding affinity suggests a lower dose could be effective, potentially mitigating some of the DILI risk. The solubility issue is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 11:56:59,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (61.92) is better than Ligand A (76.46).

**logP:** Ligand A (1.68) is optimal, while Ligand B (3.471) is at the higher end of the optimal range. This could potentially lead to solubility issues for Ligand B, but it's not a major concern yet.

**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 QED values above 0.5, indicating good drug-like properties. Ligand A (0.849) is slightly better than Ligand B (0.699).

**DILI:** Ligand A (46.452) has a lower DILI risk than Ligand B (55.797), which is a positive attribute.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.625) has a slightly better BBB score than Ligand B (54.595).

**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 absolute difference is significant. Ligand A (-4.699) is better than Ligand B (-4.803).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.684) is better than Ligand B (-3.888).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.554 and 0.909 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (67.643) has lower microsomal clearance than Ligand B (73.793), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-22.044) has a significantly longer in vitro half-life than Ligand B (10.987). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.192 and 0.551 respectively).

**Binding Affinity:** Both ligands have strong binding affinities (-8.5 and -9.3 kcal/mol). Ligand B is slightly more potent. However, the difference of 0.8 kcal/mol is not substantial enough to outweigh the ADME advantages of Ligand A.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), better solubility, lower DILI risk, and a slightly better QED score. These factors are particularly important for an enzyme target like SRC kinase.

Output:
0
2025-04-17 11:56:59,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 and 354.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.56) is slightly above the preferred <140, but acceptable. Ligand B (58.64) is well within the range.

**logP:** Both ligands have good logP values (3.24 and 2.04), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.684 and 0.621), indicating good drug-likeness.

**DILI:** Ligand A (56.69%) has a higher DILI risk than Ligand B (31.56%), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB score (91.47%) than Ligand A (60.88%), but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.275) has a negative Caco-2 value, which is concerning. Ligand B (-4.598) is also negative, but less so. Both suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.699 and -2.462), indicating poor solubility. This is a significant drawback.

**hERG:** Both ligands have low hERG risk (0.154 and 0.367), which is good.

**Microsomal Clearance:** Ligand A (-6.945) has significantly lower (better) microsomal clearance than Ligand B (22.188). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (38.16 hours) has a much longer half-life than Ligand B (-17.79 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.104 and 0.04), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.9 kcal/mol). Ligand B is slightly better, but the difference is relatively small.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. Its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk outweigh the slightly weaker binding and negative Caco-2/solubility values. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies. The improved metabolic stability is crucial for an enzyme target, as it translates to a longer duration of action and potentially lower dosing requirements.

Output:
1
2025-04-17 11:56:59,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.431 and 368.587 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.15) is better than Ligand B (40.62), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.673) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (3.65) is within the optimal range.

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

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.68 and 0.657), indicating good drug-likeness.

**7. DILI:** Ligand A (25.475) has a significantly lower DILI risk than Ligand B (17.759), which is a substantial advantage.

**8. BBB:** Ligand A (69.562) has a lower BBB penetration than Ligand B (85.925). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.479) has worse Caco-2 permeability than Ligand B (-4.75).

**10. Aqueous Solubility:** Ligand A (-1.859) has better aqueous solubility than Ligand B (-3.347).

**11. hERG Inhibition:** Ligand A (0.345) has a lower hERG inhibition risk than Ligand B (0.601), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (67.792) has lower microsomal clearance than Ligand B (82.217), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.592) has a worse in vitro half-life than Ligand B (1.957).

**14. P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.433), which is favorable.

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.7), a difference of 0.6 kcal/mol.

**Overall Assessment:**

Ligand A demonstrates a significantly better safety profile with lower DILI and hERG risk, and better metabolic stability (lower Cl_mic). It also has better solubility and lower P-gp efflux. While Ligand B has a slightly better binding affinity and BBB penetration, the safety and metabolic advantages of Ligand A are more critical for an enzyme target like SRC kinase. The 0.6 kcal/mol difference in binding affinity is not substantial enough to outweigh the ADME/Tox benefits of Ligand A.

Output:
0
2025-04-17 11:56:59,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.403 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.48) is higher than Ligand B (43.86). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.218) is quite low, potentially hindering membrane permeability. Ligand B (1.432) 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 3 HBA. Both are within acceptable limits, but Ligand B's lower HBD count could contribute to better permeability.

**QED:** Both ligands have good QED scores (0.735 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 57.464, which is approaching a moderate risk. Ligand B has a very low DILI risk of 9.655, a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (73.905) has a higher BBB percentile than Ligand A (51.725).

**Caco-2 Permeability:** Ligand A (-5.113) has poor Caco-2 permeability, while Ligand B (-4.838) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.879 and -1.959). This is a concern for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.06) has a slightly higher hERG risk than Ligand B (0.443), though both are relatively low.

**Microsomal Clearance:** Ligand A (21.74 mL/min/kg) has a higher microsomal clearance than Ligand B (10.665 mL/min/kg), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (9.378 hours) has a longer in vitro half-life than Ligand A (12.52 hours).

**P-gp Efflux:** Ligand A (0.068) has slightly lower P-gp efflux than Ligand B (0.066), which is a minor advantage.

**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 can outweigh some of the ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. It has a significantly better binding affinity, lower DILI risk, improved metabolic stability (lower Cl_mic), longer half-life, and a more favorable logP value. While both have poor solubility and Caco-2 permeability, the superior potency and safety profile of Ligand B make it the better choice for further development.

Output:
1
2025-04-17 11:56:59,799 - INFO - Batch 89 complete. Total preferences: 1424
2025-04-17 11:56:59,799 - INFO - Processing batch 90/512...
2025-04-17 11:57:47,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.394 and 347.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.5) is slightly above the optimal <140, but acceptable. Ligand B (44.29) is well within the ideal range.

**logP:** Ligand A (0.779) is a bit low, potentially hindering permeability. Ligand B (3.883) is near the upper limit of the optimal range (1-3), but still acceptable.

**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, well within the guidelines.

**QED:** Both ligands have similar QED values (0.676 and 0.651), indicating good drug-likeness.

**DILI:** Ligand A (42.885) has a slightly higher DILI risk than Ligand B (23.73), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (74.758 and 89.492), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.745 and -4.823). This is unusual and suggests poor permeability. However, Caco-2 values can be unreliable and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.505 and -3.214). This is also concerning, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.557) has a slightly lower hERG risk than Ligand B (0.969), which is preferable.

**Microsomal Clearance:** Ligand A (3.413 mL/min/kg) has significantly lower microsomal clearance than Ligand B (52.893 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.686 hours) has a negative half-life, which is impossible. This is a data error. Ligand B (55.744 hours) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.134) has lower P-gp efflux than Ligand B (0.555), which is favorable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the questionable Caco-2 and solubility values for both, Ligand A appears to be the better candidate. Its superior binding affinity (-7.7 vs -7.2 kcal/mol), lower microsomal clearance, and lower P-gp efflux outweigh the slightly higher DILI risk and the problematic negative half-life value (which suggests a data error). The lower hERG risk is also a plus. The negative half-life for Ligand A is a major red flag, but assuming it's a data error, the other properties favor it.

Output:
0
2025-04-17 11:57:47,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.471 and 368.396 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (87.66).  A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**3. logP:** Both ligands have good logP values (2.292 and 1.516), 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:** Ligand A (3) is better than Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand B (0.576) has a better QED score than Ligand A (0.286), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.571) has a much lower DILI risk than Ligand B (20.9). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (70.764 and 77.937). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

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

**10. Aqueous Solubility:** Both have negative values, indicating very poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.313) has a lower hERG inhibition risk than Ligand B (0.465), which is favorable.

**12. Microsomal Clearance:** Ligand A (5) has a lower microsomal clearance than Ligand B (3.75), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-12.952) has a much longer in vitro half-life than Ligand A (-1.414). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.1) has lower P-gp efflux than Ligand B (0.058), which is preferable.

**15. Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A has advantages in TPSA, HBD, HBA, DILI risk, hERG inhibition, and metabolic stability. Ligand B has a better QED score and a significantly longer half-life. Both have poor Caco-2 permeability and solubility. The slightly better affinity of Ligand A, combined with its significantly lower DILI risk and better metabolic stability, outweigh the longer half-life of Ligand B. The poor permeability and solubility of both are concerning and would require formulation strategies. However, given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial.

Output:
0
2025-04-17 11:57:47,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 337.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (71.09), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.76 and 1.494), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Ligand B (0.818) has a significantly better QED score than Ligand A (0.528), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (35.324 and 30.748), both below the 40 threshold.

**BBB:** Ligand A (63.164) has a higher BBB penetration percentile than Ligand B (46.646), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.256) has a worse Caco-2 permeability than Ligand B (-4.662), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.966) has slightly better aqueous solubility than Ligand B (-2.955).

**hERG:** Both ligands have very low hERG inhibition liability (0.171 and 0.091), which is excellent.

**Microsomal Clearance:** Ligand B (0.913 mL/min/kg) has significantly lower microsomal clearance than Ligand A (29.301 mL/min/kg), indicating much better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-5.321 hours) has a significantly longer in vitro half-life than Ligand A (5.285 hours). This is another key advantage for an enzyme target.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.015).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 0.3 kcal/mol difference is not substantial enough to outweigh the significant ADME advantages of Ligand B.

**Conclusion:**

Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic) and half-life. While Ligand A has a marginally better binding affinity, the improvements in drug-likeness (QED), permeability, and especially metabolic stability make Ligand B the more promising drug candidate.

Output:
1
2025-04-17 11:57:47,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.369 Da and 348.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.18) is well below the 140 threshold, suggesting good absorption. Ligand B (115.57) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (2.877) is optimal (1-3). Ligand B (-0.815) is below 1, which may impede permeation. This is a significant drawback for 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, both within the acceptable limit of 10.

**QED:** Ligand A (0.871) has a very good drug-likeness score, while Ligand B (0.545) is acceptable but less optimal.

**DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (53.354), but both are below the concerning threshold of 60.

**BBB:** Ligand A (90.617) has good BBB penetration, while Ligand B (22.257) has very poor BBB penetration. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for A.

**Caco-2 Permeability:** Ligand A (-4.78) and Ligand B (-5.003) both have negative Caco-2 values. This is unusual and suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Ligand A (-4.044) and Ligand B (-2.622) both have negative solubility values, indicating poor solubility. B is slightly better than A.

**hERG Inhibition:** Ligand A (0.451) has a lower hERG risk than Ligand B (0.04), which is a significant advantage for A.

**Microsomal Clearance:** Ligand A (19.135) has a moderate clearance, while Ligand B (-33.996) has a negative clearance, suggesting very high metabolic stability. This is a major advantage for B.

**In vitro Half-Life:** Ligand A (52.866) has a reasonable half-life, while Ligand B (-20.197) has a negative half-life, which is not physically possible and suggests an issue with the data or prediction.

**P-gp Efflux:** Ligand A (0.166) has low P-gp efflux, while Ligand B (0.01) has very low P-gp efflux. Both are good.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better overall drug-like properties (QED, BBB, hERG). While its solubility and Caco-2 permeability are poor, the strong binding affinity (-9.1 kcal/mol) is a major advantage. Ligand B has better metabolic stability (Cl_mic) but suffers from a significantly lower logP, potentially hindering permeability, and a weaker binding affinity. The negative half-life for B is also concerning.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A outweighs its drawbacks, making it the more promising candidate.

Output:
0
2025-04-17 11:57:47,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.422 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the preferred <140, but acceptable. Ligand B (67.43) is well within the ideal range.

**logP:** Both ligands have good logP values (1.844 and 2.49), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is good. Ligand B has 2 HBD, also good.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Both ligands have acceptable QED scores (0.755 and 0.646), indicating good drug-likeness.

**DILI:** Ligand A (44.862) has a slightly higher DILI risk than Ligand B (26.25), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (74.758) has a higher BBB score than Ligand A (60.45), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.72) shows poor permeability, while Ligand B (-5.128) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.898) has better solubility than Ligand B (-3.171).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.189 and 0.463).

**Microsomal Clearance:** Ligand A (2.851) has significantly lower microsomal clearance than Ligand B (67.284), indicating better metabolic stability. This is a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand B (19.55) has a much longer in vitro half-life than Ligand A (1.431). This is also a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.145).

**Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has a longer half-life and slightly better solubility, Ligand A's significantly lower microsomal clearance is a major advantage for an enzyme target like SRC kinase. Lower clearance translates to a longer duration of action *in vivo* and potentially less frequent dosing. The slightly poorer Caco-2 permeability of Ligand A is less concerning than the high clearance of Ligand B. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 11:57:47,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (376.766 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.04) is significantly better than Ligand B (110.01). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (4.501) is high, potentially causing solubility issues or off-target effects. Ligand B (-0.055) is quite low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.783 and 0.623), indicating good drug-like properties.

**DILI:** Ligand A (71.811) has a higher DILI risk than Ligand B (34.277). This is a significant concern for A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (76.58) shows better penetration than Ligand B (60.838).

**Caco-2 Permeability:** Ligand A (-4.628) has poor Caco-2 permeability, while Ligand B (-5.347) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.776) has poor solubility, consistent with its high logP. Ligand B (-1.037) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.346) has a slightly higher hERG risk than Ligand B (0.104), but both are relatively low.

**Microsomal Clearance:** Ligand A (59.289) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (25.767). This is a major drawback for A.

**In vitro Half-Life:** Ligand A (22.088) has a shorter half-life than Ligand B (-3.472). A negative half-life is unusual and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.534) shows moderate P-gp efflux, while Ligand B (0.012) has very low efflux.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although both are excellent. The 1.6 kcal/mol difference is significant.

**Conclusion:**

Despite the slightly better affinity of Ligand B, Ligand A's high logP, poor solubility, high DILI risk, high clearance, and short half-life are major liabilities. Ligand B, while having a lower logP and solubility, has a much more favorable ADME profile, with lower DILI, clearance, and P-gp efflux. The small difference in binding affinity is outweighed by the significant improvements in ADME properties for Ligand B.

Output:
1
2025-04-17 11:57:47,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.857 Da) is slightly higher than Ligand B (350.394 Da), but both are acceptable.

**TPSA:** Ligand A (90.41) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (73.29) is well within the acceptable range.

**logP:** Ligand A (1.891) and Ligand B (0.689) are both within the optimal range of 1-3, but Ligand B is closer to the lower limit, which *could* indicate permeability issues.

**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 similar QED values (0.7 and 0.735), indicating good drug-likeness.

**DILI:** Ligand A (78.402) has a higher DILI risk than Ligand B (48.623). This is a significant concern.

**BBB:** Ligand A (52.772) has a lower BBB penetration percentile than Ligand B (91.663). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.738) has a lower Caco-2 permeability than Ligand B (-4.685), but both are negative values, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-3.713) has lower aqueous solubility than Ligand B (-2.512). Solubility is important for bioavailability, and Ligand B is better in this regard.

**hERG Inhibition:** Ligand A (0.103) has a slightly higher hERG inhibition risk than Ligand B (0.301), but both are relatively low.

**Microsomal Clearance:** Ligand A (72.17) has a higher microsomal clearance than Ligand B (-2.93). This suggests Ligand B is more metabolically stable, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand A (-12.392) has a significantly shorter in vitro half-life than Ligand B (-0.875). This further supports Ligand B's better metabolic stability.

**P-gp Efflux:** Ligand A (0.109) has a slightly higher P-gp efflux liability than Ligand B (0.029).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 1.0 kcal/mol difference is substantial and could potentially outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand A, its significantly higher DILI risk, lower solubility, and poorer metabolic stability (higher clearance, shorter half-life) make it a less desirable candidate. Ligand B, while having slightly weaker binding, presents a much more favorable ADME profile, particularly regarding metabolic stability and safety (DILI). For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity are crucial.

Output:
1
2025-04-17 11:57:47,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 350.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.02) is slightly higher than Ligand B (78.67). Both are below the 140 threshold for oral absorption, but B is preferable.

**logP:** Ligand A (-0.19) is quite low, potentially hindering permeability. Ligand B (1.274) 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:** Both have 5 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.669 and 0.766), indicating drug-likeness.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (24.234), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.078) and Ligand B (50.911) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -4.926), 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 (-1.669 and -0.749), which is also unusual and suggests poor solubility. This is a concern for both, but doesn't differentiate them.

**hERG:** Ligand A (0.026) has a very low hERG risk, slightly better than Ligand B (0.226).

**Microsomal Clearance:** Ligand A (-7.812) has *much* lower (better) microsomal clearance than Ligand B (25.754). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-4.919) has a negative half-life, which is unusual. Ligand B (8.619) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.022 and 0.073).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.8 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B has a better logP, which is crucial for permeability. However, Ligand A has significantly better metabolic stability (lower Cl_mic) and a slightly lower hERG risk. The negative Caco-2 and solubility values are concerning for both, but the difference in Cl_mic is substantial. Given the enzyme-specific priorities, metabolic stability is highly important. The slightly better affinity of Ligand B is unlikely to overcome the substantial difference in metabolic stability.

Output:
0
2025-04-17 11:57:47,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.419 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (120.32) is significantly better than Ligand B (59.07). A TPSA under 140 is good for oral absorption, and Ligand A is comfortably within that range, while Ligand B is excellent.

**logP:** Ligand A (-0.156) is quite low, potentially hindering permeation. Ligand B (3.825) is very good, 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, which are acceptable. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.473, B: 0.639), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (29.042) has a much lower DILI risk than Ligand B (85.537). This is a major advantage for Ligand A.

**BBB:** Ligand A (47.305) has a lower BBB penetration score than Ligand B (89.492). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.363 and -5.181), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.847 and -4.182), which is also concerning and suggests poor solubility. This will likely cause formulation issues.

**hERG Inhibition:** Ligand A (0.186) has a lower hERG risk than Ligand B (0.933). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (3.784) has a much lower microsomal clearance than Ligand B (106.814), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-0.29) has a shorter half-life than Ligand B (63.904). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.009) has a lower P-gp efflux liability than Ligand B (0.581), which is favorable.

**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 of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in potency (binding affinity), DILI risk, hERG inhibition, and metabolic stability. Its logP and solubility are concerning, but the strong binding affinity might compensate. Ligand B has better logP, QED, BBB, and in vitro half-life, but suffers from a much higher DILI risk, poorer metabolic stability, and weaker binding affinity.

Given the enzyme-specific priorities, potency and metabolic stability are paramount. Ligand A's superior binding affinity and lower clearance are decisive factors. While its solubility and permeability are problematic, these can potentially be addressed through formulation strategies. The higher DILI risk associated with Ligand B is a significant concern.

Output:
0
2025-04-17 11:57:47,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (64.15) is significantly better than Ligand B (37.38). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3), but Ligand B (4.812) is pushing the upper limit and could present solubility issues. Ligand A (2.797) is ideal.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=0, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.843) has a higher QED score than Ligand B (0.625), indicating a more drug-like profile.

**DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (35.673). This is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (77.511) is slightly better than Ligand B (73.401). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability & Aqueous Solubility:** Ligand A (-5.006, -1.734) shows better Caco-2 permeability and solubility than Ligand B (-4.753, -4.514).

**hERG Inhibition:** Both ligands have similar hERG inhibition liabilities (0.54 and 0.666), which is acceptable.

**Microsomal Clearance & In vitro Half-Life:** Ligand B has a significantly higher microsomal clearance (76.77) and longer half-life (60.908) than Ligand A (15.253 and 0.26 respectively). This is a major advantage for Ligand B, indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.115 and 0.811), which is good.

**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 of the ADME drawbacks. The difference of 1.0 kcal/mol is significant.

**Overall Assessment:**

Ligand A has a better overall ADME profile (lower DILI, better solubility, permeability, and QED). However, Ligand B's significantly stronger binding affinity (-8.2 vs -7.2 kcal/mol) is a critical factor for an enzyme inhibitor. The improved metabolic stability (longer half-life) of Ligand B is also a significant benefit. While Ligand B's logP is slightly higher, the potency advantage is likely to be more important.

Output:
1
2025-04-17 11:57:47,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.407 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.69) is slightly above the preferred <140 for good oral absorption, while Ligand B (71.26) is well within the range.

**logP:** Ligand A (2.576) is optimal (1-3). Ligand B (4.155) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (7/5) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.822 and 0.892), indicating good drug-like properties.

**DILI:** Ligand A (87.747) has a higher DILI risk than Ligand B (67.003), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (95.153) has a much higher BBB penetration than Ligand A (32.92).

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling. However, the values are close enough to not be a major differentiator.

**hERG:** Both ligands have similar hERG inhibition liabilities (0.452 and 0.455), which are acceptable.

**Microsomal Clearance:** Ligand B (57.196) has significantly lower microsomal clearance than Ligand A (76.892), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (16.018 hours) has a longer half-life than Ligand A (21.814 hours).

**P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.218 and 0.557), which are acceptable.

**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 the more promising candidate. While Ligand A has a slightly better half-life, Ligand B excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly improved metabolic stability (lower Cl_mic), and a slightly better binding affinity. The lower TPSA of Ligand B is also favorable. The slightly higher logP of Ligand B is a minor concern, but the benefits outweigh this potential drawback.

Output:
1
2025-04-17 11:57:47,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Ligand A:**
*   **MW:** 334.463 Da - Good (within 200-500 range)
*   **TPSA:** 32.34 A<sup>2</sup> - Excellent (well below 140)
*   **logP:** 3.681 - Good (within 1-3 range, slightly high but acceptable)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 2 - Good (<=10)
*   **QED:** 0.929 - Excellent (>=0.5)
*   **DILI:** 37.456 - Good (low risk, <40)
*   **BBB:** 91.121 - Excellent (high, but not crucial for a non-CNS target)
*   **Caco-2:** -4.788 - Poor (negative value is concerning)
*   **Solubility:** -4.246 - Poor (negative value is concerning)
*   **hERG:** 0.922 - Good (low risk)
*   **Cl_mic:** 45.81 mL/min/kg - Moderate (higher clearance, less stable)
*   **t1/2:** -7.953 hours - Excellent (very long half-life)
*   **Pgp:** 0.686 - Good (low efflux)
*   **Affinity:** -8.3 kcal/mol - Excellent (strong binding)

**Ligand B:**
*   **MW:** 349.435 Da - Good (within 200-500 range)
*   **TPSA:** 116.19 A<sup>2</sup> - Moderate (above ideal, may affect absorption)
*   **logP:** 2.356 - Good (within 1-3 range)
*   **HBD:** 2 - Good (<=5)
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.288 - Poor (below 0.5, less drug-like)
*   **DILI:** 35.479 - Good (low risk, <40)
*   **BBB:** 43.815 - Poor (low, not a concern for this target)
*   **Caco-2:** -5.214 - Poor (negative value is concerning)
*   **Solubility:** -1.994 - Poor (negative value is concerning)
*   **hERG:** 0.202 - Excellent (very low risk)
*   **Cl_mic:** 27.67 mL/min/kg - Good (lower clearance, more stable)
*   **t1/2:** 23.982 hours - Good (long half-life)
*   **Pgp:** 0.021 - Excellent (very low efflux)
*   **Affinity:** -7.9 kcal/mol - Good (strong binding, but slightly weaker than A)

**Comparison and Decision:**

Both ligands have concerning Caco-2 and Solubility values. However, Ligand A exhibits a significantly stronger binding affinity (-8.3 vs -7.9 kcal/mol). While Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, the difference isn't substantial enough to outweigh the potency advantage of Ligand A. Ligand A also has a better QED score. Given the enzyme target class, potency is paramount. The slightly higher logP of Ligand A is acceptable, and its DILI and hERG risks are low.

Output:
1
2025-04-17 11:57:47,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.383 and 346.402 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.59) is better than Ligand B (71.45), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.56 and 2.648) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (4).

**QED:** Both ligands have good QED scores (0.795 and 0.808), indicating good drug-likeness.

**DILI:** Ligand A (90.733) has a significantly higher DILI risk than Ligand B (30.903). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (69.252) is better than Ligand B (47.383).

**Caco-2 Permeability:** Ligand A (-5.412) is worse than Ligand B (-4.548), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.696) is worse than Ligand B (-3.095), indicating lower solubility.

**hERG:** Both ligands have relatively low hERG risk (0.354 and 0.405).

**Microsomal Clearance:** Ligand A (40.823) has a higher Cl_mic than Ligand B (35.404), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.367) has a significantly longer half-life than Ligand A (0.309), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.197) is preferable to Ligand B (0.13).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better TPSA, HBD, HBA, BBB and P-gp efflux, Ligand B excels in the critical areas for an enzyme inhibitor: significantly lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and longer half-life), and slightly better binding affinity. The higher DILI risk for Ligand A is a major red flag.

Output:
1
2025-04-17 11:57:47,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.415 and 344.411 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.42) is slightly higher than Ligand B (66.9). While both are under the 140 threshold for oral absorption, Ligand B's lower TPSA is preferable for better absorption.

**3. logP:** Both ligands have logP values within the optimal 1-3 range (1.505 and 2.816). Ligand B is slightly higher, which could potentially lead to some off-target interactions, but is 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 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have very similar QED values (0.807 and 0.808), indicating good drug-like properties.

**7. DILI:** Ligand B (24.157) has a significantly lower DILI risk than Ligand A (45.056). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (77.976) has a higher BBB penetration percentile than Ligand A (57.968). While not a primary concern for a non-CNS target like SRC, it's a slight positive for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.111) has worse Caco-2 permeability than Ligand B (-4.656). Lower (more negative) values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.884) has slightly worse solubility than Ligand B (-2.149). Both are negative, indicating poor solubility, but Ligand B is better.

**11. hERG Inhibition:** Ligand A (0.119) has a slightly lower hERG inhibition liability than Ligand B (0.614). This is a slight advantage for Ligand A, but both are relatively low risk.

**12. Microsomal Clearance:** Ligand A (14.334) has a lower microsomal clearance than Ligand B (21.641), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-15.137) has a much longer in vitro half-life than Ligand B (3.836). This is a major advantage for Ligand A, suggesting less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.027) has lower P-gp efflux liability than Ligand B (0.286). This is a positive for Ligand A.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.6). While the difference is small (0.2 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand B has advantages in binding affinity, lower DILI risk, better Caco-2 permeability, and better solubility. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. The difference in binding affinity is small, and the improvements in ADME properties for Ligand A, particularly the significantly longer half-life and lower DILI, are more critical for an enzyme target like SRC kinase. The longer half-life translates to potentially less frequent dosing, a major benefit. The lower DILI risk is also crucial for safety.

Output:
1
2025-04-17 11:57:47,019 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [346.471, 69.64, 2.287, 2, 3, 0.83, 24.777, 46.375, -4.354, -2.372, 0.449, 35.148, 16.044, 0.16, -8.3]
**Ligand B:** [375.535, 71.11, 0.438, 1, 6, 0.597, 21.404, 66.809, -5.218, -1.194, 0.249, 4.927, -2.225, 0.01, -6.2]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (346.471) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** Both are reasonably low (A: 69.64, B: 71.11), suggesting good potential for oral absorption.
3. **logP:** A (2.287) is optimal. B (0.438) is quite low, potentially hindering membrane permeability and absorption. This is a significant drawback for B.
4. **HBD:** Both are acceptable (A: 2, B: 1).
5. **HBA:** Both are acceptable (A: 3, B: 6). B is higher, but still within the reasonable limit of 10.
6. **QED:** A (0.83) is excellent, indicating a very drug-like profile. B (0.597) is acceptable but less favorable.
7. **DILI:** Both have low DILI risk (A: 24.777, B: 21.404), which is good.
8. **BBB:** B (66.809) has a better BBB penetration potential than A (46.375), but this isn't a primary concern for a non-CNS target like SRC.
9. **Caco-2:** A (-4.354) is significantly better than B (-5.218), indicating better intestinal absorption.
10. **Solubility:** A (-2.372) is better than B (-1.194), which is important for bioavailability.
11. **hERG:** Both have low hERG risk (A: 0.449, B: 0.249).
12. **Cl_mic:** A (35.148) has higher metabolic clearance than B (4.927), meaning B is more metabolically stable. This is a positive for B.
13. **t1/2:** A (16.044) has a longer half-life than B (-2.225). This is a positive for A.
14. **Pgp:** Both have low P-gp efflux (A: 0.16, B: 0.01), which is good.
15. **Binding Affinity:** A (-8.3) has a significantly stronger binding affinity than B (-6.2). This is a crucial advantage for A. A difference of 2.1 kcal/mol is substantial and can often outweigh minor ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A is significantly better.
*   **Metabolic Stability:** B is better (lower Cl_mic).
*   **Solubility:** A is better.
*   **hERG:** Both are good.
*   **Half-life:** A is better.

**Conclusion:**

Despite B having better metabolic stability and BBB penetration, the significantly stronger binding affinity of A (-8.3 kcal/mol vs -6.2 kcal/mol), combined with its better solubility, Caco-2 permeability, and half-life, makes it the more promising drug candidate. The lower logP of B is a significant concern, potentially hindering its absorption. The substantial affinity advantage of A outweighs the slightly higher clearance.

Output:
1
2025-04-17 11:57:47,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.479 and 354.416 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.79) is well below the 140 threshold, suggesting good absorption. Ligand B (33.2) is even better, indicating potentially excellent absorption.

**logP:** Ligand A (1.898) is within the optimal 1-3 range. Ligand B (4.671) 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 7 HBA, both within acceptable limits. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.725 and 0.667), suggesting good drug-like properties.

**DILI:** Ligand A (20.861) has a much lower DILI risk than Ligand B (24.544), which is preferable. Both are below the 40 threshold.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (92.051) shows higher BBB penetration than Ligand A (53.625).

**Caco-2 Permeability:** Ligand A (-5.427) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.511) is also negative, but less so.

**Aqueous Solubility:** Ligand A (-1.605) has slightly better aqueous solubility than Ligand B (-4.698).

**hERG Inhibition:** Ligand A (0.169) has a lower hERG risk than Ligand B (0.712), which is a significant advantage.

**Microsomal Clearance:** Ligand A (11.737) has significantly lower microsomal clearance than Ligand B (64.995), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (19.425) has a longer in vitro half-life than Ligand B (3.649), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux liability than Ligand B (0.493), which is favorable.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a *substantially* stronger binding affinity than Ligand B (-7.0 kcal/mol). This difference of 2.4 kcal/mol is a major advantage, easily outweighing any minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has a slightly better logP and BBB, Ligand A excels in the crucial areas for a kinase inhibitor: significantly higher binding affinity, lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and lower P-gp efflux. The negative Caco-2 values are concerning for both, but the superior potency and safety profile of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 11:57:47,020 - INFO - Batch 90 complete. Total preferences: 1440
2025-04-17 11:57:47,020 - INFO - Processing batch 91/512...
2025-04-17 11:58:26,949 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.39 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (49.85), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.765) is slightly below the optimal 1-3 range, while Ligand B (3.143) is within the optimal range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 10.

**QED:** Both ligands have similar QED values (0.681 and 0.632), indicating good drug-likeness.

**DILI:** Ligand A (33.695) has a significantly lower DILI risk than Ligand B (16.906), which is a major advantage.

**BBB:** Ligand A (76.658) and Ligand B (90.461) both have high BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.528 and -4.481). This 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 (-2.279 and -2.092). This is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.093) has a lower hERG inhibition liability than Ligand B (0.635), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (75.58) has a significantly lower microsomal clearance than Ligand A (8.919), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-5.49) has a shorter in vitro half-life than Ligand B (-4.897), indicating faster metabolism.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.389).

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has a better logP and significantly better metabolic stability (lower Cl_mic, longer t1/2), Ligand A has a much lower DILI risk and lower hERG liability. Given the enzyme-specific priorities, metabolic stability is highly important. However, the significantly lower DILI and hERG risk of Ligand A are also very important considerations. Since the binding affinity is identical, the lower toxicity profile of Ligand A makes it the more viable candidate.

Output:
0
2025-04-17 11:58:26,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (339.443 and 350.438 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.05) is well below the 140 threshold for oral absorption, and even below the 90 for CNS penetration. Ligand B (78.09) is also below 140, but higher than A.

**3. logP:** Both ligands have good logP values (3.756 and 2.354), 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 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have similar and good QED values (0.871 and 0.856), indicating good drug-like properties.

**7. DILI:** Ligand A (38.62) has a lower DILI risk than Ligand B (50.097), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (80.962) has better BBB penetration than Ligand B (70.997), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.741 and -4.905). This 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 negative solubility values (-4.056 and -3.444), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.676 and 0.438), which is excellent.

**12. Microsomal Clearance:** Ligand B (29.792) has significantly lower microsomal clearance than Ligand A (59.673), suggesting better metabolic stability. This is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-31.544) has a much longer in vitro half-life than Ligand A (21.728), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.158 and 0.091).

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.8 kcal/mol).

**Overall Assessment:**

While both ligands have excellent binding affinity and acceptable physicochemical properties, Ligand B is superior due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The poor solubility and permeability (indicated by negative Caco-2 and solubility values) are concerning for both, but the metabolic advantage of Ligand B outweighs these concerns. Given that SRC is an enzyme, metabolic stability is a critical factor.

Output:
1
2025-04-17 11:58:26,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.467 and 356.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.68) is slightly higher than Ligand B (62.98). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Ligand A (3.315) is within the optimal 1-3 range. Ligand B (4.505) is a bit higher, potentially leading to solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 6. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.665 and 0.712), indicating good drug-like properties.

**DILI:** Ligand A (64.87) has a higher DILI risk than Ligand B (56.146). Lower is better, so Ligand B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.95) has a higher BBB score than Ligand A (45.715).

**Caco-2 Permeability:** Ligand A (-4.772) has a worse Caco-2 permeability than Ligand B (-5.282). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.802) has a worse solubility than Ligand B (-4.748). Higher values indicate better solubility.

**hERG Inhibition:** Ligand A (0.398) has a slightly lower hERG risk than Ligand B (0.73). Lower is better.

**Microsomal Clearance:** Ligand A (88.867) has a higher microsomal clearance than Ligand B (80.18). Lower clearance is preferred for better metabolic stability, so Ligand B is preferable.

**In vitro Half-Life:** Ligand B (78.824) has a significantly longer in vitro half-life than Ligand A (-4.423). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.502) has a lower P-gp efflux liability than Ligand B (0.353). Lower efflux 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 substantial advantage, potentially outweighing some minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better hERG profile and P-gp efflux, Ligand B excels in the most crucial areas for an enzyme inhibitor: significantly better binding affinity, longer half-life, lower DILI risk, better solubility, and better Caco-2 permeability. The slightly higher logP of Ligand B is a minor concern, but the substantial improvement in potency and metabolic stability makes it the more promising drug candidate.

Output:
1
2025-04-17 11:58:26,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (349.402 and 354.397 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.63) is better than Ligand B (69.64), both are below the 140 threshold for oral absorption, but closer to the 90 threshold is better.

**3. logP:** Both ligands (2.49 and 2.791) 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 (3). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.83 and 0.791), indicating good drug-likeness.

**7. DILI:** Ligand B (23.42) has a significantly lower DILI risk than Ligand A (46.956), making it more attractive from a safety perspective.

**8. BBB:** Ligand A (95.153) has a higher BBB penetration percentile than Ligand B (74.913). However, since SRC is not a CNS target, this is less important.

**9. Caco-2 Permeability:** Ligand A (-4.737) has slightly better Caco-2 permeability than Ligand B (-4.707), but the difference is minimal.

**10. Aqueous Solubility:** Ligand A (-3.497) has slightly better aqueous solubility than Ligand B (-3.198), but the difference is minimal.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.699 and 0.68), which is acceptable.

**12. Microsomal Clearance:** Ligand B (21.411) has significantly lower microsomal clearance than Ligand A (46.235), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-3.09) has a significantly longer in vitro half-life than Ligand A (16.611), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.319 and 0.078).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override the ADME advantages of Ligand B.

**Conclusion:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has slightly better Caco-2 and solubility, Ligand B's significantly lower DILI risk, lower microsomal clearance, and longer half-life outweigh these minor differences. The binding affinity is comparable between the two.

Output:
1
2025-04-17 11:58:26,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.39 Da) is slightly lower, which could be beneficial for permeability. Ligand B (399.292 Da) is also good.

**TPSA:** Ligand A (85.09) is better than Ligand B (61.92) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Both ligands have good logP values (A: 3.285, B: 3.471), falling within the optimal range of 1-3.

**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 (A: 0.692, B: 0.699), indicating good drug-likeness.

**DILI:** Ligand A (80.225) has a higher DILI risk than Ligand B (55.797). This is a significant concern.

**BBB:** Ligand A (32.183) has a much lower BBB penetration than Ligand B (54.595). Since SRC is not a CNS target, this is less critical, but a higher BBB value is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.266) has a worse Caco-2 permeability than Ligand B (-4.803).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.07 for A, -3.888 for B). This is a concern for both, but Ligand B is slightly worse.

**hERG Inhibition:** Ligand A (0.111) has a slightly lower hERG inhibition risk than Ligand B (0.909). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (19.11 mL/min/kg) has significantly lower microsomal clearance than Ligand B (73.793 mL/min/kg). This suggests better metabolic stability for Ligand A, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand A (46.427 hours) has a much longer in vitro half-life than Ligand B (10.987 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.372) has lower P-gp efflux than Ligand B (0.551), which is favorable.

**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, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly lower hERG risk, the significantly stronger binding affinity of Ligand B (-9.3 vs -7.7 kcal/mol) is the most crucial factor for an enzyme inhibitor. The higher DILI risk for Ligand A is also a major concern. The improved affinity of Ligand B is likely to translate to greater efficacy and could potentially allow for a lower dose, mitigating some of the ADME concerns.

Output:
1
2025-04-17 11:58:26,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.455 and 366.849 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.46 and 85.77) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.951) is optimal, while Ligand B (0.378) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Both 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 (0.87 and 0.786), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 61.613, which is moderately high. Ligand B has a much lower DILI risk of 28.461, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (43.273) and Ligand B (30.787) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.298 and -5.025), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.128 and -1.618), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.26 and 0.113), which is excellent.

**Microsomal Clearance:** Ligand A has a very low (and favorable) Cl_mic of -0.067 mL/min/kg, suggesting high metabolic stability. Ligand B has a high Cl_mic of -43.083 mL/min/kg, indicating rapid metabolism and a potential issue with dosing.

**In vitro Half-Life:** Ligand A has a half-life of 11.981 hours, which is reasonable. Ligand B has a longer half-life of 23.785 hours, which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.1 and 0.012), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Conclusion:**

While both compounds have excellent binding affinity and low hERG risk, Ligand B is the better candidate. Its significantly lower DILI risk and longer half-life outweigh the slight disadvantage in logP and solubility. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. Ligand A's high DILI risk and rapid metabolism are more problematic.

Output:
1
2025-04-17 11:58:26,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (346.383 and 345.403 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.15) is better than Ligand B (95.33), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Both ligands have similar logP values (1.514 and 1.682), 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 4 HBAs, and Ligand B has 5. Both are below the limit of <=10.

**6. QED:** Both ligands have high QED scores (0.873 and 0.913), indicating good drug-like properties.

**7. DILI:** Ligand A (50.523) has a significantly lower DILI risk than Ligand B (66.964). This is a crucial advantage.

**8. BBB:** Ligand A (76.037) has a better BBB percentile than Ligand B (38.077), but this is less important for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, indicating very poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.02 and 0.154), which is excellent.

**12. Microsomal Clearance:** Ligand A (22.417) has a lower microsomal clearance than Ligand B (51.093), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-18.46) has a much longer in vitro half-life than Ligand B (-39.416). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.02).

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

**Overall Assessment:**

Given the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While both have poor Caco-2 and solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The binding affinity is identical, so these ADME advantages outweigh any minor drawbacks.

Output:
0
2025-04-17 11:58:26,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.412 Da) is slightly higher than Ligand B (355.435 Da), but both are acceptable.

**TPSA:** Ligand A (88.16) is better than Ligand B (96.97) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (2.294) is optimal (1-3). Ligand B (-0.327) is below 1, which could impede 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 are within the acceptable limit of <=10.

**QED:** Ligand A (0.786) has a better QED score than Ligand B (0.59), indicating a more drug-like profile.

**DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (9.461). This is a concern for Ligand A.

**BBB:** Ligand A (53.742) and Ligand B (67.584) are both relatively low, which is not a major concern for a kinase inhibitor not targeting the CNS.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.249 and -5.029). 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 (-3.144 and -1.299). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.258) has a lower hERG risk than Ligand B (0.096), which is favorable.

**Microsomal Clearance:** Ligand A (13.883) has a higher microsomal clearance than Ligand B (-1.608). This means Ligand B is likely more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (54.995) has a longer half-life than Ligand B (-12.821). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.238) has lower P-gp efflux than Ligand B (0.001), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a significant advantage in terms of metabolic stability (lower Cl_mic) and a much lower DILI risk. While its logP is suboptimal, the strong binding affinity mitigates this somewhat. Ligand A has a better QED and hERG risk, but the higher DILI and higher clearance are concerning. The solubility and permeability issues are present in both, but the metabolic stability is a more critical factor for kinase inhibitors.

Output:
1
2025-04-17 11:58:26,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.479 and 357.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.94) is significantly better than Ligand B (105.25). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (1.127) is within the optimal 1-3 range. Ligand B (-0.991) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**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 (0.772) has a better QED score than Ligand B (0.587), indicating a more drug-like profile.

**DILI:** Ligand A (10.237) has a much lower DILI risk than Ligand B (38.736). This is a significant advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (61.962 and 62.233), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.269 and -5.03), which is unusual and suggests poor permeability. However, these values are on a log scale, so the difference isn't huge.

**Aqueous Solubility:** Both have negative solubility values (-0.107 and -0.331), indicating poor solubility. This is a concern, but can be addressed with formulation strategies.

**hERG:** Both ligands have very low hERG inhibition risk (0.489 and 0.077). This is excellent.

**Microsomal Clearance:** Ligand A (-3.64) has significantly better metabolic stability (lower clearance) than Ligand B (33.586). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (18.141) has a better in vitro half-life than Ligand B (-5.21).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.006).

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** While both ligands have good potency, Ligand A demonstrates superior ADMET properties: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a higher QED score. The slightly better TPSA and logP values also contribute to its favorability. Although both have poor solubility and Caco-2 permeability, these issues can potentially be mitigated through formulation. The significant advantage in metabolic stability and DILI risk makes Ligand A the preferred choice for further development.

Output:
1
2025-04-17 11:58:26,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.547 and 356.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold and excellent for oral absorption. Ligand B (129.56) is still within acceptable limits but less favorable than A.

**logP:** Ligand A (4.138) is slightly above the optimal 1-3 range, potentially leading to solubility issues or off-target effects, but not drastically. Ligand B (-2.151) is significantly below the optimal range, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (3 HBD, 7 HBA) is acceptable, but higher counts could affect permeability.

**QED:** Ligand A (0.732) has a strong drug-like profile. Ligand B (0.455) is below the desirable 0.5 threshold, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (22.722) has a very low DILI risk. Ligand B (60.217) has a moderately elevated DILI risk, though not critically high.

**BBB:** Ligand A (82.474) shows reasonable BBB penetration, while Ligand B (14.23) is very poor. While not a primary concern for a kinase inhibitor, it's a slight advantage for A.

**Caco-2 Permeability:** Ligand A (-4.688) is poor, indicating low intestinal absorption. Ligand B (-5.535) is also poor, but slightly worse than A.

**Aqueous Solubility:** Ligand A (-3.374) is poor. Ligand B (-1.211) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.699) has a low hERG risk. Ligand B (0.133) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (67.607) has moderate clearance. Ligand B (1.517) has very low clearance, indicating excellent metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand A (-12.669) has a negative half-life, which is nonsensical. This is a major red flag. Ligand B (-2.308) also has a negative half-life, which is also a major red flag.

**P-gp Efflux:** Both ligands (0.503 and 0.008) show low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands (-9 and -8 kcal/mol) have excellent binding affinity. The difference of 1 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite both ligands having good binding affinity, Ligand A has a nonsensical in vitro half-life, making it a poor candidate. Ligand B also has a nonsensical in vitro half-life, but has better metabolic stability (lower Cl_mic) and slightly better solubility. However, its lower logP and QED are concerning. Considering the enzyme-specific priorities, metabolic stability is crucial. Given the issues with both half-lives, I would still lean towards Ligand B due to its superior metabolic stability.

Output:
1
2025-04-17 11:58:26,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.385 Da and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is well below the 140 threshold, and good for oral absorption. Ligand B (93.26) is also below the threshold, but closer.

**logP:** Both ligands have optimal logP values (2.092 and 1.487, respectively), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**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 high QED scores (0.902 and 0.856), indicating good drug-like properties.

**DILI:** Ligand A (40.83) has a slightly higher DILI risk than Ligand B (54.634), but both are below the concerning threshold of 60.

**BBB:** Ligand A (92.827) has significantly better BBB penetration than Ligand B (68.282). While not a primary concern for a kinase inhibitor, it's a potential advantage.

**Caco-2 Permeability:** Ligand A (-4.685) has a worse Caco-2 permeability than Ligand B (-5.055).

**Aqueous Solubility:** Ligand A (-2.57) has better aqueous solubility than Ligand B (-1.788). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.458) has a much lower hERG inhibition liability than Ligand B (0.084). This is a significant advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (-10.61) has a much lower microsomal clearance than Ligand B (48.946). This indicates better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-5.258) has a much longer in vitro half-life than Ligand B (-23.603). This is another strong indicator of better metabolic stability and potentially less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.057 respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 kcal/mol and -8.4 kcal/mol). Ligand A is slightly better.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better Caco-2 permeability, Ligand A excels in crucial areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity. The better solubility of Ligand A is also a plus. The slightly higher DILI risk for Ligand A is not a major concern given the overall profile.

Output:
1
2025-04-17 11:58:26,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.463 and 353.388 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is higher than Ligand B (38.13). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have similar logP values (4.23 and 4.398), slightly above the optimal range of 1-3, but not drastically so. This could potentially lead to some solubility issues, but isn't a major concern at this stage.

**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 good QED scores (0.834 and 0.799), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (81.427%) compared to Ligand B (52.772%). This is a major red flag for Ligand A.

**BBB:** Ligand A (70.919%) has moderate BBB penetration, while Ligand B (91.121%) has excellent BBB penetration. While SRC is not necessarily a CNS target, better BBB penetration generally correlates with better overall bioavailability and distribution.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.544 and -4.309), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.859 and -4.521). This is a significant drawback for both compounds and would require formulation strategies.

**hERG Inhibition:** Ligand A (0.295) has a slightly higher hERG inhibition risk than Ligand B (0.833), but both are relatively low.

**Microsomal Clearance:** Ligand A (111.24) has a much higher microsomal clearance than Ligand B (43.154). This indicates that Ligand A will be metabolized more quickly, leading to a shorter half-life and potentially lower efficacy.

**In vitro Half-Life:** Ligand A (29.664) has a shorter half-life than Ligand B (-18.538). The negative value for Ligand B is unusual, but it still indicates better stability compared to Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.36 and 0.461), which is good.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although the difference is relatively small.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both ligands have poor solubility and permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, better half-life), lower DILI risk, and better BBB penetration. The slightly improved binding affinity of Ligand B further supports this conclusion. The enzyme-specific priorities of potency and metabolic stability heavily favor Ligand B.

Output:
1
2025-04-17 11:58:26,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Ligand A (453.324 Da) is within the ideal range, while Ligand B (358.389 Da) is also acceptable, though slightly lower.
**TPSA:** Ligand A (53.6) is good for oral absorption. Ligand B (87.32) is higher, potentially impacting absorption, but not drastically.
**logP:** Ligand A (4.468) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.897) is low, which could hinder permeation.
**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit.
**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both acceptable.
**QED:** Both ligands have good QED scores (0.609 and 0.723).
**DILI:** Ligand A has a DILI risk of 65.684, which is moderately high. Ligand B has a much lower DILI risk of 36.254, which is preferable.
**BBB:** Both ligands have similar BBB penetration (68.554 and 62.97), which isn't a primary concern for a non-CNS target like SRC.
**Caco-2:** Both have negative Caco-2 values which is unusual and potentially problematic.
**Solubility:** Ligand A has a very poor solubility (-5.244). Ligand B has a slightly better, but still poor, solubility (-1.741).
**hERG:** Ligand A has a low hERG risk (0.904), which is good. Ligand B also has a low hERG risk (0.585).
**Cl_mic:** Ligand A has a moderate microsomal clearance (113.274 mL/min/kg). Ligand B has a very low (and favorable) clearance (-16.997 mL/min/kg), indicating better metabolic stability.
**t1/2:** Ligand A has a moderate in vitro half-life (57.759 hours). Ligand B has a very short in vitro half-life (-15.714 hours), which is a significant drawback.
**Pgp:** Ligand A has a low Pgp efflux liability (0.594). Ligand B also has a low Pgp efflux liability (0.024).
**Binding Affinity:** Both ligands have excellent binding affinities (-7.2 and -7.3 kcal/mol), with Ligand B being slightly better.

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand B is the more promising candidate. Its significantly lower DILI risk and dramatically improved metabolic stability (lower Cl_mic) outweigh its slightly lower logP and shorter half-life. The solubility of both is poor, but this can be addressed through formulation strategies. Ligand A's higher logP and DILI risk are more concerning. The negative Caco-2 values are concerning for both, and would need investigation.

Output:
1
2025-04-17 11:58:26,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (372.462 Da) is also well within range.

**TPSA:** Ligand A (138.78) is close to the upper limit for good oral absorption (<=140), while Ligand B (84.5) is excellent.

**logP:** Ligand A (-1.421) is a bit low, potentially hindering permeation. Ligand B (1.875) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 6 HBA, acceptable values. Ligand B has 2 HBD and 4 HBA, also acceptable and potentially better for permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.327, B: 0.765), but Ligand B is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (15.083) has a very low DILI risk, which is excellent. Ligand B (60.217) is approaching a higher risk level, but not critically high.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable, and other parameters should be considered.

**Aqueous Solubility:** Ligand A (-0.014) has very poor solubility, a significant drawback. Ligand B (-3.389) also has poor solubility, but is slightly better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.045, B: 0.38).

**Microsomal Clearance:** Ligand A (-1.767) has a negative clearance, which is not physically possible and likely indicates a data error or an *in vitro* to *in vivo* extrapolation issue. Ligand B (52.664) has a high clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (-18.103) has a negative half-life, which is not physically possible and indicates a data error. Ligand B (-5.794) has a short half-life, indicating rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.007, B: 0.161).

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -9.5 kcal/mol, B: -8.7 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its extremely poor solubility, and the physically impossible clearance and half-life values make it a very unlikely candidate. Ligand B, while having a higher DILI risk and poorer metabolic stability, has a better overall profile with a more reasonable QED, logP, TPSA, and acceptable hERG risk. The solubility is still a concern, but potentially addressable through formulation strategies. The negative values for Caco-2 and half-life are concerning, but the other properties of Ligand B are superior to Ligand A.

Output:
1
2025-04-17 11:58:26,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.467 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (28.6) is significantly better than Ligand B (78.87). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.382) is optimal, while Ligand B (1.659) 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, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.858) has a significantly higher QED score than Ligand B (0.642), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (14.385 and 14.424, respectively).

**BBB:** Ligand A (97.674) has a much higher BBB percentile than Ligand B (51.377). While SRC is not a CNS target, higher BBB can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.504) is slightly better than Ligand B (-4.774), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.341 and -2.058). This is a significant concern for both, but may be mitigated by formulation strategies.

**hERG Inhibition:** Ligand A (0.949) has a slightly better hERG profile than Ligand B (0.207), meaning lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (47.982) has significantly lower microsomal clearance than Ligand B (66.832), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.421) has a much longer in vitro half-life than Ligand B (1.198), which is a major advantage.

**P-gp Efflux:** Ligand A (0.338) has lower P-gp efflux liability than Ligand B (0.047), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While a 1.5 kcal/mol advantage is usually significant, the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the far more promising drug candidate. It has superior drug-likeness (QED), permeability (TPSA, Caco-2), metabolic stability (Cl_mic, t1/2), lower P-gp efflux, and a better safety profile (hERG). The solubility is a concern for both, but the other advantages of Ligand A outweigh this drawback. The significantly better ADME profile of Ligand A suggests it will have better *in vivo* exposure and efficacy.

Output:
0
2025-04-17 11:58:26,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.438 and 353.809 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.92) is better than Ligand B (50.75), both are below 140, suggesting good absorption potential.

**3. logP:** Ligand A (1.916) is optimal (1-3), while Ligand B (4.454) is higher, potentially leading to solubility issues and off-target effects.

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

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.706) has a better QED score than Ligand B (0.498), indicating a more drug-like profile.

**7. DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (71.113), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.168) has better BBB penetration than Ligand B (64.211), but it's not a primary concern here.

**9. Caco-2 Permeability:** Ligand A (-4.118) is better than Ligand B (-5.196), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.837) is better than Ligand B (-3.907), which is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.223) has a much lower hERG inhibition risk than Ligand B (0.702), a critical safety parameter.

**12. Microsomal Clearance:** Ligand A (50.452) has lower microsomal clearance than Ligand B (77.615), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (96.773) has a significantly longer in vitro half-life than Ligand A (-9.628). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.79), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-9.628). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a significantly better safety profile (lower DILI, hERG), better ADME properties (solubility, permeability, metabolic stability, P-gp efflux), and a better QED score. The difference in binding affinity (-8.0 vs -9.628) is not large enough to overcome the substantial ADME/Tox advantages of Ligand A, especially considering SRC is an enzyme target where metabolic stability and safety are paramount. The longer half-life of Ligand B is a positive, but can potentially be addressed through formulation or structural modifications.

Output:
0
2025-04-17 11:58:26,953 - INFO - Batch 91 complete. Total preferences: 1456
2025-04-17 11:58:26,953 - INFO - Processing batch 92/512...
2025-04-17 11:59:07,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.419 and 345.403 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.22) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (98.97) is still acceptable but less optimal.

**3. logP:** Ligand A (0.2) is a bit low, potentially hindering permeation. Ligand B (-0.507) is even lower, raising concerns about membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher HBD can sometimes impact permeability.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.689 and 0.628), indicating good drug-like properties.

**7. DILI:** Ligand A (31.059) has a significantly lower DILI risk than Ligand B (41.877), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (76.309) is better than Ligand B (26.25).

**9. Caco-2 Permeability:** Ligand A (-4.918) is significantly better than Ligand B (-5.537), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.225) is better than Ligand B (-1.755), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.045) has a very low hERG risk, while Ligand B (0.316) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (1.89) has a much lower Cl_mic than Ligand B (-6.083), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.227) has a negative half-life, which is unusual and suggests very high stability. Ligand B (12.519) is a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, while Ligand B (0.004) is even lower. This is not a major concern for either.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile, with lower DILI risk, better solubility, better Caco-2 permeability, and significantly better metabolic stability (lower Cl_mic). While Ligand B has slightly better binding affinity, the ADME advantages of Ligand A are more critical for overall drug development success, especially for an enzyme target where metabolic stability and bioavailability are crucial.

Output:
1
2025-04-17 11:59:07,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is better than Ligand B (91.64). Both are below 140, but A is closer to the preferred value for good absorption.

**logP:** Ligand A (3.002) is optimal (1-3). Ligand B (-0.02) is significantly lower, potentially hindering permeation.

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

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

**QED:** Ligand A (0.769) is excellent, indicating strong drug-likeness. Ligand B (0.56) is acceptable, but lower.

**DILI:** Ligand A (43.66) has a lower DILI risk than Ligand B (35.944), indicating a better safety profile.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.921) is better than Ligand B (30.593).

**Caco-2 Permeability:** Ligand A (-4.743) is better than Ligand B (-5.177). Both are negative, indicating low permeability, but A is less negative.

**Aqueous Solubility:** Ligand A (-3.704) is better than Ligand B (-0.894). Both are negative, indicating poor solubility, but A is less negative.

**hERG:** Ligand A (0.359) has a lower hERG risk than Ligand B (0.157).

**Microsomal Clearance:** Ligand A (90.64) has higher clearance than Ligand B (20.539). This means Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-16.536) has a shorter half-life than Ligand B (-6.954). Again, Ligand B is preferable.

**P-gp Efflux:** Ligand A (0.446) has higher P-gp efflux than Ligand B (0.063). Ligand B is preferable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B has significantly better ADME properties, specifically lower microsomal clearance, longer half-life, lower P-gp efflux, and better solubility. Ligand A has a better TPSA and DILI score, but the metabolic stability and permeability advantages of Ligand B are more crucial for an enzyme target like SRC kinase. The lower logP of Ligand B is a concern, but the strong binding affinity may compensate for this.

Output:
1
2025-04-17 11:59:07,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.426 and 366.315 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.16) is better than Ligand B (87.32), both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand B (1.348) is better than Ligand A (0.023). A logP between 1-3 is optimal, and Ligand A is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is acceptable.

**QED:** Both ligands have similar QED values (0.769 and 0.744), indicating good drug-likeness.

**DILI:** Ligand A (22.102) is significantly better than Ligand B (59.946). Lower DILI is crucial. Ligand B is approaching a concerning percentile.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (64.25) is better than Ligand A (46.568).

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the absolute value for Ligand A (-4.48) is less negative than Ligand B (-4.9), suggesting slightly better permeability.

**Aqueous Solubility:** Ligand A (-0.47) is better than Ligand B (-2.453). Higher solubility is preferred.

**hERG Inhibition:** Ligand A (0.194) is significantly better than Ligand B (0.412). Lower hERG inhibition is critical to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand B (-4.792) has a *negative* clearance, which is not physically possible and indicates an error or outlier in the data. Ligand A (10.211) is reasonable. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand B (-26.919) has a negative half-life, also not physically possible and indicating a data issue. Ligand A (-20.621) is also negative, but less so.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.045).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.4 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the superior candidate. While Ligand B has a slightly better logP and BBB, it suffers from significantly higher DILI risk, higher hERG inhibition, and *impossible* values for microsomal clearance and half-life. Ligand A has better solubility, lower DILI and hERG, and more plausible ADME properties. The binding affinity is comparable. The negative values for clearance and half-life in Ligand B are red flags that suggest data quality issues.

Output:
0
2025-04-17 11:59:07,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (339.395 and 346.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.86) is slightly above the preferred <140, but still acceptable. Ligand B (58.64) is well within the acceptable range.

**3. logP:** Both ligands (2.718 and 2.431) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors (HBA):** Ligand A (5) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.749 and 0.796), indicating drug-like properties.

**7. DILI:** Ligand A (66.731) has a higher DILI risk than Ligand B (36.681). This is a significant concern.

**8. BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (75.107) has a higher BBB percentile than Ligand A (32.532).

**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 not specified, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.647 and 0.327).

**12. Microsomal Clearance (Cl_mic):** Ligand A (99.192) has a very high microsomal clearance, indicating poor metabolic stability. Ligand B (27.452) has much lower clearance, which is preferable.

**13. In vitro Half-Life (t1/2):** Ligand A (-42.251) has a very short half-life, which is unfavorable. Ligand B (2.593) has a slightly longer half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.401 and 0.14).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Comparison:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. While both have similar affinity, the ADME properties of Ligand B are far more favorable. The negative solubility and Caco-2 values are concerning for both, but the metabolic stability and DILI risk are more critical for kinase inhibitors.

Output:
1
2025-04-17 11:59:07,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.336 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.15) is better than Ligand B (58.44), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (2.394) is optimal (1-3), while Ligand A (0.168) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**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 good QED scores (0.701 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (43.234), both are below the 40 threshold.

**BBB:** Both ligands have acceptable BBB penetration (76.309 and 72.082). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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:** Ligand A (0.253) has a lower hERG risk than Ligand B (0.527), which is preferable.

**Microsomal Clearance:** Ligand A (13.717) has significantly lower microsomal clearance than Ligand B (56.925), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-32.37) has a more negative in vitro half-life, which is unusual and suggests a very short half-life. Ligand B (-10.029) is also negative, but less so.

**P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux liability than Ligand B (0.291), which is favorable.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.2), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, hERG, and P-gp efflux) and better metabolic stability (lower Cl_mic). While its logP is low, its superior metabolic stability and safety profile outweigh this drawback. Ligand B has slightly better binding affinity, but the ADME properties are less favorable. Given the enzyme-specific priorities, metabolic stability and safety are crucial.

Output:
0
2025-04-17 11:59:07,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.402 and 358.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.63) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for good oral absorption, but B is better.

**3. logP:** Both ligands (2.066 and 2.344) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) 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 (0.816 and 0.793) have excellent drug-likeness scores, well above 0.5.

**7. DILI:** Ligand A (27.142) and Ligand B (22.761) both have low DILI risk, well below the 40 threshold. B is slightly better.

**8. BBB:** Ligand A (66.305) and Ligand B (86.817) are both acceptable, but not particularly high. BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.401 and -4.584), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.615 and -2.367), also unusual and concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Ligand A (0.34) and Ligand B (0.428) both have low hERG risk, which is positive.

**12. Microsomal Clearance:** Ligand A (23.792) has a higher microsomal clearance than Ligand B (8.975). This indicates that Ligand B is more metabolically stable, which is a key priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (6.495) and Ligand B (6.432) have similar in vitro half-lives.

**14. P-gp Efflux:** Ligand A (0.074) and Ligand B (0.039) both have low P-gp efflux, which is good.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This 0.3 kcal/mol difference is significant, but needs to be weighed against the ADME properties.

**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 a slightly lower DILI risk. The negative Caco-2 and solubility values for both are concerning and would require further investigation (e.g., salt formation, formulation strategies). However, given the enzyme-specific priorities, the improved metabolic stability of Ligand B makes it the more promising candidate. The affinity difference is not large enough to overcome the ADME advantages of Ligand B.

Output:
1
2025-04-17 11:59:07,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.913 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is better than Ligand B (87.74), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.285) is optimal (1-3), while Ligand B (0.683) is a bit low, potentially hindering permeation.

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

**QED:** Both ligands have good QED scores (0.572 and 0.705), indicating drug-likeness.

**DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (7.445). This is a significant negative for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand B (76.154) has a higher BBB score than Ligand A (47.15).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the absolute value is smaller for Ligand A (-4.22 vs -4.876), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.22) is slightly better than Ligand B (-1.344).

**hERG:** Ligand A (0.297) has a lower hERG risk than Ligand B (0.163), which is favorable.

**Microsomal Clearance:** Ligand A (74.323) has significantly higher microsomal clearance than Ligand B (11.121), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-13.069) has a negative half-life, which is not possible. This is a red flag. Ligand A (36.84) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.012), which is better.

**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 could outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity and acceptable metabolic properties despite higher DILI. Ligand B has a very low clearance, but a significantly weaker binding affinity and a problematic negative in vitro half-life. The DILI risk for Ligand A is concerning, but potentially manageable with structural modifications. The negative half-life for Ligand B is a showstopper.

Output:
0
2025-04-17 11:59:07,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (332.367 and 343.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.49) is better than Ligand B (46.61) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (2.919) is optimal, while Ligand B (4.287) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (0 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.604 and 0.605), indicating good drug-likeness.

**DILI:** Ligand A (88.329) has a higher DILI risk than Ligand B (52.385), which is a concern.

**BBB:** Ligand A (36.371) has a low BBB penetration, while Ligand B (71.656) is better, but BBB is not a priority for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.317) has poor Caco-2 permeability, while Ligand B (-4.5) is slightly better, but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.98) has slightly better solubility than Ligand B (-5.116).

**hERG Inhibition:** Ligand A (0.585) has a lower hERG inhibition risk than Ligand B (0.308), which is favorable.

**Microsomal Clearance:** Ligand A (13.868 mL/min/kg) has significantly lower microsomal clearance than Ligand B (95.521 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (39.352 hours) has a much longer half-life than Ligand B (-16.985 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux than Ligand B (0.411), which is favorable.

**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 of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While it has a higher DILI risk, its superior binding affinity, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better solubility outweigh the DILI concern. The significantly better affinity suggests a higher likelihood of efficacy. Ligand B's high metabolic clearance and short half-life are major drawbacks.

Output:
0
2025-04-17 11:59:07,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (58.2) is significantly better than Ligand B (29.54). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (3.621) being slightly higher than Ligand B (4.62). Ligand B is pushing the upper limit and could have solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, while Ligand B has 0 HBD and 2 HBA. Both are acceptable, but the presence of some H-bond donors in Ligand A could improve solubility.

**QED:** Both ligands have good QED scores (A: 0.557, B: 0.644), indicating a generally drug-like profile.

**DILI:** Ligand A (33.23) has a much lower DILI risk than Ligand B (63.978). This is a significant advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (A: 87.088, B: 82.164), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and indicates poor permeability.

**Aqueous Solubility:** Ligand A (-3.79) is better than Ligand B (-5.532), although both are quite poor. Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.802, B: 0.833).

**Microsomal Clearance:** Ligand A (25.972) has significantly lower microsomal clearance than Ligand B (94.508), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (20.833) has a shorter half-life than Ligand B (35.55), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.418, B: 0.729).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a major advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic), significantly stronger binding affinity, and better solubility. While both have poor Caco-2 permeability, the superior binding and metabolic properties of Ligand A make it more likely to succeed.

Output:
1
2025-04-17 11:59:07,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (409.328 Da and 395.937 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.35) and Ligand B (62.3) are both below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.697) and Ligand B (3.713) are both 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:** 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 (0.702 and 0.809), indicating good drug-like properties.

**7. DILI:** Ligand A (47.344) has a lower DILI risk than Ligand B (67.817). Both are below 60, indicating acceptable risk, but A is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (82.125) has a slightly higher BBB penetration than Ligand B (68.088).

**9. Caco-2 Permeability:** Both have negative values (-5.12 and -5.193) which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative values (-3.135 and -4.692), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.53 and 0.335), which is good.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance rates (73.179 and 71.893 mL/min/kg), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand B (14.983 hours) has a significantly longer half-life than Ligand A (8.917 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.222 and 0.411), which is favorable.

**15. Binding Affinity:** Ligand B (-9.4 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.

**Enzyme-Specific Priorities:** For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Conclusion:**

While both compounds have significant solubility and permeability issues, Ligand B is the better candidate. Its substantially stronger binding affinity (-9.4 vs -7.5 kcal/mol) and longer half-life (14.983 vs 8.917 hours) outweigh the slightly higher DILI risk and lower BBB penetration. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the superior potency and stability of Ligand B make it the more promising starting point.

Output:
1
2025-04-17 11:59:07,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 351.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (78.95) is well within the ideal range.

**logP:** Both ligands have good logP values (2.127 and 1.23), falling within the optimal 1-3 range.

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

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

**QED:** Both ligands have good QED scores (0.637 and 0.7), indicating drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (34.432 and 34.471 percentile), suggesting minimal liver injury potential.

**BBB:** Ligand A (32.803) has a low BBB penetration score, while Ligand B (73.711) has a significantly higher score. This isn't a primary concern for a non-CNS target like SRC kinase, but it's a slight advantage for B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.813 and -4.672). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is not huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.54 and -1.954). Again, these are on a log scale, indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.373 and 0.272 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (32.056 mL/min/kg) and Ligand B (33.194 mL/min/kg) have comparable, moderate microsomal clearance values. Lower is better, but these aren't alarmingly high.

**In vitro Half-Life:** Ligand B (-12.943 hours) has a negative half-life, which is not possible. This is a significant red flag. Ligand A (24.116 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.115 and 0.111 percentile), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This 0.5 kcal/mol difference is significant and could outweigh some minor ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability predictions for both compounds, Ligand B is the more promising candidate. Its significantly better binding affinity (-7.6 vs -7.1 kcal/mol) is a key advantage for an enzyme inhibitor. The higher BBB score is a minor benefit. However, the negative in vitro half-life for Ligand B is a major concern and likely indicates an error in the data or a very unstable molecule. Given the choice between the two, and assuming the half-life data for Ligand B is incorrect, I would select Ligand B due to its superior binding affinity.

Output:
1
2025-04-17 11:59:07,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight (MW):** Both ligands (350.415 and 356.398 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.89) is better than Ligand B (113.44), both are under the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have good logP values (1.7 and 1.149), 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 5 HBA, while Ligand B has 6. Both are acceptable, under the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.679 and 0.675), indicating good drug-likeness.

**7. DILI:** Ligand A (47.926) has a lower DILI risk than Ligand B (63.086). This is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.576) is slightly better than Ligand B (55.797).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.459) is slightly better than Ligand B (-4.862).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.915) is slightly better than Ligand B (-2.38).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.212 and 0.154).

**12. Microsomal Clearance (Cl_mic):** Ligand B (41.567) has lower microsomal clearance than Ligand A (50.318), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-28.919) has a longer in vitro half-life than Ligand A (-19.346), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.089 and 0.023).

**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 substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), the significantly stronger binding affinity of Ligand A (-8.6 vs -6.7 kcal/mol) outweighs the slight drawbacks in metabolic stability and solubility. The lower DILI risk for Ligand A is also a positive factor. For an enzyme target like SRC kinase, potency is paramount, and Ligand A clearly excels in this area.

Output:
1
2025-04-17 11:59:07,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.45 and 347.415 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is excellent, well below the 140 threshold for oral absorption. Ligand B (100.55) is still acceptable but less optimal.

**logP:** Ligand A (3.123) is optimal. Ligand B (0.889) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of 5.

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

**QED:** Both ligands have reasonable QED scores (0.757 and 0.68), suggesting good drug-like properties.

**DILI:** Ligand A (37.224) has a very favorable DILI score, indicating low liver injury risk. Ligand B (23.924) is even better, with a very low risk.

**BBB:** Ligand A (88.406) has good BBB penetration, while Ligand B (49.67) is lower. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.367) has poor Caco-2 permeability, which is a concern. Ligand B (-5.014) is even worse.

**Aqueous Solubility:** Ligand A (-3.608) has poor aqueous solubility, which is a concern. Ligand B (-1.708) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.424) has a very low hERG risk. Ligand B (0.065) is excellent, with minimal hERG liability.

**Microsomal Clearance:** Ligand A (61.483) has moderate microsomal clearance. Ligand B (11.662) has very low clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-7.876) has a long in vitro half-life, which is positive. Ligand B (1.556) has a very short half-life, a significant drawback.

**P-gp Efflux:** Ligand A (0.178) has low P-gp efflux, which is good. Ligand B (0.012) 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 (-7.2 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and a good safety profile (DILI, hERG). However, it suffers from poor Caco-2 permeability and solubility. Ligand B has excellent metabolic stability (low Cl_mic) and very low hERG/Pgp, but its binding affinity is weaker and its half-life is very short.

Given that we are targeting a kinase (enzyme), potency (affinity) and metabolic stability are paramount. The 1.4 kcal/mol difference in affinity for Ligand A is substantial. While the permeability and solubility are concerns, these can potentially be addressed through formulation strategies. The short half-life of Ligand B is a more difficult issue to resolve.

Output:
0
2025-04-17 11:59:07,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (334.419 and 343.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (55.56) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.09) is still acceptable but less favorable than A.

**logP:** Ligand A (4.366) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.461) is within the optimal 1-3 range.

**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 (0.681 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (72.858) has a higher DILI risk than Ligand B (18.728). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.047) has better BBB penetration than Ligand B (61.923), but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates 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, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.906) has a slightly higher hERG risk than Ligand B (0.253).

**Microsomal Clearance:** Ligand B (47.598) has significantly lower microsomal clearance than Ligand A (78.429), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-27.009) has a much longer in vitro half-life than Ligand A (-3.593). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.724) has higher P-gp efflux liability than Ligand B (0.148), which is less desirable.

**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 for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk, higher hERG risk, higher P-gp efflux, and poorer metabolic stability (higher Cl_mic, shorter t1/2) are major drawbacks. Ligand B, despite slightly weaker binding, presents a much more favorable ADMET profile. The difference in binding affinity (1.6 kcal/mol) is substantial, but the ADMET liabilities of Ligand A are too concerning for a viable drug candidate. The improved metabolic stability and reduced toxicity risks of Ligand B outweigh the binding affinity difference.

Output:
1
2025-04-17 11:59:07,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.503 Da) and Ligand B (340.431 Da) are both acceptable.

**TPSA:** Ligand A (85.16) is better than Ligand B (66.29) for oral absorption, being closer to the <140 threshold.

**logP:** Both ligands have good logP values (Ligand A: 1.898, Ligand B: 0.751), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD and HBA counts (Ligand A: 0/6, Ligand B: 1/6), well within the guidelines.

**QED:** Both ligands have high QED scores (Ligand A: 0.813, Ligand B: 0.89), indicating good drug-likeness.

**DILI:** Ligand A (64.87) has a higher DILI risk than Ligand B (37.922). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.272) is higher than Ligand B (67.041).

**Caco-2 Permeability:** Ligand B (-5.113) shows better permeability than Ligand A (-4.602).

**Aqueous Solubility:** Ligand B (-0.673) has better solubility than Ligand A (-3.497). This is a positive for Ligand B.

**hERG Inhibition:** Ligand A (0.161) has a slightly lower hERG risk than Ligand B (0.564), which is favorable.

**Microsomal Clearance:** Ligand B (19.004) has significantly lower microsomal clearance than Ligand A (30.697), indicating better metabolic stability. This is a strong advantage for Ligand B.

**In vitro Half-Life:** Ligand B (2.072) has a much shorter half-life than Ligand A (34.677). This is a negative for Ligand B.

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux than Ligand B (0.01), which is favorable.

**Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (-8.3). A 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better hERG and P-gp efflux, Ligand B excels in critical areas for an enzyme inhibitor: significantly better binding affinity, lower DILI risk, better solubility, and improved metabolic stability (lower Cl_mic). The longer half-life of Ligand A is a plus, but the substantial affinity advantage of Ligand B, coupled with the lower DILI risk, is more important.

Output:
1
2025-04-17 11:59:07,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.463 and 351.422 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (72.54 and 70.67) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.743) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (1.642) is within 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:** Ligand A (0.79) has a better QED score than Ligand B (0.552), indicating a more drug-like profile.

**DILI:** Ligand A (16.092) has a significantly lower DILI risk than Ligand B (35.479), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (77.123) is slightly better than Ligand A (68.205). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 unusual and suggesting poor solubility. This is a concern for both.

**hERG:** Ligand A (0.212) has a much lower hERG inhibition liability than Ligand B (0.552), a critical advantage for safety.

**Microsomal Clearance:** Ligand A (-3.681) has a much lower (better) microsomal clearance than Ligand B (-1.397), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-15.57) has a much longer in vitro half-life than Ligand B (17.461), which is highly desirable.

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.105), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage and could potentially outweigh some of the ADME drawbacks of Ligand B. However, the difference is not *massive* (only 2.4 kcal/mol).

**Overall Assessment:**

Ligand A has a superior ADME profile: lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. Its QED is also higher. However, Ligand B has a significantly stronger binding affinity.

Given the priorities for enzyme inhibitors, metabolic stability and safety (DILI, hERG) are crucial. The substantial differences in these parameters, coupled with the longer half-life and lower efflux for Ligand A, make it the more promising candidate despite the slightly weaker binding affinity. The 2.4 kcal/mol difference in binding can potentially be overcome with further optimization of Ligand A. The poor solubility and permeability for both compounds are concerning and would need to be addressed, but are more readily optimized than fundamental safety issues.

Output:
0
2025-04-17 11:59:07,442 - INFO - Batch 92 complete. Total preferences: 1472
2025-04-17 11:59:07,442 - INFO - Processing batch 93/512...
2025-04-17 11:59:51,578 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.304 Da) is slightly higher than Ligand B (354.479 Da), but both are acceptable.

**TPSA:** Ligand A (47.56) is better than Ligand B (51.02) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Both ligands have good logP values (A: 4.446, B: 3.313), falling within the optimal range of 1-3. Ligand B is preferable here.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=0, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (A: 0.801, B: 0.661), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Both ligands have similar DILI risk (A: 62.699, B: 60.062), both are acceptable but not ideal.

**BBB:** Both ligands have good BBB penetration (A: 65.801, B: 73.827). This is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a calculation error. However, comparing the values, Ligand B (-5.112) is slightly better than Ligand A (-4.773).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or a calculation error. Ligand A (-4.504) is slightly better than Ligand B (-2.543).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.73, B: 0.675), which is excellent.

**Microsomal Clearance:** Ligand B (51.876) has significantly lower microsomal clearance than Ligand A (79.015), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-19.841) has a much longer in vitro half-life than Ligand A (71.892), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.776, B: 0.705).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.2 kcal/mol, B: -9.5 kcal/mol). Ligand B is slightly better.

**Overall:**

Ligand B is the better candidate. While Ligand A has a slightly better QED and TPSA, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. The negative solubility and Caco-2 values are concerning for both, but the difference in metabolic stability is a significant factor for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:59:51,578 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.8) is better than Ligand B (53.51), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.629) is a bit low, potentially hindering permeation, while Ligand B (2.786) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.719 and 0.831), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (20.24 and 20.396), which is low and favorable.

**BBB:** Ligand A (48.119) has a lower BBB penetration percentile than Ligand B (84.917). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.614) has a worse Caco-2 permeability than Ligand B (-4.728), however both are bad.

**Aqueous Solubility:** Ligand A (-1.436) has better solubility than Ligand B (-2.114). Solubility is important for enzymes.

**hERG:** Ligand A (0.091) has a significantly lower hERG inhibition liability than Ligand B (0.341), which is a major advantage.

**Microsomal Clearance:** Ligand A (13.12) has a much lower microsomal clearance than Ligand B (25.606), indicating better metabolic stability. This is crucial for enzymes.

**In vitro Half-Life:** Ligand A (8.766) has a better in vitro half-life than Ligand B (-14.813).

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.143).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.2 kcal/mol difference, which is significant but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A has a better safety profile (lower hERG, lower Cl_mic, better half-life), better solubility, and acceptable binding affinity. Ligand B has a slightly better binding affinity and better logP, but suffers from higher hERG risk and poorer metabolic stability. Given the enzyme-specific priorities, the improved metabolic stability and safety profile of Ligand A outweigh the slightly weaker binding affinity.

Output:
0
2025-04-17 11:59:51,578 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.292 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.62) is slightly above the optimal <140, but acceptable. Ligand B (66.92) is excellent, well below 140.

**logP:** Both ligands (0.983 and 1.866) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good.

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also good.

**QED:** Both ligands have good QED scores (0.577 and 0.701), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 85.576, which is high and concerning. Ligand B has a very low DILI risk of 12.33, a significant advantage.

**BBB:** Both have reasonable BBB penetration (68.127 and 86.002), but this is less critical for a non-CNS target like SRC.

**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 (0.204 and 0.201).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (33.421 and 34.66 mL/min/kg).

**In vitro Half-Life:** Ligand A has a negative half-life (-31.913), which is not possible. Ligand B has a negative half-life (-7.121), also not possible.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.041).

**Binding Affinity:** Ligand A has a slightly better binding affinity (-8.9 kcal/mol) than Ligand B (-7.6 kcal/mol). This is a 1.3 kcal/mol difference, which is significant.

**Conclusion:**

Despite Ligand A's slightly better binding affinity, the significantly higher DILI risk (85.576 vs 12.33) makes it a less favorable candidate. The negative half-life and solubility values for both are concerning, but the DILI risk is the most critical factor in this comparison. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 11:59:51,578 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.388 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.13) is well below the 140 threshold, and even below 90, suggesting good permeability. Ligand B (69.72) is still under 140, but higher than A, potentially impacting absorption slightly.

**logP:** Ligand A (4.398) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.869) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0/1) and HBA (3/3) counts, well within the recommended limits.

**QED:** Both ligands have similar QED values (0.799 and 0.75), indicating good drug-likeness.

**DILI:** Ligand A (52.772) has a moderate DILI risk, while Ligand B (19.465) has a very low DILI risk, which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (91.121 and 52.268), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.309) and Ligand B (-4.696) 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 (-4.521 and -2.361). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.833) has a slightly higher hERG risk than Ligand B (0.217), which is preferable.

**Microsomal Clearance:** Ligand A (43.154) has a higher microsomal clearance than Ligand B (3.219), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-8.816) has a longer in vitro half-life than Ligand A (-18.538), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.461) has lower P-gp efflux liability than Ligand B (0.03), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is less than 1.5 kcal/mol, it contributes to the overall preference for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The slightly better binding affinity also contributes to its favorability. The lower logP of ligand B is a concern, but the superior ADME properties outweigh this drawback.

Output:
1
2025-04-17 11:59:51,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.446 and 343.427 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (78.6). Lower TPSA generally correlates with better cell permeability, which is beneficial.

**logP:** Both ligands have good logP values (3.644 and 2.757), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 5. Lower HBA is generally preferred for better permeability.

**QED:** Both ligands have good QED scores (0.706 and 0.808), indicating good drug-likeness.

**DILI:** Ligand A (23.226) has a much lower DILI risk than Ligand B (46.219). This is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A is better (80.574 vs 71.384). While not a primary concern for a kinase inhibitor, it's a slight positive for Ligand A.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar, so this doesn't strongly favor either.

**Solubility:** Both have negative solubility values, which is also unusual and requires further investigation. Again, the values are similar.

**hERG:** Ligand A (0.46) has a lower hERG inhibition liability than Ligand B (0.776), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (26.781) has a lower microsomal clearance than Ligand A (42.126), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (4.497) has a shorter half-life than Ligand A (17.253). A longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux liability than Ligand B (0.554), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This is a significant advantage, as potency is a primary concern for kinase inhibitors. The difference of 0.8 kcal/mol is substantial enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and lower microsomal clearance, which are key advantages for an enzyme inhibitor. However, Ligand A has a significantly lower DILI risk, lower hERG liability, better TPSA, and a longer half-life. The difference in binding affinity (0.8 kcal/mol) is substantial, and the improved metabolic stability of Ligand B is also very important. Given the priorities for kinase inhibitors, the stronger binding of Ligand B is the deciding factor, despite the slightly higher DILI and hERG risks.

Output:
1
2025-04-17 11:59:51,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.917 Da) is slightly higher than Ligand B (352.391 Da), but both are acceptable.

**TPSA:** Ligand A (82.53) is well below the 140 threshold for oral absorption. Ligand B (117.79) is also below the threshold, but higher than A.

**logP:** Ligand A (1.817) is within the optimal range (1-3). Ligand B (-0.575) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7 HBA. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.642, B: 0.703), indicating good drug-like properties.

**DILI:** Ligand A (38.62) has a lower DILI risk than Ligand B (49.011), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (56.029) is lower than Ligand B (48.197), but neither is particularly high.

**Caco-2 Permeability:** Both have negative values (-4.92 and -5.15), suggesting poor permeability. This is concerning, but could be offset by other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.547 and -1.148), which is a significant drawback. Poor solubility can hinder bioavailability. Ligand B is slightly better than A.

**hERG Inhibition:** Ligand A (0.327) has a much lower hERG risk than Ligand B (0.102), which is a major advantage.

**Microsomal Clearance:** Ligand A (30.742) has a higher microsomal clearance than Ligand B (7.228), meaning it's less metabolically stable. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (23.256) has a longer half-life than Ligand B (-1.078), which is a positive. However, the negative half-life for B is a major concern.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.101 and 0.01), which is good.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly 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:**

Ligand B has a significantly better binding affinity, which is paramount for an enzyme inhibitor. While its solubility is also slightly better than A, its metabolic stability (lower Cl_mic, longer half-life) is much better. The biggest drawback for B is the negative half-life, but the strong binding affinity could compensate for this. Ligand A has a better DILI and hERG profile but is significantly weaker in binding and has poorer metabolic stability. Given the importance of potency and metabolic stability for kinase inhibitors, Ligand B is the more promising candidate, despite its solubility and half-life issues.

Output:
1
2025-04-17 11:59:51,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.9) is slightly higher than Ligand B (78.68). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand B (1.445) is better than Ligand A (0.619). Ligand A is a bit low, potentially hindering permeation. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Ligand A (0.836) has a slightly better QED score than Ligand B (0.729), indicating a more drug-like profile.

**DILI:** Ligand B (12.641) has a significantly lower DILI risk than Ligand A (58.976). This is a major advantage for Ligand B.

**BBB:** Both have moderate BBB penetration, with Ligand B (61.38) being slightly better than Ligand A (57.968). BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.652) has worse Caco-2 permeability than Ligand B (-5.168). Lower values are worse.

**Aqueous Solubility:** Ligand A (-1.919) has slightly better aqueous solubility than Ligand B (-1.116).

**hERG:** Both ligands have very low hERG inhibition risk (0.196 and 0.217 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (11.186) has lower microsomal clearance than Ligand B (12.421), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.378 hours) has a longer half-life than Ligand B (17.897 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.018 respectively).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better QED, longer half-life, and better solubility, Ligand B possesses a much stronger binding affinity (-9.2 vs -8.5 kcal/mol) and a significantly lower DILI risk (12.641 vs 58.976). The superior binding affinity and reduced toxicity risk of Ligand B are critical for an enzyme target like SRC kinase, making it the more promising drug candidate.

Output:
1
2025-04-17 11:59:51,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.318 and 357.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.03) is better than Ligand B (45.15). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.238) is within the optimal 1-3 range, while Ligand B (3.639) is approaching the upper limit.

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

**H-Bond Acceptors:** Ligand A (8) is slightly higher than Ligand B (6), but both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.522 and 0.754, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (98.255) has a significantly higher DILI risk than Ligand B (58.434). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (73.517 and 78.364), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.486) is slightly better than Ligand B (-4.932).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.354) is slightly better than Ligand B (-4.467).

**hERG:** Ligand A (0.346) has a lower hERG risk than Ligand B (0.833), which is favorable.

**Microsomal Clearance:** Ligand A (60.463) has a much lower microsomal clearance than Ligand B (114.374), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-11.377) has a negative half-life, indicating very poor stability, while Ligand B (36.984) is positive, indicating better stability.

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.566), which is favorable.

**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 B has a better binding affinity and QED score, but suffers from higher DILI risk, higher P-gp efflux, and significantly higher microsomal clearance (lower in vitro half-life). Ligand A has a lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and a slightly better hERG profile. The poor solubility and permeability are a concern for both. However, the significantly higher DILI risk and poor metabolic stability of Ligand B are major drawbacks.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and DILI risk are crucial. Ligand A's lower Cl_mic and DILI risk outweigh the slightly better affinity of Ligand B.

Output:
0
2025-04-17 11:59:51,579 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [353.507, 70.67, 1.543, 2, 4, 0.625, 10.702, 65.452, -4.712, -1.543, 0.218, 38.824, 0.925, 0.02, -7.5]
**Ligand B:** [390.418, 40.62, 3.514, 0, 3, 0.596, 34.161, 97.014, -4.702, -3.355, 0.731, 27.446, -10.4, 0.244, 0]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (353.5) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (70.67) is higher than B (40.62).  Both are below 140, but B is significantly better for oral absorption.
3. **logP:** A (1.543) is optimal, while B (3.514) is pushing the upper limit. B's higher logP could lead to solubility issues or off-target interactions.
4. **HBD:** A (2) is good, B (0) is also acceptable.
5. **HBA:** A (4) is good, B (3) is also acceptable.
6. **QED:** Both are reasonably good (A: 0.625, B: 0.596), indicating drug-like properties.
7. **DILI:** A (10.702) is significantly better than B (34.161). Lower DILI risk is crucial.
8. **BBB:** B (97.014) is much higher than A (65.452). While SRC isn't a CNS target, higher BBB is generally a positive indicator of reduced off-target effects.
9. **Caco-2:** Both are negative, indicating poor permeability.
10. **Solubility:** A (-1.543) is worse than B (-3.355). Solubility is a concern for both, but B is worse.
11. **hERG:** A (0.218) is much better than B (0.731). Lower hERG risk is vital.
12. **Cl_mic:** B (27.446) is significantly better than A (38.824). Lower clearance indicates better metabolic stability.
13. **t1/2:** A (0.925) is very poor, while B (-10.4) is also poor. Both have very short half-lives.
14. **Pgp:** A (0.02) is much better than B (0.244). Lower Pgp efflux is desirable.
15. **Binding Affinity:** A (-7.5) is significantly better than B (0). A has a strong binding affinity.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

Ligand A has a significantly better binding affinity (-7.5 vs 0 kcal/mol), a much lower DILI risk, and a much lower hERG risk. While its solubility and half-life are poor, the strong binding affinity could potentially compensate for these drawbacks, especially in early-stage optimization. Ligand B has better metabolic stability (Cl_mic) and BBB, but its significantly weaker binding affinity, higher DILI, and higher hERG risk are major concerns. The poor solubility of both compounds would need to be addressed, but starting with the more potent and safer compound (A) is the better strategy.

Output:
1
2025-04-17 11:59:51,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.559 Da and 351.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is slightly higher than Ligand B (41.15), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (2.11) is within the optimal 1-3 range. Ligand B (3.758) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.714 and 0.813), indicating drug-like properties.

**DILI:** Ligand A (19.193) has a slightly higher DILI risk than Ligand B (15.626), but both are well below the concerning threshold of 60.

**BBB:** Ligand A (68.282) has a lower BBB penetration percentile than Ligand B (86.661). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.478) has poorer Caco-2 permeability compared to Ligand B (-4.801), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.792) has poorer aqueous solubility compared to Ligand B (-3.354). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.429) has a lower hERG inhibition risk than Ligand B (0.928), which is favorable.

**Microsomal Clearance:** Ligand A (33.818) has lower microsomal clearance than Ligand B (38.972), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.055) has a longer half-life than Ligand B (0.893), which is desirable.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.519), indicating better bioavailability.

**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 can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has better solubility and Caco-2 permeability, Ligand A demonstrates superior binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slightly higher DILI risk for Ligand A is not a major concern given its other favorable properties. The improved binding affinity of Ligand A is a key advantage for an enzyme target like SRC kinase.

Output:
1
2025-04-17 11:59:51,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 and 351.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.72) is better than Ligand B (72.88), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.55) is optimal, while Ligand B (0.99) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Both are within acceptable ranges.

**QED:** Both ligands have similar QED values (0.798 and 0.717), indicating good drug-likeness.

**DILI:** Ligand A (60.92) has a higher DILI risk than Ligand B (5.24). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (78.75) is better than Ligand B (65.80).

**Caco-2 Permeability:** Ligand A (-4.999) has poor Caco-2 permeability, while Ligand B (-5.063) is also poor.

**Aqueous Solubility:** Ligand A (-4.474) has poor aqueous solubility, while Ligand B (-1.108) is slightly better.

**hERG:** Both ligands have low hERG inhibition risk (0.378 and 0.302).

**Microsomal Clearance:** Ligand A (97.18) has high microsomal clearance, indicating poor metabolic stability. Ligand B (14.67) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand B (13.76 hours) has a much longer half-life than Ligand A (-9.33 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.512 and 0.007).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a crucial advantage for an enzyme inhibitor.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has a slightly better logP and BBB, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity, much better metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and slightly better solubility. The poor Caco-2 permeability is a concern for both, but can be addressed through formulation strategies. The substantial affinity advantage of Ligand B outweighs the minor ADME drawbacks.

Output:
1
2025-04-17 11:59:51,579 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (346.427 Da) is within the ideal range (200-500). Ligand B (362.367 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (73.99) is better than Ligand B (42.43). Lower TPSA generally favors better cell permeability.

3. **logP:** Ligand A (1.799) is within the optimal range (1-3). Ligand B (3.52) is at the higher end of the optimal range, potentially hinting at some solubility issues.

4. **HBD:** Ligand A (1) is good. Ligand B (0) is also good, but a single HBD can sometimes improve solubility.

5. **HBA:** Ligand A (4) is good. Ligand B (3) is also good.

6. **QED:** Ligand A (0.829) is excellent, indicating high drug-likeness. Ligand B (0.525) is acceptable, but lower than A.

7. **DILI:** Ligand A (48.895) has a slightly higher DILI risk than Ligand B (30.399), but both are below the concerning threshold of 60.

8. **BBB:** Ligand A (58.511) has a lower BBB penetration than Ligand B (97.053). However, SRC is not a CNS target, so this is less critical.

9. **Caco-2:** Ligand A (-4.575) is worse than Ligand B (-4.06). Higher values are better, indicating better absorption.

10. **Solubility:** Ligand A (-2.089) is worse than Ligand B (-3.626). Higher values are better.

11. **hERG:** Ligand A (0.309) has a lower hERG risk than Ligand B (0.867), which is preferable.

12. **Cl_mic:** Ligand A (47.328) has a lower microsomal clearance than Ligand B (59.723), suggesting better metabolic stability. This is important for kinase inhibitors.

13. **t1/2:** Ligand A (16.12) has a shorter half-life than Ligand B (23.318). Longer half-life is generally preferred.

14. **Pgp:** Ligand A (0.252) has lower P-gp efflux than Ligand B (0.612), which is good for bioavailability.

15. **Binding Affinity:** Ligand B (-9.2) has a slightly better binding affinity than Ligand A (-8.8), a 0.4 kcal/mol difference. This is a significant advantage.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a better affinity, but Ligand A has better metabolic stability and lower hERG risk. Solubility is better for Ligand B.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, the superior metabolic stability (lower Cl_mic), lower Pgp efflux, and lower hERG risk of Ligand A, combined with its excellent QED score, make it a more promising candidate. The solubility difference is a concern, but can potentially be addressed through formulation. The slightly shorter half-life of A is less concerning than the potential for rapid metabolism of B.

Output:
0
2025-04-17 11:59:51,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.377 and 356.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.68) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (90.98) is still within acceptable limits, but less favorable.

**logP:** Ligand A (4.511) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.413) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.815) has a strong drug-like profile. Ligand B (0.586) is acceptable, but less optimal.

**DILI:** Ligand A (56.572) has a moderate DILI risk, which is acceptable. Ligand B (13.3) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 86.429, Ligand B: 62.466). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.337) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.217) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.384) has poor aqueous solubility, consistent with its high logP. Ligand B (-0.688) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.8) shows a low risk of hERG inhibition, which is excellent. Ligand B (0.094) also has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (65.884) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (1.599) has very low clearance, indicating excellent metabolic stability, a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (50.728) has a reasonable half-life. Ligand B (-13.351) has a very short half-life, a major disadvantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.7, Ligand B: 0.004), which is good.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.1), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand B has several advantages: significantly better metabolic stability (lower Cl_mic, though a very short half-life), lower DILI risk, and slightly better binding affinity. However, its low logP and poor Caco-2 permeability are concerning. Ligand A has better permeability characteristics (TPSA, Caco-2) and a reasonable half-life, but suffers from a higher logP, moderate metabolic clearance, and a slightly lower binding affinity.

Given the enzyme-specific priorities, metabolic stability is crucial. While Ligand B's half-life is a major drawback, its extremely low Cl_mic suggests that formulation strategies might be able to overcome the short half-life. The poor permeability of both compounds is a concern, but the better binding affinity and lower toxicity of Ligand B make it the more promising candidate, assuming permeability can be addressed.

Output:
1
2025-04-17 11:59:51,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.4 and 353.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.87) is better than Ligand B (102.17) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (2.95) is optimal (1-3). Ligand B (-0.493) is below 1, which could impede permeation.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.767) has a better QED score than Ligand B (0.593), indicating a more drug-like profile.

**DILI:** Ligand A (51.03) has a slightly higher DILI risk than Ligand B (22.99), but both are below the concerning threshold of 60.

**BBB:** Ligand A (46.03) has a lower BBB penetration than Ligand B (84.34). This is not a primary concern for a kinase inhibitor unless CNS effects are desired or problematic.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data. However, the values are similar, so it doesn't heavily favor one ligand.

**Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar, so it doesn't heavily favor one ligand.

**hERG:** Both ligands have very low hERG inhibition risk (0.214 and 0.192).

**Microsomal Clearance:** Ligand A (48.35) has a higher microsomal clearance than Ligand B (22.60). This suggests Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (7.33) has a significantly longer in vitro half-life than Ligand A (1.04). This further supports Ligand B's better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.013).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). This 0.7 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and QED, Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic, longer t1/2) and better logP. For an enzyme like SRC kinase, metabolic stability is crucial for maintaining therapeutic concentrations. The slightly weaker binding affinity of Ligand B can potentially be optimized in subsequent iterations, while improving metabolic stability is often more challenging. The negative solubility and Caco-2 values are concerning for both, but similar.

Output:
1
2025-04-17 11:59:51,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.375 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.15) is higher than Ligand B (69.89). While both are reasonably good, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (-0.318) is a bit low, potentially hindering permeability. Ligand B (2.158) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits, but Ligand B's lower count might slightly improve permeability.

**QED:** Both ligands have similar QED values (0.77 and 0.706), indicating good drug-likeness.

**DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (51.493), which is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.831) has a higher BBB percentile, but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.557) is slightly less negative than Ligand A (-5.76), potentially indicating marginally better absorption.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.632) is slightly better than Ligand B (-2.416).

**hERG Inhibition:** Ligand A (0.02) has a very low hERG risk, which is excellent. Ligand B (0.413) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-20.177) has significantly *lower* (better) microsomal clearance than Ligand B (55.253), indicating greater metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (28.365) has a much longer half-life than Ligand B (1.236), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.146), which is favorable.

**Binding Affinity:** Both ligands have similar binding affinities (-9 and -8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and has a significantly lower hERG risk. While its logP and solubility are slightly less ideal, the superior pharmacokinetic properties and safety profile outweigh these drawbacks. Ligand B has a better TPSA and logP, but its metabolic instability and higher DILI risk are concerning. Given the enzyme-kinase target class priority, metabolic stability and safety are paramount.

Output:
0
2025-04-17 11:59:51,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.455 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (94.05), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.44) is within the optimal 1-3 range. Ligand B (-0.665) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 1, respectively) and HBA (5 each) counts.

**QED:** Both ligands have good QED scores (0.826 and 0.717), indicating good drug-like properties.

**DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (42.458). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.044) is slightly better than Ligand B (32.144).

**Caco-2 Permeability:** Ligand A (-5.072) is worse than Ligand B (-4.594). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.019) is worse than Ligand B (-0.88). Solubility is a concern for both, but more so for A.

**hERG:** Both ligands have very low hERG risk (0.197 and 0.068), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand A (-15.687) has significantly lower (better) microsomal clearance than Ligand B (-6.581), suggesting better metabolic stability.

**In vitro Half-Life (t1/2):** Ligand A (12.965 hours) has a longer half-life than Ligand B (17.46 hours). This is a positive for A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.016).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). The difference is 0.4 kcal/mol, which is not huge, but still a factor.

**Overall Assessment:**

Ligand A has better potency (affinity) and metabolic stability (Cl_mic), and a longer half-life. However, it has significantly higher DILI risk and poorer solubility and Caco-2 permeability. Ligand B has a lower DILI risk, better solubility and permeability, but slightly weaker binding affinity and poorer metabolic stability. Given the importance of minimizing toxicity (DILI) and ensuring reasonable solubility for an enzyme inhibitor, Ligand B is the more promising candidate. The slight difference in binding affinity can potentially be optimized in later stages of drug development.

Output:
1
2025-04-17 11:59:51,581 - INFO - Batch 93 complete. Total preferences: 1488
2025-04-17 11:59:51,581 - INFO - Processing batch 94/512...
2025-04-17 12:00:32,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.463 and 372.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.45) is slightly higher than Ligand B (75.71), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (1.847 and 1.315), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.632 and 0.731), indicating drug-like properties.

**DILI:** Ligand B (12.33) has a significantly lower DILI risk than Ligand A (33.579). This is a major advantage for Ligand B.

**BBB:** Ligand B (68.554) has a higher BBB penetration percentile than Ligand A (41.528). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.87 and -4.588). These values are unusual and suggest 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 (-2.937 and -1.533). Similar to Caco-2, these are likely representing very low solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.336 and 0.224).

**Microsomal Clearance:** Ligand B (30.623) has lower microsomal clearance than Ligand A (38.969), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (2.701) has a slightly lower in vitro half-life than Ligand A (13.926). This is a disadvantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028).

**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.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates significantly better safety (lower DILI) and metabolic stability (lower Cl_mic). The lower half-life of Ligand B is a concern, but can potentially be addressed through structural modifications. The poor Caco-2 and solubility values are shared by both, and would require attention during lead optimization. The difference in binding affinity is not substantial enough to outweigh the ADME advantages of Ligand B.

Output:
1
2025-04-17 12:00:32,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.502 and 392.518 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (75.71) is still acceptable but less optimal.

**logP:** Ligand A (3.777) is within the optimal 1-3 range. Ligand B (2.084) is a bit lower, potentially impacting permeability, but still reasonable.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 for A, 5 for B) counts, well within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.862 and 0.688), indicating good drug-like properties.

**DILI:** Ligand A (41.411) has a lower DILI risk than Ligand B (58.976), which is a significant advantage.

**BBB:** While not crucial for a non-CNS target like SRC, Ligand A (95.347) has a much higher BBB penetration percentile than Ligand B (81.194).

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

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and indicates poor solubility. This is a significant concern for both.

**hERG:** Both ligands show low hERG inhibition liability (0.778 and 0.738), which is good.

**Microsomal Clearance:** Ligand A (24.53) has a lower microsomal clearance than Ligand B (43.266), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.102) has a negative half-life, which is not possible. Ligand B (3.903) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.543 and 0.228), which is favorable.

**Binding Affinity:** Ligand A (-10.3 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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly stronger binding affinity (-10.3 vs -7.0 kcal/mol) is the most important factor. It also has better DILI risk, better metabolic stability (lower Cl_mic), and higher BBB penetration. While both have concerning Caco-2 and solubility values, the strong binding affinity of Ligand A makes it more likely to be optimized to overcome these issues. The negative half-life for Ligand A is a data error that would need to be investigated, but doesn't negate the other advantages.

Output:
1
2025-04-17 12:00:32,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.379 Da and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.48) is better than Ligand B (98.66), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.099) is optimal (1-3), while Ligand B (1.122) is on the lower side, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Both have 3 HBD and 4 HBA, which are acceptable.

**QED:** Ligand A (0.668) is better than Ligand B (0.516), indicating a more drug-like profile.

**DILI:** Ligand B (22.179) has a significantly lower DILI risk than Ligand A (83.133), which is a major advantage.

**BBB:** Ligand A (41.722) has a slightly better BBB penetration than Ligand B (30.283), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.93) has better Caco-2 permeability than Ligand B (-5.096), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.038) has better aqueous solubility than Ligand B (-2.243).

**hERG Inhibition:** Ligand B (0.096) has a lower hERG inhibition liability than Ligand A (0.622), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (14.035) has a lower microsomal clearance than Ligand A (28.071), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (44.92) has a longer in vitro half-life than Ligand B (-12.254). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.092).

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.3). However, the difference is only 0.4 kcal/mol, which is not substantial enough to outweigh other significant ADME differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better affinity and half-life, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, lower hERG inhibition, and better metabolic stability (lower Cl_mic). The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization, but the safety and metabolic advantages are more crucial.

Output:
1
2025-04-17 12:00:32,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.383 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.27) is slightly above the optimal <140, but acceptable. Ligand B (62.3) is excellent, well below 90.

**logP:** Ligand A (2.272) is within the optimal 1-3 range. Ligand B (3.315) is slightly higher but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the ideal limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBAs, acceptable. Ligand B has 3 HBAs, also acceptable.

**QED:** Both ligands have good QED scores (0.568 and 0.773), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 86.39, which is high. Ligand B has a much lower DILI risk of 32.028, which is very favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.872) and Ligand B (59.364) are both moderate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.799 and -4.694), 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 (-3.795 and -3.246), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.727) has a slightly elevated hERG risk, while Ligand B (0.218) has a very low risk.

**Microsomal Clearance:** Ligand A (80.539) has higher clearance than Ligand B (38.804). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.891) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand A (7.65) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.191 and 0.066).

**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 other drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.1 vs -8.5 kcal/mol) is a major advantage. Critically, it also has a much lower DILI risk (32.028 vs 86.39) and a lower hERG risk (0.218 vs 0.727). While the negative half-life is concerning, it is likely a data error. The lower microsomal clearance also suggests better metabolic stability.

Output:
1
2025-04-17 12:00:32,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (338.451 and 352.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (75.35 and 78.87) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.74) is optimal, while Ligand B (1.482) is slightly below the optimal range, potentially impacting permeability.

**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 (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.758 and 0.649), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively low DILI risk (15.626 and 16.673), both below the 40 threshold.

**8. BBB:** Both ligands have low BBB penetration (49.67 and 44.94). This is not a major concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Ligand A (-4.936) has better Caco-2 permeability than Ligand B (-4.464), suggesting better absorption.

**10. Aqueous Solubility:** Ligand A (-2.647) has better aqueous solubility than Ligand B (-1.888).

**11. hERG Inhibition:** Ligand A (0.731) has a lower hERG inhibition risk than Ligand B (0.239).

**12. Microsomal Clearance:** Ligand A (3.31 mL/min/kg) has significantly lower microsomal clearance than Ligand B (35.619 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.932 hours) has a much longer in vitro half-life than Ligand B (-6.166 hours).

**14. P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux than Ligand B (0.08), potentially improving bioavailability.

**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 crucial factor for enzyme inhibitors.

**Enzyme-Specific Considerations:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in all these areas. Its significantly stronger binding affinity (-9.5 kcal/mol vs 0.0 kcal/mol) is a major advantage, and its superior metabolic stability (lower Cl_mic and longer t1/2) are also highly desirable. While both have acceptable DILI and hERG, Ligand A is better in both.

Output:
1
2025-04-17 12:00:32,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.5 and 380.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.7) is higher than Ligand B (34.6). While both are reasonably low, B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (3.533) is within the optimal 1-3 range. Ligand B (4.621) is slightly higher, potentially leading to solubility issues and off-target interactions, but still acceptable.

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

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

**QED:** Both ligands have good QED scores (0.906 and 0.669, respectively), indicating drug-like properties.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (30.865). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.488) has a higher BBB score than Ligand A (60.993).

**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 interpret these as very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor solubility for both compounds.

**hERG Inhibition:** Ligand A (0.155) has a lower hERG risk than Ligand B (0.851). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand B (73.428) has a higher microsomal clearance than Ligand A (35.885), suggesting lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (23.83) has a longer half-life than Ligand A (14.41), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.429 and 0.612).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -9.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A has a better hERG profile and lower microsomal clearance, which are crucial for enzyme inhibitors. However, it has a significantly higher DILI risk. Ligand B has a better TPSA, BBB, and in vitro half-life, but a higher DILI risk and worse microsomal clearance. Given the importance of metabolic stability and the relatively small difference in binding affinity, Ligand A is slightly more promising, despite the DILI concern. The DILI risk could potentially be mitigated through structural modifications.

Output:
0
2025-04-17 12:00:32,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.342 and 355.347 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.33) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (135.96) is still within the acceptable range for oral absorption (<140), but significantly higher than A.

**logP:** Ligand A (3.743) is optimal. Ligand B (-1.674) is quite low, potentially hindering permeation and absorption.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (3 HBD, 8 HBA) is higher, potentially impacting permeability.

**QED:** Ligand A (0.833) is very good, indicating high drug-likeness. Ligand B (0.259) is poor, suggesting potential issues.

**DILI:** Ligand A (17.914) has a very low DILI risk. Ligand B (47.926) is moderate, but acceptable.

**BBB:** Ligand A (96.2) shows good BBB penetration, though not crucial for a non-CNS target like SRC. Ligand B (30.167) is low.

**Caco-2 Permeability:** Ligand A (-4.73) is poor. Ligand B (-5.622) is also poor.

**Aqueous Solubility:** Ligand A (-3.613) is poor. Ligand B (-1.308) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.824) is low risk. Ligand B (0.069) is very low risk.

**Microsomal Clearance:** Ligand A (3.284) is low, indicating good metabolic stability. Ligand B (8.521) is higher, suggesting faster metabolism.

**In vitro Half-Life:** Both ligands have similar and good in vitro half-lives (-9.484 and -9.08).

**P-gp Efflux:** Ligand A (0.155) shows low P-gp efflux. Ligand B (0.014) shows very low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.8 kcal/mol). Ligand B is slightly better (-8.8 vs -8.2), but the difference is less than 1.5 kcal/mol.

**Conclusion:**

Ligand A is significantly better overall. While both have good binding affinity and acceptable half-lives, Ligand A excels in key areas: TPSA, logP, QED, and DILI risk. The poor Caco-2 and solubility of both are concerning, but the superior overall profile of Ligand A, especially its better predicted permeability (lower TPSA, better logP) and drug-likeness, makes it the more promising candidate. Ligand B's low logP and poor QED are significant drawbacks.

Output:
1
2025-04-17 12:00:32,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.39 and 358.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is better than Ligand B (61.88) as it is closer to the ideal range for oral absorption.

**logP:** Ligand A (1.899) is optimal, while Ligand B (4.476) is high, potentially leading to solubility issues and off-target effects.

**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 (3 and 4, respectively), well below the threshold of 10.

**QED:** Both ligands have good QED scores (0.813 and 0.531), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (51.725 and 53.858), falling within an acceptable range (<60).

**BBB:** Ligand A (77.976) has better BBB penetration than Ligand B (64.133), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.558) has a better Caco-2 permeability than Ligand B (-5.173), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.909) has better aqueous solubility than Ligand B (-4.099).

**hERG Inhibition:** Ligand A (0.447) has a lower hERG inhibition liability than Ligand B (0.652), which is a significant advantage.

**Microsomal Clearance:** Ligand A (4.566) has lower microsomal clearance than Ligand B (72.696), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have similar negative in vitro half-lives (-19.292 and -19.599), indicating rapid metabolism.

**P-gp Efflux:** Ligand A (0.188) has lower P-gp efflux liability than Ligand B (0.56), suggesting better bioavailability.

**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.

**Conclusion:**

Considering all factors, Ligand A is the superior candidate. It exhibits a better balance of properties, including optimal logP, better solubility, lower hERG risk, lower P-gp efflux, and significantly stronger binding affinity. While both have similar DILI risks and rapid metabolism, the superior potency and ADME profile of Ligand A make it more likely to be a viable drug candidate for SRC kinase.

Output:
1
2025-04-17 12:00:32,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (456.384 Da) is higher, but still acceptable. Ligand B (360.479 Da) is slightly better.

**TPSA:** Ligand A (105.67) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (60.45) is excellent.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.069) is slightly better than Ligand B (3.922), which is nearing the upper limit and could potentially cause solubility issues.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.681, B: 0.76), indicating good drug-like properties.

**DILI:** Both have similar DILI risk (A: 76.154, B: 73.245), indicating moderate risk. This isn't a major differentiating factor.

**BBB:** Both have low BBB penetration (A: 56.534, B: 52.268), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.666) is slightly better than Ligand B (-4.923).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand A (-3.191) is slightly better than Ligand B (-4.236).

**hERG Inhibition:** Both have low hERG inhibition liability (A: 0.137, B: 0.357), which is excellent.

**Microsomal Clearance:** Ligand A (43.972) has significantly lower microsomal clearance than Ligand B (117.212), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.67 hours) has a positive half-life, while Ligand B (-8.183 hours) has a negative half-life, which is not possible. This is a significant issue for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.17, B: 0.625).

**Binding Affinity:** Both have very similar and excellent binding affinities (A: -8.8 kcal/mol, B: -8.1 kcal/mol). Ligand A has a slight advantage.

**Conclusion:**

Ligand A is the more promising candidate. While both ligands have similar affinities, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, positive t1/2), slightly better solubility, and a slightly better logP. The negative half-life for Ligand B is a major red flag. Although both have poor Caco-2 and solubility, the metabolic stability advantage of Ligand A is critical for an enzyme target like SRC kinase.

Output:
0
2025-04-17 12:00:32,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.531 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is better than Ligand B (52.65), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (3.697 and 2.228), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but not excessively high.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (1 HBD, 3 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.734 and 0.824), indicating good drug-like properties.

**DILI:** Ligand A (17.759) has a significantly lower DILI risk than Ligand B (24.467), which is a major advantage.

**BBB:** Ligand A (91.276) has a higher BBB penetration percentile than Ligand B (70.88). While not a primary concern for a kinase inhibitor, it's a slight benefit.

**Caco-2 Permeability:** Ligand A (-4.348) has a worse Caco-2 permeability than Ligand B (-4.541).

**Aqueous Solubility:** Ligand A (-4.166) has a worse aqueous solubility than Ligand B (-2.164). Solubility is important for bioavailability, so B is better here.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.555 and 0.525), and are within an acceptable range.

**Microsomal Clearance:** Ligand A (92.253) has a higher microsomal clearance than Ligand B (39.974). This means Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (36.82) has a longer half-life than Ligand B (17.11), which is desirable.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.324 and 0.1).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has advantages in BBB, DILI, and half-life. However, Ligand B has better solubility and significantly better metabolic stability (lower Cl_mic). Given that we are targeting a kinase, metabolic stability is a crucial factor. The slightly lower solubility of Ligand B can potentially be addressed with formulation strategies. The similar binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 12:00:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.539 and 342.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (35.58) is well below the 140 threshold, and even below 90, suggesting good permeability. Ligand B (49.41) is also below 140, but higher than A.

**3. logP:** Both ligands have logP values within the optimal range (A: 4.478, B: 3.196). 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 2. Both are below the limit of 10.

**6. QED:** Both ligands have reasonable QED scores (A: 0.858, B: 0.798), indicating good drug-like properties.

**7. DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (13.843), but both are below the concerning threshold of 60.

**8. BBB:** Both have high BBB penetration (A: 90.733, B: 86.661), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2:** Both have negative Caco-2 values (-4.801 and -4.905). These values are unusual and suggest very poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.243 and -4.058). These values are also unusual and suggest very poor aqueous solubility. This is a major issue for both compounds.

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.925, B: 0.41).

**12. Cl_mic:** Ligand A (40.292) has a lower microsomal clearance than Ligand B (48.492), suggesting better metabolic stability.

**13. t1/2:** Ligand A (65.999) has a significantly longer in vitro half-life than Ligand B (-3.811). This is a major advantage for Ligand A.

**14. Pgp:** Ligand A (0.406) has lower P-gp efflux liability than Ligand B (0.186), suggesting better bioavailability.

**15. 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 B has a much better binding affinity (-9.3 vs -6.8 kcal/mol). However, both compounds suffer from very poor predicted solubility and permeability (negative Caco-2 and solubility values). Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. Given the importance of potency for enzyme inhibitors, the superior binding affinity of Ligand B is a critical factor. While the solubility and permeability issues are concerning, they might be addressable through formulation strategies or further chemical modifications. The improved metabolic stability of Ligand A is attractive, but the large difference in binding affinity favors Ligand B.

Output:
1
2025-04-17 12:00:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (369.437 Da and 355.36 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.99) is slightly above the preferred <140, but acceptable. Ligand B (71.09) is well within the acceptable range.

**3. logP:** Both ligands have good logP values (3.07 and 2.286), 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:** Both ligands have good QED scores (0.739 and 0.796), indicating good drug-like properties.

**7. DILI:** Ligand A (57.115) has a slightly higher DILI risk than Ligand B (44.591), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have acceptable BBB penetration, but Ligand B (81.698) is slightly better than Ligand A (76.968). This is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.548 and -4.719). This is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.796 and -2.672). This is also a significant drawback, indicating very poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.682 and 0.113), which is excellent.

**12. Microsomal Clearance:** Ligand A (30.058) has a higher microsomal clearance than Ligand B (4.738), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-15.443) has a significantly longer in vitro half-life than Ligand A (34.457). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.213 and 0.029).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity and low hERG risk, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better Caco-2 permeability and BBB penetration. The poor solubility and permeability of both are concerning, but the metabolic stability advantage of Ligand B is more critical for an enzyme inhibitor.

Output:
1
2025-04-17 12:00:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 346.402 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is slightly higher than Ligand B (71.34). Both are below the 140 threshold for good oral absorption, but neither are optimized for CNS penetration (below 90).

**logP:** Ligand A (2.273) and Ligand B (3.114) are both 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 (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.844) has a better QED score than Ligand A (0.675), indicating a more drug-like profile.

**DILI:** Ligand A (34.432) has a significantly lower DILI risk than Ligand B (57.076). This is a major advantage for Ligand A.

**BBB:** Ligand B (89.531) has a higher BBB penetration percentile than Ligand A (53.083). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.953 and -4.684), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand B (-3.817) has worse solubility than Ligand A (-1.627). Solubility is important for bioavailability, favoring Ligand A.

**hERG Inhibition:** Ligand A (0.5) has a lower hERG inhibition liability than Ligand B (0.736), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (-13.614) has a much lower (better) microsomal clearance than Ligand B (28.217), indicating greater metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (88.617) has a significantly longer in vitro half-life than Ligand A (35.11). This is a positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux liability than Ligand B (0.274), which is favorable for bioavailability.

**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 is noticeable, it might not be enough to overcome the other significant drawbacks of Ligand B.

**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 an enzyme inhibitor: lower DILI risk, better solubility, significantly better metabolic stability (lower Cl_mic), and lower P-gp efflux. The negative Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh the slight affinity difference.

Output:
0
2025-04-17 12:00:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (397.591 Da) is still well within the range.

**TPSA:** Ligand A (87.46) is better than Ligand B (66.32), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (A: 2.156, B: 3.576), falling within the optimal 1-3 range. Ligand B is a bit higher, potentially raising concerns about off-target effects, but not drastically.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.714, B: 0.807), indicating good drug-like properties.

**DILI:** Ligand A (45.677) has a lower DILI risk than Ligand B (65.917). This is a significant advantage for Ligand A.

**BBB:** Ligand A (62.621) has a better BBB penetration percentile than Ligand B (45.328), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.748) has a worse Caco-2 permeability than Ligand B (-5.36).

**Aqueous Solubility:** Ligand A (-3.316) has a better aqueous solubility than Ligand B (-3.752). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.187) has a much lower hERG inhibition liability than Ligand B (0.511). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (81.155) has a higher microsomal clearance than Ligand B (51.465), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-21.582) has a much worse in vitro half-life than Ligand B (14.028). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.196) has a lower P-gp efflux liability than Ligand B (0.553).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks. The difference of 2.1 kcal/mol is substantial.

**Conclusion:**

While Ligand A has advantages in DILI, hERG, solubility and P-gp efflux, Ligand B's significantly stronger binding affinity (-8.9 vs -6.8 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are more critical for an enzyme inhibitor. The lower DILI and hERG risk of Ligand A are positive, but the potency and stability advantages of Ligand B are more impactful.

Output:
1
2025-04-17 12:00:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.825 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (78.09), both are acceptable but A is preferable.

**logP:** Both ligands have good logP values (3.724 and 3.052), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3 HBA, which is acceptable.

**QED:** Both ligands have reasonable QED values (0.821 and 0.72), indicating good drug-likeness.

**DILI:** Ligand B (36.409) has a significantly lower DILI risk than Ligand A (80.729). This is a major advantage for Ligand B.

**BBB:** Ligand A (77.162) has a higher BBB penetration score than Ligand B (64.482), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.559) is slightly better than Ligand B (-4.947).

**Aqueous Solubility:** Ligand B (-3.626) has better aqueous solubility than Ligand A (-5.733). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.552 and 0.412), which is excellent.

**Microsomal Clearance:** Ligand B (71.774) has lower microsomal clearance than Ligand A (89.959), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-2.751) has a significantly longer in vitro half-life than Ligand A (56.704), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.149).

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

**Conclusion:**

While both ligands have good potency, Ligand B is superior due to its significantly lower DILI risk, better solubility, and substantially improved metabolic stability (lower Cl_mic and longer t1/2). The slightly lower BBB penetration is not a concern for a non-CNS target like SRC kinase. The Caco-2 permeability is a concern for both, but the other advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 12:00:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (360.336 Da) is also acceptable.

**TPSA:** Ligand A (47.34) is significantly better than Ligand B (87.32). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (3.446) is optimal, while Ligand B (1.152) is a bit low. A logP below 1 can sometimes hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Fewer hydrogen bonds generally improve membrane permeability.

**QED:** Both ligands have similar, good QED values (0.846 and 0.843), indicating good drug-like properties.

**DILI:** Ligand A (76.58) has a higher DILI risk than Ligand B (65.917), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.488) is slightly better than Ligand B (67.158).

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests issues with the prediction method or the compounds themselves. However, the values are similar.

**Aqueous Solubility:** Ligand A (-4.994) is worse than Ligand B (-3.015). Solubility is a key factor for bioavailability, and Ligand B has a better score.

**hERG Inhibition:** Ligand A (0.923) has a slightly higher risk of hERG inhibition than Ligand B (0.387), which is preferable.

**Microsomal Clearance:** Ligand B (5.221) has a significantly lower microsomal clearance than Ligand A (51.942), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-5.054) has a longer in vitro half-life than Ligand A (-8.564), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.645) has lower P-gp efflux than Ligand B (0.018), which is better.

**Binding Affinity:** Ligand B (-7.4 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 minor ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better TPSA and P-gp efflux, Ligand B's significantly superior binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and better solubility are more critical for an enzyme inhibitor targeting SRC. The slightly lower logP and higher TPSA of Ligand B are less concerning given the strong binding affinity.

Output:
1
2025-04-17 12:00:32,358 - INFO - Batch 94 complete. Total preferences: 1504
2025-04-17 12:00:32,359 - INFO - Processing batch 95/512...
2025-04-17 12:01:13,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.515 and 341.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.32 and 71.96) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.67 and 3.246) are 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:** Both have 2 HBD, well 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 high QED scores (0.838 and 0.84), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 57.076, while Ligand B has 46.297. Both are acceptable (below 60), but Ligand B is preferable.

**BBB:** Both have moderate BBB penetration (62.311 and 72.005). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.169 and -5.103). This 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 (-3.051 and -3.136), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.324 and 0.716), which is positive.

**Microsomal Clearance:** Ligand B has a lower microsomal clearance (32.33 mL/min/kg) than Ligand A (36.573 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (34.741 hours) than Ligand A (14.442 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.107 and 0.109).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference of 0.1 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the better candidate. While both have similar potency and acceptable safety profiles, Ligand B exhibits better metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower DILI risk. The solubility is a concern for both, but the ADME profile of Ligand B is slightly more favorable overall.

Output:
1
2025-04-17 12:01:13,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.519 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold for good absorption, while Ligand B (91.32) is still acceptable but closer to the limit.

**logP:** Ligand A (3.868) is at the higher end of the optimal 1-3 range, while Ligand B (2.652) is comfortably within it.  Ligand A's higher logP *could* lead to off-target effects, but isn't a major concern yet.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED values (0.684 and 0.599, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (51.725) has a higher DILI risk than Ligand B (33.773), which is a significant negative.

**BBB:** BBB is not a primary concern for a kinase inhibitor, but Ligand A (63.28) has a slightly better value than Ligand B (40.946).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.865 and -4.867), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.01 and -3.796), indicating very poor aqueous solubility. This is a significant issue for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.397 and 0.29), which is positive.

**Microsomal Clearance:** Ligand A (55.07) has lower microsomal clearance than Ligand B (77.203), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (3.305 hours) has a shorter half-life than Ligand B (-32.422 hours). The negative value for Ligand B is suspect and likely indicates a very long half-life, which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.332 and 0.047).

**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 has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. It also has a lower DILI risk and a potentially very long half-life. While its TPSA is a bit higher and solubility is poor (like Ligand A), the superior affinity and safety profile are compelling. Ligand A has better metabolic stability (lower Cl_mic), but the weaker binding and higher DILI risk are significant drawbacks. The negative solubility and Caco-2 values for both are concerning and would require addressing during optimization, but the potency advantage of Ligand B is more easily addressed through structural modifications than improving the affinity of Ligand A.

Output:
1
2025-04-17 12:01:13,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.419 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (54.12) is significantly better than Ligand B (80.64). A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**logP:** Ligand A (4.923) is higher than ideal (1-3), potentially leading to solubility issues. Ligand B (1.035) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is better balanced. Ligand B (HBD=1, HBA=5) has a higher number of HBA, which could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.711, B: 0.841), indicating good drug-like properties.

**DILI:** Ligand A (83.637) has a higher DILI risk than Ligand B (47.421). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (70.609) is slightly better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**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 (-6.754) has significantly worse solubility than Ligand B (-2.414). This is a major concern given the high logP of Ligand A.

**hERG Inhibition:** Ligand A (0.815) has a slightly higher hERG risk than Ligand B (0.361).

**Microsomal Clearance:** Ligand B (35.439) has significantly lower microsomal clearance than Ligand A (69.806), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-23.817) has a longer half-life than Ligand A (37.423). Again, this is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.777) has slightly higher P-gp efflux than Ligand B (0.032), meaning Ligand B is less likely to be pumped out of cells.

**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's still a factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is a bit low, it's compensated for by significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, better solubility, and slightly better binding affinity. Ligand A suffers from high logP, poor solubility, and a higher DILI risk, which are major liabilities. The slightly better BBB of Ligand A is not enough to offset these drawbacks.

Output:
1
2025-04-17 12:01:13,069 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.391 and 353.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.19) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (96.87) is well within the ideal range.

**logP:** Ligand A (0.38) is quite low, potentially hindering permeability. Ligand B (1.721) 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 7 HBA, both acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.599 and 0.703), indicating drug-like properties.

**DILI:** Ligand A (53.315) has a moderate DILI risk, while Ligand B (91.508) has a higher DILI risk. This favors Ligand A.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (54.634) and Ligand B (24.506) are both low, which is fine.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.143 and -5.575), 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 (-2.075 and -3.028), indicating poor aqueous solubility. Ligand B is slightly worse.

**hERG:** Both ligands have very low hERG inhibition liability (0.135 and 0.073), which is excellent.

**Microsomal Clearance:** Ligand A (-10.102) has significantly lower (better) microsomal clearance than Ligand B (14.358), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Both have similar in vitro half-lives (16.042 and 17.313 hours), which are acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.032), which is good.

**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 notable.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic). While its logP is lower and DILI risk is slightly higher, the superior potency and metabolic stability outweigh these drawbacks, especially for a kinase inhibitor where maintaining adequate concentrations at the target site is crucial. Ligand B has a better logP and TPSA, but its weaker binding affinity and poorer metabolic stability are significant disadvantages. The solubility issues are similar for both.

Output:
0
2025-04-17 12:01:13,069 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.535 and 362.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.01) is significantly better than Ligand B (61.02). A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**logP:** Both ligands have logP values (3.913 and 4.433) within the optimal 1-3 range, although Ligand B is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 3 HBA) as it has fewer hydrogen bond donors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.75 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (4.343 percentile) has a much lower DILI risk than Ligand B (51.725 percentile). This is a significant advantage for Ligand A.

**BBB:** Ligand A (93.408 percentile) shows excellent BBB penetration, while Ligand B (70.958 percentile) is good but lower. While not a primary concern for a kinase inhibitor, higher BBB is never detrimental.

**Caco-2 Permeability:** Ligand A (-4.358) has poor Caco-2 permeability, while Ligand B (-5.079) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.542) is better than Ligand B (-4.183) in terms of aqueous solubility. Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.91 and 0.9), indicating a potential risk for cardiotoxicity.

**Microsomal Clearance:** Ligand A (38.65 mL/min/kg) has significantly lower microsomal clearance than Ligand B (80.682 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.742 hours) has a much longer in vitro half-life than Ligand B (69.005 hours). This is a substantial advantage for Ligand A, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.279 and 0.366).

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). While the difference is not huge, it's still a positive for Ligand A.

**Overall:**

Ligand A is superior to Ligand B. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and slightly better binding affinity. While Caco-2 permeability is poor for both, the other advantages of Ligand A outweigh this drawback, especially considering the target is a kinase and not necessarily reliant on high intestinal absorption.



Output:
1
2025-04-17 12:01:13,069 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.375 and 367.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.49) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (98.17) is excellent, well below 140.

**logP:** Ligand A (0.522) is a bit low, potentially hindering permeability. Ligand B (2.96) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.755) has a good drug-likeness score. Ligand B (0.405) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (69.756) has a moderate DILI risk, but still acceptable. Ligand B (37.185) has a lower, and thus preferable, DILI risk.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.892) has poor predicted Caco-2 permeability. Ligand B (-5.216) also has poor predicted Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-2.642 and -2.951 respectively). This is a significant concern.

**hERG Inhibition:** Ligand A (0.071) has a very low hERG risk, which is excellent. Ligand B (0.312) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (20.729) has a lower, and thus preferable, microsomal clearance, indicating better metabolic stability. Ligand B (46.856) has a higher clearance.

**In vitro Half-Life:** Ligand A (38.117) has a reasonable in vitro half-life. Ligand B (-9.345) has a very short, and thus undesirable, in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -8.1 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a better logP, lower DILI risk, and slightly better binding affinity. However, it suffers from a significantly lower QED score, a much shorter in vitro half-life, and a higher microsomal clearance. Ligand A, while having a slightly lower logP and a higher DILI risk, boasts a much better QED, significantly better metabolic stability (lower Cl_mic, longer t1/2), and a very low hERG risk. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies. Given the enzyme-specific priorities, the metabolic stability and safety profile (hERG) of Ligand A are more crucial than the slightly better binding affinity of Ligand B.

Output:
0
2025-04-17 12:01:13,069 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (93.46) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (A: 1.867, B: 2.882), 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 (A: 0.747, B: 0.853), indicating a drug-like profile.

**DILI:** Ligand B (31.02) has a significantly lower DILI risk than Ligand A (41.411), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.658) has a higher BBB score than Ligand A (55.874).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, these values are on a log scale and negative values indicate low permeability. Ligand A (-5.342) is worse than Ligand B (-5.088).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.174) is slightly better than Ligand B (-3.12).

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.139, B: 0.255), which is good.

**Microsomal Clearance:** Ligand B (32.82) has a lower microsomal clearance than Ligand A (50.219), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-1.469) has a slightly better in vitro half-life than Ligand A (-22.219).

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.137, B: 0.279).

**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 be considered, especially given the other favorable properties of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), better Caco-2 permeability, and slightly better binding affinity. While both have poor solubility, the other advantages of Ligand B outweigh this drawback. The lower TPSA of Ligand B is also a plus.

Output:
1
2025-04-17 12:01:13,069 - INFO - Here's a step-by-step reasoning for selecting the better drug candidate, followed by the final output:

**Reasoning:**

We are evaluating two ligands (A and B) for their potential as kinase inhibitors (targeting SRC, an enzyme). Our priorities are potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

1. **Molecular Weight:** Both ligands (351.403 and 358.467 Da) fall within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (133.74) is better than Ligand B (68.09) as it is closer to the threshold for good oral absorption (<=140).

3. **logP:** Both ligands have good logP values (1.88 and 2.022), falling within the optimal 1-3 range.

4. **H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (0), 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:** Ligand B (0.818) has a significantly better QED score than Ligand A (0.526), indicating a more drug-like profile.

7. **DILI:** Ligand B (55.758) has a lower DILI risk than Ligand A (60.915), which is favorable. Both are below the concerning threshold of 60.

8. **BBB:** Both ligands have similar BBB penetration (64.87 and 63.358), which isn't a primary concern for a non-CNS target like SRC.

9. **Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.168 and -5.307). 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 (-3.782 and -1.982). This is also concerning, indicating poor solubility. Ligand B is slightly better than Ligand A.

11. **hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.291 and 0.256), which is excellent.

12. **Microsomal Clearance:** Ligand B (41.918) has a significantly lower microsomal clearance than Ligand A (65.08), suggesting better metabolic stability. This is a key advantage.

13. **In vitro Half-Life:** Ligand B (-10.359) has a much longer in vitro half-life than Ligand A (-24.791), indicating better stability. This is another key advantage.

14. **P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.124 and 0.047).

15. **Binding Affinity:** Both ligands have similar and strong binding affinities (-8.4 and -8.9 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While Ligand A has a slightly better TPSA, Ligand B demonstrates superior drug-like properties (QED), lower DILI risk, significantly improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. Given our priorities for enzyme inhibitors, the improved metabolic stability and drug-likeness of Ligand B make it the more promising candidate.

**Output:**
1
2025-04-17 12:01:13,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (399.288 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.26) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (94.92) is still under 140, but less favorable than A.

**logP:** Ligand A (4.093) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-0.633) is below 1, which is less ideal for permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 7 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.656 and 0.758, respectively), indicating drug-like properties.

**DILI:** Ligand A (68.244) has a higher DILI risk than Ligand B (48.623), but both are acceptable (<60 is good).

**BBB:** Both have similar BBB penetration (44.552 and 43.815), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.008 and -4.986), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-4.32 and -0.758). This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.702) has a slightly higher hERG risk than Ligand B (0.117), but both are relatively low.

**Microsomal Clearance:** Ligand A (25.89) has a higher microsomal clearance than Ligand B (1.915), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (104.269) has a much longer in vitro half-life than Ligand B (4.163), which is a strong positive for Ligand A.

**P-gp Efflux:** Ligand A (0.56) has lower P-gp efflux than Ligand B (0.006), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol) - a difference of 1.8 kcal/mol, which is substantial.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, the significantly stronger binding affinity of Ligand A (-9.2 kcal/mol vs -7.4 kcal/mol) and its longer half-life (104.269 vs 4.163) outweigh the slightly higher DILI risk and higher clearance. The improved P-gp efflux is also a benefit. The binding affinity difference is large enough to potentially overcome the ADME liabilities with appropriate formulation strategies.

Output:
1
2025-04-17 12:01:13,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.375 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.76) is slightly above the preferred <140, but acceptable. Ligand B (61.44) is excellent, well below 140.

**logP:** Ligand A (0.246) is quite low, potentially hindering permeability. Ligand B (2.476) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

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

**QED:** Ligand A (0.805) has a very good QED score, indicating high drug-likeness. Ligand B (0.629) is still acceptable, but lower than A.

**DILI:** Ligand A (76.192) has a concerningly high DILI risk (above 60). Ligand B (14.657) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.578) is higher, but this isn't a major deciding factor. Ligand A (25.785) is low.

**Caco-2:** Both have negative Caco-2 values, which is unusual and likely indicates poor permeability in this assay. This is a concern for both.

**Solubility:** Both ligands have negative solubility values, which is also unusual and indicates very poor solubility. This is a significant drawback for both.

**hERG:** Ligand A (0.042) has a very low hERG risk, which is excellent. Ligand B (0.46) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (4.83) has a low Cl_mic, suggesting good metabolic stability. Ligand B (40.611) has a much higher Cl_mic, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (-2.951) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (-11.008) also has a negative half-life, indicating a data issue.

**P-gp:** Both ligands have very low P-gp efflux liability, which is good.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.5 and -8.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

Despite having a better QED score, Ligand A is significantly hampered by its high DILI risk, low logP, and questionable half-life data. Ligand B, while having a lower QED and higher Cl_mic, has a much more favorable DILI profile and a better logP. The similar binding affinities mean that the ADME properties become the deciding factor. The poor solubility and permeability (negative Caco-2) are concerning for both, but the DILI risk for Ligand A is a major red flag.

Output:
1
2025-04-17 12:01:13,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (58.44) is better than Ligand B (29.54). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (2.0) is optimal, while Ligand B (4.463) is high. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 0, Ligand B: 0).

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 4, Ligand B: 3).

**QED:** Ligand A (0.819) has a significantly better QED score than Ligand B (0.623), indicating a more drug-like profile.

**DILI:** Ligand A (30.826) has a much lower DILI risk than Ligand B (11.865), which is a significant advantage.

**BBB:** Ligand A (74.176) and Ligand B (97.053) both have high BBB penetration, but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-4.74) and Ligand B (-4.443) have similar Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.703) is better than Ligand B (-5.285). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.202) has a lower hERG risk than Ligand B (0.771), which is a crucial safety factor.

**Microsomal Clearance:** Ligand B (75.534) has higher microsomal clearance than Ligand A (40.563), meaning it's metabolized faster. Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand A (8.153) has a longer half-life than Ligand B (2.781), which is desirable.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.386), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.1 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. A 1.9 kcal/mol difference is quite significant.

**Conclusion:**

While Ligand A has superior ADME properties (better solubility, lower DILI, lower hERG, better metabolic stability, longer half-life, lower P-gp efflux, and higher QED), Ligand B boasts a much stronger binding affinity. Given that we are targeting an enzyme (SRC kinase), potency is paramount. The 1.9 kcal/mol difference in binding affinity is substantial enough to overcome the ADME liabilities of Ligand B, assuming these can be addressed through further optimization.

Output:
1
2025-04-17 12:01:13,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (346.515 and 349.391 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (96.77) is still acceptable, but higher, potentially indicating slightly reduced absorption.

**3. logP:** Ligand A (3.402) is optimal. Ligand B (-1.002) is significantly low, which could hinder membrane permeability and bioavailability.

**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):** Ligand A (2) is excellent. Ligand B (6) is acceptable, but higher.

**6. QED:** Both ligands have reasonable QED values (0.819 and 0.703), indicating good drug-like properties.

**7. DILI:** Ligand A (33.23) has a much lower DILI risk than Ligand B (57.076). This is a significant advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (73.866) is better than Ligand B (53.432), but not a deciding factor.

**9. 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 (-4.68) is slightly better than Ligand B (-4.753).

**10. Aqueous Solubility:** Ligand A (-4.326) is better than Ligand B (-1.39), indicating better solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.415 and 0.042).

**12. Microsomal Clearance (Cl_mic):** Ligand A (24.097) has a higher clearance than Ligand B (-9.767). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand B (-3.92) has a significantly longer half-life than Ligand A (38.02). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.142 and 0.012).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Overall Assessment:**

Ligand A excels in TPSA, logP, solubility, and DILI risk. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better half-life, which are crucial for kinase inhibitors. While Ligand A has a better solubility profile, the metabolic advantages of Ligand B are more important for an enzyme target. The binding affinity is the same for both, so this doesn't differentiate them.

Output:
1
2025-04-17 12:01:13,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (349.519 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is better than Ligand B (67.23), both are below the 140 A^2 threshold for good absorption.

**3. logP:** Both ligands (2.167 and 2.063) 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 (3) is lower than Ligand B (5), both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.66 and 0.839), indicating drug-likeness.

**7. DILI:** Ligand A (19.465) has a significantly lower DILI risk than Ligand B (29.779). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (68.166 and 66.615), which isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.656) is better than Ligand B (-5.3), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.8) is better than Ligand B (-2.46), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.532 and 0.605).

**12. Microsomal Clearance:** Ligand A (16.977) has significantly lower microsomal clearance than Ligand B (35.501), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.381) has a better in vitro half-life than Ligand B (-8.142).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.048 and 0.059).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 1 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It demonstrates better DILI risk, metabolic stability (lower Cl_mic, better t1/2), solubility, Caco-2 permeability, and a slightly improved binding affinity, all crucial factors for an enzyme inhibitor. While both compounds are generally drug-like, Ligand A's profile is more favorable for development.

Output:
1
2025-04-17 12:01:13,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.459 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (59.08), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.157) is optimal, while Ligand B (0.919) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (3) is acceptable, and Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (0.663 and 0.709), indicating drug-likeness.

**DILI:** Ligand A (35.556) has a lower DILI risk than Ligand B (23.149), which is preferable.

**BBB:** Both have similar BBB penetration (60.682 and 68.166). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.303) is worse than Ligand B (-4.636), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.305) is worse than Ligand B (-1.425), which is a concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.135 and 0.389).

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (34.289 and 33.596 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (5.931) has a significantly better in vitro half-life than Ligand A (-9.948). This is a major advantage for dosing considerations.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.094 and 0.098).

**Binding Affinity:** Both ligands have identical binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

While Ligand A has a slightly better DILI score and TPSA, Ligand B is superior overall due to its better logP, Caco-2 permeability, aqueous solubility, and significantly improved in vitro half-life. The binding affinity is the same for both, so the ADME properties become the deciding factors. The improved solubility and half-life of Ligand B are particularly important for an enzyme inhibitor.

Output:
1
2025-04-17 12:01:13,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.483 Da) is slightly lower, which could be beneficial for permeability. Ligand B (362.407 Da) is also good.

**TPSA:** Ligand A (37.39) is excellent, well below the 140 threshold for oral absorption. Ligand B (87.49) is higher, but still acceptable, though it *may* have slightly reduced absorption compared to A.

**logP:** Ligand A (4.816) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.852) is within the optimal range (1-3). This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (0 HBD, 7 HBA) is also reasonable.

**QED:** Ligand A (0.819) has a very good drug-likeness score. Ligand B (0.443) is lower, suggesting a less ideal overall drug-like profile.

**DILI:** Ligand A (36.293) has a low DILI risk, which is excellent. Ligand B (87.902) has a high DILI risk, a major concern.

**BBB:** Both have reasonable BBB penetration, but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted cautiously.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk, which is positive.

**Microsomal Clearance:** Ligand A (110.476) has higher clearance, indicating lower metabolic stability. Ligand B (86.914) has lower clearance, suggesting better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand A (7.889 hours) has a reasonable half-life. Ligand B (-0.752 hours) has a very short half-life, a significant drawback.

**P-gp Efflux:** Both ligands show low P-gp efflux, which is good.

**Binding Affinity:** Both ligands have very strong binding affinities (-9.0 and -9.3 kcal/mol), with Ligand B being slightly better. The affinity difference is small enough that it's unlikely to outweigh other factors.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its lower logP, better metabolic stability (lower Cl_mic), and significantly lower DILI risk outweigh the lower QED and very short half-life. The short half-life of B is a concern, but could potentially be addressed through structural modifications. The high DILI risk of A is a more serious issue that is harder to mitigate.

Output:
1
2025-04-17 12:01:13,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (415.288 Da) is slightly higher than Ligand B (366.447 Da), but both are acceptable.

**2. TPSA:** Ligand A (84.0) is well below the 140 threshold for oral absorption. Ligand B (114.94) is also below the threshold, but closer to it. This favors Ligand A.

**3. logP:** Both ligands have acceptable logP values (Ligand A: 1.737, Ligand B: 0.588), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands have reasonable 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: 8), below the limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.81, Ligand B: 0.702), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (Ligand A: 73.052, Ligand B: 74.719), and are within an acceptable range (<40 is good, >60 is high risk).

**8. BBB:** Ligand A (68.67) has a better BBB percentile than Ligand B (47.421). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**9. Caco-2 Permeability:** Ligand A (-4.399) shows better Caco-2 permeability than Ligand B (-5.78). This suggests better intestinal absorption for Ligand A.

**10. Aqueous Solubility:** Ligand A (-2.453) has better solubility than Ligand B (-1.925). Solubility is important for bioavailability, favoring Ligand A.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (Ligand A: 0.295, Ligand B: 0.035). Both are excellent.

**12. Microsomal Clearance:** Ligand A (28.646) has lower microsomal clearance than Ligand B (33.017), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-13.954) has a significantly longer in vitro half-life than Ligand B (-0.162). This is a substantial advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.039, Ligand B: 0.017).

**15. Binding Affinity:** Ligand A (-9.6 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 and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially binding affinity, metabolic stability (lower Cl_mic, longer t1/2), solubility, and Caco-2 permeability. While both have acceptable profiles, the superior potency and pharmacokinetic properties of Ligand A make it the more promising drug candidate for targeting SRC kinase.

Output:
1
2025-04-17 12:01:13,072 - INFO - Batch 95 complete. Total preferences: 1520
2025-04-17 12:01:13,072 - INFO - Processing batch 96/512...
2025-04-17 12:01:55,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.475 and 361.389 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.87) is better than Ligand B (70.16), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have similar logP values (1.218 and 1.322), 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:** Both ligands have 4 HBA, which is within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.666 and 0.741), indicating drug-like properties.

**7. DILI:** Ligand A (19.504) has a significantly lower DILI risk than Ligand B (47.305). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (84.102) has a higher BBB penetration percentile than Ligand A (42.148). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.82) has a worse Caco-2 permeability than Ligand B (-3.993).

**10. Aqueous Solubility:** Ligand A (-2.201) has a worse aqueous solubility than Ligand B (-1.609).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.149 and 0.415).

**12. Microsomal Clearance:** Ligand A (22.778) has a lower microsomal clearance than Ligand B (41.336), suggesting better metabolic stability. This is a key advantage for enzyme targets.

**13. In vitro Half-Life:** Ligand B (-23.354) has a longer in vitro half-life than Ligand A (2.779). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.068).

**15. Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.5 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is preferable due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic). While Ligand B has slightly better Caco-2 permeability, aqueous solubility, and in vitro half-life, the lower DILI and Cl_mic of Ligand A are more critical for an enzyme target like SRC kinase. The binding affinities are comparable, so the ADME properties become the deciding factor.

Output:
0
2025-04-17 12:01:55,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.491 and 382.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is significantly better than Ligand B (49.41), being well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.036) is optimal, while Ligand B (4.509) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.61 and 0.763), indicating drug-likeness.

**DILI:** Ligand A (4.382) has a very low DILI risk, while Ligand B (20.396) is higher, though still relatively low.

**BBB:** Ligand A (68.127) and Ligand B (86.623) are both acceptable, but not particularly high, which isn't a major concern for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-5.205) is poor, while Ligand B (-4.908) is also poor.

**Aqueous Solubility:** Ligand A (-1.923) is poor, while Ligand B (-3.71) is even worse.

**hERG Inhibition:** Ligand A (0.34) has a very low hERG risk, which is excellent. Ligand B (0.637) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-3.238) indicates very low clearance and good metabolic stability. Ligand B (55.76) shows high clearance and poor metabolic stability.

**In vitro Half-Life:** Ligand A (-15.342) suggests a very long half-life, which is desirable. Ligand B (17.095) is reasonable.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.375) is slightly higher.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). The difference of 0.9 kcal/mol is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand B's higher logP, lower solubility, and higher clearance, its substantially better binding affinity (-8.5 vs -7.6 kcal/mol) is a critical advantage for an enzyme inhibitor. The difference in binding is significant enough to overcome the ADME liabilities. Ligand A has better ADME properties overall, but the potency advantage of Ligand B is too large to ignore.

Output:
1
2025-04-17 12:01:55,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (353.507 and 350.423 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.67) is significantly better than Ligand B (128.69). TPSA < 140 is good for oral absorption, and A is much closer to the ideal.

**3. logP:** Both ligands have acceptable logP values (1.544 and 0.689), falling within the 1-3 range.

**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 (6) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.694) is better than Ligand B (0.469). A QED > 0.5 is desirable, and A is comfortably above this threshold.

**7. DILI:** Ligand B (54.556) has a lower DILI risk than Ligand A (8.802), which is preferable. Both are below the 60 threshold.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (58.278) is better than Ligand B (9.616).

**9. Caco-2 Permeability:** Ligand A (-4.941) is better than Ligand B (-5.645). Higher values are better, indicating better absorption.

**10. Aqueous Solubility:** Ligand A (-1.012) is better than Ligand B (-2.178). Higher values are better.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.32 and 0.337), which is good.

**12. Microsomal Clearance:** Ligand B (-10.681) has significantly lower (better) microsomal clearance than Ligand A (24.483). Lower clearance indicates greater metabolic stability, a key priority for enzymes.

**13. In vitro Half-Life:** Ligand B (-7.274) has a longer in vitro half-life than Ligand A (-3.575), which is desirable.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.009 and 0.131), which is low and favorable.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.9 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While Ligand B has a slight edge in binding affinity and significantly better metabolic stability (lower Cl_mic and longer t1/2) and DILI risk, Ligand A performs better in TPSA, QED, Caco-2 permeability, and solubility. Given that SRC is an enzyme, metabolic stability and a lower DILI risk are paramount. The difference in binding affinity is small enough that it is outweighed by the superior ADME properties of Ligand B.

Output:
1
2025-04-17 12:01:55,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.423 and 343.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.74 and 96.88) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (0.138) is quite low, potentially hindering permeation. Ligand B (2.696) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (8) are within the acceptable range of <=10.

**QED:** Ligand A (0.776) has a better QED score than Ligand B (0.567), suggesting a more drug-like profile overall.

**DILI:** Ligand A (43.234) has a much lower DILI risk than Ligand B (66.421). This is a substantial advantage for Ligand A.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (40.558) is slightly higher than Ligand A (27.026).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.009 and -4.892), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.968 and -3.975), indicating very poor solubility. This is a major concern for both.

**hERG Inhibition:** Ligand A (0.071) shows very low hERG inhibition risk, a significant advantage. Ligand B (0.606) has a moderate risk.

**Microsomal Clearance:** Ligand A (-25.31) has a negative clearance, which is not possible and likely an error in the data. Ligand B (75.726) has a high clearance, indicating poor metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-4.306) has a negative half-life, which is not possible and likely an error in the data. Ligand B (15.087) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, a positive attribute. Ligand B (0.052) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, lower DILI risk, and lower hERG risk. However, its solubility and permeability appear very poor (negative values), and the negative clearance and half-life are data errors. Ligand B has better logP and a reasonable half-life, but suffers from higher DILI risk, moderate hERG risk, and a very poor metabolic stability (high clearance) and very weak binding affinity.

Despite the questionable data for Ligand A, the significantly superior binding affinity (-8.7 vs -0.0 kcal/mol) is a decisive factor. A 1.5 kcal/mol advantage is considered significant, and here the difference is over 8 kcal/mol. The solubility and permeability issues, while serious, might be addressable through formulation or further chemical modifications. The negative values for clearance and half-life are likely errors and would need to be re-evaluated.

Output:
1
2025-04-17 12:01:55,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (355.347 and 369.418 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (135.96) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (87.74) is excellent, well below 140, suggesting good absorption.

**3. logP:** Ligand A (-1.674) is a bit low, potentially hindering permeation. Ligand B (1.495) is within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (3 and 2 respectively), below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (8 and 5 respectively), below the threshold of 10.

**6. QED:** Ligand B (0.845) has a significantly better QED score than Ligand A (0.259), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.926) has a lower DILI risk than Ligand B (65.258), which is preferable.

**8. BBB:**  BBB is less critical for a non-CNS target like SRC kinase. Ligand B (60.644) has a higher BBB percentile than Ligand A (30.167), but this is not a primary concern here.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. Both are similarly poor.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.308) is slightly better than Ligand B (-3.176).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.069 and 0.154 respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand B (-7.908) has a *much* lower (better) Cl_mic than Ligand A (8.521). This suggests significantly improved metabolic stability for Ligand B.

**13. In vitro Half-Life (t1/2):** Ligand B (-22.302) has a much longer half-life than Ligand A (-9.08). This is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.043 respectively).

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.8 and -7.7 kcal/mol). The difference of 1.1 kcal/mol is not substantial enough to override other significant differences.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both have good affinity and hERG profiles, Ligand B excels in metabolic stability (Cl_mic and t1/2) and has a better QED score. Ligand A has a slightly better DILI score, but the benefits of Ligand B's improved pharmacokinetic properties outweigh this. The solubility is poor for both, but Ligand A is slightly better.

Output:
1
2025-04-17 12:01:55,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.43 and 380.54 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is higher than Ligand B (60.25). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**3. logP:** Both ligands (1.848 and 2.766) are 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 HBD can improve solubility.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (7), which is preferable.

**6. QED:** Both ligands have acceptable QED scores (0.824 and 0.739), indicating good drug-like properties.

**7. DILI:** Ligand A (23.50) has a significantly lower DILI risk than Ligand B (70.22), which is a major advantage.

**8. BBB:** Both have moderate BBB penetration, but Ligand B (68.59) is slightly higher. This isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.767) is slightly better than Ligand B (-5.099).

**10. Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.681) is slightly better than Ligand B (-2.978).

**11. hERG:** Both ligands have low hERG inhibition risk (0.379 and 0.352).

**12. Cl_mic:** Ligand A (46.81) has significantly lower microsomal clearance than Ligand B (69.44), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-18.17) has a negative half-life, which is concerning. Ligand B (6.28) has a positive half-life, which is much better.

**14. Pgp:** Both have low Pgp efflux liability (0.075 and 0.167).

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-6.9). The difference is 0.8 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. While Ligand A has a negative in vitro half-life, the other advantages outweigh this drawback, especially given that in vitro half-life doesn't always translate directly to in vivo performance. Ligand B has a better in vitro half-life, but its high DILI risk is a significant concern. The slight differences in solubility and Caco-2 permeability are less critical than the DILI and metabolic stability profiles.

Output:
0
2025-04-17 12:01:55,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.391 and 350.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.14) is slightly above the preferred <140 for good absorption, while Ligand B (84.42) is well within the range.

**logP:** Ligand A (-0.138) is quite low, potentially hindering permeation. Ligand B (0.501) is better, falling within the 1-3 optimal range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, which is acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.735 and 0.774), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (48.43 and 52.152), below the concerning threshold of 60.

**BBB:** This isn't a high priority for a non-CNS target like SRC, but Ligand B (82.513) shows better potential penetration than Ligand A (53.819).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.174 and -4.937). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily mean zero permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.943 and -0.895). Again, these are likely on a log scale and suggest poor solubility.

**hERG Inhibition:** Ligand A (0.025) has a very low hERG risk, which is excellent. Ligand B (0.121) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-17.933) shows significantly lower (better) microsomal clearance than Ligand B (-4.363), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (17.152) has a longer half-life than Ligand B (-6.083), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.016 and 0.013).

**Binding Affinity:** Ligand B (-10.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a lower hERG risk, Ligand B's significantly stronger binding affinity (-10.4 vs -8.1 kcal/mol) outweighs its slightly less favorable ADME properties. The difference in affinity is substantial enough to potentially overcome the lower solubility and permeability. The logP value for Ligand B is also more favorable. Given the enzyme-specific priorities, potency is paramount.

Output:
1
2025-04-17 12:01:55,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.447 and 339.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is slightly above the preferred <140, but acceptable. Ligand B (62.3) is well within the range.

**3. logP:** Both ligands have good logP values (1.347 and 2.467), 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 5 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.779 and 0.857), indicating good drug-like properties.

**7. DILI:** Ligand A (37.922) and Ligand B (23.885) both have low DILI risk, well below the 40 threshold.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.858) and Ligand B (79.062) are both moderate.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.928 and -4.905). This is unusual and suggests poor permeability. However, these values are on a log scale and close to zero, so the actual permeability might not be terrible, but it's a concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.361 and -2.486). Again, these are on a log scale and indicate poor solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.241 and 0.316).

**12. Microsomal Clearance:** Ligand A (18.371) has lower microsomal clearance than Ligand B (26.819), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.906 hours) has a significantly longer half-life than Ligand B (-12.726 hours). 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 (0.026 and 0.103).

**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 major advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values for both compounds, Ligand B is significantly more promising due to its much stronger binding affinity (-7.9 kcal/mol vs 0.0 kcal/mol). The longer half-life of Ligand A is attractive, but the lack of binding affinity is a critical flaw. The lower clearance of Ligand A is also a positive, but not enough to overcome the binding issue. Given the enzyme-kinase focus, potency is paramount. While solubility/permeability would need to be addressed through formulation or further chemical modification, the strong binding of Ligand B provides a solid starting point.

Output:
1
2025-04-17 12:01:55,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is slightly higher than Ligand B (58.64), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (2.135) is within the optimal 1-3 range. Ligand B (3.373) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, fulfilling the criteria of <=5 and <=10 respectively.

**QED:** Ligand A (0.857) has a better QED score than Ligand B (0.718), indicating a more drug-like profile.

**DILI:** Ligand A (12.408) has a significantly lower DILI risk than Ligand B (35.944). This is a major advantage.

**BBB:** Both ligands have good BBB penetration (78.054 and 76.192), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.59 and -4.696), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.878 and -2.917), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.149) shows a much lower hERG inhibition liability than Ligand B (0.643). This is a critical advantage, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (21.874) has a lower microsomal clearance than Ligand B (66.076), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.279) has a negative half-life, which is not physically possible. Ligand B (16.347) has a reasonable half-life. This is a critical disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux liability, while Ligand B (0.473) has a moderate level.

**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.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability. However, it has a nonsensical negative in vitro half-life and poor solubility/permeability. Ligand B has a reasonable half-life, but suffers from higher DILI and hERG risk, and lower binding affinity.

Despite the solubility/permeability issues for both, the significantly stronger binding affinity and improved safety profile (lower DILI and hERG) of Ligand A, coupled with better metabolic stability, make it the more promising candidate *assuming the negative half-life is a data error*. The 1.1 kcal/mol difference in binding affinity is substantial and can outweigh the ADME concerns, *if* those can be addressed through formulation or structural modification.

Output:
1
2025-04-17 12:01:55,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.427 and 388.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is better than Ligand B (78.87), both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.763 and 2.004), 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 maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.91) has a significantly better QED score than Ligand B (0.779), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (47.344 and 50.136, respectively), below the 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.107) is slightly better than Ligand B (65.917).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.345 and -4.983), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.105 and -3.718), which is also concerning, indicating very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.213) has a much lower hERG inhibition liability than Ligand B (0.777), which is a major advantage.

**Microsomal Clearance:** Ligand A (46.15 mL/min/kg) has a significantly better (lower) microsomal clearance than Ligand B (14.276 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (34.532 hours) has a much longer in vitro half-life than Ligand B (20.675 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.181).

**Binding Affinity:** Ligand B (-8.1 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, and can be outweighed by the other ADME properties.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the superior candidate. Ligand A demonstrates significantly better QED, lower hERG risk, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. While both have poor Caco-2 permeability and solubility, Ligand A's other advantages make it more likely to be developed into a viable drug candidate. The solubility and permeability issues would need to be addressed through formulation strategies, but the other properties are more difficult to improve.

Output:
0
2025-04-17 12:01:55,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.381 and 342.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (42.54) is well below the 140 threshold and favorable. Ligand B (62.55) is still acceptable, but less optimal.

**3. logP:** Both ligands have good logP values (3.394 and 2.82), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is excellent, while Ligand B (1) is still 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 good QED scores (0.687 and 0.837), indicating good drug-like properties.

**7. DILI:** Ligand A (55.138) has a moderate DILI risk, while Ligand B (15.51) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Both ligands have reasonable BBB penetration (90.617 and 66.344). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.387 and -4.89), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.462 and -2.772), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.87) and Ligand B (0.177) both have low hERG inhibition risk, which is good. Ligand B is significantly better.

**12. Microsomal Clearance:** Ligand A (63.982) has higher microsomal clearance than Ligand B (37.767), meaning it is less metabolically stable. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (21.527) has a longer half-life than Ligand B (12.221), which is favorable.

**14. P-gp Efflux:** Ligand A (0.878) has slightly higher P-gp efflux than Ligand B (0.102), meaning B will have better bioavailability.

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.8 kcal/mol).

**Overall Assessment:**

Despite both ligands having excellent binding affinity, Ligand B is the more promising candidate. It has a significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While both have poor solubility and permeability, the lower DILI and improved metabolic stability of Ligand B outweigh the slightly shorter half-life and slightly higher BBB penetration of Ligand A. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but starting with a molecule with a better safety profile and metabolic stability is preferable.

Output:
1
2025-04-17 12:01:55,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.417 and 381.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (106.96), being comfortably below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have good logP values (2.99 and 3.366), falling within the optimal 1-3 range.

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

**QED:** Ligand A (0.747) has a significantly better QED score than Ligand B (0.296), indicating a more drug-like profile.

**DILI:** Ligand A (37.999) has a lower DILI risk than Ligand B (47.964), both are acceptable but A is better.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (67.197) is better than Ligand B (43.273).

**Caco-2 Permeability:** Ligand A (-4.767) is better than Ligand B (-5.023).

**Aqueous Solubility:** Ligand A (-3.084) is better than Ligand B (-3.383).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.267 and 0.496).

**Microsomal Clearance:** Ligand A (42.548) has higher clearance than Ligand B (25.449), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (25.266) has a much longer half-life than Ligand A (-3.735). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.055 and 0.1).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand A has advantages in QED, DILI, solubility, and Caco-2 permeability. However, Ligand B excels in metabolic stability (lower Cl_mic, longer half-life) and has slightly better binding affinity. Given that we are targeting a kinase (enzyme), metabolic stability and potency are paramount. The substantial difference in half-life and the slightly better affinity of Ligand B outweigh the advantages of Ligand A.

Output:
1
2025-04-17 12:01:55,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.362 and 367.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.5) is slightly higher than Ligand B (78.43). Both are acceptable, but Ligand B is better for oral absorption.

**logP:** Ligand A (0.092) is quite low, potentially hindering permeation. Ligand B (1.308) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.758 and 0.786), indicating drug-likeness.

**DILI:** Ligand A (41.062) has a slightly higher DILI risk than Ligand B (29.973), but both are below the concerning threshold of 60.

**BBB:** Ligand A (83.637) has better BBB penetration than Ligand B (40.403). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.885) has significantly worse Caco-2 permeability than Ligand B (-5.369). Both are negative, indicating poor permeability, but Ligand B is slightly better.

**Aqueous Solubility:** Ligand A (-3.235) has slightly better solubility than Ligand B (-0.753). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.172 and 0.101), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance (6.853 and 6.856 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (27.046 hours) has a much longer half-life than Ligand A (-6.446 hours). 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 (0.068 and 0.039), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent and the most important factor.

**Conclusion:**

While both ligands have good binding affinity, Ligand B is superior due to its better logP, longer half-life, and slightly lower DILI risk. Ligand A's low logP and poor Caco-2 permeability are significant drawbacks. The slightly better solubility of Ligand A is not enough to offset these issues.

Output:
1
2025-04-17 12:01:55,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.487 and 353.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (54.34) is well below the 140 threshold and very favorable. Ligand B (99.49) is still within the acceptable range but less optimal.

**logP:** Ligand A (3.144) is optimal. Ligand B (0.321) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but edging towards the higher end.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is acceptable, but higher.

**QED:** Ligand A (0.891) is excellent. Ligand B (0.563) is acceptable, but less favorable.

**DILI:** Ligand A (20.434) has a very low DILI risk. Ligand B (28.655) is also low, but higher than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.054) is moderate, while Ligand B (27.801) is low.

**Caco-2 Permeability:** Ligand A (-4.67) is poor. Ligand B (-5.232) is also poor. Both are problematic, but B is slightly worse.

**Aqueous Solubility:** Ligand A (-2.628) is poor. Ligand B (-0.555) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.382) is very low risk. Ligand B (0.184) is also very low risk. Both are excellent.

**Microsomal Clearance:** Ligand A (40.455) is moderate. Ligand B (19.87) is low, indicating better metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand A (9.216) is moderate. Ligand B (11.699) is better.

**P-gp Efflux:** Ligand A (0.148) is low. Ligand B (0.01) is very low, suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.0) is significantly more potent than Ligand A (-7.8). This 1.5+ kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better TPSA, QED, and DILI, Ligand B's superior binding affinity (-8.0 vs -7.8 kcal/mol) and lower microsomal clearance (better metabolic stability) are crucial for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a concern, but the strong binding affinity and improved metabolic stability are more important. The lower P-gp efflux is also a positive.

Output:
1
2025-04-17 12:01:55,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.39 and 348.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.16) is borderline, but acceptable for an enzyme inhibitor. Ligand B (40.62) is excellent, well below the 140 threshold, suggesting good absorption.

**logP:** Ligand A (-0.459) is a bit low, potentially hindering permeability. Ligand B (3.841) is very good, 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:** Ligand A (5) is acceptable. Ligand B (2) is also good.

**QED:** Both ligands have good QED scores (0.575 and 0.732), indicating drug-like properties.

**DILI:** Ligand A (37.46) has a low DILI risk. Ligand B (18.11) has an even lower DILI risk, which is favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (35.44) and Ligand B (87.09) are not particularly relevant here, but B is better.

**Caco-2 Permeability:** Ligand A (-5.668) is very poor, indicating poor intestinal absorption. Ligand B (-4.69) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.107) is poor. Ligand B (-3.943) is also poor. Both ligands have solubility concerns.

**hERG Inhibition:** Ligand A (0.051) has very low hERG risk, which is excellent. Ligand B (0.641) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-16.242) has very low microsomal clearance, indicating high metabolic stability. Ligand B (77.937) has high microsomal clearance, suggesting rapid metabolism. This is a significant drawback for B.

**In vitro Half-Life:** Ligand A (10.779) has a reasonable half-life. Ligand B (-2.204) has a very short half-life, which is a major concern.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.003 and 0.484).

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is not substantial enough to outweigh the significant ADME deficiencies of Ligand B.

**Conclusion:**

Ligand A is the better candidate despite the slightly lower binding affinity. It has a much better metabolic profile (lower Cl_mic, longer t1/2), a lower DILI risk, and a significantly lower hERG risk. While both have solubility and permeability issues, Ligand A's superior metabolic stability and safety profile make it more likely to succeed as a drug candidate.

Output:
0
2025-04-17 12:01:55,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.754 Da) is slightly higher than Ligand B (369.487 Da), but both are acceptable.

**TPSA:** Ligand A (54.02) is significantly better than Ligand B (87.74). Lower TPSA generally improves cell permeability.

**logP:** Ligand A (4.558) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.499) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 5. Both are within acceptable limits (<=10).

**QED:** Both ligands have similar QED values (0.688 and 0.684), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 48.081, Ligand B: 45.366).

**BBB:** Ligand A (65.219) has a better BBB percentile than Ligand B (40.403), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.186 and -5.255), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.428 and -1.776), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.504) has a slightly higher hERG risk than Ligand B (0.313), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (39.518) has a higher microsomal clearance than Ligand B (24.407), meaning it's less metabolically stable. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-21.61) has a negative half-life, which is not possible. This is a major red flag for Ligand B. Ligand A (84.471) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux than Ligand B (0.033), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). The difference is 0.3 kcal/mol, which is not huge, but still favors Ligand A.

**Conclusion:**

Despite both ligands having significant issues with solubility and permeability, Ligand A is the better candidate. It has a better binding affinity, better metabolic stability (lower Cl_mic, higher t1/2), lower P-gp efflux, and a more reasonable (though still problematic) logP. Ligand B's negative half-life is a critical flaw. While both need substantial optimization, Ligand A presents a slightly more promising starting point.

Output:
0
2025-04-17 12:01:55,238 - INFO - Batch 96 complete. Total preferences: 1536
2025-04-17 12:01:55,238 - INFO - Processing batch 97/512...
2025-04-17 12:02:37,573 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.422 and 348.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.62) is significantly better than Ligand B (99.23). A TPSA under 140 is good for oral absorption, and A is comfortably within that range while B is approaching the upper limit.

**logP:** Ligand A (3.341) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (1.805) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 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 (0.688 and 0.875), indicating good drug-like properties.

**DILI:** Ligand A (64.366) has a higher DILI risk than Ligand B (52.889), but both are below the concerning threshold of 60.

**BBB:** Both have reasonable BBB penetration, but Ligand B (87.088) is better than Ligand A (73.905). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 have negative solubility values, again suggesting issues with the prediction.

**hERG:** Both ligands have very low hERG risk (0.371 and 0.394), which is excellent.

**Microsomal Clearance:** Ligand B (29.873) has significantly lower microsomal clearance than Ligand A (40.664), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-38.491) has a much longer in vitro half-life than Ligand A (26.139), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.194 and 0.099).

**Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent and removes this as a differentiating factor.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While Ligand A has a slightly better TPSA, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Given the enzyme-specific priorities for SRC kinase inhibitors, metabolic stability is crucial. The similar binding affinities mean the ADME advantages of Ligand B outweigh any minor differences in other properties.

Output:
1
2025-04-17 12:02:37,574 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (339.414 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.92) is slightly higher than Ligand B (58.64), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.803) is at the upper end of the optimal range (1-3), while Ligand B (2.801) 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:** 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 A (0.841) has a better QED score than Ligand B (0.751), indicating a more drug-like profile.

**DILI:** Ligand B (9.771) has a significantly lower DILI risk than Ligand A (56.921). This is a major advantage for Ligand B.

**BBB:** Ligand B (85.459) shows better BBB penetration than Ligand A (70.027), but since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.797 and -4.697), which is unusual and problematic. This suggests poor intestinal absorption for both, but the values are very similar.

**Aqueous Solubility:** Ligand B (-2.51) has better aqueous solubility than Ligand A (-4.59), which is a significant advantage for *in vivo* performance.

**hERG Inhibition:** Ligand A (0.883) has a slightly higher hERG inhibition risk than Ligand B (0.512), but both are reasonably low.

**Microsomal Clearance:** Ligand B (45.531) has a lower microsomal clearance than Ligand A (61.108), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (38.025) has a longer in vitro half-life than Ligand B (-0.846). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.279) shows lower P-gp efflux than Ligand B (0.176), which is slightly favorable.

**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 concerns. A difference of 3 kcal/mol is considerable.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity, which is paramount for an enzyme target like SRC. However, it has concerningly higher DILI risk and lower solubility. Ligand B has a significantly better safety profile (lower DILI) and improved solubility and metabolic stability, but its binding affinity is considerably weaker.

Given the substantial difference in binding affinity, and the fact that SRC is not a CNS target, I believe the stronger potency of Ligand A is likely to be more important than its slightly worse ADME properties. Optimization efforts could then focus on improving the ADME profile of Ligand A.

Output:
1
2025-04-17 12:02:37,574 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.5) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (24.06) is significantly better than Ligand B (43.86). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (4.437) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.606) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 3 HBA). Both are within acceptable limits, but a balance is generally preferred.

**QED:** Ligand A (0.845) has a much better QED score than Ligand B (0.608), indicating a more drug-like profile.

**DILI:** Ligand A (10.779) has a significantly lower DILI risk than Ligand B (5.196), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (Ligand A: 87.631, Ligand B: 83.288). While not a primary concern for a kinase inhibitor, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-5.198) and Ligand B (-4.689) 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 (-3.15) and Ligand B (-0.858) both have negative values, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.935) has a lower hERG risk than Ligand B (0.669), which is a positive.

**Microsomal Clearance:** Ligand A (-9.301) has a *much* better microsomal clearance (lower is better) than Ligand B (31.157), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (0.758) has a poor in vitro half-life, while Ligand B (-13.073) is extremely poor. Both are concerning, but Ligand B is significantly worse.

**P-gp Efflux:** Ligand A (0.238) has a lower P-gp efflux liability than Ligand B (0.069), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a critical advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from poor metabolic stability (high Cl_mic, very poor t1/2), poor solubility, and a higher DILI risk. Ligand A has better ADME properties across the board (DILI, metabolic stability, solubility, QED, TPSA, P-gp efflux), but its binding affinity is very weak.

Despite the superior binding affinity of Ligand B, the extremely poor metabolic stability and solubility are major red flags. It's unlikely to achieve sufficient *in vivo* exposure to be effective, even with strong binding. Ligand A, while weaker in binding, presents a more optimizable starting point due to its better ADME profile. It would be easier to improve the affinity of Ligand A through medicinal chemistry than to fix the severe metabolic and solubility issues of Ligand B.

Output:
0
2025-04-17 12:02:37,574 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.371 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.51) is better than Ligand B (69.72) as it is still within the acceptable range for oral absorption (<140), while ligand B is excellent.

**logP:** Ligand B (1.566) is optimal (1-3), while Ligand A (0.385) is a bit low, potentially hindering permeation.

**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, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.666 and 0.56), indicating good drug-like properties.

**DILI:** Ligand B (31.563) has a significantly lower DILI risk than Ligand A (63.978), which is a major advantage.

**BBB:** Ligand B (68.321) has a better BBB penetration score than Ligand A (41.218), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.413) has poor Caco-2 permeability, while Ligand B (-4.724) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.602 and -2.07). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.035) has a very low hERG risk, which is excellent. Ligand B (0.469) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-2.684) has a negative Cl_mic, indicating high metabolic stability, which is a significant advantage. Ligand B (53.744) has a high Cl_mic, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (5.849) has a shorter half-life than Ligand B (-24.636), but the negative value for B is suspect.

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is favorable. Ligand B (0.252) is slightly higher.

**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 relatively small.

**Overall Assessment:**

Ligand A has a better metabolic stability profile (lower Cl_mic, better half-life) and lower P-gp efflux, and a significantly lower hERG risk. However, its low logP and poor Caco-2 permeability are major drawbacks. Ligand B has a better logP, lower DILI risk, and slightly better binding affinity, but suffers from high metabolic clearance.

Given the priority for metabolic stability and safety (hERG) for enzyme inhibitors, and the relatively small difference in binding affinity, **Ligand A is the more promising candidate**, despite its permeability concerns. Formulation strategies could potentially mitigate the solubility and permeability issues. The improved metabolic stability and safety profile are more critical for long-term drug development.

Output:
0
2025-04-17 12:02:37,575 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.531 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.34) is slightly higher than Ligand B (85.89), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.648) is within the optimal 1-3 range. Ligand B (0.538) is a bit low, potentially hindering permeation, but not drastically.

**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 within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.61 and 0.653), indicating good drug-likeness.

**DILI:** Ligand A (34.626) has a slightly higher DILI risk than Ligand B (25.553), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (63.28 and 61.923), which isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-5.123) and Ligand B (-5.334) have negative values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-2.209) and Ligand B (-1.294) both have negative solubility values, indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.319) has a slightly higher hERG risk than Ligand B (0.133), but both are relatively low.

**Microsomal Clearance:** Ligand B (3.962) has significantly lower microsomal clearance than Ligand A (37.39), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (16.395) has a much longer in vitro half-life than Ligand A (5.234), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.147 and 0.012), which is favorable.

**Binding Affinity:** Ligand B (-9.0) has a substantially stronger binding affinity than Ligand A (-6.7). This difference of 2.3 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having poor Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.0 vs -6.7 kcal/mol), coupled with its much better metabolic stability (lower Cl_mic and longer t1/2), outweighs the slightly lower logP. The DILI and hERG risks are acceptable for both. Improving solubility and permeability would be critical for further development, but the potency and stability advantages of Ligand B make it the better starting point.

Output:
1
2025-04-17 12:02:37,575 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 and 364.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (83.98) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.94 and 2.45), falling within the 1-3 range.

**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.

**QED:** Both ligands have good QED scores (0.771 and 0.668), indicating drug-likeness.

**DILI:** Ligand A (5.82) has a significantly lower DILI risk than Ligand B (39.20). This is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (61.69) is slightly better than Ligand B (57.43).

**Caco-2 Permeability:** Ligand A (-4.715) is better than Ligand B (-5.328), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.617 and -2.776). This is a significant concern for both, but could be mitigated with formulation strategies.

**hERG:** Both ligands have low hERG risk (0.432 and 0.155), which is excellent.

**Microsomal Clearance:** Ligand A (40.997) has slightly higher Cl_mic than Ligand B (38.798), indicating slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (12.614) has a significantly longer half-life than Ligand A (-7.41). This is a substantial advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.218).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -9.1 kcal/mol). Ligand A is slightly more potent. The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is better overall. While Ligand B has a better half-life, Ligand A has a significantly lower DILI risk, better TPSA, better Caco-2 permeability, and slightly better binding affinity. The solubility is a concern for both, but the lower DILI risk is a critical factor for progressing a candidate.

Output:
0
2025-04-17 12:02:37,575 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.451 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (97.92 and 96.11) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (1.394 and 1.095) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 5 HBAs, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.64 and 0.718), indicating drug-like properties.

**DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (31.369). Both are below the 40 threshold, but A is preferable.

**BBB:** Ligand A (82.009) has a much higher BBB penetration percentile than Ligand B (58.24). While not a primary concern for a non-CNS target like SRC, higher BBB is generally not detrimental.

**Caco-2 Permeability:** Ligand A (-4.636) has a worse Caco-2 permeability than Ligand B (-5.512). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.076 and -2.152). This is a significant concern for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.253 and 0.129).

**Microsomal Clearance:** Ligand A (29.386) has a higher microsomal clearance than Ligand B (0.24). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (5.155) has a significantly longer in vitro half-life than Ligand A (1.738). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.01).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). This difference, while not huge, is meaningful.

**Overall Assessment:**

Ligand B appears to be the better candidate. While both have poor solubility, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity outweigh Ligand A's slightly lower DILI risk and better Caco-2 permeability. The difference in binding affinity, though small, is clinically relevant. The solubility issue would need to be addressed through formulation strategies for either compound.

Output:
1
2025-04-17 12:02:37,575 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (353.463 and 347.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (98.74 and 84.23) below 140, suggesting reasonable oral absorption potential.

**3. logP:** Ligand A (0.561) is slightly low, potentially hindering permeation. Ligand B (2.0) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) 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 (0.623 and 0.765), indicating drug-like properties.

**7. DILI:** Ligand A (10.508) has a very low DILI risk, significantly better than Ligand B (35.789).

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (46.724) is higher, but not a deciding factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.171 and -5.034), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.411 and -2.243), also unusual and concerning. Poor solubility can limit bioavailability.

**11. hERG Inhibition:** Ligand A (0.097) shows very low hERG inhibition risk, a major advantage. Ligand B (0.25) is slightly higher but still relatively low.

**12. Microsomal Clearance:** Ligand A (-15.822) exhibits excellent metabolic stability (low clearance), significantly better than Ligand B (26.651).

**13. In vitro Half-Life:** Ligand B (36.357) has a substantially longer half-life than Ligand A (0.885). This is a significant advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.036).

**15. 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 large enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, and metabolic stability. However, its low logP and poor Caco-2/solubility are major drawbacks. Ligand B has a better logP and a significantly longer half-life, but its DILI risk is higher. Given the enzyme-specific priorities, metabolic stability (Ligand A) and potency (Ligand B) are key. The difference in binding affinity is relatively small. The poor solubility and permeability of both are concerning, but the superior safety profile (DILI, hERG) and metabolic stability of Ligand A, coupled with its good binding affinity, make it the more promising candidate, assuming solubility/permeability can be addressed through formulation or further chemical modification.

Output:
0
2025-04-17 12:02:37,575 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 368.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is excellent, well below the 140 threshold for oral absorption. Ligand B (102.24) is still acceptable but less optimal.

**logP:** Ligand A (1.253) is within the optimal 1-3 range. Ligand B (-0.351) is slightly below 1, potentially hindering 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 limit of 10, but Ligand A is preferable.

**QED:** Ligand A (0.83) has a significantly better QED score than Ligand B (0.626), indicating better overall drug-likeness.

**DILI:** Ligand A (29.43) has a much lower DILI risk than Ligand B (58.627), a significant advantage.

**BBB:** Both ligands have similar BBB penetration (65.025 and 66.537), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.652) shows poor Caco-2 permeability, while Ligand B (-5.56) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.013 and -1.832). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.196 and 0.053).

**Microsomal Clearance:** Ligand A (52.215) has higher microsomal clearance than Ligand B (19.412), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-19.278) has a much longer in vitro half-life than Ligand A (-9.608), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.016).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better QED, and a much lower DILI risk. However, it has poorer Caco-2 permeability and higher microsomal clearance. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, but its binding affinity is weaker, and DILI risk is higher.

Given the priority for potency in enzyme inhibition, the stronger binding affinity of Ligand A is a critical advantage. While the solubility and permeability are concerns, these can be addressed through formulation. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 12:02:37,576 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.394 Da) is slightly lower, which could be beneficial for permeability. Ligand B (346.387 Da) is also good.

**TPSA:** Ligand A (33.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (97.44) is higher, potentially indicating lower absorption, but still within a reasonable range.

**logP:** Ligand A (4.774) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.054) is very low, which is problematic for membrane permeability and could result in poor bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is acceptable, but the higher number of HBAs could slightly hinder permeability.

**QED:** Both ligands have good QED scores (A: 0.676, B: 0.78), indicating drug-like properties.

**DILI:** Ligand A (69.794) has a slightly higher DILI risk than Ligand B (62.001), but both are reasonably acceptable.

**BBB:** This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (91.508) has better BBB penetration than Ligand B (59.325).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.632 and -4.82), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.851 and -2.218), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.924) has a slightly higher hERG risk than Ligand B (0.059), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (-8.197) has significantly lower (better) microsomal clearance than Ligand A (76.472), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.847) has a much longer in vitro half-life than Ligand A (41.241), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.832) has a slightly higher P-gp efflux liability than Ligand B (0.031), meaning B is less likely to be pumped out of cells.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While both are good, the 0.6 kcal/mol difference is noticeable.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, slightly better binding affinity, and lower logP outweigh the slightly higher DILI risk and lower BBB penetration. The extremely low logP of Ligand B is a concern, but the superior metabolic properties are critical for an enzyme inhibitor. The poor solubility of both compounds would need to be addressed through formulation strategies, but the metabolic advantages of Ligand B make it the better starting point for optimization.

Output:
1
2025-04-17 12:02:37,576 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.463 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.69) is slightly higher than Ligand B (62.74), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.249 and 1.45), 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 reasonable QED scores (0.751 and 0.64), indicating good drug-like properties.

**DILI:** Ligand A (27.336) has a slightly higher DILI risk than Ligand B (23.226), but both are below the concerning threshold of 40, indicating low liver injury risk.

**BBB:** Ligand A (72.043) has a lower BBB penetration than Ligand B (87.941). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.463) has lower Caco-2 permeability than Ligand B (-4.659), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.82) has lower aqueous solubility than Ligand B (-0.469), which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.908) has a slightly higher hERG inhibition risk than Ligand B (0.479), but both are relatively low.

**Microsomal Clearance:** Ligand A (38.127) has a higher microsomal clearance than Ligand B (22.46), indicating lower metabolic stability. This is a significant drawback for an enzyme target.

**In vitro Half-Life:** Ligand A (65.996) has a longer in vitro half-life than Ligand B (6.336), which is a positive attribute. However, this is somewhat offset by the higher clearance.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux than Ligand B (0.069), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.0), a difference of 0.6 kcal/mol. This is a meaningful difference, but must be weighed against the ADME properties.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and longer half-life, Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic) and solubility. The lower clearance of Ligand B is crucial for an enzyme target like SRC kinase, as it suggests a longer duration of action and potentially lower dosing requirements. The slightly better Caco-2 permeability and lower hERG risk of Ligand B also contribute to its overall better profile. The difference in binding affinity (0.6 kcal/mol) is unlikely to outweigh the significant ADME advantages of Ligand B.

Output:
1
2025-04-17 12:02:37,576 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.411 Da) is slightly lower, which is generally favorable for permeability. Ligand B (360.445 Da) is also good.

**TPSA:** Ligand A (71.63) is higher than Ligand B (49.85). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (A: 2.524, B: 2.196), 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 3 HBA. Both are within acceptable limits.

**QED:** Both have reasonable QED scores (A: 0.818, B: 0.624), indicating drug-like properties. Ligand A is better.

**DILI:** Ligand A (58.744) has a higher DILI risk than Ligand B (21.287). This is a significant advantage for Ligand B.

**BBB:** Ligand A (70.182) and Ligand B (93.68) both have good BBB penetration, but Ligand B is significantly better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 (-4.63 for A, -4.347 for B).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-1.705) is slightly better than Ligand A (-4.028).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.677, B: 0.722).

**Microsomal Clearance:** Ligand A (73.728) has higher microsomal clearance than Ligand B (42.145), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (9.985 hours) has a longer half-life than Ligand A (7.618 hours). This is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.362, B: 0.294).

**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 enough to be considered.

**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 solubility, and slightly better binding affinity. While Ligand A has a slightly better QED score and lower molecular weight, the advantages of Ligand B in terms of safety (DILI) and pharmacokinetics (metabolic stability, half-life) are more crucial for an enzyme inhibitor.



Output:
1
2025-04-17 12:02:37,576 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). A (431.338) and B (389.543) are both acceptable.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption. A (92.34) and B (97.39) are both acceptable.

**logP:** Both ligands have logP values within the optimal range (1-3). A (1.578) and B (2.078) are both acceptable.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. A (0.71) and B (0.63) are both acceptable.

**DILI:** Ligand A (75.068) has a higher DILI risk than Ligand B (65.723). Both are acceptable, but B is better.

**BBB:** This is less critical for a non-CNS target like SRC. A (42.071) and B (59.558) are both low, which is fine.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. A (-5.495) is slightly better than B (-4.763).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. A (-3.454) is slightly better than B (-3.071).

**hERG Inhibition:** Both ligands have low hERG inhibition risk. A (0.344) and B (0.381) are both acceptable.

**Microsomal Clearance:** Ligand A (-3.703) has significantly lower (better) microsomal clearance than Ligand B (61.645). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (26.505) has a shorter half-life than Ligand B (-45.79). This is a negative for A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability. A (0.138) and B (0.441) are both acceptable, with A being slightly better.

**Binding Affinity:** Ligand A (-8.7 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 significantly better binding affinity and better metabolic stability (lower Cl_mic). While its half-life is shorter, the strong binding affinity is a major advantage for an enzyme inhibitor. The slightly better DILI and P-gp efflux profiles also favor Ligand A. The solubility and Caco-2 permeability are poor for both, but the potency advantage of A outweighs these concerns.

Output:
1
2025-04-17 12:02:37,577 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 341.411 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (64.96) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (76.39) is still acceptable but less favorable.

**logP:** Ligand A (0.498) is a bit low, potentially hindering permeation. Ligand B (2.177) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 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 good QED scores (0.839 and 0.891), indicating generally drug-like properties.

**DILI:** Ligand A (36.06) has a much lower DILI risk than Ligand B (61.574), which is approaching a higher risk category. This is a significant advantage for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.891) and Ligand B (-5.236) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted carefully.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.244 and -1.952), which is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.323 and 0.285), which is positive.

**Microsomal Clearance:** Ligand A (-9.831) has a much lower (better) microsomal clearance than Ligand B (29.722), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (45.554) has a significantly longer in vitro half-life than Ligand B (1.683), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.02 and 0.113).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.8 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP and solubility concerns. Solubility can be addressed with formulation strategies, but mitigating metabolic instability and liver toxicity is more challenging.

Output:
0
2025-04-17 12:02:37,577 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (344.419 Da and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.84) is slightly higher than Ligand B (71.09), but both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.3) is within the optimal range (1-3). Ligand B (3.138) 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 (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 4 HBA, both are below the limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.755 and 0.699), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (55.487 and 57.348), both are acceptable (<60).

**8. BBB:** Ligand B (57.968) has a higher BBB penetration percentile than Ligand A (41.024). However, SRC is not a CNS target, so this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.267 and -5.108), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.393 and -3.744), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.197 and 0.253).

**12. Microsomal Clearance (Cl_mic):** Ligand A has a significantly lower Cl_mic (16.196 mL/min/kg) than Ligand B (57.363 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (5.525 hours) has a slightly shorter half-life than Ligand B (7.309 hours), but both are reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.015 and 0.472).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it's a positive for Ligand B.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic) and comparable DILI and hERG risk. The poor solubility and permeability are concerning for both, but metabolic stability is often easier to address through structural modifications than improving solubility drastically. The slight advantage in binding affinity of Ligand B is unlikely to outweigh the substantial difference in metabolic stability.

Output:
0
2025-04-17 12:02:37,577 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (373.787 and 337.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is well below the 140 threshold, while Ligand B (99.77) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (1.663) is optimal, while Ligand B (0.796) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 4 HBA) both meet the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.608 and 0.679, respectively), indicating drug-like properties.

**DILI:** Ligand A (54.75) has a lower DILI risk than Ligand B (60.682), which is preferable. Both are acceptable, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.937) has a significantly higher BBB percentile than Ligand B (20.357).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.148) is slightly better than Ligand B (-5.229).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.531) is slightly better than Ligand B (-2.633).

**hERG Inhibition:** Ligand A (0.692) has a lower hERG risk than Ligand B (0.115), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-27.048) exhibits much lower microsomal clearance than Ligand A (17.569), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-19.15) has a longer in vitro half-life than Ligand A (23.384), further supporting its improved metabolic stability.

**P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.015), which is better for oral bioavailability.

**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 less than the 1.5 kcal/mol threshold to outweigh significant ADME issues, it's still a positive factor.

**Overall Assessment:**

Ligand B has a substantial advantage in metabolic stability (lower Cl_mic and longer t1/2). This is a critical factor for kinase inhibitors. While Ligand A has slightly better solubility, permeability, and hERG risk, the metabolic stability of Ligand B is more important. The affinity difference is not large enough to overcome the ADME advantages of Ligand B.

Output:
1
2025-04-17 12:02:37,577 - INFO - Batch 97 complete. Total preferences: 1552
2025-04-17 12:02:37,578 - INFO - Processing batch 98/512...
2025-04-17 12:03:25,084 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.382 and 343.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (37.61) is better than Ligand B (46.61). Both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands have logP values (3.946 and 4.287) within the optimal range of 1-3, suggesting good permeability.

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

**H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.675 and 0.605), indicating good drug-likeness.

**DILI:** Ligand A (68.05) has a higher DILI risk than Ligand B (52.385). Lower is better, so B is preferable here.

**BBB:** Ligand A (93.408) has a higher BBB penetration percentile than Ligand B (71.656). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.488) has slightly better Caco-2 permeability than Ligand B (-4.5). Both are negative values, which is unusual and requires further investigation, but the difference is minor.

**Aqueous Solubility:** Ligand A (-4.786) has slightly better aqueous solubility than Ligand B (-5.116). Both are negative values, which is unusual and requires further investigation, but the difference is minor.

**hERG:** Ligand A (0.821) has a higher hERG risk than Ligand B (0.308). Lower is much better here, making B preferable.

**Microsomal Clearance:** Ligand A (90.221) has a higher microsomal clearance than Ligand B (95.521). Higher clearance means lower metabolic stability, so B is preferable.

**In vitro Half-Life:** Ligand A (39.911) has a longer in vitro half-life than Ligand B (-16.985). This is a significant advantage for A.

**P-gp Efflux:** Ligand A (0.585) has lower P-gp efflux than Ligand B (0.411). Lower efflux is preferable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.5 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. The 1.5 kcal/mol advantage threshold is easily met.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a longer half-life and slightly better permeability/solubility, Ligand B's significantly improved binding affinity (-7.7 vs -10.5 kcal/mol) and lower hERG and DILI risks outweigh these minor differences. The improved metabolic stability (lower Cl_mic) also contributes to its favorability.

Output:
1
2025-04-17 12:03:25,084 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight (MW):** Both ligands (346.475 and 375.441 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (78.09 and 75.44) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.652 and 1.735) are within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands (2 and 1) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (3 and 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.797 and 0.749) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (24.351) has a significantly lower DILI risk than Ligand B (37.65). This is a major advantage.

**8. BBB:** Both ligands have reasonable BBB penetration (67.352 and 73.711). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.308 and -5.042). This is unusual and indicates poor permeability. However, these values are on a log scale, so the absolute difference isn't massive.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.369 and -2.115). This is also concerning, and suggests formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.432 and 0.253).

**12. Microsomal Clearance (Cl_mic):** Ligand A (18.234) has a lower Cl_mic than Ligand B (33.902), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand B (-42.967) has a longer half-life than Ligand A (-24.467). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.109 and 0.144).

**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, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, and a longer half-life. However, it has a higher DILI risk and higher microsomal clearance. Ligand A has a much lower DILI risk and better metabolic stability. Both have poor Caco-2 and solubility. Given the enzyme-specific priorities, the stronger binding affinity of Ligand B is the most important factor. While the DILI risk is higher, it's not excessively high (37.65 is still below 60). The improved half-life also contributes to its favorability. The solubility and permeability issues could be addressed through formulation strategies.

Output:
1
2025-04-17 12:03:25,084 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.376 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is well below the 140 threshold and good for oral absorption. Ligand B (78.87) is also acceptable, but higher.

**logP:** Ligand A (3.333) is optimal. Ligand B (2.48) is also within the optimal range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 threshold.

**QED:** Ligand A (0.916) has a superior QED score compared to Ligand B (0.503), indicating better overall drug-likeness.

**DILI:** Ligand A (56.185) has a higher DILI risk than Ligand B (18.883). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (A: 78.596, B: 69.523), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.437) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.099) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -3.938, B: -3.049). This is a concern for both, but may be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.544, B: 0.698).

**Microsomal Clearance:** Ligand A (66.082) has higher microsomal clearance than Ligand B (62.474), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-13.781) has a significantly longer in vitro half-life than Ligand A (2.724), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.187, B: 0.125).

**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:**

Ligand A has a significantly better binding affinity, and a better QED. However, it suffers from poor Caco-2 permeability, higher DILI risk, and lower metabolic stability. Ligand B has a lower binding affinity, but a much better safety profile (lower DILI), and better metabolic stability (longer half-life). The difference in binding affinity (1.6 kcal/mol) is substantial enough to potentially overcome some of the ADME drawbacks of Ligand A, *if* the solubility and permeability issues can be addressed through formulation. However, the higher DILI risk is a serious concern. Given the enzyme class, metabolic stability and safety are paramount.

Output:
1
2025-04-17 12:03:25,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (418.316 and 382.291 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is better than Ligand B (71.09). Both are acceptable, but lower TPSA generally favors better absorption.

**3. logP:** Both ligands have good logP values (3.698 and 2.954), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD counts are generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3). Lower HBA counts are generally preferred for better permeability.

**6. QED:** Both ligands have good QED scores (0.688 and 0.77), indicating good drug-like properties.

**7. DILI:** Ligand B (44.552) has a significantly lower DILI risk than Ligand A (70.105). This is a major advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (75.882) is slightly better than Ligand B (67.623). However, BBB isn't a high priority for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.98 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 (-3.523 and -4.249), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.71) is better than Ligand B (0.331), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (12.496) has significantly lower microsomal clearance than Ligand A (69.7), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (13.876) has a longer in vitro half-life than Ligand A (91.813). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.542) is better than Ligand B (0.083), indicating lower P-gp efflux.

**15. Binding Affinity:** Ligand B (-10.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a major advantage for Ligand B, and can potentially overcome some of the ADME liabilities.

**Overall Assessment:**

Despite both ligands having poor solubility and permeability, Ligand B is the superior candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and substantially stronger binding affinity outweigh the slightly better BBB and P-gp efflux of Ligand A. The strong binding affinity of Ligand B suggests it may be effective at lower doses, potentially mitigating some of the solubility issues.

Output:
1
2025-04-17 12:03:25,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.39 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.31) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (93.43) is well within the acceptable range.

**logP:** Ligand A (-0.085) is a bit low, potentially hindering permeation. Ligand B (1.821) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar and good QED values (0.677 and 0.683, respectively).

**DILI:** Ligand A (79.682) has a significantly higher DILI risk than Ligand B (14.541). This is a major concern.

**BBB:** BBB is not a high priority for a non-CNS target like SRC. Ligand B has a higher BBB percentile (66.615) than Ligand A (38.038), but this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.354 and -5.023), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.785 and -2.035), which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.092) has a slightly lower hERG risk than Ligand B (0.705), which is favorable.

**Microsomal Clearance:** Ligand A (-27.756) has a much lower (better) microsomal clearance than Ligand B (9.883), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (5.935) has a longer half-life than Ligand B (1.297), which is desirable.

**P-gp Efflux:** Ligand A (0.028) has a much lower P-gp efflux liability than Ligand B (0.197), suggesting better bioavailability.

**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 factor.

**Overall Assessment:**

Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly lower hERG risk. However, its DILI risk is significantly higher, and its logP is suboptimal. Ligand B has a better logP and slightly better binding affinity, but suffers from higher DILI risk, higher Cl_mic, shorter half-life, and higher P-gp efflux.

Given the enzyme-specific priorities, metabolic stability and minimizing toxicity (DILI, hERG) are crucial. While Ligand B has a slightly better affinity, the significantly higher DILI risk and poorer metabolic profile of Ligand B make it less attractive. The lower DILI risk of Ligand A, despite its other drawbacks, makes it a more promising starting point for optimization.

Output:
0
2025-04-17 12:03:25,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (391.23 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.55) is better than Ligand B (107.03), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands (1.617 and 1.169) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands (5) are below the threshold of 10.

**QED:** Both ligands (0.764 and 0.755) are good, indicating a strong drug-like profile.

**DILI:** Ligand A (64.599) has a higher DILI risk than Ligand B (48.197), but both are acceptable.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a kinase inhibitor not targeting the CNS. Ligand A (79.062) is slightly better than Ligand B (66.072).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.001) is slightly better than Ligand B (-5.279).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand A (-3.398) is slightly better than Ligand B (-2.445).

**hERG Inhibition:** Ligand A (0.378) has a lower hERG inhibition risk than Ligand B (0.116), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-15.413) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (11.946). This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-8.358) has a longer in vitro half-life than Ligand B (-19.407), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.091).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 1 kcal/mol difference is noticeable.

**Overall:**

Ligand A is superior to Ligand B. While both have issues with solubility and Caco-2 permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and slightly better binding affinity. These factors are particularly important for kinase inhibitors. The slightly better DILI and BBB scores are also beneficial.

Output:
1
2025-04-17 12:03:25,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.531 and 377.897 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is well below the 140 threshold for good absorption, and favorable for kinase inhibitors. Ligand B (69.12) is still acceptable, but less optimal.

**3. logP:** Both ligands have logP values (3.698 and 4.06) within the optimal 1-3 range, suggesting good permeability. Ligand B is slightly higher, potentially increasing off-target interactions.

**4. H-Bond Donors:** Ligand A (0) is excellent, minimizing potential issues with permeability. Ligand B (1) is acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (4) is still within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.734 and 0.754), indicating good drug-like properties.

**7. DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (36.448), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.71) has better BBB penetration than Ligand B (65.568), but this is not a deciding factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.604 and -4.647), which 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 (-3.075 and -5.266), indicating very poor aqueous solubility. This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.633) has a lower hERG risk than Ligand B (0.853), which is a positive.

**12. Microsomal Clearance:** Ligand A (75.343) has a higher Cl_mic than Ligand B (48.993), meaning it's cleared more quickly and has lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (39.594) has a significantly longer in vitro half-life than Ligand A (-21.609), indicating better metabolic stability.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.288 and 0.293).

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a substantially better binding affinity than Ligand A (-6.2 kcal/mol). This 1.1 kcal/mol difference is significant and can outweigh other drawbacks.

**Conclusion:**

Despite the poor solubility and permeability predictions (Caco-2 and solubility values), Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.3 vs -6.2 kcal/mol) and better metabolic stability (longer half-life, lower Cl_mic) are crucial for an enzyme inhibitor. The lower DILI risk of Ligand A is attractive, but the substantial affinity advantage of Ligand B is more important. Further work would be needed to address the solubility issues, but the potency and stability profile of Ligand B make it the better starting point.

Output:
1
2025-04-17 12:03:25,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.833 and 383.558 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.65) is slightly above the preferred <140, but acceptable. Ligand B (38.13) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (1.426) is within the optimal 1-3 range. Ligand B (3.833) is towards the higher end 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 5 HBA, also acceptable.

**QED:** Ligand A (0.762) has a better QED score than Ligand B (0.64), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (40.713 and 41.373), both being good (below 40 is ideal, but these are acceptable).

**BBB:** Ligand A (60.411) has a lower BBB penetration percentile than Ligand B (96.743). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.127) has poor Caco-2 permeability, while Ligand B (-4.575) is slightly better but still low.

**Aqueous Solubility:** Ligand A (-2.894) has poor aqueous solubility, while Ligand B (-4.417) is even worse. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.197) has a very low hERG risk, which is excellent. Ligand B (0.716) has a higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-12.927) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (105.905) has a high microsomal clearance, suggesting rapid metabolism. This is a major drawback.

**In vitro Half-Life:** Ligand A (8.003) has a reasonable half-life. Ligand B (16.511) has a longer half-life, which is positive.

**P-gp Efflux:** Ligand A (0.05) has very low P-gp efflux, which is favorable. Ligand B (0.848) has higher P-gp efflux, potentially reducing bioavailability.

**Binding Affinity:** Ligand B (-7.8 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 some ADME drawbacks.

**Conclusion:**

Despite Ligand B's higher logP and poorer solubility, its significantly stronger binding affinity (-7.8 vs -8.5 kcal/mol) and better half-life are crucial for an enzyme target like SRC kinase. The metabolic stability of Ligand A is attractive, but the affinity difference is too large to ignore. The solubility issues of both compounds would need to be addressed through formulation strategies.

Output:
1
2025-04-17 12:03:25,086 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.358 and 346.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (33.2) is excellent, well below the 140 threshold for good absorption. Ligand B (96.17) is higher, but still acceptable, though potentially impacting absorption.

**3. logP:** Ligand A (4.619) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.324) is optimal.

**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:** Ligand A (2) and Ligand B (7) are both within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.731 and 0.665), indicating good drug-likeness.

**7. DILI:** Ligand A (40.713) has a lower DILI risk than Ligand B (59.907), which is a significant advantage.

**8. BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand A (93.137) has a higher BBB percentile than Ligand B (40.946).

**9. Caco-2 Permeability:** Ligand A (-4.433) and Ligand B (-5.164) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-4.651) and Ligand B (-1.345) both have negative values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.812) has a lower hERG risk than Ligand B (0.178), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (23.869) has higher microsomal clearance than Ligand B (-2.176), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (30.197) has a significantly longer in vitro half-life than Ligand A (0.196), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.435) has lower P-gp efflux liability than Ligand B (0.045), which is a slight advantage.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.6 kcal/mol difference is a critical factor, outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better DILI and hERG profiles, Ligand B's significantly stronger binding affinity (-8.2 vs -7.6 kcal/mol) and much longer half-life are critical advantages for an enzyme inhibitor. The slightly higher logP and DILI risk of Ligand B are less concerning given the potency and metabolic stability. The poor Caco-2 and solubility are shared concerns, but can be addressed through formulation strategies.

Output:
1
2025-04-17 12:03:25,086 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 B (78.68) is significantly better than Ligand A (105.66). Lower TPSA generally improves oral absorption.

**logP:** Ligand B (2.046) is within the optimal range (1-3), while Ligand A (-0.202) is below 1, potentially hindering permeation. This is a significant negative for Ligand A.

**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 (A: 0.592, B: 0.799), indicating drug-like properties.

**DILI:** Ligand A (11.981) has a much lower DILI risk than Ligand B (54.556). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (78.48) has a higher BBB penetration percentile than Ligand A (18.534). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.481 and -4.941), which is unusual and suggests poor permeability. However, the values are close, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values (-1.799 and -3.08). This is concerning for both, but Ligand B's is worse.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.136, B: 0.096), which is excellent.

**Microsomal Clearance:** Ligand A (-10.259) has significantly lower (better) microsomal clearance than Ligand B (57.138), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.7) has a negative half-life, which is nonsensical. Ligand B (10.626) has a reasonable half-life. This is a critical flaw for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.004, B: 0.064).

**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 and could potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic) and lower DILI risk. However, it has a very concerning negative in vitro half-life and a poor logP. Ligand B has a better logP and a reasonable half-life, but its binding affinity is very weak, and it has a significantly higher DILI risk and worse metabolic stability.

Given the enzyme-specific priorities, potency (affinity) and metabolic stability are paramount. While Ligand A's negative half-life is a major red flag, the substantial binding affinity advantage (-8.0 vs 0.0) is compelling. The poor logP and negative half-life would require significant medicinal chemistry effort to address. Ligand B's weak affinity makes it unlikely to be a viable candidate, even with its better logP.

Output:
0
2025-04-17 12:03:25,086 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (441.156 Da) is slightly higher than Ligand B (363.403 Da), but both are acceptable.

**TPSA:** Ligand A (45.23) is well below the 140 threshold for oral absorption. Ligand B (125.99) is also below the threshold, but higher than A.

**logP:** Ligand A (4.908) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-0.307) is quite low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=2, HBA=8) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar, good QED values (A: 0.674, B: 0.691), indicating generally drug-like properties.

**DILI:** Ligand B (76.386) has a lower DILI risk than Ligand A (59.519), which is a significant advantage.

**BBB:** Both have moderate BBB penetration, but Ligand A (88.29) is better than Ligand B (58.976). BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.713) has poor predicted Caco-2 permeability, while Ligand B (-5.84) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-5.824) has poor predicted solubility, while Ligand B (-2.261) is slightly better.

**hERG Inhibition:** Ligand A (0.524) shows a slightly higher risk of hERG inhibition than Ligand B (0.046), which is a significant advantage for B.

**Microsomal Clearance:** Ligand B (-7.849) has a *negative* microsomal clearance, which is extremely favorable, indicating excellent metabolic stability. Ligand A (60.928) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand B (-10.211) has a very long predicted half-life, further supporting its metabolic stability. Ligand A (52.371) has a moderate half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.396, B: 0.021), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -9.5 kcal/mol), with a negligible difference.

**Overall Assessment:**

Despite Ligand A having a slightly better BBB score, Ligand B is the superior candidate. The key advantages of Ligand B are its significantly lower DILI risk, *much* better metabolic stability (negative Cl_mic and long half-life), and lower hERG risk. While its logP and Caco-2 permeability are less ideal, the strong binding affinity and favorable ADME properties related to metabolism and toxicity outweigh these concerns, especially for an enzyme target where potency is already established. The poor solubility of Ligand A is also a concern.

Output:
1
2025-04-17 12:03:25,086 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (360.483 and 350.35 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.04) is significantly better than Ligand B (106.2). TPSA < 140 is good for oral absorption, and A is well within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.602 and 2.422, respectively), 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 (6), which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.729 and 0.82), indicating good drug-like properties.

**7. DILI:** Ligand A (60.915) has a slightly higher DILI risk than Ligand B (88.251), but both are acceptable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.845) is better than Ligand B (64.482).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.94 and -4.421), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**10. Aqueous Solubility:** Both ligands have similarly poor aqueous solubility (-3.95 and -3.892). This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Ligand A (0.13) has a much lower hERG risk than Ligand B (0.299), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (78.198) has a higher microsomal clearance than Ligand B (77.594), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-20.506) has a significantly longer in vitro half-life than Ligand A (11.801), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.407 and 0.111).

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.4), a difference of 0.6 kcal/mol. This is a meaningful difference, but not overwhelming.

**Overall Assessment:**

While Ligand B has a better binding affinity and a significantly longer half-life, Ligand A has a much lower hERG risk and better TPSA. The poor solubility and Caco-2 permeability are concerns for both. However, the hERG risk is a critical factor for kinase inhibitors, and Ligand A's significantly lower risk outweighs the slightly better affinity and half-life of Ligand B.

Output:
0
2025-04-17 12:03:25,086 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [344.419, 84.22, 0.479, 0, 6, 0.726, 53.083, 76.658, -5.106, -2.238, 0.034, 36.412, -7.131, 0.165, -7.9]
**Ligand B:** [346.515, 49.41, 3.668, 1, 2, 0.746, 19.426, 77.084, -4.796, -3.764, 0.602, 80.058, -15.979, 0.348, -7.8]

**Step-by-step comparison:**

1. **MW:** Both ligands (344.419 Da and 346.515 Da) are within the ideal range (200-500 Da).
2. **TPSA:** Ligand A (84.22) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.
3. **logP:** Ligand A (0.479) is a bit low, potentially hindering permeability. Ligand B (3.668) is within the optimal range (1-3).
4. **HBD:** Ligand A (0) is excellent, minimizing potential issues. Ligand B (1) is acceptable.
5. **HBA:** Ligand A (6) is good. Ligand B (2) is also good.
6. **QED:** Both ligands (0.726 and 0.746) have strong drug-like profiles.
7. **DILI:** Ligand A (53.083) has a higher DILI risk than Ligand B (19.426). This is a significant advantage for Ligand B.
8. **BBB:** Both ligands have good BBB penetration (76.658 and 77.084). This isn't a primary concern for SRC kinase, as it's not a CNS target.
9. **Caco-2:** Both have negative values, which is unusual. Assuming these are log scale values, both are poor.
10. **Solubility:** Both ligands have poor solubility (-2.238 and -3.764).
11. **hERG:** Ligand A (0.034) has a much lower hERG risk than Ligand B (0.602). This is a significant advantage for Ligand A.
12. **Cl_mic:** Ligand A (36.412) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (80.058).
13. **t1/2:** Ligand B (-15.979) has a much longer in vitro half-life than Ligand A (-7.131). This is a significant advantage for Ligand B.
14. **Pgp:** Ligand A (0.165) has lower P-gp efflux liability than Ligand B (0.348).
15. **Affinity:** Both ligands have very similar binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Similar for both.
*   **Metabolic Stability:** Ligand A is better (lower Cl_mic). Ligand B has a much longer half-life.
*   **Solubility:** Both are poor.
*   **hERG Risk:** Ligand A is significantly better.
*   **DILI:** Ligand B is significantly better.

**Conclusion:**

While Ligand A has better metabolic stability and a lower hERG risk, Ligand B has a significantly lower DILI risk and a much longer half-life. The longer half-life is a substantial advantage. The DILI risk for Ligand A is concerning. Given the similar affinities and the importance of metabolic stability and safety (DILI, hERG) for kinase inhibitors, **Ligand B is the more promising candidate.**

1
2025-04-17 12:03:25,087 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (372.824 Da) is also well within range.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (81.18) is slightly higher than Ligand B (75.71), but both are acceptable.

**logP:** Ligand A (3.808) is at the upper end of the optimal range (1-3), while Ligand B (1.672) is closer to the lower end. A higher logP can sometimes lead to off-target effects, but isn't a major concern here.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, balancing solubility and permeability.

**QED:** Both ligands have QED values above 0.5 (0.855 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (79.798%) compared to Ligand B (42.846%). This is a major red flag for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand B (76.309%) shows better penetration than Ligand A (61.846%).

**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 show low hERG inhibition risk (0.359 and 0.279).

**Microsomal Clearance:** Ligand A (107.395) has a much higher microsomal clearance than Ligand B (4.182), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-11.663) has a negative half-life, which is not possible. This is a major issue with Ligand B. Ligand A (7.516) has a reasonable half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.111 and 0.075).

**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 for Ligand B, potentially outweighing some of its other weaknesses.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the most critical factors for an enzyme inhibitor are potency, metabolic stability, and safety. Ligand B has a much stronger binding affinity and significantly better metabolic stability (lower Cl_mic) and lower DILI risk. Although the half-life of Ligand B is nonsensical, the other factors strongly favor it. Ligand A's high DILI risk and poor metabolic stability are major concerns.

Output:
1
2025-04-17 12:03:25,087 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**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 (385.511 Da) is also well within range.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (90.71) is better than Ligand A (101.16), getting closer to the 90 threshold for CNS penetration, though that's not a primary concern here.

**logP:** Ligand A (0.154) has a very low logP, which is a significant concern for membrane permeability and bioavailability. Ligand B (1.017) is much better, falling within the optimal 1-3 range.

**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:** Ligand A (0.729) has a higher QED score than Ligand B (0.559), indicating better overall drug-likeness. However, this is somewhat offset by its poor logP.

**DILI:** Ligand B (53.819) has a higher DILI risk than Ligand A (43.66), but both are below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.697) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.684) is better, but still low.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.579) is slightly better than Ligand B (-2.992).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.145 and 0.395, respectively). This is excellent.

**Microsomal Clearance:** Ligand A (-25.255) has a significantly *lower* (better) microsomal clearance than Ligand B (73.814), suggesting much greater metabolic stability.

**In vitro Half-Life:** Ligand A (29.14) has a better in vitro half-life than Ligand B (-32.614).

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.006 and 0.1, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent and a primary driver of activity.

**Conclusion:**

Despite Ligand A's better QED and lower DILI, its extremely low logP and resulting poor Caco-2 permeability are major drawbacks. The significantly better logP and metabolic stability (lower Cl_mic and better half-life) of Ligand B outweigh its slightly lower QED and higher DILI. The equal binding affinity makes the ADME properties the deciding factor. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:03:25,087 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.487 and 338.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.4) is slightly above the preferred <140, while Ligand B (77.63) is well within. This favors B for absorption.

**logP:** Both ligands (2.732 and 2.342) are 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:** Ligand A (4) and Ligand B (6) are both acceptable, below the threshold of 10.

**QED:** Both ligands (0.802 and 0.774) have excellent drug-likeness scores, well above 0.5.

**DILI:** Ligand A (54.75) and Ligand B (60.915) are both reasonably low risk, below the 60 threshold.

**BBB:** Both ligands have moderate BBB penetration (66.615 and 62.737). This is not a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.608) and Ligand B (-5.098) both have negative Caco-2 values, indicating poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-4.242) and Ligand B (-2.466) both have negative solubility values, indicating poor solubility. This is a significant concern for both.

**hERG:** Both ligands (0.24 and 0.372) have low hERG inhibition liability, which is excellent.

**Microsomal Clearance:** Ligand A (56.38) has a higher clearance than Ligand B (6.362). This suggests Ligand B is more metabolically stable, a key consideration for kinases.

**In vitro Half-Life:** Ligand A (-7.472) has a longer half-life than Ligand B (9.864). This is a positive for A.

**P-gp Efflux:** Both ligands (0.089 and 0.204) have low P-gp efflux, which is good.

**Binding Affinity:** Ligand A (-9.9) has a significantly stronger binding affinity than Ligand B (-6.8). This is a >3 kcal/mol difference, which is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A's significantly stronger binding affinity (-9.9 kcal/mol vs -6.8 kcal/mol) and longer half-life are compelling advantages. While Ligand B has better metabolic stability, the potency difference is substantial enough to favor Ligand A. The kinase target class prioritizes potency, and the difference here is significant.

Output:
1
2025-04-17 12:03:25,087 - INFO - Batch 98 complete. Total preferences: 1568
2025-04-17 12:03:25,087 - INFO - Processing batch 99/512...
2025-04-17 12:04:08,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.236 Da) is slightly higher than Ligand B (339.363 Da), but both are acceptable.

**TPSA:** Ligand A (47.28) is well below the 140 threshold for oral absorption. Ligand B (118.37) is also below the threshold, but higher than Ligand A.

**logP:** Ligand A (4.81) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.173) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are within acceptable limits. Ligand B has 1 HBD and 8 HBA, which is acceptable, but the higher HBA count could impact permeability.

**QED:** Both ligands have similar QED values (0.741 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (28.732) has a significantly lower DILI risk than Ligand B (78.247), which is a major advantage.

**BBB:** Ligand A (70.415) has better BBB penetration than Ligand B (50.95), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.892) has poor Caco-2 permeability, while Ligand B (-5.554) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.178) has poor aqueous solubility, while Ligand B (-2.144) is better.

**hERG Inhibition:** Ligand A (0.964) has a moderate hERG risk, while Ligand B (0.043) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (28.581) has a moderate microsomal clearance, while Ligand B (3.282) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.966) has a moderate half-life, while Ligand B (-9.294) has a very short half-life, a major disadvantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.681 and 0.037).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, significantly lower microsomal clearance (better metabolic stability), and a very low hERG risk. However, it suffers from poor logP and Caco-2 permeability, and a very short in vitro half-life. Ligand A has better solubility, BBB penetration, and a lower DILI risk, but its binding affinity is very weak, and its Caco-2 permeability is poor.

Given the enzyme-specific priorities, the strong binding affinity of Ligand B is the most critical factor. While its ADME properties are suboptimal, these can potentially be improved through further optimization. The weak binding affinity of Ligand A makes it a less promising starting point, even with its better ADME profile.

Output:
1
2025-04-17 12:04:08,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (361.463 and 350.409 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (56.79) is better than Ligand B (64.33) as it is closer to the <140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (3.635 and 3.252), falling 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 5 HBA, and Ligand B has 3. Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.693 and 0.743), indicating good drug-like properties.

**7. DILI:** Ligand A (53.742) has a higher DILI risk than Ligand B (13.959). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (88.29) is better than Ligand A (79.721). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Ligand A (-4.586) has worse Caco-2 permeability than Ligand B (-4.187). Lower (more negative) values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-4.358) has worse solubility than Ligand B (-3.501). Lower (more negative) values indicate poorer solubility.

**11. hERG Inhibition:** Ligand A (0.75) has a slightly higher hERG risk than Ligand B (0.907), but both are acceptable.

**12. Microsomal Clearance:** Ligand B (44.152) has significantly lower microsomal clearance than Ligand A (75.004), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (18.859) has a longer half-life than Ligand A (8.564), which is desirable.

**14. P-gp Efflux:** Ligand A (0.671) has slightly lower P-gp efflux than Ligand B (0.409), which is favorable.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant and can outweigh some minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in critical areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and slightly better binding affinity. The improved ADME profile of Ligand B makes it a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 12:04:08,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.374 and 358.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.23) is well below the 140 threshold, suggesting good absorption. Ligand B (105.17) is still acceptable, but less optimal.

**logP:** Ligand A (2.887) is within the optimal 1-3 range. Ligand B (0.08) is quite 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 4 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 (0.596), indicating a more drug-like profile.

**DILI:** Ligand B (40.287) has a lower DILI risk than Ligand A (63.086), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.193) is slightly better than Ligand B (32.726).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.767 and -4.922), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't massive.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.928 and -0.979), which is also concerning. Ligand B is slightly better in this regard.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.192 and 0.154), which is excellent.

**Microsomal Clearance:** Ligand A (43.074) has lower microsomal clearance than Ligand B (52.687), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.604) has a positive half-life, while Ligand B (-2.503) has a negative half-life, which is highly problematic and suggests rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.071 and 0.057).

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.9), but the difference is small (0.1 kcal/mol).

**Overall Assessment:**

Ligand A has better QED, metabolic stability (lower Cl_mic, positive t1/2), and a slightly better BBB score. However, Ligand B has a significantly lower DILI risk and a marginally better binding affinity. The negative Caco-2 and solubility values for both are concerning, but the rapid degradation of Ligand B (negative half-life) is a major drawback. Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) is crucial.

Output:
0
2025-04-17 12:04:08,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.463 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (78.95 and 72.96) below 140, suggesting reasonable oral absorption potential.

**3. logP:** Ligand A (0.777) is within the optimal range (1-3). Ligand B (-0.33) is slightly below 1, which *could* indicate potential permeability issues, 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:** 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 (0.652 and 0.706), indicating drug-like properties.

**7. DILI:** Ligand A (6.049) has a very low DILI risk, significantly better than Ligand B (35.789), which is moderately concerning.

**8. BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (71.772) is slightly better than Ligand B (64.637).

**9. Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are log values, they are similar and suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have negative values, indicating poor solubility. Ligand A (-0.705) is slightly better than Ligand B (-1.017).

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.234 and 0.147).

**12. Microsomal Clearance:** Ligand A (6.126) has significantly lower microsomal clearance than Ligand B (20.352), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-26.762) has a slightly longer in vitro half-life than Ligand A (-22.249), but both are negative values which is unusual.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.012).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). This 0.3 kcal/mol difference is notable, but not overwhelmingly large.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A excels in critical areas for an enzyme inhibitor: significantly lower DILI risk and substantially better metabolic stability (lower Cl_mic). The slightly better solubility of Ligand A is also a plus. The difference in binding affinity is unlikely to outweigh the advantages in safety and pharmacokinetics.

Output:
1
2025-04-17 12:04:08,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.479 and 370.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.45) is slightly above the preferred <140, while Ligand B (95.42) is well within. This favors Ligand B for better absorption.

**logP:** Ligand A (-0.633) is a bit low, potentially hindering permeation. Ligand B (1.068) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both ligands have 2 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:** Ligand B (0.808) has a higher QED score than Ligand A (0.558), indicating a more drug-like profile.

**DILI:** Ligand A (47.15) and Ligand B (51.725) both have acceptable DILI risk, below the 60 threshold.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand B (63.746) has a higher BBB value than Ligand A (48.623).

**Caco-2 Permeability:** Both have negative values (-5.653 and -5.049), which is unusual and suggests poor permeability. This is a concern for both, but less so for Ligand B.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.949 and -2.443), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.476) has a lower hERG risk than Ligand B (0.203), which is favorable.

**Microsomal Clearance:** Ligand A (22.765) has a higher microsomal clearance than Ligand B (0.922), suggesting lower metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-3.516) has a longer in vitro half-life than Ligand A (-15.773), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.071).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.7). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. It has a more favorable logP, QED, metabolic stability (lower Cl_mic and longer t1/2), and binding affinity. While both have poor solubility and Caco-2 permeability, Ligand B's overall profile is superior. The slightly higher hERG risk for Ligand B is less concerning than the lower metabolic stability of Ligand A.

Output:
1
2025-04-17 12:04:08,184 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both A (349.431 Da) and B (344.459 Da) are within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (96.87) is slightly higher than Ligand B (86.88), but both are below the 140 threshold for good oral absorption.

3. **logP:** Ligand A (0.383) is quite low, potentially hindering permeation. Ligand B (2.103) is within the optimal 1-3 range. This is a significant advantage for B.

4. **HBD:** Both A (3) and B (3) are within the acceptable limit of <=5.

5. **HBA:** Ligand A (4) and B (3) are both below the acceptable limit of <=10.

6. **QED:** Both A (0.692) and B (0.764) are above 0.5, indicating good drug-like properties. B is slightly better.

7. **DILI:** Ligand A (31.02) and B (33.424) both have low DILI risk, well below the 40 threshold.

8. **BBB:** Ligand A (22.412) has poor BBB penetration, while Ligand B (64.715) is better, but still not ideal. Since SRC is not a CNS target, this is less critical.

9. **Caco-2:** Both ligands have negative Caco-2 values (-5.118 and -5.23), which is unusual and suggests poor permeability. This is a significant concern for both.

10. **Solubility:** Ligand A (-1.707) and B (-3.36) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

11. **hERG:** Ligand A (0.278) and B (0.357) both have low hERG inhibition liability, which is good.

12. **Cl_mic:** Ligand A (-12.906) has a *negative* microsomal clearance, which is impossible. This suggests an error in the data or a very unusual metabolic profile. Ligand B (32.786) has a higher clearance, indicating faster metabolism. This is a significant advantage for A (assuming the negative value is an error).

13. **t1/2:** Ligand A (10.664) has a longer in vitro half-life than Ligand B (1.842). This is a positive for A.

14. **Pgp:** Ligand A (0.055) has lower P-gp efflux than Ligand B (0.17), which is favorable.

15. **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 for A, potentially outweighing some of its other weaknesses.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a significantly better binding affinity (-9.6 vs -8.0 kcal/mol) and a longer half-life (10.664 vs 1.842). However, the negative Cl_mic value is a red flag and needs investigation. If this is an error, then A is the clear winner. Ligand B has better logP and slightly better QED, but its weaker binding affinity and faster metabolism are concerning. The poor Caco-2 and solubility for both are problematic, but could potentially be addressed with formulation strategies.

Given the substantial affinity advantage of Ligand A, and *assuming the negative Cl_mic is an error*, I would select Ligand A as the more promising candidate.

Output:
1
2025-04-17 12:04:08,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.362 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.07) is slightly higher than Ligand B (69.3). Both are below the 140 threshold for oral absorption, but lower is generally better. Ligand B has a more favorable TPSA.

**logP:** Both ligands have good logP values (2.696 and 2.469), 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). Ligand B is slightly better here.

**QED:** Both ligands have good QED scores (0.746 and 0.786), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 83.598, which is high. Ligand B has a much lower DILI risk of 41.76, which is good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration (63.358 and 67.158). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.906 and -5.169). 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 (-3.82 and -2.959). Similar to Caco-2, the scale is unknown, making interpretation difficult.

**hERG:** Ligand A (0.551) has a slightly higher hERG risk than Ligand B (0.484), but both are relatively low.

**Microsomal Clearance:** Ligand A (43.491) has a lower microsomal clearance than Ligand B (59.498), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (34.946) has a longer half-life than Ligand B (-0.594). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux than Ligand B (0.203), which is favorable.

**Binding Affinity:** Ligand B (-8.9 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 much better safety profile (lower DILI) and significantly stronger binding affinity. While Ligand A has better metabolic stability and half-life, the DILI risk associated with Ligand A is concerning. The improved potency of Ligand B is likely to be more impactful for an enzyme inhibitor, and the lower DILI risk makes it a more promising candidate. The negative Caco-2 and solubility values are a concern for both, but the potency advantage of B is significant.

Output:
1
2025-04-17 12:04:08,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.318 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (67.6), being well below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.677 and 2.9), 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 5. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.572 and 0.781), indicating drug-like properties.

**DILI:** Ligand A (46.452) has a slightly higher DILI risk than Ligand B (8.841), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (95.308 and 91.508), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.864 and -4.698), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.969 and -3.033), indicating very poor aqueous solubility, a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.272) has a much lower hERG inhibition liability than Ligand B (0.583), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-3.486) has a much lower (better) microsomal clearance than Ligand B (51.625), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.355) has a much longer in vitro half-life than Ligand B (4.767), which is also a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.03 and 0.111).

**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:**

Despite both ligands having poor solubility and permeability, Ligand A is the more promising candidate. Its significantly stronger binding affinity, lower hERG risk, and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher DILI risk. The poor solubility and permeability would need to be addressed through formulation or structural modifications, but the superior potency and safety profile of Ligand A make it the better starting point.

Output:
1
2025-04-17 12:04:08,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.435 Da and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.04) is slightly above the preferred <140, but acceptable. Ligand B (99.35) is well within the range.

**3. logP:** Ligand A (-0.293) is a bit low, potentially hindering permeation. Ligand B (0.145) is also on the lower side, but slightly better than A.

**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 (6 and 5 respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.509 and 0.702), indicating drug-like properties. Ligand B is superior here.

**7. DILI:** Ligand A (27.142) has a much lower DILI risk than Ligand B (47.77), which is a significant advantage.

**8. BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-5.275 and -5.179). This is a potential issue for oral bioavailability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.65 and -1.949). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.137) has a slightly lower hERG risk than Ligand B (0.212), which is preferable.

**12. Microsomal Clearance:** Ligand B (-9.706) has significantly lower microsomal clearance than Ligand A (37.48), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-9.3) has a significantly longer in vitro half-life than Ligand A (31.37), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux (0.02 and 0.012).

**15. Binding Affinity:** Ligand A (-9.3) has a significantly stronger binding affinity than Ligand B (0.0). This is the most important factor for an enzyme inhibitor. A difference of 9.3 kcal/mol is substantial.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a higher QED score, the dramatically superior binding affinity of Ligand A (-9.3 kcal/mol vs 0.0 kcal/mol) outweighs these benefits. The binding affinity difference is so large that it is likely to overcome the issues with slightly lower solubility and higher DILI. The poor Caco-2 permeability is a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 12:04:08,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 & 362.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (97.11).  A TPSA under 140 is desirable for oral absorption, and both meet this, but A is much closer to the ideal for good permeability.

**logP:** Both ligands have good logP values (2.63 & 2.24), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=5) as it has fewer hydrogen bond donors and acceptors, which generally improves permeability.

**QED:** Both ligands have acceptable QED values (0.83 & 0.72), indicating good drug-likeness.

**DILI:** Ligand A (16.21) has a much lower DILI risk than Ligand B (62.47). This is a significant advantage for A.

**BBB:**  BBB is less important for a non-CNS target like SRC, but Ligand A (71.85) is better than Ligand B (61.92).

**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, suggesting poor solubility. Again, the scale is not specified, making interpretation difficult.

**hERG:** Ligand A (0.26) has a significantly lower hERG risk than Ligand B (0.51). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (36.36) has a higher (worse) microsomal clearance than Ligand B (-0.85). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (22.62) has a significantly longer half-life than Ligand A (9.76). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.10) has a lower P-gp efflux liability than Ligand B (0.08), which is slightly better.

**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.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A excels in safety parameters (DILI, hERG) and has better TPSA and fewer H-bonds. The significantly lower DILI and hERG risk for Ligand A are crucial for drug development. While the affinity difference is notable, the safety profile of Ligand A, combined with its better permeability indicators (TPSA, H-bonds), makes it a more promising candidate. The poor solubility and permeability indicated by the negative Caco-2 and solubility values are a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 12:04:08,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (376.519 and 372.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.57) is better than Ligand B (112.81), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.885) is better than Ligand B (0.264). Ligand B is a bit low and may have permeability issues.

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

**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 similar QED values (0.589 and 0.595), indicating good drug-likeness.

**DILI:** Ligand A (40.054) is slightly higher than Ligand B (33.501), but both are below the 60 threshold and considered low risk.

**BBB:** Both ligands have relatively low BBB penetration (55.874 and 62.233). This isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.275 and -5.269). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.957 and -2.369). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG risk (0.235 and 0.087).

**Microsomal Clearance:** Ligand A (26.743) has higher clearance than Ligand B (24.425). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-16.889) has a negative half-life, which is not possible. Ligand A (13.66) is more reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.041 and 0.006).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 0.3 kcal/mol, which is not huge, but still a factor.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and better metabolic stability (lower Cl_mic). However, it has a lower logP, which could lead to permeability issues. Both have unusual negative Caco-2 and solubility values. Ligand A has a more reasonable half-life. Given the slight affinity advantage of Ligand B and its better metabolic stability, it is marginally more promising. However, the negative solubility and permeability values for both are concerning and would require further investigation.

Output:
1
2025-04-17 12:04:08,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.451 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (66.92). Lower TPSA generally favors better absorption, which is important for oral bioavailability.

**logP:** Both ligands have acceptable logP values (2.435 and 1.02), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have low HBD counts (0). Ligand A has 2 HBA, while Ligand B has 4. Both are within acceptable limits (<=10).

**QED:** Both ligands have similar QED scores (0.777 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (40.054) has a significantly lower DILI risk than Ligand B (12.33). This is a crucial advantage.

**BBB:** Both ligands have similar BBB penetration (80.264 and 82.047), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.264 and -4.481), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference isn't huge.

**Aqueous Solubility:** Ligand A (-3.081) has slightly better solubility than Ligand B (-1.533), though both are quite poor.

**hERG:** Both ligands have low hERG inhibition liability (0.47 and 0.238), which is excellent.

**Microsomal Clearance:** Ligand B (31.763) has lower microsomal clearance than Ligand A (38.365), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Both have negative in vitro half-lives (-10.968 and -10.286), which is also unusual and suggests rapid degradation. The difference is small.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.204 and 0.045).

**Binding Affinity:** Both ligands have identical binding affinities (-8.2 kcal/mol), so this factor doesn't differentiate them.

**Overall Assessment:**

Ligand A is better in terms of TPSA, logP, DILI risk, and solubility. Ligand B has better metabolic stability (lower Cl_mic). However, the significantly lower DILI risk for Ligand A is a major advantage, especially in oncology where long-term toxicity is a critical concern. The slightly better TPSA and solubility of Ligand A also contribute to its favorability. The similar binding affinity means the ADME properties become the deciding factors.

Output:
1
2025-04-17 12:04:08,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 356.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.83) is higher than Ligand B (58.2). Both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets, which isn't relevant here.

**logP:** Ligand A (1.197) is slightly lower than the optimal 1-3 range, while Ligand B (2.923) is well within it. This favors Ligand B for 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 the same QED score of 0.77, indicating good drug-likeness.

**DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (32.183). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (67.39 and 67.623), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.088 and -5.162), which is unusual and suggests poor permeability. However, these values are on a log scale, so small differences can be significant. They are very similar.

**Aqueous Solubility:** Ligand A (-1.549) has slightly better solubility than Ligand B (-3.124).

**hERG Inhibition:** Ligand A (0.511) has a slightly higher hERG risk than Ligand B (0.168). This favors Ligand B.

**Microsomal Clearance:** Ligand A (-17.78) has *much* lower microsomal clearance than Ligand B (43.881). This indicates significantly better metabolic stability for Ligand A, a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand A (13.973) has a longer half-life than Ligand B (-10.427). This is a strong advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.252), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar 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 the better candidate. While Ligand B has a slightly better logP and lower hERG risk, Ligand A excels in key areas for an enzyme inhibitor: significantly lower DILI risk, dramatically improved metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better solubility. The similar binding affinities make these ADME/Tox advantages decisive.

Output:
0
2025-04-17 12:04:08,185 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.402 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.46) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.87) is still under 140, but less optimal than A.

**3. logP:** Ligand A (3.61) is within the optimal 1-3 range. Ligand B (1.32) is at the lower end, potentially impacting 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 are within the acceptable limit of 10.

**6. QED:** Ligand A (0.841) has a strong drug-like profile. Ligand B (0.388) is significantly lower, indicating a less favorable overall drug-likeness.

**7. DILI:** Ligand A (62.35) is moderately high risk, while Ligand B (17.449) is very low risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (82.086) shows reasonable BBB penetration, while Ligand B (57.619) is lower. BBB isn't a primary concern for SRC kinase, but it's a slight edge for A.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.582 and -4.682), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-4.677) and Ligand B (-1.927) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Ligand A (0.774) has a slightly higher hERG risk than Ligand B (0.192). Lower is better, so Ligand B is preferable.

**12. Cl_mic:** Ligand A (86.929) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (14.138) has much lower clearance, suggesting better metabolic stability. This is a crucial advantage for Ligand B.

**13. t1/2:** Ligand A (28.651) has a moderate in vitro half-life, while Ligand B (4.265) has a very short half-life. A longer half-life is generally preferred, giving a slight edge to Ligand A.

**14. Pgp:** Ligand A (0.425) has lower P-gp efflux than Ligand B (0.045), which is preferable.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic) are critical advantages for an enzyme target like SRC kinase. While Ligand A has slightly better BBB penetration and in vitro half-life, the risks associated with its higher DILI and poor metabolic stability outweigh these benefits. Both compounds have poor solubility and permeability, which would need to be addressed during optimization.

Output:
1
2025-04-17 12:04:08,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (388.917 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.66 and 75.71) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.469) is optimal, while Ligand B (1.37) is slightly low, potentially impacting 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.

**QED:** Both ligands have good QED scores (0.645 and 0.827), indicating drug-likeness.

**DILI:** Ligand A (36.487) has a slightly higher DILI risk than Ligand B (27.685), but both are below the concerning threshold of 60.

**BBB:** Ligand A (69.329) has lower BBB penetration than Ligand B (89.066). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.765) has worse Caco-2 permeability than Ligand B (-4.588). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.607) has worse aqueous solubility than Ligand B (-2.173). This is a concern for both, but more so for Ligand A.

**hERG Inhibition:** Ligand A (0.367) has a slightly higher hERG risk than Ligand B (0.111), but both are relatively low.

**Microsomal Clearance:** Ligand A (56.88) has significantly higher microsomal clearance than Ligand B (19.181). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (46.635) has a longer half-life than Ligand B (-6.453). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux than Ligand B (0.044), which is favorable.

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having slightly higher DILI and hERG risk and lower solubility and permeability, its *significantly* stronger binding affinity (-7.6 vs 0.0 kcal/mol) makes it the more promising candidate. The difference in binding affinity is substantial and likely to be more impactful than the minor ADME differences, especially considering the enzyme target class. The very short half-life of Ligand B is a major red flag.

Output:
1
2025-04-17 12:04:08,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.482 and 368.287 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold for good absorption, and favorable. Ligand B (105.49) is still below 140, but less optimal than A.

**logP:** Both ligands (2.272 and 1.317) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (3 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED scores (0.681 and 0.627), indicating good drug-likeness.

**DILI:** Ligand A (15.355) has a significantly lower DILI risk than Ligand B (61.691). This is a major advantage for Ligand A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (89.957) has a better percentile than Ligand B (77.898).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.745 and -4.835), 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 (-2.517 and -2.681), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Ligand A (0.864) has a lower hERG risk than Ligand B (0.237), which is a significant advantage.

**Microsomal Clearance:** Ligand A (26.529) has a much lower microsomal clearance than Ligand B (40.252), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.717) has a slightly better in vitro half-life than Ligand B (-46.746).

**P-gp Efflux:** Ligand A (0.201) has a lower P-gp efflux liability than Ligand B (0.015).

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

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is significantly better. It has a much lower DILI risk, lower microsomal clearance (better metabolic stability), lower hERG risk, lower P-gp efflux, and slightly better half-life. While both have poor predicted solubility and permeability, the ADME properties of Ligand A are substantially more favorable overall. The equal binding affinity makes the ADME advantages decisive.

Output:
0
2025-04-17 12:04:08,185 - INFO - Batch 99 complete. Total preferences: 1584
2025-04-17 12:04:08,185 - INFO - Processing batch 100/512...
2025-04-17 12:04:47,090 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.507 and 361.921 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.98) is better than Ligand B (49.74), being under the 140 threshold for good oral absorption.

**logP:** Ligand A (1.212) is optimal (1-3), while Ligand B (3.994) is approaching the upper limit.

**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 (6 and 4, respectively), well below the threshold of 10.

**QED:** Both ligands have good QED scores (0.714 and 0.734), indicating good drug-like properties.

**DILI:** Ligand A (69.95) has a higher DILI risk than Ligand B (21.481). This is a significant negative for Ligand A.

**BBB:** Both ligands have similar BBB penetration (71.733 and 70.997). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.13 and -5.292). This is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable without knowing the exact scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.259 and -3.236). This is also unusual and suggests poor aqueous solubility.

**hERG:** Ligand A (0.145) has a lower hERG risk than Ligand B (0.763). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand B (32.527) has a lower microsomal clearance than Ligand A (41.326), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (34.754) has a longer in vitro half-life than Ligand A (-29.653). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.186) has lower P-gp efflux than Ligand B (0.413).

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-6.4). This is a crucial advantage, as a 2.6 kcal/mol difference can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better logP and lower hERG risk, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.0 vs -6.4 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic) and a longer in vitro half-life, which are critical for *in vivo* efficacy. While both have poor predicted solubility and permeability, the potency and stability benefits of Ligand B are more likely to be addressable through formulation or further chemical modifications. The lower DILI risk for Ligand B is also a significant benefit.

Output:
1
2025-04-17 12:04:47,090 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.439 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.55) is slightly higher than Ligand B (81.67), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.472 and 1.433), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. 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 (0.685 and 0.755), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 84.102, which is high. Ligand B has a much lower DILI risk of 22.218, which is excellent. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (49.903) and Ligand B (61.38) are both relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.821 and -4.911), which is unusual and suggests poor permeability. However, these values are on a log scale and need to be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.567 and -1.698), indicating poor aqueous solubility. Ligand B is slightly better in this regard.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.298 and 0.168), which is favorable.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (77.238), indicating poor metabolic stability. Ligand B has a negative clearance (-7.997), which is very favorable and suggests excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (24.208 hours) has a reasonable half-life, while Ligand B (23.254 hours) is comparable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.415 and 0.024), which is good.

**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 for Ligand A. The difference of 1.7 kcal/mol is significant enough to potentially outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand B has a much better safety profile (lower DILI) and significantly better metabolic stability (negative Cl_mic). However, Ligand A has a substantially stronger binding affinity. Given the enzyme-specific priorities, metabolic stability and safety are crucial. While the affinity difference is notable, the high DILI risk and poorer metabolic stability of Ligand A are concerning. The slightly better solubility of Ligand B is also a benefit.

Output:
1
2025-04-17 12:04:47,090 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (95) is higher than Ligand B (51.02). While both are reasonably low, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (0.499) is quite low, potentially hindering membrane permeability. Ligand B (3.417) 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, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits, but lower is generally better for permeability. Ligand B has a slight edge here.

**QED:** Both ligands have good QED scores (A: 0.823, B: 0.766), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 61.962, B: 63.629), placing them in a moderate risk category. This isn't a major differentiating factor.

**BBB:** Ligand A (60.295) and Ligand B (84.451). Since SRC is not a CNS target, BBB is not a major consideration, but Ligand B is better.

**Caco-2 Permeability:** Ligand A (-5.25) and Ligand B (-4.614). Both are negative, which is not ideal, but similar.

**Aqueous Solubility:** Ligand A (-1.503) and Ligand B (-3.449). Both are negative, indicating poor solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.228) and Ligand B (0.309). Both are low, indicating low cardiotoxicity risk. Ligand A is slightly better.

**Microsomal Clearance:** Ligand A (-10.071) is significantly better than Ligand B (48.497). This indicates much greater metabolic stability for Ligand A, a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand A (-1.578) is much better than Ligand B (-27.301). This further supports Ligand A's superior metabolic stability.

**P-gp Efflux:** Ligand A (0.008) is significantly better than Ligand B (0.527), indicating lower efflux and potentially better bioavailability.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) is slightly better than Ligand B (-8.1 kcal/mol). While both are excellent, the small advantage for Ligand A is worth noting.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), P-gp efflux, and has a slightly better binding affinity. Its lower logP is a concern, but the strong metabolic stability and affinity outweigh this drawback for an enzyme target like SRC kinase. Ligand B has a better TPSA and logP, but suffers from significantly worse metabolic stability and higher P-gp efflux.

Output:
0
2025-04-17 12:04:47,090 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.351 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (84.5) is significantly better than Ligand A (127.9). Lower TPSA generally improves oral absorption, a key consideration.

**logP:** Ligand A (-2.107) is suboptimal, being slightly below the preferred range of 1-3. Ligand B (3.22) is within the optimal range. This favors Ligand B for permeability and potential off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=9) is slightly better than Ligand B (HBD=2, HBA=5) in terms of staying within the recommended limits, but both are acceptable.

**QED:** Both ligands have similar QED values (0.634 and 0.613), indicating good drug-likeness.

**DILI:** Ligand B (46.724) has a lower DILI risk than Ligand A (72.043), which is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand B (68.748) is higher than Ligand A (43.815), but this is less important.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both, but the lower TPSA of Ligand B might mitigate this somewhat.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.721 and -3.785 respectively). This is a serious drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.013) has a much lower hERG risk than Ligand B (0.517), which is a critical advantage. Cardiotoxicity is a major concern in drug development.

**Microsomal Clearance:** Ligand A (-0.737) has a significantly lower (better) microsomal clearance than Ligand B (50.834), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (21.165) has a longer half-life than Ligand A (7.551), which is generally desirable.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.099), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (-0.0). This is the most important factor, and the >1.5 kcal/mol advantage outweighs many of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Despite solubility concerns for both, Ligand B's significantly superior binding affinity (-8.3 kcal/mol vs -0.0 kcal/mol) and lower DILI risk are decisive. While Ligand A has better hERG and clearance profiles, the potency difference is too large to ignore. The better logP and TPSA of Ligand B also contribute to its potential for better absorption, despite the poor Caco-2 values. Solubility would need to be addressed through formulation strategies.

Output:
1
2025-04-17 12:04:47,090 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.331 and 383.945 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.98) is slightly higher than Ligand B (62.3). Both are acceptable, but B is better for permeability.

**logP:** Ligand A (1.052) is within the optimal range, while Ligand B (3.757) is approaching the upper limit. This could potentially lead to solubility issues with B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the criteria of <=5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well within the acceptable limit of <=10.

**QED:** Both ligands have similar and good QED values (A: 0.707, B: 0.729), indicating good drug-like properties.

**DILI:** Ligand A (53.276) has a higher DILI risk than Ligand B (39.977), though both are reasonably low.

**BBB:** Both have acceptable BBB penetration, but Ligand A (72.276) is slightly better than Ligand B (69.523). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.867 and -4.895), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.887 and -4.346), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.17) has a much lower hERG risk than Ligand B (0.714). This is a significant advantage for A.

**Microsomal Clearance:** Ligand A (26.008) has lower microsomal clearance than Ligand B (74.805), suggesting better metabolic stability. This is a key advantage for A.

**In vitro Half-Life:** Ligand A (-49.047) has a negative half-life, which is not physically meaningful. Ligand B (36.212) has a reasonable half-life. This is a significant concern for A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.01, B: 0.311), which is favorable.

**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 for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates better metabolic stability (lower Cl_mic) and a significantly lower hERG risk. Both suffer from poor solubility and permeability. However, the strong affinity of Ligand B is a major advantage. The negative half-life for ligand A is a critical flaw. Considering the enzyme-specific priorities, the binding affinity is paramount.

Output:
1
2025-04-17 12:04:47,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.37 and 346.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.18) is slightly higher than Ligand B (67.23), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.95 and 2.62), 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 similar QED scores (0.786 and 0.736), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (74.33) compared to Ligand B (39.67). This is a major concern for Ligand A.

**BBB:** Both ligands have comparable BBB penetration (71.50 and 71.23), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar (-5.06 and -4.86), so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.11 and -2.81), which is also unusual. Again, the values are similar.

**hERG:** Both ligands show low hERG inhibition liability (0.59 and 0.64), which is good.

**Microsomal Clearance:** Ligand A (57.90) has a lower microsomal clearance than Ligand B (71.24), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (13.35 hours) compared to Ligand A (6.94 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.31 and 0.33).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -7.0 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 metabolic stability, the significantly higher DILI risk is a major drawback. Ligand B has a substantially better safety profile (lower DILI) and a longer half-life, which are critical for a viable drug candidate, especially for an enzyme target. The slight difference in binding affinity is outweighed by these ADME-Tox advantages.

Output:
1
2025-04-17 12:04:47,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.5 & 368.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (87.66) is still under 140, but less favorable.

**logP:** Ligand A (2.825) is optimal (1-3). Ligand B (0.423) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the ideal range (<=10).

**QED:** Both ligands have reasonable QED scores (A: 0.862, B: 0.678), indicating good drug-like properties.

**DILI:** Ligand A (68.05) has a higher DILI risk than Ligand B (55.719), but both are acceptable.

**BBB:** Ligand A (67.003) shows moderate BBB penetration, while Ligand B (53.625) is lower. Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.986) has poor Caco-2 permeability, while Ligand B (-5.402) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.971 and -2.884 respectively). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.865) has a lower hERG risk than Ligand B (0.39), which is a positive.

**Microsomal Clearance:** Ligand A (54.586) has moderate clearance, while Ligand B (7.519) has very low clearance, suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (54.609) has a moderate half-life, while Ligand B (6.656) has a very short half-life.

**P-gp Efflux:** Ligand A (0.653) has moderate P-gp efflux, while Ligand B (0.046) has very low efflux.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has *significantly* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a massive difference.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A's exceptionally strong binding affinity (-9.9 kcal/mol) overwhelmingly outweighs its other drawbacks. The difference in affinity is so large that it is likely to compensate for the solubility issues, especially considering formulation strategies can be employed to address solubility. Ligand B's low logP, short half-life, and very weak binding affinity make it a much less promising candidate.

Output:
1
2025-04-17 12:04:47,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (385.932 Da) is still well within the acceptable range.

**TPSA:** Ligand A (75.44) is better than Ligand B (21.7). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (2.589) is optimal, while Ligand B (4.842) is pushing the upper limit. High logP can lead 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 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.819) has a significantly better QED score than Ligand B (0.584), indicating a more drug-like profile.

**DILI:** Ligand A (31.873) has a much lower DILI risk than Ligand B (11.439). This is a significant advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration, but Ligand A (91.392) is slightly better than Ligand B (85.459). While not a primary concern for a kinase inhibitor, it's a minor positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.893) and Ligand B (-4.58) have negative values, which is unusual. It is difficult to interpret these values without knowing the scale.

**Aqueous Solubility:** Ligand A (-2.865) and Ligand B (-4.824) have negative values, which is also unusual. It is difficult to interpret these values without knowing the scale.

**hERG Inhibition:** Ligand A (0.309) has a much lower hERG inhibition liability than Ligand B (0.966), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (17.184) has a lower microsomal clearance than Ligand B (84.483), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-4.002) has a negative value, which is unusual. Ligand B (62.667) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux than Ligand B (0.738), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.7) has a slightly stronger binding affinity than Ligand A (-7.4). However, the difference is only 0.3 kcal/mol, which is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising drug candidate. It has a better QED score, significantly lower DILI and hERG risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. While Ligand B has slightly better binding affinity, the difference is small and is overshadowed by Ligand A's superior ADME properties and safety profile.

Output:
0
2025-04-17 12:04:47,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.43 and 363.57 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.65) is higher than Ligand B (45.23). Both are below 140, suggesting reasonable absorption potential.

**logP:** Ligand A (1.64) is optimal, while Ligand B (4.344) is pushing the upper limit and could present solubility issues.

**H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the threshold of 5.

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

**QED:** Both ligands have high QED scores (0.834 and 0.846), indicating good drug-likeness.

**DILI:** Ligand A (16.60) has a significantly lower DILI risk than Ligand B (36.45), which is a substantial advantage.

**BBB:** Both have similar BBB penetration (68.67% and 64.83%), which isn't a primary concern for a non-CNS target like SRC.

**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, making interpretation difficult.

**hERG:** Ligand A (0.143) has a much lower hERG inhibition liability than Ligand B (0.562), a critical advantage for safety.

**Microsomal Clearance:** Ligand A (62.80) has higher microsomal clearance than Ligand B (42.08), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand B (5.33) has a longer in vitro half-life than Ligand A (2.17), which is preferable.

**P-gp Efflux:** Ligand A (0.022) has lower P-gp efflux liability than Ligand B (0.287), which is a positive.

**Binding Affinity:** Ligand A (-9.5 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 the stronger candidate. Its significantly superior binding affinity (-9.5 vs -6.3 kcal/mol) is a major driver. While it has higher microsomal clearance, its lower DILI risk and hERG liability are crucial safety advantages. The slightly lower half-life could be addressed through structural modifications. Although both have unusual Caco-2 and solubility values, the superior potency and safety profile of Ligand A make it the more promising starting point for drug development.

Output:
1
2025-04-17 12:04:47,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (75.87) is better than Ligand B (38.77) as it is closer to the threshold of 140.

**logP:** Ligand A (1.635) is optimal, while Ligand B (3.974) is approaching the upper limit. Higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0).

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is acceptable.

**QED:** Both ligands have similar QED values (0.775 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (7.794) has a significantly lower DILI risk than Ligand B (27.181). This is a major advantage.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (88.29) is slightly better. However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability 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 (0.519 and 0.687).

**Microsomal Clearance:** Ligand A (-8.563) has a much lower (better) microsomal clearance than Ligand B (81.616). This indicates greater metabolic stability.

**In vitro Half-Life:** Ligand A (-6.725) has a significantly longer in vitro half-life than Ligand B (30.128). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.012 and 0.696).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have good binding affinity, Ligand A demonstrates significantly better ADME properties: lower DILI risk, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. The slightly better logP and TPSA values also contribute to its favorability. The negative Caco-2 and solubility values are concerning for both, but the superior metabolic stability and safety profile of Ligand A outweigh these concerns.

Output:
0
2025-04-17 12:04:47,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (353.419 and 350.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.18) is better than Ligand B (94.05), both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets. This isn't a primary concern for a non-CNS target like SRC.

**3. logP:** Ligand A (-0.482) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.459) is closer to 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):** Both ligands have 5 HBA, within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.69 and 0.804), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (39.395) has a slightly higher DILI risk than Ligand B (24.583), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for SRC, but Ligand A (53.974) has a better BBB score than Ligand B (34.083).

**9. Caco-2 Permeability:** Ligand A (-4.458) shows very poor Caco-2 permeability, while Ligand B (-5.009) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-1.007) has slightly better solubility than Ligand B (-0.499), both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.07 and 0.024).

**12. Microsomal Clearance (Cl_mic):** Ligand A (8.36) has significantly lower microsomal clearance than Ligand B (30.229), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-12.555) has a much longer in vitro half-life than Ligand B (-6.575). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.005).

**15. Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.3). The difference is 0.6 kcal/mol, which is not huge, but noticeable.

**Overall Assessment:**

Given that we are targeting a kinase (SRC), potency (affinity), metabolic stability (Cl_mic, t1/2), and solubility are paramount. Ligand B has a slightly better binding affinity, but Ligand A shows significantly improved metabolic stability (lower Cl_mic, longer t1/2) and better solubility. The poor Caco-2 permeability of both is a concern, but can potentially be addressed with formulation strategies. The slightly lower logP of Ligand A is a minor drawback compared to the substantial benefits in metabolic stability and half-life.

Output:
1
2025-04-17 12:04:47,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 363.575 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (37.19) is well within the optimal range.

**logP:** Ligand A (0.437) is a bit low, potentially hindering permeation. Ligand B (3.623) is excellent, falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also good.

**QED:** Both ligands have similar QED values (0.675 and 0.646), indicating good drug-like properties.

**DILI:** Ligand A (12.408) has a much lower DILI risk than Ligand B (16.053), which is a significant advantage.

**BBB:** Ligand A (53.16) has a lower BBB penetration score than Ligand B (69.523). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-4.674) has poor Caco-2 permeability. Ligand B (-5.146) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.263) has slightly better aqueous solubility than Ligand B (-2.173).

**hERG Inhibition:** Ligand A (0.06) has a very low hERG inhibition risk, a major advantage. Ligand B (0.915) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (34.79) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (19.99).

**In vitro Half-Life:** Ligand A (-7.429) has a significantly longer in vitro half-life than Ligand B (28.915).

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is favorable. Ligand B (0.37) has a moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.6) has a significantly stronger binding affinity than Ligand A (-7.1). This is a 1.5 kcal/mol advantage, which is substantial.

**Conclusion:**

While Ligand B boasts a superior binding affinity, Ligand A presents a much more favorable ADMET profile. Specifically, its lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and lower P-gp efflux are crucial advantages for an enzyme target like SRC kinase. The slightly lower logP and Caco-2 permeability of Ligand A are concerns, but the strong affinity of Ligand B might be enough to overcome these issues. However, the substantial difference in safety and metabolic stability makes Ligand A a more promising starting point for optimization.

Output:
0
2025-04-17 12:04:47,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (358.429 Da and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly higher than Ligand B (49.41), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.344 and 3.42), falling within the optimal 1-3 range. Ligand B is a bit higher, which could potentially lead to slight solubility issues, 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 2. Both are well below the 10 limit.

**6. QED:** Both ligands have a QED of 0.793 and 0.795, indicating good drug-likeness.

**7. DILI:** Ligand A (22.761) has a significantly lower DILI risk than Ligand B (13.532), which is a major advantage.

**8. BBB:** Both have reasonable BBB penetration, but Ligand A (86.817) is better than Ligand B (76.154). While not a primary concern for a kinase inhibitor, it's a slight positive for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.584) has better Caco-2 permeability than Ligand B (-4.82), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.367) has better aqueous solubility than Ligand B (-3.86), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.428 and 0.385), which is excellent.

**12. Microsomal Clearance:** Ligand A (8.975) has significantly lower microsomal clearance than Ligand B (39.431), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (6.432) has a longer in vitro half-life than Ligand B (-6.632), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.039 and 0.098).

**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 acceptable physicochemical properties, Ligand A is significantly better due to its lower DILI risk, better solubility, better Caco-2 permeability, and, most importantly, much better metabolic stability (lower Cl_mic and longer t1/2). These factors are critical for a kinase inhibitor to have a reasonable in vivo exposure.

Output:
1
2025-04-17 12:04:47,092 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.431 and 353.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (116.76) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (91.16) is well within the range.

**logP:** Ligand A (0.318) is quite low, potentially hindering permeation. Ligand B (1.685) 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 8 HBA, also acceptable.

**QED:** Ligand A (0.792) has a better QED score than Ligand B (0.505), indicating a more drug-like profile.

**DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (42.769), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (75.184) has a higher BBB percentile than Ligand A (54.634).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual. This could indicate issues with the prediction method or the compounds themselves.

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual. This could indicate issues with the prediction method or the compounds themselves.

**hERG:** Both ligands have very low hERG inhibition risk (0.046 and 0.093 respectively).

**Microsomal Clearance:** Ligand A (21.428) has significantly lower microsomal clearance than Ligand B (67.565), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.412) has a positive half-life, while Ligand B (-20.285) has a negative half-life. This is unusual and suggests potential issues with the prediction.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.043 and 0.115 respectively).

**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.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is slightly favored. While its logP is low, its significantly lower microsomal clearance and positive half-life are strong advantages. The higher QED score also contributes to its favorability. The negative Caco-2 and solubility values are concerning for both, but the difference in metabolic stability is a key differentiator.

Output:
0
2025-04-17 12:04:47,092 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.483 and 366.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.34) is significantly better than Ligand B (75.27).  A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.582 and 2.56), falling within the optimal 1-3 range.

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

**QED:** Both ligands have good QED scores (0.796 and 0.841), indicating good drug-like properties.

**DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (61.497). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (88.639) is better than Ligand B (74.06). While not a primary concern for a non-CNS target like SRC, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.508 and -4.682), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.946 and -3.762), which is also unusual and suggests poor solubility. This is also a concern for both.

**hERG:** Ligand A (0.955) has a slightly higher hERG risk than Ligand B (0.252). This favors Ligand B.

**Microsomal Clearance:** Ligand A (70.644) has a higher microsomal clearance than Ligand B (58.82). This suggests Ligand B is more metabolically stable, which is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-22.15) has a much shorter in vitro half-life than Ligand B (-6.541). This further supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.276 and 0.305).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While the difference is not huge, it is a factor.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk, but suffers from higher metabolic clearance and shorter half-life. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, but slightly weaker binding affinity and higher DILI. Given the enzyme-specific priorities, metabolic stability and avoiding toxicity are crucial. The difference in binding affinity (0.7 kcal/mol) is less important than the substantial differences in DILI and metabolic stability.

Output:
1
2025-04-17 12:04:47,092 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.853 and 373.463 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.6) is significantly better than Ligand B (96.87). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (3.898 and 2.163), falling within the 1-3 range. Ligand A is slightly higher, which *could* pose a minor solubility concern, but is not a major issue.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6-7 HBA, which are within acceptable limits (<=5 and <=10, respectively).

**QED:** Both ligands have similar QED values (0.681 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (79.992) has a slightly higher DILI risk than Ligand B (84.8), but both are reasonably low.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (29.12) is lower than Ligand B (24.351), meaning less brain penetration. This is not a negative for this target.

**Caco-2 Permeability:** Ligand A (-5.063) has a more negative Caco-2 value, suggesting *better* permeability than Ligand B (-5.66).

**Aqueous Solubility:** Ligand A (-4.252) has better solubility than Ligand B (-3.013). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.589) has a significantly lower hERG risk than Ligand B (0.136). This is a major advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (22.992) has a lower microsomal clearance than Ligand A (35.393), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (100.757) has a much longer in vitro half-life than Ligand B (25.136), which is highly desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.545) has lower P-gp efflux than Ligand B (0.039), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a *significantly* stronger binding affinity than Ligand B (-8.0 kcal/mol). This >1.5 kcal/mol difference in affinity is a major advantage and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand B having slightly better metabolic stability, Ligand A is the superior candidate. The significantly stronger binding affinity (-9.8 vs -8.0 kcal/mol), better solubility, lower hERG risk, better Caco-2 permeability, and longer half-life outweigh the slightly higher clearance. The TPSA is also more favorable for Ligand A.

Output:
1
2025-04-17 12:04:47,092 - INFO - Batch 100 complete. Total preferences: 1600
2025-04-17 12:04:47,092 - INFO - Processing batch 101/512...
2025-04-17 12:05:34,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.467 and 353.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is higher than Ligand B (53.74). Both are acceptable, but Ligand B is preferable as lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have similar logP values (2.556 and 2.511), 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.862 and 0.71), indicating good drug-like properties.

**DILI:** Ligand A (62.35) has a lower DILI risk than Ligand B (88.406). This is a significant advantage for Ligand A.

**BBB:** Both have good BBB penetration (70.027 and 78.907), but this is less crucial for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.459 and -4.938). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not necessarily indicative of complete lack of permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.009 and -3.623). This is concerning, as solubility is important for bioavailability.

**hERG:** Ligand A (0.408) has a lower hERG risk than Ligand B (0.738). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (75.083) has a higher microsomal clearance than Ligand A (31.992), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (-16.603) has a shorter half-life than Ligand A (-14.964). Both are negative, indicating rapid degradation, but Ligand A is slightly better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.37 and 0.519).

**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 can outweigh some ADME drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.5 vs -6.8 kcal/mol) is a major advantage. While both have solubility concerns, Ligand A exhibits lower DILI risk and hERG inhibition, and better metabolic stability (lower Cl_mic) and half-life. The slightly better TPSA of Ligand B is overshadowed by these other factors.

Output:
0
2025-04-17 12:05:34,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (91.02), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.423 and 1.305), falling within the 1-3 range. Ligand A is slightly better.

**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 (0.675 and 0.872), indicating good drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (35.673) has a lower DILI risk than Ligand B (43.66), both are below the 40 threshold.

**BBB:** Both ligands have similar BBB penetration (71.733 and 70.027). BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.969 and -4.818). 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 ligands have negative solubility values (-4.098 and -3.551). This is also unusual and suggests very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.392 and 0.358).

**Microsomal Clearance:** Ligand B (29.84) has significantly lower microsomal clearance than Ligand A (56.755), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-5.399) has a longer in vitro half-life than Ligand A (-10.702). Again, this is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.162 and 0.108).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor, and the difference of 8.1 kcal/mol is substantial.

**Conclusion:**

While Ligand A has a slightly better logP and TPSA, Ligand B is superior in almost every other critical aspect. Its significantly stronger binding affinity (-8.1 vs 0.0 kcal/mol), lower microsomal clearance, longer half-life, and lower DILI risk outweigh any minor advantages of Ligand A. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The substantial binding affinity advantage of Ligand B makes it the more promising drug candidate.

Output:
1
2025-04-17 12:05:34,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.487 Da) is slightly higher than Ligand B (342.399 Da), but both are acceptable.

**TPSA:** Ligand A (60.78) is significantly better than Ligand B (79.54). Lower TPSA generally improves cell permeability, which is important for kinase inhibitors.

**logP:** Ligand A (3.531) is within the optimal range (1-3), while Ligand B (1.982) is at the lower end. While not a dealbreaker, a slightly higher logP can aid in membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBDs (0) and HBAs (7 for A, 5 for B), falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.569 for A, 0.852 for B), indicating good drug-like properties. Ligand B has a slightly better QED.

**DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (53.276). This is a concern, as higher DILI is undesirable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (75.533) has a higher BBB percentile than Ligand A (48.313).

**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 negative, it doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue. Ligand A (-5.378) is slightly worse than Ligand B (-1.638).

**hERG Inhibition:** Ligand A (0.391) has a lower hERG risk than Ligand B (0.157), which is a significant advantage. Avoiding hERG inhibition is crucial.

**Microsomal Clearance:** Ligand A (104.323) has a higher microsomal clearance than Ligand B (19.229), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (19.391) has a significantly longer in vitro half-life than Ligand A (-34.217), further reinforcing the metabolic stability concern for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.4 for A, 0.089 for B).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 kcal/mol for A, -9.4 kcal/mol for B). Ligand B has a slightly better affinity, but the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly lower, it excels in key areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a slightly better binding affinity. Ligand A's high DILI risk and poor metabolic stability are significant concerns that outweigh its slightly better TPSA and hERG profile. The solubility and Caco-2 values are questionable for both, but the ADME profile of B is superior.

Output:
1
2025-04-17 12:05:34,983 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [381.234, 58.2, 4.185, 2, 3, 0.781, 76.076, 74.098, -4.421, -5.604, 0.296, 47.207, 39.759, 0.256, -8.3]
**Ligand B:** [348.353, 97.11, 1.767, 3, 4, 0.741, 73.052, 66.886, -5.09, -4.008, 0.489, 33.711, 7.933, 0.036, -7]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (348.353 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 140 threshold. Ligand B (97.11) is higher, but still reasonable.
3. **logP:** Ligand A (4.185) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.767) is very good, within the optimal range.
4. **HBD:** Both ligands have acceptable HBD counts (2 and 3 respectively), below the threshold of 5.
5. **HBA:** Both ligands have acceptable HBA counts (3 and 4 respectively), below the threshold of 10.
6. **QED:** Both ligands have good QED scores (0.781 and 0.741), indicating drug-like properties.
7. **DILI:** Both ligands have relatively high DILI risk (76.076 and 73.052). This is a concern, but not a deal-breaker at this stage.
8. **BBB:** Ligand A (74.098) has better BBB penetration than Ligand B (66.886). However, since SRC is not a CNS target, this is less critical.
9. **Caco-2:** Ligand A (-4.421) has a lower Caco-2 value than Ligand B (-5.09), suggesting lower intestinal absorption.
10. **Solubility:** Ligand A (-5.604) has lower solubility than Ligand B (-4.008).
11. **hERG:** Both ligands have low hERG risk (0.296 and 0.489).
12. **Cl_mic:** Ligand B (33.711) has significantly lower microsomal clearance than Ligand A (47.207), indicating better metabolic stability. This is a key advantage for an enzyme target.
13. **t1/2:** Ligand B (7.933) has a longer in vitro half-life than Ligand A (39.759). This is also a significant advantage for an enzyme target.
14. **Pgp:** Ligand A (0.256) has lower P-gp efflux than Ligand B (0.036), which could improve bioavailability.
15. **Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. Ligand A has a much better affinity, but Ligand B has better metabolic stability, solubility, and a slightly better Pgp profile. The DILI risk is similar for both.

**Conclusion:**

While Ligand A's significantly stronger binding affinity is very attractive, the combination of better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and acceptable Pgp efflux of Ligand B make it the more promising drug candidate. The 1.3 kcal/mol difference in affinity, while substantial, can potentially be overcome with further optimization of Ligand B. The higher logP of Ligand A is a concern.

Output:
1
2025-04-17 12:05:34,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.324 Da) is slightly higher than Ligand B (386.539 Da), but both are acceptable.

**TPSA:** Ligand A (59.59) is well below the 140 threshold for oral absorption. Ligand B (89.87) is also below, but closer to the limit.

**logP:** Ligand A (4.89) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.321) is within the optimal range.

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

**QED:** Both ligands have good QED values (A: 0.658, B: 0.71), indicating generally drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 56.844, B: 55.642), and are within an acceptable range (<60).

**BBB:** Ligand A has a higher BBB percentile (83.637) than Ligand B (25.591). However, BBB penetration isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.568) has poor Caco-2 permeability, while Ligand B (-5.307) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.111) has very poor aqueous solubility, a significant drawback. Ligand B (-3.239) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.749) has a slightly higher hERG risk than Ligand B (0.271), but both are relatively low.

**Microsomal Clearance:** Ligand A (104.787) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (40.016) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (29.03) has a moderate half-life. Ligand B (13.023) has a shorter half-life, which is less desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.544, B: 0.1).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has *significantly* stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is substantial.

**Conclusion:**

Despite Ligand A's better BBB penetration, Ligand B is the far superior candidate. Its significantly stronger binding affinity (-7.4 vs 0.0 kcal/mol) outweighs the slightly less favorable solubility and permeability. The lower microsomal clearance of Ligand B also indicates better metabolic stability, a critical factor for kinase inhibitors. The solubility of Ligand B, while not ideal, is better than that of Ligand A.

Output:
1
2025-04-17 12:05:34,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.455 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.84) is well below the 140 threshold, suggesting good absorption. Ligand B (127.51) is still within acceptable limits but higher, potentially impacting absorption slightly.

**logP:** Ligand A (2.684) is optimal (1-3). Ligand B (-0.665) is below 1, which could hinder permeation.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.561 and 0.672), indicating drug-likeness.

**DILI:** Ligand A (14.114) has a very low DILI risk. Ligand B (39.628) is also relatively low, but higher than A.

**BBB:** Both have reasonably good BBB penetration (81.466 and 75.029), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.468) has poor Caco-2 permeability. Ligand B (-5.376) is also poor.

**Aqueous Solubility:** Ligand A (-3.252) has poor aqueous solubility. Ligand B (-2.425) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.894) shows low hERG inhibition risk. Ligand B (0.14) also shows low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (68.215) has moderate clearance. Ligand B (-11.692) has negative clearance, which is unusual and suggests high metabolic stability.

**In vitro Half-Life:** Ligand A (-13.144) has a negative half-life, which is unusual and suggests high stability. Ligand B (1.884) has a short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.557 and 0.016).

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-9.0). This is a crucial advantage for an enzyme inhibitor.

**Conclusion:**

Despite Ligand A's lower DILI risk and slightly better TPSA, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.3 kcal/mol vs -9.0 kcal/mol) outweighs the slightly lower solubility and higher DILI risk. The negative clearance and low P-gp efflux are also very favorable. While both have poor Caco-2 permeability, this can be addressed through formulation strategies. The higher metabolic stability of Ligand B is also a major advantage.

Output:
1
2025-04-17 12:05:34,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.471 and 368.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (104.73). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Ligand A (3.025) is optimal (1-3), while Ligand B (0.323) is quite low, potentially leading to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improves permeability.

**QED:** Both ligands have similar QED values (0.715 and 0.643), indicating good drug-likeness.

**DILI:** Ligand A (16.44) has a much lower DILI risk than Ligand B (46.607). This is a significant advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (75.107) is better than Ligand B (43.699).

**Caco-2 Permeability:** Ligand A (-4.433) is better than Ligand B (-5.603), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.712) is better than Ligand B (-1.954), though both are quite poor.

**hERG Inhibition:** Ligand A (0.42) has a lower hERG risk than Ligand B (0.227), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (66.022) has higher clearance than Ligand B (3.078). This means Ligand B is more metabolically stable, a key advantage for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-2.399) has a longer half-life than Ligand B (-0.826).

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux than Ligand B (0.027), which is favorable for bioavailability.

**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).

**Overall Assessment:**

Ligand A is superior in almost all ADME-Tox properties (TPSA, logP, DILI, hERG, solubility, Caco-2, P-gp efflux, and half-life). While Ligand B has slightly better binding affinity and metabolic stability, the substantial advantages of Ligand A in safety (DILI, hERG) and absorption/permeability outweigh this minor difference in potency. The poor logP and solubility of Ligand B are significant concerns.

Output:
0
2025-04-17 12:05:34,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.463 Da) is slightly higher than Ligand B (340.387 Da), but both are acceptable.

**TPSA:** Ligand A (127.39) is slightly above the preferred <140 for good oral absorption, while Ligand B (88.55) is well within the range. This favors Ligand B.

**logP:** Ligand A (-0.522) is a bit low, potentially hindering permeation. Ligand B (0.938) is closer to the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, fitting the guidelines. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.635, B: 0.747), indicating drug-like properties.

**DILI:** Ligand A (56.689) has a moderate DILI risk, while Ligand B (73.517) has a higher risk. This favors Ligand A.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**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. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, which is excellent. Ligand B (0.194) is slightly higher, but still relatively low. This favors Ligand A.

**Microsomal Clearance:** Ligand A (-9.504) has a negative clearance, which is impossible and likely an error in the data. Ligand B (9.327) has a moderate clearance. This strongly favors Ligand B.

**In vitro Half-Life:** Ligand A (-5.554) has a negative half-life, which is impossible. Ligand B (18.537) has a reasonable half-life. This strongly favors Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A's significantly superior binding affinity (-8.7 vs -0.0 kcal/mol) and very low hERG risk are compelling advantages. However, the negative values for clearance and half-life are concerning and suggest data errors. Ligand B has better TPSA, logP, and more reasonable ADME properties (clearance and half-life), but its binding affinity is extremely weak.

Given the enzyme-specific priorities, potency is paramount. Assuming the negative values for Ligand A are data errors, its much stronger binding affinity outweighs the slightly higher DILI risk and lower logP. If the negative values are accurate, then Ligand B is the better choice despite its weak binding.

Output:
1
2025-04-17 12:05:34,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.403 and 352.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.74) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (67.43) is well within the range.

**3. logP:** Ligand A (0.627) is a bit low, potentially hindering permeability. Ligand B (3.341) 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:** Ligand A (0.785) has a better QED score than Ligand B (0.468), indicating better overall drug-likeness.

**7. DILI:** Ligand A (32.842) has a lower DILI risk than Ligand B (26.871), which is preferable.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 71.811, Ligand B: 73.75). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.749) and Ligand B (-4.822) both have negative values, which is unusual and suggests poor permeability. However, the values are very close.

**10. Aqueous Solubility:** Ligand A (-1.952) and Ligand B (-3.194) both have negative values, indicating poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.16) has a significantly lower hERG risk than Ligand B (0.583), which is a major advantage.

**12. Microsomal Clearance:** Ligand A (-43.109) has a much lower (better) microsomal clearance than Ligand B (67.917), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.376) has a negative value, which is unusual, but Ligand B (-10.455) is significantly worse.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (Ligand A: 0.007, Ligand B: 0.395).

**15. Binding Affinity:** Both ligands have very similar binding affinities (Ligand A: -8.9 kcal/mol, Ligand B: -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. It has a significantly better hERG profile, lower DILI risk, and much better metabolic stability (lower Cl_mic). While Ligand B has a slightly better logP, the advantages of Ligand A in safety and metabolic stability outweigh this. The solubility and permeability are poor for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 12:05:34,985 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [368.547, 74.13, 3.225, 1, 5, 0.669, 32.299, 73.943, -5.078, -3.828, 0.442, 60.539, -4.117, 0.074, -8]
**Ligand B:** [340.387, 85.43, 0.469, 1, 5, 0.878, 53.703, 33.075, -5.036, -2.719, 0.532, -4.836, 11.042, 0.002, -9.5]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (368.547) is slightly higher, but acceptable.
2. **TPSA:** A (74.13) is better than B (85.43), both are acceptable but A is preferred.
3. **logP:** A (3.225) is optimal, while B (0.469) is quite low, potentially hindering permeability. This is a significant drawback for B.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** Both have 5 HBA, which is good.
6. **QED:** B (0.878) is better than A (0.669), indicating a slightly more drug-like profile.
7. **DILI:** A (32.299) is significantly better than B (53.703), indicating lower liver injury risk. This is a major advantage for A.
8. **BBB:** A (73.943) is much better than B (33.075). While SRC isn't a CNS target, higher BBB is generally favorable.
9. **Caco-2:** Both are negative, indicating poor permeability. However, the scale is not specified, so it is hard to compare.
10. **Solubility:** A (-3.828) is worse than B (-2.719), but both are poor. Solubility is a concern for both, but B is slightly better.
11. **hERG:** Both are very low, indicating minimal hERG inhibition risk.
12. **Cl_mic:** A (60.539) is higher than B (-4.836), meaning B has better metabolic stability. This is a key advantage for B.
13. **t1/2:** B (11.042) has a significantly longer half-life than A (-4.117). This is a substantial benefit for B.
14. **Pgp:** A (0.074) is better than B (0.002), indicating less P-gp efflux.
15. **Binding Affinity:** B (-9.5) has a significantly stronger binding affinity than A (-8). This is a major advantage for B, potentially outweighing some ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

*   **Affinity:** B is significantly better.
*   **Metabolic Stability:** B is significantly better (lower Cl_mic, longer t1/2).
*   **Solubility:** A is slightly better.
*   **hERG:** Both are good.
*   **DILI:** A is significantly better.
*   **LogP:** A is better.

**Conclusion:**

While Ligand A has better DILI and LogP, Ligand B's significantly stronger binding affinity, superior metabolic stability (longer half-life and lower clearance), and slightly better solubility are more critical for a kinase inhibitor. The lower logP of B is a concern, but the substantial potency advantage could potentially be overcome with formulation strategies.

Therefore, I recommend **Ligand B** as the more viable drug candidate.

1
2025-04-17 12:05:34,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.74) is significantly better than Ligand B (122.27). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (1.234) is better than Ligand B (0.57). Both are within the 1-3 range, but B is closer to 1, which might slightly hinder permeation.

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

**H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (6). Fewer HBAs generally improve permeability.

**QED:** Ligand A (0.871) is significantly better than Ligand B (0.491). A higher QED indicates a more drug-like profile.

**DILI:** Ligand A (19.426) is much better than Ligand B (29.159). Both are below 40, indicating low risk, but A is considerably lower.

**BBB:** Both ligands have similar BBB penetration (55.487 and 57.736). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.803) is better than Ligand B (-5.568). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-0.991) is better than Ligand B (-2.042). Higher solubility is desirable.

**hERG Inhibition:** Ligand A (0.225) is much better than Ligand B (0.431). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (13.321) is worse than Ligand B (1.298). Lower clearance is preferred for metabolic stability, and B is significantly better.

**In vitro Half-Life:** Ligand A (-10.098) is better than Ligand B (12.548). A more negative value indicates a longer half-life.

**P-gp Efflux:** Ligand A (0.036) is much better than Ligand B (0.019). Lower P-gp efflux is preferred.

**Binding Affinity:** Ligand B (-7.5) is slightly better than Ligand A (-7.2). While both are excellent, the 0.3 kcal/mol difference is not enough to overcome A's superior ADME profile.

**Overall:** Ligand A has a significantly better overall profile. It excels in most ADME properties (TPSA, logP, HBD, HBA, QED, DILI, solubility, hERG, P-gp efflux, in vitro half-life) and has acceptable binding affinity. Ligand B has a slightly better binding affinity, but its poorer ADME profile, particularly the higher DILI, lower QED, and higher microsomal clearance, make it a less desirable candidate.

Output:
0
2025-04-17 12:05:34,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (373.9 Da) is also good.

**TPSA:** Ligand A (113.66) is better than Ligand B (47.36) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (0.555) is a bit low, potentially hindering permeation. Ligand B (3.744) 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 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.647, B: 0.763), indicating drug-like properties.

**DILI:** Ligand A (12.641) has a significantly lower DILI risk than Ligand B (22.993), which is a major advantage.

**BBB:** Ligand A (18.147) has a very low BBB penetration, which is not a concern for a non-CNS target like SRC. Ligand B (95.076) has high BBB penetration, which isn't necessarily detrimental but doesn't offer any benefit for this target.

**Caco-2 Permeability:** Ligand A (-5.242) has poor Caco-2 permeability, while Ligand B (-4.27) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.626) has poor solubility, while Ligand B (-3.562) is even worse.

**hERG Inhibition:** Ligand A (0.189) has very low hERG inhibition risk, which is excellent. Ligand B (0.611) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-7.505) has excellent metabolic stability (negative value indicates low clearance). Ligand B (43.527) has high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-2.185) has a long in vitro half-life, consistent with its low clearance. Ligand B (6.174) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.033, B: 0.179).

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand B having a better logP, the significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk of Ligand A make it the more promising drug candidate. The solubility and Caco-2 permeability are concerns for both, but these can potentially be addressed through formulation strategies. The superior ADME-Tox profile of Ligand A outweighs the slightly less optimal logP.

Output:
0
2025-04-17 12:05:34,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.462 Da) and Ligand B (341.503 Da) are both acceptable.

**TPSA:** Ligand A (104.45) is slightly higher than ideal (<140), but still reasonable. Ligand B (55.63) is excellent, well below the threshold.

**logP:** Both ligands have good logP values (Ligand A: 2.022, Ligand B: 3.601), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.454, Ligand B: 0.734). Ligand B's QED is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A has a DILI risk of 49.05, which is good (below 60). Ligand B has a very low DILI risk of 25.204, which is excellent.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (55.332) and Ligand B (83.56) are both moderate, with B being better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.658 and -5.26), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.686 and -3.763), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.432, Ligand B: 0.33), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (Ligand A: 36.418, Ligand B: 36.806), which are moderate.

**In vitro Half-Life:** Ligand A has a negative half-life (-26.001), which is problematic. Ligand B has a negative half-life as well (-6.632), but less negative. Both suggest rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.022, Ligand B: 0.341), which is favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While both ligands have significant issues with solubility and permeability, Ligand B is the better candidate. It has a superior QED score, a lower DILI risk, a significantly stronger binding affinity, and a slightly better BBB score. The negative half-life is a concern for both, but the stronger binding of Ligand B suggests it might still be effective *in vivo* even with faster metabolism, and could be optimized through structural modifications.

Output:
1
2025-04-17 12:05:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.5 and 352.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (78.35). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (2.965 and 1.663), falling within the 1-3 range. Ligand A is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 5. Lower HBA counts are generally preferred for better permeability.

**QED:** Both ligands have good QED scores (0.752 and 0.843), indicating drug-like properties.

**DILI:** Ligand A (37.03) has a lower DILI risk than Ligand B (49.17), which is a significant advantage.

**BBB:** Both have high BBB penetration (85.033 and 80.69), but SRC is not a CNS target, so this is less critical.

**Caco-2:** Ligand A (-5.322) has a worse Caco-2 permeability than Ligand B (-4.907), but both are negative values which is unusual and suggests a potential issue with this metric.

**Solubility:** Ligand A (-3.575) has slightly worse solubility than Ligand B (-2.963), but both are negative values which is unusual and suggests a potential issue with this metric.

**hERG:** Both ligands have low hERG risk (0.51 and 0.385), which is excellent.

**Microsomal Clearance:** Ligand A (8.016) has a higher microsomal clearance than Ligand B (0.512). This means Ligand B is likely more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (18.747) has a significantly longer in vitro half-life than Ligand A (15.433), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux (0.15 and 0.036), which is good.

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.0). While both are excellent, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better logP and BBB, Ligand B excels in the most critical areas for an enzyme inhibitor: metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity. The TPSA of Ligand A is better, but the difference isn't large enough to outweigh the metabolic advantages of Ligand B. The unusual negative values for Caco-2 and Solubility for both ligands are concerning and would require further investigation, but do not change the overall ranking.

Output:
1
2025-04-17 12:05:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.507 Da and 347.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is well below the 140 threshold for oral absorption, while Ligand B (93.7) is approaching it. This favors Ligand A.

**logP:** Ligand A (1.544) is within the optimal 1-3 range. Ligand B (-0.109) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**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 below the 10 limit, but Ligand A is better.

**QED:** Both ligands have good QED scores (0.694 and 0.772), indicating good drug-like properties.

**DILI:** Ligand A (8.104) has a significantly lower DILI risk than Ligand B (56.65). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.186) is higher than Ligand B (55.37).

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, making interpretation difficult. Ligand A (-4.768) is slightly better than Ligand B (-5.088).

**Aqueous Solubility:** Both have negative values, which is also unusual. Again, the scale is not specified. Ligand A (-1.741) is slightly better than Ligand B (-1.908).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.387 and 0.288), which is good.

**Microsomal Clearance:** Ligand A (37.66) has a higher microsomal clearance than Ligand B (17.661). This suggests Ligand B is more metabolically stable, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand B (9.418) has a significantly longer in vitro half-life than Ligand A (2.117), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.004).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 0.4 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and has slightly better solubility and Caco-2 permeability. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly stronger binding affinity. Given the enzyme-specific priorities, metabolic stability is crucial. While the affinity difference is notable, the substantial improvement in DILI risk and the better metabolic profile of Ligand B outweigh the minor affinity advantage of Ligand A.

Output:
1
2025-04-17 12:05:34,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.393 and 365.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (49.41 and 47.36) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (3.34 and 3.718) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 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 scores (0.802 and 0.722), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 51.958, considered moderate. Ligand B has a significantly lower DILI risk of 23.769, which is a strong advantage.

**BBB:** Both ligands have high BBB penetration (78.79 and 89.027), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.234 and -4.793). This 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 (-5.37 and -3.008). Again, these are on a log scale and indicate poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.39, which is good. Ligand B has a slightly higher risk of 0.539, but still relatively low.

**Microsomal Clearance:** Ligand A has a Cl_mic of 58.767, while Ligand B has 68.353. Lower is better, so Ligand A has a slight advantage in metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of -2.303 hours, while Ligand B has -4.936 hours. These negative values are unusual and likely indicate rapid degradation. Ligand A is slightly better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.301).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.7 kcal/mol). The difference of 0.1 kcal/mol is negligible.

**Conclusion:**

While both ligands have good potency, Ligand B is preferable due to its significantly lower DILI risk (23.769 vs 51.958). Although both have poor predicted solubility and permeability, the lower toxicity profile of Ligand B outweighs the slight advantage Ligand A has in metabolic stability and half-life.

Output:
1
2025-04-17 12:05:34,986 - INFO - Batch 101 complete. Total preferences: 1616
2025-04-17 12:05:34,986 - INFO - Processing batch 102/512...
2025-04-17 12:06:23,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 351.491 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.6) is better than Ligand B (72.88). Both are below the 140 threshold for oral absorption, but closer to the ideal for enzyme inhibitors.

**logP:** Ligand A (3.116) is optimal, while Ligand B (0.985) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Both are within the acceptable range.

**QED:** Both ligands have similar QED values (0.796 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (8.492), which is a major advantage.

**BBB:** Ligand A (46.995) has a better BBB penetration score than Ligand B (32.726), although BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.69) is better than Ligand B (-5.051). Higher (less negative) values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.099) is better than Ligand B (-1.824). Higher values indicate better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.391 and 0.461), which is excellent.

**Microsomal Clearance:** Ligand A (76.601) has higher microsomal clearance than Ligand B (6.787). This means Ligand B is more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (28.644) has a longer in vitro half-life than Ligand A (21.164), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.096 and 0.036).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.8 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, HBD, DILI, Caco-2 permeability, and solubility. However, Ligand B exhibits superior metabolic stability (lower Cl_mic, longer t1/2), which is a critical factor for kinase inhibitors. The difference in binding affinity is minor. Given the importance of metabolic stability for kinases, and the acceptable profile of Ligand B across other parameters, it is the more promising candidate.

Output:
1
2025-04-17 12:06:23,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.5 and 354.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.1) is significantly better than Ligand B (89.9). Lower TPSA generally improves permeability.

**logP:** Both ligands have acceptable logP values (1.016 and 1.443), falling within the 1-3 range.

**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 permeability.

**QED:** Both ligands have reasonable QED scores (0.759 and 0.645), indicating good drug-likeness.

**DILI:** Both have low DILI risk (8.6 and 9.2 percentile), which is good.

**BBB:** Both have moderate BBB penetration (64.5 and 67.4 percentile), not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.96 and -4.8), which is unusual and problematic. This suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values (-0.234 and -1.675), also unusual and problematic. This suggests poor solubility.

**hERG Inhibition:** Ligand A (0.592) is significantly better than Ligand B (0.368) regarding hERG inhibition risk. Lower is better here.

**Microsomal Clearance:** Ligand A (1.692) has much lower microsomal clearance than Ligand B (13.905). This indicates better metabolic stability for Ligand A, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-1.088 hours) has a very short half-life, while Ligand B (-26.666 hours) has a very long half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.026 and 0.069), which is good.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). A 1 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Despite the unusual Caco-2 and solubility values, Ligand A is the better candidate. Its superior metabolic stability (lower Cl_mic) and lower hERG risk are critical advantages for an enzyme inhibitor. While Ligand B has a better half-life and slightly better affinity, the metabolic stability and safety profile of Ligand A outweigh these benefits. The poor permeability and solubility of both compounds would need to be addressed through further optimization, but Ligand A provides a better starting point.

Output:
0
2025-04-17 12:06:23,207 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.487, 58.64, 2.487, 1, 3, 0.802, 22.451, 76.541, -4.737, -3.171, 0.463, 65.923, 8.561, 0.11, -7.1]
**Ligand B:** [375.559, 29.54, 4.551, 0, 4, 0.678, 42.691, 92.555, -5.054, -4.732, 0.769, 107.866, 39.258, 0.732, -9]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (348.487) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (58.64) is better than B (29.54). Lower TPSA generally correlates with better cell permeability.
3. **logP:** A (2.487) is optimal. B (4.551) is pushing the upper limit and could lead to solubility issues or off-target interactions.
4. **HBD:** A (1) is good. B (0) is also acceptable.
5. **HBA:** A (3) is good. B (4) is acceptable.
6. **QED:** A (0.802) is excellent, indicating high drug-likeness. B (0.678) is still acceptable, but less favorable.
7. **DILI:** A (22.451) is very good (low risk). B (42.691) is also reasonably low risk, but higher than A.
8. **BBB:** A (76.541) is good, while B (92.555) is excellent. However, since SRC is not a CNS target, this is less critical.
9. **Caco-2:** A (-4.737) is poor, indicating low permeability. B (-5.054) is also poor, but slightly better than A.
10. **Solubility:** A (-3.171) is poor. B (-4.732) is also poor. Both compounds have solubility concerns.
11. **hERG:** A (0.463) is very low risk. B (0.769) is slightly higher, but still acceptable.
12. **Cl_mic:** A (65.923) is moderate. B (107.866) is high, indicating faster metabolism and potentially lower *in vivo* exposure. This is a significant drawback for B.
13. **t1/2:** A (8.561) is reasonable. B (39.258) is excellent, suggesting a longer duration of action.
14. **Pgp:** A (0.11) is low efflux, which is good. B (0.732) is higher, suggesting more P-gp mediated efflux.
15. **Affinity:** B (-9) is significantly better than A (-7.1). A difference of 1.9 kcal/mol is substantial and can often outweigh other ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both compounds have solubility issues, B has a much better binding affinity and a longer half-life, which are crucial for an enzyme target. The higher metabolic clearance of B is a concern, but the significantly improved potency could compensate for this.

**Conclusion:**

Despite the higher logP and metabolic clearance, **Ligand B** is the more promising candidate due to its substantially superior binding affinity (-9 kcal/mol vs -7.1 kcal/mol). The potency advantage is likely to be more impactful for an enzyme target like SRC kinase than the slightly better ADME properties of Ligand A.

1
2025-04-17 12:06:23,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.434 and 353.438 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.59) is slightly higher than Ligand B (56.59), but both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (3.541) is optimal, while Ligand B (1.65) is on the lower side. A logP below 1 can sometimes hinder permeation, making Ligand A preferable here.

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

**5. H-Bond Acceptors:** Ligand A (3) is acceptable, Ligand B (5) is acceptable.

**6. QED:** Ligand A (0.873) is excellent, indicating strong drug-likeness. Ligand B (0.6) is still reasonable, but less optimal.

**7. DILI:** Ligand A (31.873) has a significantly lower DILI risk than Ligand B (11.632), which is a major advantage.

**8. BBB:** Both ligands have high BBB penetration, but Ligand B (97.247) is higher than Ligand A (84.529). However, since SRC is not a CNS target, this is less important.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.406 and -4.43), indicating poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Ligand A (-3.379) has slightly better solubility than Ligand B (-1.257), but both are poor.

**11. hERG Inhibition:** Ligand A (0.438) has a lower hERG risk than Ligand B (0.698), which is a positive.

**12. Microsomal Clearance:** Ligand A (28.888) has a lower Cl_mic, suggesting better metabolic stability, than Ligand B (53.442). This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (22.565 and 22.753 hours).

**14. P-gp Efflux:** Ligand A (0.125) has lower P-gp efflux than Ligand B (0.185), which is favorable.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has *significantly* stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor, and the >1.5 kcal/mol advantage easily outweighs the other drawbacks.

**Overall:**

Ligand A is the superior candidate. While both have poor Caco-2 permeability and solubility, Ligand A's dramatically improved binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and lower hERG risk outweigh the slightly lower BBB penetration and higher TPSA. The strong binding affinity suggests that even with potential absorption challenges, Ligand A is more likely to be efficacious.

Output:
1
2025-04-17 12:06:23,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:**
* Ligand A: 429.292 Da - Within the ideal range (200-500 Da).
* Ligand B: 347.38 Da - Also within the ideal range.
* *No clear advantage here.*

**2. TPSA:**
* Ligand A: 89.71 A<sup>2</sup> - Good for oral absorption (<=140 A<sup>2</sup>).
* Ligand B: 29.1 A<sup>2</sup> - Excellent for oral absorption.
* *Ligand B has a significant advantage in TPSA.*

**3. logP:**
* Ligand A: 2.009 - Optimal (1-3).
* Ligand B: 4.403 - Slightly high, potential solubility/off-target issues.
* *Ligand A has an advantage here.*

**4. H-Bond Donors:**
* Ligand A: 0 - Acceptable (<=5).
* Ligand B: 1 - Acceptable (<=5).
* *No clear advantage.*

**5. H-Bond Acceptors:**
* Ligand A: 6 - Acceptable (<=10).
* Ligand B: 1 - Acceptable (<=10).
* *Ligand A has a slight advantage.*

**6. QED:**
* Ligand A: 0.726 - Good drug-like profile (>=0.5).
* Ligand B: 0.816 - Excellent drug-like profile.
* *Ligand B has a slight advantage.*

**7. DILI:**
* Ligand A: 84.645 - High risk (>60).
* Ligand B: 50.601 - Moderate risk, but better than Ligand A.
* *Ligand B has a significant advantage.*

**8. BBB:**
* Ligand A: 79.915 - Not a priority for an oncology target.
* Ligand B: 91.663 - Not a priority for an oncology target.
* *No clear advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -4.592 - Indicates poor permeability.
* Ligand B: -4.503 - Indicates poor permeability.
* *Similar, both are poor.*

**10. Aqueous Solubility:**
* Ligand A: -2.975 - Indicates poor solubility.
* Ligand B: -4.897 - Indicates very poor solubility.
* *Ligand A has a slight advantage.*

**11. hERG Inhibition:**
* Ligand A: 0.395 - Low risk.
* Ligand B: 0.883 - Moderate risk.
* *Ligand A has an advantage.*

**12. Microsomal Clearance:**
* Ligand A: 27.14 mL/min/kg - Relatively high clearance, suggesting lower metabolic stability.
* Ligand B: 74.413 mL/min/kg - Very high clearance, suggesting poor metabolic stability.
* *Ligand A has a significant advantage.*

**13. In vitro Half-Life:**
* Ligand A: 78.505 hours - Good.
* Ligand B: 24.337 hours - Moderate.
* *Ligand A has a significant advantage.*

**14. P-gp Efflux:**
* Ligand A: 0.105 - Low efflux, good.
* Ligand B: 0.659 - Moderate efflux.
* *Ligand A has an advantage.*

**15. Binding Affinity:**
* Ligand A: -7.5 kcal/mol - Excellent.
* Ligand B: -8.0 kcal/mol - Excellent, slightly better.
* *Ligand B has a slight advantage.*

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and QED, Ligand A is significantly better regarding metabolic stability (lower Cl_mic, longer t1/2), DILI risk, and hERG inhibition. Solubility is slightly better for Ligand A. The poor Caco-2 permeability is a concern for both, but can be addressed with formulation strategies. Given the enzyme target class and the importance of metabolic stability and safety (DILI, hERG), Ligand A is the more promising candidate. The 0.5 kcal/mol difference in binding affinity is unlikely to outweigh the substantial advantages of Ligand A in ADME-Tox properties.

Output:
0
2025-04-17 12:06:23,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is well below the 140 threshold, while Ligand B (99.24) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.336) is optimal, while Ligand B (1.839) is a bit 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 4 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values (0.854 and 0.78) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (59.829), but both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (68.554 and 71.656), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.549 and -4.98), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.863 and -3.077), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.228) has a lower hERG risk than Ligand B (0.422), which is favorable.

**Microsomal Clearance:** Ligand A (82.903) has higher microsomal clearance than Ligand B (14.934), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (38.074) has a significantly longer in vitro half-life than Ligand A (1.234), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 and 0.065).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.1 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility predictions for both compounds, the significantly stronger binding affinity of Ligand A (-8.8 kcal/mol vs -7.7 kcal/mol) and its lower hERG risk make it the more promising candidate. While Ligand B has better metabolic stability and half-life, the potency advantage of Ligand A is crucial for an enzyme target like SRC kinase. The poor permeability and solubility would need to be addressed through formulation or further chemical modifications, but the initial binding affinity is a strong starting point.

Output:
1
2025-04-17 12:06:23,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 345.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.81) is slightly above the preferred <140, but acceptable. Ligand B (61.14) is well within the range.

**logP:** Ligand A (0.656) is a bit low, potentially hindering permeation. Ligand B (3.379) is optimal.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (6) is also good.

**QED:** Both ligands have reasonable QED scores (0.701 and 0.566), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (42.264 and 42.187).

**BBB:** Ligand A (40.132) has poor BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (78.558) has better BBB penetration, but again, this isn't critical here.

**Caco-2 Permeability:** Ligand A (-5.021) shows poor permeability. Ligand B (-4.504) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.938) has poor solubility. Ligand B (-3.614) has even poorer solubility.

**hERG Inhibition:** Ligand A (0.242) has a very low hERG risk, which is excellent. Ligand B (0.913) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (35.325) has lower clearance, suggesting better metabolic stability. Ligand B (74.756) has significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (33.941) has a shorter half-life, but still reasonable. Ligand B (64.586) has a longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.13) has very low P-gp efflux, which is good. Ligand B (0.532) has moderate P-gp efflux.

**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.

**Conclusion:**

The most critical factor for an enzyme inhibitor is binding affinity. Ligand A's affinity is 1.7 kcal/mol better than Ligand B. While Ligand A has some drawbacks (low logP, poor solubility, and permeability), the significantly stronger binding affinity likely outweighs these concerns, especially considering the acceptable DILI and very low hERG risk. Ligand B has better metabolic stability (longer half-life, lower clearance) but the weaker binding makes it less promising.

Output:
0
2025-04-17 12:06:23,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.299 Da and 368.865 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.39) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.53) is excellent, well below 140, suggesting good absorption potential.

**logP:** Both ligands (1.634 and 1.941) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 8 HBA, while Ligand B has 4 HBA. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.88) has a significantly better QED score than Ligand A (0.409), indicating a more drug-like profile.

**DILI:** Ligand A (97.984) has a very high DILI risk, which is a major concern. Ligand B (53.587) has a moderate DILI risk, which is much more acceptable.

**BBB:** Both have moderate BBB penetration (68.282 and 66.964). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.163 and -5.06), which is unusual and suggests poor permeability. This needs further investigation, but is a negative for both.

**Aqueous Solubility:** Both have negative solubility values (-3.968 and -3.286), which is also unusual and suggests poor solubility. This is another area needing investigation.

**hERG:** Ligand A (0.132) has a slightly higher hERG risk than Ligand B (0.463), but both are relatively low.

**Microsomal Clearance:** Ligand A (51.473) has a moderate microsomal clearance, while Ligand B (11.718) has a very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.409) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand A (29.071) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.25).

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

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, Ligand B is the superior candidate. Its significantly stronger binding affinity, much better QED score, lower DILI risk, and superior metabolic stability (lower Cl_mic) outweigh the concerns. The negative half-life for Ligand B is a data quality issue that needs to be resolved, but the other properties strongly favor it. Ligand A's very high DILI risk is a deal-breaker.

Output:
1
2025-04-17 12:06:23,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.551 and 339.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (92.02).  TPSA < 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Both ligands have good logP values (2.656 and 1.8), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=0, HBA=8). While both are within acceptable limits, Ligand A has a more balanced profile.

**QED:** Both ligands have similar QED scores (0.67 and 0.606), indicating good drug-likeness.

**DILI:** Ligand A (4.343) has a much lower DILI risk than Ligand B (80.341). This is a *major* advantage for Ligand A.

**BBB:**  BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (62.156) is slightly better than Ligand B (57.774).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.772 and -4.697), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.893 and -2.746), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG:** Both ligands have low hERG inhibition liability (0.41 and 0.136), which is good.

**Microsomal Clearance:** Ligand A (24.443) has significantly lower microsomal clearance than Ligand B (74.417), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (4.358) has a positive half-life, while Ligand B (-24.41) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.006 and 0.09).

**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, it's still a positive factor.

**Overall Assessment:**

Ligand A is clearly the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand A excels in critical areas for an enzyme target: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and positive half-life), and slightly better binding affinity. The TPSA is also more favorable for Ligand A. The solubility issues would need to be addressed through formulation strategies, but the ADME and toxicity profile of Ligand A is far more promising.

Output:
1
2025-04-17 12:06:23,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.471 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (50.16 and 50.36) are slightly above the optimal <140 for good oral absorption, but not drastically so.

**logP:** Ligand A (2.761) is within the optimal 1-3 range. Ligand B (4.345) is slightly higher, potentially leading to solubility issues or off-target interactions, but still within a reasonable range.

**H-Bond Donors & Acceptors:** Ligand A has 1 HBD and 4 HBA, well within the guidelines. Ligand B has 2 HBD and 2 HBA, also acceptable.

**QED:** Ligand A (0.88) has a significantly better QED score than Ligand B (0.748), indicating a more drug-like profile.

**DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (23.846), a significant advantage.

**BBB:** Both ligands have high BBB penetration (87.67 and 85.459), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.052) and Ligand B (-4.667) both have negative Caco-2 values, which is unusual and suggests poor permeability. Further investigation would be needed to understand these values.

**Aqueous Solubility:** Ligand A (-2.362) has better solubility than Ligand B (-4.363).

**hERG Inhibition:** Ligand A (0.929) has a lower hERG risk than Ligand B (0.67), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (4.68 mL/min/kg) has significantly lower microsomal clearance than Ligand B (62.285 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.065 hours) has a much longer half-life than Ligand B (24.77 hours).

**P-gp Efflux:** Ligand A (0.398) shows lower P-gp efflux than Ligand B (0.195).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This 1.5 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is a much more promising drug candidate. It exhibits a significantly better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a higher QED score. The slightly weaker binding affinity of Ligand A can potentially be optimized through further medicinal chemistry efforts, whereas improving the ADMET properties of Ligand B would be more challenging.

Output:
0
2025-04-17 12:06:23,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.519 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is slightly higher than Ligand B (40.62). Both are below the 140 threshold for good absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (2.813 and 3.722), 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 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 acceptable QED values (0.731 and 0.627), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 20.047, which is excellent (low risk). Ligand B has a DILI risk of 8.647, also very good.

**BBB:** Ligand A (72.237) and Ligand B (89.298) both have good BBB penetration, but Ligand B is better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.496 and -4.604). These values are unusual and suggest 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 (-2.221 and -3.447), which is also unusual and suggests poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.568 and 0.667), which is excellent.

**Microsomal Clearance:** Ligand A (50.415) has lower microsomal clearance than Ligand B (87.56), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-2.539) has a negative half-life, which is not possible. Ligand B (-18.98) also has a negative half-life, which is also not possible. This suggests issues with the experimental setup or data quality.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.661 and 0.264), 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.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the key differentiating factors are metabolic stability and binding affinity. Ligand A has significantly better metabolic stability (lower Cl_mic) and a reasonably close binding affinity to Ligand B. The slightly better BBB penetration of Ligand B is not a major factor for a kinase inhibitor. The DILI risk is low for both. The negative half-life values are concerning, but since Ligand A has better metabolic stability, it is more likely to have a longer *in vivo* half-life.

Output:
0
2025-04-17 12:06:23,209 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.427 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (90.75 and 89.45) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.39) is higher than optimal (1-3), potentially leading to solubility issues. Ligand B (2.403) is 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, well within the guidelines.

**QED:** Both ligands have acceptable QED values (0.498 and 0.604), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (58.434) has a higher DILI risk than Ligand B (15.2), which is a significant concern.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC kinase, but Ligand A (74.254) has a better BBB percentile than Ligand B (46.413).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.954 and -4.887), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.801 and -1.945), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Ligand A (0.841) has a slightly higher hERG inhibition risk than Ligand B (0.545), but both are relatively low.

**Microsomal Clearance:** Ligand A (62.934) has a higher microsomal clearance than Ligand B (-0.875), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-15.313) has a significantly longer in vitro half-life than Ligand A (12.356), which is highly desirable.

**P-gp Efflux:** Ligand A (0.462) has lower P-gp efflux liability than Ligand B (0.235), which is slightly favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-9.3 and -8.3 kcal/mol), with Ligand A being slightly better. However, the 1.0 kcal/mol difference is unlikely to outweigh the significant ADME deficiencies of Ligand A.

**Conclusion:**

Despite having slightly better binding affinity and P-gp efflux, Ligand A suffers from significantly higher DILI risk, higher microsomal clearance (lower metabolic stability), and poor solubility. Ligand B, while having a slightly weaker binding affinity, demonstrates a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable logP. Given the enzyme-kinase specific priorities, metabolic stability and safety are crucial. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 12:06:23,209 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.852 and 383.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (124.6). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (2.728) is optimal (1-3). Ligand B (-1.19) is below 1, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (4 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.832) is excellent, indicating high drug-likeness. Ligand B (0.399) is below the desirable threshold of 0.5.

**DILI:** Ligand A (33.501) has a much lower DILI risk than Ligand B (44.746), both are acceptable but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.041) is better than Ligand B (65.064).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is concerning, but we can look at other parameters.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is also concerning.

**hERG:** Ligand A (0.316) has a lower hERG risk than Ligand B (0.227), which is preferable.

**Microsomal Clearance:** Ligand A (8.243) has a slightly better (lower) clearance than Ligand B (7.484), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.321) has a significantly longer half-life than Ligand B (-29.941), a major advantage.

**P-gp Efflux:** Both are very low (0.074 and 0.011), indicating minimal P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.3 kcal/mol). Ligand A is 1 kcal/mol better, which is a substantial advantage and can outweigh some of the ADME drawbacks.

**Overall:**

Ligand A is clearly superior. While both have poor Caco-2 and solubility, Ligand A excels in crucial areas: QED, DILI, hERG, metabolic stability (lower Cl_mic and longer t1/2), and a significantly better binding affinity. The logP value is also optimal for A, while B is concerningly low. The better TPSA of A is also a plus. The 1 kcal/mol difference in binding affinity is significant.

Output:
0
2025-04-17 12:06:23,209 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.515 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (104.29). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (3.946) is optimal, while Ligand B (0.492) is quite low, potentially hindering membrane permeability.

**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:** Both ligands have similar QED values (0.767 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (6.669) has a much lower DILI risk than Ligand B (35.169), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.443) has a higher BBB percentile than Ligand B (53.974).

**Caco-2 Permeability:** Ligand A (-4.659) is better than Ligand B (-5.457), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.525) is better than Ligand B (-0.839), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.753 and 0.053), which is excellent.

**Microsomal Clearance:** Ligand A (18.11) has a higher microsomal clearance than Ligand B (13.906), suggesting lower metabolic stability. However, both are reasonably acceptable.

**In vitro Half-Life:** Ligand B (17.779) has a longer half-life than Ligand A (14.276), which is preferable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.121 and 0.002).

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-9.0), but the difference is not substantial enough to outweigh the multiple ADME advantages of Ligand A.

**Overall:** Considering all factors, Ligand A is the more promising drug candidate. It has better physicochemical properties (TPSA, logP, solubility), a significantly lower DILI risk, and better Caco-2 permeability. While Ligand B has a slightly better binding affinity and half-life, the ADME profile of Ligand A is superior, making it more likely to succeed as a drug.

Output:
1
2025-04-17 12:06:23,209 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.463 and 380.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.08) is slightly higher than Ligand B (94.07). Both are below the 140 threshold for good oral absorption, but Ligand B is closer to the 90 threshold for CNS penetration (though that's not a primary concern here).

**logP:** Ligand A (-0.025) is quite low, potentially hindering permeability. Ligand B (1.809) 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 (7 and 8 respectively), satisfying the criteria.

**QED:** Both ligands have similar QED values (0.782 and 0.736), indicating good drug-likeness.

**DILI:** Both ligands have elevated DILI risk (59.403 and 69.678), but Ligand B is slightly higher. This is a concern for both, requiring further investigation.

**BBB:** Both have moderate BBB penetration (68.36 and 62.97). Not a primary concern for a non-CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.62 and -4.873), which is unusual and indicates very poor permeability. This is a major red flag for both compounds.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.17 and -2.559). This is a significant issue for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.048 and 0.062). This is positive.

**Microsomal Clearance:** Ligand A (20.799) has significantly lower microsomal clearance than Ligand B (79.196), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Both have negative in vitro half-life (-17.964 and -16.906), which is impossible. This suggests an issue with the data or the assay.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.046 and 0.074).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage for Ligand B, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the poor solubility and permeability of both compounds, Ligand B appears more promising due to its superior binding affinity (-9.6 vs -8.0 kcal/mol) and more favorable logP (1.809 vs -0.025). The stronger binding is likely to outweigh the slightly higher DILI risk. The metabolic stability of Ligand A is better, but the significantly weaker binding makes it less likely to be a viable candidate. The negative Caco-2 and solubility values are concerning for both and would need to be addressed through structural modifications.

Output:
1
2025-04-17 12:06:23,209 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.373 and 356.329 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.47) is well below the 140 threshold and favorable for oral absorption. Ligand B (100.63) is still within acceptable range, but less optimal.

**logP:** Ligand A (2.449) is within the optimal 1-3 range. Ligand B (-0.238) is below 1, which may impede permeation.

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

**QED:** Both ligands have acceptable QED values (A: 0.824, B: 0.573), indicating good drug-like properties.

**DILI:** Ligand A (82.784) has a higher DILI risk than Ligand B (64.521), but both are within acceptable limits.

**BBB:** Both have moderate BBB penetration (A: 57.193, B: 60.682). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.65) has poor Caco-2 permeability, which is a concern. Ligand B (-5.131) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.445) has poor solubility. Ligand B (-2.061) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.317) has a very low hERG risk, which is excellent. Ligand B (0.086) is also very low, and excellent.

**Microsomal Clearance:** Ligand A (59.443) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (3.61) has very low clearance, indicating excellent metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand A (6.896) has a moderate half-life. Ligand B (-31.504) has a very long half-life, which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.466, B: 0.009).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage for A. The difference is >1.5 kcal/mol, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability and solubility, and higher metabolic clearance. Ligand B has excellent metabolic stability (low Cl_mic, long half-life), better solubility, and a lower DILI risk, but its binding affinity is considerably weaker.

Given the strong affinity of Ligand A, it is more likely to be a viable drug candidate *despite* its ADME liabilities. Optimization efforts could focus on improving its solubility and permeability while retaining its potent binding. The superior binding affinity is a significant advantage that can be addressed through medicinal chemistry.

Output:
0
2025-04-17 12:06:23,209 - INFO - Batch 102 complete. Total preferences: 1632
2025-04-17 12:06:23,209 - INFO - Processing batch 103/512...
2025-04-17 12:07:05,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.446 and 363.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is well below the 140 threshold, and even preferable for oral absorption. Ligand B (72.7) is still acceptable, but less optimal.

**logP:** Both ligands have logP values around 4 (4.208 and 4.074), which is slightly high. This could potentially lead to solubility issues or off-target effects, but is not a dealbreaker if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is better than Ligand B (1 HBD, 6 HBA). Lower HBA counts are generally preferred for better permeability.

**QED:** Both ligands have reasonable QED scores (0.4 and 0.718), with Ligand B being significantly better.

**DILI:** Ligand A (40.752) has a lower DILI risk than Ligand B (65.917), which is a significant advantage.

**BBB:** This is less crucial for a non-CNS target like SRC kinase, but Ligand A (76.076) has a better BBB percentile than Ligand B (55.68).

**Caco-2 Permeability:** Ligand A (-4.717) has a much better Caco-2 permeability than Ligand B (-5.091).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.413 and -4.285). This is a concern, but can sometimes be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.79) has a lower hERG inhibition risk than Ligand B (0.308), which is a major advantage.

**Microsomal Clearance:** Ligand A (71.419) has a lower microsomal clearance than Ligand B (74.233), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (30.849 hours) has a significantly longer half-life than Ligand B (11.806 hours), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.542 and 0.299).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), although both are good. The 0.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the superior candidate. It exhibits a better safety profile (lower DILI, lower hERG), better permeability (Caco-2), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have somewhat high logP and poor solubility, the advantages of Ligand A outweigh these drawbacks. The improved ADME properties and potency make it a more promising drug candidate.

Output:
1
2025-04-17 12:07:05,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 370.837 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.46) is better than Ligand B (113.44), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.646 and 0.46), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both have 3 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 (0.694 and 0.642), indicating good drug-likeness.

**DILI:** Ligand A (35.479) has a significantly lower DILI risk than Ligand B (50.136). This is a major advantage.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 unspecified.

**hERG:** Both ligands have very low hERG inhibition risk (0.166 and 0.066).

**Microsomal Clearance:** Ligand A (-0.583) has a *negative* microsomal clearance, which is not physically possible. This is likely an error in the data. Ligand B (7.247) has a higher clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (23.11 hours) has a longer half-life than Ligand B (25.959 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.046).

**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.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The significantly lower DILI risk is a major advantage. The negative microsomal clearance for Ligand A is a data error and should be investigated, but assuming it's a reasonable value, the longer half-life is also favorable. The slightly better TPSA and logP of Ligand A also contribute to its overall better profile. The unusual negative values for Caco-2 and solubility are concerning for both, but the DILI risk is the most critical factor in this comparison.

Output:
1
2025-04-17 12:07:05,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.515 and 343.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) and Ligand B (55.63) are both below the 140 A^2 threshold for good oral absorption, which is good.

**3. logP:** Both ligands have logP values (3.572 and 3.469) 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 (2) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.66 and 0.859), indicating good drug-like properties.

**7. DILI:** This is a critical factor. Ligand A has a DILI risk of 9.771%, which is excellent (low risk). Ligand B has a significantly higher DILI risk of 30.593%, which is a moderate concern.

**8. BBB:** Both ligands have good BBB penetration (71.035% and 77.2%), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.676 and -5.073). This suggests potential absorption issues, but can be mitigated with formulation strategies.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.094 and -4.399). This is a concern and may require formulation work.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.317 and 0.37).

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (80.792) than Ligand B (43.435). This suggests Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-7.319 hours) than Ligand B (-2.295 hours). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.094 and 0.225).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.1 and -7.3 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is substantial, but not overwhelmingly so.

**Overall Assessment:**

Ligand A is the better candidate. While both have similar binding affinities and permeability issues, Ligand A's significantly lower DILI risk and longer half-life outweigh the slightly higher clearance. The DILI risk for Ligand B is a significant concern, and the shorter half-life means more frequent dosing would likely be required. The affinity difference, while present, isn't large enough to overcome the ADME liabilities of Ligand B.

Output:
0
2025-04-17 12:07:05,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.49 and 383.857 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (92.51). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (3.649) is optimal, while Ligand B (1.995) is at the lower end of the optimal range. While still acceptable, A's logP is more favorable for membrane permeability.

**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 0.852), indicating good drug-like properties.

**DILI:** Ligand B (84.335) has a considerably higher DILI risk than Ligand A (44.242). This is a significant negative for Ligand B.

**BBB:** Both ligands have relatively low BBB penetration (57.115 and 53.625). This isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.758) is slightly better than Ligand B (-5.069).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand A (-4.321) is slightly better than Ligand B (-4.098).

**hERG Inhibition:** Ligand A (0.565) has a slightly better hERG profile than Ligand B (0.331), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (69.124) has a lower microsomal clearance than Ligand A (85.267), suggesting better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand A (8.984) has a significantly longer half-life than Ligand B (-20.129). A negative half-life is not possible, so this value is suspect, and indicates very rapid degradation of Ligand B.

**P-gp Efflux:** Ligand A (0.086) has a lower P-gp efflux liability than Ligand B (0.245), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This 1.5 kcal/mol difference is significant, and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability, but suffers from a significantly higher DILI risk, a very short half-life, and poor solubility. Ligand A, while having slightly weaker binding, has a much better safety profile (lower DILI, better hERG), better P-gp efflux, and a reasonable half-life. Given the enzyme-specific priorities, metabolic stability and potency are key. However, the extremely short half-life and high DILI risk of Ligand B are major concerns. The slightly better affinity of Ligand B is unlikely to overcome these significant liabilities.

Output:
0
2025-04-17 12:07:05,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (379.913 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is well below the 140 threshold, indicating good absorption potential. Ligand B (98.4) is still within acceptable range, but less optimal.

**logP:** Ligand A (2.957) is optimal (1-3). Ligand B (0.45) is below 1, which could hinder 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 good QED scores (0.773 and 0.808), indicating drug-like properties.

**DILI:** Ligand A (47.15) has a slightly higher DILI risk than Ligand B (36.642), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.886) has a higher BBB score than Ligand B (54.207).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the scale is not specified, making interpretation difficult.

**hERG:** Ligand A (0.342) has a much lower hERG risk than Ligand B (0.196), which is a significant advantage.

**Microsomal Clearance:** Ligand A (4.502) has a better (lower) microsomal clearance than Ligand B (-3.014), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.064) has a better (longer) half-life than Ligand B (-36.169), further supporting its metabolic stability.

**P-gp Efflux:** Ligand A (0.373) has lower P-gp efflux liability than Ligand B (0.014), which is favorable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This 1.5 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADMET properties. Specifically, its significantly lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux are crucial advantages for a kinase inhibitor. The slightly lower affinity of Ligand A can potentially be optimized through further medicinal chemistry efforts, while mitigating the poor ADMET properties of Ligand B would be more challenging. The solubility and permeability issues are shared, but the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 12:07:05,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.491 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (74.33 and 71.09) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.531) is optimal, while Ligand B (3.374) is at the higher end of the optimal range, potentially raising concerns about off-target effects and solubility.

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

**QED:** Both ligands have good QED scores (0.71 and 0.814), indicating good drug-like properties.

**DILI:** Ligand A (8.492) has a significantly lower DILI risk than Ligand B (47.732). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (74.952) has a higher BBB penetration than Ligand A (52.268).

**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:** Ligand A (-0.674) has slightly better solubility than Ligand B (-5.068), although both are quite poor.

**hERG Inhibition:** Ligand A (0.117) shows very low hERG inhibition risk, while Ligand B (0.356) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (14.039) has a much lower microsomal clearance than Ligand B (73.655), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (30.068) has a significantly longer half-life than Ligand B (9.873). This is another significant advantage.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, while Ligand B (0.155) has slightly higher efflux.

**Binding Affinity:** Ligand B (-8.1 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 much stronger binding affinity, Ligand A demonstrates superior ADMET properties, particularly regarding metabolic stability (lower Cl_mic, longer t1/2), DILI risk, and P-gp efflux. The significantly better binding affinity of Ligand B is a strong point, but the poor metabolic stability and higher DILI risk are major concerns. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The large difference in binding affinity *could* potentially be overcome with further optimization of Ligand A, while mitigating the ADMET issues of Ligand B would be more challenging.

Output:
0
2025-04-17 12:07:05,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**
*   **MW:** 369.487 Da - Acceptable.
*   **TPSA:** 104.37 A<sup>2</sup> - Acceptable, but approaching the upper limit for oral absorption.
*   **logP:** 0.437 - Low. May have permeability issues.
*   **HBD:** 3 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.513 - Good drug-like properties.
*   **DILI:** 31.214 - Low risk.
*   **BBB:** 56.378 - Low. Not a concern for a non-CNS target.
*   **Caco-2:** -5.314 - Very poor permeability. A major red flag.
*   **Solubility:** -2.386 - Poor solubility.
*   **hERG:** 0.099 - Very low risk. Excellent.
*   **Cl_mic:** 42.773 mL/min/kg - Moderate clearance. Not ideal, but manageable.
*   **t1/2:** -28.12 hours - Very short half-life. A significant drawback.
*   **Pgp:** 0.031 - Low efflux. Good.
*   **Affinity:** -7.5 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 363.498 Da - Acceptable.
*   **TPSA:** 29.54 A<sup>2</sup> - Excellent. Promotes good absorption.
*   **logP:** 4.272 - High. Could lead to solubility issues and off-target effects.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 3 - Acceptable.
*   **QED:** 0.678 - Very good drug-like properties.
*   **DILI:** 32.067 - Low risk.
*   **BBB:** 88.445 - High. Not a primary concern for SRC kinase.
*   **Caco-2:** -4.791 - Poor permeability, but better than Ligand A.
*   **Solubility:** -4.598 - Poor solubility.
*   **hERG:** 0.859 - Moderate risk. Needs consideration.
*   **Cl_mic:** 107.941 mL/min/kg - High clearance. A significant drawback.
*   **t1/2:** -8.2 hours - Short half-life, but better than Ligand A.
*   **Pgp:** 0.691 - Moderate efflux.
*   **Affinity:** -9.4 kcal/mol - Exceptional binding affinity.

**Comparison & Decision:**

Ligand B has a significantly better binding affinity (-9.4 vs -7.5 kcal/mol). This is a substantial advantage for an enzyme target like SRC kinase. However, it suffers from high metabolic clearance and moderate hERG risk. Ligand A has very poor permeability and solubility, and a very short half-life, despite its good affinity.

The high affinity of Ligand B is a strong driver. While the high clearance is a concern, it might be addressable through structural modifications. The moderate hERG risk is also manageable with further optimization. The poor permeability and solubility of Ligand A, coupled with the very short half-life, are more difficult to overcome.

Therefore, Ligand B is the more promising candidate, despite its drawbacks.

Output:
1
2025-04-17 12:07:05,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.383 and 364.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.54) is slightly above the preferred <140, but acceptable. Ligand B (80.57) is well within the range.

**3. logP:** Ligand A (3.521) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.724) is excellent, 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:** Ligand B (0.687) has a better QED score than Ligand A (0.289), indicating a more drug-like profile.

**7. DILI:** Ligand B (51.997) has a significantly lower DILI risk than Ligand A (72.974). This is a major advantage for Ligand B.

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand A (65.297) is slightly higher than Ligand B (57.154). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 (0.486) has a slightly higher hERG risk than Ligand B (0.132), which is preferable.

**12. Microsomal Clearance:** Ligand B (32.345) has significantly lower microsomal clearance than Ligand A (98.771), indicating better metabolic stability. This is a critical advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (24.438) has a much longer in vitro half-life than Ligand A (7.771), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.347) has lower P-gp efflux than Ligand B (0.102), which is slightly better.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While the difference is small, it is still a positive factor.

**Overall Assessment:**

Ligand B is the superior candidate. It demonstrates better predicted ADME properties (lower DILI, lower Cl_mic, longer t1/2, lower hERG) and a slightly better binding affinity. While both ligands have issues with Caco-2 permeability and solubility, the ADME profile of Ligand B is significantly more favorable for development as an enzyme inhibitor. The slightly higher logP of Ligand A is a concern, and its poorer metabolic stability is a significant drawback.

Output:
1
2025-04-17 12:07:05,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**1. Molecular Weight:** Both ligands (361.477 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is slightly higher than Ligand B (49.41). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**3. logP:** Ligand A (2.267) and Ligand B (3.521) are both 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 (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=10. Ligand B is slightly better.

**6. QED:** Both ligands have good QED scores (0.662 and 0.8), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (8.259) has a significantly lower DILI risk than Ligand B (19.93). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (88.29 and 84.141), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.833 and -4.867), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-1.608) has better aqueous solubility than Ligand B (-4.046). This is a significant advantage for Ligand A.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.535 and 0.575), which is excellent.

**12. Microsomal Clearance:** Ligand A (27.201) has significantly lower microsomal clearance than Ligand B (55.501), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-9.978) has a much longer in vitro half-life than Ligand B (23.018). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.107).

**15. Binding Affinity:** Ligand A (0) has a slightly weaker binding affinity than Ligand B (0). However, the difference is minimal.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better logP and QED, Ligand A excels in critical areas for an enzyme target: lower DILI risk, better aqueous solubility, significantly lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The minimal difference in binding affinity is outweighed by these ADME/Tox advantages. The negative Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 12:07:05,009 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (362.495 Da) and Ligand B (371.432 Da) both fall within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (75.27) is higher than Ligand B (62.73). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

3. **logP:** Ligand A (2.573) is within the optimal 1-3 range. Ligand B (4.555) is slightly above, potentially leading to solubility issues and off-target interactions.

4. **HBD:** Both Ligand A (2) and Ligand B (2) are within the acceptable limit of <=5.

5. **HBA:** Ligand A (4) is better than Ligand B (6), which is approaching the upper limit of 10.

6. **QED:** Ligand A (0.845) has a better QED score than Ligand B (0.78), indicating a more drug-like profile.

7. **DILI:** Ligand A (38.852) has a significantly lower DILI risk than Ligand B (72.819). This is a major advantage for Ligand A.

8. **BBB:** Ligand A (57.154) has a lower BBB penetration than Ligand B (77.937). However, since SRC is not a CNS target, this is less critical.

9. **Caco-2:** Ligand A (-5.228) and Ligand B (-4.852) both have negative values, indicating poor permeability. This is a concern for both, but the values are similar.

10. **Solubility:** Ligand A (-2.32) has better solubility than Ligand B (-5.514).

11. **hERG:** Ligand A (0.099) has a much lower hERG risk than Ligand B (0.486). This is a significant safety advantage for Ligand A.

12. **Cl_mic:** Ligand A (23.331) has a lower microsomal clearance than Ligand B (68.199), suggesting better metabolic stability. This is crucial for an enzyme target.

13. **t1/2:** Ligand A (-6.937) has a negative half-life, which is unusual, but could indicate rapid metabolism. Ligand B (31.288) has a much longer half-life, which is desirable.

14. **Pgp:** Ligand A (0.211) has lower P-gp efflux liability than Ligand B (0.137).

15. **Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-9.8). While a 1.5 kcal/mol difference is usually significant, the other ADME properties of Ligand A are much more favorable.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in metabolic stability (lower Cl_mic), solubility, and hERG risk. While Ligand B has a slightly better affinity, the significant drawbacks in DILI, Cl_mic, and hERG outweigh this benefit. The negative half-life for Ligand A is concerning, but could be addressed with structural modifications.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its superior ADME properties, particularly the lower DILI and hERG risk, and better metabolic stability, make it a more viable starting point for optimization, despite the slightly weaker binding affinity.

Output:
0
2025-04-17 12:07:05,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.443 and 350.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (56.9 and 53.43) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.566 and 3.248) are within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for off-target effects, but is still acceptable.

**H-Bond Donors:** Both have 1 HBD, well within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are below the 10 limit.

**QED:** Both ligands have good QED scores (0.717 and 0.821), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 39.667, which is good (low risk). Ligand B has a DILI risk of 22.683, even better.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (91.276) is significantly higher than Ligand A (75.572). This isn't a primary concern for a kinase inhibitor, but could be beneficial if off-target CNS effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.311 and -4.451). This 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 have negative solubility values (-2.694 and -3.367). This is also concerning, and suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.894 and 0.56).

**Microsomal Clearance:** Ligand A has a Cl_mic of 69.372, while Ligand B has 31.777. Ligand B shows better metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 31.867 hours, while Ligand B has -7.547 hours. This is a *major* difference. A negative half-life is highly unusual and indicates very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.38 and 0.394).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a >1.5 kcal/mol difference, which is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.3 vs -7.7 kcal/mol) is a major advantage. Furthermore, Ligand B has a lower DILI risk, better metabolic stability (lower Cl_mic), and higher BBB penetration. The negative half-life for Ligand B is a critical flaw, but the superior binding affinity and other favorable properties make it worth further investigation to determine the cause of the rapid degradation. Ligand A's half-life is reasonable, but its weaker binding affinity is a significant drawback.

Output:
1
2025-04-17 12:07:05,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 341.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.97) is slightly higher than Ligand B (71.96), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.528) is quite low, potentially hindering permeability. Ligand B (3.246) 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 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.861 and 0.84), indicating good drug-likeness.

**DILI:** Ligand A (35.091) has a lower DILI risk than Ligand B (46.297), which is favorable.

**BBB:** Ligand A (61.691) has a lower BBB penetration than Ligand B (72.005). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.086 and -5.103), which 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 (-1.292 and -3.136), indicating poor aqueous solubility. Ligand B is worse in this regard.

**hERG Inhibition:** Ligand A (0.163) has a much lower hERG inhibition risk than Ligand B (0.716). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-4.076) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (32.33). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-26.988) has a much longer in vitro half-life than Ligand B (34.741). This is another significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.022) has lower P-gp efflux than Ligand B (0.109), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While a 1.0 kcal/mol difference is noticeable, the ADME properties are more concerning.

**Overall Assessment:**

Ligand A demonstrates superior ADME properties, particularly regarding metabolic stability (Cl_mic, t1/2), hERG risk, and P-gp efflux. While Ligand B has a slightly better binding affinity, the poor solubility, higher DILI risk, and worse metabolic stability of Ligand B are significant drawbacks. The low logP of Ligand A is a concern, but the substantial advantages in other ADME parameters outweigh this.

Output:
0
2025-04-17 12:07:05,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.423 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (49.85), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (2.588 and 1.808), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.677 and 0.731), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 61.807, placing it in the higher risk category (>60). Ligand B has a much lower DILI risk of 13.3, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both ligands show reasonable BBB penetration (67.313 and 70.027). Since SRC is not a CNS target, this is less critical, but Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.461 and -4.291), which is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.902 and -1.865), also suggesting poor solubility. Again, these need cautious interpretation.

**hERG Inhibition:** Ligand A (0.65) has a higher hERG risk than Ligand B (0.257). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A has a Cl_mic of 47.274, while Ligand B has 20.022. Lower is better for metabolic stability, giving Ligand B a clear advantage.

**In vitro Half-Life:** Ligand A has a negative half-life (-6.669), which is problematic. Ligand B has a negative half-life as well (-10.424), but is slightly worse. Both are concerning and require further investigation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.429 and 0.116), which is 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 for Ligand A (a difference of 1.1 kcal/mol).

**Overall Assessment:**

The key differentiating factors are DILI risk, microsomal clearance, and binding affinity. Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic). However, Ligand A has a significantly stronger binding affinity. Given the enzyme-kinase target class, metabolic stability and safety (DILI, hERG) are crucial. While the affinity difference is substantial, it can potentially be addressed through further optimization. The high DILI risk associated with Ligand A is a major concern, and the negative half-life values for both are worrisome.

Output:
1
2025-04-17 12:07:05,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.5 and 354.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (67.43), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.57 and 2.48), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 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:** Both ligands have acceptable QED scores (0.685 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (8.41) has a much lower DILI risk than Ligand B (34.47), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (79.57) is slightly better than Ligand B (70.80). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.653 and -4.753).

**Aqueous Solubility:** Ligand A (-1.764) is better than Ligand B (-3.005), indicating better solubility.

**hERG:** Both ligands show low hERG inhibition risk (0.431 and 0.512), which is positive.

**Microsomal Clearance:** Ligand A (34.89) has a considerably higher microsomal clearance than Ligand B (14.72). This suggests Ligand B will be more metabolically stable.

**In vitro Half-Life:** Ligand B (22.40) has a much longer half-life than Ligand A (-0.45), indicating better in vitro stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.202).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol). The difference is minimal.

**Conclusion:**

While both ligands have good potency, Ligand A is superior due to its lower DILI risk, better TPSA, better solubility, and slightly better BBB penetration. Ligand B has a better half-life and lower clearance, but the significantly higher DILI risk is a major concern. Given the enzyme-specific priorities, the lower DILI risk of Ligand A outweighs the slightly better metabolic stability of Ligand B.

Output:
1
2025-04-17 12:07:05,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (378.881 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 58.64, which is acceptable for oral absorption (<=140).

**logP:** Both ligands have logP values within the optimal range (2.949 and 2.593).

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 3 HBA, both are acceptable (<=10).

**QED:** Both ligands have QED values above 0.5 (0.84 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 60.566, which is borderline high. Ligand B has a significantly lower DILI risk of 9.306, which is excellent. This is a major advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (71.772 and 73.827), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.992 and -4.55), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.286 and -2.179), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.605 and 0.418), which is positive.

**Microsomal Clearance:** Ligand A has a Cl_mic of 43.446, while Ligand B has 67. Ligand A is better here, suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 7.117 hours, while Ligand B has a negative half-life (-6.519 hours), which is not physically possible and likely indicates a very short half-life. This is a significant disadvantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.316 and 0.102).

**Binding Affinity:** Ligand A has a binding affinity of -7.9 kcal/mol, while Ligand B has -6.9 kcal/mol. Ligand A has a 1 kcal/mol advantage in binding affinity, which is substantial.

**Overall Assessment:**

Ligand A has a stronger binding affinity and better metabolic stability. However, Ligand B has a much lower DILI risk and a slightly better BBB penetration. Both ligands suffer from poor solubility and permeability. The binding affinity difference is significant, and for an enzyme target like SRC kinase, potency is paramount. While the DILI risk for Ligand A is a concern, it's potentially manageable with further optimization. The negative half-life for Ligand B is a dealbreaker.

Output:
0
2025-04-17 12:07:05,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (379.375 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.62) is slightly above the preferred <140, but acceptable. Ligand B (96.89) is well within the ideal range.

**logP:** Ligand A (2.204) is optimal (1-3). Ligand B (0.132) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but approaching the upper limit.

**H-Bond Acceptors:** Ligand A (9) is acceptable. Ligand B (5) is good.

**QED:** Ligand A (0.685) is good (>0.5). Ligand B (0.405) is below the preferred threshold, indicating a less drug-like profile.

**DILI:** Ligand A (99.496) has a very high DILI risk, a major concern. Ligand B (13.959) has a low DILI risk, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.691) and Ligand B (44.668) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.97) is poor, suggesting low intestinal absorption. Ligand B (-5.365) is also poor.

**Aqueous Solubility:** Ligand A (-4.009) is poor. Ligand B (-1.39) is also poor, but slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.335) has a low hERG risk, which is good. Ligand B (0.188) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (29.753) is moderate. Ligand B (22.176) is lower, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (45.942) is moderate. Ligand B (11.954) is relatively short, which is a concern.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.239 and 0.01 respectively), which is favorable.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). The 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, its extremely high DILI risk is a major red flag. Its poor Caco-2 and solubility are also concerning. Ligand B has a better safety profile (low DILI, low hERG), better metabolic stability, and acceptable H-bonding characteristics, but its low logP and QED, coupled with weaker binding affinity, are significant drawbacks.

Despite the superior binding affinity of Ligand A, the high DILI risk makes it a less viable candidate. While medicinal chemistry efforts could potentially mitigate the DILI risk, starting with a safer scaffold like Ligand B is generally preferable, even if it requires more extensive optimization to achieve comparable potency.

Output:
1
2025-04-17 12:07:05,010 - INFO - Batch 103 complete. Total preferences: 1648
2025-04-17 12:07:05,010 - INFO - Processing batch 104/512...
2025-04-17 12:07:43,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (391.509 and 379.888 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is slightly higher than Ligand B (49.15), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (3.114) is within the optimal 1-3 range. Ligand B (4.64) is a bit high, potentially leading to solubility issues or off-target interactions.

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

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have similar QED scores (0.717 and 0.703), indicating good drug-likeness.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (31.601). This is a significant negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (86.041 and 76.464), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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. This is concerning, but again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.524) has a slightly higher hERG risk than Ligand B (0.867), but both are reasonably low.

**Microsomal Clearance:** Ligand A (63.163) has lower microsomal clearance than Ligand B (76.525), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (10.676) has a slightly longer half-life than Ligand B (7.11), which is desirable.

**P-gp Efflux:** Ligand A (0.472) has lower P-gp efflux than Ligand B (0.587), suggesting better bioavailability.

**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 Ligand B, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A having better metabolic stability and P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.6 vs -7.0 kcal/mol) and its much lower DILI risk outweigh the advantages of Ligand A. The solubility and permeability concerns are present in both, but the potency and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 12:07:43,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.5) is slightly better positioned.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (96.77). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values, but Ligand A (2.35) is closer to the optimal range (1-3) than Ligand B (0.236), which is quite low and could hinder permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6). Fewer HBA are generally preferred.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-likeness. Ligand B (0.66) is slightly better.

**DILI:** Ligand A (8.414) has a much lower DILI risk than Ligand B (56.572). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (81.388) is better than Ligand A (73.013). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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.

**hERG:** Ligand A (0.473) has a much lower hERG risk than Ligand B (0.06). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (11.826) has a higher microsomal clearance than Ligand B (10.843), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-14.316) has a much shorter half-life than Ligand B (-2.825). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-6.4 kcal/mol). This is a 1.0 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A excels in DILI risk and hERG inhibition, which are critical for safety. It also has better TPSA and logP values. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has better binding affinity and BBB penetration, but its DILI risk and hERG inhibition are concerning.

Given the enzyme-specific priorities, the lower DILI and hERG risk of Ligand A are more important than the slightly better binding affinity of Ligand B. The shorter half-life and higher clearance of Ligand A could be addressed through structural modifications, whereas mitigating the safety concerns of Ligand B would likely be more challenging.

Output:
0
2025-04-17 12:07:43,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which could be advantageous for permeability. Ligand B (362.514 Da) is also good.

**TPSA:** Ligand A (65.2) is better than Ligand B (25.36). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.079) is optimal, while Ligand B (4.827) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 2 HBA) is better than Ligand B (0 HBD, 4 HBA). A balance is good, and Ligand A is closer to this.

**QED:** Ligand A (0.899) has a significantly better QED score than Ligand B (0.673), indicating a more drug-like profile.

**DILI:** Ligand A (47.421) has a slightly higher DILI risk than Ligand B (30.826), but both are within acceptable limits (<60).

**BBB:** Ligand A (78.945) is good, but not exceptional. Ligand B (95.231) is excellent, but BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.016) is better than Ligand B (-4.503). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-4.421) is better than Ligand B (-5.635). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.737) has a slightly better hERG profile than Ligand B (0.886). Lower is better.

**Microsomal Clearance:** Ligand A (44.578) has significantly lower microsomal clearance than Ligand B (105.886). This suggests better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-2.784) has a better in vitro half-life than Ligand B (3.753).

**P-gp Efflux:** Ligand A (0.138) is better than Ligand B (0.869). Lower efflux is preferred.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.3 kcal/mol). The difference is minimal and doesn't outweigh other factors.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most ADME properties, particularly in solubility, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While Ligand B has a slightly better BBB score, this is less critical for an SRC kinase inhibitor. The similar binding affinities mean that the superior ADME profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 12:07:43,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.475 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.11) is slightly higher than the preferred <140, but acceptable. Ligand B (52.65) is excellent, well below 90.

**logP:** Both ligands (2.384 and 2.26) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Ligand B (0.828) has a significantly better QED score than Ligand A (0.598), indicating a more drug-like profile.

**DILI:** Ligand A (41.76) has a slightly higher DILI risk than Ligand B (8.414), but both are below the concerning threshold of 60.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand B (88.174) is higher than Ligand A (68.166), but this is less important.

**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. Again, the scale is undefined.

**hERG:** Ligand A (0.673) has a slightly higher hERG risk than Ligand B (0.355), but both are relatively low.

**Microsomal Clearance:** Ligand B (24.163 mL/min/kg) has significantly lower microsomal clearance than Ligand A (44.852 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.447 hours) has a negative half-life, which is impossible. This is a major red flag. Ligand A (5.162 hours) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 and 0.069), which is good.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), but the difference is small (0.3 kcal/mol) and may not be decisive.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising candidate. It has a much better QED score, significantly lower microsomal clearance (better metabolic stability), and a lower DILI risk. However, the negative in vitro half-life for Ligand B is a critical issue. The negative solubility and Caco-2 values for both are concerning, but the other factors favor Ligand B *if* the half-life issue can be resolved (e.g., data error). Considering the enzyme-specific priorities, metabolic stability and lower toxicity are crucial.

Output:
1
2025-04-17 12:07:43,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 348.403 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.25) is better than Ligand B (108.46). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred value for oral absorption.

**logP:** Ligand A (0.634) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.136) is better, falling within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being less than 10.

**QED:** Ligand A (0.838) is better than Ligand B (0.706), indicating a more drug-like profile.

**DILI:** Ligand A (38.813) has a significantly lower DILI risk than Ligand B (54.207), which is a major advantage. Both are below the concerning threshold of 60, but A is preferable.

**BBB:** Ligand A (49.787) is lower than Ligand B (69.213). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.268) is worse than Ligand B (-4.763). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-0.824) is better than Ligand B (-2.687). Solubility is important for bioavailability, making A more favorable.

**hERG Inhibition:** Ligand A (0.192) has a much lower hERG risk than Ligand B (0.589). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (8.528) has a lower clearance than Ligand B (38.057), indicating better metabolic stability. This is a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (4.878) has a lower half-life than Ligand B (9.581). While longer is generally better, the difference isn't dramatic.

**P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.162), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.4) has a slightly better binding affinity than Ligand A (-8.7). This is a 0.7 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly lower hERG risk, better metabolic stability (lower Cl_mic), better solubility, and lower P-gp efflux. The QED score is also higher for Ligand A. The slightly weaker binding affinity of Ligand A can potentially be optimized during lead optimization.

Output:
0
2025-04-17 12:07:43,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.454 Da and 364.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (65.54 and 64.68) below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have logP values (2.254 and 1.212) within the optimal range of 1-3. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (1 HBD) is preferable to Ligand B (2 HBDs).

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

**6. QED:** Both ligands have good QED scores (0.656 and 0.796), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (41.838) has a lower DILI risk than Ligand B (13.339), which is a significant advantage.

**8. BBB:** Both ligands have reasonable BBB penetration (83.908 and 74.292), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.736) has worse Caco-2 permeability than Ligand B (-5.448).

**10. Aqueous Solubility:** Ligand A (-2.42) has worse solubility than Ligand B (-2.052).

**11. hERG Inhibition:** Ligand A (0.845) has a slightly higher hERG risk than Ligand B (0.498), which is unfavorable.

**12. Microsomal Clearance:** Ligand A (67.457) has significantly higher microsomal clearance than Ligand B (13.153), indicating lower metabolic stability. This is a major drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (26.406) has a shorter half-life than Ligand B (9.013).

**14. P-gp Efflux:** Ligand A (0.137) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**15. Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). This difference, while not huge, is enough to consider alongside other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has some advantages (lower DILI, lower P-gp efflux), Ligand B excels in critical areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), better binding affinity, and lower hERG risk. The slightly worse solubility and Caco-2 permeability of Ligand B are less concerning than the poor metabolic stability of Ligand A.

Output:
1
2025-04-17 12:07:43,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (390.571 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.76) is better than Ligand B (91.4), being comfortably below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.404 and 1.583), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.657 and 0.764), suggesting good drug-like properties.

**DILI:** Both ligands have low DILI risk (38.736 and 37.456 percentile), which is favorable.

**BBB:** Both ligands have moderate BBB penetration (62.466 and 66.576 percentile). Since SRC is not a CNS target, this is not a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.129 and -5.176). 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 very poor aqueous solubility (-2.3 and -3.392). This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.185 and 0.348), which is excellent.

**Microsomal Clearance:** Ligand A (15.711 mL/min/kg) has significantly lower microsomal clearance than Ligand B (35.017 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.376 hours) has a better in vitro half-life than Ligand B (-11.985 hours). A negative half-life is not physically meaningful, indicating a very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.133 and 0.028).

**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 difference (1.7 kcal/mol) and is a major advantage.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -7.5 kcal/mol) outweighs the concerns about solubility and permeability, especially for an enzyme target where potency is crucial. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic) and a positive in vitro half-life, while Ligand B has a nonsensical negative half-life. The DILI and hERG profiles are comparable and favorable for both.

Output:
0
2025-04-17 12:07:43,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.329 Da and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.39) is better than Ligand B (93.21), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have similar logP values (1.416 and 1.391), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (5).

**QED:** Ligand A (0.885) is significantly better than Ligand B (0.548), indicating a more drug-like profile.

**DILI:** Ligand A (90.733) has a high DILI risk, while Ligand B (52.423) is much lower and acceptable. This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.205) is better than Ligand B (42.303).

**Caco-2:** Ligand A (-4.528) is better than Ligand B (-5.353), indicating better intestinal absorption.

**Solubility:** Ligand A (-3.084) is better than Ligand B (-1.708), indicating better aqueous solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.141 and 0.26).

**Microsomal Clearance:** Ligand A (-7.211) is *much* better than Ligand B (8.744), indicating significantly higher metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-2.726) is better than Ligand B (8.289), indicating a longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032 and 0.079).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.7 kcal/mol and -8.0 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a superior QED, better TPSA, HBD, HBA, Caco-2, Solubility, microsomal clearance, and half-life. However, it has a significantly higher DILI risk. Ligand B has a much lower DILI risk, which is a critical safety parameter. While Ligand A has better ADME properties overall, the high DILI risk is a major concern. Given the enzyme-specific priorities, metabolic stability (Cl_mic) is very important, and Ligand A is significantly better in this regard. However, the DILI risk is too high to ignore.

Considering the balance of potency, ADME properties, and safety, and the enzyme-specific focus, I would choose Ligand A, but with a strong caveat that further investigation into the DILI risk is absolutely necessary.

Output:
1
2025-04-17 12:07:43,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.478 and 362.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is higher than Ligand B (53.43). While both are reasonably good, Ligand B is better positioned for oral absorption.

**logP:** Both ligands have logP values within the optimal 1-3 range (2.35 and 3.151 respectively). Ligand B is slightly higher, potentially leading to some solubility concerns, but not critically.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**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 (0.836 and 0.791), indicating good drug-like properties.

**DILI:** Ligand A (42.109) has a slightly higher DILI risk than Ligand B (17.449). This is a significant advantage for Ligand B.

**BBB:** Both have high BBB penetration (79.837 and 80.962), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.951 and -4.62) and don't significantly differentiate the ligands.

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor aqueous solubility. Ligand B (-3.885) is slightly better than Ligand A (-3.185), but both are problematic.

**hERG:** Both ligands have low hERG inhibition liability (0.366 and 0.62), which is excellent.

**Microsomal Clearance:** Ligand A (18.346 mL/min/kg) has significantly lower microsomal clearance than Ligand B (45.927 mL/min/kg). This indicates better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (13.556 hours) has a longer half-life than Ligand B (23.813 hours). This is a positive attribute for Ligand A, supporting less frequent dosing.

**P-gp Efflux:** Both have low P-gp efflux liability (0.132 and 0.563), which is favorable.

**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.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, the significantly superior binding affinity of Ligand B (-8.6 vs -7.7 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. The slightly higher metabolic clearance and DILI risk of Ligand B are acceptable trade-offs for the stronger binding. The solubility issues are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 12:07:43,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.439 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is slightly higher than Ligand B (49.85). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands have good logP values (3.894 and 2.894), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**QED:** Ligand A (0.888) has a significantly higher QED score than Ligand B (0.475), indicating a more drug-like profile.

**DILI:** Ligand A (63.358) has a higher DILI risk than Ligand B (17.798). This is a significant concern for Ligand A.

**BBB:** Both have good BBB penetration, with Ligand A at 86.351 and Ligand B at 90.655. Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.639 and -4.579). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development.

**Aqueous Solubility:** Ligand A (-5.362) has worse solubility than Ligand B (-2.044). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.644 and 0.602), which is good.

**Microsomal Clearance:** Ligand A (97.725) has a higher microsomal clearance than Ligand B (67.201), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-8.732) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (18.85) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.455 and 0.304).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.3 and -7.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. It has a significantly lower DILI risk, better solubility, and lower microsomal clearance (better metabolic stability). While the negative Caco-2 values are concerning for both, the other ADME properties of Ligand B are superior. The erroneous half-life value for Ligand B is a data quality issue, but doesn't change the overall assessment. Ligand A's higher DILI and lower metabolic stability are significant liabilities.

Output:
1
2025-04-17 12:07:43,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.355 and 351.535 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (102.53) is slightly above the preferred <140, but acceptable. Ligand B (61.44) is well within the ideal range.

**logP:** Both ligands (2.123 and 2.841) 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, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.642 and 0.671), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.376, which is high. Ligand B has a much lower DILI risk of 11.09, which is very favorable.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (72.78) shows better BBB penetration than A (43.273), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.008) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.877) also has poor Caco-2 permeability, but is slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.167 and -2.121 respectively). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.643) has a slightly higher hERG risk than Ligand B (0.492), but both are relatively low.

**Microsomal Clearance:** Ligand A (38.396) has higher microsomal clearance than Ligand B (20.161), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (17.623 hours) has a much longer half-life than Ligand A (-1.09 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.212 and 0.038 respectively).

**Binding Affinity:** Ligand B (-7.8 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 significantly better due to its much lower DILI risk, superior metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, these are formulation challenges that can be addressed. The high DILI risk and poor metabolic stability of Ligand A are major red flags.

Output:
1
2025-04-17 12:07:43,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (415.316 Da) is slightly higher than Ligand B (350.503 Da), but both are reasonable.

**TPSA:** Both ligands have TPSA values around 70, which is acceptable for oral absorption, but not ideal for CNS penetration (not a priority here).

**logP:** Ligand A (4.904) is high, potentially leading to solubility issues and off-target effects. Ligand B (2.33) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both have acceptable HBD/HBA counts.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (89.841) has a high DILI risk, which is a significant concern. Ligand B (14.114) has a very low DILI risk, a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and are less critical than other factors.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is more concerning for Ligand A due to its higher logP.

**hERG Inhibition:** Ligand A (0.818) has a slightly higher hERG risk than Ligand B (0.462), though both are relatively low.

**Microsomal Clearance:** Ligand A (58.209 mL/min/kg) has higher clearance than Ligand B (34.29 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-15.637 hours) has a significantly longer half-life than Ligand A (82.514 hours). This is a strong positive for Ligand B. Note the negative value for Ligand B is likely an error.

**P-gp Efflux:** Ligand A (0.634) has a higher P-gp efflux liability than Ligand B (0.269).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a 1.3 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand A has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, its high DILI risk, poor metabolic stability (higher clearance), higher P-gp efflux, and poor solubility are major drawbacks. Ligand B, while having slightly weaker affinity, presents a much more favorable ADME-Tox profile with a very low DILI risk, better metabolic stability, and lower P-gp efflux. The difference in binding affinity (1.3 kcal/mol) is not substantial enough to overcome the significant safety and pharmacokinetic concerns associated with Ligand A.

Output:
1
2025-04-17 12:07:43,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.53 and 358.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.69) is better than Ligand B (69.64). Both are below 140, suggesting good absorption potential.

**logP:** Both ligands have good logP values (2.82 and 2.10), 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 similar QED scores (0.777 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (35.79) has a lower DILI risk than Ligand B (28.15), which is preferable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (76.15) is better than Ligand B (65.84). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar negative Caco-2 values (-4.68 and -4.66), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have similar negative solubility values (-2.19 and -2.06), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.615) has a lower hERG risk than Ligand B (0.468), which is a significant advantage.

**Microsomal Clearance:** Ligand A (0.809) has significantly lower microsomal clearance than Ligand B (14.792), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (49.58 hours) has a much longer half-life than Ligand B (-16.60 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.399) has lower P-gp efflux than Ligand B (0.131), which is preferable.

**Binding Affinity:** Ligand B (-9.7 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 of Ligand B. However, the poor solubility and permeability of Ligand B are concerning.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. The poor solubility and permeability of both compounds are concerning, but Ligand A's other properties are more balanced. Given the enzyme-kinase target class, metabolic stability and safety (hERG) are paramount. The 2.7 kcal/mol difference in binding affinity might be overcome with further optimization of Ligand A, while addressing the solubility/permeability issues.

Output:
0
2025-04-17 12:07:43,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.395 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.45) is slightly higher than Ligand B (78.51), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.985 and 1.55), falling within the optimal 1-3 range. Ligand B is slightly lower, which could potentially improve solubility.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (3 and 2 respectively) and HBA (3 for both) counts, within the recommended limits.

**QED:** Both ligands have acceptable QED scores (0.802 and 0.651), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (69.135 percentile) compared to Ligand B (13.067 percentile). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (77.705 and 70.803 percentile), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.955 and -5.105), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the specific assay details.

**Aqueous Solubility:** Ligand B (-1.761) has better (less negative) solubility than Ligand A (-4.176), which is beneficial.

**hERG Inhibition:** Ligand A (0.536) shows slightly higher hERG inhibition risk than Ligand B (0.322), but both are reasonably low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (36.54 and 37.168 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-13.19 hours) compared to Ligand A (-0.123 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.015).

**Binding Affinity:** Ligand B (-9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7 kcal/mol). This 2 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While both ligands have acceptable MW, TPSA, logP, and QED values, Ligand B demonstrates significantly better safety (lower DILI), metabolic stability (longer half-life), solubility, and, crucially, a much stronger binding affinity. The negative Caco-2 values are a concern for both, but the superior overall profile of Ligand B makes it the preferred choice.

Output:
1
2025-04-17 12:07:43,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (444.347 Da) is slightly higher than Ligand B (355.869 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (55.4) is higher than Ligand B (45.23).

**logP:** Both ligands have logP values around 4.7, which is slightly above the optimal range of 1-3. This could potentially lead to solubility issues or off-target effects, but is not a dealbreaker.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 for A, 3 for B), falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.601 for A, 0.804 for B), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A has a DILI risk of 87.01, which is high. Ligand B has a DILI risk of 64.948, which is still elevated but better than Ligand A. This is a significant concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (66.188 for A, 82.474 for B), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.726 and -4.768). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.091 and -4.555). This is also concerning and could hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.612 and 0.736).

**Microsomal Clearance:** Ligand A (91.695) has higher microsomal clearance than Ligand B (61.482), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (68.489) has a longer in vitro half-life than Ligand A (54.654), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.659 and 0.642).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has significantly better binding affinity than Ligand A (-7.4 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While both have solubility and permeability issues, Ligand B has a significantly better binding affinity, a lower DILI risk, and better metabolic stability (lower Cl_mic, longer t1/2). The higher affinity of Ligand B is a major advantage.

Output:
1
2025-04-17 12:07:43,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.489 and 385.291 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (55.57), both are below the 140 threshold for good absorption.

**logP:** Ligand A (3.849) is within the optimal 1-3 range, while Ligand B (4.464) is slightly higher, potentially increasing off-target effects.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as a single donor can aid solubility without significantly hindering permeability.

**H-Bond Acceptors:** Ligand A (2) is better than Ligand B (5). Lower HBA counts generally improve permeability.

**QED:** Both ligands have similar QED values (0.669 and 0.628), indicating reasonable drug-likeness.

**DILI:** Ligand A (14.773) has a significantly lower DILI risk than Ligand B (39.511), a major advantage.

**BBB:** Both ligands have good BBB penetration (92.323 and 75.378), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.364 and -4.645), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.871 and -3.774), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.751).

**Microsomal Clearance:** Ligand A (72.219) has lower microsomal clearance than Ligand B (83.096), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (43.758) has a significantly longer half-life than Ligand A (1.263), which is a substantial advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.15 and 0.615).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol), a difference of 0.6 kcal/mol. This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better predicted ADME properties (lower DILI, lower Cl_mic, better TPSA, HBD and HBA), Ligand B has a substantially stronger binding affinity (-8.2 vs -7.6 kcal/mol). Given that we are targeting an enzyme (SRC kinase), potency is paramount. The improved half-life of Ligand B is also a significant benefit. The slightly higher logP and DILI risk of Ligand B are acceptable trade-offs for the increased potency and half-life.

Output:
1
2025-04-17 12:07:43,439 - INFO - Batch 104 complete. Total preferences: 1664
2025-04-17 12:07:43,439 - INFO - Processing batch 105/512...
2025-04-17 12:08:23,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (87.3), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have similar and good logP values (1.714 and 1.68), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is slightly better than Ligand B (HBD=3, HBA=3) regarding the number of hydrogen bond donors and acceptors, both are within acceptable limits.

**QED:** Ligand A (0.686) has a better QED score than Ligand B (0.46), indicating a more drug-like profile.

**DILI:** Ligand A (20.434) has a significantly lower DILI risk than Ligand B (32.842), which is a major advantage.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 59.946, Ligand B: 62.233). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.924) has better Caco-2 permeability than Ligand B (-5.377).

**Aqueous Solubility:** Ligand A (-2.131) has better aqueous solubility than Ligand B (-2.71).

**hERG:** Both ligands have very low hERG risk (Ligand A: 0.088, Ligand B: 0.097).

**Microsomal Clearance:** Ligand A (11.905) has significantly lower microsomal clearance than Ligand B (26.043), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.656) has a slightly better in vitro half-life than Ligand B (-2.218).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.013, Ligand B: 0.039).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and is a key factor.

**Conclusion:**

Ligand A is superior to Ligand B. It exhibits a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic and better t1/2), better solubility, and, most importantly, a significantly stronger binding affinity. While both ligands are within acceptable ranges for most parameters, the combination of improved ADME properties and substantially higher potency makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 12:08:23,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.455 and 363.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.92) is better than Ligand B (63.05), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (3.483 and 3.777) are 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 6. Ligand A is better here, staying further below the 10 threshold.

**QED:** Both ligands have similar QED values (0.715 and 0.698), indicating good drug-likeness.

**DILI:** Ligand A (33.307) has a significantly lower DILI risk than Ligand B (55.487). This is a major advantage.

**BBB:** Ligand B (76.58) has a better BBB penetration score than Ligand A (49.554), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.067 and -5.023), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.834) has better solubility than Ligand B (-3.611).

**hERG Inhibition:** Ligand A (0.768) has a slightly lower hERG risk than Ligand B (0.877), which is preferable.

**Microsomal Clearance:** Ligand A (9.457) has significantly lower microsomal clearance than Ligand B (98.452), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (54.01) has a shorter half-life than Ligand B (75.715), but still reasonable.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.772), which is better for bioavailability.

**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 a positive factor.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic), better solubility, lower P-gp efflux, and slightly better binding affinity. While both have concerning Caco-2 permeability values, the ADME and toxicity profile of Ligand A is substantially more favorable for development as a drug candidate targeting SRC kinase.

Output:
0
2025-04-17 12:08:23,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (341.451 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.56) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.43) is still under 140, but less favorable than A.

**3. logP:** Ligand A (4.418) is slightly above the optimal 1-3 range, potentially leading to solubility issues. Ligand B (3.455) is 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 (4) is good. Ligand B (3) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.758 and 0.707), indicating good drug-likeness.

**7. DILI:** Ligand A (62.427) has a higher DILI risk than Ligand B (32.183). This is a significant negative for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.993) and Ligand B (51.105) are both moderate.

**9. Caco-2 Permeability:** Both ligands 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 ligands have negative solubility values, suggesting poor solubility. Again, the values are close.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.823 and 0.737), which is excellent.

**12. Microsomal Clearance:** Ligand A (134.278) has higher microsomal clearance than Ligand B (64.125), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-11.32) has a much longer in vitro half-life than Ligand A (-5.168), indicating better stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.702 and 0.267), which is favorable.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the superior candidate. While both have some solubility concerns, Ligand B has a significantly better binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic, longer t1/2). The stronger binding affinity is particularly important for an enzyme target like SRC kinase. The slightly better logP of Ligand B is also a plus.

Output:
1
2025-04-17 12:08:23,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (82.53) is significantly better than Ligand B (33.95). Lower TPSA generally correlates with better cell permeability, a crucial factor for kinase inhibitors.

**logP:** Ligand A (1.057) is optimal, while Ligand B (4.506) 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 4 HBA, which are within acceptable limits. Ligand B has 0 HBD and 4 HBA, also acceptable, but the lack of HBDs might slightly hinder aqueous solubility.

**QED:** Ligand A (0.808) has a better QED score than Ligand B (0.641), indicating a more drug-like profile.

**DILI:** Ligand A (20.706) has a much lower DILI risk than Ligand B (27.608). This is a crucial advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B (88.057) has a higher BBB value than Ligand A (28.344), but this is not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual.

**Aqueous Solubility:** Ligand A (-1.222) is better than Ligand B (-4.573), which is a significant advantage for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.161) has a much lower hERG risk than Ligand B (0.652). This is a critical safety parameter.

**Microsomal Clearance:** Ligand A (17.867) has lower microsomal clearance than Ligand B (30.858), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (32.889) has a longer half-life than Ligand A (20.131), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.035) has much lower P-gp efflux liability than Ligand B (0.693), improving bioavailability.

**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 for Ligand B. The difference of 1.7 kcal/mol is significant.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, its high logP, moderate DILI risk, and higher hERG risk are concerning. Ligand A, while having a slightly weaker binding affinity, presents a much more balanced profile with better solubility, lower toxicity risks (DILI, hERG), better metabolic stability, and improved predicted permeability. The difference in binding affinity, while substantial, can potentially be overcome with further optimization of Ligand A, while mitigating the ADME/Tox liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 12:08:23,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.467 and 357.449 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.49) is better than Ligand B (56.07) as it is closer to the 140 A^2 threshold for good oral absorption. Ligand B is very low, which could indicate issues with solubility.

**logP:** Both ligands have good logP values (1.248 and 2.854), falling 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 6 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.583 and 0.603), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 41.915, which is good (low risk). Ligand B has a significantly lower DILI risk of 14.308, which is excellent.

**BBB:** Ligand A has a BBB penetration of 70.26, which is good, but not exceptional. Ligand B has a very high BBB penetration of 98.333, which is excellent. However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.358), which is concerning and suggests poor permeability. Ligand B also has a negative Caco-2 value (-4.547), also concerning.

**Aqueous Solubility:** Ligand A has a solubility of -1.989, which is poor. Ligand B has a solubility of -3.74, which is even worse.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.391, which is good. Ligand B has a slightly higher risk of 0.516, but still acceptable.

**Microsomal Clearance:** Ligand A has a Cl_mic of 39.334 mL/min/kg, which is moderate. Ligand B has a Cl_mic of 42.107 mL/min/kg, slightly higher. Lower is better for metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of -3.689 hours, which is poor. Ligand B has a t1/2 of -5.862 hours, even worse.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.213).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly better binding affinity than Ligand A (-7.6 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has poorer solubility and half-life, its significantly stronger binding affinity (-8.4 vs -7.6 kcal/mol) and lower DILI risk are compelling advantages. The slightly higher Cl_mic is a minor concern compared to the potency difference. The negative Caco-2 values for both are concerning, but can be addressed with formulation strategies. Given the enzyme-specific priority of potency, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:08:23,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.889 Da) is slightly higher than Ligand B (351.447 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (93.45 and 98.74) that are a bit high for optimal oral absorption (ideally <140), but not drastically so.

**logP:** Ligand A (2.158) has a good logP value, falling within the optimal range of 1-3. Ligand B (0.171) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is better balanced than Ligand B (3 HBD, 4 HBA), which is closer to the upper limits.

**QED:** Both ligands have reasonable QED scores (0.759 and 0.58), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (68.244) has a higher DILI risk than Ligand B (12.796). This is a significant drawback for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 very low hERG inhibition risk (0.291 and 0.086), which is excellent.

**Microsomal Clearance:** Ligand A (28.902 mL/min/kg) has a higher microsomal clearance than Ligand B (13.551 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (36.495 hours) has a longer half-life than Ligand B (11.524 hours), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.172 and 0.02).

**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.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly lower DILI risk and better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme inhibitor. Ligand A's higher DILI risk is a major concern. The slightly better half-life of Ligand A is outweighed by its other drawbacks. The similar binding affinities mean that the ADME properties are the deciding factor.

Output:
1
2025-04-17 12:08:23,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.463 Da) and Ligand B (340.339 Da) are both acceptable.

**TPSA:** Ligand A (68.54) is well below the 140 threshold for oral absorption. Ligand B (96.55) is also below, but closer to the limit.

**logP:** Ligand A (4.967) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.227) is quite low, which could hinder membrane permeability.

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

**QED:** Both ligands have QED values above 0.5 (A: 0.506, B: 0.472), indicating good drug-like properties.

**DILI:** Ligand A (68.941) has a moderate DILI risk, while Ligand B (81.427) has a higher risk.

**BBB:** Ligand A (83.327) has better BBB penetration than Ligand B (38.232), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and are less critical than other factors.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.938 and -3.402 respectively). This is a significant concern.

**hERG Inhibition:** Ligand A (0.648) has a lower hERG risk than Ligand B (0.148), which is a major advantage.

**Microsomal Clearance:** Ligand A (120.349) has a higher microsomal clearance than Ligand B (-31.79). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (64.099) has a longer half-life than Ligand B (-25.399), which is favorable.

**P-gp Efflux:** Ligand A (0.799) has slightly higher P-gp efflux than Ligand B (0.008), suggesting better bioavailability for B.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.5 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the slightly higher logP and DILI risk, Ligand A is the more promising candidate. The significantly better hERG profile and slightly better binding affinity are crucial for an enzyme inhibitor. The longer half-life is also a benefit. While both have poor solubility, the stronger binding of Ligand A suggests it might be possible to overcome this with formulation strategies. The improved metabolic stability of Ligand B is attractive, but the weaker binding and higher hERG risk are more concerning.

Output:
0
2025-04-17 12:08:23,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.447 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly higher than Ligand B (76.02). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable here.

**logP:** Both ligands have good logP values (1.834 and 2.277), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.555 and 0.709), indicating good drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (36.758) has a slightly higher DILI risk than Ligand B (23.071), but both are below the concerning threshold of 60. Ligand B is preferable.

**BBB:** Both ligands have similar BBB penetration (70.609 and 70.027). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.079) has significantly *worse* Caco-2 permeability than Ligand B (-4.751). This suggests lower intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-2.774) has slightly worse solubility than Ligand B (-3.163). While both are negative, indicating low solubility, Ligand B is better.

**hERG Inhibition:** Ligand A (0.218) has a slightly higher hERG inhibition risk than Ligand B (0.077). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (41.051) has lower microsomal clearance than Ligand B (45.988), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.082) has a substantially *longer* in vitro half-life than Ligand B (2.595). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.011), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.1). While the difference is less than the 1.5 kcal/mol threshold to override other issues, it's still a factor.

**Overall Assessment:**

Ligand A has significant advantages in metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux. Ligand B has a slightly better binding affinity, DILI, solubility and hERG. However, the poor Caco-2 permeability of Ligand A is a major concern, potentially limiting its oral bioavailability. The longer half-life and better metabolic stability of Ligand A are valuable, but may not fully compensate for the absorption issues.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), and the significant absorption concern with Ligand A, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:08:23,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.463 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (113.66) is better than Ligand B (75.44), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.803) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.625) is within the optimal range.

**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 (4) is also good.

**6. QED:** Both ligands have good QED scores (0.597 and 0.769, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (11.361) has a significantly lower DILI risk than Ligand B (21.985), which is a major advantage.

**8. BBB:** Ligand A (38.813) has a lower BBB penetration than Ligand B (71.501). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.18) is worse than Ligand B (-4.785), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.758) is worse than Ligand B (-1.501).

**11. hERG Inhibition:** Ligand A (0.268) has a much lower hERG inhibition liability than Ligand B (0.059), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (-6.501) has a much lower (better) microsomal clearance than Ligand B (57.997), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.999) has a shorter half-life than Ligand B (-12.091). This is a drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.007) has lower P-gp efflux than Ligand B (0.092), which is favorable.

**15. Binding Affinity:** Ligand B (-8.3 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.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk (11.361 vs 21.985) and hERG inhibition liability (0.268 vs 0.059), and better metabolic stability (lower Cl_mic). While Ligand B has slightly better binding affinity and half-life, the safety and metabolic advantages of Ligand A outweigh these minor differences, especially considering we are dealing with a kinase target where metabolic stability is crucial. The lower Caco-2 and solubility of Ligand A are concerns, but potentially addressable through formulation strategies.

Output:
0
2025-04-17 12:08:23,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.292 Da) is slightly higher than Ligand B (356.413 Da), but both are acceptable.

**TPSA:** Ligand A (61.88) is better than Ligand B (83.63). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (4.207) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.496) is within the optimal range (1-3).

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD (1 & 2 respectively) and HBA (3 each) counts.

**QED:** Both ligands have the same QED score (0.676), indicating similar drug-likeness.

**DILI:** Ligand A (64.172) has a higher DILI risk than Ligand B (17.604). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (78.48) is better than Ligand A (65.723). However, BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.416) has very poor Caco-2 permeability, while Ligand B (-4.58) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.604 and -3.355 respectively). This could be a formulation challenge.

**hERG:** Both ligands have a similar, low hERG risk (0.845 and 0.853).

**Microsomal Clearance:** Ligand B (48.278) has significantly lower microsomal clearance than Ligand A (66.826), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (72.503) has a longer in vitro half-life than Ligand B (0.3). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.436 and 0.291).

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Conclusion:**

Despite the similar binding affinity and half-life, Ligand B is the more promising candidate. Its lower logP, significantly lower DILI risk, and lower microsomal clearance outweigh the slightly lower BBB penetration and poor Caco-2 permeability. The poor permeability of both is a concern, but can potentially be addressed with formulation strategies. The higher DILI risk of Ligand A is a major red flag, and the higher logP could lead to off-target effects.

Output:
1
2025-04-17 12:08:23,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.463 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.13) is better than Ligand B (47.36), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (4.799) is slightly high, potentially leading to solubility issues, while Ligand B (2.71) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (1) is good, and Ligand B (5) is acceptable, though approaching the upper limit.

**QED:** Both ligands have similar QED values (0.828 and 0.787), indicating good drug-likeness.

**DILI:** Ligand A (43.932) has a moderate DILI risk, while Ligand B (10.237) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have high BBB penetration (90.035 and 94.921), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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:** Ligand A (-5.839) has poor solubility, which is concerning given its high logP. Ligand B (-2.57) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.851) has a moderate hERG risk, while Ligand B (0.716) has a lower risk.

**Microsomal Clearance:** Ligand A (54.98) has moderate clearance, while Ligand B (72.716) has higher clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (43.539) has a longer half-life than Ligand B (-2.597), which is a positive.

**P-gp Efflux:** Ligand A (0.377) has lower P-gp efflux, which is favorable. Ligand B (0.218) is even lower, which is better.

**Binding Affinity:** Ligand A (-8.0) has a slightly stronger binding affinity than Ligand B (-7.6), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and half-life, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, lower hERG risk, better logP, and lower P-gp efflux. The solubility of both is poor, but Ligand B is better. The higher clearance of Ligand B is a drawback, but can potentially be addressed through structural modifications. The slightly weaker binding of Ligand B is less concerning given its superior ADME properties.

Output:
1
2025-04-17 12:08:23,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (380.945 and 353.369 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (59.81 and 60.5) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.669 and 3.243) 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:** Both ligands have 5 HBAs, which is within the acceptable range (<=10).

**QED:** Both ligands have QED scores above 0.5 (0.674 and 0.513), indicating good drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (48.313 and 41.024 percentiles), which is good.

**BBB:** Ligand A (51.066) has a lower BBB penetration percentile than Ligand B (84.451). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.27) has lower Caco-2 permeability than Ligand B (-4.739), suggesting potentially poorer absorption.

**Aqueous Solubility:** Ligand A (-3.808) has lower aqueous solubility than Ligand B (-2.082). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.39 and 0.627), which is favorable.

**Microsomal Clearance:** Ligand A (82.748) has higher microsomal clearance than Ligand B (71.501), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (16.016 hours) has a significantly longer in vitro half-life than Ligand A (51.454 hours). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.406 and 0.396).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity and acceptable initial properties, Ligand B is preferable due to its better Caco-2 permeability, higher aqueous solubility, and significantly improved in vitro half-life. These factors contribute to better absorption and less frequent dosing, making it a more viable drug candidate.

Output:
1
2025-04-17 12:08:23,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (333.343 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is well below the 140 threshold for good absorption and is favorable. Ligand B (91.56) is still acceptable but closer to the limit.

**logP:** Ligand A (2.308) is optimal (1-3). Ligand B (0.157) is quite low, potentially hindering permeation.

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

**QED:** Both ligands have good QED scores (A: 0.796, B: 0.837), indicating drug-like properties.

**DILI:** Ligand A (80.186) has a higher DILI risk than Ligand B (53.044). This is a significant concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (21.171) and B (47.964) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.826 and -4.808), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.622 and -1.2), which is also unusual and suggests poor solubility. This is a significant issue.

**hERG:** Ligand A (0.136) has a very low hERG risk, which is excellent. Ligand B (0.232) also shows low hERG risk.

**Microsomal Clearance:** Ligand A (0.766) has a much lower Cl_mic, indicating better metabolic stability than Ligand B (28.528).

**In vitro Half-Life:** Ligand A (-9.678) has a more negative half-life, indicating a longer half-life and better stability than Ligand B (-4.857).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.059, B: 0.063).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). The difference is 1.3 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a better binding affinity, lower DILI risk, and acceptable HBA. However, its low logP is a major concern, potentially leading to poor absorption. Ligand A has a better logP and significantly better metabolic stability (lower Cl_mic, longer half-life) and a very low hERG risk. The main drawback for Ligand A is its higher DILI risk.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), and the fact that the affinity difference is not enormous, the improved metabolic stability and lower hERG risk of Ligand A outweigh its higher DILI risk, especially since the DILI risk is still below the 60% threshold. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 12:08:23,541 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.443 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (76.66 and 71.97) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (1.158 and 0.942) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is within the preferred limit of <=5. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.706 and 0.815), indicating good drug-like properties.

**7. DILI:** Ligand A (50.33) and Ligand B (65.064) both have acceptable DILI risk, but Ligand B is slightly higher.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (73.129) has a slightly higher BBB penetration, but it's not a major factor here.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, they are both very low, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, they are both very low, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.154 and 0.268), which is excellent.

**12. Microsomal Clearance:** Ligand A (22.164 mL/min/kg) has significantly lower microsomal clearance than Ligand B (54.536 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.574 hours) has a positive half-life, while Ligand B (-32.588 hours) has a negative half-life, which is impossible. This is a major red flag for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.068).

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol), a 0.5 kcal/mol difference.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, the negative in vitro half-life is a critical flaw. This suggests rapid metabolism and a very short duration of action, making it a poor candidate. Ligand A, while having a slightly weaker binding affinity, exhibits better metabolic stability (lower Cl_mic, positive t1/2) and acceptable values for other ADME properties. The poor Caco-2 and solubility values for both are concerning and would need to be addressed during optimization, but the metabolic stability advantage of Ligand A is more immediately important for an enzyme target.

Output:
0
2025-04-17 12:08:23,541 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.511 and 346.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.76) is well below the 140 threshold, suggesting good absorption. Ligand B (119.57) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (3.501) 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 below 1, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 9 HBA) is acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have reasonable QED values (0.751 and 0.583), indicating drug-like properties.

**DILI:** Ligand A (48.623) has a lower DILI risk than Ligand B (63.397), which is better.

**BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (77.045) has a better BBB score than Ligand B (40.558).

**Caco-2 Permeability:** Ligand A (-4.827) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.878) is also poor, but slightly worse than A.

**Aqueous Solubility:** Ligand A (-3.8) has better solubility than Ligand B (-1.561).

**hERG Inhibition:** Ligand A (0.578) has a lower hERG risk than Ligand B (0.1), which is a significant advantage.

**Microsomal Clearance:** Ligand A (75.97) has higher clearance than Ligand B (-2.369), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (12.783) has a shorter half-life than Ligand B (23.003), which is less desirable.

**P-gp Efflux:** Ligand A (0.644) has lower P-gp efflux than Ligand B (0.042), which is favorable.

**Binding Affinity:** Ligand B (-7.7 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 A has advantages in solubility, DILI risk, P-gp efflux, and TPSA. However, it suffers from poor Caco-2 permeability, higher microsomal clearance, and a shorter half-life. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity, but has a higher DILI risk, lower solubility, and higher P-gp efflux.

Given the priority for metabolic stability and potency for kinase inhibitors, and the relatively small difference in binding affinity, **Ligand B** is the more promising candidate despite its slightly higher DILI risk. The metabolic liabilities of Ligand A are concerning and could lead to rapid clearance *in vivo*.

Output:
1
2025-04-17 12:08:23,541 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.767 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is slightly higher than Ligand B (49.85), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (4.023) is at the upper end of the optimal range (1-3), while Ligand B (2.162) is well within it. Ligand A's higher logP *could* lead to solubility issues or off-target effects, but isn't immediately disqualifying.

**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 good QED scores (0.713 and 0.785, respectively), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.337, which is high. Ligand B has a much lower DILI risk of 30.787, which is very favorable. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonably high BBB penetration (81.621 and 75.843), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.86 and -4.305). These values are unusual and suggest poor permeability. However, these values are on a log scale and can be misleading, and are less critical than other factors.

**Aqueous Solubility:** Ligand A (-5.314) has very poor aqueous solubility, while Ligand B (-1.607) is better, though still poor. This is a concern for Ligand A, given its higher logP.

**hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.255), though both are relatively low.

**Microsomal Clearance:** Ligand A (46.271) has lower microsomal clearance than Ligand B (62.333), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (14.075) has a longer half-life than Ligand B (-15.223). The negative value for Ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Ligand A (0.629) has slightly lower P-gp efflux than Ligand B (0.138), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.0 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is substantial.

**Conclusion:**

While Ligand A has a better binding affinity and metabolic stability, the significantly higher DILI risk and very poor aqueous solubility are major drawbacks. Ligand B, despite a slightly lower affinity and potentially faster metabolism, presents a much more favorable safety profile (DILI) and better solubility. The difference in binding affinity (0.8 kcal/mol) can potentially be overcome with further optimization, while mitigating the high DILI risk of Ligand A would be far more challenging. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:08:23,541 - INFO - Batch 105 complete. Total preferences: 1680
2025-04-17 12:08:23,541 - INFO - Processing batch 106/512...
2025-04-17 12:09:01,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.447 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.42) is slightly higher than Ligand B (79.31), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.482) is optimal, while Ligand B (0.26) is quite low. A logP below 1 can hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.673 and 0.783), indicating drug-like properties.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (20.706). This is a concern for Ligand A.

**BBB:** Both ligands have low BBB penetration (44.901 and 40.907), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.656 and -4.419), which is unusual and suggests poor permeability. This is a concern for both, but the negative values are close enough that it's not a major differentiator.

**Aqueous Solubility:** Ligand A (-2.77) has worse solubility than Ligand B (-0.601). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.433) has a slightly higher hERG risk than Ligand B (0.197), but both are relatively low.

**Microsomal Clearance:** Ligand A (44.524) has significantly higher microsomal clearance than Ligand B (8.876). This indicates that Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A (39.12) has a longer half-life than Ligand B (-0.015), but the negative value for Ligand B is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.016).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol), with Ligand A being slightly better. However, the difference is less than 1.5 kcal/mol, so it's not decisive.

**Conclusion:**

While Ligand A has slightly better binding affinity and half-life, Ligand B is superior overall. Its significantly lower DILI risk, much better metabolic stability (lower Cl_mic), and acceptable solubility outweigh the minor advantage in binding affinity of Ligand A. The low logP of Ligand B is a concern, but the excellent metabolic stability and low toxicity profile make it the more promising candidate.

Output:
1
2025-04-17 12:09:01,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.515 and 353.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is better than Ligand B (53.09), both are acceptable but lower is better for permeability.

**logP:** Ligand A (3.834) is good, while Ligand B (1.447) is on the lower side, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as a small number of HBDs are generally better.

**H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (4).

**QED:** Both ligands have good QED scores (0.679 and 0.768), indicating good drug-like properties.

**DILI:** Ligand A (13.532) has a significantly lower DILI risk than Ligand B (11.516), which is a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand A (88.29) is better than Ligand B (51.454).

**Caco-2 Permeability:** Ligand A (-4.827) is better than Ligand B (-4.442).

**Aqueous Solubility:** Ligand A (-3.233) is better than Ligand B (-0.183).

**hERG Inhibition:** Ligand A (0.664) has a lower hERG inhibition liability than Ligand B (0.439), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (48.701) has higher clearance than Ligand B (18.459). This means Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-21.312) has a negative half-life, which is concerning. Ligand B (0.818) is better.

**P-gp Efflux:** Ligand A (0.437) is better than Ligand B (0.036).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly better binding affinity than Ligand A (-8.2 kcal/mol). This is a crucial factor.

**Overall Assessment:**

While Ligand A has better solubility, lower DILI and hERG risk, and better permeability, Ligand B's substantially stronger binding affinity (-7.4 vs -8.2 kcal/mol) is a major advantage for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic, higher t1/2) of Ligand B also contributes to its favorability. The slightly higher DILI and hERG risks of Ligand B could be addressed through further optimization, but the potency advantage is harder to recover.

Output:
1
2025-04-17 12:09:01,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.4 and 349.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.5) is better than Ligand B (116.6), being closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (1.52) is within the optimal 1-3 range. Ligand B (-1.279) is below 1, which might impede permeation.

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

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Ligand A (0.723) has a better QED score than Ligand B (0.612), indicating a more drug-like profile.

**DILI:** Ligand B (32.6) has a significantly lower DILI risk than Ligand A (94.6), which is a major advantage.

**BBB:** Ligand A (57.2) has a higher BBB penetration percentile than Ligand B (13.9), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.389) has better Caco-2 permeability than Ligand B (-5.578), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.842) has better aqueous solubility than Ligand B (-1.289).

**hERG Inhibition:** Ligand A (0.121) has a slightly higher hERG inhibition risk than Ligand B (0.016), but both are very low.

**Microsomal Clearance:** Ligand B (-1.272) has significantly lower microsomal clearance than Ligand A (10.076), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.281) has a significantly longer in vitro half-life than Ligand A (99.953).

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.002), which is favorable.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a stronger binding affinity than Ligand B (-8.1 kcal/mol), with a difference of 1.3 kcal/mol. This is a substantial advantage.

**Conclusion:**

While Ligand B has a significantly better safety profile (lower DILI, better metabolic stability, longer half-life) and acceptable solubility, Ligand A's substantially stronger binding affinity (-9.4 vs -8.1 kcal/mol) is a critical advantage for an enzyme target. The 1.3 kcal/mol difference is large enough to outweigh the ADME drawbacks of Ligand A, especially considering the low hERG risk for both compounds.

Output:
1
2025-04-17 12:09:01,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (454.312 and 439.14 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.94) is higher than Ligand B (37.61). While both are acceptable, Ligand B's lower TPSA is preferable for better absorption.

**3. logP:** Ligand A (2.905) is within the optimal 1-3 range. Ligand B (4.888) is slightly higher, potentially leading to solubility issues or off-target interactions, but not critically so.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, staying under the 5 threshold.

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

**6. QED:** Both ligands have reasonable QED scores (0.699 and 0.542), indicating drug-like properties.

**7. DILI:** Ligand A (53.199) has a lower DILI risk than Ligand B (75.378), which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.978) has better BBB penetration, but it's not a primary concern here.

**9. Caco-2 Permeability:** Ligand A (-5.594) has worse Caco-2 permeability than Ligand B (-4.637), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.186) has better aqueous solubility than Ligand B (-6.23), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.465) has a lower hERG inhibition liability than Ligand B (0.72), a crucial advantage for cardiac safety.

**12. Microsomal Clearance:** Ligand A (22.426) has lower microsomal clearance than Ligand B (52.936), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (95.303) has a significantly longer in vitro half-life than Ligand A (26.876), which is a strong positive.

**14. P-gp Efflux:** Ligand A (0.28) has lower P-gp efflux than Ligand B (0.798), potentially leading to better bioavailability.

**15. Binding Affinity:** Ligand B (-10.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 2.4 kcal/mol is significant and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity and a longer half-life, which are critical for an enzyme inhibitor. While it has a higher DILI risk, higher logP, and worse P-gp efflux, the substantial improvement in potency and metabolic stability makes it the more promising candidate. The better solubility and lower hERG risk of Ligand A are valuable, but the binding affinity difference is too large to ignore.

Output:
1
2025-04-17 12:09:01,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.4 and 355.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (96.97), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.501 and 0.512), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is slightly better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED scores (0.639 and 0.588), indicating reasonable drug-likeness.

**DILI:** Ligand A (27.491) has a significantly lower DILI risk than Ligand B (34.587), which is a major advantage. Both are below the 40 threshold.

**BBB:** Both ligands have high BBB penetration (80.962 and 78.79), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are log values, they indicate poor permeability. Ligand A (-4.987) is slightly better than Ligand B (-4.887).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Assuming these are log values, they indicate poor solubility. Ligand A (-2.452) is slightly better than Ligand B (-1.499).

**hERG:** Both ligands have low hERG inhibition liability (0.213 and 0.168), which is excellent.

**Microsomal Clearance:** Ligand A (16.412 mL/min/kg) has a higher microsomal clearance than Ligand B (4.418 mL/min/kg), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-6.406 hours) has a longer half-life than Ligand A (-10.79 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.018).

**Binding Affinity:** Ligand B (-8.0 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 better candidate. While Ligand A has a slightly better TPSA and logP, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer half-life), a lower DILI risk, and a slightly better binding affinity. The metabolic stability and DILI are crucial for enzyme inhibitors, outweighing the minor advantages of Ligand A. The solubility and permeability are poor for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 12:09:01,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.471 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (73.99 and 71.53) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands have logP values (3.062 and 2.535) 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 (2) is lower than Ligand B (4), both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.743 and 0.91), indicating good drug-like properties.

**7. DILI:** Ligand A (29.779) has a significantly lower DILI risk than Ligand B (49.632). This is a substantial advantage.

**8. BBB:** Ligand A (71.656) has a better BBB penetration percentile than Ligand B (60.45). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**9. Caco-2 Permeability:** Ligand A (-5.088) has worse Caco-2 permeability than Ligand B (-4.467).

**10. Aqueous Solubility:** Ligand A (-3.941) has worse aqueous solubility than Ligand B (-2.871). This is a drawback for Ligand A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.601 and 0.256).

**12. Microsomal Clearance:** Ligand B (33.223) has lower microsomal clearance than Ligand A (49.115), indicating better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-6.46) has a much longer in vitro half-life than Ligand A (1.348). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.255 and 0.161).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.6 and -8.7 kcal/mol). Ligand A is slightly better (-9.6 vs -8.7), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADMET properties. Specifically, the significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility of Ligand B outweigh the minor affinity difference. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity (DILI) are crucial.

Output:
1
2025-04-17 12:09:01,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (72.53), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.308 and 1.79), falling within the optimal 1-3 range. Ligand B is slightly lower, which could be beneficial for solubility.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 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 (0.704 and 0.863), indicating good drug-like properties.

**DILI:** Ligand A (29.236) has a significantly lower DILI risk than Ligand B (35.595), both are below the 40 threshold.

**BBB:** Both ligands have moderate BBB penetration (60.876 and 57.115). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.278 and -5.049). This is unusual and suggests poor permeability. However, these values could be experimental artifacts or indicate issues with the prediction model.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.656 and -1.627). This is also concerning and suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.398 and 0.143).

**Microsomal Clearance:** Ligand B (20.99 mL/min/kg) has significantly lower microsomal clearance than Ligand A (38.144 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (54.82 hours) has a much longer in vitro half-life than Ligand A (-16.325 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.026).

**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 less than the 1.5 kcal/mol threshold for outweighing other issues, it's still a positive factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. It exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and a lower DILI risk. While both have concerningly low/negative Caco-2 and solubility predictions, the improved metabolic profile of Ligand B is crucial for kinase inhibitors, which often suffer from rapid metabolism.

Output:
1
2025-04-17 12:09:01,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.809 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.55) is better than Ligand B (76.46), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.649) is optimal, while Ligand B (1.051) is a bit 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 (4) and Ligand B (5) are both acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.659 and 0.797 respectively), indicating good drug-like properties.

**DILI:** Ligand B (29.042) has a significantly lower DILI risk than Ligand A (73.362), a major advantage.

**BBB:** Ligand B (56.107) has a higher BBB penetration score than Ligand A (37.96), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.991 and -4.968), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.14 and -0.814), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.63) has a slightly higher hERG risk than Ligand B (0.12), which is preferable for Ligand B.

**Microsomal Clearance:** Ligand B (19.758) has significantly lower microsomal clearance than Ligand A (41.837), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (29.628) has a slightly longer in vitro half-life than Ligand A (25.341).

**P-gp Efflux:** Ligand A (0.575) has lower P-gp efflux than Ligand B (0.017), which is preferable.

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

**Conclusion:**

While both ligands have good potency, Ligand B is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and slightly better solubility. The lower logP of Ligand B is a minor drawback, but the benefits outweigh this. The poor Caco-2 and solubility values are concerning for both, and would need to be addressed through further optimization.

Output:
1
2025-04-17 12:09:01,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.378 Da and 354.416 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.58) is higher than Ligand B (33.2). While both are reasonably low, Ligand B is significantly better, potentially aiding in cell permeability.

**logP:** Ligand A (1.533) is within the optimal 1-3 range. Ligand B (4.565) is slightly above this, which could lead to solubility issues and off-target interactions.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.84) has a better QED score than Ligand B (0.719), indicating a more drug-like profile.

**DILI:** Ligand B (14.23) has a much lower DILI risk than Ligand A (53.276), which is a significant advantage.

**BBB:** Ligand A (71.733) has a moderate BBB penetration, while Ligand B (97.208) has very high BBB penetration. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.644) has poor Caco-2 permeability, while Ligand B (-4.225) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.572) has slightly better solubility than Ligand B (-4.734).

**hERG Inhibition:** Ligand A (0.194) has a lower hERG risk than Ligand B (0.737), which is a crucial advantage.

**Microsomal Clearance:** Ligand B (62.252) has a lower microsomal clearance than Ligand A (14.823), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.513) has a longer half-life than Ligand B (-6.164), which is desirable.

**P-gp Efflux:** Ligand A (0.057) has lower P-gp efflux than Ligand B (0.204), which is favorable.

**Binding Affinity:** Ligand A (-10.1) has a significantly stronger binding affinity than Ligand B (-6.5). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity (-10.1 kcal/mol vs -6.5 kcal/mol) and a lower hERG risk. However, it has poorer Caco-2 permeability, higher DILI risk, and higher microsomal clearance. Ligand B has better metabolic stability (lower Cl_mic) and a much lower DILI risk, but its binding affinity is considerably weaker.

Given the priority for potency in kinase inhibitors, the substantial difference in binding affinity (-3.6 kcal/mol) is a critical factor. While Ligand A has some ADME liabilities, these can potentially be addressed through further optimization. The strong binding affinity suggests a higher probability of achieving efficacy.

Output:
0
2025-04-17 12:09:01,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.373 and 363.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.02) is well below the 140 threshold for oral absorption, while Ligand B (38.77) is even better.

**logP:** Ligand A (1.714) is within the optimal 1-3 range. Ligand B (3.65) is slightly higher but still acceptable.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good.

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

**QED:** Ligand A (0.795) has a strong drug-like profile. Ligand B (0.47) is lower, suggesting a less ideal overall profile.

**DILI:** Ligand A (43.117) has a low DILI risk. Ligand B (16.712) has an even lower DILI risk, which is excellent.

**BBB:** Ligand A (66.615) has moderate BBB penetration. Ligand B (88.29) has significantly higher BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.999), which is unusual and potentially problematic. This suggests poor permeability, though negative values can sometimes be artifacts of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.267 and -3.152), which is concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.679 and 0.758).

**Microsomal Clearance:** Ligand A (11.526 mL/min/kg) has a lower clearance than Ligand B (92.546 mL/min/kg), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-2.886 hours) has a negative half-life, which is not physically possible and indicates a prediction issue. Ligand B (9.323 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.071 and 0.72).

**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.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility predictions for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.7 vs -6.7 kcal/mol) is a major advantage for an enzyme target. It also has a better half-life and lower DILI risk. While Ligand A has better metabolic stability, the affinity difference is more critical in this case. The negative solubility and permeability predictions would need to be investigated experimentally, but the potency advantage of Ligand B makes it the preferred choice for further development.

Output:
1
2025-04-17 12:09:01,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.385 Da and 363.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is better than Ligand B (90.55), being comfortably below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.965 and 0.869), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, below the 10 threshold.

**QED:** Both ligands have good QED scores (0.794 and 0.84), indicating good drug-likeness.

**DILI:** Ligand A (52.695) has a slightly better DILI score than Ligand B (43.622), indicating lower potential for liver injury. Both are below the 60 threshold.

**BBB:** Ligand A (87.476) has a significantly better BBB penetration score than Ligand B (61.38). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.776) has a worse Caco-2 permeability than Ligand B (-4.921). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.894) has better aqueous solubility than Ligand B (-3.117). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.412 and 0.115).

**Microsomal Clearance:** Ligand B (-0.707) has a *much* better microsomal clearance than Ligand A (10.211). Lower clearance indicates greater metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-27.995) has a significantly longer in vitro half-life than Ligand A (-15.151). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03 and 0.035).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.5 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better TPSA, logP, DILI, BBB, and solubility, Ligand B excels in metabolic stability (Cl_mic) and half-life. For a kinase inhibitor, metabolic stability and duration of action (half-life) are crucial. The small difference in binding affinity is outweighed by the substantial improvements in pharmacokinetic properties of Ligand B.

Output:
1
2025-04-17 12:09:01,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.401 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (135.78) is approaching the upper limit for good oral absorption but is still acceptable.

**logP:** Ligand A (1.795) is within the optimal 1-3 range. Ligand B (0.372) is slightly below 1, which *could* indicate permeability issues, although not severely.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 7 HBA) is also acceptable, though slightly higher.

**QED:** Ligand A (0.877) has a very strong drug-like profile. Ligand B (0.689) is also good, but not as high.

**DILI:** Ligand A (40.636) has a low DILI risk. Ligand B (66.421) is approaching a higher risk, but still below the critical 60 threshold.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.7) is poor, while Ligand B (-5.602) is also poor. This is a concern for both, but the scale is not clearly defined.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.303 and -2.629 respectively). This is a significant drawback for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.356 and 0.17 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (43.934) has moderate clearance. Ligand B (26.668) has lower clearance, indicating better metabolic stability, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-10.663) has a significantly longer half-life than Ligand A (-3.416), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.044 and 0.003 respectively), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-10.4 and -9.1 kcal/mol respectively). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Conclusion:**

While Ligand A has a slightly better binding affinity and QED score, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The solubility is poor for both, but the improved metabolic stability and half-life of Ligand B are more critical for an enzyme inhibitor like an SRC kinase inhibitor. The slightly lower logP of Ligand B is a minor concern, outweighed by its other advantages.

Output:
1
2025-04-17 12:09:01,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.433 and 363.868 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.39) is slightly higher than Ligand B (55.63), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.198 and 3.588 respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both have good QED scores (0.813 and 0.901), indicating drug-like properties.

**DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (47.305). This is a major advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target, Ligand B (88.445) shows better BBB penetration than Ligand A (75.998).

**Caco-2 Permeability:** Ligand A (-4.691) has a worse Caco-2 permeability than Ligand B (-5.055). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand B (-4.104) has a worse aqueous solubility than Ligand A (-2.25).

**hERG Inhibition:** Ligand A (0.69) has a slightly higher hERG inhibition risk than Ligand B (0.337), but both are relatively low.

**Microsomal Clearance:** Ligand A (24.332) has a lower microsomal clearance than Ligand B (33.779), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand B (22.859) has a longer in vitro half-life than Ligand A (6.982).

**P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux than Ligand B (0.557), which is favorable for bioavailability.

**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 for Ligand B, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a stronger binding affinity, a longer half-life, and better BBB penetration. However, Ligand A demonstrates a significantly better safety profile (lower DILI) and better metabolic stability (lower Cl_mic), and lower P-gp efflux. The difference in binding affinity is significant, but the improved safety and metabolic stability of Ligand A are crucial for kinase inhibitors, which often require chronic administration. The solubility of Ligand A is also better.

Considering the enzyme-specific priorities, the superior binding affinity of Ligand B is the most important factor.

Output:
1
2025-04-17 12:09:01,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.382 and 345.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.17) is well below the 140 threshold, suggesting good absorption. Ligand B (120.24) is also below the threshold, but higher than A.

**logP:** Ligand A (3.646) is within the optimal 1-3 range. Ligand B (-0.463) is significantly below 1, which could hinder permeation.

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

**QED:** Both ligands have similar QED values (0.725 and 0.621), indicating good drug-likeness.

**DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (49.826), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.508) has better BBB penetration than Ligand B (52.889).

**Caco-2 Permeability:** Ligand A (-4.758) and Ligand B (-5.861) 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:** Ligand A (-5.482) and Ligand B (-2.469) both have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.913) has a lower hERG risk than Ligand B (0.469), which is preferable.

**Microsomal Clearance:** Ligand A (9.649) has a higher microsomal clearance than Ligand B (3.997), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-18.311) has a much longer half-life than Ligand A (32.32).

**P-gp Efflux:** Ligand A (0.683) has lower P-gp efflux than Ligand B (0.006), which is better.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial difference and a major advantage.

**Conclusion:**

Despite Ligand A having a higher DILI risk and faster clearance, its *significantly* stronger binding affinity (-10.1 vs -8.4 kcal/mol) outweighs these drawbacks. The difference in binding is >1.5 kcal/mol, making it a strong deciding factor. While the negative Caco-2 and solubility values are concerning, the superior potency of Ligand A makes it the more promising candidate, assuming these values are not drastically poor.

Output:
1
2025-04-17 12:09:01,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (466.662 Da) is higher, but still acceptable. Ligand B (366.477 Da) is slightly better.

**TPSA:** Ligand A (68.29) is higher than Ligand B (33.2). Both are below 140, but Ligand B is significantly better for absorption.

**logP:** Both ligands have similar logP values around 4.6, which is slightly above the optimal range of 1-3. This could potentially lead to solubility issues or off-target effects, but is not a dealbreaker if other properties are favorable.

**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 B (0.716) has a better QED score than Ligand A (0.455), indicating a more drug-like profile.

**DILI:** Ligand A has a very high DILI risk (98.255%), which is a major concern. Ligand B has a much lower DILI risk (32.299%), which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (86.817%) has a higher value than Ligand A (56.805%).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, 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 undefined.

**hERG:** Ligand A (0.485) has a slightly higher hERG risk than Ligand B (0.834), but both are relatively low.

**Microsomal Clearance:** Ligand A (97.011) has a very high microsomal clearance, indicating poor metabolic stability. Ligand B (68.914) has a lower clearance, which is preferable.

**In vitro Half-Life:** Ligand A (92.113) has a longer half-life than Ligand B (11.306). This is a positive for Ligand A, but is overshadowed by its other issues.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.449 and 0.441 respectively).

**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.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both have issues with Caco-2 and solubility, Ligand B has a significantly lower DILI risk, better QED, lower microsomal clearance (better metabolic stability), and slightly better binding affinity. The high DILI risk and poor metabolic stability of Ligand A are major drawbacks that outweigh its slightly longer half-life.

Output:
1
2025-04-17 12:09:01,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.559 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (67.87) is still acceptable but less favorable.

**logP:** Both ligands have good logP values (2.11 and 1.033), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which is within acceptable limits.

**QED:** Both ligands have good QED scores (0.714 and 0.755), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (19.193 and 20.9), which is excellent.

**BBB:** Both ligands have acceptable BBB penetration (68.282 and 70.531). This isn't a primary concern for a non-CNS target like SRC, but it's not detrimental.

**Caco-2 Permeability:** Ligand A (-5.478) has poor Caco-2 permeability, while Ligand B (-4.61) is slightly better, but still quite poor. This is a potential issue for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.792 and -2.256). This is a significant concern for *in vivo* performance.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.429 and 0.134), which is very favorable.

**Microsomal Clearance:** Both ligands have reasonable microsomal clearance (33.818 and 31.916 mL/min/kg), suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand B (13.778 hours) has a significantly longer half-life than Ligand A (8.055 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.077 and 0.013), which is good.

**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 (0.3 kcal/mol), it's still a positive.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a significantly longer half-life and slightly better binding affinity. The longer half-life is particularly important for an enzyme target, as it suggests a potentially lower dosing frequency. The slightly better affinity could also translate to improved efficacy. The TPSA and logP are comparable between the two.

Output:
1
2025-04-17 12:09:01,754 - INFO - Batch 106 complete. Total preferences: 1696
2025-04-17 12:09:01,754 - INFO - Processing batch 107/512...
2025-04-17 12:09:43,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.471 and 357.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.53) is well below the 140 threshold, suggesting good absorption. Ligand B (110.67) is still acceptable, but less optimal.

**logP:** Ligand A (4.334) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.948) is within the optimal range.

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

**QED:** Both ligands have reasonable QED scores (0.881 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A (35.401) has a much lower DILI risk than Ligand B (66.576), which is a significant advantage.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (79.217) has a better percentile than Ligand B (28.15).

**Caco-2 Permeability:** Ligand A (-4.914) has a negative value which is not ideal. Ligand B (-5.62) is also not ideal.

**Aqueous Solubility:** Ligand A (-5.226) has a very poor solubility score. Ligand B (-3.835) is better but still not great.

**hERG:** Ligand A (0.679) has a lower hERG risk than Ligand B (0.45), which is preferable.

**Microsomal Clearance:** Ligand A (51.636) has a higher clearance than Ligand B (-13.105), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-4.468) has a negative half-life, which is not ideal. Ligand B (2.45) is better, but still not great.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.397 and 0.044).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a crucial advantage, potentially outweighing some of its ADME drawbacks. The difference of 2.7 kcal/mol is substantial.

**Conclusion:**

Despite Ligand A having a lower DILI risk and better BBB penetration, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.2 vs -6.5 kcal/mol) is paramount for an enzyme inhibitor. While Ligand B has a higher DILI risk and lower solubility, these can potentially be addressed through further optimization. The metabolic stability of Ligand A is a major concern, and its solubility is very poor.

Output:
1
2025-04-17 12:09:43,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.435 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.79) is well below the 140 threshold for oral absorption, while Ligand B (110.32) is still acceptable but closer to the limit.

**logP:** Ligand A (2.824) is optimal (1-3). Ligand B (0.041) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.834 and 0.783), indicating drug-like properties.

**DILI:** Ligand A (69.988) has a higher DILI risk than Ligand B (43.66), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (70.958) shows better penetration than Ligand B (55.138).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is more important, and Ligand A (-5.22) is slightly better than Ligand B (-5.487).

**Aqueous Solubility:** Ligand A (-4.111) is better than Ligand B (-2.339), indicating better solubility.

**hERG:** Ligand A (0.72) has a lower hERG risk than Ligand B (0.132), which is a significant advantage.

**Microsomal Clearance:** Ligand A (51.458) has a higher (worse) clearance than Ligand B (-1.19). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (68.977) has a longer half-life than Ligand B (15.254), which is desirable.

**P-gp Efflux:** Ligand A (0.757) shows lower P-gp efflux than Ligand B (0.012), which is better for bioavailability.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). This is a 1.7 kcal/mol difference, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic). However, Ligand A has better solubility, lower hERG risk, and a longer half-life. The low logP of Ligand B is a major concern, potentially leading to poor absorption. The slightly better affinity of Ligand B is appealing, but the combination of better solubility, lower toxicity (hERG), and acceptable half-life makes Ligand A the more promising candidate.

Output:
1
2025-04-17 12:09:43,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (339.439 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (75.43 and 76.46) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (3.138) is optimal, while Ligand B (1.133) is a bit 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 (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.814) has a significantly better QED score than Ligand B (0.567), indicating a more drug-like profile.

**7. DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (54.75), both are acceptable but A is better.

**8. BBB:** Both are acceptable, but Ligand A (71.656) has a better BBB penetration percentile than Ligand B (64.327). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.977 and -4.649). This is unusual and suggests poor permeability. However, the values are similar, so it doesn't strongly differentiate them.

**10. Solubility:** Both ligands have negative solubility values (-3.444 and -2.604). This is also concerning, indicating poor aqueous solubility. Again, the values are similar.

**11. hERG:** Ligand A (0.848) has a lower hERG risk than Ligand B (0.309), which is a significant advantage.

**12. Cl_mic:** Ligand A (-6.923) exhibits much lower microsomal clearance than Ligand B (37.852), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. t1/2:** Ligand A (68.401) has a longer in vitro half-life than Ligand B (-12.851), further supporting its better metabolic stability.

**14. Pgp:** Ligand A (0.128) has lower P-gp efflux liability than Ligand B (0.049), suggesting better oral bioavailability.

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.9 and -6.9 kcal/mol). Ligand A has a significantly better affinity.

**Overall Assessment:**

Ligand A is clearly superior. It exhibits a better QED score, lower DILI risk, lower hERG risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a better binding affinity. While both have issues with Caco-2 and solubility, Ligand A's advantages in ADME-Tox properties and potency outweigh these concerns.

Output:
1
2025-04-17 12:09:43,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.39 and 350.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.43) is higher than Ligand B (58.64). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good oral absorption.

**logP:** Ligand A (0.999) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (3.047) is within the optimal 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, but Ligand B is slightly more favorable due to lower HBD/HBA counts.

**QED:** Both ligands have acceptable QED values (0.711 and 0.65), indicating good drug-like properties.

**DILI:** Ligand A (82.862) has a considerably higher DILI risk than Ligand B (9.19). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (71.966 and 81.233), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.103) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.359) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-3.729) has poor aqueous solubility, while Ligand B (-2.178) is better. Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.093) has a very low hERG inhibition risk, which is excellent. Ligand B (0.387) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (2.68 mL/min/kg) has much lower microsomal clearance than Ligand B (70.712 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (35.377 hours) has a significantly longer half-life than Ligand B (-1.548 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.007) shows very low P-gp efflux, which is favorable. Ligand B (0.116) is slightly higher.

**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 of 2 kcal/mol is significant.

**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 suffers from poor solubility and Caco-2 permeability, and a higher DILI risk. Ligand B has better TPSA, logP, solubility, and a much lower DILI risk, but weaker binding affinity and poorer metabolic stability.

Given that we are targeting a kinase (enzyme), potency (affinity) and metabolic stability are paramount. The 2 kcal/mol difference in binding affinity is substantial, and the longer half-life of Ligand A is also very attractive. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The DILI risk is a concern, but not insurmountable.

Output:
1
2025-04-17 12:09:43,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.96) is significantly better than Ligand B (112.66). A TPSA under 90 is preferred, and Ligand A is comfortably within this range, suggesting better permeability. Ligand B is pushing the upper limit for good oral absorption.

**logP:** Both ligands have acceptable logP values (0.498 and 1.49), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.839) has a higher QED score than Ligand B (0.626), indicating a more drug-like profile.

**DILI:** Ligand A (36.06) has a much lower DILI risk than Ligand B (49.632). Both are below the 60 threshold, but A is significantly safer.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.699) has a higher BBB score than Ligand A (44.126), but this isn't a major deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.891) is better than Ligand B (-5.476). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-1.244) is better than Ligand B (-2.362). Higher values are preferred.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.323 and 0.051), which is excellent.

**Microsomal Clearance:** Ligand A (-9.831) has a much lower (better) microsomal clearance than Ligand B (26.335). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (45.554) has a longer in vitro half-life than Ligand B (-12.235), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.045).

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent and meets the > -7.0 kcal/mol criteria.

**Conclusion:**

Ligand A is superior to Ligand B. While both have excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better ADME properties: lower DILI risk, better TPSA, better solubility, and dramatically improved metabolic stability (lower Cl_mic, longer t1/2). These factors are crucial for developing a viable drug candidate for a kinase target like SRC.

Output:
0
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

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

**2. TPSA:** Ligand A (63.91) is better than Ligand B (69.72). Both are below the 140 threshold for oral absorption, but lower TPSA is generally preferred.

**3. logP:** Ligand A (2.613) is optimal, while Ligand B (1.062) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands are acceptable (0 and 1 respectively), well below the 5 limit.

**5. H-Bond Acceptors:** Both ligands are acceptable (6 and 4 respectively), well below the 10 limit.

**6. QED:** Both ligands are very similar and good (0.825 and 0.818), indicating good drug-like properties.

**7. DILI:** Ligand B (51.493) has a significantly lower DILI risk than Ligand A (70.919). This is a major advantage for Ligand B.

**8. BBB:** Ligand A (80.264) has better BBB penetration than Ligand B (54.052), but BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.433) has better Caco-2 permeability than Ligand B (-5.075), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.58 and -2.569). This is a significant drawback for both, potentially impacting bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.287 and 0.272). This is positive for both.

**12. Microsomal Clearance:** Ligand B (-12.365) has significantly lower microsomal clearance than Ligand A (34.099), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (-7.531) has a much longer in vitro half-life than Ligand A (-1.627), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.553 and 0.018).

**15. Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.1). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility, Ligand B excels in key areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The slightly lower logP of Ligand B is a minor concern, but is outweighed by the advantages in safety and pharmacokinetics.

Output:
1
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.547 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (107.53) is still within acceptable limits, but less favorable.

**logP:** Ligand A (4.135) is slightly above the optimal 1-3 range, potentially causing solubility issues or off-target interactions. Ligand B (0.463) is significantly below the optimal range, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (4 HBD, 4 HBA) is acceptable, but higher than ideal.

**QED:** Both ligands have reasonable QED scores (0.602 and 0.533), indicating drug-like properties.

**DILI:** Ligand A (30.322) has a very low DILI risk, which is highly desirable. Ligand B (13.804) also has a low DILI risk, but higher than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.498) has better BBB penetration than Ligand B (56.572), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-5.008) has poor Caco-2 permeability. Ligand B (-5.539) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.487) has poor aqueous solubility. Ligand B (-1.143) has better aqueous solubility than A.

**hERG Inhibition:** Ligand A (0.752) has a low hERG risk, which is excellent. Ligand B (0.066) has a very low hERG risk, which is also excellent.

**Microsomal Clearance:** Ligand A (82.108) has relatively high microsomal clearance, suggesting lower metabolic stability. Ligand B (-10.984) has negative clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (6.383) has a moderate half-life. Ligand B (-9.88) has a very long half-life.

**P-gp Efflux:** Ligand A (0.575) has moderate P-gp efflux. Ligand B (0.007) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-7.4 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.

**Conclusion:**

While Ligand A has a slightly better binding affinity and lower DILI risk, Ligand B is superior overall. Ligand B's significantly better metabolic stability (negative Cl_mic, long half-life), lower P-gp efflux, and better aqueous solubility outweigh the slightly weaker binding affinity. The poor Caco-2 permeability of both is a concern, but can be addressed with formulation strategies. The higher logP of Ligand A is also a concern.

Output:
1
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.463 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.59) is better than Ligand B (78.43), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (0.92) is slightly lower than optimal (1-3), but acceptable. Ligand B (2.622) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.825) has a significantly better QED score than Ligand B (0.529), indicating a more drug-like profile.

**DILI:** Ligand A (19.038) has a much lower DILI risk than Ligand B (13.92), which is a significant advantage.

**BBB:** Ligand A (81.582) has better BBB penetration than Ligand B (48.003), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.146) has worse Caco-2 permeability than Ligand B (-4.803), but both are negative and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-0.7) has better solubility than Ligand B (-4.129). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.436 and 0.515, respectively), which is good.

**Microsomal Clearance:** Ligand A (-7.222) has significantly lower microsomal clearance than Ligand B (58.264), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (11.173 hours) has a better in vitro half-life than Ligand B (-8.173 hours).

**P-gp Efflux:** Ligand A (0.014) has lower P-gp efflux than Ligand B (0.403), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have good binding affinity (-8.4 and -7.8 kcal/mol). Ligand A is slightly more potent, with a 0.6 kcal/mol advantage.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have acceptable binding affinities, Ligand A excels in crucial ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, lower P-gp efflux, and a higher QED score. The slight advantage in binding affinity further supports the selection of Ligand A. The Caco-2 permeability is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.318 and 366.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (69.48). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (1.677 and 2.997), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (0 HBD, 7 HBA). While both are within acceptable limits, a slight increase in hydrogen bonding potential can aid solubility.

**QED:** Both ligands have good QED scores (0.572 and 0.682), indicating good drug-like properties.

**DILI:** Ligand A (46.452) has a lower DILI risk than Ligand B (57.154), which is a significant advantage.

**BBB:** Ligand A (95.308) shows much better BBB penetration than Ligand B (54.013). While SRC is not a CNS target, higher BBB penetration can sometimes correlate with better overall permeability.

**Caco-2 Permeability:** Ligand A (-4.864) has slightly better Caco-2 permeability than Ligand B (-4.663).

**Aqueous Solubility:** Ligand A (-1.969) has slightly better aqueous solubility than Ligand B (-2.256).

**hERG:** Ligand A (0.272) has a substantially lower hERG risk than Ligand B (0.654). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (-3.486) has a significantly lower microsomal clearance (better metabolic stability) than Ligand B (84.523). This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-12.355) has a longer in vitro half-life than Ligand B (-16.513).

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux than Ligand B (0.28).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better than Ligand B across several critical ADME-Tox properties. It has lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better solubility and permeability. While both have good potency, the superior ADME profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.463 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.77) is well below the 140 threshold, and even better, below 90, indicating good permeability. Ligand B (96.69) is still under 140 but less favorable than A.

**logP:** Ligand A (0.685) is a bit low, potentially impacting permeability, but still within an acceptable range. Ligand B (0.202) is even lower, raising more concern about permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have similar QED values (0.672 and 0.666), indicating generally good drug-like properties.

**DILI:** Ligand A (16.906) has a significantly lower DILI risk than Ligand B (44.591), making it more favorable from a toxicity standpoint.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (59.325) shows slightly better BBB penetration than Ligand B (16.983).

**Caco-2 Permeability:** Ligand A (-4.777) shows better Caco-2 permeability than Ligand B (-5.422).

**Aqueous Solubility:** Ligand A (-0.605) has better aqueous solubility than Ligand B (-1.217). Solubility is important for bioavailability, especially for kinases.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.171 and 0.063), which is excellent.

**Microsomal Clearance:** Ligand B (-4.739) exhibits *negative* microsomal clearance, which is unusual and suggests very high metabolic stability. Ligand A (54.133) has moderate clearance.

**In vitro Half-Life:** Ligand A (24.877) has a better in vitro half-life than Ligand B (17.815).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.008).

**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 is the stronger candidate. While its logP is a bit low, its superior binding affinity, better solubility, lower DILI risk, and improved Caco-2 permeability outweigh this minor drawback. Ligand B's extremely low logP is a significant concern, and while its negative microsomal clearance is attractive, the very weak binding affinity is a major disadvantage. The large difference in binding affinity (-7.0 vs -0.0 kcal/mol) is likely to be the deciding factor, as it can compensate for other less-than-ideal properties.

Output:
1
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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, while Ligand B (386.543 Da) is still well within the range.

**TPSA:** Both ligands have TPSA values around 92, which is acceptable for oral absorption, though not optimal (ideally <140).

**logP:** Ligand A (1.598) has a better logP value than Ligand B (0.596), falling squarely within the optimal 1-3 range. Ligand B is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 6.  Ligand A is preferable here, as fewer HBAs generally improve permeability.

**QED:** Both ligands have similar QED scores (0.563 and 0.575), indicating good drug-likeness.

**DILI:** Ligand A (18.845) has a significantly lower DILI risk than Ligand B (35.052). This is a major advantage for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand A (64.793) is better than Ligand B (52.268). While not a primary concern for a kinase inhibitor, it's a slight positive for 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:** Both have negative solubility values, indicating poor solubility. Again, the scale is unclear, so the severity is hard to assess.

**hERG Inhibition:** Ligand A (0.094) has a much lower hERG inhibition risk than Ligand B (0.37). This is a critical advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (46.084) has higher microsomal clearance than Ligand B (3.619), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-19.725) has a slightly better in vitro half-life than Ligand A (-20.014).

**P-gp Efflux:** Both have very 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 for Ligand B, potentially outweighing some of its ADME drawbacks. The difference of 1.7 kcal/mol is significant.

**Overall Assessment:**

While Ligand A has advantages in terms of DILI risk, hERG inhibition, and logP, Ligand B's substantially stronger binding affinity (-9.6 vs -7.9 kcal/mol) is the most crucial factor for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic) of Ligand B is also a significant benefit. The slightly higher DILI and hERG risks of Ligand B might be manageable with further optimization, but the potency difference is harder to overcome.

Output:
1
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.411 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.07) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Ligand A (1.26) is within the optimal range, while Ligand B (2.655) is closer to the upper limit but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.83) has a significantly better QED score than Ligand B (0.686), indicating a more drug-like profile.

**DILI:** Ligand B (14.541) has a much lower DILI risk than Ligand A (30.516), which is a significant advantage.

**BBB:** Ligand B (77.278) has a higher BBB penetration percentile than Ligand A (53.819), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-4.528) and Ligand B (-4.785) 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 (-1.16) and Ligand B (-2.16) both have negative solubility values, indicating poor solubility. B is slightly worse.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.263 and 0.274 respectively).

**Microsomal Clearance:** Ligand B (39.676) has a lower microsomal clearance than Ligand A (43.354), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.165) has a negative half-life, which is unusual. Ligand A (12.188) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.213 and 0.159 respectively).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's better QED and half-life, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.5 vs -10.2 kcal/mol) is a major advantage for an enzyme target. Additionally, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the potency advantage of Ligand B is likely to be more impactful in early development.

Output:
1
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 343.303 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.88) is well below the 140 A^2 threshold for good absorption. Ligand B (132.21) is still within acceptable limits, but higher.

**logP:** Ligand A (1.98) is optimal. Ligand B (0.941) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (9) is approaching the upper limit of 10, which could slightly hinder permeability.

**QED:** Ligand A (0.826) has a significantly better QED score than Ligand B (0.414), indicating a more drug-like profile.

**DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (91.663). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (72.431 and 71.966), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.823) shows better Caco-2 permeability than Ligand B (-5.079), though both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.541) has better aqueous solubility than Ligand B (-2.891), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.425) has a lower hERG inhibition liability than Ligand B (0.09), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-4.79) has significantly lower microsomal clearance than Ligand B (33.289), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.436) has a longer in vitro half-life than Ligand B (-8.779), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux liability than Ligand B (0.159).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.4 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more viable drug candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior drug-like properties across multiple critical ADME parameters, including lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, lower hERG risk, and a higher QED score. These factors are particularly important for an enzyme target like SRC kinase, where metabolic stability and safety are crucial.

Output:
0
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (356.394 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is excellent, well below the 140 threshold for oral absorption. Ligand B (104.7) is still acceptable but less favorable.

**logP:** Ligand A (0.421) is a bit low, potentially hindering permeability. Ligand B (0.988) 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 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.57 and 0.664), indicating drug-likeness.

**DILI:** Ligand A (27.685) has a significantly lower DILI risk than Ligand B (40.364), which is a major advantage.

**BBB:** Ligand A (75.998) has better BBB penetration than Ligand B (25.475), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.511) shows poor permeability. Ligand B (-5.882) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.844) has slightly better solubility than Ligand B (-0.915).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.349 and 0.219).

**Microsomal Clearance:** Ligand A (31.844) has higher microsomal clearance than Ligand B (-22.023). This suggests Ligand B is more metabolically stable, which is highly desirable for an enzyme target.

**In vitro Half-Life:** Ligand B (-5.432) has a better in vitro half-life than Ligand A (-24.61).

**P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux, which is good. Ligand B (0.014) is even lower.

**Binding Affinity:** Ligand A (-7.9) has a significantly stronger binding affinity than Ligand B (0.0). This is a crucial factor for enzyme inhibition. The difference of 7.9 kcal/mol is substantial.

**Conclusion:**

Despite Ligand A's low logP and poor Caco-2 permeability, its significantly superior binding affinity (-7.9 vs 0.0 kcal/mol) and lower DILI risk outweigh these drawbacks. The strong binding affinity is particularly important for an enzyme target like SRC kinase. Ligand B has better metabolic stability and slightly better solubility, but the much weaker binding makes it a less promising candidate.

Output:
1
2025-04-17 12:09:43,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.379 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.8) is better than Ligand B (92.55), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.392 and 1.2), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Ligand A (0.925) has a significantly better QED score than Ligand B (0.425), indicating a more drug-like profile.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (11.128). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (63.203 and 63.746), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.572) is slightly better than Ligand B (-5.046).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.943) is slightly better than Ligand B (-2.166).

**hERG:** Ligand A (0.474) has a slightly higher hERG risk than Ligand B (0.143), but both are relatively low.

**Microsomal Clearance:** Ligand B (-17.729) has a *much* better microsomal clearance (lower is better) than Ligand A (54.031), indicating greater metabolic stability. This is a crucial advantage.

**In vitro Half-Life:** Ligand B (-10.949) has a significantly longer in vitro half-life than Ligand A (4.363), again indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.598) has slightly higher P-gp efflux than Ligand B (0.017), meaning B is less likely to be pumped out of cells.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While both are good, the difference is significant enough to consider.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED score and slightly better logP, Ligand B excels in crucial areas for an enzyme inhibitor: metabolic stability (Cl_mic and t1/2), lower DILI risk, and slightly better binding affinity. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies. The superior metabolic stability of Ligand B is a key advantage, as it suggests a longer duration of action and potentially lower dosing requirements.

Output:
1
2025-04-17 12:09:43,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.447 and 353.398 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (89.35), both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (1.069) is slightly better than Ligand B (0.595), both 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 (5) is better than Ligand B (6), both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.764 and 0.775), indicating good drug-likeness.

**7. DILI:** Ligand A (33.23) has a significantly lower DILI risk than Ligand B (68.98). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (58.511) has a lower BBB penetration than Ligand B (79.798). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.111) is worse than Ligand B (-4.895). Both are negative, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.188) is better than Ligand B (-2.342). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.053) has a slightly lower hERG risk than Ligand B (0.08). Both are very low, but A is slightly preferable.

**12. Microsomal Clearance:** Ligand A (6.333) has significantly lower microsomal clearance than Ligand B (18.274), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (14.585) has a positive half-life, while Ligand B (-17.714) has a negative half-life. This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.035 and 0.025), which is good.

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.4). While the difference is relatively small, it's still a favorable factor.

**Overall Assessment:**

Ligand A is the superior candidate. It demonstrates a significantly lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), and slightly better solubility and binding affinity. While Ligand B has slightly better Caco-2 permeability and BBB penetration, these are less critical for a non-CNS enzyme target like SRC kinase. The combination of improved safety (DILI, hERG) and pharmacokinetics (Cl_mic, t1/2) makes Ligand A the more promising drug candidate.

Output:
0
2025-04-17 12:09:43,019 - INFO - Batch 107 complete. Total preferences: 1712
2025-04-17 12:09:43,019 - INFO - Processing batch 108/512...
2025-04-17 12:10:23,949 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.869 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.22) is better than Ligand B (62.62), both are acceptable but A is closer to the <140 target for oral absorption.

**logP:** Ligand A (3.914) is good, while Ligand B (1.846) is on the lower side, potentially impacting 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 (0.816) has a higher QED score than Ligand B (0.618), indicating better overall drug-likeness.

**DILI:** Ligand A (29.391) has a significantly lower DILI risk than Ligand B (57.154), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (73.827 and 74.564), which is not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-4.737 and -4.5).

**Solubility:** Ligand A (-4.58) has better solubility than Ligand B (-2.744).

**hERG:** Ligand A (0.54) has a slightly higher hERG risk than Ligand B (0.252), but both are relatively low.

**Microsomal Clearance:** Ligand A (95.384) has a higher microsomal clearance than Ligand B (49.941), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-19.931) has a much longer in vitro half-life than Ligand A (0.378), which is a major advantage.

**P-gp Efflux:** Ligand A (0.246) has lower P-gp efflux than Ligand B (0.399), which is slightly favorable.

**Binding Affinity:** Ligand A (-9.6 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 superior binding affinity and better drug-likeness (QED, DILI, solubility) but suffers from higher microsomal clearance and a shorter half-life. Ligand B has better metabolic stability and a longer half-life, but its lower logP and higher DILI risk are concerning. The substantial difference in binding affinity (-9.6 vs -7.8 kcal/mol) is a key factor. For an enzyme target like SRC kinase, potency is paramount. While metabolic stability is important, it can often be improved through structural modifications. The lower DILI risk of Ligand A is also a significant benefit.

Output:
1
2025-04-17 12:10:23,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is better than Ligand B (88.08), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (0.919 and 1.553), falling within the 1-3 range. Ligand B is slightly higher, which could be beneficial for 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 (0.656 and 0.861), indicating good drug-like properties.

**DILI:** Ligand A (11.4) has a significantly lower DILI risk than Ligand B (57.154). This is a major advantage for Ligand A.

**BBB:** Ligand A (73.129) has a higher BBB penetration than Ligand B (57.736). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.727 and -4.792). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar, so the difference is not significant.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.658 and -2.302). This is also unusual and suggests poor solubility. Ligand B has slightly worse solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.158 and 0.217).

**Microsomal Clearance:** Ligand A (34.512) has lower microsomal clearance than Ligand B (40.767), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.007) has a shorter half-life than Ligand B (24.672). This is a negative for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.068).

**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 for Ligand B, potentially outweighing some of its ADME drawbacks. The difference of 1.3 kcal/mol is significant.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is the most critical factor for an enzyme inhibitor. While Ligand A has better DILI and metabolic stability, the potency advantage of Ligand B is likely to be more important. The solubility and permeability issues are similar for both, and can be addressed through formulation strategies.

Output:
1
2025-04-17 12:10:23,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.349 and 388.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.03) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.87) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.023 and 2.004), falling within the optimal 1-3 range.

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

**QED:** Both ligands have good QED scores (0.605 and 0.779), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 65.452, which is moderately high. Ligand B has a lower DILI risk of 50.136, which is better.

**BBB:** Both have reasonable BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have similar, very poor Caco-2 permeability values (-4.982 and -4.983). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.774 and -3.718). This is a major drawback.

**hERG Inhibition:** Ligand A (0.166) has a slightly higher hERG risk than Ligand B (0.777), but both are relatively low.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (4.765) than Ligand B (14.276), suggesting better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (20.675 hours) than Ligand A (4.165 hours). This is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.051 and 0.181).

**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.

**Conclusion:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. It has a lower DILI risk, a significantly longer half-life, and slightly better binding affinity. The improved metabolic stability of Ligand A is attractive, but the longer half-life of B is more valuable for kinase inhibitors. The slight improvement in binding affinity of B also tips the balance.

Output:
1
2025-04-17 12:10:23,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.435 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.45) is better than Ligand B (90.12), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.718) is optimal, while Ligand B (1.105) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Ligand A (7) is better than Ligand B (4), both are within the acceptable range.

**QED:** Both ligands have reasonable QED scores (0.85 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (68.903) has a higher DILI risk than Ligand B (10.585). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.758) is better than Ligand B (60.644).

**Caco-2 Permeability:** Ligand A (-4.443) is better than Ligand B (-5.66), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.556) is better than Ligand B (-1.489), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.699) has a lower hERG risk than Ligand B (0.238), which is a major advantage.

**Microsomal Clearance:** Ligand B (-21.345) has significantly lower microsomal clearance than Ligand A (56.094), indicating better metabolic stability. This is a critical advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-22.519) has a much longer in vitro half-life than Ligand A (-11.222), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand B (0.011) has very low P-gp efflux, while Ligand A (0.187) has slightly higher efflux.

**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 that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for an enzyme inhibitor. It also has better solubility, Caco-2 permeability, and a lower hERG risk. However, it suffers from a higher DILI risk and significantly worse metabolic stability (higher Cl_mic, shorter t1/2) compared to Ligand B.

Ligand B exhibits excellent metabolic stability and a very low DILI risk, but its binding affinity is very weak. The weak binding affinity is a major concern.

Despite the DILI risk, the substantial binding affinity advantage of Ligand A is likely to be more impactful in driving efficacy. Optimization efforts could focus on mitigating the DILI risk of Ligand A through structural modifications.

Output:
1
2025-04-17 12:10:23,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.889 Da) is slightly higher than Ligand B (351.495 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable absorption potential. Ligand A (78.95) is preferable to Ligand B (82.54) as lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.145) is slightly lower than Ligand B (1.596), but both are good.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=7) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.821) has a significantly higher QED score than Ligand B (0.59), indicating a more drug-like profile.

**DILI:** Ligand B (15.122) has a much lower DILI risk than Ligand A (61.807), which is a significant advantage.

**BBB:** Both have moderate BBB penetration, but Ligand A (61.031) is slightly better than Ligand B (57.968). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.675) has a more negative Caco-2 value, suggesting *lower* permeability than Ligand B (-5.23). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-2.215) has a more negative solubility value, indicating lower solubility than Ligand B (-0.949). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.164) has a lower hERG inhibition liability than Ligand B (0.806), which is a significant advantage regarding cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (-6.053) has a *lower* (better) microsomal clearance than Ligand A (29.304), indicating greater metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (62.682) has a significantly longer in vitro half-life than Ligand A (11.864), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.04), which is slightly preferable.

**Binding Affinity:** Both ligands have strong binding affinities (-9.1 kcal/mol for A and -8.0 kcal/mol for B). Ligand A has a 1.1 kcal/mol advantage in binding, which is substantial and can potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and QED score, but suffers from higher DILI risk, lower solubility, higher clearance, and shorter half-life. Ligand B has a significantly better safety profile (lower DILI, lower hERG), better metabolic stability (lower clearance, longer half-life), and better solubility, but slightly weaker binding affinity.

Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are critical. The 1.1 kcal/mol difference in binding affinity, while significant, is likely less important than the substantial improvements in ADME/Tox properties offered by Ligand B.

Output:
1
2025-04-17 12:10:23,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 & 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.79) is better than Ligand B (70.67), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (1.768) is optimal, while Ligand B (0.487) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as fewer donors generally improve permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Ligand A (0.868) has a significantly better QED score than Ligand B (0.637), indicating better overall drug-likeness.

**DILI:** Ligand B (21.869) has a much lower DILI risk than Ligand A (32.028), which is a significant advantage.

**BBB:** Ligand B (74.176) has better BBB penetration than Ligand A (62.931), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.014) has a worse Caco-2 permeability than Ligand B (-4.848).

**Aqueous Solubility:** Ligand A (-1.17) has better aqueous solubility than Ligand B (-2.122). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.423 and 0.487 respectively).

**Microsomal Clearance:** Ligand A (2.763) has a lower microsomal clearance than Ligand B (39.849), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (58.931) has a much longer in vitro half-life than Ligand B (-7.57), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.03 respectively).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.7 and -7.7 kcal/mol). While Ligand A is slightly better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a better QED, solubility, metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. However, Ligand B has a significantly lower DILI risk and a slightly better Caco-2 permeability. Given the importance of metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, Ligand A is the more promising candidate. The lower DILI risk of Ligand B is attractive, but can potentially be addressed with further structural modifications.

Output:
0
2025-04-17 12:10:23,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.231 Da) is slightly higher than Ligand B (356.467 Da), but both are acceptable.

**TPSA:** Ligand A (76.66) is well below the 140 threshold for oral absorption. Ligand B (133.55) is approaching the limit but still acceptable.

**logP:** Ligand A (3.978) is at the upper end of the optimal range (1-3), while Ligand B (0.387) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=5, HBA=4) both fall within acceptable limits.

**QED:** Ligand A (0.791) has a good drug-likeness score, while Ligand B (0.382) is significantly lower, indicating a less favorable overall profile.

**DILI:** Ligand A (86.972) has a higher DILI risk than Ligand B (10.818). This is a significant concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 57.193, Ligand B: 58.666), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.711) has poor Caco-2 permeability, while Ligand B (-5.497) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.186) has poor aqueous solubility, while Ligand B (-1.573) is also poor, but better than Ligand A.

**hERG:** Ligand A (0.51) has a slightly elevated hERG risk, while Ligand B (0.191) has a very low risk.

**Microsomal Clearance:** Ligand A (33.826) has a moderate clearance, while Ligand B (-2.684) has a negative clearance, indicating excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (10.103) has a reasonable half-life, while Ligand B (-6.087) has a very long half-life, which is highly desirable.

**P-gp Efflux:** Ligand A (0.314) has low P-gp efflux, while Ligand B (0.013) has very low P-gp efflux.

**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 for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor solubility, poor permeability, a high DILI risk, and moderate metabolic clearance. Ligand B, while having a very weak binding affinity, exhibits excellent metabolic stability, low hERG risk, low P-gp efflux, and a slightly better solubility and permeability profile.

Despite the significant affinity difference, the poor ADME properties of Ligand A, particularly the high DILI risk, make it a less viable candidate. The weak binding of Ligand B could potentially be improved through further optimization, while mitigating the ADME issues of Ligand A would be much more challenging.

Output:
1
2025-04-17 12:10:23,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.833 Da) and Ligand B (339.395 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (99.88) is slightly higher than Ligand B (83.38), but both are good.

**logP:** Ligand A (1.615) is within the optimal range (1-3). Ligand B (3.385) is at the higher end of the optimal range, potentially increasing off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, which are within the acceptable limits for balancing solubility and permeability.

**QED:** Both ligands have QED values above 0.5 (0.688 and 0.845 respectively), indicating good drug-like properties.

**DILI:** Ligand A (51.221) has a lower DILI risk than Ligand B (76.076), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.388) has a better BBB score than Ligand B (59.364), but this is not a primary concern.

**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 absolute difference is important. Ligand A (-4.884) is slightly better than Ligand B (-4.679).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.463) is slightly better than Ligand B (-4.427).

**hERG Inhibition:** Ligand A (0.153) has a significantly lower hERG risk than Ligand B (0.815). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (31.896) has a lower microsomal clearance than Ligand B (72.853), indicating better metabolic stability. This is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-17.797) has a negative half-life, which is problematic. Ligand B (17.898) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.139 and 0.249 respectively).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). The difference is 0.8 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a better binding affinity and a more reasonable in vitro half-life. However, Ligand A demonstrates superior safety profiles with lower DILI and hERG risk, and better metabolic stability. The slightly better binding affinity of Ligand B might be offset by its poorer ADME properties, particularly the higher DILI and hERG risks. Considering the enzyme-specific priorities, metabolic stability and safety are paramount.

Output:
0
2025-04-17 12:10:23,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.455 and 343.347 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.01) is significantly better than Ligand B (115.96). A TPSA under 140 is good for oral absorption, but Ligand B's value is quite high, potentially hindering absorption.

**logP:** Ligand A (2.796) is optimal, while Ligand B (0.773) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to 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 (0.786 and 0.661), indicating good drug-like properties.

**DILI:** Ligand A (25.94) has a much lower DILI risk than Ligand B (94.184), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.831) has better BBB penetration than Ligand B (63.086), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.515) is better than Ligand B (-5.221), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.545) is better than Ligand B (-2.7), indicating better solubility.

**hERG Inhibition:** Ligand A (0.829) has a lower hERG risk than Ligand B (0.276), which is a critical safety consideration.

**Microsomal Clearance:** Ligand A (2.678) has significantly lower microsomal clearance than Ligand B (46.571), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.486) has a better in vitro half-life than Ligand B (59.986).

**P-gp Efflux:** Ligand A (0.403) has lower P-gp efflux than Ligand B (0.056), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Conclusion:**

Ligand A is significantly superior to Ligand B based on a comprehensive assessment of ADME-Tox properties. While both have excellent binding affinity, Ligand A demonstrates substantially lower DILI risk, better solubility, permeability, metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. Ligand B's high TPSA and DILI risk are major drawbacks.

Output:
0
2025-04-17 12:10:23,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (371.453 Da) is still well within the acceptable range.

**TPSA:** Ligand A (92.77) is slightly above the preferred <140, but still reasonable. Ligand B (62.3) is excellent, suggesting good absorption.

**logP:** Ligand A (-0.721) is a bit low, potentially hindering membrane permeability. Ligand B (2.998) is near optimal.

**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 (A: 0.751, B: 0.888), indicating drug-like properties.

**DILI:** Ligand A (25.165) has a very low DILI risk, which is excellent. Ligand B (46.142) is still relatively low, but higher than A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (90.074) has a higher BBB percentile than A (35.595), but this is less critical here.

**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 hard to interpret.

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

**hERG Inhibition:** Ligand A (0.36) has a very low hERG risk, which is highly desirable. Ligand B (0.533) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-5.023) has a negative clearance, which is impossible. This is likely an error in the data. Ligand B (4.654) has a moderate clearance, which is less ideal but not a major red flag.

**In vitro Half-Life:** Ligand A (0.602) has a very short half-life, which is a significant drawback. Ligand B (-1.641) has a negative half-life, which is impossible and likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.008, B: 0.193), which is good.

**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 of the ADME concerns.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the primary driver here is binding affinity. Ligand B has a much stronger affinity for SRC. While Ligand A has a better DILI profile and hERG risk, the negative clearance and half-life values are concerning. Ligand B's affinity advantage is substantial and, assuming the negative values are data errors, makes it the more promising candidate.

Output:
1
2025-04-17 12:10:23,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.471 and 340.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (2.991 and 2.085), 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 below the limit of <=10.

**6. QED:** Ligand B (0.893) has a significantly higher QED score than Ligand A (0.574), indicating a more drug-like profile.

**7. DILI:** Ligand B (57.697) has a lower DILI risk than Ligand A (17.371), which is a significant advantage. Both are below the 60 threshold.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (70.88) is slightly better than Ligand B (67.274). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. This suggests poor permeability. Ligand A (-4.44) is slightly worse than Ligand B (-4.697).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-4.119) is slightly better than Ligand B (-3.219).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.491 and 0.373), which is good.

**12. Microsomal Clearance:** Ligand B (27.305) has significantly lower microsomal clearance than Ligand A (69.654), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-5.013) has a longer in vitro half-life than Ligand A (4.198), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.172 and 0.08), which is favorable.

**15. Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.5 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 the superior candidate. It demonstrates a better drug-like profile (higher QED), lower DILI risk, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both ligands have issues with Caco-2 permeability and solubility, the metabolic stability advantage of Ligand B is particularly important for a kinase inhibitor.

Output:
1
2025-04-17 12:10:23,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.503 and 348.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (69.64 and 71.78) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.351 and 2.594) 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:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.693 and 0.888), indicating drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 8.569%, which is excellent (low risk). Ligand B has a DILI risk of 25.165%, still good, but higher than Ligand A.

**8. BBB:** Both ligands have relatively low BBB penetration (57.154% and 70.919%). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.682 and -4.643). 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 negative solubility values (-2.015 and -2.317). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.394 and 0.278).

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (44.308) than Ligand B (11.377). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-14.192), which is not physically possible. Ligand B has a half-life of 25.993 hours. This is a significant advantage for Ligand B. The negative value for Ligand A is a major red flag.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.07 and 0.066).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.1 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. The primary reasons are its significantly better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable DILI score. The negative half-life for Ligand A is a critical issue, indicating a potential problem with the data or a highly unstable molecule. While both have poor solubility and permeability, the metabolic advantage of Ligand B outweighs this concern, especially for an enzyme target where maintaining therapeutic concentrations is crucial.

Output:
1
2025-04-17 12:10:23,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.455 and 348.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is slightly higher than the ideal <140, but acceptable. Ligand B (58.64) is well within the acceptable range.

**logP:** Both ligands (2.069 and 1.761) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both below the threshold of 5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both below the threshold of 10.

**QED:** Both ligands have good QED scores (0.709 and 0.729), indicating good drug-like properties.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (28.189). This is a significant drawback for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (78.519) is better than Ligand A (61.07). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.94 and -4.43), 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 (-3.067 and -2.863), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.28) has a slightly higher hERG risk than Ligand B (0.698), but both are relatively low.

**Microsomal Clearance:** Ligand B (64.865) has significantly lower microsomal clearance than Ligand A (8.936), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-7.443) has a longer in vitro half-life than Ligand A (-12.743), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.015) has slightly lower P-gp efflux than Ligand B (0.113), which is a minor advantage.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This 1.8 kcal/mol difference is substantial and outweighs many of the minor drawbacks of Ligand B.

**Conclusion:**

Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) are critical advantages. While both ligands have poor solubility and permeability, these issues can potentially be addressed through formulation. The lower DILI risk and better metabolic profile of Ligand B make it a more promising starting point for further optimization.

Output:
1
2025-04-17 12:10:23,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (366.49 and 362.54 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.32) is better than Ligand B (49.41). While both are acceptable, lower TPSA generally favors better cell permeability.

**3. logP:** Ligand A (1.35) is optimal, while Ligand B (4.522) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**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 (5) and Ligand B (3) are both good, well below the threshold of 10.

**6. QED:** Ligand A (0.821) is significantly better than Ligand B (0.518), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.77) is higher than Ligand B (32.96), indicating a slightly higher, but still acceptable, risk of drug-induced liver injury.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.29) has a higher BBB percentile, but this isn't a major factor here.

**9. Caco-2 Permeability:** Ligand A (-5.202) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-4.9) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-3.345) and Ligand B (-3.701) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.213) is much better than Ligand B (0.707), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (24.91) is significantly better than Ligand B (73.63), suggesting much greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.378) is much better than Ligand B (34.487), indicating a longer half-life.

**14. P-gp Efflux:** Ligand A (0.078) is better than Ligand B (0.658), suggesting lower P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.3), a difference of 0.9 kcal/mol.

**Overall Assessment:**

Despite Ligand B having a slightly better binding affinity, Ligand A is the stronger candidate. The significantly better QED, lower DILI, much better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and lower P-gp efflux outweigh the small difference in binding affinity. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. Ligand B's high logP and higher DILI risk are less desirable.

Output:
0
2025-04-17 12:10:23,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.483 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.73) is better than Ligand B (73.64), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.67 and 2.094), falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.724 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (48.623) has a higher DILI risk than Ligand B (22.722). This is a significant drawback for Ligand A.

**BBB:** Ligand A (81.698) has better BBB penetration than Ligand B (63.474), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.738) has slightly better Caco-2 permeability than Ligand B (-4.322), but both are negative, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-2.458) has slightly better solubility than Ligand B (-1.478), but both are negative, suggesting poor solubility.

**hERG:** Both ligands have similar hERG inhibition liability (0.301 and 0.437), which is relatively low risk.

**Microsomal Clearance:** Ligand A (70.887) has higher microsomal clearance than Ligand B (27.43), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand B (-9.94) has a longer in vitro half-life than Ligand A (-12.74), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.282 and 0.021).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.5 kcal/mol). The difference is minimal.

**Conclusion:**

Ligand B is the more promising candidate. While both have good potency, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. Although Ligand A has slightly better Caco-2 and solubility, the metabolic and toxicity profiles of Ligand B are more favorable for development as an enzyme inhibitor.

Output:
1
2025-04-17 12:10:23,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.789 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (75.52) is significantly better than Ligand A (117.67). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.812, Ligand B: 3.444), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but is still acceptable.

**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 reasonable QED scores (Ligand A: 0.724, Ligand B: 0.629), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Both ligands have relatively high DILI risk, but Ligand B (69.135) is slightly better than Ligand A (73.517). Lower is better.

**BBB:** Ligand A (57.736) has a better BBB percentile than Ligand B (41.799), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.307) is slightly better than Ligand B (-5.766).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-3.367) is slightly better than Ligand B (-3.847).

**hERG Inhibition:** Ligand A (0.162) has a much lower hERG inhibition liability than Ligand B (0.46). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (31.646) has lower microsomal clearance than Ligand A (18.028), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (30.424 hours) has a significantly longer in vitro half-life than Ligand A (69.821 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.035) has lower P-gp efflux liability than Ligand B (0.359), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This difference is significant, as a 0.3 kcal/mol advantage can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and lower hERG risk and P-gp efflux. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better DILI profile. The poor Caco-2 and solubility for both are concerning, but the affinity advantage of Ligand A, coupled with the lower hERG risk, makes it the more promising candidate. The slightly better metabolic stability of Ligand B is valuable, but the affinity difference is more critical for an enzyme inhibitor.

Output:
0
2025-04-17 12:10:23,952 - INFO - Batch 108 complete. Total preferences: 1728
2025-04-17 12:10:23,952 - INFO - Processing batch 109/512...
2025-04-17 12:11:13,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.349 and 346.347 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is well below the 140 threshold and favorable for oral absorption. Ligand B (136.47) is approaching the upper limit, but still acceptable.

**logP:** Ligand A (2.491) is within the optimal 1-3 range. Ligand B (-0.524) is below 1, which could hinder permeation.

**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 8. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.581 and 0.545), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (68.244 and 68.786), placing them in a moderate risk category. This isn't a major differentiating factor.

**BBB:** Both ligands have similar BBB penetration (63.203 and 69.523), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.972) and Ligand B (-5.498) both have negative Caco-2 values. This is unusual and suggests poor permeability. However, these values are on a log scale, so the difference isn't huge.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.944 and -2.416). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.335) has a lower hERG risk than Ligand B (0.126), which is preferable.

**Microsomal Clearance:** Ligand A (58.803) has a higher microsomal clearance than Ligand B (5.596), indicating lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand A (29.802) has a longer half-life than Ligand B (-39.442). The negative value for Ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.26 and 0.006).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-10.0 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. The significantly stronger binding affinity (-7.6 vs -10.0 kcal/mol) outweighs the slightly higher microsomal clearance. The lower hERG risk is also a positive factor. Ligand B's extremely short in vitro half-life is a major drawback, even with its better metabolic stability. While both have solubility issues, improving solubility is often easier than significantly improving potency.

Output:
0
2025-04-17 12:11:13,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.363 Da) and Ligand B (349.387 Da) are both acceptable.

**TPSA:** Ligand A (63.25) is well below the 140 threshold, indicating good absorption potential. Ligand B (97.92) is still below 140, but closer to the upper limit, potentially indicating slightly reduced absorption.

**logP:** Ligand A (4.052) is at the higher end of the optimal range, potentially leading to solubility issues or off-target effects. Ligand B (-0.07) is significantly below the optimal range and may have poor membrane permeability.

**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 reasonable QED scores (A: 0.716, B: 0.569), suggesting good drug-like properties.

**DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (55.758). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.519) is slightly higher than Ligand B (52.268).

**Caco-2 Permeability:** Ligand A (-4.974) and Ligand B (-5.557) both have negative Caco-2 values which is unusual. This suggests very poor permeability.

**Aqueous Solubility:** Ligand A (-4.793) and Ligand B (-1.372) both have negative solubility values which is also unusual. This suggests very poor solubility.

**hERG:** Ligand A (0.527) has a lower hERG risk than Ligand B (0.113), which is a significant advantage.

**Microsomal Clearance:** Ligand A (85.808) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (-0.126) which is excellent.

**In vitro Half-Life:** Ligand A (2.67) has a shorter half-life than Ligand B (-19.07), which is excellent.

**P-gp Efflux:** Ligand A (0.219) has lower P-gp efflux than Ligand B (0.01), which is a slight advantage.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B exhibits a significantly better binding affinity, excellent metabolic stability, and a lower DILI risk. While its logP is low, the strong binding affinity is a major advantage for an enzyme target like SRC. Ligand A has a better hERG profile, but suffers from poorer metabolic stability, a higher DILI risk, and a weaker binding affinity. The negative solubility and Caco-2 values for both are concerning and would require further investigation, but the superior potency of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 12:11:13,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.353 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is well below the 140 threshold for good absorption, and even below 90, which is good. Ligand B (99.18) is still under 140, but closer to the limit.

**logP:** Ligand A (1.604) is optimal. Ligand B (0.343) is a bit low and could potentially hinder 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, and Ligand B has 5, both within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.5 (0.79 and 0.654), indicating good drug-likeness.

**DILI:** Ligand A (54.556) has a moderate DILI risk, while Ligand B (18.418) has a very low DILI risk, which is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, suggesting poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. This is also concerning.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.252 and 0.155), which is excellent.

**Microsomal Clearance:** Ligand A (7.101) has a moderate clearance, while Ligand B (-6.779) has a negative clearance, indicating very high metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-1.362) has a negative half-life, which is unusual and suggests rapid metabolism. Ligand B (-27.834) also has a negative half-life, but is even more negative, suggesting extremely slow metabolism.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.005).

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

**Conclusion:**

While both ligands have excellent binding affinity and low hERG risk, Ligand B is the better candidate. It has a significantly lower DILI risk and dramatically improved metabolic stability (negative Cl_mic and t1/2). Although both have poor Caco-2 and solubility, the metabolic advantage of Ligand B is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:11:13,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.901 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (88.32 and 87.74) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.888) is optimal, while Ligand B (1.03) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 2 HBDs, 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:** Both ligands have good QED scores (0.595 and 0.75), indicating good drug-like properties.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (18.651). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (75.145) is better than Ligand A (66.731). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.166 and -4.889), 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 (-3.731 and -2.821), which is also unusual. This suggests poor aqueous solubility which could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.705) has a slightly higher hERG risk than Ligand B (0.207). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand B (2.98 mL/min/kg) has significantly lower microsomal clearance than Ligand A (49.566 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-16.167 hours) has a negative half-life which is unusual. Ligand A (14.332 hours) is more reasonable.

**P-gp Efflux:** Ligand A (0.453) has lower P-gp efflux than Ligand B (0.027), which is preferable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are good, the 0.8 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have unusual solubility and permeability data, Ligand B demonstrates superior metabolic stability (lower Cl_mic), lower DILI risk, better hERG profile, and slightly better binding affinity. The lower logP of Ligand B is a minor concern, but the other advantages outweigh this drawback. The negative half-life for Ligand B is concerning and needs further investigation, but the other factors are more important.

Output:
1
2025-04-17 12:11:13,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 360.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.41) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (104.02) is well within the range.

**logP:** Ligand A (-0.252) is a bit low, potentially hindering permeability. Ligand B (0.613) is better, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 6 HBA) is better than Ligand B (3 HBD, 10 HBA). Ligand B has a higher number of HBA, which could impact permeability.

**QED:** Both ligands have reasonable QED scores (0.275 and 0.563), with Ligand B being better.

**DILI:** Ligand A (65.995) has a moderate DILI risk, while Ligand B (83.753) has a higher risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (32.416) has a higher BBB score than Ligand A (15.471), but it's not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.758 and -5.587), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.832 and -2.463), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.077) has a very low hERG risk, which is excellent. Ligand B (0.471) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (27.453) has a moderate clearance, while Ligand B (20.261) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (53.795) has a significantly longer half-life than Ligand A (-16.344), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.006).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate despite its higher DILI risk and poor solubility. Its significantly stronger binding affinity (-8.3 vs -7.3 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The longer half-life (53.795 vs -16.344) is also a significant benefit. While both have poor Caco-2 and solubility, the potency and stability advantages of Ligand B are more critical for initial optimization. The DILI risk can be addressed through structural modifications. The low logP of Ligand A is a more difficult property to improve without sacrificing affinity.

Output:
1
2025-04-17 12:11:13,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.427 and 360.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is better than Ligand B (55.57), being below the 140 threshold for good absorption.

**logP:** Ligand A (1.633) is optimal, while Ligand B (3.769) is approaching the upper limit of the optimal range.

**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 (0.556 and 0.736, respectively), indicating drug-likeness.

**DILI:** Both ligands have similar DILI risk (50.136 and 58.744), both being acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Both are around 50-55%.

**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. Again, the scale is not defined.

**hERG Inhibition:** Ligand A (0.066) has a much lower hERG inhibition liability than Ligand B (0.416), a significant advantage.

**Microsomal Clearance:** Ligand A (20.521) has significantly lower microsomal clearance than Ligand B (70.68), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.858) has a negative half-life, which is strange. Ligand B (30.707) is positive and suggests a longer half-life.

**P-gp Efflux:** Ligand A (0.033) has lower P-gp efflux liability than Ligand B (0.299), which is beneficial.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.2 and -7.0 kcal/mol), with Ligand A being slightly better.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have similar affinities, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower hERG 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 outweigh these issues, especially given the importance of metabolic stability and safety (hERG) for kinase inhibitors.

Output:
1
2025-04-17 12:11:13,498 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [364.389, 104.73 ,   0.457,   3.   ,   5.   ,   0.569,  36.448,  67.197, -4.938,  -2.17 ,   0.279,  44.89 , -53.462,   0.025,  -8.4  ]
**Ligand B:** [355.494,  46.61 ,   3.835,   0.   ,   3.   ,   0.56 ,  15.665,  95.308, -3.973,  -4.798,   0.849, 123.486,  -6.738,   0.348,  -7.3  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (364.389) is slightly higher than B (355.494), but both are acceptable.
2. **TPSA:** A (104.73) is higher than B (46.61). While A is still within a reasonable range for oral absorption (<=140), B's lower TPSA is preferable.
3. **logP:** A (0.457) is quite low, potentially hindering permeability. B (3.835) is excellent, falling within the optimal 1-3 range. This is a significant advantage for B.
4. **HBD:** A (3) is acceptable, B (0) is even better, minimizing potential for off-target interactions and improving permeability.
5. **HBA:** Both A (5) and B (3) are within the acceptable limit of <=10.
6. **QED:** Both A (0.569) and B (0.56) are good, indicating drug-like properties.
7. **DILI:** A (36.448) is better than B (15.665), indicating lower liver injury risk.
8. **BBB:** A (67.197) is lower than B (95.308). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.
9. **Caco-2:** A (-4.938) is very poor, indicating very low intestinal absorption. B (-3.973) is also poor, but slightly better than A.
10. **Solubility:** A (-2.17) is poor, while B (-4.798) is even worse. Both are problematic, but B is worse.
11. **hERG:** A (0.279) is very low risk, while B (0.849) is slightly higher. A is preferable here.
12. **Cl_mic:** A (44.89) is better than B (123.486), indicating better metabolic stability. This is a critical factor for kinase inhibitors.
13. **t1/2:** A (-53.462) is very poor, suggesting rapid clearance. B (-6.738) is better, but still not ideal.
14. **Pgp:** A (0.025) is very low efflux, while B (0.348) is slightly higher. A is preferable.
15. **Affinity:** A (-8.4) is significantly better than B (-7.3), a difference of 1.1 kcal/mol. This is a substantial advantage for A.

**Prioritization for Kinase Inhibitors:**

For enzyme targets like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

While Ligand A has a significantly better binding affinity (-8.4 kcal/mol vs -7.3 kcal/mol), its poor Caco-2 permeability, solubility, and in vitro half-life are major drawbacks. Ligand B has better logP, TPSA, and lower DILI risk, but its affinity is weaker. The difference in affinity is substantial (1.1 kcal/mol), and for a kinase inhibitor, potency is paramount. However, the poor ADME properties of A are likely to severely limit its *in vivo* efficacy. The metabolic stability of A is also better than B.

Considering the balance, the superior binding affinity of A, coupled with its better metabolic stability and lower hERG risk, outweighs its ADME deficiencies *if* formulation strategies can be employed to address the solubility and permeability issues.

1
2025-04-17 12:11:13,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.381 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (42.54) is significantly better than Ligand B (55.84). Lower TPSA generally correlates with better cell permeability, crucial for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have good logP values (A: 3.394, B: 3.747), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0) and HBA (A: 4, B: 5) counts, unlikely to cause significant issues.

**QED:** Both have good QED scores (A: 0.687, B: 0.7), indicating drug-like properties.

**DILI:** Ligand A (55.138) has a lower DILI risk than Ligand B (69.794), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (90.617) has better BBB penetration than Ligand B (70.027).

**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 for both, but Ligand B (-5.472) is worse than Ligand A (-3.462).

**hERG Inhibition:** Ligand A (0.87) has a much lower hERG inhibition liability than Ligand B (0.262), a critical safety parameter.

**Microsomal Clearance:** Ligand B (97.859) has a significantly higher microsomal clearance than Ligand A (63.982), indicating poorer metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (21.527 hours) has a much longer half-life than Ligand B (-13.328 hours), which is highly desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.878, B: 0.264), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 kcal/mol and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** It has better TPSA, lower DILI risk, significantly lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and better aqueous solubility. While both have poor Caco-2 permeability and solubility, A is better on these metrics. The binding affinity is comparable, so the improved ADME/Tox profile of Ligand A outweighs any minor differences in potency.

Output:
0
2025-04-17 12:11:13,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.367 and 362.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (131.06) is slightly above the preferred <140, but acceptable. Ligand B (82.61) is excellent, well below 140.

**logP:** Ligand A (-1.861) is a bit low, potentially hindering permeability. Ligand B (0.651) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 9 HBA) is acceptable. Ligand B (1 HBD, 5 HBA) is also good.

**QED:** Both ligands have good QED scores (0.6 and 0.837 respectively), indicating drug-likeness.

**DILI:** Ligand A (66.654) has a moderate DILI risk. Ligand B (47.732) has a lower, more favorable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (58.938) has a higher BBB score than Ligand A (21.946), but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.643 and -5.06), 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 (-1.064 and -1.737), indicating poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.023) has a very low hERG risk, which is excellent. Ligand B (0.154) also shows low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-2.864) has a lower (better) microsomal clearance than Ligand B (-3.688), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.968 hours) has a significantly longer half-life than Ligand B (-0.329 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.039 respectively).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.0 kcal/mol). This difference of 2.7 kcal/mol is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's excellent hERG profile and longer half-life, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.7 vs -7.0 kcal/mol) is a critical advantage for an enzyme inhibitor. While both have solubility issues, the better logP and lower DILI risk of Ligand B, coupled with its superior potency, make it the preferred choice. The negative Caco-2 and solubility values would require further investigation and potential formulation strategies, but the potency advantage is substantial.

Output:
1
2025-04-17 12:11:13,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is slightly higher than the preferred <140, but acceptable. Ligand B (49.41) is excellent, well below 140.

**logP:** Ligand A (1.785) is optimal (1-3). Ligand B (3.066) is also within the optimal range, but closer to the upper limit.

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

**H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.781 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (31.136) has a lower DILI risk than Ligand B (14.889), both are good.

**BBB:** Ligand A (55.874) has a lower BBB penetration than Ligand B (94.843). This is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.858) has worse Caco-2 permeability than Ligand B (-4.5). Both are negative, but B is better.

**Aqueous Solubility:** Ligand A (-1.682) has better aqueous solubility than Ligand B (-3.504). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.38) has a lower hERG inhibition liability than Ligand B (0.603). This is a significant advantage, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (26.439) has lower microsomal clearance than Ligand B (34.8), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.768) has a longer in vitro half-life than Ligand B (-17.793). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.15 and 0.156).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has a better TPSA and BBB, Ligand A excels in critical areas for kinase inhibitors: significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better aqueous solubility. The slightly higher TPSA of Ligand A is not a major concern. The superior binding affinity of Ligand A is a decisive factor.

Output:
1
2025-04-17 12:11:13,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.348 Da and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is higher than Ligand B (49.41). Both are acceptable, but Ligand B is better, being closer to the optimal <140 for oral absorption.

**logP:** Both ligands have similar logP values (3.566 and 3.666), 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). Ligand B is slightly more favorable.

**QED:** Ligand A (0.803) has a significantly better QED score than Ligand B (0.538), indicating a more drug-like profile.

**DILI:** Ligand A (62.001) has a higher DILI risk than Ligand B (10.198). This is a significant drawback for Ligand A.

**BBB:** Ligand A (70.027) and Ligand B (93.757) both have good BBB penetration, but Ligand B is better. This isn't a primary concern for a kinase inhibitor, but can be a bonus.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.596 and -4.883), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.287 and -3.95). This is also a concern for both, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.641 and 0.689), which is good.

**Microsomal Clearance:** Ligand A (70.267) has a higher microsomal clearance than Ligand B (54.556), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (-3.649) has a longer in vitro half-life than Ligand A (2.392), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.141 and 0.173), which is favorable.

**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, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a better QED score, Ligand B is superior overall. The most important factors are the significantly stronger binding affinity of Ligand B and its much lower DILI risk. Ligand B also exhibits better metabolic stability (lower Cl_mic, longer t1/2) and better Caco-2/solubility profiles (though both are poor). The negative Caco-2 and solubility values are concerning for both, but the potency advantage of Ligand B is substantial enough to make it the more promising candidate.

Output:
1
2025-04-17 12:11:13,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 346.406 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.78) is significantly better than Ligand B (80.36). A TPSA under 140 is good for oral absorption, and both are under, but A is preferable.

**logP:** Both ligands have good logP values (1.774 and 2.12), falling within the optimal 1-3 range.

**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 (0.817 and 0.786), indicating good drug-like properties.

**DILI:** Ligand A (37.185) has a much lower DILI risk than Ligand B (59.984).  This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (74.758) is better than Ligand B (68.67). While not a primary concern for a non-CNS target like SRC, it's a slight positive for A.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the absolute value is smaller for Ligand A (-4.308) than for Ligand B (-4.881), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.686) is slightly better than Ligand B (-2.636). Solubility is a key concern for kinase inhibitors, and both need improvement, but A is better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.49 and 0.585), which is good.

**Microsomal Clearance:** Ligand A (33.15) has a lower microsomal clearance than Ligand B (29.986), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (29.036) has a significantly longer in vitro half-life than Ligand A (11.233). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.273 and 0.096), which is favorable.

**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 small (0.3 kcal/mol), it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in DILI risk, TPSA, and metabolic stability (Cl_mic). Ligand B has a longer half-life and slightly better binding affinity. Solubility is a concern for both, but A is slightly better. Considering the priorities for enzyme inhibitors, metabolic stability and low toxicity (DILI) are crucial. The better DILI profile and metabolic stability of Ligand A, combined with its slightly better solubility, outweigh the small advantage in binding affinity and half-life of Ligand B.

Output:
0
2025-04-17 12:11:13,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (385.251 and 348.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (96.26 and 89.07) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (3.63) is slightly higher than Ligand B (2.303), 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.701) has a better QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand B (57.425) has a significantly lower DILI risk than Ligand A (85.227), which is a major advantage.

**BBB:** Both ligands have relatively low BBB penetration (61.846 and 57.193), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.822 and -5.425), which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.097 and -2.159). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.159) has a slightly lower hERG risk than Ligand B (0.198), which is preferable.

**Microsomal Clearance:** Ligand B (31.024 mL/min/kg) has a lower microsomal clearance than Ligand A (33.7 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (12.452 hours) has a significantly longer half-life than Ligand A (58.096 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.105).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a much stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most critical factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand B is the superior candidate due to its significantly stronger binding affinity (-8.2 vs 0 kcal/mol), lower DILI risk (57.425 vs 85.227), and longer half-life (12.452 vs 58.096 hours). While Ligand A has a slightly better QED and lower hERG risk, the affinity difference is too large to ignore. The poor solubility and permeability would need to be addressed through formulation strategies, but a strong starting point with high potency is crucial.

Output:
1
2025-04-17 12:11:13,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (346.431 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is better than Ligand B (67.6) as it is still within the acceptable range for oral absorption, while Ligand B is significantly lower, potentially indicating better absorption.

**logP:** Both ligands have good logP values (1.377 and 2.478), 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.778 and 0.817), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (54.75 and 52.423 percentile), below the 60 threshold.

**BBB:** Ligand A (74.835) has a better BBB penetration score than Ligand B (49.942). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.1 and -5.096), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.003 and -4.151), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.168) has a significantly lower hERG inhibition risk than Ligand B (0.42). This is a substantial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (29.364 mL/min/kg) has a lower microsomal clearance than Ligand B (61.544 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (6.004 hours) has a shorter half-life than Ligand B (9.163 hours). While longer is generally preferred, the difference isn't drastic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.014 and 0.192), which is favorable.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference of 0.6 kcal/mol is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower hERG risk, and a slightly better BBB score. The binding affinity difference is not large enough to favor Ligand B, especially considering the other advantages of Ligand A. The poor solubility and permeability are critical issues that would need to be addressed through formulation or further chemical modification, but Ligand A provides a better starting point.

Output:
0
2025-04-17 12:11:13,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (447.164 Da) is higher, but still acceptable. Ligand B (352.36 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (73.91) is higher than Ligand B (49.42). Both are below 140, suggesting reasonable absorption, but Ligand B is better.

**logP:** Ligand A (4.272) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.529) is optimal.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.739, B: 0.81), indicating drug-like properties.

**DILI:** Ligand A (63.125) has a higher DILI risk than Ligand B (71.384), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.661) is higher than Ligand B (71.656).

**Caco-2 Permeability:** Ligand A (-5.269) has a worse Caco-2 permeability than Ligand B (-4.585).

**Aqueous Solubility:** Ligand A (-4.494) has worse solubility than Ligand B (-2.985).

**hERG:** Ligand A (0.655) has a slightly higher hERG risk than Ligand B (0.838), but both are acceptable.

**Microsomal Clearance:** Ligand A (17.767) has a higher microsomal clearance than Ligand B (16.53), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (8.26) has a longer half-life than Ligand B (-0.528).

**P-gp Efflux:** Ligand A (0.471) has lower P-gp efflux than Ligand B (0.119), which is favorable.

**Binding Affinity:** This is the most crucial factor. Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol) - a difference of 0.5 kcal/mol. This difference is substantial enough to outweigh some of the ADME drawbacks of Ligand A.

**Conclusion:**

While Ligand A has a longer half-life and lower P-gp efflux, Ligand B demonstrates superior binding affinity, better logP, TPSA, solubility, and Caco-2 permeability. The stronger binding affinity of Ligand B is a significant advantage for an enzyme inhibitor, and its ADME properties are still within acceptable ranges. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:11:13,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (342.4 & 352.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.94) is better than Ligand B (59.08), both are below the 140 threshold for oral absorption.

**3. logP:** Ligand B (1.844) is optimal (1-3), while Ligand A (0.222) is quite low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (A: 2, B: 0).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (A: 5, B: 4).

**6. QED:** Both ligands have good QED scores (A: 0.782, B: 0.732), indicating drug-like properties.

**7. DILI:** Ligand B (34.24) has a significantly lower DILI risk than Ligand A (47.15), placing it in a more favorable category.

**8. BBB:** Ligand B (77.05) shows better BBB penetration than Ligand A (44.59), though this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.044) has a worse Caco-2 permeability than Ligand B (-4.183).

**10. Aqueous Solubility:** Ligand A (-1.401) has slightly better aqueous solubility than Ligand B (-1.272).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.246, B: 0.478).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-10.696) has significantly lower microsomal clearance than Ligand B (69.313), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.356) has a longer in vitro half-life than Ligand A (-7.475).

**14. P-gp Efflux:** Ligand A (0.02) has much lower P-gp efflux than Ligand B (0.143), which is favorable for bioavailability.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -9.7 kcal/mol, B: -8.6 kcal/mol). Ligand A has a 1.1 kcal/mol advantage, which is substantial.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic) and P-gp efflux. However, its low logP is a major concern for permeability. Ligand B has better permeability characteristics (logP, Caco-2), lower DILI risk, and a longer half-life, but its affinity is lower and Cl_mic is higher.

The 1.1 kcal/mol difference in binding affinity is significant. Given that SRC is an enzyme, the potency advantage of Ligand A, coupled with its better metabolic stability, likely outweighs the permeability concerns, especially considering optimization strategies could be employed to improve its logP.

Output:
0
2025-04-17 12:11:13,500 - INFO - Batch 109 complete. Total preferences: 1744
2025-04-17 12:11:13,500 - INFO - Processing batch 110/512...
2025-04-17 12:11:59,580 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**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,  -8.9  ]
**Ligand B:** [345.443,  73.74 ,   1.553,   1.   ,   4.   ,   0.899,  11.322,  70.027, -4.507,  -1.015,   0.44 ,   0.864, -10.24 ,   0.029,  -8.9  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (349.391) and B (345.443) are very similar.
2. **TPSA:** Ligand A (108.77) is higher than the preferred <140 for oral absorption, but still reasonable. Ligand B (73.74) is excellent, well below 140 and suggesting good absorption.
3. **logP:** Both ligands have good logP values (A: 1.393, B: 1.553), falling within the optimal 1-3 range.
4. **HBD:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential issues with permeability.
5. **HBA:** Ligand A (6) is acceptable, while Ligand B (4) is even better.
6. **QED:** Ligand B (0.899) has a significantly better QED score than Ligand A (0.548), indicating a more drug-like profile.
7. **DILI:** Ligand B (11.322) has a much lower DILI risk than Ligand A (62.35), a major advantage.
8. **BBB:** Ligand B (70.027) has a better BBB penetration score than Ligand A (59.48), though neither are exceptionally high, this isn't a primary concern for a non-CNS target like SRC.
9. **Caco-2:** Ligand A (-5.093) and Ligand B (-4.507) are both negative, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret.
10. **Solubility:** Ligand B (-1.015) has better solubility than Ligand A (-2.802).
11. **hERG:** Both ligands have very low hERG risk (A: 0.432, B: 0.44).
12. **Cl_mic:** Both ligands have similar, and good, microsomal clearance values (A: -10.01, B: -10.24) indicating good metabolic stability.
13. **t1/2:** Both ligands have similar in vitro half-lives (A: 25.887, B: -10.24).
14. **Pgp:** Both ligands have very low Pgp efflux liability (A: 0.018, B: 0.029).
15. **Binding Affinity:** Both ligands have identical binding affinities (-8.9 kcal/mol), which is excellent.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Both ligands have excellent binding affinity and metabolic stability. However, Ligand B has significantly better solubility and a much lower DILI risk. While Caco-2 permeability appears poor for both, the other advantages of Ligand B outweigh this concern.

**Conclusion:**

Ligand B is the more promising drug candidate due to its superior QED, significantly lower DILI risk, better solubility, and better TPSA, while maintaining excellent binding affinity and metabolic stability.

Output:
1
2025-04-17 12:11:59,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.611 Da) is slightly higher, but acceptable. Ligand B (348.443 Da) is also good.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold. Ligand B (78.87) is still reasonable, but less optimal.

**3. logP:** Ligand A (4.584) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.48) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 2 HBDs, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBAs, while Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.538 and 0.503), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 88.91, which is high and concerning. Ligand B has a much lower DILI risk of 18.883, a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.843) and Ligand B (69.523) are both reasonable.

**9. Caco-2 Permeability:** Ligand A (-4.586) and Ligand B (-5.099) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-5.566) and Ligand B (-3.049) both have negative values, indicating poor solubility. Ligand B is better than A.

**11. hERG Inhibition:** Ligand A (0.543) is better than Ligand B (0.698) indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (39.656) has lower clearance, suggesting better metabolic stability. Ligand B (62.474) has higher clearance, a drawback.

**13. In vitro Half-Life:** Ligand A (103.897) has a significantly longer half-life than Ligand B (-13.781), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.551) has lower P-gp efflux, which is favorable. Ligand B (0.125) has very low P-gp efflux, which is even better.

**15. 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 of the 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, its high DILI risk and slightly elevated logP are major concerns. Ligand B has a much better safety profile (lower DILI) and better solubility, but weaker binding affinity and poorer metabolic stability.

Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity (-8.4 vs -7.3), Ligand A is the more promising candidate *despite* the DILI concern. Further medicinal chemistry efforts should focus on mitigating the DILI risk of Ligand A while preserving its high affinity.

Output:
1
2025-04-17 12:11:59,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.482 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold and favorable for oral absorption. Ligand B (75.19) is still within acceptable limits but less optimal.

**logP:** Both ligands (2.637 and 2.659) are 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 good QED scores (0.628 and 0.823), indicating drug-likeness.

**DILI:** Ligand A (11.439 percentile) has a significantly lower DILI risk than Ligand B (73.129 percentile). This is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (90.617) has a higher BBB penetration than Ligand B (79.139).

**Caco-2 Permeability:** Ligand A (-4.237) has a worse Caco-2 permeability than Ligand B (-5.272), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.722) has better aqueous solubility than Ligand B (-3.126). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.811) has a lower hERG inhibition risk than Ligand B (0.532), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (48.086 mL/min/kg) has a lower microsomal clearance than Ligand B (60.545 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.105 hours) has a longer half-life than Ligand B (2.698 hours), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.122), which could improve bioavailability.

**Binding Affinity:** Ligand B (-8.1 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 has a superior binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic, longer t1/2). The difference in binding affinity (0.9 kcal/mol) is significant, but the substantial improvements in ADME-Tox properties for Ligand A, particularly the DILI and hERG risk, are compelling. Considering SRC is an enzyme, prioritizing metabolic stability and safety is crucial. The slightly lower Caco-2 permeability of Ligand A is a concern, but could potentially be addressed with formulation strategies.

Output:
0
2025-04-17 12:11:59,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (370.848 and 363.498 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.6) is higher than Ligand B (29.54). Both are below 140, but B is significantly lower, suggesting potentially better absorption.

**3. logP:** Both ligands have good logP values (4.784 and 4.272), falling within the 1-3 optimal range, though slightly high.

**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 within the acceptable limit of 10.

**6. QED:** Both ligands have acceptable QED scores (0.715 and 0.678), indicating good drug-like properties.

**7. DILI:** Ligand A (40.054) and Ligand B (32.067) both have low DILI risk, below the 40 threshold. Ligand B is slightly better.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (88.445) is significantly higher than Ligand A (73.943). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.094 and -4.791), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-5.991 and -4.598). This is a major concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.278) has a slightly better hERG profile than Ligand B (0.859), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Both have similar microsomal clearance (107.237 and 107.941 mL/min/kg), indicating similar metabolic stability. This is not ideal, as lower clearance is preferred.

**13. In vitro Half-Life:** Ligand B (-8.2) has a significantly *longer* in vitro half-life than Ligand A (34.127). This is a major advantage for Ligand B, as it suggests less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.691), which is preferable.

**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, as a 1.3 kcal/mol difference is substantial and can outweigh other drawbacks.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -8.1 kcal/mol) and longer in vitro half-life are major advantages for an enzyme inhibitor. The slightly better DILI score and higher BBB penetration also contribute to its favorability. While Ligand A has a slightly better hERG profile and P-gp efflux, the potency and half-life advantages of Ligand B are more critical for kinase inhibitors.

Output:
1
2025-04-17 12:11:59,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.447 Da) is slightly higher than Ligand B (356.463 Da), but both are acceptable.

**TPSA:** Ligand A (126.65) is slightly above the optimal <140 for oral absorption, while Ligand B (87.15) is well within the range. This favors Ligand B.

**logP:** Ligand A (0.637) is a bit low, potentially hindering permeation. Ligand B (0.901) 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, 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 similar QED values (0.605 and 0.588), indicating reasonable drug-likeness.

**DILI:** Ligand A has a DILI risk of 64.831, which is concerning (high risk). Ligand B has a much lower DILI risk of 14.541, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (64.637 and 64.715), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**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. This suggests poor solubility, a potential issue for bioavailability.

**hERG:** Ligand A (0.301) has a slightly higher hERG risk than Ligand B (0.289), but both are relatively low.

**Microsomal Clearance:** Ligand A has a Cl_mic of 13.081 mL/min/kg, while Ligand B has a much higher Cl_mic of 94.213 mL/min/kg. Lower is better for metabolic stability, so Ligand A is favored here.

**In vitro Half-Life:** Ligand A has a negative half-life (-11.135 hours), which is impossible and indicates a problem with the data. Ligand B has a half-life of -36.403 hours, also impossible. This suggests issues with the experimental setup or data reporting.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.072, while Ligand B has 0.07. Both are very low, indicating minimal P-gp efflux.

**Binding Affinity:** Ligand A has a binding affinity of 0 kcal/mol, while Ligand B has a binding affinity of -8.3 kcal/mol. This is a *huge* difference. A binding affinity of -8.3 kcal/mol is excellent and significantly outweighs many of the other drawbacks.

**Conclusion:**

Despite some concerning solubility and permeability values (likely data errors), Ligand B is the far superior candidate. Its significantly stronger binding affinity (-8.3 kcal/mol vs 0 kcal/mol) is the most important factor for an enzyme inhibitor. Furthermore, it has a much lower DILI risk, which is crucial for drug development. The higher metabolic clearance of Ligand B is a concern, but the potency advantage is likely to outweigh this. The negative half-life values for both compounds are suspect and require further investigation, but the affinity difference is decisive.

Output:
1
2025-04-17 12:11:59,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (385.917 and 358.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (40.62). Both are below the 140 A^2 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (2.65 and 3.245), 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 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.674 and 0.827), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.568, which is moderately high. Ligand B has a lower DILI risk of 49.593, which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB score (87.127) than Ligand A (50.679), but this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are on a similar scale, so this doesn't strongly favor one ligand.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.316) has a slightly lower hERG inhibition risk than Ligand B (0.719), which is favorable.

**Microsomal Clearance:** Ligand A (37.898) has a higher microsomal clearance than Ligand B (32.962), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (4.15 hours) has a significantly shorter half-life than Ligand A (39.647 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.232) has lower P-gp efflux than Ligand B (0.436), 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 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, which are crucial for an enzyme inhibitor. While it has a higher DILI risk and lower solubility, the strong binding affinity (-8.9 kcal/mol) is a major advantage that could be addressed through further optimization. Ligand B has better ADME properties (lower DILI, lower clearance, better TPSA) but its significantly weaker binding affinity makes it less likely to be a viable drug candidate.

Output:
1
2025-04-17 12:11:59,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (377.535 Da and 364.72 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is significantly better than Ligand B (114.25).  A TPSA under 90 is preferable, and A is closer to that. B is quite high, potentially hindering absorption.

**logP:** Both ligands have good logP values (3.419 and 3.96), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable.

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

**QED:** Ligand A (0.75) has a much better QED score than Ligand B (0.344), indicating a more drug-like profile.

**DILI:** Ligand B (87.98) has a significantly higher DILI risk than Ligand A (69.872).  This is a major concern for B.

**BBB:** Both have reasonable BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.105) has a better Caco-2 permeability than Ligand B (-4.264).

**Aqueous Solubility:** Ligand A (-3.75) has better aqueous solubility than Ligand B (-5.325). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.491) has a lower hERG risk than Ligand B (0.253), which is preferable.

**Microsomal Clearance:** Ligand B (97.795) has a much higher microsomal clearance than Ligand A (53.22). This suggests Ligand B will be cleared more rapidly, reducing its duration of action.

**In vitro Half-Life:** Ligand A (7.073) has a better in vitro half-life than Ligand B (55.595).

**P-gp Efflux:** Ligand A (0.469) has lower P-gp efflux than Ligand B (0.416).

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-0.0). This is a critical factor.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, QED, solubility, hERG risk, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and binding affinity. While Ligand B has a slightly better logP, the significant drawbacks in DILI risk, metabolic stability, and QED outweigh this benefit. The substantial difference in binding affinity (-7.7 vs 0.0) is a decisive advantage for Ligand A.



Output:
1
2025-04-17 12:11:59,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.857 Da) is slightly higher, but acceptable. Ligand B (345.487 Da) is also good.

**TPSA:** Ligand A (116.07) is approaching the upper limit for good oral absorption (<=140), while Ligand B (63.13) is well within the acceptable range.

**logP:** Both ligands have good logP values (A: 1.974, B: 3.114), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=9) and Ligand B (HBD=2, 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 QED values (A: 0.664, B: 0.64), indicating good drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.806%), which is a major red flag. Ligand B has a much lower DILI risk (33.424%), which is significantly better.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (56.417%) shows slightly better BBB penetration than Ligand A (46.026%), but this isn't a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.908 and -4.85), which is unusual and suggests poor permeability. However, these values can be unreliable and are less critical than other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.759 and -3.06), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.265) shows a slightly lower hERG inhibition risk than Ligand B (0.478), which is preferable.

**Microsomal Clearance:** Ligand A (45.321) and Ligand B (49.508) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (110.316 hours) has a significantly longer in vitro half-life than Ligand B (48.791 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.433, B: 0.285), which is good.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's longer half-life and slightly lower hERG risk, the extremely high DILI risk (99.806%) is a critical issue. The significantly better DILI profile of Ligand B (33.424%), coupled with its superior binding affinity (-9.6 kcal/mol vs -8.5 kcal/mol), makes it the more promising candidate. While solubility and permeability are concerns for both, these are more readily addressable than a high risk of liver injury.

Output:
1
2025-04-17 12:11:59,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.387 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (90.98). Lower TPSA generally correlates with better cell permeability, a crucial factor for kinase inhibitors.

**logP:** Ligand A (4.368) is higher than the optimal range (1-3), but still potentially acceptable. Ligand B (-1.291) is too low, potentially hindering membrane permeation and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=6) as it has fewer hydrogen bond forming groups, which can improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.706) has a significantly better QED score than Ligand B (0.46), indicating a more drug-like profile.

**DILI:** Ligand B (25.165) has a much lower DILI risk than Ligand A (93.37), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.162) shows better BBB penetration than Ligand B (59.791).

**Caco-2 Permeability:** Ligand A (-4.725) has a worse Caco-2 permeability than Ligand B (-5.266), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-6.303) has a worse aqueous solubility than Ligand B (-0.715). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.738) has a slightly higher hERG inhibition risk than Ligand B (0.133), which is preferable.

**Microsomal Clearance:** Ligand B (-5.71) has a significantly *lower* (better) microsomal clearance than Ligand A (66.935), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-31.92) has a much longer in vitro half-life than Ligand A (33.551), a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.82) shows higher P-gp efflux liability than Ligand B (0.007), which is undesirable.

**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 A has a better QED and BBB penetration, Ligand B excels in several critical ADME properties for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), better solubility, lower P-gp efflux, and lower hERG risk. The slightly lower logP of Ligand B is a concern, but the substantial benefits in metabolic stability and safety outweigh this drawback, especially given the comparable binding affinities.

Output:
1
2025-04-17 12:11:59,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is better than Ligand B (67.23), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.291 and 2.306), falling within the 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

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

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**QED:** Ligand B (0.785) has a higher QED score than Ligand A (0.489), indicating a more drug-like profile overall.

**DILI:** Ligand A (14.851) has a significantly lower DILI risk than Ligand B (21.753), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (79.217) is better than Ligand A (66.344). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.482) has a better Caco-2 permeability than Ligand B (-4.972).

**Aqueous Solubility:** Ligand A (-1.541) has better aqueous solubility than Ligand B (-2.288). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.404) has a lower hERG inhibition liability than Ligand B (0.612), which is a critical safety advantage.

**Microsomal Clearance:** Ligand A (27.458) has significantly lower microsomal clearance than Ligand B (50.806), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.716) has a better in vitro half-life than Ligand B (-23.876).

**P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux liability than Ligand B (0.262), which is favorable for bioavailability.

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity and QED score, Ligand A demonstrates a significantly better safety profile (lower DILI, hERG) and improved ADME properties (lower Cl_mic, better half-life, lower P-gp efflux, better solubility). The difference in binding affinity (-1.6 kcal/mol) is substantial, but the ADME/Tox advantages of Ligand A are compelling, especially considering the potential for optimization of Ligand A's affinity. For an enzyme target like SRC kinase, metabolic stability and safety are paramount.

Output:
0
2025-04-17 12:11:59,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.435 and 346.523 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.97) is better than Ligand B (56.32) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (-0.593) is slightly low, potentially hindering permeation, while Ligand B (2.577) is within the optimal range (1-3). This favors Ligand B.

**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 good QED scores (0.485 and 0.791, respectively), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (17.216) has a lower DILI risk than Ligand B (14.114), which is favorable.

**BBB:** Ligand A (45.87) has a lower BBB penetration score than Ligand B (80.69). Since SRC is not a CNS target, this is not a major concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.249 and -5.319), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.033 and -1.642), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition liability than Ligand B (0.942), which is a significant advantage.

**Microsomal Clearance:** Ligand A (18.072) has a higher microsomal clearance than Ligand B (-4.579), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (26.194 hours) has a longer in vitro half-life than Ligand A (19.178 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.014) has lower P-gp efflux liability than Ligand B (0.023), which is slightly favorable.

**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 small, it's enough to potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is slightly better overall. It has a more favorable logP, a longer half-life, better metabolic stability (lower Cl_mic), and slightly better binding affinity. While both compounds have concerningly poor solubility and permeability, the slight advantage in potency and metabolic stability makes Ligand B the more promising candidate. The lower hERG risk of Ligand A is a positive, but the other factors tip the balance towards Ligand B.

Output:
1
2025-04-17 12:11:59,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (382.247 and 349.337 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.29) is better than Ligand B (66.65), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.743 and 2.168), 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.

**QED:** Both ligands have similar QED scores (0.847 and 0.833), indicating good drug-likeness.

**DILI:** Both ligands have high DILI risk (79.449 and 78.325), which is a concern.

**BBB:** Ligand B (83.986) has a much higher BBB penetration percentile than Ligand A (23.11). However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-5.058) has a worse Caco-2 permeability than Ligand B (-4.054).

**Aqueous Solubility:** Ligand A (-3.804) has worse aqueous solubility than Ligand B (-2.397).

**hERG Inhibition:** Ligand A (0.117) has a lower hERG inhibition liability than Ligand B (0.354), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-19.749) has significantly lower (better) microsomal clearance than Ligand B (61.268), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-23.076) has a longer in vitro half-life than Ligand B (-54.387), which is also a positive.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux liability than Ligand B (0.29).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial difference (1.8 kcal/mol), and a key driver in the decision.

**Conclusion:**

Despite both ligands having concerning DILI scores, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.5 vs -7.7 kcal/mol) outweighs the slightly worse solubility and Caco-2 permeability. Furthermore, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. These factors are critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:11:59,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (367.324 and 367.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.97) is slightly higher than Ligand B (80.32). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**3. logP:** Ligand A (0.191) is quite low, potentially hindering permeation. Ligand B (2.38) 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:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.654 and 0.7), indicating drug-like properties.

**7. DILI:** Ligand B (33.773) has a lower DILI risk than Ligand A (40.675), making it more favorable. Both are below the 40 threshold.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.211) has slightly better BBB penetration than Ligand B (50.601), but this is not a deciding factor.

**9. Caco-2 Permeability:** Both have negative values (-5.042 and -5.148), which is unusual and suggests poor permeability. This is a concern for both, but similar.

**10. Aqueous Solubility:** Both have negative values (-1.505 and -2.935), indicating poor solubility. Ligand B is worse.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.155 and 0.261).

**12. Microsomal Clearance:** Ligand A (15.856) has a significantly lower microsomal clearance than Ligand B (58.791), indicating better metabolic stability. This is a major advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-28.457) has a negative half life, which is unusual. Ligand B (15.387) is more reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.026).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and a slightly better BBB score, Ligand B has a significantly better logP, lower DILI risk, and a more reasonable in vitro half-life. The poor logP of Ligand A is a major concern, as it could severely limit its absorption. The negative half life of Ligand A is also concerning. Although both have poor Caco-2 and solubility, the better ADME profile of Ligand B, particularly its logP and DILI, outweighs the slight advantage of Ligand A in metabolic stability.

Output:
1
2025-04-17 12:11:59,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.845 and 367.386 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.91) is well below the 140 threshold, suggesting good absorption. Ligand B (97.39) is still acceptable, but less optimal.

**logP:** Ligand A (4.036) is at the higher end of the optimal range, potentially causing solubility issues. Ligand B (2.082) is well within the optimal range.

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

**QED:** Both ligands have similar QED values (0.661 and 0.686), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 74.99, which is concerning (high risk). Ligand B has a much lower DILI risk of 36.138, which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.084) and Ligand B (65.258) are both moderate.

**Caco-2 Permeability:** Ligand A (-4.681) shows poor permeability, which is a significant drawback. Ligand B (-5.048) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.699) has poor solubility, consistent with its higher logP. Ligand B (-1.656) has better, but still poor solubility.

**hERG Inhibition:** Ligand A (0.587) has a moderate hERG risk. Ligand B (0.097) has a very low hERG risk, a major advantage.

**Microsomal Clearance:** Ligand A (101.957) has moderate clearance, suggesting moderate metabolic stability. Ligand B (21.556) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (107.127 hours) has a good half-life. Ligand B (10.155 hours) has a short half-life, which could necessitate more frequent dosing.

**P-gp Efflux:** Ligand A (0.373) has low P-gp efflux, which is good. Ligand B (0.022) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). While both are strong binders, the 0.6 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in key areas for an enzyme target: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, though shorter half-life), lower hERG risk, and a slightly stronger binding affinity. Ligand A's high DILI risk and poor permeability are major concerns. The slightly shorter half-life of Ligand B can be addressed through formulation or structural modifications.

Output:
1
2025-04-17 12:11:59,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Ligand A (453.2 Da) is within the ideal range, while Ligand B (348.491 Da) is towards the lower end but still acceptable.

**TPSA:** Ligand A (127.68) is slightly above the preferred <140 for good oral absorption, but not drastically. Ligand B (74.33) is well within the acceptable range.

**logP:** Both ligands (A: 1.419, B: 2.053) have optimal logP values.

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

**H-Bond Acceptors:** Ligand A has 8 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Ligand B (0.716) has a better QED score than Ligand A (0.442), indicating a more drug-like profile.

**DILI:** Ligand A (98.953) has a very high DILI risk, which is a major concern. Ligand B (21.908) has a low DILI risk, a significant advantage.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, this is less critical than other factors.

**Solubility:** Both have negative solubility values, also unusual.

**hERG:** Both ligands have similar hERG values (A: 0.3, B: 0.47), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (47.383) has higher microsomal clearance than Ligand B (19.449), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (59.219) has a significantly longer in vitro half-life than Ligand A (21.234), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.171, B: 0.017).

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

**Conclusion:**

Despite having comparable binding affinity, Ligand B is the far superior candidate. The extremely high DILI risk associated with Ligand A is a deal-breaker. Ligand B has a better QED score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and comparable hERG and P-gp profiles. The unusual negative values for Caco-2 and solubility are concerning but are outweighed by the significant advantages of Ligand B.

Output:
1
2025-04-17 12:11:59,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (348.447 and 357.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.56) is better than Ligand B (122.83). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**3. logP:** Ligand A (1.03) is within the optimal 1-3 range. Ligand B (-0.898) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**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 A (0.684) has a better QED score than Ligand B (0.46), indicating a more drug-like profile.

**7. DILI:** Ligand A (9.965) has a significantly lower DILI risk than Ligand B (19.775). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (74.758) has a higher BBB penetration percentile than Ligand A (44.242). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.467 and -5.737), 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 (-1.678 and -1.723), also unusual and concerning. Again, similar for both.

**11. hERG Inhibition:** Ligand A (0.207) has a much lower hERG inhibition liability than Ligand B (0.028). This is a significant advantage for Ligand A, minimizing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-9.348) has a much lower (better) microsomal clearance than Ligand B (-3.724), indicating greater metabolic stability. This is crucial for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-21.328) has a much longer in vitro half-life than Ligand B (-5.277), further supporting its improved metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.002), which is good.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While a 1.4 kcal/mol difference is noticeable, the ADME advantages of Ligand A are substantial.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties: lower DILI risk, lower hERG inhibition, much better metabolic stability (lower Cl_mic, longer t1/2), and a better QED score. The negative Caco-2 and solubility values are concerning for both, but the other advantages of A outweigh the small affinity difference. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 12:11:59,584 - INFO - Batch 110 complete. Total preferences: 1760
2025-04-17 12:11:59,584 - INFO - Processing batch 111/512...
2025-04-17 12:12:38,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.355 and 343.395 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.53) is better than Ligand B (118.6). Both are below 140, suggesting good oral absorption potential, but A is closer to the preferred range.

**3. logP:** Ligand A (2.123) is optimal (1-3). Ligand B (0.696) 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 (8) and Ligand B (10) are both acceptable (<=10).

**6. QED:** Ligand A (0.642) is slightly better than Ligand B (0.511), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand A (89.376) has a higher DILI risk than Ligand B (77.782), but both are reasonably low.

**8. BBB:** Both ligands have similar BBB penetration (43.273 and 46.413), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative values (-5.008 and -5.684), which is unusual and likely indicates poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative values (-3.167 and -1.681), indicating poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Both ligands show similar, low hERG inhibition risk (0.643 and 0.608).

**12. Microsomal Clearance:** Ligand A (38.396) has a higher microsomal clearance than Ligand B (17.949), suggesting lower metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (26.848) has a much longer in vitro half-life than Ligand A (-1.09), which is a substantial advantage.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.212 and 0.028).

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

**Conclusion:**

While both compounds have excellent binding affinity, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better DILI profile. The lower logP and Caco-2/Solubility values are concerning for both, but the metabolic advantages of Ligand B outweigh these drawbacks, especially for a kinase inhibitor where maintaining therapeutic concentrations is crucial.

Output:
1
2025-04-17 12:12:38,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.419 Da and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.9) is slightly higher than Ligand B (76.02). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (0.878 and 1.024), 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:** Ligand A (0.754) has a better QED score than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Ligand B (37.456) has a lower DILI risk than Ligand A (26.134), which is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration (43.505 and 48.313), which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.933) is slightly worse than Ligand A (-4.661).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.456) is slightly worse than Ligand A (-1.912).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.143 and 0.086), which is excellent.

**Microsomal Clearance:** Ligand B (6.104 mL/min/kg) has significantly lower microsomal clearance than Ligand A (16.326 mL/min/kg), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-7.355 hours) has a longer in vitro half-life than Ligand A (-8.895 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.039).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Conclusion:**

While Ligand A has a slightly better QED and Caco-2 permeability, Ligand B demonstrates superior ADME properties, particularly lower DILI risk and significantly improved metabolic stability (lower Cl_mic and longer t1/2). Given that we are targeting an enzyme (SRC kinase), metabolic stability is paramount. The slightly lower DILI risk is also a significant benefit. The similar binding affinity makes the ADME advantages of Ligand B decisive.

Output:
1
2025-04-17 12:12:38,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 Da and 384.933 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (60.25) as it is closer to the 140 threshold.

**logP:** Ligand A (1.53) is optimal, while Ligand B (3.686) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Ligand A (3) is within the acceptable limit of 5, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) is within the acceptable limit of 10, and Ligand B (6) is also good.

**QED:** Both ligands have good QED scores (0.578 and 0.661, respectively), indicating drug-like properties.

**DILI:** Ligand A (35.712) has a significantly lower DILI risk than Ligand B (55.487), which is a major advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.407) has a higher BBB penetration than Ligand A (40.171), but this is not a primary concern here.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values, which is unusual and suggests poor absorption. However, the values are similar (-5.112 and -4.913).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-2.27) is slightly better than Ligand B (-3.403).

**hERG Inhibition:** Ligand A (0.225) has a much lower hERG inhibition liability than Ligand B (0.632), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (35.524) has lower microsomal clearance than Ligand B (69.502), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (52.923) has a longer in vitro half-life than Ligand A (6.287), which is generally desirable.

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux liability than Ligand B (0.728), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.7), a 0.5 kcal/mol difference. While affinity is paramount, the other ADME properties need to be considered.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A demonstrates significantly better safety (lower DILI and hERG), better metabolic stability (lower Cl_mic), and lower P-gp efflux. The solubility and permeability are poor for both, but the other advantages of Ligand A outweigh the small affinity difference.

Output:
0
2025-04-17 12:12:38,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.364 Da) is slightly higher than Ligand B (352.395 Da), but this difference is not significant.

**TPSA:** Ligand A (81.08) is well below the 140 threshold for good oral absorption. Ligand B (109.66) is also acceptable, but less optimal.

**logP:** Ligand A (0.379) is a bit low, potentially hindering permeation. Ligand B (-1.266) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.759, B: 0.684), indicating generally drug-like properties.

**DILI:** Ligand A (21.171) has a significantly lower DILI risk than Ligand B (64.366). This is a major advantage for Ligand A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand A (70.182) is better than Ligand B (49.128) but not crucial.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.795) is slightly better than Ligand B (-4.952).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-1.507) is slightly better than Ligand B (-0.527).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.424, B: 0.059), which is excellent.

**Microsomal Clearance:** Ligand A (-7.962) has *much* lower microsomal clearance than Ligand B (11.585), indicating significantly better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-4.373) has a longer in vitro half-life than Ligand B (2.13), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.037, B: 0.014).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.6 kcal/mol, B: -7.9 kcal/mol). Ligand A has a 0.7 kcal/mol advantage, which is significant.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have good potency, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better solubility and permeability. The small advantage in binding affinity further reinforces this conclusion. The lower logP of both is a concern, but the other advantages of Ligand A outweigh this drawback.

Output:
0
2025-04-17 12:12:38,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.459 Da and 348.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.4) is slightly higher than Ligand B (70.39). Both are below 140, suggesting reasonable absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (2.812 and 2.412), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are within the acceptable limit of <=5.

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

**QED:** Ligand B (0.673) has a higher QED score than Ligand A (0.476), indicating a more drug-like profile.

**DILI:** Ligand B (13.532) has a significantly lower DILI risk than Ligand A (54.207), which is a major advantage. Ligand A is approaching the concerning threshold.

**BBB:** Both have moderate BBB penetration (62.544 and 58.278), which isn't a primary concern for a non-CNS target like SRC.

**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.

**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 (0.376 and 0.258), which is excellent.

**Microsomal Clearance:** Ligand B (44.641) has slightly lower microsomal clearance than Ligand A (41.44), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (50.158) has a significantly longer in vitro half-life than Ligand A (0.812), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.097 and 0.138), which is favorable.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a better binding affinity than Ligand B (-6.5 kcal/mol). This is a 0.9 kcal/mol difference, which is significant, but not overwhelming.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B demonstrates superior ADMET properties. Specifically, its lower DILI risk, higher QED, and significantly longer half-life are crucial advantages for a drug candidate. The slightly better metabolic stability of Ligand B also contributes to its favorability. The unusual negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh the affinity difference.

Output:
1
2025-04-17 12:12:38,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 369.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.33) is slightly higher than Ligand B (77.04), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands (2.273 and 2.715) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.777 and 0.814), indicating good drug-likeness.

**DILI:** Ligand A (29.624) has a significantly lower DILI risk than Ligand B (41.411). This is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (83.792) is slightly higher than Ligand A (77.2). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.007) is worse than Ligand B (-4.729).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-2.102) is slightly better than Ligand B (-3.722).

**hERG:** Both have very low hERG risk (0.209 and 0.296).

**Microsomal Clearance:** Ligand A (42.8) has a slightly higher microsomal clearance than Ligand B (37.844), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-13.899) has a significantly longer in vitro half-life than Ligand A (-0.456). This is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.066 and 0.071).

**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 has a much better DILI profile, which is crucial for kinase inhibitors. However, Ligand B has a significantly longer half-life and slightly better binding affinity. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation. Given the importance of metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, the longer half-life of Ligand B is a more compelling advantage. The lower DILI risk of Ligand A is attractive, but the half-life difference is more substantial.

Output:
1
2025-04-17 12:12:38,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.391 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.13) is slightly above the optimal <140 for good oral absorption, but acceptable. Ligand B (98.32) is well within the range.

**logP:** Ligand A (-0.469) is a bit low, potentially hindering permeation. Ligand B (1.319) is within the optimal 1-3 range.

**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.

**QED:** Both ligands have good QED scores (0.63 and 0.722), indicating drug-like properties.

**DILI:** Ligand A (29.973) has a lower DILI risk than Ligand B (33.424), both are good (<40).

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unexpected and problematic, indicating very poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also problematic.

**hERG:** Both ligands show low hERG inhibition liability (0.143 and 0.384), which is excellent.

**Microsomal Clearance:** Ligand A (-10.218) has significantly *lower* (better) microsomal clearance than Ligand B (-18.809). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-2.759) has a shorter half-life than Ligand B (-11.599). This is a negative for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.033).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -9.1 kcal/mol), with Ligand B 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 DILI score and significantly better metabolic stability (lower Cl_mic). However, it has a lower logP and shorter half-life. Ligand B has a slightly better binding affinity and a longer half-life, but a slightly higher DILI risk and worse metabolic stability. The poor Caco-2 and solubility for both are concerning. Given the enzyme-specific priorities, metabolic stability is crucial. The significantly better Cl_mic of Ligand A outweighs its other minor drawbacks.

Output:
0
2025-04-17 12:12:38,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (360.772 and 362.396 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.35) is better than Ligand B (78.09), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.015 and 2.745), 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) regarding the number of hydrogen bond donors and acceptors, both are within acceptable limits.

**QED:** Ligand A (0.909) has a significantly better QED score than Ligand B (0.709), indicating a more drug-like profile.

**DILI:** Ligand B (47.732) has a much lower DILI risk than Ligand A (89.221), which is a significant advantage.

**BBB:** Ligand B (79.682) has a higher BBB penetration percentile than Ligand A (58.821), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.571) and Ligand B (-4.96) have negative values, indicating poor permeability. Ligand B is slightly worse.

**Aqueous Solubility:** Ligand A (-5.005) has slightly better solubility than Ligand B (-3.261), both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.677 and 0.764).

**Microsomal Clearance:** Ligand A (21.756) has lower microsomal clearance than Ligand B (24.116), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (43.279) has a significantly longer in vitro half-life than Ligand B (0.351), which is a major advantage.

**P-gp Efflux:** Ligand A (0.337) has lower P-gp efflux than Ligand B (0.242), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger 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:**

Ligand B's primary advantage is its significantly higher binding affinity (-8.5 vs -7.6 kcal/mol). This is a critical factor for an enzyme target like SRC. While Ligand A has better QED, half-life, and lower DILI, the substantial affinity difference of Ligand B is more important. The lower DILI of Ligand B is also a positive. The solubility and Caco-2 permeability are poor for both, but the affinity advantage of B is likely to be more impactful in initial optimization.

Output:
1
2025-04-17 12:12:38,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.5 and 372.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.75) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (84.5) is still under 140, but less optimal than A.

**logP:** Both ligands (2.07 and 1.88) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent, minimizing potential issues with permeability. Ligand B (2) is acceptable.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10.

**QED:** Both ligands (0.83 and 0.77) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (57.3) and Ligand B (60.2) are both acceptable, below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.7) is higher than Ligand B (62.5).

**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.

**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 (0.57) is better than Ligand B (0.38), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (52.7) has a lower Cl_mic than Ligand A (59.5), indicating better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-5.79) has a much longer half-life than Ligand A (-0.72), which is a substantial benefit.

**P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux than Ligand B (0.16), which is slightly better.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor for an enzyme target. The >1.5 kcal/mol advantage of B over A outweighs any ADME drawbacks.

**Conclusion:**

Despite some unusual negative values for Caco-2 and solubility, the significantly superior binding affinity of Ligand B, coupled with its better metabolic stability (lower Cl_mic) and longer half-life, make it the more promising drug candidate. The slightly higher hERG risk is a minor concern compared to the substantial potency advantage.

Output:
1
2025-04-17 12:12:38,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.901 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is well below the 140 threshold, suggesting good absorption. Ligand B (89.16) is also under the threshold, but closer to it.

**logP:** Ligand A (4.281) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.262) is a bit low, which might hinder permeation.

**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).

**QED:** Both ligands have similar QED values (0.771 and 0.754), indicating good drug-likeness.

**DILI:** Ligand A (34.161) has a slightly higher DILI risk than Ligand B (26.871), but both are below the 40 threshold and considered good.

**BBB:** Ligand A (70.997) has better BBB penetration than Ligand B (49.205), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.411) has a negative Caco-2 value, which is concerning and suggests poor permeability. Ligand B (-5.41) is also negative, but worse.

**Aqueous Solubility:** Ligand A (-5.092) has poor solubility, likely due to its high logP. Ligand B (-0.831) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.765) shows a slightly higher hERG risk than Ligand B (0.212), which is preferable.

**Microsomal Clearance:** Ligand A (17.483) has a higher clearance than Ligand B (-8.548). Ligand B's negative value suggests very good metabolic stability, a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (37.114) has a longer half-life than Ligand B (18.79), which is desirable.

**P-gp Efflux:** Ligand A (0.599) has lower P-gp efflux than Ligand B (0.02), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better BBB penetration and P-gp efflux, Ligand B is superior overall. The key advantages of Ligand B are its significantly better metabolic stability (negative Cl_mic) and slightly improved binding affinity. The lower hERG risk is also a plus. Although its solubility and Caco-2 permeability are not ideal, the strong binding affinity and metabolic stability are more critical for an enzyme target like SRC.

Output:
1
2025-04-17 12:12:38,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.559 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (61.44 and 58.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.441 and 2.579) 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.

**QED:** Both ligands have similar QED values (0.777 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A (11.206) has a significantly lower DILI risk than Ligand B (15.355). This is a substantial advantage.

**BBB:** Ligand B (87.515) has a higher BBB penetration potential than Ligand A (64.87), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.301) has a worse Caco-2 permeability than Ligand B (-4.658), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.521 and -2.596). This is a significant concern for both, but may be mitigated through formulation strategies.

**hERG Inhibition:** Ligand A (0.838) has a slightly higher hERG inhibition risk than Ligand B (0.405), which is unfavorable.

**Microsomal Clearance:** Ligand A (7.686) has a much lower microsomal clearance than Ligand B (22.559), indicating better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-27.46) has a much longer in vitro half-life than Ligand B (5.311), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.03) has a lower P-gp efflux liability than Ligand B (0.098), which is favorable.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.0). While both are good, the 0.7 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor solubility, Ligand A excels in key areas for an enzyme target: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The slightly worse Caco-2 permeability and higher hERG risk are less concerning given the substantial advantages in metabolic stability and safety.

Output:
1
2025-04-17 12:12:38,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.44) is better than Ligand B (92.5). Both are under 140, but lower TPSA generally improves absorption.

**logP:** Both ligands have good logP values (2.763 and 1.286), 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=2, HBA=3) as it has fewer hydrogen bond donors, potentially improving membrane permeability. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.889 and 0.757), indicating good drug-like properties.

**DILI:** Ligand A (33.889) has a significantly lower DILI risk than Ligand B (19.426). This is a major advantage for Ligand A.

**BBB:** Ligand A (82.513) has a higher BBB penetration percentile than Ligand B (65.413). While not a primary concern for a non-CNS target, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.674) has a slightly better Caco-2 permeability than Ligand B (-5.12), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.012 and -3.107). This is a potential issue for both, requiring formulation strategies.

**hERG Inhibition:** Ligand A (0.357) has a lower hERG inhibition liability than Ligand B (0.102), indicating a lower risk of cardiotoxicity. This is a significant advantage.

**Microsomal Clearance:** Ligand B (29.341) has a significantly lower microsomal clearance than Ligand A (63.367), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (0.445) has a longer in vitro half-life than Ligand A (-22.193), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.043) has a lower P-gp efflux liability than Ligand B (0.019), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a crucial factor, and the 0.5 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic and longer t1/2) and a slightly better binding affinity. These are key priorities for an enzyme inhibitor. However, Ligand A has a much lower DILI risk and a lower hERG risk, which are critical safety parameters. The solubility is poor for both.

The difference in binding affinity (0.5 kcal/mol) is significant, but the improved safety profile of Ligand A (lower DILI and hERG) and its slightly better permeability are also important. Given the importance of metabolic stability for kinases, and the relatively small difference in binding affinity, Ligand B is the slightly better candidate.

Output:
1
2025-04-17 12:12:38,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.845 and 367.446 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.25) is better than Ligand B (91.32). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (4.236) is slightly higher than the optimal range (1-3), while Ligand B (2.459) is within the ideal range. This favors B.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.859) has a significantly better QED score than Ligand B (0.509), indicating a more drug-like profile.

**DILI:** Ligand A (70.066) has a higher DILI risk than Ligand B (50.33). B is preferred.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand A (82.745) is higher than Ligand B (45.444).

**Caco-2 Permeability:** Ligand A (-4.331) is better than Ligand B (-5.184). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-5.344) is better than Ligand B (-3.601). Higher solubility is crucial.

**hERG Inhibition:** Both ligands have similar, very low hERG inhibition risk (0.207 and 0.234).

**Microsomal Clearance:** Ligand A (70.377) has a higher microsomal clearance than Ligand B (52.358), suggesting lower metabolic stability. B is preferred.

**In vitro Half-Life:** Ligand B (-3.625) has a longer half-life than Ligand A (11.414). B is preferred.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.082 and 0.097).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a major advantage that can outweigh some ADME drawbacks.

**Overall:** While Ligand A has better QED and solubility, Ligand B exhibits a substantially stronger binding affinity (-8.9 vs -7.9 kcal/mol), a more favorable logP, lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2). The superior binding affinity is the most critical factor for an enzyme inhibitor, and the other advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 12:12:38,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.555 Da) is slightly higher than Ligand B (370.471 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (87.54) is better than Ligand B (92.78).

**logP:** Ligand A (-0.375) is slightly below the optimal range (1-3), potentially hindering permeation. Ligand B (0.43) is closer to the ideal range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 8, Ligand B: 5) counts.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.736) is slightly better than Ligand B (0.685).

**DILI:** Ligand B (39.24) has a significantly lower DILI risk than Ligand A (74.68), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.135) has a higher BBB percentile than Ligand A (31.756), but this isn't a deciding 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, suggesting poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG risk (0.079 and 0.071), which is excellent.

**Microsomal Clearance:** Ligand B (0.804) has significantly lower microsomal clearance than Ligand A (42.913), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (3.594) has a longer half-life than Ligand A (1.05), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03 and 0.055).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This 1.6 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly regarding DILI risk and metabolic stability (lower Cl_mic and longer t1/2). Given that SRC is an enzyme target, metabolic stability and safety (DILI) are paramount. The affinity difference, while noticeable, might be overcome with further optimization of Ligand B. The poor solubility and permeability are concerning for both, but could be addressed with formulation strategies.

Output:
1
2025-04-17 12:12:38,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.371 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.24) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (71.53) is well within the optimal range.

**logP:** Ligand A (-0.173) is quite low, potentially hindering permeability. Ligand B (1.598) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands (A: 5, B: 4) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.564, B: 0.901), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (32.299). Both are below the concerning threshold of 60, but B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (75.998) has a higher BBB penetration, but it's not a primary concern here. Ligand A (16.014) is low.

**Caco-2 Permeability:** Ligand A (-5.461) has poor predicted permeability. Ligand B (-4.498) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor predicted solubility (A: -3.031, B: -2.063). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG risk (A: 0.247, B: 0.176).

**Microsomal Clearance:** Ligand A (-16.006) shows significantly better metabolic stability (lower clearance) than Ligand B (14.489). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-1.834) has a slightly better (longer) half-life than Ligand B (-6.53).

**P-gp Efflux:** Ligand A (0.024) has slightly lower P-gp efflux than Ligand B (0.022), which is preferable.

**Binding Affinity:** Ligand A (-9.2) has a substantially stronger binding affinity than Ligand B (-0.0). This is a crucial factor. A difference of >1.5 kcal/mol often outweighs other concerns.

**Overall Assessment:**

Ligand A's significantly superior binding affinity (-9.2 kcal/mol vs -0.0 kcal/mol) is the dominant factor. While it has a lower logP and poorer Caco-2 permeability, the strong binding is likely to compensate. Its metabolic stability (Cl_mic) is also much better. Ligand B has better solubility and a lower DILI risk, but the lack of potency is a major drawback. The solubility issues of both are concerning, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 12:12:38,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (383.853 and 363.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.88) is significantly better than Ligand B (109). TPSA < 140 is good for oral absorption, and A is much closer to the ideal for CNS penetration (though that's not a priority here) than B.

**logP:** Both ligands have good logP values (3.604 and 2.487), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Lower HBDs generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.68 and 0.617), indicating reasonable drug-likeness.

**DILI:** Ligand A (76.154) has a much lower DILI risk than Ligand B (98.759). This is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (70.027) is better than Ligand B (40.52).

**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.

**hERG Inhibition:** Ligand A (0.226) has a much lower hERG inhibition liability than Ligand B (0.723), a crucial advantage for safety.

**Microsomal Clearance:** Ligand B (27.904) has significantly lower microsomal clearance than Ligand A (68.385), suggesting better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand B (49.551) has a longer in vitro half-life than Ligand A (22.818), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.329) has lower P-gp efflux liability than Ligand B (0.097). Lower efflux is generally preferred.

**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, potentially outweighing some of the ADME drawbacks of B. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, it has a higher DILI risk and hERG inhibition liability. Ligand A has a better safety profile (lower DILI, lower hERG) and better TPSA. The affinity difference is significant. Given the enzyme-specific priorities, the stronger binding affinity of Ligand B is the most important factor. While the DILI and hERG risks are concerning, they might be mitigated through further structural modifications.

Output:
1
2025-04-17 12:12:38,834 - INFO - Batch 111 complete. Total preferences: 1776
2025-04-17 12:12:38,834 - INFO - Processing batch 112/512...
2025-04-17 12:13:28,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.43 and 349.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.48) is slightly above the optimal <140, but acceptable. Ligand B (80.34) is well within the ideal range.

**logP:** Ligand A (1.501) and Ligand B (0.739) are both 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 (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Ligand B (0.848) has a significantly better QED score than Ligand A (0.418), indicating a more drug-like profile.

**DILI:** Ligand A (52.152) has a lower DILI risk than Ligand B (60.217), but both are still within an acceptable range (<60 is preferred).

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (83.831) is higher than Ligand A (68.321). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.165) is worse than Ligand B (-4.605).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility. Ligand A (-2.92) is worse than Ligand B (-1.374).

**hERG Inhibition:** Ligand A (0.74) has a slightly higher hERG risk than Ligand B (0.383), which is preferable.

**Microsomal Clearance:** Ligand B (5.566) has a significantly lower microsomal clearance than Ligand A (44.845), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (3.825) has a longer in vitro half-life than Ligand A (0.745), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.063, B: 0.03).

**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 is still a positive factor.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. Its superior QED, lower microsomal clearance, longer half-life, better solubility, and slightly improved binding affinity outweigh the slightly higher DILI risk and lower BBB penetration. The poor Caco-2 and solubility values for both compounds are concerning and would require further investigation (e.g., salt formation, formulation strategies) but are less critical than metabolic stability for an enzyme inhibitor.

Output:
1
2025-04-17 12:13:28,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.399 and 345.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.11) is slightly above the optimal <140, while Ligand B (102.46) is well within. This favors Ligand B slightly for absorption.

**logP:** Ligand A (0.739) is a bit low, potentially hindering permeation. Ligand B (0.126) 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 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.73 and 0.82), indicating good drug-like properties.

**DILI:** Ligand A (41.838) has a lower DILI risk than Ligand B (52.966), which is a positive for A.

**BBB:** Both ligands have similar BBB penetration (45.134 and 45.715), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.066) is slightly worse than Ligand B (-4.776).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.766 and -2.176). This is a significant drawback for both.

**hERG:** Ligand A (0.157) has a lower hERG risk than Ligand B (0.296), which is a positive for A.

**Microsomal Clearance:** Ligand A (-20.828) has significantly lower (better) microsomal clearance than Ligand B (-0.585), indicating much better metabolic stability. This is a major advantage for A.

**In vitro Half-Life:** Ligand A (5.848) has a shorter half-life than Ligand B (7.968), but both are relatively low.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.016 and 0.116), which is good.

**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 a reasonable advantage.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and TPSA, but Ligand A excels in metabolic stability (Cl_mic), DILI risk, and hERG inhibition. The poor solubility and permeability are concerning for both. However, the significantly improved metabolic stability of Ligand A is crucial for an enzyme target like SRC. The slightly better affinity of Ligand B is not enough to overcome the metabolic liability.

Output:
0
2025-04-17 12:13:28,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (329.363 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.6 and 82.53) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.469 and 1.306) within the optimal 1-3 range. Ligand B is slightly lower, which could potentially affect permeability, but it's not a major concern.

**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 QED values (0.729 and 0.626) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 87.01, which is high. Ligand B has a much lower DILI risk of 20.589, which is excellent. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (51.803) is higher than Ligand A (40.093), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative values (-5.275 and -4.882). This is unusual and suggests poor permeability. However, Caco-2 values can be unreliable and are less important than other factors for kinase inhibitors.

**Aqueous Solubility:** Both have negative values (-3.775 and -1.031). Again, this is unusual and suggests poor solubility. Solubility is important for kinase inhibitors, so this is a concern.

**hERG Inhibition:** Ligand A (0.509) has a slightly higher hERG risk than Ligand B (0.153), which is preferable.

**Microsomal Clearance:** Ligand A (41.918 mL/min/kg) has a higher clearance than Ligand B (10.41 mL/min/kg), indicating lower metabolic stability. Lower clearance is preferred for enzymes.

**In vitro Half-Life:** Ligand A (-3.146 hours) has a negative half-life, which is not possible and likely an error in the data. Ligand B (0.957 hours) is very short, but still a valid value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.207 and 0.055).

**Binding Affinity:** Both ligands have very 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 outweigh other factors.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. The significantly lower DILI risk (20.589 vs 87.01) and lower microsomal clearance (10.41 vs 41.918) are major advantages. While both have concerning solubility and permeability values, the metabolic stability and safety profile of Ligand B are superior. The invalid half-life value for Ligand A further diminishes its viability.

Output:
1
2025-04-17 12:13:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.45 and 352.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, suggesting good absorption. Ligand B (101.41) is still within acceptable limits, but less favorable than A.

**logP:** Both ligands (2.211 and 2.16) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Ligand A (0.789) has a significantly better QED score than Ligand B (0.37), indicating a more drug-like profile.

**DILI:** Ligand A (35.285) has a much lower DILI risk than Ligand B (12.214). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (89.531) has a higher BBB percentile than Ligand B (51.299).

**Caco-2 Permeability:** Ligand A (-4.633) has a more favorable Caco-2 permeability than Ligand B (-5.158), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.055) has better aqueous solubility than Ligand B (-0.911). This is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.307 and 0.287).

**Microsomal Clearance:** Ligand A (40.197) has a higher microsomal clearance than Ligand B (-2.939). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-8.856) has a significantly longer in vitro half-life than Ligand A (-7.313). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.008).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -7.6 kcal/mol). Ligand A is slightly better (-9.0 vs -7.6), but the difference is less than the 1.5 kcal/mol threshold where we'd prioritize affinity over other factors.

**Overall Assessment:**

Ligand A has advantages in QED, DILI, solubility, Caco-2 permeability, and slightly better binding affinity. Ligand B shines in metabolic stability (lower Cl_mic, longer t1/2). Given the enzyme-kinase focus, metabolic stability is important. However, the substantial advantages of Ligand A in drug-likeness (QED), safety (DILI), and absorption (Solubility, Caco-2) outweigh the slightly better metabolic stability of Ligand B. The binding affinity difference is not large enough to shift the balance.

Output:
0
2025-04-17 12:13:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.475 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (58.44) is better than Ligand B (53.99).

**logP:** Ligand A (2.0) is within the optimal range (1-3). Ligand B (4.24) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both ligands have acceptable HBD counts (0 and 0 respectively), falling within the desired limit of <=5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 5 respectively), falling within the desired limit of <=10.

**QED:** Ligand A (0.819) has a significantly higher QED score than Ligand B (0.528), indicating a more drug-like profile.

**DILI:** Ligand A (30.826) has a much lower DILI risk than Ligand B (77.2), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (74.176) is better than Ligand B (50.097).

**Caco-2 Permeability:** Both are negative, which is unusual and indicates poor permeability. Ligand A (-4.74) is slightly better than Ligand B (-4.531).

**Aqueous Solubility:** Ligand A (-1.703) is better than Ligand B (-5.286).

**hERG Inhibition:** Ligand A (0.202) has a lower hERG risk than Ligand B (0.469).

**Microsomal Clearance:** Ligand A (40.563) has lower clearance, suggesting better metabolic stability, than Ligand B (108.981).

**In vitro Half-Life:** Ligand A (8.153) has a shorter half-life than Ligand B (31.076). However, the difference isn't dramatic and can be addressed through structural modifications.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux liability than Ligand B (0.588).

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

Ligand A is superior to Ligand B across most critical parameters. It has a better QED score, lower DILI risk, better solubility, lower hERG risk, better metabolic stability, lower P-gp efflux, and a significantly better binding affinity. While both have poor Caco-2 permeability, Ligand A's other advantages outweigh this drawback. The affinity difference is substantial enough to prioritize Ligand A despite the permeability concern.

Output:
0
2025-04-17 12:13:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.401 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is better than Ligand B (67.43), both being below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.694) is optimal, while Ligand B (3.173) is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 3 HBA) as lower values generally improve permeability. Both are within acceptable ranges.

**QED:** Ligand A (0.827) has a significantly better QED score than Ligand B (0.659), indicating a more drug-like profile.

**DILI:** Ligand A (34.432) has a much lower DILI risk than Ligand B (15.2), which is a significant advantage.

**BBB:** Both ligands have reasonably high BBB penetration (Ligand A: 92.943, Ligand B: 71.656), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.531 and -4.53), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.77 and -3.128), indicating poor aqueous solubility. This is a significant drawback.

**hERG:** Both ligands show very low hERG inhibition liability (0.516 and 0.483), which is excellent.

**Microsomal Clearance:** Ligand A (29.086) has a much lower microsomal clearance than Ligand B (65.321), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.67) has a more negative in vitro half-life, indicating a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.212), which is favorable.

**Binding Affinity:** Both ligands have similar binding affinities (-9.4 and -9.1 kcal/mol), which are both excellent and meet the > -7.0 kcal/mol criterion.

**Overall Assessment:**

Ligand A is significantly better due to its superior QED, lower DILI risk, lower microsomal clearance, and longer in vitro half-life. While both have poor solubility and permeability, the better ADME profile of Ligand A outweighs the slightly better logP of Ligand B. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 12:13:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 418.169 Da - Within the ideal range (200-500 Da).
* Ligand B: 352.45 Da - Also within the ideal range.
* *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 92.18 - Acceptable, but approaching the upper limit for good oral absorption (<=140).
* Ligand B: 69.64 - Excellent, well below the 140 threshold.
* *Ligand B has a clear advantage here.*

**3. Lipophilicity (logP):**
* Ligand A: 2.929 - Optimal (1-3).
* Ligand B: 1.925 - Also optimal, slightly lower.
* *Ligand A has a slight advantage.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Meets the <=5 criteria.
* Ligand B: 2 - Meets the <=5 criteria.
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 4 - Meets the <=10 criteria.
* Ligand B: 3 - Meets the <=10 criteria.
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.779 - Excellent, well above the 0.5 threshold.
* Ligand B: 0.815 - Excellent, slightly better than Ligand A.
* *Ligand B has a slight advantage.*

**7. DILI:**
* Ligand A: 93.098 - High risk (>60). This is a significant concern.
* Ligand B: 19.038 - Very low risk (<40).
* *Ligand B has a massive advantage here.*

**8. BBB:**
* Ligand A: 53.432 - Not particularly high, not a major concern for a non-CNS target like SRC.
* Ligand B: 72.082 - Moderate, not a major factor here.
* *Ligand B has a slight advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -5.22 - Poor permeability.
* Ligand B: -5.007 - Poor permeability.
* *No clear advantage.*

**10. Aqueous Solubility:**
* Ligand A: -3.547 - Poor solubility.
* Ligand B: -3.066 - Poor solubility.
* *No clear advantage.*

**11. hERG Inhibition:**
* Ligand A: 0.188 - Low risk.
* Ligand B: 0.358 - Low risk.
* *No clear advantage.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 24.075 - Moderate clearance.
* Ligand B: 1.657 - Very low clearance, indicating good metabolic stability.
* *Ligand B has a significant advantage.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -14.067 - Short half-life.
* Ligand B: -3.483 - Longer half-life.
* *Ligand B has a significant advantage.*

**14. P-gp Efflux:**
* Ligand A: 0.083 - Low efflux.
* Ligand B: 0.079 - Low efflux.
* *No clear advantage.*

**15. Binding Affinity:**
* Ligand A: -9.4 kcal/mol - Excellent.
* Ligand B: -9.2 kcal/mol - Excellent, slightly weaker than Ligand A.
* *Ligand A has a slight advantage.*

**Overall Assessment:**

While Ligand A has a slightly better binding affinity (-9.4 vs -9.2 kcal/mol), the significant drawbacks of high DILI risk (93.098) and poor metabolic stability (Cl_mic = 24.075, short half-life) are major concerns. Ligand B, despite slightly weaker binding, demonstrates a much more favorable ADME profile: low DILI risk (19.038), excellent metabolic stability (Cl_mic = 1.657, longer half-life), and better TPSA.  For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity (DILI) are crucial. The small difference in binding affinity can likely be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 12:13:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.322 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.123) is within the optimal range, while Ligand B (3.227) is approaching the upper limit. This favors Ligand A slightly, as high logP can cause issues.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Lower is generally better for permeability, so Ligand B is favored.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**QED:** Ligand B (0.791) has a significantly better QED score than Ligand A (0.462), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (48.468 and 46.375), which is good.

**BBB:** Ligand B (70.105) has a better BBB penetration score than Ligand A (50.523). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.264) has a worse Caco-2 permeability than Ligand B (-4.904).

**Aqueous Solubility:** Ligand A (-2.196) has a worse aqueous solubility than Ligand B (-3.58). Solubility is important for bioavailability, favoring Ligand B.

**hERG:** Both ligands have low hERG inhibition liability (0.413 and 0.519), which is excellent.

**Microsomal Clearance:** Ligand A (5.289) has a significantly lower microsomal clearance than Ligand B (55.119), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-13.428) has a worse in vitro half-life than Ligand B (5.365). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.565), which is a positive.

**Binding Affinity:** Ligand B (-8.7) has a significantly stronger binding affinity than Ligand A (-6.8). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a better QED, BBB, solubility, Caco-2 permeability, and *significantly* better binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux. The binding affinity difference is substantial (-8.7 vs -6.8 kcal/mol), and potency is the highest priority for enzyme inhibitors. While Ligand A's metabolic stability is good, the superior binding of Ligand B is likely to translate to efficacy even with faster metabolism.

Output:
1
2025-04-17 12:13:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.769 and 350.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.55) is slightly higher than the ideal <140, but acceptable. Ligand B (58.2) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands (2.885 and 3.334) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=2) both have reasonable H-bond characteristics, well within the suggested limits.

**QED:** Both ligands have acceptable QED scores (0.671 and 0.558), indicating good drug-like properties.

**DILI:** Ligand A (89.88) has a significantly higher DILI risk than Ligand B (39.822). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (75.223 and 81.233), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a non-standard scale. However, assuming they represent low permeability, Ligand B (-4.483) appears slightly better than Ligand A (-4.725).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or a non-standard scale. Assuming they represent low solubility, Ligand B (-3.494) appears slightly better than Ligand A (-5.474).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.539). This is positive for both.

**Microsomal Clearance:** Ligand B (29.673 mL/min/kg) has a considerably lower microsomal clearance than Ligand A (56.653 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (18.267 hours) has a longer in vitro half-life than Ligand A (32.184 hours). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.201 and 0.307).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -9.0 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have good potency, Ligand B exhibits a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and permeability. The DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 12:13:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.443 and 355.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.7) is better than Ligand B (46.61), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.201 and 3.835), falling within the 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:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within the acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.728) has a better QED score than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand A (85.615) has a significantly higher DILI risk than Ligand B (15.665). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (95.308) has a higher BBB penetration, but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.248) has a worse Caco-2 permeability than Ligand B (-3.973), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.249) has worse aqueous solubility than Ligand B (-4.798). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.133) has a slightly better hERG profile than Ligand B (0.849), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (13.265) has a significantly lower microsomal clearance than Ligand B (123.486), suggesting better metabolic stability. This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (23.172) has a longer in vitro half-life than Ligand B (-6.738). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux than Ligand B (0.348), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.4 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has advantages in metabolic stability (Cl_mic, t1/2), P-gp efflux, and QED. However, the significantly higher DILI risk and lower solubility/permeability are major drawbacks. Ligand B, while having a slightly less favorable QED and higher clearance, has a much better safety profile (DILI) and better solubility/permeability. Given the enzyme-specific priorities, a lower DILI risk is crucial. The similar binding affinities make the safety profile the deciding factor.

Output:
1
2025-04-17 12:13:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.849 and 363.761 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.24) is significantly better than Ligand B (105.16). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (4.995) is higher than ideal (1-3), potentially causing solubility issues and off-target effects. Ligand B (2.02) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is better than Ligand B (0 HBD, 9 HBA). Ligand B has a high number of HBA which could impact permeability.

**QED:** Both ligands have similar QED values (0.717 and 0.612), indicating reasonable drug-likeness.

**DILI:** Ligand A (59.907) has a lower DILI risk than Ligand B (97.712), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.854) is slightly better than Ligand B (57.852).

**Caco-2 Permeability:** Both have negative values (-4.951 and -4.587) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative values (-4.327 and -3.589) which is also unusual and suggests poor solubility.

**hERG:** Both ligands have a low hERG risk (0.691 and 0.104), which is positive.

**Microsomal Clearance:** Ligand A (62.41) has a lower Cl_mic than Ligand B (103.429), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (185.663) has a much longer half-life than Ligand B (-14.686), which is a significant advantage.

**P-gp Efflux:** Both ligands have similar Pgp efflux liability (0.757 and 0.265).

**Binding Affinity:** Both ligands have the same binding affinity (-9.3 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand A's slightly higher logP, its significantly better TPSA, lower DILI risk, lower Cl_mic, and much longer half-life make it the more promising candidate. The binding affinity is identical, so the ADME properties become the deciding factors. Ligand B's high DILI risk and poor metabolic stability are major drawbacks.

Output:
0
2025-04-17 12:13:28,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.419 and 351.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.6) is better than Ligand B (118.06), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.102) is optimal (1-3), while Ligand B (0.294) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both 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 within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED scores (0.846 and 0.756, both > 0.5).

**DILI:** Ligand A (38.154) has a significantly lower DILI risk than Ligand B (77.976). This is a major advantage.

**BBB:** Both have similar low BBB penetration (32.92 and 39.977). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.085 and -5.358), 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 (-1.571 and -1.751), indicating poor aqueous solubility. This is a concern, but can be addressed through formulation.

**hERG Inhibition:** Both have very low hERG inhibition liability (0.02 and 0.017), which is excellent.

**Microsomal Clearance:** Ligand A (-14.098) has significantly lower (better) microsomal clearance than Ligand B (-28.473), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-32.263) has a longer (better) in vitro half-life than Ligand B (-12.909).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.006).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Ligand A is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP and solubility. While both have poor Caco-2 and solubility, these are formulation challenges that can be addressed. The substantial affinity difference makes Ligand A the more promising starting point for optimization.

Output:
1
2025-04-17 12:13:28,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.284 and 358.316 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.02) is better than Ligand B (68.73), both are below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands (2.462 and 2.358) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

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

**QED:** Both ligands (0.765 and 0.756) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (70.686) and Ligand B (68.592) are both acceptable, below the 60 percentile threshold.

**BBB:** Ligand B (90.772) is significantly better than Ligand A (35.091). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.853) is worse than Ligand B (-4.122), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.173) is worse than Ligand B (-3.429), indicating lower solubility.

**hERG:** Both ligands (0.603 and 0.434) show low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (31.454) has significantly lower clearance than Ligand B (85.244), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-12.738) has a much longer half-life than Ligand B (-44.817), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands (0.117 and 0.223) have low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands (-8.6 and -8.2 kcal/mol) have excellent binding affinity. The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Ligand A is the better candidate. While Ligand B has better BBB penetration and Caco-2 permeability, the significantly improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand A is crucial for an enzyme inhibitor like an SRC kinase inhibitor. Solubility is also better for Ligand A. The binding affinity difference is small.

Output:
1
2025-04-17 12:13:28,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 362.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is better than Ligand B (33.2). While both are reasonably low, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (4.729) is higher than Ligand A (2.719). Ligand B is pushing the upper limit of the optimal range, potentially leading to solubility issues. Ligand A 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 acceptable, falling within the guidelines.

**QED:** Both ligands have similar QED scores (0.859 and 0.733), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (25.048 and 24.661), which is excellent.

**BBB:** Both have good BBB penetration (72.082 and 78.054), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.871 and -4.986), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.848) is better than Ligand B (-4.234), indicating better solubility. Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.205) has a much lower hERG risk than Ligand B (0.694). This is a significant advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (100.136) has a much higher microsomal clearance than Ligand A (14.453). This means Ligand B will be metabolized much faster, leading to a shorter duration of action and potentially requiring higher doses.

**In vitro Half-Life:** Ligand B (7.093) has a longer half-life than Ligand A (-0.791). However, the negative value for Ligand A is concerning and likely indicates a very short half-life or an issue with the assay.

**P-gp Efflux:** Ligand A (0.015) has much lower P-gp efflux than Ligand B (0.706), which is favorable for oral bioavailability.

**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 1.2 kcal/mol difference is quite significant.

**Conclusion:**

Despite Ligand B's higher logP and clearance, its substantially better binding affinity (-10.0 vs -8.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The difference in binding is large enough to potentially overcome the ADME liabilities. While Ligand A has better solubility and lower hERG risk, the potency of Ligand B is a critical factor. The negative Caco-2 values for both are concerning and require further investigation, but the binding affinity difference is the deciding factor.

Output:
1
2025-04-17 12:13:28,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 351.359 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, suggesting good absorption. Ligand B (110.11) is still within acceptable limits, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (3.332) is optimal. Ligand B (0.111) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is excellent. Ligand B (2 HBD, 6 HBA) is acceptable, but higher numbers can sometimes reduce permeability.

**QED:** Both ligands have good QED scores (0.717 and 0.779), indicating generally drug-like properties.

**DILI:** Ligand A (13.339) has a significantly lower DILI risk than Ligand B (57.929). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.164) has a better BBB score than Ligand B (50.679), but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or potential problems with permeability. However, given the other factors, we'll proceed with caution.

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

**hERG:** Ligand A (0.544) has a much lower hERG risk than Ligand B (0.128). This is a significant advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (60.133) has a higher microsomal clearance than Ligand B (-40.235). This means Ligand B is likely more metabolically stable, a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (8.194 hours) has a much longer half-life than Ligand A (-1.014 hours). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.204 and 0.009), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While both are excellent, the 0.8 kcal/mol difference is not enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. Despite the negative solubility and Caco-2 values, its superior logP, significantly lower DILI and hERG risk, and acceptable metabolic stability outweigh the slightly weaker binding affinity and shorter half-life compared to Ligand B. The low logP of Ligand B is a major concern, likely leading to poor bioavailability. The much higher DILI and hERG risk for Ligand B are also significant liabilities. The longer half-life of Ligand B is attractive, but can be addressed through formulation or structural modifications.

Output:
0
2025-04-17 12:13:28,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 357.841 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.8) is slightly above the preferred <140, but still reasonable. Ligand B (55.32) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.402) is a bit low, potentially hindering permeation. Ligand B (3.507) is optimal.

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

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

**QED:** Both ligands have good QED scores (0.756 and 0.821), indicating drug-like properties.

**DILI:** Ligand A (54.207) has a slightly higher DILI risk than Ligand B (38.581), but both are acceptable (<60).

**BBB:** Ligand A (25.824) has low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (83.288) has good BBB penetration, but this is less important here.

**Caco-2 Permeability:** Ligand A (-4.884) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.465) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.625) has poor aqueous solubility. Ligand B (-4.307) has very poor aqueous solubility. This is a concern for both, but potentially more so for B.

**hERG Inhibition:** Ligand A (0.238) has a very low hERG risk, which is excellent. Ligand B (0.553) has a slightly elevated hERG risk, but is still acceptable.

**Microsomal Clearance:** Ligand A (31.734) has a moderate microsomal clearance. Ligand B (92.968) has a high microsomal clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (9.81) has a moderate half-life. Ligand B (-23.733) has a very short half-life, which is a major concern.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.127 and 0.103), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-5.7 and -6.7 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B has a better logP, slightly better affinity, and lower DILI risk. However, it suffers from significantly worse metabolic stability (high Cl_mic, very short t1/2) and very poor aqueous solubility. Ligand A has poor Caco-2 permeability and a low logP, but its metabolic stability is better, and its hERG risk is very low. Given the enzyme-specific priorities, metabolic stability and hERG risk are crucial. While both have solubility issues, the significantly better metabolic stability of Ligand A makes it the more promising candidate, despite its lower logP and Caco-2 permeability. The solubility and permeability issues can be addressed through formulation or further chemical modifications, but poor metabolic stability is harder to fix.

Output:
0
2025-04-17 12:13:28,434 - INFO - Batch 112 complete. Total preferences: 1792
2025-04-17 12:13:28,434 - INFO - Processing batch 113/512...
2025-04-17 12:14:14,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Ligand A (347.415 Da) is within the ideal range (200-500 Da). Ligand B (525.657 Da) is at the upper limit and slightly above, potentially impacting permeability.

**TPSA:** Both ligands (A: 80.23, B: 87.55) are below 140, suggesting reasonable absorption.

**logP:** Ligand A (0.683) is a bit low, potentially hindering permeation. Ligand B (5.308) is high, raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is favorable. Ligand B (HBD=2, HBA=8) is also acceptable, but higher HBA could slightly reduce permeability.

**QED:** Ligand A (0.811) has a strong drug-like profile. Ligand B (0.257) is significantly lower, indicating a less desirable overall profile.

**DILI:** Ligand A (44.591) has a low DILI risk. Ligand B (85.537) has a considerably higher DILI risk.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (76.735) is moderate, while Ligand B (62.35) is lower.

**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 (-4.894).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.498) is better than Ligand B (-4.332).

**hERG:** Ligand A (0.192) has a very low hERG risk. Ligand B (0.939) has a higher, though not alarming, hERG risk.

**Microsomal Clearance:** Ligand A (28.408 mL/min/kg) is relatively low, suggesting better metabolic stability. Ligand B (98.313 mL/min/kg) has high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (12.893 hours) is a reasonable half-life. Ligand B (52.087 hours) is significantly longer, which is positive.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.161, B: 0.913).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Conclusion:**

Despite Ligand A's lower logP and Caco-2 permeability, its superior binding affinity, much lower DILI risk, better QED score, and lower microsomal clearance make it the more promising candidate. The strong binding affinity can potentially compensate for the slightly lower logP, and the improved ADME properties (DILI, clearance, QED) are crucial for drug development. Ligand B's high logP, poor QED, and high DILI risk are significant drawbacks.

Output:
0
2025-04-17 12:14:14,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.491 and 353.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.77) is better than Ligand B (55.84), both are acceptable, but lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (3.76 and 3.408), within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, Ligand B has 0. Both are acceptable, staying within the limit of 5.

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

**QED:** Ligand A (0.694) has a slightly better QED score than Ligand B (0.565), indicating slightly better overall drug-likeness. Both are above the 0.5 threshold.

**DILI:** Ligand A (44.436) has a higher DILI risk than Ligand B (15.355). This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (73.129) is slightly better than Ligand B (66.576). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.697 and -4.687). These values are unusual and suggest poor permeability. However, since both are similar, this isn't a deciding factor.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.348 and -3.647), 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 (0.794 and 0.797), which is good.

**Microsomal Clearance:** Ligand A (107.153) has a higher microsomal clearance than Ligand B (101.292). Lower clearance is preferred for better metabolic stability, giving a slight edge to Ligand B.

**In vitro Half-Life:** Ligand A (67.744) has a longer half-life than Ligand B (0.997). This is a significant advantage for Ligand A, as longer half-life can lead to less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.832 and 0.542).

**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 of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's superior DILI and slightly better solubility, Ligand A's significantly stronger binding affinity (-8.2 vs -7.6 kcal/mol) and longer half-life are critical advantages for an enzyme inhibitor. The difference in binding affinity is large enough to compensate for the slightly higher DILI risk and lower QED.

Output:
1
2025-04-17 12:14:14,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.463 and 344.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.13) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (97.78) is still under 140, but less optimal than A.

**logP:** Both ligands have good logP values (3.465 and 2.325), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 8.  Ligand A is better here, as fewer HBA generally improves permeability.

**QED:** Both ligands have similar QED scores (0.544 and 0.532), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 73.556, which is concerning, placing it in the higher risk category (>60). Ligand B has a much lower DILI risk (52.036), which is preferable.

**BBB:** Both have reasonable BBB penetration (81.97 and 71.074), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.044), which is highly unusual and suggests very poor permeability. Ligand B has a negative value as well (-5.519), but is still comparable to A.

**Aqueous Solubility:** Both have negative solubility values (-4.114 and -2.277), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.761 and 0.642), which is good.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (78.99) than Ligand B (40.24), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (58.241) than Ligand B (17.465), which is positive. However, the poor metabolic stability indicated by Cl_mic suggests this half-life might not be reliable *in vivo*.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.735 and 0.163), which is favorable.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-8.9 kcal/mol) than Ligand B (-7.1 kcal/mol). This is a substantial advantage (over 1.5 kcal/mol difference).

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its extremely poor predicted permeability (negative Caco-2) and high DILI risk are major concerns. The higher Cl_mic also suggests poor metabolic stability. Ligand B, while having a slightly weaker affinity, has a much better safety profile (lower DILI) and, while still poor, a less problematic permeability prediction. The difference in binding affinity is significant, but can potentially be overcome with further optimization. Given the enzyme-specific priorities, metabolic stability and safety are crucial, making Ligand B the more viable starting point.

Output:
1
2025-04-17 12:14:14,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.5 and 363.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.9 and 75.4) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (1.95 and 2.95). Ligand B is slightly higher, potentially offering better membrane permeability.

**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 (0.662 and 0.782), indicating drug-like properties.

**DILI:** Ligand A (14.23) has a significantly lower DILI risk than Ligand B (50.45). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB penetration (71.2) than Ligand A (34.4), but this is less important here.

**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, which is also unusual and concerning. Ligand B is slightly worse (-2.403 vs -1.311).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.32 and 0.528), which is good.

**Microsomal Clearance:** Ligand B (87.92) has a significantly higher microsomal clearance than Ligand A (41.73), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (8.37 and 8.01 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.049 and 0.272).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand B has a superior binding affinity, Ligand A presents a much better safety profile with a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The solubility issues are concerning for both, but the DILI risk for Ligand B is a major red flag. Given the enzyme-kinase focus, metabolic stability and safety are crucial. The affinity difference, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 12:14:14,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.813 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.16) is well below the 140 threshold, suggesting good absorption. Ligand B (98.32) is still within acceptable limits but higher, potentially impacting absorption slightly.

**logP:** Ligand A (3.452) is optimal. Ligand B (1.521) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both have reasonable H-bonding characteristics, within the suggested limits.

**QED:** Both ligands have similar QED values (0.721 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A (84.219) has a higher DILI risk than Ligand B (48.313). This is a significant concern for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (68.166) is higher than Ligand B (33.385), but this is less important.

**Caco-2 Permeability:** Ligand A (-4.952) has poor Caco-2 permeability, while Ligand B (-5.572) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-3.903) has slightly better solubility than Ligand B (-1.444), which is beneficial.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.33 and 0.494).

**Microsomal Clearance:** Ligand B (-7.158) exhibits significantly *lower* (better) microsomal clearance than Ligand A (46.255). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-21.446) has a much longer half-life than Ligand A (7.509), which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.277 and 0.042).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.9 and -9.3 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk are crucial advantages for an enzyme target. While both have poor Caco-2 permeability, the other benefits of Ligand B outweigh this drawback. Ligand A's higher DILI risk and faster clearance are major liabilities.

Output:
1
2025-04-17 12:14:14,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 346.406 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.27) is slightly higher than Ligand B (78.09). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.649 and 1.984), 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:** Ligand A (0.842) has a better QED score than Ligand B (0.718), indicating a more drug-like profile.

**DILI:** Ligand A (31.989) has a significantly lower DILI risk than Ligand B (55.874). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (72.082) is slightly better than Ligand B (67.352). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.749) is slightly better than Ligand B (-5.144).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.605) is slightly better than Ligand B (-2.651).

**hERG Inhibition:** Ligand A (0.229) has a much lower hERG inhibition liability than Ligand B (0.478). This is a significant advantage for Ligand A, reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (10.874) has a lower microsomal clearance than Ligand B (33.657), suggesting better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (58.409) has a much longer in vitro half-life than Ligand A (-12.081). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux liability than Ligand B (0.083).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.8 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. However, Ligand A demonstrates superior safety profiles with lower DILI and hERG risk, and better metabolic stability (lower Cl_mic). The solubility and permeability are poor for both. The affinity difference is substantial, and for an enzyme target, potency is paramount. While the ADME profile of Ligand A is better, the increased potency of Ligand B is likely to be more impactful, and the ADME issues can be addressed through further optimization.

Output:
1
2025-04-17 12:14:14,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.43) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (70.08) is higher than Ligand B (58.12). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (0.389) is quite low, potentially hindering permeation. Ligand B (3.792) 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 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 scores (A: 0.748, B: 0.8), indicating good drug-like properties.

**DILI:** Both have relatively high DILI risk (A: 21.6, B: 51.3), but are still below the concerning threshold of 60.

**BBB:** Ligand A (51.5) has a lower BBB penetration percentile than Ligand B (87.9). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Ligand A (-4.367) has poor Caco-2 permeability, while Ligand B (-5.119) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.96) has poor solubility, while Ligand B (-3.997) is even worse. This is a concern for both, but more so for B.

**hERG Inhibition:** Ligand A (0.169) shows a very low risk of hERG inhibition, which is excellent. Ligand B (0.628) is higher, indicating a moderate risk. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-2.778) has a negative clearance, suggesting very good metabolic stability. Ligand B (92.872) has a high clearance, indicating rapid metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (0.829) has a short half-life, while Ligand B (28.644) has a much longer half-life. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is favorable. Ligand B (0.714) has moderate P-gp efflux. This favors Ligand A.

**Binding Affinity:** Ligand B (-7.9) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage for Ligand B and could potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and longer half-life. However, it suffers from poor solubility, high metabolic clearance, and moderate hERG risk. Ligand A has excellent metabolic stability, low hERG risk, and low P-gp efflux, but its binding affinity is very weak, and it has poor permeability and solubility.

Given the enzyme-specific priorities, *binding affinity is paramount*. The substantial difference in binding affinity (-7.9 vs 0.0 kcal/mol) is likely to be the deciding factor. While Ligand B has ADME liabilities, these can potentially be addressed through further optimization. The lack of binding affinity in Ligand A makes it a less promising starting point, even with its better ADME profile.

Output:
1
2025-04-17 12:14:14,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (464.117 Da) is higher, but still acceptable. Ligand B (368.543 Da) is preferable.

**TPSA:** Ligand A (71.42) is higher than Ligand B (49.85). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Ligand A (4.602) is slightly high, potentially leading to solubility issues and off-target effects. Ligand B (2.562) is within the optimal range (1-3).

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

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range.

**QED:** Both ligands have good QED scores (A: 0.466, B: 0.648), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A has a high DILI risk (96.82%), which is a significant concern. Ligand B has a very low DILI risk (19.891%), a major advantage.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (73.943%) has better BBB penetration than Ligand A (48.119%).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.072) is worse than Ligand B (-4.655).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-5.338) is worse than Ligand B (-2.544).

**hERG Inhibition:** Ligand A (0.898) has a higher hERG risk than Ligand B (0.529), which is preferable.

**Microsomal Clearance:** Both have similar microsomal clearance rates (A: 45.254, B: 47.031).

**In vitro Half-Life:** Ligand A (63.127) has a longer half-life than Ligand B (-0.916), which is a positive.

**P-gp Efflux:** Ligand A (0.867) has higher P-gp efflux than Ligand B (0.1), which is a negative.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk, poor solubility, and higher P-gp efflux are major drawbacks. Ligand B, while having weaker binding affinity, demonstrates a much more favorable safety profile (low DILI, lower hERG), better solubility, and lower P-gp efflux. The difference in binding affinity (7.6 kcal/mol) is substantial, but the safety concerns with Ligand A are too significant to ignore. For an enzyme target like SRC kinase, a good balance of potency and ADME properties is crucial. Given the significant safety liabilities of Ligand A, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 12:14:14,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.395 and 360.885 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (101.73) is higher than Ligand B (59.47). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**logP:** Ligand A (0.664) is quite low, potentially hindering permeability. Ligand B (4.64) is higher, approaching the upper limit, which could raise solubility concerns, but is more favorable for membrane permeation.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 8 HBAs, while Ligand B has 3. Both are below the limit of 10, but Ligand B is preferable.

**QED:** Ligand B (0.863) has a much higher QED score than Ligand A (0.476), indicating a more drug-like profile.

**DILI:** Ligand A (69.058) has a higher DILI risk than Ligand B (31.989), which is a significant concern.

**BBB:** Ligand A (36.526) has poor BBB penetration, while Ligand B (75.998) is much better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired or off-target CNS activity is a worry.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.887 and -4.782). This is unusual and suggests poor permeability *in vitro*. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.107 and -3.565), indicating poor aqueous solubility. This is a considerable drawback for both.

**hERG Inhibition:** Ligand A (0.067) has a very low hERG risk, which is excellent. Ligand B (0.767) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (53.664) has a moderate microsomal clearance, while Ligand B (8.92) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (98.682) has a much longer in vitro half-life than Ligand A (-10.786), indicating significantly better metabolic stability.

**P-gp Efflux:** Ligand A (0.111) has low P-gp efflux, while Ligand B (0.543) has moderate P-gp efflux.

**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 of the ADME concerns.

**Conclusion:**

Despite both ligands having solubility issues, Ligand B is the superior candidate. It has a significantly better QED score, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and, crucially, a much stronger binding affinity. The higher logP is a potential concern, but the strong binding affinity and improved ADME properties make Ligand B the more promising drug candidate.

Output:
1
2025-04-17 12:14:14,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.324 Da) is slightly higher, but still acceptable. Ligand B (366.487 Da) is preferable.

**TPSA:** Both ligands have TPSA values (98.72 and 95.74 respectively) that are acceptable for oral absorption (<140).

**logP:** Both ligands have good logP values (2.687 and 1.453), falling within the optimal range of 1-3. Ligand A is slightly more lipophilic, which could be beneficial for cell permeability but also raises potential off-target concerns.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2) and HBA (7/4) counts, within the guidelines.

**QED:** Both ligands have good QED scores (0.638 and 0.729), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (73.09%) compared to Ligand B (22.722%). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (77.937%) has a higher BBB score, but this is less important here.

**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 for both, but could be addressed through formulation.

**hERG Inhibition:** Ligand A (0.548) has a slightly higher hERG risk than Ligand B (0.117), though both are relatively low.

**Microsomal Clearance:** Ligand B has a significantly higher microsomal clearance (31.708 mL/min/kg) than Ligand A (13.38 mL/min/kg). This suggests Ligand A is more metabolically stable, a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B has a negative in vitro half-life (-2.033 hours), which is problematic. Ligand A has a more reasonable half-life (44.602 hours).

**P-gp Efflux:** Ligand B has a very low P-gp efflux liability (0.016), which is favorable. Ligand A has a higher, but still relatively low, P-gp efflux (0.449).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-8.5 kcal/mol) compared to Ligand A (-7.0 kcal/mol). This 1.5 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite the superior metabolic stability of Ligand A, the significantly higher DILI risk is a major red flag. The substantially better binding affinity of Ligand B (-8.5 kcal/mol vs -7.0 kcal/mol) is a critical advantage for an enzyme inhibitor, and the lower DILI risk makes it the more promising candidate. While the negative half-life and solubility are concerns, these can potentially be addressed through formulation or structural modifications.

Output:
1
2025-04-17 12:14:14,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.22 Da) is slightly higher than Ligand B (343.435 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand B (80.99 A^2) is lower than Ligand A (97.11 A^2), which is slightly favorable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.658) and Ligand B (1.71) are both good.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 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 (A: 0.685, B: 0.828), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (97.169%) than Ligand B (65.064%). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (75.107%) has a higher BBB value than Ligand A (16.983%), but this is less critical.

**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 (0.064) has a lower hERG risk than Ligand B (0.4), which is favorable.

**Microsomal Clearance:** Ligand B has a much higher microsomal clearance (57.966 mL/min/kg) than Ligand A (0.982 mL/min/kg). This indicates that Ligand A is much more metabolically stable, which is a significant advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (14.469 hours) than Ligand B (9.296 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.015, B: 0.019).

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) than Ligand B. However, it has a significantly higher DILI risk. The difference in binding affinity (-1.2 kcal/mol) is substantial and could be critical for efficacy. Given the enzyme-specific priorities, metabolic stability and potency are key. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The solubility and permeability issues are shared by both compounds and would need to be addressed regardless.

Output:
1
2025-04-17 12:14:14,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.403 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.01) is better than Ligand B (65.12) as it is still within the acceptable range for oral absorption (<140), while B is significantly lower, which is favorable.

**logP:** Ligand A (1.028) is within the optimal 1-3 range. Ligand B (-0.314) is slightly below 1, which *could* indicate potential permeability issues, but not dramatically so.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (5) meet the <=10 criteria.

**QED:** Both ligands (0.697 and 0.666) are above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (55.176) has a higher DILI risk than Ligand B (15.2). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (52.85) is higher than Ligand A (30.399), but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.633) and Ligand B (-5.004) are both 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 (-2.387) and Ligand B (-1.074) are both negative values, indicating poor solubility. This is a concern for both, but B is slightly better.

**hERG Inhibition:** Ligand A (0.607) has a slightly higher hERG risk than Ligand B (0.316), but both are relatively low.

**Microsomal Clearance:** Ligand A (-28.31) has *much* lower (better) microsomal clearance than Ligand B (21.317). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-6.484) has a longer half-life than Ligand B (2.371). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands (0.013 and 0.007) have very low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This >1.5 kcal/mol advantage is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk and poorer solubility, its *much* stronger binding affinity (-9.4 vs -7.1 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The potency advantage is substantial and outweighs the concerns regarding DILI and solubility, which can potentially be addressed through formulation strategies or further chemical modifications.

Output:
1
2025-04-17 12:14:14,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.325 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.61) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for oral absorption, but B is significantly better.

**logP:** Both ligands (1.524 and 2.019) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable, being less than 10.

**QED:** Both ligands have good QED scores (0.823 and 0.794), indicating drug-like properties.

**DILI:** Ligand A (53.625) has a moderate DILI risk, while Ligand B (14.618) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (70.803 and 78.519). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.87 and -4.76), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.656 and -3.259), indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.254 and 0.211).

**Microsomal Clearance:** Ligand A (10.089) has a lower microsomal clearance than Ligand B (21.058), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.734) has a longer half-life than Ligand B (0.249). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.163 and 0.032).

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

**Overall Assessment:**

Ligand B has a significantly lower DILI risk and a lower TPSA, which are both desirable. However, Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life. Both have poor solubility and permeability. Given the importance of metabolic stability for kinase inhibitors and the slightly longer half-life of Ligand A, it is marginally preferred. However, the low DILI risk of Ligand B is very attractive. The poor solubility and permeability are concerning for both, and would need to be addressed through formulation or further chemical modification. Since the binding affinity is almost identical, the ADME properties are the deciding factor.

Output:
0
2025-04-17 12:14:14,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.5 and 370.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.23) is better than Ligand B (80.57). Both are below 140, suggesting reasonable absorption, but lower TPSA is generally preferred.

**logP:** Both ligands have good logP values (3.76 and 3.15), falling 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.659 and 0.772), indicating good drug-like properties.

**DILI:** Ligand A (38.3) has a significantly lower DILI risk than Ligand B (60.6). This is a major advantage for Ligand A.

**BBB:** Ligand A (76.3) has a higher BBB penetration score than Ligand B (46.2). While not critical for a non-CNS target like SRC, it isn't a detriment.

**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. Comparing the magnitude of the negative values, Ligand A (-4.8) is slightly better than Ligand B (-4.911).

**Aqueous Solubility:** Both ligands exhibit poor aqueous solubility (-4.513 and -3.577). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.562) has a slightly higher hERG risk than Ligand B (0.169). This is a negative for Ligand A, and a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (69.4) has a higher microsomal clearance than Ligand B (22.5). This indicates Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (56.1) has a longer in vitro half-life than Ligand A (38.6), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.106 and 0.133).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.0 kcal/mol difference is substantial and outweighs many of the other drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a higher DILI risk, the significantly improved binding affinity (-8.7 vs -7.7 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are critical for an enzyme inhibitor. The lower hERG risk for Ligand B is also a positive. The solubility issues are a concern for both, but can potentially be overcome with formulation.



Output:
1
2025-04-17 12:14:14,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.356 and 372.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is slightly higher than Ligand B (43.18). Both are well below the 140 threshold for oral absorption.

**logP:** Both ligands (3.767 and 3.936) are within the optimal 1-3 range, suggesting good permeability.

**H-Bond Donors:** Ligand A has 1 HBD, and 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 range (<=10), but Ligand A is preferable.

**QED:** Both ligands have reasonable QED scores (0.791 and 0.634), indicating good drug-like properties.

**DILI:** Ligand A (54.323) has a higher DILI risk than Ligand B (30.826). This is a significant drawback for Ligand A.

**BBB:** Both have high BBB penetration, but Ligand A (95.386) is slightly better than Ligand B (79.992). However, BBB is less critical for a non-CNS target like SRC.

**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 (0.651) has a slightly higher hERG risk than Ligand B (0.859). Lower is better here, so Ligand B is preferable.

**Microsomal Clearance:** Ligand B (63.18) has lower microsomal clearance than Ligand A (75.321), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (19.479) has a significantly longer in vitro half-life than Ligand A (-2.906). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.174) has lower P-gp efflux than Ligand B (0.281), which is preferable.

**Binding Affinity:** Ligand B (-7.4 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 B is the better candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better binding affinity. While Ligand A has slightly better BBB penetration and P-gp efflux, these are less critical for a non-CNS enzyme target like SRC. The poor solubility and permeability indicated by the negative values are concerning for both, but the other advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 12:14:14,599 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [350.463, 76.46, 2.431, 1, 5, 0.8, 17.681, 81.233, -4.614, -1.259, 0.494, 30.337, -14.031, 0.109, -9]
**Ligand B:** [339.487, 53.94, 4.288, 1, 5, 0.9, 51.377, 72.896, -4.995, -4.137, 0.86, 87.414, 21.322, 0.351, -8.5]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (350.463) and B (339.487) are comparable.
2. **TPSA:** A (76.46) is slightly higher than B (53.94). Both are below the 140 A^2 threshold for oral absorption, but B is better.
3. **logP:** A (2.431) is optimal, while B (4.288) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** Both have 5 HBA, which is good.
6. **QED:** Both have good QED scores (A: 0.8, B: 0.9), indicating drug-likeness.
7. **DILI:** A (17.681) has a significantly lower DILI risk than B (51.377). This is a major advantage for ligand A.
8. **BBB:** A (81.233) has better BBB penetration than B (72.896), although this is less critical for a non-CNS target like SRC.
9. **Caco-2:** A (-4.614) and B (-4.995) are both negative, which is not ideal. Lower values suggest poor permeability. B is slightly worse.
10. **Solubility:** A (-1.259) is better than B (-4.137). Solubility is important for bioavailability.
11. **hERG:** A (0.494) has a lower hERG risk than B (0.86). This is a significant safety advantage for A.
12. **Cl_mic:** A (30.337) has a lower microsomal clearance than B (87.414), indicating better metabolic stability. This is crucial for kinase inhibitors.
13. **t1/2:** A (-14.031) has a longer in vitro half-life than B (21.322). A negative value indicates a very long half-life, which is highly desirable.
14. **Pgp:** A (0.109) has lower P-gp efflux than B (0.351), which is favorable for bioavailability.
15. **Binding Affinity:** Both have excellent binding affinities (A: -9 kcal/mol, B: -8.5 kcal/mol). A is slightly better, but the difference is relatively small.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in all these areas. While ligand B has a good affinity, its higher logP, DILI risk, hERG risk, and higher clearance are significant drawbacks. The longer half-life of ligand A is a major advantage.

**Conclusion:**

Ligand A is the more promising drug candidate due to its superior ADME-Tox profile (lower DILI, hERG, Cl_mic, better solubility, and Pgp efflux) and longer half-life, despite the slightly lower TPSA and Caco-2 values. The small advantage in binding affinity is overshadowed by the substantial improvements in drug-like properties.

Output:
0
2025-04-17 12:14:14,599 - INFO - Batch 113 complete. Total preferences: 1808
2025-04-17 12:14:14,599 - INFO - Processing batch 114/512...
2025-04-17 12:15:02,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (383.319 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.36) is significantly better than Ligand B (100.27). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B is approaching a concerning level.

**logP:** Ligand A (4.234) is higher than optimal (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.039) is on the low side, which could hinder permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBD, which is acceptable. Ligand B has 6 HBA, which is at the upper limit of preference, while Ligand A has only 2, which is good.

**QED:** Both ligands have reasonable QED scores (0.729 and 0.585), indicating acceptable drug-likeness.

**DILI:** Both ligands have similar DILI risk (18.379 and 19.504), and are both considered low risk (<40).

**BBB:** Ligand A (74.176) has better BBB penetration than Ligand B (49.787), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.596) has better Caco-2 permeability than Ligand B (-4.987), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-4.327) has better aqueous solubility than Ligand B (-1.92), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.669) has a lower hERG inhibition liability than Ligand B (0.083), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand B (-7.353) has a much lower (better) microsomal clearance than Ligand A (-3.012), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (30.796) has a longer in vitro half-life than Ligand B (23.154), which is desirable.

**P-gp Efflux:** Ligand A (0.272) has lower P-gp efflux than Ligand B (0.024), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This difference of 2.2 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic), the significantly stronger binding affinity of Ligand A (-9.6 vs -7.4 kcal/mol), combined with better solubility, permeability, hERG risk, and P-gp efflux, makes it the more promising candidate. The higher logP of Ligand A is a concern, but the potency advantage is likely to be more critical for an enzyme inhibitor.

Output:
1
2025-04-17 12:15:02,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.522 and 360.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold for absorption. Ligand B (119.33) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (2.246) is optimal (1-3). Ligand B (-0.884) is below 1, which could hinder permeation.

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

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is also acceptable.

**QED:** Ligand A (0.743) is strong, indicating good drug-likeness. Ligand B (0.468) is lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (27.801) has a very low DILI risk. Ligand B (11.128) also has a low DILI risk, but is slightly higher than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.133) is reasonable. Ligand B (38.581) is lower.

**Caco-2:** Ligand A (-4.707) is quite poor, suggesting very limited intestinal absorption. Ligand B (-5.087) is similarly poor.

**Solubility:** Ligand A (-3.731) is poor. Ligand B (-0.68) is also poor, but slightly better than Ligand A.

**hERG:** Ligand A (0.652) has a low hERG risk. Ligand B (0.17) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (50.233) is moderate. Ligand B (-1.56) is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (-1.794) is good. Ligand B (-18.784) is excellent, suggesting a very long half-life.

**P-gp Efflux:** Ligand A (0.232) is low, suggesting minimal efflux. Ligand B (0.014) is very low, indicating minimal efflux.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) is significantly stronger than Ligand B (-7.6 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A's poor Caco-2 and solubility, its significantly superior binding affinity (-8.5 vs -7.6 kcal/mol) and favorable DILI and hERG profiles make it the more promising candidate. The strong binding is a critical advantage for an enzyme inhibitor. Ligand B has better metabolic stability and slightly better solubility, but the weaker binding affinity is a major drawback.

Output:
1
2025-04-17 12:15:02,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.299 Da and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.16) is borderline, but acceptable for oral absorption. Ligand B (62.55) is excellent, well below the 140 threshold.

**logP:** Ligand A (1.001) is optimal. Ligand B (3.23) is also acceptable, though approaching the upper limit.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.654 and 0.786), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (97.247), which is a significant concern. Ligand B has a very low DILI risk (21.908), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (60.644) and Ligand B (55.874) are both relatively low.

**Caco-2:** Both ligands have negative Caco-2 values (-4.708 and -4.615), which is unusual and suggests poor permeability. This is a potential issue for both.

**Solubility:** Both ligands have negative solubility values (-5.295 and -2.289), which is also unusual and suggests poor solubility. This is a potential issue for both.

**hERG:** Both ligands have low hERG risk (0.418 and 0.441), which is positive.

**Microsomal Clearance:** Ligand A (26.959) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (68.798).

**In vitro Half-Life:** Both have good in vitro half-lives (70.832 and 73.259 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.285 and 0.259), which is favorable.

**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 small.

**Conclusion:**

While Ligand A has slightly better metabolic stability, the extremely high DILI risk is a deal-breaker. Ligand B, despite slightly higher clearance, has a significantly lower DILI risk, acceptable logP and TPSA, and comparable binding affinity. The negative Caco-2 and solubility values are concerning for both, but the DILI risk for Ligand A is a more immediate and serious issue. Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:15:02,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.46 and 352.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (116.92). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (1.366) is optimal (1-3), while Ligand B (-0.758) is slightly below this, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is preferable to Ligand B (3 HBD, 7 HBA). Both are within acceptable ranges, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.712 and 0.641), indicating good drug-like properties.

**DILI:** Ligand A (19.27) has a much lower DILI risk than Ligand B (52.42), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (65.37) is better than Ligand B (20.51).

**Caco-2 Permeability:** Ligand A (-5.069) and Ligand B (-5.071) are similar, suggesting comparable intestinal absorption, although the negative values are unusual and require further investigation.

**Aqueous Solubility:** Ligand A (-2.782) is slightly better than Ligand B (-1.176), both are poor, and this is a potential concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.215 and 0.056), which is excellent.

**Microsomal Clearance:** Ligand A (53.96) is higher than Ligand B (-9.55). A negative value for B suggests very high metabolic stability, which is a substantial advantage.

**In vitro Half-Life:** Ligand A (-9.78) is better than Ligand B (-11.87), indicating a longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.023).

**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 noteworthy.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While Ligand A has better TPSA and a lower DILI risk, Ligand B's significantly superior metabolic stability (negative Cl_mic) and comparable binding affinity outweigh these drawbacks. The negative Cl_mic suggests very slow metabolism, which is crucial for maintaining therapeutic concentrations. The slightly lower logP of B is a minor concern that could be addressed through further optimization.

Output:
1
2025-04-17 12:15:02,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.387 and 358.473 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.18) is slightly above the optimal <140, but acceptable. Ligand B (58.2) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.636) is a bit low, potentially hindering permeation. Ligand B (3.302) 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 2 HBA, also acceptable.

**QED:** Ligand B (0.699) has a better QED score than Ligand A (0.345), indicating a more drug-like profile.

**DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (16.402). This is a significant concern.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (89.259) is higher, but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.479) has very poor predicted permeability. Ligand B (-4.616) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor predicted solubility (-2.781 and -3.752 respectively).

**hERG Inhibition:** Ligand A (0.064) has a very low hERG risk, which is excellent. Ligand B (0.624) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (1.496) has a much lower microsomal clearance than Ligand B (38.794), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15) has a negative half-life, which is not physically possible and indicates a potential issue with the prediction or the molecule itself. Ligand B (24.76) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.096 and 0.116).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic, reasonable t1/2). Ligand A's negative half-life is a major red flag. Although Ligand A has a very low hERG risk, the superior potency and safety profile of Ligand B outweigh this advantage.

Output:
1
2025-04-17 12:15:02,624 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.391, 104.98 ,  -0.041,   1.   ,   6.   ,   0.604,  62.66 ,  43.815, -4.92 ,  -1.538,   0.075,  18.257, -11.541,   0.012,  -7.7  ]
**Ligand B:** [386.239, 104.23 ,   1.785,   2.   ,   6.   ,   0.834,  86.002,  13.377, -4.885,  -3.116,   0.104,  -2.082, -25.654,   0.051,   0.   ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (352.391) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** Both are acceptable at ~104-105, below the 140 threshold for oral absorption.
3. **logP:** A (-0.041) is a bit low, potentially hindering permeability. B (1.785) is much better, within the optimal 1-3 range.
4. **HBD:** Both are reasonable (A: 1, B: 2), well below the 5 limit.
5. **HBA:** Both are equal and acceptable (6).
6. **QED:** Both are good (A: 0.604, B: 0.834), indicating drug-like properties, with B being slightly better.
7. **DILI:** A (62.66) is acceptable, but B (86.002) is higher, indicating a greater risk of liver injury. This is a significant drawback for B.
8. **BBB:** A (43.815) is low, not a major concern for a non-CNS target like SRC. B (13.377) is even lower.
9. **Caco-2:** Both are very poor (-4.92 and -4.885). This is a significant issue for both.
10. **Solubility:** Both are very poor (-1.538 and -3.116). This is also a significant issue for both.
11. **hERG:** Both are very low risk (A: 0.075, B: 0.104).
12. **Cl_mic:** A (18.257) is higher than B (-2.082), suggesting faster metabolism and lower metabolic stability. B is significantly better here.
13. **t1/2:** A (-11.541) is very poor, indicating rapid clearance. B (-25.654) is even worse.
14. **Pgp:** Both are very low (A: 0.012, B: 0.051).
15. **Affinity:** A (-7.7) is significantly better than B (0.0). A has a much stronger binding affinity.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand A is *much* better.
*   **Metabolic Stability:** Ligand B is significantly better (lower Cl_mic, though both are problematic).
*   **Solubility:** Both are very poor, a major concern.
*   **hERG:** Both are good.
*   **DILI:** Ligand A is better.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, **Ligand A** is the more promising candidate. The substantially stronger binding affinity (-7.7 kcal/mol vs 0.0 kcal/mol) is a critical advantage for an enzyme inhibitor. While Ligand B has better metabolic stability, the difference in affinity is so large that it outweighs this benefit. The DILI risk is also lower for Ligand A. Addressing the solubility issues will be crucial for either compound, but the superior potency of A makes it the better starting point for optimization.

Output:
0
2025-04-17 12:15:02,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 347.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (101.41 and 97.81) below 140, suggesting reasonable absorption potential.

**logP:** Both ligands have logP values (1.017 and 0.705) 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 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.77 and 0.855), indicating drug-like properties.

**DILI:** Ligand A (36.758) has a lower DILI risk than Ligand B (57.076), which is a significant advantage. Both are below the concerning threshold of 60, but A is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (64.056) has a slightly higher BBB penetration than Ligand B (48.701), but this is not a major factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.667 and -5.164). 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 physicochemical properties.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.164 and -1.54). Similar to Caco-2, these are on a log scale and suggest poor solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.047 and 0.119), which is excellent.

**Microsomal Clearance:** Ligand B (20.419 mL/min/kg) has significantly lower microsomal clearance than Ligand A (43.279 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (22.581 hours) has a much longer in vitro half-life than Ligand A (-15.726 hours). This is a substantial benefit, potentially allowing for less frequent dosing. The negative value for A is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.041), which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-9.0 and -8.5 kcal/mol). Ligand A is slightly better (-9.0 vs -8.5), but the difference is less than the 1.5 kcal/mol threshold that would heavily favor it.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and lower DILI risk, Ligand B's significantly improved metabolic stability (lower Cl_mic) and longer half-life are more critical for an enzyme target like SRC. The solubility and permeability concerns are present in both, but can be addressed during formulation.

Output:
1
2025-04-17 12:15:02,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.451 and 348.422 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (106.14) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (58.44) is excellent, well below 140.

**logP:** Both ligands have good logP values (0.936 and 1.16), 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 a QED of 0.82, indicating a strong drug-like profile.

**DILI:** Ligand A has a DILI risk of 38.62, which is good (low risk). Ligand B has a DILI risk of 20.783, even better.

**BBB:** Both ligands have moderate BBB penetration, with Ligand B (86.894) being significantly higher than Ligand A (67.197). However, BBB is less crucial for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.461) has poor Caco-2 permeability, which is a concern. Ligand B (-4.752) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.433) has poor solubility, while Ligand B (-0.566) is slightly better, but still not ideal.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.069 and 0.287), which is excellent.

**Microsomal Clearance:** Ligand A (8.875) has a lower microsomal clearance than Ligand B (11.412), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have a negative half-life (-16.436 and -16.317), which is unusual and likely indicates an issue with the experimental setup or a very rapidly degrading compound. This is a significant concern for both.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.061), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent and the most important factor here.

**Conclusion:**

Despite the similar binding affinities, Ligand B is slightly preferred. While both have poor solubility and half-lives, Ligand B has a significantly lower DILI risk, better BBB penetration, and a slightly better Caco-2 permeability. The lower microsomal clearance of Ligand A is a positive, but the other factors tip the balance towards Ligand B. The negative half-life values are concerning for both, and would require further investigation.

Output:
1
2025-04-17 12:15:02,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (333.391 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.15) is well below the 140 threshold, while Ligand B (78.87) is also acceptable.

**logP:** Ligand A (3.2) is at the upper end of the optimal range (1-3), while Ligand B (1.851) is closer to the lower end.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, fitting the criteria. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.641 and 0.731), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 78.945, which is concerning (high risk, >60). Ligand B has a much lower DILI risk of 20.706, which is excellent. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.784) has better BBB penetration than Ligand B (56.65).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.012 and -4.586), which is unusual and suggests poor permeability. However, these values are on a log scale and need careful interpretation.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.471 and -1.569), indicating poor aqueous solubility. Ligand B is slightly better in this regard.

**hERG Inhibition:** Ligand A (0.823) has a slightly higher hERG risk than Ligand B (0.268), which is preferable.

**Microsomal Clearance:** Ligand A (1.583) has significantly lower microsomal clearance than Ligand B (46.376), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (35.02) has a much longer half-life than Ligand B (-1.757), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.721) has lower P-gp efflux than Ligand B (0.055), which is preferable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 1.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior 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. Ligand B has a much better safety profile (lower DILI, lower hERG), but weaker binding affinity and poorer metabolic stability.

Given the enzyme-kinase specific priorities, potency and metabolic stability are crucial. The 1.9 kcal/mol difference in binding affinity is substantial. While the DILI risk for Ligand A is concerning, it may be mitigated through structural modifications during lead optimization. The poor solubility and permeability of both compounds would need to be addressed, but these are often more readily optimized than significant potency or metabolic stability issues.

Output:
0
2025-04-17 12:15:02,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.386 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is well below the 140 threshold for good absorption, and even favorable for potential CNS penetration. Ligand B (81.33) is still under 140, but less optimal than A.

**logP:** Ligand A (2.736) is within the optimal 1-3 range. Ligand B (1.418) is at the lower end of the optimal range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 4 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED scores (0.863 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (51.493) has a moderate DILI risk, while Ligand B (12.757) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (94.184) shows excellent BBB penetration, but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired. Ligand B (68.36) is lower, but still reasonable.

**Caco-2 Permeability:** Ligand A (-4.524) has poor Caco-2 permeability. Ligand B (-5.174) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.093) has poor aqueous solubility. Ligand B (-1.681) has better aqueous solubility, though still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.717 and 0.674).

**Microsomal Clearance:** Ligand A (25.547) has moderate microsomal clearance. Ligand B (-5.849) has *negative* clearance, which is highly unusual and suggests exceptional metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-17.532) has a negative half-life, which is also unusual and suggests very slow metabolism. Ligand B (-24.567) has an even longer predicted half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.172 and 0.036).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), a difference of 1 kcal/mol.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties. Specifically, the significantly lower DILI risk and exceptionally low (negative) microsomal clearance and long half-life are critical advantages for an enzyme inhibitor. The slightly lower affinity of Ligand B can potentially be optimized in subsequent iterations, while improving the ADME profile of Ligand A would be more challenging. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:15:02,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (393.412 and 346.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (88.16 and 78.09) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (target <90). This isn't a major concern for a non-CNS target like SRC.

**logP:** Both ligands (2.294 and 2.074) are within the optimal range of 1-3, suggesting good permeability and avoiding potential solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is acceptable. Ligand A has 6 HBAs and Ligand B has 3 HBAs, both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.786 and 0.742), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (88.251 percentile) compared to Ligand B (23.769 percentile). This is a major concern for Ligand A.

**BBB:** Both have low BBB penetration, which is not critical for a non-CNS target.

**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 likely low.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.258 and 0.387), which is positive.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (13.883 mL/min/kg) compared to Ligand B (12.705 mL/min/kg), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B has a significantly longer *in vitro* half-life (25.513 hours) compared to Ligand A (54.995 hours). This is a significant advantage for Ligand B, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.156), which is good.

**Binding Affinity:** Ligand A has a slightly better binding affinity (-7.8 kcal/mol) compared to Ligand B (-7.5 kcal/mol). While this difference is notable, it may not be enough to overcome the other significant drawbacks of Ligand A.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While Ligand A has slightly better binding affinity, Ligand B demonstrates a significantly lower DILI risk, a longer *in vitro* half-life, and comparable properties across other key ADME parameters. The lower DILI risk is a critical advantage, as liver toxicity is a major cause of drug attrition. The improved metabolic stability (longer half-life) also increases the likelihood of achieving therapeutic concentrations *in vivo*.

Output:
1
2025-04-17 12:15:02,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (373.45 Da) is also good.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (83.72) is lower than Ligand A (91.57), which is slightly preferable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (0.837) is a bit lower, potentially impacting permeability, while Ligand B (1.635) is better positioned.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.784) is slightly better than Ligand B (0.692).

**DILI:** Ligand A (31.795) has a significantly lower DILI risk than Ligand B (51.26), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (94.223) is significantly higher than Ligand A (82.474). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.159) has a negative Caco-2 value, which is concerning and suggests poor permeability. Ligand B (-4.636) is also negative, but slightly less so.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.073) is slightly better than Ligand B (-2.346).

**hERG Inhibition:** Ligand A (0.277) has a lower hERG inhibition risk than Ligand B (0.597), which is a significant advantage.

**Microsomal Clearance:** Ligand A (22.341) has a much lower microsomal clearance than Ligand B (46.333), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.582) has a positive half-life, while Ligand B (-55.172) has a negative half-life, which is a major concern.

**P-gp Efflux:** Ligand A (0.057) has lower P-gp efflux than Ligand B (0.141), which is preferable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better 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. While both have solubility issues, Ligand A excels in crucial areas: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and positive t1/2), lower hERG risk, lower P-gp efflux, and superior binding affinity. The negative Caco-2 values are a concern for both, but the strong binding affinity of Ligand A and its favorable ADME properties outweigh this drawback. Ligand B's very poor half-life and higher DILI/hERG risks are major liabilities.

Output:
0
2025-04-17 12:15:02,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.471 and 357.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is slightly above the preferred <90 for CNS targets, but acceptable for a non-CNS focused kinase inhibitor. Ligand B (43.86) is well within the acceptable range.

**logP:** Both ligands (3.011 and 2.155) are 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, <=10 HBA).

**QED:** Ligand A (0.776) has a better QED score than Ligand B (0.494), indicating a more drug-like profile.

**DILI:** Ligand A (21.83) has a significantly lower DILI risk than Ligand B (25.553), which is a major advantage. Both are below the 40 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target. Ligand B (90.074) has a higher BBB penetration than Ligand A (64.831), but this isn't a primary concern here.

**Caco-2 Permeability:** Ligand A (-5.1) has a worse Caco-2 permeability than Ligand B (-4.557).

**Aqueous Solubility:** Ligand A (-2.342) has a worse aqueous solubility than Ligand B (-0.637). Solubility is important for bioavailability, so B is better here.

**hERG Inhibition:** Ligand A (0.876) has a slightly higher hERG risk than Ligand B (0.73), but both are reasonably low.

**Microsomal Clearance:** Ligand A (0.112) has a much lower microsomal clearance than Ligand B (34.766), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (64.713) has a significantly longer in vitro half-life than Ligand B (-0.266), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.084), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.0), a 0.8 kcal/mol difference. While affinity is paramount, the other ADME properties must be considered.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and solubility, but Ligand A excels in crucial ADME properties for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The difference in binding affinity (0.8 kcal/mol) is not substantial enough to outweigh the substantial advantages of Ligand A in terms of safety and pharmacokinetic properties.

Output:
1
2025-04-17 12:15:02,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.348 and 357.523 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.18) is higher than Ligand B (56.99). While both are reasonably low, Ligand B is better positioned for oral absorption.

**3. logP:** Ligand A (1.789) is within the optimal range (1-3). Ligand B (4.02) is at the upper end, potentially leading to solubility issues or 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 have a reasonable number of HBA (Ligand A: 5, Ligand B: 4), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.714, Ligand B: 0.772), indicating good drug-like properties.

**7. DILI:** Ligand A (51.493) has a slightly higher DILI risk than Ligand B (38.697), but both are below the concerning threshold of 60.

**8. BBB:** This is less crucial for a non-CNS target like SRC, but Ligand B (77.821) has a higher BBB percentile than Ligand A (68.864).

**9. Caco-2 Permeability:** Ligand A (-5.071) and Ligand B (-4.77) both have negative values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.806) has slightly better solubility than Ligand B (-4.97), though both are poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.512, Ligand B: 0.549).

**12. Microsomal Clearance:** Ligand A (18.733) has significantly lower microsomal clearance than Ligand B (74.33), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (5.646) has a shorter half-life than Ligand B (-2.774), which is unusual given the clearance data.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.135, Ligand B: 0.401).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.6), a 0.3 kcal/mol difference. While a 1.5 kcal/mol advantage is significant, 0.3 kcal/mol is less impactful and can be overcome by other factors.

**Conclusion:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), **Ligand A is the more promising candidate**. While Ligand B has slightly better binding affinity and BBB penetration, Ligand A exhibits significantly better metabolic stability (lower Cl_mic) and slightly better solubility. The difference in binding affinity is not substantial enough to outweigh the benefits of improved metabolic stability. The poor Caco-2 permeability is a concern for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 12:15:02,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.503 and 345.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (88.58). Both are below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have good logP values (2.04 and 2.563 respectively), 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 (5) is higher than Ligand A (3), but both are within the acceptable range (<=10).

**6. QED:** Ligand B (0.9) is significantly better than Ligand A (0.738), indicating a more drug-like profile.

**7. DILI:** Ligand A (11.09) has a much lower DILI risk than Ligand B (54.866). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, with Ligand B (71.229) being slightly better than Ligand A (65.839). However, BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.77 and -4.734), which is unusual and suggests poor permeability. This is a potential issue for both, but the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.786 and -2.798), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.587) has a much lower hERG inhibition risk than Ligand B (0.199). This is a critical advantage for Ligand A.

**12. Microsomal Clearance:** Ligand B (41.3) has a higher microsomal clearance than Ligand A (31.209), indicating lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (3.69) has a better in vitro half-life than Ligand B (-20.329). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.166) has a lower P-gp efflux liability than Ligand B (0.118), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-10.0) 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 significantly stronger binding affinity, the ADME properties of Ligand A are far superior. Ligand A has a much lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and higher t1/2), and lower P-gp efflux. The poor solubility and permeability are concerns for both, but the potent binding of Ligand B might be able to overcome these issues with formulation strategies. However, the safety profile of Ligand A is much more favorable. Given the enzyme class (kinase) and the priorities of potency, metabolic stability, solubility, and hERG risk, the superior ADME profile of Ligand A outweighs the binding affinity advantage of Ligand B.

Output:
0
2025-04-17 12:15:02,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (340.379 and 344.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.8) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**3. logP:** Both ligands have good logP values (2.392 and 3.371), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting solubility but not excessively.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable, being less than 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:** Ligand A (0.925) has a significantly higher QED score than Ligand B (0.721), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (32.183). This is a significant concern, as lower DILI is preferred.

**8. BBB:** Both ligands have similar BBB penetration (63.203 and 65.607). Not a primary concern for a kinase inhibitor, but higher is generally better.

**9. Caco-2:** Both have negative Caco-2 values (-4.572 and -4.746). These values are unusual and suggest poor permeability. However, the absolute values are similar.

**10. Solubility:** Both have negative solubility values (-2.943 and -3.537), indicating poor aqueous solubility. Ligand B is slightly worse.

**11. hERG:** Both ligands have low hERG inhibition liability (0.474 and 0.402), which is good.

**12. Cl_mic:** Both ligands have similar microsomal clearance values (54.031 and 54.685). These are moderate, suggesting reasonable metabolic stability.

**13. t1/2:** Ligand A (4.363) has a slightly longer in vitro half-life than Ligand B (-6.805). A positive half-life is preferred.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.598 and 0.364), which is favorable.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). This 0.4 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and slightly better half-life, Ligand B has a substantially lower DILI risk, better TPSA, and significantly improved binding affinity. The lower DILI risk is a critical advantage, and the improved binding affinity is also highly desirable for an enzyme inhibitor. The slightly lower solubility of Ligand B is a concern, but potentially addressable through formulation strategies. The negative Caco-2 and solubility values are concerning for both, and would require further investigation.

Output:
1
2025-04-17 12:15:02,627 - INFO - Batch 114 complete. Total preferences: 1824
2025-04-17 12:15:02,627 - INFO - Processing batch 115/512...
2025-04-17 12:15:50,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (365.459 Da and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (117.42 and 114.69) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Both ligands have low logP values (0.238 and 0.165). While not ideal (optimal is 1-3), they aren't excessively low. This might present formulation challenges but isn't a dealbreaker given the other properties.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.641) has a significantly better QED score than Ligand B (0.399), indicating a more drug-like profile.

**DILI:** Ligand B (67.895) has a higher DILI risk than Ligand A (47.344), making A preferable.

**BBB:** Both have similar BBB penetration (52.811 and 55.254), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.609 and -5.097), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.221 and -2.165), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Ligand A (0.039) has a much lower hERG inhibition liability than Ligand B (0.491), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-6.396) has a much lower (better) microsomal clearance than Ligand B (56.752), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.85) has a negative half-life, which is not physically possible and indicates a serious issue. Ligand A (-4.302) is also negative, but less so. Both are problematic.

**P-gp Efflux:** Both have low P-gp efflux liability (0.009 and 0.051).

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Conclusion:**

Despite the poor permeability and solubility of both compounds, Ligand A is significantly better. It has a higher QED, lower DILI risk, much lower hERG inhibition, and significantly better metabolic stability (lower Cl_mic). The negative half-life for both is a major concern, but less extreme for Ligand A. The equal binding affinity means the ADME properties are the deciding factor.

Output:
0
2025-04-17 12:15:50,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.4 and 362.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is better than Ligand B (112.92). Both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (1.569 and 1.271), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=4, HBA=4) is slightly better than Ligand B (HBD=3, HBA=8). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have acceptable QED scores (0.639 and 0.576), indicating reasonable drug-likeness.

**DILI:** Ligand A (56.921) has a significantly lower DILI risk than Ligand B (63.862). This is a crucial advantage.

**BBB:** Ligand A (53.587) has a better BBB penetration score than Ligand B (38.193), although BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.202 and -5.609), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.855 and -2.726). This is a major drawback and could limit bioavailability.

**hERG Inhibition:** Ligand A (0.045) has a much lower hERG inhibition risk than Ligand B (0.282). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (-29.308) has significantly lower microsomal clearance than Ligand B (60.053), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-8.923) has a shorter half-life than Ligand B (19.657), which is a disadvantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.021).

**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 is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand A demonstrates significantly better safety (lower DILI, lower hERG) and metabolic stability (lower Cl_mic). The slightly better binding affinity of Ligand B is outweighed by these critical ADME/Tox advantages of Ligand A. The longer half-life of Ligand B is a minor benefit compared to the other advantages of Ligand A.

Output:
0
2025-04-17 12:15:50,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.72 and 63.42) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.788) is optimal, while Ligand B (3.621) is approaching the upper limit of the optimal range.

**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 6 HBA. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.711 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A (10.973) has a significantly lower DILI risk than Ligand B (77.549). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (79.527 and 70.764), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar, so it doesn't strongly favor one over the other.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.304) is slightly better than Ligand B (-4.645). Solubility is a concern for both, but less so for A.

**hERG Inhibition:** Ligand A (0.226) has a much lower hERG inhibition risk than Ligand B (0.936). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (39.422) has a lower microsomal clearance than Ligand B (85.203), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand B (74.72) has a significantly longer in vitro half-life than Ligand A (-6.876). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.189).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, lower hERG inhibition, and better metabolic stability (lower Cl_mic). While Ligand B has a longer half-life, the safety and metabolic advantages of Ligand A outweigh this benefit. Solubility is a concern for both, but Ligand A is slightly better. The binding affinities are comparable. Given the enzyme-specific priorities, Ligand A is the more promising candidate.

Output:
0
2025-04-17 12:15:50,828 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (348.447 and 346.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (68.62 and 67.87) well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.74) is optimal, while Ligand B (2.428) is also acceptable.

**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:** Ligand A (0.903) has a significantly better QED score than Ligand B (0.657), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.299) has a lower DILI risk than Ligand B (41.334), both are below the 40 threshold.

**8. BBB:** Both ligands have high BBB penetration (81.466 and 89.027), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.846 and -4.649). This is unusual and suggests poor permeability, but the scale isn't clearly defined.

**10. Aqueous Solubility:** Both have negative solubility values (-1.389 and -2.345). This is also unusual and suggests poor solubility, but the scale isn't clearly defined.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.2 and 0.557), which is excellent.

**12. Microsomal Clearance:** Ligand A (2.026 mL/min/kg) has significantly lower microsomal clearance than Ligand B (61.526 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.623 hours) has a much longer in vitro half-life than Ligand B (1.049 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.154).

**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 A is clearly superior. While both ligands have excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better drug-like properties (higher QED), lower DILI risk, and substantially improved metabolic stability (lower Cl_mic, longer t1/2). The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A outweigh these concerns.

Output:
1
2025-04-17 12:15:50,828 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.335 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.54) is good for oral absorption (<140), while Ligand B (32.34) is excellent.

**logP:** Ligand A (-2.098) is a bit low, potentially hindering permeation. Ligand B (4.567) is slightly high, potentially causing solubility or off-target issues, but not drastically so.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 9 HBAs, acceptable. Ligand B has 2 HBAs, also acceptable.

**QED:** Both ligands have good QED scores (0.612 and 0.702), indicating drug-like properties.

**DILI:** Ligand A (69.252) has a moderate DILI risk, while Ligand B (12.641) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (61.846) and Ligand B (85.459). BBB is not a high priority for a kinase inhibitor, but higher is generally better.

**Caco-2 Permeability:** Ligand A (-5.058) has poor Caco-2 permeability. Ligand B (-4.801) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.054) has poor aqueous solubility. Ligand B (-4.471) also has poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.005) has very low hERG inhibition risk, which is excellent. Ligand B (0.893) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-14.953) has very low microsomal clearance, indicating high metabolic stability. Ligand B (63.336) has a high microsomal clearance, indicating poor metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (3.926) has a short half-life. Ligand B (0.003) has an extremely short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.512).

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-0.0). This is a crucial advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand B's higher logP and poor metabolic stability, its *much* stronger binding affinity (-7.3 kcal/mol vs -0.0 kcal/mol) is the most critical factor for an enzyme inhibitor. The substantial difference in binding affinity is likely to overcome the issues with metabolic stability, especially given the potential for further optimization. Ligand A has better metabolic stability and lower DILI, but its extremely weak binding affinity makes it unlikely to be effective.

Output:
1
2025-04-17 12:15:50,828 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.431 and 366.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is well below the 140 threshold for good oral absorption and even below 90, which would be relevant for CNS targets (though SRC is not a CNS target). Ligand B (117.26) is still within acceptable limits for oral absorption, but less optimal than A.

**logP:** Ligand A (0.884) is slightly below the optimal 1-3 range but still reasonable. Ligand B (0.437) is even lower, potentially indicating permeability issues.

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

**QED:** Both ligands have good QED scores (0.543 and 0.605), indicating drug-like properties.

**DILI:** Ligand A (48.662) has a much lower DILI risk than Ligand B (67.235), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Both are around 40-46.

**Caco-2 Permeability:** Ligand A (-4.637) has a better (less negative) Caco-2 value than Ligand B (-5.478), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.021 and -2.061). This is a concern for both, but might be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.088 and 0.061).

**Microsomal Clearance:** Ligand A (32.1) has a significantly better (lower) microsomal clearance than Ligand B (-8.705, indicating very rapid clearance). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-4.608) has a better (less negative) in vitro half-life than Ligand B (18.118), further supporting its superior metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.051 and 0.031).

**Binding Affinity:** Ligand B (-10.3 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 ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, it suffers from significantly worse metabolic stability (high Cl_mic, low t1/2) and a higher DILI risk. Ligand A has superior ADME properties across the board (lower DILI, better metabolic stability, better permeability), but a weaker binding affinity.

Given the substantial difference in binding affinity (-10.3 vs -7.9 kcal/mol), and the fact that SRC is not a CNS target, the potency advantage of Ligand B is likely to be decisive. While the ADME issues are concerning, they might be addressable through further optimization.

Output:
1
2025-04-17 12:15:50,828 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [343.387, 105.12 ,   0.945,   3.   ,   5.   ,   0.567,  87.786,  51.842, -5.017,  -4.632,   0.177,   6.214,  70.236,   0.101,  -7.6  ]
**Ligand B:** [350.459,  67.87 ,   1.215,   1.   ,   4.   ,   0.75 ,  23.226,  77.743, -4.693,  -1.613,   0.365,  35.701,   9.626,   0.039,  -7.3  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (343.387) is slightly lower than B (350.459), but both are acceptable.
2. **TPSA:** A (105.12) is higher than B (67.87). While A is still reasonable for oral absorption (<=140), B is significantly better.
3. **logP:** Both are within the optimal range (1-3). A (0.945) is a bit lower, potentially impacting permeability, while B (1.215) is better positioned.
4. **HBD:** A (3) is higher than B (1). Both are acceptable, but B is preferable for permeability.
5. **HBA:** A (5) is higher than B (4). Again, B is slightly better regarding permeability.
6. **QED:** Both have good QED scores (A: 0.567, B: 0.75), indicating drug-like properties. B is better.
7. **DILI:** A (87.786) has a significantly higher DILI risk than B (23.226). This is a major concern for A.
8. **BBB:** A (51.842) has lower BBB penetration than B (77.743). Not a primary concern for SRC kinase inhibitors (not CNS targets), but B is better.
9. **Caco-2:** A (-5.017) is much lower than B (-4.693), indicating poorer intestinal absorption for A.
10. **Solubility:** A (-4.632) is worse than B (-1.613), indicating lower aqueous solubility for A.
11. **hERG:** Both have low hERG inhibition risk (A: 0.177, B: 0.365). B is slightly higher, but both are acceptable.
12. **Cl_mic:** A (6.214) has lower microsomal clearance than B (35.701), suggesting better metabolic stability. This is a positive for A.
13. **t1/2:** A (70.236) has a much longer in vitro half-life than B (9.626). This is a significant advantage for A.
14. **Pgp:** A (0.101) has lower P-gp efflux than B (0.039), suggesting better absorption.
15. **Affinity:** A (-7.6) has a slightly better binding affinity than B (-7.3). While the difference is not huge, it's a factor.

**Enzyme-Kinase Specific Priorities:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Overall Assessment:**

Ligand A has better affinity and metabolic stability (lower Cl_mic, longer t1/2) and Pgp efflux. However, it suffers from significantly higher DILI risk, lower solubility, and poorer Caco-2 permeability. Ligand B has a much better safety profile (DILI), better solubility, and Caco-2 permeability, and a good QED score. The slightly lower affinity of B is likely outweighed by its superior ADME properties and safety.

**Conclusion:**

Considering the enzyme-specific priorities and the overall profile, **Ligand B** is the more viable drug candidate. The lower DILI risk and improved solubility/permeability are critical advantages that outweigh the slightly weaker binding affinity.

Output:
1
2025-04-17 12:15:50,829 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.543 and 368.474 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is better than Ligand B (59.5), both being acceptable for oral absorption (<140).

**3. logP:** Both ligands have good logP values (3.232 and 3.036), 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 (0.597 and 0.66), indicating good drug-like properties.

**7. DILI:** Ligand A (31.369) has a lower DILI risk than Ligand B (41.915), which is preferable. Both are under the 40 threshold.

**8. BBB:** Both have reasonable BBB penetration, with Ligand B (86.041) being slightly better than Ligand A (73.866). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.791 and -4.65). This 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 have negative solubility values (-2.385 and -3.194), indicating poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.673 and 0.598), which is excellent.

**12. Microsomal Clearance:** Ligand A (104.757) has a higher microsomal clearance than Ligand B (86.966), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (-1.299) has a significantly longer in vitro half-life than Ligand A (42.283). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.203 and 0.207), which is good.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 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 issues with solubility and Caco-2 permeability, Ligand B's significantly stronger binding affinity (-8.2 vs -7.1 kcal/mol) and longer half-life outweigh the slightly higher DILI risk and lower BBB penetration. The improved metabolic stability (lower Cl_mic) is also a significant benefit for an enzyme inhibitor.

Output:
1
2025-04-17 12:15:50,829 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.833 Da) is slightly higher than Ligand B (349.399 Da), but this difference isn't significant.

**TPSA:** Ligand A (95.42) is better than Ligand B (123.72). TPSA is good for both, being under 140, but lower is generally preferred for absorption.

**logP:** Ligand A (1.01) is within the optimal range (1-3), while Ligand B (-0.902) is slightly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=9) both fall within acceptable limits, though Ligand B has a higher number of HBA.

**QED:** Ligand A (0.834) has a significantly better QED score than Ligand B (0.589), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 59.791, Ligand B: 60.14), and are acceptable, but not ideal.

**BBB:** Ligand A (45.909) and Ligand B (39.783) both have low BBB penetration, which is not a major concern for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.102) is slightly better than Ligand B (-5.805).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand B (-0.615) is slightly better than Ligand A (-2.859).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.145, Ligand B: 0.03).

**Microsomal Clearance:** Ligand A (-14.804) has a much lower (better) microsomal clearance than Ligand B (34.429), indicating greater metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-1.366) has a slightly better in vitro half-life than Ligand B (15.809).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its superior binding affinity, better QED score, and significantly improved metabolic stability (lower Cl_mic) are critical advantages for an enzyme inhibitor. While both have poor solubility and permeability, the strong binding and metabolic stability of Ligand A make it more likely to be successful after further optimization.

Output:
1
2025-04-17 12:15:50,829 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.438 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.21) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (58.2) is excellent, well below 140.

**logP:** Ligand A (-0.006) is a bit low, potentially hindering permeation. Ligand B (3.735) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 2 HBD and 2 HBA, also good.

**QED:** Both ligands have similar QED values (0.649 and 0.625), indicating good drug-likeness.

**DILI:** Ligand A (54.168) has a moderate DILI risk. Ligand B (23.187) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.686) shows reasonable BBB penetration, while Ligand A (37.65) is lower.

**Caco-2 Permeability:** Ligand A (-5.867) shows poor permeability, which is concerning. Ligand B (-4.81) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.215) has poor solubility. Ligand B (-4.006) also has poor solubility, but slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.032) has very low hERG risk. Ligand B (0.27) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-31.012) has very low microsomal clearance, indicating high metabolic stability, a major advantage. Ligand B (50.649) has moderate clearance.

**In vitro Half-Life:** Ligand A (-7.587) has a very long half-life, which is excellent. Ligand B (-5.592) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.007 and 0.332), which is good.

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

**Conclusion:**

While both ligands have excellent binding affinity, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and very low hERG risk. The poor solubility and permeability of Ligand A are concerns, but could potentially be addressed with formulation strategies. Ligand B's lower DILI risk is also a positive, but doesn't outweigh the metabolic advantages of Ligand A.

Output:
1
2025-04-17 12:15:50,829 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.491 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is excellent, well below the 140 threshold for oral absorption. Ligand B (107.97) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (3.801) is optimal. Ligand B (-0.593) is quite low, raising concerns about permeability and potentially bioavailability.

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

**QED:** Both ligands have reasonable QED scores (0.853 and 0.566), indicating drug-like properties.

**DILI:** Ligand A (55.68) has a moderate DILI risk, but acceptable. Ligand B (11.322) has a very low DILI risk, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.45) and Ligand B (36.06) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.591) is poor, indicating low intestinal absorption. Ligand B (-5.256) is also poor.

**Aqueous Solubility:** Ligand A (-5.175) is poor. Ligand B (-0.574) is also poor.

**hERG:** Ligand A (0.575) has a low hERG risk, which is favorable. Ligand B (0.053) has an even lower hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (90.275) has high microsomal clearance, suggesting poor metabolic stability. Ligand B (-18.662) has negative clearance, which is excellent and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-18.137) has negative half-life, which is excellent. Ligand B (15.872) has a relatively short half-life, which is a concern.

**P-gp Efflux:** Ligand A (0.314) has low P-gp efflux, which is good. Ligand B (0.002) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better TPSA and a slightly better QED, Ligand B is superior overall. The most critical factors are the significantly stronger binding affinity (-8.5 vs -7.5 kcal/mol) and the much better metabolic stability (negative clearance and low P-gp efflux) of Ligand B. Although its logP is low and Caco-2 permeability is poor, the strong binding and metabolic stability are more crucial for an enzyme target like SRC kinase. The low DILI and hERG risks are also highly favorable.

Output:
1
2025-04-17 12:15:50,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.483 and 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.13) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (82.19) is still under 140, but less favorable than A.

**logP:** Ligand A (4.247) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.654) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 1 HBA) is excellent. Ligand B (1 HBD, 4 HBA) is also acceptable, but slightly higher HBA count.

**QED:** Both ligands have similar QED values (0.812 and 0.792), indicating good drug-likeness.

**DILI:** Ligand A (40.054) has a lower DILI risk than Ligand B (62.776), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.084) has better BBB penetration than Ligand B (77.007).

**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 ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.426) is slightly better than Ligand A (-4.354).

**hERG Inhibition:** Ligand A (0.9) has a slightly higher hERG risk than Ligand B (0.081), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (60.497) has a higher clearance than Ligand B (22.669), meaning it's less metabolically stable. This is a major drawback for A.

**In vitro Half-Life:** Ligand B (-13.84) has a negative half-life, which is concerning. Ligand A (4.108) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.711 and 0.076).

**Binding Affinity:** Ligand A (-7.4) has a significantly stronger binding affinity than Ligand B (-6.8), a difference of 0.6 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a better DILI profile, but suffers from higher logP, higher clearance, and a slightly higher hERG risk. Ligand B has better solubility, lower hERG, and lower clearance, but its binding affinity is weaker. The affinity difference is substantial (0.6 kcal/mol), and for an enzyme target, potency is paramount. While Ligand A's logP and clearance are concerns, these can potentially be addressed through further optimization. The weaker affinity of Ligand B is harder to overcome.

Output:
1
2025-04-17 12:15:50,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.204 and 350.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.46) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (87.46) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (1.689) is within the optimal 1-3 range. Ligand B (0.827) is a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, both within acceptable limits. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.376) is below the desired 0.5, indicating a less drug-like profile. Ligand B (0.744) is above 0.5, suggesting better drug-likeness.

**DILI:** Ligand A (99.147) has a very high DILI risk, a major concern. Ligand B (55.293) has a moderate DILI risk, which is significantly better.

**BBB:** Both ligands have reasonable BBB penetration (72.16 and 75.107), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a significant issue for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.378) has a low hERG risk, which is good. Ligand B (0.286) also has a low hERG risk, equally good.

**Microsomal Clearance:** Ligand A (80.406) has moderate clearance, suggesting moderate metabolic stability. Ligand B (9.309) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (0.16) has a very short half-life, a significant drawback. Ligand B (-6.046) has a very long half-life, a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.198 and 0.037), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand B is the much more promising candidate. The primary reasons are its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and superior QED score. While both have poor solubility and permeability, the metabolic and toxicity profiles of Ligand B are far more favorable for further development. Ligand A's extremely high DILI risk is a deal-breaker.

Output:
1
2025-04-17 12:15:50,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (375.803 and 373.812 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.32 and 83.72) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.172 and 2.098) are 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.

**QED:** Both ligands have good QED scores (0.798 and 0.73), indicating drug-like properties.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (60.217), but both are acceptable.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand B (85.033) has a higher BBB score than Ligand A (65.723).

**Caco-2 Permeability:** Ligand A (-5.038) has slightly better Caco-2 permeability than Ligand B (-4.478).

**Aqueous Solubility:** Ligand A (-2.761) has slightly better aqueous solubility than Ligand B (-2.273).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.201 and 0.146).

**Microsomal Clearance:** Ligand A (8.707 mL/min/kg) has significantly lower microsomal clearance than Ligand B (23.154 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.286 hours) has a much longer in vitro half-life than Ligand B (-0.245 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.059 and 0.296).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2), slightly better solubility and Caco-2 permeability, and marginally better binding affinity outweigh the slightly higher DILI risk compared to Ligand B. The longer half-life is a particularly important advantage for an enzyme inhibitor, potentially allowing for less frequent dosing.

Output:
1
2025-04-17 12:15:50,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (348.418 and 374.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.55) is well below the 140 threshold and favorable for oral absorption. Ligand B (101.98) is still below 140, but higher than A, potentially indicating slightly reduced absorption.

**3. logP:** Ligand A (2.754) is optimal (1-3). Ligand B (-0.913) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Ligand A (1) is within the acceptable limit of 5. Ligand B (3) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is within the acceptable limit of 10. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have reasonable QED scores (0.832 and 0.508), indicating good drug-like properties. Ligand A is better.

**7. DILI:** Ligand A (34.742) has a lower DILI risk than Ligand B (21.908), which is preferable.

**8. BBB:** Ligand A (70.997) has a better BBB penetration score than Ligand B (10.779). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**9. Caco-2 Permeability:** Ligand A (-4.376) is better than Ligand B (-5.686) indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.764) is better than Ligand B (-1.105), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.374 and 0.034).

**12. Microsomal Clearance:** Ligand A (33.441) has higher microsomal clearance than Ligand B (22.155), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-24.845) has a longer half-life than Ligand B (-9.959), which is desirable.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.06 and 0.007).

**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.

**Enzyme-Specific Priorities:** For kinases, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a slightly better affinity, but Ligand A has better solubility, a longer half-life, and lower DILI risk. The difference in affinity (0.5 kcal/mol) is not substantial enough to overcome the ADME advantages of Ligand A.

Output:
1
2025-04-17 12:15:50,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.46 and 361.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is well below the 140 threshold, indicating good absorption potential. Ligand B (71.33) is still acceptable but slightly higher.

**logP:** Ligand A (3.056) is optimal (1-3). Ligand B (1.491) is a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, well within the limits. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.737 and 0.83), suggesting drug-like properties.

**DILI:** Ligand A (14.89) has a significantly lower DILI risk than Ligand B (54.91). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (86.35) has better BBB penetration than Ligand B (58.82), but this is less important.

**Caco-2 Permeability:** Ligand A (-4.785) has better Caco-2 permeability than Ligand B (-5.112), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.915) has better aqueous solubility than Ligand B (-1.761), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.645) has a lower hERG risk than Ligand B (0.197), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (45.55) has higher microsomal clearance than Ligand B (34.11). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (10.92) has a slightly longer half-life than Ligand A (19.76), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.174 and 0.115).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 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, and better metabolic stability (lower Cl_mic and longer t1/2). However, Ligand A demonstrates a much better safety profile with significantly lower DILI and hERG risk, and better solubility and permeability. While the affinity difference is notable, the improved safety and ADME properties of Ligand A make it the more promising candidate, especially considering the potential for chronic administration in oncology.

Output:
0
2025-04-17 12:15:50,831 - INFO - Batch 115 complete. Total preferences: 1840
2025-04-17 12:15:50,831 - INFO - Processing batch 116/512...
2025-04-17 12:16:39,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 342.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is better than Ligand B (59.81), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.23) is optimal, while Ligand B (3.914) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Both have 1 HBD, which is good.

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

**QED:** Ligand A (0.881) has a significantly better QED score than Ligand B (0.712), indicating a more drug-like profile.

**DILI:** Ligand A (49.477) has a slightly higher DILI risk than Ligand B (40.403), but both are below the concerning threshold of 60.

**BBB:** Ligand A (80.651) has better BBB penetration than Ligand B (64.831), though this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.547) has a worse Caco-2 permeability than Ligand B (-5.012). Lower values indicate lower permeability, so B is better.

**Solubility:** Ligand A (-3.032) has better solubility than Ligand B (-4.17).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.38 and 0.423).

**Microsomal Clearance:** Ligand A (21.677) has significantly lower microsomal clearance than Ligand B (73.798), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-7.435) has a much longer in vitro half-life than Ligand B (19.954). This is another significant advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.14 and 0.58).

**Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (-6.8). This is a 1.5 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most crucial factor for an enzyme target. While Ligand A has better QED, solubility, metabolic stability, and half-life, the substantial affinity difference of Ligand B outweighs these advantages. The slightly higher logP of Ligand B is not a major concern.

Output:
1
2025-04-17 12:16:39,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.359 Da and 358.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.08) is better than Ligand B (58.2). While both are acceptable, lower TPSA generally indicates better permeability.

**logP:** Ligand B (3.363) is slightly higher than Ligand A (1.717). Both fall within the optimal 1-3 range, but Ligand B is approaching the upper limit.

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

**H-Bond Acceptors:** Ligand A (8) is higher than Ligand B (2). Both are within the acceptable limit of 10, but Ligand B is significantly better.

**QED:** Both ligands have similar QED values (0.695 and 0.749), indicating good drug-likeness.

**DILI:** Ligand B (43.117) has a significantly lower DILI risk than Ligand A (68.98). This is a major advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (78.868 and 71.035), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.343) has worse Caco-2 permeability than Ligand B (-4.593). Lower values indicate poorer absorption.

**Aqueous Solubility:** Ligand A (-1.709) has better aqueous solubility than Ligand B (-3.974). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.138) has a lower hERG inhibition risk than Ligand B (0.684). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (11.617) has lower microsomal clearance than Ligand B (12.98), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.659) has a significantly longer in vitro half-life than Ligand A (14.355). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.06). Lower efflux is generally preferred.

**Binding Affinity:** Both ligands have very similar binding affinities (-9.3 kcal/mol and -8.0 kcal/mol). Ligand A has a slight advantage in binding affinity.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and hERG risk, but Ligand B excels in metabolic stability (longer half-life), DILI risk, and has acceptable solubility. The longer half-life and lower DILI risk of Ligand B are more critical for an enzyme inhibitor than the minor binding affinity difference. The better solubility of Ligand A is a plus, but can be addressed through formulation.

Output:
1
2025-04-17 12:16:39,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (376.762 and 370.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.21) is better than Ligand B (66.71), both are acceptable but lower is better for permeability.

**logP:** Ligand A (4.157) is a bit high, potentially leading to solubility issues. Ligand B (1.209) is quite low, which might hinder permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit.

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

**QED:** Both ligands have good QED scores (0.737 and 0.859), indicating good drug-like properties.

**DILI:** Ligand A (72.509) has a higher DILI risk than Ligand B (50.989). This is a significant concern for Ligand A.

**BBB:** Ligand A (58.007) and Ligand B (78.558). BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.608) and Ligand B (-5.004). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.645) and Ligand B (-1.751). Both are poor, but Ligand B is better.

**hERG:** Both ligands have similar hERG risk (0.606 and 0.602).

**Microsomal Clearance:** Ligand A (71.483) has a considerably higher microsomal clearance than Ligand B (16.155). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (6.394) has a longer half-life than Ligand B (-1.827). However, 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 (0.507 and 0.039).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has a slightly longer half-life, its significantly higher DILI risk and higher microsomal clearance are major drawbacks. Ligand B, despite its lower logP and Caco-2 permeability, exhibits a much better safety profile (lower DILI) and improved metabolic stability (lower Cl_mic). The similar binding affinities make the ADME/Tox profile the deciding factor. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:16:39,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.39 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is higher than Ligand B (56.75). Both are below the 140 A^2 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands (1.368 and 1.618) are 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:** Ligand A has 4 HBA, and Ligand B has 6. Both are below the 10 threshold.

**QED:** Ligand A (0.844) has a significantly higher QED score than Ligand B (0.654), indicating better overall drug-likeness.

**DILI:** Ligand A (24.157) has a much lower DILI risk than Ligand B (52.85), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (82.706 and 78.519), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

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

**hERG:** Both ligands have similar, low hERG risk (0.457 and 0.57).

**Microsomal Clearance:** Ligand A (17.599) has a lower microsomal clearance than Ligand B (56.625), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.832) has a negative half-life, which is unusual. Ligand B (10.462) has a more reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.034 and 0.108).

**Binding Affinity:** Both ligands have very similar, strong binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is more promising. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a higher QED score. While Ligand B has a more reasonable in vitro half-life, the advantages of Ligand A in terms of safety (DILI) and metabolic stability outweigh this. 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 12:16:39,017 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [346.475, 58.44, 2.0, 0.0, 4.0, 0.819, 30.826, 74.176, -4.74, -1.703, 0.202, 40.563, 8.153, 0.112, -7.2]
**Ligand B:** [364.431, 123.84, -0.419, 3.0, 7.0, 0.64, 76.464, 45.715, -5.549, -3.037, 0.225, 6.839, 10.439, 0.029, -8.3]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (346.475) is slightly preferred.
2. **TPSA:** A (58.44) is excellent, well below the 140 threshold. B (123.84) is still acceptable, but less optimal for oral absorption.
3. **logP:** A (2.0) is optimal. B (-0.419) is below 1, which could hinder permeation.
4. **HBD:** A (0.0) is good. B (3.0) is acceptable, but higher HBD can sometimes lead to issues.
5. **HBA:** A (4.0) is good. B (7.0) is acceptable, but higher HBA can sometimes lead to issues.
6. **QED:** A (0.819) is excellent. B (0.64) is still reasonable, but less drug-like.
7. **DILI:** A (30.826) is very good (low risk). B (76.464) is significantly higher, indicating a greater potential for liver injury.
8. **BBB:** A (74.176) is good. B (45.715) is lower, less favorable. While SRC isn't necessarily a CNS target, higher BBB is generally a positive.
9. **Caco-2:** A (-4.74) is a negative value, which is unusual and could indicate an issue with the measurement or a very poor permeability. B (-5.549) is also negative, but slightly worse.
10. **Solubility:** A (-1.703) is poor. B (-3.037) is even worse. This is a significant concern for both.
11. **hERG:** Both A (0.202) and B (0.225) have low hERG risk, which is good.
12. **Cl_mic:** A (40.563) is moderate. B (6.839) is very low, indicating better metabolic stability. This is a significant advantage for B.
13. **t1/2:** A (8.153) is reasonable. B (10.439) is better, suggesting a longer duration of action.
14. **Pgp:** Both A (0.112) and B (0.029) have low P-gp efflux, which is good.
15. **Affinity:** B (-8.3) is significantly better than A (-7.2). A difference of >1.5 kcal/mol is considered substantial.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a substantially better binding affinity (-8.3 vs -7.2 kcal/mol). It also demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a lower Pgp efflux. However, it has a concerningly higher DILI risk and poor solubility. Ligand A has better TPSA, QED, DILI, and BBB, but its solubility is also poor, and its affinity is significantly weaker.

The affinity difference is large enough to potentially overcome the solubility and DILI concerns of ligand B, *provided* formulation strategies can address the solubility issue and the DILI risk can be mitigated through further structural modifications. The poor Caco-2 values for both are concerning, but the higher affinity of B is a strong driver.

Output:
1
2025-04-17 12:16:39,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.471 and 350.419 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.31) is slightly higher than Ligand B (87.9), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.532) is within the optimal 1-3 range. Ligand B (-0.078) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria.

**H-Bond Acceptors:** Both ligands (6) meet the HBA <=10 criteria.

**QED:** Both ligands have good QED scores (0.606 and 0.824, respectively), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (62.35) has a higher DILI risk than Ligand B (54.323), but both are acceptable (<60 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.382) is slightly higher than Ligand B (42.962).

**Caco-2 Permeability:** Ligand A (-5.548) and Ligand B (-4.918) both have negative values, which is unusual. Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.639) and Ligand B (-0.473) both have negative solubility values, indicating poor solubility. Ligand B is slightly better.

**hERG:** Both ligands have very low hERG inhibition liability (0.115 and 0.121, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (4.142) has significantly lower microsomal clearance than Ligand B (30.845). This suggests better metabolic stability for Ligand A, a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (-0.697) has a negative half-life, which is unusual. Ligand B (21.373) has a much more reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.038, respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.4 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is slightly favored. Its significantly lower microsomal clearance (better metabolic stability) is a major advantage. While its half-life is unusual, the lower clearance is more critical. Ligand B has slightly better solubility and QED, but the difference isn't large enough to overcome the metabolic stability advantage of Ligand A.

Output:
0
2025-04-17 12:16:39,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.446 and 362.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.39) is significantly better than Ligand B (58.2), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.768 and 3.176), 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 hydrogen bonding potential, being closer to the ideal thresholds.

**QED:** Ligand A (0.83) has a higher QED score than Ligand B (0.604), indicating better overall drug-likeness.

**DILI:** Ligand B (47.732) has a lower DILI risk than Ligand A (34.665), which is preferable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (84.451) is better than Ligand B (77.007). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. However, the values are similar (-4.764 vs -4.587).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the values are similar (-3.461 vs -4.678).

**hERG Inhibition:** Ligand A (0.936) has a slightly higher hERG risk than Ligand B (0.542), which is unfavorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (61.436 and 62.377), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (21.082) has a longer half-life than Ligand B (15.543), which is desirable.

**P-gp Efflux:** Ligand A (0.499) has a lower P-gp efflux liability than Ligand B (0.186), which is preferable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of 8.5 kcal/mol is substantial and likely outweighs the minor ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand B having a slightly lower DILI risk and hERG inhibition, Ligand A's dramatically superior binding affinity (-8.5 vs 0.0 kcal/mol) makes it the far more promising candidate. The better QED, BBB, half-life and P-gp efflux also contribute to its favorability. The poor solubility and permeability are concerns, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:16:39,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.447 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is better than Ligand B (60.85), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand B (2.428) is slightly higher than Ligand A (1.378), both fall 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 has 5 HBA, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.818) has a significantly better QED score than Ligand B (0.513), indicating a more drug-like profile.

**DILI:** Ligand A (30.71) has a much lower DILI risk than Ligand B (10.508), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.774) is better than Ligand B (59.636).

**Caco-2 Permeability:** Ligand A (-4.997) is better than Ligand B (-4.491), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.96) is better than Ligand B (-1.825), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.061 and 0.549 respectively), which is excellent.

**Microsomal Clearance:** Ligand B (24.372) has a lower microsomal clearance than Ligand A (49.256), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-6.042) has a longer in vitro half-life than Ligand A (-16.662), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.454 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), Ligand A demonstrates superior overall drug-like properties. Its significantly better QED, lower DILI risk, and improved solubility and permeability outweigh the slightly higher clearance. The binding affinity is identical, so the ADME properties become the deciding factor.

Output:
1
2025-04-17 12:16:39,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 355.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (62.74). Both are below 140, suggesting good absorption potential.

**logP:** Ligand A (3.569) is slightly higher than Ligand B (1.731). While both are within the optimal 1-3 range, Ligand B is closer to the lower bound, which *could* indicate permeability issues.

**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 and <=10 HBA).

**QED:** Both ligands have similar QED values (0.706 and 0.713), indicating good drug-likeness.

**DILI:** Ligand A (24.195) has a significantly lower DILI risk than Ligand B (34.936). This is a major advantage for Ligand A.

**BBB:** Ligand B (96.355) has a much higher BBB penetration percentile than Ligand A (68.67). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.736) has a slightly better Caco-2 permeability than Ligand B (-4.123), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.312) has a slightly better aqueous solubility than Ligand B (-1.541).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.432 and 0.253), which is excellent.

**Microsomal Clearance:** Ligand B (20.737) has a lower microsomal clearance than Ligand A (46.1). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (-5.788 and -5.64 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.274 and 0.039).

**Binding Affinity:** Ligand B (-8.4) has a slightly stronger binding affinity than Ligand A (-8.0). This is a 0.4 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A has a significantly lower DILI risk, better solubility, and better Caco-2 permeability. The lower DILI risk is a crucial advantage in drug development, and the slight difference in binding affinity can potentially be optimized in later stages.

Output:
1
2025-04-17 12:16:39,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.491 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.26 and 73.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.548) is a bit low, potentially hindering permeation. Ligand B (2.39) is within the optimal 1-3 range. This favors Ligand B.

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

**H-Bond Acceptors:** Ligand A (7) is good. Ligand B (3) is also good.

**QED:** Both ligands (0.772 and 0.801) have strong drug-like profiles.

**DILI:** Ligand A (43.389) has a slightly higher DILI risk than Ligand B (15.859), but both are below the concerning threshold of 60.

**BBB:** Both ligands (71.035 and 71.268) have similar BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands (-4.944 and -4.803) have similar, and poor, Caco-2 permeability.

**Aqueous Solubility:** Both ligands (-2.165 and -3.772) have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.721) has slightly higher hERG inhibition risk than Ligand B (0.406), but both are acceptable.

**Microsomal Clearance:** Ligand A (39.795) has higher microsomal clearance than Ligand B (10.932), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-40.324) has a very short in vitro half-life, while Ligand B (1.316) is better, but still short.

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux than Ligand B (0.057), which is slightly favorable.

**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 a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite similar MW, TPSA, BBB, and acceptable DILI/hERG profiles, Ligand B is the superior candidate. Its optimal logP, significantly stronger binding affinity, and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly lower P-gp efflux and solubility issues. Ligand A's poor metabolic stability and weaker binding affinity are significant concerns.

Output:
1
2025-04-17 12:16:39,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (432.271 Da) is slightly higher, but acceptable. Ligand B (348.403 Da) is also good.

**TPSA:** Ligand A (89.55) is excellent, well below the 140 threshold for oral absorption. Ligand B (105.83) is still reasonable, but less optimal.

**logP:** Ligand A (3.723) is within the optimal range (1-3). Ligand B (-0.397) is significantly below this, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.703, B: 0.533), indicating good drug-like properties.

**DILI:** Ligand A (97.596) has a very high DILI risk, which is a major concern. Ligand B (34.742) has a low DILI risk, which is highly favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.613) and Ligand B (78.48) are both moderate.

**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 (0.276) has a low hERG risk, which is good. Ligand B (0.289) is also low risk.

**Microsomal Clearance:** Ligand A (91.581) has high microsomal clearance, indicating poor metabolic stability. Ligand B (29.238) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (42.2) has a moderate half-life. Ligand B (1.519) has a very short half-life, which is undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.309, B: 0.077), which is positive.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk and poor metabolic stability are major drawbacks. Ligand B, while having weaker binding, exhibits a much more favorable safety profile (low DILI) and better metabolic stability. Given the enzyme-specific priorities, metabolic stability and safety are crucial. While the solubility and permeability data are concerning for both, the DILI risk for Ligand A is a deal-breaker.

Output:
1
2025-04-17 12:16:39,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.494 and 379.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is slightly higher than Ligand B (63.25), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (1.815) is optimal, while Ligand B (3.964) is approaching the upper limit. This could potentially cause solubility issues for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.795) has a better QED score than Ligand B (0.636), indicating a more drug-like profile.

**DILI:** Ligand A (39.201) has a significantly lower DILI risk than Ligand B (88.329). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 76.309, Ligand B: 70.027). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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 negative solubility values, which is also unusual. This suggests poor solubility.

**hERG:** Ligand A (0.229) has a much lower hERG inhibition liability than Ligand B (0.864), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (98.502) has a significantly higher microsomal clearance than Ligand A (34.299), indicating lower metabolic stability. This is a critical disadvantage for Ligand B.

**In vitro Half-Life:** Ligand B (54.026) has a longer half-life than Ligand A (-1.154), but the negative value for Ligand A is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux liability than Ligand B (0.849), which is favorable for bioavailability.

**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.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from significant drawbacks: high DILI risk, high microsomal clearance (poor metabolic stability), higher hERG risk, and higher P-gp efflux. Ligand A has a better safety profile (lower DILI and hERG), better metabolic stability, and lower P-gp efflux. While its binding affinity is weaker, the difference may be outweighed by the improved ADME properties. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 12:16:39,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.407 and 364.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is slightly higher than Ligand B (60.85), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.423 and 2.707) 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 scores (0.791 and 0.789), indicating good drug-likeness.

**DILI:** Ligand A (62.233) has a higher DILI risk than Ligand B (43.66). This is a significant negative for Ligand A.

**BBB:** Ligand B (71.307) shows better BBB penetration than Ligand A (36.526), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.586 and -4.757).

**Aqueous Solubility:** Both ligands have negative solubility values (-4.141 and -3.57), indicating poor aqueous solubility. This is a concern for both, but slightly better for Ligand B.

**hERG Inhibition:** Ligand A (0.653) has a slightly higher hERG inhibition risk than Ligand B (0.812), but both are relatively low.

**Microsomal Clearance:** Ligand B (33.726 mL/min/kg) has significantly lower microsomal clearance than Ligand A (82.151 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (30.882 hours) has a much longer in vitro half-life than Ligand A (-27.44 hours). The negative value for Ligand A is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.379 and 0.691).

**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 the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and slightly better binding affinity. The negative half-life for Ligand A is a major red flag. The enzyme-specific priorities clearly favor Ligand B due to its improved pharmacokinetic properties.

Output:
1
2025-04-17 12:16:39,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.43 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.84) is slightly above the optimal <140 for oral absorption, while Ligand B (87.53) is well within the range.

**logP:** Ligand A (0.374) is a bit low, potentially hindering permeability. Ligand B (2.861) is nearly ideal.

**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 (0.729) has a good drug-likeness score, while Ligand B (0.383) is significantly lower, indicating a less drug-like profile.

**DILI:** Ligand A (48.313) has a moderate DILI risk, while Ligand B (23.769) has a very low risk, which is a significant advantage.

**BBB:** Both have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (72.664) is better than Ligand A (54.595).

**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 indicates poor solubility. This is a concern for both.

**hERG:** Ligand A (0.077) has a very low hERG risk, a major advantage. Ligand B (0.538) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (1.91) has a lower clearance, indicating better metabolic stability than Ligand B (53.273).

**In vitro Half-Life:** Ligand A (60.92) has a much longer half-life than Ligand B (4.824), a significant advantage.

**P-gp Efflux:** Ligand A (0.033) has very low P-gp efflux, while Ligand B (0.199) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a crucial factor.

**Overall Assessment:**

Ligand A excels in binding affinity, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and hERG risk. Its QED is also good. The main drawbacks are its low logP and negative Caco-2/solubility values. However, the strong binding affinity can potentially compensate for permeability issues.

Ligand B has a better logP and lower DILI risk, but suffers from a significantly weaker binding affinity, lower QED, and poorer metabolic stability.

Given the priority for potency in enzyme inhibitors, the significantly stronger binding affinity of Ligand A (-8.1 vs -6.5 kcal/mol) is the deciding factor, outweighing its slightly less favorable ADME properties.

Output:
1
2025-04-17 12:16:39,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.231 Da) is slightly higher than Ligand B (356.482 Da), but both are acceptable.

**TPSA:** Ligand A (85.25) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (60.85) is excellent.

**logP:** Both ligands have good logP values (A: 1.725, B: 2.514), falling within the optimal range of 1-3.

**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: 0.734, B: 0.762), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.259, which is high. Ligand B has a much lower DILI risk of 19.232, which is very favorable. This is a significant advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 70.803, which is acceptable but not exceptional. Ligand B has a high BBB penetration of 92.904. While SRC is not a CNS target, higher BBB penetration generally correlates with better overall permeability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.855 and -4.286). This is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable without knowing the specific assay details.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.116 and -2.369), indicating poor aqueous solubility. This is a concern for both compounds and may require formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.61, B: 0.552), which is good.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (52.818 mL/min/kg). Ligand B has a lower clearance (29.505 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A has a half-life of 10.143 hours. Ligand B has a negative half-life (-12.435 hours), which is not physically possible and suggests an issue with the data or the assay.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.47, B: 0.164). Ligand B has a slightly lower value, suggesting less efflux.

**Binding Affinity:** Ligand B has a significantly better binding affinity (-8.5 kcal/mol) compared to Ligand A (0.0 kcal/mol). This is a decisive advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

Ligand B is significantly more promising. While both have solubility and permeability concerns, Ligand B excels in key areas: significantly better binding affinity, lower DILI risk, and better metabolic stability. The negative half-life for Ligand B is a red flag, but the substantial affinity advantage outweighs this concern, assuming the half-life data is an outlier or error. Ligand A's high DILI risk is a major drawback.

Output:
1
2025-04-17 12:16:39,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.439 and 345.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.45) is acceptable, being under 140, while Ligand B (26.79) is excellent, well below 140.

**logP:** Both ligands (2.368 and 2.152) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.75 and 0.837), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 80.535, which is considered high risk (>60). Ligand B has a much lower DILI risk of 8.53, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (49.205) and Ligand B (95.153) are not particularly relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.697 and -4.742), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading; we'll consider this a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.51 and -1.761), also unusual and indicating poor solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.123) has a very low hERG risk, which is excellent. Ligand B (0.942) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (24.718) and Ligand B (29.902) have moderate microsomal clearance values. Lower is better, but these aren't alarming.

**In vitro Half-Life:** Ligand A (-11.611) has a negative half-life, which is impossible and indicates a data error or a very rapidly metabolized compound. Ligand B (-31.951) also has a negative half-life, indicating a similar issue.

**P-gp Efflux:** Ligand A (0.309) and Ligand B (0.153) have 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 (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity, but suffers from a high DILI risk and an impossible in vitro half-life. Ligand B has a much better safety profile (low DILI, low hERG), but its binding affinity is extremely weak. The negative half-life values for both are concerning and suggest data quality issues.

Despite the strong affinity of Ligand A, the high DILI risk and the impossible half-life make it a less viable candidate. While Ligand B's affinity is poor, its safety profile is significantly better. Given the enzyme-specific priorities, a starting point with a better safety profile and the possibility of optimization is preferable to a potent but potentially toxic compound.

Output:
1
2025-04-17 12:16:39,019 - INFO - Batch 116 complete. Total preferences: 1856
2025-04-17 12:16:39,019 - INFO - Processing batch 117/512...
2025-04-17 12:17:18,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.463 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.19) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (84.5) is excellent, well below 140.

**logP:** Ligand A (-0.109) is a bit low, potentially hindering permeation. Ligand B (2.557) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is good. Ligand B (2 HBD, 4 HBA) is also good. Both are within acceptable limits.

**QED:** Ligand A (0.589) is good, above the 0.5 threshold. Ligand B (0.492) is slightly below, but still reasonable.

**DILI:** Ligand A (59.829) is moderately risky, approaching the higher end of acceptable. Ligand B (17.875) is excellent, indicating low liver injury risk.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand B (70.609) shows better penetration than Ligand A (58.085).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.538 and -4.653), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.097 and -2.837), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Ligand A (0.121) has a slightly higher hERG risk than Ligand B (0.398), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.297) has significantly lower microsomal clearance than Ligand B (83.401), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.965) has a negative half-life, which is problematic. Ligand B (-20.593) is even worse. These negative values suggest issues with the assay or compound stability.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable. Ligand B (0.153) is slightly higher, but still reasonable.

**Binding Affinity:** Both ligands have strong binding affinities (-7 and -8 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Despite the strong binding affinity of both compounds, the negative Caco-2 and solubility values are major red flags. However, considering the enzyme-specific priorities, metabolic stability (Cl_mic) is crucial. Ligand A demonstrates significantly better metabolic stability (lower Cl_mic) and lower P-gp efflux. While Ligand B has better logP and lower DILI, the extremely high Cl_mic and poor half-life are concerning. The negative solubility and permeability values for both are problematic and would require significant optimization. Given the slightly better metabolic profile of Ligand A, and the fact that solubility/permeability issues can sometimes be addressed with formulation strategies, I would cautiously favor Ligand A.

Output:
0
2025-04-17 12:17:18,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.422 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.66) is slightly higher than the ideal <140, but still reasonable. Ligand B (49.41) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.536 and 3.355), 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 1 HBD and 2 HBA, also acceptable and potentially favoring permeability.

**QED:** Both ligands have good QED scores (0.678 and 0.768), indicating good drug-like properties.

**DILI:** Ligand A (36.797) has a slightly higher DILI risk than Ligand B (23.653), but both are below the concerning threshold of 60.

**BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand B (73.827) has a higher BBB percentile than Ligand A (61.768), but this is not a major factor here.

**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:** Both ligands have low hERG risk (0.525 and 0.487), which is excellent.

**Microsomal Clearance:** Ligand A (-2.614) has significantly *lower* (better) microsomal clearance than Ligand B (57.594). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (17.871) has a longer half-life than Ligand B (-2.164), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand B (0.299) has lower P-gp efflux than Ligand A (0.039), which could translate to better bioavailability.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.2). While both are excellent, the 0.3 kcal/mol difference is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and P-gp efflux, Ligand A exhibits significantly better metabolic stability (lower Cl_mic and longer t1/2). The negative Caco-2 and solubility values are concerning for both, but metabolic stability is paramount for kinase inhibitors. The slightly better DILI profile of Ligand B is a minor advantage.

Output:
0
2025-04-17 12:17:18,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (377.725 and 352.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.24) is better than Ligand B (67.87), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.939 and 1.516), falling within the 1-3 range. Ligand B is slightly lower, which could potentially affect permeability.

**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 4 HBA, well below the limit of <=10.

**QED:** Both ligands have good QED scores (0.715 and 0.843), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 69.484, which is concerning (approaching the high-risk threshold of >60). Ligand B has a much lower DILI risk of 31.718, which is preferable.

**BBB:** Ligand A has a BBB penetration of 61.962, while Ligand B has 93.641. While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.08) has poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.385) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.968) and Ligand B (-2.131) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.652) has a slightly higher hERG risk than Ligand B (0.596), but both are relatively low.

**Microsomal Clearance:** Ligand A (11.891) has a higher microsomal clearance than Ligand B (10.481), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (42.225) has a significantly longer half-life than Ligand B (1.495), which is a major advantage.

**P-gp Efflux:** Ligand A (0.222) has lower P-gp efflux than Ligand B (0.156), indicating better bioavailability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a much stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and longer half-life, which are crucial for an enzyme inhibitor. However, its DILI risk is concerning, and its Caco-2 permeability is poor. Ligand B has a much better safety profile (lower DILI), better BBB penetration, and slightly better Caco-2 permeability, but its binding affinity is extremely weak.

Despite the DILI concern, the significantly stronger binding affinity of Ligand A (-8.3 vs 0.0 kcal/mol) is a major advantage that could outweigh the other drawbacks, especially if further modifications can mitigate the DILI risk. The difference in binding affinity is so large that it's likely to translate to significantly greater efficacy.

Output:
1
2025-04-17 12:17:18,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 353.419 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.43) is excellent, well below the 140 threshold for good absorption. Ligand B (124.6) is still acceptable, but less optimal.

**logP:** Ligand A (1.2) is within the optimal range of 1-3. Ligand B (-0.399) is slightly below 1, which *could* indicate potential permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both within acceptable limits. Ligand B has 4 HBD and 5 HBA, also acceptable, but the higher HBD count could slightly impact permeability.

**QED:** Ligand A (0.808) has a very strong drug-like profile. Ligand B (0.464) is below the 0.5 threshold, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (39.24) has a low DILI risk. Ligand B (22.993) also has a very low DILI risk, both are excellent.

**BBB:** Ligand A (78.558) has a good BBB penetration percentile. Ligand B (46.762) is lower, but BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.636) has poor Caco-2 permeability. Ligand B (-5.788) is also poor, but slightly worse than A.

**Aqueous Solubility:** Ligand A (-2.043) has poor aqueous solubility. Ligand B (-1.653) is also poor, but slightly better than A.

**hERG Inhibition:** Both ligands (0.194 and 0.038) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (22.616 mL/min/kg) has moderate clearance. Ligand B (-24.383 mL/min/kg) has *negative* clearance, which is impossible and likely an error in the data. This suggests very high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (11.476 hours) has a reasonable half-life. Ligand B (-4.112 hours) is also impossible and likely an error in the data.

**P-gp Efflux:** Both ligands (0.029 and 0.005) have very low P-gp efflux, which is good.

**Binding Affinity:** Both ligands (-8.3 and -8.2 kcal/mol) have excellent binding affinity, very close to each other. The difference of 0.1 kcal/mol is unlikely to be decisive.

**Conclusion:**

Despite both compounds having excellent binding affinity and low hERG risk, Ligand B is the better candidate. The negative values for microsomal clearance and in vitro half-life are likely errors, but they point to a compound with potentially exceptional metabolic stability. Ligand A has poor Caco-2 permeability and solubility, and a lower QED score. While Ligand B's Caco-2 and solubility are also poor, the potential for superior metabolic stability outweighs these drawbacks, especially for an enzyme target where maintaining therapeutic concentrations is crucial.

Output:
1
2025-04-17 12:17:18,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.405 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is better than Ligand B (92.58), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.873) is optimal (1-3), while Ligand B (-0.276) is slightly low, potentially hindering permeation.

**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:** Ligand A (0.872) is excellent, indicating high drug-likeness. Ligand B (0.689) is still acceptable but less optimal.

**DILI:** Both ligands have low DILI risk (47.732 and 45.638, respectively), both well below the 60 threshold.

**BBB:** Both ligands have high BBB penetration (81.97 and 86.351), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.547) and Ligand B (-5.017) are both very poor, indicating very low intestinal absorption. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-2.826) is better than Ligand B (-1.244), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.317 and 0.282, respectively).

**Microsomal Clearance:** Ligand A (21.044) has significantly higher clearance than Ligand B (2.542). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-18.883) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability. Ligand B (9.214) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.073 and 0.058, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-9.4 kcal/mol), which is excellent.

**Conclusion:**

Despite both having excellent binding affinity, Ligand B is the more promising candidate. Ligand A has a nonsensical negative half-life and higher microsomal clearance, suggesting poor metabolic stability. While both have poor Caco-2 permeability, Ligand B's better solubility and significantly improved metabolic stability make it the preferred choice. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization.

Output:
1
2025-04-17 12:17:18,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (374.497 Da) is still well within the range.

**TPSA:** Ligand A (54.46) is better than Ligand B (58.2), both are acceptable for oral absorption.

**logP:** Ligand A (4.277) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.988) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which is good. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.779) has a better QED score than Ligand B (0.482), indicating better overall drug-likeness.

**DILI:** Ligand B (29.624) has a significantly lower DILI risk than Ligand A (69.329), which is a major advantage.

**BBB:** Ligand B (83.443) has a higher BBB penetration score than Ligand A (55.991), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.539) has a worse Caco-2 permeability than Ligand B (-5.094).

**Aqueous Solubility:** Ligand A (-5.009) has a worse solubility than Ligand B (-3.858).

**hERG:** Ligand A (0.803) has a slightly higher hERG risk than Ligand B (0.622), but both are relatively low.

**Microsomal Clearance:** Ligand B (56.85) has a significantly lower microsomal clearance than Ligand A (103.695), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (34.434) has a longer half-life than Ligand B (-5.929), which is a positive.

**P-gp Efflux:** Ligand A (0.573) has a lower P-gp efflux than Ligand B (0.151), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.1 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better QED and in vitro half-life, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic), and better solubility. The logP value for Ligand B is also more optimal. The similar binding affinities make these secondary factors decisive.

Output:
1
2025-04-17 12:17:18,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.292 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (400.276 Da) is also well within range.

**TPSA:** Ligand A (110.25) is better than Ligand B (56.15). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.099) is within the optimal range, while Ligand B (3.752) is approaching the upper limit. Higher logP can lead to solubility issues and off-target effects.

**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:** Both ligands have reasonable QED values (A: 0.773, B: 0.686), suggesting good drug-like properties.

**DILI:** Ligand A (67.39) has a moderate DILI risk, while Ligand B (84.645) has a higher DILI risk. Lower DILI is preferred.

**BBB:** Both ligands have similar BBB penetration (A: 62.97, B: 64.095). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.804) has a worse Caco-2 permeability than Ligand B (-5.023).

**Aqueous Solubility:** Ligand A (-1.869) has better aqueous solubility than Ligand B (-4.683). Good solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.076) has a very low hERG risk, while Ligand B (0.724) has a slightly elevated risk. Minimizing hERG liability is critical.

**Microsomal Clearance:** Ligand A (41.317 mL/min/kg) has lower microsomal clearance than Ligand B (63.745 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-40.233 hours) has a much longer in vitro half-life than Ligand B (43.231 hours). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.083, B: 0.445).

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While both are good, the 0.3 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A is the more promising candidate. It has better solubility, lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better binding affinity. While Ligand B has a slightly better Caco-2 permeability, the other advantages of Ligand A outweigh this. The lower hERG risk for Ligand A is also a significant positive.

Output:
0
2025-04-17 12:17:18,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.372 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for good absorption and is favorable. Ligand B (87.74) is higher, but still within a reasonable range, though less optimal.

**logP:** Ligand A (3.743) is within the optimal 1-3 range. Ligand B (0.683) is below 1, which could indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is excellent. Ligand B (HBD=2, HBA=4) is acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.823 and 0.705, respectively), indicating drug-like properties.

**DILI:** Ligand A (37.922) has a low DILI risk. Ligand B (11.361) has an even lower DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.508) has better BBB penetration than Ligand B (60.644).

**Caco-2 Permeability:** Ligand A (-4.232) has poor Caco-2 permeability. Ligand B (-5.056) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.84) has poor solubility. Ligand B (-1.482) has better solubility, which is a positive.

**hERG:** Ligand A (0.645) has a low hERG risk. Ligand B (0.198) has a very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (51.296) has moderate clearance. Ligand B (-11.218) has negative clearance, which is extremely favorable, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (33.613) has a moderate half-life. Ligand B (-1.65) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.361) has low P-gp efflux. Ligand B (0.01) has very low P-gp efflux, which is a positive.

**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 huge, but is still a positive for Ligand B.

**Overall Assessment:**

Ligand B demonstrates a superior profile regarding key enzyme-specific properties. Its significantly lower microsomal clearance and hERG risk are major advantages. While its Caco-2 permeability and solubility are still not ideal, they are better than Ligand A. The slightly better binding affinity of Ligand B further strengthens its candidacy. The poor half-life of Ligand B is concerning, but could potentially be addressed through structural modifications. Ligand A's poor Caco-2 permeability and solubility are more difficult to remedy.

Output:
1
2025-04-17 12:17:18,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.559 Da and 360.498 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (33.2). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.544) is optimal, while Ligand B (4.539) is pushing the upper limit and could present solubility issues.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides a balance between solubility and permeability.

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

**QED:** Both ligands have good QED scores (0.678 and 0.805), indicating good drug-like properties.

**DILI:** Ligand A (21.714) has a significantly lower DILI risk than Ligand B (56.844), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (75.998 and 86.817). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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:** Ligand A (-2.851) is slightly better than Ligand B (-4.642), though both are poor.

**hERG Inhibition:** Ligand A (0.496) has a lower hERG risk than Ligand B (0.642), which is favorable.

**Microsomal Clearance:** Ligand A (60.465) has lower microsomal clearance than Ligand B (63.126), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.227) has a longer half-life than Ligand B (4.245), which is desirable.

**P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux than Ligand B (0.76), which is preferable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 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, **Ligand A** is the more promising drug candidate. While both have poor Caco-2 permeability and solubility, Ligand A demonstrates significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly lower hERG risk. These factors are crucial for kinase inhibitors. The similar binding affinities make the superior ADME properties of Ligand A the deciding factor.

Output:
0
2025-04-17 12:17:18,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.435 and 346.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (88.18) is better than Ligand B (40.62), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (-0.234) is slightly low, potentially hindering permeation, while Ligand B (3.618) is within the optimal 1-3 range. This favors Ligand B.

**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, good QED values (0.711 and 0.73).

**7. DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (13.687), a major advantage.

**8. BBB:** Ligand A (55.021) has a lower BBB penetration than Ligand B (82.862). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.977) has poor Caco-2 permeability, while Ligand B (-4.571) is slightly better, but still poor.

**10. Aqueous Solubility:** Ligand A (-0.682) has poor solubility, while Ligand B (-3.259) is even worse. Both are problematic.

**11. hERG Inhibition:** Ligand A (0.072) has a very low hERG risk, a significant advantage. Ligand B (0.402) is higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (3.245) has lower microsomal clearance (better metabolic stability) than Ligand B (59.18). This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-2.888) has a longer in vitro half-life than Ligand B (2.334). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, while Ligand B (0.167) is slightly higher.

**15. Binding Affinity:** Ligand B (-7.6) has a stronger binding affinity than Ligand A (-9.4). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a better binding affinity and logP, but suffers from worse solubility, higher DILI risk, and higher metabolic clearance. Ligand A has a significantly better safety profile (DILI, hERG), better metabolic stability (Cl_mic, t1/2), and lower P-gp efflux, but its logP is suboptimal and Caco-2 permeability is poor.

The stronger binding affinity of Ligand B is a significant advantage for an enzyme target. While the solubility and metabolic stability are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The improved safety profile of Ligand A is attractive, but the weaker binding affinity is a major drawback.

Output:
1
2025-04-17 12:17:18,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.459 and 372.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.84) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (83.55) is well within the range.

**logP:** Ligand A (0.741) is a bit low, potentially hindering permeation. Ligand B (1.745) is better, falling 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 4 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.717 and 0.703), indicating good drug-likeness.

**DILI:** Ligand A (59.093) has a higher DILI risk than Ligand B (37.379). This is a significant negative for Ligand A.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (68.631) is slightly better than Ligand A (57.852).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability. Ligand A (-4.872) is slightly better than Ligand B (-5.037).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-1.393) is slightly better than Ligand B (-2.458).

**hERG Inhibition:** Both have low hERG inhibition risk (0.225 and 0.285).

**Microsomal Clearance:** Ligand A (14.049) has significantly lower microsomal clearance than Ligand B (21.772), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.656) has a much longer in vitro half-life than Ligand B (1.714), which is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.042 and 0.227).

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's better metabolic stability and half-life, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.9 vs -9.1 kcal/mol) is a critical factor for an enzyme inhibitor. While Ligand B has slightly worse solubility and a higher DILI risk, these can potentially be addressed through formulation or further structural modifications. The improved logP of Ligand B also suggests better permeability.

Output:
1
2025-04-17 12:17:18,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.531 and 344.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (49.41) is still under 140, but less optimal than A.

**logP:** Ligand A (4.513) is slightly above the optimal 1-3 range, potentially leading to solubility issues. Ligand B (2.901) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 2 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.704 and 0.893), indicating drug-like properties.

**DILI:** Ligand A (21.753) has a lower DILI risk than Ligand B (24.351), which is preferable. Both are below the 40 threshold.

**BBB:** Both ligands have high BBB penetration (96.084 and 94.494), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed with the assumption these are percentile scores and higher is better. Ligand A (-4.304) is slightly worse than Ligand B (-4.647).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, assuming percentile scores, Ligand A (-4.39) is slightly better than Ligand B (-3.669).

**hERG:** Both ligands have low hERG inhibition liability (0.938 and 0.847), which is excellent.

**Microsomal Clearance:** Ligand A (91.112) has significantly higher microsomal clearance than Ligand B (22.006), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (36.356) has a longer half-life than Ligand B (-9.021). However, the negative value for B is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.636) has lower P-gp efflux than Ligand B (0.221), which is better for bioavailability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite Ligand A having slightly better DILI and P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.0 vs -7.7 kcal/mol) outweighs the slightly higher logP and lower P-gp efflux of Ligand A. The lower microsomal clearance of Ligand B is a major advantage, indicating better metabolic stability, which is critical for an enzyme inhibitor. The negative values for Caco-2 and solubility are concerning for both, but the differences are small.

Output:
1
2025-04-17 12:17:18,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.531 and 356.369 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (57.7) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (79.82) is still acceptable but less optimal.

**logP:** Ligand A (2.395) is within the optimal 1-3 range. Ligand B (0.811) is slightly below 1, which *could* indicate permeability issues, though not critically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also acceptable, but slightly higher donor count.

**QED:** Ligand A (0.838) has a very good drug-likeness score. Ligand B (0.451) is below the 0.5 threshold, indicating a less favorable overall drug-like profile.

**DILI:** Ligand A (31.679) has a low DILI risk. Ligand B (48.042) is slightly higher, but still acceptable.

**BBB:** Both have reasonable BBB penetration, but Ligand A is better (80.845 vs 71.501). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.618) has poor Caco-2 permeability. Ligand B (-5.157) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.285 and -1.275 respectively). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.89 and 0.709).

**Microsomal Clearance:** Ligand A (22.879) has moderate clearance. Ligand B (0.484) has *very* low clearance, suggesting excellent metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (23.814) has a moderate half-life. Ligand B (-10.651) has a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.434 and 0.1).

**Binding Affinity:** Both ligands have identical and strong binding affinity (-7.6 kcal/mol).

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is the better candidate. Its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux outweigh the slightly lower QED and Caco-2 permeability. The poor solubility of both compounds is a concern that would need to be addressed through formulation strategies. Ligand A's poor Caco-2 permeability is also a negative.

Output:
1
2025-04-17 12:17:18,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good absorption, while Ligand B (134.58) is closer to the upper limit but still acceptable.

**logP:** Ligand A (1.215) is within the optimal 1-3 range. Ligand B (0.315) 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) is excellent. Ligand B (3 HBD, 7 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.75 and 0.695, respectively), indicating drug-like properties.

**DILI:** Ligand A (23.226) has a much lower DILI risk than Ligand B (43.622). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration (77.743 and 80.031), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.693) has poor Caco-2 permeability, which is concerning. Ligand B (-5.261) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.613 and -2.355). This could present formulation challenges, but is not a knockout factor.

**hERG Inhibition:** Both ligands have low hERG risk (0.365 and 0.402).

**Microsomal Clearance:** Ligand A (35.701) has a moderate clearance, while Ligand B (-2.74) has *negative* clearance, which is highly favorable and suggests excellent metabolic stability.

**In vitro Half-Life:** Ligand A (9.626 hours) has a reasonable half-life. Ligand B (-21.69 hours) is also good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.016).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better safety profile (lower DILI) and slightly better TPSA, Ligand B's significantly superior binding affinity (-8.0 vs -7.3 kcal/mol) and excellent metabolic stability (negative Cl_mic) are critical advantages for an enzyme inhibitor. The slightly lower logP of Ligand B is a minor concern, and the solubility is similar for both. The Caco-2 permeability is poor for both, but the potency and stability of Ligand B are more important for this target class.

Output:
1
2025-04-17 12:17:18,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.463 and 382.473 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.89 and 89.87) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.99) is optimal, while Ligand B (0.861) is slightly below the ideal range, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

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

**QED:** Ligand A (0.76) has a better QED score than Ligand B (0.522), indicating higher drug-likeness.

**DILI:** Ligand A (33.773) has a significantly lower DILI risk than Ligand B (17.72). Lower is better, and Ligand A is well below the 40% threshold. Ligand B is also good, but less so.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.79) is higher than Ligand B (55.603).

**Caco-2 Permeability:** Ligand A (-4.509) has a better Caco-2 permeability than Ligand B (-5.025). Higher is better.

**Aqueous Solubility:** Ligand A (-2.421) has better aqueous solubility than Ligand B (-1.394). Higher is better.

**hERG Inhibition:** Both ligands (0.219 and 0.161) show low hERG inhibition liability, which is excellent.

**Microsomal Clearance:** Ligand A (44.427) has a higher microsomal clearance than Ligand B (22.303), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-13.321) has a much longer in vitro half-life than Ligand A (-1.3). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands (0.021 and 0.034) have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While both are strong binders, the 0.8 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A has advantages in QED, DILI, solubility and Caco-2 permeability. However, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. Given the enzyme-specific priorities, metabolic stability and potency are paramount. The substantial difference in half-life and the slight advantage in binding affinity make Ligand B the more promising candidate, despite its slightly lower QED and higher DILI risk (both still acceptable).

Output:
1
2025-04-17 12:17:18,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.507 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.1) is significantly better than Ligand B (82.71).  A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands have good logP values (1.016 and 0.743), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0/1) and HBA (4/4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.759 and 0.819), indicating good drug-likeness.

**DILI:** Ligand A (8.647) has a much lower DILI risk than Ligand B (39.473). This is a significant advantage for Ligand A.

**BBB:** Both have similar BBB penetration (64.482 and 68.166). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.956 and -4.559). These are unusual and suggest poor permeability. However, the values are close, so this isn't a major differentiator.

**Aqueous Solubility:** Ligand A (-0.234) has slightly better solubility than Ligand B (-2.422), although both are poor.

**hERG:** Ligand A (0.592) has a slightly better hERG profile than Ligand B (0.361), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (1.692) has significantly lower microsomal clearance than Ligand B (30.013). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-1.088) has a better (longer) in vitro half-life than Ligand B (-35.277). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux (0.026 and 0.024).

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.6). This is a 0.8 kcal/mol difference, which is significant, but needs to be weighed against the other factors.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME-Tox properties. Specifically, its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and hERG profile make it a much more promising drug candidate. The difference in binding affinity (0.8 kcal/mol) is not enough to overcome these substantial ADME advantages.

Output:
1
2025-04-17 12:17:18,770 - INFO - Batch 117 complete. Total preferences: 1872
2025-04-17 12:17:18,770 - INFO - Processing batch 118/512...
2025-04-17 12:18:04,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.372 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.13) is significantly better than Ligand B (71.33), being well below the 140 threshold for good absorption.

**logP:** Ligand A (3.484) is optimal, while Ligand B (1.474) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is more favorable than Ligand B (0 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.907 and 0.833), indicating good drug-like properties.

**DILI:** Ligand A (38.736) has a lower DILI risk than Ligand B (52.579), which is preferable.

**BBB:** Both have high BBB penetration, but Ligand A (94.067) is slightly better than Ligand B (89.027). While not a primary concern for a non-CNS target like SRC, it's a minor positive for 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 are negative, indicating poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.803) has a lower hERG risk than Ligand B (0.242), which is a significant advantage.

**Microsomal Clearance:** Ligand A (19.203) has a much lower microsomal clearance than Ligand B (60.283), suggesting better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-0.984) has a better in vitro half-life than Ligand B (-21.132).

**P-gp Efflux:** Ligand A (0.228) has lower P-gp efflux than Ligand B (0.193).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.8 kcal/mol), with Ligand B being slightly better. However, the difference is small and can likely be overcome with further optimization.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties like metabolic stability (lower Cl_mic), hERG risk, DILI risk, and TPSA. These factors are particularly important for enzyme inhibitors, as they directly impact bioavailability, safety, and duration of action. The slightly better logP and H-bonding characteristics of Ligand A also contribute to its overall better profile.

Output:
0
2025-04-17 12:18:04,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.486 and 356.323 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.27) is significantly better than Ligand B (58.95). TPSA < 140 is desirable for oral absorption, and both meet this, but A is much closer to the <90 range for CNS penetration if that were a consideration.

**logP:** Both ligands have good logP values (3.174 and 2.826), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.889) has a substantially better QED score than Ligand B (0.657), indicating a more drug-like profile.

**DILI:** Ligand B (67.003) has a higher DILI risk than Ligand A (54.75), placing it in a higher risk category.

**BBB:** Both have good BBB penetration (85.925 and 89.298), but this is less critical for a non-CNS target like SRC.

**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. It's difficult to interpret these values directly.

**Aqueous Solubility:** Both have negative solubility values, again indicating a problem with the prediction.

**hERG:** Ligand A (0.962) has a slightly higher hERG risk than Ligand B (0.498), but both are relatively low.

**Microsomal Clearance:** Ligand A (42.283) has a higher microsomal clearance than Ligand B (23.003), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (29.664) has a longer in vitro half-life than Ligand A (23.637), which is desirable.

**P-gp Efflux:** Ligand A (0.546) has lower P-gp efflux than Ligand B (0.219), which is favorable.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.8). This 0.2 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a better QED and lower DILI risk, the significantly stronger binding affinity of Ligand B (-9.0 vs -8.8 kcal/mol) is the most important factor for an enzyme inhibitor. Additionally, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. The slightly higher DILI risk for Ligand B is a concern, but potentially manageable with further optimization. The negative solubility and Caco-2 values are concerning for both, but could be artifacts of the prediction method.

Output:
1
2025-04-17 12:18:04,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.815 Da) is slightly higher than Ligand B (361.555 Da), but both are acceptable.

**TPSA:** Ligand A (100.03) is higher than Ligand B (46.09). While both are below 140, Ligand B's lower TPSA is preferable for oral absorption.

**logP:** Ligand A (2.85) is within the optimal range (1-3). Ligand B (4.536) 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 7 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.673 and 0.638), indicating good drug-likeness.

**DILI:** Ligand A (81.66) has a significantly higher DILI risk than Ligand B (41.877). This is a major concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (78.015) is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.211 and -5.102), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation as these values are not typical.

**Aqueous Solubility:** Both have negative solubility values (-4.566 and -4.082), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.311) has a slightly lower hERG risk than Ligand B (0.474), which is preferable.

**Microsomal Clearance:** Ligand A (24.997) has a much lower microsomal clearance than Ligand B (122.139). This suggests significantly better metabolic stability for Ligand A, a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (2.487) has a shorter half-life than Ligand B (-1.291). The negative value for Ligand B is concerning and likely indicates rapid degradation.

**P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux than Ligand B (0.539), which is favorable for bioavailability.

**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 a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic) and P-gp efflux. However, it has a much higher DILI risk and shorter half-life. Ligand B has better TPSA and lower DILI, but suffers from very high metabolic clearance and a questionable in vitro half-life.

Considering the priorities for enzyme inhibitors, metabolic stability is crucial. The significantly lower Cl_mic of Ligand A outweighs its higher DILI risk, *provided* the DILI risk can be mitigated through structural modifications. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies. The binding affinity difference, while present, is not large enough to be decisive on its own.

Output:
0
2025-04-17 12:18:04,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.451 and 367.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (91.57 and 91.76) slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (2.614) is within the optimal 1-3 range. Ligand B (1.605) is slightly lower, potentially impacting permeability, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, likely not posing significant issues.

**QED:** Ligand A (0.737) has a better QED score than Ligand B (0.414), indicating a more drug-like profile.

**DILI:** Ligand A (54.207) has a slightly higher DILI risk than Ligand B (50.95), but both are below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. This likely indicates very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.305 and 0.332), which is excellent.

**Microsomal Clearance:** Ligand B (-7.488) has significantly *lower* (better) microsomal clearance than Ligand A (34.969), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (5.844 hours) has a longer half-life than Ligand A (62.87 hours). This is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.32 and 0.088), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Conclusion:**

While Ligand A has a slightly better QED and binding affinity, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic, longer half-life) and a slightly lower DILI risk. Given that we are targeting a kinase (enzyme), metabolic stability is paramount. The slight advantage in binding affinity for Ligand A is outweighed by the substantial improvement in pharmacokinetic properties of Ligand B. The poor solubility and permeability of both compounds are concerning and would require attention during lead optimization, but the metabolic advantage of B is more immediately impactful.

Output:
1
2025-04-17 12:18:04,971 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 Da and 337.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is slightly higher than Ligand B (64.45). Both are below the 140 threshold for oral absorption, but neither is optimized for CNS penetration (below 90).

**logP:** Ligand A (1.586) is within the optimal range (1-3), while Ligand B (3.106) is at the higher end, potentially raising concerns about solubility and off-target effects.

**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 acceptable limits (<=10), but Ligand A is preferable.

**QED:** Both ligands have similar QED values (0.708 and 0.608), indicating good drug-likeness.

**DILI:** Both ligands have the same DILI risk (73.245 percentile), which is relatively high and a concern.

**BBB:** Ligand A (73.245) has better BBB penetration potential than Ligand B (57.852), but neither is particularly high, which isn't a major concern for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-4.737) shows better Caco-2 permeability than Ligand B (-4.917).

**Aqueous Solubility:** Ligand A (-1.736) has better aqueous solubility than Ligand B (-3.558). This is a significant advantage for an enzyme inhibitor.

**hERG Inhibition:** Ligand A (0.31) has a much lower hERG inhibition risk than Ligand B (0.867). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (40.188) has a lower microsomal clearance than Ligand A (44.538), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (40.74) has a longer in vitro half-life than Ligand A (-22.892). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.706), which is favorable for bioavailability.

**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 the better candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in crucial areas like solubility, hERG risk, and P-gp efflux. The slightly better binding affinity of Ligand A also contributes to its favorability. The DILI risk is a concern for both, but can be addressed in later optimization stages. The better solubility and lower hERG risk of Ligand A make it a more promising starting point for further development.

Output:
0
2025-04-17 12:18:04,971 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.22 Da) is slightly higher than Ligand B (368.543 Da), but both are acceptable.

**TPSA:** Ligand A (97.11) is higher than Ligand B (67.43). While both are below 140, the lower TPSA of Ligand B is preferable for absorption.

**logP:** Both ligands have good logP values (A: 2.658, B: 2.49), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (A: 5, B: 4), satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED scores (A: 0.685, B: 0.646), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (97.169) compared to Ligand B (26.25). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (74.758) than Ligand A (16.983).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the value for Ligand B (-5.128) is less negative than Ligand A (-5.411), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-3.171) is slightly better than Ligand A (-3.429).

**hERG:** Both have low hERG inhibition liability (A: 0.064, B: 0.463), which is good.

**Microsomal Clearance:** Ligand A has a much lower Cl_mic (0.982) than Ligand B (67.284), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a shorter half-life (14.469 hours) than Ligand B (19.55 hours), but both are reasonably good.

**P-gp Efflux:** Ligand A has lower P-gp efflux (0.015) than Ligand B (0.145), which is favorable.

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, lower P-gp efflux). However, it has a very high DILI risk and poor solubility. Ligand B has a lower DILI risk, slightly better solubility and permeability, but weaker binding affinity and poorer metabolic stability.

Given the enzyme-specific priorities, potency (binding affinity) and metabolic stability are key. The substantial difference in binding affinity (-9.2 vs -8.4 kcal/mol) and the significantly better metabolic stability of Ligand A are compelling advantages. While the high DILI risk is concerning, it might be mitigated through structural modifications in subsequent optimization rounds. The solubility issues could also be addressed with formulation strategies. The weaker binding of Ligand B makes it less likely to be a successful drug candidate, even with its better ADME properties.

Output:
1
2025-04-17 12:18:04,971 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (349.519 and 342.451 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.44) is well below the 140 threshold for good absorption, and is favorable. Ligand B (117.43) is still under 140, but less optimal than A.

**3. logP:** Both ligands (2.764 and 2.068) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (7) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.471 and 0.634), indicating reasonable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (8.647) has a significantly lower DILI risk than Ligand B (56.146). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a kinase inhibitor, but Ligand A (82.164) has better BBB penetration than Ligand B (56.223).

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.165) is slightly better than Ligand B (-5.765).

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.292) is slightly better than Ligand B (-3.126).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.703 and 0.463).

**12. Microsomal Clearance:** Ligand B (9.72) has lower microsomal clearance than Ligand A (14.731), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.249) has a longer in vitro half-life than Ligand A (-15.231), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.151 and 0.014).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.5). While the difference is small (0.3 kcal/mol), it is still a positive factor for Ligand A.

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a slightly better binding affinity and a significantly lower DILI risk. Ligand B has better metabolic stability and half-life. However, the substantial difference in DILI risk for Ligand A outweighs the slightly better metabolic stability of Ligand B. The solubility and permeability are poor for both, but similar.

Output:
0
2025-04-17 12:18:04,971 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.495 Da) is slightly preferred due to being lower in MW.

**TPSA:** Ligand A (59.13) is significantly better than Ligand B (72). Lower TPSA generally improves absorption.

**logP:** Ligand A (0.417) is a bit low, potentially hindering permeation, while Ligand B (2.125) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, which is good. Ligand B has 7, which is acceptable but less ideal.

**QED:** Both ligands have reasonable QED scores (A: 0.797, B: 0.677), indicating good drug-like properties.

**DILI:** Ligand A (5.196) has a very low DILI risk, significantly better than Ligand B (27.608).

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (76.658) is better than Ligand B (56.262).

**Caco-2 Permeability:** Ligand A (-4.899) is poor, while Ligand B (-5.312) is also poor. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-0.359) is slightly better than Ligand B (-2.387), but both are quite poor.

**hERG Inhibition:** Ligand A (0.494) has a very low hERG risk, much better than Ligand B (0.595).

**Microsomal Clearance:** Ligand A (-31.166) shows excellent metabolic stability (negative value indicates low clearance), significantly better than Ligand B (35.97).

**In vitro Half-Life:** Ligand A (-16.51) has a longer half-life, again indicating better metabolic stability, compared to Ligand B (25.062).

**P-gp Efflux:** Both ligands show very low P-gp efflux (A: 0.002, B: 0.14).

**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 has a substantially better binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better ADME properties (DILI, metabolic stability, hERG), the large difference in binding affinity (-8.4 vs -0.0 kcal/mol) likely outweighs these concerns. The potency advantage of Ligand B is significant enough to warrant further optimization, even if it means addressing the solubility and Caco-2 permeability issues.

Output:
1
2025-04-17 12:18:04,971 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.475 and 345.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is significantly better than Ligand B (95.04).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (1.556 and 1.837), 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 6. Both are below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.673 and 0.761), indicating good drug-like properties.

**7. DILI:** Ligand A (22.024) has a much lower DILI risk than Ligand B (32.067). Both are below the concerning threshold of 60, but A is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.864) is slightly better than Ligand B (53.625).

**9. Caco-2 Permeability:** Ligand A (-4.496) shows better Caco-2 permeability than Ligand B (-5.245). Higher values are better, and A is closer to 0.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.585 and -1.698). This is a potential concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.508 and 0.505).

**12. Microsomal Clearance:** Both have similar microsomal clearance (33.513 and 34.031 mL/min/kg). This indicates similar metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.516 hours) has a significantly longer half-life than Ligand B (6.124 hours). This is a major advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.279 and 0.16).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.9 kcal/mol). The difference is minimal.

**Conclusion:**

While both ligands exhibit good binding affinity, Ligand A is the superior candidate. It has a lower DILI risk, better Caco-2 permeability, a significantly longer half-life, and a lower TPSA. The solubility is a concern for both, but the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 12:18:04,971 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.41 and 353.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (71.33 and 70.67) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.363) is slightly low, potentially hindering permeation. Ligand B (1.543) is within the optimal range of 1-3. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have QED values (0.77 and 0.694) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (27.918) has a significantly lower DILI risk than Ligand B (5.235), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (90.694 and 72.043), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.845 and -4.887), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.925 and -1.682), indicating very poor aqueous solubility, a significant drawback for oral bioavailability.

**hERG Inhibition:** Ligand A (0.105) has a much lower hERG inhibition risk than Ligand B (0.443), which is a crucial safety consideration.

**Microsomal Clearance:** Ligand A (-2.12 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (25.256 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.93 hours) has a negative half-life, which is not possible. Ligand B (2.621 hours) has a short half-life, which might necessitate frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.005).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). The 1 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower DILI risk, lower hERG risk, and better metabolic stability. However, both ligands suffer from poor solubility and permeability. The superior potency and safety profile of Ligand A make it the more promising candidate, despite the solubility/permeability issues. These issues could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:18:04,971 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (354.397 and 368.792 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption, and even favorable for potential CNS penetration. Ligand B (91.57) is still within acceptable limits, but less optimal.

**3. logP:** Both ligands (2.042 and 2.808) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (3) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.621 and 0.756), indicating drug-like properties.

**7. DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (67.39), placing it in the "good" category while Ligand B is approaching the higher risk threshold.

**8. BBB:** Ligand A (91.47) shows better BBB penetration potential than Ligand B (38.387), though this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.598 and -4.691). This is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, since both are similarly poor, this doesn't differentiate them.

**10. Aqueous Solubility:** Ligand A (-2.462) has slightly better solubility than Ligand B (-4.098), but both are quite poor.

**11. hERG Inhibition:** Ligand A (0.367) has a much lower hERG inhibition liability than Ligand B (0.505), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (22.188) has a lower microsomal clearance than Ligand B (25.515), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.787) has a negative half-life, which is not physically possible. This is a major red flag. Ligand B (118.585) has a very long in vitro half-life, which is highly desirable.

**14. P-gp Efflux:** Ligand A (0.04) has very low P-gp efflux, while Ligand B (0.303) has slightly higher efflux.

**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 substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Despite the problematic negative half-life for Ligand A, its significantly superior binding affinity (-8.9 vs -0.0 kcal/mol) and lower DILI/hERG risk make it the more promising candidate. The affinity difference is substantial. The negative half-life is likely an experimental error and would need to be re-evaluated. Ligand B has a good half-life, but its weak binding affinity is a major drawback.

Output:
0
2025-04-17 12:18:04,971 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.455 and 350.315 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (45.55 and 44.1) are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (2.741) is optimal, while Ligand B (4.134) is approaching the upper limit and could potentially cause solubility issues or off-target effects.

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

**H-Bond Acceptors:** Ligand A has 3, and Ligand B has 2, both are within the acceptable range of <=10.

**QED:** Both ligands have similar QED values (0.794 and 0.761), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (43.234 and 48.042), below the 60 threshold.

**BBB:** Both have reasonable BBB penetration, but Ligand B (84.374) is significantly higher than Ligand A (71.229). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.796 and -4.209), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.986 and -5.062), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.392) has a lower hERG risk than Ligand B (0.932), which is preferable.

**Microsomal Clearance:** Ligand A (71.535) has higher microsomal clearance than Ligand B (51.405), meaning it is less metabolically stable. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-15.65) has a negative half-life, which is impossible and indicates a problem with the data or the molecule. Ligand A (38.533) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux (0.413 and 0.4), which is good.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having significant solubility and permeability issues, Ligand B is the more promising candidate. The substantially stronger binding affinity (-9.0 vs -8.3 kcal/mol) is a critical advantage for an enzyme inhibitor. While Ligand A has better hERG and a plausible half-life, the difference in binding affinity is more important. The negative half-life value for Ligand B is a red flag, but the overall profile, especially the binding affinity, makes it the better choice *assuming the half-life data is an error*.

Output:
1
2025-04-17 12:18:04,972 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (383.583 and 362.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is better than Ligand B (62.66), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have good logP values (3.428 and 3.032), 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 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.797 and 0.722), indicating good drug-likeness.

**7. DILI:** Ligand A (55.525) has a higher DILI risk than Ligand B (23.769). This is a significant drawback for Ligand A.

**8. BBB:** Both have acceptable BBB penetration, but Ligand A (75.843) is better than Ligand B (59.093). This is less critical for a kinase inhibitor than other properties.

**9. Caco-2 Permeability:** Ligand A (-5.004) is better than Ligand B (-4.76), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-5.133) is worse than Ligand B (-2.866). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.789 and 0.26), which is excellent.

**12. Microsomal Clearance:** Ligand A (97.087) has higher microsomal clearance than Ligand B (46.483), meaning it's less metabolically stable. This is a major negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (12.462) has a significantly longer in vitro half-life than Ligand A (-22.272), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.398 and 0.413).

**15. Binding Affinity:** Both ligands have identical binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and BBB penetration, Ligand B is significantly superior in terms of metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. Solubility is also better for Ligand B. Given the enzyme-specific priorities, metabolic stability and low toxicity are crucial. The identical binding affinity removes that as a differentiating factor. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:18:04,972 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.495 and 353.394 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.96) is slightly above the optimal <140, but acceptable. Ligand B (87.74) is excellent, well below 140.

**logP:** Ligand A (3.691) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.73) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 4 HBAs, both within the acceptable limit of <=10.

**QED:** Ligand B (0.78) has a better QED score than Ligand A (0.375), indicating a more drug-like profile.

**DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (39.434), which is a major advantage. Both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 58.821, Ligand B: 65.801), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.781 and -4.829), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.022 and -2.29), which is also concerning and suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.329 and 0.211), which is excellent.

**Microsomal Clearance:** Ligand A (62.31) has a higher microsomal clearance than Ligand B (-26.687). The negative value for Ligand B is unusual and suggests very high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand B (-8.849) has a much longer in vitro half-life than Ligand A (-2.752), which is a major positive. Again, the negative value for Ligand B is unusual and suggests a very long half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.141 and 0.014), which is good.

**Binding Affinity:** Ligand B (-9.7 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 drawbacks.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.7 vs -7.6 kcal/mol), superior QED (0.78 vs 0.375), and exceptionally high metabolic stability (indicated by the negative Cl_mic and long in vitro half-life) outweigh the slightly lower DILI score of Ligand A and the slightly better TPSA. The low logP of Ligand B is a concern, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 12:18:04,972 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.399 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (123.22) is better than Ligand B (55.32) as it is closer to the ideal threshold of <=140 for oral absorption.

**logP:** Ligand A (-0.973) is slightly low, potentially hindering permeation. Ligand B (2.899) is optimal.

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

**H-Bond Acceptors:** Ligand A (10) is at the upper limit of acceptable, while Ligand B (4) is excellent.

**QED:** Both ligands have good QED scores (A: 0.523, B: 0.59), indicating drug-likeness.

**DILI:** Ligand A (56.999) is slightly higher than Ligand B (44.591), but both are within an acceptable range (<60).

**BBB:** Ligand A (73.788) is good, while Ligand B (92.478) is excellent. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.316) is poor, indicating low intestinal absorption. Ligand B (-4.413) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.33) is poor, while Ligand B (-3.968) is very poor. This is a significant concern for both, but more so for B.

**hERG Inhibition:** Ligand A (0.264) is very low risk, while Ligand B (0.386) is also low risk.

**Microsomal Clearance:** Ligand A (36.667) is better than Ligand B (54.273), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.914) is better than Ligand B (-19.377), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.11) is very low, while Ligand B (0.226) is also low.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) is significantly stronger 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, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. While its logP and solubility are less ideal, the strong binding affinity and favorable safety profile are crucial for an enzyme inhibitor. Ligand B has a better logP, but suffers from poor solubility, worse metabolic stability, and a weaker binding affinity. The solubility issues with both are concerning, but can be addressed with formulation strategies. The superior potency and metabolic stability of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 12:18:04,972 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [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]
**Ligand B:** [345.399, 95.67, 1.786, 2, 5, 0.76, 28.965, 28.616, -5.543, -2.047, 0.1, 59.74, -25.977, 0.032, -7.3]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da).  A (350.419) and B (345.399) are comparable.
2. **TPSA:** A (87.9) is excellent, well below the 140 threshold. B (95.67) is still acceptable, but slightly higher.
3. **logP:** A (0.025) is very low, potentially causing permeability issues. B (1.786) is much better, falling within the optimal 1-3 range.
4. **HBD:** A (1) and B (2) are both good, below the 5 threshold.
5. **HBA:** A (6) and B (5) are both good, below the 10 threshold.
6. **QED:** A (0.809) is excellent, indicating high drug-likeness. B (0.76) is also good, but slightly lower.
7. **DILI:** A (38.736) is very good, low risk. B (28.965) is even better, indicating a very low DILI risk.
8. **BBB:** A (39.24) is low, not a concern for a non-CNS target like SRC. B (28.616) is also low, not a concern.
9. **Caco-2:** A (-4.755) is very poor, suggesting extremely low intestinal absorption. B (-5.543) is also poor, but slightly better.
10. **Solubility:** A (0.06) is very poor. B (-2.047) is also poor, but better than A.
11. **hERG:** A (0.256) is excellent, very low risk of cardiotoxicity. B (0.1) is even better.
12. **Cl_mic:** A (-14.53) is excellent, indicating very high metabolic stability. B (59.74) is poor, suggesting rapid metabolism.
13. **t1/2:** A (7.092) is good. B (-25.977) is excellent, indicating a very long half-life.
14. **Pgp:** A (0.023) is excellent, suggesting minimal efflux. B (0.032) is also excellent.
15. **Affinity:** A (-7) and B (-7.3) are both very good, with B being slightly better. The difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly hampered by its extremely low logP, poor Caco-2 permeability, and very poor solubility. These factors will likely lead to very poor oral bioavailability. Ligand B, despite a slightly higher TPSA and poorer solubility than ideal, has a much more favorable logP, better permeability, and a significantly better metabolic stability profile (lower Cl_mic, longer t1/2). The DILI and hERG risk are also lower for Ligand B. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:18:04,973 - INFO - Batch 118 complete. Total preferences: 1888
2025-04-17 12:18:04,973 - INFO - Processing batch 119/512...
2025-04-17 12:18:45,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.865 and 368.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (64.63 and 60.03) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.5) is slightly above the optimal 1-3 range, potentially leading to solubility issues. Ligand B (3.78) is within the optimal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.591 and 0.876), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A has a DILI risk of 90.733, which is high and concerning. Ligand B has a much lower DILI risk of 60.489, still elevated but significantly better.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (91.431) has better BBB penetration than Ligand A (50.523), but this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.605 and -4.485), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.111 and -4.854). This is a major issue, especially considering the slightly high logP of Ligand A.

**hERG Inhibition:** Ligand A (0.502) has a slightly higher hERG risk than Ligand B (0.763), but both are reasonably low.

**Microsomal Clearance:** Ligand B (43.481 mL/min/kg) has significantly lower microsomal clearance than Ligand A (104.44 mL/min/kg), indicating better metabolic stability. This is a crucial advantage.

**In vitro Half-Life:** Ligand B (24.618 hours) has a longer half-life than Ligand A (12.235 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.413 and 0.441).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). However, the difference is only 0.2 kcal/mol, which is not substantial 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. The primary reasons are its significantly lower DILI risk and much better metabolic stability (lower Cl_mic and longer t1/2). While both have poor solubility and permeability, the lower DILI and improved metabolic profile of Ligand B make it a more viable starting point for optimization. The small difference in binding affinity can likely be addressed during lead optimization without sacrificing the improved ADME properties.

Output:
1
2025-04-17 12:18:45,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 and 334.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold for oral absorption. Ligand B (105.2) is still acceptable, but higher, potentially impacting absorption.

**logP:** Both ligands have good logP values (2.51 and 1.10), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is ideal.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 8 HBA. Both are acceptable, but Ligand A is preferable.

**QED:** Both ligands have similar QED values (0.75 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (25.98) has a significantly lower DILI risk than Ligand B (69.83), which is a major advantage.

**BBB:** Ligand A (81.12) has better BBB penetration than Ligand B (46.49), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.798) has a higher Caco-2 permeability than Ligand B (-5.731), suggesting better intestinal absorption.

**Solubility:** Ligand A (-3.546) has better aqueous solubility than Ligand B (-2.469).

**hERG:** Ligand A (0.388) has a much lower hERG risk than Ligand B (0.078), which is a critical safety consideration.

**Microsomal Clearance:** Ligand A (64.03) has a higher microsomal clearance than Ligand B (-5.74). This suggests Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (26.73) has a significantly longer in vitro half-life than Ligand A (9.08), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.141) has lower P-gp efflux than Ligand B (0.046), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a significant advantage that could outweigh some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, it has a higher DILI risk, lower solubility, and a higher hERG risk. Ligand A has better ADME properties across the board except for affinity and metabolic stability.

Given the priorities for enzyme inhibitors, the substantial affinity advantage of Ligand B is crucial. While the ADME properties of Ligand B are less ideal, they are not prohibitive, and optimization could potentially mitigate the higher DILI and hERG risks. The stronger binding is likely to translate to greater efficacy.

Output:
1
2025-04-17 12:18:45,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 358.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is well below the 140 threshold for good absorption and is even favorable for potential CNS penetration (though not a priority here). Ligand B (109) is still under 140, but less optimal than A.

**logP:** Ligand A (1.237) is within the optimal 1-3 range. Ligand B (-0.678) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.707) has a better QED score than Ligand B (0.506), suggesting a more drug-like profile.

**DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (19.271), which is a crucial advantage.

**BBB:** Both ligands have similar BBB penetration (68.864 and 69.523), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.517) has a worse Caco-2 permeability than Ligand B (-5.155), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.759) has better aqueous solubility than Ligand B (-0.361). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.214) has a much lower hERG inhibition risk than Ligand B (0.091), a significant safety advantage.

**Microsomal Clearance:** Ligand A (27.105) has a higher microsomal clearance than Ligand B (-2.97), meaning Ligand B is more metabolically stable. This is a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (1.495) has a shorter in vitro half-life than Ligand B (-1.363). This supports the observation that Ligand B is more metabolically stable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.001).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.4 and -7.5 kcal/mol), with Ligand B being slightly better. However, the difference is small and likely not enough to overcome other significant ADME issues.

**Overall Assessment:**

Ligand A excels in several critical areas: lower DILI risk, lower hERG risk, and better solubility. While its Caco-2 permeability and half-life are less favorable, the safety profile and solubility advantages are substantial. Ligand B has better metabolic stability and slightly better binding affinity, but its higher DILI and hERG risk are concerning. For an oncology target, metabolic stability is important, but safety is paramount.

Output:
0
2025-04-17 12:18:45,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 348.447 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.91) is better than Ligand B (104.21). Both are acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (0.636 and 1.29), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=3, HBA=5) as it has fewer HBDs. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.776 and 0.657), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (29.934 and 28.577), which is excellent.

**BBB:** Both have similar BBB penetration (67.623 and 65.801), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.904 and -4.911), which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.893 and -2.271). This is a major drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.187 and 0.158), which is excellent.

**Microsomal Clearance:** Ligand A (9.711) has significantly lower microsomal clearance than Ligand B (35.818), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (8.624) has a positive half-life, while Ligand B (-18.623) has a negative half-life, indicating very rapid degradation. This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.004).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.7 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While both ligands have excellent binding affinity and low hERG/DILI risk, Ligand A is the superior candidate due to its significantly better metabolic stability (lower Cl_mic, positive t1/2), lower TPSA, and fewer H-bond donors. The poor solubility and Caco-2 permeability are concerning for both, but metabolic stability is paramount for kinase inhibitors. The slight advantage in binding affinity of Ligand B is outweighed by its poor metabolic profile.

Output:
0
2025-04-17 12:18:45,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.705 Da) is slightly higher than Ligand B (352.431 Da), but both are acceptable.

**TPSA:** Ligand A (55.76) is significantly better than Ligand B (84.94). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (4.326) is high, potentially leading to solubility issues and off-target effects. Ligand B (0.68) is quite low, which could hinder membrane permeability. This is a significant drawback for Ligand B.

**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 (0.621) is better than Ligand B (0.487), indicating a more drug-like profile.

**DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (34.277). This is a concern for Ligand A.

**BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (48.662) and Ligand B (56.611) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.82 and -4.852), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.894 and -1.027), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.635) has a slightly higher hERG risk than Ligand B (0.061). Ligand B is much better here.

**Microsomal Clearance:** Ligand A (84.451) has a higher microsomal clearance than Ligand B (21.138), indicating lower metabolic stability. Ligand B is much better here.

**In vitro Half-Life:** Ligand A (23.745) has a longer half-life than Ligand B (-4.309). This is a positive for Ligand A. However, the negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Both ligands have a Pgp efflux score of 0.539 and 0.016, respectively.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B appears to be the better candidate despite its low logP. While its low logP is a concern for permeability, the significantly better metabolic stability (lower Cl_mic, longer half-life), lower DILI risk, and much lower hERG risk outweigh this drawback. Both ligands have poor solubility and permeability (Caco-2). The strong binding affinity is a positive for both, but the ADME properties are more critical for initial selection. The poor solubility of both compounds will need to be addressed through formulation strategies.

Output:
1
2025-04-17 12:18:45,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (87.7) is excellent, well below the 140 threshold for oral absorption. Ligand B (35.58) is also very good.

**logP:** Both ligands have good logP values (A: 2.455, B: 2.251), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, which is favorable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.732, B: 0.842), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 80.109, which is concerning (high risk). Ligand B has a much lower DILI risk of 23.653, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Ligand A (77.007) shows reasonable BBB penetration, while Ligand B (90.074) is even better. However, BBB is less critical for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.541 and -4.418), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.321 and -1.647), indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Ligand A (0.421) has a slightly better hERG profile than Ligand B (0.943), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (51.895) has a moderate microsomal clearance, while Ligand B (-31.537) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (9.469) has a moderate half-life, while Ligand B (-4.895) has a negative half-life, which is also unusual and suggests very high stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.109, B: 0.173).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -10.7 kcal/mol, B: -10.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have good potency and acceptable physicochemical properties (except for solubility and Caco-2), Ligand B is significantly better due to its dramatically lower DILI risk and exceptionally high metabolic stability (negative Cl_mic and t1/2). The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies. The lower DILI risk and increased metabolic stability are more difficult to improve post-hoc.

Output:
1
2025-04-17 12:18:45,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight (MW):** Both ligands (368.474 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is well below the 140 threshold, while Ligand B (81.75) is still acceptable but closer to the limit.

**3. logP:** Both ligands have good logP values (2.407 and 1.03), 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 (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 3, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.857) has a significantly higher QED score than Ligand B (0.643), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.813) has a slightly higher DILI risk than Ligand B (27.801), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (86.894) has a better BBB penetration score than Ligand B (66.188). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.764 and -4.964). These values are unusual and likely indicate poor permeability *in vitro*. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.985 and -1.527). This is also a major concern, suggesting poor aqueous solubility and potential bioavailability issues.

**11. hERG Inhibition:** Ligand A (0.475) shows a slightly higher hERG inhibition risk than Ligand B (0.086). This is a significant advantage for Ligand B.

**12. Microsomal Clearance (Cl_mic):** Ligand B (11.71) has a lower microsomal clearance than Ligand A (18.559), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (9.841) has a significantly longer in vitro half-life than Ligand A (3.126), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.265) has lower P-gp efflux than Ligand B (0.005), which is a slight advantage.

**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 still a positive for Ligand B.

**Overall Assessment:**

Despite both ligands having concerning Caco-2 and solubility values, Ligand B emerges as the more promising candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity outweigh the slightly lower QED and BBB scores. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the ADME profile of Ligand B is more favorable overall.

Output:
1
2025-04-17 12:18:45,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.249 Da) is slightly higher than Ligand B (353.459 Da), but both are acceptable.

**TPSA:** Ligand A (105.32) is higher than Ligand B (68.23). While both are below 140, Ligand B's lower TPSA is preferable for oral absorption.

**logP:** Both ligands have good logP values (Ligand A: 2.251, Ligand B: 1.064), falling within the optimal range of 1-3.

**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 good QED scores (Ligand A: 0.612, Ligand B: 0.707), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 90.461, which is high. Ligand B has a much lower DILI risk of 15.006, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 33.695, while Ligand B has 71.772. Since SRC is not a CNS target, this isn't a major deciding factor, but higher BBB is generally less concerning.

**Caco-2 Permeability:** Ligand A (-5.041) has poor Caco-2 permeability, while Ligand B (-4.717) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.434) and Ligand B (-1.552) both have poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.125) has a slightly higher hERG risk than Ligand B (0.41), but both are relatively low.

**Microsomal Clearance:** Ligand A (58.171) has a higher microsomal clearance than Ligand B (25.513), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-43.218) has a significantly shorter in vitro half-life than Ligand B (20.405), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux than Ligand B (0.079), which is slightly favorable.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a stronger binding affinity than Ligand A (-8.5 kcal/mol). This 1.2 kcal/mol difference is substantial and outweighs many of the minor ADME drawbacks of Ligand B.

**Conclusion:**

Ligand B is the more promising drug candidate. While both ligands have some issues with solubility and Caco-2 permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a substantially stronger binding affinity. The superior binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:18:45,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.714 Da) is slightly higher than Ligand B (389.283 Da), but both are acceptable.

**TPSA:** Ligand A (64.74) is better than Ligand B (74.77), being closer to the ideal <140 for oral absorption.

**logP:** Ligand A (3.695) is within the optimal range (1-3), while Ligand B (1.299) is at the lower end. A lower logP can sometimes hinder permeability, but isn't a dealbreaker.

**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: 0.591, B: 0.712), indicating good drug-like properties.

**DILI:** Ligand A (77.743) has a higher DILI risk than Ligand B (49.593). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (58.976) and Ligand B (66.072) are both moderate.

**Caco-2 Permeability:** Ligand A (-5.331) has poor Caco-2 permeability, whereas Ligand B (-4.723) is slightly better. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.914) has lower solubility than Ligand B (-2.543). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.846) has a slightly higher hERG risk than Ligand B (0.447), but both are relatively low.

**Microsomal Clearance:** Ligand A (61.007) has significantly higher microsomal clearance than Ligand B (14.596). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (43.874) has a longer half-life than Ligand B (7.957). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.738) has lower P-gp efflux than Ligand B (0.013), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A's longer half-life and lower P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-8.3 vs -10.1 kcal/mol) outweighs the slightly lower half-life and higher P-gp efflux. Furthermore, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic), both critical for drug development. While both have poor Caco-2 permeability and solubility, the potency and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 12:18:45,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.503 Da) is slightly better, being closer to the lower end which can aid permeability. Ligand B (410.243 Da) is still acceptable.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (64.55), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands have good logP values (A: 2.593, B: 3.209), 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 (HBD=1, HBA=3) is preferable to Ligand B (HBD=0, HBA=6). While both are within acceptable limits, fewer hydrogen bond donors and acceptors generally improve permeability.

**QED:** Ligand A (0.768) has a substantially better QED score than Ligand B (0.57), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (A: 8.026, B: 80.807). Ligand B's DILI risk is very high and concerning.

**BBB:** Ligand A (73.478) has a good BBB percentile, while Ligand B (93.486) is excellent. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.533 and -4.451), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.504 and -4.574), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.421, B: 0.53), which is good.

**Microsomal Clearance:** Ligand A (46.762) has a much lower microsomal clearance than Ligand B (102.009), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-3.613) has a better (less negative) in vitro half-life than Ligand B (-12.273), indicating greater stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.046, B: 0.317), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -7.9 kcal/mol, B: -8.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is significantly better overall. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A demonstrates superior drug-likeness (QED), metabolic stability (lower Cl_mic, better t1/2), and a much lower DILI risk. The binding affinity is comparable. The poor solubility and permeability are significant drawbacks for both, but can potentially be addressed through formulation strategies. However, the high DILI risk of Ligand B is a major red flag.

Output:
0
2025-04-17 12:18:45,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.438 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.49) is significantly better than Ligand B (101.8). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.304 and 0.847), 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 4 HBAs, while Ligand B has 6. Lower HBA counts are generally preferred for better permeability, giving a slight edge to Ligand A.

**QED:** Both ligands have similar QED scores (0.855 and 0.81), indicating good drug-likeness.

**DILI:** Ligand A (36.565) has a much lower DILI risk than Ligand B (56.805). This is a significant advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (81.039) has a better BBB percentile than Ligand B (48.74).

**Caco-2 Permeability:** Ligand A (-4.699) has a much better Caco-2 permeability than Ligand B (-5.189).

**Aqueous Solubility:** Ligand A (-2.724) has a better aqueous solubility than Ligand B (-2.12).

**hERG:** Both ligands have very low hERG inhibition liability (0.587 and 0.408), which is excellent.

**Microsomal Clearance:** Ligand A (34.585) has a higher microsomal clearance than Ligand B (0.2). This indicates that Ligand B is metabolically more stable.

**In vitro Half-Life:** Ligand A (35.883) has a longer in vitro half-life than Ligand B (2.509).

**P-gp Efflux:** Ligand A (0.11) has a lower P-gp efflux liability than Ligand B (0.029).

**Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.3). However, the difference is only 0.4 kcal/mol, which is not substantial enough to outweigh other factors.

**Overall:**

Ligand A has advantages in TPSA, DILI risk, Caco-2 permeability, solubility, half-life, and P-gp efflux. Ligand B has a slight advantage in metabolic stability and binding affinity. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), the better metabolic stability of Ligand B is a positive, but the significantly lower DILI risk, better permeability, and solubility of Ligand A make it a more promising candidate. The 0.4 kcal/mol difference in binding affinity is not enough to overcome these advantages.

Output:
1
2025-04-17 12:18:45,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.435 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.78) is slightly higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable due to the lower value.

**3. logP:** Both ligands have good logP values (1.981 and 2.893), 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. Ligand B is slightly better.

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

**6. QED:** Both ligands have acceptable QED values (0.754 and 0.65), above the 0.5 threshold.

**7. DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (31.059). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (66.925) and Ligand B (78.868) are both acceptable, but not particularly high. BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-5.668) has a very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.628) is better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.777 and -3.157). This could pose formulation challenges, but is not a dealbreaker if other properties are favorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.489 and 0.494).

**12. Microsomal Clearance:** Ligand A (47.9 mL/min/kg) has a lower clearance than Ligand B (81.987 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (33.097 hours) has a significantly longer half-life than Ligand B (17.545 hours). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.512 and 0.288).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has advantages in TPSA, H-bond donors/acceptors, and DILI risk. However, Ligand A shines in metabolic stability (lower Cl_mic) and has a much longer in vitro half-life. The poor Caco-2 permeability of Ligand A is a concern, but the improved metabolic stability and longer half-life are more critical for an enzyme inhibitor. The significantly lower DILI risk of Ligand B is also a strong point. Considering the balance, and the importance of metabolic stability for kinases, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:18:45,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (364.339 and 364.511 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 58.64, which is well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.826) is optimal, while Ligand B (2.942) is also within the acceptable 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 3 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (41.179) has a slightly higher DILI risk than Ligand B (37.263), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (87.476) has a significantly higher BBB penetration percentile than Ligand B (68.67). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**9. Caco-2 Permeability:** Ligand A (-4.649) has a worse Caco-2 permeability than Ligand B (-4.961). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.749) has slightly worse aqueous solubility than Ligand B (-2.434). Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.42 and 0.331, respectively).

**12. Microsomal Clearance:** Ligand A (35.102 mL/min/kg) has a lower microsomal clearance than Ligand B (40.689 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.01 hours) has a negative half-life, which is unusual and likely an error in the data. Ligand B (28.368 hours) has a much more reasonable and desirable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.12 and 0.103, respectively).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 0.3 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A's superior binding affinity and lower clearance, the negative in vitro half-life is a major red flag. A negative half-life is not physically possible and indicates a data error or a significant instability issue. Ligand B, while having slightly weaker affinity, possesses a reasonable half-life, acceptable ADME properties, and a low hERG risk. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 12:18:45,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.439 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (87.32) is still acceptable but less optimal.

**logP:** Ligand A (3.151) is within the optimal 1-3 range. Ligand B (0.867) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 4. Both are acceptable, being under the 10 limit.

**QED:** Both ligands have good QED scores (0.638 and 0.776), indicating drug-likeness.

**DILI:** Ligand A (20.279) has a significantly lower DILI risk than Ligand B (44.281). This is a major advantage.

**BBB:** Ligand A (64.676) has a moderate BBB penetration, while Ligand B (58.821) is lower. Not a major factor for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.674 and -4.868), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation (negative values may indicate an issue with the prediction method).

**Aqueous Solubility:** Both have negative solubility values (-4.168 and -2.776), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Both ligands have low hERG risk (0.399 and 0.262).

**Microsomal Clearance:** Ligand A (48.85) has higher microsomal clearance than Ligand B (-7.383). This means Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand B (-0.628) has a slightly better in vitro half-life than Ligand A (-5.095).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.028 and 0.052).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This 0.8 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and improved metabolic stability (lower Cl_mic, better t1/2). However, Ligand A has a significantly lower DILI risk and a better TPSA. Both have concerningly poor predicted solubility and permeability. Considering the enzyme-specific priorities, the slightly better affinity of Ligand B is a key advantage. The lower DILI risk of Ligand A is also important, but the affinity difference is more substantial. The solubility/permeability issues would need to be addressed through formulation or further chemical modifications for either compound.

Output:
1
2025-04-17 12:18:45,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.547 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 49.41, which is well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values around 3.6, which 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 2 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.796) has a significantly better QED score than Ligand B (0.565), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (22.179 and 23.226 percentile), which is good.

**8. BBB:** Ligand A has a higher BBB penetration (90.306%) than Ligand B (64.676%). While SRC isn't a CNS target, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Ligand A (-4.547) has worse Caco-2 permeability than Ligand B (-5.085). Lower (more negative) values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-4.26) has slightly better aqueous solubility than Ligand B (-4.006).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.738 and 0.549), which is excellent.

**12. Microsomal Clearance:** Ligand A (91.927 mL/min/kg) has higher microsomal clearance than Ligand B (66.464 mL/min/kg), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.453 hours) has a longer in vitro half-life than Ligand A (1.719 hours), which is preferable.

**14. P-gp Efflux:** Ligand A (0.255) has lower P-gp efflux than Ligand B (0.639), which is favorable for bioavailability.

**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 >1.5 kcal/mol difference, which is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.4 vs -7.0 kcal/mol) outweighs the minor ADME drawbacks. The longer half-life of Ligand B is also a significant advantage for kinase inhibitors, which often benefit from sustained target engagement. The slightly lower Caco-2 permeability is a minor concern, but the strong binding affinity suggests it can be overcome with formulation strategies.

Output:
1
2025-04-17 12:18:45,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.379 Da and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.91) is better than Ligand B (72.88), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (1.516) is optimal (1-3), while Ligand A (0.468) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5), both are within the acceptable limit of 10.

**QED:** Ligand B (0.851) has a significantly better QED score than Ligand A (0.226), indicating a more drug-like profile.

**DILI:** Ligand B (25.281) has a much lower DILI risk than Ligand A (46.413), which is a significant advantage.

**BBB:** Ligand A (70.105) has a better BBB penetration score than Ligand B (55.021), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.477) has better Caco-2 permeability than Ligand B (-5.166), though both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.463) has better solubility than Ligand B (-2.138), which is a positive.

**hERG:** Ligand A (0.133) has a lower hERG risk than Ligand B (0.522), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand B (1.477) has significantly lower microsomal clearance than Ligand A (18.79), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (10.65) has a better in vitro half-life than Ligand A (-20.487).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035).

**Binding Affinity:** Both ligands have similar binding affinities (-7.7 and -7.8 kcal/mol), which are both excellent.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and solubility, and a lower hERG risk, Ligand B excels in several critical areas for a kinase inhibitor: QED, DILI, metabolic stability (Cl_mic and t1/2), and logP. The similar binding affinities mean the ADME properties become the deciding factor. The lower DILI and improved metabolic stability of Ligand B are particularly important for a drug candidate targeting oncology, where chronic administration is often required.

Output:
1
2025-04-17 12:18:45,333 - INFO - Batch 119 complete. Total preferences: 1904
2025-04-17 12:18:45,333 - INFO - Processing batch 120/512...
2025-04-17 12:19:27,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.18) is higher than Ligand B (67.43). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Ligand A (0.121) is quite low, potentially hindering permeability. Ligand B (2.559) 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 3. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have acceptable QED scores (0.661 and 0.596, both >0.5).

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (37.611), which is a substantial positive for Ligand A.

**BBB:** Both have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.953) has poor Caco-2 permeability, while Ligand B (-5.035) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.928) has slightly better solubility than Ligand B (-3.199).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.242 and 0.294).

**Microsomal Clearance:** Ligand A (-4.284) has significantly lower (better) microsomal clearance than Ligand B (42.99). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-19.599) has a much longer in vitro half-life than Ligand B (-4.037), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.327).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B's superior binding affinity (-8.6 vs -6.3 kcal/mol) is the most important factor. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, the potency advantage of Ligand B is substantial. The slightly lower logP of Ligand A is a concern, but the strong binding affinity of Ligand B likely compensates for this. The solubility difference is minor.

Output:
1
2025-04-17 12:19:27,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.332 and 349.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.35) is well below the 140 threshold, while Ligand B (87.74) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.909) is optimal, while Ligand B (0.047) is significantly low, potentially hindering permeability.

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

**H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.904 and 0.687), indicating drug-like properties.

**DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (33.501), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.364) is slightly better than Ligand B (34.975).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the assay or prediction. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-1.933) is slightly better than Ligand A (-3.853).

**hERG Inhibition:** Ligand A (0.345) has a much lower hERG risk than Ligand B (0.064), which is a significant advantage.

**Microsomal Clearance:** Ligand B (8.198) has a significantly lower Cl_mic, indicating better metabolic stability, which is crucial for an enzyme target. Ligand A (36.488) is considerably higher.

**In vitro Half-Life:** Ligand B (-10.065) has a longer half-life than Ligand A (-24.771), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.063).

**Binding Affinity:** Both ligands have similar strong binding affinities (-7.8 and -8.0 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer half-life) and a lower DILI risk, Ligand A has a much better logP and significantly lower hERG risk. The very low logP of Ligand B is a major concern, as it will likely severely limit its permeability and bioavailability. The slightly higher DILI risk of Ligand A is less concerning than the permeability issues of Ligand B. Given the importance of metabolic stability for kinase inhibitors, and the similar binding affinities, Ligand B appears slightly more promising. However, the solubility and permeability issues with both compounds are concerning and would require further investigation.

Output:
1
2025-04-17 12:19:27,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.379 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.24) is higher than Ligand B (79.62). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (-0.096) is quite low, potentially hindering permeation. Ligand B (2.591) 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 HBAs, while Ligand B has 4. Both are within the acceptable limit of 10, but Ligand B is preferable.

**QED:** Both ligands have similar QED values (0.782 and 0.732), indicating good drug-likeness.

**DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (35.595). This is a considerable drawback for Ligand A.

**BBB:** Ligand A (46.336) has lower BBB penetration than Ligand B (60.566). While BBB isn't a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.196) has poor Caco-2 permeability, while Ligand B (-4.648) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.838) has poor aqueous solubility, while Ligand B (-2.773) is also poor. This is a concern for both, but Ligand B is slightly worse.

**hERG Inhibition:** Ligand A (0.157) has a slightly lower hERG risk than Ligand B (0.229). This is a minor advantage for Ligand A.

**Microsomal Clearance:** Ligand A (54.96) has higher microsomal clearance than Ligand B (36.555), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-40.1) has a very short in vitro half-life, while Ligand B (1.084) is better, but still not ideal. This is a major drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux than Ligand B (0.095), which is a slight advantage for Ligand A.

**Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (-8.7). This is a crucial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While its solubility and Caco-2 permeability are not ideal, its superior binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and optimal logP outweigh the slight disadvantages. Ligand A suffers from poor solubility, poor permeability, high DILI risk, and poor metabolic stability, despite having a slightly better hERG profile and P-gp efflux. The binding affinity difference is also substantial.

Output:
1
2025-04-17 12:19:27,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 & 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.6) is better than Ligand B (81.08), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (2.955) is optimal, while Ligand B (0.86) 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 5 HBA, and Ligand B has 4, both are below the acceptable limit of <=10.

**QED:** Ligand A (0.871) has a better QED score than Ligand B (0.743), indicating a more drug-like profile.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (23.226). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (85.459) has a better BBB score than Ligand B (41.373).

**Caco-2 Permeability:** Ligand A (-4.439) is better than Ligand B (-4.655), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.204) is better than Ligand B (-1.411), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.81) has a slightly higher hERG risk than Ligand B (0.338), but both are reasonably low.

**Microsomal Clearance:** Ligand A (53.191) has a higher clearance than Ligand B (3.864), meaning Ligand B is more metabolically stable. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (87.277) has a longer half-life than Ligand B (7.143), which is desirable.

**P-gp Efflux:** Ligand A (0.461) has lower P-gp efflux than Ligand B (0.093), which is preferable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a better binding affinity, solubility, Caco-2 permeability, half-life, and P-gp efflux. However, it has a significantly higher DILI risk and higher microsomal clearance. Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic), but its logP is lower, and its binding affinity is slightly weaker.

Given that we are targeting a kinase (SRC), metabolic stability and minimizing toxicity (DILI) are critical. The substantial difference in DILI risk and the good metabolic stability of Ligand B outweigh the slightly weaker binding affinity and lower logP. While the affinity difference is notable, it's not so large that it completely overrides the safety and metabolic advantages of Ligand B.

Output:
1
2025-04-17 12:19:27,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.471 and 341.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (108.48). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (2.841) is optimal (1-3), while Ligand B (1.189) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.713 and 0.653), indicating good drug-likeness.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (56.844). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (86.274) has a higher BBB percentile than Ligand B (67.041).

**Caco-2 Permeability:** Ligand A (-4.041) has a worse Caco-2 permeability than Ligand B (-5.756), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.491 and -2.361). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Ligand A (0.571) shows lower hERG inhibition liability than Ligand B (0.212), which is a positive.

**Microsomal Clearance:** Ligand A (98.882) has a much higher microsomal clearance than Ligand B (34.93). This indicates lower metabolic stability for A, a major drawback.

**In vitro Half-Life:** Ligand A (1.191) has a very short half-life compared to Ligand B (-4.957). This is a significant disadvantage for A.

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.083), which is slightly better.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.4 and -9.2 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has advantages in TPSA, logP, DILI, hERG, and P-gp efflux, its significantly higher microsomal clearance and very short half-life are major concerns. Ligand B, despite its higher TPSA and DILI risk, exhibits much better metabolic stability and a longer half-life, which are crucial for an enzyme inhibitor. The similar binding affinities make the ADME properties the deciding factor. Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:19:27,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (443.706 Da) is towards the upper end, while Ligand B (371.482 Da) is more favorably positioned.

**TPSA:** Both ligands have TPSA values (81.28 and 88.91) that are acceptable for oral absorption (<140), but not optimal for CNS penetration (<90). This is less critical for a non-CNS target like SRC.

**logP:** Ligand A (4.269) is higher than optimal (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.159) is slightly below the optimal range but still reasonable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, fitting the guidelines. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.596 and 0.603), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (94.959 percentile), a significant concern. Ligand B has a much lower DILI risk (61.807 percentile), which is still above the preferred <40, but considerably better than Ligand A.

**BBB:** BBB is not a high priority for SRC, but Ligand B (73.788) has a better score than Ligand A (25.165).

**Caco-2 Permeability:** Ligand A (-4.805) shows poor permeability, while Ligand B (-5.501) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.199) has very poor solubility, a major drawback. Ligand B (-2.002) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.53) has a slightly elevated hERG risk, while Ligand B (0.192) has a very low risk, a significant advantage.

**Microsomal Clearance:** Ligand A (20.055 mL/min/kg) has a higher clearance, suggesting lower metabolic stability. Ligand B (15.574 mL/min/kg) has better metabolic stability.

**In vitro Half-Life:** Ligand A (38.981 hours) has a reasonable half-life. Ligand B (-2.677 hours) has a very short half-life, a major concern.

**P-gp Efflux:** Ligand A (0.545) has moderate P-gp efflux, while Ligand B (0.074) has very low efflux, which is favorable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This 1.5 kcal/mol difference is substantial and could outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, its high DILI risk, poor solubility, and higher clearance are significant liabilities. Ligand B has a weaker binding affinity but exhibits a much more favorable ADME profile, particularly regarding DILI and hERG risk. The extremely short half-life of Ligand B is a major concern, but could potentially be addressed through structural modifications. Given the importance of minimizing toxicity and improving developability, and the substantial difference in binding affinity, I would still lean towards Ligand A, but with a strong caveat that further optimization to address the DILI and solubility issues is critical.

Output:
1
2025-04-17 12:19:27,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.403 and 354.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.25) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned for potential CNS penetration if desired.

**logP:** Ligand A (0.46) is quite low, potentially hindering permeability. Ligand B (2.965) 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 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.782 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A (71.345) has a higher DILI risk than Ligand B (8.647). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (52.268 and 70.686), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.604 and -4.6), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.102 and -3.13), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.197) has a slightly lower hERG risk than Ligand B (0.607), which is favorable.

**Microsomal Clearance:** Ligand A (19.18) has significantly lower microsomal clearance than Ligand B (67.31), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-14.391) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (-5.162) also has a negative half-life, indicating data issues for both.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.088 and 0.055).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), though both are good. The 0.5 kcal/mol difference is not huge, but is a factor.

**Overall Assessment:**

Ligand B is the better candidate despite the negative Caco-2 and solubility values. Its logP is within the optimal range, and its DILI risk is much lower than Ligand A's. While Ligand A has better metabolic stability, the high DILI risk is a significant concern. The negative half-life and solubility values for both compounds are concerning and require further investigation, but the other properties favor Ligand B.

Output:
1
2025-04-17 12:19:27,461 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (74.08) is excellent, well below the 140 threshold for oral absorption. Ligand B (98.74) is still reasonable but less favorable.

**logP:** Ligand A (2.89) is optimal. Ligand B (0.443) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 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 acceptable QED values (A: 0.782, B: 0.626), indicating good drug-like properties.

**DILI:** Ligand A (63.086) has a moderate DILI risk, while Ligand B (12.796) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (77.627) has better BBB penetration than Ligand B (24.738).

**Caco-2 Permeability:** Ligand A (-4.326) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.618) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.173) has poor solubility. Ligand B (-1.04) is also poor, but better than A.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.201, B: 0.233).

**Microsomal Clearance:** Ligand A (78.69) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-1.906) has *excellent* metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-24.45) has a very short half-life. Ligand B (-40.183) has an even shorter half-life, but the negative values indicate these are percentile scores, and lower is worse.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.291, B: 0.008), which is favorable.

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability, poor solubility, and high microsomal clearance. Ligand B has superior ADME properties (low DILI, excellent metabolic stability, better solubility), but its binding affinity is weaker.

Given the priorities for enzyme inhibitors, the strong binding affinity of Ligand A is a critical advantage. While the ADME properties are suboptimal, these can potentially be addressed through further medicinal chemistry optimization. The excellent metabolic stability of Ligand B is attractive, but the weaker binding affinity is a significant hurdle.

Output:
1
2025-04-17 12:19:27,461 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.388 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.77) is better than Ligand B (23.55). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (3.437) is within the optimal 1-3 range, while Ligand B (4.423) is slightly higher. While still acceptable, higher logP can sometimes lead to off-target effects.

**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 (0.899 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (29.469) has a lower DILI risk than Ligand B (20.318), which is preferable.

**BBB:** Both ligands have high BBB penetration (79.333 and 92.904), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.279) and Ligand B (-4.606) 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 (-3.679 and -3.739). This is a major drawback, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.835 and 0.915), which is good.

**Microsomal Clearance:** Ligand A (28.506) has a lower microsomal clearance than Ligand B (69.06), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-17.355) has a negative half-life, which is not possible. This is a red flag. Ligand B (17.042) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.515 and 0.808).

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate despite its slightly higher logP and DILI risk. The significantly stronger binding affinity (-7.8 vs -9.0 kcal/mol) is a major advantage for an enzyme target. While both have poor solubility and Caco-2 permeability, the improved metabolic stability (lower Cl_mic) and reasonable half-life of Ligand B are preferable. The negative half-life reported for Ligand A is a critical flaw.

Output:
1
2025-04-17 12:19:27,461 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.423 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.82) is borderline, but acceptable for oral absorption. Ligand B (69.3) is excellent, well below the 140 threshold.

**logP:** Ligand A (-0.45) is a bit low, potentially hindering permeation. Ligand B (2.216) is optimal.

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

**H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.49 and 0.83), indicating reasonable drug-likeness.

**DILI:** Ligand A (15.2) has a very favorable DILI score. Ligand B (42.846) is higher, indicating a moderate risk, but still acceptable.

**BBB:** Ligand A (29.12) has low BBB penetration, which is not a concern for a non-CNS target like SRC. Ligand B (84.413) has high BBB penetration, which is irrelevant here.

**Caco-2 Permeability:** Ligand A (-5.649) has poor Caco-2 permeability, a significant drawback. Ligand B (-4.456) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.192) has poor aqueous solubility, a major concern. Ligand B (-2.363) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.038) has very low hERG risk. Ligand B (0.562) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-11.859) indicates very low clearance and excellent metabolic stability. Ligand B (20.985) has higher clearance, suggesting poorer metabolic stability.

**In vitro Half-Life:** Ligand A (3.962) has a short half-life. Ligand B (-22.079) has a very long half-life, a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.003 and 0.12).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has a very favorable DILI and hERG profile and excellent metabolic stability. However, its poor Caco-2 permeability and aqueous solubility are major liabilities. Ligand B has a slightly higher DILI risk and poorer metabolic stability, but its superior logP, TPSA, and significantly longer half-life make it a more promising candidate. The similar binding affinity means the ADME properties become the deciding factor. While both have solubility issues, the better permeability and stability of Ligand B outweigh the slightly higher DILI risk.

Output:
1
2025-04-17 12:19:27,461 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.375 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (350.463 Da) is also good.

**TPSA:** Ligand A (60.7) is significantly better than Ligand B (96.11). A TPSA under 140 is desirable for oral absorption, and both meet this, but Ligand A is much closer to the optimal range for good absorption.

**logP:** Ligand A (3.588) is optimal, while Ligand B (1.578) is on the lower side. Lower logP can sometimes hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=4). Both are within acceptable limits, but fewer H-bond donors generally improve permeability.

**QED:** Ligand A (0.79) is better than Ligand B (0.663), indicating a more drug-like profile.

**DILI:** Ligand A (68.941) has a higher DILI risk than Ligand B (38.581). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (72.625) is slightly better than Ligand B (65.374). This isn't a primary concern for a kinase inhibitor, but it's a minor positive for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the experimental setup or prediction method. We'll proceed cautiously with this data point.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, we'll proceed cautiously.

**hERG Inhibition:** Ligand A (0.876) has a slightly higher hERG risk than Ligand B (0.288). Lower hERG risk is preferred.

**Microsomal Clearance:** Ligand A (65.034) has a higher microsomal clearance than Ligand B (43.973), meaning it's less metabolically stable. Lower clearance is preferred.

**In vitro Half-Life:** Ligand A (94.48) has a much longer half-life than Ligand B (-1.304). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.873) has a slightly higher P-gp efflux liability than Ligand B (0.053). Lower efflux is preferred.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A has advantages in QED, BBB, and *especially* in vitro half-life. However, it suffers from higher DILI risk, higher hERG risk, higher microsomal clearance, and slightly higher P-gp efflux. Ligand B has a better binding affinity, lower DILI and hERG risk, lower clearance, and lower P-gp efflux.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and safety (DILI, hERG) are crucial. Ligand B's superior metabolic stability and safety profile, combined with its slightly better binding affinity, outweigh Ligand A's longer half-life. The negative Caco-2 and solubility values are concerning for both, but the other properties favor Ligand B.

Output:
1
2025-04-17 12:19:27,462 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (365.539 Da) is also good.

**TPSA:** Ligand A (42.01) is well below the 140 threshold for oral absorption. Ligand B (55.4) is also acceptable, but higher.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.197) is slightly better, being closer to the middle of the range. Ligand B (3.668) is a bit higher, potentially increasing off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (1 HBD, 3 HBA) in terms of balancing solubility and permeability. Fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (A: 0.792, B: 0.802), indicating good drug-like properties.

**DILI:** Ligand A (9.771) has a significantly lower DILI risk than Ligand B (36.06). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (A: 85.072, B: 81), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 proceed with caution, assuming this indicates low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility for both compounds. Ligand A (-1.571) is slightly better than Ligand B (-4.463).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.87, B: 0.779), which is good.

**Microsomal Clearance:** Ligand A (56.031) has lower microsomal clearance than Ligand B (67.794), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-9.982) has a significantly longer in vitro half-life than Ligand B (-31.296). This is another major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.259, B: 0.516), which is favorable.

**Binding Affinity:** Ligand B (-9.5 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 advantages of Ligand A in other crucial ADME properties.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. While Ligand B has a slightly better binding affinity, the ADME advantages of Ligand A are more critical for overall drug development success.

Output:
0
2025-04-17 12:19:27,462 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (376.519 and 382.473 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (103.78) is slightly above the optimal <140, but acceptable. Ligand B (89.87) is well within the acceptable range.

**logP:** Both ligands (0.717 and 0.861) are within the optimal range of 1-3.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

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

**QED:** Ligand A (0.617) is better than Ligand B (0.522), indicating a more drug-like profile.

**DILI:** Both ligands have similar, relatively low DILI risk (17.449 and 17.72 percentile). Both are well below the concerning threshold of 60.

**BBB:** Both ligands have similar, low BBB penetration (54.091 and 55.603 percentile). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.28 and -5.025). This is unusual and suggests poor permeability. However, these values may be reported on different scales or represent transformed data, making direct comparison difficult.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.293 and -1.394). Again, this is unusual and requires careful consideration. Negative values might indicate very low solubility, which is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.255 and 0.161 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (-10.091) has significantly *lower* (better) microsomal clearance than Ligand B (22.303). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (1.379) has a very short half-life, while Ligand B (-13.321) has a very long half-life. The negative value for Ligand B is concerning and likely represents transformed data.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.019 and 0.034 percentile).

**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 difference (1.6 kcal/mol) and is a major advantage.

**Conclusion:**

Despite the questionable solubility and permeability data, the significantly stronger binding affinity of Ligand B (-8.9 kcal/mol vs -7.3 kcal/mol) and its much longer in vitro half-life outweigh the slightly better QED and metabolic stability of Ligand A. The difference in binding affinity is substantial enough to overcome the potential issues with solubility and permeability, *assuming* these can be addressed through further optimization.

Output:
1
2025-04-17 12:19:27,462 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.415 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.71 and 79.37) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Both ligands (2.16 and 2.461) are within the optimal 1-3 range, suggesting good permeability and avoiding solubility issues.

**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 (0.582 and 0.731), indicating a drug-like profile.

**DILI:** Ligand A (52.074) has a slightly higher DILI risk than Ligand B (33.773), but both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (68.592 and 64.676), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.748) shows better Caco-2 permeability than Ligand B (-5.043), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.335) has slightly better aqueous solubility than Ligand B (-2.306), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.368) has a significantly lower hERG inhibition liability than Ligand B (0.063), a crucial advantage for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (-39.89) has a much lower microsomal clearance than Ligand B (41.959), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.573) has a longer in vitro half-life than Ligand B (-22.802), suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.094).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.8 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, Ligand A demonstrates a superior ADMET profile. It has better solubility, significantly lower hERG risk, better metabolic stability (lower Cl_mic and longer half-life), and better Caco-2 permeability. The difference in binding affinity (0.9 kcal/mol) is outweighed by the substantial improvements in ADMET properties, particularly the lower hERG risk and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (like hERG inhibition) are critical.

Output:
0
2025-04-17 12:19:27,462 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (440.761 Da) is higher, but still acceptable. Ligand B (351.422 Da) is slightly preferred.

**TPSA:** Both ligands have TPSA values (79.37 and 75.44) below the 140 threshold for good oral absorption. This is good for both.

**logP:** Both ligands have logP values (3.822 and 2.139) within the optimal range of 1-3. Ligand B is slightly preferred as it is closer to the lower end of the range, potentially mitigating solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6 and 4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.782 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A has a very high DILI risk (98.604), which is a major concern. Ligand B has a low DILI risk (25.785), a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (89.531) than Ligand A (50.601), but this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.604 and -4.591), which is unusual and suggests poor permeability. This is a potential issue for both, but the negative values make direct comparison difficult.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.803 and -2.449), which is also unusual and suggests poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A has a slightly higher hERG inhibition risk (0.343) than Ligand B (0.4), but both are relatively low.

**Microsomal Clearance:** Ligand A has a very low microsomal clearance (0.72 mL/min/kg), indicating good metabolic stability. Ligand B has a much higher clearance (23.55 mL/min/kg), which is a significant drawback.

**In vitro Half-Life:** Ligand A has a long in vitro half-life (89.747 hours), which is excellent. Ligand B has a very short half-life (8.399 hours), a major disadvantage.

**P-gp Efflux:** Ligand A has a low P-gp efflux liability (0.57), while Ligand B has a very high P-gp efflux liability (0.097).

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-10.2 kcal/mol) than Ligand B (-8.5 kcal/mol). This is a substantial advantage that could potentially outweigh some of its 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, its major drawback is the extremely high DILI risk. Ligand B has a much better safety profile (lower DILI) and slightly better solubility, but suffers from poor metabolic stability, short half-life, and high P-gp efflux.

Given the enzyme-specific priorities, potency and metabolic stability are key. The substantial difference in binding affinity (-1.7 kcal/mol) is a significant advantage for Ligand A. While the high DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The poor ADME properties of Ligand B are more difficult to address without significantly altering the core structure and potentially losing potency.

Output:
1
2025-04-17 12:19:27,463 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (400.957 Da) is slightly higher than Ligand B (350.354 Da), but both are acceptable.

**TPSA:** Ligand A (86.88) is well below the 140 threshold for oral absorption and is also favorable. Ligand B (133.15) is approaching the upper limit, potentially impacting absorption, but is still within acceptable bounds.

**logP:** Ligand A (2.969) is optimal. Ligand B (0.981) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (4 HBD, 8 HBA) both fall within acceptable limits.

**QED:** Both ligands have similar and good QED values (A: 0.565, B: 0.581), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 75.145, B: 77.394), indicating moderate risk, which isn't ideal but not immediately disqualifying.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (50.485) and B (47.15) are both low.

**Caco-2 Permeability:** Both have negative values (-5.721 and -5.448), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative values (-3.989 and -3.1), indicating poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.659) has a slightly better hERG profile than Ligand B (0.372), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (51.74) has a higher clearance than Ligand B (31.381), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-15.588) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the compound. Ligand A (22.892) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.393, B: 0.031), which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (A: -7.0 kcal/mol, B: -7.7 kcal/mol), with Ligand B being slightly better. However, the difference is small.

**Conclusion:**

Despite the similar binding affinities, Ligand B has a significantly better metabolic stability (lower Cl_mic) and a more reasonable in vitro half-life. Ligand A has a negative solubility and higher clearance. The negative half-life for ligand B is a data quality issue, but the other parameters favor it. The poor solubility and permeability of both compounds are concerning, but the better metabolic profile of Ligand B makes it slightly more promising.

Output:
1
2025-04-17 12:19:27,463 - INFO - Batch 120 complete. Total preferences: 1920
2025-04-17 12:19:27,463 - INFO - Processing batch 121/512...
2025-04-17 12:20:08,307 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (363.38 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (95.5), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (though that's not a priority here).

**logP:** Ligand A (2.696) is optimal (1-3), while Ligand B (-0.293) is quite low, potentially hindering permeation.

**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 (4 and 5, respectively), well below the limit of 10.

**QED:** Both ligands have similar good QED values (0.744 and 0.74), indicating good drug-like properties.

**DILI:** Ligand A (58.511) has a slightly better DILI risk profile than Ligand B (64.754), both are acceptable but A is preferred.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (74.06) is better than Ligand B (53.276).

**Caco-2:** Both have negative values, indicating poor permeability. Ligand A (-4.775) is slightly better than Ligand B (-4.503).

**Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.047) is slightly better than Ligand B (-1.317).

**hERG:** Both ligands show low hERG inhibition liability (0.452 and 0.139, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (52.705) has lower microsomal clearance than Ligand B (57.778), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.508) has a significantly longer in vitro half-life than Ligand B (-39.491), a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.157 and 0.024, respectively).

**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 meaningful.

**Overall:** Ligand A is superior to Ligand B. It has a better logP, slightly better solubility, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both have acceptable DILI and hERG profiles, A is slightly better on DILI. The lower logP of Ligand B is a significant concern for permeability.

Output:
1
2025-04-17 12:20:08,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.379 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.39) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (66.92) is well within the optimal range.

**logP:** Ligand A (-0.444) is a bit low, potentially hindering permeation. Ligand B (1.634) 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 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.637 and 0.665), indicating good drug-likeness.

**DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (44.824), which is preferable.

**BBB:** Both have similar BBB penetration scores (58.278 and 53.703), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.516 and -4.625), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.946 and -2.586), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.042) has a very low hERG risk, which is excellent. Ligand B (0.368) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-3.288) has a negative clearance, suggesting very high metabolic stability, which is excellent. Ligand B (86.609) has a high clearance, indicating poor metabolic stability, a significant concern.

**In vitro Half-Life:** Ligand A (10.045 hours) has a reasonable half-life. Ligand B (-20.099 hours) has a negative half-life, which is not physically possible and likely indicates an issue with the prediction or the molecule itself.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.152).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), but both are good.

**Overall Assessment:**

Despite both compounds having issues with solubility and Caco-2 permeability, Ligand A is the more promising candidate. Its significantly better metabolic stability (negative Cl_mic) and excellent hERG profile outweigh the slightly lower logP and higher DILI risk. The negative half-life for Ligand B is a major red flag. The superior binding affinity of Ligand A further supports its selection. Addressing the solubility and permeability issues will be crucial for either compound, but Ligand A starts from a stronger position regarding key ADME-Tox properties relevant to kinase inhibitors.

Output:
0
2025-04-17 12:20:08,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.53 and 384.97 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (41.57), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.749 and 3.668), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.76 and 0.742), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (32.261 and 32.803 percentile), which is excellent.

**BBB:** Ligand B (71.229) shows better BBB penetration than Ligand A (67.468), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.533) has better Caco-2 permeability than Ligand B (-4.897), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.035) has better aqueous solubility than Ligand B (-5.094), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.5) has a significantly lower hERG inhibition risk than Ligand B (0.871). This is a critical advantage.

**Microsomal Clearance:** Ligand B (84.344) has a much higher microsomal clearance than Ligand A (40.395), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (52.133) has a longer in vitro half-life than Ligand A (-7.633), which is a positive attribute. However, the negative value for Ligand A is concerning and suggests a very short half-life.

**P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux than Ligand B (0.494), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-10.1) has a substantially stronger binding affinity than Ligand B (-6.5). This is a major advantage, as a >1.5 kcal/mol difference can outweigh other ADME concerns.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better BBB penetration and in vitro half-life, Ligand A's significantly stronger binding affinity (-10.1 vs -6.5 kcal/mol), lower hERG risk, better solubility, and lower microsomal clearance outweigh these advantages. The negative in vitro half-life for Ligand A is a concern, but the strong binding affinity suggests it might still be a viable starting point for optimization.

Output:
0
2025-04-17 12:20:08,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.829 Da and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.42) is slightly higher than Ligand B (54.34). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (3.86 and 3.394, respectively) 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 (0.763 and 0.804), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (84.296) compared to Ligand B (26.444). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B is slightly better (80.419 vs 63.125). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.598) is slightly worse than Ligand B (-4.612).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-5.329) is slightly worse than Ligand B (-3.277).

**hERG:** Both ligands have low hERG inhibition liability (0.633 and 0.625), which is good.

**Microsomal Clearance:** Ligand A (89.212) has a higher microsomal clearance than Ligand B (45.372), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (65.196) has a longer half-life than Ligand B (5.78), which is favorable. However, this is somewhat offset by the higher clearance.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.234 and 0.393), which is good.

**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.

**Conclusion:**

Despite the comparable binding affinities and acceptable physicochemical properties, Ligand B is the more promising candidate. The significantly lower DILI risk (26.444 vs 84.296) is a critical advantage. While both have poor Caco-2 and solubility, the lower clearance of Ligand B suggests better metabolic stability, which is crucial for an enzyme inhibitor. The slightly better BBB and solubility also contribute to its favorability.

Output:
1
2025-04-17 12:20:08,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (353.507 and 352.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.88) is better than Ligand B (81.01). Both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Both ligands (1.399 and 1.608) 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 (0.708 and 0.769), indicating good drug-like properties.

**7. DILI:** Ligand A (13.571) has a significantly lower DILI risk than Ligand B (23.187). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (40.675) has a lower BBB penetration than Ligand B (60.101). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.771 and -4.69). This is unusual and suggests poor permeability. However, the values are very close, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.02 and -1.404), indicating poor solubility. This is a concern, but again, similar for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.279 and 0.431).

**12. Microsomal Clearance:** Ligand A (38.208) has higher microsomal clearance than Ligand B (18.602). This means Ligand B is more metabolically stable, which is a priority for kinases.

**13. In vitro Half-Life:** Ligand B (25.733) has a significantly longer in vitro half-life than Ligand A (2.942). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.025).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.5 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk), Ligand B emerges as the more promising candidate. While Ligand A has a lower DILI risk, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better BBB penetration outweigh this advantage. Both have poor solubility and permeability, which would need to be addressed in further optimization, but these are issues common to many kinase inhibitors. The affinity is comparable.

Output:
1
2025-04-17 12:20:08,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 Da and 349.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is significantly better than Ligand B (93.45). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.276 and 1.708), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Lower HBD is generally favored. Both are within acceptable limits.

**QED:** Both have similar QED scores (0.419 and 0.467), indicating moderate drug-likeness.

**DILI:** Ligand A (31.679) has a much lower DILI risk than Ligand B (54.052). This is a significant advantage for A.

**BBB:** Both have good BBB penetration (77.2 and 81.466), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.803 and -4.957), 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 (-2.654 and -3.903), indicating poor solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.209) has a much lower hERG inhibition risk than Ligand B (0.584). This is a critical advantage for A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (80.717) has a higher microsomal clearance than Ligand B (47.586), indicating lower metabolic stability. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (6.677) has a significantly longer in vitro half-life than Ligand A (-6.007). This is a major advantage for B, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.207).

**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 less than the 1.5 kcal/mol threshold, it's still a positive for A.

**Overall Assessment:**

Ligand A is favored due to its significantly lower DILI and hERG risk, and slightly better binding affinity. While it has higher microsomal clearance and negative solubility, the safety profiles are paramount. Ligand B has a better half-life, but the higher DILI and hERG risks are concerning. Given the enzyme-kinase target class, prioritizing metabolic stability and solubility is important, but safety (DILI and hERG) is crucial.

Output:
0
2025-04-17 12:20:08,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (420.298 Da) is slightly higher than Ligand B (348.447 Da), but both are acceptable.

**TPSA:** Ligand A (56.67) is significantly better than Ligand B (75.51). Lower TPSA generally improves permeability, which is beneficial.

**logP:** Both ligands have good logP values (A: 2.947, B: 1.198) falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=0, HBA=5) both have reasonable H-bond characteristics, within the acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.769, B: 0.822), indicating good drug-like properties.

**DILI:** Ligand A (9.151) has a much lower DILI risk than Ligand B (40.054). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration (A: 82.125, B: 78.713), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.829 and -4.433), 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 (-1.513 and -1.432), which is also unusual. This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.922, B: 0.253), which is excellent.

**Microsomal Clearance:** Ligand A (-17.58) has *much* lower microsomal clearance than Ligand B (36.797), indicating significantly better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (12.126 hours) has a longer half-life than Ligand B (-4.404 hours). This is beneficial for dosing frequency.

**P-gp Efflux:** Both ligands show similar P-gp efflux liability (A: 0.461, B: 0.089).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). However, the difference is small (0.4 kcal/mol) and may not outweigh the other advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a lower TPSA. These factors are particularly important for an enzyme inhibitor like an SRC kinase inhibitor. The solubility and permeability issues are present in both, but the superior ADME profile of Ligand A makes it the preferred choice for further optimization.

Output:
1
2025-04-17 12:20:08,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.378 and 354.401 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.1) is slightly higher than Ligand B (76.02). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets (not a priority here).

**logP:** Both ligands have good logP values (1.884 and 2.33), 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, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Ligand B (0.738) has a significantly higher QED score than Ligand A (0.381), indicating better overall drug-likeness.

**DILI:** Ligand A (32.997) has a lower DILI risk than Ligand B (52.423), which is preferable.

**BBB:** Ligand B (73.943) has a higher BBB penetration percentile than Ligand A (60.527), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.084 and -4.961), which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.728 and -2.933), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.546) has a slightly higher hERG inhibition liability than Ligand B (0.183), making Ligand B safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (15.806) has a much lower microsomal clearance than Ligand A (48.129), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-12.755) has a longer in vitro half-life than Ligand A (-20.015), which is also favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.102 and 0.063).

**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, potentially outweighing some of the ADME concerns.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand B is the more promising candidate. Its superior binding affinity (-8.1 vs -7.0 kcal/mol), better QED (0.738 vs 0.381), lower DILI risk (52.423 vs 32.997), significantly lower microsomal clearance (15.806 vs 48.129), and longer half-life outweigh the slightly higher DILI risk and lower BBB. The strong binding affinity is particularly important for an enzyme target. Addressing the solubility and permeability issues would be critical in further development, but Ligand B provides a better starting point.

Output:
1
2025-04-17 12:20:08,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.451 and 356.897 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.7) is better than Ligand B (32.34) as it is closer to the 140 A^2 threshold for good oral absorption. Ligand B is very low, which could indicate poor solubility.

**logP:** Ligand A (1.642) is optimal (1-3), while Ligand B (4.564) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has only 1 HBA, which is very low and could affect solubility.

**QED:** Both ligands have similar QED scores (0.81 and 0.808), indicating good drug-likeness.

**DILI:** Ligand A (23.187) has a significantly lower DILI risk than Ligand B (35.556), which is a major advantage.

**BBB:** Both have high BBB penetration (85.459 and 86.545), but this is less critical for a kinase inhibitor unless CNS involvement is specifically desired.

**Caco-2 Permeability:** Both have similar, very negative Caco-2 values (-4.477), which is concerning and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-1.417) is better than Ligand B (-5.243), indicating better solubility.

**hERG:** Ligand A (0.525) has a lower hERG risk than Ligand B (0.839), which is favorable.

**Microsomal Clearance:** Ligand A (12.116 mL/min/kg) has a lower clearance than Ligand B (82.727 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (54.282 hours) has a much longer half-life than Ligand A (5.412 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux than Ligand B (0.387), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.0 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. A difference of >1.5 kcal/mol is considered significant.

**Conclusion:**

Despite Ligand B's higher logP and clearance, its significantly superior binding affinity (-9.0 vs -6.2 kcal/mol) and longer half-life are compelling. The lower DILI and P-gp efflux of Ligand A are attractive, but the substantial potency advantage of Ligand B is likely to be more important for an enzyme inhibitor. The solubility and permeability issues of both are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:20:08,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.76 and 90.98) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (which would require <90 A^2). This is acceptable for an oncology target where CNS penetration isn't necessarily required.

**logP:** Both ligands (1.265 and 1.891) are 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 QED values (0.783 and 0.717) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (41.915) has a lower DILI risk than Ligand B (58.55), which is a significant advantage. Lower DILI is crucial for drug development.

**BBB:** Ligand B (65.878) has a higher BBB penetration percentile than Ligand A (38.232), but this is less important for an oncology target.

**Caco-2 Permeability:** Ligand B (-5.078) has a slightly better Caco-2 permeability than Ligand A (-4.708), indicating potentially better intestinal absorption.

**Aqueous Solubility:** Ligand B (-3.582) has better aqueous solubility than Ligand A (-2.462). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.165) has a lower hERG inhibition liability than Ligand B (0.417), which is a critical safety advantage.

**Microsomal Clearance:** Ligand B (32.6) has a lower microsomal clearance than Ligand A (38.922), indicating better metabolic stability. This is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-3.326) has a longer in vitro half-life than Ligand A (-23.577), which is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand B (0.067) has lower P-gp efflux liability than Ligand A (0.026), potentially improving bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This >1.5 kcal/mol difference in affinity is a major driver in the decision.

**Conclusion:**

While Ligand A has advantages in DILI and hERG, Ligand B's significantly stronger binding affinity (-8.8 vs -6.9 kcal/mol), better metabolic stability (lower Cl_mic), longer half-life, and improved solubility outweigh the slightly higher DILI and hERG risk. The potency advantage is substantial and critical for an enzyme inhibitor.

Output:
1
2025-04-17 12:20:08,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (398.981 Da) is also acceptable.

**TPSA:** Ligand A (93.21) is better than Ligand B (49.41). Both are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (1.377) is within the optimal range (1-3). Ligand B (3.216) is at the higher end of the optimal range, potentially increasing off-target effects or solubility issues, 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 acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.778 and 0.775), indicating good drug-likeness.

**DILI:** Ligand A (54.75) has a slightly higher DILI risk than Ligand B (40.713), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 74.835, Ligand B: 76.309). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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 very poor aqueous solubility (Ligand A: -2.003, Ligand B: -4.5). This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.168) has a much lower hERG inhibition liability than Ligand B (0.515), which is a significant advantage.

**Microsomal Clearance:** Ligand B (52.908) has higher microsomal clearance than Ligand A (29.364), indicating lower metabolic stability. This is a negative for Ligand B.

**In vitro Half-Life:** Ligand A (6.004) has a better in vitro half-life than Ligand B (-12.533). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.014) has significantly lower P-gp efflux liability than Ligand B (0.518), which is favorable for oral bioavailability and potentially CNS exposure.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This 1.1 kcal/mol difference is substantial and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from significantly worse metabolic stability (higher Cl_mic, lower t1/2), higher P-gp efflux, and higher hERG risk. Ligand A has better ADME properties across the board (lower Cl_mic, better t1/2, lower P-gp efflux, lower hERG risk) despite slightly weaker binding affinity. The poor solubility and Caco-2 values are concerning for both, but can potentially be addressed with formulation strategies. Given the importance of metabolic stability and safety (hERG) for kinase inhibitors, and the substantial difference in these parameters, Ligand A is the more promising candidate.

Output:
0
2025-04-17 12:20:08,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.483 and 354.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (33.2). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.888) is optimal (1-3), while Ligand B (4.774) is slightly higher, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (2) and Ligand B (3) are both acceptable (<=10).

**QED:** Both ligands have similar QED values (0.781 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (15.859) has a significantly lower DILI risk than Ligand B (17.371), which is preferable.

**BBB:** Both ligands have high BBB penetration (79.217 and 83.249), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar, negative Caco-2 values (-4.944 and -4.933). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have similar, negative solubility values (-3.97 and -4.065). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.454) has a lower hERG inhibition risk than Ligand B (0.67), which is a significant advantage.

**Microsomal Clearance:** Ligand A (40.816) has a lower microsomal clearance than Ligand B (86.733), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-3.136) has a longer in vitro half-life than Ligand B (-6.296), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.192) has lower P-gp efflux liability than Ligand B (0.567), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.4 and -9.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have excellent binding affinity, Ligand A demonstrates a better safety profile (lower DILI, lower hERG), improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slight disadvantage in TPSA is outweighed by these factors. The poor solubility and permeability are concerning for both, but can be addressed during formulation.

Output:
0
2025-04-17 12:20:08,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (375.535 Da and 363.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.37) is better than Ligand B (38.77) as it is below the 140 A^2 threshold.

**logP:** Ligand A (1.294) is within the optimal 1-3 range, while Ligand B (4.129) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while 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 (0.565 and 0.629, respectively), indicating good drug-like properties.

**DILI:** Ligand A (42.691) has a lower DILI risk than Ligand B (51.144), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (81.698) has a higher BBB penetration than Ligand A (56.65), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.224) shows poor permeability, while Ligand B (-4.279) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.353) has better solubility than Ligand B (-4.164).

**hERG Inhibition:** Ligand A (0.17) has a much lower hERG inhibition liability than Ligand B (0.888), a significant advantage.

**Microsomal Clearance:** Ligand A (41.721) has a lower microsomal clearance, indicating better metabolic stability, which is crucial for kinase inhibitors. Ligand B (121.637) has high clearance.

**In vitro Half-Life:** Ligand A (-32.593) has a longer half-life than Ligand B (18.463), which is desirable.

**P-gp Efflux:** Ligand A (0.06) has lower P-gp efflux liability than Ligand B (0.631), which is beneficial for bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.0 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. While both have good binding affinity and QED, Ligand A excels in crucial ADME properties: lower DILI risk, better solubility, significantly lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. Ligand B's higher logP and Caco-2 permeability are offset by its poorer metabolic stability and higher hERG risk.

Output:
0
2025-04-17 12:20:08,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.435 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.55) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (75.44) is excellent, well below 140.

**logP:** Ligand A (0.181) is quite low, potentially hindering permeability. Ligand B (2.54) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is at the upper limit of the preferred range (<=5). Ligand B (1) is excellent.

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

**QED:** Both ligands have acceptable QED scores (0.442 and 0.609, both >0.5).

**DILI:** Both ligands have low DILI risk (31.33 and 32.842, both <40).

**BBB:** Both ligands have good BBB penetration (78.519 and 70.997). While not a primary concern for a kinase inhibitor, it's not detrimental.

**Caco-2 Permeability:** Ligand A (-5.286) has very poor Caco-2 permeability. Ligand B (-4.877) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.573 and -2.115). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.076 and 0.331).

**Microsomal Clearance:** Ligand A (30.313) has moderate clearance, while Ligand B (11.719) has significantly lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.808) has a reasonable half-life. Ligand B (-21.692) has a *negative* half-life, which is impossible and likely indicates an issue with the data or the model. This is a major red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.019 and 0.225).

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-6.9). However, the difference is less than the 1.5 kcal/mol threshold where affinity strongly outweighs other factors.

**Conclusion:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. Ligand B has a better logP, fewer H-bond donors, and significantly better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is a critical issue that needs investigation, but assuming it is a data error, the other properties make it preferable. Ligand A's very low logP and poor Caco-2 permeability are significant drawbacks.

Output:
1
2025-04-17 12:20:08,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.467 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is significantly better than Ligand B (95.86). A TPSA under 140 is good for oral absorption, and both are within this range, but A is much more favorable.

**logP:** Ligand A (3.388) is optimal (1-3), while Ligand B (0.319) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 6 HBA). Both are within acceptable limits, but lower is generally preferred.

**QED:** Both ligands have good QED scores (0.713 and 0.845), indicating good drug-like properties.

**DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (61.807), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (91.276) is better than Ligand B (51.066).

**Caco-2 Permeability:** Ligand A (-4.546) and Ligand B (-4.406) are both negative, indicating poor permeability. However, these values are on a scale where negative values are possible, and the difference isn't huge.

**Aqueous Solubility:** Ligand A (-2.363) is slightly better than Ligand B (-1.532), but both are poor.

**hERG Inhibition:** Ligand A (0.695) has a lower hERG risk than Ligand B (0.237), which is a significant advantage.

**Microsomal Clearance:** Ligand A (45.485) has higher clearance than Ligand B (19.066), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-18.602) has a longer half-life than Ligand A (-21.485), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.558) has lower P-gp efflux than Ligand B (0.135), which is a slight advantage.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, lower DILI risk, lower hERG risk, and better logP. While its metabolic stability (Cl_mic) is worse and solubility is slightly lower than Ligand B, the superior binding affinity and safety profiles are more important for an enzyme target like SRC. The difference in binding affinity is substantial (>1.5 kcal/mol).

Output:
1
2025-04-17 12:20:08,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.558 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is significantly better than Ligand B (92.26). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is much closer to the 90 threshold for CNS penetration should that become a consideration.

**logP:** Ligand A (3.564) is optimal, while Ligand B (1.046) is on the lower side, potentially impacting permeability.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improves permeability.

**QED:** Both ligands have good QED scores (0.403 and 0.837), indicating drug-like properties. Ligand B is significantly better here.

**DILI:** Ligand A (20.202) has a much lower DILI risk than Ligand B (47.615), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (77.821 and 73.905), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.605) and Ligand B (-5.147) 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 (-4.556) and Ligand B (-2.951) both have negative solubility values, indicating poor solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.831) is much better than Ligand B (0.237), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (92.54) has a higher microsomal clearance than Ligand B (33.861), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (12.787 hours) has a much longer half-life than Ligand A (-6.233 hours), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.846) has better P-gp efflux profile than Ligand B (0.012).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has lower logP and solubility, its significantly superior binding affinity (-8.8 vs -7.4 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme inhibitor. The lower DILI risk of Ligand A is appealing, but the potency and stability advantages of Ligand B are more important in this case.

Output:
1
2025-04-17 12:20:08,312 - INFO - Batch 121 complete. Total preferences: 1936
2025-04-17 12:20:08,312 - INFO - Processing batch 122/512...
2025-04-17 12:20:48,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.359 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.89) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (70.47) is excellent, well below 140, suggesting good absorption.

**logP:** Both ligands (0.81 and 0.939) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable and potentially better for permeability due to fewer hydrogen bonds.

**QED:** Ligand B (0.833) has a significantly higher QED score than Ligand A (0.458), indicating a more drug-like profile.

**DILI:** Ligand A (79.333) has a higher DILI risk than Ligand B (16.285). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (91.043) has a higher BBB percentile, but this isn't a major deciding factor here.

**Caco-2 Permeability:** Ligand A (-6.108) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.15) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.157) has very poor aqueous solubility, which is a major drawback. Ligand B (-1.586) is better, but still relatively low.

**hERG Inhibition:** Ligand A (0.072) has a very low hERG risk, which is excellent. Ligand B (0.549) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-7.819) has very low microsomal clearance, indicating high metabolic stability, which is a significant advantage. Ligand B (22.882) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (18.911) and Ligand B (17.193) have similar in vitro half-lives.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.08, respectively).

**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:**

Ligand A has a better binding affinity and excellent metabolic stability (low Cl_mic) and low hERG risk. However, its poor solubility, poor Caco-2 permeability, and high DILI risk are major concerns. Ligand B has a better overall drug-like profile (higher QED), better TPSA, lower DILI risk, and better Caco-2 permeability, despite slightly weaker binding affinity and higher clearance.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), and the significant liabilities of Ligand A (solubility, DILI, permeability), Ligand B is the more promising candidate. The 0.5 kcal/mol difference in binding affinity can likely be overcome with further optimization, while addressing the solubility and DILI issues of Ligand A would be more challenging.

Output:
1
2025-04-17 12:20:48,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.471 and 363.292 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.28) is significantly better than Ligand B (106.62). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.08 and 0.983), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) is slightly better than Ligand B (HBD=2, HBA=6) in terms of adhering to the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.883) has a much higher QED score than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand B (85.576) has a significantly higher DILI risk than Ligand A (66.072).  Ligand B is concerningly high, being well above the 60 threshold.

**BBB:** Both ligands have reasonable BBB penetration (75.145 and 68.127). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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:** Both ligands have low hERG inhibition risk (0.489 and 0.204), which is excellent.

**Microsomal Clearance:** Ligand A (25.879) has a lower microsomal clearance than Ligand B (33.421), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (28.921) has a positive half-life, while Ligand B (-31.913) has a negative half-life. This is a major red flag for Ligand B, indicating very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.153 and 0.02).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -8.9 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering all factors, **Ligand A** is the superior candidate. While both have similar binding affinities, Ligand A demonstrates significantly better drug-like properties (higher QED), lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), and a more favorable TPSA. The negative solubility and Caco-2 values are concerning for both, but the other advantages of A outweigh these issues. Ligand B's extremely negative half-life is a critical flaw.

Output:
0
2025-04-17 12:20:48,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (362.5 and 351.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.3) is better than Ligand B (73.78) as it is closer to the <140 threshold for good absorption.

**3. logP:** Both ligands have acceptable logP values (1.999 and 2.051, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it can contribute to solubility.

**5. H-Bond Acceptors:** Ligand B (6) is preferable to Ligand A (4) as it can contribute to binding.

**6. QED:** Both ligands have similar QED values (0.832 and 0.7), indicating good drug-likeness.

**7. DILI:** Ligand B (43.4) has a slightly lower DILI risk than Ligand A (48.7), which is favorable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.5) has a higher BBB percentile than Ligand A (60.6), but this is not a major deciding factor.

**9. Caco-2 Permeability:** Ligand A (-5.341) has significantly better Caco-2 permeability than Ligand B (-4.44). This suggests better intestinal absorption for Ligand A.

**10. Aqueous Solubility:** Ligand A (-2.832) has better aqueous solubility than Ligand B (-1.887), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.356 and 0.431, respectively).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (47.36 and 47.98 mL/min/kg).

**13. In vitro Half-Life:** Ligand B (15.973) has a significantly longer in vitro half-life than Ligand A (-19.604). This is a major advantage for Ligand B, suggesting less frequent dosing potential.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.16 and 0.222, 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 less than the 1.5 kcal/mol threshold to outweigh other factors, it is still a positive.

**Overall Assessment:**

Ligand B has a better half-life and lower DILI risk. Ligand A has better solubility and Caco-2 permeability, and slightly better binding affinity. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the longer half-life of Ligand B is a significant advantage. The slight difference in binding affinity is less important than the improved pharmacokinetic profile.

Output:
1
2025-04-17 12:20:48,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.435 and 337.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.03) is slightly higher than Ligand B (70.9). Both are acceptable, but Ligand B is better for absorption.

**logP:** Ligand A (0.382) is quite low, potentially hindering permeation. Ligand B (1.949) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 7. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (0.574 and 0.716), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (25.902) has a significantly lower DILI risk than Ligand B (62.35). This is a major advantage for Ligand A.

**BBB:** Ligand A (40.713) has a lower BBB penetration than Ligand B (76.309). Since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also problematic. Again, the magnitude is similar.

**hERG Inhibition:** Ligand A (0.33) has a lower hERG risk than Ligand B (0.952). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-17.931) has a *much* lower (better) microsomal clearance than Ligand B (29.155), indicating greater metabolic stability. This is a crucial advantage.

**In vitro Half-Life:** Ligand A (9.699) has a better in vitro half-life than Ligand B (0.853).

**P-gp Efflux:** Ligand A (0.063) has a lower P-gp efflux liability than Ligand B (0.042), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a better binding affinity and logP, and a higher BBB score (though BBB is not a priority here). However, Ligand A has significantly better DILI, hERG, microsomal clearance, and in vitro half-life. The lower clearance and hERG risk for Ligand A are particularly important for an enzyme target like SRC kinase. While the affinity difference is notable, the improved safety and pharmacokinetic properties of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 12:20:48,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.332 and 401.304 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.6) is higher than Ligand B (51.22). While both are reasonably low, Ligand B is preferable as lower TPSA generally correlates with better cell permeability.

**3. logP:** Both ligands have good logP values (2.987 and 3.769), 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 2 HBDs, and Ligand B has 1. 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 (0.742 and 0.852), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 84.645, which is relatively high. Ligand B has a significantly lower DILI risk of 60.915, still above the ideal <40, but considerably better than Ligand A. This is a significant advantage for Ligand B.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (80.458) than Ligand A (62.97), but this is not a major factor in this case.

**9. Caco-2 Permeability:** Both have negative values (-5.353 and -4.891), which is unusual. However, the scale is not specified, so we can't interpret this directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.867 and -4.017), which is also unusual. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.612 and 0.647), which is good.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (3.713) than Ligand B (37.306), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand B has a much longer in vitro half-life (72.423) than Ligand A (24.969). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.262 and 0.653).

**15. Binding Affinity:** Ligand B has a slightly better binding affinity (-7.9 kcal/mol) 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 is the better candidate. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B has a significantly lower DILI risk, a longer half-life, and a slightly better binding affinity. The lower TPSA of Ligand B is also favorable. The unusual negative values for Caco-2 and solubility are concerning for both, but the difference in DILI and half-life are more critical for an enzyme target like SRC.

Output:
1
2025-04-17 12:20:48,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.422 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (66.4) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally indicates better cell permeability.

**logP:** Both ligands have good logP values (1.649 and 2.257), 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 good QED scores (0.663 and 0.791), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (34.432 and 32.299 percentile), which is favorable.

**BBB:** Ligand B (95.89) has a significantly higher BBB penetration percentile than Ligand A (58.821). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.78) has a much better Caco-2 permeability than Ligand B (-4.103).

**Aqueous Solubility:** Ligand A (-1.21) has better aqueous solubility than Ligand B (-2.809). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.512) has a slightly higher hERG inhibition risk than Ligand B (0.345), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (29.591 mL/min/kg) has significantly lower microsomal clearance than Ligand B (54.74 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.254 hours) has a much longer in vitro half-life than Ligand B (-13.079 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux than Ligand B (0.02), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-8.7 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.

**Conclusion:**

While Ligand A has better ADME properties (solubility, permeability, metabolic stability, half-life, and P-gp efflux), the significantly stronger binding affinity of Ligand B (-8.7 vs -7.1 kcal/mol) outweighs these differences. The potency advantage is substantial and crucial for an enzyme inhibitor. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:20:48,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.861 Da and 354.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values around 94-95, which is acceptable for general oral absorption, but not ideal for CNS penetration. This isn't a major concern for a non-CNS target like SRC.

**logP:** Ligand A (3.208) is within the optimal range (1-3). Ligand B (-0.039) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2) and HBA (4 & 6) counts, staying within the guidelines.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (38.658) has a much lower DILI risk than Ligand B (9.965), which is a significant advantage.

**BBB:** This is less critical for SRC, but Ligand A (74.176) has a higher BBB percentile than Ligand B (32.299).

**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:** Ligand A (0.466) has a lower hERG risk than Ligand B (0.104), which is preferable.

**Microsomal Clearance:** Ligand A (35.856 mL/min/kg) has a higher (worse) microsomal clearance than Ligand B (-4.62 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (27.131 hours) has a longer half-life than Ligand B (11.244 hours), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh many ADME concerns.

**Overall Assessment:**

Ligand A is the stronger candidate. The significantly improved binding affinity (-9.1 vs -7.5 kcal/mol) is the most important factor. While both have issues with solubility and Caco-2 permeability, the superior affinity of Ligand A is likely to be more impactful in driving efficacy. The lower DILI risk and hERG inhibition liability of Ligand A are also significant advantages. Although Ligand B has better metabolic stability (lower Cl_mic), the longer half-life of Ligand A partially mitigates this concern.

Output:
1
2025-04-17 12:20:48,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Ligand A (65.79) is better than Ligand B (100.11). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have similar logP values (A: 1.705, B: 1.854), 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=8). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar QED values (A: 0.797, B: 0.716), indicating good drug-likeness.

**DILI:** Ligand A (30.942) has a significantly lower DILI risk than Ligand B (65.917). This is a major advantage for Ligand A.

**BBB:** Ligand A (69.252) has a better BBB percentile than Ligand B (38.736), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.022) is better than Ligand B (-5.366), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.86) is better than Ligand B (-2.537). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.614) has a lower hERG risk than Ligand B (0.31). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (43.168) has a slightly better microsomal clearance than Ligand B (47.84), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.11) has a significantly longer half-life than Ligand A (33.507). This is a positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.134) has a lower P-gp efflux liability than Ligand B (0.039), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is the most important factor for an enzyme inhibitor, and the 1.8 kcal/mol difference is substantial.

**Overall:**

Ligand A is superior due to its significantly better binding affinity, lower DILI risk, lower hERG risk, better solubility, and better Caco-2 permeability. While Ligand B has a longer half-life, the advantages of Ligand A in potency and safety outweigh this benefit.

Output:
1
2025-04-17 12:20:48,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.413 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is slightly higher than Ligand B (53.09), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have optimal logP values (1.644 and 1.447), 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 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.833 and 0.768), indicating good drug-likeness.

**DILI:** Ligand A (13.804) has a significantly lower DILI risk than Ligand B (11.516), suggesting better liver safety.

**BBB:** Ligand A (75.107) has a higher BBB penetration percentile than Ligand B (51.454). While SRC isn't a CNS target, higher BBB is generally a positive indicator of reduced off-target effects.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.572 and -4.442). This is unusual and suggests poor permeability. However, these values might be experimental artifacts or indicate a specific transport mechanism.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.164 and -0.183). This is also concerning and suggests poor aqueous solubility, which could hinder bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.509 and 0.439), which is favorable.

**Microsomal Clearance:** Ligand A (22.967) has a higher microsomal clearance than Ligand B (18.459), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (0.818) has a slightly longer in vitro half-life than Ligand A (-2.029).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.036).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) exhibits significantly stronger binding affinity compared to Ligand B (-7.4 kcal/mol). This is a substantial difference (2.1 kcal/mol), and a strong affinity is paramount for an enzyme inhibitor.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.5 vs -7.4 kcal/mol) outweighs the slightly higher microsomal clearance and lower half-life. Furthermore, its lower DILI risk is a significant advantage. The solubility and permeability issues would need to be addressed through formulation strategies or further chemical modifications, but the potency advantage of Ligand A is too significant to ignore.

Output:
1
2025-04-17 12:20:48,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.559 Da and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (84.42) is still under 140, but less optimal than A.

**logP:** Both ligands (2.688 and 2.075) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.634 and 0.631), indicating good drug-likeness.

**DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (61.225). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (74.758) is slightly better than Ligand A (63.125). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.074) has worse Caco-2 permeability than Ligand B (-4.772), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.37) has worse aqueous solubility than Ligand B (-2.585), which is a concern.

**hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.104). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (79.999) has a higher microsomal clearance than Ligand B (45.749), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (10.145) has a longer half-life than Ligand A (16.299). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.313) has lower P-gp efflux than Ligand B (0.051), which is favorable.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4). While both are excellent, the 1.5kcal/mol difference could be significant.

**Overall Assessment:**

Ligand B is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While Ligand A has better TPSA and P-gp efflux, the ADME/Tox profile of Ligand B is more favorable for development as an enzyme inhibitor. The solubility and permeability are both poor, but can be addressed with formulation strategies.

Output:
1
2025-04-17 12:20:48,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.834 and 365.821 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (21.06) is significantly better than Ligand B (100.21). A TPSA under 140 is good for oral absorption, and A is well within this range, while B is approaching the upper limit.

**logP:** Ligand A (4.739) is slightly high, potentially leading to solubility issues, but still within a manageable range. Ligand B (2.109) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.774 and 0.763), indicating good drug-likeness.

**DILI:** Ligand A (25.165) has a much lower DILI risk than Ligand B (81.892). This is a significant advantage for A.

**BBB:** Ligand A (90.151) shows good BBB penetration, while Ligand B (27.414) is poor. While SRC is not necessarily a CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.838) has poor Caco-2 permeability, while Ligand B (-5.382) is also poor. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-4.936) has poor aqueous solubility, while Ligand B (-2.945) is better. Solubility is a concern for A.

**hERG Inhibition:** Ligand A (0.914) has a lower hERG risk than Ligand B (0.161). This is a significant advantage for A.

**Microsomal Clearance:** Ligand A (35.94) has a higher microsomal clearance than Ligand B (22.279), indicating lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand A (-6.769) has a longer in vitro half-life than Ligand B (4.73). This favors A.

**P-gp Efflux:** Ligand A (0.81) has higher P-gp efflux than Ligand B (0.03), which is unfavorable. This favors B.

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

**Overall Assessment:**

Ligand A has significant advantages in DILI risk, hERG inhibition, and in vitro half-life. However, it suffers from poor Caco-2 permeability and aqueous solubility, and higher P-gp efflux. Ligand B has better solubility, lower clearance, and lower P-gp efflux, but has a much higher DILI risk and a lower BBB score.

Given the enzyme-kinase specific priorities, metabolic stability (Cl_mic and t1/2) and safety (DILI, hERG) are critical. While ligand B has better metabolic stability, the significantly higher DILI and hERG risk are major concerns. The slight difference in clearance is outweighed by the substantial safety advantages of Ligand A. The poor solubility of A could potentially be addressed through formulation strategies.

Output:
0
2025-04-17 12:20:48,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (341.411 and 348.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.69) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (81.47) is still under 140, but less favorable than A.

**3. logP:** Ligand A (2.281) is within the optimal 1-3 range. Ligand B (3.8) is slightly higher, potentially increasing off-target interactions 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 4, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.817) has a significantly better QED score than Ligand B (0.44), indicating a more drug-like profile.

**7. DILI:** Ligand A (66.111) has a higher DILI risk than Ligand B (44.591), but both are reasonably acceptable.

**8. BBB:** Both have good BBB penetration, but Ligand B (82.047) is slightly better than Ligand A (67.468). However, BBB isn't a high priority for a kinase inhibitor.

**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, indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG:** Ligand A (0.821) has a slightly higher hERG risk than Ligand B (0.672), but both are relatively low.

**12. Cl_mic:** Ligand A (89.082) has a higher microsomal clearance than Ligand B (64.384), suggesting lower metabolic stability. This is a significant negative for Ligand A.

**13. t1/2:** Ligand B (3.369) has a longer in vitro half-life than Ligand A (-8.574), which is a significant advantage.

**14. Pgp:** Both have low Pgp efflux liability (0.341 and 0.444 respectively).

**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:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is superior. It has better metabolic stability (lower Cl_mic, longer t1/2), a better QED score, lower DILI risk, and slightly better Caco-2 and BBB penetration. The binding affinity is comparable. The poor solubility and permeability are concerning for both, but can be addressed with formulation strategies. The improved metabolic stability of Ligand B is more critical for an enzyme inhibitor.

Output:
1
2025-04-17 12:20:48,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.455 and 351.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is excellent, well below the 140 threshold for oral absorption. Ligand B (120.24) is still acceptable but less favorable.

**logP:** Ligand A (3.135) is optimal. Ligand B (-0.235) is significantly low, potentially hindering membrane permeability and absorption.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is acceptable, but higher.

**QED:** Ligand A (0.878) is excellent, indicating high drug-likeness. Ligand B (0.595) is acceptable, but less optimal.

**DILI:** Ligand A (32.959) has a very low DILI risk. Ligand B (26.444) also has a low DILI risk, but slightly lower than A.

**BBB:** Ligand A (73.788) shows reasonable BBB penetration, while Ligand B (41.373) is lower. This is less critical for a non-CNS target like SRC, but still a factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.07 and -5.82), which is unusual and suggests poor permeability. This needs further investigation, but the negative values are difficult to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.27 and -1.687), again unusual and suggesting poor solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.642) has a lower hERG risk than Ligand B (0.07).

**Microsomal Clearance:** Ligand A (81.283) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (-15.012) has a negative clearance, which is not physically possible and indicates a data error or unusual behavior.

**In vitro Half-Life:** Ligand A (13.494) has a moderate half-life. Ligand B (-10.892) has a negative half-life, which is impossible and suggests a data error.

**P-gp Efflux:** Ligand A (0.574) has moderate P-gp efflux. Ligand B (0.002) has very low P-gp efflux.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.5 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand A is the more promising candidate. Its superior binding affinity, better logP, lower hERG risk, and excellent QED outweigh the higher microsomal clearance. The negative values for solubility and permeability are concerning and require further investigation, but the strong binding and favorable drug-like properties make it a better starting point for optimization. Ligand B has several unfavorable properties (low logP, negative clearance and half-life) and is less likely to be a viable drug candidate.

Output:
0
2025-04-17 12:20:48,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.4 and 356.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.32) is well below the 140 threshold for good absorption, while Ligand B (134.19) is closer to the limit but still acceptable.

**logP:** Ligand A (1.055) is within the optimal 1-3 range. Ligand B (-1.925) is below 1, which might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (4 HBD, 7 HBA) both have acceptable counts, staying within the recommended limits.

**QED:** Ligand A (0.731) has a significantly better QED score than Ligand B (0.322), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (65.6% and 64.5%), placing them in a moderate risk category.

**BBB:** Ligand A (33.7%) has a lower BBB penetration percentile than Ligand B (23.2%), but BBB is not a primary concern for a non-CNS target like SRC kinase.

**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 solubility, which is a significant drawback. Ligand B (-1.264) is slightly better than Ligand A (-3.414).

**hERG Inhibition:** Ligand A (0.255) shows a much lower hERG inhibition liability than Ligand B (0.142), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-10.978) has a much lower (better) microsomal clearance than Ligand B (24.151), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.701 hours) has a shorter half-life than Ligand B (-16.363 hours). The negative value for B is suspect and likely indicates a very long half-life, but without knowing the scale, it's hard to say definitively.

**P-gp Efflux:** Ligand A (0.018) has a very low P-gp efflux liability, while Ligand B (0.089) is slightly higher, but still low.

**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 difference, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly stronger binding affinity (-8.5 vs 0 kcal/mol) is the most important factor. It also has better QED, lower hERG risk, and better metabolic stability (lower Cl_mic). While both have poor solubility and Caco-2 permeability, the strong binding of Ligand A makes it more likely to be optimized to overcome these issues. The negative values for solubility and Caco-2 need further investigation. Ligand B's low logP and suspect half-life are also concerning.

Output:
0
2025-04-17 12:20:48,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.57) is slightly higher than Ligand B (69.64), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.775 and 2.578), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, meeting the criteria of <=5 and <=10 respectively.

**QED:** Both ligands have high QED scores (0.828 and 0.865), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (39.744 and 37.456), well below the concerning threshold of 60.

**BBB:** Both have moderate BBB penetration (65.762 and 77.007). Since SRC is not a CNS target, this is not a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.784 and -4.913). This is unusual and suggests poor permeability, but the scale is not clearly defined. It's a potential concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.371 and -2.965). Similar to Caco-2, this is concerning, and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.337 and 0.434), which is excellent.

**Microsomal Clearance:** Ligand B (23.529) has significantly lower microsomal clearance than Ligand A (31.587), indicating better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-22.403) has a *negative* half-life, which is impossible. This is a major red flag and indicates a significant issue with the data or the compound itself. Ligand A has a reasonable half-life (44.941).

**P-gp Efflux:** Both have low P-gp efflux (0.147 and 0.217), which is favorable.

**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 less than the 1.5 kcal/mol threshold to outweigh other issues, it's still a positive.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, the *negative* in vitro half-life is a critical flaw. This suggests either a data error or a fundamentally unstable compound. Ligand A, while not perfect (poor Caco-2 and solubility), has a reasonable half-life and acceptable ADME properties overall. Therefore, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 12:20:48,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.47 and 359.495 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.16) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (59.23) is still under 140, but less optimal than A.

**logP:** Both ligands (4.733 and 4.534) are slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects, but not drastically so.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 5 HBA, which is within acceptable limits.

**QED:** Ligand A (0.611) has a better QED score than Ligand B (0.804), indicating a more drug-like profile.

**DILI:** Ligand A (43.234) has a lower DILI risk than Ligand B (55.68), which is preferable. Both are below the concerning 60 threshold.

**BBB:** Ligand A (95.231) shows excellent BBB penetration, while Ligand B (84.917) is still reasonable but less favorable. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-4.933) has a worse Caco-2 permeability than Ligand B (-5.092), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.708) has slightly better aqueous solubility than Ligand B (-4.075).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.884 and 0.448).

**Microsomal Clearance:** Ligand A (55.846) has lower microsomal clearance than Ligand B (66.462), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (94.662) has a significantly longer in vitro half-life than Ligand B (-32.372). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.91 and 0.453).

**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 and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better Caco-2 permeability, Ligand A excels in key areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, better QED, and a stronger binding affinity. The slightly higher logP of both is a minor concern, but the benefits of A outweigh this.

Output:
1
2025-04-17 12:20:48,750 - INFO - Batch 122 complete. Total preferences: 1952
2025-04-17 12:20:48,750 - INFO - Processing batch 123/512...
2025-04-17 12:21:37,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.443 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.84) is slightly higher than Ligand B (58.64), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have excellent logP values (2.891 and 2.737) 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:** Ligand A (0.9) has a better QED score than Ligand B (0.75), indicating a more drug-like profile.

**DILI:** Ligand B (12.485) has a significantly lower DILI risk than Ligand A (43.622), which is a major advantage.

**BBB:** Ligand A (81.66) has a higher BBB penetration percentile than Ligand B (69.252), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.641) has a worse Caco-2 permeability than Ligand B (-4.536), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.712) has slightly worse solubility than Ligand B (-3.099).

**hERG:** Both ligands have very low hERG inhibition liability (0.318 and 0.334), which is excellent.

**Microsomal Clearance:** Ligand B (16.129) has a lower microsomal clearance than Ligand A (24.586), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.511) has a slightly better in vitro half-life than Ligand A (-9.64).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.062).

**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 a meaningful advantage.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and QED score, Ligand B demonstrates significantly better safety (DILI) and pharmacokinetic properties (microsomal clearance, half-life, solubility). The 0.9 kcal/mol difference in binding affinity, while noticeable, is likely outweighed by the substantial improvements in ADME-Tox properties offered by Ligand B, especially the lower DILI risk and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (like liver toxicity) are crucial.

Output:
1
2025-04-17 12:21:37,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.34 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.52) is better than Ligand B (96.6), both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets.

**logP:** Ligand A (2.744) is optimal (1-3), while Ligand B (0.81) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 & 1) and HBA (6 & 5) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.786 and 0.802), indicating drug-likeness.

**DILI:** Ligand A (85.227) has a higher DILI risk than Ligand B (47.964). This is a significant drawback for Ligand A.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (62.699) is slightly better than Ligand A (57.425).

**Caco-2 Permeability:** Ligand A (-4.815) is better than Ligand B (-5.22), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.445) is better than Ligand B (-2.12), which is crucial for bioavailability.

**hERG:** Ligand A (0.392) has a lower hERG risk than Ligand B (0.132), a positive attribute.

**Microsomal Clearance:** Ligand B (-8.199) has a *negative* clearance, which is unusual and suggests very high metabolic stability. Ligand A (83.787) has a high clearance, indicating rapid metabolism. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-10.237) has a negative half-life, which is also unusual and suggests very high stability. Ligand A (-13.58) has a negative half-life as well, but is less stable than Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.207 and 0.061).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although both are good.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better solubility and Caco-2 permeability, Ligand B's significantly lower DILI risk and *much* better metabolic stability (indicated by negative Cl_mic and t1/2) are critical advantages for an enzyme target like SRC kinase. The slightly better binding affinity of Ligand B further strengthens its position. The lower logP of Ligand B is a minor concern, but can be addressed with further optimization.

Output:
1
2025-04-17 12:21:37,319 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [357.426, 78.95, 0.337, 1, 5, 0.734, 28.306, 79.217, -4.43, -1.363, 0.51, 43.995, -8.688, 0.015, -7.8]
**Ligand B:** [351.447, 95.67, 1.785, 2, 5, 0.781, 31.136, 55.874, -4.858, -1.682, 0.38, 26.439, -10.768, 0.15, -8.6]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (357.426) and B (351.447) are very similar.
2. **TPSA:** A (78.95) is better than B (95.67). TPSA is acceptable for both, but lower is generally preferred for oral absorption.
3. **logP:** A (0.337) is lower than B (1.785). Both are within the optimal range, but A is approaching the lower limit, which could affect permeability.
4. **HBD:** A (1) is better than B (2). Lower HBD generally improves permeability.
5. **HBA:** Both A (5) and B (5) are within the acceptable range (<=10).
6. **QED:** Both A (0.734) and B (0.781) are good, indicating drug-like properties. B is slightly better.
7. **DILI:** A (28.306) is better than B (31.136). Both are low risk, but A has a lower percentile.
8. **BBB:** A (79.217) is significantly better than B (55.874). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.
9. **Caco-2:** A (-4.43) is better than B (-4.858). Higher values indicate better absorption.
10. **Solubility:** A (-1.363) is better than B (-1.682). Higher solubility is preferred.
11. **hERG:** A (0.51) is better than B (0.38). Lower hERG inhibition is crucial for avoiding cardiotoxicity.
12. **Cl_mic:** A (43.995) is worse than B (26.439). Lower clearance is better for metabolic stability. This is a significant advantage for B.
13. **t1/2:** A (-8.688) is worse than B (-10.768). Longer half-life is generally preferred. This is a significant advantage for B.
14. **Pgp:** A (0.015) is significantly better than B (0.15). Lower P-gp efflux is desirable for better bioavailability.
15. **Binding Affinity:** Both A (-7.8) and B (-8.6) have excellent binding affinity. B is 0.8 kcal/mol better, which is a substantial advantage and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B has a slightly better affinity (-8.6 vs -7.8).
*   **Metabolic Stability:** B has significantly better metabolic stability (lower Cl_mic, longer t1/2).
*   **Solubility:** A has slightly better solubility.
*   **hERG:** A has a slightly better hERG profile.

**Overall Assessment:**

While Ligand A has some advantages in solubility, hERG, and Pgp efflux, Ligand B's superior binding affinity and *significantly* improved metabolic stability (lower Cl_mic and longer t1/2) are more critical for a kinase inhibitor. The 0.8 kcal/mol difference in binding is substantial. The slightly worse solubility and Pgp efflux of B are less concerning given its strong metabolic profile.

Therefore, I predict **Ligand B** is the more viable drug candidate.

Output:
1
2025-04-17 12:21:37,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.83 and 371.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.42) is slightly higher than Ligand B (73.14), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.86) is at the upper end of the optimal 1-3 range, while Ligand B (2.51) is comfortably within it. Ligand A's higher logP *could* lead to off-target effects, but isn't a major concern yet.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (0 HBD, 7 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.763 and 0.713), indicating good drug-likeness.

**DILI:** Ligand A (84.30) has a significantly higher DILI risk than Ligand B (41.30). This is a substantial negative for Ligand A.

**BBB:**  BBB is not a primary concern for a kinase inhibitor, but Ligand B (93.49) has better BBB penetration than Ligand A (63.13).

**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 close enough to not be a deciding factor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, a concern for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.633) has a slightly higher hERG risk than Ligand B (0.489), but both are reasonably low.

**Microsomal Clearance:** Ligand B (48.67) has significantly lower microsomal clearance than Ligand A (89.21). This suggests better metabolic stability for Ligand B, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-3.60) has a negative half-life, which is unusual. Ligand A (65.20) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.234 and 0.218).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the stronger binding affinity of Ligand A, its significantly higher DILI risk and higher microsomal clearance are major concerns. Ligand B, while having slightly weaker binding, presents a much better ADME profile, particularly regarding metabolic stability and liver toxicity. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity are crucial. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:21:37,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.435 Da) is slightly higher than Ligand B (345.389 Da), but both are acceptable.

**TPSA:** Ligand A (76.82) is higher than Ligand B (29.54). While both are below 140, Ligand B's lower TPSA is more favorable for absorption.

**logP:** Ligand A (2.896) is within the optimal range (1-3). Ligand B (4.492) is slightly above this, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 2. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (Ligand A: 0.556, Ligand B: 0.747), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (88.949) has a higher DILI risk than Ligand B (59.984). This is a significant concern for Ligand A.

**BBB:** Ligand A (69.756) and Ligand B (85.964) both have acceptable BBB penetration, but it's less critical for a kinase inhibitor than 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, again unusual and suggesting poor solubility. The scale is not specified.

**hERG:** Ligand A (0.563) has a lower hERG risk than Ligand B (0.91). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (76.23) has lower microsomal clearance than Ligand B (115.044). This suggests better metabolic stability for Ligand A, which is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (83.628) has a significantly longer in vitro half-life than Ligand B (15.917). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.47) has lower P-gp efflux than Ligand B (0.934), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is only 0.2 kcal/mol, which is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has a better QED, lower TPSA, and slightly better binding affinity. However, Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and significantly lower DILI risk. Given the enzyme-specific priorities, metabolic stability and minimizing toxicity (DILI) are critical. The slightly better affinity of Ligand B does not compensate for its higher DILI risk and poorer metabolic profile.

Output:
0
2025-04-17 12:21:37,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.379 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.94) is better than Ligand B (67.23), both are under the 140 threshold for good absorption.

**logP:** Ligand A (-1.387) is a bit low, potentially hindering permeation. Ligand B (2.206) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 threshold.

**H-Bond Acceptors:** Ligand A (8) and Ligand B (4) are both acceptable, below the 10 threshold.

**QED:** Ligand B (0.803) has a significantly higher QED score than Ligand A (0.44), indicating a more drug-like profile.

**DILI:** Ligand A (49.36) has a slightly higher DILI risk than Ligand B (35.867), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (67.158) is higher than Ligand A (32.416).

**Caco-2 Permeability:** Ligand A (-5.311) and Ligand B (-4.978) are both negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.947) is slightly better than Ligand B (-1.79), but both are poor.

**hERG Inhibition:** Ligand A (0.035) has a much lower hERG risk than Ligand B (0.208), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-5.609) has a much lower (better) microsomal clearance than Ligand B (38.12), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (14.423 hours) has a longer half-life than Ligand B (3.52 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.188).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better hERG, Cl_mic, t1/2, and Pgp profiles, Ligand B's significantly stronger binding affinity (-8.8 vs -7.3 kcal/mol) is the most critical factor for an enzyme inhibitor. The higher QED score of Ligand B also supports its drug-likeness. The lower logP of Ligand A is concerning. Although solubility is poor for both, the superior potency of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 12:21:37,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.321 and 363.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (81.43 and 85.00) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.639 and 2.858) 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 5 HBA, and Ligand B has 6 HBA, both are within the acceptable range (<=10).

**6. QED:** Both ligands have very similar QED values (0.858 and 0.853), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 92.516, which is high. Ligand B has a DILI risk of 61.574, which is also high, but lower than Ligand A.

**8. BBB:** Both ligands have high BBB penetration (82.396 and 85.459), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.592 and -4.885), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.767 and -3.93), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.477 and 0.454).

**12. Microsomal Clearance:** Ligand A has a Cl_mic of 59.789, while Ligand B has 34.842. Ligand B has significantly lower clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-13.305), which is not physically meaningful. Ligand B has a half-life of 8.19 hours, which is reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.202 and 0.137).

**15. 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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.0 vs -8.1 kcal/mol) and better metabolic stability (lower Cl_mic, positive half-life) outweigh the slightly higher DILI risk. The poor solubility and permeability would need to be addressed through formulation or further chemical modifications, but the improved potency and stability provide a better starting point for optimization.

Output:
1
2025-04-17 12:21:37,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.395 and 347.503 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (138.26) is borderline but acceptable for oral absorption, while Ligand B (61.44) is well below the 140 threshold and excellent.

**logP:** Ligand A (-1.658) is a bit low, potentially hindering permeation. Ligand B (2.086) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, both acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable and slightly more favorable.

**QED:** Both ligands have good QED scores (0.499 and 0.693), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (52.036) has a moderate DILI risk, while Ligand B (4.343) has a very low risk, which is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B is slightly better (70.531 vs 62.389).

**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 unusual and indicates very poor solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.31 and 0.363), which is good.

**Microsomal Clearance:** Both ligands have similar, relatively low microsomal clearance (-23.987 and -21.433), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (-9.365) has a slightly worse half-life than Ligand B (-5.91), but both are negative, which is concerning.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.001 and 0.032).

**Binding Affinity:** Both ligands have similar binding affinities (-9.0 and -10.9 kcal/mol). Ligand B is significantly more potent.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the superior candidate. It has a significantly better binding affinity, a much lower DILI risk, a slightly better logP, and a better QED score. The improved potency and reduced toxicity risk outweigh the similar metabolic stability and P-gp efflux profiles. 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 12:21:37,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.459 Da and 362.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (74.33 and 78.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.818 and 1.915) are within the optimal 1-3 range.

**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 (0.754) has a significantly better QED score than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand A (49.011) has a slightly higher DILI risk than Ligand B (18.651), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (76.658 and 79.488), which isn't a primary concern for a non-CNS target like SRC kinase.

**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 (0.653) has a slightly higher hERG risk than Ligand B (0.336), but both are relatively low.

**Microsomal Clearance:** Ligand A (47.564 mL/min/kg) has a higher microsomal clearance than Ligand B (24.424 mL/min/kg), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-8.933 hours) has a negative half-life, which is not possible. Ligand A (17.469 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.076).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial.

**Conclusion:**

Despite Ligand A having a better QED score, the significantly better binding affinity of Ligand B (-8.2 vs -7.0 kcal/mol) and its lower microsomal clearance (24.424 vs 47.564 mL/min/kg) outweigh the benefits of Ligand A's slightly better QED and half-life. The negative solubility and Caco-2 values are concerning for both, but the potency and metabolic stability advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 12:21:37,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.479 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.76) is slightly higher than Ligand B (52.57). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands (2.223 and 2.658) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (3). Ligand B is preferable.

**QED:** Ligand A (0.867) has a significantly better QED score than Ligand B (0.744), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (52.423 and 5.312 percentile), well below the 60% threshold. Ligand B is significantly better.

**BBB:** Ligand B (81.388) shows better BBB penetration than Ligand A (63.901). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.232) has worse Caco-2 permeability than Ligand B (-4.898).

**Aqueous Solubility:** Ligand A (-2.295) has better aqueous solubility than Ligand B (-3.148). This is a positive for formulation and bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.404 and 0.805). Ligand A is preferable.

**Microsomal Clearance:** Ligand B (52.559) has a lower microsomal clearance than Ligand A (17.906), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (33.74) has a longer half-life than Ligand B (14.838). This is a positive.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.058 and 0.262). Ligand A is preferable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.6 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic) and a slightly better binding affinity. It also has better Caco-2 permeability. Ligand A has a better QED score, solubility, half-life, and P-gp efflux. However, the improved metabolic stability of Ligand B is more critical for a kinase inhibitor, as kinases often require sustained target engagement. The slightly better binding affinity of Ligand B is also a significant advantage.

Output:
1
2025-04-17 12:21:37,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.03) is significantly better than Ligand B (105.98). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (2.656) is optimal, while Ligand B (0.85) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.828) has a higher QED score than Ligand B (0.678), indicating better overall drug-likeness.

**DILI:** Ligand A (20.589) has a much lower DILI risk than Ligand B (53.432), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (91.392) has better BBB penetration than Ligand B (56.883).

**Caco-2 Permeability:** Ligand A (-4.671) and Ligand B (-5.056) 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 (-2.495 and -2.564 respectively). This is a major concern.

**hERG Inhibition:** Ligand A (0.532) has a slightly higher hERG risk than Ligand B (0.027), but both are relatively low.

**Microsomal Clearance:** Ligand A (3.398) has significantly lower microsomal clearance than Ligand B (29.171), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (19.855) has a longer in vitro half-life than Ligand B (-7.145), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.053).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand A is the superior candidate. Its advantages in TPSA, logP, QED, DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and slightly better hERG profile outweigh its slightly lower solubility and higher (but still acceptable) hERG risk. The poor solubility of both compounds is a significant issue that would need to be addressed during optimization, but Ligand A's other properties make it a more promising starting point.

Output:
1
2025-04-17 12:21:37,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (375.372 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (72.48 and 75.44) are below the 140 A^2 threshold for good oral absorption, which is good.

**3. logP:** Both ligands have logP values (3.503 and 2.928) within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both ligands (2 and 1) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (5 and 4) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.785 and 0.823), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 89.841, which is high. Ligand B has a much lower DILI risk of 21.791, which is very favorable. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have high BBB penetration (95.308 and 91.392). While not crucial for a non-CNS target like SRC, it doesn't detract from their potential.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.827 and -4.899). This 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:** Both ligands have negative solubility values (-4.94 and -2.59). This suggests poor aqueous solubility, which could be a formulation challenge.

**11. hERG Inhibition:** Ligand A has a hERG risk of 0.721, which is reasonable. Ligand B has a very low hERG risk of 0.416, which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A has a Cl_mic of 46.893 mL/min/kg, which is moderate. Ligand B has a higher Cl_mic of 54.47 mL/min/kg, indicating faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A has a half-life of 38.008 hours, which is good. Ligand B has a negative half-life (-29.12 hours), which is problematic and suggests very rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.4 and 0.159).

**15. Binding Affinity:** Ligand B has a significantly better binding affinity (-6.8 kcal/mol) compared to Ligand A (0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and hERG risk. Ligand A has a better half-life and slightly better Cl_mic, but the DILI risk is a major concern. The significantly stronger binding affinity of Ligand B is a decisive factor, even considering its lower half-life. The solubility issues are addressable with formulation strategies.

Output:
1
2025-04-17 12:21:37,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.26 Da) is slightly higher than Ligand B (346.515 Da), but both are acceptable.

**TPSA:** Ligand A (78.92) is higher than Ligand B (49.41). Both are below 140, supporting good oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (A: 4.019, B: 3.648), falling within the optimal 1-3 range. Ligand A is slightly higher, which *could* lead to off-target effects, but is not a major concern.

**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 range (<=10), with Ligand B being slightly more favorable.

**QED:** Both ligands have reasonable QED scores (A: 0.704, B: 0.512), indicating drug-like properties. Ligand A is better.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (8.259). This is a significant drawback for Ligand A.

**BBB:** Ligand A (49.593) has a lower BBB penetration than Ligand B (89.337). While not a primary concern for a kinase inhibitor, higher BBB is generally preferable.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.193) is worse than Ligand B (-4.768).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.824) is slightly worse than Ligand B (-3.796).

**hERG:** Both have low hERG inhibition liability (A: 0.795, B: 0.703), which is good.

**Microsomal Clearance:** Ligand B (43.7) has significantly lower microsomal clearance than Ligand A (64.194), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (124.993) has a longer half-life than Ligand B (3.498). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.453, B: 0.309), which is good.

**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 a positive for Ligand A.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and half-life, but suffers from significantly higher DILI risk, worse Caco-2 permeability, and worse solubility. Ligand B excels in metabolic stability (lower Cl_mic), lower DILI risk, and better Caco-2 permeability. Given the enzyme-specific priorities (metabolic stability, solubility, and hERG), and the substantial DILI risk associated with Ligand A, Ligand B is the more promising candidate. The small difference in binding affinity is unlikely to outweigh these ADME/Tox advantages.

Output:
1
2025-04-17 12:21:37,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.36 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.02) is well below the 140 threshold and favorable for oral absorption. Ligand B (82.53) is still acceptable, but less optimal.

**logP:** Ligand A (4.278) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.381) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 4 HBA, both within acceptable limits (<=10).

**QED:** Both ligands (0.863 and 0.766) have good drug-likeness scores.

**DILI:** Both ligands have acceptable DILI risk (52.579 and 48.468, both <60).

**BBB:** Ligand A (85.576) has better BBB penetration than Ligand B (59.325), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both 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 have negative solubility values, which is also unusual and problematic. It suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.611 and 0.168), which is excellent.

**Microsomal Clearance:** Ligand B (3.84 mL/min/kg) has significantly lower microsomal clearance than Ligand A (36.725 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-4.983) has a longer in vitro half-life than Ligand A (-14.354), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.279 and 0.03).

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

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the primary differentiating factor is metabolic stability. Ligand B demonstrates significantly better metabolic stability (lower Cl_mic and longer t1/2) than Ligand A. Given the enzyme-specific priorities, this is the most crucial factor. The slightly lower logP of Ligand B is less concerning than the high Cl_mic of Ligand A.

Output:
1
2025-04-17 12:21:37,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Ligand A:**

*   **MW:** 371.853 Da - Good (within 200-500 Da range)
*   **TPSA:** 80.66 - Good (<=140)
*   **logP:** 3.561 - Good (1-3)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 6 - Good (<=10)
*   **QED:** 0.69 - Good (>=0.5)
*   **DILI:** 88.6 - High risk (>60)
*   **BBB:** 62.97 - Not a priority for a non-CNS target
*   **Caco-2:** -5.285 - Poor (negative value indicates very low permeability)
*   **Solubility:** -3.661 - Poor (negative value indicates very low solubility)
*   **hERG:** 0.145 - Low risk
*   **Cl_mic:** 52.878 mL/min/kg - Moderate (higher is less desirable)
*   **t1/2:** 27.166 hours - Good
*   **Pgp:** 0.12 - Low efflux
*   **Affinity:** -9.4 kcal/mol - Excellent (strong binding)

**Ligand B:**

*   **MW:** 372.487 Da - Good (within 200-500 Da range)
*   **TPSA:** 95.94 - Acceptable (<=140, but approaching the upper limit)
*   **logP:** 0.427 - Marginal (close to 1, may impede permeation)
*   **HBD:** 2 - Good (<=5)
*   **HBA:** 5 - Good (<=10)
*   **QED:** 0.632 - Good (>=0.5)
*   **DILI:** 40.752 - Good (<40)
*   **BBB:** 42.924 - Not a priority for a non-CNS target
*   **Caco-2:** -5.299 - Poor (negative value indicates very low permeability)
*   **Solubility:** -1.521 - Poor (negative value indicates very low solubility)
*   **hERG:** 0.123 - Low risk
*   **Cl_mic:** 15.32 mL/min/kg - Good (low clearance, good metabolic stability)
*   **t1/2:** 0.608 hours - Poor (very short half-life)
*   **Pgp:** 0.029 - Low efflux
*   **Affinity:** -7.4 kcal/mol - Good (strong binding, but not as strong as A)

**Comparison and Decision:**

Both compounds have poor Caco-2 permeability and aqueous solubility, which are significant drawbacks. However, Ligand A has a substantially stronger binding affinity (-9.4 kcal/mol vs -7.4 kcal/mol). This difference in potency is significant enough to potentially overcome the solubility/permeability issues, especially considering the enzyme target class. Ligand A also has a better half-life. Ligand B has a better DILI score and Cl_mic, but the significantly weaker binding affinity and short half-life are more critical concerns for an enzyme inhibitor. The DILI risk for Ligand A could potentially be mitigated through structural modifications.

Output:
1
2025-04-17 12:21:37,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.483 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.53) is better than Ligand B (84.42), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (1.478 and 1.952), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable, below the 10 threshold.

**QED:** Ligand A (0.88) has a significantly better QED score than Ligand B (0.685), indicating better overall drug-likeness.

**DILI:** Ligand B (52.191) has a slightly lower DILI risk than Ligand A (57.27), but both are reasonably low and below the concerning 60 threshold.

**BBB:** Ligand A (73.129) has a better BBB penetration score than Ligand B (44.281), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.242) has a slightly better Caco-2 permeability than Ligand B (-4.735), but both are negative values which is unusual and suggests low permeability.

**Aqueous Solubility:** Ligand A (-2.838) has slightly better aqueous solubility than Ligand B (-2.047), but both are negative values which is concerning.

**hERG Inhibition:** Ligand A (0.278) has a much lower hERG inhibition risk than Ligand B (0.104), which is a significant advantage.

**Microsomal Clearance:** Ligand B (77.883) has a significantly lower microsomal clearance than Ligand A (8.574), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (4.482) has a slightly better in vitro half-life than Ligand A (-10.219), but both are concerning.

**P-gp Efflux:** Ligand A (0.041) has a lower P-gp efflux liability than Ligand B (0.03), which is slightly beneficial.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.0), but the difference is minimal.

**Overall Assessment:**

Ligand A excels in QED, BBB, hERG risk, and has comparable binding affinity. However, Ligand B has a much better microsomal clearance and slightly better half-life, which are critical for kinase inhibitors. The negative solubility and Caco-2 values for both are concerning and would require further investigation (formulation strategies, prodrug approaches). Despite the slightly better affinity of Ligand A, the significantly improved metabolic stability of Ligand B outweighs this advantage, making it the more promising candidate.

Output:
1
2025-04-17 12:21:37,321 - INFO - Batch 123 complete. Total preferences: 1968
2025-04-17 12:21:37,321 - INFO - Processing batch 124/512...
2025-04-17 12:22:26,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.425 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (92.01) is still acceptable, but less optimal.

**logP:** Ligand A (3.546) is at the upper end of the optimal range (1-3), while Ligand B (0.954) is slightly below, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are within acceptable limits (<=10), but Ligand A is preferable.

**QED:** Both ligands have reasonable QED scores (0.871 and 0.716), indicating good drug-like properties.

**DILI:** Ligand A (51.028) has a slightly higher DILI risk than Ligand B (34.471), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.474) has better BBB penetration than Ligand B (46.879), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.534 and -4.869), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.866 and -1.415), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.758) has a slightly higher hERG risk than Ligand B (0.144), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (40.523) has a higher microsomal clearance than Ligand B (-4.556). The negative value for Ligand B suggests excellent metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (24.521) has a longer half-life than Ligand B (18.549), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.071 and 0.023), which is good.

**Binding Affinity:** Ligand B (-8.0 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 of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B's significantly stronger binding affinity (-8.0 vs -6.8 kcal/mol) and superior metabolic stability (negative Cl_mic) are critical advantages for an enzyme inhibitor. The lower hERG risk is also a positive. Although Ligand A has a slightly longer half-life, the potency and stability benefits of Ligand B are more important. Addressing the solubility and permeability issues would be the next step in optimization.

Output:
1
2025-04-17 12:22:26,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 450.32 Da - Within the ideal range (200-500 Da).
* Ligand B: 369.487 Da - Also within the ideal range.
* *Advantage: Neither is problematic.*

**2. TPSA:**
* Ligand A: 41.57 A^2 - Good for oral absorption (<=140).
* Ligand B: 78.95 A^2 - Still good for oral absorption, but higher than A.
* *Advantage: A*

**3. logP:**
* Ligand A: 4.813 - Slightly high, potential for solubility issues or off-target effects.
* Ligand B: 1.077 - Good, within the optimal range.
* *Advantage: B*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Good.
* Ligand B: 1 - Good.
* *Advantage: Neither*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 2 - Good.
* Ligand B: 5 - Acceptable, but higher than A.
* *Advantage: A*

**6. QED:**
* Ligand A: 0.68 - Good, above the 0.5 threshold.
* Ligand B: 0.726 - Good, slightly better than A.
* *Advantage: B*

**7. DILI:**
* Ligand A: 41.76 - Low risk.
* Ligand B: 42.536 - Low risk, very similar to A.
* *Advantage: Neither*

**8. BBB:**
* Ligand A: 89.725 - High, but SRC is not a CNS target, so this is less important.
* Ligand B: 63.125 - Lower, also not critical.
* *Advantage: A (slightly, but not a major factor)*

**9. Caco-2 Permeability:**
* Ligand A: -4.766 - Negative values are unusual and suggest poor permeability.
* Ligand B: -4.993 - Also negative and suggests poor permeability, but similar to A.
* *Advantage: Neither*

**10. Aqueous Solubility:**
* Ligand A: -5.397 - Very poor solubility. This is a significant concern.
* Ligand B: -2.318 - Poor solubility, but better than A.
* *Advantage: B*

**11. hERG Inhibition:**
* Ligand A: 0.912 - Relatively low risk.
* Ligand B: 0.143 - Very low risk, excellent.
* *Advantage: B*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 58.442 mL/min/kg - High clearance, suggesting poor metabolic stability.
* Ligand B: 12.605 mL/min/kg - Low clearance, good metabolic stability.
* *Advantage: B*

**13. In vitro Half-Life:**
* Ligand A: 39.296 hours - Good.
* Ligand B: 1.208 hours - Very short half-life, a significant drawback.
* *Advantage: A*

**14. P-gp Efflux:**
* Ligand A: 0.7 - Moderate efflux.
* Ligand B: 0.026 - Very low efflux, excellent.
* *Advantage: B*

**15. Binding Affinity:**
* Ligand A: -7.7 kcal/mol - Excellent.
* Ligand B: -9.3 kcal/mol - Exceptional, 1.6 kcal/mol stronger than A.
* *Advantage: B*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. While Ligand A has a better half-life and acceptable hERG, its poor solubility and high clearance are major liabilities. Ligand B exhibits superior binding affinity, excellent hERG inhibition, low P-gp efflux, and good metabolic stability. Although its half-life is short, the significantly stronger binding affinity (-9.3 kcal/mol vs -7.7 kcal/mol) and other favorable ADME properties outweigh this drawback. The solubility is also better than Ligand A.

Output:
1
2025-04-17 12:22:26,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B as potential drug candidates targeting SRC, a kinase. Our priorities are potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.423 and 362.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.35) is better than Ligand B (56.75), both are acceptable but lower is preferred for permeability.

**logP:** Both ligands have good logP values (2.829 and 2.072), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 5 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.786 and 0.826), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (56.107 and 57.348), which is acceptable, though not ideal.

**BBB:** Ligand A (90.074) has better BBB penetration potential than Ligand B (85.731), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.967) has slightly better Caco-2 permeability than Ligand B (-4.625).

**Aqueous Solubility:** Ligand A (-3.463) has slightly better aqueous solubility than Ligand B (-2.879).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.613 and 0.568), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand B (59.507) has lower microsomal clearance than Ligand A (68.749), suggesting better metabolic stability. This is a key advantage for kinase inhibitors.

**In vitro Half-Life (t1/2):** Ligand B (-0.72) has a significantly better in vitro half-life than Ligand A (-14.686). This is a major advantage.

**P-gp Efflux:** Ligand B (0.245) has lower P-gp efflux liability than Ligand A (0.641), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor. A >7.3 kcal/mol advantage is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand B having better metabolic stability and P-gp efflux, the significantly stronger binding affinity of Ligand A (-7.3 vs 0.0 kcal/mol) makes it the more promising drug candidate. The difference in binding affinity is large enough to compensate for the slightly less favorable metabolic properties.

Output:
1
2025-04-17 12:22:26,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.455 Da and 376.538 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (75.63 and 69.64) below the 140 threshold for good oral absorption, but higher than the 90 threshold for CNS targets (not a primary concern here).

**3. logP:** Ligand A (1.17) is within the optimal 1-3 range. Ligand B (2.37) is also acceptable, though trending higher.

**4. H-Bond Donors:** Ligand A has 0 HBD, which is good. Ligand B has 2 HBD, still acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.804) has a significantly better QED score than Ligand B (0.648), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.126) has a slightly higher DILI risk than Ligand B (14.541). This is a concern for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (75.805 and 78.209), but this isn't a high priority for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.886 and -4.79), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.917 and -3.051), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.159 and 0.292), which is excellent.

**12. Microsomal Clearance:** Ligand A (24.331) has a much lower microsomal clearance than Ligand B (70.044), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (2.726) has a shorter half-life than Ligand B (-43.667). The negative value for Ligand B is concerning and likely indicates a very rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.134 and 0.019).

**15. 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.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate. Ligand A has a significantly better QED score and, crucially, much better metabolic stability (lower Cl_mic). The DILI risk is slightly higher for Ligand A, but the improved metabolic stability is more critical for an enzyme target like SRC kinase. Both have poor solubility and permeability, which would need to be addressed through formulation or further chemical modifications. The negative half-life for Ligand B is a red flag.

Output:
0
2025-04-17 12:22:26,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.4 and 382.848 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.99) is significantly better than Ligand B (82.26).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have logP values around 4.1-4.6, slightly above the optimal 1-3 range. This could potentially lead to solubility issues or off-target effects, but it's not a major disqualifier if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is better than Ligand B (4 HBD, 3 HBA). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.865) has a much higher QED score than Ligand B (0.583), indicating a more drug-like profile.

**DILI:** Ligand B (88.639) has a considerably higher DILI risk than Ligand A (44.281). This is a significant concern.

**BBB:** Ligand A (95.541) shows excellent BBB penetration, while Ligand B (53.276) is moderate. While SRC isn't a CNS target, good BBB penetration isn't necessarily a negative.

**Caco-2 Permeability:** Ligand A (-4.452) has a more negative Caco-2 value, suggesting better permeability than Ligand B (-4.743).

**Aqueous Solubility:** Ligand A (-5.173) has better aqueous solubility than Ligand B (-5.7).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.771 and 0.555 respectively).

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (35.217 and 34.767 mL/min/kg). These are reasonable, indicating acceptable metabolic stability.

**In vitro Half-Life:** Ligand B (95.978) has a significantly longer in vitro half-life than Ligand A (20.45). This is a strong advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.619) has lower P-gp efflux than Ligand B (0.22), which is desirable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.7 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a longer half-life, Ligand A excels in most other critical areas: better TPSA, HBD/HBA counts, QED, significantly lower DILI risk, better solubility, and slightly better binding affinity. The lower DILI risk is a major advantage, and the better ADME properties overall make Ligand A a more favorable starting point for further optimization.

Output:
0
2025-04-17 12:22:26,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.431 and 365.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.28) is well below the 140 threshold for oral absorption, and even favorable for CNS penetration. Ligand B (119.74) is still acceptable for oral absorption, but less favorable than A.

**logP:** Both ligands (1.817 and 1.102) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is better than Ligand B (4 HBD, 4 HBA) regarding the balance between solubility and permeability.

**QED:** Ligand A (0.887) has a significantly better QED score than Ligand B (0.613), indicating a more drug-like profile.

**DILI:** Ligand A (37.922) has a much lower DILI risk than Ligand B (68.476). This is a significant advantage.

**BBB:** Ligand A (78.364) shows good BBB penetration, while Ligand B (30.632) is poor. While not a primary concern for a non-CNS target like SRC, it's a bonus for A.

**Caco-2 Permeability:** Ligand A (-4.776) has a better Caco-2 permeability than Ligand B (-5.761).

**Aqueous Solubility:** Ligand A (-2.065) has better aqueous solubility than Ligand B (-2.959).

**hERG:** Both ligands (0.268 and 0.357) have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (5.896) has a significantly lower microsomal clearance than Ligand B (32.506), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.257 hours) has a much longer half-life than Ligand B (-29.44 hours - a negative value suggests very rapid degradation). This is a major advantage.

**P-gp Efflux:** Both ligands (0.103 and 0.115) have similar, low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold where affinity overwhelmingly dictates choice.

**Overall Assessment:**

Ligand A is superior in almost every ADME-Tox property: QED, DILI, solubility, metabolic stability (Cl_mic and t1/2). While Ligand B has a slightly better binding affinity, the substantial advantages of Ligand A in drug-like properties and safety outweigh this difference. The improved metabolic stability and longer half-life of Ligand A are particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:22:26,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (377.535 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand B (53.51) is better than Ligand A (60.85).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.463) is slightly better than Ligand B (3.331).

**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 QED values above 0.5, indicating good drug-likeness. Ligand A (0.891) is better than Ligand B (0.776).

**DILI:** Ligand A (31.02) has a significantly lower DILI risk than Ligand B (48.081), which is a major advantage.

**BBB:** Ligand B (77.084) has a better BBB penetration than Ligand A (57.968), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.385) is slightly better than Ligand B (-4.539).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.924) is slightly better than Ligand B (-2.609).

**hERG Inhibition:** Ligand A (0.566) has a lower hERG inhibition risk than Ligand B (0.274), which is a significant advantage.

**Microsomal Clearance:** Ligand B (60.298) has a higher microsomal clearance than Ligand A (41.763), indicating lower metabolic stability. This is a critical disadvantage for Ligand B.

**In vitro Half-Life:** Ligand B (20.366) has a longer in vitro half-life than Ligand A (-2.544), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.684) has a lower P-gp efflux liability than Ligand B (0.209), which is a positive attribute.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a longer half-life and better BBB penetration, Ligand A excels in the most critical areas for an enzyme inhibitor: significantly better binding affinity, lower DILI risk, lower hERG risk, and better metabolic stability (lower Cl_mic). The solubility and permeability issues are present in both, but can be addressed through formulation strategies. The superior potency and safety profile of Ligand A outweigh the advantages of Ligand B.

Output:
0
2025-04-17 12:22:26,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties: affinity, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.341 and 353.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.37) is well below the 140 threshold for good oral absorption. Ligand B (116.76) is still acceptable, but less ideal.

**logP:** Ligand A (2.805) is within the optimal range of 1-3. Ligand B (-0.092) is below 1, which could impede permeation.

**H-Bond Donors:** Ligand A (2) is within the acceptable limit of <=5. Ligand B (4) is also acceptable.

**H-Bond Acceptors:** Ligand A (6) is within the acceptable limit of <=10. Ligand B (5) is also acceptable.

**QED:** Ligand A (0.778) has a good drug-like profile (>=0.5). Ligand B (0.377) is below this threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (87.902) has a higher DILI risk, being above 60, which is concerning. Ligand B (19.969) has a very low DILI risk, which is excellent.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (60.76) is slightly higher than Ligand A (55.021). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative values (-4.628 and -4.662) which is unusual and suggests poor permeability. This needs further investigation, but is a negative for both.

**Aqueous Solubility:** Both have negative values (-4.134 and -1.548) which is also unusual and suggests poor solubility. This needs further investigation, but is a negative for both.

**hERG Inhibition:** Ligand A (0.388) has a lower hERG risk, which is preferable. Ligand B (0.126) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (32.374) has a higher clearance than Ligand B (18.575), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-13.214) has a negative half-life, which is impossible and indicates a data error. Ligand B (-32.82) also has a negative half-life, indicating a data error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.206 and 0.005).

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-9.1). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a higher DILI risk and a higher microsomal clearance. The negative half-lives for both compounds are concerning and suggest data errors. Despite the DILI risk, the significantly better affinity of Ligand A makes it the more promising candidate, assuming the DILI risk can be mitigated through structural modifications. The poor solubility and permeability are also concerns that would need to be addressed.

Output:
0
2025-04-17 12:22:26,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.49 and 349.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (82.87), being comfortably below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.94 and 0.647), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (0 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED scores (0.771 and 0.728), indicating good drug-likeness.

**DILI:** Ligand A (5.816 percentile) has a significantly lower DILI risk than Ligand B (23.187 percentile). This is a major advantage.

**BBB:** Ligand B (85.343 percentile) has a higher BBB penetration score than Ligand A (61.691 percentile). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.715) has a worse Caco-2 permeability than Ligand B (-4.376).

**Aqueous Solubility:** Ligand A (-2.617) has a worse aqueous solubility than Ligand B (-1.409).

**hERG:** Both ligands have very low hERG inhibition liability (0.432 and 0.386), which is excellent.

**Microsomal Clearance:** Ligand A (40.997 mL/min/kg) has a better (lower) microsomal clearance than Ligand B (5.3 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.41 hours) has a better (longer) half-life than Ligand B (5.341 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.073).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. The difference in binding affinity is not large enough to overcome these advantages.

Output:
1
2025-04-17 12:22:26,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.53 and 342.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (83.04). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (2.13 and 2.71), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is more favorable than Ligand B (0 HBD, 7 HBA). While both are within acceptable limits, a balance is preferred.

**QED:** Ligand A (0.842) has a significantly higher QED score than Ligand B (0.614), indicating a more drug-like profile.

**DILI:** Ligand B (64.06) has a higher DILI risk than Ligand A (13.3). This is a significant concern, making Ligand A much safer.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (80.42) has a higher BBB penetration than Ligand A (59.36), but this is not a major factor in this case.

**Caco-2 Permeability:** Both show 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, indicating poor solubility. This is a drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.21 and 0.29), which is good.

**Microsomal Clearance:** Ligand B (95.92) has a much higher microsomal clearance than Ligand A (0.61). This means Ligand A is significantly more metabolically stable.

**In vitro Half-Life:** Ligand A (-3.34) has a much longer in vitro half-life than Ligand B (-22.29). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.027 and 0.624)

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering all factors, particularly the enzyme-specific priorities, **Ligand A is the more promising drug candidate.** It has a better QED score, significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable HBD/HBA balance. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far superior, making it more likely to succeed as a drug.

Output:
0
2025-04-17 12:22:26,296 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [421.371, 68.29, 4.062, 1, 5, 0.791, 81.388, 46.413, -4.672, -5.281, 0.417, 72.313, 10.133, 0.617, -8.5]
**Ligand B:** [348.462, 58.2, 2.426, 2, 2, 0.802, 25.979, 83.482, -4.758, -3.914, 0.416, 5.519, 15.2, 0.184, -7.7]

**Step-by-step comparison:**

1. **MW:** Ligand A (421.371 Da) is within the ideal range, while Ligand B (348.462 Da) is towards the lower end, but still acceptable.
2. **TPSA:** Both are below 140, suggesting reasonable absorption potential. Ligand B (58.2) is better than A (68.29).
3. **logP:** Ligand A (4.062) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.426) is optimal.
4. **HBD:** Both have acceptable HBD counts (A: 1, B: 2).
5. **HBA:** Both have acceptable HBA counts (A: 5, B: 2).
6. **QED:** Both have good QED scores (A: 0.791, B: 0.802), indicating drug-like properties.
7. **DILI:** Ligand A (81.388%) has a significantly higher DILI risk than Ligand B (25.979%). This is a major concern.
8. **BBB:** Ligand B (83.482%) shows better BBB penetration, but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.
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 have low hERG inhibition risk (A: 0.417, B: 0.416).
12. **Cl_mic:** Ligand B (5.519 mL/min/kg) has much lower microsomal clearance than Ligand A (72.313 mL/min/kg), indicating better metabolic stability.
13. **t1/2:** Ligand B (15.2 hours) has a longer in vitro half-life than Ligand A (10.133 hours).
14. **Pgp:** Ligand A (0.617) has higher P-gp efflux liability than Ligand B (0.184).
15. **Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), but the difference is not substantial.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While Ligand A has slightly better affinity, its significantly higher DILI risk and much higher microsomal clearance are major drawbacks. Ligand B excels in metabolic stability, has a much lower DILI risk, and acceptable affinity. The solubility and permeability data are concerning for both, but the ADME profile of Ligand B is far superior.

**Conclusion:**

Considering the enzyme-specific priorities and the overall profile, Ligand B is the more viable drug candidate. The better ADME properties, particularly the lower DILI risk and improved metabolic stability, outweigh the slightly weaker binding affinity.

Output:
1
2025-04-17 12:22:26,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.25) is significantly better than Ligand B (96.25).  A TPSA under 140 is desirable for oral absorption, and both meet this, but A is much closer to the preferred range for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (1.316 and 1.0), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (3 HBD, 5 HBA). Lower HBDs are generally preferred.

**QED:** Both ligands have reasonable QED scores (0.804 and 0.654), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (34.82 and 39.473), well below the concerning threshold of 60.

**BBB:** Ligand A (80.884) has a much higher BBB percentile than Ligand B (39.511). While SRC isn't a CNS target, higher BBB is generally a positive indicator of reduced off-target effects.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.37 and -4.872). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar.

**Aqueous Solubility:** Ligand A (-1.067) is better than Ligand B (-2.943), indicating slightly better solubility. Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.671 and 0.098), which is excellent.

**Microsomal Clearance:** Ligand A (3.428 mL/min/kg) has significantly lower microsomal clearance than Ligand B (36.458 mL/min/kg). This suggests much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (15.505 hours) has a significantly longer half-life than Ligand B (-14.898 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.057).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is the superior candidate. While both have good potency, Ligand A excels in ADME properties, particularly metabolic stability (lower Cl_mic, longer t1/2) and solubility. Its lower TPSA is also favorable. The slightly better BBB score is a bonus. The Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 12:22:26,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.399 Da) is slightly lower, which could be beneficial for permeability. Ligand B (382.473 Da) is also good.

**TPSA:** Ligand A (103.01) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (75.71) is excellent, well below 140, suggesting better absorption potential.

**logP:** Ligand A (0.572) is a bit low, potentially hindering permeation. Ligand B (1.471) 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 4 HBA, also acceptable and potentially slightly better due to fewer hydrogen bonds.

**QED:** Both ligands have acceptable QED scores (A: 0.722, B: 0.645), indicating good drug-like properties.

**DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (40.403). This is a major advantage for Ligand A.

**BBB:** Ligand B (89.298) has a much higher BBB penetration potential than Ligand A (38.852). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.145) has poor Caco-2 permeability. Ligand B (-4.924) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.553 and -2.718 respectively). This is a concern for both, but might be addressed through formulation.

**hERG Inhibition:** Ligand A (0.267) has a lower hERG inhibition liability than Ligand B (0.623), which is favorable.

**Microsomal Clearance:** Ligand A (-23.636) has a much lower microsomal clearance, indicating better metabolic stability, a key factor for kinase inhibitors. Ligand B (54.551) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (46.368) has a longer in vitro half-life than Ligand B (-30.928), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.013 and 0.105 respectively).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.1 and -7.0 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has better TPSA and BBB penetration (irrelevant here), Ligand A excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. The slightly lower logP and Caco-2 permeability of Ligand A are less concerning given its superior safety and pharmacokinetic profiles. The binding affinities are comparable, so the ADME advantages of Ligand A outweigh any minor differences in potency.

Output:
0
2025-04-17 12:22:26,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (355.385 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (75.44 and 74.33) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (2.517 and 1.633) within the optimal 1-3 range. Ligand B is slightly more hydrophilic.

**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 (5 HBA) in terms of permeability.

**6. QED:** Both ligands have acceptable QED scores (0.815 and 0.735), indicating good drug-like properties.

**7. DILI:** Ligand A (33.773 percentile) has a significantly lower DILI risk than Ligand B (22.722 percentile). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.763) has better BBB penetration than Ligand B (41.644), but it's not a primary concern.

**9. Caco-2 Permeability:** Ligand A (-4.338) has better Caco-2 permeability than Ligand B (-5.56).

**10. Aqueous Solubility:** Ligand A (-2.851) has better aqueous solubility than Ligand B (-0.799). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.378 and 0.207), which is good.

**12. Microsomal Clearance:** Ligand B (-17.009 mL/min/kg) has *much* lower microsomal clearance than Ligand A (48.914 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (6.069 hours) has a longer in vitro half-life than Ligand A (-23.382 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.024).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.1 and -8.0 kcal/mol). Ligand A has a 1.1 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has advantages in binding affinity, solubility, permeability, and DILI risk. However, Ligand B exhibits significantly better metabolic stability (lower Cl_mic and longer t1/2). Given that we are targeting a kinase (enzyme), metabolic stability is a crucial factor. The 1.1 kcal/mol affinity difference can potentially be overcome with further optimization, while poor metabolic stability is harder to fix later in development.

Output:
1
2025-04-17 12:22:26,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 349.377 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is higher than Ligand B (42.68). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Ligand A (2.231) is within the optimal 1-3 range. Ligand B (4.511) is slightly higher, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable.

**H-Bond Acceptors:** Both ligands have 3 HBAs, well within the limit of 10.

**QED:** Both ligands have similar QED values (0.824 and 0.815), indicating good drug-likeness.

**DILI:** Ligand A (36.022) has a lower DILI risk than Ligand B (56.572), which is a significant advantage.

**BBB:** Ligand A (63.358) has a lower BBB penetration than Ligand B (86.429). However, BBB is not a primary concern for SRC kinase inhibitors as SRC is not a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.376 and -4.337), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.501) has better aqueous solubility than Ligand B (-4.384). Solubility is important for bioavailability.

**hERG:** Ligand A (0.724) has a slightly better hERG profile than Ligand B (0.8). Lower is better.

**Microsomal Clearance:** Ligand A (54.594) has lower microsomal clearance than Ligand B (65.884), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.439) has a negative half-life, which is not possible. This is a major red flag. Ligand B (50.728) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.484) has lower P-gp efflux than Ligand B (0.7), which is favorable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has significantly better binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's better DILI, solubility, and P-gp efflux, the significantly superior binding affinity of Ligand B (-7.1 vs 0.0 kcal/mol) and its acceptable metabolic stability (half-life of 50.728) outweigh the slightly higher logP and DILI risk. The negative half-life for Ligand A is a critical flaw. The Caco-2 values are concerning for both, but the potency advantage of Ligand B is decisive.

Output:
1
2025-04-17 12:22:26,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.317 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (115.3 and 108.46) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (0.689 and 0.588) are a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 8 HBA, while Ligand B has 6. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.781) has a significantly better QED score than Ligand B (0.36), indicating a more drug-like profile.

**DILI:** Ligand A (72.547) has a higher DILI risk than Ligand B (35.285), which is concerning. However, the difference isn't extreme.

**BBB:** Both have reasonable BBB penetration (68.205 and 64.482), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-5.069 and -5.381), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Solubility:** Both have negative solubility values (-1.871 and -2.749), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG:** Ligand A (0.096) has a slightly lower hERG risk than Ligand B (0.556), which is preferable.

**Microsomal Clearance:** Ligand A (9.592) has a better (lower) microsomal clearance than Ligand B (-4.218). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (9.478) has a significantly longer in vitro half-life than Ligand B (-21.26). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.026).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol), with Ligand A being slightly better.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. It has a significantly better QED score, longer half-life, and slightly better affinity and hERG risk. The DILI risk is higher, but the improved metabolic stability and drug-likeness outweigh this concern, especially given the similar potency. The poor solubility and permeability would need to be addressed through formulation strategies. Ligand B's extremely negative half-life is a major red flag.

Output:
0
2025-04-17 12:22:26,297 - INFO - Batch 124 complete. Total preferences: 1984
2025-04-17 12:22:26,298 - INFO - Processing batch 125/512...
2025-04-17 12:23:04,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.434 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (75.71). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.842 and 1.336), falling within the 1-3 range.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Fewer HBDs generally improve permeability.

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

**QED:** Ligand A (0.766) has a better QED score than Ligand B (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (44.281) has a slightly higher DILI risk than Ligand B (32.067), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (84.529) has a higher BBB percentile than Ligand B (46.026).

**Caco-2 Permeability:** Ligand A (-4.134) is better than Ligand B (-4.678). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.266) is better than Ligand B (-2.588). Higher solubility is preferred.

**hERG:** Ligand A (0.745) has a better hERG profile than Ligand B (0.074), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (33.169) has significantly lower microsomal clearance than Ligand A (84.206), suggesting better metabolic stability. This is a key consideration for kinases.

**In vitro Half-Life:** Ligand B (3.571) has a longer half-life than Ligand A (-10.017). This is also a key consideration for kinases.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux than Ligand B (0.017). Lower efflux is generally preferred.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.6 and -7.5 kcal/mol). The difference of 0.1 kcal/mol is not substantial enough to outweigh other ADME considerations.

**Overall Assessment:**

Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2), which is crucial for kinase inhibitors. While Ligand A has better scores in several other areas (TPSA, QED, solubility, hERG), the improved metabolic stability of Ligand B is a more significant advantage for this target class.

Output:
1
2025-04-17 12:23:04,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (443.75 Da) is higher, but still acceptable. Ligand B (360.42 Da) is slightly preferred.

**TPSA:** Ligand A (66.48) is higher than Ligand B (49.41). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands have good logP values (A: 4.339, B: 3.117) within the optimal 1-3 range. A is slightly higher, potentially leading to off-target effects, but not drastically.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBAs, Ligand B has 2. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.764, B: 0.841), indicating good drug-like properties. B is slightly better.

**DILI:** This is a critical parameter. Ligand A has a high DILI risk (90.423%), while Ligand B has a very low risk (25.397%). This is a significant advantage for B.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (93.486%) is higher, but it's less important in this case.

**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 is a concern for both, but the scale is undefined.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.679, B: 0.605), which is good.

**Microsomal Clearance:** Ligand A (17.658) has lower clearance than Ligand B (19.768), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (78.287) has a significantly longer half-life than Ligand B (-12.69). This is a substantial advantage for A.

**P-gp Efflux:** Ligand A (0.526) has lower P-gp efflux than Ligand B (0.101), indicating better bioavailability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This is a good advantage for B, but not overwhelming.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life and lower P-gp efflux, the extremely high DILI risk associated with Ligand A is a major red flag. Ligand B has a much lower DILI risk, a slightly better binding affinity, and a better QED score. The solubility and Caco-2 values are concerning for both, but the DILI risk is the most critical factor here.

Output:
1
2025-04-17 12:23:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (98.98), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration if that were a consideration.

**logP:** Ligand A (3.001) is optimal (1-3), while Ligand B (-0.554) is below 1, which could hinder permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have reasonable QED scores (0.857 and 0.712), indicating good drug-like properties.

**DILI:** Ligand A (58.434) has a higher DILI risk than Ligand B (13.067). This is a concern for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand A (65.839) is slightly better than Ligand B (53.974). This isn't a primary concern for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-4.615) has poor Caco-2 permeability, while Ligand B (-5.34) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.844) has poor aqueous solubility, while Ligand B (-1.178) is also poor, but better.

**hERG:** Both ligands have very low hERG risk (0.151 and 0.142), which is excellent.

**Microsomal Clearance:** Ligand B (-32.261) has significantly lower microsomal clearance than Ligand A (55.206), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-11.797) has a longer in vitro half-life than Ligand A (-22.241), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.133 and 0.002), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent and strong enough to outweigh minor ADME concerns.

**Conclusion:**

While Ligand A has a better logP and slightly better BBB, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better solubility and Caco-2 permeability. The equal binding affinity makes the ADME properties the deciding factor. Given the enzyme-specific priorities, metabolic stability and reduced toxicity are paramount.

Output:
1
2025-04-17 12:23:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly preferred due to being lower in weight.

**2. TPSA:** Ligand A (83.98) is well below the 140 threshold for oral absorption, and good for kinase inhibitors. Ligand B (104.81) is still acceptable, but less optimal.

**3. logP:** Ligand A (1.605) is within the optimal range (1-3). Ligand B (0.272) 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 4 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 similar QED values (0.584 and 0.516), indicating good drug-like properties.

**7. DILI:** Ligand A (52.617) has a lower DILI risk than Ligand B (60.954), making it more favorable.

**8. BBB:** Both have similar BBB penetration (around 53%), which isn't a primary concern for a systemic oncology drug.

**9. Caco-2 Permeability:** Ligand A (-4.798) has better Caco-2 permeability than Ligand B (-5.571), suggesting better absorption.

**10. Aqueous Solubility:** Ligand A (-3.133) has better aqueous solubility than Ligand B (-2.865), important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.079) has a lower hERG inhibition liability than Ligand B (0.181), which is crucial for avoiding cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (15.5 mL/min/kg) has significantly lower microsomal clearance than Ligand B (64.008 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.303 hours) has a much longer in vitro half-life than Ligand B (-30.841 hours), which is highly desirable for less frequent dosing.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.022).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.3 kcal/mol). While both are good, the 1.6 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties (solubility, permeability, metabolic stability, DILI, hERG) and has a slightly better binding affinity. Ligand B's lower logP is a concern, and its significantly higher clearance and shorter half-life are major drawbacks. Given the enzyme-kinase target class, metabolic stability and potency are paramount.

Output:
0
2025-04-17 12:23:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.465 and 352.381 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is better than Ligand B (50.8), both are under the 140 threshold for oral absorption.

**logP:** Ligand A (3.44) is optimal, while Ligand B (1.798) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (1), both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4), both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.72 and 0.821), indicating good drug-like properties.

**DILI:** Ligand A (47.034) has a slightly higher DILI risk than Ligand B (39.201), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (94.378 and 83.094), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.763) is worse than Ligand B (-4.458), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.336) is worse than Ligand B (-2.676), indicating lower solubility.

**hERG Inhibition:** Ligand A (0.887) has a slightly higher hERG risk than Ligand B (0.352), but both are reasonably low.

**Microsomal Clearance:** Ligand B (30.963) has significantly lower microsomal clearance than Ligand A (60.908), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-0.001) has a significantly longer half-life than Ligand A (-32.534). This is a major advantage.

**P-gp Efflux:** Ligand A (0.531) has lower P-gp efflux than Ligand B (0.061), indicating better bioavailability.

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

**Conclusion:**

While Ligand A has a slightly better logP and lower P-gp efflux, Ligand B is superior due to its significantly improved metabolic stability (lower Cl_mic) and longer in vitro half-life. These factors are crucial for an enzyme inhibitor, as they determine how long the drug remains active in the body. The slightly lower solubility and permeability of Ligand B are less concerning than the faster clearance of Ligand A.

Output:
1
2025-04-17 12:23:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (347.455 and 347.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.63) is well below the 140 threshold, suggesting good absorption. Ligand B (129.03) is also below the threshold, but higher than A.

**3. logP:** Ligand A (3.248) is within the optimal range (1-3). Ligand B (0.129) is significantly below this range, which could hinder permeability.

**4. H-Bond Donors:** Ligand A (1) is within the acceptable limit of <=5. Ligand B (3) is also within the limit.

**5. H-Bond Acceptors:** Ligand A (4) is within the acceptable limit of <=10. Ligand B (7) is also within the limit.

**6. QED:** Both ligands have acceptable QED values (0.733 and 0.681, both >= 0.5).

**7. DILI:** Ligand A (29.43) has a much lower DILI risk than Ligand B (71.268), indicating a safer profile.

**8. BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (70.531) has a higher BBB percentile than Ligand B (18.147).

**9. Caco-2 Permeability:** Ligand A (-3.972) has a better Caco-2 permeability than Ligand B (-5.512).

**10. Aqueous Solubility:** Ligand A (-3.756) has better aqueous solubility than Ligand B (-2.867).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.335 and 0.064).

**12. Microsomal Clearance:** Ligand A (90.715) has a higher microsomal clearance than Ligand B (-5.27). This suggests that Ligand B is metabolically more stable.

**13. In vitro Half-Life:** Ligand B (-27.52) has a significantly longer in vitro half-life than Ligand A (4.88).

**14. P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux than Ligand B (0.012).

**15. Binding Affinity:** Ligand B (-7.9) has a significantly stronger binding affinity than Ligand A (-6.2). This is a substantial advantage.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much stronger binding affinity, a longer half-life, and better metabolic stability. While Ligand A has better solubility and lower DILI risk, the significant advantage in binding affinity of Ligand B outweighs these factors.

Output:
1
2025-04-17 12:23:04,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 351.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is better than Ligand B (80.12). Both are below 140, suggesting reasonable absorption.

**logP:** Both ligands (1.127 and 1.291) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 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 similar QED values (0.827 and 0.803), indicating good drug-likeness.

**DILI:** Ligand A (20.706) has a slightly higher DILI risk than Ligand B (19.504), but both are well below the concerning threshold of 60.

**BBB:** Both have high BBB penetration (81.698 and 88.135), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.145) is worse than Ligand B (-5.07), indicating lower intestinal absorption.

**Solubility:** Ligand A (-1.929) is better than Ligand B (-1.683), suggesting better aqueous solubility.

**hERG:** Ligand A (0.383) has a lower hERG risk than Ligand B (0.081), which is a significant advantage.

**Microsomal Clearance:** Ligand A (35.958) has higher microsomal clearance than Ligand B (-1.597), suggesting lower metabolic stability. This is a key negative for Ligand A.

**In vitro Half-Life:** Ligand A (-6.896) has a shorter half-life than Ligand B (-1.556), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux than Ligand B (0.024), which is a slight advantage.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Conclusion:**

While Ligand A has better solubility and a lower hERG risk, Ligand B is superior due to its significantly higher binding affinity and better metabolic stability (lower Cl_mic and longer half-life). The stronger binding affinity is the most critical factor for an enzyme inhibitor, and the improved metabolic stability will likely translate to better *in vivo* exposure.

Output:
1
2025-04-17 12:23:04,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 360.445 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (98.14) is slightly higher than the preferred <140, but acceptable. Ligand B (49.85) is excellent, well below 140.

**logP:** Both ligands (1.29 and 2.054) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good.

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

**QED:** Both ligands have reasonable QED scores (0.751 and 0.623), 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 20.861, a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (50.523) and Ligand B (90.074) are not particularly relevant here, but 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 ligands have negative solubility values, suggesting poor solubility. Again, the scale is undefined.

**hERG Inhibition:** Ligand A (0.151) shows very low hERG inhibition risk, which is excellent. Ligand B (0.695) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (35.469 and 35.065 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (7.219 hours) compared to Ligand A (-4.208 hours). This is a substantial advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux, which is favorable. Ligand B (0.195) has slightly higher efflux, but still reasonable.

**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. A difference of >7 kcal/mol is extremely significant and can outweigh many other drawbacks.

**Conclusion:**

Despite the questionable Caco-2 and solubility values for both, Ligand B is the far superior candidate. Its significantly stronger binding affinity, lower DILI risk, and longer half-life outweigh the slightly higher hERG risk and P-gp efflux. The binding affinity difference is so large that it overrides the concerns about the other parameters.

Output:
1
2025-04-17 12:23:04,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (356.463 and 354.466 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.89) is slightly above the preferred <140, but acceptable. Ligand B (58.64) is well within the acceptable range.

**3. logP:** Both ligands have logP values within the optimal range (1.069 and 2.44).

**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 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.604 and 0.681), indicating good drug-like properties.

**7. DILI:** Ligand A (27.453) has a significantly lower DILI risk than Ligand B (10.469). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for an oncology target, but Ligand B (94.455) shows higher BBB penetration than Ligand A (72.237).

**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 and requires further investigation. The magnitude is similar.

**11. hERG Inhibition:** Ligand A (0.214) exhibits a lower hERG inhibition liability than Ligand B (0.678), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (36.318) has a slightly higher microsomal clearance than Ligand B (32.814), indicating potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.276) has a significantly longer in vitro half-life than Ligand A (-3.24). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux liability than Ligand B (0.275), which is a positive attribute.

**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 crucial advantage, as a >1.5 kcal/mol difference can outweigh other concerns.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, hERG inhibition, and P-gp efflux, the substantially stronger binding affinity of Ligand B (-8.9 vs -6.5 kcal/mol) and its longer half-life are critical for an enzyme target. The difference in binding affinity is significant enough to potentially overcome the slightly higher DILI risk and P-gp efflux. The negative solubility and Caco-2 values for both are concerning and would require further investigation, but the potency advantage of Ligand B is compelling.

Output:
1
2025-04-17 12:23:04,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.443 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.07) is slightly higher than Ligand B (58.64), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.357) is at the upper end of the optimal range (1-3), while Ligand B (2.691) is comfortably within it.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 6 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.715 and 0.856), indicating drug-like properties.

**DILI:** Ligand B (40.83) has a significantly lower DILI risk than Ligand A (54.556), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (65.413 and 64.948), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.03) has a worse Caco-2 permeability than Ligand B (-4.488), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.414 and -3.255), which is concerning. However, this is a relative scale, and the difference isn't huge.

**hERG Inhibition:** Ligand A (0.813) has a slightly higher hERG risk than Ligand B (0.443), which is preferable.

**Microsomal Clearance:** Ligand B (52.7) has a lower microsomal clearance than Ligand A (54.619), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.841) has a significantly longer in vitro half-life than Ligand A (60.531), which is a substantial benefit.

**P-gp Efflux:** Ligand A (0.693) has a slightly higher P-gp efflux liability than Ligand B (0.274).

**Binding Affinity:** Ligand B (-9.1) has a substantially stronger binding affinity than Ligand A (-6.0). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have acceptable physicochemical properties, Ligand B demonstrates a significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The improved binding affinity is the most important factor, given the enzyme-specific priorities.

Output:
1
2025-04-17 12:23:04,904 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.338 and 363.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (114.09) is slightly above the preferred <140, but acceptable. Ligand B (72.48) is well within the ideal range.

**logP:** Ligand A (1.613) is optimal. Ligand B (3.465) is also within the optimal range, but approaching the upper limit.

**H-Bond Donors:** Both ligands have 2 HBDs, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBAs, acceptable. Ligand B has 5 HBAs, also acceptable.

**QED:** Both ligands have good QED scores (0.786 and 0.859), indicating good drug-like properties.

**DILI:** Ligand A (79.992) has a higher DILI risk than Ligand B (54.478). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (89.027) shows better BBB penetration than Ligand A (64.87), but this isn't a primary factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.578 and -4.905), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.211 and -4.08), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG:** Both ligands have low hERG inhibition liability (0.299 and 0.399), which is excellent.

**Microsomal Clearance:** Ligand B (40.012) has significantly lower microsomal clearance than Ligand A (61.279), suggesting better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand B (47.904) has a longer half-life than Ligand A (17.718), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.147), which is good.

**Binding Affinity:** Ligand B (-9.6 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 threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.6 vs -8.0 kcal/mol), lower DILI risk (54.478 vs 79.992), and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the similar P-gp and hERG profiles. The poor solubility and permeability would need to be addressed through formulation or structural modifications, but the superior potency and safety profile of Ligand B make it the better starting point for optimization.

Output:
1
2025-04-17 12:23:04,904 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.415 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.26) is slightly higher than Ligand B (83.56). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (1.756 and 1.681), 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 5 HBA, which is within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.678 and 0.629), indicating good drug-likeness.

**7. DILI:** Ligand A (55.37) has a slightly higher DILI risk than Ligand B (49.283), but both are reasonably low and below the concerning threshold of 60.

**8. BBB:** Both ligands have acceptable BBB penetration (67.235 and 62.117), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Both have negative values (-5.275 and -4.826), indicating poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative values (-2.908 and -2.137), indicating poor solubility. This is also a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.336) shows slightly higher hERG inhibition liability than Ligand B (0.505). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand B (36.867) has lower microsomal clearance than Ligand A (46.152), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (40.775) has a significantly longer in vitro half-life than Ligand A (25.327), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.074 and 0.049).

**15. Binding Affinity:** This is the most critical factor. Ligand B (-7.2 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This >1.5 kcal/mol difference is substantial and outweighs the minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B's significantly stronger binding affinity, lower microsomal clearance, and longer half-life make it a much more promising starting point for further optimization. The slightly better hERG profile and lower DILI risk are additional benefits.

Output:
1
2025-04-17 12:23:04,904 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.382 and 351.491 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.33) is slightly higher than Ligand B (78.51). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Ligand A (-0.246) is quite low, potentially hindering permeability. Ligand B (1.692) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.763 and 0.685), indicating good drug-like properties.

**DILI:** Ligand A (72.741) has a higher DILI risk than Ligand B (12.214). This is a substantial negative for Ligand A.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (75.262) has a slightly better score than Ligand B (56.65).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.055 and -5.021), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.944 and -1.389), indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.349 and 0.329).

**Microsomal Clearance:** Ligand A (-1.532) has a *much* lower (better) microsomal clearance than Ligand B (6.191). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (6.95) has a better in vitro half-life than Ligand B (-16.57).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.057).

**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 for Ligand A, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from a low logP and higher DILI risk. Ligand B has a better logP and significantly lower DILI risk, but weaker binding affinity and poorer metabolic stability.

The binding affinity difference is substantial (-8.9 vs -7.5 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. While the solubility and logP of Ligand A are concerning, these issues can sometimes be addressed through formulation or prodrug strategies. The DILI risk is also a concern, but potentially mitigatable with further optimization. The significantly improved potency of Ligand A outweighs the ADME liabilities, especially considering the potential for further optimization.

Output:
0
2025-04-17 12:23:04,904 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.543 and 385.291 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (53.76 and 55.57) well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (3.596 and 4.464) within the optimal 1-3 range, although Ligand B is slightly higher.

**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 HBA, both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.592 and 0.628), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (35.944 and 39.511), below the 40 threshold.

**8. BBB:** Both have reasonable BBB penetration (67.933 and 75.378), but this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.96 and -4.645), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-2.627 and -3.774). This is a major drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.886 and 0.751).

**12. Microsomal Clearance:** Ligand A has a higher Cl_mic (92.805) than Ligand B (83.096), suggesting faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (43.758 hours) compared to Ligand A (76.541 hours). This is a substantial advantage.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.62 and 0.615).

**15. Binding Affinity:** Ligand B has a slightly better binding affinity (-8.2 kcal/mol) than Ligand A (-8.0 kcal/mol).

**Overall Assessment:**

Both compounds have significant issues with solubility and Caco-2 permeability. However, Ligand B is preferable due to its longer half-life and slightly better binding affinity. The lower microsomal clearance of Ligand B is also beneficial. While both have poor solubility, the longer half-life of Ligand B could potentially offset some of the bioavailability issues.

Output:
1
2025-04-17 12:23:04,905 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.519 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is better than Ligand B (69.48), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.618 and 2.548), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (0 HBD, 6 HBA) regarding the number of hydrogen bond donors and acceptors, both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.662 and 0.647), indicating good drug-likeness.

**DILI:** Ligand A (8.918 percentile) has a significantly lower DILI risk than Ligand B (42.691 percentile). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration (76.58 and 80.496 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual. However, the absolute value for Ligand A (-4.895) is more negative than Ligand B (-4.287), suggesting potentially lower permeability for A.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. The absolute value for Ligand A (-2.342) is better than Ligand B (-3.514) suggesting better solubility for A.

**hERG:** Both ligands have low hERG inhibition liability (0.393 and 0.359), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (36.889 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (85.921 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-3.769 hours) has a better (less negative) in vitro half-life than Ligand B (-17.913 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.4).

**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 only 0.3 kcal/mol, and the other advantages of Ligand A likely outweigh this.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and a better in vitro half-life. While Ligand B has slightly better binding affinity, the difference is small and is offset by the superior ADME properties of Ligand A.

Output:
0
2025-04-17 12:23:04,905 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.361 and 355.341 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.56) is slightly higher than Ligand B (87.74). Both are below the 140 threshold for good oral absorption, but Ligand B is closer to the 90 threshold for CNS penetration (though that's not a priority here).

**logP:** Ligand A (-0.671) is a bit low, potentially hindering permeability. Ligand B (0.061) is better, falling within the optimal 1-3 range, but still on the lower end.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 8 HBAs, while Ligand B has 4. Both are acceptable (<=10), but Ligand B is preferable.

**QED:** Both ligands have good QED scores (0.689 and 0.724), indicating drug-like properties.

**DILI:** Ligand A (55.68) has a slightly higher DILI risk than Ligand B (46.452), but both are below the concerning 60 threshold.

**BBB:** This isn't a high priority for a kinase inhibitor, but Ligand A (78.364) has better BBB penetration than Ligand B (63.358).

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.942 and -4.922). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.865 and -2.643). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.45 and 0.202), which is excellent.

**Microsomal Clearance:** Ligand A (-7.839) has a lower (better) microsomal clearance than Ligand B (-7.354), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.204) has a longer half-life than Ligand B (-35.316), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.01), which is good.

**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.

**Conclusion:**

While Ligand A has slightly better metabolic stability and half-life, the significantly stronger binding affinity of Ligand B (-9.3 vs -7.9 kcal/mol) is the deciding factor. The affinity difference is large enough to compensate for the slightly lower metabolic stability and solubility. Both have poor Caco-2 permeability and solubility, which would need to be addressed in further optimization, but potency is paramount for an enzyme inhibitor.

Output:
1
2025-04-17 12:23:04,905 - INFO - Batch 125 complete. Total preferences: 2000
2025-04-17 12:23:04,905 - INFO - Processing batch 126/512...
2025-04-17 12:23:47,146 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (98.56) is better than Ligand B (54.34), being closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (0.737) is a bit low, potentially hindering permeation. Ligand B (2.917) is within the optimal range (1-3). This favors Ligand B.

**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:** Ligand A (0.869) has a significantly better QED score than Ligand B (0.649), indicating a more drug-like profile.

**DILI:** Ligand A (58.511) has a higher DILI risk than Ligand B (32.183). This is a significant drawback for Ligand A.

**BBB:** Ligand A (50.523) and Ligand B (65.413) are both relatively low, but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.647) is significantly worse than Ligand B (-5.426), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.806) is worse than Ligand B (-2.575), indicating lower solubility.

**hERG:** Ligand A (0.171) has a lower hERG risk than Ligand B (0.801). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-10.254) has a much lower (better) microsomal clearance than Ligand B (74.353), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.022) has a shorter half-life than Ligand B (11.008), but both are reasonable.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is good. Ligand B (0.638) is higher, but still acceptable.

**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 is still a factor.

**Overall Assessment:**

Ligand A has a better QED, slightly better affinity, lower hERG risk, and significantly better metabolic stability (lower Cl_mic). However, it suffers from lower solubility, lower Caco-2 permeability, and a higher DILI risk. Ligand B has better logP and lower DILI, but worse QED, higher hERG, and significantly worse metabolic stability.

Given the enzyme-specific priorities, metabolic stability (Cl_mic) is crucial. The substantial difference in Cl_mic strongly favors Ligand A. The slightly better affinity also contributes. While the DILI risk is a concern, it's not as critical as poor metabolic stability, and could potentially be addressed through further optimization. The lower solubility and permeability are also concerns, but could be mitigated with formulation strategies.

Output:
0
2025-04-17 12:23:47,146 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.28 and 358.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.22) is well below the 140 threshold for good absorption. Ligand B (108.33) is still within acceptable limits, but less favorable.

**logP:** Ligand A (2.566) is optimal (1-3). Ligand B (-0.169) is below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher donors can sometimes impact permeability.

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also acceptable.

**QED:** Ligand A (0.793) is excellent, indicating strong drug-likeness. Ligand B (0.411) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (87.282) has a higher DILI risk, but is still below the concerning 60 threshold. Ligand B (21.287) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (94.184) has better BBB penetration than Ligand B (29.818).

**Caco-2:** Ligand A (-4.229) and Ligand B (-5.156) 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 is important. Without knowing the scale, it's hard to interpret.

**Solubility:** Ligand A (-4.842) and Ligand B (-0.827) both have negative solubility values, indicating poor solubility. Again, the scale is unknown.

**hERG:** Ligand A (0.344) has a low hERG risk. Ligand B (0.234) has even lower hERG risk, which is a major advantage.

**Cl_mic:** Ligand A (31.996) has a moderate clearance. Ligand B (-12.554) has a *negative* clearance, which is impossible. This is likely an error in the data, or a different unit. Assuming it's a percentile, it suggests extremely high metabolic stability.

**t1/2:** Ligand A (31.971) has a good in vitro half-life. Ligand B (8.524) has a shorter half-life, which is less desirable.

**Pgp:** Ligand A (0.194) has low Pgp efflux liability. Ligand B (0.02) has very low Pgp efflux liability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better safety profile (lower DILI and hERG) and potentially much better metabolic stability (indicated by the anomalous Cl_mic value). While Ligand A has slightly better affinity and BBB penetration, the issues with solubility and the higher DILI risk are concerning. The negative Cl_mic for Ligand B is a data anomaly that needs investigation, but even if it's a moderate value, the overall profile is more favorable. The poor solubility and Caco-2 values for both compounds are concerning and would need to be addressed in further optimization.

Output:
1
2025-04-17 12:23:47,146 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (346.471 and 363.845 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (67.43 and 67.6) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**3. logP:** Both ligands have logP values within the optimal range (3.521 and 2.751).

**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 (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.757 and 0.854), indicating drug-like properties.

**7. DILI:** Ligand A (28.383) has a significantly lower DILI risk than Ligand B (42.536). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration percentiles (76.968 and 77.821). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.254 and -4.861). 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. Without knowing the scale, it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.087 and -3.66). Similar to Caco-2, this requires understanding the scale.

**11. hERG Inhibition:** Ligand A (0.578) shows slightly higher hERG inhibition risk than Ligand B (0.352), but both are relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (85.576) has higher microsomal clearance than Ligand B (23.775), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand B (46.023) has a significantly longer in vitro half-life than Ligand A (4.283). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux than Ligand B (0.218), which is favorable.

**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 for Ligand A, potentially outweighing some ADME drawbacks.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Overall Assessment:**

Ligand A has a substantially better binding affinity (-8.1 vs -7.0 kcal/mol) and lower DILI risk. However, it has higher microsomal clearance and a shorter half-life. Ligand B has better metabolic stability and a longer half-life, but its binding affinity is weaker and its DILI risk is higher.

The significant difference in binding affinity favors Ligand A. While the metabolic stability is a concern, it might be addressable through structural modifications. The lower DILI risk is also a significant benefit. The negative Caco-2 and solubility values are concerning for both, and would need further investigation.

Output:
1
2025-04-17 12:23:47,146 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (403.972 Da) is also acceptable.

**TPSA:** Ligand A (82.11) is significantly better than Ligand B (40.54), falling well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.221) is quite low, potentially hindering permeation. Ligand B (4.608) is higher, approaching the upper limit where solubility issues could arise, but still within an acceptable 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 similar QED values (0.712 and 0.729), indicating good drug-like properties.

**DILI:** Ligand A (15.006) has a much lower DILI risk than Ligand B (38.62), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.309) has a higher BBB score, but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.916) has a negative Caco-2 value, indicating poor permeability. Ligand B (-5.061) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-0.567) has poor aqueous solubility. Ligand B (-5.507) is even worse. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.179) has a very low hERG risk, which is excellent. Ligand B (0.686) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-8.449) has a negative clearance, suggesting excellent metabolic stability. Ligand B (111.035) has a high clearance, indicating rapid metabolism, which is a significant negative.

**In vitro Half-Life:** Ligand A (16.05) has a reasonable half-life. Ligand B (-24.644) has a negative half-life, which is not physically possible and indicates a severe instability issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.015 and 0.493).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from significantly higher DILI risk, very poor solubility, and extremely high metabolic clearance/low half-life. Ligand A has better ADME properties (lower DILI, better metabolic stability, lower hERG), but its low logP and poor Caco-2 permeability are concerning, and its affinity is weaker.

Despite the superior affinity of Ligand B, the extremely poor metabolic stability and high DILI risk make it a less viable candidate. While the affinity is strong, the rapid metabolism will likely result in low *in vivo* exposure. Ligand A, while weaker in binding, has a far more favorable ADME profile. Further optimization of Ligand A to improve its logP and permeability would be a more promising strategy than attempting to fix the severe issues with Ligand B.

Output:
0
2025-04-17 12:23:47,146 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.463 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (71.11) is well within the acceptable range.

**logP:** Ligand A (0.386) is a bit low, potentially hindering permeability. Ligand B (0.977) is better, closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, fitting the <5 and <10 rules. Ligand B has 1 HBD and 5 HBA, also fitting the rules.

**QED:** Both ligands have good QED scores (0.693 and 0.737, respectively), indicating drug-like properties.

**DILI:** Ligand A (10.392) has a very low DILI risk, which is excellent. Ligand B (15.316) is also low, but higher than Ligand A.

**BBB:** Ligand A (46.84) has a low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (70.531) has good BBB penetration, but again, this is less critical for SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.607 and -4.93), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.267 and -1.047), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.372 and 0.147, respectively).

**Microsomal Clearance:** Ligand A (38.17 mL/min/kg) has a higher clearance than Ligand B (10.49 mL/min/kg), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (18.214 hours) has a significantly longer half-life than Ligand A (-11.73 hours, which is effectively zero). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.015 and 0.008, respectively).

**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 a positive for Ligand B.

**Overall:**

Ligand B is the better candidate. While both have issues with solubility and permeability, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and a lower DILI risk. The slightly better logP also suggests better permeability potential. The negative Caco-2 and solubility values are concerning for both, and would require significant medicinal chemistry effort to address, but Ligand B's other advantages make it the more promising starting point.

Output:
1
2025-04-17 12:23:47,146 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.451 and 348.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.19) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (-0.951) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.534) is within the optimal range.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 3. Both are within the acceptable limits (<=10).

**QED:** Both ligands have good QED scores (0.575 and 0.695, respectively), indicating drug-like properties.

**DILI:** Ligand A (8.414) has a much lower DILI risk than Ligand B (12.524). This is a significant advantage for Ligand A.

**BBB:** Ligand A (17.216) has a very low BBB penetration, while Ligand B (68.554) is reasonably good. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.623) has poor Caco-2 permeability, while Ligand B (-4.823) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (0.365) has very poor solubility, while Ligand B (-2.478) is also poor. This is a concern for both, but more so for Ligand A.

**hERG Inhibition:** Ligand A (0.026) has a very low hERG risk, a major advantage. Ligand B (0.298) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (2 mL/min/kg) has significantly lower microsomal clearance than Ligand B (21.737 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-14.617) has a very long half-life, while Ligand B (22.698) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, while Ligand B (0.112) has slightly higher 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 factor.

**Overall Assessment:**

Ligand A excels in metabolic stability (low Cl_mic, long t1/2), DILI risk, hERG risk, and P-gp efflux. However, it suffers from poor solubility, permeability, and a suboptimal logP. Ligand B has better solubility, permeability, and logP, but has a higher DILI risk, higher Cl_mic, and a slightly lower binding affinity.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, hERG), the superior metabolic stability and safety profile (DILI, hERG) of Ligand A outweigh its solubility and permeability concerns, especially given the relatively small difference in binding affinity. Further optimization of Ligand A could address its solubility and permeability issues.

Output:
0
2025-04-17 12:23:47,146 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.447 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (96.89 and 91.76) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.066) is quite low, potentially hindering permeation. Ligand B (1.605) is within the optimal 1-3 range. This favors Ligand B.

**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:** Ligand A (0.509) is slightly better than Ligand B (0.414), indicating a more drug-like profile.

**DILI:** Ligand A (18.883) has a significantly lower DILI risk than Ligand B (50.95). This is a substantial advantage for Ligand A.

**BBB:** This is less crucial for a non-CNS target like SRC, but Ligand A (57.968) is better than Ligand B (36.952).

**Caco-2 Permeability:** Both are negative (-5.333 and -5.472), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both are negative (-1.666 and -0.99), indicating poor aqueous solubility. This is a significant drawback for both, but slightly better for Ligand B.

**hERG Inhibition:** Ligand A (0.266) has a much lower hERG risk than Ligand B (0.332), which is a critical advantage.

**Microsomal Clearance:** Ligand A (18.841) has higher clearance than Ligand B (-7.488). This means Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (7.977) has a slightly longer half-life than Ligand B (5.844), which is a minor advantage.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.088), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol, so it's not decisive.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG inhibition, P-gp efflux, and binding affinity. Ligand B has advantages in logP and metabolic stability (Cl_mic). The poor solubility and Caco-2 permeability are concerning for both. However, the significantly lower DILI and hERG risk for Ligand A, combined with slightly better binding affinity, outweigh the benefits of Ligand B's slightly improved metabolic stability. The low logP of Ligand A is a concern, but can potentially be addressed with further optimization.

Output:
0
2025-04-17 12:23:47,146 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.335 and 337.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.57) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (63.13) is well within the optimal range.

**logP:** Both ligands (2.58 and 2.549) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.693 and 0.763), indicating drug-like properties.

**DILI:** Ligand A (85.692) has a higher DILI risk than Ligand B (52.772). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (66.111) is slightly better than Ligand B (36.409).

**Caco-2 Permeability:** Ligand A (-4.702) is better than Ligand B (-5.021), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.581) is better than Ligand B (-3.343), indicating better solubility.

**hERG:** Both ligands have low hERG risk (0.275 and 0.369), which is good.

**Microsomal Clearance:** Ligand A (77.973) has higher clearance than Ligand B (32.907), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (13.479) has a longer half-life than Ligand A (26.314). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.455 and 0.161).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B has a significantly stronger binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2). The stronger binding affinity is particularly important for an enzyme target like SRC kinase, and the lower DILI risk is a critical safety factor.

Output:
1
2025-04-17 12:23:47,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 377.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.36) is better than Ligand B (82.96), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.237) is optimal (1-3), while Ligand B (3.753) is approaching the upper limit.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (8), both are below the 10 threshold.

**QED:** Ligand A (0.68) is better than Ligand B (0.527), both are above the 0.5 threshold.

**DILI:** Ligand A (28.306) is significantly better than Ligand B (79.333). Ligand B is in the high-risk category (>60).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.97) is better than Ligand B (46.724).

**Caco-2:** Ligand A (-4.663) is better than Ligand B (-5.506), indicating better intestinal absorption.

**Solubility:** Ligand A (-2.198) is better than Ligand B (-3.498).

**hERG:** Ligand A (0.172) is much better than Ligand B (0.821), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (45.961) is significantly better than Ligand B (75.451), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.667) is less than Ligand B (85.226), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.139) is better than Ligand B (0.498), suggesting less efflux.

**Binding Affinity:** Ligand A (-7.6) is slightly better than Ligand B (-7.2), although the difference is relatively small.

**Overall:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties (DILI, hERG, Cl_mic, solubility, P-gp efflux) and has a slightly better binding affinity. While Ligand B has a longer in vitro half-life, the significantly higher DILI and hERG risk, coupled with poorer metabolic stability and solubility, make it a less desirable candidate. The small difference in binding affinity is outweighed by the substantial improvements in safety and pharmacokinetic properties offered by Ligand A.

Output:
0
2025-04-17 12:23:47,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.531 and 358.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.96) is higher than Ligand B (42.43). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good oral absorption.

**logP:** Both ligands have good logP values (3.205 and 3.656), falling within the optimal 1-3 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.

**QED:** Ligand A (0.856) has a higher QED score than Ligand B (0.677), indicating a more drug-like profile.

**DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (20.163). This is a significant negative for Ligand A.

**BBB:** Ligand A (89.104) has a moderate BBB penetration, whereas Ligand B (96.161) is higher. While not a primary concern for a kinase inhibitor, higher BBB is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.3) has worse Caco-2 permeability than Ligand B (-4.106). Lower (more negative) values suggest lower permeability.

**Aqueous Solubility:** Ligand A (-4.709) has worse aqueous solubility than Ligand B (-3.775). This is a crucial factor for bioavailability, and Ligand B is better.

**hERG Inhibition:** Ligand A (0.535) has slightly higher hERG inhibition risk than Ligand B (0.636), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.824) has significantly lower microsomal clearance than Ligand B (67.514), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (17.893) has a longer in vitro half-life than Ligand B (-6.615). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.038) has much lower P-gp efflux than Ligand B (0.215), indicating better absorption and potentially higher bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.7 kcal/mol), with Ligand A being slightly better. The difference is small and likely not decisive.

**Overall Assessment:**

Ligand B demonstrates a superior ADME profile, particularly with its significantly lower DILI risk, better solubility, and better Caco-2 permeability. While Ligand A has a slightly better affinity and metabolic stability, the higher DILI risk and poorer solubility are major drawbacks. The small affinity difference is outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 12:23:47,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 and 354.491 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is better than Ligand B (59.08), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.828) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.909) is within the ideal range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 threshold.

**QED:** Both ligands have similar and good QED values (A: 0.619, B: 0.639), indicating good drug-like properties.

**DILI:** Ligand A (12.369) has a significantly lower DILI risk than Ligand B (28.887). This is a major advantage for Ligand A.

**BBB:** Ligand B (77.627) has a higher BBB penetration percentile than Ligand A (47.344), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.07) has a worse Caco-2 permeability than Ligand B (-4.411), suggesting potentially lower absorption.

**Aqueous Solubility:** Ligand A (-1.97) has a slightly better aqueous solubility than Ligand B (-2.586).

**hERG Inhibition:** Ligand A (0.173) has a much lower hERG inhibition liability than Ligand B (0.637). This is a crucial advantage, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (16.113 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (67.16 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.54 hours) has a slightly longer half-life than Ligand B (-5.116 hours).

**P-gp Efflux:** Ligand A (0.063) has a lower P-gp efflux liability than Ligand B (0.231).

**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 significant.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability and BBB penetration, Ligand A excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, much lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a slightly better binding affinity. The lower DILI and hERG are particularly important for mitigating potential toxicity. The affinity difference is also substantial enough to outweigh the minor Caco-2 disadvantage.

Output:
1
2025-04-17 12:23:47,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Ligand A (87.74) is significantly better than Ligand B (108.47). Lower TPSA generally correlates with better absorption. Both are below the 140 threshold, but A is closer to the preferred <90 for CNS targets (though not a primary concern here).

**logP:** Ligand A (0.991) is slightly better than Ligand B (0.588). Both are acceptable, but ligand A is closer to the optimal 1-3 range. Ligand B is a bit low and might have permeability issues.

**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. Ligand A is preferable as it is closer to the ideal of <=10.

**QED:** Both ligands have similar QED values (0.637 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (30.826) has a much lower DILI risk than Ligand B (75.766). This is a significant advantage for Ligand A.

**BBB:** Ligand A (69.523) has better BBB penetration than Ligand B (53.625), though this isn't a primary concern for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-4.817) has better Caco-2 permeability than Ligand B (-5.009), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.039) has better aqueous solubility than Ligand B (-2.731). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.085 and 0.14), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (43.238 and 45.944), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (-15.487) has a slightly longer half-life than Ligand B (-19.638).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.033).

**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 substantial enough to outweigh the numerous advantages of Ligand A.

**Conclusion:**

Ligand A is significantly more promising due to its superior DILI risk, TPSA, logP, solubility, and Caco-2 permeability. While Ligand B has slightly better binding affinity, the difference is small and is overshadowed by the better ADME properties of Ligand A. Given the enzyme-specific priorities, the lower DILI risk and better solubility of Ligand A make it the more viable drug candidate.

Output:
1
2025-04-17 12:23:47,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.482 and 388.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, suggesting good absorption. Ligand B (139.1) is close to the upper limit, potentially impacting absorption, but still acceptable.

**logP:** Ligand A (2.272) is optimal (1-3). Ligand B (0.008) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is within the ideal range. Ligand B (HBD=3, HBA=9) is at the upper limit for HBA, which could affect permeability.

**QED:** Ligand A (0.681) is good, indicating drug-likeness. Ligand B (0.514) is acceptable, but less ideal than A.

**DILI:** Ligand A (15.355) has a very low DILI risk. Ligand B (83.986) has a significantly higher DILI risk, which is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.957) is reasonable, while Ligand B (22.528) is low.

**Caco-2 Permeability:** Ligand A (-4.745) is poor, suggesting low intestinal absorption. Ligand B (-5.751) is also poor.

**Aqueous Solubility:** Both ligands (-2.517 and -2.373) have poor aqueous solubility, which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.864) has a low hERG risk. Ligand B (0.201) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (26.529) has moderate clearance. Ligand B (20.513) has lower clearance, indicating better metabolic stability, which is a priority for enzymes.

**In vitro Half-Life:** Ligand A (0.717 hours) has a very short half-life. Ligand B (-27.909 hours) has a very long half-life, a significant advantage.

**P-gp Efflux:** Both ligands (0.201 and 0.061) have low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a superior binding affinity and a much lower DILI risk. However, its Caco-2 permeability and in vitro half-life are poor. Ligand B has better metabolic stability and a longer half-life, but its low logP, higher DILI risk, and weaker binding affinity are significant drawbacks. Considering the enzyme-specific priorities, the strong binding affinity of Ligand A is a critical factor that can potentially be optimized through further medicinal chemistry efforts to address its permeability and half-life issues. The high DILI risk of Ligand B is a major red flag.

Output:
0
2025-04-17 12:23:47,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 347.331 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is well below the 140 threshold and excellent for oral absorption. Ligand B (123.47) is still within acceptable limits but less favorable than A.

**logP:** Ligand A (1.923) is optimal (1-3). Ligand B (-0.684) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 8 HBA) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar and good QED values (0.656 and 0.658), indicating good drug-like properties.

**DILI:** Ligand A (11.051) has a much lower DILI risk than Ligand B (69.019). This is a significant advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (80.574) shows better penetration than Ligand B (48.003).

**Caco-2 Permeability:** Ligand A (-4.258) is better than Ligand B (-4.947), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.805) is better than Ligand B (-2.057), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.49) has a much lower hERG risk than Ligand B (0.032), a critical safety parameter.

**Microsomal Clearance:** Ligand A (40.189) has higher clearance than Ligand B (28.832), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-28.733) has a significantly longer half-life than Ligand A (-0.897), which is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.104 and 0.053).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), a 0.6 kcal/mol difference. This is a notable advantage for Ligand B, but not overwhelming.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, solubility, DILI, hERG) and has good Caco-2 permeability. However, it suffers from higher microsomal clearance and a shorter half-life.

Ligand B has a slightly better binding affinity and a significantly longer half-life, but it has poorer solubility, higher DILI risk, and a concerningly low logP. The higher TPSA is also less desirable.

Considering the priorities for enzyme inhibitors, the superior ADME profile of Ligand A, particularly the significantly lower DILI and hERG risk, outweighs the slightly weaker binding affinity. The metabolic stability issue of Ligand A could be addressed through structural modifications, whereas the solubility and DILI issues of Ligand B are more challenging to fix without significantly impacting potency.

Output:
0
2025-04-17 12:23:47,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (347.419 Da and 364.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.35 and 108.56) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.064) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (1.275) is within the optimal range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7 HBA, both within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.777 and 0.799), indicating good drug-likeness.

**DILI:** Ligand A (43.389) has a lower DILI risk than Ligand B (61.807), which is a significant advantage.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

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

**Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility, a major drawback.

**hERG:** Both ligands have very low hERG inhibition risk (0.065 and 0.063).

**Microsomal Clearance:** Ligand A (-11.987) exhibits much lower (better) microsomal clearance than Ligand B (4.795), suggesting significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (13.748 hours) has a longer half-life than Ligand B (23.874 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.051).

**Binding Affinity:** Both ligands have similar binding affinities (-8.8 and -8.9 kcal/mol), indicating comparable potency.

**Overall Assessment:**

While both compounds have similar potency, Ligand A is superior due to its significantly lower DILI risk and much better metabolic stability (lower Cl_mic). The poor solubility and Caco-2 permeability are concerns for both, but the metabolic advantage of Ligand A is crucial for an enzyme target. The slightly better logP of Ligand B is offset by the higher DILI and poorer metabolic stability.

Output:
0
2025-04-17 12:23:47,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight (MW):** Both ligands (348.378 and 367.877 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.23) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (65.64) is well within the optimal range.

**3. logP:** Both ligands have logP values within the optimal range (Ligand A: 1.805, Ligand B: 2.548).

**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 within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (Ligand A: 0.875, Ligand B: 0.869), indicating good drug-like properties.

**7. DILI:** Ligand A (52.889) has a slightly higher DILI risk than Ligand B (35.324), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (87.088) shows better BBB penetration than Ligand B (71.501), but this is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Ligand A (-4.554) has a lower (worse) Caco-2 permeability than Ligand B (-4.735).

**10. Aqueous Solubility:** Ligand A (-3.515) has slightly better aqueous solubility than Ligand B (-3.308).

**11. hERG Inhibition:** Ligand A (0.394) has a lower hERG inhibition liability than Ligand B (0.578), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (29.873) has a higher microsomal clearance than Ligand B (10.418), indicating lower metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (-38.491) has a much shorter in vitro half-life than Ligand B (0.729), suggesting faster metabolism.

**14. P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux than Ligand B (0.141), which is beneficial.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a crucial factor for enzyme inhibitors.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in binding affinity and has significantly better metabolic stability (lower Cl_mic, longer t1/2) than Ligand A. While Ligand A has slightly better hERG inhibition, the substantial advantage in binding affinity and metabolic stability of Ligand B outweighs this minor difference.

Output:
1
2025-04-17 12:23:47,148 - INFO - Batch 126 complete. Total preferences: 2016
2025-04-17 12:23:47,148 - INFO - Processing batch 127/512...
2025-04-17 12:24:26,220 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.402 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.59) is better than Ligand B (84.23), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (3.562 and 2.803, respectively), 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 and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.749 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 59.442, which is approaching the higher risk threshold (>60), while Ligand B has a much lower DILI risk of 25.397, which is excellent. This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (61.962) and Ligand B (46.646) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.486 and -4.954). These values are unusual and suggest poor permeability. However, these are relative values and hard to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.038 and -2.499). Similar to Caco-2, these are relative values and suggest poor solubility. Ligand B is slightly better.

**hERG:** Ligand A (0.674) has a slightly higher hERG risk than Ligand B (0.097). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (72.783) has a higher microsomal clearance than Ligand B (19.158), indicating lower metabolic stability. Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A (4.971) has a longer half-life than Ligand B (1.629). This is a positive for Ligand A, but the difference isn't huge.

**P-gp Efflux:** Ligand A (0.361) has lower P-gp efflux liability than Ligand B (0.056), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and strong 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 is the better candidate. While Ligand A has a slightly longer half-life and lower P-gp efflux, Ligand B demonstrates significantly better safety profiles with a much lower DILI risk and hERG inhibition liability. Furthermore, Ligand B has better metabolic stability (lower Cl_mic). The similar binding affinities make the ADMET advantages of Ligand B decisive.

Output:
1
2025-04-17 12:24:26,220 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.424 and 376.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.33) is significantly better than Ligand B (84.94).  A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (4.22) is higher than the optimal 1-3 range, while Ligand B (1.14) is on the lower side.  High logP can cause issues, but in this case, the difference in binding affinity may outweigh this concern.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better than Ligand B (1 HBD, 5 HBA) as it has a more balanced profile.

**QED:** Ligand A (0.766) has a better QED score than Ligand B (0.578), indicating a more drug-like profile.

**DILI:** Ligand B (25.204) has a much lower DILI risk than Ligand A (46.297), which is a significant advantage.

**BBB:** Both have acceptable BBB penetration, but Ligand B (75.611) is better than Ligand A (57.619). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 concerning. Ligand B (-1.802) is slightly better than Ligand A (-4.173).

**hERG:** Ligand A (0.737) has a slightly better hERG profile than Ligand B (0.578), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (23.321) has significantly lower microsomal clearance than Ligand A (69.735), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-26.63) has a negative half-life, which is problematic. Ligand A (19.648) is positive, indicating a reasonable half-life.

**P-gp Efflux:** Ligand B (0.096) has lower P-gp efflux than Ligand A (0.774), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a *much* stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. A difference of >7 kcal/mol is highly significant.

**Overall Assessment:**

Despite Ligand B's advantages in DILI, metabolic stability, and P-gp efflux, the dramatically superior binding affinity of Ligand A (-9.6 vs 0.0 kcal/mol) is the deciding factor. The potency difference is so large that it likely outweighs the concerns regarding its slightly higher logP, TPSA, and DILI risk. The negative solubility and Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 12:24:26,220 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.471 and 364.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.37) is better than Ligand B (53.33), being under the 140 threshold for oral absorption.

**logP:** Ligand A (2.617) is optimal (1-3), while Ligand B (4.123) is pushing the upper limit and could present solubility issues.

**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 reasonable QED values (0.752 and 0.661), indicating good drug-like properties.

**DILI:** Ligand A (58.123) has a slightly higher DILI risk than Ligand B (47.654), but both are below the concerning threshold of 60.

**BBB:** Ligand A (49.205) has lower BBB penetration than Ligand B (80.574). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.761) and Ligand B (-4.508) have similar, very low Caco-2 permeability values. This is a concern for both compounds.

**Aqueous Solubility:** Ligand A (-2.006) is better than Ligand B (-4.462), indicating better solubility.

**hERG:** Ligand A (0.227) has a significantly lower hERG risk than Ligand B (0.885), which is a major advantage.

**Microsomal Clearance:** Ligand A (24.034) has a much lower microsomal clearance than Ligand B (105.97), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.757) has a longer half-life than Ligand B (5.715), which is desirable.

**P-gp Efflux:** Ligand A (0.026) has much lower P-gp efflux than Ligand B (0.361), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.3) has a stronger binding affinity than Ligand A (-7.0), a difference of 1.3 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates significantly better ADMET properties, particularly regarding metabolic stability (Cl_mic, t1/2), hERG risk, and P-gp efflux. The higher affinity of Ligand B might be overcome with further optimization, but the poor ADMET profile presents significant hurdles. The combination of reasonable potency and substantially improved drug-like properties makes Ligand A the more promising candidate.

Output:
0
2025-04-17 12:24:26,220 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.439 Da and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.42) is better than Ligand B (112.48), both are acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.477) is within the optimal 1-3 range. Ligand B (-0.262) is below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

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

**QED:** Ligand A (0.895) has a significantly better QED score than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand B (38.62) has a much lower DILI risk than Ligand A (75.766), which is a significant advantage.

**BBB:** Ligand A (75.107) has a better BBB penetration score than Ligand B (14.541), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.865) has a worse Caco-2 permeability than Ligand B (-5.459), but both are negative and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-2.955) has better aqueous solubility than Ligand B (-1.256), which is important for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.219 and 0.1 respectively).

**Microsomal Clearance:** Ligand B (1.641) has significantly lower microsomal clearance than Ligand A (11.673), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (19.028) has a longer in vitro half-life than Ligand A (-26.729), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.085 and 0.006 respectively).

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-6.8), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and QED score, Ligand B demonstrates superior ADMET properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and solubility. The lower logP of Ligand B is a concern, but the significantly improved metabolic stability and reduced toxicity risk outweigh this drawback for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:24:26,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.419 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.55) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (89.95) is excellent, well below 140.

**logP:** Ligand A (-0.069) is a bit low, potentially hindering permeation. Ligand B (0.758) 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 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.569 and 0.736), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (39.046 and 32.299), which is favorable.

**BBB:** Both have low BBB penetration (21.171 and 26.367), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.522 and -4.797). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.507 and -1.642). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.076 and 0.258), which is excellent.

**Microsomal Clearance:** Ligand A has a low Cl_mic (1.75 mL/min/kg), indicating good metabolic stability. Ligand B has a much higher Cl_mic (38.885 mL/min/kg), suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A has a poor in vitro half-life (-7.591 hours). Ligand B has a better, but still concerning, half-life (-12.062 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.02 and 0.025).

**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 some ADME concerns.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.5 vs -7.3 kcal/mol) is a major advantage for an enzyme target. Furthermore, while both have poor metabolic stability, Ligand A's clearance is lower than Ligand B's, but the difference in binding affinity is more critical. The low hERG risk for both is a significant positive. Addressing the solubility and permeability issues through formulation or prodrug strategies would be crucial for further development.

Output:
1
2025-04-17 12:24:26,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.443 and 351.422 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is better than Ligand B (93.45), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.059 and 1.623), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within reasonable limits.

**QED:** Ligand A (0.817) has a significantly better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Ligand B (44.087) has a lower DILI risk than Ligand A (64.909), which is a significant advantage.

**BBB:** Ligand B (82.862) has a higher BBB penetration potential than Ligand A (52.268), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.09) is slightly better than Ligand B (-4.834).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.298) is slightly better than Ligand B (-3.042).

**hERG Inhibition:** Ligand A (0.355) has a lower hERG inhibition liability than Ligand B (0.603), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (19.987) has a lower microsomal clearance than Ligand B (33.007), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.721) has a significantly longer in vitro half-life than Ligand B (0.73), which is a major advantage.

**P-gp Efflux:** Ligand A (0.118) has lower P-gp efflux liability than Ligand B (0.052), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.5) has a better binding affinity than Ligand A (-9.2). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.5 kcal/mol vs -9.2 kcal/mol). However, Ligand A demonstrates superior drug-like properties (QED, metabolic stability, half-life, hERG) and a lower DILI risk. While the affinity difference is notable, the improved ADMET profile of Ligand A, particularly the lower hERG risk and better metabolic stability, makes it a more promising starting point for drug development. The poor solubility and permeability of both compounds would need to be addressed through further optimization, but Ligand A's better baseline characteristics provide a stronger foundation.

Output:
0
2025-04-17 12:24:26,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.511 and 369.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.64) is well below the 140 threshold for oral absorption, and even better for kinase inhibitors. Ligand B (80.76) is still acceptable but less optimal.

**logP:** Both ligands (1.539 and 1.934) are within the optimal 1-3 range.

**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 (0.773 and 0.794), indicating drug-like properties.

**DILI:** Ligand A (7.91) has a significantly lower DILI risk than Ligand B (53.742). This is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (78.364) has a better BBB score than Ligand B (48.585), but this isn't a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.031) is slightly better than Ligand B (-4.821), but both are concerning.

**Aqueous Solubility:** Ligand A (-0.034) has slightly better solubility than Ligand B (-2.272). Solubility is important for bioavailability.

**hERG:** Ligand A (0.664) has a much lower hERG risk than Ligand B (0.298). This is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-7.856) has a much lower (better) microsomal clearance than Ligand B (24.963), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (32.918) has a longer half-life than Ligand B (17.309), which is desirable.

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.127), suggesting better oral bioavailability.

**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 meaningful.

**Conclusion:**

Ligand A is significantly superior to Ligand B. It has a much lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have concerning Caco-2 permeability values, the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 12:24:26,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (336.443 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.56) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.87) is still under 140, but less optimal than A.

**logP:** Ligand A (2.923) is within the optimal 1-3 range. Ligand B (1.583) is also acceptable, but closer to the lower limit, potentially impacting permeability.

**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 (0.717 and 0.788), indicating drug-like properties.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (12.641). This is a significant drawback for Ligand A.

**BBB:** Both ligands have high BBB penetration (81.466 and 83.831), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.073) has poor Caco-2 permeability, while Ligand B (-4.399) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-3.457) has poor aqueous solubility, and Ligand B (-2.181) is also low. Both are concerning.

**hERG Inhibition:** Ligand A (0.607) has a slightly higher hERG risk than Ligand B (0.272), which is preferable.

**Microsomal Clearance:** Ligand A (58.104) has higher microsomal clearance than Ligand B (47.125), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (24.592) has a longer half-life than Ligand B (-0.706), which is a positive.

**P-gp Efflux:** Ligand A (0.758) has higher P-gp efflux than Ligand B (0.021), which is less desirable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having a longer half-life, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.3 vs -6.1 kcal/mol) is a major advantage for an enzyme target like SRC. Furthermore, Ligand B demonstrates a much lower DILI risk and lower P-gp efflux, and better hERG inhibition. While both have poor solubility and Caco-2 permeability, the potency and safety profile of Ligand B make it the better choice for further optimization.

Output:
1
2025-04-17 12:24:26,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.439 and 344.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.67) is slightly higher than the preferred <140, but acceptable. Ligand B (78.43) is well within the acceptable range.

**logP:** Both ligands (1.58 and 1.83) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable, being less than 10.

**QED:** Ligand A (0.779) has a significantly better QED score than Ligand B (0.404), indicating a more drug-like profile.

**DILI:** Ligand A (57.658) has a higher DILI risk than Ligand B (29.43), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (43.311) has a slightly higher BBB score than Ligand A (36.371).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.395) is slightly better than Ligand B (-4.813), but both are problematic.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand B (-2.54) is slightly better than Ligand A (-1.422), but both are concerning.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.149 and 0.224), which is excellent.

**Microsomal Clearance:** Ligand A (-1.099) has a negative clearance, which is excellent and indicates high metabolic stability. Ligand B (34.564) has a high clearance, indicating poor metabolic stability. This is a major drawback.

**In vitro Half-Life:** Ligand A (22 hours) has a much longer half-life than Ligand B (-19.607 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.062 and 0.269), which is favorable.

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, its poor metabolic stability (high Cl_mic, negative half-life) and poor solubility are major concerns. Ligand A has a better overall ADME profile (better QED, metabolic stability, half-life) despite a weaker binding affinity. Given the enzyme-specific priorities, metabolic stability and solubility are crucial. The 1.4 kcal/mol difference in binding affinity, while significant, may be overcome with further optimization of Ligand A. The poor Caco-2 and solubility of both are concerning and would require formulation strategies. However, the better ADME profile of Ligand A makes it the more promising starting point for further development.

Output:
0
2025-04-17 12:24:26,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is higher than Ligand B (49.41). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.154 and 3.215), falling within the 1-3 range. Ligand B is slightly higher, potentially improving membrane permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.61 and 0.795), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have similar DILI risk (35.324 and 35.983), both are below the 40 threshold and therefore have low risk.

**BBB:** Ligand B (71.772) has a better BBB percentile than Ligand A (52.772), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.659 and -4.438). These values are unusual and likely indicate poor permeability *in vitro*. However, these values are on a scale where higher is better, so the less negative value is better. Ligand B is slightly better here.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.546 and -3.953). Similar to Caco-2, these values are unusual and likely indicate poor solubility. The less negative value is better, so Ligand B is slightly better here.

**hERG:** Both ligands have low hERG risk (0.121 and 0.449).

**Microsomal Clearance:** Ligand A (12.065 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (41.896 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-5.554 hours) has a negative half-life, which is unusual. Ligand B (-12.423 hours) also has a negative half-life. These values are likely errors or represent a very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.026 and 0.088).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has slightly better scores for some ADME properties (logP, QED, Caco-2, Solubility, BBB), Ligand A stands out due to its significantly lower microsomal clearance, indicating better metabolic stability. Given that we are targeting an enzyme (SRC kinase), metabolic stability is a critical factor. The similar binding affinities make the ADME profile the deciding factor.

Output:
0
2025-04-17 12:24:26,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.397 Da) is slightly lower, which could be advantageous for permeability. Ligand B (374.434 Da) is also good.

**TPSA:** Ligand A (58.95) is excellent, well below the 140 threshold for oral absorption. Ligand B (92.78) is still reasonable, but less optimal.

**logP:** Ligand A (3.891) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.732) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is very favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly higher HBA count.

**QED:** Both ligands have similar QED values (A: 0.861, B: 0.741), indicating good drug-like properties.

**DILI:** Ligand A (56.185) has a slightly higher DILI risk than Ligand B (47.421), but both are below the concerning threshold of 60.

**BBB:** Ligand A (83.986) has better BBB penetration potential than Ligand B (62.35), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.578) shows poor Caco-2 permeability. Ligand B (-4.329) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-5.154) has very poor aqueous solubility. Ligand B (-2.208) is also poor, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.435, B: 0.332).

**Microsomal Clearance:** Ligand A (43.532) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (49.455).

**In vitro Half-Life:** Ligand A (40.433) has a longer in vitro half-life than Ligand B (0.206), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.22, B: 0.076).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This difference of 0.5 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's better metabolic stability and slightly lower DILI risk, Ligand B's significantly stronger binding affinity (-8.4 vs -7.9 kcal/mol) is the deciding factor. The improved potency is crucial for an enzyme target like SRC kinase. While Ligand B has lower logP and Caco-2 permeability, these can potentially be addressed through further optimization without sacrificing the strong binding affinity. Ligand A's poor solubility is a major concern.

Output:
1
2025-04-17 12:24:26,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (383.25 and 348.531 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is better than Ligand B (58.2), both are acceptable but A is closer to the ideal <140 for oral absorption.

**logP:** Both ligands have good logP values (3.968 and 3.793), 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=2) as it has fewer HBDs, which can be beneficial for permeability. Both are within acceptable limits.

**QED:** Ligand A (0.813) has a higher QED score than Ligand B (0.688), indicating a more drug-like profile.

**DILI:** Ligand B (27.685) has a significantly lower DILI risk than Ligand A (66.421). This is a major advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (70.841 and 71.539), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.31 and -4.679). This is unusual and suggests poor permeability. It's likely these are logP-scaled values where negative values indicate low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.101 and -4.778). This is also unusual and suggests poor aqueous solubility.

**hERG:** Ligand A (0.569) has a slightly higher hERG risk than Ligand B (0.351), though both are relatively low.

**Microsomal Clearance:** Ligand B (63.466) has a lower microsomal clearance than Ligand A (74.937), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.624) has a negative half-life, which is not possible. This is likely an error or a scaled value indicating very rapid degradation. Ligand A (41.018) has a much better half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.151 and 0.237).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.8 kcal/mol), which is the most important factor. The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand B appears to be a more promising drug candidate. Its significantly lower DILI risk and better metabolic stability (lower Cl_mic) are crucial advantages. While the negative Caco-2 and solubility values are concerning, the strong binding affinity might compensate for these issues with appropriate formulation strategies. The half-life for Ligand B is suspect due to the negative value, but even if it's a low positive value, Ligand A still has a much better half-life. The slightly better QED score of Ligand A is not enough to offset the higher DILI risk and lower metabolic stability.

Output:
1
2025-04-17 12:24:26,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.414 and 346.406 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (75.19). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have good logP values (2.787 and 1.78), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (3 & 4) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar and good QED scores (0.878 and 0.852), indicating good drug-likeness.

**DILI:** Both ligands have very similar and acceptable DILI risk (35.944 and 35.479 percentile), well below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (88.949 and 82.513 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.696) has a worse Caco-2 permeability than Ligand B (-4.872), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.651) has slightly better aqueous solubility than Ligand B (-2.061). Solubility is important for bioavailability.

**hERG:** Ligand A (0.944) has a lower hERG inhibition liability than Ligand B (0.11), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (15.201 mL/min/kg) has a much lower microsomal clearance than Ligand B (25.871 mL/min/kg), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-1.162 hours) has a slightly worse in vitro half-life than Ligand B (3.138 hours).

**P-gp Efflux:** Ligand B (0.014) has a lower P-gp efflux liability than Ligand A (0.312), which could improve bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.4 kcal/mol), and the difference is negligible.

**Overall Assessment:**

Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic) and lower hERG risk. While Ligand B has slightly better Caco-2 permeability and P-gp efflux, the improved safety and pharmacokinetic profile of Ligand A outweigh these minor advantages for an enzyme target like SRC kinase. The difference in half-life is also less concerning than the potential for cardiotoxicity or rapid metabolism.

Output:
0
2025-04-17 12:24:26,222 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.49 Da and 347.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (88.39 and 84.66) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (1.886 and 2.434) within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values (0.748 and 0.672) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (69.252) has a higher DILI risk than Ligand B (43.971). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (81.233) has a higher BBB percentile than Ligand A (53.664), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.414 and -4.646), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.391 and -3.643) which is also unusual and suggests poor solubility. This is a red flag for both.

**hERG Inhibition:** Ligand A (0.191) has a lower hERG inhibition liability than Ligand B (0.664), which is favorable.

**Microsomal Clearance:** Ligand A (78.167) has a higher microsomal clearance than Ligand B (65.87), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-29.14) has a significantly longer in vitro half-life than Ligand A (30.252), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.096).

**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:**

Ligand B is the more promising candidate. Despite similar MW, logP, HBD, HBA, QED, and P-gp efflux, it has a significantly better in vitro half-life, lower DILI risk, and slightly better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh these drawbacks. The lower hERG risk of Ligand A is a positive, but the higher DILI and lower half-life are more critical concerns for an enzyme target.

Output:
1
2025-04-17 12:24:26,222 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.853 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.25 and 75.19) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (which would require <90).

**logP:** Both ligands (2.927 and 2.719) 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 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.622 and 0.859), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 91.082, which is high. Ligand B has a much lower DILI risk of 25.048, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration (35.169 and 72.082). Since SRC is not a CNS target, this is not a major concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.037 and -4.871). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading, and are less important than other ADME properties.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.509 and -1.848). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.285 and 0.205), which is good.

**Microsomal Clearance:** Ligand A has a Cl_mic of 17.369 mL/min/kg, while Ligand B has a Cl_mic of 14.453 mL/min/kg. Lower is better, so Ligand B has a slight advantage in metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 31.972 hours, while Ligand B has a t1/2 of -0.791 hours. This is a *major* difference. A negative half-life is highly unusual and indicates very rapid metabolism.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.252 and 0.015), which is favorable.

**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 less than the 1.5 kcal/mol threshold to outweigh other issues, it's still a positive.

**Conclusion:**

Despite the similar MW, logP, TPSA, and H-bond properties, Ligand B is significantly better. The major advantages of Ligand B are its much lower DILI risk and better metabolic stability (lower Cl_mic). The primary drawback of Ligand B is its extremely short in vitro half-life, but this is a property that can be addressed with structural modifications. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 12:24:26,222 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.487 and 363.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is better than Ligand B (54.79), both are below the 140 threshold for oral absorption.

**3. logP:** Ligand A (2.751) is optimal, while Ligand B (4.027) is approaching the upper limit and could potentially cause solubility issues.

**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 within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.501 and 0.735, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (40.364), which is a major advantage. Ligand B is approaching a moderate risk.

**8. BBB:** Both have high BBB penetration, but Ligand A (89.88) is slightly better than Ligand B (80.69). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.655) has better Caco-2 permeability than Ligand B (-4.821).

**10. Aqueous Solubility:** Ligand A (-2.481) has better aqueous solubility than Ligand B (-4.328). This is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.602) has a slightly better hERG profile than Ligand B (0.473), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (66.685) has a slightly better microsomal clearance than Ligand B (66.159).

**13. In vitro Half-Life:** Ligand A (-15.544) has a significantly longer in vitro half-life than Ligand B (20.308). This is a crucial advantage for dosing frequency.

**14. P-gp Efflux:** Ligand A (0.296) has lower P-gp efflux than Ligand B (0.626), which is beneficial for bioavailability.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -0.0 kcal/mol respectively). However, Ligand B has a much better affinity.

**Overall Assessment:**

Ligand A is generally superior in terms of ADME properties (DILI, solubility, half-life, P-gp efflux, and Caco-2 permeability). Ligand B has a better binding affinity. However, the substantial advantage in ADME properties, particularly the significantly lower DILI risk and longer half-life of Ligand A, outweigh the affinity difference. While a 1.5 kcal/mol advantage in binding is usually significant, the other factors make Ligand A the more promising candidate.

Output:
0
2025-04-17 12:24:26,222 - INFO - Batch 127 complete. Total preferences: 2032
2025-04-17 12:24:26,222 - INFO - Processing batch 128/512...
2025-04-17 12:25:06,395 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (380.279 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.43) is significantly better than Ligand B (80.32). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.715) is slightly higher than Ligand B (2.373), both within the optimal 1-3 range.

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

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

**QED:** Ligand B (0.727) has a higher QED score than Ligand A (0.464), indicating better overall drug-likeness.

**DILI:** Ligand B (41.877) has a much lower DILI risk than Ligand A (64.754). This is a significant advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration, but Ligand A (65.607) is slightly higher than Ligand B (53.974). This is not a major concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.163) has better Caco-2 permeability than Ligand B (-4.834). Higher values are better.

**Aqueous Solubility:** Ligand A (-3.553) has better aqueous solubility than Ligand B (-2.187). Higher values are better.

**hERG Inhibition:** Ligand A (0.724) has a slightly higher hERG risk than Ligand B (0.16). Lower is better, making Ligand B preferable.

**Microsomal Clearance:** Ligand B (22.716) has significantly lower microsomal clearance than Ligand A (93.208), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (16.055) has a longer in vitro half-life than Ligand A (44.447). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.512) has lower P-gp efflux than Ligand B (0.091), which is better.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While a 1.5 kcal/mol difference is significant, the other ADME properties of Ligand B are more favorable.

**Overall Assessment:**

Ligand B demonstrates a superior ADME profile, particularly regarding metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG inhibition. While Ligand A has slightly better binding affinity and Caco-2 permeability, the substantial advantages of Ligand B in key ADME parameters outweigh this difference. The slightly weaker binding of Ligand B can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 12:25:06,395 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (78.67) is slightly higher than Ligand B (75.94), but both are acceptable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.051) is closer to the lower end, while Ligand B (2.058) is more central. This isn't a major differentiating factor.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 6 respectively). This is within acceptable limits for both.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand B (0.642) is slightly better than Ligand A (0.506).

**DILI:** Ligand A (28.499) has a significantly lower DILI risk than Ligand B (49.244). This is a substantial advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (56.611) has a slightly higher BBB penetration, but it's not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.104 for A, -5.34 for B).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-0.319) is slightly better than Ligand B (-1.662), but both are problematic.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.2 and 0.54 respectively), which is excellent.

**Microsomal Clearance:** Ligand B (18.619 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (34.748 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (58.234 hours) has a much longer in vitro half-life than Ligand A (22.946 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.134 and 0.153 respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.5 kcal/mol). Ligand B is slightly better (-8.5 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A has a clear advantage in DILI risk and slightly better solubility. However, Ligand B excels in metabolic stability (lower Cl_mic and longer t1/2) and has a marginally better binding affinity. Given that we are targeting a kinase (enzyme), metabolic stability is a critical factor. The lower DILI risk of Ligand A is attractive, but the substantial improvement in metabolic stability with Ligand B outweighs this benefit. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:25:06,395 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.435 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.55) is slightly above the preferred <140, but acceptable. Ligand B (75.27) is well within the range, and more favorable for absorption.

**logP:** Both ligands have acceptable logP values (0.936 and 1.559), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which is acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable, and potentially slightly better for permeability.

**QED:** Both ligands have reasonable QED scores (0.706 and 0.624), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 56.146, which is moderate but acceptable. Ligand B has a significantly lower DILI risk of 15.626, a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (87.476) has a higher BBB score, but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.809 and -5.047), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.529), indicating very poor aqueous solubility, a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.265 and 0.183), which is excellent.

**Microsomal Clearance:** Ligand A (4.813 mL/min/kg) has a lower microsomal clearance than Ligand B (8.162 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (-39.019 hours) than Ligand B (26.766 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.014), which is good.

**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 less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and permeability, Ligand B has a significantly lower DILI risk, a better logP, and a slightly better binding affinity. The improved metabolic stability of Ligand A is a plus, but the lower DILI risk of Ligand B outweighs this benefit. 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 12:25:06,395 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.479 Da and 349.41 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands are below the 140 A^2 threshold (89.95 and 79.26), suggesting good absorption potential.

**logP:** Ligand A (0.756) is slightly better than Ligand B (0.446). Both are a bit low, potentially impacting permeability, but not drastically.

**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 within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.705 and 0.731), indicating good drug-likeness.

**DILI:** Ligand A (12.524) has a significantly lower DILI risk than Ligand B (39.434). This is a major advantage for Ligand A.

**BBB:** Ligand A (18.457) has a very low BBB penetration, while Ligand B (76.735) has good BBB penetration. However, since SRC is not a CNS target, BBB is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.144 and -4.934). These are unusual and suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.811 and -1.432). These are also unusual and suggest poor solubility.

**hERG:** Ligand A (0.114) has a much lower hERG risk than Ligand B (0.426). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (12.406) has a higher microsomal clearance than Ligand B (3.561), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-11.267) has a longer in vitro half-life than Ligand A (-9.162), indicating better stability. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.045).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 2.2 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has advantages in DILI and hERG risk, which are crucial for enzyme inhibitors. However, it suffers from higher microsomal clearance and lower binding affinity. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and significantly better binding affinity, despite a higher DILI and hERG risk. The binding affinity difference is substantial. Given the enzyme target class, the potency advantage of Ligand B is likely to be more important than the slightly increased risk of DILI and hERG inhibition, especially considering that these risks can be further mitigated during lead optimization. The solubility and permeability issues are concerning for both, but can also be addressed during optimization.

Output:
1
2025-04-17 12:25:06,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.371 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.88) is higher than the preferred <140, but acceptable. Ligand B (40.62) is excellent, well below 90, suggesting better permeability.

**logP:** Both ligands have good logP values (2.177 and 3.697), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 2 HBA, which is also acceptable and might contribute to better permeability.

**QED:** Both ligands have good QED scores (0.673 and 0.734), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 84.374, which is high and concerning. Ligand B has a much lower DILI risk of 17.759, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (91.276) than Ligand A (40.326), but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.473) and Ligand B (-4.348) both have negative values, which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.226 and -4.166). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.162) shows a slightly higher risk of hERG inhibition than Ligand B (0.555), although both are relatively low.

**Microsomal Clearance:** Ligand A (-1.692) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (92.253) has a high clearance, indicating rapid metabolism, which is a significant drawback.

**In vitro Half-Life:** Ligand A (-9.887) has a negative half-life, which is also unusual and suggests extremely long half-life. Ligand B (36.82) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.06 and 0.324).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand B is the more promising candidate. The primary reason is the significantly lower DILI risk (17.759 vs 84.374). While Ligand A has better metabolic stability and half-life (though the negative values are suspect and require further investigation), the high DILI risk is a major red flag. Ligand B's lower TPSA also suggests better permeability, and its hERG risk is slightly lower. The higher clearance of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 12:25:06,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is slightly above the preferred <140, but acceptable. Ligand B (82.11) is well within the ideal range.

**logP:** Both ligands (-0.483 and -0.247) are a bit low, potentially hindering permeability. However, they are not excessively low.

**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 good QED scores (0.544 and 0.59), indicating good drug-like properties.

**DILI:** Ligand A (52.191) has a moderate DILI risk, while Ligand B (6.592) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration (27.491 and 19.969), which is not a major concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.56 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 (-1.001 and -1.281). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.022) has a very low hERG risk, while Ligand B (0.201) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (4.866) has a moderate microsomal clearance, while Ligand B (-0.126) has a *very* low (and favorable) clearance. This suggests Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A (24.017 hours) has a reasonable half-life, while Ligand B (10.824 hours) is shorter, though still potentially acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.009).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a crucial advantage, as a 1.4 kcal/mol difference is substantial.

**Conclusion:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the superior candidate. It has a significantly better binding affinity, a much lower DILI risk, and substantially improved metabolic stability (lower Cl_mic). The slightly shorter half-life of Ligand B is less concerning than the other advantages it possesses. The improved affinity likely outweighs the permeability concerns, and formulation strategies can be explored to address the solubility issue.

Output:
1
2025-04-17 12:25:06,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.5 and 346.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is higher than Ligand B (49.85). While both are acceptable, Ligand B's lower TPSA is slightly preferable for permeability.

**logP:** Both ligands have good logP values (0.929 and 2.505), falling within the optimal 1-3 range. Ligand B is slightly better.

**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 (0.687 and 0.789), indicating good drug-like properties.

**DILI:** Ligand A (17.84) has a significantly lower DILI risk than Ligand B (34.35). This is a major advantage for Ligand A.

**BBB:** Ligand B (91.43) has a much higher BBB penetration score than Ligand A (57.93). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.45) has worse Caco-2 permeability than Ligand B (-4.37), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.467 and -2.673). This is a concern for both, but needs to be balanced against other factors.

**hERG:** Both ligands have very low hERG inhibition risk (0.086 and 0.553). This is excellent for both.

**Microsomal Clearance:** Ligand A (12.7) has lower microsomal clearance than Ligand B (54.6), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-14.7) has a longer in vitro half-life than Ligand B (-11.95), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.376).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic and longer t1/2). While Ligand B has slightly better Caco-2 permeability and a higher BBB score (irrelevant here), the improved safety and pharmacokinetic profile of Ligand A outweigh these minor advantages. The similar binding affinities make the ADME/Tox differences the deciding factor.

Output:
1
2025-04-17 12:25:06,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.358 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (80.32) is slightly lower than Ligand B (83.98), which is marginally favorable.

**logP:** Ligand A (3.101) is within the optimal range (1-3), while Ligand B (1.871) is at the lower end. A slightly higher logP is generally preferred for kinases to aid cell permeability, giving Ligand A an edge.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6. Lower HBA counts are generally preferred for better permeability, making Ligand A slightly better.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.878) is slightly better than Ligand B (0.785).

**DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (49.864). This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Both are around 60-65, which is not particularly high or low.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.442) is slightly better than Ligand B (-5.717).

**Aqueous Solubility:** Ligand A (-5.359) has slightly better solubility than Ligand B (-2.945), but both are quite poor.

**hERG Inhibition:** Ligand A (0.478) has a lower hERG risk than Ligand B (0.088), which is a significant advantage.

**Microsomal Clearance:** Ligand B (30.334 mL/min/kg) has significantly lower microsomal clearance than Ligand A (68.444 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (4.955 hours) has a slightly longer half-life than Ligand A (33.424 hours). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.31) has lower P-gp efflux than Ligand B (0.079), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.0 kcal/mol). This is a crucial advantage, as a 2.9 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has some advantages in logP, solubility, and hERG, Ligand B's significantly stronger binding affinity (-8.9 vs -6.0 kcal/mol) and much better metabolic stability (lower Cl_mic and longer half-life) are critical for an enzyme target like SRC kinase. The lower DILI risk for Ligand B is also a significant benefit. The poor Caco-2 values are a concern for both, but can be addressed through formulation strategies.



Output:
1
2025-04-17 12:25:06,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (366.483 and 366.414 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (86.71 and 85.36) are below 140, suggesting good oral absorption potential.

**3. logP:** Ligand A (0.707) is a bit low, potentially hindering permeation. Ligand B (1.584) is 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 (5) and Ligand B (6) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have a high QED (0.801 and 0.809), indicating good drug-like properties.

**7. DILI:** Ligand A (9.616) has a very low DILI risk, significantly better than Ligand B (75.029), which is considered high risk. This is a major advantage for Ligand A.

**8. BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand B (82.164) has better BBB penetration than Ligand A (54.478).

**9. Caco-2 Permeability:** Ligand A (-5.383) and Ligand B (-4.624) both have negative values, which is unusual. Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-1.675) and Ligand B (-3.071) both have negative values, suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.28) has a very low hERG risk, whereas Ligand B (0.629) is slightly higher.

**12. Microsomal Clearance:** Ligand A (-9.849) has significantly lower (better) microsomal clearance than Ligand B (35.862), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (6.539) has a shorter half-life than Ligand B (28.533). While longer is generally preferred, the difference isn't massive.

**14. P-gp Efflux:** Ligand A (0.056) has very low P-gp efflux, while Ligand B (0.144) has slightly higher efflux.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.3 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better logP and in vitro half-life, Ligand A excels in critical areas: significantly lower DILI risk, much better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. The binding affinity difference is minimal. Given the enzyme-specific priorities, the improved safety and pharmacokinetic profile of Ligand A make it the more viable drug candidate.

Output:
0
2025-04-17 12:25:06,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.435 and 371.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.87) is better than Ligand B (118.84), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.978) is slightly better than Ligand B (0.485), both being on the lower side of the optimal 1-3 range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is preferable to Ligand B (1 HBD, 6 HBA). Both are within acceptable limits.

**QED:** Ligand A (0.827) has a significantly better QED score than Ligand B (0.288), indicating a more drug-like profile.

**DILI:** Ligand B (33.075) has a much lower DILI risk than Ligand A (52.617), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (60.644) is better than Ligand B (30.554).

**Caco-2 Permeability:** Both are negative (-5.543 and -5.196), suggesting poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative (-2.574 and -1.327), indicating poor aqueous solubility, which is a concern for bioavailability. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.049) has a lower hERG inhibition risk than Ligand B (0.132), which is a positive.

**Microsomal Clearance:** Both have similar microsomal clearance (14.135 and 14.37 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-13.922) has a much longer in vitro half-life than Ligand B (-2.362), which is a significant advantage for dosing frequency.

**P-gp Efflux:** Both have low P-gp efflux liability (0.067 and 0.024).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, BBB, and in vitro half-life, Ligand B's significantly stronger binding affinity (-8.6 vs -7.9 kcal/mol) and lower DILI risk are crucial advantages for an enzyme target like SRC kinase. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The stronger binding of Ligand B suggests it may be more potent and require a lower dose, potentially mitigating some of the solubility issues.

Output:
1
2025-04-17 12:25:06,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.507 Da and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.1) is well below the 140 threshold and very favorable. Ligand B (78.43) is still under the threshold, but less optimal than A.

**logP:** Ligand A (0.584) is a bit low, potentially hindering permeability. Ligand B (1.876) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher than ideal.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also good.

**QED:** Both ligands (0.728 and 0.584) have acceptable QED values, indicating reasonable drug-likeness.

**DILI:** Ligand A (3.373) has a very low DILI risk, which is excellent. Ligand B (14.424) is higher, indicating a moderate risk, but still within acceptable limits.

**BBB:** Ligand A (78.868) has good BBB penetration, while Ligand B (67.08) is lower. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.783) has poor Caco-2 permeability, which is a significant concern. Ligand B (-4.939) is similarly poor.

**Aqueous Solubility:** Ligand A (-0.051) has slightly better solubility than Ligand B (-2.559).

**hERG Inhibition:** Ligand A (0.527) has a lower hERG risk than Ligand B (0.26). Both are acceptable.

**Microsomal Clearance:** Ligand A (-10.221) has *very* low microsomal clearance, suggesting excellent metabolic stability. Ligand B (18.77) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-10.867) has a very long in vitro half-life, consistent with its low clearance. Ligand B (-2.802) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.063) is slightly higher, but still low.

**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 minor ADME drawbacks.

**Conclusion:**

Despite Ligand A's low logP and Caco-2 permeability, its significantly superior binding affinity (-8.6 vs -7.5 kcal/mol), excellent metabolic stability (very low Cl_mic and long t1/2), low DILI risk, and low P-gp efflux make it the more promising candidate. The strong binding affinity is a key advantage for an enzyme target like SRC kinase. While permeability is a concern, it might be addressed through formulation strategies. Ligand B has better logP, but its weaker binding, higher DILI, and faster metabolism are less desirable.

Output:
0
2025-04-17 12:25:06,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (372.877 and 364.555 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.22) is slightly higher than Ligand B (42.43). Both are acceptable, being below 140, but B is preferable.

**3. logP:** Both ligands have similar logP values (4.633 and 4.167), slightly above the optimal 1-3 range. This could potentially lead to solubility issues, but is not a major concern at this stage.

**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 (0.71 and 0.771), indicating good drug-like properties.

**7. DILI:** Ligand A (78.247) has a significantly higher DILI risk than Ligand B (37.611). This is a major concern for Ligand A.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (65.18) has a higher BBB value than Ligand A (29.275), but this is less important.

**9. Caco-2 Permeability:** Ligand A (-4.942) has slightly better Caco-2 permeability than Ligand B (-4.711), suggesting better absorption.

**10. Aqueous Solubility:** Ligand A (-5.382) has slightly better aqueous solubility than Ligand B (-4.527), which is a positive attribute.

**11. hERG Inhibition:** Ligand A (0.443) has a slightly lower hERG inhibition risk than Ligand B (0.822), which is preferable.

**12. Microsomal Clearance:** Ligand B (71.946) has a higher microsomal clearance than Ligand A (59.653), indicating lower metabolic stability. This is a negative for Ligand B.

**13. In vitro Half-Life:** Ligand B (31.426) has a much longer in vitro half-life than Ligand A (-0.034), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.455) has lower P-gp efflux than Ligand B (0.573), which is preferable.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This difference of 0.5 kcal/mol is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has better binding affinity, solubility, Caco-2 permeability, hERG, and P-gp efflux. However, it has a substantially higher DILI risk. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The difference in binding affinity (0.5 kcal/mol) is important, but the significantly lower DILI risk of Ligand B is a critical factor for drug development. Given the enzyme-kinase focus, metabolic stability and safety (DILI) are paramount.

Output:
1
2025-04-17 12:25:06,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.123 Da) is slightly higher, but acceptable. Ligand B (352.435 Da) is good.

**TPSA:** Ligand A (59.29) is excellent, well below the 140 threshold for oral absorption. Ligand B (91.07) is still reasonable, but approaching the upper limit.

**logP:** Ligand A (3.369) is optimal. Ligand B (-0.093) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is within acceptable limits. Ligand B (HBD=2, HBA=7) is also acceptable, though slightly higher in HBA.

**QED:** Both ligands have good QED scores (A: 0.401, B: 0.765), indicating reasonable drug-likeness. Ligand B is significantly better.

**DILI:** Ligand A (94.765) has a very high DILI risk, which is a major concern. Ligand B (15.51) has a very low DILI risk, a significant advantage.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (76.658) is better than Ligand B (43.001).

**Caco-2 Permeability:** Ligand A (-4.403) is poor, indicating low intestinal absorption. Ligand B (-5.204) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.516) is very poor. Ligand B (-0.003) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.516) has a moderate hERG risk. Ligand B (0.208) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (52.588) has moderate clearance. Ligand B (-51.293) has negative clearance, which is very good, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (64.186) has a reasonable half-life. Ligand B (13.257) has a short half-life, which is a drawback.

**P-gp Efflux:** Ligand A (0.574) has moderate P-gp efflux. Ligand B (0.014) has very low P-gp efflux, a significant advantage.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has significantly better binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage (1.4 kcal/mol difference).

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk, poor solubility, and poor Caco-2 permeability are major red flags. Ligand B, while having a slightly lower affinity, exhibits a much more favorable ADME profile: low DILI and hERG risk, excellent metabolic stability (negative Cl_mic), and low P-gp efflux. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand B, whereas mitigating the severe liabilities of Ligand A would be far more challenging. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 12:25:06,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is better than Ligand B (82.53). Both are below 140, suggesting good absorption potential.

**logP:** Both ligands have logP values (2.396 and 2.748) 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) as it has fewer H-bond donors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.733 and 0.743), indicating good drug-likeness.

**DILI:** Ligand A (39.899) has a significantly lower DILI risk than Ligand B (47.693), which is a crucial advantage. Both are below the concerning threshold of 60.

**BBB:** Ligand A (69.678) has a better BBB percentile than Ligand B (36.371), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.509) has a more favorable Caco-2 permeability value than Ligand B (-5.441), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.617) has better aqueous solubility than Ligand B (-3.491). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.499 and 0.618), which is good.

**Microsomal Clearance:** Ligand A (37.834) has significantly lower microsomal clearance than Ligand B (83.084), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.55 hours) has a much longer half-life than Ligand B (-19.987 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.229 and 0.202).

**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 potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADMET properties, particularly in terms of DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life. For an enzyme target like SRC kinase, metabolic stability and a reasonable half-life are critical for maintaining therapeutic concentrations. The lower DILI risk is also a major benefit. The affinity difference, while notable, isn't so large that it completely overrides the significant advantages of Ligand A's ADMET profile.

Output:
0
2025-04-17 12:25:06,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.427 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (50.6) is significantly better than Ligand B (89.87). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 1.479, B: 1.862) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 5 HBA). Lower HBD is generally preferred.

**QED:** Ligand A (0.846) has a much better QED score than Ligand B (0.586), indicating a more drug-like profile.

**DILI:** Ligand A (38.93) has a lower DILI risk than Ligand B (19.193), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (90.617) is better than Ligand B (40.946).

**Caco-2 Permeability:** Ligand A (-4.59) is better than Ligand B (-5.131) suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.746) is better than Ligand B (-1.624), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.653, B: 0.502).

**Microsomal Clearance:** Ligand A (47.385) has higher clearance than Ligand B (33.311), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (20.322) has a significantly longer half-life than Ligand A (-17.159), which is a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.235, B: 0.165).

**Binding Affinity:** Both ligands have very similar binding affinities (A: -8.4 kcal/mol, B: -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, QED, DILI, Solubility, Caco-2) and has comparable binding affinity. However, its higher microsomal clearance and shorter half-life are concerning. Ligand B has a better half-life and lower clearance, but suffers from a higher DILI risk, poorer solubility, and lower QED.

Considering the priorities for an enzyme target (SRC kinase), metabolic stability (half-life and clearance) and solubility are critical. While Ligand A has better overall drug-likeness, Ligand B's superior metabolic stability and acceptable (though not ideal) DILI risk make it the more promising candidate. The small difference in binding affinity is outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 12:25:06,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 364.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (81.08), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (0.703) is slightly better than Ligand B (0.379), both are a bit low, potentially impacting permeability. However, they are not excessively low.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.632 and 0.759), indicating drug-like properties.

**DILI:** Ligand A (4.731) has a significantly lower DILI risk than Ligand B (21.171). This is a major advantage for Ligand A.

**BBB:** Ligand B (70.182) has a higher BBB penetration score than Ligand A (36.371). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.856 and -4.795), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.599) is better than Ligand B (-1.507), indicating slightly better solubility.

**hERG:** Ligand A (0.198) has a lower hERG risk than Ligand B (0.424), which is favorable.

**Microsomal Clearance:** Ligand A (-7.488) has a significantly lower (better) microsomal clearance than Ligand B (-7.962), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.337) has a better in vitro half-life than Ligand B (-4.373).

**P-gp Efflux:** Ligand A (0.014) has a lower P-gp efflux liability than Ligand B (0.037).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). The difference is 1 kcal/mol, which is substantial, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties, particularly regarding DILI risk, metabolic stability (Cl_mic and t1/2), and hERG risk. These factors are crucial for kinase inhibitors. The slightly lower affinity of Ligand A can potentially be optimized in subsequent iterations, but mitigating the higher risk profile of Ligand B would be more challenging. The negative Caco-2 values are concerning for both, and would need to be addressed, but the other advantages of Ligand A make it the more promising starting point.

Output:
0
2025-04-17 12:25:06,397 - INFO - Batch 128 complete. Total preferences: 2048
2025-04-17 12:25:06,397 - INFO - Processing batch 129/512...
2025-04-17 12:25:47,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (419.662 Da) is higher, but still acceptable. Ligand B (349.431 Da) is slightly preferred.

**TPSA:** Both are reasonably low (Ligand A: 82.28, Ligand B: 83.66), suggesting good potential for cell permeability. Both are well below the 140 A^2 threshold.

**logP:** Ligand A (4.273) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.473) is within the optimal range (1-3). Ligand B is preferred.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both fall within acceptable limits.

**QED:** Ligand B (0.73) has a significantly better QED score than Ligand A (0.388), indicating a more drug-like profile.

**DILI:** Ligand A (98.178) has a very high DILI risk, a major concern. Ligand B (34.161) has a low DILI risk, a significant advantage.

**BBB:**  BBB is less critical for a non-CNS target like SRC, but Ligand A (71.617) is better than Ligand B (49.981).

**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. Again, the scale is unknown.

**hERG:** Both have low hERG inhibition liability (Ligand A: 0.316, Ligand B: 0.32), which is good.

**Microsomal Clearance:** Ligand A (94.01) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (23.565) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (61.173) has a reasonable half-life, but Ligand B (12.786) is much lower, indicating faster metabolism.

**P-gp Efflux:** Both have low P-gp efflux liability (Ligand A: 0.456, Ligand B: 0.048). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand A, its extremely high DILI risk and high microsomal clearance are major drawbacks. The poor solubility and permeability (indicated by negative Caco-2 and solubility values) are also concerning. Ligand B, while having a weaker affinity, exhibits a much better safety profile (low DILI), improved metabolic stability (low Cl_mic), and a better QED score. The difference in binding affinity (1 kcal/mol) is not large enough to overcome the significant ADME/Tox liabilities of Ligand A.

Output:
1
2025-04-17 12:25:47,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.63) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (87.32) is good.

**logP:** Both ligands have good logP values (2.717 and 1.92), 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.699 and 0.65), indicating good drug-likeness.

**DILI:** Ligand A (55.176) has a slightly higher DILI risk than Ligand B (50.33), but both are acceptable (<60).

**BBB:** Ligand A (70.492) has better BBB penetration than Ligand B (51.725), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.628) has worse Caco-2 permeability than Ligand B (-5.165), meaning lower intestinal absorption.

**Aqueous Solubility:** Ligand B (-3.283) has better aqueous solubility than Ligand A (-2.105). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.567 and 0.46).

**Microsomal Clearance:** Ligand B (46.756) has significantly lower microsomal clearance than Ligand A (64.614), indicating better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-35.394) has a much longer in vitro half-life than Ligand A (30.298), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.064 and 0.051), which is favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This is a 0.8 kcal/mol difference, which is significant.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, specifically in metabolic stability (lower Cl_mic and longer t1/2) and solubility. For an enzyme target like SRC kinase, metabolic stability and solubility are crucial for *in vivo* efficacy. The 0.8 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, while improving its ADME profile is more challenging.

Output:
1
2025-04-17 12:25:47,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 376.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.58) is better than Ligand B (98.66), both being acceptable for oral absorption (<140).

**logP:** Both are good (2.45 and 1.273), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 5 HBA) as it has fewer HBDs, which can improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.899) has a significantly better QED score than Ligand B (0.576), indicating a more drug-like profile.

**DILI:** Ligand B (38.852) has a lower DILI risk than Ligand A (60.644), which is a significant advantage.

**BBB:** Ligand A (70.182) has a better BBB penetration score than Ligand B (58.007), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.894) has a better Caco-2 permeability than Ligand B (-5.201).

**Aqueous Solubility:** Ligand A (-3.165) has better aqueous solubility than Ligand B (-2.048).

**hERG:** Ligand A (0.13) has a much lower hERG risk than Ligand B (0.305). This is a critical advantage.

**Microsomal Clearance:** Ligand B (-5.105) has a lower (better) microsomal clearance than Ligand A (40.003), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.297) has a significantly longer in vitro half-life than Ligand A (-5.273), which is a major advantage.

**P-gp Efflux:** Ligand A (0.055) has a lower P-gp efflux liability than Ligand B (0.032), which is slightly preferable.

**Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.3), but the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, which are key priorities for kinase inhibitors. The slightly better binding affinity of Ligand B is a bonus. While Ligand A has better QED, solubility, and hERG, the metabolic and toxicity profiles of Ligand B are more favorable. The 0.5 kcal/mol difference in binding affinity is unlikely to outweigh the significant advantages of Ligand B regarding metabolic stability and safety.

Output:
1
2025-04-17 12:25:47,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (372.466 Da) is still well within range.

**TPSA:** Ligand A (54.78) is significantly better than Ligand B (101.05). A TPSA under 140 is good for oral absorption, but Ligand B's value is higher and may present absorption challenges.

**logP:** Both ligands have acceptable logP values (A: 0.65, B: 1.573), falling within the optimal 1-3 range. Ligand B is slightly better, indicating a potentially improved balance between solubility and permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower HBD/HBA generally leads to better permeability.

**QED:** Both ligands have good QED scores (A: 0.74, B: 0.753), indicating good drug-like properties.

**DILI:** Ligand A (32.842) has a significantly lower DILI risk than Ligand B (55.176), which is a crucial advantage.

**BBB:** Both have moderate BBB penetration, but Ligand B (79.992) is better than Ligand A (62.97). However, BBB isn't a primary concern for SRC kinase inhibitors unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.341) is slightly better than Ligand B (-4.973).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.404) is slightly better than Ligand B (-3.373).

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.102, B: 0.226), which is good. Ligand A is slightly better.

**Microsomal Clearance:** Ligand A (10.347 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (17.421 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (31.956 hours) has a much longer in vitro half-life than Ligand A (8.157 hours), which is a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.025, B: 0.15).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, hERG, and metabolic stability, the significantly stronger binding affinity of Ligand B (-8.3 vs -6.7 kcal/mol) outweighs these benefits. The longer half-life of Ligand B is also a substantial positive. The higher TPSA and DILI risk of Ligand B are concerns, but can potentially be addressed through further optimization. The poor Caco-2 and solubility values are shared by both, and would need to be addressed in either case. Given the enzyme-specific priorities, potency is paramount, and Ligand B's superior affinity makes it the more promising candidate.

Output:
1
2025-04-17 12:25:47,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.53 and 348.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (24.5) is excellent, well below the 140 threshold, suggesting good absorption. Ligand B (84.42) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (3.693) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.711) is well within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA, both within the acceptable limit of 10.

**QED:** Both ligands have similar and good QED values (0.853 and 0.876), indicating good drug-like properties.

**DILI:** Ligand A (1.745) has a very low DILI risk, which is excellent. Ligand B (33.346) has a moderate DILI risk, but still acceptable.

**BBB:** Ligand A (92.594) shows excellent BBB penetration, while Ligand B (70.027) is good, but less pronounced. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.951) and Ligand B (-4.637) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Ligand A (-2.864) and Ligand B (-1.917) both have negative solubility values, indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.947) has a low hERG risk, which is favorable. Ligand B (0.17) has a very low hERG risk, even better.

**Microsomal Clearance:** Ligand A (8.647) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (15.448) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (6.258) has a longer half-life, which is desirable. Ligand B (-11.316) has a negative half-life, which is not possible and indicates a problem with the data or the compound.

**P-gp Efflux:** Ligand A (0.126) has low P-gp efflux, which is good. Ligand B (0.031) has very low P-gp efflux, even better.

**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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly higher binding affinity (-8.7 vs -7.4 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. While the solubility and permeability issues need to be addressed through formulation or structural modifications, the potency advantage of Ligand A makes it the better starting point for optimization. The negative half-life of Ligand B is a showstopper.

Output:
0
2025-04-17 12:25:47,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.455 and 345.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.5) is slightly above the preferred <140, but still reasonable. Ligand B (63.05) is well within the acceptable range.

**3. logP:** Both ligands have good logP values (1.777 and 3.044), 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 4 H-bond acceptors, well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.764 and 0.892), indicating good drug-like properties.

**7. DILI:** Ligand A (64.288) has a higher DILI risk than Ligand B (29.081). This is a significant concern, as lower DILI is preferred.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.87) has a slightly higher BBB score than Ligand A (77.317), but it's not a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-4.972) has a significantly *lower* Caco-2 permeability than Ligand B (-4.805). While both are negative, a less negative value is better.

**10. Aqueous Solubility:** Ligand A (-3.959) has slightly lower aqueous solubility than Ligand B (-3.23). Both are negative, indicating poor solubility, but B is better.

**11. hERG Inhibition:** Ligand A (0.793) has a slightly higher hERG risk than Ligand B (0.112). Lower hERG is strongly preferred.

**12. Microsomal Clearance:** Ligand A (43.634) has lower microsomal clearance than Ligand B (47.745), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.076) has a significantly longer in vitro half-life than Ligand A (6.639). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.127 and 0.144).

**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 favorable.

**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. Specifically, it has a significantly lower DILI risk, better Caco-2 permeability, better aqueous solubility, a much longer half-life, and a lower hERG risk. These factors are crucial for developing a viable drug candidate, especially for an enzyme target like SRC kinase. The small difference in binding affinity is outweighed by the substantial improvements in ADME properties.

Output:
1
2025-04-17 12:25:47,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.375 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.51) is slightly above the optimal <140 for good absorption, while Ligand B (111.27) is well within the range.

**logP:** Ligand A (-0.103) is a bit low, potentially hindering permeation. Ligand B (0.22) is better, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=3, HBA=6) both have reasonable H-bond properties, within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.543, B: 0.611), indicating drug-like properties.

**DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (57.929), which is preferable.

**BBB:** Both have similar BBB penetration (A: 71.966, B: 79.256), which isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.273 and -5.632), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-2.468 and -2.549), also unusual and concerning.

**hERG:** Ligand A (0.094) has a slightly lower hERG risk than Ligand B (0.38), which is better.

**Microsomal Clearance:** Ligand A (20.873) has a higher microsomal clearance than Ligand B (14.298), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (5.405) has a significantly longer in vitro half-life than Ligand A (-13.574), which is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.013, B: 0.024).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol).

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, Ligand B is the more promising candidate. The key advantages of Ligand B are its lower DILI risk, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and better logP. While both have concerningly low/negative Caco-2 and solubility values, the metabolic stability and safety profile of Ligand B outweigh the small difference in binding affinity. The negative solubility and permeability values would need to be addressed in further optimization, but the starting point is better with Ligand B.

Output:
1
2025-04-17 12:25:47,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (341.415 and 346.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.77) is better than Ligand B (69.64). Both are below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have acceptable logP values (1.136 and 1.862, respectively), falling within the optimal range of 1-3.

**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 3 HBA. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.689) has a better QED score than Ligand B (0.495), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.846) has a significantly lower DILI risk than Ligand B (6.32), which is a major advantage.

**8. BBB:** Both ligands have similar BBB penetration (57.193 and 58.821), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-5.249) has a worse Caco-2 permeability than Ligand B (-4.701).

**10. Aqueous Solubility:** Ligand A (-2.429) has a worse aqueous solubility than Ligand B (-1.972).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.098 and 0.211, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand A (0.366) has significantly lower microsomal clearance than Ligand B (21.541), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life (t1/2):** Ligand A (-4.806) has a much longer in vitro half-life than Ligand B (-11.198), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.016, respectively).

**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 crucial factor for kinase inhibitors. The difference of 2 kcal/mol is substantial.

**Overall Assessment:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability and solubility, Ligand A's significantly stronger binding affinity, lower DILI risk, and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh these minor drawbacks. The large difference in binding affinity is particularly compelling.

Output:
1
2025-04-17 12:25:47,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (86.88 and 87.91) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.772) is optimal, while Ligand B (0.66) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) are both within the acceptable limit of <=5.

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

**QED:** Both ligands have good QED scores (0.676 and 0.727), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (31.601 and 36.099 percentiles), which is favorable.

**BBB:** Both ligands have moderate BBB penetration (57.193 and 64.986 percentiles). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.112 and -4.894). This is unusual and concerning, indicating poor intestinal absorption. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.032 and -0.804). This is also concerning, suggesting poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.395 and 0.153 percentiles), which is excellent.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (57.93 mL/min/kg) compared to Ligand B (14.799 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (1.623 hours) compared to Ligand A (-19.622 hours). The negative value for Ligand A is suspect and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.116 and 0.009 percentiles), which is favorable.

**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 difference (2.2 kcal/mol), which could outweigh some ADME drawbacks.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility values for both, Ligand A's significantly superior binding affinity (-9.7 kcal/mol vs -7.5 kcal/mol) and lower microsomal clearance, combined with acceptable DILI and hERG risk, make it the more promising candidate. The affinity difference is large enough to potentially overcome the solubility/permeability issues through formulation strategies. Ligand B's better metabolic stability is appealing, but the weaker binding is a major drawback for an enzyme target.

Output:
0
2025-04-17 12:25:47,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight (MW):** Both ligands (350.547 and 364.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (80.57). TPSA < 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**3. logP:** Ligand A (4.302) is higher than the optimal 1-3 range, potentially leading to solubility issues. Ligand B (1.724) is within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 2, respectively), below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (2 and 5, respectively), below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.63 and 0.687), indicating good drug-likeness.

**7. DILI:** Ligand A (17.72) has a much lower DILI risk than Ligand B (51.997). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (77.007) has a better BBB penetration percentile than Ligand B (57.154). While not a primary concern for a kinase inhibitor (unless CNS off-target effects are a concern), it's a slight positive for Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.632 and -4.82), which is unusual and suggests very poor permeability. This is a major red flag for both compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.844 and -3.485), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.666) has a slightly higher hERG inhibition risk than Ligand B (0.132). This is a negative for Ligand A.

**12. Microsomal Clearance (Cl_mic):** Ligand B (32.345) has a significantly lower Cl_mic, indicating better metabolic stability, than Ligand A (55.968). This is a major advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (24.438) has a much longer in vitro half-life than Ligand A (3.78). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.333) has lower P-gp efflux liability than Ligand B (0.102), which is a slight advantage.

**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 A has advantages in DILI risk, BBB, and P-gp efflux. However, Ligand B excels in metabolic stability (Cl_mic and t1/2) and has a more favorable logP. The poor Caco-2 and solubility for both compounds are concerning and would require significant optimization. Given the enzyme-specific priorities, metabolic stability is crucial for kinase inhibitors. The significantly better metabolic stability and longer half-life of Ligand B outweigh the slightly higher hERG risk and lower BBB.

Output:
1
2025-04-17 12:25:47,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (58.64) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (A: 2.37, B: 2.657) 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 3 HBA, which is acceptable.

**6. QED:** Both ligands have acceptable QED scores (A: 0.514, B: 0.769), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (10.585) has a significantly lower DILI risk than Ligand B (27.065). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (A: 80.962, B: 81.078), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.697 and -4.811). 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 (-2.579 and -2.41). This is also unusual and suggests poor solubility. Again, these values need careful interpretation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.488, B: 0.459).

**12. Microsomal Clearance:** Ligand A (57.645) has lower microsomal clearance than Ligand B (73.832), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-8.882) has a slightly longer in vitro half-life than Ligand B (-8.435).

**14. P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.057, B: 0.283).

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial difference (1.2 kcal/mol), and likely outweighs minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While both ligands have some concerning solubility and permeability predictions (negative Caco-2 and solubility values), Ligand A's significantly stronger binding affinity (-7.4 vs -6.2 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2) make it a more promising starting point for optimization. The affinity difference is large enough to prioritize over the ADME concerns, which can be addressed through structural modifications.

Output:
0
2025-04-17 12:25:47,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.293 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (75.88) is well within the range.

**logP:** Both ligands (1.995 and 1.88) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have QED values (0.753 and 0.779) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (96.627) has a higher DILI risk than Ligand B (48.119). This is a significant concern.

**BBB:** Both ligands have reasonable BBB penetration (65.607 and 70.609), but this is less critical for a non-CNS target like SRC.

**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 still relatively close to zero.

**Aqueous Solubility:** Both ligands have negative solubility values, which are also unusual.

**hERG Inhibition:** Ligand A (0.414) has a slightly higher hERG risk than Ligand B (0.153), but both are relatively low.

**Microsomal Clearance:** Ligand A (-1.912) has a negative clearance, suggesting excellent metabolic stability. Ligand B (36.185) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (69.269) has a much longer half-life than Ligand B (-29.124). This is a major advantage.

**P-gp Efflux:** Ligand A (0.163) has lower P-gp efflux liability than Ligand B (0.047), which is favorable.

**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 small.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both ligands have similar potency and drug-likeness, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. The higher DILI risk is a concern, but the substantial improvement in pharmacokinetic properties outweighs this risk, especially given the relatively small difference in binding affinity. The negative solubility and Caco-2 values are concerning for both, and would need further investigation, but the metabolic stability advantage of A is key for an enzyme target.

Output:
1
2025-04-17 12:25:47,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.45 and 365.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.39) is better than Ligand B (78.43), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.117 and 0.918), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 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 good QED scores (0.764 and 0.811), indicating good drug-like properties.

**DILI:** Ligand A (8.647) has a significantly lower DILI risk than Ligand B (16.169). This is a major advantage.

**BBB:** Ligand A (75.029) has a better BBB penetration score than Ligand B (67.08), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.61) and Ligand B (-5.54) have similar Caco-2 permeability values.

**Aqueous Solubility:** Ligand A (-0.855) and Ligand B (-0.727) have similar aqueous solubility values.

**hERG:** Ligand A (0.8) has a slightly better hERG profile than Ligand B (0.127), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-24.158) has a significantly lower (better) microsomal clearance than Ligand B (-21.652), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (17.346 hours) has a much longer in vitro half-life than Ligand B (1.703 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.018) has a lower P-gp efflux liability than Ligand B (0.025), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.1 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 advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. These factors are crucial for developing a viable drug candidate.

Output:
0
2025-04-17 12:25:47,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.55) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (62.99) is excellent, well below 140.

**logP:** Ligand A (0.121) is quite low, potentially hindering permeation. Ligand B (2.137) is 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 (5) is acceptable. Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (0.675 and 0.823), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (52.113 and 37.611), both below the 40 threshold.

**BBB:** Ligand A (36.371) is low, not a major concern for a non-CNS target like SRC. Ligand B (72.276) is good, but not critical here.

**Caco-2 Permeability:** Ligand A (-5.737) is very poor, suggesting poor intestinal absorption. Ligand B (-4.513) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.614) is poor. Ligand B (-2.143) is also poor.

**hERG Inhibition:** Both ligands have very low hERG risk (0.177 and 0.452), which is excellent.

**Microsomal Clearance:** Ligand A (2.877) is relatively low, indicating better metabolic stability. Ligand B (13.502) is significantly higher, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (25.748) is moderate. Ligand B (57.491) is significantly longer, a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.015 and 0.2).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol) - a difference of 1.6 kcal/mol, which is substantial.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic), its poor logP, Caco-2 permeability, and solubility are significant drawbacks. Ligand B, despite higher Cl_mic, excels in binding affinity, logP, TPSA, and has a longer half-life. The substantial affinity advantage of Ligand B outweighs the slightly higher clearance, especially considering the poor permeability of Ligand A.

Output:
1
2025-04-17 12:25:47,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.503 and 348.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (78.67 and 79.54) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (0.673) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (1.106) is closer to the ideal range.

**4. H-Bond Donors:** Both have 1 HBD, well 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.

**6. QED:** Both ligands have good QED scores (0.799 and 0.727), indicating drug-like properties.

**7. DILI:** Ligand A (43.428) has a lower DILI risk than Ligand B (58.434), which is a significant advantage. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (25.126) has a very low BBB penetration, while Ligand B (84.141) has a much higher value. Since SRC is not a CNS target, this is less critical, but a higher value is generally preferred.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.157) is slightly better than Ligand B (-4.718).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.621) is slightly better than Ligand B (-1.691).

**11. hERG Inhibition:** Ligand A (0.16) has a much lower hERG inhibition liability than Ligand B (0.712), which is a crucial advantage for safety.

**12. Microsomal Clearance:** Ligand A (35.97) has a lower microsomal clearance than Ligand B (46.693), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (61.075) has a significantly longer in vitro half-life than Ligand A (-7.573). This is a major advantage for dosing convenience.

**14. P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux than Ligand B (0.241), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.573 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 a longer half-life, which are key for an enzyme inhibitor. However, it has higher DILI risk, higher hERG inhibition, and higher P-gp efflux. Ligand A has better safety profiles (DILI, hERG) and lower efflux, but its affinity and half-life are weaker.

Given the priorities for enzyme inhibitors, the stronger binding affinity of Ligand B is a decisive factor, despite its ADME liabilities. Optimization efforts could focus on improving the ADME properties of Ligand B while maintaining its potency.

Output:
1
2025-04-17 12:25:47,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.531 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (86.09).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal range for good absorption.

**logP:** Both ligands have acceptable logP values (3.89 and 2.03, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 4. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (0.723 and 0.851), indicating good drug-like properties.

**DILI:** Ligand A (12.679) has a much lower DILI risk than Ligand B (53.548). This is a significant advantage for Ligand A.

**BBB:** Ligand A (78.015) has a better BBB penetration score than Ligand B (64.133), though BBB isn't a primary concern for a non-CNS target like SRC.

**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 (-4.549 vs -4.871), indicating slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. The absolute value is smaller for Ligand A (-4.278 vs -3.692), suggesting slightly better solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.657 and 0.571), which is good.

**Microsomal Clearance:** Ligand A (83.792) has a higher microsomal clearance than Ligand B (15.764), meaning it is cleared more quickly and has lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-15.501) has a significantly longer in vitro half-life than Ligand A (17.747). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.214 and 0.091).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has advantages in TPSA, DILI, and slightly better permeability and solubility, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2) is crucial for an enzyme target like SRC kinase. The equal binding affinity removes that as a differentiating factor. The lower DILI risk for Ligand A is a plus, but can be addressed through further optimization. The longer half-life of Ligand B translates to potentially less frequent dosing and better *in vivo* exposure.

Output:
1
2025-04-17 12:25:47,348 - INFO - Batch 129 complete. Total preferences: 2064
2025-04-17 12:25:47,348 - INFO - Processing batch 130/512...
2025-04-17 12:26:26,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.359 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.01) is better than Ligand B (65.64). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (2.033) is optimal (1-3), while Ligand A (-0.733) is below 1, potentially hindering permeation. This is a significant negative for Ligand A.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, being lower.

**H-Bond Acceptors:** Ligand A (7) is acceptable, while Ligand B (3) is even better.

**QED:** Ligand B (0.906) is excellent, indicating high drug-likeness. Ligand A (0.289) is poor, suggesting potential issues.

**DILI:** Ligand B (42.458) has a lower DILI risk than Ligand A (60.915), which is approaching a concerning level.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.48) is higher, but it's not a deciding factor here.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.365) is worse than Ligand B (-4.514).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.08) is slightly better than Ligand B (-2.34).

**hERG:** Ligand B (0.537) has a lower hERG risk than Ligand A (0.146), which is concerning.

**Microsomal Clearance:** Ligand A (-17.71) has significantly lower (better) microsomal clearance than Ligand B (17.879). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-30.057) has a longer half-life than Ligand B (-2.381), indicating better in vitro stability.

**P-gp Efflux:** Ligand B (0.122) has lower P-gp efflux than Ligand A (0.024), which is favorable.

**Binding Affinity:** Both ligands have comparable binding affinities (-7.5 and -7.3 kcal/mol), which are both good. The difference of 0.2 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

Ligand B is significantly better overall. While Ligand A has better metabolic stability and half-life, Ligand B excels in crucial areas like logP, QED, DILI risk, and hERG inhibition. The poor logP and QED of Ligand A, coupled with its higher DILI and hERG risk, make it a less desirable candidate despite its slightly better metabolic profile. The binding affinity is comparable, so the ADME properties are the deciding factors.

Output:
1
2025-04-17 12:26:26,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.441 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 potential. Ligand A (49.41) is slightly higher than Ligand B (42.68), but both are good.

**logP:** Ligand A (3.131) is within the optimal range (1-3). Ligand B (4.616) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (0 HBD, 3 HBA) both fall within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.771) is slightly better than Ligand B (0.63).

**DILI:** Ligand A (19.698) has a significantly lower DILI risk than Ligand B (9.228), which is a major advantage.

**BBB:** Both ligands have high BBB penetration, but Ligand B (96.743) is slightly higher than Ligand A (91.314). However, BBB is less critical for a non-CNS target like SRC.

**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 and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.498) has a lower hERG inhibition liability than Ligand B (0.884), which is a positive.

**Microsomal Clearance:** Ligand A (30.34 mL/min/kg) has a lower microsomal clearance than Ligand B (81.84 mL/min/kg), indicating better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (40.019 hours) has a significantly longer in vitro half-life than Ligand A (-2.687 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux liability than Ligand B (0.52), which is favorable.

**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 and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and a longer half-life. However, it has a higher logP, higher DILI risk, and higher microsomal clearance. Ligand A has better solubility, lower DILI risk, lower hERG risk, and lower P-gp efflux. The difference in binding affinity is significant (-7.5 vs -10.1 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. While the ADME properties of Ligand B are less ideal, the stronger binding affinity is likely to be the deciding factor, especially if further optimization can address the metabolic stability and DILI concerns.

Output:
1
2025-04-17 12:26:26,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.355 Da and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.33) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (96.69) is excellent, well below 140.

**logP:** Ligand A (2.124) is within the optimal 1-3 range. Ligand B (0.653) is a bit low, potentially impacting permeability.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.636 and 0.703), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 82.319, which is high, exceeding the >60 threshold. Ligand B has a much lower DILI risk of 44.552, which is good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration (55.913 and 58.278). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.616) and Ligand B (-5.249) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-4.445) and Ligand B (-1.399) both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.337) has a low hERG risk, which is excellent. Ligand B (0.286) also has a low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (32.547) has moderate clearance. Ligand B (-10.612) has negative clearance, which is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (12.856) has a reasonable half-life. Ligand B (11.185) has a similar half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.048), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

While both ligands have some ADME liabilities (poor Caco-2 and solubility), Ligand B is the superior candidate. Its significantly stronger binding affinity (-8.1 vs -7.1 kcal/mol) and substantially lower DILI risk (44.552 vs 82.319) are critical advantages. The negative clearance value for Ligand B is also a major positive, indicating excellent metabolic stability.

Output:
1
2025-04-17 12:26:26,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.434 and 369.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.08) is slightly higher than Ligand B (80.76). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (2.014 and 1.233), falling within the 1-3 range. Ligand B is slightly lower, which could potentially impact permeability, but is 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:** Both ligands have good QED scores (0.695 and 0.745), indicating drug-like properties.

**DILI:** Ligand A (65.491) has a slightly higher DILI risk than Ligand B (62.195), but both are reasonably acceptable.

**BBB:** Both ligands have moderate BBB penetration (68.786 and 55.176). This isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.236 and -5.104), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.173 and -1.12), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.629) shows a slightly higher hERG risk than Ligand B (0.097). Ligand B is significantly better here.

**Microsomal Clearance:** Ligand A (14.102 mL/min/kg) has a much lower (better) microsomal clearance than Ligand B (30.412 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.977 hours) has a significantly longer half-life than Ligand B (24.12 hours). This is a positive for Ligand A. Note the negative value for A is likely an error.

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux than Ligand B (0.064), which is favorable.

**Binding Affinity:** Ligand B (-8.1 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 difference threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower hERG risk, and better TPSA. However, Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life. Both compounds suffer from poor predicted solubility and permeability. Given the importance of potency for kinase inhibitors, the superior binding affinity of Ligand B outweighs the benefits of Ligand A's metabolic stability, *assuming* the solubility and permeability issues can be addressed through formulation or structural modification.

Output:
1
2025-04-17 12:26:26,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.376 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (384.933 Da) is also well within the range.

**TPSA:** Both ligands have TPSA values below 140 (A: 62.3, B: 60.25), suggesting good oral absorption potential.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.321) is slightly better than Ligand B (3.686), as higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=0, HBA=6). Lower HBA is generally better for permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.85, B: 0.661), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (17.798) has a significantly lower DILI risk than Ligand B (55.487), which is a major advantage.

**BBB:** Ligand A (82.202) has a better BBB percentile than Ligand B (69.407), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.791 for A, -4.913 for B).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility. Again, the values are similar (-2.488 for A, -3.403 for B).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.594, B: 0.632).

**Microsomal Clearance:** Ligand A (-8.882) has *much* lower microsomal clearance than Ligand B (69.502). This indicates significantly better metabolic stability for Ligand A, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-4.173) has a better in vitro half-life than Ligand B (52.923), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.043, B: 0.728). Ligand A is better.

**Binding Affinity:** Ligand B (-8.2) has slightly better binding affinity than Ligand A (-7.9), but the difference is relatively small (0.3 kcal/mol). Given the substantial advantages of Ligand A in other key ADME properties, this difference is unlikely to be decisive.

**Conclusion:**

Ligand A is the more promising drug candidate. It exhibits significantly lower DILI risk and much better metabolic stability (lower Cl_mic, longer t1/2) than Ligand B. While Ligand B has slightly better binding affinity, the improvements in ADME properties, especially DILI and metabolic stability, outweigh this minor difference. The similar solubility and permeability issues would need to be addressed in either case, but Ligand A provides a better starting point for optimization.

Output:
0
2025-04-17 12:26:26,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.462 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.37) is better than Ligand B (102.48). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (2.423) is optimal, while Ligand B (0.759) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), both are under the 10 threshold.

**QED:** Both ligands have similar QED values (0.884 and 0.781), indicating good drug-likeness.

**DILI:** Ligand A (48.391) has a higher DILI risk than Ligand B (24.816). This is a significant advantage for B.

**BBB:** Both have high BBB penetration (79.488 and 83.366), but this is less crucial for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar.

**Solubility:** Ligand A (-3.196) has slightly better solubility than Ligand B (-2.258).

**hERG:** Ligand A (0.171) has a significantly lower hERG risk than Ligand B (0.408). This is a major advantage for A.

**Microsomal Clearance:** Ligand A (-1.225) has a better (lower) microsomal clearance than Ligand B (-8.425), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.815) has a slightly longer half-life than Ligand B (12.464).

**P-gp Efflux:** Ligand A (0.096) has lower P-gp efflux than Ligand B (0.028), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite Ligand B's lower DILI risk, Ligand A's substantially superior binding affinity (-8.7 vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic) are decisive. The improved hERG profile and P-gp efflux also contribute to its favorability. While Ligand B has a lower DILI score, the difference isn't large enough to overcome the significant potency advantage of Ligand A.

Output:
1
2025-04-17 12:26:26,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.405 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.45) is well below the 140 threshold, and favorable for oral absorption. Ligand B (113.49) is still within acceptable limits, but less optimal.

**logP:** Ligand A (4.142) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.633) is quite low, which could 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 Ligand A is slightly better.

**QED:** Both ligands have QED values (0.83 and 0.676) above the 0.5 threshold, indicating good drug-like properties.

**DILI:** Ligand A (93.37) has a significantly higher DILI risk than Ligand B (38.387). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for SRC kinase inhibitors, as it's not a CNS target.

**Caco-2 Permeability:** Ligand A (-4.897) and Ligand B (-5.315) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-5.052) has very poor aqueous solubility, which is concerning. Ligand B (-1.214) is also poor, but better than Ligand A.

**hERG:** Ligand A (0.112) has a lower hERG risk than Ligand B (0.182), which is favorable.

**Microsomal Clearance:** Ligand A (6.079) has a lower microsomal clearance, suggesting better metabolic stability, which is a key priority for kinase inhibitors. Ligand B (21.784) has a higher clearance.

**In vitro Half-Life:** Ligand A (28.108 hours) has a significantly longer half-life than Ligand B (-17.429 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.061).

**Binding Affinity:** Both ligands have very strong binding affinities (-9.4 and -8.4 kcal/mol). Ligand A has a 1 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. However, its high DILI risk and very poor solubility are major drawbacks. Ligand B has a lower DILI risk and slightly better solubility, but its lower binding affinity and poorer metabolic stability are significant concerns.

Given the importance of metabolic stability and potency for kinase inhibitors, and the substantial difference in half-life, Ligand A is the more promising candidate *despite* the DILI and solubility concerns. These issues might be addressed through further structural modifications. The 1 kcal/mol difference in binding affinity is substantial enough to prioritize Ligand A for further optimization.

Output:
1
2025-04-17 12:26:26,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.441 Da) is slightly higher than Ligand B (345.399 Da), but both are acceptable.

**TPSA:** Ligand A (69.72) is better than Ligand B (88.58). Lower TPSA generally improves oral absorption, and both are reasonably low.

**logP:** Ligand A (1.1) is optimal, while Ligand B (2.361) is also within the acceptable range (1-3), but closer to the upper limit.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are below the threshold of 10.

**QED:** Both ligands have good QED values (A: 0.751, B: 0.899), indicating drug-like properties.

**DILI:** Ligand A (23.071) has a significantly lower DILI risk than Ligand B (46.297). This is a major advantage for Ligand A.

**BBB:** Ligand A (83.482) has better BBB penetration than Ligand B (63.048), but this is less critical for a kinase inhibitor unless CNS activity is desired.

**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. Again, the magnitude is similar.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.363, B: 0.316).

**Microsomal Clearance:** Ligand A (-14.043) has *much* lower (better) microsomal clearance than Ligand B (21.016). This indicates significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-42.11) has a much longer half-life than Ligand B (1.652). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.011, B: 0.103).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a 1.3 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 superior overall due to its significantly better ADMET profile. The lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and better BBB penetration are crucial for developing a viable drug candidate. The 1.3 kcal/mol difference in binding affinity, while notable, is less important than these factors, especially for a kinase inhibitor where achieving sufficient potency can often be addressed through further optimization.

Output:
0
2025-04-17 12:26:26,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (378.441 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (86.34) is better than Ligand B (92.34).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.286) is slightly higher than Ligand B (1.176), which is closer to the lower limit.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (1 & 2 respectively) and HBA (4 each) counts, unlikely to cause significant issues.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.858) is slightly better than Ligand B (0.703).

**DILI:** Ligand A (22.838) has a significantly lower DILI risk than Ligand B (45.25). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (82.9) has a higher BBB percentile than Ligand A (63.009), but this isn't a deciding factor.

**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, indicating poor solubility. This is a concern for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.425 and 0.151 respectively), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (-5.692) has a *much* lower (better) microsomal clearance than Ligand B (-12.342). This indicates significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (22.843 hours) has a longer in vitro half-life than Ligand B (14.559 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.066 and 0.085 respectively).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate due to its significantly better DILI score and dramatically improved metabolic stability (lower Cl_mic and longer t1/2). The improved QED score also favors Ligand A. The solubility and permeability concerns are present in both, but the ADME advantages of Ligand A outweigh the modest potency difference. For an enzyme target, metabolic stability and safety (DILI) are crucial, and Ligand A excels in these areas.

Output:
0
2025-04-17 12:26:26,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.391 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (66.15) is significantly better than Ligand B (98.66). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.2) is optimal, while Ligand B (1.453) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 6 HBA). Both are within acceptable limits, but a balance is generally preferred.

**QED:** Both ligands have good QED scores (A: 0.641, B: 0.793), indicating good drug-like properties.

**DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (54.207), which is a concern. However, the difference isn't drastic.

**BBB:** Both have reasonable BBB penetration, but Ligand A (82.784) is slightly better than Ligand B (70.764). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**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, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.823) has a slightly higher hERG risk than Ligand B (0.492), but both are relatively low.

**Microsomal Clearance:** Ligand A (1.583) has significantly better metabolic stability (lower clearance) than Ligand B (14.258). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (35.02) has a much longer half-life than Ligand B (-2.843). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.721) has slightly lower P-gp efflux than Ligand B (0.171), which is favorable.

**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 small (0.5 kcal/mol).

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better metabolic stability (lower Cl_mic, longer t1/2), better logP, and more balanced H-bonding properties. The slightly higher DILI risk of Ligand A is a concern, but the substantial improvements in pharmacokinetic properties outweigh this risk, especially for an enzyme target where maintaining therapeutic concentrations is crucial. The unusual negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand A.

Output:
1
2025-04-17 12:26:26,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 338.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.46) is better than Ligand B (40.62). Both are below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.239 and 3.27), falling within the 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:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.698 and 0.806), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (56.495 and 52.734), and are both below the concerning threshold of 60.

**BBB:** Ligand A (69.678) has a lower BBB penetration than Ligand B (90.112). However, since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Ligand A (-5.045) has significantly worse Caco-2 permeability than Ligand B (-4.319). This suggests lower intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-2.199) has better aqueous solubility than Ligand B (-3.762).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.414 and 0.629).

**Microsomal Clearance:** Ligand A (25.368) has significantly lower microsomal clearance than Ligand B (61.323). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-0.252) has a slightly better in vitro half-life than Ligand B (5.097).

**P-gp Efflux:** Ligand A (0.338) has lower P-gp efflux than Ligand B (0.432), which is favorable.

**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.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has slightly better Caco-2 permeability and BBB penetration (irrelevant for this target), Ligand A demonstrates significantly improved metabolic stability (lower Cl_mic) and a slightly better half-life, which are crucial for an enzyme target like SRC kinase. The similar binding affinities make these ADME properties the deciding factors.

Output:
0
2025-04-17 12:26:26,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**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, but both are acceptable.

**TPSA:** Ligand A (95.42) is better than Ligand B (49.41) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally improves permeability.

**logP:** Ligand A (1.045) is within the optimal range (1-3), while Ligand B (3.287) is towards the higher end. This suggests Ligand B might have potential solubility issues or off-target effects.

**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:** Both ligands have similar and good QED scores (A: 0.801, B: 0.846), indicating good drug-like properties.

**DILI:** Ligand A (38.969) has a significantly lower DILI risk than Ligand B (14.889). This is a major advantage for Ligand A.

**BBB:** Ligand B (73.556) has a higher BBB percentile than Ligand A (30.593). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.28 and -5.204), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.334 and -2.902), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.043) has a much lower hERG risk than Ligand B (0.425). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (12.679) has a lower microsomal clearance than Ligand B (47.95), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-9.848) has a longer in vitro half-life than Ligand B (-9.151). While both are negative, a less negative value indicates a longer half-life.

**P-gp Efflux:** Ligand A (0.016) has a lower P-gp efflux liability than Ligand B (0.249), suggesting better oral bioavailability.

**Binding Affinity:** Ligand A (-10.0) has a slightly better binding affinity than Ligand B (-8.7). While both are strong binders, the 1.3 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), better P-gp efflux, and slightly better binding affinity. While both have poor solubility and permeability, the superior ADME-Tox profile of Ligand A makes it the preferred choice.

Output:
0
2025-04-17 12:26:26,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (364.511 and 370.837 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is better than Ligand B (104.65). Both are under 140, but A is closer to the preferred value for good absorption.

**3. logP:** Ligand A (2.943) is optimal, while Ligand B (0.557) is a bit low, potentially hindering permeation.

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

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both within the limit of 10.

**6. QED:** Both ligands have good QED values (0.696 and 0.758), indicating drug-like properties.

**7. DILI:** Ligand A (31.524) has a significantly lower DILI risk than Ligand B (51.493), which is a major advantage. Both are below the 60 threshold, but A is much safer.

**8. BBB:** This is less critical for an oncology target, but Ligand A (76.347) has a better BBB score than Ligand B (51.609).

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.803) is slightly better than Ligand B (-4.754).

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.188) is slightly better than Ligand B (-1.801).

**11. hERG Inhibition:** Ligand A (0.437) has a lower hERG risk than Ligand B (0.171), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (68.26) has higher clearance than Ligand B (11.551), meaning it is less metabolically stable. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (4.149) has a longer half-life than Ligand A (35.607). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.297) has lower P-gp efflux than Ligand B (0.017), which is a slight advantage for ligand A.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a significant advantage for Ligand B. The difference is >1.5 kcal/mol, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better TPSA and P-gp efflux, Ligand B excels in key areas: significantly better binding affinity, lower DILI risk, and a longer in vitro half-life. The lower logP of Ligand B is a concern, but the superior binding affinity and improved safety profile (DILI, hERG) are more critical for an oncology kinase inhibitor. The metabolic stability (lower Cl_mic and longer t1/2) of Ligand B is also a major benefit.

Output:
1
2025-04-17 12:26:26,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (360.357 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.01) is better than Ligand B (52.65) as it is still within the acceptable range for oral absorption (<=140), but Ligand B is significantly lower and could indicate better absorption.

**3. logP:** Both ligands have good logP values (1.601 and 1.788), 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 5 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.712 and 0.773), indicating good drug-like properties.

**7. DILI:** Ligand A (31.485) has a much lower DILI risk than Ligand B (9.151), which is a significant advantage.

**8. BBB:** Ligand A (94.455) shows better BBB penetration than Ligand B (83.676), although BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.676) has a worse Caco-2 permeability than Ligand B (-4.99).

**10. Aqueous Solubility:** Ligand A (-2.39) has better aqueous solubility than Ligand B (-2.656). Solubility is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.689) has a slightly higher hERG inhibition risk than Ligand B (0.393), but both are relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-1.494) has a significantly lower (better) microsomal clearance than Ligand B (28.763), indicating greater metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-9.06) has a much longer in vitro half-life than Ligand B (15.07), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux than Ligand B (0.065), suggesting better bioavailability.

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

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and has a significantly lower DILI risk. While Ligand B has slightly better Caco-2 permeability, the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 12:26:26,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.917 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.13) is excellent, well below the 140 threshold for oral absorption. Ligand B (98.66) is higher but still acceptable, though it might slightly hinder absorption compared to A.

**logP:** Ligand A (4.032) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.724) 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 (0.742 and 0.632), indicating good drug-likeness.

**DILI:** Ligand A (25.126) has a significantly lower DILI risk than Ligand B (37.65). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (83.637 and 83.172), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.539) has poor Caco-2 permeability, while Ligand B (-5.216) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.132) has poor aqueous solubility, which is a concern given its higher logP. Ligand B (-2.52) is better, though still not ideal.

**hERG Inhibition:** Ligand A (0.568) has a slightly higher hERG risk than Ligand B (0.165). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (84.996) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (60.791) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.531) has a shorter half-life than Ligand B (0.867). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.453) has lower P-gp efflux, which is good. Ligand B (0.208) has even lower efflux, which is even better.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a lower DILI risk and slightly better P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-7.9 vs -6.7 kcal/mol) is the most important factor for an enzyme inhibitor. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. Although Ligand B has a higher TPSA and slightly worse solubility, the potency advantage and improved ADME properties outweigh these concerns.

Output:
1
2025-04-17 12:26:26,887 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (346.431 Da) is within the ideal range (200-500). Ligand B (379.551 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (88.33) is good for oral absorption. Ligand B (62.3) is even better, falling well below the 140 threshold. Advantage: B.

3. **logP:** Both ligands (A: 1.812, B: 2.79) are within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability, but not dramatically so.

4. **HBD:** Both ligands have 1 HBD, which is acceptable. No difference.

5. **HBA:** Both ligands have 5 HBA, which is acceptable. No difference.

6. **QED:** Ligand A (0.898) has a better QED score than Ligand B (0.772), indicating a more drug-like profile. Advantage: A.

7. **DILI:** Ligand A (44.397) has a slightly higher DILI risk than Ligand B (29.585), but both are below the concerning threshold of 60. Advantage: B.

8. **BBB:** Both are fairly high, but Ligand A (74.719) is higher than Ligand B (68.67). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

9. **Caco-2:** Both are negative (-5.187 and -5.151). This is unusual and suggests very poor permeability. This is a significant concern for both.

10. **Solubility:** Both are negative (-2.984 and -3.575). This is also concerning, indicating poor aqueous solubility.

11. **hERG:** Ligand A (0.137) has a slightly lower hERG risk than Ligand B (0.428). Advantage: A.

12. **Cl_mic:** Both have similar microsomal clearance values (A: 58.323, B: 59.211). No significant difference.

13. **t1/2:** Ligand B (5.238) has a significantly longer in vitro half-life than Ligand A (-6.787). This is a major advantage for Ligand B, suggesting less frequent dosing potential. Advantage: B.

14. **Pgp:** Both have low Pgp efflux liability (A: 0.135, B: 0.184). No significant difference.

15. **Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.2 kcal/mol). This difference of 0.6 kcal/mol is meaningful, especially considering the other factors. Advantage: B.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in binding affinity and has a significantly better half-life. While both have poor solubility and Caco-2 permeability, the stronger binding and improved stability of Ligand B are more critical for an enzyme inhibitor. The slightly lower DILI and hERG risk are also beneficial.

**Conclusion:**

Considering the balance of properties and the priorities for a kinase inhibitor, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:26:26,887 - INFO - Batch 130 complete. Total preferences: 2080
2025-04-17 12:26:26,887 - INFO - Processing batch 131/512...
2025-04-17 12:27:16,594 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both A (344.459 Da) and B (347.459 Da) are within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (91.22) is slightly higher than Ligand B (60.93). Both are below the 140 threshold for oral absorption, but B is significantly better, potentially indicating better permeability.

3. **logP:** Both ligands have good logP values (A: 1.888, B: 1.269), falling within the optimal 1-3 range. B is slightly lower, which *could* be a minor drawback, but still acceptable.

4. **HBD:** Ligand A has 3 HBD, while Ligand B has 0.  Both are within the acceptable limit of <=5. Ligand B's lower HBD count may contribute to better permeability.

5. **HBA:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

6. **QED:** Both ligands have similar QED values (A: 0.762, B: 0.704), both above the 0.5 threshold, indicating good drug-like properties.

7. **DILI:** Ligand B (24.157) has a significantly lower DILI risk than Ligand A (30.826). This is a major advantage for B.

8. **BBB:** Ligand B (71.772) has a better BBB penetration percentile than Ligand A (64.754). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

9. **Caco-2:** Ligand A (-5.36) has a worse Caco-2 permeability than Ligand B (-4.598). Lower (more negative) values suggest poorer permeability.

10. **Solubility:** Ligand A (-2.934) has worse solubility than Ligand B (-1.446). Solubility is important for bioavailability.

11. **hERG:** Ligand B (0.126) has a much lower hERG inhibition liability than Ligand A (0.598). This is a crucial advantage, reducing the risk of cardiotoxicity.

12. **Cl_mic:** Ligand A (-2.864) has better (lower) microsomal clearance than Ligand B (30.78). This suggests better metabolic stability for A.

13. **t1/2:** Ligand A (-6.542) has a much longer in vitro half-life than Ligand B (0.024). This is a significant advantage for A, potentially allowing for less frequent dosing.

14. **Pgp:** Ligand A (0.072) has lower Pgp efflux liability than Ligand B (0.042). Lower Pgp is generally preferred.

15. **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.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and hERG, while Ligand A has better metabolic stability and half-life. Solubility is better for B. DILI is also much better for B.

**Overall Assessment:**

While Ligand A has a better half-life and metabolic stability, Ligand B's significantly superior binding affinity (-0.0 kcal/mol vs -6.8 kcal/mol), lower DILI risk, better solubility, and lower hERG inhibition liability are more critical for a kinase inhibitor. The difference in affinity is substantial. The better TPSA and lower HBD of ligand B also suggest better permeability.

Output:
1
2025-04-17 12:27:16,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.379 and 355.479 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.39) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (89.95) is excellent, well below 140 and potentially better for absorption.

**logP:** Ligand A (-0.144) is a bit low, potentially hindering permeability. Ligand B (0.758) is 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 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Ligand B (0.736) has a significantly better QED score than Ligand A (0.361), indicating a more drug-like profile.

**DILI:** Ligand B (32.299) has a much lower DILI risk than Ligand A (46.452), both are acceptable but B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.335) is higher than Ligand B (26.367).

**Caco-2:** Both are negative, indicating poor permeability, but Ligand A (-5.152) is worse than Ligand B (-4.797).

**Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility, but Ligand A (-1.896) is slightly better than Ligand B (-1.642).

**hERG:** Both ligands have very low hERG risk (0.121 and 0.258), which is excellent.

**Microsomal Clearance:** Ligand A (23.808) has a significantly lower microsomal clearance than Ligand B (38.885), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.077) has a positive half-life, while Ligand B (-12.062) has a negative half-life, indicating Ligand A is more stable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.025).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.5 kcal/mol). Ligand A is slightly better, but the difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a superior QED score, lower DILI risk, and a better logP. However, Ligand A has better metabolic stability (lower Cl_mic, positive half-life) and slightly better binding affinity. The poor Caco-2 and solubility for both are concerning, but the superior ADME profile of Ligand B, particularly the lower DILI and better QED, outweighs the slight advantage in binding affinity and metabolic stability of Ligand A.

Output:
1
2025-04-17 12:27:16,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.5 and 344.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is better than Ligand B (68.84), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.087 and 1.934), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=0, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.819 and 0.77), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (37.611 and 34.238), both below the 40 threshold.

**BBB:** Ligand B (70.686) has a better BBB penetration percentile than Ligand A (52.579), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.937 and -4.932). This is unusual and suggests a potential issue with in vitro permeability assessment. However, we'll proceed assuming this is an artifact of the prediction method.

**Aqueous Solubility:** Ligand B (-0.892) has better aqueous solubility than Ligand A (-3.229). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.132 and 0.212).

**Microsomal Clearance:** Ligand A (20.061) has significantly lower microsomal clearance than Ligand B (41.063), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-13.819) has a longer in vitro half-life than Ligand B (-5.985). This is another significant advantage for metabolic stability and potentially less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.112 and 0.173).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial difference (1.4 kcal/mol), and is a significant factor.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better H-bonding characteristics, Ligand B's significantly stronger binding affinity (-8.2 vs -6.8 kcal/mol) outweighs these advantages. The difference in affinity is large enough to overcome the slightly higher clearance and lower solubility of Ligand B. Solubility is not a major concern given the low values for both.

Output:
1
2025-04-17 12:27:16,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.391 and 372.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.84) is slightly above the optimal <140 for good absorption, while Ligand B (95.94) is well within the range.

**logP:** Ligand A (-1.093) is a bit low, potentially hindering permeation. Ligand B (0.427) is better, falling within the 1-3 range.

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

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

**QED:** Ligand B (0.632) has a significantly better QED score than Ligand A (0.181), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (33.385 and 40.752, both <40).

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.634 and -5.299). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.6 and -1.521). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.044 and 0.123). This is excellent.

**Microsomal Clearance:** Ligand A (-26.687) has much lower (better) microsomal clearance than Ligand B (15.32), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.543) has a slightly better in vitro half-life than Ligand B (0.608).

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.006 and 0.029).

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.1), although the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand B has a better overall profile due to its superior QED, logP, and binding affinity. While both have poor solubility and Caco-2 permeability, the slightly better metabolic stability of Ligand A is not enough to offset the advantages of Ligand B. The small affinity difference is unlikely to outweigh the other ADME properties.

Output:
1
2025-04-17 12:27:16,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.447 and 347.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (75.94 and 76.07) below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have logP values (2.518 and 2.427) 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 acceptable (<=10).

**QED:** Both ligands have high QED scores (0.903 and 0.8), indicating good drug-like properties.

**DILI:** Ligand A (66.382) has a slightly higher DILI risk than Ligand B (60.915), but both are moderately risky.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.788) has a slightly better BBB score than Ligand B (55.332).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.115 and -4.644), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.769 and -2.706). This is a major drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.089 and 0.138), which is excellent.

**Microsomal Clearance:** Ligand A (41.41 mL/min/kg) has significantly better metabolic stability (lower clearance) than Ligand B (9.323 mL/min/kg).

**In vitro Half-Life:** Ligand A (17.61 hours) has a longer half-life than Ligand B (10.386 hours), which is favorable.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.14 and 0.051), which is good.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.9 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B is the more promising candidate due to its significantly stronger binding affinity (-8.6 kcal/mol vs -7.7 kcal/mol) and better metabolic stability (lower Cl_mic). The improved binding affinity is a critical factor for an enzyme target like SRC kinase, and the difference is large enough to potentially overcome the solubility and permeability issues through formulation strategies.

Output:
1
2025-04-17 12:27:16,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.375 and 344.371 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (130.14) is slightly above the preferred <140 for good oral absorption, while Ligand B (117.52) is well within the range.

**3. logP:** Both ligands (0.457 and 0.483) are a bit low, potentially hindering permeation. Ideally, we want 1-3.

**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 4 HBA, both within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.722 and 0.689, both >=0.5).

**7. DILI:** Ligand A (58.434) has a better DILI score than Ligand B (65.646), indicating lower liver injury risk. Both are acceptable, but A is preferable.

**8. BBB:** Ligand A (61.535) has a slightly better BBB penetration score than Ligand B (43.815), but BBB isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.532 and -5.981), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.99 and -3.181), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.186 and 0.159), which is excellent.

**12. Microsomal Clearance:** Ligand A (4.713) has a much lower microsomal clearance than Ligand B (-18.126). This suggests significantly better metabolic stability for Ligand A, a critical factor for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-46.246) has a much longer in vitro half-life than Ligand B (-16.384). This further supports its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.018).

**15. Binding Affinity:** Ligand B (-9.3) has a slightly better binding affinity than Ligand A (-8.8), a difference of 0.5 kcal/mol. While a difference of >1.5 kcal/mol would be highly influential, 0.5 kcal/mol is not enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the better candidate despite the slightly weaker binding affinity. Its superior metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and slightly better BBB penetration outweigh the small difference in binding affinity. Both compounds have poor Caco-2 and solubility, which would need to be addressed in further optimization, but Ligand A's profile is more favorable overall.

Output:
0
2025-04-17 12:27:16,595 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (345.403 and 350.415 Da) fall comfortably within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Both ligands (107.19 and 103.01) are below the 140 A^2 threshold for good oral absorption. Ligand B is slightly better, closer to the ideal.

3. **logP:** Ligand A (0.308) is quite low, potentially hindering permeation. Ligand B (0.912) is better, falling within the optimal 1-3 range. This is a notable advantage for Ligand B.

4. **HBD:** Both have 3 HBD, which is acceptable.

5. **HBA:** Both have 5 HBA, also acceptable.

6. **QED:** Both ligands have good QED scores (0.712 and 0.732), indicating good drug-like properties.

7. **DILI:** Ligand A (51.609) has a higher DILI risk than Ligand B (37.03). Lower is better, so Ligand B is preferred.

8. **BBB:** This is less critical for a non-CNS target like SRC. Ligand B (47.111) shows better BBB penetration than Ligand A (25.94), but this isn't a major deciding factor.

9. **Caco-2:** Ligand A (-5.668) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.939) is still not great, but better than A.

10. **Solubility:** Ligand A (-2.023) has poor aqueous solubility. Ligand B (-1.61) is slightly better. Solubility is important for enzymes.

11. **hERG:** Both ligands have low hERG inhibition risk (0.069 and 0.151). This is good.

12. **Cl_mic:** Ligand A (-12.383) has a much lower (better) microsomal clearance than Ligand B (-4.217), indicating greater metabolic stability. This is a significant advantage for Ligand A.

13. **t1/2:** Ligand A (-31.369) has a very poor in vitro half-life. Ligand B (0.919) is much better, suggesting a longer duration of action.

14. **Pgp:** Both have very low Pgp efflux liability (0.01 and 0.046).

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 crucial advantage, potentially outweighing some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a substantial advantage in binding affinity. Ligand A has better metabolic stability, but its poor solubility and half-life are concerning. The significantly better binding affinity of Ligand B is likely to be more important, especially if further optimization can address its metabolic stability.

**Conclusion:**

Considering all factors, especially the strong binding affinity and better overall ADME profile (despite slightly lower metabolic stability), Ligand B is the more promising drug candidate.

Output:
1

2025-04-17 12:27:16,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.47 and 362.50 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is slightly higher than Ligand B (55.57). Both are below the 140 threshold for good oral absorption, but B is better.

**logP:** Both ligands have good logP values (3.188 and 3.582), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

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

**QED:** Ligand A (0.827) has a higher QED score than Ligand B (0.682), indicating better overall drug-likeness.

**DILI:** Ligand B (39.201) has a significantly lower DILI risk than Ligand A (61.884). This is a major advantage for Ligand B.

**BBB:** Ligand B (96.316) has a much higher BBB penetration percentile than Ligand A (55.293). While not a primary concern for a non-CNS target like SRC, it's not detrimental.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, it indicates poor permeability for both. Ligand A (-5.003) is slightly worse than Ligand B (-4.729).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, it indicates poor solubility for both. Ligand A (-4.971) is slightly worse than Ligand B (-4.284).

**hERG Inhibition:** Ligand A (0.243) has a lower hERG inhibition liability than Ligand B (0.762), which is preferable.

**Microsomal Clearance:** Ligand B (125.244) has a significantly higher microsomal clearance than Ligand A (48.021), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (55.426) has a longer in vitro half-life than Ligand B (41.043), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux liability than Ligand B (0.662), which is better.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). The difference is 0.6 kcal/mol, which is a meaningful advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity and lower DILI risk, which are key advantages. However, its significantly higher microsomal clearance and shorter half-life are major concerns. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), better solubility and permeability (although both are poor), and lower P-gp efflux. The binding affinity difference, while present, isn't large enough to overcome the metabolic liabilities of Ligand B. Given the enzyme-specific priorities, metabolic stability is crucial.

Output:
0
2025-04-17 12:27:16,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.415 and 372.523 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.55) is better than Ligand B (68.52), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.452) is optimal, while Ligand B (3.591) is approaching the upper limit.

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

**H-Bond Acceptors:** Ligand A (5) and Ligand B (8) are both within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED scores (0.743 and 0.686, both >0.5).

**DILI:** Ligand B (69.058) has a higher DILI risk than Ligand A (57.697), though both are above the preferred <40.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (71.307) is slightly better than Ligand A (49.981).

**Caco-2 Permeability:** Ligand A (-4.983) is better than Ligand B (-5.776), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.334) is better than Ligand B (-3.526), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.199 and 0.132).

**Microsomal Clearance:** Ligand B (45.407) has lower microsomal clearance than Ligand A (49.926), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (6.788) has a longer half-life than Ligand A (-15.895), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.34).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.7 kcal/mol). This difference is negligible.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, Caco-2 permeability, and solubility. However, Ligand B has a significantly longer in vitro half-life and lower microsomal clearance, which are critical for an enzyme target. The slightly higher DILI risk for Ligand B is a concern, but the improved metabolic stability is a stronger factor for kinase inhibitors. The binding affinity is essentially the same.

Output:
1
2025-04-17 12:27:16,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.463 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than Ligand B (60.85). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.575) is quite low, potentially hindering permeability. Ligand B (1.614) 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 1 HBD and 3 HBA. Both are within acceptable limits, but Ligand B's lower count may slightly favor permeability.

**QED:** Both ligands have good QED scores (0.646 and 0.765), indicating drug-like properties.

**DILI:** Ligand A (7.445) has a very favorable DILI score, significantly lower than Ligand B (8.104). This is a strong point for Ligand A.

**BBB:** Ligand A (60.954) and Ligand B (83.56) both have scores that are not particularly relevant for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-4.993) has poor Caco-2 permeability, while Ligand B (-4.548) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.934) and Ligand B (-2.335) both have poor solubility.

**hERG:** Ligand A (0.101) has a very low hERG risk, a significant advantage. Ligand B (0.433) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-2.265) shows excellent metabolic stability (negative value suggests slow clearance), while Ligand B (28.256) has a high clearance, indicating rapid metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-7.626) has a very long half-life, consistent with its low clearance. Ligand B (-14.932) has a very short half-life.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, while Ligand B (0.111) is slightly higher.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG) and metabolic stability (Cl_mic, t1/2), and P-gp efflux. However, its low logP and poor Caco-2 permeability are concerning. Ligand B has a much better binding affinity and a more favorable logP, but suffers from poor metabolic stability and a slightly higher DILI risk.

Given that SRC is an enzyme, potency (affinity) and metabolic stability are paramount. While Ligand A has superior ADME properties, the significantly stronger binding affinity of Ligand B (-8.0 vs -6.1 kcal/mol) is a decisive factor. A 1.9 kcal/mol difference is substantial and can be addressed through further optimization. The metabolic instability of Ligand B is a concern, but potentially mitigable through structural modifications.

Output:
1
2025-04-17 12:27:16,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.387 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.87) is slightly higher than Ligand B (77.57), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.973) is within the optimal 1-3 range. Ligand B (0.408) is a bit low, potentially hindering permeation.

**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 good QED scores (0.74 and 0.808), indicating drug-like properties.

**DILI:** Ligand A (75.029) has a higher DILI risk than Ligand B (19.155). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.721) is better than Ligand B (43.273), but not a deciding factor.

**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 have very low hERG inhibition risk (0.169 and 0.19), which is excellent.

**Microsomal Clearance:** Ligand A (24.817) has a much better (lower) microsomal clearance than Ligand B (-34.371). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand B (13.053) has a slightly longer half-life than Ligand A (12.024), but the difference is minor.

**P-gp Efflux:** Both have low P-gp efflux liability (0.121 and 0.005), which is favorable.

**Binding Affinity:** Ligand B (-9.9 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 threshold.

**Conclusion:**

Despite Ligand A's better metabolic stability, the significantly stronger binding affinity of Ligand B (-9.9 vs -7.2 kcal/mol) and its much lower DILI risk (19.155 vs 75.029) outweigh the potential concerns regarding its slightly lower logP. The affinity difference is large enough to likely overcome any permeability issues. The DILI risk for Ligand A is a major red flag.

Output:
1
2025-04-17 12:27:16,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (383.455 and 372.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.54) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (84.5) is well within the optimal range.

**logP:** Ligand A (0.042) is quite low, potentially hindering permeability. Ligand B (1.875) is 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 9 HBA, close to the upper limit of 10. Ligand B has 4 HBA, well within the acceptable range.

**QED:** Both ligands have good QED scores (0.693 and 0.765), indicating drug-like properties.

**DILI:** Ligand A (72.005) has a higher DILI risk than Ligand B (60.217), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.466) has a higher BBB value than Ligand A (21.598).

**Caco-2 Permeability:** Ligand A (-5.893) shows poor permeability. Ligand B (-4.935) is better, but still not great.

**Aqueous Solubility:** Ligand A (-1.6) has slightly better solubility than Ligand B (-3.389).

**hERG:** Both ligands have very low hERG risk (0.101 and 0.38), which is excellent.

**Microsomal Clearance:** Ligand A (-9.321) has significantly *lower* (better) microsomal clearance than Ligand B (52.664), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.642) has a longer half-life than Ligand B (-5.794), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03 and 0.161).

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity and acceptable QED and hERG profiles, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility. Ligand B has a better logP and TPSA, but the metabolic liabilities of Ligand B are concerning. The poor Caco-2 permeability of Ligand A is a drawback, but the improved metabolic stability is more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:27:16,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.395 & 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.43) is slightly higher than Ligand B (73.2). Both are below the 140 threshold for good oral absorption, which is positive.

**logP:** Both ligands have good logP values (3.607 & 3.273), 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 within the acceptable limit of 10.

**QED:** Ligand A (0.811) has a significantly better QED score than Ligand B (0.685), indicating a more drug-like profile.

**DILI:** Ligand A (77.2) has a higher DILI risk than Ligand B (19.349). This is a significant negative for Ligand A.

**BBB:** Ligand A (85.459) has better BBB penetration than Ligand B (58.24), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.396) has worse Caco-2 permeability than Ligand B (-4.651). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-5.481) has worse solubility than Ligand B (-3.073). Solubility is important for bioavailability.

**hERG:** Ligand A (0.261) has a lower hERG risk than Ligand B (0.619), which is a positive.

**Microsomal Clearance:** Ligand A (94.958) has a much higher microsomal clearance than Ligand B (42.313). This suggests Ligand A will be cleared more quickly, reducing its duration of action. Lower clearance is preferred.

**In vitro Half-Life:** Ligand A (-0.424) has a shorter half-life than Ligand B (-0.567). This further supports the concern about metabolic stability.

**P-gp Efflux:** Ligand A (0.379) has lower P-gp efflux than Ligand B (0.136). Lower efflux is generally preferred.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.0 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Despite having slightly better QED, BBB, and P-gp efflux, Ligand A suffers from significantly higher DILI risk, poorer solubility, and substantially higher microsomal clearance/shorter half-life. These ADME properties are critical for a successful kinase inhibitor. Ligand B, while having a slightly lower QED, presents a much more favorable safety profile (lower DILI) and better metabolic stability (lower Cl_mic, longer t1/2), alongside acceptable solubility. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:27:16,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.39 and 372.506 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (51.66) is well within the ideal range.

**logP:** Both ligands (2.514 and 3.708) are within the optimal 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not critically.

**H-Bond Donors:** Ligand A has 3 HBD, which is good. Ligand B has 0, also good.

**H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.671 and 0.62), indicating good drug-like properties.

**DILI:** Ligand A (35.479) has a slightly higher DILI risk than Ligand B (20.202), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (97.751) has a much higher BBB penetration than Ligand A (63.746).

**Caco-2 Permeability:** Ligand A (-5.075) has poor Caco-2 permeability, which is a significant concern. Ligand B (-4.397) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.706 and -4.234). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.14) has a lower hERG inhibition liability than Ligand B (0.425), which is preferable.

**Microsomal Clearance:** Ligand A (35.056) has significantly lower microsomal clearance than Ligand B (99.4), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-12.303) has a negative half-life, which is concerning and likely an error in the data. Ligand B (13.542) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.026 and 0.285), which is favorable.

**Binding Affinity:** Ligand B (-10.0 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 both have poor solubility, Ligand B's significantly improved binding affinity (-10.0 vs -7.7 kcal/mol), better metabolic stability (lower Cl_mic), and reasonable half-life outweigh the slightly higher logP and hERG risk. Ligand A's extremely poor Caco-2 permeability and negative half-life are major red flags. The difference in binding affinity is substantial enough to prioritize Ligand B despite the solubility issues, which could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:27:16,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 338.382 Da - Within the ideal range (200-500).
* Ligand B: 364.427 Da - Also within the ideal range.
* *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 40.62  - Excellent, well below the 140 threshold for oral absorption.
* Ligand B: 117.09 - Still acceptable for oral absorption, but higher than Ligand A.
* *Ligand A is better.*

**3. Lipophilicity (logP):**
* Ligand A: 2.222 - Optimal (1-3).
* Ligand B: 0.839 - Slightly low, potentially impacting permeability.
* *Ligand A is better.*

**4. H-Bond Donors (HBD):**
* Ligand A: 0 - Good, minimizes potential issues.
* Ligand B: 3 - Acceptable, but higher than A.
* *Ligand A is better.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 2 - Good.
* Ligand B: 6 - Acceptable, but higher than A.
* *Ligand A is better.*

**6. QED:**
* Ligand A: 0.776 - Excellent, strong drug-like profile.
* Ligand B: 0.639 - Good, but slightly lower than A.
* *Ligand A is better.*

**7. DILI:**
* Ligand A: 47.926 - Low risk.
* Ligand B: 72.082 - Moderate risk, higher than A.
* *Ligand A is better.*

**8. BBB:**
* Ligand A: 87.476 - Good, but SRC is not a CNS target, so this is less critical.
* Ligand B: 25.785 - Low.
* *Not a major deciding factor.*

**9. Caco-2 Permeability:**
* Ligand A: -4.36 - This is a negative value, which is unusual. Assuming this is a log scale, it indicates very poor permeability.
* Ligand B: -5.788 - Also poor permeability, but slightly worse than A.
* *Ligand A is slightly better.*

**10. Aqueous Solubility:**
* Ligand A: -3.585 - Poor solubility.
* Ligand B: -2.864 - Better solubility than A, though still poor.
* *Ligand B is better.*

**11. hERG Inhibition:**
* Ligand A: 0.473 - Low risk.
* Ligand B: 0.125 - Very low risk.
* *Ligand B is better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 18.828 mL/min/kg - Moderate clearance.
* Ligand B: 37.786 mL/min/kg - Higher clearance, less metabolic stability.
* *Ligand A is better.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -11.122 hours - Negative half-life is not possible. Assuming this is a log scale, it indicates a very short half-life.
* Ligand B: -23.159 hours - Also a very short half-life.
* *Both are poor.*

**14. P-gp Efflux:**
* Ligand A: 0.202 - Low efflux, good.
* Ligand B: 0.035 - Very low efflux, excellent.
* *Ligand B is better.*

**15. Binding Affinity:**
* Ligand A: -6.7 kcal/mol - Good affinity.
* Ligand B: -7.0 kcal/mol - Slightly better affinity.
* *Ligand B is better.*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a slightly better binding affinity and significantly better hERG risk and P-gp efflux. While Ligand A has better TPSA, logP, QED, and DILI, the solubility and metabolic stability of Ligand B are more crucial for an enzyme inhibitor. The poor half-life for both is a concern, but can be addressed in later optimization. The poor permeability of both is also a concern.

Output:
1
2025-04-17 12:27:16,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.5 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is better than Ligand B (80.56), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.273) is optimal (1-3), while Ligand B (0.676) is a bit low, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A (3) is good, and Ligand B (6) is still within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.685 and 0.723), indicating drug-likeness.

**DILI:** Ligand A (19.349) has a significantly lower DILI risk than Ligand B (42.575), which is a major advantage. Both are below the 60 threshold, but A is much preferred.

**BBB:** Ligand B (78.364) has a higher BBB penetration percentile than Ligand A (58.24), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.651) and Ligand B (-4.939) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.073) is better than Ligand B (-0.931), indicating better solubility.

**hERG:** Ligand A (0.619) has a lower hERG risk than Ligand B (0.08), which is a significant advantage.

**Microsomal Clearance:** Ligand A (42.313) and Ligand B (41.12) are similar. Both are relatively low, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (-0.567) has a slightly better half-life than Ligand B (-4.548).

**P-gp Efflux:** Ligand A (0.136) has lower P-gp efflux liability than Ligand B (0.075), which is preferable.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.0), but the difference is less than the 1.5 kcal/mol threshold that could outweigh other issues.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk, better solubility, lower hERG risk, and slightly better half-life and P-gp efflux. While Ligand B has a slightly better binding affinity and BBB penetration, the ADME-Tox profile of Ligand A is more favorable for development as a kinase inhibitor. The lower logP of Ligand B is also a concern.

Output:
0
2025-04-17 12:27:16,596 - INFO - Batch 131 complete. Total preferences: 2096
2025-04-17 12:27:16,596 - INFO - Processing batch 132/512...
2025-04-17 12:27:59,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.5 and 346.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (99.23). A TPSA under 140 is good for oral absorption, and A is much closer to the ideal.

**logP:** Both ligands have acceptable logP values (1.498 and 2.032, 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 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.605 and 0.849), indicating drug-likeness.

**DILI:** Ligand A (9.965) has a significantly lower DILI risk than Ligand B (31.989). This is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (70.57) is slightly better than Ligand B (61.535).

**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 (-4.822) is slightly better than Ligand B (-4.991).

**Aqueous Solubility:** Both have negative solubility values, again unusual. Assuming these are logS-like scales, lower values indicate poorer solubility. Ligand A (-1.192) is better than Ligand B (-2.491).

**hERG:** Ligand A (0.691) has a lower hERG risk than Ligand B (0.233), which is preferable.

**Microsomal Clearance:** Both have similar microsomal clearance values (32.901 and 32.576 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-10.54) has a *longer* in vitro half-life than Ligand B (-19.787). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.077), which is good.

**Binding Affinity:** Ligand B (-8.5 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 offset by other factors.

**Overall:**

Ligand A has several advantages: lower DILI risk, better TPSA, better solubility, better hERG risk, and a longer half-life. While Ligand B has slightly better binding affinity, the other ADME properties of Ligand A are significantly more favorable, making it a more promising drug candidate.

Output:
1
2025-04-17 12:27:59,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.547 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.71) is significantly better than Ligand B (115.9). A TPSA under 140 is good for oral absorption, but A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (1.724) is within the optimal 1-3 range. Ligand B (-0.374) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=3, HBA=6). Both are acceptable, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.883, B: 0.531), indicating good drug-like properties.

**DILI:** Ligand A (13.416) has a much lower DILI risk than Ligand B (34.587). This is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (76.541) is higher than Ligand B (45.522), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.801) is better than Ligand B (-5.788), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.457) is better than Ligand B (-1.423). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (A: 0.654, B: 0.033), which is excellent.

**Microsomal Clearance:** Ligand A (-24.064) has a significantly *lower* (better) microsomal clearance than Ligand B (-4.906). This suggests better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.17) has a longer half-life than Ligand B (3.133). This is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.023, B: 0.007).

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

**Conclusion:**

Ligand A is clearly superior. While both ligands exhibit excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better ADME properties: lower DILI risk, better TPSA, better solubility, better permeability, lower clearance, and longer half-life. These factors are crucial for developing a viable drug candidate targeting a kinase like SRC.

Output:
1
2025-04-17 12:27:59,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.575 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, while Ligand B (87.32) is still acceptable but higher. Lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (2.357 and 1.532), falling within the optimal 1-3 range.

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

**QED:** Ligand A (0.748) has a significantly better QED score than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (34.742), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (65.529) is better than Ligand B (55.37).

**Caco-2 Permeability:** Ligand A (-4.999) has a more negative Caco-2 value, indicating lower permeability, while Ligand B (-5.223) is also low. This is a potential concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.099 and -2.024). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.426 and 0.549), which is positive.

**Microsomal Clearance:** Ligand B (16.229) has a lower microsomal clearance than Ligand A (45.327), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-12.56) has a negative half-life, which is not possible and indicates a very short half-life, while Ligand A (14.863) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.051 and 0.202), which is favorable.

**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 significantly better binding affinity and better metabolic stability (lower Cl_mic). However, it has a concerningly short in vitro half-life and higher DILI risk. Ligand A has a better QED score, lower DILI risk, and a reasonable half-life, but its solubility and Caco-2 permeability are poor, and its binding affinity is weaker.

Given the enzyme-specific priorities, binding affinity and metabolic stability are paramount. The 1.5 kcal/mol difference in binding affinity is substantial. While the short half-life of Ligand B is concerning, it might be addressable through structural modifications. The poor solubility of both compounds is a significant issue, but could potentially be overcome with formulation strategies. The lower DILI risk of Ligand A is also a positive.

Considering all factors, the stronger binding affinity of Ligand B is the most important factor, making it the more promising candidate despite its drawbacks.

Output:
1
2025-04-17 12:27:59,185 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (366.849 Da) and Ligand B (351.426 Da) both fall within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (87.32) is slightly higher than Ligand B (80.12), but both are well below the 140 A^2 threshold for good oral absorption.

3. **logP:** Ligand A (2.486) is optimal, while Ligand B (1.113) is a bit low, potentially impacting permeability.

4. **HBD:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of 5. Ligand B is slightly better.

5. **HBA:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of 10.

6. **QED:** Ligand B (0.798) has a significantly better QED score than Ligand A (0.42), indicating a more drug-like profile.

7. **DILI:** Ligand A (59.519) has a higher DILI risk than Ligand B (35.673). Ligand B is preferable.

8. **BBB:** Ligand B (71.578) has a higher BBB percentile than Ligand A (44.668), but this is less critical for a non-CNS target like SRC.

9. **Caco-2:** Ligand A (-5.338) and Ligand B (-4.978) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

10. **Solubility:** Ligand A (-3.191) and Ligand B (-1.876) both have negative values, suggesting poor solubility. Again, the scale is not specified.

11. **hERG:** Ligand A (0.415) has a slightly better hERG profile than Ligand B (0.083).

12. **Cl_mic:** Ligand B (-6.793) has a *much* lower (and therefore better) microsomal clearance than Ligand A (7.159), indicating greater metabolic stability. This is a key consideration for kinase inhibitors.

13. **t1/2:** Ligand B (-3.589) has a better in vitro half-life than Ligand A (-16.682).

14. **Pgp:** Ligand A (0.092) has a slightly better Pgp efflux profile than Ligand B (0.019).

15. **Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Conclusion:**

Ligand B clearly outperforms Ligand A. It has a significantly better QED score, lower DILI risk, much better metabolic stability (Cl_mic and t1/2), and a slightly better binding affinity. While both have issues with Caco-2 and solubility, the metabolic stability advantage of Ligand B is crucial for an enzyme target. The slightly lower logP of Ligand B is a minor concern compared to the benefits.

Output:
1
2025-04-17 12:27:59,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.442 and 348.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.12) is better than Ligand B (66.48), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (4.513) is higher than ideal (1-3), potentially causing solubility issues. Ligand B (1.623) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) and Ligand B (HBD=1, HBA=3) both have reasonable H-bond counts, well within the acceptable limits.

**QED:** Ligand A (0.805) has a significantly better QED score than Ligand B (0.606), indicating a more drug-like profile.

**DILI:** Ligand B (32.803) has a much lower DILI risk than Ligand A (55.68), which is a significant advantage.

**BBB:** Ligand B (92.943) has a higher BBB penetration percentile than Ligand A (80.962). While not a primary concern for a kinase inhibitor, it isn't detrimental.

**Caco-2 Permeability:** Ligand A (-4.745) and Ligand B (-5.021) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand B (-2.767) is better than Ligand A (-5.754), indicating better solubility.

**hERG Inhibition:** Ligand A (0.837) has a slightly higher hERG risk than Ligand B (0.124), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (18.098) has a much lower microsomal clearance than Ligand A (70.326), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-35.758) has a negative in vitro half-life, which is very concerning. Ligand A (25.659) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux than Ligand B (0.211), which is a slight advantage.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a better binding affinity than Ligand B (-7.8 kcal/mol). This is a 0.7 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a reasonable half-life, but suffers from higher logP, DILI risk, hERG risk, and clearance. Ligand B has better ADME properties (lower DILI, hERG, clearance, better solubility) but a weaker binding affinity and a concerning negative half-life.

The binding affinity difference is significant. However, the poor half-life of Ligand B is a major drawback. While the ADME profile of Ligand B is generally better, the negative half-life suggests rapid degradation, which would likely necessitate very high doses and frequent administration. The improved affinity of Ligand A, combined with a reasonable half-life, makes it the more promising candidate, despite its other shortcomings. Optimization could focus on reducing logP and improving solubility while retaining the strong binding affinity.

Output:
0
2025-04-17 12:27:59,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (374.438 Da) is still well within the acceptable range.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (112.23) is lower than Ligand A (130.9), which is slightly favorable.

**logP:** Ligand A (1.235) is within the optimal range (1-3), while Ligand B (0.21) is quite low. A low logP can hinder membrane permeability and potentially reduce binding affinity. This is a significant drawback for Ligand B.

**H-Bond Donors & Acceptors:** Both ligands have acceptable numbers of HBDs (Ligand A: 4, Ligand B: 2) and HBAs (both 5), falling within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.563, Ligand B: 0.739), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Both ligands have DILI risk above 60, indicating a moderate to high risk of liver injury. This is a concern for both, but not a deciding factor between them.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (55.874) has a higher BBB percentile than Ligand A (11.439), but this is not a primary concern.

**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 very poor solubility. This is a significant issue for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.718, Ligand B: 0.331), which is excellent and minimizes cardiotoxicity risk. Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (5.776) has a lower clearance than Ligand B (-6.424), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Both ligands have the same in vitro half-life (-29.1 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.093, Ligand B: 0.048).

**Binding Affinity:** Both ligands have similar binding affinities (Ligand A: -9.5 kcal/mol, Ligand B: -9.1 kcal/mol). The difference is less than 1.5 kcal/mol, so this is not a deciding factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While both have solubility and permeability concerns, Ligand A has a significantly better logP value, which is crucial for membrane permeability and binding. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic). The binding affinity difference is minimal. Therefore, Ligand A is more likely to be a viable drug candidate.

Output:
0
2025-04-17 12:27:59,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.299 Da and 355.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.59) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (95.67) is excellent, well below 140.

**logP:** Both ligands (1.288 and 1.628) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (8) and Ligand B (5) are both within the acceptable limit of <=10.

**QED:** Ligand B (0.775) has a significantly better QED score than Ligand A (0.491), indicating a more drug-like profile.

**DILI:** Ligand B (54.168) has a much lower DILI risk than Ligand A (88.368). This is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (70.143) has a slightly better BBB score than Ligand B (59.868).

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.948 and -4.911). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.95 and -2.081). This is a significant drawback that would need to be addressed.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.312 and 0.326), which is excellent.

**Microsomal Clearance:** Ligand B (29.062) has a lower microsomal clearance than Ligand A (40.63), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-6.282) has a longer in vitro half-life than Ligand A (-3.312), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.234 and 0.142).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). Although the difference is small, it's still a positive.

**Overall Assessment:**

Ligand B is the superior candidate. It has a better QED score, significantly lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both ligands have poor solubility and Caco-2 permeability, the ADME advantages of Ligand B outweigh the small difference in binding affinity. The lower DILI risk is particularly important for an oncology target.

Output:
1
2025-04-17 12:27:59,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.39 and 378.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.58) is better than Ligand B (138.67). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (-0.395 and -1.323, respectively), falling within the 1-3 range, although on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.701 and 0.526), indicating drug-likeness.

**DILI:** Ligand A (24.31) has a significantly lower DILI risk than Ligand B (39.43), which is a major advantage.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 (-1.769 and -1.973). This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.039 and 0.087), which is excellent.

**Microsomal Clearance:** Ligand A (-18.15) has a much lower (better) microsomal clearance than Ligand B (-27.93). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-13.395) has a negative half-life, which is not possible. This is a red flag. Ligand B (21.851) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.009 and 0.016).

**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).

**Overall Assessment:**

Ligand A has several advantages: lower DILI risk, better TPSA, and significantly better microsomal clearance. However, the negative in vitro half-life is a critical flaw. Ligand B has a reasonable half-life, but suffers from higher DILI risk and worse metabolic stability. The slightly better binding affinity of Ligand B is unlikely to overcome the ADME liabilities. Given the importance of metabolic stability for kinase inhibitors, and the severe issue with Ligand A's half-life, neither is ideal. However, the DILI risk is a major concern for Ligand B.

Output:
0
2025-04-17 12:27:59,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (433.368 and 407.243 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is well below the 140 threshold for good absorption and is also favorable. Ligand B (77.29) is still acceptable but less optimal.

**3. logP:** Both ligands have logP values within the optimal range (2.371 and 3.315).

**4. H-Bond Donors:** Ligand A has 0 HBD, which is excellent. Ligand B has 1 HBD, still acceptable.

**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 (0.59 and 0.706), indicating drug-like properties.

**7. DILI:** Ligand A (29.391) has a much lower DILI risk than Ligand B (77.045). This is a significant advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.6) has a higher BBB score than Ligand A (72.082), but this isn't a major factor here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.712 and -4.845), 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 (-1.888 and -4.221), indicating poor aqueous solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.732 and 0.752).

**12. Microsomal Clearance:** Ligand A (77.593) has a higher microsomal clearance than Ligand B (39.946), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-2.772) has a significantly longer in vitro half-life than Ligand A (27.5). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.219 and 0.345).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.9 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and a lower DILI risk. The superior binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:27:59,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 354.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (65.12), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.683) is slightly better than Ligand B (0.158), both are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1), both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (4) is less than Ligand B (5), both are within the acceptable limit of 10.

**QED:** Ligand B (0.598) is better than Ligand A (0.471), indicating a more drug-like profile.

**DILI:** Ligand B (3.8) is significantly better than Ligand A (13.532), indicating a much lower risk of drug-induced liver injury. This is a crucial advantage.

**BBB:** Ligand A (65.684) is better than Ligand B (53.354), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.881) is better than Ligand B (-5.029), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand B (-0.007) is better than Ligand A (-2.25), indicating better solubility.

**hERG Inhibition:** Ligand A (0.165) is better than Ligand B (0.596), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-7.021) is significantly better than Ligand A (54.149), indicating much higher metabolic stability. This is a major advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-20.566) is better than Ligand A (-24.605), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.039) is better than Ligand B (0.006), indicating lower P-gp efflux.

**Binding Affinity:** Ligand A (-8.9) is significantly better than Ligand B (-6.8), a difference of 2.1 kcal/mol. This is a substantial advantage in potency.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much more favorable ADMET profile. Specifically, the significantly lower DILI risk and dramatically improved metabolic stability (lower Cl_mic, longer t1/2) of Ligand B are critical advantages for an enzyme inhibitor. The better solubility of Ligand B is also beneficial. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand B, whereas mitigating the poor ADMET properties of Ligand A would be more challenging.

Output:
1
2025-04-17 12:27:59,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (342.483 and 345.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (65.18). A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (2.868 and 2.116), 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 6. Ligand A is preferable here, as staying below 10 is ideal.

**6. QED:** Both ligands have good QED scores (0.723 and 0.832), indicating good drug-like properties.

**7. DILI:** Ligand B (42.846) has a slightly better DILI score than Ligand A (11.245), indicating lower potential for liver injury. However, both are below the concerning threshold of 60.

**8. BBB:** Both ligands have reasonable BBB penetration (70.764 and 66.344). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a major worry.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.6 and -4.774), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Ligand A (-4.179) is slightly better than Ligand B (-1.838), indicating better solubility. Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.394 and 0.26), which is excellent.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (40.726 and 42.994 mL/min/kg), suggesting similar metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.737 hours) has a significantly longer half-life than Ligand B (4.868 hours). This is a major advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.148).

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 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 DILI score, Ligand A is superior overall. The longer half-life of Ligand A is a significant advantage for a kinase inhibitor. Ligand A also has better TPSA, HBA, and solubility. The Caco-2 permeability is poor for both, but the other advantages of Ligand A outweigh the slight affinity benefit of Ligand B.

Output:
1
2025-04-17 12:27:59,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Ligand A (343.431 Da) is well within the ideal range (200-500 Da). Ligand B (459.078 Da) is at the upper limit, but still acceptable.

**TPSA:** Both ligands (A: 83.28, B: 81.07) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.75) is within the optimal range (1-3). Ligand B (3.485) is slightly higher but still reasonable.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.783, B: 0.694), indicating good drug-like properties.

**DILI:** Ligand A (50.136) has a lower DILI risk than Ligand B (74.835), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.562) is slightly lower than Ligand B (78.286).

**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 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 have very low hERG inhibition risk (A: 0.188, B: 0.236), which is excellent.

**Microsomal Clearance:** Ligand A (-2.476) has *much* lower (better) microsomal clearance than Ligand B (31.415). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (17.207 hours) has a longer half-life than Ligand B (34.076 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.053, B: 0.332), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), but the difference is small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of DILI risk and microsomal clearance. The lower DILI and significantly improved metabolic stability of Ligand A are crucial for a successful drug candidate. The small difference in binding affinity is unlikely to outweigh the substantial benefits in ADME. The negative values for Caco-2 and solubility are concerning for both, but the other factors heavily favor Ligand A.

Output:
0
2025-04-17 12:27:59,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (82.81) is significantly better than Ligand B (48.3). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (2.792) being slightly preferred. Ligand B (4.35) is approaching the upper limit and could potentially cause solubility issues.

**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, but the presence of some HBDs in Ligand A can aid solubility.

**QED:** Ligand A (0.755) has a much better QED score than Ligand B (0.366), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (Ligand A: 74.603, Ligand B: 76.464). This is a concern, but not a deciding factor at this stage.

**BBB:** Ligand B (71.772) has a better BBB score than Ligand A (51.725). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.849 and -4.843). This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.517 and -4.589). This is a concern, but could potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.879 and 0.246), which is positive. Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (52.742) has significantly better microsomal clearance than Ligand B (119.837), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-17.124) has a better (longer) in vitro half-life than Ligand B (40.739). This is another advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.406 and 0.789).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand A's superior QED, metabolic stability (lower Cl_mic, longer t1/2), and slightly better logP outweigh the slightly better BBB penetration of Ligand B. The binding affinity is comparable. Given the enzyme-specific priorities, metabolic stability and a drug-like profile are paramount.

Output:
0
2025-04-17 12:27:59,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.799 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (58.12 and 58.64) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (3.247) is slightly higher than Ligand B (2.114), both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, meeting the criteria of <=5 and <=10 respectively.

**QED:** Ligand A (0.844) has a higher QED score than Ligand B (0.777), indicating a more drug-like profile.

**DILI:** Ligand A (85.653) has a significantly higher DILI risk than Ligand B (37.456). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (80.07) is higher than Ligand B (57.619). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.688) has a worse Caco-2 permeability than Ligand B (-5.218), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.423) has worse aqueous solubility than Ligand B (-3.011).

**hERG:** Ligand A (0.566) has a higher hERG risk than Ligand B (0.159). This is a significant safety concern for Ligand A.

**Microsomal Clearance:** Ligand A (66.513) has a higher microsomal clearance than Ligand B (51.792), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.719) has a significantly longer in vitro half-life than Ligand A (31.202). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.236) has a higher P-gp efflux liability than Ligand B (0.112).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol), with Ligand A being slightly better. However, the difference is less than the 1.5 kcal/mol threshold that would outweigh other issues.

**Conclusion:**

Despite slightly better affinity and BBB penetration, Ligand A has significant liabilities: high DILI risk, higher hERG risk, lower solubility, lower Caco-2 permeability, and lower metabolic stability. Ligand B, while having slightly lower affinity, presents a much more favorable ADMET profile, with lower toxicity risks, better solubility, better permeability, and improved metabolic stability. Given the priorities for enzyme inhibitors, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:27:59,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (351.359 and 350.547 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (110.97) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (58.2) is excellent, well below 90, suggesting good permeability.

**3. logP:** Ligand A (0.023) is quite low, potentially hindering permeation. Ligand B (3.896) is near the upper end of the optimal range (1-3), but still acceptable.

**4. H-Bond Donors (HBD):** Ligand A (1) is good. Ligand B (2) is also good, both are <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (7) is good, below the threshold of 10. Ligand B (2) is excellent.

**6. QED:** Both ligands have reasonable QED scores (0.745 and 0.663), indicating good drug-like properties.

**7. DILI:** Ligand A (62.195) has a moderate DILI risk. Ligand B (20.202) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (60.876) has moderate BBB penetration. Ligand B (73.052) has good BBB penetration. While SRC isn't a CNS target, better BBB penetration can sometimes correlate with better overall bioavailability.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.609 and -4.639), which is unusual and suggests poor permeability based on this metric. This is concerning for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.993 and -4.095), also unusual and suggesting poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.075) has very low hERG inhibition risk. Ligand B (0.454) has a slightly higher, but still acceptable, hERG risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (45.216) has moderate clearance. Ligand B (72.282) has higher clearance, indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.28) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (5.954) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, which is good. Ligand B (0.184) has low P-gp efflux, also good.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Enzyme-Specific Priorities:** For kinases like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Overall Assessment:**

Ligand B is the better candidate despite its higher Cl_mic. Its significantly stronger binding affinity (-7.2 vs -8.3 kcal/mol) is a major advantage. It also has a much lower DILI risk and a reasonable half-life. While both have issues with Caco-2 and solubility, the affinity advantage of Ligand B is likely to be more impactful in driving efficacy. The negative half-life for Ligand A is a showstopper.

Output:
1
2025-04-17 12:27:59,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (397.871 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is slightly higher than Ligand B (53.51), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.389 and 2.827), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED scores (0.73 and 0.791), indicating good drug-like properties.

**DILI:** Ligand B (28.073) has a significantly lower DILI risk than Ligand A (55.836). This is a major advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (77.705 and 85.072), but this is less critical for a non-CNS target like SRC.

**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 difference isn't huge.

**Aqueous Solubility:** Ligand B (-1.726) has slightly better solubility than Ligand A (-4.234), though both are quite poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.598 and 0.335), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (60.758 and 60.489), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (11.872 hours) has a significantly longer half-life than Ligand A (-31.235 hours). The negative value for ligand A is concerning and suggests very rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.226 and 0.288).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have good potency and acceptable physicochemical properties, Ligand B demonstrates a significantly lower DILI risk and a much longer in vitro half-life. The slightly better solubility also contributes to its favorability. The negative Caco-2 values are a concern for both, but the other advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 12:27:59,187 - INFO - Batch 132 complete. Total preferences: 2112
2025-04-17 12:27:59,187 - INFO - Processing batch 133/512...
2025-04-17 12:28:49,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (358.825 and 350.409 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (67.43 and 64.33) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (3.724 and 3.252) 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:** Both ligands (3) are below the HBA threshold of <=10.

**6. QED:** Both ligands (0.821 and 0.743) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A has a DILI risk of 80.729, which is high (>60). Ligand B has a much lower DILI risk of 13.959, which is excellent (<40). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have high BBB penetration (77.162 and 88.29), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.559 and -4.187), which 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 (-5.733 and -3.501), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.552) and Ligand B (0.907) both show some hERG inhibition risk, but Ligand B is slightly higher.

**12. Microsomal Clearance:** Ligand A has a high microsomal clearance (89.959), indicating poor metabolic stability. Ligand B has a significantly lower clearance (44.152), suggesting better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A has a half-life of 56.704 hours, while Ligand B has a shorter half-life of 18.859 hours. Ligand A is preferable here.

**14. P-gp Efflux:** Ligand A (0.211) and Ligand B (0.409) both have low P-gp efflux, which is favorable.

**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 not huge, it is a consideration.

**Overall Assessment:**

Ligand B is the more promising candidate despite the slightly weaker binding affinity. The significantly lower DILI risk and improved metabolic stability (lower Cl_mic) are crucial advantages for an enzyme inhibitor. While both have poor solubility and permeability, the DILI and metabolic stability concerns with Ligand A are more problematic. The small difference in binding affinity can potentially be addressed through further optimization, but mitigating high DILI risk is more challenging.

Output:
1
2025-04-17 12:28:49,137 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (346.471 Da) is within the ideal range (200-500). Ligand B (366.546 Da) is also within range. No clear advantage here.
2. **TPSA:** Ligand A (60.85) is better than Ligand B (33.2). Lower TPSA generally favors better cell permeability, which is important for kinase inhibitors to reach their intracellular target.
3. **logP:** Ligand A (1.792) is optimal (1-3). Ligand B (4.848) is a bit high, potentially leading to solubility issues and off-target interactions.
4. **HBD:** Ligand A (1) is good. Ligand B (0) is also acceptable.
5. **HBA:** Both Ligand A (3) and Ligand B (3) are within the acceptable limit of 10.
6. **QED:** Ligand A (0.79) is better than Ligand B (0.691), indicating a more drug-like profile.
7. **DILI:** Ligand A (5.118) has a significantly lower DILI risk than Ligand B (20.938). This is a major advantage for Ligand A.
8. **BBB:** Both are relatively high, but Ligand B (90.074) is better than Ligand A (70.648). However, since SRC is not a CNS target, this is less critical.
9. **Caco-2:** Ligand A (-4.453) is better than Ligand B (-4.62). Higher values indicate better absorption.
10. **Solubility:** Ligand A (-1.731) is better than Ligand B (-4.907). Better solubility is crucial for bioavailability.
11. **hERG:** Ligand A (0.182) has a much lower hERG inhibition liability than Ligand B (0.723). This is a significant safety advantage.
12. **Cl_mic:** Ligand B (70.808) has lower microsomal clearance than Ligand A (11.579), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.
13. **t1/2:** Ligand B (24.226) has a much longer in vitro half-life than Ligand A (-15.848). This is a substantial advantage, potentially allowing for less frequent dosing.
14. **Pgp:** Ligand A (0.025) has lower P-gp efflux liability than Ligand B (0.762). Lower efflux is favorable for bioavailability.
15. **Binding Affinity:** Ligand B (-9.4) has a slightly better binding affinity than Ligand A (-8.5). While a 1.5 kcal/mol advantage is usually significant, the other ADME properties of Ligand B are concerning.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B has a better affinity and t1/2, but suffers from higher logP, DILI, hERG, and lower solubility. Ligand A has a more balanced profile with better solubility, lower toxicity (DILI, hERG), and acceptable affinity.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, the significantly improved safety profile (DILI, hERG) and better solubility of Ligand A, combined with acceptable affinity, make it the more promising drug candidate. The longer half-life of Ligand B is attractive, but the other liabilities are too significant to ignore.

Output:
0
2025-04-17 12:28:49,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.296 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.79) is well below the 140 threshold, suggesting good absorption. Ligand B (98.32) is higher, but still within a reasonable range, though potentially impacting absorption slightly.

**logP:** Ligand A (3.854) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.161) is lower, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.846 and 0.718), indicating good drug-like properties.

**DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (21.753). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.062) is higher than Ligand B (36.642), but not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.259) is very poor, indicating extremely low intestinal absorption. Ligand B (-5.152) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-5.766) has very poor solubility, which is a major concern. Ligand B (-1.572) is better, but still low.

**hERG Inhibition:** Ligand A (0.809) has a slightly elevated hERG risk, but not alarming. Ligand B (0.222) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (88.964) has a high microsomal clearance, suggesting poor metabolic stability. Ligand B (-15.661) has a negative clearance, indicating excellent metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (2.015) has a short half-life. Ligand B (-24.013) has a very long half-life, a major benefit.

**P-gp Efflux:** Ligand A (0.504) has moderate P-gp efflux. Ligand B (0.012) has very low P-gp efflux, improving bioavailability.

**Binding Affinity:** Ligand A (-8.3 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 its logP is a bit low and solubility is not ideal, its significantly better metabolic stability (negative Cl_mic, long half-life), lower DILI risk, and very low hERG and P-gp efflux liabilities are crucial advantages for an enzyme inhibitor. Ligand A's poor solubility, high DILI risk, and poor metabolic stability are major drawbacks that outweigh its slightly better binding affinity.

Output:
1
2025-04-17 12:28:49,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.483 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (86.88 and 80.12) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.181) is optimal, while Ligand B (1.546) is a bit low, potentially impacting permeability.

**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.

**QED:** Both ligands have similar QED scores (0.6 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (53.625) has a slightly higher DILI risk than Ligand B (39.899), but both are still reasonably low.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.407) has a higher BBB score, but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.738) and Ligand B (-4.883) both have negative values, which is unusual. Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.396 and -3.305). This is a significant concern.

**hERG Inhibition:** Ligand A (0.593) has a slightly higher hERG risk than Ligand B (0.123). This is a negative for Ligand A.

**Microsomal Clearance:** Ligand B (45.417 mL/min/kg) has a lower (better) microsomal clearance than Ligand A (25.614 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.454 hours) has a longer half-life than Ligand A (-8.444 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.186 and 0.102).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -8.3 kcal/mol). The difference is minimal.

**Conclusion:**

While both ligands exhibit good potency, Ligand B is preferable. It has a better metabolic stability profile (lower Cl_mic, longer t1/2), lower hERG risk, and a slightly better DILI score. The only drawback for Ligand B is a slightly lower logP, but this is outweighed by the improvements in ADME properties. The poor solubility of both is a concern that would need to be addressed through formulation strategies, but is not a deciding factor between the two.

Output:
1
2025-04-17 12:28:49,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.76 and 95.26) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (which requires <90). This isn't a major concern for a non-CNS targeted kinase inhibitor.

**logP:** Ligand A (0.508) is borderline low, potentially hindering permeation. Ligand B (0.295) is even lower, raising more concern about permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are within acceptable limits. Ligand B has 0 HBD and 9 HBA, also acceptable, but the lack of HBDs might slightly impact aqueous solubility.

**QED:** Both ligands (0.782 and 0.689) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (60.915), which is approaching a higher risk category. This is a substantial advantage for Ligand A.

**BBB:** Both have moderate BBB penetration, which isn't critical for a non-CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.145 and 0.144).

**Microsomal Clearance:** Ligand A (-8.946) has *much* lower (better) microsomal clearance than Ligand B (31.175), indicating significantly improved metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.28 hours) has a better in vitro half-life than Ligand B (-6.712 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.006).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has slightly better binding affinity than Ligand B (-8.0 kcal/mol). While the difference isn't huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While both have permeability and solubility concerns, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The slightly better binding affinity further supports this conclusion. The lower logP of Ligand B is also a concern. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial, making Ligand A the more promising drug candidate.

Output:
1
2025-04-17 12:28:49,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.535 Da and 362.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (75.94). A TPSA under 90 is generally acceptable, but lower is better for permeability. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.653 and 1.899), 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 7.  Lower HBA is generally preferred for better permeability, giving a slight edge to Ligand A.

**QED:** Both ligands have good QED scores (0.749 and 0.849), indicating good drug-like properties.

**DILI:** Ligand A (8.298) has a much lower DILI risk than Ligand B (78.247). This is a significant advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (70.531 and 76.347). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.926 and -5.155). These values are unusual and suggest poor permeability, but are likely on a log scale where negative values indicate low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.079 and -3.039), again likely on a log scale indicating poor solubility. Ligand B has worse solubility.

**hERG Inhibition:** Ligand A (0.704) has a lower hERG risk than Ligand B (0.567), which is favorable.

**Microsomal Clearance:** Ligand A (18.932) has significantly lower microsomal clearance than Ligand B (77.992), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-3.661) has a negative half-life, which is unusual. Ligand B (22.778) has a reasonable half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.103 and 0.285).

**Binding Affinity:** Ligand B (-9.5) has a slightly better binding affinity than Ligand A (-8.8). However, the difference is 0.7 kcal/mol, which is not a huge difference and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. It has a much lower DILI risk, better metabolic stability (lower Cl_mic), and lower hERG risk. While Ligand B has slightly better binding affinity and half-life, the ADME advantages of Ligand A are more critical for a successful kinase inhibitor. The solubility and permeability are poor for both, but Ligand A is better in these aspects.

Output:
0
2025-04-17 12:28:49,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (385.243 and 355.454 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.99) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (92.5) is still under 140, but less optimal than A.

**3. logP:** Ligand A (3.664) is within the optimal 1-3 range. Ligand B (1.235) is at the lower end of the range, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) both meet the <=10 criteria.

**6. QED:** Both ligands have similar QED values (0.703 and 0.686), indicating good drug-likeness.

**7. DILI:** Ligand A (59.907) is approaching the higher risk threshold, but still acceptable. Ligand B (16.324) has a significantly lower DILI risk, which is a strong positive.

**8. BBB:** Ligand A (47.654) has a lower BBB percentile, while Ligand B (92.827) has a very high BBB percentile. However, as SRC is not a CNS target, BBB is less critical here.

**9. Caco-2:** Ligand A (-4.581) and Ligand B (-5.219) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but B is slightly worse.

**10. Solubility:** Ligand A (-4.113) and Ligand B (-3.066) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both compounds.

**11. hERG:** Ligand A (0.639) and Ligand B (0.492) both have low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand A (75.449) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (10.623) has a much lower clearance, indicating better metabolic stability, a key priority for enzyme inhibitors.

**13. t1/2:** Ligand A (22.305) has a reasonable in vitro half-life. Ligand B (-17.146) has a negative half-life, which is impossible and indicates a significant issue with the data or the compound itself.

**14. Pgp:** Ligand A (0.479) and Ligand B (0.028) both have low P-gp efflux, which is favorable.

**15. 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:**

Despite the poor solubility and Caco-2 values for both, Ligand B stands out due to its significantly higher binding affinity and much better metabolic stability (lower Cl_mic). The negative half-life is a major red flag, but assuming this is a data error, the overall profile of B is superior. Ligand A has a slightly better DILI profile, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 12:28:49,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (395.262 Da) is slightly higher than Ligand B (348.451 Da), but both are acceptable.

**2. TPSA:** Ligand A (76.58) is well below the 140 threshold for oral absorption. Ligand B (106.14) is also below, but closer to the limit.

**3. logP:** Ligand A (3.913) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.936) is slightly below the optimal range, which could impact permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the HBD criteria (<=5).

**5. H-Bond Acceptors:** Both ligands (A: 6, B: 6) are within the acceptable range (<=10).

**6. QED:** Ligand B (0.823) has a significantly better QED score than Ligand A (0.473), indicating a more drug-like profile.

**7. DILI:** Ligand B (38.62) has a much lower DILI risk than Ligand A (70.803), which is a significant advantage.

**8. BBB:** Both ligands have acceptable BBB penetration, but Ligand A (76.037) is slightly higher than Ligand B (67.197). This is less important for a kinase inhibitor than for a CNS-targeting drug.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.652) is slightly better than Ligand B (-5.461).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.433) is slightly better than Ligand A (-4.775).

**11. hERG Inhibition:** Ligand B (0.069) has a much lower hERG inhibition liability than Ligand A (0.369), a critical advantage for safety.

**12. Microsomal Clearance:** Ligand B (8.875) has a significantly lower microsomal clearance than Ligand A (63.539), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.436) has a negative half-life, which is not possible. This is a major red flag. Ligand A (13.523) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.177, B: 0.016).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is not huge.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B has superior metabolic stability, lower hERG risk, and slightly better affinity. However, the negative half-life is a serious concern. Ligand A has a reasonable half-life but suffers from higher DILI risk, higher clearance, and higher hERG risk.

**Conclusion:**

Despite the negative half-life value for Ligand B, the significant advantages in DILI, hERG, and metabolic stability, coupled with slightly better affinity, make it the more promising candidate *if* the half-life value is an error. The negative half-life is a critical issue that needs to be investigated. If the half-life is indeed negative, Ligand A would be the better choice, despite its drawbacks, due to its reasonable half-life. Assuming the half-life for B is a data error, I will select B.

Output:
1
2025-04-17 12:28:49,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.519 and 352.431 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (84.94). A TPSA under 90 is preferable, and A is closer to the ideal <140 for oral absorption.

**3. logP:** Ligand A (2.719) is optimal (1-3). Ligand B (0.536) 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:** Both ligands have acceptable HBA counts (3 and 5, respectively), well below the threshold of 10.

**6. QED:** Both ligands have similar, acceptable QED values (0.74 and 0.534), indicating good drug-like properties.

**7. DILI:** Ligand A (15.626) has a much lower DILI risk than Ligand B (39.589). This is a significant advantage.

**8. BBB:** Both have reasonable BBB penetration (66.576 and 63.901), but this is less critical for a non-CNS target like SRC.

**9. Caco-2:** Both have negative Caco-2 values (-4.701 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 difference is small.

**10. Solubility:** Ligand A (-2.829) has slightly better solubility than Ligand B (-1.693), though both are poor. Solubility is a concern for both.

**11. hERG:** Ligand A (0.559) has a lower hERG risk than Ligand B (0.076), which is a major advantage.

**12. Cl_mic:** Ligand A (48.822) has a higher microsomal clearance than Ligand B (27.537), meaning it's less metabolically stable. This is a drawback for Ligand A.

**13. t1/2:** Ligand B (-35.601) has a much longer in vitro half-life than Ligand A (-10.449). This is a significant advantage for Ligand B.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.467 and 0.033).

**15. Binding Affinity:** Ligand A (-8.0) has a significantly better binding affinity than Ligand B (-6.6). A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower DILI/hERG risk. However, Ligand B has better metabolic stability (lower Cl_mic and longer t1/2). The strong binding affinity of Ligand A (-8.0 kcal/mol) is a major advantage that can potentially outweigh the drawbacks of higher Cl_mic and slightly lower solubility. The lower DILI and hERG risks for Ligand A are also important considerations. While solubility is a concern for both, the superior potency and safety profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 12:28:49,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme guidelines.

**Molecular Weight:** Both ligands (360.483 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.02 and 77.1) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.698) is optimal, while Ligand B (0.816) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (5) meet the <=10 criteria.

**QED:** Both ligands (0.759 and 0.762) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (66.964) has a higher DILI risk than Ligand B (34.277). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (70.105) is slightly better. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.268) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.55) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-3.982) has very poor solubility, a major concern. Ligand B (-1.848) is better, but still relatively low.

**hERG Inhibition:** Both ligands (0.345 and 0.247) have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (60.773) has higher microsomal clearance than Ligand B (8.891), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (48.212) has a longer half-life than Ligand B (4.944), which is favorable. However, this is offset by the higher clearance.

**P-gp Efflux:** Both ligands (0.2 and 0.024) have low P-gp efflux, which is good.

**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 a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP and solubility are not ideal, they are better than Ligand A's. Critically, Ligand B has significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. Ligand A's poor solubility and higher DILI risk are major red flags. The slightly longer half-life of Ligand A is not enough to compensate for these significant drawbacks.

Output:
1
2025-04-17 12:28:49,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (376.513 and 373.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.35) is well below the 140 threshold for oral absorption, and even below 90 for CNS penetration, while Ligand B (93.11) is still within acceptable limits but closer to the upper bound.

**logP:** Ligand A (2.804) is optimal (1-3), while Ligand B (-0.48) is below 1, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.774 and 0.582), indicating drug-like properties, with Ligand A being slightly better.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (13.3). Both are below the 40 threshold, indicating low risk.

**BBB:** Ligand A (92.904) shows good BBB penetration, while Ligand B (13.765) is very low. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.298 and -5.521), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.627 and -1.176), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.732) has a lower hERG risk than Ligand B (0.089), which is a significant advantage.

**Microsomal Clearance:** Ligand A (17.486) has higher microsomal clearance than Ligand B (-6.469). A negative value for B suggests very high metabolic stability, which is excellent.

**In vitro Half-Life:** Ligand A (20.262) has a longer half-life than Ligand B (-2.719). Again, a negative value for B suggests an extremely long half-life, which is very favorable.

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux than Ligand B (0.006), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -6.4 kcal/mol). Ligand A is significantly more potent, with a 1.6 kcal/mol advantage.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, lower hERG risk, and lower DILI risk. While both have poor solubility and permeability, the potency advantage of Ligand A is substantial enough to outweigh these drawbacks, especially for a kinase inhibitor where potency is critical. The better metabolic stability of Ligand B is a plus, but the much weaker binding affinity makes it less attractive.

Output:
1
2025-04-17 12:28:49,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.415 and 340.423 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.16) is better than Ligand B (66.48), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.033 and 2.167) 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.839) has a significantly better QED score than Ligand B (0.448), indicating a more drug-like profile.

**DILI:** Ligand A (40.326) and Ligand B (34.742) both have low DILI risk, below the 40 threshold. Ligand B is slightly better here.

**BBB:** Ligand A (43.583) and Ligand B (76.929). BBB isn't a primary concern for a non-CNS target like SRC, but Ligand B is better.

**Caco-2 Permeability:** Ligand A (-5.173) and Ligand B (-4.632) are both negative, which is unusual and suggests poor permeability. However, the scale isn't fully defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-2.157) and Ligand B (-3.401) are both negative, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.028) and Ligand B (0.297) both have very low hERG inhibition risk, which is excellent. Ligand A is better.

**Microsomal Clearance:** Ligand A (8.052) has a lower (better) microsomal clearance than Ligand B (48.014), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (48.902) has a much longer in vitro half-life than Ligand B (-38.58), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, while Ligand B (0.174) has slightly higher efflux.

**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.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-9.4 vs -7.5 kcal/mol), which is the most crucial factor for an enzyme inhibitor. While Ligand A has better QED, metabolic stability (lower Cl_mic and longer t1/2), and slightly better hERG profile, the potency advantage of Ligand B is likely to outweigh these benefits. Both have poor solubility and permeability, which would need to be addressed in further optimization.

Output:
1
2025-04-17 12:28:49,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (375.782 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.84) is better than Ligand B (103.09), both are below 140, but A is closer to the optimal threshold for good absorption.

**logP:** Ligand A (3.902) is good, while Ligand B (1.336) is a bit low, potentially hindering permeability.

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

**QED:** Both ligands have similar QED scores (0.578 and 0.513), indicating reasonable drug-likeness.

**DILI:** Ligand B (31.601) has a significantly lower DILI risk than Ligand A (75.649), which is a major advantage.

**BBB:** Ligand A (64.25) is slightly better than Ligand B (57.464), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.108) has a better Caco-2 permeability than Ligand B (-5.256).

**Aqueous Solubility:** Ligand A (-4.899) has a better aqueous solubility than Ligand B (-2.833).

**hERG Inhibition:** Ligand A (0.569) has a slightly better hERG profile than Ligand B (0.134).

**Microsomal Clearance:** Ligand B (5.178) has significantly lower microsomal clearance than Ligand A (22.813), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.752) has a better in vitro half-life than Ligand B (-9.332).

**P-gp Efflux:** Ligand A (0.315) has a slightly better P-gp efflux profile than Ligand B (0.013).

**Binding Affinity:** Both ligands have very similar binding affinities (-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 B has a much better safety profile (DILI) and metabolic stability (Cl_mic). While Ligand A has slightly better solubility, permeability, and half-life, the lower DILI and improved metabolic stability of Ligand B are more critical for an enzyme inhibitor. The binding affinity difference is minimal.

Output:
1
2025-04-17 12:28:49,140 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [342.439, 56.52, 4.241, 1, 5, 0.881, 59.248, 87.67, -4.936, -3.672, 0.697, 70.158, 3.664, 0.54, -8.9]
**Ligand B:** [389.989, 60.77, 4.387, 2, 4, 0.623, 13.61, 62.117, -4.655, -3.84, 0.777, 83.811, 66.075, 0.71, 0]

**Step-by-step comparison:**

1. **MW:** Ligand A (342.439 Da) is within the ideal range (200-500 Da). Ligand B (389.989 Da) is also within the ideal range. No clear advantage here.
2. **TPSA:** Ligand A (56.52) is excellent, well below the 140 threshold for oral absorption. Ligand B (60.77) is also good, but slightly higher. A favors better absorption.
3. **logP:** Both ligands (A: 4.241, B: 4.387) 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 manageable. No clear advantage.
4. **HBD:** Ligand A (1) is better than Ligand B (2) - fewer HBDs generally improve permeability.
5. **HBA:** Ligand A (5) is better than Ligand B (4) - fewer HBAs generally improve permeability.
6. **QED:** Ligand A (0.881) is significantly better than Ligand B (0.623), indicating a more drug-like profile.
7. **DILI:** Ligand A (59.248) has a higher DILI risk than Ligand B (13.61). This is a significant concern for Ligand A.
8. **BBB:** Ligand A (87.67) has better BBB penetration than Ligand B (62.117), but this isn't a primary concern for an oncology target like SRC kinase.
9. **Caco-2:** Ligand A (-4.936) is better than Ligand B (-4.655) - higher (less negative) Caco-2 values indicate better absorption.
10. **Solubility:** Ligand A (-3.672) is better than Ligand B (-3.84) - higher (less negative) solubility values are preferred.
11. **hERG:** Ligand A (0.697) has a slightly better hERG profile than Ligand B (0.777), indicating lower cardiotoxicity risk.
12. **Cl_mic:** Ligand A (70.158) has lower microsomal clearance than Ligand B (83.811), suggesting better metabolic stability.
13. **t1/2:** Ligand A (3.664) has a shorter in vitro half-life than Ligand B (66.075). This is a significant disadvantage for Ligand A.
14. **Pgp:** Ligand A (0.54) has lower P-gp efflux than Ligand B (0.71), which is favorable for bioavailability.
15. **Affinity:** Ligand A (-8.9 kcal/mol) has *significantly* better binding affinity than Ligand B (0 kcal/mol). This is a crucial factor for an enzyme inhibitor.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a *much* stronger binding affinity, better metabolic stability (lower Cl_mic), better solubility, and a slightly better hERG profile. However, it has a significantly shorter half-life and higher DILI risk. The massive difference in binding affinity (-8.9 vs 0) is likely to outweigh the drawbacks of the shorter half-life and higher DILI risk, especially in the context of oncology where rapid tumor targeting is often desired. The DILI risk could be mitigated with further structural modifications.

**Conclusion:**

Despite the higher DILI risk and shorter half-life, the dramatically superior binding affinity of Ligand A makes it the more promising drug candidate.

1
2025-04-17 12:28:49,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.374 and 354.491 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 (<=140).

**3. logP:** Both ligands have logP values within the optimal range (1.287 and 1.85). Ligand B is slightly more lipophilic, which could be beneficial for cell permeability but needs to be balanced against solubility.

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

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

**6. QED:** Both have QED values above 0.5 (0.575 and 0.627), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 35.324, which is good (low risk). Ligand B has a significantly lower DILI risk of 10.237, which is excellent. This is a major advantage for Ligand B.

**8. BBB:** Both have relatively low BBB penetration (56.611 and 76.347). Since SRC is not a CNS target, this is not a critical factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.637 and -4.602), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.152 and -1.248), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.411 and 0.223), which is positive. Ligand B has a slightly lower risk.

**12. Microsomal Clearance:** Ligand A has a negative Cl_mic (-1.527), indicating high metabolic stability. Ligand B has a positive Cl_mic (20.948), suggesting faster metabolism and potentially lower *in vivo* exposure. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A has a longer half-life (18.332 hours) than Ligand B (-8.4 hours). This is a clear advantage for Ligand A, suggesting less frequent dosing.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.091 and 0.024).

**15. Binding Affinity:** Ligand B has a slightly better binding affinity (-8.0 kcal/mol) than Ligand A (-7.7 kcal/mol). While the difference is not huge (0.3 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand B has a much better safety profile (lower DILI) and slightly better binding affinity. However, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer half-life). The poor Caco-2 and solubility for both are concerning and would require formulation strategies. Given the enzyme-specific priorities, metabolic stability and half-life are crucial for kinase inhibitors. The 0.3 kcal/mol difference in binding affinity is unlikely to overcome the significant difference in metabolic stability.

Output:
0
2025-04-17 12:28:49,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (344.367 and 341.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (90.7 and 91.94) are below the 140 A^2 threshold for good oral absorption, but relatively high. This isn't a major concern for a non-CNS target like SRC.

**3. logP:** Both ligands (3.619 and 3.072) are 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 6 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.489 and 0.419), indicating moderate drug-likeness. Improvement is possible, but not a dealbreaker.

**7. DILI:** Ligand A (83.404) has a significantly higher DILI risk than Ligand B (40.481). This is a major concern, as a lower DILI risk is highly desirable.

**8. BBB:** This is less critical for SRC, a non-CNS target. Ligand B (80.496) has a higher BBB value than Ligand A (50.446), but this is not a primary factor in this case.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It suggests poor permeability. However, we'll consider other factors.

**10. Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.692 and 0.596).

**12. Microsomal Clearance:** Ligand A (106.084) has a higher microsomal clearance than Ligand B (30.452), indicating lower metabolic stability. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand B (18.505 hours) has a significantly longer half-life than Ligand A (-18.618 hours - which is nonsensical and suggests instability). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.361 and 0.311).

**15. 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.

**Enzyme-Specific Priorities:** For kinases like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a significantly lower DILI risk. While both have poor solubility and permeability, the superior metabolic profile and safety of Ligand B outweigh the slightly better affinity of Ligand A.

Output:
1
2025-04-17 12:28:49,141 - INFO - Batch 133 complete. Total preferences: 2128
2025-04-17 12:28:49,141 - INFO - Processing batch 134/512...
2025-04-17 12:29:38,002 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [386.426, 106.38 ,   2.683,   1.   ,   6.   ,   0.582,  86.661,  63.086, -5.151,  -3.004,   0.341,  13.283,  26.112,   0.395,  -8.3  ]
**Ligand B:** [363.483,  71.53 ,   2.166,   1.   ,   5.   ,   0.806,  44.552,  74.254, -5.031,  -3.013,   0.242,  23.036,  11.454,   0.109,   0.   ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (386.426) is slightly higher than B (363.483), but both are acceptable.
2. **TPSA:** A (106.38) is higher than B (71.53). While both are below 140, B is significantly better, suggesting better permeability.
3. **logP:** Both are within the optimal range (1-3). A (2.683) is slightly higher than B (2.166).
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A has 6 HBA, B has 5. Both are acceptable (<=10).
6. **QED:** A (0.582) is slightly lower than B (0.806). B has a better drug-like profile.
7. **DILI:** A (86.661) has a significantly higher DILI risk than B (44.552). This is a major concern for A.
8. **BBB:** A (63.086) is lower than B (74.254). While not a primary concern for a non-CNS target like SRC, B is better.
9. **Caco-2:** Both are negative, which is not ideal. Lower values indicate poor permeability.
10. **Solubility:** Both are negative, indicating poor solubility. This is a concern for both.
11. **hERG:** A (0.341) is slightly higher than B (0.242), indicating a slightly higher risk of hERG inhibition.
12. **Cl_mic:** A (13.283) has lower microsomal clearance than B (23.036), suggesting better metabolic stability. This is a positive for A.
13. **t1/2:** A (26.112) has a longer half-life than B (11.454), which is desirable.
14. **Pgp:** A (0.395) has higher P-gp efflux than B (0.109), which is undesirable.
15. **Binding Affinity:** A (-8.3) has a *much* stronger binding affinity than B (-0.0). This is a substantial advantage for A.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A's affinity is significantly better (-8.3 vs -0.0). This is a massive advantage.
*   **Metabolic Stability:** A has better metabolic stability (lower Cl_mic).
*   **Half-life:** A has a longer half-life.
*   **DILI:** B has a significantly lower DILI risk.
*   **Solubility:** Both are poor.
*   **hERG:** B has a slightly lower hERG risk.

**Conclusion:**

Despite the higher DILI risk and slightly worse TPSA and Pgp for Ligand A, the *dramatic* difference in binding affinity (-8.3 kcal/mol vs -0.0 kcal/mol) is the dominating factor. A difference of 8.3 kcal/mol is huge and likely outweighs the ADME liabilities. The improved metabolic stability and half-life of A further support its selection. While solubility is a concern for both, it can be addressed through formulation strategies. The DILI risk is concerning, but could potentially be mitigated through structural modifications in further optimization.

1
2025-04-17 12:29:38,002 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.463 and 344.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (74.35) is better than Ligand B (87.46), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.398) is optimal (1-3), while Ligand B (0.179) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2), staying within the preferred limit of <=5.

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

**QED:** Both ligands have acceptable QED scores (0.895 and 0.798, both >=0.5).

**DILI:** Ligand A (25.824) has a significantly lower DILI risk than Ligand B (33.463), indicating a better safety profile. Both are below the 40 threshold.

**BBB:** Ligand B (72.858) has a higher BBB penetration than Ligand A (55.06), but BBB isn't a high priority for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.223) has a worse Caco-2 permeability than Ligand B (-4.994), but both are very poor.

**Aqueous Solubility:** Ligand A (-0.851) has better solubility than Ligand B (-2.032). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.447 and 0.228), which is good.

**Microsomal Clearance:** Ligand A (-17.107) has *much* lower microsomal clearance than Ligand B (6.681). This suggests significantly better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-5.519) has a longer in vitro half-life than Ligand B (12.984). This further supports better metabolic stability for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.045).

**Binding Affinity:** Both ligands have comparable binding affinity (-8.3 and -8.6 kcal/mol). The difference is minimal.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability and BBB penetration, Ligand A excels in critical areas for kinase inhibitors: metabolic stability (lower Cl_mic, longer t1/2), solubility, and lower DILI risk. The binding affinities are very similar, so the ADME advantages of Ligand A outweigh any minor differences in permeability.

Output:
1
2025-04-17 12:29:38,002 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.55) is better than Ligand B (65.64), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.588 and 2.033) 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 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.906) has a significantly better QED score than Ligand A (0.557), indicating a more drug-like profile.

**DILI:** Ligand B (42.458) has a lower DILI risk than Ligand A (54.789), which is preferable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (78.48) is better than Ligand A (65.413). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired/undesired.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.496) is slightly better than Ligand B (-4.514).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.24) is slightly better than Ligand B (-2.34).

**hERG:** Both ligands have low hERG inhibition risk (0.541 and 0.537).

**Microsomal Clearance:** Ligand B (17.879 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (32.628 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.381 hours) has a better in vitro half-life than Ligand A (-5.585 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.091 and 0.122).

**Binding Affinity:** Ligand B (-7.3 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 to override other issues, it's still a positive.

**Conclusion:**

Ligand B is the more promising candidate. It exhibits a significantly better QED score, lower DILI risk, better metabolic stability (lower Cl_mic and better t1/2), and slightly better binding affinity. While both have poor Caco-2 and solubility, the improvements in ADME properties and drug-likeness make Ligand B the preferred choice.

Output:
1
2025-04-17 12:29:38,002 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.5 and 353.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (100.89). TPSA < 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (3.079) is optimal (1-3), while Ligand B (0.075) is quite low, potentially hindering permeation. This is a significant advantage for A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.759 and 0.725), indicating good drug-likeness.

**DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (36.758). This is a crucial advantage for A.

**BBB:** Ligand A (75.107) has a better BBB percentile than Ligand B (55.797), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.344) and Ligand B (-4.947) are both negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.495) is slightly better than Ligand B (-1.24), but both are poor.

**hERG:** Ligand A (0.648) has a lower hERG risk than Ligand B (0.139), which is a significant advantage.

**Microsomal Clearance:** Ligand A (43.102) has a higher (worse) microsomal clearance than Ligand B (-8.214). This suggests Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-8.057) has a longer half-life than Ligand B (20.411). This is a positive for A.

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.01), which is preferable.

**Binding Affinity:** Ligand A (-10.8 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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic) and a slightly better half-life, Ligand A excels in most other critical areas. Its significantly stronger binding affinity, lower DILI risk, lower hERG risk, and better logP make it a much more promising candidate. The solubility and Caco-2 permeability are concerns for both, but the potency advantage of A is substantial.

Output:
1
2025-04-17 12:29:38,002 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.29 and 355.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.54) is better than Ligand B (46.61), being below the 140 A^2 threshold for good absorption. Ligand B is very low, which could be a concern for binding.

**logP:** Ligand A (0.86) is slightly below the optimal 1-3 range, while Ligand B (3.295) is within the optimal range.

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

**H-Bond Acceptors:** Ligand A (7) is good, while Ligand B (4) is also acceptable.

**QED:** Both ligands have good QED scores (0.419 and 0.794), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (85.77) has a higher DILI risk than Ligand B (56.844). This is a significant concern for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration (72.237 and 77.511). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.943 and -4.733), which is unusual and suggests poor permeability. This is a major red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.702 and -4.087), indicating very poor aqueous solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.214) has a slightly higher hERG risk than Ligand B (0.457), but both are relatively low.

**Microsomal Clearance:** Ligand A (31.671) has significantly lower microsomal clearance than Ligand B (121.046), suggesting better metabolic stability. This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (15.721) has a slightly longer half-life than Ligand B (12.645).

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux than Ligand B (0.644), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-10 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME liabilities.

**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 and poor solubility/permeability. Ligand B has better QED, lower DILI, and acceptable logP, but significantly weaker binding affinity and worse metabolic stability.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the significantly stronger binding affinity of Ligand A is a major factor. While the solubility and permeability are concerning, these can potentially be addressed through formulation strategies. The DILI risk is also a concern, but may be manageable. The weaker affinity of Ligand B makes it less likely to be a viable candidate, even with better ADME properties.

Output:
1
2025-04-17 12:29:38,003 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.833 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.66) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (78.43) is well within the acceptable range.

**logP:** Both ligands have good logP values (1.246 and 2.375), 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 3 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.562 and 0.617), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 52.191, which is moderate but acceptable (<60 is good). Ligand B has a significantly lower DILI risk of 10.198, which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB penetration (53.974) than Ligand A (18.845).

**Caco-2 Permeability:** Ligand A (-6.409) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.729) also has poor Caco-2 permeability, but is better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.285) has poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-3.039) also has poor aqueous solubility, and is worse than Ligand A.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.033 and 0.37), which is excellent.

**Microsomal Clearance:** Ligand A has a significantly lower (better) microsomal clearance (-36.174) than Ligand B (49.367), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (19.892 hours) than Ligand B (-18.619 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.09).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.3 and -6.3 kcal/mol). Ligand A has a significantly better binding affinity.

**Overall Assessment:**

Ligand A has a much better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and a moderate DILI risk. However, it suffers from poor Caco-2 permeability and aqueous solubility. Ligand B has a better DILI profile, but weaker binding affinity and poorer metabolic stability. The binding affinity difference is substantial (>1.5 kcal/mol). Given that we are targeting an enzyme, potency and metabolic stability are crucial. While solubility and permeability are important, they can sometimes be addressed through formulation strategies. The significantly stronger binding affinity of Ligand A, coupled with acceptable metabolic stability, outweighs its solubility and permeability concerns.

Output:
1
2025-04-17 12:29:38,003 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.515 Da) is slightly lower, which could be advantageous for permeability. Ligand B (381.845 Da) is also good.

**TPSA:** Ligand A (65.54) is excellent, well below the 140 threshold for oral absorption. Ligand B (130.23) is still acceptable, but less ideal.

**logP:** Both ligands have good logP values (A: 1.523, B: 1.418), 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=7) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.86) has a significantly higher QED score than Ligand B (0.579), indicating a more drug-like profile.

**DILI:** Ligand A (23.769) has a much lower DILI risk than Ligand B (79.333). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (62.854) is better than Ligand B (46.336).

**Caco-2 Permeability:** Ligand A (-4.968) has a more favorable Caco-2 permeability value than Ligand B (-5.297), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-1.527) is better than Ligand B (-4.371) in terms of aqueous solubility.

**hERG:** Both ligands have low hERG risk (A: 0.171, B: 0.391), which is good.

**Microsomal Clearance:** Ligand A (22.387) has a higher microsomal clearance than Ligand B (8.381), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-16.782) has a significantly longer in vitro half-life than Ligand A (8.128), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.048, B: 0.039).

**Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.8), but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, QED, DILI, solubility, Caco-2) and has a good binding affinity. However, its higher microsomal clearance and shorter half-life are concerning. Ligand B has a better half-life and lower clearance, but suffers from a higher DILI risk, higher TPSA, and lower QED.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), and the relatively small difference in binding affinity, the improved ADME profile of Ligand A, particularly the dramatically lower DILI risk, outweighs the slightly worse metabolic stability. While metabolic stability is important, the DILI risk is a more critical factor to address early in development.

Output:
0
2025-04-17 12:29:38,003 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.361 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.7) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (56.57) is well within the acceptable range.

**logP:** Both ligands have logP values (2.578 and 3.778) within the optimal 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not drastically.

**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 ligands have good QED scores (0.762 and 0.82), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 69.678%, which is considered high risk. Ligand B has a much lower DILI risk of 29.779%, which is good. This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (75.572%) than Ligand A (33.734%), but this is not a primary concern.

**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 (-3.62 and -3.758). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.658) has a slightly higher hERG inhibition risk than Ligand B (0.911), but both are relatively low.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (17.297 mL/min/kg) compared to Ligand B (54.039 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (33.149 hours) than Ligand B (8.741 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.136 and 0.208).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-7.8 kcal/mol) than Ligand A (-7.5 kcal/mol). While the difference is small (0.3 kcal/mol), it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B has a significantly lower DILI risk, which is a major advantage. It also has slightly better binding affinity and BBB penetration. However, Ligand A exhibits superior metabolic stability (lower Cl_mic and longer half-life). Both have poor solubility. Considering the enzyme-specific priorities, metabolic stability is crucial. However, the high DILI risk associated with Ligand A is a major concern, potentially leading to clinical failures. The slightly better affinity of Ligand B, combined with the much lower DILI risk, outweighs the better metabolic stability of Ligand A.

Output:
1
2025-04-17 12:29:38,003 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.494 and 338.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.3 and 84.53) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.942) is optimal, while Ligand B (0.712) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, fitting the guidelines. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.621 and 0.762), indicating drug-likeness.

**DILI:** Both ligands have DILI risk above 60, indicating a moderate to high risk of liver injury. This is a concern for both. Ligand B (64.754) is slightly higher than Ligand A (60.876).

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (59.248) and Ligand B (32.144) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.904) is slightly better than Ligand B (-5.14).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-2.086) is slightly better than Ligand A (-3.461).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.646 and 0.379), which is positive. Ligand B is better.

**Microsomal Clearance:** Ligand A (37.333 mL/min/kg) has a higher clearance than Ligand B (8.201 mL/min/kg), suggesting lower metabolic stability for Ligand A. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (11.417 hours) has a longer half-life than Ligand A (46.642 hours), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.183 and 0.023), which is good. Ligand B is better.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are good, this difference is significant.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have DILI concerns, Ligand B has a better binding affinity, significantly lower microsomal clearance (better metabolic stability), longer half-life, and better P-gp efflux profile. The slightly lower logP of Ligand B is a minor drawback compared to the benefits in metabolic stability and potency.

Output:
1
2025-04-17 12:29:38,003 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.522 and 338.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is better than Ligand B (77.63), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.884 and 2.342), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Ligand A is preferable here, as lower HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.594 and 0.774), indicating drug-like properties.

**DILI:** Ligand A (19.542 percentile) has a significantly lower DILI risk than Ligand B (60.915 percentile). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (90.772) is better than Ligand B (62.737).

**Caco-2 Permeability:** Ligand A (-4.685) is better than Ligand B (-5.098), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.199) is better than Ligand B (-2.466), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.785) has a lower hERG risk than Ligand B (0.372). Lower is better.

**Microsomal Clearance:** Ligand A (30.707 mL/min/kg) has a higher (worse) microsomal clearance than Ligand B (6.362 mL/min/kg), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (9.864 hours) has a longer half-life than Ligand A (-12.834 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.41) has lower P-gp efflux than Ligand B (0.204), which is preferable.

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a better binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand A has advantages in terms of DILI risk, solubility, Caco-2 permeability, P-gp efflux, and TPSA. However, Ligand B excels in binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and has a reasonable safety profile. The superior binding affinity of Ligand B (-6.8 kcal/mol vs -9.0 kcal/mol) is a critical factor for an enzyme inhibitor, and the better metabolic stability is also highly desirable. While Ligand A's lower DILI is attractive, the difference isn't large enough to overcome the potency and stability advantages of Ligand B.

Output:
1
2025-04-17 12:29:38,003 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (370.475 Da) is also well within range.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand B (84.74 A^2) is lower than Ligand A (97.94 A^2), which is slightly favorable.

**logP:** Ligand A (0.172) is quite low, potentially hindering permeation. Ligand B (0.601) is better, falling within the optimal range of 1-3, although still on the lower end.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 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: 0.723, B: 0.626), indicating good drug-like properties.

**DILI:** Ligand A (62.35) has a higher DILI risk than Ligand B (46.956). This is a significant concern, as lower DILI is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.162) has a higher BBB penetration than Ligand A (51.066), but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.242) is worse than Ligand B (-4.591).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.941 and -1.715, respectively). This is a major drawback.

**hERG Inhibition:** Ligand A (0.084) has a much lower hERG inhibition risk than Ligand B (0.684). This is a substantial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (21.924 mL/min/kg) has significantly lower microsomal clearance than Ligand B (59.511 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.888 hours) has a negative half-life, which is not possible. This is a major red flag. Ligand B (-43.424 hours) also has a negative half-life, also a major red flag.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, while Ligand B (0.317) has slightly higher efflux.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Despite the better hERG and metabolic stability of Ligand A, the negative in vitro half-life is a showstopper. The negative half-life for both compounds is concerning and suggests issues with the data or the compounds themselves. However, if we disregard the half-life data as potentially erroneous, Ligand B emerges as the better candidate due to its superior binding affinity (-8.0 vs -7.7 kcal/mol) and lower DILI risk. The slightly better logP and TPSA also contribute to its favorability. The solubility is poor for both, but that can be addressed with formulation strategies.

Output:
1
2025-04-17 12:29:38,003 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.543 and 352.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 49.85, which is well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.393) is within the optimal 1-3 range. Ligand B (3.08) is also acceptable, leaning towards the upper end but still reasonable.

**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 HBA, both are below the 10 threshold.

**6. QED:** Ligand A (0.767) has a better QED score than Ligand B (0.568), indicating a more drug-like profile.

**7. DILI:** Ligand A (34.432) has a significantly lower DILI risk than Ligand B (7.29), which is a major advantage.

**8. BBB:** Ligand A (66.886) has a lower BBB penetration than Ligand B (93.563). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.709 and -4.401). This is unusual and suggests poor permeability. However, these values should be interpreted cautiously, as negative values can sometimes occur due to experimental error or limitations of the model.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.723 and -1.424). This is concerning, as poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Ligand A (0.353) has a lower hERG inhibition liability than Ligand B (0.749), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand B (56.334 mL/min/kg) has a lower microsomal clearance than Ligand A (68.398 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-21.889 hours) has a negative half-life, which is not physically possible and likely indicates an issue with the data. Ligand A (6.356 hours) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.196) has a lower P-gp efflux liability than Ligand B (0.351), which is favorable.

**15. Binding Affinity:** Ligand A (-6.8 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A is the stronger candidate. While both ligands have concerning solubility and permeability issues (negative Caco-2 and solubility values), Ligand A demonstrates superior properties in key areas for an enzyme inhibitor: significantly lower DILI risk, lower hERG inhibition, better binding affinity, and a more favorable QED score. The negative half-life for Ligand B is a red flag, suggesting a data quality issue or inherent instability. While Ligand B has better metabolic stability, the other advantages of Ligand A outweigh this benefit.

Output:
0
2025-04-17 12:29:38,004 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.559 Da and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold. Ligand B (109.39) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (2.688) is optimal (1-3). Ligand B (0.834) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have good QED scores (0.634 and 0.718), indicating generally drug-like properties.

**DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (54.323), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.125) is higher than Ligand B (32.299).

**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 this directly.

**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 (0.613) has a lower hERG risk than Ligand B (0.253), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (79.999) has higher clearance than Ligand B (-14.674). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (35.474) has a longer half-life than Ligand A (16.299), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.313) has lower P-gp efflux liability than Ligand B (0.058), which is favorable.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol) - a difference of 2 kcal/mol. This is a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B exhibits a much stronger binding affinity, which is paramount for an enzyme inhibitor. It also has superior metabolic stability (lower Cl_mic, longer t1/2). While its logP is slightly lower and DILI risk is higher, the substantial affinity advantage and metabolic stability outweigh these drawbacks. The negative solubility and Caco-2 values are concerning, but could be addressed through formulation or structural modifications.

Output:
1
2025-04-17 12:29:38,004 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [354.447, 99.1, 0.042, 3, 5, 0.648, 25.165, 34.044, -4.978, -1.226, 0.098, 4.738, 3.138, 0.018, -9.8]
**Ligand B:** [345.407, 119.66, 0.518, 3, 5, 0.73, 50.136, 36.487, -5.668, -2.013, 0.105, -26.809, 6.905, 0.018, -7.8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (354.447) and B (345.407) are comparable.
2. **TPSA:** A (99.1) is better than B (119.66), falling comfortably under the 140 threshold for oral absorption. B is still acceptable, but less optimal.
3. **logP:** A (0.042) is very low, potentially hindering permeability. B (0.518) is better, but still on the lower side of the optimal 1-3 range.
4. **HBD:** Both have 3 HBD, which is good.
5. **HBA:** Both have 5 HBA, which is good.
6. **QED:** Both have good QED scores (A: 0.648, B: 0.73), suggesting drug-like properties. B is slightly better.
7. **DILI:** A (25.165) has a significantly lower DILI risk than B (50.136), which is a major advantage.
8. **BBB:** Both have low BBB penetration (A: 34.044, B: 36.487), which is not a major concern for a non-CNS target like SRC kinase.
9. **Caco-2:** A (-4.978) and B (-5.668) are both very poor, indicating poor intestinal absorption.
10. **Solubility:** A (-1.226) and B (-2.013) are both poor, indicating low aqueous solubility.
11. **hERG:** Both have very low hERG risk (A: 0.098, B: 0.105).
12. **Cl_mic:** A (4.738) has a much lower microsomal clearance than B (-26.809), indicating better metabolic stability. This is a crucial advantage for an enzyme target.
13. **t1/2:** B (6.905) has a longer in vitro half-life than A (3.138), which is desirable.
14. **Pgp:** Both have very low Pgp efflux (A: 0.018, B: 0.018).
15. **Binding Affinity:** A (-9.8) has a significantly stronger binding affinity than B (-7.8), a difference of 2 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Conclusion:**

Ligand A is the better candidate. While both have poor Caco-2 and solubility, A's significantly stronger binding affinity (-9.8 vs -7.8 kcal/mol) and much lower microsomal clearance (4.738 vs -26.809) outweigh B's slightly longer half-life. The lower DILI risk for A is also a significant benefit. The low logP for A is a concern, but the strong binding affinity might compensate for that.

Output:
1
2025-04-17 12:29:38,004 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.45 and 353.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.29) is well below the 140 threshold for oral absorption, while Ligand B (118.37) is closer but still acceptable.

**logP:** Ligand A (2.921) is optimal (1-3). Ligand B (-0.496) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 7 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.71 and 0.515), indicating good drug-like properties.

**DILI:** Ligand A (78.64) has a higher DILI risk than Ligand B (48.47), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (58.09) has a slightly higher BBB value than Ligand A (46.84).

**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 isn't specified.

**hERG:** Ligand A (0.752) has a lower hERG risk than Ligand B (0.048), which is a significant advantage.

**Microsomal Clearance:** Ligand A (52.56 mL/min/kg) has a higher clearance than Ligand B (18.91 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (3.39 hours) has a much shorter half-life than Ligand A (111.77 hours), which is a major drawback.

**P-gp Efflux:** Ligand A (0.527) has lower P-gp efflux than Ligand B (0.01), which is preferable.

**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 of the ADME concerns.

**Conclusion:**

Despite Ligand B's lower logP and solubility, its significantly superior binding affinity (-7.9 vs -9.3 kcal/mol) and longer half-life (3.39 vs 111.77 hours) are compelling. The lower DILI risk and hERG inhibition liability of Ligand A are positives, but the potency difference is substantial. For an enzyme target like SRC kinase, strong binding is paramount. The metabolic stability of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 12:29:38,004 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (398.94 and 362.86 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.69) is better than Ligand B (64.35), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.79 and 3.39), 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.

**QED:** Both ligands have good QED scores (0.80 and 0.80), indicating good drug-like properties.

**DILI:** Ligand A (70.96) has a higher DILI risk than Ligand B (51.49). This is a concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (68.13 and 65.37), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.56), which is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are common.

**Aqueous Solubility:** Ligand A (-4.77) has slightly better solubility than Ligand B (-3.27), but both are poor.

**hERG:** Ligand A (0.73) has a slightly better hERG profile than Ligand B (0.24), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (43.50) has lower microsomal clearance than Ligand A (60.38), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (14.51) has a much longer in vitro half-life than Ligand A (-31.63), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.46 and 0.46).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This 1.0 kcal/mol difference is substantial and outweighs many of the other minor drawbacks.

**Conclusion:**

While Ligand A has slightly better solubility and hERG profile, Ligand B is superior overall. The significantly stronger binding affinity (-9.6 vs -8.6 kcal/mol) and much better metabolic stability (lower Cl_mic and longer t1/2) make Ligand B a more promising drug candidate for SRC kinase inhibition. The lower DILI risk is also a benefit.

Output:
1
2025-04-17 12:29:38,004 - INFO - Batch 134 complete. Total preferences: 2144
2025-04-17 12:29:38,004 - INFO - Processing batch 135/512...
2025-04-17 12:30:23,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.422 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.53 and 76.02) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.657 and 2.261) are 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 (0.845 and 0.795), indicating drug-likeness.

**DILI:** Ligand A (39.899) has a slightly higher DILI risk than Ligand B (32.028), but both are below the concerning threshold of 60.

**BBB:** Both have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.643 and -4.86), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.069 and -3.245), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.366 and 0.499), which is positive.

**Microsomal Clearance:** Ligand A (19.185 mL/min/kg) has significantly lower microsomal clearance than Ligand B (41.819 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.773 hours) has a negative half-life, which is not physically possible. Ligand B (1.243 hours) has a very short half-life. Both are concerning.

**P-gp Efflux:** Both have low P-gp efflux liability (0.122 and 0.111).

**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, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite the poor Caco-2 permeability and solubility for both, Ligand A is the more promising candidate. Its significantly higher binding affinity (-8.1 vs -6.8 kcal/mol) and lower microsomal clearance (19.185 vs 41.819) outweigh the slightly higher DILI risk. The negative half-life for Ligand A is a data error and needs to be investigated, but the superior binding affinity makes it the better starting point for optimization. Addressing the solubility and permeability issues will be critical, but a strong starting affinity is essential.

Output:
1
2025-04-17 12:30:23,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.451 and 376.909 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.22) is better than Ligand B (53.43). Both are below 140, indicating good potential for absorption.

**logP:** Ligand A (1.557) is optimal (1-3). Ligand B (4.145) is pushing the upper limit and could present solubility issues.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) both satisfy the <=5 rule.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) both satisfy the <=10 rule.

**QED:** Both ligands have similar, good QED values (0.742 and 0.769, both >0.5).

**DILI:** Ligand A (53.509) has a slightly higher DILI risk than Ligand B (46.452), but both are below the concerning threshold of 60.

**BBB:** Ligand A (27.84) and Ligand B (49.748) are both low, which is acceptable for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.185 and -5.294), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.456 and -4.686), which is also concerning.

**hERG Inhibition:** Ligand A (0.416) has a lower hERG risk than Ligand B (0.704), which is a significant advantage.

**Microsomal Clearance:** Ligand A (1.647) has significantly lower microsomal clearance than Ligand B (91.761), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (16.838) has a longer half-life than Ligand B (-27.172), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.546), which is favorable for bioavailability.

**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. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B's significantly stronger binding affinity (-9.5 kcal/mol vs -7.3 kcal/mol) is a major advantage for an enzyme inhibitor. While Ligand A has better ADME properties (lower Cl_mic, longer t1/2, lower hERG, lower Pgp efflux), the potency difference is substantial enough to favor Ligand B. The poor solubility and permeability would need to be addressed through formulation strategies, but the strong binding is a critical starting point.

Output:
1
2025-04-17 12:30:23,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (370.278 Da and 347.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.49) is better than Ligand B (100.16), both are acceptable, but lower is preferred for absorption.

**3. logP:** Both ligands have good logP values (1.992 and 2.275, respectively) within the optimal range of 1-3.

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

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA, both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.472 and 0.729), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A has a DILI risk of 65.529, which is moderately high. Ligand B has a lower DILI risk of 43.622, which is preferable.

**8. BBB:** Both ligands have similar BBB penetration (66.576 and 65.374), which is not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.031 and -5.186), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.873 and -1.494), indicating very poor aqueous solubility. This is a major concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.46 and 0.126), which is excellent.

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (13.278) than Ligand B (34.391), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-28.554), which is not physically possible and indicates a problem with the data or the molecule. Ligand B has a half-life of 20.555, which is reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.041), which is good.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-7.8 kcal/mol) than Ligand B (-7.1 kcal/mol). This 0.7 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability, but suffers from a problematic negative half-life and higher DILI risk. Ligand B has a better QED, lower DILI, and a reasonable half-life, but weaker binding and poorer metabolic stability. The negative Caco-2 and solubility values for both are major concerns. However, the negative half-life for Ligand A is a fatal flaw.

Output:
1
2025-04-17 12:30:23,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 343.343 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (101.66), both are acceptable, but A is more favorable for absorption.

**logP:** Ligand A (1.772) is optimal, while Ligand B (0.359) is a bit low, 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, while Ligand B (7) is higher, but still within the acceptable range.

**QED:** Both ligands have similar QED values (0.822 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (33.734) has a significantly lower DILI risk than Ligand B (73.09), which is a major advantage.

**BBB:** BBB is not a primary concern for a kinase inhibitor, but Ligand B (61.807) is higher than Ligand A (32.726).

**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.

**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 very low hERG inhibition risk (0.289 and 0.151), which is excellent.

**Microsomal Clearance:** Ligand B (9.684) has lower clearance than Ligand A (15.188), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.957) has a positive half-life, while Ligand B (-5.228) has a negative half-life, which is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.028), which is favorable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). The difference is 0.6 kcal/mol, which 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 slightly better binding affinity and metabolic stability, Ligand A has a significantly lower DILI risk, a better logP, and a more reasonable in vitro half-life. The lower DILI risk is a critical advantage, and the difference in binding affinity is not large enough to offset the other benefits of Ligand A.

Output:
0
2025-04-17 12:30:23,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.43 and 355.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.78) is better than Ligand B (49.56) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (1.81) is optimal, while Ligand B (4.79) is high, potentially leading to solubility issues and off-target effects.

**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 reasonable QED scores (0.738 and 0.668), indicating good drug-like properties.

**DILI:** Ligand A (28.50) has a significantly lower DILI risk than Ligand B (50.33). This is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (69.02) is higher than Ligand A (51.42).

**Caco-2:** Ligand A (-4.92) is better than Ligand B (-5.16), indicating better intestinal absorption.

**Solubility:** Ligand A (-2.57) is better than Ligand B (-4.42), which is crucial for bioavailability.

**hERG:** Ligand A (0.22) has a much lower hERG inhibition liability than Ligand B (0.86), significantly reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (36.76) has a lower Cl_mic than Ligand B (56.17), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (28.95) has a longer half-life than Ligand A (15.54), which is generally desirable.

**P-gp Efflux:** Ligand A (0.16) has a lower P-gp efflux liability than Ligand B (0.81), indicating better bioavailability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive factor.

**Overall:**

Ligand A is superior due to its significantly better binding affinity, lower DILI risk, lower hERG inhibition, better solubility, lower Cl_mic, and lower P-gp efflux. While Ligand B has a longer half-life, the other advantages of Ligand A outweigh this single benefit. The high logP of Ligand B is also a concern.

Output:
1
2025-04-17 12:30:23,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.371 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.44) is better than Ligand B (78.87), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.644) is slightly better than Ligand B (0.931), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (4), both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.687 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (9.306). This is a significant drawback for Ligand A.

**BBB:** Ligand A (53.083) has a higher BBB penetration than Ligand B (34.548), but BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.279) has worse Caco-2 permeability than Ligand B (-4.508), but both are poor.

**Aqueous Solubility:** Ligand A (-3.745) has worse aqueous solubility than Ligand B (-0.851). Solubility is important for bioavailability, making Ligand B preferable.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.186 and 0.214), which is excellent.

**Microsomal Clearance:** Ligand A (74.324) has a higher microsomal clearance than Ligand B (12.421). This indicates Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-23.464) has a negative half-life, which is concerning. Ligand B (2.532) has a short half-life, but is still better than a negative value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.069 and 0.047).

**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 favorable.

**Overall:**

Ligand B is the stronger candidate. It has a significantly lower DILI risk, better solubility, and better metabolic stability (lower Cl_mic, better t1/2). Although Ligand A has slightly better TPSA and BBB, these are less critical for a kinase inhibitor. The slight improvement in binding affinity for Ligand B further supports its selection.

Output:
1
2025-04-17 12:30:23,862 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A: [359.411, 108.09 ,   0.746,   1.   ,   6.   ,   0.847,  79.915,  46.646, -5.105,  -4.02 ,   0.367,  46.211,  13.221,   0.194,  -7.7  ]**
**Ligand B: [354.451, 105.48 ,   1.449,   3.   ,   6.   ,   0.59 ,  58.705,  36.293, -4.74 ,  -2.253,   0.228,  43.023,  -4.426,   0.09 ,  -7.3  ]**

**Step-by-step comparison:**

1. **MW:** Both ligands (359.411 and 354.451 Da) are within the ideal 200-500 Da range.
2. **TPSA:** Both ligands (108.09 and 105.48) are slightly above the optimal <140 for oral absorption, but not drastically so.
3. **logP:** Ligand A (0.746) is a bit low, potentially hindering permeation. Ligand B (1.449) is better, falling within the 1-3 optimal range.
4. **HBD:** Ligand A (1) is excellent. Ligand B (3) is acceptable, but higher.
5. **HBA:** Both ligands (6) are within the acceptable limit of <=10.
6. **QED:** Ligand A (0.847) has a much better drug-likeness score than Ligand B (0.59).
7. **DILI:** Ligand A (79.915) has a significantly higher DILI risk than Ligand B (58.705). This is a major concern.
8. **BBB:** Both are relatively low, which is fine for an oncology target, as CNS penetration isn't a priority. Ligand B (36.293) is slightly lower than Ligand A (46.646).
9. **Caco-2:** Both are negative, indicating poor permeability. Ligand A (-5.105) is worse than Ligand B (-4.74).
10. **Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.02) is worse than Ligand B (-2.253).
11. **hERG:** Both ligands have very low hERG inhibition risk (0.367 and 0.228).
12. **Cl_mic:** Ligand B (43.023) has slightly lower microsomal clearance than Ligand A (46.211), suggesting better metabolic stability.
13. **t1/2:** Ligand A (13.221) has a longer in vitro half-life than Ligand B (-4.426). This is a positive.
14. **Pgp:** Both ligands have low P-gp efflux liability (0.194 and 0.09).
15. **Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), a difference of 0.4 kcal/mol.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand A has a slightly better affinity and half-life, its significantly higher DILI risk, lower solubility, and lower Caco-2 permeability are major drawbacks. Ligand B has a better safety profile (DILI), better metabolic stability, and better solubility/permeability. The 0.4 kcal/mol difference in binding affinity is unlikely to outweigh the ADME/Tox advantages of Ligand B.

**Conclusion:**

Considering the balance of properties and the priorities for an enzyme target, **Ligand B** is the more promising drug candidate.

1
2025-04-17 12:30:23,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 364.555 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.67) is well below the 140 threshold for good absorption, while Ligand B (49.41) is even better.

**logP:** Ligand A (1.612) is within the optimal range of 1-3. Ligand B (3.561) is slightly higher, 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 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.842) has a significantly better QED score than Ligand B (0.476), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (35.169 and 36.758), both being good (below 40).

**BBB:** Ligand A (77.162) has a slightly better BBB penetration percentile than Ligand B (73.672), but this isn't a primary concern for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-4.577) has a worse Caco-2 permeability than Ligand B (-5.03). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.443) has better aqueous solubility than Ligand B (-3.932).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.255 and 0.463).

**Microsomal Clearance:** Ligand A (22.083) has a significantly lower microsomal clearance than Ligand B (86.613), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.953) has a much longer in vitro half-life than Ligand B (4.179).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.305).

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.0). However, the difference is only 0.4 kcal/mol.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties: significantly better QED, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The better solubility of Ligand A is also a plus. The small difference in binding affinity is outweighed by these substantial ADME advantages.

Output:
0
2025-04-17 12:30:23,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.479 Da and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (58.2) is well within the range.

**logP:** Ligand A (2.941) is optimal (1-3). Ligand B (4.103) is pushing the upper limit, potentially leading to solubility issues.

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

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (2) is also good.

**QED:** Ligand A (0.842) is excellent, indicating strong drug-likeness. Ligand B (0.487) is below the desirable threshold of 0.5, raising concerns about its developability.

**DILI:** Ligand A (60.682) is approaching the higher risk threshold (>60), while Ligand B (18.651) is very good, indicating low liver injury risk.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand A (60.993) and Ligand B (77.084) are both moderate.

**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 Inhibition:** Ligand A (0.584) is better than Ligand B (0.616), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (37.561) is better than Ligand B (59.979), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.346) is better than Ligand B (-1.044), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.43) is better than Ligand B (0.569), suggesting lower efflux.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is small (0.2 kcal/mol) and may not be enough to overcome the other deficiencies in Ligand B.

**Overall Assessment:**

Ligand A has a significantly better QED score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly lower hERG risk. While both have poor Caco-2 and solubility, the superior ADME properties of Ligand A, coupled with its good drug-likeness, make it the more promising candidate. The slightly better binding affinity of Ligand B is unlikely to outweigh the significant ADME liabilities.

Output:
1
2025-04-17 12:30:23,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.387 and 369.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (119.23 and 104.37) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.615) is optimal, while Ligand B (0.437) is slightly low, potentially hindering permeation.

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

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

**QED:** Both ligands have reasonable QED scores (0.673 and 0.513), indicating good drug-likeness.

**DILI:** Ligand A (64.327) has a higher DILI risk than Ligand B (31.214). This is a significant drawback for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**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.

**Aqueous Solubility:** Both ligands 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 (0.135 and 0.099).

**Microsomal Clearance:** Ligand A (14.713 mL/min/kg) has significantly lower microsomal clearance than Ligand B (42.773 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.812 hours) has a shorter half-life than Ligand B (-28.12 hours). The negative value for Ligand B is concerning and likely an error or outlier.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.031).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol), a difference of 1.1 kcal/mol. This is a substantial advantage.

**Conclusion:**

Despite Ligand A's higher DILI risk, its significantly superior binding affinity (-8.6 vs -7.5 kcal/mol) and better metabolic stability (lower Cl_mic) outweigh the DILI concern, especially given the relatively moderate risk (64.327). The negative solubility and Caco-2 values are concerning for both, but the binding affinity difference is a critical factor for an enzyme target. The negative half-life for Ligand B is a red flag.

Output:
1
2025-04-17 12:30:23,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.334 and 348.349 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.34) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (65.22) is well within the acceptable range.

**logP:** Ligand A (0.661) is a bit low, potentially hindering permeation. Ligand B (3.746) is near the upper limit of the optimal range (1-3), but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, fitting the guidelines. Ligand B has 0 HBD and 5 HBA, also fitting the guidelines.

**QED:** Both ligands have similar QED values (0.771 and 0.744), indicating good drug-likeness.

**DILI:** Ligand A (86.002) shows a higher DILI risk than Ligand B (63.823). This is a significant concern.

**BBB:** Both ligands have high BBB penetration (80.962 and 96.937), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with the experimental setup or a need for further investigation. However, the values are similar, so this doesn't differentiate them significantly.

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

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.127 and 0.207).

**Microsomal Clearance:** Ligand A (46.465) has significantly lower microsomal clearance than Ligand B (75.804), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.477) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (-20.698) also has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.14 and 0.301).

**Binding Affinity:** Both ligands have identical binding affinities (-9.3 kcal/mol), which is excellent.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B exhibits a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The negative half-life values for both are concerning and require further investigation, but the lower DILI risk of Ligand B is a crucial advantage for an oncology drug. The slightly better logP of Ligand B is also a minor benefit.

Output:
1
2025-04-17 12:30:23,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.394 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is significantly better than Ligand B (83.36). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is much more favorable.

**logP:** Ligand A (4.774) is higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (1.81) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.676) has a better QED score than Ligand B (0.554), indicating higher drug-likeness.

**DILI:** Ligand B (34.858) has a much lower DILI risk than Ligand A (69.794). This is a significant advantage for Ligand B.

**BBB:** Ligand A (91.508) has a higher BBB penetration than Ligand B (23.924). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.632) has a more negative Caco-2 value, suggesting lower permeability than Ligand B (-5.207).

**Aqueous Solubility:** Ligand A (-4.851) has lower solubility than Ligand B (-2.99).

**hERG Inhibition:** Ligand A (0.924) has a higher hERG risk than Ligand B (0.241). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (1.766) has much lower microsomal clearance than Ligand A (76.472), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.715) has a longer in vitro half-life than Ligand A (41.241).

**P-gp Efflux:** Ligand A (0.832) has higher P-gp efflux than Ligand B (0.036).

**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 deficiencies of Ligand A.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties: lower DILI risk, lower hERG inhibition, significantly better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and lower P-gp efflux. These factors are critical for developing a viable drug candidate, especially for an enzyme target like SRC kinase. The higher logP of Ligand A is a concern, and the lower solubility and higher hERG risk are major drawbacks.

Output:
1
2025-04-17 12:30:23,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (381.57 & 353.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is excellent, well below the 140 threshold. Ligand B (104.9) is still reasonable but higher, potentially impacting absorption.

**3. logP:** Both ligands have good logP values (2.78 & 1.09), falling within the 1-3 optimal range. Ligand A is slightly better.

**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 (5 & 6 respectively).

**6. QED:** Both ligands have acceptable QED scores (0.82 & 0.68), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (26.06 & 33.70), both are good.

**8. BBB:** Ligand A (76.77) has a better BBB percentile than Ligand B (52.27), but BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.19) is significantly better than Ligand B (-4.93), suggesting superior intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.35) is better than Ligand B (-1.65), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.37 & 0.36).

**12. Microsomal Clearance (Cl_mic):** Ligand A (54.08) has a higher clearance than Ligand B (6.77), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand B (5.16) has a longer half-life than Ligand A (-18.52), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.06 & 0.17).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). The difference of 1.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a significantly better binding affinity. While Ligand A has better TPSA and Caco-2 permeability, the superior affinity and metabolic stability of Ligand B are more crucial for an enzyme target.

Output:
1
2025-04-17 12:30:23,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (374.815 and 361.877 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (67.43 and 66.97) are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (3.336 and 3.157) 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 3 HBA, and Ligand B has 6. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.75 and 0.642), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 57.193, while Ligand B is significantly lower at 25.591. This is a major advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration (87.67 and 68.127), but this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.467) shows poor Caco-2 permeability, while Ligand B (-5.076) is even worse. Both are quite poor, but B is slightly worse.

**10. Aqueous Solubility:** Ligand A (-4.545) shows poor solubility, while Ligand B (-2.968) is better. This favors Ligand B.

**11. hERG Inhibition:** Ligand A (0.639) has a slightly higher hERG risk than Ligand B (0.873). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (47.612 and 46.538 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (56.264 hours) has a significantly longer half-life than Ligand A (8.086 hours). This is a substantial advantage for Ligand B, reducing dosing frequency.

**14. P-gp Efflux:** Ligand A (0.179) has lower P-gp efflux than Ligand B (0.513). Lower is better, favoring Ligand A.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in critical areas: significantly lower DILI risk, better aqueous solubility, a much longer half-life, and, most importantly, a substantially higher binding affinity. The improved binding affinity is a key driver for enzyme inhibitors. The solubility and DILI improvements are also significant.

Output:
1
2025-04-17 12:30:23,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.415 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (94.56), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.541) is within the optimal 1-3 range. Ligand B (0.958) is slightly below 1, which *could* indicate potential permeability issues, though not dramatically.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 6 HBA) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.728) has a better QED score than Ligand B (0.593), indicating a more drug-like profile.

**DILI:** Ligand A (22.14) has a significantly lower DILI risk than Ligand B (59.752). This is a major advantage for Ligand A.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (70.997) is better than Ligand B (35.014).

**Caco-2 Permeability:** Ligand A (-4.247) is better than Ligand B (-5.512), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.546) is better than Ligand B (-2.096), suggesting better solubility.

**hERG Inhibition:** Ligand A (0.266) has a lower hERG risk than Ligand B (0.552). This is a significant advantage.

**Microsomal Clearance:** Ligand A (38.013) has higher microsomal clearance than Ligand B (8.424), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (18.58) has a significantly longer half-life than Ligand A (-13.762). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.023), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.5 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:**

Ligand A excels in most ADME properties (DILI, hERG, solubility, permeability, QED) and has slightly better binding affinity. However, Ligand B has a significantly longer half-life and better metabolic stability. Given that SRC is an enzyme, metabolic stability and half-life are crucial. The small difference in binding affinity is outweighed by the significant improvement in pharmacokinetic properties of Ligand B.

Output:
1
2025-04-17 12:30:23,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.407 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.79) is slightly above the preferred <140 for oral absorption, while Ligand B (121.52) is well within the range.

**logP:** Ligand A (0.363) is a bit low, potentially hindering permeation. Ligand B (-0.164) is even lower, raising more concerns about permeability.

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

**QED:** Both ligands have similar QED values (0.446 and 0.477), indicating moderate drug-likeness.

**DILI:** Ligand A has a DILI risk of 57.076, which is moderate. Ligand B has a significantly lower DILI risk of 16.712, which is preferable.

**BBB:** Both ligands have low BBB penetration (11.865 and 44.668), which is not a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.938 and -5.838), which is unusual and suggests poor permeability. This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.866 and -2.57), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.268) has a slightly higher hERG risk than Ligand B (0.082), but both are relatively low.

**Microsomal Clearance:** Ligand A (-0.935) has better metabolic stability (lower clearance) than Ligand B (5.678). This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (23.032 and 23.124 hours), which is good.

**P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, which is favorable. Ligand B (0.024) is also very low.

**Binding Affinity:** Ligand A (0.0) has slightly better binding affinity than Ligand B (-9.0 kcal/mol). This is a substantial difference and a major factor in favor of Ligand A.

**Overall Assessment:**

Ligand B has a much better DILI score and slightly better hERG. However, Ligand A has significantly better binding affinity and better metabolic stability (lower Cl_mic). Both have poor solubility and permeability, which are major issues. The superior binding affinity of Ligand A (-9.0 kcal/mol vs 0.0 kcal/mol) is a significant advantage that could potentially overcome some of the ADME liabilities, especially if formulation strategies can improve solubility and permeability.

Output:
0
2025-04-17 12:30:23,863 - INFO - Batch 135 complete. Total preferences: 2160
2025-04-17 12:30:23,863 - INFO - Processing batch 136/512...
2025-04-17 12:31:03,721 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.69) is still acceptable, but less optimal.

**logP:** Ligand A (2.045) is optimal (1-3). Ligand B (0.548) is a bit low, potentially hindering permeability.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, well within the limit of 10. Ligand B has 6 HBA, still acceptable but higher.

**QED:** Both ligands have similar QED values (0.663 and 0.566), indicating reasonable drug-likeness.

**DILI:** Ligand A (57.619) has a moderate DILI risk, but is better than Ligand B (32.299) which is quite low.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.25) is slightly better than Ligand B (55.68).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. This is also concerning.

**hERG Inhibition:** Ligand A (0.359) has a very low hERG risk, which is excellent. Ligand B (0.059) is also very low, and comparable.

**Microsomal Clearance:** Ligand A (30.026) has lower clearance, suggesting better metabolic stability, which is a priority for enzymes. Ligand B (37.938) has higher clearance.

**In vitro Half-Life:** Ligand A (17.337 hours) has a better half-life than Ligand B (-7.248 hours, which is likely an error or very poor stability).

**P-gp Efflux:** Both have low P-gp efflux liability (0.323 and 0.031), which is good.

**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.

**Overall Assessment:**

Ligand A is preferable. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in metabolic stability (lower Cl_mic, longer t1/2) and hERG risk. The poor Caco-2 and solubility for both are concerning and would require further optimization, but the better metabolic profile of Ligand A makes it a more promising starting point for optimization.

Output:
0
2025-04-17 12:31:03,722 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.391 and 354.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.22) is higher than Ligand B (78.43). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (-0.772) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.868) is within the optimal range.

**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.

**QED:** Both ligands have acceptable QED scores (0.681 and 0.528, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (56.689) has a higher DILI risk than Ligand B (16.014). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (58.666 and 59.946). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.271 and -4.541).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.968) is slightly better than Ligand B (-3.137).

**hERG Inhibition:** Ligand A (0.041) has a very low hERG risk, which is excellent. Ligand B (0.607) has a moderate hERG risk. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-6.464) has a much lower (better) microsomal clearance than Ligand B (53.967), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (6.556 hours) has a longer half-life than Ligand B (5.338 hours).

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, while Ligand B (0.288) has a slightly higher efflux.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand B has a better logP and binding affinity, but Ligand A excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a very low hERG risk. The slightly better solubility of Ligand A is also a plus. While Ligand B's affinity is marginally better, the ADME/Tox profile of Ligand A is far superior, making it a more promising drug candidate.

Output:
0
2025-04-17 12:31:03,722 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.849 and 360.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is significantly better than Ligand B (113.32). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.421) is optimal, while Ligand B (1.08) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.902) has a much better drug-likeness score than Ligand B (0.432).

**DILI:** Both ligands have similar DILI risk (71.656 vs 73.439), and are acceptable.

**BBB:** Ligand A (71.307) has a better BBB penetration score than Ligand B (42.536), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.359) is better than Ligand B (-5.536), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.877) is better than Ligand B (-4.819), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.454) is preferable to Ligand B (0.657), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (83.319) has higher clearance than Ligand B (6.597). This means Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (66.29) has a longer half-life than Ligand B (23.508).

**P-gp Efflux:** Ligand A (0.288) has lower P-gp efflux than Ligand B (0.035), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is small.

**Overall Assessment:**

Ligand A is superior in almost every ADME property (TPSA, logP, QED, solubility, hERG, Caco-2, P-gp efflux, half-life) and has a comparable binding affinity to Ligand B. While Ligand B has better metabolic stability (lower Cl_mic), the overall profile of Ligand A is much more favorable for drug development. The slightly stronger binding of Ligand B does not outweigh the significant ADME advantages of Ligand A.

Output:
1
2025-04-17 12:31:03,722 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.865 Da) and Ligand B (347.405 Da) are both acceptable.

**TPSA:** Ligand A (70.9) is reasonably good, suggesting decent permeability. Ligand B (21.7) is excellent, indicating very good permeability.

**logP:** Ligand A (1.899) is optimal. Ligand B (4.146) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a tolerable range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being less than 10.

**QED:** Both ligands have good QED values (Ligand A: 0.735, Ligand B: 0.811), indicating generally drug-like properties.

**DILI:** Ligand A (40.054) has a slightly higher DILI risk than Ligand B (27.026), but both are below the 40 threshold and considered good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.913) and Ligand B (91.198) are both reasonably good.

**Caco-2 Permeability:** Ligand A (-5.049) is poor, suggesting poor absorption. Ligand B (-4.366) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.494) is poor, while Ligand B (-4.344) is very poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.682) is better than Ligand B (0.98), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-1.234) is excellent, suggesting high metabolic stability. Ligand B (67.161) is very high, indicating rapid metabolism and potentially low bioavailability.

**In vitro Half-Life:** Ligand A (51.577) is good, while Ligand B (4.035) is poor.

**P-gp Efflux:** Ligand A (0.056) is excellent, indicating low efflux. Ligand B (0.818) is moderate.

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-9.2). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity (-7.8 kcal/mol vs -9.2 kcal/mol). This is a significant advantage that can potentially overcome some of its drawbacks. However, its major weaknesses are its poor solubility, high microsomal clearance, and short half-life. Ligand A has better solubility, metabolic stability, and lower P-gp efflux, but its binding affinity is considerably weaker.

Considering the enzyme-specific priorities, potency (affinity) is paramount. The 1.5 kcal/mol difference in binding affinity is substantial. While Ligand B's ADME properties are less favorable, these can potentially be addressed through further optimization. The poor solubility and high clearance are more readily tackled than significantly improving binding affinity. Ligand A's weak binding makes it less likely to be a viable candidate even with better ADME properties.

Output:
1
2025-04-17 12:31:03,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (69.72 and 62.3) well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.953) is within the optimal 1-3 range. Ligand B (3.441) is at the higher end, but still acceptable.

**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 (0.68 and 0.769), indicating drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (42.187 and 43.505 percentile).

**BBB:** Both have low BBB penetration, which isn't a major concern for an oncology target.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.167 and 0.359), which is excellent.

**Microsomal Clearance:** Ligand A (63.202) has lower microsomal clearance than Ligand B (71.019), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.682) has a negative half-life, which is problematic. Ligand B (16.121) has a positive and reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.133 and 0.287).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol) - a difference of 1.5 kcal/mol. This is a substantial advantage.

**Conclusion:**

While both compounds have issues with solubility and permeability, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.6 vs -8.1 kcal/mol) outweighs the slightly higher microsomal clearance and logP. The positive in vitro half-life of Ligand B is also a major advantage over Ligand A's negative value. The similar DILI and hERG profiles are positive for both. Addressing the solubility and permeability issues through formulation or structural modifications would be the next step, but based on the current data, Ligand B is the better starting point.

Output:
1
2025-04-17 12:31:03,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.427 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.87 and 67.43) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.9) is optimal, while Ligand B (2.54) is still within the acceptable range of 1-3.

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

**H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (3) is also acceptable.

**QED:** Ligand A (0.846) is excellent, indicating a strong drug-like profile. Ligand B (0.549) is acceptable, but less ideal than A.

**DILI:** Both ligands have low DILI risk (31.718 and 34.277), which is favorable.

**BBB:** Both ligands have moderate BBB penetration (65.839 and 71.268). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.399 and -4.702). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon. It's important to note this as a potential issue.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.894 and -3.167). Similar to Caco-2, these values are on a log scale, and negative values indicate poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands have very low hERG risk (0.266 and 0.59), which is excellent.

**Microsomal Clearance:** Ligand A (25.742) has lower microsomal clearance than Ligand B (36.487), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-8.293) has a longer in vitro half-life than Ligand B (6.503), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.07 and 0.173), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent and meets the criteria.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. It has a better QED score, lower microsomal clearance, and a longer in vitro half-life, all crucial for an enzyme inhibitor. While both have poor predicted solubility and permeability, the superior ADME properties of Ligand A make it the better choice for further optimization.

Output:
0
2025-04-17 12:31:03,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.316 Da) is slightly lower, which could be beneficial for permeability. Ligand B (374.547 Da) is also good.

**TPSA:** Ligand A (61.94) is better than Ligand B (78.87). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 2.991, B: 1.659), 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=0, HBA=6) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of hydrogen bond donors and acceptors, within the guidelines.

**QED:** Both ligands have similar QED values (A: 0.68, B: 0.642), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (60.682) compared to Ligand B (14.424). This is a major concern for Ligand A.

**BBB:** Ligand A (89.027) has a better BBB penetration potential than Ligand B (51.377), but BBB is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.476) has a worse Caco-2 permeability than Ligand B (-4.774). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.511) has slightly better aqueous solubility than Ligand B (-2.058), which is good.

**hERG:** Ligand A (0.725) has a slightly higher hERG risk than Ligand B (0.207). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (53.338) has a lower microsomal clearance than Ligand B (66.832), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (4.475) has a longer half-life than Ligand B (1.198). This is a strong advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.529) has lower P-gp efflux than Ligand B (0.047), which is preferable.

**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 small.

**Overall Assessment:**

Ligand A has advantages in metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, solubility and a slightly better binding affinity. However, its significantly higher DILI risk is a major drawback. Ligand B has a much lower DILI risk and a better hERG profile, which are critical for drug development. Although Ligand B has slightly lower metabolic stability and binding affinity, the safety profile is more favorable. Given the enzyme-specific priorities, the lower DILI risk of Ligand B outweighs the slightly weaker potency and stability.

Output:
1
2025-04-17 12:31:03,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (377.413 and 374.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (113.76). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (1.715) is within the optimal 1-3 range. Ligand B (-0.957) is slightly below 1, which *could* hinder permeation, though not drastically.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 8. Ligand A is preferable here, as higher HBA can sometimes negatively impact permeability.

**QED:** Both have reasonable QED scores (0.79 and 0.632), indicating good drug-like properties.

**DILI:** Ligand A (58.434) has a slightly higher DILI risk than Ligand B (61.303), but both are acceptable (below 60).

**BBB:** Ligand A (67.468) has better BBB penetration than Ligand B (24.544), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.899) and Ligand B (-5.248) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-2.489) has better solubility than Ligand B (-0.874), although both are negative and indicate poor aqueous solubility.

**hERG:** Ligand A (0.441) has a significantly lower hERG risk than Ligand B (0.086), which is a major advantage.

**Microsomal Clearance:** Ligand A (3.98) has a lower Cl_mic than Ligand B (-9.284), indicating better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (-16.186) has a much longer half-life than Ligand B (20.363). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux than Ligand B (0.011), which is preferable.

**Binding Affinity:** Ligand B (-9.0 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 concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity (-9.0 vs -8.5 kcal/mol). However, it suffers from poorer metabolic stability (higher Cl_mic, shorter half-life), lower solubility, and a higher hERG risk. Ligand A has better ADME properties across the board *except* for binding affinity. The difference in binding affinity is significant (1.5 kcal/mol), and for an enzyme target, potency is paramount. While the ADME properties of Ligand B are concerning, they might be addressable through further optimization. The strong binding affinity gives it a higher probability of success.

Output:
1
2025-04-17 12:31:03,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.471 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (70.39), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands (1.868 and 1.921) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.749 and 0.872), indicating good drug-like properties.

**DILI:** Ligand A (70.725) has a higher DILI risk than Ligand B (8.957). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration (65.374 and 75.107), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.475) has worse Caco-2 permeability than Ligand B (-4.757).

**Aqueous Solubility:** Ligand A (-3.682) has worse aqueous solubility than Ligand B (-2.058). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.314 and 0.336).

**Microsomal Clearance:** Ligand A (53.485) has significantly better microsomal clearance (lower) than Ligand B (14.262), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (53.003) has a much longer in vitro half-life than Ligand B (-1.647). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.149 and 0.04).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic and longer t1/2). However, it suffers from higher DILI risk and poorer solubility/permeability. Ligand B has a much lower DILI risk and better solubility/permeability but weaker binding affinity and poorer metabolic stability.

Given that we are targeting a kinase (SRC), potency and metabolic stability are paramount. The 1 kcal/mol difference in binding affinity, coupled with the substantially improved metabolic stability of Ligand A, outweighs the concerns about its slightly higher DILI risk and lower solubility. The DILI risk, while elevated, is still below the 60% threshold considered highly problematic. Solubility can potentially be improved through formulation strategies.

Output:
1
2025-04-17 12:31:03,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.515 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.3 and 85.05) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.245) is optimal, while Ligand B (1.235) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) are both within the acceptable limit of <=5.

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

**QED:** Both ligands (0.721 and 0.782) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (44.591) has a lower DILI risk than Ligand B (59.829), indicating a better safety profile. Both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.898) is higher than Ligand B (68.554).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.774 and -4.864), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.882 and -2.889), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.354 and 0.145), which is positive.

**Microsomal Clearance:** Ligand A (28.925 mL/min/kg) has a lower clearance than Ligand B (43.584 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (16.631 hours) has a significantly longer half-life than Ligand A (-0.851 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.095 and 0.124).

**Binding Affinity:** Ligand A (-9.2 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 concerning negative Caco-2 and solubility values for both, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.2 vs -7.8 kcal/mol) outweighs the slightly higher DILI risk and lower half-life. The lower microsomal clearance of Ligand A also contributes to its favorability. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the potency advantage is crucial for an enzyme inhibitor.

Output:
0
2025-04-17 12:31:03,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.455 and 358.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.35) is slightly higher than Ligand B (85.25). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Ligand A (2.511) and Ligand B (1.489) are both within the optimal 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for cell permeability, but Ligand B is still acceptable.

**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 and <=10 HBA).

**QED:** Both ligands have similar QED values (0.764 and 0.737), indicating good drug-likeness.

**DILI:** Ligand A (69.135) has a higher DILI risk than Ligand B (47.77). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (75.301 and 81.039), but this is less crucial for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand B (-4.307) is slightly better than Ligand A (-5.245).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-3.134) is slightly better than Ligand A (-2.98).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.275 and 0.185). This is excellent.

**Microsomal Clearance:** Ligand A (21.704) has significantly lower microsomal clearance than Ligand B (47.11). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (31.201) has a longer half-life than Ligand B (-32.272). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.166 and 0.043).

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand B has advantages in DILI risk, Caco-2 permeability, solubility, and binding affinity. However, Ligand A has a significant advantage in metabolic stability (lower Cl_mic and longer half-life), which is crucial for kinase inhibitors. The slightly better binding affinity of Ligand B is unlikely to outweigh the improved pharmacokinetic profile of Ligand A.

Output:
1
2025-04-17 12:31:03,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.467 and 368.781 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.37) is well below the 140 threshold, suggesting good absorption. Ligand B (133.21) is still within acceptable limits but higher, potentially impacting absorption slightly.

**logP:** Ligand A (2.973) is optimal (1-3). Ligand B (-0.98) is below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is acceptable, but higher.

**QED:** Both ligands have reasonable QED scores (0.908 and 0.6), indicating good drug-like properties.

**DILI:** Ligand A (59.984) has a lower DILI risk than Ligand B (67.468), which is preferable. Both are reasonably safe, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (94.61) is much higher than Ligand B (11.4).

**Caco-2 Permeability:** Ligand A (-4.366) is poor, while Ligand B (-5.678) is even worse. Both are quite low, suggesting potential absorption issues.

**Aqueous Solubility:** Ligand A (-3.686) is better than Ligand B (-1.946), indicating better solubility.

**hERG Inhibition:** Ligand A (0.42) has a significantly lower hERG risk than Ligand B (0.045). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (51.487) has a higher (worse) clearance than Ligand B (-14.93). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (29.681) has a shorter half-life than Ligand B (36.307), indicating faster metabolism.

**P-gp Efflux:** Ligand A (0.117) has lower P-gp efflux than Ligand B (0.044), which is preferable.

**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, potentially outweighing some ADME concerns. The 2.1 kcal/mol difference is significant.

**Conclusion:**

Despite Ligand B's better metabolic stability and half-life, Ligand A is the superior candidate. The significantly stronger binding affinity (-9.3 vs -7.2 kcal/mol) is a major driver. Additionally, Ligand A has a lower DILI risk, better solubility, and lower hERG inhibition liability. While Caco-2 permeability is poor for both, the overall profile of Ligand A is more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 12:31:03,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (380.539) is also good.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (68.21) is preferable to Ligand A (78.87) as it is closer to the ideal range.

**logP:** Ligand A (0.685) is a bit low, potentially hindering permeation. Ligand B (3.081) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (0 HBD, 7 HBA) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (0.5 and 0.593), indicating good drug-like properties.

**DILI Risk:** Ligand A (10.392) has a much lower DILI risk than Ligand B (23.769). This is a major advantage for Ligand A.

**BBB:** Ligand B (78.868) has a higher BBB penetration percentile than Ligand A (47.189), but BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.868) has significantly poorer Caco-2 permeability than Ligand B (-5.048). Both are poor, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.456) has slightly better aqueous solubility than Ligand B (-2.069).

**hERG Inhibition:** Ligand A (0.198) has a lower hERG risk than Ligand B (0.477). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-2.055) has a much lower (better) microsomal clearance than Ligand B (72.291). This indicates significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.213) has a shorter half-life than Ligand B (1.369), but the difference is not substantial.

**P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux liability than Ligand B (0.291).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic), DILI risk, hERG risk, and P-gp efflux. Ligand B has better logP and slightly better binding affinity. The significantly better metabolic stability and lower toxicity profile of Ligand A outweigh the small affinity difference and slightly lower logP. The poor Caco-2 permeability of both is a concern, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 12:31:03,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.415 and 358.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (84.3 and 79.54) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (0.707 and 1.222).

**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 (0.77 and 0.768), indicating good drug-likeness.

**DILI:** Ligand A (56.146) has a lower DILI risk than Ligand B (74.874), which is preferable.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (68.36) has a slightly better BBB score than Ligand B (54.246), but this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.017 and -4.659), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.649 and -2.529), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.134 and 0.124), which is excellent.

**Microsomal Clearance:** Ligand A (23.061) has significantly lower microsomal clearance than Ligand B (50.852), suggesting better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (-12.635) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (-46.644) also has a negative half-life. Both are problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.205).

**Binding Affinity:** Ligand B (-7.6 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 for Ligand B.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, the significantly lower microsomal clearance of Ligand A is a major advantage. The negative half-life values for both are concerning and require further investigation. The poor solubility and permeability are also significant drawbacks for both. However, given the enzyme-specific priorities, metabolic stability (lower Cl_mic) is crucial. The lower DILI risk of Ligand A is also a plus.

Output:
1
2025-04-17 12:31:03,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.876) is slightly higher than Ligand B (364.427), but both are acceptable.

**TPSA:** Ligand A (71.09) is significantly better than Ligand B (106.35). Lower TPSA generally indicates better permeability.

**logP:** Ligand A (3.459) is optimal, while Ligand B (1.234) is a bit low, 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 preferable.

**QED:** Both ligands have similar QED values (0.802 and 0.765), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (68.244 and 69.135), placing them in a moderate risk category. This isn't a major differentiating factor.

**BBB:** Ligand A (63.784) and Ligand B (59.325) both have low BBB penetration, which isn't a major concern for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.734 and -4.757), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Ligand A (-4.738) and Ligand B (-2.406) both have negative solubility values, indicating poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.618) has a slightly higher hERG risk than Ligand B (0.082). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (69.937) has a higher microsomal clearance than Ligand B (26.104), indicating lower metabolic stability. This is a major disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-38.354) has a negative half-life, which is not possible. Ligand A (40.876) has a reasonable half-life. This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.411) has lower P-gp efflux than Ligand B (0.075), which is preferable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage for Ligand A, and can potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, a reasonable half-life, and lower P-gp efflux. However, it suffers from higher microsomal clearance and a slightly higher hERG risk. Ligand B has better hERG inhibition, but its lower binding affinity, poor metabolic stability, and negative half-life are major drawbacks.

Given the enzyme-specific priorities, binding affinity is paramount. The 1.8 kcal/mol difference in binding affinity is substantial. While Ligand A has some ADME liabilities, these could potentially be addressed through further optimization. Ligand B's weak binding affinity is a more fundamental issue.

Output:
1
2025-04-17 12:31:03,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.431 and 356.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.01) is well below the 140 threshold for good oral absorption. Ligand B (118.89) is also acceptable, but higher.

**logP:** Ligand A (2.945) is optimal (1-3). Ligand B (0.679) is a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is excellent. Ligand B (HBD=5, HBA=5) is acceptable, but higher HBD could slightly impact permeability.

**QED:** Ligand A (0.901) is excellent, indicating high drug-likeness. Ligand B (0.422) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (42.303) has a low DILI risk. Ligand B (24.351) also has a low DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.449) is reasonable. Ligand B (18.069) is low.

**Caco-2 Permeability:** Ligand A (-4.303) is poor. Ligand B (-5.681) is even worse, indicating poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.377) is poor. Ligand B (-1.27) is also poor, but slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.559) has a low hERG risk. Ligand B (0.366) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (21.542) is moderate. Ligand B (-9.189) is *excellent* - a negative value suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (26.005) is reasonable. Ligand B (8.782) is lower, suggesting faster metabolism.

**P-gp Efflux:** Ligand A (0.159) has low P-gp efflux, which is good. Ligand B (0.04) has even lower P-gp efflux.

**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:**

Ligand B has a significantly better binding affinity, and excellent metabolic stability (negative Cl_mic). While its Caco-2 and solubility are poor, and QED is low, the strong binding affinity and metabolic stability are crucial for an enzyme inhibitor. Ligand A has better QED and TPSA, but weaker binding and moderate metabolic stability. The difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 12:31:03,725 - INFO - Batch 136 complete. Total preferences: 2176
2025-04-17 12:31:03,725 - INFO - Processing batch 137/512...
2025-04-17 12:31:44,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.467 and 367.559 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.5) is slightly higher than the preferred <140, while Ligand B (65.2) is well within the range.

**logP:** Ligand A (1.785) is optimal (1-3). Ligand B (3.52) is at the higher end of optimal, but still acceptable.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the criteria of <=5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (3) both meet the criteria of <=10.

**QED:** Both ligands have similar QED values (0.665 and 0.691), indicating good drug-likeness.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (37.263).  Ligand B is preferable here.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**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 very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.355) has a lower hERG inhibition liability than Ligand B (0.701), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (74.807) has lower microsomal clearance than Ligand B (85.125), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand B (33.511) has a significantly longer in vitro half-life than Ligand A (7.137). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.133) has lower P-gp efflux than Ligand B (0.218), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a crucial advantage, as a 1.4 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity and a longer half-life, which are critical for an enzyme inhibitor. While its DILI risk and P-gp efflux are slightly higher, and solubility is poor, the significantly improved potency outweighs these drawbacks. Both compounds suffer from poor solubility and permeability, but these can potentially be addressed through formulation strategies. Ligand A has a better hERG profile and lower clearance, but the weaker binding affinity is a major disadvantage.

Output:
1
2025-04-17 12:31:44,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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. Ligand B (388.53 Da) is also acceptable.

**TPSA:** Ligand A (111.49) is better than Ligand B (66.48), being closer to the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (A: 2.398, B: 3.131), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 4 HBA. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.604, B: 0.814), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (88.057) has a higher DILI risk than Ligand B (63.242). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (87.01) has a higher BBB value than Ligand A (57.736), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.653) is slightly worse than Ligand B (-5.064).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.245) is slightly better than Ligand B (-4.339).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.099, B: 0.811), which is excellent.

**Microsomal Clearance:** Ligand B (36.303 mL/min/kg) has significantly lower microsomal clearance than Ligand A (106.579 mL/min/kg). This suggests better metabolic stability for Ligand B, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-6.625 hours) has a slightly better in vitro half-life than Ligand A (-41.377 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.174, B: 0.372).

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and lower microsomal clearance (better metabolic stability) outweigh the slightly worse TPSA and Caco-2 permeability. The solubility is also slightly better. While both have poor Caco-2 and solubility, metabolic stability is more critical for kinase inhibitors, and the lower DILI risk is a major advantage.

Output:
1
2025-04-17 12:31:44,124 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (348.447 & 364.511 Da) fall comfortably within the ideal 200-500 Da range.
2. **TPSA:** Both ligands (76.46 & 70.5) are below the 140 A^2 threshold for good oral absorption.
3. **logP:** Ligand A (1.371) is optimal, while Ligand B (3.028) is at the higher end of the optimal range, but still acceptable.
4. **HBD:** Both ligands have 1 HBD, which is within the ideal limit of <=5.
5. **HBA:** Both ligands have 5 HBA, which is within the ideal limit of <=10.
6. **QED:** Both ligands have good QED scores (0.755 & 0.842), indicating good drug-like properties.
7. **DILI:** Both ligands have low DILI risk (30.865 & 31.989 percentile), which is favorable.
8. **BBB:** Both ligands have good BBB penetration (74.99 & 70.182 percentile), though not critical for a non-CNS target like SRC.
9. **Caco-2:** Ligand A (-4.801) has a worse Caco-2 permeability than Ligand B (-4.527), suggesting potentially lower intestinal absorption.
10. **Solubility:** Ligand A (-1.144) has better aqueous solubility than Ligand B (-3.024).
11. **hERG:** Both ligands have low hERG inhibition liability (0.549 & 0.145), which is excellent.
12. **Cl_mic:** Ligand A (14.377 mL/min/kg) has significantly lower microsomal clearance than Ligand B (59.556 mL/min/kg), indicating better metabolic stability.
13. **t1/2:** Ligand B (-11.724 hours) has a much longer in vitro half-life than Ligand A (-5.745 hours), which is a significant advantage.
14. **Pgp:** Both ligands have low P-gp efflux liability (0.076 & 0.31).
15. **Binding Affinity:** Ligand B (-9.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.0 kcal/mol) - a difference of 2.8 kcal/mol. This is a very significant difference.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and half-life, while Ligand A has better solubility and metabolic stability. However, the 2.8 kcal/mol difference in binding affinity is substantial and likely to outweigh the benefits of Ligand A's slightly better metabolic stability and solubility.

**Conclusion:**

Considering the enzyme-specific priorities and the overall profile, **Ligand B** is the more promising drug candidate. The significantly stronger binding affinity is a major advantage that likely outweighs the slightly higher clearance and lower solubility.

Output:
1
2025-04-17 12:31:44,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk, as appropriate for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.275 Da) is slightly higher, but acceptable. Ligand B (348.407 Da) is also good.

**TPSA:** Ligand A (85.83) is well below the 140 threshold for oral absorption. Ligand B (104.45) is also acceptable, though slightly higher.

**logP:** Ligand A (2.393) is within the optimal range (1-3). Ligand B (-0.829) is below 1, which *could* indicate permeability issues. This is a significant negative for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have acceptable QED scores (Ligand A: 0.814, Ligand B: 0.673), indicating good drug-like properties.

**DILI:** Ligand A (55.138) has a moderate DILI risk, but is acceptable. Ligand B (39.279) has a lower DILI risk, which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.407) and Ligand B (27.646) are both relatively low, which isn't a concern.

**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, again, unusual and suggesting poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.291) has a very low hERG risk, which is excellent. Ligand B (0.03) also has a very low hERG risk, equally good.

**Microsomal Clearance:** Ligand A (3.729) has a lower clearance, suggesting better metabolic stability. Ligand B (9.534) has a significantly higher clearance, indicating faster metabolism and potentially lower *in vivo* exposure. This is a major negative for Ligand B.

**In vitro Half-Life:** Ligand A (13.55 hours) has a reasonable half-life. Ligand B (-17.125 hours) has a negative half-life, which is impossible and likely an error or outlier. This is a critical flaw for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.191, Ligand B: 0.02), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.6 kcal/mol and -7.5 kcal/mol), with Ligand A being slightly better. The difference is not large enough to overcome other significant issues.

**Conclusion:**

Ligand A is the more promising candidate. While its solubility is concerning, it has better metabolic stability (lower Cl_mic, longer t1/2), a more favorable logP, and a slightly better binding affinity. Ligand B has a negative half-life, which is a showstopper, and a significantly higher clearance. The lower logP of Ligand B also raises concerns about permeability.

Output:
0
2025-04-17 12:31:44,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.363 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (367.921 Da) is also well within range.

**TPSA:** Ligand A (123.92) is better than Ligand B (58.36) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (-0.83) is a bit low, potentially hindering permeation. Ligand B (3.389) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 8 HBA) is better than Ligand B (1 HBD, 4 HBA) as it is closer to the ideal range.

**QED:** Both ligands have good QED scores (A: 0.7, B: 0.838), indicating good drug-like properties.

**DILI:** Ligand A (82.435) has a significantly higher DILI risk than Ligand B (19.736). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.97) is better than Ligand A (50.679).

**Caco-2 Permeability:** Ligand A (-5.36) is significantly worse than Ligand B (-4.662).

**Aqueous Solubility:** Ligand A (-1.94) is better than Ligand B (-3.13).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.174, B: 0.594).

**Microsomal Clearance:** Ligand A (16.862) has a lower Cl_mic, suggesting better metabolic stability than Ligand B (61.903).

**In vitro Half-Life:** Ligand A (23.75) has a slightly longer half-life than Ligand B (16.819).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.009, B: 0.666).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (A: -8.4 kcal/mol, B: -8.1 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slightly better binding affinity, solubility, metabolic stability, and half-life. However, its significantly higher DILI risk, lower Caco-2 permeability, and low logP are major drawbacks. Ligand B, while having a slightly weaker affinity, exhibits a much more favorable safety profile (low DILI), better permeability, and an optimal logP. Given the enzyme-specific priorities, minimizing toxicity and ensuring reasonable permeability are crucial. The slightly better affinity of Ligand A is unlikely to outweigh the significant safety concerns.

Output:
1
2025-04-17 12:31:44,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.5 and 348.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.93) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (81.75) is still within acceptable limits, but less favorable.

**logP:** Ligand A (3.292) is optimal (1-3). Ligand B (-0.12) is significantly below this, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2 respectively) and HBA (4 each) counts.

**QED:** Ligand A (0.822) has a very strong drug-like profile. Ligand B (0.55) is acceptable, but less desirable.

**DILI:** Ligand A (6.475) has a low DILI risk. Ligand B (22.489) is higher, but still within a reasonable range.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.531) is better than Ligand B (46.452).

**Caco-2 Permeability:** Ligand A (-4.723) is poor, while Ligand B (-5.128) is also poor. Both are problematic.

**Aqueous Solubility:** Both ligands show poor aqueous solubility (-1.661 and -1.645 respectively). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.945) has a lower hERG risk than Ligand B (0.198), which is a significant advantage.

**Microsomal Clearance:** Ligand A (15.496) has a higher clearance than Ligand B (-5.393), indicating lower metabolic stability. Ligand B is significantly more stable.

**In vitro Half-Life:** Ligand A (3.837) has a shorter half-life than Ligand B (-13.047), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.492) has lower P-gp efflux liability than Ligand B (0.011), which is favorable.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better safety profiles (DILI, hERG). However, it suffers from poorer Caco-2 permeability, higher clearance, and shorter half-life compared to Ligand B. The significantly stronger binding affinity of Ligand A is a major advantage for an enzyme target like SRC kinase. While the ADME properties of Ligand A are not ideal, they are potentially addressable through formulation or further chemical modifications. Ligand B's main advantage is its metabolic stability, but its weaker binding affinity is a critical drawback.

Output:
1
2025-04-17 12:31:44,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.379 Da and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.38) is well below the 140 threshold and favorable for oral absorption. Ligand B (109.67) is still acceptable but less optimal.

**logP:** Ligand A (3.076) is within the optimal 1-3 range. Ligand B (0.647) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 & 3) and HBA (5 & 5) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.75 and 0.566), indicating good drug-like properties.

**DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (36.758). This is a significant negative for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (35.052) is lower than Ligand B (39.007).

**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. Ligand A (-3.924) is slightly worse than Ligand B (-1.41).

**hERG:** Ligand A (0.565) has a slightly higher hERG risk than Ligand B (0.044), but both are relatively low.

**Microsomal Clearance:** Ligand A (65.877) has a significantly higher microsomal clearance than Ligand B (1.319), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-29.39) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (23.446) is a reasonable half-life.

**P-gp Efflux:** Ligand A (0.336) has a lower P-gp efflux liability than Ligand B (0.01), which is favorable.

**Binding Affinity:** Ligand A (-8.4) has a *much* stronger binding affinity than Ligand B (0.0). This is a substantial advantage that could potentially outweigh some of the ADME concerns.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its significantly higher DILI risk, higher microsomal clearance, and impossible half-life are major concerns. The low logP of Ligand B is a drawback, but its superior metabolic stability (low Cl_mic, reasonable t1/2), lower DILI risk, and lower hERG risk make it the more promising candidate. The negative solubility and Caco-2 values are concerning for both, but the other factors heavily favor Ligand B. The large difference in binding affinity is significant, but can sometimes be overcome with further optimization, while fixing the ADME issues of Ligand A would be more challenging.

Output:
1
2025-04-17 12:31:44,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.215 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (84.94) is well below the 140 threshold for oral absorption. Ligand B (95.67) is also acceptable, but closer to the limit.

**logP:** Ligand A (3.542) is within the optimal range (1-3). Ligand B (1.12) is at the lower end, potentially impacting permeability.

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD (1 & 2 respectively) and HBA (5 each) counts.

**QED:** Both ligands have good QED scores (0.687 and 0.769), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (88.523) compared to Ligand B (31.563). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (64.599) and Ligand B (52.734) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.981) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.185) is also poor, but comparable.

**Aqueous Solubility:** Ligand A (-4.315) has poor aqueous solubility. Ligand B (-0.84) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.241) has a very low hERG inhibition risk, which is excellent. Ligand B (0.052) is even lower, also excellent.

**Microsomal Clearance:** Ligand A (97.106) has high microsomal clearance, indicating poor metabolic stability. Ligand B (10.413) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.15 hours) has a relatively short half-life. Ligand B (16.884 hours) has a significantly longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.431) shows some P-gp efflux, while Ligand B (0.045) has minimal efflux.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability, poor solubility, high DILI risk, and high metabolic clearance. These significant ADME liabilities are concerning.

Ligand B, while having a weak binding affinity, exhibits a much more favorable ADME profile: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and better solubility.

Given the enzyme-specific priorities, the improved ADME properties of Ligand B, despite its weaker binding affinity, make it a more promising starting point for optimization. The strong binding affinity of Ligand A is tempting, but the ADME issues are substantial hurdles. It's easier to improve affinity through medicinal chemistry than to fix severe ADME problems.

Output:
1
2025-04-17 12:31:44,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (343.471 and 344.346 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.34) is significantly better than Ligand B (69.91). Lower TPSA generally correlates with better cell permeability, which is beneficial for kinase inhibitors needing intracellular access.

**3. logP:** Both ligands have good logP values (2.544 and 2.363), 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 7.  Ligand A is preferable here.

**6. QED:** Both ligands have similar QED values (0.774 and 0.766), indicating good drug-likeness.

**7. DILI:** Ligand A (15.045 percentile) has a much lower DILI risk than Ligand B (95.463 percentile). This is a significant advantage for Ligand A.

**8. BBB:** Both have reasonably good BBB penetration (78.907 and 71.539 percentile), but this is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2:** Ligand A (-4.824) and Ligand B (-4.42) both have negative Caco-2 values, which is unusual and indicates poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-2.4) is slightly better than Ligand B (-3.749), but both are quite poor. Solubility can be improved with formulation strategies, but it's a drawback.

**11. hERG:** Ligand A (0.243) has a much lower hERG inhibition liability than Ligand B (0.85). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**12. Cl_mic:** Ligand B (29.622) has a slightly lower microsomal clearance than Ligand A (32.791), suggesting better metabolic stability. However, the difference is not substantial.

**13. t1/2:** Ligand B (4.008 hours) has a slightly longer in vitro half-life than Ligand A (3.74 hours). Again, the difference is not large.

**14. Pgp:** Ligand A (0.091) has a lower P-gp efflux liability than Ligand B (0.398), which is favorable for bioavailability.

**15. 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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.6 vs -10 kcal/mol). However, Ligand A demonstrates a much more favorable safety profile with significantly lower DILI and hERG risk. While both have poor Caco-2 permeability and solubility, the safety concerns with Ligand B are more critical. The slightly better metabolic stability and half-life of Ligand B are not enough to offset the higher risk. Given the enzyme-specific priorities, the lower hERG and DILI risk of Ligand A make it the more promising candidate, even with the weaker binding affinity. Further optimization of Ligand A to improve its affinity could yield a highly viable drug candidate.

Output:
0
2025-04-17 12:31:44,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 which can aid permeability.

**TPSA:** Ligand B (37.38) is significantly better than Ligand A (58.64). Lower TPSA generally improves oral absorption.

**logP:** Ligand A (2.658) is optimal, while Ligand B (4.806) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Having some HBDs can improve solubility.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable range.

**QED:** Both ligands have similar QED values (0.542 and 0.442), indicating reasonable drug-likeness.

**DILI:** Ligand A (8.22) has a much lower DILI risk than Ligand B (12.912), which is a significant advantage.

**BBB:** Ligand B (94.145) has a much higher BBB penetration than Ligand A (71.927). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.724) is slightly better than Ligand B (-4.686), but both are problematic.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand A (-2.176) is slightly better than Ligand B (-3.839).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.437 and 0.805).

**Microsomal Clearance:** Ligand A (47.154) has lower microsomal clearance than Ligand B (63.887), suggesting better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-8.98) has a significantly longer in vitro half-life than Ligand A (0.805). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.529).

**Binding Affinity:** Ligand B (-9.4) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is small (0.4 kcal/mol) and may not outweigh other ADME issues.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI) and better metabolic stability (lower Cl_mic). Ligand B has a longer half-life and slightly better affinity, but suffers from higher DILI risk and a higher logP. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate despite the slightly lower affinity and poor permeability. The poor solubility and permeability of both compounds are concerning and would require further optimization. However, the lower DILI risk and better metabolic stability of Ligand A make it a better starting point.

Output:
0
2025-04-17 12:31:44,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.379 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.29) is slightly above the optimal <140 for good oral absorption, but acceptable. Ligand B (63.57) is well within the range.

**logP:** Both ligands have good logP values (2.929 and 1.975), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 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 (0.525 and 0.884), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A has a DILI risk of 93.176, which is high. Ligand B has a much lower DILI risk of 34.238, which is good. This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (82.435) is higher than Ligand B (65.413).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.833 and -4.538). 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 (-3.7 and -1.899). Similar to Caco-2, these are on a scale where negative values are possible, and direct comparison is difficult.

**hERG:** Ligand A (0.119) has a slightly higher hERG risk than Ligand B (0.371), but both are relatively low.

**Microsomal Clearance:** Ligand A (41.26) has significantly lower microsomal clearance than Ligand B (59.942), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (8.13) has a shorter half-life than Ligand B (18.137). Ligand B is better here.

**P-gp Efflux:** Ligand A (0.561) has lower P-gp efflux than Ligand B (0.156), suggesting better bioavailability. Ligand A is better here.

**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 substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significant advantage in binding affinity and metabolic stability (lower Cl_mic), and P-gp efflux. However, its high DILI risk is a major concern. Ligand B has a much better safety profile (lower DILI) and a longer half-life, but weaker binding affinity and poorer metabolic stability.

Considering the enzyme-specific priorities, potency (affinity) and metabolic stability are crucial. The 0.6 kcal/mol difference in affinity is substantial. While the DILI risk for Ligand A is high, it might be mitigated through structural modifications during lead optimization. The better metabolic stability of Ligand A also makes it a more attractive starting point.

Output:
0
2025-04-17 12:31:44,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.487 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is better than Ligand B (92.51). Lower TPSA generally improves permeability, which is beneficial.

**logP:** Both ligands have good logP values (3.027 and 1.963), falling within the optimal 1-3 range. Ligand B is slightly lower, which might slightly improve solubility.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBAs, while Ligand B has 5. Both are below the 10 threshold, but Ligand A is preferable.

**QED:** Both ligands have good QED scores (0.594 and 0.736), indicating good drug-like properties.

**DILI:** Ligand A (8.918) has a significantly lower DILI risk than Ligand B (39.899). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (75.998 and 71.888), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.809 and -4.563). 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 (-2.172 and -2.231). This is also unusual and indicates poor aqueous solubility. Again, the difference is small.

**hERG Inhibition:** Ligand A (0.473) has a lower hERG inhibition liability than Ligand B (0.076), which is a significant advantage.

**Microsomal Clearance:** Ligand A (12.257) has a much lower microsomal clearance than Ligand B (39.953). This suggests better metabolic stability for Ligand A, a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (-16.134) has a longer in vitro half-life than Ligand B (8.744). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.113 and 0.101).

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is 1.2 kcal/mol, and the other advantages of Ligand A likely outweigh this.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties, particularly lower DILI risk, lower microsomal clearance (better metabolic stability), longer half-life, and lower hERG inhibition. These factors are crucial for developing a viable kinase inhibitor. The slight difference in binding affinity is likely surmountable with further optimization.

Output:
0
2025-04-17 12:31:44,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 346.446 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (86.88) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have a logP around 2.8-2.9, which is 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.772) has a significantly better QED score than Ligand A (0.569), indicating a more drug-like profile.

**DILI:** Ligand B (30.826) has a much lower DILI risk than Ligand A (54.711), which is a significant advantage.

**BBB:** Ligand A (60.644) has a moderate BBB penetration, while Ligand B (93.37) has excellent BBB penetration. While SRC is not a CNS target, higher BBB is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.066) has poor Caco-2 permeability, while Ligand B (-4.559) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.871 and -3.002 respectively). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.329) has a slightly lower hERG risk than Ligand B (0.849), which is favorable.

**Microsomal Clearance:** Ligand B (58.596) has better metabolic stability (lower clearance) than Ligand A (74.143).

**In vitro Half-Life:** Ligand B (9.834 hours) has a significantly longer half-life than Ligand A (-11.932 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.188) has lower P-gp efflux than Ligand B (0.435), which is preferable.

**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 not huge, it is still a positive factor.

**Overall Assessment:**

Ligand B is the better candidate. It has a significantly better QED score, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better binding affinity. While both have poor solubility and Caco-2 permeability, these can be addressed through formulation. The hERG risk is slightly higher for Ligand B, but the other advantages outweigh this concern.

Output:
1
2025-04-17 12:31:44,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.22 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (91.23) is preferable to Ligand A (104.05) due to being lower.

**logP:** Ligand A (3.048) is optimal, while Ligand B (0.73) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts, within the acceptable limits.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (97.169 percentile), which is a significant concern. Ligand B has a very low DILI risk (27.414 percentile), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (55.254) is slightly better than Ligand B (44.203).

**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 very poor aqueous solubility (-5.454 and -1.994 respectively), which is a significant drawback.

**hERG Inhibition:** Ligand A (0.572) has a slightly higher hERG risk than Ligand B (0.139), making Ligand B preferable.

**Microsomal Clearance:** Ligand A (55.406 mL/min/kg) has a higher clearance than Ligand B (2.358 mL/min/kg), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (29.944 hours) has a much longer half-life than Ligand A (74.88 hours), which is a strong advantage.

**P-gp Efflux:** Ligand A (0.259) has lower P-gp efflux than Ligand B (0.035), which is slightly better.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), but the difference is small (0.2 kcal/mol) and may not outweigh other factors.

**Overall Assessment:**

Despite Ligand A having slightly better binding affinity and P-gp efflux, the significantly higher DILI risk, poorer metabolic stability (higher Cl_mic, shorter t1/2), and higher hERG risk make it a less desirable candidate. Ligand B's superior safety profile (low DILI, low hERG), better metabolic stability, and longer half-life outweigh the slightly weaker binding affinity. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 12:31:44,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.829 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is well below the 140 threshold, while Ligand B (83.56) is still acceptable but closer to the limit.

**logP:** Ligand A (3.233) is optimal, while Ligand B (1.357) is a bit low, potentially impacting permeability.

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

**QED:** Ligand A (0.857) has a significantly higher QED score than Ligand B (0.547), indicating better overall drug-likeness.

**DILI:** Ligand B (35.905) has a much lower DILI risk than Ligand A (77.588), which is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (68.748) is slightly better than Ligand A (53.276).

**Caco-2 Permeability:** Ligand A (-4.572) has poor Caco-2 permeability, while Ligand B (-5.227) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.97) has better aqueous solubility than Ligand B (-1.523).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.34 and 0.325 respectively).

**Microsomal Clearance:** Ligand B (1.962) has significantly lower microsomal clearance than Ligand A (78.046), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (5.277) has a longer in vitro half-life than Ligand A (38.959), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.025 respectively).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), although the difference is small.

**Conclusion:**

While Ligand A has a slightly better logP and solubility, Ligand B is superior overall. The key advantages of Ligand B are its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. These factors are crucial for an enzyme inhibitor like an SRC kinase inhibitor. The slightly lower logP and Caco-2 permeability of Ligand B are less concerning than the higher DILI and poor metabolic stability of Ligand A.

Output:
1
2025-04-17 12:31:44,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (75.45) is excellent, well below 140.

**logP:** Ligand A (-0.534) is a bit low, potentially hindering permeation. Ligand B (3.428) is 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 (8) is acceptable. Ligand B (6) is also good.

**QED:** Both ligands have good QED scores (0.589 and 0.625), indicating drug-like properties.

**DILI:** Ligand A (43.311) has a moderate DILI risk, but is still acceptable. Ligand B (28.461) has a lower, more favorable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (66.072) is higher than Ligand A (53.432), but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.311) is very poor, suggesting poor absorption. Ligand B (-4.471) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.837) is poor. Ligand B (-3.1) is very poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.124) has a very low hERG risk, which is excellent. Ligand B (0.548) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-11.806) has very low clearance, indicating good metabolic stability. This is a major advantage. Ligand B (82.617) has high clearance, suggesting rapid metabolism, which is a significant drawback.

**In vitro Half-Life:** Ligand A (8.525) has a moderate half-life. Ligand B (30.569) has a much longer half-life, a positive attribute.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.228) has slightly higher efflux, but still acceptable.

**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 concerns.

**Conclusion:**

While Ligand B has a better logP and significantly better binding affinity, Ligand A's superior metabolic stability (much lower Cl_mic) and very low hERG risk are highly desirable for an enzyme inhibitor. The poor Caco-2 and solubility of both are concerns, but the strong binding affinity of B and its longer half-life are compelling. However, the significantly better metabolic stability of A is a strong advantage for kinase inhibitors, where prolonged target engagement is often desired. Considering the balance, the stronger binding affinity of B is likely to be more important than the slightly better metabolic stability of A.

Output:
1
2025-04-17 12:31:44,126 - INFO - Batch 137 complete. Total preferences: 2192
2025-04-17 12:31:44,126 - INFO - Processing batch 138/512...
2025-04-17 12:32:24,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.415 and 341.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.24) is slightly higher than Ligand B (88.91), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (2.505) is optimal, while Ligand B (1.237) 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 6 HBA, and Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.717 and 0.756, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (64.366) has a higher DILI risk than Ligand B (43.273). This is a concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.923) and Ligand B (46.026) are both relatively low.

**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. Again, the scale is not specified, but suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.429) has a slightly higher hERG risk than Ligand B (0.257), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-9.092) has significantly *lower* (better) microsomal clearance than Ligand A (23.603), indicating greater metabolic stability. This is a major advantage.

**13. In vitro Half-Life:** Ligand B (6.746) has a longer half-life than Ligand A (18.631). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.008).

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol) - a difference of 1.9 kcal/mol. This is a substantial advantage that can outweigh minor ADME concerns.

**Conclusion:**

Despite both ligands having some unfavorable solubility and permeability values (which need further investigation with defined scales), Ligand B is the more promising candidate. Its significantly stronger binding affinity, lower DILI risk, and superior metabolic stability (lower Cl_mic and longer half-life) outweigh the slightly lower logP. The substantial affinity difference is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:32:24,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (349.381 and 347.434 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (64.6 and 62.3) below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.091 and 2.851) 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 (0.75 and 0.891), indicating a drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (46.297 and 44.126 percentile), below the concerning threshold of 60.

**BBB:** Ligand B has a significantly higher BBB penetration percentile (86.817) compared to Ligand A (52.966). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-5.128) has worse Caco-2 permeability than Ligand B (-4.557), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.052 and -3.575). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.773) shows a slightly higher hERG inhibition liability than Ligand B (0.354). Lower hERG is preferred.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (46.613 and 46.037 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-15.238 hours) than Ligand A (-7.187 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.159 and 0.121).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). While both are excellent, the difference is substantial.

**Conclusion:**

Considering the priorities for an enzyme (SRC kinase) inhibitor, Ligand B is the more promising candidate. While both have acceptable ADME properties, Ligand B exhibits a significantly longer half-life and slightly better binding affinity. The slightly lower hERG risk is also a benefit. The slightly better Caco-2 permeability is also a plus. Although both have poor solubility, this can be mitigated through formulation. The difference in binding affinity is substantial enough to outweigh the slight solubility concern.

Output:
1
2025-04-17 12:32:24,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant to enzyme (kinase) inhibitors.

**1. Molecular Weight:** Both ligands (352.381 and 363.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (55.57) is significantly better than Ligand B (75.55).  A TPSA under 90 is generally acceptable, but lower is preferred for better absorption. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (4.005) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (2.525) is within the optimal range. However, for kinases, a slightly higher logP can be tolerated if other properties are favorable.

**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 (6). Fewer H-bond acceptors also generally improve permeability.

**6. QED:** Both ligands have similar, good QED values (0.72 and 0.741), indicating good drug-like properties.

**7. DILI:** Ligand A (40.636) is slightly higher than Ligand B (46.258), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a kinase inhibitor, but Ligand A (84.374) has a better BBB percentile than Ligand B (44.901).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.202 and -4.75). This is unusual and suggests a potential issue with the data or the model used to predict it. It's difficult to interpret without further information.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.51 and -2.211). Similar to Caco-2, this is problematic and suggests issues with the prediction.

**11. hERG Inhibition:** Ligand A (0.639) is better than Ligand B (0.393), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (59.429) has lower clearance than Ligand B (64.692), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.742) has a much better (longer) half-life than Ligand B (-22.663). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.22) is better than Ligand B (0.17), suggesting lower P-gp efflux and potentially better bioavailability.

**15. 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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the issues with the Caco-2 and Solubility predictions, Ligand B's substantially stronger binding affinity (-9.3 vs -8.2 kcal/mol) is the most important factor for an enzyme inhibitor. This difference in potency is likely to outweigh the slightly less favorable ADME properties of Ligand B. Ligand A has better TPSA, hERG, clearance, and half-life, but the potency difference is too significant to ignore.

Output:
1
2025-04-17 12:32:24,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.442 Da) is slightly better positioned.

**TPSA:** Ligand A (55.12) is significantly better than Ligand B (115.72). Lower TPSA generally favors better absorption, which is important for oral bioavailability.

**logP:** Ligand A (4.513) is higher than the optimal range (1-3), but still potentially manageable. Ligand B (-0.265) is too 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 (2) is better than Ligand B (6), as fewer HBAs are generally preferred for permeability.

**QED:** Both ligands have acceptable QED values (A: 0.805, B: 0.712), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (A: 55.68, B: 70.841). Ligand A is slightly better here.

**BBB:** Ligand A (80.962) has a better BBB percentile than Ligand B (43.777), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.745) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.361) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.754) has very poor solubility, which is a major concern. Ligand B (-2.936) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.837) has a slightly higher hERG risk than Ligand B (0.11), which is a concern.

**Microsomal Clearance:** Ligand A (70.326) has a higher clearance than Ligand B (-11.096). This suggests Ligand B is more metabolically stable, which is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (25.659) has a shorter half-life than Ligand B (-43.922). This further supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux than Ligand B (0.023), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 kcal/mol and -8.3 kcal/mol). The difference is not significant enough to outweigh other factors.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility outweigh the drawbacks of its lower logP and higher DILI. Ligand A's extremely poor solubility and permeability are major red flags. While Ligand A has slightly better BBB penetration and P-gp efflux, these are less critical for a non-CNS enzyme target like SRC.

Output:
1
2025-04-17 12:32:24,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 352.435 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values around 101-102 A<sup>2</sup>, which is acceptable for oral absorption (<=140 A<sup>2</sup>) but not optimal for CNS penetration. This is less critical for a non-CNS target like SRC.

**logP:** Ligand A (0.591) is borderline low, potentially hindering permeability. Ligand B (-0.903) is even lower, raising more concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.755) has a significantly better QED score than Ligand B (0.388), indicating a more drug-like profile.

**DILI:** Ligand A (52.074) has a considerably lower DILI risk than Ligand B (22.761), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.053 and -5.062), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.852 and -0.771), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.049 and 0.07), which is excellent.

**Microsomal Clearance:** Ligand A (18.949 mL/min/kg) has a much better (lower) microsomal clearance than Ligand B (-5.21 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-7.761 hours) has a significantly longer in vitro half-life than Ligand B (-20.873 hours). This is a strong advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.005).

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity and low hERG risk, Ligand A is clearly superior. It has a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better H-bond donor/acceptor balance.  The poor permeability and solubility are concerns for both, but the other advantages of Ligand A outweigh these drawbacks. The negative Caco-2 and solubility values are concerning and would require further investigation (e.g., salt formation, formulation strategies), but are less critical than the metabolic stability and toxicity profiles.

Output:
1
2025-04-17 12:32:24,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (357.435 and 354.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.37) is higher than Ligand B (58.64). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**3. logP:** Both ligands have similar logP values (3.21 and 3.229), 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:** Ligand A (0.856) has a higher QED score than Ligand B (0.763), indicating a more drug-like profile.

**7. DILI:** Ligand A (86.196) has a significantly higher DILI risk than Ligand B (16.479). This is a major concern for Ligand A.

**8. BBB:** Both have good BBB penetration (80.264 and 70.609), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.504 and -4.474), which is unusual and suggests poor permeability. However, these values are close enough to be considered similar.

**10. Aqueous Solubility:** Ligand A (-6.098) has worse solubility than Ligand B (-3.314). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.628 and 0.513).

**12. Microsomal Clearance:** Ligand B (88.919) has a significantly higher microsomal clearance than Ligand A (43.863). This means Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (75.342) has a much longer in vitro half-life than Ligand B (5.13). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.418 and 0.074).

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.3). While the difference is small (0.3 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand A has a better QED, metabolic stability (lower Cl_mic, longer t1/2) and slightly better BBB penetration. However, its major drawback is the significantly higher DILI risk and poorer solubility. Ligand B has a lower DILI risk, better solubility, and slightly better binding affinity. The difference in binding affinity is small enough to be outweighed by the significant improvement in safety (DILI) and solubility.

Given the enzyme-kinase specific priorities, and the substantial difference in DILI risk, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:32:24,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (358.36 and 354.43 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is well below the 140 threshold and favorable. Ligand B (83.56) is also below the threshold but closer, potentially indicating slightly reduced absorption compared to A.

**3. logP:** Ligand A (3.223) is optimal. Ligand B (0.589) is quite low, potentially hindering membrane permeability and bioavailability.

**4. H-Bond Donors (HBD):** Both ligands (A: 1, B: 2) 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 (A: 0.84, B: 0.643) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (51.38) is moderately risky, but acceptable. Ligand B (30.32) shows a significantly lower DILI risk, which is a strong advantage.

**8. BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand A (94.61) has better BBB penetration than Ligand B (78.71), but this is less important here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.54 and -4.583), 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 (-3.822 and -0.482), also unusual. Similar to Caco-2, the meaning of negative values needs context.

**11. hERG Inhibition:** Ligand A (0.74) has a slightly higher hERG risk than Ligand B (0.434), but both are relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (51.73) has higher clearance than Ligand B (29.76), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (12.37) has a much longer half-life than Ligand A (-0.65), which is a substantial advantage.

**14. P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.128, B: 0.024), which is good.

**15. Binding Affinity:** Ligand B (-6.8 kcal/mol) has a slightly better binding affinity than Ligand A (-5.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to outweigh other issues, it contributes to B's favorability.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. While both have unusual solubility and permeability values, Ligand B has a significantly lower DILI risk. Ligand A's higher clearance is a major concern.

Output:
1
2025-04-17 12:32:24,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (376.913 and 370.871 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.7) is higher than Ligand B (32.34). While both are reasonably low, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have good logP values (4.789 and 4.261), falling within the optimal 1-3 range, suggesting good partitioning properties.

**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.

**QED:** Both ligands have good QED scores (0.612 and 0.759), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 71.152, which is concerning (high risk). Ligand B has a much lower DILI risk of 17.449, which is excellent. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (93.098) than Ligand A (46.336), but this isn't a major deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.098 and -4.816), which 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.

**Aqueous Solubility:** Both have negative solubility values (-5.383 and -4.782), indicating poor aqueous solubility. This is a drawback for both.

**hERG Inhibition:** Ligand A (0.169) has a slightly lower hERG risk than Ligand B (0.942), which is preferable.

**Microsomal Clearance:** Ligand A (65.188) has higher microsomal clearance than Ligand B (39.717), indicating lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (9.481 hours) than Ligand A (-2.451 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.569), which is preferable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.3 kcal/mol difference is substantial and outweighs most other concerns.

**Conclusion:**

While both ligands have some drawbacks (poor solubility, potentially poor permeability based on Caco-2), Ligand B is clearly superior. Its significantly stronger binding affinity, lower DILI risk, and longer half-life are crucial advantages for an enzyme inhibitor. The lower P-gp efflux is also a positive. The slightly higher hERG risk is a minor concern compared to the other benefits.

Output:
1
2025-04-17 12:32:24,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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. Ligand B (371.815 Da) is also good.

**TPSA:** Ligand A (85.05) is better than Ligand B (62.13). Both are below the 140 A^2 threshold for good oral absorption, but Ligand A is closer to the 90 A^2 threshold for CNS penetration, although that's not a primary concern here.

**logP:** Ligand A (0.506) is quite low, potentially hindering permeability. Ligand B (4.101) is high, potentially causing solubility and off-target issues.

**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 3 HBA. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.875 and 0.831), indicating good drug-likeness.

**DILI:** Ligand A (43.234) has a lower DILI risk than Ligand B (53.858), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (43.311) has a lower BBB penetration than Ligand B (77.976). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Ligand A (-5.314) has poor Caco-2 permeability, while Ligand B (-4.748) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.298) has poor solubility, while Ligand B (-4.658) is even worse. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.245) has a lower hERG risk than Ligand B (0.392), which is preferable. Both are relatively low risk.

**Microsomal Clearance:** Ligand A (-15.494) has significantly lower microsomal clearance than Ligand B (53.588), indicating much better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (3.23) has a shorter half-life than Ligand B (14.836). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, while Ligand B (0.158) is slightly higher. This is better for Ligand A.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has 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 is the better candidate. Despite its poor solubility and Caco-2 permeability, its significantly improved metabolic stability (lower Cl_mic and lower P-gp efflux) and slightly better binding affinity outweigh these drawbacks. The lower DILI risk and hERG inhibition liability are also favorable. Ligand B's high logP and poor solubility are major concerns, and its higher metabolic clearance is undesirable.

Output:
0
2025-04-17 12:32:24,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.413 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (80.32), being well below the 140 threshold for oral absorption.

**logP:** Both ligands (2.339 and 2.168) 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, while Ligand B has 5. Both are below the threshold of 10, but A is preferable.

**QED:** Both ligands have good QED scores (0.751 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (43.622), which is a significant advantage. Both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (53.625 and 53.974). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.517 and -4.818), which is unusual and suggests poor permeability. However, these values are on a log scale and need careful interpretation.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.697 and -2.682), also unusual and indicating poor solubility. This is a concern.

**hERG Inhibition:** Ligand A (0.538) has a lower hERG risk than Ligand B (0.159), which is a significant advantage.

**Microsomal Clearance:** Ligand A (24.744) has a lower microsomal clearance than Ligand B (30.491), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (23.768 and 23.411 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.133 and 0.068).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a 0.7 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A has better TPSA, DILI risk, hERG risk, and microsomal clearance. The solubility and permeability issues are shared by both. The improved safety profile and metabolic stability of Ligand A are attractive, but the affinity difference is significant. Given the 0.7 kcal/mol difference in binding affinity, and the importance of potency for kinase inhibitors, Ligand B is the more promising candidate despite its slightly worse ADME properties.

Output:
1
2025-04-17 12:32:24,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (384.259 and 363.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.79) is well below the 140 threshold, while Ligand B (95.67) is closer but still acceptable.

**logP:** Ligand A (3.23) is optimal. Ligand B (0.743) is a bit low, 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 4 HBA, and Ligand B has 6 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.769 and 0.819), indicating good drug-like properties.

**DILI:** Ligand A (58.24) has a lower DILI risk than Ligand B (80.341), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (34.626) has a lower BBB penetration than Ligand B (53.548).

**Caco-2 Permeability:** Ligand A (-4.854) has a worse Caco-2 permeability than Ligand B (-5.522).

**Aqueous Solubility:** Ligand A (-3.887) has slightly better solubility than Ligand B (-2.56), though both are quite poor.

**hERG:** Ligand A (0.762) has a lower hERG risk than Ligand B (0.127), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand B (57.683) has a lower microsomal clearance than Ligand A (41.262), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.258) has a longer half-life than Ligand B (1.4), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.605) has lower P-gp efflux than Ligand B (0.109), which is a positive.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is only 0.7 kcal/mol, which is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity, Ligand A has a significantly better safety profile (lower DILI and hERG risk), better metabolic stability (longer half-life), and better P-gp efflux. The solubility is comparable, and the slightly lower Caco-2 permeability is less concerning given the target is not reliant on high intestinal absorption. The difference in binding affinity is not large enough to overcome these advantages.

Output:
0
2025-04-17 12:32:24,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.316 and 352.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.02) is well below the 140 threshold, suggesting good absorption. Ligand B (127.34) is also below the threshold, but closer to it.

**logP:** Ligand A (2.095) is optimal (1-3). Ligand B (0.467) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is within the acceptable limit of <=5. Ligand B (5) is at the upper limit, potentially impacting permeability.

**H-Bond Acceptors:** Ligand A (4) is within the acceptable limit of <=10. Ligand B (5) is also within the limit.

**QED:** Ligand A (0.885) is excellent, indicating strong drug-likeness. Ligand B (0.465) is below the desirable threshold of 0.5.

**DILI:** Ligand A (74.952) has a moderate DILI risk, but is acceptable. Ligand B (29.43) has a very low DILI risk, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.482) is higher than Ligand B (17.565).

**Caco-2:** Ligand A (-4.896) and Ligand B (-5.577) both have negative values which is unusual. Assuming these are percentile scores, lower is worse.

**Solubility:** Ligand A (-3.799) and Ligand B (-1.805) both have negative values which is unusual. Assuming these are percentile scores, lower is worse.

**hERG:** Ligand A (0.462) has a low hERG risk, which is excellent. Ligand B (0.061) has an even lower hERG risk, which is also excellent.

**Microsomal Clearance:** Ligand A (23.275) has moderate clearance. Ligand B (-5.878) has negative clearance, which is unusual. Assuming this is a percentile score, this suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (44.002) has a reasonable half-life. Ligand B (-14.444) has a negative half-life, which is unusual.

**P-gp Efflux:** Ligand A (0.442) has low P-gp efflux, which is good. Ligand B (0.017) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand B (-8.7 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 some ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates a significantly better binding affinity (-8.7 vs -6.2 kcal/mol) and superior metabolic stability (indicated by negative Cl_mic and t1/2 values, assuming percentile scores). It also has a lower DILI risk and P-gp efflux. While its logP is lower and QED is lower than Ligand A, the strong binding affinity and favorable metabolic profile are critical for an enzyme target like SRC. The lower logP might be mitigated with formulation strategies.

Output:
1
2025-04-17 12:32:24,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.467 Da) is slightly lower, which could be beneficial for permeability. Ligand B (393.355 Da) is still acceptable.

**TPSA:** Ligand A (88.73) is better than Ligand B (58.64), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 2.665, B: 3.13), falling within the optimal range of 1-3.

**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, <=10 HBA).

**QED:** Ligand A (0.635) has a better QED score than Ligand B (0.484), indicating a more drug-like profile.

**DILI:** Ligand A (57.774) has a higher DILI risk than Ligand B (10.237). This is a significant concern for Ligand A.

**BBB:** Ligand B (84.451) has a much higher BBB penetration percentile than Ligand A (53.432). While not a primary concern for a kinase inhibitor, higher BBB penetration could be a benefit.

**Caco-2 Permeability:** Ligand A (-5.935) has a lower Caco-2 permeability than Ligand B (-4.915).

**Aqueous Solubility:** Ligand A (-2.976) has a lower solubility than Ligand B (-2.663).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.58, B: 0.625).

**Microsomal Clearance:** Ligand B (17.91) has a slightly lower microsomal clearance than Ligand A (19.136), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (20.118) has a longer half-life than Ligand B (-0.582).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.145, B: 0.159).

**Binding Affinity:** Ligand A (-7.0) has a slightly better binding affinity than Ligand B (-6.8). However, the difference is relatively small.

**Overall Assessment:**

Ligand A has a better binding affinity and half-life, but suffers from a significantly higher DILI risk and lower solubility/permeability. Ligand B has a much better safety profile (lower DILI), better solubility and permeability, and comparable binding affinity. The slight advantage in binding affinity of Ligand A is likely outweighed by the substantial safety concerns and ADME drawbacks. Given the focus on metabolic stability, solubility, and safety for enzyme inhibitors, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:32:24,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.383 Da and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.76) is slightly above the optimal <140, while Ligand B (87.74) is well within. This favors Ligand B for absorption.

**logP:** Ligand A (-0.33) is a bit low, potentially hindering permeation. Ligand B (0.823) 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 acceptable, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.635 and 0.766), indicating generally drug-like properties.

**DILI:** Ligand A (51.919) has a moderate DILI risk, while Ligand B (22.334) has a low DILI risk. This is a clear advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (63.94) is higher than Ligand A (16.828), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative values (-4.985 and -5.046), 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 (-1.88 and -1.049), indicating poor aqueous solubility. This is a concern for both, but less so for Ligand B.

**hERG:** Both ligands have very low hERG risk (0.095 and 0.128). This is excellent for both.

**Microsomal Clearance:** Ligand A (-29.557) has significantly lower (better) microsomal clearance than Ligand B (-0.183). This suggests much greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-13.807) has a negative half-life, which is not possible, and indicates a problem with the data. Ligand B (-2.078) also has a negative half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.008 and 0.014).

**Binding Affinity:** Ligand B (-10.5 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. The difference is >1.5 kcal/mol, making it a key factor.

**Conclusion:**

Despite Ligand A's better metabolic stability, Ligand B is the more promising candidate. The significantly stronger binding affinity (-10.5 vs -7.3 kcal/mol) is the most important factor for an enzyme inhibitor. Ligand B also has a better logP, TPSA, and lower DILI risk. The solubility and permeability issues are concerning for both, but the potency advantage of Ligand B is likely to be more impactful in early development. The negative half-life values are a data quality issue, but do not change the overall comparison.

Output:
1
2025-04-17 12:32:24,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (395.874 and 362.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.33) is better than Ligand B (53.43), both are acceptable for an enzyme target, being below 140.

**logP:** Both ligands have similar logP values (4.725 and 4.375), both are slightly high but acceptable, potentially leading to some solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.709 and 0.83), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (36.216 and 32.261), which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.231) is slightly better than Ligand B (69.833).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.609 and -4.592), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.584 and -5.321), which is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.72 and 0.628), which is positive.

**Microsomal Clearance:** Ligand A (33.757 mL/min/kg) has significantly better metabolic stability than Ligand B (90.067 mL/min/kg). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (14.799 hours) has a much longer half-life than Ligand B (-14.426 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.259 and 0.303), which is favorable.

**Binding Affinity:** Ligand B (-9.7 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:**

Despite the poor solubility and permeability of both compounds, Ligand B's significantly higher binding affinity (-9.7 kcal/mol vs -7.2 kcal/mol) is a decisive factor. The potency advantage outweighs the concerns regarding metabolic stability (though Ligand A is better in this regard) and solubility, especially considering that formulation strategies can sometimes mitigate solubility issues. The better half-life of Ligand A is a plus, but the large difference in binding affinity makes Ligand B the more promising candidate.

Output:
1
2025-04-17 12:32:24,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.407 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.49) is well below the 140 threshold for good absorption, and favorable. Ligand B (93.53) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (3.191) is optimal (1-3). Ligand B (0.342) is quite low, which could hinder membrane permeability and bioavailability.

**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 6. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.751 and 0.717), indicating good drug-like properties.

**DILI:** Ligand A (67.546) has a higher DILI risk than Ligand B (37.611). This is a concern for Ligand A.

**BBB:** Both have reasonable BBB penetration (72.237 and 60.062), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-4.764 and -4.713), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-4.236) has slightly better solubility than Ligand B (-1.819), though both are poor.

**hERG:** Ligand A (0.806) has a lower hERG risk than Ligand B (0.223), which is favorable.

**Microsomal Clearance:** Ligand A (79.606) has a higher microsomal clearance than Ligand B (50.601), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-19.091) has a negative half-life, which is impossible and indicates a data error or a very rapidly metabolized compound. Ligand A (16.393) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.828) has a lower P-gp efflux liability than Ligand B (0.016), which is favorable.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk and lower metabolic stability, its significantly superior binding affinity (-7.9 vs -6.3 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The negative Caco-2 values are concerning for both, but the potency difference is substantial. The negative half-life for Ligand B is a critical flaw. Therefore, Ligand A is the more promising candidate, assuming the Caco-2 issue can be addressed through structural modifications.

Output:
1
2025-04-17 12:32:24,532 - INFO - Batch 138 complete. Total preferences: 2208
2025-04-17 12:32:24,532 - INFO - Processing batch 139/512...
2025-04-17 12:33:10,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.535 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is well below the 140 threshold and is favorable. Ligand B (107.19) is still under 140, but less optimal than A.

**3. logP:** Ligand A (2.653) is within the optimal 1-3 range. Ligand B (0.465) is slightly below 1, which *could* indicate permeability issues, though not severely.

**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 (4) is acceptable.

**6. QED:** Both ligands have reasonable QED scores (0.749 and 0.602), indicating good drug-like properties.

**7. DILI:** Ligand A (8.298) has a very low DILI risk, which is excellent. Ligand B (31.485) is higher, but still below the concerning 60 threshold.

**8. BBB:** Ligand A (70.531) has moderate BBB penetration. Ligand B (47.15) has lower BBB penetration. Since SRC is not a CNS target, this is less critical.

**9. Caco-2:** Ligand A (-4.926) and Ligand B (-5.225) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-1.079) and Ligand B (-1.386) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Ligand A (0.704) has a low hERG risk, which is excellent. Ligand B (0.109) also has a very low hERG risk.

**12. Cl_mic:** Ligand A (18.932) has a moderate microsomal clearance. Ligand B (1.464) has *very* low clearance, indicating excellent metabolic stability. This is a major advantage for Ligand B.

**13. t1/2:** Ligand A (-3.661) has a negative in vitro half-life, which is concerning. Ligand B (-12.312) has a much more negative half-life, which is even more concerning. Both are very poor.

**14. Pgp:** Ligand A (0.103) has low P-gp efflux. Ligand B (0.01) has very low P-gp efflux. Both are good.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -9.2 kcal/mol), with Ligand B being slightly better. The difference in affinity is not large enough to overcome other issues.

**Overall Assessment:**

While both compounds have excellent binding affinity, their poor solubility and permeability (Caco-2) are major concerns. Ligand B has a significant advantage in metabolic stability (Cl_mic) and very low P-gp efflux, which are highly desirable for an enzyme target. However, its half-life is worse than Ligand A. Ligand A has a better DILI score and slightly better BBB penetration (though not critical here). Given the importance of metabolic stability for kinase inhibitors, and the slightly better affinity of Ligand B, I would lean towards Ligand B as the more promising starting point, *despite* the poor solubility/permeability and half-life. These issues can be addressed through medicinal chemistry optimization, while a poor affinity is much harder to fix.

Output:
1
2025-04-17 12:33:10,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 350.315 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (44.1), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.68) is optimal, while Ligand B (4.134) is approaching the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (3) is acceptable, while Ligand B (2) is also good.

**QED:** Ligand B (0.761) has a better QED score than Ligand A (0.46), indicating a more drug-like profile.

**DILI:** Ligand A (32.842) has a significantly lower DILI risk than Ligand B (48.042), which is preferable.

**BBB:** Ligand B (84.374) shows better BBB penetration than Ligand A (62.233), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.377) has better Caco-2 permeability than Ligand B (-4.209).

**Aqueous Solubility:** Ligand A (-2.71) has better aqueous solubility than Ligand B (-5.062).

**hERG Inhibition:** Ligand A (0.097) has a much lower hERG inhibition liability than Ligand B (0.932), which is a significant advantage.

**Microsomal Clearance:** Ligand A (26.043) has a lower microsomal clearance than Ligand B (51.405), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.218) has a better in vitro half-life than Ligand B (-15.65).

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.4).

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.6). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most crucial factor for an enzyme inhibitor. While it has some ADME liabilities (higher logP, higher DILI, higher hERG, higher Cl_mic, shorter half-life, higher Pgp efflux), the significantly stronger binding affinity (-9.0 vs -7.6) is likely to be decisive. The difference of 1.4 kcal/mol is substantial. The better QED score also favors Ligand B. Although Ligand A has better solubility and lower toxicity, the potency advantage of Ligand B is more important for an enzyme target.

Output:
1
2025-04-17 12:33:10,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.475 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (89.87 and 79.31) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (-0.085) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.26) is closer to the ideal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 5. Both are below the acceptable limit of <=10.

**QED:** Both ligands have QED values (0.8 and 0.676) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (37.999) has a slightly higher DILI risk than Ligand B (12.912), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (64.25 and 63.009), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.896 and -4.713) which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.724 and -0.688) which is also unusual and suggests poor solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.478) has a slightly higher hERG risk than Ligand B (0.213), but both are relatively low.

**Microsomal Clearance:** Ligand A (26.971) has a higher microsomal clearance than Ligand B (12.137), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (16.887) has a significantly longer in vitro half-life than Ligand A (-1.548), which is a major advantage.

**P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux liability than Ligand B (0.024), which is favorable.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a crucial advantage.

**Conclusion:**

Despite both ligands having issues with Caco-2 and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.0 kcal/mol vs 0.0 kcal/mol) outweighs the slightly higher P-gp efflux. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic and longer t1/2) and a lower DILI risk. While the solubility and permeability are concerning for both, the superior potency and pharmacokinetic properties of Ligand B make it the better choice for further optimization.

Output:
1
2025-04-17 12:33:10,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (356.463 Da) is also good.

**TPSA:** Ligand A (67.59) is well below the 140 threshold for oral absorption and is quite favorable. Ligand B (99.1) is still acceptable but less optimal.

**logP:** Ligand A (2.544) is within the optimal range (1-3). Ligand B (0.288) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=3, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.744, B: 0.675), indicating generally drug-like properties.

**DILI:** Ligand A (55.448) has a moderate DILI risk, while Ligand B (30.322) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (71.927) has better BBB penetration than Ligand B (35.401), but BBB isn't a primary concern for a non-CNS target like SRC.

**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 (0.689) has a slightly higher hERG risk than Ligand B (0.134), which is favorable for Ligand B.

**Microsomal Clearance:** Ligand A (114.871) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (16.803). This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-14.635) has a negative half-life, which is not possible. Ligand B (8.815) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.299) has lower P-gp efflux than Ligand B (0.018), which is favorable for Ligand A.

**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 is the better candidate. While Ligand A has slightly better BBB penetration and P-gp efflux, Ligand B's superior binding affinity (-8.2 vs -7.2 kcal/mol), significantly lower microsomal clearance (better metabolic stability), lower DILI risk, and lower hERG risk are more crucial for an enzyme inhibitor. The low logP of Ligand B is a concern, but the strong binding affinity might compensate for that. The unusual negative values for Caco-2 and solubility are concerning for both, and would need further investigation.

Output:
1
2025-04-17 12:33:10,494 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [347.419, 87.54, 0.161, 1, 5, 0.769, 36.177, 56.34, -4.806, -1.088, 0.031, -1.872, -2.97, 0.007, -8.2]
**Ligand B:** [350.503, 69.64, 2.328, 2, 3, 0.706, 9.383, 52.385, -4.814, -2.251, 0.392, 29.089, -5.158, 0.206, -7.8]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (347.419) and B (350.503) are very similar.
2. **TPSA:** A (87.54) is slightly higher than B (69.64). Both are below 140, suggesting reasonable absorption.
3. **logP:** A (0.161) is quite low, potentially hindering membrane permeability. B (2.328) is much better, falling within the optimal 1-3 range.
4. **HBD:** A (1) and B (2) are both acceptable, well below the limit of 5.
5. **HBA:** A (5) and B (3) are both acceptable, well below the limit of 10.
6. **QED:** Both ligands have good QED scores (A: 0.769, B: 0.706), indicating drug-like properties.
7. **DILI:** A (36.177) has a significantly lower DILI risk than B (9.383), which is a major advantage.
8. **BBB:** Both have relatively low BBB penetration (A: 56.34, B: 52.385). Not a primary concern for a non-CNS target like SRC.
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:** A (0.031) has a very low hERG risk, which is excellent. B (0.392) is slightly higher but still relatively low.
12. **Cl_mic:** A (-1.872) has a *negative* microsomal clearance, which is highly unusual and suggests extreme metabolic stability. B (29.089) has a moderate clearance.
13. **t1/2:** A (-2.97) has a negative in vitro half-life, which is impossible. B (-5.158) also has a negative in vitro half-life, which is impossible.
14. **Pgp:** A (0.007) has very low P-gp efflux, which is favorable. B (0.206) is slightly higher.
15. **Affinity:** A (-8.2) has a significantly stronger binding affinity than B (-7.8). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite the unusual negative values for Caco-2, solubility, and half-life, Ligand A is the better candidate. It has a significantly stronger binding affinity (-8.2 vs -7.8), a much lower DILI risk, and a very low hERG risk. The negative clearance is a red flag, but could be an artifact of the modeling. The low logP of A is a concern, but the strong affinity might compensate. The negative half-life and solubility values are concerning and would require further investigation, but the superior binding and safety profile of A make it the more promising candidate.

1
2025-04-17 12:33:10,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (352.375 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (24.92) is excellent, well below the 140 threshold for oral absorption. Ligand B (74.77) is still acceptable, but less favorable.

**logP:** Ligand A (4.907) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.785) is quite low, which could hinder membrane permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5 HBA, both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.54 and 0.739, respectively), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (33.579 and 37.224, respectively), well below the 60 threshold.

**BBB:** Ligand A (77.705) has better BBB penetration potential than Ligand B (49.67), but BBB is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.665) and Ligand B (-4.59) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-5.021) has very poor predicted solubility. Ligand B (-0.749) is also poor, but slightly better than Ligand A.

**hERG:** Ligand A (0.953) has a slightly higher hERG risk than Ligand B (0.184), which is preferable.

**Microsomal Clearance:** Ligand A (32.172) has a higher microsomal clearance than Ligand B (-9.173). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-1.64) has a shorter half-life than Ligand B (-3.207). Again, favoring Ligand B.

**P-gp Efflux:** Ligand A (0.592) has slightly lower P-gp efflux liability than Ligand B (0.01).

**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, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite Ligand A's higher logP and poor solubility, its *much* stronger binding affinity (-8.7 vs -6.7 kcal/mol) is a decisive factor. The potency advantage outweighs the ADME concerns, especially considering the metabolic stability and half-life benefits offered by Ligand B are not substantial enough to overcome the potency difference. While both have permeability issues, the stronger binding of Ligand A suggests it may still be effective *in vivo* at a lower concentration, potentially mitigating some of the permeability concerns.

Output:
1
2025-04-17 12:33:10,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.459 and 362.865 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.3) is significantly better than Ligand B (84.73), being well below the 140 threshold for oral absorption.

**logP:** Both ligands (2.351 and 1.996) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand B (6) is slightly higher than Ligand A (3), but both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.772 and 0.768), indicating good drug-likeness.

**DILI:** Ligand A (13.649) has a much lower DILI risk than Ligand B (61.38), which is a significant advantage. Ligand B is bordering on high risk.

**BBB:** Both ligands have similar BBB penetration (82.164 and 80.574), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.946) and Ligand B (-5.31) have similar Caco-2 permeability, suggesting comparable intestinal absorption.

**Solubility:** Ligand A (-2.181) has slightly better solubility than Ligand B (-2.72), although both are negative values and could be a concern.

**hERG:** Both ligands have very low hERG inhibition risk (0.284 and 0.521).

**Microsomal Clearance:** Ligand A (26.797) has a higher microsomal clearance than Ligand B (19.977), meaning Ligand B is more metabolically stable, which is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (36.238) has a significantly longer in vitro half-life than Ligand A (-23.912), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.11).

**Binding Affinity:** Both ligands have identical binding affinities (-8.7 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The slightly higher TPSA and HBD of Ligand B are minor drawbacks compared to these advantages, especially given the strong binding affinity.

Output:
1
2025-04-17 12:33:10,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.483 and 342.439 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.23) is slightly higher than Ligand B (71.34), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.23 and 2.712), falling within the optimal 1-3 range.

**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).

**QED:** Both ligands have good QED scores (0.635 and 0.749), indicating good drug-like properties.

**DILI:** Ligand B (41.838) has a significantly lower DILI risk than Ligand A (53.276). This is a substantial advantage.

**BBB:** Both have similar BBB penetration (56.34 and 58.007), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.094 and -4.613). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference isn't huge.

**Aqueous Solubility:** Ligand B (-4.429) has better solubility than Ligand A (-2.637), which is a positive.

**hERG:** Ligand A (0.558) has a slightly higher hERG risk than Ligand B (0.377), but both are reasonably low.

**Microsomal Clearance:** Ligand B (26.498) has a much lower microsomal clearance than Ligand A (5.367), indicating better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (14.839) has a longer in vitro half-life than Ligand A (17.912).

**P-gp Efflux:** Both have low P-gp efflux liability (0.112 and 0.328).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.3 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Ligand B is the better candidate. While both have good potency and drug-like properties, Ligand B demonstrates significantly improved ADME characteristics: lower DILI risk, better solubility, and *much* better metabolic stability (lower Cl_mic and longer t1/2). These factors are crucial for an enzyme target like SRC kinase. The slightly better solubility of Ligand B further supports its selection.

Output:
1
2025-04-17 12:33:10,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.255 and 370.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.92) is significantly better than Ligand B (75.27). A TPSA under 140 is good for oral absorption, both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (4.596 and 3.249), falling within the 1-3 range. Ligand B is slightly better here.

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

**QED:** Ligand A (0.731) has a higher QED score than Ligand B (0.534), indicating better overall drug-likeness.

**DILI:** Ligand A (72.819) has a higher DILI risk than Ligand B (25.94). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration (67.197 and 62.582), but this isn't a primary concern for a non-CNS target like SRC.

**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:** Ligand A (-4.713) has worse solubility than Ligand B (-2.458). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.855) has a slightly higher hERG risk than Ligand B (0.29). Lower is better here.

**Microsomal Clearance:** Ligand A (44.326) has lower microsomal clearance than Ligand B (51.084), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (44.56) has a longer half-life than Ligand B (24.376), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.516 and 0.099).

**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, potentially outweighing some ADME concerns.

**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 (-8.2 vs -9.0 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B has a much lower DILI risk and better solubility, which are critical for drug development. The slightly higher logP of Ligand A is less concerning than the DILI and solubility issues.

Output:
1
2025-04-17 12:33:10,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.471 Da) is slightly higher than Ligand B (338.459 Da), but both are acceptable.

**TPSA:** Ligand A (97.39) is slightly higher than Ligand B (66.83). Both are below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.773) is a bit low, potentially hindering permeation. Ligand B (3.429) is within the optimal range (1-3). This favors Ligand B.

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

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

**QED:** Ligand B (0.921) has a significantly higher QED score than Ligand A (0.596), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 56.146, Ligand B: 56.805), and are within an acceptable range (<60).

**BBB:** Ligand B (69.794) has a better BBB percentile than Ligand A (35.052), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.886) shows poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.157) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-2.834) and Ligand B (-4.3) both have poor aqueous solubility. This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.291) has a lower hERG risk than Ligand B (0.838), which is a significant advantage.

**Microsomal Clearance:** Ligand A (10.488) has a lower microsomal clearance than Ligand B (77.246), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-28.944) has a much longer in vitro half-life than Ligand B (-3.288), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux than Ligand B (0.103), which is a minor advantage.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (0.0). This is a significant advantage, and can outweigh 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 hERG risk. While its logP and solubility are less ideal, the strong binding affinity and metabolic stability are critical for an enzyme inhibitor. Ligand B has a better QED and slightly better logP, but suffers from significantly worse metabolic stability and a higher hERG risk.

Output:
0
2025-04-17 12:33:10,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (382.291 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for good oral absorption, but neither is optimized for CNS penetration (below 90).

**logP:** Both ligands (2.954 and 2.267) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (3) meet the <=10 criteria.

**QED:** Both ligands (0.77 and 0.777) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (23.187), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (67.623 and 69.213), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.047 and -4.681), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.249 and -2.872), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.331 and 0.132), which is excellent.

**Microsomal Clearance:** Ligand B (65.299) has significantly higher microsomal clearance than Ligand A (12.496), suggesting lower metabolic stability. This is a critical disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (13.876) has a longer in vitro half-life than Ligand B (6.134), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.083 and 0.065).

**Binding Affinity:** Ligand A (-10.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-10.8 vs -8.7 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target like SRC kinase. While the solubility and permeability issues need to be addressed through formulation or further structural modifications, the potency and metabolic advantages of Ligand A make it the better starting point.

Output:
1
2025-04-17 12:33:10,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.289 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.63) is higher than Ligand B (56.59). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands (2.533 and 2.581) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both have 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.623 and 0.685), indicating drug-likeness.

**DILI:** Ligand A (84.762) has a significantly higher DILI risk than Ligand B (50.136). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.731) has a higher BBB score than Ligand B (67.197).

**Caco-2 Permeability:** Ligand A (-3.871) has a worse Caco-2 permeability than Ligand B (-4.691), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.29) has a worse aqueous solubility than Ligand B (-3.256).

**hERG Inhibition:** Ligand A (0.275) has a lower hERG inhibition risk than Ligand B (0.507), which is favorable.

**Microsomal Clearance:** Ligand A (118.049) has a higher microsomal clearance than Ligand B (98.623), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (8.078) has a much longer in vitro half-life than Ligand A (-34.453), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.426) has a lower P-gp efflux liability than Ligand B (0.321), which is preferable.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.7). However, the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity and lower P-gp efflux, the significantly higher DILI risk, lower solubility, worse Caco-2 permeability, and substantially shorter half-life outweigh this benefit. Ligand B demonstrates a better balance of properties, particularly regarding safety (DILI) and pharmacokinetic parameters (half-life, solubility). The difference in binding affinity is not large enough to overcome the ADME/Tox liabilities of Ligand A.

Output:
1
2025-04-17 12:33:10,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.471 and 352.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.74) is significantly better than Ligand B (109.66).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal for good absorption.

**logP:** Ligand A (4.238) is higher than the optimal range of 1-3, but still potentially manageable. Ligand B (-1.266) is too low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (1 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improves permeability.

**QED:** Both ligands have similar QED values (0.791 and 0.684), indicating good drug-likeness.

**DILI:** Ligand A (32.183) has a much lower DILI risk than Ligand B (64.366). This is a significant advantage for Ligand A.

**BBB:** Ligand A (74.292) has better BBB penetration than Ligand B (49.128), though neither is exceptionally high. This isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.874 and -4.952). This is unusual and suggests poor permeability. However, these values might be artifacts of the prediction model.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.917 and -0.527). Again, this is concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.695) has a lower hERG risk than Ligand B (0.059). This is a significant advantage.

**Microsomal Clearance:** Ligand A (56.796) has a higher (worse) microsomal clearance than Ligand B (11.585). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (2.13) has a longer half-life than Ligand A (-2.915). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.335) has lower P-gp efflux than Ligand B (0.014), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This is a 0.8 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has significantly better DILI and hERG profiles, better TPSA, and lower P-gp efflux. The poor solubility and permeability predictions for both are concerning, but the affinity difference is notable. Considering the enzyme-specific priorities, the slightly better affinity of Ligand B, coupled with its improved metabolic stability, outweighs the concerns about its higher DILI and hERG risk, *assuming* the solubility/permeability issues can be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 12:33:10,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzyme targets: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.303 and 341.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.21) is better than Ligand B (53.08) as it is closer to the 140 A^2 threshold for good oral absorption. Ligand B is very low, which could indicate issues with solubility.

**logP:** Ligand A (0.941) is within the optimal 1-3 range. Ligand B (3.216) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 9 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.832) has a significantly better QED score than Ligand A (0.414), indicating a more drug-like profile.

**DILI:** Ligand A (91.663) has a high DILI risk, which is a major concern. Ligand B (32.842) has a much lower, and acceptable, DILI risk.

**BBB:** Both ligands have good BBB penetration (Ligand A: 71.966, Ligand B: 94.029). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests potential issues with in vitro permeability assays.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests potential issues with in vitro solubility assays.

**hERG Inhibition:** Ligand A (0.09) has a very low hERG risk, which is excellent. Ligand B (0.928) has a moderate hERG risk, which is less ideal.

**Microsomal Clearance:** Ligand A (33.289) has a lower microsomal clearance than Ligand B (39.101), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.779) has a negative half-life, which is not possible. Ligand B (27.546) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.159) has lower P-gp efflux than Ligand B (0.081), which is preferable.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is not substantial enough to outweigh other significant drawbacks.

**Overall Assessment:**

Ligand A has a very high DILI risk and a negative in vitro half-life, which are major red flags. While it has better metabolic stability and lower P-gp efflux, the safety concerns are too significant. Ligand B has a better QED score, lower DILI risk, and a reasonable half-life, despite a slightly higher logP and moderate hERG risk. The negative Caco-2 and solubility values for both are concerning and would require further investigation, but the DILI risk for Ligand A is a dealbreaker.

Output:
1
2025-04-17 12:33:10,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (366.458 Da) is also good.

**TPSA:** Ligand A (87.13) is better than Ligand B (55.57) as it is closer to the optimal threshold of 140 for oral absorption.

**logP:** Both ligands have good logP values (A: 3.132, B: 3.851), falling within the 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 has 3 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 (0.779) has a better QED score than Ligand B (0.5), indicating a more drug-like profile.

**DILI:** Ligand A (62.156) has a higher DILI risk than Ligand B (34.626). This is a significant drawback for Ligand A.

**BBB:** Ligand B (88.833) has a much higher BBB penetration percentile than Ligand A (52.85). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.121) has a negative Caco-2 value, indicating poor permeability. Ligand B (-4.95) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.78 and -4.285 respectively). This is a concern for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.528, B: 0.661).

**Microsomal Clearance:** Ligand A (40.122 mL/min/kg) has significantly lower microsomal clearance than Ligand B (121.246 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (74.705 hours) has a much longer in vitro half-life than Ligand B (24.029 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.269, B: 0.468).

**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 has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), and a better QED score. However, it has a higher DILI risk and significantly poorer Caco-2 permeability. Ligand B has a lower DILI risk and slightly better Caco-2 permeability, but significantly weaker binding affinity and poorer metabolic stability.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is the most critical factor. While the DILI risk and permeability are concerns, these can potentially be mitigated through further optimization or formulation strategies. The substantial difference in binding affinity (-2 kcal/mol) is likely to have a greater impact on efficacy than the ADME liabilities of Ligand A.

Output:
1
2025-04-17 12:33:10,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 140, suggesting reasonable oral absorption potential. Ligand A (64.43) is higher than Ligand B (58.64), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.088) is slightly higher than Ligand B (2.513), which is preferable.

**H-Bond Donors/Acceptors:** Ligand A has 0 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 (A: 0.564, B: 0.719), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A has a significantly higher DILI risk (75.339) compared to Ligand B (21.675). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (83.676) is better than Ligand B (71.811). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

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

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a significant issue for both compounds.

**hERG Inhibition:** Ligand A (0.483) has a slightly higher hERG risk than Ligand B (0.346), but both are relatively low.

**Microsomal Clearance:** Ligand B (43.312) has a lower microsomal clearance than Ligand A (84.83), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-11.696) has a negative half-life, which is not possible. This is a major issue for Ligand B. Ligand A (44.859) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.864) has a higher P-gp efflux liability than Ligand B (0.261), meaning Ligand B is less likely to be pumped out of cells.

**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 for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is the primary driver for enzyme inhibitors. However, its high DILI risk is a major concern. Ligand B has better metabolic stability and lower P-gp efflux, but its binding affinity is very weak and its half-life is impossible. The negative Caco-2 and solubility values are problematic for both. Given the importance of potency for kinase inhibitors, and the fact that the affinity difference is so large, Ligand A is the more promising candidate *if* the DILI risk can be mitigated through structural modifications.

Output:
1
2025-04-17 12:33:10,496 - INFO - Batch 139 complete. Total preferences: 2224
2025-04-17 12:33:10,496 - INFO - Processing batch 140/512...
2025-04-17 12:33:49,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.402 and 365.396 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.76) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (72.88) is still under 140, but less favorable than A.

**logP:** Ligand A (2.268) is within the optimal 1-3 range. Ligand B (0.749) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.789 and 0.729), indicating good drug-like properties.

**DILI:** Ligand A (31.989) has a significantly lower DILI risk than Ligand B (21.946), which is a major advantage.

**BBB:** While not crucial for a non-CNS target like SRC, Ligand A (78.286) shows better BBB penetration potential than Ligand B (64.831).

**Caco-2 Permeability:** Ligand A (-4.313) is better than Ligand B (-4.859), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.359) is better than Ligand B (-1.259), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG risk (0.509 and 0.655).

**Microsomal Clearance:** Ligand A (19.858) has a higher (worse) microsomal clearance than Ligand B (-9.151). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-9.644) has a significantly longer in vitro half-life than Ligand A (-5.216), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.308 and 0.023).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 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 most ADME properties (TPSA, logP, solubility, DILI, Caco-2) and has excellent binding affinity. However, its higher microsomal clearance and shorter half-life are concerning. Ligand B has slightly weaker ADME properties but demonstrates superior metabolic stability (lower Cl_mic, longer t1/2). Given the enzyme-specific priorities, metabolic stability is crucial. While Ligand A has a slightly better solubility profile, the difference in metabolic stability is more significant.

Output:
1
2025-04-17 12:33:49,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.435 Da) is slightly higher than Ligand B (338.419 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (93.44) is better than Ligand A (107.02).

**logP:** Ligand A (-0.103) is quite low, potentially hindering permeability. Ligand B (1.802) is within the optimal range (1-3). 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 8. Both are acceptable, but lower is generally preferred.

**QED:** Ligand B (0.803) has a much better QED score than Ligand A (0.444), indicating a more drug-like profile.

**DILI:** Both ligands have high DILI risk (Ligand A: 17.487, Ligand B: 59.636). Ligand A has a lower DILI risk, which is a positive.

**BBB:** Both have low BBB penetration. This isn't a primary concern for a non-CNS target like SRC.

**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 have very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (-6.254) has *much* lower (better) microsomal clearance than Ligand B (47.449), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.593) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (4.18) is a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**Binding Affinity:** Both have the same binding affinity (0 kcal/mol).

**Overall Assessment:**

Ligand B has better logP and QED, which are positive attributes. However, Ligand A exhibits much better metabolic stability (lower Cl_mic) and a lower DILI risk. The negative values for Caco-2 and solubility are concerning for both, but the metabolic stability advantage of Ligand A is crucial for an enzyme target. The negative half-life for Ligand A is a major red flag, however. Given the equal binding affinity, the better metabolic stability of Ligand A would make it the better candidate *if* the half-life data were corrected. However, the negative half-life is a significant issue. Considering the data as presented, Ligand B is the better option.

Output:
1
2025-04-17 12:33:49,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (353.423 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.78) is better than Ligand B (49.41). While both are below 140, Ligand B is significantly lower, which *could* indicate better absorption, but isn't a major concern for a non-CNS target like SRC.

**logP:** Ligand A (-0.454) is a bit low, potentially hindering permeability. Ligand B (3.746) 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.655 and 0.645), indicating good drug-likeness.

**DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (11.981). This is a substantial advantage for Ligand A.

**BBB:** This is less important for a non-CNS target like SRC. Ligand B (90.229) has better BBB penetration, but it's not a primary concern here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.241 and -4.849), which is unusual and suggests poor permeability. This is a concern for both, but the scale is not clear, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-0.405) has slightly better solubility than Ligand B (-3.73). Solubility is important for bioavailability, giving a slight edge to Ligand A.

**hERG Inhibition:** Ligand A (0.114) has a lower hERG risk than Ligand B (0.836). This is a significant advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (33.488) has lower microsomal clearance than Ligand B (69.37), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-22.34) has a negative half-life, which is not possible. Ligand B (-9.502) also has a negative half-life, which is concerning. The scale is unclear and these values are likely errors.

**P-gp Efflux:** Ligand A (0.005) has lower P-gp efflux than Ligand B (0.561), suggesting better bioavailability.

**Binding Affinity:** Both ligands have similar binding affinities (-7.4 and -7.1 kcal/mol), which are both excellent. The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is preferable due to its significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), and lower P-gp efflux. While Ligand B has a better logP, the other advantages of Ligand A outweigh this. The negative half-life values are concerning for both, but the other ADME properties of Ligand A are more favorable.

Output:
0
2025-04-17 12:33:49,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.475 Da) is slightly higher than Ligand B (348.403 Da), but both are acceptable.

**TPSA:** Ligand A (75.55) is better than Ligand B (117.52). TPSA is important for permeability, and Ligand A is closer to the preferred threshold of <=140.

**logP:** Ligand A (3.168) is optimal (1-3), while Ligand B (-0.128) is significantly below this range. Low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=8) is better than Ligand B (HBD=3, HBA=4). Both are within acceptable limits, but Ligand A has a more favorable balance.

**QED:** Both ligands have similar QED values (A: 0.706, B: 0.664), indicating good drug-like properties.

**DILI:** Ligand A (92.361) has a higher DILI risk than Ligand B (44.552). This is a significant drawback for Ligand A.

**BBB:** Not a primary concern for a kinase inhibitor, but Ligand A (60.838) is slightly better than Ligand B (53.625).

**Caco-2 Permeability:** Ligand A (-4.8) is better than Ligand B (-5.468), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.128) is better than Ligand B (-3.044), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.639) has a slightly higher hERG risk than Ligand B (0.116), but both are relatively low.

**Microsomal Clearance:** Ligand A (80.844) has higher clearance than Ligand B (-6.56). Lower clearance is preferred for metabolic stability, so Ligand B is better.

**In vitro Half-Life:** Ligand A (22.499) has a longer half-life than Ligand B (-0.715), which is desirable.

**P-gp Efflux:** Ligand A (0.402) has lower P-gp efflux than Ligand B (0.004), which is better for bioavailability.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much lower DILI risk. While its logP is suboptimal, its superior potency and safety profile are crucial for an oncology drug target. Ligand A has better solubility and half-life, but the high DILI risk is a major concern. The difference in binding affinity is also significant.

Output:
1
2025-04-17 12:33:49,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.852 and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.55) is significantly better than Ligand B (88.18). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.776) is optimal (1-3), while Ligand B (0.014) is very low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.806) has a much better drug-likeness score than Ligand B (0.588).

**DILI:** Ligand A (41.062) has a slightly higher DILI risk than Ligand B (26.444), but both are acceptable (<60).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.161) is much higher than Ligand B (55.138), but this is not a major factor in this case.

**Caco-2 Permeability:** Ligand A (-4.701) is better than Ligand B (-4.94), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.802) is better than Ligand B (-0.213). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.457) has a much lower hERG risk than Ligand B (0.088), which is a significant advantage.

**Microsomal Clearance:** Ligand A (18.361) has higher clearance than Ligand B (16.653), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.547) has a positive half-life, whereas Ligand B (-30.305) has a negative half-life.

**P-gp Efflux:** Ligand A (0.237) has lower P-gp efflux than Ligand B (0.009), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.1 and -7.9 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Conclusion:**

Ligand A is significantly better overall. It has a superior logP, TPSA, QED, solubility, and hERG profile. While Ligand B has a slightly lower DILI risk and clearance, the advantages of Ligand A in permeability, drug-likeness, and safety (hERG) are more important for an enzyme inhibitor. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 12:33:49,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (447.376 Da) is higher, but still acceptable. Ligand B (365.503 Da) is slightly better.

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand B (71.33 A^2) is lower than Ligand A (85.36 A^2), which is favorable.

**logP:** Both are within the optimal range (1-3). Ligand A (3.22) is at the higher end, potentially raising concerns about off-target effects, while Ligand B (1.41) is closer to the ideal.

**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 6 HBAs, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.521, B: 0.762). Ligand B is better here.

**DILI:** Ligand A has a DILI risk of 85.537, which is high. Ligand B has a DILI risk of 59.48, which is still elevated but considerably better than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (75.533) has a better BBB score than Ligand A (45.638).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.077 and -5.059). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is minimal.

**Aqueous Solubility:** Both have negative solubility values (-4.479 and -2.541). This indicates poor aqueous solubility for both compounds, which is a significant drawback. Ligand B is slightly better.

**hERG Inhibition:** Both have low hERG inhibition liability (A: 0.355, B: 0.284), which is excellent.

**Microsomal Clearance:** Ligand A (105.212 mL/min/kg) has higher clearance than Ligand B (68.443 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-22.069 hours) than Ligand A (-1.802 hours), which is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.471, B: 0.231). Ligand B is better.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME concerns.

**Conclusion:**

While both compounds have solubility issues, Ligand B is significantly better overall. It has a superior binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better QED and P-gp efflux properties. The slightly better logP and TPSA values also contribute to its favorability. The difference in binding affinity is large enough to overcome the shared solubility concerns.

Output:
1
2025-04-17 12:33:49,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 Da and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is better than Ligand B (96.45), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.727) is optimal (1-3), while Ligand B (0.459) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both are acceptable (Ligand A: 1, Ligand B: 2), staying within the recommended limit of 5.

**H-Bond Acceptors:** Both are acceptable (Ligand A: 4, Ligand B: 6), staying within the recommended limit of 10.

**QED:** Both ligands have reasonable QED values (A: 0.677, B: 0.523), indicating good drug-like properties.

**DILI:** Ligand A (26.444) has a significantly lower DILI risk than Ligand B (35.983), which is a major advantage.

**BBB:** Both have similar BBB penetration (A: 65.452, B: 61.923). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.727) is better than Ligand B (-5.505), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.755) is better than Ligand B (-0.99), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.273, B: 0.25).

**Microsomal Clearance:** Ligand A (63.473) has a higher (worse) microsomal clearance than Ligand B (-10.378), suggesting Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (13.236) has a significantly longer in vitro half-life than Ligand A (-11.343), which is a substantial benefit.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.18, B: 0.009), which is good.

**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's still a positive factor.

**Overall Assessment:**

Ligand A has advantages in solubility, DILI risk, Caco-2 permeability, and binding affinity. However, Ligand B has a significantly better metabolic stability (lower Cl_mic, longer half-life) and a slightly better logP. Given that we are targeting a kinase (enzyme), metabolic stability and half-life are critical. The slightly stronger binding of Ligand A is outweighed by the superior pharmacokinetic properties of Ligand B.

Output:
1
2025-04-17 12:33:49,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.467 Da) is slightly higher than Ligand B (345.363 Da), but both are acceptable.

**TPSA:** Ligand A (72.48) is well below the 140 threshold for oral absorption. Ligand B (127.94) is still within acceptable limits, but closer to the threshold.

**logP:** Ligand A (3.818) is at the higher end of the optimal range (1-3), while Ligand B (-0.621) is significantly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 5 HBAs, acceptable. Ligand B has 10 HBAs, which is at the upper limit and could impact permeability.

**QED:** Both ligands have acceptable QED values (A: 0.786, B: 0.681), indicating good drug-like properties.

**DILI:** Ligand A (76.968) has a higher DILI risk than Ligand B (65.917), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.682) has a better BBB percentile than Ligand B (54.052).

**Caco-2 Permeability:** Ligand A (-4.539) has poor Caco-2 permeability, while Ligand B (-5.383) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.506) has poor aqueous solubility, while Ligand B (-1.847) is also poor, but better than A.

**hERG:** Ligand A (0.523) has a slightly higher hERG risk than Ligand B (0.029), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (76.382) has higher microsomal clearance, indicating lower metabolic stability, than Ligand B (23.552). This is a key disadvantage for A.

**In vitro Half-Life:** Ligand A (20.468) has a longer half-life than Ligand B (3.905), which is a positive for A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.439, B: 0.046), which is good.

**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 for B, and can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having a slightly longer half-life, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.3 vs 0.0 kcal/mol) is the most important factor for an enzyme inhibitor. Furthermore, Ligand B has better predicted permeability (Caco-2), solubility, and a much lower hERG risk and microsomal clearance. Ligand A's higher logP and poor solubility are concerning.

Output:
1
2025-04-17 12:33:49,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.515 and 346.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (88.33). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hint at poorer permeability.

**logP:** Ligand A (0.379) is a bit low, potentially causing permeability issues. Ligand B (1.86) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 5 HBA and are within acceptable limits (<=10). Ligand A has 0 HBD, while Ligand B has 1. This difference is minor.

**QED:** Both ligands have good QED scores (0.658 and 0.916), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (29.43) has a much lower DILI risk than Ligand B (74.021). This is a significant advantage for Ligand A.

**BBB:**  Not a primary concern for a non-CNS target like SRC kinase, but Ligand B (83.56) shows better penetration than Ligand A (58.938).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.502 and -4.652), which is unusual and suggests poor permeability. However, these values are on a log scale and need careful interpretation.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.871 and -2.856), also unusual and suggesting poor solubility.

**hERG:** Both ligands have low hERG risk (0.265 and 0.296), which is excellent.

**Microsomal Clearance:** Ligand A (39.312) has a higher microsomal clearance than Ligand B (17.719), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (8.205) has a significantly longer in vitro half-life than Ligand A (1.102). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.049 and 0.033), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

While Ligand A has a lower DILI risk, Ligand B is superior overall. The significantly stronger binding affinity (-8.4 vs -6.9 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly higher DILI risk and lower BBB penetration. The TPSA of Ligand B is also more favorable. The solubility and permeability issues are present in both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 12:33:49,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.388 and 355.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.36) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (56.15) is well within the ideal range.

**logP:** Ligand A (1.2) is optimal. Ligand B (4.188) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is good.

**QED:** Ligand A (0.836) has a superior QED score compared to Ligand B (0.6), indicating better overall drug-likeness.

**DILI:** Ligand A (62.737) has a moderate DILI risk, while Ligand B (96.898) has a very high DILI risk, a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (93.37) has a better BBB percentile than Ligand B (61.342).

**Caco-2 Permeability:** Ligand A (-4.928) has better Caco-2 permeability than Ligand B (-4.734).

**Aqueous Solubility:** Ligand A (-2.957) has better aqueous solubility than Ligand B (-4.682).

**hERG Inhibition:** Ligand A (0.69) has a lower hERG inhibition liability than Ligand B (0.828), which is preferable.

**Microsomal Clearance:** Ligand A (-10.748) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (75.964).

**In vitro Half-Life:** Ligand A (5.114) has a shorter half-life than Ligand B (16.606), but the difference isn't dramatic.

**P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux liability than Ligand B (0.857).

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.0), but 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 crucial ADME properties: lower DILI risk, better solubility, better permeability, lower hERG inhibition, and significantly better metabolic stability. The QED score also favors Ligand A. The slightly lower affinity of Ligand A can likely be optimized during lead optimization without sacrificing its favorable ADME profile. The high DILI risk associated with Ligand B is a major red flag.

Output:
0
2025-04-17 12:33:49,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.394 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.3) is slightly higher than Ligand B (89.95), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.813) is within the optimal range (1-3), while Ligand B (-0.125) is slightly below, potentially impacting permeability.

**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 (0.663 and 0.743, respectively), indicating drug-like properties.

**DILI:** Ligand B (24.351) has a significantly lower DILI risk than Ligand A (44.242), which is a major advantage.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.159) shows poor Caco-2 permeability, while Ligand B (-4.878) is also low, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.398 and -2.121 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.265 and 0.088 respectively).

**Microsomal Clearance:** Ligand A (1.819) has a much lower microsomal clearance than Ligand B (7.659), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.341) has a longer in vitro half-life than Ligand B (-6.043).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.024 respectively).

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-8.9 and -8.8 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands show excellent binding affinity, Ligand A is favored due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability. Ligand B has a lower DILI risk, which is a definite plus, but the metabolic stability of Ligand A is a more critical factor for an enzyme target like SRC kinase. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 12:33:49,703 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.41 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is well below the 140 threshold and is favorable. Ligand B (85.89) is still acceptable but less optimal.

**logP:** Ligand A (4.147) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.197) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (5) counts.

**QED:** Ligand A (0.72) has a better QED score than Ligand B (0.539), indicating better overall drug-likeness.

**DILI:** Ligand A (88.251) has a significantly higher DILI risk than Ligand B (30.748). This is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (83.87) has a higher value than Ligand A (64.831).

**Caco-2 Permeability:** Ligand A (-4.922) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.587) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-5.148) has very poor aqueous solubility, which is a significant drawback. Ligand B (-1.965) is better, but still not ideal.

**hERG:** Ligand A (0.623) has a slightly higher hERG risk than Ligand B (0.262), but both are relatively low.

**Microsomal Clearance:** Ligand A (70.519) has higher microsomal clearance than Ligand B (60.598), meaning faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (9.918) has a significantly longer in vitro half-life than Ligand A (-24.598), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.519) has slightly higher P-gp efflux than Ligand B (0.091), which could reduce bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better QED score, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.6 vs -7.6 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B demonstrates substantially lower DILI risk, better metabolic stability (longer half-life, lower clearance), and better solubility, all critical factors for drug development. While both have less than ideal Caco-2 permeability, the other benefits of Ligand B outweigh this concern. The high DILI risk and poor solubility of Ligand A are deal-breakers.

Output:
1
2025-04-17 12:33:49,703 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.365 and 349.475 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.85) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (65.79) is still acceptable but less optimal.

**logP:** Both ligands (2.926 and 2.203) fall 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 (0.774 and 0.855), indicating drug-like properties.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (21.093). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (85.459) shows better penetration than Ligand B (63.94).

**Caco-2 Permeability:** Ligand A (-4.712) has a worse Caco-2 permeability than Ligand B (-4.866), suggesting potentially lower absorption.

**Aqueous Solubility:** Ligand A (-3.545) has worse solubility than Ligand B (-1.347). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG risk (0.654 and 0.746).

**Microsomal Clearance:** Ligand A (6.43 mL/min/kg) has significantly lower microsomal clearance than Ligand B (0.305 mL/min/kg). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (11.4 hours) has a much longer half-life than Ligand B (27.795 hours). This is a positive for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.275 and 0.194).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, a lower DILI risk, and better solubility. While Ligand A has better metabolic stability and a longer half-life, the significantly stronger binding of Ligand B is paramount for an enzyme target. The DILI risk associated with Ligand A is a major concern. The slightly lower Caco-2 permeability of Ligand B is a minor drawback compared to the other advantages.

Output:
1
2025-04-17 12:33:49,703 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.471 and 349.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.5) is slightly above the preferred <140, while Ligand B (80.12) is well within. This favors B for absorption.

**logP:** Both ligands have acceptable logP values (0.962 and 2.364), falling within the 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.751 and 0.742), indicating good drug-likeness.

**DILI:** Ligand A (32.338) has a significantly lower DILI risk than Ligand B (52.54). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (76.774) has a higher BBB penetration percentile than Ligand A (57.736). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.841 and -4.604), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.754 and -2.723). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.222) has a lower hERG inhibition liability than Ligand B (0.066), indicating a lower risk of cardiotoxicity. This is a key advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-8.56) has much lower microsomal clearance than Ligand B (50.755), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-10.979) has a longer in vitro half-life than Ligand B (0.319), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux liability than Ligand B (0.092), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -8.6 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and lower hERG inhibition. These factors are crucial for developing a safe and effective drug. The slightly better binding affinity of Ligand B is not enough to compensate for these significant ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 12:33:49,703 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.487 and 366.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold, suggesting good absorption. Ligand B (122.46) is also below the threshold, but higher than A.

**logP:** Ligand A (2.081) is optimal (1-3). Ligand B (-0.491) is below 1, which could impede permeation.

**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 within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (9.035 percentile) has a much lower DILI risk than Ligand B (48.43 percentile). This is a significant advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (56.301) is higher than Ligand B (47.615).

**Caco-2 Permeability:** Ligand A (-4.814) and Ligand B (-5.517) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.195) is better than Ligand B (-1.984). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.406) has a lower hERG risk than Ligand B (0.096). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (38.685 mL/min/kg) has a higher (worse) clearance than Ligand B (-12.618 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (1.35 hours) has a shorter half-life than Ligand B (-17.925 hours). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.008), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.5 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has better metabolic stability and a longer half-life, Ligand A is superior overall. The significantly lower DILI risk and hERG inhibition liability of Ligand A are critical advantages. The slightly better solubility and lower P-gp efflux also contribute to its favorability. The similar binding affinity makes these ADME properties the deciding factors.

Output:
1
2025-04-17 12:33:49,703 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.868 and 385.291 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is better than Ligand B (55.57), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.542) is optimal (1-3), while Ligand B (4.464) is pushing the upper limit and could present solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=0, HBA=5) both fall within acceptable ranges.

**QED:** Ligand A (0.803) has a significantly better QED score than Ligand B (0.628), indicating a more drug-like profile.

**DILI:** Both ligands have similar, acceptable DILI risk (Ligand A: 38.736, Ligand B: 39.511), both below the 40 threshold.

**BBB:** Ligand A (83.831) has a better BBB penetration score than Ligand B (75.378), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.763 and -4.645), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.633 and -3.774), indicating very poor aqueous solubility. This is a major concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.803, Ligand B: 0.751).

**Microsomal Clearance:** Ligand B (83.096) has a much higher microsomal clearance than Ligand A (3.908), indicating lower metabolic stability. This is a significant disadvantage for Ligand B.

**In vitro Half-Life:** Ligand B (43.758) has a slightly longer half-life than Ligand A (40.91), but the difference is not substantial.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.097, Ligand B: 0.615).

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher microsomal clearance and a less favorable logP. Ligand A has better QED, lower clearance, and a better BBB score, but its binding affinity is weaker. The poor Caco-2 and solubility for both are problematic, but could potentially be addressed with formulation strategies. Given the substantial affinity advantage of Ligand B, I would prioritize it for further investigation, despite its ADME liabilities.

Output:
1
2025-04-17 12:33:49,703 - INFO - Batch 140 complete. Total preferences: 2240
2025-04-17 12:33:49,703 - INFO - Processing batch 141/512...
2025-04-17 12:34:34,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.519 and 353.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.39) is better than Ligand B (79.72), both are acceptable, but lower is generally preferred for absorption.

**logP:** Both ligands have good logP values (1.776 and 2.638), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is slightly better than Ligand B (1 HBD, 8 HBA). Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.855 and 0.755), indicating good drug-likeness.

**DILI:** Ligand B (81.621) has a significantly higher DILI risk than Ligand A (56.223). This is a major concern.

**BBB:** Ligand A (78.868) has better BBB penetration than Ligand B (48.779), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.213 and -5.34), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.323 and -3.001), indicating very poor aqueous solubility. This is a major formulation challenge.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.482 and 0.498), which is good.

**Microsomal Clearance:** Ligand A (-0.955) has a much lower (better) microsomal clearance than Ligand B (55.557), indicating greater metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (14.013 hours) has a much longer half-life than Ligand B (1.212 hours). This is a substantial advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.026).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has a superior binding affinity, the significantly higher DILI risk and much poorer metabolic stability (higher Cl_mic, shorter t1/2) are major concerns. The poor solubility and permeability are also problematic for both, but the ADME profile of Ligand A is considerably more favorable. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. Therefore, despite the weaker binding affinity, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 12:34:34,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.411 and 357.881 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.68) is significantly better than Ligand B (21.7). Lower TPSA generally improves permeability, which is beneficial.

**logP:** Ligand A (0.955) is within the optimal range (1-3), while Ligand B (4.594) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (A: 3, B: 3) are within the ideal range of <=10.

**QED:** Both ligands have similar QED values (A: 0.804, B: 0.781), indicating good drug-likeness.

**DILI:** Ligand A (47.034) has a lower DILI risk than Ligand B (51.493), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand B (76.115) has a better BBB penetration score than Ligand A (49.826), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.65), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.629 and -4.392), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.411) has a much lower hERG inhibition risk than Ligand B (0.77), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (-9.97) exhibits significantly lower microsomal clearance than Ligand B (21.666), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-10.229) has a longer in vitro half-life than Ligand B (44.8), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.724), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-6.8), although the difference is less than the 1.5 kcal/mol threshold that would definitively swing the decision.

**Overall Assessment:**

While both ligands share some drawbacks (poor Caco-2 and solubility), Ligand A is significantly superior due to its lower hERG risk, much better metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and lower P-gp efflux. The slightly better binding affinity of Ligand A adds to its advantage. The higher logP of Ligand B is a concern. Given the enzyme-kinase target class, metabolic stability and safety (hERG, DILI) are paramount.

Output:
0
2025-04-17 12:34:34,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.316 and 351.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.11) is better than Ligand B (118.06), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.247) is optimal (1-3), while Ligand B (0.294) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands are acceptable (3 and 2, respectively), being less than 5.

**H-Bond Acceptors:** Both ligands are acceptable (4 and 6, respectively), being less than 10.

**QED:** Both ligands have good QED scores (0.738 and 0.756), indicating drug-like properties.

**DILI:** Both ligands have similar, relatively high DILI risk (77.549 and 77.976), which is a concern but not a deciding factor at this stage.

**BBB:** Ligand A (72.237) has a better BBB percentile than Ligand B (39.977), although BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.073) is better than Ligand B (-5.358), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.06) is better than Ligand B (-1.751), which is crucial for bioavailability.

**hERG:** Ligand A (0.423) has a significantly lower hERG risk than Ligand B (0.017), a major advantage.

**Microsomal Clearance:** Ligand A (7.618) has a much lower Cl_mic than Ligand B (-28.473), indicating significantly better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (13.17) has a longer half-life than Ligand B (-12.909), further supporting better metabolic stability.

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux than Ligand B (0.006), indicating better bioavailability.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.1), a 0.8 kcal/mol difference. While affinity is paramount, the substantial ADME advantages of Ligand A can potentially outweigh this difference.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising drug candidate. Its superior logP, solubility, metabolic stability (Cl_mic and t1/2), lower hERG risk, and better Caco-2 permeability and BBB penetration outweigh the small difference in binding affinity. The DILI risk is similar for both, but the other ADME properties of Ligand A make it a much more viable starting point for optimization.

Output:
1
2025-04-17 12:34:34,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (350.321 and 352.337 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.77) is slightly above the preferred <140, but still reasonable. Ligand B (67.87) is well within the optimal range.

**3. logP:** Both ligands (1.644 and 2.259) 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 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.876 and 0.848), indicating good drug-like properties.

**7. DILI:** Ligand A (54.634) has a lower DILI risk than Ligand B (68.98), which is preferable.

**8. BBB:** BBB is not a primary concern for an oncology target unless CNS penetration is specifically desired. Both are relatively high (82.047 and 89.957).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.585 and -4.465). 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 (-3.13 and -3.918), again suggesting poor solubility. Similar to Caco-2, the scale is needed for proper interpretation.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.603 and 0.602).

**12. Microsomal Clearance:** Ligand A (-1.434) has significantly lower (better) microsomal clearance than Ligand B (21.473), indicating greater metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (-9.211) has a much longer in vitro half-life than Ligand B (12.993), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.156).

**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 slightly better binding affinity, Ligand A is significantly superior in terms of metabolic stability (lower Cl_mic, longer t1/2) and has a lower DILI risk. Given that we are targeting a kinase in oncology, metabolic stability and safety (DILI) are critical. The small difference in binding affinity is outweighed by these advantages. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 12:34:34,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.49 and 343.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.76) is well below the 140 threshold, suggesting good absorption. Ligand B (129.89) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (3.723) is at the higher end of the optimal 1-3 range, while Ligand B (0.513) is quite low, potentially hindering permeation.

**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 similar and good QED values (0.719 and 0.744), indicating drug-likeness.

**DILI:** Ligand A (28.97) has a much lower DILI risk than Ligand B (68.28), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.15) is higher than Ligand B (55.91).

**Caco-2 Permeability:** Ligand A (-4.063) is better than Ligand B (-5.661).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.427 and -3.435). This is a concern for both, but might be addressable with formulation strategies.

**hERG Inhibition:** Ligand A (0.602) has a lower hERG risk than Ligand B (0.356), which is a positive.

**Microsomal Clearance:** Ligand A (107.36) has higher clearance than Ligand B (-19.47). This means Ligand B is more metabolically stable, which is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-17.25) has a much longer half-life than Ligand A (50.43), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.747) has higher P-gp efflux liability than Ligand B (0.025), meaning B will have better bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, logP, and lower DILI and hERG risk, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity are more critical for an enzyme target like SRC kinase. The solubility issues are a concern for both, but the potency and metabolic advantages of Ligand B are more impactful.

Output:
1
2025-04-17 12:34:34,744 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [351.324, 51.47, 3.655, 1, 3, 0.918, 48.197, 94.998, -4.4, -4.281, 0.71, 39.095, 38.645, 0.347, -7.8]
**Ligand B:** [360.885, 64.35, 4.765, 2, 3, 0.677, 47.732, 69.523, -5.056, -4.701, 0.797, 59.053, 76.9, 0.565, -8.9]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (351.324) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (51.47) is better than B (64.35).  Both are acceptable, but A is closer to the <140 threshold for good absorption.
3. **logP:** A (3.655) is optimal, while B (4.765) is pushing the upper limit.  Higher logP can lead to off-target effects and solubility issues. A is preferred.
4. **HBD:** A (1) is better than B (2). Lower HBD generally improves permeability.
5. **HBA:** Both A (3) and B (3) are good.
6. **QED:** A (0.918) is significantly better than B (0.677), indicating a more drug-like profile.
7. **DILI:** Both are good, with A (48.197) and B (47.732) being relatively low risk.
8. **BBB:** A (94.998) is much better than B (69.523). While not crucial for a non-CNS target like SRC, it's a positive attribute.
9. **Caco-2:** A (-4.4) is better than B (-5.056). Higher is better, indicating better intestinal absorption.
10. **Solubility:** A (-4.281) is better than B (-4.701). Higher solubility is crucial for bioavailability.
11. **hERG:** Both A (0.71) and B (0.797) are acceptable, with low risk of cardiotoxicity.
12. **Cl_mic:** A (39.095) is significantly better than B (59.053). Lower clearance indicates better metabolic stability.
13. **t1/2:** B (76.9) is better than A (38.645). Longer half-life is generally preferred.
14. **Pgp:** A (0.347) is better than B (0.565). Lower P-gp efflux is desirable.
15. **Binding Affinity:** B (-8.9) is significantly better than A (-7.8). This is a substantial advantage (1.1 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.9 kcal/mol vs. -7.8 kcal/mol). This is a substantial advantage that outweighs most of the other drawbacks. While A has better properties in many ADME categories (TPSA, logP, QED, Cl_mic, solubility, Pgp), the difference in binding affinity is large enough to likely translate to a more efficacious drug. The longer half-life of B is also a plus. The slightly higher logP and lower QED of B are manageable.

Therefore, I recommend **Ligand B** as the more viable drug candidate.

Output:
1
2025-04-17 12:34:34,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.219 Da) is slightly higher than Ligand B (361.511 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (54.88 and 59.23) below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (4.937 and 4.064) that are slightly high, potentially leading to solubility issues or off-target effects. Ligand B is preferable here.

**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 good QED scores (0.523 and 0.746), indicating a generally drug-like profile. Ligand B is 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 (38.697%), making it significantly more favorable.

**BBB:** Both ligands have reasonable BBB penetration (73.168% and 83.831%). This isn't a primary concern for a kinase inhibitor, but higher is generally better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.836 and -4.907), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.713 and -3.486). This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.739 and 0.338). This is good.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (81.086), while Ligand B has a high clearance (91.401). Ligand A is preferable regarding metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (124.989 hours) than Ligand B (-14.666 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.555 and 0.493).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.2 and -9.3 kcal/mol). The difference is negligible.

**Conclusion:**

Despite Ligand A having a better half-life and lower clearance, the extremely high DILI risk (99.147%) is a deal-breaker. The poor solubility of both is also a major concern, but DILI is a more immediate safety issue. Ligand B, while having a higher clearance and slightly lower QED, presents a much more acceptable safety profile with a DILI risk of 38.697%. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 12:34:34,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.392 and 350.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold, while Ligand B (83.36) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (1.636) is optimal, while Ligand B (0.29) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the 5 limit.

**H-Bond Acceptors:** Ligand A (3) is good, while Ligand B (6) is also acceptable but higher.

**QED:** Both ligands have similar QED values (0.723 and 0.692), indicating good drug-likeness.

**DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (19.038), which is a crucial advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (82.513) shows better potential for BBB penetration than Ligand B (48.74).

**Caco-2 Permeability:** Ligand A (-5.079) is better than Ligand B (-5.399), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.617) has better solubility than Ligand B (0.001), which is a significant advantage for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.526) has a lower hERG risk than Ligand B (0.087), which is a critical safety parameter.

**Microsomal Clearance:** Ligand A (-0.821) has a lower (better) microsomal clearance than Ligand B (-12.52), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-9.082) has a much longer in vitro half-life than Ligand B (1.563), suggesting less frequent dosing potential.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux liability than Ligand B (0.012), improving bioavailability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to outweigh other issues, it contributes to the overall favorability of Ligand A.

**Overall:** Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, including DILI, solubility, hERG risk, metabolic stability, and permeability. While both have acceptable MW, QED, and H-bond parameters, Ligand A's superior profile makes it a much more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 12:34:34,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 365.47 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (38.77) as it is closer to the ideal range for good oral absorption (<=140).

**3. logP:** Both ligands (3.521 and 3.263) are within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as it balances solubility and permeability.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.757 and 0.776), indicating drug-like properties.

**7. DILI:** Ligand A (28.383) has a significantly lower DILI risk than Ligand B (39.395), making it safer. Both are below the 40 threshold.

**8. BBB:** Both ligands have good BBB penetration (76.968 and 85.033), but this is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.254 and -4.6), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.087 and -3.833), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.578) has a lower hERG inhibition risk than Ligand B (0.911), which is favorable.

**12. Microsomal Clearance:** Ligand A (85.576) has lower microsomal clearance than Ligand B (88.813), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.951) has a negative half-life, which is not possible. Ligand A (4.283) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux than Ligand B (0.532), indicating better bioavailability.

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, the poor solubility and permeability (negative Caco-2 and solubility values) of both compounds are major concerns. Ligand A is preferable due to its lower DILI risk, better metabolic stability, lower hERG risk, lower P-gp efflux, and a reasonable half-life. Ligand B has a nonsensical half-life value. The affinity difference is significant (1.1 kcal/mol), but the ADME profile of Ligand A is more favorable.

Output:
0
2025-04-17 12:34:34,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.487 and 379.839 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (72.96 and 72.28) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.927) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.544) is within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is well within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are below the 10 limit.

**QED:** Ligand A (0.841) has a better QED score than Ligand B (0.556), indicating a more drug-like profile.

**DILI:** Ligand A (25.785) has a significantly lower DILI risk than Ligand B (58.434), which is a major advantage.

**BBB:** Ligand A (65.491) has a lower BBB penetration than Ligand B (92.051). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.912 and -4.702), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.025 and -2.712), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.497) shows a lower hERG inhibition liability than Ligand B (0.338), which is preferable.

**Microsomal Clearance:** Ligand A (9.297) has a lower microsomal clearance than Ligand B (65.14), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-44.909) has a much longer in vitro half-life than Ligand B (20.553), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.011) has much lower P-gp efflux liability than Ligand B (0.343), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-10.1 kcal/mol). While a difference of 1.2 kcal/mol is noticeable, the other ADME properties are more concerning.

**Overall Assessment:**

Despite Ligand B's slightly better binding affinity, Ligand A is the more promising candidate. Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower P-gp efflux, and lower hERG inhibition. While both have poor solubility and permeability, the metabolic advantages of Ligand A are more critical for an enzyme target like SRC kinase. The better QED score also supports its drug-like potential.

Output:
0
2025-04-17 12:34:34,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.47 and 358.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (95.42).  A TPSA under 140 is good for oral absorption, and both are under, but A is much more favorable.

**logP:** Ligand A (4.325) is a bit high, potentially leading to solubility issues, while Ligand B (1.726) is closer to the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 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 (0.903 and 0.868), indicating generally drug-like properties.

**DILI:** Ligand A (39.71) has a much lower DILI risk than Ligand B (60.22), which is bordering on high risk. This is a significant advantage for Ligand A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (81.47) is better than Ligand B (40.09).

**Caco-2 Permeability:** Ligand A (-4.588) is significantly better than Ligand B (-5.306). Higher values indicate better absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.27 and -4.126). This is a potential issue for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have very low hERG risk (0.712 and 0.09). This is excellent.

**Microsomal Clearance:** Ligand B (37.354) has lower microsomal clearance than Ligand A (56.359), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-26.268) has a much longer in vitro half-life than Ligand A (3.781), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.207 and 0.035).

**Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent and removes this as a differentiating factor.

**Overall Assessment:**

Ligand A excels in TPSA, Caco-2 permeability, and DILI risk. However, its higher logP and microsomal clearance are drawbacks. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, which are crucial for an enzyme target. While its TPSA is higher and logP lower, the significantly improved metabolic stability and longer half-life outweigh these concerns, especially given the equal binding affinity. The DILI risk for Ligand B is a concern, but not insurmountable.

Output:
1
2025-04-17 12:34:34,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (349.431 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is significantly better than Ligand B (110.76). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.819 and 1.102), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=8) as it has fewer H-bonds, which generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.759 and 0.734), indicating good drug-likeness.

**DILI:** Ligand A (34.626) has a much lower DILI risk than Ligand B (59.131). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.378) is better than Ligand B (47.964).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so direct comparison is difficult.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is not specified, making direct comparison difficult.

**hERG:** Both ligands show very low hERG inhibition risk (0.134 and 0.041), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (49.418 and 50.088), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-19.824) has a significantly *longer* half-life than Ligand B (22.651). This is a major advantage for A, potentially allowing for less frequent dosing. Note the negative value for A is unusual, but relative to B, it's more favorable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.093 and 0.047).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.9 kcal/mol difference, which is notable but not overwhelmingly decisive.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in several critical ADME properties: lower DILI risk, better TPSA, longer half-life, and better BBB penetration. The differences in solubility and Caco-2 permeability are difficult to assess without knowing the scale. Given the enzyme-specific priorities, the improved metabolic stability (half-life) and safety profile (DILI) of Ligand A outweigh the modest affinity difference.

Output:
1
2025-04-17 12:34:34,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, but both are acceptable.

**TPSA:** Ligand A (101.29) is better than Ligand B (122.31), falling comfortably under the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.034) is optimal (1-3), while Ligand B (0.174) is quite low, potentially hindering permeation. This is a significant drawback for Ligand B.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 8. Ligand A is better here, staying well below the 10 HBA threshold.

**QED:** Both ligands have similar QED values (0.554 and 0.531), indicating good drug-likeness.

**DILI:** Ligand A (22.722) has a much lower DILI risk than Ligand B (79.798). This is a substantial advantage for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand B (61.691) is slightly better than Ligand A (57.193). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. However, the values are on a similar scale, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.119) has a much lower hERG risk than Ligand B (0.343), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (41.761) has lower microsomal clearance than Ligand B (54.187), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (6.018) has a longer half-life than Ligand A (1.506), which is generally desirable. However, this is somewhat offset by its poorer metabolic stability (higher Cl_mic).

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.023), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.1 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.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme target. However, it suffers from a very low logP, high DILI risk, and a higher hERG risk. Ligand A has better ADME properties across the board (logP, DILI, hERG, Cl_mic), but its binding affinity is weaker.

Despite the affinity advantage of Ligand B, the combination of poor logP and elevated toxicity risks makes it a less attractive candidate. The lower logP will likely translate to poor oral bioavailability, and the higher DILI/hERG risks are major concerns. The affinity difference, while substantial, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 12:34:34,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.46 and 353.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the preferred <140, while Ligand B (56.59) is well within the range.

**logP:** Both ligands have good logP values (2.69 and 1.65), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are acceptable.

**QED:** Both ligands have similar QED values (0.64 and 0.6), indicating good drug-likeness.

**DILI:** Ligand A (27.07) has a slightly higher DILI risk than Ligand B (11.63), but both are below the concerning threshold of 40.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (97.25) has much higher BBB penetration than Ligand A (46.10), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.05) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.43) is also negative, but less so.

**Aqueous Solubility:** Ligand A (-2.88) has very poor aqueous solubility, while Ligand B (-1.26) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.13) has a very low hERG risk, which is excellent. Ligand B (0.70) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (26.67 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (53.44 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.90 hours) has a negative half-life, which is concerning and likely an error or indicates very rapid degradation. Ligand B (22.75 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.05) has very low P-gp efflux, while Ligand B (0.19) has slightly higher efflux.

**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.

**Conclusion:**

Despite Ligand A's superior binding affinity, its extremely poor solubility, negative Caco-2 permeability, and negative in vitro half-life are major red flags. These issues would likely lead to poor bioavailability and rapid clearance, negating the benefit of strong binding. Ligand B, while having weaker affinity, has better solubility, permeability, metabolic stability, and a reasonable half-life.

Output:
1
2025-04-17 12:34:34,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.491 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.21) is slightly above the preferred <140 for good absorption, while Ligand B (81.67) is well within the range.

**logP:** Ligand A (0.126) is quite low, potentially hindering permeation. Ligand B (1.201) is better, falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.506 and 0.574), indicating drug-like properties.

**DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (4.498), which is a major advantage.

**BBB:** Ligand A (15.432) has a very low BBB penetration, while Ligand B (52.656) is moderate. Since SRC is not a CNS target, this is less critical, but still a point for B.

**Caco-2 Permeability:** Ligand A (-6.079) shows poor permeability, while Ligand B (-5.3) is slightly better, but still concerning.

**Aqueous Solubility:** Ligand A (-0.996) has poor solubility, while Ligand B (-1.585) is also poor, but slightly worse.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.155 and 0.179).

**Microsomal Clearance:** Ligand A (-14.797) has significantly lower (better) microsomal clearance than Ligand B (-3.513), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.979) has a slightly longer half-life than Ligand B (3.618).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.009 and 0.008).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol), a difference of 0.9 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better logP, which are key for an enzyme inhibitor. However, Ligand A demonstrates a significantly lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). The poor solubility and permeability of both are concerning, but the strong affinity of Ligand B and its better logP outweigh the advantages of Ligand A's improved ADME properties. The difference in binding affinity is substantial enough to potentially overcome the ADME liabilities, especially given that formulation strategies can be employed to address solubility and permeability issues.

Output:
1
2025-04-17 12:34:34,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.405 and 332.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is well below the 140 threshold, while Ligand B (75.01) is also acceptable, though slightly higher.

**logP:** Ligand A (4.198) is a bit high, potentially leading to solubility issues. Ligand B (2.781) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 3 HBA) both have reasonable counts, well within the recommended limits.

**QED:** Both ligands have similar QED values (0.757 and 0.724), indicating good drug-likeness.

**DILI:** Ligand A (92.284) has a significantly higher DILI risk than Ligand B (70.919). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (73.866) shows better penetration than Ligand A (66.886).

**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 solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.563) shows a slightly higher hERG risk than Ligand B (0.861), but both are relatively low.

**Microsomal Clearance:** Ligand B (27.974 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (43.268 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (4.03 hours) has a very short half-life, while Ligand A (56.959 hours) has a much longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.505 and 0.49), which is favorable.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's longer half-life, Ligand B is the more promising candidate. The stronger binding affinity (-9.4 vs -8.6 kcal/mol) is a significant advantage for an enzyme target. Furthermore, Ligand B exhibits a lower DILI risk and better metabolic stability (lower Cl_mic). While both have solubility concerns, the lower DILI risk and superior potency of Ligand B make it the better choice.

Output:
1
2025-04-17 12:34:34,745 - INFO - Batch 141 complete. Total preferences: 2256
2025-04-17 12:34:34,745 - INFO - Processing batch 142/512...
2025-04-17 12:35:14,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. 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.

**2. TPSA:** Ligand A (102.36) is better than Ligand B (136.3), falling well below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (1.143) is within the optimal range (1-3). Ligand B (-0.392) is slightly below 1, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher donors can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (8) is good. Ligand B (7) is also good.

**6. QED:** Ligand A (0.861) is excellent, indicating high drug-likeness. Ligand B (0.571) is acceptable, but lower.

**7. DILI:** Ligand A (93.757) has a significantly higher DILI risk than Ligand B (50.33). This is a major concern for Ligand A.

**8. BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand B (62.233) is slightly better than Ligand A (56.611).

**9. Caco-2 Permeability:** Ligand A (-4.501) is very poor, suggesting poor intestinal absorption. Ligand B (-5.498) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-3.045) is poor. Ligand B (-2.617) is also poor, but slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.187 and 0.047 respectively), which is excellent.

**12. Microsomal Clearance:** Ligand A (29.048) has higher clearance than Ligand B (14.891), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-30.036) has a very short half-life. Ligand B (4.653) is better, but still relatively short.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.011 and 0.032 respectively), which is good.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). Although A is slightly better, the difference is small.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a stronger binding affinity. The lower logP of Ligand B is a minor drawback that might be addressed with further optimization, but the high DILI risk of Ligand A is a significant obstacle. The binding affinity difference is small and doesn't outweigh the other factors.

Output:
1
2025-04-17 12:35:14,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.363 and 365.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.84) is better than Ligand B (61.38) as it is closer to the 140 A^2 threshold for oral absorption. Ligand B is very low, which could indicate issues with solubility.

**logP:** Ligand A (-0.549) is a bit low, potentially hindering permeation. Ligand B (3.462) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, which is acceptable. Ligand B has 4 HBA, which is also acceptable.

**QED:** Both ligands have good QED scores (0.628 and 0.752), indicating good drug-like properties.

**DILI:** Ligand A (54.634) has a slightly higher DILI risk than Ligand B (37.922), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (63.164) has a higher BBB percentile than Ligand A (34.548), but this is not a major factor in this case.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This requires further investigation, but it's a red flag for both.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility. This is a significant concern for both compounds.

**hERG Inhibition:** Ligand A (0.04) has a very low hERG risk, which is excellent. Ligand B (0.91) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand B (30.274) has significantly lower microsomal clearance than Ligand A (45.343), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (109.046) has a much longer in vitro half-life than Ligand A (0.986), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is good. Ligand B (0.771) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.9 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 both ligands have issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.9 vs -8.3 kcal/mol), lower microsomal clearance, and longer half-life are critical advantages for an enzyme inhibitor. The slightly higher logP and lower TPSA are also favorable. The higher hERG risk is a minor concern compared to the metabolic stability and potency benefits.

Output:
1
2025-04-17 12:35:14,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.371 Da) is slightly higher than Ligand B (366.462 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (A: 68.29, B: 71.25) below the 140 threshold for good oral absorption.

**logP:** Ligand A (4.062) is at the upper end of the optimal range (1-3), while Ligand B (2.778) is well within it. Ligand A's higher logP *could* potentially lead to solubility issues or off-target interactions, but it's not drastically high.

**H-Bond Donors/Acceptors:** Both ligands have acceptable numbers of HBD (1) and HBA (A: 5, B: 6), falling within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.791, B: 0.818), indicating generally drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (81.388%) than Ligand B (40.83%). This is a major concern for Ligand A.

**BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B has a higher BBB percentile (79.217) than Ligand A (46.413), but this isn't a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.672 and -4.639). These values are unusual and suggest very poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.281 and -2.222). This is a significant drawback for both, but could be mitigated through formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.417, B: 0.665), which is positive.

**Microsomal Clearance:** Ligand B has a much lower microsomal clearance (25.061 mL/min/kg) than Ligand A (72.313 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B has a negative in vitro half-life (-18.599 hours), which is nonsensical. Ligand A has a reasonable half-life (10.133 hours). The negative value for Ligand B is a clear red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.617, B: 0.215).

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.5 kcal/mol, B: -8.1 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.4 kcal/mol) is not substantial enough to outweigh other concerns.

**Conclusion:**

Ligand B is the more promising candidate. While both have solubility and permeability concerns, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a plausible half-life. Ligand A has a higher DILI risk and a higher Cl_mic, making it less favorable. The negative half-life for Ligand B is concerning, but could be a data error.

Output:
1
2025-04-17 12:35:14,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.87 and 80.76) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.419 and 1.083) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.691 and 0.814), indicating drug-like properties.

**DILI:** Ligand A (16.402) has a significantly lower DILI risk than Ligand B (41.877). This is a major advantage for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (58.782 and 56.34). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values (-4.739 and -4.978), which 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.

**Solubility:** Both ligands have negative solubility values (-1.271 and -2.421), which suggests poor solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG:** Both ligands have very low hERG risk (0.249 and 0.419). This is excellent.

**Microsomal Clearance:** Ligand A (34.1 mL/min/kg) has a higher microsomal clearance than Ligand B (25.337 mL/min/kg), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (18.713 hours) has a longer in vitro half-life than Ligand A (11.991 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.043).

**Binding Affinity:** Ligand B (-7.3 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 is often enough to outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite the higher DILI risk. The significantly improved binding affinity (-7.3 vs -0.0 kcal/mol) is a decisive factor for an enzyme target. The better metabolic stability (lower Cl_mic, longer t1/2) also favors Ligand B. While the DILI risk for Ligand B is higher, it is still below 60 and may be manageable. The solubility and permeability concerns are similar for both compounds.

Output:
1
2025-04-17 12:35:14,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.48 and 352.44 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (96.69). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (3.156) is optimal, while Ligand B (1.068) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have similar QED scores (0.784 and 0.747), indicating good drug-likeness.

**DILI:** Ligand A (19.814 percentile) has a much lower DILI risk than Ligand B (39.434 percentile). This is a significant advantage.

**BBB:** Ligand A (85.925 percentile) shows better BBB penetration than Ligand B (50.097 percentile), although BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.557) shows better Caco-2 permeability than Ligand B (-5.155), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.357) has slightly better solubility than Ligand B (-1.45), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.761) has a lower hERG risk than Ligand B (0.512). Lower is better here.

**Microsomal Clearance:** Ligand A (55.915 mL/min/kg) has a higher clearance than Ligand B (25.609 mL/min/kg), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-6.633 hours) has a longer half-life than Ligand B (-4.269 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.227) has lower P-gp efflux than Ligand B (0.083), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 0.8 kcal/mol difference, which is a notable advantage.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability. However, Ligand A excels in almost all other ADME properties (TPSA, logP, DILI, solubility, hERG, permeability, half-life, P-gp efflux). The difference in binding affinity (0.8 kcal/mol) is not substantial enough to outweigh the significant improvements in ADME properties offered by Ligand A. The lower DILI risk of Ligand A is also a major factor. For an enzyme target like SRC kinase, metabolic stability is important, but a good balance of ADME properties is crucial for *in vivo* efficacy.

Output:
0
2025-04-17 12:35:14,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (370.471 Da) is also good.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (88.85) is better than Ligand A (99.18).

**logP:** Ligand A (-0.968) is a bit low, potentially hindering membrane permeability. Ligand B (1.36) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.621, B: 0.813), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (54.052). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.554) has a higher BBB score than Ligand A (28.073), but it's not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.048) is slightly better than Ligand B (-4.866).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand A (-0.91) is slightly better than Ligand B (-2.228).

**hERG Inhibition:** Ligand A (0.047) has a very low hERG risk, which is excellent. Ligand B (0.268) is also low, but higher than Ligand A.

**Microsomal Clearance:** Ligand A (2.747) has much lower microsomal clearance, indicating better metabolic stability, which is crucial for an enzyme target. Ligand B (9.506) has higher clearance.

**In vitro Half-Life:** Ligand A (-7.182) has a much longer in vitro half-life, further supporting its better metabolic stability. Ligand B (41.174) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This 0.1 kcal/mol difference is not substantial enough to overcome the ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and hERG inhibition. The poor solubility and permeability of both compounds are concerning, but the superior safety and pharmacokinetic profile of Ligand A make it the more promising starting point for optimization.

Output:
0
2025-04-17 12:35:14,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.308 Da and 347.434 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.43) is better than Ligand B (52.65), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.001 and 1.941), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 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 good QED scores (0.777 and 0.82), indicating good drug-like properties.

**DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (29.236). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (87.786 and 81.815), but this is less critical for a non-CNS target like SRC.

**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 negative solubility values, which is also unusual. Ligand B (-1.715) is slightly better than Ligand A (-3.305).

**hERG Inhibition:** Ligand A (0.121) has a slightly higher hERG inhibition risk than Ligand B (0.769), but both are relatively low.

**Microsomal Clearance:** Ligand A (25.877) has a lower microsomal clearance than Ligand B (33.456), suggesting better metabolic stability, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-12.813) has a significantly longer in vitro half-life than Ligand B (9.051), which is highly desirable.

**P-gp Efflux:** Ligand A (0.113) has lower P-gp efflux than Ligand B (0.067), indicating better bioavailability.

**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 factor.

**Overall Assessment:**

Ligand B is better overall. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, the significantly higher DILI risk is a major concern. Ligand B has a lower DILI risk, slightly better affinity, and is comparable in other key properties. The slightly better affinity of Ligand B outweighs the minor advantages of Ligand A.

Output:
1
2025-04-17 12:35:14,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.439 and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.34) is slightly higher than Ligand B (49.41). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Both ligands (2.589 and 3.16) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.591 and 0.798), indicating drug-likeness.

**DILI:** Ligand A (19.232) has a lower DILI risk than Ligand B (24.506), which is favorable.

**BBB:** Ligand A (54.517) has a lower BBB penetration percentile than Ligand B (97.286). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.742) has lower Caco-2 permeability than Ligand B (-4.595). Both are negative, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-2.658) has slightly better aqueous solubility than Ligand B (-3.805). Both are negative, suggesting poor solubility.

**hERG:** Ligand A (0.336) has a lower hERG inhibition liability than Ligand B (0.762), which is a significant advantage.

**Microsomal Clearance:** Ligand A (36.392) and Ligand B (37.89) have similar microsomal clearance values. Both are relatively low, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (14.8) has a longer half-life than Ligand B (-16.024). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.137) has lower P-gp efflux liability than Ligand B (0.46), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, Ligand A is the more promising candidate. It has a lower DILI risk, lower hERG inhibition, a longer half-life, and lower P-gp efflux. While Ligand B has better BBB penetration and slightly better Caco-2 permeability, these are less important for a non-CNS enzyme target like SRC. The similar binding affinities make the ADME/Tox advantages of Ligand A decisive.

Output:
0
2025-04-17 12:35:14,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.417 and 360.351 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is slightly higher than Ligand B (42.43). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Ligand A (1.147) is within the optimal 1-3 range. Ligand B (3.326) is at the higher end, 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.

**QED:** Ligand A (0.695) has a better QED score than Ligand B (0.278), indicating a more drug-like profile.

**DILI:** Ligand A (22.024) has a much lower DILI risk than Ligand B (32.997), a significant advantage.

**BBB:** Ligand A (76.347) has a good BBB percentile, while Ligand B (97.131) is excellent. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.78) and Ligand B (-4.271) both have negative values, indicating poor permeability. Ligand B is slightly better.

**Aqueous Solubility:** Ligand A (-1.413) is better than Ligand B (-3.39), which is a crucial advantage for an enzyme inhibitor.

**hERG:** Ligand A (0.682) has a lower hERG risk than Ligand B (0.723), a favorable characteristic.

**Microsomal Clearance:** Ligand A (8.514) has a much lower Cl_mic than Ligand B (55.116), suggesting significantly better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-7.689) has a better (longer) half-life than Ligand B (-5.791).

**P-gp Efflux:** Ligand A (0.302) has a lower P-gp efflux liability than Ligand B (0.207), which is beneficial.

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-6.8). While both are good, the 1.5 kcal/mol difference is significant.

**Overall:**

Ligand A is superior. It has a better QED score, significantly lower DILI risk, better solubility, much better metabolic stability (lower Cl_mic and longer half-life), and slightly better binding affinity. While Ligand B has better Caco-2 permeability and BBB penetration, these are less critical for a non-CNS enzyme target like SRC kinase. The improved ADME properties of Ligand A outweigh the minor advantage of Ligand B in permeability.

Output:
1
2025-04-17 12:35:14,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (435.368 Da) is slightly higher than Ligand B (349.519 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is better than Ligand B (53.93). Both are reasonably good for oral absorption, being under 140, but lower is generally preferred.

**logP:** Ligand A (4.527) is a bit high, potentially leading to solubility issues and off-target effects, while Ligand B (3.481) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.754, B: 0.827), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (83.947%) compared to Ligand B (8.181%). This is a major concern for Ligand A.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC kinase, but Ligand B (90.074%) has better penetration than Ligand A (79.992%).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.889 and -4.78), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.714 and -4.071). This is a major issue for both, potentially hindering bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.674 and 0.596), which is good.

**Microsomal Clearance:** Ligand A (49.36 mL/min/kg) has higher clearance than Ligand B (42.885 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (3.706 hours) has a significantly shorter half-life than Ligand A (58.754 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.641) has slightly higher P-gp efflux than Ligand B (0.163), which is less desirable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a much stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a significant advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. However, it suffers from a high DILI risk, higher logP, and higher microsomal clearance. Ligand B has a better safety profile (lower DILI), better logP, and lower P-gp efflux, but its binding affinity is weaker and its half-life is much shorter.

Given the priorities for enzyme inhibitors, 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 and permeability are shared issues that would need to be addressed regardless of which ligand is chosen. The longer half-life is also a significant benefit.

Output:
1
2025-04-17 12:35:14,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.435 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.35) is slightly higher than Ligand B (76.66). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (0.261) is quite low, potentially hindering permeability. Ligand B (1.836) 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, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Ligand A (0.735) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Both ligands have very similar DILI risk (27.608% and 27.724%), and both are below the concerning 40% threshold.

**BBB:** Both have moderate BBB penetration (60.838% and 64.482%). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.931 and -4.828), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both have negative solubility values (-1.776 and -2.997), which is also unusual and indicates very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both have low hERG inhibition liability (0.081 and 0.198), which is excellent.

**Microsomal Clearance:** Ligand A (10.427 mL/min/kg) has considerably lower microsomal clearance than Ligand B (44.482 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (0.722 hours) has a very short half-life, while Ligand B (-0.615 hours) is even shorter and negative. Both are poor.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.011 and 0.026).

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic). However, Ligand B has a more favorable logP and TPSA. Both suffer from poor predicted solubility and permeability. Given the enzyme-specific priorities, metabolic stability is crucial. The slightly better affinity of Ligand A, combined with its superior metabolic stability, outweighs the logP advantage of Ligand B. The poor solubility and permeability are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 12:35:14,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.348 Da) is slightly higher than Ligand B (335.411 Da), but both are acceptable.

**TPSA:** Ligand A (30.49) is excellent, well below the 140 threshold for oral absorption. Ligand B (67.94) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 4.927, B: 3.882), falling within the 1-3 range, although A is a bit high.

**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:** Both ligands have similar and good QED values (A: 0.677, B: 0.723), indicating good drug-like properties.

**DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (91.47). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (78.596) is better than Ligand B (57.852).

**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 close.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.323 and -5.158 respectively). This is a potential formulation challenge for both.

**hERG:** Ligand A (0.931) has a slightly better hERG profile than Ligand B (0.551), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (61.523) has slightly better microsomal clearance than Ligand A (64.626), suggesting better metabolic stability. However, the difference is small.

**In vitro Half-Life:** Ligand A (21.207 hours) has a significantly longer half-life than Ligand B (-11.178 hours). This is a substantial advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.714, B: 0.449).

**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 more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand A excels in critical areas: significantly lower DILI risk, a longer half-life, and slightly better binding affinity and hERG profile. The higher logP of Ligand A is a minor concern, but the benefits outweigh this drawback. The substantial difference in DILI risk is a key factor.

Output:
1
2025-04-17 12:35:14,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 362.495 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.9) is better than Ligand B (60.85), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.51) is slightly low, potentially hindering permeation. Ligand B (2.515) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.795 and 0.894), indicating drug-like properties.

**DILI:** Ligand A (47.964) has a slightly higher DILI risk than Ligand B (33.656), but both are below the concerning 60 threshold.

**BBB:** Both have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (62.117) is slightly better than Ligand A (56.611).

**Caco-2 Permeability:** Ligand A (-4.537) has very poor Caco-2 permeability, a significant drawback. Ligand B (-5.138) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.106) has poor aqueous solubility. Ligand B (-3.472) is even worse. This is a concern for both.

**hERG Inhibition:** Ligand A (0.14) has a very low hERG risk, which is excellent. Ligand B (0.312) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-3.673) has a negative clearance, indicating high metabolic stability, which is very favorable. Ligand B (45.222) has a high clearance, suggesting rapid metabolism. This is a major disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-3.103) has a negative half-life, indicating high stability, which is very favorable. Ligand B (-11.193) has a negative half-life, indicating high stability, which is also very favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.114), which is good.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's low logP and poor Caco-2 permeability, its significantly superior binding affinity (-8.2 vs -7.3 kcal/mol) and excellent metabolic stability (negative Cl_mic and t1/2) make it the more promising candidate. The strong binding is a key advantage for an enzyme inhibitor, and the metabolic stability will contribute to a longer duration of action. While solubility is a concern for both, it can be addressed through formulation strategies. Ligand B's higher logP is beneficial, but it is offset by its poor metabolic stability.

Output:
0
2025-04-17 12:35:14,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 351.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.53 and 73.89) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have acceptable logP values (2.535 and 1.366), falling within the 1-3 range. Ligand B is slightly better here, being closer to 1.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 8. Both are within the acceptable limit of <=10, but Ligand A is better.

**QED:** Both ligands have good QED scores (0.91 and 0.75), indicating drug-likeness. Ligand A is slightly better.

**DILI:** Both ligands have similar, acceptable DILI risk (49.632 and 47.421 percentile).

**BBB:** Ligand B has a significantly higher BBB penetration (89.531%) compared to Ligand A (60.45%). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.467 and -4.85), which is unusual and indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.871 and -2.106), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.256 and 0.344), which is excellent.

**Microsomal Clearance:** Ligand B has a lower microsomal clearance (18.183 mL/min/kg) than Ligand A (33.223 mL/min/kg), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (8.797 hours) than Ligand A (-6.46 hours). This is a major advantage, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.161 and 0.188).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better logP. The difference in half-life and clearance is substantial enough to favor Ligand B, especially given the similar binding affinities.

Output:
1
2025-04-17 12:35:14,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.447 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is better than Ligand B (87.13), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Ligand A (1.357) is optimal, while Ligand B (3.132) is at the higher end of the optimal range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3), as fewer donors generally improve permeability.

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

**6. QED:** Both ligands have similar QED scores (0.807 and 0.779), indicating good drug-likeness.

**7. DILI:** Ligand A (39.434) has a significantly lower DILI risk than Ligand B (62.156), which is a substantial advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.813) is better than Ligand B (52.85).

**9. Caco-2 Permeability:** Ligand A (-4.584) is better than Ligand B (-5.121), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.28) is better than Ligand B (-3.78), which is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.172) has a much lower hERG risk than Ligand B (0.528), a critical safety parameter.

**12. Microsomal Clearance:** Ligand A (21.024) has a lower clearance than Ligand B (40.122), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (74.705) has a significantly longer half-life than Ligand A (5.294). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux than Ligand B (0.269).

**15. Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.3), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties (DILI, hERG, solubility, metabolic stability, permeability, P-gp efflux). While Ligand B has a better half-life and slightly better binding affinity, the superior safety profile and overall drug-likeness of Ligand A outweigh these advantages. The difference in binding affinity is not substantial enough to overcome the ADME liabilities of Ligand B.

Output:
0
2025-04-17 12:35:14,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.447 and 346.479 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.46 and 79.1) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.325) is optimal, while Ligand B (2.481) is also within the acceptable range (1-3).

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability, though both are acceptable.

**QED:** Ligand A (0.894) has a significantly better QED score than Ligand B (0.764), indicating a more drug-like profile.

**DILI:** Ligand A (33.618) has a much lower DILI risk than Ligand B (60.682). This is a significant advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (80.419) has a higher percentile than Ligand A (52.811).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual. We will assume these are percentile values and that higher is better. Ligand A (-4.898) is slightly better than Ligand B (-5.027).

**Aqueous Solubility:** Ligand A (-1.271) has slightly better solubility than Ligand B (-2.84).

**hERG Inhibition:** Ligand A (0.249) shows much lower hERG inhibition liability than Ligand B (0.891), which is a crucial advantage.

**Microsomal Clearance:** Ligand B (52.848) has a lower microsomal clearance than Ligand A (33.587), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (71.738) has a significantly longer in vitro half-life than Ligand A (9.024), which is a major benefit.

**P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.414), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.4 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 to outweigh other issues, it is still a positive factor.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, lower hERG inhibition, better QED, and slightly better solubility and P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, the safety concerns associated with its higher DILI and hERG values are substantial drawbacks. The slightly better binding affinity of Ligand A also contributes to its favorability.

Output:
0
2025-04-17 12:35:14,979 - INFO - Batch 142 complete. Total preferences: 2272
2025-04-17 12:35:14,979 - INFO - Processing batch 143/512...
2025-04-17 12:36:01,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.43 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.99 and 76.66) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Both ligands have logP values within the optimal range (2.05 and 1.39). Ligand B is slightly lower, but still acceptable.

**H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (2 HBDs), as fewer donors generally improve permeability.

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

**QED:** Ligand A (0.847) has a significantly higher QED score than Ligand B (0.512), indicating a more drug-like profile.

**DILI:** Ligand A (29.78%) has a lower DILI risk than Ligand B (18.65%), which is a significant advantage.

**BBB:** Ligand A (66.19%) has a higher BBB penetration score than Ligand B (50.87%). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.701 and -4.951). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close, making this a less decisive factor.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.648 and -2.259). This is also concerning, indicating poor solubility. Ligand B is slightly worse.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.136 and 0.23), which is excellent.

**Microsomal Clearance:** Ligand A (15.14 mL/min/kg) has a slightly higher microsomal clearance than Ligand B (13.30 mL/min/kg), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand A (26.42 hours) has a significantly longer half-life than Ligand B (9.41 hours), which is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.168 and 0.04), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.5 kcal/mol). The difference of 0.1 kcal/mol is negligible.

**Conclusion:**

Ligand A is the more promising candidate. It has a better QED score, lower DILI risk, higher BBB penetration, and a significantly longer half-life. While both have poor solubility and permeability (indicated by negative Caco-2 and solubility values), Ligand A's other advantages outweigh these drawbacks. The binding affinity is comparable, and the slight difference in metabolic stability is less critical than the other factors.

Output:
1
2025-04-17 12:36:01,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.398 Da) is slightly lower, which could be advantageous for permeability. Ligand B (390.952 Da) is also good.

**TPSA:** Ligand A (66.56) is better than Ligand B (49.41). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have a logP around 3 (A: 3.135, B: 3.043), which is optimal for good absorption and distribution.

**H-Bond Donors & Acceptors:** Both ligands have a reasonable number of HBD (A: 2, B: 1) and HBA (both 3), falling within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.619, B: 0.734), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (52.385) has a higher DILI risk than Ligand B (23.187). This is a significant advantage for Ligand B.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand B (95.58) has a higher BBB percentile than Ligand A (84.529).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-5.014 for A, -4.968 for B).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.438 for A, -4.244 for B). This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.915, B: 0.737), which is excellent.

**Microsomal Clearance:** Ligand A (28.177 mL/min/kg) has lower microsomal clearance than Ligand B (47.306 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-32.642 hours) has a much longer in vitro half-life than Ligand B (-17.696 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.274, B: 0.327).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent and a primary driver of potency.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is superior due to its significantly lower DILI risk. The lower metabolic stability and shorter half-life of Ligand B are drawbacks, but the DILI risk is a more critical factor, especially early in drug development. The solubility is poor for both, but can be addressed with formulation strategies. The slightly better TPSA and half-life of Ligand A are not enough to overcome the higher DILI risk.

Output:
1
2025-04-17 12:36:01,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.439 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (73.99) is still acceptable but less optimal.

**logP:** Both ligands (2.922 and 2.17) are 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 (0.915 and 0.819), indicating drug-likeness.

**DILI:** Ligand A (41.877) has a slightly higher DILI risk than Ligand B (12.524), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (78.674) has a better BBB percentile than Ligand B (59.674).

**Caco-2 Permeability:** Ligand A (-4.997) has a slightly better Caco-2 permeability than Ligand B (-4.594).

**Aqueous Solubility:** Ligand A (-3.208) has a slightly better aqueous solubility than Ligand B (-1.145).

**hERG:** Both ligands have very low hERG inhibition liability (0.362 and 0.228), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand A (45.236) has a higher Cl_mic than Ligand B (25.493), meaning it's cleared more quickly and has lower metabolic stability. This is a significant drawback.

**In vitro Half-Life (t1/2):** Ligand B (47.597) has a longer in vitro half-life than Ligand A (41.343), which is beneficial.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.288 and 0.081).

**Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.5), although both are excellent (below -7.0 kcal/mol). The difference of 0.4 kcal/mol is not huge, but is still a factor.

**Conclusion:**

While Ligand A has slightly better permeability and solubility, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer half-life), lower DILI risk, and slightly better binding affinity. The difference in binding affinity is not substantial enough to overcome the metabolic stability concerns with Ligand A. Given the enzyme-kinase target class priority on metabolic stability, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:36:01,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.411 and 362.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.77) is slightly higher than Ligand B (60.85), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.512 and 1.615), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (4/3) counts, well within the limits of 5 and 10, respectively.

**QED:** Ligand A (0.905) has a significantly higher QED score than Ligand B (0.7), indicating a more drug-like profile.

**DILI:** Ligand A (62.699) has a higher DILI risk than Ligand B (19.193). This is a concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (77.433) has a higher BBB percentile than Ligand A (62.233), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the absolute values are similar (-4.924 and -4.592), suggesting similar absorption potential.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. The values are similar (-1.746 and -1.64), suggesting similar solubility challenges.

**hERG Inhibition:** Ligand A (0.042) has a much lower hERG inhibition risk than Ligand B (0.667). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (6.443) has a significantly lower microsomal clearance than Ligand A (17.95), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-3.107) has a longer in vitro half-life than Ligand A (8.119), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.102), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (0.0). This is the most crucial factor for an enzyme inhibitor. A difference of >7 kcal/mol is substantial.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a better QED and lower hERG risk, Ligand B's dramatically superior binding affinity (-7.1 vs 0.0 kcal/mol) and significantly better metabolic stability (lower Cl_mic and longer t1/2) outweigh the drawbacks. The lower DILI risk for Ligand B is also a positive. The similar solubility and permeability profiles are not decisive. The strong binding affinity of Ligand B is likely to overcome any minor ADME issues through optimization.

Output:
1
2025-04-17 12:36:01,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (368.459 Da) is also good.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption (A: 91.81, B: 93.65).

**logP:** Ligand A (3.806) is optimal, while Ligand B (1.037) is on the lower side. A logP below 1 can sometimes hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (7) compared to Ligand A (5), but both are within the acceptable range of <=10.

**QED:** Ligand A (0.829) has a significantly higher QED score than Ligand B (0.541), indicating a more drug-like profile.

**DILI:** Ligand A (48.119) has a lower DILI risk than Ligand B (56.572), both are acceptable, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.459) has better BBB penetration than Ligand B (69.717).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.698) is slightly better than Ligand B (-5.133), but both are concerning.

**Aqueous Solubility:** Both ligands have negative solubility values, which is a major red flag. Ligand B (-2.238) is slightly better than Ligand A (-4.763), but both are very poor.

**hERG Inhibition:** Ligand A (0.378) has a much lower hERG risk than Ligand B (0.167), which is a significant advantage.

**Microsomal Clearance:** Both have similar microsomal clearance values (A: 29.477, B: 28.685), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (18.22 hours) has a longer half-life than Ligand B (10.282 hours), which is preferable.

**P-gp Efflux:** Ligand A (0.197) has lower P-gp efflux than Ligand B (0.022), which is favorable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most critical factor, and the >1.5 kcal/mol advantage outweighs many of the ADME concerns.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the far superior candidate. Its significantly stronger binding affinity (-8.5 vs -0.0 kcal/mol) is a decisive advantage for an enzyme target. It also has a better QED score, lower DILI risk, lower hERG risk, longer half-life, and lower P-gp efflux. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies or further structural modifications. The potency advantage of Ligand A is too significant to ignore.

Output:
0
2025-04-17 12:36:01,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.455 and 358.276 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.12) is better than Ligand B (103.7), both are acceptable but closer to the upper limit for good oral absorption.

**logP:** Ligand A (2.358) is optimal (1-3), while Ligand B (0.11) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both are within acceptable ranges.

**QED:** Both ligands have good QED scores (0.748 and 0.823), indicating good drug-like properties.

**DILI:** Ligand A (58.976) has a lower DILI risk than Ligand B (67.429), both are acceptable but A is preferred.

**BBB:** Both have relatively low BBB penetration (57.774 and 54.246), which is not a major concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-5.383 and -5.2), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both have negative solubility values (-3.057 and -2.168), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Ligand A (0.235) has a lower hERG risk than Ligand B (0.041), which is preferable.

**Microsomal Clearance:** Ligand A (65.74) has a higher (worse) microsomal clearance than Ligand B (-18.849). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-25.284) has a much longer in vitro half-life than Ligand A (26.21), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.138) has lower P-gp efflux than Ligand B (0.004), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has 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 much better binding affinity, lower hERG risk, and lower DILI risk. However, Ligand B has superior metabolic stability and a longer half-life. Both compounds suffer from poor solubility and Caco-2 permeability. The significantly stronger binding affinity of Ligand A is a critical factor for an enzyme inhibitor. While the ADME properties of A are not ideal, optimization efforts could focus on improving solubility and permeability. The weaker binding of Ligand B makes it less likely to be a viable candidate, even with better metabolic stability.

Output:
1
2025-04-17 12:36:01,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.422 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is well below the 140 threshold for good absorption, and even below 90, which is good. Ligand B (97.62) is still under 140, but higher than A.

**logP:** Ligand A (1.659) is within the optimal 1-3 range. Ligand B (0.533) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**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 6. Both are under the 10 limit, but A is preferable.

**QED:** Both ligands have similar QED values (0.783 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A (31.291) has a significantly lower DILI risk than Ligand B (65.917). This is a major advantage for Ligand A.

**BBB:** Ligand A (71.811) has better BBB penetration than Ligand B (55.099), though this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-4.613) has better Caco-2 permeability than Ligand B (-5.194), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-1.927) has better aqueous solubility than Ligand B (-3.184). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.485) has a lower hERG inhibition risk than Ligand B (0.229), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (20.147) has a higher microsomal clearance than Ligand B (14.024), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (28.432) has a significantly longer in vitro half-life than Ligand A (-9.2). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux than Ligand B (0.034), which is preferable.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.2). While A's affinity is good, the 0.8 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A excels in several key areas: DILI risk, solubility, hERG inhibition, and Caco-2 permeability. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a better half-life and slightly better affinity, but its DILI risk and hERG inhibition are concerning. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and safety), the lower DILI and hERG risk of Ligand A are crucial. While the lower half-life is a concern, it might be addressable through structural modifications. The affinity difference is not large enough to overcome the safety concerns with Ligand B.

Output:
0
2025-04-17 12:36:01,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (350.369 Da and 359.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.26) is slightly higher than Ligand B (64.86), but both are well below the 140 threshold for good absorption.

**3. logP:** Ligand A (2.51) is within the optimal 1-3 range. Ligand B (3.373) 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 5 HBAs, and Ligand B has 7. Both are below the 10 limit.

**6. QED:** Ligand A (0.897) has a significantly better QED score than Ligand B (0.744), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (49.011), but both are reasonably acceptable.

**8. BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (87.088) has better BBB penetration than Ligand B (77.511).

**9. Caco-2 Permeability:** Ligand A (-4.875) shows poorer Caco-2 permeability compared to Ligand B (-5.369), indicating potentially lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.615) has slightly better solubility than Ligand B (-3.191).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.656 and 0.261 respectively), which is excellent.

**12. Microsomal Clearance:** Ligand A (40.158) has lower microsomal clearance than Ligand B (47.806), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.18) has a longer in vitro half-life than Ligand B (-3.77), which is a significant advantage.

**14. P-gp Efflux:** Both ligands show similar low P-gp efflux liability (0.205 and 0.267).

**15. Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.0), but the difference is not substantial.

**Overall Assessment:**

Ligand A excels in QED, metabolic stability (lower Cl_mic, longer t1/2), and solubility. While its Caco-2 permeability is slightly lower, its superior metabolic profile and drug-likeness outweigh this drawback. Ligand B has a slightly better binding affinity and Caco-2 permeability, but its lower QED and higher Cl_mic are concerning. Given the enzyme-specific priorities, the improved metabolic stability and drug-like properties of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 12:36:01,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.415 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.96) is better than Ligand B (86.88), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (1.429 and 1.702) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands have a similar number of HBA (6 and 5 respectively), and are below the threshold of 10.

**QED:** Both ligands have similar QED values (0.722 and 0.721), indicating good drug-likeness.

**DILI:** Ligand B (22.683) has a significantly lower DILI risk than Ligand A (50.679), making it more favorable.

**BBB:** Both ligands have reasonable BBB penetration (72.586 and 68.67), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2:** Both ligands 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.

**Solubility:** Both ligands have negative solubility values, again unusual. This is a concern, but similar for both.

**hERG:** Both ligands have very low hERG risk (0.137 and 0.704), which is excellent.

**Microsomal Clearance:** Ligand B (41.706) has lower microsomal clearance than Ligand A (53.818), indicating better metabolic stability, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand B (-4.506) has a significantly longer in vitro half-life than Ligand A (-25.288), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.049 and 0.549).

**Binding Affinity:** Both ligands have the same binding affinity (-9.4 kcal/mol), which is excellent and a primary driver of potency.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is superior due to its significantly lower DILI risk, lower microsomal clearance, and longer in vitro half-life. These factors are crucial for an enzyme inhibitor, as metabolic stability and minimizing toxicity are paramount. The slightly better TPSA and HBD count of Ligand A are outweighed by these more important ADME properties of Ligand B.

Output:
1
2025-04-17 12:36:01,734 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [347.317, 59.75, 3.147, 0., 4., 0.783, 83.753, 81.698, -3.997, -4.092, 0.421, 13.463, 15.382, 0.422, -10.]
**Ligand B:** [366.443, 91.84, 0.351, 1., 6., 0.784, 61.07, 54.75, -4.583, -1.997, 0.118, 38.267, 6.491, 0.023, -8.6]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (347.317) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (59.75) is excellent, well below the 140 threshold. B (91.84) is still reasonable, but higher, potentially impacting absorption.
3. **logP:** A (3.147) is optimal. B (0.351) is quite low, raising concerns about permeability and potentially requiring higher doses.
4. **HBD:** A (0) is good. B (1) is acceptable.
5. **HBA:** A (4) is good. B (6) is acceptable, but higher.
6. **QED:** Both are very similar and good (0.783 and 0.784), indicating good drug-like properties.
7. **DILI:** A (83.753) is a significant concern, indicating high potential for liver injury. B (61.07) is still above the preferred <40, but considerably lower risk than A.
8. **BBB:** A (81.698) is good, but not critical for a non-CNS target like SRC. B (54.75) is lower.
9. **Caco-2:** A (-3.997) is very poor, suggesting very low intestinal absorption. B (-4.583) is also poor, but slightly better.
10. **Solubility:** A (-4.092) is very poor. B (-1.997) is also poor, but better than A.
11. **hERG:** A (0.421) is good, indicating low cardiotoxicity risk. B (0.118) is even better.
12. **Cl_mic:** A (13.463) is reasonable. B (38.267) is higher, suggesting faster metabolism and potentially lower *in vivo* exposure.
13. **t1/2:** A (15.382) is good. B (6.491) is shorter, potentially requiring more frequent dosing.
14. **Pgp:** A (0.422) is good, indicating low efflux. B (0.023) is excellent, suggesting minimal efflux.
15. **Affinity:** A (-10.0) is significantly stronger than B (-8.6). This is a substantial difference (>1.5 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While A has a much better binding affinity, its poor solubility, poor Caco-2 permeability, and *very* high DILI risk are major red flags. B has a lower affinity, but better solubility, lower DILI, and better Pgp efflux. The higher Cl_mic and shorter half-life of B are concerns, but potentially addressable through structural modifications.

**Conclusion:**

Despite the significantly better binding affinity of Ligand A, its poor ADME properties, especially the high DILI risk and poor absorption, make it a less viable drug candidate. Ligand B, while having a weaker binding affinity, presents a more balanced profile with lower toxicity and better predicted absorption. Therefore, I would prioritize **Ligand B** for further optimization.

Output:
1
2025-04-17 12:36:01,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.371 and 345.487 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.16) is higher than Ligand B (62.3). While both are acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (0.782) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (3.191) is within the optimal 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 (0.749 and 0.787), indicating drug-like properties.

**DILI:** Ligand A (67.817) has a higher DILI risk than Ligand B (30.593). This is a significant drawback for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (70.919) has a higher percentile, suggesting better distribution.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, both are quite poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, both are quite poor.

**hERG:** Ligand A (0.353) has a slightly lower hERG risk than Ligand B (0.513), which is favorable.

**Microsomal Clearance:** Ligand A (35.416) has a lower microsomal clearance than Ligand B (56.327), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (20.152) has a longer half-life than Ligand B (-3.54). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux than Ligand B (0.235), which is preferable.

**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 small (0.4 kcal/mol), it's a factor.

**Overall Assessment:**

Ligand B has better logP, lower TPSA, and slightly better binding affinity. However, Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower DILI risk. The difference in binding affinity is minor, and the improvements in ADME properties for Ligand A are substantial, particularly the lower DILI and better metabolic stability. Given the enzyme-specific priorities, Ligand A is the more promising candidate.

Output:
1
2025-04-17 12:36:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.466 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (60.85 and 61.36) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values within the optimal range (2.293 and 2.918).

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD counts (1 each) and HBA counts (3 and 5 respectively), staying within the guidelines.

**QED:** Both ligands have good QED scores (0.537 and 0.77), indicating drug-likeness.

**DILI:** Ligand A (11.516) has a significantly lower DILI risk than Ligand B (37.224), which is a major advantage.

**BBB:** Both have good BBB penetration, but Ligand B (90.229) is slightly better than Ligand A (79.915). This is less critical for a non-CNS target like SRC.

**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, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.558) has a lower hERG inhibition risk than Ligand B (0.902), which is a significant advantage.

**Microsomal Clearance:** Ligand A (45.308) has a lower microsomal clearance than Ligand B (62.809), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.647) has a significantly longer in vitro half-life than Ligand B (-0.058), which is a substantial positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.253 and 0.268).

**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 slightly better binding affinity and BBB penetration, Ligand A is superior overall. The key advantages of Ligand A are its significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and a more favorable in vitro half-life. These factors are particularly important for an enzyme target like SRC kinase, where metabolic stability and minimizing off-target effects (like hERG inhibition and liver toxicity) are crucial. The difference in binding affinity, while noticeable, can potentially be optimized in later stages of drug development. The solubility issue is a concern for both, but manageable.

Output:
0
2025-04-17 12:36:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.849 and 336.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.24) is well below the 140 threshold, suggesting good absorption. Ligand B (99.83) is higher, but still within an acceptable range, though potentially impacting absorption slightly.

**logP:** Ligand A (4.995) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.382) is optimal.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 6. Both are within the acceptable limit of 10, but Ligand B is approaching the upper end.

**QED:** Both ligands have similar QED values (0.717 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (59.907) is moderately risky, while Ligand B (92.168) is significantly higher risk. This is a major concern for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.854) is slightly better than Ligand B (52.268).

**Caco-2 Permeability:** Ligand A (-4.951) is poor, indicating poor intestinal absorption. Ligand B (-5.058) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.327) is poor, which is concerning given its high logP. Ligand B (-3.261) is better, though still not ideal.

**hERG Inhibition:** Ligand A (0.691) has a moderate risk, while Ligand B (0.5) has a lower risk.

**Microsomal Clearance:** Ligand A (62.41) is relatively high, suggesting faster metabolism. Ligand B (-5.598) is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (185.663) is good. Ligand B (0.224) is extremely poor.

**P-gp Efflux:** Ligand A (0.757) is moderate. Ligand B (0.103) is very low, suggesting minimal efflux.

**Binding Affinity:** Ligand A (-9.3) has significantly stronger binding affinity than Ligand B (-8.3). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, it suffers from poor solubility, poor Caco-2 permeability, and moderate DILI risk. Ligand B has better solubility and metabolic stability (excellent Cl_mic and reasonable t1/2), lower hERG risk, and lower P-gp efflux, but its binding affinity is weaker and its DILI risk is high.

The difference in binding affinity (-9.3 vs -8.3 kcal/mol) is significant (1 kcal/mol difference). This advantage can potentially outweigh the ADME liabilities of Ligand A, *provided* that solubility and permeability can be improved through further optimization. The DILI risk is also a concern, but could be mitigated with structural modifications. Ligand B's DILI risk is too high to make it a viable candidate without significant modification.

Output:
0
2025-04-17 12:36:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (489.233 Da) is higher, but still acceptable. Ligand B (374.937 Da) is preferable.

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand A (45.67 A^2) is slightly higher than Ligand B (41.13 A^2), but both are good.

**logP:** Both ligands have logP values between 3.5 and 4.0, which is slightly high but still within a reasonable range. Ligand A (3.574) is slightly better than Ligand B (4.044).

**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 scores (A: 0.645, B: 0.847). Ligand B is better.

**DILI:** Ligand A has a DILI risk of 53.781, while Ligand B has 35.595. Ligand B is significantly better in terms of liver toxicity risk.

**BBB:** Both have high BBB penetration (A: 87.321, B: 80.38). This isn't a primary concern for a kinase inhibitor, but it's not detrimental.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.523) is slightly better than Ligand B (-5.21). This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-3.081) is slightly better than Ligand B (-4.466). This is a significant drawback for both.

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.798, B: 0.719).

**Microsomal Clearance:** Ligand A has a lower Cl_mic (32.438 mL/min/kg) than Ligand B (68.803 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (45.48 hours) than Ligand B (37.055 hours). This is another advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.715, B: 0.567).

**Binding Affinity:** Both have excellent binding affinities (A: -8.9 kcal/mol, B: -9.1 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B has a better QED, lower DILI risk, and slightly better binding affinity. However, Ligand A has significantly better metabolic stability (lower Cl_mic, longer half-life), slightly better solubility and permeability, and a better logP. Given the enzyme-specific priorities, metabolic stability and half-life are crucial. The small advantage in binding affinity of Ligand B is unlikely to outweigh the metabolic liabilities. The poor solubility and permeability are concerning for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 12:36:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.375 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.28) is slightly above the preferred <90 for CNS penetration, but acceptable for a non-CNS target like SRC. Ligand B (88.39) is excellent.

**logP:** Both ligands have good logP values (1.422 and 1.353), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (2 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED scores (0.85 and 0.777), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (91.431) than Ligand B (69.717). This is a major concern for Ligand A.

**BBB:** This is less critical for SRC, but Ligand A (76.541) has a better BBB score than Ligand B (61.691).

**Caco-2 Permeability:** Ligand A (-4.783) shows poor permeability, while Ligand B (-5.452) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.266 and -2.723). This is a significant drawback for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.05) has a very low hERG risk, which is excellent. Ligand B (0.301) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-2.366) has a lower (better) microsomal clearance than Ligand B (36.407), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (29.902) has a longer half-life than Ligand B (11.061), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.036).

**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 override other factors.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Ligand A's extremely high DILI risk and poor Caco-2 permeability are major red flags. While Ligand B also has poor solubility, this is a more manageable issue than a high DILI risk. The better metabolic stability and half-life of Ligand A are outweighed by the safety concerns.

Output:
1
2025-04-17 12:36:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (75.44). Both are below the 140 A^2 threshold for good absorption, but lower is generally preferred.

**logP:** Both ligands (2.559 and 2.858) 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 (3) is lower than Ligand B (4), both are acceptable (<=10).

**QED:** Ligand B (0.858) has a significantly better QED score than Ligand A (0.471), indicating a more drug-like profile.

**DILI:** Ligand A (22.373) has a much lower DILI risk than Ligand B (41.373), which is a substantial advantage.

**BBB:** Ligand B (84.606) has a higher BBB penetration percentile than Ligand A (60.644). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.128 and -5.013), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.659 and -2.58), also concerning and suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.501 and 0.357), which is good.

**Microsomal Clearance:** Ligand A (38.438) has a lower microsomal clearance than Ligand B (47.424), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.054 hours) has a shorter half-life than Ligand B (-19.822 hours - negative value is unusual and likely an error, but we'll assume it means very long).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.307 and 0.282).

**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 has a superior binding affinity and QED score, and a potentially longer half-life. However, it has a higher DILI risk and a higher Caco-2 value (less negative). Ligand A has a lower DILI risk and better metabolic stability. The poor solubility and permeability (negative Caco-2 and solubility values) are concerning for both, but the significantly stronger binding affinity of Ligand B is a major advantage for an enzyme target like SRC. Given the importance of potency in enzyme inhibition, and the relatively minor impact of the other differences, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:36:01,736 - INFO - Batch 143 complete. Total preferences: 2288
2025-04-17 12:36:01,736 - INFO - Processing batch 144/512...
2025-04-17 12:36:41,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (369.799 and 367.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.37) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (82.97) is still under 140, but less optimal than A.

**3. logP:** Ligand A (4.894) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.136) 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 3 HBAs, and Ligand B has 6. Both are below the 10 threshold, but B is closer to the upper limit.

**6. QED:** Both ligands have similar QED values (0.837 and 0.815), indicating good drug-likeness.

**7. DILI:** Ligand A (72.392) has a higher DILI risk than Ligand B (47.15). This is a significant concern.

**8. BBB:** BBB is not a primary concern for an oncology target, but Ligand A (96.2) has a much higher percentile than Ligand B (50.872).

**9. Caco-2 Permeability:** Ligand A (-4.444) has a more negative Caco-2 value, indicating better permeability than Ligand B (-4.641).

**10. Aqueous Solubility:** Ligand A (-5.52) has a more negative solubility value, indicating lower solubility than Ligand B (-0.804).

**11. hERG Inhibition:** Ligand A (0.661) has a higher hERG inhibition risk than Ligand B (0.139). This is a significant concern.

**12. Microsomal Clearance:** Ligand A (37.893) has higher microsomal clearance than Ligand B (7.575), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (7.612) has a longer in vitro half-life than Ligand A (-4.228), indicating better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.464) has lower P-gp efflux than Ligand B (0.104), which is favorable.

**15. 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 factor.

**Overall Assessment:**

Ligand A has better permeability and P-gp efflux, but suffers from higher DILI risk, hERG inhibition, and lower metabolic stability (higher clearance, shorter half-life) and solubility. Ligand B has a slightly better binding affinity, much lower DILI and hERG risk, and better metabolic stability. Given the priorities for an enzyme target (potency, metabolic stability, solubility, hERG risk), **Ligand B is the more promising candidate.** The slightly lower permeability is less concerning than the significant safety and metabolic liabilities of Ligand A.

Output:
1
2025-04-17 12:36:41,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.418 and 378.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.34) is well below the 140 threshold for good absorption, while Ligand B (133.24) is closer to the limit but still acceptable.

**logP:** Ligand A (2.918) is within the optimal 1-3 range. Ligand B (-1.408) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is favorable. Ligand B (HBD=3, HBA=7) is also acceptable, though slightly higher in HBA.

**QED:** Both ligands have reasonable QED scores (A: 0.83, B: 0.535), indicating good drug-like properties.

**DILI:** Ligand A (37.767) has a lower DILI risk than Ligand B (41.062), both being acceptable (<40 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.541) has better BBB penetration than Ligand B (33.967).

**Caco-2 Permeability:** Ligand A (-4.654) has poor Caco-2 permeability, which is concerning. Ligand B (-5.973) is similarly poor.

**Aqueous Solubility:** Ligand A (-3.59) has slightly better solubility than Ligand B (-1.23). Both are poor.

**hERG Inhibition:** Ligand A (0.324) has a significantly lower hERG risk than Ligand B (0.111), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (14.817 mL/min/kg) has a higher, and thus worse, clearance than Ligand B (-21.918 mL/min/kg, negative value indicates higher stability). This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (31.657 hours) has a longer half-life than Ligand B (23.703 hours), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.123, B: 0.018).

**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 A has a better binding affinity and lower hERG risk, but suffers from poor Caco-2 permeability and higher metabolic clearance. Ligand B has better metabolic stability (lower Cl_mic, longer half-life) and a slightly better solubility, but has a lower binding affinity and a higher hERG risk. Given the enzyme-specific priorities, metabolic stability is crucial. The 0.4 kcal/mol difference in binding affinity can be overcome with optimization, while a high hERG risk is a major red flag. The poor Caco-2 permeability of both is a concern, but can be addressed through formulation strategies.

Output:
1
2025-04-17 12:36:41,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.336 Da) is slightly higher than Ligand B (371.796 Da), but both are acceptable.

**TPSA:** Ligand A (50.36) is well below the 140 threshold for oral absorption. Ligand B (91.76) is also below the threshold, but closer to it.

**logP:** Ligand A (4.277) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.825) is within the optimal range (1-3).

**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).

**QED:** Both ligands have similar QED values (0.723 and 0.744), indicating good drug-likeness.

**DILI:** Ligand A (49.438) has a slightly higher DILI risk than Ligand B (57.115), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (69.252 and 68.941). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**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 (0.912) has a slightly higher hERG risk than Ligand B (0.192). Lower is better here.

**Microsomal Clearance:** Ligand A (105.162) has a higher microsomal clearance than Ligand B (-1.662). This suggests Ligand B is more metabolically stable, which is a high priority for enzymes.

**In vitro Half-Life:** Ligand A (19.449 hours) has a longer half-life than Ligand B (-28.565 hours). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Ligand A (0.507) has lower P-gp efflux than Ligand B (0.038), which is preferable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better DILI score and P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.4 vs -7.1 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic, although the negative value is concerning and needs further investigation) and a more favorable logP. The solubility and permeability issues are shared by both, but the potency advantage of Ligand B is substantial.

Output:
1
2025-04-17 12:36:41,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (372.46 and 363.933 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have similar TPSA values (41.05 and 41.29 A^2), which are acceptable for oral absorption (<=140 A^2).

**3. logP:** Both ligands have similar logP values (3.97 and 3.965), which are optimal (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 5 HBA, and Ligand B has 4 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.847) has a higher QED score than Ligand B (0.733), suggesting a more drug-like profile.

**7. DILI:** Ligand A (61.419) has a higher DILI risk than Ligand B (8.104). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (92.71) has a higher BBB penetration percentile than Ligand B (74.952). While not a primary concern for a kinase inhibitor, it could be a bonus.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.854 and -4.89), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.672 and -3.901), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.831) has a slightly higher hERG inhibition liability than Ligand B (0.947), but both are relatively low risk.

**12. Microsomal Clearance:** Ligand B (51.71 mL/min/kg) has lower microsomal clearance than Ligand A (57.729 mL/min/kg), indicating better metabolic stability. This is a positive for Ligand B.

**13. In vitro Half-Life:** Ligand B (97.181 hours) has a significantly longer in vitro half-life than Ligand A (14.756 hours). This is a major advantage for Ligand B, reducing dosing frequency.

**14. P-gp Efflux:** Ligand A (0.271) has lower P-gp efflux liability than Ligand B (0.759), which could lead to better bioavailability.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in key areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), and stronger binding affinity. The lower DILI risk for Ligand B is also a critical advantage. The slightly higher P-gp efflux of Ligand B is a minor concern compared to the benefits it offers.



Output:
1
2025-04-17 12:36:41,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.941 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.4) is significantly better than Ligand B (69.64). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (3.941 and 2.336), falling within the 1-3 range. Ligand A is slightly higher, which *could* pose a minor solubility issue, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=3). Both are within acceptable limits, but fewer H-bonds can improve permeability.

**QED:** Both ligands have good QED scores (0.82 and 0.832), indicating good drug-like properties.

**DILI:** Ligand A (30.903) has a much lower DILI risk than Ligand B (20.744). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.009) has a higher BBB percentile than Ligand B (68.864), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.048) has a better Caco-2 permeability than Ligand B (-4.745), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.646) has better aqueous solubility than Ligand B (-2.902). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.627) has a lower hERG risk than Ligand B (0.449). Lower hERG is crucial to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (50.497) has a higher microsomal clearance than Ligand B (9.811). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-13.04) has a significantly longer in vitro half-life than Ligand A (-0.546). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.607) has lower P-gp efflux than Ligand B (0.157), which is favorable.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-8.0). While both are excellent, the difference is minimal.

**Overall Assessment:**

Ligand B has a significant advantage in metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A excels in several other critical areas: lower DILI risk, better solubility, lower hERG risk, and better Caco-2 permeability. The slightly better binding affinity of Ligand A is also a plus. Given the importance of metabolic stability for kinases, and the substantial difference in half-life, Ligand B is the better candidate.

Output:
1
2025-04-17 12:36:41,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.463 and 354.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.59) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (133.99) is still under 140, but closer to the upper limit, potentially indicating slightly reduced permeability.

**logP:** Ligand A (0.92) is slightly below the optimal 1-3 range, but acceptable. Ligand B (-1.961) is considerably lower, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is within the preferred limits. Ligand B (3 HBD, 8 HBA) is also acceptable, but slightly higher, potentially impacting permeability.

**QED:** Ligand A (0.825) has a strong drug-like profile. Ligand B (0.484) is below the 0.5 threshold, indicating a less desirable overall drug-likeness.

**DILI:** Ligand A (19.038) has a very low DILI risk. Ligand B (39.705) is higher, but still relatively low.

**BBB:** Ligand A (81.582) shows reasonable BBB penetration, while Ligand B (36.06) is low. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.146 and -5.258), which is unusual and suggests poor permeability *in vitro*. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.7 and -0.112), also unusual and concerning. This suggests poor aqueous solubility, which could lead to bioavailability issues.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.436 and 0.151).

**Microsomal Clearance:** Ligand A (-7.222) exhibits excellent metabolic stability (low clearance). Ligand B (-3.685) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (11.173 hours) has a good in vitro half-life. Ligand B (9.779 hours) is slightly lower, but still reasonable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.014 and 0.043).

**Binding Affinity:** Both ligands have strong binding affinities (-8.4 and -8.7 kcal/mol). Ligand B is slightly better (-8.7 vs -8.4), but the difference is small.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While both have strong binding affinities, Ligand A excels in QED, DILI risk, metabolic stability (Cl_mic), and has a better TPSA. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand A, particularly its metabolic stability and drug-likeness, makes it the preferred choice. The slightly better affinity of Ligand B is unlikely to overcome the significant drawbacks in its ADME properties.

Output:
0
2025-04-17 12:36:41,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.495 and 372.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (81.75 and 84.5) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.596) is a bit low, potentially hindering permeation. Ligand B (1.875) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.563 and 0.765), indicating drug-like properties.

**DILI:** Ligand A (9.655) has a much lower DILI risk than Ligand B (60.217), which is a significant advantage.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC kinase.

**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:** Ligand A (-1.104) has slightly better (less negative) solubility than Ligand B (-3.389).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.248 and 0.38), which is positive.

**Microsomal Clearance:** Ligand A (2.585 mL/min/kg) has significantly lower microsomal clearance than Ligand B (52.664 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.418 hours) has a shorter half-life than Ligand B (-5.794 hours - negative value is odd, but implies a longer half-life).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.006 and 0.161).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol) - a difference of 1.5 kcal/mol. This is a substantial advantage.

**Conclusion:**

While Ligand A has better DILI, solubility, and metabolic stability, the significantly stronger binding affinity of Ligand B (-8.7 vs -7.2 kcal/mol) outweighs these ADME drawbacks, especially for an enzyme target where potency is paramount. The difference in binding affinity is substantial enough to overcome the higher DILI risk and worse metabolic stability of Ligand B.

Output:
1
2025-04-17 12:36:41,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.439 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.21) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (76.02) is excellent, well below 140.

**logP:** Ligand A (-1.28) is a bit low, potentially hindering permeation. Ligand B (2.068) is within the optimal 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 similar QED values (0.443 and 0.472), indicating moderate drug-likeness.

**DILI:** Ligand A (22.334) has a significantly lower DILI risk than Ligand B (50.136), which is a major advantage.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (57.154) has a higher BBB value than Ligand A (30.012), but this is less critical here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.775 and -4.742), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret directly.

**Aqueous Solubility:** Ligand A (-0.431) has slightly better solubility than Ligand B (-3.662), though both are poor. Solubility is a concern for both, but less so than metabolic stability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.052 and 0.078).

**Microsomal Clearance:** Ligand A (-25.485) exhibits *much* lower microsomal clearance (better metabolic stability) than Ligand B (28.896). This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-2.737) has a slightly longer half-life than Ligand B (2.13), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.095).

**Binding Affinity:** Ligand A (-7.4 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 the overall preference for Ligand A.

**Conclusion:**

Ligand A is the more promising candidate. Its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP and solubility. The slightly better binding affinity is a bonus. While both have poor Caco-2 permeability, the metabolic advantages of Ligand A are more critical for an enzyme inhibitor.

Output:
0
2025-04-17 12:36:41,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.439 and 380.897 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (53.76 and 51.66) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.473 and 3.433) are 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.

**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 reasonable QED scores (0.848 and 0.69), indicating good drug-like properties.

**7. DILI:** Ligand A (31.059) has a significantly lower DILI risk than Ligand B (52.772). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (74.835 and 83.094). While not a primary concern for a kinase inhibitor, it's not detrimental.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.806 and -4.636). 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 (-2.462 and -3.786). This is concerning, as poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.59 and 0.57).

**12. Microsomal Clearance:** Ligand B (81.517) has a much higher microsomal clearance than Ligand A (28.907). This suggests Ligand B will be metabolized more quickly, leading to lower exposure.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (39.951 and 39.829 hours).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.29 and 0.443).

**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 not huge (less than 1.5 kcal/mol), it's a positive factor for Ligand A.

**Overall Assessment:**

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. While both ligands have poor predicted solubility and permeability, the other advantages of Ligand A outweigh this concern. The lower DILI risk is particularly important, as liver toxicity is a common issue in drug development.

Output:
0
2025-04-17 12:36:41,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (348.447 and 339.355 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.21) is better than Ligand B (112.91). Both are below 140, but A is closer to the optimal threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.759 and 1.414), 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 (5 each), being less than 10.

**6. QED:** Both ligands have reasonable QED scores (0.783 and 0.65), indicating good drug-like properties.

**7. DILI:** Ligand A (41.489) has a significantly lower DILI risk than Ligand B (81.621). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.88) is better than Ligand B (45.909), but neither is a strong point.

**9. Caco-2 Permeability:** Ligand A (-4.817) is better than Ligand B (-5.582), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.554) is better than Ligand B (-3.284), which is crucial for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition liability than Ligand B (0.403), reducing cardiotoxicity risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (47.467) has a higher Cl_mic than Ligand B (18.743), indicating *lower* metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand A (-7.369) has a longer half-life than Ligand B (-7.151).

**14. P-gp Efflux:** Ligand A (0.034) has lower P-gp efflux liability than Ligand B (0.177), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5). However, the difference is less than 1.5 kcal/mol, so it doesn't completely overshadow the other ADME advantages of Ligand A.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has slightly better affinity, Ligand A excels in DILI risk, solubility, hERG, and P-gp efflux. The lower Cl_mic for Ligand A is a concern, but the other advantages, particularly the significantly lower DILI risk, outweigh this drawback.

Output:
0
2025-04-17 12:36:41,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.491 and 360.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.43) is higher than Ligand B (66.91). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Ligand A (1.014) is within the optimal range, while Ligand B (4.332) is high. High logP can lead to solubility issues and off-target effects.

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

**QED:** Both ligands have similar QED values (0.636 and 0.619), indicating good drug-likeness.

**DILI:** Ligand A (38.465) has a significantly lower DILI risk than Ligand B (51.028). This is a substantial advantage.

**BBB:** Ligand A (51.377) has a lower BBB penetration than Ligand B (73.672). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.221 and -5.319), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.229 and -3.971), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.093) has a much lower hERG inhibition risk than Ligand B (0.792). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (25.988) has a lower microsomal clearance than Ligand B (83.343), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (64.312) has a significantly longer in vitro half-life than Ligand A (8.628). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.013) has a much lower P-gp efflux liability than Ligand B (0.742), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While both have poor solubility and permeability, Ligand A exhibits significantly better safety profiles (lower DILI and hERG risk) and better metabolic stability (lower Cl_mic). The slightly better binding affinity and lower P-gp efflux also contribute to its favorability. Ligand B's longer half-life is a positive, but is outweighed by the higher risks and poorer metabolic profile.

Output:
0
2025-04-17 12:36:41,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 and 349.52 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.24) is significantly higher than Ligand B (43.86). While both are under 140, the lower TPSA of Ligand B is preferable for absorption.

**logP:** Ligand A (1.023) is slightly lower than the optimal 1-3 range, while Ligand B (2.378) is well within it. Ligand B's logP is more favorable for both permeability and reducing off-target effects.

**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 (0.866 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (10.702) has a much lower DILI risk than Ligand B (18.728), which is a significant advantage.

**BBB:** Ligand A (86.468) has better BBB penetration than Ligand B (78.209), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.456) has worse Caco-2 permeability than Ligand B (-4.334), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.015) has slightly better aqueous solubility than Ligand B (-2.049). Solubility is important for formulation and bioavailability.

**hERG:** Ligand A (0.72) has a lower hERG risk than Ligand B (0.456), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (15.195) has significantly lower microsomal clearance than Ligand B (56.289), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (25.046) has a much longer in vitro half-life than Ligand B (1.101), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.329) has lower P-gp efflux than Ligand B (0.167), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.4) has a stronger binding affinity than Ligand A (-7.8). The difference is 0.6 kcal/mol, which is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A demonstrates a superior ADMET profile, with lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better P-gp efflux, and a slightly better solubility. Ligand B has a better logP and a significantly stronger binding affinity. Given the enzyme-specific priorities, the improved metabolic stability and safety profile of Ligand A are highly valuable. While the affinity difference is notable, the ADMET advantages of Ligand A are more critical for overall drug development success.

Output:
0
2025-04-17 12:36:41,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 Da and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.53) is better than Ligand B (56.15), being below the 140 threshold for good oral absorption. Ligand B is very good, and potentially better for cell permeability.

**logP:** Ligand A (-0.061) is slightly low, potentially hindering permeation. Ligand B (4.13) is high, potentially causing solubility/off-target issues.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.668, B: 0.842), indicating drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (A: 21.908, B: 58.976), but Ligand B is significantly higher.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the compounds themselves. It's difficult to interpret without further information.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual and problematic.

**hERG Inhibition:** Ligand A (0.073) has a much lower hERG risk than Ligand B (0.277), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-6.492) has a negative clearance, which is not physically possible and indicates a problem with the prediction. Ligand B (59.657) has high clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (17.3) has a reasonable half-life. Ligand B (23.469) is also acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.009, B: 0.448).

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.3, B: -9.9). Ligand B is 1.6 kcal/mol better, which is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from a high logP, high DILI risk, and high microsomal clearance. Ligand A has a lower binding affinity but better logP, lower hERG risk, and a more reasonable (though still problematic) clearance. The negative values for Caco-2 and solubility are concerning for both, but the hERG and metabolic stability issues with Ligand B are more critical. Given the enzyme-specific priorities, the binding affinity advantage of Ligand B is substantial enough to outweigh the other drawbacks, *assuming* the solubility and permeability issues can be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 12:36:41,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.395 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 140 threshold for oral absorption. Ligand B (98.14) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.363) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.723) is quite low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 1 HBA, which is ideal. Ligand B has 2 HBD and 6 HBA, which is acceptable, but the higher HBA count could slightly reduce permeability.

**QED:** Both ligands have similar QED values (0.593 and 0.605), indicating good drug-likeness.

**DILI:** Ligand A (29.159) has a lower DILI risk than Ligand B (23.846), which is preferable.

**BBB:** Ligand A (95.076) shows excellent BBB penetration, while Ligand B (63.707) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a bonus for A.

**Caco-2 Permeability:** Ligand A (-4.519) has poor Caco-2 permeability, while Ligand B (-5.377) is even worse. Both are concerning.

**Aqueous Solubility:** Ligand A (-4.363) has poor solubility, consistent with its high logP. Ligand B (-0.667) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.929) has a low hERG risk, which is excellent. Ligand B (0.126) also has a very low hERG risk, which is also excellent.

**Microsomal Clearance:** Ligand A (48.86) has a higher microsomal clearance than Ligand B (17.976), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-10.19) has a very short half-life, further confirming its poor metabolic stability. Ligand B (-2.036) has a better, though still not ideal, half-life.

**P-gp Efflux:** Ligand A (0.672) has moderate P-gp efflux, while Ligand B (0.013) has very low P-gp efflux, which is beneficial.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 0.2 kcal/mol difference, while present, is unlikely to overcome the substantial ADME deficiencies of Ligand A.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its poor Caco-2 permeability, high microsomal clearance, short half-life, and relatively high logP make it a less desirable candidate. Ligand B, while having a lower binding affinity, presents a more balanced profile with lower clearance, better P-gp efflux, and a slightly better solubility profile. Given the enzyme-kinase focus, metabolic stability and solubility are critical.

Output:
1
2025-04-17 12:36:41,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.439 Da) is slightly higher than Ligand B (353.423 Da), but both are acceptable.

**TPSA:** Ligand A (89.98) is excellent, well below the 140 threshold for oral absorption. Ligand B (117.33) is still reasonable, but less optimal.

**logP:** Ligand A (1.319) is within the optimal range (1-3). Ligand B (-0.936) is slightly below 1, which *could* indicate potential permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though the 2 HBDs might slightly reduce permeability compared to Ligand A.

**QED:** Both ligands have good QED scores (A: 0.555, B: 0.584), indicating generally drug-like properties.

**DILI:** Ligand A (78.17) has a higher DILI risk than Ligand B (17.759). This is a significant concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (A: 65.529, B: 69.097), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.505) has poor Caco-2 permeability, which is a major red flag. Ligand B (-5.733) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.843) has poor aqueous solubility. Ligand B (-0.969) is better, but still not ideal.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.241, B: 0.049), which is excellent.

**Microsomal Clearance:** Ligand A (103.747) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (3.324) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-48.248) has a very short in vitro half-life, consistent with the high clearance. Ligand B (-3.85) has a better half-life, but still not outstanding.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.303, B: 0.005), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.2 kcal/mol, B: -8.6 kcal/mol). Ligand A is slightly better (-9.2 vs -8.6), but the difference is less than 1.5 kcal/mol and therefore less impactful given the other ADME concerns.

**Conclusion:**

Despite Ligand A's slightly better binding affinity, its significantly higher DILI risk, poor Caco-2 permeability, poor aqueous solubility, and higher microsomal clearance make it a much less desirable candidate. Ligand B, while having a slightly lower affinity, exhibits a much more favorable ADME profile, particularly regarding metabolic stability (low Cl_mic) and lower DILI risk. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 12:36:41,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 Da and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is slightly higher than Ligand B (67.23), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.175 and 1.568, respectively), falling within the 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 within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.643 and 0.822, respectively), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (8.298) has a significantly lower DILI risk than Ligand B (51.648). This is a major advantage for Ligand A.

**BBB:** Ligand A (71.384) and Ligand B (82.435) both have good BBB penetration, but Ligand B is better. However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.66 and -4.761). These values are unusual and suggest poor permeability. However, these are likely reported as logP values and are therefore negative.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.287 and -2.581). These values are also unusual and suggest poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.599 and 0.41, respectively). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (32.563) has a higher microsomal clearance than Ligand B (22.258). This suggests lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (-7.667) has a longer in vitro half-life than Ligand A (-6.061), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.102 and 0.128, respectively).

**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 significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly lower DILI risk and a slightly better binding affinity, which are key advantages for an oncology drug targeting a kinase. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better BBB penetration, the lower DILI risk and stronger binding of Ligand A are more critical. The solubility and permeability issues are similar for both compounds and would require further investigation and potential formulation strategies.

Output:
0
2025-04-17 12:36:41,614 - INFO - Batch 144 complete. Total preferences: 2304
2025-04-17 12:36:41,614 - INFO - Processing batch 145/512...
2025-04-17 12:37:22,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (352.519 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (58.64 and 53.76) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have a logP around 3.1 (3.127 and 3.193), which is optimal.

**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 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.693 and 0.771), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 8.414, which is very low and excellent. Ligand B has a DILI risk of 17.798, still relatively low, but higher than Ligand A.

**8. BBB:** Both ligands have good BBB penetration (74.564 and 77.2). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.237 and -4.535). 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 (-3.02 and -3.269), indicating poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Ligand A has a very low hERG risk (0.464), which is excellent. Ligand B has a slightly higher hERG risk (0.692), but still relatively low.

**12. Microsomal Clearance:** Ligand A has a high microsomal clearance (100.365), indicating poor metabolic stability. Ligand B has a much lower clearance (62.655), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a very short in vitro half-life (-4.723), consistent with the high clearance. Ligand B has a significantly longer half-life (15.554).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.088 and 0.41).

**15. Binding Affinity:** Ligand B has a significantly better binding affinity (-7.4 kcal/mol) compared to Ligand A (-0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

While both ligands have acceptable physicochemical properties, Ligand B is significantly better due to its much stronger binding affinity and superior metabolic stability (lower Cl_mic, longer t1/2). Ligand A's extremely short half-life and weak binding are major drawbacks. The solubility issues are concerning for both, but can potentially be addressed with formulation strategies. The slightly higher DILI risk for Ligand B is less concerning than the poor pharmacokinetics of Ligand A.

Output:
1
2025-04-17 12:37:22,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 343.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.82) is higher than Ligand B (55.63). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (3.068) is within the optimal 1-3 range. Ligand B (4.219) is slightly higher, potentially increasing off-target effects 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.

**QED:** Both ligands have good QED scores (0.742 and 0.903), indicating good drug-like properties.

**DILI:** Ligand A (12.33) has a significantly lower DILI risk than Ligand B (49.283), which is a major advantage.

**BBB:** Both have high BBB penetration (84.606 and 88.174), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the value is slightly less negative for Ligand A (-4.682 vs -4.907).

**Aqueous Solubility:** Ligand A (-1.623) is better than Ligand B (-4.618), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.79) has a slightly higher hERG risk than Ligand B (0.491), but both are relatively low.

**Microsomal Clearance:** Ligand A (-9.828) has *much* lower microsomal clearance than Ligand B (46.825), indicating significantly better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-2.289) has a negative half-life, which is unusual and suggests rapid metabolism or instability. Ligand B (34.267) has a good in vitro half-life. This is a significant drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.173) has lower P-gp efflux than Ligand B (0.604), which is favorable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

While Ligand B has a better binding affinity and in vitro half-life, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, and better solubility. The superior metabolic stability and safety profile of Ligand A are crucial for an enzyme target like SRC kinase. The slightly weaker binding of Ligand A might be overcome with further optimization, while mitigating the poor permeability would be essential. The poor permeability of both is a concern, but the other advantages of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 12:37:22,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.406 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.99) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.222 and 3.89), within the 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but not drastically.

**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 (0.586 and 0.838), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 54.478, while Ligand B has 7.057. This is a significant difference; Ligand B has a much lower risk of liver injury.

**BBB:** Ligand A has a BBB penetration of 68.67, while Ligand B has 83.288. BBB is not a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.002 and -4.668). This is unusual and suggests poor permeability. However, these are relative scales and the absolute values are not directly comparable without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.949 and -3.748), again suggesting poor solubility. Similar to Caco-2, the scale is important, but both are likely to have formulation challenges.

**hERG Inhibition:** Ligand A has a hERG risk of 0.814, while Ligand B has 0.643. Both are relatively low, but Ligand B is slightly better.

**Microsomal Clearance:** Ligand A has a Cl_mic of 28.243, while Ligand B has 57.215. Ligand A has significantly better metabolic stability (lower clearance).

**In vitro Half-Life:** Ligand A has a half-life of -5.908, while Ligand B has -17.566. Again, these are relative scales, but both suggest short half-lives. Ligand B is considerably worse.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.366, while Ligand B has 0.085. Ligand B has much lower P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-9.4 and -8.4 kcal/mol). Ligand A has a 1 kcal/mol advantage, which is significant.

**Conclusion:**

Ligand A has a better binding affinity and metabolic stability, while Ligand B has a much lower DILI risk and P-gp efflux. The binding affinity difference is substantial, and for an enzyme target like SRC kinase, potency is paramount. The metabolic stability of Ligand A is also a significant advantage. While Ligand B has a better safety profile regarding DILI, the potency and metabolic stability of Ligand A outweigh this concern, especially considering further optimization could potentially mitigate the DILI risk. The solubility and permeability issues are shared by both and would need to be addressed in subsequent optimization.

Output:
0
2025-04-17 12:37:22,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.327 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.09) is slightly above the preferred <140, but acceptable. Ligand B (54.34) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.277 and 2.59), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 9 HBA, which is acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.518 and 0.895), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (97.867), which is a major concern. Ligand B has a low DILI risk (26.095), a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (76.27) is better than Ligand B (65.607).

**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 (-2.571 and -3.134). This is a significant drawback for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A shows very low hERG inhibition risk (0.165), while Ligand B is slightly higher (0.39), but still acceptable.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (80.8) than Ligand B (25.281), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (7.055 hours) compared to Ligand A (-23.026 hours), indicating better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.467 and 0.103).

**Binding Affinity:** Ligand B has a much stronger binding affinity (-7.9 kcal/mol) compared to Ligand A (-9.8 kcal/mol). This is a substantial advantage for Ligand B.

**Conclusion:**

Despite similar molecular weights and logP values, Ligand B is significantly more promising. Its lower DILI risk, better metabolic stability (lower Cl_mic, longer half-life), and *much* stronger binding affinity outweigh the slightly lower BBB penetration and solubility concerns. The poor solubility of both compounds is a concern, but is a formulation challenge rather than a fundamental flaw. Ligand A's extremely high DILI risk is a deal-breaker.

Output:
1
2025-04-17 12:37:22,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.909 Da) is slightly higher than Ligand B (348.374 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (89.54) is slightly higher than Ligand B (78.87), but both are good.

**logP:** Ligand A (3.345) is optimal, while Ligand B (1.287) is on the lower side. A logP too low can hinder 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.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.79, Ligand B: 0.575), indicating drug-like properties.

**DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (35.324). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (38.426) and Ligand B (56.611) are both relatively low.

**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.

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

**hERG:** Ligand A (0.27) has a slightly better hERG profile than Ligand B (0.411), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-1.527) has a *much* lower (better) microsomal clearance than Ligand A (44.974). This suggests significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A (48.904) has a longer half-life than Ligand B (18.332). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux liability than Ligand B (0.091), which is favorable.

**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 substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and longer half-life, but suffers from a significantly higher DILI risk and poorer metabolic stability (higher Cl_mic). Ligand B has a lower DILI risk, much better metabolic stability, and a reasonable half-life, but its binding affinity is slightly weaker and logP is lower. The poor solubility and Caco-2 values for both are concerning, but the difference in DILI and Cl_mic are more critical for an enzyme target. Given the importance of metabolic stability for kinase inhibitors, and the significant DILI risk associated with Ligand A, I would favor Ligand B.

Output:
1
2025-04-17 12:37:22,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.455 and 342.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (57.5) is slightly higher than Ligand B (40.62). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (2.218 and 2.984), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.847) has a slightly higher QED than Ligand B (0.74), indicating better overall drug-likeness.

**DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (17.72). Both are good, but A is better.

**BBB:** Ligand A (51.997) has a lower BBB penetration percentile than Ligand B (71.656). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.868) has lower Caco-2 permeability than Ligand B (-4.74). Both are negative, suggesting poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-2.124) has slightly better aqueous solubility than Ligand B (-3.289). Both are negative, suggesting poor solubility.

**hERG:** Ligand A (0.844) has a slightly higher hERG risk than Ligand B (0.335). B is significantly better here.

**Microsomal Clearance:** Ligand A (31.062) has a lower microsomal clearance than Ligand B (63.316), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (68.92) has a longer in vitro half-life than Ligand B (-9.169). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.573) has lower P-gp efflux than Ligand B (0.158). This is better for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.3 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2), DILI risk, QED, and P-gp efflux. Ligand B has slightly better Caco-2 permeability, BBB, and hERG risk, and a marginally better binding affinity. However, the superior metabolic stability and lower DILI risk of Ligand A are more critical for an enzyme target like SRC kinase. The slight solubility and permeability issues of A can be addressed with formulation strategies.

Output:
1
2025-04-17 12:37:22,417 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.547 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (87.74). A TPSA under 140 is desired for oral absorption, and both meet this, but A is preferable.

**logP:** Ligand A (4.349) is higher than the optimal range of 1-3, potentially causing solubility issues. Ligand B (0.825) is quite low, which could hinder permeation.

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

**H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 4. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have similar QED values (0.607 and 0.676), indicating good drug-likeness.

**DILI:** Ligand A (21.404) has a much lower DILI risk than Ligand B (19.969), indicating a safer profile.

**BBB:** Ligand A (64.211) has a better BBB penetration percentile than Ligand B (59.364), though neither are particularly high. This isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.605) has better Caco-2 permeability than Ligand B (-4.829).

**Aqueous Solubility:** Ligand A (-4.617) has better aqueous solubility than Ligand B (-1.598). Solubility is a key factor for kinases.

**hERG Inhibition:** Ligand A (0.343) has a significantly lower hERG inhibition liability than Ligand B (0.089), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (51.932) has a lower microsomal clearance than Ligand A (79.24), suggesting better metabolic stability. This is a crucial factor for kinases.

**In vitro Half-Life:** Ligand B (2.885) has a longer in vitro half-life than Ligand A (13.569), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.257) has lower P-gp efflux than Ligand B (0.013), which is preferable for bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from poor solubility, low logP, and a higher hERG risk. Ligand A has better solubility, lower hERG risk, and better Caco-2 permeability but weaker binding and worse metabolic stability.

The binding affinity difference is substantial (-0.6 kcal/mol). For a kinase inhibitor, potency is paramount. While Ligand B's ADME properties are less ideal, the stronger binding could be optimized through further medicinal chemistry efforts. The solubility and hERG issues are addressable. The metabolic stability is a concern, but not insurmountable.

Output:
1
2025-04-17 12:37:22,417 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.844 Da) is slightly better positioned.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold, indicating good absorption potential. Ligand B (122.31) is higher, but still acceptable, though less favorable.

**logP:** Ligand A (4.484) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.174) is very low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is optimal. Ligand B (3 HBD, 8 HBA) is acceptable, but slightly less ideal.

**QED:** Ligand A (0.752) is very good, indicating strong drug-likeness. Ligand B (0.531) is acceptable, but lower.

**DILI:** Ligand A (48.468) has a low DILI risk. Ligand B (79.798) has a higher, though not critically high, DILI risk.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (93.68) is higher, but this is less relevant.

**Caco-2 Permeability:** Ligand A (-4.506) is poor, suggesting low intestinal absorption. Ligand B (-5.621) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.866) is very poor, a significant drawback. Ligand B (-2.554) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.927) has a low hERG risk, which is excellent. Ligand B (0.343) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (72.674) has a relatively high clearance, suggesting lower metabolic stability. Ligand B (54.187) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.024) has a very short half-life, a major concern. Ligand B (6.018) has a longer half-life, which is more desirable.

**P-gp Efflux:** Ligand A (0.611) has moderate P-gp efflux. Ligand B (0.023) has very low P-gp efflux, which is favorable.

**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 is the more promising candidate. While its logP is low and Caco-2 permeability is poor, its significantly superior binding affinity (-9.1 vs -7.0 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. Ligand A suffers from very poor solubility and a short half-life, which are major liabilities. The higher DILI risk for Ligand B is a concern, but potentially manageable with further optimization.

Output:
1
2025-04-17 12:37:22,417 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.5 & 357.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is excellent, well below the 140 threshold for oral absorption. Ligand B (108.41) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.289) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (-1.797) is quite low, which could hinder membrane permeability.

**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:** Ligand A (0.813) is excellent, indicating strong drug-likeness. Ligand B (0.543) is acceptable, but lower than A.

**DILI:** Ligand A (46.801) has a moderate DILI risk, but is acceptable. Ligand B (34.432) has a lower DILI risk, which is a positive.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (63.784) is moderate, while Ligand B (18.147) is low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.05 and -5.035), which is unusual and suggests poor permeability *in vitro*. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.267 and -0.772). This is a major drawback for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.8) has a low hERG risk. Ligand B (0.096) also shows a low risk of hERG inhibition.

**Microsomal Clearance:** Ligand A (117.764) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-0.365) has *very* low (and negative) clearance, indicating excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (26.868) has a moderate half-life. Ligand B (-14.641) has a very long (and negative) half-life, indicating excellent *in vitro* stability.

**P-gp Efflux:** Ligand A (0.706) shows moderate P-gp efflux. Ligand B (0.011) shows very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). While the difference is not huge, it is a factor.

**Overall Assessment:**

Ligand B is the more promising candidate despite the poor Caco-2 and solubility. Its significantly improved metabolic stability (extremely low Cl_mic and long t1/2), low P-gp efflux, and acceptable DILI risk outweigh the slightly weaker binding affinity and lower logP. The poor solubility is a significant concern for both, but can potentially be addressed through formulation strategies. Ligand A's higher logP and faster metabolism are less desirable.

Output:
1
2025-04-17 12:37:22,417 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.443 and 354.382 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.31) is slightly above the preferred <140 for good oral absorption, while Ligand B (85.69) is well within the range.

**logP:** Ligand A (1.183) is within the optimal 1-3 range. Ligand B (-0.109) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.535 and 0.704), indicating drug-like properties.

**DILI:** Ligand A (84.102) has a higher DILI risk than Ligand B (48.313). This is a significant concern.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.149) has poor Caco-2 permeability, which is concerning. Ligand B (-4.493) is also not great, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.816) has poor aqueous solubility, a significant drawback. Ligand B (-1.76) is better, but still not ideal.

**hERG:** Both ligands have very low hERG inhibition risk (0.267 and 0.151), which is excellent.

**Microsomal Clearance:** Ligand A (90.55) has higher microsomal clearance, suggesting lower metabolic stability, while Ligand B (3.259) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.074) has a very short half-life, which is undesirable. Ligand B (-19.638) is better, but still relatively short.

**P-gp Efflux:** Both have low P-gp efflux (0.139 and 0.031), which is favorable.

**Binding Affinity:** Ligand A (-7.7) has slightly better binding affinity than Ligand B (-7.5), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B is the more promising candidate. While its Caco-2 and solubility are not ideal, its significantly lower DILI risk and much better metabolic stability (lower Cl_mic, better t1/2) outweigh the slightly weaker binding affinity and slightly lower logP. The poor solubility and permeability of Ligand A, combined with its higher DILI risk and poor metabolic stability, make it a less attractive candidate despite its slightly better binding affinity. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 12:37:22,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (378.46 Da) is also good.

**TPSA:** Ligand A (127.93) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (49.41) is excellent, well below the 140 threshold, suggesting good absorption.

**logP:** Ligand A (-1.357) is a bit low, potentially hindering permeation. Ligand B (3.483) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, both within acceptable limits. Ligand B has 1 HBD and 3 HBA, also good.

**QED:** Both ligands have acceptable QED values (A: 0.431, B: 0.72), with Ligand B being significantly better.

**DILI:** Both ligands have low DILI risk (A: 26.406, B: 34.471), which is positive.

**BBB:** Ligand A (23.071) has very low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (90.074) has high BBB penetration, which is irrelevant here and could even be a slight negative if off-target CNS effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.859) has poor Caco-2 permeability, a significant drawback. Ligand B (-4.871) also has poor Caco-2 permeability, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.23) has poor solubility, which is a concern. Ligand B (-4.184) also has poor solubility, and is worse than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.022, B: 0.526), which is excellent.

**Microsomal Clearance:** Ligand A (-15.619) has very low microsomal clearance, indicating good metabolic stability. Ligand B (39.846) has high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (10.381) has a reasonable half-life. Ligand B (-32.492) has a very short half-life, a major concern.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.004, B: 0.199), which is favorable.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-6.7), a difference of 0.9 kcal/mol.

**Overall Assessment:**

Ligand A suffers from poor Caco-2 permeability and solubility, and a low logP. While its metabolic stability is excellent, these ADME properties are significant liabilities. Ligand B has better logP, QED, and binding affinity, but suffers from poor solubility, poor Caco-2 permeability, and very rapid metabolism.

Given the priorities for an enzyme target (SRC kinase), metabolic stability and potency are key. While Ligand B has better potency, its extremely rapid metabolism is a major drawback. Ligand A's better metabolic stability, despite its other issues, makes it slightly more promising as a starting point for optimization. However, both compounds have significant ADME liabilities.

Output:
0
2025-04-17 12:37:22,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.419 Da and 346.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (86.28 and 84.42) are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (2.889) is optimal, while Ligand B (1.5) is slightly lower but still acceptable.

**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.

**QED:** Both ligands have good QED scores (0.845 and 0.873), indicating drug-likeness.

**DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (43.428). This is a significant concern.

**BBB:** This is less important for a non-CNS target like SRC. Ligand A (92.4) has higher BBB penetration than Ligand B (70.531).

**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 very low hERG inhibition risk (0.174 and 0.19). This is excellent.

**Microsomal Clearance:** Ligand A (57.951) has higher microsomal clearance than Ligand B (43.862), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-13.989) has a longer in vitro half-life than Ligand A (-21.214), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.179 and 0.075).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol), a difference of 1.6 kcal/mol. This is a substantial advantage.

**Conclusion:**

Despite Ligand A's superior binding affinity, the higher DILI risk and lower metabolic stability are significant drawbacks. Ligand B, while having slightly lower affinity, presents a much better safety profile (lower DILI) and improved metabolic stability (lower Cl_mic, longer t1/2). Given the enzyme-specific priorities, and the fact that the affinity difference is not *massive*, the improved ADME properties of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 12:37:22,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.453 and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (104.36). A TPSA under 140 is good for oral absorption, and A is comfortably within that range while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.854 and 1.63), falling within the 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 maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.885) has a much higher QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Both ligands have similar, acceptable DILI risk (49.787 and 49.128). Both are well below the 60 threshold.

**BBB:** Ligand A (90.229) has a significantly higher BBB penetration percentile than Ligand B (36.448). While not a primary concern for a non-CNS target like SRC, higher BBB is generally not detrimental.

**Caco-2 Permeability:** Ligand A (-4.879) is better than Ligand B (-5.06), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.612) is better than Ligand B (-3.422), indicating better solubility.

**hERG:** Both ligands have similar, low hERG risk (0.421 and 0.568).

**Microsomal Clearance:** Ligand A (31.992) has a significantly lower microsomal clearance than Ligand B (57.164), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.354) has a much longer in vitro half-life than Ligand B (22.289), which is a strong positive.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.179 and 0.099).

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-7.4). However, the difference is small (0.2 kcal/mol) and can be outweighed by other factors.

**Overall:**

Ligand A is superior to Ligand B across most critical ADME properties (TPSA, QED, solubility, metabolic stability, half-life) and has a comparable binding affinity. The slightly better affinity of Ligand B is not enough to offset the significant advantages of Ligand A in terms of drug-likeness and pharmacokinetic properties. Given the enzyme-specific priorities, the improved metabolic stability (lower Cl_mic, longer t1/2) and solubility of Ligand A are particularly important.

Output:
1
2025-04-17 12:37:22,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (potency, metabolic stability, solubility, and hERG risk).

**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.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand B (66.57 A^2) is significantly lower than Ligand A (86.88 A^2), suggesting potentially better absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (3.912) is slightly higher than Ligand A (2.806), potentially raising concerns about solubility and off-target effects, but still acceptable.

**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 (0.625 and 0.694), indicating good drug-likeness.

**DILI:** Ligand B (39.395) has a significantly lower DILI risk than Ligand A (75.533), which is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (67.546) has a higher BBB percentile than Ligand A (43.505), but this is not a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not well defined.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. However, the scale is not well defined.

**hERG Inhibition:** Ligand A (0.68) has a slightly lower hERG inhibition risk than Ligand B (0.797), which is preferable.

**Microsomal Clearance:** Ligand A (-5.968) has a much lower (better) microsomal clearance than Ligand B (97.882), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand B (38.918) has a slightly longer in vitro half-life than Ligand A (40.056), which is a minor advantage.

**P-gp Efflux:** Ligand A (0.08) has a much lower P-gp efflux liability than Ligand B (0.917), suggesting better bioavailability.

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's superior binding affinity, Ligand A presents a more favorable ADME profile. The significantly lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux for Ligand A are crucial for developing a viable drug candidate. While the affinity difference is notable, the improved safety and pharmacokinetic properties of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 12:37:22,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.39 and 345.40 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.93) is well below the 140 threshold, and favorable for oral absorption. Ligand B (103.25) is still acceptable, but less optimal.

**logP:** Ligand A (0.939) is slightly below the optimal 1-3 range, but acceptable. Ligand B (0.556) is even lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands (0.738 and 0.682) have good drug-likeness scores (>0.5).

**DILI:** Both ligands have similar, acceptable DILI risk (39.67 and 40.29 percentile).

**BBB:** Ligand A (71.81) has a better BBB penetration score than Ligand B (17.37), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.754) has a much better Caco-2 permeability score than Ligand B (-5.517), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.014) has better aqueous solubility than Ligand B (-1.997).

**hERG:** Both ligands have very low hERG risk (0.399 and 0.223).

**Microsomal Clearance:** Ligand A (37.86 mL/min/kg) has a higher, less desirable, microsomal clearance than Ligand B (-10.08 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.71 hours) has a significantly longer in vitro half-life than Ligand A (-4.61 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.007).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). The difference is 1.7 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity, Caco-2 permeability, solubility, and BBB penetration. However, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2). Given that SRC is an enzyme, metabolic stability is a crucial factor. The 1.7 kcal/mol difference in binding affinity can potentially be overcome with further optimization, while poor metabolic stability is more difficult to address later in development.

Output:
1
2025-04-17 12:37:22,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (374.459 Da) is also acceptable.

**TPSA:** Ligand A (71.33) is significantly better than Ligand B (104.22). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (1.021) is within the optimal range (1-3), while Ligand B (-1.122) is slightly below 1. This could potentially hinder permeation for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is more favorable than Ligand B (1 HBD, 6 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.817) has a better QED score than Ligand B (0.668), indicating a more drug-like profile.

**DILI:** Ligand A (35.479) has a much lower DILI risk than Ligand B (45.289), which is a significant advantage. Both are below the 60 threshold, but A is clearly better.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (71.229) is better than Ligand B (49.826).

**Caco-2 Permeability:** Ligand A (-5.108) and Ligand B (-4.886) are both negative, indicating poor permeability. However, the scale is not specified, so it's hard to interpret the absolute values.

**Aqueous Solubility:** Ligand A (-1.428) and Ligand B (-0.766) are both negative, indicating poor solubility. Again, the scale is not specified, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.301) has a significantly lower hERG risk than Ligand B (0.036), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (29.383) has a better (lower) microsomal clearance than Ligand B (0.029), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.371) has a better (longer) in vitro half-life than Ligand B (3.491).

**P-gp Efflux:** Ligand A (0.056) has a lower P-gp efflux liability than Ligand B (0.018), which is beneficial for bioavailability.

**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 for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has superior ADME properties across the board (lower DILI, better solubility, better metabolic stability, lower hERG risk, lower P-gp efflux). However, Ligand B boasts a much stronger binding affinity (-6.8 vs 0 kcal/mol). For an enzyme target like SRC kinase, binding affinity is paramount. A difference of 6.8 kcal/mol is very significant and likely to translate into much greater efficacy. While Ligand B has some ADME liabilities, these could be addressed through further optimization. The strong binding affinity makes it a more promising starting point.

Output:
1
2025-04-17 12:37:22,418 - INFO - Batch 145 complete. Total preferences: 2320
2025-04-17 12:37:22,419 - INFO - Processing batch 146/512...
2025-04-17 12:38:12,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 353.379 Da - Within the ideal range (200-500 Da).
* Ligand B: 369.615 Da - Within the ideal range (200-500 Da).
* *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 127.92  - Good for oral absorption (<=140).
* Ligand B: 40.54 - Excellent for oral absorption (<=140).
* *Ligand B is better here.*

**3. Lipophilicity (logP):**
* Ligand A: -2.812 - A bit low, potentially hindering permeation.
* Ligand B: 4.582 - High, potentially causing solubility or off-target issues.
* *Ligand A is better, despite being a bit low.*

**4. H-Bond Donors (HBD):**
* Ligand A: 3 - Acceptable (<=5).
* Ligand B: 1 - Acceptable (<=5).
* *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 6 - Acceptable (<=10).
* Ligand B: 3 - Acceptable (<=10).
* *Both are acceptable.*

**6. QED:**
* Ligand A: 0.442 - Below the desired threshold of 0.5.
* Ligand B: 0.681 - Above the desired threshold of 0.5.
* *Ligand B is better.*

**7. DILI:**
* Ligand A: 35.324 - Low risk (good, <40).
* Ligand B: 12.641 - Very low risk (excellent, <40).
* *Ligand B is better.*

**8. BBB:**
* Ligand A: 57.736 - Not a priority for a non-CNS target like SRC.
* Ligand B: 79.682 - Not a priority for a non-CNS target like SRC.
* *Neither is particularly important here.*

**9. Caco-2 Permeability:**
* Ligand A: -5.727 - Indicates poor permeability.
* Ligand B: -4.981 - Indicates poor permeability.
* *Neither is good, but B is slightly better.*

**10. Aqueous Solubility:**
* Ligand A: -1.91 - Poor solubility.
* Ligand B: -4.546 - Very poor solubility.
* *Ligand A is better.*

**11. hERG Inhibition:**
* Ligand A: 0.013 - Very low risk (excellent).
* Ligand B: 0.85 - Moderate risk.
* *Ligand A is significantly better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: -18.267 - Indicates very slow clearance (good metabolic stability).
* Ligand B: 100.069 - Indicates rapid clearance (poor metabolic stability).
* *Ligand A is significantly better.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -13.34 - Indicates a very long half-life (good).
* Ligand B: 4.128 - Relatively short half-life.
* *Ligand A is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.001 - Very low efflux (good).
* Ligand B: 0.781 - Moderate efflux.
* *Ligand A is better.*

**15. Binding Affinity:**
* Ligand A: -8.2 kcal/mol - Excellent binding.
* Ligand B: -7.7 kcal/mol - Good binding, but less potent than A.
* *Ligand A is better.*

**Summary & Enzyme-Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in all these areas. While Ligand B has a better QED and DILI, its poor solubility, rapid clearance, shorter half-life, and lower affinity are significant drawbacks. The affinity difference of 0.5 kcal/mol is substantial enough to outweigh the slightly better QED and DILI of Ligand B. The poor permeability of both is a concern, but can be addressed with formulation strategies.

Output:
0
2025-04-17 12:38:12,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (354.491 and 389.708 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (76.66 and 75.48) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (2.57) is optimal, while Ligand B (3.548) is slightly higher but still acceptable.

**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 each), below the threshold of 10.

**6. QED:** Ligand A (0.591) has a better QED score than Ligand B (0.419), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.458) has a significantly lower DILI risk than Ligand B (76.89), which is a major advantage.

**8. BBB:** Both ligands have similar BBB penetration (71.811 and 71.539), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close enough that this isn't a deciding factor.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Again, the values are close.

**11. hERG Inhibition:** Ligand A (0.343) has a lower hERG inhibition risk than Ligand B (0.709), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (32.382) has significantly lower microsomal clearance than Ligand B (73.89), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (55.839) has a longer in vitro half-life than Ligand A (11.275), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.226), which is a positive.

**15. 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).

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in DILI risk, hERG inhibition, and Cl_mic, while Ligand B has a slightly better affinity and half-life. The differences in affinity are not substantial enough to outweigh the significantly better ADME properties of Ligand A. The poor solubility and permeability of both compounds are concerning, but can be addressed with formulation strategies.

Output:
0
2025-04-17 12:38:12,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.479 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.47) is well below the 140 threshold for oral absorption, while Ligand B (94.81) is still acceptable but closer to the limit.

**logP:** Ligand A (3.092) is optimal, while Ligand B (1.373) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is still within acceptable limits, but higher.

**QED:** Ligand A (0.91) is very strong, indicating excellent drug-likeness. Ligand B (0.623) is still acceptable, but lower.

**DILI:** Ligand A (66.654) is moderately high, while Ligand B (11.361) is very low, a significant advantage for B.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (56.65) is better than Ligand B (26.561).

**Caco-2 Permeability:** Ligand A (-4.878) is poor, while Ligand B (-5.347) is also poor. Both are negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.319) is poor, while Ligand B (-1.042) is slightly better, but still poor.

**hERG:** Ligand A (0.396) has a slightly higher risk, while Ligand B (0.285) is lower, favoring B.

**Microsomal Clearance:** Ligand A (43.284) is moderate, while Ligand B (-2.442) is excellent, indicating much better metabolic stability. This is a crucial advantage for B.

**In vitro Half-Life:** Ligand A (4.78) is moderate, while Ligand B (36.507) is very good, further supporting B's better metabolic stability.

**P-gp Efflux:** Ligand A (0.248) is low, while Ligand B (0.023) is very low, indicating less efflux and better bioavailability.

**Binding Affinity:** Ligand A (-8.1) is significantly more potent than Ligand B (-7.8). This 1.5 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B has a much better ADMET profile, particularly regarding DILI risk, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While Ligand A has a slightly better binding affinity, the significant improvements in safety and pharmacokinetic properties of Ligand B make it the more promising drug candidate. The poor solubility and permeability of both are concerning, but could be addressed with formulation strategies. The lower DILI risk and improved metabolic stability of Ligand B are particularly valuable for an oncology target.

Output:
1
2025-04-17 12:38:12,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (370.475 Da and 351.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.61) is higher than Ligand B (71.53). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**3. logP:** Ligand A (0.38) is quite low, potentially hindering permeability. Ligand B (2.065) 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:** Ligand A (5) and Ligand B (4) are both within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.582 and 0.778), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (50.834) has a slightly higher DILI risk than Ligand B (32.842), though both are within a reasonable range (<60 is good).

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (91.819) has a higher BBB percentile, but it's not a major factor here.

**9. Caco-2:** Ligand A (-5.608) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-3.889) is better, but still not ideal.

**10. Solubility:** Ligand A (-1.846) has poor solubility. Ligand B (-2.258) is also poor, but slightly better.

**11. hERG:** Ligand A (0.136) has a slightly higher hERG risk than Ligand B (0.304), but both are relatively low.

**12. Cl_mic:** Ligand A (23.509) has a lower microsomal clearance, indicating better metabolic stability, which is a key priority for enzymes. Ligand B (65.134) has significantly higher clearance.

**13. t1/2:** Ligand A (-7.215) has a longer in vitro half-life than Ligand B (-23.167), further supporting its better metabolic stability.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.011 and 0.055).

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.2), but the difference is not huge.

**Overall Assessment:**

Ligand B has better logP, TPSA, QED, and binding affinity. However, Ligand A exhibits significantly better metabolic stability (lower Cl_mic and longer t1/2) and slightly lower DILI risk. Given that SRC is an enzyme, metabolic stability is a crucial factor. The slightly better affinity of Ligand B is unlikely to outweigh the substantial difference in metabolic stability. The poor Caco-2 and solubility of both are concerning, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 12:38:12,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (367.427 Da) is also acceptable.

**TPSA:** Ligand A (81.67) is well below the 140 threshold for oral absorption. Ligand B (116.67) is still reasonably low, but higher than A.

**logP:** Ligand A (1.433) is within the optimal range (1-3). Ligand B (-0.2) is below 1, which could indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, both within acceptable limits. Ligand B has 2 HBD and 6 HBA, also acceptable, but the higher HBA count might slightly impact permeability.

**QED:** Both ligands have similar QED values (A: 0.755, B: 0.761), indicating good drug-like properties.

**DILI:** Ligand A (22.218) has a significantly lower DILI risk than Ligand B (43.66), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.38) is lower than Ligand B (38.232).

**Caco-2 Permeability:** Ligand A (-4.911) is better than Ligand B (-5.263), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.698) is better than Ligand B (-2.899), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (A: 0.168, B: 0.061), which is excellent.

**Microsomal Clearance:** Ligand A (-7.997) has a much lower (better) microsomal clearance than Ligand B (-19.501), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (23.254 hours) has a much longer half-life than Ligand B (3.147 hours), which is highly desirable for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.024, B: 0.009).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-9.3 kcal/mol). While B is stronger, the difference isn't massive and is outweighed by A's superior ADME properties.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, including lower DILI risk, better solubility, improved permeability, and dramatically improved metabolic stability (lower Cl_mic and longer t1/2). These factors are critical for developing a viable drug candidate, especially for an enzyme target where metabolic stability and bioavailability are paramount.

Output:
0
2025-04-17 12:38:12,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.21) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (78.51) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (-0.436) is a bit low, potentially hindering permeation. Ligand B (1.838) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable and potentially better for permeability.

**QED:** Both ligands have reasonable QED scores (0.426 and 0.7), with Ligand B being better.

**DILI:** Ligand A (44.746) has a moderate DILI risk, while Ligand B (14.424) has a very low DILI risk, a significant advantage.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the assay or the compounds themselves. We'll proceed cautiously with this data.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests very poor solubility, a major concern.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.112 and 0.282), which is good.

**Microsomal Clearance:** Ligand A (8.85 mL/min/kg) has lower clearance than Ligand B (17.558 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.186) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (-9.81) also has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.006 and 0.058), which is favorable.

**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 B is the better candidate. Despite the unusual Caco-2 and solubility values, it has a significantly lower DILI risk, a more favorable logP, and a slightly better binding affinity. The lower metabolic clearance of Ligand A is appealing, but the negative half-life is a major red flag. The solubility issues for both compounds are concerning and would need to be addressed through formulation strategies or further chemical modification. However, considering the enzyme-specific priorities, Ligand B's lower toxicity profile and better physicochemical properties make it the more promising starting point.

Output:
1
2025-04-17 12:38:12,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.869 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.22) is excellent, well below the 140 threshold for oral absorption. Ligand B (102.57) is still acceptable but less favorable.

**logP:** Ligand A (4.073) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (-0.447) is below 1, which could impede permeability.

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

**QED:** Both ligands have reasonable QED scores (0.818 and 0.551), indicating good drug-like properties.

**DILI:** Ligand A (46.297) has a moderate DILI risk, but is still acceptable. Ligand B (11.322) shows very low DILI risk, a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (66.615) is higher than Ligand B (40.597).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.57) is better than Ligand B (-5.674).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.911) is better than Ligand B (-1.211).

**hERG Inhibition:** Ligand A (0.571) has a slightly higher hERG risk than Ligand B (0.087), which is a substantial advantage for B.

**Microsomal Clearance:** Ligand A (30.609) has better metabolic stability (lower clearance) than Ligand B (-53.786). This is a major advantage for A.

**In vitro Half-Life:** Ligand A (26.226) has a longer half-life than Ligand B (8.451), which is desirable.

**P-gp Efflux:** Ligand A (0.374) has lower P-gp efflux than Ligand B (0.001), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-10.4 and -9.4 kcal/mol). Ligand A is slightly better (-10.4 kcal/mol).

**Overall Assessment:**

Ligand A has a slightly better binding affinity, better metabolic stability, longer half-life, and lower P-gp efflux. However, Ligand B has a significantly lower DILI risk and hERG inhibition liability, and a slightly better TPSA. The difference in binding affinity is not large enough to overcome the safety advantages of Ligand B. Given the enzyme-specific priorities, minimizing toxicity (DILI and hERG) is crucial.

Output:
1
2025-04-17 12:38:12,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.491 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (106). Lower TPSA generally correlates with better absorption.

**logP:** Ligand A (2.361) is optimal, while Ligand B (-0.199) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands are acceptable (Ligand A: 2, Ligand B: 3), within the limit of 5.

**H-Bond Acceptors:** Both ligands are acceptable (Ligand A: 4, Ligand B: 7), within the limit of 10.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.681, Ligand B: 0.595), indicating good drug-like properties.

**DILI:** Ligand A (29.236) has a much lower DILI risk than Ligand B (41.218), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.482) is better than Ligand B (9.732).

**Caco-2 Permeability:** Ligand A (-4.935) is better than Ligand B (-5.393). Both are negative, but A is less negative.

**Aqueous Solubility:** Ligand A (-2.806) is better than Ligand B (-0.805). Both are negative, but A is less negative.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.146, Ligand B: 0.118).

**Microsomal Clearance:** Ligand A (55.586) is higher than Ligand B (-28.36). A negative value for Ligand B is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (-3.689) is better than Ligand B (16.02). A negative value for Ligand A is excellent, indicating a long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.116, Ligand B: 0.05).

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-6.9), but the difference is not substantial (0.3 kcal/mol).

**Overall Assessment:**

Ligand A is superior overall. While Ligand B has slightly better binding affinity and excellent metabolic stability, Ligand A excels in crucial ADME properties like logP, TPSA, solubility, and DILI risk. The lower logP and higher TPSA of Ligand B raise concerns about permeability and absorption. The significantly lower DILI risk for Ligand A is a major advantage. The better half-life and solubility of Ligand A are also beneficial. The 0.3 kcal/mol difference in binding affinity is unlikely to outweigh the ADME advantages of Ligand A.

Output:
1
2025-04-17 12:38:12,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.195 Da) and Ligand B (381.885 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (84.22) and Ligand B (71.53) are both good.

**logP:** Both ligands have logP values between 1-3, which is optimal. Ligand A (3.092) and Ligand B (2.253) are both 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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have QED values above 0.5, indicating a good drug-like profile. Ligand A (0.703) and Ligand B (0.812) are both good.

**DILI:** Ligand A has a DILI risk of 93.718, which is high. Ligand B has a DILI risk of 61.031, which is also elevated but significantly lower than Ligand A. This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (23.226) and Ligand B (79.604) have percentile scores.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and could indicate issues with permeability predictions.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual.

**hERG Inhibition:** Ligand A (0.487) and Ligand B (0.335) have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (28.436 mL/min/kg) has a higher clearance than Ligand B (21.256 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (11.634 hours) has a longer half-life than Ligand B (0.271 hours). However, the extremely short half-life of Ligand B is a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.25, Ligand B: 0.274).

**Binding Affinity:** Ligand B (-7.4 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 issues.

**Overall Assessment:**

Ligand B is the superior candidate despite the low solubility and Caco-2 permeability predictions. The significantly stronger binding affinity (-7.4 kcal/mol vs 0.0 kcal/mol) is a major advantage. While the DILI risk is still elevated, it's much lower than that of Ligand A. The extremely short half-life of Ligand B is a concern, but can potentially be addressed through structural modifications. Ligand A's high DILI risk is a major red flag, and its lack of binding affinity makes it a poor candidate.

Output:
1
2025-04-17 12:38:12,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.434 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (90.98) is still under 140, but less optimal than A.

**logP:** Ligand A (2.609) is within the optimal 1-3 range. Ligand B (-0.209) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both have reasonable H-bond counts, within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.803, B: 0.69), indicating good drug-like properties.

**DILI:** Ligand A (21.055) has a very low DILI risk, significantly better than Ligand B (14.23).

**BBB:** BBB is not a primary concern for a kinase inhibitor, but Ligand A (89.531) has a higher percentile than Ligand B (46.879).

**Caco-2 Permeability:** Ligand A (-4.391) has a negative Caco-2 value, which is concerning, while Ligand B (-5.208) is also negative, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.368) and Ligand B (-0.796) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.741) has a lower hERG risk than Ligand B (0.185), which is a positive.

**Microsomal Clearance:** Ligand A (-2.594) has a negative clearance, suggesting high metabolic stability, a crucial factor for kinases. Ligand B (-38.777) has a very high (negative) clearance, indicating very rapid metabolism.

**In vitro Half-Life:** Ligand A (5.363) has a better half-life than Ligand B (-7.719).

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux liability than Ligand B (0.001).

**Binding Affinity:** Ligand A (-9.5 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 concerns.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand A is the superior candidate. It exhibits a significantly stronger binding affinity, a much lower DILI risk, better metabolic stability (lower clearance, longer half-life), lower P-gp efflux, and a lower hERG risk. The slightly better TPSA and BBB values also contribute to its favorability. While the negative Caco-2 values are concerning for both, the substantial potency advantage of Ligand A makes it a more promising starting point for optimization, where solubility can be addressed through formulation or structural modifications.

Output:
1
2025-04-17 12:38:12,056 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.449 and 392.855 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 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.856 and 2.041), 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 within acceptable limits.

**QED:** Both ligands have similar QED values (0.8 and 0.722), indicating good drug-likeness.

**DILI:** Ligand A (40.83) has a slightly higher DILI risk than Ligand B (37.263), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (95.89 and 90.772), however, this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.422 and -4.879), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.217 and -3.534), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.681) has a slightly higher hERG risk than Ligand B (0.495), but both are relatively low.

**Microsomal Clearance:** Ligand B (35.595 mL/min/kg) has lower microsomal clearance than Ligand A (41.86 mL/min/kg), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand B (-7.573 hours) has a significantly longer half-life than Ligand A (-0.011 hours). This is a major advantage, suggesting less frequent dosing potential.

**P-gp Efflux:** Ligand A (0.657) has lower P-gp efflux than Ligand B (0.096), which could lead to better bioavailability.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand A's significantly stronger binding affinity (-9.6 vs -8.4 kcal/mol) is a major advantage for an enzyme inhibitor. The slightly lower P-gp efflux is also beneficial. Ligand B has better metabolic stability and half-life, but the difference in affinity is more critical. The DILI risk is acceptable for both.

Output:
1
2025-04-17 12:38:12,056 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (421.733 Da) is higher, but not excessively so. Ligand B (344.346 Da) is slightly preferred here.

**TPSA:** Both ligands have TPSA values (75.27 and 89.01) that are acceptable for oral absorption (<140), but not optimized for CNS penetration.

**logP:** Ligand A (4.587) is higher than Ligand B (2.533). While both are within the optimal range (1-3), Ligand A is pushing the upper limit and could potentially have solubility issues or off-target effects. Ligand B is 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 Ligand A is slightly preferred.

**QED:** Both ligands have similar QED values (0.716 and 0.712), indicating good drug-likeness.

**DILI:** Both ligands have high DILI risk (90.539 and 88.251). This is a significant concern for both, but they are very similar.

**BBB:** Both have low BBB penetration (43.815 and 66.615). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.684 and -4.846). This is unusual and suggests poor permeability. Ligand A is slightly better.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.011 and -4.106). This is a major drawback for both compounds. Ligand B is slightly better.

**hERG Inhibition:** Both have low hERG inhibition risk (0.623 and 0.657), which is good.

**Microsomal Clearance:** Ligand B (52.978 mL/min/kg) has significantly lower microsomal clearance than Ligand A (12.643 mL/min/kg). This suggests better metabolic stability for Ligand B, a crucial factor for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (15.902 hours) has a longer half-life than Ligand A (139.182 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.489 and 0.351), which is good.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have concerning DILI and solubility issues, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and, crucially, a much stronger binding affinity. The improved affinity is likely to be more impactful for an enzyme inhibitor than minor differences in other properties. The slightly better solubility and lower P-gp efflux of Ligand B further support this conclusion.

Output:
1
2025-04-17 12:38:12,056 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.343 and 367.446 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (78.87 and 71.53) are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (0.434) is slightly low, potentially hindering permeation. Ligand B (2.777) 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:** Ligand A (4) and Ligand B (5) are both acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.608 and 0.813), indicating drug-like properties.

**DILI:** Ligand A (22.838) has a significantly lower DILI risk than Ligand B (60.062). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (83.986) is slightly better than Ligand A (77.898). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.832 and -4.729), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.198 and -4.335), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.384 and 0.453), which is good.

**Microsomal Clearance:** Ligand A (-3.302) has a much lower (better) microsomal clearance than Ligand B (59.226), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-23.554) has a significantly longer in vitro half-life than Ligand B (-19.23), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.134), which is favorable.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-7.7 and -7.9 kcal/mol). The difference is negligible.

**Conclusion:**

Despite both ligands having good binding affinity, Ligand A is the more promising candidate. Its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP and solubility concerns. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The superior safety profile and metabolic stability of Ligand A make it a better starting point for further optimization.

Output:
0
2025-04-17 12:38:12,056 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 361.433 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (109.5) is higher than Ligand B (72.88). While both are reasonably good, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Ligand A (-0.014) is slightly negative, which *could* hinder permeability. Ligand B (0.984) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

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

**QED:** Both ligands have similar QED values (0.696 and 0.676), indicating good drug-likeness.

**DILI:** Ligand A (47.344) has a higher DILI risk than Ligand B (10.198). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.558) has a higher BBB value than Ligand A (16.363), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-5.099) and Ligand B (-4.883) have similar, and poor, Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-2.193) has slightly better solubility than Ligand B (-0.654), but both are poor.

**hERG Inhibition:** Ligand A (0.166) has a slightly lower hERG risk than Ligand B (0.342), which is preferable.

**Microsomal Clearance:** Ligand A (-4.892) has a *much* lower (better) microsomal clearance than Ligand B (11.697). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-9.219) has a significantly longer half-life than Ligand B (-33.065). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.018 and 0.014), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has better TPSA, logP, and DILI, Ligand A has significantly better metabolic stability (lower Cl_mic) and a longer half-life. Given that SRC is an enzyme, metabolic stability and duration of action are critical. The slightly lower solubility and negative logP of Ligand A are less concerning than the poor metabolic profile of Ligand B. The similar binding affinity means potency isn't a differentiating factor. The slightly higher hERG risk for Ligand B is also a minor negative.

Output:
0
2025-04-17 12:38:12,056 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 347.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.77) is slightly above the preferred <90 for CNS targets, but acceptable for a non-CNS target like SRC. Ligand B (92.77) is better, falling comfortably below 100.

**logP:** Ligand A (-1.576) is a bit low, potentially hindering permeability. Ligand B (-0.376) is better, closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and acceptable HBA counts (7 and 5 respectively).

**QED:** Both ligands have good QED scores (0.614 and 0.728), indicating drug-likeness.

**DILI:** Ligand A (30.361) has a lower DILI risk than Ligand B (37.185), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (21.287) has a slightly higher BBB percentile than Ligand B (11.555).

**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 very low solubility values (-5.347 and -5.263), which is a major drawback. Poor solubility can severely limit bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.073 and 0.165), which is excellent.

**Microsomal Clearance:** Ligand A (-27.38) has significantly lower (better) microsomal clearance than Ligand B (-11.521). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (-28.472) has a longer in vitro half-life than Ligand A (6.182), which is generally desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.033).

**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. While not a huge difference, it's a noticeable advantage.

**Overall Assessment:**

Ligand B has a better binding affinity and a longer half-life. However, Ligand A has better metabolic stability (lower Cl_mic), lower DILI risk, and slightly better BBB penetration. Both have poor solubility and permeability. The binding affinity difference is not large enough to overcome the solubility and permeability issues, and the metabolic stability of ligand A is a significant advantage for an enzyme target.

Output:
0
2025-04-17 12:38:12,057 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.487, 60.85, 2.177, 1, 3, 0.85, 10.43, 70.997, -4.62, -1.968, 0.353, 20.297, -1.425, 0.133, -8.8]
**Ligand B:** [383.539, 92.5, 0.803, 2, 5, 0.733, 20.861, 56.65, -5.498, -3.062, 0.116, 13.851, -14.148, 0.014, -7.8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (348.487) is slightly preferred due to being closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (60.85) is significantly better than B (92.5).  A is well below the 140 threshold for oral absorption, while B is approaching it.
3. **logP:** A (2.177) is optimal. B (0.803) is a bit low, potentially hindering membrane permeability.
4. **HBD:** Both are acceptable (A: 1, B: 2), within the recommended limit of 5.
5. **HBA:** Both are acceptable (A: 3, B: 5), within the recommended limit of 10.
6. **QED:** A (0.85) is better than B (0.733), indicating a more drug-like profile.
7. **DILI:** A (10.43) is *much* better than B (20.861).  A is well below the 40% threshold, while B is approaching a concerning level.
8. **BBB:** A (70.997) is good, while B (56.65) is moderate. While SRC isn't a CNS target, higher BBB is generally favorable.
9. **Caco-2:** A (-4.62) is better than B (-5.498). Higher values indicate better absorption.
10. **Solubility:** A (-1.968) is better than B (-3.062). Higher values indicate better solubility.
11. **hERG:** Both are very low (A: 0.353, B: 0.116), indicating minimal hERG inhibition risk.
12. **Cl_mic:** B (13.851) is significantly better than A (20.297), indicating better metabolic stability.
13. **t1/2:** B (-14.148) is *much* better than A (-1.425), suggesting a significantly longer half-life.
14. **Pgp:** A (0.133) is better than B (0.014). Lower values indicate less P-gp efflux.
15. **Affinity:** A (-8.8) is slightly better than B (-7.8), though both are good. A has a 1 kcal/mol advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A has a slight edge.
*   **Metabolic Stability:** B is significantly better (lower Cl_mic, much longer t1/2).
*   **Solubility:** A is better.
*   **hERG:** Both are good.
*   **DILI:** A is significantly better.

**Overall Assessment:**

While Ligand B has a substantial advantage in metabolic stability and half-life, the significantly better DILI profile, TPSA, solubility, and QED of Ligand A, coupled with a slightly better binding affinity, make it the more promising candidate. The improved ADME properties of A are crucial for *in vivo* efficacy and safety. The difference in half-life could potentially be addressed through further optimization, but mitigating DILI risk is more challenging.

Output:
0
2025-04-17 12:38:12,057 - INFO - Batch 146 complete. Total preferences: 2336
2025-04-17 12:38:12,057 - INFO - Processing batch 147/512...
2025-04-17 12:38:52,379 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.543 and 376.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is better than Ligand B (76.15), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.593) is slightly higher than optimal (1-3) but still acceptable. Ligand B (1.089) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 5 HBA) both have reasonable counts, within the guidelines.

**QED:** Both ligands have similar, acceptable QED values (0.641 and 0.694).

**DILI:** Both ligands have low DILI risk (40.016 and 38.852), which is good.

**BBB:** Not a primary concern for a kinase inhibitor, but Ligand B (82.009) has a higher BBB percentile than Ligand A (62.97).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.765) is slightly worse than Ligand B (-4.294).

**Aqueous Solubility:** Ligand A (-3.849) has slightly better solubility than Ligand B (-1.68), though both are poor.

**hERG:** Ligand A (0.468) has a lower hERG risk than Ligand B (0.507), which is preferable.

**Microsomal Clearance:** Ligand B (51.15) has significantly lower microsomal clearance than Ligand A (84.901), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-56.212) has a dramatically longer half-life than Ligand A (-1.003). This is a major positive for Ligand B.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability.

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better TPSA and hERG profile, Ligand B's superior binding affinity (-7.2 vs -9.5 kcal/mol), significantly better metabolic stability (lower Cl_mic), and much longer half-life are decisive advantages for an enzyme inhibitor like an SRC kinase inhibitor. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed with further optimization. The poor Caco-2 and solubility are shared concerns, but the potency and metabolic stability of Ligand B are more critical in this context.

Output:
1
2025-04-17 12:38:52,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.389 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (75.19) is still acceptable but less favorable.

**logP:** Both ligands have good logP values (2.816 and 1.886), 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 HBA, both are acceptable.

**QED:** Ligand A (0.905) has a significantly higher QED than Ligand B (0.578), indicating a more drug-like profile.

**DILI:** Ligand A (79.139) has a higher DILI risk than Ligand B (35.091). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration (69.407 and 60.838), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.702) has a slightly higher hERG risk than Ligand B (0.382), but both are relatively low.

**Microsomal Clearance:** Ligand A (23.14) has a lower (better) microsomal clearance than Ligand B (33.091), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (60.245) has a significantly longer in vitro half-life than Ligand B (-10.044). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.416) has lower P-gp efflux than Ligand B (0.06), indicating better bioavailability.

**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 A has a superior QED, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. Its binding affinity is slightly better. However, it has a significantly higher DILI risk. Ligand B has a much lower DILI risk, but suffers from poorer QED, metabolic stability, and P-gp efflux.

Given the enzyme-specific priorities, metabolic stability and potency are crucial. While the DILI risk for Ligand A is concerning, the substantially improved half-life and slightly better affinity could be optimized through further medicinal chemistry efforts. The poor permeability and solubility are shared concerns that would need to be addressed for either molecule.

Output:
1
2025-04-17 12:38:52,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.345 Da and 376.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.7) is better than Ligand B (91.4), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (3.033) is optimal, while Ligand B (1.394) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 5 HBA) as it has a lower number of HBDs. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.625 and 0.614), indicating good drug-likeness.

**DILI:** Ligand B (72.043) has a significantly lower DILI risk than Ligand A (98.759). This is a major advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration, but Ligand A (74.176) is slightly better than Ligand B (66.925). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.338) is slightly better than Ligand B (-4.999), but both are concerning.

**Aqueous Solubility:** Ligand A (-4.661) is better than Ligand B (-3.241), suggesting better solubility.

**hERG Inhibition:** Ligand A (0.302) has a slightly higher hERG risk than Ligand B (0.179), but both are relatively low.

**Microsomal Clearance:** Ligand B (17.588) has significantly lower microsomal clearance than Ligand A (88.151), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-11.669) has a negative half-life, which is concerning. Ligand A (26.822) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.367) has lower P-gp efflux than Ligand B (0.066), which is favorable.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.1 kcal/mol).

**Overall Assessment:**

Ligand B excels in metabolic stability (lower Cl_mic) and DILI risk, which are high priorities for kinase inhibitors. While its Caco-2 permeability and half-life are concerning, the superior metabolic stability and lower toxicity profile outweigh these drawbacks, especially given the equal binding affinity. Ligand A has better solubility and P-gp efflux, but the high DILI risk and high clearance are significant liabilities.

Output:
1
2025-04-17 12:38:52,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.356 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.34) is significantly better than Ligand B (89.55). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (4.621) is higher than Ligand B (1.21). While 4.621 is approaching the upper limit, it's still within a reasonable range. Ligand B's logP is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is more favorable than Ligand B (2 HBD, 5 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have similar QED values (0.806 and 0.736), indicating good drug-like properties.

**DILI:** Ligand A (61.342) has a higher DILI risk than Ligand B (49.438), but both are acceptable.

**BBB:** Ligand A (98.178) shows excellent BBB penetration, while Ligand B (54.634) is moderate. BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.422 and -4.921), which is unusual and suggests poor permeability *in vitro*. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-5.328) has slightly better solubility than Ligand B (-1.9), but both are poor. This is a major drawback.

**hERG Inhibition:** Ligand A (0.824) has a slightly higher hERG risk than Ligand B (0.19). Lower is better here, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (32.632) has higher microsomal clearance than Ligand B (23.402), suggesting lower metabolic stability. Ligand B is better in this regard.

**In vitro Half-Life:** Ligand B (18.596 hours) has a significantly longer half-life than Ligand A (-12.125 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.839) has higher P-gp efflux than Ligand B (0.025), which is unfavorable.

**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 better candidate. While Ligand A has better TPSA and BBB penetration, Ligand B excels in critical areas for an enzyme inhibitor: lower microsomal clearance (better metabolic stability), longer half-life, lower P-gp efflux, and lower hERG risk. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies. The slightly lower logP of Ligand B is a minor drawback compared to the advantages it offers in ADME properties.

Output:
1
2025-04-17 12:38:52,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.459 Da and 367.599 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.32) is better than Ligand B (29.54) as it is closer to the ideal range for oral absorption (<140). Ligand B is very low, which might indicate issues with solubility.

**logP:** Ligand A (2.209) is optimal (1-3), while Ligand B (4.908) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, well within the acceptable limits. Ligand B has 0 HBD and 3 HBA, also acceptable, but potentially impacting aqueous solubility.

**QED:** Ligand A (0.88) has a significantly better QED score than Ligand B (0.473), indicating a more drug-like profile.

**DILI:** Ligand A (47.964) has a better DILI score than Ligand B (21.714), suggesting lower potential for liver injury.

**BBB:** Both ligands have similar BBB penetration (76.347 and 75.533), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.074 and -5.04), which is unusual and problematic. This suggests poor intestinal absorption for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.157 and -4.519). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.377) has a much lower hERG inhibition risk than Ligand B (0.719), which is a critical advantage.

**Microsomal Clearance:** Ligand A (7.909) has a significantly lower microsomal clearance than Ligand B (100.918), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.93) has a negative half-life, which is impossible. Ligand B (5.096) is a reasonable half-life, but not exceptional. The negative value for A is a major red flag.

**P-gp Efflux:** Ligand A (0.039) has much lower P-gp efflux liability than Ligand B (0.699), suggesting better bioavailability.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-7.2 and -7.1 kcal/mol). The difference is negligible.

**Conclusion:**

Despite both ligands having good binding affinity, Ligand A is the superior candidate. It has a better QED score, lower DILI risk, significantly lower microsomal clearance (better metabolic stability), lower hERG inhibition, and lower P-gp efflux. The negative half-life for Ligand A is a data error that needs to be investigated, but even ignoring that, the other properties make it preferable. Ligand B's high logP and very high clearance are major concerns. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 12:38:52,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.383 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.27) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.87) is well within the ideal range.

**logP:** Ligand A (-0.938) is a bit low, potentially hindering permeation. Ligand B (0.879) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 8 HBAs, while Ligand B has 5. Both are within the acceptable limits of <=10.

**QED:** Both ligands have good QED scores (0.637 and 0.726), indicating drug-like properties.

**DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (35.285). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (54.246) and Ligand B (35.828) are both low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.534 and -4.929), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-0.663 and -2.977), indicating poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Ligand A (0.037) has a very low hERG risk, which is excellent. Ligand B (0.249) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-11.02) has a negative clearance, which is not physically possible. This suggests a data error or a very stable compound. Ligand B (39.572) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-23.796) has a negative half-life, which is not physically possible. This is a major issue. Ligand B (-2.345) has a low half-life, which is not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0 and 0.058), which is favorable.

**Binding Affinity:** Ligand A (-7.9) has a significantly better binding affinity than Ligand B (0). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, the negative values for clearance and half-life are critical flaws. These suggest data errors or fundamentally problematic properties. Ligand B, while having a weaker binding affinity, has more reasonable (though still not ideal) ADME properties. The lower DILI risk for Ligand B is also a significant advantage. The poor Caco-2 and solubility for both are concerning, but could potentially be addressed with formulation strategies. Given the data issues with Ligand A, Ligand B is the more viable candidate, even with its weaker binding.

Output:
1
2025-04-17 12:38:52,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.331 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (61.88).  A TPSA under 140 is good for oral absorption, and both are well within this limit, but A is preferable.

**logP:** Ligand A (4.204) is slightly higher than the optimal 1-3 range, while Ligand B (1.169) is on the lower side. While high logP can cause issues, the difference isn't drastic.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 4. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have good QED scores (0.756 and 0.809), indicating good drug-like properties.

**DILI:** Ligand A (68.205) has a higher DILI risk than Ligand B (23.575). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration (73.827 and 65.839), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**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 poor solubility. This is a major concern for both, but Ligand B (-1.483) is slightly better than Ligand A (-5.391).

**hERG:** Ligand A (0.831) has a slightly higher hERG risk than Ligand B (0.252). Lower is better here, so B is preferable.

**Microsomal Clearance:** Ligand A (59.72) has a significantly better (lower) microsomal clearance than Ligand B (7.298). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.094) has a very short half-life, while Ligand B (15.755) has a much longer half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.334 and 0.064), which is good.

**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 has advantages in TPSA and microsomal clearance, but suffers from higher DILI risk, poor solubility, and a very short half-life. Ligand B has better solubility, a much longer half-life, lower DILI and hERG risk, but has a higher TPSA. Given the priorities for enzyme inhibitors (metabolic stability, solubility, and safety), Ligand B is the more promising candidate despite the slightly higher TPSA. The longer half-life and lower toxicity profile are more valuable than the slightly better TPSA of Ligand A.

Output:
1
2025-04-17 12:38:52,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.43 and 349.43 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (82.78 and 86.88) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (1.81 and 1.62) are within the optimal 1-3 range, suggesting good permeability and avoiding solubility issues.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria. Ligand B is slightly better here.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.738 and 0.843), indicating drug-likeness. Ligand B is better.

**7. DILI:** Both ligands have acceptable DILI risk (28.5 and 35.7 percentile), well below the concerning threshold of 60. Ligand B is slightly better.

**8. BBB:** This isn't a primary concern for a non-CNS target like SRC kinase. Both are moderate (51.4 and 49.0).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.56), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.57 and -1.41), which is also concerning and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.22 and 0.40), which is excellent.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (36.76 and 37.44 mL/min/kg), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand B (32.57 hours) has a significantly longer half-life than Ligand A (15.54 hours). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.16 and 0.45), which is good.

**15. Binding Affinity:** Ligand A (-8.3 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 automatically outweigh other factors.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior overall. The most significant advantage of Ligand B is its substantially longer in vitro half-life. This is a critical factor for an enzyme inhibitor, as it directly impacts dosing frequency and potential patient compliance. Ligand B also has slightly better QED, DILI, and P-gp efflux scores. The poor Caco-2 and solubility scores are concerning for both, but the improved half-life of Ligand B makes it the more promising candidate, assuming these solubility/permeability issues can be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 12:38:52,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (345.359 and 350.434 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (106.51) is better than Ligand B (67.43) as it is closer to the ideal threshold of 140.

**logP:** Both ligands have acceptable logP values (0.938 and 1.852), falling within the optimal range of 1-3. Ligand B is slightly better.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.719) has a better QED score than Ligand B (0.519), indicating a more drug-like profile.

**DILI:** Ligand B (16.557) has a significantly lower DILI risk than Ligand A (76.89), which is a major advantage.

**BBB:** Both have high BBB penetration (80.69 and 83.443), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unexpected and problematic. However, the scale is not defined, so we can't interpret this definitively.

**Aqueous Solubility:** Both have negative solubility values, which is also problematic. Again, the scale is undefined.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.266 and 0.325). This is excellent.

**Microsomal Clearance:** Ligand B (15.093) has a slightly lower microsomal clearance than Ligand A (12.514), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (14.946 hours) has a longer in vitro half-life than Ligand A (26.468 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.057).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a substantially better binding affinity than Ligand A (-10.0 kcal/mol). This is the most critical factor for an enzyme inhibitor. The difference of 2.6 kcal/mol is substantial and likely outweighs minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having a better QED and TPSA, Ligand B is the superior candidate. The significantly improved binding affinity (-7.4 vs -10.0 kcal/mol) and lower DILI risk are decisive advantages for an oncology kinase inhibitor. The slightly better metabolic stability and longer half-life of Ligand B further solidify its position as the more promising drug candidate. The negative Caco-2 and Solubility values are concerning for both, but the binding affinity difference is likely to be the deciding factor in initial optimization.

Output:
1
2025-04-17 12:38:52,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.531 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (67.43).  A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**3. logP:** Both ligands have acceptable logP values (3.482 and 2.64), falling within the 1-3 optimal 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 reasonable QED values (0.716 and 0.672), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (12.718 and 12.214 percentile), which is excellent.

**8. BBB:** Both have reasonable BBB penetration (86.274 and 74.06 percentile), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.407) has a significantly *better* Caco-2 permeability value than Ligand B (-4.73), suggesting better absorption. Note that these values are negative, and closer to zero is better.

**10. Aqueous Solubility:** Ligand A (-3.9) has a slightly better aqueous solubility than Ligand B (-3.25). Both are reasonable, but higher is preferred.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.394 and 0.379 percentile), which is crucial.

**12. Microsomal Clearance:** Ligand B (58.007 mL/min/kg) has a lower microsomal clearance than Ligand A (74.079 mL/min/kg), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (16.399 hours) has a significantly longer half-life than Ligand B (6.002 hours). This is a substantial advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.087 percentile), which is favorable.

**15. 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 and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity, better Caco-2 permeability, better solubility, and a significantly longer half-life. Ligand B has better metabolic stability (lower Cl_mic). However, the longer half-life and slightly improved binding affinity of Ligand A are more critical for an enzyme target like SRC kinase. The differences in metabolic stability, while present, are not so large as to negate the benefits of the other properties.

Output:
1
2025-04-17 12:38:52,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (478.225 Da) is towards the higher end, while Ligand B (345.399 Da) is comfortably within the range.

**TPSA:** Ligand A (42.96) is excellent, well below the 140 threshold for oral absorption. Ligand B (93.46) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Both ligands have good logP values (A: 3.002, B: 1.874), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (A: 1, B: 2) and HBA (A: 5, B: 5) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (A: 0.554, B: 0.762), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (56.34). This is a major advantage for Ligand A.

**BBB:**  BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (77.2) shows better penetration potential than Ligand B (56.534).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. However, the absolute value is more important than the sign. Ligand A (-5.127) is slightly better than Ligand B (-4.86).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand A (-2.767) is slightly better than Ligand B (-2.307). This is a significant concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.848, B: 0.329). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (38.037) has a slightly higher microsomal clearance than Ligand B (34.532), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (36.932) has a significantly longer in vitro half-life than Ligand A (5.465), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.459, B: 0.045). Ligand B is significantly better here.

**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 not huge (0.3 kcal/mol), it is still a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in DILI risk and has slightly better Caco-2 and solubility. However, Ligand B has a significantly longer half-life, better P-gp efflux, slightly better affinity, and a higher QED score. The longer half-life and better affinity of Ligand B are crucial for an enzyme target, outweighing the slightly higher DILI risk. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 12:38:52,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (392.861 and 370.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.96) is better than Ligand B (85.69), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.766) is slightly better than Ligand B (0.283), both are a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 6 HBA) is slightly better than Ligand B (1 HBD, 7 HBA), both are within acceptable ranges.

**QED:** Both ligands have good QED scores (0.566 and 0.742), indicating good drug-like properties.

**DILI:** Ligand A (59.403) has a lower DILI risk than Ligand B (64.327), both are acceptable but A is preferable.

**BBB:** Both ligands have low BBB penetration (48.352 and 56.146), which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.256 and -5.104), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.182 and -2.187). This is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.118 and 0.051), which is excellent.

**Microsomal Clearance:** Ligand A (-5.383) has significantly better metabolic stability (lower clearance) than Ligand B (11.024). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (58.036) has a much longer half-life than Ligand B (-18.709), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.026), which is favorable.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). While the difference is not huge, it's enough to be considered.

**Conclusion:**

Considering all factors, **Ligand A is the more promising candidate.** It has a slightly better binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and slightly better TPSA. While both ligands suffer from poor solubility and permeability, the improved metabolic profile of Ligand A is critical for an enzyme target like SRC kinase. The small advantage in binding affinity further strengthens its position.

Output:
1
2025-04-17 12:38:52,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 B (67.87) is significantly better than Ligand A (91.73). Lower TPSA generally translates to better cell permeability.

**logP:** Both ligands have good logP values (A: 2.649, B: 1.288) falling within the optimal 1-3 range. Ligand B is slightly lower, which could potentially impact permeability, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.869) has a higher QED score than Ligand B (0.731), indicating a more drug-like profile.

**DILI:** Ligand B (23.575) has a much lower DILI risk than Ligand A (90.733). This is a significant advantage for Ligand B.

**BBB:** Ligand B (68.554) has a slightly better BBB penetration percentile than Ligand A (59.325), but this isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.035) has a more negative Caco-2 value, which is less favorable than Ligand B (-4.92).

**Aqueous Solubility:** Ligand A (-4.675) has a more negative solubility value, indicating lower solubility than Ligand B (-2.347). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.259, B: 0.285), which is good.

**Microsomal Clearance:** Ligand A (-11.955) has significantly lower (better) microsomal clearance than Ligand B (37.679). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (41.209 hours) has a much longer in vitro half-life than Ligand B (5.936 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.162, B: 0.039).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.3 kcal/mol). The difference is 1.4 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, longer half-life, and lower clearance. However, Ligand B has a significantly lower DILI risk, better solubility, and a lower TPSA. The DILI risk for Ligand A is quite high. While the affinity difference is notable, the improved safety profile (DILI) and solubility of Ligand B are more important considerations for an enzyme inhibitor. The longer half-life of Ligand A is attractive, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:38:52,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is better than Ligand B (86.47) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand B (2.425) is optimal (1-3), while Ligand A (0.494) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7 HBA, both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.735 and 0.776, respectively), indicating drug-like properties.

**DILI:** Ligand A (11.051) has a significantly lower DILI risk than Ligand B (50.174), which is a major advantage.

**BBB:** Both have low BBB penetration, which isn't critical for an oncology target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the scale isn't specified, so it's hard to interpret.

**Solubility:** Ligand A (-0.883) has slightly better solubility than Ligand B (-3.239).

**hERG:** Ligand A (0.17) has a much lower hERG risk than Ligand B (0.068), a critical safety parameter.

**Microsomal Clearance:** Ligand A (-15.714) has a much lower (better) microsomal clearance than Ligand B (35.269), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.337) has a shorter half-life than Ligand B (-35.541). This is a negative for Ligand A.

**P-gp:** Both have low P-gp efflux liability.

**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.

**Overall Assessment:**

Despite Ligand A's better TPSA, DILI, hERG, and clearance, the significantly superior binding affinity of Ligand B (-8.6 vs -0.0 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. A strong binding advantage can often outweigh minor ADME drawbacks. While the low logP of Ligand A is concerning, the substantial potency of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 12:38:52,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (333.391 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.39) is well below the 140 threshold, while Ligand B (93.46) is closer but still acceptable.

**logP:** Ligand A (3.86) is at the higher end of the optimal 1-3 range, while Ligand B (2.271) is comfortably within it. Ligand A's higher logP *could* lead to off-target effects, but isn't immediately disqualifying.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bonds, within the recommended limits.

**QED:** Both ligands have acceptable QED scores (0.683 and 0.583, both > 0.5).

**DILI:** Both ligands have similar DILI risk (65.917 and 64.521), indicating a moderate risk. This isn't ideal, but not a major differentiator.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.302) and Ligand B (-5.046) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Ligand A (-5.469) and Ligand B (-3.46) both have very poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.557 and 0.139), which is excellent.

**Microsomal Clearance:** Ligand B (39.935) has significantly lower microsomal clearance than Ligand A (123.917). This suggests better metabolic stability for Ligand B, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-16.699) has a negative half-life, which is concerning and indicates very rapid metabolism. Ligand A (20.52) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.333 and 0.17).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.6 kcal/mol). This is a strong point for both.

**Overall Assessment:**

Despite similar binding affinities, Ligand B appears to be the more promising candidate. While its half-life is concerning, its significantly lower microsomal clearance suggests better metabolic stability overall. Ligand A has a better half-life, but its higher clearance is a significant disadvantage. Both have poor solubility and permeability, which would require formulation strategies to address. The DILI risk is moderate for both. Given the enzyme-specific priorities, metabolic stability (reflected in lower Cl_mic) is crucial, making Ligand B slightly preferable.

Output:
1
2025-04-17 12:38:52,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (346.471 and 357.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (99.69).  A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B is approaching a level that could hinder absorption.

**3. logP:** Both ligands (2.249 and 2.103) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors (HBA):** Ligand A (3) is good, while Ligand B (7) is higher.  Keeping HBA below 10 is preferred.

**6. QED:** Ligand A (0.889) is considerably better than Ligand B (0.672), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.556) has a much lower DILI risk than Ligand B (80.729).  Ligand B's DILI is concerningly high.

**8. BBB:**  Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (57.193) is lower than Ligand B (33.501).

**9. Caco-2:** Ligand A (-4.369) is better than Ligand B (-5.805), suggesting better intestinal absorption.

**10. Solubility:** Ligand A (-1.868) is better than Ligand B (-2.886), indicating better aqueous solubility.

**11. hERG:** Both ligands (0.687 and 0.421) have low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand B (37.589) has a lower microsomal clearance than Ligand A (65.161), suggesting better metabolic stability. This is a key factor for kinases.

**13. t1/2:** Ligand B (35.181) has a much longer in vitro half-life than Ligand A (-5.307). This is a significant advantage.

**14. Pgp:** Both ligands (0.439 and 0.149) have low P-gp efflux liability.

**15. Binding Affinity:** Ligand A (-9.3) has a significantly stronger binding affinity than Ligand B (-8.0). A difference of >1.5 kcal/mol is substantial.

**Overall Assessment:**

Ligand A excels in most drug-like properties (QED, solubility, TPSA, DILI, affinity) and absorption (Caco-2). However, it has a higher Cl_mic and shorter half-life. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), but suffers from a higher TPSA, significantly higher DILI risk, and weaker binding affinity.

For an enzyme like SRC kinase, potency (affinity) and metabolic stability are crucial. While Ligand B's metabolic stability is better, the substantial difference in binding affinity (-9.3 vs -8.0 kcal/mol) and the concerning DILI risk of Ligand B outweigh this benefit. The stronger binding of Ligand A suggests it will be more effective at lower doses, potentially mitigating some of the metabolic concerns.

Output:
0
2025-04-17 12:38:52,383 - INFO - Batch 147 complete. Total preferences: 2352
2025-04-17 12:38:52,383 - INFO - Processing batch 148/512...
2025-04-17 12:39:32,100 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.6) is better than Ligand B (81.65) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (3.927 and 2.882, respectively) within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=2, HBA=6) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.826 and 0.706), indicating good drug-likeness.

**DILI:** Ligand A (54.168) has a slightly better DILI score than Ligand B (60.217), indicating a lower risk of liver injury. Both are acceptable (<60 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.588) has a higher BBB score than Ligand A (62.854), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.529) has a worse Caco-2 permeability than Ligand B (-5.496), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.96) has a worse solubility than Ligand B (-2.953).

**hERG Inhibition:** Ligand A (0.318) has a significantly lower hERG inhibition liability than Ligand B (0.796), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand B (45.963) has a significantly lower microsomal clearance than Ligand A (103.281), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (29.304) has a much longer in vitro half-life than Ligand A (-2.724), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.196), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is the most important factor for an enzyme target. The 1.6 kcal/mol difference is substantial.

**Conclusion:**

While Ligand A has advantages in terms of DILI and hERG, Ligand B's superior binding affinity (-8.2 vs -6.6 kcal/mol) and significantly better metabolic stability (lower Cl_mic and longer t1/2) outweigh the drawbacks in solubility and Caco-2 permeability. The strong binding affinity is paramount for an enzyme inhibitor.

Output:
1
2025-04-17 12:39:32,100 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.403 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.05) is better than Ligand B (94.56), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have acceptable logP values (1.235 and 0.784), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is slightly better than Ligand B (HBD=3, HBA=5) in terms of H-bonding potential, staying within the recommended limits.

**QED:** Ligand A (0.782) has a significantly better QED score than Ligand B (0.605), indicating a more drug-like profile.

**DILI:** Ligand B (33.579) has a much lower DILI risk than Ligand A (59.829), which is a significant advantage.

**BBB:** Ligand A (68.554) has a better BBB penetration score than Ligand B (27.608), but BBB is not a high priority for a kinase inhibitor unless CNS effects are specifically desired.

**Caco-2 Permeability:** Ligand A (-4.864) has better Caco-2 permeability than Ligand B (-5.294), indicating better absorption.

**Aqueous Solubility:** Ligand B (-1.27) has better aqueous solubility than Ligand A (-2.889), which is a positive.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.145 and 0.159).

**Microsomal Clearance:** Ligand B (-16.376) exhibits significantly lower microsomal clearance than Ligand A (43.584), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (11.513 hours) has a longer in vitro half-life than Ligand A (16.631 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.124 and 0.007).

**Binding Affinity:** Ligand B (-8.4 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.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better Caco-2 permeability and BBB penetration, Ligand B excels in critical areas for kinase inhibitors: significantly lower DILI risk, substantially improved metabolic stability (lower Cl_mic and longer t1/2), better aqueous solubility, and a slightly improved binding affinity. The higher QED of Ligand A is beneficial, but the ADME advantages of Ligand B are more impactful for this target class.

Output:
1
2025-04-17 12:39:32,100 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.342 Da and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is slightly higher than Ligand B (67.43), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.869 and 3.341, respectively), 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 3. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.836) has a significantly better QED score than Ligand B (0.468), indicating a more drug-like profile.

**DILI:** Ligand B (26.871) has a much lower DILI risk than Ligand A (88.639). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (74.254 and 73.75). BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 sometimes be overcome with formulation strategies.

**hERG:** Both ligands have low hERG inhibition risk (0.58 and 0.583).

**Microsomal Clearance:** Ligand B (67.917) has lower microsomal clearance than Ligand A (79.761), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (29.024) has a longer half-life than Ligand B (-10.455). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Both have similar P-gp efflux liability (0.247 and 0.395).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.7 kcal/mol and -8.6 kcal/mol). Ligand A has a 1.1 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a better QED score and slightly better binding affinity and half-life, but suffers from significantly higher DILI risk and higher microsomal clearance. Ligand B has a much lower DILI risk and better metabolic stability, but a lower QED score and a potentially problematic negative half-life value.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), and the substantial difference in DILI and Cl_mic, **Ligand B is the more promising candidate**. The binding affinity difference, while significant, is likely outweighed by the improved safety and metabolic stability profile of Ligand B. The poor solubility and Caco-2 values are drawbacks, but formulation strategies could potentially address these. The negative half-life for Ligand B is a red flag, but could be an artifact of the measurement or a rapidly reversible binding event.

Output:
1
2025-04-17 12:39:32,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.362 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.58) is higher than Ligand B (58.64). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands (2.29 and 2.216) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.919) has a much higher QED score than Ligand B (0.484), indicating better overall drug-likeness.

**DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (10.237). This is a significant concern for Ligand A.

**BBB:** Ligand A (75.107) has a moderate BBB penetration, while Ligand B (88.406) has a higher one. While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.741) is slightly better than Ligand A (-4.439).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-2.12) is slightly better than Ligand A (-2.933).

**hERG Inhibition:** Ligand A (0.19) has a lower hERG risk than Ligand B (0.578), which is a significant advantage.

**Microsomal Clearance:** Ligand A (42.668) has lower microsomal clearance than Ligand B (50.179), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.811) has a much longer in vitro half-life than Ligand A (-2.408), a major advantage.

**P-gp Efflux:** Ligand A (0.032) has lower P-gp efflux than Ligand B (0.207), which is better.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.9). 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 (lower Cl_mic, lower P-gp efflux) and hERG risk. However, it has a significantly higher DILI risk and a much shorter half-life. Ligand B has a better safety profile (lower DILI) and a longer half-life, but its binding affinity is considerably weaker and its QED score is lower.

Given the priority for potency in enzyme inhibition, the significantly stronger binding affinity of Ligand A (-9.0 kcal/mol vs -7.9 kcal/mol) is a crucial factor. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The shorter half-life is also a concern, but could also be addressed through medicinal chemistry. The weaker affinity of Ligand B makes it less likely to be a successful starting point, even with its better ADME properties.

Output:
1
2025-04-17 12:39:32,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (339.355 and 350.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.48) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (55.89) is well within the optimal range.

**3. logP:** Ligand A (1.925) is within the optimal 1-3 range. Ligand B (0.918) is slightly below 1, which *could* indicate potential permeability issues, but isn't a dealbreaker.

**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 7 HBAs, and Ligand B has 4. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.729 and 0.819, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (98.488 percentile), which is a significant concern. Ligand B has a very low DILI risk (9.616 percentile), a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.237) and Ligand B (64.25) are both moderate.

**9. Caco-2 Permeability:** Ligand A (-4.967) and Ligand B (-4.93) are similar and suggest poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.819) and Ligand B (-1.332) both suggest poor solubility. Ligand B is better.

**11. hERG Inhibition:** Ligand A (0.231) and Ligand B (0.406) are both low, indicating low cardiotoxicity risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (95.155) has high clearance, suggesting poor metabolic stability. Ligand B (-5.911) has *negative* clearance, which is unusual and suggests very high metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (4.219) has a relatively short half-life. Ligand B (-1.433) has a very long half-life.

**14. P-gp Efflux:** Ligand A (0.181) and Ligand B (0.021) both indicate low P-gp efflux, which is favorable.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). The difference of 2 kcal/mol is substantial and can often outweigh minor ADME drawbacks.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and metabolic stability, has a better solubility profile, and comparable hERG risk. While both have poor Caco-2 permeability, the superior binding affinity and significantly improved metabolic stability of Ligand B make it the more promising candidate. The high DILI risk of Ligand A is a major red flag.

Output:
1
2025-04-17 12:39:32,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.5 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is better than Ligand B (82.53), both are acceptable, but lower is generally preferred for permeability.

**logP:** Ligand A (2.406) is optimal (1-3), while Ligand B (0.972) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 4 HBA), both are within acceptable limits.

**QED:** Ligand B (0.83) has a significantly higher QED score than Ligand A (0.563), indicating better overall drug-likeness.

**DILI:** Ligand A (22.8) has a much lower DILI risk than Ligand B (32.726), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.83) is better than Ligand B (63.164).

**Caco-2 Permeability:** Ligand A (-5.19) is better than Ligand B (-4.752). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.579) is better than Ligand B (-1.821). Higher solubility is desirable.

**hERG Inhibition:** Ligand A (0.808) is better than Ligand B (0.185), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (38.065) has a higher (worse) microsomal clearance than Ligand B (-0.162), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-23.759) has a much longer in vitro half-life than Ligand A (-37.473), a significant advantage.

**P-gp Efflux:** Ligand A (0.086) is better than Ligand B (0.025), indicating lower P-gp efflux.

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -7.4 kcal/mol), both are good, but Ligand A is slightly better.

**Overall Assessment:**

Ligand A excels in binding affinity, solubility, DILI risk, and hERG inhibition. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a higher QED score. The slightly lower logP of Ligand B is a concern, but the substantial improvements in metabolic stability and QED, coupled with acceptable binding affinity, make it the more promising candidate. While Ligand A has a slightly better affinity, the metabolic liabilities of Ligand A are concerning for *in vivo* efficacy.

Output:
1
2025-04-17 12:39:32,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (368.459 Da and 342.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (113.44) is better than Ligand B (67.23) as it is still within the acceptable range for oral absorption (<140), while ligand B is significantly lower, potentially indicating a lack of necessary interactions.

**3. logP:** Ligand B (2.154) is optimal (1-3), while Ligand A (0.368) is quite low, 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 (7) is acceptable, while Ligand B (4) is also good.

**6. QED:** Both ligands have similar and good QED values (0.607 and 0.61).

**7. DILI:** Ligand B (35.324) has a much lower DILI risk than Ligand A (68.903), which is a significant advantage.

**8. BBB:** Ligand B (52.772) has a better BBB penetration than Ligand A (23.42), but BBB is not a high priority for SRC kinase inhibitors as it is not a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.49) is significantly worse than Ligand B (-4.659).

**10. Aqueous Solubility:** Ligand A (-2.251) is slightly better than Ligand B (-2.546).

**11. hERG Inhibition:** Ligand A (0.078) has a lower hERG risk than Ligand B (0.121).

**12. Microsomal Clearance:** Ligand B (12.065) has a lower microsomal clearance, indicating better metabolic stability, than Ligand A (15.769).

**13. In vitro Half-Life:** Ligand B (-5.554) has a longer in vitro half-life than Ligand A (-13.09).

**14. P-gp Efflux:** Ligand A (0.006) has lower P-gp efflux liability than Ligand B (0.026).

**15. Binding Affinity:** Ligand A (-9.6 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 threshold.

**Enzyme-Specific Priorities:** For enzyme inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a much better binding affinity. Ligand B has better metabolic stability and lower DILI risk. Solubility is similar. hERG risk is also better for ligand A.

**Overall Assessment:** The significantly stronger binding affinity of Ligand A (-9.6 kcal/mol vs -7.8 kcal/mol) is a major advantage that likely outweighs the slightly higher DILI risk and lower metabolic stability. The difference in binding affinity is substantial.

Output:
1
2025-04-17 12:39:32,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 and 373.55 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (37.61) as it is closer to the ideal value for oral absorption (<140).

**logP:** Both ligands have logP values (3.56 and 4.35) within the optimal 1-3 range, but Ligand B is slightly higher, potentially increasing off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (0 HBD, 5 HBA) as it is closer to the ideal values.

**QED:** Both ligands have acceptable QED scores (0.8 and 0.551), indicating good drug-likeness.

**DILI:** Ligand A (55.06) has a slightly higher DILI risk than Ligand B (50.14), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (85.03) has a higher BBB score than Ligand B (77.82).

**Caco-2 Permeability:** Ligand A (-4.53) has a lower Caco-2 permeability than Ligand B (-5.55), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.90) has a lower solubility than Ligand B (-3.53).

**hERG Inhibition:** Ligand A (0.68) has a lower hERG inhibition liability than Ligand B (0.95), which is a significant advantage.

**Microsomal Clearance:** Ligand A (0.53) has significantly lower microsomal clearance than Ligand B (125.94), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (8.84) has a shorter half-life than Ligand B (49.68), but the difference is less important given the low clearance of Ligand A.

**P-gp Efflux:** Ligand A (0.40) has lower P-gp efflux than Ligand B (0.92), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Overall:** Considering all factors, Ligand A is the more promising candidate. While Ligand B has slightly better Caco-2 permeability and solubility, Ligand A excels in metabolic stability (much lower Cl_mic), lower hERG risk, and lower P-gp efflux. These are crucial properties for an enzyme inhibitor, and the similar binding affinities make these ADMET properties the deciding factors.

Output:
0
2025-04-17 12:39:32,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.443 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.39) is higher than Ligand B (58.64). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Ligand A (0.306) is quite low, potentially hindering membrane permeability. Ligand B (2.072) 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. Ligand B has 1 HBD and 3 HBA. Both are acceptable, but Ligand B's lower count is slightly preferable for permeability.

**QED:** Both ligands have good QED scores (0.72 and 0.771), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 74.99, which is concerning (high risk). Ligand B has a much lower DILI risk of 21.404, a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (95.657) than Ligand A (32.765), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.504) has poor Caco-2 permeability, while Ligand B (-4.497) is better, though still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.731 and -2.96). This could pose formulation challenges, but is not a dealbreaker.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.595 and 0.665), which is good.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (34.908), indicating poor metabolic stability. Ligand B has a lower clearance (22.35), suggesting better stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-39.788), which is problematic. Ligand B has a negative half-life as well (-7.957), but it is less negative.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.134), which is favorable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has slightly better binding affinity than Ligand B (-6.9 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold that would strongly favor A despite other drawbacks.

**Overall:**

Ligand B is the stronger candidate. While its solubility and Caco-2 permeability are not ideal, its significantly lower DILI risk, better logP, lower microsomal clearance, and acceptable binding affinity outweigh the slightly weaker affinity compared to Ligand A. Ligand A's high DILI risk and poor metabolic stability are major red flags.

Output:
1
2025-04-17 12:39:32,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.47 & 387.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.82) is better than Ligand B (70.58), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (1.577 & 1.997) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (0), but both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.773 & 0.808), indicating drug-like properties.

**DILI:** Ligand A (54.48) has a lower DILI risk than Ligand B (62.20), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (85.46) has a higher BBB score than Ligand A (55.64).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.433) is slightly better than Ligand B (-4.819), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-2.311) is slightly better than Ligand B (-3.712).

**hERG Inhibition:** Ligand A (0.208) has a significantly lower hERG risk than Ligand B (0.737), a major advantage.

**Microsomal Clearance:** Ligand A (27.453) has a higher (worse) microsomal clearance than Ligand B (16.853), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-25.474) has a significantly longer in vitro half-life than Ligand A (45.971), a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.088 & 0.081).

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a crucial difference, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite Ligand B having better metabolic stability (lower Cl_mic, longer t1/2) and slightly better BBB penetration, Ligand A's substantially stronger binding affinity (-10.5 vs -7.8 kcal/mol) and lower hERG risk are decisive. The poor solubility and permeability are concerning for both, but the potency advantage of Ligand A is likely to be more impactful in driving efficacy, and the lower hERG risk is critical for safety.

Output:
1
2025-04-17 12:39:32,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 and 340.43 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.53 and 85.94) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.058 and 1.908), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability, although both are within reasonable limits.

**QED:** Both ligands have good QED scores (0.837 and 0.724), indicating drug-like properties.

**DILI:** Ligand A (32.45) has a significantly lower DILI risk than Ligand B (65.37), which is a major advantage. Ligand B is approaching a concerning DILI percentile.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (73.67) has a higher BBB penetration than Ligand A (46.88).

**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 this definitively.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern, but can often be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.225) has a much lower hERG inhibition liability than Ligand B (0.771), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-10.525) has a much *lower* (better) microsomal clearance than Ligand B (40.076), indicating better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (4.246) has a shorter half-life than Ligand B (8.353), but both are relatively low.

**P-gp Efflux:** Ligand A (0.033) has a lower P-gp efflux liability than Ligand B (0.071), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.3 kcal/mol), although both are good. The 0.9 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the superior candidate. It has a significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, these are formulation challenges that can be addressed. The safety and pharmacokinetic advantages of Ligand A outweigh the slight difference in half-life and the higher BBB penetration of Ligand B.

Output:
0
2025-04-17 12:39:32,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.455 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is better than Ligand B (87.3), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Ligand B (1.126) is slightly better than Ligand A (0.186). A is quite low, potentially hindering permeability. B is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (3).

**QED:** Ligand A (0.827) is significantly better than Ligand B (0.629), indicating a more drug-like profile.

**DILI:** Ligand B (29.43) is much better than Ligand A (49.593). Lower DILI is crucial.

**BBB:** Both ligands have similar BBB penetration (56.495 and 54.207), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Both ligands have similar negative Caco-2 values (-5.183 and -5.06), indicating poor permeability.

**Solubility:** Both ligands have similar negative solubility values (-2.277 and -2.961), suggesting poor aqueous solubility.

**hERG:** Ligand A (0.036) is significantly better than Ligand B (0.074), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (49.566) is slightly better than Ligand A (26.499) - lower is better for metabolic stability.

**In vitro Half-Life:** Ligand B (-1.277) is better than Ligand A (16.382). A negative value is unusual and likely indicates a very rapid clearance, while B has a short half-life, but still better than A.

**P-gp Efflux:** Ligand A (0.015) is much better than Ligand B (0.058), indicating lower efflux.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly better binding affinity than Ligand A (-8.1 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most critical factor for an enzyme inhibitor. While Ligand A has better QED, P-gp efflux, and hERG, Ligand B's superior affinity and lower DILI risk are more important. The slightly better metabolic stability of B is also a plus. The solubility and permeability issues are similar for both and would need to be addressed in further optimization.

Output:
1
2025-04-17 12:39:32,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.829 and 367.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is slightly higher than Ligand B (61.44), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.372 and 2.767, respectively), 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 A (0.826) has a significantly better QED score than Ligand B (0.705), indicating a more drug-like profile.

**DILI:** Ligand B (33.501) has a much lower DILI risk than Ligand A (84.917), which is a significant advantage.

**BBB:** Ligand B (54.052) has a higher BBB penetration percentile than Ligand A (18.147). While not a primary concern for a kinase inhibitor, it's a slight positive for B.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.96 and -4.953). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.05 and -2.582). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.01) has a much lower hERG inhibition risk than Ligand B (0.56), which is a major advantage.

**Microsomal Clearance:** Ligand A (23.757) has a significantly lower microsomal clearance than Ligand B (60.421), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (59.068) has a much longer in vitro half-life than Ligand A (-1.301), which is a significant advantage.

**P-gp Efflux:** Ligand B (0.221) has lower P-gp efflux liability than Ligand A (0.03), which is a positive.

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-7.2), although the difference is small (0.1 kcal/mol).

**Overall Assessment:**

Ligand A has better QED, lower hERG risk, and better metabolic stability (lower Cl_mic). However, Ligand B has a much lower DILI risk, longer half-life, and lower P-gp efflux. Both have poor solubility and Caco-2 permeability. Given the enzyme-specific priorities, metabolic stability (Cl_mic) and hERG risk are crucial. While the difference in binding affinity is minimal, the significantly lower DILI and longer half-life of Ligand B, combined with acceptable hERG, make it the more promising candidate despite the slightly lower QED and affinity. The poor solubility and permeability are shared concerns that would need to be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 12:39:32,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.375 Da and 354.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.11) is higher than Ligand B (58.64). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.213) is quite low, potentially hindering membrane permeability. Ligand B (3.373) 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, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits, but Ligand B is slightly more balanced.

**QED:** Both ligands have similar QED values (0.664 and 0.654), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 66.421, which is concerning (high risk). Ligand B has a much lower DILI risk of 10.741, a major advantage.

**BBB:** Both ligands have good BBB penetration (71.772 and 80.419), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.541 and -4.404), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.996) and Ligand B (-3.018) both have negative solubility values, indicating poor aqueous solubility, which could hinder bioavailability. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.143) has a very low hERG risk, which is excellent. Ligand B (0.433) is slightly higher, but still acceptable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (85.834 and 85.855), indicating similar metabolic stability. This isn't ideal (relatively high clearance), but comparable between the two.

**In vitro Half-Life:** Ligand A (11.359 hours) has a slightly longer half-life than Ligand B (9.059 hours), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.096), which is good.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a massive difference and a strong argument in favor of Ligand A.

**Overall Assessment:**

While Ligand A has a concerningly high DILI risk and low logP, its *significantly* superior binding affinity (-8.3 vs -0.0 kcal/mol) is a decisive factor. The potency advantage is so large that it could potentially outweigh the other drawbacks, especially if further modifications can address the DILI and solubility issues. Ligand B, while having better physicochemical properties in some areas (logP, TPSA, DILI), simply doesn't bind with sufficient affinity to be a viable candidate.

Output:
0
2025-04-17 12:39:32,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.418 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is better than Ligand B (87.66). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**logP:** Ligand A (2.534) is optimal, while Ligand B (1.398) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=3, HBA=5). Both are within acceptable limits, but A has a more favorable balance.

**QED:** Both ligands have similar QED values (0.746 and 0.647), indicating good drug-likeness.

**DILI:** Ligand A (27.685) has a significantly lower DILI risk than Ligand B (35.595), which is a substantial advantage. Both are below the 40 threshold.

**BBB:** Ligand A (81.233) shows better BBB penetration than Ligand B (40.403), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.692) is worse than Ligand B (-5.288). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.437) is better than Ligand B (-1.953). Both are negative, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.458 and 0.266).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (34.022 and 34.074), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-0.263) has a slightly better in vitro half-life than Ligand B (29.749).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.105).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -8.7 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, logP, lower DILI risk, better BBB penetration, and slightly better solubility and half-life. While both have poor Caco-2 permeability and solubility, Ligand A's other properties make it a more promising candidate. The similar binding affinities mean that the ADME/Tox profile is the deciding factor.

Output:
1
2025-04-17 12:39:32,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.443 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (71.84) is significantly better than Ligand B (139.1). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (3.074) is optimal, while Ligand B (0.008) is very low. Low logP can hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better balanced. Ligand B has 3 HBD and 9 HBA, which is higher and could impact permeability.

**QED:** Ligand A (0.826) has a much better drug-likeness score than Ligand B (0.514).

**DILI:** Ligand B (83.986) has a significantly higher DILI risk than Ligand A (66.731). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.037) is better than Ligand B (22.528).

**Caco-2 Permeability:** Both have negative values, indicating low permeability. Ligand A (-5.273) is slightly less negative than Ligand B (-5.751), suggesting marginally better permeability.

**Aqueous Solubility:** Both have negative values, indicating low solubility. Ligand A (-3.628) is slightly better than Ligand B (-2.373).

**hERG:** Both ligands have very low hERG inhibition liability (0.205 and 0.201), which is excellent.

**Microsomal Clearance:** Ligand A (14.881) has lower microsomal clearance than Ligand B (20.513), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (55.008 hours) has a much longer half-life than Ligand B (-27.909 hours). This is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.38 and 0.061).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is less than 1.5 kcal/mol, and the other ADME properties of Ligand A are far superior.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the much more promising drug candidate. It has better drug-likeness, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable logP and TPSA. The solubility and permeability are both poor, but similar between the two, and can be addressed with formulation strategies. The superior ADME profile of Ligand A outweighs the small difference in binding affinity.

Output:
0
2025-04-17 12:39:32,102 - INFO - Batch 148 complete. Total preferences: 2368
2025-04-17 12:39:32,102 - INFO - Processing batch 149/512...
2025-04-17 12:40:10,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (329.403 and 358.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.04) is well below the 140 threshold and very favorable. Ligand B (58.64) is also acceptable, but slightly higher.

**logP:** Ligand A (4.845) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.998) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4/3) counts, well within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.727 and 0.642), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (84.684%) compared to Ligand B (18.728%). This is a major concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (74.06% and 81.776%), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.938 and -4.576), which is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon for compounds with specific structural features.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.857 and -2.809). This is a significant drawback for both, but could be mitigated through formulation strategies.

**hERG Inhibition:** Ligand A (0.751) has a slightly higher hERG risk than Ligand B (0.453), but both are reasonably low.

**Microsomal Clearance:** Ligand A (79.597) has a higher microsomal clearance than Ligand B (10.79), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-11.551) has a slightly longer in vitro half-life than Ligand A (-13.213), but both are negative values, suggesting rapid degradation.

**P-gp Efflux:** Ligand A (0.447) has lower P-gp efflux than Ligand B (0.075), which is favorable.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 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, which is the most important factor for an enzyme inhibitor. However, its high DILI risk and higher microsomal clearance are major concerns. Ligand B has a better safety profile (lower DILI) and metabolic stability, but its binding affinity is weaker. Given the substantial difference in binding affinity, and the potential to mitigate solubility issues with formulation, Ligand A is the more promising candidate *despite* the ADME liabilities. Further optimization could focus on reducing the DILI risk and improving metabolic stability while maintaining the strong binding affinity.

Output:
0
2025-04-17 12:40:10,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.475 and 345.359 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (109.14) is better than Ligand B (130.24). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal value.

**logP:** Both ligands have similar logP values (-0.18 and -0.246), which are slightly below the optimal range of 1-3. This could potentially impact permeability, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, while Ligand B has 3 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.681) has a better QED score than Ligand A (0.477), indicating a more drug-like profile.

**DILI:** Ligand A (44.513) has a significantly lower DILI risk than Ligand B (73.982). This is a crucial advantage.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.671 and -5.447), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.418 and -2.451), also unusual and indicating very poor solubility. This is a major concern for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.035). This is excellent.

**Microsomal Clearance:** Ligand A (-12.708) has a much lower (better) microsomal clearance than Ligand B (4.159), indicating greater metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (41.059) has a substantially longer in vitro half-life than Ligand B (9.311). This is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.016 and 0.01).

**Binding Affinity:** Both have similar and strong binding affinities (-8.6 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a slightly better QED score, Ligand A is significantly better in terms of DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and has comparable binding affinity. The poor Caco-2 and solubility for both are concerning, but the superior ADME profile of Ligand A, particularly the lower DILI and better metabolic stability, makes it the more promising candidate. The enzyme-specific priorities heavily favor Ligand A.

Output:
0
2025-04-17 12:40:10,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (381.523 Da) is still acceptable.

**TPSA:** Ligand A (71.35) is better than Ligand B (92.5). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal value.

**logP:** Both ligands have good logP values (A: 2.637, B: 1.136) within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and good QED values (A: 0.714, B: 0.741), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 36.06, B: 36.293), both well below the 40 threshold.

**BBB:** Ligand A (35.207) has a lower BBB penetration percentile than Ligand B (74.486). However, since SRC is not a CNS target, BBB is not a critical factor here.

**Caco-2 Permeability:** Ligand A (-4.689) has worse Caco-2 permeability than Ligand B (-5.605). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.522) has better aqueous solubility than Ligand B (-2.242). Solubility is important for bioavailability, making A preferable.

**hERG:** Ligand A (0.818) has a slightly better hERG profile than Ligand B (0.189), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (62.694) has a higher microsomal clearance than Ligand B (24.107). This means Ligand B is more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (4.926) has a shorter half-life than Ligand B (-19.648). The negative value for B suggests a very long half-life, which is highly desirable.

**P-gp Efflux:** Ligand A (0.28) has lower P-gp efflux than Ligand B (0.097), meaning A is less likely to be pumped out of cells.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility, hERG, and P-gp efflux, Ligand B's significantly stronger binding affinity (-8.4 vs -6.9 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are more critical for an enzyme inhibitor. The slightly lower solubility and permeability of Ligand B can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 12:40:10,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.39 and 345.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (139.22) is borderline acceptable for oral absorption, while Ligand B (64.86) is well within the desirable range.

**logP:** Ligand A (-0.724) is a bit low, potentially hindering permeation. Ligand B (2.818) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 9 HBA, both acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.61 and 0.859), indicating drug-like properties.

**DILI:** Ligand A (84.65) has a higher DILI risk than Ligand B (37.61), which is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (74.06) has a better score than Ligand A (25.17).

**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 indicating potential issues with the prediction method or the compounds. The values are similar.

**hERG:** Ligand A (0.028) has a very low hERG risk, which is excellent. Ligand B (0.285) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (16.86) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (26.24).

**In vitro Half-Life:** Ligand B (7.65) has a much longer half-life than Ligand A (-3.57), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol) - a difference of 1.7 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better hERG profile and lower clearance, Ligand B's significantly superior binding affinity (-9.1 vs -7.4 kcal/mol) outweighs these minor drawbacks, especially for an enzyme target where potency is paramount. The lower DILI risk and longer half-life of Ligand B are also very favorable. The slightly better logP and TPSA of Ligand B also contribute to its overall better profile.

Output:
1
2025-04-17 12:40:10,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.46 and 356.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is well below the 140 threshold, while Ligand B (107.89) is still acceptable but higher. Lower TPSA generally favors better absorption.

**logP:** Ligand A (1.836) is optimal (1-3), while Ligand B (0.334) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (4 HBD, 5 HBA) both have acceptable counts, within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED scores (0.696 and 0.549), indicating good drug-like properties.

**DILI:** Ligand A (16.6) has a significantly lower DILI risk than Ligand B (12.6), making it safer from a liver toxicity perspective.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (83.3) has a higher BBB percentile than Ligand B (27.3).

**Caco-2 Permeability:** Ligand A (-4.534) is significantly better than Ligand B (-5.09), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.202) is better than Ligand B (-0.86), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.599) has a lower hERG risk than Ligand B (0.063), which is a significant advantage.

**Microsomal Clearance:** Ligand A (69.283) has a higher (worse) microsomal clearance than Ligand B (-1.854), indicating lower metabolic stability. This is a key drawback for Ligand A.

**In vitro Half-Life:** Ligand A (11.551) has a longer half-life than Ligand B (5.687), which is generally desirable.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux liability than Ligand B (0.01), which is favorable.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.0), but the difference is small (0.1 kcal/mol).

**Overall Assessment:**

Ligand A has several advantages: better TPSA, logP, solubility, DILI risk, Caco-2 permeability, hERG risk, and P-gp efflux. However, its major drawback is the higher microsomal clearance, indicating poorer metabolic stability. Ligand B has better metabolic stability and slightly better binding affinity, but suffers from a lower logP, higher DILI risk, and poorer permeability. Given that SRC kinases are intracellular targets, metabolic stability is crucial. However, the difference in binding affinity is minimal, and Ligand A's other favorable properties, especially the lower DILI and hERG risks, make it a more promising candidate. The metabolic stability issue of Ligand A could potentially be addressed through structural modifications.

Output:
1
2025-04-17 12:40:10,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.431 and 357.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is significantly better than Ligand B (46.09), being well below the 140 threshold for oral absorption.

**logP:** Ligand A (1.698) is optimal (1-3), while Ligand B (4.428) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**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 ranges.

**QED:** Both ligands have similar QED values (0.83 and 0.795), indicating good drug-likeness.

**DILI:** Ligand A (43.195) has a slightly higher DILI risk than Ligand B (27.685), but both are below the concerning threshold of 60.

**BBB:** Ligand A (45.909) has a lower BBB penetration than Ligand B (89.802). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.079) and Ligand B (-4.766) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a potential concern for both.

**Aqueous Solubility:** Ligand A (-1.428) has better solubility than Ligand B (-4.196). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.137) has a much lower hERG inhibition liability than Ligand B (0.417), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (40.338) has lower microsomal clearance than Ligand B (72.435), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.653) has a longer half-life than Ligand B (-1.373), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.018) has lower P-gp efflux than Ligand B (0.277), improving oral bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have excellent binding affinity, Ligand A demonstrates superior ADME properties: better logP, solubility, lower hERG risk, lower microsomal clearance, longer half-life, and lower P-gp efflux. The slightly higher DILI risk is outweighed by these advantages. The negative Caco-2 values are a concern for both, but the other favorable properties of Ligand A make it the better choice for further optimization.

Output:
0
2025-04-17 12:40:10,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.399 and 361.433 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.54) is better than Ligand B (87.3), both being below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.982 and 1.739), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3). Both are below the 10 threshold.

**QED:** Ligand A (0.852) has a significantly better QED score than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand A (53.276) has a higher DILI risk than Ligand B (23.924), but both are below the concerning 60 threshold.

**BBB:** Both ligands have reasonable BBB penetration (75.533 and 80.613), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and potentially problematic. However, the values are similar (-4.693 and -4.893).

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and potentially problematic. Ligand B (-2.207) is slightly better than Ligand A (-1.638).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.157 and 0.224), which is excellent.

**Microsomal Clearance:** Ligand A (19.229) has a higher microsomal clearance than Ligand B (16.591), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (19.391) has a better in vitro half-life than Ligand B (-5.534).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.089 and 0.015).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand B having slightly better metabolic stability and DILI risk, Ligand A is the superior candidate. The significantly stronger binding affinity (-9.4 vs -8.5 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Ligand A also has a better QED score and fewer H-bond donors, contributing to a more favorable drug-like profile. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of Ligand A is likely to be more impactful in early development.

Output:
1
2025-04-17 12:40:10,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.354 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.2) is better than Ligand B (69.48). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (1.916) is optimal (1-3), while Ligand A (-0.492) is slightly below, which could hinder permeation.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0), as some H-bond donors are good for solubility. Both are within the acceptable limit of <=5.

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

**QED:** Both ligands have good QED scores (0.62 and 0.785, respectively), indicating drug-like properties.

**DILI:** Ligand B (47.77) has a lower DILI risk than Ligand A (59.829), making it more favorable. Both are below the 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (75.572) is higher than Ligand A (59.364).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.228) is worse than Ligand B (-4.584).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.099) is worse than Ligand B (-2.353).

**hERG Inhibition:** Both ligands have very low hERG risk (0.104 and 0.115).

**Microsomal Clearance:** Ligand A (-31.781) has significantly lower (better) microsomal clearance than Ligand B (49.247), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (18.623) has a much longer half-life than Ligand A (4.168), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.054).

**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 substantial enough to overcome other issues.

**Overall Assessment:**

Ligand A has a better binding affinity and better metabolic stability (lower Cl_mic). However, Ligand B has better solubility, permeability, lower DILI risk, and a significantly longer half-life. Given the enzyme-specific priorities, metabolic stability and half-life are crucial. The slightly better affinity of Ligand A is not enough to outweigh the significant advantage of Ligand B's pharmacokinetic properties.

Output:
1
2025-04-17 12:40:10,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.25) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (89.87) is excellent, well below 140.

**logP:** Ligand A (0.094) is quite low, potentially hindering permeability. Ligand B (1.52) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.627 and 0.754, both >0.5).

**DILI:** Ligand A (35.014) has a slightly higher DILI risk than Ligand B (20.706), but both are below the concerning threshold of 60.

**BBB:**  BBB is not a major concern for a non-CNS target like SRC kinase, but Ligand A (52.734) is higher than Ligand B (18.147).

**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.

**Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unclear.

**hERG:** Both ligands have very low hERG inhibition risk (0.198 and 0.285).

**Microsomal Clearance:** Ligand A (0.831) has significantly lower microsomal clearance than Ligand B (5.856), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (17.766 hours) has a much longer half-life than Ligand B (-21.282 hours - this is a negative value and likely an error or outlier).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.011 and 0.038).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand A has a major drawback in its very low logP, which could severely limit its permeability. While it has better metabolic stability (lower Cl_mic, longer t1/2), the poor logP is a significant concern. Ligand B has a more favorable logP and a slightly better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the more favorable ADME profile of Ligand B, particularly the logP and metabolic stability, makes it the more promising candidate. The negative half-life for Ligand B is suspicious and would need further investigation, but even discounting that, the other factors favor Ligand B.

Output:
1
2025-04-17 12:40:10,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (360.443 and 350.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (101.8 and 107.95) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (0.905 and 1.282) are within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 7 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (65.723) has a higher DILI risk than Ligand B (29.934). This is a significant drawback for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (72.005) has a higher BBB penetration than Ligand A (46.607), but this is not a major deciding factor here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is less important than the trend. Ligand A (-5.935) is slightly worse than Ligand B (-5.362).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-1.492) is slightly better than Ligand B (-1.983).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.04 and 0.069), which is excellent.

**12. Microsomal Clearance:** Ligand A (9.325) has significantly lower microsomal clearance than Ligand B (21.718). This indicates better metabolic stability for Ligand A, a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (32.353) has a longer in vitro half-life than Ligand B (-1.654). This further supports the better metabolic stability of Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.092 and 0.029), which is favorable.

**15. 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 (0.2 kcal/mol).

**Overall Assessment:**

While Ligand B has slightly better binding affinity and BBB penetration, Ligand A is significantly better in terms of metabolic stability (lower Cl_mic, longer t1/2) and has a much lower DILI risk. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the improved metabolic stability and reduced toxicity of Ligand A outweigh the minor difference in binding affinity. The negative Caco-2 and solubility values are concerning for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 12:40:10,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.849 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.5) is higher than Ligand B (49.41). While both are reasonably low, B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (3.014 and 3.355), 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 2. Both are acceptable, but B is slightly better.

**QED:** Ligand A (0.907) has a significantly higher QED score than Ligand B (0.793), indicating a more drug-like profile.

**DILI:** Ligand A (71.617) has a higher DILI risk than Ligand B (10.585). This is a significant negative for Ligand A.

**BBB:** Ligand A (83.249) has a good BBB penetration score, while Ligand B (96.743) is even better. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.985 and -4.713). 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 (-3.763 and -3.391). Again, the scale is unknown, but these suggest poor solubility.

**hERG:** Ligand A (0.269) has a slightly higher hERG risk than Ligand B (0.687), but both are relatively low.

**Microsomal Clearance:** Ligand A (65.275) has a higher microsomal clearance than Ligand B (18.625), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-12.667) has a negative half-life, which is impossible and suggests an issue with the data. Ligand A (18.19) is reasonable.

**P-gp Efflux:** Ligand A (0.133) has lower P-gp efflux than Ligand B (0.077), which is slightly favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Conclusion:**

Despite Ligand A having a better QED and BBB score, Ligand B is the superior candidate. The dramatically stronger binding affinity (-7.7 vs 0 kcal/mol) of Ligand B outweighs the slightly lower QED. Furthermore, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is concerning, but the affinity difference is so large that it's worth investigating if that data point is an error. The poor solubility and permeability are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 12:40:10,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.397 and 373.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.43) is significantly better than Ligand B (107.97). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (2.124) is optimal (1-3), while Ligand B (-1.03) is below 1, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=6) both fall within acceptable ranges, but A is slightly better.

**QED:** Ligand A (0.798) has a better QED score than Ligand B (0.527), indicating better overall drug-likeness.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (29.236), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (92.904) has a much higher BBB percentile than Ligand B (27.026).

**Caco-2 Permeability:** Ligand A (-5.051) and Ligand B (-5.686) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.186) is slightly better than Ligand B (-1.443), both are poor.

**hERG:** Ligand A (0.782) has a lower hERG risk than Ligand B (0.089), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-8.666) has a much lower (better) microsomal clearance than Ligand B (-14.878), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.874) has a longer half-life than Ligand B (-6.861), which is desirable.

**P-gp Efflux:** Ligand A (0.091) has a lower P-gp efflux liability than Ligand B (0.005), which is preferable.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This difference of 1.7 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall:** Ligand A is superior. It has a better logP, QED, hERG, microsomal clearance, half-life, P-gp efflux, and binding affinity. While Ligand B has a slightly lower DILI risk, the other advantages of Ligand A, particularly its improved predicted permeability and metabolic stability, make it the more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 12:40:10,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (52.65), both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.577 and 2.296), 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 HBA, both are acceptable.

**QED:** Both ligands have good QED scores (0.543 and 0.683), indicating good drug-like properties.

**DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (10.857). This is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A is better (78.79 vs 63.086). While not a primary concern for a kinase inhibitor, it's a slight positive for A.

**Caco-2 Permeability:** Ligand A (-4.924) has a worse Caco-2 permeability than Ligand B (-5.249). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.247) has slightly worse solubility than Ligand B (-1.059).

**hERG Inhibition:** Ligand A (0.26) shows a much lower hERG inhibition liability than Ligand B (0.701). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (58.778) has a significantly higher microsomal clearance than Ligand B (24.562). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (8.77) has a much longer in vitro half-life than Ligand A (-11.264). This is a significant advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux than Ligand B (0.212), which is favorable.

**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 and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a much lower DILI risk and hERG inhibition liability. The difference in binding affinity (1.2 kcal/mol) is substantial enough to likely overcome the slightly worse solubility and permeability of Ligand B, especially given the importance of potency for kinase inhibitors. The lower DILI and hERG risk of Ligand A are valuable, but the potency advantage of Ligand B is more critical.

Output:
1
2025-04-17 12:40:10,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (346.383 and 361.397 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.94) is better than Ligand B (110.45). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred value for oral absorption.

**3. logP:** Ligand A (1.272) is optimal, while Ligand B (0.278) is slightly low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands (A: 2, B: 3) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (5) is better than Ligand B (9), as lower HBA generally improves permeability.

**6. QED:** Ligand A (0.756) has a significantly better QED score than Ligand B (0.541), indicating a more drug-like profile.

**7. DILI:** Ligand B (57.658) has a slightly better DILI score than Ligand A (65.374), but both are acceptable (<60 is good).

**8. BBB:** Ligand B (68.282) has a slightly better BBB score than Ligand A (56.611), but BBB is not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both are negative, but Ligand A (-5.07) is less negative than Ligand B (-5.288), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both are negative, but Ligand A (-3.572) is less negative than Ligand B (-2.696), suggesting slightly better solubility.

**11. hERG Inhibition:** Ligand A (0.154) has a much lower hERG risk than Ligand B (0.63). This is a significant advantage.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-11.455) has a much lower (better) microsomal clearance than Ligand B (10.321), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.104) has a better in vitro half-life than Ligand B (-17.938).

**14. P-gp Efflux:** Ligand A (0.061) has a much lower P-gp efflux liability than Ligand B (0.002), suggesting better bioavailability.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This difference in potency is substantial.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. Ligand A excels in all these areas. The affinity difference is significant, and the improved metabolic stability and reduced hERG risk are crucial for drug development.

Output:
1
2025-04-17 12:40:10,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.5 & 365.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.16) is better than Ligand B (23.47) as it is closer to the 140 threshold, and ligand B is quite low, which might indicate poor solubility.

**logP:** Ligand A (2.357) is optimal (1-3). Ligand B (4.84) is slightly high, potentially leading to solubility issues and off-target effects.

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

**QED:** Both ligands have similar, good QED values (0.835 and 0.838).

**DILI:** Ligand A (82.435) has a higher DILI risk than Ligand B (12.796). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (64.831 and 83.831), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.924 and -4.877), which is unusual and suggests a potential issue with permeability prediction or data quality. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.721 and -3.851), which is also unusual and suggests a potential issue with solubility prediction or data quality. However, the values are similar.

**hERG:** Ligand A (0.323) has a lower hERG risk than Ligand B (0.988), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand B (14.373) has significantly lower microsomal clearance than Ligand A (45.624), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (24.631) has a slightly longer half-life than Ligand A (28.962), although the difference is not substantial.

**P-gp Efflux:** Ligand A (0.48) shows lower P-gp efflux than Ligand B (0.958), which is favorable.

**Binding Affinity:** Ligand B (-9.1 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, and can often outweigh minor ADME concerns.

**Conclusion:**

Despite Ligand A's lower hERG and P-gp efflux, the significantly better binding affinity, lower DILI risk, and improved metabolic stability of Ligand B make it the more promising drug candidate. The slightly higher logP of Ligand B is a minor concern that could be addressed with further optimization, but the potency and safety advantages are substantial.

Output:
1
2025-04-17 12:40:10,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (67.87) is better than Ligand B (78.43). Both are below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have good logP values (A: 1.421, B: 2.065), 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=3) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.582) has a better QED score than Ligand B (0.447), indicating a more drug-like profile.

**DILI:** Ligand B (29.003) has a significantly lower DILI risk than Ligand A (35.052), which is a major advantage.

**BBB:** Ligand A (71.501) has a higher BBB percentile than Ligand B (65.452). While not crucial for a non-CNS target like SRC, it's a minor positive.

**Caco-2 Permeability:** Ligand A (-4.587) shows better Caco-2 permeability than Ligand B (-5.052).

**Aqueous Solubility:** Ligand A (-2.592) has better aqueous solubility than Ligand B (-2.881). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.138) has a lower hERG inhibition liability than Ligand B (0.551), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (23.262) has a lower microsomal clearance than Ligand A (29.301), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (0.376) has a slightly better in vitro half-life than Ligand A (-3.507), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.047) shows lower P-gp efflux than Ligand B (0.057).

**Binding Affinity:** Ligand B (-10.0 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.

**Conclusion:**

While Ligand A has advantages in solubility, Caco-2 permeability, and BBB, Ligand B's significantly stronger binding affinity (-10.0 vs -7.3 kcal/mol) and better metabolic stability (lower Cl_mic and better t1/2) are crucial for an enzyme inhibitor. The lower DILI and hERG risks for Ligand B further strengthen its profile. The QED score is lower for Ligand B, but the potency advantage is likely to outweigh this.

Output:
1
2025-04-17 12:40:10,325 - INFO - Batch 149 complete. Total preferences: 2384
2025-04-17 12:40:10,325 - INFO - Processing batch 150/512...
2025-04-17 12:40:51,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.406 and 341.386 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (47.48), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (1.455) is optimal, while Ligand B (3.601) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, which is also acceptable.

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

**QED:** Both ligands have acceptable QED scores (0.866 and 0.685, respectively), indicating good drug-like properties.

**DILI:** Ligand A (41.411) has a much lower DILI risk than Ligand B (70.88). This is a significant advantage for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (77.2) is slightly better than Ligand A (57.154).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.801) is slightly better than Ligand B (-4.409).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand A (-2.022) is slightly better than Ligand B (-4.203).

**hERG Inhibition:** Ligand A (0.679) has a lower hERG risk than Ligand B (0.921). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-12.092) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (75.62). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (13.66 hours) has a shorter half-life than Ligand B (28.621 hours). However, the difference isn't drastic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.564 respectively).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is the better candidate. While both ligands have good binding affinity, Ligand A demonstrates significantly better ADME properties, specifically a much lower DILI risk and significantly improved metabolic stability (lower Cl_mic). The slightly better solubility and hERG risk profile of Ligand A further contribute to its superiority. The poor Caco-2 and solubility are concerning for both, but the metabolic stability and safety profile of Ligand A outweigh these drawbacks.

Output:
0
2025-04-17 12:40:51,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.303 Da and 389.708 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (75.48) is still under 140, but less optimal than A.

**logP:** Both ligands (4.053 and 3.548) are within the optimal 1-3 range, but Ligand A is slightly higher.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4 HBA, both acceptable (<=10).

**QED:** Ligand A (0.794) has a significantly better QED score than Ligand B (0.419), indicating a more drug-like profile.

**DILI:** Both ligands have similar, high DILI risk (76.309 and 76.89). This is a concern for both, but not a differentiating factor.

**BBB:** Both have reasonable BBB penetration (68.786 and 71.539), but this isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.381 and -4.704), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.968 and -4.295), indicating poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG risk (0.687 and 0.709), which is positive.

**Microsomal Clearance:** Ligand A (63.158) has lower microsomal clearance than Ligand B (73.89), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.766) has a slightly better (less negative) in vitro half-life than Ligand B (55.839).

**P-gp Efflux:** Both have low P-gp efflux liability (0.193 and 0.226), which is good.

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility profiles of both compounds, the significantly stronger binding affinity of Ligand B (-8.5 kcal/mol vs -7.6 kcal/mol) is a decisive factor. The improved potency outweighs the slightly worse QED and microsomal clearance. While both have high DILI risk, this is a concern that can be addressed during further optimization. The better metabolic stability of Ligand A is a plus, but the potency difference is more critical for an enzyme target.

Output:
1
2025-04-17 12:40:51,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (369.531 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is slightly higher than Ligand B (70.15), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.843) is within the optimal 1-3 range. Ligand B (3.556) is at the higher end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.588 and 0.642), indicating generally drug-like properties.

**DILI:** Ligand A (11.4) has a significantly lower DILI risk than Ligand B (57.348). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (69.95) has a higher BBB value than Ligand A (31.485), but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.439) has a worse Caco-2 permeability than Ligand B (-4.663), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.127) shows slightly better aqueous solubility than Ligand B (-3.937).

**hERG:** Ligand A (0.408) has a lower hERG risk than Ligand B (0.629), which is favorable.

**Microsomal Clearance:** Ligand A (8.344) has a significantly lower microsomal clearance than Ligand B (69.036), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (24.1) has a shorter half-life than Ligand B (-33.472, which is very good). However, the negative value for B is likely an error or represents a very long half-life.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux liability than Ligand B (0.738), which is beneficial for oral bioavailability.

**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). This difference is unlikely to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A exhibits significantly better metabolic stability (lower Cl_mic), lower DILI risk, lower hERG risk, and lower P-gp efflux. These factors are critical for a successful enzyme inhibitor, outweighing the minor difference in binding affinity.

Output:
0
2025-04-17 12:40:51,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.36 and 355.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (110.52 and 107.97) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.192) is optimal, while Ligand B (-0.594) is below 1, which may impede permeation.

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

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

**QED:** Both ligands have QED values above 0.5 (0.75 and 0.512), indicating good drug-likeness.

**DILI:** Ligand A (63.09%) has a higher DILI risk than Ligand B (24.12%). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.4%) is slightly better than Ligand B (43.1%).

**Caco-2:** Both have negative values, indicating poor permeability. However, the scale is not specified, making direct comparison difficult.

**Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (0.533 and 0.082), which is good.

**Microsomal Clearance:** Ligand A (49.301) has a higher clearance than Ligand B (12.187), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-0.905) has a slightly better half-life than Ligand A (-23.627).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.023).

**Binding Affinity:** Both ligands have strong binding affinities (-9.3 and -8.7 kcal/mol). Ligand A is slightly better (-9.3 kcal/mol), but the difference (0.6 kcal/mol) is not substantial enough to overcome its other drawbacks.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has slightly better binding affinity, Ligand B exhibits significantly better predicted ADME properties, specifically lower DILI risk and better metabolic stability (lower Cl_mic and better half-life). The logP value for Ligand B is also more favorable. The slightly lower binding affinity of Ligand B is likely surmountable with further optimization, while addressing the ADME issues of Ligand A would be more challenging.

Output:
1
2025-04-17 12:40:51,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (355.438 and 360.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly higher than Ligand B (55.57), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have logP values around 4.1-4.3, which is slightly high. This could potentially lead to solubility issues or 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:** 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 (0.612 and 0.726), indicating a generally drug-like profile.

**7. DILI:** Ligand A has a DILI risk of 71.152, which is concerning (high risk). Ligand B has a much lower DILI risk of 46.452, which is good. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (69.523) and Ligand B (89.608) both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.297 and -4.837). This is unusual and suggests poor permeability, but these values can sometimes be unreliable or indicate issues with the prediction method.

**10. Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-4.798 and -5.166). This is a significant drawback for both, but could be mitigated through formulation strategies.

**11. hERG Inhibition:** Ligand A (0.624) has a slightly higher hERG risk than Ligand B (0.569), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (80.834) has lower microsomal clearance than Ligand B (101.079), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (0.995) has a very short in vitro half-life, while Ligand B (-2.832) has a negative value, which is also concerning. Both suggest poor stability.

**14. P-gp Efflux:** Ligand A (0.885) has moderate P-gp efflux, while Ligand B (0.533) has lower efflux. Lower efflux is preferable.

**15. Binding Affinity:** Ligand B (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.8 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 and permeability concerns, Ligand B's significantly stronger binding affinity (-10.1 vs -7.8 kcal/mol) and much lower DILI risk (46.452 vs 71.152) are decisive advantages. The slightly better metabolic stability of Ligand A is outweighed by these factors. The negative Caco-2 and half-life values are concerning for both, and would require further investigation, but the potency and safety profile of Ligand B make it the better choice.

Output:
1
2025-04-17 12:40:51,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.53) is slightly higher than Ligand B (350.42), but both are acceptable.

**TPSA:** Ligand A (78.43) is better than Ligand B (96.55). Lower TPSA generally favors oral absorption.

**logP:** Ligand A (3.073) is optimal, while Ligand B (-0.105) is significantly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds can improve permeability.

**QED:** Both ligands have good QED scores (A: 0.661, B: 0.747), indicating drug-like properties.

**DILI:** Ligand A (39.05) has a slightly higher DILI risk than Ligand B (29.43), but both are considered good (below 40).

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (55.293) is higher than Ligand A (44.281), but this is less important.

**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 very low hERG risk (A: 0.266, B: 0.233), which is excellent.

**Microsomal Clearance:** Ligand A (38.373) has a higher clearance than Ligand B (-2.446). This means Ligand B is likely more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-6.118) has a significantly longer half-life than Ligand A (14.877). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.283, B: 0.013), 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 small, it's within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better logP and TPSA, Ligand B excels in metabolic stability (lower Cl_mic, longer half-life), and has a slightly better binding affinity. The low logP of Ligand A is a significant concern for permeability. The negative solubility and Caco-2 values for both are concerning, but the other factors favor Ligand B.

Output:
1
2025-04-17 12:40:51,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.785 and 343.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.75) is slightly higher than the preferred <140, but acceptable. Ligand B (54.26) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.981 and 2.69), falling within the 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 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.84 and 0.809), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 85.847, which is high and concerning. Ligand B has a much lower DILI risk of 48.546, which is preferable.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (79.139) has a higher BBB percentile than Ligand A (69.833), but this isn't a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we'll assume these represent low permeability for now.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. This suggests poor solubility. Ligand B (-2.83) is slightly better than Ligand A (-4.146).

**hERG:** Ligand A (0.281) has a slightly higher hERG risk than Ligand B (0.53), but both are relatively low.

**Microsomal Clearance:** Ligand B (87.403) has significantly higher microsomal clearance than Ligand A (36.187). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (23.845) has a longer half-life than Ligand B (19.68), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.224 and 0.344).

**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:**

Ligand B is the stronger binder, which is the most important factor for an enzyme inhibitor. While both have solubility issues, Ligand B's significantly lower DILI risk and superior binding affinity outweigh Ligand A's better metabolic stability and slightly longer half-life. The solubility issues would need to be addressed through formulation strategies.

Output:
1
2025-04-17 12:40:51,983 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (343.35 and 372.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (115.96 and 108.99) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (0.773) is within the optimal 1-3 range. Ligand B (-0.112) is slightly below 1, which *could* indicate permeability issues, but not drastically.

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

**5. H-Bond Acceptors:** Ligand A has 8 HBA, and Ligand B has 7, both under the limit of 10.

**6. QED:** Both ligands have good QED scores (0.661 and 0.746), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 94.184, which is high. Ligand B has a much lower DILI risk of 55.758, which is still above the ideal <40, but significantly better. This is a major concern for Ligand A.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern. Ligand A (63.09) and Ligand B (48.97) are both low.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.221 and -5.012), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-2.7 and -1.903), which is also unusual and suggests poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have low hERG risk (0.276 and 0.265), which is excellent.

**12. Cl_mic:** Ligand A has a moderate microsomal clearance (46.571), while Ligand B has a very low clearance (1.399). This indicates much better metabolic stability for Ligand B, a key factor for kinase inhibitors.

**13. t1/2:** Ligand A has a half-life of 59.986 hours, while Ligand B has a very short half-life (-0.049 hours). This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.056 and 0.024), which is good.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-7.8 kcal/mol) than Ligand B (-7.1 kcal/mol). The difference is 0.7 kcal/mol, which is a meaningful advantage.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity and longer half-life, its significantly higher DILI risk and moderate clearance make it a less desirable candidate. Ligand B, while having a weaker affinity and a very short half-life, exhibits a much lower DILI risk and excellent metabolic stability (very low Cl_mic). Given the enzyme-kinase specific priorities, metabolic stability and safety (DILI) are crucial. The poor Caco-2 and solubility for both ligands are concerning, but could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 12:40:51,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.45 and 370.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.36) is slightly above the optimal <140 for oral absorption, while Ligand B (93.65) is well within the range.

**logP:** Both ligands (0.775 and 0.945) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 4 HBA, within the acceptable range. Ligand B has 7 HBA, still within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.592 and 0.768), indicating good drug-like properties.

**DILI:** Ligand A (50.989) has a lower DILI risk than Ligand B (68.786), both are acceptable, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (59.054) and Ligand B (48.119) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.57 and -4.878). This is unusual and indicates poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.073 and -2.332). This is also unusual and indicates poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.31 and 0.173).

**Microsomal Clearance:** Ligand A (3.691) has significantly lower microsomal clearance than Ligand B (28.448), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-20.503) has a longer in vitro half-life than Ligand B (4.924), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.091 and 0.083).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better ADME properties (lower DILI, lower Cl_mic, longer t1/2), Ligand B boasts a considerably stronger binding affinity. For an enzyme target like SRC kinase, potency is paramount. The difference in binding affinity is significant enough to favor Ligand B, despite its slightly worse ADME profile. The poor Caco-2 and solubility values are concerning for both, but these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:40:51,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.762 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (64.21) is significantly better than Ligand B (91.76). Lower TPSA generally favors better absorption.

**logP:** Ligand A (4.157) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.437) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar, acceptable QED values (Ligand A: 0.737, Ligand B: 0.675).

**DILI:** Ligand A (72.509) has a higher DILI risk than Ligand B (12.408). This is a significant drawback for Ligand A.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**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 them relatively.

**Aqueous Solubility:** Both ligands have very poor predicted solubility (-4.608 and -1.263).

**hERG Inhibition:** Ligand A (0.606) has a slightly better hERG profile than Ligand B (0.06).

**Microsomal Clearance:** Ligand B (34.79) has significantly lower microsomal clearance than Ligand A (71.483), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-7.429) has a longer half-life than Ligand A (6.394).

**P-gp Efflux:** Ligand A (0.507) has lower P-gp efflux than Ligand B (0.015), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially better binding affinity than Ligand B (-7.1 kcal/mol). This 1.6 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher logP, and poorer metabolic stability. Ligand B has a better safety profile (lower DILI), better metabolic stability, and longer half-life, but its binding affinity is considerably weaker and its logP is too low.

Given the importance of potency for enzyme inhibition, and the substantial difference in binding affinity, I would cautiously favor Ligand A, *provided* that the DILI risk can be mitigated through structural modifications. The solubility issues of both compounds need to be addressed.

Output:
1
2025-04-17 12:40:51,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.441) is slightly higher than Ligand B (333.439), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 59, well below the 140 threshold for oral absorption.

**logP:** Ligand A (1.196) is optimal, while Ligand B (4.073) 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 (1 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.594, B: 0.783), indicating drug-likeness.

**DILI:** Ligand A (35.479) has a lower DILI risk than Ligand B (41.954), both are acceptable.

**BBB:** Ligand A (90.772) has a much higher BBB penetration potential than Ligand B (53.703). While not crucial for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.725) has a worse Caco-2 permeability than Ligand B (-5.229).

**Aqueous Solubility:** Ligand A (-2.24) has a better aqueous solubility than Ligand B (-4.395). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.689, B: 0.602).

**Microsomal Clearance:** Ligand A (25.946) has a higher microsomal clearance than Ligand B (20.667), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-52.107) has a significantly longer in vitro half-life than Ligand A (12.28), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.1, B: 0.469).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and BBB penetration, Ligand B's significantly stronger binding affinity and longer half-life are more critical for an enzyme inhibitor targeting SRC. The slightly higher logP of Ligand B is a minor concern compared to the substantial improvement in potency and metabolic stability.

Output:
1
2025-04-17 12:40:51,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (355.479 and 354.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is slightly higher than Ligand B (77.1). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets (not a priority here).

**3. logP:** Ligand A (0.783) is a bit lower than Ligand B (0.918), both are 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 (4) is lower than Ligand B (5), both are below the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.63 and 0.656), indicating good drug-like properties.

**7. DILI:** Ligand A (27.453) has a slightly lower DILI risk than Ligand B (29.934), both are well below the concerning threshold of 60.

**8. BBB:** Ligand B (72.237) has a higher BBB penetration percentile than Ligand A (53.781). This isn't a major concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.987) has a more negative Caco-2 value than Ligand B (-4.753), indicating potentially *lower* permeability. This is a slight negative for Ligand A.

**10. Aqueous Solubility:** Ligand A (-1.757) has a more negative solubility value than Ligand B (-2.25), indicating *lower* solubility. This is a negative for Ligand A.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.215 and 0.285), which is excellent.

**12. Microsomal Clearance:** Ligand A (27.452) has significantly lower microsomal clearance than Ligand B (49.046), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (7.27) has a lower in vitro half-life than Ligand B (16.272). This is a negative for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.042).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While Ligand A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a clear advantage in metabolic stability (lower Cl_mic) and a slightly lower DILI risk. However, it suffers from lower Caco-2 permeability, lower solubility, and a shorter half-life. Ligand B has better permeability, solubility, and half-life, and only slightly weaker binding affinity. Given the importance of metabolic stability for kinase inhibitors (to ensure sufficient exposure), and the relatively small difference in binding affinity, Ligand A appears to be the better candidate.

Output:
0
2025-04-17 12:40:51,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.451 and 349.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.69) is better than Ligand B (71.53), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (1.942 and 1.349), falling within the optimal 1-3 range.

**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 similar QED values (0.884 and 0.807), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 68.476, which is moderately high. Ligand B has a much lower DILI risk of 25.165, which is very favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (87.515) has a higher BBB penetration than Ligand A (51.454), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.831 and -4.499). This is unusual and suggests poor permeability *in vitro*. However, these values are on a scale where negative values are possible, and the absolute value is more important. They are relatively similar.

**Aqueous Solubility:** Both have negative solubility values (-2.037 and -2.384), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.403 and 0.419), which is excellent.

**Microsomal Clearance:** Ligand A (11.973) has a lower microsomal clearance than Ligand B (15.966), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (1.934) has a slightly longer half-life than Ligand B (-4.37), which is preferable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.086 and 0.084).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand B has a much better DILI profile, Ligand A's significantly superior binding affinity (-9.5 vs -8.6 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme inhibitor. The DILI risk of Ligand A is moderate, and formulation strategies could potentially mitigate the solubility issues of both compounds. The stronger binding affinity is likely to translate to greater efficacy, making Ligand A the more promising candidate.

Output:
1
2025-04-17 12:40:51,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.49 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (79.26), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands have good logP values (1.487 and 1.183), 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, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.743 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A (20.9) has a significantly lower DILI risk than Ligand B (33.424). This is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (70.919) is slightly better than Ligand B (68.282). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.148) is better than Ligand B (-4.914), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.073) is better than Ligand B (-2.505), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.432) has a lower hERG risk than Ligand B (0.362), which is a positive attribute.

**Microsomal Clearance:** Ligand A (-2.095) has a much lower (better) microsomal clearance than Ligand B (33.636). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-1.168) has a better in vitro half-life than Ligand B (17.927). This aligns with the improved metabolic stability.

**P-gp Efflux:** Ligand A (0.064) has a lower P-gp efflux liability than Ligand B (0.043).

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is 1.1 kcal/mol, which, while noticeable, isn't huge enough to overcome the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly regarding DILI risk, metabolic stability (Cl_mic and t1/2), solubility, and Caco-2 permeability. These factors are crucial for kinase inhibitors, where maintaining adequate systemic exposure is vital. The lower DILI risk is a significant safety advantage.

Output:
1
2025-04-17 12:40:51,985 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.49 and 370.56 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (66.48) as both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have similar and optimal logP values (2.82 and 2.77), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are acceptable.

**QED:** Ligand B (0.782) has a higher QED score than Ligand A (0.515), suggesting a more drug-like profile.

**DILI:** Ligand A (18.07) has a significantly lower DILI risk than Ligand B (32.84), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (87.94) is better than Ligand A (71.77). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which indicates poor permeability. Ligand A (-4.75) is slightly better than Ligand B (-4.95).

**Aqueous Solubility:** Ligand A (-1.95) has better aqueous solubility than Ligand B (-4.20). This is important for formulation and bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.48 and 0.63), which is good.

**Microsomal Clearance:** Ligand B (80.02) has a higher microsomal clearance than Ligand A (44.79), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-29.999) has a longer in vitro half-life than Ligand B (-36.398), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.21 and 0.15).

**Binding Affinity:** Ligand A (-7.7 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:**

Considering all factors, Ligand A is the more promising candidate. While Ligand B has a better QED and BBB penetration, Ligand A excels in crucial areas for an enzyme inhibitor: lower DILI risk, better aqueous solubility, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The small difference in binding affinity is outweighed by the substantial improvements in ADME properties.

Output:
0
2025-04-17 12:40:51,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (347.379 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.17) is slightly above the preferred <140, but acceptable. Ligand B (93.09) is well within the range.

**3. logP:** Ligand A (-0.249) is a bit low, potentially hindering permeability. Ligand B (2.101) 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 (8) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.74 and 0.704), indicating good drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk (73.982 and 69.794), below the concerning threshold of 60.

**8. BBB:** Both ligands have reasonable BBB penetration (70.997 and 81.698). While not critical for a non-CNS target like SRC, higher is generally better.

**9. Caco-2 Permeability:** Ligand A (-5.434) shows poor permeability, while Ligand B (-4.7) is slightly better, but still concerning.

**10. Aqueous Solubility:** Ligand A (-1.661) and Ligand B (-3.763) both show poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.131 and 0.129).

**12. Microsomal Clearance:** Ligand A (1.098) has significantly lower microsomal clearance than Ligand B (55.265), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (3.647 and 3.614 hours).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.217).

**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.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much better binding affinity. Ligand A has better metabolic stability, but the affinity difference is significant enough to outweigh this. Both have poor solubility, which would need to be addressed in formulation.

**Conclusion:**

Despite Ligand A's slightly better metabolic stability, the significantly stronger binding affinity of Ligand B (-8.5 vs -7.4 kcal/mol) makes it the more promising drug candidate. The affinity difference is a major advantage that outweighs the slightly higher clearance.

Output:
1
2025-04-17 12:40:51,985 - INFO - Batch 150 complete. Total preferences: 2400
2025-04-17 12:40:51,985 - INFO - Processing batch 151/512...
2025-04-17 12:41:43,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (351.359 Da and 354.363 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (117.16) is better than Ligand B (123), both are below the 140 threshold for good absorption.

**3. logP:** Ligand A (0.944) is slightly better than Ligand B (0.15), both are within the optimal range of 1-3, but ligand B is quite low and could indicate permeability 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 7 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.636 and 0.771, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (71.539) has a slightly higher DILI risk than Ligand B (64.754), but both are acceptable (<60 is good, and both are below 80).

**8. BBB:** Both ligands have similar BBB penetration (62.117 and 68.786), which isn't a primary concern for a non-CNS oncology target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.507 and -4.765). This is unusual and suggests a potential issue with the experimental setup or the compounds themselves. However, we'll proceed with relative comparison.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.718 and -2.027). Similar to Caco-2, this is concerning and requires further investigation.

**11. hERG Inhibition:** Ligand A (0.313) has a lower hERG risk than Ligand B (0.143), which is preferable.

**12. Microsomal Clearance:** Ligand B (-37.821) has a significantly lower (better) microsomal clearance than Ligand A (-19.684), indicating greater metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-37.821) has a much longer in vitro half-life than Ligand A (-19.684), further supporting its improved metabolic stability.

**14. P-gp Efflux:** Ligand A (0.164) has slightly higher P-gp efflux than Ligand B (0.008), which is less desirable.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor for an enzyme target.

**Overall Assessment:**

Despite the concerning negative values for Caco-2 and solubility, the significantly stronger binding affinity and improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand B make it the more promising drug candidate. The affinity difference is substantial and likely outweighs the slight drawbacks in DILI and P-gp efflux. The lower hERG risk of Ligand A is a minor advantage, but not enough to overcome the potency and stability benefits of Ligand B.

Output:
1
2025-04-17 12:41:43,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.364 and 364.368 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.09) is better than Ligand B (85.25) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.908 and 1.26), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<10).

**QED:** Both ligands have similar QED values (0.799 and 0.646), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (39.046 and 39.434 percentile).

**BBB:** Ligand B (78.868) has a higher BBB penetration percentile than Ligand A (67.701), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.909). This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.79 and -1.502). This is also a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.628 and 0.686).

**Microsomal Clearance:** Ligand B (29.973) has a slightly better (lower) microsomal clearance than Ligand A (20.698), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (30.089) has a much better in vitro half-life than Ligand B (-23.278). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.213 and 0.152).

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.7 kcal/mol).

**Conclusion:**

While both compounds have excellent binding affinity, Ligand A is slightly favored due to its better TPSA, logP, and significantly better in vitro half-life. The poor Caco-2 permeability and solubility are concerning for both, but the longer half-life of Ligand A could potentially compensate for lower absorption. The slightly better metabolic stability of Ligand B is a plus, but the significantly shorter half-life is a major drawback. Given the enzyme-specific priorities, the longer half-life is more important.

Output:
1
2025-04-17 12:41:43,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (375.372 and 349.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.48) is well below the 140 threshold, suggesting good absorption. Ligand B (131.54) is still within acceptable limits but closer to the upper bound.

**logP:** Ligand A (3.503) is slightly above the optimal range but still reasonable. Ligand B (1.829) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.785) has a strong drug-like profile. Ligand B (0.288) is significantly lower, indicating a less favorable drug-like profile.

**DILI:** Ligand A (89.841) has a higher DILI risk than Ligand B (34.277). This is a concern for Ligand A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand A (95.308) has better BBB penetration than Ligand B (38.426), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.827 and -4.976). This is unusual and could indicate issues with the prediction method or the molecule's behavior in the assay. However, the values are similar, so it doesn't strongly differentiate them.

**Aqueous Solubility:** Ligand A (-4.94) has worse solubility than Ligand B (-1.009). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.721) has a slightly higher hERG risk than Ligand B (0.172). Lower is better here.

**Microsomal Clearance:** Ligand A (46.893) has a higher microsomal clearance than Ligand B (2.406), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (38.008) has a longer half-life than Ligand B (23.524), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.4) has lower P-gp efflux than Ligand B (0.031), which is favorable.

**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 difference. A >1.5 kcal/mol advantage in binding can outweigh other issues.

**Overall Assessment:**

Ligand B is the stronger candidate. Despite its lower QED and slightly lower TPSA, its *significantly* superior binding affinity (-8.9 vs 0.0 kcal/mol) is the most important factor for an enzyme inhibitor. The lower DILI and hERG risk are also beneficial. While Ligand A has a longer half-life and lower P-gp efflux, these advantages are overshadowed by its weak binding, higher DILI risk, and higher clearance. The solubility difference is also a concern for Ligand A.

Output:
1
2025-04-17 12:41:43,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (335.363 and 343.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.06) is slightly higher than Ligand B (68.39), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (2.029) is within the optimal 1-3 range. Ligand B (3.743) is pushing the upper limit, potentially raising concerns about solubility and off-target effects.

**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 acceptable QED scores (0.724 and 0.641), indicating good drug-likeness.

**DILI:** Ligand A (90.694) has a significantly higher DILI risk than Ligand B (67.429). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.85) shows better BBB penetration than Ligand A (65.607), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.04) shows poor Caco-2 permeability, which is a concern for oral absorption. Ligand B (-4.528) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-3.857) has very poor aqueous solubility. Ligand B (-5.007) is also poor, but slightly better than Ligand A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.282 and 0.477), which is positive.

**Microsomal Clearance:** Ligand A (58.76) has a lower microsomal clearance than Ligand B (94.346), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (5.512) has a slightly longer half-life than Ligand B (0.426).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.421 and 0.429).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol) - a difference of 1.8 kcal/mol. This is a substantial advantage that can potentially outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's poor solubility, Caco-2 permeability, and higher DILI risk, its *significantly* stronger binding affinity (-8.9 vs -7.1 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The potency advantage is substantial enough to warrant further investigation and potential optimization to address the solubility and DILI issues. Ligand B, while having better ADME properties overall, lacks the necessary potency for a viable drug candidate.

Output:
0
2025-04-17 12:41:43,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.43 & 344.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.05) is significantly better than Ligand B (74.33). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (4.549) is higher than the optimal range (1-3), potentially causing solubility issues or off-target effects. Ligand B (1.818) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 4 HBA) are both acceptable, falling within the recommended limits.

**QED:** Both ligands have similar QED values (0.84 and 0.754), indicating good drug-likeness.

**DILI:** Ligand A (28.54) has a much lower DILI risk than Ligand B (49.01), which is a significant advantage. Both are below the concerning threshold of 60, but A is preferable.

**BBB:** Both ligands have similar BBB penetration (77.28 and 76.66), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.601 and -4.762). This is unusual and suggests poor permeability, but the scale isn't clearly defined.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.722 and -3.149), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.955) has a lower hERG risk than Ligand B (0.653), which is a positive.

**Microsomal Clearance:** Ligand A (45.32) and Ligand B (47.56) have similar microsomal clearance values, indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (25.16 hours) has a significantly longer half-life than Ligand B (17.47 hours), which is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.482) has lower P-gp efflux than Ligand B (0.074), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.5 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 of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher logP, its significantly stronger binding affinity (-8.5 vs -7.0 kcal/mol), lower DILI risk, longer half-life, and lower P-gp efflux make it a more promising drug candidate. The solubility and permeability issues are concerns, but potentially addressable with formulation strategies. The potency advantage is substantial and outweighs the less favorable logP.

Output:
1
2025-04-17 12:41:43,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (361.873 Da) is also good.

**TPSA:** Ligand A (46.34) is excellent, well below the 140 threshold for oral absorption. Ligand B (71.09) is still reasonable, but higher, potentially impacting absorption.

**logP:** Both ligands have good logP values (A: 4.375, B: 3.179), falling within the 1-3 optimal range. Ligand A is a bit high, potentially leading to off-target effects, but the difference isn't drastic.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) is favorable. Ligand B (HBD=2, HBA=3) is also acceptable.

**QED:** Ligand A (0.833) has a very strong drug-like profile. Ligand B (0.551) is still acceptable, but less ideal.

**DILI:** Both ligands have low DILI risk (A: 34.82, B: 35.905), both below the 40 threshold.

**BBB:** Ligand A (88.872) has a good BBB percentile, while Ligand B (61.225) is lower. This isn't a primary concern for a kinase inhibitor, but could be a bonus if CNS penetration is desired.

**Caco-2 Permeability:** Ligand A (-4.588) has poor Caco-2 permeability. Ligand B (-5.005) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -5.23, B: -3.333). This is a significant concern.

**hERG Inhibition:** Ligand A (0.854) has a slightly higher hERG risk than Ligand B (0.302).

**Microsomal Clearance:** Ligand A (102.548) has higher microsomal clearance than Ligand B (38.168), indicating lower metabolic stability. This is a key disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (17.879) has a longer in vitro half-life than Ligand A (-16.562). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.796, B: 0.144). Ligand B is better.

**Binding Affinity:** Both ligands have very similar binding affinities (A: -8.1 kcal/mol, B: -8.2 kcal/mol). This difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. While both have similar binding affinities, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better P-gp efflux. Although both have poor solubility and permeability, the metabolic stability and safety profiles of Ligand B outweigh the slight advantages of Ligand A in terms of TPSA and QED.

Output:
1
2025-04-17 12:41:43,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.411 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.72) is better than Ligand B (80.37), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.104 and 2.52), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6/5) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.749 and 0.905), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (54.052 and 57.658), both are acceptable (below 60).

**BBB:** Ligand B (62.699) has a slightly better BBB penetration percentile than Ligand A (38.193), but this is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.1) has better Caco-2 permeability than Ligand B (-4.853).

**Aqueous Solubility:** Ligand A (-2.799) has better solubility than Ligand B (-4.088).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.233 and 0.259).

**Microsomal Clearance:** Ligand A (8.355) has significantly lower microsomal clearance than Ligand B (37.089), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-22.107) has a much longer in vitro half-life than Ligand B (30.755). This is also a critical advantage for kinase inhibitors.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.04).

**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 minimal (0.3 kcal/mol) and is likely outweighed by the superior ADME properties of Ligand A.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A exhibits significantly improved metabolic stability (lower Cl_mic) and a longer half-life, along with better solubility and Caco-2 permeability. These factors are crucial for *in vivo* efficacy and a favorable pharmacokinetic profile for a kinase inhibitor.

Output:
0
2025-04-17 12:41:43,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.355 and 343.427 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (123.77) is better than Ligand B (61.88) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Both ligands have good logP values (1.317 and 0.999), falling within the optimal range of 1-3.

**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 (0.616 and 0.783), indicating drug-like properties.

**DILI:** Ligand B (30.632) has a significantly lower DILI risk than Ligand A (82.59), which is a major advantage.

**BBB:** Ligand B (76.192) has a higher BBB penetration score than Ligand A (38.813), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.497) has a worse Caco-2 permeability than Ligand B (-4.821).

**Aqueous Solubility:** Ligand A (-3.334) has a worse aqueous solubility than Ligand B (-1.322).

**hERG Inhibition:** Ligand A (0.117) has a slightly lower hERG inhibition risk than Ligand B (0.752), which is preferable.

**Microsomal Clearance:** Ligand A (-0.871) has a lower (better) microsomal clearance than Ligand B (33.92), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (5.467) has a longer in vitro half-life than Ligand A (-37.343), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.018) has a lower P-gp efflux liability than Ligand B (0.146), which is preferable.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.2). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. It has a significantly lower DILI risk, better solubility, and a longer half-life, all crucial for an enzyme inhibitor. While Ligand A has slightly better metabolic stability and P-gp efflux, the advantages of Ligand B in safety (DILI) and PK (half-life, solubility) are more important. The binding affinity difference is small.

Output:
1
2025-04-17 12:41:43,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.4 and 351.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.55) is better than Ligand B (114.79), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.455) is optimal, while Ligand B (-1.127) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the limit of 5.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (7), both are below the limit of 10.

**QED:** Both ligands have similar QED values (0.762 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A (41.88) has a significantly lower DILI risk than Ligand B (79.84), making it more favorable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (54.05) has a higher BBB percentile than Ligand A (27.03).

**Caco-2:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability.

**Solubility:** Ligand A (-2.973) has better solubility than Ligand B (-1.93), which is crucial for bioavailability.

**hERG:** Ligand A (0.285) has a much lower hERG risk than Ligand B (0.06), a significant advantage.

**Microsomal Clearance:** Ligand A (22.37) has higher microsomal clearance than Ligand B (-14.67). This means Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-10.098) has a longer in vitro half-life than Ligand A (-22.369), which is desirable.

**P-gp efflux:** Both ligands have low P-gp efflux liability.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability and half-life, Ligand A's superior binding affinity (-10.6 vs -8.7 kcal/mol) is a major advantage for an enzyme target. It also has a significantly better safety profile (lower DILI and hERG risk) and better solubility. The slightly lower logP of Ligand B is a concern, and the higher TPSA is less ideal. The Caco-2 values are concerning for both, but the stronger binding and better safety profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 12:41:43,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (88.49). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is closer to the optimal range for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (0.953 and 0.596), 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 HBD/HBA generally improves permeability.

**QED:** Both ligands have reasonable QED scores (0.761 and 0.68), indicating good drug-likeness.

**DILI:** Ligand A (9.035 percentile) has a much lower DILI risk than Ligand B (34.432 percentile). This is a significant advantage.

**BBB:** Ligand A (70.027 percentile) has better BBB penetration than Ligand B (63.086 percentile), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.438) is worse than Ligand B (-5.061), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.556) is better than Ligand B (-1.294), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.425) has a lower hERG inhibition risk than Ligand B (0.224), which is a crucial safety parameter.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (18.649 and 17.175 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (4.518 hours) has a lower in vitro half-life than Ligand B (14.433 hours). This is a disadvantage for A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.017).

**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 A is the better candidate. It has a significantly lower DILI risk, better solubility, and lower hERG inhibition. The slightly better binding affinity and TPSA are also beneficial. While Ligand A has lower Caco-2 permeability and a shorter half-life, the safety advantages and potency are more important for an enzyme target like SRC kinase.

Output:
0
2025-04-17 12:41:43,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 351.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.15) is better than Ligand B (99.18), both are under the 140 threshold for oral absorption.

**logP:** Ligand A (1.249) is within the optimal range (1-3). Ligand B (-0.968) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern at this stage.

**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. Both are within the acceptable range (<=10).

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (36.293) has a slightly higher DILI risk than Ligand B (18.728), but both are below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**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 unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.108 and 0.047), which is excellent.

**Microsomal Clearance:** Ligand A (23.268) has a higher microsomal clearance than Ligand B (2.747). This suggests Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-7.971) has a longer in vitro half-life than Ligand B (-7.182), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.5 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is slightly favored. The stronger binding affinity (-7.9 vs -7.4 kcal/mol) is a significant advantage for an enzyme target. While Ligand B has better metabolic stability (lower Cl_mic), the affinity difference is more crucial in this case. The DILI risk is slightly higher for Ligand A, but still acceptable. The poor permeability and solubility are major concerns that would need to be addressed in further optimization, but the initial potency advantage of Ligand A makes it the more promising starting point.

Output:
0
2025-04-17 12:41:43,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.343 and 373.538 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.03) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (61.44) is well within the ideal range.

**logP:** Ligand A (0.039) is quite low, potentially hindering permeation. Ligand B (1.965) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.504 and 0.649, respectively), indicating drug-like properties.

**DILI:** Ligand A (61.031) has a higher DILI risk than Ligand B (35.789). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic, but we will consider other factors.

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

**hERG Inhibition:** Ligand A (0.179) has a slightly higher hERG risk than Ligand B (0.771), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.046) has significantly lower microsomal clearance than Ligand B (47.013), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.01) has a negative half-life, which is not possible. This is a major red flag. Ligand B (7.435) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is favorable. Ligand B (0.272) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), although both are excellent.

**Overall Assessment:**

Ligand A has a concerning negative in vitro half-life, and a higher DILI risk. While it has better metabolic stability and lower P-gp efflux, the negative half-life is a deal-breaker. Ligand B, despite a slightly lower affinity and higher clearance, presents a more viable profile with a reasonable half-life, lower DILI risk, and good affinity. The unusual negative solubility and Caco-2 values for both are concerning and would require further investigation, but are less critical than the negative half-life of Ligand A.

Output:
1
2025-04-17 12:41:43,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 342.395 Da - Within the ideal range (200-500 Da).
* Ligand B: 359.415 Da - Within the ideal range (200-500 Da).
* *Both are acceptable.*

**2. TPSA:**
* Ligand A: 70.42 A<sup>2</sup> - Good, well below the 140 A<sup>2</sup> threshold for oral absorption.
* Ligand B: 116.8 A<sup>2</sup> - Still acceptable for oral absorption, but higher than Ligand A.
* *Ligand A is preferred.*

**3. logP:**
* Ligand A: 2.725 - Optimal (1-3).
* Ligand B: 0.304 - Below the optimal range, potentially hindering permeation.
* *Ligand A is preferred.*

**4. H-Bond Donors (HBD):**
* Ligand A: 0 - Acceptable (<=5).
* Ligand B: 1 - Acceptable (<=5).
* *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 6 - Acceptable (<=10).
* Ligand B: 8 - Acceptable (<=10).
* *Both are acceptable.*

**6. QED:**
* Ligand A: 0.545 - Good, above the 0.5 threshold.
* Ligand B: 0.793 - Very good, above the 0.5 threshold.
* *Ligand B is preferred.*

**7. DILI:**
* Ligand A: 44.552 - Low risk (below 40 is good).
* Ligand B: 67.003 - Moderate risk (above 60 is high risk).
* *Ligand A is preferred.*

**8. BBB:**
* Ligand A: 82.125 - Good, but not critical for a non-CNS target like SRC.
* Ligand B: 48.352 - Lower, not a major concern here.
* *Ligand A is slightly preferred.*

**9. Caco-2 Permeability:**
* Ligand A: -4.452 - Negative values are unusual and suggest very poor permeability.
* Ligand B: -5.599 - Also poor permeability, but similar to A.
* *Neither is good, but both are similar.*

**10. Aqueous Solubility:**
* Ligand A: -3.815 - Poor solubility.
* Ligand B: -2.982 - Poor solubility, but slightly better than A.
* *Ligand B is slightly preferred.*

**11. hERG Inhibition:**
* Ligand A: 0.407 - Low risk.
* Ligand B: 0.071 - Very low risk.
* *Ligand B is preferred.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 113.766 mL/min/kg - High clearance, indicating poor metabolic stability.
* Ligand B: 6.796 mL/min/kg - Low clearance, indicating good metabolic stability.
* *Ligand B is significantly preferred.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -25.472 hours - Negative values are unusual and suggest rapid degradation.
* Ligand B: -0.413 hours - Also short half-life, but slightly better than A.
* *Neither is good, but both are similar.*

**14. P-gp Efflux:**
* Ligand A: 0.387 - Low efflux, good.
* Ligand B: 0.031 - Very low efflux, excellent.
* *Ligand B is preferred.*

**15. Binding Affinity:**
* Ligand A: -8.5 kcal/mol - Excellent binding affinity.
* Ligand B: 0.0 kcal/mol - Very weak binding affinity.
* *Ligand A is overwhelmingly preferred.*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (binding affinity) and metabolic stability are paramount. Ligand A has a significantly stronger binding affinity (-8.5 kcal/mol vs 0.0 kcal/mol for Ligand B). While Ligand B has better QED, lower DILI, hERG, and P-gp efflux, the extremely weak binding affinity of Ligand B makes it unlikely to be a viable drug candidate. Ligand A's poor Caco-2 permeability and solubility are concerns, but these can potentially be addressed through formulation strategies. The high clearance of Ligand A is also a concern, but the strong binding affinity might allow for a lower dose to compensate.

Output:
1
2025-04-17 12:41:43,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.34 Da) is slightly higher than Ligand B (347.409 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (53.01) is higher than Ligand B (45.23), but both are good.

**logP:** Both ligands have logP values between 1 and 3, which is optimal. Ligand A (2.367) and Ligand B (3.278) are both within the desired range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 for A, 3 for B) counts, balancing solubility and permeability.

**QED:** Both ligands have high QED scores (0.827 and 0.923), indicating good drug-like properties.

**DILI:** Ligand B (54.789) has a significantly lower DILI risk than Ligand A (11.361), which is a major advantage. A DILI percentile below 40 is preferred, and Ligand B is closer to that threshold.

**BBB:** Both ligands have high BBB penetration (85.498 and 89.957). While not a primary concern for a kinase inhibitor, it doesn't hurt.

**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. We'll need to consider other factors.

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

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.825 and 0.817), which is excellent.

**Microsomal Clearance:** Ligand A (-4.183) has significantly *lower* (better) microsomal clearance than Ligand B (32.669). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (78.301) has a much longer in vitro half-life than Ligand B (35.235), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.604 and 0.466).

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, it has a higher DILI risk and poorer solubility. Ligand B has a much lower DILI risk but weaker binding affinity and poorer metabolic stability.

Given the enzyme-specific priorities, **binding affinity is paramount**. The 2.2 kcal/mol difference in binding affinity is a significant advantage for Ligand A. While the DILI risk for Ligand A is higher, it's still below 20, and the solubility issues might be addressable with formulation strategies. The improved metabolic stability also contributes to a more favorable profile.

Output:
1
2025-04-17 12:41:43,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (94.48 and 96.89) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (which requires <90). This is acceptable for an oncology target where CNS penetration isn't necessarily required.

**logP:** Ligand A (0.11) is quite low, potentially hindering permeability. Ligand B (0.743) is better, falling within the optimal 1-3 range.

**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 limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.617 and 0.53), indicating good drug-like properties.

**DILI:** Ligand A (41.218) has a slightly higher DILI risk than Ligand B (18.573), but both are below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for an oncology target.

**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 validated experimentally.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a significant concern for *in vivo* bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.279 and 0.228), which is excellent.

**Microsomal Clearance:** Ligand A (0.613 mL/min/kg) has significantly lower microsomal clearance than Ligand B (30.694 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (10.378 hours) has a much longer half-life than Ligand B (4.433 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.039), which is favorable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is relatively small, and Ligand A already has excellent potency.

**Overall Assessment:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic and longer t1/2) and slightly better binding affinity, despite its lower logP and solubility. While both have poor solubility, the improved metabolic profile of Ligand A is more critical for an enzyme inhibitor, as it will lead to higher *in vivo* exposure. The lower logP of Ligand A is a drawback, but the strong binding affinity might compensate for it.

Output:
0
2025-04-17 12:41:43,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.387 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (73.14) is significantly lower than Ligand A (101.22), which is favorable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.961) and Ligand B (2.268) are both acceptable.

**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 (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.914) has a significantly higher QED score than Ligand B (0.762), indicating a more drug-like profile.

**DILI:** Ligand A (79.333) has a higher DILI risk than Ligand B (51.338). This is a concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (70.997), which is acceptable but not a high priority for a non-CNS target like SRC.

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both compounds.

**hERG:** Ligand A (0.158) has a lower hERG inhibition liability than Ligand B (0.28), which is preferable.

**Microsomal Clearance:** Ligand A (18.734 mL/min/kg) has a much lower microsomal clearance than Ligand B (58.099 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-2.286 hours) has a negative half-life, which is not possible. This is a major red flag. Ligand B (-26.91 hours) also has a negative half-life, which is also not possible. Both values are likely errors and need experimental validation.

**P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux liability than Ligand B (0.134), which is favorable.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This difference in affinity is substantial and outweighs many other considerations.

**Overall Assessment:**

Despite the issues with solubility and the questionable half-life values, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-7.3 vs -0.0 kcal/mol) is a major advantage. It also has better metabolic stability (lower Cl_mic), lower P-gp efflux, and a better QED score. While the DILI risk is higher, the substantial potency difference could allow for lower dosing, potentially mitigating this risk. The negative half-life values are concerning and require further investigation, but the overall profile of Ligand A is superior.

Output:
0
2025-04-17 12:41:43,398 - INFO - Batch 151 complete. Total preferences: 2416
2025-04-17 12:41:43,398 - INFO - Processing batch 152/512...
2025-04-17 12:42:24,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.495 and 372.481 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is higher than Ligand B (41.57). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (3.126 and 2.904), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 1. Both are acceptable.

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

**QED:** Both ligands have good QED scores (0.663 and 0.799), indicating good drug-likeness.

**DILI:** Ligand A (42.613) has a slightly higher DILI risk than Ligand B (36.138), but both are below the concerning threshold of 60.

**BBB:** Ligand B (91.276) has significantly better BBB penetration than Ligand A (68.67). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both 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 a more precise interpretation would require understanding the scale's origin.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.992 and -3.209), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.349) has a slightly lower hERG risk than Ligand B (0.796), which is favorable.

**Microsomal Clearance:** Ligand B (61.841) has lower microsomal clearance than Ligand A (68.335), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (35.177 hours) has a much longer in vitro half-life than Ligand A (-11.658 hours). This is a substantial advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.425) has lower P-gp efflux than Ligand B (0.169), which could translate to better oral bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.7 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While both ligands have good potency, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), and better BBB penetration. The lower DILI risk is also a plus. The poor solubility and Caco-2 permeability are concerns for both, but the improved pharmacokinetic profile of Ligand B outweighs these drawbacks.

Output:
1
2025-04-17 12:42:24,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (379.781 Da) is still well within the range.

**TPSA:** Ligand A (71.78) is better than Ligand B (29.54) regarding TPSA, suggesting better potential for oral absorption.

**logP:** Ligand A (2.053) is optimal, while Ligand B (4.004) 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 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.78) has a significantly better QED score than Ligand B (0.552), indicating a more drug-like profile.

**DILI:** Ligand B (37.999) has a higher DILI risk than Ligand A (21.52), though both are below the concerning threshold of 60.

**BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand B (88.406) has a higher BBB percentile than Ligand A (69.523), but this is not a major factor in this case.

**Caco-2 Permeability:** Both ligands 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 relative permeability, with lower values indicating lower permeability.

**Aqueous Solubility:** Ligand A (-1.571) has better solubility than Ligand B (-4.61). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.212) has a much lower hERG risk than Ligand B (0.653), which is a significant advantage.

**Microsomal Clearance:** Ligand A (17.036 mL/min/kg) has a lower microsomal clearance than Ligand B (88.615 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (35.043 hours) has a significantly longer half-life than Ligand B (-25.752 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux than Ligand B (0.233), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While affinity is paramount, the difference of 1.5 kcal/mol is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It demonstrates a superior drug-like profile (higher QED), better solubility, lower hERG risk, significantly improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity, the substantial ADME advantages of Ligand A outweigh this difference, especially for an enzyme target where metabolic stability and bioavailability are critical.

Output:
0
2025-04-17 12:42:24,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.289 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.7) is better than Ligand B (106.79). Both are acceptable, but A is closer to the preferred <140 for oral absorption.

**logP:** Ligand A (3.127) is optimal (1-3). Ligand B (0.037) is very low, potentially hindering permeation. This is a significant drawback for B.

**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 (7) are both within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED values (0.809 and 0.738), indicating good drug-like properties.

**DILI:** Ligand A (99.38) has a very high DILI risk, which is a major concern. Ligand B (61.07) is elevated but less concerning than A.

**BBB:** Ligand A (18.379) has very poor BBB penetration. Ligand B (79.566) is better, but not particularly high. BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.727) is poor, while Ligand B (-5.1) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-4.158) is poor, while Ligand B (-1.516) is also poor. Both are problematic.

**hERG:** Ligand A (0.067) and Ligand B (0.065) are both very low risk, which is excellent.

**Microsomal Clearance:** Ligand A (10.168) and Ligand B (11.32) are comparable and acceptable, indicating reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (14.809) and Ligand B (10.276) are comparable and acceptable.

**P-gp Efflux:** Ligand A (0.048) and Ligand B (0.014) are both low, which is favorable.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This 1.4 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, but a very high DILI risk and poor solubility/permeability. Ligand B has a lower affinity but better solubility, permeability, and a lower (though still elevated) DILI risk. The strong affinity of Ligand A is a major advantage for an enzyme inhibitor. However, the extremely high DILI risk is a major red flag. While solubility and permeability are concerns for both, the potency difference is significant. Given the enzyme class, prioritizing potency is crucial, and the hERG risk is low for both. The DILI risk for A is so high that it's unlikely to be a viable candidate without significant modification.

Output:
1
2025-04-17 12:42:24,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (406.284 Da and 454.316 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.05) is better than Ligand B (66.29), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.979 and 1.884), 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:** Ligand A (0.73) has a better QED score than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand B (55.448) has a lower DILI risk than Ligand A (64.754), making it slightly preferable. Both are below the concerning 60 threshold.

**BBB:** Both ligands have reasonable BBB penetration (71.966 and 66.886). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.25 and -5.125). This is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.845 and -2.521). This is a significant drawback that needs to be addressed.

**hERG Inhibition:** Ligand A (0.24) has a much lower hERG inhibition liability than Ligand B (0.752), which is a major advantage.

**Microsomal Clearance:** Ligand B (40.816) has a lower microsomal clearance than Ligand A (11.279), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (12.06 hours) has a longer in vitro half-life than Ligand A (38.087 hours). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux liability than Ligand B (0.227), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 kcal/mol and -10.2 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a slight edge in binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a significantly better hERG profile and lower P-gp efflux. Both have poor solubility and permeability. Given the importance of minimizing off-target effects (hERG) for kinase inhibitors, and the slightly better drug-likeness (QED) of Ligand A, I would lean towards **Ligand A** as the more promising candidate, despite the slightly lower metabolic stability. Solubility would need to be addressed through formulation or further chemical modifications.

Output:
0
2025-04-17 12:42:24,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.819 Da) is slightly higher than Ligand B (348.491 Da), but both are acceptable.

**TPSA:** Ligand A (45.33) is well below the 140 threshold for oral absorption. Ligand B (86.88) is also below the threshold, but higher than Ligand A.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.683) is slightly higher, potentially raising concerns about solubility and off-target effects, while Ligand B (3.069) is closer to the ideal range.

**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, staying within the guidelines.

**QED:** Both ligands have QED values above 0.5 (A: 0.714, B: 0.641), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (86.623%) compared to Ligand B (19.504%). This is a major concern for Ligand A.

**BBB:**  BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (78.558%) has a higher value than Ligand B (55.487%).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.799) is slightly better than Ligand B (-5.244).

**Aqueous Solubility:** Ligand A (-6.248) has slightly better solubility than Ligand B (-2.726), but both are quite poor.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.666, B: 0.266), which is favorable. Ligand B is better.

**Microsomal Clearance:** Ligand A (52.344) has higher microsomal clearance than Ligand B (23.882), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (-31.453 hours) compared to Ligand A (26.28 hours), which is a substantial advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.608, B: 0.113). Ligand B is better.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have similar potency, Ligand B demonstrates significantly better ADMET properties: much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better P-gp efflux, and better hERG. Although solubility and Caco-2 permeability are poor for both, the superior safety and pharmacokinetic profile of Ligand B outweigh these concerns. The slightly higher logP of Ligand A is also a negative.

Output:
1
2025-04-17 12:42:24,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.495 and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is well below the 140 threshold for good absorption, and more importantly, suitable for kinase inhibitors. Ligand B (100.13) is higher, but still within a reasonable range, though less optimal.

**logP:** Ligand A (2.62) is within the optimal 1-3 range. Ligand B (-0.883) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.838) has a very good drug-likeness score. Ligand B (0.522) is acceptable, but lower than A.

**DILI:** Ligand A (21.908) has a very low DILI risk. Ligand B (4.343) also has a low DILI risk, but slightly higher than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.351) is higher than Ligand B (43.35).

**Caco-2 Permeability:** Ligand A (-4.638) is concerningly low, indicating poor permeability. Ligand B (-5.391) is also low, but similar to A.

**Aqueous Solubility:** Ligand A (-2.892) is poor. Ligand B (-0.753) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.489) has a low hERG risk. Ligand B (0.23) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (20.532) has moderate clearance. Ligand B (-30.881) has *negative* clearance, which is not physically possible and likely indicates an error in the data or a very stable compound. This is a major positive for B.

**In vitro Half-Life:** Ligand A (8.955) has a moderate half-life. Ligand B (21.605) has a significantly longer half-life, which is desirable.

**P-gp Efflux:** Both ligands (0.094 and 0.015) have very low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a >1.5 kcal/mol advantage and is a major driver in the decision.

**Conclusion:**

Despite the poor Caco-2 and solubility scores for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.3 vs -7.4 kcal/mol) outweighs the slightly higher TPSA and lower logP. Furthermore, the negative (and therefore very low) microsomal clearance and longer half-life of Ligand B are highly desirable for an enzyme inhibitor, indicating greater metabolic stability. Ligand A's poor Caco-2 permeability is also a significant concern.

Output:
1
2025-04-17 12:42:24,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.42 and 367.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (54.9). Both are acceptable, being below 140, but B is better.

**logP:** Both ligands have good logP values (1.398 and 2.247), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**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 (0.776 and 0.772), indicating good drug-likeness.

**DILI:** Ligand A (49.166) has a slightly higher DILI risk than Ligand B (28.693), but both are below the concerning threshold of 60.

**BBB:** Ligand A (74.06) and Ligand B (84.606) both have acceptable BBB penetration, but B is better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired/undesired.

**Caco-2 Permeability:** Ligand A (-4.865) has worse Caco-2 permeability than Ligand B (-4.478). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.809) has slightly worse aqueous solubility than Ligand B (-2.138). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.28) has a lower hERG inhibition risk than Ligand B (0.551), which is favorable.

**Microsomal Clearance:** Ligand A (28.433) has significantly lower microsomal clearance than Ligand B (56.695), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-10.948) has a much longer in vitro half-life than Ligand B (-3.645), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.137), which is a slight advantage.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.2). While both are good, the 0.5 kcal/mol difference is significant.

**Conclusion:**

Ligand A is the more promising candidate. It has a slightly better binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. While Ligand B has slightly better Caco-2 permeability and solubility, the metabolic stability and safety profile of Ligand A are more critical for an enzyme inhibitor. The difference in binding affinity is also a significant factor.

Output:
0
2025-04-17 12:42:24,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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, while Ligand B (373.465 Da) is also good.

**TPSA:** Ligand A (100.09) is better than Ligand B (49.77) as it is still below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.259) is quite low, potentially hindering permeation. Ligand B (3.429) 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 acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar and good QED values (0.798 and 0.797).

**DILI:** Ligand A (30.903) has a slightly higher DILI risk than Ligand B (20.9), but both are below the concerning threshold of 60.

**BBB:** Ligand A (46.452) has a lower BBB penetration percentile than Ligand B (86.545). Since SRC is not a CNS target, this is less critical, but a higher value is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.433) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.492) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-2.018) has poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-3.433) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.084) has very low hERG inhibition risk, which is excellent. Ligand B (0.711) has a slightly higher risk, but is still relatively low.

**Microsomal Clearance:** Ligand A (-22.827) has very low microsomal clearance, indicating high metabolic stability, which is a major advantage. Ligand B (47.509) has significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-17.134) has a very long in vitro half-life, consistent with its low clearance. Ligand B (22.871) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is favorable. Ligand B (0.544) has slightly higher efflux.

**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 difference, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's excellent metabolic stability and low hERG risk, its very poor logP, Caco-2 permeability, solubility, and especially its *extremely* weak binding affinity make it a poor candidate. Ligand B, while having moderate metabolic clearance and slightly higher hERG risk, has a much better logP, and a *significantly* stronger binding affinity. The strong binding affinity of Ligand B is the most important factor for an enzyme inhibitor, and it outweighs the moderate ADME concerns.

Output:
1
2025-04-17 12:42:24,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.487 Da and 358.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is slightly above the preferred <140, but acceptable. Ligand B (58.64) is well within the acceptable range.

**logP:** Ligand A (4.117) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (3.223) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBAs, acceptable. Ligand B has 4 HBAs, also acceptable.

**QED:** Ligand A (0.661) and Ligand B (0.84) both have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (88.212) has a concerningly high DILI risk (above 60). Ligand B (51.377) is better, but still warrants attention.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (46.646) and Ligand B (94.61) are less relevant here.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and needs further investigation, but we'll proceed assuming these are percentile scores and lower is worse. Ligand B (-4.54) is slightly better than Ligand A (-5.001).

**Aqueous Solubility:** Both ligands have very poor solubility (-4.631 and -3.822 respectively). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.551) has a slightly higher hERG risk than Ligand B (0.74). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (75.952) has higher clearance than Ligand B (51.726), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (3.357) has a shorter half-life than Ligand B (-0.649). A negative half-life is unusual and suggests very rapid degradation.

**P-gp Efflux:** Ligand A (0.365) has slightly higher P-gp efflux than Ligand B (0.128), which is less desirable.

**Binding Affinity:** Ligand B (-5.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand B is significantly better. While both have solubility issues and poor Caco-2 permeability, Ligand B's substantially stronger binding affinity (-5.9 vs 0.0 kcal/mol) outweighs the drawbacks. Its lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), and lower hERG risk further solidify its superiority. Ligand A's high DILI risk and very weak binding affinity make it a less attractive candidate.

Output:
1
2025-04-17 12:42:24,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (346.515 Da) is within the ideal range (200-500 Da). Ligand B (467.932 Da) is at the upper limit, but still acceptable.

**TPSA:** Ligand A (49.41) is excellent, well below the 140 threshold for oral absorption. Ligand B (90.28) is still reasonable, but less favorable.

**logP:** Ligand A (3.217) is optimal (1-3). Ligand B (5.098) is high, potentially leading to solubility issues and off-target effects.

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

**QED:** Ligand A (0.686) is good, indicating drug-likeness. Ligand B (0.448) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (18.922) has a very low DILI risk. Ligand B (86.623) has a significantly higher DILI risk, which is a major concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (64.948) and Ligand B (35.324) are both not particularly high, which is not a major drawback here.

**Caco-2 Permeability:** Ligand A (-4.387) and Ligand B (-4.971) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, this is a scale-dependent value and needs to be interpreted cautiously.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.091 and -5.417 respectively). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.269) has a very low hERG risk. Ligand B (0.862) has a higher, but still moderate, hERG risk.

**Microsomal Clearance:** Ligand A (65.344) has moderate clearance, while Ligand B (76.667) has higher clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.28 hours) has a reasonable half-life. Ligand B (158.95 hours) has a very long half-life, which is generally favorable, but could also indicate slow metabolism or poor absorption.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.172 and 0.859 respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.1 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other significant ADME differences.

**Conclusion:**

Considering all factors, Ligand A is the more promising candidate. While both have poor solubility, Ligand A has a much lower DILI risk, better QED, and lower logP. The slightly longer half-life of Ligand B is offset by its higher logP, higher DILI risk, and higher microsomal clearance. The binding affinity difference is not significant enough to favor Ligand B.

Output:
0
2025-04-17 12:42:24,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.366 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.96) is well below the 140 threshold for oral absorption, and even better for kinase inhibitors. Ligand B (82.43) is still acceptable, but less optimal.

**logP:** Ligand A (3.013) is right in the sweet spot (1-3). Ligand B (1.991) is a little low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is excellent. Ligand B (1 HBD, 4 HBA) is also good, but slightly higher HBA count.

**QED:** Both ligands have good QED scores (0.772 and 0.843), indicating drug-like properties.

**DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (24.157). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (77.162) is higher than Ligand B (61.923).

**Caco-2 Permeability:** Ligand A (-5.077) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.844) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.317) has poor solubility. Ligand B (-1.906) has better solubility.

**hERG:** Ligand A (0.801) has a slightly elevated hERG risk compared to Ligand B (0.156), which is very favorable.

**Microsomal Clearance:** Ligand A (25.861) has higher microsomal clearance than Ligand B (6.646), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (30.42) has a significantly longer half-life than Ligand A (6.013).

**P-gp Efflux:** Ligand A (0.386) has lower P-gp efflux than Ligand B (0.028), which is favorable.

**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 overcome the other issues with Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly low and Caco-2 permeability is poor, it excels in crucial areas for an enzyme inhibitor: low DILI risk, good solubility, excellent metabolic stability (low Cl_mic and long t1/2), and very low hERG risk. Ligand A suffers from significant drawbacks in DILI, solubility, Caco-2 permeability, and metabolic stability, despite a slightly better binding affinity. The superior ADME properties of Ligand B outweigh the small difference in binding affinity.

Output:
1
2025-04-17 12:42:24,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (350.547 and 351.451 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (122.27). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (4.138) is slightly high, potentially leading to solubility issues, but still within a manageable range. Ligand B (0.424) is quite low, which could hinder membrane permeability and potentially reduce potency.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (4 HBD, 6 HBA) is acceptable but less optimal; more H-bonds can sometimes reduce permeability.

**QED:** Both ligands have reasonable QED scores (0.732 and 0.592), indicating generally good drug-like properties.

**DILI:** Ligand A (22.722) has a much lower DILI risk than Ligand B (43.932), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (82.474) has a better percentile than Ligand B (63.358).

**Caco-2 Permeability:** Ligand A (-4.688) shows poor permeability, while Ligand B (-5.456) is also poor. Both are negative values, suggesting limited intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.374) is better than Ligand B (-2.325), though both are quite poor.

**hERG:** Ligand A (0.699) has a lower hERG risk than Ligand B (0.252), a critical safety parameter.

**Microsomal Clearance:** Ligand A (67.607) has a higher clearance than Ligand B (4.102), meaning Ligand B is more metabolically stable. This is a key advantage for B.

**In vitro Half-Life:** Ligand A (-12.669) has a negative half-life, indicating very rapid metabolism. Ligand B (0.687) has a short half-life, but is far better than A.

**P-gp Efflux:** Ligand A (0.503) has lower P-gp efflux than Ligand B (0.022), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and significantly improved metabolic stability (lower Cl_mic, better t1/2). While its logP is low and TPSA is higher, the potency advantage is substantial. The DILI risk is higher for B, but manageable. The poor Caco-2 and solubility for both are concerns that would need to be addressed through formulation or further optimization. However, the binding affinity difference is significant enough to prioritize Ligand B.

Output:
1
2025-04-17 12:42:24,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.451 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (52.65), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (3.361 and 2.428), falling 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 3 HBA, both are acceptable.

**QED:** Ligand A (0.856) has a better QED score than Ligand B (0.776), indicating a more drug-like profile.

**DILI:** Ligand A (27.879) has a significantly lower DILI risk than Ligand B (10.741), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (88.135) is slightly better than Ligand B (69.058).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.676 and -4.749), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.619 and -2.447), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG:** Both ligands have low hERG risk (0.577 and 0.523), which is positive.

**Microsomal Clearance:** Ligand A (66.817) has higher microsomal clearance than Ligand B (16.188), meaning Ligand B is more metabolically stable. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-11.214) has a negative half-life, which is not possible. This is a major red flag for Ligand B. Ligand A (3.196) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux (0.442 and 0.031), which is good.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This 1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a better QED score, lower DILI risk, and a slightly better binding affinity. However, Ligand B has significantly better metabolic stability (lower Cl_mic) and a more reasonable in vitro half-life. The negative half-life for Ligand B is a critical issue. The poor solubility and permeability are concerns for both. Considering the enzyme-specific priorities, metabolic stability is crucial. However, the negative half-life for Ligand B is a showstopper.

Output:
0
2025-04-17 12:42:24,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.434 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is slightly higher than Ligand B (56.15), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (2.894) is optimal, while Ligand B (4.13) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.

**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 (0.858 and 0.842), indicating good drug-likeness.

**DILI:** Ligand A (43.079) has a lower DILI risk than Ligand B (58.976), which is preferable. Both are below the concerning threshold of 60, but A is better.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (75.029) is higher than Ligand B (64.948).

**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:** Ligand A (0.497) has a significantly lower hERG risk than Ligand B (0.277), which is a major advantage.

**Microsomal Clearance:** Ligand A (49.9 mL/min/kg) has lower clearance than Ligand B (59.657 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.422 hours) has a better half-life than Ligand B (23.469 hours). This is counterintuitive and likely an error in the data.

**P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux than Ligand B (0.448), which is favorable for bioavailability.

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand A having better ADME properties (DILI, hERG, Cl_mic, Pgp), the substantially stronger binding affinity of Ligand B (-9.9 vs -8.2 kcal/mol) is a critical factor for an enzyme target. The potency difference is large enough to compensate for the slightly higher logP and DILI risk. The unusual negative values for Caco-2 and solubility are concerning, but the potency difference is the deciding factor.

Output:
1
2025-04-17 12:42:24,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (397.909 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (75.44), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.773) is slightly higher than Ligand B (2.541), both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 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 (0.684 and 0.822, respectively), indicating good drug-likeness.

**DILI:** Ligand B (35.789) has a significantly lower DILI risk than Ligand A (94.843). This is a major advantage for Ligand B.

**BBB:** Ligand A (69.833) and Ligand B (76.696) both have acceptable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.21) is worse than Ligand B (-4.986), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.461) is worse than Ligand B (-2.699), indicating lower solubility.

**hERG:** Ligand A (0.595) is slightly higher than Ligand B (0.314), indicating a slightly higher hERG risk, but both are relatively low.

**Microsomal Clearance:** Ligand A (53.162) has lower clearance than Ligand B (58.275), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (37.504) has a longer half-life than Ligand B (-3.595). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.265) has lower P-gp efflux than Ligand B (0.321), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 0.3 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand B has a much better safety profile due to its significantly lower DILI risk. It also has better solubility and Caco-2 permeability. Ligand A has a slightly better binding affinity and longer half-life, but the DILI risk is a major concern. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The slightly better affinity of Ligand A is outweighed by the substantial DILI risk.

Output:
1
2025-04-17 12:42:24,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly preferred due to being lower in MW.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (91.81) is slightly higher than Ligand B (88.6), but both are acceptable.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 3.806, Ligand B: 2.53), which is optimal. Ligand B is slightly better here.

**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 less than 10.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.829, Ligand B: 0.704), indicating good drug-like properties. Ligand A is better here.

**DILI:** Ligand A (48.119) has a lower DILI risk than Ligand B (79.721). This is a significant advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (85.459) is better than Ligand B (77.2).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we will assume 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:** Both ligands have very low hERG inhibition risk (Ligand A: 0.378, Ligand B: 0.342), which is excellent.

**Microsomal Clearance:** Ligand A (29.477 mL/min/kg) has significantly lower microsomal clearance than Ligand B (71.612 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 18.22 hours, Ligand B: 18.564 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.197, Ligand B: 0.279).

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.5 kcal/mol, Ligand B: -8.6 kcal/mol). The difference is minimal.

**Overall:**

Ligand A is superior due to its lower DILI risk, lower microsomal clearance (better metabolic stability), and higher QED. While Ligand B has a slightly better logP and marginally better binding affinity, the ADME properties of Ligand A are more favorable, particularly the reduced risk of liver injury and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and safety are crucial.

Output:
0
2025-04-17 12:42:24,080 - INFO - Batch 152 complete. Total preferences: 2432
2025-04-17 12:42:24,080 - INFO - Processing batch 153/512...
2025-04-17 12:43:04,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (366.531 and 351.393 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.44) is better than Ligand B (60.77), both are below the 140 threshold for oral absorption.

**3. logP:** Both ligands (2.006 and 2.415) 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 (5) is preferable to Ligand B (3), as fewer HBA's generally improve permeability.

**6. QED:** Both ligands (0.741 and 0.707) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (11.981) has a significantly lower DILI risk than Ligand B (13.3), both are below the 40 threshold.

**8. BBB:** Ligand A (72.78) and Ligand B (83.249) both have good BBB penetration, but B is slightly better. This isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.02) is better than Ligand B (-4.273), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.423) is better than Ligand B (-2.897), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.513) is better than Ligand B (0.8), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (57.215) has higher microsomal clearance than Ligand B (25.54), indicating lower metabolic stability. This is a significant drawback.

**13. In vitro Half-Life:** Ligand A (-11.276) has a shorter half-life than Ligand B (4.198), indicating lower stability. This is a significant drawback.

**14. P-gp Efflux:** Ligand A (0.071) is better than Ligand B (0.373), indicating lower P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.9), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A has advantages in most ADME properties (DILI, solubility, Caco-2, hERG, P-gp) and a slightly better binding affinity. However, Ligand B has significantly better metabolic stability (lower Cl_mic and longer t1/2). Given that we are targeting an enzyme (kinase), metabolic stability is crucial. While the affinity difference is small, the substantial difference in metabolic stability favors Ligand B.

Output:
1
2025-04-17 12:43:04,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.479 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is better than Ligand B (70.67) as it's closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.079) is optimal (1-3), while Ligand B (1.298) is on the lower side and might have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=4) as it has fewer hydrogen bond forming groups, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.824 and 0.691), indicating good drug-like properties.

**DILI:** Ligand A (55.913) has a higher DILI risk than Ligand B (6.553). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.237) is better than Ligand B (53.044), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.762) is better than Ligand B (-5.269), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.935) is better than Ligand B (-1.088) indicating better solubility.

**hERG:** Ligand A (0.632) has a lower hERG risk than Ligand B (0.289), which is favorable.

**Microsomal Clearance:** Ligand B (8.938) has a significantly lower microsomal clearance than Ligand A (50.463), suggesting better metabolic stability. This is a crucial advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (8.146 hours) has a longer half-life than Ligand A (5.204 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux than Ligand B (0.013), which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-7.9 and -7.7 kcal/mol), which are both excellent. The 0.2 kcal/mol difference is not substantial enough to outweigh other factors.

**Overall:**

Ligand B is the better candidate. While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B has a dramatically lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a lower hERG risk. These factors are more critical for an enzyme inhibitor targeting SRC kinase. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed with further optimization, but the superior ADME profile makes it the preferred choice.

Output:
1
2025-04-17 12:43:04,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.11) is slightly higher than Ligand B (71.34). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (1.882) and Ligand B (3.265) are both within the optimal 1-3 range. Ligand B is closer to the upper limit, which could potentially lead to off-target effects, but is still acceptable.

**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 good QED scores (0.758 and 0.832, respectively), indicating good drug-like properties.

**DILI:** Ligand A (54.362) has a higher DILI risk than Ligand B (33.695). This is a significant advantage for Ligand B.

**BBB:** Ligand A (34.626) has a lower BBB penetration percentile than Ligand B (55.099). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.331) has worse Caco-2 permeability than Ligand B (-4.807). Both are negative which is not ideal, but B is better.

**Aqueous Solubility:** Ligand A (-2.841) has worse aqueous solubility than Ligand B (-4.009). Solubility is important for bioavailability, so Ligand B is favored.

**hERG:** Ligand A (0.207) has a slightly better hERG profile than Ligand B (0.355), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (37.768) has a lower microsomal clearance than Ligand B (49.639), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.578) has a shorter half-life than Ligand B (44.461). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.302), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 1.5 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior profile overall. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, Ligand B excels in crucial areas: significantly stronger binding affinity, lower DILI risk, better solubility, and a longer half-life. The stronger binding affinity is the most important factor for an enzyme inhibitor, and the lower DILI risk is critical for safety. The better solubility and half-life further strengthen its position.

Output:
1
2025-04-17 12:43:04,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.503 and 348.531 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.82) is better than Ligand B (40.62), both are below the 140 threshold for oral absorption, but generally lower is preferred.

**logP:** Both ligands have acceptable logP values (2.641 and 3.842), 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 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both have reasonable QED scores (0.861 and 0.757), indicating good drug-like properties.

**DILI:** Ligand A (19.193) has a significantly lower DILI risk than Ligand B (16.906), which is a major advantage. Lower DILI is crucial for drug development.

**BBB:** Both have high BBB penetration (84.413 and 92.827), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.98 and -4.567). This is unusual and suggests poor permeability. However, kinase inhibitors aren't always expected to have high Caco-2 values.

**Aqueous Solubility:** Ligand A (-1.759) has better (less negative) solubility than Ligand B (-3.526). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.886) has a slightly higher hERG risk than Ligand B (0.683), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (-12.061) has *much* lower (better) microsomal clearance than Ligand B (72.515). This indicates significantly improved metabolic stability for Ligand A, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (16.185 hours) has a significantly longer half-life than Ligand B (-3.673 hours). This is a substantial advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.351), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While a 0.8 kcal/mol difference is noticeable, the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and lower P-gp efflux. These factors are paramount for an enzyme inhibitor, outweighing the small difference in binding affinity.

Output:
0
2025-04-17 12:43:04,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.373 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.32 and 84.5) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.059 and 1.416) are within the optimal 1-3 range.

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

**QED:** Ligand B (0.71) has a better QED score than Ligand A (0.485), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (52.85 and 47.266, both <60). Ligand B is slightly better.

**BBB:** Ligand A (84.296) has a higher BBB penetration percentile than Ligand B (68.941). However, BBB is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.934 and -5.22). 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 have negative solubility values (-2.162 and -3.766), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG:** Both ligands have low hERG inhibition liability (0.453 and 0.432).

**Microsomal Clearance:** Ligand A (9.402 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (53.465 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-15.821 hours) has a negative half-life, which is not physically possible. This is likely an error in the data. Ligand B (5.36 hours) is a more reasonable value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.067).

**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 substantial and outweighs many of the other drawbacks.

**Conclusion:**

Despite the negative Caco-2 and solubility values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.5 vs -7.0 kcal/mol) is the most important factor for an enzyme target like SRC. While Ligand A has better metabolic stability (lower Cl_mic), the difference in affinity is more critical. The QED score is also better for Ligand B. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 12:43:04,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**2. TPSA:** Ligand A (91.56) is slightly higher than Ligand B (66.48). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**3. logP:** Both ligands have similar and optimal logP values (A: 3.242, B: 3.181), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). While both are acceptable (<=5), B is better.

**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 (A: 0.684, B: 0.755), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have similar DILI risk (A: 56.689, B: 53.858), and are both acceptable (below 60).

**8. BBB:** Ligand A (60.876) and Ligand B (78.751). BBB is not a major priority for SRC kinase inhibitors as it's not a CNS target. Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-5.275) and Ligand B (-4.956). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.699) and Ligand B (-3.383). Both are negative, indicating poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.154) and Ligand B (0.641). Ligand A has a significantly lower hERG inhibition liability, which is crucial for avoiding cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-6.945) and Ligand B (41.325). Ligand A has a negative value, indicating very low clearance and excellent metabolic stability. This is a significant advantage.

**13. In vitro Half-Life:** Ligand A (38.16) and Ligand B (33.645). Ligand A has a slightly longer half-life, which is desirable.

**14. P-gp Efflux:** Ligand A (0.104) and Ligand B (0.528). Ligand A has lower P-gp efflux liability, which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand A (-8.1) and Ligand B (-8.5). Ligand B has a slightly better binding affinity, but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and QED, Ligand A demonstrates superior ADMET properties, particularly regarding metabolic stability (Cl_mic), hERG inhibition, and P-gp efflux. The significantly lower hERG risk and higher metabolic stability of Ligand A are critical advantages for an enzyme inhibitor, outweighing the minor difference in binding affinity. The slightly better Caco-2 and TPSA of Ligand B are not enough to offset the ADMET advantages of Ligand A.

Output:
0
2025-04-17 12:43:04,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (61.88) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (3.006) is optimal, while Ligand B (1.005) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 2 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 (0.765 and 0.823), indicating good drug-like properties.

**DILI:** Ligand A (31.059) has a significantly lower DILI risk than Ligand B (8.026), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.007) is higher than Ligand B (63.048).

**Caco-2 Permeability:** Ligand A (-4.962) is significantly better than Ligand B (-4.835).

**Aqueous Solubility:** Ligand A (-2.9) is better than Ligand B (-0.891), which is important for formulation and bioavailability.

**hERG:** Ligand A (0.399) has a lower hERG risk than Ligand B (0.172), a critical safety parameter.

**Microsomal Clearance:** Ligand A (6.033) has a higher clearance than Ligand B (1.225), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (19.709) has a significantly longer half-life than Ligand A (8.841), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux than Ligand B (0.005), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). The 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI and hERG risks. It also has better solubility and Caco-2 permeability. However, it suffers from higher microsomal clearance and shorter half-life compared to Ligand B. The substantial binding affinity advantage of Ligand A, coupled with the lower safety liabilities (DILI, hERG), makes it the more promising candidate despite the metabolic stability concerns. The metabolic stability can be addressed through structural modifications in subsequent optimization rounds.

Output:
1
2025-04-17 12:43:04,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.316 and 355.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.42) is slightly higher than Ligand B (72.88), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.137) is within the optimal range (1-3), while Ligand B (1.479) is at the lower end. This could potentially impact permeability for Ligand 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 (0.541 and 0.692), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.915, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (6.282), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (74.564) is higher than Ligand B (55.487).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.551 and -4.811), which is unusual and suggests poor permeability. However, these values are on a log scale and the absolute value is more important. Ligand B has a slightly more negative value, suggesting potentially worse permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.244 and -1.075), indicating poor aqueous solubility. Ligand B is better in this regard.

**hERG Inhibition:** Ligand A (0.652) has a slightly higher hERG risk than Ligand B (0.544), but both are relatively low.

**Microsomal Clearance:** Ligand B (-9.653) has a *much* lower (better) microsomal clearance than Ligand A (55.595), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand B (-4.964) has a longer in vitro half-life than Ligand A (2.693), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.08 and 0.028).

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.5), a 0.5 kcal/mol difference. While this is a positive for Ligand A, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B exhibits a significantly better safety profile (much lower DILI risk), superior metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The difference in binding affinity (0.5 kcal/mol) is unlikely to outweigh the substantial advantages of Ligand B in terms of ADME/Tox properties, especially for an enzyme target where metabolic stability is crucial. The permeability concerns for both are a drawback, but Ligand B is slightly better.



Output:
1
2025-04-17 12:43:04,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.371 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.01 and 95.41) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (target <90).

**logP:** Ligand A (0.523) is a bit low, potentially hindering permeation. Ligand B (1.927) is within 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.

**QED:** Both ligands have good QED scores (0.821 and 0.581), indicating drug-like properties.

**DILI:** Ligand A (68.786) has a higher DILI risk than Ligand B (56.96), but both are reasonably acceptable.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.175 and 0.228), which is good.

**Microsomal Clearance:** Ligand A (-3.583) has significantly lower (better) microsomal clearance than Ligand B (33.185), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.311) has a longer in vitro half-life than Ligand B (-28.084), which is desirable.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.131), which is favorable.

**Binding Affinity:** Ligand A (-7.9 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. While both have issues with Caco-2 permeability and solubility, Ligand A's substantially superior binding affinity (-7.9 vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are critical for an enzyme target like SRC kinase. The slightly higher DILI risk is less concerning given the strong potency and improved metabolic profile. The lower logP of Ligand A is a concern, but could potentially be addressed with further optimization.

Output:
1
2025-04-17 12:43:04,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (367.559 Da and 351.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.36) is well below the 140 threshold and favorable. Ligand B (73.91) is still acceptable, but higher.

**3. logP:** Both ligands (3.222 and 3.437) are within the optimal 1-3 range.

**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 (0.728 and 0.677) have good drug-likeness scores, exceeding 0.5.

**7. DILI:** Ligand A (9.965) has a significantly lower DILI risk than Ligand B (11.322), indicating a safer profile. Both are below the 40 threshold.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.921) has a higher BBB penetration than Ligand B (62.233).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.676 and -4.476), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.209 and -3.357), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.338) has a lower hERG inhibition risk than Ligand B (0.821), which is preferable. Both are relatively low, but A is better.

**12. Microsomal Clearance:** Ligand A (96.389) has a higher microsomal clearance than Ligand B (58.417), suggesting lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (40.524) has a much longer in vitro half-life than Ligand A (4.163), indicating better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux liability than Ligand B (0.871), which is favorable.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate. Despite slightly higher TPSA and P-gp efflux, it exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and a slightly better hERG profile. The poor Caco-2 and solubility are concerning for both, but metabolic stability is a higher priority for kinase inhibitors.

Output:
1
2025-04-17 12:43:04,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) inhibitor targeting oncology.

**1. Molecular Weight:** Both ligands (342.311 and 370.837 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (120.35) is slightly higher than ideal (<=140), but acceptable. Ligand B (98.95) is well within the acceptable range.

**3. logP:** Both ligands (1.831 and 1.845) are within the optimal range of 1-3.

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

**5. H-Bond Acceptors:** Ligand A (8) is good. Ligand B (5) is also good.

**6. QED:** Ligand A (0.674) is better than Ligand B (0.588), indicating a more drug-like profile.

**7. DILI:** Ligand A (94.843) has a significantly higher DILI risk than Ligand B (39.977). This is a major concern for Ligand A.

**8. BBB:** BBB is less critical for an oncology target, but Ligand A (61.962) is lower than Ligand B (43.001).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.772 and -4.956). 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 (-3.079 and -2.064). Similar to Caco-2, this is possible on the scale and doesn't immediately disqualify them.

**11. hERG Inhibition:** Ligand A (0.123) has a lower hERG risk than Ligand B (0.427), which is favorable.

**12. Microsomal Clearance:** Ligand B (-18.35) has significantly lower (better) microsomal clearance than Ligand A (83.909), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (35.37) has a much longer in vitro half-life than Ligand A (-7.897), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux than Ligand B (0.091), which is slightly favorable.

**15. Binding Affinity:** Ligand A (-9.3) has a significantly stronger binding affinity than Ligand B (-7.4). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its extremely high DILI risk and poor metabolic stability (high Cl_mic, short t1/2) are major drawbacks. Ligand B, despite a slightly weaker binding affinity, presents a much more favorable ADMET profile, particularly its low DILI risk and improved metabolic stability. For an oncology kinase inhibitor, metabolic stability and minimizing toxicity are paramount. The 1.9 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, whereas mitigating the DILI risk of Ligand A would be far more challenging.

Output:
1
2025-04-17 12:43:04,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 361.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.35) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (81.21) is well within the range.

**logP:** Ligand A (-0.955) is a bit low, potentially hindering permeation. Ligand B (0.291) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 8 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.558 and 0.667), indicating drug-like properties.

**DILI:** Ligand A (44.552) has a lower DILI risk than Ligand B (57.58), which is preferable.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (83.908) has a higher percentile, suggesting better potential for CNS penetration if needed.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.554 and -5.203), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.08 and -1.678), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.109) has a much lower hERG risk than Ligand B (0.323), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-8.125) has significantly lower (better) microsomal clearance than Ligand B (4.689), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.016) has a longer (better) in vitro half-life than Ligand B (-24.136).

**P-gp Efflux:** Ligand A (0.006) has much lower P-gp efflux liability than Ligand B (0.239), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -9.3 kcal/mol), with Ligand B being slightly better. However, the affinity difference is not large enough to overcome the significant ADME deficiencies of Ligand B.

**Conclusion:**

While Ligand B has slightly better binding affinity and BBB penetration, Ligand A is the more promising candidate due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. The poor solubility and permeability are concerns for both, but the ADME profile of Ligand A is considerably more favorable.

Output:
0
2025-04-17 12:43:04,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.768 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (399.343 Da) is still well within the acceptable range.

**TPSA:** Ligand A (88.49) is better than Ligand B (72.19) as it is closer to the 90 A^2 threshold for CNS targets, although SRC is not a CNS target, lower TPSA generally improves permeability.

**logP:** Ligand A (2.772) is optimal, while Ligand B (4.017) is pushing the upper limit. Higher logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Ligand A (0.85) has a significantly better QED score than Ligand B (0.745), indicating a more drug-like profile.

**DILI:** Ligand B (64.056) has a lower DILI risk than Ligand A (96.704), which is a significant advantage.

**BBB:** Ligand B (75.107) has a better BBB penetration score than Ligand A (58.666), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.659) has a worse Caco-2 permeability than Ligand B (-5.078).

**Aqueous Solubility:** Ligand A (-4.581) has a worse aqueous solubility than Ligand B (-3.824).

**hERG Inhibition:** Ligand A (0.158) has a lower hERG inhibition risk than Ligand B (0.841), which is a critical advantage.

**Microsomal Clearance:** Ligand A (16.56 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (26.629 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (101.247 hours) has a much longer in vitro half-life than Ligand A (38.852 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.084) has a lower P-gp efflux liability than Ligand B (0.591), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 kcal/mol and -8.0 kcal/mol, respectively). The difference of 0.9 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has advantages in DILI risk, in vitro half-life, and Caco-2 permeability. However, Ligand A has better QED, lower hERG risk, lower P-gp efflux, and lower microsomal clearance. Given the enzyme-kinase focus, metabolic stability (Cl_mic and t1/2) and hERG risk are crucial. While Ligand B has a better half-life, Ligand A's significantly lower Cl_mic and hERG risk are more important. The slightly better solubility of Ligand B is also a plus. The affinity difference is minimal.

Output:
1
2025-04-17 12:43:04,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.76 and 95.5) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.756) is within the optimal 1-3 range, while Ligand B (-0.293) is slightly below 1. This is a minor negative for Ligand B, potentially impacting permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 threshold.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (5), below the 10 threshold.

**QED:** Both ligands have good QED scores (0.791 and 0.74), indicating good drug-like properties.

**DILI:** Ligand A (32.299) has a significantly lower DILI risk than Ligand B (64.754). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (50.679 and 53.276), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.688 and -4.503). 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 (-1.702 and -1.317). This is also unusual and suggests poor solubility. Again, the difference is small.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.234 and 0.139), which is excellent.

**Microsomal Clearance:** Ligand A (-2.692 mL/min/kg) exhibits significantly lower microsomal clearance than Ligand B (57.778 mL/min/kg). This indicates much better metabolic stability for Ligand A, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (10.707 hours) has a much longer in vitro half-life than Ligand B (-39.491 hours). This is a major advantage for Ligand A, suggesting less frequent dosing potential. The negative value for Ligand B is concerning.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.099 and 0.024).

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Conclusion:**

Despite the similar binding affinity, Ligand A is the superior candidate. Its significantly lower DILI risk, dramatically improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better logP outweigh any minor concerns about the Caco-2 and solubility values (which are similar between the two). The improved ADME profile of Ligand A makes it much more likely to succeed as a drug candidate.

Output:
0
2025-04-17 12:43:04,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.467 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.59) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (96.69) is still under 140, but less optimal.

**logP:** Ligand A (2.976) is within the optimal 1-3 range. Ligand B (0.13) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.767 and 0.805), indicating drug-like properties.

**DILI:** Ligand A (75.96) has a higher DILI risk than Ligand B (37.805). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.197) and Ligand B (46.724) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.759) has poor Caco-2 permeability, which is concerning. Ligand B (-5.26) is also poor, but similar.

**Aqueous Solubility:** Ligand A (-3.679) and Ligand B (-1.038) both have poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.322 and 0.301).

**Microsomal Clearance:** Ligand A (49.218) has a moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (-18.802) has *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 (20.031 hours) has a reasonable half-life. Ligand B (-9.449 hours) has a negative half-life, which is not possible.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.443 and 0.053).

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This 2.6 kcal/mol difference is substantial and could potentially outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk and poor Caco-2 permeability, its *significantly* superior binding affinity (-9.0 vs -6.4 kcal/mol) and reasonable half-life make it the more promising candidate. The negative values for clearance and half-life of Ligand B are impossible and indicate a data quality issue, making it a non-starter. While solubility is a concern for both, the potency advantage of Ligand A is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:43:04,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.415 and 347.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (123.41) is slightly higher than Ligand B (105.12), but both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.169) is within the optimal 1-3 range. Ligand B (-0.192) is slightly below 1, potentially hindering permeation.

**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 (5) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.717) has a better QED score than Ligand B (0.567), suggesting a more drug-like profile.

**7. DILI:** Ligand B (40.287) has a significantly lower DILI risk than Ligand A (90.733). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (41.218) has a higher BBB penetration percentile than Ligand A (17.642), but this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.405 and -5.861), 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 ligands have negative solubility values (-3.516 and -1.673), again unusual and suggesting poor solubility. Similar to Caco-2, interpretation is difficult without knowing the scale.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.022 and 0.029).

**12. Microsomal Clearance:** Ligand A (11.921) has a lower microsomal clearance than Ligand B (-14.506), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-20.784) has a longer in vitro half-life than Ligand B (22.811), further supporting better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.008).

**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:**

Ligand B has a significantly better DILI profile and slightly better binding affinity. However, Ligand A exhibits superior metabolic stability (lower Cl_mic and longer t1/2) and a better QED score. Given that SRC is an enzyme, metabolic stability is a crucial factor. While the solubility and permeability data are concerning for both, the difference in metabolic stability and QED leans towards Ligand A. The 0.2 kcal/mol difference in binding affinity is unlikely to outweigh the metabolic benefits of Ligand A.

Output:
1
2025-04-17 12:43:04,479 - INFO - Batch 153 complete. Total preferences: 2448
2025-04-17 12:43:04,479 - INFO - Processing batch 154/512...
2025-04-17 12:43:55,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (345.487 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is better than Ligand B (78.51). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range.

**3. logP:** Ligand A (2.147) is optimal (1-3), while Ligand B (0.974) is slightly 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 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.606 and 0.729), indicating drug-like properties.

**7. DILI:** Ligand A (30.012) has a significantly lower DILI risk than Ligand B (14.23). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (70.415 and 60.644). Since SRC is not a CNS target, this is less critical, but A is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.283 and -5.142). This is unusual and suggests poor permeability. However, the values are very close.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.685 and -2.536). This is also unusual and suggests poor solubility. Again, the values are very close.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.407 and 0.094). This is excellent. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (37) has a higher microsomal clearance than Ligand B (-2.239). This indicates lower metabolic stability for Ligand A, which is a disadvantage.

**13. In vitro Half-Life:** Ligand A (16.401) has a longer half-life than Ligand B (-3.531). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.067 and 0.014). This is excellent. Ligand B is slightly better.

**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 A is favored due to its significantly lower DILI risk, better TPSA, and longer half-life. While Ligand B has slightly better logP, hERG, and P-gp efflux, the DILI risk associated with Ligand B is concerning. The slightly better metabolic stability of Ligand B is offset by the longer half-life of Ligand A. Given the enzyme-kinase target class, metabolic stability and DILI are critical.

Output:
0
2025-04-17 12:43:55,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.794 and 350.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.94) is slightly above the preferred <90 for CNS targets, but acceptable for a non-CNS kinase inhibitor. Ligand B (52.23) is well within the acceptable range.

**logP:** Both ligands have good logP values (3.402 and 2.918), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are both acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 54.634, which is acceptable (below 60). Ligand B has a significantly lower DILI risk of 6.747, which is excellent.

**BBB:** Both ligands have high BBB penetration (80.419 and 86.933), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.705 and -4.951), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.468 and -1.956), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.631) shows a slightly higher hERG risk than Ligand B (0.906), but both are relatively low.

**Microsomal Clearance:** Ligand A (22.478) has lower microsomal clearance than Ligand B (30.006), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.654) has a longer in vitro half-life than Ligand B (-3.701), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.357) has lower P-gp efflux than Ligand B (0.115), suggesting better bioavailability.

**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 concerns.

**Conclusion:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-8.8 kcal/mol vs -7.3 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The lower DILI risk for Ligand B is attractive, but the substantial difference in binding affinity is the deciding factor for an enzyme target like SRC. Addressing the solubility and permeability issues through formulation or prodrug strategies would be the next steps for Ligand A.

Output:
1
2025-04-17 12:43:55,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (383.539 and 371.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is well below the 140 threshold and favorable. Ligand B (114.43) is still within acceptable limits but less optimal.

**logP:** Ligand A (2.356) is within the optimal 1-3 range. Ligand B (0.771) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, both within acceptable limits. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.799 and 0.593), indicating drug-like properties.

**DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (35.479). This is a significant concern.

**BBB:** BBB is less important for a non-CNS target like SRC, but Ligand B (74.254) has a better percentile than Ligand A (57.464).

**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, we can still compare relative values. Ligand A (-4.656) is slightly better than Ligand B (-5.381).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.849) is slightly better than Ligand A (-4.169).

**hERG:** Both ligands have low hERG inhibition risk (0.361 and 0.309).

**Microsomal Clearance:** Ligand B (26.402) has significantly lower microsomal clearance than Ligand A (70.126), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (4.106 hours) has a slightly better half-life than Ligand A (-16.413 hours - a negative value is concerning).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.371 and 0.074).

**Binding Affinity:** Ligand B (-7.9 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 difference threshold.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the overall profile of Ligand B is superior. Its significantly stronger binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic and better t1/2) outweigh the slightly less favorable TPSA and logP values. The higher binding affinity is the most important factor for an enzyme inhibitor. Ligand A's higher DILI risk is a major red flag.

Output:
1
2025-04-17 12:43:55,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (380.411 Da) is also well within range.

**TPSA:** Ligand B (72.11) is significantly better than Ligand A (101.7). Lower TPSA generally improves oral absorption.

**logP:** Ligand B (3.433) is optimal, while Ligand A (0.192) 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, acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.733 and 0.702), indicating good drug-likeness.

**DILI:** Ligand B (39.201) has a much lower DILI risk than Ligand A (70.105). This is a significant advantage for Ligand B.

**BBB:** Ligand B (93.912) has a high BBB percentile, while Ligand A (53.974) is moderate. While SRC is not a CNS target, higher BBB is generally a positive indicator of reduced off-target effects.

**Caco-2 Permeability:** Ligand A (-5.349) has a very poor Caco-2 permeability, while Ligand B (-4.621) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.706) has poor aqueous solubility, while Ligand B (-4.806) is even worse. This could pose formulation challenges for both, but is more concerning for Ligand B.

**hERG Inhibition:** Ligand A (0.292) has a lower hERG risk than Ligand B (0.783). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (4.69) has significantly lower microsomal clearance than Ligand B (34.292). Lower clearance indicates better metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand A (6.929) has a shorter half-life than Ligand B (15.006). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.249), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.9) has a significantly stronger binding affinity than Ligand B (-0.0). This is the most crucial factor. A difference of almost 8 kcal/mol is substantial.

**Overall Assessment:**

Ligand B has better physicochemical properties regarding TPSA, logP, and DILI. However, its solubility and Caco-2 permeability are poor, and its metabolic stability is concerning due to high Cl_mic. Most importantly, its binding affinity is dramatically weaker than Ligand A.

Ligand A, despite its lower logP and solubility, boasts a much stronger binding affinity (-7.9 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. The superior binding affinity of Ligand A is likely to outweigh its ADME drawbacks, especially if formulation strategies can address the solubility issue. The lower clearance is also a positive.

Output:
1
2025-04-17 12:43:55,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.4 and 346.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.81) is slightly above the optimal <140, but acceptable. Ligand B (93.7) is excellent, well below 140.

**logP:** Ligand A (0.384) is a bit low, potentially hindering permeability. Ligand B (1.663) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (8) and Ligand B (4) are both within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED values (0.804 and 0.624), indicating good drug-like properties.

**DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (32.61), which is preferable.

**BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (68.75) is slightly better.

**Caco-2:** Ligand A (-4.507) and Ligand B (-5.244) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have poor aqueous solubility (-1.687 and -2.545). This is a drawback for both.

**hERG:** Ligand A (0.078) has a very low hERG risk, which is excellent. Ligand B (0.421) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand B (-12.785) has significantly lower microsomal clearance than Ligand A (20.612), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (-5.276) has a longer in vitro half-life than Ligand A (-25.742), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.007).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.9 kcal/mol difference is substantial and outweighs many of the minor drawbacks.

**Conclusion:**

While both ligands have some issues (poor Caco-2 and solubility), Ligand B is the more promising candidate. Its superior binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower DILI risk outweigh the slightly lower logP and TPSA. The strong binding affinity is a critical factor for an enzyme inhibitor.

Output:
1
2025-04-17 12:43:55,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.403 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.89) is higher than Ligand B (67.23). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have similar logP values (1.923 and 1.856), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBAs, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.712 and 0.871), indicating drug-like properties.

**DILI:** Ligand A (62.272) has a higher DILI risk than Ligand B (27.724). This is a significant concern.

**BBB:**  BBB is less critical for a non-CNS target like SRC kinase. Ligand A (73.401) is slightly higher than Ligand B (54.207).

**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:** Ligand A (0.106) has a slightly better hERG profile than Ligand B (0.238), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (29.286 mL/min/kg) has significantly lower microsomal clearance than Ligand A (66.273 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (18.384 hours) has a much longer half-life than Ligand A (-7.477 hours). This is a major advantage, potentially allowing for less frequent dosing. The negative value for Ligand A is concerning.

**P-gp Efflux:** Both have low P-gp efflux liability (0.02 and 0.033), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the superior candidate. While both have good potency, Ligand B demonstrates significantly better ADMET properties. Specifically, its lower DILI risk, lower microsomal clearance (higher metabolic stability), and substantially longer half-life are critical advantages for an enzyme inhibitor. The slightly lower TPSA and better solubility (less negative value) also contribute to its favorability. The small difference in binding affinity is outweighed by the superior ADMET profile of Ligand B.

Output:
1
2025-04-17 12:43:55,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 360.483 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.25) is slightly higher than Ligand B (78.09), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.425 and 2.048), 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, and Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.76 and 0.828), indicating good drug-likeness.

**DILI:** Ligand A (34.626) has a significantly lower DILI risk than Ligand B (44.048). This is a substantial advantage.

**BBB:** Ligand A (68.786) has a higher BBB penetration score than Ligand B (39.473). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.835) has a more negative Caco-2 value than Ligand B (-5.628), suggesting slightly *lower* permeability. This is a minor drawback.

**Aqueous Solubility:** Ligand A (-1.623) has a better solubility score than Ligand B (-2.738). This is a positive.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.114 and 0.226).

**Microsomal Clearance:** Ligand A (65.299) has a higher microsomal clearance than Ligand B (25.87). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-6.579) has a significantly longer in vitro half-life than Ligand A (11.863). This is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.031 and 0.102).

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, Ligand A has a significantly lower DILI risk and better solubility. Given the enzyme-specific priorities, the lower DILI risk of Ligand A is a critical advantage. The equal binding affinity removes that as a differentiating factor. Therefore, Ligand A is the more promising candidate.

Output:
0
2025-04-17 12:43:55,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.332 and 364.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.5 and 87.9) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.475) is optimal, while Ligand B (0.253) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, within the limit. Ligand B has 5, also within the limit.

**QED:** Both ligands have similar QED values (0.753 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (41.838) has a slightly higher DILI risk than Ligand B (50.756), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (81.388) has a higher BBB penetration than Ligand A (60.45), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-4.724) has a worse Caco-2 permeability than Ligand B (-5.046).

**Aqueous Solubility:** Ligand A (-2.735) has a worse aqueous solubility than Ligand B (-1.805).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.304 and 0.196).

**Microsomal Clearance:** Ligand B (-2.326) exhibits significantly lower (better) microsomal clearance than Ligand A (60.251), indicating improved metabolic stability.

**In vitro Half-Life:** Ligand B (12.936 hours) has a much longer in vitro half-life than Ligand A (-23.03 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.024 and 0.039).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol).

**Conclusion:**

Ligand B is the more promising candidate. While both ligands have acceptable properties overall, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. The slightly lower logP of Ligand B is a minor concern outweighed by its improved pharmacokinetic profile. The better solubility of Ligand B is also a positive factor.

Output:
1
2025-04-17 12:43:55,368 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [395.677, 59.81, 4.466, 1, 4, 0.709, 86.002, 64.986, -4.851, -5.379, 0.512, 85.211, -21.537, 0.304, -9]
**Ligand B:** [348.349, 61.19, 3.162, 0, 5, 0.629, 60.915, 83.637, -4.424, -2.876, 0.247, 76.418, -11.637, 0.747, -8.6]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (348.349 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.
2. **TPSA:** Both are above the optimal <140 for good oral absorption, but not drastically so. Ligand A (59.81) is slightly better than Ligand B (61.19).
3. **logP:** Ligand A (4.466) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (3.162) is much better, falling within the optimal 1-3 range.
4. **HBD:** Ligand A (1) is good. Ligand B (0) is also good, minimizing potential issues with hydrogen bonding.
5. **HBA:** Both ligands are acceptable (Ligand A: 4, Ligand B: 5), staying below the 10 threshold.
6. **QED:** Both are reasonably good (A: 0.709, B: 0.629), indicating drug-like properties.
7. **DILI:** Ligand A (86.002) has a significantly higher DILI risk than Ligand B (60.915). This is a major concern.
8. **BBB:** Both have reasonable BBB penetration, but Ligand B (83.637) is better than Ligand A (64.986). Not a primary concern for an oncology target.
9. **Caco-2:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.851) is slightly worse than Ligand B (-4.424).
10. **Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-2.876) is better than Ligand A (-5.379).
11. **hERG:** Both have low hERG inhibition risk (A: 0.512, B: 0.247), which is good.
12. **Cl_mic:** Ligand B (76.418) has a lower microsomal clearance, suggesting better metabolic stability than Ligand A (85.211).
13. **t1/2:** Ligand B (-11.637) has a longer in vitro half-life than Ligand A (-21.537), which is desirable.
14. **Pgp:** Both have low P-gp efflux liability (A: 0.304, B: 0.747).
15. **Binding Affinity:** Both have excellent binding affinity (A: -9 kcal/mol, B: -8.6 kcal/mol). The difference is relatively small (0.4 kcal/mol) and likely less important than the ADME differences.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B clearly outperforms Ligand A in metabolic stability (lower Cl_mic, longer t1/2), solubility, and significantly reduces the risk of DILI. While both have good affinity, the ADME profile of Ligand B is far superior.

**Conclusion:**

Ligand B is the more viable drug candidate.

1
2025-04-17 12:43:55,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Ligand A:**

*   **MW:** 352.45 Da - Within the ideal range (200-500).
*   **TPSA:** 67.43 A<sup>2</sup> - Acceptable, though higher than optimal for CNS penetration.
*   **logP:** 2.525 - Optimal.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 3 - Acceptable.
*   **QED:** 0.495 - Slightly below the desired 0.5, but not a major concern.
*   **DILI:** 36.177 - Good, low risk.
*   **BBB:** 82.396 - Moderate, not a primary concern for a non-CNS target.
*   **Caco-2:** -4.993 - Very poor permeability. A significant drawback.
*   **Solubility:** -3.59 - Very poor solubility. A significant drawback.
*   **hERG:** 0.356 - Low risk, good.
*   **Cl_mic:** 16.84 mL/min/kg - Moderate clearance, not ideal but manageable.
*   **t1/2:** -4.618 hours - Very short half-life. A significant drawback.
*   **Pgp:** 0.214 - Low efflux, good.
*   **Affinity:** -7.9 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 359.579 Da - Within the ideal range (200-500).
*   **TPSA:** 20.31 A<sup>2</sup> - Excellent, favorable for permeability.
*   **logP:** 4.895 - High, potentially causing solubility issues and off-target effects.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 2 - Acceptable.
*   **QED:** 0.629 - Good, drug-like profile.
*   **DILI:** 35.052 - Good, low risk.
*   **BBB:** 78.868 - Moderate, not a primary concern.
*   **Caco-2:** -5.33 - Very poor permeability. A significant drawback.
*   **Solubility:** -5.475 - Very poor solubility. A significant drawback.
*   **hERG:** 0.694 - Moderate risk, needs consideration.
*   **Cl_mic:** 104.185 mL/min/kg - High clearance, poor metabolic stability. A significant drawback.
*   **t1/2:** 12.865 hours - Good half-life.
*   **Pgp:** 0.755 - Moderate efflux, not ideal.
*   **Affinity:** -8.1 kcal/mol - Excellent binding affinity, slightly better than Ligand A.

**Comparison & Decision:**

Both ligands suffer from extremely poor Caco-2 permeability and aqueous solubility, which are critical for oral bioavailability. However, considering the priorities for enzyme inhibitors, we need to weigh affinity, metabolic stability, and safety.

Ligand B has a slightly better affinity (-8.1 vs -7.9 kcal/mol) and a significantly better half-life (12.865 hours vs -4.618 hours). While its logP is higher and hERG risk is slightly elevated, the poor metabolic stability (high Cl_mic) of Ligand A is a more significant concern. The very short half-life of Ligand A would necessitate frequent dosing, which is undesirable. The solubility and permeability issues are severe for both, but can be addressed with formulation strategies.

Therefore, despite the drawbacks, Ligand B is the more promising candidate due to its superior metabolic stability and longer half-life, which are crucial for an enzyme inhibitor.

Output:
1
2025-04-17 12:43:55,368 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision, considering the guidelines and the target class (enzyme - kinase in oncology):

**1. Molecular Weight (MW):**
*   Ligand A: 351.491 Da - Within the ideal range (200-500 Da).
*   Ligand B: 346.471 Da - Within the ideal range (200-500 Da).
*   *Both are good.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 61.88 - Good for oral absorption (<140).
*   Ligand B: 49.85 - Excellent for oral absorption (<140).
*   *Ligand B is slightly better.*

**3. Lipophilicity (logP):**
*   Ligand A: 1.393 - Optimal (1-3).
*   Ligand B: 2.054 - Optimal (1-3).
*   *Both are good.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 1 - Meets the criteria (<=5).
*   Ligand B: 0 - Meets the criteria (<=5).
*   *Both are good.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 4 - Meets the criteria (<=10).
*   Ligand B: 3 - Meets the criteria (<=10).
*   *Both are good.*

**6. QED:**
*   Ligand A: 0.753 - Excellent (>0.5).
*   Ligand B: 0.716 - Excellent (>0.5).
*   *Both are good.*

**7. DILI Risk:**
*   Ligand A: 11.09 - Low risk (<40 is good).
*   Ligand B: 12.214 - Low risk (<40 is good).
*   *Both are good, very similar.*

**8. BBB Penetration:**
*   Ligand A: 75.029 - Acceptable, but not ideal for CNS targets. Not a primary concern for an oncology target unless CNS penetration is specifically desired.
*   Ligand B: 76.154 - Acceptable, but not ideal for CNS targets. Not a primary concern for an oncology target unless CNS penetration is specifically desired.
*   *Similar, not a major differentiator.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.691 - Suggests poor permeability.
*   Ligand B: -4.415 - Suggests poor permeability.
*   *Both are poor, but B is slightly better.*

**10. Aqueous Solubility:**
*   Ligand A: -1.338 - Suggests poor solubility.
*   Ligand B: -2.138 - Suggests very poor solubility.
*   *Ligand A is better.*

**11. hERG Inhibition:**
*   Ligand A: 0.296 - Low risk.
*   Ligand B: 0.371 - Low risk.
*   *Both are good, very similar.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 15.218 mL/min/kg - Relatively high clearance, suggesting lower metabolic stability.
*   Ligand B: 37.244 mL/min/kg - Very high clearance, suggesting poor metabolic stability.
*   *Ligand A is significantly better.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: 34.171 hours - Good.
*   Ligand B: -10.087 hours - Very poor (negative value is concerning).
*   *Ligand A is significantly better.*

**14. P-gp Efflux:**
*   Ligand A: 0.038 - Low efflux, good.
*   Ligand B: 0.117 - Low efflux, good.
*   *Both are good, A is slightly better.*

**15. Binding Affinity:**
*   Ligand A: -8.5 kcal/mol - Excellent.
*   Ligand B: -6.9 kcal/mol - Good, but significantly weaker than A.
*   *Ligand A is significantly better.*

**Overall Assessment:**

Considering the target is a kinase in oncology, potency (binding affinity) and metabolic stability are key. Ligand A has a substantially better binding affinity (-8.5 vs -6.9 kcal/mol) and significantly better metabolic stability (lower Cl_mic, positive t1/2). While both have some solubility issues, A is better. The difference in binding affinity is large enough to outweigh the slight drawbacks in solubility and Caco-2 permeability.

1
2025-04-17 12:43:55,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.407 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.77) is slightly above the optimal <140 for oral absorption, while Ligand B (74.33) is well within the range.

**logP:** Both ligands have good logP values (1.031 and 1.355), falling within the 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.564 and 0.817), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 59.519, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 21.908, which is excellent.

**BBB:** Both ligands have moderate BBB penetration (44.746 and 59.093). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.981) and Ligand B (-5.104) both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-2.373) and Ligand B (-1.93) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.261 and 0.396).

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (51.308), while Ligand B has a very low clearance (8.117). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A has a negative half-life (-11.36), which is not possible. Ligand B has a short half-life (1.834), but still better than a negative value.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.07 and 0.014).

**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 outweighs minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. It has a significantly better binding affinity, a much lower DILI risk, and better metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the strong binding affinity of Ligand B makes it more likely to be a viable drug candidate, especially considering the potential for optimization of solubility/permeability. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 12:43:55,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.7) is slightly above the preferred <90 for CNS targets, but acceptable for a non-CNS target like SRC. Ligand B (84.42) is well within the acceptable range.

**3. logP:** Both ligands (1.663 and 1.5) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good, potentially offering better permeability.

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

**6. QED:** Both ligands have good QED scores (0.624 and 0.873), indicating good drug-like properties.

**7. DILI:** Ligand A (32.61) has a lower DILI risk than Ligand B (43.428), which is preferable.

**8. BBB:** Both ligands have reasonable BBB penetration, but this isn't a primary concern for SRC, a non-CNS target. Ligand B (70.531) 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 we can't definitively say how bad this is.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified, so we can't definitively say how bad this is.

**11. hERG:** Both ligands have low hERG risk (0.421 and 0.19), which is excellent.

**12. Cl_mic:** Ligand A (-12.785) has *much* lower (better) microsomal clearance than Ligand B (43.862), indicating significantly better metabolic stability. This is a crucial advantage for an enzyme target.

**13. t1/2:** Ligand A (-5.276) has a negative half-life, which is unusual. Ligand B (-13.989) is also negative. Again, the scale is not specified, so we can't definitively say how bad this is.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.007 and 0.075), which is favorable.

**15. Binding Affinity:** Ligand A (-9.6 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 minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 and Solubility values (scale unknown), Ligand A's significantly better binding affinity (-9.6 vs -7.5 kcal/mol) and dramatically improved metabolic stability (lower Cl_mic, -12.785 vs 43.862) are decisive advantages for an enzyme target like SRC. The lower DILI risk is also a bonus. The unusual negative values for half-life and Caco-2/Solubility are concerning, but the potency and metabolic stability of A are compelling.

Output:
1
2025-04-17 12:43:55,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.4 and 367.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.01) is slightly higher than the preferred <140, but acceptable. Ligand B (61.44) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.062 and 2.767), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (5 and 4 respectively), satisfying the <5 and <10 rules.

**QED:** Ligand A (0.849) has a better QED score than Ligand B (0.705), indicating a more drug-like profile.

**DILI:** Ligand A (45.68) has a slightly higher DILI risk than Ligand B (33.50), but both are below the concerning threshold of 60.

**BBB:** This is less crucial for a non-CNS target like SRC, but Ligand B (54.05) shows slightly better penetration potential than Ligand A (49.83).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and likely indicates 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:** Ligand A (0.144) has a much lower hERG risk than Ligand B (0.56), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-17.16) has a *much* better (lower) microsomal clearance than Ligand B (60.42). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (59.07) has a longer half-life than Ligand A (23.01), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.221), which is favorable.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.1). This 0.9 kcal/mol difference is meaningful, but not overwhelming.

**Overall Assessment:**

Despite the better binding affinity of Ligand B, Ligand A is the more promising candidate. The key factors driving this decision are: significantly better metabolic stability (much lower Cl_mic), lower hERG risk, and a better QED score. The poor Caco-2 permeability and solubility are concerning for both, but metabolic stability and safety (hERG) are more critical at this stage for an enzyme target. The slightly better affinity of Ligand B is not enough to overcome these significant ADME/Tox liabilities.

Output:
0
2025-04-17 12:43:55,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.475 and 364.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (78.51 and 76.44) are below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands (1.59 and 1.25) are 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:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.621 and 0.718), indicating drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (15.355 and 16.712), and are both below the 40 threshold, indicating low risk.

**8. BBB:** Ligand A has a higher BBB penetration percentile (69.407) than Ligand B (57.154). While not a primary concern for a non-CNS target like SRC, it's a slight advantage for A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.063 and -5.227). This is unusual and suggests poor permeability. However, these values are on a log scale and the absolute value is more important. Both are similarly poor.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.182 and -2.247). This is also unusual and suggests poor solubility. Both are similarly poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.269 and 0.486), which is excellent.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (29.803) than Ligand B (34.975), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-15.962) than Ligand B (-1.448). This is a major advantage, suggesting less frequent dosing potential.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.011).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good potency and low hERG risk, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic) and longer half-life. The slightly better BBB penetration is a minor bonus. The poor Caco-2 and solubility are concerning for both, but the metabolic stability and half-life differences are more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:43:55,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.435 and 362.392 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.36) is slightly higher than Ligand B (60.85). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands (1.878 and 1.939) are within the optimal range of 1-3.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, Ligand B has 3. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.88 and 0.813), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 72.199, which is concerning (approaching the high-risk threshold of >60). Ligand B has a much lower DILI risk of 18.612, a significant advantage.

**BBB:** Both have reasonable BBB penetration (64.211 and 78.829), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.018) and Ligand B (-4.629) both have negative values, which is unusual. It suggests very poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.372 and -3.01). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.22) has a lower hERG risk than Ligand B (0.465), which is favorable.

**Microsomal Clearance:** Ligand A (30.878) has a higher microsomal clearance than Ligand B (24.409), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (78.384) has a longer half-life than Ligand B (-7.798), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.161), which is preferable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities and acceptable physicochemical properties (MW, logP, HBD/HBA, QED), Ligand B is the more promising candidate. The primary driver is the significantly lower DILI risk (18.612 vs. 72.199). While both have poor solubility and Caco-2 permeability, the lower DILI risk outweighs the slightly better half-life and P-gp efflux of Ligand A. The hERG risk is also slightly better for Ligand A, but the DILI difference is more critical for an enzyme inhibitor.

Output:
1
2025-04-17 12:43:55,369 - INFO - Batch 154 complete. Total preferences: 2464
2025-04-17 12:43:55,369 - INFO - Processing batch 155/512...
2025-04-17 12:44:34,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.385 Da and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.92) is higher than Ligand B (56.59). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (0.821) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.581) is within the optimal range.

**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.

**QED:** Both ligands have reasonable QED scores (0.731 and 0.685), indicating good drug-like properties.

**DILI:** Ligand A (30.322) has a significantly lower DILI risk than Ligand B (50.136), which is a major advantage.

**BBB:** Ligand A (76.735) shows better BBB penetration than Ligand B (67.197), but this is less critical for a non-CNS target like SRC.

**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. Ligand A (-1.288) is slightly better than Ligand B (-3.256).

**hERG:** Ligand A (0.203) has a much lower hERG inhibition liability than Ligand B (0.507), a crucial safety parameter.

**Microsomal Clearance:** Ligand A (-10.542) exhibits significantly lower microsomal clearance, indicating better metabolic stability, which is highly desirable for an enzyme target. Ligand B (98.623) has very high clearance.

**In vitro Half-Life:** Ligand A (-9.941) has a longer in vitro half-life than Ligand B (8.078), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux liability than Ligand B (0.321).

**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 can be offset by other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME-Tox properties: significantly lower DILI risk, lower hERG inhibition, much better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The solubility and permeability concerns are present in both, but the superior safety and pharmacokinetic profile of Ligand A outweigh the small difference in binding affinity.

Output:
0
2025-04-17 12:44:34,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (360.42 and 377.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.2) is well below the 140 threshold and favorable for oral absorption. Ligand B (79.39) is still acceptable, but less optimal.

**3. logP:** Ligand A (2.815) is within the optimal 1-3 range. Ligand B (-0.536) is below 1, which could hinder permeation.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 0, respectively), well below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (2 and 6, respectively), below the 10 limit.

**6. QED:** Both ligands have reasonable QED scores (0.81 and 0.565), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (30.826 and 27.336), both well below the 40 threshold.

**8. BBB:** Ligand A (91.896) has a significantly higher BBB penetration score than Ligand B (63.086). While SRC isn't a CNS target, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.585 and -4.651). This is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method and should be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.424 and -1.324), which is also concerning. Similar to Caco-2, these values may be unreliable predictions.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.547 and 0.579).

**12. Microsomal Clearance (Cl_mic):** Ligand A (26.426) has lower microsomal clearance than Ligand B (32.215), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.504) has a better in vitro half-life than Ligand B (-46.56). The negative value for Ligand B is concerning and likely an artifact of the prediction.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.007).

**15. 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 override other factors.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A demonstrates superior metabolic stability (lower Cl_mic, better t1/2) and a slightly better overall profile in terms of predicted permeability and solubility, despite both having negative values. Ligand B's negative logP and half-life are significant drawbacks.

Considering all factors, Ligand A is the more promising candidate.

Output:
1
2025-04-17 12:44:34,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (382.869 and 382.81 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is higher than Ligand B (58.64). While both are below 140, the lower TPSA of Ligand B is preferable for absorption.

**logP:** Both ligands (2.073 and 2.222) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Lower is generally better, so Ligand B is slightly favored.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the threshold of 10.

**QED:** Both ligands have good QED scores (0.609 and 0.758), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (52.385) has a higher DILI risk than Ligand B (25.436). This is a significant advantage for Ligand B.

**BBB:** Ligand A (12.602) has very low BBB penetration, while Ligand B (85.459) has high BBB penetration. Since SRC is not a CNS target, this is less important, but still a point for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.687) has poor Caco-2 permeability, while Ligand B (-4.809) is better, but still not great.

**Aqueous Solubility:** Ligand A (-2.802) has poor aqueous solubility, while Ligand B (-3.35) is also poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.454) has a slightly lower hERG inhibition risk than Ligand B (0.602), which is favorable.

**Microsomal Clearance:** Ligand A (30.482) has higher microsomal clearance than Ligand B (15.968), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand A (-13.197) has a very short in vitro half-life, while Ligand B (2.625) is slightly better.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.13 and 0.142).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic), and better BBB penetration. While both have poor solubility and Caco-2 permeability, the ADME profile of Ligand B is more favorable, especially the DILI and metabolic stability. The binding affinity is comparable.

Output:
1
2025-04-17 12:44:34,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.5 and 365.9 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.6) is better than Ligand B (82.5) as it is closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.75 and 1.28), falling within the 1-3 range. Ligand A's is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as it has fewer hydrogen bond donors, which can sometimes hinder permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.747 and 0.744), indicating good drug-like properties.

**DILI:** Ligand B (23.2) has a significantly lower DILI risk than Ligand A (49.3), which is a major advantage. Lower DILI is highly desirable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.4) is better than Ligand B (34.4), but both are relatively low.

**Caco-2 Permeability:** Ligand A (-4.72) shows better Caco-2 permeability than Ligand B (-5.30), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.26) has better aqueous solubility than Ligand B (-1.68), which is important for formulation and bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.57 and 0.26), which is excellent.

**Microsomal Clearance:** Ligand B (-14.5) has significantly lower microsomal clearance than Ligand A (73.7). This indicates better metabolic stability for Ligand B, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (0.98) has a slightly better in vitro half-life than Ligand A (-28.1), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.09 and 0.03), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent and removes this as a differentiating factor.

**Conclusion:**

While Ligand A has slightly better TPSA, logP, Caco-2 permeability, and solubility, Ligand B demonstrates a significantly better safety profile (DILI) and metabolic stability (Cl_mic, t1/2). Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the improved metabolic stability and lower DILI risk of Ligand B outweigh the minor advantages of Ligand A.

Output:
1
2025-04-17 12:44:34,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.503 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (95.58).  A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (2.275) is optimal (1-3), while Ligand B (0.78) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 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 QED scores (0.717 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (5.777) has a much lower DILI risk than Ligand B (44.436). This is a significant advantage for A.

**BBB:** Ligand A (81) is better than Ligand B (68.127), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.59) is significantly better than Ligand B (-5.446), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.752) is better than Ligand B (-3.12). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.582) has a much lower hERG risk than Ligand B (0.046). This is a critical advantage for A, minimizing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand B (18.715) has lower microsomal clearance than Ligand A (23.524), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.791) has a longer half-life than Ligand B (3.217), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux than Ligand B (0.03), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.2) has a slightly better binding affinity than Ligand A (-8.3), a 0.9 kcal/mol difference. While affinity is a key factor, the other substantial advantages of Ligand A outweigh this difference.

**Conclusion:**

Ligand A demonstrates a significantly more favorable ADMET profile, with lower DILI and hERG risk, better solubility, permeability, and half-life. While Ligand B has slightly better binding affinity, the superior overall profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 12:44:34,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.385 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (78.09 and 83.98) are below 140, indicating good potential for oral absorption.

**3. logP:** Both ligands (1.584 and 2.101) are within the optimal range of 1-3.

**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 threshold of 10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (56.727) has a higher DILI risk than Ligand B (35.944). This is a significant drawback for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (80.729) has a higher BBB percentile than Ligand B (63.125).

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are very close, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are very close, so this isn't a major differentiator.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.247 and 0.258).

**12. Microsomal Clearance:** Ligand A (21.538) has significantly lower microsomal clearance than Ligand B (44.063), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.087) has a much longer in vitro half-life than Ligand B (-6.395), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.044).

**15. 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 difference of >1.5 kcal/mol is considered significant, and here it's >7.9 kcal/mol.

**Conclusion:**

Despite Ligand A's better metabolic stability (lower Cl_mic and longer t1/2) and slightly higher BBB penetration, the dramatically superior binding affinity of Ligand B (-7.9 vs 0.0 kcal/mol) outweighs these advantages. The lower DILI risk of Ligand B is also a significant benefit. While both have poor solubility and permeability, the potency advantage of Ligand B is paramount for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:44:34,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 349.435 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold and favorable for oral absorption. Ligand B (70.91) is still within acceptable limits but less optimal.

**logP:** Ligand A (2.618) is within the optimal 1-3 range. Ligand B (-0.266) is below 1, which could hinder permeability.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have good QED scores (0.634 and 0.732), indicating drug-like properties.

**DILI:** Ligand A (29.701) has a lower DILI risk than Ligand B (25.165), both are good.

**BBB:** Both ligands have reasonable BBB penetration (71.966 and 65.801), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. This is a red flag for both.

**Aqueous Solubility:** Ligand A (-2.85) has very poor solubility, while Ligand B (0.19) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.599) has a slightly higher hERG risk than Ligand B (0.321), but both are relatively low.

**Microsomal Clearance:** Ligand A (62.802) has higher clearance than Ligand B (-5.968). Ligand B's negative value is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (12.906) has a reasonable half-life, while Ligand B (-2.297) is very high, suggesting exceptional stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.271 and 0.02), which is favorable.

**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.

**Conclusion:**

Despite Ligand A having better TPSA and slightly lower DILI, Ligand B is the superior candidate. The significantly stronger binding affinity (-8.6 vs 0 kcal/mol) outweighs the concerns about its slightly higher TPSA and lower solubility. The exceptionally low microsomal clearance and high in vitro half-life of Ligand B are also very attractive features for an enzyme inhibitor. The negative Caco-2 values are concerning for both, but the potency advantage of B is significant.

Output:
1
2025-04-17 12:44:34,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is better than Ligand B (78.51). Lower TPSA generally favors better absorption, though it's not a strict requirement for kinases.

**logP:** Both ligands have acceptable logP values (1.415 and 1.612), 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 adhering to the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.735) has a better QED score than Ligand B (0.565), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (20.706 and 22.063), both below the 40 threshold.

**BBB:** Both have moderate BBB penetration, but Ligand B (70.26) is better than Ligand A (62.156). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.659) is worse than Ligand B (-5.022). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-1.181) is better than Ligand B (-2.226). Higher solubility is beneficial.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.1 and 0.199), which is excellent.

**Microsomal Clearance:** Ligand B (20.901) has lower microsomal clearance than Ligand A (30.179), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-2.824) has a longer in vitro half-life than Ligand A (-19.628), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 and 0.046).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 and -8.9 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While Ligand A has a slightly better TPSA and solubility, Ligand B demonstrates superior metabolic stability (lower Cl_mic and longer t1/2) and a slightly better BBB score. Given the enzyme-specific priorities, metabolic stability is crucial for kinase inhibitors, and Ligand B excels in this area. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 12:44:34,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.5 and 353.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.88) is slightly higher than Ligand B (61.88). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (3.471) is at the upper end of the optimal range (1-3), while Ligand B (1.641) is closer to the lower end. Ligand B is better here.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

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

**QED:** Ligand A (0.853) has a higher QED score than Ligand B (0.684), indicating a more drug-like profile.

**DILI:** Ligand A (72.819) has a higher DILI risk than Ligand B (7.949). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (78.209 and 76.541 respectively). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.749) is slightly worse than Ligand B (-4.557).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand B (-1.452) is slightly better than Ligand A (-4.399).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.569 and 0.55 respectively).

**Microsomal Clearance:** Ligand A (46.728) has lower microsomal clearance than Ligand B (54.365), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.986) has a negative half-life, which is not possible. Ligand B (0.512) has a very short half-life. Both are undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.252 and 0.037 respectively).

**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 positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a higher QED and slightly better metabolic stability, Ligand B has a significantly lower DILI risk, better logP, and a slightly better binding affinity. The solubility and Caco-2 permeability are poor for both, but Ligand B is marginally better. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 12:44:34,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for enzyme (kinase) inhibitors like SRC.

**1. Molecular Weight:** Both ligands (361.408 and 347.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (63.05). A TPSA under 140 is good for oral absorption, and both are well below this.

**3. logP:** Both ligands have acceptable logP values (1.525 and 2.816, respectively), 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 preferred.

**6. QED:** Both ligands have good QED scores (0.766 and 0.859), indicating good drug-like properties.

**7. DILI:** Ligand A (17.371) has a much lower DILI risk than Ligand B (27.453). This is a significant advantage.

**8. BBB:** Both ligands have reasonably high BBB penetration (85.964 and 82.047), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.466) is better than Ligand B (-5.251). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-1.638) is better than Ligand B (-2.991). Better solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.584) has a lower hERG risk than Ligand B (0.4). Lower is better.

**12. Microsomal Clearance:** Ligand A (-2.622) has significantly lower (better) microsomal clearance than Ligand B (53.423). This indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.994) has a better in vitro half-life than Ligand B (-8.991).

**14. P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.26). Lower is better.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.4). However, the difference is less than 1.5 kcal/mol, and can be overcome by other properties.

**Overall Assessment:**

Ligand A is clearly superior. It has better DILI risk, metabolic stability (Cl_mic), half-life, solubility, permeability, P-gp efflux, and H-bonding characteristics. While Ligand B has a slightly better binding affinity, the advantages of Ligand A across multiple crucial ADME-Tox properties, particularly the significantly lower DILI and Cl_mic, outweigh this minor difference in potency. For an enzyme target like SRC, metabolic stability and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 12:44:34,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.714 Da) is higher, but still acceptable. Ligand B (350.419 Da) is slightly better.

**TPSA:** Ligand A (84.08) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.06) is still reasonable, but less optimal.

**logP:** Ligand A (3.398) is within the optimal range (1-3). Ligand B (0.126) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is good. Ligand B (HBD=3, HBA=5) is also acceptable.

**QED:** Both ligands have similar QED values (A: 0.6, B: 0.648), indicating good drug-likeness.

**DILI:** Ligand A (70.105) is higher than Ligand B (51.609), indicating a slightly elevated risk of liver injury, but still within acceptable limits.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (46.413) is lower than Ligand A (41.411).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the absolute value is more important. Ligand A (-5.502) is slightly better than Ligand B (-5.19).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-3.41) is slightly better than Ligand B (-2.935).

**hERG Inhibition:** Ligand A (0.741) has a lower hERG risk than Ligand B (0.072), which is a significant advantage.

**Microsomal Clearance:** Ligand A (57.471) has a higher (worse) microsomal clearance than Ligand B (-3.841). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-13.975) has a significantly longer half-life than Ligand A (27.676).

**P-gp Efflux:** Ligand A (0.295) has lower P-gp efflux than Ligand B (0.026), which is favorable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.5 kcal/mol difference is a significant advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A having better TPSA, logP, hERG, and P-gp properties, Ligand B's significantly superior binding affinity (-8.8 vs -7.3 kcal/mol) and better metabolic stability (lower Cl_mic, longer half-life) are crucial for an enzyme inhibitor. While the low logP and solubility are concerns for Ligand B, these can potentially be addressed through formulation strategies. The stronger binding is likely to translate to greater efficacy.

Output:
1
2025-04-17 12:44:34,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.96) is well below the 140 threshold for oral absorption, while Ligand B (94.66) is still acceptable but closer to the limit.

**logP:** Ligand A (-0.086) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.75) is within the ideal range.

**H-Bond Donors:** Ligand A (1) and Ligand B (3) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the <=10 criteria.

**QED:** Both ligands (A: 0.704, B: 0.748) have excellent drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (21.714) has a significantly lower DILI risk than Ligand B (37.418), which is a major advantage. Both are below the concerning 60 threshold.

**BBB:** Ligand A (65.413) has moderate BBB penetration, while Ligand B (22.644) is quite low. BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -5.025), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.956 and -2.307), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.177, B: 0.281).

**Microsomal Clearance:** Ligand A (20.911) has a higher microsomal clearance than Ligand B (7.361), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-7.389) has a more negative in vitro half-life, suggesting a longer half-life than Ligand B (-6.518).

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (A: 0.007, B: 0.047).

**Binding Affinity:** Ligand A (-8.3) has a significantly stronger binding affinity than Ligand B (-9.4). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity (-8.3 vs -9.4 kcal/mol) and a significantly lower DILI risk. However, it suffers from higher microsomal clearance and lower solubility. Ligand B has better solubility and metabolic stability, but weaker binding affinity and a higher DILI risk. The strong binding affinity of Ligand A is a critical factor for an enzyme inhibitor, and the lower DILI risk is a significant safety advantage. While the solubility and permeability issues are concerning, these could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:44:34,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.706 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.81) is slightly higher than Ligand B (75.19). Both are below the 140 A^2 threshold for good oral absorption, but ligand B is preferable.

**logP:** Both ligands (1.888 and 2.053) 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.

**QED:** Both ligands have similar QED scores (0.805 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 87.864, which is high. Ligand B has a much lower DILI risk of 31.369, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (76.154) has a higher BBB percentile than Ligand A (48.391).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.83 and -4.669), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.387 and -2.705), indicating poor aqueous solubility. This is a significant drawback for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.157) has a slightly lower hERG inhibition risk than Ligand B (0.491), which is preferable.

**Microsomal Clearance:** Ligand A (-2.315) has a significantly *lower* (better) microsomal clearance than Ligand B (70.83). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (13.25 hours) has a much longer in vitro half-life than Ligand B (-22.788 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.098) has lower P-gp efflux liability than Ligand B (0.056), which is preferable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. However, it has a high DILI risk. Ligand B has a much lower DILI risk and slightly better solubility, but suffers from poor metabolic stability and a weaker binding affinity.

Given the importance of potency for kinase inhibitors, and the fact that the affinity difference is substantial (1.1 kcal/mol), I would prioritize Ligand A, *despite* the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications during lead optimization. The poor solubility and permeability of both compounds would need to be addressed, but the stronger binding and better metabolic profile of Ligand A make it the more promising starting point.

Output:
0
2025-04-17 12:44:34,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.422 and 350.463 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.16) is better than Ligand B (87.47), being closer to the <140 threshold for good absorption.

**logP:** Both ligands (2.072 and 1.728) are 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:** Ligand B (5) is better than Ligand A (3), both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.748 and 0.745), indicating good drug-likeness.

**DILI:** Ligand B (28.383) has a significantly lower DILI risk than Ligand A (47.732), which is a major advantage.

**BBB:** Ligand A (73.866) has a better BBB penetration than Ligand B (67.197), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.743) has better Caco-2 permeability than Ligand B (-5.125).

**Aqueous Solubility:** Ligand B (-1.552) has better aqueous solubility than Ligand A (-2.486).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.402 and 0.385).

**Microsomal Clearance:** Ligand B (17.858) has a lower microsomal clearance than Ligand A (26.736), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.401) has a significantly longer in vitro half-life than Ligand A (86.693).

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.045).

**Binding Affinity:** Ligand B (-8.0) has a better binding affinity than Ligand A (-6.4). This is a substantial difference (>1.5 kcal/mol) and a key factor.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has slightly better Caco-2 permeability and BBB, Ligand B excels in crucial areas for an enzyme inhibitor: significantly better binding affinity (-8.0 vs -6.4 kcal/mol), lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and better aqueous solubility. The affinity difference is large enough to outweigh the minor drawbacks of Ligand B.

Output:
1
2025-04-17 12:44:34,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.59 and 67.43) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (though not a priority here).

**logP:** Both ligands (3.028 and 2.265) are within the optimal 1-3 range. Ligand B is slightly better.

**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 (0.785 and 0.862), indicating good drug-like properties.

**DILI:** Ligand A (19.736) has a significantly lower DILI risk than Ligand B (31.214). This is a substantial advantage.

**BBB:** BBB is not a high priority for a non-CNS target like SRC. Ligand A (79.527) has a higher BBB percentile than Ligand B (61.846).

**Caco-2 Permeability:** Ligand A (-4.417) has a worse Caco-2 permeability than Ligand B (-5.148), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.012) has slightly better aqueous solubility than Ligand B (-2.645).

**hERG Inhibition:** Ligand A (0.381) has a slightly higher hERG inhibition risk than Ligand B (0.181), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (10.002) has significantly lower microsomal clearance than Ligand A (31.173), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (38.082) has a longer in vitro half-life than Ligand A (28.49), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.263) has lower P-gp efflux than Ligand B (0.041), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This difference of 1.4 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk and better solubility, Ligand B's superior binding affinity (-8.3 vs -6.9 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are critical for an enzyme target like SRC kinase. The stronger binding affinity is likely to translate to greater efficacy, and the improved metabolic stability will lead to a more favorable pharmacokinetic profile. The slightly higher DILI risk of Ligand B is acceptable given its other advantages.

Output:
1
2025-04-17 12:44:34,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.375 and 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.38) is slightly higher than Ligand B (79.26). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (0.829) is slightly higher than Ligand B (0.446). Both are below the optimal 1-3 range, which could slightly hinder permeation. Ligand A is better here.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2), as lower HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (5). Both are within the acceptable limit of 10.

**QED:** Ligand A (0.88) is better than Ligand B (0.731), indicating a more drug-like profile.

**DILI:** Ligand B (39.434) has a significantly lower DILI risk than Ligand A (74.99). This is a major advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 71.85, Ligand B: 76.735). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.007) is slightly better than Ligand B (-4.934).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.376) is slightly better than Ligand B (-1.432).

**hERG:** Ligand A (0.191) has a lower hERG risk than Ligand B (0.426), which is a significant advantage.

**Microsomal Clearance:** Ligand B (3.561) has significantly lower microsomal clearance than Ligand A (26.416), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-11.267) has a longer in vitro half-life than Ligand A (21.409), which is also a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.054, Ligand B: 0.045).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better logP and hERG, Ligand B excels in critical areas for kinase inhibitors: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and superior binding affinity. The better binding affinity is a key factor, and the improved metabolic stability will likely translate to better *in vivo* exposure. The slightly lower solubility and permeability are concerns, but the strong affinity and metabolic stability are more important for an enzyme target.

Output:
1
2025-04-17 12:44:34,823 - INFO - Batch 155 complete. Total preferences: 2480
2025-04-17 12:44:34,823 - INFO - Processing batch 156/512...
2025-04-17 12:45:20,647 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.43 and 352.34 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (79.54), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.296) is optimal (1-3), while Ligand B (0.667) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) 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 (0.831 and 0.744, both >=0.5).

**DILI:** Ligand A (28.62) has a significantly lower DILI risk than Ligand B (43.66), indicating a safer profile. Both are below the concerning threshold of 60.

**BBB:** Ligand A (95.43) has excellent BBB penetration, while Ligand B (78.52) is good but lower. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2:** Both ligands have negative Caco-2 values (-4.632 and -4.692), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.194 and -2.344), which is also unusual and suggests poor solubility. This is also a significant drawback for both.

**hERG:** Ligand A (0.489) has a lower hERG risk than Ligand B (0.161), which is preferable.

**Microsomal Clearance:** Ligand A (19.88) has higher microsomal clearance than Ligand B (-1.151), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-1.095) has a negative half-life, which is not possible. Ligand B (-26.295) also has a negative half-life, which is not possible. This is a significant drawback for both.

**P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux than Ligand B (0.034), which is preferable.

**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 of the ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2, solubility, and half-life, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.5 vs -7.0 kcal/mol) is a major advantage. It also has a lower DILI risk and a better hERG profile. While its metabolic stability is worse than Ligand B, the potency advantage is likely to be more impactful for an enzyme inhibitor. The negative values for Caco-2, solubility, and half-life are concerning and would require further investigation (e.g., experimental validation, checking data input).

Output:
1
2025-04-17 12:45:20,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.38 and 343.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (104.45) as it is closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.27 & 2.03), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 4 HBDs and 4 HBAs, which is acceptable.

**QED:** Ligand A (0.661) has a significantly better QED score than Ligand B (0.284), indicating a more drug-like profile.

**DILI:** Ligand A (26.99) has a much lower DILI risk than Ligand B (41.26), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (71.97) is better than Ligand B (35.44).

**Caco-2 Permeability:** Ligand A (-4.645) is better than Ligand B (-5.502).

**Aqueous Solubility:** Ligand A (-1.79) is better than Ligand B (-3.292).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.356 & 0.477).

**Microsomal Clearance:** Ligand A (8.265) has a lower microsomal clearance than Ligand B (5.638), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-29.983) has a longer in vitro half-life than Ligand A (-19.493), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.017 & 0.057).

**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.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity and half-life, Ligand A excels in crucial ADME properties: QED, DILI risk, solubility, and metabolic stability. The lower DILI risk alone is a significant advantage, and the better QED score suggests a more balanced and favorable drug-like profile. The difference in binding affinity is not substantial enough to outweigh these ADME benefits, especially for a kinase inhibitor where metabolic stability is crucial for maintaining therapeutic concentrations.

Output:
1
2025-04-17 12:45:20,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.435 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.17) is slightly higher than the ideal <140, but acceptable. Ligand B (49.85) is excellent, well below 140.

**logP:** Ligand A (0.344) is quite low, potentially hindering permeability. Ligand B (2.054) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.566 and 0.716), indicating drug-likeness.

**DILI:** Ligand A (26.638) has a low DILI risk, which is excellent. Ligand B (12.214) also has a low DILI risk.

**BBB:** Ligand A (60.062) has moderate BBB penetration, while Ligand B (76.154) is better, but not crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.727 and -4.415). This is unusual and concerning, suggesting poor permeability. However, negative values can sometimes be artifacts of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.802 and -2.138), which is also concerning and suggests poor solubility. Again, these values should be interpreted cautiously.

**hERG Inhibition:** Ligand A (0.1) has very low hERG risk, excellent. Ligand B (0.371) also has low hERG risk.

**Microsomal Clearance:** Ligand A (56.776) has a moderate microsomal clearance. Ligand B (37.244) has a lower clearance, suggesting better metabolic stability, which is a priority for enzymes.

**In vitro Half-Life:** Ligand A (-6.743) has a negative half-life, which is problematic. Ligand B (-10.087) also has a negative half-life, which is even more concerning. These negative values are likely artifacts of the prediction method.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.117).

**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 significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the concerning negative values for Caco-2 and solubility, Ligand A appears to be the better candidate. Its superior binding affinity (-7.9 vs -6.9 kcal/mol) is a significant advantage for an enzyme target like SRC kinase. It also has a lower DILI risk and a slightly better BBB score. While Ligand B has better logP and lower microsomal clearance, the difference in binding affinity is the deciding factor. The negative values for solubility and permeability need to be investigated further experimentally, but the potency advantage of Ligand A makes it the more promising starting point.

Output:
0
2025-04-17 12:45:20,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.511 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.64 and 59.51) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (3.125 and 2.828) within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, well within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are below the 10 limit.

**QED:** Both ligands have QED values (0.873 and 0.731) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (47.15) has a slightly higher DILI risk than Ligand B (39.667), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.009) has a lower BBB penetration percentile than Ligand B (97.286). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.9 and -4.896), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.135 and -3.169), which is also a major concern. Poor solubility will hinder bioavailability.

**hERG Inhibition:** Ligand A (0.445) has a lower hERG inhibition liability than Ligand B (0.869), which is favorable.

**Microsomal Clearance:** Ligand A (37.291) has lower microsomal clearance than Ligand B (73.185), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (33.963) has a longer in vitro half-life than Ligand A (20.654), which is generally desirable.

**P-gp Efflux:** Ligand A (0.376) has lower P-gp efflux liability than Ligand B (0.174), which is preferable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.5 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B appears to be the more promising candidate. Its significantly stronger binding affinity (-8.1 vs -7.6 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has a longer half-life and better BBB penetration (though BBB isn't crucial here). While Ligand A has slightly better hERG and P-gp profiles, the potency and stability advantages of Ligand B are more important for this target class. The solubility and permeability issues would need to be addressed through formulation strategies, but the core potency and PK properties of Ligand B are superior.

Output:
1
2025-04-17 12:45:20,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.447 and 367.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.91) is better than Ligand B (71), both are good for oral absorption (<140).

**logP:** Both ligands have good logP values (2.038 and 2.18), falling within the optimal 1-3 range.

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

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

**QED:** Ligand B (0.781) has a significantly better QED score than Ligand A (0.529), indicating a more drug-like profile.

**DILI:** Ligand B (33.618) has a much lower DILI risk than Ligand A (49.709), a significant advantage.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (61.38) is slightly better than Ligand A (56.805).

**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 have negative solubility values, also unusual and indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.043) has a slightly lower hERG inhibition liability than Ligand B (0.189), which is preferable.

**Microsomal Clearance:** Ligand B (31.571) has significantly lower microsomal clearance than Ligand A (48.412), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.124 hours) has a slightly better in vitro half-life than Ligand A (-13.645 hours).

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands have issues with Caco-2 permeability and solubility, Ligand B's significantly stronger binding affinity (-9.2 vs -7.5 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic) are compelling advantages. The better QED score also supports its drug-like properties. The slightly better half-life is a bonus. Although Ligand A has a slightly lower hERG risk, the potency and safety profile of Ligand B are more favorable for further development as an SRC kinase inhibitor.

Output:
1
2025-04-17 12:45:20,648 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A: [386.901, 66.92, 2.37, 0., 4., 0.796, 60.954, 63.746, -4.411, -3.963, 0.401, 53.565, -33.435, 0.203, -9.4]**
**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, -7.4]**

Here's a breakdown, comparing each property and considering the enzyme-specific priorities (potency, metabolic stability, solubility, hERG):

1. **MW:** Both are within the ideal range (200-500 Da). A (386.9) is slightly higher than B (369.5).
2. **TPSA:** Both are acceptable, but A (66.92) is higher than B (56.99). Lower TPSA generally favors better absorption.
3. **logP:** A (2.37) is optimal, while B (4.265) is pushing the upper limit. High logP can lead to off-target effects and solubility issues.
4. **HBD:** Both have 0 HBD, which is good.
5. **HBA:** Both have 4 HBA, which is good.
6. **QED:** Both are good (A: 0.796, B: 0.721), indicating drug-like properties.
7. **DILI:** A (60.954) is borderline high risk, while B (32.842) is good. This is a significant advantage for B.
8. **BBB:** A (63.746) is moderate, while B (89.608) is very good.  While SRC isn't a CNS target, better BBB penetration can sometimes correlate with better overall distribution.
9. **Caco-2:** Both are very poor (-4.411 and -4.376). This is a major concern for both.
10. **Solubility:** Both are very poor (-3.963 and -4.809). This is a major concern for both.
11. **hERG:** Both are low risk (A: 0.401, B: 0.678).
12. **Cl_mic:** A (53.565) is better (lower) than B (69.909), indicating better metabolic stability.
13. **t1/2:** A (-33.435) is better (longer) than B (-12.859). This is a significant advantage for A.
14. **Pgp:** Both are low (A: 0.203, B: 0.296).
15. **Binding Affinity:** A (-9.4) is significantly better than B (-7.4). This is a 2 kcal/mol difference, which is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, significantly better metabolic stability (Cl_mic and t1/2), and a lower Pgp efflux liability. However, it has a higher DILI risk and a higher TPSA. Ligand B has a better DILI profile and BBB penetration, but suffers from a weaker binding affinity and poorer metabolic stability.

Given that we are targeting an enzyme (SRC kinase), potency (binding affinity) and metabolic stability are paramount. The 2 kcal/mol difference in binding affinity is a large advantage for A. While the DILI risk for A is a concern, it's not catastrophic at 60.954 and could be addressed through further structural modifications. The poor Caco-2 and solubility for both are concerning, but these can be addressed with formulation strategies.

Therefore, I would prioritize **Ligand A** for further development.

1
2025-04-17 12:45:20,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 366.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (65.54), both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.96 and 1.913), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable, below the 10 threshold.

**QED:** Ligand A (0.892) has a significantly better QED score than Ligand B (0.687), indicating a more drug-like profile.

**DILI:** Ligand A (52.423) has a slightly higher DILI risk than Ligand B (16.44), but both are below the concerning 60 threshold.

**BBB:** Ligand B (75.882) has a better BBB penetration percentile than Ligand A (69.794). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.85) has a worse Caco-2 permeability than Ligand B (-5.022). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.395) has slightly better solubility than Ligand B (-1.726). Both are negative, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.161 and 0.284).

**Microsomal Clearance:** Ligand A (3.503) has significantly lower microsomal clearance than Ligand B (60.036), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-6.964) has a much longer in vitro half-life than Ligand B (4.989), further supporting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.036).

**Binding Affinity:** Ligand A (-8.2 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 some ADME drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has slightly better BBB penetration and Caco-2 permeability, Ligand A's superior binding affinity, QED, metabolic stability (lower Cl_mic and longer t1/2), and acceptable DILI risk outweigh these minor advantages. The strong binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:45:20,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.74) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (92.55) is well within the ideal range.

**logP:** Ligand A (1.88) is within the optimal 1-3 range. Ligand B (0.974) is slightly below, potentially impacting permeability, but not drastically.

**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:** Ligand A (0.526) is above the 0.5 threshold, indicating good drug-likeness. Ligand B (0.356) is below, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (60.915) is approaching the higher risk threshold (>60), while Ligand B (17.449) is very low risk. This is a significant advantage for Ligand B.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.291) has a slightly higher hERG risk than Ligand B (0.069), which is preferable.

**Microsomal Clearance:** Ligand A (65.08) shows higher clearance, indicating lower metabolic stability. Ligand B (-18.347) shows negative clearance, which is not possible and indicates a potential error in the data. However, even if we interpret this as very low clearance, it suggests significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.791) has a negative half-life, which is not possible. Ligand B (-13.171) also has a negative half-life, indicating a potential error in the data.

**P-gp Efflux:** Both are very low, suggesting minimal efflux.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.4 and -8.1 kcal/mol), which are both excellent. The difference of 0.3 kcal/mol is unlikely to be decisive.

**Conclusion:**

Despite the questionable negative values for half-life and clearance, Ligand B is the more promising candidate. Its significantly lower DILI risk and potentially much better metabolic stability (indicated by the negative clearance value) outweigh the slightly lower QED and logP. The binding affinities are comparable. The negative values for Caco-2 and solubility are concerning for both and would require further investigation/optimization.

Output:
1
2025-04-17 12:45:20,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.26 Da) is slightly higher, but acceptable. Ligand B (348.491 Da) is also good.

**TPSA:** Ligand A (104.18) is approaching the upper limit for good oral absorption (<=140), while Ligand B (58.44) is well within the range.

**logP:** Both ligands have good logP values (A: 1.399, B: 2.576), falling within the optimal 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 good QED scores (A: 0.664, B: 0.84), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (85.537) than Ligand B (19.193). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (76.347) is better than Ligand A (67.197). While not a primary concern for a kinase inhibitor, it's a slight advantage for B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.332) is worse than Ligand B (-4.544).

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.615) is slightly worse than Ligand B (-2.376).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.174, B: 0.294), which is good.

**Microsomal Clearance:** Ligand A has a much lower (better) microsomal clearance (-17.5 mL/min/kg) than Ligand B (36.326 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (59.711 hours) than Ligand B (8.926 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.016, B: 0.073).

**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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, its significantly higher DILI risk and worse solubility are major concerns. Ligand B has a better safety profile (lower DILI) and slightly better solubility, but weaker binding affinity and poorer metabolic stability.

Given the enzyme-specific priorities, potency and metabolic stability are crucial. The 0.8 kcal/mol difference in binding affinity is substantial. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications in later optimization stages. The improved metabolic stability and half-life are also valuable.

Output:
1
2025-04-17 12:45:20,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.378 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.09) is slightly higher than the preferred <140, but acceptable. Ligand B (67.6) is well within the range.

**logP:** Ligand A (0.303) is quite low, potentially hindering permeability. Ligand B (2.974) is near optimal.

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

**H-Bond Acceptors:** Ligand A (3) is acceptable. Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.629 and 0.885), indicating drug-likeness.

**DILI:** Ligand A (60.644) is borderline high risk for DILI. Ligand B (23.963) is very good, indicating low DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.79) is higher, but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands 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 ligands have negative solubility values, which is also unusual. This suggests poor solubility, a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.235 and 0.358).

**Microsomal Clearance:** Ligand A (-19.358) has a *negative* clearance, which is impossible and likely an error in the data. Ligand B (61.704) is high, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (21.338) has a reasonable half-life. Ligand B (-11.615) has a negative half-life, which is impossible and likely an error in the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.007 and 0.229).

**Binding Affinity:** Both ligands have comparable binding affinities (-9.8 and -8.1 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, the negative values for microsomal clearance and half-life are major red flags, indicating data errors or fundamentally problematic metabolism. The higher DILI risk is also concerning. Ligand B, while having a higher clearance, has a much lower DILI risk and more reasonable (though still problematic) values for solubility and permeability. Given the errors in Ligand A's data, and prioritizing metabolic stability and safety for an enzyme target, Ligand B is the more viable candidate, *assuming the negative values are data errors and can be corrected*.

Output:
1
2025-04-17 12:45:20,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.71) is better than Ligand B (72.09), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.004) is optimal, while Ligand B (4.627) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as lower HBD generally improves permeability. Both are within the acceptable limit of 5.

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

**QED:** Both ligands have good QED scores (0.673 and 0.728, respectively), indicating drug-like properties.

**DILI:** Ligand A (42.032) has a significantly lower DILI risk than Ligand B (73.517). This is a crucial advantage.

**BBB:** Both ligands have similar BBB penetration (82.823 and 82.358), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.577 and -4.834). This is unusual and suggests poor permeability, but could be an artifact of the prediction method.

**Aqueous Solubility:** Ligand A (-3.577) is better than Ligand B (-5.566), indicating better solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.571 and 0.427), which is good.

**Microsomal Clearance:** Ligand A (24.15 mL/min/kg) has significantly lower microsomal clearance than Ligand B (64.043 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.599 hours) has a shorter half-life than Ligand B (120.517 hours). This is a drawback for Ligand A, but the significant difference in clearance suggests Ligand B might be more susceptible to other metabolic liabilities.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.217).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.4 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Conclusion:**

Ligand A is the better candidate. While Ligand B has a longer half-life, Ligand A demonstrates superior properties in key areas for an enzyme inhibitor: lower DILI risk, better solubility, and significantly improved metabolic stability (lower Cl_mic). The slightly lower half-life of Ligand A is a concern, but can potentially be addressed through structural modifications without significantly impacting the other favorable properties. The higher logP of Ligand B is a potential drawback.

Output:
0
2025-04-17 12:45:20,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.455 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.01) is slightly higher than Ligand B (84.5). Both are below the 140 threshold for good absorption, but closer to the 90 threshold for CNS targets (not relevant here).

**logP:** Ligand A (3.588) is at the upper end of the optimal range (1-3), while Ligand B (1.775) is closer to the lower end. Ligand A's higher logP *could* lead to solubility issues, but isn't drastically high.

**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 similar QED values (0.76 and 0.686), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (79.294%) compared to Ligand B (28.965%). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (61.38%) and Ligand B (56.65%) are both relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the scale is not specified, so it is hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.182 and -3.175). This is a significant drawback for both, but potentially more manageable if potency is high.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.225 and 0.139), which is excellent.

**Microsomal Clearance:** Ligand A (14.517 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (75.348 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (64.375 hours) has a much longer half-life than Ligand B (-14.47 hours). The negative value for B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.116 and 0.115).

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the solubility issues, Ligand A is the more promising candidate. Its significantly higher binding affinity (-8.0 vs -6.5 kcal/mol) is a major advantage for an enzyme target. It also has better metabolic stability (lower Cl_mic, longer half-life) and a lower hERG risk. The biggest drawback is the higher DILI risk, but this could potentially be mitigated through structural modifications. Ligand B's extremely short half-life is a dealbreaker, and its lower affinity makes it less attractive.

Output:
1
2025-04-17 12:45:20,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.431 and 365.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.8) is better than Ligand B (61.44) as it is closer to the threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.744 and 2.603, respectively), falling within the 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 within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.628 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A (36.099) has a significantly lower DILI risk than Ligand B (9.19), which is a major advantage.

**BBB:** Ligand A (50.795) has a lower BBB penetration than Ligand B (79.217). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.028 and -5.084), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.683 and -2.187), indicating poor aqueous solubility, which is problematic for bioavailability.

**hERG Inhibition:** Ligand A (0.232) has a much lower hERG inhibition liability than Ligand B (0.659), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand B (-9.043) has a negative clearance, indicating very high metabolic stability, which is a significant advantage over Ligand A (4.552).

**In vitro Half-Life:** Ligand B (-14.837) has a negative half-life, indicating very high stability, which is a significant advantage over Ligand A (48.892).

**P-gp Efflux:** Ligand A (0.144) has lower P-gp efflux liability than Ligand B (0.019), which is preferable.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a much better safety profile (lower DILI and hERG), but suffers from moderate metabolic clearance and permeability issues. Ligand B has excellent metabolic stability and permeability, but has a higher DILI and hERG risk. Given the enzyme-kinase target class, metabolic stability and potency are key. However, the significant safety concerns with Ligand B (DILI and hERG) are difficult to ignore. The slightly better affinity of Ligand A, coupled with its superior safety profile, makes it the more promising candidate, despite the permeability and solubility concerns. These concerns could potentially be addressed through formulation strategies.

Output:
0
2025-04-17 12:45:20,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (377.5 and 360.8 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.59) is slightly above the optimal <140 for good oral absorption, but still acceptable. Ligand B (51.66) is well within the ideal range.

**logP:** Ligand A (0.268) is quite low, potentially hindering permeability. Ligand B (2.983) is near optimal.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

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

**QED:** Both ligands have good QED scores (0.559 and 0.794), indicating drug-likeness.

**DILI:** Both ligands have similar, low DILI risk (36.6 and 36.4 percentile).

**BBB:** Ligand A (56.5) is lower than Ligand B (80.5), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.479) is very poor, suggesting poor intestinal absorption. Ligand B (-4.765) is also poor, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.72) is poor. Ligand B (-3.059) is also poor.

**hERG Inhibition:** Ligand A (0.189) has very low hERG risk, which is excellent. Ligand B (0.5) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (31.223) has lower clearance, suggesting better metabolic stability. Ligand B (63.953) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-35.912) has a negative half-life, which is not possible and indicates an issue with the data or prediction method. Ligand B (51.549) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable. Ligand B (0.255) has slightly higher efflux.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a crucial difference.

**Conclusion:**

Despite Ligand A having better hERG and P-gp properties, the extremely poor Caco-2 permeability, negative half-life, and *especially* the lack of binding affinity make it a very poor candidate. Ligand B, while having slightly higher hERG and P-gp efflux, possesses a much stronger binding affinity, a reasonable half-life, and acceptable ADME properties overall. The substantial affinity advantage of Ligand B outweighs its minor ADME drawbacks.

Output:
1
2025-04-17 12:45:20,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.463 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is better than Ligand B (91.32), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.697 and 2.512, respectively), falling within the 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 5 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.818) has a significantly better QED score than Ligand B (0.583), indicating a more drug-like profile.

**DILI:** Ligand A (25.359) has a much lower DILI risk than Ligand B (56.146). This is a significant advantage for Ligand A.

**BBB:** Ligand A (40.093) and Ligand B (65.801) both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.77) has better Caco-2 permeability than Ligand B (-5.188), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.424) has better aqueous solubility than Ligand B (-3.569). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.124) shows lower hERG inhibition liability than Ligand B (0.601), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (7.374) has significantly lower microsomal clearance than Ligand B (36.611), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.5) has a worse in vitro half-life than Ligand B (-8.263), but the negative value for Ligand B is unusual and may indicate an issue with the data.

**P-gp Efflux:** Ligand A (0.014) has lower P-gp efflux liability than Ligand B (0.496), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage for Ligand B, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable ADMET profile. Specifically, its lower DILI risk, better solubility, lower hERG inhibition, and improved metabolic stability are critical advantages for drug development. The difference in binding affinity (2 kcal/mol) is considerable, but the more favorable ADMET properties of Ligand A, particularly the safety aspects (DILI, hERG), make it a more promising candidate. The better QED score also supports this conclusion.

Output:
0
2025-04-17 12:45:20,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (361.467 and 361.389 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.27) is well below the 140 threshold for oral absorption and is quite favorable. Ligand B (89.95) is still acceptable but less optimal.

**3. logP:** Ligand A (1.904) is within the optimal range of 1-3. Ligand B (-0.164) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (2) is acceptable.

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

**6. QED:** Both ligands have reasonable QED values (0.788 and 0.659), indicating good drug-like properties.

**7. DILI:** Ligand A (52.423) has a moderate DILI risk, but is still acceptable. Ligand B (27.918) has a much lower DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (73.129) shows reasonable BBB penetration. Ligand B (57.193) is lower, but not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.11 and -4.943), which is unusual and suggests poor permeability. This is a serious concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.326 and -0.899), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.266 and 0.19). This is positive.

**12. Microsomal Clearance:** Ligand A (24.435) has a higher microsomal clearance than Ligand B (-16.738).  Ligand B's negative value suggests very high metabolic stability, a major advantage.

**13. In vitro Half-Life:** Ligand A (-0.616) has a short half-life. Ligand B (-11.409) has a very long half-life, which is highly desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.273 and 0.011).

**15. Binding Affinity:** Ligand A (-9.6) has a significantly stronger binding affinity than Ligand B (-8.0). This is a substantial advantage.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison & Conclusion:**

Ligand A has a much better binding affinity, but suffers from poor permeability and solubility (negative Caco-2 and solubility values) and a shorter half-life. Ligand B has significantly better metabolic stability (negative Cl_mic, longer half-life), lower DILI risk, and better solubility, but a weaker binding affinity.

The difference in binding affinity (-9.6 vs -8.0) is substantial (1.6 kcal/mol). Given that a 1.5 kcal/mol advantage can outweigh ADME drawbacks, and considering the importance of metabolic stability for kinase inhibitors, I believe **Ligand A** is the more promising candidate, *despite* the permeability and solubility concerns. These issues could potentially be addressed through formulation strategies or further chemical modifications. The strong binding affinity is a critical starting point for a kinase inhibitor.

Output:
0
2025-04-17 12:45:20,650 - INFO - Batch 156 complete. Total preferences: 2496
2025-04-17 12:45:20,651 - INFO - Processing batch 157/512...
2025-04-17 12:46:08,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.385 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.64) is significantly better than Ligand B (98.74). A TPSA under 140 is desired for oral absorption, both are under, but A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (1.32) is within the optimal 1-3 range. Ligand B (-0.216) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=4) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.886) has a much higher QED score than Ligand B (0.437), indicating a more drug-like profile.

**DILI:** Ligand A (27.801) has a lower DILI risk than Ligand B (21.946), indicating a better safety profile.

**BBB:** Ligand A (77.821) has a better BBB percentile than Ligand B (32.726). While not a primary concern for a non-CNS target, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.538) is better than Ligand B (-4.851), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.515) is better than Ligand B (-1.612), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.661) has a lower hERG inhibition liability than Ligand B (0.108), which is a significant advantage for cardiac safety.

**Microsomal Clearance:** Ligand A (10.507) has a lower microsomal clearance than Ligand B (22.558), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.738) has a significantly longer in vitro half-life than Ligand B (-38.56), indicating a more prolonged duration of action.

**P-gp Efflux:** Ligand A (0.045) has a lower P-gp efflux liability than Ligand B (0.018), which is a slight advantage for bioavailability.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-6.9). While both are good, the 1.5 kcal/mol difference is notable.

**Overall:** Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, including solubility, metabolic stability, hERG risk, and DILI. It also has a slightly better binding affinity and a significantly better QED score. While Ligand B has a slightly lower P-gp efflux, the overall profile of Ligand A is far superior for drug development.

Output:
1
2025-04-17 12:46:08,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.471 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.79) is better than Ligand B (66.4), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.808) is slightly higher than Ligand B (2.351), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Lower is generally preferred.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5).

**QED:** Ligand A (0.736) is better than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Ligand B (31.02) has a significantly lower DILI risk than Ligand A (42.458), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (74.874 and 74.176), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.154 and -4.821).

**Aqueous Solubility:** Ligand B (-1.946) has better solubility than Ligand A (-4.437).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.486 and 0.415).

**Microsomal Clearance:** Ligand B (33.808) has significantly lower microsomal clearance than Ligand A (90.231), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.24) has a longer in vitro half-life than Ligand A (-6.498).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.436 and 0.474).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.8 and -8.4 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

While Ligand A has a slightly better QED and TPSA, Ligand B demonstrates superior ADME properties. Specifically, the significantly lower DILI risk, lower microsomal clearance, and longer half-life of Ligand B are crucial advantages for a kinase inhibitor. The slightly better solubility of Ligand B is also beneficial. The binding affinities are comparable, making the ADME profile the deciding factor.

Output:
1
2025-04-17 12:46:08,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.383 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.03) is better than Ligand B (42.43). Ligand A is close to the 140 threshold for good oral absorption, while Ligand B is well below, suggesting better permeability.

**logP:** Ligand A (0.968) is within the optimal 1-3 range. Ligand B (4.342) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED values (0.597 and 0.678), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 91.857, which is high. Ligand B has a much lower DILI risk of 13.61, a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration (32.144 and 90.772). Since SRC is not a CNS target, this is not a major concern.

**Caco-2 Permeability:** Ligand A (-5.856) has poor Caco-2 permeability. Ligand B (-4.467) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.978) has poor solubility. Ligand B (-4.623) is also poor.

**hERG:** Ligand A (0.154) has a slightly elevated hERG risk, but manageable. Ligand B (0.536) has a higher hERG risk.

**Microsomal Clearance:** Ligand A (-0.263) has very low microsomal clearance, indicating high metabolic stability. Ligand B (110.23) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (22.515 hours) has a good half-life. Ligand B (4.801 hours) has a short half-life.

**P-gp Efflux:** Ligand A (0.027) has low P-gp efflux, which is favorable. Ligand B (0.527) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

While Ligand A has a high DILI risk and poor solubility/permeability, its *significantly* superior binding affinity (-9.3 vs -6.6 kcal/mol) and excellent metabolic stability (low Cl_mic, good t1/2) make it the more promising candidate. The strong binding could potentially allow for a lower dose, mitigating some of the toxicity concerns. Ligand B, while having a better safety profile (lower DILI), suffers from weaker binding and poor metabolic stability. For an enzyme target like SRC kinase, potency and metabolic stability are paramount.

Output:
0
2025-04-17 12:46:08,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.439 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.38) is slightly higher than Ligand B (76.66). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands (1.365 and 1.183) are 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:** Ligand A (0.833) has a better QED score than Ligand B (0.678), suggesting a more drug-like profile overall.

**DILI:** Ligand B (29.081) has a significantly lower DILI risk than Ligand A (55.176). This is a major advantage for Ligand B.

**BBB:** Ligand B (74.913) has a better BBB penetration score than Ligand A (54.634), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.996) has a worse Caco-2 permeability than Ligand B (-5.214). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.926 and -1.768). This is a concern for both, but may be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.115 and 0.144).

**Microsomal Clearance:** Ligand B (35.534) has a significantly higher microsomal clearance than Ligand A (6.679), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-3.144) has a longer in vitro half-life than Ligand B (4.965).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.054).

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

While Ligand A has a better QED and metabolic stability (lower Cl_mic, longer t1/2), the significantly stronger binding affinity of Ligand B (-8.5 vs -6.8 kcal/mol) and its much lower DILI risk outweigh these advantages. The solubility is a concern for both, but can be addressed with formulation. The higher Caco-2 permeability of Ligand B is also a plus. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:46:08,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.403 and 378.845 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (112.91 and 110.17) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.565) is within the optimal 1-3 range. Ligand B (2.63) is also within range, but approaching the upper limit.

**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 (8) are both acceptable, with Ligand B being closer to the upper limit of 10.

**6. QED:** Both ligands have similar QED values (0.735 and 0.72), indicating good drug-likeness.

**7. DILI:** Ligand A (67.197) has a moderate DILI risk, while Ligand B (93.68) has a high DILI risk. This is a significant concern for Ligand B.

**8. BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**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 can be misleading without context.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.212) has a very low hERG risk, while Ligand B (0.618) has a moderate risk. This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (7.51 mL/min/kg) has a much lower microsomal clearance than Ligand B (21.526 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.178 hours) has a shorter half-life than Ligand B (16.828 hours). While a longer half-life is generally preferred, the difference is less critical than metabolic stability.

**14. P-gp Efflux:** Ligand A (0.064) has very low P-gp efflux, while Ligand B (0.147) has slightly higher efflux.

**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 for Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from a significantly higher DILI risk, moderate hERG risk, and higher microsomal clearance. Ligand A has a better safety profile (lower DILI and hERG) and better metabolic stability, but its binding affinity is weaker.

Considering the enzyme-specific priorities, the improved metabolic stability and safety profile of Ligand A outweigh the affinity difference. While the affinity of Ligand B is attractive, the potential for liver toxicity and cardiotoxicity is a major concern. Further optimization of Ligand A to improve its affinity while maintaining its favorable ADME properties would be a reasonable next step.

Output:
0
2025-04-17 12:46:08,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.463 and 341.317 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (47.36), being well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have good logP values (3.864 and 3.19), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 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 (0.869 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (32.726) has a much lower DILI risk than Ligand B (90.461), which is a significant advantage. Ligand B's DILI is quite high.

**BBB:** Both ligands have similar BBB penetration (73.129 and 75.107), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the values are similar (-4.742 and -4.187) and likely indicate poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.43 and -4.104), which is also unusual and suggests poor solubility. The values are similar.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.904 and 0.883), which is good.

**Microsomal Clearance:** Ligand A (93.296) has a higher microsomal clearance than Ligand B (50.532), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-6.479) has a longer in vitro half-life than Ligand A (8.496), which is a significant advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.769 and 0.707).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). The difference is 0.8 kcal/mol, which is a moderate advantage.

**Overall Assessment:**

Ligand A has a significantly lower DILI risk and slightly better binding affinity. However, Ligand B has better metabolic stability (lower Cl_mic, longer half-life). The poor solubility and permeability are concerning for both, but the DILI risk for Ligand B is a major red flag. Given the enzyme-specific priorities (potency, metabolic stability, solubility, hERG), the lower DILI risk and slightly better affinity of Ligand A outweigh the metabolic stability advantage of Ligand B. The solubility issues would need to be addressed through formulation strategies.

Output:
1
2025-04-17 12:46:08,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.65 and 90.9) are below 140, suggesting reasonable absorption potential.

**logP:** Ligand A (1.534) is optimal, while Ligand B (0.269) is quite low, potentially hindering membrane permeability.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.696 and 0.552, both >=0.5).

**DILI:** Ligand A (38.852) has a much lower DILI risk than Ligand B (5.894), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (58.24) is better than Ligand B (27.375).

**Caco-2 Permeability:** Ligand A (-5.008) is better than Ligand B (-5.313), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.567) is better than Ligand B (0.048), which is a crucial factor for bioavailability.

**hERG Inhibition:** Ligand A (0.421) shows a lower hERG inhibition liability than Ligand B (0.076), reducing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (-6.219) has significantly better metabolic stability (lower clearance) than Ligand B (-12.405).

**In vitro Half-Life:** Ligand A (21.058 hours) has a much longer half-life than Ligand B (1.832 hours), a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.173) has lower P-gp efflux than Ligand B (0.007), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across nearly all critical ADME-Tox properties, including DILI, solubility, metabolic stability (Cl_mic and t1/2), hERG risk, and P-gp efflux. While the binding affinity difference is small, the substantial improvements in drug-like properties make Ligand A a much more promising drug candidate. Ligand B's low logP and poor metabolic stability are significant drawbacks.

Output:
1
2025-04-17 12:46:08,897 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [380.897, 58.64, 4.135, 1, 5, 0.733, 77.549, 71.772, -4.44, -4.691, 0.491, 122.109, 64.887, 0.299, -7.1]
**Ligand B:** [335.411, 89.89, 4.303, 2, 2, 0.476, 56.572, 70.803, -4.724, -4.001, 0.535, 20.615, -1.455, 0.198, -10.2]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand A (380.897) is slightly higher, but both are acceptable.
2. **TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold. Ligand B (89.89) is still reasonable, but less optimal for oral absorption.
3. **logP:** Both are around 4.1-4.3, 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. **HBD:** Ligand A (1) is good. Ligand B (2) is also acceptable.
5. **HBA:** Ligand A (5) is good. Ligand B (2) is excellent.
6. **QED:** Ligand A (0.733) is very good, indicating strong drug-like properties. Ligand B (0.476) is lower, suggesting a less ideal overall profile.
7. **DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (56.572). This is a concern for Ligand A.
8. **BBB:** Both have good BBB penetration (A: 71.772, B: 70.803), though not exceptionally high. Not a major factor here as SRC isn't a CNS target.
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 very poor aqueous solubility. This is a significant concern for both.
11. **hERG:** Both have low hERG risk (A: 0.491, B: 0.535).
12. **Cl_mic:** Ligand B (20.615) has significantly lower microsomal clearance than Ligand A (122.109), indicating better metabolic stability. This is a major advantage for Ligand B.
13. **t1/2:** Ligand A (64.887) has a longer in vitro half-life than Ligand B (-1.455). This is a positive for Ligand A, but the negative value for B is concerning.
14. **Pgp:** Both have very low Pgp efflux liability (A: 0.299, B: 0.198).
15. **Binding Affinity:** Ligand B (-10.2 kcal/mol) has a *much* stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and metabolic stability. While both have issues with solubility and Caco-2, the significantly improved binding affinity and metabolic stability of Ligand B are more critical for a kinase inhibitor. The longer half-life of A is good, but the negative half-life of B is a red flag. However, the large difference in binding affinity is a strong driver.

**Conclusion:**

Despite the poor solubility and permeability predictions for both, the significantly stronger binding affinity and better metabolic stability of **Ligand B** make it the more promising drug candidate. The DILI risk is also lower for Ligand B.

Output:
1

2025-04-17 12:46:08,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.447 and 349.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.1) is better than Ligand B (110.37), being closer to the <140 threshold for good absorption.

**3. logP:** Ligand B (1.239) is better, falling within the optimal 1-3 range. Ligand A (0.042) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand B (6) is better than Ligand A (5), both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.648 and 0.613), indicating good drug-likeness.

**7. DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (47.421). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (87.476) shows better BBB penetration than Ligand A (34.044), but BBB is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.978 and -4.859), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.226 and -2.758), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Ligand A (0.098) has a much lower hERG inhibition risk than Ligand B (0.352). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (4.738) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (9.966). This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-24.469) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand A (3.138) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.091), which is favorable for oral bioavailability.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While both are good, the difference is significant.

**Overall Assessment:**

Ligand A is the superior candidate. It has better metabolic stability (lower Cl_mic, positive t1/2), lower DILI and hERG risk, lower P-gp efflux, and slightly better binding affinity. While both have poor Caco-2 and solubility, the ADME profile of Ligand A is considerably more favorable, particularly its metabolic stability and safety profiles, which are critical for kinase inhibitors. The negative half-life for Ligand B is a major red flag. The lower logP of Ligand A is a concern, but can be addressed through further optimization.

Output:
0
2025-04-17 12:46:08,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.394 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.17) is slightly higher than Ligand B (78.51). Both are below the 140 threshold for good oral absorption, but B is better.

**logP:** Both ligands have good logP values (2.823 and 1.59), falling within the 1-3 optimal range. Ligand B is slightly lower, which could slightly improve solubility.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.621) has a better QED score than Ligand A (0.466), suggesting a more drug-like profile.

**DILI:** Ligand A (35.828) has a significantly higher DILI risk than Ligand B (15.355). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (71.539) is slightly better than Ligand B (69.407). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 (-5.063).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand B (-2.182) is slightly better than Ligand A (-3.247).

**hERG Inhibition:** Ligand A (0.549) has a slightly higher hERG risk than Ligand B (0.269).

**Microsomal Clearance:** Ligand B (29.803) has a significantly lower microsomal clearance than Ligand A (7.974), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-15.962) has a much longer in vitro half-life than Ligand A (-0.908), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux values (0.021 and 0.045), suggesting minimal efflux.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.3 kcal/mol difference is substantial and outweighs many of the minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have poor solubility and permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and, crucially, a much stronger binding affinity. The improved QED score also favors Ligand B. The stronger binding affinity is a key advantage for an enzyme inhibitor, and the better ADME properties mitigate potential issues.

Output:
1
2025-04-17 12:46:08,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.467 Da) is slightly better, being closer to the lower end which generally favors permeability.

**TPSA:** Ligand A (38.77) is significantly better than Ligand B (91.24). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's high TPSA could hinder absorption.

**logP:** Both ligands have good logP values (A: 3.764, B: 3.277), falling within the optimal 1-3 range.

**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 acceptable QED values (A: 0.763, B: 0.666), indicating reasonable drug-likeness.

**DILI:** Ligand A (18.185) has a much lower DILI risk than Ligand B (89.841). This is a significant advantage for Ligand A.

**BBB:** Ligand A (83.249) has better BBB penetration than Ligand B (51.105), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.478) has better Caco-2 permeability than Ligand B (-4.748).

**Aqueous Solubility:** Ligand A (-3.795) has better aqueous solubility than Ligand B (-5.287). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.906) has a lower hERG risk than Ligand B (0.315). Lower hERG is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (91.762) has a higher microsomal clearance than Ligand B (24.823), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (1.178) has a longer in vitro half-life than Ligand A (-15.658). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.562) has lower P-gp efflux than Ligand B (0.222), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, H-bonds, DILI, BBB, Caco-2, Solubility, hERG, P-gp) and has equal binding affinity. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a longer half-life and lower clearance, but is significantly worse in TPSA, DILI, solubility, and hERG. Given the importance of metabolic stability for kinase inhibitors, and the significant advantages Ligand A has in other critical ADME properties and safety (DILI, hERG), the slightly worse metabolic stability of Ligand A can be potentially addressed through structural modifications. The poor ADME profile of Ligand B is more difficult to overcome.

Output:
0
2025-04-17 12:46:08,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.419 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (72.64) is significantly better than Ligand A (100.35), being well below the 140 threshold for good absorption.

**logP:** Ligand B (3.84) is higher than Ligand A (0.344). While 3.84 is approaching the upper limit, it's still acceptable. Ligand A's 0.344 is quite low and could hinder membrane permeability.

**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 have reasonable QED scores (A: 0.693, B: 0.503), indicating good drug-like properties.

**DILI:** Ligand B (34.548) has a much lower DILI risk than Ligand A (50.136), making it safer.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (87.088) is higher, but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.095) has a very poor Caco-2 permeability, while Ligand B (-4.234) is better, though still not ideal.

**Aqueous Solubility:** Ligand A (-2.219) has better solubility than Ligand B (-4.903). Solubility is important for bioavailability.

**hERG:** Ligand A (0.038) has a slightly better hERG profile than Ligand B (0.349), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (113.852) has significantly higher microsomal clearance than Ligand A (15.15). This means Ligand A is much more metabolically stable.

**In vitro Half-Life:** Ligand B (-5.682) has a longer half-life than Ligand A (-1.277).

**P-gp Efflux:** Ligand B (0.174) has lower P-gp efflux than Ligand A (0.048).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has better solubility, metabolic stability, and a slightly better hERG profile. However, its extremely low logP and poor Caco-2 permeability are major drawbacks. Ligand B, despite having higher clearance, presents a much more balanced profile with acceptable logP, TPSA, and DILI risk. The slightly better binding affinity of Ligand B, combined with its better absorption characteristics, makes it the more promising candidate.

Output:
1
2025-04-17 12:46:08,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.39 and 364.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (112.66 and 101.91) are below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have similar logP values (1.295 and 1.228), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.627 and 0.818), indicating a drug-like profile. Ligand B is slightly better.

**DILI:** Both ligands have relatively high DILI risk (64.56 and 67.12), which is a concern, but not dramatically different.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Both are relatively low (41.14 and 45.56).

**Caco-2 Permeability:** Ligand A (-5.69) shows significantly *worse* Caco-2 permeability than Ligand B (-4.738). This is a major drawback for Ligand A.

**Aqueous Solubility:** Ligand A (-2.158) has slightly better aqueous solubility than Ligand B (-2.623), which is a positive.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.104 and 0.141), which is excellent.

**Microsomal Clearance:** Ligand A (3.152 mL/min/kg) has significantly *lower* microsomal clearance than Ligand B (5.723 mL/min/kg). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (28.168 hours) has a much longer in vitro half-life than Ligand A (1.809 hours). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.092), which is favorable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). This 0.6 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A has better binding affinity and metabolic stability (lower Cl_mic), and slightly better solubility. However, it suffers from significantly worse Caco-2 permeability and a much shorter half-life. Ligand B has better permeability, a longer half-life, and a slightly better QED score. The difference in binding affinity (0.6 kcal/mol) is not substantial enough to overcome the significant ADME liabilities of Ligand A. Given the importance of metabolic stability and reasonable permeability for kinase inhibitors, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 12:46:08,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 341.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is better than Ligand B (70.51) as it is closer to the threshold for good oral absorption.

**logP:** Ligand B (0.82) is slightly better than Ligand A (0.493), being closer to the optimal 1-3 range. Ligand A is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (8) is acceptable but closer to the upper limit.

**QED:** Ligand B (0.813) has a higher QED score than Ligand A (0.574), indicating better overall drug-likeness.

**DILI:** Ligand A (9.616) has a significantly lower DILI risk than Ligand B (84.102). This is a major advantage for Ligand A.

**BBB:** Ligand B (70.841) has a higher BBB penetration percentile than Ligand A (43.156). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.74 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 (-1.27 and -2.193), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.313) has a lower hERG inhibition liability than Ligand B (0.578), which is favorable.

**Microsomal Clearance:** Ligand A (32.783) has a lower microsomal clearance than Ligand B (41.032), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.442) has a slightly longer half-life than Ligand A (2.187), but the difference is small.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.027), which is better.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.4 vs 0 kcal/mol) outweighs the slightly less favorable logP and BBB. Furthermore, Ligand A has a much lower DILI risk and better metabolic stability (lower Cl_mic) and hERG inhibition liability. The higher QED of Ligand B is not enough to overcome the massive difference in binding affinity and the safety concerns.

Output:
0
2025-04-17 12:46:08,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.5 & 384.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (82.78) is well within the range.

**3. logP:** Both ligands (1.822 & 1.805) are optimal (1-3).

**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 (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.582 & 0.806), indicating drug-likeness. Ligand B is better.

**7. DILI:** Both ligands have similar DILI risk (43.12 & 45.25), both are good (below 60).

**8. BBB:** Both ligands have low BBB penetration (40.68 & 36.22), which is not a priority for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.132 & -5.163), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.123 & -3.438), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.19 & 0.167), which is excellent.

**12. Microsomal Clearance:** Ligand B (23.872) has significantly lower microsomal clearance than Ligand A (34.167), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (10.306) has a longer in vitro half-life than Ligand A (6.404), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.126 & 0.038).

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol), although both are excellent. The 0.7 kcal/mol difference is meaningful.

**Conclusion:**

While both ligands have good potency and acceptable safety profiles (DILI, hERG), Ligand B is superior due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and higher QED score. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, metabolic stability is crucial, making Ligand B the more promising candidate.

Output:
1
2025-04-17 12:46:08,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (354.479 and 342.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.12) is slightly above the preferred <140, but still reasonable. Ligand B (40.62) is well within the acceptable range.

**3. logP:** Ligand A (3.856) is at the higher end of the optimal range (1-3), potentially causing solubility issues. Ligand B (2.984) is well within the optimal 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 (4 and 2 respectively), being less than or equal to 10.

**6. QED:** Both ligands have good QED scores (0.656 and 0.721), indicating drug-like properties.

**7. DILI:** Ligand A (62.156) has a higher DILI risk than Ligand B (27.065). This is a significant concern.

**8. BBB:** Both ligands have reasonable BBB penetration (74.176 and 70.997). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**9. Caco-2 Permeability:** Both have negative 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 values, suggesting poor solubility. Again, the scale is undefined.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.775 and 0.527).

**12. Microsomal Clearance (Cl_mic):** Ligand A (77.388) has higher clearance than Ligand B (42.862), indicating lower metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (36.395) has a shorter half-life than Ligand B (13.108).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.377 and 0.34).

**15. Binding Affinity:** Ligand B (-7.7 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.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a lower DILI risk. Ligand A has a slightly better binding affinity, but the higher DILI risk and poorer metabolic stability are significant drawbacks. The solubility issues for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 12:46:08,898 - INFO - Batch 157 complete. Total preferences: 2512
2025-04-17 12:46:08,898 - INFO - Processing batch 158/512...
2025-04-17 12:46:50,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.455 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (87.36). A TPSA under 140 is good for oral absorption, and both are under, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (3.377) is optimal, while Ligand B (1.29) 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 4 HBA, and Ligand B has 5, both are under the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.909 and 0.806), indicating good drug-like properties.

**DILI:** Ligand A (17.759) has a much lower DILI risk than Ligand B (35.905). This is a significant advantage.

**BBB:** Ligand A (96.627) shows excellent BBB penetration, while Ligand B (61.535) is moderate. BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired, but it's a bonus.

**Caco-2 Permeability:** Ligand A (-5.117) is worse than Ligand B (-4.212), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.094 and -2.988). This is a significant drawback for both, and formulation strategies would be critical.

**hERG Inhibition:** Ligand A (0.854) has a slightly higher hERG risk than Ligand B (0.463), but both are relatively low.

**Microsomal Clearance:** Ligand A (23.956) has significantly lower microsomal clearance than Ligand B (38.355), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (41.969) has a much longer in vitro half-life than Ligand A (6.555). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.461) has lower P-gp efflux than Ligand B (0.03), suggesting better bioavailability.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, BBB penetration, and metabolic stability. However, it suffers from poor Caco-2 permeability and a shorter half-life. Ligand B has a longer half-life and better Caco-2 permeability, but its affinity is weaker, and it has a higher DILI risk.

Given the priority for potency in kinase inhibitors, the significantly stronger binding affinity of Ligand A (-9.9 vs -7.2 kcal/mol) is a decisive factor. While the solubility and permeability are concerns, these can be addressed through formulation strategies. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 12:46:50,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.435 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.12) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (98.32) is well within the acceptable range.

**logP:** Ligand A (-0.917) is a bit low, potentially hindering permeation. Ligand B (1.318) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (5 HBD, 6 HBA) is at the upper limit for both, but still acceptable. Ligand B (3 HBD, 4 HBA) is better positioned for permeability.

**QED:** Ligand B (0.747) has a significantly better QED score than Ligand A (0.322), indicating a more drug-like profile.

**DILI:** Ligand A (18.457) has a much lower DILI risk than Ligand B (33.191), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (52.423) is higher than Ligand A (23.187).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.554 and -5.015), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.269 and -2.544), indicating very poor aqueous solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.091) has a very low hERG risk, which is excellent. Ligand B (0.502) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (19.3 mL/min/kg) has a higher clearance than Ligand B (3.329 mL/min/kg), suggesting lower metabolic stability. Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand B (-38.318 hours) has a much longer half-life than Ligand A (4.89 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.036).

**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:**

Ligand B is superior due to its better QED score, significantly improved metabolic stability (lower Cl_mic, longer t1/2), better logP, and slightly better binding affinity. While both have poor solubility and permeability, the metabolic advantages of Ligand B are more critical for an enzyme target like SRC kinase. The lower DILI risk of Ligand A is attractive, but the substantial improvements in metabolic stability with Ligand B outweigh this benefit.

Output:
1
2025-04-17 12:46:50,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.475 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is slightly higher than Ligand B (61.88). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**3. logP:** Both ligands have good logP values (1.46 and 1.006), 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, well below the limit of <=10.

**6. QED:** Both ligands have similar QED values (0.624 and 0.664), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 16.712, while Ligand B has a much lower risk of 5.312. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have similar BBB penetration (64.211 and 65.297). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.027) has poorer Caco-2 permeability compared to Ligand B (-4.96).

**10. Aqueous Solubility:** Ligand A (-2.166) has poorer solubility than Ligand B (-1.156). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.425 and 0.328), which is excellent.

**12. Microsomal Clearance:** Ligand A (41.985) has significantly better metabolic stability (lower clearance) than Ligand B (-12.736). This is a major advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (31.583) has a longer half-life than Ligand B (-19.681). This is also a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.088 and 0.019).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). The difference is 0.9 kcal/mol, which is a meaningful advantage.

**Overall Assessment:**

Ligand B has a substantial advantage in DILI risk and slightly better solubility and binding affinity. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), which is a critical factor for kinase inhibitors. The 0.9 kcal/mol difference in binding affinity is not enough to outweigh the significant improvement in metabolic stability and reduced liver toxicity offered by Ligand A.

Output:
0
2025-04-17 12:46:50,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.411 and 356.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.02) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (94.17) is well within the ideal range.

**logP:** Both ligands have near-optimal logP values (-0.226 and -0.046), 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 (6) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.745 and 0.643), indicating good drug-like properties.

**DILI:** Ligand A (70.803) has a higher DILI risk than Ligand B (38.62). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Both are moderate (48.662 and 51.415).

**Caco-2:** Both ligands have negative Caco-2 values (-5.54 and -4.643) which is unusual and suggests poor permeability. This is a significant drawback for both.

**Solubility:** Both ligands have negative solubility values (-3.008 and -1.528) which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG:** Both ligands have very low hERG risk (0.063 and 0.164), which is excellent.

**Microsomal Clearance:** Ligand A (-30.35) has significantly lower (better) microsomal clearance than Ligand B (28.969), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.945) has a longer half-life than Ligand B (-14.163), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.021), which is favorable.

**Binding Affinity:** Both ligands have similar binding affinities (-9.2 and -8.8 kcal/mol), both of which are excellent. The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have good potency and low hERG risk, Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic, longer half-life) and lower DILI risk. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 12:46:50,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.422 and 375.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is well below the 140 threshold for good absorption, while Ligand B (111.55) is still acceptable but higher.

**logP:** Ligand A (2.202) is optimal (1-3), while Ligand B (0.799) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (4 HBD, 6 HBA) both fall within acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar and good QED scores (0.577 and 0.588, respectively), indicating good drug-likeness.

**DILI:** Ligand A (51.493) has a better DILI score than Ligand B (60.14), indicating lower potential for liver injury.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (89.027) is higher than Ligand B (44.591), but this is not a major factor in this decision.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.952 and -5.129), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.746 and -2.686), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.603) has a lower hERG risk than Ligand B (0.368), which is a positive.

**Microsomal Clearance:** Ligand A (45.733) has significantly lower microsomal clearance than Ligand B (8.789), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-7.978) has a longer half-life than Ligand A (-3.8), which is generally desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.279 and 0.031), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.4 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Ligand A is slightly favored due to its better metabolic stability (lower Cl_mic), lower DILI risk, and slightly better binding affinity, despite both having poor predicted permeability and solubility. The difference in binding affinity is not large enough to overcome the significant ADME concerns of Ligand B. The lower clearance of Ligand A is a significant advantage for an enzyme target, as it suggests a longer duration of action.

Output:
0
2025-04-17 12:46:50,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.341 and 368.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (107.89), both being under the 140 A^2 threshold for good absorption.

**logP:** Ligand A (0.061) is slightly better than Ligand B (-0.166), but both are quite low. This could potentially hinder membrane permeability, but is less critical than other factors for a non-CNS target.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is preferable to Ligand B (4 HBD, 6 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.724 and 0.508), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (46.452 and 42.536), below the 60 threshold.

**BBB:** This is less important for a non-CNS target like SRC. Ligand A (63.358) is better than Ligand B (13.726).

**Caco-2 Permeability:** Ligand A (-4.922) is significantly better than Ligand B (-5.993), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.643) is better than Ligand B (-2.054), though both are quite poor. Solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.202) is significantly better than Ligand B (0.12), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-7.354) is *much* better than Ligand B (5.371). A negative value indicates very high metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-35.316) is significantly better than Ligand B (9.022), suggesting a much longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.031).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) is *substantially* better than Ligand B (-7.2 kcal/mol). This 2.1 kcal/mol difference is a major advantage, easily outweighing any minor ADME drawbacks.

**Conclusion:**

Ligand A is the far superior candidate. Its significantly stronger binding affinity, coupled with much better metabolic stability (Cl_mic and t1/2), lower hERG risk, and better Caco-2 permeability, make it a much more promising drug candidate despite slightly lower logP and solubility compared to Ligand B. The superior potency and pharmacokinetic properties of Ligand A outweigh the minor concerns.

Output:
1
2025-04-17 12:46:50,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.785 Da) is slightly higher than Ligand B (340.383 Da), but both are acceptable.

**TPSA:** Ligand A (108.49) is higher than Ligand B (79.54). While both are reasonably low, Ligand B is preferable as lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 1.913, B: 1.58), 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:** Both ligands have good QED scores (A: 0.725, B: 0.844), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.841, which is high. Ligand B has a much lower DILI risk of 49.632, which is good. This is a significant advantage for Ligand B.

**BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand B (83.986) has a higher BBB score than Ligand A (26.638), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.549) has poor Caco-2 permeability, while Ligand B (-4.937) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-3.232) has poor aqueous solubility, while Ligand B (-1.668) is also poor but better.

**hERG Inhibition:** Ligand A (0.033) has a very low hERG inhibition risk, which is excellent. Ligand B (0.348) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-24.739) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (44.115) has a significantly higher clearance, suggesting lower metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-17.296) has a long in vitro half-life, which is desirable. Ligand B (3.718) has a short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.043, B: 0.014).

**Binding Affinity:** Ligand B (-7.2 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 has superior metabolic stability (lower Cl_mic, longer t1/2) and a much lower hERG risk. However, it suffers from poor solubility and permeability, and a high DILI risk. Ligand B has better solubility, permeability, and a much lower DILI risk, but its metabolic stability is a concern.

Given the priorities for enzyme inhibitors, metabolic stability and safety (DILI, hERG) are crucial. The significantly higher DILI risk for Ligand A is a major drawback. While Ligand A has a slightly better binding affinity and metabolic stability, the DILI risk is too high to ignore.

Output:
1
2025-04-17 12:46:50,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.402 and 390.615 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (49.85) as it is closer to the ideal threshold of <140 for oral absorption.

**logP:** Both ligands have good logP values (2.202 and 2.939), 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, 5 HBA) in terms of H-bonding potential, being closer to the ideal thresholds of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED scores (0.635 and 0.597), indicating good drug-likeness.

**DILI:** Ligand A (37.96) has a significantly lower DILI risk than Ligand B (49.283), which is a major advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.529) has a higher BBB percentile than Ligand B (57.542), but this is not a deciding factor.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.646 and -4.644). This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.486 and -3.313). This is a concern for both.

**hERG Inhibition:** Ligand A (0.769) has a lower hERG inhibition liability than Ligand B (0.341), which is a significant advantage. Lower is better.

**Microsomal Clearance:** Ligand A (31.456) has a significantly lower microsomal clearance than Ligand B (63.966), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-0.624) has a slightly better in vitro half-life than Ligand B (18.492).

**P-gp Efflux:** Ligand A (0.299) has a lower P-gp efflux liability than Ligand B (0.311), which is slightly favorable.

**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 of the ADME concerns. The difference is >1.5kcal/mol.

**Conclusion:**

Ligand A is the more promising drug candidate. While both have issues with Caco-2 permeability and solubility, Ligand A demonstrates superior binding affinity, lower DILI risk, lower hERG inhibition, and better metabolic stability (lower Cl_mic). The significantly stronger binding affinity (-8.8 vs -7.0 kcal/mol) is a major driver, and the improved safety profile (DILI, hERG) and metabolic stability further solidify its position.

Output:
1
2025-04-17 12:46:51,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.41 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.56) is slightly higher than Ligand B (78.51), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.302) is a bit low, potentially hindering permeation. Ligand B (1.756) is within the optimal 1-3 range. This favors 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 similar QED values (0.586 and 0.518), indicating good drug-likeness.

**DILI:** Ligand A (20.279) has a lower DILI risk than Ligand B (18.108), which is preferable.

**BBB:** Ligand A (37.573) has a lower BBB penetration than Ligand B (66.46). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.263 and -5.041), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.135 and -2.632), indicating very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.136 and 0.227), which is good.

**Microsomal Clearance:** Ligand A (-16.365) has significantly lower (better) microsomal clearance than Ligand B (38.093), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-6.777) has a more negative (longer) half-life than Ligand B (-2.276), indicating better in vitro stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.053).

**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 less than the 1.5 kcal/mol threshold to override other issues, it's still a positive.

**Overall Assessment:**

Ligand A is superior due to its better metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and lower DILI risk. While both compounds suffer from poor predicted solubility and permeability, the improved pharmacokinetic properties of Ligand A make it the more promising candidate. The slightly lower logP of Ligand A is a concern, but the substantial difference in metabolic stability outweighs this drawback.

Output:
0
2025-04-17 12:46:51,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.343 and 356.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.17) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (95.94) is well within the ideal range.

**logP:** Ligand A (1.51) is optimal. Ligand B (-0.192) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 6 HBA) is within acceptable limits. Ligand B (2 HBD, 5 HBA) is also good.

**QED:** Both ligands have good QED scores (0.534 and 0.659), indicating drug-like properties.

**DILI:** Ligand A (94.765) has a high DILI risk, which is a significant concern. Ligand B (31.252) has a low DILI risk, a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (44.591) and Ligand B (57.115) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.468 and -5.092), which is unusual and suggests poor permeability. This needs further investigation but is a negative for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.011 and -1.091), indicating very poor solubility. This is a significant drawback for both compounds.

**hERG:** Ligand A (0.126) has a low hERG risk, which is good. Ligand B (0.101) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (0.554) has low clearance, suggesting good metabolic stability. Ligand B (-8.119) has *very* low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (68.84) has a reasonable half-life. Ligand B (0.061) has a very short half-life, a major drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.024).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). The 1.9 kcal/mol difference is substantial and could outweigh some ADME issues.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -7.5 kcal/mol) is a major advantage for an enzyme target. Furthermore, it has a much lower DILI risk (31.252 vs 94.765) and excellent metabolic stability (very negative Cl_mic). The short half-life is a concern, but could potentially be addressed through structural modifications. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 12:46:51,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.809 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (84.42). Lower TPSA generally indicates better permeability, which is beneficial.

**logP:** Both ligands have acceptable logP values (2.893 and 1.18), within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is preferable to Ligand B (HBD=1, HBA=6). While both are within acceptable limits, the higher number of HBA in Ligand B could potentially lead to off-target interactions.

**QED:** Both ligands have similar QED values (0.782 and 0.677), indicating good drug-likeness.

**DILI:** Ligand B (52.423) has a significantly lower DILI risk than Ligand A (74.641). This is a major advantage for Ligand B.

**BBB:** Ligand A (65.413) has a slightly better BBB penetration potential than Ligand B (58.24), but this is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.577) shows better Caco-2 permeability than Ligand B (-5.405), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-0.774) has better aqueous solubility than Ligand A (-5.095). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.141 and 0.035).

**Microsomal Clearance:** Ligand A (38.65) has lower microsomal clearance than Ligand B (45.989), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (24.921) has a significantly longer in vitro half-life than Ligand A (-5.582). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.221 and 0.035).

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

**Overall Assessment:**

Ligand A has better binding affinity and Caco-2 permeability, and lower microsomal clearance. However, Ligand B has significantly lower DILI risk, better solubility, and a much longer half-life. Given the enzyme-specific priorities, metabolic stability (lower Cl_mic and longer t1/2) and reduced toxicity (lower DILI) are critical. The slightly better affinity of Ligand A is unlikely to outweigh the substantial advantages of Ligand B in terms of safety and pharmacokinetics.

Output:
1
2025-04-17 12:46:51,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.423 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**TPSA:** Ligand A (87.9) is better than Ligand B (94.22) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (0.253) is quite low, potentially hindering permeation. Ligand B (1.653) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 3 HBA) as it has fewer HBDs, which can improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.715) has a better QED score than Ligand B (0.567), indicating a more drug-like profile.

**DILI:** Ligand B (41.915) has a lower DILI risk than Ligand A (50.756), which is a positive attribute.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.388) is higher than Ligand B (57.115), but this is not a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.046) is slightly better than Ligand B (-5.475).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.805) is slightly better than Ligand B (-2.806).

**hERG:** Both ligands have very low hERG inhibition liability (0.196 and 0.166 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-2.326) has a *much* lower (better) microsomal clearance than Ligand B (9.511). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (12.936 hours) has a longer half-life than Ligand B (-3.569 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.039 and 0.095 respectively), which is favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This is a 0.3 kcal/mol difference, which is not huge, but still relevant.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and a lower DILI risk, Ligand A is superior in several critical ADME properties. Specifically, its significantly lower microsomal clearance and longer half-life are crucial for an enzyme inhibitor. The better QED score and slightly better solubility/permeability also contribute. The lower logP of Ligand A is a concern, but the substantial advantage in metabolic stability outweighs this drawback.

Output:
0
2025-04-17 12:46:51,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.46 and 349.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is well below the 140 threshold, while Ligand B (97.92) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (0.817) is slightly below the optimal 1-3 range, but acceptable. Ligand B (-0.07) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is within the preferred limits. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Ligand A (0.766) has a better QED score than Ligand B (0.569), indicating a more drug-like profile.

**DILI:** Ligand A (22.33) has a significantly lower DILI risk than Ligand B (55.76), a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (44.90) is lower than Ligand B (52.27).

**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 ligands have negative solubility values, indicating poor solubility. Again, the scale is not defined, so it is hard to interpret.

**hERG:** Both ligands have very low hERG inhibition liability (0.144 and 0.113 respectively).

**Microsomal Clearance:** Ligand A (-5.442) has a much lower (better) microsomal clearance than Ligand B (-0.126), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.512 hours) has a shorter half-life than Ligand B (-19.07 hours). The negative value for Ligand B is unusual and potentially an error.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.01 respectively).

**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 concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity. However, it suffers from a lower logP, higher TPSA, higher DILI risk, and potentially poor metabolic stability. Ligand A has better ADME properties (lower DILI, better logP and TPSA, better metabolic stability) but weaker binding affinity. Given the importance of potency for kinase inhibitors, the 1.8 kcal/mol difference in binding affinity is significant. While Ligand A's ADME profile is more favorable, the stronger binding of Ligand B is likely to be more critical for efficacy.

Output:
1
2025-04-17 12:46:51,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.451 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.43) is well below the 140 threshold, indicating good absorption potential. Ligand B (105.9) is still within acceptable limits, but higher than A.

**logP:** Ligand A (4.049) is at the upper end of the optimal range (1-3), potentially causing solubility issues. Ligand B (0.186) is significantly low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.772 and 0.83), indicating drug-like properties.

**DILI:** Ligand A (23.187) has a very low DILI risk, which is excellent. Ligand B (80.07) has a higher DILI risk, which is concerning.

**BBB:** Ligand A (75.843) has a good BBB percentile, while Ligand B (41.024) is lower. This isn't a primary concern for a kinase inhibitor, but a bonus for A.

**Caco-2 Permeability:** Ligand A (-4.898) has poor Caco-2 permeability, while Ligand B (-5.502) is also poor.

**Aqueous Solubility:** Ligand A (-3.936) has poor solubility, while Ligand B (-1.509) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.879) has a low hERG risk, which is favorable. Ligand B (0.101) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (81.185) has high microsomal clearance, indicating poor metabolic stability. Ligand B (3.343) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-10.453) has a very short half-life, which is unfavorable. Ligand B (4.695) has a short half-life, but better than A.

**P-gp Efflux:** Ligand A (0.524) has moderate P-gp efflux, while Ligand B (0.009) has very low efflux.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and excellent metabolic stability (low Cl_mic) and P-gp efflux. While its logP is low and solubility is poor, the strong binding and favorable metabolic profile are crucial for a kinase inhibitor. Ligand A has a better TPSA and lower DILI, but suffers from poor metabolic stability, short half-life, and poor Caco-2 permeability. The higher binding affinity of Ligand B is a significant advantage.

Output:
1
2025-04-17 12:46:51,001 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (350.503 and 360.483 Da) fall comfortably within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (58.64) is better than Ligand B (66.4). Both are under the 140 threshold for oral absorption, but lower TPSA is generally preferred.

3. **logP:** Both ligands have good logP values (2.925 and 1.745), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but not dramatically so.

4. **HBD:** Ligand A (1) is better than Ligand B (0). While both are low, a single HBD can contribute to solubility without significantly impacting permeability.

5. **HBA:** Ligand A (3) is better than Ligand B (5). Lower HBA is generally preferred for better permeability.

6. **QED:** Ligand B (0.821) has a significantly better QED score than Ligand A (0.487), indicating a more drug-like profile overall.

7. **DILI:** Ligand A (12.02) has a much lower DILI risk than Ligand B (49.011). This is a substantial advantage for Ligand A.

8. **BBB:** Ligand A (69.407) has a better BBB percentile than Ligand B (56.611), but neither are particularly high. Not a major factor for SRC kinase, as it's not a CNS target.

9. **Caco-2:** Ligand A (-4.355) and Ligand B (-4.95) both have negative Caco-2 values, which is unusual and suggests poor permeability. These values are likely on a log scale where negative values indicate low permeability.

10. **Solubility:** Ligand A (-2.541) is better than Ligand B (-2.98). Both are poor, but A is slightly better.

11. **hERG:** Ligand A (0.637) has a lower hERG risk than Ligand B (0.211). This is a significant advantage for Ligand A.

12. **Cl_mic:** Ligand B (52.619) has a lower microsomal clearance than Ligand A (82.779), indicating better metabolic stability. This is a key advantage for Ligand B.

13. **t1/2:** Ligand A (-4.759) has a longer in vitro half-life than Ligand B (-4.095). This is a positive for Ligand A.

14. **Pgp:** Ligand A (0.205) has lower P-gp efflux liability than Ligand B (0.114). Lower is better, so A is slightly preferable.

15. **Binding Affinity:** Ligand A (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI and hERG risk. It also has a longer half-life and slightly better solubility and permeability. Ligand B has better metabolic stability (lower Cl_mic) and a better QED score. However, the substantial affinity advantage of Ligand A, coupled with the lower toxicity liabilities, outweighs the metabolic benefit of Ligand B. The poor Caco-2 values for both are concerning, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 12:46:51,001 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Ligand A:**
*   **MW:** 346.391 Da - Good (within 200-500 range)
*   **TPSA:** 113.14 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** -0.138 - Low. Could lead to poor membrane permeability.
*   **HBD:** 1 - Good.
*   **HBA:** 7 - Good.
*   **QED:** 0.735 - Excellent.
*   **DILI:** 48.43 - Good (low risk).
*   **BBB:** 53.819 - Low. Not a concern for a non-CNS target.
*   **Caco-2:** -5.174 - Very poor permeability.
*   **Solubility:** -1.943 - Poor solubility.
*   **hERG:** 0.025 - Very low risk. Excellent.
*   **Cl_mic:** -17.933 - Excellent metabolic stability (negative value suggests very low clearance).
*   **t1/2:** 17.152 - Good in vitro half-life.
*   **Pgp:** 0.016 - Low efflux.
*   **Affinity:** -8.1 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 362.539 Da - Good (within 200-500 range)
*   **TPSA:** 49.41 - Excellent.
*   **logP:** 2.987 - Excellent.
*   **HBD:** 1 - Good.
*   **HBA:** 3 - Good.
*   **QED:** 0.507 - Acceptable.
*   **DILI:** 25.359 - Good (low risk).
*   **BBB:** 67.158 - Moderate. Not a concern for a non-CNS target.
*   **Caco-2:** -4.949 - Poor permeability.
*   **Solubility:** -3.448 - Poor solubility.
*   **hERG:** 0.442 - Moderate risk.
*   **Cl_mic:** 63.111 - High metabolic clearance.
*   **t1/2:** 1.876 - Poor in vitro half-life.
*   **Pgp:** 0.418 - Moderate efflux.
*   **Affinity:** -7.2 kcal/mol - Good binding affinity.

**Comparison & Decision:**

Ligand A has a significantly better binding affinity (-8.1 vs -7.2 kcal/mol), which is a primary consideration for enzyme inhibitors. It also exhibits excellent metabolic stability (Cl_mic) and a good half-life. While its logP is low and Caco-2 permeability is poor, the strong binding affinity might compensate for these issues. The hERG risk is also exceptionally low.

Ligand B has better TPSA and logP values, but suffers from high metabolic clearance, a short half-life, and moderate hERG risk. Its binding affinity is also weaker.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), **Ligand A is the more promising candidate** despite its permeability and solubility concerns. The superior binding affinity and excellent metabolic stability outweigh the drawbacks, and formulation strategies could potentially address the solubility and permeability issues.

Output:
0
2025-04-17 12:46:51,001 - INFO - Batch 158 complete. Total preferences: 2528
2025-04-17 12:46:51,001 - INFO - Processing batch 159/512...
2025-04-17 12:47:35,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (379.404 and 350.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.29) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (84.42) is excellent, well below 140.

**logP:** Both ligands (1.271 and 1.535) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (6) is also acceptable.

**QED:** Both ligands (0.693 and 0.716) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (41.877) is better than Ligand B (57.387), both are acceptable, but A has lower risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (92.943) is higher, but it doesn't significantly impact the decision. Ligand A (61.38) is lower.

**Caco-2 Permeability:** Ligand A (-5.433) is very poor, suggesting poor absorption. Ligand B (-4.41) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-2.882) is poor. Ligand B (-3.303) is also poor. Both are concerning.

**hERG:** Both ligands (0.455 and 0.44) show low hERG inhibition liability, which is excellent.

**Microsomal Clearance:** Ligand A (3.783) is much better (lower clearance) than Ligand B (94.46), indicating significantly higher metabolic stability.

**In vitro Half-Life:** Ligand A (-27.696) is very poor. Ligand B (-2.959) is also poor, but better than A.

**P-gp Efflux:** Both ligands (0.047 and 0.096) have low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly better binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.1 vs -8.8 kcal/mol), which is the most important factor for an enzyme target. While its solubility and Caco-2 permeability are poor, the superior binding affinity and better metabolic stability (lower Cl_mic) and half-life outweigh these drawbacks. Ligand A has better DILI risk and lower Cl_mic, but the very poor Caco-2 and half-life are major concerns. The affinity difference is substantial enough to favor Ligand B despite the ADME liabilities.

Output:
1
2025-04-17 12:47:35,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.411 and 354.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is better than Ligand B (44.81), being below 140, suggesting good absorption potential.

**logP:** Ligand A (1.589) is optimal (1-3). Ligand B (4.236) is higher, potentially leading to solubility issues and off-target effects.

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

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

**QED:** Both ligands have QED values above 0.5 (0.778 and 0.625), indicating good drug-like properties.

**DILI:** Ligand A (34.393) has a lower DILI risk than Ligand B (42.536), both are acceptable (<40 is good).

**BBB:** Ligand A (86.002) has better BBB penetration than Ligand B (55.099), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.353) has a better Caco-2 permeability than Ligand B (-5.656).

**Aqueous Solubility:** Ligand A (-2.211) has better aqueous solubility than Ligand B (-3.677).

**hERG Inhibition:** Ligand A (0.368) has a lower hERG inhibition risk than Ligand B (0.853), which is a significant advantage.

**Microsomal Clearance:** Ligand A (30.946) has a lower microsomal clearance than Ligand B (54.679), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.692) has a longer in vitro half-life than Ligand B (35.696), which is desirable.

**P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux than Ligand B (0.438), which is preferable.

**Binding Affinity:** Ligand B (-8.5) 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 crucial ADME-Tox properties, including solubility, metabolic stability (Cl_mic, t1/2), hERG risk, and P-gp efflux. While Ligand B has a slightly better binding affinity, the superior ADME profile of Ligand A, particularly its lower hERG risk and better metabolic stability, makes it the more promising drug candidate for SRC kinase inhibition. The difference in binding affinity is not large enough to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 12:47:35,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (337.47 & 349.48 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (36.44) is significantly better than Ligand B (65.79). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (3.47 & 2.20), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.692 & 0.855), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (24.04 & 21.09), which is excellent.

**BBB:** Ligand A (92.01) has a much higher BBB penetration percentile than Ligand B (63.94). While not a primary concern for a non-CNS target like SRC, it isn't a detriment.

**Caco-2 Permeability:** Ligand A (-4.644) has a worse Caco-2 permeability than Ligand B (-4.866). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.711) has better solubility than Ligand B (-1.347). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.913 & 0.746), which is favorable.

**Microsomal Clearance:** Ligand A (93.697) has a significantly higher microsomal clearance than Ligand B (0.305). This indicates lower metabolic stability for Ligand A, a significant drawback for an enzyme target.

**In vitro Half-Life:** Ligand A (10.239 hours) has a shorter half-life than Ligand B (27.795 hours). This further supports the concern about metabolic stability for Ligand A.

**P-gp Efflux:** Ligand A (0.437) has lower P-gp efflux than Ligand B (0.194), which is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.7 & -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic and longer t1/2) and slightly better Caco-2 permeability outweigh the slight advantages of Ligand A in TPSA, solubility, and P-gp efflux. The enzyme-specific priorities clearly favor Ligand B.

Output:
1
2025-04-17 12:47:35,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (348.4 & 368.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.01) is slightly above the preferred <140, but acceptable. Ligand B (75.62) is well within the acceptable range.

**3. logP:** Ligand A (0.575) is a bit low, potentially hindering permeability. Ligand B (4.047) is at the upper end of the optimal range, potentially causing solubility issues but acceptable.

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

**5. H-Bond Acceptors (HBA):** 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 (0.555 and 0.768 respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (20.512) has a significantly lower DILI risk than Ligand B (67.623). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand B (71.268) is better than Ligand A (46.568). However, since SRC is not a CNS target, this is less critical.

**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:** Ligand A (0.361) has a lower hERG risk than Ligand B (0.541), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-9.851) has a much lower (better) Cl_mic than Ligand B (39.894), indicating greater metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life (t1/2):** Ligand A (0.375) has a shorter half-life than Ligand B (41.902). This is a disadvantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.151) has lower P-gp efflux than Ligand B (0.087), which is slightly better.

**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 substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (binding affinity) and metabolic stability are crucial. Ligand B has a significantly better binding affinity (-8.7 vs -7.2 kcal/mol). While Ligand A has better DILI and Cl_mic profiles, the difference in binding affinity is substantial. The poorer metabolic stability of Ligand B could potentially be addressed through structural modifications, but improving the affinity of Ligand A to reach -8.7 kcal/mol might be more challenging. The solubility and permeability issues are shared by both, and would need to be addressed in either case.

Output:
1
2025-04-17 12:47:35,384 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [349.347, 126.13 ,  -1.173,   2.   ,   7.   ,   0.69 ,  60.915,  45.909, -5.502,  -1.628,   0.045, -12.06 ,  33.161,   0.017,   0.   ]
**Ligand B:** [359.539,  45.23 ,   3.183,   1.   ,   4.   ,   0.847,  16.208,  79.566, -5.258,  -3.487,   0.57 ,  69.397,   9.326,   0.219,  -6.4  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (349.347) is slightly preferred.
2. **TPSA:** A (126.13) is higher than ideal for oral absorption (<140), but still acceptable. B (45.23) is excellent.
3. **logP:** A (-1.173) is a bit low, potentially hindering permeation. B (3.183) is optimal.
4. **HBD:** A (2) and B (1) are both good, within the acceptable limit of 5.
5. **HBA:** A (7) and B (4) are both good, within the acceptable limit of 10.
6. **QED:** Both A (0.69) and B (0.847) are good, indicating drug-like properties. B is slightly better.
7. **DILI:** A (60.915) is approaching a concerning level. B (16.208) is excellent, indicating low liver injury risk.
8. **BBB:** A (45.909) is low, while B (79.566) is good. Since SRC is not a CNS target, this is less critical, but a bonus for B.
9. **Caco-2:** Both are negative, indicating poor permeability.
10. **Solubility:** Both are negative, indicating poor solubility.
11. **hERG:** A (0.045) is very low risk. B (0.57) is slightly higher, but still acceptable.
12. **Cl_mic:** A (-12.06) is excellent (low clearance, good metabolic stability). B (69.397) is high, indicating rapid metabolism.
13. **t1/2:** A (33.161) is good. B (9.326) is relatively short, which could necessitate more frequent dosing.
14. **Pgp:** A (0.017) is very low efflux, while B (0.219) is also low.
15. **Binding Affinity:** B (-6.4) is significantly stronger than A (-0.0). This is a crucial difference for an enzyme target.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Decision:**

Despite Ligand B's better logP, TPSA, QED, and lower DILI risk, the *massive* difference in binding affinity (-6.4 kcal/mol vs -0.0 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) of Ligand A are decisive. A binding advantage of this magnitude can often overcome minor ADME drawbacks. The poor Caco-2 and solubility of ligand A are concerning, but can be addressed with formulation strategies. The slightly elevated DILI risk is also manageable. The weak binding of ligand B makes it unlikely to be effective *in vivo*, regardless of its other properties.

Output:
1
2025-04-17 12:47:35,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight (MW):** Both ligands (341.411 and 362.308 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.46) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (99.77) is still under 140, but less optimal than A.

**3. logP:** Ligand A (2.725) is within the optimal 1-3 range. Ligand B (0.107) is quite low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 for A, 6 for B), below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.808 and 0.816), indicating drug-like properties.

**7. DILI:** Ligand A (43.117) has a slightly better DILI score than Ligand B (55.293), indicating lower potential for liver injury. Both are below the concerning 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (79.992 and 83.715), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.905 and -4.924), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.827 and -1.444), which is also concerning, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.171 and 0.102), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (41.986) has a higher (worse) Cl_mic than Ligand B (9.53), meaning it's cleared more quickly and has lower metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (-18.736) has a longer half-life than Ligand A (-16.285), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.494 and 0.017), which is good.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-9.2 and -8.8 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Despite the negative Caco-2 and solubility values for both, Ligand A is slightly favored due to its better logP, lower DILI risk, and while it has a higher Cl_mic, the affinity difference is minimal. The poor permeability and solubility are major drawbacks for both, but the slightly more favorable profile of Ligand A makes it marginally more promising. Further optimization would be needed to address the solubility and permeability issues for either compound.

Output:
0
2025-04-17 12:47:35,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.519 and 357.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.44) is well below the 140 threshold and excellent for oral absorption. Ligand B (122.83) is still within acceptable limits, but less favorable.

**logP:** Ligand A (2.452) is optimal (1-3). Ligand B (-0.898) is below 1, which could hinder permeation.

**H-Bond Donors & Acceptors:** Ligand A (HBD=2, HBA=3) is well within the limits. Ligand B (HBD=3, HBA=6) is also acceptable, but closer to the upper bounds.

**QED:** Ligand A (0.637) has a better QED score than Ligand B (0.46), indicating better overall drug-likeness.

**DILI:** Ligand A (9.306) has a significantly lower DILI risk than Ligand B (19.775), a crucial advantage.

**BBB:** Both ligands have reasonably good BBB penetration (A: 69.407, B: 74.758), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.922) and Ligand B (-5.737) both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability. Ligand A is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.095 and -1.723 respectively). This is a potential issue, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.418) has a much lower hERG risk than Ligand B (0.028), a significant safety advantage.

**Microsomal Clearance:** Ligand A (38.046) has a higher microsomal clearance than Ligand B (-3.724). This suggests Ligand B is more metabolically stable, which is a priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (9.358) has a better in vitro half-life than Ligand B (-5.277).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.054, B: 0.002).

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is small and may not be significant.

**Overall Assessment:**

Ligand A is superior due to its better QED, significantly lower DILI risk, and lower hERG risk. While Ligand B has better metabolic stability and slightly higher binding affinity, the safety and drug-likeness profiles of Ligand A are more favorable. The solubility issues are a concern for both, but can potentially be overcome. The slightly better permeability of Ligand A is also a plus.

Output:
1
2025-04-17 12:47:35,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.447 and 370.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.1) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (94.48) is well within the optimal range.

**logP:** Both ligands have low logP values (0.143 and 0.193), which is a concern. Values between 1-3 are preferred. These low values might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 2 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.549 and 0.571), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (63.397 and 60.915), which is a concern. Lower values are preferred.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (60.023) has a higher BBB percentile than Ligand A (11.865).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-6.062 and -5.622), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.477 and -2.149), which is also concerning. Higher solubility is desired.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.128 and 0.185), which is positive.

**Microsomal Clearance:** Ligand A (1.158 mL/min/kg) has significantly lower microsomal clearance than Ligand B (18.958 mL/min/kg), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (20.325 and 20.968 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.021).

**Binding Affinity:** Ligand A (-10.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite the low logP and solubility concerns for both, Ligand A is the more promising candidate. The significantly stronger binding affinity (-10.6 vs -8.1 kcal/mol) and much better metabolic stability (lower Cl_mic) outweigh the slightly higher DILI risk and lower BBB. The negative Caco-2 and solubility values are concerning for both, and would require further investigation (e.g., salt formation, formulation strategies). However, potency and metabolic stability are paramount for enzyme inhibitors, and Ligand A excels in these areas.

Output:
0
2025-04-17 12:47:35,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.375 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.08) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (70.67) is excellent, well below 140.

**logP:** Ligand A (0.368) is a bit low, potentially hindering permeability. Ligand B (1.546) 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 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.74 and 0.585), indicating good drug-like properties.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (5.118). This is a significant negative for Ligand A.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.266) has poor predicted Caco-2 permeability, while Ligand B (-5.183) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor predicted solubility (-3.559 and -1.457). This is a major concern for both.

**hERG Inhibition:** Ligand A (0.129) has a slightly higher hERG risk than Ligand B (0.678), but both are relatively low.

**Microsomal Clearance:** Ligand A (-4.863) has a much lower (better) microsomal clearance than Ligand B (17.411), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.066) has a shorter half-life than Ligand B (-3.102), suggesting faster metabolism.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.015 and 0.035).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8), but the difference is small.

**Overall Assessment:**

Ligand B is significantly better due to its much lower DILI risk, better logP, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the lower DILI risk and more favorable logP of Ligand B outweigh the slightly better metabolic stability of Ligand A. Solubility and permeability would need to be addressed in either case through formulation or further chemical modification.

Output:
1
2025-04-17 12:47:35,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.351 Da) is slightly higher than Ligand B (340.379 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 62, which is acceptable for oral absorption, though not optimal for CNS penetration (not a priority here).

**logP:** Ligand A (4.268) is higher than Ligand B (2.037). Ligand A is approaching the upper limit where solubility issues might arise, while Ligand B is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 2 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.683, B: 0.858), indicating good drug-like properties.

**DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (60.682). This is a major advantage for Ligand A.

**BBB:** Both have similar BBB penetration (A: 81.853, B: 81.737), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, they are similarly poor.

**Aqueous Solubility:** Ligand A (-5.141) has worse solubility than Ligand B (-2.647). Solubility is a priority for enzymes, so this favors Ligand B.

**hERG Inhibition:** Ligand A (0.724) has a slightly higher hERG risk than Ligand B (0.167). This favors Ligand B.

**Microsomal Clearance:** Ligand A (51.769) has higher microsomal clearance than Ligand B (39.454), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (83.968) has a significantly longer in vitro half-life than Ligand A (44.889), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.452) has higher P-gp efflux than Ligand B (0.089), meaning less bioavailability. This favors Ligand B.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. The 1.5 kcal/mol difference is substantial.

**Conclusion:**

Despite Ligand A's lower DILI risk, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.6 vs -8.1 kcal/mol) outweighs the slightly higher DILI and lower solubility. Furthermore, Ligand B demonstrates better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk. These factors are all critical for a viable enzyme inhibitor drug candidate.

Output:
1
2025-04-17 12:47:35,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.383 and 362.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (68.84 and 67.35) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.214) is optimal, while Ligand B (3.82) 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 (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.668 and 0.848), indicating drug-like properties.

**DILI:** Ligand A (61.574) has a higher DILI risk than Ligand B (57.348), but both are reasonably acceptable.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand A (52.268) and Ligand B (43.815) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.451 and -4.717), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.58 and -3.676), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.2), which is preferable.

**Microsomal Clearance:** Ligand A (107.537) has higher microsomal clearance than Ligand B (63.904), suggesting lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand B (24.048) has a significantly longer in vitro half-life than Ligand A (-3.489), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.346 and 0.039).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

While both ligands have significant drawbacks (poor solubility and permeability), Ligand B is the more promising candidate. Its superior binding affinity, longer half-life, lower microsomal clearance, and lower hERG risk outweigh the slightly higher logP. The difference in binding affinity is substantial (>1.5 kcal/mol) and can compensate for some of the ADME liabilities. Ligand A's higher clearance and negative half-life are particularly concerning.

Output:
1
2025-04-17 12:47:35,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.411 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.78) is well below the 140 threshold and excellent for oral absorption. Ligand B (128.85) is still within acceptable limits but less favorable.

**logP:** Ligand A (2.244) is optimal (1-3). Ligand B (-0.442) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is excellent. Ligand B (HBD=4, HBA=5) is slightly higher, but still reasonable.

**QED:** Ligand A (0.832) is very good, indicating high drug-likeness. Ligand B (0.479) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (35.944) has a low DILI risk. Ligand B (52.423) has a moderate risk, but still acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.402) is better than Ligand B (41.218).

**Caco-2 Permeability:** Ligand A (-4.671) is poor, while Ligand B (-5.283) is also poor. Both are unfavorable.

**Aqueous Solubility:** Both ligands (-2.778 and -2.884) have very poor aqueous solubility, which is a significant concern.

**hERG Inhibition:** Both ligands (0.26 and 0.041) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (31.314) has higher clearance than Ligand B (12.71), indicating lower metabolic stability. Ligand B is much better here.

**In vitro Half-Life:** Ligand A (59.244) has a reasonable half-life, while Ligand B (-16.786) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both ligands (0.065 and 0.02) have low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-7.4), a difference of 0.6 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.0 vs -7.4 kcal/mol). While it has a lower logP and QED, the potency advantage is substantial enough to potentially overcome these drawbacks. However, the very short in vitro half-life of Ligand B is a major concern. Ligand A has better solubility and metabolic stability, but its lower affinity is a significant disadvantage. Considering the enzyme-specific priorities, the binding affinity is paramount. The poor solubility of both is a concern that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 12:47:35,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.375 Da) is slightly lower, which could be beneficial for permeability. Ligand B (385.647 Da) is also good.

**TPSA:** Ligand A (103.4) is better than Ligand B (55.63). A lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (-0.092) is lower than optimal (1-3), potentially hindering permeability. Ligand B (4.097) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 7 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.542, B: 0.612), suggesting good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 71.152, B: 54.323), though A is slightly higher.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (74.564) has a higher BBB percentile, but this is less important here.

**Caco-2 Permeability:** Ligand A (-4.867) has a very poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.656) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.345) has poor solubility, while Ligand B (-4.151) is even worse. This is a concern for both.

**hERG Inhibition:** Ligand A (0.079) has a very low hERG risk, which is excellent. Ligand B (0.617) has a higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (27.896) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (83.091) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-12.119) has a very short half-life, which is a major issue. Ligand B (15.976) has a better, but still not ideal, half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.039, B: 0.636), which is favorable.

**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 significant.

**Overall Assessment:**

Ligand A has a better binding affinity and lower hERG risk, and better metabolic stability. However, it suffers from very poor Caco-2 permeability and a very short half-life, and poor solubility. Ligand B has a higher logP, which could cause issues, and a high microsomal clearance, leading to a short half-life, but its permeability is slightly better than A.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A's superior binding affinity and lower hERG risk are attractive. While its permeability and half-life are concerning, these properties might be improved through structural modifications without significantly sacrificing binding. Ligand B's high logP and clearance are more difficult to address without potentially impacting potency.

Output:
0
2025-04-17 12:47:35,386 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**Step-by-step comparison:**

1. **Molecular Weight:** Both ligands (A: 344.415, B: 347.459) fall comfortably within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Both ligands are also good (A: 84.42, B: 82.53) and below the 140 A^2 threshold for oral absorption.

3. **logP:** Both ligands have good logP values (A: 1.706, B: 1.386), 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 permeability.

5. **H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Lower HBA is generally preferred for permeability.

6. **QED:** Ligand A (0.899) has a significantly better QED score than Ligand B (0.707), indicating a more drug-like profile.

7. **DILI:** Ligand B (5.7) has a much lower DILI risk than Ligand A (63.125). This is a significant advantage for Ligand B.

8. **BBB:** Ligand A (67.895) has a better BBB score than Ligand B (51.725). However, as SRC is not a CNS target, this is less important.

9. **Caco-2 Permeability:** Ligand A (-4.692) has better Caco-2 permeability than Ligand B (-4.78).

10. **Aqueous Solubility:** Ligand A (-3.116) has better solubility than Ligand B (-1.115). Solubility is important for bioavailability.

11. **hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.196, B: 0.2).

12. **Microsomal Clearance:** Ligand B (18.63) has lower microsomal clearance than Ligand A (32.254), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

13. **In vitro Half-Life:** Ligand A (-19.331) has a longer in vitro half-life than Ligand B (0.759). This is a positive for Ligand A.

14. **P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.13, B: 0.008).

15. **Binding Affinity:** Both ligands have very similar binding affinities (A: -8.2 kcal/mol, B: -8.0 kcal/mol). The difference is negligible.

**Enzyme-Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

*   **Affinity:** Essentially equal.
*   **Metabolic Stability:** Ligand B is significantly better (lower Cl_mic).
*   **Solubility:** Ligand A is better.
*   **hERG Risk:** Both are good.
*   **DILI:** Ligand B is *much* better.

**Conclusion:**

While Ligand A has better solubility and half-life, Ligand B's significantly lower DILI risk and better metabolic stability are more critical for a kinase inhibitor. The slight advantage in half-life for A is outweighed by the substantial improvement in safety (DILI) and metabolic stability (Cl_mic) offered by Ligand B. The binding affinities are essentially the same.

Output:
1
2025-04-17 12:47:35,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.559 and 363.571 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.36) is slightly higher than Ligand B (41.29). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (3.089) is within the optimal 1-3 range. Ligand B (4.381) is a bit high, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.729 and 0.757), indicating good drug-like properties.

**DILI:** Ligand A (16.402) has a much lower DILI risk than Ligand B (8.414), which is a significant advantage.

**BBB:** Both have good BBB penetration (70.415 and 72.315), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.759) and Ligand B (-5.057) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.764) and Ligand B (-3.48) both have poor solubility.

**hERG:** Ligand A (0.336) has a lower hERG risk than Ligand B (0.913), which is preferable.

**Microsomal Clearance:** Ligand A (62.596) has a higher microsomal clearance than Ligand B (41.857), indicating lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (11.645) has a longer half-life than Ligand A (22.473), which is a benefit.

**P-gp Efflux:** Ligand A (0.318) has lower P-gp efflux than Ligand B (0.572), which is better for bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better DILI, hERG, and P-gp efflux profiles, Ligand B's significantly superior binding affinity (-8.8 vs -7.4 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target like SRC kinase. The slightly higher logP and DILI risk of Ligand B are acceptable trade-offs for the potency and metabolic stability gains.

Output:
1
2025-04-17 12:47:35,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.467 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.84) is slightly higher than Ligand B (66.4), both are below the 140 threshold for oral absorption, and acceptable for kinase inhibitors.

**logP:** Ligand A (4.464) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.783) is within the optimal range.

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

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**QED:** Both ligands (A: 0.709, B: 0.66) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (77.007) has a higher DILI risk than Ligand B (38.891), which is preferable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (76.813) is slightly better than Ligand A (50.64). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.034 and -5.249), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.419 and -1.625), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.478) has a slightly higher hERG risk than Ligand B (0.239), making Ligand B preferable.

**Microsomal Clearance:** Ligand A (67.237) has higher microsomal clearance than Ligand B (36.826), indicating lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand A (90.14) has a significantly longer half-life than Ligand B (-1.914), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.31, B: 0.032), which is good.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand B is the more promising candidate. Its superior binding affinity (-8.4 vs -7.5 kcal/mol), lower DILI risk, lower hERG risk, and better metabolic stability outweigh the longer half-life of Ligand A. The strong binding affinity suggests that potency is less of a concern, and formulation strategies could potentially address the solubility issues.

Output:
1
2025-04-17 12:47:35,386 - INFO - Batch 159 complete. Total preferences: 2544
2025-04-17 12:47:35,387 - INFO - Processing batch 160/512...
2025-04-17 12:48:15,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.4 and 348.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.53) is slightly higher than Ligand B (89.07), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.138) is within the optimal range, while Ligand B (2.303) is leaning towards the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 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 reasonable QED scores (0.486 and 0.555), indicating decent drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have similar DILI risk (54.79 and 57.43), both being acceptable (below 60).

**BBB:** Both have low BBB penetration (59.09 and 57.19), which is not a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.158 and -5.425), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.468 and -2.159), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.041 and 0.198), which is excellent.

**Microsomal Clearance:** Ligand A (20.215 mL/min/kg) has significantly lower microsomal clearance than Ligand B (31.024 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-8.192 hours) has a negative half-life, which is problematic. Ligand B (12.452 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.105).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has 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.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B has a significantly better *in vitro* half-life and a slightly better binding affinity. Critically, Ligand A has a negative half-life, which is a major red flag. The lower microsomal clearance of Ligand A is a positive, but the negative half-life outweighs this benefit.

Output:
1
2025-04-17 12:48:15,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.415 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.85 and 88.91) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.052) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (1.771) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable H-bond characteristics, within the suggested limits.

**QED:** Both ligands have acceptable QED scores (0.757 and 0.526), indicating good drug-likeness.

**DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (35.905). This is a significant concern.

**BBB:** This isn't a primary concern for a non-CNS target like SRC kinase, but Ligand A (65.529) is slightly better than Ligand B (54.478).

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests very poor permeability. Ligand A (-4.666) is slightly better than Ligand B (-5.253).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility, which is a major issue for bioavailability. Ligand A (-1.888) is slightly better than Ligand B (-1.613).

**hERG Inhibition:** Ligand A (0.408) has a lower hERG inhibition risk than Ligand B (0.164), which is favorable.

**Microsomal Clearance:** Ligand A (56.414) has a higher microsomal clearance than Ligand B (28.407), suggesting lower metabolic stability. This is a significant disadvantage.

**In vitro Half-Life:** Ligand A (-14.17) has a negative half-life, which is impossible and indicates a severe instability issue. Ligand B (-4.647) is also negative, but less so. Both are problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.068).

**Binding Affinity:** Ligand B (-8.1 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 many ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.1 vs -6.6 kcal/mol) is a major advantage for an enzyme target. While Ligand B has a slightly higher hERG risk, the lower DILI risk and significantly better metabolic stability (lower Cl_mic, less negative half-life) compared to Ligand A are crucial. Ligand A's extremely poor predicted half-life is a deal-breaker. The solubility and permeability issues would need to be addressed through formulation strategies, but the potency and stability profile of Ligand B make it the better starting point for optimization.

Output:
1
2025-04-17 12:48:15,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.39 and 365.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.36) is slightly above the preferred <140 for good absorption, while Ligand B (71.33) is well within the range.

**logP:** Ligand A (-0.569) is a bit low, potentially hindering permeability. Ligand B (1.41) 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 (0.631 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A (35.83) has a lower DILI risk than Ligand B (59.48), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (75.53) has a higher BBB percentile than Ligand A (46.76).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-5.849 and -5.059).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, values are similar (-2.643 and -2.541).

**hERG:** Both ligands show low hERG inhibition liability (0.126 and 0.284), which is excellent.

**Microsomal Clearance:** Ligand A (-17.36) has significantly *lower* (better) microsomal clearance than Ligand B (68.44). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-14.79) has a shorter half-life than Ligand B (-22.07), which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.231).

**Binding Affinity:** Both ligands have strong binding affinities (-9.7 and -8.0 kcal/mol). Ligand A has a 1.7 kcal/mol advantage in binding affinity, which is substantial.

**Overall Assessment:**

Ligand A possesses a significantly better binding affinity and lower DILI risk, and better metabolic stability (lower Cl_mic). While its logP is slightly low and half-life is shorter, the strong binding affinity is a major advantage for an enzyme target like SRC kinase. The similar solubility and permeability values are less concerning than the differences in DILI and metabolic stability. Ligand B has a slightly better logP and half-life, but the higher DILI risk and worse metabolic stability are significant drawbacks.

Output:
1
2025-04-17 12:48:15,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (372.531 Da and 369.853 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.71) is excellent, well below the 140 A^2 threshold for good absorption. Ligand B (109) is still acceptable but less optimal.

**3. logP:** Both ligands (0.907 and 1.151) are within 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 (4) and Ligand B (5) are both acceptable, below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.597 and 0.605), indicating drug-like properties.

**7. DILI:** Ligand A (10.702) has a significantly lower DILI risk than Ligand B (56.301). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Both are around 50%, indicating limited brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.951) and Ligand B (-5.505) are both negative, which is unusual. Lower values suggest poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-1.481) and Ligand B (-2.587) are both negative, suggesting poor solubility. This is a concern, but can be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.123 and 0.191).

**12. Microsomal Clearance:** Ligand A (41.29) has higher microsomal clearance than Ligand B (24.871), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (25.213) has a longer half-life than Ligand A (14.63), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.058).

**15. Binding Affinity:** Ligand A (-7.2) has significantly stronger binding affinity than Ligand B (-0.0). 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 a much stronger binding affinity, a significantly lower DILI risk, and a better TPSA. However, it has higher microsomal clearance and a shorter half-life, and slightly worse solubility. Ligand B has better metabolic stability and half-life, but significantly weaker binding affinity and a higher DILI risk.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is the most important factor. The lower DILI risk is also a significant benefit. While the metabolic stability is a concern, it can potentially be addressed through structural modifications during lead optimization. The solubility issue is also manageable. The substantial binding affinity advantage of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 12:48:15,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.539 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (82.53). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 3.127, B: 1.746), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=4) regarding the number of hydrogen bond donors and acceptors, which is favorable for permeability.

**QED:** Both ligands have similar QED values (A: 0.836, B: 0.77), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (A: 31.059, B: 31.718), which is excellent.

**BBB:** Ligand A (76.89) has a much better BBB percentile than Ligand B (29.508). While SRC isn't a CNS target, higher BBB can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-5.142) has a better (more negative) Caco-2 value than Ligand B (-4.826), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.669) has a better (less negative) solubility value than Ligand B (-1.738), indicating better solubility.

**hERG Inhibition:** Ligand A (0.55) has a significantly lower hERG inhibition liability than Ligand B (0.188), which is a major advantage. Lower hERG risk is crucial for safety.

**Microsomal Clearance:** Ligand A (84.212) has a higher microsomal clearance than Ligand B (17.652). This means Ligand B is more metabolically stable, a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-12.62) has a longer in vitro half-life than Ligand A (6.619). This is a significant advantage, suggesting less frequent dosing might be possible.

**P-gp Efflux:** Ligand A (0.275) has lower P-gp efflux than Ligand B (0.096), which is preferable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.6 kcal/mol). This 1.2 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the better candidate. Despite having a slightly higher molecular weight and a higher microsomal clearance, its superior binding affinity (-7.8 vs -6.6 kcal/mol), much lower hERG risk, better solubility, and better Caco-2 permeability outweigh these drawbacks. The improved TPSA and BBB are also beneficial. The longer half-life of Ligand B is attractive, but the potency difference is substantial.

Output:
1
2025-04-17 12:48:15,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.462 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is well below the 140 threshold and favorable for oral absorption. Ligand B (65.54) is still acceptable but less optimal.

**logP:** Ligand A (4.125) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.84) is within the optimal range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (5) compared to Ligand A (2), but both are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.84 and 0.764), indicating good drug-like properties.

**DILI:** Ligand A (18.961) has a significantly lower DILI risk than Ligand B (24.544), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (94.378) has better BBB penetration than Ligand B (76.309), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.39) shows poor permeability, while Ligand B (-5.009) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.547) has poor aqueous solubility. Ligand B (-2.109) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.844) has a slightly higher hERG risk than Ligand B (0.441), which is preferable.

**Microsomal Clearance:** Ligand A (41.629) has higher microsomal clearance than Ligand B (33.385), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (14.552) has a longer half-life than Ligand A (16.627), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.451 and 0.048), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is better overall. While Ligand A has a lower DILI risk, Ligand B has better solubility, metabolic stability (lower Cl_mic, longer t1/2), and a more optimal logP. The slightly higher hERG risk of Ligand A is also a concern. Given the enzyme-specific priorities, metabolic stability and solubility are crucial, making Ligand B the more promising candidate.

Output:
1
2025-04-17 12:48:15,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.885 and 369.908 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.78) is better than Ligand B (40.54), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.937) is optimal, while Ligand B (4.522) is slightly high, potentially leading 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 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.8 and 0.767), indicating good drug-likeness.

**DILI:** Ligand A (73.866) has a higher DILI risk than Ligand B (15.587). This is a significant drawback for Ligand A.

**BBB:** Ligand A (24.738) has very low BBB penetration, while Ligand B (91.508) has excellent BBB penetration. While not a primary concern for a kinase inhibitor, it's a neutral to slightly positive factor for B.

**Caco-2 Permeability:** Ligand A (-5.085) shows poor permeability, while Ligand B (-4.354) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.683 and -4.83). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.654) has a slightly higher hERG risk than Ligand B (0.873).

**Microsomal Clearance:** Ligand A (42.442) has lower microsomal clearance than Ligand B (70.729), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (41.558) has a longer half-life than Ligand B (1.684), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.283) has lower P-gp efflux than Ligand B (0.501), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This difference is substantial enough to potentially outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has superior potency (binding affinity) and metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, which are key for an enzyme inhibitor. However, it suffers from a higher DILI risk, poor Caco-2 permeability, and poor solubility. Ligand B has significantly lower DILI risk and better BBB penetration, but weaker potency and poorer metabolic stability.

The difference in binding affinity between A and B is 1.5 kcal/mol which is significant. The lower DILI risk of B is attractive, but the superior potency and metabolic stability of A are more critical for a kinase inhibitor. Solubility and permeability can be addressed through formulation.

Output:
0
2025-04-17 12:48:15,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (366.571 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 140 threshold for absorption. Ligand B (100.55) is still acceptable but less favorable.

**logP:** Ligand A (3.309) is optimal. Ligand B (0.638) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is acceptable, but higher values can sometimes impact permeability.

**QED:** Both ligands (0.752 and 0.726) have good drug-likeness scores.

**DILI:** Ligand A (20.822) has a significantly lower DILI risk than Ligand B (37.069), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (78.868) shows better potential for BBB penetration than Ligand B (57.193).

**Caco-2 Permeability:** Both have negative values (-5.175 and -5.1), which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.216 and -1.456), which is concerning. Solubility is a critical factor for bioavailability.

**hERG Inhibition:** Ligand A (0.563) has a lower hERG risk than Ligand B (0.111), which is a significant advantage.

**Microsomal Clearance:** Ligand A (76.131) has higher clearance, indicating lower metabolic stability, compared to Ligand B (-8.08), which is a significant advantage for B.

**In vitro Half-Life:** Ligand A (-0.397) has a slightly better half-life than Ligand B (7.432).

**P-gp Efflux:** Ligand A (0.391) has lower P-gp efflux than Ligand B (0.006), which is a positive.

**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 override other significant differences.

**Overall Assessment:**

Ligand A has a better overall profile. While both have similar binding affinities, Ligand A excels in TPSA, logP, DILI risk, and hERG inhibition. Ligand B has a better microsomal clearance and half-life, but the lower logP and higher DILI/hERG risks are major drawbacks. 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 12:48:15,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.426 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (49.41). A TPSA under 140 is good for oral absorption, and both are well below this, but lower is generally preferred.

**logP:** Both ligands have similar logP values (3.973 and 3.834), 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, 2 HBA) regarding the number of hydrogen bond donors. Both are within acceptable limits.

**QED:** Ligand A (0.842) has a higher QED score than Ligand B (0.679), indicating a more drug-like profile.

**DILI:** Ligand A (50.989) has a higher DILI risk than Ligand B (13.532). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 82.047, Ligand B: 88.29). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.65 and -4.827). This is unusual and suggests poor permeability. However, negative values can occur in certain modeling scenarios and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.445 and -3.233). This is a concern, as poor solubility can hinder bioavailability. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.835 and 0.664).

**Microsomal Clearance:** Ligand A (82.832) has a higher microsomal clearance than Ligand B (48.701). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand B (-21.312) has a significantly longer in vitro half-life than Ligand A (-11.503). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.798 and 0.437).

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

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and TPSA, Ligand B demonstrates significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. The binding affinities are essentially identical. For an enzyme target like SRC kinase, metabolic stability and safety (DILI) are critical, outweighing the slight advantages of Ligand A in other areas.

Output:
1
2025-04-17 12:48:15,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 343.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.64 and 54.26) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.37 and 2.69) are 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.768 and 0.809), indicating drug-like properties.

**DILI:** Ligand A (14.23) has a significantly lower DILI risk than Ligand B (48.546). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (82.202 and 79.139), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.732 and -4.723). This is unusual and suggests poor permeability. However, these values are very close, so it's not a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.467 and -2.83). This is concerning, but again, the values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.482 and 0.53).

**Microsomal Clearance:** Ligand A (40.087) has significantly lower microsomal clearance than Ligand B (87.403), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand B (19.68) has a much longer in vitro half-life than Ligand A (3.48). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux than Ligand B (0.344), which is favorable.

**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 the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme target. While it has a higher DILI risk and higher microsomal clearance, the significantly improved potency is likely to be more impactful. The half-life is also much better for Ligand B. The solubility and Caco-2 values are similarly poor for both.

Output:
1
2025-04-17 12:48:15,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.423 and 342.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (118.37 and 117.43) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (-0.288) is slightly low, potentially hindering permeation. Ligand B (2.068) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (3) and Ligand B (4) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (7) are below the 10 threshold.

**QED:** Both ligands (0.532 and 0.634) have good drug-likeness scores, exceeding 0.5.

**DILI:** Ligand A (52.385) and Ligand B (56.146) are both reasonably low risk, below 60.

**BBB:** Both ligands have similar low BBB penetration (52.966 and 56.223). This isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.937 and -5.765), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.632 and -3.126), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.062) has a slightly lower hERG risk than Ligand B (0.463), which is preferable.

**Microsomal Clearance:** Ligand A (19.15 mL/min/kg) has a higher, and therefore worse, microsomal clearance than Ligand B (9.72 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-7.249) has a longer in vitro half-life than Ligand A (-4.898), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux values (0.04 and 0.014), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Conclusion:**

While both compounds have excellent binding affinity, Ligand B is more favorable overall. It has a better logP value, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly lower hERG risk. The poor solubility and Caco-2 permeability are concerning for both, but the other ADME properties of Ligand B are superior.

Output:
1
2025-04-17 12:48:15,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (373.475 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.8) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (84.5) is well within the ideal range.

**logP:** Ligand A (-0.678) is a bit low, potentially hindering permeation. Ligand B (2.165) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.588 and 0.718), indicating drug-likeness.

**DILI:** Ligand A (19.504) has a significantly lower DILI risk than Ligand B (40.364). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (68.554) has a higher BBB value than Ligand A (15.743), but this isn't a primary concern here.

**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:** Ligand A (0.075) has a very low hERG risk, a significant advantage. Ligand B (0.112) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (1.682) has a much lower microsomal clearance than Ligand B (25.033), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-22.475) has a very negative half-life, which is concerning. Ligand B (-4.872) is also negative, but less so. This is a significant drawback for both, but more so for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (-8.4 and -0.042).

**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 could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has advantages in DILI risk and microsomal clearance, and a very low hERG risk. However, it suffers from a low logP, and a concerningly negative in vitro half-life. Ligand B has a superior binding affinity, a better logP, and a less negative half-life, but a higher DILI risk and slightly higher hERG risk.

Given the enzyme-specific priorities, the stronger binding affinity of Ligand B (-9.0 kcal/mol vs -8.4 kcal/mol) is a critical factor. The 0.6 kcal/mol difference is substantial and likely to be more impactful than the slightly higher DILI and hERG risks of Ligand B, especially considering the negative half-life of Ligand A. The metabolic stability of Ligand A is appealing, but the potency advantage of B is more important for an enzyme target.

Output:
1
2025-04-17 12:48:15,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.469 and 370.559 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.3) is better than Ligand B (66.48), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands have a logP around 2.7, which is within the optimal range of 1-3.

**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 similar QED scores (0.762 and 0.714), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (39.667 and 40.054 percentile).

**BBB:** Ligand A (87.282) has a significantly higher BBB penetration percentile than Ligand B (72.237). While SRC is not a CNS target, higher BBB is generally a positive indicator of reduced off-target effects.

**Caco-2 Permeability:** Ligand A (-4.754) has better Caco-2 permeability than Ligand B (-5.05), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.091) has better aqueous solubility than Ligand B (-3.905). Solubility is crucial for bioavailability.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.395 and 0.611).

**Microsomal Clearance:** Ligand A (37.793) has significantly lower microsomal clearance than Ligand B (86.201). This suggests better metabolic stability for Ligand A, which is a high priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-4.293) has a much longer in vitro half-life than Ligand B (-40.592). This is a significant advantage for Ligand A, reducing the need for frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.133 and 0.308).

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Conclusion:**

Ligand A is the superior candidate. While both ligands exhibit excellent binding affinity and acceptable ADME properties, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and solubility, which are critical for an enzyme inhibitor. It also has better Caco-2 permeability and BBB penetration. These advantages outweigh the slightly higher TPSA.

Output:
1
2025-04-17 12:48:15,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.35 Da and 372.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.42) is better than Ligand B (119.39), being closer to the <140 threshold for good absorption.

**logP:** Both ligands (-0.894 and -0.833) are slightly below the optimal 1-3 range. This could potentially impact permeability, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand B (0.644) has a better QED score than Ligand A (0.32), indicating a more drug-like profile.

**DILI:** Ligand A (44.126) has a significantly lower DILI risk than Ligand B (62.233), which is a major advantage.

**BBB:** Ligand A (83.87) has a better BBB penetration score than Ligand B (48.895), but this is less important for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.473 and -5.342). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.058 and -1.765). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.198 and 0.117), which is excellent.

**Microsomal Clearance:** Ligand A (-1.077) exhibits much lower microsomal clearance than Ligand B (6.787), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-8.999) has a much longer in vitro half-life than Ligand B (45.599), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.014).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.6 kcal/mol). The difference is minimal and doesn't outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have poor Caco-2 and solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and a slightly better TPSA. The binding affinity is comparable. Given the enzyme-kinase focus, metabolic stability and safety (DILI) are paramount, making Ligand A the preferred choice.

Output:
0
2025-04-17 12:48:15,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.82) is slightly higher than Ligand B (80.37), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.146) is quite low, potentially hindering permeation. 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 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.882) has a much higher QED score than Ligand A (0.505), indicating a more drug-like profile.

**DILI:** Ligand A (40.364) is marginally better than Ligand B (61.846), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.233) is better than Ligand B (46.142), but this isn't a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.194 and -5.086), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.168 and -3.094), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.056) has a much lower hERG inhibition liability than Ligand B (0.166), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (26.632) has a higher microsomal clearance than Ligand B (18.162), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (34.735) has a significantly longer in vitro half-life than Ligand A (-6.987), which is a major advantage for dosing convenience and maintaining therapeutic levels.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.085).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This difference of 1.9 kcal/mol 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 and solubility, Ligand B's superior logP, QED, metabolic stability (lower Cl_mic, longer t1/2), and significantly better binding affinity outweigh the slightly higher DILI risk and lower BBB. The strong binding affinity is particularly important for an enzyme target like SRC kinase. Ligand A's low logP and poor metabolic stability are significant drawbacks.

Output:
1
2025-04-17 12:48:15,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.431 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (82.23 and 84.23) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.363) is optimal, while Ligand B (3.078) is also within the optimal range, but approaching the upper limit.

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

**QED:** Both ligands have similar QED scores (0.808 and 0.792), indicating good drug-likeness.

**DILI:** Both ligands have very similar, and acceptable, DILI risk (35.479 and 35.091 percentile).

**BBB:** Both ligands have reasonable BBB penetration (73.827 and 80.419 percentile), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.789 and -4.745), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.641 and -3.593), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.194 and 0.376).

**Microsomal Clearance:** Ligand A (25.218 mL/min/kg) has significantly lower microsomal clearance than Ligand B (76.391 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.897 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability. Ligand B (-23.047 hours) also has a negative half-life, indicating a similar issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.166).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol) - a difference of 1.4 kcal/mol. This is a substantial advantage.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand B is the better candidate due to its significantly stronger binding affinity (-9.2 vs -7.8 kcal/mol). The improved affinity could potentially overcome the solubility issues with appropriate formulation strategies. The lower microsomal clearance of Ligand A is appealing, but the negative in vitro half-life is a major red flag. The negative half-lives for both compounds suggest experimental error or inherent instability. However, the affinity difference is large enough to favor Ligand B.

Output:
1
2025-04-17 12:48:15,283 - INFO - Batch 160 complete. Total preferences: 2560
2025-04-17 12:48:15,283 - INFO - Processing batch 161/512...
2025-04-17 12:48:57,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.354 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.56) is slightly higher than Ligand B (52.65). Both are below the 140 threshold for good absorption.

**logP:** Ligand A (3.373) is optimal, while Ligand B (1.975) is a bit low, potentially impacting permeability.

**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.

**QED:** Ligand A (0.859) has a significantly better QED score than Ligand B (0.648), indicating better overall drug-likeness.

**DILI:** Ligand B (6.592) has a much lower DILI risk than Ligand A (67.429). This is a significant advantage for Ligand B.

**BBB:** Ligand A (76.541) has a higher BBB penetration score than Ligand B (64.87). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.089) has a worse Caco-2 permeability than Ligand B (-4.528).

**Aqueous Solubility:** Ligand A (-4.179) has a worse aqueous solubility than Ligand B (-1.62). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.708) has a slightly higher hERG risk than Ligand B (0.46). Lower hERG risk is preferred.

**Microsomal Clearance:** Ligand A (10.231) has a lower microsomal clearance than Ligand B (18.922), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-17.866) has a significantly longer in vitro half-life than Ligand B (-1.644). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.314) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Ligand B (-8.4) has a stronger binding affinity than Ligand A (-6.9), with a difference of 1.5 kcal/mol. This is a substantial advantage that can potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much lower DILI risk. However, Ligand A exhibits superior metabolic stability (lower Cl_mic, longer t1/2), better QED, and lower P-gp efflux. Ligand B's lower logP could be a permeability concern. Given the enzyme-specific priorities, the stronger binding affinity of Ligand B is the most important factor, and the lower DILI risk is a significant benefit. The slightly lower logP is a manageable concern.

Output:
1
2025-04-17 12:48:57,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.375 and 354.801 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (70.65) is excellent, well below 140.

**logP:** Ligand A (0.14) is quite low, potentially hindering permeability. Ligand B (3.186) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (A: 7, B: 7) are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (A: 0.625, B: 0.565), indicating good drug-like properties.

**DILI:** Ligand A (61.303) is borderline, but acceptable. Ligand B (92.865) is significantly higher, indicating a higher risk of drug-induced liver injury. This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (54.827) is higher than Ligand A (34.393), but not a deciding factor here.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.422) is slightly better than Ligand B (-4.773).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-1.636) is better than Ligand B (-3.853).

**hERG Inhibition:** Ligand A (0.066) has a very low hERG risk, which is excellent. Ligand B (0.33) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-4.721) indicates very low clearance and therefore good metabolic stability. Ligand B (48.127) suggests faster clearance and lower metabolic stability.

**In vitro Half-Life:** Ligand A (64.155) has a longer half-life than Ligand B (-14.613), which is desirable.

**P-gp Efflux:** Both are very low (A: 0.008, B: 0.601), suggesting minimal efflux.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage (1.9 kcal/mol difference).

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, its high DILI risk and poorer metabolic stability (higher clearance, shorter half-life) are significant drawbacks. Ligand A has a better safety profile (lower DILI, lower hERG), better metabolic stability, and better solubility, but its lower affinity and poor permeability are concerning.

Despite the affinity difference, the safety and metabolic concerns with Ligand B are too significant. While the affinity difference is substantial, it might be possible to improve Ligand A's affinity through further optimization without drastically altering its favorable ADME properties. The DILI risk associated with Ligand B is a major red flag that would likely halt its development.

Output:
0
2025-04-17 12:48:57,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.435 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.42) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (49.41) is excellent, well below 140.

**logP:** Ligand A (0.953) is a bit low, potentially hindering permeation. Ligand B (3.834) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both acceptable. Ligand B has 1 HBD and 2 HBA, also good.

**QED:** Ligand A (0.824) has a strong drug-like profile. Ligand B (0.679) is still reasonable, above the 0.5 threshold.

**DILI:** Ligand A (43.622) has a moderate DILI risk, but acceptable. Ligand B (13.532) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (38.348) is low, while Ligand B (88.29) is high, but this is not a major factor here.

**Caco-2:** Ligand A (-5.271) is very poor. Ligand B (-4.827) is also poor, but slightly better.

**Solubility:** Both ligands have poor solubility (-2.167 and -3.233 respectively). This is a concern for both.

**hERG:** Ligand A (0.208) has a very low hERG risk, a significant advantage. Ligand B (0.664) has a slightly elevated hERG risk, but still within acceptable limits.

**Microsomal Clearance:** Ligand A (-6.068) indicates very low clearance and excellent metabolic stability. Ligand B (48.701) indicates high clearance and poor metabolic stability, a major drawback.

**In vitro Half-Life:** Ligand A (8.022) has a reasonable half-life. Ligand B (-21.312) has a very short half-life, a significant issue.

**P-gp Efflux:** Ligand A (0.083) has low P-gp efflux, which is good. Ligand B (0.437) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (0.0) has no binding affinity. Ligand B (-8.2) has excellent binding affinity.

**Overall Assessment:**

Ligand B is the better candidate despite its solubility issues. The significantly stronger binding affinity (-8.2 kcal/mol vs 0.0 kcal/mol) outweighs the moderate solubility and P-gp efflux concerns. The low DILI risk is also a substantial benefit. Ligand A's excellent metabolic stability and low hERG are positive, but the lack of binding affinity makes it unsuitable. The poor Caco-2 values for both are a concern that would need to be addressed in further optimization.

Output:
1
2025-04-17 12:48:57,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.334 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.34 and 97.6) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (though that's not a priority here).

**logP:** Ligand A (0.661) is slightly better than Ligand B (0.368), being closer to the optimal 1-3 range. Ligand B is quite low, potentially causing permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (2 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.771 and 0.692), indicating good drug-like properties.

**DILI:** Ligand A (86.002) has a significantly higher DILI risk than Ligand B (8.414). This is a major concern for Ligand A.

**BBB:** BBB is not a high priority for a non-CNS target like SRC. Ligand A (80.962) is better than Ligand B (27.84), but this is less important.

**Caco-2 Permeability:** Ligand A (-4.821) has a worse Caco-2 permeability than Ligand B (-5.44). Both are negative, indicating poor permeability, but Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-3.072) is better than Ligand B (-0.339) in terms of solubility.

**hERG:** Ligand A (0.127) has a slightly better hERG profile than Ligand B (0.066), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-18.876) has a much lower (better) microsomal clearance than Ligand A (46.465). This suggests significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-2.398) has a better in vitro half-life than Ligand A (-5.477).

**P-gp Efflux:** Ligand A (0.14) has a slightly better P-gp efflux profile than Ligand B (0.002).

**Binding Affinity:** Ligand A (-9.3 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 threshold.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand A, its high DILI risk is a major red flag. The improved metabolic stability (lower Cl_mic and better half-life) and low DILI risk of Ligand B make it a more promising candidate, even with the slightly weaker binding. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. The poor permeability of both is a concern, but can be addressed through formulation strategies or further structural modifications.

Output:
1
2025-04-17 12:48:57,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.519 and 362.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is slightly higher than Ligand B (64.16), but both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.787 and 3.237), falling within the optimal 1-3 range.

**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 3 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.558 and 0.721), indicating good drug-like properties.

**7. DILI:** Ligand A (13.377) has a significantly lower DILI risk than Ligand B (43.66). This is a crucial advantage.

**8. BBB:** Ligand B (78.558) has a better BBB penetration score than Ligand A (41.838), but BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.638) has a worse Caco-2 permeability than Ligand B (-5.096). Both are quite poor, but B is slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.912 and -2.826). This is a potential issue, but can be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.186 and 0.215).

**12. Microsomal Clearance:** Ligand A (51.246) has significantly lower microsomal clearance than Ligand B (89.818), indicating better metabolic stability. This is a major advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (8.543) has a longer in vitro half-life than Ligand B (-1.159). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.273).

**15. 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 not huge.

**Overall Assessment:**

Ligand A is the better candidate. While both ligands have acceptable physicochemical properties, Ligand A demonstrates a significantly better safety profile (lower DILI) and superior pharmacokinetic properties (lower Cl_mic, longer t1/2). The slightly better binding affinity of Ligand A further supports this conclusion. The slightly worse Caco-2 permeability of A is less concerning than the higher DILI and clearance of B, especially for a kinase inhibitor where metabolic stability is paramount.

Output:
0
2025-04-17 12:48:57,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.376 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.19 and 72.53) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.532) is optimal, while Ligand B (1.79) is at the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.807 and 0.863), indicating drug-likeness.

**DILI:** Ligand A (52.113) has a slightly higher DILI risk than Ligand B (35.595), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.227) has better BBB penetration than Ligand B (57.115).

**Caco-2 Permeability:** Ligand A (-4.384) shows poor permeability, while Ligand B (-5.049) is even worse. Both are quite low.

**Aqueous Solubility:** Ligand A (-4.087) has slightly better solubility than Ligand B (-1.627), though both are poor.

**hERG Inhibition:** Ligand A (0.534) has a lower hERG risk than Ligand B (0.143), which is a significant advantage.

**Microsomal Clearance:** Ligand B (20.99 mL/min/kg) has significantly lower microsomal clearance than Ligand A (37.083 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (54.82 hours) has a much longer half-life than Ligand A (-21.134 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.166 and 0.026).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better logP and slightly better solubility and hERG risk, Ligand B's superior binding affinity (-9.2 vs -8.5 kcal/mol), significantly better metabolic stability (lower Cl_mic), and longer half-life are critical advantages for an enzyme target like SRC kinase. The slightly lower solubility and higher DILI risk of Ligand B are less concerning given the potency and PK advantages. The poor Caco-2 permeability is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 12:48:57,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.507) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (55.89) is significantly better than Ligand B (89.69). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 0.774, B: 2.126), 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.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=0, HBA=10). Ligand B has a higher number of HBA which could affect permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.737, B: 0.613), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (2.792) has a much lower DILI risk than Ligand B (90.112). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.79) is better than Ligand B (51.221).

**Caco-2 Permeability:** Ligand A (-5.18) is better than Ligand B (-5.598), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.648) is better than Ligand B (-3.071), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.458) has a much lower hERG risk than Ligand B (0.067). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (8.684) has lower microsomal clearance, suggesting better metabolic stability, compared to Ligand B (69.106).

**In vitro Half-Life:** Ligand A (-1.709) has a better in vitro half-life than Ligand B (-27.002).

**P-gp Efflux:** Ligand A (0.003) has significantly lower P-gp efflux than Ligand B (0.375), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 1.2 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical ADME properties (DILI, hERG, solubility, metabolic stability, permeability) and has a slightly better binding affinity. Ligand B's higher logP and HBA, combined with poor metabolic stability and high DILI/hERG risk, make it a less desirable candidate.

Output:
0
2025-04-17 12:48:57,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.555 and 367.833 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (112.73). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (2.729) is optimal (1-3), while Ligand B (0.826) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than 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 (0.728 and 0.631), indicating good drug-likeness.

**DILI:** Ligand A (19.542) has a much lower DILI risk than Ligand B (24.583), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (88.406) is better than Ligand B (73.401). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.965) is better than Ligand B (-5.399). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.587) is better than Ligand B (-2.624). Both are poor, but A is slightly better.

**hERG Inhibition:** Ligand A (0.735) is much better than Ligand B (0.222), indicating a lower risk of cardiotoxicity. This is a critical advantage.

**Microsomal Clearance:** Ligand A (80.332) has a higher (worse) clearance than Ligand B (-0.377). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-6.116) has a shorter half-life than Ligand B (19.375). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.299) is better than Ligand B (0.024) indicating less efflux.

**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 B has a much better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from a higher TPSA, lower logP, higher DILI risk, and a higher risk of hERG inhibition. Ligand A has better ADME properties overall, particularly regarding safety (DILI, hERG) and permeability.

The difference in binding affinity (2.2 kcal/mol) is substantial. For an enzyme target, potency is paramount. While Ligand A has better ADME properties, the significantly stronger binding of Ligand B is likely to be more impactful, especially in early stages of development where optimization can address the ADME issues.

Output:
1
2025-04-17 12:48:57,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (373.387 and 350.507 Da) fall within the ideal 200-500 Da range. No significant difference here.

**TPSA:** Ligand A (135.92) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (50.6) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.278 and 2.294), 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.45 and 0.722), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A has a DILI risk of 83.443, which is high and concerning. Ligand B has a much lower DILI risk of 11.322, which is excellent.

**BBB:** Both ligands have high BBB penetration (70.415 and 83.482), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.8 and -4.381), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.549 and -1.797). This is a significant drawback for both compounds and will likely require formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.438 and 0.507), which is positive.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (61.675), while Ligand B has a higher clearance (74.642). Lower is better for metabolic stability, so Ligand A is slightly favored here.

**In vitro Half-Life:** Ligand A has a longer half-life (30.486 hours) than Ligand B (13.498 hours). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.157 and 0.343), which is good.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.3 kcal/mol) compared to Ligand B (-7.1 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 Ligand A has a higher DILI risk and poorer solubility, its significantly stronger binding affinity (-9.3 vs -7.1 kcal/mol) and longer half-life are major advantages. The higher DILI risk is concerning, but could potentially be mitigated through structural modifications during lead optimization. The solubility issue is also addressable with formulation. Ligand B's lower DILI is good, but its weaker binding affinity makes it less likely to be a successful drug candidate.

Output:
1
2025-04-17 12:48:57,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.347 Da) is slightly higher than Ligand B (349.519 Da), but both are acceptable.

**TPSA:** Ligand A (97.39) is higher than Ligand B (52.65). While both are below 140, Ligand B's lower TPSA is more favorable for absorption.

**logP:** Both ligands have good logP values (A: 1.689, B: 2.26), 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 (A: 0.569, B: 0.828), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a very high DILI risk (99.031%), which is a major red flag. Ligand B has a low DILI risk (8.414%), which is excellent.

**BBB:** Ligand A (46.879%) has poor BBB penetration, while Ligand B (88.174%) has good BBB penetration. Since SRC is not a CNS target, this is less critical, but still a positive for Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.973) is slightly better than Ligand B (-4.709), but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.771) is slightly better than Ligand B (-1.885).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.181, B: 0.355), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (7.806) than Ligand B (24.163), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a negative half-life (-24.644), which is problematic. Ligand B has a negative half-life as well (-4.447), but is slightly better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.131, B: 0.069), which is favorable.

**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 could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability, but suffers from a very high DILI risk and a negative in vitro half-life. Ligand B has a better safety profile (low DILI), better QED, and better BBB penetration, but weaker binding affinity and poorer metabolic stability.

Given the enzyme-specific priorities, potency (affinity) and metabolic stability are crucial. The substantial affinity advantage of Ligand A is compelling. However, the extremely high DILI risk is a major concern. While optimization could potentially mitigate the DILI risk, it's a significant hurdle. Ligand B, while less potent, presents a much cleaner starting point from a safety perspective.

Considering the balance, and the possibility of optimizing Ligand A to address the DILI risk, I would initially favor Ligand A due to its superior binding affinity.

Output:
0
2025-04-17 12:48:57,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.467 and 357.801 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.63 and 77.05) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (3.065 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 0 HBD and 6 HBA. Both are acceptable.

**QED:** Both ligands have similar QED scores (0.74 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (56.146) has a lower DILI risk than Ligand B (72.392), which is a significant advantage.

**BBB:** Ligand B (70.997) has a higher BBB penetration percentile than Ligand A (30.283). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.072 and -5.156), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.762 and -2.417), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.48) has a slightly higher hERG inhibition risk than Ligand B (0.068), which is unfavorable.

**Microsomal Clearance:** Ligand B (30.632) has significantly lower microsomal clearance than Ligand A (68.171), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-0.192) has a slightly longer in vitro half-life than Ligand A (-10.328).

**P-gp Efflux:** Ligand B (0.356) has a lower P-gp efflux liability than Ligand A (0.226), which is a slight advantage.

**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 for Ligand A.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, the significantly stronger binding affinity of Ligand A (-8.1 kcal/mol vs 0.0 kcal/mol) and its lower DILI risk outweigh the advantages of Ligand B (better metabolic stability and lower hERG). The potency difference is substantial and likely to be crucial for efficacy. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:48:57,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.451 and 344.415 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is significantly better than Ligand B (84.42).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (4.013) is higher than optimal (1-3), but still potentially manageable. Ligand B (1.706) is within the ideal range. High logP can sometimes be offset by strong binding.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a slightly higher HBA count (5) compared to Ligand A (3), but both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.823 and 0.899), indicating good drug-like properties.

**DILI:** Ligand A (37.728) has a lower DILI risk than Ligand B (63.125). This is a significant advantage.

**BBB:** Ligand A (81.039) has better BBB penetration than Ligand B (67.895), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.855 and -4.692), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.632 and -3.116), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.702) has a lower hERG risk than Ligand B (0.196). This is a significant advantage.

**Microsomal Clearance:** Ligand A (83.041) has a higher microsomal clearance than Ligand B (32.254), meaning it's less metabolically stable. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-19.331) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the compound itself. Ligand A (10.803) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.729) has lower P-gp efflux than Ligand B (0.13), which is preferable.

**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 of the ADME concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a concerning negative half-life and higher DILI risk. Ligand A has better solubility, lower hERG risk, and a more reasonable half-life, but its affinity is weaker and logP is higher. The negative half-life for Ligand B is a major red flag, suggesting instability or a data error. While the affinity difference is significant, the negative half-life makes Ligand B a very risky candidate.

Output:
0
2025-04-17 12:48:57,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.413 and 357.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (71.09 and 69.72) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands have good logP values (2.694 and 1.738), falling within the optimal 1-3 range. Ligand B is slightly lower, potentially indicating better 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 3 HBA, well below the limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.855 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 37.301, which is good (below 40). Ligand B has a much lower DILI risk of 15.82, which is excellent.

**8. BBB:** Both ligands have high BBB penetration (84.374 and 90.035), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.633 and -4.667). This is unusual and suggests poor permeability. However, these values are on a log scale and need careful interpretation.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.695 and -2.068), also on a log scale, indicating poor aqueous solubility. Ligand B is slightly better in this regard.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.279 and 0.404), which is excellent.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (32.813) than Ligand B (21.831), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-31.837) than Ligand A (-24.255), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.021), which is favorable.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.2 kcal/mol) compared to Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Conclusion:**

While both ligands have acceptable physicochemical properties, Ligand B is superior. It exhibits a significantly stronger binding affinity, a much lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2). The slightly better solubility of Ligand B is also a plus. The negative Caco-2 and solubility values are concerning for both, but the substantial affinity advantage of Ligand B outweighs these concerns, especially given the enzyme-specific priority on potency.

Output:
1
2025-04-17 12:48:57,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.395 and 352.45 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (60.25) is better than Ligand B (49.85) as it is closer to the ideal threshold of <=140.

**logP:** Both ligands (1.911 and 2.143) are within the optimal range of 1-3.

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

**H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 3. Both are below the threshold of 10.

**QED:** Both ligands have similar QED values (0.786 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (41.838) has a slightly higher DILI risk than Ligand B (19.271), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration, but Ligand B (97.751) is better than Ligand A (81.776). However, BBB is less important for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.634 and -4.34). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.748 and -2.969). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.43 and 0.576).

**Microsomal Clearance:** Ligand B (16.27) has significantly lower microsomal clearance than Ligand A (47.282), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (0.001) has a very short half-life, while Ligand B (16.462) has a much longer half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.505 and 0.087).

**Binding Affinity:** Ligand B (-7.2 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 the ADME concerns.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. It exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and a slightly better binding affinity. While both ligands have poor solubility and permeability, the improved metabolic profile of Ligand B is crucial for an enzyme inhibitor.

Output:
1
2025-04-17 12:48:57,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (356.413 and 341.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.34) is slightly higher than Ligand B (61.36), but both are well below the 140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (3.202 and 2.198, respectively) 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 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.788 and 0.89), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (44.591 and 44.979, respectively), well below the concerning threshold of 60.

**8. BBB:** Both ligands have high BBB penetration (87.515 and 81.349, respectively). While not critical for a non-CNS target like SRC, it doesn't detract from their potential.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.432 and -4.953), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.779 and -3.001), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.519 and 0.741, respectively). This is positive.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (42.109) than Ligand B (79.029), indicating better metabolic stability. This is a significant advantage.

**13. In vitro Half-Life:** Ligand B has a negative half-life (-9.932), which is not physically possible and suggests a significant issue with the data or the compound's stability. Ligand A has a half-life of 33.18, which is reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.172 and 0.1, respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -9.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand A is the more promising candidate. Ligand B has a nonsensical negative in vitro half-life, which is a critical flaw. Ligand A also exhibits better metabolic stability (lower Cl_mic) and a more reasonable half-life. While both have poor solubility and permeability, the metabolic stability advantage of Ligand A is more readily addressable through formulation strategies than a fundamentally unstable compound.

Output:
0
2025-04-17 12:48:57,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (379.222 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (80.04 and 85.62) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (4.585) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.04) is within the optimal range (1-3).

**4. H-Bond Donors:** Both ligands are acceptable (3 and 2, respectively), being less than 5.

**5. H-Bond Acceptors:** Both ligands are acceptable (3 and 5, respectively), being less than 10.

**6. QED:** Both ligands have good QED scores (0.583 and 0.819), indicating drug-like properties.

**7. DILI:** Ligand A (92.168) has a significantly higher DILI risk than Ligand B (42.691). This is a major concern.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (89.104) than Ligand A (72.78), but this isn't a deciding factor.

**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:** Ligand A (0.661) has a slightly higher hERG risk than Ligand B (0.39), but both are reasonably low.

**12. Microsomal Clearance:** Ligand B (29.231) has a lower microsomal clearance than Ligand A (40.808), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (51.815) has a longer in vitro half-life than Ligand A (109.409). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.215 and 0.105).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2) are major red flags. Ligand B, despite its weaker binding, presents a much more favorable ADME profile, with lower DILI risk, better metabolic stability, and a longer half-life. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. The 1.6 kcal/mol difference in binding affinity, while substantial, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 12:48:57,559 - INFO - Batch 161 complete. Total preferences: 2576
2025-04-17 12:48:57,559 - INFO - Processing batch 162/512...
2025-04-17 12:49:45,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.46 and 349.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.93) is well below the 140 threshold for good absorption. Ligand B (115.21) is still within acceptable limits, but higher.

**logP:** Ligand A (1.247) is within the optimal 1-3 range. Ligand B (-0.081) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 7 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.671 and 0.694), indicating generally drug-like properties.

**DILI:** Ligand A (29.55) has a significantly lower DILI risk than Ligand B (78.87). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.44) has better BBB penetration than Ligand B (42.54).

**Caco-2 Permeability:** Ligand A (-4.26) is very poor, while Ligand B (-5.40) is also poor. This is a concern for both, but slightly worse for A.

**Aqueous Solubility:** Ligand A (-2.722) is poor, while Ligand B (-1.83) is also poor. Both are problematic, but B is better.

**hERG:** Both ligands have very low hERG risk (0.175 and 0.013).

**Microsomal Clearance:** Ligand A (52.16) has higher clearance than Ligand B (-20.13). This means Ligand B is likely to have better metabolic stability.

**In vitro Half-Life:** Ligand B (20.88 hours) has a longer half-life than Ligand A (18.18 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.034 and 0.02).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 0.4 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand A has a much better safety profile (lower DILI) and better logP. However, it suffers from poor Caco-2 permeability and solubility, and higher metabolic clearance. Ligand B has better solubility, metabolic stability (lower Cl_mic, longer t1/2), and a slightly better binding affinity. The poor Caco-2 and solubility of both are concerning, but the superior binding affinity and metabolic stability of Ligand B, combined with the lower DILI risk, make it the more promising candidate. While the solubility and permeability need to be addressed through further optimization, the stronger binding and improved PK profile of Ligand B give it a higher likelihood of success.

Output:
1
2025-04-17 12:49:45,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.53 and 353.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is well below the 140 threshold for oral absorption, while Ligand B (93.46) is still acceptable but closer to the limit.

**logP:** Ligand A (3.57) is at the upper end of the optimal 1-3 range, while Ligand B (1.74) is towards the lower end. While both are within range, a slightly higher logP can sometimes be beneficial for kinase inhibitors.

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

**QED:** Both ligands have identical QED scores of 0.76, indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (67.39 and 65.92 percentile), placing them in a moderate risk category, but not alarming.

**BBB:** Both ligands have relatively low BBB penetration (62.85 and 74.91 percentile), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.95), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.19 and -1.86), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.513) has a slightly higher hERG risk than Ligand B (0.149). Lower is better here.

**Microsomal Clearance:** Ligand B (31.25 mL/min/kg) has a lower microsomal clearance than Ligand A (39.28 mL/min/kg), suggesting better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (-11.11 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound's stability. Ligand A has a half-life of 66.22 hours, which is very good.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.053), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B's significantly stronger binding affinity (-10.2 vs -8.4 kcal/mol) and better metabolic stability (lower Cl_mic) are compelling advantages. The negative half-life for Ligand B is a major red flag and suggests the data is unreliable or the compound is unstable. However, assuming the half-life is an error, the binding affinity difference is substantial enough to favor Ligand B. Ligand A has a better hERG profile and half-life, but the binding affinity is not strong enough to overcome the other issues.

Output:
1
2025-04-17 12:49:45,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be favorable for permeability, but both are acceptable.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (75.44). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Ligand A (0.426) is quite low, potentially hindering permeation. Ligand B (3.04) 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 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.692, B: 0.786), indicating drug-like properties.

**DILI:** Ligand B (54.323) has a lower DILI risk than Ligand A (13.959), which is a positive.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (73.943) has a higher BBB score than Ligand A (57.154), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both have negative values (-4.568 and -4.866), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative values (-1.56 and -4.791), indicating poor solubility. Ligand B is worse in this regard.

**hERG Inhibition:** Ligand A (0.254) has a much lower hERG risk than Ligand B (0.184), which is a significant advantage.

**Microsomal Clearance:** Ligand A (12.275) has a much lower Cl_mic than Ligand B (36.747), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (6.088) has a shorter half-life than Ligand B (-7.302). A negative value for half-life is unusual and may indicate rapid degradation.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.018, B: 0.277).

**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 less than 1.5 kcal/mol, it's still a positive.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG, better metabolic stability), but suffers from poor logP and solubility. Ligand B has better logP, but has higher DILI, hERG, and Cl_mic. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the better metabolic stability and lower hERG risk of Ligand A are more important than the slightly better binding affinity and logP of Ligand B. The solubility issues of both are concerning, but can be addressed with formulation strategies.

Output:
0
2025-04-17 12:49:45,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.82 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.66) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (80.12) is still under 140, but less optimal than A.

**logP:** Ligand A (4.099) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.768) is comfortably within the optimal range.

**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 (0.645 and 0.777), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 75.766, which is considered high risk (>60). Ligand B has a much lower DILI risk of 53.509, which is good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (77.007 and 59.403), but this is less critical for a kinase inhibitor unless CNS off-target effects are a major concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.55 and -1.94). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.678) and Ligand B (0.195) both have relatively low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (75.358) and Ligand B (51.636) both have moderate microsomal clearance. Lower is better, so Ligand B is slightly favored.

**In vitro Half-Life:** Ligand A (53.764) and Ligand B (-0.07) have very different half-lives. Ligand A has a reasonable half-life, while Ligand B has a negative half-life, which is not possible and likely indicates an issue with the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.88 and 0.189), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.0 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand B is significantly more favorable due to its much lower DILI risk and better logP. The solubility is a concern for both, but the DILI risk for Ligand A is a major red flag. The negative half-life for Ligand B is a data quality issue that would need to be investigated, but assuming it is an error, the rest of its profile is superior.

Output:
1
2025-04-17 12:49:45,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.381 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.12) is significantly better than Ligand B (75.44).  A TPSA under 90 is generally good, and A is much closer to the optimal <60 for good absorption.

**3. logP:** Both ligands have good logP values (2.33 and 2.458), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is also acceptable.

**6. QED:** Both have high QED scores (0.903 and 0.859), indicating good drug-likeness.

**7. DILI:** Ligand B (23.885) has a much lower DILI risk than Ligand A (49.166). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (92.633) has better BBB penetration than Ligand B (68.166), but BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.849 and -4.842), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.271 and -2.534), which is also concerning and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.81) has a slightly higher hERG risk than Ligand B (0.367). Lower is better, so B is preferable.

**12. Microsomal Clearance:** Ligand A (26.891) has a significantly lower microsomal clearance than Ligand B (41.638), indicating better metabolic stability. This is a crucial advantage for A.

**13. In vitro Half-Life:** Ligand B (13.043) has a slightly longer half-life than Ligand A (11.812), which is a minor advantage.

**14. P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.049), which is preferable.

**15. Binding Affinity:** Ligand A (-10.4 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 concerns. A difference of >1.5 kcal/mol is significant.

**Overall Assessment:**

While Ligand B has better safety profiles (lower DILI, lower hERG), Ligand A's significantly stronger binding affinity (-10.4 vs -8.0 kcal/mol) and better metabolic stability (lower Cl_mic) are critical for an enzyme inhibitor. The poor Caco-2 and solubility for both are concerning, but these can potentially be addressed through formulation strategies. The strong binding affinity of Ligand A suggests it may be more effective at lower doses, potentially mitigating some of the ADME issues.

Output:
1
2025-04-17 12:49:45,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:**
*   Ligand A: 448.217 Da - Within the ideal range (200-500 Da).
*   Ligand B: 366.527 Da - Also within the ideal range.
*   *No clear advantage here.*

**2. TPSA:**
*   Ligand A: 114.46  - Acceptable, but approaching the upper limit for good oral absorption (<=140).
*   Ligand B: 62.55 - Excellent, well below the threshold for good absorption.
*   *Ligand B has a significant advantage.*

**3. logP:**
*   Ligand A: 1.232 - Optimal.
*   Ligand B: 3.446 - Optimal, but closer to the upper limit.
*   *Ligand A has a slight advantage.*

**4. H-Bond Donors:**
*   Ligand A: 2 - Good.
*   Ligand B: 1 - Good.
*   *No clear advantage.*

**5. H-Bond Acceptors:**
*   Ligand A: 6 - Good.
*   Ligand B: 4 - Good.
*   *Ligand A has a slight advantage.*

**6. QED:**
*   Ligand A: 0.5 - Meets the threshold for drug-likeness.
*   Ligand B: 0.68 - Better drug-like properties.
*   *Ligand B has an advantage.*

**7. DILI Risk:**
*   Ligand A: 78.131 - High risk. This is a significant concern.
*   Ligand B: 20.744 - Low risk.
*   *Ligand B has a major advantage.*

**8. BBB Penetration:**
*   Ligand A: 63.474 - Not a primary concern for an oncology target, but moderate.
*   Ligand B: 62.544 - Similar to A, not a primary concern.
*   *No clear advantage.*

**9. Caco-2 Permeability:**
*   Ligand A: -5.098 - Very poor permeability.
*   Ligand B: -5.305 - Very poor permeability.
*   *Similar poor permeability for both.*

**10. Aqueous Solubility:**
*   Ligand A: -3.625 - Poor solubility.
*   Ligand B: -3.27 - Poor solubility.
*   *Similar poor solubility for both.*

**11. hERG Inhibition:**
*   Ligand A: 0.4 - Low risk.
*   Ligand B: 0.629 - Slightly higher risk, but still acceptable.
*   *Ligand A has a slight advantage.*

**12. Microsomal Clearance:**
*   Ligand A: 46.276 - Moderate clearance.
*   Ligand B: 55.816 - Higher clearance, indicating lower metabolic stability.
*   *Ligand A has an advantage.*

**13. In vitro Half-Life:**
*   Ligand A: -24.4 - Very short half-life.
*   Ligand B: 40.155 - Good half-life.
*   *Ligand B has a major advantage.*

**14. P-gp Efflux:**
*   Ligand A: 0.022 - Low efflux, good.
*   Ligand B: 0.181 - Higher efflux, less favorable.
*   *Ligand A has an advantage.*

**15. Binding Affinity:**
*   Ligand A: -7.7 kcal/mol - Excellent.
*   Ligand B: -7.5 kcal/mol - Very good, but slightly weaker than A.
*   *Ligand A has a slight advantage.*

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, the significant drawbacks of high DILI risk, poor permeability, poor solubility, and short half-life are major concerns. Ligand B, despite slightly weaker binding, presents a much more favorable ADME-Tox profile: low DILI risk, better QED, and a good in vitro half-life. For an enzyme target in oncology, metabolic stability and safety (DILI) are critical. The better ADME properties of Ligand B outweigh the small difference in binding affinity.

Output:
1
2025-04-17 12:49:45,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.264 and 353.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (119.23) is slightly above the optimal <140, while Ligand B (101.74) is well within.

**logP:** Ligand A (0.5) is a bit low, potentially hindering permeability. Ligand B (0.138) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 8 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.746 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 79.915, which is concerning (high risk). Ligand B has a much lower DILI risk of 43.234, which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (71.229) is higher than Ligand B (27.026).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.022 and -5.009), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.925 and -0.968), indicating very poor aqueous solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.044 and 0.071).

**Microsomal Clearance:** Ligand A (43.995) has a moderate clearance, while Ligand B (-25.31) has a negative clearance, which is not physically possible and likely indicates an issue with the prediction or data. However, interpreting it as very low clearance, it suggests better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.294) has a negative half-life, which is not physically possible. Ligand B (-4.306) also has a negative half-life. Both suggest issues with the prediction.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.007).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly better binding affinity than Ligand A (-7.8 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME concerns.

**Conclusion:**

Despite both ligands having issues with permeability and solubility, Ligand B is the more promising candidate. Its significantly better binding affinity (-8.7 vs -7.8 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B has a much lower DILI risk, which is critical. The negative values for clearance and half-life are concerning and require further investigation, but the prediction suggests better metabolic stability than Ligand A. The lower logP of Ligand B is a drawback, but the strong binding affinity might compensate for it.

Output:
1
2025-04-17 12:49:45,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.841 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.4) is well below the 140 threshold, suggesting good absorption. Ligand B (113.33) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.355) is within the optimal 1-3 range. Ligand B (0.522) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is acceptable but slightly higher, potentially impacting permeability.

**QED:** Both ligands have reasonable QED values (0.893 and 0.734), indicating good drug-like properties.

**DILI:** Ligand A (65.413) has a higher DILI risk than Ligand B (56.572), though both are reasonably acceptable.

**BBB:** Ligand A (74.564) has better BBB penetration than Ligand B (37.456), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.742) has a significantly *better* Caco-2 permeability than Ligand B (-5.416), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.283) has better aqueous solubility than Ligand B (-2.335). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.617) has a slightly higher hERG risk than Ligand B (0.051), but both are relatively low.

**Microsomal Clearance:** Ligand B (-1.761) has a *much* lower (better) microsomal clearance than Ligand A (19.057), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (34.694) has a longer half-life than Ligand B (15.458).

**P-gp Efflux:** Ligand A (0.259) has lower P-gp efflux than Ligand B (0.02), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-10.2) has a significantly stronger binding affinity than Ligand A (-8.0). This is a crucial factor for an enzyme target. A difference of >2 kcal/mol is substantial.

**Overall Assessment:**

While Ligand A has advantages in solubility, permeability, and half-life, Ligand B's *significantly* stronger binding affinity (-10.2 vs -8.0 kcal/mol) and much better metabolic stability (lower Cl_mic) are decisive. The lower logP of Ligand B is a concern, but the substantial affinity advantage can often compensate for minor ADME drawbacks. The lower hERG risk for Ligand B is also a bonus.

Output:
1
2025-04-17 12:49:45,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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, while Ligand B (402.34 Da) is still acceptable.

**TPSA:** Ligand A (67.43) is better than Ligand B (36.66). Lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (A: 3.034, B: 3.358), 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:** Both ligands have good QED scores (A: 0.684, B: 0.79), indicating good drug-like properties.

**DILI:** Ligand A (14.851) has a significantly lower DILI risk than Ligand B (30.826), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (73.943) is better than Ligand B (66.576). While not a primary concern for a kinase inhibitor, higher BBB is never detrimental.

**Caco-2 Permeability:** Ligand A (-4.291) has a worse Caco-2 permeability than Ligand B (-5.087). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.342) has better aqueous solubility than Ligand B (-3.121). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.44) has a much lower hERG inhibition liability than Ligand B (0.843). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (92.946) has higher microsomal clearance than Ligand B (68.076), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-41.07) has a significantly longer in vitro half-life than Ligand A (-21.115), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.134) has lower P-gp efflux liability than Ligand B (0.667), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.8). However, the difference is only 0.6 kcal/mol, which is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and half-life, but Ligand A excels in several critical areas: lower DILI risk, lower hERG inhibition, better solubility, and lower P-gp efflux. The lower metabolic stability of Ligand A is a concern, but the significantly improved safety profile (DILI and hERG) and better solubility make it a more promising candidate. The difference in binding affinity is not large enough to overcome these advantages.

Output:
0
2025-04-17 12:49:45,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.853 and 396.657 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (58.56 and 59.42) are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (4.108 and 4.972) are slightly above the optimal 1-3 range, but still within acceptable limits. Ligand B is a bit higher, potentially raising concerns about off-target effects, but not dramatically.

**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 (0.867 and 0.632) have acceptable drug-likeness scores, with Ligand A being slightly better.

**7. DILI:** Ligand A (67.895) and Ligand B (72.199) both have DILI risk above the preferred <40, but below the high-risk >60 threshold. Ligand B has a slightly higher risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.197) and Ligand B (56.805) are both moderate.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.575 and -4.829). This is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.424 and -4.944). This is also a major concern, indicating very poor aqueous solubility, which will hinder bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.69 and 0.517), which is positive.

**12. Microsomal Clearance:** Ligand A (28.055) has significantly lower microsomal clearance than Ligand B (71.172), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (82.6) has a slightly lower in vitro half-life than Ligand B (84.795), but both are reasonably good.

**14. P-gp Efflux:** Both ligands show low P-gp efflux (0.574 and 0.658), which is favorable.

**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 not huge, it's enough to consider, especially given the other factors.

**Overall Assessment:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility. However, Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic), slightly better binding affinity, and slightly better QED. The DILI risk is comparable. The solubility and permeability issues would need to be addressed through formulation strategies or further chemical modifications, but starting with the more metabolically stable and potent compound (Ligand A) is the better approach.

Output:
0
2025-04-17 12:49:45,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (386.279 Da and 363.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.32 and 76.82) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.311 and 2.896) 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.581 and 0.556), indicating good drug-likeness.

**DILI:** Ligand A (54.401) has a significantly lower DILI risk than Ligand B (88.949). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (57.464 and 69.756), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.624 and -4.687), 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 (-4.487 and -3.897), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.208) has a much lower hERG inhibition liability than Ligand B (0.563), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (47.107) has lower microsomal clearance than Ligand B (76.23), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (83.628) has a substantially longer in vitro half-life than Ligand A (23.34). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.038) has much lower P-gp efflux liability than Ligand B (0.47), which could improve bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). The difference is 0.9 kcal/mol, which is a moderate advantage.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and longer half-life, Ligand A demonstrates significantly better safety profiles with much lower DILI and hERG inhibition risks. It also has lower P-gp efflux, which is beneficial for bioavailability. The solubility and permeability concerns are present in both, but the safety advantages of Ligand A outweigh the modest potency/stability benefit of Ligand B. For an oncology target, minimizing off-target effects and toxicity is crucial.

Output:
0
2025-04-17 12:49:45,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.5 and 345.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is significantly better than Ligand B (81.99).  A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have similar logP values (2.523 and 2.641), 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:** Ligand A (0.845) has a better QED score than Ligand B (0.696), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (23.23 and 29.97), well below the concerning threshold of 60.

**BBB:** Ligand A (64.48) has a slightly better BBB penetration percentile than Ligand B (58.90), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.307) is worse than Ligand B (-4.63), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.875) is worse than Ligand B (-3.91), indicating lower solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.254 and 0.372), which is excellent.

**Microsomal Clearance:** Ligand A (32.204) has significantly lower microsomal clearance than Ligand B (53.814). Lower clearance is desirable for better metabolic stability.

**In Vitro Half-Life:** Ligand A (31.308 hours) has a much longer in vitro half-life than Ligand B (-11.395 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.149 and 0.167).

**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 relatively small (0.5 kcal/mol).

**Overall Assessment:**

While Ligand B has slightly better Caco-2 permeability, solubility, and binding affinity, Ligand A is superior in several key areas for an enzyme inhibitor: QED, microsomal clearance, and especially in vitro half-life. The longer half-life and better metabolic stability of Ligand A are crucial for maintaining therapeutic concentrations and reducing dosing frequency. The difference in binding affinity is not large enough to outweigh the ADME advantages of Ligand A.

Output:
1
2025-04-17 12:49:45,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.287 Da) is slightly higher than Ligand B (346.471 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (61.36) is slightly higher than Ligand B (58.64), but both are good.

**logP:** Ligand A (4.968) is higher than the optimal range (1-3), which could lead to solubility issues and off-target effects. Ligand B (2.127) is within the optimal range.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.703, Ligand B: 0.592), indicating good drug-like properties.

**DILI:** Ligand A (42.691) has a slightly higher DILI risk than Ligand B (37.03), but both are below the concerning threshold of 60.

**BBB:** Ligand A (41.373) has a lower BBB penetration percentile than Ligand B (78.713). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.032) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.536) also has a negative value, but is less negative, suggesting slightly better permeability.

**Aqueous Solubility:** Ligand A (-5.138) has very poor aqueous solubility, a significant drawback. Ligand B (-2.815) has better solubility, although still not ideal.

**hERG Inhibition:** Ligand A (0.558) has a higher hERG inhibition liability than Ligand B (0.402), increasing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (55.737) has a higher microsomal clearance than Ligand B (37.516), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (35.998) has a shorter in vitro half-life than Ligand B (-13.887), which is a negative value and suggests very high stability.

**P-gp Efflux:** Ligand A (0.114) has a lower P-gp efflux liability than Ligand B (0.209), which is favorable.

**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.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both ligands have good binding affinity and QED, Ligand B has significantly better solubility, metabolic stability (lower Cl_mic, higher t1/2), and lower hERG risk. Ligand A's poor solubility and higher clearance are major drawbacks. The slightly better P-gp efflux of Ligand A is not enough to offset these issues. The Caco-2 values for both are poor, but Ligand B is slightly better.



Output:
1
2025-04-17 12:49:45,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (355.389 and 365.543 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (88.91) is better than Ligand B (53.51), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.415) is within the optimal range (1-3), while Ligand B (3.271) is at the higher end but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 2, Ligand B: 0).

**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 similar QED values (A: 0.738, B: 0.71), indicating good drug-likeness.

**7. DILI:** Ligand A (56.727) has a higher DILI risk than Ligand B (16.014). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (A: 74.486, B: 83.366), but Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-5.14) is worse than Ligand B (-4.788), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.865) is worse than Ligand B (-2.059), indicating lower solubility.

**11. hERG Inhibition:** Ligand A (0.093) has a slightly higher hERG risk than Ligand B (0.56), but both are relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (0.019) has much lower clearance than Ligand B (55.6), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.003) has a much longer half-life than Ligand B (3.866), which is highly desirable.

**14. P-gp Efflux:** Ligand A (0.018) has lower P-gp efflux than Ligand B (0.325), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand B (-8.7) has a stronger binding affinity than Ligand A (-8.1), a difference of 0.6 kcal/mol.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand B has a better affinity, but Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, and a better TPSA. The DILI risk for Ligand A is concerning, but the substantial improvement in metabolic stability and half-life, combined with the only moderate difference in binding affinity, makes Ligand A more promising. The solubility is a concern for ligand A, but can be addressed with formulation.

Output:
0
2025-04-17 12:49:45,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.395 and 361.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.68) is slightly above the preferred <140, while Ligand B (78.74) is well within. This favors Ligand B for absorption.

**logP:** Both ligands (2.113 and 2.429) 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 acceptable, staying within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.774 and 0.881), indicating good drug-like properties.

**DILI:** Ligand A (33.695) has a much lower DILI risk than Ligand B (63.086). This is a significant advantage for Ligand A.

**BBB:** Ligand B (75.107) has a higher BBB penetration score than Ligand A (40.403), but BBB is not a primary concern for a kinase inhibitor unless CNS targets are specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.145 and -4.956), which is unusual and suggests poor permeability. However, these values are on a log scale and need careful interpretation.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.127 and -3.366), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.124) has a lower hERG inhibition liability than Ligand B (0.435), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (10.992) has a higher microsomal clearance than Ligand B (-0.855). This means Ligand B is likely more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (8.19) has a longer in vitro half-life than Ligand A (-3.079), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.041).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.8 kcal/mol). Ligand B is slightly better (-8.8 vs -8.6), but the difference is small.

**Overall Assessment:**

Ligand A has a significant advantage in terms of DILI risk and hERG inhibition. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The poor solubility and Caco-2 permeability are concerns for both. Given the enzyme-kinase focus, metabolic stability is crucial. While the DILI and hERG are important, the slight advantage in potency and metabolic stability of Ligand B outweighs the slightly higher risk profile.

Output:
1
2025-04-17 12:49:45,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.419 and 343.427 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.54) is better than Ligand B (73.74), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (2.125) is optimal (1-3), while Ligand A (0.161) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.769 and 0.831, respectively), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (36.177 and 35.905 percentile), which is excellent.

**BBB:** Ligand B (63.94) has a better BBB penetration score than Ligand A (56.34), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.806) has significantly worse Caco-2 permeability than Ligand B (-4.468).

**Aqueous Solubility:** Ligand A (-1.088) has better solubility than Ligand B (-2.554).

**hERG:** Ligand A (0.031) has a much lower hERG risk than Ligand B (0.136), a crucial factor for enzyme inhibitors.

**Microsomal Clearance:** Ligand A (-1.872) has a lower (better) microsomal clearance than Ligand B (60.48). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-2.97) has a significantly longer half-life than Ligand B (-34.724).

**P-gp Efflux:** Ligand A (0.007) has much lower P-gp efflux liability than Ligand B (0.136).

**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 difference is usually significant, the other ADME properties of Ligand A are much more favorable.

**Overall Assessment:**

Ligand A, despite slightly weaker binding affinity, is the more promising candidate. Its superior metabolic stability (lower Cl_mic, longer half-life), lower hERG risk, better P-gp efflux, and better solubility outweigh the minor difference in binding affinity. Ligand B's low logP and poor metabolic properties are significant drawbacks.

Output:
0
2025-04-17 12:49:45,594 - INFO - Batch 162 complete. Total preferences: 2592
2025-04-17 12:49:45,594 - INFO - Processing batch 163/512...
2025-04-17 12:50:26,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (347.346 and 369.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is better than Ligand B (124.84), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.108) is optimal (1-3), while Ligand B (-1.663) is below 1, which might impede permeation.

**H-Bond Donors:** Both have acceptable HBD counts (2 and 3, respectively), below the threshold of 5.

**H-Bond Acceptors:** Both have acceptable HBA counts (5 each), below the threshold of 10.

**QED:** Ligand A (0.829) has a significantly better QED score than Ligand B (0.549), indicating a more drug-like profile.

**DILI:** Ligand A (65.762) has a higher DILI risk than Ligand B (25.514). This is a concern for Ligand A.

**BBB:** Both have moderate BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.894) is worse than Ligand B (-5.647), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.176) is worse than Ligand B (-2.003), which is problematic for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.389 and 0.041, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (-17.333) has a significantly lower (better) microsomal clearance than Ligand A (33.387), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-0.266) has a slightly better in vitro half-life than Ligand A (-32.239).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.049 and 0.001, respectively).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), though both are excellent. The 0.4 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED score, Ligand B excels in crucial areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, better t1/2), better solubility, and a slightly improved binding affinity. Ligand A's higher DILI risk and poorer permeability are concerning. The slightly better affinity of Ligand B, combined with its superior ADME properties, outweighs the small difference in QED.

Output:
1
2025-04-17 12:50:26,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.415 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is slightly higher than Ligand B (60.85). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better permeability.

**logP:** Both ligands (2.243 and 2.425) 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:** Both ligands have good QED scores (0.741 and 0.847), indicating drug-like properties.

**DILI:** Ligand A (57.193) has a higher DILI risk than Ligand B (8.104). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (71.656 and 71.733), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.705 and -4.499). This is unusual and suggests poor permeability *in vitro*. However, these values are close enough that they don't strongly differentiate the ligands.

**Aqueous Solubility:** Ligand B (-1.699) has better aqueous solubility than Ligand A (-3.017). This is a positive for Ligand B.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.433 and 0.492).

**Microsomal Clearance:** Ligand A (35.93) has lower microsomal clearance than Ligand B (48.407), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (6.436) has a longer half-life than Ligand B (-8.522). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.053).

**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 less than the 1.5 kcal/mol threshold to outweigh other issues, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand B has significant advantages in DILI risk and solubility. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. Given the importance of metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, the longer half-life and lower clearance of Ligand A make it the more promising candidate. The DILI risk of Ligand A is moderate but manageable, while the negative Caco-2 values for both are a concern that would require further investigation.

Output:
0
2025-04-17 12:50:26,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly better positioned.

**TPSA:** Ligand A (69.64) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.08) is still acceptable but less favorable.

**logP:** Ligand A (2.652) is optimal (1-3). Ligand B (-0.33) is too low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (4) are both acceptable, but Ligand A is better.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable, but Ligand A is better.

**QED:** Both ligands have reasonable QED scores (A: 0.832, B: 0.537), indicating good drug-like properties. Ligand A is significantly better.

**DILI:** Ligand A (20.047) has a very low DILI risk, which is excellent. Ligand B (65.452) has a higher, though not critically high, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.193) and Ligand B (24.738) are both relatively low.

**Caco-2:** Ligand A (-4.642) and Ligand B (-5.818) are both negative, indicating poor permeability. This is a concern for both.

**Solubility:** Ligand A (-2.964) and Ligand B (-2.293) are both negative, indicating poor solubility. This is a concern for both.

**hERG:** Ligand A (0.243) has a very low hERG risk, which is excellent. Ligand B (0.166) is also low, but slightly higher than Ligand A.

**Microsomal Clearance:** Ligand A (32.239) has moderate clearance. Ligand B (-1.929) has *very* low clearance, indicating excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (0.929) has a short half-life. Ligand B (44.552) has a very long half-life, a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.039, B: 0.009), which is good.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-11.3 kcal/mol). This is a substantial advantage, and can often outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a better overall profile in terms of drug-likeness (QED, DILI, hERG) and significantly stronger binding affinity. However, Ligand B has markedly better metabolic stability (lower Cl_mic, longer t1/2). The poor Caco-2 and solubility for both are concerning, but could potentially be addressed with formulation strategies. Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity (-9.9 vs -11.3 kcal/mol), Ligand A is the more promising candidate despite the metabolic concerns.

Output:
0
2025-04-17 12:50:26,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.459 Da and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.26) is slightly higher than Ligand B (74.57), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.838 and 1.944), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 4 HBD and 3 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 (0.658 and 0.753), indicating drug-like properties.

**DILI:** Ligand A (35.052) has a higher DILI risk than Ligand B (24.467). This is a significant advantage for Ligand B.

**BBB:** Ligand A (62.389) has a higher BBB penetration score than Ligand B (47.732), but BBB is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.509) shows poorer Caco-2 permeability than Ligand B (-4.737), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.08 and -1.715), indicating poor aqueous solubility. This is a concern for both, but the value is slightly better for Ligand B.

**hERG Inhibition:** Ligand A (0.23) has a slightly higher hERG inhibition liability than Ligand B (0.343), meaning Ligand B is slightly less likely to cause cardiotoxicity.

**Microsomal Clearance:** Ligand A (-0.285) has a significantly *lower* (better) microsomal clearance than Ligand B (23.067). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (8.484) has a longer in vitro half-life than Ligand B (4.414), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.164), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is the most critical factor for an enzyme target. The 1.5 kcal/mol advantage is substantial.

**Conclusion:**

While Ligand A demonstrates better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, the significantly stronger binding affinity of Ligand B (-7.4 kcal/mol vs -9.4 kcal/mol) outweighs these benefits. Additionally, Ligand B has a lower DILI risk. The solubility issues are a concern for both, but can be addressed with formulation strategies. Given the enzyme-specific priority on potency, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:50:26,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (366.483 and 360.439 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (83.55 and 84.42) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (1.17 and 1.392) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.757 and 0.891), indicating good drug-like properties.

**7. DILI:** Ligand A (46.84) has a significantly lower DILI risk than Ligand B (79.604). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (62.233) has a better BBB penetration score than Ligand B (31.834), but BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.073) has worse Caco-2 permeability than Ligand B (-4.912). Both are quite poor, suggesting potential absorption issues.

**10. Aqueous Solubility:** Ligand A (-3.03) has slightly better solubility than Ligand B (-2.093).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.107 and 0.208).

**12. Microsomal Clearance (Cl_mic):** Ligand A (7.318) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (11.628).

**13. In vitro Half-Life (t1/2):** Ligand A (44.504) has a significantly longer half-life than Ligand B (-14.015). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.039).

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (0.0). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in affinity and metabolic stability (longer half-life, lower Cl_mic), and has a better DILI score. While both have acceptable hERG and solubility, the superior affinity of Ligand A outweighs the slightly worse Caco-2 permeability.

Output:
1
2025-04-17 12:50:26,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.347 and 376.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.96) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (110.29) is well within the desired range.

**logP:** Both ligands (-1.674 and -1.186) are a bit low. While not severely problematic, higher logP values (1-3) are generally preferred for better permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, which are within acceptable limits. Ligand B has 0 HBD and 7 HBA, also within limits.

**QED:** Ligand B (0.438) has a better QED score than Ligand A (0.259), indicating a more drug-like profile.

**DILI:** Ligand A (47.926) has a lower DILI risk than Ligand B (55.68), which is favorable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (65.297) has a higher BBB penetration than Ligand A (30.167), but this is not a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.622 and -4.807), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.308 and -0.889), indicating very poor aqueous solubility. This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.069 and 0.146), which is excellent.

**Microsomal Clearance:** Ligand A (8.521) has significantly lower microsomal clearance than Ligand B (28.808), suggesting better metabolic stability. This is a crucial advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-27.984) has a much longer in vitro half-life than Ligand A (-9.08), which is a significant positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.032).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.8 and -8.0 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its lower DILI risk and significantly lower microsomal clearance (better metabolic stability) are key advantages for an enzyme inhibitor. While both have poor solubility and permeability, the metabolic stability is a more critical factor for SRC kinase inhibition. The longer half-life of Ligand B is attractive, but the higher clearance is a concern.

Output:
0
2025-04-17 12:50:26,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.349 and 389.989 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (61.19 and 60.77) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.162) is optimal, while Ligand B (4.387) is slightly higher, potentially leading to solubility issues.

**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 similar QED scores (0.629 and 0.623), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 60.915, which is borderline high. Ligand B has a significantly lower DILI risk of 13.61, which is excellent. This is a major advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration (83.637 and 62.117). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.424 and -4.655). This is unusual and suggests poor permeability, but the scale is not specified.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.876 and -3.84). This is also unusual and suggests poor solubility, but the scale is not specified.

**hERG Inhibition:** Ligand A (0.247) has a very low hERG risk, while Ligand B (0.777) is slightly higher. This favors Ligand A.

**Microsomal Clearance:** Ligand A (76.418) and Ligand B (83.811) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (66.075 hours) compared to Ligand A (-11.637 hours). This is a substantial advantage for Ligand B, indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.747) has a moderate P-gp efflux liability, while Ligand B (0.71) is similar.

**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.

**Overall Assessment:**

Ligand A has a much better binding affinity and a lower hERG risk. However, Ligand B has a significantly lower DILI risk and a much longer half-life, indicating better metabolic stability. The solubility and permeability values are concerning for both, but the difference in binding affinity is substantial. Given the enzyme-specific priorities, the strong binding affinity of Ligand A is a critical factor. While the DILI risk is a concern, it might be mitigated with further optimization.

Output:
0
2025-04-17 12:50:26,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (341.459 Da and 349.337 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.18) is better than Ligand B (85.43), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have good logP values (2.223 and 1.43, respectively) within the optimal 1-3 range. Ligand B is slightly lower, which could potentially affect permeability.

**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 (3). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.894 and 0.781), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (52.734 and 56.34), both are acceptable.

**8. BBB:** Ligand A (61.535) is better than Ligand B (43.699). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Ligand A (-5.109) is better than Ligand B (-4.753). Higher Caco-2 values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.224) is better than Ligand B (-2.716). Better solubility is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.806) is better than Ligand B (0.529). Lower hERG risk is critical to avoid cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-24.288) is significantly better than Ligand B (-17.779). Lower clearance indicates better metabolic stability, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (22.506) is better than Ligand B (-13.164). Longer half-life is desirable for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.099) is better than Ligand B (0.045). Lower P-gp efflux improves bioavailability.

**15. Binding Affinity:** Ligand B (-8.7) has a significantly stronger binding affinity than Ligand A (-6.4). This is a >2.3 kcal/mol advantage, which is substantial.

**Overall Assessment:**

While Ligand A demonstrates superior ADME properties across almost all parameters (solubility, permeability, metabolic stability, hERG, P-gp efflux), Ligand B's significantly stronger binding affinity (-8.7 kcal/mol vs -6.4 kcal/mol) is a major advantage. For a kinase inhibitor, potency is paramount. The improved ADME profile of Ligand A is valuable, but the substantial potency difference of Ligand B likely outweighs these benefits, especially considering the acceptable ADME profile of Ligand B.

Output:
1
2025-04-17 12:50:26,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.439 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (385.936 Da) is also good.

**TPSA:** Ligand A (83.42) is better than Ligand B (38.13). Lower TPSA generally favors better absorption.

**logP:** Ligand A (1.996) is optimal, while Ligand B (4.545) is a bit high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.713) has a better QED score than Ligand B (0.563), indicating a more drug-like profile.

**DILI:** Ligand B (34.703) has a significantly lower DILI risk than Ligand A (69.639), which is a major advantage.

**BBB:** Both have good BBB penetration, but Ligand B (89.88) is better than Ligand A (76.696). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.581) and Ligand B (-4.987) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-2.013) and Ligand B (-4.017) both have negative values, indicating very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.315) has a lower hERG risk than Ligand B (0.819), which is preferable.

**Microsomal Clearance:** Ligand A (10.129) has a much lower microsomal clearance than Ligand B (83.788), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (44.98) has a significantly longer in vitro half-life than Ligand A (8.585), which is desirable.

**P-gp Efflux:** Ligand A (0.22) has lower P-gp efflux than Ligand B (0.834), which is better for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.8 kcal/mol), with Ligand B being slightly better. However, the affinity difference is small and might not outweigh other ADME issues.

**Overall Assessment:**

Ligand B has a better binding affinity and longer half-life. However, it has a significantly higher logP, higher P-gp efflux, and a higher hERG risk. Ligand A has better TPSA, QED, lower clearance, and lower P-gp efflux. The biggest issue for both is the very poor Caco-2 permeability and solubility. However, the lower DILI risk and better metabolic stability of Ligand A are more critical for an enzyme inhibitor.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), and considering the significant DILI risk associated with Ligand B, I would choose Ligand A despite its lower half-life and permeability/solubility issues. These issues could potentially be addressed through formulation strategies or further chemical modifications, while a high DILI risk is harder to overcome.

Output:
0
2025-04-17 12:50:26,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (89.87) is excellent, well below the 140 threshold for oral absorption. Ligand B (49.41) is also very good.

**logP:** Ligand A (1.52) is optimal. Ligand B (3.475) is also within the optimal range, but approaching the upper limit.

**H-Bond Donors:** Ligand A (3) is good. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also good.

**QED:** Both ligands have similar QED values (A: 0.754, B: 0.702), indicating good drug-like properties.

**DILI:** Ligand A (20.706) has a much lower DILI risk than Ligand B (8.492). This is a significant advantage for Ligand A.

**BBB:** Ligand B (76.89) has a higher BBB penetration percentile than Ligand A (18.147). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.045) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-4.705) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values (A: -2.759, B: -3.876), indicating poor solubility. This is a concern for both, but Ligand B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.285, B: 0.607), which is positive. Ligand A is slightly better.

**Microsomal Clearance:** Ligand A (5.856) has significantly lower microsomal clearance than Ligand B (89.673). This suggests much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-21.282) has a negative half-life, which is highly problematic and suggests rapid degradation. Ligand B (4.256) has a short half-life, but is positive and therefore better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.038, B: 0.057).

**Binding Affinity:** Both ligands have similar binding affinities (A: -8.3 kcal/mol, B: -8.1 kcal/mol). The difference is small and unlikely to be decisive.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. It has a significantly lower DILI risk and much better metabolic stability (lower Cl_mic). While its Caco-2 permeability and in vitro half-life are concerning, the superior safety profile and metabolic stability outweigh these drawbacks, especially given the similar potency. Ligand B's poor solubility and very high Cl_mic are major liabilities.

Output:
0
2025-04-17 12:50:26,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.857 and 348.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (75.11 and 79.31) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (though that's not a priority here).

**3. logP:** Ligand A (3.468) is optimal, while Ligand B (1.072) is a bit low, potentially impacting permeability.

**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 5, respectively), well below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.828 and 0.832), indicating good drug-like properties.

**7. DILI:** Ligand A (58.395) has a higher DILI risk than Ligand B (37.185). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration, which isn't critical for a non-CNS target like SRC.

**9. Caco-2:** 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 indicate a complete lack of absorption.

**10. Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both, but might be more manageable if the compounds are formulated appropriately.

**11. hERG:** Both ligands have very low hERG risk (0.484 and 0.356), which is excellent.

**12. Cl_mic:** Ligand B (11.906 mL/min/kg) has significantly lower microsomal clearance than Ligand A (29.36 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand B.

**13. t1/2:** Ligand B (-10.61 hours) has a negative in vitro half-life, which is also unusual. Ligand A (21.265 hours) has a reasonable half-life.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.296 and 0.081), which is favorable.

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

**Overall Assessment:**

While both ligands have strong binding affinity, Ligand B is the more promising candidate. Its significantly lower microsomal clearance (better metabolic stability) and lower DILI risk outweigh the slightly lower logP and unusual half-life value. The solubility issues are a concern for both, but can potentially be addressed through formulation. The similar binding affinities mean the ADME properties become the deciding factor.

Output:
1
2025-04-17 12:50:26,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.46 and 347.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.61) is significantly better than Ligand B (106.96). A TPSA under 140 is good for oral absorption, but lower is generally preferred, and Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (4.299 and 3.08), falling within the 1-3 range. Ligand B is slightly better here.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=3) as it has a lower number of H-bond donors.

**QED:** Ligand A (0.735) has a much better QED score than Ligand B (0.274), indicating a more drug-like profile.

**DILI:** Ligand A (41.84) has a lower DILI risk than Ligand B (17.68). Both are below the 40 threshold, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (60.18) is slightly better than Ligand A (52.89).

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.7) has a slightly higher hERG risk than Ligand B (0.27), but both are relatively low.

**Microsomal Clearance:** Ligand A (79.92) has a significantly higher microsomal clearance than Ligand B (24.84), meaning it is less metabolically stable. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-0.167) has a slightly better in vitro half-life than Ligand A (0.466).

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and QED score, and a lower DILI risk. However, it suffers from significantly higher microsomal clearance and poor Caco-2 permeability and solubility. Ligand B has better metabolic stability and slightly better solubility, but its binding affinity is considerably weaker, and its QED score is poor.

Given the importance of potency for enzyme inhibitors, the 1.4 kcal/mol difference in binding affinity is substantial. While Ligand A's metabolic stability is a concern, it could potentially be addressed through structural modifications. The poor solubility and permeability are also concerning, but potentially addressable. Ligand B's weak binding affinity is a more fundamental issue that would be harder to overcome.

Output:
1
2025-04-17 12:50:26,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.483 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for oral absorption, but not particularly optimized for CNS penetration (90).

**logP:** Both ligands have good logP values (1.198 and 1.958), 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, under the 10 HBA limit.

**QED:** Both ligands have reasonable QED scores (0.85 and 0.748), indicating good drug-like properties.

**DILI:** Ligand A (40.442) has a slightly higher DILI risk than Ligand B (16.402). Ligand B is significantly better here, falling well below the 40% threshold.

**BBB:** Both ligands have similar BBB penetration (60.838 and 60.45), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.675 and -4.716), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.621 and -2.999). This is a drawback, but can potentially be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.267 and 0.284), which is excellent.

**Microsomal Clearance:** Ligand B (33.833 mL/min/kg) has a higher microsomal clearance than Ligand A (26.75 mL/min/kg), indicating faster metabolism and lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (26.701 hours) has a considerably longer half-life than Ligand B (17.189 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.213 and 0.075).

**Binding Affinity:** Ligand B (-8.9 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 difference threshold.

**Overall Assessment:**

Ligand B's substantially better binding affinity (-8.9 vs -7.5 kcal/mol) is the most important factor. While it has a slightly higher DILI risk and faster clearance than Ligand A, the potency difference is large enough to outweigh these concerns, especially given the acceptable DILI score. The poor Caco-2 permeability and solubility are drawbacks for both, but can be addressed during formulation.

Output:
1
2025-04-17 12:50:26,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.5 and 358.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (113.33). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (3.372) is optimal (1-3), while Ligand B (0.244) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.71) has a better QED score than Ligand B (0.432), indicating a more drug-like profile.

**DILI:** Ligand A (17.642) has a much lower DILI risk than Ligand B (50.33), a significant advantage.

**BBB:** Both have reasonably high BBB penetration (A: 88.484, B: 83.288), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.495 and -4.881), which 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 (-3.521 and -2.947), again unusual. This indicates very poor aqueous solubility, which is a major concern.

**hERG Inhibition:** Ligand A (0.567) has a lower hERG risk than Ligand B (0.3), which is preferable.

**Microsomal Clearance:** Ligand A (93.754) has a higher microsomal clearance than Ligand B (20.409), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-1.385) has a negative half-life, which is not possible and indicates a problem with the data. Ligand A (11.052) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.511) has lower P-gp efflux than Ligand B (0.048), which is beneficial.

**Binding Affinity:** Ligand B (-10.4 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 has a significantly better binding affinity, which is the most crucial factor for an enzyme inhibitor. However, it suffers from very low logP, poor solubility, and a concerning DILI risk. Ligand A has better ADME properties (logP, TPSA, DILI, P-gp efflux, hERG) and a reasonable half-life, but its binding affinity is weaker and it has higher microsomal clearance.

Given the substantial affinity difference, and acknowledging that solubility and permeability issues *can* sometimes be addressed through formulation, I would cautiously favor Ligand B. The stronger binding is likely to be more impactful than the ADME liabilities, especially if initial studies confirm the affinity *in vivo*. However, significant medicinal chemistry effort would be required to improve Ligand B's solubility and reduce its DILI risk.

Output:
1
2025-04-17 12:50:26,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.833 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (77.83 and 70.08) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have a logP of approximately 1.4, which is optimal (1-3).

**4. H-Bond Donors:** Both ligands have 1 HBD, well within the acceptable limit of <=5.

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

**6. QED:** Both ligands have high QED scores (0.858 and 0.831), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 54.827, while Ligand B has a significantly lower risk of 9.616. This is a major advantage for Ligand B.

**8. BBB:** Both ligands have moderate BBB penetration (68.282 and 54.478). Since SRC is not a CNS target, this is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.71 and -4.508). These values are unusual and suggest poor permeability, but the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.831 and -0.965). Again, the scale is not defined, so it's hard to interpret.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.482 and 0.385).

**12. Microsomal Clearance:** Ligand A has a significantly higher (less favorable) microsomal clearance (-16.015 mL/min/kg) than Ligand B (14.374 mL/min/kg). This suggests Ligand A will be metabolized more quickly.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (10.521 hours) than Ligand A (17.934 hours). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.118).

**15. Binding Affinity:** Ligand B has a slightly better binding affinity (-8.7 kcal/mol) than Ligand A (-7.6 kcal/mol). This 1.1 kcal/mol difference is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both ligands have acceptable properties for MW, logP, HBD, HBA, QED, hERG, and P-gp efflux, Ligand B has a substantially lower DILI risk, a longer half-life, and a better binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the difference in DILI and binding affinity is more critical for an enzyme target like SRC. The better metabolic stability (lower Cl_mic, longer t1/2) of Ligand B is also a significant advantage.

Output:
1
2025-04-17 12:50:26,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 345.399 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.47) is better than Ligand B (71.97), both are below the 140 threshold for oral absorption, and acceptable for kinase inhibitors.

**logP:** Ligand B (0.942) is slightly better than Ligand A (-0.555). A logP between 1-3 is optimal, and Ligand A is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Lower is generally preferred.

**H-Bond Acceptors:** Ligand A (6) is slightly worse than Ligand B (5). Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.735 and 0.815), indicating good drug-like properties.

**DILI:** Ligand A (27.142) is significantly better than Ligand B (65.064). Lower DILI is crucial, and Ligand B is approaching a concerning level.

**BBB:** Ligand B (73.129) is better than Ligand A (57.154). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative values (-4.606 and -4.32), which is unusual and suggests very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both have negative values (-1.56 and -1.997), indicating very poor solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.09) is significantly better than Ligand B (0.268). Lower hERG inhibition is vital to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (-18) is much better than Ligand B (54.536). Lower clearance indicates better metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand B (-32.588) is much better than Ligand A (-1.072). A longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.005) is much better than Ligand B (0.068). Lower P-gp efflux is desirable for improved bioavailability.

**Binding Affinity:** Ligand B (-8.9) is significantly better than Ligand A (-7.7). A difference of >1.5 kcal/mol is substantial and can outweigh some ADME issues.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and in vitro half-life. However, it suffers from higher DILI risk, worse hERG inhibition, and higher P-gp efflux. Ligand A has better metabolic stability (lower Cl_mic), lower DILI, and better hERG inhibition and P-gp efflux, but its binding affinity is weaker. Both compounds have very poor solubility and permeability.

The superior binding affinity of Ligand B is a major advantage for an enzyme inhibitor. While the ADME properties of Ligand B are less favorable, the potency difference is substantial enough to prioritize it for further optimization. Addressing the solubility and permeability issues would be critical, but the strong binding provides a good starting point.

Output:
1
2025-04-17 12:50:26,516 - INFO - Batch 163 complete. Total preferences: 2608
2025-04-17 12:50:26,516 - INFO - Processing batch 164/512...
2025-04-17 12:51:13,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.403 and 359.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.62) is better than Ligand B (101.64), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.33) is a bit low, potentially hindering permeation. Ligand B (3.751) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (8) are both acceptable, being less than 10.

**QED:** Ligand A (0.719) has a significantly better QED score than Ligand B (0.463), indicating a more drug-like profile.

**DILI:** Ligand A (41.024) has a much lower DILI risk than Ligand B (69.135), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 65.839, Ligand B: 60.45), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.549 and -5.314), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.853 and -4.017), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.141) has a much lower hERG risk than Ligand B (0.556), a crucial safety parameter.

**Microsomal Clearance:** Ligand A (-16.573) shows significantly better metabolic stability (lower clearance) than Ligand B (75.796).

**In vitro Half-Life:** Ligand A (-10.055) has a longer in vitro half-life than Ligand B (18.059), indicating slower metabolism.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.137).

**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 ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity (-7.6 vs -10.2 kcal/mol), which is the most important factor for an enzyme inhibitor. While Ligand B has some ADME liabilities (higher logP, higher DILI, poorer solubility, higher Cl_mic), the significantly stronger binding affinity is likely to be the dominant factor. Ligand A has better ADME properties, but the weaker binding affinity is a major drawback.

Output:
1
2025-04-17 12:51:13,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (350.5 and 341.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.7 and 62.3) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.1) is optimal, while Ligand B (3.1) is slightly higher but still acceptable.

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

**H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (6) is acceptable.

**QED:** Both ligands have good QED scores (0.597 and 0.807), indicating drug-like properties.

**DILI:** Both have relatively high DILI risk (5.8 and 63.5), but these values are not drastically different.

**BBB:** Ligand A (63.5) is lower than Ligand B (92.1). Since SRC is not a CNS target, BBB is not a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.68 and -4.75), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.51 and -3.18), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.81 and 0.95).

**Microsomal Clearance:** Ligand A (8.0) has a significantly lower Cl_mic than Ligand B (34.5), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (36.3) has a longer half-life than Ligand A (3.8), which is generally desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.08).

**Binding Affinity:** Both have excellent binding affinities (-8.7 and -8.1 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand A is the slightly better candidate. Its significantly lower microsomal clearance (8.0 vs 34.5) indicates better metabolic stability, a critical factor for kinase inhibitors. While both have poor solubility and permeability, the metabolic advantage of Ligand A outweighs the longer half-life of Ligand B. The DILI risk is similar for both.

Output:
0
2025-04-17 12:51:13,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.387 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.26) is slightly higher than Ligand B (70.67). Both are below the 140 threshold for good absorption, but B is better.

**logP:** Both ligands have good logP values (0.912 and 1.443), 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.

**QED:** Ligand A (0.891) has a better QED score than Ligand B (0.76), indicating a more drug-like profile.

**DILI:** Ligand B (12.524) has a significantly lower DILI risk than Ligand A (48.895), which is a major advantage.

**BBB:** Ligand B (55.603) has a higher BBB penetration percentile than Ligand A (42.924), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.31 and -5.115).

**Aqueous Solubility:** Both ligands have negative solubility values (-1.539 and -1.707), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.106) has a slightly lower hERG inhibition risk than Ligand B (0.382), which is preferable.

**Microsomal Clearance:** Ligand B (8.546 mL/min/kg) has a lower microsomal clearance than Ligand A (16.31 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (5.836 hours) has a significantly longer in vitro half-life than Ligand A (-1.645 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.036).

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a crucial factor, as a 1.5 kcal/mol advantage is considered substantial.

**Conclusion:**

While Ligand A has a slightly better QED and lower hERG risk, Ligand B is the superior candidate. The substantially stronger binding affinity (-10.3 vs -7.8 kcal/mol), lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the minor drawbacks in QED and hERG. The poor solubility and permeability are concerns for both, but are addressable through formulation. For an enzyme target like SRC kinase, potency and metabolic stability are paramount.

Output:
1
2025-04-17 12:51:13,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.423 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.43) is better than Ligand B (66.92), both are below the 140 threshold for good absorption.

**logP:** Ligand A (2.892) is optimal (1-3), while Ligand B (1.601) is on the lower end, potentially impacting permeability.

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

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**QED:** Ligand A (0.758) is significantly better than Ligand B (0.572), indicating a more drug-like profile.

**DILI:** Ligand A (63.203) has a higher DILI risk than Ligand B (25.514). This is a significant drawback for Ligand A.

**BBB:** Ligand B (83.443) has a much higher BBB penetration percentile than Ligand A (54.866). While not a primary concern for a kinase inhibitor, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-5.312) has poor Caco-2 permeability, while Ligand B (-4.316) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.272 and -2.011 respectively). This is a concern for both.

**hERG Inhibition:** Ligand A (0.846) has a slightly higher hERG risk than Ligand B (0.216), but both are relatively low.

**Microsomal Clearance:** Ligand A (-7.385) has *much* lower microsomal clearance (better metabolic stability) than Ligand B (69.689). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (75.818) has a significantly longer half-life than Ligand B (-13.598). This is another major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.537) has lower P-gp efflux than Ligand B (0.102), which is favorable.

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-7.7). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has superior metabolic stability (Cl_mic, t1/2) and P-gp efflux, and a better QED score. However, it has a higher DILI risk and poorer Caco-2 permeability. Ligand B has better binding affinity and lower DILI, but suffers from poor metabolic stability and a lower QED.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) is crucial. Ligand A's significantly better metabolic profile and longer half-life outweigh its slightly higher DILI risk and lower binding affinity, especially considering the difference in binding affinity is not substantial. The poor solubility and permeability of both are concerns that would need to be addressed in further optimization, but the metabolic advantage of A is more critical at this stage.

Output:
0
2025-04-17 12:51:13,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.367 Da and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.23) is well below the 140 threshold, suggesting good absorption. Ligand B (107.53) is still acceptable but less optimal.

**logP:** Ligand A (2.822) is within the optimal 1-3 range. Ligand B (0.463) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is favorable. Ligand B (4 HBD, 4 HBA) is also acceptable, though slightly higher HBD count could be a minor concern.

**QED:** Both ligands have reasonable QED scores (0.692 and 0.533), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (91.78), which is a significant concern. Ligand B has a very low DILI risk (13.804), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (61.38) and Ligand B (56.572) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.624) shows poor permeability. Ligand B (-5.539) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.277) has poor solubility. Ligand B (-1.143) has slightly better solubility, but still not ideal.

**hERG:** Ligand A (0.64) has a slightly elevated hERG risk, but manageable. Ligand B (0.066) shows very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (109.338) has a relatively high microsomal clearance, indicating lower metabolic stability. Ligand B (-10.984) has excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-1.65) has a short half-life. Ligand B (-9.88) has a very long half-life, a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.084 and 0.007).

**Binding Affinity:** Both ligands have strong binding affinities (-7.5 and -8.3 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

While Ligand B has slightly lower logP and Caco-2 permeability, its significantly better DILI score, hERG risk, metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity outweigh these drawbacks. Ligand A's high DILI risk and poor metabolic stability are major red flags. Given the enzyme-kinase target class, metabolic stability and safety (DILI, hERG) are paramount.

Output:
1
2025-04-17 12:51:13,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.455 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is significantly better than Ligand B (78.43). Lower TPSA generally correlates with better cell permeability, which is beneficial.

**logP:** Ligand A (4.576) is higher than Ligand B (2.378). While both are within the acceptable range (1-3 is optimal, and 4 is the upper limit), Ligand A is approaching the higher end, potentially raising concerns about solubility and off-target effects. Ligand B is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=3) as lower HBDs generally improve permeability.

**QED:** Ligand A (0.888) has a much higher QED score than Ligand B (0.529), indicating a more drug-like profile.

**DILI:** Ligand A (51.221) has a higher DILI risk than Ligand B (10.857). This is a significant advantage for Ligand B.

**BBB:** Ligand A (86.274) shows better BBB penetration than Ligand B (48.313), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.373) has a higher Caco-2 value than Ligand B (-4.689), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.932) has a better solubility score than Ligand B (-3.089).

**hERG:** Ligand A (0.777) has a lower hERG inhibition liability than Ligand B (0.225), which is a significant advantage, reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (40.912) has a lower microsomal clearance than Ligand A (65.504), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-15.623) has a much longer in vitro half-life than Ligand A (26.696), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.216) has lower P-gp efflux than Ligand B (0.145), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B demonstrates a superior profile regarding key enzyme inhibitor characteristics: significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a substantially stronger binding affinity. While Ligand A has better solubility and a higher QED score, the advantages of Ligand B in metabolic stability and potency are more critical for a kinase inhibitor. The slightly higher logP of Ligand A is a minor concern compared to the significant benefits of Ligand B.

Output:
1
2025-04-17 12:51:13,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.487 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.57) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (77.32) is well within the acceptable range.

**logP:** Ligand A (0.126) is quite low, potentially hindering permeability. Ligand B (2.103) is 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 (5) is acceptable. Ligand B (6) is also good.

**QED:** Both ligands have good QED scores (0.588 and 0.615), indicating good drug-like properties.

**DILI:** Ligand A (29.779) has a lower DILI risk than Ligand B (48.701), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (46.375) and Ligand B (51.066) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.529) has poor predicted permeability. Ligand B (-4.331) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.282) and Ligand B (-2.975) both have poor predicted solubility.

**hERG Inhibition:** Ligand A (0.07) has a very low hERG risk, a significant advantage. Ligand B (0.097) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-2.563) suggests good metabolic stability (negative value). Ligand B (98.404) indicates very high clearance and poor metabolic stability. This is a major drawback.

**In vitro Half-Life:** Ligand A (17.254) has a reasonable half-life. Ligand B (-13.979) suggests a very short half-life, which is undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.066).

**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 advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the highest priority for an enzyme inhibitor. However, its major drawbacks are its very high microsomal clearance and short half-life, which would likely necessitate very frequent dosing or poor *in vivo* exposure. Ligand A has a lower affinity, but its better metabolic stability (lower clearance, longer half-life), lower DILI risk, and very low hERG risk make it a more promising starting point for optimization. The low logP and solubility of Ligand A are concerning, but potentially addressable through chemical modifications.

Output:
0
2025-04-17 12:51:13,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.473 and 384.933 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (67.23), being well below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (3.505 and 2.26), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 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 (0.628 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A (21.714) has a much lower DILI risk than Ligand B (47.693), which is a significant advantage.

**BBB:** Ligand A (91.392) has a much higher BBB penetration percentile than Ligand B (31.912). While SRC is not necessarily a CNS target, higher BBB is generally a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.561) has a worse Caco-2 permeability than Ligand B (-5.025), but both are quite poor.

**Aqueous Solubility:** Ligand A (-4.438) has a slightly better solubility than Ligand B (-3.697).

**hERG Inhibition:** Ligand A (0.707) has a slightly better hERG inhibition profile than Ligand B (0.089), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (67.676) has a higher microsomal clearance than Ligand B (56.629), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (8.653) has a significantly longer in vitro half-life than Ligand A (-6.424), which is a major advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.25) has a better P-gp efflux liability profile than Ligand B (0.074).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.7 kcal/mol), with a negligible difference.

**Overall Assessment:**

Despite Ligand B having a better in vitro half-life and slightly better Caco-2 permeability, Ligand A is the superior candidate. The significantly lower DILI risk, better TPSA, better BBB penetration, better solubility, and slightly better hERG profile outweigh the disadvantage in metabolic stability and permeability. The binding affinity is comparable, making the ADME/Tox profile the deciding factor.

Output:
1
2025-04-17 12:51:13,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 344.39 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (100.19) is better than Ligand B (67.23). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.869) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.535) is within the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, favoring permeability.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range.

**QED:** Ligand B (0.906) has a significantly higher QED score than Ligand A (0.618), indicating a more drug-like profile.

**DILI:** Ligand A (37.301) has a lower DILI risk than Ligand B (53.858), which is preferable.

**BBB:** Ligand B (82.086) shows better BBB penetration than Ligand A (53.276), but this is not a primary concern for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.193) has a much worse Caco-2 permeability than Ligand B (-4.59).

**Aqueous Solubility:** Ligand A (-2.082) has better aqueous solubility than Ligand B (-2.661).

**hERG Inhibition:** Ligand A (0.09) has a significantly lower hERG inhibition risk than Ligand B (0.56), which is a major advantage.

**Microsomal Clearance:** Ligand A (7.705) has a much lower microsomal clearance than Ligand B (21.113), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.977) has a longer in vitro half-life than Ligand A (-5.056), which is desirable.

**P-gp Efflux:** Ligand A (0.01) has much lower P-gp efflux than Ligand B (0.162).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a better QED score, better permeability and longer half-life. However, Ligand A has a much lower DILI risk, lower hERG inhibition, lower microsomal clearance, and lower P-gp efflux. Given the enzyme-kinase specific priorities, metabolic stability (lower Cl_mic) and reduced toxicity (lower DILI and hERG) are crucial. The slightly better permeability of Ligand B is outweighed by these significant safety and metabolic advantages of Ligand A. The binding affinity is essentially the same.

Output:
0
2025-04-17 12:51:13,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.406 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is better than Ligand B (85.25). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**logP:** Both ligands (1.767 and 1.589) are 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 5. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.869) has a significantly better QED score than Ligand B (0.745), indicating a more drug-like profile.

**DILI:** Ligand A (50.33) has a slightly higher DILI risk than Ligand B (36.681), but both are below the concerning threshold of 60.

**BBB:** Both have good BBB penetration (74.254 and 70.027), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.775) has better Caco-2 permeability than Ligand B (-4.583), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.628) has better aqueous solubility than Ligand B (-2.355), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.447) has a lower hERG inhibition liability than Ligand B (0.329), which is a significant advantage regarding cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-15.147) has *much* lower microsomal clearance than Ligand B (39.732), indicating significantly better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-0.433) has a slightly better in vitro half-life than Ligand B (-14.887).

**P-gp Efflux:** Ligand A (0.019) has lower P-gp efflux than Ligand B (0.057), which is favorable for bioavailability.

**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:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic), better solubility, lower hERG risk, better QED, and better Caco-2 permeability. While Ligand B has a slightly better binding affinity, the ADME advantages of Ligand A outweigh this small difference in potency, particularly for an enzyme target where metabolic stability and bioavailability are critical.

Output:
1
2025-04-17 12:51:13,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.383 and 349.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (84.92 and 80.23) below 140, suggesting reasonable absorption potential.

**logP:** Ligand A (1.851) is slightly higher than Ligand B (0.955), both are within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Ligand A (0.863) has a significantly better QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand A (56.185) has a higher DILI risk than Ligand B (9.306). This is a significant drawback for Ligand A.

**BBB:** Ligand A (38.193) and Ligand B (68.67) both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.858) has poorer Caco-2 permeability than Ligand B (-5.017), although both are negative and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-1.648) has slightly poorer solubility than Ligand B (-1.381), but both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.208 and 0.243).

**Microsomal Clearance:** Ligand A (2.888) has a higher microsomal clearance than Ligand B (0.535), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (17.017 hours) has a longer half-life than Ligand B (-6.262 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.059 and 0.024).

**Binding Affinity:** Ligand B (-6.5 kcal/mol) has a better binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

Ligand A has a better QED score and longer half-life, but suffers from higher DILI risk, poorer Caco-2 permeability, and higher microsomal clearance. Critically, Ligand B has significantly better binding affinity (-6.5 vs -8.1 kcal/mol). The difference in binding affinity is substantial enough to outweigh the slightly lower QED and solubility of Ligand B. The lower DILI risk of Ligand B is also a significant advantage.

Output:
1
2025-04-17 12:51:13,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.386 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.59) is better than Ligand B (62.13), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.416 and 3.727), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.874) has a significantly better QED score than Ligand B (0.714), indicating a more drug-like profile.

**DILI:** Ligand A (59.519) has a higher DILI risk than Ligand B (23.032). This is a significant drawback for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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, again suggesting poor solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.857 and 0.84).

**Microsomal Clearance:** Ligand B (99.354) has significantly higher microsomal clearance than Ligand A (48.584), indicating lower metabolic stability. This is a major disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (24.716 hours) has a much longer in vitro half-life than Ligand B (9.942 hours), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.457 and 0.522).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While it has a higher DILI risk, its significantly better QED score, lower microsomal clearance (better metabolic stability), and longer half-life outweigh this concern. The similar binding affinities make the ADME properties the deciding factor. Ligand B's high microsomal clearance is a substantial drawback.

Output:
0
2025-04-17 12:51:13,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.463 Da and 366.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.42) is slightly higher than Ligand B (81.08). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (0.068) is quite low, potentially hindering permeation. Ligand B (0.625) is better, though still on the lower side of the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (2) is even better, contributing to a better balance of solubility and permeability.

**H-Bond Acceptors:** Ligand A (8) is acceptable, while Ligand B (4) is excellent.

**QED:** Both ligands have good QED scores (0.635 and 0.748), indicating drug-like properties.

**DILI:** Ligand A (79.682) has a significantly higher DILI risk than Ligand B (20.783). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (57.154) has a higher BBB value than Ligand A (25.01), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.489) has poor Caco-2 permeability. Ligand B (-4.716) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.851) has poor aqueous solubility. Ligand B (-1.078) is better, but still relatively low.

**hERG Inhibition:** Ligand A (0.166) has a slightly higher hERG inhibition risk than Ligand B (0.537), but both are relatively low.

**Microsomal Clearance:** Ligand A (11.856) has higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (-7.273) which is excellent.

**In vitro Half-Life:** Ligand A (15.536 hours) has a reasonable half-life, but Ligand B (-12.409 hours) is significantly better, suggesting a longer duration of action.

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux, which is slightly favorable. Ligand B (0.036) is even better.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 kcal/mol and -8.7 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to override other significant ADME differences.

**Conclusion:**

Ligand B is the superior candidate. While both ligands exhibit strong binding affinity, Ligand B demonstrates significantly better ADME properties, particularly regarding DILI risk, metabolic stability (Cl_mic and t1/2), and solubility. Ligand A's high DILI risk and poor solubility are major drawbacks. The slightly better P-gp and H-bonding characteristics of Ligand B further contribute to its favorability.

Output:
1
2025-04-17 12:51:13,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.507 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is well below the 140 threshold for oral absorption, and significantly better than Ligand B (69.72).

**logP:** Both ligands (1.593 and 1.787) are 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) as lower HBD/HBA generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.728 and 0.768), indicating drug-likeness.

**DILI:** Ligand A (11.206) has a significantly lower DILI risk than Ligand B (20.706), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (81.582) is slightly better than Ligand B (73.633). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired or problematic.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.326 and -4.406), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.683) is better than Ligand B (-2.26), indicating better solubility.

**hERG:** Both ligands have very low hERG risk (0.414 and 0.189), which is excellent.

**Microsomal Clearance:** Ligand A (33.526) has lower microsomal clearance than Ligand B (38.017), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.99) has a longer in vitro half-life than Ligand B (-20.392).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.052 and 0.045).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-9.0 kcal/mol). While both are excellent, the 1.2 kcal/mol difference is significant.

**Overall:**

Ligand A is superior to Ligand B. It has a lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and longer t1/2), slightly better binding affinity, and a lower TPSA. While both have poor Caco-2 permeability, the other advantages of Ligand A outweigh this concern, especially given the enzyme-specific priorities. The stronger binding affinity of Ligand A also contributes to its higher potential.

Output:
1
2025-04-17 12:51:13,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.429 and 363.908 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is better than Ligand B (21.06) as it is closer to the ideal range for good oral absorption (<=140).

**logP:** Ligand A (2.343) is optimal (1-3), while Ligand B (4.893) is slightly high, potentially leading to solubility issues and off-target effects.

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

**H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is within the acceptable range.

**QED:** Ligand A (0.842) has a better QED score than Ligand B (0.728), indicating a more drug-like profile.

**DILI:** Ligand A (32.067) has a significantly lower DILI risk than Ligand B (13.804), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (Ligand A: 91.392, Ligand B: 95.967), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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:** Ligand A (0.462) has a much lower hERG inhibition liability than Ligand B (0.94), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand B (33.971) has a higher microsomal clearance than Ligand A (4.752), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (38.97) has a significantly longer in vitro half-life than Ligand A (2.449), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux liability than Ligand B (0.793), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-10.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 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, which is the most important factor for an enzyme inhibitor. However, it suffers from higher logP, higher DILI risk, higher hERG inhibition, and higher microsomal clearance. Ligand A has better ADME properties across the board (lower DILI, hERG, Cl_mic, Pgp, better logP and TPSA) but weaker binding affinity.

The difference in binding affinity (-1.9 kcal/mol) is significant. While the ADME profile of Ligand A is more favorable, the potency of Ligand B is likely to be more impactful, especially in the context of kinase inhibition where achieving sufficient target engagement is critical. The longer half-life of Ligand B is also a plus.

Output:
1
2025-04-17 12:51:13,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:**
* Ligand A: 335.363 Da - Within the ideal range (200-500).
* Ligand B: 392.905 Da - Also within the ideal range, but approaching the upper limit.
* *Advantage: A*

**2. TPSA:**
* Ligand A: 65.38 - Good for oral absorption (<140).
* Ligand B: 95.94 - Still acceptable for oral absorption, but higher than A.
* *Advantage: A*

**3. logP:**
* Ligand A: 3.204 - Optimal (1-3).
* Ligand B: 0.579 - Below the optimal range, potentially hindering permeation.
* *Advantage: A*

**4. H-Bond Donors:**
* Ligand A: 1 -  Good.
* Ligand B: 2 - Acceptable.
* *Advantage: A*

**5. H-Bond Acceptors:**
* Ligand A: 5 - Good.
* Ligand B: 5 - Good.
* *No Advantage*

**6. QED:**
* Ligand A: 0.798 - Excellent drug-like properties.
* Ligand B: 0.689 - Good, but slightly lower than A.
* *Advantage: A*

**7. DILI:**
* Ligand A: 96.937 - High DILI risk. This is a significant concern.
* Ligand B: 41.877 - Low DILI risk.
* *Advantage: B*

**8. BBB:**
* Ligand A: 72.082 - Not a primary concern for a non-CNS oncology target.
* Ligand B: 45.987 - Not a primary concern.
* *No Advantage*

**9. Caco-2 Permeability:**
* Ligand A: -4.674 - Poor permeability.
* Ligand B: -5 - Poor permeability.
* *No Advantage*

**10. Aqueous Solubility:**
* Ligand A: -4.962 - Poor solubility.
* Ligand B: -2.15 - Poor solubility, but better than A.
* *Advantage: B*

**11. hERG Inhibition:**
* Ligand A: 0.765 - Relatively low risk.
* Ligand B: 0.35 - Very low risk.
* *Advantage: B*

**12. Microsomal Clearance:**
* Ligand A: 64.237 - Moderate clearance.
* Ligand B: 12.91 - Low clearance, indicating better metabolic stability.
* *Advantage: B*

**13. In vitro Half-Life:**
* Ligand A: 23.549 - Moderate half-life.
* Ligand B: -5.741 - Very short half-life.
* *Advantage: A*

**14. P-gp Efflux:**
* Ligand A: 0.534 - Relatively low efflux.
* Ligand B: 0.047 - Very low efflux.
* *Advantage: B*

**15. Binding Affinity:**
* Ligand A: -7.9 kcal/mol - Excellent binding.
* Ligand B: -7.3 kcal/mol - Very good binding, but slightly weaker than A.
* *Advantage: A*

**Overall Assessment:**

Ligand A has a superior binding affinity and a better half-life. However, it suffers from very poor solubility and permeability, and a high DILI risk. Ligand B has a lower binding affinity, but exhibits significantly better ADME properties: lower DILI, better solubility, lower hERG risk, lower P-gp efflux, and better metabolic stability.

For an enzyme target in oncology, metabolic stability (Cl_mic, t1/2), solubility, and safety (DILI, hERG) are crucial. While the affinity of Ligand A is attractive, the poor ADME profile and high DILI risk are major drawbacks. Ligand B, despite slightly weaker binding, presents a more balanced and potentially developable profile. The 0.6 kcal/mol difference in binding affinity might be overcome with further optimization of Ligand B, while addressing the severe ADME issues of Ligand A would be much more challenging.

Output:
1
2025-04-17 12:51:13,954 - INFO - Batch 164 complete. Total preferences: 2624
2025-04-17 12:51:13,954 - INFO - Processing batch 165/512...
2025-04-17 12:51:53,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.292 Da) is slightly higher than Ligand B (391.427 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (88.4) is slightly higher than Ligand B (74.73).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.079) is slightly lower than Ligand B (3.159).

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED scores (0.691 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (87.786) has a higher DILI risk than Ligand B (93.059), which is concerning. Both are relatively high, but B is worse.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.352) has a better BBB score than Ligand B (46.413).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined and could be a percentile, where negative values are possible.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not defined and could be a percentile, where negative values are possible.

**hERG Inhibition:** Ligand A (0.431) shows a lower hERG inhibition risk than Ligand B (0.737), which is a significant advantage.

**Microsomal Clearance:** Ligand A (66.367) has a lower microsomal clearance than Ligand B (11.077), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-5.576) has a negative half-life, which is not possible, indicating a potential data error. Ligand B (25.326) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.764) has slightly lower P-gp efflux liability than Ligand B (0.434).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. While it has a higher DILI risk and lower metabolic stability than Ligand A, the potency difference is significant. The negative solubility and Caco-2 values for both are concerning and need further investigation, but the binding affinity advantage of Ligand B is likely to be more impactful in initial optimization. The half-life for Ligand A is also suspect.

Output:
1
2025-04-17 12:51:53,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.77) is slightly higher than Ligand B (53.76). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (1.078) is at the lower end of the optimal range (1-3), while Ligand B (2.473) is well within it. Ligand A's lower logP could potentially hinder membrane 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.

**QED:** Both ligands have good QED scores (0.743 and 0.848), indicating good drug-like properties.

**DILI:** Ligand A (21.442) has a much lower DILI risk than Ligand B (31.059), which is a significant advantage.

**BBB:** Ligand A (68.282) has a lower BBB penetration than Ligand B (74.835). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the molecules themselves. It's difficult to draw conclusions from this data point.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and problematic. Again, difficult to interpret.

**hERG:** Ligand A (0.488) shows a slightly better hERG profile than Ligand B (0.59), indicating lower cardiotoxicity risk.

**Microsomal Clearance (Cl_mic):** Ligand A (-25.846) has a *much* lower (better) Cl_mic than Ligand B (28.907). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life (t1/2):** Ligand B (39.951) has a longer half-life than Ligand A (13.614). This is a positive for Ligand B, but the difference might be offset by its higher Cl_mic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.051 and 0.29), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 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 the most crucial factor for an enzyme inhibitor. However, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic and lower DILI risk) and a slightly better hERG profile. The solubility and Caco-2 values are concerning for both, but the affinity difference is substantial. Given the importance of potency for kinase inhibitors, and the relatively minor impact of the other differences, Ligand B is the more promising candidate.

Output:
1
2025-04-17 12:51:53,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is significantly better than Ligand B (106.94).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (2.679) is optimal (1-3), while Ligand B (0.622) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.805 and 0.532), indicating good drug-like properties.

**DILI:** Ligand A (37.611) has a much lower DILI risk than Ligand B (14.114), which is a significant advantage.

**BBB:** Ligand A (70.221) has a better BBB percentile than Ligand B (19.232), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.868) has better Caco-2 permeability than Ligand B (-5.134). Both are negative, indicating poor permeability, but A is slightly better.

**Aqueous Solubility:** Ligand A (-3.262) has better solubility than Ligand B (-0.475). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.557 and 0.1), which is excellent.

**Microsomal Clearance:** Ligand A (35.33 mL/min/kg) has a higher microsomal clearance than Ligand B (1.226 mL/min/kg), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.87 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (-4.668 hours) is also negative, which is not possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.168 and 0.029).

**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.

**Conclusion:**

Despite Ligand A having a better solubility and a lower DILI risk, the significantly lower metabolic stability (higher Cl_mic) and the impossible half-life value are major concerns. Ligand B, while having a slightly lower logP and higher DILI, exhibits much better metabolic stability and a more plausible half-life (even if still low). The binding affinities are comparable. Given the enzyme-specific priorities, metabolic stability is crucial.

Output:
1
2025-04-17 12:51:53,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.471 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (88.91) is significantly better than Ligand B (32.7). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.868) is optimal, while Ligand B (4.702) is high. High logP can lead to solubility issues and off-target effects.

**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 reasonable QED scores (A: 0.749, B: 0.632), indicating good drug-like properties.

**DILI:** Ligand A (70.725) has a higher DILI risk than Ligand B (11.439). This is a significant concern for Ligand A.

**BBB:** Both have similar BBB penetration (A: 65.374, B: 69.833). Not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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, but it suggests potential formulation challenges.

**hERG Inhibition:** Ligand A (0.314) has a lower hERG risk than Ligand B (0.976). This is a positive attribute for Ligand A.

**Microsomal Clearance:** Ligand A (53.485) has lower microsomal clearance than Ligand B (78.922), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (53.003) has a slightly longer half-life than Ligand B (46.974).

**P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.836), which is favorable for bioavailability.

**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 factor.

**Overall Assessment:**

Ligand B has a better binding affinity and significantly lower DILI risk. However, it suffers from a high logP, which could cause solubility and off-target issues, and higher P-gp efflux and microsomal clearance. Ligand A has better TPSA, logP, metabolic stability, and P-gp efflux, but a higher DILI risk.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), and the relatively small difference in binding affinity, the improved metabolic stability and lower P-gp efflux of Ligand A are more compelling. The DILI risk is a concern, but could potentially be mitigated through structural modifications. The high logP of Ligand B is a more fundamental issue.

Output:
0
2025-04-17 12:51:53,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.36 and 380.86 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.07) is better than Ligand B (111.06), being comfortably under the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.42 and 2.47), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable ranges.

**QED:** Ligand A (0.852) has a significantly better QED score than Ligand B (0.376), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (71.23 and 75.30), but this isn't a dealbreaker at this stage.

**BBB:** Ligand A (67.58) has a better BBB penetration score than Ligand B (41.72), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.915 and -4.759). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.619 and -3.42). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.161 and 0.261), which is excellent.

**Microsomal Clearance:** Ligand A (5.959) has a lower microsomal clearance than Ligand B (6.711), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.06) has a significantly longer in vitro half-life than Ligand B (-14.79), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.26).

**Binding Affinity:** Ligand A (-7.4 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 the superior candidate. It exhibits a significantly better QED score, longer half-life, better metabolic stability (lower Cl_mic), and a slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the substantial advantage in binding affinity and pharmacokinetic properties (half-life, Cl_mic) of Ligand A outweighs these concerns. The DILI risk is similar for both.

Output:
1
2025-04-17 12:51:53,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.451 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands are below the 140 A^2 threshold (99.77 and 91.32 A^2), suggesting good potential for absorption.

**logP:** Ligand A (0.229) is quite low, potentially hindering permeation. Ligand B (2.537) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

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

**QED:** Both ligands have good QED scores (0.57 and 0.599), indicating drug-likeness.

**DILI:** Ligand A (29.624) has a slightly higher DILI risk than Ligand B (23.226), but both are below the concerning threshold of 60.

**BBB:** Ligand A (73.672) has better BBB penetration than Ligand B (26.638), but this is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.866) has significantly worse Caco-2 permeability than Ligand B (-5.163), although both are negative values which is not ideal.

**Aqueous Solubility:** Ligand A (-1.04) has better aqueous solubility than Ligand B (-2.742). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.269) has a slightly lower hERG risk than Ligand B (0.093), which is favorable.

**Microsomal Clearance:** Ligand A (-11.81 mL/min/kg) has a *much* lower microsomal clearance than Ligand B (30.553 mL/min/kg). This indicates significantly better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (3.144 hours) has a significantly longer half-life than Ligand B (-13.671 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.014).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a 0.5 kcal/mol difference, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a better logP and binding affinity. However, Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a slightly lower hERG risk. The lower logP of Ligand A is a concern, but the substantial improvements in metabolic stability and half-life are critical for a kinase inhibitor. The binding affinity difference, while present, is not large enough to overcome these ADME advantages.

Output:
0
2025-04-17 12:51:53,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.443 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.52) is higher than Ligand B (56.57). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good oral absorption.

**logP:** Both ligands have acceptable logP values (0.846 and 1.957, respectively), falling within the 1-3 optimal range.

**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 (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar and good QED scores (0.781 and 0.784).

**DILI:** Ligand A has a DILI risk of 74.68%, which is concerning (high risk). Ligand B has a much lower DILI risk of 12.679% (good). This is a major advantage for Ligand B.

**BBB:** Both ligands show moderate BBB penetration (62.466% and 73.439%). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-4.852 and -4.655).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the values are similar (-2.162 and -2.624).

**hERG Inhibition:** Ligand A (0.285) has a slightly lower hERG inhibition risk than Ligand B (0.878), which is preferable.

**Microsomal Clearance:** Ligand A (36.925 mL/min/kg) has a lower microsomal clearance than Ligand B (45.176 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-32.206 hours) has a negative half-life, which is nonsensical. Ligand B (-1.273 hours) also has a negative half-life, indicating a problem with the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.098 and 0.125).

**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 ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand B is the more promising candidate. Its significantly lower DILI risk is a major advantage, and its superior binding affinity is crucial for an enzyme inhibitor. While Ligand A has slightly better metabolic stability (lower Cl_mic) and hERG risk, the DILI and affinity advantages of Ligand B are more important for this target class. The negative half-life values for both compounds are concerning and need to be investigated further, but the overall profile of Ligand B is more favorable.

Output:
1
2025-04-17 12:51:53,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.36 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is better than Ligand B (70.47). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range.

**logP:** Ligand A (3.203) is optimal (1-3). Ligand B (0.72) is low, potentially hindering permeation. This is a significant drawback for B.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both below the limit of 10.

**QED:** Both ligands have similar QED values (0.869 and 0.787), indicating good drug-likeness.

**DILI:** Ligand A (15.781) has a much lower DILI risk than Ligand B (11.206), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.957) is better than Ligand B (55.797).

**Caco-2 Permeability:** Ligand A (-4.333) is better than Ligand B (-5.066) - higher values are preferred.

**Aqueous Solubility:** Ligand A (-3.277) is better than Ligand B (-0.237) - higher values are preferred.

**hERG Inhibition:** Ligand A (0.674) has a lower hERG risk than Ligand B (0.25), which is a significant advantage.

**Microsomal Clearance:** Ligand A (9.831) has higher microsomal clearance than Ligand B (4.857), indicating lower metabolic stability. This is a negative for A.

**In vitro Half-Life:** Ligand A (-26.035) has a much longer half-life than Ligand B (4.985), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.006), which is preferable.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is substantially better. While it has slightly higher microsomal clearance, its superior binding affinity, lower DILI risk, better solubility, lower hERG risk, better Caco-2 permeability, and longer half-life outweigh this drawback. Ligand B's low logP is a major concern, potentially leading to poor absorption. The significant difference in binding affinity (-10.2 vs -8.0 kcal/mol) is also a key factor.

Output:
1
2025-04-17 12:51:53,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.419 and 342.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is higher than Ligand B (50.16). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.088) is quite low, potentially hindering membrane permeability. Ligand B (2.751) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable.

**QED:** Both ligands have similar QED values (0.782 and 0.787), indicating good drug-likeness.

**DILI:** Ligand A (44.048) has a slightly higher DILI risk than Ligand B (27.414), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (92.323) has a higher BBB percentile than Ligand A (54.595).

**Caco-2 Permeability:** Ligand A (-4.675) has poor Caco-2 permeability, while Ligand B (-4.957) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.973) has poor solubility, while Ligand B (-3.632) has even worse solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.135) has a lower hERG risk than Ligand B (0.619), which is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (7.947) has much lower microsomal clearance than Ligand B (59.365), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-0.978) has a negative half-life, which is unusual and likely indicates very rapid degradation. Ligand B (10.715) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, while Ligand B (0.303) has moderate efflux. This favors Ligand A.

**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 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 logP and TPSA values. However, it suffers from significantly higher microsomal clearance, worse solubility, and higher P-gp efflux. Ligand A has better metabolic stability (lower Cl_mic), lower P-gp efflux, and lower hERG risk, but its logP is very low and Caco-2 permeability is poor. The substantial difference in binding affinity (-8.8 vs -7.1 kcal/mol) is a critical factor. While Ligand A has better ADME properties overall, the potency advantage of Ligand B is likely to be decisive for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:51:53,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.397 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold and excellent for oral absorption. Ligand B (77.57) is still acceptable but less optimal.

**logP:** Ligand A (2.497) is within the optimal 1-3 range. Ligand B (0.96) is slightly below 1, which *could* indicate permeability issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both have reasonable H-bond characteristics, well within the guidelines.

**QED:** Both ligands have similar QED values (0.73 and 0.686), indicating good drug-likeness.

**DILI:** Ligand A (46.297) has a slightly higher DILI risk than Ligand B (37.456), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.694) has better BBB penetration than Ligand B (63.784), but this is not a primary driver in the decision.

**Caco-2 Permeability:** Ligand A (-4.469) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.091) is also negative and similarly poor. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-2.722) and Ligand B (-1.449) both have negative solubility values, indicating very poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Ligand A (0.703) and Ligand B (0.35) both have low hERG inhibition risk, which is favorable.

**Microsomal Clearance:** Ligand A (44.348) has a higher microsomal clearance than Ligand B (-21.484). The negative value for Ligand B suggests *very* high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (37.967) and Ligand B (31.479) have similar in vitro half-lives.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.26 and 0.006), which is good.

**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 has a much better binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability and solubility, and higher metabolic clearance. Ligand B has better solubility and metabolic stability, but its binding affinity is considerably weaker. Given the strong affinity of Ligand A, and the fact that solubility/permeability can sometimes be improved through formulation or prodrug strategies, I would prioritize Ligand A. The difference in binding affinity is significant enough to warrant further investigation despite the ADME liabilities.

Output:
1
2025-04-17 12:51:53,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.461 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.54) is slightly higher than Ligand B (76.66). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.001 and 1.497), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.615 and 0.678), indicating good drug-likeness.

**DILI:** Ligand B (30.865) has a significantly lower DILI risk than Ligand A (46.336). This is a major advantage for Ligand B.

**BBB:** Ligand B (89.957) shows better BBB penetration than Ligand A (50.795), but BBB isn't a high priority for a kinase inhibitor unless CNS activity is desired.

**Caco-2 Permeability:** Ligand A (-5.353) has worse Caco-2 permeability than Ligand B (-4.748), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.717) has worse aqueous solubility than Ligand B (-2.093). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.28 and 0.31), which is good.

**Microsomal Clearance:** Ligand B (32.765) has a much higher microsomal clearance than Ligand A (-1.74). This means Ligand A is more metabolically stable, which is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-13.041) has a much longer in vitro half-life than Ligand B (-6.013). This is another significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.014 and 0.024).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.3 kcal/mol). This 2.1 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). However, Ligand B has a significantly lower DILI risk and better solubility and Caco-2 permeability. The difference in binding affinity is substantial, and for a kinase inhibitor, potency and metabolic stability are paramount. While the lower DILI risk of Ligand B is appealing, the stronger binding and improved metabolic profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 12:51:53,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (383.319 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is slightly higher than Ligand B (53.96), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.139) is optimal, while Ligand B (1.106) is a bit low, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A (2) is good, while Ligand B (7) is acceptable, but approaching the upper limit.

**QED:** Both ligands have similar QED values (0.768 and 0.762), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (36.448 and 38.348 percentile), which is favorable.

**BBB:** Ligand A (61.962) has a lower BBB penetration than Ligand B (88.833). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.075) has poor Caco-2 permeability, while Ligand B (-4.716) is also poor.

**Aqueous Solubility:** Ligand A (-3.859) has poor aqueous solubility, while Ligand B (-1.49) is also poor.

**hERG Inhibition:** Ligand A (0.434) has a lower hERG risk than Ligand B (0.847), which is a significant advantage.

**Microsomal Clearance:** Ligand A (17.183 mL/min/kg) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (33.266 mL/min/kg).

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (20.936 and 19.131 hours).

**P-gp Efflux:** Ligand A (0.262) has lower P-gp efflux, which is favorable for bioavailability, than Ligand B (0.035).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol), with a difference of 0.8 kcal/mol. This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While both have poor Caco-2 and solubility, Ligand A's significantly stronger binding affinity (-8.3 vs -7.5 kcal/mol), lower hERG risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic) outweigh the slightly lower BBB penetration and higher TPSA. The affinity difference is particularly important.

Output:
1
2025-04-17 12:51:53,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.515 Da and 369.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (87.74). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (4.512) is higher than Ligand B (1.495). While 4.512 is approaching the upper limit, it's still acceptable. Ligand B's logP 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 within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.641 and 0.845), indicating drug-like properties.

**DILI:** Ligand A (87.01) has a higher DILI risk than Ligand B (65.258), which is a concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (55.099) and Ligand B (60.644) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.178) and Ligand B (-4.938) 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 (-4.336) and Ligand B (-3.176) both have negative solubility values, which is concerning. Poor solubility can hinder bioavailability.

**hERG:** Ligand A (0.832) has a slightly higher hERG risk than Ligand B (0.154). Ligand B is significantly better here.

**Microsomal Clearance:** Ligand B (-7.908) has a *much* lower (better) microsomal clearance than Ligand A (50.79). This suggests significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-22.302) has a much longer in vitro half-life than Ligand A (54.515), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.657) has lower P-gp efflux than Ligand B (0.043), which is favorable.

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is the most critical factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher hERG risk, poorer metabolic stability (higher Cl_mic, shorter t1/2), and lower P-gp efflux. Ligand B has a much better safety profile (lower DILI, lower hERG), excellent metabolic stability, and better solubility. The lower binding affinity of Ligand B is a concern, but the substantial difference in metabolic stability and safety profile makes it a more promising starting point for optimization. The strong binding of Ligand A could be offset by rapid metabolism and potential toxicity.

Output:
1
2025-04-17 12:51:53,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.459 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.65) is better than Ligand B (75.71). Both are below 140, supporting good oral absorption.

**logP:** Both ligands have acceptable logP values (1.504 and 0.959), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.846 and 0.754), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (31.912 and 35.479), both below the 40 threshold.

**BBB:** Ligand A (55.603) has a lower BBB penetration percentile than Ligand B (76.309). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.578) is significantly worse than Ligand B (-5.098), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.066 and -2.399). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.278 and 0.311).

**Microsomal Clearance:** Ligand A (9.6 mL/min/kg) has significantly lower microsomal clearance than Ligand B (37.623 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-17.794 hours) has a much longer in vitro half-life than Ligand B (16.787 hours), further supporting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.154).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -9.4 kcal/mol). Ligand B is slightly better (-9.4 vs -8.8), but the difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A's significantly better metabolic stability (lower Cl_mic and longer t1/2) is crucial for an enzyme target like SRC kinase. The solubility is a concern for both, but formulation strategies can be employed. The lower TPSA of ligand A is also a slight advantage.

Output:
0
2025-04-17 12:51:53,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.507 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.54) is better than Ligand B (95.33), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (0.955 and 1.682), 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 (0.755 and 0.913), indicating drug-likeness.

**DILI:** Ligand A (35.052) has a significantly lower DILI risk than Ligand B (66.964). This is a major advantage for Ligand A.

**BBB:** Ligand A (75.107) has better BBB penetration than Ligand B (38.077), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.927) has slightly better Caco-2 permeability than Ligand B (-4.732).

**Aqueous Solubility:** Ligand A (-1.686) has better aqueous solubility than Ligand B (-2.491).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.319 and 0.154).

**Microsomal Clearance:** Ligand A (19.037) has significantly lower microsomal clearance than Ligand B (51.093), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-55.624) has a longer in vitro half-life than Ligand B (-39.416).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.02).

**Binding Affinity:** Both ligands have similar binding affinities (-9.3 and -8.5 kcal/mol), both are very good. The difference of 0.8 kcal/mol is not enough to outweigh the ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the better candidate. It demonstrates superior predicted ADME properties, specifically lower DILI risk, lower microsomal clearance, longer half-life, and better solubility, while maintaining comparable binding affinity to Ligand B. These factors are crucial for an enzyme target like SRC kinase, where metabolic stability and bioavailability are paramount.

Output:
0
2025-04-17 12:51:53,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (352.475 and 372.893 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.66) is slightly higher than Ligand B (78.87), but both are below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.674 and 2.379), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. 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 similar QED values (0.58 and 0.506), indicating good drug-likeness.

**7. DILI:** Ligand A (19.969) has a significantly lower DILI risk than Ligand B (33.424). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration (60.605 and 67.817). Since this is an oncology target, BBB penetration is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.048 and -5.058). This 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 (-1.644 and -2.457), indicating poor aqueous solubility. Again, similar for both.

**11. hERG Inhibition:** Ligand A (0.118) has a lower hERG inhibition liability than Ligand B (0.402), which is favorable.

**12. Microsomal Clearance:** Ligand A (20.566) has a higher microsomal clearance than Ligand B (6.816), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (1.585) has a slightly longer in vitro half-life than Ligand A (-2.978), which is preferable.

**14. P-gp Efflux:** Ligand A (0.042) has significantly lower P-gp efflux liability than Ligand B (0.125), which is a positive.

**15. Binding Affinity:** Ligand B (-9.0) has a stronger binding affinity than Ligand A (-7.9). 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 (-9.0 kcal/mol vs -7.9 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a much lower DILI risk and lower hERG liability, and lower P-gp efflux. Considering this is a kinase target in oncology, potency (binding affinity) and metabolic stability are paramount. The 1.1 kcal/mol difference in binding affinity is significant. While Ligand A has better safety profiles, the improved potency of Ligand B is likely to be more critical for efficacy.

Output:
1
2025-04-17 12:51:53,840 - INFO - Batch 165 complete. Total preferences: 2640
2025-04-17 12:51:53,841 - INFO - Processing batch 166/512...
2025-04-17 12:52:33,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.392 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is significantly better than Ligand B (83.98). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (2.63 and 1.988), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 H-bond donors and 4 acceptors, which are acceptable.

**QED:** Both ligands have good QED scores (0.775 and 0.857), indicating good drug-likeness.

**DILI:** Ligand A (20.822) has a much lower DILI risk than Ligand B (47.77), which is a significant advantage. Lower DILI is crucial.

**BBB:** BBB is less important for a non-CNS target like SRC. Ligand A (82.513) is better than Ligand B (54.246).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.505) is slightly better than Ligand B (-5.012).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.669) is slightly better than Ligand B (-2.975).

**hERG:** Both ligands have very low hERG inhibition liability (0.613 and 0.178), which is excellent.

**Microsomal Clearance:** Ligand B (16.356) has a lower microsomal clearance than Ligand A (25.775), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-1.639) has a slightly longer in vitro half-life than Ligand A (-19.234), which is also beneficial.

**P-gp Efflux:** Both have low P-gp efflux liability (0.109 and 0.067).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and meets the > -7.0 kcal/mol threshold.

**Conclusion:**

While both ligands have excellent binding affinity and acceptable physicochemical properties, Ligand A is preferable due to its significantly lower DILI risk and better TPSA. Ligand B has better metabolic stability and half-life, but the DILI risk associated with Ligand B is a major concern. Given the enzyme-specific priorities, the lower DILI risk of Ligand A outweighs the slightly better metabolic stability of Ligand B.

Output:
0
2025-04-17 12:52:33,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.01) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (88.16) is well within the acceptable range.

**logP:** Both ligands (1.802 and 2.067) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being <=5.

**H-Bond Acceptors:** Both ligands (4) are well below the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.593 and 0.776), indicating drug-like properties.

**DILI:** Both ligands have elevated DILI risk (56.689 and 59.519), but are still below the high-risk threshold of 60.

**BBB:** Both ligands have low BBB penetration (38.581 and 59.364). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.956 and -4.97), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.862 and -3.131), which is also concerning and suggests very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.674) has a slightly higher hERG risk than Ligand B (0.154). This is a point in favor of Ligand B.

**Microsomal Clearance:** Ligand A (56.434) has higher microsomal clearance than Ligand B (45.235), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-48.83) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the compound itself. Ligand A (13.154) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.148 and 0.071).

**Binding Affinity:** Ligand B (-8.1 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:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic). While both have concerning permeability and solubility issues, the negative half-life for Ligand B is a major red flag. Ligand A, despite its slightly higher hERG risk and lower metabolic stability, has a plausible half-life. The substantial affinity difference (-0.4 kcal/mol) is significant for an enzyme target. However, the poor solubility and permeability of both compounds are major drawbacks.

Output:
1
2025-04-17 12:52:33,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.288 Da) is slightly higher than Ligand B (359.352 Da), but both are acceptable.

**TPSA:** Ligand A (47.56) is well below the 140 threshold for oral absorption. Ligand B (71.33) is still within acceptable limits, but higher.

**logP:** Ligand A (3.587) is optimal. Ligand B (1.108) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, well within the guidelines. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.687, B: 0.811), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 58.511, B: 50.911), below the 60 threshold.

**BBB:** Ligand A (43.893) has a lower BBB penetration percentile than Ligand B (85.925). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.756 and -4.568), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.079 and -2.064), also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.791) has a slightly higher hERG risk than Ligand B (0.232), but both are relatively low.

**Microsomal Clearance:** Ligand A (45.971) has a higher microsomal clearance than Ligand B (16.648). This suggests Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-21.351) has a negative half-life, which is impossible and indicates a significant issue with the data or the compound's stability. Ligand A (33.635) is reasonable.

**P-gp Efflux:** Ligand A (0.472) has lower P-gp efflux than Ligand B (0.076), which is favorable.

**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.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility values for both compounds, Ligand B stands out due to its significantly higher binding affinity (-7.8 kcal/mol vs -6.6 kcal/mol) and better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is a major red flag and suggests a data error or inherent instability. However, assuming this is an error, the superior affinity makes it the more promising candidate. The slightly lower logP of Ligand B is a minor concern compared to the substantial affinity difference.

Output:
1
2025-04-17 12:52:33,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (386.5 and 340.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (87.14) is excellent, well below 140.

**logP:** Ligand A (0.453) is a bit low, potentially hindering permeation. Ligand B (2.351) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 3 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.695 and 0.722), indicating drug-like properties.

**DILI:** Ligand A (49.632) has a slightly better DILI score than Ligand B (54.207), but both are reasonably low risk.

**BBB:** Both have moderate BBB penetration (65.452 and 61.923), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.618) and Ligand B (-4.824) both have negative Caco-2 values. This is unusual and suggests very poor permeability. The scale is not specified, so it's hard to interpret.

**Solubility:** Both have negative solubility values (-2.182 and -3.034). Again, the scale is not specified, but negative values suggest poor aqueous solubility, a significant drawback.

**hERG:** Ligand A (0.122) has a much lower hERG risk than Ligand B (0.566), which is a major advantage.

**Microsomal Clearance:** Ligand A (-26.99) has a significantly *lower* (better) microsomal clearance than Ligand B (3.417), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (17.387) has a longer half-life than Ligand B (14.551), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.025 and 0.044).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage (1.9 kcal/mol difference).

**Overall Assessment:**

Ligand B has a superior binding affinity, a better logP, and a lower TPSA. However, Ligand A has a significantly better metabolic profile (lower Cl_mic, longer half-life), lower hERG risk, and slightly better DILI. Both have poor Caco-2 and solubility. The affinity difference is substantial, and for an enzyme target, potency is paramount. While the ADME properties of Ligand A are better, the difference in potency is likely to outweigh those advantages, *assuming* the solubility and permeability issues can be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 12:52:33,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.5 and 363.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is significantly better than Ligand B (105.9), being well below the 140 threshold for good absorption. Ligand B is higher, potentially impacting absorption.

**logP:** Ligand A (3.582) is optimal, while Ligand B (0.558) is quite low. Low logP can hinder membrane permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 8. Ligand B is higher, potentially impacting permeability.

**QED:** Both ligands have similar, good QED values (0.892 and 0.851).

**DILI:** Ligand A (11.2) has a much lower DILI risk than Ligand B (66.3), indicating a safer profile.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.0) is higher than Ligand B (46.5).

**Caco-2:** Ligand A (-4.577) is better than Ligand B (-5.581), indicating better intestinal absorption.

**Solubility:** Ligand A (-2.558) is better than Ligand B (-2.037), indicating better aqueous solubility.

**hERG:** Both ligands have low hERG risk (0.77 and 0.095).

**Microsomal Clearance:** Ligand A (-2.225) has significantly lower (better) microsomal clearance than Ligand B (14.462), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (38.77) has a much longer half-life than Ligand B (0.543), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.102 and 0.042).

**Binding Affinity:** Ligand B (-8.6) has a significantly stronger binding affinity than Ligand A (-0.0). This is a crucial factor. A difference of >1.5 kcal/mol can outweigh other issues.

**Overall Assessment:**

Ligand B has a substantially better binding affinity. However, it suffers from a high TPSA, low logP, high DILI risk, and poor metabolic stability (high Cl_mic, low t1/2). Ligand A, while having a weak binding affinity, exhibits a much more favorable ADME-Tox profile: better TPSA, logP, DILI, solubility, metabolic stability, and half-life.

Given the enzyme-specific priorities, metabolic stability and a reasonable ADME profile are crucial. While the affinity difference is significant, the poor ADME properties of Ligand B are likely to lead to rapid clearance and potential toxicity issues *in vivo*. It's possible to optimize Ligand A's affinity through further medicinal chemistry efforts, while the ADME profile provides a solid starting point.

Output:
0
2025-04-17 12:52:33,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.511 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.54) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (75.27) is well within the range.

**logP:** Both ligands have good logP values (1.589 and 2.573), falling 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 4 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Ligand B (0.845) has a significantly better QED score than Ligand A (0.519), suggesting a more drug-like profile.

**DILI:** Ligand B (38.852) has a lower DILI risk than Ligand A (18.108), which is preferable.

**BBB:** Ligand A (73.827) has a better BBB penetration score than Ligand B (57.154), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.892) has a worse Caco-2 permeability than Ligand B (-5.228). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.103 and -2.32). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.634) has a slightly better hERG profile than Ligand B (0.099), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (23.331 mL/min/kg) has significantly lower microsomal clearance than Ligand A (35.123 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.937 hours) has a much longer in vitro half-life than Ligand A (0.024 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.013) has lower P-gp efflux than Ligand B (0.211), which is preferable.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has a slightly better BBB score and P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.8 vs -8.6 kcal/mol), better QED, lower DILI risk, and *much* improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly poorer BBB and P-gp scores. Solubility is a concern for both, but can be addressed through formulation. As SRC is a kinase (enzyme), potency and metabolic stability are the highest priorities.

Output:
1
2025-04-17 12:52:33,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.443 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.82) is significantly better than Ligand B (96.89). TPSA < 140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Ligand A (1.766) is optimal (1-3), while Ligand B (0.598) is slightly below the optimal range, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) 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 (0.732 and 0.621), indicating good drug-likeness.

**DILI:** Both ligands have very similar and acceptable DILI risk (27.995 and 27.181, both <40).

**BBB:** Ligand A (59.364) is better than Ligand B (41.838), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.067 and -5.119), which is unusual and suggests poor permeability. However, these values are on a log scale, so small differences can be significant. They are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.04 and -2.139), indicating poor aqueous solubility. This is a concern and needs to be addressed in further optimization. They are very similar.

**hERG Inhibition:** Ligand A (0.801) is slightly better than Ligand B (0.272), indicating a lower risk of cardiotoxicity. Lower is better.

**Microsomal Clearance:** Ligand A (24.232) has a lower microsomal clearance than Ligand B (31.882), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-3.192) has a significantly longer in vitro half-life than Ligand B (10.369). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux liability than Ligand B (0.035), suggesting better oral bioavailability. Lower is better.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a stronger binding affinity than Ligand B (-8.6 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. While both have issues with solubility and Caco-2 permeability, Ligand A demonstrates a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly better hERG profile. The improved affinity is a critical factor for an enzyme inhibitor, and the better pharmacokinetic properties further support its selection.

Output:
1
2025-04-17 12:52:33,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.419 and 341.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.53) is slightly above the preferred <140, while Ligand B (92.93) is well within.

**logP:** Ligand A (-0.236) is a bit low, potentially hindering permeability. Ligand B (3.155) is optimal.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

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

**QED:** Both ligands (0.794 and 0.686) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (28.422) has a significantly lower DILI risk than Ligand B (53.083), which is a major advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (90.151) has a higher BBB value than Ligand A (62.97), but this is less important here.

**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 unspecified.

**hERG:** Ligand A (0.135) has a much lower hERG risk than Ligand B (0.796), a crucial factor for kinase inhibitors.

**Microsomal Clearance:** Ligand A (-9.082) has a *negative* clearance, which is impossible. This is likely an error in the data. Ligand B (92.178) has a high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (-1.738) has a negative half-life, which is impossible. This is also likely a data error. Ligand B (22.55) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.011 and 0.169).

**Binding Affinity:** Both ligands have similar strong binding affinities (-8.3 and -8.5 kcal/mol).

**Conclusion:**

Despite the issues with negative values for clearance and half-life for Ligand A, the significantly lower DILI and hERG risk, combined with a comparable binding affinity, make Ligand A the more promising candidate. The negative values are likely data errors and would need to be investigated. Ligand B's high DILI, hERG risk, and high microsomal clearance are significant drawbacks. The slightly better logP and TPSA of Ligand B are outweighed by these ADME-Tox concerns.

Output:
0
2025-04-17 12:52:33,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (80.56), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.905) is within the optimal 1-3 range, while Ligand B (0.082) is slightly below 1. This could potentially hinder permeation for Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both under the 10 threshold.

**QED:** Both ligands have good QED scores (0.67 and 0.758), indicating good drug-like properties.

**DILI:** Ligand A (8.957) has a significantly lower DILI risk than Ligand B (50.33). This is a major advantage for Ligand A.

**BBB:** Ligand A (36.409) and Ligand B (65.995). BBB is not a high priority for a kinase inhibitor, but ligand B is better.

**Caco-2 Permeability:** Ligand A (-4.847) and Ligand B (-4.619) are similar.

**Aqueous Solubility:** Ligand A (-1.019) and Ligand B (-1.26) are similar.

**hERG Inhibition:** Ligand A (0.141) has a lower hERG inhibition liability than Ligand B (0.187), which is favorable.

**Microsomal Clearance:** Ligand A (18.077) has a lower microsomal clearance than Ligand B (26.296), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.612) has a shorter half-life than Ligand B (8.246), but both are reasonable.

**P-gp Efflux:** Ligand A (0.028) has lower P-gp efflux liability than Ligand B (0.104), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.9 kcal/mol). Ligand B is slightly better, but the difference is not huge.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has slightly better binding affinity and BBB penetration, Ligand A demonstrates significantly better safety (much lower DILI risk), metabolic stability (lower Cl_mic), and P-gp efflux liability, and a lower hERG risk. These factors are crucial for kinase inhibitors. The slightly lower logP of Ligand B is also a concern.



Output:
0
2025-04-17 12:52:33,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.4 and 386.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (86.95 and 79.31) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.245) is within the optimal 1-3 range. Ligand B (-0.273) is slightly below 1, which *could* indicate potential permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, well within acceptable limits.

**QED:** Both ligands have good QED scores (0.806 and 0.701), indicating drug-like properties.

**DILI:** Ligand A (19.7%) has a significantly lower DILI risk than Ligand B (39.9%). This is a substantial advantage.

**BBB:** Both have reasonable BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**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 can be misleading. We'll need to consider other factors.

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

**hERG Inhibition:** Ligand A (0.556) has a slightly higher hERG risk than Ligand B (0.228), but both are relatively low.

**Microsomal Clearance:** Ligand A (19.552) has a higher microsomal clearance than Ligand B (13.664), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-7.284) has a significantly longer in vitro half-life than Ligand A (6.215). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 1.5 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer half-life) and a lower hERG risk. The solubility and permeability issues are concerning for both, but the potency advantage of Ligand A is substantial. Considering SRC is a kinase, metabolic stability is crucial for maintaining therapeutic concentrations. The longer half-life of Ligand B is a significant benefit. While the affinity difference is good for Ligand A, the ADME profile of Ligand B is more favorable overall.

Output:
1
2025-04-17 12:52:33,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.37 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (365.352 Da) is still well within the acceptable range.

**TPSA:** Ligand A (67.01) is significantly better than Ligand B (102.66). A TPSA below 140 is good for oral absorption, and both meet this, but Ligand A is closer to the ideal for better absorption.

**logP:** Ligand A (3.428) is optimal, while Ligand B (0.585) is quite low. Low logP can hinder membrane permeability. 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 (5 vs 3), which isn't a major concern but slightly less favorable.

**QED:** Both ligands have good QED scores (A: 0.534, B: 0.655), indicating drug-like properties.

**DILI:** Ligand A (86.933) has a higher DILI risk than Ligand B (25.048). This is a significant concern for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (71.772) has a slightly better BBB score than Ligand B (61.535).

**Caco-2 Permeability:** Ligand A (-5.144) has a negative Caco-2 value, which is concerning, suggesting poor permeability. Ligand B (-4.801) is also negative, but less so.

**Aqueous Solubility:** Both have negative solubility values, which is not ideal. Ligand A (-4.466) is slightly better than Ligand B (-1.856).

**hERG Inhibition:** Ligand A (0.884) has a slightly higher hERG risk than Ligand B (0.427), but both are relatively low.

**Microsomal Clearance:** Ligand B (-6.778) has a *negative* microsomal clearance, which is highly unusual and suggests very high metabolic stability. Ligand A (33.859) has a moderate clearance. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (9.8) has a significantly longer half-life than Ligand A (-6.446). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.503, B: 0.021), which is good.

**Binding Affinity:** Both have similar, strong binding affinities (A: 0.0, B: -6.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better logP and slightly better BBB penetration, it suffers from a high DILI risk, poor Caco-2 permeability, and a shorter half-life. Ligand B's exceptionally low (negative) microsomal clearance and long half-life are major advantages for an enzyme inhibitor, indicating high metabolic stability. The lower DILI risk is also a significant plus. The lower logP is a concern, but the strong binding affinity and metabolic stability likely outweigh this drawback.

Output:
1
2025-04-17 12:52:33,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 358.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.13) is significantly better than Ligand B (96.89). A TPSA under 140 is good for oral absorption, and both meet this, but A is preferable.

**logP:** Ligand A (2.554) is optimal, while Ligand B (0.99) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.893) has a much better QED score than Ligand B (0.601), indicating a more drug-like profile.

**DILI:** Ligand A (19.659) has a significantly lower DILI risk than Ligand B (11.4). Both are below 40, which is good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.94) is higher than Ligand B (38.813).

**Caco-2 Permeability:** Ligand A (-4.776) is better than Ligand B (-5.138), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.121) is better than Ligand B (-1.231).

**hERG:** Ligand A (0.718) has a lower hERG risk than Ligand B (0.177), which is a significant advantage.

**Microsomal Clearance:** Ligand A (50.555) has a higher (worse) microsomal clearance than Ligand B (19.509), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (23.523) has a longer half-life than Ligand B (17.203), which is a positive.

**P-gp Efflux:** Ligand A (0.705) has a lower P-gp efflux liability than Ligand B (0.017), which is preferable.

**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 threshold.

**Overall Assessment:**

Ligand A has a more favorable overall ADME profile (better solubility, lower hERG, lower DILI, better QED, better P-gp efflux) and a longer half-life. However, Ligand B's significantly stronger binding affinity (-8.4 vs -6.9 kcal/mol) is a major advantage that likely outweighs the ADME drawbacks. The difference in binding affinity is substantial enough to overcome the slightly worse ADME properties of Ligand B.

Output:
1
2025-04-17 12:52:33,289 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 347.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (120.52) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (100.55) is excellent, well below 140.

**logP:** Ligand A (0.428) is quite low, potentially hindering permeability. Ligand B (0.797) 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 4 HBD and 5 HBA, acceptable. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.36) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.604) is above 0.5, suggesting better drug-likeness.

**DILI:** Ligand A (49.283) is better than Ligand B (41.915) in terms of DILI risk, but both are within an acceptable range (<60).

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (43.505) is slightly better than Ligand A (22.063).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.193 and -4.901), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.105 and -2.111), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG risk (0.113 and 0.047), which is excellent.

**Microsomal Clearance:** Ligand A (46.265) has a higher clearance than Ligand B (3.904), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-32.27) has a longer in vitro half-life than Ligand A (-37.479), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.07 and 0.046), which is good.

**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, potentially outweighing some of the ADME concerns.

**Conclusion:**

Despite the poor permeability and solubility predictions (negative Caco-2 and solubility values), Ligand A's *much* stronger binding affinity (-8.3 kcal/mol vs -6.8 kcal/mol) is a critical factor for an enzyme inhibitor. The difference of 1.5 kcal/mol is significant. While Ligand B has better QED and metabolic stability, the potency advantage of Ligand A is likely to be more impactful in driving efficacy. The poor ADME properties of Ligand A would need to be addressed through further optimization, but the initial potency makes it the more promising starting point.

Output:
0
2025-04-17 12:52:33,289 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.423 and 357.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is slightly higher than Ligand B (47.36). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Ligand A (4.049) is a bit high, potentially leading to solubility issues. Ligand B (2.633) is within the optimal 1-3 range.

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

**QED:** Ligand A (0.827) 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 (84.025). This is a significant advantage for Ligand B.

**BBB:** Ligand A (71.462) has a reasonable BBB penetration, while Ligand B (96.161) is excellent. However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.624 and -4.289), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.23 and -3.033), indicating poor aqueous solubility. Ligand B is slightly better.

**hERG:** Ligand A (0.724) has a slightly higher hERG risk than Ligand B (0.664), but both are reasonably low.

**Microsomal Clearance:** Ligand A (55.008) has lower microsomal clearance than Ligand B (67.614), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (35.151) has a positive half-life, while Ligand B (-14.677) has a negative half-life, indicating very rapid degradation. This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.23 and 0.432).

**Binding Affinity:** Both ligands have very strong binding affinities (-9.1 and -8.1 kcal/mol). Ligand A is slightly more potent. The difference of 1 kcal/mol is significant.

**Overall Assessment:**

Ligand A has a better QED score, better metabolic stability (lower Cl_mic, positive t1/2), and slightly better binding affinity. However, Ligand B has a much lower DILI risk and better BBB penetration. Both have poor solubility and permeability. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), the superior potency and metabolic stability of Ligand A outweigh the DILI risk, especially considering the strong binding affinity. The solubility and permeability issues are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 12:52:33,289 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (408.888 Da) is still well within the acceptable range.

**TPSA:** Both ligands have TPSA values below 140 (A: 88.91, B: 84.5), suggesting good oral absorption potential.

**logP:** Ligand A (0.969) is at the lower end of the optimal range (1-3), potentially impacting permeability. Ligand B (3.22) is well within the optimal range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable and balance solubility and permeability.

**QED:** Both ligands have QED values above 0.5 (A: 0.687, B: 0.613), indicating good drug-like properties.

**DILI:** Ligand A (36.758) has a lower DILI risk than Ligand B (46.724), which is favorable. Both are below the 60 threshold.

**BBB:** Both have moderate BBB penetration, but Ligand B (68.748) is higher than Ligand A (54.595). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 relative. The absolute value of A (-5.438) is more negative than B (-5.03), indicating potentially worse permeability for A.

**Aqueous Solubility:** Ligand A (-1.587) has better solubility than Ligand B (-3.785), which is a significant advantage for bioavailability.

**hERG Inhibition:** Ligand A (0.015) has a much lower hERG inhibition risk than Ligand B (0.517). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (-4.734) has lower (better) microsomal clearance than Ligand B (50.834), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.993 hours) has a shorter half-life than Ligand B (21.165 hours), but both are reasonable.

**P-gp Efflux:** Ligand A (0.019) has lower P-gp efflux than Ligand B (0.099), which is favorable for bioavailability.

**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 notable, but not overwhelmingly large.

**Overall Assessment:**

Ligand A is superior due to its significantly lower hERG risk, better solubility, lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. While Ligand B has slightly better binding affinity and BBB penetration, the ADME/Tox profile of Ligand A is substantially more favorable, particularly the low hERG risk. The slight difference in binding affinity can potentially be optimized in later stages of drug development. The Caco-2 values are concerning for both, but the other advantages of A outweigh this concern.

Output:
0
2025-04-17 12:52:33,289 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.5 and 352.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is slightly higher than Ligand B (42.43). Both are acceptable, being below 140, but B is better.

**logP:** Ligand A (3.833) is within the optimal 1-3 range, while Ligand B (4.55) is slightly above. This suggests potentially better permeability for A, but B isn't drastically outside the acceptable 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, <=10 HBA).

**QED:** Ligand A (0.769) has a significantly better QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Ligand B (85.15) has a much higher DILI risk than Ligand A (15.78). This is a significant concern for B.

**BBB:** Both have similar BBB penetration (55.29 and 59.91), which is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.528 and -4.58), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-4.415 and -5.933), indicating very poor solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.58 and 0.537).

**Microsomal Clearance:** Ligand A (101.98) has slightly higher clearance than Ligand B (100.97), meaning B is marginally more metabolically stable.

**In vitro Half-Life:** Ligand B (26.25) has a significantly longer half-life than Ligand A (-12.63). This is a substantial advantage for B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.268 and 0.508).

**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 of its ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.7 vs 0.0 kcal/mol) is a crucial advantage for an enzyme inhibitor. The longer half-life of B is also beneficial. While the DILI risk is higher for B, the substantial potency difference makes it a more worthwhile candidate for further optimization to address the DILI and solubility issues. Ligand A's poor affinity makes it less likely to succeed even with better ADME properties.

Output:
1
2025-04-17 12:52:33,289 - INFO - Batch 166 complete. Total preferences: 2656
2025-04-17 12:52:33,290 - INFO - Processing batch 167/512...
2025-04-17 12:53:14,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.5) is slightly higher than Ligand B (366.4).

**TPSA:** Ligand A (69.64) is well below the 140 threshold for oral absorption. Ligand B (117.34) is also below, but closer to the limit.

**logP:** Ligand A (1.727) is within the optimal range (1-3). Ligand B (0.461) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 7 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.555, B: 0.642), indicating drug-like properties.

**DILI:** Ligand A (34.28) has a significantly lower DILI risk than Ligand B (60.95), placing it in the good risk category while B is approaching the higher risk threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.03) has a better BBB score than Ligand B (32.92), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.917) has a worse Caco-2 permeability than Ligand B (-6.001). Lower values are less desirable.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.573 and -2.089 respectively). This could present formulation challenges.

**hERG Inhibition:** Ligand A (0.734) has a lower hERG risk than Ligand B (0.006), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-0.244) has a much *lower* (better) microsomal clearance than Ligand B (-27.598), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.997) has a better in vitro half-life than Ligand B (-0.134).

**P-gp Efflux:** Ligand A (0.266) has lower P-gp efflux than Ligand B (0.003), which is favorable.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage and can outweigh some of the ADME drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While both have solubility issues, Ligand A excels in key areas for an enzyme target: significantly better binding affinity, lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. The slightly worse Caco-2 permeability is less concerning than the substantial advantages in potency and safety.

Output:
1
2025-04-17 12:53:14,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (361.389 and 388.917 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (98.66), both are below the 140 threshold for oral absorption, but closer to the 90 threshold is preferable.

**3. logP:** Ligand B (1.475) is better than Ligand A (0.149). 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 (2) and Ligand B (4) 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 scores (0.428 and 0.568), indicating acceptable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (33.695) has a significantly better DILI score than Ligand B (41.411), indicating a lower risk of liver injury.

**8. BBB:** Ligand A (87.476) has a better BBB score than Ligand B (34.238), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.186 and -5.358), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.428 and -2.56), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.402) has a much lower hERG inhibition risk than Ligand B (0.112). This is a crucial advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (-1.101) has a lower (better) microsomal clearance than Ligand B (16.198), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.479) has a much longer in vitro half-life than Ligand B (5.261), indicating better stability.

**14. P-gp Efflux:** Ligand A (0.025) has a lower P-gp efflux than Ligand B (0.117), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (0.0) has a slightly better binding affinity than Ligand A (-9.2). However, the difference is not substantial enough to outweigh the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate despite the slightly weaker binding affinity. Its significantly better DILI score, lower hERG risk, improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux outweigh the slightly weaker binding. Both ligands have poor solubility and permeability (Caco-2), which are major concerns that would need to be addressed through formulation or further chemical modifications. However, Ligand A's superior safety profile and pharmacokinetic properties make it the better starting point for optimization.

Output:
0
2025-04-17 12:53:14,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.407 and 371.453 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.49) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (62.3) is well within the desired range.

**logP:** Both ligands have good logP values (1.852 and 2.854), 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:** Ligand B (0.885) has a significantly better QED score than Ligand A (0.443), indicating a more drug-like profile.

**DILI:** Ligand B (49.787) has a much lower DILI risk than Ligand A (87.902). This is a major advantage.

**BBB:** Ligand B (90.229) has a higher BBB penetration percentile than Ligand A (67.933). While not critical for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.823 and -4.879), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.518 and -3.612), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.238) has a slightly lower hERG inhibition risk than Ligand B (0.421), which is preferable.

**Microsomal Clearance:** Ligand B (31.992) has a significantly lower microsomal clearance than Ligand A (86.914), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-24.354) has a much longer in vitro half-life than Ligand A (-0.752). This is another significant advantage.

**P-gp Efflux:** Ligand A (0.422) has a lower P-gp efflux liability than Ligand B (0.179), which is slightly better.

**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.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A in most ADME properties (DILI, BBB, Cl_mic, t1/2, QED). While both have poor solubility and permeability, the significantly better metabolic stability and lower toxicity of Ligand B are highly desirable for an enzyme target like SRC kinase. The substantial difference in binding affinity (-9.3 vs -7.4 kcal/mol) is a major factor favoring Ligand A. However, the ADME profile of Ligand B is so much more favorable that it is likely to be more successful as a drug candidate. The poor solubility and permeability of both compounds would need to be addressed through formulation or structural modifications, but starting with a better ADME profile is advantageous.

Output:
1
2025-04-17 12:53:14,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (70.08), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.49) is optimal, while Ligand B (0.879) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have acceptable HBD counts (2 and 1 respectively), well below the 5 limit.

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

**QED:** Both ligands have similar QED values (0.794 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (26.173) has a significantly lower DILI risk than Ligand B (17.216), which is a major advantage.

**BBB:** Ligand B (90.074) has a higher BBB penetration percentile than Ligand A (70.648). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.511 and -4.506), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.923 and -0.84), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.164) has a lower hERG inhibition liability than Ligand B (0.369), which is preferable.

**Microsomal Clearance:** Ligand B (-6.141) has a *negative* microsomal clearance, which is not physically possible. This is a red flag and suggests an issue with the data or prediction method. Ligand A (70.279) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (-4.324) also has a negative half-life, which is impossible. Ligand A (-36.556) has a negative half-life as well, which is also concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.06).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol), although both are strong binders.

**Overall Assessment:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand A is the more promising candidate. Its significantly lower DILI risk, lower hERG inhibition, and slightly better binding affinity outweigh the higher BBB penetration of Ligand B. The negative values for clearance and half-life are concerning for both, but the negative values for Ligand B are more problematic. The negative clearance and half-life values suggest a data quality issue for Ligand B.

Output:
0
2025-04-17 12:53:14,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.406 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.94) is significantly better than Ligand B (113.93). A TPSA under 140 is good for oral absorption, but A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.58) is optimal, while Ligand B (0.843) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=6). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.885) has a much better drug-likeness score than Ligand B (0.643).

**DILI:** Ligand A (27.297) has a significantly lower DILI risk than Ligand B (67.158). This is a major advantage for A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (89.686) is better than Ligand B (55.603).

**Caco-2 Permeability:** Ligand A (-4.434) is better than Ligand B (-5.455), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.761) is better than Ligand B (-3.273), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.492) is much better than Ligand B (0.085), indicating a lower risk of cardiotoxicity. This is a critical advantage.

**Microsomal Clearance:** Ligand A (18.257) is worse than Ligand B (-3.057). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (41.683) is much better than Ligand B (4.139), indicating a longer half-life and potentially less frequent dosing.

**P-gp Efflux:** Ligand A (0.063) is better than Ligand B (0.073), suggesting less efflux and better bioavailability.

**Binding Affinity:** Ligand A (-8.3 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:**

Ligand A is overwhelmingly superior. While Ligand B has better metabolic stability (lower Cl_mic), the advantages of Ligand A in terms of potency (binding affinity), safety (DILI, hERG), drug-likeness (QED), solubility, and permeability far outweigh this single drawback. The strong binding affinity of Ligand A (-8.3 kcal/mol) is a decisive factor.

Output:
1
2025-04-17 12:53:14,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 357.361 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.78) is better than Ligand B (98.14), both are below the 140 threshold for oral absorption, but ligand A is closer to the 90 threshold for CNS penetration if that were a goal.

**logP:** Both ligands have near-optimal logP values (-0.14 and -0.039), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 6 HBA) as fewer HBDs generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.52 and 0.68), indicating drug-likeness.

**DILI:** Ligand A (38.116) has a significantly lower DILI risk than Ligand B (65.956). This is a major advantage.

**BBB:** Ligand B (74.564) has a better BBB penetration score than Ligand A (59.636), but BBB isn't a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-4.541) has a worse Caco-2 permeability than Ligand B (-5.434). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.681) has better aqueous solubility than Ligand B (-1.564). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.025) has a much lower hERG inhibition liability than Ligand B (0.145). This is a significant safety advantage.

**Microsomal Clearance:** Ligand A (6.737) has a better (lower) microsomal clearance than Ligand B (-14.513). Lower clearance indicates better metabolic stability.

**In vitro Half-Life:** Ligand B (6.775) has a slightly better in vitro half-life than Ligand A (-25.846).

**P-gp Efflux:** Ligand A (0.02) has a lower P-gp efflux liability than Ligand B (0.011).

**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, potentially outweighing some of the ADME drawbacks of Ligand B. The difference of 1.4 kcal/mol is meaningful.

**Conclusion:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic). The difference in binding affinity is significant, but the ADME/Tox profile of Ligand A is substantially better. Considering the enzyme-specific priorities, the improved safety and metabolic stability of Ligand A make it the more viable drug candidate, despite the slightly weaker binding.

Output:
0
2025-04-17 12:53:14,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 357.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.15) is slightly above the optimal <140, but acceptable. Ligand B (29.54) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (1.837) is within the optimal 1-3 range. Ligand B (4.503) is slightly high, potentially leading to solubility issues and off-target interactions.

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

**QED:** Both ligands have similar QED scores (0.719 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (36.293) has a low DILI risk. Ligand B (11.516) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (66.77) has moderate BBB penetration. Ligand B (96.084) has excellent BBB penetration, but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.418) has poor Caco-2 permeability. Ligand B (-4.507) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-2.014) has poor aqueous solubility. Ligand B (-4.294) has even poorer aqueous solubility.

**hERG Inhibition:** Ligand A (0.13) has very low hERG inhibition risk. Ligand B (0.892) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (13.74) has moderate microsomal clearance. Ligand B (72.939) has high microsomal clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (28.104) has a reasonable in vitro half-life. Ligand B (-2.97) has a very short half-life, a major drawback.

**P-gp Efflux:** Ligand A (0.048) has low P-gp efflux. Ligand B (0.577) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.6) has significantly stronger binding affinity than Ligand B (-7.1), a difference of 1.5 kcal/mol.

**Conclusion:**

Despite Ligand B's excellent BBB penetration and very low DILI, its significantly higher logP, poor solubility, high microsomal clearance, and very short half-life are major concerns. Ligand A, while having slightly less favorable permeability and solubility, possesses a substantially stronger binding affinity (-8.6 vs -7.1 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2). The superior binding affinity outweighs the moderate ADME drawbacks, especially for an enzyme target where potency is paramount.

Output:
0
2025-04-17 12:53:14,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.411 and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.53 and 75.27) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.524 and 2.123) are 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.

**QED:** Both ligands (0.82 and 0.774) have strong drug-like profiles, exceeding the 0.5 threshold.

**DILI:** Ligand A (61.691) has a higher DILI risk than Ligand B (37.728). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (73.905 and 68.67), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.473 and -4.924). This 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 very poor aqueous solubility (-3.022 and -3.074). This is a significant issue that would require formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.43 and 0.542), which is good.

**Microsomal Clearance:** Ligand B (20.233 mL/min/kg) has significantly lower microsomal clearance than Ligand A (60.703 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.792 hours) has a longer in vitro half-life than Ligand A (28.95 hours). Note that negative values here are unusual and likely indicate a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.134 and 0.165).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.0 kcal/mol). This 1.9 kcal/mol difference is a major advantage, easily outweighing minor ADME concerns.

**Conclusion:**

Ligand B is the superior candidate. While both have poor solubility and permeability, Ligand B demonstrates a significantly better binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2). The stronger binding affinity is a critical advantage for an enzyme inhibitor, and the lower DILI risk is a major safety benefit.

Output:
1
2025-04-17 12:53:14,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.46 and 361.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is well below the 140 threshold for good absorption, while Ligand B (91.32) is still acceptable but closer to the limit.

**logP:** Both ligands have logP values (2.54 and 2.33) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar QED scores (0.773 and 0.706), indicating good drug-likeness.

**DILI:** Ligand A (32.38) has a significantly lower DILI risk than Ligand B (52.77), which is a major advantage.

**BBB:** Ligand A (74.72) has better BBB penetration than Ligand B (26.21), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.872) shows better Caco-2 permeability than Ligand B (-5.452).

**Aqueous Solubility:** Ligand A (-3.118) has better aqueous solubility than Ligand B (-2.854).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.34 and 0.228).

**Microsomal Clearance:** Ligand A (31.55) has a slightly higher, but still acceptable, microsomal clearance than Ligand B (28.29). Lower is better, so B is slightly favored here.

**In vitro Half-Life:** Ligand B (-3.658) has a longer in vitro half-life than Ligand A (-1.39), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.048 and 0.07).

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.4), a difference of 0.6 kcal/mol. This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better ADME properties (lower DILI, better solubility, permeability, and BBB), Ligand B possesses a significantly higher binding affinity (-9.0 vs -8.4 kcal/mol). Given that we are targeting an enzyme (SRC kinase), potency is the highest priority. The 0.6 kcal/mol difference in binding affinity is substantial. The ADME properties of Ligand B are still within acceptable ranges, and the longer half-life is a bonus. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 12:53:14,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.439 Da and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.45) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (58.64) is well within the acceptable range.

**logP:** Both ligands (2.368 and 2.431) are within the optimal 1-3 range.

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

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

**QED:** Both ligands have good QED scores (0.75 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A (80.535) has a higher DILI risk than Ligand B (36.681). This is a significant concern, as a lower DILI percentile is preferred.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (75.107) has a higher BBB score than Ligand A (49.205), but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-5.697 and -4.592).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. Ligand B (-3.163) is slightly better than Ligand A (-2.51).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.123 and 0.327), which is good.

**Microsomal Clearance:** Ligand A (24.718) has lower microsomal clearance than Ligand B (27.452), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.611) has a significantly longer in vitro half-life than Ligand B (2.593), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.309 and 0.14).

**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 override other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have similar binding affinities and acceptable physicochemical properties, Ligand A's significantly longer half-life and lower DILI risk outweigh the slightly better solubility of Ligand B. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies. The lower DILI risk for Ligand A is a crucial advantage in early drug development.

Output:
0
2025-04-17 12:53:14,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.483 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.78) is well below the 140 threshold for good absorption, while Ligand B (95.67) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (2.361 and 1.643), 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 acceptable QED scores (0.888 and 0.761), indicating good drug-like properties.

**DILI:** Both ligands show low DILI risk (32.687 and 31.059 percentile), which is favorable.

**BBB:** Ligand A (74.254) has a better BBB penetration score than Ligand B (24.622), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.651) has a worse Caco-2 permeability score than Ligand B (-5.228). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.527) has a slightly better solubility score than Ligand B (-1.11), but both are negative, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.207 and 0.077), which is excellent.

**Microsomal Clearance:** Ligand A (25.325 mL/min/kg) has a higher microsomal clearance than Ligand B (8.612 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-11.417 hours) has a significantly longer in vitro half-life than Ligand A (44.642 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.158 and 0.056).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). This 1.1 kcal/mol difference is significant, and could potentially outweigh some ADME drawbacks.

**Conclusion:**

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. The solubility and permeability are poor for both, but the improved metabolic stability of Ligand B is more critical for an enzyme inhibitor. The difference in binding affinity, while notable, is unlikely to overcome the significant advantage in pharmacokinetic properties offered by Ligand B.

Output:
1
2025-04-17 12:53:14,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (387.85 Da) is still well within the range.

**TPSA:** Ligand A (101.21) is better than Ligand B (78.86) as it is still below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.75) is optimal, while Ligand B (3.462) is approaching the upper limit. Higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 7. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have acceptable QED values (A: 0.827, B: 0.709), indicating good drug-like properties.

**DILI:** Both ligands have high DILI risk (A: 85.964, B: 84.645). This is a significant concern and would require further investigation.

**BBB:** Both ligands have relatively low BBB penetration (A: 62.233, B: 76.464). Since SRC is not a CNS target, this is not a major concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.106 and -5.072). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.159 and -4.041). This is also a significant concern, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.399) has a lower hERG risk than Ligand B (0.835), which is a positive attribute.

**Microsomal Clearance:** Ligand A (2.076 mL/min/kg) has significantly lower microsomal clearance than Ligand B (8.819 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-17.79 hours) has a negative half-life, which is not possible. This indicates an issue with the data or the compound's stability. Ligand B (36.132 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.013, B: 0.306).

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.9 kcal/mol, B: -9.1 kcal/mol). The difference is minimal.

**Conclusion:**

Despite the similar binding affinities, Ligand A appears to be the more promising candidate. It has a lower logP, lower hERG risk, and significantly better metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the metabolic advantage of Ligand A is critical for an enzyme target like SRC kinase. The negative half-life for Ligand A is a red flag and needs to be investigated. However, assuming this is a data error, Ligand A is the better choice.

Output:
0
2025-04-17 12:53:14,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.463 Da) is slightly lower, which could be beneficial for permeability. Ligand B (352.483 Da) is also good.

**TPSA:** Ligand A (32.34) is excellent, well below the 140 threshold for oral absorption. Ligand B (101.41) is higher, but still potentially acceptable, though it might slightly hinder absorption.

**logP:** Both ligands have good logP values (A: 3.681, B: 2.16), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 2, B: 4) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Ligand A (0.929) has a very high QED score, indicating excellent drug-likeness. Ligand B (0.37) is significantly lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (37.456) has a low DILI risk, which is very positive. Ligand B (12.214) also shows a low DILI risk.

**BBB:** Ligand A (91.121) has a high BBB percentile, which isn't crucial for a non-CNS target like SRC, but isn't detrimental. Ligand B (51.299) is lower.

**Caco-2 Permeability:** Ligand A (-4.788) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.158) also has a negative Caco-2 value, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-4.246) and Ligand B (-0.911) both have negative solubility values, which is concerning.

**hERG Inhibition:** Ligand A (0.922) has a low hERG risk, which is excellent. Ligand B (0.287) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (45.81) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (-2.939) has negative clearance, which is not physically possible and likely indicates an issue with the data or model.

**In vitro Half-Life:** Ligand A (-7.953) has a negative half-life, which is not physically possible and suggests an issue with the data or model. Ligand B (-8.856) also has a negative half-life, which is not physically possible and suggests an issue with the data or model.

**P-gp Efflux:** Ligand A (0.686) and Ligand B (0.008) both have low P-gp efflux liability, which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.3 kcal/mol, B: -7.6 kcal/mol). Ligand A is slightly better (-8.3 vs -7.6).

**Overall Assessment:**

Ligand A is superior despite the negative Caco-2 and solubility values. Its significantly higher QED score, coupled with a slightly better binding affinity and comparable safety profiles (DILI, hERG), makes it the more promising candidate. The negative values for Caco-2, solubility, half-life and clearance for both ligands are concerning and suggest potential issues with the data or the predictive model. However, given the choice between the two, A is preferable.

Output:
0
2025-04-17 12:53:14,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.482 and 360.336 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (76.46), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.572) is slightly higher than optimal (1-3), but acceptable. Ligand B (1.531) is on the lower side, potentially impacting permeability.

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

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

**QED:** Both ligands have similar QED values (0.733 and 0.617), indicating good drug-likeness.

**DILI:** Ligand A (19.698) has a significantly lower DILI risk than Ligand B (52.423), a major advantage.

**BBB:** Both ligands have high BBB penetration (82.862 and 88.523), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.302) and Ligand B (-4.833) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.63) and Ligand B (-2.639) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.664) has a slightly higher hERG risk than Ligand B (0.164), which is a concern.

**Microsomal Clearance:** Ligand A (57.528) has a higher microsomal clearance than Ligand B (4.327), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-24.296) has a much longer in vitro half-life than Ligand A (-3.609), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.187 and 0.031).

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a significantly better 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.

**Conclusion:**

Despite Ligand A having a lower DILI risk, Ligand B is a much stronger candidate. The significantly improved binding affinity (-6.8 vs 0.0 kcal/mol) and substantially better metabolic stability (longer half-life, lower clearance) are crucial for an enzyme target like SRC kinase. While Ligand B has a slightly higher hERG risk and lower logP, the potency and metabolic stability advantages are more important.

Output:
1
2025-04-17 12:53:14,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.551 and 354.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (28.16) is excellent, well below the 140 threshold for oral absorption. Ligand B (112.24) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (4.366) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.394) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (0.747 and 0.615), indicating good drug-like properties.

**DILI:** Ligand A (6.592) has a very low DILI risk, which is excellent. Ligand B (10.702) is also relatively low, but higher than A.

**BBB:** Ligand A (76.541) shows moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (24.893) has very low BBB penetration, which is also not a concern here.

**Caco-2 Permeability:** Ligand A (-5.539) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.214) also has poor Caco-2 permeability, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.063 and -0.685). This is a major concern for both.

**hERG Inhibition:** Ligand A (0.957) has a low hERG risk, which is excellent. Ligand B (0.226) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (26.288) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (-2.071) has *negative* clearance, which is not physically possible and suggests an error in the data or a very unusual metabolic profile. This is a significant red flag.

**In vitro Half-Life:** Ligand A (9.265) has a reasonable half-life. Ligand B (5.729) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.321) has low P-gp efflux, which is favorable. Ligand B (0.033) also has very low P-gp efflux.

**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 and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B's substantially improved binding affinity (-8.0 vs -7.7 kcal/mol) and low hERG risk make it the more promising candidate. The negative microsomal clearance for Ligand B is a major concern and would need further investigation, but the potency advantage is significant. Ligand A's slightly better DILI profile and moderate clearance are not enough to overcome the weaker binding.

Output:
1
2025-04-17 12:53:14,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.39 and 362.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand B (74.33) is significantly better than Ligand A (109.78). Lower TPSA generally indicates better permeability.

**logP:** Ligand B (1.994) is within the optimal 1-3 range, while Ligand A (0.482) is below 1, potentially hindering permeation.

**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 reasonable QED scores (0.442 and 0.52), indicating acceptable drug-likeness.

**DILI:** Both ligands have low DILI risk (37.22 and 31.56), which is good.

**BBB:** Ligand B (40.68) has a higher BBB percentile than Ligand A (23.15), but BBB is less critical for a non-CNS target like SRC.

**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 (0.046) has a slightly lower hERG risk than Ligand B (0.149), which is preferable.

**Microsomal Clearance:** Ligand B (8.619) has a significantly higher microsomal clearance than Ligand A (2.89). This suggests lower metabolic stability for Ligand B, a critical drawback for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (17.79) has a longer half-life than Ligand A (-15.599). The negative value for Ligand A is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a significant advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is paramount for an enzyme inhibitor. While it has higher microsomal clearance, the significantly improved potency is likely to be more impactful. The lower TPSA and more favorable logP of Ligand B also contribute to its potential. The negative solubility and Caco-2 values are concerning for both, but the potency advantage of Ligand B is substantial.

Output:
1
2025-04-17 12:53:14,150 - INFO - Batch 167 complete. Total preferences: 2672
2025-04-17 12:53:14,150 - INFO - Processing batch 168/512...
2025-04-17 12:53:58,755 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.539 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is well below the 140 threshold, suggesting good absorption. Ligand B (82.61) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (4.021) is at the higher end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (0.651) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly less optimal.

**QED:** Both ligands have good QED scores (0.686 and 0.837), indicating drug-like properties.

**DILI:** Ligand A (32.338) has a lower DILI risk than Ligand B (47.732), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.772) has a better BBB score than Ligand B (58.938).

**Caco-2 Permeability:** Ligand A (-4.664) and Ligand B (-5.06) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-5.298) and Ligand B (-1.737) both have negative values, indicating poor solubility. Ligand B is slightly better than A.

**hERG Inhibition:** Ligand A (0.791) has a lower hERG risk than Ligand B (0.154), which is a significant advantage.

**Microsomal Clearance:** Ligand A (79.575) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (-3.688) has a negative clearance, which is excellent and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-27.49) has a negative half-life, which is unusual and suggests very rapid metabolism. Ligand B (-0.329) has a slightly better, but still very short, half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.495 and 0.039), which is good.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, and significantly better metabolic stability (lower Cl_mic and better half-life). While its logP and solubility are less ideal than Ligand A, the strong binding affinity is crucial for an enzyme inhibitor. Ligand A has a better hERG profile, but the superior potency of Ligand B is more important in this context. The poor Caco-2 and solubility of both are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 12:53:58,755 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (350.463 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.25) is better than Ligand B (93.43). Both are below the 140 A^2 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Both ligands have good logP values (2.285 and 1.893), 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 4. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.634 and 0.688), indicating drug-like properties.

**7. DILI:** Ligand A (52.966) has a slightly higher DILI risk than Ligand B (8.375). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration (68.399 and 70.143), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.075 and -4.914). This is unusual and suggests poor permeability. However, kinases are often systemically administered, so this is less critical than for oral drugs.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.963 and -2.225). This is a concern, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.34 and 0.284), which is excellent.

**12. Microsomal Clearance:** Ligand B (-10.182) has significantly lower (better) microsomal clearance than Ligand A (32.365). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-14.6) has a much longer in vitro half-life than Ligand A (6.155). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.065 and 0.02).

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.4). However, the difference is only 0.3 kcal/mol, which may not be enough to overcome other ADME deficiencies.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates significantly better ADME properties, particularly in terms of DILI risk, microsomal clearance, and in vitro half-life. These factors are crucial for kinase inhibitors, as metabolic stability and minimizing toxicity are paramount. The solubility issues for both are a concern, but potentially addressable. The slightly better affinity of Ligand A is unlikely to outweigh the superior ADME profile of Ligand B.

Output:
1
2025-04-17 12:53:58,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.479 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.65) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (94.48) is still within acceptable limits for oral absorption (<140), but less optimal.

**logP:** Ligand A (3.565) is within the optimal 1-3 range. Ligand B (0.218) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, both within acceptable limits. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.574 and 0.735), indicating drug-like properties.

**DILI:** Ligand A (49.399) has a lower DILI risk than Ligand B (57.464), both are acceptable but A is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (51.725) has a higher BBB score than Ligand A (29.12), but this is not a major factor in this case.

**Caco-2 Permeability:** Ligand A (-4.792) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-5.113) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.533) has poor aqueous solubility. Ligand B (-1.879) has better solubility.

**hERG Inhibition:** Ligand A (0.541) has a low hERG risk, which is excellent. Ligand B (0.06) also has a very low hERG risk, equally good.

**Microsomal Clearance:** Ligand A (96.574) has high microsomal clearance, suggesting poor metabolic stability. Ligand B (21.74) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.382 hours) has a short half-life. Ligand B (12.52 hours) has a significantly longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.65) has moderate P-gp efflux. Ligand B (0.068) has very low P-gp efflux, which is preferable.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk, but suffers from poor Caco-2 permeability, poor solubility, high metabolic clearance, short half-life, and moderate P-gp efflux. Ligand B, while having slightly weaker affinity, exhibits significantly better ADME properties: better solubility, much better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux.

Given the enzyme-specific priorities, metabolic stability and solubility are crucial. The superior ADME profile of Ligand B outweighs the slightly weaker binding affinity.



Output:
1
2025-04-17 12:53:58,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.873 Da) and Ligand B (344.411 Da) are both acceptable.

**TPSA:** Ligand A (62.3) is excellent, well below the 140 threshold for oral absorption. Ligand B (76.66) is still reasonable, but less optimal.

**logP:** Ligand A (3.633) is at the higher end of the optimal range (1-3), potentially raising concerns about off-target effects. Ligand B (0.843) is quite low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 4 HBA) is also good, within acceptable limits.

**QED:** Both ligands have acceptable QED scores (Ligand A: 0.814, Ligand B: 0.568), indicating reasonable drug-likeness.

**DILI:** Both ligands have low DILI risk (Ligand A: 48.623, Ligand B: 43.622), which is positive.

**BBB:** Ligand A (80.031) shows better BBB penetration potential than Ligand B (57.619), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.994 and -4.8), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.15 and -2.514), which is also unusual and suggests very poor solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.59) has a slightly higher risk of hERG inhibition than Ligand B (0.301), but both are relatively low.

**Microsomal Clearance:** Ligand A (43.409 mL/min/kg) has higher clearance than Ligand B (15.307 mL/min/kg), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-0.037 hours) has a very short half-life, which is a major concern. Ligand A (35.767 hours) has a much more reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.126, Ligand B: 0.119).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a reasonable half-life, but suffers from higher clearance and a potentially problematic logP. Ligand B has better TPSA, lower logP, and lower clearance, but has a very poor half-life and weaker binding affinity. The poor solubility and permeability for both are concerning, but the significantly better binding affinity of Ligand A makes it the more promising candidate, assuming solubility/permeability can be addressed through formulation or structural modification. The difference in binding affinity is substantial enough to prioritize Ligand A despite its other issues.

Output:
1
2025-04-17 12:53:58,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.801 and 359.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.91) is better than Ligand B (91.32). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral absorption.

**logP:** Both ligands (2.699 and 2.11) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Both are within the acceptable range of <=10.

**QED:** Ligand A (0.811) is significantly better than Ligand B (0.66), indicating a more drug-like profile.

**DILI:** Ligand A (81.311) has a higher DILI risk than Ligand B (55.797). This is a concern for Ligand A.

**BBB:** Ligand A (55.448) is better than Ligand B (33.501). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.696) is better than Ligand B (-5.495). Higher (less negative) values indicate better permeability.

**Aqueous Solubility:** Ligand A (-3.427) is better than Ligand B (-3.16). Both are quite poor, but A is slightly better.

**hERG Inhibition:** Both ligands (0.274 and 0.247) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand B (39.862) has lower microsomal clearance than Ligand A (55.36), suggesting better metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (-14.991) has a longer in vitro half-life than Ligand A (11.649). This is a major advantage for B.

**P-gp Efflux:** Both ligands (0.125 and 0.067) have low P-gp efflux liability, which is good.

**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 for A. The difference of 9.5 kcal/mol is substantial and likely outweighs many of the ADME concerns.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and slightly poorer solubility, its *significantly* superior binding affinity (-9.5 vs 0.0 kcal/mol) is the most important factor for an enzyme inhibitor. The potency advantage is so large that it likely overcomes the other drawbacks. Ligand B has better ADME properties (clearance, half-life, DILI), but the lack of binding affinity makes it a non-starter.

Output:
1
2025-04-17 12:53:58,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.81) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (58.22) is well within the acceptable range.

**logP:** Ligand A (0.422) is a bit low, potentially hindering permeation. Ligand B (3.287) is within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD and are within acceptable limits (<=5 for HBD, <=10 for HBA). Ligand B has 4 HBA, slightly better than Ligand A's 5.

**QED:** Both ligands have good QED scores (0.808 and 0.768), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (24.118 and 21.714), which is favorable.

**BBB:** Ligand A (45.522) has a lower BBB penetration percentile than Ligand B (66.731). Since SRC is not a CNS target, this is less critical, but still a slight advantage to B.

**Caco-2 Permeability:** Ligand A (-4.73) shows poor permeability. Ligand B (-5.234) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.125) shows very poor solubility, which is a significant concern. Ligand B (-3.604) also has poor solubility, but is better than A.

**hERG Inhibition:** Ligand A (0.139) has a very low hERG risk, which is excellent. Ligand B (0.639) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-11.745) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (86.83) has a high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (9.355) has a reasonable half-life. Ligand B (-13.027) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.265).

**Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (-6.8). This is a substantial advantage (1.3 kcal/mol difference).

**Overall Assessment:**

Ligand A has a superior binding affinity and excellent metabolic stability (low Cl_mic) and low hERG risk. However, its poor solubility and permeability are major concerns. Ligand B has better solubility and permeability, but suffers from poor metabolic stability (high Cl_mic) and a shorter half-life.

Given the enzyme class (kinase), potency and metabolic stability are prioritized. The 1.3 kcal/mol difference in binding affinity is substantial and could outweigh the solubility/permeability issues of Ligand A, *provided* formulation strategies can be employed to address those issues. The poor metabolic stability of Ligand B is a more difficult problem to overcome.

Output:
0
2025-04-17 12:53:58,757 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 354.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.32) is better than Ligand B (96.35), both being acceptable, but A is closer to the preferred <140 for oral absorption.

**logP:** Ligand A (2.376) is optimal (1-3), while Ligand B (-1.92) is significantly lower, potentially hindering permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**QED:** Ligand A (0.669) is better than Ligand B (0.515), indicating a more drug-like profile.

**DILI:** Ligand A (47.15) has a lower DILI risk than Ligand B (6.863), which is excellent. Both are below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (9.965) is very low, while Ligand A (36.293) is also low.

**Caco-2 Permeability:** Ligand A (-4.634) is better than Ligand B (-5.477), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.146) is better than Ligand B (-0.32), suggesting better formulation potential.

**hERG:** Ligand A (0.176) is much better than Ligand B (0.12), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (42.466) is higher than Ligand B (-8.994), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-18.415) is much worse than Ligand B (2.125), indicating a very short half-life and potential dosing issues.

**P-gp Efflux:** Ligand A (0.166) is better than Ligand B (0.002), indicating lower efflux.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand B has a superior binding affinity and significantly better metabolic stability and half-life. However, its low logP is a major concern for permeability. Ligand A has better solubility, lower DILI risk, and better Caco-2 permeability, but suffers from poor metabolic stability and a short half-life.

Given the enzyme-specific priorities, metabolic stability and half-life are crucial. While Ligand A has better solubility and lower toxicity, the poor metabolic profile is a significant hurdle. The slightly better affinity of Ligand B, coupled with its improved metabolic stability, outweighs its lower logP. Optimization of Ligand B's logP might be possible, whereas improving Ligand A's metabolic stability is generally more challenging.

Output:
1
2025-04-17 12:53:58,757 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [356.495, 48.47, 3.97, 1, 4, 0.886, 72.392, 70.57, -4.647, -4.026, 0.591, 52.681, 43.413, 0.353, -8.5]
**Ligand B:** [374.547, 83.55, 1.989, 1, 4, 0.704, 27.142, 68.941, -5.037, -2.69, 0.34, 16.49, 4.65, 0.133, -7]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (356.5) is slightly better.
2. **TPSA:** A (48.47) is excellent, well below 140. B (83.55) is still acceptable, but less ideal.
3. **logP:** A (3.97) is optimal. B (1.989) is a bit low, potentially impacting permeability.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** Both have 4 HBA, which is good.
6. **QED:** A (0.886) is very good. B (0.704) is still decent, but lower.
7. **DILI:** A (72.392) is concerning, indicating a higher risk of liver injury. B (27.142) is excellent, very low risk.
8. **BBB:** A (70.57) is good. B (68.941) is acceptable, but not as high.  BBB isn't a primary concern for a non-CNS target like SRC kinase, but it's a bonus.
9. **Caco-2:** A (-4.647) is very poor, suggesting very low intestinal absorption. B (-5.037) is also poor, but slightly better than A.
10. **Solubility:** A (-4.026) is poor. B (-2.69) is better, but still not great.
11. **hERG:** A (0.591) is acceptable. B (0.34) is even better, lower risk of cardiotoxicity.
12. **Cl_mic:** A (52.681) is moderate. B (16.49) is much better, indicating higher metabolic stability.
13. **t1/2:** A (43.413) is moderate. B (4.65) is very short, which is a significant drawback.
14. **Pgp:** A (0.353) is good, indicating low efflux. B (0.133) is even better.
15. **Binding Affinity:** A (-8.5) is significantly better than B (-7). This is a >1.5 kcal/mol advantage, which is substantial.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

Despite Ligand A's superior binding affinity, its poor Caco-2 permeability, poor solubility, and concerning DILI risk are major drawbacks. Ligand B has a significantly better safety profile (DILI, hERG) and metabolic stability (Cl_mic). While its half-life is very short, and its affinity is lower, the improved ADME properties are crucial for a viable drug candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand B. The poor permeability and solubility of A are harder to fix without drastically altering the core structure and potentially losing affinity.

Therefore, I recommend **Ligand B** as the more promising candidate.

1
2025-04-17 12:53:58,757 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (354.347 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.29) is well below the 140 threshold and even the 90 for CNS targets, suggesting good absorption. Ligand B (65.54) is still under 140, but higher than A, potentially impacting absorption slightly.

**logP:** Ligand A (4.282) is slightly above the optimal 1-3 range, potentially leading to solubility issues or off-target effects. Ligand B (2.297) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.787 and 0.834), indicating drug-like properties.

**DILI:** Ligand A (65.839) has a higher DILI risk than Ligand B (46.142), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (85.576) has better BBB penetration than Ligand B (73.401).

**Caco-2 Permeability:** Ligand A (-5.038) has a worse Caco-2 permeability than Ligand B (-4.706), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.372) has worse solubility than Ligand B (-2.596).

**hERG Inhibition:** Ligand A (0.958) has a slightly higher hERG risk than Ligand B (0.398), which is better.

**Microsomal Clearance:** Ligand A (24.311) has lower microsomal clearance than Ligand B (32.289), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (9.855) has a longer in vitro half-life than Ligand A (5.635), which is preferable.

**P-gp Efflux:** Ligand A (0.603) has lower P-gp efflux than Ligand B (0.081), which is preferable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). The difference of 0.6 kcal/mol is significant and can outweigh some of the ADME drawbacks of Ligand A.

**Overall:** Ligand B is the better candidate. While Ligand A has some advantages in BBB and P-gp efflux, Ligand B has a better logP, lower DILI risk, better solubility, longer half-life, and, crucially, significantly stronger binding affinity. The stronger binding affinity is a key factor for an enzyme target like SRC kinase, and the other advantages of Ligand B make it a more promising drug candidate.

Output:
1
2025-04-17 12:53:58,757 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.333 Da) is slightly higher than Ligand B (351.451 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is well below the 140 threshold and suitable for oral absorption. Ligand B (128.32) is also below the threshold, but closer to it.

**logP:** Ligand A (3.439) is within the optimal range (1-3). Ligand B (0.73) is a bit low, potentially impacting 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 acceptable limits.

**QED:** Both ligands have acceptable QED scores (Ligand A: 0.79, Ligand B: 0.557), indicating good drug-like properties.

**DILI:** Ligand A (46.491) has a moderate DILI risk, while Ligand B (29.081) has a low DILI risk, which is a significant advantage for B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.066) has better BBB penetration than Ligand B (68.127), but this is not a major factor here.

**Caco-2 Permeability:** Ligand A (-4.873) shows poor permeability, while Ligand B (-5.304) also shows poor permeability.

**Aqueous Solubility:** Ligand A (-3.593) has poor solubility, while Ligand B (-1.982) has slightly better solubility.

**hERG Inhibition:** Ligand A (0.514) has a slightly higher hERG risk than Ligand B (0.473), but both are relatively low.

**Microsomal Clearance:** Ligand A (9.965) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (-9.502) has a negative clearance, indicating excellent metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-2.04) has a short half-life, while Ligand B (4.523) has a longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.16, Ligand B: 0.018).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has a slightly better BBB score and QED, Ligand B's significantly stronger binding affinity (-8.2 vs 0.0 kcal/mol) and superior metabolic stability (negative Cl_mic and longer half-life) are critical advantages for an enzyme inhibitor. The lower DILI risk for Ligand B is also a positive factor. The slightly lower logP of Ligand B is a minor drawback that can potentially be addressed through further optimization.

Output:
1
2025-04-17 12:53:58,758 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.511 and 365.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption. Ligand B (109.32) is still within acceptable limits, but higher.

**logP:** Ligand A (3.545) is optimal. Ligand B (-0.171) is significantly below the ideal 1-3 range, potentially hindering permeability.

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

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is a bit higher, but still within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.645 and 0.765, respectively), indicating drug-like properties.

**DILI:** Ligand A (42.536) has a lower DILI risk than Ligand B (66.731), which is moderately elevated.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.996) is higher than Ligand B (24.932).

**Caco-2 Permeability:** Ligand A (-4.754) is poor, while Ligand B (-5.257) is also poor. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-3.708) is poor, while Ligand B (-2.432) is also poor. Both are unfavorable.

**hERG Inhibition:** Ligand A (0.86) has a lower hERG risk than Ligand B (0.377), which is concerning.

**Microsomal Clearance:** Ligand A (108.082) has higher clearance than Ligand B (-28.14), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (42.949) has a longer half-life than Ligand B (10.138).

**P-gp Efflux:** Ligand A (0.66) has lower P-gp efflux than Ligand B (0.072), which is good.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B's lower logP and higher DILI, its significantly superior binding affinity (-8.4 vs -7.7 kcal/mol) and better metabolic stability (lower Cl_mic, higher t1/2) make it the more promising candidate. The strong binding is likely to be more impactful for an enzyme target like SRC kinase. While the low logP is a concern, it might be addressed through formulation strategies. The hERG risk is also a concern for Ligand B, but is not as high as the metabolic instability of Ligand A.

Output:
1
2025-04-17 12:53:58,758 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, following the provided guidelines.

**Step-by-step comparison:**

1. **MW:** Both A (370.471 Da) and B (383.945 Da) are within the ideal range (200-500 Da).
2. **TPSA:** Ligand A (88.85) is better than Ligand B (47.36), both are well below the 140 threshold for oral absorption.
3. **logP:** Both ligands have acceptable logP values (A: 1.612, B: 3.174), falling within the 1-3 range.
4. **HBD:** Ligand A (1) is better than Ligand B (0). Both are acceptable.
5. **HBA:** Both A (5) and B (5) are within the acceptable range (<=10).
6. **QED:** Both ligands have similar QED values (A: 0.788, B: 0.757), both are above the 0.5 threshold.
7. **DILI:** Ligand A (44.048) has a slightly higher DILI risk than Ligand B (37.65), but both are below the concerning 60 threshold.
8. **BBB:** Ligand A (82.513) has a slightly higher BBB penetration than Ligand B (79.721). Not a critical factor for a non-CNS target like SRC.
9. **Caco-2:** Ligand A (-4.819) and Ligand B (-5.044) are both negative, indicating poor permeability.
10. **Solubility:** Ligand A (-3.235) and Ligand B (-3.661) are both negative, indicating poor solubility.
11. **hERG:** Both ligands have similar, low hERG inhibition liability (A: 0.548, B: 0.538).
12. **Cl_mic:** Ligand A (36.834) has a significantly lower microsomal clearance than Ligand B (62.155), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.
13. **t1/2:** Ligand A (1.291) has a shorter in vitro half-life than Ligand B (17.101). This is a significant advantage for Ligand B.
14. **Pgp:** Both ligands have similar Pgp efflux liability (A: 0.066, B: 0.484).
15. **Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). A 0.2 kcal/mol difference is not huge, but it's a positive for B.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Decision:**

Ligand B is the more promising candidate. While Ligand A has a slightly better TPSA and DILI, Ligand B possesses a significantly longer half-life, better binding affinity, and lower microsomal clearance. The improved metabolic stability and potency outweigh the minor drawbacks in TPSA and DILI. Both ligands have poor solubility and permeability, which would need to be addressed in further optimization.

Output:
1
2025-04-17 12:53:58,758 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.527 Da and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly above the preferred <60 for optimal permeability, but still reasonable. Ligand B (52.65) is excellent, well below 60.

**logP:** Both ligands have good logP values (3.374 and 2.119), 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 and <=10 HBA).

**QED:** Both ligands have similar QED values (0.814 and 0.799), indicating good drug-likeness.

**DILI:** Ligand A (47.732) has a slightly higher DILI risk than Ligand B (4.963), but both are below the concerning threshold of 60.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (74.952) is higher than Ligand B (90.19).

**Caco-2 Permeability:** Ligand A (-4.894) has poor Caco-2 permeability, while Ligand B (-4.689) is also poor.

**Aqueous Solubility:** Ligand A (-5.068) has very poor solubility, while Ligand B (-1.872) is better, though still not ideal.

**hERG Inhibition:** Ligand A (0.356) has a slightly higher hERG risk than Ligand B (0.542), but both are reasonably low.

**Microsomal Clearance:** Ligand A (73.655) has significantly higher microsomal clearance than Ligand B (41.814), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (9.873) has a longer half-life than Ligand B (3.455).

**P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux than Ligand B (0.064).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a 0.6 kcal/mol stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial difference.

**Conclusion:**

While Ligand A has a slightly longer half-life and lower P-gp efflux, Ligand B is significantly better overall. The most important factors are the much better metabolic stability (lower Cl_mic, longer half-life is a bonus), better solubility, and critically, the stronger binding affinity. The lower DILI risk is also a positive. The slightly higher BBB is irrelevant here. The poor Caco-2 permeability of both is a concern, but can be addressed with formulation strategies. The superior binding affinity of Ligand B outweighs the minor ADME drawbacks of both compounds.

Output:
1
2025-04-17 12:53:58,758 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.248 Da) is slightly higher than Ligand B (338.382 Da), but both are acceptable.

**TPSA:** Ligand A (86.88) is better than Ligand B (51.22) as it is closer to the threshold for good oral absorption.

**logP:** Both ligands have logP values (3.222 and 4.723) within the optimal range of 1-3, but Ligand B is slightly higher and could potentially lead to off-target effects or solubility issues.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.591 and 0.732), indicating good drug-like properties.

**DILI:** Both ligands have high DILI risk (98.527 and 93.292), which is a significant concern. However, this is a prediction and needs experimental validation.

**BBB:** Ligand A (34.122) has a lower BBB penetration percentile than Ligand B (62.233). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.208) has worse Caco-2 permeability than Ligand B (-4.617).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.336 and -5.685). This is a major drawback that needs to be addressed.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.367 and 0.696), which is good.

**Microsomal Clearance:** Ligand A (14.791) has significantly lower microsomal clearance than Ligand B (113.382), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (49.148) has a better in vitro half-life than Ligand B (57.293).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.231 and 0.636).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Despite both ligands having excellent binding affinity and acceptable hERG risk, Ligand A is the more promising candidate due to its significantly better metabolic stability (lower Cl_mic) and longer half-life. While both have poor solubility and high DILI risk, metabolic stability is a more critical factor for enzyme inhibitors. The slightly better TPSA and acceptable Caco-2 permeability also favor Ligand A.

Output:
0
2025-04-17 12:53:58,759 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (448.217 Da) is higher, but still acceptable. Ligand B (350.547 Da) is slightly better.

**TPSA:** Ligand A (114.46) is approaching the upper limit for good oral absorption (<=140), while Ligand B (58.2) is well within the optimal range. This favors Ligand B.

**logP:** Ligand A (1.232) is within the optimal range (1-3). Ligand B (4.04) is slightly high, potentially leading to solubility issues and off-target effects. This favors 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, and Ligand B has 2 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.5, B: 0.659), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 78.131, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 18.302, which is very favorable. This strongly favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (63.474) and Ligand B (74.758) are both reasonable.

**Caco-2 Permeability:** Ligand A (-5.098) and Ligand B (-4.589) are both negative, indicating poor permeability. This is a concern for both, but less so for Ligand B.

**Aqueous Solubility:** Ligand A (-3.625) and Ligand B (-4.802) both have poor solubility. Ligand B is slightly worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.4, B: 0.575), which is excellent.

**Microsomal Clearance:** Ligand A (46.276) has a lower clearance than Ligand B (76.63), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-24.4) has a negative half-life, which is concerning. Ligand B (9.739) has a reasonable half-life. This strongly favors Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.022, B: 0.233), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better logP and microsomal clearance, Ligand B has a significantly lower DILI risk, better TPSA, and a more reasonable in vitro half-life. The DILI risk associated with Ligand A is a major concern. The binding affinity is the same for both, so the ADME properties become the deciding factor.

Output:
1
2025-04-17 12:53:58,759 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.431 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is better than Ligand B (67.23), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.099) is slightly lower than optimal (1-3), while Ligand B (2.293) is within the ideal range. This favors Ligand B for permeability.

**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 good QED scores (A: 0.628, B: 0.861), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (21.675) has a significantly lower DILI risk than Ligand B (30.593), which is a substantial advantage.

**BBB:** Ligand A (47.615) has a lower BBB penetration than Ligand B (83.443). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.958 and -4.814), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.642 and -2.796), indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.079) has a lower hERG risk than Ligand B (0.451), which is a positive attribute.

**Microsomal Clearance:** Ligand A (35.745) has a higher microsomal clearance than Ligand B (24.523), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (20.411) has a longer half-life than Ligand B (1.906), which is a positive for dosing considerations.

**P-gp Efflux:** Ligand A (0.006) has much lower P-gp efflux liability than Ligand B (0.069), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a major advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and better logP and metabolic stability. However, Ligand A has a lower DILI risk, lower hERG risk, and lower P-gp efflux. Both have poor solubility and permeability. The substantial difference in binding affinity (-9.6 vs -8.3 kcal/mol) is a critical factor for an enzyme target like SRC kinase. While the ADME properties of Ligand B are not ideal, the increased potency is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 12:53:58,759 - INFO - Batch 168 complete. Total preferences: 2688
2025-04-17 12:53:58,759 - INFO - Processing batch 169/512...
2025-04-17 12:54:40,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.407 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (108.8 and 101.78) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (0.656) is slightly better than Ligand B (0.04), as it's closer to the optimal 1-3 range. Ligand B is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.846) has a significantly better QED score than Ligand B (0.539), indicating a more drug-like profile.

**DILI:** Ligand B (24.467) has a much lower DILI risk than Ligand A (67.003). This is a significant advantage for Ligand B.

**BBB:** Ligand B (54.595) has a higher BBB penetration percentile than Ligand A (26.483), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.326 and -5.107). This 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 (-2.224 and -1.932). This is also unusual and suggests poor solubility. Again, the values are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.106 and 0.095), which is excellent.

**Microsomal Clearance:** Ligand A (-3.996) has a lower (better) microsomal clearance than Ligand B (-4.795), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (9.394) has a significantly longer in vitro half-life than Ligand A (-7.37), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.007 and 0.019).

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.8 kcal/mol). While the difference is small, it's within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. It has a significantly lower DILI risk, a longer half-life, and slightly better binding affinity. While Ligand A has a better QED and slightly better metabolic stability, the lower DILI and longer half-life of Ligand B are more critical for an enzyme target like SRC kinase. The similar poor permeability and solubility are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 12:54:40,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (390.774 and 338.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.9 and 75.35) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (4.261) is slightly higher than optimal (1-3), potentially leading to solubility issues. Ligand B (2.74) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 3 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.7 and 0.758), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (98.643 percentile), which is a significant concern. Ligand B has a much lower DILI risk (15.626 percentile), a major advantage.

**BBB:** Both have moderate BBB penetration (52.889 and 49.67 percentile), not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.733 and -4.936). This is unusual and suggests potential issues with intestinal absorption, but the scale is not clearly defined.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.447 and -2.647). This is also unusual and suggests poor aqueous solubility, which could hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.778 and 0.731 percentile), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (41.941 mL/min/kg) than Ligand B (3.31 mL/min/kg), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (8.932 hours) than Ligand A (20.047 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.766 and 0.307 percentile).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.7 and -9.5 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly better logP of Ligand A. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The high DILI risk associated with Ligand A is a major red flag that makes it less likely to progress as a drug candidate.

Output:
1
2025-04-17 12:54:40,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (341.367 Da and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.57) is slightly above the optimal <140, but still reasonable. Ligand B (78.51) is excellent, well below 140.

**3. logP:** Ligand A (2.95) is within the optimal 1-3 range. Ligand B (1.47) is also acceptable, though closer to the lower limit.

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

**5. H-Bond Acceptors (HBA):** Ligand A (6) is good. Ligand B (3) is excellent.

**6. QED:** Both ligands have good QED scores (0.472 and 0.651, respectively), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A (63.668) has a moderate DILI risk, while Ligand B (14.773) has a very low risk. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have acceptable BBB penetration (73.75 and 64.87, respectively), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 magnitude matters. Ligand A (-4.964) is slightly worse than Ligand B (-5.039).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude matters. Ligand A (-4.007) is slightly better than Ligand B (-2.109).

**11. hERG Inhibition:** Ligand A (0.756) has a slightly higher hERG risk than Ligand B (0.195). Ligand B is much better here.

**12. Microsomal Clearance (Cl_mic):** Ligand A (60.51) has a higher clearance than Ligand B (29.276), indicating lower metabolic stability. Ligand B is significantly better.

**13. In vitro Half-Life (t1/2):** Ligand A (1.53 hours) has a short half-life, while Ligand B (-13.612 hours) has a negative half-life, which is not physically possible and likely an error or outlier.

**14. P-gp Efflux:** Ligand A (0.35) has lower P-gp efflux than Ligand B (0.025).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity, DILI risk, hERG, and Cl_mic. While the half-life is suspect, the other advantages are compelling. Ligand A has a better P-gp efflux profile, but the other drawbacks are more significant. The negative half-life for Ligand B is concerning, but the substantial affinity advantage and better overall ADME profile make it the more promising candidate.

Output:
1
2025-04-17 12:54:40,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is higher than Ligand B (67.87). While both are reasonably good, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (0.999) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (2.319) is well within the optimal range.

**H-Bond Donors:** Ligand A (4) is higher than Ligand B (1). Lower HBD is generally preferred for permeability, making Ligand B better.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.537 and 0.611), indicating good drug-like properties.

**DILI:** Ligand A (24.351) has a significantly lower DILI risk than Ligand B (12.253), a major advantage.

**BBB:** Ligand A (17.138) has a very low BBB penetration, while Ligand B (69.756) is quite high. Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Ligand A (-5.01) has poor Caco-2 permeability, while Ligand B (-4.488) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.209) has poor solubility, while Ligand B (-1.441) is better, but still suboptimal.

**hERG:** Ligand A (0.099) has a very low hERG risk, a significant advantage. Ligand B (0.327) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-15.045) has much lower microsomal clearance (better metabolic stability) than Ligand B (42.528). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (2.019) has a shorter half-life than Ligand B (8.585). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.043) has very low P-gp efflux, while Ligand B (0.069) is slightly higher. Lower is preferable.

**Binding Affinity:** Ligand B (-8.1) has a stronger binding affinity than Ligand A (-7.3), a 1.5 kcal/mol difference. This is a substantial advantage that can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a clear advantage in binding affinity and better ADME properties (logP, TPSA, Caco-2, solubility, half-life). However, Ligand A has a significantly lower DILI risk and hERG inhibition liability, and much better metabolic stability (lower Cl_mic). The stronger binding affinity of Ligand B is a significant factor, and while its DILI and Cl_mic are not ideal, they might be acceptable given the potency. The poor solubility and permeability of Ligand A are concerning.

Output:
1
2025-04-17 12:54:40,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.834 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (21.06) is excellent, well below the 140 threshold, suggesting good absorption. Ligand B (85.17) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.739) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.547) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also acceptable, but the higher HBA count could slightly reduce permeability.

**QED:** Both ligands have similar QED values (0.774 and 0.724), indicating good drug-likeness.

**DILI:** Both ligands have similar, low DILI risk (25.165 and 25.553 percentile).

**BBB:** Both ligands have high BBB penetration (90.151 and 84.257 percentile), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.838) has poor Caco-2 permeability, which is a significant concern. Ligand B (-5.379) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.936) has poor aqueous solubility, consistent with its high logP. Ligand B (-1.184) has better solubility, but is still not ideal.

**hERG Inhibition:** Ligand A (0.914) has a slightly elevated hERG risk, but it's not critically high. Ligand B (0.116) has very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (35.94) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (18.102) has lower clearance, indicating better metabolic stability, which is crucial for kinases.

**In vitro Half-Life:** Ligand A (-6.769) has a relatively short half-life. Ligand B (-0.468) has a longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.81) has moderate P-gp efflux. Ligand B (0.071) has very low P-gp efflux, improving bioavailability.

**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 is over the 1.5 kcal/mol threshold.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. It exhibits better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, lower P-gp efflux, and slightly better binding affinity. While both have poor Caco-2 permeability, the other advantages of Ligand B outweigh this drawback. Ligand A's high logP and resulting poor solubility and permeability are significant liabilities.

Output:
1
2025-04-17 12:54:40,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (376.475 and 365.518 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.17) is slightly above the optimal <140 for good absorption, but still reasonable. Ligand B (49.25) is excellent, well below 140.

**logP:** Ligand A (-0.48) is a bit low, potentially hindering permeability. Ligand B (4.095) is approaching the upper limit of the optimal range (1-3) but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is within the preferred ranges. Ligand B (1 HBD, 5 HBA) is also favorable.

**QED:** Both ligands have good QED scores (0.465 and 0.689, respectively), indicating drug-like properties.

**DILI:** Ligand A (33.773) has a lower DILI risk than Ligand B (17.449), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (73.905) has a higher BBB score, but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.531 and -4.845), 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 (-1.66 and -3.016), also unusual and indicating poor solubility.

**hERG:** Ligand A (0.128) has a much lower hERG risk than Ligand B (0.948), a critical advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (18.94) has a significantly lower Cl_mic than Ligand B (40.605), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (67.778) has a much longer half-life than Ligand A (-4.293), which is a positive.

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.837), which is beneficial.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This >1.5 kcal/mol difference in affinity is a major deciding factor.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the substantially stronger binding affinity of Ligand A, combined with its lower DILI risk, lower hERG risk, lower Cl_mic, and lower P-gp efflux, make it the more promising drug candidate. The improved metabolic stability and reduced toxicity risks outweigh the potential permeability/solubility concerns, especially given the strong binding affinity.

Output:
0
2025-04-17 12:54:40,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.416 and 385.291 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is slightly higher than Ligand B (55.57), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.27) is optimal, while Ligand B (4.464) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as a single HBD can aid solubility without significantly impacting permeability.

**H-Bond Acceptors:** Both ligands have a similar number of HBA (Ligand A: 4, Ligand B: 5), both well within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.757, Ligand B: 0.628), indicating good drug-like properties.

**DILI:** Ligand A (56.572) has a higher DILI risk than Ligand B (39.511), which is a significant concern.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 76.735, Ligand B: 75.378), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the values are similar (-5.004 for A and -4.645 for B) and don't strongly differentiate the two.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-2.893 for A and -3.774 for B) and don't strongly differentiate the two.

**hERG Inhibition:** Ligand A (0.272) shows a much lower hERG inhibition liability than Ligand B (0.751), which is a crucial advantage.

**Microsomal Clearance:** Ligand B (83.096) has a significantly higher microsomal clearance than Ligand A (5.826), indicating poorer metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (43.758) has a longer in vitro half-life than Ligand A (-1.83), which is generally desirable. However, the negative value for A is concerning and likely an artifact.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.047, Ligand B: 0.615).

**Binding Affinity:** Both ligands have very similar, strong binding affinities (Ligand A: -8.6 kcal/mol, Ligand B: -8.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is preferable despite the higher DILI risk. It has a better logP, lower hERG risk, and significantly better metabolic stability (lower Cl_mic). The similar binding affinities mean that the ADME advantages of Ligand A are more important. While the negative solubility and Caco-2 values are concerning for both, they are similar. The DILI risk for Ligand A would need to be investigated further, but the other advantages make it the more promising candidate.

Output:
0
2025-04-17 12:54:40,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.479 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.01) is slightly above the preferred <140, but acceptable. Ligand B (78.95) is well within the acceptable range.

**logP:** Ligand A (2.333) is optimal (1-3). Ligand B (0.243) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.575 and 0.736), indicating good drug-likeness.

**DILI:** Ligand A (88.755) has a higher DILI risk than Ligand B (17.836). This is a significant concern for Ligand A.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (70.919) shows better BBB penetration than Ligand A (55.176).

**Caco-2 Permeability:** Ligand A (-5.631) has poor Caco-2 permeability, while Ligand B (-4.531) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-3.009) and Ligand B (-1.765) both have poor aqueous solubility.

**hERG:** Both ligands show low hERG inhibition risk (0.213 and 0.283).

**Microsomal Clearance:** Ligand A (37.48) has a higher microsomal clearance than Ligand B (9.424), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (48.101) has a longer half-life than Ligand B (0.918), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.189 and 0.013).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A's higher DILI risk, poor Caco-2 permeability, and higher clearance, its *significantly* stronger binding affinity (-9.4 vs -8.3 kcal/mol) makes it the more promising candidate. The potency advantage is likely to be crucial for efficacy, and the other issues could potentially be addressed through further optimization. Ligand B's lower logP and poor solubility are also significant drawbacks.

Output:
1
2025-04-17 12:54:40,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.379 Da) is slightly higher than Ligand B (343.431 Da), but both are acceptable.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (72.28). Lower TPSA generally improves cell permeability, which is beneficial.

**logP:** Ligand A (3.667) is slightly higher than the optimal range (1-3), but still reasonable. Ligand B (1.363) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand B has 6 HBA, which is acceptable, while Ligand A has only 2, which is also good.

**QED:** Both ligands have good QED scores (A: 0.819, B: 0.908), indicating drug-like properties.

**DILI:** Ligand A (39.977) has a slightly higher DILI risk than Ligand B (32.105), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (91.431) has a much higher BBB percentile than Ligand B (60.45).

**Caco-2 Permeability:** Ligand A (-4.621) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.458) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.865) has poor solubility, while Ligand B (-0.551) is slightly better, but still not ideal.

**hERG Inhibition:** Both ligands have low hERG risk (A: 0.867, B: 0.425), which is excellent.

**Microsomal Clearance:** Ligand A (9.691) has a much lower (better) microsomal clearance than Ligand B (-14.387). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (20.798) has a significantly longer half-life than Ligand A (-5.32). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.254, B: 0.026), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.6 kcal/mol, B: -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to be a deciding factor.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While it has poorer solubility and Caco-2 permeability, its significantly better metabolic stability (lower Cl_mic, though negative half-life) and lower TPSA outweigh these drawbacks. The binding affinity is comparable between the two. The slightly higher DILI risk for Ligand A is not a major concern given that it's still below the threshold. The improved metabolic stability is particularly crucial for an enzyme target like SRC kinase, as it will likely translate to a longer duration of action *in vivo*.

Output:
0
2025-04-17 12:54:40,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.463 and 355.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is well below the 140 threshold for oral absorption. Ligand B (138.6) is approaching the upper limit, but still acceptable.

**logP:** Ligand A (0.491) is a bit low, potentially hindering permeation. Ligand B (-1.07) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (4 HBD, 8 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED scores (0.371 and 0.504), with Ligand B being slightly more drug-like.

**DILI:** Ligand B (68.05) has a higher DILI risk than Ligand A (6.863). This is a significant negative for Ligand B.

**BBB:** Ligand A (72.858) has better BBB penetration than Ligand B (26.483), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.931) and Ligand B (-5.116) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.079 and -1.241), indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Ligand A (0.412) has a lower hERG risk than Ligand B (0.032), which is a significant advantage.

**Microsomal Clearance:** Ligand A (13.328 mL/min/kg) has a higher (worse) microsomal clearance than Ligand B (-8.118 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (34.762 hours) has a significantly longer half-life than Ligand A (-34.013 hours), which is a major positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.006).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), which are high priorities for an enzyme target. However, it has a significantly higher DILI risk and lower solubility. Ligand A has a lower DILI risk and hERG liability, but suffers from lower binding affinity and poorer metabolic stability. The poor solubility of both is a major concern.

Given the importance of potency and metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, the longer half-life and better metabolic stability of Ligand B are more compelling, *provided* the DILI risk can be mitigated through structural modifications.

Output:
1
2025-04-17 12:54:40,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.857 and 358.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.32) is higher than Ligand B (36.36). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Both ligands have logP values (3.827 and 4.727) within the optimal 1-3 range, but Ligand B is slightly higher. This could potentially lead to solubility issues, but isn't a major concern.

**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 good QED scores (0.754 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 46.064, while Ligand B has a much lower risk of 9.965. This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (79.062 and 78.519), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.36 and -4.847), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.606 and -4.322), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A has a hERG risk of 0.508, while Ligand B has a higher risk of 0.827. Ligand A is preferable here.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (112.257) than Ligand B (44.528), indicating lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (-6.574) than Ligand A (-25.639), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.157, while Ligand B has 0.567. Ligand A is better here.

**Binding Affinity:** Ligand B has a significantly better binding affinity (-9.3 kcal/mol) than Ligand A (0.0 kcal/mol). This is a substantial advantage that can outweigh many of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both compounds suffer from poor solubility and permeability, Ligand B's significantly superior binding affinity (-9.3 vs 0.0 kcal/mol) and much better metabolic stability (lower Cl_mic, longer half-life) are critical advantages for an enzyme inhibitor. The lower DILI risk is also a significant plus. The slightly higher logP and hERG risk are less concerning given the potency and metabolic stability. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modifications, but the core potency and stability profile of Ligand B make it the more promising starting point.

Output:
1
2025-04-17 12:54:40,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.356 and 367.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.94) is significantly better than Ligand B (91.32). A TPSA under 140 is desirable for oral absorption, and both meet this, but lower is generally better.

**logP:** Ligand A (4.466) is higher than optimal (1-3), potentially leading to solubility issues. Ligand B (1.86) is within the ideal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.865) has a much better QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (52.966 and 52.152), both being acceptable (below 60).

**BBB:** Both ligands have similar BBB penetration (61.535 and 60.411), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.472) has a worse Caco-2 permeability than Ligand B (-5.258). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-6.039) has worse solubility than Ligand B (-3.171). Solubility is important for bioavailability.

**hERG:** Ligand A (0.87) has a slightly higher hERG risk than Ligand B (0.374), but both are relatively low.

**Microsomal Clearance:** Ligand B (39.898) has significantly lower microsomal clearance than Ligand A (74.832), suggesting better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-11.27) has a negative half-life, which is not possible, and indicates a very short half-life. Ligand A (23.592) has a much more reasonable half-life.

**P-gp Efflux:** Ligand A (0.602) has lower P-gp efflux than Ligand B (0.071), which is preferable.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.5), but the difference is not substantial.

**Overall Assessment:**

Ligand A has a better QED score, lower P-gp efflux, and a reasonable half-life. However, it suffers from a high logP, poor solubility, and higher microsomal clearance. Ligand B has better logP, solubility, and significantly better metabolic stability (lower Cl_mic). The slightly better affinity of Ligand B is a bonus. The negative half-life for Ligand B is a major red flag and likely an error in the data.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), Ligand B is the more promising candidate despite the negative half-life value. The better metabolic stability and solubility outweigh the slightly lower affinity and higher P-gp efflux.

Output:
1
2025-04-17 12:54:40,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.394 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.74 and 78.87) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (0.591) is a bit low, potentially hindering permeation. Ligand B (1.848) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Both have 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.684 and 0.824), indicating drug-likeness.

**DILI:** Ligand A (42.846) has a slightly higher DILI risk than Ligand B (23.497), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.898) is higher than Ligand B (63.862), but this is not a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close, and this isn't a strong differentiator.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Ligand B (-3.681) is slightly better than Ligand A (-2.14), but both are problematic.

**hERG:** Both ligands have very low hERG inhibition risk (0.227 and 0.379), which is excellent.

**Microsomal Clearance:** Ligand A (22.117 mL/min/kg) has significantly lower microsomal clearance than Ligand B (46.806 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-38.071 hours) has a much longer in vitro half-life than Ligand B (-18.174 hours). This is a strong positive for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.03 and 0.075), which is favorable.

**Binding Affinity:** Ligand A (-8.0 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 demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. While Ligand B has a better logP and slightly better solubility, the metabolic advantages of Ligand A are more critical for an enzyme target like SRC kinase. The solubility issue is a concern for both, but can be addressed with formulation strategies. The slightly lower logP of Ligand A is a minor drawback compared to the metabolic benefits.

Output:
1
2025-04-17 12:54:40,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.403 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.49) is higher than Ligand B (73.2). While both are reasonably good, Ligand B is preferable as it's closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.591) is a bit low, potentially hindering permeability. Ligand B (3.027) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Ligand B is preferable as it's closer to the ideal <10.

**QED:** Both ligands have acceptable QED values (0.755 and 0.594, both >0.5).

**DILI:** Ligand A (52.074) has a higher DILI risk than Ligand B (8.918). This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration (69.911 and 75.998). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.053) and Ligand B (-4.809) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar.

**Solubility:** Ligand A (-0.852) has slightly better solubility than Ligand B (-2.172), but both are quite poor.

**hERG:** Ligand A (0.049) has a lower hERG risk than Ligand B (0.473). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (18.949) has a higher microsomal clearance than Ligand B (12.257), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (-16.134) has a significantly longer in vitro half-life than Ligand A (-7.761). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.011) has lower P-gp efflux than Ligand B (0.113), which is preferable.

**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 for Ligand B, potentially outweighing some of its minor ADME drawbacks.

**Overall:**

Ligand B is the better candidate. It has superior binding affinity, a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable logP and HBA count. While Ligand A has a slightly lower hERG risk and P-gp efflux, the advantages of Ligand B in potency, safety (DILI), and PK (metabolic stability) are more critical for an enzyme target like SRC. The solubility of both is poor, but this can be addressed with formulation strategies.

Output:
1
2025-04-17 12:54:40,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.475 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.67) is better than Ligand B (91.32). Both are below 140, suggesting reasonable absorption, but lower TPSA is generally preferred.

**3. logP:** Both ligands have good logP values (1.785 and 1.567), 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:** Both have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.601 and 0.708), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (35.75). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (53.315) has a higher BBB value than Ligand A (40.403), but this is not a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-5.188) has worse Caco-2 permeability than Ligand B (-4.976), but both are negative values, which is not ideal.

**10. Aqueous Solubility:** Ligand A (-0.894) has slightly better solubility than Ligand B (-2.301). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.411 and 0.059). Ligand B is slightly better here.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (7.762 and 7.74 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (47.908) has a longer half-life than Ligand B (-7.752). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.113 and 0.014).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 and -8.5 kcal/mol). The difference of 0.5 kcal/mol is not enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a slightly better QED and hERG profile, Ligand A's significantly lower DILI risk and longer in vitro half-life are more critical for an enzyme target like SRC kinase. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 12:54:40,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (380.388 and 359.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.5 and 80.12) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have a logP of approximately 1.27, which is 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.777 and 0.872), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (59.907 and 60.644), placing them in a moderate risk category, but not alarmingly high.

**BBB:** Both ligands have relatively low BBB penetration (68.748 and 55.138), which is not a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.339 and -5.178), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.035 and -1.944), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.484 and 0.049), which is excellent.

**Microsomal Clearance:** Ligand A has a significantly lower (better) microsomal clearance (-14.412) compared to Ligand B (28.138). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (26.466 hours) than Ligand B (10.445 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.11 and 0.021).

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-10.7 kcal/mol) compared to Ligand A (-7.5 kcal/mol). This is a substantial advantage (3.2 kcal/mol difference).

**Conclusion:**

Despite the poor solubility and permeability of both compounds, the significantly stronger binding affinity of Ligand B (-10.7 kcal/mol vs -7.5 kcal/mol) is a decisive factor. The 3.2 kcal/mol difference is large enough to outweigh the slightly worse metabolic stability compared to Ligand A. While solubility and permeability are critical issues that would need to be addressed through further optimization, the superior potency of Ligand B makes it the more promising starting point for drug development.

Output:
1
2025-04-17 12:54:40,519 - INFO - Batch 169 complete. Total preferences: 2704
2025-04-17 12:54:40,519 - INFO - Processing batch 170/512...
2025-04-17 12:55:21,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.359 and 346.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.71) is better than Ligand B (50.28) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (-0.114) is suboptimal, being below 1, which might hinder permeation. Ligand B (4.406) is high, potentially causing solubility issues and off-target effects, but within the acceptable range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.73) has a better QED score than Ligand B (0.502), indicating a more drug-like profile.

**DILI:** Ligand B (27.918) has a significantly lower DILI risk than Ligand A (69.058), which is a major advantage.

**BBB:** Ligand B (89.182) shows better BBB penetration than Ligand A (19.814), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.062 and -4.702), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.115 and -4.651), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.046) has a slightly lower hERG inhibition liability than Ligand B (0.868), which is preferable.

**Microsomal Clearance:** Ligand A (-15.551) has a much lower (better) microsomal clearance than Ligand B (92.594), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (36.299) has a longer in vitro half-life than Ligand A (-34.443), which is desirable.

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux liability than Ligand B (0.835), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). The difference is not substantial enough to outweigh the other factors.

**Conclusion:**

Despite Ligand B having a slightly better binding affinity and longer half-life, Ligand A is the more promising candidate. Ligand A has a better QED score, lower hERG risk, significantly better metabolic stability (lower Cl_mic), and lower P-gp efflux. The biggest drawbacks for both are the negative Caco-2 and solubility values, which need to be addressed through formulation or structural modifications. However, the metabolic stability of Ligand A is a crucial advantage for an enzyme inhibitor.

Output:
0
2025-04-17 12:55:21,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.949 and 361.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (44.37) is significantly better than Ligand B (59.23). A TPSA under 140 is good for oral absorption, and both are well below this, but lower is generally preferred.

**3. logP:** Both ligands have logP values around 4.4-4.6, which is slightly high. This could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker.

**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 2 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.717 and 0.756), indicating good drug-likeness.

**7. DILI:** Ligand A (22.102) has a much lower DILI risk than Ligand B (41.14). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (88.717 and 84.606), but SRC is not a CNS target, so this is less important.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.597 and -4.714), which is unusual and suggests poor permeability. This is a concerning aspect for both.

**10. Aqueous Solubility:** Ligand A (-3.255) has slightly better solubility than Ligand B (-5.409), though both are quite poor.

**11. hERG Inhibition:** Ligand A (0.849) has a slightly higher hERG risk than Ligand B (0.552), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (34.117) has significantly lower microsomal clearance than Ligand B (99.586), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (109.248) has a much longer in vitro half-life than Ligand B (6.628). This is a major advantage, as it suggests less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.398 and 0.374).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While a 1.2 kcal/mol difference is noticeable, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better solubility. The poor Caco-2 permeability is a concern for both, but can potentially be addressed through formulation strategies. The better ADME profile of Ligand A outweighs the small difference in binding affinity, especially for an enzyme target like SRC kinase.

Output:
0
2025-04-17 12:55:21,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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. Ligand B (403.328 Da) is still acceptable.

**TPSA:** Ligand A (91.76) is better than Ligand B (58.87) as it is closer to the threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 2.203, B: 3.283), 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 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.868, B: 0.853), indicating good drug-likeness.

**DILI:** Ligand A (67.507) has a higher DILI risk than Ligand B (47.383). This is a significant drawback for Ligand A.

**BBB:** Ligand B (83.017) has a higher BBB percentile than Ligand A (36.177). While not a primary concern for a non-CNS target like SRC, it's a minor positive for B.

**Caco-2 Permeability:** Ligand A (-4.681) has a lower Caco-2 permeability than Ligand B (-5.073). Both are poor.

**Aqueous Solubility:** Ligand A (-3.209) has better aqueous solubility than Ligand B (-2.906). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.209) has a lower hERG inhibition liability than Ligand B (0.64). This is a significant advantage for Ligand A, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (27.401) has a lower microsomal clearance than Ligand A (34.741), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (37.767) has a longer in vitro half-life than Ligand A (-11.471). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux liability than Ligand B (0.397). This is a minor advantage for Ligand A.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is a major factor, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -7.4 kcal/mol) is the most important factor. It also demonstrates better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. While Ligand A has better solubility and lower hERG risk, the superior potency and metabolic profile of Ligand B are more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:55:21,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.467 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.54) is slightly higher than Ligand B (59.08). While both are reasonably low, Ligand B is better positioned for good oral absorption.

**logP:** Both ligands have similar logP values (1.577 and 1.681), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable.

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

**QED:** Ligand A (0.88) has a significantly higher QED score than Ligand B (0.443), indicating a more drug-like profile.

**DILI:** Ligand B (12.641) has a much lower DILI risk than Ligand A (49.864), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (78.635 and 79.488), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-4.982 and -4.275).

**Aqueous Solubility:** Ligand B (-1.049) has slightly better solubility than Ligand A (-3.177), though both are poor.

**hERG Inhibition:** Ligand A (0.195) has a slightly higher hERG risk than Ligand B (0.526), but both are relatively low.

**Microsomal Clearance:** Ligand A (14.839) and Ligand B (13.027) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand B (-7.592) has a negative half-life, which is not possible and indicates a data error or unusual behavior. Ligand A has a half-life of 28.2 hours, which is a significant advantage.

**P-gp Efflux:** Ligand A (0.139) has lower P-gp efflux than Ligand B (0.071), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.1 kcal/mol). Ligand A has a 1.5 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior QED score, a significantly longer half-life, better P-gp efflux, and a stronger binding affinity. However, Ligand B has a much lower DILI risk and slightly better solubility. The negative half-life for Ligand B is a major red flag. While the difference in binding affinity is significant, the DILI risk for Ligand A is concerning. Given the enzyme-kinase target class, metabolic stability (half-life) and minimizing toxicity (DILI) are crucial.

Despite the slightly higher DILI risk, Ligand A's superior binding affinity, better half-life, and overall drug-likeness (QED) make it the more promising candidate. The binding affinity advantage is substantial enough to potentially mitigate the DILI risk with further optimization.

Output:
1
2025-04-17 12:55:21,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.37 and 358.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (106.91 and 98.32) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.869 and 1.127) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, satisfying the <5 and <10 rules, respectively.

**QED:** Both ligands have acceptable QED scores (0.796 and 0.616), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (83.99%) compared to Ligand B (39.55%). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (55.06% and 56.15%), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.145 and -5.162). This 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 (-4.506 and -2.169), indicating poor aqueous solubility. Ligand B is slightly better in this regard.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.444 and 0.346).

**Microsomal Clearance:** Ligand A (11.244 mL/min/kg) has a higher microsomal clearance than Ligand B (0.879 mL/min/kg). This indicates lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (70.662 hours) compared to Ligand A (-13.993 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.025).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), although the difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

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 improved binding affinity further supports this conclusion. The DILI risk associated with Ligand A is a major red flag, making it less likely to progress as a drug candidate.

Output:
1
2025-04-17 12:55:21,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (379.404 and 363.424 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.08) is slightly higher than Ligand B (61.44), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands (2.449 and 2.214) are 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 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.768 and 0.66), indicating good drug-like properties.

**DILI:** Ligand A (66.654) has a higher DILI risk than Ligand B (12.524). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (85.459) has better BBB penetration than Ligand A (68.282).

**Caco-2 Permeability:** Ligand A (-4.949) and Ligand B (-5.052) have similar, very poor Caco-2 permeability values. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-4.128) has slightly worse solubility than Ligand B (-2.57).

**hERG:** Ligand A (0.424) has a slightly higher hERG risk than Ligand B (0.574), but both are relatively low.

**Microsomal Clearance:** Ligand B (0.473) has significantly lower microsomal clearance than Ligand A (70.693), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (-17.229) has a much longer in vitro half-life than Ligand A (-11.277). This is another significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.035).

**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 notable but may not be enough to overcome the other issues.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is the more promising candidate. Ligand A has a significantly higher DILI risk and much poorer metabolic stability (higher Cl_mic, shorter half-life). The Caco-2 permeability is poor for both, but the other ADME properties of Ligand B are substantially better, making it more likely to succeed as a drug candidate.

Output:
1
2025-04-17 12:55:21,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (374.241 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.58) is better than Ligand B (60.85), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.587 and 2.276), 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 acceptable limits.

**QED:** Ligand A (0.768) has a significantly better QED score than Ligand B (0.472), indicating a more drug-like profile.

**DILI:** Ligand A (69.523) has a higher DILI risk than Ligand B (20.008). This is a significant drawback for Ligand A.

**BBB:** Both have good BBB penetration (70.609 and 77.2). Not a major consideration for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values which is not typical. This could indicate an issue with the data or the compounds.

**Solubility:** Ligand A (-2.808) has very poor solubility, while Ligand B (-1.487) is also poor, but better than A. Solubility is a critical factor for oral bioavailability.

**hERG:** Ligand A (0.155) has a slightly higher hERG risk than Ligand B (0.328), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.165) has a lower (better) microsomal clearance than Ligand B (12). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-44.222) has a significantly longer in vitro half-life than Ligand B (-24.305). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.008) has much lower P-gp efflux liability than Ligand B (0.17), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other 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 suffers from poor solubility and higher DILI risk. Ligand B has better solubility and DILI, but weaker binding affinity and poorer metabolic stability.

Given the importance of potency for kinase inhibitors, the significantly stronger binding affinity of Ligand A (-10.3 vs -8.8 kcal/mol) is the deciding factor. While the solubility and DILI risks of Ligand A are concerning, these can potentially be addressed through formulation strategies or further chemical modifications. The improved metabolic stability and reduced efflux also contribute to a more favorable pharmacokinetic profile.

Output:
1
2025-04-17 12:55:21,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.367 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both are acceptable, but Ligand A (92.78) is preferable as it's below 140 and closer to the 90 threshold for potential CNS penetration (though not a primary concern here). Ligand B (107.19) is still reasonable.

**logP:** Ligand A (-0.193) is a bit low, potentially hindering permeation. Ligand B (0.188) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=6) as it has fewer hydrogen bond donors and acceptors, generally improving permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.433, B: 0.58), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (46.801) has a significantly lower DILI risk than Ligand B (60.915), which is a substantial advantage.

**BBB:** Not a primary concern for a kinase inhibitor, but Ligand B (41.566) has slightly better BBB penetration than Ligand A (38.232).

**Caco-2 Permeability:** Both are very poor (-4.8 and -5.986). This is a major concern for both.

**Aqueous Solubility:** Both are very poor (-2.043 and -2.839). This is also a major concern for both.

**hERG Inhibition:** Both have very low hERG risk (0.025 and 0.068), which is excellent.

**Microsomal Clearance:** Ligand A (-7.515) has a much lower (better) microsomal clearance than Ligand B (11.279), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-11.9) has a longer half-life than Ligand B (-14.662), which is also favorable.

**P-gp Efflux:** Both have very low P-gp efflux (0.015 and 0.019), which is good.

**Binding Affinity:** Ligand B (-9.6 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. The difference is greater than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-9.6 kcal/mol vs -7.0 kcal/mol) is the most important factor. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, the potency difference is substantial enough to prioritize Ligand B. The poor Caco-2 and solubility for both are concerning, but can be addressed through formulation strategies. The slightly better logP of Ligand B is also a plus.

Output:
1
2025-04-17 12:55:21,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.547 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (84.67), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have similar logP values (1.029 and 1.142), falling 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 (4) and Ligand B (5) are both within the acceptable range (<=10).

**QED:** Ligand A (0.731) has a better QED score than Ligand B (0.564), indicating a more drug-like profile.

**DILI:** Ligand A (14.967) has a significantly lower DILI risk than Ligand B (49.128), which is a major advantage. Ligand B is approaching a concerning level.

**BBB:** Both ligands have similar BBB penetration (66.576 and 63.358), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.089 and -4.815), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.986 and -1.817), which is also unusual and suggests poor solubility. This is a potential issue for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.22 and 0.119), which is excellent.

**Microsomal Clearance:** Ligand A (-6.076) has a much lower (better) microsomal clearance than Ligand B (13.095), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-3.059) has a longer in vitro half-life than Ligand B (-0.342), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.093), which is favorable.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.2), a difference of 0.9 kcal/mol. While this is a notable difference, the ADME properties of Ligand A are significantly better.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly in terms of DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and QED score. The poor Caco-2 and solubility values are a concern for both, but the superior safety and pharmacokinetic profile of Ligand A outweigh the modest affinity difference.

Output:
0
2025-04-17 12:55:21,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.382 and 358.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (126.07) is still within acceptable limits for oral absorption (<140), but less favorable than A.

**logP:** Ligand A (3.332) is optimal (1-3). Ligand B (-1.828) is significantly lower, potentially hindering permeation and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is excellent, well within the guidelines. Ligand B (HBD=3, HBA=7) is acceptable but less ideal, potentially impacting permeability.

**QED:** Ligand A (0.931) is very high, indicating excellent drug-likeness. Ligand B (0.238) is poor, suggesting potential issues.

**DILI:** Ligand A (53.276) has a moderate DILI risk, acceptable. Ligand B (35.595) has a lower DILI risk, which is favorable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (78.209) is better than Ligand B (54.207). While not a primary concern for a kinase inhibitor, it's a slight advantage for A.

**Caco-2 Permeability:** Ligand A (-4.684) and Ligand B (-5.279) both have negative values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-4.072) and Ligand B (-1.407) both have negative values, suggesting poor solubility. Again, the scale is not defined, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.739) has a low hERG risk, which is excellent. Ligand B (0.14) also indicates low hERG risk.

**Microsomal Clearance:** Ligand A (65.907) has moderate clearance, while Ligand B (21.402) has lower clearance, indicating better metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand A (21.352) has a reasonable half-life. Ligand B (-31.456) has a negative half-life, which is impossible and indicates a data error or unusual scale.

**P-gp Efflux:** Ligand A (0.617) has moderate P-gp efflux. Ligand B (0.002) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.9 kcal/mol), with Ligand B being slightly better. This is a crucial factor.

**Overall Assessment:**

Ligand B has a slight advantage in binding affinity and significantly better metabolic stability (lower Cl_mic). However, it suffers from a very low logP, poor QED, and a nonsensical in vitro half-life value. Ligand A has a much better overall profile with good drug-likeness, acceptable metabolic stability, and a reasonable logP. The questionable permeability and solubility values for both are concerning, but the superior overall properties of Ligand A make it the more promising candidate. The negative half-life for Ligand B is a critical flaw.

Output:
1
2025-04-17 12:55:21,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.387 and 347.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.21 and 103.89) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.566) is slightly low, potentially hindering permeation. Ligand B (1.456) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands (5) are below the 10 limit.

**QED:** Both ligands (0.765 and 0.671) are above 0.5, indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (55.874 and 52.074), below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Both ligands have moderate BBB penetration (45.56 and 47.577).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.396 and -5.581), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.923 and -3.155), which is also unusual and indicates very poor solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.239 and 0.456).

**Microsomal Clearance:** Ligand A (-13.721) has *much* lower (better) microsomal clearance than Ligand B (22.552), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.895) has a more negative (better) in vitro half-life than Ligand B (-32.819), suggesting a longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.043).

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.1 kcal/mol). While the difference isn't huge (1.1 kcal/mol), it's a positive factor.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, more negative t1/2) and slightly stronger binding affinity outweigh the slightly lower logP. The poor solubility and permeability are serious issues that would need to be addressed through formulation or further chemical modification, but the improved pharmacokinetic profile of Ligand A gives it a better starting point for optimization.

Output:
0
2025-04-17 12:55:21,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.356) is slightly higher than Ligand B (347.415), but both are acceptable.

**TPSA:** Both ligands have TPSA values (81.7 and 84.71) below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.275 and 2.813) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.812) has a significantly higher QED score than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand A (63.746) has a slightly higher DILI risk than Ligand B (54.207), but both are still within a moderate risk range.

**BBB:** Ligand A (71.268) and Ligand B (89.492) both have acceptable BBB penetration, but Ligand B is better. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.635 and -4.703), indicating poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.14 and -3.404), indicating poor solubility. This is also a significant concern for both.

**hERG Inhibition:** Ligand A (0.546) has a slightly lower hERG inhibition risk than Ligand B (0.692), which is preferable.

**Microsomal Clearance:** Ligand B (37.468) has a significantly lower microsomal clearance than Ligand A (55.164), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (15.9) has a much longer in vitro half-life than Ligand A (-46.739). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.196).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This is a 0.5 kcal/mol difference, which is not huge, but still noticeable.

**Overall Assessment:**

While Ligand A has a better QED and slightly better affinity, Ligand B demonstrates superior ADME properties, specifically significantly improved metabolic stability (lower Cl_mic) and a much longer half-life. The poor Caco-2 and solubility for both are concerning, but the improved PK profile of Ligand B is more critical for an enzyme target like SRC. The slightly better affinity of Ligand A is unlikely to overcome the PK advantages of Ligand B.

Output:
1
2025-04-17 12:55:21,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.817 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.84) is well below the 140 threshold, suggesting good absorption. Ligand B (120) is also acceptable, but less optimal.

**logP:** Ligand A (2.284) is within the optimal 1-3 range. Ligand B (0.923) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, both within acceptable limits. Ligand B has 4 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.5 (0.722 and 0.607), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 87.631, which is high and concerning. Ligand B has a much lower DILI risk of 56.146, which is still not ideal but significantly better.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (67.313) and Ligand B (36.371) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.135 and -5.396). This is unusual and suggests poor permeability *in vitro*. However, these values can be unreliable and should be confirmed experimentally.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.409 and -2.667), also unusual and indicating poor aqueous solubility. Again, experimental validation is needed.

**hERG Inhibition:** Ligand A (0.213) has a very low hERG risk, which is excellent. Ligand B (0.06) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (7.305) has a low microsomal clearance, suggesting good metabolic stability. Ligand B (16.629) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-8.551) has a very long in vitro half-life, which is highly desirable. Ligand B (-15.387) has an even longer half-life, which is excellent.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.308 and 0.037).

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial difference (3 kcal/mol), which can often outweigh minor ADME drawbacks.

**Conclusion:**

Despite the unusual Caco-2 and solubility values, the significantly stronger binding affinity of Ligand A (-10.1 kcal/mol vs -7.1 kcal/mol) and its favorable metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The major drawback of Ligand A is its high DILI risk. However, the potency advantage is significant, and DILI risk can sometimes be mitigated through structural modifications. Ligand B's lower potency, despite its better DILI profile, makes it less attractive.

Output:
1
2025-04-17 12:55:21,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.65) is slightly above the preferred <140, while Ligand B (85.69) is well within. This favors B for absorption.

**logP:** Both ligands (0.716 and 0.822) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**QED:** Both ligands have similar QED scores (0.717 and 0.711), indicating good drug-likeness.

**DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (39.511), but both are below the concerning threshold of 60.

**BBB:** Both have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (62.233) is slightly better than A (50.64).

**Caco-2 Permeability:** Ligand A (-4.883) has a lower Caco-2 permeability than Ligand B (-4.597), suggesting B may have better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.558) has lower solubility than Ligand B (-1.092). Solubility is important for bioavailability, favoring B.

**hERG Inhibition:** Ligand A (0.068) has a slightly higher hERG risk than Ligand B (0.217), but both are very low.

**Microsomal Clearance:** Ligand A (29.611) has significantly lower microsomal clearance than Ligand B (7.556). This indicates better metabolic stability for A, a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (1.183) has a shorter half-life than Ligand B (-10). A negative value for B suggests a very long half-life, which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.059).

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.4). While both are good, the 0.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B has several advantages: better TPSA, Caco-2 permeability, solubility, and a slightly better binding affinity. Its significantly longer half-life is also a major plus. While Ligand A has better metabolic stability (lower Cl_mic), the superior overall profile of Ligand B, particularly its solubility and half-life, outweighs this benefit. The binding affinity difference, while not huge, further tips the scales.

Output:
1
2025-04-17 12:55:21,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 357.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (93.46). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have acceptable logP values (0.835 and 1.657, respectively), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA). Lower values are generally preferred for permeability.

**QED:** Both ligands have similar QED scores (0.667 and 0.656), indicating good drug-likeness.

**DILI:** Ligand A (5.7) has a much lower DILI risk than Ligand B (49.942). This is a significant advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (81.078 and 85.731), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show negative Caco-2 values (-4.516 and -4.417), which is unusual and suggests poor permeability. However, these values are on a log scale and close to zero, so they might not be drastically different in absolute terms.

**Aqueous Solubility:** Ligand A (-0.638) has slightly better solubility than Ligand B (-2.898). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.288) has a much lower hERG inhibition liability than Ligand B (0.179). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (2.493 mL/min/kg) has significantly lower microsomal clearance than Ligand B (34.347 mL/min/kg). Lower clearance indicates better metabolic stability, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-2.892 hours) has a longer half-life than Ligand B (-10.603 hours). This is also a positive for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.038).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While affinity is crucial, the difference of 1.4 kcal/mol is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A demonstrates a superior ADME profile with lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. While Ligand B has a marginally better binding affinity, the ADME advantages of Ligand A are more critical for developing a viable drug candidate, especially considering the enzyme class.

Output:
0
2025-04-17 12:55:21,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.857 Da) is slightly higher, but acceptable. Ligand B (359.817 Da) is also good.

**TPSA:** Ligand A (116.07) is borderline, potentially impacting absorption, while Ligand B (88.17) is well within the desirable range for oral absorption (<140).

**logP:** Both ligands have acceptable logP values (Ligand A: 1.974, Ligand B: 3.235), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 1 HBD and 9 HBA, while Ligand B has 3 HBD and 6 HBA. Both are within the acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (Ligand A: 0.664, Ligand B: 0.776), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.806%), which is a significant concern. Ligand B has a lower, though still elevated, DILI risk (85.459%).

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (72.896) than Ligand A (46.026), but this is not a primary factor.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.908) is slightly better than Ligand B (-5.121).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.759) is slightly better than Ligand B (-4.214).

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.265, Ligand B: 0.284), which is positive.

**Microsomal Clearance:** Ligand A (45.321) has a higher microsomal clearance than Ligand B (23.668), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (43.273 hours) has a significantly longer in vitro half-life than Ligand A (110.316 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.433, Ligand B: 0.073). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-8.5 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 concerns.

**Conclusion:**

Despite Ligand A's superior binding affinity, the extremely high DILI risk and higher microsomal clearance are major red flags. Ligand B, while having weaker affinity, presents a much more favorable ADME profile, with lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better solubility and permeability. The large difference in binding affinity is concerning, but the ADME profile of Ligand A is too problematic.

Output:
1
2025-04-17 12:55:21,172 - INFO - Batch 170 complete. Total preferences: 2720
2025-04-17 12:55:21,172 - INFO - Processing batch 171/512...
2025-04-17 12:56:02,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.523 and 380.279 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.36) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (55.43) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands have logP values within the optimal range (2.535 and 3.715). Ligand B is slightly higher, potentially leading to some solubility concerns, but not critically.

**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 (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.878) has a significantly better QED score than Ligand B (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (77.937) has a higher DILI risk than Ligand B (64.754), but both are within a tolerable range, though A is approaching the concerning >60 threshold.

**BBB:** Both ligands have reasonable BBB penetration (81.97 and 65.607), but this is less critical for a non-CNS target like SRC.

**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 proceed with relative comparison.

**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 relatively low hERG inhibition risk (0.57 and 0.724), which is good.

**Microsomal Clearance:** Ligand A (19.609) has significantly lower microsomal clearance than Ligand B (93.208), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (37.875) has a shorter half-life than Ligand B (44.447), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.282 and 0.512).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.7 kcal/mol). This difference of 1.2 kcal/mol is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A's better QED and lower DILI risk, the significantly stronger binding affinity of Ligand B (-7.9 vs -6.7 kcal/mol) and its superior metabolic stability (lower Cl_mic) make it the more promising drug candidate for SRC kinase inhibition. The slightly higher logP of Ligand B is a minor concern, but the potency advantage is likely to be more important.

Output:
1
2025-04-17 12:56:02,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.344 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.91) is well below the 140 threshold for good absorption, while Ligand B (115.39) is still acceptable but higher.

**logP:** Ligand A (3.622) is optimal, while Ligand B (-0.709) is significantly low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3 respectively), staying within the <5 guideline.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both under the 10 threshold.

**QED:** Both ligands have reasonable QED values (0.81 and 0.588), indicating good drug-likeness.

**DILI:** Ligand A (76.076) has a higher DILI risk than Ligand B (35.595). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.731) has a slightly better BBB penetration than Ligand B (16.324).

**Caco-2 Permeability:** Ligand A (-4.922) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.394) is also poor, but only slightly worse.

**Aqueous Solubility:** Ligand A (-3.936) has poor solubility, while Ligand B (-2.462) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.537) shows a low hERG risk, which is excellent. Ligand B (0.11) is even lower, indicating very low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (17.811) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (4.302) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.806) has a negative half-life, which is not possible. This is likely an error in the data, but it is a significant red flag. Ligand A (12.251) has a reasonable half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.046 and 0.007).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -9.0 kcal/mol). The difference is minimal.

**Conclusion:**

Despite Ligand A's better logP and lower hERG risk, its poor Caco-2 permeability, poor solubility, higher DILI risk, and higher microsomal clearance are significant drawbacks. Ligand B, despite the questionable half-life data, has better solubility, lower DILI, and significantly better metabolic stability. The negative half-life is a major concern, but the other factors lean towards Ligand B being a more viable candidate *if* the half-life data can be corrected or explained. Given the enzyme-specific priorities, metabolic stability is crucial.

Output:
1
2025-04-17 12:56:02,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 354.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is better than Ligand B (86.6), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.914) is within the optimal 1-3 range. Ligand B (-0.096) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5), aligning with the goal of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.759 and 0.638, both > 0.5).

**DILI:** Ligand A (30.05) has a significantly lower DILI risk than Ligand B (16.014), which is a strong advantage.

**BBB:**  BBB is less critical for a non-CNS target like SRC, but Ligand A (67.197) is better than Ligand B (36.177).

**Caco-2:** Ligand A (-4.729) and Ligand B (-5.19) are both negative, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.465) is better than Ligand B (-0.468), indicating slightly better solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.1 and 0.143), which is good.

**Microsomal Clearance:** Ligand B (-9.758) has *much* lower microsomal clearance than Ligand A (19.582), indicating significantly better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (4.744) has a longer half-life than Ligand A (0.31), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.065 and 0.006).

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-8.7). However, the difference is less than 1.5 kcal/mol, so it doesn't overwhelmingly outweigh other factors.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is a more promising drug candidate due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility. The Caco-2 values are concerning for both, but the metabolic advantages of Ligand B are crucial for an enzyme target like SRC.

Output:
1
2025-04-17 12:56:02,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (378.47 and 364.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.81) is better than Ligand B (49.41) as it's closer to the 140 A^2 threshold for good oral absorption. Ligand B is quite low, which might suggest permeability issues.

**logP:** Ligand A (-0.795) is suboptimal, potentially hindering permeation. Ligand B (4.518) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is better balanced than Ligand B (1 HBD, 3 HBA). Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.651 and 0.621), indicating good drug-likeness.

**DILI:** Ligand A (44.668) has a slightly higher DILI risk than Ligand B (35.479), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (66.033 and 69.407), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.477) has poor Caco-2 permeability, while Ligand B (-4.895) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.564) has poor solubility, while Ligand B (-3.898) is even worse.

**hERG Inhibition:** Ligand A (0.283) has a lower hERG risk than Ligand B (0.525), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-3.031) has significantly better metabolic stability (lower clearance) than Ligand B (115.552). This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-26.171) has a much longer half-life than Ligand B (48.436), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.361), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.0) 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 the better candidate. While its logP and solubility are suboptimal, its significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux outweigh the slightly weaker binding affinity. The poor solubility and logP could be addressed with formulation strategies or further chemical modifications. Ligand B's high metabolic clearance and worse solubility are major drawbacks for an enzyme inhibitor.



Output:
0
2025-04-17 12:56:02,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.5 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is well below the 140 threshold, while Ligand B (98.74) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (2.337) is optimal (1-3). Ligand B (-0.216) is below 1, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) both meet the <=10 criteria.

**QED:** Ligand A (0.622) is better than Ligand B (0.437), indicating a more drug-like profile.

**DILI:** Ligand A (38.5) has a lower DILI risk than Ligand B (21.9). Both are acceptable, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.6) is higher than Ligand B (32.7).

**Caco-2 Permeability:** Ligand A (-5.149) is significantly worse than Ligand B (-4.851), suggesting lower intestinal absorption. However, this is less important than other factors.

**Aqueous Solubility:** Ligand A (-2.223) is better than Ligand B (-1.612), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.594) has a lower hERG risk than Ligand B (0.108). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (32.3) has higher clearance than Ligand B (22.6), meaning it's less metabolically stable. This favors Ligand B.

**In vitro Half-Life:** Ligand A (15.0) has a shorter half-life than Ligand B (-38.6). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.185) has lower P-gp efflux than Ligand B (0.018), which is slightly favorable.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.1 kcal/mol). This 0.8 kcal/mol difference is significant, but must be weighed against other factors.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, QED, DILI, solubility, and hERG risk. However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The poor logP of Ligand B is a major concern, potentially leading to poor absorption. The hERG risk for Ligand B is also concerning. While the affinity difference is notable, the combination of better ADME properties for Ligand A, particularly the favorable logP and hERG profile, makes it the more promising candidate.

Output:
0
2025-04-17 12:56:02,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (349.431 and 341.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.9) is better than Ligand B (84.97), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Both ligands (2.169 and 2.055) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3), as fewer donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5), for similar reasons as HBD.

**6. QED:** Both ligands have similar and good QED values (0.799 and 0.798), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (44.126 and 42.264), well below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (86.002) has a higher BBB percentile than Ligand A (53.974), but this is not a primary concern.

**9. Caco-2 Permeability:** Ligand A (-4.816) is better than Ligand B (-5.736), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.486) is better than Ligand B (-1.805), indicating better aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.271 and 0.819), which is excellent.

**12. Microsomal Clearance:** Ligand B (-21.109) has significantly lower (better) microsomal clearance than Ligand A (24.499), suggesting better metabolic stability. This is a key factor for kinases.

**13. In vitro Half-Life:** Ligand B (19.029) has a substantially longer half-life than Ligand A (9.95), which is highly desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.123).

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-8.0), but the difference is small.

**Overall Assessment:**

While Ligand A has slightly better TPSA, Caco-2, and solubility, Ligand B exhibits significantly improved metabolic stability (lower Cl_mic, longer t1/2). For an enzyme target like SRC kinase, metabolic stability is crucial for maintaining therapeutic concentrations. The slightly better affinity of Ligand B further strengthens its position. The difference in affinity is not large enough to overcome the substantial difference in metabolic stability.

Output:
1
2025-04-17 12:56:02,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.363 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (371.497 Da) is still well within the acceptable range.

**TPSA:** Ligand A (84.08) is better than Ligand B (45.23). Lower TPSA generally indicates better cell permeability.

**logP:** Both ligands have good logP values (A: 2.679, B: 3.919), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* lead to some off-target effects or solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (A: 2, B: 1) and HBA (A: 4, B: 4) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (A: 0.555, B: 0.873), indicating good drug-like properties. Ligand B has a significantly higher QED, suggesting a more favorable overall profile.

**DILI:** Ligand A has a concerningly high DILI risk (90.112%), while Ligand B has a very low DILI risk (24.04%). This is a major red flag for Ligand A.

**BBB:** Both have moderate BBB penetration (A: 54.246, B: 91.314). Since SRC is not a CNS target, this is less critical, but B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.168 and -4.862). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.833 and -3.721). This is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (A: 0.572, B: 0.683).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (88.599) than Ligand B (23.744), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-1.619) than Ligand A (-12.756).

**P-gp Efflux:** Both have low P-gp efflux (A: 0.241, B: 0.449).

**Binding Affinity:** Ligand B has a substantially stronger binding affinity (-8.8 kcal/mol) compared to Ligand A (-7.3 kcal/mol). This difference of 1.5 kcal/mol is significant and can outweigh some minor ADME drawbacks.

**Conclusion:**

Ligand B is significantly superior to Ligand A. While both have issues with Caco-2 and solubility, Ligand B demonstrates a much better safety profile (lower DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a substantially stronger binding affinity. The higher QED score also supports its selection. The slight increase in logP is a minor concern compared to the other advantages.

Output:
1
2025-04-17 12:56:02,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight:** Both ligands (343.471 Da and 348.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (54.34) is well below the 140 threshold and is very favorable. Ligand B (119.46) is still below 140, but higher than A, potentially impacting absorption.

**3. logP:** Both ligands have acceptable logP values (2.544 and 1.074), falling within the 1-3 range. Ligand A is slightly better.

**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 (0.774 and 0.761), indicating good drug-likeness.

**7. DILI:** Ligand A (15.045) has a significantly lower DILI risk than Ligand B (54.944). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a kinase inhibitor, but Ligand A (78.907) has a higher BBB percentile than Ligand B (27.957).

**9. Caco-2 Permeability:** Ligand A (-4.824) has a worse Caco-2 permeability than Ligand B (-5.023).

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.4 and -2.426). This is a concern for both, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.243 and 0.276).

**12. Microsomal Clearance:** Ligand B (-4.782) has a *negative* clearance, which is unusual and suggests very high metabolic stability. Ligand A (32.791) has a higher, and less favorable, clearance.

**13. In vitro Half-Life:** Ligand B (12.699) has a significantly longer half-life than Ligand A (3.74). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.091 and 0.072).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-10.0 and -8.1 kcal/mol). Ligand A has a 1.9 kcal/mol advantage, which is substantial.

**Enzyme-Kinase Specific Priorities:** Given this is a kinase target, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has superior affinity, but Ligand B has much better metabolic stability (negative Cl_mic, longer half-life) and a lower DILI risk. Solubility is poor for both.

**Overall Assessment:** While Ligand A has a significant binding affinity advantage, the superior metabolic stability and lower DILI risk of Ligand B are more critical for an enzyme target. The difference in affinity, while substantial, can potentially be optimized in later stages of drug development. The poor solubility of both compounds is a concern, but formulation strategies can be explored.

Output:
1
2025-04-17 12:56:02,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.391 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (365.411 Da) is also acceptable.

**TPSA:** Ligand A (63.25) is significantly better than Ligand B (110.53). Lower TPSA generally correlates with better cell permeability, a crucial factor for kinase inhibitors.

**logP:** Ligand A (4.725) is higher than optimal (1-3), potentially leading to solubility issues or off-target effects. Ligand B (1.17) is within the ideal range.

**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 good QED values (A: 0.664, B: 0.762), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk, but Ligand B (77.782) is slightly lower than Ligand A (86.002).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.425) is better than Ligand B (60.566).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.849 and -4.838), which is unusual and suggests poor permeability based on this metric.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.887 and -3.727). This is a significant concern.

**hERG Inhibition:** Ligand A (0.748) has a slightly higher hERG risk than Ligand B (0.198), which is a major advantage for Ligand B.

**Microsomal Clearance:** Ligand B (42.255) has significantly lower microsomal clearance than Ligand A (93.479), indicating better metabolic stability. This is a critical advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-28.566) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound's stability. Ligand A (58.112) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.568) has lower P-gp efflux than Ligand B (0.128), which is favorable.

**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 substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and P-gp efflux, but suffers from higher logP, DILI, and microsomal clearance, and a less favorable TPSA. Ligand B has better TPSA, logP, hERG, and significantly better metabolic stability (lower Cl_mic). The solubility for both is very poor, and the Caco-2 values are problematic. The negative half-life for Ligand B is a major red flag.

Despite the better affinity of Ligand A, the superior metabolic stability and lower hERG risk of Ligand B are more critical for an enzyme inhibitor. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies. The negative half-life for Ligand B is a showstopper.

Output:
0
2025-04-17 12:56:02,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.491 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.19) is better than Ligand B (85.23), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.157) is optimal, while Ligand B (1.277) is a bit low, potentially impacting permeability.

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

**H-Bond Acceptors:** Both ligands (4) are within the acceptable range of <= 10.

**QED:** Both ligands have good QED scores (0.738 and 0.759), indicating good drug-like properties.

**DILI:** Ligand A (15.743) has a significantly lower DILI risk than Ligand B (12.292), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.529) is better than Ligand B (50.679).

**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 absolute difference is significant. Ligand A (-5.242) is better than Ligand B (-5.337).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.766) is slightly better than Ligand B (-1.926).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.47 and 0.496), which is positive.

**Microsomal Clearance:** Ligand B (-17.114) has significantly lower (better) microsomal clearance than Ligand A (-6.936), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (26.739 hours) has a slightly longer half-life than Ligand A (24.109 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.099 and 0.035).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -9.4 kcal/mol). Ligand B is slightly better (-9.4 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand B has a significant advantage in metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. However, Ligand A has a much lower DILI risk and slightly better permeability and solubility. Considering SRC is an enzyme, metabolic stability is paramount. The slightly better affinity of Ligand B, combined with its superior metabolic stability, outweighs the slightly higher DILI risk and lower solubility.

Output:
1
2025-04-17 12:56:02,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (359.348 and 356.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.66) is better than Ligand B (42.43), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have acceptable logP values (2.106 and 3.592), 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:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good.

**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 (0.623 and 0.731), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 65.723, which is concerning, placing it in the higher risk category (>60). Ligand B has a significantly lower DILI risk of 31.834, which is favorable.

**8. BBB:** Both ligands have good BBB penetration (80.613 and 77.007), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.289 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 (-3.251 and -4.38), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**11. hERG Inhibition:** Ligand A (0.614) has a slightly higher hERG risk than Ligand B (0.485), but both are reasonably low.

**12. Microsomal Clearance:** Ligand A has a negative clearance (-5.645), which is excellent, indicating high metabolic stability. Ligand B has a high clearance (117.506), suggesting rapid metabolism and a shorter half-life.

**13. In vitro Half-Life:** Ligand A has a very long half-life (-8.583), which is excellent. Ligand B has a short half-life (-40.312).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.276).

**15. Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-6.9). This is a substantial advantage.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison:**

Ligand A has a much better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) than Ligand B. However, it has a significantly higher DILI risk. Both ligands have poor solubility and permeability. The strong affinity of Ligand A is a major advantage, and could potentially outweigh the DILI risk if further modifications can reduce it. The poor solubility and permeability are concerning for both, but could be addressed through formulation strategies.

Considering these factors, despite the higher DILI risk, Ligand A is the more promising candidate due to its substantially superior binding affinity and metabolic stability.

Output:
1
2025-04-17 12:56:02,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.65) is close to the 140 limit, while Ligand B (65.98) is well below, suggesting potentially better absorption for B.

**logP:** Ligand A (-0.301) is slightly low, potentially hindering permeation. Ligand B (1.066) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands (A: 5, B: 6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.51, B: 0.78), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 30.167, B: 34.393), below the 40 threshold.

**BBB:** Both ligands have moderate BBB penetration (A: 55.487, B: 67.041). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.471 and -4.846), which is unusual and likely indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.422 and -1.183), which is also unusual and a major red flag. Poor solubility will severely hamper bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.022, B: 0.165).

**Microsomal Clearance:** Ligand A (5.352) has a slightly higher clearance than Ligand B (3.356), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (3.963) has a better in vitro half-life than Ligand A (-14.378).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.004, B: 0.11).

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.3), a difference of 0.5 kcal/mol.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, the significantly better physicochemical properties of Ligand B make it the more promising candidate. Ligand B has a more optimal logP, fewer H-bond donors, a better half-life, and a lower microsomal clearance. Both ligands have concerningly poor predicted solubility and permeability. However, the slight advantage in affinity for A is unlikely to overcome the solubility/permeability issues. Given the enzyme-specific priorities, metabolic stability and solubility are crucial, and Ligand B is better positioned in those areas.

Output:
1
2025-04-17 12:56:02,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.369 Da and 358.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is better than Ligand B (87.32), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (1.889 and 0.897), falling within the 1-3 range. Ligand A is slightly preferred.

**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:** Ligand A (0.897) has a significantly better QED score than Ligand B (0.723), indicating a more drug-like profile.

**DILI:** Ligand A (48.313) has a slightly higher DILI risk than Ligand B (36.254), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.941) has a better BBB score than Ligand B (62.97).

**Caco-2 Permeability:** Both 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. Ligand A (-4.755) is slightly better than Ligand B (-4.853).

**Aqueous Solubility:** Ligand A (-2.963) has better aqueous solubility than Ligand B (-1.741). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.258) has a much lower hERG inhibition liability than Ligand B (0.585), which is a significant advantage.

**Microsomal Clearance:** Ligand A (2.724) has a much lower microsomal clearance than Ligand B (-16.997), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (8.465) has a significantly longer in vitro half-life than Ligand B (-15.714), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux liability than Ligand B (0.024), which is favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is the most important factor, and the 1.4 kcal/mol difference is substantial.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical parameters. Its superior binding affinity, metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, better solubility, and higher QED score make it a much more promising drug candidate for SRC kinase inhibition. While Ligand B has a slightly lower DILI risk, the other advantages of Ligand A outweigh this minor difference.

Output:
1
2025-04-17 12:56:02,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.36 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (78.51), both are below the 140 threshold for good absorption.

**logP:** Both ligands (1.946 and 1.197) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.763 and 0.805), indicating good drug-likeness.

**DILI:** Ligand A (40.985) has a slightly higher DILI risk than Ligand B (27.453), but both are below the concerning threshold of 60.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (59.325) is slightly better than Ligand B (45.909).

**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 is unknown.

**hERG:** Both ligands have very low hERG inhibition liability (0.075 and 0.066), which is excellent.

**Microsomal Clearance:** Ligand A (-4.467) exhibits significantly better metabolic stability (lower clearance) than Ligand B (12.561). This is a major advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-11.355) has a longer predicted half-life than Ligand B (7.31), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.03).

**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, and the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly improved metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The negative Caco-2 and solubility values are concerning for both, but the superior pharmacokinetic profile of Ligand A outweighs the small affinity difference. For an enzyme target like SRC kinase, metabolic stability and avoiding toxicity are paramount.

Output:
1
2025-04-17 12:56:02,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.33 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.4) is better than Ligand B (104.21), both are acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.228 and 1.678), 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 it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Ligand A (0.837) has a significantly better QED score than Ligand B (0.595), indicating a more drug-like profile.

**DILI:** Ligand A (98.565) has a very high DILI risk, which is a major concern. Ligand B (42.303) has a much lower, and acceptable, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.748) is better than Ligand B (30.283).

**Caco-2 Permeability:** Ligand A (-4.748) is slightly better than Ligand B (-5.272), but both are very poor.

**Aqueous Solubility:** Ligand A (-4.414) is slightly better than Ligand B (-2.324), but both are very poor.

**hERG:** Ligand A (0.161) has a much lower hERG risk than Ligand B (0.265), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-6.473) has significantly lower (better) microsomal clearance than Ligand B (21.168), indicating improved metabolic stability.

**In vitro Half-Life:** Ligand A (33.881) has a longer half-life than Ligand B (13.882), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.035).

**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:**

While Ligand A has better QED, metabolic stability, and lower hERG risk, its extremely high DILI risk is a major red flag. Ligand B, despite its lower QED and higher DILI, has a significantly stronger binding affinity, which is the most important factor for an enzyme inhibitor. The difference in binding affinity (-8.6 vs -6.9 kcal/mol) is substantial and likely outweighs the drawbacks of Ligand B. The DILI risk for Ligand B is still within a manageable range, and further optimization could potentially reduce it. The poor solubility and Caco-2 permeability of both compounds would need to be addressed, but these are formulation challenges.

Output:
1
2025-04-17 12:56:02,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.861 Da and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is well below the 140 threshold for good absorption, while Ligand B (91.34) is still acceptable but closer to the limit.

**logP:** Ligand A (2.371) is optimal (1-3). Ligand B (0.767) is slightly low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 3 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 (0.894 and 0.818), indicating drug-like properties.

**DILI:** Ligand A (33.152) has a significantly lower DILI risk than Ligand B (66.731). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (77.162) shows better penetration than Ligand B (54.866).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.523 and -4.632), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.627 and -0.705), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.581) has a lower hERG risk than Ligand B (0.214), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-12.153) has a *much* lower (better) microsomal clearance than Ligand B (-19.076), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (2.39 hours) has a better in vitro half-life than Ligand B (-17.49 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.082 and 0.018).

**Binding Affinity:** Ligand B (-8.9 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, and can be overcome by the superior ADME properties of Ligand A.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic and better t1/2), and lower hERG risk are crucial advantages for an enzyme inhibitor. The slightly lower logP of Ligand B is a concern, and the poor solubility and Caco-2 permeability are problematic for both. However, these can potentially be addressed through formulation strategies. The superior safety profile and metabolic stability of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 12:56:02,052 - INFO - Batch 171 complete. Total preferences: 2736
2025-04-17 12:56:02,052 - INFO - Processing batch 172/512...
2025-04-17 12:56:41,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.69) is slightly higher than Ligand B (71.33), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.125) is a bit low, potentially hindering permeability. Ligand B (2.045) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**QED:** Both ligands have similar QED values (0.8 and 0.817), indicating good drug-likeness.

**DILI:** Ligand A (30.128) has a significantly lower DILI risk than Ligand B (58.511). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (68.399 and 71.307), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.889 and -4.836). This is unusual and suggests poor permeability. However, the values are very close.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.761 and -2.291). This is also concerning, but again, the difference is not huge.

**hERG Inhibition:** Ligand A (0.17) has a lower hERG risk than Ligand B (0.238), which is favorable.

**Microsomal Clearance:** Ligand A (-18.603) has *much* lower microsomal clearance than Ligand B (42.61). This indicates significantly better metabolic stability for Ligand A, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (14.994) has a shorter half-life than Ligand B (23.242), but both are reasonably acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.195).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -9.5 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to outweigh other factors.

**Conclusion:**

While Ligand B has slightly better logP and binding affinity, Ligand A is significantly better in terms of DILI risk and, crucially, metabolic stability (lower Cl_mic). The solubility and permeability issues are present in both, but the superior safety and pharmacokinetic profile of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 12:56:41,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is well below the 140 threshold, while Ligand B (67.43) is also acceptable.

**3. logP:** Both ligands have logP values (2.511 and 2.847) 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 (3) are well below the limit of <=10.

**6. QED:** Ligand A (0.751) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**7. DILI:** Ligand A (25.979) has a significantly lower DILI risk than Ligand B (21.52). Both are good, but A is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.117) is better than Ligand B (57.193).

**9. Caco-2 Permeability:** Ligand A (-4.798) is better than Ligand B (-5.152), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.546) is better than Ligand B (-2.602), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.388 and 0.356).

**12. Microsomal Clearance:** Ligand B (40.323) has a lower microsomal clearance than Ligand A (64.033), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-12.134) has a longer in vitro half-life than Ligand A (9.082), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have similar low P-gp efflux liability (0.141 and 0.169).

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.1), a difference of 0.5 kcal/mol.

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic and longer t1/2) and a slightly better binding affinity. These are key factors for an enzyme target like SRC. While Ligand A has a better QED, DILI, solubility, and Caco-2 permeability, the metabolic stability advantage of Ligand B is more crucial. The 0.5 kcal/mol difference in binding affinity is enough to outweigh the minor ADME advantages of Ligand A.

Output:
1
2025-04-17 12:56:41,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.427 and 359.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.89) is slightly higher than Ligand B (74.07), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.422) is within the optimal range (1-3), while Ligand B (3.514) is at the higher end, potentially leading to solubility issues.

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

**H-Bond Acceptors:** Both ligands have 7 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.795 and 0.815), indicating good drug-like properties.

**DILI:** Ligand A (69.446) has a higher DILI risk than Ligand B (59.364), but both are below the concerning threshold of 60.

**BBB:** Ligand A (48.972) has lower BBB penetration than Ligand B (83.288). This is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.498 and -4.595), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-2.889) has better solubility than Ligand B (-5.037), which is a crucial advantage.

**hERG Inhibition:** Ligand A (0.567) has a lower hERG risk than Ligand B (0.916), which is a significant advantage.

**Microsomal Clearance:** Ligand A (53.635) has lower microsomal clearance than Ligand B (89.107), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-4.046) has a longer in vitro half-life than Ligand B (57.899), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.487) has lower P-gp efflux than Ligand B (0.195), which is preferable.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-7.7), but the difference is small (0.5 kcal/mol). Given the other ADME advantages of Ligand A, this difference is unlikely to be decisive.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has better solubility, lower hERG risk, lower microsomal clearance, longer half-life, and lower P-gp efflux. While Ligand B has a slightly better binding affinity, the ADME properties of Ligand A are significantly more favorable, outweighing the small difference in potency. The negative Caco-2 values are a concern for both, but Ligand A's other advantages make it the better choice for further optimization.

Output:
0
2025-04-17 12:56:41,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.5 and 348.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71 and 79.62) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (1.792 and 2.591) within the optimal 1-3 range.

**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:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (28.27%) has a slightly better DILI score than Ligand B (35.60%), indicating a lower risk of liver injury. Both are well below the concerning threshold of 60%.

**BBB:** Both ligands have similar BBB penetration (59.4 and 60.6%), which isn't a primary concern for a non-CNS target like SRC.

**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, indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.152 and 0.229), which is excellent.

**Microsomal Clearance:** Ligand A (30.73 mL/min/kg) has a slightly lower microsomal clearance than Ligand B (36.56 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.595 hours) has a significantly longer in vitro half-life than Ligand B (1.084 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.07 and 0.095).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). The difference is 0.5 kcal/mol, which is significant.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic) and in vitro half-life. The longer half-life is a substantial benefit for kinase inhibitors, potentially allowing for less frequent dosing. The slightly lower DILI risk is also a positive. The solubility and permeability concerns are shared by both, but the improved PK profile of Ligand A outweighs the small difference in binding affinity.

Output:
1
2025-04-17 12:56:41,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.364 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (26.3) is significantly better than Ligand B (78.6). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (4.862) is higher than Ligand B (2.757). While both are within the acceptable range (1-3 is optimal, up to 4 is tolerable), Ligand A is pushing the upper limit and could potentially have solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is more favorable than Ligand B (2 HBD, 5 HBA). Lower numbers are generally better for permeability.

**QED:** Both ligands have good QED scores (0.74 and 0.808), indicating good drug-like properties.

**DILI:** Ligand A (38.852) has a slightly better DILI score than Ligand B (46.219), both are acceptable.

**BBB:** Ligand A (87.127) has a better BBB score than Ligand B (71.384), but this isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.337) has a worse Caco-2 permeability than Ligand B (-4.977).

**Aqueous Solubility:** Ligand A (-5.835) has a worse aqueous solubility than Ligand B (-2.481). This is a concern for Ligand A given its higher logP.

**hERG:** Both ligands have very low hERG risk (0.869 and 0.776), which is excellent.

**Microsomal Clearance:** Ligand A (67.336) has a higher microsomal clearance than Ligand B (26.781). This suggests Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (26.106) has a longer half-life than Ligand B (4.497). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.515 and 0.554).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.7 kcal/mol and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has a slightly better BBB score and in vitro half-life, Ligand B is superior in several critical areas for an enzyme inhibitor. Specifically, its lower logP, better solubility, and significantly lower microsomal clearance (indicating better metabolic stability) outweigh the minor advantages of Ligand A. The comparable binding affinity makes these ADME properties the deciding factors.

Output:
1
2025-04-17 12:56:41,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly better positioned.

**TPSA:** Ligand A (74.57) is well below the 140 threshold for good absorption, while Ligand B (125.55) is still acceptable but less optimal.

**logP:** Ligand A (2.026) is within the optimal range (1-3). Ligand B (-0.911) is below 1, potentially hindering permeation.

**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 reasonable QED scores (A: 0.791, B: 0.616), indicating good drug-likeness.

**DILI:** Ligand A (36.642) has a significantly lower DILI risk than Ligand B (63.552). This is a major advantage.

**BBB:** BBB is not a primary concern for SRC kinase inhibitors as it's not a CNS target. Ligand A (35.052) and Ligand B (56.378) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.747) and Ligand B (-5.592) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without knowing the original units.

**Aqueous Solubility:** Ligand A (-2.569) and Ligand B (-1.263) both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unknown.

**hERG Inhibition:** Ligand A (0.398) has a much lower hERG risk than Ligand B (0.021). This is a critical advantage.

**Microsomal Clearance:** Ligand A (42.384) has a higher microsomal clearance than Ligand B (1.154), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (17.46 hours) has a longer in vitro half-life than Ligand A (19.493 hours), which is a slight advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.206, B: 0.005).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), but the difference is not substantial enough to overcome the significant ADME liabilities of Ligand B.

**Overall:**

Ligand A is the more promising candidate. While its metabolic stability (Cl_mic) is a concern, it exhibits significantly better DILI and hERG profiles, a more favorable logP, and a lower TPSA. The slightly weaker binding affinity of Ligand A can likely be addressed through further optimization. Ligand B's poor logP and higher DILI/hERG risks are substantial drawbacks that would be difficult to overcome.



Output:
0
2025-04-17 12:56:41,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.463 and 350.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is slightly higher than Ligand B (67.87). Both are below the 140 threshold for oral absorption, but Ligand B is preferable due to the lower TPSA.

**logP:** Both ligands have good logP values (2.332 and 1.501), falling within the optimal 1-3 range. Ligand B is slightly lower, which might slightly improve solubility.

**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 good QED scores (0.678 and 0.737), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 42.148, while Ligand B has 21.636. Ligand B is significantly better here, indicating a lower risk of liver injury.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.333) is better than Ligand B (65.801), but this is not a major deciding factor.

**Caco-2 Permeability:** Both have negative values (-4.528 and -4.662), which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability. They are both similarly poor.

**Aqueous Solubility:** Ligand A (-3.75) has poorer solubility than Ligand B (-1.925). Solubility is important for bioavailability, making Ligand B more favorable.

**hERG Inhibition:** Ligand A (0.266) has a slightly higher hERG risk than Ligand B (0.129). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (58.916) has higher microsomal clearance than Ligand B (45.253), suggesting lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (24.288 hours) has a significantly longer half-life than Ligand A (12.295 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.03), which is good.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B demonstrates superior ADMET properties, particularly in terms of DILI risk, solubility, metabolic stability (lower Cl_mic and longer t1/2), and hERG risk. The 1.3 kcal/mol difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. Given the enzyme-specific priorities, the improved ADMET profile of Ligand B makes it the more promising drug candidate.

Output:
1
2025-04-17 12:56:41,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.475 and 351.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is higher than Ligand B (43.86). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Both ligands (2.52 and 2.914) are 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 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.825) has a significantly higher QED score than Ligand B (0.474), indicating a more drug-like profile.

**DILI:** Ligand A (23.536) has a much lower DILI risk than Ligand B (10.934), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (84.878) is higher than Ligand A (76.231). This is less critical for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-5.287) is worse than Ligand B (-4.406), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.235) is worse than Ligand B (-1.501). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands (0.586 and 0.621) have similar, relatively low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (36.312) has lower microsomal clearance than Ligand B (79.046), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.566) has a longer in vitro half-life than Ligand B (4.61), which is desirable.

**P-gp Efflux:** Both ligands (0.127) have similar P-gp efflux liability.

**Binding Affinity:** Ligand A (-6.8) has slightly better binding affinity than Ligand B (-6.7), though the difference is small.

**Overall Assessment:**

Ligand A excels in key areas for an enzyme inhibitor: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. Its QED score is also significantly higher. While Ligand A has poorer Caco-2 permeability and solubility, the benefits in safety and metabolic stability outweigh these drawbacks, especially considering the small difference in binding affinity. Ligand B has better permeability and solubility, but the higher DILI risk and poorer metabolic stability are concerning.

Output:
0
2025-04-17 12:56:41,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.41 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is well below the 140 threshold, while Ligand B (95.08) is approaching it. This favors Ligand A for better absorption.

**logP:** Both ligands (0.539 and 0.639) are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors:** Ligand A has 0 HBD, which is excellent. Ligand B has 1, still acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable range.

**QED:** Both ligands have good QED scores (0.749 and 0.64), indicating drug-likeness.

**DILI:** Ligand A (33.23) has a significantly lower DILI risk than Ligand B (52.617), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.702) is higher than Ligand B (65.374).

**Caco-2:** Ligand A (-4.573) and Ligand B (-5.5) are both negative, which is unusual and suggests poor permeability. However, the absolute values are close.

**Solubility:** Ligand A (-0.848) is better than Ligand B (-1.397), suggesting better aqueous solubility.

**hERG:** Both ligands have very low hERG risk (0.135 and 0.043), which is excellent.

**Microsomal Clearance:** Ligand A (4.893) has a much lower Cl_mic than Ligand B (16.8), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.803) has a slightly better (less negative) half-life than Ligand B (-17.774), suggesting better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.068).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -7.9 kcal/mol), which are both excellent. The difference is negligible.

**Conclusion:**

Considering all factors, Ligand A is the more promising candidate. While both have good potency, Ligand A excels in crucial ADME properties: lower DILI risk, better solubility, and significantly improved metabolic stability (lower Cl_mic and better half-life). The slightly better TPSA and BBB values also contribute to its favorability. The slightly lower logP is a minor concern, but the substantial advantages in safety and metabolism outweigh this.

Output:
1
2025-04-17 12:56:41,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.422 and 350.375 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.16) is significantly better than Ligand B (121.08).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.072 and 1.171), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is slightly better balanced than Ligand B (HBD=2, HBA=6). Both are acceptable, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.748) has a better QED score than Ligand B (0.562), indicating a more drug-like profile.

**DILI:** Ligand B (67.197) has a higher DILI risk than Ligand A (47.732), though both are reasonably acceptable.

**BBB:** Ligand A (73.866) has better BBB penetration than Ligand B (33.075), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a major concern.

**Caco-2 Permeability:** Ligand A (-4.743) has better Caco-2 permeability than Ligand B (-5.196). Higher values are better.

**Aqueous Solubility:** Ligand A (-2.486) has better aqueous solubility than Ligand B (-2.206). Higher values are better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.402 and 0.132).

**Microsomal Clearance:** Ligand A (26.736) has a higher microsomal clearance than Ligand B (15.111). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand A (86.693) has a significantly longer in vitro half-life than Ligand B (2.579). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.091 and 0.081).

**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, exceeding the 1.5 kcal/mol threshold where it can outweigh other drawbacks.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.8 vs -6.4 kcal/mol) is the most important factor. While Ligand A has better ADME properties (TPSA, QED, solubility, half-life), the potency difference is large enough to compensate for the slightly higher DILI and lower metabolic stability. For an enzyme target like SRC kinase, potency is paramount.

Output:
1
2025-04-17 12:56:41,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.351 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.3) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (62.99) is well within the range.

**logP:** Both ligands have good logP values (3.068 and 2.088), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, fitting the <5 and <10 rules respectively. Ligand B has 0 HBD and 4 HBA, also fitting the rules.

**QED:** Both ligands have acceptable QED scores (0.786 and 0.722), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 81.427, which is high. Ligand B has a much lower DILI risk of 25.94, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (71.733 and 77.472), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.994 and -4.312), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.74 and -1.309), which is also unusual and suggests poor solubility. This is a potential issue for both.

**hERG Inhibition:** Ligand A has a hERG risk of 0.892, which is relatively low. Ligand B has a very low hERG risk of 0.237, which is excellent.

**Microsomal Clearance:** Ligand A has a Cl_mic of 48.562 mL/min/kg, which is moderate. Ligand B has a higher Cl_mic of 64.771 mL/min/kg, indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 33.063 hours, which is good. Ligand B has a shorter t1/2 of 29.793 hours, which is still acceptable but less desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.438 and 0.213).

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.1 kcal/mol) compared to 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 has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a significantly higher DILI risk. Ligand B has a much better safety profile (lower DILI, lower hERG) but weaker binding affinity. Considering the importance of potency for kinase inhibitors, the 1.6 kcal/mol difference in binding affinity is substantial. While the poor Caco-2 and solubility are concerning for both, these can potentially be addressed through formulation strategies. The high DILI risk of Ligand A is a major concern that is harder to mitigate.

Output:
1
2025-04-17 12:56:41,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.431 and 364.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is better than Ligand B (84.5), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.679 and 2.005), 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) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.779 and 0.837), indicating good drug-like properties.

**DILI:** Ligand A (51.105) has a significantly lower DILI risk than Ligand B (67.003). This is a substantial advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (67.158) is better than Ligand B (44.668).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.011 and -4.869), which 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 (-1.79 and -2.926) which is also unusual and suggests poor solubility. Ligand A is better than Ligand B.

**hERG:** Both ligands have very low hERG inhibition liability (0.172 and 0.212), which is excellent.

**Microsomal Clearance:** Ligand A (-2.471) has a much lower (better) microsomal clearance than Ligand B (59.144). This indicates significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (14.729 hours) has a better in vitro half-life than Ligand B (-18.221 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.223), which is favorable.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). The difference is 1.4 kcal/mol, which is significant but not overwhelming.

**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: lower DILI risk, significantly lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The solubility and permeability are poor for both, but the ADME advantages of Ligand A outweigh the small difference in binding affinity.

Output:
0
2025-04-17 12:56:41,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.423 and 364.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.33) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (42.43) is well below 140, indicating good absorption potential.

**logP:** Ligand A (1.243) is within the optimal 1-3 range. Ligand B (4.617) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 9 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.737 and 0.676), indicating good drug-like properties.

**DILI:** Ligand A (52.423) has a slightly higher DILI risk than Ligand B (31.291), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (81.698) has a higher BBB value than Ligand A (67.701), but this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability assessment. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Ligand A (-2.1) has better solubility than Ligand B (-5.006). Solubility is a key factor for enzyme inhibitors.

**hERG Inhibition:** Ligand A (0.165) has a much lower hERG risk than Ligand B (0.773), a significant advantage.

**Microsomal Clearance:** Ligand A (46.3 mL/min/kg) has lower clearance and therefore better metabolic stability than Ligand B (94.832 mL/min/kg).

**In vitro Half-Life:** Ligand A (-10.947 hours) has a longer half-life than Ligand B (18.278 hours). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux than Ligand B (0.86), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol), a difference of 1.0 kcal/mol. This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better ADME properties (solubility, hERG, metabolic stability, P-gp efflux), the significantly stronger binding affinity of Ligand B (-8.4 vs -7.4 kcal/mol) is a critical factor for an enzyme inhibitor. The 1.0 kcal/mol difference in binding is substantial and likely to translate to greater efficacy. The slightly higher logP and clearance of Ligand B are manageable concerns that could be addressed through further optimization.

Output:
1
2025-04-17 12:56:41,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.451 and 370.465 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (61.96 and 58.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.905 and 3.371) are within the optimal range of 1-3.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.891) has a higher QED than Ligand B (0.773), suggesting a more drug-like profile.

**DILI:** Ligand A (70.221) has a higher DILI risk than Ligand B (43.117). This is a significant negative for Ligand A.

**BBB:** Ligand A (61.807) has a lower BBB penetration than Ligand B (89.957). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.712 and -4.729). This is a concern for oral bioavailability.

**Aqueous Solubility:** Ligand A (-5.354) has worse solubility than Ligand B (-3.82). Solubility is important for formulation and bioavailability.

**hERG:** Ligand A (0.427) has a lower hERG risk than Ligand B (0.758). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (27.249) has significantly lower microsomal clearance than Ligand B (46.137), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-11.275) has a shorter in vitro half-life than Ligand B (25.437). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.379) has lower P-gp efflux than Ligand B (0.316), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-7.8). While the difference is small (0.3 kcal/mol), it is still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity, better metabolic stability (lower Cl_mic), lower P-gp efflux, and a better QED score. However, it has a higher DILI risk, worse solubility, and a shorter half-life. Ligand B has a lower DILI risk, better solubility, and a longer half-life, but it has lower binding affinity and worse metabolic stability.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the improved metabolic stability and binding affinity of Ligand A outweigh its drawbacks, especially considering the relatively small difference in binding affinity. The DILI risk is a concern, but could potentially be mitigated with further structural modifications. The solubility issue is also addressable through formulation strategies.

Output:
1
2025-04-17 12:56:41,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.5 and 344.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.51) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (117.52) is still under 140, but less favorable than A.

**logP:** Ligand A (3.896) is optimal (1-3). Ligand B (0.483) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3 respectively), within the guideline of <=5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 each), within the guideline of <=10.

**QED:** Both ligands have good QED scores (0.768 and 0.689), indicating drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (67.5 and 65.6), below the 60 threshold.

**BBB:** Ligand A (68.1) is better than Ligand B (43.8), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation, but we can assume they are both low permeability.

**Solubility:** Both have negative solubility values, which is also unusual and requires further investigation, but we can assume they are both low solubility.

**hERG:** Ligand A (0.817) has a lower hERG risk than Ligand B (0.159), which is preferable.

**Microsomal Clearance:** Ligand A (64.731) has a higher (worse) clearance than Ligand B (-18.126). Ligand B's negative value suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (68.805) has a longer half-life than Ligand B (-16.384). Ligand B's negative value suggests very high stability.

**P-gp Efflux:** Ligand A (0.438) has lower P-gp efflux than Ligand B (0.018), which is preferable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly better binding affinity than Ligand A (-8.7 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better logP, TPSA, hERG, and P-gp properties, Ligand B's superior binding affinity (-9.3 vs -8.7 kcal/mol) and significantly improved metabolic stability (Cl_mic and t1/2) are crucial for an enzyme target like SRC kinase. The lower logP of Ligand B is a concern, but might be mitigated with formulation strategies. The negative values for Caco-2 and solubility are concerning for both, but the binding affinity difference is a significant driver.

Output:
1
2025-04-17 12:56:41,117 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.45 and 350.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (132).  A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (1.783) is optimal. Ligand B (-0.033) is slightly low, potentially hindering permeation, but not drastically.

**H-Bond Donors:** Both have acceptable HBD counts (2 and 3, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), both are below the threshold of 10.

**QED:** Ligand A (0.81) is excellent, indicating high drug-likeness. Ligand B (0.635) is still acceptable, but lower.

**DILI:** Ligand B (41.877) has a much lower DILI risk than Ligand A (11.361), which is a significant advantage.

**BBB:** Both have moderate BBB penetration, but Ligand A (51.881) is lower than Ligand B (57.464). This isn't a major concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.884) is significantly worse than Ligand B (-5.463). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.538 and -2.643 respectively). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.362) has a lower hERG risk than Ligand B (0.034), which is a positive.

**Microsomal Clearance:** Ligand A (5.726) has higher microsomal clearance than Ligand B (3.984), meaning it's less metabolically stable. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-2.447) has a longer in vitro half-life than Ligand A (11.174), indicating better stability.

**P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux than Ligand B (0.017), which is a slight advantage.

**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 factor, as a 1.7 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

While Ligand A has better QED, logP, and hERG, Ligand B's superior binding affinity (-7.7 vs -9.7 kcal/mol) and lower DILI risk are critical advantages for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic and longer t1/2) and better solubility profile (though still poor) also favor Ligand B. The slightly lower Caco-2 permeability is a concern, but the strong binding affinity is likely to compensate.

Output:
1
2025-04-17 12:56:41,117 - INFO - Batch 172 complete. Total preferences: 2752
2025-04-17 12:56:41,117 - INFO - Processing batch 173/512...
2025-04-17 12:57:20,372 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.531 and 375.416 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (100.11) is slightly above the preferred <140, but acceptable. Ligand B (47.48) is excellent, well below 140.

**logP:** Ligand A (1.854) is within the optimal 1-3 range. Ligand B (3.374) is at the higher end of optimal, but still acceptable.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good, potentially aiding permeability.

**H-Bond Acceptors:** Ligand A (8) is within the acceptable limit of <=10. Ligand B (6) is also good.

**QED:** Both ligands have similar QED values (0.716 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (31.95), which is a significant concern.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (87.708) has a higher BBB value than Ligand A (38.736), but this is less critical here.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales where lower values indicate lower permeability, Ligand A (-5.366) is worse than Ligand B (-4.448).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.537) is slightly better than Ligand B (-3.604).

**hERG:** Ligand A (0.31) has a slightly better hERG profile than Ligand B (0.732).

**Microsomal Clearance:** Ligand A (47.84) has lower microsomal clearance than Ligand B (75.336), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.11) has a negative half-life, which is impossible. This is a red flag. Ligand B (-4.967) is also negative, but slightly less problematic. These values likely indicate issues with the assay or data quality.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.173).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), although both are good. The 0.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the better candidate despite slightly worse solubility. The key advantages are significantly lower DILI risk, better binding affinity, and a more favorable TPSA. The negative half-life values are concerning for both, but the DILI risk for Ligand A is a major drawback. The slightly better metabolic stability of Ligand A is outweighed by the other factors.

Output:
1
2025-04-17 12:57:20,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.316 and 385.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.25) is better than Ligand B (80.32), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands (2.885 and 2.302) 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=6) as it has fewer HBDs, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.913) has a significantly higher QED score than Ligand B (0.682), indicating a more drug-like profile.

**DILI:** Ligand B (55.874) has a lower DILI risk than Ligand A (74.796), which is a significant advantage.

**BBB:** Ligand A (93.253) has a much higher BBB penetration score than Ligand B (57.619). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.291) is better than Ligand B (-5.078), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.413) is better than Ligand B (-3.393), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.346 and 0.392), which is excellent.

**Microsomal Clearance:** Ligand A (19.919) has significantly lower microsomal clearance than Ligand B (45.147), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.789) has a longer in vitro half-life than Ligand B (10.65), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.116 and 0.121).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While Ligand A has a better affinity, the difference is not substantial enough to outweigh the other factors.

**Overall:**

Ligand A demonstrates a superior overall profile. It has a better QED score, better solubility, better permeability, lower clearance, and longer half-life. While Ligand B has a lower DILI risk and slightly better binding affinity, the advantages of Ligand A in ADME properties, particularly metabolic stability and solubility, are more crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 12:57:20,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.848 Da) is slightly higher than Ligand B (344.43 Da), but both are acceptable.

**TPSA:** Ligand A (79.37) is higher than Ligand B (42.43). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 2.939 and Ligand B at 4.24. Ligand A is preferable here, as Ligand B is approaching the upper limit where solubility issues can arise.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable range.

**QED:** Both ligands have similar QED values (0.802 and 0.778), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 85.576, which is high. Ligand B has a much lower DILI risk of 39.938, which is good. This is a significant advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 53.47, while Ligand B has 96.123. While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.683) has worse Caco-2 permeability than Ligand B (-4.5).

**Aqueous Solubility:** Ligand A (-4.835) has worse aqueous solubility than Ligand B (-3.939).

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.422, while Ligand B has 0.908. Ligand B is better here, indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (61.444) has lower microsomal clearance than Ligand B (94.873), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (45.075) has a shorter half-life than Ligand B (29.518). This favors ligand A.

**P-gp Efflux:** Ligand A (0.251) has lower P-gp efflux than Ligand B (0.69), which is favorable.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a major advantage for Ligand B, likely outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, lower DILI risk, better BBB penetration, and better hERG inhibition. However, Ligand A has better metabolic stability (lower Cl_mic) and half-life. The significantly stronger binding affinity of Ligand B (-9.0 kcal/mol vs 0.0 kcal/mol) is a critical advantage for an enzyme inhibitor, and the lower DILI risk is also very important. While Ligand A's metabolic stability is good, the potency difference is substantial enough to make Ligand B the more promising candidate.

Output:
1
2025-04-17 12:57:20,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.377 and 340.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is well below the 140 threshold, and excellent for oral absorption. Ligand B (99.65) is still acceptable but less optimal.

**logP:** Both ligands (3.072 and 3.416) are 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 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.766 and 0.508), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 86.739, which is high. Ligand B has a much lower DILI risk of 43.389, which is good. This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (73.905) is better than Ligand B (57.736).

**Caco-2 Permeability:** Ligand A (-4.485) is better than Ligand B (-5.729), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.29) is better than Ligand B (-3.715), indicating better solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.456 and 0.469), which is good.

**Microsomal Clearance:** Ligand A (91.62) has higher clearance than Ligand B (56.257), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand A (40.201) has a longer half-life than Ligand B (-12.843), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.223 and 0.477).

**Binding Affinity:** Ligand B (-7.9 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:**

Ligand B is the better candidate. While Ligand A has slightly better Caco-2 permeability, solubility, and half-life, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The slightly improved binding affinity of Ligand B further supports its selection. The high DILI risk of Ligand A is a major concern that outweighs its minor advantages. For an enzyme target, metabolic stability and safety (DILI) are crucial.

Output:
1
2025-04-17 12:57:20,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which could be advantageous for permeability. Ligand B (384.395 Da) is also good.

**TPSA:** Ligand A (91.93) is slightly above the preferred <140 for oral absorption, but still acceptable. Ligand B (58.64) is excellent, well below 140, suggesting good absorption.

**logP:** Both ligands have good logP values (A: 1.316, B: 2.233), 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 acceptable.

**QED:** Ligand A (0.765) has a better QED score than Ligand B (0.434), indicating a more drug-like profile.

**DILI:** Ligand A (60.682) has a slightly higher DILI risk than Ligand B (53.47), but both are within an acceptable range (<60 is good, and both are below 60).

**BBB:** Both ligands have good BBB penetration (A: 76.309, B: 83.443), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.135 and -5.071), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.392 and -3.41), which is also concerning and indicates poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.368, B: 0.257), which is excellent.

**Microsomal Clearance:** Ligand A (3.538) has significantly lower microsomal clearance than Ligand B (22.691), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (43.365) has a much longer in vitro half-life than Ligand B (-28.836), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.015, B: 0.116), which is good.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 0.5 kcal/mol difference is significant, but needs to be weighed against the ADME properties.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate due to its significantly better metabolic stability (lower Cl_mic and longer t1/2), better QED score, and acceptable DILI risk. The poor Caco-2 and solubility for both are concerning, but metabolic stability is paramount for kinase inhibitors. The slightly stronger binding of Ligand B might be overcome with further optimization, but starting with a more metabolically stable scaffold like Ligand A is a more prudent approach.

Output:
0
2025-04-17 12:57:20,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.463 and 350.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.89) is slightly higher than Ligand B (58.2). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**3. logP:** Both ligands have good logP values (2.197 and 2.964), 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, while Ligand B has 2. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.539 and 0.742), indicating a drug-like profile. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 30.748%, while Ligand B has 16.479%. Both are good (below 40%), but Ligand B is preferable.

**8. BBB:** Both ligands have high BBB penetration (83.87% and 84.141%), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.587) and Ligand B (-4.688) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-1.965) and Ligand B (-3.747) both have negative solubility values. Ligand B is better, but both are poor.

**11. hERG Inhibition:** Ligand A (0.262) has a lower hERG risk than Ligand B (0.567), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (60.598) has higher microsomal clearance than Ligand B (24.756). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (9.918) and Ligand B (10.281) have similar in vitro half-lives.

**14. P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.15), which is favorable.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This 1.4 kcal/mol difference 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 substantially better binding affinity, lower DILI risk, and significantly improved metabolic stability (lower Cl_mic). The stronger binding affinity is the most important factor for an enzyme inhibitor, and the improved metabolic stability will likely translate to better *in vivo* exposure. The slightly lower hERG risk of Ligand A is a positive, but the potency advantage of Ligand B is more critical.

Output:
1
2025-04-17 12:57:20,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.45 and 368.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.21 and 98.32) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.07 and 1.15) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5 HBA, meeting the criteria of <=5 and <=10 respectively.

**QED:** Both ligands have good QED scores (0.65 and 0.72), indicating drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (37.61 and 42.54), well below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (43.89) is slightly better than Ligand B (26.10), but not a deciding factor.

**Caco-2 Permeability:** Both are negative (-5.01 and -5.39), indicating poor permeability. This is a concern.

**Aqueous Solubility:** Both are negative (-1.53 and -2.73), indicating poor solubility. This is also a concern.

**hERG Inhibition:** Both ligands have very low hERG risk (0.07 and 0.45), which is excellent.

**Microsomal Clearance:** Ligand A (13.16) has lower clearance than Ligand B (16.29), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (-22.76) has a much longer half-life than Ligand A (-5.76). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.06).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.7 kcal/mol). This 2.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While both compounds have issues with Caco-2 permeability and solubility, Ligand A's significantly stronger binding affinity (-8.4 vs -5.7 kcal/mol) and better metabolic stability (lower Cl_mic) make it the more promising candidate. The affinity difference is large enough to potentially overcome the solubility/permeability issues through formulation strategies. Ligand B's longer half-life is attractive, but the weaker binding is a major drawback for an enzyme target.

Output:
1
2025-04-17 12:57:20,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.388 and 369.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.13) is excellent, well below the 140 threshold for good absorption. Ligand B (115.21) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.398) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.244) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 8 HBA) is also reasonable, though the higher HBA count could slightly impact permeability.

**QED:** Ligand A (0.799) has a very good drug-likeness score. Ligand B (0.48) is lower, indicating a less ideal drug-like profile.

**DILI:** Ligand B (74.176) has a higher DILI risk than Ligand A (52.772), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.121) shows good BBB penetration, while Ligand B (26.134) is low.

**Caco-2 Permeability:** Ligand A (-4.309) is poor, indicating low intestinal absorption. Ligand B (-5.424) is even worse.

**Aqueous Solubility:** Ligand A (-4.521) is poor. Ligand B (-2.454) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.833) shows a lower risk of hERG inhibition than Ligand B (0.048), which is a significant advantage.

**Microsomal Clearance:** Ligand A (43.154) has moderate clearance, while Ligand B (51.835) has higher clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-18.538) has a very long half-life, a major positive. Ligand B (1.188) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.461 and 0.007 respectively).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While its logP is slightly high and Caco-2 permeability is poor, it is significantly better in terms of DILI risk, hERG inhibition, and *especially* in vitro half-life. The long half-life is a major advantage for SRC inhibitors, potentially allowing for less frequent dosing. The similar binding affinities make these ADME properties the deciding factors.

Output:
0
2025-04-17 12:57:20,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.949 Da and 364.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.73) is significantly better than Ligand B (87.9). A TPSA under 140 is good for oral absorption, and A is much closer to the ideal for CNS penetration (under 90) than B.

**logP:** Ligand A (4.492) is slightly high, potentially causing solubility issues, but still within a manageable range. Ligand B (0.253) is very low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (0 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.617 and 0.715), indicating good drug-like properties.

**DILI:** Ligand A (9.112) has a much lower DILI risk than Ligand B (50.756). This is a significant advantage.

**BBB:** Both have reasonable BBB penetration (80.031 and 81.388), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.777) is poor, while Ligand B (-5.046) is also poor. Both show poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.727) is poor, while Ligand B (-1.805) is slightly better, but still poor.

**hERG:** Ligand A (0.945) has a lower hERG risk than Ligand B (0.196), which is a significant advantage.

**Microsomal Clearance:** Ligand A (51.263) has higher clearance than Ligand B (-2.326), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand A (41.16) has a longer half-life than Ligand B (12.936).

**P-gp Efflux:** Ligand A (0.433) has lower P-gp efflux than Ligand B (0.039), which is favorable.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.4), a 0.5 kcal/mol difference.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability. However, it suffers from a very low logP, potentially hindering permeability, and a significantly higher DILI risk. Ligand A, while having slightly weaker binding, has a much better safety profile (lower DILI and hERG), a more reasonable logP, and a longer half-life. The difference in binding affinity (0.5 kcal/mol) is not substantial enough to outweigh the ADME/Tox advantages of Ligand A, especially considering SRC is an enzyme target where metabolic stability and safety are crucial.

Output:
1
2025-04-17 12:57:20,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.519 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is better than Ligand B (66.37), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.452 and 1.205), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.637 and 0.78), indicating drug-like properties.

**DILI:** Ligand A (9.306) has a significantly lower DILI risk than Ligand B (10.702), which is a major advantage.

**BBB:** Ligand A (69.407) has a better BBB penetration score than Ligand B (59.131), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.922) shows better Caco-2 permeability than Ligand B (-5.409).

**Aqueous Solubility:** Ligand A (-2.095) has better aqueous solubility than Ligand B (-0.761), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.418) has a lower hERG inhibition liability than Ligand B (0.219), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand B (-12.011) has a much lower (better) microsomal clearance than Ligand A (38.046), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (9.358) has a longer in vitro half-life than Ligand B (5.963).

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux liability than Ligand B (0.033).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While a 1.3 kcal/mol difference is good, the other factors are more important.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better solubility, and lower hERG inhibition. While Ligand B has slightly better metabolic stability and binding affinity, the safety and pharmacokinetic advantages of Ligand A outweigh these benefits. The difference in binding affinity isn't large enough to overcome the ADME/Tox advantages of Ligand A.

Output:
1
2025-04-17 12:57:20,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (379.32 and 336.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.88) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (78.13) is well within the desirable range.

**logP:** Both ligands (2.051 and 1.93) are 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:** Ligand B (0.93) has a significantly better QED score than Ligand A (0.428), indicating a more drug-like profile.

**DILI:** Ligand A has a DILI risk of 88.057, which is high. Ligand B has a DILI risk of 68.98, still elevated but better than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (39.977) and Ligand B (46.452) both have low BBB penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.457 and -4.885), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4 and -3.591), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.621) has a slightly higher hERG risk than Ligand B (0.488), but both are relatively low.

**Microsomal Clearance:** Ligand B (-12.018) has a much lower (better) microsomal clearance than Ligand A (11.766), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (20.945 hours) has a significantly longer half-life than Ligand A (52.257 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.166 and 0.119).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This difference of 1.8 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity, better QED score, lower microsomal clearance (better metabolic stability), and longer half-life outweigh the concerns about solubility and permeability. The lower DILI risk is also a plus. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 12:57:20,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (351.491 and 351.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.51) is significantly better than Ligand B (104.46). A TPSA under 90 is preferred, and A is closer to that target, suggesting better permeability.

**3. logP:** Both ligands have similar logP values (1.858 and 1.801), 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:** Ligand B (0.662) has a better QED score than Ligand A (0.466), indicating a more drug-like profile. However, this is less critical than other factors for kinase inhibitors.

**7. DILI:** Ligand A (19.038) has a much lower DILI risk than Ligand B (49.632). This is a significant advantage for A.

**8. BBB:** Ligand A (61.691) has a better BBB percentile than Ligand B (39.822), but this is not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.688 and -4.969). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.773 and -1.701), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.199 and 0.104), which is excellent.

**12. Microsomal Clearance:** Ligand B (22.643) has significantly lower microsomal clearance than Ligand A (41.662), indicating better metabolic stability. This is a critical advantage for B.

**13. In vitro Half-Life:** Ligand B (-21.82) has a much longer in vitro half-life than Ligand A (-3.996), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.097).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.4). A difference of 0.4 kcal/mol is not huge, but is noticeable.

**Overall Assessment:**

Ligand A has a better TPSA, HBD, HBA, DILI risk, and binding affinity. However, Ligand B has a significantly better QED, lower microsomal clearance, and a much longer half-life. Given that we are targeting a kinase, metabolic stability (Cl_mic and t1/2) is paramount. The slightly better affinity of A is unlikely to overcome the substantial metabolic liabilities. The poor solubility and permeability are concerns for both, but formulation strategies could potentially mitigate these.

Output:
1
2025-04-17 12:57:20,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (394.287 Da and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands are below the 140 A^2 threshold (82.22 and 85.17), suggesting good absorption potential.

**logP:** Ligand A (4.399) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.547) is quite low, which could hinder membrane permeation.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 5 HBA, well within the acceptable limits. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.688 and 0.724), indicating generally drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.841, which is high and concerning. Ligand B has a much lower DILI risk of 25.553, which is very favorable.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB score (84.257) than Ligand A (45.909), but this is not a primary concern.

**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 indicate very low permeability. Ligand A (-4.716) is slightly better than Ligand B (-5.379).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.453 and -1.184). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.747) has a slightly higher hERG risk than Ligand B (0.116), but both are relatively low.

**Microsomal Clearance:** Ligand A (49.643) has a higher microsomal clearance than Ligand B (18.102), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B has a negative half-life (-0.468), which is not physically possible and likely an error or outlier. Ligand A has a reasonable half-life of 71.794 hours.

**P-gp Efflux:** Ligand A (0.321) has lower P-gp efflux liability than Ligand B (0.071), which is favorable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.8 vs -8.1 kcal/mol) and drastically lower DILI risk (25.553 vs 89.841) are major advantages. While the negative in vitro half-life is concerning, it may be an artifact of the data. The lower metabolic stability of Ligand A is also a significant concern. The slightly higher logP of Ligand A is also less desirable.

Output:
1
2025-04-17 12:57:20,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.367 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (101.7) is better than Ligand B (51.66). Lower TPSA generally indicates better cell permeability.

**logP:** Both ligands have similar logP values (A: 3.789, B: 3.763), falling within the optimal range of 1-3.

**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 (HBD <= 5, HBA <= 10).

**QED:** Ligand B (0.813) has a significantly higher QED score than Ligand A (0.585), indicating a more drug-like profile.

**DILI:** Ligand A (89.841) has a higher DILI risk than Ligand B (66.615). Lower DILI is preferred.

**BBB:** Ligand B (85.77) has a higher BBB penetration percentile than Ligand A (16.363). While not critical for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.058) has a much lower Caco-2 permeability than Ligand B (-4.831). This is a significant disadvantage for Ligand A.

**Aqueous Solubility:** Ligand A (-4.473) has slightly lower aqueous solubility than Ligand B (-3.696).

**hERG Inhibition:** Both ligands have similar, very low hERG inhibition liability (A: 0.317, B: 0.326). This is excellent.

**Microsomal Clearance:** Ligand A (34.131) has *much* lower microsomal clearance than Ligand B (64.932). This suggests better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-18.582) has a negative in vitro half-life, which is unusual and suggests very rapid metabolism. Ligand B (4.935) has a positive half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.15, B: 0.442).

**Binding Affinity:** Both ligands have the same binding affinity (-9.6 kcal/mol). This eliminates affinity as a differentiating factor.

**Conclusion:**

Despite Ligand A's better TPSA and lower Cl_mic, the significantly lower Caco-2 permeability, negative half-life, and higher DILI risk make it a less desirable candidate. Ligand B's superior QED, better solubility, positive half-life, and lower DILI risk outweigh the slightly higher clearance. The equal binding affinity further supports choosing Ligand B.

Output:
1
2025-04-17 12:57:20,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.467 Da) is slightly higher than Ligand B (346.475 Da), but both are acceptable.

**TPSA:** Ligand A (93.65) is slightly above the preferred <140, but still reasonable. Ligand B (76.02) is well within the acceptable range.

**logP:** Both ligands have good logP values (A: 1.188, B: 2.277), 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 4 HBA. Both are within acceptable limits (HBD <=5, HBA <=10).

**QED:** Both ligands have reasonable QED values (A: 0.807, B: 0.709), indicating good drug-like properties.

**DILI:** Ligand A (78.209) has a higher DILI risk than Ligand B (23.071). This is a significant concern, as a lower DILI score is highly desirable.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (70.027) has a higher BBB value than Ligand A (36.448), but this is not a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.901 for A, -4.751 for B), so this doesn't differentiate them significantly.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.321 for A, -3.163 for B), also unusual. Again, the values are similar and don't provide a clear advantage for either.

**hERG Inhibition:** Ligand A (0.273) has a slightly higher hERG risk than Ligand B (0.077), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand B (45.988) has a lower microsomal clearance than Ligand A (30.101), suggesting better metabolic stability, which is crucial for an enzyme target.

**In vitro Half-Life:** Ligand B (2.595) has a longer in vitro half-life than Ligand A (-10.496), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.076, B: 0.011), which is good.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 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 is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B exhibits significantly better ADME properties, particularly a much lower DILI risk and improved metabolic stability (lower Cl_mic and longer t1/2). For an enzyme target like SRC kinase, metabolic stability and safety (DILI) are paramount. The affinity difference, while notable, is likely surmountable with further optimization of Ligand B.

Output:
1
2025-04-17 12:57:20,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (92.5), both are below the 140 A^2 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (1.221 and 1.598), 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 acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.643 and 0.652), indicating good drug-likeness.

**DILI:** Both ligands have very low DILI risk (11.283 and 11.128 percentile), which is excellent.

**BBB:** Ligand B (80.07) has a significantly higher BBB penetration percentile than Ligand A (51.183). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.643) has slightly better Caco-2 permeability than Ligand B (-5.425), although both are negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.002 and -2.337). This is a concern, but can be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.192 and 0.213). This is excellent.

**Microsomal Clearance:** Ligand B (7.614 mL/min/kg) has significantly lower microsomal clearance than Ligand A (29.065 mL/min/kg). Lower clearance indicates better metabolic stability, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-29.714 hours) has a much longer in vitro half-life than Ligand A (14.695 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.026 and 0.028).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). While both are good, the 0.7 kcal/mol difference is meaningful.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity outweigh the slightly lower Caco-2 permeability and higher TPSA. Both ligands have acceptable profiles regarding safety (DILI, hERG), and drug-likeness (QED). The improved pharmacokinetic properties of Ligand B make it more likely to achieve adequate exposure *in vivo*.

Output:
1
2025-04-17 12:57:20,375 - INFO - Batch 173 complete. Total preferences: 2768
2025-04-17 12:57:20,375 - INFO - Processing batch 174/512...
2025-04-17 12:58:00,939 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (73.99) is still under 140, but less optimal than A.

**logP:** Both ligands (2.365 and 2.046) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent, minimizing potential issues. Ligand B (1) is still acceptable.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Ligand B (0.847) has a significantly higher QED score than Ligand A (0.385), indicating a more drug-like profile overall.

**DILI:** Both ligands have low DILI risk (31.059 and 29.779, respectively), which is positive.

**BBB:** Both ligands have reasonable BBB penetration (69.794 and 66.188), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a problem with the data.

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and suggests a problem with the data.

**hERG:** Both ligands show very low hERG inhibition risk (0.415 and 0.136), which is excellent.

**Microsomal Clearance:** Ligand B (15.139) has significantly lower microsomal clearance than Ligand A (26.288), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (26.415) has a much longer in vitro half-life than Ligand A (8.515), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.286 and 0.168).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered significant.

**Conclusion:**

Despite Ligand B having a better QED score, the overwhelmingly stronger binding affinity (-7.6 vs 0 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) of Ligand B make it the far more promising drug candidate for SRC kinase inhibition. The slightly higher TPSA of Ligand B is a minor drawback compared to these significant advantages. The negative solubility and Caco-2 values are concerning, but could be data errors.

Output:
1
2025-04-17 12:58:00,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (370.559 Da) is also well within the range.

**TPSA:** Ligand A (107.45) is moderately above the ideal <140, but not drastically. Ligand B (49.85) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (-0.134) is a bit low, potentially hindering permeation. Ligand B (2.642) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.603, B: 0.616), indicating good drug-likeness.

**DILI:** Ligand A (25.087) has a significantly lower DILI risk than Ligand B (20.744), which is a major advantage.

**BBB:** Ligand A (11.749) has very low BBB penetration, which is not a concern for a non-CNS target like SRC. Ligand B (83.831) has high BBB penetration, which isn't detrimental but also not a priority.

**Caco-2 Permeability:** Ligand A (-5.522) has poor Caco-2 permeability, which is a concern. Ligand B (-4.639) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-0.846) has poor solubility, while Ligand B (-3.39) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.189) has very low hERG risk, a significant advantage. Ligand B (0.837) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-12.097) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (75.499) has high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (11.404) has a reasonable half-life. Ligand B (-3.495) has a very short half-life.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is good. Ligand B (0.257) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.2) has a significantly stronger binding affinity than Ligand B (-6.4). This >1.5 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite solubility and Caco-2 permeability concerns for both, Ligand A is the superior candidate. Its significantly stronger binding affinity (-8.2 vs -6.4 kcal/mol) is the most important factor. Furthermore, it exhibits much lower DILI risk, lower hERG risk, and significantly better metabolic stability (lower Cl_mic, longer t1/2) than Ligand B. The lower logP and TPSA of Ligand A are less concerning given the potency advantage and the enzyme target class. While solubility is a concern, it can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 12:58:00,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.431 and 358.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.23) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**3. logP:** Ligand A (0.933) is a bit low, potentially hindering permeation. Ligand B (2.656) 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 5 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.801) has a better QED score than Ligand B (0.743), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.718) has a significantly lower DILI risk than Ligand B (41.334). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (63.048) has a lower BBB penetration than Ligand B (90.151). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.743) has a worse Caco-2 permeability than Ligand B (-4.548). Both are negative, suggesting poor permeability, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.666) has slightly better aqueous solubility than Ligand B (-2.803).

**11. hERG Inhibition:** Ligand A (0.11) has a much lower hERG inhibition risk than Ligand B (0.425). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (13.04) has a lower microsomal clearance than Ligand B (39.915), indicating better metabolic stability. This is crucial for an enzyme target.

**13. In vitro Half-Life:** Ligand A (8.007) has a shorter half-life than Ligand B (-2.742). This is a drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, while Ligand B (0.15) has slightly higher efflux.

**15. Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (0). This is the most important factor for an enzyme target. The difference of 7.7 kcal/mol is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is paramount for an enzyme inhibitor. While Ligand A has better QED, DILI, hERG, and metabolic stability, the substantial difference in binding affinity outweighs these advantages. The slightly better logP and TPSA of Ligand B are also beneficial. The lower half-life of Ligand A is a concern, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 12:58:00,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.853 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Ligand A (95.86) is higher than Ligand B (61.44). While both are below 140, Ligand B's lower TPSA is preferable for absorption.

**logP:** Both ligands have good logP values (A: 2.383, B: 2.004), 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 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED values (A: 0.736, B: 0.694), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 53.858, while Ligand B has 10.275. Ligand B is significantly better regarding liver injury risk.

**BBB:** Ligand A (20.318) has very low BBB penetration, while Ligand B (71.307) has good BBB penetration. Since SRC is not a CNS target, this is less critical, but still a point in favor of B.

**Caco-2 Permeability:** Ligand A (-5.45) has poor Caco-2 permeability, while Ligand B (-4.979) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.336) has poor solubility, while Ligand B (-2.061) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.353) and Ligand B (0.264) both have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (25.267) has higher microsomal clearance than Ligand B (18.181). This suggests Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-6.421) has a shorter in vitro half-life than Ligand B (10.435). This further supports Ligand B's better metabolic stability.

**P-gp Efflux:** Ligand A (0.182) has slightly higher P-gp efflux than Ligand B (0.033). Lower efflux is preferable.

**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. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand B has superior ADME properties (lower DILI, better metabolic stability, slightly better solubility and permeability, lower P-gp efflux), Ligand A boasts a significantly stronger binding affinity (-9.3 vs -7.9 kcal/mol). Given that we are targeting an enzyme (kinase), potency is paramount. The substantial affinity advantage of Ligand A is likely to outweigh its less favorable ADME profile, especially considering optimization strategies can be employed to improve its solubility and metabolic stability.

Output:
1
2025-04-17 12:58:00,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.43 and 352.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.65) is significantly better than Ligand B (87.66). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (2.32 and 1.37), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Fewer H-bond donors are generally better for permeability.

**QED:** Ligand A (0.773) has a higher QED score than Ligand B (0.585), indicating a more drug-like profile.

**DILI:** Ligand A (31.52) has a much lower DILI risk than Ligand B (6.75), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (91.20) is better than Ligand B (55.18).

**Caco-2 Permeability:** Ligand A (-4.759) is better than Ligand B (-5.134). Higher values indicate better absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.812 and -1.897). This is a concern for both, but needs to be addressed during lead optimization.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.377 and 0.273).

**Microsomal Clearance:** Ligand B (24.35) has lower microsomal clearance than Ligand A (42.15), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (18.36) has a significantly longer in vitro half-life than Ligand A (-17.48). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.173 and 0.016).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Overall Assessment:**

Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), which is crucial for an enzyme target. However, Ligand A has a significantly better safety profile (lower DILI), better QED, and slightly better permeability. The solubility is poor for both. Given the similar binding affinities, the lower DILI and better overall drug-likeness of Ligand A make it a slightly more promising starting point, despite the metabolic concerns which can be addressed through structural modifications.

Output:
0
2025-04-17 12:58:00,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.5 and 350.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is slightly higher than Ligand B (49.85), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.487 and 2.687), 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:** Both ligands have similar and good QED scores (0.737 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (35.789) has a slightly higher DILI risk than Ligand B (6.282), but both are below the concerning threshold of 40, indicating low risk.

**BBB:** Ligand B (83.443) has a much higher BBB penetration percentile than Ligand A (61.768). However, since SRC is not a CNS target, BBB is a lower priority.

**Caco-2 Permeability:** Ligand A (-5.056) has a lower Caco-2 permeability than Ligand B (-4.22), suggesting slightly poorer intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.349 and -2.011), which is a concern.

**hERG Inhibition:** Ligand A (0.776) has a slightly higher hERG inhibition liability than Ligand B (0.479), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (63.63) has a significantly higher microsomal clearance than Ligand A (17.947), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (5.269) has a longer in vitro half-life than Ligand B (-10.012), further supporting better metabolic stability for Ligand A.

**P-gp Efflux:** Ligand A (0.432) has lower P-gp efflux liability than Ligand B (0.106), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.6 kcal/mol), with Ligand B being slightly more potent. However, the difference is small and can be potentially overcome with optimization.

**Conclusion:**

Despite the slightly better potency of Ligand B, Ligand A is the more promising drug candidate. The significantly better metabolic stability (lower Cl_mic and longer t1/2) and lower P-gp efflux of Ligand A outweigh the slightly lower Caco-2 permeability and slightly higher DILI risk. The solubility is a concern for both, but can be addressed through formulation strategies. Given the enzyme-specific priorities, metabolic stability is paramount, making Ligand A the better choice.

Output:
0
2025-04-17 12:58:00,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.483 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.26) is slightly higher than Ligand B (60.93), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (4.155) is higher than the optimal range of 1-3, potentially leading to solubility issues. Ligand B (1.051) is at the lower end 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:** Both ligands have reasonable QED scores (0.892 and 0.759), indicating good drug-like properties.

**DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (20.706). This is a significant concern.

**BBB:** Both ligands have high BBB penetration (95.153 and 93.331), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.808 and -4.503), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Ligand A (-4.11) and Ligand B (-1.363) both have very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.455) has a slightly higher hERG risk than Ligand B (0.243), but both are relatively low.

**Microsomal Clearance:** Ligand A (57.196) has a higher microsomal clearance than Ligand B (19.428), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.806) has a slightly longer in vitro half-life than Ligand A (16.018).

**P-gp Efflux:** Ligand A (0.557) has a slightly higher P-gp efflux liability than Ligand B (0.064).

**Binding Affinity:** Ligand A (-8.8) has a slightly better binding affinity than Ligand B (-8.5). However, the difference is only 0.3 kcal/mol, which isn't substantial enough to overcome other issues.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While both have poor solubility and permeability, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slightly weaker binding affinity of Ligand B is less concerning than the higher DILI and lower metabolic stability of Ligand A.

Output:
1
2025-04-17 12:58:00,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is better than Ligand B (83.98). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**3. logP:** Both ligands (2.286 and 2.333) are 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 (4) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.825) has a higher QED score than Ligand B (0.532), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (43.001), which is a crucial advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.574) is higher than Ligand B (56.378).

**9. Caco-2 Permeability:** Ligand A (-4.692) is better than Ligand B (-5.187) indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.035) is better than Ligand B (-2.233).

**11. hERG Inhibition:** Both ligands (0.436 and 0.153) have low hERG inhibition liability, which is excellent. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (39.753) has lower microsomal clearance than Ligand B (47.641), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.653) has a longer in vitro half-life than Ligand B (-4.997), which is desirable.

**14. P-gp Efflux:** Both ligands (0.196 and 0.095) have low P-gp efflux liability.

**15. Binding Affinity:** Both ligands have similar binding affinity (-8.0 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better QED score, lower DILI risk, better TPSA, better solubility, better permeability, and better metabolic stability (lower Cl_mic and longer half-life). While both have excellent hERG profiles and comparable binding affinity, the ADME properties of Ligand A make it a more promising drug candidate.

Output:
1
2025-04-17 12:58:00,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.367 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.48) is slightly higher than Ligand B (72.88), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.063) is optimal, while Ligand B (1.399) is a bit low, potentially hindering permeation.

**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 similar QED values (0.711 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A (89.647) has a significantly higher DILI risk than Ligand B (13.571). This is a major concern for Ligand A.

**BBB:** Ligand A (70.027) has better BBB penetration than Ligand B (40.675), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.542 and -4.771), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Ligand A (-4.066) has slightly better solubility than Ligand B (-1.02), but both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.714 and 0.279).

**Microsomal Clearance:** Ligand A (79.318) has a higher microsomal clearance than Ligand B (38.208), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (2.942 hours) has a slightly longer half-life than Ligand A (14.904 hours), but both are relatively short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.278 and 0.032).

**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.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While its logP is a bit low and solubility is poor, its significantly lower DILI risk and better metabolic stability (lower Cl_mic) are crucial advantages. The slightly better binding affinity of Ligand B further supports this conclusion. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 12:58:00,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (43.78) is significantly better than Ligand B (53.01). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3), but Ligand B (4.193) is pushing the upper limit, potentially leading to solubility issues and off-target effects. Ligand A (2.827) is preferable.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 3, B: 5) counts.

**QED:** Both ligands have similar, good QED values (A: 0.775, B: 0.748).

**DILI:** Ligand A (10.585) has a much lower DILI risk than Ligand B (77.433), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (84.141) has a higher BBB percentile than Ligand B (58.511).

**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. Ligand A (-2.385) is slightly better than Ligand B (-4.746).

**hERG Inhibition:** Ligand A (0.921) has a lower hERG risk than Ligand B (0.512), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (31.614) has a lower microsomal clearance than Ligand B (37.64), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (29.229) has a longer half-life than Ligand B (-4.501), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.723) has lower P-gp efflux liability than Ligand B (0.238), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.5 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, the significant drawbacks in DILI risk, logP, solubility, and hERG inhibition are concerning. Ligand A, despite its slightly weaker binding, presents a much more balanced profile with better ADME-Tox properties, particularly the low DILI and hERG risk, and better metabolic stability. For an enzyme target like SRC kinase, prioritizing metabolic stability, solubility, and safety (hERG, DILI) alongside potency is crucial. The 1.4 kcal/mol difference in binding affinity, while notable, is not enough to overcome the substantial ADME/Tox liabilities of Ligand B.

Output:
0
2025-04-17 12:58:00,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (333.355 and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.41) is slightly above the preferred <140, while Ligand B (91.5) is well within. This favors B for absorption.

**logP:** Ligand A (3.09) is at the upper end of the optimal 1-3 range, while Ligand B (1.777) is closer to the lower end. Both are acceptable, but A could potentially have off-target issues.

**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 B is slightly better.

**QED:** Both ligands have good QED scores (0.578 and 0.764), indicating good drug-like properties.

**DILI:** Ligand A (86.39) has a significantly higher DILI risk than Ligand B (64.288). This is a major concern for A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.317) has a higher BBB score than A (29.818), but it's not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are on a similar scale, so this doesn't strongly favor either.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, similar and not a deciding factor.

**hERG:** Both ligands have relatively low hERG risk (0.743 and 0.793), which is good.

**Microsomal Clearance:** Ligand A (13.92) has a significantly lower (better) microsomal clearance than Ligand B (43.634). This suggests better metabolic stability for A.

**In vitro Half-Life:** Ligand A (-15.561) has a negative half-life, which is not possible and suggests a problem with the data or the molecule. Ligand B (6.639) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux (0.101 and 0.127), which is good.

**Binding Affinity:** Both have excellent binding affinities (-8.5 and -8.0 kcal/mol). The difference of 0.5 kcal/mol is not large enough to outweigh other significant differences.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand B is the more promising candidate. While Ligand A has better metabolic stability (lower Cl_mic), its significantly higher DILI risk and the impossible half-life value are major drawbacks. Ligand B has a lower DILI risk, a reasonable half-life, and comparable binding affinity. The slightly better TPSA and HBA count also favor Ligand B.

Output:
1
2025-04-17 12:58:00,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.308 Da) is slightly higher than Ligand B (358.479 Da), but both are acceptable.

**TPSA:** Ligand A (68.29) is significantly better than Ligand B (95.94). TPSA < 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Ligand A (4.239) is higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.193) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (A: 0.575, B: 0.572), indicating similar drug-likeness.

**DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (12.718). This is a significant advantage for Ligand B.

**BBB:** Ligand A (70.027) shows good BBB penetration, while Ligand B (25.94) is poor. However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.95) and Ligand B (-4.716) are both very poor, suggesting low intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.927) and Ligand B (-0.81) are both poor, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.746) has a slightly higher hERG risk than Ligand B (0.176). This favors Ligand B.

**Microsomal Clearance:** Ligand A (113.618) has higher microsomal clearance than Ligand B (78.887), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (77.953) has a longer half-life than Ligand B (-29.451). This is a strong advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.413) has lower P-gp efflux than Ligand B (0.023), meaning better bioavailability. This favors Ligand A.

**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 for Ligand B.

**Overall Assessment:**

Ligand B is clearly superior. While Ligand A has a longer half-life and better P-gp efflux, Ligand B excels in critical areas for an enzyme inhibitor: lower DILI risk, better metabolic stability (lower Cl_mic), slightly better binding affinity, and a more favorable logP. The solubility and Caco-2 permeability are poor for both, but these can be addressed with formulation strategies. The higher TPSA of Ligand B is less concerning than the higher DILI and lower metabolic stability of Ligand A.

Output:
1
2025-04-17 12:58:00,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.431 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is slightly higher than Ligand B (67.43), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (0.836) is a bit low, potentially hindering permeation, while Ligand B (2.701) is 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 (3).

**6. QED:** Both ligands have similar QED values (0.721 and 0.695), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (32.183 and 34.277), which is excellent.

**8. BBB:** Both ligands have reasonable BBB penetration (68.437 and 62.233), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these are often modeled values and can be unreliable.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, these are modeled values.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.131 and 0.203), which is highly desirable.

**12. Microsomal Clearance:** Ligand A (9.283) has significantly lower microsomal clearance than Ligand B (45.873), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (9.589) has a longer in vitro half-life than Ligand B (7.403), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.121).

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While both have acceptable DILI and hERG profiles, Ligand A boasts significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much stronger binding affinity. The slightly lower logP of Ligand A is a minor concern that could potentially be addressed through further optimization, but the superior potency and metabolic stability make it the preferred choice.

Output:
1
2025-04-17 12:58:00,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (366.868 Da) is also good.

**TPSA:** Ligand A (87.91) is better than Ligand B (51.02). Both are below the 140 A^2 threshold for good oral absorption, but Ligand A is closer to the 90 A^2 threshold for CNS penetration (though CNS penetration isn't a primary concern here).

**logP:** Ligand A (-0.486) is a bit low, potentially hindering permeation. Ligand B (3.885) is excellent, falling 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 is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.638, B: 0.712), indicating drug-like properties.

**DILI:** Ligand B (40.83) has a slightly higher DILI risk than Ligand A (19.504), but both are still considered relatively low risk (<40 is good).

**BBB:** Ligand B (81.621) has better BBB penetration than Ligand A (36.526), but this is not a primary concern for a non-CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.821 and -4.706), which is unusual and suggests poor permeability. This is a red flag for both compounds.

**Aqueous Solubility:** Both have negative solubility values (-1.016 and -4.018), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.065) has a much lower hERG risk than Ligand B (0.791). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-6.09) has a much lower (better) microsomal clearance than Ligand B (82.013). This indicates better metabolic stability for Ligand A, a critical factor for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-0.091) has a very short half-life, while Ligand B (32.359) has a much longer one. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is favorable. Ligand B (0.512) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -7.3 kcal/mol, B: -7.1 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has advantages in hERG risk, metabolic stability (Cl_mic), and P-gp efflux. However, Ligand B has a better logP, longer half-life, and better BBB penetration. Both compounds have concerningly poor solubility and permeability. Given the importance of metabolic stability for kinase inhibitors, and the lower hERG risk, Ligand A is slightly favored. However, the poor solubility and permeability of both compounds are major drawbacks that would need to be addressed through further optimization.

Output:
0
2025-04-17 12:58:00,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.299 Da) is slightly lower, which is generally favorable for permeability. Ligand B (365.543 Da) is also good.

**TPSA:** Ligand A (127.94) is borderline for good oral absorption (<=140), while Ligand B (43.86) is well within the optimal range.

**logP:** Ligand A (0.877) is a bit low, potentially hindering permeation. Ligand B (1.98) is better, falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 9 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.668, B: 0.699), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (97.635), which is a major concern. Ligand B has a very low DILI risk (16.092), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (59.248) has a higher BBB score than Ligand A (38.813), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.577) has poor Caco-2 permeability, indicating poor absorption. Ligand B (-5.105) also has poor Caco-2 permeability, but is slightly better than A.

**Aqueous Solubility:** Ligand A (-3.786) has poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-2.015) is better, but still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.227, B: 0.264), which is good.

**Microsomal Clearance:** Ligand A (51.818) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (25.729) has lower clearance, indicating better metabolic stability, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand B (7.948) has a significantly longer half-life than Ligand A (-7.144), which is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.072, B: 0.127), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.6 kcal/mol). While A has a better affinity, the difference is not substantial enough to overcome the other significant drawbacks.

**Conclusion:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising drug candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better logP outweigh the small difference in binding affinity. The poor solubility and permeability of both compounds are concerns, but can be addressed with formulation strategies. The high DILI risk of Ligand A is a major red flag that makes it less likely to progress as a drug candidate.

Output:
1
2025-04-17 12:58:00,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.406 and 360.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (79.96) is still acceptable, but less optimal than A.

**logP:** Both ligands (2.317 and 3.205) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.657 and 0.856), indicating drug-likeness.

**DILI:** Ligand A (58.55) has a slightly better DILI score than Ligand B (61.807), indicating lower potential for liver injury. Both are acceptable, but lower is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (89.104) has a higher BBB score than Ligand A (76.231), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.619) has a worse Caco-2 permeability than Ligand B (-5.3), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.285) has better aqueous solubility than Ligand B (-4.709), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.604 and 0.535), which is excellent.

**Microsomal Clearance:** Ligand A (35.187) has a significantly lower microsomal clearance than Ligand B (52.824), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (17.893) has a much longer in vitro half-life than Ligand A (2.115). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.278 and 0.038), which is good.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). The 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, solubility, and metabolic stability (lower Cl_mic). Ligand B has a better half-life and Caco-2 permeability. However, the stronger binding affinity of Ligand A, combined with its acceptable ADME properties, makes it the more promising candidate. The improved metabolic stability is particularly important for an enzyme target like SRC kinase. The slightly lower Caco-2 permeability of A is a concern, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 12:58:00,942 - INFO - Batch 174 complete. Total preferences: 2784
2025-04-17 12:58:00,942 - INFO - Processing batch 175/512...
2025-04-17 12:58:54,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.451 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (102.96 and 91.76) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Both ligands (1.189 and 1.265) are within the optimal 1-3 range, indicating good partitioning properties.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have acceptable QED scores (0.448 and 0.783), with Ligand B being significantly better.

**DILI:** Both ligands have similar, acceptable DILI risk (40.636 and 41.915 percentile).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.527) is slightly better than Ligand B (38.232).

**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:** Both ligands have very low hERG inhibition liability (0.385 and 0.165), which is excellent.

**Microsomal Clearance:** Ligand B (38.922 mL/min/kg) has significantly lower microsomal clearance than Ligand A (75.747 mL/min/kg), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (-23.577 hours) has a slightly better (less negative) in vitro half-life than Ligand A (-27.609 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.063 and 0.026).

**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 is not huge.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. It exhibits better metabolic stability (lower Cl_mic), a slightly improved in vitro half-life, and a better QED score. While both have concerning Caco-2 and solubility values, the improved metabolic profile of Ligand B is crucial for an enzyme inhibitor. The binding affinity difference is not large enough to overcome the ADME advantages of Ligand B.

Output:
1
2025-04-17 12:58:54,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):**
* Ligand A: 337.463 Da - Within the ideal range (200-500).
* Ligand B: 386.25 Da - Also within the ideal range.
* *Both are acceptable.*

**2. TPSA:**
* Ligand A: 38.33 A^2 - Excellent, well below the 140 A^2 threshold for oral absorption.
* Ligand B: 42.68 A^2 - Still good, below the 140 A^2 threshold.
* *Both are acceptable.*

**3. logP:**
* Ligand A: 4.575 - Slightly high, potentially leading to solubility issues or off-target interactions.
* Ligand B: 4.937 - Also high, similar concerns as Ligand A.
* *Both are slightly concerning, but not disqualifying.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Good, within the recommended limit of <=5.
* Ligand B: 0 - Excellent, even better.
* *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 2 - Good, within the recommended limit of <=10.
* Ligand B: 3 - Good, within the recommended limit of <=10.
* *Both are acceptable.*

**6. QED:**
* Ligand A: 0.803 - Excellent, indicating a highly drug-like profile.
* Ligand B: 0.707 - Very good, still a strong drug-like profile.
* *Both are acceptable.*

**7. DILI:**
* Ligand A: 39.744 - Excellent, low risk of drug-induced liver injury.
* Ligand B: 37.611 - Excellent, low risk of drug-induced liver injury.
* *Both are acceptable.*

**8. BBB:**
* Ligand A: 69.911 - Not a priority for a non-CNS target like SRC.
* Ligand B: 84.529 - Not a priority for a non-CNS target like SRC.
* *Both are acceptable.*

**9. Caco-2 Permeability:**
* Ligand A: -4.666 - Poor permeability.
* Ligand B: -4.16 - Poor permeability.
* *Both are concerning.*

**10. Aqueous Solubility:**
* Ligand A: -5.402 - Very poor solubility.
* Ligand B: -5.325 - Very poor solubility.
* *Both are concerning.*

**11. hERG Inhibition:**
* Ligand A: 0.573 - Low risk of hERG inhibition.
* Ligand B: 0.778 - Low risk of hERG inhibition.
* *Both are acceptable.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 111.14 mL/min/kg - High clearance, indicating poor metabolic stability.
* Ligand B: 88.798 mL/min/kg - High clearance, but slightly better than Ligand A.
* *Both are concerning, but B is slightly better.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -5.948 hours - Very short half-life.
* Ligand B: 65.181 hours - Long half-life.
* *Ligand B is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.507 - Low efflux, favorable.
* Ligand B: 0.46 - Low efflux, favorable.
* *Both are acceptable.*

**15. Binding Affinity:**
* Ligand A: -8.2 kcal/mol - Excellent, very strong binding.
* Ligand B: -7.0 kcal/mol - Good, strong binding.
* *Ligand A has a substantial advantage in potency.*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency, metabolic stability, solubility, and hERG risk are key. Ligand A boasts significantly higher binding affinity (-8.2 kcal/mol vs -7.0 kcal/mol), which is a major advantage. However, it suffers from very poor solubility, poor permeability, and high metabolic clearance (short half-life). Ligand B has better metabolic stability (longer half-life) and slightly better permeability, but its binding affinity is weaker.

The difference in binding affinity (1.2 kcal/mol) is substantial enough to potentially overcome the ADME liabilities of Ligand A *if* formulation strategies can address the solubility and permeability issues. However, the poor metabolic stability of Ligand A is a significant concern. Ligand B, while not as potent, has a much more favorable ADME profile, particularly the significantly longer half-life.

Considering the balance, and the potential to mitigate solubility issues with formulation, **Ligand A is the more promising candidate**, *provided* that solubility and permeability can be improved. The potency advantage is significant.

Output:
0
2025-04-17 12:58:54,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.523 and 338.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.29 and 100.97) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (2.217) is within the optimal 1-3 range. Ligand B (0.528) is a bit low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A (3 HBD, 3 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.591 and 0.771), indicating good drug-like properties.

**DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (68.98), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (62.699) is slightly better than Ligand B (31.02).

**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 don't necessarily disqualify the compounds.

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

**hERG:** Ligand A (0.277) has a lower hERG risk than Ligand B (0.103), which is preferable.

**Microsomal Clearance:** Ligand A (65.08) has higher microsomal clearance than Ligand B (18.994), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (3.856 hours) has a longer half-life than Ligand A (-5.109 hours), which is a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a substantially better binding affinity than Ligand B (-7.1 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Overall Assessment:**

Ligand A's significantly stronger binding affinity (-8.6 vs -7.1 kcal/mol) is a major advantage, and outweighs some of its drawbacks. While its solubility and permeability appear poor (negative values), the DILI risk is much lower than Ligand B, and the hERG risk is also lower. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), but the weaker binding affinity is a critical disadvantage for an enzyme target. Given the priorities for enzyme inhibitors, potency is paramount.

Output:
1
2025-04-17 12:58:54,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.374 and 390.456 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.47) is slightly higher than Ligand B (58.12), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (3.42) is within the optimal 1-3 range, while Ligand B (4.853) is slightly higher. While still potentially acceptable, the higher logP of B could lead to solubility issues or off-target interactions.

**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 (0.8 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (87.243) has a higher DILI risk than Ligand B (68.98). This is a significant drawback for Ligand A.

**BBB:** Ligand A (64.095) has a lower BBB penetration than Ligand B (94.843). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.821 and -4.817). This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-4.725 and -4.872). This is a significant concern for both, but slightly worse for B.

**hERG Inhibition:** Ligand A (0.633) has a slightly higher hERG risk than Ligand B (0.779), but both are relatively low.

**Microsomal Clearance:** Ligand A (22.57) has a significantly lower microsomal clearance than Ligand B (35.042), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (96.39) has a much longer in vitro half-life than Ligand B (-7.844), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.221) has lower P-gp efflux than Ligand B (0.581), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-10.6 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. The difference of 2.7 kcal/mol is quite large.

**Conclusion:**

Despite Ligand A's better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, the significantly stronger binding affinity of Ligand B (-10.6 vs -7.9 kcal/mol) is the deciding factor. The potency advantage is large enough to potentially overcome the slightly higher logP and DILI risk. The poor Caco-2 and solubility are concerns for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 12:58:54,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (344.405 and 354.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (33.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (66.71) is still acceptable, but higher, potentially impacting absorption.

**3. logP:** Ligand A (4.431) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.006) is within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of 5 (A: 0, B: 1).

**5. H-Bond Acceptors (HBA):** Both are within the acceptable limit of 10 (A: 2, B: 5).

**6. QED:** Both ligands have reasonable QED scores (A: 0.822, B: 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A (47.693) has a lower DILI risk than Ligand B (72.276), which is a significant advantage.

**8. BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (90.927) has higher BBB penetration than Ligand B (72.741), but it's not a deciding factor here.

**9. Caco-2 Permeability:** Ligand A (-4.693) has poor Caco-2 permeability, which is concerning. Ligand B (-5.06) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-4.916) has poor aqueous solubility, consistent with its high logP. Ligand B (-3.615) is better, but still not ideal.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.842, B: 0.672).

**12. Microsomal Clearance (Cl_mic):** Ligand A (43.468) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (48.883).

**13. In vitro Half-Life:** Ligand A (1.019) has a shorter half-life than Ligand B (17.681), which is a significant drawback.

**14. P-gp Efflux:** Ligand A (0.623) has lower P-gp efflux than Ligand B (0.175), which is favorable.

**15. 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, potentially outweighing some of the ADME concerns.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand B excels in binding affinity and has a much better half-life. While its solubility and Caco-2 permeability are not ideal, the strong binding affinity and better metabolic stability are more important for an enzyme target. Ligand A's poor Caco-2 and solubility, combined with a shorter half-life, are significant liabilities.

Output:
1
2025-04-17 12:58:54,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.813 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.99) is slightly higher than Ligand B (61.44), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.651 and 2.086), 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 similar QED values (0.728 and 0.628), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (74.952) compared to Ligand B (14.347). This is a major concern for Ligand A.

**BBB:** Ligand B (68.709) has a higher BBB penetration percentile than Ligand A (54.866), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.21) has a worse Caco-2 permeability than Ligand B (-4.843), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.871) has lower aqueous solubility than Ligand B (-2.563). Solubility is important for bioavailability.

**hERG:** Ligand A (0.614) has a slightly higher hERG risk than Ligand B (0.377), but both are relatively low.

**Microsomal Clearance:** Ligand B (62.53) has a significantly higher microsomal clearance than Ligand A (18.395). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-2.647) has a longer in vitro half-life than Ligand B (17.427). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux than Ligand B (0.307), which is favorable.

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-10). The difference of 2.2 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability and half-life, the significantly higher DILI risk and lower binding affinity are major drawbacks. Ligand B, despite slightly higher clearance, has a much better safety profile (lower DILI) and a substantially stronger binding affinity. The potency advantage of Ligand B is significant enough to overcome its slightly less favorable metabolic stability.

Output:
1
2025-04-17 12:58:54,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.873 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (82.49) is still under 140, but less optimal than A.

**logP:** Ligand A (3.428) is slightly above the optimal range but acceptable. Ligand B (2.32) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also good, but slightly higher counts.

**QED:** Both ligands have good QED scores (0.814 and 0.837), indicating drug-likeness.

**DILI:** Ligand A (33.075) has a lower DILI risk than Ligand B (29.818), both are very good.

**BBB:** Ligand A (90.151) has a significantly higher BBB penetration percentile than Ligand B (43.815). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.396) has a much better Caco-2 permeability than Ligand B (-5.145).

**Aqueous Solubility:** Ligand A (-4.569) has better aqueous solubility than Ligand B (-1.808). This is important for bioavailability.

**hERG:** Ligand A (0.622) has a lower hERG risk than Ligand B (0.365), which is a significant advantage.

**Microsomal Clearance:** Ligand A (68.607) has higher microsomal clearance than Ligand B (34.096), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (28.851) has a significantly longer in vitro half-life than Ligand A (-4.342). This is a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.21) has lower P-gp efflux than Ligand B (0.058), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.0). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in potency (affinity), permeability (Caco-2, TPSA), solubility, hERG risk, and P-gp efflux. Ligand B shines in metabolic stability (lower Cl_mic, longer t1/2). While Ligand B's metabolic stability is attractive, the superior potency, solubility, and safety profile (hERG) of Ligand A make it the more promising candidate. The 1.8 kcal/mol difference in binding affinity is significant.

Output:
1
2025-04-17 12:58:54,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (363.929 Da and 334.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.33) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (72.19) is still under 140, but less optimal than A.

**3. logP:** Ligand A (4.66) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (3.407) is 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 2 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.772 and 0.884, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (22.257) has a significantly lower DILI risk than Ligand B (62.195). This is a major advantage for A.

**8. BBB:** Both have good BBB penetration, but Ligand B (80.264) is slightly better than Ligand A (76.774). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.76) has worse Caco-2 permeability than Ligand B (-5.176), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.931 and -4.014, respectively). This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.653 and 0.62, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand B (17.135) has lower microsomal clearance than Ligand A (68.24), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (28.12) has a longer in vitro half-life than Ligand A (16.75), which is favorable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.707 and 0.671, respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9 kcal/mol and -8.6 kcal/mol, respectively). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has better metabolic stability and half-life, while Ligand A has a significantly lower DILI risk. Solubility is a concern for both. However, the lower DILI risk of Ligand A is a significant advantage, and the difference in metabolic stability isn't large enough to overcome that.

Output:
0
2025-04-17 12:58:54,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (336.351 and 352.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.71) is better than Ligand B (50.6). While both are acceptable, lower TPSA generally correlates with better cell permeability, which is beneficial.

**logP:** Both ligands have good logP values (1.419 and 2.758), falling within the optimal 1-3 range.

**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:** Both ligands have similar QED values (0.658 and 0.686), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (82.435) compared to Ligand B (12.253). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand B shows higher penetration (81.194) than Ligand A (26.638).

**Caco-2 Permeability:** Ligand A (-5.367) has a very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.451) is also poor, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-4.39) has poor aqueous solubility, while Ligand B (-1.99) is slightly better. Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.188) has a slightly better hERG profile than Ligand B (0.748), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-13.166) has significantly lower microsomal clearance, suggesting better metabolic stability than Ligand B (87.721). This is a significant advantage.

**In vitro Half-Life:** Ligand A (41.792) has a better in vitro half-life than Ligand B (26.791).

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux liability than Ligand B (0.097), which is favorable.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.2). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly better hERG profile. However, its major drawbacks are the very poor Caco-2 permeability, poor aqueous solubility, and significantly higher DILI risk.

Ligand B, while having a slightly weaker binding affinity and poorer metabolic stability, has a much lower DILI risk, better Caco-2 permeability, and better aqueous solubility.

Given the enzyme-specific priorities, metabolic stability is important, but DILI and solubility are critical. The high DILI risk and poor absorption of Ligand A are deal-breakers.

Output:
1
2025-04-17 12:58:54,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.385 and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (58.64), both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand B (3.523) is slightly higher than Ligand A (0.68). While Ligand A is a bit low, it's not a major concern. Ligand B is closer to 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 A (0.775) has a better QED score than Ligand B (0.592), indicating a more drug-like profile.

**DILI:** Ligand A (25.785) has a significantly lower DILI risk than Ligand B (53.354). This is a crucial advantage.

**BBB:** Both ligands have high BBB penetration (83.715 and 84.684), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed assuming these represent permeability, with lower values indicating poorer permeability. Ligand A (-4.702) is worse than Ligand B (-4.316).

**Solubility:** Ligand A (-2.536) has better solubility than Ligand B (-3.411).

**hERG:** Both ligands have low hERG risk (0.488 and 0.526).

**Microsomal Clearance:** Ligand A (-16.469) has significantly lower microsomal clearance than Ligand B (107.122). This indicates much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (23.102) has a longer in vitro half-life than Ligand B (19.02).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.025 and 0.543).

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is small (0.3 kcal/mol) and may not be 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, Ligand A demonstrates superior drug-like properties, particularly in DILI risk and metabolic stability (lower Cl_mic and longer t1/2). The better solubility and QED score also contribute to its favorability. The small difference in binding affinity is outweighed by the substantial improvements in ADME properties.

Output:
0
2025-04-17 12:58:54,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 369.374 Da - Within the ideal range (200-500 Da).
* Ligand B: 407.308 Da - Also within the ideal range.
* *No clear advantage here.*

**2. TPSA:**
* Ligand A: 108.22  - Acceptable, but approaching the upper limit for good oral absorption.
* Ligand B: 43.82 - Excellent, well below the 140 threshold and favorable for permeability.
* *Ligand B has a significant advantage in TPSA.*

**3. logP:**
* Ligand A: 1.157 - Optimal.
* Ligand B: 4.035 - High, potentially leading to solubility issues and off-target interactions.
* *Ligand A has a clear advantage in logP.*

**4. H-Bond Donors (HBD):**
* Ligand A: 0 - Good.
* Ligand B: 0 - Good.
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 8 - Acceptable.
* Ligand B: 5 - Acceptable.
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.532 - Good, above the 0.5 threshold.
* Ligand B: 0.766 - Excellent, indicating a strong drug-like profile.
* *Ligand B has an advantage in QED.*

**7. DILI:**
* Ligand A: 87.01 - High risk of liver injury.
* Ligand B: 40.83 - Low risk of liver injury.
* *Ligand B has a significant advantage in DILI.*

**8. BBB:**
* Ligand A: 72.741 - Acceptable, but not exceptionally high.
* Ligand B: 79.411 - Acceptable, slightly better than A.
* *Not a primary concern for SRC kinase, so the difference isn't crucial.*

**9. Caco-2 Permeability:**
* Ligand A: -4.785 - Poor permeability.
* Ligand B: -4.648 - Poor permeability.
* *Both are poor, but B is slightly better.*

**10. Aqueous Solubility:**
* Ligand A: -2.418 - Poor solubility.
* Ligand B: -4.717 - Very poor solubility.
* *Ligand A is slightly better, but both are problematic.*

**11. hERG Inhibition:**
* Ligand A: 0.031 - Very low risk of hERG inhibition.
* Ligand B: 0.888 - Moderate risk of hERG inhibition.
* *Ligand A has a significant advantage in hERG safety.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 45.725 mL/min/kg - Moderate clearance, suggesting moderate metabolic stability.
* Ligand B: 91.271 mL/min/kg - High clearance, suggesting poor metabolic stability.
* *Ligand A has a significant advantage in metabolic stability.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 14.219 hours - Moderate half-life.
* Ligand B: 23.357 hours - Good half-life.
* *Ligand B has an advantage in half-life.*

**14. P-gp Efflux:**
* Ligand A: 0.335 - Low efflux, favorable.
* Ligand B: 0.487 - Moderate efflux.
* *Ligand A has a slight advantage.*

**15. Binding Affinity:**
* Ligand A: -8.5 kcal/mol - Excellent binding affinity.
* Ligand B: -6.9 kcal/mol - Good binding affinity, but significantly weaker than A.
* *Ligand A has a substantial advantage in potency.*

**Overall Assessment:**

Given that we are targeting a kinase (SRC), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A demonstrates significantly stronger binding affinity (-8.5 vs -6.9 kcal/mol), lower DILI risk, better hERG safety, and improved metabolic stability (lower Cl_mic). While Ligand B has better TPSA and QED, the substantial advantage of Ligand A in potency and crucial ADME/Tox properties outweighs these benefits. The solubility issues with both compounds are a concern, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 12:58:54,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.471 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold for good absorption, and even favorable. Ligand B (88.1) is still acceptable, but less optimal.

**logP:** Ligand A (3.856) is at the higher end of the optimal range (1-3), but still acceptable. Ligand B (0.696) is quite low, 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 3 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**QED:** Ligand A (0.816) has a significantly higher QED score than Ligand B (0.668), indicating better overall drug-likeness.

**DILI:** Ligand A (66.344) has a higher DILI risk than Ligand B (15.316). This is a significant drawback for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (88.29) is higher than Ligand B (62.427).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.647) is slightly worse than Ligand B (-4.618).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-5.227) is slightly worse than Ligand B (-1.113).

**hERG Inhibition:** Ligand A (0.338) has a slightly higher hERG risk than Ligand B (0.243), but both are relatively low.

**Microsomal Clearance:** Ligand A (45.203) has a higher microsomal clearance than Ligand B (14.141), suggesting lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (30.75) has a longer half-life than Ligand B (6.923), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.189 and 0.024, respectively).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a lower QED and a lower BBB score, its significantly better binding affinity (-7.4 vs -8.1 kcal/mol) and much lower DILI risk (15.3 vs 66.3) outweigh the drawbacks. The lower logP is a concern, but the strong binding affinity could compensate. The better metabolic stability (lower Cl_mic) and longer half-life of Ligand A are positives, but not enough to overcome the DILI risk and weaker binding.

Output:
1
2025-04-17 12:58:54,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.877 and 366.527 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is higher than Ligand B (58.64). While both are reasonably low, Ligand B is better positioned for good oral absorption (<140).

**logP:** Both ligands have similar logP values (2.717 and 2.708), 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 and <=10 HBA).

**QED:** Both ligands have similar QED values (0.748 and 0.731), indicating good drug-like properties.

**DILI:** Ligand A (34.471) has a slightly higher DILI risk than Ligand B (13.532). Ligand B is significantly better here, falling well below the 40 threshold.

**BBB:** Ligand A (60.915) has a lower BBB penetration percentile than Ligand B (82.202). This isn't a primary concern for a kinase inhibitor, but it's a slight advantage for B.

**Caco-2 Permeability:** Ligand A (-4.78) has a worse Caco-2 permeability than Ligand B (-4.933). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.663) has worse aqueous solubility than Ligand B (-2.067). Solubility is a key factor for enzymes, and B is better here.

**hERG:** Both ligands have similar hERG inhibition liability (0.452 and 0.558), which is acceptable.

**Microsomal Clearance (Cl_mic):** Ligand A (-11.91) has a much lower (better) microsomal clearance than Ligand B (25.682). This indicates greater metabolic stability for Ligand A, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (32.85) has a significantly longer half-life than Ligand B (9.271). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.059) has lower P-gp efflux than Ligand B (0.139), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2). While both are excellent, the 0.2 kcal/mol difference is a positive for A.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), P-gp efflux, and has a slightly better binding affinity. Ligand B shines in DILI risk and solubility. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), Ligand A is the more promising candidate. The superior metabolic stability and longer half-life outweigh the slightly higher DILI risk and lower solubility.

Output:
0
2025-04-17 12:58:54,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.328 Da and 338.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.97) is slightly above the preferred <140, but acceptable. Ligand B (50.16) is excellent, well below 140.

**logP:** Both ligands have good logP values (2.262 and 3.142), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, which is acceptable (<=10). Ligand B has 4 HBA, which is also good.

**QED:** Both ligands have excellent QED scores (0.858 and 0.88), indicating good drug-likeness.

**DILI:** Ligand A has a concerning DILI risk (85.459), indicating a high potential for liver injury. Ligand B has a much lower and acceptable DILI risk (30.516). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (89.104) than Ligand A (50.019), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with absorption prediction. However, it's not a definitive dealbreaker without further investigation.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, further investigation is needed, but it's not a primary concern at this stage.

**hERG Inhibition:** Ligand A (0.633) has a slightly higher hERG risk than Ligand B (0.875), but both are reasonably low.

**Microsomal Clearance:** Ligand A (33.236) has a lower (better) microsomal clearance than Ligand B (69.731), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (6.071 and 6.653 hours), which are acceptable.

**P-gp Efflux:** Ligand A (0.042) has significantly lower P-gp efflux liability than Ligand B (0.639), which is a positive.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This 0.5 kcal/mol difference is significant, but must be weighed against the other factors.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity and lower P-gp efflux, the extremely high DILI risk (85.459) is a major red flag. The significantly lower DILI risk of Ligand B (30.516) makes it the more viable candidate, even with slightly lower affinity and higher P-gp efflux. The enzyme-specific priorities emphasize metabolic stability and safety (hERG, DILI), and Ligand B is superior in the critical safety aspect.

Output:
1
2025-04-17 12:58:54,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (383.25 and 370.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 49.41, which is well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.968) is slightly higher than Ligand B (2.973), both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 2 HBA, meeting the criteria of <=5 and <=10 respectively.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (66.421) has a significantly higher DILI risk than Ligand B (19.62). This is a major concern for Ligand A.

**BBB:** Ligand A (70.841) has moderate BBB penetration, while Ligand B (93.098) has high BBB penetration. While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.31 and -4.669). These values are unusual and suggest poor permeability. However, these values are on a log scale and the negative values are likely indicating very low permeability.

**Aqueous Solubility:** Ligand A (-5.101) has worse solubility than Ligand B (-3.129). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.569 and 0.609).

**Microsomal Clearance:** Ligand A (74.937) has significantly higher microsomal clearance than Ligand B (6.292). This suggests Ligand A is less metabolically stable.

**In vitro Half-Life:** Ligand B (-22.928) has a much longer in vitro half-life than Ligand A (41.018). A longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.151) has slightly higher P-gp efflux liability than Ligand B (0.033).

**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.

**Conclusion:**

Despite Ligand A's superior binding affinity, its significantly higher DILI risk, higher microsomal clearance, shorter half-life, and lower solubility make it a less desirable candidate. Ligand B, while having weaker binding affinity, exhibits a much better safety profile (lower DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The substantial difference in binding affinity *could* 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 12:58:54,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.543 and 370.465 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is better than Ligand B (58.2) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.392 and 3.371), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 3 HBA) as it has fewer H-bond donors, generally improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED values (0.767 and 0.773), indicating good drug-like properties.

**DILI:** Ligand A (21.869) has a significantly lower DILI risk than Ligand B (43.117). This is a major advantage for Ligand A.

**BBB:** Both have good BBB penetration (77.007 and 89.957), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.269) has a much lower hERG risk than Ligand B (0.758). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (53.017) has a higher microsomal clearance than Ligand B (46.137), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (25.437) has a significantly longer in vitro half-life than Ligand A (-9.013). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.066 and 0.316).

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.0), but the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand A excels in safety parameters (DILI and hERG) and has better TPSA and H-bonding characteristics. However, it suffers from lower metabolic stability (higher Cl_mic, shorter half-life) and poor solubility/permeability. Ligand B has better metabolic stability and a slightly better binding affinity, but it has higher DILI and hERG risks.

Considering the priorities for enzyme inhibitors, metabolic stability and potency are key. While Ligand B has a slight edge in potency and a significantly better half-life, the lower DILI and hERG risks associated with Ligand A are crucial for a viable drug candidate. The poor solubility/permeability of both is a concern that would need to be addressed through formulation or further chemical modifications. However, starting with a safer molecule is generally preferable.

Output:
0
2025-04-17 12:58:54,782 - INFO - Batch 175 complete. Total preferences: 2800
2025-04-17 12:58:54,782 - INFO - Processing batch 176/512...
2025-04-17 12:59:34,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for oral absorption. Ligand B (104.73) is still within acceptable limits, but less favorable.

**logP:** Ligand A (1.503) is optimal. Ligand B (0.359) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.763) is strong, indicating good drug-likeness. Ligand B (0.574) is acceptable, but less optimal.

**DILI:** Ligand A (31.718) has a very low DILI risk. Ligand B (13.339) also has a low DILI risk, but slightly higher than A.

**BBB:** Both ligands have low BBB penetration (63.358 and 31.214 respectively), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.752) has poor Caco-2 permeability, which is a concern. Ligand B (-5.095) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.935 and -1.59 respectively). This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.232 and 0.095 respectively).

**Microsomal Clearance:** Ligand A (45.418) has higher clearance than Ligand B (26.036), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-0.879) has a slightly longer half-life than Ligand A (9.839).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.009 respectively).

**Binding Affinity:** Ligand A (-9.4 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 has a superior binding affinity, which is paramount for an enzyme inhibitor. However, it has poorer Caco-2 permeability and higher microsomal clearance. Ligand B has better metabolic stability and a slightly longer half-life, but its binding affinity is considerably weaker. The solubility for both is quite poor. Considering the priorities for kinase inhibitors, the strong binding affinity of Ligand A is the most critical factor. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The difference in binding affinity (1.8 kcal/mol) is substantial enough to favor Ligand A despite its other weaknesses.

Output:
1
2025-04-17 12:59:34,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.419 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.95) is slightly above the preferred <140, but still reasonable. Ligand B (80.32) is excellent, well below 140.

**logP:** Both ligands have good logP values (2.419 and 1.687), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6/5 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.715 and 0.77), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 60.682, which is borderline high. Ligand B has a much lower DILI risk of 36.681, which is favorable.

**BBB:** Both have reasonable BBB penetration (70.182 and 64.25), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.208 and -5.373), 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 (-2.998 and -1.531), also unusual and suggesting poor solubility. Again, these are on a log scale.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.143 and 0.217), which is excellent.

**Microsomal Clearance:** Ligand A has a moderate Cl_mic (51.448), while Ligand B has a very low Cl_mic (2.742). This indicates significantly better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A has a negative half-life (-22.705), which is nonsensical. Ligand B has a reasonable half-life of 15.045 hours.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.072).

**Binding Affinity:** Ligand A has a significantly better binding affinity (-7.4 kcal/mol) than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the unusual solubility and permeability values, the most critical factor for an enzyme inhibitor is binding affinity and metabolic stability. Ligand A has a much stronger binding affinity, which is a significant advantage. However, Ligand B has a much better DILI score and significantly better metabolic stability (lower Cl_mic and a positive half-life). The negative half-life of Ligand A is a major red flag. Considering these factors, the superior binding affinity of Ligand A *could* outweigh its other drawbacks if the negative half-life can be addressed through structural modifications. However, the more balanced profile of Ligand B, with its better safety and metabolic properties, makes it a more immediately viable candidate.

Output:
1
2025-04-17 12:59:34,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.459 Da and 342.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.88) is better than Ligand B (71.58), both are below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (1.815 and 1.686), falling 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 3 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.854 and 0.848), indicating good drug-likeness.

**7. DILI:** Ligand A (26.871) has a significantly lower DILI risk than Ligand B (46.917). This is a substantial advantage.

**8. BBB:** Ligand A (77.898) has a better BBB penetration score than Ligand B (52.074). While not a primary concern for a non-CNS target, it's a slight positive.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.549) is slightly better than Ligand B (-4.691).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.928) is slightly better than Ligand B (-1.384).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.447 and 0.248).

**12. Microsomal Clearance:** Ligand B (34.559) has a lower microsomal clearance than Ligand A (41.5), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (37.368) has a longer in vitro half-life than Ligand A (-9.498). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.058).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.8 kcal/mol). Ligand B is slightly better (-8.8 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and in vitro half-life, Ligand A demonstrates a significantly lower DILI risk and slightly better solubility and permeability. Given the enzyme-specific priorities, the lower DILI risk of Ligand A is a critical advantage, outweighing the minor differences in other parameters. The binding affinity is comparable for both.

Output:
0
2025-04-17 12:59:34,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.455 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.79) is significantly better than Ligand B (96.11).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (3.322 and 2.151, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 4 HBA) in terms of HBD count, falling comfortably within the recommended limits. Both have acceptable HBA counts.

**QED:** Ligand A (0.858) has a superior QED score compared to Ligand B (0.669), indicating a more drug-like profile.

**DILI:** Ligand B (38.62) has a lower DILI risk than Ligand A (54.75), which is a significant advantage.

**BBB:** Ligand B (60.644) has a higher BBB percentile than Ligand A (44.397). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.802 and -4.872), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.678 and -3.715), which is also concerning and indicates poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.431 and 0.383), which is good.

**Microsomal Clearance:** Ligand A (23.902 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (50.935 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (30.646 hours) has a much longer in vitro half-life than Ligand B (1.112 hours), a major advantage.

**P-gp Efflux:** Ligand A (0.235) has a lower P-gp efflux liability than Ligand B (0.056), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial factor, and the 1.2 kcal/mol difference is very significant.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, the significantly stronger binding affinity of Ligand B (-7.2 kcal/mol vs 0.0 kcal/mol) is a decisive factor. This advantage in potency can potentially overcome the ADME liabilities, especially considering the enzyme target class. While Ligand A has better metabolic stability and a slightly better QED, the binding affinity difference is too large to ignore. The lower DILI risk for Ligand B is also a plus.

Output:
1
2025-04-17 12:59:34,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.41 and 340.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.68) is slightly higher than Ligand B (71.34). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands have good logP values (1.804 and 3.253), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**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, <=10 HBA).

**QED:** Both ligands have similar QED scores (0.557 and 0.515), indicating good drug-likeness.

**DILI:** Ligand A (25.475) has a significantly lower DILI risk than Ligand B (54.517). This is a major advantage for Ligand A.

**BBB:** Ligand A (84.917) has a higher BBB penetration percentile than Ligand B (61.729). While not crucial for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.816) and Ligand B (-4.959) have similar, poor Caco-2 permeability values.

**Aqueous Solubility:** Ligand A (-2.648) has better aqueous solubility than Ligand B (-3.517). This is important for bioavailability.

**hERG Inhibition:** Ligand A (0.585) has a lower hERG inhibition liability than Ligand B (0.828). This is a significant advantage for Ligand A, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (63.993) has a higher microsomal clearance than Ligand B (17.02). This indicates lower metabolic stability for Ligand A. This is a significant drawback.

**In vitro Half-Life:** Ligand B (71.668) has a much longer in vitro half-life than Ligand A (-20.93). This is a major advantage for Ligand B, suggesting less frequent dosing.

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.412).

**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 ADME drawbacks.

**Overall Assessment:**

Ligand A boasts a significantly better binding affinity and lower DILI/hERG risk, and better solubility. However, it suffers from higher microsomal clearance and poor Caco-2 permeability. Ligand B has a longer half-life, lower clearance, and slightly better TPSA, but its binding affinity is very weak, and it has higher DILI and hERG risks.

Given the priority for potency in enzyme inhibitors, the substantial binding affinity advantage of Ligand A (-8.4 vs 0.0 kcal/mol) is decisive. While the metabolic stability of Ligand A is a concern, it can be addressed through structural modifications during lead optimization. The lower DILI and hERG risks are also very favorable.

Output:
1
2025-04-17 12:59:34,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.37 and 364.56 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.05) is slightly higher than Ligand B (79.96). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets (less relevant here).

**logP:** Both ligands have good logP values (3.23 and 3.70), 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar, good QED scores (0.785 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A (82.78) has a higher DILI risk than Ligand B (62.66). This is a significant concern, as a DILI percentile >60 is considered high risk.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand B (84.14) has a higher BBB penetration than Ligand A (58.78), but this is less important in this case.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.87 and -5.16). This is unusual and suggests poor permeability. However, negative values can occur with certain modeling methods and aren't always directly interpretable.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.93 and -5.07). This is also unusual and suggests poor solubility. Similar to Caco-2, these values require careful interpretation.

**hERG Inhibition:** Ligand A (0.164) has a slightly lower hERG risk than Ligand B (0.633), which is preferable.

**Microsomal Clearance:** Ligand A (47.74) has significantly lower microsomal clearance than Ligand B (84.92). Lower clearance indicates better metabolic stability, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-33.73) has a much longer in vitro half-life than Ligand B (26.51). This is a substantial advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.162).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This difference of 2.6 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the significantly stronger binding affinity of Ligand A (-9.4 kcal/mol vs -6.8 kcal/mol), coupled with its superior metabolic stability (lower Cl_mic and longer t1/2) and lower hERG risk, make it the more promising candidate. While Ligand A has a higher DILI risk, the potency advantage is substantial and could potentially be mitigated through structural modifications during lead optimization.

Output:
1
2025-04-17 12:59:34,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.447 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is well below the 140 threshold for good absorption, while Ligand B (100.55) is also acceptable.

**logP:** Both ligands have good logP values (1.067 and 0.797) 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 acceptable QED scores (0.75 and 0.604), indicating good drug-likeness.

**DILI:** Ligand A (23.575) has a significantly lower DILI risk than Ligand B (41.915). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.731) has a better BBB score than Ligand B (43.505), but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-5.035) and Ligand B (-4.901) have similar Caco-2 permeability values.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.816 and -2.111), indicating poor solubility. This is a concern for both, but we need to consider other factors.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.061 and 0.047).

**Microsomal Clearance:** Ligand A (26.152) has a higher microsomal clearance than Ligand B (3.904). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-32.27) has a significantly longer in vitro half-life than Ligand A (-9.467). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.046).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a 2.0 kcal/mol difference, which is a substantial advantage, and outweighs many other concerns.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk than Ligand A, the significantly stronger binding affinity of Ligand A (-8.8 vs -6.8 kcal/mol) is the most important factor for an enzyme inhibitor. The 2.0 kcal/mol difference is a large advantage. The solubility issues are a concern for both, but can be addressed with formulation strategies. The lower DILI risk of Ligand A is also beneficial.

Output:
1
2025-04-17 12:59:34,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.336 Da) is slightly higher than Ligand B (372.809 Da), but both are acceptable.

**TPSA:** Ligand A (50.36) is well below the 140 threshold for oral absorption. Ligand B (102.88) is also below the threshold, but closer to it.

**logP:** Ligand A (4.277) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.273) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is well within the acceptable ranges. Ligand B (1 HBD, 8 HBA) is also acceptable, though the higher HBA count might slightly affect permeability.

**QED:** Both ligands have similar QED values (0.723 and 0.68), indicating good drug-likeness.

**DILI:** Ligand A (49.438) has a slightly better DILI score than Ligand B (70.182), indicating a lower risk of liver injury.

**BBB:** Both ligands have similar BBB penetration (69.252 and 68.748), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.882 and -4.82), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.952 and -2.651), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.912) has a slightly higher hERG risk than Ligand B (0.103), but both are relatively low.

**Microsomal Clearance:** Ligand B (67.119 mL/min/kg) has significantly lower microsomal clearance than Ligand A (105.162 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.449 hours) has a longer half-life than Ligand B (12.689 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.507) has lower P-gp efflux than Ligand B (0.015), suggesting better bioavailability.

**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 substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor permeability and solubility of both compounds, Ligand B stands out due to its significantly higher binding affinity (-8.6 kcal/mol vs -7.1 kcal/mol) and better metabolic stability (lower Cl_mic). The stronger binding is a crucial advantage for an enzyme inhibitor. While Ligand A has a slightly better DILI score and half-life, the potency of Ligand B is more critical. The solubility and permeability issues would need to be addressed through formulation strategies, but the superior binding makes Ligand B the more promising candidate.

Output:
1
2025-04-17 12:59:34,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (363.527 Da and 343.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.09) is slightly above the preferred <140, but still reasonable. Ligand B (62.3) is well within the acceptable range.

**3. logP:** Both ligands (3.142 and 2.936) 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 (4) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.697 and 0.864), indicating good drug-like properties.

**7. DILI:** Ligand A (40.52) is slightly higher than Ligand B (32.299), but both are below the concerning threshold of 60. Ligand B is preferable here.

**8. BBB:** This is less critical for an oncology target, but Ligand B (78.519) has a higher percentile than Ligand A (54.672).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.016) is slightly worse than Ligand B (-4.803).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.193) is slightly worse than Ligand B (-2.843).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.111 and 0.48). Ligand B is preferable.

**12. Microsomal Clearance:** Ligand B (42.02) has a lower clearance than Ligand A (52.846), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (16.912) has a longer half-life than Ligand A (13.732). This is also a positive for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.25 and 0.147). Ligand B is preferable.

**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 minor ADME drawbacks.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most relevant parameters. The most significant advantage is the stronger binding affinity (-8.4 vs -7.6 kcal/mol). Furthermore, Ligand B demonstrates better metabolic stability (lower Cl_mic), longer half-life, lower DILI risk, and better BBB penetration. While both have poor Caco-2 and solubility, the superior binding and ADME properties of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 12:59:34,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.689 Da) is closer to the upper limit, while Ligand B (365.455 Da) is more central.

**TPSA:** Ligand A (61.44) is well below the 140 threshold for oral absorption, and good. Ligand B (95.58) is also below the threshold, but higher than A.

**logP:** Ligand A (4.265) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.307) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is acceptable. Ligand A has 2 HBAs, while Ligand B has 5. Both are within the acceptable range of <=10.

**QED:** Both ligands have QED values above 0.5 (A: 0.764, B: 0.667), indicating good drug-like properties.

**DILI:** Ligand A (79.333) has a higher DILI risk than Ligand B (44.436). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.517) is better than Ligand B (27.646).

**Caco-2 Permeability:** Ligand A (-4.517) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.778) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.806) has very poor aqueous solubility, a major concern. Ligand B (-2.936) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.763) has a slightly elevated hERG risk, but manageable. Ligand B (0.028) has very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (46.377) has moderate clearance, suggesting reasonable metabolic stability. Ligand B (7.954) has very low clearance, indicating high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (88.421) has a long half-life, which is positive. Ligand B (4.266) has a very short half-life, a major drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.221, B: 0.015), which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage, as a 1.5 kcal/mol advantage is considered significant, and here the difference is over 8 kcal/mol.

**Overall Assessment:**

Ligand B is the stronger candidate despite its low logP and Caco-2 permeability. The significantly superior binding affinity (-8.2 vs 0.0 kcal/mol) and excellent metabolic stability (low Cl_mic, although short half-life) outweigh its drawbacks. Ligand A suffers from poor solubility, poor permeability, and a higher DILI risk, despite a longer half-life. The binding affinity of Ligand A is also very weak.

Output:
1
2025-04-17 12:59:34,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (341.459 and 367.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.97) is better than Ligand B (63.69) as it is closer to the threshold of 140, indicating better potential for oral absorption.

**3. logP:** Both ligands have similar logP values (2.055 and 2.14), 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 (5) and Ligand B (6) are both within the acceptable limit of 10.

**6. QED:** Ligand A (0.798) has a higher QED score than Ligand B (0.642), indicating a more drug-like profile.

**7. DILI:** Ligand B (30.438) has a significantly lower DILI risk than Ligand A (42.264), which is a major advantage.

**8. BBB:** Ligand A (86.002) has a higher BBB penetration potential than Ligand B (36.332), but BBB is not a primary concern for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.736 and -5.231), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, and both are similarly poor.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.805 and -1.174), indicating poor aqueous solubility. This is a concern, but can be addressed through formulation.

**11. hERG Inhibition:** Ligand A (0.819) has a slightly lower hERG inhibition risk than Ligand B (0.392), which is favorable.

**12. Microsomal Clearance:** Ligand A (-21.109) has a much lower (better) microsomal clearance than Ligand B (57.571), indicating greater metabolic stability. This is a critical advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (19.029) has a slightly longer in vitro half-life than Ligand B (17.045), which is a minor benefit.

**14. P-gp Efflux:** Ligand A (0.123) has a lower P-gp efflux liability than Ligand B (0.18), which is a slight advantage.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.3 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has advantages in QED, metabolic stability (Cl_mic), and P-gp efflux. However, Ligand B has a significantly lower DILI risk, which is a crucial safety parameter. While both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies. Given the importance of metabolic stability for kinase inhibitors and the similar binding affinities, Ligand A appears slightly more promising.

Output:
0
2025-04-17 12:59:34,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.491 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.45) is slightly higher than Ligand B (49.41), but both are acceptable for oral absorption (<140).

**logP:** Both ligands have good logP values (4.303 and 3.832), falling within the optimal 1-3 range.

**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 (0.693 and 0.712), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (64.754) compared to Ligand B (21.869). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (82.319) than Ligand A (59.364).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the measurement or the compounds themselves. However, the values are similar (-4.427 and -4.689).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.55 and -3.855). This is a significant drawback that would require formulation strategies.

**hERG Inhibition:** Ligand A (0.631) has a slightly higher hERG risk than Ligand B (0.541), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (66.396 and 66.904), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a negative half-life (-2.646), which is impossible and indicates a measurement error or instability. Ligand A has a half-life of 33.427 hours, which is good.

**P-gp Efflux:** Ligand A (0.699) has slightly higher P-gp efflux than Ligand B (0.318).

**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 could outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. Its significantly lower DILI risk, much better binding affinity, and more favorable P-gp efflux profile outweigh the issues with its reported half-life (which is likely erroneous) and slightly lower BBB penetration. The stronger binding affinity is a critical advantage for an enzyme inhibitor. Ligand A's higher DILI risk is a major red flag.

Output:
1
2025-04-17 12:59:34,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.479 Da and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is better than Ligand B (104.9), both are below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (0.99 and 0.737, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 6 HBA) as it has fewer HBDs. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.601 and 0.668), indicating good drug-likeness.

**DILI:** Ligand A (11.4) has a significantly lower DILI risk than Ligand B (30.748), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (43.273) has a slightly better BBB penetration score than Ligand A (38.813).

**Caco-2 Permeability:** Ligand A (-5.138) has a better Caco-2 permeability than Ligand B (-4.727).

**Aqueous Solubility:** Ligand A (-1.231) has slightly better aqueous solubility than Ligand B (-1.34).

**hERG:** Ligand A (0.177) has a significantly lower hERG inhibition liability than Ligand B (0.466), a crucial safety factor.

**Microsomal Clearance:** Ligand A (19.509 mL/min/kg) has a lower microsomal clearance than Ligand B (22.029 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (17.203 hours) has a much longer in vitro half-life than Ligand B (3.438 hours), which is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.017) has a lower P-gp efflux liability than Ligand B (0.236), indicating better bioavailability.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol) - a difference of 1.2 kcal/mol. This is a substantial difference and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is clearly the superior candidate. It exhibits a significantly better safety profile (lower DILI and hERG), improved metabolic stability (lower Cl_mic, longer t1/2), better P-gp efflux, and a substantially stronger binding affinity. While Ligand B has slightly better BBB penetration, this is not a priority for a non-CNS target like SRC.

Output:
0
2025-04-17 12:59:34,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.187 Da) is slightly higher than Ligand B (344.503 Da), but both are acceptable.

**TPSA:** Ligand A (98.34) is higher than Ligand B (38.82). While both are under 140, the lower TPSA of Ligand B is more favorable for absorption.

**logP:** Ligand A (4.062) is at the upper limit of the optimal range, potentially leading to solubility issues. Ligand B (2.641) is comfortably within the optimal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 4. Both are within the acceptable limit of 10, but Ligand B is preferable.

**QED:** Both ligands have good QED scores (A: 0.682, B: 0.861), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a high DILI risk (95.89%), which is a significant concern. Ligand B has a much lower DILI risk (19.193%), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (84.413%) has a higher BBB score than Ligand A (37.495%), but this is not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. It's difficult to interpret these values without further context, but they suggest poor permeability.

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

**hERG:** Ligand A (0.202) has a slightly higher hERG risk than Ligand B (0.886), meaning Ligand B is safer in this regard.

**Microsomal Clearance:** Ligand A (90.975) has a much higher microsomal clearance than Ligand B (-12.061). This means Ligand B is likely to have better metabolic stability and a longer half-life.

**In vitro Half-Life:** Ligand A has a negative half-life (-27.16), which is not possible. Ligand B has a half-life of 16.185 hours, which is reasonable. The negative value for Ligand A is a red flag.

**P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux than Ligand B (0.045), which is slightly favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate**. While both have excellent binding affinity, Ligand B has significantly better ADME properties: lower DILI risk, better logP, lower TPSA, better metabolic stability (lower Cl_mic and positive t1/2), and a lower hERG risk. The negative values for solubility and Caco-2 permeability are concerning for both, but the other advantages of Ligand B outweigh these issues. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 12:59:34,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.378 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is better than Ligand B (49.41). Both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.468) is within the optimal 1-3 range, while Ligand B (3.42) 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.829 and 0.777), suggesting good drug-like properties.

**DILI:** Ligand A (51.221) has a higher DILI risk than Ligand B (17.449). This is a significant concern.

**BBB:** Both ligands have similar BBB penetration (61.652 and 68.282), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.979 and -4.884) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.105 and -3.813), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.415 and 0.355).

**Microsomal Clearance:** Ligand A (-11.972) has significantly lower (better) microsomal clearance than Ligand B (53.011), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-32.295) has a negative half-life, which is not physically possible. Ligand B (-4.605) also has a negative half-life, which is also not physically possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.272).

**Binding Affinity:** Ligand B (-10.1 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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-10.1 vs -7.5 kcal/mol) outweighs the higher logP and slightly higher DILI risk. The lower microsomal clearance of Ligand A is attractive, but the large difference in binding affinity is the deciding factor. The negative half-life values for both compounds are concerning and would require further investigation.

Output:
1
2025-04-17 12:59:34,549 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.369 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is better than Ligand B (80.12), both are below the 140 threshold for good oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.523) is optimal, while Ligand B (1.069) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both below the 10 threshold.

**QED:** Both ligands have good QED scores (0.874 and 0.764), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (35.983 and 33.23), which is favorable.

**BBB:** Ligand A (85.615) has a significantly higher BBB percentile than Ligand B (58.511). While not a primary concern for a kinase inhibitor, it's a small positive for A.

**Caco-2 Permeability:** Ligand A (-4.678) has a worse Caco-2 permeability than Ligand B (-5.111), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.184) has a worse aqueous solubility than Ligand B (-1.188). This is a significant drawback for A.

**hERG Inhibition:** Ligand A (0.455) has a slightly higher hERG risk than Ligand B (0.053), but both are relatively low.

**Microsomal Clearance:** Ligand A (-14.969) has a *much* lower (better) microsomal clearance than Ligand B (6.333). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-15.135) has a much longer half-life than Ligand B (14.585).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.035).

**Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (0.0). This is a crucial difference. A difference of >1.5 kcal/mol is considered important.

**Overall Assessment:**

Ligand B's primary advantage is its significantly higher binding affinity (-7.7 kcal/mol vs 0.0 kcal/mol). This is a major factor for an enzyme inhibitor. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better TPSA, the lack of binding affinity is a deal-breaker. Ligand A's solubility is also poor. Ligand B's slightly lower logP is a minor concern that could potentially be addressed through further optimization, but the strong binding affinity makes it the more promising candidate.

Output:
1
2025-04-17 12:59:34,549 - INFO - Batch 176 complete. Total preferences: 2816
2025-04-17 12:59:34,549 - INFO - Processing batch 177/512...
2025-04-17 13:00:14,395 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.447 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.64) is well below the 140 threshold for good absorption, while Ligand B (122.03) is still acceptable but less optimal.

**logP:** Ligand A (1.305) is within the optimal 1-3 range. Ligand B (0.048) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (7) is acceptable.

**QED:** Both ligands have reasonable QED scores (0.768 and 0.635), indicating good drug-like properties.

**DILI:** Ligand A (25.553) has a significantly lower DILI risk than Ligand B (49.438), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (79.721) has a much higher percentile than Ligand B (17.332).

**Caco-2 Permeability:** Ligand A (-5.391) is very poor, while Ligand B (-5.416) is also poor. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.931) is better than Ligand B (-1.965), though both are quite poor.

**hERG:** Ligand A (0.759) has a much lower hERG risk than Ligand B (0.045), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-4.752) indicates very good metabolic stability (negative value suggests slow clearance), while Ligand B (2.668) suggests faster clearance.

**In vitro Half-Life:** Ligand A (22.424 hours) has a much longer half-life than Ligand B (0.191 hours).

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux than Ligand B (0.006).

**Binding Affinity:** Ligand B (-8.2 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 substantial.

**Conclusion:**

Despite the superior binding affinity of Ligand B, the significant drawbacks in ADME properties (high DILI, poor solubility, fast clearance, short half-life, and low P-gp efflux) make it a less desirable candidate. Ligand A, while having slightly weaker binding, exhibits a much more favorable safety profile (low DILI, low hERG), better metabolic stability (low Cl_mic, long t1/2), and better BBB penetration. The improved ADME profile of Ligand A is likely to translate to better *in vivo* efficacy and a reduced risk of adverse effects. The binding affinity difference, while notable, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 13:00:14,395 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.296 and 354.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.79) is significantly better than Ligand B (104.97). A TPSA under 90 is preferred, and Ligand A is comfortably within this range, suggesting better permeability. Ligand B is approaching a level that could hinder absorption.

**logP:** Ligand A (3.854) is optimal (1-3), while Ligand B (0.167) is quite low, potentially causing permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better balanced than Ligand B (2 HBD, 4 HBA). Both are within acceptable limits, but lower counts generally favor permeability.

**QED:** Both ligands have reasonable QED scores (0.846 and 0.68), indicating good drug-like properties.

**DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (19.038). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (79.062 and 80.845), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.259 and -4.997), which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Ligand A (-5.766) has significantly worse solubility than Ligand B (-1.142). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.809) has a slightly higher hERG risk than Ligand B (0.17), but both are relatively low.

**Microsomal Clearance:** Ligand A (88.964) has a higher microsomal clearance than Ligand B (0.877), indicating lower metabolic stability. This is a significant concern.

**In vitro Half-Life:** Ligand B (-3.217) has a longer in vitro half-life than Ligand A (2.015), which is desirable.

**P-gp Efflux:** Ligand A (0.504) has lower P-gp efflux than Ligand B (0.004), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.5 kcal/mol), with Ligand B being slightly better. The affinity difference is small enough that other factors become more important.

**Overall Assessment:**

Ligand A has a better logP and P-gp efflux, but suffers from significantly higher DILI risk, lower solubility, and higher microsomal clearance. Ligand B, despite its lower logP, has a much better safety profile (DILI), solubility, and metabolic stability. The slightly better affinity of Ligand B is a bonus. Given the enzyme-specific priorities, the superior ADME properties of Ligand B outweigh the minor affinity difference.

Output:
1
2025-04-17 13:00:14,395 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.67 and 96.25) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.675) is optimal, while Ligand B (0.393) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) 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 (0.743 and 0.662), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (36.06 and 38.503), below the 40 threshold.

**BBB:** Ligand B (69.833) has a higher BBB penetration percentile than Ligand A (55.254), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.883) has better Caco-2 permeability than Ligand B (-5.197), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-1.169) has better aqueous solubility than Ligand B (-2.124).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.303 and 0.105).

**Microsomal Clearance:** Ligand B (-12.193) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand A (21.135).

**In vitro Half-Life:** Ligand B (1.116) has a slightly longer in vitro half-life than Ligand A (-12.974).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.166 and 0.02).

**Binding Affinity:** Both ligands have identical binding affinities (-7.9 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has slightly better metabolic stability and half-life, Ligand A has better logP, Caco-2 permeability, and solubility. Given the importance of solubility and permeability for enzyme inhibitors, and the equal binding affinity, Ligand A is slightly more favorable.

Output:
1
2025-04-17 13:00:14,395 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.49 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold for absorption. Ligand B (89.8) is still acceptable but less favorable.

**logP:** Both ligands have good logP values (2.437 and 1.261), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.474 and 0.737), with Ligand B being slightly more drug-like.

**DILI:** Both ligands have low DILI risk (35.983 and 32.842 percentile), which is good.

**BBB:** Ligand A has a higher BBB penetration (81.815%) than Ligand B (62.97%), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.689) shows poor permeability, while Ligand B (-5.086) is also poor. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-2.961) has slightly better solubility than Ligand B (-1.596), but both are quite poor.

**hERG:** Ligand A (0.486) has a much lower hERG risk than Ligand B (0.153), which is a significant advantage.

**Microsomal Clearance:** Ligand A (72.584) has a higher clearance than Ligand B (7.079), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-0.828) has a very short half-life, while Ligand B (31.267) has a much longer half-life.

**P-gp Efflux:** Ligand A (0.27) has lower P-gp efflux than Ligand B (0.022), which is favorable.

**Binding Affinity:** Ligand A (-8.7 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 ADME liabilities.

**Conclusion:**

Despite Ligand A's poor permeability, solubility, and metabolic stability, its *much* stronger binding affinity (-8.7 vs -6.5 kcal/mol) is a decisive factor. For an enzyme target like SRC kinase, potency is paramount. While the ADME properties of Ligand A are concerning, they could potentially be addressed through further optimization. Ligand B's better ADME profile is overshadowed by its weaker binding affinity.

Output:
1
2025-04-17 13:00:14,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.463 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.47) is slightly higher than Ligand B (60.85). Both are below the 140 A^2 threshold for good oral absorption, but lower is generally preferred.

**logP:** Ligand A (0.871) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (2.509) is within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are acceptable, below the 10 threshold.

**QED:** Ligand A (0.829) has a better QED score than Ligand B (0.613), suggesting a more drug-like profile.

**DILI:** Ligand A (21.52) has a significantly lower DILI risk than Ligand B (13.959), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 65.452, Ligand B: 68.127). This isn't a primary concern for a kinase inhibitor, but it's good to see they aren't completely blocked.

**Caco-2 Permeability:** Ligand A (-4.988) has slightly better Caco-2 permeability than Ligand B (-4.54), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-0.994) has better aqueous solubility than Ligand B (-1.571). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.219, Ligand B: 0.22). This is excellent.

**Microsomal Clearance:** Ligand A (-6.571) has *much* lower microsomal clearance than Ligand B (22.628). This indicates significantly better metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (14.23) has a better in vitro half-life than Ligand B (-4.157).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.013, Ligand B: 0.13).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial difference (1.7 kcal/mol), and is a significant advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is superior in almost every ADMET property. The significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better solubility of Ligand A are critical advantages for a kinase inhibitor. The slightly weaker binding affinity of Ligand A (-6.9 kcal/mol) is still considered good, and the improvements in ADMET properties are likely to translate to better *in vivo* efficacy. The affinity difference is not large enough to overcome the substantial ADMET advantages of Ligand A.

Output:
0
2025-04-17 13:00:14,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (356.423 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (116.84 and 108.12) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.244) is slightly low, potentially hindering permeation. Ligand B (1.453) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (4) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (8) are both acceptable, being less than 10.

**QED:** Both ligands have reasonable QED scores (0.499 and 0.38), indicating moderate drug-likeness.

**DILI:** Ligand A (35.014) has a significantly lower DILI risk than Ligand B (47.15), both are under the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.205) is slightly better than Ligand B (54.091).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.305 and -5.467), indicating poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.859 and -2.189), indicating poor solubility. This is also a significant concern for both.

**hERG Inhibition:** Ligand A (0.102) has a much lower hERG risk than Ligand B (0.763). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (23.054) has a lower microsomal clearance, suggesting better metabolic stability, compared to Ligand B (48.852). This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-21.779) has a negative half-life, which is unusual and suggests very rapid degradation. Ligand B (55.45) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.12).

**Binding Affinity:** Ligand B (-7.2 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 B has a significantly better binding affinity, which is paramount for an enzyme inhibitor. 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 hERG risk, and lower P-gp efflux. The negative Caco-2 and solubility values are concerning for both. The half-life of Ligand A is problematic.

Despite the superior affinity of Ligand B, the lower hERG and better metabolic stability of Ligand A, combined with the lower DILI risk, make it a slightly more promising starting point for optimization. The affinity difference, while significant, might be addressable through further medicinal chemistry, whereas mitigating the safety concerns of Ligand B could be more challenging.

Output:
0
2025-04-17 13:00:14,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.503 and 338.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (50.16). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable due to the lower TPSA.

**3. logP:** Both ligands have good logP values (2.807 and 3.142), falling 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.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.595 and 0.88), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (12.796) has a significantly lower DILI risk than Ligand B (30.516). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (70.105) and Ligand B (89.104) both have good BBB penetration, but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.772 and -4.898). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.898 and -3.058). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.372) has a lower hERG inhibition liability than Ligand B (0.875), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (64.213) and Ligand B (69.731) have similar microsomal clearance values. Neither is exceptionally low, but they aren't alarmingly high either.

**13. In vitro Half-Life:** Ligand B (6.653) has a much longer in vitro half-life than Ligand A (-3.908). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.639). This is a slight advantage for Ligand A.

**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 has advantages in DILI risk and hERG inhibition, while Ligand B has a better QED score, longer half-life, and lower TPSA. The negative solubility and Caco-2 values are concerning for both. However, given the importance of metabolic stability for kinase inhibitors, and the substantial difference in half-life, Ligand B is the slightly more promising candidate. The better QED score also contributes to its favorability.

Output:
1
2025-04-17 13:00:14,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.47 and 346.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is slightly higher than Ligand B (49.85). Both are below the 140 threshold for good oral absorption, which is favorable.

**logP:** Both ligands have similar logP values (3.176 and 3.259), 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 3 HBA, which is well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.604 and 0.679), indicating drug-like properties.

**DILI:** Ligand A (47.732) has a slightly better DILI score than Ligand B (54.634), both are acceptable (<60).

**BBB:** Ligand B (98.139) has a much higher BBB percentile than Ligand A (77.007). However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.587 and -4.349). This is unusual and suggests poor permeability. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.678 and -3.863). Similar to Caco-2, this is concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.542) has a slightly higher hERG risk than Ligand B (0.418), but both are relatively low.

**Microsomal Clearance:** Ligand B (81.17) has a significantly higher microsomal clearance than Ligand A (62.377), indicating lower metabolic stability. This is a crucial disadvantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (15.543) has a positive half-life, while Ligand B (-5.476) has a negative half-life. This is a major red flag for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.186 and 0.176).

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage.

**Conclusion:**

Despite the concerning permeability and solubility data, the significantly stronger binding affinity of Ligand B (-7.8 kcal/mol vs 0.0 kcal/mol) is a major advantage that likely outweighs the poorer metabolic stability and half-life. The higher affinity suggests a lower dose could be effective, potentially mitigating some ADME issues. Ligand A's better metabolic stability is appealing, but its almost non-existent binding affinity makes it unlikely to be a viable candidate. The negative Caco-2 and solubility values for both are concerning and would require further investigation (e.g., salt screening, formulation studies).

Output:
1
2025-04-17 13:00:14,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.458 Da and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.33) is slightly above the preferred <60 for optimal absorption, while Ligand B (53.09) is well within.

**logP:** Ligand A (-0.599) is a bit low, potentially hindering permeability. Ligand B (1.225) 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 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.687 and 0.699), indicating good drug-likeness.

**DILI:** Ligand A (6.32) has a very low DILI risk, significantly better than Ligand B (15.587).

**BBB:** Ligand A (36.293) has a low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (82.047) has good BBB penetration, but this is less relevant here.

**Caco-2 Permeability:** Ligand A (-5.024) shows poor permeability, which is a significant drawback. Ligand B (-4.223) is also not great, but slightly better than A.

**Aqueous Solubility:** Ligand A (0.656) has poor solubility, while Ligand B (-1.148) is even worse. Both are concerning.

**hERG Inhibition:** Ligand A (0.245) has a very low hERG risk, which is excellent. Ligand B (0.457) is also relatively low, but higher than A.

**Microsomal Clearance:** Ligand A (-19.659) indicates very low clearance and therefore good metabolic stability. Ligand B (21.85) has a positive clearance value, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-31.215) shows a long half-life, which is desirable. Ligand B (-26.547) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable. Ligand B (0.14) has slightly higher efflux.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.5). However, the difference is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Conclusion:**

Despite Ligand B having slightly better binding affinity and BBB penetration, Ligand A is the more promising candidate. Its significantly lower DILI risk, excellent hERG profile, very low clearance (high metabolic stability), long half-life, and minimal P-gp efflux outweigh the slightly lower solubility and permeability. The poor permeability of Ligand A could potentially be addressed through formulation strategies. The solubility issue is also less critical given the other favorable properties.

Output:
0
2025-04-17 13:00:14,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.395 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (43.18) is significantly better than Ligand A (94.38). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have acceptable logP values (A: 2.573, B: 4.019). Ligand A is slightly better, being closer to the optimal 1-3 range. Ligand B is approaching the upper limit where solubility issues might arise.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits, but Ligand A's profile is slightly more balanced.

**QED:** Both ligands have good QED scores (A: 0.553, B: 0.67), indicating good drug-like properties.

**DILI:** Ligand A (83.133) has a significantly higher DILI risk than Ligand B (35.75). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.79) has a higher BBB score, but it's not a deciding factor here.

**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, and it's hard to interpret.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.838, B: 0.796).

**Microsomal Clearance:** Ligand A (-7.835) has *much* lower microsomal clearance than Ligand B (50.503). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (31.239 hours) has a much longer half-life than Ligand B (13.803 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.21, B: 0.575).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.8 kcal/mol, B: -7.9 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A has a superior metabolic stability profile (lower Cl_mic, longer t1/2) and slightly better binding affinity. However, its significantly higher DILI risk is a major drawback. Ligand B has a much better DILI profile, a lower TPSA, but suffers from poorer metabolic stability and a shorter half-life.

Given the enzyme-specific priorities, metabolic stability is crucial. However, a high DILI risk is a significant safety concern that would likely halt development. While Ligand A's affinity and stability are attractive, the DILI risk is too high. Therefore, Ligand B is the more viable candidate, despite its metabolic shortcomings, as these can potentially be addressed through further optimization.

Output:
1
2025-04-17 13:00:14,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.4 and 370.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.33) is slightly higher than Ligand B (51.22), but both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (2.932) is optimal, while Ligand B (4.127) is approaching the higher end of the optimal range. This could potentially lead to solubility issues for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.777) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Ligand A (74.254) has a higher DILI risk than Ligand B (68.786), but both are still reasonably acceptable.

**BBB:** Both ligands have good BBB penetration, but Ligand B (80.419) is better than Ligand A (70.997). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close enough to each other that this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-5.006) is slightly worse than Ligand B (-4.904).

**hERG Inhibition:** Ligand A (0.787) has a slightly higher hERG risk than Ligand B (0.681), but both are relatively low.

**Microsomal Clearance:** Ligand A (58.589) has a slightly higher microsomal clearance than Ligand B (55.039), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.639 hours) has a significantly longer half-life than Ligand A (-0.921 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.597) has lower P-gp efflux than Ligand B (0.273), which is favorable.

**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 better candidate. Its superior binding affinity, significantly longer half-life, and lower P-gp efflux outweigh the slightly higher logP and DILI risk. While both have poor solubility, the longer half-life of Ligand B suggests it might be more effectively distributed and maintained in the body despite solubility limitations.

Output:
1
2025-04-17 13:00:14,396 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.419 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.65) is better than Ligand B (119.28), both are below the 140 threshold for oral absorption, but A is closer to the optimal range.

**logP:** Ligand A (0.55) is slightly better than Ligand B (0.333). Both are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar and good QED scores (0.857 and 0.828).

**DILI:** Ligand A (45.173) has a significantly lower DILI risk than Ligand B (60.915), which is a major advantage.

**BBB:** Ligand A (81.97) has a better BBB percentile than Ligand B (73.827), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-4.986) has a better Caco-2 permeability than Ligand B (-5.502).

**Aqueous Solubility:** Ligand A (-1.139) has better aqueous solubility than Ligand B (-2.391). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.301 and 0.306), which is excellent.

**Microsomal Clearance:** Ligand A (-8.116) has a much better (lower) microsomal clearance than Ligand B (-10.34), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.857) has a better (longer) in vitro half-life than Ligand B (-17.883). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.017).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). The difference of 1.4 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall:** Ligand A is superior to Ligand B across most critical parameters. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a stronger binding affinity. While both have acceptable profiles, Ligand A presents a more favorable profile for development as a kinase inhibitor.

Output:
1
2025-04-17 13:00:14,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.383 Da) is slightly lower than Ligand B (371.503 Da), which is not a significant difference.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption. Ligand A (95.94 A^2) is slightly better than Ligand B (98.74 A^2).

**logP:** Ligand A (1.31) is within the optimal range (1-3). Ligand B (-0.019) is slightly below 1, which *could* indicate potential permeability issues, but is not a major concern at this stage.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (Ligand A: 2/5, Ligand B: 3/5), staying within the guidelines.

**QED:** Ligand A (0.784) has a better QED score than Ligand B (0.529), indicating a more drug-like profile.

**DILI:** Ligand A (54.207) has a higher DILI risk than Ligand B (13.843). This is a significant negative for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't critical for a non-CNS target like SRC kinase. Ligand A (52.074) is slightly better than Ligand B (36.371).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.858) is slightly better than Ligand B (-5.522).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.494) is slightly better than Ligand B (-1.457).

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.18, Ligand B: 0.109), which is excellent.

**Microsomal Clearance:** Ligand B (10.528 mL/min/kg) has significantly lower microsomal clearance than Ligand A (40.01 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Both ligands have negative half-life values, which is not physically possible. This suggests an issue with the data or the assay. However, the magnitude of negativity is similar for both (-16.251 for A, -18.221 for B).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.023, Ligand B: 0.008), which is favorable.

**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 better candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The slightly better binding affinity also contributes to its favorability. Ligand A's higher DILI risk is a major concern. The negative half-life values are concerning for both, but don't strongly sway the decision as they are similar.

Output:
1
2025-04-17 13:00:14,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 349.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.97) is better than Ligand B (116.56), both are below the 140 threshold for good absorption.

**logP:** Ligand A (-0.981) is slightly below the optimal 1-3 range, while Ligand B (-1.279) is even lower. Both could potentially have permeability issues, but it's not a major concern at this stage.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5/6 HBA, which are within acceptable limits.

**QED:** Ligand B (0.612) has a better QED score than Ligand A (0.462), indicating a more drug-like profile.

**DILI:** Ligand B (32.571) has a significantly lower DILI risk than Ligand A (15.083), which is a major advantage.

**BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (29.275) is better than Ligand B (13.92).

**Caco-2 Permeability:** Ligand A (-4.853) is better than Ligand B (-5.578), suggesting slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.995) is better than Ligand B (-1.289), which is important for formulation and bioavailability.

**hERG:** Both ligands have very low hERG risk (0.026 and 0.016), which is excellent.

**Microsomal Clearance:** Ligand B (-1.272) has a significantly *lower* (better) microsomal clearance than Ligand A (2.775), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.907) has a better in vitro half-life than Ligand B (-5.281).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.002).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -8.1 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 slightly better solubility and half-life, the safety and metabolic advantages of Ligand B outweigh these minor differences, especially for an enzyme target where metabolic stability is crucial. The binding affinities are essentially the same.

Output:
1
2025-04-17 13:00:14,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (342.443 and 352.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.78) is better than Ligand B (77.1), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.014) is optimal, while Ligand B (0.18) is quite low, potentially hindering permeation.

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

**5. H-Bond Acceptors:** Ligand A (2) is good, while Ligand B (5) is acceptable.

**6. QED:** Both ligands have good QED scores (0.691 and 0.764, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (54.207) has a higher DILI risk than Ligand B (29.779). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand A (61.613) is slightly better than Ligand B (52.579). This is less critical for a kinase inhibitor than for a CNS-targeting drug.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests poor permeability. However, the scale is not well-defined and might not be directly comparable.

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

**11. hERG Inhibition:** Ligand A (0.491) has a slightly higher hERG risk than Ligand B (0.216), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (19.734) exhibits lower microsomal clearance than Ligand A (4.832), indicating better metabolic stability, which is crucial for enzymes.

**13. In vitro Half-Life:** Ligand B (21.014) has a longer in vitro half-life than Ligand A (24.757).

**14. P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux liability than Ligand B (0.017), which is favorable.

**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 positive for Ligand B.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a more favorable logP. The slightly better affinity of Ligand A is unlikely to outweigh these substantial ADME advantages of Ligand B.

Output:
1
2025-04-17 13:00:14,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.503 and 367.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (88.18 and 89.35) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.557) is optimal, while Ligand B (1.411) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, well within the limits. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Ligand B (0.784) has a better QED score than Ligand A (0.439), indicating a more drug-like profile.

**DILI:** Ligand A (59.364) has a slightly better DILI percentile than Ligand B (63.513), suggesting lower liver injury risk. Both are acceptable, but lower is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (51.066) is slightly better than Ligand B (45.677).

**Caco-2 Permeability:** Both are negative (-5.116 and -5.237), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.702 and -2.738). This will require formulation strategies.

**hERG Inhibition:** Ligand A (0.213) has a much lower hERG inhibition liability than Ligand B (0.068), which is a substantial advantage.

**Microsomal Clearance:** Ligand B (40.213) has significantly lower microsomal clearance than Ligand A (57.584), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-12.192) has a much longer in vitro half-life than Ligand A (-3.214), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.214 and 0.062).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand B has a superior QED, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. However, Ligand A has a better hERG profile and slightly better DILI. Both have poor Caco-2 permeability and solubility. The improved metabolic stability and binding affinity of Ligand B outweigh the slightly higher hERG risk, especially considering that the hERG value is still relatively low.

Output:
1
2025-04-17 13:00:14,397 - INFO - Batch 177 complete. Total preferences: 2832
2025-04-17 13:00:14,397 - INFO - Processing batch 178/512...
2025-04-17 13:00:54,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.535 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is well below the 140 threshold, suggesting good absorption. Ligand B (72.88) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.403) is within the optimal 1-3 range. Ligand B (0.764) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have QED values above 0.5 (0.789 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A (5.351 percentile) has a significantly lower DILI risk than Ligand B (10.392 percentile). This is a major advantage for Ligand A.

**BBB:** While not crucial for a non-CNS target like SRC, Ligand A (80.07 percentile) shows better BBB penetration than Ligand B (61.691 percentile).

**Caco-2 Permeability:** Ligand A (-4.683) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.152) is also poor, but similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.956 and -1.695), indicating very poor aqueous solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.818 percentile) has a very low hERG inhibition risk, which is excellent. Ligand B (0.399 percentile) is also very low, but slightly higher than A.

**Microsomal Clearance:** Ligand A (6.215 mL/min/kg) has a much lower microsomal clearance than Ligand B (15.065 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (6.983 hours) has a shorter half-life than Ligand B (12.127 hours). This is a slight advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.056).

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage, as potency is a primary concern for kinase inhibitors.

**Overall Assessment:**

Ligand A is the superior candidate. While both have poor solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, and a substantially stronger binding affinity. The slightly shorter half-life of Ligand A is less concerning than the poor metabolic stability and weaker binding of Ligand B. The negative Caco-2 values are concerning for both, and would require further investigation, but the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 13:00:54,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.523 and 348.447 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.1) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (87.32) is still under 140, but less favorable than A.

**logP:** Both ligands (1.262 and 1.532) fall within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent, minimizing potential permeability issues. Ligand B (2) is acceptable.

**H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of 10.

**QED:** Ligand A (0.617) is better than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (2.986) has a significantly lower DILI risk than Ligand B (34.742), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.941) is better than Ligand B (55.37).

**Caco-2 Permeability:** Ligand A (-4.936) is substantially better than Ligand B (-5.223).

**Aqueous Solubility:** Ligand A (0.179) is better than Ligand B (-2.024).

**hERG Inhibition:** Both ligands (0.523 and 0.549) show similar, low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (0.326) has much lower microsomal clearance than Ligand B (16.229), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-26.936) has a significantly longer half-life than Ligand B (-12.56), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands (0.007 and 0.202) have low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands (-8.9 and -8.5 kcal/mol) have excellent binding affinity, but Ligand A is slightly better. The 0.4 kcal/mol difference is not enough to overcome the substantial ADME advantages of Ligand A.

**Conclusion:**

Ligand A is significantly superior to Ligand B. It exhibits better QED, much lower DILI risk, better solubility, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both ligands have acceptable logP and hERG values, the substantial improvements in ADME properties make Ligand A the more promising drug candidate.

Output:
0
2025-04-17 13:00:54,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (379.364 and 363.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.13) is better than Ligand B (38.13), being closer to the 140 threshold for oral absorption.

**logP:** Ligand B (3.964) is higher than Ligand A (0.715). While Ligand B is approaching the upper limit of the optimal range (1-3), it's still acceptable. Ligand A is quite low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A has 3 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 similar QED values (0.679 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (65.723) has a significantly higher DILI risk than Ligand B (13.804). This is a major concern for Ligand A.

**BBB:** Ligand B (82.862) has a higher BBB penetration percentile than Ligand A (28.228). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.517) has poor Caco-2 permeability, while Ligand B (-4.819) is slightly better. Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.763) has better aqueous solubility than Ligand B (-3.968). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.328) has a lower hERG inhibition liability than Ligand B (0.636), which is desirable.

**Microsomal Clearance:** Ligand B (97.021) has a much higher microsomal clearance than Ligand A (0.073), indicating poor metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (25.234) has a longer in vitro half-life than Ligand A (5.592).

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux liability than Ligand B (0.505).

**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 overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has better solubility, lower hERG risk, lower P-gp efflux, and significantly better metabolic stability (lower Cl_mic, longer t1/2). However, it has a higher DILI risk and poor Caco-2 permeability. Ligand B has a better binding affinity, but suffers from high DILI risk, poor metabolic stability, and higher P-gp efflux.

Considering the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and DILI risk are crucial. Ligand A's significantly better metabolic stability and lower DILI risk outweigh its lower logP and Caco-2 permeability. The affinity difference is not large enough to favor Ligand B.

Output:
0
2025-04-17 13:00:54,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.46 and 349.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold and favorable. Ligand B (78.95) is still under 140, but less optimal than A.

**logP:** Ligand A (3.355) is within the optimal 1-3 range. Ligand B (0.472) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 4 HBA, both are within the acceptable range of <=10.

**QED:** Ligand A (0.793) has a strong drug-like profile. Ligand B (0.445) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (29.78) has a low DILI risk. Ligand B (39.20) is also relatively low, but higher than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.30) is higher than Ligand B (57.97).

**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:** Ligand A (0.677) has a lower hERG risk than Ligand B (0.064).

**Microsomal Clearance:** Ligand A (26.40) has a higher clearance than Ligand B (19.65), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-21.63) has a significantly longer half-life than Ligand A (-10.41), which is a major advantage.

**P-gp Efflux:** Ligand A (0.145) has a lower P-gp efflux liability than Ligand B (0.034).

**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 difference.

**Overall Assessment:**

Ligand A excels in binding affinity and has a better QED, TPSA, logP, DILI, and hERG profile. However, Ligand B has a substantially longer in vitro half-life. The large difference in binding affinity (-8.6 vs 0.0 kcal/mol) is a critical advantage for Ligand A. While the negative solubility and Caco-2 values are concerning for both, the superior potency of Ligand A is likely to outweigh these issues, especially if formulation strategies can be employed to address solubility. The longer half-life of Ligand B is attractive, but insufficient to overcome the significant potency difference.

Output:
1
2025-04-17 13:00:54,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (356.388 and 347.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (91.23) is still acceptable, but higher, potentially impacting absorption.

**3. logP:** Ligand A (3.263) is optimal. Ligand B (0.73) 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 2 HBA, well within the limit of 10. Ligand B has 5 HBA, also acceptable.

**6. QED:** Both ligands have reasonable QED scores (0.822 and 0.693), suggesting good drug-like properties.

**7. DILI:** Ligand A (53.47) has a moderate DILI risk, but still acceptable. Ligand B (27.414) has a very low DILI risk, a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.949) shows better BBB penetration than Ligand B (44.203).

**9. Caco-2 Permeability:** Ligand A (-4.406) shows poor permeability. Ligand B (-5.026) shows even poorer permeability.

**10. Aqueous Solubility:** Ligand A (-4.031) has poor solubility. Ligand B (-1.994) has better solubility.

**11. hERG Inhibition:** Ligand A (0.449) has a very low risk of hERG inhibition. Ligand B (0.139) has an even lower risk, which is excellent.

**12. Microsomal Clearance:** Ligand A (56.007) has moderate clearance. Ligand B (2.358) has very low clearance, indicating better metabolic stability, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (0.697) has a short half-life. Ligand B (29.944) has a significantly longer half-life, a major advantage.

**14. P-gp Efflux:** Ligand A (0.064) has low P-gp efflux. Ligand B (0.035) has even lower P-gp efflux, improving bioavailability.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 0.1 kcal/mol difference is not substantial enough to overcome the ADME deficiencies of Ligand A.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, better solubility, and lower P-gp efflux. The lower logP of Ligand B is a concern, but the other advantages outweigh this drawback. The poor Caco-2 permeability of both compounds is a concern that would need to be addressed in further optimization.

Output:
1
2025-04-17 13:00:54,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.717 Da) is slightly higher than Ligand B (350.463 Da), but both are acceptable.

**TPSA:** Ligand A (50.36) is well below the 140 threshold for good absorption. Ligand B (68.74) is also acceptable, though higher.

**logP:** Ligand A (4.985) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.219) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) and Ligand B (HBD=1, HBA=7) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.704, B: 0.732), indicating good drug-likeness.

**DILI:** Ligand A (54.634) has a moderate DILI risk, while Ligand B (33.579) has a lower, more favorable risk.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (89.066) has a higher BBB percentile than Ligand A (58.085), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.66 and -4.83), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.717 and -2.0). This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.787 and 0.689). This is positive.

**Microsomal Clearance:** Ligand A (78.728) has a higher microsomal clearance than Ligand B (35.17), suggesting lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (59.313) has a longer in vitro half-life than Ligand A (37.027), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.374 and 0.069).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. While both have concerning solubility and permeability issues, Ligand B demonstrates better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a more favorable logP. Ligand A's higher logP and clearance are significant drawbacks. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but Ligand B provides a better starting point for optimization.

Output:
1
2025-04-17 13:00:54,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 373.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (67.43 and 63.68) well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have logP values (3.197 and 3.054) 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 reasonable QED scores (0.361 and 0.583), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (11.632) has a significantly lower DILI risk than Ligand B (39.938), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (72.082 and 74.06), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.743 and -4.796), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.684 and -3.263), indicating very poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.492 and 0.625).

**Microsomal Clearance:** Ligand A (28.64) has a considerably lower microsomal clearance than Ligand B (45.153), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-4.403) has a much longer in vitro half-life than Ligand B (12.618). This is a significant advantage, implying less frequent dosing potential.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.521).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.6 and -8.3 kcal/mol), both being excellent. The difference of 0.3 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While both have poor solubility and permeability, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The binding affinity is comparable. The lower DILI and improved metabolic stability outweigh the slightly lower QED score and similar binding affinity.

Output:
0
2025-04-17 13:00:54,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.337 and 348.403 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is better than Ligand B (95.75). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**logP:** Ligand A (2.9) is optimal, while Ligand B (0.385) is quite low. A logP below 1 can hinder membrane permeability.

**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 good QED scores (0.718 and 0.83), indicating generally drug-like properties.

**DILI:** Ligand A (91.431) has a significantly higher DILI risk than Ligand B (42.807). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (76.27) has a higher BBB percentile than Ligand A (54.207).

**Caco-2 Permeability:** Ligand A (-4.793) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.983) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.132) has poor solubility, while Ligand B (-0.888) is slightly better, but still not ideal.

**hERG:** Both ligands have very low hERG inhibition liability (0.119 and 0.052), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (33.506 and 31.928), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (-31.271) has a very poor in vitro half-life, indicating rapid metabolism. Ligand B (-7.672) is better, but still not great.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.083 and 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 (1.4 kcal/mol difference).

**Conclusion:**

Despite the significantly better binding affinity of Ligand A, its poor Caco-2 permeability, poor solubility, high DILI risk, and very short half-life are major drawbacks. Ligand B, while having a weaker affinity, exhibits better ADME properties overall, particularly a lower DILI risk and slightly better solubility and permeability. For an enzyme target like SRC kinase, metabolic stability and avoiding toxicity are crucial. The affinity difference, while significant, might be overcome with further optimization of Ligand B, whereas fixing the severe ADME issues of Ligand A would be much more challenging.

Output:
1
2025-04-17 13:00:54,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.467 Da) is slightly higher than Ligand B (344.43 Da), but both are acceptable.

**TPSA:** Ligand A (119.81) is better than Ligand B (49.41) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (-0.747) is a bit low, potentially hindering permeation. Ligand B (2.532) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is slightly higher in both counts, but still within acceptable limits. Ligand B (1 HBD, 2 HBA) is very favorable.

**QED:** Both ligands have good QED scores (Ligand A: 0.515, Ligand B: 0.779), indicating drug-likeness. Ligand B is better.

**DILI:** Ligand A (37.611) has a slightly higher DILI risk than Ligand B (27.608), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.746) and Ligand B (98.022). BBB is not a primary concern for SRC kinase inhibitors, but higher is generally better.

**Caco-2 Permeability:** Ligand A (-5.503) and Ligand B (-4.684). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.654) and Ligand B (-3.463). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.244) has a lower hERG risk than Ligand B (0.55), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-10.377) has much lower (better) microsomal clearance than Ligand B (29.448), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.77) has a shorter half-life than Ligand B (-18.145), which is less desirable.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, while Ligand B (0.286) is higher. Lower is better.

**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 drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand B having better logP, QED, and BBB, Ligand A's significantly superior binding affinity (-8.5 vs -7.3 kcal/mol) and much better metabolic stability (lower Cl_mic) are critical for an enzyme inhibitor. The lower hERG risk and P-gp efflux also contribute positively. While the solubility and permeability are poor for both, the potency and stability advantages of Ligand A are more important for this target class.

Output:
1
2025-04-17 13:00:54,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.451 and 358.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.67) is higher than Ligand B (53.33). Both are below 140, suggesting reasonable absorption, but B is better.

**logP:** Both ligands (3.816 and 3.952) are within the optimal range of 1-3.

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

**H-Bond Acceptors:** Ligand A has 6, and Ligand B has 4. Both are below the threshold of 10.

**QED:** Ligand B (0.774) has a significantly better QED score than Ligand A (0.356), indicating a more drug-like profile.

**DILI:** Ligand B (38.813) has a lower DILI risk than Ligand A (47.848), both are acceptable (<60).

**BBB:** Both have good BBB penetration (77.007 and 80.264). This isn't a high priority for a non-CNS target like SRC, but it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.452) and Ligand B (-5.117) 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 (-5.836 and -4.781), which is concerning. Solubility is a key factor for enzymes, and both are problematic.

**hERG Inhibition:** Both ligands have low hERG risk (0.461 and 0.604).

**Microsomal Clearance:** Ligand B (75.502) has lower microsomal clearance than Ligand A (117.812), indicating better metabolic stability. This is a crucial factor for enzymes.

**In vitro Half-Life:** Ligand B (24.417) has a longer half-life than Ligand A (-28.691). A negative half-life is not physically possible and indicates a problem with the data or the assay.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.621 and 0.677).

**Binding Affinity:** Ligand B (-11.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is the most important factor for an enzyme inhibitor. The difference of 3.6 kcal/mol is substantial.

**Conclusion:**

Ligand B is the superior candidate. While both have solubility concerns, Ligand B's significantly stronger binding affinity, better QED, lower DILI, and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the similar logP and hERG values. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 13:00:54,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.403 and 340.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.45) is better than Ligand B (95.45), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (0.795 and 0.719), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is slightly better than Ligand B (1 HBD, 8 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand B (0.713) has a slightly higher QED score than Ligand A (0.504), suggesting a more drug-like profile. However, A still exceeds the 0.5 threshold.

**DILI:** Ligand A (40.869) has a significantly lower DILI risk than Ligand B (69.639). This is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.288) is better than Ligand B (62.699).

**Caco-2 Permeability:** Ligand A (-4.192) shows better Caco-2 permeability than Ligand B (-5.063).

**Aqueous Solubility:** Ligand A (-0.899) has a better solubility score than Ligand B (-2.444).

**hERG:** Ligand A (0.766) has a much more favorable hERG profile than Ligand B (0.086), indicating lower cardiotoxicity risk. This is a significant advantage.

**Microsomal Clearance:** Ligand B (7.644) has a much lower microsomal clearance than Ligand A (60.692), suggesting better metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (16.688 hours) has a significantly longer half-life than Ligand A (9.155 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.104) has lower P-gp efflux than Ligand B (0.086).

**Binding Affinity:** Ligand B (-9.0 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. The difference is greater than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and has a slightly better QED score. However, it has a higher DILI risk and a worse hERG profile. Ligand A has a much better safety profile (DILI and hERG) and better solubility and permeability.

The strong binding affinity of Ligand B is a compelling factor. While the higher DILI and hERG risks are concerning, the substantial potency advantage (-9.0 vs -7.7 kcal/mol) could be worth further investigation, potentially with structural modifications to mitigate the safety concerns. However, considering the enzyme-specific priorities (potency, metabolic stability, solubility, hERG), and the significant safety advantages of Ligand A, I would initially favor Ligand A as a more viable starting point for drug development. The difference in binding affinity, while substantial, might be addressable through further optimization, whereas mitigating significant toxicity risks is often more challenging.

Output:
0
2025-04-17 13:00:54,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.291 Da) is slightly higher than Ligand B (349.391 Da), but both are acceptable.

**TPSA:** Ligand A (51.02) is well below the 140 threshold for oral absorption. Ligand B (105.56) is also below the threshold, but closer to it.

**logP:** Ligand A (3.554) is within the optimal range (1-3). Ligand B (-0.956) is below 1, which could impede permeation. This is a significant drawback for Ligand B.

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

**QED:** Both ligands have similar QED values (A: 0.802, B: 0.713), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (A: 54.207, B: 56.185), and are within an acceptable range (<60).

**BBB:** Ligand A (83.288) has a better BBB percentile than Ligand B (42.032), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**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 issue for both.

**hERG Inhibition:** Ligand A (0.297) has a very low hERG risk, which is excellent. Ligand B (0.084) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (30.375) has a moderate clearance. Ligand B (-5.734) has a *negative* clearance, which is impossible and likely indicates an error in the data or a very unusual compound behavior. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (8.584 hours) has a reasonable half-life. Ligand B (31.007 hours) has a longer half-life, which is generally desirable.

**P-gp Efflux:** Ligand A (0.549) has moderate P-gp efflux. Ligand B (0.017) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (0.0 kcal/mol) has a much weaker binding affinity than Ligand B (-6.7 kcal/mol). The difference of 6.7 kcal/mol is substantial and likely outweighs many of the other drawbacks of Ligand B.

**Conclusion:**

Despite the issues with solubility and Caco-2 permeability for both, Ligand B's significantly stronger binding affinity (-6.7 kcal/mol vs 0.0 kcal/mol) is the most important factor for an enzyme inhibitor. The negative clearance for Ligand B is a serious concern and suggests a data error, but even if we disregard that, the affinity difference is substantial. Ligand A has better logP and hERG, but these are less critical than potency for a kinase inhibitor.

Output:
1
2025-04-17 13:00:54,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (67.18) is significantly better than Ligand A (117.37). Lower TPSA generally improves oral absorption.

**logP:** Ligand A (0.595) is quite low, potentially hindering membrane permeability. Ligand B (4.678) is high, potentially causing solubility issues and off-target effects.

**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 similar QED values (A: 0.596, B: 0.571), indicating good drug-likeness.

**DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (63.513), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.772) is slightly better than Ligand B (43.893).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.059) is slightly better than Ligand B (-5.334).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.122 and -5.486 respectively). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.172) has a much lower hERG risk than Ligand B (0.802). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-19.65) has a much lower (better) microsomal clearance than Ligand B (59.301), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (80.216) has a longer half-life than Ligand A (49.518), which is desirable.

**P-gp Efflux:** Ligand A (0.007) has a much lower P-gp efflux liability than Ligand B (0.295), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly better 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's superior binding affinity is a major plus. However, its high logP, poor solubility, higher hERG risk, and higher P-gp efflux are significant concerns. Ligand A has better ADME properties (lower logP, hERG, P-gp, and Cl_mic), but its binding affinity is considerably weaker. Given the importance of potency for kinase inhibitors, the difference in binding affinity (-7.9 vs -9.3 kcal/mol) is substantial. While Ligand A has a better safety profile and metabolic stability, the potency of Ligand B is likely to be more critical for efficacy.

Output:
1
2025-04-17 13:00:54,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.408 and 358.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (76.66). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have acceptable logP values (1.732 and 2.274), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 4 HBA) in terms of balancing solubility and permeability. Lower counts are generally favored.

**QED:** Ligand A (0.719) has a significantly better QED score than Ligand B (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (31.601). This is a significant advantage for A.

**BBB:** Both ligands have similar BBB penetration (85.964 and 84.529), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values (-4.634 and -4.935), 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 (-1.843 and -2.928), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.841) has a lower hERG inhibition liability than Ligand B (0.513), which is preferable.

**Microsomal Clearance:** Ligand A (-13.34) has a much lower microsomal clearance than Ligand B (37.016), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-2.201) has a better in vitro half-life than Ligand B (-10.856), further supporting its improved metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.146 and 0.153).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). However, the difference (1.1 kcal/mol) isn't large enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A is the superior candidate. It has a better QED score, significantly lower DILI and microsomal clearance, better hERG profile, and improved solubility. While Ligand B has slightly better binding affinity, the ADME properties of Ligand A are far more favorable for development as a drug.

Output:
0
2025-04-17 13:00:54,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.434 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.53) is better than Ligand B (104.53), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (0.974 and 1.246), falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA. Both are below the 10 threshold.

**QED:** Both ligands have acceptable QED scores (0.733 and 0.627), indicating good drug-likeness.

**DILI:** Ligand A (68.205) has a higher DILI risk than Ligand B (26.173). This is a significant drawback for Ligand A.

**BBB:** Ligand B (67.817) has a better BBB penetration score than Ligand A (48.275), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and concerning. However, the values are similar (-5.525 and -5.112).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also concerning. Again, they are similar (-2.34 and -2.226).

**hERG Inhibition:** Ligand A (0.453) has a slightly higher hERG inhibition risk than Ligand B (0.191), but both are relatively low.

**Microsomal Clearance:** Ligand A (-20.862) has significantly lower (better) microsomal clearance than Ligand B (17.956), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.804) has a much longer half-life than Ligand B (0.127), which is a major advantage.

**P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux than Ligand B (0.015), suggesting better bioavailability.

**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, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite Ligand A's higher DILI risk, its significantly superior binding affinity (-8.8 vs -6.7 kcal/mol), much better metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux outweigh the DILI concern. The similar, and concerning, negative values for Caco-2 and solubility would need further investigation for both compounds, but the potency and PK advantages of Ligand A are compelling for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:00:54,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (354.441 and 348.407 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (109.3) is also below the threshold, but higher than A.

**3. logP:** Ligand A (2.762) is within the optimal range (1-3). Ligand B (-0.13) is below 1, which may impede permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 8 HBA. Both are within the acceptable range (<=10), but B is higher.

**6. QED:** Both ligands have similar QED values (0.825 and 0.797), indicating good drug-likeness.

**7. DILI:** Ligand A (11.283) has a much lower DILI risk than Ligand B (50.485), which is a significant advantage.

**8. BBB:** BBB is less critical for an oncology target, but Ligand A (87.01) has a higher BBB percentile than Ligand B (24.544).

**9. Caco-2 Permeability:** Ligand A (-4.765) has a negative value, indicating poor permeability. Ligand B (-5.159) is also poor, but similar to A.

**10. Aqueous Solubility:** Ligand A (-3.421) has better solubility than Ligand B (-0.998).

**11. hERG Inhibition:** Ligand A (0.569) has a lower hERG risk than Ligand B (0.089).

**12. Microsomal Clearance:** Ligand A (29.335) has a higher (worse) microsomal clearance than Ligand B (-14.411), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.27) has a longer half-life than Ligand B (24.08).

**14. P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux than Ligand B (0.019).

**15. Binding Affinity:** Ligand A (-6.6) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

For an enzyme target in oncology, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a better binding affinity, lower DILI risk, better solubility, and lower hERG risk. While Ligand A has a higher Cl_mic, its significantly better affinity and safety profile outweigh this drawback. Ligand B's low logP is a major concern for permeability.

Output:
1
2025-04-17 13:00:54,979 - INFO - Batch 178 complete. Total preferences: 2848
2025-04-17 13:00:54,979 - INFO - Processing batch 179/512...
2025-04-17 13:01:45,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.479 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (58.2) is significantly better than Ligand A (96.89). Lower TPSA generally improves oral absorption.

**logP:** Ligand A (0.989) is optimal, while Ligand B (4.479) is high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 2 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.541) has a better QED score than Ligand B (0.428), indicating a more drug-like profile.

**DILI:** Ligand B (22.102) has a much lower DILI risk than Ligand A (6.747), which is a significant advantage.

**BBB:** Both have acceptable BBB penetration, but Ligand B (70.686) is slightly better than Ligand A (67.429). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.167) has a slightly lower hERG inhibition liability than Ligand B (0.5), which is preferable.

**Microsomal Clearance:** Ligand A (27.959) has significantly lower microsomal clearance than Ligand B (74.609), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (38.688) has a significantly longer half-life than Ligand A (-22.76). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.006) has lower P-gp efflux than Ligand B (0.303), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This difference, while not huge, is significant.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much longer half-life. However, it suffers from a higher logP, potentially leading to solubility and off-target issues, and a higher hERG risk. Ligand A has better physicochemical properties (logP, TPSA, QED, metabolic stability, P-gp efflux), but its binding affinity is slightly weaker and half-life is poor.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, hERG), the slightly better binding affinity and significantly improved half-life of Ligand B outweigh its drawbacks, *provided* the solubility and hERG risks can be mitigated through formulation or further structural modifications. The lower DILI risk of Ligand B is also a significant positive.

Output:
1
2025-04-17 13:01:45,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.301 Da) is slightly higher than Ligand B (366.29 Da), but both are acceptable.

**TPSA:** Ligand A (54.88) is well below the 140 threshold for oral absorption. Ligand B (79.95) is also acceptable, but higher.

**logP:** Ligand A (4.618) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.705) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both fall within acceptable limits.

**QED:** Ligand A (0.624) has a good drug-likeness score. Ligand B (0.201) is quite low, indicating a less drug-like profile.

**DILI:** Ligand A (86.933) has a higher DILI risk than Ligand B (51.687). Both are reasonably acceptable, but Ligand B is preferred.

**BBB:** Both ligands have high BBB penetration (Ligand A: 87.321, Ligand B: 82.047), but this is less critical for a non-CNS target like SRC.

**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. This suggests poor solubility for both compounds.

**hERG Inhibition:** Ligand A (0.484) has a lower hERG risk than Ligand B (0.827). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (49.401) has a higher microsomal clearance than Ligand B (-4.826). This suggests Ligand B is more metabolically stable, which is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (33.404) has a shorter half-life than Ligand B (-20.383). Again, indicating Ligand B is more stable.

**P-gp Efflux:** Ligand A (0.429) has lower P-gp efflux than Ligand B (0.133), which is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8.9 kcal/mol, Ligand B: -9.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has several advantages: better logP, lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While Ligand A has a lower hERG risk and P-gp efflux, the metabolic stability of Ligand B is a more critical factor for an enzyme target like SRC kinase. The poor solubility and permeability for both compounds are concerning, but can potentially be addressed with formulation strategies. The low QED score for Ligand B is a drawback, but the superior ADME properties outweigh this concern.

Output:
1
2025-04-17 13:01:45,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (360.42 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (58.64), both are acceptable but A is closer to the preferred <140.

**3. logP:** Both ligands have good logP values (3.247 and 3.045), 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 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.507 and 0.65), indicating good drug-like properties.

**7. DILI:** Ligand A (26.483) has a significantly lower DILI risk than Ligand B (9.965), making it more favorable. Both are below the 40 threshold.

**8. BBB:** Ligand A (87.747) has a higher BBB penetration percentile than Ligand B (75.107). While not critical for a non-CNS target like SRC, it's a slight advantage.

**9. Caco-2 Permeability:** Ligand A (-4.34) has a better Caco-2 permeability than Ligand B (-4.518), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.73) has better aqueous solubility than Ligand B (-2.306). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.748) has a slightly higher hERG inhibition risk than Ligand B (0.361), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (56.24) has lower microsomal clearance than Ligand A (65.395), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.02) has a significantly longer in vitro half-life than Ligand A (-7.776), which is a major advantage.

**14. P-gp Efflux:** Ligand B (0.103) has lower P-gp efflux than Ligand A (0.165), which is favorable.

**15. Binding Affinity:** Ligand B (-10.02 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. While Ligand A has better solubility and lower DILI risk, the substantial difference in binding affinity and half-life of Ligand B makes it the more promising candidate. The slightly higher P-gp efflux and DILI risk of Ligand B are less concerning given the strong potency and improved metabolic stability.

Output:
1
2025-04-17 13:01:45,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.415 and 358.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.96) is higher than Ligand B (58.12). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.429) is within the optimal 1-3 range. Ligand B (3.65) is at the higher end but still acceptable.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve 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 scores (0.722 and 0.782, respectively), indicating drug-likeness.

**DILI:** Ligand B (39.124) has a significantly lower DILI risk than Ligand A (50.679), making it more favorable.

**BBB:** Both have reasonable BBB penetration, but Ligand B (87.437) is better than Ligand A (72.586). While not a primary concern for a non-CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.28) has a worse Caco-2 permeability than Ligand B (-5.199). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-1.134) has better aqueous solubility than Ligand B (-2.988). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.137) has a lower hERG inhibition risk than Ligand B (0.836). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (53.818) has lower microsomal clearance than Ligand B (61.035), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (44.489) has a longer in vitro half-life than Ligand A (-25.288). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.049 and 0.467, respectively).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.4 and -9.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has advantages in DILI risk, BBB penetration, and in vitro half-life. Ligand A has advantages in solubility and hERG risk, and slightly better metabolic stability. The binding affinity is comparable. Considering the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and hERG risk are crucial. While Ligand A has slightly better metabolic stability and a much better hERG profile, the longer half-life of Ligand B is a significant advantage. The lower DILI risk of Ligand B is also a strong positive. The solubility difference is not substantial enough to outweigh the other benefits of Ligand B.

Output:
1
2025-04-17 13:01:45,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.383 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.58) is better than Ligand B (87.32), both are below the 140 A^2 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.712) is optimal, while Ligand B (1.512) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (0) is preferred over Ligand B (2), as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4), both are within the acceptable range.

**QED:** Both ligands have good QED scores (0.634 and 0.833), indicating drug-likeness.

**DILI:** Ligand B (63.978) has a lower DILI risk than Ligand A (75.184), which is a significant advantage.

**BBB:** Ligand A (89.957) has a better BBB penetration than Ligand B (43.273). However, BBB is less crucial for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2:** Both ligands have negative Caco-2 permeability values, which is unusual. Assuming these are percentile scores, it indicates poor permeability for both. Ligand A (-4.396) is slightly better than Ligand B (-4.953).

**Solubility:** Both ligands have similar, very poor aqueous solubility (-3.72 and -3.648). This is a major concern for both.

**hERG:** Ligand A (0.538) has a lower hERG risk than Ligand B (0.236), which is preferable.

**Microsomal Clearance:** Ligand B (25.148) has significantly lower microsomal clearance than Ligand A (83.888), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-24.151) has a much longer in vitro half-life than Ligand A (2.218), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.408) has lower P-gp efflux than Ligand B (0.094), which is preferable.

**Binding Affinity:** Ligand A (-9.3 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, which is the most important factor for an enzyme inhibitor. However, Ligand B shows significantly better metabolic stability (lower Cl_mic and longer t1/2) and lower DILI risk. The poor solubility and Caco-2 permeability are concerning for both. The difference in binding affinity (-9.3 vs -8.0) is substantial (1.3 kcal/mol), and is likely to overcome the ADME deficiencies.

Output:
0
2025-04-17 13:01:45,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.37 and 348.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is slightly higher than Ligand B (58.64), both are acceptable for oral absorption (<140).

**logP:** Ligand A (3.963) is at the higher end of the optimal range (1-3), while Ligand B (2.657) 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 has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.739 and 0.686), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (85.58%) compared to Ligand B (10.39%). This is a major concern for Ligand A.

**BBB:** Both have good BBB penetration (70.997% and 74.254%), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.725 and -4.357). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.906 and -2.479), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.819) has a slightly higher hERG risk than Ligand B (0.278).

**Microsomal Clearance:** Ligand A (85.249) has a higher microsomal clearance than Ligand B (73.557), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (12.972 hours) has a significantly longer in vitro half-life than Ligand A (47.899 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.334) has lower P-gp efflux than Ligand B (0.083), which is slightly favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although both are excellent. The 0.8 kcal/mol difference is substantial enough to be a key differentiator.

**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 lower hERG risk outweigh the slightly lower binding affinity and slightly higher P-gp efflux. The solubility issues are a concern for both, but potentially addressable. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 13:01:45,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.483 and 349.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (84.67). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.082) is optimal, while Ligand B (1.59) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is better than Ligand B (1 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand B (0.873) has a higher QED score than Ligand A (0.576), suggesting a more drug-like profile overall.

**DILI:** Both ligands have low DILI risk (31.64 and 35.983, respectively), which is excellent.

**BBB:** Both ligands have moderate BBB penetration (49.67 and 51.493). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.703) is better than Ligand B (-5.093), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.78) is better than Ligand B (-0.997), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.156) has a slightly better hERG profile than Ligand B (0.099), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (16.924) has significantly lower microsomal clearance than Ligand A (45.148), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-1.749) has a longer half-life than Ligand A (-4.11), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.185 and 0.054).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.2 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol), but the difference is less than 1.5 kcal/mol, so it's not decisive.

**Overall Assessment:**

Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and a higher QED score. Ligand A has better solubility and a slightly better binding affinity. However, for an enzyme target like SRC kinase, metabolic stability is paramount. The difference in binding affinity is not substantial enough to outweigh the significant advantage of Ligand B in terms of metabolic stability.

Output:
1
2025-04-17 13:01:45,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.823 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (63.99) and Ligand B (61.68) are very similar.

**logP:** Ligand A (3.026) is optimal, while Ligand B (0.486) is quite low. Low logP can hinder membrane permeability. This is a significant drawback for Ligand B.

**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: 0.734, B: 0.795), indicating drug-like properties.

**DILI:** Ligand A (82.59) has a higher DILI risk than Ligand B (18.922). This is a concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (66.227) and Ligand B (56.262) are comparable.

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, the scale is unknown, but negative values likely indicate poor solubility.

**hERG Inhibition:** Ligand A (0.753) has a slightly higher hERG risk than Ligand B (0.167). Lower is better, so Ligand B is preferable here.

**Microsomal Clearance:** Ligand A (48.896) has a significantly better (lower) microsomal clearance than Ligand B (9.465). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (43.783) has a longer half-life than Ligand B (9.959), which is desirable.

**P-gp Efflux:** Ligand A (0.605) has lower P-gp efflux than Ligand B (0.021), indicating better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 kcal/mol and -8.7 kcal/mol respectively). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B has a better safety profile (lower DILI, lower hERG), but suffers from a very low logP, which is a major concern for permeability and bioavailability. Ligand A has a higher DILI risk, but has a much better logP, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux profile. Given the importance of metabolic stability and permeability for an enzyme inhibitor, and the relatively small difference in binding affinity, Ligand A is the more promising candidate. The DILI risk can be addressed through further structural modifications.

Output:
1
2025-04-17 13:01:45,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.383 and 353.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.15) is better than Ligand B (107.81). TPSA < 140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Ligand A (1.519) is optimal, while Ligand B (0.424) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 8. Both are within the acceptable limit of <=10, but A is better.

**QED:** Both ligands have similar QED values (0.781 and 0.765), indicating good drug-likeness.

**DILI:** Ligand A (65.956) has a slightly better DILI risk profile than Ligand B (69.794), but both are moderately high.

**BBB:** Ligand A (44.591) has a lower BBB penetration percentile than Ligand B (79.488). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data. However, the values are similarly poor.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data. The values are similarly poor.

**hERG:** Ligand A (0.584) has a slightly better hERG profile than Ligand B (0.058), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (31.313 mL/min/kg) has significantly lower microsomal clearance than Ligand B (48.057 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.559 hours) has a negative half-life, which is not possible. Ligand B (-2.918 hours) also has a negative half-life. This suggests a data issue.

**P-gp Efflux:** Ligand A (0.346) has lower P-gp efflux than Ligand B (0.013), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a significant advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite the questionable solubility and half-life data, Ligand B's superior binding affinity (-8.1 vs -7.5 kcal/mol) is the most important factor for an enzyme inhibitor. The slightly higher logP of Ligand A is a minor advantage, but the difference in binding affinity is more significant. The metabolic stability of Ligand A is better, but the binding affinity difference is larger.

Output:
1
2025-04-17 13:01:45,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (394.362 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is excellent, well below the 140 threshold for oral absorption. Ligand B (109.04) is still acceptable but less optimal.

**3. logP:** Ligand A (0.624) is a bit low, potentially hindering permeation. Ligand B (0.996) is better, 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 6 HBA, both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.668 and 0.691), indicating good drug-like properties.

**7. DILI:** Ligand A (55.138) has a slightly higher DILI risk than Ligand B (41.062), but both are below the concerning 60 threshold.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (80.574) is higher than Ligand B (42.148), but this is less important.

**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, indicating poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.432) shows a much lower hERG inhibition risk than Ligand B (0.165), which is a critical advantage.

**12. Microsomal Clearance:** Ligand A (-12.89) has significantly lower (better) microsomal clearance than Ligand B (38.867), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.445) has a longer in vitro half-life than Ligand B (-6.218), further supporting its improved metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.054).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly lower hERG risk and much better metabolic stability (lower Cl_mic and longer t1/2). The solubility issues are a concern for both, but the improved safety and pharmacokinetic profile of Ligand A outweigh the slightly weaker binding. The lower logP of Ligand A is a minor concern, but can potentially be addressed through further optimization.

Output:
0
2025-04-17 13:01:45,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (385.877 and 375.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (66.32), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.3 and 2.834), falling 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 has 8 HBA, while Ligand B has 6. Both are below the 10 threshold.

**QED:** Both ligands have similar, good QED scores (0.735 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A (74.952) has a higher DILI risk than Ligand B (54.478). This is a significant negative for Ligand A.

**BBB:** Ligand A (40.52) has a lower BBB penetration percentile than Ligand B (29.934). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.675) has a worse Caco-2 permeability than Ligand B (-5.32). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.405) has better aqueous solubility than Ligand B (-2.953).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.353 and 0.323).

**Microsomal Clearance:** Ligand A (76.406) has a higher microsomal clearance than Ligand B (60.834), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (11.032 hours) has a significantly longer in vitro half-life than Ligand A (27.839 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.122 and 0.269).

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Conclusion:**

Despite having similar binding affinity, Ligand B is the better candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better Caco-2 permeability. While Ligand A has slightly better solubility and TPSA, the improvements in safety (DILI) and pharmacokinetics (t1/2, Cl_mic) for Ligand B outweigh these minor differences.

Output:
1
2025-04-17 13:01:45,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.36 and 357.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (73.91 and 73.32) well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.20) is optimal (1-3), while Ligand B (-0.37) is below 1, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.754 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (88.52) has a higher DILI risk than Ligand B (20.9), which is a concern. However, DILI prediction is imperfect.

**BBB:** Ligand A (70.18) shows reasonable BBB penetration, while Ligand B (43.58) is lower. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.01) has poor Caco-2 permeability, while Ligand B (-4.61) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.67 and -0.38). This is a major issue that would require formulation strategies.

**hERG Inhibition:** Ligand A (0.61) has a slightly higher hERG risk than Ligand B (0.23), but both are relatively low.

**Microsomal Clearance:** Ligand A (30.97) has a higher microsomal clearance than Ligand B (-15.95). This suggests Ligand B is more metabolically stable, a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.65) has a shorter half-life than Ligand B (-17.71), further supporting Ligand B's better metabolic stability.

**P-gp Efflux:** Ligand A (0.16) has lower P-gp efflux than Ligand B (0.03), which is favorable.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor Caco-2 permeability, its *significantly* superior binding affinity (-9.2 vs -7.6 kcal/mol) is the deciding factor. For an enzyme target, potency is paramount. While Ligand B has better metabolic stability and lower DILI, the difference in binding affinity is too large to ignore. Formulation strategies can be explored to address the solubility issues.

Output:
1
2025-04-17 13:01:45,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.379 and 351.359 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.19) is better than Ligand B (102.18), being comfortably below the 140 threshold for oral absorption.

**logP:** Ligand A (1.183) is within the optimal range of 1-3, while Ligand B (0.208) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, well within acceptable limits. Ligand B has 0 HBD and 7 HBA, also acceptable, but slightly higher HBA could potentially affect permeability.

**QED:** Both ligands have reasonable QED scores (0.833 and 0.714), indicating good drug-like properties.

**DILI:** Ligand A (54.556) has a lower DILI risk than Ligand B (62.001), both are acceptable, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.195) has a slightly higher BBB value than Ligand A (36.409), but it's not a major factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.805 and -4.665), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.494 and -1.644), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.105 and 0.031), which is excellent.

**Microsomal Clearance:** Ligand A (-15.938) has significantly lower (better) microsomal clearance than Ligand B (-7.071), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.844) has a longer in vitro half-life than Ligand B (-5.54), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.009 and 0.056), which is favorable.

**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.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the far superior candidate. Its significantly stronger binding affinity (-8.1 vs -0.0 kcal/mol) outweighs the permeability and solubility concerns. Furthermore, Ligand A demonstrates better metabolic stability (lower Cl_mic and longer t1/2) and a lower DILI risk. The affinity difference is substantial enough to warrant further optimization efforts to address the solubility and permeability issues. Ligand B's very weak binding affinity makes it a poor starting point.

Output:
0
2025-04-17 13:01:45,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 378.881 Da - Within the ideal range (200-500 Da).
* Ligand B: 403.585 Da - Also within the ideal range.
* *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 62.66 A<sup>2</sup> - Good for oral absorption (<140 A<sup>2</sup>).
* Ligand B: 20.31 A<sup>2</sup> - Excellent for oral absorption.
* *Ligand B has a significant advantage here, suggesting potentially better absorption.*

**3. Lipophilicity (logP):**
* Ligand A: 3.822 - Towards the higher end of optimal (1-3), but acceptable.
* Ligand B: 4.633 - Slightly above the optimal range, potentially leading to solubility issues or off-target effects.
* *Ligand A has a slight advantage.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Within the ideal limit (<=5).
* Ligand B: 0 - Also within the ideal limit.
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 5 - Within the ideal limit (<=10).
* Ligand B: 4 - Also within the ideal limit.
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.878 - Excellent drug-likeness.
* Ligand B: 0.63 - Good drug-likeness, but lower than Ligand A.
* *Ligand A has a clear advantage.*

**7. DILI Risk:**
* Ligand A: 56.844 - Moderate risk, acceptable.
* Ligand B: 30.787 - Low risk, preferable.
* *Ligand B has a significant advantage.*

**8. BBB Penetration:**
* Ligand A: 77.705 - Moderate, not a primary concern for a non-CNS target like SRC.
* Ligand B: 93.408 - Higher, but not critical for SRC.
* *Ligand B has a slight advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -4.503 - Poor permeability.
* Ligand B: -4.868 - Also poor permeability.
* *Both are poor, but Ligand B is slightly worse.*

**10. Aqueous Solubility:**
* Ligand A: -5.023 - Poor solubility.
* Ligand B: -5.053 - Also poor solubility.
* *Both are poor, with a slight disadvantage to Ligand B.*

**11. hERG Inhibition:**
* Ligand A: 0.758 - Acceptable risk.
* Ligand B: 0.873 - Slightly higher risk.
* *Ligand A has a slight advantage.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 27.221 mL/min/kg - Relatively high clearance, suggesting lower metabolic stability.
* Ligand B: 77.093 mL/min/kg - Very high clearance, indicating poor metabolic stability.
* *Ligand A has a significant advantage here.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 14.852 hours - Good half-life.
* Ligand B: -1.138 hours - Very short half-life, a major drawback.
* *Ligand A has a massive advantage.*

**14. P-gp Efflux:**
* Ligand A: 0.65 - Moderate efflux.
* Ligand B: 0.534 - Moderate efflux.
* *No clear advantage.*

**15. Binding Affinity:**
* Ligand A: -10.3 kcal/mol - Excellent binding affinity.
* Ligand B: -7.0 kcal/mol - Good binding affinity, but significantly weaker than Ligand A.
* *Ligand A has a substantial advantage.*

**Enzyme-Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand A excels in affinity and half-life, and has better metabolic stability and hERG risk. Ligand B has a lower DILI risk and better TPSA, but suffers from very poor metabolic stability and a much weaker binding affinity. The substantial difference in binding affinity (-10.3 vs -7.0 kcal/mol) outweighs the advantages of Ligand B.

Output:
1
2025-04-17 13:01:45,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (368.455 and 339.355 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.56) is better than Ligand B (123.76), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.498 and 2.044), falling within the optimal 1-3 range.

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

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4) as lower HBAs generally improve permeability.

**6. QED:** Ligand A (0.738) has a significantly better QED score than Ligand B (0.579), indicating a more drug-like profile.

**7. DILI:** Ligand A (57.697) has a much lower DILI risk than Ligand B (87.049). This is a significant advantage.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (56.495) is slightly better than Ligand B (27.414).

**9. Caco-2 Permeability:** Ligand A (-4.937) is better than Ligand B (-5.886), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-3.156 and -3.179). This could be a formulation challenge for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.197 and 0.133), which is excellent.

**12. Microsomal Clearance:** Ligand B (-21.936) has a significantly lower (better) microsomal clearance than Ligand A (31.626), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (40.012) has a longer in vitro half-life than Ligand A (-38.252), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.062 and 0.024).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Ligand A is generally superior due to its better QED, significantly lower DILI risk, better TPSA, lower HBD/HBA counts, and slightly better binding affinity. While Ligand B has better metabolic stability (lower Cl_mic) and half-life, the DILI risk associated with Ligand B is a major concern. The slightly better potency of Ligand A combined with its superior ADME properties make it the more promising candidate.

Output:
0
2025-04-17 13:01:45,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (370.739 Da and 357.284 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.4) is better than Ligand B (88.02), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have good logP values (2.865 and 2.462), falling within the 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.

**6. QED:** Ligand A (0.821) has a higher QED score than Ligand B (0.765), indicating a more drug-like profile.

**7. DILI:** Ligand B (70.686) has a higher DILI risk than Ligand A (87.01), which is unfavorable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.941) is better than Ligand B (35.091).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.723) is slightly better than Ligand B (-4.853).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-4.299) is slightly better than Ligand B (-3.173).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.308 and 0.603).

**12. Microsomal Clearance:** Ligand B (31.454) has a lower microsomal clearance than Ligand A (45.462), indicating better metabolic stability, which is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (48.988) has a significantly longer in vitro half-life than Ligand B (-12.738), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.252 and 0.117).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 kcal/mol and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its better QED score, lower DILI risk, longer half-life, and slightly better TPSA, solubility, and Caco-2 permeability. While Ligand B has better metabolic stability, the longer half-life of Ligand A is a more significant advantage for an enzyme target, as it suggests less frequent dosing. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 13:01:45,606 - INFO - Batch 179 complete. Total preferences: 2864
2025-04-17 13:01:45,606 - INFO - Processing batch 180/512...
2025-04-17 13:02:26,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.455 Da) is slightly preferred due to being lower in weight.

**2. TPSA:** Both ligands have TPSA values (62.3 and 65.55) well below the 140 threshold for oral absorption.

**3. logP:** Both ligands have logP values (2.113 and 2.99) within the optimal range (1-3). Ligand B is slightly higher, which *could* pose a minor solubility issue, 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 7. Both are below the limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.553 and 0.556), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 13.183, while Ligand B has 32.959. Ligand A is significantly better here, indicating a much lower risk of liver injury. This is a crucial factor.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.821) has a higher BBB penetration than Ligand A (52.811), but this is not a major concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.673 and -4.975). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**10. Aqueous Solubility:** Both have negative solubility values (-2.6 and -3.08). This is also concerning, indicating poor aqueous solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.273) has a much lower hERG inhibition risk than Ligand B (0.772). This is a significant advantage for Ligand A, minimizing potential cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (59.716) and Ligand B (58.479) have similar microsomal clearance values. This suggests comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (73.73) has a significantly longer in vitro half-life than Ligand A (-4.808). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux liability than Ligand B (0.48). This is preferable for bioavailability.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.5 kcal/mol difference, which is a meaningful advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity and half-life, Ligand A is significantly better regarding safety (DILI and hERG) and has lower P-gp efflux. The solubility and permeability issues are concerning for both, but the safety profile is paramount. The 0.5 kcal/mol difference in binding affinity is unlikely to overcome the substantial safety advantages of Ligand A, especially for an enzyme target where metabolic stability is also important.

Output:
0
2025-04-17 13:02:26,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.821 and 373.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.36 and 92.85) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (<90).

**logP:** Ligand A (0.646) is a bit low, potentially hindering permeation. Ligand B (2.578) is within the optimal 1-3 range. This favors Ligand B.

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

**H-Bond Acceptors:** Ligand A (5) and Ligand B (9) are both acceptable, below the 10 threshold.

**QED:** Both ligands have good QED scores (0.694 and 0.71), indicating good drug-like properties.

**DILI:** Both ligands have high DILI risk (76.89 and 77.356), which is a concern.

**BBB:** Both ligands have moderate BBB penetration (50.523 and 64.56). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.087 and -5.637) which is unusual and indicates poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.569 and -2.725) which is also unusual and indicates poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.584 and 0.633), which is good.

**Microsomal Clearance:** Ligand A has a significantly lower (better) microsomal clearance (-5.076) than Ligand B (42.202). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A has a significantly longer (better) in vitro half-life (-33.863) than Ligand B (4.77). This further supports better metabolic stability for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.043 and 0.148).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better 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 superior binding affinity, which is the most critical factor for an enzyme inhibitor. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better hERG profile, the substantial difference in binding affinity (-7.2 vs -10.2 kcal/mol) makes Ligand B the more promising candidate. The poor solubility and permeability of both compounds are concerning, but can be addressed with formulation strategies. The high DILI risk is a concern for both, but can be investigated further.

Output:
1
2025-04-17 13:02:26,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.513 Da) and Ligand B (353.463 Da) are both acceptable.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for oral absorption and is favorable. Ligand B (89.95) is still below the threshold, but higher than A, potentially indicating slightly reduced absorption.

**logP:** Ligand A (3.31) is within the optimal range (1-3). Ligand B (0.227) is quite low, which could hinder membrane permeability and bioavailability.

**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 the suggested limits.

**QED:** Both ligands have good QED scores (A: 0.595, B: 0.669), indicating generally drug-like properties.

**DILI:** Ligand A (15.743) has a much lower DILI risk than Ligand B (18.185), suggesting a safer profile. Both are below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (94.184) has a higher BBB penetration than Ligand B (38.465).

**Caco-2 Permeability:** Ligand A (-4.981) has a better Caco-2 permeability than Ligand B (-5.154), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.94) has better solubility than Ligand B (-0.953), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.8, B: 0.152), which is good.

**Microsomal Clearance:** Ligand A (34.036) has a higher microsomal clearance than Ligand B (4.092), meaning it's metabolized faster and has lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (-4.348) has a longer in vitro half-life than Ligand A (-2.011), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.17, B: 0.022).

**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.

**Conclusion:**

While Ligand A has better solubility, permeability, and lower DILI risk, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a slightly improved binding affinity. Given that we are targeting a kinase (enzyme), metabolic stability is a critical factor. The small difference in binding affinity is less important than the substantial difference in metabolic clearance. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 13:02:26,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 352.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is higher than Ligand B (42.01). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have good logP values (1.599 and 2.539), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 4 HBD, which is acceptable. Ligand B has 0, which is also acceptable, and potentially beneficial for permeability.

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

**QED:** Both ligands have good QED scores (0.507 and 0.673), indicating good drug-like properties.

**DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (11.206). This is a significant advantage for Ligand A.

**BBB:** Ligand B (84.529) has a higher BBB penetration percentile than Ligand A (29.12). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.426) has a negative Caco-2 value, which is concerning. Ligand B (-4.678) is also negative, but less so. Both suggest poor intestinal absorption, but A is worse.

**Aqueous Solubility:** Ligand A (-0.968) has slightly better solubility than Ligand B (-1.666), though both are quite poor.

**hERG Inhibition:** Ligand A (0.237) has a lower hERG inhibition liability than Ligand B (0.627), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-18.144) has a much lower (better) microsomal clearance than Ligand B (60.05). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-22.326) has a longer in vitro half-life than Ligand B (33.901). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.03) has a lower P-gp efflux liability than Ligand B (0.194), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.7). While this is a positive for Ligand B, the difference (1 kcal/mol) isn't substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG inhibition, and lower P-gp efflux. The solubility and Caco-2 values are poor for both, but Ligand A is less problematic in these areas. The difference in binding affinity is not large enough to overcome the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 13:02:26,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.45 and 364.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.68) is better than Ligand B (87.58), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have similar logP values (1.503 and 1.482), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=7) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.816 and 0.807), indicating good drug-like properties.

**DILI:** Ligand A (26.44) has a significantly lower DILI risk than Ligand B (63.71). This is a major advantage for Ligand A.

**BBB:** Ligand A (70.18) has a better BBB penetration score than Ligand B (62.97), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.95) has a slightly better Caco-2 permeability than Ligand B (-4.91), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.042) has better aqueous solubility than Ligand B (-1.984). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.193) has a significantly lower hERG inhibition liability than Ligand B (0.562). This is a crucial advantage, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (26.94) has a lower microsomal clearance than Ligand B (44.94), indicating better metabolic stability.

**In Vitro Half-Life:** Ligand B (53.52) has a significantly longer in vitro half-life than Ligand A (0.212). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.013) has a lower P-gp efflux liability than Ligand B (0.054), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.1). While a 1.5 kcal/mol difference is usually significant, the other advantages of Ligand A outweigh this.

**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 critical ADME properties: lower DILI risk, lower hERG inhibition, better solubility, lower P-gp efflux, and better metabolic stability. These factors are particularly important for an enzyme target like SRC kinase, where minimizing off-target effects and ensuring adequate bioavailability are crucial.

Output:
0
2025-04-17 13:02:26,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.302 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (51.66 and 52.65) are reasonably low, suggesting good potential for cell permeability.

**logP:** Ligand A (3.143) is slightly higher than Ligand B (2.548), both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 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 (0.57 and 0.768), indicating drug-like properties.

**DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (4.653), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (85.731 and 79.217), but this is less critical for a kinase inhibitor unless CNS activity is desired.

**Caco-2 Permeability:** Ligand A (-4.507) and Ligand B (-5.027) both have negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poor permeability.

**Aqueous Solubility:** Ligand A (-3.819) and Ligand B (-1.546) both have negative values, indicating poor aqueous solubility. Ligand B is better here.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.561 and 0.585).

**Microsomal Clearance:** Ligand A (53.576) has significantly higher microsomal clearance than Ligand B (-2.043). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-16.802) has a negative half-life, which is impossible. This is a major red flag. Ligand B (-2.044) is also negative, but less so. Both are problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.131 and 0.035).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a considerably stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME concerns.

**Conclusion:**

Despite both ligands having issues with Caco-2 and Solubility, Ligand B is the superior candidate. The significantly better binding affinity (-9.4 vs -7.5 kcal/mol) and much improved metabolic stability (lower Cl_mic, less negative half-life) are crucial for an enzyme inhibitor. The lower DILI risk is also a positive. The negative half-life values are concerning for both, but less so for Ligand B.

Output:
1
2025-04-17 13:02:26,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.383) is slightly better being closer to the middle of the range.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption. Ligand B (89.95) is significantly better, being closer to the 90 A^2 threshold for CNS penetration (though that's not a primary concern here).

**logP:** Ligand A (0.684) is a bit low, potentially impacting permeability. Ligand B (-0.275) is even lower, raising concerns about absorption. Both are suboptimal.

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

**QED:** Ligand B (0.669) has a better QED score than Ligand A (0.476), indicating a more drug-like profile.

**DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (12.214). This is a significant advantage for Ligand B.

**BBB:** This isn't a primary concern for a non-CNS target, but Ligand B (49.67) is lower than Ligand A (59.054).

**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 (0.051) has a slightly better hERG profile than Ligand B (0.395), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-4.415) has a much lower (better) microsomal clearance than Ligand B (14.961), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (10.828 hours) has a better in vitro half-life than Ligand B (-16.835 hours).

**P-gp Efflux:** Both are very low, indicating potential efflux issues.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly better 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 superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). While its logP is suboptimal, the strong binding affinity is a major advantage for an enzyme inhibitor. Ligand B has a better QED and significantly lower DILI risk, but its weaker binding affinity and worse metabolic stability are concerning. Given the enzyme-specific priorities, the potency advantage of Ligand A is the most critical factor.

Output:
1
2025-04-17 13:02:26,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (331.419 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (54.88) is preferable to Ligand B (49.41) as lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have logP values between 3-4, which is acceptable. Ligand A (4.0) is slightly higher, potentially leading to some solubility issues, but still within the acceptable range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which is ideal.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.789) is slightly better than Ligand B (0.8).

**DILI:** Both ligands have DILI risk around 70, which is acceptable, but not ideal.

**BBB:** Ligand B (85.266) has a significantly higher BBB penetration percentile than Ligand A (66.344). However, since SRC is not a CNS target, this is less important.

**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 and suggests poor solubility. This is a concern for both compounds, but needs experimental confirmation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.574 and 0.561), which is excellent.

**Microsomal Clearance:** Ligand B (20.963 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (37.633 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-25.904 hours) has a much longer in vitro half-life than Ligand A (73.898 hours). Again, this is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.578 and 0.332), which is good.

**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. A 1.7 kcal/mol difference is significant.

**Conclusion:**

While Ligand A has slightly better TPSA and QED, Ligand B clearly outperforms it in the most critical areas for an enzyme inhibitor: binding affinity, metabolic stability (lower Cl_mic), and in vitro half-life. The stronger binding affinity is particularly important. The solubility and permeability concerns are present in both, and would need to be addressed through formulation or further chemical modifications, but the superior potency and PK profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 13:02:26,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.4 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.99) is well below the 140 threshold and favorable for oral absorption. Ligand B (93.73) is higher, but still within a reasonable range, though potentially impacting absorption slightly.

**logP:** Ligand A (4.145) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.298) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.865) has a very good drug-likeness score. Ligand B (0.531) is acceptable, but lower.

**DILI:** Ligand A (44.281) has a slightly elevated DILI risk, but still within a reasonable range. Ligand B (33.656) has a lower, more favorable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (95.541) has high BBB penetration, while Ligand B (41.373) has low BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.452) has poor Caco-2 permeability, which is concerning. Ligand B (-5.068) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.173) has very poor aqueous solubility, a significant drawback. Ligand B (-1.301) has better, though still poor, solubility.

**hERG Inhibition:** Ligand A (0.771) has a moderate hERG risk. Ligand B (0.103) has a very low hERG risk, which is highly desirable.

**Microsomal Clearance:** Ligand A (35.217) has moderate clearance, suggesting reasonable metabolic stability. Ligand B (0.091) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (20.45) has a moderate half-life. Ligand B (-4.384) has a very short half-life, which is a major concern.

**P-gp Efflux:** Ligand A (0.619) has moderate P-gp efflux. Ligand B (0.033) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.6 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 much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from poor solubility and Caco-2 permeability, and has a slightly elevated DILI risk. Ligand B has better ADME properties (lower DILI, hERG, P-gp, and higher metabolic stability), but significantly weaker binding affinity.

Given the strong binding affinity of Ligand A, and the fact that solubility/permeability issues can sometimes be addressed through formulation strategies, I believe Ligand A is the more promising candidate. The potency advantage is substantial enough to prioritize it for further optimization, focusing on improving its solubility and permeability.

Output:
0
2025-04-17 13:02:26,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.377 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (71.09) is significantly better than Ligand A (118.97). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (-1.144) is suboptimal, being below 1, which could hinder permeation. Ligand B (3.718) is within the optimal range (1-3). 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 6 HBA. Both are acceptable, but Ligand B's lower HBD count is slightly favorable.

**QED:** Both ligands have reasonable QED scores (A: 0.39, B: 0.571), with Ligand B being slightly more drug-like.

**DILI:** Ligand B (70.686) has a higher DILI risk than Ligand A (25.824). This is a concern for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Both are around 45-50 percentile.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.49 and -5.253), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.434 and -4.447). This is a major issue for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.267 and 0.744), which is good.

**Microsomal Clearance:** Ligand A (-28.497) has a much lower (better) microsomal clearance than Ligand B (15.128), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand B (114.159) has a significantly longer in vitro half-life than Ligand A (-5.934). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.37).

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a better logP, QED, and in vitro half-life, Ligand A is favored due to its significantly better metabolic stability (lower Cl_mic), lower DILI risk, and slightly better molecular weight. The poor solubility and Caco-2 permeability are concerns for both, but metabolic stability is critical for kinase inhibitors. The equal binding affinity means this doesn't factor into the decision.

Output:
0
2025-04-17 13:02:26,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.78 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.46 and 78.67) are acceptable, being under 140, suggesting reasonable absorption.

**logP:** Ligand A (3.42) is optimal, while Ligand B (0.46) is quite 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 (0.756 and 0.781), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 85.54, which is high. Ligand B has a much lower DILI risk of 52.11, which is preferable.

**BBB:** Both have reasonable BBB penetration (74.56 and 70.80), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.435 and -4.592). This is unusual and suggests poor permeability, but the scale is not clearly defined. We'll consider this a potential negative for both.

**Aqueous Solubility:** Both have negative solubility values (-4.447 and -0.859). Again, the scale is unclear, but this indicates poor solubility for both compounds.

**hERG:** Both ligands have low hERG inhibition liability (0.291 and 0.258), which is excellent.

**Microsomal Clearance:** Ligand A has a high Cl_mic (82.92 mL/min/kg), suggesting rapid metabolism. Ligand B has a much lower Cl_mic (24.05 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 57.62 hours, which is good. Ligand B has a negative half-life (-17.54 hours), which is problematic and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Both have low P-gp efflux liability (0.551 and 0.159), which is favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), though the difference is relatively small.

**Overall Assessment:**

Ligand B is the better candidate despite the negative half-life value. While Ligand A has a better half-life, its high DILI risk and high metabolic clearance are significant drawbacks. Ligand B has a much lower DILI risk, better metabolic stability, and slightly better binding affinity. The low logP of Ligand B is a concern, but the improved safety and stability profiles outweigh this. The negative values for Caco-2 and solubility are concerning for both, but could be addressed through formulation strategies. The negative half-life for Ligand B is a major red flag, however, and would require further investigation.

Output:
1
2025-04-17 13:02:26,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (351.451 and 346.362 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (120.0) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (87.46) is well within the ideal range.

**3. logP:** Ligand A (0.923) is a bit low, potentially hindering permeation. Ligand B (1.299) is better, falling 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 (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.607, B: 0.877), indicating drug-like properties. Ligand B is superior here.

**7. DILI:** Both ligands have similar DILI risk (A: 56.146, B: 53.276), both are acceptable (below 60).

**8. BBB:** This is less critical for a systemic oncology target. Ligand B (58.55) is higher than Ligand A (36.371), but neither is particularly high.

**9. Caco-2 Permeability:** Both have negative values (-5.396 and -4.754), 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.

**10. Aqueous Solubility:** Both have negative values (-2.667 and -2.4), indicating poor solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG risk (A: 0.06, B: 0.161).

**12. Microsomal Clearance:** Ligand B (-7.531) has significantly *lower* (better) microsomal clearance than Ligand A (16.629), indicating greater metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (-22.412) has a much longer in vitro half-life than Ligand A (-15.387), further supporting its improved metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.037, B: 0.02).

**15. Binding Affinity:** Ligand B (-10.1 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 minor ADME drawbacks.

**Conclusion:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), **Ligand B is the superior candidate**. Its significantly stronger binding affinity, lower microsomal clearance, longer half-life, and slightly better logP and QED outweigh the slightly lower TPSA and solubility concerns. While both have poor solubility and permeability, the superior potency and metabolic stability of Ligand B make it more likely to succeed as a drug candidate.

Output:
1
2025-04-17 13:02:26,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.415 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (87.32 and 89.87) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.26 and 2.293) are 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:** Both ligands (4) are below the 10 threshold.

**6. QED:** Both ligands have acceptable QED scores (0.787 and 0.705), indicating good drug-like properties.

**7. DILI:** Ligand A (59.131) has a moderate DILI risk, while Ligand B (11.128) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have similar BBB penetration (50.097 and 50.872), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.175 and -5.013), 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 negative solubility values (-3.59 and -3.285), suggesting poor aqueous solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.371 and 0.397).

**12. Microsomal Clearance:** Ligand A (9.247) has significantly lower microsomal clearance than Ligand B (48.637), indicating better metabolic stability. This is a major advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-8.357) has a much longer in vitro half-life than Ligand B (-14.982). This further supports the better metabolic stability of Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.014).

**15. Binding Affinity:** Ligand B (-10.0) has a significantly stronger binding affinity than Ligand A (-7.2). This difference of 2.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better safety profile (lower DILI) and significantly stronger binding affinity. While Ligand A exhibits better metabolic stability (lower Cl_mic, longer t1/2), the substantial affinity advantage of Ligand B is critical for an enzyme inhibitor. The poor solubility and permeability (indicated by negative values) are concerns for both, but can potentially be addressed through formulation strategies. Given the importance of potency for kinase inhibitors, the stronger binding of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 13:02:26,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.387 and 343.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.77) is better than Ligand B (114.35), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinases.

**3. logP:** Ligand B (1.902) is within the optimal 1-3 range, while Ligand A (0.303) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.644 and 0.828), indicating good drug-like properties.

**7. DILI:** Ligand A (49.128) has a lower DILI risk than Ligand B (60.062), which is approaching a higher risk category.

**8. BBB:** Both ligands have reasonable BBB penetration (77.821 and 70.105), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values which is not ideal, but similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values which is not ideal, but similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.188 and 0.186).

**12. Microsomal Clearance:** Ligand A (-9.249) has *significantly* lower (better) microsomal clearance than Ligand B (32.79). This suggests much greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (15.42) has a much longer half-life than Ligand B (-33.367).

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

**15. Binding Affinity:** Ligand B (-9.0) has a much stronger binding affinity than Ligand A (0.0). This is a substantial difference.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, the significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk of Ligand A are crucial for kinase inhibitors. The slightly lower logP of Ligand A is a concern, but the substantial advantage in metabolic stability and safety profile outweighs this. The difference in binding affinity is large, but not insurmountable in subsequent optimization rounds.

Output:
0
2025-04-17 13:02:26,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 345.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is well below the 140 threshold, and good for absorption. Ligand B (106.73) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.404) is optimal (1-3). Ligand B (0.862) is a bit low, potentially hindering permeation, but not a major concern.

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

**H-Bond Acceptors:** Ligand A (3) and Ligand B (7) are both acceptable (<=10), though B is higher.

**QED:** Both ligands have good QED scores (0.72 and 0.774), indicating drug-likeness.

**DILI:** Ligand A (34.82) has a lower DILI risk than Ligand B (64.521), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.811) is better than Ligand B (49.748).

**Caco-2 Permeability:** Ligand A (-4.704) and Ligand B (-5.196) are both negative, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.57 and -2.763). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.35) has a much lower hERG risk than Ligand B (0.068), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (60.893) has higher clearance than Ligand B (8.461), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (18.721) has a shorter half-life than Ligand B (-0.82), further supporting the concern about metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.183 and 0.055).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While it has a slightly lower logP and higher TPSA, its significantly better binding affinity (-8.5 vs -7.4 kcal/mol), lower DILI risk, and *much* better metabolic stability (lower Cl_mic, longer t1/2) outweigh the minor drawbacks. The hERG risk is also much lower for Ligand B. Although both have poor solubility and Caco-2 permeability, the superior potency and pharmacokinetic properties of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 13:02:26,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.559 Da and 357.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (52.65 and 54.38) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (2.11 and 2.062) are 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:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.714 and 0.808), indicating drug-likeness.

**DILI:** Ligand A (19.193) has a significantly lower DILI risk than Ligand B (62.35). This is a major advantage for Ligand A.

**BBB:** Ligand A (68.282) and Ligand B (89.027) both have reasonable BBB penetration, but Ligand B is better. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.478) and Ligand B (-4.607) both have negative Caco-2 values, which is not ideal, but not a dealbreaker.

**Aqueous Solubility:** Ligand A (-1.792) has better aqueous solubility than Ligand B (-3.936). This is important for bioavailability.

**hERG Inhibition:** Ligand A (0.429) has a lower hERG inhibition liability than Ligand B (0.667), reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (33.818) has lower microsomal clearance than Ligand B (42.164), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (8.055 and 7.962 hours).

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.032), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better BBB penetration and P-gp efflux, Ligand A excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity, lower DILI risk, better aqueous solubility, and lower hERG inhibition. The improved metabolic stability (lower Cl_mic) further strengthens its profile.

Output:
1
2025-04-17 13:02:26,460 - INFO - Batch 180 complete. Total preferences: 2880
2025-04-17 13:02:26,460 - INFO - Processing batch 181/512...
2025-04-17 13:03:06,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.391 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (103.41) is better than Ligand B (69.64). While both are reasonably low, Ligand B is particularly good, suggesting better potential for cell permeability.

**logP:** Ligand A (0.524) is quite low, potentially hindering permeability. Ligand B (2.183) 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 8 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits, but Ligand B has a more balanced profile.

**QED:** Both ligands have similar, good QED values (0.702 and 0.705).

**DILI:** Ligand A has a DILI risk of 69.988, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (20.396), a significant advantage.

**BBB:** Ligand A (36.487) has a low BBB penetration, as expected for a molecule with low logP. Ligand B (77.162) shows reasonable BBB penetration, but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.469) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.852) is also not great, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.683) has poor aqueous solubility, while Ligand B (-3.057) is even worse. This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.118) has very low hERG inhibition risk, a significant advantage. Ligand B (0.541) is slightly higher, but still reasonably low.

**Microsomal Clearance:** Ligand A (16.729) has lower microsomal clearance than Ligand B (27.355), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.244) has a longer half-life than Ligand B (-1.313). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is favorable. Ligand B (0.344) has higher P-gp efflux.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a >1 kcal/mol difference, which can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a stronger binding affinity, a more optimal logP, and a significantly lower DILI risk. While its solubility and Caco-2 permeability are not ideal, these can potentially be addressed through formulation. Ligand A has better metabolic stability and lower P-gp efflux, but its low logP and poor solubility are major concerns, and the affinity difference is substantial. Given the priority for potency in kinase inhibitors, the stronger binding affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 13:03:06,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.443 and 355.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.43) is slightly higher than Ligand B (64.09), but both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have optimal logP values (1.574 and 1.429) 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 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.822 and 0.783), indicating drug-like properties.

**7. DILI:** Ligand A (11.632) has a significantly lower DILI risk than Ligand B (15.161). This is a major advantage.

**8. BBB:** Ligand A (71.966) has a better BBB penetration percentile than Ligand B (48.391). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**9. Caco-2 Permeability:** Ligand A (-4.827) has worse Caco-2 permeability than Ligand B (-4.559), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.674) has worse aqueous solubility than Ligand B (-0.593). Solubility is important for bioavailability, so this favors Ligand B.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.529 and 0.425).

**12. Microsomal Clearance:** Ligand A (13.683) has lower microsomal clearance than Ligand B (20.782), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-19.932) has a significantly longer in vitro half-life than Ligand B (3.823). This is a substantial advantage, potentially enabling less frequent dosing.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.06).

**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, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B possesses a much stronger binding affinity for the SRC kinase. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, the substantial difference in binding affinity (-7.7 vs 0.0 kcal/mol) is the most critical factor for an enzyme inhibitor. The slightly worse solubility and permeability of Ligand B can potentially be addressed through formulation strategies. The lower DILI risk of Ligand A is good, but potency is paramount.

Output:
1
2025-04-17 13:03:06,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.401 and 348.531 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.88) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (49.41) is well within the acceptable range.

**logP:** Ligand A (0.329) is quite low, potentially hindering permeability. Ligand B (3.601) is closer to 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 has 4 HBAs, and Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.667 and 0.764, respectively), indicating good drug-like properties.

**DILI:** Ligand A (34.781) has a significantly lower DILI risk than Ligand B (13.067), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (78.868 and 78.558), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.443 and -4.547), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.631 and -3.953), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.341) has a lower hERG risk than Ligand B (0.56), which is preferable.

**Microsomal Clearance:** Ligand A (-7.949) has *much* lower microsomal clearance (better metabolic stability) than Ligand B (55.312). This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-10.281) has a longer in vitro half-life than Ligand B (-6.136), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.032) has very low P-gp efflux, while Ligand B (0.22) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.4). While the difference is not huge, it's still a positive factor.

**Conclusion:**

Ligand A is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG risk, and slightly better binding affinity. The low logP of Ligand A is a concern, but the superior ADME properties and safety profile outweigh this drawback.

Output:
0
2025-04-17 13:03:06,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.343 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (385.266 Da) is still well within the acceptable range.

**TPSA:** Ligand A (117.57) is better than Ligand B (49.41) as it is below 140, suggesting good oral absorption. Ligand B is also below 140, so both are acceptable.

**logP:** Ligand A (0.315) is lower than optimal (1-3), potentially hindering permeation. Ligand B (3.298) is within the optimal 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 2 HBA, also acceptable.

**QED:** Ligand A (0.333) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.639) is above 0.5, suggesting a better drug-like profile.

**DILI:** Ligand A (65.762) has a higher DILI risk than Ligand B (57.697), though both are reasonably acceptable.

**BBB:** Not a primary concern for a kinase inhibitor, but Ligand B (86.623) has better BBB penetration than Ligand A (59.093).

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.977 and -4.953 respectively). This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.119 and -4.358 respectively). This is also a significant concern for both.

**hERG Inhibition:** Ligand A (0.18) has a lower hERG risk than Ligand B (0.554), which is a positive attribute.

**Microsomal Clearance:** Ligand A (-0.571) has a lower (better) microsomal clearance than Ligand B (14.968), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.992) has a longer half-life than Ligand B (-17.217), which is desirable.

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux than Ligand B (0.242), suggesting better bioavailability.

**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 many ADME drawbacks.

**Conclusion:**

Despite Ligand A's better metabolic stability, half-life, lower P-gp efflux, and lower hERG risk, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.3 vs -7.2 kcal/mol) is a major advantage for an enzyme inhibitor. While Ligand B has a slightly higher DILI risk and a less optimal logP, the potency advantage is likely to be more critical for efficacy. Both compounds have poor solubility and permeability, which would need to be addressed through formulation or further structural modifications, but the superior affinity of Ligand B makes it the better starting point.

Output:
1
2025-04-17 13:03:06,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (357.405 and 357.401 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.91) is slightly higher than Ligand B (78.51), but both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have optimal logP values (1.431 and 1.196), 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 5 HBA, while Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.62 and 0.75), indicating good drug-like properties.

**7. DILI:** Ligand A (32.144) has a slightly higher DILI risk than Ligand B (27.608), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have high BBB penetration (83.055 and 83.366), but this is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5 and -4.863). 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 (-1.99 and -2.23). This is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.093 and 0.154), which is excellent.

**12. Microsomal Clearance:** Ligand A (18.643 mL/min/kg) has significantly higher microsomal clearance than Ligand B (1.054 mL/min/kg). This indicates lower metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-15.368 hours) has a negative half-life, which is not physically possible. This is likely an error in the data. Ligand B (-1.634 hours) also has a negative half-life, suggesting poor stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.01).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While both are excellent, the 0.4 kcal/mol difference could be significant.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While both have issues with solubility and permeability, Ligand B exhibits significantly better metabolic stability (much lower Cl_mic and a less negative t1/2) and slightly better binding affinity. The negative half-life values for both are concerning and require further investigation, but the difference in Cl_mic is a key differentiator.

Output:
1
2025-04-17 13:03:06,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.45 & 347.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (75.44). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**3. logP:** Both ligands have good logP values (3.297 & 2.333), 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 (2) is lower than Ligand B (4), which is favorable.

**6. QED:** Both ligands have good QED scores (0.744 & 0.887), indicating good drug-like properties.

**7. DILI:** Ligand A (21.753) has a much lower DILI risk than Ligand B (47.964). This is a significant advantage.

**8. BBB:** Both ligands have high BBB penetration (81.039 & 88.057), but SRC is not a CNS target, so this is less crucial.

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

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.513 & -3.791), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.568) has a lower hERG inhibition risk than Ligand B (0.323), which is a positive.

**12. Microsomal Clearance:** Ligand A (40.399) has a lower microsomal clearance than Ligand B (46.94), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.472) has a slightly better in vitro half-life than Ligand B (-19.992).

**14. P-gp Efflux:** Ligand A (0.147) has a slightly lower P-gp efflux liability than Ligand B (0.149).

**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.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, the significantly higher DILI risk and worse metabolic stability (higher Cl_mic) are major drawbacks. Ligand A, despite a weaker binding affinity, presents a much more favorable safety profile (lower DILI, lower hERG) and better metabolic stability. The negative Caco-2 and solubility values are concerning for both, but these can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, the balance of properties favors Ligand A. The potency difference (1.9 kcal/mol) is substantial, but not insurmountable, and the improved ADMET properties of Ligand A are likely to translate to a more viable drug candidate.

Output:
0
2025-04-17 13:03:06,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (378.441 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (49.41), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (3.417 and 3.127) 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:** Ligand A (4) is slightly higher than Ligand B (3), both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.794 and 0.836), indicating good drug-likeness.

**DILI:** Ligand B (31.059) has a significantly lower DILI risk than Ligand A (71.539), which is a major advantage.

**BBB:** Ligand B (76.89) has a higher BBB penetration score than Ligand A (64.831), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.797) has a worse Caco-2 permeability than Ligand B (-5.142). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-3.874 and -3.669).

**hERG Inhibition:** Ligand A (0.734) has slightly higher hERG inhibition risk than Ligand B (0.55), but both are acceptable.

**Microsomal Clearance:** Ligand B (84.212) has a higher microsomal clearance than Ligand A (47.616), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (6.619) has a much shorter in vitro half-life than Ligand A (-15.891). This is a major disadvantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.209 and 0.275).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While a 1.5 kcal/mol difference is significant, the other factors weigh more heavily.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and Caco-2 permeability, and a lower DILI risk. While Ligand B has slightly better binding affinity, the significantly worse metabolic stability and shorter half-life are major concerns for *in vivo* efficacy. The lower DILI risk for Ligand B is attractive, but the other ADME properties of Ligand A are more favorable for an enzyme target.

Output:
0
2025-04-17 13:03:06,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.415 Da) and Ligand B (347.463 Da) are both acceptable.

**TPSA:** Ligand A (133.31) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (98.17) is excellent, well below 140.

**logP:** Ligand A (1.741) is within the optimal range (1-3). Ligand B (3.178) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.597) is good, indicating drug-like properties. Ligand B (0.394) is below 0.5, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (82.435) has a higher DILI risk than Ligand B (24.506). This is a significant concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (32.028) and Ligand B (71.811) are both not particularly high, but this is not a major differentiating factor.

**Caco-2 Permeability:** 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:** Both have negative values, again unusual and suggesting poor solubility. The scale is not defined, so it's hard to interpret.

**hERG:** Ligand A (0.15) has a slightly higher hERG risk than Ligand B (0.478), but both are relatively low.

**Microsomal Clearance:** Ligand A (34.765) has lower clearance, indicating better metabolic stability, which is a key priority for enzymes. Ligand B (63.157) has higher clearance.

**In vitro Half-Life:** Ligand A (-13.851) has a negative half-life, which is impossible. This is a major red flag. Ligand B (-11.669) also has a negative half-life, also a major red flag.

**P-gp Efflux:** Both are very low (0.014 and 0.049), indicating minimal P-gp efflux.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.5), although both are good (below -7.0).

**Overall Assessment:**

Ligand B is the better candidate despite the negative half-life and solubility values. The significantly lower DILI risk, better QED, and slightly better binding affinity outweigh the slightly higher logP. The negative half-life is a serious issue, but could be addressed with structural modifications. Ligand A's high DILI risk and impossible half-life are major drawbacks.

Output:
1
2025-04-17 13:03:06,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.519 and 347.434 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.01) is better than Ligand B (52.65), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.066) is optimal, while Ligand B (0.799) is a bit low, potentially hindering permeation.

**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 and 3, respectively), well below the limit of 10.

**QED:** Both ligands have good QED scores (0.569 and 0.723), indicating good drug-like properties.

**DILI:** Ligand A (34.471) has a lower DILI risk than Ligand B (6.592), which is preferable.

**BBB:** Both ligands have reasonable BBB penetration (75.456 and 72.237), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.082) and Ligand B (-4.767) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-4.13) and Ligand B (-1.633) both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.342 and 0.354), which is excellent.

**Microsomal Clearance:** Ligand B (-9.686) has significantly *lower* (better) microsomal clearance than Ligand A (83.653), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-24.553) has a longer in vitro half-life than Ligand A (-29.773), which is beneficial.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.294 and 0.011), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 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 B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. The lower DILI risk is also a plus. The slightly lower logP of Ligand B is a minor concern, but the superior metabolic properties and binding outweigh this.

Output:
1
2025-04-17 13:03:06,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.37 and 342.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (20.31) is excellent, well below 140, suggesting good absorption. Ligand B (80.68) is higher but still acceptable for an enzyme inhibitor, though potentially impacting permeability slightly.

**logP:** Ligand A (4.778) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (3.75) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 1 HBA) is very favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.69 and 0.797), indicating good drug-like properties.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (71.423). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (97.247) has a high BBB score, while Ligand B (38.426) is low.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, it's likely a scaling issue and doesn't necessarily disqualify either.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.711 and -4.873). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.952) has a slightly higher hERG risk than Ligand B (0.12). This favors Ligand B.

**Microsomal Clearance:** Ligand A (37.337) has higher microsomal clearance than Ligand B (23.209), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-25.232) has a significantly longer in vitro half-life than Ligand A (-16.784), indicating better metabolic stability. This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.592 and 0.042).

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.1), but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a significantly better DILI profile and a more favorable TPSA and H-bonding profile. However, its higher logP, higher microsomal clearance, and shorter half-life are concerning. Ligand B, while having a higher DILI risk, exhibits better metabolic stability (lower Cl_mic, longer t1/2), a more optimal logP, and a slightly better binding affinity. The solubility is poor for both, but the metabolic stability and lower hERG risk of Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 13:03:06,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.435 and 341.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.98) is better than Ligand B (38.56) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (1.36) is optimal (1-3), while Ligand B (4.781) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.75 and 0.787), indicating good drug-likeness.

**DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (34.161), which is a crucial advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (84.141) has a better BBB score than Ligand A (55.991).

**Caco-2 Permeability:** Ligand A (-5.396) has a worse Caco-2 permeability than Ligand B (-4.661).

**Aqueous Solubility:** Ligand A (-1.468) has better aqueous solubility than Ligand B (-4.287).

**hERG Inhibition:** Ligand A (0.26) has a much lower hERG inhibition liability than Ligand B (0.928), a significant safety advantage.

**Microsomal Clearance:** Ligand A (-4.678) has a lower (better) microsomal clearance than Ligand B (52.675), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-13.504) has a longer in vitro half-life than Ligand B (66.642), which is desirable.

**P-gp Efflux:** Ligand A (0.018) has a lower P-gp efflux liability than Ligand B (0.812), improving bioavailability.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.5). 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 a slightly better binding affinity, Ligand A excels in crucial ADME-Tox properties. Specifically, its significantly lower DILI risk, hERG inhibition, and P-gp efflux, combined with better solubility, metabolic stability, and half-life, make it a much more promising drug candidate. The slightly lower Caco-2 permeability is a minor drawback compared to the substantial safety and pharmacokinetic advantages of Ligand A.

Output:
0
2025-04-17 13:03:06,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.817 Da) and Ligand B (347.463 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values around 79-80, which is acceptable for oral absorption, being below the 140 threshold.

**logP:** Ligand A (2.1) is optimal, while Ligand B (0.605) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.598, B: 0.79), indicating drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (65.917%) compared to Ligand B (14.889%). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.698%) has a higher BBB penetration than Ligand B (41.218%), but it's not a deciding factor here.

**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 show low hERG inhibition liability (A: 0.08, B: 0.137), which is good.

**Microsomal Clearance:** Ligand B has a much lower (better) microsomal clearance (-23.733 mL/min/kg) compared to Ligand A (41.292 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (14.369 hours) than Ligand A (2.056 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.195, B: 0.008), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although both are good. The 1.2 kcal/mol difference is significant enough to consider.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While both have acceptable MW, TPSA, and QED, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2), has a lower DILI risk, and slightly better binding affinity. Ligand A's high DILI risk is a significant drawback. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization, but the benefits outweigh this drawback.

Output:
1
2025-04-17 13:03:06,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.414 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is significantly better than Ligand B (108.29). A TPSA under 90 is not critical for kinases, but lower is generally preferred for better absorption. Ligand A is well within the acceptable range, while Ligand B is approaching the upper limit for good oral absorption (<=140).

**logP:** Both ligands have acceptable logP values (4.007 and 3.045, respectively) within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within the recommended limits.

**QED:** Ligand A (0.804) has a significantly higher QED score than Ligand B (0.683), indicating a more drug-like profile.

**DILI:** Ligand B (72.741) has a higher DILI risk than Ligand A (49.981). Ligand A is comfortably below the 60% threshold, while Ligand B is above, raising a concern.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (60.644) and Ligand B (52.734) are both moderate.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.295 and -4.947), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-5.495 and -4.345), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.777) has a lower hERG risk than Ligand B (0.192), which is a significant advantage.

**Microsomal Clearance:** Ligand A (115.451) has a higher microsomal clearance than Ligand B (52.661), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (25.801) has a significantly longer half-life than Ligand A (5.353), which is a major advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.213) has lower P-gp efflux than Ligand B (0.034), which is preferable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This 1.6 kcal/mol difference is substantial and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and a significantly longer half-life, which are crucial for a kinase inhibitor. However, it has a higher DILI risk, lower hERG safety, and worse solubility. Ligand A has better solubility, lower DILI and hERG risk, and better P-gp efflux, but suffers from higher clearance and a weaker binding affinity.

Given the importance of potency for kinase inhibitors, the 1.6 kcal/mol advantage of Ligand B is significant. While the DILI risk is a concern, it might be mitigated through structural modifications. The longer half-life also makes Ligand B more attractive. The poor solubility and permeability are shared issues that would need to be addressed regardless of which ligand is chosen.

Output:
1
2025-04-17 13:03:06,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.435 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 88.18, Ligand B: 86.71), suggesting good oral absorption potential.

**logP:** Ligand A (0.319) is a bit low, potentially hindering permeation. Ligand B (1.248) 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.58, Ligand B: 0.762), indicating drug-like properties. Ligand B is better.

**DILI:** Both ligands have low DILI risk (Ligand A: 35.712, Ligand B: 31.175), which is positive. Ligand B is slightly better.

**BBB:** Both have similar BBB penetration (Ligand A: 60.799, Ligand B: 61.613). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.886) has poor Caco-2 permeability. Ligand B (-5.238) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.347) has poor aqueous solubility. Ligand B (-3.055) has even worse solubility.

**hERG Inhibition:** Ligand A (0.14) has very low hERG inhibition risk, which is excellent. Ligand B (0.505) is higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-8.189) has very low microsomal clearance, suggesting good metabolic stability. Ligand B (33.781) has high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-9.92) has a long in vitro half-life, consistent with low clearance. Ligand B (-19.704) has a very long half-life, but this is likely an artifact of the high clearance value being negative.

**P-gp Efflux:** Both ligands have negligible P-gp efflux (Ligand A: 0.006, Ligand B: 0.089).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand B having worse solubility and Caco-2 permeability, its *significantly* superior binding affinity (-9.2 vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic) make it the more promising candidate. The large difference in binding affinity is the deciding factor for an enzyme target like SRC kinase. The lower logP of Ligand A is also a concern.

Output:
1
2025-04-17 13:03:06,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 346.431 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (92.52) is slightly higher than Ligand B (72.96). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.256) is within the optimal range (1-3). Ligand B (-0.844) is slightly below 1, which *could* indicate potential permeability issues, but is not a major concern.

**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 A (0.819) has a higher QED than Ligand B (0.674), indicating a more drug-like profile.

**DILI:** Ligand A (57.425) has a higher DILI risk than Ligand B (21.442). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.868) has a higher BBB percentile than Ligand B (43.04).

**Caco-2 Permeability:** Ligand A (-4.996) has a lower Caco-2 permeability than Ligand B (-5.093). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.586) has lower solubility than Ligand B (-1.114). Solubility is important for bioavailability, favoring Ligand B.

**hERG Inhibition:** Ligand A (0.521) has a slightly higher hERG risk than Ligand B (0.057). Ligand B is significantly better here.

**Microsomal Clearance:** Ligand A (2.483) has a higher microsomal clearance than Ligand B (-3.29). Lower clearance is better for metabolic stability, favoring Ligand B.

**In vitro Half-Life:** Ligand A (-3.302) has a shorter half-life than Ligand B (-1.144). Longer half-life is preferable, favoring Ligand B.

**P-gp Efflux:** Ligand A (0.01) has a slightly higher P-gp efflux liability than Ligand B (0.006). Lower efflux is better, favoring Ligand B.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This 1.2 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 QED, Ligand B demonstrates significantly better ADMET properties. Specifically, the much lower DILI risk, hERG inhibition, and microsomal clearance, coupled with better solubility and half-life, make it a more promising candidate. The difference in binding affinity, while notable, is likely surmountable with further optimization, whereas addressing severe ADMET liabilities is often much more challenging. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 13:03:06,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.463 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (68.54 and 67.43) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.967) is high, potentially causing solubility and off-target issues. Ligand B (1.614) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (2 HBD, 3 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.506 and 0.72), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 68.941, which is moderately high. Ligand B has a much lower DILI risk of 29.624, a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (83.327) has a higher BBB percentile than Ligand B (48.74).

**Caco-2 Permeability:** Ligand A (-4.686) and Ligand B (-5.012) both have negative Caco-2 values, which is unusual and indicates very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-5.938) and Ligand B (-3.429) both have poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.648) has a slightly higher hERG risk than Ligand B (0.142), which is preferable.

**Microsomal Clearance:** Ligand A (120.349) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (2.6). This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (64.099) has a longer half-life than Ligand B (21.647), which is desirable.

**P-gp Efflux:** Ligand A (0.799) has slightly higher P-gp efflux than Ligand B (0.085), which is less desirable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a longer half-life and higher BBB penetration, Ligand B is the superior candidate. The significantly stronger binding affinity (-8.7 vs -7.9 kcal/mol), much lower DILI risk (29.624 vs 68.941), and dramatically improved metabolic stability (lower Cl_mic and higher t1/2) outweigh the slight drawbacks in BBB and half-life. Both compounds have poor Caco-2 permeability and solubility, which would need to be addressed in further optimization, but the superior potency and safety profile of Ligand B make it the more promising starting point.

Output:
1
2025-04-17 13:03:06,735 - INFO - Batch 181 complete. Total preferences: 2896
2025-04-17 13:03:06,735 - INFO - Processing batch 182/512...
2025-04-17 13:03:47,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.466 and 370.787 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.25) is still under 140, but less favorable than A.

**3. logP:** Both ligands (2.294 and 2.278) 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 3 HBA, and Ligand B has 5. Both are within the acceptable limit of 10, but A is preferable.

**6. QED:** Both ligands have very similar QED values (0.843 and 0.838), indicating good drug-likeness.

**7. DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (54.634), which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.135) has a higher BBB percentile than Ligand B (53.509).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.401 and -4.447). This is unusual and suggests poor permeability *in vitro*. However, it's not a dealbreaker, and other factors can compensate.

**10. Aqueous Solubility:** Both have negative solubility values (-3.707 and -3.266). This is also concerning, and could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.477) has a lower hERG risk than Ligand B (0.19), which is a crucial advantage.

**12. Microsomal Clearance:** Ligand A (61.379) has a higher microsomal clearance than Ligand B (14.977), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-9.445) has a longer in vitro half-life than Ligand A (-15.128), indicating better stability.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.206 and 0.109).

**15. Binding Affinity:** Ligand B (-10.0) has a significantly stronger binding affinity than Ligand A (-8.7). This is a substantial advantage that can potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a better half-life, and lower DILI risk. While it has a slightly higher TPSA, the difference isn't substantial. The biggest concern for Ligand B is the negative solubility and Caco-2 values, but the strong binding affinity could compensate for these issues. Ligand A has better hERG inhibition, but its higher clearance is a major drawback for an enzyme inhibitor.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate due to its superior binding affinity and metabolic stability.

Output:
1
2025-04-17 13:03:47,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.379 Da) is slightly lower, which is generally favorable for permeability. Ligand B (377.495 Da) is also acceptable.

**TPSA:** Ligand A (62.99) is well below the 140 threshold for oral absorption. Ligand B (71.45) is also acceptable.

**logP:** Both ligands have a logP around 2 (A: 2.037, B: 2.075), which is optimal for permeability and solubility.

**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, but isn't a major concern.

**QED:** Both ligands have acceptable QED scores (A: 0.858, B: 0.756), indicating good drug-like properties.

**DILI:** Ligand A (60.682) is borderline, but acceptable. Ligand B (93.059) has a significantly higher DILI risk, which is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.737) has better BBB penetration than Ligand B (75.533).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, it's likely a scaling issue and doesn't necessarily disqualify either compound.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility. Ligand A (-2.647) is slightly better than Ligand B (-4.363).

**hERG Inhibition:** Ligand A (0.167) has a very low hERG risk, which is excellent. Ligand B (0.613) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (39.454) has lower microsomal clearance, indicating better metabolic stability. Ligand B (77.368) has significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (83.968) has a much longer in vitro half-life than Ligand B (-29.625), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.089, B: 0.272).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a lower hERG risk. While both have issues with solubility and Caco-2 permeability, Ligand A's superior potency and safety profile make it the more promising drug candidate.

Output:
0
2025-04-17 13:03:47,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.312 and 363.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.68) is well below the 140 threshold for good absorption. Ligand B (80.76) is still acceptable, but less optimal.

**logP:** Ligand A (2.225) is within the optimal 1-3 range. Ligand B (0.417) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 6 HBA) is also good, staying within the recommended limits.

**QED:** Both ligands have similar and good QED values (0.763 and 0.767).

**DILI:** Ligand A (63.358) has a higher DILI risk than Ligand B (56.572), but both are still within an acceptable range (<60 is good).

**BBB:** Ligand A (98.41) shows excellent BBB penetration, while Ligand B (51.415) is much lower. This is less critical for a non-CNS target like SRC, but a bonus.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.115 and -4.684). This is unusual and suggests a potential issue with the calculation or data quality. It's difficult to interpret without further investigation, but it's a flag.

**Aqueous Solubility:** Both have negative solubility values (-3.412 and -1.787). Similar to Caco-2, this is concerning and needs further investigation.

**hERG:** Ligand A (0.586) has a slightly higher hERG risk than Ligand B (0.107), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (35.543) has a higher microsomal clearance than Ligand B (-6.894), indicating lower metabolic stability. This is a key negative for A.

**In vitro Half-Life:** Ligand A (-1.7 hours) has a shorter half-life than Ligand B (-2.85 hours). This is another negative for A.

**P-gp Efflux:** Ligand A (0.339) has lower P-gp efflux than Ligand B (0.03), which is slightly favorable.

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the questionable solubility and Caco-2 values, the significantly stronger binding affinity of Ligand A (-8.7 vs -7.5 kcal/mol) is a major advantage. However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and a lower DILI score. Considering the enzyme-specific priorities, metabolic stability and safety (hERG) are crucial. While the affinity difference is substantial, the ADME properties of Ligand B are considerably more favorable, making it a more promising starting point for drug development. The negative solubility and Caco-2 values for both are concerning and would require further investigation, but the overall profile of B is better.

Output:
1
2025-04-17 13:03:47,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.857 Da) is slightly higher than Ligand B (345.447 Da), but both are acceptable.

**TPSA:** Ligand A (62.4) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (87.22) is also below the threshold, but closer.

**logP:** Ligand A (3.51) is within the optimal range (1-3). Ligand B (1.058) 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 reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.576, B: 0.722), indicating drug-like properties.

**DILI:** Ligand A (57.697) has a moderate DILI risk, while Ligand B (20.279) has a very low DILI risk, which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (54.013) and Ligand B (64.87) are both moderate.

**Caco-2 Permeability:** Ligand A (-4.684) has poor Caco-2 permeability, while Ligand B (-5.32) is similarly poor. This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Ligand A (-3.672) has poor solubility, while Ligand B (-1.54) is slightly better, but still poor. Solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.482) has a low hERG risk, which is excellent. Ligand B (0.137) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (88.09) has relatively high microsomal clearance, indicating faster metabolism. Ligand B (-6.133) has *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**In vitro Half-Life:** Ligand A (51.401) has a moderate half-life. Ligand B (2.99) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.456, B: 0.003).

**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 but not overwhelming.

**Overall Assessment:**

Ligand B is superior despite the slightly lower binding affinity. Its significantly lower DILI risk and *exceptionally* low microsomal clearance (negative value) are major advantages for an enzyme inhibitor. While its solubility and Caco-2 permeability are poor, the metabolic stability is a critical factor for kinases. Ligand A's higher clearance is a significant concern. The slightly better affinity of Ligand A is outweighed by the superior ADME profile of Ligand B.

Output:
1
2025-04-17 13:03:47,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.27 and 340.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (74.25 and 68.44) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.084) is optimal, while Ligand B (1.449) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, fitting the <5 and <10 rules. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.733 and 0.889), indicating drug-like properties.

**DILI:** Ligand A (54.75) has a moderate DILI risk, while Ligand B (36.45) has a lower, more favorable DILI risk.

**BBB:** Both ligands have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 misleading.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.613 and -2.767). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.597 and 0.612).

**Microsomal Clearance:** Ligand A (36.497) has a moderate clearance, while Ligand B (-18.611) has a *negative* clearance, which is impossible and likely an error in the data. This indicates very high metabolic stability, a major advantage.

**In vitro Half-Life:** Ligand A (12.463) has a reasonable half-life, while Ligand B (-0.239) has a negative half-life, which is also impossible and indicates a data error.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.126 and 0.068), which is favorable.

**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 advantage, potentially outweighing other drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity (-7.9 vs 0.0 kcal/mol) is a major advantage for an enzyme inhibitor. While the negative values for Cl_mic and t1/2 are data errors, the overall profile of Ligand B, including lower DILI risk and good P-gp efflux, makes it a better starting point for optimization. The solubility issue would need to be addressed through formulation or structural modifications.

Output:
1
2025-04-17 13:03:47,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.395 and 351.422 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.44) is better than Ligand B (93.45). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range for oral bioavailability.

**logP:** Both ligands have good logP values (2.008 and 1.623), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=3, HBA=4). Both are within acceptable limits.

**QED:** Ligand A (0.904) has a significantly higher QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Ligand A (32.842) has a much lower DILI risk than Ligand B (44.087), which is a significant advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** Both ligands have good BBB penetration (78.209 and 82.862). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.051 and -4.834), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.429 and -3.042), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.355) has a lower hERG risk than Ligand B (0.603), which is a positive attribute.

**Microsomal Clearance:** Ligand A (8.221) has a significantly lower microsomal clearance than Ligand B (33.007), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-15.133) has a negative half-life, which is concerning. Ligand B (0.73) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.052).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial difference and a major advantage for Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A excels in several key ADME properties: QED, DILI, microsomal clearance, and hERG risk. The negative Caco-2 and solubility values are concerning for both, but the superior affinity of Ligand B outweighs these drawbacks. The better metabolic stability of Ligand A is also a significant plus.

Considering the balance, the stronger binding affinity of Ligand B is the deciding factor. While the ADME profile of Ligand A is better, the potency advantage of Ligand B is substantial enough to warrant further investigation and optimization.

Output:
1
2025-04-17 13:03:47,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.535 and 368.493 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is excellent, under the 140 threshold, and even closer to the 90 threshold for CNS penetration (though not a CNS target here). Ligand B (33.2) is also very good.

**logP:** Ligand A (0.398) is a bit low, potentially hindering permeability. Ligand B (4.541) is slightly high, potentially causing solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, fitting well within the guidelines. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.609 and 0.6), indicating good drug-likeness.

**DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (24.544). This is a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand B (84.917) has a higher BBB penetration than Ligand A (49.36).

**Caco-2 Permeability:** Ligand A (-5.232) has a negative Caco-2 value, which is concerning. Ligand B (-4.734) is also negative, but slightly less so.

**Aqueous Solubility:** Ligand A (-1.296) has slightly better solubility than Ligand B (-4.611).

**hERG Inhibition:** Ligand A (0.376) has a much lower hERG inhibition liability than Ligand B (0.889), a critical advantage for safety.

**Microsomal Clearance:** Ligand A (35.116) has a significantly lower microsomal clearance, indicating better metabolic stability, which is crucial for kinase inhibitors. Ligand B (80.226) is much higher.

**In vitro Half-Life:** Ligand A (-44.815) has a much longer in vitro half-life than Ligand B (-4.787), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux liability, while Ligand B (0.412) is higher.

**Binding Affinity:** Both ligands have similar and good binding affinities (-7.0 and -6.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly low and Caco-2 permeability is concerning, its superior DILI, hERG, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux profiles outweigh these drawbacks. The similar binding affinity means these ADME/Tox properties become the deciding factors. The lower risk profile of Ligand A makes it more likely to succeed in development.

Output:
0
2025-04-17 13:03:47,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.43 and 373.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.82) is slightly higher than Ligand B (87.3), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.84 and 2.94), 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 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.618 and 0.621), indicating good drug-like properties.

**DILI:** Ligand A (89.26) has a higher DILI risk than Ligand B (60.88). This is a significant concern, as a lower DILI risk is preferred.

**BBB:** Both ligands have similar, relatively low BBB penetration (58.01 and 59.25). This isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.42 and -4.90). This suggests potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.72 and -3.46). This is a major drawback, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.262) shows a lower hERG inhibition liability than Ligand B (0.646), which is favorable.

**Microsomal Clearance:** Ligand A (48.02 mL/min/kg) has a higher microsomal clearance than Ligand B (37.33 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (46.64 hours) has a significantly longer in vitro half-life than Ligand A (-17.19 hours). This is a major advantage, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.358 and 0.183).

**Binding Affinity:** Ligand B (-7.9 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.

**Conclusion:**

Despite the similar molecular weights, QED, and P-gp efflux, Ligand B is the more promising candidate. The most significant factor is the substantially stronger binding affinity (-7.9 vs -8.6 kcal/mol). The longer half-life (46.64 vs -17.19 hours) is also a major benefit. While Ligand B has slightly higher logP and a higher hERG risk than Ligand A, the superior affinity and metabolic stability are more critical for an enzyme target like SRC kinase. The DILI risk for Ligand A is concerning. The poor solubility and Caco-2 permeability are drawbacks for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:03:47,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (343.423 and 348.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.79) is significantly better than Ligand B (88.85).  For an enzyme target, TPSA is less critical than for CNS targets, but lower TPSA generally correlates with better permeability.

**3. logP:** Ligand A (3.005) is optimal, while Ligand B (1.282) is slightly 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 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.84 and 0.81), indicating good drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk (42.885 and 44.164, both <60).

**8. BBB:** Both ligands have high BBB penetration (82.823 and 85.459), but this is less important for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Ligand A (-4.398) is better than Ligand B (-4.428), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.874) is better than Ligand B (-3.253), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.705) has a lower hERG risk than Ligand B (0.409), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (71.809) has higher microsomal clearance than Ligand B (51.527), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-8.524) has a much longer in vitro half-life than Ligand A (22.539), which is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.347) has lower P-gp efflux than Ligand B (0.133), which is favorable.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 1.1 kcal/mol, which is a meaningful advantage for an enzyme target.

**Overall Assessment:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand B appears to be the more promising candidate. While Ligand A has better solubility and lower P-gp efflux, Ligand B's significantly longer half-life, slightly better binding affinity, and lower hERG risk outweigh these advantages. The lower logP of Ligand B is a minor concern, but the superior affinity and metabolic stability are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 13:03:47,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.853 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.56) is better than Ligand B (61.88), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (4.3) is higher than the optimal range (1-3), potentially causing solubility issues, while Ligand B (1.535) is within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 threshold.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, below the 10 threshold.

**QED:** Both ligands have similar QED values (0.836 and 0.756), indicating good drug-likeness.

**DILI:** Ligand A (33.191) has a significantly lower DILI risk than Ligand B (6.747), which is a major advantage.

**BBB:** Ligand A (38.813) has a lower BBB penetration than Ligand B (68.941). This is not a primary concern for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.795 and -4.808), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-4.929) and Ligand B (-1.256) both have negative solubility values, indicating very poor aqueous solubility. This is a major concern.

**hERG Inhibition:** Ligand A (0.543) has a slightly higher hERG risk than Ligand B (0.325), but both are relatively low.

**Microsomal Clearance:** Ligand A (72.328) has a higher microsomal clearance than Ligand B (14.559), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (11.183) and Ligand B (12.687) have similar in vitro half-lives.

**P-gp Efflux:** Ligand A (0.159) has lower P-gp efflux than Ligand B (0.018), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 and -8.8 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the better candidate. The primary driver is the significantly lower DILI risk (33.191 vs 6.747). While both have poor solubility and permeability, the lower DILI risk outweighs the slightly worse metabolic stability and higher logP of Ligand A. The P-gp efflux is also slightly better for Ligand A.

Output:
0
2025-04-17 13:03:47,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.411 and 357.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.49) is better than Ligand B (121.02). TPSA <140 is good for oral absorption, both are within range, but A is preferable.

**logP:** Ligand A (1.107) is within the optimal 1-3 range. Ligand B (-1.657) is below 1, which may impede permeation. This is a significant negative for Ligand B.

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

**H-Bond Acceptors:** Ligand A (7) and Ligand B (8) are both acceptable (<=10).

**QED:** Ligand A (0.756) is better than Ligand B (0.514), indicating a stronger drug-like profile.

**DILI:** Ligand A (89.841) has a higher DILI risk than Ligand B (34.781). This favors Ligand B.

**BBB:** Both are low, not a major concern for a non-CNS target like SRC. Ligand A (39.511) is slightly better than Ligand B (29.12).

**Caco-2 Permeability:** Ligand A (-5.358) and Ligand B (-5.324) are both very poor, indicating very low intestinal absorption. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-3.067) is slightly better than Ligand B (-0.37), but both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.111 and 0.036), which is excellent.

**Microsomal Clearance:** Ligand A (25.885) has higher clearance than Ligand B (15.08), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (3.144) has a longer half-life than Ligand B (0.897). This favors Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.006), which is good.

**Binding Affinity:** Ligand A (-9.2 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. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a slightly longer half-life and better QED. However, Ligand B has a much lower DILI risk and better metabolic stability. The biggest issue with Ligand B is its low logP, which could severely impact permeability. Both have poor Caco-2 permeability and solubility. Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity (-9.2 vs -8.7 kcal/mol), Ligand A is the more promising candidate, despite its higher DILI risk and slightly worse metabolic stability. The poor permeability and solubility of both compounds would need to be addressed in subsequent optimization.

Output:
0
2025-04-17 13:03:47,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (337.379 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.32) is slightly above the preferred <90 for good absorption, while Ligand B (83.36) is comfortably below.

**3. logP:** Both ligands have good logP values (2.622 and 2.074), 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 (0.578 and 0.605), indicating drug-like properties.

**7. DILI:** Ligand B (29.624) has a significantly lower DILI risk than Ligand A (51.842). This is a major advantage for Ligand B.

**8. BBB:** Both have moderate BBB penetration (54.478 and 50.679). Since SRC is not a CNS target, this is not a primary concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.152 and -4.893), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-4.317 and -2.292), indicating poor aqueous solubility. This is a concern for both, potentially impacting bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.202 and 0.284), which is excellent.

**12. Microsomal Clearance:** Ligand B (28.045) has a slightly lower microsomal clearance than Ligand A (31.72), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.75) has a significantly longer in vitro half-life than Ligand A (-21.984). This is a substantial advantage for Ligand B, suggesting less frequent dosing might be possible.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.265), which is favorable.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both compounds have similar binding affinities, Ligand B is the more promising candidate. Its lower DILI risk, better metabolic stability (lower Cl_mic), and longer half-life are significant advantages for an enzyme target like SRC kinase. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies. The slightly lower TPSA of Ligand B is also a minor benefit.

Output:
1
2025-04-17 13:03:47,572 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.459 Da and 359.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.18) is better than Ligand B (101.73), as it's closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.223) is optimal (1-3), while Ligand B (0.757) is slightly low, potentially hindering permeation.

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

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

**QED:** Ligand A (0.894) is significantly better than Ligand B (0.7), indicating a more drug-like profile.

**DILI:** Ligand B (34.393) has a much lower DILI risk than Ligand A (52.734), which is a significant advantage.

**BBB:** Ligand B (78.829) shows better BBB penetration than Ligand A (61.535), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.109 and -5.006), 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 (-2.224 and -2.762), indicating poor solubility. This is a significant drawback for both, but Ligand B is slightly worse.

**hERG Inhibition:** Ligand A (0.806) has a higher hERG risk than Ligand B (0.365), which is a critical safety concern.

**Microsomal Clearance:** Ligand A (-24.288) has much lower (better) microsomal clearance than Ligand B (18.589), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.506 hours) has a much longer half-life than Ligand B (-10.746 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.099) has a slightly higher P-gp efflux liability than Ligand B (0.065), but both are relatively low.

**Binding Affinity:** Ligand A (-6.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial factor, and the >1.5 kcal/mol difference outweighs many of the ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand B's better DILI and hERG profiles, Ligand A's significantly superior binding affinity (-6.4 vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are decisive. The strong binding is likely to overcome some of the solubility and permeability issues, and the metabolic stability is crucial for *in vivo* efficacy. The hERG risk of Ligand A is a concern, but can be addressed through further structural modifications.

Output:
1
2025-04-17 13:03:47,572 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Ligand A (345.33 Da) is well within the ideal range. Ligand B (486.601 Da) is at the upper limit, but still acceptable.

**TPSA:** Ligand A (115.36) is good for oral absorption. Ligand B (82.62) is excellent.

**logP:** Ligand A (1.857) is optimal. Ligand B (5.104) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is within the ideal range. Ligand B (2) is also good.

**H-Bond Acceptors:** Ligand A (5) is within the ideal range. Ligand B (8) is acceptable, but approaching the upper limit.

**QED:** Ligand A (0.715) is excellent, indicating good drug-likeness. Ligand B (0.352) is poor, suggesting potential issues.

**DILI:** Ligand A (74.021) is acceptable, indicating a moderate risk. Ligand B (96.588) is high, a significant concern.

**BBB:** Ligand A (22.528) is low, not a major concern for a non-CNS target like SRC. Ligand B (38.852) is also low.

**Caco-2 Permeability:** Ligand A (-4.848) is very poor, suggesting poor absorption. Ligand B (-5.013) is also poor.

**Aqueous Solubility:** Ligand A (-3.856) is poor. Ligand B (-5.007) is very poor.

**hERG Inhibition:** Ligand A (0.442) is low risk, excellent. Ligand B (0.88) is moderate risk.

**Microsomal Clearance:** Ligand A (10.998) is relatively low, suggesting good metabolic stability. Ligand B (48.178) is high, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (89.733) is excellent, indicating a long half-life. Ligand B (47.908) is moderate.

**P-gp Efflux:** Ligand A (0.069) is very low, suggesting minimal efflux. Ligand B (0.86) is moderate.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) is excellent. Ligand B (-7.4 kcal/mol) is also good, but less potent.

**Overall Assessment:**

Ligand A is significantly better overall. While both ligands have acceptable binding affinities, Ligand A excels in key ADME properties: QED, DILI, hERG, metabolic stability (Cl_mic and t1/2), and P-gp efflux. Ligand B's high logP, poor QED, high DILI risk, and rapid metabolism are major drawbacks. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation. However, the ADME profile of Ligand A is far superior, making it the more promising drug candidate.

Output:
0
2025-04-17 13:03:47,572 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.885 and 371.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (71.53). A TPSA under 140 is good for oral absorption, and both are under this, but A is preferable.

**logP:** Both ligands have acceptable logP values (3.699 and 2.27), 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 5. Both are under the 10 limit, but A is better.

**QED:** Both ligands have similar QED values (0.818 and 0.771), indicating good drug-likeness.

**DILI:** Ligand A (32.842) has a much lower DILI risk than Ligand B (80.535). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (66.266) has a slightly higher BBB percentile than Ligand A (54.75).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.702) is slightly better than Ligand B (-4.873).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-4.062) is slightly better than Ligand B (-3.687).

**hERG:** Both ligands have low hERG inhibition liability (0.77 and 0.658), which is good.

**Microsomal Clearance:** Ligand B (46.09) has significantly lower microsomal clearance than Ligand A (68.092), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-32.108) has a negative half-life, which is not possible. Ligand A (52.037) has a reasonable half-life. This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.181 and 0.22).

**Binding Affinity:** Both ligands have strong binding affinities (-8.9 and -8.1 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A has advantages in DILI risk, TPSA, HBA, solubility, and binding affinity. Ligand B has an advantage in microsomal clearance. However, the negative half-life for Ligand B is a critical flaw. The lower DILI risk and slightly higher binding affinity of Ligand A, combined with a reasonable half-life, make it the more promising candidate despite the slightly higher clearance.

Output:
0
2025-04-17 13:03:47,572 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.483 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.57) is slightly higher than Ligand B (58.44). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (0.57) is quite low, potentially hindering permeability. Ligand B (1.929) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the 5 threshold.

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

**QED:** Both ligands have good QED scores (0.662 and 0.741), indicating drug-like properties.

**DILI:** Ligand A (31.097) and Ligand B (19.659) both have low DILI risk, well below the concerning threshold of 60. Ligand B is slightly better.

**BBB:** Ligand A (18.147) has a very low BBB penetration score. Ligand B (78.558) has a high BBB score, but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.202) has poor Caco-2 permeability. Ligand B (-4.716) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.558) and Ligand B (-1.281) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.175) has a very low hERG risk, which is excellent. Ligand B (0.397) also has low hERG risk, but slightly higher than Ligand A.

**Microsomal Clearance:** Ligand A (-5.664) has excellent metabolic stability (negative value indicates low clearance). Ligand B (54.837) has high microsomal clearance, indicating poor metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (7.16) has a reasonable half-life. Ligand B (-30.489) has a very short half-life, which is a significant concern.

**P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux, which is favorable. Ligand B (0.217) has slightly higher P-gp efflux.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-8.5). However, the difference is not substantial enough to overcome the ADME deficiencies of Ligand A.

**Conclusion:**

Despite Ligand A's slightly better binding affinity and lower hERG risk, Ligand B is the more promising candidate. Ligand A's extremely low logP and Caco-2 permeability, coupled with its poor solubility, are major liabilities. Ligand B has a much more favorable logP, better Caco-2 permeability, and a significantly better metabolic stability profile (lower Cl_mic, longer t1/2). While solubility is still a concern for Ligand B, it is less problematic than the permeability issues of Ligand A. For an enzyme target like SRC kinase, metabolic stability and reasonable permeability are crucial.

Output:
1
2025-04-17 13:03:47,573 - INFO - Batch 182 complete. Total preferences: 2912
2025-04-17 13:03:47,573 - INFO - Processing batch 183/512...
2025-04-17 13:04:25,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (381.9 Da) is still well within the range.

**TPSA:** Ligand A (111.26) is significantly better than Ligand B (37.38) regarding TPSA. Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (0.911) is within the optimal range (1-3), while Ligand B (4.812) is slightly high. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=0, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.642 and 0.625), indicating good drug-likeness.

**DILI:** Ligand A (24.855) has a much lower DILI risk than Ligand B (35.673), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (73.401) has a higher percentile than Ligand A (56.534).

**Caco-2 Permeability:** Ligand A (-5.329) has a worse Caco-2 permeability than Ligand B (-4.753).

**Aqueous Solubility:** Ligand A (-1.37) has better aqueous solubility than Ligand B (-4.514). Solubility is crucial for bioavailability.

**hERG:** Ligand A (0.451) has a significantly lower hERG risk than Ligand B (0.666), which is a major safety concern.

**Microsomal Clearance:** Ligand A (-4.346) exhibits better metabolic stability (lower clearance) than Ligand B (76.77). This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-9.334) has a longer in vitro half-life than Ligand B (60.908), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.008) has a lower P-gp efflux liability than Ligand B (0.811), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). 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 superior binding affinity, Ligand A demonstrates a significantly better safety profile (lower DILI and hERG risk), better metabolic stability (lower Cl_mic and longer t1/2), and improved solubility. The higher logP of Ligand B is a concern. The difference in binding affinity, while notable, might be overcome with further optimization of Ligand A, given its more favorable ADME properties. For an enzyme target like SRC kinase, metabolic stability and safety are paramount, making Ligand A the more promising candidate.

Output:
0
2025-04-17 13:04:25,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.5) is slightly preferred due to being lower in MW.

**TPSA:** Ligand A (33.1) is significantly better than Ligand B (105.2). Lower TPSA generally improves absorption.

**logP:** Both ligands have acceptable logP values (A: 3.12, B: 1.36), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=8) as it has fewer H-bonds.

**QED:** Ligand A (0.91) has a much better QED score than Ligand B (0.39), indicating better overall drug-likeness.

**DILI:** Ligand B (81.5) has a significantly higher DILI risk than Ligand A (7.1). This is a major concern for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (88.6) is better, but not a deciding factor.

**Caco-2 Permeability:** Both have negative values, which is unusual. Without knowing the scale, it's difficult to interpret.

**Aqueous Solubility:** Both have negative values, which is also unusual. Without knowing the scale, it's difficult to interpret.

**hERG Inhibition:** Ligand A (0.91) has a lower hERG risk than Ligand B (0.27).

**Microsomal Clearance:** Ligand A (-0.094) has much lower (better) microsomal clearance than Ligand B (19.9). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (7.59) has a longer half-life than Ligand B (25.5).

**P-gp Efflux:** Ligand A (0.23) has lower P-gp efflux than Ligand B (0.2).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 kcal/mol and 0.0 kcal/mol respectively). The affinity of Ligand A is much better.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. It has better drug-likeness (QED), a much lower DILI risk, better metabolic stability (lower Cl_mic, longer half-life), lower hERG risk, lower P-gp efflux, and a better binding affinity. While the Caco-2 and Solubility values are unusual, the other properties of Ligand A strongly suggest it is a more viable drug candidate.

Output:
1
2025-04-17 13:04:25,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.445 Da) is slightly higher than Ligand B (342.399 Da), but both are acceptable.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (79.74). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**logP:** Both ligands have good logP values (A: 1.727, B: 1.821), 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) as it has fewer hydrogen bond acceptors. Excessive HBA can sometimes hinder permeability.

**QED:** Both ligands have good QED scores (A: 0.815, B: 0.877), indicating good drug-like properties.

**DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (65.529). This is a significant advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 81.039, B: 80.264), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.744) is better than Ligand B (-5.029), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.481) is better than Ligand B (-3.0), indicating better solubility. Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.559) has a lower hERG inhibition liability than Ligand B (0.823), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-14.461) has a significantly lower (better) microsomal clearance than Ligand B (50.301). This suggests greater metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-6.411) has a longer in vitro half-life than Ligand B (33.266), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux liability than Ligand B (0.149), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-9.3) has a slightly better binding affinity than Ligand A (-8.6), but the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A. A 0.7 kcal/mol difference is not a decisive factor.

**Overall:** Ligand A demonstrates superior ADME properties (lower DILI, better solubility, lower hERG, significantly better metabolic stability, lower P-gp efflux) and comparable binding affinity to Ligand B. Given the priorities for enzyme inhibitors, Ligand A is the more promising candidate.

Output:
0
2025-04-17 13:04:25,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.495 and 354.451 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.74) is better than Ligand B (122.55). TPSA < 140 is good for oral absorption, and both are within this limit, but A is closer to the preferred <90 for CNS targets (though not a primary concern here).

**3. logP:** Both ligands have similar logP values (0.585 and 0.546), which are acceptable (1-3).

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). 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 (0.633) has a slightly better QED score than Ligand B (0.508), indicating a more drug-like profile.

**7. DILI:** Ligand A (10.392) has a significantly lower DILI risk than Ligand B (29.469). This is a crucial advantage.

**8. BBB:** Both ligands have similar BBB penetration (64.56 and 67.313), which isn't a high priority for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.359 and -5.777), indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.217 and -1.893), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.161) has a much lower hERG inhibition liability than Ligand B (0.075), which is a significant safety advantage. Lower is better.

**12. Microsomal Clearance:** Ligand A (17.956) has a higher microsomal clearance than Ligand B (8.312), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (5.875) has a significantly longer in vitro half-life than Ligand A (-19.749), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.001 and 0.014).

**15. Binding Affinity:** Both ligands have comparable binding affinities (-7.0 and -7.5 kcal/mol). The difference is minimal.

**Overall Assessment:**

While Ligand B has better metabolic stability (longer half-life, lower Cl_mic), Ligand A is superior in several critical areas: lower DILI risk, lower hERG inhibition, better QED, and lower HBD count. The similar binding affinities mean the ADME/Tox profile becomes the deciding factor. The lower DILI and hERG risks for Ligand A are substantial advantages, outweighing the slightly poorer metabolic stability. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:04:25,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (327.343 Da) is slightly lower, which could be beneficial for permeability. Ligand B (350.459 Da) is also good.

**TPSA:** Ligand A (70.92) is significantly better than Ligand B (87.66). Lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (4.715) is higher than optimal (1-3), potentially leading to solubility issues and off-target effects. Ligand B (0.974) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=3, HBA=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.493, Ligand B: 0.666), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (96.433) has a very high DILI risk, which is a major concern. Ligand B (23.575) has a very low DILI risk, a significant advantage.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both 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 very poor aqueous solubility (-5.995 and -2.144). This is a significant drawback, but could potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.896) has a slightly higher hERG risk than Ligand B (0.183). Ligand B is much better here.

**Microsomal Clearance:** Ligand A (33.671) has higher microsomal clearance than Ligand B (16.989), indicating lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand A (159.828) has a significantly longer half-life than Ligand B (21.592), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.671) has higher P-gp efflux than Ligand B (0.029), which is less desirable. Ligand B is preferred.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly better binding affinity than Ligand A (-7.1 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's longer half-life, its very high DILI risk, higher logP, and higher P-gp efflux make it a less desirable candidate. Ligand B has a significantly better safety profile (low DILI, low hERG), better metabolic stability (lower Cl_mic), and substantially better binding affinity. While its solubility and Caco-2 permeability are also poor, the strong binding affinity and improved ADME properties make it the more promising candidate.

Output:
1
2025-04-17 13:04:25,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.435 and 368.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (101.8) is slightly higher than Ligand B (78.87). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (1.014 and 0.941), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD and are within the acceptable limit of 5. Ligand A has 6 HBA, while Ligand B has 5, both are below the 10 limit.

**QED:** Both ligands have good QED scores (0.684 and 0.722), indicating good drug-like properties.

**DILI:** Ligand B (36.293) has a significantly lower DILI risk than Ligand A (49.128), making it more favorable.

**BBB:** Ligand A (73.905) has a better BBB penetration score than Ligand B (17.914). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.179) is slightly worse than Ligand B (-4.965).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.14) is slightly better than Ligand B (-2.559).

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.019 and 0.162), which is excellent.

**Microsomal Clearance:** Ligand B (31.599) has lower microsomal clearance than Ligand A (43.344), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-2.148) has a slightly better (less negative) in vitro half-life than Ligand A (-4.78).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.08 and 0.142), which is 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 (1.3 kcal/mol difference) and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having better DILI and metabolic stability, the significantly stronger binding affinity of Ligand A (-8.8 vs -7.5 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The 1.3 kcal/mol difference is substantial. While the Caco-2 and solubility are poor for both, the potency advantage of Ligand A is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 13:04:25,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.47 and 353.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly above the preferred <140, but acceptable. Ligand B (62.3) is well within the range.

**logP:** Ligand A (0.138) is quite low, potentially hindering permeability. Ligand B (2.763) is optimal.

**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.

**QED:** Ligand A (0.429) is marginally below the desirable threshold of 0.5. Ligand B (0.855) is excellent.

**DILI:** Ligand A (18.651) has a very low DILI risk, which is excellent. Ligand B (39.899) is also low, but higher than A.

**BBB:** Both have acceptable BBB penetration, but Ligand B (90.617) is significantly higher than Ligand A (63.862). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.173) shows poor permeability. Ligand B (-3.915) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-0.851) shows poor solubility. Ligand B (-3.377) is also poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.13 and 0.405 respectively).

**Microsomal Clearance:** Ligand A (22.737) has lower clearance, suggesting better metabolic stability. Ligand B (67.094) has significantly higher clearance.

**In vitro Half-Life:** Ligand A (-4.905) has a negative half-life, which is unusual and likely indicates rapid degradation. Ligand B (26.676) has a good half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.057).

**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.

**Conclusion:**

Despite Ligand A's lower DILI risk and better metabolic stability, Ligand B is the superior candidate. The significantly stronger binding affinity (-7.5 vs -6.2 kcal/mol) outweighs the slightly higher DILI and poorer metabolic stability. The better QED score, logP, and half-life also contribute to its favorability. The poor solubility and permeability of both are concerns that would need to be addressed in further optimization, but the potency advantage of B is crucial for an enzyme inhibitor.

Output:
1
2025-04-17 13:04:25,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.369 Da and 342.395 Da) are within the ideal 200-500 Da range.

**TPSA:** Both ligands (68.82 and 67.87) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.174) is optimal, while Ligand B (0.896) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 limit.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 each), below the 10 limit.

**QED:** Both ligands have good QED scores (0.869 and 0.638), indicating drug-likeness.

**DILI:** Ligand A (61.342) has a higher DILI risk than Ligand B (40.364). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (95.812) has a higher BBB penetration than Ligand B (52.656), but this isn't a primary factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.608 and -4.849), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.468 and -2.578), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.7) has a slightly higher hERG risk than Ligand B (0.177). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand B (-17.985) has significantly lower microsomal clearance than Ligand A (45.79), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (11.701) has a longer half-life than Ligand B (3.237). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.26 and 0.019).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a stronger binding affinity than Ligand B (-6.8 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:**

While Ligand A has superior binding affinity and a longer half-life, its higher DILI risk and significantly higher microsomal clearance are concerning. Ligand B, despite a weaker binding affinity, demonstrates much better metabolic stability (lower Cl_mic) and a lower DILI risk, along with a lower hERG risk. The poor Caco-2 and solubility for both are concerning, but the metabolic stability and safety profile of Ligand B are more favorable for further development as an enzyme inhibitor.

Output:
1
2025-04-17 13:04:25,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.316 Da) is slightly higher than Ligand B (345.407 Da), but both are acceptable.

**TPSA:** Ligand A (68.73) is well below the 140 threshold for oral absorption. Ligand B (97.94) is still within range, but less optimal.

**logP:** Ligand A (2.358) is within the optimal range (1-3). Ligand B (0.089) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar and good QED values (A: 0.756, B: 0.767), indicating good drug-like properties.

**DILI:** Ligand A (68.592) has a higher DILI risk than Ligand B (53.47), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.772) has a higher BBB percentile than Ligand B (43.583).

**Caco-2 Permeability:** Ligand A (-4.122) is better than Ligand B (-5.485), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.429) is better than Ligand B (-1.006), which is a significant advantage for bioavailability.

**hERG Inhibition:** Ligand A (0.434) has a much lower hERG risk than Ligand B (0.03), which is a major advantage.

**Microsomal Clearance:** Ligand A (85.244) has higher clearance than Ligand B (-11.556), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-44.817) has a much shorter half-life than Ligand B (26.275), further supporting the metabolic stability concern.

**P-gp Efflux:** Ligand A (0.223) has lower P-gp efflux than Ligand B (0.007), which is favorable.

**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 of the ADME concerns.

**Conclusion:**

Despite Ligand A's higher DILI risk and poorer metabolic stability (higher clearance, shorter half-life), its *significantly* stronger binding affinity (-8.2 vs -6.8 kcal/mol) and lower hERG risk make it the more promising candidate. The potency advantage is substantial and, in the context of an enzyme target, can often justify optimization efforts to address the metabolic stability issues. The lower hERG risk is also a critical safety factor. Ligand B's low logP and solubility are also concerning.

Output:
1
2025-04-17 13:04:25,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.411 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (131.12) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (76.46) is excellent, well below 140.

**logP:** Ligand A (-0.287) is a bit low, potentially hindering permeability. Ligand B (1.056) 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 5 HBA, also good.

**QED:** Both ligands have good QED scores (0.585 and 0.834), suggesting generally drug-like properties.

**DILI:** Ligand A (72.392) has a higher DILI risk than Ligand B (29.779). This is a significant concern.

**BBB:** Both have moderate BBB penetration (50.523 and 73.362). Since SRC is not a CNS target, this is less critical.

**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 can be difficult to interpret without knowing the base.

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

**hERG:** Ligand A (0.04) has a very low hERG risk, which is excellent. Ligand B (0.102) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-4.211) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (7.747) has a moderate clearance, suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (2.729) has a short half-life. Ligand B (7.017) has a significantly longer half-life, which is preferable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.014 and 0.034), which is good.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-6.9). However, the difference is only 0.5 kcal/mol, which isn't huge.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, its significantly higher DILI risk, short half-life, and questionable clearance (negative value) are major drawbacks. Ligand B has a much better safety profile (lower DILI), better metabolic stability (longer half-life), and a more favorable logP. The solubility and Caco-2 values are concerning for both, but the other factors make Ligand B a stronger candidate for further optimization.

Output:
1
2025-04-17 13:04:25,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 359.436 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (74.57) is better than Ligand B (36.44), being closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (1.944) is optimal, while Ligand B (4.252) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are both acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.753 and 0.683), indicating good drug-likeness.

**DILI:** Ligand A (24.467) has a significantly lower DILI risk than Ligand B (27.608), which is a crucial advantage.

**BBB:** Ligand A (47.732) has a lower BBB penetration than Ligand B (90.965). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.737) is worse than Ligand B (-4.461), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.715) is better than Ligand B (-4.803) which is a significant advantage for formulation and bioavailability.

**hERG:** Ligand A (0.343) has a much lower hERG inhibition liability than Ligand B (0.858), a critical safety consideration.

**Microsomal Clearance:** Ligand A (23.067) has a lower microsomal clearance than Ligand B (74.441), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.414) has a shorter half-life than Ligand B (10.576), but the difference isn't drastic.

**P-gp Efflux:** Ligand A (0.164) and Ligand B (0.167) are similar.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.4 and -7.3 kcal/mol), which are both excellent. The slight difference is unlikely to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a lower DILI risk, lower hERG inhibition, better solubility, and better metabolic stability (lower Cl_mic) despite slightly lower Caco-2 permeability. The similar binding affinities make these ADME/Tox advantages decisive.

Output:
0
2025-04-17 13:04:25,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.406 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.25) is better than Ligand B (67.6), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.42 and 3.041), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target effects, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 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 (0.806 and 0.855), indicating good drug-like properties.

**DILI:** Ligand A (56.146) has a significantly higher DILI risk than Ligand B (17.1). This is a major concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (83.404 and 89.725), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the model or data.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting issues with the model or data.

**hERG:** Ligand A (0.383) has a slightly better hERG profile than Ligand B (0.562), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (51.43) has a significantly better microsomal clearance than Ligand B (39.676), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (12.851) has a much longer in vitro half-life than Ligand A (-7.402). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.305) has lower P-gp efflux than Ligand B (0.214), which is favorable.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.8). While the difference is less than 1.5 kcal/mol, 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 efflux, the significantly higher DILI risk and much shorter half-life are major drawbacks. Ligand B's lower DILI risk, longer half-life, and slightly better binding affinity outweigh the minor disadvantages. The negative solubility and Caco-2 values for both are concerning and would require further investigation, but don't immediately disqualify Ligand B.

Output:
1
2025-04-17 13:04:25,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.28 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.84) is higher than the preferred <140, but still acceptable. Ligand B (55.57) is excellent, well below 140.

**logP:** Ligand A (-1.51) is a bit low, potentially hindering permeability. Ligand B (3.582) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

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

**QED:** Both ligands have good QED scores (0.515 and 0.682, respectively), indicating drug-likeness.

**DILI:** Ligand A (58.86) is better than Ligand B (39.201) in terms of DILI risk, both are good.

**BBB:** Ligand A (62.854) is lower than Ligand B (96.316). BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.289) is very poor, indicating very low intestinal absorption. Ligand B (-4.729) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.014) is poor, while Ligand B (-4.284) is also poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.089) has a very low hERG risk, which is excellent. Ligand B (0.762) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-23.995) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (125.244) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-0.162) has a very short half-life, which is concerning. Ligand B (41.043) has a much longer half-life, which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.662, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is significantly better overall due to its superior logP, BBB, in vitro half-life, and acceptable hERG risk. Ligand A has better DILI and microsomal clearance but is severely hampered by its poor Caco-2 permeability and solubility, and short half-life. For an enzyme target like SRC kinase, metabolic stability and reasonable half-life are crucial, and Ligand B excels in these areas. The slightly lower solubility and higher DILI risk of Ligand B are less concerning than the permeability issues of Ligand A.

Output:
1
2025-04-17 13:04:25,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (388.917 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (84.23), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands (2.469 and 2.751) are 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 below the 10 threshold.

**QED:** Both ligands have good QED scores (0.645 and 0.811), indicating drug-likeness.

**DILI:** Ligand A (36.487) has a significantly lower DILI risk than Ligand B (52.966). This is a major advantage.

**BBB:** Both have moderate BBB penetration (69.329 and 65.839). This isn't critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual. Assuming these are logP-scale values, they suggest poor permeability.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Assuming these are logS values, they suggest poor solubility.

**hERG:** Both ligands have low hERG risk (0.367 and 0.311).

**Microsomal Clearance:** Ligand B (30.646) has a considerably lower microsomal clearance than Ligand A (56.88), suggesting better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (22.526) has a longer half-life than Ligand A (46.635). This is also a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.102 and 0.243).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 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 a slightly better P-gp efflux profile. While Ligand A has a lower DILI risk, the substantial difference in binding affinity of Ligand B is a critical advantage for an enzyme target like SRC kinase. The slightly higher DILI risk of Ligand B can be investigated and potentially mitigated during further optimization. The solubility and permeability values are concerning for both, but can be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 13:04:25,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.4 and 358.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.78) is slightly higher than the preferred <140, but acceptable. Ligand B (67.23) is well within the acceptable range.

**logP:** Ligand A (0.582) is a bit low, potentially hindering permeation. Ligand B (2.777) is optimal.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand B (0.914) has a significantly better QED score than Ligand A (0.56), indicating a more drug-like profile.

**DILI:** Ligand A (41.722) has a lower DILI risk than Ligand B (67.623), which is a positive.

**BBB:** Both have moderate BBB penetration (66.5% and 64.9%), not a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.731) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-5.238) is also poor, but slightly better than A.

**Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.004) is slightly better than Ligand B (-3.728), but both are problematic.

**hERG:** Ligand A (0.055) has a very low hERG risk, a significant advantage. Ligand B (0.522) has a moderate hERG risk.

**Microsomal Clearance:** Ligand B (24.986) has a lower microsomal clearance, suggesting better metabolic stability than Ligand A (33.276).

**In vitro Half-Life:** Ligand B (17.03) has a longer in vitro half-life than Ligand A (-15.795), which is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.029 and 0.218).

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.0), but the difference is relatively small.

**Overall Assessment:**

Ligand B is superior in most key ADME properties (QED, metabolic stability, half-life, logP) and has a slightly better binding affinity. While Ligand A has a lower DILI risk and hERG inhibition liability, the poor Caco-2 permeability and lower QED are major drawbacks. The slightly better affinity of B can likely overcome the slightly higher DILI risk, especially given that SRC kinase inhibitors are often used in combination therapies where toxicity profiles can be managed. The poor solubility of both is a concern that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 13:04:25,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.371 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (382.551 Da) is also well within range.

**TPSA:** Ligand A (117.51) is better than Ligand B (67.43), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.385) is a bit low, potentially hindering permeation. Ligand B (2.593) is within the optimal range (1-3).

**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, good QED values (0.666 and 0.678).

**DILI:** Ligand A (63.978) has a higher DILI risk than Ligand B (47.344), which is preferable.

**BBB:** Ligand A (41.218) has a lower BBB penetration than Ligand B (69.523). Since SRC is not a CNS target, this is less critical.

**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 concerning and suggests poor solubility.

**hERG:** Ligand A (0.035) has a much lower hERG risk than Ligand B (0.542), which is a major advantage.

**Microsomal Clearance:** Ligand A (-2.684) has a lower (better) microsomal clearance than Ligand B (72.796), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.849 hours) has a lower half-life than Ligand B (12.076 hours), which is less desirable.

**P-gp Efflux:** Ligand A (0.025) has a lower P-gp efflux liability than Ligand B (0.246), which is preferable.

**Binding Affinity:** Ligand B (-8.3 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 has a significantly better binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). While it has a higher hERG risk and slightly worse DILI, the potency advantage is substantial for an enzyme target like SRC kinase. The negative Caco-2 and solubility values are concerning for both, but these could potentially be addressed through formulation strategies. Ligand A has a better hERG profile, but its weaker binding affinity and poorer metabolic stability are significant drawbacks.

Output:
1
2025-04-17 13:04:25,739 - INFO - Batch 183 complete. Total preferences: 2928
2025-04-17 13:04:25,739 - INFO - Processing batch 184/512...
2025-04-17 13:05:16,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.422 and 336.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is significantly better than Ligand B (112.7). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.45 and 1.282), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower HBD/HBA generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.64 and 0.854), indicating good drug-like properties.

**DILI:** Ligand A (23.226) has a much lower DILI risk than Ligand B (75.339). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (87.941) is better than Ligand B (38.077).

**Caco-2 Permeability:** Ligand A (-4.659) is better than Ligand B (-5.055), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.469) is better than Ligand B (-3.683), which is a crucial factor for bioavailability.

**hERG Inhibition:** Ligand A (0.479) has a lower hERG risk than Ligand B (0.334). Lower is better.

**Microsomal Clearance:** Ligand B (27.006) has slightly better microsomal clearance than Ligand A (22.46), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.505) has a better in vitro half-life than Ligand A (6.336).

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.033), which is favorable.

**Binding Affinity:** Ligand B (-9.7 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 threshold.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable ADMET profile, particularly regarding DILI risk, solubility, and hERG inhibition. The affinity difference, while significant, might be overcome with further optimization of Ligand A. The higher DILI risk and poorer solubility of Ligand B are major concerns that would likely necessitate substantial modifications, potentially impacting its potency. Given the enzyme-kinase focus, metabolic stability (slightly better for B) and solubility (better for A) are key. The strong affinity of B is tempting, but the ADMET liabilities are too significant.

Output:
0
2025-04-17 13:05:16,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.4 and 347.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.84) is significantly better than Ligand B (91.02). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (1.94 and 1.25), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 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 (0.733 and 0.784), indicating good drug-like properties.

**DILI:** Ligand A (65.57) has a higher DILI risk than Ligand B (47.73). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration (76.08 and 69.02), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.94 and -4.83), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.83 and -2.70), which is also concerning, suggesting very low solubility.

**hERG:** Both ligands exhibit low hERG inhibition liability (0.41 and 0.18), which is excellent.

**Microsomal Clearance:** Ligand B (2.78) has significantly lower microsomal clearance than Ligand A (31.21), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-14.98) has a longer in vitro half-life than Ligand A (-44.37), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.24 and 0.04).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.7 and -8.3 kcal/mol). The difference isn't large enough to outweigh other factors.

**Conclusion:**

While both ligands have good potency and acceptable logP/QED values, Ligand B is the more promising candidate. Its significantly lower DILI risk and much improved metabolic stability (lower Cl_mic and longer t1/2) are crucial advantages for an enzyme inhibitor. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:05:16,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.41 and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.53) is significantly better than Ligand B (58.64).  A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**logP:** Ligand A (4.29) is slightly higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.681) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 4 HBA). Lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.704 and 0.805), indicating good drug-like properties.

**DILI:** Ligand A (60.217) has a higher DILI risk than Ligand B (27.608). This is a significant concern.

**BBB:** Both ligands have high BBB penetration (84.025 and 90.112), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.142) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.038) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-6.012) has very poor aqueous solubility, which is a major drawback. Ligand B (-2.651) is better, but still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.619 and 0.479).

**Microsomal Clearance:** Ligand A (97.786) has very high microsomal clearance, indicating poor metabolic stability. Ligand B (11.772) has much lower clearance and better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.595) has a very short half-life, consistent with its high clearance. Ligand B (17.596) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.439 and 0.096), which is favorable.

**Binding Affinity:** Both ligands have similar strong binding affinities (-8.0 and -8.1 kcal/mol).

**Conclusion:**

Despite similar binding affinities, Ligand B is the far more promising candidate. Ligand A suffers from poor solubility, poor permeability, high DILI risk, and very poor metabolic stability (high clearance, short half-life). Ligand B, while not perfect, has significantly better ADME properties, particularly regarding metabolic stability and DILI risk. The slightly lower logP and better solubility of Ligand B are also advantageous.



Output:
1
2025-04-17 13:05:16,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly preferred due to being lower in MW.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (63.69) is better than Ligand A (87.47).

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (2.539) is slightly higher, which could be beneficial for membrane permeability but needs to be balanced with solubility.

**4. H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1), as a small number of HBDs can aid permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is acceptable.

**6. QED:** Ligand A (0.865) has a significantly better QED score than Ligand B (0.663), indicating a more drug-like profile.

**7. DILI:** Ligand B (11.788) has a much lower DILI risk than Ligand A (60.644), which is a significant advantage.

**8. BBB:** Ligand B (81.737) has a higher BBB penetration potential than Ligand A (44.785), but this isn't a primary concern for a non-CNS target like SRC.

**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 absolute difference might not be huge.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.045) is slightly better than Ligand A (-3.006).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.35, Ligand B: 0.566).

**12. Microsomal Clearance:** Ligand B (14.716) has a slightly lower microsomal clearance than Ligand A (15.461), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (69.169 hours) has a significantly longer in vitro half-life than Ligand A (18.477 hours), a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.017, Ligand B: 0.05).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), although the difference is small.

**Overall Assessment:**

While Ligand A has a better QED score, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, substantially longer half-life, slightly better metabolic stability, and slightly better binding affinity. The solubility and permeability issues are similar for both, and the slight advantage in TPSA for Ligand B is also a positive. The small difference in binding affinity is likely outweighed by the improvements in ADME properties.

Output:
1
2025-04-17 13:05:16,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.36 Da) is slightly higher, but acceptable. Ligand B (351.491 Da) is also good.

**TPSA:** Both ligands have TPSA values (A: 49.41, B: 53.09) that are acceptable for oral absorption (<140).

**logP:** Ligand A (4.442) is at the upper end of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (1.718) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=0, HBA=4) both have reasonable numbers of hydrogen bond donors and acceptors, likely not causing significant issues with permeability or solubility.

**QED:** Both ligands have similar QED values (A: 0.745, B: 0.731), indicating good drug-likeness.

**DILI:** Ligand A (53.858) has a moderate DILI risk. Ligand B (12.214) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 73.711, B: 74.254), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (A: -4.852, B: -4.507), suggesting potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.044, B: -0.722). This is a major concern for both.

**hERG Inhibition:** Ligand A (0.537) has a slightly elevated hERG risk, while Ligand B (0.434) is better.

**Microsomal Clearance:** Ligand A (50.302) has a higher microsomal clearance, indicating faster metabolism and potentially lower *in vivo* exposure. Ligand B (17.86) has a much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.184) has a moderate half-life. Ligand B (-2.409) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.51, B: 0.024), which is favorable.

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is the primary driver for enzyme inhibitors. However, it has a higher DILI risk, higher clearance, and slightly higher hERG risk. Ligand B has a much better safety profile (DILI, hERG) and metabolic stability, but significantly weaker binding affinity. The difference in binding affinity (~2.8 kcal/mol) is substantial and likely to be critical for *in vivo* efficacy. While the solubility and permeability are poor for both, these can potentially be addressed with formulation strategies. Given the importance of potency for kinase inhibitors, and the relatively manageable risks associated with Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 13:05:16,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.455 Da and 356.507 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.11) is higher than Ligand B (78.87). While both are reasonably good, Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (2.23 and 1.953, respectively), 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 acceptable, but Ligand B has a slight advantage with fewer HBDs, potentially improving permeability.

**QED:** Both ligands have similar QED values (0.612 and 0.627), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (75.533) compared to Ligand B (13.3). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (41.295) than Ligand A (26.483), but this is less important.

**Caco-2 Permeability:** Ligand A (-5.418) has poor Caco-2 permeability, while Ligand B (-4.854) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-3.676) has very poor solubility, while Ligand B (-1.54) is better, but still relatively low.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.203 and 0.398, respectively), which is positive.

**Microsomal Clearance:** Ligand A has a much lower (better) microsomal clearance (-10.552) than Ligand B (45.112). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (33.291 hours) than Ligand A (-6.852 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.078 and 0.088).

**Binding Affinity:** Ligand A has a stronger binding affinity (-8.2 kcal/mol) than Ligand B (-7.1 kcal/mol). This is a 1.1 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability, but suffers from poor solubility, poor Caco-2 permeability, and a high DILI risk. Ligand B has better solubility, permeability, a lower DILI risk, and a longer half-life, but its binding affinity is weaker.

Given the priorities for enzyme inhibitors, the strong binding affinity of Ligand A is a significant advantage. However, the high DILI risk and poor solubility are major liabilities that would likely hinder its development. While metabolic stability is important, the 1.1 kcal/mol difference in binding affinity is substantial enough to potentially overcome the poorer metabolic stability of Ligand B with further optimization. The lower DILI risk of Ligand B is also a critical factor.

Output:
1
2025-04-17 13:05:16,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). A (387.571) is slightly higher than B (354.451), but both are acceptable.

**TPSA:** Ligand A (87.3) is well below the 140 threshold for good oral absorption, and even below the 90 threshold for CNS penetration (though that's not a priority here). Ligand B (98.82) is still under 140, but closer. A is better.

**logP:** Ligand A (1.642) is within the optimal range (1-3). Ligand B (-0.269) is slightly below 1, which *could* indicate permeability issues. A is better.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, both within acceptable limits. Ligand B has 2 HBD and 4 HBA, also good. No significant difference here.

**QED:** Both ligands have good QED scores (A: 0.589, B: 0.615), indicating drug-like properties.

**DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (26.638), but both are below the concerning threshold of 60. B is better.

**BBB:** Both have similar, moderate BBB penetration (A: 45.25, B: 45.328). Not a major factor for a kinase inhibitor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.513 and -4.873). This is unusual and suggests potential issues with intestinal absorption, but the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-2.143 and -1.459). Again, the scale is undefined, but suggests poor solubility.

**hERG:** Both ligands have very low hERG risk (A: 0.042, B: 0.034), which is excellent.

**Microsomal Clearance:** Ligand A (16.428) has significantly lower microsomal clearance than Ligand B (29.434), indicating better metabolic stability. A is better.

**In vitro Half-Life:** Ligand A (15.422) has a positive half-life, while Ligand B (-18.77) has a negative half-life. This is concerning for Ligand B. A is significantly better.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.015, B: 0.004), which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage (1.1 kcal/mol), and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a concerning negative in vitro half-life, and a slightly lower solubility. Ligand A has better metabolic stability (lower Cl_mic, positive half-life), better TPSA and logP, but a weaker binding affinity.

Given the significant advantage in binding affinity for Ligand B, and the fact that the other issues *might* be addressable through formulation or further optimization, I would choose Ligand B as the more promising candidate. The strong binding is likely to be more impactful than the slightly less favorable ADME properties, especially in the early stages of drug development.

Output:
1
2025-04-17 13:05:16,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.431 and 349.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is significantly better than Ligand B (43.86), being well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (0.989 and 1.654, respectively), 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.

**QED:** Ligand A (0.781) has a better QED score than Ligand B (0.519), indicating a more drug-like profile.

**DILI:** Ligand A (32.067) has a much lower DILI risk than Ligand B (14.541), which is a significant advantage.

**BBB:** Ligand B (86.545) has a higher BBB penetration percentile than Ligand A (70.027). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.114) has a worse Caco-2 permeability than Ligand B (-4.301).

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-1.471 and -1.459). This is a concern for both.

**hERG Inhibition:** Ligand A (0.067) has a lower hERG inhibition liability than Ligand B (0.42), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (10.02) has a lower microsomal clearance than Ligand A (18.521), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.031) has a longer in vitro half-life than Ligand A (-2.059), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.058), which is favorable.

**Binding Affinity:** Ligand A (-9.8 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.

**Conclusion:**

Despite the better metabolic stability and half-life of Ligand B, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.8 vs -7.7 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, Ligand A exhibits a lower DILI risk and lower hERG inhibition, both crucial for safety. While both have poor solubility, the other advantages of Ligand A make it the better choice.

Output:
1
2025-04-17 13:05:16,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.371 and 352.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.81) is better than Ligand B (50.36) as it is still within the acceptable range for oral absorption (<140), while Ligand B is significantly lower.

**logP:** Ligand A (0.81) is within the optimal 1-3 range. Ligand B (4.205) is slightly high, 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 5 HBA, while Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.585 and 0.834), indicating good drug-like properties.

**DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (35.246). This is a concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (77.239) is better than Ligand A (65.219). This isn't a primary concern for a non-CNS target like SRC.

**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 ligands have negative solubility values, which is also unusual. Again, the scale is not defined.

**hERG:** Ligand A (0.084) has a much lower hERG inhibition liability than Ligand B (0.494), which is a significant advantage.

**Microsomal Clearance:** Ligand A (40.094) has slightly higher microsomal clearance than Ligand B (37.739), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (39.455) has a significantly longer in vitro half-life than Ligand A (0.67), which is a major advantage.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux liability, while Ligand B (0.236) has moderate efflux. This is favorable for Ligand A.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. While its logP is slightly high, the strong binding affinity and better ADME properties outweigh this concern. Ligand A has a better hERG profile and P-gp efflux, but the weaker binding affinity and higher DILI risk are significant drawbacks.

Output:
1
2025-04-17 13:05:16,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (386.231 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.7) is slightly higher than Ligand B (84.67), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.615 and 1.774), 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 (0.811) has a significantly better QED score than Ligand A (0.446), indicating a more drug-like profile.

**DILI:** Ligand B (38.658) has a much lower DILI risk than Ligand A (72.819), which is a significant advantage.

**BBB:** Ligand B (85.731) has a higher BBB penetration score than Ligand A (51.997), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.19) is slightly worse than Ligand B (-4.395).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.19) is slightly worse than Ligand B (-3.163).

**hERG Inhibition:** Ligand A (0.058) has a slightly lower hERG inhibition risk than Ligand B (0.263), which is preferable.

**Microsomal Clearance:** Ligand A (29.804) has a lower microsomal clearance than Ligand B (46.169), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.173) has a significantly longer in vitro half-life than Ligand B (-1.256), which is a major advantage.

**P-gp Efflux:** Ligand A (0.04) has a lower P-gp efflux liability than Ligand B (0.287), which is beneficial.

**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.

**Conclusion:**

While Ligand B has better QED, DILI, and BBB scores, Ligand A boasts a significantly stronger binding affinity (-9.5 vs -7.5 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2). The superior affinity of Ligand A is crucial for an enzyme target like SRC kinase. The longer half-life and lower P-gp efflux also contribute to better *in vivo* exposure. Although Ligand A has a higher DILI risk, the strong binding affinity and metabolic stability make it the more promising candidate, assuming further optimization can address the DILI concern.

Output:
1
2025-04-17 13:05:16,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.419 and 359.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.39) is slightly above the optimal <140, while Ligand B (108.05) is well within. This favors B slightly for absorption.

**logP:** Ligand A (0.432) is quite low, potentially hindering permeation. Ligand B (0.19) is even lower. Both are below the optimal 1-3 range, which is a concern.

**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:** Both ligands have good QED scores (0.728 and 0.81), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (62.156 and 61.884), placing them in a moderate risk category. Not a major differentiator.

**BBB:** Ligand A (15.161) has very low BBB penetration, while Ligand B (39.667) is still low but significantly better. Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.322 and -5.675), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.566 and -2.707). This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.101 and 0.172), which is positive.

**Microsomal Clearance:** Ligand A (-3.851) has a lower (better) microsomal clearance than Ligand B (-12.043). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-4.856) has a slightly better in vitro half-life than Ligand B (-24.32), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.044 and 0.009), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a *very* substantial difference. A >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite the poor logP and solubility for both compounds, and the negative Caco-2 values, the *dramatic* difference in binding affinity heavily favors Ligand B. The significantly stronger binding affinity (-9.1 kcal/mol vs 0.0 kcal/mol) is likely to overcome the ADME liabilities, especially given that SRC is not a CNS target. The better metabolic stability of Ligand A is a plus, but not enough to compensate for the much weaker binding.

Output:
1
2025-04-17 13:05:16,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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, but both are acceptable.

**TPSA:** Ligand A (58.38) is significantly better than Ligand B (96.67). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.538) is optimal, while Ligand B (0.838) 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 fall within acceptable ranges.

**QED:** Both ligands have similar and good QED scores (0.835 and 0.789 respectively).

**DILI:** Ligand B (84.102) has a higher DILI risk than Ligand A (65.491), making Ligand A preferable.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.58) has a worse Caco-2 permeability than Ligand B (-5.291), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.488) has better aqueous solubility than Ligand B (-4.486).

**hERG Inhibition:** Ligand A (0.797) has a slightly higher hERG risk than Ligand B (0.424), but both are reasonably low.

**Microsomal Clearance:** Ligand A (86.717) has a higher microsomal clearance than Ligand B (46.144), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-28.941) has a significantly longer in vitro half-life than Ligand A (16.643), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.406) has lower P-gp efflux than Ligand B (0.057), which is favorable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better solubility and lower DILI risk, Ligand B's significantly improved binding affinity (-8.9 vs -7.6 kcal/mol) and much better metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target like SRC kinase. The lower logP of Ligand B is a concern, but the strong binding affinity can compensate.

Output:
1
2025-04-17 13:05:16,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.395 and 359.832 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is better than Ligand B (41.29), being closer to the 140 A^2 threshold.

**logP:** Both ligands have good logP values (2.64 and 3.83), 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:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.873) has a significantly better QED score than Ligand B (0.727), indicating a more drug-like profile.

**DILI:** Ligand A (67.739) has a higher DILI risk than Ligand B (44.281), which is a negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (78.907) is better than Ligand B (66.499). This is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.536 and -4.546). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.505 and -3.88). This is also unusual and suggests very poor solubility.

**hERG:** Ligand A (0.54) has a lower hERG risk than Ligand B (0.875), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (100.044) has a higher microsomal clearance than Ligand B (51.435), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand B (59.44) has a significantly longer in vitro half-life than Ligand A (6.508), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux than Ligand B (0.675), which is a positive for Ligand A.

**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 not huge.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a better QED and lower P-gp efflux, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity. The poor solubility and permeability are concerning for both, but the metabolic stability and safety profile are more critical for an enzyme inhibitor. The small advantage in binding affinity for Ligand B further supports this conclusion.

Output:
1
2025-04-17 13:05:16,697 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [338.338, 71.17, 3.81, 2, 4, 0.58, 79.604, 53.974, -4.99, -4.782, 0.841, -2.94, 48.235, 0.605, -7.9]
**Ligand B:** [392.543, 103.78, 0.175, 2, 6, 0.571, 34.82, 31.485, -5.838, -1.791, 0.206, -3.447, 21.109, 0.075, -8.3]

**Step-by-step comparison:**

1. **MW:** Ligand A (338.338 Da) is within the ideal range (200-500). Ligand B (392.543 Da) is also acceptable, though approaching the upper limit.
2. **TPSA:** Ligand A (71.17) is excellent, well below the 140 threshold for oral absorption. Ligand B (103.78) is still reasonable, but higher and potentially impacting absorption.
3. **logP:** Ligand A (3.81) is optimal. Ligand B (0.175) is significantly low, which could lead to poor membrane permeability and bioavailability.
4. **HBD:** Both ligands have 2 HBD, which is within the acceptable limit of 5.
5. **HBA:** Ligand A has 4 HBA, within the limit of 10. Ligand B has 6 HBA, also within the limit, but slightly higher.
6. **QED:** Both ligands have similar QED values (0.58 and 0.571), indicating good drug-likeness.
7. **DILI:** Ligand A (79.604) has a higher DILI risk, being above the 60 threshold. Ligand B (34.82) has a much lower and favorable DILI risk.
8. **BBB:** Ligand A (53.974) has moderate BBB penetration. Ligand B (31.485) has low BBB penetration. This is less critical for a non-CNS target like SRC kinase.
9. **Caco-2:** Ligand A (-4.99) has poor Caco-2 permeability. Ligand B (-5.838) also has poor Caco-2 permeability.
10. **Solubility:** Ligand A (-4.782) has poor solubility. Ligand B (-1.791) has slightly better solubility, but still low.
11. **hERG:** Ligand A (0.841) has a low hERG risk. Ligand B (0.206) has a very low hERG risk. Both are good.
12. **Cl_mic:** Ligand A (-2.94) has a negative value, indicating good metabolic stability. Ligand B (-3.447) also has good metabolic stability.
13. **t1/2:** Ligand A (48.235) has a longer in vitro half-life, which is desirable. Ligand B (21.109) has a shorter half-life.
14. **Pgp:** Ligand A (0.605) has moderate P-gp efflux. Ligand B (0.075) has very low P-gp efflux, which is favorable.
15. **Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). The difference is 0.4 kcal/mol.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has a slightly better affinity, Ligand A has a significantly better in vitro half-life, and a lower DILI risk. However, the very low logP of Ligand B is a major concern, likely leading to poor absorption. The poor Caco-2 and solubility for both are problematic, but the low logP is more critical.

**Conclusion:**

Despite the slightly better affinity of Ligand B, **Ligand A** is the more viable drug candidate. The significantly better logP, longer half-life, and lower DILI risk outweigh the slightly weaker binding affinity. The poor solubility and Caco-2 values are drawbacks for both, but can be addressed with formulation strategies. The low logP of Ligand B is a more fundamental issue that is harder to overcome.

Output:
1
2025-04-17 13:05:16,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.865 and 356.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.32) is better than Ligand B (108.05), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.763) is within the optimal 1-3 range, while Ligand B (-1.419) is below 1, potentially hindering permeation.

**H-Bond Donors:** Both have 2 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:** Ligand A (0.847) has a significantly better QED score than Ligand B (0.527), indicating a more drug-like profile.

**DILI:** Ligand A (67.623) has a higher DILI risk than Ligand B (18.224). This is a significant drawback for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.993) is worse than Ligand B (-5.337), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.437) is worse than Ligand B (-0.495), indicating lower solubility.

**hERG:** Both ligands have very low hERG risk (0.13 and 0.055 respectively).

**Microsomal Clearance:** Ligand B (-2.143) has a much lower (better) microsomal clearance than Ligand A (29.411), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.281) has a longer half-life than Ligand A (13.115), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.001 respectively).

**Binding Affinity:** Both ligands have comparable binding affinities (-7.3 and -7.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better TPSA and comparable affinity, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. Ligand A's higher DILI risk and poor solubility are major concerns. The slightly lower logP of Ligand B is a minor drawback that could potentially be addressed through further optimization.

Output:
1
2025-04-17 13:05:16,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.447 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.55) is slightly higher than Ligand B (67.87), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (3.322) is optimal, while Ligand B (1.725) is on the lower side, potentially impacting permeability.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 limit.

**QED:** Ligand A (0.871) has a significantly better QED score than Ligand B (0.642), indicating a more drug-like profile.

**DILI:** Ligand B (15.471) has a much lower DILI risk than Ligand A (56.068). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (86.778) has a higher BBB score than Ligand B (67.08), but this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.62 and -4.868), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.976 and -2.157), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.383) has a slightly higher hERG risk than Ligand B (0.621), but both are relatively low.

**Microsomal Clearance:** Ligand B (30.247) has a lower microsomal clearance than Ligand A (40.959), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (37.013) has a longer half-life than Ligand B (11.343). This is a positive for Ligand A.

**P-gp Efflux:** Ligand B (0.154) has lower P-gp efflux than Ligand A (0.083), potentially leading to better bioavailability.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most crucial factor, and the 18.6 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand B has advantages in DILI risk, metabolic stability, and P-gp efflux, the overwhelmingly stronger binding affinity of Ligand A (-8.6 kcal/mol vs 0.0 kcal/mol) is decisive. The substantial potency advantage is likely to outweigh the drawbacks of slightly higher DILI risk and shorter half-life, especially in the context of an oncology target where rapid and potent inhibition is often desired. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:05:16,697 - INFO - Batch 184 complete. Total preferences: 2944
2025-04-17 13:05:16,697 - INFO - Processing batch 185/512...
2025-04-17 13:05:56,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.817 Da and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is slightly higher than the preferred <140, but acceptable. Ligand B (49.41) is excellent, well below 140.

**logP:** Ligand A (2.402) is within the optimal 1-3 range. Ligand B (4.135) is at the upper end of acceptable, potentially raising concerns about solubility and off-target effects.

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

**QED:** Ligand A (0.872) has a very strong drug-like profile. Ligand B (0.602) is still acceptable, but lower.

**DILI:** Ligand A (87.204) has a high DILI risk, a significant concern. Ligand B (30.322) has a low DILI risk, a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (33.656) and Ligand B (85.498) are not particularly relevant here.

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

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a red flag for both.

**hERG:** Ligand A (0.071) has very low hERG risk, excellent. Ligand B (0.752) has a moderate hERG risk, which is not ideal but manageable.

**Microsomal Clearance:** Ligand A (19.495) has a relatively low clearance, suggesting better metabolic stability. Ligand B (82.108) has a high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (28.808) has a reasonable half-life. Ligand B (6.383) has a very short half-life, requiring frequent dosing.

**P-gp Efflux:** Ligand A (0.047) has low P-gp efflux, which is good. Ligand B (0.575) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.4). 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 P-gp efflux. However, its high DILI risk is a major drawback. Ligand B has a much lower DILI risk, better TPSA, but weaker binding affinity, poorer metabolic stability, and a shorter half-life.

Given the priorities for enzyme inhibitors, the binding affinity is paramount. The 1.6 kcal/mol difference in binding affinity is substantial. While the DILI risk of Ligand A is concerning, it might be mitigated through structural modifications. The poor permeability and solubility of both compounds are also concerning and would need to be addressed in either case. However, the potency advantage of Ligand A is significant enough to make it the more promising candidate *as a starting point*, assuming the DILI risk can be addressed through further optimization.

Output:
0
2025-04-17 13:05:56,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.483 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is better than Ligand B (102.3), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.378 and 1.052), 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 acceptable, within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Ligand B (0.716) has a better QED score than Ligand A (0.493), indicating a more drug-like profile.

**DILI:** Ligand A (27.995) has a significantly lower DILI risk than Ligand B (13.92), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (62.737 and 62.621), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.841 and -4.985). This is unusual and suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.721 and -1.627), indicating poor aqueous solubility. Ligand B is slightly better.

**hERG:** Both ligands have very low hERG inhibition risk (0.124 and 0.089), which is excellent.

**Microsomal Clearance:** Ligand A (86.736) has a higher microsomal clearance than Ligand B (24.978), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (0.005) has a very short in vitro half-life, while Ligand A (-28.83) has a negative value, which is also problematic. Both are poor.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.054 and 0.002).

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent and meets the criteria for a good starting point.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand A is preferable due to its significantly lower DILI risk and better TPSA. Although Ligand A has higher microsomal clearance (lower metabolic stability) and a negative in vitro half-life, the DILI risk is a more critical factor to address early in drug development. The solubility issues are present in both, and the Caco-2 permeability is concerning for both, but these can be addressed through formulation strategies or further chemical modifications. The metabolic stability of Ligand A is a concern, but can be improved through structural modifications.

Output:
0
2025-04-17 13:05:56,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.403 and 361.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.74) is better than Ligand B (69.22), being below the 140 A^2 threshold, suggesting good absorption potential for both.

**logP:** Both ligands have acceptable logP values (1.292 and 2.983), falling within the 1-3 range. Ligand B is slightly higher, potentially indicating a slightly higher risk of off-target effects, but still within acceptable limits.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within the recommended limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.743 and 0.748), indicating good drug-like properties.

**DILI:** Ligand A (48.391) has a higher DILI risk than Ligand B (15.898). This is a significant advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration, with Ligand B (82.396) being better than Ligand A (67.507). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.523 and -4.483). This is unusual and suggests poor permeability, but the values are very close and may not be a major differentiating factor.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.689 and -2.588), indicating poor aqueous solubility. Ligand B is slightly worse.

**hERG Inhibition:** Ligand A (0.119) has a lower hERG inhibition risk than Ligand B (0.773). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (54.381) has a higher microsomal clearance than Ligand B (25.712), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-30.946) has a much longer in vitro half-life than Ligand A (-4.142), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.062 and 0.051).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates a superior ADME profile, particularly regarding DILI risk, microsomal clearance, and in vitro half-life. While Ligand A has a slightly better binding affinity, the improved metabolic stability and reduced toxicity risk of Ligand B are more critical for a viable drug candidate targeting a kinase. The negative solubility and Caco-2 values are concerning for both, but could be addressed with formulation strategies.

Output:
1
2025-04-17 13:05:56,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.446 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.29) is significantly better than Ligand B (66.92). A TPSA under 140 is good for oral absorption, and both are well within this limit, but A is preferable.

**logP:** Ligand A (4.176) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.866) is 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 acceptable.

**QED:** Ligand A (0.886) has a better QED score than Ligand B (0.701), indicating a more drug-like profile.

**DILI:** Ligand A (18.961) has a much lower DILI risk than Ligand B (12.33). Both are below 40, which is good.

**BBB:** Both ligands have high BBB penetration (89.104 and 86.002), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.959 and -4.397), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.898 and -1.152) which is also a concern.

**hERG Inhibition:** Ligand A (0.847) has a slightly higher hERG risk than Ligand B (0.201). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (70.414) has a higher microsomal clearance than Ligand B (34.66). Lower clearance is preferred for better metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand A (-19.793) has a significantly shorter in vitro half-life than Ligand B (-7.121). This is a major drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.452) has lower P-gp efflux than Ligand B (0.041), which is favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a >1 kcal/mol difference, which can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a better QED score, but suffers from higher logP, higher microsomal clearance, and a much shorter half-life. Ligand B has better ADME properties (lower logP, lower clearance, longer half-life, lower hERG risk) but weaker binding affinity.

Given the enzyme-specific priorities, the substantial difference in binding affinity (-8.7 vs -7.6 kcal/mol) is a critical factor. While Ligand B has better ADME properties, the potency advantage of Ligand A is likely to be more impactful in driving efficacy. However, the poor half-life of Ligand A is a major concern. Further optimization might be needed to improve its metabolic stability.

Output:
1
2025-04-17 13:05:56,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.415 and 359.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is better than Ligand B (29.54) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (1.891) is optimal, while Ligand B (4.137) is approaching the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (0 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.717 and 0.803), indicating drug-like properties.

**DILI:** Ligand A (58.55) has a slightly higher DILI risk than Ligand B (37.611), but both are reasonably low.

**BBB:** Ligand A (65.878) is lower than Ligand B (95.696). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.078) is worse than Ligand B (-4.557), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.582) is better than Ligand B (-4.885), which is important for formulation and bioavailability.

**hERG:** Ligand A (0.417) has a significantly lower hERG risk than Ligand B (0.861), a crucial factor for kinase inhibitors.

**Microsomal Clearance:** Ligand A (32.6) has a much lower Cl_mic than Ligand B (86.453), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.326) has a lower half-life than Ligand B (17.471), which is a negative.

**P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux than Ligand B (0.81), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have identical binding affinities (-8.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is preferable due to its better logP, lower hERG risk, significantly lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While its Caco-2 permeability and in vitro half-life are less favorable, the superior metabolic stability and safety profile (hERG) outweigh these drawbacks, especially given the equal binding affinity. Ligand B's high logP and clearance are concerning.

Output:
0
2025-04-17 13:05:56,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.515 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is slightly higher than Ligand B (76.66), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.057 and 2.331), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (5 and 4 respectively), satisfying the criteria.

**QED:** Ligand B (0.827) has a significantly better QED score than Ligand A (0.494), indicating a more drug-like profile.

**DILI:** Ligand A (35.324) has a lower DILI risk than Ligand B (56.223), which is a positive attribute.

**BBB:** Both have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B is higher at 71.811.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.429) is worse than Ligand B (-4.674).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.465) is slightly better than Ligand B (-3.215).

**hERG Inhibition:** Both have low hERG inhibition liability (0.105 and 0.46), which is good.

**Microsomal Clearance:** Ligand B (23.039) has a significantly lower microsomal clearance than Ligand A (43.168), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (32.305 hours) has a much longer in vitro half-life than Ligand A (11.758 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.18 and 0.171).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its superior binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), and higher QED score outweigh the slightly higher DILI risk and lower solubility compared to Ligand A. The strong binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:05:56,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.813 and 375.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (72.39 and 71.09) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have a logP around 2.77, which is 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.

**QED:** Both have good QED scores (0.603 and 0.844), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 74.99, which is concerning (high risk). Ligand B has a much lower DILI risk of 58.976, which is still above the ideal <40, but significantly better than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.276) is better than Ligand B (46.219).

**Caco-2 Permeability:** Ligand A (-4.727) and Ligand B (-5.165) both have negative values, suggesting poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.778 and -3.309). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.342 and 0.298).

**Microsomal Clearance:** Ligand A (90.298) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (10.415) has significantly lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (19.786 hours) has a much longer half-life than Ligand A (-4.485 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.162).

**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 a major advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite both having solubility issues, Ligand B is the more promising candidate. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and comparable P-gp efflux make it a superior choice. The higher QED score is also a plus. While the Caco-2 permeability is poor for both, the potency advantage of Ligand B is substantial.

Output:
1
2025-04-17 13:05:56,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.479 and 385.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.24) is significantly better than Ligand B (109.57).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (2.893) is optimal, while Ligand B (0.844) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED values (0.911 and 0.783), indicating good drug-like properties.

**DILI:** Ligand A (61.342) has a slightly higher DILI risk than Ligand B (56.689), but both are still acceptable (<60 is good).

**BBB:** Ligand A (69.407) has better BBB penetration than Ligand B (54.052), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.684) shows better Caco-2 permeability than Ligand B (-5.583).

**Aqueous Solubility:** Ligand A (-5.574) has better aqueous solubility than Ligand B (-2.3). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.621) has a lower hERG inhibition liability than Ligand B (0.203), which is a significant advantage. Lower hERG risk is crucial.

**Microsomal Clearance:** Ligand A (72.654) has higher microsomal clearance than Ligand B (-5.483). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-23.348) has a much longer in vitro half-life than Ligand A (-42.591), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.273) has lower P-gp efflux than Ligand B (0.081), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.7 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. However, Ligand A has better TPSA, logP, solubility, and crucially, a much lower hERG risk. Given that SRC is an enzyme, metabolic stability and potency are prioritized, but hERG risk is a major concern. The slightly better affinity of B is outweighed by the significantly higher hERG risk.

Output:
0
2025-04-17 13:05:56,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.445 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold and favorable for absorption. Ligand B (79.53) is still acceptable but higher, potentially slightly impacting absorption.

**logP:** Both ligands have good logP values (2.541 and 1.876), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.757 and 0.904), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (22.257 and 21.753 percentile), which is excellent.

**BBB:** Both ligands have acceptable BBB penetration (86.002 and 94.378 percentile), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.168 and -4.894), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.296 and -2.55), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.47 and 0.772), which is positive.

**Microsomal Clearance:** Ligand A (35.704 mL/min/kg) has higher microsomal clearance than Ligand B (15.792 mL/min/kg). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-12.694 hours) has a longer in vitro half-life than Ligand A (-25.155 hours). This is a positive for Ligand B. Note that negative values are unusual and may indicate issues with the experimental setup or data interpretation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.041), which is favorable.

**Binding Affinity:** Ligand B (-10.2 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.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-10.2 vs -7.4 kcal/mol) outweighs the slightly higher TPSA and the higher clearance compared to Ligand A. The longer in vitro half-life is also a benefit. Addressing the solubility and permeability issues through formulation or structural modifications would be crucial for further development, but the superior potency of Ligand B makes it the better starting point.

Output:
1
2025-04-17 13:05:56,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.5 and 362.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is significantly better than Ligand B (86.55). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand A is excellent, while Ligand B is pushing the upper limit.

**logP:** Ligand A (4.174) is slightly high, potentially leading to solubility issues, but still within a reasonable range. Ligand B (1.14) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have a reasonable number of HBDs (0) and HBAs (3 for A, 7 for B), staying within the guidelines.

**QED:** Both ligands have similar, good QED values (0.706 and 0.73).

**DILI:** Both have similar DILI risk (57.3 and 59.4), which is acceptable, falling below the 60 threshold.

**BBB:** Both have high BBB penetration (81.7 and 94.3), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can still compare them relatively. A less negative value is better, so Ligand A (-4.745) is slightly better than Ligand B (-4.318).

**Aqueous Solubility:** Ligand A (-4.375) is better than Ligand B (-2.707). Solubility is important for kinases.

**hERG:** Both have very low hERG risk (0.95 and 0.036), which is excellent.

**Microsomal Clearance:** Ligand A (121.38) has significantly higher clearance than Ligand B (48.56). Lower clearance is preferred for kinases, indicating better metabolic stability. Ligand B is much better here.

**In vitro Half-Life:** Ligand B (-24.988) has a much longer half-life than Ligand A (33.896). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux (0.728 and 0.037), which is good.

**Binding Affinity:** Ligand A (0 kcal/mol) has a better binding affinity than Ligand B (0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and better solubility. However, Ligand A has a better binding affinity and a lower TPSA. The higher logP of Ligand A is a concern, but the significantly better binding affinity outweighs this drawback. Given the importance of potency for kinase inhibitors, and the acceptable ADME profile of Ligand A, it is the more promising candidate.

Output:
0
2025-04-17 13:05:56,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (424.32 Da) is slightly higher than Ligand B (344.507 Da), but both are acceptable.

**TPSA:** Ligand A (89.02) is better than Ligand B (50.08), being closer to the ideal threshold of <=140.

**logP:** Both ligands have good logP values (A: 2.993, B: 3.39), 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar, good QED values (A: 0.797, B: 0.804), indicating good drug-like properties.

**DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (58.395). This is a significant concern, as a lower DILI score is preferred.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (95.967) has a higher BBB penetration than Ligand A (62.466), but this is not a primary concern here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the values are close enough that this is not a major differentiator.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.046 and -4.229 respectively). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition risk than Ligand B (0.942), which is favorable.

**Microsomal Clearance:** Ligand B (94.42) has a significantly higher microsomal clearance than Ligand A (21.65). This suggests Ligand B will be metabolized more quickly, leading to lower exposure.

**In vitro Half-Life:** Both have similar half-lives (A: 33.428, B: 33.602).

**P-gp Efflux:** Ligand A (0.212) has lower P-gp efflux than Ligand B (0.798), which is preferable for bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). The difference is 0.6 kcal/mol, which is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate despite the slightly weaker binding affinity. It has a significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While both have poor solubility, the other advantages of Ligand A make it more likely to be a viable drug candidate.

Output:
0
2025-04-17 13:05:56,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.39 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (78.87), both are below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (-0.063) is slightly lower than optimal (1-3), but still acceptable. Ligand B (0.951) is within the optimal range.

**H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), below the threshold of 5.

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

**QED:** Both ligands have good QED scores (0.684 and 0.699), indicating drug-like properties.

**DILI:** Ligand A (21.946) has a significantly lower DILI risk than Ligand B (9.965), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (58.24) is better than Ligand B (46.336).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.823 and -4.771) which is unusual and indicates poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.85 and -1.279), indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.181 and 0.147), which is excellent.

**Microsomal Clearance:** Ligand A (-17.753) has a much lower (better) microsomal clearance than Ligand B (15.408), indicating higher metabolic stability.

**In vitro Half-Life:** Ligand A (-18.765) has a much longer in vitro half-life than Ligand B (2.179), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.011 and 0.049).

**Binding Affinity:** Both ligands have comparable binding affinities (-7.4 and -7.5 kcal/mol), which are both excellent.

**Conclusion:**

While both ligands have good binding affinity and acceptable drug-like properties, Ligand A is significantly better due to its substantially lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better TPSA. The solubility and permeability issues are shared by both, and would need to be addressed in further optimization, but the superior safety and pharmacokinetic profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 13:05:56,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.71 Da) is slightly higher than Ligand B (368.507 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (99.25). Lower TPSA generally improves absorption.

**logP:** Ligand A (3.912) is optimal, while Ligand B (0.491) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both have acceptable HBD counts (Ligand A: 1, Ligand B: 3).

**H-Bond Acceptors:** Both have acceptable HBA counts (Ligand A: 3, Ligand B: 7).

**QED:** Ligand A (0.6) is better than Ligand B (0.314), indicating a more drug-like profile.

**DILI:** Ligand B (34.277) has a much lower DILI risk than Ligand A (63.823), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A is slightly better (80.109 vs 70.997). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.934) is better than Ligand B (-5.715), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.431) is better than Ligand B (-1.775), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.311) has a lower hERG risk than Ligand B (0.209), which is a significant advantage.

**Microsomal Clearance:** Ligand B (68.793) has a higher microsomal clearance than Ligand A (40.255), suggesting lower metabolic stability. This is a critical disadvantage for an enzyme target.

**In vitro Half-Life:** Ligand A (14.025) has a shorter half-life than Ligand B (26.23), but both are acceptable.

**P-gp Efflux:** Ligand A (0.427) has lower P-gp efflux than Ligand B (0.017), which is beneficial.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly better binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.5 vs -10.1 kcal/mol). However, it suffers from a low logP, higher DILI risk, and higher microsomal clearance. Ligand A has better ADME properties overall (logP, solubility, hERG, clearance, Pgp), but its binding affinity is weaker. Given the importance of potency for enzyme inhibitors, the 1.6 kcal/mol difference in binding affinity is substantial. While Ligand B's ADME profile isn't ideal, it's potentially optimizable. The stronger binding is a key advantage that could be leveraged through further medicinal chemistry efforts.

Output:
1
2025-04-17 13:05:56,869 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.447 and 377.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.51) is better than Ligand B (99.18), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (0.78) is within the optimal 1-3 range, while Ligand B (-0.345) is slightly below 1, which *could* indicate potential permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 6 HBA) as both are within acceptable ranges, but lower counts generally improve permeability.

**QED:** Ligand A (0.688) has a significantly better QED score than Ligand B (0.399), indicating better overall drug-likeness.

**DILI:** Ligand B (4.769) has a much lower DILI risk than Ligand A (30.942), which is a significant advantage.

**BBB:** Ligand A (61.846) has a higher BBB penetration score than Ligand B (19.038), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.833) has a worse Caco-2 permeability than Ligand B (-5.557), both are quite poor.

**Aqueous Solubility:** Ligand B (0.837) has better aqueous solubility than Ligand A (-1.584), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.198) shows a lower hERG inhibition liability than Ligand B (0.113), which is a positive.

**Microsomal Clearance:** Ligand B (-16.776) exhibits significantly lower microsomal clearance than Ligand A (33.4), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-18.354) has a much longer in vitro half-life than Ligand A (-8.269), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.017) has lower P-gp efflux liability than Ligand B (0.006), which is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -8.7 kcal/mol), with Ligand B being slightly stronger. The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better BBB penetration and slightly lower hERG risk, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, substantially better metabolic stability (lower Cl_mic and longer t1/2), and improved aqueous solubility. The slightly lower logP of Ligand B is a minor concern that could be addressed through further optimization, but the benefits in metabolic stability and safety outweigh this drawback.

Output:
1
2025-04-17 13:05:56,869 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.305 and 344.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (91.58 and 88.42) are reasonably low, suggesting good absorption potential, though slightly above the optimal <90 for CNS targets (not a primary concern here).

**3. logP:** Both ligands (2.804 and 2.564) are within the optimal 1-3 range, indicating a good balance between solubility and 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 here.

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

**6. QED:** Both ligands (0.838 and 0.732) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (64.211) has a higher DILI risk than Ligand B (51.997), though both are acceptable (below 60).

**8. BBB:** This is less critical for a non-CNS target. Ligand A (57.619) and Ligand B (49.128) are both relatively low.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.71 and -4.1), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.352 and -4.034), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.768) has a slightly higher hERG risk than Ligand B (0.271). Ligand B is much preferred here.

**12. Microsomal Clearance:** Ligand A (46.259) has lower microsomal clearance than Ligand B (60.203), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-1.416) has a negative half-life, which is not physically possible and indicates a potential data error or a very rapidly metabolized compound. Ligand B (-7.974) also has a negative half-life, indicating a similar issue.

**14. P-gp Efflux:** Both ligands (0.344 and 0.059) have low P-gp efflux, which is favorable. Ligand B is slightly better.

**15. 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, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand A stands out due to its significantly stronger binding affinity (-8.6 vs -7.2 kcal/mol) and better metabolic stability (lower Cl_mic). While the negative half-life is concerning, the superior affinity could potentially overcome some ADME challenges. Ligand B has a better safety profile (lower DILI and hERG), but the weaker binding affinity is a major drawback for an enzyme inhibitor. Given the priority on potency for kinase inhibitors, Ligand A is the more promising candidate, *assuming the negative half-life can be investigated and resolved*.

Output:
1
2025-04-17 13:05:56,869 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.491 Da) and Ligand B (350.503 Da) are both acceptable.

**TPSA:** Ligand A (92.51) is slightly higher than ideal (<140), but still reasonable. Ligand B (58.64) is excellent, well below the 140 threshold.

**logP:** Ligand A (0.584) is a bit low, potentially hindering permeability. Ligand B (2.759) is optimal.

**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 (A: 0.683, B: 0.75), indicating drug-like properties.

**DILI:** Ligand A (36.293) has a slightly higher DILI risk than Ligand B (13.377), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.658) has a better BBB score than Ligand A (45.909), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.28) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.646) is also not great, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.547 and -2.893 respectively). This could pose formulation challenges, but is not a deal-breaker if other properties are strong.

**hERG Inhibition:** Ligand A (0.284) has a slightly higher hERG risk than Ligand B (0.403), but both are relatively low.

**Microsomal Clearance:** Ligand A (-0.255) has a negative clearance, indicating very high metabolic stability, which is excellent. Ligand B (36.473) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (19.637 hours) has a much longer half-life than Ligand B (2.123 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.021 and 0.097 respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.2 kcal/mol respectively). Ligand A has a 0.9 kcal/mol advantage, which is substantial.

**Conclusion:**

Despite Ligand A's slightly better binding affinity, its poor Caco-2 permeability and low logP are major concerns. The significantly better metabolic stability (negative Cl_mic) and longer half-life of Ligand A are attractive, but these benefits are likely outweighed by the absorption issues. Ligand B, while having a slightly weaker affinity, possesses a much better logP, TPSA, and a more reasonable (though still not ideal) metabolic profile. The improved permeability profile of Ligand B makes it a more promising starting point for optimization.

Output:
1
2025-04-17 13:05:56,869 - INFO - Batch 185 complete. Total preferences: 2960
2025-04-17 13:05:56,870 - INFO - Processing batch 186/512...
2025-04-17 13:06:37,565 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (352.519 Da and 346.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (60.85), but both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.863 and 1.792), falling 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 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.67 and 0.79), indicating a drug-like profile.

**7. DILI:** Ligand A (11.943) has a higher DILI risk than Ligand B (5.118). This is a significant concern. Ligand B is well below the 40 threshold.

**8. BBB:** Both ligands have similar BBB penetration (59.093 and 70.648). BBB is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.498 and -4.453). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar, so the difference is likely not significant.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.915 and -1.731). Again, these are on a log scale and indicate poor aqueous solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.602) has a higher hERG inhibition risk than Ligand B (0.182). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (70.618) has higher microsomal clearance than Ligand B (11.579). This indicates lower metabolic stability for Ligand A. Ligand B is much more metabolically stable.

**13. In vitro Half-Life:** Ligand A (13.304 hours) has a longer half-life than Ligand B (-15.848 hours). However, the negative value for Ligand B is problematic and likely indicates a very short half-life.

**14. P-gp Efflux:** Ligand A (0.289) has lower P-gp efflux than Ligand B (0.025). Lower efflux is generally preferred.

**15. 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 substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in key areas: significantly lower DILI risk, much better metabolic stability (lower Cl_mic), a longer (and positive) in vitro half-life, lower hERG risk, and a substantially stronger binding affinity. The higher affinity of Ligand B is a major advantage for an enzyme inhibitor. Ligand A's higher DILI risk and lower metabolic stability are significant drawbacks.

Output:
1
2025-04-17 13:06:37,565 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 366.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.44 and 78.43) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values within the optimal range (2.709 and 3.361).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 3 HBA) in terms of balancing solubility and permeability, although both are acceptable.

**QED:** Both ligands have good QED scores (0.824 and 0.722), indicating a drug-like profile.

**DILI:** Ligand A (54.207) has a higher DILI risk than Ligand B (35.828). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (85.731) has better BBB penetration than Ligand B (67.623).

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests potential issues with intestinal absorption. However, the values are relatively close (-4.974 vs -4.762).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.486 and -4.052). This is a major concern for both compounds and would require formulation strategies to improve bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.376 and 0.35). This is a positive attribute.

**Microsomal Clearance:** Ligand B (32.911) has significantly lower microsomal clearance than Ligand A (75.641), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (44.435) has a much longer in vitro half-life than Ligand A (-4.457), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.254 and 0.092).

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME concerns.

**Conclusion:**

While both ligands have issues with aqueous solubility, Ligand B is the more promising candidate. It exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), a substantially stronger binding affinity, and a lower DILI risk. The stronger binding affinity is particularly important for an enzyme target.

Output:
1
2025-04-17 13:06:37,565 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.422 and 368.865 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.44) is significantly better than Ligand B (107.11).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (0.974 and 1.629), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (4 HBD, 4 HBA). Lower HBD/HBA generally leads to better permeability.

**QED:** Ligand A (0.803) has a better QED score than Ligand B (0.633), indicating a more drug-like profile.

**DILI:** Ligand A (12.796) has a much lower DILI risk than Ligand B (54.789). This is a significant advantage.

**BBB:** Ligand A (74.292) has a better BBB penetration score than Ligand B (25.591), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.971) and Ligand B (-5.385) 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:** Both ligands have very poor aqueous solubility (-2.922 and -3.067), which is a major concern.

**hERG Inhibition:** Ligand A (0.584) has a lower hERG risk than Ligand B (0.147), which is a significant advantage.

**Microsomal Clearance:** Ligand A (8.496) has a higher (worse) microsomal clearance than Ligand B (-10.801). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (8.908) has a significantly longer in vitro half-life than Ligand A (-0.638), which is a major advantage.

**P-gp Efflux:** Ligand A (0.011) has a lower P-gp efflux liability than Ligand B (0.086), which is preferable.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better 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 is the better candidate despite the solubility issues. Its superior binding affinity, lower DILI risk, lower hERG risk, and better QED score outweigh the slightly higher microsomal clearance. The solubility issue is a concern, but formulation strategies could potentially address this. Ligand B's better metabolic stability and half-life are attractive, but the higher DILI and hERG risks, coupled with the weaker binding affinity, make it less desirable.

Output:
0
2025-04-17 13:06:37,565 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.371 and 349.45 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 140 threshold for oral absorption.

**logP:** Ligand A (-0.513) is a bit low, potentially hindering permeation. Ligand B (1.516) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent, while Ligand B (1) is acceptable.

**H-Bond Acceptors:** Ligand A (6) is good, and Ligand B (3) is also good.

**QED:** Both ligands (0.646 and 0.74) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (55.487) has a moderate DILI risk, while Ligand B (12.369) has a very low risk, which is a significant advantage.

**BBB:** Ligand A (61.923) and Ligand B (97.014). BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.191) has a very low hERG risk, while Ligand B (0.63) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-0.698) indicates low clearance and good metabolic stability, while Ligand B (6.337) suggests higher clearance and potentially lower stability.

**In vitro Half-Life:** Ligand A (4.577) has a reasonable half-life, while Ligand B (0.944) has a very short half-life, which is a concern.

**P-gp Efflux:** Ligand A (0.021) has low P-gp efflux, while Ligand B (0.057) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a significantly lower DILI risk, and a lower hERG risk. The slightly lower logP of Ligand A is a concern, but can potentially be addressed through further optimization. The overall profile of Ligand A is more favorable for progressing as a drug candidate.

Output:
0
2025-04-17 13:06:37,565 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.515 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 (89.87). Lower TPSA generally correlates with better cell permeability, a crucial factor for kinase inhibitors.

**logP:** Ligand A (3.665) is optimal, while Ligand B (1.357) 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=5). Lower counts generally improve permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.772, B: 0.649), indicating reasonable drug-likeness.

**DILI:** Ligand A (20.783) has a much lower DILI risk than Ligand B (45.483), which is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (91.702) shows better BBB penetration than Ligand B (64.482).

**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 values are similar.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.554, B: 0.31), which is good.

**Microsomal Clearance:** Ligand A (59.253) has a higher microsomal clearance than Ligand B (6.467), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (3.945) has a longer half-life than Ligand A (2.342), which is favorable.

**P-gp Efflux:** Ligand A (0.295) shows lower P-gp efflux than Ligand B (0.065), which is a positive.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 kcal/mol and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has several advantages: better TPSA, logP, H-bond properties, and significantly lower DILI risk and better P-gp efflux. However, Ligand B has better metabolic stability (lower Cl_mic and longer half-life). Given the importance of metabolic stability for kinase inhibitors, and the similar binding affinities, Ligand B is slightly more promising. However, the negative solubility and Caco-2 values for both compounds are concerning and would need to be addressed.

Output:
1
2025-04-17 13:06:37,565 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (71.33) is slightly higher than Ligand B (69.38), but both are acceptable.

**logP:** Ligand A (1.645) is within the optimal range (1-3). Ligand B (3.583) is at the higher end, which could lead to solubility issues or off-target interactions, but isn't drastically outside the range.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and reasonable HBA counts (5 and 6 respectively). This is good for balancing solubility and permeability.

**QED:** Ligand A (0.761) has a significantly better QED score than Ligand B (0.439), indicating a more drug-like profile.

**DILI:** Ligand A (44.591) has a much lower DILI risk than Ligand B (74.254). This is a significant advantage.

**BBB:** Both ligands have similar BBB penetration percentiles (64.521 and 67.895). Not a major factor for a kinase inhibitor unless CNS off-target effects are a concern.

**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:** Ligand A (-1.698) has better solubility than Ligand B (-4.418). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.124 and 0.366). This is excellent.

**Microsomal Clearance:** Ligand A (17.768 mL/min/kg) has significantly lower microsomal clearance than Ligand B (75.064 mL/min/kg). This suggests better metabolic stability for Ligand A, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (46.795 hours) has a much longer in vitro half-life than Ligand A (6.804 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 (0.071 and 0.682).

**Binding Affinity:** Ligand B (-8.1 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:**

Ligand B has a much stronger binding affinity and a longer half-life, which are key for an enzyme inhibitor. However, it suffers from higher DILI risk, lower solubility, and higher metabolic clearance. Ligand A has a better overall ADME profile (lower DILI, better solubility, better metabolic stability, higher QED) but weaker binding affinity.

Given the substantial difference in binding affinity (-8.1 vs -7.5 kcal/mol), and the fact that SRC kinases are intracellular targets where metabolic stability and solubility can be somewhat mitigated by formulation strategies, the stronger binding affinity of Ligand B is likely to be the deciding factor.

Output:
1
2025-04-17 13:06:37,566 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (390.311 and 368.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.3) is better than Ligand B (97.55), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (2.155 and 1.817), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is slightly better than Ligand B (2 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.608 and 0.765), indicating good drug-like properties.

**DILI:** Ligand A (24.234) has a significantly lower DILI risk than Ligand B (45.25), which is a major advantage.

**BBB:** Both have moderate BBB penetration, but Ligand B (78.558) is better than Ligand A (64.87). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.606) is slightly better than Ligand B (-5.158).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.59) is slightly better than Ligand B (-2.339).

**hERG Inhibition:** Ligand A (0.22) has a much lower hERG risk than Ligand B (0.536), which is a significant advantage.

**Microsomal Clearance:** Ligand A (3.82 mL/min/kg) has significantly lower microsomal clearance than Ligand B (15.697 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.194 hours) has a much longer in vitro half-life than Ligand B (8.569 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.206), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a crucial factor for enzyme inhibitors. The difference of 2 kcal/mol is substantial.

**Conclusion:**

Ligand A is the superior candidate. It has a significantly better binding affinity, lower DILI risk, lower hERG 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, Ligand A is slightly better in these aspects as well. The strong binding affinity of Ligand A outweighs any minor drawbacks.

Output:
1
2025-04-17 13:06:37,566 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (338.386 and 347.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.81) is significantly better than Ligand B (106.96).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have similar logP values (3.447 and 3.367), 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 (2) is lower than Ligand B (3), both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.682) has a much better QED score than Ligand B (0.319). A QED > 0.5 is desirable, and A clearly meets this criterion, suggesting a more drug-like profile.

**7. DILI:** Ligand A (61.884) has a higher DILI risk than Ligand B (35.75). While both are below 60 (good), B is preferable.

**8. BBB:** Ligand A (81) has better BBB penetration than Ligand B (55.293), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.93) has better Caco-2 permeability than Ligand B (-4.758). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-4.315) has better aqueous solubility than Ligand B (-3.206). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.802) has a slightly higher hERG inhibition risk than Ligand B (0.215). Lower is better, making B more favorable.

**12. Microsomal Clearance:** Ligand A (-3.29) has significantly better metabolic stability (lower clearance) than Ligand B (51.602). This is a crucial factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (20.424) has a much longer in vitro half-life than Ligand B (-3.486). This is also a critical factor for enzyme inhibitors.

**14. P-gp Efflux:** Ligand A (0.339) has lower P-gp efflux than Ligand B (0.118). Lower efflux is generally preferred.

**15. Binding Affinity:** Ligand A (-9.7) has a significantly stronger binding affinity than Ligand B (-8.3). A difference of >1.5 kcal/mol is substantial and can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is clearly the better candidate. While it has a slightly higher DILI risk, its superior binding affinity (-9.7 vs -8.3 kcal/mol), QED, metabolic stability (Cl_mic and t1/2), solubility, and Caco-2 permeability outweigh this concern. The strong binding affinity is particularly important for an enzyme target like SRC kinase. Ligand B, while having a lower DILI and hERG risk, suffers from poor metabolic stability and a weaker binding affinity.

Output:
1
2025-04-17 13:06:37,566 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.423 and 355.414 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.56) is slightly above the preferred <140 for good absorption, while Ligand B (100.35) is well within the range.

**logP:** Ligand A (-1.892) is a bit low, potentially hindering permeation. Ligand B (0.406) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, which are acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.334 and 0.658), with Ligand B being significantly better.

**DILI:** Ligand A (8.802) has a very low DILI risk, significantly better than Ligand B (48.817), which is approaching a moderate risk.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (74.447) has a higher BBB percentile than Ligand A (36.099), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.281 and -5.07), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.291 and -2.08), also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.082) has a very low hERG risk, much better than Ligand B (0.182).

**Microsomal Clearance:** Ligand A (4.55) has significantly lower microsomal clearance than Ligand B (35.963), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.653) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (-5.616) also has a negative half-life, indicating a similar issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.007 and 0.084).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial difference (1 kcal/mol) and a major advantage.

**Overall Assessment:**

Despite the strong binding affinity of Ligand B, the negative Caco-2 and solubility values for both compounds are major red flags. The negative half-life values are also problematic. However, Ligand A has a significantly better safety profile (lower DILI and hERG) and better metabolic stability (lower Cl_mic). Ligand B's stronger binding affinity is tempting, but the ADME liabilities are too significant to ignore. Given the enzyme-specific priorities, metabolic stability and safety are crucial. While both have issues, Ligand A is marginally better due to its superior ADME properties.

Output:
0
2025-04-17 13:06:37,566 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.785 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.49) is slightly higher than Ligand B (78.43). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (1.913 and 3.258), falling within the optimal 1-3 range. Ligand B is at the higher end, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are within the desired limits.

**QED:** Ligand A (0.725) has a better QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand A (89.841) has a significantly higher DILI risk than Ligand B (38.387). This is a major concern for Ligand A.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (39.162) is slightly better than Ligand A (26.638).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.549 and -5.046), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-3.232 and -3.024), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.033) has a much lower hERG inhibition risk than Ligand B (0.687), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-24.739) has a much lower (better) microsomal clearance than Ligand B (54.788), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.296) has a longer in vitro half-life than Ligand B (49.749), which is desirable.

**P-gp Efflux:** Ligand A (0.043) has a lower P-gp efflux liability than Ligand B (0.659), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a significant advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a lower DILI risk, which are key priorities for an enzyme inhibitor. However, it suffers from higher metabolic clearance, higher P-gp efflux, and a higher hERG risk. Ligand A has better metabolic stability, lower hERG, and better QED, but its DILI risk is very high, and its binding affinity is slightly weaker.

Despite the poor solubility and permeability for both, the stronger binding affinity of Ligand B and its lower DILI risk are more compelling, especially considering the potential for optimization of solubility/permeability. The high DILI risk of Ligand A is a significant red flag.

Output:
1
2025-04-17 13:06:37,566 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.238 Da) is slightly higher than Ligand B (352.475 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (A: 59.59, B: 67.87) well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.019) is at the upper end of the optimal range (1-3), while Ligand B (1.866) is towards the lower end. While A's logP isn't alarming, it's closer to a potential issue with solubility or off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 2/3, B: 1/4), well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.706, B: 0.792), indicating drug-like properties.

**DILI:** Ligand A (68.088) has a significantly higher DILI risk than Ligand B (14.734). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 74.99, B: 74.758), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.554 and -4.799), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.998 and -2.129), suggesting very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.86, B: 0.243), which is good. Ligand B has a slightly lower risk.

**Microsomal Clearance:** Ligand A (71.882) has a higher microsomal clearance than Ligand B (21.234), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (14.722) has a longer in vitro half-life than Ligand A (33.68), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.537, B: 0.063). Ligand B is better in this regard.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Conclusion:**

Despite having identical binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux liability outweigh the slightly lower logP. Both compounds suffer from poor predicted solubility and permeability, but these issues might be addressed through formulation strategies. The high DILI risk associated with Ligand A is a critical factor that makes it less desirable.

Output:
1
2025-04-17 13:06:37,566 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (352.435 Da and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.69) is better than Ligand B (113.44), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.384) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.869) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 6 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.591 and 0.609), indicating good drug-likeness.

**DILI:** Ligand A (19.969) has a significantly lower DILI risk than Ligand B (47.732), which is a major advantage. Ligand B's DILI is approaching a concerning level.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (46.762) has a higher BBB value than Ligand A (12.059), but this is not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.507 and -5.126), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.469 and -2.88), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.187 and 0.108), which is positive.

**Microsomal Clearance:** Ligand A (-5.33 mL/min/kg) has much lower microsomal clearance than Ligand B (32.267 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-3.792 hours) has a slightly better in vitro half-life than Ligand B (-8.711 hours), though both are negative values, which is unusual.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.026).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.6 kcal/mol and -7.5 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its significantly lower DILI risk and substantially better metabolic stability (lower Cl_mic) are critical advantages for an enzyme target like SRC kinase. While both ligands suffer from poor predicted permeability and solubility, the ADME properties of Ligand A are considerably better overall, making it the preferred choice for further development.

Output:
0
2025-04-17 13:06:37,566 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.491 and 358.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (93.84), both are below the 140 threshold for oral absorption, but closer to the 90 threshold is preferred.

**logP:** Both ligands have good logP values (1.598 and 2.092), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.559 and 0.683), indicating good drug-like properties.

**DILI:** Ligand A (21.287) has a significantly lower DILI risk than Ligand B (51.377). This is a major advantage.

**BBB:** Ligand A (73.866) has a better BBB penetration score than Ligand B (60.101), but BBB isn't a primary concern for SRC kinase inhibitors unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.144 and -5.311). This 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 very low aqueous solubility (-2 and -2.509). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.163 and 0.16), which is good.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (35.397 and 37.702 mL/min/kg), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand B (-9.099) has a significantly longer in vitro half-life than Ligand A (3.794). This is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.09).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This 1.1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a longer half-life, which are key for an enzyme inhibitor. However, Ligand A has a significantly lower DILI risk and better BBB penetration. The solubility is poor for both. The Caco-2 permeability is concerning for both. Given the importance of potency and metabolic stability for kinase inhibitors, and the substantial affinity advantage of Ligand B, I would prioritize Ligand B despite the higher DILI risk. Further optimization could focus on mitigating the DILI risk while maintaining the strong binding affinity.

Output:
1
2025-04-17 13:06:37,567 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.42 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is significantly better than Ligand B (75.71). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (3.778) is optimal, while Ligand B (1.871) is on the lower side. While not a dealbreaker, lower logP can sometimes indicate permeability issues.

**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 similar QED values (0.842 and 0.742), indicating good drug-likeness.

**DILI:** Ligand A (41.954) has a slightly higher DILI risk than Ligand B (28.228), but both are below the concerning threshold of 60.

**BBB:** Both have reasonable BBB penetration, but Ligand A (88.406) is significantly better than Ligand B (68.864). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2:** Both have negative Caco-2 values, which is unusual. This suggests poor permeability.

**Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a significant concern for both compounds.

**hERG:** Ligand A (0.797) has a better hERG profile (lower risk) than Ligand B (0.226). This is a crucial factor given the potential for cardiotoxicity.

**Microsomal Clearance:** Ligand A (60.111) has higher microsomal clearance than Ligand B (57.84). Lower is better for metabolic stability.

**In vitro Half-Life:** Ligand B (-14.626) has a significantly longer half-life than Ligand A (12.337). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.19) has lower P-gp efflux than Ligand B (0.071), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, logP, BBB, hERG profile, and P-gp efflux. However, Ligand B has a significantly longer half-life, lower DILI risk, and better solubility. Both have poor Caco-2 permeability and solubility. Given the enzyme-specific priorities, the stronger binding affinity of Ligand A is a significant advantage. The slightly higher DILI risk of Ligand A is acceptable given the potency. The hERG risk is also lower for Ligand A.

Output:
1
2025-04-17 13:06:37,567 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.543 and 363.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (85).  The threshold is <140, both are under, but lower is better for absorption.

**logP:** Both ligands have good logP values (3.271 and 2.858), falling 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:** Ligand A (4) is better than Ligand B (6). Lower is better for permeability.

**QED:** Both ligands have good QED scores (0.71 and 0.853), indicating good drug-likeness.

**DILI:** Ligand A (16.014) has a much lower DILI risk than Ligand B (61.574). This is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (83.366 and 85.459). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.788 and -4.885). 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 (-2.059 and -3.93). This is also unusual and suggests poor solubility, but the scale is not specified, so it's hard to interpret.

**hERG:** Both ligands have low hERG risk (0.56 and 0.454), which is good.

**Microsomal Clearance:** Ligand A (55.6) has higher microsomal clearance than Ligand B (34.842), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (8.19) has a longer in vitro half-life than Ligand A (3.866), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.325 and 0.137).

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.7). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is better overall. While Ligand A has a better TPSA, HBD, and HBA, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh the small affinity difference.

Output:
1
2025-04-17 13:06:37,567 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.375 and 367.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (106.15 and 105.04) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.777) is better than Ligand B (0.214). While both are relatively low, Ligand B is quite low and could struggle with membrane permeability.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (2 HBD, 8 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.776 and 0.801), indicating good drug-like properties.

**DILI:** Ligand A (72.354) has a slightly better DILI percentile than Ligand B (79.333), suggesting lower potential for liver injury. Both are acceptable, but lower is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Both are around 50%, so this isn't a major differentiator.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and concerning. It suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.029) is significantly better than Ligand B (0.34), indicating a much lower risk of cardiotoxicity. This is a crucial advantage.

**Microsomal Clearance:** Ligand A (19.53 mL/min/kg) has a much lower microsomal clearance than Ligand B (4.175 mL/min/kg). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-16.897 hours) has a negative half-life, which is nonsensical. Ligand B (28.708 hours) has a reasonable half-life. This is a major drawback for Ligand A.

**P-gp Efflux:** Both are very low, suggesting minimal P-gp efflux.

**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 significantly better binding affinity (-8.4 vs -6.7 kcal/mol), which is paramount for an enzyme inhibitor. While its logP is lower and DILI is slightly higher, the substantial improvement in potency is a major advantage. Ligand A has a better hERG profile and clearance, but the negative half-life is a critical flaw. The solubility and permeability issues are shared by both.

Output:
1
2025-04-17 13:06:37,568 - INFO - Batch 186 complete. Total preferences: 2976
2025-04-17 13:06:37,568 - INFO - Processing batch 187/512...
2025-04-17 13:07:16,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.402 and 333.395 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (47.36) is significantly better than Ligand B (77.97).  A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (2.997 and 2.555), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (1 HBD, 6 HBA). Lower counts are generally preferred for better permeability, and A is closer to the ideal.

**QED:** Both ligands have acceptable QED scores (0.857 and 0.797), indicating good drug-likeness.

**DILI:** Ligand A (51.842) has a lower DILI risk than Ligand B (64.793), which is a significant advantage. Both are below the concerning threshold of 60, but lower is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.413) has a higher BBB percentile than Ligand B (50.679).

**Caco-2 Permeability:** Ligand A (-4.217) has a better Caco-2 permeability than Ligand B (-5.029). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.578) shows better aqueous solubility than Ligand B (-3.277). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.698) has a lower hERG inhibition liability than Ligand B (0.929), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (46.85) has a lower microsomal clearance than Ligand B (51.359), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.419) has a much longer in vitro half-life than Ligand B (26.033). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.554 and 0.536).

**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 other ADME properties of Ligand A are significantly more favorable.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates substantial advantages in DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), solubility, and Caco-2 permeability. These factors are crucial for developing a safe and effective kinase inhibitor. The small difference in binding affinity is likely surmountable through further optimization, while addressing the ADME deficiencies of Ligand B would be more challenging.

Output:
0
2025-04-17 13:07:16,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.865 and 354.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (83.56 and 86.33) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (target <90). This is less critical for a non-CNS oncology target.

**3. logP:** Ligand A (2.581) is optimal, while Ligand B (1.154) is slightly low, potentially impacting permeability.

**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 (5 and 6, respectively).

**6. QED:** Both ligands have reasonable QED scores (0.834 and 0.501), indicating good drug-like properties. Ligand A is superior.

**7. DILI:** Both ligands have similar DILI risk (54.556 and 54.789), categorized as acceptable.

**8. BBB:** Both ligands have low BBB penetration, which is not a primary concern for an oncology target. Ligand B is slightly higher (75.572 vs 63.629).

**9. Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a significant concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.362 and 0.366), which is excellent.

**12. Microsomal Clearance:** Ligand B (40.854) has a significantly lower Cl_mic than Ligand A (52.219), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-17.342) has a much longer half-life than Ligand A (14.988), further supporting its superior metabolic stability. Note the negative values suggest a scale where lower is better.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.081).

**15. Binding Affinity:** Ligand A (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand B exhibits better metabolic stability (lower Cl_mic and longer half-life) and slightly better BBB penetration. Both have poor Caco-2 and solubility. The affinity difference is significant enough to favor Ligand A, despite the metabolic concerns. Optimization efforts would focus on improving the metabolic stability of Ligand A.

Output:
0
2025-04-17 13:07:16,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 371.373 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (114.35 and 115.16) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.955) is slightly low, potentially hindering permeation. Ligand B (1.228) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.558 and 0.44), suggesting drug-like properties.

**DILI:** Ligand A (44.552) has a lower DILI risk than Ligand B (63.164), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (67.972) has a higher BBB score than Ligand A (33.424), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.554 and -5.028), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.08 and -1.544), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.109 and 0.092). This is excellent.

**Microsomal Clearance:** Ligand A (-8.125) has a much lower (better) microsomal clearance than Ligand B (5.81). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-6.016) has a longer in vitro half-life than Ligand B (-1.538), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.043).

**Binding Affinity:** Ligand B (0) has a significantly better binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While it has a slightly higher DILI risk and a worse metabolic profile (higher Cl_mic, shorter t1/2) than Ligand A, the substantial improvement in binding affinity is likely to be decisive. Both compounds suffer from poor predicted solubility and permeability, which would need to be addressed through formulation or structural modifications. However, potency is paramount, and Ligand B wins on that front.

Output:
1
2025-04-17 13:07:16,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.445 and 345.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is slightly higher than Ligand B (55.63), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (2.134) is within the optimal 1-3 range. Ligand B (4.12) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable, being under the 10 limit.

**QED:** Both ligands have good QED scores (0.721 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (25.087) has a significantly lower DILI risk than Ligand B (32.105), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (82.047 and 81.621), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.384) shows better Caco-2 permeability than Ligand B (-5.307), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.271) has better aqueous solubility than Ligand B (-4.289). This is a significant advantage for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.541 and 0.406), which is good.

**Microsomal Clearance:** Ligand A (38.896) has lower microsomal clearance than Ligand B (42.743), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.744) has a significantly longer in vitro half-life than Ligand B (4.79), which is a major advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.13 and 0.605).

**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, and the ADME advantages of Ligand A are substantial.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile compared to Ligand B. It has lower DILI risk, better solubility, better permeability, better metabolic stability (lower Cl_mic and longer t1/2), and a comparable binding affinity. While Ligand B has a slightly better binding affinity, the ADME advantages of Ligand A outweigh this small difference, especially considering SRC is an enzyme target where metabolic stability and solubility are crucial.

Output:
1
2025-04-17 13:07:16,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.411 and 357.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is better than Ligand B (29.54) as it is closer to the 140 threshold.

**logP:** Ligand A (1.425) is within the optimal 1-3 range. Ligand B (4.358) is slightly high, potentially leading 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 2 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.839) has a significantly better QED score than Ligand B (0.646), indicating a more drug-like profile.

**DILI:** Ligand A (26.173) has a much lower DILI risk than Ligand B (19.31), which is preferable.

**BBB:** Ligand A (46.336) has a lower BBB penetration than Ligand B (96.859). However, since SRC is not a CNS target, this is not a major concern.

**Caco-2 Permeability:** Ligand A (-4.634) has a lower Caco-2 permeability than Ligand B (-4.147), which is less desirable.

**Aqueous Solubility:** Ligand A (-1.824) has better aqueous solubility than Ligand B (-4.81).

**hERG:** Ligand A (0.213) has a lower hERG inhibition liability than Ligand B (0.877), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-13.67) has a much lower microsomal clearance than Ligand B (91.022), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (3.89) has a shorter half-life than Ligand B (19.1). However, the significantly better metabolic stability of Ligand A suggests that *in vivo* half-life might be comparable or even better.

**P-gp Efflux:** Ligand A (0.163) has lower P-gp efflux than Ligand B (0.433), which is preferable.

**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). Given the other substantial advantages of Ligand A, this difference is unlikely to be decisive.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. It has a better QED score, significantly lower DILI and microsomal clearance, better solubility, and lower hERG risk. While Ligand B has slightly better binding affinity and BBB penetration, the advantages of Ligand A in ADME-Tox properties, particularly metabolic stability and safety, outweigh these minor differences.

Output:
0
2025-04-17 13:07:16,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.475 and 362.836 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is better than Ligand B (50.28) as it is still within the acceptable range for oral absorption (<=140), while ligand B is significantly lower.

**logP:** Ligand A (-1.03) is slightly low, potentially hindering permeation. Ligand B (3.525) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is better than Ligand B (1 HBD, 5 HBA) as it is within the ideal range.

**QED:** Ligand B (0.901) has a significantly higher QED score than Ligand A (0.527), indicating better overall drug-likeness.

**DILI:** Ligand A (29.236) has a much lower DILI risk than Ligand B (68.515), which is a significant advantage.

**BBB:** Ligand B (81.039) has a higher BBB penetration percentile than Ligand A (27.026). However, SRC is not a CNS target, so this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and concerning. However, the values are similar (-5.686 and -4.82).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also concerning. Ligand A (-1.443) is slightly better than Ligand B (-4.565).

**hERG Inhibition:** Ligand A (0.089) has a much lower hERG inhibition liability than Ligand B (0.893), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-14.878) has a significantly lower (better) microsomal clearance than Ligand B (69.802), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (39.774) has a much longer in vitro half-life than Ligand A (-6.861), which is a positive.

**P-gp Efflux:** Ligand B (0.27) has lower P-gp efflux than Ligand A (0.005), which is slightly better.

**Binding Affinity:** Ligand B (-8.3 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.

**Conclusion:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and half-life, Ligand A demonstrates significantly lower DILI and hERG risk, and better metabolic stability (lower Cl_mic). The solubility and Caco-2 values are concerning for both, but Ligand A is slightly better. The slightly lower logP of Ligand A is a minor drawback compared to the safety advantages.

Output:
0
2025-04-17 13:07:16,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403 Da) is slightly lower, which could be advantageous for permeability. Ligand B (390.311 Da) is still acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (87.3) is better than Ligand A (103.25).

**logP:** Ligand A (0.556) is a bit low, potentially hindering membrane permeability. Ligand B (2.155) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 3. Lower HBA is generally preferred.

**QED:** Both ligands have acceptable QED scores (A: 0.682, B: 0.608), indicating drug-like properties.

**DILI:** Ligand A (40.287) has a slightly higher DILI risk than Ligand B (24.234), but both are below the concerning threshold of 60.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (64.87) has a higher BBB score than Ligand A (17.371).

**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 liability (0.223 and 0.22), which is excellent.

**Microsomal Clearance:** Ligand A (-10.084) has significantly lower (better) microsomal clearance than Ligand B (3.82). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-12.706) has a much longer in vitro half-life than Ligand B (26.194), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.007 and 0.043).

**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 threshold.

**Conclusion:**

While Ligand A exhibits better metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower DILI risk, the significantly superior binding affinity of Ligand B (-8.6 vs -6.9 kcal/mol) outweighs the drawbacks of its slightly higher logP and lower metabolic stability. The difference in binding affinity is substantial and likely to translate to greater efficacy. The solubility and permeability are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:07:16,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.27 and 346.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.19) is slightly higher than Ligand B (41.57). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (3.068 and 2.104), 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:** Ligand B (0.911) has a significantly higher QED score than Ligand A (0.465), indicating a more drug-like profile.

**DILI:** Ligand A (68.205) has a higher DILI risk than Ligand B (20.396). Ligand B is well below the 40 threshold, indicating low risk.

**BBB:** Both ligands have high BBB penetration (96.2 and 89.298), but this is less critical for a non-CNS target like SRC.

**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.

**hERG:** Both ligands have low hERG risk (0.706 and 0.763).

**Microsomal Clearance:** Ligand A (86.382) has a higher microsomal clearance than Ligand B (34.378), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-10.441) has a negative half-life, which is impossible and suggests a data error. Ligand A has a reasonable half-life of 7.255 hours.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.554 and 0.232).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While both are excellent, the 1 kcal/mol difference is noteworthy.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand B appears to be the more promising candidate. It has a significantly better QED score, a much lower DILI risk, and better metabolic stability (lower Cl_mic). The binding affinity difference is small, and the slight advantage of Ligand B is enough to tip the scales, especially considering the improved ADME properties. The negative half-life for Ligand B is a major red flag and would require further investigation to determine if it is a data error or a true observation. However, assuming the binding affinity data is reliable, Ligand B is still preferred due to the other favorable properties.

Output:
1
2025-04-17 13:07:16,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (385.222 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, while Ligand B (87.47) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.919) is at the upper end of the optimal range (1-3), while Ligand B (1.3) is at the lower end. Ligand B's low logP could hinder membrane permeability.

**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, giving a slight edge to Ligand A.

**QED:** Both ligands have similar QED values (0.767 and 0.683), indicating good drug-likeness.

**DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (28.81). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (70.027) is slightly better than Ligand B (50.795).

**Caco-2 Permeability:** Ligand A (-4.461) shows poor permeability, while Ligand B (-5.572) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.547) has very poor solubility, while Ligand B (-2.337) is also poor, but better than Ligand A. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.61) has a slightly higher hERG risk than Ligand B (0.331), but both are relatively low.

**Microsomal Clearance:** Ligand A (85.787) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (25.769). This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (47.034) has a longer half-life than Ligand B (37.683), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux than Ligand B (0.05), which is better.

**Binding Affinity:** Both ligands have very strong binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better BBB and P-gp efflux, its significantly higher DILI risk, poor solubility, and higher microsomal clearance outweigh these benefits. Ligand B, despite a lower logP and Caco-2 permeability, has a much better safety profile (DILI) and metabolic stability, which are crucial for an enzyme inhibitor. The binding affinity is comparable between the two.

Output:
1
2025-04-17 13:07:16,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.419 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.25) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good oral absorption.

**logP:** Both ligands have similar logP values (3.668 and 3.524), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 2. Lower HBA is generally preferred for permeability, giving Ligand B an advantage.

**QED:** Ligand A (0.769) has a higher QED score than Ligand B (0.513), indicating a more drug-like profile overall.

**DILI:** Ligand A has a very high DILI risk (99.341 percentile), which is a major red flag. Ligand B has a much lower DILI risk (6.824 percentile), making it significantly safer.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.139) has a higher BBB value than Ligand A (58.007).

**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 (-5.103) is slightly worse than Ligand B (-4.761).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-5.482) is slightly worse than Ligand B (-3.515).

**hERG:** Both ligands have low hERG inhibition liability (0.606 and 0.594), which is good.

**Microsomal Clearance:** Ligand A (93.893) has a higher microsomal clearance than Ligand B (77.552), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-5.838) has a negative half-life, which is concerning. Ligand A (54.099) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.149 and 0.106).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand A having a better QED and in vitro half-life, the extremely high DILI risk (99.341 percentile) is a deal-breaker. The lower DILI risk, better TPSA, and lower HBA of Ligand B make it a much more promising candidate, even with its slightly lower QED and negative half-life. The similar binding affinity means potency isn't a differentiating factor. The solubility and permeability issues are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 13:07:16,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (378.425 Da and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is better than Ligand B (95.42), as it's closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.26 and 1.01), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 5 HBA) as both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Ligand B (0.834) has a significantly higher QED score than Ligand A (0.467), indicating a more drug-like profile overall.

**DILI:** Ligand A (18.922) has a much lower DILI risk than Ligand B (59.791). This is a significant advantage for Ligand A.

**BBB:** This isn't a primary concern for a kinase inhibitor, but Ligand A (72.237) is better than Ligand B (45.909).

**Caco-2 Permeability:** Ligand A (-4.866) is better than Ligand B (-5.102), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.514) is better than Ligand B (-2.859), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.466) has a lower hERG risk than Ligand B (0.145), which is a major safety advantage.

**Microsomal Clearance:** Ligand B (-14.804) has significantly lower (better) microsomal clearance than Ligand A (33.094). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-1.366) has a longer half-life than Ligand A (1.038), which is desirable.

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux than Ligand B (0.012), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-9.6 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. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and a higher QED score. While Ligand A has advantages in DILI risk, hERG, solubility, and P-gp efflux, the potency difference is substantial. For an enzyme target like SRC kinase, potency is paramount. The improved metabolic stability of Ligand B also addresses a key concern for kinase inhibitors. The slightly higher DILI risk and lower solubility of Ligand B are acceptable trade-offs given the much stronger binding.

Output:
1
2025-04-17 13:07:16,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.446 Da) is slightly lower, which could be advantageous for permeability. Ligand B (391.915 Da) is still acceptable.

**TPSA:** Ligand A (58.2) is better than Ligand B (41.29). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (3.331) being slightly lower and Ligand B (4.16) being slightly higher. Ligand B is approaching the upper limit where solubility issues could arise.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is better than Ligand B (1 HBD, 5 HBA). Lower numbers of both are generally preferred for better permeability.

**QED:** Both ligands have good QED values (Ligand A: 0.71, Ligand B: 0.77), indicating good drug-like properties.

**DILI:** Ligand A (22.761) has a significantly lower DILI risk than Ligand B (34.626), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (Ligand A: 81.698, Ligand B: 82.784), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**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, the values are similar (-4.535 for A, -4.721 for B), so this doesn't differentiate them significantly.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-3.978 for A, -4.441 for B), so this doesn't differentiate them significantly.

**hERG Inhibition:** Ligand A (0.616) has a lower hERG inhibition liability than Ligand B (0.882), which is a significant advantage.

**Microsomal Clearance:** Ligand B (57.707) has lower microsomal clearance than Ligand A (64.51), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (16.187) has a significantly longer in vitro half-life than Ligand A (5.82), which is a major advantage.

**P-gp Efflux:** Ligand A (0.132) has lower P-gp efflux liability than Ligand B (0.665), which is a positive.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (Ligand A: -7.7 kcal/mol, Ligand B: -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, P-gp efflux, and TPSA. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2). The binding affinities are essentially the same. Given the enzyme-specific priorities, metabolic stability is important, but the significantly lower DILI and hERG risk of Ligand A are more compelling, particularly in the early stages of drug development. The slightly better permeability profile (lower TPSA) of Ligand A is also a plus.

Output:
0
2025-04-17 13:07:16,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.431 and 354.47 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.15) is better than Ligand B (47.1). Both are below 140, suggesting good oral absorption potential.

**logP:** Both ligands have similar logP values (0.55 and 0.431), which are a bit low, potentially hindering permeation. However, it's not a major concern.

**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 and good QED scores (0.73 and 0.738).

**DILI:** Ligand A (37.03) has a much lower DILI risk than Ligand B (8.841), which is a significant advantage.

**BBB:** Ligand A (57.193) has a lower BBB penetration than Ligand B (76.541). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.413) has a lower Caco-2 permeability than Ligand B (-4.747). Both are quite low, suggesting potential absorption issues.

**Aqueous Solubility:** Ligand A (-1.603) has a slightly better solubility than Ligand B (-1.12). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.157) has a much lower hERG inhibition liability than Ligand B (0.477), which is a critical advantage for safety.

**Microsomal Clearance:** Ligand B (-22.906) has significantly lower microsomal clearance than Ligand A (40.565), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-23.267) has a much longer in vitro half-life than Ligand A (-0.597), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.053) has a slightly lower P-gp efflux liability than Ligand B (0.008).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.0 and -7.3 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, Ligand A demonstrates significantly better safety profiles with much lower DILI and hERG inhibition liabilities. Considering the enzyme-specific priorities, the safety profile is paramount. The slightly better metabolic stability of Ligand B is not enough to outweigh the substantial safety concerns.

Output:
0
2025-04-17 13:07:16,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.447 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.8) is well below the 140 threshold for good absorption, and even favorable for potential CNS penetration. Ligand B (114.18) is still acceptable but less optimal.

**logP:** Ligand A (0.629) is a bit low, potentially hindering permeation. Ligand B (1.368) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (0.719 and 0.644), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (20.24 and 48.817), but Ligand A is significantly lower, which is a positive.

**BBB:** Ligand A (48.119) has a lower BBB penetration percentile than Ligand B (65.607). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.614) shows poor Caco-2 permeability, while Ligand B (-5.431) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.436) has slightly better solubility than Ligand B (-3.442).

**hERG Inhibition:** Ligand A (0.091) has a very low hERG risk, which is excellent. Ligand B (0.247) is also relatively low, but higher than A.

**Microsomal Clearance:** Ligand A (13.12) has a higher microsomal clearance than Ligand B (8.751), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (18.761) has a significantly longer half-life than Ligand A (8.766), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.042).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 2.2 kcal/mol is significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better safety profile (lower DILI, lower hERG), the significantly superior binding affinity of Ligand B (-9.9 vs -7.7 kcal/mol) and its longer half-life are crucial for an enzyme target like SRC. The slightly higher logP of Ligand B is also beneficial. The lower Caco-2 and solubility of both are concerns, but the potency advantage of Ligand B is likely to be more impactful in driving *in vivo* efficacy.

Output:
1
2025-04-17 13:07:16,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.459 and 367.921 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is better than Ligand B (47.36). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.347 and 3.798), 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:** Both ligands have 0 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.794 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (31.485) has a significantly lower DILI risk than Ligand B (16.092). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (86.817 and 87.631), however, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.82 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 preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.283 and -2.874). This is concerning, as poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.371 and 0.661), which is good.

**Microsomal Clearance:** Ligand A (39.044) has lower microsomal clearance than Ligand B (77.685), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.669) has a negative half-life, which is unusual and concerning. Ligand B (16.213) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.329 and 0.685), which is favorable.

**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.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While it has a concerning negative in vitro half-life, its significantly lower DILI risk and lower microsomal clearance outweigh the slightly worse solubility and Caco-2 permeability. The binding affinity is comparable. The negative half-life would require further investigation, but the other ADME properties make Ligand A the better choice.

Output:
0
2025-04-17 13:07:16,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.427 and 346.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.56) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (58.64) is well within the ideal range.

**logP:** Both ligands have good logP values (3.242 and 2.243), 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 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.684 and 0.849), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 56.689, which is moderate but acceptable. Ligand B has a significantly lower DILI risk of 14.618, which is excellent.

**BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand A (60.876) and Ligand B (78.558) are both reasonable, with B being slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.275 and -4.725). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute permeability may not be terrible.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.699 and -2.803). This is concerning, as poor solubility can hinder bioavailability.

**hERG:** Ligand A (0.154) has a slightly higher hERG risk than Ligand B (0.404), but both are relatively low.

**Microsomal Clearance:** Ligand A has a significantly better (lower) microsomal clearance (-6.945) compared to Ligand B (24.557). This indicates much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (38.16 hours) than Ligand B (2.702 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.104 and 0.093).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2) and has a moderate DILI risk. Its solubility and permeability are concerning, but the strong binding affinity (-8.1 kcal/mol) might compensate. Ligand B has a superior DILI profile and slightly better binding affinity, but suffers from poor metabolic stability and a shorter half-life.

Given the enzyme-specific priorities, metabolic stability and potency are key. While Ligand B has a slightly better affinity, the substantial difference in metabolic stability and half-life in favor of Ligand A is more critical. The solubility issues of both compounds would need to be addressed through formulation strategies.

Output:
0
2025-04-17 13:07:16,798 - INFO - Batch 187 complete. Total preferences: 2992
2025-04-17 13:07:16,798 - INFO - Processing batch 188/512...
2025-04-17 13:07:58,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (337.427 and 349.406 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (70.15 and 71.53) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands have logP values within the optimal range (2.506 and 1.807).

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (2 and 1, respectively).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (5 and 4, respectively).

**6. QED:** Both ligands have good QED scores (0.9 and 0.85), indicating drug-likeness.

**7. DILI:** Ligand A (60.76) has a higher DILI risk than Ligand B (38.387). This is a significant negative for Ligand A.

**8. BBB:**  While not a primary concern for a non-CNS target like SRC, Ligand B (88.561) shows better BBB penetration than Ligand A (77.2).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.78) is slightly worse than Ligand B (-4.366).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-2.814) is better than Ligand A (-3.96).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.718 and 0.544).

**12. Microsomal Clearance (Cl_mic):** Ligand B (24.619 mL/min/kg) has significantly lower microsomal clearance than Ligand A (58.412 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life (t1/2):** Ligand B (-39.122 hours) has a much longer in vitro half-life than Ligand A (7.405 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.122 and 0.05).

**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 a positive factor.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. It also has a significantly lower DILI risk and better solubility. While both have poor Caco-2 permeability, the other advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 13:07:58,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.487 and 357.885 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is higher than Ligand B (49.25). Both are below 140, suggesting reasonable absorption, but B is preferable.

**logP:** Ligand A (1.744) is within the optimal 1-3 range. Ligand B (3.842) is at the higher end, potentially leading to solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 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 (0.812 and 0.887), indicating drug-like properties.

**DILI:** Ligand A (42.924) has a slightly better DILI score than Ligand B (50.795), both are acceptable.

**BBB:** Ligand A (71.501) and Ligand B (90.074). BBB is less critical for a non-CNS target like SRC, but B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.664 and -4.852), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.539) is better than Ligand B (-4.773), indicating better solubility. Solubility is important for bioavailability.

**hERG:** Ligand A (0.247) has a much lower hERG risk than Ligand B (0.713), a significant advantage.

**Microsomal Clearance:** Ligand A (70.189) has a higher Cl_mic than Ligand B (52.543), indicating lower metabolic stability. B is preferable.

**In vitro Half-Life:** Ligand A (-2.755) has a negative half-life, which is not possible. Ligand B (27.909) has a much better half-life.

**P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux than Ligand B (0.811), which is preferable.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 permeability for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.5 vs -6.4 kcal/mol) is a major advantage for an enzyme target. It also has better metabolic stability (lower Cl_mic, longer half-life) and a better BBB score. While its hERG risk is higher, the strong binding affinity and better metabolic profile outweigh this concern. Ligand A's negative half-life is a major red flag.

Output:
1
2025-04-17 13:07:58,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing enzyme characteristics.

**1. Molecular Weight (MW):** Both ligands (342.443 and 384.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.35) is well below the 140 threshold, while Ligand B (82.61) is still acceptable but approaching the limit.

**3. logP:** Both ligands have good logP values (2.898 and 1.312), 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):** Ligand A has 5 HBAs, and Ligand B has 6. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.799 and 0.717), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (57.348 and 57.154), placing them in a moderate risk category, but still acceptable.

**8. BBB:** Ligand A (61.613) has a slightly better BBB penetration percentile than Ligand B (43.699), but BBB is not a high priority for a kinase inhibitor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.577 and -4.976), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.638 and -2.123), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.655 and 0.154).

**12. Microsomal Clearance (Cl_mic):** Ligand A has a higher Cl_mic (94.011) than Ligand B (20.223). This suggests Ligand B has better metabolic stability, a key factor for kinase inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand B has a significantly longer half-life (10.332 hours) compared to Ligand A (-0.367 hours). This is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.104) has lower P-gp efflux than Ligand B (0.044), which is slightly favorable.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.0 vs -7.8 kcal/mol), lower microsomal clearance (20.223 vs 94.011), and longer half-life (10.332 vs -0.367) are crucial advantages for an enzyme inhibitor. While the solubility and permeability are problematic, these can potentially be addressed through formulation strategies. The superior potency and pharmacokinetic properties of Ligand B make it the better choice for further development.

Output:
1
2025-04-17 13:07:58,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.435 and 340.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is better than Ligand B (69.73), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.327) is slightly low, potentially hindering permeation. Ligand B (3.464) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.59 and 0.761), indicating good drug-like properties.

**DILI:** Ligand A (9.461) has a significantly lower DILI risk than Ligand B (71.113). This is a major advantage for Ligand A.

**BBB:** Ligand A (67.584) and Ligand B (76.735) are both reasonable, but not particularly high. BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.029 and -5.165), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.299 and -4.223), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.096) has a very low hERG risk, while Ligand B (0.918) has a moderate risk. This strongly favors Ligand A.

**Microsomal Clearance:** Ligand A (-1.608) has a negative clearance, which is excellent and indicates high metabolic stability. Ligand B (46.817) has a high clearance, suggesting rapid metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.821) has a negative half-life, which is excellent and indicates very high stability. Ligand B (35.769) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux, while Ligand B (0.236) has a slightly higher efflux. This favors Ligand A.

**Binding Affinity:** Ligand B (-9.3 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 the ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG) and metabolic stability (Cl_mic, t1/2), and P-gp efflux. However, it has a lower binding affinity and a slightly low logP. Ligand B has a superior binding affinity, a good logP, but suffers from higher DILI risk, higher hERG risk, and poorer metabolic stability.

Given the enzyme-kinase target class, potency (affinity) is paramount. The 1.7 kcal/mol difference in binding affinity is substantial. While Ligand A has a better safety profile and metabolic stability, the stronger binding of Ligand B is likely to be more critical for achieving efficacy. The poor solubility and permeability of both compounds are concerning and would need to be addressed through formulation or further chemical modification, but these are addressable issues.

Output:
1
2025-04-17 13:07:58,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.889 Da) is slightly higher than Ligand B (352.391 Da), but both are acceptable.

**TPSA:** Ligand A (93.45) is better than Ligand B (133.67) as it is closer to the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.158) is optimal (1-3), while Ligand B (-1.078) is below 1, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is better than Ligand B (HBD=4, HBA=7) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.759) has a significantly better QED score than Ligand B (0.459), indicating a more drug-like profile.

**DILI:** Ligand B (53.858) has a lower DILI risk than Ligand A (68.244), which is favorable.

**BBB:** Ligand B (35.052) has a higher BBB penetration than Ligand A (17.449). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.24 and -5.308). 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 negative solubility values (-3.502 and -1.215). This is also unusual and suggests poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.291 and 0.119), which is excellent.

**Microsomal Clearance:** Ligand A (28.902) has a higher microsomal clearance than Ligand B (7.906), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-24.933) has a negative half-life, which is not physically possible. This is a significant red flag. Ligand A (36.495) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.172 and 0.005).

**Binding Affinity:** Both ligands have similar strong binding affinities (-8.6 and -8.4 kcal/mol). The difference is less than 1.5 kcal/mol, so this doesn't strongly favor either ligand.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate despite its slightly higher DILI risk. Ligand B has a nonsensical negative in vitro half-life, which is a critical flaw. Ligand A has better TPSA, logP, QED, and a reasonable half-life. While both have poor Caco-2 and solubility, these are areas for optimization and are less critical than the half-life issue with Ligand B.

Output:
0
2025-04-17 13:07:58,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.395 and 347.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.54) is slightly above the optimal <140, but acceptable. Ligand B (93.18) is excellent, well below 140.

**logP:** Ligand A (-1.295) is a bit low, potentially hindering permeability. Ligand B (0.657) 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:** Ligand A (5) is acceptable. Ligand B (8) is also within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.565 and 0.657), indicating drug-likeness.

**DILI:** Ligand A (49.321) has a slightly higher DILI risk than Ligand B (36.448), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (66.576) has a higher BBB percentile than Ligand A (42.032), but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.216 and -5.359), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.746 and -0.3), also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.19 and 0.085), which is excellent.

**Microsomal Clearance:** Ligand A (-13.716) has a much *lower* (better) microsomal clearance than Ligand B (13.882), indicating greater metabolic stability. This is a key advantage.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (3.621 and 3.819 hours), which are moderate.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.025), which is favorable.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.9 and -8.6 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Despite both ligands having good binding affinity and low hERG risk, Ligand A is the more promising candidate. Its significantly lower microsomal clearance (higher metabolic stability) is a crucial advantage for an enzyme target. While both have concerningly low Caco-2 permeability and solubility, the metabolic stability of Ligand A makes it more likely to achieve adequate *in vivo* exposure. The slightly lower logP of Ligand A is a minor drawback compared to the metabolic benefit.

Output:
1
2025-04-17 13:07:58,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.821 Da) is slightly lower, which could be advantageous for permeability. Ligand B (423.786 Da) is still acceptable.

**TPSA:** Ligand A (110.53) is better than Ligand B (33.95). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.542) is within the optimal range (1-3). Ligand B (4.506) is slightly high, potentially leading to solubility issues and off-target interactions.

**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 similar QED values (0.637 and 0.641), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.917, which is moderately high. Ligand B has a significantly lower DILI risk (27.608), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (88.057) has a higher BBB value than Ligand A (61.613), but this is less important in this case.

**Caco-2 Permeability:** Ligand A (-4.842) has a negative value, which is concerning. Ligand B (-5.299) is also negative, but the values are similar.

**Aqueous Solubility:** Ligand A (-2.999) has very poor solubility. Ligand B (-4.573) also has poor solubility, but is slightly better.

**hERG Inhibition:** Ligand A (0.101) has a very low hERG risk, which is excellent. Ligand B (0.652) has a higher hERG risk, which is a concern.

**Microsomal Clearance:** Ligand A (61.545) has a moderate clearance, indicating moderate metabolic stability. Ligand B (30.858) has a significantly lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.983) has a negative half-life, which is not possible. This is a red flag. Ligand B (32.889) has a good half-life.

**P-gp Efflux:** Ligand A (0.088) has low P-gp efflux, which is good. Ligand B (0.693) has higher P-gp efflux, which could reduce bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly 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.

**Conclusion:**

Despite Ligand B having a higher logP, the significantly better binding affinity (-8.7 vs -7.6 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic and a positive half-life) make it the more promising candidate. The solubility of both is poor, but can be addressed with formulation strategies. The negative half-life of Ligand A is a critical flaw.

Output:
1
2025-04-17 13:07:58,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 Da and 371.493 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.21) is better than Ligand B (40.54), being below the 140 threshold, suggesting good absorption.

**logP:** Ligand A (2.204) is optimal (1-3), while Ligand B (4.516) is slightly higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.716 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (23.885) has a significantly lower DILI risk than Ligand B (14.385), which is a crucial advantage.

**BBB:** Ligand A (72.974) has a good BBB penetration, while Ligand B (92.943) is even better. However, as SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.487 and -4.569), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.108 and -4.043), indicating poor solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.432) has a lower hERG risk than Ligand B (0.746), which is preferable.

**Microsomal Clearance:** Ligand A (49.77) has a lower microsomal clearance than Ligand B (55.042), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.212) has a negative half-life, which is concerning. Ligand B (7.789) has a much better half-life.

**P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux than Ligand B (0.414), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.8 kcal/mol and -8.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is slightly better. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. While both have poor solubility and permeability, the lower DILI and better metabolic profile of Ligand A are more critical for an enzyme target. The slightly better half-life of Ligand B is not enough to overcome the other advantages of Ligand A.

Output:
0
2025-04-17 13:07:58,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.491 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly higher than Ligand B (76.02), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.113) is a bit low, potentially hindering permeation. Ligand B (2.029) is within the optimal 1-3 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 below the 10 limit.

**QED:** Both ligands have good QED scores (0.679 and 0.756), indicating drug-like properties.

**DILI:** Ligand A (40.287) is slightly higher than Ligand B (24.506), but both are below the concerning threshold of 60, suggesting acceptable liver injury risk.

**BBB:** Both have similar BBB penetration (63.203 and 65.684), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.276 and -5.114). 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 (-1.377 and -1.904). This is also concerning and suggests poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.14 and 0.188).

**Microsomal Clearance:** Ligand A (-6.987) has *much* lower (better) microsomal clearance than Ligand B (19.797). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-21.135) has a much longer (better) in vitro half-life than Ligand B (2.388). This further supports the improved metabolic stability of Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.086).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). The difference is 1.0 kcal/mol, which is substantial.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is significantly better in terms of metabolic stability (Cl_mic and t1/2) and has a more favorable logP. The poor solubility and permeability of both are concerning, but the improved metabolic profile of Ligand A is crucial for an enzyme target like SRC kinase. A slightly weaker binding affinity can sometimes be overcome with improved pharmacokinetic properties, especially for a kinase inhibitor where prolonged target engagement is beneficial. The difference in affinity (1.0 kcal/mol) isn't so large that it completely outweighs the substantial improvements in metabolic stability.

Output:
1
2025-04-17 13:07:58,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.46 and 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (93.45). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.475) is optimal, while Ligand B (1.711) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Lower counts generally improve permeability.

**QED:** Ligand A (0.559) is good, indicating drug-likeness. Ligand B (0.341) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (21.91) has a much lower DILI risk than Ligand B (54.79). This is a significant advantage.

**BBB:** Both have relatively high BBB penetration, but Ligand A (93.91) is better than Ligand B (83.09). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.303) is better than Ligand B (-5.011). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.942) is better than Ligand B (-3.378). Higher solubility is desirable.

**hERG Inhibition:** Both ligands have similar, low hERG risk (0.749 and 0.744).

**Microsomal Clearance:** Ligand A (36.104) has lower microsomal clearance than Ligand B (46.327), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.994) has a longer in vitro half-life than Ligand B (-2.636), which is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.302 and 0.162).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a stronger binding affinity than Ligand B (-6.6 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is clearly superior to Ligand B. It has better TPSA, logP, QED, DILI risk, Caco-2 permeability, solubility, metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. While both have acceptable hERG risk and BBB penetration, the overall profile of Ligand A makes it a much more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 13:07:58,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 358.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.87) is higher than Ligand B (46.34). Both are acceptable, but Ligand B is better, potentially leading to improved cell permeability.

**logP:** Ligand A (1.58) is optimal, while Ligand B (4.822) is high. High logP can lead to solubility issues and off-target effects, making Ligand A preferable.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). A small number of HBDs is generally preferred for permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**QED:** Both ligands have similar QED values (0.788 and 0.743), indicating good drug-likeness.

**DILI:** Ligand A (9.228) has a significantly lower DILI risk than Ligand B (37.069). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (78.48 and 80.031), but this is less critical for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the value for Ligand A (-4.565) is less negative than Ligand B (-4.897), suggesting slightly better permeability.

**Aqueous Solubility:** Ligand A (-2.177) has better solubility than Ligand B (-4.748). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.393 and 0.557).

**Microsomal Clearance:** Ligand A (31.603) has significantly lower microsomal clearance than Ligand B (75.491), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.765) has a lower in vitro half-life than Ligand B (41.091). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.774).

**Binding Affinity:** Both ligands have excellent binding affinity (-9 and -8 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Ligand A is superior due to its lower DILI risk, better solubility, lower logP, and lower microsomal clearance. While Ligand B has a better in vitro half-life, the other advantages of Ligand A outweigh this single benefit. The slightly better binding affinity of Ligand A also contributes to its favorability.

Output:
0
2025-04-17 13:07:58,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.364 and 351.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (130.6). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Ligand A (2.053) is optimal (1-3). Ligand B (-0.014) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=7). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Ligand A (0.896) is excellent, indicating high drug-likeness. Ligand B (0.421) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (47.964) has a lower DILI risk than Ligand B (64.366), both are acceptable, but A is better.

**BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (93.874) is higher than Ligand B (57.968).

**Caco-2 Permeability:** Ligand A (-4.628) is better than Ligand B (-5.006). Both are negative, indicating poor permeability, but A is slightly better.

**Aqueous Solubility:** Ligand A (-2.984) is better than Ligand B (-2.592). Both are poor, but A is slightly better.

**hERG:** Both ligands have very low hERG risk (0.284 and 0.118, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (7.407) has significantly lower microsomal clearance than Ligand B (13.626). Lower clearance means better metabolic stability, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-11.123) has a longer in vitro half-life than Ligand B (3.724). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.125 and 0.116, respectively).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior to Ligand B based on multiple factors crucial for kinase inhibitors. It has a better TPSA, logP, QED, DILI, solubility, metabolic stability (lower Cl_mic and longer t1/2), and Caco-2 permeability. While both have good hERG profiles and binding affinity, the ADME properties of Ligand A make it a more promising drug candidate.

Output:
1
2025-04-17 13:07:58,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.575 Da) is slightly lower, which could be beneficial for permeability. Ligand B (380.579 Da) is also good.

**TPSA:** Ligand A (32.34) is excellent, well below the 140 threshold for oral absorption. Ligand B (58.2) is still reasonable, but higher.

**logP:** Ligand A (4.9) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (3.611) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD and HBA counts. Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 4 HBA) are both within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.74, B: 0.652), indicating good drug-like properties.

**DILI:** Ligand A (13.532) has a significantly lower DILI risk than Ligand B (44.591). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 79.992, B: 70.997), but this is less critical for a kinase inhibitor unless CNS exposure is specifically desired.

**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 very close.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both, but the values are very close.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.895, B: 0.61), which is positive.

**Microsomal Clearance:** Ligand A (62.387) has lower microsomal clearance than Ligand B (79.676), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand B (24.349) has a significantly longer half-life than Ligand A (8.915). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.433, B: 0.513).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While a 0.6 kcal/mol difference is noticeable, it may not be enough to overcome the ADME liabilities of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While its logP is slightly high, it has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The binding affinity difference is relatively small. The poor Caco-2 and solubility values are a concern for both, but can be addressed with formulation strategies. The lower DILI and better metabolic stability of Ligand A are more critical for an enzyme inhibitor.

Output:
0
2025-04-17 13:07:58,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.864 Da) is slightly higher than Ligand B (342.527 Da), but both are acceptable.

**TPSA:** Ligand A (55.4) is higher than Ligand B (23.55). While both are reasonably low, Ligand B's TPSA is significantly better, potentially aiding absorption.

**logP:** Both ligands have good logP values (A: 4.04, B: 4.183), 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 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (A: 0.797, B: 0.742), indicating good drug-likeness.

**DILI:** Ligand B (5.118) has a much lower DILI risk than Ligand A (46.258), a significant advantage.

**BBB:** Both have good BBB penetration, but Ligand B (92.555) is slightly better than Ligand A (83.172). This isn't a major concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.267) is slightly worse than Ligand B (-4.7).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.935) is slightly better than Ligand B (-3.622).

**hERG Inhibition:** Ligand A (0.46) has a slightly lower hERG risk than Ligand B (0.938), which is preferable.

**Microsomal Clearance:** Ligand B (79.487) has a lower microsomal clearance than Ligand A (114.945), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-7.321) has a significantly longer in vitro half-life than Ligand A (15.632). This is another crucial advantage for an enzyme target.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.467, B: 0.448).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 0.3 kcal/mol difference, while present, is unlikely to overcome 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 ADME properties, particularly in DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and slightly better Caco-2 permeability. These factors are more critical for an enzyme inhibitor like an SRC kinase inhibitor than a small advantage in binding affinity. The lower DILI risk is a significant safety advantage.

Output:
1
2025-04-17 13:07:58,152 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.5) is slightly higher than Ligand B (344.4).

**TPSA:** Ligand A (63.7) is well below the 140 threshold for oral absorption. Ligand B (127.2) is still acceptable, but less ideal.

**logP:** Both ligands have good logP values (A: 2.85, B: 1.14), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is more favorable than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both have acceptable QED scores (A: 0.73, B: 0.55), indicating good drug-like properties.

**DILI:** Ligand A (39.2) has a significantly lower DILI risk than Ligand B (75.4). This is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.7) shows better potential for BBB penetration than Ligand B (46.2).

**Caco-2 Permeability:** Ligand A (-4.52) shows better Caco-2 permeability than Ligand B (-5.15).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.34 and -4.12 respectively). This is a significant concern for both, but may be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.75) has a lower hERG risk than Ligand B (0.19), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (108.3) has higher microsomal clearance than Ligand B (42.2), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-31.6) has a longer in vitro half-life than Ligand A (-48.9), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.31, B: 0.05).

**Binding Affinity:** Ligand B (-9.5 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 has a significantly stronger binding affinity, and better metabolic stability (lower Cl_mic, longer t1/2). However, it has a substantially higher DILI risk and a lower hERG safety profile. Ligand A has a much better safety profile (DILI and hERG) and better permeability, but weaker binding affinity and lower metabolic stability.

Given the enzyme-specific priorities, the stronger binding affinity of Ligand B is a crucial factor. While the DILI and hERG risks are concerning, they might be addressed through further structural modifications during optimization. The difference in binding affinity (-9.5 vs -7.9) is substantial and likely outweighs the ADME drawbacks, *especially* considering that ADME properties can be improved through iterative design. The solubility issues are present in both, and would need to be addressed regardless.

Output:
1
2025-04-17 13:07:58,152 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.491 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (101.47) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.55 and 1.572), falling within the optimal 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 acceptable QED scores (0.651 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (49.67). This is a major advantage.

**BBB:** Both ligands have good BBB penetration (70.803 and 72.664), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.105 and -5.129). This is unusual and suggests poor permeability. However, these values are on a log scale and close to zero, so the actual permeability may not be drastically low.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.761 and -1.233), indicating poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.322 and 0.279). This is excellent.

**Microsomal Clearance:** Ligand A (37.168) has higher microsomal clearance than Ligand B (17.562). This means Ligand B is more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-17.044) has a longer in vitro half-life than Ligand A (-13.19). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.109).

**Binding Affinity:** Both ligands have comparable binding affinity (-9.0 and -9.7 kcal/mol), both being excellent. The difference of 0.7 kcal/mol is unlikely to outweigh other factors.

**Conclusion:**

While both ligands have good binding affinity and low hERG risk, Ligand B is preferable due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. Although both have poor solubility and permeability, metabolic stability is more critical for an enzyme target.

Output:
1
2025-04-17 13:07:58,152 - INFO - Batch 188 complete. Total preferences: 3008
2025-04-17 13:07:58,152 - INFO - Processing batch 189/512...
2025-04-17 13:08:40,100 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (339.355 and 341.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (111.61 and 111.38) below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have logP values (1.024 and 1.247) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is slightly better than Ligand B (4 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.671) has a significantly higher QED score than Ligand B (0.445), indicating a more drug-like profile.

**DILI:** Ligand B (70.841) has a lower DILI risk than Ligand A (85.964), which is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration (62.117 and 51.377), which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.309 and -5.437), which is unusual and suggests poor intestinal absorption. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.331 and -2.806), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.304) has a lower hERG inhibition liability than Ligand B (0.555), which is favorable.

**Microsomal Clearance:** Ligand A (50.693 mL/min/kg) has a higher microsomal clearance than Ligand B (25.903 mL/min/kg), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (2.747 hours) has a slightly longer in vitro half-life than Ligand A (25.18 hours), which is a minor advantage.

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux liability than Ligand B (0.092), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.7 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:**

Ligand A has a better QED score, lower hERG risk, and lower P-gp efflux. However, it has significantly higher DILI risk and lower metabolic stability (higher Cl_mic). Ligand B has a lower DILI risk, better metabolic stability, and slightly better binding affinity. Both ligands suffer from very poor predicted solubility and permeability.

Given the importance of metabolic stability and lower toxicity (DILI) for kinase inhibitors, and the small advantage in binding affinity for Ligand B, **Ligand B is the more promising candidate**, despite the slightly lower QED. The solubility and permeability issues would need to be addressed through formulation or structural modifications.

Output:
1
2025-04-17 13:08:40,100 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.304 Da) is higher, but still acceptable. Ligand B (343.475 Da) is slightly preferred.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (61.36) is lower than Ligand A (76.57), giving it a slight advantage.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.289) and Ligand B (1.918) are comparable.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD and HBA counts, within the acceptable limits. Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. This is not a significant differentiating factor.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-likeness. Ligand B (0.885) is slightly better than Ligand A (0.735).

**DILI:** Ligand B (31.718) has a significantly lower DILI risk than Ligand A (84.296). This is a major advantage for Ligand B.

**BBB:** Ligand B (91.508) has a higher BBB penetration score than Ligand A (67.003). While SRC is not a CNS target, higher BBB generally correlates with better overall permeability.

**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 (-5.011) is slightly worse than Ligand B (-4.836).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.899) is slightly worse than Ligand B (-2.337).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.361 and 0.666 respectively), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand B (59.434) has a significantly lower microsomal clearance than Ligand A (7.693), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (23.392 hours) has a longer in vitro half-life than Ligand A (49.97 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.285 and 0.041 respectively). Ligand B is better.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This is a 0.2 kcal/mol difference, which is not substantial enough to outweigh the significant ADME advantages of Ligand B.

**Overall:** Considering the enzyme-specific priorities, Ligand B is the better candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and slightly better BBB penetration, all while maintaining comparable binding affinity to Ligand A. The slight difference in binding affinity is outweighed by the superior ADME profile of Ligand B.

Output:
1
2025-04-17 13:08:40,100 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (353.463 Da and 360.361 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (89.95 and 85.69) below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have similar logP values (0.369 and 0.35), which are a bit low. While not ideal, they aren't excessively low and could be compensated for by other properties.

**4. H-Bond Donors:** Ligand A (2) has a slightly higher HBD count than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) has fewer HBAs than Ligand B (6), which is preferable. Higher HBA can sometimes reduce permeability.

**6. QED:** Both ligands have good QED scores (0.747 and 0.791), indicating a generally drug-like profile.

**7. DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (60.062). This is a major advantage for Ligand A. A DILI percentile above 60 is concerning.

**8. BBB:** Ligand B (84.141) shows better BBB penetration than Ligand A (53.781), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.934 and -4.824), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.227 and -1.263) which is also unusual and suggests very poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.101 and 0.192).

**12. Microsomal Clearance:** Ligand A (-5.845) has a much lower (better) microsomal clearance than Ligand B (5.051), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.178) has a much longer in vitro half-life than Ligand B (21.166), again indicating greater stability.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.062).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly stronger binding affinity than Ligand A (-7.3), a difference of 0.6 kcal/mol.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B has a slightly better affinity, but Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and has a *much* lower DILI risk. The poor solubility and permeability are concerning for both, but the DILI risk for Ligand B is a significant red flag. The slightly better affinity of Ligand B is unlikely to outweigh the substantial advantages of Ligand A in terms of safety and metabolic stability.

Output:
0
2025-04-17 13:08:40,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (385.873 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.74 and 80.76) are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (0.424) is slightly low, potentially hindering permeation. Ligand B (1.083) is within the optimal 1-3 range.

**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 and 6, respectively), well below the threshold of 10.

**QED:** Both ligands have good QED scores (0.666 and 0.814), indicating drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (39.744 and 41.877), below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (55.874 and 56.34), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.275 and -4.978), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.625 and -2.421), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.126 and 0.419), which is positive.

**Microsomal Clearance:** Ligand A (0.262) has significantly lower microsomal clearance than Ligand B (25.337), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (12.358) has a better in vitro half-life than Ligand B (18.713).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.043).

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.3 kcal/mol). This difference of 3 kcal/mol is highly significant and can outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and aqueous solubility for both, Ligand A is the more promising candidate. The significantly stronger binding affinity (-10.3 vs -7.3 kcal/mol) and superior metabolic stability (lower Cl_mic and better half-life) outweigh the slightly lower logP. The similar DILI and hERG profiles are also favorable. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The potency advantage of Ligand A is critical for an enzyme inhibitor.

Output:
0
2025-04-17 13:08:40,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.291 Da) is slightly higher than Ligand B (358.439 Da), but both are acceptable.

**TPSA:** Ligand A (64.63) is well below the 140 threshold for oral absorption. Ligand B (109) is also below the threshold, but closer to it.

**logP:** Ligand A (3.783) is within the optimal range (1-3). Ligand B (-0.678) is significantly below this, which could hinder membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.754, Ligand B: 0.506), indicating good drug-like properties.

**DILI:** Ligand A (51.687) has a moderate DILI risk, while Ligand B (19.271) has a very low DILI risk, which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 64.366, Ligand B: 69.523). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.313) has poor Caco-2 permeability, while Ligand B (-5.155) is also poor.

**Aqueous Solubility:** Ligand A (-4.858) has poor aqueous solubility, while Ligand B (-0.361) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.253) has a very low hERG risk, which is excellent. Ligand B (0.091) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (96.681) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-2.97) has negative clearance, which is very good.

**In vitro Half-Life:** Ligand A (8.974) has a short half-life, consistent with the high clearance. Ligand B (-1.363) has a negative half-life, which is very good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.109, Ligand B: 0.001).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -7.6 kcal/mol, Ligand B: -7.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Conclusion:**

While both ligands have good binding affinity and low hERG risk, Ligand B is significantly better due to its much lower DILI risk, superior metabolic stability (negative clearance and half-life), and slightly better solubility. Ligand A's high clearance and poor Caco-2 permeability are major drawbacks. The lower logP of Ligand B is a concern, but the other advantages outweigh this.

Output:
1
2025-04-17 13:08:40,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.411 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is better than Ligand B (71.53), both are below the 140 threshold for good absorption.

**logP:** Both ligands (1.589 and 1.916) are within the optimal 1-3 range.

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

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

**QED:** Both ligands have acceptable QED scores (0.778 and 0.679), indicating good drug-likeness.

**DILI:** Ligand B (27.259) has a significantly lower DILI risk than Ligand A (34.393), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (86.002 and 80.264), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.353) is slightly better than Ligand B (-4.912), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.211 and -2.245). This is a significant concern for both, but might be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.368 and 0.431).

**Microsomal Clearance:** Ligand A (30.946) has a lower microsomal clearance than Ligand B (44.006), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.692) has a longer in vitro half-life than Ligand B (10.355), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.058).

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is small (0.2 kcal/mol) and may not be enough to overcome other drawbacks.

**Overall:**

Ligand A has better permeability (Caco-2), metabolic stability (Cl_mic, t1/2), fewer H-bonds, and a slightly better binding affinity. However, Ligand B has a significantly lower DILI risk, which is critical. Given the enzyme-specific priorities, metabolic stability and DILI are key. While the affinity difference is small, the lower DILI risk of Ligand B is more important.

Output:
1
2025-04-17 13:08:40,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (367.515 and 353.482 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (43.86). Both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have acceptable logP values (1.006 and 2.057), falling within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable range (Ligand A: 2, Ligand B: 0).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable range (Ligand A: 4, Ligand B: 3).

**6. QED:** Both ligands have good QED scores (0.711 and 0.777), indicating drug-like properties.

**7. DILI:** Ligand A (31.02) has a significantly lower DILI risk than Ligand B (5.894), suggesting better hepatotoxicity potential.

**8. BBB:** Ligand B (96.355) has a much higher BBB penetration percentile than Ligand A (62.233). However, SRC is not a CNS target, so this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.245) is worse than Ligand B (-4.573), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.371) is worse than Ligand B (-1.337), indicating lower solubility.

**11. hERG Inhibition:** Ligand A (0.182) has a lower hERG inhibition liability than Ligand B (0.588), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (31.064) has a higher microsomal clearance than Ligand B (4.756), indicating lower metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (7.15) has a slightly longer half-life than Ligand A (6.156).

**14. P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.038), which is preferable.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). The difference is 0.8 kcal/mol, which is significant.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. Ligand B has a better affinity and half-life. However, Ligand A has a much better DILI score and hERG risk profile, and lower P-gp efflux. The higher Cl_mic for Ligand A is a concern, but the superior safety profile and slightly better TPSA make it a more promising candidate. The affinity difference is not large enough to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 13:08:40,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.475 and 352.519 Da) fall comfortably within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.68) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.43) is still acceptable but less optimal.

**logP:** Both ligands (3.949 and 3.193) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of hydrogen bond donors and acceptors, contributing to drug-likeness.

**QED:** Ligand A (0.823) has a higher QED score than Ligand B (0.659), indicating a more drug-like profile.

**DILI:** Ligand A (31.214) has a significantly lower DILI risk than Ligand B (19.426), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (70.919 and 75.378), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.048) has a worse Caco-2 permeability than Ligand B (-4.486).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.93 and -3.709). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.751) exhibits a slightly higher hERG inhibition risk than Ligand B (0.192). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (41.226) has a lower microsomal clearance than Ligand B (68.48), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (52.487) has a much longer in vitro half-life than Ligand B (4.851), a substantial benefit.

**P-gp Efflux:** Ligand A (0.565) has lower P-gp efflux than Ligand B (0.056), indicating better bioavailability.

**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 factor, as a 1.9 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A excels in binding affinity, metabolic stability (lower Cl_mic, longer t1/2), DILI risk, QED, and P-gp efflux. While its Caco-2 permeability and hERG risk are slightly less favorable than Ligand B, the substantial advantage in binding affinity and the lower DILI risk outweigh these drawbacks. The improved metabolic stability and longer half-life are also critical for an enzyme inhibitor. Solubility is a concern for both, but can be addressed.

Output:
1
2025-04-17 13:08:40,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.427 and 335.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (64.74 and 62.97) well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.354) is optimal, while Ligand B (1.375) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, fitting the guidelines. Ligand B has 0 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.776 and 0.702), indicating drug-like properties.

**DILI:** Ligand A (55.68) has a slightly higher DILI risk than Ligand B (42.846), but both are still reasonably low.

**BBB:** This isn't a primary concern for a non-CNS target like SRC kinase, but Ligand B (64.676) shows slightly better BBB penetration than Ligand A (58.782).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are logP values, Ligand A (-4.937) is worse than Ligand B (-5.032).

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual. Ligand A (-2.837) is better than Ligand B (-1.25).

**hERG:** Both ligands have low hERG inhibition liability (0.745 and 0.711), which is excellent.

**Microsomal Clearance:** Ligand A (37.713) has a significantly better (lower) microsomal clearance than Ligand B (11.224), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.3 hours) has a much longer half-life than Ligand B (-39.054 hours). The negative value for Ligand B is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.378 and 0.029).

**Binding Affinity:** Ligand A (-7.0 kcal/mol) has a stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage, as a 7 kcal/mol difference is substantial.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has slightly better solubility and a slightly lower DILI risk, Ligand A's significantly stronger binding affinity (-7.0 vs 0.0 kcal/mol), better metabolic stability (lower Cl_mic, longer t1/2), and acceptable ADME properties outweigh the minor drawbacks. The negative Caco-2 and solubility values are concerning for both, but the much stronger binding affinity of Ligand A makes it the better choice for further optimization.

Output:
1
2025-04-17 13:08:40,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.371 and 369.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (98.07 and 100.35) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (which requires <90).

**logP:** Ligand A (0.285) is borderline low, potentially hindering permeation. Ligand B (0.173) is even lower, raising more concerns about permeability.

**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:** Both ligands have good QED scores (0.71 and 0.753), indicating generally drug-like properties.

**DILI:** Ligand A (57.348) has a better DILI score than Ligand B (65.491), indicating lower potential for liver injury. Both are acceptable, but A is preferable.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**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 unusual and indicates very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.02) shows very low hERG inhibition risk, a significant advantage. Ligand B (0.506) has a higher, though still relatively low, risk.

**Microsomal Clearance:** Ligand A (-0.835) has much lower (better) microsomal clearance than Ligand B (26.902), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.714 hours) has a better in vitro half-life than Ligand B (-21.703 hours). The negative value for B is highly concerning.

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is favorable. Ligand B (0.087) is slightly higher but still relatively low.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-9.0 kcal/mol). While both are excellent, the difference is not substantial enough to override other significant issues.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. The key advantages of Ligand A are its lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), very low hERG risk, and lower P-gp efflux. While both ligands have poor solubility and permeability, the metabolic stability and safety profile of Ligand A make it the more promising candidate. The slightly better affinity of A is a bonus.

Output:
0
2025-04-17 13:08:40,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (359.367 and 382.595 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (39.5 and 41.57) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.892 and 3.694) are 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 (4 and 5) are below the 10 threshold.

**6. QED:** Both ligands (0.702 and 0.696) are above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (15.898) has a significantly lower DILI risk than Ligand B (23.032). This is a major advantage.

**8. BBB:** Both have high BBB penetration, but Ligand A (93.292) is higher than Ligand B (80.884). While not a primary concern for a kinase inhibitor, it's a slight benefit.

**9. Caco-2 Permeability:** Ligand A (-4.287) has better Caco-2 permeability than Ligand B (-5.37).

**10. Aqueous Solubility:** Ligand A (-2.37) has better aqueous solubility than Ligand B (-3.984). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands (0.981 and 0.872) have low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (12.756) has much lower microsomal clearance than Ligand B (75.674), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-10.696) has a significantly longer in vitro half-life than Ligand B (32.054). This is another key advantage for dosing considerations.

**14. P-gp Efflux:** Both ligands (0.247 and 0.647) have low P-gp efflux liability.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) and Ligand B (-8.1 kcal/mol) both have good binding affinity. Ligand A is slightly better.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is clearly superior. It has a lower DILI risk, better solubility, significantly lower microsomal clearance (better metabolic stability), and a longer half-life. While both have good affinity, Ligand A's ADME properties are substantially more favorable. The slight advantage in binding affinity of Ligand A further solidifies its position as the better candidate.

Output:
0
2025-04-17 13:08:40,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.366 and 361.486 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.52) is higher than Ligand B (46.09). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (2.537) and Ligand B (3.946) are both within the optimal 1-3 range, but Ligand B is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are acceptable, but Ligand B's lower HBD count might slightly favor permeability.

**QED:** Both ligands have good QED scores (0.577 and 0.783), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (69.562) has a higher DILI risk than Ligand B (36.293). This is a significant advantage for Ligand B.

**BBB:** Ligand A (37.069) has a low BBB penetration, while Ligand B (88.019) has a high BBB penetration. Since SRC is not a CNS target, this is less important, but a higher value is generally preferable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.879 and -4.685), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.143 and -3.465), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Ligand A (0.338) has a slightly lower hERG risk than Ligand B (0.568), which is favorable.

**Microsomal Clearance:** Ligand A (36.256) has a lower microsomal clearance than Ligand B (48.999), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-10.024) has a negative half-life, which is not possible. Ligand B (6.142) has a reasonable half-life. This is a significant issue for Ligand A.

**P-gp Efflux:** Ligand A (0.367) has lower P-gp efflux than Ligand B (0.291), which is favorable.

**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 concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a slightly higher logP and hERG risk, its significantly improved binding affinity (-8.4 vs -7.5 kcal/mol) and much lower DILI risk are major advantages. The better BBB penetration is a bonus, even though SRC is not a CNS target. Ligand A has a concerning negative in vitro half-life, which is a critical flaw. The lower clearance is good, but the negative half-life overrides that benefit.

Output:
1
2025-04-17 13:08:40,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.391 and 358.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.03) is slightly above the preferred <140 for good absorption, while Ligand B (79.54) is well within the range.

**logP:** Ligand A (0.048) is quite low, potentially hindering permeation. Ligand B (1.222) is 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 (7) is acceptable. Ligand B (6) is also good.

**QED:** Both ligands have good QED scores (0.635 and 0.768, respectively), indicating drug-like properties.

**DILI:** Ligand A (49.438) has a lower DILI risk than Ligand B (74.874). Both are acceptable, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (54.246) has a higher BBB score than Ligand A (17.332), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.416 and -4.659), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.965 and -2.529), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.045) has a very low hERG risk, which is excellent. Ligand B (0.124) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (2.668 mL/min/kg) has significantly lower microsomal clearance than Ligand B (50.852 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.191 hours) has a very short half-life, while Ligand B (-46.644 hours) has a negative half-life, which is not possible. This suggests a potential issue with the data for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.006 and 0.205, respectively).

**Binding Affinity:** Ligand B (-7.6 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 concerns with Ligand B.

**Overall Assessment:**

Ligand A has a better overall profile despite the poor Caco-2 and solubility. Its lower logP, better metabolic stability (lower Cl_mic, longer t1/2), and significantly lower hERG risk are crucial advantages for an enzyme inhibitor. Ligand B's slightly better affinity is overshadowed by its poor metabolic stability, questionable half-life, and higher DILI risk. The negative solubility and Caco-2 values for both are concerning and would require significant medicinal chemistry effort to address, but Ligand A appears to be a more promising starting point.

Output:
0
2025-04-17 13:08:40,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.37 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is well below the 140 threshold, while Ligand B (83.92) is still acceptable but higher.

**logP:** Ligand A (3.358) is optimal, while Ligand B (1.011) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.819 and 0.853).

**DILI:** Ligand A (75.766) has a higher DILI risk than Ligand B (38.426). This is a concern for Ligand A.

**BBB:** Both have similar BBB penetration (64.986 and 60.876), not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both.

**Solubility:** Ligand A (-4.367) has very poor solubility, while Ligand B (-1.641) is better, though still not ideal.

**hERG:** Ligand A (0.723) has a slightly higher hERG risk than Ligand B (0.166).

**Microsomal Clearance:** Ligand B (-18.868) shows significantly better metabolic stability (lower clearance) than Ligand A (62.635). This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (25.872) has a longer half-life than Ligand A (15.486).

**P-gp Efflux:** Ligand A (0.243) has lower P-gp efflux than Ligand B (0.014), which is favorable.

**Binding Affinity:** Ligand A (-7.8) has slightly better binding affinity than Ligand B (-8.0). However, the difference is small and may not outweigh other factors.

**Overall:**

Ligand B is the more promising candidate. While both have poor Caco-2 permeability, Ligand B excels in metabolic stability (Cl_mic and t1/2), has a lower DILI risk, better solubility, and lower hERG risk. The slightly weaker binding affinity of Ligand B is less concerning given its superior ADME properties. The poor solubility of Ligand A is a significant hurdle.

Output:
1
2025-04-17 13:08:40,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.471 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (67.43), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.071) is within the optimal 1-3 range, while Ligand B (3.173) is at the higher end, potentially causing solubility issues.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**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 QED values above 0.5 (0.719 and 0.659), indicating good drug-likeness.

**DILI:** Ligand A (25.087) has a significantly lower DILI risk than Ligand B (15.2). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (65.878 and 71.656), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.351) has a negative Caco-2 value which is concerning. Ligand B (-4.53) is also negative but less so.

**Aqueous Solubility:** Ligand A (-1.994) has better solubility than Ligand B (-3.128).

**hERG:** Ligand A (0.099) has a significantly lower hERG risk than Ligand B (0.483). This is a critical advantage.

**Microsomal Clearance:** Ligand B (65.321) has a much higher microsomal clearance than Ligand A (5.542), indicating poorer metabolic stability.

**In vitro Half-Life:** Ligand A (7.319) has a better in vitro half-life than Ligand B (-19.506).

**P-gp Efflux:** Ligand A (0.017) has lower P-gp efflux liability than Ligand B (0.212).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold that would strongly favor Ligand B despite other drawbacks.

**Overall Assessment:**

Ligand A demonstrates a superior ADMET profile, with lower DILI and hERG risk, better solubility, better metabolic stability (lower Cl_mic and higher t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity, the ADMET advantages of Ligand A are more critical for overall drug development success, particularly given the enzyme-kinase target class. The negative Caco-2 values are concerning for both, but Ligand A is still better.

Output:
1
2025-04-17 13:08:40,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Ligand A:**
*   **MW:** 362.411 Da - Good, within the ideal range.
*   **TPSA:** 108.47 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 0.791 - Low, potentially hindering permeation.
*   **HBD:** 2 - Good.
*   **HBA:** 7 - Good.
*   **QED:** 0.754 - Excellent, highly drug-like.
*   **DILI:** 74.68 - High risk of liver injury.
*   **BBB:** 57.968 - Low, not a concern for a non-CNS target like SRC.
*   **Caco-2:** -5.363 - Very poor permeability.
*   **Solubility:** -3.703 - Very poor solubility.
*   **hERG:** 0.062 - Very low risk of hERG inhibition.
*   **Cl_mic:** 29.36 mL/min/kg - Moderate clearance, suggesting moderate metabolic stability.
*   **t1/2:** -4.918 hours - Short half-life.
*   **Pgp:** 0.238 - Low efflux, favorable.
*   **Affinity:** -9.2 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 412.324 Da - Good, within the ideal range.
*   **TPSA:** 64.63 - Excellent, promotes good absorption.
*   **logP:** 3.628 - Slightly high, could lead to solubility issues, but manageable.
*   **HBD:** 1 - Good.
*   **HBA:** 4 - Good.
*   **QED:** 0.695 - Good, drug-like.
*   **DILI:** 37.03 - Low risk of liver injury.
*   **BBB:** 73.672 - Not a primary concern for SRC.
*   **Caco-2:** -4.534 - Poor permeability.
*   **Solubility:** -4.222 - Poor solubility.
*   **hERG:** 0.387 - Low risk of hERG inhibition.
*   **Cl_mic:** 110.867 mL/min/kg - High clearance, poor metabolic stability.
*   **t1/2:** 6.949 hours - Moderate half-life.
*   **Pgp:** 0.39 - Low efflux, favorable.
*   **Affinity:** -7.1 kcal/mol - Good binding affinity.

**Comparison and Decision:**

Ligand A has significantly better binding affinity (-9.2 kcal/mol vs -7.1 kcal/mol). This is a substantial advantage for an enzyme target like SRC. However, Ligand A suffers from very poor solubility and permeability, and a high DILI risk. Ligand B has better solubility and permeability, lower DILI risk, but weaker binding affinity and poor metabolic stability.

Despite the superior affinity of Ligand A, its poor ADME properties, particularly solubility and permeability, are major drawbacks. A kinase inhibitor needs to reach its target in sufficient concentration to be effective. The poor solubility and permeability of Ligand A would likely limit its bioavailability. The high DILI risk is also concerning. Ligand B, while having weaker affinity, has a more balanced profile with better solubility, permeability, and a lower DILI risk. The metabolic instability of Ligand B could be addressed with structural modifications, but the poor ADME of Ligand A would be more challenging to fix.

Therefore, considering the enzyme-specific priorities and the overall balance of properties, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 13:08:40,102 - INFO - Batch 189 complete. Total preferences: 3024
2025-04-17 13:08:40,103 - INFO - Processing batch 190/512...
2025-04-17 13:09:22,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.789 Da and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.48) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable due to the lower TPSA.

**logP:** Both ligands have good logP values (2.479 and 2.083), 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 3. Ligand B is preferable here, as fewer HBA generally improves permeability.

**QED:** Both ligands have acceptable QED scores (0.869 and 0.722), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (82.396%) compared to Ligand B (13.067%). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (65.529%) is slightly better than Ligand B (47.15%).

**Caco-2 Permeability:** Ligand A (-4.867) has worse Caco-2 permeability than Ligand B (-4.623).

**Aqueous Solubility:** Ligand A (-4.108) has worse aqueous solubility than Ligand B (-2.829). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG risk (0.261 and 0.141), which is good.

**Microsomal Clearance:** Ligand A (28.3 mL/min/kg) has higher microsomal clearance than Ligand B (22.693 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.587 hours) has a significantly longer in vitro half-life than Ligand A (43.014 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.169) has slightly higher P-gp efflux than Ligand B (0.032).

**Binding Affinity:** Ligand B (-8.7 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:**

Ligand B is significantly better overall. It has a much lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While Ligand A has slightly better BBB penetration and Caco-2 permeability, the safety and PK advantages of Ligand B outweigh these minor differences.

Output:
1
2025-04-17 13:09:22,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.463 and 373.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.99) is significantly better than Ligand B (108.29). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal range for permeability.

**logP:** Ligand A (3.105) is optimal, while Ligand B (1.554) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED scores (0.765 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A (79.604) has a higher DILI risk than Ligand B (44.436). This is a concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (50.407) is slightly better than Ligand B (38.542).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.169 and -5.114), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.207 and -3.414), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.613) shows a slightly higher hERG risk than Ligand B (0.468), but both are relatively low.

**Microsomal Clearance:** Ligand A (42.825) has a slightly better (lower) microsomal clearance than Ligand B (40.251), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-27.065) has a significantly longer in vitro half-life than Ligand A (-11.543). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.377) has lower P-gp efflux than Ligand B (0.026), which is favorable.

**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 many other drawbacks.

**Conclusion:**

Despite Ligand A's better TPSA, logP, and lower P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.0 vs -8.4 kcal/mol) is the most important factor for an enzyme inhibitor. Furthermore, Ligand B has a much longer in vitro half-life and a lower DILI risk. The poor solubility and permeability are concerns for both, but the potency and stability advantages of Ligand B are more critical for initial optimization.

Output:
1
2025-04-17 13:09:22,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.45 and 342.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (69.64) is still under 140, but less optimal than A.

**3. logP:** Both ligands (1.516 and 2.073) are 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:** Both ligands (3) are well below the 10 threshold.

**6. QED:** Both ligands (0.74 and 0.614) have good drug-likeness scores, exceeding 0.5.

**7. DILI:** Ligand A (12.369) has a significantly lower DILI risk than Ligand B (41.45). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (97.014) has better BBB penetration than Ligand B (40.558), but this is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative values (-4.881 and -4.81), which is unusual and requires further investigation. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have negative values (-1.943 and -2.342), indicating poor aqueous solubility. This is a potential issue for both, but needs to be addressed during formulation.

**11. hERG Inhibition:** Ligand A (0.63) has a lower hERG risk than Ligand B (0.351), which is favorable.

**12. Microsomal Clearance:** Ligand A (6.337) has significantly lower microsomal clearance than Ligand B (18.591), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (0.944) has a shorter half-life than Ligand B (4.302), but still acceptable.

**14. P-gp Efflux:** Ligand A (0.057) has lower P-gp efflux liability than Ligand B (0.196), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This 1.6 kcal/mol difference is substantial and outweighs many of the minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It demonstrates significantly better binding affinity, lower DILI risk, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While both have poor solubility, the superior potency and safety profile of Ligand A make it more likely to succeed as a drug candidate.

Output:
1
2025-04-17 13:09:22,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.443 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.38) is better than Ligand B (83.81). Both are below 140, suggesting reasonable absorption, but lower TPSA is generally preferred.

**3. logP:** Ligand A (3.236) is optimal, while Ligand B (1.312) is slightly 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 5. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.754) has a significantly better QED score than Ligand B (0.519), indicating a more drug-like profile.

**7. DILI:** Ligand B (22.8) has a much lower DILI risk than Ligand A (32.377), which is a significant advantage.

**8. BBB:** Both ligands have moderate BBB penetration (Ligand A: 57.619, Ligand B: 61.923). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.846) has poor Caco-2 permeability, while Ligand B (-5) is also poor. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-2.991) has poor aqueous solubility, while Ligand B (-1.599) is slightly better, but still poor.

**11. hERG Inhibition:** Ligand A (0.65) has a higher hERG risk than Ligand B (0.371), which is a significant concern.

**12. Microsomal Clearance:** Ligand B (-9.218) has significantly lower microsomal clearance than Ligand A (41.113), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (56.311) has a longer half-life than Ligand B (5.711).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (Ligand A: 0.165, Ligand B: 0.029).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor Caco-2 and aqueous solubility, Ligand B's significantly stronger binding affinity (-7.7 vs 0.0 kcal/mol) and dramatically improved metabolic stability (Cl_mic = -9.218 vs 41.113) outweigh the slightly lower logP and higher TPSA. The lower DILI and hERG risk are also important advantages. The longer half-life of Ligand A is less important than the other factors, and can potentially be improved with prodrug strategies.

Output:
1
2025-04-17 13:09:22,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.5 and 360.4 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.9) is better than Ligand B (81.3), both are acceptable, but lower is generally preferred for absorption.

**3. logP:** Ligand A (0.8) is slightly better than Ligand B (3.09), falling within the optimal 1-3 range. Ligand B is at the higher end, potentially leading to solubility issues.

**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:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.767 and 0.77), indicating good drug-likeness.

**7. DILI:** Ligand A (41.8) has a lower DILI risk than Ligand B (52.7), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (28.3) has a significantly lower BBB penetration than Ligand B (87.9). However, since SRC is not a CNS target, this is less important.

**9. Caco-2 Permeability:** Ligand A (-4.958) has better Caco-2 permeability than Ligand B (-4.507), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.061) has better aqueous solubility than Ligand B (-3.683), which is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.236) has a much lower hERG inhibition liability than Ligand B (0.676). This is a significant advantage for safety.

**12. Microsomal Clearance:** Ligand A (46.2) has lower microsomal clearance than Ligand B (53.7), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.4) has a longer half-life than Ligand B (-10.9), which is a positive attribute. Note the negative value for Ligand B is unusual and suggests rapid degradation.

**14. P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux liability than Ligand B (0.267), which is favorable for oral bioavailability.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.7 and -8.5 kcal/mol), which are both excellent and well below the -7.0 threshold. The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is superior to Ligand B. It demonstrates better solubility, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and lower P-gp efflux. While Ligand B has better BBB penetration, this is not a priority for a non-CNS target like SRC. The binding affinities are comparable.

Output:
0
2025-04-17 13:09:22,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 348.462 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.23) is better than Ligand B (40.62), being closer to the upper limit for good oral absorption (<=140). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (2.437 and 3.444), falling within the optimal range of 1-3. Ligand B is slightly higher, which *could* present a minor solubility issue, but is not a major concern.

**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:** Ligand A (0.709) has a better QED score than Ligand B (0.579), indicating a more drug-like profile.

**DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (44.242), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand B (85.498) has a higher BBB penetration percentile than Ligand A (70.88). However, as SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.492 and -4.349). This is unusual and suggests a potential issue with the experimental setup or a very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.766 and -3.164). This is also unusual and suggests low aqueous solubility, which could hinder bioavailability. This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.3 and 0.47), which is good.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (56.881 and 55.474 mL/min/kg). These are relatively high, suggesting moderate metabolic instability.

**In vitro Half-Life:** Ligand A (-18.388 hours) has a worse in vitro half-life than Ligand B (-23.407 hours). Both are negative, which is unusual.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.127 and 0.463).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol), both of which are excellent. The difference is negligible.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand A is slightly favored due to its better QED score, lower DILI risk, and slightly better TPSA. The binding affinity is essentially the same. The negative values for Caco-2 and solubility are concerning and would require further investigation (e.g., experimental validation, salt screening, formulation studies). However, given the enzyme-specific priorities, the slightly better ADME profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 13:09:22,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (379.356 and 350.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.7) is well below the 140 threshold, suggesting good absorption. Ligand B (127.8) is still acceptable, but less optimal.

**3. logP:** Ligand A (2.275) is within the optimal 1-3 range. Ligand B (0.812) is slightly below 1, 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:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (A: 0.812, B: 0.555), indicating good drug-like properties.

**7. DILI:** Ligand A (63.746) has a slightly higher DILI risk than Ligand B (57.58), but both are still within an acceptable range (<60 is good).

**8. BBB:** Both ligands have good BBB penetration (A: 71.268, B: 76.735), although this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.635) has poor Caco-2 permeability, while Ligand B (-5.214) is also poor. Both are concerning.

**10. Aqueous Solubility:** Ligand A (-4.14) has poor aqueous solubility, while Ligand B (-2.378) is better, but still not ideal.

**11. hERG Inhibition:** Ligand A (0.546) shows a slightly higher hERG inhibition risk than Ligand B (0.163), which is a significant advantage for B.

**12. Microsomal Clearance:** Ligand A (55.164) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (13.311). This is a major drawback for A.

**13. In vitro Half-Life:** Ligand A (-46.739) has a very short in vitro half-life, while Ligand B (15.401) is better.

**14. P-gp Efflux:** Ligand A (0.108) has slightly higher P-gp efflux than Ligand B (0.033).

**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.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand A, its poor Caco-2 permeability, aqueous solubility, metabolic stability (high Cl_mic, short half-life), and slightly higher hERG risk are major concerns. Ligand B, while having a weaker binding affinity, exhibits better ADME properties, particularly regarding metabolic stability, solubility and hERG risk. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (hERG) are crucial. The substantial difference in binding affinity *could* be overcome with further optimization of Ligand B, whereas fixing the ADME issues of Ligand A would likely require more extensive structural changes.

Output:
1
2025-04-17 13:09:22,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.9 and 101.22) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.488) is slightly low, potentially hindering permeation. Ligand B (1.364) is within the optimal 1-3 range. This favors Ligand B.

**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 (6) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.773 and 0.814), indicating drug-likeness.

**DILI:** Ligand A (47.034) has a lower DILI risk than Ligand B (60.605), which is a significant advantage.

**BBB:** Both have relatively low BBB penetration, which is not critical for a non-CNS target like SRC. Ligand B is slightly better (74.37 vs 62.621).

**Caco-2:** Both have negative Caco-2 values, which is unusual and problematic. These values likely represent logP-scaled Caco-2 permeability, and negative values suggest very poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.55 and -2.047). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG:** Both ligands have low hERG inhibition liability (0.198 and 0.258), which is excellent.

**Microsomal Clearance:** Ligand A (4.847) has significantly lower microsomal clearance than Ligand B (56.445), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (-7.632) has a much longer in vitro half-life than Ligand B (-21.792), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.053).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a 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.

**Overall Assessment:**

While Ligand A has better DILI and significantly better metabolic stability (lower Cl_mic, longer t1/2), Ligand B boasts a considerably stronger binding affinity. Given the enzyme-specific priority on potency, the 1 kcal/mol difference in binding is substantial. The solubility issues are a concern for both, but could be addressed through formulation. The Caco-2 values are concerning for both, but the stronger binding of Ligand B makes it more likely to be effective *in vivo* even with limited absorption.

Output:
1
2025-04-17 13:09:22,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.415 and 362.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.29) is slightly higher than the preferred <140, but acceptable. Ligand B (58.64) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.89) is a bit low, potentially hindering permeation. Ligand B (2.253) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

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

**QED:** Both ligands have good QED scores (0.799 and 0.835), indicating drug-like properties.

**DILI:** Ligand A (54.323) has a moderate DILI risk, while Ligand B (24.195) has a very low DILI risk, a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (91.198) is higher than Ligand A (72.005). While not a primary concern for a kinase inhibitor, it's a slight positive for 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, also unusual. Again, the scale is unknown, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.176) has a very low hERG risk, excellent. Ligand B (0.375) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (48.769) has moderate clearance, while Ligand B (16.395) has significantly lower clearance, suggesting better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand A (12.613) has a reasonable half-life. Ligand B (-4.318) has a negative half-life, which is impossible and likely an error in the data.

**P-gp Efflux:** Both have low P-gp efflux liability (0.058 and 0.067), which is good.

**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 substantial and outweighs many minor ADME concerns.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the superior binding affinity of Ligand B, coupled with its lower DILI risk and significantly improved metabolic stability (lower Cl_mic), make it the more promising drug candidate. The negative half-life for Ligand B is a red flag, but the large difference in binding affinity is a strong driver.

Output:
1
2025-04-17 13:09:22,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.446 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.25) is better than Ligand B (66.57), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.119) is optimal, while Ligand B (3.68) is approaching the upper limit. This favors Ligand A.

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

**H-Bond Acceptors:** Ligand A (7) is better than Ligand B (5), both are within the acceptable range.

**QED:** Ligand B (0.851) has a higher QED score than Ligand A (0.578), indicating a more drug-like profile.

**DILI:** Ligand A (63.203) has a higher DILI risk than Ligand B (22.838). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.319) is higher than Ligand B (52.23).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.493) is slightly better than Ligand B (-4.806).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.954) is slightly better than Ligand B (-2.594).

**hERG:** Both ligands have low hERG inhibition risk (0.442 and 0.362 respectively).

**Microsomal Clearance:** Ligand B (40.522) has significantly lower microsomal clearance than Ligand A (79.667), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (46.344) has a longer in vitro half-life than Ligand A (-29.882), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.234 and 0.341 respectively).

**Binding Affinity:** Ligand B (-7.5 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 overcome other issues.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better binding affinity. While both have poor solubility and permeability, the metabolic advantages of Ligand B are crucial for an enzyme target like SRC kinase. The lower DILI risk is also a significant factor.

Output:
1
2025-04-17 13:09:22,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.451 and 365.312 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.23) is better than Ligand B (139.34), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.197) is within the optimal 1-3 range. Ligand B (-1.119) is slightly below 1, which might hinder permeation.

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

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 each), below the threshold of 10.

**QED:** Both ligands have similar QED values (0.545 and 0.485), indicating reasonable drug-likeness.

**DILI:** Ligand B (42.691) has a lower DILI risk than Ligand A (56.844), which is favorable.

**BBB:** Ligand A (74.641) has a better BBB penetration score than Ligand B (37.96). However, BBB isn't a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.284) has a worse Caco-2 permeability than Ligand B (-5.834). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.938) has better aqueous solubility than Ligand B (-1.356). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.48) has a slightly higher hERG risk than Ligand B (0.058), which is a concern.

**Microsomal Clearance:** Ligand B (1.481) has significantly lower microsomal clearance than Ligand A (45.402), indicating better metabolic stability. This is a major advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-8.867) has a better in vitro half-life than Ligand A (-15.794).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.099 and 0.01 respectively).

**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 factor. A difference of 8.4 kcal/mol is substantial and likely outweighs many of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability, solubility, and lower hERG risk, the dramatically superior binding affinity of Ligand A (-8.4 vs 0.0 kcal/mol) makes it the more promising candidate. The potency advantage is significant enough to potentially overcome the slightly higher DILI and lower permeability.

Output:
1
2025-04-17 13:09:22,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.5 and 343.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (75.87), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.515) is optimal (1-3), while Ligand B (4.355) is pushing the upper limit and could lead to solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 6 HBA) as both are within acceptable ranges, but lower counts generally improve permeability.

**QED:** Both ligands have similar QED scores (0.894 and 0.812), indicating good drug-likeness.

**DILI:** Ligand A (33.66) has a significantly lower DILI risk than Ligand B (55.53), which is a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand B (76.23) is higher than Ligand A (62.12).

**Caco-2 Permeability:** Ligand A (-5.138) has a worse Caco-2 permeability than Ligand B (-4.968), but both are negative values which are difficult to interpret without knowing the scale.

**Aqueous Solubility:** Ligand A (-3.472) has better aqueous solubility than Ligand B (-4.898). This is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.312) has a much lower hERG risk than Ligand B (0.567), a critical safety parameter.

**Microsomal Clearance:** Ligand A (45.222) has a significantly lower microsomal clearance than Ligand B (88.927), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.193) has a worse in vitro half-life than Ligand B (13.742).

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.125), which is slightly favorable.

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (0.0). This is a substantial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall:**

Ligand A is clearly the superior candidate. It has a better safety profile (lower DILI, lower hERG), better solubility, better metabolic stability (lower Cl_mic), and a significantly stronger binding affinity. While Ligand B has a slightly better half-life and BBB penetration, these are less critical for a non-CNS enzyme target. The logP of Ligand B is also a concern. The superior binding affinity of Ligand A is a significant factor, outweighing the slightly worse Caco-2 and half-life.

Output:
1
2025-04-17 13:09:22,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.471 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.3) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (80.12) is well within the range.

**logP:** Ligand A (1.359) is optimal. Ligand B (0.433) 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:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.727, B: 0.806), indicating drug-like properties.

**DILI:** Ligand A (52.772) has a moderate DILI risk, while Ligand B (36.642) has a lower, more favorable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (60.644) has a higher BBB value than Ligand A (34.199), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.999) has poor Caco-2 permeability, while Ligand B (-5.212) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.677, B: -2.021). This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.402, B: 0.08). This is excellent.

**Microsomal Clearance:** Ligand A (29.767) has a moderate microsomal clearance, indicating moderate metabolic stability. Ligand B (0.256) has very low clearance, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (45.053) has a reasonable half-life. Ligand B (-2.258) has a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.125, B: 0.035), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge, it's a 0.4 kcal/mol advantage.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and a slightly stronger binding affinity. The slightly lower logP of Ligand B is a minor concern, but the benefits in metabolic stability and safety outweigh this.

Output:
1
2025-04-17 13:09:22,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.4 and 355.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.73) is better than Ligand B (98.68), both are below the 140 threshold for oral absorption, but closer to the 90 threshold is better.

**logP:** Both ligands have good logP values (1.814 and 1.486), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=5) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.744) has a significantly better QED score than Ligand B (0.59), indicating a more drug-like profile.

**DILI:** Ligand A (65.723) has a higher DILI risk than Ligand B (16.479). This is a significant drawback for Ligand A.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (74.874) has a better BBB percentile than Ligand B (32.803).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-5.537) is slightly better than Ligand B (-5.019).

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and suggests poor solubility. Ligand A (-2.135) is slightly better than Ligand B (-1.484).

**hERG:** Ligand A (0.086) has a much lower hERG risk than Ligand B (0.597), which is a significant advantage.

**Microsomal Clearance:** Ligand B (20.556) has a lower microsomal clearance than Ligand A (26.094), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-19.633) has a negative half-life, which is impossible. This is a major red flag and suggests a serious issue with the data or the compound itself. Ligand A (30.496) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux liability than Ligand B (0.399), which is favorable.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better QED, lower hERG risk, and lower P-gp efflux. However, it has a higher DILI risk and slightly worse metabolic stability than Ligand B. The negative half-life for Ligand B is a critical flaw, making it highly unlikely to be a viable candidate. While Ligand A's DILI risk is concerning, the significantly stronger binding affinity and better overall drug-like properties make it the more promising candidate. Further optimization could focus on mitigating the DILI risk.

Output:
0
2025-04-17 13:09:22,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (386.788 and 378.778 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.29) is higher than Ligand B (68.29). While both are reasonably low, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (1.989) is within the optimal range (1-3), while Ligand B (3.607) is slightly higher. This could potentially lead to solubility issues for Ligand B, but isn't a major concern.

**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.

**QED:** Both ligands have good QED scores (0.552 and 0.606), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.488), which is a significant concern. Ligand B has a much lower DILI risk (59.17), making it more favorable.

**BBB:** Both have reasonable BBB penetration, but Ligand B (88.174) is better than Ligand A (71.229). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.518 and -4.576). This is unusual and suggests poor permeability, though the scale isn't fully defined.

**Aqueous Solubility:** Both have negative solubility values (-3.285 and -4.481), indicating poor solubility. This is a concern for both, but could be mitigated with formulation strategies.

**hERG:** Ligand A (0.024) has a very low hERG risk, which is excellent. Ligand B (0.37) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (45.948) has lower clearance than Ligand B (83.768), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (29.417) has a longer half-life than Ligand B (12.023), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.262 and 0.258).

**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 noticeable advantage.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a significantly lower hERG risk. However, its DILI risk is extremely high, which is a major red flag. Ligand B has a lower DILI risk, better TPSA, and slightly better binding affinity, but suffers from higher metabolic clearance and a shorter half-life.

Given the priorities for enzyme inhibitors, metabolic stability and safety (DILI and hERG) are crucial. While Ligand A's metabolic stability is better, the extremely high DILI risk outweighs this benefit. Ligand B, despite its slightly less favorable metabolic profile, presents a much safer profile. The affinity difference is small enough that it can potentially be addressed through further optimization.

Output:
1
2025-04-17 13:09:22,994 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [373.869, 63.05, 3.345, 1, 6, 0.764, 79.411, 73.401, -5.16, -4.116, 0.593, 72.152, 46.79, 0.675, -7.7]
**Ligand B:** [359.369, 68.23, 1.759, 1, 5, 0.804, 39.434, 83.172, -4.316, -1.918, 0.455, 6.469, -11.86, 0.173, -7.3]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (373.869) is slightly higher, but acceptable.
2. **TPSA:** Both are below the 140 A^2 threshold for oral absorption. A (63.05) is better than B (68.23).
3. **logP:** A (3.345) is optimal, while B (1.759) is a bit low, potentially hindering permeation.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A has 6, B has 5. Both are acceptable (<=10).
6. **QED:** Both are good (>0.5), with B (0.804) being slightly better.
7. **DILI:** A (79.411) has a significantly higher DILI risk than B (39.434). This is a major concern for A.
8. **BBB:** A (73.401) is reasonable, but B (83.172) is better. Not a primary concern for a non-CNS target like SRC.
9. **Caco-2:** Both are negative, which is unusual and suggests poor permeability. B (-4.316) is slightly better (less negative).
10. **Solubility:** Both are negative, suggesting poor solubility. B (-1.918) is better (less negative).
11. **hERG:** Both are low risk. A (0.593) is slightly higher than B (0.455).
12. **Cl_mic:** A (72.152) has a higher microsomal clearance, indicating lower metabolic stability, compared to B (6.469). This is a significant drawback for A.
13. **t1/2:** A (46.79) has a better in vitro half-life than B (-11.86). However, the negative value for B is concerning and likely indicates very rapid degradation.
14. **Pgp:** A (0.675) has slightly higher P-gp efflux liability than B (0.173).
15. **Binding Affinity:** A (-7.7) has a slightly better binding affinity than B (-7.3), but the difference is less than 1.5 kcal/mol.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its significantly higher DILI risk and higher microsomal clearance are major liabilities. Ligand B, while having a slightly lower affinity and poorer logP, exhibits much better metabolic stability, lower DILI risk, and better solubility. The better Caco-2 and Pgp values also suggest better absorption. Considering the enzyme-specific priorities, **Ligand B** is the more promising drug candidate.

Output:
1

2025-04-17 13:09:22,994 - INFO - Batch 190 complete. Total preferences: 3040
2025-04-17 13:09:22,994 - INFO - Processing batch 191/512...
2025-04-17 13:10:04,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.929 Da) is slightly higher than Ligand B (356.398 Da), but both are acceptable.

**TPSA:** Ligand A (63.25) is significantly better than Ligand B (96.7). Lower TPSA generally favors better absorption.

**logP:** Ligand A (4.492) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (0.313) is *below* the optimal range, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a slightly higher HBA count (6) compared to Ligand A (4), but both are within the acceptable limit of 10.

**QED:** Both ligands have similar and acceptable QED values (A: 0.742, B: 0.696), indicating good drug-like properties.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (28.926). This is a significant concern for Ligand A.

**BBB:** Ligand B (78.519) has a better BBB penetration score than Ligand A (33.579), but BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.759 and -4.872), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.104 and -2.079). This is a major drawback.

**hERG:** Both ligands have low hERG inhibition liability (0.254 and 0.305), which is good.

**Microsomal Clearance:** Ligand B (6.125) has significantly lower microsomal clearance than Ligand A (82.358), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (7.904) has a longer in vitro half-life than Ligand A (33.802), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.294 and 0.027), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.6 kcal/mol), with Ligand B being slightly better. The difference is small and likely not decisive.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower BBB and the lower logP. The poor solubility and Caco-2 permeability are concerning for both, but can potentially be addressed through formulation strategies. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 13:10:04,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.411 Da and 338.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (123.41) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (84.85) is excellent, well below 140.

**3. logP:** Ligand A (0.685) is a bit low, potentially hindering permeability. Ligand B (3.171) is 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 (7) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.668 and 0.684), indicating good drug-likeness.

**7. DILI:** Ligand A (62.815) has a moderate DILI risk, but still acceptable. Ligand B (90.927) has a significantly higher DILI risk, which is concerning.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (58.976) is higher than Ligand A (39.55), but not a deciding factor here.

**9. Caco-2 Permeability:** Ligand A (-5.632) has poor Caco-2 permeability. Ligand B (-4.888) is also poor, but slightly better than Ligand A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.092 and -4.615). This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.114) has a very low hERG risk, which is excellent. Ligand B (0.814) has a moderate hERG risk, which is less desirable.

**12. Microsomal Clearance:** Ligand A (3.452) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (98.911) has very high clearance, suggesting rapid metabolism.

**13. In vitro Half-Life:** Ligand A (3.919) has a slightly longer half-life than Ligand B (17.198).

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.032 and 0.135), which is favorable.

**15. 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 other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While both have poor solubility, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a much lower hERG risk. The slightly lower logP and Caco-2 permeability of Ligand A are less concerning than the higher DILI and clearance of Ligand B. The binding affinity difference is minimal.

Output:
0
2025-04-17 13:10:04,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.414 and 385.421 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.13 and 81.93) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (4.351) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.892) 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, while Ligand B has 8. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.611) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand A (79.256) has a lower DILI risk than Ligand B (95.812), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.319) has a slightly better BBB score than Ligand B (65.413).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.685 and -5.093), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.693 and -4.015), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.546) has a lower hERG risk than Ligand B (0.452), which is favorable.

**Microsomal Clearance:** Ligand A (54.429) has a lower microsomal clearance than Ligand B (67.779), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.604) has a longer half-life than Ligand B (4.29), which is desirable.

**P-gp Efflux:** Ligand A (0.513) has lower P-gp efflux than Ligand B (0.254), which is favorable.

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand A demonstrates better ADME properties (lower DILI, better metabolic stability, longer half-life, lower P-gp efflux, and lower hERG risk), Ligand B's significantly stronger binding affinity (-9.0 vs -8.4 kcal/mol) is a critical factor for an enzyme inhibitor. The potency advantage is likely to be more impactful than the ADME drawbacks, especially considering optimization can address those issues.

Output:
1
2025-04-17 13:10:04,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.376 and 378.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (114.19). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Both ligands have similar logP values (1.724 and 1.791), both within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 7.  Ligand A is preferable here, as higher HBA can sometimes reduce permeability.

**QED:** Both ligands have good QED scores (0.593 and 0.648), indicating drug-like properties.

**DILI:** Ligand A (32.028) has a much lower DILI risk than Ligand B (92.672). This is a significant advantage for Ligand A.

**BBB:**  BBB isn't a high priority for a non-CNS target like SRC, but Ligand A (70.997) is better than Ligand B (38.775).

**Caco-2 Permeability:** Ligand A (-4.894) is better than Ligand B (-5.754), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.669) is better than Ligand B (-2.748), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.419) has a lower hERG risk than Ligand B (0.265), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-1.409) has a lower (better) microsomal clearance than Ligand B (0.174), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.093) has a much longer in vitro half-life than Ligand B (42.258), suggesting less frequent dosing potential.

**P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux than Ligand B (0.065), which is favorable.

**Binding Affinity:** Ligand B (-0.0) has a significantly weaker binding affinity than Ligand A (-7.2). This is the most critical factor for an enzyme inhibitor.

**Overall:**

Ligand A is superior in almost every ADME-Tox property (DILI, solubility, hERG, clearance, half-life, P-gp efflux) and has a *much* stronger binding affinity. While Ligand B has a slightly better QED, the other advantages of Ligand A far outweigh this minor difference. The significantly better binding affinity of Ligand A (-7.2 kcal/mol) is a decisive factor, and the improved ADME profile further solidifies its potential as a viable drug candidate.

Output:
1
2025-04-17 13:10:04,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.403 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.38) is slightly above the preferred <140, but acceptable. Ligand B (58.64) is excellent, well below 140.

**logP:** Ligand A (-1.01) is a bit low, potentially hindering permeability. Ligand B (2.491) is within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 6 HBA) is good. Ligand B (1 HBD, 3 HBA) is also excellent. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.592 and 0.769), indicating drug-like properties.

**DILI:** Ligand A (25.165) has a very low DILI risk, which is excellent. Ligand B (9.965) also has a very low DILI risk.

**BBB:** Ligand A (45.909) has a moderate BBB penetration score, while Ligand B (68.631) is better. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.694 and -4.782), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.121 and -2.884), which is also concerning and suggests poor solubility.

**hERG:** Ligand A (0.112) has a very low hERG risk, which is excellent. Ligand B (0.444) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (25.769) has a moderate clearance, while Ligand B (47.829) has a higher clearance. Lower is better for metabolic stability, so Ligand A is preferable here.

**In vitro Half-Life:** Ligand A (-0.916) has a negative half-life, which is concerning. Ligand B (-5.838) is even worse. Both are very unstable.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is excellent. Ligand B (0.126) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-0.0). This is a significant advantage.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity (-7.3 vs -0.0 kcal/mol). While both have concerning permeability and solubility issues (negative Caco-2 and solubility values), the strong binding affinity of Ligand A could potentially overcome these issues with appropriate formulation strategies. Ligand A also has a lower microsomal clearance and a much lower hERG risk. The half-life is concerning for both, but the binding affinity difference is the deciding factor.

Output:
1
2025-04-17 13:10:04,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.555 and 365.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.43) is still under 140, but less favorable than A.

**logP:** Ligand A (4.518) is slightly high, potentially leading to solubility issues or off-target effects, but not drastically so. Ligand B (0.918) is quite low, potentially hindering permeation.

**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 more favorable.

**QED:** Both ligands have good QED scores (0.621 and 0.811), indicating drug-like properties.

**DILI:** Ligand A (35.479) has a low DILI risk, which is excellent. Ligand B (16.169) also has a low DILI risk, but slightly higher than A.

**BBB:** Both have reasonable BBB penetration (69.407 and 67.08), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.895) has poor Caco-2 permeability, which is a significant concern. Ligand B (-5.54) also has poor Caco-2 permeability, but slightly worse than A.

**Aqueous Solubility:** Ligand A (-3.898) has poor aqueous solubility, consistent with its high logP. Ligand B (-0.727) has better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.525 and 0.127), which is excellent.

**Microsomal Clearance:** Ligand A (115.552) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-21.652) has excellent metabolic stability. This is a major advantage for B.

**In vitro Half-Life:** Ligand A (48.436) has a moderate half-life. Ligand B (1.703) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.361 and 0.025), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (Cl_mic and t1/2), and better solubility. While Ligand A has a slightly better TPSA and DILI score, the poor metabolic stability and permeability of A are major drawbacks for an enzyme target. The slightly better affinity of B is a bonus. The poor Caco-2 permeability of both is concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:10:04,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.471 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.88) is higher than Ligand B (43.86). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Both ligands have acceptable logP values (1.7 and 2.667), falling within the 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for cell permeability.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Lower HBA is generally preferred for better permeability, giving an edge to Ligand B.

**QED:** Both ligands have similar QED values (0.774 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (50.485) has a slightly higher DILI risk than Ligand B (5.7). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.135) and Ligand B (92.323) are both reasonably high.

**Caco-2 Permeability:** Both have negative values (-4.776 and -4.509), which is unusual. It's difficult to interpret without knowing the scale, but assuming lower is worse, they are similarly poor.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.146 and -1.509), which is concerning. Ligand B is slightly better, but both require improvement.

**hERG:** Ligand A (0.823) has a slightly higher hERG risk than Ligand B (0.354). Lower is better, so Ligand B is favored.

**Microsomal Clearance:** Ligand A (65.98) has higher microsomal clearance than Ligand B (45.474), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-8.689) has a longer in vitro half-life than Ligand A (6.317). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.202) has lower P-gp efflux than Ligand B (0.062), which is slightly better.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While this is a positive for Ligand A, the difference (0.5 kcal/mol) is not substantial enough to outweigh the numerous advantages of Ligand B.

**Overall:** Ligand B demonstrates a superior ADME-Tox profile, with lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and fewer HBA. The slightly weaker binding affinity of Ligand B is unlikely to be a major issue, given the other benefits.

Output:
1
2025-04-17 13:10:04,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.475 and 339.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is slightly higher than Ligand B (61.44), but both are well below the 140 A^2 threshold for good absorption.

**3. logP:** Both ligands have similar logP values (1.542 and 1.528), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 2. Both are acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, well within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.783 and 0.8), indicating good drug-like properties.

**7. DILI:** Ligand A (24.544) has a significantly lower DILI risk than Ligand B (45.483). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.158) is higher than Ligand B (39.007), but this is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.742 and -4.9), which is unusual and suggests poor permeability. However, these values are on a log scale and require careful interpretation.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.919 and -2.965), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.134) has a lower hERG risk than Ligand B (0.33). This is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand B (-24.748) has a *much* lower (better) microsomal clearance than Ligand A (26.119). This suggests significantly better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (0.144) has a lower half-life than Ligand A (2.245). This is a negative for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.025).

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic). However, Ligand A has a much lower DILI risk and hERG liability. The poor solubility and permeability are concerns for both. Given the enzyme-specific priorities, the stronger binding affinity of Ligand B is the most important factor, and the improved metabolic stability is a significant bonus. While the DILI risk is higher for Ligand B, this can potentially be mitigated during further optimization.

Output:
1
2025-04-17 13:10:04,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.519 Da and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.47) is better than Ligand B (88.1), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.201) is within the optimal 1-3 range. Ligand B (-0.082) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**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, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have similar QED values (0.792 and 0.698), indicating good drug-likeness.

**DILI:** Ligand A (29.857) has a significantly lower DILI risk than Ligand B (14.424), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (49.011 and 48.468), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.189) and Ligand B (-4.886) have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so the difference isn't massive.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.669 and -1.406). This is a significant drawback and would require formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.135 and 0.195).

**Microsomal Clearance:** Ligand A (4.145) has slightly higher microsomal clearance than Ligand B (2.343), meaning Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand B (29.095) has a slightly longer in vitro half-life than Ligand A (27.096).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.012).

**Binding Affinity:** Ligand B (-8.5 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.

**Conclusion:**

While Ligand A has a better safety profile (lower DILI) and slightly better TPSA, Ligand B's significantly superior binding affinity (-8.5 vs -7.1 kcal/mol) is the most critical factor for an enzyme inhibitor. The slightly better metabolic stability (lower Cl_mic, longer t1/2) of Ligand B further supports its selection. The poor solubility of both compounds is a concern, but formulation strategies can be explored. The slightly lower logP of Ligand B is a minor concern, but the strong binding affinity is more important.

Output:
1
2025-04-17 13:10:04,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.463 and 377.941 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.63) is higher than Ligand B (46.09). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Ligand A (3.612) is within the optimal range (1-3), while Ligand B (4.969) is slightly above, potentially raising concerns about solubility and off-target effects.

**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 (0.734 and 0.684), indicating good drug-likeness.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (41.334), which is preferable.

**BBB:** Ligand A (51.415) has a lower BBB penetration than Ligand B (84.451). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.31) has worse Caco-2 permeability than Ligand B (-4.992), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.559) has worse aqueous solubility than Ligand B (-5.167). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.295) has a lower hERG inhibition risk than Ligand B (0.689), which is a significant advantage.

**Microsomal Clearance:** Ligand A (3.171) has a lower microsomal clearance than Ligand B (90.208), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (8.786) has a shorter in vitro half-life than Ligand B (31.263). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux than Ligand B (0.721), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a better hERG profile, lower P-gp efflux, and significantly better metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from lower solubility and permeability. Ligand B has better solubility and permeability, but higher DILI risk, higher P-gp efflux, and poorer metabolic stability.

Given the enzyme-specific priorities, metabolic stability and minimizing off-target effects (hERG) are crucial. The slight advantage in binding affinity for Ligand A is not enough to overcome the significant metabolic liabilities of Ligand B. Therefore, Ligand A is the more promising candidate.

Output:
0
2025-04-17 13:10:04,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (368.455 and 354.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (88.1) is slightly above the preferred <90 for kinase inhibitors, while Ligand B (77.1) is well within the range.

**3. logP:** Both ligands have good logP values (1.71 and 1.23), 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:** Ligand A (6) and Ligand B (5) both meet the HBA criteria of <=10.

**6. QED:** Both ligands have good QED scores (0.563 and 0.744), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (58.434) has a moderate DILI risk, while Ligand B (25.785) has a low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.733) is better than Ligand B (48.662) but not a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-5.324) and Ligand B (-4.581) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.621) and Ligand B (-1.169) both have negative values, indicating poor solubility. Ligand B is better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.628 and 0.19). Ligand B is better.

**12. Microsomal Clearance:** Ligand A (27.397) and Ligand B (29.092) have similar microsomal clearance values, suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (-38.861) has a very negative half-life, which is concerning. Ligand B (-2.744) has a better half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.121 and 0.037).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.5 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand B is the superior candidate. While both have good potency, Ligand B demonstrates significantly lower DILI risk, better solubility, a better half-life, and a slightly better binding affinity. The slightly better TPSA and QED scores also contribute to its favorability. The permeability is poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:10:04,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.479 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.11) is slightly above the preferred <140, but acceptable. Ligand B (47.36) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (-0.187) is a bit low, potentially hindering permeation. Ligand B (3.182) is optimal.

**H-Bond Donors:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.533, B: 0.664), indicating drug-like properties.

**DILI:** Ligand A (4.769) has a very low DILI risk, which is excellent. Ligand B (26.638) is also good, well below the 40 threshold.

**BBB:** Ligand A (43.699) has a low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (83.249) has good BBB penetration, though not critical here.

**Caco-2 Permeability:** Ligand A (-5.207) has poor Caco-2 permeability, which is concerning. Ligand B (-4.639) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.05) has poor aqueous solubility, which is a significant drawback. Ligand B (-3.464) also has poor solubility, but is worse than A.

**hERG Inhibition:** Ligand A (0.149) has very low hERG inhibition risk, which is excellent. Ligand B (0.649) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-5.728) has very low microsomal clearance, indicating good metabolic stability. Ligand B (93.131) has high microsomal clearance, suggesting rapid metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (8.43) has a reasonable half-life. Ligand B (29.854) has a significantly longer half-life, which is a major advantage.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.365) has slightly higher efflux, but still acceptable.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-6.8). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a better safety profile (DILI, hERG) and metabolic stability (Cl_mic) and slightly better binding affinity. However, its poor solubility and Caco-2 permeability are significant liabilities. Ligand B has better permeability (lower TPSA) and a much longer half-life, which are important for *in vivo* efficacy. While its solubility is also poor, its longer half-life and better logP might compensate to some extent. The high metabolic clearance of Ligand B is a concern.

Considering the priorities for kinase inhibitors, the longer half-life of Ligand B is a substantial advantage, potentially outweighing its higher metabolic clearance and slightly lower affinity. The poor solubility of both is a concern that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 13:10:04,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.543 and 360.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (51.66 and 51.02) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.637 and 3.893) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 0 HBDs, which is acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBAs, which is acceptable.

**QED:** Both ligands have QED values above 0.5 (0.668 and 0.752), indicating good drug-likeness.

**DILI:** Ligand A (31.834) has a lower DILI risk than Ligand B (41.024), which is favorable. Both are below the 60 threshold.

**BBB:** Both ligands have good BBB penetration (79.449 and 90.074). However, this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.817 and -5.106). This is unusual and suggests poor permeability, but the scale is not specified.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.994 and -4.031). This is also unusual and suggests poor solubility, but the scale is not specified.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.781 and 0.469).

**Microsomal Clearance:** Ligand A (80.597) has a lower microsomal clearance than Ligand B (104.482), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (57.788) has a significantly longer in vitro half-life than Ligand B (17.015). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.765 and 0.561).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.0 kcal/mol difference, which is significant.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic) and longer half-life. Given the enzyme-specific priorities, these factors outweigh the modest difference in binding affinity. The poor solubility and permeability indicated by the negative values are concerning, but could be addressed through formulation or structural modifications.

Output:
0
2025-04-17 13:10:04,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.475 and 362.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (70.08 and 71.25) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.414) is optimal, while Ligand B (2.862) is also 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 6. Both are below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.831 and 0.822), indicating good drug-likeness.

**7. DILI:** Ligand A (9.616) has a significantly lower DILI risk than Ligand B (52.152). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.699) has a slightly higher BBB value than Ligand A (54.478).

**9. Caco-2 Permeability:** Both have negative values (-4.508 and -4.864). These values are not directly comparable without knowing the scale, but generally, lower (more negative) values suggest poorer permeability.

**10. Aqueous Solubility:** Both have negative values (-0.965 and -2.96). Similar to Caco-2, lower values suggest poorer solubility. Ligand B appears to have lower solubility.

**11. hERG Inhibition:** Ligand A (0.385) has a lower hERG inhibition liability than Ligand B (0.169), which is favorable.

**12. Microsomal Clearance:** Ligand A (14.374) has a significantly lower microsomal clearance than Ligand B (39.222), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (10.521) has a shorter half-life than Ligand B (19.724), but both are reasonable.

**14. P-gp Efflux:** Ligand A (0.118) has lower P-gp efflux liability than Ligand B (0.446), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While a 1.5 kcal/mol difference is significant, the other ADME properties of Ligand A are far superior.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), **Ligand A** is the more viable drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, lower hERG inhibition, and lower P-gp efflux. These factors are critical for *in vivo* efficacy and safety. The solubility and permeability concerns are present in both, but the superior safety and PK profile of Ligand A outweigh the slight affinity difference.

Output:
0
2025-04-17 13:10:04,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.467 Da) is slightly better positioned.

**TPSA:** Both are below the 140 A^2 threshold for good absorption. Ligand B (72.01) is slightly better than Ligand A (82.53).

**logP:** Both are within the optimal range (1-3). Ligand B (2.141) is slightly higher, which could be beneficial for membrane permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 7 HBA. Both are acceptable, but Ligand A is slightly better.

**QED:** Both have reasonable QED scores (A: 0.841, B: 0.738), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (15.394). This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (79.721) has a higher BBB score than Ligand A (25.359), but this isn't a major factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-5.744) is slightly better than Ligand A (-5.151).

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.252) is slightly better than Ligand A (-2.795).

**hERG Inhibition:** Ligand A (0.167) has a slightly higher hERG risk than Ligand B (0.397), but both are relatively low.

**Microsomal Clearance:** Ligand B (-1.024) has a significantly *lower* (better) microsomal clearance than Ligand A (31.685). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (24.758) has a much longer in vitro half-life than Ligand A (-23.028). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.131) has slightly higher P-gp efflux liability than Ligand B (0.066).

**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 significantly better binding affinity of Ligand A, the poor DILI score, high microsomal clearance, and short half-life are major concerns. Ligand B, while having weaker binding, exhibits a much more favorable ADME profile: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. For an enzyme target like SRC kinase, metabolic stability and a manageable safety profile are crucial. The difference in binding affinity, while substantial, may be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 13:10:04,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.355 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.77) is better than Ligand B (85.69), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.317) is slightly better than Ligand B (0.777), 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 6 H-bond acceptors, which is within the acceptable limit of <=10.

**QED:** Ligand B (0.819) has a better QED score than Ligand A (0.616), indicating a more drug-like profile.

**DILI:** Ligand B (54.634) has a significantly lower DILI risk than Ligand A (82.59), making it more favorable.

**BBB:** Ligand B (73.905) has a higher BBB penetration percentile than Ligand A (38.813), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.497) has a worse Caco-2 permeability than Ligand B (-4.856), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.334) has a worse aqueous solubility than Ligand B (-1.75), which is a concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.117 and 0.156), which is excellent.

**Microsomal Clearance:** Ligand A (-0.871) has a much lower (better) microsomal clearance than Ligand B (14.062), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-37.343) has a much longer in vitro half-life than Ligand B (22.553), which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.038).

**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 small.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2) and binding affinity, while Ligand B has better solubility, DILI risk, and QED. The significantly better metabolic stability and half-life of Ligand A are crucial for an enzyme target like SRC. While Ligand B has a slightly better binding affinity, the difference isn't substantial enough to outweigh the superior pharmacokinetic properties of Ligand A. The solubility of Ligand A is a concern, but formulation strategies could potentially address this.

Output:
1
2025-04-17 13:10:04,691 - INFO - Batch 191 complete. Total preferences: 3056
2025-04-17 13:10:04,691 - INFO - Processing batch 192/512...
2025-04-17 13:10:54,049 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [360.458, 58.12, 4.162, 1, 4, 0.89, 51.26, 85.847, -4.758, -4.301, 0.239, 34.416, 1.196, 0.183, -6.8]
**Ligand B:** [341.371, 112.95, 1.192, 2, 6, 0.819, 61.07, 53.819, -5.091, -3.627, 0.101, 3.097, 31.236, 0.038, -8.2]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (360.458) is slightly higher, but both are acceptable.
2. **TPSA:** A (58.12) is excellent, well below the 140 threshold. B (112.95) is higher, but still potentially acceptable, though less favorable for absorption.
3. **logP:** A (4.162) is a bit high, potentially leading to solubility issues or off-target interactions. B (1.192) is good, within the optimal range.
4. **HBD:** A (1) and B (2) are both acceptable, below the 5 threshold.
5. **HBA:** A (4) and B (6) are both acceptable, below the 10 threshold.
6. **QED:** Both are good (A: 0.89, B: 0.819), indicating drug-like properties.
7. **DILI:** A (51.26) is better than B (61.07), indicating a lower risk of liver injury. Both are acceptable, but A is preferred.
8. **BBB:** A (85.847) is much better than B (53.819). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.
9. **Caco-2:** A (-4.758) is better than B (-5.091), indicating better intestinal absorption.
10. **Solubility:** A (-4.301) is better than B (-3.627), indicating better aqueous solubility.
11. **hERG:** Both are very low (A: 0.239, B: 0.101), indicating minimal cardiotoxicity risk.
12. **Cl_mic:** A (34.416) is significantly higher than B (3.097), indicating *lower* metabolic stability. This is a major drawback for A.
13. **t1/2:** A (1.196) is much lower than B (31.236), indicating a shorter half-life and potentially more frequent dosing requirements. This is another significant drawback for A.
14. **Pgp:** A (0.183) is better than B (0.038), indicating lower P-gp efflux.
15. **Affinity:** B (-8.2) is significantly better than A (-6.8). A difference of 1.4 kcal/mol is substantial and can often outweigh minor ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Conclusion:**

While Ligand A has some favorable properties (better DILI, BBB, Pgp, solubility, and Caco-2), Ligand B clearly wins due to its *significantly* better binding affinity (-8.2 vs -6.8 kcal/mol) and *much* improved metabolic stability (lower Cl_mic and longer t1/2). The higher affinity is a critical advantage for an enzyme inhibitor, and the improved metabolic stability will likely translate to better *in vivo* exposure. The slightly higher TPSA and logP of Ligand B are less concerning given the strong affinity and metabolic profile.

Output:
1

2025-04-17 13:10:54,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (358.869 and 377.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.35) is well below the 140 threshold, and excellent for oral absorption. Ligand B (134.27) is still within the acceptable range, but less optimal.

**3. logP:** Ligand A (4.375) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-1.847) is quite low, which could hinder 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):** Ligand A (3) is good. Ligand B (7) is higher, but still within the acceptable limit of <=10.

**6. QED:** Ligand A (0.805) has a very strong drug-like profile. Ligand B (0.495) is below the desirable threshold of 0.5.

**7. DILI:** Ligand A (38.891) has a low DILI risk. Ligand B (52.385) is moderately higher, but still acceptable.

**8. BBB:** Ligand A (70.88) shows good BBB penetration, while Ligand B (19.077) is very low. While SRC is not a CNS target, good BBB penetration isn't necessarily a negative.

**9. Caco-2 Permeability:** Ligand A (-4.995) is poor, indicating low intestinal absorption. Ligand B (-5.604) is also poor.

**10. Aqueous Solubility:** Ligand A (-4.201) is poor. Ligand B (-0.823) is also poor, but slightly better than A.

**11. hERG Inhibition:** Ligand A (0.751) has a low hERG risk. Ligand B (0.069) has a very low hERG risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (26.014) has moderate clearance. Ligand B (-22.4) has negative clearance, which is not possible, and likely indicates a very stable compound.

**13. In vitro Half-Life:** Ligand A (53.316) has a reasonable half-life. Ligand B (-34.265) has a negative half-life, which is not possible.

**14. P-gp Efflux:** Ligand A (0.382) has low P-gp efflux. Ligand B (0.004) has very low P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). The 1.1 kcal/mol difference is substantial.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand A has significantly better binding affinity. While both have poor solubility and Caco-2 permeability, the strong binding of Ligand A can potentially compensate for these issues. Ligand B has implausible negative values for Cl_mic and t1/2, making it immediately less viable.

Output:
1
2025-04-17 13:10:54,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.459 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.8) is higher than Ligand B (41.57). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**3. logP:** Both ligands have logP values within the optimal range (2.462 and 3.663). Ligand B is slightly higher, which *could* pose a minor solubility issue, but is 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 3. Both are below the limit of 10.

**6. QED:** Ligand A (0.853) has a better QED score than Ligand B (0.771), suggesting a more drug-like profile overall.

**7. DILI:** Ligand A (19.349) has a higher DILI risk than Ligand B (13.804). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (82.513 and 89.608). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.557 and -4.729). 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 (-2.16) has slightly better solubility than Ligand B (-3.5).

**11. hERG Inhibition:** Ligand A (0.43) has a lower hERG risk than Ligand B (0.702). This is a crucial advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (59.54) has lower microsomal clearance than Ligand B (75.842), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.18) has a longer half-life than Ligand B (7.055). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.237) has lower P-gp efflux than Ligand B (0.458), suggesting better bioavailability.

**15. Binding Affinity:** Ligand A (-7.4) has a significantly better binding affinity than Ligand B (-0.0). This is the most important factor for an enzyme inhibitor. A difference of 7.4 kcal/mol is substantial.

**Overall Assessment:**

Ligand A clearly outperforms Ligand B in the most critical areas for an enzyme inhibitor: binding affinity, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While Ligand B has a lower DILI risk and a better TPSA, the significantly stronger binding affinity of Ligand A outweighs these benefits. The slightly better solubility of Ligand A and lower hERG risk are also positive factors. The negative Caco-2 values are concerning for both, but the strong binding affinity of Ligand A suggests it might overcome this limitation.

Output:
1
2025-04-17 13:10:54,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (395.493 Da) is slightly higher than Ligand B (340.467 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (71.52) is higher than Ligand B (58.2), but both are within acceptable limits.

**logP:** Both ligands have logP values between 1-3 (Ligand A: 2.911, Ligand B: 3.142), which is optimal for permeability and avoiding off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within the recommended limits (HBD <= 5, HBA <= 10).

**QED:** Ligand A (0.786) has a better QED score than Ligand B (0.564), indicating a more drug-like profile.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (37.96). This is a significant concern.

**BBB:** Both ligands have acceptable BBB penetration (Ligand A: 86.739, Ligand B: 65.801), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.722 and -4.778), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.399 and -3.443), indicating very poor aqueous solubility. This is a major formulation challenge for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.844, Ligand B: 0.449), which is good.

**Microsomal Clearance:** Ligand A (31.299 mL/min/kg) has lower microsomal clearance than Ligand B (43.571 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.408 hours) has a shorter half-life than Ligand B (-16.282 hours), which is less desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.583, Ligand B: 0.385).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a substantial advantage. The difference of 1.1 kcal/mol is large enough to potentially overcome some ADME liabilities.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better QED, and better metabolic stability. However, it has a higher DILI risk, a shorter half-life, and poor solubility/permeability. Ligand B has lower DILI risk and a longer half-life, but weaker binding affinity and worse QED.

Given the priority for potency in enzyme inhibition, the significantly stronger binding affinity of Ligand A (-9.9 kcal/mol vs -8.8 kcal/mol) is the most important factor. While the DILI risk is a concern, it might be mitigated through structural modifications. The poor solubility and permeability are also significant challenges, but could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:10:54,050 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [357.797, 95.08, 2.214, 3, 4, 0.667, 79.062, 32.299, -5.323, -4.41, 0.322, 2.187, 48.668, 0.142, -9.4]
**Ligand B:** [493.225, 69.21, 3.13, 0, 8, 0.55, 74.719, 74.486, -5.294, -3.985, 0.406, 49.122, 39.696, 0.464, -8.5]

**Step-by-step comparison:**

1. **MW:** Ligand A (357.797 Da) is within the ideal range (200-500 Da). Ligand B (493.225 Da) is at the upper limit, potentially impacting permeability.
2. **TPSA:** Ligand A (95.08) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (69.21) is excellent, suggesting good absorption.
3. **logP:** Both ligands (A: 2.214, B: 3.13) are within the optimal range (1-3).
4. **HBD:** Ligand A (3) is good. Ligand B (0) is also good, potentially improving membrane permeability.
5. **HBA:** Ligand A (4) is good. Ligand B (8) is acceptable, but higher HBA can sometimes reduce permeability.
6. **QED:** Both ligands (A: 0.667, B: 0.55) are above the 0.5 threshold, indicating good drug-like properties.
7. **DILI:** Both ligands have relatively high DILI risk (A: 79.062, B: 74.719), but are still within a range that is manageable with further optimization.
8. **BBB:** Ligand A (32.299) has very low BBB penetration. Ligand B (74.486) has better, though not exceptional, BBB penetration. Since SRC is not a CNS target, this is less critical.
9. **Caco-2:** Both ligands have negative Caco-2 values (-5.323 and -5.294), which is unusual and suggests issues with the assay or the compounds themselves. This is a red flag for both.
10. **Solubility:** Both ligands have negative solubility values (-4.41 and -3.985), which is also unusual and suggests issues with the assay or the compounds themselves. This is a red flag for both.
11. **hERG:** Both ligands have low hERG risk (A: 0.322, B: 0.406).
12. **Cl_mic:** Ligand A (2.187) has lower microsomal clearance, indicating better metabolic stability. Ligand B (49.122) has significantly higher clearance, which is a concern.
13. **t1/2:** Ligand A (48.668) has a longer in vitro half-life, which is desirable. Ligand B (39.696) has a shorter half-life.
14. **Pgp:** Both ligands have low Pgp efflux (A: 0.142, B: 0.464).
15. **Affinity:** Both ligands have excellent binding affinity (A: -9.4, B: -8.5). Ligand A is slightly better (-9.4 vs -8.5).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. Ligand A clearly wins on metabolic stability (lower Cl_mic, longer t1/2) and has slightly better affinity. The negative solubility and Caco-2 values are concerning for both, but could be assay artifacts.

**Conclusion:**

Despite the concerning solubility and Caco-2 values, Ligand A is the more promising candidate due to its superior metabolic stability and slightly better binding affinity. The lower clearance and longer half-life are significant advantages for an enzyme inhibitor.

1
2025-04-17 13:10:54,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 345.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.13) is better than Ligand B (123.92). Both are acceptable, but lower TPSA generally favors better absorption.

**logP:** Ligand A (-0.279) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (-0.83) is also below the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is better than Ligand B (2 HBD, 8 HBA). Both are within acceptable limits, but fewer H-bonds are generally preferred.

**QED:** Both ligands have good QED scores (0.598 and 0.7), indicating drug-like properties.

**DILI:** Ligand A (34.82) has a significantly lower DILI risk than Ligand B (82.435). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (47.809 and 50.679), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similarly poor Caco-2 permeability (-5.159 and -5.36).

**Aqueous Solubility:** Ligand A (-0.532) is slightly better than Ligand B (-1.94), though both are quite poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.123 and 0.174).

**Microsomal Clearance:** Ligand A (-12.025) has a much lower (better) microsomal clearance than Ligand B (16.862), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (23.75) has a significantly longer half-life than Ligand A (1.587). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.009).

**Binding Affinity:** Both ligands have comparable and strong binding affinity (-8.6 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A excels in DILI risk and microsomal clearance, both crucial for enzyme inhibitors. While its solubility and Caco-2 permeability are poor, the significantly lower DILI and better metabolic stability outweigh these drawbacks. Ligand B has a longer half-life, but the substantially higher DILI risk is a major concern. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are paramount.

Output:
0
2025-04-17 13:10:54,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.555 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (396.925 Da) is still acceptable.

**TPSA:** Ligand A (32.26) is significantly better than Ligand B (66.4). Lower TPSA generally correlates with better cell permeability, a crucial factor for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (A: 4.937, B: 2.686), falling within the 1-3 range. Ligand A is on the higher end, potentially leading to solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is more favorable than Ligand B (HBD=0, HBA=6). A balance is good, and Ligand A achieves this better.

**QED:** Both ligands have similar QED values (A: 0.701, B: 0.675), indicating good drug-like properties.

**DILI:** Ligand B (56.146) has a considerably lower DILI risk than Ligand A (8.414). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (A: 67.468, B: 64.017), which isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.758 and -4.837). This indicates poor permeability, which is concerning.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.708 and -2.826), indicating poor solubility.

**hERG Inhibition:** Ligand A (0.893) shows a slightly higher risk of hERG inhibition than Ligand B (0.197). Lower hERG risk is preferred.

**Microsomal Clearance:** Ligand A (44.665) has significantly lower microsomal clearance than Ligand B (62.124), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (32.697) has a longer in vitro half-life than Ligand B (21.513), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.809) has lower P-gp efflux than Ligand B (0.218), which is favorable for bioavailability.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and lower DILI risk, which are critical for a kinase inhibitor. However, it has a higher TPSA, more HBA, and higher microsomal clearance. Ligand A has better TPSA, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. The solubility and permeability are poor for both. The affinity difference is substantial (-7.3 vs -8.0 kcal/mol), and a 0.3 kcal/mol difference is often decisive.

Output:
1
2025-04-17 13:10:54,050 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [343.471, 56.41, 3.052, 1, 2, 0.836, 31.834, 68.36, -4.56, -2.477, 0.372, 53.409, -18.816, 0.219, -8.2]
**Ligand B:** [367.427, 114.48, 2.098, 2, 6, 0.563, 69.794, 66.886, -5.267, -3.994, 0.22, 15.207, 5.382, 0.094, 0]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (343.471) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (56.41) is excellent, well below the 140 threshold for oral absorption. B (114.48) is higher, but still within a reasonable range.
3. **logP:** Both are within the optimal range (1-3). A (3.052) is slightly higher, which could be a minor concern for off-target effects, but not a major issue. B (2.098) is a bit lower, which might slightly hinder permeability.
4. **HBD:** Both are acceptable (A: 1, B: 2), well below the limit of 5.
5. **HBA:** A (2) is good. B (6) is higher, potentially impacting permeability.
6. **QED:** A (0.836) is very good, indicating high drug-likeness. B (0.563) is acceptable, but less optimal.
7. **DILI:** A (31.834) has a significantly lower DILI risk than B (69.794). This is a crucial advantage.
8. **BBB:** Both have reasonable BBB penetration, but A (68.36) is slightly better than B (66.886). While not a primary concern for a non-CNS target like SRC, it's a positive.
9. **Caco-2:** A (-4.56) is better than B (-5.267), indicating better intestinal absorption.
10. **Solubility:** A (-2.477) is better than B (-3.994), which is important for bioavailability.
11. **hERG:** Both are low, indicating minimal cardiotoxicity risk. A (0.372) is slightly better than B (0.22).
12. **Cl_mic:** A (53.409) has a higher microsomal clearance than B (15.207), meaning it's metabolized faster. This is a disadvantage for A.
13. **t1/2:** A (-18.816) has a negative in vitro half-life, which is a major red flag. B (5.382) has a positive half-life, indicating better metabolic stability.
14. **Pgp:** A (0.219) has lower P-gp efflux than B (0.094), which is favorable for bioavailability.
15. **Binding Affinity:** A (-8.2) has a significantly stronger binding affinity than B (0). This is a very substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite Ligand A's superior binding affinity (-8.2 kcal/mol vs 0 kcal/mol) and better solubility, lower DILI risk, and lower Pgp efflux, its *extremely* poor in vitro half-life (-18.816 hours) and higher microsomal clearance (53.409) are major liabilities. A negative half-life is essentially non-viable. Ligand B, while having a weaker binding affinity, possesses a much more reasonable half-life (5.382 hours) and lower clearance (15.207), indicating better metabolic stability. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand B.

Therefore, **Ligand B** is the more viable drug candidate.

Output:
1
2025-04-17 13:10:54,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.379 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.73 and 71.78) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.713 and 2.512) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable values.

**QED:** Both ligands have high QED scores (0.929 and 0.911), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 82.939, which is high (>60). Ligand B has a much lower DILI risk of 44.591, which is good (<60). This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (70.648) than Ligand A (52.617), but this is less important.

**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 isn't specified, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.061) has a very low hERG risk, which is excellent. Ligand B (0.225) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (8.428) than Ligand B (24.673), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A has a shorter half-life (10.092 hours) than Ligand B (28.098 hours). Longer half-life is generally preferred, giving Ligand B an advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.017 and 0.278).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 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 Ligand A has better metabolic stability and a lower hERG risk, Ligand B's significantly higher binding affinity (-9.2 vs -8.6 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand B has a much lower DILI risk, which is a critical safety parameter. The longer half-life of Ligand B is also favorable. The unusual negative values for Caco-2 and solubility are concerning for both, but the affinity and safety profile of Ligand B are more compelling.

Output:
1
2025-04-17 13:10:54,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.58) is better than Ligand B (68.73), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.145) is quite low, potentially hindering permeation. Ligand B (2.331) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (0) is excellent.

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

**QED:** Ligand B (0.723) has a significantly better QED score than Ligand A (0.478), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (41.838 and 52.966, both <60).

**BBB:** Ligand A (53.819) and Ligand B (81.853). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.982 and -4.575). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.323 and -2.549). This is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.235 and 0.244).

**Microsomal Clearance:** Ligand A (9.184) has a lower Cl_mic than Ligand B (71.45), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (15.98) has a longer half-life than Ligand B (9.709), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.011 and 0.416).

**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 concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better logP and QED score. However, Ligand A has better metabolic stability (lower Cl_mic and longer half-life). The poor Caco-2 and solubility values for both are concerning, but the significantly stronger binding affinity of Ligand B is a critical factor for an enzyme inhibitor. While the lower logP of Ligand A might cause permeability issues, the difference in binding affinity is substantial enough to favor Ligand B, assuming formulation strategies can address the solubility/permeability issues.

Output:
1
2025-04-17 13:10:54,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (333.391 and 352.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.39) is well below the 140 threshold, while Ligand B (120.67) is still acceptable but closer to the limit.

**logP:** Ligand A (3.86) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-0.498) is significantly lower, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have the same QED score (0.683), indicating good drug-likeness.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (51.842), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.501) has a better BBB score than Ligand A (54.478), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.302) has poor predicted permeability, while Ligand B (-5.305) is also poor.

**Aqueous Solubility:** Ligand A (-5.469) has very poor solubility, a significant drawback. Ligand B (-1.13) is better, but still low.

**hERG Inhibition:** Ligand A (0.557) has a higher hERG risk than Ligand B (0.037), which is a major advantage for Ligand B.

**Microsomal Clearance:** Ligand B (10.35) has much lower microsomal clearance than Ligand A (123.917), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (14.534 hours) has a longer half-life than Ligand A (20.52 hours).

**P-gp Efflux:** Ligand A (0.333) has lower P-gp efflux than Ligand B (0.006), which is preferable.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better P-gp efflux, Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk are crucial advantages for an enzyme target like SRC kinase. While Ligand B has lower solubility and permeability, the strong binding affinity might compensate for these issues, and formulation strategies can be employed to address solubility concerns.

Output:
1
2025-04-17 13:10:54,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.447 Da) is slightly higher than Ligand B (338.455 Da), but both are acceptable.

**TPSA:** Ligand A (95.94) is better than Ligand B (59.07) as it is still within the acceptable range for oral absorption (<140), while Ligand B is significantly lower, potentially indicating better absorption.

**logP:** Ligand A (0.845) is within the optimal range (1-3), while Ligand B (4.116) is slightly high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (Ligand A: 0.598, Ligand B: 0.532), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (Ligand A: 15.626, Ligand B: 52.385), both are within the acceptable range (<40 is good, >60 is high risk).

**BBB:** Ligand A (52.191) and Ligand B (54.246) both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.704) and Ligand B (-4.975) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.217) is better than Ligand B (-4.366), indicating better solubility. Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.191) has a significantly lower hERG inhibition risk than Ligand B (0.929). This is a major advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (51.519) has lower microsomal clearance than Ligand B (81.118), suggesting better metabolic stability. This is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-13.899) has a shorter half-life than Ligand B (10.816). This is a drawback for Ligand A, as a longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (Ligand A: 0.03, Ligand B: 0.519).

**Binding Affinity:** Both ligands have similar binding affinity (Ligand A: -8.0 kcal/mol, Ligand B: -8.6 kcal/mol). Ligand B has a slightly better affinity, 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 binding affinity and a longer half-life, Ligand A has significantly lower hERG inhibition risk and better solubility. The lower hERG risk is a critical advantage, and the better solubility will likely improve bioavailability. The slightly shorter half-life of Ligand A can potentially be addressed through structural modifications. The higher logP of Ligand B is a concern.



Output:
0
2025-04-17 13:10:54,051 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [344.39 ,  69.3  ,   1.841,   1.   ,   3.   ,   0.92 ,  38.969,  87.437, -4.744,  -2.583,   0.55 ,  -5.653, -18.124,   0.035,  -9.2  ]
**Ligand B:** [348.447,  89.27 ,   1.575,   2.   ,   6.   ,   0.781,  26.134,  31.834, -5.197,  -2.324,   0.08 ,   8.799,   9.223,   0.044,  -8.2  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (344.39) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.
2. **TPSA:** Ligand A (69.3) is significantly better than Ligand B (89.27).  Lower TPSA generally indicates better permeability.
3. **logP:** Both are within the optimal range (1-3). Ligand A (1.841) is slightly higher, which is acceptable.
4. **HBD:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.
5. **HBA:** Ligand A (3) is preferable to Ligand B (6). Lower HBA generally improves permeability.
6. **QED:** Ligand A (0.92) is significantly better than Ligand B (0.781), indicating a more drug-like profile.
7. **DILI:** Ligand A (38.969) is better than Ligand B (26.134) - lower risk of liver injury.
8. **BBB:** Ligand A (87.437) is much better than Ligand B (31.834). While not a primary concern for a kinase inhibitor, higher BBB is generally a plus.
9. **Caco-2:** Ligand A (-4.744) is better than Ligand B (-5.197). Higher Caco-2 indicates better intestinal absorption.
10. **Solubility:** Ligand A (-2.583) is better than Ligand B (-2.324). Higher solubility is important for bioavailability.
11. **hERG:** Ligand A (0.55) is better than Ligand B (0.08) - lower risk of cardiotoxicity.
12. **Cl_mic:** Ligand A (-5.653) is *much* better than Ligand B (8.799).  A negative value for Cl_mic suggests very slow metabolism and high metabolic stability, a key advantage for an enzyme inhibitor.
13. **t1/2:** Ligand A (-18.124) is better than Ligand B (9.223). A longer half-life is desirable.
14. **Pgp:** Ligand A (0.035) is better than Ligand B (0.044) - lower efflux, improving bioavailability.
15. **Binding Affinity:** Ligand A (-9.2) is slightly better than Ligand B (-8.2). While both are good, the 1 kcal/mol difference is significant.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in all these areas. The superior metabolic stability (Cl_mic) and longer half-life are particularly compelling. The slightly better affinity of Ligand A further strengthens its position.

**Conclusion:**

Ligand A is significantly more likely to be a viable drug candidate than Ligand B.

Output:
1

2025-04-17 13:10:54,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.415 and 362.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.01) is well below the 140 threshold for good absorption, while Ligand B (123.41) is still acceptable but higher.

**logP:** Ligand A (1.528) is within the optimal 1-3 range. Ligand B (0.685) is slightly below 1, which *could* indicate a permeability issue, though not severely.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 6 HBA) are both within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.596 and 0.668, respectively), indicating drug-like properties.

**DILI:** Ligand A (43.971) has a lower DILI risk than Ligand B (62.815), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (70.997) has a better BBB score than Ligand B (39.55).

**Caco-2 Permeability:** Ligand A (-4.79) has a worse Caco-2 permeability than Ligand B (-5.632).

**Aqueous Solubility:** Ligand A (-1.825) has better aqueous solubility than Ligand B (-3.092). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.371 and 0.114, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (39.622) has a significantly higher microsomal clearance than Ligand B (3.452). This means Ligand B is much more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (10.657) has a longer half-life than Ligand B (3.919).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.032, respectively).

**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 (0.2 kcal/mol), it's within the range where it could outweigh other factors.

**Overall Assessment:**

Ligand B has a significantly better metabolic stability profile (lower Cl_mic, longer half-life) and a slightly better binding affinity. While Ligand A has better solubility and a lower DILI risk, the improved metabolic stability of Ligand B is more critical for an enzyme target like SRC kinase. The small difference in affinity is not enough to overcome the metabolic advantage of Ligand B.

Output:
1
2025-04-17 13:10:54,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.335 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.46) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (51.54) is well within the ideal range.

**logP:** Ligand A (3.673) is at the upper end of the optimal 1-3 range, while Ligand B (2.713) is comfortably within it.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5, both acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.451 and 0.573 respectively), indicating moderate drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (80.341) has a higher DILI risk than Ligand B (34.238). This is a significant concern for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand B (71.927) is better than Ligand A (56.766). BBB is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-4.282 and -4.4), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Solubility:** Both have negative solubility values (-6.103 and -2.228), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG:** Both ligands have low hERG inhibition risk (0.697 and 0.422).

**Microsomal Clearance:** Ligand A (71.187) has higher microsomal clearance than Ligand B (51.576), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (15.046) has a significantly longer in vitro half-life than Ligand A (5.843).

**P-gp Efflux:** Both have low P-gp efflux liability (0.497 and 0.521).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a 0.7 kcal/mol difference, which is substantial.

**Conclusion:**

While both compounds have significant drawbacks (poor solubility and permeability), Ligand B is the more promising candidate. It has a significantly better binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic, longer t1/2). The stronger binding affinity could potentially outweigh the solubility and permeability issues, especially if formulation strategies can be employed to address these. Ligand A's higher DILI risk is a major red flag.

Output:
1
2025-04-17 13:10:54,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**
*   **MW:** 387.511 Da - Good (within 200-500 range)
*   **TPSA:** 61.44 - Good (<=140)
*   **logP:** 3.675 - Good (1-3 range)
*   **HBD:** 2 - Good (<=5)
*   **HBA:** 5 - Good (<=10)
*   **QED:** 0.72 - Excellent (>=0.5)
*   **DILI:** 85.964 - High risk (>60)
*   **BBB:** 69.407 - Moderate (not a primary concern for a non-CNS target)
*   **Caco-2:** -4.976 - Poor (negative value suggests very low permeability)
*   **Solubility:** -5.125 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.551 - Low risk
*   **Cl_mic:** 55.451 - Moderate (higher clearance, lower metabolic stability)
*   **t1/2:** 52.25 - Good (relatively long half-life)
*   **Pgp:** 0.396 - Low efflux
*   **Affinity:** -8.4 kcal/mol - Excellent (strong binding)

**Ligand B:**
*   **MW:** 345.407 Da - Good (within 200-500 range)
*   **TPSA:** 138.68 - Borderline (close to the 140 limit, could be problematic)
*   **logP:** 0.65 - Low (below 1, potentially impacting permeability)
*   **HBD:** 4 - Good (<=5)
*   **HBA:** 6 - Good (<=10)
*   **QED:** 0.581 - Acceptable (>=0.5)
*   **DILI:** 63.746 - Moderate risk (>60)
*   **BBB:** 35.246 - Low (not a primary concern)
*   **Caco-2:** -5.915 - Poor (negative value suggests very low permeability)
*   **Solubility:** -2.251 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.198 - Very Low risk
*   **Cl_mic:** 0.479 - Very Low (excellent metabolic stability)
*   **t1/2:** -12.944 - Very short half-life (negative value suggests very short half-life)
*   **Pgp:** 0.008 - Very Low efflux
*   **Affinity:** -8.8 kcal/mol - Excellent (very strong binding, 0.4 kcal/mol better than Ligand A)

**Comparison & Decision:**

Both compounds have excellent binding affinities, with Ligand B being slightly better (-8.8 vs -8.4 kcal/mol). However, both suffer from very poor predicted solubility and Caco-2 permeability. Ligand A has a higher DILI risk and moderate metabolic clearance, while Ligand B has a moderate DILI risk and excellent metabolic stability. Ligand B also has a much lower Pgp efflux.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) is crucial. Ligand B's extremely low Cl_mic is a significant advantage, despite its short predicted half-life. The slightly better affinity of Ligand B, combined with its superior metabolic stability and low Pgp efflux, outweighs the concerns about its slightly higher TPSA and lower logP. While both have poor solubility and permeability, these can potentially be addressed through formulation strategies. The DILI risk is moderate for both, and the hERG risk is low for both.

Therefore, I would choose Ligand B as the more promising drug candidate.

Output:
1
2025-04-17 13:10:54,052 - INFO - Batch 192 complete. Total preferences: 3072
2025-04-17 13:10:54,052 - INFO - Processing batch 193/512...
2025-04-17 13:11:35,014 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.45 and 338.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (103.95 and 97.78) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.385) is optimal, while Ligand B (2.533) is also within the acceptable range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 4/3 HBA, respectively, which are within the acceptable limits.

**QED:** Both ligands have QED values above 0.5 (0.692 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (48.51) has a lower DILI risk than Ligand B (59.64), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (55.22) has a slightly higher BBB penetration than Ligand B (32.80).

**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 very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.385) is slightly better than Ligand B (-4.446).

**hERG Inhibition:** Ligand A (0.119) has a significantly lower hERG risk than Ligand B (0.713), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (29.5 mL/min/kg) has a higher microsomal clearance than Ligand B (14.46 mL/min/kg), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (33.37 hours) has a significantly longer half-life than Ligand A (-24.93 hours, which is nonsensical and indicates very rapid degradation). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.163).

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower hERG risk, which are crucial for an enzyme inhibitor. However, Ligand B has better metabolic stability (lower Cl_mic, longer half-life) and a slightly lower DILI risk. The negative solubility and Caco-2 values are concerning for both, but the superior binding affinity of Ligand A is a compelling factor. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 13:11:35,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.375 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.79) is slightly above the preferred <140, but acceptable. Ligand B (78.51) is excellent, well below 140.

**logP:** Ligand A (-1.786) is a bit low, potentially hindering permeability. Ligand B (1.614) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also good.

**QED:** Both ligands have QED values > 0.5 (0.623 and 0.715), indicating good drug-like properties.

**DILI:** Ligand A (46.452) has a moderate DILI risk, but is still acceptable. Ligand B (15.122) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (66.344) has a higher BBB percentile than Ligand A (16.479), but it's not a deciding factor here.

**Caco-2:** Both ligands have negative Caco-2 values (-5.14 and -5.023), which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Both ligands have negative solubility values (-1.218 and -1.886), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Ligand A (0.017) has a very low hERG risk, which is excellent. Ligand B (0.24) has a slightly higher, but still acceptable, hERG risk.

**Cl_mic:** Ligand A (-18.907) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (-1.179) has a low, but not as impressively low, clearance.

**t1/2:** Ligand A (5.044) has a short in vitro half-life. Ligand B (-2.227) has a negative half-life, which is not possible and indicates a potential issue with the data or prediction.

**Pgp:** Both ligands have very low Pgp efflux liability (0.009 and 0.043).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and solubility, Ligand B is the better candidate. Its significantly stronger binding affinity (-9.8 vs -8.5 kcal/mol) is a major advantage for an enzyme target. It also has a much lower DILI risk and a better (though questionable) half-life. While Ligand A has a better hERG profile and better metabolic stability, the potency advantage of Ligand B is more critical for kinase inhibitors. The negative half-life for Ligand B is concerning and would need further investigation, but the overall profile is still more promising.

Output:
1
2025-04-17 13:11:35,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.419 Da and 362.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.18) is higher than Ligand B (40.85). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.263) is quite low, potentially hindering permeability. Ligand B (3.502) is within the optimal range of 1-3. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.707 and 0.685), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (28.306 and 27.065), which is favorable.

**BBB:** Ligand B (85.343) has a much higher BBB percentile than Ligand A (62.195). While SRC isn't a CNS target, higher BBB is generally a positive indicator of reduced off-target effects.

**Caco-2 Permeability:** Ligand A (-4.906) and Ligand B (-4.955) have similar, and poor, Caco-2 permeability scores.

**Aqueous Solubility:** Ligand A (-0.965) and Ligand B (-2.045) have poor aqueous solubility scores.

**hERG:** Both ligands have low hERG inhibition liability (0.142 and 0.892), which is excellent.

**Microsomal Clearance:** Ligand A (5.815) has significantly lower microsomal clearance than Ligand B (54.19). Lower clearance indicates better metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-28.526) has a much longer in vitro half-life than Ligand B (24.135). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux liability, while Ligand B (0.616) has moderate liability. Lower P-gp efflux is preferable.

**Binding Affinity:** Ligand B (-9.9) has a significantly stronger binding affinity than Ligand A (-8.3). A 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior logP, TPSA, and binding affinity. However, Ligand A exhibits better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. The binding affinity difference is substantial. Considering the enzyme-specific priorities, the stronger binding affinity of Ligand B is the most important factor. While Ligand A's metabolic stability is attractive, the potency advantage of Ligand B is likely to be more impactful in driving efficacy. The solubility and Caco-2 permeability are poor for both, which would need to be addressed in further optimization.

Output:
1
2025-04-17 13:11:35,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (330.347 Da) is slightly lower, which is generally favorable for permeability. Ligand B (348.487 Da) is also good.

**TPSA:** Ligand A (87.9) is better than Ligand B (49.85). Both are below 140, indicating good oral absorption potential.

**logP:** Both ligands have good logP values (A: 3.276, B: 2.607), 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 (HBD <= 5, HBA <= 10).

**QED:** Ligand A (0.793) has a better QED score than Ligand B (0.634), suggesting a more drug-like profile.

**DILI:** Ligand A (98.876) has a significantly higher DILI risk than Ligand B (6.747). This is a major concern for Ligand A.

**BBB:** Ligand B (84.917) has a higher BBB penetration percentile than Ligand A (48.042), but BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.888) has a lower Caco-2 permeability than Ligand B (-4.443). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-5.748) has poorer aqueous solubility than Ligand B (-2.019). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.746) has a higher hERG inhibition risk than Ligand B (0.371). Lower is better here, favoring Ligand B.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (A: 52.373, B: 53.891). These are relatively high, indicating moderate metabolic instability.

**In vitro Half-Life:** Ligand B (-4.832) has a negative half-life, which is not possible. This is likely an error in the data, but it is a significant red flag. Ligand A (14.193) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.322) has lower P-gp efflux liability than Ligand B (0.048), which is favorable.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and better P-gp efflux, but suffers from high DILI risk, poor solubility, and lower Caco-2 permeability. Ligand B has a better safety profile (DILI, hERG), better solubility, and slightly better permeability, but significantly weaker binding affinity.

Given the enzyme-specific priorities, binding affinity is paramount. The 1.3 kcal/mol difference in binding affinity is substantial. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications during lead optimization. The solubility and permeability issues are also addressable. The erroneous half-life for Ligand B is a major issue.

Output:
1
2025-04-17 13:11:35,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 342.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.55) is better than Ligand B (83.68) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (-0.138) is quite low, potentially hindering permeability. Ligand B (3.155) 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) is slightly higher in both counts than Ligand B (1 HBD, 4 HBA), but both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.642 and 0.559), indicating reasonable drug-likeness.

**DILI:** Ligand A (39.434) has a slightly better DILI score than Ligand B (47.732), indicating lower potential for liver injury. Both are still acceptable (<60).

**BBB:** Ligand A (69.833) has a better BBB score than Ligand B (54.052), but BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.315 and -4.913), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.321 and -3.112), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.095) has a slightly better hERG profile than Ligand B (0.521), suggesting lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (16.407) has a higher microsomal clearance than Ligand B (13.184), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-18.962) has a significantly longer in vitro half-life than Ligand A (5.527), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.049), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

While Ligand A has a slightly better DILI and hERG profile, Ligand B is significantly better in terms of logP, metabolic stability (half-life and clearance), and has a reasonable TPSA. The poor solubility and permeability are concerns for both, but the superior pharmacokinetic properties of Ligand B, particularly its metabolic stability, outweigh the slight advantages of Ligand A. Given the enzyme-kinase specific priorities, metabolic stability and potency are key. Since the potency is the same, the better metabolic stability of Ligand B makes it the more viable candidate.

Output:
1
2025-04-17 13:11:35,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (382.404 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is better than Ligand B (49.41) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (1.293) is optimal, while Ligand B (3.911) 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) is preferable to Ligand B (1 HBD, 2 HBA). Fewer hydrogen bond donors and acceptors generally improve membrane permeability.

**QED:** Both ligands have good QED scores (0.648 and 0.766), indicating drug-like properties.

**DILI:** Ligand A (47.732) has a slightly higher DILI risk than Ligand B (16.208), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (70.57 and 73.711), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.459) and Ligand B (-4.37) have similar, poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-2.671) is slightly better than Ligand B (-4.415), but both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.356 and 0.166), which is excellent.

**Microsomal Clearance:** Ligand A (56.76) has lower microsomal clearance than Ligand B (79.523), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-17.31) has a much longer in vitro half-life than Ligand B (3.824), indicating better persistence.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.071).

**Binding Affinity:** Both ligands have comparable binding affinity (-8.0 and -8.2 kcal/mol).

**Overall Assessment:**

Ligand A is slightly better due to its more optimal logP, lower microsomal clearance, and significantly longer half-life. While its solubility and Caco-2 permeability are poor, the improved metabolic stability and half-life are more critical for an enzyme inhibitor. The DILI risk is slightly higher, but still acceptable. The binding affinity is comparable between the two.

Output:
1
2025-04-17 13:11:35,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is slightly higher than Ligand B (60.93). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.214 and 1.051), 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 similar QED scores (0.799 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A (14.889) has a significantly lower DILI risk than Ligand B (20.706), which is a strong advantage.

**BBB:** Ligand B (93.331) has a much higher BBB penetration score than Ligand A (51.066). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.791 and -4.503), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.463 and -1.363), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.133) has a lower hERG inhibition liability than Ligand B (0.243), which is preferable.

**Microsomal Clearance:** Ligand A (-3.312) has a much *lower* (better) microsomal clearance than Ligand B (19.428). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (21.872) has a longer in vitro half-life than Ligand B (-8.806). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.024) has a lower P-gp efflux liability than Ligand B (0.064), which is beneficial.

**Binding Affinity:** Ligand B (-8.5) has a *much* stronger binding affinity than Ligand A (0). This is a substantial advantage, potentially outweighing some of the ADME concerns. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand A has superior ADME properties (lower DILI, better metabolic stability, longer half-life, lower P-gp efflux, lower hERG), Ligand B's binding affinity is dramatically better. For an enzyme target like SRC kinase, potency is paramount. The strong binding affinity of Ligand B (-8.5 kcal/mol) is a significant advantage that likely outweighs the ADME liabilities, *provided* that solubility and permeability can be addressed through formulation or structural modifications. The negative Caco-2 and solubility values are concerning, but not insurmountable.

Output:
1
2025-04-17 13:11:35,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 Da and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is well below the 140 threshold for good absorption and is preferable. Ligand B (102.34) is still acceptable, but less ideal.

**logP:** Ligand A (1.237) is within the optimal 1-3 range. Ligand B (-1.055) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.707) has a better QED score than Ligand B (0.58), indicating a more drug-like profile.

**DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (15.51), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.864) is lower than Ligand B (27.918).

**Caco-2 Permeability:** Ligand A (-4.517) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.37) is similarly poor. This is a potential red flag for both.

**Aqueous Solubility:** Ligand A (-1.759) and Ligand B (0.023) both have poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.214) has a very low hERG risk, which is excellent. Ligand B (0.038) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (27.105) has a higher microsomal clearance than Ligand B (2.049), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (1.495) has a very short half-life, consistent with the higher clearance. Ligand B (6.838) has a much better half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.003, respectively).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although both are good. The 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor Caco-2 and solubility, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and lower DILI risk outweigh Ligand A's slightly better TPSA and QED. The poor permeability of both is a concern that would need to be addressed in further optimization, but Ligand B's overall profile is more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 13:11:35,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.359 and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.51) is better than Ligand B (121.96), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.938) is slightly better than Ligand B (0.19), both are a bit low, potentially hindering permeation, but not severely.

**H-Bond Donors:** Both have 3 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 5. Both are within the acceptable range (<=10).

**QED:** Ligand A (0.719) has a better QED score than Ligand B (0.535), indicating a more drug-like profile.

**DILI:** Ligand B (33.307) has a significantly lower DILI risk than Ligand A (76.89), which is a major advantage.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand A (80.69) is slightly better than Ligand B (32.532).

**Caco-2:** Both have negative Caco-2 values (-5.245 and -5.762), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-3.502) has slightly better solubility than Ligand B (-1.44), but both are quite poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.266 and 0.194), which is excellent.

**Microsomal Clearance:** Ligand B (10.783) has a lower microsomal clearance than Ligand A (12.514), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-6.269) has a negative half-life, which is concerning and suggests rapid degradation. Ligand A (26.468) has a much more reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.02 and 0.023).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.8 vs -10 kcal/mol) and lower DILI risk (33.3 vs 76.9). It also exhibits better metabolic stability (lower Cl_mic). However, it has a concerning negative in vitro half-life and lower solubility. Ligand A has a better QED and a more reasonable half-life, but its DILI risk is high and its binding affinity is weaker.

Given the importance of potency for kinase inhibitors, and the relatively manageable ADME issues of Ligand B (solubility and half-life could be addressed with formulation or further optimization), Ligand B is the more promising candidate.

Output:
1
2025-04-17 13:11:35,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.323 and 372.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.18) is slightly higher than Ligand B (83.98), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.845 and 2.214), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 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 (0.516 and 0.641), indicating good drug-like properties.

**DILI:** Ligand A (79.721) has a slightly higher DILI risk than Ligand B (70.958), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (71.268 and 72.354), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.649 and -4.873), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.153 and -3.676), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.604) has a slightly higher hERG inhibition risk than Ligand B (0.279). Lower is better, so Ligand B is preferable here.

**Microsomal Clearance:** Ligand A (97.133) has significantly higher microsomal clearance than Ligand B (18.262). This means Ligand A is likely to be metabolized more quickly, reducing its duration of action. Ligand B is much better in terms of metabolic stability.

**In vitro Half-Life:** Ligand A (-42.939) has a negative half-life, which is not possible and suggests a very rapid degradation. Ligand B (7.383) has a short but positive half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.815 and 0.049), 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 crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

While both ligands have significant drawbacks (poor solubility and permeability), Ligand B is the better candidate. Its substantially stronger binding affinity (-7.7 vs -8.3 kcal/mol) is a major advantage. Furthermore, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, positive half-life) and lower hERG risk. The slightly lower DILI risk is also a plus. The poor solubility and permeability would need to be addressed through formulation strategies, but the superior potency and pharmacokinetic properties of Ligand B make it the more promising starting point.

Output:
1
2025-04-17 13:11:35,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (383.539 Da and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is slightly higher than Ligand B (68.3). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets (not a priority here).

**logP:** Ligand A (1.295) is optimal, while Ligand B (3.241) is approaching the upper limit of the optimal range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.672 and 0.668), indicating good drug-likeness.

**DILI:** Ligand A (37.456) has a slightly better DILI score than Ligand B (34.665), both are below 40, indicating low risk.

**BBB:** Ligand A (46.762) has a lower BBB penetration percentile than Ligand B (90.306). BBB is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.568) and Ligand B (-5.043) both have negative values, which is unusual. Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.36) and Ligand B (-3.004) both have negative solubility values, which is also unusual. Lower values indicate lower solubility.

**hERG Inhibition:** Ligand A (0.199) has a significantly lower hERG inhibition liability than Ligand B (0.879). This is a crucial advantage.

**Microsomal Clearance:** Ligand B (75.675) has a much higher microsomal clearance than Ligand A (7.263), suggesting Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand B (30.048) has a longer in vitro half-life than Ligand A (4.995).

**P-gp Efflux:** Ligand A (0.055) has a much lower P-gp efflux liability than Ligand B (0.306), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). The difference is 0.8 kcal/mol.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and a longer half-life, Ligand A is superior in several critical ADME-Tox properties. Specifically, Ligand A exhibits significantly lower hERG inhibition, lower P-gp efflux, and much better metabolic stability (lower Cl_mic). The 0.8 kcal/mol difference in binding affinity is unlikely to outweigh these substantial advantages in ADME-Tox, especially considering the target is an enzyme. The solubility and permeability values are concerning for both, but the other advantages of Ligand A make it a more promising candidate.

Output:
0
2025-04-17 13:11:35,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (75.44) is still under 140, but less favorable than A.

**logP:** Both ligands (2.365 and 1.999) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (1 HBD, 4 HBA) is also acceptable, but slightly less optimal.

**QED:** Ligand B (0.846) has a significantly higher QED score than Ligand A (0.385), suggesting a more drug-like profile overall.

**DILI:** Ligand A (31.059) has a lower DILI risk than Ligand B (44.048), which is preferable. Both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.794) is better than Ligand B (45.832), but neither is particularly high.

**Caco-2 Permeability:** Ligand A (-4.519) has a more negative Caco-2 value, indicating *lower* permeability than Ligand B (-5.079). This is a negative for Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.195 and -2.534). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.415) has a lower hERG risk than Ligand B (0.082), which is a major advantage.

**Microsomal Clearance:** Ligand A (26.288) has a lower microsomal clearance, indicating better metabolic stability than Ligand B (42.371).

**In vitro Half-Life:** Ligand A (8.515) has a longer in vitro half-life than Ligand B (1.743), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.286 and 0.057).

**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. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's advantages in DILI, hERG, metabolic stability, and half-life, the significantly superior binding affinity of Ligand B (-8.9 vs 0.0 kcal/mol) is the overriding factor. While Ligand B has some ADME concerns (lower QED, solubility, and slightly higher DILI), the potency advantage is substantial. The solubility issues could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:11:35,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.446 and 376.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is slightly higher than Ligand B (67.43), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.169 and 2.79), falling within the 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:** Ligand A (0.725) has a better QED score than Ligand B (0.576), indicating a more drug-like profile.

**DILI:** Ligand B (36.565) has a significantly lower DILI risk than Ligand A (12.641), which is a major advantage.

**BBB:** Ligand B (79.682) has a higher BBB penetration percentile than Ligand A (57.231), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.817 and -4.826), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.369 and -2.682), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.227) has a lower hERG inhibition liability than Ligand B (0.635), which is favorable.

**Microsomal Clearance:** Ligand B (44.381) has a much higher microsomal clearance than Ligand A (0.853), indicating poorer metabolic stability. This is a significant disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-3.307) has a more favorable (longer) in vitro half-life than Ligand B (-21.353).

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux liability than Ligand B (0.062), which is slightly better.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, 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. The key factors are Ligand A's significantly better metabolic stability (lower Cl_mic, longer t1/2), better QED score, and lower hERG risk. While both have poor solubility and permeability, the metabolic advantages of Ligand A outweigh the small affinity difference. The lower DILI risk of Ligand B is attractive, but the poor metabolic stability is a critical flaw.

Output:
0
2025-04-17 13:11:35,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (130.23) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (94.11) is well within the optimal range.

**3. logP:** Ligand A (0.401) is a bit low, potentially hindering permeation. Ligand B (-0.687) is even lower, raising more concerns about permeability.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (2) 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: 0.528, B: 0.596), indicating drug-like properties.

**7. DILI:** Ligand A (54.75) has a moderate DILI risk, but is still acceptable. Ligand B (24.855) has a significantly lower DILI risk, which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.774) and Ligand B (28.538) are both low.

**9. Caco-2 Permeability:** Both have negative values (-5.47 and -5.272), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative values (-2.303 and -1.823), indicating poor aqueous solubility, which could hinder bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.127, B: 0.064), which is excellent.

**12. Microsomal Clearance:** Ligand A (15.247) has a higher microsomal clearance, suggesting faster metabolism and lower metabolic stability. Ligand B (-21.834) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.457) has a negative half-life, which is impossible and likely an error in the data. Ligand B (-6.173) also has a negative half-life, also an error.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.007, B: 0.002), which is favorable.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, and the impossible half-life values, Ligand B is the more promising candidate. Its significantly lower DILI risk and *exceptionally* low (and likely erroneous) microsomal clearance are major advantages. While both have poor predicted permeability and solubility, the metabolic stability advantage of Ligand B outweighs the slight TPSA difference. The binding affinities are comparable. The negative half-life values are concerning and warrant further investigation, but the other factors favor Ligand B.

Output:
1
2025-04-17 13:11:35,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.427 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (55.21) is significantly better than Ligand B (86.71). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 2.9, B: 1.391) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=2, HBA=4) as it has fewer hydrogen bond donors, which can improve membrane permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED values (A: 0.776, B: 0.749), indicating good drug-like properties.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (43.66). This is a negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.921) is better than Ligand B (48.972).

**Caco-2 Permeability:** Ligand A (-4.783) is better than Ligand B (-5.191), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.809) is better than Ligand B (-3.427). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.924, B: 0.495), which is good.

**Microsomal Clearance:** Ligand B (42.27) has a lower microsomal clearance than Ligand A (56.589), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-37.088) has a significantly longer in vitro half-life than Ligand A (17.281). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.477) has lower P-gp efflux than Ligand B (0.283), which is favorable.

**Binding Affinity:** Ligand A (-7.5) has a slightly stronger binding affinity than Ligand B (-7.3). While a 1.5 kcal/mol difference is generally significant, the other ADME properties of Ligand B are more compelling.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B demonstrates superior ADME properties crucial for an enzyme inhibitor. Specifically, its lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and better solubility outweigh the minor difference in binding affinity. The TPSA is also more favorable for permeability.

Output:
1
2025-04-17 13:11:35,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.304 Da) is slightly higher than Ligand B (368.371 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (55.56) is higher than Ligand B (49.85), but both are well within the acceptable range.

**logP:** Both ligands have logP values between 1 and 3, which is optimal. Ligand A (3.32) is slightly higher than Ligand B (2.153).

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within the recommended limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.859) is slightly better than Ligand B (0.715).

**DILI:** Ligand A (31.563) has a lower DILI risk than Ligand B (25.553), which is favorable.

**BBB:** Both ligands have high BBB penetration, but Ligand B (87.864) is slightly better than Ligand A (82.513). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.035) is worse than Ligand B (-4.252).

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting very poor solubility. Ligand A (-3.802) is worse than Ligand B (-2.248).

**hERG Inhibition:** Both ligands have low hERG inhibition risk, which is good. Ligand A (0.884) is slightly higher than Ligand B (0.625).

**Microsomal Clearance:** Ligand A (19.539 mL/min/kg) has a lower microsomal clearance than Ligand B (25.93 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (24.18 hours) has a significantly longer half-life than Ligand B (-15.162 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.417) has lower P-gp efflux than Ligand B (0.027), suggesting better bioavailability.

**Binding Affinity:** Both ligands have strong binding affinities (-9.5 kcal/mol and -8.5 kcal/mol, respectively). Ligand A has a 1 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A exhibits a significantly longer half-life, lower microsomal clearance, lower P-gp efflux, and a slightly better binding affinity. The lower DILI risk is also a positive factor. The binding affinity difference is large enough to potentially overcome the solubility/permeability concerns, especially given that these can be addressed through formulation strategies.

Output:
1
2025-04-17 13:11:35,018 - INFO - Batch 193 complete. Total preferences: 3088
2025-04-17 13:11:35,018 - INFO - Processing batch 194/512...
2025-04-17 13:12:30,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (379.825 and 360.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (108.19) is better than Ligand B (114.12), both are acceptable but closer to the upper limit for good oral absorption.

**logP:** Both ligands (2.161 and 2.364) are within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Ligand A (0.747) has a significantly better QED score than Ligand B (0.348), indicating a more drug-like profile.

**DILI:** Ligand A (91.237) has a higher DILI risk than Ligand B (50.097). This is a concern for Ligand A.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**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, which is also unusual and suggests poor solubility. Again, values are similar.

**hERG:** Ligand A (0.16) has a much lower hERG risk than Ligand B (0.42), which is a significant advantage.

**Microsomal Clearance:** Ligand A (6.781) has a much lower microsomal clearance than Ligand B (30.029), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-27.674) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound itself. Ligand B (13.978) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability.

**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 relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand B has a better binding affinity and half-life, but Ligand A excels in QED, hERG risk, and significantly better metabolic stability (lower Cl_mic). The negative half-life for Ligand A is a major red flag. The higher DILI risk for Ligand A is concerning, but can potentially be mitigated with structural modifications. Given the importance of metabolic stability for enzyme inhibitors, and the relatively small difference in binding affinity, Ligand A is the more promising candidate *if* the half-life data can be corrected or explained. However, the negative half-life is a serious issue.

Considering the issues with the data for Ligand A, and the better overall profile of Ligand B, I will choose Ligand B.

Output:
1
2025-04-17 13:12:30,152 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.442 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.11 and 91.81) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (-0.485) is slightly low, potentially hindering permeation. Ligand B (1.398) is within the optimal 1-3 range. This favors Ligand B.

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

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

**QED:** Both ligands have QED values above 0.5 (0.595 and 0.633), indicating good drug-like properties.

**DILI:** Ligand A (13.804) has a significantly lower DILI risk than Ligand B (49.593). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (35.401) has a higher BBB value than Ligand A (23.42), but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.141 and -5.525), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.471 and -2.82), indicating very poor aqueous solubility. This is a significant drawback for both, but worse for Ligand B.

**hERG:** Both ligands have low hERG inhibition liability (0.248 and 0.272), which is positive.

**Microsomal Clearance:** Ligand A (-6.475) has a much lower (better) microsomal clearance than Ligand B (6.887), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (1.659) has a lower in vitro half-life than Ligand B (8.288). This favors Ligand B, but the difference isn't huge.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.022 and 0.04), which is good.

**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 of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While it has a higher DILI risk and worse solubility, the strong binding affinity is a significant advantage. Ligand A has better metabolic stability (lower Cl_mic) and lower DILI, but its weaker binding affinity is a major drawback. Given the potency advantage of Ligand B, it is the more promising candidate, despite its ADME liabilities.

Output:
1
2025-04-17 13:12:30,152 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 345.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (81.75) is better than Ligand B (43.86) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (1.605) is better than Ligand A (-0.12). A negative logP can indicate poor membrane permeability. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). While both are acceptable, a small number of HBDs can sometimes improve permeability.

**H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3). Both are within the acceptable range.

**QED:** Both ligands have similar, good QED values (0.55 and 0.562).

**DILI:** Ligand B (6.592) is significantly better than Ligand A (22.489). Lower DILI risk is crucial.

**BBB:** Ligand B (61.613) is better than Ligand A (46.452), but neither is particularly high. BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.128) is better than Ligand B (-4.631). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-1.645) is better than Ligand B (-0.968). Higher solubility is preferred.

**hERG Inhibition:** Ligand A (0.198) is better than Ligand B (0.307). Lower hERG inhibition is critical to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (-5.393) is significantly better than Ligand B (-10.9). Lower clearance indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-13.047) is better than Ligand B (-4.708). A longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.011) is significantly better than Ligand B (0.042). Lower P-gp efflux is preferable.

**Binding Affinity:** Ligand B (-8.7) is slightly better than Ligand A (-7.8). A 0.9 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and logP, but Ligand A excels in metabolic stability (Cl_mic, t1/2), DILI risk, hERG inhibition, and P-gp efflux. Given the enzyme-specific priorities, the improved metabolic stability and safety profile of Ligand A are more important than the slightly better affinity of Ligand B. The negative logP of Ligand A is a concern, but the other advantages are substantial.

Output:
0
2025-04-17 13:12:30,152 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.411 and 337.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (1.087) is closer to the lower end of the optimal 1-3 range, while Ligand B (2.296) is more centrally located. Both are acceptable, but Ligand B's logP is slightly preferred.

**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 good QED scores (0.786 and 0.897, respectively), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (35.634 and 32.842 percentiles), which is excellent.

**BBB:** Ligand A (54.091) has a lower BBB penetration percentile than Ligand B (71.733). Since SRC is not a CNS target, this is less critical, but higher is generally better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.488 and -4.619), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.629 and -2.382), also indicating poor solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.178 and 0.027 percentiles), which is excellent.

**Microsomal Clearance:** Ligand A (-6.375 mL/min/kg) has significantly lower (better) microsomal clearance than Ligand B (43.685 mL/min/kg). This suggests much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-0.05 hours) has a very short half-life, while Ligand B (-10.127 hours) is also short, but significantly longer than A. Both are concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.028 percentiles), which is favorable.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). 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). However, it has a very short in vitro half-life and poor Caco-2 permeability and solubility. Ligand B has better solubility and a longer half-life but has significantly worse metabolic stability. The poor permeability and solubility of both compounds are major concerns.

Given the enzyme-specific priorities, metabolic stability is crucial. The substantial difference in Cl_mic favors Ligand A. The slightly better binding affinity of A further strengthens its position. While the poor half-life of A is a concern, it might be addressable through structural modifications. The poor metabolic stability of B is harder to fix.

Output:
0
2025-04-17 13:12:30,152 - INFO - Okay, let's analyze these two ligands (A and B) as potential drug candidates targeting SRC, a kinase. I will follow the provided guidelines and protein-class-specific priorities (enzymes: potency, metabolic stability, solubility, and hERG risk).

**Ligand A: [340.442, 55.12, 4.513, 2, 2, 0.805, 55.68, 80.962, -4.745, -5.754, 0.837, 70.326, 25.659, 0.303, -8.5]**
**Ligand B: [394.871, 58.64, 3.386, 1, 4, 0.771, 55.68, 82.862, -4.775, -4.122, 0.612, 22.621, -0.423, 0.285, -7.3]**

**1. Molecular Weight (MW):**
   - A: 340.442 Da - Excellent, within the ideal range.
   - B: 394.871 Da - Good, still within the ideal range, but approaching the upper limit.

**2. TPSA:**
   - A: 55.12  - Good, well below the 140 threshold for oral absorption.
   - B: 58.64 - Good, still below the threshold.

**3. logP:**
   - A: 4.513 - Slightly high, could potentially lead to solubility issues or off-target interactions.
   - B: 3.386 - Optimal, within the 1-3 range.

**4. H-Bond Donors (HBD):**
   - A: 2 - Good, within the acceptable limit.
   - B: 1 - Good, within the acceptable limit.

**5. H-Bond Acceptors (HBA):**
   - A: 2 - Good, within the acceptable limit.
   - B: 4 - Good, within the acceptable limit.

**6. QED:**
   - A: 0.805 - Excellent, highly drug-like.
   - B: 0.771 - Good, still drug-like.

**7. DILI:**
   - A: 55.68 - Moderate risk, but acceptable.
   - B: 55.68 - Moderate risk, but acceptable. Both are the same.

**8. BBB:**
   - A: 80.962 - Good, suggests some potential for CNS penetration, but not a primary concern for SRC.
   - B: 82.862 - Good, similar to A.

**9. Caco-2 Permeability:**
   - A: -4.745 - Poor permeability.
   - B: -4.775 - Poor permeability. Both are similar.

**10. Aqueous Solubility:**
   - A: -5.754 - Very poor solubility. A significant concern.
   - B: -4.122 - Poor solubility, but better than A.

**11. hERG Inhibition:**
   - A: 0.837 - Acceptable risk.
   - B: 0.612 - Lower risk, slightly better.

**12. Microsomal Clearance (Cl_mic):**
   - A: 70.326 - Moderate clearance, suggesting moderate metabolic stability.
   - B: 22.621 - Low clearance, indicating good metabolic stability. This is a significant advantage for B.

**13. In vitro Half-Life (t1/2):**
   - A: 25.659 - Moderate half-life.
   - B: -0.423 - Very long half-life. A significant advantage for B.

**14. P-gp Efflux:**
   - A: 0.303 - Low efflux, good.
   - B: 0.285 - Low efflux, good.

**15. Binding Affinity:**
   - A: -8.5 kcal/mol - Excellent, very strong binding.
   - B: -7.3 kcal/mol - Good, strong binding, but 1.2 kcal/mol weaker than A.

**Overall Assessment:**

Ligand A has a superior binding affinity (-8.5 kcal/mol vs -7.3 kcal/mol). However, its poor solubility (-5.754) and moderate permeability (-4.745) are major drawbacks. While the binding affinity is a significant advantage, poor solubility can severely limit bioavailability.

Ligand B, while having a slightly weaker binding affinity, possesses significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility. Its logP is also more optimal. For a kinase inhibitor, metabolic stability is crucial for maintaining therapeutic concentrations.

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), **Ligand B** is the more promising candidate. The 1.2 kcal/mol difference in binding affinity can potentially be overcome with further optimization, while addressing the solubility issues of Ligand A would be more challenging.

Output:
1
2025-04-17 13:12:30,152 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (336.391 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (67.43 and 67.35) well below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.614 and 2.015) 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:** Both ligands have good QED scores (0.846 and 0.908), indicating a drug-like profile.

**DILI:** Ligand A has a DILI risk of 77.627, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 26.173, which is good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (69.95 and 77.627). BBB is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.918 and -4.947), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values might indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.308 and -1.33). Again, these are on a log scale and indicate poor aqueous solubility. Ligand B is slightly better in this regard.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.461 and 0.326), which is positive.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (25.533 mL/min/kg) than Ligand B (11.141 mL/min/kg). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand A has a longer half-life (13.414 hours) than Ligand B (4.195 hours). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.404 and 0.053).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.9 kcal/mol) than Ligand A (-8.1 kcal/mol). While both are excellent, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly longer half-life, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The solubility and permeability issues are similar for both, and the hERG risk is low for both. Given the enzyme-specific priorities, the lower DILI and better metabolic stability of Ligand B outweigh the slightly longer half-life of Ligand A.

Output:
1
2025-04-17 13:12:30,152 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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, while Ligand B (371.418 Da) is still well within the range.

**TPSA:** Ligand B (70.16) is significantly better than Ligand A (107.19). Lower TPSA generally correlates with better cell permeability, a crucial factor for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (A: 0.526, B: 0.737), falling within the 1-3 range. Ligand B is slightly better.

**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:** Both ligands have similar and good QED values (A: 0.651, B: 0.667), indicating good drug-like properties.

**DILI:** Ligand B (15.355) has a much lower DILI risk than Ligand A (41.411). This is a significant advantage, as minimizing liver toxicity is critical.

**BBB:** Ligand A (40.093) has a slightly better BBB penetration potential than Ligand B (32.067), but this is less important for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-5.33) has a worse Caco-2 permeability than Ligand B (-4.769).

**Aqueous Solubility:** Ligand A (-2.517) has a worse aqueous solubility than Ligand B (-0.959). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.157, B: 0.226).

**Microsomal Clearance:** Ligand A (-4.665) has a much lower (better) microsomal clearance than Ligand B (9.958). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-15.438) has a much longer in vitro half-life than Ligand B (0.656). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.014, B: 0.026).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.7 kcal/mol, B: -8.0 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other significant ADME differences.

**Overall Assessment:**

Ligand B is superior due to its significantly lower DILI risk, better TPSA, and better solubility. While Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, the lower DILI risk of Ligand B is a more critical factor for drug development, especially for an oncology target where chronic administration is likely. The slight difference in binding affinity is not enough to overcome the ADME advantages of Ligand B.

Output:
1
2025-04-17 13:12:30,153 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.73) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (76.66) is well within the ideal range.

**logP:** Ligand A (0.348) is a bit low, potentially hindering permeation. Ligand B (1.335) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are reasonable. Ligand B has 2 HBD and 5 HBA, also reasonable.

**QED:** Both ligands have acceptable QED scores (0.785 and 0.661, both >0.5).

**DILI:** Both ligands have low DILI risk (41.722 and 33.656, both <40).

**BBB:** Ligand A (36.836) has a low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (62.544) is better, but still not high.

**Caco-2 Permeability:** Ligand A (-4.415) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.493) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.113 and -1.878). This is a concern for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.177 and 0.276).

**Microsomal Clearance:** Ligand A (44.129) has a higher microsomal clearance than Ligand B (24.113), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.845) has a significantly longer in vitro half-life than Ligand A (-19.623), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.049 and 0.055).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.9 and -9.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a significantly longer half-life and better metabolic stability (lower Cl_mic). Its logP is also more favorable. The slightly better BBB penetration is a minor benefit. The binding affinity difference is negligible. The poor solubility and permeability would need to be addressed in further optimization, but the improved pharmacokinetic properties of Ligand B make it the more promising starting point.

Output:
1
2025-04-17 13:12:30,153 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.503 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (104.46).  A TPSA under 90 is preferred, and Ligand A is comfortably within this range, suggesting better permeability. Ligand B is pushing the upper limit for good oral absorption.

**3. logP:** Both ligands have good logP values (2.76 and 1.941), 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 (5) for similar reasons as HBD.

**6. QED:** Both ligands have similar and acceptable QED values (0.651 and 0.664), indicating good drug-like properties.

**7. DILI:** Ligand A (16.751) has a much lower DILI risk than Ligand B (30.361). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (83.288) has a better BBB percentile than Ligand B (57.774), although BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.4) has slightly better Caco-2 permeability than Ligand B (-4.856).

**10. Aqueous Solubility:** Ligand A (-3.187) has slightly better aqueous solubility than Ligand B (-2.804).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.47 and 0.256), which is excellent.

**12. Microsomal Clearance:** Ligand A (95.752) has a higher microsomal clearance than Ligand B (49.494). This means Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-2.012) has a better in vitro half-life than Ligand A (-13.421). This further supports the better metabolic stability of Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.317 and 0.09).

**15. Binding Affinity:** Both ligands have identical binding affinities (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B demonstrates superior metabolic stability (lower Cl_mic, better t1/2), Ligand A has advantages in TPSA, HBD/HBA counts, DILI risk, and solubility. Given the equal binding affinity, the better ADME profile of Ligand A, particularly the lower DILI risk and improved permeability characteristics (lower TPSA), makes it the more promising candidate. The metabolic stability of Ligand B is a concern that might be addressed through structural modifications, but the immediate advantage lies with Ligand A's more balanced profile.

Output:
1
2025-04-17 13:12:30,153 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which could be advantageous for permeability. Ligand B (376.408 Da) is also acceptable.

**TPSA:** Ligand A (65.46) is well below the 140 threshold for good oral absorption. Ligand B (97.03) is still under the threshold but less favorable than A.

**logP:** Both ligands have good logP values (A: 3.093, B: 2.029) 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 7 HBA. Lower HBA is generally preferred for better permeability, giving A an edge.

**QED:** Both ligands have similar QED values (A: 0.899, B: 0.83), indicating good drug-likeness.

**DILI:** Ligand A (21.985) has a significantly lower DILI risk than Ligand B (61.807). This is a major advantage for Ligand A.

**BBB:** Both have good BBB penetration (A: 72.005, B: 78.945), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.776) has a more negative Caco-2 value, suggesting *lower* permeability. Ligand B (-5.406) is even lower. This is a potential concern for both, but more so for B.

**Aqueous Solubility:** Ligand A (-2.522) has better solubility than Ligand B (-3.79). Solubility is important for bioavailability.

**hERG:** Ligand A (0.502) has a lower hERG risk than Ligand B (0.328), which is favorable.

**Microsomal Clearance:** Ligand A (-7.245) has a much lower (better) microsomal clearance than Ligand B (16.046). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (22.788 hours) has a much longer half-life than Ligand B (-13.967 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.086, B: 0.008).

**Binding Affinity:** Ligand B (-8.2 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 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: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. The Caco-2 permeability is a concern for both, but the other advantages of A outweigh this. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are paramount, making Ligand A the more promising drug candidate.

Output:
0
2025-04-17 13:12:30,153 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and priorities for enzymes.

**Step-by-step comparison:**

1. **MW:** Ligand A (344.474 Da) is well within the ideal range (200-500). Ligand B (372.55 Da) is also within range. No clear advantage here.

2. **TPSA:** Ligand A (32.34) is excellent, well below the 140 threshold for absorption. Ligand B (58.2) is still reasonable, but higher. A is better.

3. **logP:** Ligand A (4.829) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.305) is within the optimal range. B is better.

4. **HBD:** Ligand A (1) is good. Ligand B (2) is also acceptable. No significant difference.

5. **HBA:** Ligand A (1) is good. Ligand B (3) is also acceptable. No significant difference.

6. **QED:** Ligand A (0.78) is strong, indicating good drug-likeness. Ligand B (0.653) is still acceptable, but slightly lower. A is better.

7. **DILI:** Ligand A (23.226) has a very low DILI risk, excellent. Ligand B (28.306) is also low, but higher than A. A is better.

8. **BBB:** Both ligands have high BBB penetration (A: 94.572, B: 83.443). BBB is less crucial for a non-CNS target like SRC, but higher is generally preferable. A is slightly better.

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 solubility values, indicating poor solubility. This is concerning.

11. **hERG:** Ligand A (0.764) has a lower hERG risk than Ligand B (0.592). A is better.

12. **Cl_mic:** Ligand A (71.28) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (76.095) is slightly higher. A is better.

13. **t1/2:** Ligand A (44.16) has a significantly longer in vitro half-life than Ligand B (16.076). This is a major advantage for dosing convenience. A is much better.

14. **Pgp:** Ligand A (0.47) has lower P-gp efflux, which is favorable for bioavailability. Ligand B (0.33) is also low. No significant difference.

15. **Binding Affinity:** Ligand A (-10.5 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial difference (2.7 kcal/mol) and a key factor.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Overall Assessment:**

Ligand A significantly outperforms Ligand B in several critical areas: binding affinity, metabolic stability (t1/2, Cl_mic), DILI risk, and hERG risk. While both have poor Caco-2 and solubility, the superior binding affinity and pharmacokinetic properties of Ligand A are likely to outweigh these drawbacks, especially considering that formulation strategies can sometimes address solubility issues. The higher logP of A is a minor concern, but the substantial affinity advantage is likely to compensate.

Output:
1
2025-04-17 13:12:30,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.813 Da) is slightly higher than Ligand B (339.395 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (74.02) is slightly higher than Ligand B (66.24).

**logP:** Both ligands have logP values between 1-3 (A: 2.974, B: 3.034), which is optimal.

**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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties (A: 0.85, B: 0.646). Ligand A is better here.

**DILI:** Both ligands have DILI risk below 78, suggesting low risk. Ligand A (78.054) is slightly higher than Ligand B (72.043), but both are acceptable.

**BBB:** Both ligands have good BBB penetration, but Ligand A (86.351) is better than Ligand B (68.67). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and likely indicates poor permeability. Ligand A (-4.627) is slightly better than Ligand B (-4.641), but both are problematic.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-4.549) is slightly better than Ligand B (-3.786). This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.807, B: 0.402). Ligand B is better here.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (50.652 mL/min/kg) than Ligand B (101.895 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A has a shorter in vitro half-life (3.302 hours) than Ligand B (8.093 hours). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.529, B: 0.676).

**Binding Affinity:** Ligand A (-6.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, and metabolic stability (lower Cl_mic). However, Ligand B has a longer half-life and lower hERG risk. Both have poor solubility and permeability, which are significant drawbacks. The better metabolic stability of Ligand A is a crucial advantage for an enzyme inhibitor, potentially allowing for lower doses and less frequent administration. The slightly better binding affinity also tips the balance.

Output:
1
2025-04-17 13:12:30,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.419 and 350.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (46.34), being closer to the upper limit for good oral absorption (<=140). Ligand B is excellent.

**logP:** Ligand A (0.344) is quite low, potentially hindering permeability. Ligand B (4.236) is higher, approaching the upper limit where solubility issues might arise, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also reasonable.

**QED:** Both ligands have acceptable QED scores (0.849 and 0.715, respectively), indicating good drug-like properties.

**DILI:** Ligand A (47.421) has a slightly higher DILI risk than Ligand B (23.963), but both are below the concerning threshold of 60.

**BBB:** Ligand A (60.954) has a lower BBB penetration than Ligand B (80.419). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.231) has very poor predicted Caco-2 permeability, a significant drawback. Ligand B (-4.593) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-1.743) has poor predicted solubility. Ligand B (-3.857) is also poor, but worse than A.

**hERG Inhibition:** Ligand A (0.04) has a very low hERG risk, which is excellent. Ligand B (0.763) is also relatively low.

**Microsomal Clearance:** Ligand A (-1.723) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand B (93.286) has very high clearance, suggesting rapid metabolism and a potential issue.

**In vitro Half-Life:** Ligand A (17.282) has a moderate half-life. Ligand B (9.541) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is favorable. Ligand B (0.263) has slightly higher efflux.

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-9.0 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so doesn't heavily sway the decision.

**Conclusion:**

Despite the similar binding affinities, Ligand A is significantly hampered by its very poor Caco-2 permeability and solubility, and while its metabolic stability is excellent, the poor absorption properties are a major concern. Ligand B, while having higher metabolic clearance, has better permeability and solubility, making it a more promising candidate.

Output:
1
2025-04-17 13:12:30,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.479 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (78.43) is better than Ligand B (40.62). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.479) is optimal, while Ligand B (4.465) is high. High logP can lead to solubility issues and off-target effects. This favors Ligand A.

**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:** Both ligands have reasonable QED scores (A: 0.769, B: 0.643), indicating drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (17.138) has a much lower DILI risk than Ligand B (11.439). This is a significant advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (84.413) has a higher BBB score, but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.015) has a lower (worse) Caco-2 permeability than Ligand B (-4.617).

**Aqueous Solubility:** Ligand A (-0.254) has slightly better aqueous solubility than Ligand B (-4.147). Solubility is important for bioavailability.

**hERG:** Ligand A (0.089) has a much lower hERG risk than Ligand B (0.862). This is a critical advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (22.695) has significantly lower microsomal clearance than Ligand B (75.506), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 20.164, B: 21.94).

**P-gp Efflux:** Ligand A (0.001) has much lower P-gp efflux liability than Ligand B (0.374), indicating better absorption and bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). However, the difference (1.2 kcal/mol) is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A demonstrates a superior ADME profile, with lower DILI, hERG, and P-gp efflux, and better metabolic stability. While Ligand B has slightly better binding affinity, the ADME benefits of Ligand A are more critical for developing a viable drug candidate, especially for an enzyme target where metabolic stability and minimizing toxicity are paramount.

Output:
0
2025-04-17 13:12:30,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.426 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (96.25 and 99.5) are below 140, suggesting reasonable absorption potential.

**logP:** Both ligands have logP values (1.199 and 0.844) within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.588 and 0.718), indicating drug-like properties.

**DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (30.71), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (59.791 and 59.364), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.947 and -4.696), which is unusual. This suggests very poor permeability, and needs further investigation.

**Aqueous Solubility:** Both ligands have negative solubility scores (-2.799 and -2.148), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.144 and 0.364).

**Microsomal Clearance:** Ligand A (16.608 mL/min/kg) has significantly lower microsomal clearance than Ligand B (29.684 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (2.485 hours) than Ligand A (-1.581 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.05).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

Despite the poor Caco-2 and solubility scores for both, Ligand A is slightly favored due to its significantly lower microsomal clearance (better metabolic stability). The binding affinity is identical, and the DILI risk is only marginally higher for Ligand A. The longer half-life of Ligand B is a benefit, but the increased clearance is a greater concern for an enzyme target where maintaining therapeutic concentrations is crucial.

Output:
0
2025-04-17 13:12:30,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 and 381.929 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (73.2), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.759 and 3.842), falling within the 1-3 range. Ligand B is slightly higher, which *could* pose a minor solubility issue, but isn't a major concern.

**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 (0.685 and 0.779), indicating good drug-like properties.

**DILI:** Ligand A (17.255) has a much lower DILI risk than Ligand B (39.201). This is a significant advantage.

**BBB:** Both have similar BBB penetration (75.921 and 75.378), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.37 and -4.946), which is unusual and suggests poor permeability. However, these values are on a log scale and are not directly comparable without knowing the base of the log. We'll need to consider this with caution.

**Aqueous Solubility:** Ligand A (-2.798) has better solubility than Ligand B (-4.503). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.445) has a lower hERG risk than Ligand B (0.78). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (76.671) has higher microsomal clearance than Ligand B (36.251), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (9.738) has a significantly longer half-life than Ligand A (3.863). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux than Ligand B (0.397), which is favorable for bioavailability.

**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 DILI risk, hERG inhibition, solubility, and P-gp efflux. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a longer half-life, better metabolic stability, and slightly better binding affinity. The Caco-2 permeability values are concerning for both, but the other advantages of Ligand B, particularly the improved metabolic stability and half-life, outweigh the slight advantage of Ligand A in a few other parameters. The DILI risk of Ligand A is good, but the overall profile of Ligand B is more balanced and suggests a higher probability of success as a drug candidate.

Output:
1
2025-04-17 13:12:30,154 - INFO - Batch 194 complete. Total preferences: 3104
2025-04-17 13:12:30,154 - INFO - Processing batch 195/512...
2025-04-17 13:13:11,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.371 and 333.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.13) is better than Ligand B (48.13) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (1.666) is optimal, while Ligand B (3.393) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 2. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.849) has a better QED score than Ligand B (0.772), indicating a more drug-like profile.

**DILI:** Ligand B (59.519) has a higher DILI risk than Ligand A (53.47), though both are within a moderate risk range.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.743) has better BBB penetration than Ligand B (87.088).

**Caco-2 Permeability:** Ligand A (-4.417) has a higher Caco-2 permeability than Ligand B (-5.175).

**Aqueous Solubility:** Ligand A (-3.098) has better aqueous solubility than Ligand B (-4.096).

**hERG Inhibition:** Ligand A (0.388) has a significantly lower hERG inhibition risk than Ligand B (0.938). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (8.07 mL/min/kg) has a higher microsomal clearance than Ligand B (5.185 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (20.613 hours) has a significantly longer in vitro half-life than Ligand A (-6.333 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux than Ligand B (0.538).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, and a much longer half-life. While its logP is slightly higher and DILI risk is a bit elevated, the substantial improvement in affinity and half-life are critical for an enzyme target. The hERG risk is higher for Ligand B, but still within a manageable range. Ligand A has better solubility and lower hERG, but its weaker binding and poor half-life are significant drawbacks.

Output:
1
2025-04-17 13:13:11,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.431 and 372.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is slightly higher than Ligand B (83.55), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.273) is quite low, potentially hindering permeability. Ligand B (1.743) 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 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.572 and 0.703), indicating drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (33.773 and 34.471 percentile).

**BBB:** Ligand B (69.562) has a better BBB penetration score than Ligand A (41.566), but this isn't a primary concern for a non-CNS target like SRC.

**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:** Both ligands have very low hERG risk (0.115 and 0.247), which is excellent.

**Microsomal Clearance:** Ligand A (3.896 mL/min/kg) has significantly lower microsomal clearance than Ligand B (12.243 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (22.393 hours) has a longer in vitro half-life than Ligand B (16.873 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.083), which is favorable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially 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 the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), the significantly superior binding affinity of Ligand B (-9.3 vs -7.4 kcal/mol) is a decisive factor for an enzyme target. The slightly better logP of Ligand B also supports better permeability. The unusual 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 development.

Output:
1
2025-04-17 13:13:11,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.5 and 352.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is better than Ligand B (76.15), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (0.653 and 0.98), falling within the 1-3 range.

**H-Bond Donors:** Both have 0 HBDs, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are acceptable (<10).

**QED:** Both ligands have similar QED scores (0.669 and 0.639), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (30.71 and 33.66), well below the concerning threshold of 60.

**BBB:** Both have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (78.87) is slightly better than Ligand A (60.84).

**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 not directly comparable without knowing the scale.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown, making direct comparison difficult.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.146 and 0.176), which is excellent.

**Microsomal Clearance:** Ligand A (46.83) has significantly lower microsomal clearance than Ligand B (64.63), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Both have negative half-lives (-16.13 and -16.63), which is not physically meaningful and suggests an issue with the data or the model used to predict it.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.048 and 0.04), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better TPSA and microsomal clearance, the significantly stronger binding affinity of Ligand B (-8.3 vs -7.1 kcal/mol) is the most crucial factor for an enzyme inhibitor. The relatively similar and acceptable ADME properties of both compounds make the potency difference the deciding factor.

Output:
1
2025-04-17 13:13:11,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.226 Da) is slightly higher than Ligand B (365.861 Da), but both are acceptable.

**TPSA:** Ligand A (41.99) is well below the 140 threshold for oral absorption. Ligand B (82.53) is also below the threshold, but higher than A.

**logP:** Ligand A (4.695) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.282) 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.

**QED:** Both ligands (A: 0.689, B: 0.744) have good QED scores, indicating drug-like properties.

**DILI:** Ligand A (79.682) has a higher DILI risk than Ligand B (23.226). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (88.406) is higher than Ligand B (34.393).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.543) is slightly better than Ligand B (-5.295).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand B (-1.677) is slightly better than Ligand A (-5.516).

**hERG Inhibition:** Ligand A (0.555) has a slightly higher hERG risk than Ligand B (0.256), but both are relatively low.

**Microsomal Clearance:** Ligand B (-14.545) has significantly lower (better) microsomal clearance than Ligand A (45.623), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (47.83) has a longer half-life than Ligand B (0.979).

**P-gp Efflux:** Ligand A (0.37) has lower P-gp efflux than Ligand B (0.034), which is favorable.

**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.

**Conclusion:**

While Ligand A has a much better binding affinity, its high DILI risk, poor solubility, and higher clearance are major drawbacks. Ligand B, despite its weaker affinity, has a significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic), and slightly better solubility. The difference in binding affinity (-1.7 kcal/mol) is substantial, but the ADME/Tox profile of Ligand A is concerning enough to favor Ligand B as a starting point for optimization. The weaker affinity can be addressed through medicinal chemistry efforts, while mitigating the DILI risk and improving solubility of Ligand A would be more challenging.

Output:
1
2025-04-17 13:13:11,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 346.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.45) is slightly higher than the preferred <140, but acceptable. Ligand B (58.64) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands have good logP values (1.45 and 2.57), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, fitting the <5 and <10 guidelines. Ligand B has 1 HBD and 3 HBA, also well within the desired ranges.

**QED:** Both ligands have similar QED scores (0.755 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 56.26%, which is moderate. Ligand B shows a much lower DILI risk of 18.30%, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (74.10) than Ligand A (33.23), but this is less important here.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-5.53), indicating potential absorption issues. Ligand B has a slightly better, but still concerning, value of -4.58.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.52 and -2.86). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A has a very low hERG inhibition risk (0.028), which is excellent. Ligand B has a slightly higher, but still acceptable, hERG risk (0.152).

**Microsomal Clearance:** Ligand A exhibits excellent metabolic stability with a negative Cl_mic (-5.14), indicating slow clearance. Ligand B has a significantly higher Cl_mic (48.18), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A has a very long in vitro half-life (-11.79 hours), further supporting its metabolic stability. Ligand B has a very short half-life (0.12 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.013 and 0.055), which is favorable.

**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.

**Conclusion:**

While Ligand A has a superior binding affinity and excellent metabolic stability (low Cl_mic, long t1/2) and low hERG risk, its poor Caco-2 permeability and moderate DILI risk are concerning. Ligand B has a better TPSA and lower DILI, but suffers from poor metabolic stability (high Cl_mic, short t1/2) and a weaker binding affinity.

Given the priority for potency and metabolic stability for kinase inhibitors, and the substantial affinity difference, **Ligand A** is the more promising candidate *despite* its permeability issues. Solubility can potentially be addressed through formulation strategies, but improving metabolic stability is often more challenging. The affinity advantage of Ligand A is large enough to potentially overcome its other drawbacks.

Output:
0
2025-04-17 13:13:11,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.471 and 351.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (123.58) is still under 140, but less optimal than A.

**logP:** Ligand A (2.991) is within the optimal 1-3 range. Ligand B (0.293) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 7. Both are within the acceptable limit of 10, but B is approaching the higher end.

**QED:** Both ligands have good QED scores (0.574 and 0.706), indicating drug-like properties.

**DILI:** Ligand A (17.371) has a significantly lower DILI risk than Ligand B (57.348). This is a substantial advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand B (85.149) has a higher BBB penetration than Ligand A (70.88).

**Caco-2 Permeability:** Ligand A (-4.44) has a more negative Caco-2 value, which suggests lower permeability. Ligand B (-4.874) is also low, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.119) has slightly better solubility than Ligand B (-2.836).

**hERG Inhibition:** Ligand A (0.491) has a lower hERG risk than Ligand B (0.719). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (69.654) has a significantly higher microsomal clearance than Ligand B (27.159), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-7.032) has a much longer in vitro half-life than Ligand A (4.198). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.172) has lower P-gp efflux than Ligand B (0.027), which is a slight advantage.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.5 kcal/mol). This difference of 2.6 kcal/mol is very significant and can outweigh many ADME drawbacks.

**Conclusion:**

Despite Ligand A's better TPSA, logP, solubility, and lower P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.1 vs -6.5 kcal/mol), lower DILI risk, lower hERG risk, and longer half-life outweigh the slightly less favorable TPSA and logP values. The lower microsomal clearance of Ligand B is also a major benefit for metabolic stability.

Output:
1
2025-04-17 13:13:11,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.348 Da) is slightly higher than Ligand B (351.491 Da), but both are acceptable.

**TPSA:** Ligand A (30.49) is significantly better than Ligand B (70.67). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (4.927) is higher than Ligand B (1.154). While both are within the acceptable range (1-3 is optimal), Ligand A is pushing the upper limit and could potentially have solubility issues or off-target effects. Ligand B's logP is quite low, which could hinder permeability.

**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 and acceptable QED values (Ligand A: 0.677, Ligand B: 0.722).

**DILI:** Ligand A (18.728) has a much lower DILI risk than Ligand B (9.616), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (78.596) is better than Ligand B (63.28). This isn't a primary concern for a kinase inhibitor, but is a bonus.

**Caco-2 Permeability:** Ligand A (-4.878) is better than Ligand B (-4.994), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.323) is better than Ligand B (-2.243), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.931) has a lower hERG risk than Ligand B (0.426), a critical safety parameter.

**Microsomal Clearance:** Ligand A (64.626) has higher clearance than Ligand B (23.807), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (21.207) has a slightly longer half-life than Ligand B (20.542), but the difference is minimal.

**P-gp Efflux:** Ligand A (0.714) has lower P-gp efflux than Ligand B (0.007), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage and could outweigh some of the ADME drawbacks. The 1.1 kcal/mol difference is significant.

**Conclusion:**

Despite Ligand A's higher logP and slightly higher microsomal clearance, its superior binding affinity, lower DILI risk, lower hERG risk, and better solubility make it the more promising drug candidate. The strong binding affinity is the most important factor here, and the other advantages outweigh the minor drawbacks.

Output:
1
2025-04-17 13:13:11,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (356.53 and 370.47 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 50, well below the 140 Angstroms threshold for good absorption.

**3. logP:** Both ligands have logP values around 4, 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 (1 HBD) is better than Ligand B (0 HBD) as it provides a slight benefit for solubility.

**5. H-Bond Acceptors:** Ligand B (4 HBA) is slightly higher than Ligand A (2 HBA), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.716 and 0.693), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (30.94 and 32.45), which is excellent.

**8. BBB:** Both ligands have high BBB penetration (93.53 and 92.52), which isn't a primary concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.31 and -4.45), which is unusual and concerning. This suggests poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.39 and -3.65), indicating very poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.692) has a slightly better hERG profile than Ligand B (0.345), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (44.11 mL/min/kg) has significantly lower microsomal clearance than Ligand A (81.24 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-4.31 hours) has a slightly better in vitro half-life than Ligand A (-11.91 hours), although both are negative values which is unusual.

**14. P-gp Efflux:** Ligand A (0.452) has a slightly better P-gp efflux profile than Ligand B (0.328).

**15. 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 the ADME drawbacks.

**Overall Assessment:**

While both ligands have poor solubility and Caco-2 permeability, Ligand B's significantly stronger binding affinity (-9.1 kcal/mol vs -0.0 kcal/mol) and better metabolic stability (lower Cl_mic) make it the more promising candidate. The strong binding affinity is a critical factor for an enzyme inhibitor, and the improved metabolic stability will likely lead to higher *in vivo* exposure. The slightly better hERG profile of Ligand A is a minor advantage, but doesn't outweigh the substantial difference in potency and stability.

Output:
1
2025-04-17 13:13:11,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.441 Da) is slightly better positioned.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, indicating good absorption potential. Ligand B (81.16) is higher, but still acceptable, though less optimal.

**logP:** Ligand A (2.967) is within the optimal range (1-3). Ligand B (-0.339) is below 1, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 2 HBA, well below the limit of 10. Ligand B has 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.825, B: 0.63), indicating good drug-like properties.

**DILI:** Ligand A (14.036) has a very low DILI risk, significantly better than Ligand B (4.188), which is still relatively low but higher than A.

**BBB:** Ligand A (89.608) shows good BBB penetration, while Ligand B (35.246) is poor. While not a primary concern for a kinase inhibitor, it's a positive attribute for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.759) has poor Caco-2 permeability, which is a concern. Ligand B (-5.186) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.151) and Ligand B (-0.064) both have poor aqueous solubility. This is a potential formulation challenge for both.

**hERG Inhibition:** Ligand A (0.652) has a low hERG risk, which is excellent. Ligand B (0.215) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (24.723) has moderate clearance, while Ligand B (-0.955) has negative clearance, suggesting very high metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-17.461) has a negative half-life, which is nonsensical and indicates a potential data error or a very rapidly metabolized compound. Ligand B (-8.568) also has a negative half-life, also indicating a data issue.

**P-gp Efflux:** Ligand A (0.115) has low P-gp efflux, which is good. Ligand B (0.008) has very low P-gp efflux, also good.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 permeability and questionable half-life data for both compounds, Ligand A is the more promising candidate. Its significantly superior binding affinity (-9.5 vs -7.1 kcal/mol) is a crucial advantage for an enzyme inhibitor. It also exhibits a much lower DILI risk. While Ligand B has better metabolic stability, the substantial difference in binding affinity makes Ligand A the preferred choice. The negative half-life values are concerning and would require further investigation, but the potency advantage of A is too significant to ignore.

Output:
0
2025-04-17 13:13:11,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzyme targets: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.463 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.31) is better than Ligand B (49.85), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.648) is a bit low, potentially hindering permeability, while Ligand B (2.784) is within the optimal 1-3 range.

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

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

**QED:** Both ligands have acceptable QED values (0.756 and 0.691, respectively), indicating good drug-like properties.

**DILI:** Ligand A (30.012) has a significantly lower DILI risk than Ligand B (43.66), which is preferable.

**BBB:** Both have reasonable BBB penetration, but Ligand B (76.696) is slightly better than Ligand A (68.748). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the molecules themselves. It's hard to draw conclusions from this.

**Aqueous Solubility:** Ligand A (-0.914) has slightly better solubility than Ligand B (-2.784).

**hERG:** Ligand A (0.23) has a much lower hERG risk than Ligand B (0.586), a critical advantage.

**Microsomal Clearance:** Ligand A (20.545) has significantly lower microsomal clearance than Ligand B (90.084), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.495) has a better in vitro half-life than Ligand B (-13.575).

**P-gp Efflux:** Ligand A (0.046) has a much lower P-gp efflux liability than Ligand B (0.465), which is favorable for bioavailability.

**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:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity and BBB penetration, Ligand A excels in critical ADME properties: lower DILI risk, significantly lower hERG risk, much better metabolic stability (lower Cl_mic and higher t1/2), and lower P-gp efflux. The slightly lower logP of Ligand A is a minor concern that could potentially be addressed through further optimization, but the ADME advantages are substantial. The small difference in binding affinity is unlikely to outweigh the significant improvements in safety and pharmacokinetic properties.

Output:
0
2025-04-17 13:13:11,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.435 and 354.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is better than Ligand B (58.64) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (-0.336) is slightly low, potentially hindering permeation. Ligand B (3.229) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable, and Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.526 and 0.763, respectively), indicating drug-like properties.

**DILI:** Ligand A (21.132) has a significantly lower DILI risk than Ligand B (16.479), which is a major advantage.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (70.609) is better than Ligand A (57.464). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.887) is very poor, suggesting very low intestinal absorption. Ligand B (-4.474) is also poor, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.872) is slightly better than Ligand B (-3.314), but both are poor.

**hERG Inhibition:** Ligand A (0.041) has a very low hERG risk, which is excellent. Ligand B (0.513) is higher, representing a moderate risk.

**Microsomal Clearance:** Ligand A (2.587) has a much lower microsomal clearance than Ligand B (88.919), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-3.424) has a negative half-life, which is concerning. Ligand B (5.13) has a positive half-life, which is good.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is favorable. Ligand B (0.074) is slightly higher, but still relatively low.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.4 and -8.6 kcal/mol), which are both excellent.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, very low hERG) and metabolic stability (lower Cl_mic). While its solubility and Caco-2 permeability are poor, the strong binding affinity and favorable safety/stability profile outweigh these drawbacks. Ligand B has better permeability and half-life, but the higher DILI and hERG risk are concerning. Given that SRC is an enzyme, metabolic stability and safety are paramount.

Output:
0
2025-04-17 13:13:11,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (363.849 Da) is also well within range.

**TPSA:** Ligand A (129.89) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (85.09) is excellent, well below 140, suggesting better absorption potential.

**logP:** Ligand A (0.513) is a bit low, potentially hindering permeation. Ligand B (1.594) is better, falling within the optimal 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 (A: 0.744, B: 0.81), indicating drug-like properties.

**DILI:** Ligand A (68.282) has a higher DILI risk than Ligand B (53.083), though both are reasonably acceptable.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (55.913) and Ligand B (62.699) are both relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.661 and -5.512), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.435 and -2.254), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Ligand A (0.356) has a slightly higher hERG risk than Ligand B (0.129), which is preferable.

**Microsomal Clearance:** Ligand A (-19.467) has significantly lower (better) microsomal clearance than Ligand B (9.108), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (-17.245) has a longer half-life than Ligand B (14.638), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.294), which is good.

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, the significantly stronger binding affinity of Ligand B (-9.3 vs -8.1 kcal/mol) and its better logP, lower hERG risk, and acceptable DILI make it the more promising candidate. The improved metabolic stability of Ligand A is attractive, but the potency advantage of Ligand B is more crucial for an enzyme target like SRC. Further optimization would be needed to address the solubility and permeability issues for either compound, but Ligand B starts from a stronger position due to its superior binding.

Output:
1
2025-04-17 13:13:11,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (377.725 and 357.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (88.24 and 87.74) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.939) is optimal, while Ligand B (0.383) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the limit of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 each), below the limit of 10.

**QED:** Both ligands have good QED scores (0.715 and 0.69), indicating drug-like properties.

**DILI:** Ligand A (69.484) has a higher DILI risk than Ligand B (28.189). This is a significant negative for Ligand A.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand B (75.572) has a better BBB score than Ligand A (61.962).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, Ligand B (-4.821) is significantly worse than Ligand A (-3.968), indicating very poor absorption.

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, Ligand A (-3.968) is slightly better than Ligand B (-1.693).

**hERG:** Ligand A (0.652) has a slightly higher hERG risk than Ligand B (0.285), but both are relatively low.

**Microsomal Clearance:** Ligand B (-1.121) has significantly lower (better) microsomal clearance than Ligand A (11.891), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (6.945) has a shorter half-life than Ligand A (42.225), which is a negative.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.222 and 0.015).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.7 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better in vitro half-life and solubility, Ligand B's significantly better metabolic stability (lower Cl_mic), lower DILI risk, and slightly better binding affinity outweigh these drawbacks. The low logP of Ligand B is a concern, but the strong binding affinity might compensate for that. The Caco-2 permeability is a concern for both, but worse for B. However, the metabolic stability and safety profile of Ligand B are more critical for an enzyme target like SRC.

Output:
1
2025-04-17 13:13:11,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.475 and 348.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.19) is significantly better than Ligand B (88.75). Lower TPSA generally improves cell permeability.

**3. logP:** Both ligands have similar logP values (4.253 and 4.32), slightly above the optimal range of 1-3, but not drastically so. This could potentially lead to some solubility issues, but is not a major concern.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (6). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.753) has a better QED score than Ligand B (0.583), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (36.448). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (68.554) has a lower BBB penetration than Ligand B (92.168). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.85 and -4.935). 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 (-4.768 and -5.669). This is also concerning and suggests poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.733 and 0.781), which is good.

**12. Microsomal Clearance:** Ligand A (58.554) has a lower microsomal clearance than Ligand B (80.34), indicating better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (129.704) has a significantly longer in vitro half-life than Ligand B (34.98), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.548 and 0.139), which is good.

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.9 kcal/mol). This removes affinity as a differentiating factor.

**Overall Assessment:**

Ligand A has advantages in TPSA, HBD, HBA, QED, metabolic stability (Cl_mic), and half-life. However, it has a significantly higher DILI risk. Ligand B has better DILI risk and slightly better P-gp efflux, but is worse across most other ADME properties. Given the importance of metabolic stability and half-life for an enzyme inhibitor, and the equal binding affinity, Ligand A is slightly more promising *despite* the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications.

Output:
0
2025-04-17 13:13:11,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (344.411 and 366.397 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.78) is better than Ligand B (87.66). Both are below 140, indicating good potential for oral absorption.

**logP:** Both ligands (2.244 and 2.669) are within the optimal range of 1-3.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), both are acceptable.

**QED:** Ligand A (0.832) is significantly better than Ligand B (0.725), suggesting a more drug-like profile.

**DILI:** Ligand A (35.944) has a much lower DILI risk than Ligand B (82.435). This is a significant advantage.

**BBB:** Ligand A (78.402) is better than Ligand B (64.482), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.671) is better than Ligand B (-5.109), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.778) is better than Ligand B (-3.754), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.26) has a lower hERG risk than Ligand B (0.475), a crucial factor for safety.

**Microsomal Clearance:** Ligand A (31.314) has a lower Cl_mic than Ligand B (42.731), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (59.244) has a significantly longer half-life than Ligand B (11.136), which is highly desirable for dosing convenience.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux than Ligand B (0.256), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.0) has a stronger binding affinity than Ligand A (-7.4), with a difference of 1.6 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates superior ADMET properties across the board, particularly in DILI risk, metabolic stability (Cl_mic and t1/2), solubility, and hERG risk. The 1.6 kcal/mol difference in binding affinity, while significant, can potentially be overcome with further optimization of Ligand A, given its much more favorable safety and pharmacokinetic profile. For an enzyme target like SRC, metabolic stability and safety are paramount.

Output:
0
2025-04-17 13:13:11,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 349.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.51) is better than Ligand B (84.67), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.222 and 2.146), falling within the 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**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 reasonable QED scores (0.751 and 0.691), indicating good drug-like properties.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (39.201). This is a major advantage for Ligand A.

**BBB:** Ligand A (63.009) has a lower BBB penetration than Ligand B (79.682). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.064) has worse Caco-2 permeability than Ligand B (-4.524).

**Aqueous Solubility:** Ligand A (-2.188) has slightly better aqueous solubility than Ligand B (-2.526).

**hERG:** Ligand A (0.15) has a lower hERG risk than Ligand B (0.387), which is favorable.

**Microsomal Clearance:** Ligand A (-3.626) has a significantly lower (better) microsomal clearance than Ligand B (69.391). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-3.962) has a longer in vitro half-life than Ligand B (4.914), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.022) has lower P-gp efflux than Ligand B (0.156), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.6). The difference is 1.4 kcal/mol, which is significant, but needs to be weighed against the ADME properties.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile compared to Ligand B. It has lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. While Ligand B has a slightly better binding affinity (-7.2 vs -8.6 kcal/mol), the substantial improvements in ADME properties for Ligand A outweigh this difference, especially considering the importance of metabolic stability and safety for an enzyme target like SRC kinase.

Output:
0
2025-04-17 13:13:11,029 - INFO - Batch 195 complete. Total preferences: 3120
2025-04-17 13:13:11,029 - INFO - Processing batch 196/512...
2025-04-17 13:14:02,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as outlined for enzymes.

**Molecular Weight:** Both ligands (367.833 and 363.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.95 and 72.47) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.291 and 1.774) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.813 and 0.885), indicating drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (76.89%) compared to Ligand B (42.226%). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (70.299% and 71.772%). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic, but we'll consider other factors.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and a potential issue. However, the values are similar (-3.17 and -2.756).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.273 and 0.46).

**Microsomal Clearance:** Ligand B has lower microsomal clearance (21.685 mL/min/kg) than Ligand A (27.408 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (18.096 hours) than Ligand A (-10.2 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.142 and 0.219).

**Binding Affinity:** Ligand B has a better binding affinity (-8.5 kcal/mol) than Ligand A (-6.3 kcal/mol). This is a 2.2 kcal/mol difference, which is a significant advantage, easily outweighing minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have some unusual solubility/permeability values, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a substantially stronger binding affinity. The improved affinity and reduced toxicity risk are critical for an enzyme target in oncology.

Output:
1
2025-04-17 13:14:02,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.439 Da and 356.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.55 and 108.33) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.472) is optimal, while Ligand B (-0.801) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 6 HBA, which are within acceptable limits.

**QED:** Ligand A (0.685) has a better QED score than Ligand B (0.491), indicating a more drug-like profile.

**DILI:** Ligand A (84.102) has a higher DILI risk than Ligand B (23.808). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (49.903) and Ligand B (31.989) are both low.

**Caco-2 Permeability:** Ligand A (-4.821) and Ligand B (-5.246) are both negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.567) and Ligand B (-0.488) are both negative, indicating poor solubility.

**hERG:** Ligand A (0.298) has a lower hERG risk than Ligand B (0.089), which is favorable.

**Microsomal Clearance:** Ligand A (77.238) has higher clearance than Ligand B (-6.231). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (24.208) has a longer half-life than Ligand B (7.607), which is preferable.

**P-gp Efflux:** Ligand A (0.415) has lower P-gp efflux than Ligand B (0.02), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a crucial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a substantially better binding affinity (-7.1 vs -9.4 kcal/mol). While it has a lower logP and a slightly higher hERG risk, the significantly improved potency and better metabolic stability (lower Cl_mic, though a percentile) are crucial for an enzyme target like SRC kinase. The lower DILI risk for Ligand B is also a significant advantage. Ligand A's higher DILI risk is a major concern.

Output:
1
2025-04-17 13:14:02,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 and 364.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is slightly higher than Ligand B (58.64), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have logP values within the optimal range (2.559 and 3.125).

**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.

**QED:** Ligand B (0.873) has a higher QED score than Ligand A (0.596), suggesting a more drug-like profile.

**DILI:** Ligand A (37.611) has a lower DILI risk than Ligand B (47.15), which is preferable.

**BBB:** Both ligands have relatively low BBB penetration (58.278 and 63.009), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.035 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 (-3.199 and -3.135), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.294 and 0.445), which is good.

**Microsomal Clearance:** Ligand B (37.291) has a lower microsomal clearance than Ligand A (42.99), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (20.654 hours) has a significantly longer in vitro half-life than Ligand A (-4.037 hours). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.327 and 0.376).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 1 kcal/mol difference is significant.

**Overall Assessment:**

Despite the better binding affinity of Ligand A, the significantly improved metabolic stability (lower Cl_mic) and longer half-life of Ligand B, coupled with its higher QED score, make it a more promising candidate. The poor solubility and permeability are major concerns for both, but the improved pharmacokinetic properties of Ligand B are more likely to be addressable through formulation strategies. The slightly lower DILI risk of Ligand A is a minor advantage, but doesn't outweigh the PK benefits of Ligand B.

Output:
1
2025-04-17 13:14:02,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 and 343.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.8) is higher than Ligand B (44.81). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (3.404) is slightly higher than Ligand B (2.642), both 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 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.918) has a significantly higher QED score than Ligand A (0.539), indicating a more drug-like profile.

**DILI:** Ligand A (39.05) has a slightly higher DILI risk than Ligand B (13.80), but both are below the concerning threshold of 60.

**BBB:** Ligand A (68.75) has a lower BBB penetration percentile than Ligand B (90.62). Since SRC is not a CNS target, this is less critical.

**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.

**Aqueous Solubility:** Ligand A (-4.319) has worse solubility than Ligand B (-2.251). Solubility is a key factor for enzyme inhibitors.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.824 and 0.81 respectively).

**Microsomal Clearance:** Ligand A (106.37) has significantly higher microsomal clearance than Ligand B (0.659), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (4.962 hours) has a much longer half-life than Ligand A (-20.726 hours). The negative value for Ligand A is concerning and likely an artifact of the model.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.832 and 0.16).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-9.4 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Conclusion:**

Ligand B is the superior candidate. It has a better QED score, lower DILI risk, better solubility, significantly improved metabolic stability (lower Cl_mic and a positive half-life), and, most importantly, a substantially stronger binding affinity. While Ligand A has a slightly better binding affinity, its poor metabolic stability and solubility, combined with the questionable half-life, make it a less viable option.

Output:
1
2025-04-17 13:14:02,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (418.316 and 429.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is slightly higher than Ligand B (66.48). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (4.393 and 3.161), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable (<=5). Ligand B is preferable.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.587 and 0.756), indicating good drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 82.551, which is high (>60). Ligand B has a DILI risk of 42.148, which is good (<40). This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (79.488) and Ligand B (91.702) are both reasonably high.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.083 and -4.795), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.07 and -4.115), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.687) has a slightly higher hERG risk than Ligand B (0.706), but both are relatively low.

**Microsomal Clearance:** Ligand A (64.923) has a higher microsomal clearance than Ligand B (33.498), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (6.379) has a significantly longer in vitro half-life than Ligand A (81.075). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.48) has a higher P-gp efflux liability than Ligand B (0.547), meaning Ligand B is preferable.

**Binding Affinity:** Ligand A (-10.1 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:**

While Ligand A has a much better binding affinity, its high DILI risk, poor metabolic stability (higher Cl_mic), and shorter half-life are significant drawbacks. Ligand B has a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer half-life), and slightly better solubility and permeability characteristics, despite both being poor. The substantial difference in binding affinity is a major consideration. However, the poor ADME properties of Ligand A, particularly the high DILI risk, make it a less viable candidate. Ligand B, while having weaker binding, has a much more favorable ADME profile, making it more likely to succeed as a drug candidate, especially with further optimization to improve potency.

Output:
1
2025-04-17 13:14:02,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.378) and Ligand B (345.443) are both acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 88.1, Ligand B: 84.64), suggesting good oral absorption potential.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 1.256 and Ligand B at 1.291.

**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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (Ligand A: 0.766, Ligand B: 0.786), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 34.626, which is excellent (low risk). Ligand B has a DILI risk of 13.61, also very good.

**BBB:** Ligand A has a BBB penetration of 77.705, while Ligand B is 63.164. While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.033) and Ligand B (-4.725) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -1.186, Ligand B: -1.993). This could present formulation challenges.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.084, which is very low and desirable. Ligand B has a slightly higher risk of 0.231, but still acceptable.

**Microsomal Clearance:** Ligand A has a very low (good) microsomal clearance of -20.946, indicating high metabolic stability. Ligand B has a clearance of -3.267, which is better than many compounds but significantly higher than Ligand A.

**In vitro Half-Life:** Ligand A has a very long in vitro half-life (-25.241), further supporting its metabolic stability. Ligand B has a half-life of 21.797, which is good, but not as impressive as Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.004, Ligand B: 0.022), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand A has a binding affinity of -10.3 kcal/mol, while Ligand B has -7.5 kcal/mol. Ligand A is significantly more potent. The 2.8 kcal/mol difference in binding affinity is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 permeability and solubility for both, Ligand A is the superior candidate. Its significantly stronger binding affinity (-10.3 vs -7.5 kcal/mol) and substantially better metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme inhibitor. The lower DILI risk and hERG inhibition are also beneficial. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 13:14:02,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (373.45 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.23) is slightly higher than Ligand B (77.57). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have acceptable logP values (0.973 and 2.145, respectively), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**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 (0.693 and 0.637), indicating good drug-likeness.

**DILI:** Ligand A (66.344) has a higher DILI risk than Ligand B (42.846). This is a significant drawback for Ligand A.

**BBB:** Ligand A (55.215) and Ligand B (78.907). BBB is less critical for a non-CNS target like SRC kinase, but higher is generally better.

**Caco-2 Permeability:** Ligand A (-4.894) has worse Caco-2 permeability than Ligand B (-4.371). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.648 and -2.624). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.271) has a slightly higher hERG risk than Ligand B (0.123). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (10.906) has significantly lower microsomal clearance than Ligand B (66.952). This indicates better metabolic stability for Ligand A, a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (54.938) has a much longer in vitro half-life than Ligand B (-17.317). This is a substantial benefit for Ligand A, reducing dosing frequency.

**P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux than Ligand B (0.224), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 1.5 kcal/mol difference, which is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux. However, it has a higher DILI risk and slightly worse hERG. Ligand B has a better binding affinity and lower DILI/hERG risk, but suffers from significantly worse metabolic stability and a shorter half-life.

Given the priority for metabolic stability and longer half-life for enzyme targets, and the relatively small difference in binding affinity (1.5 kcal/mol), the improved PK profile of Ligand A is more valuable. The DILI risk is a concern, but could be investigated further.

Output:
0
2025-04-17 13:14:02,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.427 and 352.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is well below the 140 threshold for oral absorption, while Ligand B (124.6) is still acceptable but less optimal.

**logP:** Ligand A (2.354) is within the optimal 1-3 range. Ligand B (-0.585) is below 1, which could hinder permeation.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7 HBA. Both are within the acceptable range (<=10), but Ligand A is more favorable.

**QED:** Both ligands have similar QED values (0.777 and 0.73), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (43.234 and 45.173), which is good.

**BBB:** Both ligands have reasonable BBB penetration (75.223 and 77.86), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.881) has poor Caco-2 permeability, while Ligand B (-5.238) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.525) has poor aqueous solubility, while Ligand B (-1.13) is slightly better.

**hERG Inhibition:** Ligand A (0.254) has very low hERG inhibition risk, which is excellent. Ligand B (0.042) is also very low risk.

**Microsomal Clearance:** Ligand A (47.883) has moderate microsomal clearance, while Ligand B (-33.576) has *negative* clearance, which is highly unusual and suggests excellent metabolic stability.

**In vitro Half-Life:** Ligand A (7.839 hours) has a reasonable half-life. Ligand B (31.247 hours) has a significantly longer half-life, which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.33 and 0.006).

**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.

**Conclusion:**

Despite Ligand A's better TPSA and HBA count, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.0 vs -7.8 kcal/mol) and dramatically improved metabolic stability (negative Cl_mic, long half-life) are critical advantages for an enzyme inhibitor. While Ligand B has a slightly higher TPSA and lower logP, the potency and stability benefits are more important in this case. The slightly better solubility of Ligand B is also a plus.

Output:
1
2025-04-17 13:14:02,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.268 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (90.27). Lower TPSA generally improves oral absorption. Ligand B's TPSA is relatively high, potentially hindering absorption.

**logP:** Ligand A (3.213) is optimal, while Ligand B (1.649) is on the lower side, potentially impacting permeability.

**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 (A: 0.599, B: 0.842), indicating good drug-like properties.

**DILI:** Ligand A (38.077) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning threshold of 60.

**BBB:** Ligand A (97.402) has excellent BBB penetration, while Ligand B (72.082) is decent. However, BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.276) and Ligand B (-4.749) 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 (-3.815) and Ligand B (-2.605) both have negative values, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.815) has a slightly higher hERG risk than Ligand B (0.229), but both are relatively low.

**Microsomal Clearance:** Ligand B (10.874) has significantly lower microsomal clearance than Ligand A (38.146), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-12.081) has a negative half-life, which is impossible. This is a significant red flag. Ligand A (4.034) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.202) has lower P-gp efflux than Ligand B (0.063), which is favorable for bioavailability.

**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 ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability and lower P-gp efflux, the negative in vitro half-life is a critical flaw. The significantly stronger binding affinity of Ligand A (-8.8 kcal/mol vs -7.6 kcal/mol) combined with acceptable ADME properties (although solubility and permeability are concerns) makes it the more promising candidate. The TPSA is also much more favorable for Ligand A.



Output:
1
2025-04-17 13:14:02,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.411 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.71) is significantly better than Ligand B (85.25). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands (2.165 and 1.948) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5), again favoring permeability.

**QED:** Ligand A (0.869) is significantly better than Ligand B (0.63), indicating a more drug-like profile.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (29.391). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (60.838 and 60.993). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.025 and -4.915), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference is small.

**Aqueous Solubility:** Ligand A (-3.418) has slightly better solubility than Ligand B (-1.785), although both are quite poor.

**hERG Inhibition:** Ligand A (0.323) has a much lower hERG risk than Ligand B (0.576). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (55.044) has higher microsomal clearance than Ligand B (32.598), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-5.922) has a shorter half-life than Ligand B (-2.576), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux than Ligand B (0.163), which is favorable.

**Binding Affinity:** Ligand A (-8.6) has significantly stronger binding affinity than Ligand B (0.0). This is a major advantage for Ligand A. The >1.5 kcal/mol difference in affinity is substantial enough to potentially overcome some ADME liabilities.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better hERG risk, lower P-gp efflux, better QED, lower HBD/HBA, and better solubility. However, it has a higher DILI risk, higher clearance, and shorter half-life. Ligand B has a lower DILI risk and better metabolic stability, but significantly weaker binding affinity and a less favorable QED score.

Given the priority for potency in kinase inhibitors, the substantial binding affinity advantage of Ligand A outweighs its ADME liabilities, *provided* the DILI risk can be mitigated through further structural modifications. The poor solubility and metabolic stability are also areas for optimization, but the strong initial binding is a crucial starting point.

Output:
1
2025-04-17 13:14:02,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.527 and 362.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is well below the 140 threshold, while Ligand B (78.43) is also acceptable, but higher.

**logP:** Both ligands have good logP values (2.928 and 1.748), falling within the optimal 1-3 range.

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

**QED:** Ligand A (0.81) has a better QED score than Ligand B (0.646), indicating a more drug-like profile.

**DILI:** Ligand A (26.561) has a significantly lower DILI risk than Ligand B (13.416), which is a major advantage.

**BBB:** Both ligands have acceptable BBB penetration (65.607 and 70.997). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.89 and -4.983), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.693 and -2.518), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.346 and 0.398), which is good.

**Microsomal Clearance:** Ligand A (63.867) has a higher microsomal clearance than Ligand B (13.43), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-11.256) has a significantly longer in vitro half-life than Ligand A (-1.262), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.342 and 0.032).

**Binding Affinity:** Both ligands have excellent binding affinities (-8 and -9.1 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B has a better binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2) which are critical for an enzyme inhibitor. However, Ligand A has a much lower DILI risk and a better QED score. Both have poor solubility and permeability. The difference in binding affinity is relatively small (1.1 kcal/mol), and the superior metabolic stability of Ligand B outweighs the slightly higher DILI risk and lower QED.

Output:
1
2025-04-17 13:14:02,855 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [376.538, 69.64, 2.37, 2, 4, 0.648, 14.541, 78.209, -4.79, -3.051, 0.292, 70.044, -43.667, 0.019, -7.4]
**Ligand B:** [343.383, 84.67, 1.77, 1, 5, 0.894, 44.126, 41.528, -4.574, -2.705, 0.234, 16.8, 3.503, 0.029, -8.6]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (343.383) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.
2. **TPSA:** Ligand A (69.64) is better than Ligand B (84.67).  We want TPSA <= 140 for oral absorption, both are within this range, but lower is better.
3. **logP:** Both are good (between 1-3). Ligand A (2.37) is slightly higher, which is generally acceptable.
4. **HBD:** Both are acceptable (<=5). Ligand A (2) is slightly better than Ligand B (1).
5. **HBA:** Both are acceptable (<=10). Ligand A (4) is better than Ligand B (5).
6. **QED:** Both are good (>0.5). Ligand B (0.894) is better than Ligand A (0.648).
7. **DILI:** Ligand A (14.541) is significantly better than Ligand B (44.126). This is a major advantage for Ligand A.  We want <40, and A is well within that, while B is approaching a moderate risk.
8. **BBB:** Ligand A (78.209) is much better than Ligand B (41.528). While SRC isn't necessarily a CNS target, higher BBB is generally a positive indicator of permeability.
9. **Caco-2:** Both are negative, indicating poor permeability. Ligand A (-4.79) is slightly worse than Ligand B (-4.574).
10. **Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.051) is slightly worse than Ligand B (-2.705).
11. **hERG:** Both are very low (0.292 and 0.234), indicating low cardiotoxicity risk.
12. **Cl_mic:** Ligand A (70.044) is better than Ligand B (16.8). Lower is better, indicating greater metabolic stability.
13. **t1/2:** Ligand A (-43.667) is significantly better than Ligand B (3.503). A negative value suggests a very long half-life *in vitro*, which is highly desirable.
14. **Pgp:** Both are very low (0.019 and 0.029), indicating low P-gp efflux.
15. **Binding Affinity:** Ligand B (-8.6) is significantly better than Ligand A (-7.4). This is a 1.2 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand B wins decisively.
*   **Metabolic Stability:** Ligand A is better (higher t1/2, lower Cl_mic).
*   **Solubility:** Both are poor, but Ligand B is slightly better.
*   **hERG:** Both are good.
*   **DILI:** Ligand A is *much* better.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, Ligand A has a much more favorable safety profile (DILI) and metabolic stability profile (Cl_mic, t1/2). The 1.2 kcal/mol difference in binding affinity is significant, but the substantial improvement in DILI risk for Ligand A is a critical factor. The poor solubility and Caco-2 permeability are concerns for both, but these can potentially be addressed through formulation strategies. Given the importance of minimizing off-target effects and maximizing metabolic stability for kinase inhibitors, I believe the benefits of Ligand A outweigh the potency advantage of Ligand B.

Output:
1
2025-04-17 13:14:02,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (375.491 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (118.8 and 105.56) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.311) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (-0.956) is also below the optimal range, but slightly less so than A.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5-6 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.603 and 0.713), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (36.758 and 56.185), below the 60 threshold. Ligand A is slightly better.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (55.021) has a slightly better score than Ligand B (42.032).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.18 and -5.218), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.09 and -0.849), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.185 and 0.084), which is excellent.

**Microsomal Clearance:** Ligand A (7.259) has a lower microsomal clearance than Ligand B (-5.734). This suggests better metabolic stability for Ligand A, a critical factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-28.337) has a significantly longer in vitro half-life than Ligand B (31.007). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.014 and 0.017).

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.7). This is a crucial advantage, potentially outweighing some of the ADME concerns. A difference of >1.5 kcal/mol is considered significant.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.0 kcal/mol vs -6.7 kcal/mol), lower microsomal clearance, and longer half-life outweigh the slightly lower logP and solubility compared to Ligand B. The better DILI score is also a plus. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The potency advantage of Ligand A is substantial and critical for an enzyme inhibitor.

Output:
1
2025-04-17 13:14:02,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.359 and 337.402 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (101.93) is slightly above the preferred <140, but acceptable. Ligand B (64.84) is well within the acceptable range.

**logP:** Ligand A (-0.136) is a bit low, potentially hindering permeability. Ligand B (3.331) is optimal.

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

**H-Bond Acceptors:** Ligand A (7) is good. Ligand B (5) is good.

**QED:** Both ligands have good QED scores (0.683 and 0.927), indicating drug-likeness.

**DILI:** Ligand A (76.192) has a higher DILI risk than Ligand B (63.862), though both are acceptable.

**BBB:** Ligand A (70.454) and Ligand B (91.392) are both acceptable, but not critical for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values (-4.217 and -4.872), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have negative solubility values (-1.928 and -4.866), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Ligand A (0.032) has a very low hERG risk, which is excellent. Ligand B (0.973) has a higher, but still potentially manageable, hERG risk.

**Microsomal Clearance:** Ligand A (41.727) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (72.795).

**In vitro Half-Life:** Ligand A (-16.639) has a negative half-life, which is impossible and indicates an issue with the data or the compound itself. Ligand B (22.693) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is good. Ligand B (0.34) has a moderate P-gp efflux.

**Binding Affinity:** Both ligands have strong binding affinities (-7.5 and -8.0 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand A has a better hERG profile and lower P-gp efflux, and better metabolic stability. However, its negative in vitro half-life is a critical flaw. The low logP and negative solubility are also significant concerns.

Ligand B has a better logP, solubility (though still poor), and a reasonable half-life. Its DILI and hERG risks are slightly higher, but manageable. The slightly better binding affinity is also a plus.

Given the critical flaw of the negative half-life for Ligand A, and the slightly better overall profile of Ligand B despite its drawbacks, I would choose Ligand B as the more viable drug candidate. The solubility and permeability issues for both would need to be addressed through formulation or further chemical modifications.

Output:
1
2025-04-17 13:14:02,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.46 and 354.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (32.34). Lower TPSA generally favors better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (1.365) is optimal, while Ligand B (4.202) is pushing the upper limit. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2/1 for A, 1/3 for B) and HBA counts (3/3).

**QED:** Both ligands have good QED scores (0.737 and 0.816), indicating good drug-likeness.

**DILI:** Ligand A (21.95) has a significantly lower DILI risk than Ligand B (29.62). This is a crucial advantage.

**BBB:** BBB is not a primary concern for SRC kinase inhibitors (unless CNS penetration is specifically desired). Ligand B (83.443) has higher BBB penetration, but this is less important in this context.

**Caco-2 Permeability:** Ligand A (-5.156) has a negative Caco-2 value, which is concerning, while Ligand B (-4.907) is also negative, but slightly better. This suggests poor intestinal absorption for both, but A is worse.

**Aqueous Solubility:** Ligand A (-2.218) has better aqueous solubility than Ligand B (-4.439). Solubility is important for formulation and bioavailability.

**hERG:** Ligand A (0.074) has a much lower hERG risk than Ligand B (0.854). This is a significant safety advantage.

**Microsomal Clearance:** Ligand A (21.95) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (33.385).

**In vitro Half-Life:** Ligand B (30.35) has a slightly longer half-life than Ligand A (20.154).

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux than Ligand B (0.473), suggesting better bioavailability.

**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 often outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a significantly better binding affinity, lower DILI risk, lower hERG risk, better metabolic stability, and lower P-gp efflux. While its Caco-2 permeability is poor, the strong binding affinity and improved safety profile outweigh this concern. Ligand B has a higher logP and a concerning hERG risk.

Output:
0
2025-04-17 13:14:02,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.405 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (38.77) is significantly better than Ligand B (73.2). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 4.764, B: 3.246), falling within the optimal range of 1-3. Ligand A is a bit high, potentially leading to off-target effects, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) is better than Ligand B (HBD=1, HBA=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.651, B: 0.801), indicating a generally drug-like profile.

**DILI:** Ligand A (77.511) has a higher DILI risk than Ligand B (40.364). This is a significant concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 72.237, B: 70.376). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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 mean zero permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -6.05, B: -4.609). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.852) has a slightly higher hERG risk than Ligand B (0.698), but both are reasonably low.

**Microsomal Clearance:** Ligand A (30.058) has significantly lower microsomal clearance than Ligand B (41.807), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-36.219) has a much longer in vitro half-life than Ligand B (21.924). This is a major positive for Ligand A, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.498, B: 0.258).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor, and the 7.1 kcal/mol advantage is substantial.

**Conclusion:**

Despite Ligand A's superior metabolic stability and half-life, the significantly stronger binding affinity of Ligand B (-7.1 vs -0.0 kcal/mol) outweighs the drawbacks of its slightly higher TPSA and DILI risk. The potency difference is so large that it's likely to be the dominant factor in *in vivo* efficacy. The solubility issues are present in both, and could be addressed with formulation strategies. The higher DILI risk for Ligand A is a substantial concern.

Output:
1
2025-04-17 13:14:02,856 - INFO - Batch 196 complete. Total preferences: 3136
2025-04-17 13:14:02,856 - INFO - Processing batch 197/512...
2025-04-17 13:14:52,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.523 and 382.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.19) is significantly better than Ligand B (95.16). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.974 and 2.042), falling within the 1-3 optimal range.

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

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 5. Both are below the 10 limit.

**QED:** Both ligands have good QED scores (0.709 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A (8.647) has a much lower DILI risk than Ligand B (64.288). This is a significant advantage for Ligand A.

**BBB:** Ligand A (80.884) has a better BBB penetration score than Ligand B (27.724), although BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.887) has a worse Caco-2 permeability than Ligand B (-5.579). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.743) has better aqueous solubility than Ligand B (-3.286). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.745) has a lower hERG inhibition liability than Ligand B (0.358), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (23.092 and 23.169 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (26.461) has a slightly longer in vitro half-life than Ligand A (23.508), which is a minor advantage.

**P-gp Efflux:** Ligand A (0.053) has much lower P-gp efflux liability than Ligand B (0.11). This is a positive for Ligand A.

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better ADME properties (lower DILI, better solubility, lower hERG, lower P-gp efflux), the substantial difference in binding affinity makes Ligand B the more promising candidate. The slightly longer half-life of Ligand B is also a minor benefit. The ADME issues with Ligand B (higher DILI, lower solubility) could potentially be addressed through further optimization, but improving binding affinity is often more challenging.

Output:
1
2025-04-17 13:14:52,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.527 and 374.418 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.3) is well below the 140 threshold, while Ligand B (84.94) is still acceptable but higher. This favors Ligand A for better absorption.

**logP:** Both ligands have good logP values (2.807 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 within the acceptable limit of 10.

**QED:** Ligand A (0.893) has a significantly better QED score than Ligand B (0.589), indicating a more drug-like profile.

**DILI:** Ligand A (41.024) has a slightly higher DILI risk than Ligand B (22.257), but both are below the concerning threshold of 60.

**BBB:** Ligand A (54.362) has lower BBB penetration than Ligand B (74.292). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have very similar, and negative Caco-2 values (-4.965 and -4.962). This is concerning and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-3.867) has slightly worse solubility than Ligand B (-1.779), though both are poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.369 and 0.277).

**Microsomal Clearance:** Ligand A (58.193) has higher microsomal clearance than Ligand B (44.595), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (9.5) has a longer in vitro half-life than Ligand A (6.043), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.037).

**Binding Affinity:** Ligand B (-7.3) has slightly better binding affinity than Ligand A (-7.2), although the difference is small.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. While Ligand A has a better QED and TPSA, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The solubility and Caco-2 permeability are poor for both, but metabolic stability is a more critical factor for kinase inhibitors.

Output:
1
2025-04-17 13:14:52,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.443 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.17) is better than Ligand B (114.87) as it's closer to the <140 threshold for good oral absorption.

**logP:** Both ligands (-0.086 and -0.467) are slightly below the optimal 1-3 range, but not drastically so. This could potentially impact permeability, but isn't a major concern at this stage.

**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 for permeability and solubility. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.752 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (39.395) has a slightly higher DILI risk than Ligand B (29.042), but both are below the concerning threshold of 60.

**BBB:** This is less crucial for a non-CNS target like SRC kinase. Ligand A (65.801) is better than Ligand B (35.324), but this is not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.315 and -5.624), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.952 and -2.077), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands exhibit low hERG inhibition risk (0.299 and 0.071), which is excellent.

**Microsomal Clearance:** Ligand B (-10.511 mL/min/kg) has significantly lower microsomal clearance than Ligand A (31.705 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (11.865 hours) has a much longer in vitro half-life than Ligand A (-20.44 hours - a negative value is concerning). This further supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.006), which is favorable.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage for Ligand A. The difference of 2.3 kcal/mol is large enough to potentially outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor permeability and solubility of both compounds, Ligand A's significantly superior binding affinity (-9.2 kcal/mol vs -6.9 kcal/mol) is a major advantage. While Ligand B has better metabolic stability (lower Cl_mic and higher t1/2), the potency difference is substantial. For an enzyme target like SRC kinase, strong binding is paramount. The solubility and permeability issues could potentially be addressed through formulation strategies.

Output:
0
2025-04-17 13:14:52,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.414 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.86 and 85.25) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.122) is optimal, while Ligand B (0.709) is slightly low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.781 and 0.712), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.629, which is moderately high. Ligand B has a much lower DILI risk of 32.61, which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB score (50.795) than Ligand A (31.834), but it's not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.889) and Ligand B (-5.235) 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 impact.

**Aqueous Solubility:** Ligand A (-3.509) and Ligand B (-1.065) both have negative values, indicating poor solubility. Ligand B is better in this regard.

**hERG Inhibition:** Ligand A (0.671) has a slightly higher hERG risk than Ligand B (0.1), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (8.025 mL/min/kg) has a much lower microsomal clearance than Ligand A (54.247 mL/min/kg), indicating better metabolic stability. This is a critical factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (1.805 hours) has a slightly better in vitro half-life than Ligand A (-4.028 hours).

**P-gp Efflux:** Ligand A (0.56) has a slightly higher P-gp efflux than Ligand B (0.021), which is preferable for Ligand B.

**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 less than 1.5 kcal/mol, so it's not a decisive factor given the other ADME considerations.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is a significantly better drug candidate due to its superior ADME properties. Specifically, its lower DILI risk, lower hERG inhibition, significantly lower microsomal clearance (better metabolic stability), and lower P-gp efflux are all highly desirable for an enzyme inhibitor. The slightly lower logP and solubility are less concerning than the metabolic liability of Ligand A.

Output:
1
2025-04-17 13:14:52,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.754 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**TPSA:** Ligand A (54.02) is well below the 140 threshold for oral absorption. Ligand B (74.09) is also acceptable, though slightly higher.

**logP:** Ligand A (4.558) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.586) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are both within acceptable limits. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.688, B: 0.712), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk, with Ligand A at 48.081 and Ligand B at 43.738, both well below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.219) is higher than Ligand B (47.111), but neither is a major factor in this decision.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.186 and -5.142), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.428 and -2.243). This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.504) has a slightly higher hERG risk than Ligand B (0.301), but both are relatively low and not a major concern.

**Microsomal Clearance:** Ligand A (39.518) has a slightly higher microsomal clearance than Ligand B (35.612), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.861) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound itself. Ligand A (84.471) has a good in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.154 and 0.122).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability for both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity (-9.1 vs -8.1 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The slightly better logP and lower hERG risk also contribute. The negative half-life for Ligand B is a serious red flag, but assuming that is a data error, the binding affinity makes it the better choice. Ligand A's higher clearance is also a negative.

Output:
1
2025-04-17 13:14:52,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.475 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.51) is higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable due to the lower TPSA.

**3. logP:** Both ligands (1.755 and 2.489) are within the optimal 1-3 range. Ligand B is slightly better.

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

**5. H-Bond Acceptors:** Both ligands (3) meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.717 and 0.83), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (32.299) has a slightly higher DILI risk than Ligand B (16.44), but both are below the 40 threshold, indicating low risk.

**8. BBB:** Ligand A (55.487) has a lower BBB penetration percentile than Ligand B (76.037). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.844) has worse Caco-2 permeability than Ligand B (-4.691). Both are negative, which is unusual and suggests poor permeability. Ligand B is slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.393 and -2.487). This is a significant concern for both, but is similar between the two.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.089 and 0.165).

**12. Microsomal Clearance:** Ligand A (32.449) has lower microsomal clearance than Ligand B (38.798), suggesting better metabolic stability, which is a high priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (-2.615) has a negative half-life, which is not possible. Ligand B (20.148) has a reasonable half-life. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.028 and 0.081).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility, Ligand B has better Caco-2 permeability, a significantly better in vitro half-life, and a lower TPSA. The slightly improved metabolic stability of Ligand A is outweighed by the other advantages of Ligand B.

Output:
1
2025-04-17 13:14:52,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.418 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (56.15) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.45) is still under 140, but less favorable than A.

**logP:** Both ligands (3.131 and 2.661) are 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.906) has a significantly higher QED score than Ligand B (0.717), indicating better overall drug-likeness.

**DILI:** Ligand A (67.546) has a higher DILI risk than Ligand B (10.585). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (89.492) has a better BBB score than Ligand B (55.642), but this is not a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.588 and -4.638), 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 (-4.07 and -2.398), also unusual and suggesting poor solubility. Again, context is needed.

**hERG:** Ligand A (0.643) has a slightly higher hERG risk than Ligand B (0.517), but both are relatively low.

**Microsomal Clearance:** Ligand B (40.04) has significantly lower microsomal clearance than Ligand A (66.844), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (9.456) has a longer half-life than Ligand B (0.159), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.237 and 0.194).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better QED and half-life, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.4 vs -10.4 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic). While both have concerning solubility and permeability values, the potency and safety profile of Ligand B are more favorable.

Output:
1
2025-04-17 13:14:52,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.53 and 344.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (122.03) is still under 140, but less favorable than A.

**logP:** Ligand A (3.939) is within the optimal 1-3 range. Ligand B (0.043) is very low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (3 HBD, 7 HBA) is acceptable, but higher counts can sometimes impact permeability.

**QED:** Both ligands have reasonable QED scores (0.716 and 0.581), indicating drug-like properties.

**DILI:** Ligand A (30.942) has a very low DILI risk. Ligand B (52.772) is higher, but still within an acceptable range.

**BBB:** Ligand A (93.525) shows good BBB penetration, although SRC is not a CNS target, this is still a positive attribute. Ligand B (25.242) has poor BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.306) has a negative Caco-2 value, which is unusual and suggests poor permeability, despite the low TPSA. Ligand B (-5.525) is also negative and similarly concerning.

**Aqueous Solubility:** Ligand A (-4.389) and Ligand B (-2.144) both have negative solubility values. This is a significant concern for both compounds.

**hERG:** Ligand A (0.692) has a low hERG risk. Ligand B (0.028) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (81.244) has a moderate clearance, while Ligand B (5.483) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-11.913) has a negative half-life, which is not physically possible and indicates a data error. Ligand B (-8.822) also has a negative half-life, also indicating a data error.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.452 and 0.013), which is favorable.

**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 advantage.

**Conclusion:**

Despite the negative solubility and Caco-2 values for both ligands, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.3 vs 0.0 kcal/mol) outweighs the slightly higher DILI risk and the lower TPSA. The excellent metabolic stability (low Cl_mic) and low P-gp efflux are also very favorable. The negative half-life values are concerning and would need to be investigated, but the binding affinity difference is substantial.

Output:
1
2025-04-17 13:14:52,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.451 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (127.24) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (2.294) is optimal (1-3). Ligand B (-0.173) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is excellent. Ligand B (HBD=4, HBA=5) is acceptable, but higher values could impact permeability.

**QED:** Ligand A (0.855) is very strong, indicating high drug-likeness. Ligand B (0.564) is acceptable, but lower than A.

**DILI:** Ligand A (18.883) has a very low DILI risk. Ligand B (69.678) is significantly higher, indicating a concerning potential for liver injury.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (83.288) is better than Ligand B (16.014).

**Caco-2 Permeability:** Ligand A (-4.906) and Ligand B (-5.461) are both negative, 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 (-3.667 and -3.031 respectively), which is a significant concern.

**hERG Inhibition:** Both ligands have low hERG risk (0.176 and 0.247 respectively).

**Microsomal Clearance:** Ligand A (35.683) has moderate clearance. Ligand B (-16.006) has *negative* clearance, which is impossible and likely an error or artifact of the prediction method. This is a major red flag.

**In vitro Half-Life:** Ligand A (-9.575) has a negative half-life, which is impossible. Ligand B (-1.834) also has a negative half-life, indicating a problem with the prediction.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.171 and 0.024 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand A is significantly more favorable. Ligand B has a concerningly high DILI risk, a negative (and therefore impossible) microsomal clearance, and a negative in vitro half-life. Ligand A has better TPSA, logP, QED, and DILI scores. While both have poor solubility and questionable Caco-2 permeability, the issues with Ligand B's predicted metabolism make it a much less viable candidate. The negative values for clearance and half-life are critical failures.

Output:
0
2025-04-17 13:14:52,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.443 and 342.311 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.85) is excellent, well below the 140 threshold for oral absorption. Ligand B (125.79) is still acceptable, but less optimal.

**logP:** Ligand A (3.08) is optimal. Ligand B (1.29) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (3 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.648 and 0.656), indicating good drug-likeness.

**DILI:** Ligand A (60.915) is better than Ligand B (99.38), indicating a lower risk of drug-induced liver injury. This is a significant advantage.

**BBB:** Ligand A (77.162) is reasonable, while Ligand B (17.332) is very low. BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.613) and Ligand B (-5.483) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-4.539 and -4.392). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.657) is better than Ligand B (0.174), suggesting a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (108.576) has higher clearance than Ligand B (-21.908). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (29.601) has a significantly longer half-life than Ligand A (-27.49). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.163) has lower P-gp efflux than Ligand B (0.04), which is preferable for bioavailability.

**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 not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has a better metabolic profile (lower Cl_mic, longer t1/2) and slightly better binding affinity. However, Ligand A has a significantly better DILI score and hERG risk profile, and a better P-gp efflux liability. Both have poor solubility and permeability. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, hERG), the better metabolic stability and binding affinity of Ligand B are more crucial than the slightly better safety profile of Ligand A. The solubility issues would need to be addressed in either case through formulation strategies.

Output:
1
2025-04-17 13:14:52,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.323 Da) is slightly lower, which could be advantageous for permeability. Ligand B (353.507 Da) is also good.

**TPSA:** Ligand A (124.07) is better than Ligand B (61.88). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 2.379, B: 1.641), falling within the optimal range of 1-3.

**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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have similar and good QED values (A: 0.625, B: 0.684), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (97.596) compared to Ligand B (8.104). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B has a higher BBB percentile (64.482) than Ligand A (20.318).

**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 very poor aqueous solubility (-5.15 and -0.584). This is a significant drawback for both, but might be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.505) has a slightly higher hERG risk than Ligand B (0.227), but both are relatively low.

**Microsomal Clearance:** Ligand B has a much lower microsomal clearance (9.944) than Ligand A (34.599), indicating better metabolic stability. This is a critical advantage for Ligand B.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-7.356) than Ligand A (-2.571), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.069, B: 0.04).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.3 kcal/mol, B: -8.6 kcal/mol). Ligand B is slightly better, but the difference is small.

**Conclusion:**

Despite similar binding affinities and acceptable physicochemical properties (except solubility), Ligand B is the more promising candidate. The primary reason is its significantly lower DILI risk and much better metabolic stability (lower Cl_mic and longer t1/2). While both have poor solubility, this is a formulation challenge that can be addressed. The high DILI risk associated with Ligand A is a major red flag that would likely disqualify it early in development.

Output:
1
2025-04-17 13:14:52,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.849 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.29) is well below the 140 threshold, while Ligand B (97.28) is approaching the upper limit but still acceptable.

**logP:** Ligand A (4.287) is slightly high, potentially leading to solubility issues. Ligand B (1.246) is a bit low, potentially hindering 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 (0.584 and 0.672), indicating drug-likeness.

**DILI:** Ligand A (90.229) has a significantly higher DILI risk than Ligand B (40.83). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration (65.374 and 71.268), not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.058 and -4.826), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.735 and -1.782), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.686) has a slightly higher hERG risk than Ligand B (0.044). Ligand B is very favorable here.

**Microsomal Clearance:** Ligand A (72.304) has higher clearance than Ligand B (27.812), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (51.612) has a longer half-life than Ligand B (37.695), which is a positive.

**P-gp Efflux:** Ligand A (0.676) has moderate P-gp efflux, while Ligand B (0.018) has very low efflux. Ligand B is preferable.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite its superior binding affinity, Ligand A's high DILI risk and higher clearance are major drawbacks. The poor solubility and permeability of both compounds are also concerning. However, the significantly better binding affinity of Ligand A (-8.0 kcal/mol vs -0.0 kcal/mol) is a compelling factor. A strong binding affinity can sometimes outweigh ADME issues, especially if structural modifications can be made to improve those properties. Ligand B has a much better safety profile (DILI, hERG, Pgp) and metabolic stability, but its binding affinity is essentially non-existent.

Given the enzyme-kinase target class, potency is paramount. While the ADME properties of Ligand A are concerning, the substantial binding affinity advantage is likely to be more impactful in initial lead optimization.

Output:
1
2025-04-17 13:14:52,162 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [362.832, 57.28, 4.395, 3, 3, 0.609, 53.47, 51.997, -5.266, -4.406, 0.911, 43.355, 38.031, 0.683, -8.8]
**Ligand B:** [360.483, 78.09, 2.048, 2, 4, 0.828, 44.048, 39.473, -5.628, -2.738, 0.226, 25.87, -6.579, 0.102, -7.7]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A: 362.832, B: 360.483 - Similar.
2. **TPSA:** A (57.28) is well below 140, and B (78.09) is also acceptable, but getting closer to the upper limit.
3. **logP:** A (4.395) is a bit high, potentially leading to solubility issues and off-target effects. B (2.048) is within the optimal range.
4. **HBD:** A (3) is good. B (2) is also good.
5. **HBA:** A (3) is good. B (4) is good.
6. **QED:** Both are above 0.5, indicating good drug-like properties. A (0.609) and B (0.828) - B is better.
7. **DILI:** Both are reasonably low, but A (53.47) is slightly higher than B (44.048). B is preferable.
8. **BBB:** Not a primary concern for a kinase inhibitor, but A (51.997) is slightly higher than B (39.473).
9. **Caco-2:** Both are negative, indicating poor permeability. This is a concern for oral bioavailability. A (-5.266) is worse than B (-5.628).
10. **Solubility:** Both are negative, indicating poor solubility. A (-4.406) is slightly better than B (-2.738).
11. **hERG:** A (0.911) is higher than B (0.226), indicating a higher risk of hERG inhibition and potential cardiotoxicity. B is much preferable.
12. **Cl_mic:** A (43.355) is higher than B (25.87), indicating faster metabolic clearance and lower metabolic stability. B is preferable.
13. **t1/2:** A (38.031) is better than B (-6.579).
14. **Pgp:** A (0.683) is higher than B (0.102), indicating higher P-gp efflux and potentially lower bioavailability. B is preferable.
15. **Binding Affinity:** A (-8.8) is significantly better than B (-7.7), a difference of 1.1 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand A has a significantly better binding affinity.
*   **Metabolic Stability:** Ligand B has better metabolic stability (lower Cl_mic).
*   **Solubility:** Ligand A has slightly better solubility.
*   **hERG Risk:** Ligand B has a much lower hERG risk.
*   **Pgp Efflux:** Ligand B has lower Pgp efflux.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, the significant drawbacks in logP, hERG risk, Pgp efflux, and Cl_mic are concerning. The 1.1 kcal/mol advantage in binding affinity might be outweighed by these ADME/Tox liabilities. Ligand B, despite having a slightly weaker binding affinity, presents a much more favorable ADME/Tox profile, with better solubility, lower hERG risk, lower Pgp efflux, and improved metabolic stability.

Therefore, considering the overall profile and the priorities for an enzyme inhibitor, **Ligand B is the more viable drug candidate.**

Output:
1
2025-04-17 13:14:52,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 354.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.32) is better than Ligand B (41.91). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand B (3.981) is slightly higher than Ligand A (2.103). Both are within the optimal 1-3 range, but Ligand B is approaching the upper limit.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.615 and 0.752, respectively), indicating drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (48.701 and 40.016 percentile), below the 60% threshold. Ligand B is slightly better.

**BBB:** Ligand B (81.621) has a significantly higher BBB penetration percentile than Ligand A (51.066). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.331) has a worse Caco-2 permeability than Ligand B (-5.421). Lower values indicate poorer permeability.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.975 and -3.028). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.097) has a much lower hERG inhibition liability than Ligand B (0.805). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand B (65.521) has lower microsomal clearance than Ligand A (98.404), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (12.168) has a longer in vitro half-life than Ligand A (-13.979), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux than Ligand B (0.495), which is favorable.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (0.0). This is a crucial factor for enzyme inhibitors.

**Overall Assessment:**

Ligand A has a better binding affinity and a much lower hERG risk, which are critical for an enzyme inhibitor. While Ligand B has better metabolic stability and half-life, the superior binding affinity and safety profile of Ligand A outweigh these benefits. The solubility is poor for both, but this can be addressed with formulation strategies.

Output:
0
2025-04-17 13:14:52,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (388.53 Da) is still well within the range.

**TPSA:** Ligand A (96.11) is better than Ligand B (49.85). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.493, Ligand B: 2.637), falling within the optimal 1-3 range.

**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:** Ligand B (0.752) has a better QED score than Ligand A (0.442), indicating a more drug-like profile.

**DILI:** Ligand B (58.434) has a higher DILI risk than Ligand A (41.024), but both are below the concerning threshold of 60.

**BBB:** Ligand B (88.678) has a higher BBB penetration score than Ligand A (70.686), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.912) is slightly worse than Ligand B (-4.412).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility, which is a significant drawback. Ligand A (-2.91) is slightly better than Ligand B (-3.364).

**hERG Inhibition:** Ligand A (0.295) has a lower hERG inhibition liability than Ligand B (0.605), which is a significant advantage.

**Microsomal Clearance:** Ligand B (76.861) has a higher microsomal clearance than Ligand A (55.59), indicating lower metabolic stability. This is a crucial negative for Ligand B.

**In vitro Half-Life:** Ligand A (-14.572) has a negative half-life, which is concerning. Ligand B (9.349) has a positive half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.519), which is favorable.

**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 for an enzyme inhibitor. The difference of 8.2 kcal/mol is substantial and likely outweighs most other drawbacks.

**Conclusion:**

Despite Ligand B having a better QED and half-life, Ligand A's significantly superior binding affinity (-8.2 kcal/mol vs -0.0 kcal/mol) is the deciding factor. The strong binding is likely to overcome the issues with Caco-2 permeability and solubility with appropriate formulation strategies. The lower hERG risk and P-gp efflux also contribute to its favorability.

Output:
1
2025-04-17 13:14:52,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.515 and 348.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.36) is well below the 140 threshold and favorable for oral absorption. Ligand B (73.39) is also below the threshold, but higher than A.

**3. logP:** Both ligands have good logP values (2.674 and 1.644), 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:** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Ligand A (0.864) has a significantly better QED score than Ligand B (0.661), indicating a more drug-like profile.

**7. DILI:** Ligand A (2.21) has a much lower DILI risk than Ligand B (22.8), which is a substantial advantage.

**8. BBB:** Both have reasonable BBB penetration (82.202 and 79.217), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.248 and -5.286). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-1.271 and -1.376), indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.804 and 0.775).

**12. Microsomal Clearance:** Ligand A (-32.655) has significantly lower (better) microsomal clearance than Ligand B (18.288), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.56) has a longer in vitro half-life than Ligand B (3.047), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.044 and 0.029).

**15. Binding Affinity:** Ligand B (-9.6) has a slightly better binding affinity than Ligand A (-7.7), a difference of 1.9 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly superior in almost all other crucial ADME-Tox properties. Specifically, its much lower DILI risk, better QED score, and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are major advantages. The solubility and permeability issues are shared by both, and could be addressed with formulation strategies. The affinity difference is substantial enough to consider, but the ADME profile of A is far more promising for progression as a drug candidate.

Output:
0
2025-04-17 13:14:52,163 - INFO - Batch 197 complete. Total preferences: 3152
2025-04-17 13:14:52,163 - INFO - Processing batch 198/512...
2025-04-17 13:15:38,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 Da and 376.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (92.78) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.925) is within the optimal 1-3 range. Ligand B (0.837) is slightly below 1, which could potentially hinder permeation, although not drastically.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD counts (1). Ligand A has 3 HBAs, and Ligand B has 5. Both are below the 10 limit.

**QED:** Both ligands have good QED scores (0.487 and 0.677), indicating reasonable drug-likeness.

**DILI:** Ligand A (12.02) has a much lower DILI risk than Ligand B (26.406), which is a significant advantage.

**BBB:** Both have similar BBB penetration (69.407 and 66.188). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.355) has a more negative Caco-2 value, suggesting lower permeability. Ligand B (-5.046) is also low, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.541) has slightly better solubility than Ligand B (-1.487). Both are negative, indicating poor solubility, but Ligand A is preferable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.637 and 0.322), which is excellent.

**Microsomal Clearance:** Ligand A (82.779) has a higher microsomal clearance than Ligand B (24.3), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-4.759) has a negative half-life, indicating very rapid metabolism. Ligand B (11.901) has a much more favorable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.205 and 0.015).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and lower DILI risk, Ligand B is superior overall. The significantly stronger binding affinity (-8.5 vs -7.5 kcal/mol) and much better metabolic stability (lower Cl_mic, longer t1/2) are critical for an enzyme inhibitor. The slightly lower logP of Ligand B is a minor concern, but the potency advantage is likely to compensate.

Output:
1
2025-04-17 13:15:38,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (333.435 Da and 345.535 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.94) is better than Ligand B (55.63), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**3. logP:** Both ligands have logP values around 4 (4.445 and 4.12), which is slightly high. This could potentially lead to solubility issues or off-target effects, but is not a dealbreaker if other properties are favorable.

**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), both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.701 and 0.77), indicating good drug-like properties.

**7. DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (32.105). This is a significant concern, as we want to minimize liver toxicity.

**8. BBB:** Ligand A (68.399) is lower than Ligand B (81.621). BBB is not a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.131 and -5.307), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-4.839 and -4.289), indicating very poor aqueous solubility. This is a major concern for oral bioavailability.

**11. hERG:** Ligand A (0.907) has a slightly higher hERG risk than Ligand B (0.406). Lower hERG risk is preferred.

**12. Cl_mic:** Ligand A (47.721) has a lower microsomal clearance than Ligand B (42.743), suggesting better metabolic stability. This is a positive for Ligand A.

**13. t1/2:** Ligand A (21.503) has a significantly longer in vitro half-life than Ligand B (4.79). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**14. Pgp:** Ligand A (0.848) has a higher P-gp efflux liability than Ligand B (0.605), which is less desirable.

**15. 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 can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a longer half-life, which are crucial for enzyme inhibitors. However, it has a higher DILI risk and Pgp efflux. Ligand B has a lower DILI risk and Pgp efflux, but significantly weaker binding affinity and a shorter half-life. Given the importance of potency for kinase inhibitors, the stronger binding affinity of Ligand A is a major advantage. The longer half-life is also a significant benefit. While the DILI risk is a concern, it might be mitigated through structural modifications in subsequent optimization rounds. The poor Caco-2 and solubility are shared concerns, but could be addressed with formulation strategies.

Output:
1
2025-04-17 13:15:38,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.455 and 350.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.15) is slightly higher than Ligand B (58.44). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (0.87) is a bit low, potentially hindering permeation. Ligand B (2.425) is within the optimal 1-3 range. This favors Ligand B.

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

**H-Bond Acceptors:** Ligand A has 5, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.771 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (53.781) has a higher DILI risk than Ligand B (29.042). This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration, but Ligand A (71.772) is slightly better than Ligand B (64.986). However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.446 and -4.519), 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 (-2.205 and -1.915), also unusual and indicating poor solubility. Again, this is a concern for both, but doesn't differentiate them.

**hERG:** Ligand A (0.574) has a slightly higher hERG risk than Ligand B (0.312), making Ligand B safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (75.01) has higher microsomal clearance than Ligand B (73.597), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (33.856) has a significantly longer in vitro half-life than Ligand A (-31.831), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.103 and 0.127), which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This 0.8 kcal/mol difference is substantial and outweighs many of the minor ADME drawbacks of either compound.

**Overall:** Ligand B is the superior candidate. It has better logP, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and significantly stronger binding affinity. While both have issues with Caco-2 and solubility, the potency and safety profile of Ligand B make it more promising.

Output:
1
2025-04-17 13:15:38,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.411 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is significantly better than Ligand B (97.92).  A TPSA under 140 is desired for oral absorption, and both meet this, but A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (1.088) is within the optimal 1-3 range. Ligand B (-0.07) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 6 HBA).  Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.607 and 0.569), indicating reasonable drug-likeness.

**DILI:** Both ligands have similar and acceptable DILI risk (54.246 and 55.758, both <60).

**BBB:** Ligand A (75.572) has a better BBB percentile than Ligand B (52.268), but BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.455) has a *much* better Caco-2 permeability than Ligand B (-5.557). This suggests significantly better intestinal absorption for Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.465 and -1.372). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.301 and 0.113), which is excellent.

**Microsomal Clearance:** Ligand A (64.766) has a higher microsomal clearance than Ligand B (-0.126). This indicates Ligand B is likely more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-19.07) has a significantly longer in vitro half-life than Ligand A (-13.608). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.131 and 0.01).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -9.4 kcal/mol). Ligand B is slightly better (-9.4 vs -8.3), but the difference is not huge.

**Overall Assessment:**

Ligand A excels in permeability (Caco-2) and has a better TPSA and BBB. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. For a kinase inhibitor, metabolic stability is crucial. While solubility is a concern for both, the improved stability of Ligand B outweighs the permeability advantage of Ligand A.

Output:
1
2025-04-17 13:15:38,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 386.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (78.43), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.792 and 2.302), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=5) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.79) has a higher QED score than Ligand B (0.558), indicating a more drug-like profile.

**DILI:** Ligand A (5.118) has a much lower DILI risk than Ligand B (38.697), which is a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (70.648) is higher than Ligand B (43.699).

**Caco-2 Permeability:** Ligand A (-4.453) has a better (less negative) Caco-2 value than Ligand B (-5.561), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.731) has a better (less negative) solubility value than Ligand B (-2.774).

**hERG:** Both ligands have very low hERG inhibition risk (0.182 and 0.205).

**Microsomal Clearance:** Ligand A (11.579) has significantly lower microsomal clearance than Ligand B (41.84), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.848) has a much longer in vitro half-life than Ligand B (-2.444), a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.025 and 0.162).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are good, the 1.1 kcal/mol difference is noteworthy.

**Overall:** Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, especially DILI, metabolic stability (Cl_mic and t1/2), solubility, and Caco-2 permeability. The slightly better binding affinity further solidifies its position.

Output:
1
2025-04-17 13:15:38,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.418 and 378.929 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.35) is better than Ligand B (51.02), being under 140, suggesting good absorption.

**logP:** Both ligands have logP values (2.955 and 4.121) within the optimal 1-3 range, though Ligand B is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A has 3 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 good QED scores (0.719 and 0.804), indicating drug-likeness.

**DILI:** Both ligands have similar DILI risk (55.176 and 56.96), both being acceptable (<60).

**BBB:** Ligand B (85.498) has a higher BBB percentile than Ligand A (64.482), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.332 and -5.054), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.577 and -4.238), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.453 and 0.358), which is good.

**Microsomal Clearance:** Ligand A (7.54 mL/min/kg) has significantly lower microsomal clearance than Ligand B (49.189 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Both have similar in vitro half-lives (18.316 and 18.734 hours), which is good.

**P-gp Efflux:** Both have low P-gp efflux liability (0.081 and 0.768), which is favorable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME deficiencies of Ligand B.

**Conclusion:**

While Ligand B has slightly better binding affinity and BBB penetration, Ligand A is the more promising candidate due to its significantly lower microsomal clearance, suggesting better metabolic stability. Both compounds suffer from poor solubility and permeability, which would need to be addressed through formulation or structural modifications. However, metabolic stability is paramount for kinase inhibitors, making Ligand A the better choice.

Output:
0
2025-04-17 13:15:38,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.344 and 360.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.63) is better than Ligand B (42.43), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (2.199) is optimal, while Ligand B (4.286) 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 (0). While both are acceptable, a single donor can aid solubility.

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

**6. QED:** Ligand A (0.825) has a significantly better QED score than Ligand B (0.681), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.846) has a slightly higher DILI risk than Ligand B (35.091), but both are below the concerning threshold of 60.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (92.633) is better than Ligand B (79.217).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.737 and -4.795). 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 (-2.987 and -3.318). This is also unusual and suggests very poor aqueous solubility. Again, the difference is small.

**11. hERG Inhibition:** Ligand A (0.79) has a lower hERG risk than Ligand B (0.403), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (13.287 mL/min/kg) has a much lower microsomal clearance than Ligand B (65.98 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.438 hours) has a better in vitro half-life than Ligand B (-14.974 hours). A negative half-life is problematic.

**14. P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux than Ligand B (0.396), which is favorable for bioavailability.

**15. 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 other factors are more important.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior drug-like properties (QED), metabolic stability (Cl_mic, t1/2), lower hERG risk, and better P-gp efflux. The poor Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh the small affinity difference.

Output:
0
2025-04-17 13:15:38,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.447 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is slightly higher than Ligand B (62.99). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Ligand A (0.57) is quite low, potentially hindering permeability. Ligand B (2.333) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

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

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Both ligands have good QED values (0.799 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (45.173) has a moderate DILI risk, while Ligand B (12.485) has a very low DILI risk. This is a substantial advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (74.447) is better than Ligand A (65.607). While BBB isn't a primary concern for a kinase inhibitor, it's a slight positive for B.

**Caco-2 Permeability:** Both show negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poorer permeability. Ligand A (-4.657) is worse than Ligand B (-4.481).

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. Ligand A (-1.38) is slightly better than Ligand B (-1.816).

**hERG Inhibition:** Ligand A (0.171) has a very low hERG risk, while Ligand B (0.331) is slightly higher. Ligand A is preferable here.

**Microsomal Clearance:** Ligand A (4.235) has a significantly lower microsomal clearance than Ligand B (21.75). This indicates better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-7.441) has a much longer in vitro half-life than Ligand B (30.751). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.037 and 0.071).

**Binding Affinity:** Ligand A (-8.5) has a significantly stronger binding affinity than Ligand B (-6.8). 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 metabolic stability (lower Cl_mic, longer t1/2), and a lower hERG risk. While its logP is low and solubility is poor, the strong binding affinity (-8.5 kcal/mol) is a critical advantage for an enzyme inhibitor. Ligand B has better logP, DILI, and BBB, but its weaker binding affinity and poorer metabolic stability are significant drawbacks. Given the priority for potency and metabolic stability in kinase inhibitors, Ligand A is the more promising candidate.

Output:
0
2025-04-17 13:15:38,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.463 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (94.89), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.493) is slightly better than Ligand B (0.66), both are within the optimal 1-3 range. Ligand B is closer to the lower bound, which *could* indicate permeability issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are acceptable and balance solubility and permeability.

**QED:** Both ligands have good QED scores (0.746 and 0.836), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (39.162 and 37.65), which is excellent.

**BBB:** Both ligands have similar BBB penetration (56.766 and 55.176), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.401) is worse than Ligand B (-4.937), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.771 and -1.695). This is a potential issue, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG risk (0.087 and 0.107), which is excellent.

**Microsomal Clearance:** This is where the biggest difference lies. Ligand A has a Cl_mic of 20.4 mL/min/kg, while Ligand B has a much higher clearance of -32.186 mL/min/kg. A negative value for Cl_mic is unusual and suggests very high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (21.028 hours) has a significantly longer half-life than Ligand A (5.887 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.037 and 0.007), which is favorable.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better in terms of metabolic stability (Cl_mic and t1/2) and has comparable solubility and safety profiles. For an enzyme target like SRC kinase, metabolic stability is crucial for achieving adequate exposure and duration of action. The small difference in binding affinity is outweighed by the substantial improvement in pharmacokinetic properties.

Output:
1
2025-04-17 13:15:38,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.423 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both are acceptable, below the 140 A^2 threshold for oral absorption. Ligand B (100.55 A^2) is better, indicating potentially improved absorption.

**logP:** Both are within the optimal range (1-3). Ligand A (2.076) and Ligand B (2.013) are very similar.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is preferable to Ligand B (HBD=3, HBA=6) as it has fewer hydrogen bond donors and acceptors, which generally improves permeability.

**QED:** Both have reasonable QED scores, but Ligand B (0.557) is better than Ligand A (0.381), suggesting a more drug-like profile.

**DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (64.288). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (44.397) is slightly better than Ligand B (35.324).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.967) is slightly better than Ligand B (-5.199).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.584) is slightly better than Ligand B (-3.147).

**hERG Inhibition:** Both have low hERG risk (0.308 and 0.434 respectively). Ligand B is slightly higher, but both are acceptable.

**Microsomal Clearance:** Ligand B (19.591 mL/min/kg) has a lower microsomal clearance than Ligand A (30.143 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (64.778 hours) has a significantly longer half-life than Ligand A (11.848 hours), which is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.01 and 0.163 respectively). Ligand A is slightly better.

**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 A has a much better safety profile (lower DILI) and slightly better permeability/solubility. However, Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. Given the enzyme-specific priorities, metabolic stability and potency are crucial. The 0.3 kcal/mol difference in binding affinity, combined with the significantly improved half-life, outweighs the slightly higher DILI risk of Ligand B.

Output:
1
2025-04-17 13:15:38,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.46 and 346.337 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (21.26) is significantly better than Ligand B (83.98). A TPSA under 140 is good for oral absorption, and A is much closer to the ideal for CNS penetration (under 90) than B.

**logP:** Ligand A (4.683) is slightly high, potentially leading to solubility issues, but still within a manageable range. Ligand B (1.618) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.792 and 0.862), indicating generally drug-like properties.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (79.333), a significant advantage.

**BBB:** Ligand A (89.957) shows better BBB penetration potential than Ligand B (71.035), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.688) has poor Caco-2 permeability, which is a concern. Ligand B (-4.518) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.887) has very poor aqueous solubility, a major drawback. Ligand B (-3.279) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.792) has a slightly higher hERG risk than Ligand B (0.224). B is much better here.

**Microsomal Clearance:** Ligand A (13.068) has lower microsomal clearance than Ligand B (17.865), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (24.593 hours) has a significantly longer half-life than Ligand B (7.671 hours), a substantial advantage.

**P-gp Efflux:** Ligand A (0.265) has lower P-gp efflux than Ligand B (0.033), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh many ADME concerns.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability of Ligand A, its significantly superior binding affinity (-8.9 vs -7.6 kcal/mol), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux make it the more promising candidate. The strong binding affinity is the most important factor for an enzyme inhibitor, and the other advantages mitigate the solubility concerns. Formulation strategies can be employed to address solubility issues. Ligand B, while having better solubility and hERG, lacks the potency and favorable metabolic profile of Ligand A.

Output:
1
2025-04-17 13:15:38,598 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [346.431, 87.46, 0.858, 2, 5, 0.774, 42.691, 41.993, -5.033, -2.057, 0.14, 12.12, 3.247, 0.034, -7.3]
**Ligand B:** [346.435, 100.74, 1.645, 2, 6, 0.785, 47.266, 65.18, -5.091, -2.111, 0.322, 27.004, -12.117, 0.051, -9.1]

**Step-by-step comparison:**

1. **MW:** Both ligands (346.43 Da) fall within the ideal range (200-500 Da).
2. **TPSA:** Ligand A (87.46) is better than Ligand B (100.74), both are under the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (not a priority here).
3. **logP:** Ligand A (0.858) is slightly lower than optimal (1-3), but still acceptable. Ligand B (1.645) is better within the optimal range.
4. **HBD:** Both ligands have 2 HBD, which is good.
5. **HBA:** Ligand A has 5 HBA, while Ligand B has 6. Both are acceptable (<=10).
6. **QED:** Both ligands have similar QED values (0.774 and 0.785), indicating good drug-likeness.
7. **DILI:** Ligand A (42.691) has a slightly lower DILI risk than Ligand B (47.266). Both are acceptable (<60).
8. **BBB:** Ligand B (65.18) has a higher BBB penetration potential than Ligand A (41.993), but this is not a primary concern for an oncology target.
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, which is also unusual and suggests poor solubility. This is a significant concern for both.
11. **hERG:** Ligand A (0.14) has a much lower hERG inhibition liability than Ligand B (0.322). This is a significant advantage for Ligand A.
12. **Cl_mic:** Ligand A (12.12) has a significantly lower microsomal clearance than Ligand B (27.004), indicating better metabolic stability. This is a major advantage for Ligand A.
13. **t1/2:** Ligand A (3.247) has a positive in vitro half-life, while Ligand B (-12.117) has a negative value, which is not physically possible. This is a huge advantage for Ligand A.
14. **Pgp:** Ligand A (0.034) has lower P-gp efflux liability than Ligand B (0.051).
15. **Binding Affinity:** Ligand B (-9.1) has a stronger binding affinity than Ligand A (-7.3) by 1.8 kcal/mol. This is a substantial difference.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has a better binding affinity, Ligand A excels in metabolic stability, hERG risk, and has a plausible half-life. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand A, particularly the metabolic stability and lower hERG risk, outweighs the affinity difference.

**Conclusion:**

Considering the priorities for an enzyme target and the overall profile of each ligand, **Ligand A** is the more viable drug candidate.

1
2025-04-17 13:15:38,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.813 Da) is slightly lower, which could be advantageous for permeability. Ligand B (381.402 Da) is also good.

**TPSA:** Ligand A (66.92) is well below the 140 threshold for oral absorption. Ligand B (107.97) is still acceptable but higher, potentially impacting absorption.

**logP:** Ligand A (2.302) is optimal (1-3). Ligand B (0.284) is quite low, potentially hindering membrane permeation and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 8 HBA) is acceptable, but the higher HBA count could slightly reduce permeability.

**QED:** Both ligands have similar QED values (A: 0.595, B: 0.581), indicating good drug-likeness.

**DILI:** Ligand A (64.754) has a moderate DILI risk, but is better than Ligand B (87.902), which is quite high.

**BBB:** Ligand A (96.161) shows excellent BBB penetration, although this is less critical for a non-CNS target like SRC. Ligand B (46.336) has poor BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.711) has poor Caco-2 permeability, which is concerning. Ligand B (-5.765) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.91) and Ligand B (-2.821) both have poor aqueous solubility, which could present formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.258, B: 0.154).

**Microsomal Clearance:** Ligand A (55.767) has moderate clearance, while Ligand B (28.952) has lower clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-14.048) has a very short half-life, which is a major drawback. Ligand B (-17.302) is also short, but slightly longer than A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.17, B: 0.035).

**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's primary advantage is its significantly higher binding affinity. However, it suffers from poor Caco-2 permeability and a very short half-life. Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, but its logP is very low, and its DILI risk is high. The strong affinity of Ligand A is a critical factor for an enzyme inhibitor, and while the ADME properties are suboptimal, they might be addressed through further optimization. The poor logP of Ligand B is a more fundamental issue that would be harder to resolve without significantly altering the core structure.

Output:
0
2025-04-17 13:15:38,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (349.41 and 348.49 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.33) is slightly higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (0.866) is a bit low, potentially hindering permeability. Ligand B (2.511) is within the optimal 1-3 range. This favors 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 reasonable QED scores (0.791 and 0.686), indicating good drug-like properties.

**DILI:** Ligand A (36.06) has a slightly higher DILI risk than Ligand B (29.081), but both are below the concerning threshold of 60.

**BBB:** Both have good BBB penetration (79.217 and 73.866), but this is less critical for a non-CNS target like SRC.

**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. We'll proceed cautiously.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or the model's prediction. We'll proceed cautiously.

**hERG Inhibition:** Ligand A (0.117) has a much lower hERG inhibition liability than Ligand B (0.477). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (6.981) has a considerably lower microsomal clearance than Ligand B (51.525), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-6.73) has a negative half-life, which is not possible. Ligand B (2.06) is a short half-life, but is a valid value.

**P-gp Efflux:** Ligand A (0.035) has much lower P-gp efflux liability than Ligand B (0.202), suggesting better bioavailability.

**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 factor.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic), P-gp efflux, and hERG inhibition. Ligand B has a slightly better binding affinity and a more favorable logP. The negative values for Caco-2 and solubility are concerning for both, but the superior ADME profile of Ligand A, particularly its lower clearance and hERG risk, outweighs the small binding affinity difference. The negative half-life for Ligand A is a major red flag, however.

Given the importance of metabolic stability and safety (hERG) for kinase inhibitors, and the slightly better binding affinity of Ligand B, I would choose Ligand B.

Output:
1
2025-04-17 13:15:38,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.358 Da and 360.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (86.71 and 87.32) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.611 and 2.106) 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 3 HBA, and Ligand B has 5 HBA. Both are acceptable (<=10).

**QED:** Both ligands have high QED scores (0.867 and 0.855), indicating good drug-likeness.

**DILI:** Ligand A (61.07) has a slightly higher DILI risk than Ligand B (59.946), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.962) has a higher BBB score than Ligand B (49.089), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.048 and -5.154). This 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.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.891 and -4.006), indicating poor aqueous solubility. This is a significant concern for bioavailability and formulation.

**hERG Inhibition:** Both ligands have very low hERG risk (0.083 and 0.096), which is excellent.

**Microsomal Clearance:** Ligand A (0.373 mL/min/kg) has significantly lower microsomal clearance than Ligand B (10.978 mL/min/kg), indicating much better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (3.489 hours) has a shorter half-life than Ligand B (-3.981 hours - which is likely an error, and should be a positive value). However, the value for Ligand B is suspect and likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.052), which is favorable.

**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 difference (2.8 kcal/mol) and is a major driver in the decision.

**Conclusion:**

Despite the poor solubility and permeability indicated by the Caco-2 and solubility values (which need further investigation), Ligand A is the superior candidate. Its significantly stronger binding affinity (-9.1 kcal/mol vs -6.3 kcal/mol) and much better metabolic stability (lower Cl_mic) outweigh the concerns about solubility and permeability, especially for an enzyme target like SRC kinase. The lower DILI risk is also a slight advantage. The negative half-life for Ligand B is also a red flag.

Output:
0
2025-04-17 13:15:38,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.236 Da) is slightly higher than Ligand B (362.417 Da), but both are acceptable.

**TPSA:** Ligand A (92.91) is slightly above the preferred <140, while Ligand B (59.08) is well within the range. This favors Ligand B for absorption.

**logP:** Both ligands have good logP values (A: 3.273, B: 2.516), 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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (A: 0.584, B: 0.632), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 66.421%, which is considered high risk. Ligand B has a much lower DILI risk of 36.758%, which is good. This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (83.133%) has higher BBB penetration than Ligand A (53.005%), but this is not a primary concern.

**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 unusual and suggesting poor solubility. The scale is not specified, so it's difficult to interpret.

**hERG:** Ligand A (0.586) has a slightly higher hERG risk than Ligand B (0.449), but both are relatively low.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (74.007 mL/min/kg) than Ligand B (14.887 mL/min/kg). Lower clearance is preferred for metabolic stability, so Ligand B is better.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (10.508 hours) than Ligand A (-10.134 hours). This is a major advantage for Ligand B, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.473, B: 0.098). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.9 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it might not be enough to overcome the significant ADME liabilities of Ligand A.

**Overall:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates significantly better ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and potentially better permeability and solubility (although the scales are unclear). The high DILI risk associated with Ligand A is a major concern.

Output:
1
2025-04-17 13:15:38,599 - INFO - Batch 198 complete. Total preferences: 3168
2025-04-17 13:15:38,599 - INFO - Processing batch 199/512...
2025-04-17 13:16:19,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 361.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.57) is well below the 140 threshold for oral absorption, while Ligand B (118.33) is still acceptable but less optimal.

**logP:** Both ligands (1.944 and 1.481) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are both acceptable. Ligand B has 1 HBD and 7 HBA, also within reasonable limits.

**QED:** Both ligands have acceptable QED scores (0.753 and 0.651, both >0.5).

**DILI:** Ligand A (24.467) has a significantly lower DILI risk than Ligand B (75.184), which is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand B (62.97) is slightly better than Ligand A (47.732).

**Caco-2 Permeability:** Ligand A (-4.737) has a worse Caco-2 permeability than Ligand B (-5.005), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.715) has better aqueous solubility than Ligand B (-3.576). Solubility is important for formulation and bioavailability.

**hERG:** Both ligands have low hERG risk (0.343 and 0.24).

**Microsomal Clearance:** Ligand A (23.067) has a higher microsomal clearance than Ligand B (-2.733), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (18.366 hours) has a much longer in vitro half-life than Ligand A (4.414 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.164 and 0.139).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 2.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and lower DILI risk, Ligand B's significantly stronger binding affinity (-9.5 vs -7.4 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target like SRC kinase. The improved binding affinity is likely to translate to greater efficacy. The higher DILI risk of Ligand B is a concern, but could be addressed through further structural modifications.

Output:
1
2025-04-17 13:16:19,486 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (355.316 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.3) is better than Ligand B (64.41). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is closer to the 90 A^2 threshold for CNS penetration (though this isn't a primary concern for a general oncology target).

**3. logP:** Both ligands have good logP values (2.351 and 2.735) within the optimal 1-3 range.

**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 similar QED values (0.572 and 0.55), indicating good drug-likeness.

**7. DILI:** Ligand A (70.105) has a higher DILI risk than Ligand B (32.183). This is a significant concern.

**8. BBB:** Ligand A (83.947) has better BBB penetration than Ligand B (55.719), but this is less important for a general oncology target.

**9. Caco-2 Permeability:** Ligand A (-5.183) has worse Caco-2 permeability than Ligand B (-4.446). Both are negative, indicating poor permeability, but B is better.

**10. Aqueous Solubility:** Ligand A (-4.18) has worse solubility than Ligand B (-2.86). Both are negative, indicating poor solubility, but B is better.

**11. hERG Inhibition:** Ligand A (0.298) has a much lower hERG inhibition risk than Ligand B (0.576). This is a critical advantage.

**12. Microsomal Clearance:** Ligand A (-9.167) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (46.352). This is a major advantage.

**13. In vitro Half-Life:** Ligand A (14.924) has a longer half-life than Ligand B (-14.631). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.223). This is a slight advantage.

**15. Binding Affinity:** Ligand B (-8.2) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage and could outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has a higher DILI risk and worse metabolic stability than Ligand A, the substantial difference in binding affinity (-8.2 vs 0.0 kcal/mol) is likely to outweigh these drawbacks. The better Caco-2 and solubility of Ligand B are also positive. Ligand A's lower hERG risk is good, but the extremely weak binding makes it unlikely to be effective.

Output:
1
2025-04-17 13:16:19,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.39 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is slightly higher than Ligand B (66.4). Both are below the 140 threshold for oral absorption, but lower is generally preferred. Ligand B has a clear advantage here.

**3. logP:** Both ligands (2.799 and 2.14) are 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 3 HBA, Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.819 and 0.842), indicating good drug-like properties.

**7. DILI:** Ligand A (55.913) has a slightly higher DILI risk than Ligand B (46.297). Both are acceptable (<60), but lower is better.

**8. BBB:** Both ligands have high BBB penetration (77.898 and 73.827), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.749 and -4.697). This is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.95 and -2.06). This is also a major concern as it indicates very poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.412 and 0.451), which is excellent.

**12. Microsomal Clearance:** Ligand A (43.035) has lower microsomal clearance than Ligand B (46.793), suggesting better metabolic stability. This is a key advantage.

**13. In vitro Half-Life:** Ligand A (-23.982) has a significantly longer in vitro half-life than Ligand B (0.401). This is a major advantage, potentially leading to less frequent dosing.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.181).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have significant issues with Caco-2 permeability and aqueous solubility, Ligand B's substantially stronger binding affinity (-7.5 vs -10.5 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. The improved metabolic stability (lower Cl_mic) and longer half-life of Ligand A are beneficial, but the difference in binding affinity is more impactful. The DILI risk is only slightly higher for Ligand A. Given the importance of potency for kinase inhibitors, Ligand B is the more promising candidate, despite the solubility/permeability concerns which would need to be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 13:16:19,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.443 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.11) is better than Ligand B (60.85), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (2.732) is optimal (1-3), while Ligand A (0.848) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 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 (0.727 and 0.776, respectively), indicating drug-like properties.

**DILI:** Ligand B (30.322) has a significantly lower DILI risk than Ligand A (69.794), which is a major advantage.

**BBB:** Both have similar BBB penetration (60.605 and 58.782), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.957) has a much lower Caco-2 permeability than Ligand B (-4.489), suggesting poorer absorption.

**Aqueous Solubility:** Ligand A (-1.849) has slightly better solubility than Ligand B (-2.686), but both are quite poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.25 and 0.299).

**Microsomal Clearance:** Ligand A (-39.664) has significantly lower microsomal clearance than Ligand B (39.238), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.842) has a longer half-life than Ligand B (5.266), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.016 and 0.366).

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), but suffers from poor Caco-2 permeability and a higher DILI risk. Ligand B has better logP, Caco-2 permeability, and a significantly lower DILI risk. Given the enzyme-specific priorities, metabolic stability and potency are key. However, the substantial improvement in DILI risk for Ligand B, combined with acceptable potency and permeability, makes it the more promising candidate. The slight difference in binding affinity is unlikely to outweigh the significant safety advantage of Ligand B.

Output:
1
2025-04-17 13:16:19,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.419 Da and 344.375 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.98) is well below the 140 threshold for good oral absorption, and even below 90, which is good. Ligand B (121.17) is still under 140, but closer to the limit.

**logP:** Ligand A (3.029) is optimal. Ligand B (0.077) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is within acceptable limits. Ligand B (4 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (0.739 and 0.612), indicating good drug-like properties.

**DILI:** Ligand A (84.839) has a higher DILI risk than Ligand B (61.768), but both are below the concerning threshold of 60.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and should be confirmed experimentally.

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

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.56 and 0.201), which is excellent.

**Microsomal Clearance:** Ligand A (43.226) has a higher microsomal clearance than Ligand B (35.651), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-9.441) has a significantly *longer* in vitro half-life than Ligand A (33.695). This is a major advantage.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.162 and 0.019).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.9 kcal/mol and -9.3 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While Ligand A has a slightly better logP and lower DILI, Ligand B's significantly improved in vitro half-life and slightly better solubility profile are more crucial for an enzyme target. The similar binding affinities make the ADME properties the deciding factor. The negative solubility and Caco-2 values for both are concerning and require experimental validation, but the overall profile of Ligand B is more favorable.

Output:
1
2025-04-17 13:16:19,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.808 Da) is slightly higher than Ligand B (354.447 Da), but both are acceptable.

**TPSA:** Ligand A (71.53) is significantly better than Ligand B (95.94). Lower TPSA generally improves permeability, which is beneficial.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.041, Ligand B: 0.845), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could aid in cell permeability.

**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, which generally leads to better permeability. Both are within acceptable limits.

**QED:** Ligand A (0.83) has a significantly higher QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand A (50.989) has a considerably lower DILI risk than Ligand B (7.057), which is a major advantage.

**BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (89.57) has a higher BBB percentile than Ligand B (66.072), but this is less critical in this context.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.756 and -4.776). This is unusual and suggests poor permeability *in vitro*. However, these values are on a log scale and close to zero, so the actual permeability may not be drastically low.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.392 and -0.93). This is also unusual and suggests poor solubility. Ligand B is slightly better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.34 and 0.241), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 18.554, Ligand B: 18.987), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-14.995) has a significantly longer in vitro half-life than Ligand B (-35.199), which is a substantial advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This difference of 1.3 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It boasts a significantly better binding affinity, a higher QED score, a much lower DILI risk, and a longer in vitro half-life. While both have issues with predicted solubility and permeability, the stronger binding and better safety profile of Ligand A make it the more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 13:16:19,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.434 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent, well below the 140 threshold for good absorption. Ligand B (116.76) is still acceptable but less optimal.

**logP:** Ligand A (2.71) is within the optimal 1-3 range. Ligand B (-0.277) is below 1, which may hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (4 HBD, 5 HBA) is acceptable, but higher donor count could impact permeability.

**QED:** Ligand A (0.833) is very good, indicating high drug-likeness. Ligand B (0.448) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (42.071) has a low DILI risk. Ligand B (22.373) also shows a low DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.831) is higher than Ligand B (47.654).

**Caco-2 Permeability:** Ligand A (-4.542) is poor, indicating low intestinal absorption. Ligand B (-5.321) is also poor.

**Aqueous Solubility:** Ligand A (-3.051) is poor, which could hinder bioavailability. Ligand B (-0.561) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.477) has a low hERG risk. Ligand B (0.073) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (55.853) is moderate, suggesting moderate metabolic stability. Ligand B (16.514) is low, indicating good metabolic stability.

**In vitro Half-Life:** Both ligands (-19.934 and -17.232) have negative values, indicating a very short half-life. This is a significant concern for both.

**P-gp Efflux:** Ligand A (0.12) has low P-gp efflux, which is good. Ligand B (0.015) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). The 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better QED, TPSA, and P-gp efflux. However, Ligand B exhibits better metabolic stability (lower Cl_mic) and a slightly better hERG profile. Both ligands have poor Caco-2 permeability and aqueous solubility, and very short half-lives. The strong binding affinity of Ligand A is a major advantage for an enzyme target like SRC kinase. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The short half-life is a more significant issue, but could be improved through structural modifications.

Output:
1
2025-04-17 13:16:19,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.39 and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (73.48 and 70.08) below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have logP values (1.108 and 1.198) 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 5. Both are acceptable, under the limit of 10.

**QED:** Both ligands have good QED scores (0.811 and 0.85), indicating a drug-like profile.

**DILI:** Both ligands have low DILI risk (42.536 and 40.442 percentile), which is favorable.

**BBB:** Both have moderate BBB penetration (65.529 and 60.838 percentile), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.51 and -4.675), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.394 and -1.621), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.37 and 0.267), which is excellent.

**Microsomal Clearance:** Ligand A has a significantly lower (better) microsomal clearance (-6.76 mL/min/kg) compared to Ligand B (26.75 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (-31.261 hours) than Ligand B (26.701 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.213), which is good.

**Binding Affinity:** Ligand B has a slightly better binding affinity (-7.5 kcal/mol) than Ligand A (-8.2 kcal/mol). While a difference of 0.7 kcal/mol is not huge, it is noticeable.

**Overall Assessment:**

Both ligands have significant solubility and permeability issues. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly worse, but still excellent, binding affinity. The improved metabolic stability is crucial for an enzyme target. The solubility/permeability issues would need to be addressed through formulation or further structural modifications, but the better pharmacokinetic profile of Ligand A makes it the more promising starting point.

Output:
1
2025-04-17 13:16:19,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.494 and 356.333 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (121.93). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (3.544) is optimal, while Ligand B (-0.535) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have acceptable HBD counts (0 for A, 2 for B), well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (2) is better than Ligand B (7), both are under the 10 threshold.

**QED:** Both ligands have good QED scores (0.776 and 0.645), indicating drug-like properties.

**DILI:** Ligand A (24.622) has a much lower DILI risk than Ligand B (58.434), a significant advantage.

**BBB:** Ligand A (88.29) shows better BBB penetration than Ligand B (74.447), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.511) is worse than Ligand B (-4.957). Both are negative, which is not ideal, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.342) is better than Ligand B (-2.728), both are negative, but A is slightly better.

**hERG:** Ligand A (0.632) has a lower hERG risk than Ligand B (0.148), a critical advantage for safety.

**Microsomal Clearance:** Ligand A (58.261) has higher microsomal clearance than Ligand B (6.169), indicating lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand A (0.039) has a very short half-life compared to Ligand B (3.359), confirming the lower metabolic stability of A.

**P-gp Efflux:** Ligand A (0.563) has lower P-gp efflux than Ligand B (0.007), which is desirable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), but the difference is not substantial enough to outweigh the ADME issues of B.

**Overall Assessment:**

Ligand A is superior despite its higher Cl_mic and shorter half-life. This is because Ligand B has a significantly lower logP, higher TPSA, and a much higher DILI risk and lower hERG. The slightly better affinity of Ligand B is not enough to compensate for these substantial drawbacks. The lower DILI and hERG risk of Ligand A are crucial for drug development. While metabolic stability is important, it can be addressed through structural modifications.



Output:
0
2025-04-17 13:16:19,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.5 and 348.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (27.3) is significantly better than Ligand B (128.25). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (3.799) is optimal, while Ligand B (0.772) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.806) has a much better QED score than Ligand B (0.605), indicating a more drug-like profile.

**DILI:** Ligand B (47.732) has a lower DILI risk than Ligand A (11.594), which is a positive.

**BBB:** Ligand A (97.945) has a much higher BBB penetration potential than Ligand B (35.712). While SRC isn't a CNS target, higher BBB is generally not a negative.

**Caco-2 Permeability:** Ligand A (-4.918) is better than Ligand B (-5.175), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.039) is better than Ligand B (-2.519), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.981) has a lower hERG risk than Ligand B (0.168), which is a significant advantage.

**Microsomal Clearance:** Ligand B (19.532) has a lower microsomal clearance than Ligand A (23.766), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (54.755) has a better in vitro half-life than Ligand B (-26.756).

**P-gp Efflux:** Ligand A (0.217) has lower P-gp efflux than Ligand B (0.027), which is favorable.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This 0.5 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, QED, solubility, hERG, P-gp efflux, half-life) and has good binding affinity. Ligand B's main advantage is its slightly better binding affinity and lower DILI risk, but it suffers from a high TPSA, low logP, and a negative half-life. Given the importance of metabolic stability and avoiding hERG inhibition for kinase inhibitors, Ligand A is the more promising candidate. The affinity difference is not large enough to overcome the ADME liabilities of Ligand B.

Output:
0
2025-04-17 13:16:19,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.763 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.05) is better than Ligand B (129.23). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred value.

**logP:** Ligand A (1.692) is within the optimal 1-3 range. Ligand B (-0.197) is slightly below 1, which *could* hinder permeation, though not drastically.

**H-Bond Donors:** Ligand A (2) and Ligand B (4) are both acceptable, but A is preferable as it's closer to the ideal of <=5.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable range of <=10.

**QED:** Ligand A (0.766) has a significantly better QED score than Ligand B (0.512), indicating a more drug-like profile.

**DILI:** Ligand A (70.531) has a higher DILI risk than Ligand B (39.395). This is a significant drawback for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand A (52.85) is slightly better than Ligand B (28.655).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.312) is slightly better than Ligand B (-5.618).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.536) is slightly better than Ligand B (-1.041).

**hERG:** Both ligands have very low hERG inhibition risk (0.159 and 0.057), which is excellent.

**Microsomal Clearance:** Ligand A (20.009) has a higher microsomal clearance than Ligand B (0.875), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (24.034) has a longer half-life than Ligand B (6.812), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.01), which is good.

**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 small, it's still a factor.

**Overall Assessment:**

Ligand A has a better QED, half-life, and slightly better permeability/solubility, but suffers from higher DILI risk and significantly worse metabolic stability (higher Cl_mic). Ligand B has a better DILI profile, better metabolic stability, and slightly better binding affinity, but a lower QED.

Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. Ligand B's lower DILI risk and much better metabolic stability outweigh the slightly lower QED and binding affinity. The binding affinity difference is not large enough to overcome the ADME deficiencies of Ligand A.

Output:
1
2025-04-17 13:16:19,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.571 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (63.4) is significantly better than Ligand B (91.65). Lower TPSA generally translates to better cell permeability.

**logP:** Ligand A (3.535) is optimal, while Ligand B (1.154) is on the lower side. A logP below 1 can hinder 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 (A: 0.89, B: 0.772), indicating good drug-likeness.

**DILI:** Ligand A (29.546) has a much lower DILI risk than Ligand B (22.334), which is a significant advantage.

**BBB:** Ligand A (80.264) has better BBB penetration than Ligand B (48.352), although this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.79) is better than Ligand B (-5.269), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.218) is better than Ligand B (-1.34), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.86) has a lower hERG risk than Ligand B (0.172), a critical safety parameter.

**Microsomal Clearance:** Ligand A (56.363) has a higher microsomal clearance than Ligand B (2.263), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-27.951) has a much shorter half-life than Ligand B (17.025), further reinforcing the metabolic stability concern.

**P-gp Efflux:** Ligand A (0.333) has lower P-gp efflux than Ligand B (0.034), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.2). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a considerably stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has some ADME liabilities (lower solubility, higher P-gp efflux, lower BBB), these might be manageable through formulation or structural modifications. Ligand A, despite better ADME properties in many areas, suffers from significantly lower potency and poor metabolic stability. The difference in binding affinity (-9.0 vs -8.2 kcal/mol) is substantial.

Output:
1
2025-04-17 13:16:19,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.383 and 369.893 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.67) is better than Ligand B (67.59), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.644 and 2.32), 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 (0.892) has a significantly better QED score than Ligand B (0.714), indicating a more drug-like profile.

**DILI:** Ligand A (64.211) has a higher DILI risk than Ligand B (21.908). This is a significant drawback for Ligand A.

**BBB:** Ligand B (82.319) has a higher BBB percentile than Ligand A (58.976), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.674) has a lower Caco-2 permeability than Ligand B (-4.418). Both are negative, but B is better.

**Aqueous Solubility:** Ligand A (-2.118) has better aqueous solubility than Ligand B (-3.164).

**hERG Inhibition:** Ligand A (0.289) has a lower hERG inhibition risk than Ligand B (0.509), which is favorable.

**Microsomal Clearance:** Ligand A (-1.605) has a lower (better) microsomal clearance than Ligand B (60.436), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (24.494) has a longer in vitro half-life than Ligand A (22.44), which is preferable.

**P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux than Ligand B (0.524), which is favorable.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.7), although the difference is relatively small.

**Overall Assessment:**

Ligand B has a significantly lower DILI risk and a longer half-life. While Ligand A has better solubility, lower hERG risk, and lower P-gp efflux, the higher DILI risk is a major concern. Given the enzyme-specific priorities, metabolic stability (lower Cl_mic/longer half-life) and safety (lower DILI/hERG) are crucial. The slightly better binding affinity of Ligand B, coupled with its superior safety profile, makes it the more promising candidate.

Output:
1
2025-04-17 13:16:19,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 338.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.71) is better than Ligand B (70.07), both are below the 140 threshold for oral absorption, but ligand B is closer to the 90 threshold for CNS targets (though this isn't a priority here).

**logP:** Ligand A (0.82) is within the optimal 1-3 range. Ligand B (3.727) is at the higher end, 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, 5 HBA). Both are within acceptable limits, but A is more favorable.

**QED:** Ligand A (0.857) is significantly better than Ligand B (0.53), indicating a more drug-like profile.

**DILI:** Ligand A (15.82) has a much lower DILI risk than Ligand B (56.727), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (80.031) is slightly better than Ligand A (74.758). This isn't a major concern for a non-CNS target.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.252) is slightly better than Ligand B (-5.051).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-1.305) is slightly better than Ligand B (-4.03).

**hERG Inhibition:** Ligand A (0.171) has a much lower hERG risk than Ligand B (0.919), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-9.016) has a significantly lower (and therefore better) microsomal clearance than Ligand B (69.218), indicating much better metabolic stability.

**In vitro Half-Life:** Ligand A (9.385) has a better in vitro half-life than Ligand B (34.465).

**P-gp Efflux:** Ligand A (0.011) has a much lower P-gp efflux liability than Ligand B (0.409).

**Binding Affinity:** Ligand B (0.0) has a better binding affinity than Ligand A (-9.3). The difference is substantial (9.3 kcal/mol).

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising drug candidate. The significant advantages in DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), P-gp efflux, QED, and solubility outweigh the difference in binding affinity. A 9.3 kcal/mol difference in binding is substantial, but optimization of Ligand A could potentially close that gap while maintaining its superior ADME properties. Ligand B's high DILI risk, hERG inhibition, and poor metabolic stability are major red flags.

Output:
0
2025-04-17 13:16:19,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.407 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.94) is slightly higher than Ligand B (83.56). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Ligand A (0.32) is quite low, potentially hindering permeability. Ligand B (0.743) is better, but still on the lower side of 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:** Ligand A (0.805) has a significantly higher QED score than Ligand B (0.611), indicating a more drug-like profile.

**DILI:** Ligand A (53.121) has a higher DILI risk than Ligand B (27.065). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 42.536, Ligand B: 47.926). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.198) is slightly worse than Ligand B (-4.902).

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-0.624) is slightly better than Ligand B (-1.355).

**hERG Inhibition:** Ligand A (0.02) has a much lower hERG inhibition risk than Ligand B (0.195). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (2.098) has a lower microsomal clearance than Ligand B (1.433), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.605) has a longer in vitro half-life than Ligand B (24.782).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is small.

**Overall Assessment:**

Ligand B has a better DILI score, slightly better Caco-2 permeability and a slightly better binding affinity. However, Ligand A has a much better QED score, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. Given the enzyme-specific priorities, the better metabolic stability and lower hERG risk of Ligand A are more important than the slightly better binding affinity of Ligand B. The QED score also supports Ligand A as a more drug-like molecule.

Output:
0
2025-04-17 13:16:19,489 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both A (344.459 Da) and B (353.463 Da) are within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (67.23) is significantly better than Ligand B (104.2).  A is well below the 140 threshold for oral absorption, while B is approaching it.

3. **logP:** Both A (2.709) and B (2.445) are within the optimal 1-3 range.  A is slightly more lipophilic, which could be beneficial for cell permeability.

4. **HBD:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

5. **HBA:** Both A (4) and B (4) are within the acceptable limit of 10.

6. **QED:** Both A (0.66) and B (0.601) are above the 0.5 threshold, indicating good drug-like properties. A is slightly better.

7. **DILI:** Ligand A (41.024) is significantly better than Ligand B (53.354). Both are below the 60 threshold, but A has a lower risk.

8. **BBB:** Ligand A (69.794) is better than Ligand B (45.832). While not a primary concern for a kinase inhibitor (unlike a GPCR target), higher BBB is generally favorable.

9. **Caco-2:** Ligand A (-4.836) is better than Ligand B (-5.028). Both are negative, indicating poor permeability, but A is slightly less poor.

10. **Solubility:** Ligand A (-2.745) is better than Ligand B (-3.199). Both are poor, but A is slightly better.

11. **hERG:** Both A (0.255) and B (0.296) have very low hERG inhibition liability, which is excellent.

12. **Cl_mic:** Ligand A (39.648) is better than Ligand B (44.635). Lower is better for metabolic stability.

13. **t1/2:** Ligand A (-0.647) is significantly better than Ligand B (-18.195). A has a longer in vitro half-life.

14. **Pgp:** Both A (0.09) and B (0.108) have low P-gp efflux, which is good.

15. **Binding Affinity:** Ligand B (-7.7) has a significantly better binding affinity than Ligand A (0). A difference of >1.5 kcal/mol is considered substantial.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much stronger binding affinity. However, it has significantly worse metabolic stability (t1/2) and solubility, and a higher DILI risk. Ligand A has better ADME properties overall, but a significantly weaker binding affinity.

**Decision:**

Despite the superior binding affinity of Ligand B, the substantial drawbacks in metabolic stability, solubility, and DILI risk are concerning. The difference in binding affinity (-7.7 vs 0) is large, but not insurmountable with further optimization. Ligand A, while weaker in binding, presents a much more favorable starting point for optimization due to its better ADME profile. It is more likely to be a viable drug candidate *after* further medicinal chemistry efforts to improve its potency.

Output:
0
2025-04-17 13:16:19,489 - INFO - Batch 199 complete. Total preferences: 3184
2025-04-17 13:16:19,489 - INFO - Processing batch 200/512...
2025-04-17 13:16:59,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.86 and 339.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (92.02). A TPSA under 140 is good for oral absorption, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (3.07 and 1.8), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (0) and Ligand A has 3 HBA, while Ligand B has 8. This is better for Ligand A.

**QED:** Both ligands have QED values above 0.5 (0.776 and 0.606), indicating good drug-likeness.

**DILI:** Ligand A (49.63) has a much lower DILI risk than Ligand B (80.34), which is a significant advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand A (71.23) is higher than Ligand B (57.77).

**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 close.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.701) is slightly better than Ligand B (-2.746).

**hERG:** Both ligands have very low hERG inhibition liability (0.258 and 0.136), which is excellent.

**Microsomal Clearance:** Ligand A (43.12) has significantly lower microsomal clearance than Ligand B (74.42), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.27) has a positive half-life, while Ligand B (-24.41) has a negative half-life. This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.192 and 0.09).

**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.

**Conclusion:**

Ligand A is clearly superior. It has a better TPSA, lower DILI risk, lower microsomal clearance, a longer in vitro half-life, and, most importantly, a significantly stronger binding affinity. While both have issues with Caco-2 and solubility, the superior potency and ADME profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 13:16:59,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.439 and 342.483 Da) fall comfortably 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 140 A^2 threshold for good oral absorption, and acceptable for a kinase inhibitor. Ligand B is preferable here.

**3. logP:** Both ligands have a logP around 3 (3.061 and 3.081), which is optimal for permeability and avoiding solubility issues.

**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 below the acceptable limit of <=10.

**6. QED:** Ligand A (0.859) has a higher QED than Ligand B (0.789), suggesting a more drug-like profile.

**7. DILI:** Ligand A (26.328) has a significantly lower DILI risk than Ligand B (17.836). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (84.684 and 81.698), but this is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.458 and -4.558), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.657 and -3.135), indicating poor aqueous solubility. This is a significant drawback for both compounds.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.54 and 0.523), which is good.

**12. Microsomal Clearance:** Ligand A (64.605) has a lower microsomal clearance than Ligand B (78.695), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-17.577) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the compound itself. Ligand A (1.34) has a short half-life, but it's a realistic value.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.096 and 0.295).

**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 A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better safety (lower DILI), metabolic stability (lower Cl_mic), and a realistic half-life. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies. The negative half-life for Ligand B is a critical flaw.

Output:
0
2025-04-17 13:16:59,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (potency, metabolic stability, solubility, and hERG risk).

**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, but both are acceptable.

**TPSA:** Ligand A (65.54) is better than Ligand B (87.47). Lower TPSA generally favors oral absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.069, Ligand B: 2.217), 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 lower values are generally better for permeability.

**QED:** Ligand A (0.889) has a significantly better QED score than Ligand B (0.695), indicating a more drug-like profile.

**DILI:** Ligand A (19.969) has a much lower DILI risk than Ligand B (38.038), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (70.609) is slightly better than Ligand A (61.962). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability. Ligand A (-4.985) is slightly better than Ligand B (-5.033).

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer solubility. Ligand A (-1.349) is slightly better than Ligand B (-2.782).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.248, Ligand B: 0.246), which is good.

**Microsomal Clearance:** Ligand A (4.904) has significantly lower microsomal clearance than Ligand B (43.519), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (77.441) has a much longer in vitro half-life than Ligand A (11.55), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.042, Ligand B: 0.081).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a better QED score, significantly lower DILI risk, and much better metabolic stability (lower Cl_mic). While Ligand B has a slightly better binding affinity and half-life, the ADME profile of Ligand A is superior, making it more likely to succeed as a drug candidate.

Output:
0
2025-04-17 13:16:59,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.449 Da) is slightly higher than Ligand B (346.391 Da), but both are acceptable.

**TPSA:** Ligand A (54.45) is significantly better than Ligand B (104.05). Lower TPSA generally indicates better permeability, which is important for oral bioavailability.

**logP:** Ligand A (2.856) is optimal, while Ligand B (0.435) is quite low. A logP below 1 can hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 8 HBA). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have similar, good QED values (0.8 for A, 0.809 for B).

**DILI:** Ligand A (40.83) has a much lower DILI risk than Ligand B (71.113). Lower DILI is crucial for drug development.

**BBB:** Ligand A (95.89) shows excellent BBB penetration, while Ligand B (51.299) is moderate. While SRC is not a CNS target, high BBB penetration isn't necessarily a negative.

**Caco-2 Permeability:** Ligand A (-4.422) is better than Ligand B (-5.314), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.217) is better than Ligand B (-1.595), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.681) has a lower hERG risk than Ligand B (0.092). Lower hERG is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (41.86) has a higher (worse) microsomal clearance than Ligand B (20.871). Lower clearance indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.011) has a very short half-life, while Ligand B (14.807) has a longer half-life.

**P-gp Efflux:** Ligand A (0.657) has lower P-gp efflux than Ligand B (0.037), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 kcal/mol for A, -9.0 kcal/mol for B). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in most key ADME properties (TPSA, logP, solubility, DILI, hERG, P-gp efflux) and has a slightly better binding affinity. While its microsomal clearance is higher and half-life shorter than Ligand B, the substantial advantages in other areas, particularly safety (DILI, hERG) and permeability, outweigh these drawbacks. Ligand B's low logP and higher DILI/hERG risks are concerning.

Output:
1
2025-04-17 13:16:59,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.316 Da) is higher, but still acceptable. Ligand B (353.369 Da) is slightly better.

**TPSA:** Ligand A (103.78) is higher than the preferred <140, but not drastically so. Ligand B (72.37) is excellent, well below 140.

**logP:** Ligand A (1.838) is within the optimal range (1-3). Ligand B (3.761) is at the higher end of optimal, potentially raising concerns about off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 10 HBA, which is borderline high for HBA. Ligand B has 0 HBD and 5 HBA, which is excellent.

**QED:** Both ligands have good QED scores (A: 0.488, B: 0.791). Ligand B is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (75.107) has a higher DILI risk than Ligand B (56.301). Both are acceptable, but B is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (95.192) is high, while Ligand A (54.827) is moderate.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.707) is worse than Ligand B (-4.373).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.44) is slightly better than Ligand B (-4.631).

**hERG Inhibition:** Both ligands have low hERG risk (A: 0.258, B: 0.539). Both are good.

**Microsomal Clearance:** Ligand A (30.087 mL/min/kg) has lower clearance, suggesting better metabolic stability than Ligand B (43.565 mL/min/kg). This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (31.832 hours) has a longer half-life than Ligand B (-2.4 hours). This is a major advantage for A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.311, B: 0.358). Both are good.

**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 small, it's still a positive for A.

**Overall Assessment:**

Ligand B has better physicochemical properties (TPSA, QED, H-bonds) and lower DILI risk. However, Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. Given that we are targeting a kinase (enzyme), metabolic stability is crucial. The slightly better affinity of A, combined with its superior metabolic profile, outweighs the slightly less favorable physicochemical properties. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:16:59,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.551 Da) is slightly higher than Ligand B (337.387 Da), but both are acceptable.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (101.38). A TPSA under 140 is good for oral absorption, and both fall under that, but Ligand A is preferable.

**logP:** Both ligands have good logP values (A: 2.593, B: 1.432) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and acceptable HBA counts (A: 5, B: 6).

**QED:** Both ligands have good QED scores (A: 0.678, B: 0.708), indicating good drug-like properties.

**DILI:** Ligand A (47.344) has a much lower DILI risk than Ligand B (75.766). This is a significant advantage for Ligand A.

**BBB:** Ligand A (69.523) has a better BBB penetration percentile than Ligand B (57.193), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This suggests poor permeability. Ligand A (-5.183) is slightly better than Ligand B (-5.637).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.41) is slightly better than Ligand B (-2.765).

**hERG Inhibition:** Ligand A (0.542) has a lower hERG inhibition risk than Ligand B (0.081). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (72.796) has higher microsomal clearance than Ligand B (27.188), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (12.076 hours) has a positive half-life, while Ligand B (-27.131 hours) has a negative half-life, which is not possible. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.246, B: 0.095).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A has significant advantages in DILI risk, hERG inhibition, and *in vitro* half-life. While its microsomal clearance is higher (less stable), and its binding affinity is slightly lower, the safety profile and reasonable half-life are more critical for an enzyme inhibitor. Ligand B's exceptionally poor *in vitro* half-life is a major red flag. The small difference in binding affinity is unlikely to outweigh the significant ADME/Tox advantages of Ligand A.

Output:
1
2025-04-17 13:16:59,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.45 & 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is better than Ligand B (78.51). Both are below the 140 A^2 threshold for good absorption, but lower TPSA is generally preferred.

**3. logP:** Ligand A (3.123) is optimal, while Ligand B (1.614) 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 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED scores (0.757 and 0.715), indicating good drug-likeness.

**7. DILI:** Ligand A (37.224) has a much lower DILI risk than Ligand B (15.122). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (88.406) has better BBB penetration than Ligand B (66.344), though this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.367) has better Caco-2 permeability than Ligand B (-5.023).

**10. Aqueous Solubility:** Ligand A (-3.608) has better aqueous solubility than Ligand B (-1.886). This is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.424) has a slightly better hERG profile than Ligand B (0.24). Both are relatively low risk.

**12. Microsomal Clearance:** Ligand A (61.483) has a higher microsomal clearance than Ligand B (-1.179). This suggests Ligand B is more metabolically stable, a key consideration for enzymes.

**13. In vitro Half-Life:** Ligand B (-2.227) has a significantly longer in vitro half-life than Ligand A (-7.876). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.178) has lower P-gp efflux than Ligand B (0.043), which is favorable.

**15. 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 has a superior binding affinity and a much longer half-life, which are critical for an enzyme inhibitor. While Ligand A has advantages in solubility, DILI risk, and P-gp efflux, the potency and metabolic stability offered by Ligand B are more important for SRC kinase inhibition. The slightly lower logP of Ligand B is a minor concern, but the strong binding affinity likely compensates for this.

Output:
1
2025-04-17 13:16:59,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.422 and 354.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is higher than Ligand B (32.34). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**3. logP:** Ligand A (1.18) is within the optimal range (1-3). Ligand B (4.202) is slightly higher, potentially leading to solubility issues and off-target interactions, but still within a tolerable 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 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.778 and 0.816), indicating drug-like properties.

**7. DILI:** Both ligands have very similar and low DILI risk (29.042 and 29.624 percentile), which is excellent.

**8. BBB:** Both ligands have similar high BBB penetration (83.831 and 83.443 percentile). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired or need to be avoided.

**9. Caco-2 Permeability:** Ligand A (-4.592) has a more favorable Caco-2 permeability than Ligand B (-4.907), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.756) has better aqueous solubility than Ligand B (-4.439). This is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.374) has a significantly lower hERG inhibition risk than Ligand B (0.854). This is a critical advantage.

**12. Microsomal Clearance:** Ligand A (-5.537) has a much lower (better) microsomal clearance than Ligand B (33.385). This indicates greater metabolic stability, a key factor for enzymes.

**13. In vitro Half-Life:** Ligand A (12.451 hours) has a shorter half-life than Ligand B (30.35 hours). While longer is generally preferred, the difference isn't drastic.

**14. P-gp Efflux:** Ligand A (0.035) has a much lower P-gp efflux liability than Ligand B (0.473), suggesting better bioavailability.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 1.2 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. It exhibits better solubility, lower hERG risk, significantly improved metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. While Ligand B has a lower TPSA, the advantages of Ligand A in critical ADME properties and potency outweigh this benefit. Given the enzyme-specific priorities, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 13:16:59,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.965 Da) is slightly higher than Ligand B (361.829 Da), but this isn't a major concern.

**TPSA:** Ligand A (57.7) is well below the 140 threshold for oral absorption and is also favorable. Ligand B (80.32) is still acceptable but less optimal.

**logP:** Both ligands have good logP values (A: 3.742, B: 2.212), 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 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.804) has a significantly better QED score than Ligand B (0.45), indicating a more drug-like profile.

**DILI:** Ligand B (76.464) has a higher DILI risk than Ligand A (56.572), suggesting potential liver toxicity concerns.

**BBB:** Both have reasonable BBB penetration, but Ligand A (80.419) is better than Ligand B (62.117). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.676 and -4.918), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.416 and -3.168), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.656) has a lower hERG inhibition risk than Ligand B (0.173), which is a positive attribute.

**Microsomal Clearance:** Ligand A (70.363) has a slightly higher microsomal clearance than Ligand B (65.64), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (68.784) has a slightly longer in vitro half-life than Ligand A (63.603), which is a minor advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.347, B: 0.094).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 kcal/mol and -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to be a deciding factor.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have issues with solubility and permeability, Ligand A demonstrates a significantly better QED score, lower DILI risk, and lower hERG inhibition liability. These factors are crucial for overall drug safety and developability, especially for an enzyme target like SRC kinase. The slightly better BBB penetration is a bonus. Although Ligand B has a marginally longer half-life, the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 13:16:59,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.27 Da) is slightly higher than Ligand B (356.407 Da), but both are acceptable.

**TPSA:** Ligand A (53.76) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (98.58) is higher, but still within a reasonable range, although potentially impacting absorption slightly more.

**logP:** Ligand A (3.48) is optimal. Ligand B (2.111) is a bit lower, potentially impacting permeability, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also reasonable, but the higher number of HBD/HBA could slightly reduce permeability.

**QED:** Both ligands have similar QED values (A: 0.723, B: 0.665), indicating good drug-like properties.

**DILI:** Ligand B (84.684) has a significantly higher DILI risk than Ligand A (53.276). This is a major concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (85.964) is higher than Ligand B (34.277), but this is not a primary factor in this case.

**Caco-2 Permeability:** Ligand A (-4.423) is better than Ligand B (-5.683), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.617 and -3.511 respectively). This is a significant drawback for both, but formulation strategies might mitigate this.

**hERG Inhibition:** Ligand A (0.669) has a lower hERG risk than Ligand B (0.47), which is preferable.

**Microsomal Clearance:** Ligand A (56.949) has a higher microsomal clearance than Ligand B (29.168), suggesting lower metabolic stability. This is a concern for Ligand A.

**In vitro Half-Life:** Ligand B (-6.781) has a significantly shorter half-life than Ligand A (32.616), indicating faster metabolism. This is a major drawback for Ligand B.

**P-gp Efflux:** Ligand A (0.507) has lower P-gp efflux liability than Ligand B (0.055), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the highest priority for an enzyme inhibitor. However, it suffers from a high DILI risk and a very short half-life. Ligand A has better ADME properties (lower DILI, better half-life, better permeability, lower P-gp efflux, lower hERG), but a weaker binding affinity.

Considering the significant potency advantage of Ligand B, and the potential to mitigate the DILI risk through structural modifications (e.g., adding a solubilizing group or modifying the structure to reduce reactive metabolites), I believe Ligand B is the more promising starting point for drug development. The short half-life is also addressable through structural modifications.

Output:
1
2025-04-17 13:16:59,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 371.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (91.22). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.489 and 1.916), 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=5) in terms of H-bonding potential, being closer to the preferred limits.

**QED:** Both ligands have similar QED scores (0.793 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A (8.104) has a much lower DILI risk than Ligand B (59.287). This is a significant advantage for Ligand A.

**BBB:** Ligand A (66.964) has a lower BBB penetration than Ligand B (78.402). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.862 and -4.738), which is unusual and suggests poor permeability. This is a potential concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.219 and -3.635), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Both ligands have low hERG risk (0.478 and 0.584), which is good.

**Microsomal Clearance:** Ligand A (21.956) has slightly higher microsomal clearance than Ligand B (20.233), indicating potentially lower metabolic stability, but the difference is not substantial.

**In vitro Half-Life:** Ligand B (18.811) has a significantly longer in vitro half-life than Ligand A (-1.779). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.146).

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.0). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a much better safety profile (DILI) and better physicochemical properties (TPSA, H-bonds). However, Ligand B has a significantly longer half-life. The poor solubility and permeability for both are concerning, but the DILI risk for Ligand B is high enough to make it a less attractive candidate. The slightly better affinity of Ligand A, coupled with its superior safety profile, makes it the more promising candidate despite the permeability/solubility issues.

Output:
0
2025-04-17 13:16:59,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (383.853 and 375.393 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.86) is slightly higher than Ligand B (89.54), both are acceptable for oral absorption (<140).

**logP:** Both ligands have a logP around 2.3, which is optimal (1-3).

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. 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 good QED scores (0.736 and 0.798), indicating good drug-like properties.

**DILI:** Ligand A (53.858) has a lower DILI risk than Ligand B (72.392). This is a significant advantage.

**BBB:** Ligand B (75.805) has a higher BBB penetration percentile than Ligand A (20.318). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.45) has worse Caco-2 permeability than Ligand B (-4.672).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.336 and -3.249). This is a concern for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.353) has a slightly higher hERG inhibition risk than Ligand B (0.143). This is a minor concern.

**Microsomal Clearance:** Ligand A (25.267) and Ligand B (24.128) have similar microsomal clearance values. Both are acceptable.

**In vitro Half-Life:** Ligand B (-7.051) has a longer in vitro half-life than Ligand A (-6.421). This is a slight advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.182 and 0.224).

**Binding Affinity:** Ligand B (-8.3 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.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates a significantly lower DILI risk, better Caco-2 permeability, and a longer half-life. The solubility is a concern for both, but the lower DILI risk of Ligand B is a critical advantage for further development.

Output:
1
2025-04-17 13:16:59,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.483 and 387.267 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.08 and 76.46) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.629 and 1.859) are within the optimal 1-3 range.

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

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

**QED:** Both ligands have good QED scores (0.741 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A (63.552) has a higher DILI risk than Ligand B (48.468). This is a negative for Ligand A.

**BBB:** Both ligands have similar BBB penetration (65.762 and 65.801). Not a major factor here as SRC is not a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.488 and -4.749). This 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 (-2.564 and -3.274). This is also concerning and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.579) has a slightly higher hERG inhibition risk than Ligand B (0.259). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand B (37.068) has a lower microsomal clearance than Ligand A (46.174), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-6.341) has a negative half-life, which is highly unusual and suggests very rapid metabolism. Ligand A (22.544) has a reasonable half-life. This is a major negative for Ligand B.

**P-gp Efflux:** Ligand A (0.496) has lower P-gp efflux than Ligand B (0.096), which is preferable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower DILI risk, and better metabolic stability. However, it has a very concerning negative in vitro half-life. Ligand A has a more reasonable half-life but higher DILI and hERG risk. The negative Caco-2 and solubility values for both are concerning, but the superior affinity of Ligand B is a strong driver. Given the enzyme-specific priorities, the binding affinity is paramount. The negative half-life of B is a major concern, but could potentially be addressed with structural modifications.

Output:
1
2025-04-17 13:16:59,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.463 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (395.874 Da) is still well within the range.

**TPSA:** Ligand A (110.08) is better than Ligand B (40.54). Lower TPSA generally favors better absorption.

**logP:** Ligand A (-0.025) is low, potentially hindering permeation. Ligand B (4.79) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has more HBAs (7) than Ligand B (3), which could affect solubility and permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.782, B: 0.643), indicating good drug-like properties.

**DILI:** Ligand A (59.403) has a higher DILI risk than Ligand B (18.34). This is a significant concern for Ligand A.

**BBB:** Ligand B (87.01) has a much higher BBB penetration potential than Ligand A (68.36), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.62) has very poor Caco-2 permeability. Ligand B (-4.659) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.17) has poor aqueous solubility. Ligand B (-5.056) is even worse.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.048, B: 0.854), which is good.

**Microsomal Clearance:** Ligand A (20.799) has lower microsomal clearance than Ligand B (71.379), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.964) has a negative half-life, which is concerning. Ligand B (5.48) has a short, but positive half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.046, B: 0.558).

**Binding Affinity:** Both ligands have similar, strong binding affinities (A: -8.0, B: -8.5). The difference is minor.

**Overall Assessment:**

Ligand B has a significantly better safety profile (lower DILI) and better BBB penetration, but suffers from high logP and poor solubility. Ligand A has better TPSA and metabolic stability, but has a very poor Caco-2 permeability, poor solubility, and a concerning DILI risk. Considering the enzyme-specific priorities, metabolic stability (Cl_mic) is crucial. However, the extremely poor permeability and DILI risk of Ligand A are major drawbacks. While Ligand B has some ADME liabilities, they are less severe and potentially addressable through further optimization. The similar binding affinities make ADME properties the deciding factor.

Output:
1
2025-04-17 13:16:59,783 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.819 Da) is slightly higher than Ligand B (350.419 Da), but both are acceptable.

**TPSA:** Ligand A (45.33) is significantly better than Ligand B (93.53). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target. Ligand B's TPSA is relatively high.

**logP:** Ligand A (4.683) is higher than Ligand B (0.965). While Ligand A 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:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 6.  Ligand A is preferable here, as fewer H-bonds can improve permeability.

**QED:** Both ligands have similar QED values (0.714 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (86.623) has a higher DILI risk than Ligand B (42.885). This is a significant drawback for Ligand A.

**BBB:**  BBB is not a primary concern for an oncology target, but Ligand A (78.558) is better than Ligand B (56.34).

**Caco-2 Permeability:** Ligand A (-4.799) is better than Ligand B (-4.889), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-6.248) is better than Ligand B (-1.539), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.666) has a lower hERG risk than Ligand B (0.253), which is a significant advantage.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (52.344 and 50.881), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (26.28) has a longer half-life than Ligand B (-12.815). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.608) has lower P-gp efflux than Ligand B (0.088), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 0.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, better TPSA, logP, solubility, hERG, half-life, and P-gp efflux. However, it has a higher DILI risk. Ligand B has a lower DILI risk but suffers from a higher TPSA, lower logP, lower solubility, and weaker binding affinity. Given the importance of potency for kinase inhibitors, and the fact that the affinity difference is substantial, the benefits of Ligand A outweigh the higher DILI risk, *provided further investigation into mitigating the DILI risk is pursued*.

Output:
1
2025-04-17 13:16:59,783 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.487 and 344.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.51) is slightly above the preferred <140, but acceptable. Ligand B (50.28) is excellent, well below 140.

**logP:** Ligand A (2.253) is within the optimal 1-3 range. Ligand B (3.866) is approaching the upper limit, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.71 and 0.794), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 74.021, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 24.506, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (89.143) is higher than Ligand A (61.807).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.895 and -5.036), 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 (-3.523 and -3.801), also unusual and suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.261) shows a very low hERG risk, which is excellent. Ligand B (0.934) has a higher hERG risk, which is a concern.

**Microsomal Clearance:** Ligand A (93.358) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (76.498) is better, but still relatively high.

**In vitro Half-Life:** Ligand A (-38.962) has a very short in vitro half-life, further confirming poor metabolic stability. Ligand B (26.452) has a better, but still not ideal, half-life.

**P-gp Efflux:** Ligand A (0.307) has a moderate P-gp efflux liability. Ligand B (0.464) has a slightly higher efflux liability.

**Binding Affinity:** Ligand A (-7.6 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, which is a major advantage for an enzyme inhibitor. However, it suffers from high DILI risk, high microsomal clearance, and a short half-life. Ligand B has a better safety profile (lower DILI, lower hERG) and slightly better metabolic stability, but its binding affinity is extremely weak.

Given the importance of potency for enzyme inhibition, and the fact that the affinity difference is so large (7.6 kcal/mol vs 0.0 kcal/mol), I would prioritize Ligand A *despite* its ADME liabilities. The poor ADME properties could potentially be addressed through further medicinal chemistry optimization, but it's much harder to improve a weak binder. The strong binding of Ligand A suggests it has a good starting point for optimization.

Output:
1
2025-04-17 13:16:59,783 - INFO - Batch 200 complete. Total preferences: 3200
2025-04-17 13:16:59,783 - INFO - Processing batch 201/512...
2025-04-17 13:17:45,680 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [383.704, 67.01, 3.835, 2, 3, 0.609, 66.15, 65.529, -4.932, -4.575, 0.566, 24.841, -7.354, 0.386, -8.1]
**Ligand B:** [364.423, 87.9, 0.253, 0, 5, 0.715, 50.756, 81.388, -5.046, -1.805, 0.196, -2.326, 12.936, 0.039, -7.9]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (383.7) is slightly higher than B (364.4).
2. **TPSA:** A (67.01) is good, below the 140 threshold. B (87.9) is higher, but still reasonable.
3. **logP:** A (3.835) is optimal. B (0.253) is quite low, potentially hindering permeability.
4. **HBD:** A (2) is good. B (0) is also acceptable.
5. **HBA:** A (3) is good. B (5) is acceptable.
6. **QED:** Both are good (A: 0.609, B: 0.715), indicating drug-like properties. B is slightly better.
7. **DILI:** A (66.15) is concerning, indicating a higher risk of liver injury. B (50.756) is much better.
8. **BBB:** A (65.529) is moderate. B (81.388) is better, but SRC is not a CNS target, so this is less critical.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.932) is worse than B (-5.046).
10. **Solubility:** Both are negative, indicating poor solubility. A (-4.575) is slightly better than B (-1.805).
11. **hERG:** A (0.566) is better than B (0.196), indicating lower cardiotoxicity risk.
12. **Cl_mic:** A (24.841) is better (lower clearance = more stable) than B (-2.326).
13. **t1/2:** A (-7.354) is better (longer half-life) than B (12.936).
14. **Pgp:** A (0.386) is better (lower efflux) than B (0.039).
15. **Binding Affinity:** Both are excellent (-8.1 and -7.9 kcal/mol). A is slightly better.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand A has a slightly better affinity.
*   **Metabolic Stability:** Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2).
*   **Solubility:** Ligand A has slightly better solubility.
*   **hERG Risk:** Ligand A has a lower hERG risk.
*   **DILI:** Ligand B has a significantly lower DILI risk.
*   **LogP/Permeability:** Ligand B has a very low logP and poor Caco-2 permeability, which is a major drawback.

**Conclusion:**

Despite the higher DILI risk, **Ligand A** is the more promising candidate. The superior affinity, metabolic stability, solubility, and hERG profile outweigh the DILI concern, especially as DILI risk can be further mitigated through structural modifications. The extremely low logP and permeability of Ligand B are significant liabilities that would be very difficult to overcome.

Output:
1
2025-04-17 13:17:45,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 352.356 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is higher than Ligand B (44.12). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**logP:** Ligand A (3.0) is optimal, while Ligand B (4.29) is slightly high. This could lead to solubility issues and off-target interactions for Ligand B.

**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.

**QED:** Both ligands have similar and good QED values (0.769 and 0.771).

**DILI:** Ligand A (25.126) has a much lower DILI risk than Ligand B (44.552), a significant advantage.

**BBB:** Ligand A (74.641) has good BBB penetration, while Ligand B (94.921) is even better. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.733) has better Caco-2 permeability than Ligand B (-4.321).

**Aqueous Solubility:** Ligand A (-3.136) has better aqueous solubility than Ligand B (-5.491). This is important for formulation and bioavailability.

**hERG:** Both ligands have the same hERG risk (0.42), which is acceptable.

**Microsomal Clearance:** Ligand A (44.198) has lower microsomal clearance than Ligand B (62.922), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.509) has a longer half-life than Ligand B (-2.777), which is desirable.

**P-gp Efflux:** Both ligands have the same P-gp efflux liability (0.023).

**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 of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better ADME properties (lower DILI, better solubility, better metabolic stability, longer half-life, better Caco-2 permeability), Ligand B exhibits a significantly higher binding affinity. Given that we are targeting an enzyme (SRC kinase), potency is paramount. The 1.5 kcal/mol difference in binding affinity is a substantial advantage that likely outweighs the slightly higher logP, higher DILI, and lower metabolic stability of Ligand B.

Output:
1
2025-04-17 13:17:45,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.607 Da) is slightly higher than Ligand B (352.385 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is better than Ligand B (69.3), being closer to the ideal threshold of <=140 for oral absorption.

**logP:** Both ligands have good logP values (Ligand A: 2.869, Ligand B: 1.544), 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 6 HBAs, while Ligand B has 3. Both are below the threshold of <=10.

**QED:** Both ligands have high QED scores (Ligand A: 0.843, Ligand B: 0.897), indicating good drug-like properties.

**DILI:** Ligand A (69.174) has a higher DILI risk than Ligand B (41.566). Ligand B is preferred here.

**BBB:** Ligand B (80.419) has a significantly higher BBB penetration percentile than Ligand A (43.583). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.074) is slightly worse than Ligand B (-4.852).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.833 and -2.154 respectively). This is a significant concern.

**hERG Inhibition:** Ligand A (0.296) has a slightly higher hERG inhibition risk than Ligand B (0.42), but both are relatively low.

**Microsomal Clearance:** Ligand B (26.229 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (47.5 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-45.633 hours) has a much longer in vitro half-life than Ligand A (3.367 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.296) has lower P-gp efflux than Ligand B (0.063), which is favorable.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. Its significantly better binding affinity, lower DILI risk, lower microsomal clearance, and longer half-life outweigh the slightly lower P-gp and solubility concerns. While both have poor solubility and Caco-2 permeability, the potency and metabolic stability advantages of Ligand B are critical for an enzyme inhibitor.

Output:
1
2025-04-17 13:17:45,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**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, while Ligand B (383.449 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (72.7) is better than Ligand A (87.74).

**logP:** Ligand A (1.215) is within the optimal range (1-3). Ligand B (3.299) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 7 HBA) both fall within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.617, B: 0.709), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (19.271) has a significantly lower DILI risk than Ligand B (79.837). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a general oncology target. Ligand B (75.921) has a higher BBB penetration than Ligand A (54.362), but this is less important here.

**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, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.173) shows very low hERG inhibition risk, a significant advantage. Ligand B (0.518) has a slightly higher, but still relatively low, risk.

**Microsomal Clearance:** Ligand A (15.782 mL/min/kg) has a lower microsomal clearance than Ligand B (31.222 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (16.911 hours) has a longer half-life than Ligand A (8.814 hours), which is generally desirable.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux liability, while Ligand B (0.59) has a moderate liability.

**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, and the 8.4 kcal/mol advantage is substantial enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has better safety profiles (DILI, hERG) and metabolic stability (Cl_mic), and P-gp efflux. However, Ligand B has a much stronger binding affinity. Given that we are targeting a kinase in oncology, potency is paramount. The 8.4 kcal/mol difference in binding affinity is a significant advantage that likely outweighs the ADME concerns with Ligand B. While the negative solubility and Caco-2 values are concerning, these can potentially be addressed through formulation strategies. The higher DILI and hERG risk of Ligand B are also concerns, but might be acceptable given the strong potency.

Output:
1
2025-04-17 13:17:45,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.39 & 339.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.87) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (75.44) is well within the range.

**logP:** Ligand A (-0.467) is a bit low, potentially hindering permeability. Ligand B (1.999) 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 reasonable counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.721 and 0.846 respectively), indicating drug-likeness.

**DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (44.048), which is a major advantage. Both are below the concerning threshold of 60.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, suggesting poor permeability. This is concerning, but can be mitigated with formulation.

**Aqueous Solubility:** Both have negative solubility values, which is a significant drawback. Formulation strategies would be crucial.

**hERG:** Both ligands have very low hERG risk (0.071 and 0.082).

**Microsomal Clearance:** Ligand A (-10.511) exhibits *much* lower (better) microsomal clearance than Ligand B (42.371), indicating superior metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (11.865 hours) has a considerably longer half-life than Ligand B (1.743 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.006 and 0.057).

**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 difference (over 2 kcal/mol), and is a major factor.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much more favorable ADME profile, particularly regarding metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The lower logP and solubility of Ligand A are concerns, but the significantly better metabolic profile and lower toxicity risk are more critical for an enzyme target like SRC. The affinity difference, while substantial, might be overcome with further optimization of Ligand A, while fixing the ADME issues of Ligand B might prove more challenging.

Output:
0
2025-04-17 13:17:45,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.439 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.11) is slightly higher than Ligand B (80.57), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.182 and 2.664), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.703 and 0.855), indicating drug-like properties.

**DILI:** Ligand A (72.896) has a higher DILI risk than Ligand B (39.395). This is a significant concern, as we want to minimize liver injury potential.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (56.65) has a slightly better BBB score than Ligand A (48.391).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates poor permeability. Ligand A (-5.161) is worse than Ligand B (-4.918).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.427) is slightly worse than Ligand B (-2.872).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.309 and 0.452).

**Microsomal Clearance:** Ligand A (42.111) has a higher microsomal clearance than Ligand B (35.534), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (39.539) has a significantly longer in vitro half-life than Ligand A (-16.396). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.095).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a considerably stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 2.6 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have acceptable physicochemical properties, Ligand B demonstrates a significantly stronger binding affinity, a longer half-life, lower DILI risk, and better Caco-2 permeability and solubility. The substantial difference in binding affinity is the most important factor, given our prioritization of potency for an enzyme target.

Output:
1
2025-04-17 13:17:45,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.47 and 350.34 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (53.43), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.758 and 3.78), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 3 HBA) as lower numbers generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.725 and 0.773), indicating drug-like properties.

**DILI:** Ligand A (17.84) has a much lower DILI risk than Ligand B (46.06). This is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (87.48) has better BBB penetration than Ligand B (68.32).

**Caco-2 Permeability:** Ligand A (-4.793) shows better Caco-2 permeability than Ligand B (-4.396).

**Aqueous Solubility:** Ligand A (-3.276) has better aqueous solubility than Ligand B (-4.544). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.368) has a lower hERG inhibition liability than Ligand B (0.681), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (53.72) has lower microsomal clearance than Ligand B (72.996), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.997) has a significantly longer in vitro half-life than Ligand B (-37.661). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux liability than Ligand B (0.264).

**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 noteworthy.

**Overall:** Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties (DILI, hERG, Cl_mic, t1/2, solubility) and has a slightly better binding affinity. Ligand B has a slightly higher logP, which is not a major concern, but the significantly worse ADME profile makes it less desirable.

Output:
0
2025-04-17 13:17:45,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is better than Ligand B (76.66), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.134 and 1.497 respectively) within the optimal 1-3 range. Ligand B is slightly lower, which could slightly improve solubility but might marginally affect permeability.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.713 and 0.678), indicating good drug-like properties.

**DILI:** Ligand A (34.742) has a slightly higher DILI risk than Ligand B (30.865), but both are below the 40 threshold and considered good.

**BBB:** Both have good BBB penetration (78.286 and 89.957), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-3.911) has worse Caco-2 permeability than Ligand B (-4.748). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.589) has slightly better solubility than Ligand B (-2.093), but both are poor.

**hERG Inhibition:** Ligand A (0.129) has a lower hERG risk than Ligand B (0.31), which is a significant advantage.

**Microsomal Clearance:** Ligand A (105.085) has significantly higher microsomal clearance than Ligand B (32.765), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-17.406) has a much shorter half-life than Ligand B (-6.013), further confirming its lower metabolic stability.

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux than Ligand B (0.024), which is slightly favorable.

**Binding Affinity:** Ligand B (-6.3 kcal/mol) has a better binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial difference in potency.

**Conclusion:**

While Ligand A has a better binding affinity, the significantly higher microsomal clearance, shorter half-life, and worse Caco-2 permeability of Ligand A are major concerns. Ligand B, despite slightly lower affinity, exhibits better metabolic stability (lower Cl_mic, longer t1/2), better Caco-2 permeability, and a lower hERG risk. Given the enzyme-specific priorities, metabolic stability and safety (hERG) are crucial. The affinity difference is substantial, but not enough to overcome the ADME liabilities of Ligand A.

Output:
1
2025-04-17 13:17:45,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.395 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.05) is better than Ligand B (91.57), being comfortably below the 140 cutoff for oral absorption.

**logP:** Ligand A (3.34) is slightly higher than optimal (1-3), but still acceptable. Ligand B (1.694) is at the lower end of the range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBDs and 4 HBAs, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have reasonable QED scores (0.723 and 0.668), indicating good drug-like properties.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (31.369). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (50.679) and Ligand B (33.54) are both low.

**Caco-2 Permeability:** Ligand A (-4.994) is significantly better than Ligand B (-5.081), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.971) is slightly better than Ligand B (-2.442), though both are poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.425 and 0.1).

**Microsomal Clearance:** Ligand A (34.23) has a higher clearance than Ligand B (23.961), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (32.812) has a longer half-life than Ligand A (43.995).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.042 and 0.098).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 2.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better Caco-2 permeability and solubility, Ligand B's significantly higher binding affinity (-8.9 vs -6.8 kcal/mol) and lower DILI risk are decisive. The improved binding affinity is a major advantage for an enzyme target, and the lower DILI risk is crucial. The slightly lower solubility and permeability of Ligand B are less concerning given its superior potency and safety profile.

Output:
1
2025-04-17 13:17:45,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.463 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (76.46) is significantly better than Ligand B (105.4). A TPSA under 140 is good for oral absorption, but lower is generally preferred.

**logP:** Both ligands have good logP values (A: 2.3, B: 1.685) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (8) compared to Ligand A (5), which is slightly less desirable.

**QED:** Ligand A (0.827) has a much better QED score than Ligand B (0.634), indicating a more drug-like profile.

**DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (74.641). This is a major advantage for Ligand A.

**BBB:** This is less important for a non-CNS target like SRC. Ligand A (88.949) is better than Ligand B (16.983).

**Caco-2 Permeability:** Ligand A (-4.341) is better than Ligand B (-5.853), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.798) is better than Ligand B (-2.378).

**hERG:** Both ligands have very low hERG risk (0.288 and 0.051 respectively), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance values (A: 59.435, B: 60.853).

**In vitro Half-Life:** Ligand B (16.525) has a significantly longer half-life than Ligand A (-1.903). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.063 and 0.078).

**Binding Affinity:** Both ligands have similar binding affinity (A: 0, B: 0).

**Overall Assessment:**

Ligand A is superior due to its significantly better DILI score, TPSA, QED, Caco-2 permeability, and solubility. While Ligand B has a longer half-life, the lower DILI risk and better ADME properties of Ligand A outweigh this benefit, especially considering the importance of metabolic stability and safety for an oncology target.

Output:
1
2025-04-17 13:17:45,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is slightly higher than Ligand B (67.23), but both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.317 and 2.001), 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, and Ligand B has 5. Both are below the 10 limit.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (18.496) has a significantly lower DILI risk than Ligand B (39.434). This is a substantial advantage.

**BBB:** Both have reasonable BBB penetration (78.402 and 71.733), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.868 and -5.074).

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Again, the values are very similar (-2.439 and -2.486).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.286 and 0.311).

**Microsomal Clearance:** Ligand A (58.011) has lower microsomal clearance than Ligand B (51.943), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-7.93 hours) compared to Ligand B (15.076 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.104 and 0.127).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.2 kcal/mol). Ligand A is slightly better (-8.8 kcal/mol).

**Conclusion:**

While both compounds have good potency, Ligand A is the superior candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The solubility and Caco-2 permeability are similar and problematic for both, but these can be addressed with formulation strategies. The lower DILI and improved metabolic stability of Ligand A are crucial for progressing a drug candidate.

Output:
0
2025-04-17 13:17:45,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.447 and 343.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is better than Ligand B (36.44). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.555) is optimal, while Ligand B (3.231) is approaching the upper limit.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0).

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

**QED:** Both ligands have acceptable QED scores (0.832 and 0.762, both > 0.5).

**DILI:** Ligand A (25.785) has a significantly lower DILI risk than Ligand B (1.551). This is a major advantage.

**BBB:** Ligand A (78.054) is good, while Ligand B (91.586) is excellent. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.283) is worse than Ligand B (-4.989), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.703) is slightly better than Ligand B (-1.125).

**hERG Inhibition:** Ligand A (0.213) has a much lower hERG risk than Ligand B (0.875). This is a significant advantage.

**Microsomal Clearance:** Ligand A (26.217) has higher microsomal clearance than Ligand B (7.028), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-12.859) has a much longer in vitro half-life than Ligand A (-1.256). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.011) has a lower P-gp efflux liability than Ligand B (0.26).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. However, Ligand A has a significantly lower DILI risk and hERG inhibition liability, which are crucial for drug development. The Caco-2 permeability is slightly worse for Ligand A, but the other advantages outweigh this. Considering the enzyme-specific priorities, the lower toxicity profile of Ligand A is more valuable than the slightly better pharmacokinetic properties of Ligand B.

Output:
1
2025-04-17 13:17:45,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.896 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (26.79) is significantly better than Ligand B (105.48). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (3.174 and 2.068), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Lower numbers generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.817 and 0.752), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (46.297 and 48.623), and are both below the concerning threshold of 60.

**BBB:** Ligand A (97.208) shows much better BBB penetration potential than Ligand B (78.558). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.495 and -4.466), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.034 and -2.925), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.964) has a slightly better hERG profile than Ligand B (0.118), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (33.1 mL/min/kg) has lower microsomal clearance than Ligand B (44.697 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.224 hours) has a significantly longer half-life than Ligand B (-10.841 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.336) has lower P-gp efflux than Ligand B (0.023), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 kcal/mol and -9.5 kcal/mol). Ligand B is slightly better, but the difference is likely not enough to overcome the other drawbacks.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. It has better TPSA, H-bond characteristics, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. While both ligands suffer from poor solubility and permeability, Ligand A's superior ADME properties, particularly its metabolic stability and half-life, make it a more viable starting point for optimization.

Output:
0
2025-04-17 13:17:45,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.705 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (55.76) is well below the 140 threshold for oral absorption. Ligand B (81.67) is also below, but closer to the limit.

**logP:** Ligand A (4.326) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.595) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which are both acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.621, B: 0.767), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 61.962, which is considered high risk. Ligand B has a much lower DILI risk of 30.826, which is good. This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (48.662) and Ligand B (73.75) are both relatively low, but not critical in this case.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values could be experimental errors or indicate active efflux.

**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 (A: 0.635, B: 0.516), which is good.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (84.451), indicating poor metabolic stability. Ligand B has a much lower clearance (-25.8), suggesting good metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A has a half-life of 23.745 hours, which is reasonable. Ligand B has a very short half-life of 10.671 hours, which is a drawback.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.539, B: 0.02).

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.0 kcal/mol, B: -8.3 kcal/mol). Ligand B is slightly better (-8.3 vs -8.0), but the difference is small.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, the significantly lower DILI risk and much improved metabolic stability (lower Cl_mic) make it the more promising drug candidate. The poor solubility and permeability are concerning for both, but can be addressed with formulation strategies. The higher DILI risk of Ligand A is a major red flag.

Output:
1
2025-04-17 13:17:45,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (404.6 & 386.2 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.52) is slightly higher than the ideal <140, while Ligand B (75.63) is well within the range.

**logP:** Ligand A (2.9) is optimal, while Ligand B (4.465) is pushing the upper limit and could potentially lead to solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBAs (4 & 3 respectively), satisfying the criteria.

**QED:** Both ligands have similar QED values (0.799 and 0.744), indicating good drug-likeness.

**DILI:** Ligand A (86.545) has a higher DILI risk than Ligand B (97.325). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB score (34.936) than Ligand A (18.069), but it's not a major factor here.

**Caco-2 Permeability:** Ligand A (-5.143) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.662) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.749 and -4.806). This is a major drawback for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.038) has a very low hERG risk, which is excellent. Ligand B (0.143) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-17.471) has a significantly lower (better) microsomal clearance than Ligand B (7.434), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.405) has a much longer in vitro half-life than Ligand B (6.276), which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.102).

**Binding Affinity:** Ligand B (-10.8 kcal/mol) has a substantially 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:**

Ligand B's significantly higher binding affinity (-10.8 vs 0.0 kcal/mol) is the most important factor. While it has a higher logP and DILI risk than Ligand A, the potency advantage is substantial. Ligand A suffers from extremely poor Caco-2 permeability and a weaker binding affinity. The improved metabolic stability and half-life of Ligand A are beneficial, but are unlikely to compensate for the poor permeability and weak binding.

Output:
1
2025-04-17 13:17:45,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.322 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.37) is slightly higher than Ligand B (86.47). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Ligand A (0.523) is quite low, potentially hindering permeation. Ligand B (2.425) 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 limit.

**H-Bond Acceptors:** Both ligands (7) are below the 10 limit.

**QED:** Both ligands have good QED scores (0.762 and 0.776), indicating good drug-like properties.

**DILI:** Ligand A (80.69) has a higher DILI risk than Ligand B (50.174). While both are above the ideal <40, Ligand B is considerably better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.176) and Ligand B (50.95) are both moderate.

**Caco-2 Permeability:** Ligand A (-4.716) has poor Caco-2 permeability, while Ligand B (-4.469) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-2.533) and Ligand B (-3.239) both have poor solubility.

**hERG:** Both ligands have very low hERG risk (0.044 and 0.068).

**Microsomal Clearance:** Ligand A (44.266) has higher clearance than Ligand B (35.269), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-35.541) has a significantly longer in vitro half-life than Ligand A (17.196). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.067 and 0.207).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 1.8 kcal/mol is very significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B demonstrates a significantly stronger binding affinity, better logP, lower DILI risk, and a much longer half-life. The improved metabolic stability and potency are critical for an enzyme target like SRC. The slightly better TPSA and Caco-2 permeability also contribute to its favorability.

Output:
1
2025-04-17 13:17:45,682 - INFO - Batch 201 complete. Total preferences: 3216
2025-04-17 13:17:45,682 - INFO - Processing batch 202/512...
2025-04-17 13:18:26,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (380.945 Da) is also acceptable.

**TPSA:** Ligand A (81.77) is better than Ligand B (43.18). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (-0.413) is a bit low, potentially hindering membrane permeability. Ligand B (4.287) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Ligand A (0.801) has a significantly better QED score than Ligand B (0.641), indicating a more drug-like profile.

**DILI:** Both ligands have similar, acceptable DILI risk (Ligand A: 36.448, Ligand B: 37.999).

**BBB:** Ligand A (36.448) and Ligand B (71.462) both have percentile scores that are not particularly relevant for an oncology target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.895 and -4.954) which is not ideal.

**Aqueous Solubility:** Ligand A (-0.988) and Ligand B (-4.285) both have negative solubility values, which is not ideal.

**hERG:** Ligand A (0.494) has a lower hERG risk than Ligand B (0.838), which is preferable.

**Microsomal Clearance:** Ligand A (9.657) has a significantly lower microsomal clearance than Ligand B (82.208), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-10.83) has a negative half-life, which is not ideal. Ligand B (-7.209) also has a negative half-life, which is not ideal.

**P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.73), indicating better bioavailability and potentially better tissue penetration.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.2), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is the better candidate. While its logP is slightly low and solubility is poor, it excels in crucial areas for an enzyme inhibitor: metabolic stability (much lower Cl_mic), P-gp efflux (much lower), QED (higher), and hERG risk (lower). The small difference in binding affinity (0.2 kcal/mol) is outweighed by these significant ADME advantages.

Output:
0
2025-04-17 13:18:26,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (383.945 & 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (61.44 & 58.64) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (3.046 & 2.514) 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.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the threshold of 10.

**6. QED:** Ligand A (0.678) has a significantly better QED score than Ligand B (0.375), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.593) has a lower DILI risk than Ligand B (19.504), both are good.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (73.75) is slightly better than Ligand B (68.05). This is less crucial for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.364) has worse Caco-2 permeability than Ligand B (-4.264).

**10. Aqueous Solubility:** Ligand A (-2.909) has worse aqueous solubility than Ligand B (-2.343).

**11. hERG Inhibition:** Ligand A (0.696) has a slightly higher hERG risk than Ligand B (0.27). This is a concern.

**12. Microsomal Clearance:** Ligand A (0.861) has significantly lower microsomal clearance than Ligand B (61.98), indicating better metabolic stability. This is a major advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (26.166) has a much longer in vitro half-life than Ligand B (-2.602), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux than Ligand B (0.152).

**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 still a positive factor.

**Overall Assessment:**

Ligand A is the stronger candidate. Despite slightly worse Caco-2 permeability, solubility, and a marginally higher hERG risk, its significantly better QED, metabolic stability (lower Cl_mic and longer t1/2), and slightly improved binding affinity outweigh these drawbacks. For an enzyme target like SRC kinase, metabolic stability is crucial for achieving adequate exposure and efficacy. The slightly better affinity of Ligand A further strengthens its position.

Output:
1
2025-04-17 13:18:26,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.418 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, and excellent for oral absorption. Ligand B (115.9) is still acceptable but less optimal.

**logP:** Ligand A (2.379) is within the optimal 1-3 range. Ligand B (-0.374) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is excellent. Ligand B (HBD=3, HBA=6) is acceptable but has more potential for off-target interactions or reduced permeability.

**QED:** Both ligands have good QED scores (A=0.853, B=0.531), indicating drug-like properties.

**DILI:** Ligand A (43.738) has a slightly higher DILI risk than Ligand B (34.587), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.135) is higher than Ligand B (45.522).

**Caco-2 Permeability:** Ligand A (-4.514) is better than Ligand B (-5.788), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.551) is better than Ligand B (-1.423), which is crucial for bioavailability.

**hERG:** Ligand A (0.56) has a much lower hERG risk than Ligand B (0.033), a significant advantage.

**Microsomal Clearance:** Ligand A (46.901) has higher clearance than Ligand B (-4.906), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (3.133) has a longer half-life than Ligand A (17.422), which is a benefit.

**P-gp Efflux:** Ligand A (0.293) has lower P-gp efflux than Ligand B (0.007), which is favorable.

**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 ADME differences.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand B is the more promising candidate. While Ligand A has better Caco-2 permeability, solubility, and P-gp efflux, Ligand B's significantly better metabolic stability (lower Cl_mic, longer half-life) and lower hERG risk are more important. The slightly lower logP of Ligand B is a concern, but the strong binding affinity may compensate.

Output:
1
2025-04-17 13:18:26,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (394.287 Da and 358.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.22) is slightly above the preferred <140, but acceptable. Ligand B (51.14) is well within the range.

**3. logP:** Ligand A (4.399) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (3.999) is closer to the optimal 1-3 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 (5) is within the acceptable limit of <=10. Ligand B (6) is also good.

**6. QED:** Both ligands have similar QED values (0.688 and 0.7), indicating good drug-like properties.

**7. DILI:** Ligand A (89.841) has a high DILI risk, which is a significant concern. Ligand B (35.673) has a much lower and acceptable DILI risk.

**8. BBB:** Both ligands have moderate BBB penetration (45.909 and 71.307). BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.711). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.453 and -3.954), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.747) has a higher hERG inhibition risk than Ligand B (0.524), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (49.643) has a lower (better) microsomal clearance than Ligand B (69.212), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (71.794) has a significantly longer half-life than Ligand B (-27.087). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.321) has lower P-gp efflux than Ligand B (0.209), which is favorable.

**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 substantial advantage and could potentially outweigh some of its ADME liabilities.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has superior affinity and half-life, and acceptable hERG. However, its high DILI risk and poor solubility are major concerns. Ligand B has better DILI and solubility, but significantly weaker binding affinity.

**Conclusion:** Despite the poor solubility and high DILI risk, the significantly stronger binding affinity of Ligand A (-8.1 kcal/mol vs 0.0 kcal/mol) is a critical factor for an enzyme inhibitor. The improved half-life also contributes. While the ADME properties of Ligand A are concerning, they might be addressed through further optimization. Ligand B's weak binding affinity makes it a less promising starting point.

Output:
1
2025-04-17 13:18:26,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.384 Da and 360.445 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (98.17) is higher than Ligand B (49.85). While both are reasonably low, B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have a logP around 3 (3.019 and 3.058), which is optimal.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands have 3 HBAs, well within the acceptable range of <=10.

**QED:** Ligand B (0.594) has a better QED score than Ligand A (0.279), indicating a more drug-like profile.

**DILI:** Ligand A (27.181) has a slightly higher DILI risk than Ligand B (18.224), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (88.91 and 96.472), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.651) has worse Caco-2 permeability than Ligand B (-3.991), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.519 and -2.413). This is a significant concern for both, but needs to be balanced against other factors.

**hERG:** Both ligands have low hERG inhibition risk (0.602 and 0.447), which is good.

**Microsomal Clearance:** Ligand B (64.878) has significantly lower microsomal clearance than Ligand A (30.165), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.884) has a slightly longer in vitro half-life than Ligand A (-12.412), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.059 and 0.106), which is good.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have poor solubility, Ligand B's significantly stronger binding affinity (-8.1 vs -6.8 kcal/mol), better metabolic stability (lower Cl_mic), longer half-life, and better QED score outweigh the similar DILI and hERG profiles and the slightly better TPSA of Ligand A. The improved Caco-2 permeability is also a positive factor.

Output:
1
2025-04-17 13:18:26,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.511 and 386.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (83.56). A TPSA under 140 is good for oral absorption, but lower is generally preferred for enzymes. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (1.782 and 1.984), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (2 HBD, 7 HBA). Lower numbers are generally preferred for better permeability, and Ligand A is more favorable.

**QED:** Both ligands have good QED scores (0.551 and 0.697), indicating good drug-likeness.

**DILI:** Ligand A (23.381) has a much lower DILI risk than Ligand B (49.515). This is a significant advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (77.705 and 78.907). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the calculation or data quality. However, the values are similar (-4.852 and -4.91).

**Aqueous Solubility:** Both have negative solubility values, again suggesting potential data quality issues. The values are also similar (-2.623 and -2.733).

**hERG:** Ligand A (0.366) has a lower hERG risk than Ligand B (0.568), which is a positive attribute.

**Microsomal Clearance:** Ligand A (52.283) has a higher microsomal clearance than Ligand B (26.726), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (18.772) has a significantly longer in vitro half-life than Ligand A (-17.038). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.155).

**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 still a factor.

**Overall Assessment:**

Ligand A has advantages in TPSA, H-bond characteristics, DILI risk, and hERG risk. However, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. Considering the enzyme-specific priorities, metabolic stability and potency are crucial. The longer half-life of Ligand B is a significant advantage, and the slightly better binding affinity further strengthens its case. The DILI risk of Ligand A is appealing, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 13:18:26,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.865 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.77) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (112.13) is still under 140, but less optimal than A.

**logP:** Both ligands (2.298 and 1.521) are 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:** Both ligands have good QED scores (0.78 and 0.81), indicating good drug-likeness.

**DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (33.23). This is a significant negative for Ligand A.

**BBB:** Both ligands have similar BBB penetration (68.554 and 69.019), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.57) and Ligand B (-5.068) 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.

**Solubility:** Both ligands have very poor aqueous solubility (-2.789 and -2.667). This is a major concern for both.

**hERG:** Both ligands have low hERG inhibition liability (0.458 and 0.078), which is good.

**Microsomal Clearance:** Ligand B (25.245) has significantly lower microsomal clearance than Ligand A (52.292), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-22.722) has a longer in vitro half-life than Ligand A (21.413). This is another advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.073 and 0.034).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -9.0 kcal/mol). The difference is minor and unlikely to outweigh other factors.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. It has a significantly lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). While both have poor solubility, the other advantages of Ligand B make it the better choice.

Output:
1
2025-04-17 13:18:26,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.434 and 352.337 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (67.87).  A TPSA under 140 is good for oral absorption, and both are well below that, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.343 and 2.259), 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 good QED scores (0.765 and 0.848), indicating good drug-like properties.

**DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (68.98). This is a significant advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (88.174 and 89.957), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.213 and -4.465) which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Ligand A (-1.664) has better aqueous solubility than Ligand B (-3.918). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.717 and 0.602), which is positive.

**Microsomal Clearance:** Ligand A (44.147) has a higher microsomal clearance than Ligand B (21.473). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand B (12.993 hours) has a significantly longer in vitro half-life than Ligand A (-0.034 hours). This is a major advantage for Ligand B, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.125 and 0.156).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in DILI risk and solubility, while Ligand B has a much better in vitro half-life and lower microsomal clearance. While both have similar affinity, the metabolic stability offered by Ligand B is crucial for an enzyme target like SRC kinase. The poor Caco-2 permeability is a concern for both, but can potentially be addressed through formulation strategies. The lower DILI risk of Ligand A is attractive, but the significantly improved half-life of Ligand B outweighs this benefit in the context of kinase inhibition.

Output:
1
2025-04-17 13:18:26,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.405 and 385.814 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is slightly higher than Ligand B (78.59), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (1.008) is at the lower end of the optimal 1-3 range, while Ligand B (2.041) is well within it. This favors Ligand B for permeability.

**H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

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

**QED:** Ligand B (0.785) has a significantly better QED score than Ligand A (0.396), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (31.524 and 34.665 percentiles, respectively).

**BBB:** Both ligands have moderate BBB penetration (58.976 and 68.36 percentiles). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.43) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.68) is still not great, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.691) has poor solubility, while Ligand B (-2.824) is also poor, but worse. Solubility is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.408 and 0.409 percentiles).

**Microsomal Clearance:** Ligand A (3.045 mL/min/kg) has significantly lower microsomal clearance than Ligand B (22.217 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (6.481 hours) has a longer half-life than Ligand A (-8.27 hours - which is unusual and likely an error or outlier). This favors Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.052 and 0.332 percentiles).

**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 factor.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a better QED score, better logP, a longer half-life, and slightly better binding affinity. The main drawback of Ligand B is the poor solubility, but this can potentially be addressed through formulation strategies. Ligand A has a very poor Caco-2 permeability, which is a significant issue for oral bioavailability, and a shorter half-life. The improved metabolic stability of Ligand A is not enough to offset its absorption and PK liabilities.

Output:
1
2025-04-17 13:18:26,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.43 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.02) is better than Ligand B (62.55), both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (4.26 and 3.395), 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 acceptable QED scores (0.854 and 0.609), indicating good drug-likeness. Ligand A is better.

**DILI:** Ligand A (26.406) has a significantly lower DILI risk than Ligand B (45.328), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.76) is better than Ligand B (64.482).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.676) is slightly better than Ligand B (-4.711).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-4.23) is slightly better than Ligand B (-3.486).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.594 and 0.681), which is good.

**Microsomal Clearance:** Ligand A (37.175) has a lower microsomal clearance than Ligand B (79.926), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (40.012) has a longer in vitro half-life than Ligand A (26.128), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.136 and 0.764). Ligand A is better.

**Binding Affinity:** Ligand B (-8.4 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's significantly stronger binding affinity (-8.4 vs -7.7 kcal/mol) is a major advantage that outweighs its slightly higher DILI risk and lower metabolic stability. While Ligand A has better DILI, solubility, and metabolic stability, the potency difference is crucial for an enzyme target like SRC kinase. The longer half-life of Ligand B is also beneficial.

Output:
1
2025-04-17 13:18:26,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.409 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.78) is excellent, well below the 140 threshold for oral absorption. Ligand B (115.63) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (2.392) is optimal (1-3). Ligand B (-0.208) is a concern; it's below 1 and could indicate poor membrane 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 good QED scores (0.839 and 0.786), indicating drug-like properties.

**DILI:** Ligand A (8.763) has a very low DILI risk. Ligand B (39.744) is higher, but still within the acceptable range (<40 is good).

**BBB:** Ligand A (91.508) shows good BBB penetration, though this isn't a primary concern for a non-CNS target like SRC. Ligand B (64.482) is lower.

**Caco-2 Permeability:** Ligand A (-4.264) is concerning, suggesting poor permeability. Ligand B (-5.215) is even worse.

**Aqueous Solubility:** Ligand A (-1.602) is poor. Ligand B (-2.13) is also poor.

**hERG:** Ligand A (0.675) has a low hERG risk. Ligand B (0.203) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (12.539) has moderate clearance. Ligand B (-17.144) has negative clearance, which is not physically possible and likely indicates an error or outlier in the data. This is a *major* red flag.

**In vitro Half-Life:** Both ligands have similar and very short half-lives (-4.906 and -4.781 hours). This is a significant drawback for both.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.049 and 0.006).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand B has a better binding affinity, but its negative microsomal clearance is a critical flaw. Negative clearance is not possible and suggests a data error, or a fundamentally problematic compound. Ligand A has issues with Caco-2 permeability and solubility, and a short half-life, but these are potentially addressable through formulation or structural modification. The DILI risk is also very low. Given the problematic clearance of Ligand B, Ligand A is the more viable starting point for further optimization.

Output:
0
2025-04-17 13:18:26,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.19) is higher than Ligand B (59.08). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (0.476) is quite low, potentially hindering permeability. Ligand B (2.063) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**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 range of <=10.

**QED:** Both ligands have QED values above 0.5 (0.653 and 0.584), indicating good drug-like properties.

**DILI:** Ligand A (35.867) has a lower DILI risk than Ligand B (57.154), which is a positive attribute.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (66.77) is slightly better than Ligand A (49.787).

**Caco-2 Permeability:** Ligand A (-5.06) has poor Caco-2 permeability, while Ligand B (-4.398) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.821 and -2.235), indicating poor solubility. Ligand B is slightly worse.

**hERG Inhibition:** Ligand A (0.039) has a very low hERG risk, which is excellent. Ligand B (0.372) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (1.62) has significantly lower microsomal clearance than Ligand B (58.593), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.994) has a longer half-life than Ligand B (-31.639), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, while Ligand B (0.408) has moderate efflux.

**Binding Affinity:** Ligand B (-7.2) has slightly better binding affinity than Ligand A (-7.1), but the difference is minimal (0.1 kcal/mol).

**Overall Assessment:**

Ligand A excels in metabolic stability (low Cl_mic, long t1/2), low P-gp efflux, and very low hERG risk. Its main drawback is the low logP and poor Caco-2 permeability. However, for a kinase inhibitor, metabolic stability and minimizing off-target effects (hERG) are paramount. The slight difference in binding affinity is unlikely to outweigh the substantial advantages of Ligand A in ADME properties. Ligand B has a better logP and TPSA, but suffers from poor metabolic stability and a shorter half-life.

Output:
0
2025-04-17 13:18:26,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (394.287 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 (82.22) is better than Ligand B (88.91).

**logP:** Ligand A (4.399) is higher than the optimal range (1-3) and could present solubility issues. Ligand B (1.099) is slightly below the optimal range but still acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 5 HBAs, which are within the acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand B (0.784) is slightly better than Ligand A (0.688).

**DILI:** Ligand A (89.841) has a higher DILI risk than Ligand B (52.617). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (59.442) is higher than Ligand A (45.909).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.716) is slightly better than Ligand B (-5.169).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-5.453) is slightly better than Ligand B (-2.197).

**hERG:** Ligand A (0.747) has a higher hERG risk than Ligand B (0.02). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (21.404 mL/min/kg) has significantly lower microsomal clearance than Ligand A (49.643 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (71.794 hours) has a much longer half-life than Ligand B (6.696 hours). This is a strong positive for Ligand A.

**P-gp Efflux:** Ligand B (0.027) has lower P-gp efflux liability than Ligand A (0.321), suggesting better bioavailability.

**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 is the better candidate. While Ligand A has a longer half-life, its significantly higher DILI risk, higher hERG risk, and higher microsomal clearance are major drawbacks. Ligand B has a better safety profile (lower DILI and hERG), better metabolic stability, and slightly better binding affinity. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies. Given the enzyme-specific priorities, the safety and stability advantages of Ligand B outweigh the slightly shorter half-life.

Output:
1
2025-04-17 13:18:26,287 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both Ligand A (352.431 Da) and Ligand B (348.487 Da) fall comfortably within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (84.94) is better than Ligand B (69.64), both are well below the 140 A^2 threshold for good oral absorption.

3. **logP:** Ligand A (1.004) is slightly lower than Ligand B (2.391), both are within the optimal 1-3 range.

4. **HBD:** Ligand A (1) is better than Ligand B (2), both are within the acceptable limit of <=5.

5. **HBA:** Ligand A (5) is better than Ligand B (3), both are within the acceptable limit of <=10.

6. **QED:** Both Ligand A (0.691) and Ligand B (0.694) have very similar, good QED scores, exceeding the 0.5 threshold.

7. **DILI:** Ligand A (21.791) is significantly better than Ligand B (6.32). Ligand A is well below the 40% threshold for low risk, while Ligand B is also low risk but closer to the threshold.

8. **BBB:** Both Ligand A (55.099) and Ligand B (59.636) have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

9. **Caco-2:** Both Ligand A (-4.858) and Ligand B (-4.892) have similar, negative Caco-2 permeability values. This suggests poor permeability.

10. **Solubility:** Ligand A (-1.304) is better than Ligand B (-1.938), both are negative, indicating poor solubility.

11. **hERG:** Ligand A (0.104) is significantly better than Ligand B (0.225), both are low risk.

12. **Cl_mic:** Ligand A (16.913) is worse than Ligand B (-1.948). A negative value for Ligand B suggests very high metabolic stability. This is a significant advantage.

13. **t1/2:** Ligand A (4.68) is worse than Ligand B (2.259).

14. **Pgp:** Ligand A (0.031) is better than Ligand B (0.055), both are low.

15. **Binding Affinity:** Ligand A (-8.5) is better than Ligand B (-8.0), with a 0.5 kcal/mol advantage. This is a substantial difference in potency.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a significantly better binding affinity. Ligand B has a much better Cl_mic and t1/2, but Ligand A has better DILI and hERG. Solubility is poor for both.

**Conclusion:**

While Ligand B has excellent metabolic stability, the 0.5 kcal/mol advantage in binding affinity for Ligand A is substantial and likely outweighs the metabolic stability benefit, especially considering the acceptable DILI and hERG profiles of Ligand A. The poor solubility and permeability of both compounds would need to be addressed in further optimization, but the stronger initial binding of Ligand A makes it the more promising starting point.

Output:
1
2025-04-17 13:18:26,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (384.38 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.53) is better than Ligand B (109.04), both are acceptable but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.515) is slightly low, potentially hindering permeation. Ligand B (0.996) is better, still on the lower side but more favorable.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2), 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 reasonable QED scores (0.772 and 0.691), indicating good drug-like properties.

**DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (41.062). Ligand B is significantly better here.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.815) is better than Ligand B (42.148), but neither is a major concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.798) is slightly better than Ligand B (-4.993).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.655) is slightly better than Ligand B (-2.208).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.337 and 0.165), which is excellent.

**Microsomal Clearance:** Ligand A (20.353 mL/min/kg) has significantly lower clearance than Ligand B (38.867 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-40.502 hours) has a negative half-life, which is not realistic. Ligand B (-6.218 hours) is also negative, but less so. Both are problematic, but A is worse.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.113 and 0.054), which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-9.1 and -8.6 kcal/mol). Ligand A is slightly better (-9.1 kcal/mol).

**Overall Assessment:**

Ligand A has a slight edge in binding affinity, TPSA, and significantly better microsomal clearance. However, it has a higher DILI risk, negative and worse in vitro half-life, and lower solubility. Ligand B has a much better DILI profile and a slightly better in vitro half-life, but worse TPSA and clearance.

Given the importance of metabolic stability for kinase inhibitors (to ensure sufficient exposure) and the acceptable DILI risk of Ligand B, I would favor **Ligand B**. The slight advantage in binding affinity of Ligand A is unlikely to overcome its metabolic liabilities and solubility issues. The negative half-life values for both are concerning and require further investigation, but Ligand B's other properties are more promising.

Output:
1
2025-04-17 13:18:26,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 336.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.71) is slightly higher than Ligand B (78.66). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Ligand A (3.617) is within the optimal range (1-3), while Ligand B (1.663) is at the lower end. While lower logP can sometimes improve solubility, it can also hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.627 and 0.678), indicating good drug-like properties.

**DILI:** Ligand B (63.397) has a higher DILI risk than Ligand A (46.956), which is a negative for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (68.36 and 60.566), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.68) has a worse Caco-2 permeability than Ligand B (-5.045). Both are very poor.

**Aqueous Solubility:** Ligand A (-3.21) has slightly better solubility than Ligand B (-3.354).

**hERG:** Ligand A (0.757) has a better hERG profile than Ligand B (0.404). Lower is better, indicating less cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (3.582) has significantly lower microsomal clearance than Ligand B (17.397), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (40.521) has a much longer in vitro half-life than Ligand A (-1.971). This is a significant positive for Ligand B.

**P-gp Efflux:** Ligand A (0.349) has lower P-gp efflux than Ligand B (0.109), which is preferable.

**Binding Affinity:** Ligand B (-8.2 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 of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are critical for an enzyme inhibitor. While it has a higher DILI risk and worse P-gp efflux, the superior potency and metabolic stability are more important in this case. Ligand A has a better hERG profile and lower DILI, but the weaker binding affinity is a major drawback.

Output:
1
2025-04-17 13:18:26,288 - INFO - Batch 202 complete. Total preferences: 3232
2025-04-17 13:18:26,288 - INFO - Processing batch 203/512...
2025-04-17 13:19:07,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.486 and 356.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (99.33). A TPSA under 140 is good for oral absorption, and A is well within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.308) is optimal, while Ligand B (0.843) is a bit low, potentially hindering permeation.

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

**H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**QED:** Ligand A (0.752) has a better QED score than Ligand B (0.531), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (30.748 and 32.92), which is good.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (90.772) has a higher BBB percentile than Ligand B (71.772).

**Caco-2 Permeability:** Ligand A (-4.443) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.153) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.825) has poor solubility, while Ligand B (-2.506) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.828) has a lower hERG risk than Ligand B (0.17), which is a significant advantage.

**Microsomal Clearance:** Ligand A (50.147) has higher clearance than Ligand B (8.561), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (8.619) has a longer half-life than Ligand A (11.174), which is preferable.

**P-gp Efflux:** Ligand A (0.672) has lower P-gp efflux than Ligand B (0.036), which is favorable.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.7), but the difference is small.

**Overall Assessment:**

Ligand A has advantages in terms of logP, QED, hERG, and P-gp efflux. However, it suffers from very poor Caco-2 permeability, poor solubility, and higher microsomal clearance. Ligand B has better solubility, a longer half-life, and lower clearance, but has a lower logP and higher hERG risk.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and solubility are crucial. While Ligand A has a slightly better binding affinity, its poor permeability and solubility are major concerns. Ligand B, despite its lower logP, presents a more balanced profile with better metabolic stability and solubility.

Output:
1
2025-04-17 13:19:07,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.391 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.82) is slightly higher than Ligand B (96.53), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.776) is better than Ligand B (0.259). Ligand B is quite low, potentially hindering permeation. Optimal is 1-3.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (7) is preferable to Ligand B (4). Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.851) is significantly better than Ligand B (0.641), indicating a more drug-like profile.

**DILI:** Ligand B (25.94) is *much* better than Ligand A (67.817). This is a significant advantage for Ligand B.

**BBB:** Ligand A (51.532) is slightly better than Ligand B (43.699), but BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2:** Both ligands have negative Caco-2 values (-5.654 and -5.32), which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Ligand A (-3.23) is better than Ligand B (-1.667), but both are poor. Solubility is a key consideration for kinase inhibitors.

**hERG:** Ligand A (0.061) is better than Ligand B (0.099), indicating lower cardiotoxicity risk.

**Cl_mic:** Ligand B (-5.441) is *much* better than Ligand A (0.254). Negative clearance suggests very high metabolic stability, a crucial factor for kinase inhibitors.

**t1/2:** Ligand A (10.68) is slightly better than Ligand B (10.074). Both are reasonable.

**Pgp:** Ligand A (0.028) is better than Ligand B (0.013), suggesting lower P-gp efflux.

**Binding Affinity:** Ligand B (-7.0) is significantly better than Ligand A (0.0). This is a decisive advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a dramatically better binding affinity and significantly better metabolic stability (Cl_mic). It also has a much lower DILI risk. While its logP and solubility are less favorable, the strong binding affinity and metabolic stability are critical for an enzyme inhibitor. Ligand A has better QED, hERG, and Pgp, but these are less important than potency and metabolic stability in this case. The poor Caco-2 values are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:19:07,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.279 Da) is slightly higher than Ligand B (344.455 Da), but both are acceptable.

**TPSA:** Ligand A (80.32) is better than Ligand B (49.85). Lower TPSA generally favors better absorption, and both are well below the 140 A^2 threshold.

**logP:** Both ligands have good logP values (A: 3.311, B: 2.162), falling within the optimal range of 1-3.

**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 (A: 0.581, B: 0.785), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 54.401, while Ligand B has 30.787. Ligand B is significantly better, falling well below the 40 threshold for low risk.

**BBB:** Ligand A (57.464) and Ligand B (75.843). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.624 and -4.305), which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.487 and -1.607), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.208) is better than Ligand B (0.255), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (47.107 mL/min/kg) has lower clearance than Ligand B (62.333 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.34 hours) has a much longer half-life than Ligand B (-15.223 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.038, B: 0.138).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.0 vs -7.3 kcal/mol) and lower DILI risk are major advantages. While Ligand A has better metabolic stability and a longer half-life, the affinity difference is crucial for an enzyme inhibitor. The poor solubility and permeability would need to be addressed through formulation strategies, but a higher affinity starting point is more likely to yield a successful drug.

Output:
1
2025-04-17 13:19:07,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.809 Da and 346.402 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (119.03) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (62.55) is excellent, well below 140.

**logP:** Ligand A (0.399) is quite low, potentially hindering permeability. Ligand B (2.704) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.811 and 0.659), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 80.031, which is high and concerning. Ligand B has a lower DILI risk of 54.983, which is still moderate but better than Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (85.033) than Ligand A (60.256), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.355) has poor Caco-2 permeability, likely due to its low logP. Ligand B (-4.771) is also not great, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.888 and -3.493). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.424) has a slightly higher hERG risk than Ligand B (0.374), but both are relatively low.

**Microsomal Clearance:** Ligand A (-7.949) shows excellent metabolic stability (low clearance). Ligand B (40.248) has moderate clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (5.061) has a moderate half-life. Ligand B (12.194) has a longer half-life, which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.432).

**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:**

Ligand A has a much stronger binding affinity, and excellent metabolic stability. However, its low logP, poor Caco-2 permeability, and high DILI risk are major concerns. Ligand B has better physicochemical properties (logP, TPSA, solubility) and a lower DILI risk, but its binding affinity is weaker and its metabolic stability is moderate.

Despite the solubility issues of both, the significantly superior binding affinity of Ligand A (-9.6 vs -8.5) is a critical advantage for an enzyme target. While the DILI risk is high, this could potentially be mitigated through structural modifications during lead optimization. The poor permeability is also a concern, but again, modifications could address this. The improved metabolic stability of Ligand A is also a plus.

Output:
1
2025-04-17 13:19:07,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.37 and 350.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.86) is slightly above the preferred <140, while Ligand B (97.56) is well within. This favors Ligand B for absorption.

**logP:** Ligand A (0.609) is a bit low, potentially hindering permeation. Ligand B (1.056) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.651 and 0.77), indicating drug-like properties.

**DILI:** Ligand A (56.46%) has a higher DILI risk than Ligand B (36.10%). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (91.63%) has a much higher BBB score than Ligand A (21.33%).

**Caco-2 Permeability:** Ligand A (-5.521) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.872) is better, but still not great.

**Aqueous Solubility:** Ligand A (-2.441) has poor solubility, while Ligand B (-1.975) is slightly better. Both could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.065 and 0.09). This is excellent for both.

**Microsomal Clearance:** Ligand A (-37.743) has significantly lower (better) microsomal clearance than Ligand B (20.429), indicating greater metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-10.838) 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 (2.037) has a short half-life, but is a realistic value.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.038).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.5 and -8.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A's superior metabolic stability, the negative in vitro half-life is a critical flaw. This suggests a data error or a fundamentally unstable molecule. Ligand B, while having a shorter half-life and slightly higher DILI risk, has better solubility, permeability, and a realistic half-life. Considering the enzyme-specific priorities and the questionable data for Ligand A, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 13:19:07,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.378 and 357.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.15) is slightly higher than Ligand B (61.44). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned for potential CNS penetration if desired.

**logP:** Ligand A (-0.421) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.917) is within the optimal range. This favors 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 good QED scores (0.547 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (15.355) has a lower DILI risk than Ligand B (19.814), which is preferable.

**BBB:** Ligand A (54.44) has a lower BBB penetration percentile than Ligand B (83.366). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.542) has poor Caco-2 permeability, while Ligand B (-5.132) is also poor. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.407) has slightly better aqueous solubility than Ligand B (-2.517).

**hERG:** Both ligands have low hERG inhibition liability (0.287 and 0.678), which is excellent.

**Microsomal Clearance:** Ligand A (7.289) has a higher microsomal clearance than Ligand B (-13.702). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-26.806) has a significantly longer in vitro half-life than Ligand B (8.436). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.036).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 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:**

Ligand B has a better logP, indicating better permeability, and significantly better metabolic stability (lower Cl_mic). Ligand A has a slightly better binding affinity and longer half-life, but the permeability and metabolic stability of Ligand B are more crucial for an enzyme target like SRC kinase. The slightly higher DILI risk for Ligand B is acceptable given the other benefits.

Output:
1
2025-04-17 13:19:07,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (368.409 and 372.485 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is higher than Ligand B (58.12). Both are below the 140 threshold for oral absorption, but lower is generally preferred.

**3. logP:** Ligand A (2.268) is within the optimal 1-3 range. Ligand B (3.649) 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) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are well within the HBA <=10 criteria.

**6. QED:** Both ligands have good QED scores (A: 0.821, B: 0.88), indicating good drug-like properties.

**7. DILI:** Ligand A (57.619) has a higher DILI risk than Ligand B (47.15). Both are below the concerning threshold of 60, but lower is better.

**8. BBB:** Ligand A (79.721) and Ligand B (94.843) are both reasonably high, but not critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.166) is worse than Ligand B (-4.943).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.416) is slightly worse than Ligand B (-4.318).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.305, B: 0.49).

**12. Microsomal Clearance:** Ligand A (6.775) has significantly lower microsomal clearance than Ligand B (43.989), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-3.394) has a longer in vitro half-life than Ligand B (-4.496). This further supports better metabolic stability for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.083, B: 0.182).

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). While both are excellent, the 0.6 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the better candidate. It has a slightly better binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), and a lower DILI risk. While both have poor Caco-2 and solubility values, the superior potency and metabolic properties of Ligand A outweigh these drawbacks, especially for an enzyme target where maintaining therapeutic concentrations is crucial. The slightly higher TPSA of Ligand A is less concerning than the metabolic liabilities of Ligand B.

Output:
1
2025-04-17 13:19:07,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.395 Da) is slightly better positioned.

**TPSA:** Ligand A (71.53) is well below the 140 threshold for oral absorption. Ligand B (122.46) is still acceptable, but less optimal.

**logP:** Ligand A (2.64) is within the optimal range (1-3). Ligand B (-0.491) is below 1, which could indicate permeability issues.

**H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the limit of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 4, Ligand B: 5), below the limit of 10.

**QED:** Both ligands have good QED scores (Ligand A: 0.873, Ligand B: 0.728), indicating good drug-like properties.

**DILI:** Ligand A (67.739) has a higher DILI risk than Ligand B (48.43). This is a negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (78.907) is better than Ligand B (47.615).

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.536) is slightly better than Ligand B (-5.517).

**Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.505) is slightly better than Ligand B (-1.984).

**hERG:** Ligand A (0.54) has a much lower hERG risk than Ligand B (0.096). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (100.044) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-12.618) has negative clearance, which is unusual but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (6.508 hours) has a relatively short half-life. Ligand B (-17.925 hours) has a negative half-life, which is unusual.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.155, Ligand B: 0.008).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and higher clearance, its significantly stronger binding affinity (-8.1 vs -7.4 kcal/mol) and lower hERG risk outweigh these drawbacks. The negative values for Caco-2 and solubility are concerning for both, but the potency advantage of Ligand A is substantial. Ligand B's very negative clearance and half-life values are also concerning.

Output:
1
2025-04-17 13:19:07,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.308 Da) is slightly higher than Ligand B (352.431 Da), but both are acceptable.

**TPSA:** Ligand A (64.35) is well below the 140 threshold for oral absorption. Ligand B (92.01) is also below the threshold, but closer to it.

**logP:** Ligand A (3.831) is at the higher end of the optimal range (1-3), while Ligand B (1.554) is at the lower end. Ligand A's higher logP could potentially lead to off-target effects or solubility issues, but is still within acceptable limits.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2 respectively) and HBA (5) counts.

**QED:** Both ligands have similar and good QED values (0.74 and 0.741).

**DILI:** Ligand A has a DILI risk of 63.513, placing it in the higher risk category (>60). Ligand B has a significantly lower DILI risk of 37.999, which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.292) has a better BBB score than Ligand B (32.028), but this isn't a major factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.576 and -4.907), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.72 and -1.647). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.535) has a slightly higher hERG risk than Ligand B (0.311), but both are relatively low.

**Microsomal Clearance:** Ligand A (91.347) has a higher microsomal clearance than Ligand B (25.629). This indicates lower metabolic stability for Ligand A, which is undesirable.

**In vitro Half-Life:** Ligand A (68.198) has a longer half-life than Ligand B (37.2), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.749 and 0.113).

**Binding Affinity:** Both ligands have excellent binding affinity (-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 doesn't dramatically outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The slightly better half-life of Ligand A doesn't compensate for its higher DILI and lower metabolic stability. The binding affinity difference is not substantial enough to favor Ligand A given the ADME concerns.

Output:
1
2025-04-17 13:19:07,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (352.454 and 361.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (59.39) is well below the 140 threshold for oral absorption and highly favorable. Ligand B (118.28) is still under the threshold, but less optimal than A.

**3. logP:** Ligand A (2.904) is within the optimal 1-3 range. Ligand B (0.823) is slightly below 1, potentially hindering permeation.

**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 (4 and 5 respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.886 and 0.836), indicating drug-like properties.

**7. DILI:** Ligand A (13.416) has a much lower DILI risk than Ligand B (65.413), which is considered high risk. This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (82.009) shows better BBB penetration potential than Ligand B (53.509), though BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Ligand A (-4.718) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.322) also has a negative value, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.116 and -2.088 respectively). This is a concern for both, but could be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.751) has a slightly higher hERG risk than Ligand B (0.033). This is a significant advantage for Ligand B.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-3.22) has a negative value, which is unusual and suggests very low clearance (high metabolic stability). Ligand B (-26.572) has a much higher (more negative) clearance, indicating faster metabolism. This is a major advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (19.401) has a longer half-life than Ligand B (6.636).

**14. P-gp Efflux:** Ligand A (0.213) shows lower P-gp efflux than Ligand B (0.016).

**15. Binding Affinity:** Ligand A (-9.6) has a significantly stronger binding affinity than Ligand B (0.0). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in affinity and metabolic stability, while Ligand B has a lower hERG risk. However, the substantial difference in binding affinity (-9.6 vs 0.0 kcal/mol) and the significantly lower DILI risk of Ligand A outweigh the hERG advantage of Ligand B. The poor solubility and permeability are concerns for both, but can be addressed through formulation.

Output:
1
2025-04-17 13:19:07,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (364.442 Da) is more favorably positioned.

**TPSA:** Ligand A (42.96) is excellent, well below the 140 threshold for absorption. Ligand B (78.43) is still reasonable, but less optimal.

**logP:** Both ligands have logP values around 3-4, which is acceptable, but ligand B is slightly higher at 3.863.

**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 good QED scores (A: 0.554, B: 0.728), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (67.313). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (77.2) is higher than Ligand B (41.799).

**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 very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.848) has a lower hERG risk than Ligand B (0.551), which is preferable.

**Microsomal Clearance:** Ligand A (38.037) has a lower microsomal clearance than Ligand B (69.162), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand B (-9.869) has a negative half-life, which is not possible. This is a major red flag. Ligand A (5.465) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.459) has lower P-gp efflux than Ligand B (0.242), which is favorable.

**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 only 0.5 kcal/mol. Given the other ADME issues with Ligand B, this difference is unlikely to be decisive.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate**. While both have solubility and permeability issues, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, positive t1/2), lower DILI risk, and lower hERG risk. The slightly better binding affinity of Ligand B is not enough to overcome these significant drawbacks, especially the impossible negative half-life.

Output:
0
2025-04-17 13:19:07,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.594 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (80.32) is still under 140, but less optimal than A.

**logP:** Ligand A (2.91) is within the optimal 1-3 range. Ligand B (0.765) is slightly below 1, which *could* indicate permeability issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.701 and 0.681), indicating good drug-likeness.

**DILI:** Ligand A (15.936) has a significantly lower DILI risk than Ligand B (33.695). This is a substantial advantage.

**BBB:** Both have reasonable BBB penetration (A: 81.892, B: 76.658), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-4.284) has better Caco-2 permeability than Ligand B (-4.528), indicating better absorption.

**Aqueous Solubility:** Ligand A (-3.052) has slightly better solubility than Ligand B (-2.279).

**hERG Inhibition:** Ligand A (0.608) has a lower hERG risk than Ligand B (0.093), which is a significant advantage.

**Microsomal Clearance:** Ligand A (69.843) has higher microsomal clearance than Ligand B (8.919), meaning Ligand B is more metabolically stable. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-11.098) has a longer half-life than Ligand B (-5.49), which is desirable.

**P-gp Efflux:** Ligand A (0.447) has lower P-gp efflux than Ligand B (0.008), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This 1 kcal/mol difference is significant, and could potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability. However, Ligand A demonstrates significantly better safety profiles (lower DILI and hERG risk) and better permeability. Considering the enzyme-specific priorities, metabolic stability is crucial. The 1 kcal/mol difference in binding affinity is not large enough to overcome the safety concerns of Ligand B. Therefore, Ligand A is the more promising candidate.

Output:
0
2025-04-17 13:19:07,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (359.86 and 352.43 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.11) is better than Ligand B (95.94). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is closer to the preferred range.

**3. logP:** Ligand A (3.468) is optimal (1-3), while Ligand B (0.455) is quite low, potentially hindering permeation. This is a significant advantage 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 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.828) has a higher QED than Ligand B (0.677), indicating a more drug-like profile.

**7. DILI:** Ligand B (18.11) has a significantly lower DILI risk than Ligand A (58.40). This is a strong advantage for B.

**8. BBB:** Ligand A (65.61) has a higher BBB penetration percentile than Ligand B (39.98). While not a primary concern for a non-CNS target, it's a slight positive for A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.73 and -4.82), indicating poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Ligand A (-4.43) has better solubility than Ligand B (-1.243). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.484) has a lower hERG inhibition risk than Ligand B (0.241). This is a significant advantage for A, as cardiotoxicity is a major concern.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (29.36 and 28.39 mL/min/kg), suggesting similar metabolic stability.

**13. In vitro Half-Life:** Ligand A (21.27 hours) has a much longer half-life than Ligand B (2.74 hours). This is a substantial advantage for A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.296) has lower P-gp efflux than Ligand B (0.008), indicating better bioavailability.

**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 crucial advantage, as potency is a primary concern for enzyme inhibitors. The difference of 1.3 kcal/mol is substantial.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a lower DILI risk, Ligand A's superior binding affinity, better logP, QED, solubility, hERG risk, half-life, and P-gp efflux outweigh this advantage. The significantly stronger binding affinity (-8.3 vs -7.0 kcal/mol) is particularly important for an enzyme target like SRC kinase. The poor Caco-2 values for both are a concern, but can be addressed through formulation strategies.

Output:
1
2025-04-17 13:19:07,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.427 and 340.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.93) is higher than Ligand B (62.55). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (0.399) is quite low, potentially hindering permeability. Ligand B (2.221) 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.

**QED:** Both ligands have good QED scores (0.763 and 0.836), indicating good drug-like properties.

**DILI:** Ligand A (66.111) has a higher DILI risk than Ligand B (39.705). Ligand B is well below the 40% threshold for low risk.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

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

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a potential red flag for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.238 and 0.239).

**Microsomal Clearance:** Ligand A (67.283) has significantly higher microsomal clearance than Ligand B (14.797). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (33.342 hours) has a longer half-life than Ligand B (27.523 hours), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.232).

**Binding Affinity:** Ligand A (-8.0 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 concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is the most critical factor for an enzyme inhibitor. However, it suffers from low logP, higher DILI risk, and higher metabolic clearance. Ligand B has better ADME properties (logP, DILI, Cl_mic) but a weaker binding affinity.

The difference in binding affinity (1.1 kcal/mol) is substantial. Given that SRC is an enzyme, potency is paramount. While the ADME properties of Ligand A are suboptimal, the strong binding affinity suggests it might still be a viable starting point for optimization, focusing on improving its logP and metabolic stability. Ligand B, while having better ADME properties, might require significant structural changes to achieve a competitive binding affinity.

Output:
1
2025-04-17 13:19:07,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.415 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.45 and 84.73) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.05 and 2.88) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands have 6 HBAs, which is acceptable (<=10).

**QED:** Both ligands have high QED scores (0.846 and 0.877), indicating good drug-like properties.

**DILI:** Ligand A (57.387) has a slightly higher DILI risk than Ligand B (71.539), but both are reasonably acceptable.

**BBB:** Ligand A (75.378) has better BBB penetration than Ligand B (62.117), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.348 and -4.516), 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 very poor aqueous solubility (-3.983 and -3.515). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.193) has a lower hERG inhibition liability than Ligand B (0.421), which is favorable.

**Microsomal Clearance:** Ligand A (77.298) has significantly higher microsomal clearance than Ligand B (29.701), indicating lower metabolic stability. This is a major drawback.

**In vitro Half-Life:** Ligand A (-12.97) has a very short in vitro half-life, while Ligand B (1.053) is slightly better, but still short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.115 and 0.174).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly better binding affinity than Ligand A (-8.8 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.1 vs -8.8 kcal/mol) is a critical advantage for an enzyme target. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic and a slightly better half-life) and lower hERG risk than Ligand A. While solubility is a concern for both, the potency and metabolic advantages of Ligand B make it the better choice for further optimization.

Output:
1
2025-04-17 13:19:07,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.308 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.32) is significantly better than Ligand B (91.06). A TPSA under 140 is good for oral absorption, and both are under, but A is preferable.

**logP:** Ligand A (4.045) is slightly higher than the optimal range (1-3), while Ligand B (0.721) is below it. While high logP can cause issues, the difference isn't drastic for A. B's low logP could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.583 and 0.847), indicating good drug-like properties.

**DILI:** Ligand A (67.546) has a higher DILI risk than Ligand B (42.536). This is a significant drawback for A.

**BBB:** Both ligands have reasonable BBB penetration (70.531 and 62.97), but it's less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.239) has poor Caco-2 permeability, while Ligand B (-4.546) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.87) has very poor aqueous solubility, which is a major concern. Ligand B (-1.191) is also poor, but significantly better than A.

**hERG Inhibition:** Ligand A (0.844) has a slightly higher hERG risk than Ligand B (0.18), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (98.633) has very high microsomal clearance, indicating poor metabolic stability. Ligand B (1.909) has excellent metabolic stability. This is a crucial advantage for B.

**In vitro Half-Life:** Ligand A (-6.713) has a very short half-life, consistent with its high clearance. Ligand B (-7.627) has a longer half-life.

**P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux than Ligand B (0.117), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While A is better, the difference isn't massive.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better binding affinity, its extremely poor solubility, high DILI risk, and very high microsomal clearance are major liabilities. Ligand B, despite a slightly lower affinity, has a much more favorable ADME profile, particularly its excellent metabolic stability (low Cl_mic, long half-life) and lower hERG risk. The solubility is still a concern, but significantly better than A. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity are paramount.

Output:
1
2025-04-17 13:19:07,074 - INFO - Batch 203 complete. Total preferences: 3248
2025-04-17 13:19:07,075 - INFO - Processing batch 204/512...
2025-04-17 13:19:48,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.443 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.18) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (75.27) is well within the ideal range.

**logP:** Ligand A (0.398) is quite low, potentially hindering permeability. Ligand B (1.559) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.672 and 0.624), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 80.031, which is considered high risk (>60). Ligand B has a much lower DILI risk of 15.626, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (87.476) than Ligand A (17.294), but this is not a major deciding factor.

**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 original scale.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Again, these values are on a log scale and the negative values are not directly comparable without knowing the original scale.

**hERG Inhibition:** Ligand A (0.042) has a very low hERG risk, which is excellent. Ligand B (0.183) also has a low hERG risk, but slightly higher than Ligand A.

**Microsomal Clearance:** Ligand A (9.17) has lower microsomal clearance than Ligand B (8.162), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (26.766) has a significantly longer in vitro half-life than Ligand A (-7.291), a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.014), which is favorable.

**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 (0.6 kcal/mol), it's still a positive factor.

**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 an enzyme inhibitor: significantly lower DILI risk, a much longer half-life, and slightly better binding affinity. Ligand A's high DILI risk is a major concern. The slightly better hERG profile of Ligand A is outweighed by the other factors.

Output:
1
2025-04-17 13:19:48,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.462 and 361.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (89.69). A TPSA under 140 is desirable for oral absorption, and both are, but A is much closer to the ideal for better absorption.

**logP:** Both ligands have acceptable logP values (2.337 and 1.368, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have low HBD counts (0). Ligand A has 2 HBA, while Ligand B has 8. Lower HBA is generally preferable for permeability, giving an edge to Ligand A.

**QED:** Both ligands have similar, good QED values (0.716 and 0.735).

**DILI:** Ligand A (18.108) has a much lower DILI risk than Ligand B (63.513). This is a significant advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (92.943) shows better potential for this than Ligand B (63.125).

**Caco-2 Permeability:** Ligand A (-4.415) is better than Ligand B (-5.497), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.666) is better than Ligand B (-2.23), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.668) has a lower hERG risk than Ligand B (0.087). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (59.446) has a lower microsomal clearance than Ligand A (43.246), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.852) has a slightly longer half-life than Ligand A (2.447).

**P-gp Efflux:** Ligand A (0.198) has lower P-gp efflux than Ligand B (0.032), which is favorable.

**Binding Affinity:** Ligand B (-9.3 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 its ADME drawbacks. A difference of 2.4 kcal/mol is considerable.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, Ligand A demonstrates significantly better ADME properties, particularly regarding DILI risk, hERG inhibition, solubility, and Caco-2 permeability. While the difference in binding affinity is substantial, the improved safety and pharmacokinetic profile of Ligand A make it a more promising starting point for drug development. The lower DILI and hERG risks are particularly important. The slightly longer half-life of Ligand B is a minor advantage, but not enough to overcome the other significant drawbacks.

Output:
0
2025-04-17 13:19:48,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.391 Da) is slightly better positioned.

**TPSA:** Ligand B (67.4) is significantly better than Ligand A (108.8), falling well below the 140 threshold for good absorption.

**logP:** Ligand B (2.319) is optimal (1-3), while Ligand A (0.149) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0), as some H-bond donors can aid solubility.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.751 and 0.731), indicating good drug-likeness.

**DILI:** Ligand B (21.171) has a much lower DILI risk than Ligand A (61.691), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (72.431) is higher, but not a deciding factor.

**Caco-2 Permeability:** Both are negative, indicating poor permeability, but Ligand A (-5.631) is worse than Ligand B (-5.342).

**Aqueous Solubility:** Both are negative, indicating poor solubility, with Ligand A (-1.487) being slightly better than Ligand B (-1.59).

**hERG:** Ligand A (0.258) has a slightly better hERG profile than Ligand B (0.376), but both are acceptable.

**Microsomal Clearance:** Ligand A (-16.779) has significantly lower (better) microsomal clearance than Ligand B (7.121), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (34.77) has a much longer half-life than Ligand A (-5.443), which is a major advantage.

**P-gp Efflux:** Both are very low (0.019 and 0.064), suggesting minimal P-gp efflux.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This >1.5 kcal/mol difference is a substantial benefit and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability, the significantly improved binding affinity of Ligand B (-8.5 vs -6.6 kcal/mol), coupled with its lower DILI risk and longer half-life, outweigh the slightly less favorable metabolic stability. The lower logP of Ligand A is concerning for permeability.

Output:
1
2025-04-17 13:19:48,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.395 and 351.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.46) is slightly higher than Ligand B (55.63). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (3.407 and 3.084), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand B (0.8) has a better QED score than Ligand A (0.527), indicating a more drug-like profile.

**DILI:** Ligand B (44.436) has a significantly lower DILI risk than Ligand A (69.252), which is a major advantage.

**BBB:** Both ligands have high BBB penetration, but Ligand B (91.586) is better than Ligand A (70.803). While not a primary concern for a kinase inhibitor, it's a positive attribute.

**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 is difficult to interpret.

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

**hERG:** Both ligands have low hERG inhibition liability (0.53 and 0.443), which is good.

**Microsomal Clearance:** Ligand B (13.812) has much lower microsomal clearance than Ligand A (99.913), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (16.124 hours) has a longer in vitro half-life than Ligand A (11.58 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.648 and 0.545).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and better QED score outweigh the slightly higher TPSA. While both have issues with Caco-2 and solubility, the binding affinity difference is substantial enough to prioritize Ligand B for further development.

Output:
1
2025-04-17 13:19:48,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.399 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.11) is slightly above the preferred <140 for good absorption, while Ligand B (76.46) is well within the range.

**logP:** Both ligands (0.739 and 0.826) are within the optimal 1-3 range.

**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:** Ligand A (0.73) has a better QED score than Ligand B (0.559), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (41.838 and 44.242 percentile), suggesting acceptable liver safety.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (63.901) has a higher BBB penetration than Ligand A (45.134), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.066 and -4.722), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.766 and -1.886), indicating poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.157 and 0.257), which is excellent.

**Microsomal Clearance:** Ligand A (-20.828) has a significantly *lower* (better) microsomal clearance than Ligand B (68.51). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (5.848) has a longer half-life than Ligand B (2.628).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.103).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to be a deciding factor.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand A is the more promising candidate. It has a better QED score, significantly lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The binding affinity difference is negligible. While both have poor permeability/solubility, the improved ADME profile of Ligand A makes it a slightly better starting point for optimization.

Output:
0
2025-04-17 13:19:48,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.37 and 348.418 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.5) is better than Ligand B (67.43), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.563 and 1.991), 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) as lower HBD generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.787 and 0.741), indicating good drug-likeness.

**DILI:** Ligand A (56.611) has a higher DILI risk than Ligand B (30.361). This is a significant drawback for Ligand A.

**BBB:** Both have high BBB penetration, but Ligand A (98.216) is slightly better than Ligand B (89.957). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, comparing them, Ligand A (-4.158) is slightly better than Ligand B (-4.509).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.061) is slightly better than Ligand B (-3.106).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.825 and 0.739), which is excellent.

**Microsomal Clearance:** Ligand B (26.591) has significantly lower microsomal clearance than Ligand A (68.543), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (8.059) has a much longer in vitro half-life than Ligand A (-14.411), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.209 and 0.093).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.4 kcal/mol). Ligand B is slightly better.

**Overall:**

Ligand B is the superior candidate. While both have good potency and acceptable physicochemical properties, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic and longer t1/2) and lower DILI risk. These factors are critical for kinase inhibitors, outweighing the slight advantages Ligand A has in BBB penetration and Caco-2 permeability. The solubility issue is present in both, and would need to be addressed in formulation.

Output:
1
2025-04-17 13:19:48,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.391 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.66) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (62.3) is well within the ideal range.

**logP:** Both ligands (3.296 and 3.166) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both below the threshold of 5.

**H-Bond Acceptors:** Ligand A (7) and Ligand B (3) are both below the threshold of 10.

**QED:** Both ligands have similar QED values (0.584 and 0.582), indicating good drug-likeness.

**DILI:** Ligand A (96.433) has a very high DILI risk, which is a significant concern. Ligand B (31.33) has a low DILI risk, which is highly favorable.

**BBB:** Both ligands have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC. Ligand B (76.813) is slightly better than Ligand A (51.919).

**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 differentiating factor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.771) is slightly better than Ligand A (-5.471), suggesting a marginally better solubility profile.

**hERG Inhibition:** Ligand A (0.396) is slightly higher than Ligand B (0.717), indicating a slightly lower risk of hERG inhibition.

**Microsomal Clearance:** Ligand A (47.202) has lower clearance, indicating better metabolic stability, which is a key priority for kinase inhibitors. Ligand B (72.216) has higher clearance.

**In vitro Half-Life:** Ligand A (76.607) has a much longer half-life than Ligand B (-2.775), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.379 and 0.381).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 0.5 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the strong binding affinity of Ligand B, the extremely high DILI risk associated with Ligand A is a major red flag. While Ligand A has better metabolic stability and half-life, the potential for liver toxicity is too significant to ignore. Ligand B, with its low DILI risk, acceptable ADME properties, and superior binding affinity, is the more promising candidate. The negative solubility and Caco-2 values are concerning but could be addressed with formulation strategies.

Output:
1
2025-04-17 13:19:48,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.406 and 363.868 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.43) is higher than Ligand B (55.63). Both are below the 140 threshold for oral absorption, but lower is generally better.

**logP:** Ligand A (1.857) is within the optimal 1-3 range. Ligand B (3.588) 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 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 (0.823 and 0.901), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (45.715 and 47.305), and are both below the concerning threshold of 60.

**BBB:** Ligand B (88.445) shows better BBB penetration than Ligand A (74.486), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.543) has a worse Caco-2 permeability than Ligand B (-5.055), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.857) has better aqueous solubility than Ligand B (-4.104). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.577) has a slightly higher hERG risk than Ligand B (0.337), but both are relatively low.

**Microsomal Clearance:** Ligand A (21.822) has a significantly lower microsomal clearance than Ligand B (33.779), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (22.859) has a longer in vitro half-life than Ligand A (-11.445), which is generally desirable. However, the negative value for Ligand A is concerning and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.557), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and lower P-gp efflux, Ligand B has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic), and a longer half-life. The stronger binding affinity is the most critical factor for an enzyme inhibitor, and the improved metabolic stability is also highly desirable. The slightly higher logP of Ligand B is a minor concern, but the benefits outweigh this drawback.

Output:
1
2025-04-17 13:19:48,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.272 Da) is slightly higher than Ligand B (353.394 Da), but both are acceptable.

**TPSA:** Ligand A (62.22) is significantly better than Ligand B (110.52). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Ligand A (3.861) is at the higher end of the optimal range (1-3), while Ligand B (1.348) is at the lower end. While Ligand A's logP is higher, it's not excessively high and could contribute to good membrane permeability. Ligand B's lower logP might limit permeability.

**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 (Ligand A: 0.687, Ligand B: 0.613), indicating good drug-like properties.

**DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (43.66). This is a concern for Ligand A.

**BBB:** Ligand A (46.336) has a lower BBB penetration percentile than Ligand B (75.572). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.283 and -5.091). This is unusual and indicates poor permeability. However, these values are on a log scale and the negative values suggest very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.538 and -2.629). This is also unusual and suggests very low solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.652, Ligand B: 0.662), which is good.

**Microsomal Clearance:** Ligand A (32.151) has significantly lower microsomal clearance than Ligand B (51.216). This suggests better metabolic stability for Ligand A, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (53.132) has a longer in vitro half-life than Ligand B (-24.258). The negative value for Ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.444, Ligand B: 0.114).

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a substantial difference and a major advantage for Ligand A.

**Overall Assessment:**

Despite the higher DILI risk, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-10.5 vs -9.0 kcal/mol) outweighs the higher DILI risk, especially given the poor permeability and solubility of both compounds. The improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand A is also crucial for an enzyme inhibitor. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of A is substantial.

Output:
0
2025-04-17 13:19:48,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.451 and 368.396 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is better than Ligand B (67.87), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.097) is slightly lower than optimal (1-3), but acceptable. Ligand B (2.429) is well within the optimal range.

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

**H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (4), but both are acceptable (<=10).

**QED:** Ligand A (0.761) is better than Ligand B (0.528), indicating a more drug-like profile.

**DILI:** Ligand A (53.432) has a slightly higher DILI risk than Ligand B (44.63), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (A: 83.831, B: 86.002), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.983 and -4.916), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.405 and -2.844), which is also concerning and indicates poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.067) has a much lower hERG inhibition liability than Ligand B (0.537), which is a significant advantage.

**Microsomal Clearance:** Ligand A (25.971) has lower microsomal clearance than Ligand B (28.944), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.684) has a longer half-life than Ligand B (-5.177), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.394) has lower P-gp efflux liability than Ligand B (0.102), suggesting better bioavailability.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity (-8.5 vs -7.3 kcal/mol). While it has some ADME liabilities (slightly higher DILI, worse hERG, lower half-life, and higher P-gp efflux), the potency advantage is significant for an enzyme target like SRC kinase. The poor Caco-2 and solubility for both are concerning, but formulation strategies might mitigate these issues. Ligand A has better ADME properties overall, but the weaker binding affinity is a major drawback. Given the importance of potency for kinase inhibitors, Ligand B is the more promising candidate.

Output:
1
2025-04-17 13:19:48,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (368.503 Da) is also good.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (75.63). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have acceptable logP values (A: 3.522, B: 2.263), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=0, HBA=7). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.8) is significantly better than Ligand B (0.492). A QED > 0.5 is desirable, and A clearly meets this criterion.

**DILI:** Ligand B (64.831) has a higher DILI risk than Ligand A (15.626). Lower DILI is preferred.

**BBB:** Both have reasonable BBB penetration, but Ligand B (85.459) is slightly better than Ligand A (79.062). However, BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.507 and -4.797), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-4.23) is slightly better than Ligand B (-2.698), but both are very poor. Solubility is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.561, B: 0.686).

**Microsomal Clearance:** Ligand A (86.007) has lower microsomal clearance than Ligand B (113.805), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-0.728) has a better (longer) half-life than Ligand B (-14.692). This further supports its improved metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.236, B: 0.501).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). While both are good, the 1.0 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a superior QED score, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both have poor solubility and permeability, the improvements in metabolic stability and safety profile for Ligand A outweigh these concerns. The slightly better affinity also contributes to its favorability.

Output:
0
2025-04-17 13:19:48,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.386 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.42) is well below the 140 threshold for good absorption, while Ligand B (95.04) is approaching it. This favors Ligand A.

**3. logP:** Ligand A (3.744) is at the upper end of the optimal range (1-3), while Ligand B (1.837) is at the lower end. While both are acceptable, a slightly higher logP can sometimes aid in cell permeability, but needs to be balanced with 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 (4) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.656 and 0.761), indicating generally drug-like properties.

**7. DILI:** Ligand A (85.653) has a significantly higher DILI risk than Ligand B (32.067). This is a major concern for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (55.138 and 53.625). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.506) has a much worse Caco-2 permeability than Ligand B (-5.245). Both are negative, indicating poor permeability, but A is slightly better.

**10. Aqueous Solubility:** Ligand A (-5.635) has worse solubility than Ligand B (-1.698). Solubility is important for bioavailability, favoring Ligand B.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.777 and 0.505), which is good.

**12. Microsomal Clearance:** Ligand A (74.133) has a higher microsomal clearance than Ligand B (34.031), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (14.783) has a longer half-life than Ligand B (6.124), which is favorable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.286 and 0.16), which is good.

**15. Binding Affinity:** Both ligands have identical and excellent binding affinity (-8.9 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better half-life and Caco-2 permeability, its significantly higher DILI risk and worse metabolic stability (higher Cl_mic) are major concerns. Ligand B exhibits a much more favorable safety profile (lower DILI) and better metabolic stability, alongside acceptable solubility. The identical binding affinity removes that as a differentiating factor. Given the enzyme-specific priorities, metabolic stability and safety are paramount.

Output:
1
2025-04-17 13:19:48,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.431 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.21) is higher than Ligand B (40.62). While both are reasonably low, Ligand B's TPSA is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (1.526) and Ligand B (3.232) are both within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting solubility but not excessively.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.807) has a significantly higher QED score than Ligand B (0.567), indicating a more drug-like profile overall.

**DILI:** Ligand A (51.881) has a higher DILI risk than Ligand B (11.283). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 78.868, Ligand B: 76.309), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.118) and Ligand B (-4.505) both have negative values, indicating poor permeability. However, the scale is not defined, so it's difficult to assess the magnitude of the difference.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.332 and -3.546 respectively). This is a concern that would need to be addressed during formulation.

**hERG Inhibition:** Ligand A (0.17) has a slightly lower hERG risk than Ligand B (0.452), which is favorable.

**Microsomal Clearance:** Ligand A (35.566) has lower microsomal clearance than Ligand B (42.029), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.391) has a significantly longer in vitro half-life than Ligand B (-7.607). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.013 and 0.206 respectively), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol), with Ligand B being slightly better. The difference is small, and the other factors are more important.

**Conclusion:**

While Ligand B has a slightly better binding affinity and a significantly lower DILI risk and TPSA, Ligand A possesses a superior QED score, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly lower hERG risk. Given the enzyme-specific priorities, the improved metabolic stability and half-life of Ligand A outweigh the minor advantages of Ligand B. The higher QED also suggests a more balanced overall drug-like profile.

Output:
1
2025-04-17 13:19:48,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.29) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.51) is excellent, well below 140.

**logP:** Ligand A (0.993) is at the lower end of optimal, potentially impacting permeability. Ligand B (1.614) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, both acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.504 and 0.715), indicating drug-like properties.

**DILI:** Ligand A (31.64) has a low DILI risk, which is excellent. Ligand B (15.122) also has a very low DILI risk.

**BBB:** Ligand A (25.126) has low BBB penetration, as expected for a non-CNS target. Ligand B (66.344) shows moderate BBB penetration, not a major concern for an oncology target.

**Caco-2 Permeability:** Ligand A (-5.439) and Ligand B (-5.023) both have negative Caco-2 values, which is unusual and suggests poor permeability. These values are likely on a log scale where negative values indicate low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.451 and -1.886), which is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.297 and 0.24), which is positive.

**Microsomal Clearance:** Ligand A (15.749) has moderate microsomal clearance. Ligand B (-1.179) has negative clearance, which is unrealistic and likely an error in the data. Assuming this is a data error and should be a positive value, it would likely be a higher clearance than Ligand A.

**In vitro Half-Life:** Ligand A (-3.324) has a negative half-life, which is impossible. Ligand B (-2.227) also has a negative half-life. These are data errors.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.104 and 0.043), which is favorable.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Conclusion:**

Despite the questionable Caco-2 and half-life data, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.8 vs -7.3 kcal/mol) is the most important factor, outweighing the slightly less optimal logP and TPSA. The DILI and hERG risks are low for both. The solubility is a major concern for both, but can be addressed with formulation strategies. The negative clearance and half-life values are likely errors and would need to be clarified.

Output:
1
2025-04-17 13:19:48,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.483 and 341.386 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.08 and 71.09) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.198) is closer to the optimal 1-3 range than Ligand B (2.438), but both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=3) both have reasonable H-bond counts, well within the guidelines.

**QED:** Both ligands have similar QED scores (0.85 and 0.848), indicating good drug-likeness.

**DILI:** Ligand A (40.442) has a slightly better DILI score than Ligand B (50.058), indicating lower potential for liver injury. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.249) has a higher BBB score than Ligand A (60.838), but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.675 and -4.698). This is unusual and suggests poor permeability. However, these values are on a log scale and could be misinterpreted; we'll consider this a neutral point for now.

**Aqueous Solubility:** Ligand A (-1.621) has better solubility than Ligand B (-3.675). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.267 and 0.257), which is excellent.

**Microsomal Clearance:** Ligand A (26.75 mL/min/kg) has significantly lower microsomal clearance than Ligand B (37.217 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.701 hours) has a much longer half-life than Ligand B (-20.1 hours). The negative value for Ligand B is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.213 and 0.108).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage (1.4 kcal/mol difference).

**Conclusion:**

While Ligand A has better solubility, metabolic stability (lower Cl_mic, longer t1/2), and a slightly better DILI profile, the significantly stronger binding affinity of Ligand B (-8.9 vs -7.5 kcal/mol) is a major advantage for an enzyme inhibitor. The difference in affinity is large enough to outweigh the ADME drawbacks of Ligand B, particularly given that both ligands have acceptable (though not ideal) ADME properties overall. The negative half-life for Ligand B is a concern, but the potency could potentially be optimized further to compensate.

Output:
1
2025-04-17 13:19:48,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.423 and 354.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.37) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (87.32) is excellent, well below 140.

**logP:** Ligand A (-0.799) is a bit low, potentially hindering permeation. Ligand B (1.129) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.46 and 0.802), with Ligand B being significantly better.

**DILI:** Ligand A (54.556) has a moderate DILI risk, while Ligand B (45.677) has a lower risk. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (51.842) has a higher BBB score than Ligand A (25.902), but it's not a major factor here.

**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 the values accurately.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility, which is a significant concern.

**hERG Inhibition:** Ligand A (0.057) has a very low hERG risk, which is excellent. Ligand B (0.292) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-17.04) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (2.17) has a low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (3.183) has a short half-life. Ligand B (-35.655) has a negative half-life, which is not physically possible and suggests an issue with the data.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.012 and 0.034).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its superior binding affinity, lower DILI risk, better QED, and significantly better metabolic stability (lower Cl_mic) outweigh the slightly higher logP and hERG risk. The negative values for clearance and half-life for Ligand A are highly suspect and raise concerns about data quality.

Output:
1
2025-04-17 13:19:48,292 - INFO - Batch 204 complete. Total preferences: 3264
2025-04-17 13:19:48,292 - INFO - Processing batch 205/512...
2025-04-17 13:20:27,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.5 and 370.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (66.48). Both are below 140, suggesting good absorption potential.

**logP:** Both ligands have good logP values (3.28 and 2.77) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 3 HBA, both are acceptable.

**QED:** Both ligands have similar QED scores (0.778 and 0.714), indicating good drug-likeness.

**DILI:** Ligand A (16.56) has a significantly lower DILI risk than Ligand B (40.05). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration (78.87 and 72.24), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.753) has a worse Caco-2 permeability than Ligand B (-5.05), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.324) has better aqueous solubility than Ligand B (-3.905). This is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.428 and 0.611).

**Microsomal Clearance:** Ligand A (57.69) has a lower microsomal clearance than Ligand B (86.20), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-40.59) has a significantly longer in vitro half-life than Ligand A (-9.73). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.182) has lower P-gp efflux than Ligand B (0.308), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a much stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.6 vs 0.0 kcal/mol) is the most critical factor. While Ligand A has advantages in DILI, solubility, and metabolic stability, the potency difference is substantial. The longer half-life of Ligand B is also a significant benefit. The slightly higher DILI risk and lower solubility of Ligand B are less concerning given the strong binding affinity.

Output:
1
2025-04-17 13:20:27,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (334.379 and 356.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is significantly better than Ligand B (95.59).  A TPSA under 140 is good for oral absorption, but lower is generally preferred.

**logP:** Both ligands (2.649 and 2.907) are within the optimal 1-3 range.

**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 donors and acceptors, potentially improving permeability.

**QED:** Both ligands have reasonable QED scores (0.796 and 0.628), indicating good drug-likeness.

**DILI:** Both ligands have similar, moderately high DILI risk (76.89 and 77.549 percentile). This is a concern, but not a deciding factor at this stage.

**BBB:** Ligand A (68.011) has a slightly better BBB penetration score than Ligand B (57.115), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.853) has a better Caco-2 permeability score than Ligand B (-5.294), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.194) has a better aqueous solubility than Ligand B (-3.74). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.584 and 0.69), which is positive.

**Microsomal Clearance:** Ligand A (60.427) has a higher microsomal clearance than Ligand B (35.401). This suggests Ligand B is more metabolically stable, a key consideration for kinases.

**In vitro Half-Life:** Ligand B (26.041 hours) has a significantly longer in vitro half-life than Ligand A (51.557 hours). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.114 and 0.209).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and solubility, Ligand A's significantly superior binding affinity (-9.5 vs -8.8 kcal/mol) is the most critical factor for an enzyme target like SRC kinase. The difference in affinity is large enough to compensate for the slightly higher clearance and lower solubility of Ligand A.

Output:
0
2025-04-17 13:20:27,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.435 and 351.837 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.18) is better than Ligand B (56.99), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.786) is suboptimal, potentially hindering permeation. Ligand B (3.857) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) 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 similar QED values (0.624 and 0.621), indicating good drug-likeness.

**DILI:** Ligand A (32.299) has a much lower DILI risk than Ligand B (60.45), which is approaching a concerning level. This is a substantial advantage for Ligand A.

**BBB:** This is less important for a non-CNS target like SRC. Ligand B (52.889) is slightly better than Ligand A (41.528).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.949 and -4.738), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.649) is better than Ligand B (-5.181), indicating better solubility.

**hERG:** Ligand A (0.065) has a much lower hERG risk than Ligand B (0.562). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (27.577) has a lower microsomal clearance than Ligand B (98.629), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-9.953) has a negative half-life, which is concerning and suggests rapid degradation. Ligand B (11.337) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.017) has lower P-gp efflux than Ligand B (0.363), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.4 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a more favorable logP, but suffers from higher DILI risk, higher hERG risk, and higher microsomal clearance. Ligand A has better solubility, lower DILI and hERG risk, and better metabolic stability, but its logP is suboptimal and its half-life is concerning. The strong binding affinity of Ligand B is a significant advantage, and while the ADME properties are not ideal, they might be optimized further. The negative half-life of Ligand A is a major red flag.

Output:
1
2025-04-17 13:20:27,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.422 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.71 and 70.47) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.455) is optimal, while Ligand B (0.162) 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 4 HBA, and Ligand B has 5, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.529 and 0.844), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (15.394) has a slightly higher DILI risk than Ligand B (14.618), but both are well below the concerning threshold of 60.

**BBB:** Ligand A (85.459) has better BBB penetration than Ligand B (62.854), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.524) has a worse Caco-2 permeability than Ligand B (-5.191), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.777) has slightly better aqueous solubility than Ligand B (-1.099).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.244 and 0.127).

**Microsomal Clearance:** Ligand B (-11.527) has significantly lower microsomal clearance than Ligand A (37.945), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (16.42) has a longer in vitro half-life than Ligand A (-20.014), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.018) has slightly higher P-gp efflux than Ligand B (0.011), but both are very low.

**Binding Affinity:** Ligand A (-7.8) has a stronger binding affinity than Ligand B (0.0). This is a substantial difference.

**Conclusion:**

Despite Ligand B's slightly better QED and significantly improved metabolic stability (lower Cl_mic and longer t1/2), Ligand A's substantially stronger binding affinity (-7.8 vs 0.0 kcal/mol) is the dominant factor. A >7 kcal/mol difference in binding affinity can often outweigh minor ADME drawbacks, especially for an enzyme target where achieving sufficient potency is paramount. While Ligand B is more metabolically stable, the potency difference suggests Ligand A is more likely to be a viable drug candidate.

Output:
1
2025-04-17 13:20:27,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (391.274 and 357.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.23 and 61.88) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (1.9 and 1.058) 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 similar QED scores (0.78 and 0.772), indicating good drug-likeness.

**DILI:** Ligand A (37.728) has a slightly higher DILI risk than Ligand B (5.894), but both are below the concerning threshold of 60. Ligand B is significantly better here.

**BBB:** Both have reasonable BBB penetration, but Ligand B (83.831) is better than Ligand A (78.558). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.739 and -4.655), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.171 and -1.12), indicating very poor aqueous solubility. This is a major concern for bioavailability. Ligand B is slightly better.

**hERG Inhibition:** Both have low hERG inhibition liability (0.286 and 0.479), which is good.

**Microsomal Clearance:** Ligand B (-10.467 mL/min/kg) has significantly lower (better) microsomal clearance than Ligand A (50.576 mL/min/kg). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-5.844 hours) has a slightly longer half-life than Ligand A (-39.652 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.029 and 0.004), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While both are good, the 1.2 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. It exhibits significantly better metabolic stability (lower Cl_mic), slightly better half-life, a lower DILI risk, and a stronger binding affinity. The improved binding affinity is a key advantage for an enzyme inhibitor. While the solubility and permeability are problematic, they might be addressed through formulation strategies.

Output:
1
2025-04-17 13:20:27,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.384 and 367.852 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.29) is better than Ligand B (51.39), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (3.006 and 4.132), within the 1-3 range, although Ligand B is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A has 3 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 (0.702 and 0.688), indicating good drug-likeness.

**DILI:** Ligand A (23.497) has a significantly lower DILI risk than Ligand B (37.263), which is a major advantage.

**BBB:** Ligand B (91.043) has a higher BBB penetration potential than Ligand A (61.458), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.29) has a more negative Caco-2 value than Ligand B (-4.863), indicating potentially lower permeability.

**Aqueous Solubility:** Ligand A (-2.448) has better aqueous solubility than Ligand B (-3.681).

**hERG Inhibition:** Ligand A (0.944) has a slightly better hERG profile than Ligand B (0.821), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-13.112) has a significantly lower (better) microsomal clearance than Ligand B (58.615), suggesting greater metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (49.332 and 49.746 hours).

**P-gp Efflux:** Ligand A (0.442) has lower P-gp efflux liability than Ligand B (0.679), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly better binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is the most important factor for an enzyme target. While Ligand B has a higher logP and DILI risk, and lower solubility, the significantly improved potency makes it the more promising candidate. Ligand A has better ADME properties overall, but the weaker binding affinity is a critical disadvantage.

Output:
1
2025-04-17 13:20:27,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.519 Da) is slightly better positioned.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (123.95). Lower TPSA generally favors better absorption.

**logP:** Both ligands have logP values within the optimal range (1-3), but Ligand B (4.009) is slightly higher, which could potentially lead to solubility issues or off-target interactions. Ligand A (3.193) is preferable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=3, HBA=7) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.659) has a better QED score than Ligand B (0.495), indicating a more drug-like profile.

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (97.286), a critical advantage.

**BBB:** This is less crucial for a non-CNS target like SRC, but Ligand A (75.378) has a better BBB percentile than Ligand B (52.811).

**Caco-2 Permeability:** Ligand A (-4.486) is better than Ligand B (-5.171). Higher Caco-2 permeability indicates better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.709) is better than Ligand B (-5.067). Higher solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.192) has a much lower hERG inhibition liability than Ligand B (0.762), a significant safety advantage.

**Microsomal Clearance:** Ligand B (79.667) has a higher microsomal clearance than Ligand A (68.48), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (25.79) has a longer half-life than Ligand A (4.851), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux liability than Ligand B (0.633), which is better for oral bioavailability.

**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 significant ADME/Tox advantages of Ligand A.

**Overall:**

Ligand A demonstrates a significantly better overall profile, particularly in terms of safety (DILI, hERG), ADME properties (solubility, permeability, P-gp efflux, metabolic stability), and drug-likeness (QED). While Ligand B has a slightly better binding affinity, the substantial improvements in other crucial parameters make Ligand A the more promising drug candidate.

Output:
1
2025-04-17 13:20:27,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (350.459 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.59) is better than Ligand B (80.2), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Both ligands have good logP values (3.06 and 2.184), 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 high QED scores (0.883 and 0.894), indicating good drug-like properties.

**7. DILI:** Ligand B (31.214) has a significantly lower DILI risk than Ligand A (46.995), making it preferable.

**8. BBB:** Ligand A (77.821) has better BBB penetration than Ligand B (60.644), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.771) is slightly better than Ligand B (-4.82).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.571) is slightly better than Ligand B (-2.747).

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.545 and 0.645), which is good.

**12. Microsomal Clearance:** Ligand B (7.373) has significantly lower microsomal clearance than Ligand A (56.644), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-6.729) has a longer in vitro half-life than Ligand A (11.736), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.339 and 0.066), which is favorable.

**15. Binding Affinity:** Ligand A (-8.3 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 automatically outweigh other factors.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity and BBB penetration, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The poor Caco-2 and solubility for both compounds are concerning and would need to be addressed in further optimization, but the metabolic stability advantage of Ligand B is more critical at this stage.

Output:
1
2025-04-17 13:20:27,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.459 Da and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is significantly better than Ligand B (88.2), being well below the 140 threshold for good absorption. Ligand B is higher, potentially impacting absorption.

**logP:** Both ligands have acceptable logP values (3.295 and 2.092, respectively) within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.794 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (56.844) has a higher DILI risk than Ligand B (21.675). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.511) is slightly better than Ligand B (68.282).

**Caco-2 Permeability:** Ligand A (-4.733) is worse than Ligand B (-4.471), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.087) is worse than Ligand B (-2.258), which is a concern for formulation and bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.457 and 0.271), which is excellent.

**Microsomal Clearance:** Ligand A (121.046) has significantly higher microsomal clearance than Ligand B (25.386), indicating lower metabolic stability. This is a major disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-7.719) has a longer in vitro half-life than Ligand A (12.645), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.644 and 0.017), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While both ligands have good potency, Ligand B is superior due to its significantly better DILI score, lower microsomal clearance (better metabolic stability), longer half-life, and better solubility. Ligand A's higher DILI risk and poorer metabolic stability are major concerns that outweigh its slightly better BBB and Caco-2 permeability.

Output:
1
2025-04-17 13:20:27,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.851) is slightly higher than Ligand B (352.385), but both are acceptable.

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand A (72.88) is better than Ligand B (82.11).

**logP:** Both are within the optimal range (1-3), but Ligand A (0.669) is closer to the lower limit, while Ligand B (2.515) is well within the range.

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

**QED:** Both have good QED scores (A: 0.686, B: 0.75), indicating drug-like properties.

**DILI:** Ligand A (33.579) has a lower DILI risk than Ligand B (44.591), which is preferable.

**BBB:** Both have moderate BBB penetration, but Ligand B (71.811) is higher than Ligand A (53.083). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially concerning. However, the values are close enough that this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, which is also concerning. Again, the values are close, and this isn't a major differentiator.

**hERG:** Ligand A (0.322) has a significantly lower hERG risk than Ligand B (0.672), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (-7.08) has a much lower (better) microsomal clearance than Ligand B (42.013), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-9.656) has a longer half-life than Ligand B (-7.754), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.055, B: 0.071).

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.7), a difference of 0.6 kcal/mol. While affinity is a priority, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower DILI risk. These factors are crucial for an enzyme inhibitor, outweighing the minor difference in binding affinity. The negative solubility and Caco-2 values are concerning for both, but these can be addressed through formulation strategies.

Output:
0
2025-04-17 13:20:27,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (464.225 Da) is higher, but still acceptable. Ligand B (349.479 Da) is slightly lower, potentially aiding permeability.

**TPSA:** Ligand A (50.36) is good for oral absorption, while Ligand B (80.12) is higher, potentially hindering absorption.

**logP:** Ligand A (3.759) is optimal. Ligand B (1.782) is on the lower side, which could impact permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is well within acceptable limits. Ligand B (HBD=1, HBA=5) is also acceptable, though slightly higher HBA.

**QED:** Both ligands have good QED scores (A: 0.506, B: 0.898), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (67.739) has a higher DILI risk than Ligand B (35.789), which is a significant concern.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.799) has a slightly higher hERG risk than Ligand B (0.264).

**Microsomal Clearance:** Ligand A (70.815) has higher clearance than Ligand B (50.622), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.662) has a longer half-life than Ligand A (41.938).

**P-gp Efflux:** Ligand A (0.518) has slightly higher P-gp efflux than Ligand B (0.138).

**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.

**Conclusion:**

Despite Ligand B's lower logP and negative solubility/permeability, its significantly superior binding affinity (-8.7 vs -7.7 kcal/mol), lower DILI risk, better half-life, and lower hERG risk make it the more promising candidate. The potency advantage is substantial and outweighs the slight concerns regarding logP and solubility. The lower DILI risk is a major advantage.

Output:
1
2025-04-17 13:20:27,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 357.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (98.14 and 92.51) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.942) is slightly lower than ideal (1-3), potentially impacting permeability. Ligand B (1.708) is within the optimal 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:** Both ligands have good QED scores (0.714 and 0.802), indicating drug-like properties.

**DILI:** Ligand A (61.691) has a slightly higher DILI risk than Ligand B (54.556), but both are reasonably acceptable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (76.037) has a higher BBB percentile than Ligand A (55.176).

**Caco-2 Permeability:** Both ligands exhibit negative Caco-2 permeability values (-5.085 and -4.675). This is unusual and suggests a potential issue with intestinal absorption, but negative values can sometimes be artifacts of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.139 and -1.92). This is also concerning and suggests poor aqueous solubility, which could hinder bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.108 and 0.187), which is excellent.

**Microsomal Clearance:** Ligand A (40.453 mL/min/kg) has a higher microsomal clearance than Ligand B (18.04 mL/min/kg). This suggests Ligand B is more metabolically stable, a key consideration for kinases.

**In vitro Half-Life:** Ligand B (-20.927 hours) has a significantly longer in vitro half-life than Ligand A (2.785 hours). 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 (0.064 and 0.083).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.3 kcal/mol). While both are good, the 0.5 kcal/mol difference is noteworthy and could outweigh some of the ADME drawbacks of Ligand A.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand B is the more promising candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and lower DILI risk outweigh the slightly higher logP and the concerning (but potentially artifactual) negative Caco-2 and solubility values. The negative solubility and Caco-2 values would need to be investigated experimentally, but the overall profile of Ligand B is more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 13:20:27,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 356.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.4) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (79.29) is well within the range.

**logP:** Both ligands have good logP values (1.296 and 2.822), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and acceptable HBA counts (6 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have acceptable QED scores (0.824 and 0.737), indicating good drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (61.846 and 69.678), which is a concern. However, this is a percentile, and there's inherent variability in these predictions.

**BBB:** Ligand A (84.839) has a better BBB score than Ligand B (34.316), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.27 and -5.184). These values are unusual and suggest poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.987 and -4.179), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.499 and 0.563), which is positive.

**Microsomal Clearance:** Ligand A (4.604 mL/min/kg) has significantly lower microsomal clearance than Ligand B (82.525 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (7.22 hours) has a shorter half-life than Ligand B (17.089 hours), but still acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.307).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.8 kcal/mol). This 2.1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability predictions for both compounds, Ligand B's significantly higher binding affinity (-9.9 kcal/mol vs -7.8 kcal/mol) is a major advantage. The better metabolic stability of Ligand A is appealing, but the potency difference is substantial. Given the enzyme target class, potency is paramount. While the solubility and permeability issues need to be addressed through formulation or further chemical modifications, the stronger binding of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 13:20:27,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (377.575 and 377.507 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.6) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.587) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.142) is very low, which could hinder membrane permeability and thus bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, but the higher number of H-bonds could slightly reduce permeability.

**QED:** Both ligands have reasonable QED scores (0.754 and 0.529), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (45.56 and 44.668 percentile).

**BBB:** Ligand A (72.896) shows good BBB penetration, while Ligand B (38.736) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.788) has poor Caco-2 permeability, which is a significant concern. Ligand B (-5.668) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.165) has poor aqueous solubility, consistent with its high logP. Ligand B (-1.989) has better solubility, which is a significant advantage.

**hERG Inhibition:** Ligand A (0.574) shows low hERG inhibition risk, which is excellent. Ligand B (0.142) also shows very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (59.663) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (21.158) has much lower clearance, indicating better metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (19.272) has a moderate half-life. Ligand B (-11.392) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.622 and 0.025), which is favorable.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh many ADME concerns.

**Conclusion:**

Despite the slightly high logP and poor Caco-2 permeability of Ligand A, its significantly superior binding affinity (-7.6 vs -6.4 kcal/mol) and favorable hERG risk make it the more promising candidate. The better metabolic stability of Ligand B is appealing, but the weaker binding and very short half-life are critical drawbacks for a kinase inhibitor. The potency advantage of Ligand A is likely to be more impactful than the ADME liabilities, which could be addressed through further optimization.

Output:
0
2025-04-17 13:20:27,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.363 and 362.495 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (121.07) is slightly above the optimal <140 for good oral absorption, but still reasonable. Ligand B (75.27) is excellent, well below 140.

**logP:** Ligand A (-0.449) is a bit low, potentially hindering permeation. Ligand B (2.573) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 8 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.553 and 0.845, respectively), indicating drug-like properties.

**DILI:** Ligand A (68.515) has a higher DILI risk than Ligand B (38.852). Both are acceptable, but B is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (57.154) is higher than Ligand A (43.273), but not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.676) is very poor, indicating poor intestinal absorption. Ligand B (-5.228) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.078 and -2.32, respectively). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.557) has a slightly higher hERG risk than Ligand B (0.099). B is significantly better.

**Microsomal Clearance:** Ligand A (13.897) has lower microsomal clearance (better metabolic stability) than Ligand B (23.331).

**In vitro Half-Life:** Ligand B (-6.937) has a significantly longer in vitro half-life than Ligand A (-1.197).

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is good. Ligand B (0.211) has slightly higher efflux, but still reasonable.

**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 a major advantage.

**Conclusion:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B boasts significantly better binding affinity, a longer half-life, lower hERG risk, and a lower DILI score. The improved logP and TPSA values also contribute to its better overall profile. The slightly higher metabolic clearance is a minor drawback compared to the substantial benefits.

Output:
1
2025-04-17 13:20:27,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.494 and 388.599 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (58.64), both are below the 140 threshold for good absorption.

**logP:** Ligand A (3.819) is slightly higher than Ligand B (2.251), 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 2 HBA, while Ligand B has 5. Ligand A is preferable here.

**QED:** Both ligands have similar QED values (0.722 and 0.622), indicating good drug-likeness.

**DILI:** Ligand A (33.773) has a slightly higher DILI risk than Ligand B (29.469), but both are below the concerning threshold of 60.

**BBB:** Ligand A (84.141) has better BBB penetration than Ligand B (71.966). While not a primary concern for a non-CNS target like SRC, it's a minor positive.

**Caco-2 Permeability:** Ligand A (-4.378) has worse Caco-2 permeability than Ligand B (-4.904).

**Aqueous Solubility:** Ligand A (-3.84) has slightly better solubility than Ligand B (-3.598).

**hERG Inhibition:** Ligand A (0.68) has a higher hERG risk than Ligand B (0.432), which is a negative for Ligand A.

**Microsomal Clearance:** Ligand A (77.284) has higher microsomal clearance than Ligand B (67.354), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-5.771) has a significantly longer in vitro half-life than Ligand A (13.066), which is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.462) has better P-gp efflux profile than Ligand B (0.16).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol).

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity, the significant advantage of Ligand B in terms of metabolic stability (longer half-life, lower Cl_mic) and lower hERG risk outweigh this difference. The slightly better solubility of Ligand A is not enough to compensate for the other drawbacks. Ligand B also has a better P-gp efflux profile.

Output:
1
2025-04-17 13:20:27,054 - INFO - Batch 205 complete. Total preferences: 3280
2025-04-17 13:20:27,054 - INFO - Processing batch 206/512...
2025-04-17 13:21:13,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (393.412 and 385.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.91) is better than Ligand B (82.27), both are under the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.513 and 1.713) 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:** Ligand A (0.834) has a significantly higher QED score than Ligand B (0.599), indicating better overall drug-likeness.

**DILI:** Ligand B (38.154) has a much lower DILI risk than Ligand A (78.015), which is a significant advantage.

**BBB:** Ligand A (74.641) has a higher BBB penetration score than Ligand B (26.134), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.899) has a worse Caco-2 permeability than Ligand B (-5.752). Lower values here are less desirable.

**Aqueous Solubility:** Ligand A (-2.88) has slightly better aqueous solubility than Ligand B (-2.407).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.251 and 0.204).

**Microsomal Clearance:** Ligand A (6.282) has significantly lower microsomal clearance than Ligand B (39.118), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.721) has a much longer in vitro half-life than Ligand B (24.472), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.148 and 0.083).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.4 kcal/mol). Ligand B is slightly better, but the difference is small.

**Conclusion:**

While Ligand B has a better DILI score and slightly better binding affinity, Ligand A is superior overall. Its significantly higher QED, much lower microsomal clearance, and longer half-life outweigh the slightly higher DILI risk and slightly worse Caco-2 permeability. The improved metabolic stability and predicted longer duration of action are critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:21:13,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (373.425 and 369.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (108.83), both are acceptable but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.791) is optimal, while Ligand B (0.604) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.606 and 0.617), indicating good drug-likeness.

**DILI:** Ligand A (52.656) has a slightly higher DILI risk than Ligand B (44.048), but both are below the concerning threshold of 60.

**BBB:** Ligand A (67.352) has better BBB penetration than Ligand B (28.655), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not provided, so it's hard to interpret the absolute values.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is missing.

**hERG:** Ligand A (0.299) has a significantly lower hERG risk than Ligand B (0.179), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (21.887) has a higher microsomal clearance than Ligand B (15.669), suggesting lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (-34.506) has a much longer in vitro half-life than Ligand A (-6.738), indicating superior metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.059 and 0.076).

**Binding Affinity:** Ligand B (-9.0 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 minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better TPSA and logP, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.0 vs -6.7 kcal/mol) and substantially improved metabolic stability (longer half-life, lower Cl_mic) are critical for an enzyme target like SRC kinase. The lower hERG risk for Ligand A is positive, but the affinity and metabolic stability advantages of Ligand B are more important.

Output:
1
2025-04-17 13:21:13,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.411 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.85) is slightly higher than Ligand B (78.43). Both are acceptable, but Ligand B is better for absorption.

**logP:** Ligand A (1.635) and Ligand B (2.787) are both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (3). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (9) is slightly higher than Ligand B (3). Both are within acceptable limits (<=10).

**QED:** Ligand A (0.755) has a better QED score than Ligand B (0.558), indicating a more drug-like profile.

**DILI:** Ligand B (13.377) has a significantly lower DILI risk than Ligand A (90.617). This is a major advantage for Ligand B.

**BBB:** Ligand A (86.817) has a higher BBB penetration than Ligand B (41.838). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.589 and -4.638), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.646 and -2.912), also unusual and concerning.

**hERG Inhibition:** Ligand A (0.417) has a slightly higher hERG risk than Ligand B (0.186). Lower is better.

**Microsomal Clearance:** Ligand B (51.246) has a lower microsomal clearance than Ligand A (91.937), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (19.993) has a longer half-life than Ligand B (8.543). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux than Ligand B (0.079), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks. The 2.4 kcal/mol difference is substantial.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -6.3 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic) outweigh the slightly lower QED, BBB, and half-life. The binding affinity difference is particularly important for an enzyme target like SRC kinase. The poor permeability and solubility would need to be addressed through formulation or further chemical modifications, but the potent binding and improved safety profile of Ligand B make it the better starting point.

Output:
1
2025-04-17 13:21:13,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (348.487 and 368.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (97.11).  A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.559 and 2.052), 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 (3) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.596 and 0.686), indicating drug-like properties.

**7. DILI:** Ligand A (37.611) has a much lower DILI risk than Ligand B (53.354). Both are below 60, but A is preferable.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (76.58) is higher than Ligand A (58.278), but this is less important.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.035 and -5.076), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.199 and -3.36), indicating poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.294) has a lower hERG risk than Ligand B (0.475), which is desirable.

**12. Microsomal Clearance:** Ligand A (42.99) has a higher microsomal clearance than Ligand B (21.368), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (19.367) has a significantly longer in vitro half-life than Ligand A (-4.037). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.327 and 0.227).

**15. Binding Affinity:** Ligand B (-7.1 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.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor Caco-2 and solubility, Ligand B has a significantly longer half-life and better metabolic stability (lower Cl_mic), which are crucial for an enzyme target. It also has a slightly better binding affinity. Ligand A has a lower DILI risk and hERG inhibition, but these are less critical than the pharmacokinetic advantages of Ligand B.

Output:
1
2025-04-17 13:21:13,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly preferred due to being lower in MW.

**TPSA:** Ligand A (84.5) is excellent, well below the 140 threshold for good absorption. Ligand B (104.37) is still acceptable but less optimal.

**logP:** Both ligands have good logP values (A: 1.163, B: 0.611), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is better than Ligand B (HBD=3, HBA=5) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.392, B: 0.534), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (32.299) has a significantly lower DILI risk than Ligand B (43.117), which is a major advantage.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 more important.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.206 and -2.511 respectively). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.091 and 0.071 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (12.706 mL/min/kg) has significantly lower microsomal clearance than Ligand B (40.908 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-8.87 hours) has a much longer in vitro half-life than Ligand B (-36.868 hours). This is a substantial benefit.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.048 and 0.043 respectively).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), a difference of 0.8 kcal/mol. While affinity is a priority, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and a better TPSA. The poor solubility of both is a concern that would need to be addressed through formulation strategies, but the other advantages of Ligand A outweigh the slight affinity difference.

Output:
0
2025-04-17 13:21:13,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.261 and 339.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.35) is slightly higher than the preferred <140, but still reasonable. Ligand B (47.67) is excellent, well below 140.

**logP:** Both ligands (2.593 and 3.36) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.522 and 0.749), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (89.88) has a higher DILI risk than Ligand B (30.399). This is a significant concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (74.874) and Ligand B (69.407) are both moderate.

**Caco-2 Permeability:** Ligand A (-4.246) is poor, suggesting poor absorption. Ligand B (-5.205) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.279) is poor, while Ligand B (-2.863) is better, but still not ideal.

**hERG:** Ligand A (0.392) has a lower hERG risk than Ligand B (0.781), which is a positive.

**Microsomal Clearance:** Ligand A (60.575) has higher clearance than Ligand B (12.596), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (22.768) has a shorter half-life than Ligand B (11.328), which is undesirable.

**P-gp Efflux:** Ligand A (0.586) has lower P-gp efflux than Ligand B (0.335), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better solubility. While Caco-2 permeability is poor for both, the other ADME properties of Ligand B are superior. Ligand A's higher DILI risk and poorer metabolic stability are significant liabilities.

Output:
1
2025-04-17 13:21:13,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (334.379 and 336.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (60.25 and 62.55) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (2.203 and 2.426) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 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 (0.684 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A (74.021) has a higher DILI risk than Ligand B (55.913). This is a negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Both ligands have moderate BBB penetration (68.166 and 53.548).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.735 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 (-2.269 and -3.683), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.425 and 0.651), which is good.

**Microsomal Clearance:** Ligand A (48.064) has a slightly lower microsomal clearance than Ligand B (45.541), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (52.181) has a longer in vitro half-life than Ligand A (30.509), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.145 and 0.191), which is positive.

**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 can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -7.3 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The longer half-life and lower DILI risk also contribute to its favorability. While both have solubility issues, the potency advantage of Ligand B is likely to be more impactful in driving forward development, assuming solubility can be addressed through formulation strategies.

Output:
1
2025-04-17 13:21:13,911 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.519, 49.85, 3.243, 0, 3, 0.661, 22.8, 77.239, -4.355, -2.629, 0.373, 82.917, 35.087, 0.084, -7.0]
**Ligand B:** [350.463, 78.68, 1.682, 1, 5, 0.844, 15.083, 78.558, -4.914, -1.203, 0.494, 24.741, -12.927, 0.073, -9.6]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A: 352.519, B: 350.463 - very similar.
2. **TPSA:** Ligand A (49.85) is significantly better than Ligand B (78.68).  TPSA < 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.
3. **logP:** Ligand A (3.243) is optimal (1-3). Ligand B (1.682) is on the lower side, which *could* indicate permeability issues.
4. **HBD:** Ligand A (0) is excellent. Ligand B (1) is acceptable.
5. **HBA:** Ligand A (3) is good. Ligand B (5) is acceptable, but higher.
6. **QED:** Both are good, but Ligand B (0.844) is slightly better than Ligand A (0.661).
7. **DILI:** Ligand A (22.8) is much better than Ligand B (15.083). Lower is better, and A is well below the 40% threshold, while B is closer.
8. **BBB:** Both are good (A: 77.239, B: 78.558), but not critical for a non-CNS target like SRC.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.355) is slightly worse than B (-4.914).
10. **Solubility:** Both are negative, indicating poor solubility. A (-2.629) is slightly better than B (-1.203).
11. **hERG:** Both are low risk (A: 0.373, B: 0.494).
12. **Cl_mic:** Ligand B (24.741) has significantly lower microsomal clearance than Ligand A (82.917), indicating better metabolic stability. This is a key advantage for an enzyme target.
13. **t1/2:** Ligand B (-12.927) has a negative in vitro half-life, which is concerning, while Ligand A (35.087) is positive.
14. **Pgp:** Both are low (A: 0.084, B: 0.073), suggesting minimal P-gp efflux.
15. **Affinity:** Ligand B (-9.6 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).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Conclusion:**

Despite Ligand A having better TPSA and DILI, Ligand B's significantly stronger binding affinity (-9.6 vs -7.0 kcal/mol) and much lower microsomal clearance (24.741 vs 82.917) are decisive advantages. The improved affinity is likely to outweigh the slightly higher TPSA and DILI risk, and the better metabolic stability is crucial for *in vivo* efficacy. The negative half-life is concerning, but could be addressed with structural modifications.

1
2025-04-17 13:21:13,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is well below the 140 threshold, suggesting good absorption. Ligand B (115.11) is still within acceptable limits, but less favorable.

**logP:** Ligand A (1.935) is optimal. Ligand B (0.739) 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. Both are within the acceptable range of <=10.

**QED:** Both ligands have a QED of 0.73, indicating good drug-likeness.

**DILI:** Ligand A (12.214) has a significantly lower DILI risk than Ligand B (41.838), a major advantage.

**BBB:** Ligand A (73.75) has better BBB penetration than Ligand B (45.134), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.876) has a negative value, which is unusual and indicates very poor permeability. Ligand B (-5.066) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-1.609) has poor solubility, while Ligand B (-2.766) is even worse.

**hERG Inhibition:** Ligand A (0.657) has a lower hERG risk than Ligand B (0.157), which is a significant advantage.

**Microsomal Clearance:** Ligand A (1.937) has a much lower microsomal clearance than Ligand B (-20.828), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.568) has a negative half-life, which is not possible. This is a major red flag. Ligand B (5.848) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.138) has lower P-gp efflux than Ligand B (0.016), which is good.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage that could outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it has poorer solubility, higher DILI risk, and lower metabolic stability than Ligand A. Ligand A has a problematic negative half-life and poor Caco-2 permeability. The negative half-life for Ligand A is a critical flaw, indicating rapid degradation. While Ligand B's ADME profile isn't ideal, the substantial binding affinity advantage is likely to be more impactful for initial optimization efforts.

Output:
1
2025-04-17 13:21:13,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 Da and 358.433 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.64) is better than Ligand B (47.1). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.795) is optimal. Ligand B (0.337) is a bit low, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.853 and 0.727), indicating good drug-like properties.

**DILI:** Ligand A (32.261) has a lower DILI risk than Ligand B (16.479), which is preferable.

**BBB:** Ligand A (29.508) has a low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (69.639) has a higher BBB penetration, which is not particularly relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.86 and -4.593). 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 base of the logarithm.

**Aqueous Solubility:** Ligand A (-2.105) has slightly better solubility than Ligand B (-0.437), though both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.521 and 0.408).

**Microsomal Clearance:** Ligand A (20.316 mL/min/kg) has a higher microsomal clearance than Ligand B (-13.797 mL/min/kg). Negative clearance is not physically possible, so this value for Ligand B is likely an error or an artifact of the prediction method. This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-10.335 hours) has a negative half-life, which is impossible. Ligand B (-21.255 hours) also has a negative half-life, indicating issues with the prediction.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.171 and 0.012).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the questionable half-life and clearance predictions, the significantly stronger binding affinity of Ligand B (-9.0 kcal/mol vs -6.7 kcal/mol) is the deciding factor. This difference in potency is likely to outweigh the slightly lower solubility and potential permeability issues. The lower DILI risk of Ligand A is a positive, but the binding affinity difference is more critical for an enzyme target. The negative values for Caco-2 and half-life are concerning and would require experimental validation, but the potency advantage of B is too significant to ignore.

Output:
1
2025-04-17 13:21:13,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.392 Da) is slightly higher than Ligand B (343.431 Da), but both are acceptable.

**TPSA:** Ligand A (98.91) is slightly higher than Ligand B (71.33). Both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 1.153, B: 1.523), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (A: 0.493, B: 0.764), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Both ligands have similar DILI risk (A: 54.517, B: 55.758), and are within an acceptable range (<60).

**BBB:** Ligand A (52.074) has a lower BBB penetration percentile than Ligand B (71.811). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.798) has a lower Caco-2 permeability than Ligand B (-4.756). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.499) has slightly better solubility than Ligand B (-1.975). Both are still quite poor.

**hERG Inhibition:** Ligand A (0.835) has a slightly higher hERG inhibition risk than Ligand B (0.154). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (-3.483) has a much lower (better) microsomal clearance than Ligand B (56.088). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-20.623) has a much longer in vitro half-life than Ligand B (-13.8). This is a strong advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.077, B: 0.152).

**Binding Affinity:** Both ligands have similar binding affinities (A: -9.3 kcal/mol, B: -8.2 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a clear advantage in metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. While its solubility and Caco-2 permeability are poor, the improved metabolic profile is crucial for an enzyme target like SRC kinase. Ligand B has better QED, BBB, and hERG, but the significantly worse metabolic stability is a major drawback. The binding affinity difference is not large enough to overcome the metabolic concerns with Ligand B.

Output:
0
2025-04-17 13:21:13,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.391 and 361.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.32) is better than Ligand B (49.03) as it is still within the acceptable range for oral absorption, while Ligand B is excellent.

**logP:** Ligand A (-0.599) is a bit low, potentially hindering permeation. Ligand B (4.113) 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 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.636 and 0.589), indicating good drug-likeness.

**DILI:** Ligand A (47.15) has a moderate DILI risk, while Ligand B (15.859) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (85.266) has better BBB penetration than Ligand A (63.901), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.453) and Ligand B (-4.768) have negative values, which is unusual. Assuming these are log scale values, they indicate poor permeability.

**Aqueous Solubility:** Ligand A (-1.654) has poor solubility, while Ligand B (-4.702) is even worse. This is a concern for both.

**hERG Inhibition:** Ligand A (0.011) has very low hERG inhibition risk, which is excellent. Ligand B (0.861) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-7.281) has very low microsomal clearance, indicating high metabolic stability, a major advantage. Ligand B (100.77) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (13.622 hours) has a reasonable half-life. Ligand B (28.656 hours) has a longer half-life, which is beneficial.

**P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux, which is excellent. Ligand B (0.764) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.0 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) and P-gp efflux. Its hERG risk is also much lower. While its logP and solubility are less ideal, the superior metabolic stability and lower toxicity profile are crucial for an enzyme target like SRC. Ligand B's high logP and rapid metabolism are significant drawbacks.

Output:
0
2025-04-17 13:21:13,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 337.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (62.73), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.504) is within the optimal range, while Ligand B (4.32) is slightly higher. Higher logP can sometimes lead to off-target effects, but isn't a major concern here.

**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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.662 and 0.796, respectively), indicating drug-like properties.

**DILI:** Ligand A (24.467) has a significantly lower DILI risk than Ligand B (45.173). This is a substantial advantage.

**BBB:** Both have similar BBB penetration (64.25 and 66.925), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.974 and -5.101), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.094 and -4.054), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.523) has a slightly lower hERG risk than Ligand B (0.718), which is preferable.

**Microsomal Clearance:** Ligand A (53.337) has a higher microsomal clearance than Ligand B (43.981), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (41.842) has a significantly longer in vitro half-life than Ligand A (-5.768), which is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.096 and 0.154).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol) - a difference of 1.2 kcal/mol. This is a substantial advantage that can potentially outweigh some of the ADME drawbacks.

**Conclusion:**

While both compounds have significant ADME liabilities (poor solubility and permeability), Ligand B has a substantially better binding affinity (-9.1 vs -7.9 kcal/mol) and a longer half-life (41.842 vs -5.768). The improved potency and stability are crucial for an enzyme target like SRC kinase. The DILI score is higher for Ligand B, but the binding affinity advantage is significant enough to prioritize it, assuming further optimization could address the DILI risk.

Output:
1
2025-04-17 13:21:13,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (362.455 Da and 352.366 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.6) is better than Ligand B (108.73), both are under the 140 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Ligand A (0.81) is within the optimal range (1-3), while Ligand B (-0.227) is slightly below, potentially impacting permeability.

**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 (5) is preferable to Ligand B (4), as lower HBAs generally improve permeability.

**6. QED:** Both ligands have acceptable QED values (0.802 and 0.737, respectively), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (47.964 and 44.63, respectively), which is positive.

**8. BBB:** Both ligands have similar BBB penetration (62.699 and 64.637, respectively). BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.22 and -5.045), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.12 and -2.8), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.132) has a much lower hERG inhibition liability than Ligand B (0.345), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand A (-8.199) has significantly lower (better) microsomal clearance than Ligand B (-12.726), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.237) has a longer in vitro half-life than Ligand B (-4.496), which is desirable for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.012), suggesting better oral bioavailability.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). The difference of 1.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the superior candidate. While both ligands have poor Caco-2 and solubility values, Ligand A's significantly better binding affinity, lower hERG risk, improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux outweigh the shared permeability/solubility concerns. The stronger binding affinity is a critical advantage for an enzyme inhibitor.

Output:
1
2025-04-17 13:21:13,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.383 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.68) is slightly higher than Ligand B (78.87). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.471 and 1.363), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but both are 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 and <=10 HBA).

**QED:** Both ligands have similar QED values (0.77 and 0.681), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.295, which is approaching the higher risk threshold (>60). Ligand B has a significantly lower DILI risk (17.798), making it much more favorable.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A has a higher BBB penetration (74.564) than Ligand B (47.15). This is not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.462 and -4.755) which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4 and -1.621), which is also unusual and indicates very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.22 and 0.191), which is excellent.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (58.261) than Ligand B (27.779), indicating lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (-1.946) than Ligand A (-21.048), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.268 and 0.038).

**Binding Affinity:** Ligand A has a slightly better binding affinity (-7.6 kcal/mol) than Ligand B (-7.2 kcal/mol). This 0.4 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates significantly better ADMET properties, particularly a much lower DILI risk and improved metabolic stability (lower Cl_mic, longer t1/2). The poor solubility and permeability are concerns for both, but the safety profile and metabolic stability are more critical for an enzyme target like SRC. The affinity difference is not large enough to overcome the ADMET advantages of Ligand B.

Output:
1
2025-04-17 13:21:13,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.451 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.1) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (71.09) is well within the acceptable range.

**logP:** Ligand A (1.892) is within the optimal 1-3 range. Ligand B (3.142) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which are within the guidelines of <=5 and <=10 respectively.

**QED:** Ligand A (0.82) has a better QED score than Ligand B (0.697), indicating a more drug-like profile.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (40.52). Ligand B is preferable here.

**BBB:** Both are not CNS focused, so this is less important. Ligand A (61.497) and Ligand B (54.672) are comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.256 and -5.016). This is unusual and suggests poor permeability. However, the values are very close.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.521 and -3.193). This is also concerning, indicating poor solubility. Again, the values are very close.

**hERG:** Ligand A (0.321) has a slightly lower hERG risk than Ligand B (0.111), which is preferable.

**Microsomal Clearance:** Ligand A (8.676) has significantly lower microsomal clearance than Ligand B (52.846), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (27.357) has a longer in vitro half-life than Ligand B (13.732), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.11 and 0.25).

**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 better candidate. While it has a slightly higher DILI risk, its significantly stronger binding affinity (-8.8 vs -7.6 kcal/mol), lower microsomal clearance, and longer half-life are critical advantages for an enzyme inhibitor. The solubility and permeability concerns are shared by both, and the affinity difference is likely to be more impactful for *in vivo* efficacy.

Output:
1
2025-04-17 13:21:13,912 - INFO - Batch 206 complete. Total preferences: 3296
2025-04-17 13:21:13,913 - INFO - Processing batch 207/512...
2025-04-17 13:21:55,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.332 Da) is slightly higher than Ligand B (356.438 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (82.45) is slightly higher than Ligand B (70.08).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.848) is slightly higher than Ligand B (1.116).

**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 limit of 10.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand A (0.719) and Ligand B (0.823) are both strong.

**DILI:** Ligand A (55.797) has a higher DILI risk than Ligand B (30.826). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (49.864) and Ligand B (78.945) are both reasonable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, these values are on a scale where negative values can still indicate permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Lower values suggest poor solubility. Ligand A (-3.021) is worse than Ligand B (-0.905).

**hERG Inhibition:** Both ligands have low hERG inhibition liability, which is good. Ligand A (0.128) is slightly higher than Ligand B (0.39).

**Microsomal Clearance:** Ligand A (90.473) has a higher microsomal clearance than Ligand B (4.738), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (15.292 hours) has a significantly longer half-life than Ligand A (9.497 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability. Ligand A (0.082) is lower than Ligand B (0.051).

**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 can outweigh some ADME concerns.

**Conclusion:**

Ligand B is the more promising candidate. While both have some ADME liabilities (negative solubility and Caco-2 values), Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and, crucially, a substantially stronger binding affinity. The stronger binding affinity is a key advantage for an enzyme inhibitor and can compensate for minor ADME issues.

Output:
1
2025-04-17 13:21:55,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 354.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (57.69) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (84.94) is still under 140, but less favorable than A.

**logP:** Ligand A (2.385) is optimal (1-3). Ligand B (1.111) is slightly lower, potentially impacting permeability, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly less optimal.

**QED:** Both ligands have similar QED values (0.665 and 0.66), indicating good drug-likeness.

**DILI:** Ligand A (25.165) has a very low DILI risk, a significant advantage. Ligand B (19.659) is also low, but higher than A.

**BBB:** Ligand A (88.019) shows good BBB penetration, while Ligand B (62.117) is lower. While not a primary concern for a kinase inhibitor, it's a positive for A.

**Caco-2 Permeability:** Ligand A (-4.654) and B (-4.793) both have negative values, which is unusual. This suggests very poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.778 and -1.465). This is a major concern for both.

**hERG Inhibition:** Ligand A (0.199) has very low hERG risk, a major advantage. Ligand B (0.313) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (58.399) has a higher microsomal clearance than Ligand B (45.492), indicating lower metabolic stability. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (-7.969) has a negative half-life, which is not possible. This is a data error. Ligand A (13.325) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.092 and 0.041), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial difference. A >8 kcal/mol difference in binding is very substantial.

**Conclusion:**

Despite Ligand A's better TPSA, DILI, hERG, and BBB, the significantly stronger binding affinity of Ligand B (-8.1 vs 0.0 kcal/mol) outweighs the drawbacks of its slightly less favorable ADME properties. The negative half-life for Ligand B is a data error, and assuming it's a positive value, it would be a further advantage. The solubility is a concern for both, but can be addressed through formulation strategies. The improved potency of Ligand B is paramount for an enzyme inhibitor.

Output:
1
2025-04-17 13:21:55,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (349.479 Da) is a bit lower, potentially favoring permeability.

**TPSA:** Ligand A (64.35) is good for oral absorption. Ligand B (88.91) is also acceptable, but closer to the upper limit.

**logP:** Ligand A (3.941) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (1.442) is lower, which could hinder permeation, but is still within a reasonable range.

**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 limits (<=10).

**QED:** Both ligands have similar QED values (0.777 and 0.66), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (37.456 and 32.183), which is excellent.

**BBB:** Ligand A shows good BBB penetration (87.553), while Ligand B is lower (66.731). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both 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 (-5.028) is better than Ligand B (-5.314).

**Aqueous Solubility:** Both have negative solubility values, which is problematic. Ligand B (-1.305) is slightly better than Ligand A (-4.426).

**hERG Inhibition:** Both ligands have very low hERG risk (0.754 and 0.215), which is excellent.

**Microsomal Clearance:** Ligand A (13.412) has lower clearance than Ligand B (26.232), indicating better metabolic stability. This is a significant advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (25.973) has a longer half-life than Ligand B (5.525), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.291 and 0.043).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.9 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is the more promising candidate. While both have excellent binding affinity and low toxicity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better permeability (Caco-2). Although Ligand A's logP is higher, the benefits of improved metabolic stability outweigh this potential drawback. Solubility is a concern for both, but Ligand B is slightly better.

Output:
1
2025-04-17 13:21:55,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is better than Ligand B (102.74). Lower TPSA generally favors better absorption.

**logP:** Ligand A (2.483) is optimal, while Ligand B (0.627) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, below the 10 threshold.

**QED:** Both ligands have good QED scores (0.769 and 0.785), indicating drug-likeness.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (32.842). This is a significant advantage.

**BBB:** Both ligands have high BBB penetration (74.486 and 71.811), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation, but doesn't immediately disqualify either.

**Solubility:** Both have negative solubility values, which is also unusual. Again, further investigation is needed, but doesn't immediately disqualify either.

**hERG:** Ligand A (0.289) has a much lower hERG risk than Ligand B (0.16). This is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (25.362) has a better (lower) microsomal clearance than Ligand B (-43.109). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-2.449) has a slightly better (less negative) in vitro half-life than Ligand B (-2.376).

**P-gp Efflux:** Both have very low P-gp efflux liabilities (0.084 and 0.007).

**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 can be overcome by other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties, specifically lower DILI risk, lower hERG risk, and better metabolic stability (lower Cl_mic). These factors are prioritized for enzyme inhibitors. The slightly lower affinity of Ligand A can potentially be optimized in subsequent rounds of medicinal chemistry, while mitigating the ADMET liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 13:21:55,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.336 Da) is slightly higher than Ligand B (373.475 Da), but both are acceptable.

**TPSA:** Ligand A (55.56) is significantly better than Ligand B (96.97). Lower TPSA generally improves absorption, and Ligand A is well below the 140 threshold. Ligand B is approaching the upper limit, potentially hindering absorption.

**logP:** Ligand A (4.496) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (-0.764) is quite low, which could impede membrane permeability. An optimal range is 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=6). Both are within acceptable limits, but Ligand B has a higher number of HBA, which could affect permeability.

**QED:** Ligand A (0.746) is better than Ligand B (0.489). A higher QED indicates a more drug-like profile.

**DILI:** Ligand A (60.799) has a higher DILI risk than Ligand B (27.026). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.541) is better than Ligand B (44.668).

**Caco-2 Permeability:** Ligand A (-4.711) is much better than Ligand B (-5.587), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.89) is better than Ligand B (-2.053), indicating better solubility.

**hERG Inhibition:** Ligand A (0.923) is better than Ligand B (0.214), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (68.966) is higher than Ligand B (9.517), meaning Ligand A has lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (55.026) is better than Ligand B (-1.604), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.558) is better than Ligand B (0.011), meaning Ligand A is less likely to be pumped out by P-gp.

**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 significantly better binding affinity and favorable permeability/solubility parameters, but suffers from higher DILI risk and lower metabolic stability. Ligand B has a better safety profile (lower DILI, lower hERG) but weaker binding affinity and poorer permeability/solubility.

Given that SRC is an enzyme, potency (affinity) and metabolic stability are key. The 1.2 kcal/mol difference in binding affinity is substantial. While Ligand A's metabolic stability is a concern, it might be addressable through structural modifications. The DILI risk is also a concern, but could potentially be mitigated. Ligand B's affinity is simply too weak to be a promising starting point, even with its better safety profile.

Output:
1
2025-04-17 13:21:55,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.19) is better than Ligand B (116.76). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal for oral bioavailability.

**logP:** Ligand A (-1.585) is slightly lower than ideal (1-3), potentially impacting permeability. Ligand B (-0.545) is also on the lower side, but better than A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 5 HBA). Lower HBDs generally improve permeability.

**QED:** Both ligands have similar QED scores (0.471 and 0.443), indicating moderate drug-likeness.

**DILI:** Ligand A (14.773) has a significantly lower DILI risk than Ligand B (15.626), which is a strong advantage. Both are below the 40 threshold.

**BBB:** Ligand A (8.181) has very low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (39.162) has moderate penetration, but this isn't particularly relevant here.

**Caco-2:** Both ligands have negative Caco-2 values (-5.293 and -5.623), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have negative solubility values (-0.605 and -0.313), indicating poor aqueous solubility. This is a drawback for both, potentially impacting bioavailability.

**hERG:** Ligand A (0.083) has a much lower hERG risk than Ligand B (0.115), which is a critical advantage for safety.

**Microsomal Clearance:** Ligand A (-16.73) has a much lower (better) microsomal clearance than Ligand B (-11.834), indicating greater metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-3.497) has a negative half-life, which is also unusual and suggests rapid metabolism. Ligand B (13.081) has a much better in vitro half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.004).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-6.7 kcal/mol). This 0.9 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand A is superior despite the slightly lower affinity. Its significantly lower DILI risk, lower hERG risk, and much better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme target like SRC kinase. While both have poor solubility and Caco-2 permeability, the ADME/Tox profile of Ligand A is far more favorable. The improved half-life of Ligand B is offset by its higher risk profile.

Output:
0
2025-04-17 13:21:55,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (76.46) is slightly higher than Ligand B (70.67), but both are well within the acceptable range.

**logP:** Both ligands have logP values between 1 and 3 (A: 0.826, B: 1.411), which is optimal.

**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 QED values above 0.5 (A: 0.559, B: 0.606), indicating good drug-like properties.

**DILI:** Ligand A (44.242) has a higher DILI risk than Ligand B (11.865). This is a significant concern, as lower DILI is preferred.

**BBB:** Both ligands have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase. Ligand B (82.513) has a higher BBB value than Ligand A (63.901).

**Caco-2 Permeability:** Ligand A (-4.722) has a significantly *lower* Caco-2 permeability than Ligand B (-5.102). Both are negative, indicating poor permeability, but A is slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.886 and -1.617, respectively), indicating poor solubility. Solubility is a concern for both, but they are relatively close.

**hERG Inhibition:** Ligand A (0.257) has a lower hERG inhibition liability than Ligand B (0.667), which is favorable.

**Microsomal Clearance:** Ligand B (-5.501) has a *much* lower microsomal clearance than Ligand A (68.51). This suggests significantly better metabolic stability for Ligand B, a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand B (4.289) has a longer in vitro half-life than Ligand A (2.628), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.018), which is favorable.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference in affinity is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better hERG and P-gp profiles, Ligand B is the superior candidate due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2), substantially stronger binding affinity, and much lower DILI risk. The solubility and permeability are poor for both, but the potency and safety advantages of Ligand B are more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:21:55,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.463 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (67.35) is significantly better than Ligand A (112.12). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (2.757) is within the optimal range (1-3), while Ligand A (-1.226) is below 1, potentially hindering permeation. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar, good QED values (0.556 and 0.589).

**DILI:** Ligand B (43.738) has a slightly higher DILI risk than Ligand A (36.099), but both are still considered relatively low risk (<60).

**BBB:** Ligand B (85.537) has a much higher BBB penetration percentile than Ligand A (20.628). While SRC is not a CNS target, higher BBB can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-6.116) has a negative Caco-2 value, which is concerning, suggesting poor permeability. Ligand B (-4.932) is also negative, but less so.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.017 and -2.556). This is a significant drawback for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.049) shows very low hERG inhibition risk, a major advantage. Ligand B (0.548) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-14.61) has a much lower (better) microsomal clearance than Ligand B (61.893), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-7.069) has a negative half-life, which is unusual and likely indicates very rapid metabolism. Ligand B (19.136) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is favorable. Ligand B (0.121) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is relatively small (0.2 kcal/mol), and A already has excellent binding.

**Overall Assessment:**

Ligand A has a superior metabolic stability profile (lower Cl_mic, better half-life) and lower hERG risk, which are crucial for enzyme inhibitors. It also has lower P-gp efflux. However, its poor Caco-2 permeability and low logP are significant concerns. Ligand B has better TPSA and logP, but suffers from much higher metabolic clearance and a less favorable half-life. The slightly better binding affinity of Ligand B isn't enough to outweigh the ADME deficiencies.

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), **Ligand A** is the more promising candidate, despite its permeability concerns. Formulation strategies could potentially address the solubility/permeability issues.

Output:
0
2025-04-17 13:21:55,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is slightly higher than Ligand B (58.44). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands have acceptable logP values (1.004 and 1.797), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while 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 similar QED scores (0.791 and 0.758), indicating good drug-likeness.

**DILI:** Ligand A (10.12) has a significantly lower DILI risk than Ligand B (17.1). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, with Ligand B (77.007) being slightly higher than Ligand A (65.839). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands 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 negative solubility values, indicating poor solubility. Again, the values are close.

**hERG Inhibition:** Ligand A (0.24) has a lower hERG inhibition liability than Ligand B (0.32), which is preferable.

**Microsomal Clearance:** Ligand B (37.753) has a slightly higher microsomal clearance than Ligand A (31.604), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-13.417) has a much lower in vitro half-life than Ligand A (-4.958), indicating faster metabolism and potential dosing issues. This is a significant drawback for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.016 and 0.106).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.7 kcal/mol difference is substantial and outweighs most other concerns.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its superior binding affinity, lower DILI risk, lower hERG liability, and better in vitro half-life outweigh the slightly higher TPSA and lower BBB penetration compared to Ligand B. The strong binding affinity is particularly important for an enzyme inhibitor, and the improved safety profile (DILI, hERG) is crucial for clinical development.

Output:
1
2025-04-17 13:21:55,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.563 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Ligand A (42.43) is significantly better than Ligand B (83.98). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (4.633) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (2.545) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is better than Ligand B (2 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.47, Ligand B: 0.777), indicating drug-like properties. Ligand B is superior here.

**DILI:** Ligand A (52.889) has a slightly higher DILI risk than Ligand B (47.77), but both are reasonably low.

**BBB:** Both have acceptable BBB penetration, but Ligand A (69.988) is slightly better than Ligand B (67.352). This is less crucial for a kinase inhibitor than for a CNS-targeting drug.

**Caco-2 Permeability:** Ligand A (-4.935) is significantly better than Ligand B (-5.04), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.68) is better than Ligand B (-2.791), which is a significant advantage for bioavailability.

**hERG Inhibition:** Ligand A (0.736) has a lower hERG risk than Ligand B (0.282), which is a critical advantage.

**Microsomal Clearance:** Ligand A (151.37) has higher microsomal clearance than Ligand B (35.755), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (32.053) has a longer half-life than Ligand B (-5.068), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.73) has lower P-gp efflux than Ligand B (0.124), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a *much* stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a decisive factor, as a 2.9 kcal/mol difference is substantial.

**Conclusion:**

While Ligand A has some advantages in solubility, Caco-2 permeability, and P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity of Ligand B (-10.2 kcal/mol vs -7.3 kcal/mol) outweighs the drawbacks of its higher TPSA and slightly lower solubility. Furthermore, Ligand B exhibits much better metabolic stability (lower Cl_mic) which is a critical factor for kinase inhibitors. The lower hERG risk of Ligand A is a plus, but not enough to overcome the potency and metabolic stability advantages of Ligand B.

Output:
1
2025-04-17 13:21:55,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.463 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.32) is significantly better than Ligand B (65.36), being well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.66) is optimal, while Ligand B (3.331) is approaching the upper limit of the preferred range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is preferable to Ligand B (1 HBD, 5 HBA) as it has fewer HBDs, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.792) has a better QED score than Ligand B (0.661), indicating a more drug-like profile.

**DILI:** Ligand B (38.503) has a significantly lower DILI risk than Ligand A (62.35), which is a major advantage.

**BBB:** Ligand A (88.057) has better BBB penetration than Ligand B (75.107), but this is not a high priority for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.794 and -4.987), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.005 and -3.024), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.932 and 0.871), which is good.

**Microsomal Clearance:** Ligand B (83.361) has a significantly higher microsomal clearance than Ligand A (26.456), indicating poorer metabolic stability. This is a critical disadvantage for Ligand B.

**In vitro Half-Life:** Ligand B (110.608) has a much longer in vitro half-life than Ligand A (-1.182), which is a strong positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.337 and 0.316).

**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:**

Ligand A has better physicochemical properties (TPSA, logP, QED) and metabolic stability (lower Cl_mic). However, Ligand B has a significantly lower DILI risk and a much longer half-life. Both compounds suffer from very poor solubility and permeability. Given the importance of metabolic stability and DILI risk for kinase inhibitors, and the similar binding affinities, Ligand B is slightly more promising, despite its higher logP. The longer half-life could allow for less frequent dosing. The solubility and permeability issues would need to be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 13:21:55,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.387 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.35) is borderline, but acceptable for oral absorption. Ligand B (49.41) is excellent, well below the 140 threshold.

**logP:** Ligand A (0.444) is quite low, potentially hindering permeability. Ligand B (3.624) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable and potentially better for permeability.

**QED:** Both ligands have similar QED values (0.67 and 0.647), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 60.14, which is concerning (high risk). Ligand B has a much lower DILI risk of 15.936, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (85.033) than Ligand A (30.981), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.462) shows very poor permeability. Ligand B (-4.495) is better, but still relatively low.

**Aqueous Solubility:** Ligand A (-2.012) has poor solubility. Ligand B (-3.871) also has poor solubility, but is slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.127) has a slightly higher hERG risk than Ligand B (0.643), but both are relatively low.

**Microsomal Clearance:** Ligand A (27.63 mL/min/kg) has a lower clearance, indicating better metabolic stability than Ligand B (81.906 mL/min/kg).

**In vitro Half-Life:** Ligand A (-4.541 hours) has a shorter half-life than Ligand B (32.896 hours), which is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux, potentially leading to better bioavailability. Ligand B (0.295) has higher P-gp efflux.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both ligands have solubility issues, Ligand B's significantly better binding affinity (-7.2 vs -9.0 kcal/mol), lower DILI risk, and longer half-life are decisive advantages. The higher logP and lower P-gp efflux of Ligand B also contribute to its improved profile. Ligand A's low logP and poor permeability are major drawbacks.



Output:
1
2025-04-17 13:21:55,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 346.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (115.55) is still within acceptable limits, but higher than A.

**logP:** Ligand A (4.641) is slightly high, potentially leading to solubility issues or off-target effects, but not drastically so. Ligand B (0.071) is very low, which could hinder membrane permeability and thus bioavailability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 6. The higher HBA count in B could impact permeability.

**QED:** Both ligands have reasonable QED scores (0.839 and 0.722), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (49.283 and 52.191), below the concerning threshold of 60.

**BBB:** Ligand A (79.682) shows moderate BBB penetration, while Ligand B (19.465) is very low. This isn't a primary concern for a non-CNS target like SRC, but it's a point in A's favor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.554 and -4.951), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.877 and -1.501), indicating poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.573) has a slightly higher hERG risk than Ligand B (0.245), but both are relatively low.

**Microsomal Clearance:** Ligand A (58.919) has a moderate clearance, while Ligand B (-28.634) has a *negative* clearance. Negative clearance is not physically possible and suggests an error in the data or a very unusual metabolic profile. However, it effectively means very high metabolic stability.

**In vitro Half-Life:** Ligand A (31.323) has a reasonable half-life. Ligand B (26.904) is also acceptable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.487 and 0.02).

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite both compounds having issues with solubility and permeability, Ligand B's *much* stronger binding affinity (-9.5 vs -7.3 kcal/mol) is a decisive factor. The negative microsomal clearance is also a very positive sign, although it warrants further investigation. While the low logP and high TPSA are concerns, the potency advantage is likely to outweigh these drawbacks, especially for an enzyme target where high affinity is paramount. Ligand A's slightly better solubility and lower hERG risk are not enough to compensate for the weaker binding.

Output:
1
2025-04-17 13:21:55,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (70.47) is better than Ligand B (84.67) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (A: 0.625, B: 1.329), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Both have 1 HBD and are within the acceptable limits. Ligand B has 6 HBA, while Ligand A has 5. Both are acceptable.

**QED:** Both ligands have good QED scores (A: 0.85, B: 0.817), indicating good drug-like properties.

**DILI:** Ligand A (24.273) has a significantly lower DILI risk than Ligand B (52.772). This is a major advantage for Ligand A.

**BBB:** Both have moderate BBB penetration (A: 67.817, B: 61.38). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-5.047) is slightly better than Ligand B (-4.989), but both are problematic.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-1.385) is slightly better than Ligand B (-3.241), but both are concerning.

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.436, B: 0.385), which is good.

**Microsomal Clearance:** Ligand A (5.764) has significantly lower microsomal clearance than Ligand B (43.372), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (39.763) has a much longer in vitro half-life than Ligand B (11.577), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.008, B: 0.127), which is good.

**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 for Ligand B. The difference is >1.5 kcal/mol, and therefore, is a significant factor.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, metabolic stability (Cl_mic and t1/2), and slightly better solubility and permeability, the substantially stronger binding affinity of Ligand B (-7.4 vs -9.4 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. The improved binding affinity of Ligand B is likely to outweigh the ADME drawbacks, especially if formulation strategies can be employed to address the solubility and permeability issues.

Output:
1
2025-04-17 13:21:55,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (363.405 and 370.559 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.74) is higher than Ligand B (58.64). While both are reasonably low, Ligand B is better positioned for oral absorption due to its lower TPSA.

**3. logP:** Ligand A (0.272) is quite low, potentially hindering permeability. Ligand B (2.686) 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 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.512 and 0.678), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (33.424 and 31.291), both below the 40 threshold.

**8. BBB:** Both have moderate BBB penetration (60.295 and 68.205). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.846) has very poor Caco-2 permeability, while Ligand B (-5.007) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-0.75) has poor solubility, while Ligand B (-3.169) is even worse. This is a significant drawback for both, but more so for Ligand B.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.245 and 0.458), which is excellent.

**12. Microsomal Clearance:** Ligand A (9.172) has a lower (better) microsomal clearance than Ligand B (48.851), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.856) has a very long in vitro half-life, while Ligand B (3.295) is short. This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.012 and 0.286).

**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 B has a better logP and TPSA, which are important for permeability. However, it has significantly worse solubility and metabolic stability (higher Cl_mic, shorter half-life) compared to Ligand A. The very poor solubility of Ligand B is a major concern. While Ligand A has a low logP and poor Caco-2 permeability, its excellent metabolic stability and long half-life are highly desirable for an enzyme inhibitor. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 13:21:55,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.435 Da) is slightly lower, which could be advantageous for permeability, while Ligand B (375.481 Da) is still well within the acceptable range.

**TPSA:** Ligand A (49.94) is better than Ligand B (57.61). Both are below the 140 A^2 threshold for good oral absorption, but lower TPSA generally favors better cell permeability.

**logP:** Both ligands have logP values around 4 (A: 4.786, B: 4.038), which is approaching the upper limit of the optimal range. This could potentially lead to solubility issues, but is not a major concern at this stage.

**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 (A: 0.654, B: 0.663), indicating good drug-likeness.

**DILI:** Ligand B (26.328) has a significantly lower DILI risk than Ligand A (54.556). This is a major advantage for Ligand B.

**BBB:** Ligand B (80.031) has a higher BBB penetration percentile than Ligand A (57.852). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.926 and -4.54). This is unusual and suggests poor permeability. However, these values might be experimental artifacts or indicate a specific transport mechanism.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.984 and -3.296). This is also concerning and suggests poor aqueous solubility, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.935) has a slightly higher hERG inhibition risk than Ligand B (0.726), but both are relatively low.

**Microsomal Clearance:** Ligand B (77.76) has a higher microsomal clearance than Ligand A (47.052), meaning Ligand A is more metabolically stable. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-20.458) has a negative half-life, which is not physically possible and likely an experimental error. Ligand B (4.655) has a short half-life, but is at least a plausible value.

**P-gp Efflux:** Ligand A (0.81) has slightly lower P-gp efflux liability than Ligand B (0.506).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a crucial factor, as a 1.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the concerning negative values for Caco-2 and Solubility, the significantly stronger binding affinity of Ligand B (-7.7 kcal/mol vs -9.6 kcal/mol) and its much lower DILI risk (26.328 vs 54.556) make it the more promising candidate. The higher BBB penetration is also a plus. The negative half-life for Ligand A is a red flag and suggests experimental issues. While Ligand A has better metabolic stability, the potency and safety profile of Ligand B are more favorable for further development as an SRC kinase inhibitor.

Output:
1
2025-04-17 13:21:55,815 - INFO - Batch 207 complete. Total preferences: 3312
2025-04-17 13:21:55,815 - INFO - Processing batch 208/512...
2025-04-17 13:22:35,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 368.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.66) is better than Ligand B (102.24), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.898) is optimal (1-3), while Ligand B (-0.351) is slightly below 1, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable, while Ligand B (8) is approaching the upper limit of 10.

**QED:** Both ligands have good QED scores (0.59 and 0.626), indicating drug-likeness.

**DILI:** Ligand B (58.627) has a higher DILI risk than Ligand A (15.51). This is a significant concern.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (66.537) is slightly better than Ligand A (57.968).

**Caco-2:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.107) is slightly better than Ligand B (-5.56).

**Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.379) is slightly better than Ligand B (-1.832).

**hERG:** Both have very low hERG inhibition risk (0.301 and 0.053).

**Microsomal Clearance:** Ligand A (10.294) has significantly lower microsomal clearance than Ligand B (19.412), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.658) has a positive half-life, while Ligand B (-19.278) has a negative half-life, indicating very poor stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.052 and 0.016).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), but the difference is not substantial (only 0.3 kcal/mol).

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, positive t1/2), a much lower DILI risk, and slightly better solubility and Caco-2 permeability. The logP value for Ligand A is also more optimal. The small difference in binding affinity is outweighed by the substantial ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 13:22:35,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.435 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is better than Ligand B (58.64), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.935 and 2.837), falling 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 have 3 H-bond acceptors, well within the acceptable limit.

**QED:** Both ligands have high QED scores (0.848 and 0.8), indicating good drug-likeness.

**DILI:** Ligand A (37.767) has a significantly lower DILI risk than Ligand B (26.095). This is a substantial advantage.

**BBB:** Both ligands have high BBB penetration (85.459 and 80.884), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.617) is worse than Ligand B (-4.442), suggesting lower intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-3.394) is worse than Ligand B (-2.482), indicating lower solubility for Ligand A.

**hERG Inhibition:** Ligand A (0.888) has a slightly higher hERG risk than Ligand B (0.339), but both are relatively low.

**Microsomal Clearance:** Ligand A (10.772) has significantly lower microsomal clearance than Ligand B (54.549), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (42.827) has a much longer half-life than Ligand B (-9.482), which is a major advantage.

**P-gp Efflux:** Ligand A (0.371) has lower P-gp efflux than Ligand B (0.088), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.6 and -7.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability and solubility, Ligand A's significantly lower DILI risk, lower microsomal clearance, longer half-life, and lower P-gp efflux outweigh these minor drawbacks. The binding affinity is also slightly better for Ligand A. For an enzyme target like SRC kinase, metabolic stability (Cl_mic and t1/2) and minimizing toxicity (DILI, hERG) are paramount.

Output:
1
2025-04-17 13:22:35,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.478 Da and 348.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (26.3) is excellent, well below 140.

**logP:** Ligand A (3.034) is within the optimal 1-3 range. Ligand B (4.862) is a bit high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 2 HBA, which are well within acceptable limits.

**QED:** Both ligands have good QED scores (0.631 and 0.74), indicating good drug-like properties.

**DILI:** Ligand A (18.108) has a significantly lower DILI risk than Ligand B (38.852), which is a substantial advantage.

**BBB:** Both have high BBB penetration, but Ligand A (94.416) is slightly better than Ligand B (87.127). While not a primary concern for a kinase inhibitor, it's a minor positive for 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 have negative solubility values, which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG:** Both ligands have low hERG risk (0.783 and 0.869), which is excellent.

**Microsomal Clearance:** Ligand A (52.073) has a lower Cl_mic than Ligand B (67.336), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (26.106) has a significantly longer half-life than Ligand A (1.491), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.369 and 0.515).

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, and a longer half-life. However, it has a higher logP, higher DILI risk, and lower metabolic stability. Ligand A has better metabolic stability, lower DILI risk, and slightly better BBB penetration. The poor Caco-2 and solubility for both are concerning, but the affinity difference is significant. For an enzyme target like SRC kinase, potency is paramount. The improved affinity of Ligand B is likely to be more impactful than the slightly worse ADME properties, *assuming* solubility and permeability can be addressed through formulation or further optimization.

Output:
1
2025-04-17 13:22:35,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.427 and 345.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (65.9 and 67.15) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.772) is optimal, while Ligand B (3.591) is approaching the upper limit, potentially causing solubility issues.

**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 good QED scores (0.917 and 0.856), indicating drug-likeness.

**7. DILI:** Ligand A (39.473) has a slightly higher DILI risk than Ligand B (23.769), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (48.468) and Ligand B (38.542) are both relatively low.

**9. Caco-2 Permeability:** Ligand A (-4.575) and Ligand B (-5.327) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-1.227) and Ligand B (-2.721) both have negative values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.83) has a higher hERG risk than Ligand B (0.118). This is a significant advantage for Ligand B.

**12. Microsomal Clearance:** Ligand A (19.407) has a higher microsomal clearance than Ligand B (-18.601). Negative clearance is excellent and indicates high metabolic stability, making Ligand B more favorable.

**13. In vitro Half-Life:** Ligand A (34.928) has a longer half-life than Ligand B (15.879). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.26) has lower P-gp efflux than Ligand B (0.057), which is slightly better.

**15. Binding Affinity:** Ligand B (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B, and can outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor Caco-2 permeability and solubility, Ligand B's significantly stronger binding affinity (-10.3 vs 0.0 kcal/mol) and superior metabolic stability (negative Cl_mic) are crucial for an enzyme inhibitor. Its lower hERG risk is also a significant benefit. The longer half-life of Ligand A is a positive, but the substantial difference in binding affinity and metabolic stability makes Ligand B the more promising candidate.

Output:
1
2025-04-17 13:22:35,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.32) is slightly higher than Ligand B (78.51). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.16 and 1.006), 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.699 and 0.711), indicating good drug-like properties.

**DILI:** Ligand A (38.077) has a slightly higher DILI risk than Ligand B (31.02), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.233) has a higher BBB percentile than Ligand A (50.097).

**Caco-2 Permeability:** Both ligands 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 negative solubility values, indicating poor solubility. Ligand B (-3.371) is slightly better than Ligand A (-2.587), but both are problematic.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.318 and 0.182), which is excellent.

**Microsomal Clearance:** Ligand A (17.573) has significantly lower microsomal clearance than Ligand B (31.064), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-6.826) has a more negative (longer) in vitro half-life than Ligand B (6.156), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.016), which is favorable.

**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 could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly lower DILI risk, Ligand B possesses a significantly stronger binding affinity (-7.9 vs -7.2 kcal/mol). Given that SRC is an enzyme, binding affinity is the highest priority. The difference in affinity is large enough to compensate for the slightly poorer metabolic stability and solubility of Ligand B.

Output:
1
2025-04-17 13:22:35,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.4 and 350.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.98) is better than Ligand B (104.65), both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.33) is optimal, while Ligand B (0.606) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both 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 (0.615 and 0.724, respectively), indicating good drug-like properties.

**DILI:** Ligand A (59.64%) has a higher DILI risk than Ligand B (30.59%), which is a significant concern.

**BBB:** Both have reasonable BBB penetration, but Ligand A (73.52%) is better than Ligand B (65.37%). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.45) is slightly better than Ligand B (-4.901).

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.39) is slightly better than Ligand B (-1.38).

**hERG Inhibition:** Ligand A (0.79) has a slightly higher hERG risk than Ligand B (0.23), but both are relatively low.

**Microsomal Clearance:** Ligand B (30.92) has significantly lower microsomal clearance than Ligand A (59.37), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-22.79) has a much longer in vitro half-life than Ligand A (4.69), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.316 and 0.006, respectively).

**Binding Affinity:** Ligand A (-9.6 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 Assessment:**

Ligand A boasts a significantly better binding affinity, which is paramount for an enzyme inhibitor. However, its higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2) are major concerns. Ligand B, while having a weaker binding affinity, exhibits much better metabolic stability, lower DILI risk, and acceptable permeability and solubility. Given the importance of metabolic stability and safety (DILI) for kinase inhibitors, and the substantial affinity difference being 2.1 kcal/mol, I believe the superior binding affinity of Ligand A outweighs its drawbacks.

Output:
1
2025-04-17 13:22:35,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight:** Both ligands (349.431 and 351.466 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.51) is slightly higher than Ligand B (81.99), but both are below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.963 and 2.713), falling 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 (5) is preferable to Ligand B (3) as lower HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED scores (0.736 and 0.705), indicating good drug-likeness.

**7. DILI:** Ligand B (24.544) has a significantly lower DILI risk than Ligand A (39.899), making it more favorable from a toxicity perspective.

**8. BBB:** Both ligands have good BBB penetration (71.888 and 81.892), but Ligand B is slightly better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.563 and -4.683). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.231 and -3.844). This is also unusual and suggests poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.076) has a lower hERG inhibition liability than Ligand B (0.738), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (39.953) has a lower microsomal clearance than Ligand B (53.114), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.744) has a longer in vitro half-life than Ligand B (2.126), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.113).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly stronger binding affinity than Ligand B (-7.5). This 0.3 kcal/mol difference is potentially significant.

**Enzyme-Kinase Specific Considerations:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a better affinity, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. While Ligand B has a lower DILI risk, the other factors weigh more heavily in favor of Ligand A. The solubility and permeability issues are shared by both and would need to be addressed during optimization.

Output:
0
2025-04-17 13:22:35,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.44 and 76.15) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.458 and 1.452), falling within the 1-3 range. Ligand B is slightly better here, being closer to 1.

**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 (0.859) has a significantly better QED score than Ligand B (0.51), indicating a more drug-like profile.

**DILI:** Ligand A (23.885) has a lower DILI risk than Ligand B (32.067), both being good (<40).

**BBB:** Both ligands have similar BBB penetration (68.166 and 67.584), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.842 and -4.346), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.534 and -0.918), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.367) has a lower hERG inhibition liability than Ligand B (0.525), which is preferable.

**Microsomal Clearance:** Ligand A (41.638) has a lower microsomal clearance than Ligand B (57.81), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.043) has a longer in vitro half-life than Ligand B (-5.463), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux liability than Ligand B (0.094).

**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 demonstrates a significantly better overall profile, despite the poor Caco-2 and solubility. Its superior QED, lower DILI, lower hERG, lower Cl_mic, longer t1/2, and lower P-gp efflux contribute to a more favorable drug-like profile. While Ligand B has slightly better binding affinity, the other ADME properties of Ligand A are more promising. The poor solubility and permeability of both compounds are significant issues that would need to be addressed through formulation or structural modifications, but Ligand A's other properties make it a better starting point for optimization.

Output:
0
2025-04-17 13:22:35,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (343.427 and 368.374 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.43) is well below the 140 threshold for oral absorption, and is favorable. Ligand B (99.15) is also below 140, but closer to the limit.

**3. logP:** Ligand A (1.885) is within the optimal 1-3 range. Ligand B (0.324) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern at this stage.

**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 5. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-like properties. Ligand A (0.885) is slightly better than Ligand B (0.723).

**7. DILI:** Ligand A (54.556) has a slightly higher DILI risk than Ligand B (42.846), but both are below the concerning threshold of 60.

**8. BBB:** BBB is not a primary concern for an oncology target unless CNS penetration is specifically desired. Ligand B (77.937) has a higher BBB value than Ligand A (64.87), but this is not a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-4.617) has a worse Caco-2 permeability than Ligand B (-5.095). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.172) has better aqueous solubility than Ligand B (-2.351). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.568) has a slightly higher hERG inhibition risk than Ligand B (0.244). Lower values are preferred.

**12. Microsomal Clearance:** Ligand B (-6.951) has significantly lower (better) microsomal clearance than Ligand A (36.802), indicating greater metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (2.442) has a lower in vitro half-life than Ligand A (6.525). A longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.147) has lower P-gp efflux than Ligand B (0.014), which is favorable.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a crucial advantage for an enzyme inhibitor. The difference of 0.9 kcal/mol is substantial.

**Conclusion:**

While Ligand A has slightly better solubility and P-gp efflux, Ligand B excels in the most critical areas for a kinase inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2) and a substantially stronger binding affinity. The slightly lower logP of Ligand B is a minor concern that could be addressed with further optimization, but the potency and metabolic stability advantages outweigh this drawback.

Output:
1
2025-04-17 13:22:35,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.362 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.11) is higher than Ligand B (58.64). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cellular permeability.

**3. logP:** Both ligands (2.479 and 2.657) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is 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 acceptable (<=10).

**6. QED:** Ligand B (0.803) has a significantly better QED score than Ligand A (0.456), indicating a more drug-like profile.

**7. DILI:** Ligand A (75.572) has a higher DILI risk than Ligand B (15.859). Ligand B is well below the 40% threshold, while Ligand A is concerningly high.

**8. BBB:** Ligand B (78.441) has a higher BBB penetration percentile than Ligand A (43.311). While SRC isn't a CNS target, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Ligand A (-5.387) is worse than Ligand B (-4.742), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.844) is worse than Ligand B (-2.453), indicating lower solubility.

**11. hERG Inhibition:** Both ligands (0.421 and 0.436) have similar, low hERG inhibition liability, which is good.

**12. Microsomal Clearance:** Ligand A (60.377) has a lower microsomal clearance than Ligand B (63.027), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-44.03) has a much longer in vitro half-life than Ligand B (-2.273), which is a significant advantage.

**14. P-gp Efflux:** Both ligands (0.145 and 0.106) have similar, low P-gp efflux liability.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.8 kcal/mol), which are excellent. The difference is negligible.

**Overall Assessment:**

Ligand B is superior due to its significantly better DILI risk, QED, TPSA, solubility, and Caco-2 permeability. While Ligand A has a longer half-life and slightly better metabolic stability, the lower DILI risk of Ligand B is a critical advantage for an oncology drug. The similar binding affinities mean that the ADME improvements of Ligand B outweigh the slight pharmacokinetic benefit of Ligand A.

Output:
1
2025-04-17 13:22:35,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.491 and 342.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (36.44 and 33.29) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.539) is optimal, while Ligand B (4.308) is slightly higher, potentially leading to solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.775 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (27.104). This is a significant concern.

**BBB:** Both ligands have good BBB penetration (85.847 and 78.48), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.92 and -4.758), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-3.044 and -3.484), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Ligand A (0.793) has a slightly higher hERG risk than Ligand B (0.979), but both are relatively low.

**Microsomal Clearance:** Ligand A (59.762) has higher microsomal clearance than Ligand B (52.126), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (16.665) has a significantly longer in vitro half-life than Ligand A (-8.355). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.603 and 0.773).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive factor.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand B is significantly more promising. Its much stronger binding affinity (-7.7 vs 0.0 kcal/mol) outweighs the slightly higher logP and DILI risk. The significantly improved in vitro half-life of Ligand B is also a crucial advantage for a kinase inhibitor. Ligand A's very weak binding affinity makes it unlikely to be a viable candidate, even if its DILI risk were lower.

Output:
1
2025-04-17 13:22:35,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.39 and 347.507 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is slightly higher than Ligand B (64.86). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better positioned.

**3. logP:** Ligand A (1.797) is within the optimal 1-3 range. Ligand B (3.063) 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 (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.703 and 0.857, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (49.399) has a slightly higher DILI risk than Ligand B (37.301), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (85.033) is better than Ligand A (77.2). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**9. Caco-2 Permeability:** Ligand A (-4.408) has poor Caco-2 permeability, while Ligand B (-5.309) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.634 and -3.239 respectively). This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.108) has a very low hERG risk, which is excellent. Ligand B (0.356) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (33.582) has higher microsomal clearance than Ligand B (27.217), indicating lower metabolic stability. This is a significant drawback.

**13. In vitro Half-Life:** Ligand B (10.223) has a significantly longer in vitro half-life than Ligand A (5.109), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.026) has very low P-gp efflux, while Ligand B (0.209) is slightly higher. Both are acceptable.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.1 kcal/mol). This 1.3 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite similar molecular weights and acceptable QED scores, Ligand B is the superior candidate. The significantly stronger binding affinity (-7.4 vs -6.1 kcal/mol) and longer half-life (10.223 vs 5.109 hours) are crucial for an enzyme inhibitor. While both have poor solubility and permeability, these can be addressed during formulation. Ligand B also exhibits lower DILI risk and better metabolic stability.

Output:
1
2025-04-17 13:22:35,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (352.475 Da and 349.406 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is well below the 140 threshold for good oral absorption, and even better for kinase inhibitors. Ligand B (104.45) is still within acceptable limits, but less favorable than A.

**3. logP:** Both ligands have logP values within the optimal range (1.581 and 2.105).

**4. H-Bond Donors:** Ligand A (1) is excellent. Ligand B (4) is at the higher end of the acceptable range, potentially impacting permeability.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is good.

**6. QED:** Ligand A (0.788) has a significantly better QED score than Ligand B (0.25), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (42.264). This is a significant advantage.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (72.121) is higher than Ligand B (39.046), but this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.648) is better than Ligand B (-5.394), indicating potentially better absorption.

**10. Aqueous Solubility:** Ligand A (-1.708) is better than Ligand B (-2.815), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.21) has a lower hERG risk than Ligand B (0.639), reducing cardiotoxicity concerns.

**12. Microsomal Clearance:** Ligand A (53.538) has a higher (worse) microsomal clearance than Ligand B (19.236), suggesting lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (-31.095) has a significantly longer in vitro half-life than Ligand A (19.469). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.03) has a lower P-gp efflux liability than Ligand B (0.051), implying better bioavailability.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). The difference is 1.1 kcal/mol, which is substantial enough to consider.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, HBD, QED, DILI, solubility, hERG, P-gp). However, Ligand B has a significantly better half-life and a slightly better binding affinity. The metabolic stability (half-life) and potency (binding affinity) are particularly important for enzyme inhibitors. While Ligand A has a better overall ADME profile, the improved potency and metabolic stability of Ligand B outweigh the minor ADME drawbacks.

Output:
1
2025-04-17 13:22:35,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.417 Da and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is slightly higher than Ligand B (71.53), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (1.22 and 1.087, respectively), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 4 HBA, well below the 10 limit.

**QED:** Both ligands have good QED scores (0.635 and 0.786, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (32.803 and 35.634 percentiles), which is favorable.

**BBB:** Ligand A has a higher BBB penetration percentile (82.009) than Ligand B (54.091). While not a primary concern for a non-CNS target like SRC, it's a slight advantage for A.

**Caco-2 Permeability:** Ligand A (-4.904) has slightly better Caco-2 permeability than Ligand B (-4.488), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.658) has slightly better aqueous solubility than Ligand B (-2.629). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.347 and 0.178, respectively), which is excellent.

**Microsomal Clearance:** Ligand B has a negative Cl_mic value (-6.375), indicating *lower* clearance and thus *greater* metabolic stability than Ligand A (8.374). This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B has a slightly better in vitro half-life (-0.05 hours) than Ligand A (-6.051 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.017, respectively).

**Binding Affinity:** Both ligands have identical binding affinities (-8.2 kcal/mol), which is excellent and the most important factor.

**Conclusion:**

While Ligand A has slightly better solubility and Caco-2 permeability, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic and better half-life). Given the enzyme-specific priorities, metabolic stability is crucial. The identical binding affinities make this the deciding factor. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 13:22:35,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.53 and 361.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (75.43).  A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.05 and 1.95), 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 acceptable (<=10), but A is slightly better.

**QED:** Both ligands have good QED scores (0.78 and 0.85), indicating good drug-like properties.

**DILI:** Ligand A (35.09) has a lower DILI risk than Ligand B (41.22), both are acceptable (<40 is good, <60 is acceptable).

**BBB:** Ligand A (71.89) has better BBB penetration than Ligand B (63.09). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.95 and -4.78), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.596 and -2.796), which is also concerning, indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.456) has a lower hERG risk than Ligand B (0.307), which is preferable.

**Microsomal Clearance:** Ligand A (41.70) has a higher microsomal clearance than Ligand B (22.27), meaning it is less metabolically stable. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (4.20) has a longer in vitro half-life than Ligand A (14.53). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.193 and 0.276), which is good.

**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 concerns. The difference of 1.3 kcal/mol is significant.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and permeability, Ligand B's significantly stronger binding affinity (-9.1 vs -7.8 kcal/mol) and longer half-life are crucial advantages for an enzyme inhibitor. The lower microsomal clearance of Ligand B also contributes to its better metabolic stability. Although Ligand A has a slightly better DILI and hERG profile, the potency and stability advantages of Ligand B are more important in the context of SRC kinase inhibition.

Output:
1
2025-04-17 13:22:35,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.434 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (54.34) is better than Ligand B (62.3), both are acceptable but A is preferred.

**logP:** Both ligands have acceptable logP values (A: 1.811, B: 2.71), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are within the desired limits.

**QED:** Both ligands have good QED scores (A: 0.883, B: 0.833), indicating good drug-likeness.

**DILI:** Ligand A (15.083) has a significantly lower DILI risk than Ligand B (42.071). This is a major advantage for Ligand A.

**BBB:** Both have high BBB penetration, but Ligand A (94.455) is better than Ligand B (83.831). While not a primary concern for a kinase inhibitor, it's a slight positive for A.

**Caco-2 Permeability:** Ligand A (-4.866) is better than Ligand B (-4.542), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.44) is better than Ligand B (-3.051), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.4, B: 0.477), which is excellent.

**Microsomal Clearance:** Ligand A (9.112) shows significantly lower microsomal clearance than Ligand B (55.853), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-6.835) has a much longer in vitro half-life than Ligand B (-19.934), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.079, B: 0.12).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -9.4, B: -9.1). The difference is less than 1.5 kcal/mol, so it doesn't outweigh the ADME differences.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have good potency and drug-like properties, Ligand A demonstrates significantly better ADME characteristics, specifically lower DILI risk, lower microsomal clearance, and a longer half-life. These factors are critical for kinase inhibitors, making Ligand A the more viable drug candidate.

Output:
1
2025-04-17 13:22:35,488 - INFO - Batch 208 complete. Total preferences: 3328
2025-04-17 13:22:35,488 - INFO - Processing batch 209/512...
2025-04-17 13:23:15,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.328 and 354.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.65 and 2.762), 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 2 HBA. Both are within the recommended limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.692 and 0.825), indicating good drug-like properties.

**DILI:** Ligand A (51.609) has a higher DILI risk than Ligand B (11.283). This is a significant drawback for Ligand A.

**BBB:** Ligand B (87.01) shows better BBB penetration than Ligand A (74.06), but BBB is not a high priority for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-5.004) has worse Caco-2 permeability than Ligand B (-4.765).

**Aqueous Solubility:** Ligand A (-2.884) has worse aqueous solubility than Ligand B (-3.421). Solubility is important for bioavailability, making Ligand B preferable.

**hERG Inhibition:** Ligand A (0.842) has a slightly higher hERG risk than Ligand B (0.569), but both are reasonably low.

**Microsomal Clearance:** Ligand A (-2.339) has significantly better microsomal clearance (more negative value, indicating lower clearance) than Ligand B (29.335). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (21.382) has a longer in vitro half-life than Ligand B (-6.27). This is a positive attribute for Ligand A.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.109), which is slightly favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk and slightly lower solubility, its substantially stronger binding affinity (-8.7 vs -6.6 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The potency advantage is significant, and while DILI is a concern, it's not prohibitive at 51.6%. The better metabolic stability will likely translate to improved *in vivo* exposure.

Output:
1
2025-04-17 13:23:15,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.455 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (86.88).  A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (3.38 and 2.423, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is slightly better than Ligand B (HBD=3, HBA=3) regarding the number of hydrogen bond donors, being closer to the ideal of <=5. Both are within the HBA limit of <=10.

**QED:** Ligand A (0.805) has a substantially higher QED score than Ligand B (0.675), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (34.703 and 35.673 percentile), suggesting minimal liver injury potential.

**BBB:** Ligand A (92.594) has a much higher BBB penetration percentile than Ligand B (71.733). While not a primary concern for a non-CNS target like SRC, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Ligand A (-4.373) has a better Caco-2 permeability than Ligand B (-4.969), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.861 and -4.098). This is a significant concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.687) has a lower hERG inhibition risk than Ligand B (0.392), which is preferable.

**Microsomal Clearance:** Ligand B (56.755) has a significantly lower microsomal clearance than Ligand A (89.152), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-10.702) has a longer in vitro half-life than Ligand A (-13.806), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand B (0.162) has a lower P-gp efflux liability than Ligand A (0.357), which is a positive attribute.

**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:**

The critical factor is the binding affinity. Ligand A's -9.3 kcal/mol is dramatically better than Ligand B's 0.0 kcal/mol. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, the potency difference is so large that it outweighs these advantages. The solubility is poor for both, but can be addressed through formulation. The hERG risk is acceptable for Ligand A.

Output:
0
2025-04-17 13:23:15,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 359.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (49.77) as it is closer to the 140 threshold.

**logP:** Both ligands have logP values (2.878 and 3.76) within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target effects, but not drastically.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4, both within the acceptable limit of <=10.

**QED:** Ligand A (0.801) has a better QED score than Ligand B (0.694), indicating a more drug-like profile.

**DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (44.436), which is a major advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** Both ligands have good BBB penetration (81.388 and 73.129). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.756 and -4.697). This is unusual and suggests poor permeability. However, these values are very close, so it's not a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.721 and -4.348), indicating poor solubility. This is a concern, but again, the values are similar.

**hERG Inhibition:** Ligand A (0.411) has a much lower hERG inhibition liability than Ligand B (0.794), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (56.72) has a lower microsomal clearance than Ligand B (107.153), indicating better metabolic stability. This is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-4.205) has a longer in vitro half-life than Ligand B (67.744). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.29) has lower P-gp efflux liability than Ligand B (0.832), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.2 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh the other significant advantages of Ligand A.

**Conclusion:**

Ligand A is the superior candidate. It demonstrates a better drug-like profile (higher QED), significantly lower DILI risk, lower hERG inhibition, 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 make it more likely to succeed as a drug candidate.

Output:
0
2025-04-17 13:23:15,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.395 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.52) is better than Ligand B (76.46), both are within acceptable limits for oral absorption (<140).

**logP:** Ligand A (-0.641) is slightly low, potentially hindering permeation. Ligand B (0.507) is better, falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (8) is good. Ligand B (5) is also good.

**QED:** Ligand B (0.838) is significantly better than Ligand A (0.474), indicating a more drug-like profile.

**DILI:** Ligand B (42.536) has a lower DILI risk than Ligand A (55.797), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 76.696, Ligand B: 87.631), but Ligand B is better. This is less critical for a non-CNS target like SRC, but still a positive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.822 and -4.915), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.685 and -1.228), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.016) has a slightly lower hERG risk than Ligand B (0.143), which is preferable. Both are very low risk.

**Microsomal Clearance:** Ligand B (5.736) has significantly lower microsomal clearance than Ligand A (54.387), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (5.045) has a longer in vitro half-life than Ligand A (-11.553), which is also a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.015).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the difference is not huge.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the superior candidate. It demonstrates a significantly better QED score, lower DILI risk, substantially improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The improved metabolic stability is particularly important for an enzyme target like SRC kinase. While the logP of Ligand A is slightly better, the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 13:23:15,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.27) is better than Ligand B (122.28). Both are below the 140 threshold for oral absorption, but A is closer to the preferred <90 for CNS targets (though that's not a primary concern here).

**logP:** Ligand A (0.818) is within the optimal 1-3 range. Ligand B (0.29) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 6/7 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.574 and 0.714), indicating drug-like properties.

**DILI:** Ligand A (17.216) has a significantly lower DILI risk than Ligand B (69.213). This is a major advantage for Ligand A.

**BBB:** Not a primary concern for a non-CNS target, but Ligand A (40.52) is slightly better than Ligand B (35.556).

**Caco-2 Permeability:** Ligand A (-5.191) is better than Ligand B (-5.318), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.401) is better than Ligand B (-2.019), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.033) has a much lower hERG risk than Ligand B (0.125). This is a critical advantage.

**Microsomal Clearance:** Ligand A (15.978) has a higher clearance than Ligand B (6.49). This means Ligand B has better metabolic stability.

**In vitro Half-Life:** Ligand A (10.435) has a longer half-life than Ligand B (6.533).

**P-gp Efflux:** Both have low P-gp efflux liability.

**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. The difference of 1.2 kcal/mol is noteworthy.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a much higher DILI risk and hERG inhibition liability, and lower solubility. Ligand A has a better safety profile (DILI, hERG) and solubility, and better permeability, but weaker binding.

Given the priorities for enzyme inhibitors, the strong binding affinity of Ligand B is a significant advantage that likely outweighs the ADME concerns. While the DILI and hERG risks are concerning, they could potentially be mitigated through further structural modifications. The difference in binding affinity is substantial enough to prioritize Ligand B for further development.

Output:
1
2025-04-17 13:23:15,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 354.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is better than Ligand B (61.92), being closer to the upper limit for good oral absorption (<=140).

**logP:** Ligand B (3.576) is higher than Ligand A (1.052). While Ligand A is on the lower side and *could* have permeability issues, Ligand B is approaching the upper limit where solubility issues could arise.

**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 (0.69 and 0.824), indicating drug-likeness.

**DILI:** Ligand A (9.926) has a significantly lower DILI risk than Ligand B (31.989), which is a major advantage.

**BBB:** Ligand B (84.413) has a much higher BBB penetration score than Ligand A (16.363). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-5.033) has a worse Caco-2 permeability than Ligand B (-4.931). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.911) has better aqueous solubility than Ligand B (-5.08). This is a significant advantage for an enzyme inhibitor.

**hERG Inhibition:** Ligand A (0.197) has a much lower hERG inhibition liability than Ligand B (0.718), a crucial safety factor.

**Microsomal Clearance:** Ligand A (7.542) has a significantly lower microsomal clearance than Ligand B (67.223), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.251) has a much longer in vitro half-life than Ligand B (14.296). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.032) has lower P-gp efflux liability than Ligand B (0.626).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 1.6 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a stronger binding affinity, Ligand A demonstrates a significantly better safety profile (lower DILI, lower hERG), improved metabolic stability (lower Cl_mic, longer t1/2), better solubility, and lower P-gp efflux. The affinity difference, while notable, is not so large that it completely overshadows the substantial ADME/Tox advantages of Ligand A. Given the enzyme-kinase focus, prioritizing metabolic stability, solubility, and safety is crucial.

Output:
0
2025-04-17 13:23:15,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.531 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (41.05) is significantly better than Ligand B (62.66). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (A: 4.792, B: 3.143), falling within the 1-3 range, although A is a bit high.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5 HBA, both acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.835, B: 0.757), indicating good drug-likeness.

**DILI:** Ligand A (36.409) has a much lower DILI risk than Ligand B (13.3). This is a significant advantage.

**BBB:** Ligand A (93.912) has a higher BBB penetration score than Ligand B (74.254). While not a primary concern for a non-CNS target like SRC, it isn't detrimental.

**Caco-2 Permeability:** Ligand A (-5.069) has a worse Caco-2 permeability than Ligand B (-4.428), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.846) has worse aqueous solubility than Ligand B (-3.694). This is a concern, as solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.898, B: 0.494).

**Microsomal Clearance:** Ligand A (81.996) has a lower microsomal clearance than Ligand B (92.843), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.037) has a longer half-life than Ligand B (-16.519). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.579, B: 0.243).

**Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is preferable. While it has slightly worse Caco-2 permeability and solubility, its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and higher BBB penetration outweigh these drawbacks. The binding affinity is identical for both, so the ADME properties become the deciding factors. The lower DILI risk is particularly important for an oncology drug.

Output:
0
2025-04-17 13:23:15,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.4 and 342.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.85) is slightly higher than Ligand B (88.32). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**3. logP:** Both ligands have acceptable logP values (1.054 and 2.275, respectively), falling within the 1-3 range. Ligand B is slightly better here.

**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 below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.8 and 0.744), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively low DILI risk (50.45 and 46.96, respectively), both below the 60 threshold.

**8. BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (80.26) has a higher BBB percentile than Ligand A (40.48), but this is not a major deciding factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, these are relative values and we can still compare. Ligand A (-5.245) is slightly better than Ligand B (-5.13).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor predicted solubility. Ligand A (-2.027) is slightly better than Ligand B (-3.459).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.19 and 0.511, respectively).

**12. Microsomal Clearance:** Ligand B (48.515) has a significantly higher microsomal clearance than Ligand A (12.847). This suggests Ligand A is more metabolically stable, a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (24.58) has a positive in vitro half-life, while Ligand B (-17.083) has a negative one. This further supports Ligand A's better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09).

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This is a 1.2 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 demonstrates superior predicted metabolic stability (lower Cl_mic, positive t1/2) and slightly better solubility. For a kinase inhibitor, metabolic stability is crucial for maintaining therapeutic concentrations. The difference in binding affinity, while notable, may be overcome with further optimization of Ligand A. The slightly better TPSA and logP of Ligand B are not enough to offset the metabolic concerns.

Output:
0
2025-04-17 13:23:15,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.374 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.57) is slightly above the preferred <140, while Ligand B (75.87) is well within. This favors B for absorption.

**logP:** Both ligands have good logP values (2.981 and 1.934), falling within the 1-3 range.

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

**QED:** Both ligands have good QED scores (0.684 and 0.761), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 47.926, which is good (below 60). Ligand B has a very low DILI risk of 11.4, which is excellent.

**BBB:** Ligand A has a BBB penetration of 31.834, while Ligand B has 93.37. Since SRC is not a CNS target, this is less critical, but B is clearly better.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.314), which is concerning. Ligand B has a negative Caco-2 value (-4.459), which is also concerning. Both ligands may have poor intestinal absorption.

**Aqueous Solubility:** Ligand A has a solubility of -3.677, and Ligand B has -2.286. Both are poor, but B is slightly better.

**hERG:** Ligand A has a hERG risk of 0.472, which is good. Ligand B has a hERG risk of 0.666, also good.

**Microsomal Clearance:** Ligand A has a Cl_mic of 28.386 mL/min/kg, while Ligand B has 63.402 mL/min/kg. Ligand A is significantly better in terms of metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 37.698 hours, while Ligand B has -11.076 hours. This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.118).

**Binding Affinity:** Ligand A has a binding affinity of -8.8 kcal/mol, while Ligand B has -6.9 kcal/mol. Ligand A is significantly more potent.

**Overall Assessment:**

Ligand A has a much stronger binding affinity (-8.8 vs -6.9 kcal/mol), better metabolic stability (lower Cl_mic, longer t1/2), and a good DILI score. While its solubility and Caco-2 permeability are poor, the substantial potency advantage outweighs these concerns, especially for a kinase inhibitor where achieving sufficient target engagement is paramount. Ligand B has better TPSA, BBB, and DILI, but significantly weaker binding affinity and poorer metabolic stability.

Output:
0
2025-04-17 13:23:15,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.406 and 367.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.88) is better than Ligand B (83.71), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands (1.455 and 1.604) are within the optimal 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:** Both ligands (4) are well below the limit of 10.

**6. QED:** Both ligands (0.866 and 0.858) have excellent drug-likeness scores.

**7. DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (37.456), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (57.154) has a lower BBB penetration than Ligand B (88.329). However, SRC is not a CNS target, so this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.801) has a worse Caco-2 permeability than Ligand B (-4.969). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.022) has better solubility than Ligand B (-2.555). Solubility is important for kinase inhibitors.

**11. hERG Inhibition:** Ligand A (0.679) has a slightly higher hERG risk than Ligand B (0.298). Lower hERG risk is preferred.

**12. Microsomal Clearance:** Ligand A (-12.092) has significantly *lower* (better) microsomal clearance than Ligand B (-0.927), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (13.66) has a longer half-life than Ligand B (-6.193). This is also a significant advantage for an enzyme target.

**14. P-gp Efflux:** Ligand A (0.028) has a lower P-gp efflux than Ligand B (0.045).

**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 >1.1 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility and metabolic stability, the significantly stronger binding affinity of Ligand B (-8.9 vs -7.8 kcal/mol) is the most important factor for an enzyme target like SRC kinase. The difference in affinity is large enough to compensate for the slightly higher hERG risk and lower metabolic stability.

Output:
1
2025-04-17 13:23:15,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.359 Da and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.33) is better than Ligand B (103.59), both are acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.264) is within the optimal 1-3 range. Ligand B (-1.306) is slightly below 1, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A (9) is good, while Ligand B (7) is also good, both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.661 and 0.662), indicating good drug-likeness.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (33.85). This is a significant drawback for Ligand A.

**BBB:** Ligand A (65.607) has a better BBB penetration score than Ligand B (28.383), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.313 and -5.284), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.097 and -1.15). This is also concerning, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.247) has a lower hERG inhibition liability than Ligand B (0.092), which is favorable.

**Microsomal Clearance:** Ligand A (43.72) has higher microsomal clearance than Ligand B (-2.759). This indicates lower metabolic stability for Ligand A, which is undesirable.

**In vitro Half-Life:** Ligand A (-9.921) has a negative half-life, which is unrealistic. Ligand B (20.379) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux than Ligand B (0.016), which is preferable.

**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 notable.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a significantly lower DILI risk, a more realistic half-life, and a slightly better binding affinity. Ligand A has a higher DILI risk, higher clearance, and an unrealistic half-life. The slightly better BBB penetration of Ligand A is not a major factor for an oncology target like SRC.

Output:
1
2025-04-17 13:23:15,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.797 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.38) is slightly above the preferred <140, but acceptable. Ligand B (58.64) is well within the acceptable range.

**logP:** Both ligands have good logP values (3.296 and 2.442), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.778 and 0.669), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (80.729%) compared to Ligand B (15.083%). This is a major concern for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (77.821%) is better than Ligand A (65.335%). This isn't a primary concern for a non-CNS target like SRC.

**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:** Both ligands have low hERG inhibition liability (0.399 and 0.573), which is good.

**Microsomal Clearance (Cl_mic):** Both have similar Cl_mic values (50.487 and 55.004 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life (t1/2):** Ligand A (52.314 hours) has a significantly longer half-life than Ligand B (-0.57 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.441 and 0.111).

**Binding Affinity:** Both ligands have very 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.

**Conclusion:**

Despite Ligand A having a longer half-life, the significantly higher DILI risk (80.729%) is a major red flag. The lower DILI risk of Ligand B (15.083%) makes it the more promising candidate, even with a shorter half-life. The similar binding affinities and other ADME properties further support this conclusion.

Output:
1
2025-04-17 13:23:15,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (384.42 and 364.408 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (83.55 and 78.43) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.115) is optimal, while Ligand B (2.305) is also acceptable.

**4. H-Bond Donors:** Ligand A (1) is good, while Ligand B (3) is slightly higher but still within acceptable limits.

**5. H-Bond Acceptors:** Both ligands (4 and 3 respectively) are well below the 10 threshold.

**6. QED:** Ligand A (0.79) has a better QED score than Ligand B (0.579), indicating a more drug-like profile.

**7. DILI:** Ligand A (36.681) has a lower DILI risk than Ligand B (18.883), which is a significant advantage.

**8. BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (93.098) is higher than Ligand B (77.239).

**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, indicating poor aqueous solubility. This is a concern, but can be mitigated with formulation strategies.

**11. hERG:** Both ligands (0.36 and 0.362) have similar, low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand A (1.984) has significantly lower microsomal clearance than Ligand B (36.091), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**13. t1/2:** Ligand A (-30.619) has a more negative in vitro half-life, which is unusual and suggests a very short half-life. Ligand B (-24.655) is also negative, but less so. This is a concern for both, but more so for A.

**14. Pgp:** Both ligands (0.036 and 0.11) have low P-gp efflux liability.

**15. 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 has a better QED score, lower DILI risk, and significantly better metabolic stability (lower Cl_mic). However, it has a concerningly short in vitro half-life. Ligand B has slightly better binding affinity, but higher DILI risk and poorer metabolic stability. Given the enzyme-specific priorities, metabolic stability is critical. The small difference in binding affinity is outweighed by the substantial difference in Cl_mic and the lower DILI risk of Ligand A. The negative half-life is a concern, but could potentially be addressed through structural modifications.

Output:
0
2025-04-17 13:23:15,595 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.47 and 383.86 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.55) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (96.67) is well within the acceptable range.

**logP:** Ligand A (0.387) is quite low, potentially hindering permeability. Ligand B (0.838) 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 5 HBD and 4 HBA. Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.382) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.789) is above 0.5, suggesting better drug-likeness.

**DILI:** Ligand A (10.82) has a very favorable DILI risk, being quite low. Ligand B (84.10) has a significantly higher DILI risk, which is concerning.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (58.67) and Ligand B (65.45) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.50 and -5.29), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.57 and -4.49), indicating very poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Ligand A (0.191) has a very low hERG risk, which is excellent. Ligand B (0.424) also has a relatively low hERG risk.

**Microsomal Clearance:** Ligand A (-2.68) has a negative clearance, which is not physically possible and likely indicates an issue with the data. Ligand B (46.14) has a high microsomal clearance, suggesting rapid metabolism and poor metabolic stability.

**In vitro Half-Life:** Ligand A (-6.09) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (-28.94) also has a negative half-life, indicating data issues.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.057).

**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.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.9 vs 0.0 kcal/mol) is a major advantage that could outweigh some of the ADME concerns. However, the high DILI risk (84.10) and high microsomal clearance (46.14) for Ligand B are significant liabilities. The negative values for clearance and half-life for both compounds are concerning and suggest data quality issues. If the data were reliable, Ligand B would be prioritized for further optimization, focusing on improving solubility, permeability, reducing DILI risk, and enhancing metabolic stability.

Output:
1
2025-04-17 13:23:15,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.443 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is better than Ligand B (62.55), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.557) is optimal, while Ligand B (3.081) is at the higher end of the optimal range.

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

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (3), both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.774 and 0.835), indicating drug-likeness.

**DILI:** Ligand A (24.544) has a significantly lower DILI risk than Ligand B (37.456), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (75.843) is better than Ligand A (67.352). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 permeability values, which is unusual and suggests potential issues with absorption prediction. However, the values are close enough to not be a major differentiator.

**Aqueous Solubility:** Ligand A (-1.69) is better than Ligand B (-3.434), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.319 and 0.304).

**Microsomal Clearance:** Ligand A (50.542) has higher microsomal clearance than Ligand B (39.283), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (14.548 hours) has a significantly longer half-life than Ligand A (5.707 hours). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 and 0.155).

**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 has a superior binding affinity and lower DILI risk and better solubility. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better BBB penetration. However, the substantial affinity advantage of Ligand A, coupled with the lower DILI risk, makes it the more promising candidate. The longer half-life of Ligand B is attractive, but the difference in affinity is more critical for an enzyme target.

Output:
1
2025-04-17 13:23:15,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (363.527 Da) is lower, which could be advantageous for permeability.

**TPSA:** Ligand A (97.38) is higher than Ligand B (62.3). While both are reasonably good for oral absorption, Ligand B's lower TPSA is preferable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.4) and Ligand B (3.019) are both acceptable.

**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 (Ligand A: 0.527, Ligand B: 0.764). Ligand B has a slightly better QED.

**DILI:** Ligand A has a high DILI risk (96.394%), which is a significant concern. Ligand B has a much lower DILI risk (39.434%), making it significantly more favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (58.782%) and Ligand B (69.252%) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a potential issue for both.

**hERG:** Ligand A (0.157) has a lower hERG risk than Ligand B (0.237), which is better.

**Microsomal Clearance:** Ligand A has a negative clearance (-9.58), which is excellent, indicating high metabolic stability. Ligand B has a much higher clearance (57.104), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a longer half-life (72.926 hours) than Ligand B (17.66 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.379) has lower P-gp efflux than Ligand B (0.063), which is preferable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), but the difference is not substantial enough to overcome the other significant drawbacks of Ligand A.

**Conclusion:**

Despite Ligand A's slightly better binding affinity and metabolic stability, the extremely high DILI risk is a major red flag. Ligand B, while having slightly less favorable metabolic stability and a weaker binding affinity, presents a much better overall profile with a significantly lower DILI risk and a better QED score. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate.

Output:
1
2025-04-17 13:23:15,596 - INFO - Batch 209 complete. Total preferences: 3344
2025-04-17 13:23:15,596 - INFO - Processing batch 210/512...
2025-04-17 13:23:57,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (339.311 and 374.497 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (123.9) is better than Ligand B (58.2) as it is closer to the ideal range for oral absorption (<=140).

**3. logP:** Both ligands (2.44 and 2.965) 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 (7) is preferable to Ligand B (3) as lower HBAs generally improve permeability.

**6. QED:** Ligand B (0.752) has a better QED score than Ligand A (0.43), indicating a more drug-like profile.

**7. DILI:** Ligand B (37.03) has a significantly lower DILI risk than Ligand A (97.984), making it much safer from a liver toxicity perspective. This is a major advantage.

**8. BBB:** This is less critical for an oncology target, but Ligand B (85.033) has a higher BBB penetration than Ligand A (58.007).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.005 and -5.322). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.437 and -3.575), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.447) has a slightly lower hERG risk than Ligand B (0.51), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (8.016) has a much lower microsomal clearance than Ligand A (89.456), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (15.433) has a significantly longer in vitro half-life than Ligand A (-4.329), suggesting less frequent dosing potential.

**14. P-gp Efflux:** Ligand A (0.306) has lower P-gp efflux liability than Ligand B (0.15), which could lead to better oral bioavailability.

**15. Binding Affinity:** Ligand A (-10.2 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:**

While Ligand A boasts a much stronger binding affinity, Ligand B presents a significantly better ADMET profile. Specifically, the dramatically lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and higher QED score are crucial advantages for a drug candidate. The poor Caco-2 and solubility for both are concerning, but the superior potency of Ligand A might allow for formulation strategies to overcome these issues. However, the high DILI risk of Ligand A is a major red flag.

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, hERG risk), and the substantial difference in DILI and metabolic stability, Ligand B is the more promising candidate despite the lower affinity. The potency difference, while significant, might be addressable through further optimization, whereas mitigating a high DILI risk is far more challenging.

Output:
1
2025-04-17 13:23:57,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.415 and 358.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.02) is better than Ligand B (99.1), both being acceptable for oral absorption (<140).

**logP:** Ligand A (1.411) is within the optimal 1-3 range, while Ligand B (-0.393) is slightly below, which *could* hinder permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3), as lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.876) has a significantly better QED score than Ligand B (0.385), indicating a more drug-like profile.

**DILI:** Ligand A (36.06) has a much lower DILI risk than Ligand B (15.394), which is a significant advantage.

**BBB:** Ligand A (54.052) has a lower BBB penetration than Ligand B (67.468). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.137) has a worse Caco-2 permeability than Ligand B (-4.913).

**Aqueous Solubility:** Ligand A (-1.895) has better aqueous solubility than Ligand B (-2.286).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.259 and 0.333).

**Microsomal Clearance:** Ligand A (-14.625) exhibits *much* better metabolic stability (lower clearance) than Ligand B (6.898). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (3.769) has a significantly longer half-life than Ligand B (-38.76). This is a major positive.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.025 and 0.034).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.9 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is significantly better overall. It has a superior QED score, much lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. While Ligand B has slightly better Caco-2 permeability and BBB penetration, these are less important for a non-CNS enzyme target like SRC kinase. The similar binding affinities make the ADME/Tox advantages of Ligand A decisive.

Output:
1
2025-04-17 13:23:57,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.5 and 346.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (91.4), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (2.156) is optimal (1-3), while Ligand B (0.945) is slightly low, potentially impacting permeability.

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

**QED:** Both ligands have similar QED values (0.731 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (20.3) has a significantly lower DILI risk than Ligand B (41.9), a major advantage.

**BBB:** Ligand A (71.8) is better than Ligand B (52.0), but BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.7) is better than Ligand B (-5.166), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.426) is better than Ligand B (-1.562), which is a positive attribute for bioavailability.

**hERG Inhibition:** Ligand A (0.485) has a lower hERG risk than Ligand B (0.226), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (71.68) has a higher (worse) microsomal clearance than Ligand B (15.8), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-15.81) has a shorter half-life than Ligand B (9.423), which is a negative.

**P-gp Efflux:** Ligand A (0.014) has lower P-gp efflux than Ligand B (0.025), which is a slight advantage.

**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, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most critical factor for an enzyme inhibitor. While it has some ADME liabilities (lower logP, higher DILI, higher Cl_mic, shorter half-life), the significantly stronger binding (-8.7 vs -7.4 kcal/mol) is a compelling advantage. The difference in binding affinity is greater than 1.5 kcal/mol, making it the more promising candidate despite the ADME concerns, which can be addressed through further optimization.

Output:
1
2025-04-17 13:23:57,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.443 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.78) is slightly above the preferred <140, but acceptable. Ligand B (59.08) is excellent, well below 140.

**logP:** Both ligands have good logP values (2.544 and 1.623), 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 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.696) has a better QED score than Ligand B (0.493), indicating a more drug-like profile.

**DILI:** Ligand B (20.396) has a significantly lower DILI risk than Ligand A (32.881), which is a major advantage.

**BBB:** Ligand B (73.866) has a higher BBB penetration percentile than Ligand A (61.497), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.662 and -4.423), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.556 and -0.944), indicating poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.395) has a slightly better hERG profile than Ligand B (0.506), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (23.717) has a much lower microsomal clearance than Ligand A (46.104), suggesting better metabolic stability, a key factor for kinases.

**In vitro Half-Life:** Ligand B (4.29) has a slightly better in vitro half-life than Ligand A (30.809), but both are quite low.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.379 and 0.112).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly 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.

**Conclusion:**

Despite the poor Caco-2 and solubility profiles of both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.1 vs 0.0 kcal/mol) and lower DILI risk (20.4 vs 32.9) are major advantages. The improved metabolic stability (lower Cl_mic) and slightly better half-life also contribute to its favorability. While Ligand A has a slightly better QED and hERG profile, the potency difference is too large to ignore. Further work would be needed to improve the solubility and permeability of Ligand B, but its strong binding affinity makes it a better starting point.

Output:
1
2025-04-17 13:23:57,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.463 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (93.26) is still under 140, but less optimal than A.

**logP:** Ligand A (3.577) is at the upper end of the optimal range (1-3), while Ligand B (1.566) is at the lower end. While both are acceptable, a slightly higher logP can sometimes improve cell permeability.

**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 (0.83 and 0.822), indicating good drug-likeness.

**DILI:** Ligand A (74.603) has a higher DILI risk than Ligand B (56.689). This is a significant concern, as lower DILI is preferred.

**BBB:** Both ligands have reasonable BBB penetration (63.086 and 74.758), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, these values are on a log scale, and the negative values are relative. Ligand A (-4.489) is slightly worse than Ligand B (-4.945).

**Aqueous Solubility:** Both ligands have negative solubility values, again indicating poor solubility. Ligand B (-2.17) is slightly better than Ligand A (-3.945).

**hERG:** Both ligands have very low hERG inhibition risk (0.181 and 0.147), which is excellent.

**Microsomal Clearance:** Ligand B (35.797) has significantly lower microsomal clearance than Ligand A (86.254), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-6.526) has a longer in vitro half-life than Ligand A (-18.455), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.266 and 0.11).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better TPSA and logP, Ligand B is superior overall due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The binding affinities are comparable, making the ADME properties the deciding factor. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity (DILI) are crucial.

Output:
1
2025-04-17 13:23:57,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.291 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (357.455 Da) is also good.

**TPSA:** Ligand A (118.4) is better than Ligand B (105.22), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.474) is optimal (1-3). Ligand B (-2.309) is significantly lower, which is a major concern as it may hinder membrane permeability and reduce oral absorption.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher than ideal.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable range (<=10).

**QED:** Ligand A (0.575) is better than Ligand B (0.401), indicating a more drug-like profile.

**DILI:** Ligand A (99.457) has a very high DILI risk, which is a significant red flag. Ligand B (5.777) has a very low DILI risk, a major advantage.

**BBB:** Ligand A (55.099) has moderate BBB penetration, while Ligand B (3.218) has very low BBB penetration. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.525) has poor Caco-2 permeability. Ligand B (-5.86) is even worse.

**Aqueous Solubility:** Ligand A (-6.806) has poor solubility. Ligand B (0.601) has very poor solubility.

**hERG Inhibition:** Ligand A (0.713) has a low hERG risk, which is good. Ligand B (0.037) has a very low hERG risk, even better.

**Microsomal Clearance:** Ligand A (58.12) has moderate clearance. Ligand B (-28.17) has negative clearance, which is highly unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (109.827) has a good half-life. Ligand B (-11.598) has a negative half-life, which is not realistic and indicates a potential issue with the data or the molecule's stability.

**P-gp Efflux:** Both ligands have a Pgp efflux score of 0.532 and 0.001, respectively, indicating high efflux.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-9.8). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity and a reasonable half-life, but suffers from very high DILI risk and poor solubility/permeability. Ligand B has excellent safety profiles (low DILI, low hERG) and very high metabolic stability, but has a significantly weaker binding affinity and very poor solubility/permeability. The negative values for Caco-2 permeability, solubility, and half-life for Ligand B raise concerns about data quality.

Given the enzyme-specific priorities, potency (affinity) is crucial. While Ligand A's DILI risk is concerning, the substantial difference in binding affinity (-9.0 vs -9.8 kcal/mol) is likely to outweigh the other drawbacks, *provided* the DILI risk can be mitigated through structural modifications. The negative values for Ligand B suggest potential issues with the data or the molecule itself.

Output:
0
2025-04-17 13:23:57,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.451 and 358.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.34) is better than Ligand B (81.66), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.401 and 2.883), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 8. Both are within the acceptable limit of <=10, but A is preferable.

**QED:** Ligand A (0.828) has a significantly better QED score than Ligand B (0.667), indicating a more drug-like profile.

**DILI:** Ligand B (60.527) has a higher DILI risk than Ligand A (90.617). This is a significant negative for Ligand B.

**BBB:** Both have reasonable BBB penetration, but Ligand B (73.672) is slightly better than Ligand A (65.723). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.935) has a worse Caco-2 permeability than Ligand B (-5.728).

**Aqueous Solubility:** Ligand B (-2.754) has better aqueous solubility than Ligand A (-4.587). This is a positive for Ligand B.

**hERG:** Ligand A (0.289) has a much lower hERG risk than Ligand B (0.125), which is a critical advantage.

**Microsomal Clearance:** Ligand B (37.796) has a significantly lower microsomal clearance than Ligand A (72.265), suggesting better metabolic stability. This is a strong positive for Ligand B.

**In vitro Half-Life:** Ligand B (13.626) has a much longer in vitro half-life than Ligand A (1.927), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.571) has a higher P-gp efflux liability than Ligand B (0.361).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage, easily outweighing most other drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, significantly improved metabolic stability (lower Cl_mic, longer t1/2), and better solubility. While it has a slightly higher DILI risk, the strong affinity and metabolic properties are more crucial for an enzyme target like SRC. Ligand A has a better QED and lower hERG, but the weak binding affinity is a major drawback. The difference in binding affinity is so large that it overrides the other advantages of Ligand A.

Output:
1
2025-04-17 13:23:57,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.341 and 376.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (32.34) as it is closer to the 140 threshold, while ligand B is quite low.

**logP:** Ligand A (1.321) is optimal (1-3), while Ligand B (4.488) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 2 HBA) both have acceptable counts, well within the limits of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.798 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (64.172) has a higher DILI risk than Ligand B (21.171). This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (89.492) has a higher percentile than Ligand A (72.082).

**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:** Ligand A (0.163) has a better hERG profile (lower risk) than Ligand B (0.877).

**Microsomal Clearance:** Ligand A (44.117) has higher clearance than Ligand B (27.099), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (4.497) has a longer half-life than Ligand A (10.648).

**P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux liability than Ligand B (0.359), which is favorable.

**Binding Affinity:** Ligand B (-9.1 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.

**Conclusion:**

Despite Ligand A having a better hERG profile and lower P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.1 vs -8.3 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B exhibits lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). While Ligand B's logP is slightly elevated, the benefits of its potency and safety profile outweigh this concern.

Output:
1
2025-04-17 13:23:57,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (370.559 Da and 367.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (80.2), as it's closer to the <140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.878 and 1.568), falling within the optimal 1-3 range. Ligand A is slightly higher, potentially aiding membrane 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, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.62 and 0.768), indicating drug-like properties.

**7. DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (25.087), which is a crucial advantage. Both are below the 40 threshold, but lower is always preferred.

**8. BBB:** Both ligands have similar BBB penetration (68.36 and 69.058). BBB is less critical for an oncology target unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.958 and -4.679). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.28 and -2.502). This is also unusual and suggests poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.434 and 0.251), which is excellent.

**12. Microsomal Clearance:** Ligand B (31.59) has significantly lower microsomal clearance than Ligand A (68.256), indicating better metabolic stability. This is a major advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (15.352) has a longer in vitro half-life than Ligand A (9.433), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.036), which is favorable.

**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 substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand B exhibits better metabolic stability (lower Cl_mic and longer t1/2), the significantly stronger binding affinity of Ligand A (-8.4 vs -6.8 kcal/mol) is a decisive factor for an enzyme target. The lower DILI risk for Ligand A is also a significant benefit. The similar poor Caco-2 and solubility values are concerning for both, but the potency advantage of Ligand A is likely to outweigh these drawbacks, especially considering it's an oncology target where IV administration is often acceptable.

Output:
1
2025-04-17 13:23:57,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 are below the 140 A^2 threshold for good oral absorption. Ligand A (60.93) is significantly better than Ligand B (70.08), suggesting better absorption.

**logP:** Both ligands have acceptable logP values (1-3), with Ligand A (1.147) being slightly better positioned within the optimal range compared to Ligand B (0.348).

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD and HBA counts. Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) are comparable.

**QED:** Ligand A (0.714) has a better QED score than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (14.928) has a much lower DILI risk than Ligand B (32.881), a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Both are reasonable, but Ligand A (70.764) 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 hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This is a concern for both, but Ligand A (-0.626) is slightly better than Ligand B (-1.591).

**hERG:** Ligand A (0.295) has a much lower hERG inhibition liability than Ligand B (0.48), a crucial advantage for safety.

**Microsomal Clearance:** Ligand B (-3.327) has a negative clearance, which is not physically possible and indicates a potential data error. Ligand A (0.802) has a reasonable, though not ideal, clearance. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand B (-19.152) has a negative half-life, which is not physically possible and indicates a potential data error. Ligand A (-8.761) is also negative, but less so.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.041), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.761 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, the negative and unrealistic values for its clearance and half-life are major red flags. The significantly lower DILI and hERG risk, better QED, and more favorable TPSA and logP of Ligand A make it a much more promising candidate. The negative solubility and Caco-2 values are concerning for both, but the ADME properties of Ligand A are far superior and more plausible. The affinity difference, while significant, can potentially be addressed through further optimization of Ligand A.



Output:
0
2025-04-17 13:23:57,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (364.433 Da) is also good.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (81.93) is preferable to Ligand B (87.66).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.291) is slightly higher than Ligand B (1.466), potentially offering better membrane permeability, but both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 4 HBA) regarding the number of H-bonds. Fewer H-bonds generally improve permeability.

**QED:** Both ligands have QED values above 0.5, indicating a generally drug-like profile. Ligand A (0.755) is slightly better than Ligand B (0.609).

**DILI:** Ligand A (47.421) has a slightly higher DILI risk than Ligand B (28.926), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 62.854, Ligand B: 66.072). This isn't a primary concern for a kinase inhibitor, but higher is generally better.

**Caco-2 Permeability:** Ligand A (-4.71) has a worse Caco-2 permeability than Ligand B (-5.049). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.992) has a worse aqueous solubility than Ligand B (-1.944). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.172) has a lower hERG inhibition liability than Ligand B (0.545), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (71.347) has a higher microsomal clearance than Ligand B (26.621), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-21.626) has a much shorter in vitro half-life than Ligand B (-1.322), further confirming its lower metabolic stability.

**P-gp Efflux:** Ligand A (0.213) has lower P-gp efflux liability than Ligand B (0.03), which is preferable.

**Binding Affinity:** Ligand B (-9.3 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.

**Conclusion:**

Despite Ligand A having a slightly better QED and lower hERG risk, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.3 vs -7.4 kcal/mol) is crucial for an enzyme inhibitor. While Ligand A has better P-gp efflux, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2) and solubility are more important for a kinase inhibitor. The DILI risk is also lower for Ligand B.

Output:
1
2025-04-17 13:23:57,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (383.5 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (116.8 and 108.9 A^2) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.68) is optimal, while Ligand B (0.595) is slightly low, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5. Both are below the 10 limit.

**QED:** Both ligands have similar QED values (0.672 and 0.651), indicating good drug-likeness.

**DILI:** Ligand A (74.7%) has a higher DILI risk than Ligand B (60.3%). While both are acceptable, B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (32.8%) is higher than Ligand A (17.0%), but this isn't a major factor here.

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

**Solubility:** Both 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 liability (0.11 and 0.152), which is excellent.

**Microsomal Clearance:** Ligand A (-2.84 mL/min/kg) suggests better metabolic stability than Ligand B (10.905 mL/min/kg). This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (23.2 hours) has a much longer half-life than Ligand B (-19.4 hours). The negative value for B is concerning and likely an artifact, but even if it were positive, A's half-life is significantly better.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.1 and 0.025), which is favorable.

**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 (0.2 kcal/mol).

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is more promising. It has better metabolic stability (lower Cl_mic, longer t1/2), a more optimal logP, and a slightly lower DILI risk. The small difference in binding affinity is outweighed by the ADME advantages of Ligand A. The poor solubility and permeability are significant issues that would need to be addressed through formulation or further chemical modification, but the better pharmacokinetic profile of A gives it a higher chance of success.

Output:
1
2025-04-17 13:23:57,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.371 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.35) is slightly above the preferred <140, but acceptable. Ligand B (88.76) is excellent, well below 140.

**logP:** Both ligands (1.163 and 1.318) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, fitting the <5 and <10 rules. Ligand B has 1 HBD and 5 HBA, also fitting the rules.

**QED:** Both ligands have good QED scores (0.661 and 0.867), indicating good drug-like properties.

**DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (47.654), though both are acceptable.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (81.388) is better than Ligand A (62.233).

**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 a potential issue with the data or modeling. However, we'll proceed assuming these represent low solubility.

**hERG:** Ligand A (0.193) has a slightly higher hERG risk than Ligand B (0.606). Lower is better here.

**Microsomal Clearance:** Ligand B (29.016) has significantly lower microsomal clearance than Ligand A (44.08), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-20.421) has a significantly longer in vitro half-life than Ligand A (-46.264), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047).

**Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-6.9). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B demonstrates superior ADME properties (lower DILI, better metabolic stability, better hERG), the significantly stronger binding affinity of Ligand A (-10.0 kcal/mol vs -6.9 kcal/mol) is a decisive factor. The potency advantage is substantial enough to potentially overcome the slightly less favorable ADME profile of Ligand A. The negative solubility and Caco-2 values are concerning for both, but the potency difference is significant.

Output:
1
2025-04-17 13:23:57,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.885 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is well below the 140 threshold, while Ligand B (69.64) is also acceptable but higher.

**logP:** Ligand A (4.655) is slightly high, potentially leading to solubility issues, but still within a manageable range. Ligand B (2.173) is optimal.

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

**QED:** Both ligands have good QED scores (0.755 and 0.816), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 61.031, which is concerning (high risk). Ligand B has a much lower DILI risk of 18.379, which is excellent.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (83.327) is higher than Ligand A (61.458), but this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.688 and -4.906), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.646 and -2.522). This is a major concern for *in vivo* efficacy.

**hERG Inhibition:** Ligand A (0.833) has a slightly higher hERG risk than Ligand B (0.316), which is preferable.

**Microsomal Clearance:** Ligand A (80.004) has a higher microsomal clearance than Ligand B (2.126), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-10.931) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound's stability. Ligand A (78.049) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.636) has a lower P-gp efflux liability than Ligand B (0.04), which is favorable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 2.4 kcal/mol difference is substantial and can outweigh many other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. Its significantly higher binding affinity (-9.5 vs -7.1 kcal/mol) is a major advantage. Furthermore, it has a much lower DILI risk (18.379 vs 61.031) and better metabolic stability (lower Cl_mic). While the negative half-life is a data quality concern, the other factors strongly favor Ligand B. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the strong binding and improved safety profile make Ligand B the better starting point.

Output:
1
2025-04-17 13:23:57,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.805 and 357.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.34) is higher than Ligand B (70). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.594) is quite low, potentially hindering permeability. Ligand B (2.614) 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 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar, high QED values (0.809 and 0.821), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 60.178, which is approaching the higher risk threshold. Ligand B has a much lower DILI risk of 20.047, a substantial advantage.

**BBB:** Both have similar BBB penetration (around 60%), which isn't a primary concern for a non-CNS target like SRC.

**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 (0.051) has a very low hERG risk, which is excellent. Ligand B (0.788) is higher, but still relatively low.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-4.2), which is not physically possible. This is a red flag. Ligand B has a Cl_mic of 46.567, which is high, indicating faster metabolism.

**In vitro Half-Life:** Ligand A has a very short half-life (-9.717 hours), which is not physically possible. Ligand B has a short half-life of 2.258 hours.

**P-gp Efflux:** Both have low P-gp efflux liability (0.053 and 0.317).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.2 and -9.5 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand B is significantly more promising. Ligand A has physically impossible values for Cl_mic and t1/2, indicating issues with the data or the molecule itself. Ligand B has a much better logP, lower DILI risk, and while its metabolic stability and half-life are not ideal, they are at least plausible. The poor Caco-2 and solubility values are concerning for both, but the other factors make Ligand B the better candidate.

Output:
1
2025-04-17 13:23:57,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.841 and 378.881 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (60.18 and 58.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.791) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.949) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4-5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.683 and 0.84), indicating drug-like properties.

**DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (60.566), though both are not alarming.

**BBB:** Both have reasonable BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability & Aqueous Solubility:** Both ligands have negative values for Caco-2 and solubility, which is unusual and likely indicates poor permeability and solubility. This is a significant concern.

**hERG Inhibition:** Both have low hERG inhibition risk (0.803 and 0.605).

**Microsomal Clearance & In vitro Half-Life:** Ligand A has a higher Cl_mic (53.796) and a longer t1/2 (102.935) than Ligand B (43.446 and 7.117). This suggests better metabolic stability for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.587 and 0.316).

**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 (0.3 kcal/mol), it is still a factor.

**Overall Assessment:**

Ligand B is more promising. While both have issues with Caco-2 and solubility, Ligand B has a more favorable logP, and a better binding affinity. The improved binding affinity of Ligand B, combined with its lower DILI risk and more optimal logP, outweighs the slightly better metabolic stability of Ligand A. 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 13:23:57,470 - INFO - Batch 210 complete. Total preferences: 3360
2025-04-17 13:23:57,470 - INFO - Processing batch 211/512...
2025-04-17 13:24:37,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (370.455 and 374.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (61.19 and 61.92) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (4.163) is slightly higher than Ligand B (3.788). While both are above the optimal 1-3 range, Ligand A's value is closer to the upper limit and could potentially cause solubility issues.

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

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

**6. QED:** Ligand A (0.506) has a slightly better QED score than Ligand B (0.469), indicating a more drug-like profile.

**7. DILI:** Ligand B (57.193) has a significantly lower DILI risk than Ligand A (94.804). This is a major advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration (66.576 and 61.729), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.859 and -5.232). This is unusual and suggests poor permeability. However, negative values can sometimes be artifacts of the prediction method.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.734 and -4.21). This is a significant concern for both compounds, potentially hindering bioavailability.

**11. hERG Inhibition:** Ligand A (0.43) has a slightly lower hERG risk than Ligand B (0.791), which is preferable.

**12. Microsomal Clearance:** Ligand B (106.78) has a significantly higher microsomal clearance than Ligand A (36.426). This suggests Ligand A is more metabolically stable, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (51.545) has a longer in vitro half-life than Ligand B (36.012), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.681 and 0.755).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a 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:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) which are crucial for a kinase inhibitor. However, Ligand B has a much lower DILI risk, which is a critical safety parameter. Both have poor predicted solubility and permeability. The stronger binding of Ligand A is a significant advantage, and while the solubility/permeability are concerns, these can potentially be addressed through formulation strategies. The DILI risk of Ligand A is higher, but the potency advantage is likely to be more impactful in early stages of development.

Output:
0
2025-04-17 13:24:37,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.426 Da) is slightly lower, which could be beneficial for permeability. Ligand B (385.957 Da) is also acceptable.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold for oral absorption. Ligand B (60.77) is still reasonable, but less optimal.

**logP:** Ligand A (4.438) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.854) is within the optimal range (1-3).

**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 scores (A: 0.823, B: 0.7), indicating good drug-like properties.

**DILI:** Ligand A (50.33) has a slightly higher DILI risk than Ligand B (35.789), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.066) has better BBB penetration than Ligand B (61.962).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and likely indicates poor permeability. Ligand A (-4.453) is slightly better than Ligand B (-4.88).

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and likely indicates poor solubility. Ligand A (-4.503) is slightly better than Ligand B (-4.142).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.87, B: 0.67).

**Microsomal Clearance:** Ligand A (59.916) has a slightly higher microsomal clearance than Ligand B (54.964), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (30.859 hours) has a longer in vitro half-life than Ligand A (27.654 hours), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.594, B: 0.808).

**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, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

While Ligand A has some advantages in TPSA and slightly better permeability/solubility, Ligand B's substantially stronger binding affinity (-9.1 vs -7.7 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the minor drawbacks of its slightly higher logP and TPSA. The lower DILI risk is also a plus. Given the enzyme-specific priorities, potency and metabolic stability are paramount, making Ligand B the more promising candidate.

Output:
1
2025-04-17 13:24:37,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.415 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (95.74), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.243 and 1.453), falling within the 1-3 optimal range. Ligand B is slightly lower, which could potentially impact permeability, but it's not a major concern.

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

**QED:** Both ligands have similar QED scores (0.741 and 0.729), indicating good drug-likeness.

**DILI:** Ligand A (57.193) has a higher DILI risk than Ligand B (22.722). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (71.656 and 77.937), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.705) has poor Caco-2 permeability, while Ligand B (-5.227) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.017) has poor solubility, while Ligand B (-1.869) is slightly better. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.433) has a slightly higher hERG risk than Ligand B (0.117). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (35.93) has higher microsomal clearance than Ligand B (31.708), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (6.436) has a longer half-life than Ligand B (-2.033). This is a positive for Ligand A, but the negative half-life for Ligand B is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.016).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While both have acceptable MW, logP, HBD/HBA, and QED, Ligand B demonstrates significantly better safety profiles (lower DILI, lower hERG), and crucially, a substantially stronger binding affinity. Although its solubility and Caco-2 permeability are also poor, the strong binding affinity and improved safety outweigh these concerns. Ligand A's higher DILI risk and lower affinity are significant drawbacks.

Output:
1
2025-04-17 13:24:37,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.386 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.53) is still acceptable but less optimal.

**logP:** Ligand A (3.002) is within the optimal 1-3 range. Ligand B (1.689) is on the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits (<=5 and <=10, respectively).

**QED:** Both ligands have similar QED values (0.776 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (62.272), but both are reasonably acceptable.

**BBB:** Both ligands have similar BBB penetration (74.37 and 73.401), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.578) has slightly better Caco-2 permeability than Ligand B (-4.362), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-4.23) has slightly worse solubility than Ligand B (-1.9). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.851) has a higher hERG risk than Ligand B (0.27), which is a significant concern.

**Microsomal Clearance:** Ligand B (18.024) has significantly lower microsomal clearance than Ligand A (84.265), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-0.303) has a significantly longer in vitro half-life than Ligand A (22.846), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.657) has slightly higher P-gp efflux than Ligand B (0.034), potentially reducing bioavailability.

**Binding Affinity:** Ligand A (-9.3) has a slightly better binding affinity than Ligand B (-8.8). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better solubility. These factors are more critical for an enzyme inhibitor like an SRC kinase inhibitor than a small difference in binding affinity. The lower logP of Ligand B is a minor drawback, but the other advantages outweigh this.

Output:
1
2025-04-17 13:24:37,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.415 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.21) is slightly above the preferred <90 for good absorption, but still reasonable. Ligand B (70.67) is well within the ideal range.

**3. logP:** Both ligands have good logP values (2.597 and 1.385), 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 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.801) has a significantly better QED score than Ligand B (0.617), indicating a more drug-like profile.

**7. DILI:** Ligand A (45.134) has a slightly higher DILI risk than Ligand B (17.642), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.48) is higher than Ligand B (52.036).

**9. Caco-2 Permeability:** Ligand A (-4.733) has a lower Caco-2 permeability than Ligand B (-5.248), suggesting potentially lower absorption.

**10. Aqueous Solubility:** Ligand B (-1.561) has better aqueous solubility than Ligand A (-3.414), which is a significant advantage for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.236 and 0.173), which is excellent.

**12. Microsomal Clearance:** Ligand B (30.726) has significantly lower microsomal clearance than Ligand A (49.81), indicating better metabolic stability. This is a key factor for enzymes.

**13. In vitro Half-Life:** Ligand B (8.686) has a longer in vitro half-life than Ligand A (23.366). This is a bit counterintuitive as the raw value is lower, but the percentile is higher, indicating a better half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.021).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.7 kcal/mol), with Ligand A being slightly more potent. However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has slightly better potency and QED, Ligand B demonstrates superior ADME properties, particularly in terms of solubility and metabolic stability (lower Cl_mic and longer half-life). Given the enzyme-specific priorities, the improved metabolic stability and solubility of Ligand B are more crucial for its potential as a viable drug candidate. The small difference in binding affinity is outweighed by the ADME advantages.

Output:
1
2025-04-17 13:24:37,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.438 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is well below the 140 threshold for oral absorption, and favorable. Ligand B (100.35) is still acceptable but less optimal.

**logP:** Ligand A (2.157) is within the optimal 1-3 range. Ligand B (0.192) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 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 (0.815 and 0.764), indicating drug-likeness.

**DILI:** Ligand A (41.954) has a slightly higher DILI risk than Ligand B (30.787), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.319) has better BBB penetration than Ligand B (59.868).

**Caco-2 Permeability:** Ligand A (-4.568) and Ligand B (-5.064) both have negative values, indicating poor permeability. However, this scale is not intuitive, and the absolute values aren't directly comparable without knowing the scale's specifics.

**Aqueous Solubility:** Ligand A (-2.777) and Ligand B (-1.394) both have negative solubility values, indicating poor solubility. Again, the scale is not intuitive.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.429 and 0.24), which is excellent.

**Microsomal Clearance:** Ligand A (39.656) has a significantly better (lower) microsomal clearance than Ligand B (9.086), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.664) has a slightly longer half-life than Ligand A (-5.127).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.161 and 0.038).

**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, and could outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better logP and TPSA, Ligand B's significantly stronger binding affinity (-9.2 vs -8.5 kcal/mol) is the most critical factor for an enzyme target like SRC kinase. The slightly better half-life of Ligand B is also a plus. The lower logP of Ligand B is a concern, but can potentially be addressed through structural modifications. The metabolic stability of Ligand A is better, but the affinity difference is larger.

Output:
1
2025-04-17 13:24:37,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight (MW):** Both ligands (360.424 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.95) is excellent, well below the 140 threshold for oral absorption. Ligand B (91.22) is still acceptable but higher, potentially impacting absorption slightly.

**3. logP:** Ligand A (4.017) is at the higher end of the optimal range (1-3), which *could* lead to solubility issues or off-target effects. Ligand B (1.888) is well within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 3, respectively), below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 each), below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.654 and 0.762), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (39.046 and 30.826), which is favorable.

**8. BBB:** Ligand A (78.79) shows reasonable BBB penetration, while Ligand B (64.754) is lower. However, as SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.748) has poor Caco-2 permeability, while Ligand B (-5.36) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.446) has poor aqueous solubility, while Ligand B (-2.934) is slightly better.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.61 and 0.598).

**12. Microsomal Clearance (Cl_mic):** Ligand A (37.681) has higher microsomal clearance, indicating faster metabolism. Ligand B (-2.864) has negative clearance, which is unusual and suggests *very* high metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (39.068) has a moderate half-life. Ligand B (-6.542) has a very long half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.319 and 0.072).

**15. Binding Affinity:** Ligand B (-6.8 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial difference.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and metabolic stability, while Ligand A has poor affinity and moderate metabolic stability. Ligand A's high logP and poor solubility are also concerning.

**Conclusion:**

Ligand B is the superior candidate. The significantly stronger binding affinity (-6.8 kcal/mol vs 0.0 kcal/mol) outweighs the slightly higher TPSA. The exceptional metabolic stability (negative Cl_mic, very long half-life) is a major advantage for an enzyme target. While both have poor Caco-2 permeability and solubility, the potency and stability of Ligand B make it much more likely to succeed.

Output:
1
2025-04-17 13:24:37,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.406 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.27) is slightly higher than Ligand B (81.99). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (1.576) is within the optimal 1-3 range. Ligand B (3.547) is at the higher end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**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:** Ligand B (0.627) has a better QED score than Ligand A (0.449), suggesting a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 57.697, Ligand B: 53.509), below the 60 threshold.

**BBB:** Both have relatively low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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 (-2.153 and -4.782 respectively). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.089) has a much lower hERG risk than Ligand B (0.68), which is a crucial advantage.

**Microsomal Clearance:** Ligand B (81.709) has a significantly higher microsomal clearance than Ligand A (13.047), indicating lower metabolic stability. This is a major concern.

**In vitro Half-Life:** Ligand B (37.709) has a longer half-life than Ligand A (-3.618), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.025) has a much lower P-gp efflux liability than Ligand B (0.338), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.0) has a substantially stronger binding affinity than Ligand A (0.0). This is a very significant advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, a longer half-life, and a better QED score. However, it suffers from higher logP, higher microsomal clearance, and higher P-gp efflux. Ligand A has a much better hERG profile and lower P-gp efflux, but its binding affinity is very weak and its solubility is very poor.

Given the priority for potency in enzyme inhibitors, the significantly stronger binding affinity of Ligand B (-8.0 kcal/mol vs 0.0 kcal/mol) is a decisive factor. While the ADME properties of Ligand B are not ideal, they could potentially be addressed through further optimization. The poor affinity of Ligand A is a more fundamental issue that is harder to overcome.

Output:
1
2025-04-17 13:24:37,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.451 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.13) is slightly higher than Ligand B (61.36). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (-1.029) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.918) 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 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.462 and 0.77, respectively), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (6.049) has a very low DILI risk, significantly better than Ligand B (37.224).

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (90.229) has a higher BBB score than Ligand A (29.042), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.109 and -4.931), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.077 and -2.916), indicating poor aqueous solubility. Ligand A is slightly better.

**hERG:** Ligand A (0.115) has a lower hERG risk than Ligand B (0.902), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-0.811) has a lower (better) microsomal clearance than Ligand B (62.809), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.488) has a longer (better) in vitro half-life than Ligand B (-0.058).

**P-gp Efflux:** Ligand A (0.005) has lower P-gp efflux liability than Ligand B (0.268).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.7 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and P-gp efflux. However, it suffers from a low logP and poor solubility. Ligand B has a better logP and TPSA, but has a higher DILI risk, hERG risk, and poorer metabolic stability. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. While both have poor solubility and permeability, the superior safety and metabolic profile of Ligand A outweigh the slightly less optimal logP.

Output:
0
2025-04-17 13:24:37,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.434 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (44.81) is significantly better than Ligand B (88.6). Lower TPSA generally correlates with better cell permeability, crucial for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (A: 2.473, B: 1.359), 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 6. Lower HBA is generally preferred for better permeability, giving Ligand A an advantage.

**QED:** Ligand A (0.89) has a much higher QED score than Ligand B (0.688), indicating a more drug-like profile.

**DILI:** Ligand B (67.739) has a higher DILI risk than Ligand A (10.741). This is a significant concern, as a lower DILI score is highly desirable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.196) has a better BBB score than Ligand B (28.383), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.542) shows better Caco-2 permeability than Ligand B (-5.155).

**Aqueous Solubility:** Ligand A (-1.606) has better aqueous solubility than Ligand B (-3.349). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.864) has a lower hERG risk than Ligand B (0.253), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-1.244) has a much lower (better) microsomal clearance than Ligand B (48.083), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.602) has a better in vitro half-life than Ligand B (-30.721).

**P-gp Efflux:** Ligand A (0.068) shows lower P-gp efflux than Ligand B (0.07), which is slightly better.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While affinity is crucial, the difference of 0.8 kcal/mol is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Overall:** Ligand A consistently outperforms Ligand B across most crucial ADME properties (DILI, solubility, metabolic stability, permeability, hERG) and has a very respectable binding affinity. Ligand B's slightly better affinity is overshadowed by its significantly worse ADME profile, particularly the high DILI risk and poor metabolic stability.

Output:
0
2025-04-17 13:24:37,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold, and even better, below 90, suggesting good absorption. Ligand B (93.46) is still under 140, but less optimal than A.

**logP:** Both ligands have acceptable logP values (2.127 and 1.294), falling within the 1-3 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 better.

**QED:** Both have reasonable QED scores (0.822 and 0.621), indicating good drug-like properties.

**DILI:** Ligand A (37.767) has a significantly lower DILI risk than Ligand B (14.541). This is a major advantage for A.

**BBB:** Both have moderate BBB penetration (45.56 and 51.609). This isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.603 and -4.796), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.468 and -1.983), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG:** Ligand A (0.559) has a slightly higher hERG risk than Ligand B (0.071). B is much better here.

**Microsomal Clearance:** Ligand A (31.461) has a higher microsomal clearance than Ligand B (27.208), indicating lower metabolic stability. B is better here.

**In vitro Half-Life:** Ligand B (-3.052) has a negative half-life, which is not possible and indicates a very short half-life or a problem with the assay. Ligand A (5.119) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.171 and 0.007).

**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 stronger candidate despite some drawbacks. Its significantly better binding affinity (-8.0 vs -6.5 kcal/mol) is a major advantage for an enzyme target like SRC. While both have solubility and permeability issues, the superior affinity of A, combined with its lower DILI risk and reasonable half-life, make it more promising. Ligand B's negative half-life is a serious red flag. The hERG risk is slightly higher for A, but this can be addressed through further optimization.

Output:
1
2025-04-17 13:24:37,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.531 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (35.58) is significantly better than Ligand B (75.71). A TPSA under 90 is generally acceptable, but lower is better for permeability. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (4.513 and 2.652), falling within the 1-3 range. Ligand B is closer to the optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 4. Both are acceptable (<=10), but Ligand A is slightly preferred.

**6. QED:** Ligand A (0.704) has a better QED score than Ligand B (0.483), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.753) has a much lower DILI risk than Ligand B (18.108). Both are good, but A is better.

**8. BBB:** Ligand A (96.084) has a higher BBB penetration percentile than Ligand B (77.162). While not a primary concern for a kinase inhibitor, higher BBB is never detrimental.

**9. Caco-2 Permeability:** Ligand A (-4.304) and Ligand B (-4.379) have similar, very poor Caco-2 permeability values. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-4.39) and Ligand B (-2.597) have poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.938) has a slightly higher hERG risk than Ligand B (0.459). This favors Ligand B.

**12. Microsomal Clearance:** Ligand A (91.112) has a higher microsomal clearance than Ligand B (92.362). Higher clearance means lower metabolic stability, so Ligand B is slightly favored.

**13. In vitro Half-Life:** Ligand A (36.356) has a much longer in vitro half-life than Ligand B (-17.64). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.636) has lower P-gp efflux than Ligand B (0.107), which is better for bioavailability.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its better QED, lower DILI risk, higher BBB penetration, and significantly longer in vitro half-life. While Ligand B has slightly better logP, hERG, and clearance, the advantages of Ligand A in drug-like properties and metabolic stability outweigh these minor differences, especially considering the target is a kinase. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:24:37,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.841 and 395.874 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.4) is better than Ligand B (40.54), being below 140, suggesting good absorption.

**logP:** Both ligands have logP values (3.355 and 4.79) within the optimal 1-3 range, but Ligand B is pushing the upper limit.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are acceptable.

**QED:** Ligand A (0.893) has a significantly better QED score than Ligand B (0.643), indicating a more drug-like profile.

**DILI:** Ligand A (65.413) has a higher DILI risk than Ligand B (18.34), which is a significant concern.

**BBB:** Both have reasonable BBB penetration, but Ligand B (87.01) is better than Ligand A (74.564). This isn't a primary concern for a non-CNS target like SRC.

**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 have low hERG inhibition risk (0.617 and 0.854), which is good.

**Microsomal Clearance:** Ligand A (19.057) has a much lower microsomal clearance than Ligand B (71.379), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (34.694) has a longer half-life than Ligand B (5.48), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.259 and 0.558).

**Binding Affinity:** Ligand B (-8.5) has slightly better binding affinity than Ligand A (-8.0), but the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand A has a better QED, metabolic stability (lower Cl_mic, longer t1/2), and similar binding affinity. However, its DILI risk is considerably higher. Ligand B has a lower DILI risk, better BBB penetration, and slightly better binding affinity, but suffers from poorer QED and metabolic stability.

Given the enzyme-kinase focus, metabolic stability and potency are key. While the affinity difference is small, the significantly lower DILI risk of Ligand B, coupled with acceptable metabolic properties, makes it the more promising candidate despite the slightly lower QED. The poor solubility and permeability are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 13:24:37,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.447 and 364.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (112.73 and 106.34) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.322) is slightly low, potentially hindering permeation. Ligand B (1.014) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** 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 (0.64 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (13.687) has a significantly lower DILI risk than Ligand B (44.281). This is a major advantage for Ligand A.

**BBB:** Ligand B (70.531) has a better BBB penetration than Ligand A (57.736), but BBB is not a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.538 and -5.72), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.882 and -1.737), indicating poor aqueous solubility. This is a concern for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.161 and 0.122), which is excellent.

**Microsomal Clearance:** Ligand A (-10.679) has significantly lower (better) microsomal clearance than Ligand B (7.706). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-20.057) has a much longer in vitro half-life than Ligand B (-3.704), indicating greater stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.063).

**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:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and comparable binding affinity. While Ligand B has slightly better affinity and BBB penetration, the lower DILI and improved metabolic properties of Ligand A are more critical for an enzyme inhibitor. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:24:37,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.411 and 355.341 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.5) is well below the 140 threshold and good for oral absorption. Ligand B (101.73) is still acceptable but slightly higher.

**3. logP:** Ligand A (2.492) is optimal (1-3). Ligand B (0.92) is a bit low, potentially hindering permeability, but not drastically.

**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 reasonably high QED scores (0.804 and 0.741), indicating good drug-like properties.

**7. DILI:** Ligand A (76.503) has a higher DILI risk than Ligand B (39.938). This is a significant concern.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.794) is higher than Ligand B (77.433).

**9. Caco-2 Permeability:** Ligand A (-4.615) has worse Caco-2 permeability than Ligand B (-5.138), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.22) is worse than Ligand B (-2.748), indicating lower solubility.

**11. hERG Inhibition:** Ligand A (0.098) has a slightly higher hERG inhibition risk than Ligand B (0.459), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (39.022) has higher microsomal clearance than Ligand B (-8.949), indicating lower metabolic stability. This is a significant drawback.

**13. In vitro Half-Life:** Ligand A (1.687) has a shorter half-life than Ligand B (-8.148), further supporting lower metabolic stability.

**14. P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux than Ligand B (0.059).

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly lower, its superior binding affinity, lower DILI risk, better solubility, and significantly improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the minor drawbacks. The stronger binding affinity is crucial for an enzyme inhibitor. Ligand A's higher DILI and lower metabolic stability are major red flags.

Output:
1
2025-04-17 13:24:37,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (392.897 and 362.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.83) is slightly above the preferred <140, but acceptable. Ligand B (57.26) is well within the range.

**logP:** Ligand A (3.952) is approaching the upper limit of the optimal range (1-3), while Ligand B (2.911) is comfortably within it.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.584 and 0.869), indicating good drug-like properties.

**DILI:** Ligand A's DILI risk (97.867) is very high, a significant concern. Ligand B's DILI risk (20.9) is excellent, well below the 40 threshold.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (85.459) has a higher BBB score than Ligand A (63.474), but this is not a major factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.079 and -1.567). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.345) has a slightly higher hERG risk than Ligand B (0.629), but both are reasonably low.

**Microsomal Clearance:** Ligand A (37.176) has moderate clearance, while Ligand B (-17.331) has negative clearance, which is not possible and likely indicates an error or extrapolation issue. However, assuming it means very low clearance, it suggests much better metabolic stability.

**In vitro Half-Life:** Ligand A (76.464) has a good half-life. Ligand B (23.064) has a shorter half-life, which is less desirable.

**P-gp Efflux:** Ligand A (0.552) has lower P-gp efflux than Ligand B (0.171), which is preferable.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has 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:**

The primary deciding factor is the extremely high DILI risk associated with Ligand A. While its binding affinity is much better, the liver toxicity risk is a major red flag. Ligand B has a much better safety profile (DILI) and better metabolic stability (inferred from the negative Cl_mic), despite a weaker binding affinity. The solubility issues are concerning for both, but can potentially be addressed with formulation strategies. Given the enzyme-specific priorities, metabolic stability and safety are crucial.

Output:
1
2025-04-17 13:24:37,611 - INFO - Batch 211 complete. Total preferences: 3376
2025-04-17 13:24:37,611 - INFO - Processing batch 212/512...
2025-04-17 13:25:26,259 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.427 and 366.527 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (94.82) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (1.837 and 1.647), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.618 and 0.745), indicating a drug-like profile. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 89.259, which is quite high, suggesting potential liver toxicity. Ligand B has a much lower DILI risk of 40.054, which is good. This is a significant advantage for Ligand B.

**BBB:** Both have low BBB penetration (58.007 and 54.478), which is not a major concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.419 and -5.013), 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 have negative solubility values (-2.723 and -2.982), suggesting poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.262 and 0.422), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (48.016) than Ligand B (16.111). This indicates that Ligand B is more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A has a negative half-life (-17.189), which is problematic. Ligand B has a negative half-life as well (-15.378), but slightly less negative. Both are concerning.

**P-gp Efflux:** Both have low P-gp efflux liability (0.358 and 0.204).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.9 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme inhibitor. While both have issues with solubility and half-life, the toxicity profile of Ligand A is a major concern.

Output:
1
2025-04-17 13:25:26,259 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.386 Da) is slightly better positioned.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (90.21). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have good logP values (A: 2.505, B: 2.159), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=0, HBA=8). While both are acceptable, higher HBA can sometimes lead to off-target interactions.

**QED:** Both ligands have reasonable QED scores (A: 0.933, B: 0.625), indicating good drug-like properties. Ligand A is superior.

**DILI:** Ligand B (90.733) has a significantly higher DILI risk than Ligand A (60.644). This is a major concern, as liver toxicity is a common reason for drug failure.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (93.68) is much higher than Ligand B (34.626), but this is not a primary driver in this case.

**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:** Ligand A (0.635) has a slightly better hERG profile than Ligand B (0.118), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (4.919) has a much lower microsomal clearance than Ligand B (39.954). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-26.494) has a significantly longer in vitro half-life than Ligand A (-6.799). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux than Ligand B (0.25), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a crucial advantage, as potency is paramount for kinase inhibitors. The 2 kcal/mol difference is substantial.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its superior binding affinity, lower DILI risk, better TPSA, lower microsomal clearance (better metabolic stability), and lower P-gp efflux outweigh the longer half-life of Ligand B. The unusual negative values for Caco-2 and solubility are concerning for both, but the strong affinity and favorable ADME properties of Ligand A make it the better choice.

Output:
1
2025-04-17 13:25:26,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.359 Da and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.28) is slightly above the preferred <140, but acceptable. Ligand B (87.14) is excellent, well below 140.

**logP:** Ligand A (0.405) is quite low, potentially hindering permeability. Ligand B (2.554) 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 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.784 and 0.497), suggesting good drug-like properties. Ligand A is better here.

**DILI:** Both ligands have relatively high DILI risk (75.456 and 72.16), but are still within a range that can be tolerated if other properties are strong.

**BBB:** Both have moderate BBB penetration (56.572 and 58.356), not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.029 and -5.203), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.443 and -2.852). This is a major drawback.

**hERG:** Ligand A (0.062) has a very low hERG risk, which is excellent. Ligand B (0.835) has a moderate hERG risk, which is less ideal.

**Microsomal Clearance:** Ligand A (39.296) has lower clearance than Ligand B (70.586), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.305) has a very short half-life, while Ligand B (28.472) has a much longer half-life.

**P-gp Efflux:** Both have very low P-gp efflux (0.017 and 0.368).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate despite the solubility and permeability issues. The significantly stronger binding affinity (-8.1 vs -7.6 kcal/mol) is a major advantage for an enzyme inhibitor, and can potentially outweigh some of the ADME concerns. The longer half-life of Ligand B is also a significant benefit. Ligand A has better hERG and metabolic stability, but the weaker binding and very short half-life are critical drawbacks. The poor solubility and permeability of both compounds would need to be addressed through formulation or further structural modifications, but Ligand B provides a better starting point due to its potency.

Output:
1
2025-04-17 13:25:26,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (363.483 and 364.917 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is better positioned for oral absorption due to its lower TPSA.

**3. logP:** Both ligands have acceptable logP values (2.213 and 3.597), falling within the 1-3 range. Ligand B is slightly higher, which *could* present a minor solubility issue, but is still within acceptable limits.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.894) has a better QED score than Ligand B (0.782), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.952) has a higher DILI risk than Ligand B (29.43). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (77.084 and 75.805). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. We'll assume these represent low permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual. We'll assume these represent low solubility.

**11. hERG:** Both ligands have low hERG risk (0.312 and 0.44). This is good.

**12. Cl_mic:** Ligand A (31.96) has significantly lower microsomal clearance than Ligand B (71.087), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. t1/2:** Both have similar in vitro half-lives (14.629 and 14.694 hours).

**14. Pgp:** Both have low Pgp efflux (0.248 and 0.217).

**15. Binding Affinity:** Both have very similar binding affinities (-8.5 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B has advantages in DILI risk and TPSA. However, Ligand A has a significantly better QED score and, crucially, much better metabolic stability (lower Cl_mic). Given that we are targeting a kinase, metabolic stability is paramount. While both have poor solubility and permeability, the better metabolic profile of Ligand A is more critical for *in vivo* efficacy. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 13:25:26,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.414 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is well below the 140 threshold for good absorption, while Ligand B (66.92) is still acceptable but less optimal.

**logP:** Both ligands have good logP values (2.787 and 2.134), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, which is favorable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.878) has a higher QED score than Ligand B (0.713), indicating better overall drug-likeness.

**DILI:** Both ligands show low DILI risk (35.944 and 34.742 percentile), which is excellent.

**BBB:** Ligand A has a higher BBB penetration (88.949%) than Ligand B (78.286%), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.696) has a lower Caco-2 permeability than Ligand B (-3.911), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.651) has lower aqueous solubility than Ligand B (-2.589). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.944 and 0.129), which is excellent.

**Microsomal Clearance:** Ligand A (15.201 mL/min/kg) has significantly lower microsomal clearance than Ligand B (105.085 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-1.162 hours) has a slightly negative half-life, which is concerning. Ligand B (-17.406 hours) has a much longer half-life, a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.312 and 0.044), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.8 kcal/mol). Ligand B is slightly better (-8.8 vs -8.3), but the difference is small.

**Conclusion:**

While Ligand B has better solubility and a significantly longer half-life, Ligand A has better QED, lower clearance, and acceptable solubility. The longer half-life of Ligand B is a substantial benefit, but the lower clearance of Ligand A is also very attractive. Given the slight edge in binding affinity for Ligand B and the more significant advantage in half-life, I would choose Ligand B.

Output:
1
2025-04-17 13:25:26,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Ligand A (346.402 Da) is within the ideal range (200-500 Da). Ligand B (491.35 Da) is at the upper limit, but still acceptable.

**TPSA:** Ligand A (70.59) is well below the 140 threshold for oral absorption. Ligand B (76.58) is also good.

**logP:** Ligand A (3.237) is within the optimal range (1-3). Ligand B (5.384) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (3) is within the acceptable limit of <=10. Ligand B (6) is also good.

**QED:** Ligand A (0.752) is excellent, indicating good drug-likeness. Ligand B (0.369) is significantly lower, suggesting potential issues.

**DILI:** Ligand A (44.087) has a low DILI risk. Ligand B (92.516) has a considerably higher DILI risk, which is concerning.

**BBB:** Both ligands have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic, but we'll consider other factors.

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

**hERG Inhibition:** Ligand A (0.712) has a lower hERG risk than Ligand B (0.841).

**Microsomal Clearance:** Ligand A (55.556 mL/min/kg) is better than Ligand B (76.236 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (35.014 hours) has a significantly longer half-life than Ligand A (1.078 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**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 still a factor.

**Overall Assessment:**

Ligand A has better drug-likeness (QED), lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. However, Ligand B has a much longer half-life. The higher logP and DILI risk of Ligand B are concerning. Considering the enzyme-specific priorities, metabolic stability and potency are key. The difference in binding affinity is relatively small, and the significantly longer half-life of Ligand B could outweigh its drawbacks, *if* the solubility and permeability issues can be addressed. However, the DILI risk is a significant concern.

Given the balance of factors, and prioritizing lower toxicity (DILI) and better metabolic stability, I would select Ligand A.

Output:
0
2025-04-17 13:25:26,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.415 Da) is slightly lower, which could be beneficial for permeability. Ligand B (397.777 Da) is also good.

**TPSA:** Ligand A (136.4) is borderline for good oral absorption, but acceptable. Ligand B (55.4) is excellent, suggesting good absorption.

**logP:** Ligand A (0.355) is quite low, potentially hindering permeation. Ligand B (3.697) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are within acceptable limits. Ligand B has 1 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (A: 0.645, B: 0.756), indicating drug-likeness.

**DILI:** Both ligands have high DILI risk (A: 82.435, B: 89.415), which is a concern. However, this is often a starting point for optimization.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (24.195) and B (56.65) are both low.

**Caco-2 Permeability:** Ligand A (-5.73) shows poor permeability. Ligand B (-4.79) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.19) has poor solubility. Ligand B (-5.46) is even worse. Solubility is a significant concern for both.

**hERG Inhibition:** Ligand A (0.102) shows very low hERG inhibition risk, which is excellent. Ligand B (0.797) has a moderate risk.

**Microsomal Clearance:** Ligand A (-1.973) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand B (64.643) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-5.833) has a very long half-life, which is highly desirable. Ligand B (-16.56) has a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.073, B: 0.283), which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly 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:**

Despite the high DILI risk for both, Ligand B is the more promising candidate. Its superior binding affinity (-8.2 vs -7.7 kcal/mol) is a major advantage for an enzyme target. While its solubility and metabolic stability are worse than Ligand A, the strong binding should allow for optimization of these properties without losing potency. Ligand A's poor logP and Caco-2 permeability are significant drawbacks. The excellent hERG profile of Ligand A is good, but can be addressed with modifications in Ligand B.

Output:
1
2025-04-17 13:25:26,260 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.447, 85.25, 1.405, 2, 5, 0.522, 38.154, 73.401, -5.107, -1.555, 0.175, 37.594, 20.428, 0.105, -6.2]
**Ligand B:** [353.526, 30.29, 4.611, 0, 4, 0.575, 3.218, 95.618, -4.355, -2.609, 0.969, 47.266, 39.757, 0.501, -8.5]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (348.447) is slightly lower, but acceptable.
2. **TPSA:** A (85.25) is higher than optimal (<140), but not drastically so. B (30.29) is excellent, well below the 140 threshold.
3. **logP:** A (1.405) is optimal. B (4.611) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.
4. **HBD:** A (2) and B (0) are both acceptable (<=5).
5. **HBA:** A (5) and B (4) are both acceptable (<=10).
6. **QED:** Both A (0.522) and B (0.575) are good, indicating drug-like properties.
7. **DILI:** A (38.154) is good, indicating low liver injury risk. B (3.218) is *excellent* - very low risk.
8. **BBB:** A (73.401) is decent, but B (95.618) is very good. While SRC isn't a CNS target, higher BBB is generally favorable.
9. **Caco-2:** A (-5.107) and B (-4.355) are both negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.
10. **Solubility:** A (-1.555) and B (-2.609) are both negative values, again making interpretation difficult without knowing the scale.
11. **hERG:** A (0.175) is very good, indicating low cardiotoxicity risk. B (0.969) is slightly higher, but still acceptable.
12. **Cl_mic:** A (37.594) is better than B (47.266) - lower clearance suggests better metabolic stability.
13. **t1/2:** B (39.757) has a significantly longer half-life than A (20.428), which is a major advantage.
14. **Pgp:** A (0.105) is better than B (0.501) - lower efflux means better bioavailability.
15. **Affinity:** B (-8.5) has a *much* stronger binding affinity than A (-6.2) - a difference of 2.3 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B is significantly better.
*   **Metabolic Stability:** A is better (lower Cl_mic), but B has a much longer half-life which is a strong counterpoint.
*   **Solubility:** Both are difficult to assess due to the negative scale values.
*   **hERG:** A is better.

**Overall Assessment:**

While Ligand A has some advantages in terms of metabolic stability and hERG risk, the *much* stronger binding affinity of Ligand B (-8.5 vs -6.2 kcal/mol) and its significantly longer half-life outweigh these drawbacks. The slightly higher logP of B is a potential concern, but the excellent DILI score and good BBB penetration are positives. The solubility and Caco-2 values are hard to interpret. The difference in binding affinity is substantial enough to make B the more promising candidate.

Output:
1
2025-04-17 13:25:26,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (341.411 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.03) is better than Ligand B (67.23), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands (1.846 and 2.067) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands (2 and 1) are within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors (HBA):** Both ligands (3 and 4) are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.89) has a better QED score than Ligand B (0.77), indicating higher drug-likeness.

**7. DILI:** Ligand A (72.78) has a higher DILI risk than Ligand B (24.855). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (76.735) has better BBB penetration than Ligand B (61.923), but this is less important for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.766) has better Caco-2 permeability than Ligand B (-5.018).

**10. Aqueous Solubility:** Ligand A (-4.816) has better aqueous solubility than Ligand B (-1.787).

**11. hERG Inhibition:** Ligand A (0.568) has a slightly better hERG profile than Ligand B (0.203).

**12. Microsomal Clearance (Cl_mic):** Ligand A (30.066) has lower microsomal clearance than Ligand B (40.099), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.012) has a longer half-life than Ligand B (-10.549). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux than Ligand B (0.066), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-7.9) has a significantly better binding affinity than Ligand A (-10.2). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. A difference of >1.5 kcal/mol is considered substantial.

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Conclusion:**

While Ligand A has advantages in QED, half-life, solubility, and metabolic stability, the significantly stronger binding affinity of Ligand B (-7.9 vs -10.2 kcal/mol) outweighs these benefits. Furthermore, Ligand B has a much lower DILI risk, which is a critical safety consideration. The difference in affinity is substantial enough to overcome the slightly less favorable ADME properties of Ligand B.

Output:
1
2025-04-17 13:25:26,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.46 & 354.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.33) is slightly higher than Ligand B (55.57). Both are below the 140 threshold for oral absorption, but neither is optimized for CNS penetration (below 90).

**logP:** Ligand A (-0.599) is significantly lower than Ligand B (3.872). Ligand A is below the optimal 1-3 range and may have permeability issues. Ligand B is at the higher end of the optimal 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.

**QED:** Both ligands have similar QED values (0.687 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (6.32) has a much lower DILI risk than Ligand B (18.534), which is a significant advantage.

**BBB:** Ligand A (36.293) has a very low BBB penetration, while Ligand B (96.355) has excellent BBB penetration. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.024) has poor Caco-2 permeability, while Ligand B (-3.965) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (0.656) has better aqueous solubility than Ligand B (-3.964). This is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.245 and 0.878), which is good.

**Microsomal Clearance:** Ligand A (-19.659) has significantly lower microsomal clearance than Ligand B (96.226), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-31.215) has a very long in vitro half-life, while Ligand B (-12.299) is shorter. This supports the better metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, while Ligand B (0.768) has moderate efflux.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-6.5), a difference of 1.4 kcal/mol.

**Overall Assessment:**

Ligand A is superior despite the slightly weaker binding affinity. Its significantly better DILI score, lower microsomal clearance (longer half-life), better solubility, and lower P-gp efflux outweigh the minor affinity difference. The poor Caco-2 permeability and low logP are concerns, but can be addressed with formulation strategies. Ligand B's high DILI risk and high clearance are major drawbacks.

Output:
0
2025-04-17 13:25:26,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.433 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.63) is well below the 140 threshold, suggesting good absorption. Ligand B (116.76) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.11) is optimal. Ligand B (-1.32) is significantly below the 1-3 range, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (3 & 4) and HBA (4 & 5) counts.

**QED:** Ligand A (0.562) is better than Ligand B (0.425), indicating a more drug-like profile.

**DILI:** Both have relatively low DILI risk (41.411 and 33.695), both below the 40 threshold.

**BBB:** Ligand A (70.415) has good BBB penetration, while Ligand B (29.003) is low. This is less critical for a non-CNS target like SRC, but a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.76) is poor, while Ligand B (-5.204) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-2.048) is poor, while Ligand B (-1.354) is also poor. Both are problematic.

**hERG:** Both ligands have very low hERG risk (0.874 and 0.101), which is excellent.

**Microsomal Clearance:** Ligand A (34.72) is better than Ligand B (4.168) indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (58.742) is significantly better than Ligand B (-10.535), suggesting a longer duration of action.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.097 and 0.007), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), a difference of 0.7 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior overall. Ligand B's significantly negative logP is a major concern, likely leading to poor permeability and bioavailability. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), better QED, and better BBB penetration. Both have poor Caco-2 and solubility, but the other advantages of Ligand A outweigh the slightly weaker binding. The difference in binding affinity (0.7 kcal/mol) is not substantial enough to overcome the ADME liabilities of Ligand B.

Output:
1
2025-04-17 13:25:26,261 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.5 and 340.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.9) is better than Ligand B (95.7), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.66) is optimal, while Ligand B (0.50) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being <=5.

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

**QED:** Both ligands have similar, good QED values (0.64 and 0.69).

**DILI:** Ligand A (14.4) has a significantly lower DILI risk than Ligand B (58.4), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (51.4) is slightly better than Ligand B (44.6).

**Caco-2:** Ligand A (-4.77) is better than Ligand B (-5.39), indicating better intestinal absorption.

**Solubility:** Both ligands have poor solubility (-2.06 and -2.28). This is a concern for both, but could be addressed through formulation.

**hERG:** Both ligands have low hERG risk (0.21 and 0.13).

**Microsomal Clearance:** Ligand B (-14.2) has a much lower (better) microsomal clearance than Ligand A (66.8). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A (1.2) has a slightly better half-life than Ligand B (0.2).

**P-gp efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.08).

**Binding Affinity:** Ligand A (-7.1) has a significantly stronger binding affinity than Ligand B (-6.7), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand A excels in binding affinity and DILI risk, which are critical for a kinase inhibitor. While its solubility and clearance are not ideal, the strong binding and low toxicity profile are significant advantages. Ligand B has better metabolic stability but weaker binding affinity and a higher DILI risk. The difference in binding affinity is substantial enough to outweigh the better metabolic stability of Ligand B.

Output:
1
2025-04-17 13:25:26,261 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.443 and 360.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is better than Ligand B (58.98) as it is closer to the 140 threshold.

**logP:** Ligand B (3.517) is slightly higher than ideal (1-3), while Ligand A (1.541) is well within the optimal range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as it strikes a better balance between solubility and permeability.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable, falling under the 10 threshold.

**QED:** Both ligands have similar QED values (0.815 and 0.758), indicating good drug-likeness.

**DILI:** Ligand A (36.565) has a significantly lower DILI risk than Ligand B (49.399), making it more favorable.

**BBB:** Ligand B (91.431) shows better BBB penetration than Ligand A (54.207), but this is less critical for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.949 and -4.744) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.039 and -4.058) which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.115) has a lower hERG inhibition liability than Ligand B (0.336), which is a significant advantage.

**Microsomal Clearance:** Ligand A (7.097) has a lower microsomal clearance than Ligand B (58.919), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.094) has a longer in vitro half-life than Ligand B (0.719), which is desirable.

**P-gp Efflux:** Ligand A (0.033) has lower P-gp efflux liability than Ligand B (0.187).

**Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. While both ligands have excellent binding affinity, Ligand A demonstrates superior ADME properties, including lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. Although both have poor Caco-2 and solubility, the other advantages of Ligand A make it the better choice for further development as an SRC kinase inhibitor.

Output:
0
2025-04-17 13:25:26,261 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.354 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.45) is well below the 140 threshold, while Ligand B (73.83) is still acceptable but higher.

**logP:** Ligand A (3.781) is at the upper end of the optimal range (1-3), while Ligand B (1.197) is slightly below, potentially impacting permeability.

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

**QED:** Both ligands have good QED scores (0.716 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (91.819) has a high DILI risk, which is a significant concern. Ligand B (13.843) has a very low DILI risk, a major advantage.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.226) has poor Caco-2 permeability, while Ligand B (-5.088) is also poor.

**Aqueous Solubility:** Ligand A (-5.575) and Ligand B (-1.549) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.754) and Ligand B (0.511) have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (131.387) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (-17.78) has *negative* clearance, which is impossible and likely an error in the data, but suggests extremely high stability.

**In vitro Half-Life:** Ligand A (20.944 hours) has a reasonable half-life, while Ligand B (13.973 hours) is also acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.259 and 0.041), which is favorable.

**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 huge.

**Conclusion:**

Despite Ligand B's slightly lower logP and Caco-2 permeability, its overwhelmingly superior DILI score and potentially very high metabolic stability (indicated by the negative clearance value, which is likely an error but points to high stability) make it the more promising candidate. Ligand A's high DILI risk is a major red flag. The small difference in binding affinity is outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 13:25:26,261 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, potentially aiding permeability.

**TPSA:** Ligand A (88.17) is significantly better than Ligand B (41.29). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (2.483) is within the optimal range (1-3). Ligand B (4.16) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, 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 (A: 0.635, B: 0.77), indicating generally drug-like properties.

**DILI:** Ligand A (48.119) has a slightly higher DILI risk than Ligand B (34.626), but both are below the concerning threshold of 60.

**BBB:** Both have good BBB penetration, but Ligand B (82.784) is better than Ligand A (70.686). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.104) has a worse Caco-2 permeability score than Ligand B (-4.721), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.98) has a worse solubility score than Ligand B (-4.441), which is a concern for bioavailability.

**hERG:** Ligand A (0.629) has a lower hERG risk than Ligand B (0.882), which is a significant advantage. Kinase inhibitors often have hERG liabilities, so minimizing this risk is crucial.

**Microsomal Clearance:** Ligand A (70.359) has a higher microsomal clearance than Ligand B (57.707), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (16.187) has a slightly better in vitro half-life than Ligand A (26.793).

**P-gp Efflux:** Ligand A (0.068) has a much lower P-gp efflux liability than Ligand B (0.665), which is favorable for oral bioavailability.

**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, as potency is a primary concern for kinase inhibitors.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better MW and P-gp efflux, Ligand B excels in the most critical areas: significantly better binding affinity, lower logP, better solubility, and lower hERG risk. The slightly higher metabolic clearance of Ligand B is a manageable concern compared to the substantial benefits it offers. The lower TPSA of Ligand B is also a plus.

Output:
1
2025-04-17 13:25:26,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.362 and 375.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (118.8), being well below the 140 threshold for good oral absorption. Ligand B is approaching a TPSA that could hinder absorption.

**logP:** Ligand A (2.973) is optimal (1-3). Ligand B (-0.024) is slightly below 1, which *could* indicate permeability issues, though not drastically.

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

**H-Bond Acceptors:** Ligand A (2) is good, while Ligand B (5) is acceptable but higher.

**QED:** Both ligands have similar QED values (0.774 and 0.618), indicating good drug-likeness.

**DILI:** Ligand A (19.62) has a much lower DILI risk than Ligand B (30.748), making it safer from a liver toxicity perspective. Both are below the concerning threshold of 60.

**BBB:** Ligand A (93.098) shows better BBB penetration than Ligand B (64.87), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.669) is significantly better than Ligand B (-5.195), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.129) is better than Ligand B (-1.667), indicating better solubility.

**hERG Inhibition:** Ligand A (0.609) has a lower hERG risk than Ligand B (0.091), which is a significant advantage.

**Microsomal Clearance:** Ligand A (6.292) has *much* lower microsomal clearance than Ligand B (31.241), suggesting significantly better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-22.928) has a longer in vitro half-life than Ligand B (-27.547).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.019).

**Binding Affinity:** Ligand B (-7.6) has a substantially 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 boasts a significantly better binding affinity, Ligand A demonstrates superior ADMET properties. Specifically, the lower DILI risk, better solubility, lower hERG risk, and dramatically improved metabolic stability (lower Cl_mic and longer half-life) of Ligand A are highly favorable. The slightly lower affinity of Ligand A could potentially be optimized through further medicinal chemistry efforts, while addressing the poor ADMET profile of Ligand B would be more challenging. Given the enzyme-kinase focus, metabolic stability and safety are paramount.

Output:
0
2025-04-17 13:25:26,262 - INFO - Batch 212 complete. Total preferences: 3392
2025-04-17 13:25:26,262 - INFO - Processing batch 213/512...
2025-04-17 13:26:05,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.515 and 363.498 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (40.54), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.006) is within the optimal 1-3 range, while Ligand B (3.685) is approaching the upper limit.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.711 and 0.784, respectively), indicating good drug-like properties.

**DILI:** Ligand A (31.02) has a slightly higher DILI risk than Ligand B (19.969), but both are well below the concerning threshold of 60.

**BBB:** Ligand A (62.233) has a lower BBB penetration compared to Ligand B (86.545). However, BBB penetration is less critical for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.245) has worse Caco-2 permeability than Ligand B (-4.559). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.371) has slightly better solubility than Ligand B (-4.181). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.182) has a significantly lower hERG inhibition risk than Ligand B (0.85). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (31.064) has a lower microsomal clearance than Ligand B (53.138), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.156) has a slightly lower half-life than Ligand B (4.49).

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.715), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-10.1 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.

**Conclusion:**

While Ligand A has better hERG and P-gp properties, the significantly stronger binding affinity of Ligand B (-10.1 vs -7.9 kcal/mol) outweighs the drawbacks in metabolic stability and permeability. The 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 manageable.

Output:
1
2025-04-17 13:26:05,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.477 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is well below the 140 threshold and good for oral absorption. Ligand B (64.17) is still acceptable, but less optimal.

**logP:** Ligand A (2.459) is within the optimal 1-3 range. Ligand B (0.112) is quite low, potentially hindering permeability.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.634 and 0.659), indicating good drug-likeness.

**DILI:** Ligand A (11.71) has a significantly lower DILI risk than Ligand B (7.716), which is a strong advantage.

**BBB:** Both have reasonably high BBB penetration (87.941 and 79.411), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.49 and -4.586), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.999 and -0.318), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.787) has a lower hERG risk than Ligand B (0.221), which is favorable.

**Microsomal Clearance:** Ligand A (6 mL/min/kg) has a higher (worse) microsomal clearance than Ligand B (0.036 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-28.879) has a significantly longer in vitro half-life than Ligand A (-15.761), which is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.088 and 0.007).

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a crucial difference, as a 2.6 kcal/mol advantage can often outweigh other drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-10.1 vs -7.5 kcal/mol) and much longer half-life (-28.879 vs -15.761) outweigh the slightly higher DILI risk and lower logP. The lower microsomal clearance of Ligand B also contributes to its improved metabolic stability. While both have issues, the potency and stability of Ligand B make it a better starting point for optimization.

Output:
1
2025-04-17 13:26:05,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 350.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.9) is higher than Ligand B (61.02). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (1.093) is slightly lower than the optimal 1-3 range, while Ligand B (3.063) is right within it. Ligand B has a more favorable logP.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Ligand B is better here, contributing to better permeability.

**QED:** Both ligands have good QED scores (0.678 and 0.731), indicating drug-like properties.

**DILI:** Ligand A (33.695) has a lower DILI risk than Ligand B (47.421), which is a positive attribute.

**BBB:** Ligand A (52.268) has a lower BBB penetration than Ligand B (71.811). Since SRC is not a CNS target, this is less critical, but still a slight advantage for B.

**Caco-2 Permeability:** Ligand A (-4.931) has worse Caco-2 permeability than Ligand B (-5.111). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-1.654) has better aqueous solubility than Ligand B (-3.268). This is a significant advantage for Ligand A, crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.364) has a lower hERG inhibition liability than Ligand B (0.921), which is a critical safety factor.

**Microsomal Clearance:** Ligand A (6.77) has a significantly lower microsomal clearance than Ligand B (22.552), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (5.164) has a shorter half-life than Ligand B (8.065), but both are reasonable.

**P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux liability than Ligand B (0.142), which is slightly better.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This difference of 0.9 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic), solubility, and hERG risk, all critical for an enzyme inhibitor. While Ligand B has a slightly better binding affinity and logP, the advantages of Ligand A in safety and PK properties are more important. The better solubility of Ligand A is also a significant factor.

Output:
0
2025-04-17 13:26:05,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.335 Da and 387.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is well below the 140 threshold and favorable for oral absorption. Ligand B (139.83) is approaching the upper limit, but still acceptable.

**logP:** Both ligands have good logP values (2.573 and 1.306), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=8) in terms of maintaining a balance between solubility and permeability. Ligand B's higher HBA count could potentially hinder permeability.

**QED:** Both ligands have acceptable QED scores (0.649 and 0.578), indicating reasonable drug-likeness.

**DILI:** Ligand A (52.423) has a much lower DILI risk than Ligand B (98.643). This is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (85.149) shows moderate penetration, while Ligand B (9.81) is very low.

**Caco-2 Permeability:** Ligand A (-4.45) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.386) is similarly poor. This is a concern for both, but the negative values suggest these are percentile scores where lower is worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.198 and -3.012). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.605) has a lower hERG risk than Ligand B (0.025), which is a significant advantage.

**Microsomal Clearance:** Ligand A (5.862) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (-12.973). This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (10.637) has a longer half-life than Ligand B (45.447). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux liability than Ligand B (0.076).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage that could potentially outweigh some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, its significantly higher DILI risk, poor metabolic stability (high Cl_mic), and lower in vitro half-life are major concerns. Ligand A, despite its weaker affinity, presents a much more favorable ADME profile with lower DILI, better metabolic stability, and a longer half-life. The poor Caco-2 and solubility for both are concerning, but could potentially be addressed through formulation strategies. Given the enzyme-specific priorities, the improved safety and pharmacokinetic properties of Ligand A make it the more promising candidate, even with the affinity difference.

Output:
0
2025-04-17 13:26:05,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.403 and 360.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.95) is better than Ligand B (55.57), being under the 90 A^2 threshold for CNS targets, although SRC is not a CNS target. Both are well within acceptable limits for oral absorption (<140).

**3. logP:** Ligand A (1.689) is optimal (1-3). Ligand B (3.769) is at the higher end of optimal, potentially raising concerns about off-target effects, but still acceptable.

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

**5. H-Bond Acceptors:** Both Ligand A (5) and Ligand B (5) are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.663 and 0.736, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (49.283) has a slightly better DILI risk profile than Ligand B (58.744), both being below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (59.868) and Ligand B (51.221) are both relatively low.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.683 and -4.631), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.624 and -3.904). This is a major drawback.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.397 and 0.416), which is excellent.

**12. Microsomal Clearance:** Ligand A (4.137) has significantly better metabolic stability (lower clearance) than Ligand B (70.68). This is a crucial advantage.

**13. In vitro Half-Life:** Ligand A (7.955) has a better in vitro half-life than Ligand B (30.707).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.299).

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 permeability and solubility for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.1 vs -7.0 kcal/mol), coupled with better metabolic stability (lower Cl_mic and longer t1/2), and slightly lower DILI risk, outweigh the shared issues of poor permeability and solubility. The strong binding affinity suggests that formulation strategies might be able to overcome the solubility issues, and the improved metabolic stability will likely lead to better *in vivo* exposure.

Output:
0
2025-04-17 13:26:05,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 and 363.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.32 and 88.39) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (1.24 and 1.89) are 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.702 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (39.9%) has a significantly lower DILI risk than Ligand B (69.3%). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (53.7%) is slightly better than Ligand A (40.5%).

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative values, indicating low solubility. Ligand B (-3.391) has slightly worse solubility than Ligand A (-2.665).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.063 and 0.191).

**Microsomal Clearance:** Ligand A (0.419 mL/min/kg) exhibits much better metabolic stability than Ligand B (78.167 mL/min/kg). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-11.79 hours) has a negative half-life, which is unusual. Ligand B (30.252 hours) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.085).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 1.0 kcal/mol, which is not a huge difference.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, and comparable drug-likeness properties. The improved metabolic stability and reduced toxicity risk are crucial for an enzyme target like SRC kinase. The negative half-life for Ligand A is concerning and would need further investigation, but the other advantages outweigh this issue.



Output:
0
2025-04-17 13:26:05,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.527 Da) is slightly lower, which could be beneficial for permeability. Ligand B (378.485 Da) is also good.

**TPSA:** Ligand A (24.5) is excellent, well below the 140 threshold for oral absorption. Ligand B (66.48) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (4.067) is at the upper end of the optimal range, potentially leading to solubility issues. Ligand B (2.402) is well within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.893) has a very strong drug-like profile. Ligand B (0.66) is still acceptable, but less ideal.

**DILI:** Ligand A (11.4) has a very low DILI risk. Ligand B (18.922) is also relatively low, but higher than Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 83.482, Ligand B: 87.553), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both 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 have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.628) is slightly better than Ligand B (-3.082).

**hERG Inhibition:** Ligand A (0.952) has a slightly higher hERG risk than Ligand B (0.645), but both are acceptable.

**Microsomal Clearance:** Ligand A (3.121) has a much lower microsomal clearance, indicating better metabolic stability. Ligand B (18.094) has a significantly higher clearance, which is a major concern.

**In vitro Half-Life:** Ligand A (28.691) has a longer half-life than Ligand B (-40.73), which is a significant advantage. The negative value for Ligand B is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**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 can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both have solubility concerns (negative values), Ligand A's significantly better binding affinity, lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and higher QED outweigh its slightly higher logP and hERG risk. The negative Caco-2 values are a concern for both, but the potency and metabolic stability of Ligand A are critical for kinase inhibitors.

Output:
1
2025-04-17 13:26:05,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.369 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is well below the 140 threshold, while Ligand B (89.35) is still acceptable but closer to the limit.

**logP:** Ligand A (2.523) is optimal (1-3), while Ligand B (0.597) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**H-Bond Acceptors:** Ligand A (3) is good, while Ligand B (6) is also acceptable, under the 10 limit.

**QED:** Both ligands have similar and good QED values (0.874 and 0.86).

**DILI:** Ligand A (35.983) has a significantly lower DILI risk than Ligand B (54.866), indicating a better safety profile. Both are below the 60 threshold.

**BBB:** Ligand A (85.615) has better BBB penetration than Ligand B (74.06), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.678) has poor Caco-2 permeability, while Ligand B (-4.647) is also poor. This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.184 and -2.85, respectively). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.455) has a much lower hERG inhibition risk than Ligand B (0.068). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-14.969) shows significantly better metabolic stability (lower clearance) than Ligand B (37.36). This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-15.135) has a longer in vitro half-life than Ligand B (-23.772), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.027 and 0.043).

**Binding Affinity:** Ligand B (-7.3 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.

**Conclusion:**

While Ligand B boasts a much stronger binding affinity, Ligand A exhibits a far superior safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), and acceptable TPSA. The poor solubility and Caco-2 permeability are concerns for both, but the substantial difference in binding affinity makes Ligand B more promising. The difference in binding affinity is greater than 1.5 kcal/mol, and thus outweighs the ADME drawbacks.

Output:
1
2025-04-17 13:26:05,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.463 and 373.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.67) is slightly above the preferred <90 for CNS targets, but acceptable for a non-CNS focused kinase inhibitor. Ligand B (79.8) is well within the desired range.

**logP:** Ligand A (0.346) is quite low, potentially hindering permeability. Ligand B (3.349) is closer to 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 5 HBA, and Ligand B has 7 HBA, both within the acceptable limit of <=10.

**QED:** Ligand A (0.69) has a better QED score than Ligand B (0.488), indicating better overall drug-likeness.

**DILI:** Ligand A (4.459) has a significantly lower DILI risk than Ligand B (81.388), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (63.94) has a higher BBB value than Ligand A (43.777), but this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.22 and -5.58). This 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 (-0.432 and -3.616). This is concerning and suggests poor aqueous solubility, which could impact bioavailability. Ligand B has worse solubility.

**hERG Inhibition:** Ligand A (0.212) has a much lower hERG risk than Ligand B (0.8), a significant advantage.

**Microsomal Clearance:** Ligand A (-32.992) has a much lower (better) microsomal clearance than Ligand B (99.854), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-10.911) has a negative half-life, which is unusual. Ligand B (55.499) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, while Ligand B (0.283) has slightly higher efflux.

**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).

**Overall Assessment:**

Ligand A is significantly better despite the negative Caco-2 and solubility values. The primary drivers are its much lower DILI risk, lower hERG risk, and significantly better metabolic stability (lower Cl_mic). The slightly better binding affinity of Ligand B is unlikely to outweigh these substantial ADME/Tox advantages of Ligand A. The negative Caco-2 and solubility values for both are concerning and would require further investigation (e.g., salt formation, formulation strategies), but are less critical than avoiding high DILI and hERG risk.

Output:
0
2025-04-17 13:26:05,133 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.419 Da and 371.418 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (92.67) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (70.16) is well within the ideal range.

**logP:** Ligand A (-0.083) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.737) is within the optimal range.

**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 (0.702 and 0.667, both >=0.5).

**DILI:** Ligand A (34.393) has a lower DILI risk than Ligand B (15.355), both being good (<40).

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have similar, very negative Caco-2 values (-4.821 and -4.769), indicating poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have similar, very negative solubility values (-0.956 and -0.959), indicating poor solubility. This is also a significant concern.

**hERG Inhibition:** Ligand A (0.046) has a lower hERG risk than Ligand B (0.226), which is preferable.

**Microsomal Clearance:** Ligand A (0.97) has significantly lower microsomal clearance than Ligand B (9.958), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (1.046) has a slightly longer half-life than Ligand B (0.656), which is also a positive.

**P-gp Efflux:** Ligand A (0.012) has much lower P-gp efflux than Ligand B (0.026), which is preferable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While both are excellent, the 0.8 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is superior. While both compounds have poor Caco-2 and solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, lower hERG risk, and slightly better binding affinity. The improved metabolic stability is particularly important for an enzyme target like SRC kinase, as it suggests a longer duration of action and potentially lower dosing requirements. The slightly better affinity further reinforces this choice.

Output:
0
2025-04-17 13:26:05,133 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.754 Da) is slightly higher than Ligand B (354.491 Da), but both are acceptable.

**TPSA:** Ligand A (95.67) is slightly higher than Ligand B (78.87). Both are below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have similar logP values (A: 1.608, B: 1.562), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 2 HBD and similar HBA counts (A: 5, B: 4), which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.823, B: 0.759), indicating good drug-like properties.

**DILI:** Ligand A (55.448) has a significantly higher DILI risk than Ligand B (16.285). This is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (59.946) and Ligand B (70.609) are both moderate.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.852 for A, -4.449 for B).

**Aqueous Solubility:** Both ligands have negative solubility values (-2.936 for A, -1.525 for B). This is also concerning and suggests poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.319, B: 0.208), which is positive.

**Microsomal Clearance:** Ligand A (-5.685) has a much lower (better) microsomal clearance than Ligand B (29.48). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (2.371) has a slightly longer half-life than Ligand B (-0.75), which is favorable.

**P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux than Ligand B (0.036), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a crucial advantage. The difference of 8 kcal/mol is substantial and can outweigh other drawbacks.

**Conclusion:**

Despite the solubility and Caco-2 concerns, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) is a major advantage for an enzyme target. Additionally, Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life. The DILI risk is higher for Ligand A, but the large difference in binding affinity might allow for a lower dose, potentially mitigating this risk. Ligand B's significantly lower DILI is appealing, but its extremely weak binding affinity makes it unlikely to be effective.

Output:
1
2025-04-17 13:26:05,133 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.471 and 363.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.21) is slightly higher than Ligand B (79.38). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands (1.51 and 1.877) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.798 and 0.845), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (66.344 and 69.794). This is a concern, but we'll consider it in the context of other properties.

**BBB:** Both have low BBB penetration (61.342 and 76.658). Since SRC is not a CNS target, this is not a major concern.

**Caco-2:** Both have negative Caco-2 values (-5.434 and -5.133). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon, indicating low permeability.

**Solubility:** Both ligands have very poor aqueous solubility (-3.106 and -3.481). This is a significant drawback.

**hERG:** Both ligands have low hERG risk (0.163 and 0.378), which is positive.

**Microsomal Clearance:** Ligand A (17.735 mL/min/kg) has significantly lower microsomal clearance than Ligand B (57.085 mL/min/kg). This suggests better metabolic stability for Ligand A, which is a high priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (19.241 hours) has a longer half-life than Ligand B (44.209 hours). This is also favorable for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.099 and 0.044).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.8 kcal/mol). The difference is negligible.

**Conclusion:**

While both compounds have good potency, Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic) and longer half-life. Although both have poor solubility and DILI risk, metabolic stability is a critical factor for kinase inhibitors. The slightly lower TPSA of Ligand B is not enough to offset the metabolic concerns.

Output:
0
2025-04-17 13:26:05,133 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.535 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (83.66) is still under 140, but less favorable than A.

**logP:** Both ligands have logP values within the optimal 1-3 range (2.672 and 1.473).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.684 and 0.73), indicating drug-like properties.

**DILI:** Ligand A (16.324) has a significantly lower DILI risk than Ligand B (34.161). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (78.209) is higher than Ligand B (49.981), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.64) and Ligand B (-4.965) both have negative Caco-2 values, which is unusual. It suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.962 and -2.647), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.508) has a slightly higher hERG risk than Ligand B (0.32), but both are relatively low.

**Microsomal Clearance:** Ligand A (54.058) has a higher microsomal clearance than Ligand B (23.565), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (12.786 hours) has a significantly longer half-life than Ligand A (3.063 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.23 and 0.048).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a very important factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a lower DILI risk, and better TPSA. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has better metabolic stability and a longer half-life, but its binding affinity is considerably weaker and its DILI risk is higher.

Given that we are targeting an enzyme (kinase), potency (binding affinity) is paramount. The 2.4 kcal/mol difference in binding affinity is substantial. While the solubility and metabolic stability of Ligand A are concerns, these can potentially be addressed through further optimization. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 13:26:05,133 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (347.296 and 368.543 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.25) is slightly above the preferred <140, but acceptable. Ligand B (58.64) is well within the range.

**3. logP:** Ligand A (4.619) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.298) is 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 (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.724 and 0.749), indicating good drug-like properties.

**7. DILI:** Ligand A has a very high DILI risk (98.022%), which is a major concern. Ligand B has a much lower and acceptable DILI risk (21.365%).

**8. BBB:** BBB is less critical for a systemic oncology target. Ligand A (80.264) and Ligand B (69.794) are both reasonable, but not a deciding factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.571 and -5.053), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-6.055 and -3.46), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Ligand A (0.774) has a slightly higher hERG risk than Ligand B (0.421), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (59.244) has a higher microsomal clearance than Ligand B (52.366), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (89.403) has a significantly longer half-life than Ligand B (4.955), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.358) has lower P-gp efflux than Ligand B (0.064), which is favorable.

**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:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. The extremely high DILI risk associated with Ligand A is a deal-breaker. Ligand B has a better logP, lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The longer half-life of Ligand A is a positive, but doesn't outweigh the significant DILI risk. Given the focus on enzymes, metabolic stability and safety (DILI, hERG) are critical.

Output:
1
2025-04-17 13:26:05,133 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 347.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is better than Ligand B (53.4), both are below the 140 threshold for oral absorption, but Ligand B is closer to the 90 threshold for CNS penetration (though this isn't a priority for SRC).

**logP:** Both ligands have a logP of approximately 2.2, which is optimal (1-3).

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have good QED scores (0.816 and 0.887), indicating good drug-likeness.

**DILI:** Ligand B (14.308) has a significantly lower DILI risk than Ligand A (44.126). This is a major advantage for Ligand B.

**BBB:** Ligand B (68.282) has a higher BBB penetration percentile than Ligand A (52.268), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.904) has a worse Caco-2 permeability than Ligand B (-5.108). Both are negative, indicating poor permeability, but Ligand B is slightly better.

**Aqueous Solubility:** Ligand A (-1.408) has a slightly better aqueous solubility than Ligand B (-1.561). Both are poor, but A is better.

**hERG Inhibition:** Ligand A (0.24) has a lower hERG inhibition liability than Ligand B (0.524). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (32.57) has a much lower microsomal clearance than Ligand A (60.574), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (28.747) has a much longer in vitro half-life than Ligand A (7.877). This is another significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.1) has a lower P-gp efflux liability than Ligand B (0.02). This is a slight advantage for Ligand A.

**Binding Affinity:** Ligand B (-7.5) has a significantly stronger binding affinity than Ligand A (0.0). This is the most important factor, and the 7.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better solubility and hERG inhibition, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better binding affinity (-7.5 vs 0.0 kcal/mol), much lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2). The stronger binding affinity alone is enough to outweigh the minor drawbacks of Ligand B.

Output:
1
2025-04-17 13:26:05,133 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.39 and 353.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.81) is better than Ligand B (112.73), being closer to the <140 threshold for good absorption.

**logP:** Both ligands (0.213 and 0.261) are quite low. While not drastically outside the 1-3 range, they are on the lower end and could potentially impact permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.703) has a significantly better QED score than Ligand B (0.489), indicating a more drug-like profile.

**DILI:** Ligand B (5.273) has a much lower DILI risk than Ligand A (53.432), which is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration (43.583 and 49.011). This is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.118 and -5.525), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.648 and -1.345), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.18) has a slightly lower hERG risk than Ligand B (0.233), which is preferable.

**Microsomal Clearance:** Ligand A (24.677) has a higher microsomal clearance than Ligand B (2.904), meaning Ligand B is more metabolically stable. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-14.027) has a negative half-life, which is not physically possible and indicates a major issue with the data or the compound's stability. Ligand A (10.821) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.016).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a much better DILI score and significantly better metabolic stability (lower Cl_mic). However, its half-life is nonsensical. Ligand A has a better QED score and a reasonable half-life but a significantly higher DILI risk. The poor solubility and permeability are major concerns for both. Given the enzyme-specific priorities, metabolic stability is crucial. The negative half-life for Ligand B is a showstopper, even with the better DILI and Cl_mic. While Ligand A has a higher DILI risk, it's a known parameter that could be addressed through structural modifications. The negative half-life suggests a fundamental instability issue with Ligand B.

Output:
0
2025-04-17 13:26:05,133 - INFO - Batch 213 complete. Total preferences: 3408
2025-04-17 13:26:05,134 - INFO - Processing batch 214/512...
2025-04-17 13:27:00,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 355.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (72.36), both are below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.566) is optimal, while Ligand B (3.82) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Both have 1 HBD, which is good.

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

**QED:** Both ligands have good QED scores (0.56 and 0.682, respectively), indicating drug-like properties.

**DILI:** Ligand A (14.618) has a significantly lower DILI risk than Ligand B (65.762). This is a major advantage for Ligand A.

**BBB:** Both have good BBB penetration (71.229 and 76.696), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.874) and Ligand B (-5.252) both show poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.838) is better than Ligand B (-3.712), indicating better solubility.

**hERG Inhibition:** Ligand A (0.27) has a much lower hERG risk than Ligand B (0.769). This is a significant advantage.

**Microsomal Clearance:** Ligand A (56.43) has lower microsomal clearance than Ligand B (86.074), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.682) has a longer in vitro half-life than Ligand B (-24.899).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.091 and 0.495).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand A is significantly better overall. It has a much lower DILI risk, lower hERG inhibition, better solubility, and better metabolic stability (lower Cl_mic and longer t1/2). Although both have poor Caco-2 permeability, the superior safety and pharmacokinetic properties of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 13:27:00,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (362.499 and 372.481 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.33) is higher than Ligand B (49.41). Both are below 140, but Ligand B is significantly better, potentially indicating improved cell permeability.

**3. logP:** Both ligands have good logP values (1.337 and 2.877, respectively), falling within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Ligand A has 3 HBDs, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.61 and 0.73), indicating a generally drug-like profile.

**7. DILI:** Ligand A (37.611) has a slightly higher DILI risk than Ligand B (20.396). Both are below 40, which is good.

**8. BBB:** Ligand A (42.032) has a lower BBB penetration percentile than Ligand B (92.943). Since SRC is not a CNS target, this is less critical, but a higher BBB value is generally preferable.

**9. Caco-2 Permeability:** Ligand A (-5.387) has a negative Caco-2 value, which is concerning. Ligand B (-4.874) is also negative, but slightly less so. Both suggest poor intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.557) has very poor aqueous solubility. Ligand B (-3.976) is also poor, but less so than Ligand A. Solubility is important for *in vivo* bioavailability.

**11. hERG Inhibition:** Ligand A (0.306) has a lower hERG inhibition liability than Ligand B (0.83). Lower is better, making Ligand A slightly more favorable here.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-10.446) has a significantly *lower* (better) microsomal clearance than Ligand B (44.845). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (31.032) has a longer in vitro half-life than Ligand B (-1.072). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.137). Lower is better, indicating better bioavailability.

**15. Binding Affinity:** Ligand B (-10.8) has a slightly better binding affinity than Ligand A (-8.6). This is a 1.5kcal/mol difference, which is significant.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a better binding affinity, which is a major advantage. However, Ligand A excels in metabolic stability (Cl_mic, t1/2), P-gp efflux, and has a slightly better hERG profile. Both have poor Caco-2 permeability and solubility. The substantial difference in Cl_mic and t1/2, coupled with the lower P-gp efflux for Ligand A, are very important for an enzyme target. While the affinity difference is notable, the improved pharmacokinetic properties of Ligand A are likely to translate to better *in vivo* exposure and efficacy.

Output:
0
2025-04-17 13:27:00,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.401 and 353.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is slightly higher than Ligand B (51.27), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (0.937) is slightly lower than the optimal 1-3 range, but still acceptable. Ligand B (3.718) is within the optimal range.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is good.

**QED:** Both ligands have similar QED values (0.634 and 0.646), indicating good drug-likeness.

**DILI:** Ligand A (19.891) has a significantly lower DILI risk than Ligand B (26.018), which is a major advantage.

**BBB:** Ligand A (95.347) has better BBB penetration than Ligand B (87.864), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.639) is slightly worse than Ligand A (-4.45).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.084) is slightly better than Ligand B (-2.556).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.504 and 0.742).

**Microsomal Clearance:** Ligand A (19.091) has significantly lower microsomal clearance than Ligand B (66.216), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (1.655) has a positive half-life, while Ligand B (-15.124) has a negative half-life, which is highly unfavorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.076 and 0.524).

**Binding Affinity:** Both ligands have excellent binding affinity (-8 and -9 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a slightly better logP and binding affinity, but Ligand A excels in crucial ADME properties for an enzyme target. Specifically, it has a much lower DILI risk, significantly better metabolic stability (lower Cl_mic and positive half-life), and slightly better solubility. The negative Caco-2 and solubility values are concerning for both, but the superior metabolic profile of Ligand A outweighs the minor binding affinity advantage of Ligand B.

Output:
0
2025-04-17 13:27:00,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
*   Ligand A: 448.308 Da - Within the ideal range (200-500 Da).
*   Ligand B: 372.466 Da - Also within the ideal range.
*   *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 51.02 A<sup>2</sup> - Excellent, well below the 140 A<sup>2</sup> threshold for oral absorption.
*   Ligand B: 104.21 A<sup>2</sup> - Still acceptable for oral absorption, but higher than Ligand A.
*   *Ligand A is preferred.*

**3. Lipophilicity (logP):**
*   Ligand A: 4.115 - Slightly above the optimal 1-3 range, potentially leading to solubility issues or off-target effects.
*   Ligand B: 2.177 - Within the optimal range.
*   *Ligand B is preferred.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 0 - Good, minimizes potential issues.
*   Ligand B: 3 - Acceptable, within the limit of 5.
*   *Ligand A is slightly preferred.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 4 - Good, within the limit of 10.
*   Ligand B: 6 - Acceptable, within the limit of 10.
*   *Both are acceptable.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.565 - Good, above the 0.5 threshold.
*   Ligand B: 0.649 - Very good, slightly better than Ligand A.
*   *Ligand B is preferred.*

**7. DILI Risk (DILI):**
*   Ligand A: 59.17 - Moderate risk, approaching the higher risk threshold of 60.
*   Ligand B: 61.342 - Moderate risk, slightly higher than Ligand A.
*   *Ligand A is slightly preferred.*

**8. Blood-Brain Barrier Penetration (BBB):**
*   Ligand A: 79.217 - Acceptable, but not highly desirable as SRC is not a CNS target.
*   Ligand B: 65.529 - Lower BBB penetration, which is fine for a non-CNS target.
*   *Neither is a strong factor.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.889 - Indicates poor permeability.
*   Ligand B: -4.876 - Indicates poor permeability.
*   *Both are similar and concerning.*

**10. Aqueous Solubility:**
*   Ligand A: -4.085 - Poor solubility.
*   Ligand B: -4.363 - Poor solubility, slightly worse than Ligand A.
*   *Ligand A is slightly preferred.*

**11. hERG Inhibition:**
*   Ligand A: 0.847 - Acceptable risk.
*   Ligand B: 0.311 - Lower risk, very good.
*   *Ligand B is preferred.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 98.355 mL/min/kg - High clearance, indicating poor metabolic stability.
*   Ligand B: 66.233 mL/min/kg - Still relatively high, but better than Ligand A.
*   *Ligand B is preferred.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: 103.49 hours - Excellent, long half-life.
*   Ligand B: -28.196 hours - Negative value is concerning and likely indicates very rapid degradation.
*   *Ligand A is strongly preferred.*

**14. P-gp Efflux:**
*   Ligand A: 0.571 - Acceptable.
*   Ligand B: 0.331 - Lower efflux, which is beneficial.
*   *Ligand B is preferred.*

**15. Binding Affinity:**
*   Ligand A: -9.4 kcal/mol - Excellent, very strong binding.
*   Ligand B: -6.4 kcal/mol - Good, but significantly weaker than Ligand A.
*   *Ligand A is strongly preferred.*

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate despite its higher logP and DILI risk. The significantly stronger binding affinity (-9.4 kcal/mol vs -6.4 kcal/mol) and much longer half-life (103.49 hours vs -28.196 hours) outweigh the drawbacks. While both have poor Caco-2 permeability and solubility, the superior potency and stability of Ligand A make it a better starting point for optimization. Ligand B has better hERG and Pgp profiles, but the weak binding and extremely short half-life are major concerns.

Output:
1
2025-04-17 13:27:00,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.547 Da) is slightly better, being closer to the lower end which generally aids permeability.

**TPSA:** Both are acceptable, being below 140. Ligand A (78.51) is preferable as it is lower than Ligand B (82.62), suggesting better absorption.

**logP:** Ligand A (1.029) is optimal, while Ligand B (5.104) is quite high. High logP can lead to solubility issues and off-target interactions, making Ligand A more favorable.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and Ligand A has acceptable HBA (4) while Ligand B has a higher HBA (8), which could slightly hinder permeability.

**QED:** Ligand A (0.731) has a good drug-likeness score, while Ligand B (0.352) is significantly lower, indicating a less favorable overall profile.

**DILI:** Ligand A (14.967) has a very low DILI risk, while Ligand B (96.588) has a very high DILI risk. This is a major red flag for Ligand B.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (66.576) is better than Ligand B (38.852).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.986) is slightly better than Ligand B (-5.007).

**hERG Inhibition:** Ligand A (0.22) has a very low hERG risk, while Ligand B (0.88) has a moderate risk.

**Microsomal Clearance:** Ligand A (-6.076) has a negative clearance, which is excellent (indicates high metabolic stability). Ligand B (48.178) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-3.059) has a negative half-life, which is excellent (very long half-life). Ligand B (47.908) has a moderate half-life.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME liabilities of Ligand B.

**Overall:**

Ligand A is significantly better. It has a superior safety profile (DILI, hERG), better metabolic stability (Cl_mic, t1/2), better drug-likeness (QED), and a more optimal logP. While Ligand B has slightly better binding affinity, the substantial drawbacks in ADME properties make it a less viable candidate. The difference in binding affinity (0.2 kcal/mol) is unlikely to overcome the significant liabilities of Ligand B.

Output:
0
2025-04-17 13:27:00,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.293 Da) is slightly higher than Ligand B (349.387 Da), but both are acceptable.

**TPSA:** Ligand A (39.08) is significantly better than Ligand B (100.88). Lower TPSA generally improves absorption.

**logP:** Ligand A (4.475) is higher than the optimal range (1-3), potentially causing solubility issues, but not drastically so. Ligand B (0.296) is *much* lower than optimal, suggesting poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.766, B: 0.769).

**DILI:** Both ligands have similar DILI risk (A: 45.095, B: 48.623), and are both acceptable.

**BBB:** Ligand A (76.464) has a better BBB percentile than Ligand B (35.595), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.734) is better than Ligand B (-5.283), but both are poor.

**Aqueous Solubility:** Ligand A (-4.943) is better than Ligand B (-2.088), but both are poor.

**hERG:** Ligand A (0.895) has a lower hERG risk than Ligand B (0.099), which is a significant advantage.

**Microsomal Clearance:** Ligand A (46.292) is significantly better than Ligand B (-15.692). Lower clearance indicates better metabolic stability, a crucial factor for enzymes.

**In vitro Half-Life:** Ligand A (1.542) is better than Ligand B (32.408), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.85) is better than Ligand B (0.012). Lower efflux is generally preferred.

**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 less than 1.5 kcal/mol, and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly in metabolic stability (Cl_mic, t1/2), hERG risk, and TPSA. The higher logP of Ligand A is a minor concern, but the substantial improvements in other key parameters outweigh this drawback. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (hERG) are paramount.

Output:
1
2025-04-17 13:27:00,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.463 and 356.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is slightly higher than Ligand B (67.87), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.683) is a bit low, potentially hindering permeation. Ligand B (2.075) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

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

**QED:** Both ligands have similar QED values (0.672 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (11.594) has a slightly higher DILI risk than Ligand B (10.469), but both are well below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (74.021 and 70.182), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.868) has significantly worse Caco-2 permeability than Ligand B (-4.14).

**Aqueous Solubility:** Ligand A (-1.192) has slightly better aqueous solubility than Ligand B (-1.803).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.146 and 0.282).

**Microsomal Clearance:** Ligand A (16.812) has a much lower microsomal clearance than Ligand B (74.495), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.125) has a significantly longer in vitro half-life than Ligand B (2.519).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.024).

**Binding Affinity:** Ligand A (-8.0) has a substantially stronger binding affinity than Ligand B (-6.7). This is a difference of 1.3 kcal/mol, which is significant.

**Conclusion:**

Despite Ligand A's slightly lower logP and worse Caco-2 permeability, its significantly superior binding affinity (-8.0 vs -6.7 kcal/mol), much better metabolic stability (lower Cl_mic and longer t1/2), and comparable safety profiles make it the more promising drug candidate. The 1.3 kcal/mol advantage in binding affinity outweighs the minor ADME drawbacks.

Output:
1
2025-04-17 13:27:00,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (365.459 Da) is also good.

**TPSA:** Ligand A (83.04) is excellent, well below the 140 threshold for oral absorption. Ligand B (100.35) is still acceptable, but less optimal.

**logP:** Ligand A (3.367) is within the optimal range (1-3). Ligand B (0.786) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, which is good. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.663, B: 0.785), indicating drug-like properties.

**DILI:** Ligand A (78.402) has a higher DILI risk than Ligand B (64.133), which is preferable.

**BBB:** Ligand A (82.474) has better BBB penetration than Ligand B (22.412), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.34) has poor Caco-2 permeability, while Ligand B (-5.419) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-4.734) has poor aqueous solubility, while Ligand B (-2.456) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.095) has very low hERG inhibition risk, a significant advantage. Ligand B (0.277) is also low, but higher than A.

**Microsomal Clearance:** Ligand A (111.337) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (21.628) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-42.512) has a very short in vitro half-life, a major drawback. Ligand B (-0.714) has a slightly better half-life, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.3, B: 0.03) which is good.

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

**Overall Assessment:**

Ligand A has a better binding affinity and lower hERG risk, but suffers from poor Caco-2 permeability, solubility, and metabolic stability (high Cl_mic, short t1/2). Ligand B has better metabolic stability and slightly better solubility, but weaker binding affinity and a higher DILI risk.

Given the enzyme-specific priorities, metabolic stability is crucial. While Ligand A's affinity is better, its poor metabolic stability and solubility are significant concerns. Ligand B, despite the slightly weaker binding, presents a more balanced profile with better metabolic properties. The difference in binding affinity (0.9 kcal/mol) is not large enough to overcome the substantial ADME liabilities of Ligand A.

Output:
1
2025-04-17 13:27:00,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.507 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (89.35 and 76.02) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (0.857 and 1.891).

**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:** Ligand A (0.765) has a significantly better QED score than Ligand B (0.387), indicating a more drug-like profile.

**DILI:** Ligand A (47.15) has a slightly higher DILI risk than Ligand B (33.307), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (67.08) is higher than Ligand B (44.824).

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.48 and 0.392), which is favorable.

**Microsomal Clearance:** Ligand A has a significantly lower (and better) microsomal clearance (-6.955 mL/min/kg) than Ligand B (34.498 mL/min/kg), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (5.257 hours) than Ligand B (-5.355 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.257 and 0.138).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.4 kcal/mol). Ligand B is slightly more potent.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate overall. Its superior QED score, significantly better metabolic stability (lower Cl_mic and longer t1/2), and better solubility profile outweigh the minor potency difference. The lower metabolic clearance of Ligand A suggests it will have a more favorable pharmacokinetic profile.

Output:
1
2025-04-17 13:27:00,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.519 and 350.463 Da) are within the ideal range (200-500 Da).

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (74.77). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (2.5) is optimal, while Ligand B (0.685) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED scores (0.766 and 0.672), indicating good drug-likeness.

**DILI:** Ligand A (10.702) has a much lower DILI risk than Ligand B (16.906), which is a significant advantage.

**BBB:** Ligand A (83.831) has better BBB penetration than Ligand B (59.325), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.819) and Ligand B (-4.777) have similar, poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.302) is slightly better than Ligand B (-0.605), but both are poor.

**hERG Inhibition:** Ligand A (0.708) has a lower hERG risk than Ligand B (0.171), which is a crucial safety consideration.

**Microsomal Clearance:** Ligand A (44.111) has a lower microsomal clearance than Ligand B (54.133), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.012) has a shorter half-life than Ligand B (24.877). This is a drawback for Ligand A, but can be mitigated with formulation.

**P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux than Ligand B (0.008), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -7.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is significantly better than Ligand B due to its superior DILI risk, lower hERG inhibition, better logP, TPSA, and P-gp efflux. While Ligand B has a longer half-life, the safety and ADME advantages of Ligand A outweigh this drawback. The similar binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 13:27:00,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.483 and 381.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (53.51), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have similar logP values (2.925 and 2.873), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the desired range (<=10).

**QED:** Both ligands have good QED scores (0.755 and 0.787), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.978, which is moderately high. Ligand B has a much lower DILI risk of 20.861, a significant advantage.

**BBB:** Ligand A (42.032) and Ligand B (76.851). BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2:** Both ligands have negative Caco-2 values (-5.224 and -4.987), which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Both ligands have negative solubility values (-2.863 and -2.797), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG:** Ligand A (0.291) and Ligand B (0.613). Both are relatively low, but Ligand B is slightly higher, indicating a slightly increased risk of hERG inhibition.

**Microsomal Clearance:** Both have similar microsomal clearance (67.971 and 67.396), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand A (37.492) has a positive half-life, while Ligand B (-10.991) has a negative half-life. This is concerning for Ligand B.

**P-gp Efflux:** Ligand A (0.148) and Ligand B (0.262). Both are relatively low, indicating limited P-gp efflux.

**Binding Affinity:** Ligand B (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate despite its poor solubility and Caco-2 permeability. The significantly stronger binding affinity (-10.6 vs -7.6 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk (20.861 vs 63.978) and a more reasonable in vitro half-life. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The lower DILI risk is particularly important.

Output:
1
2025-04-17 13:27:00,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.43 and 380.90 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.19) is better than Ligand B (81.42), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.66 and 3.26), falling 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 4 HBA. Both are below the 10 threshold.

**QED:** Both ligands have acceptable QED scores (0.829 and 0.772), indicating good drug-likeness.

**DILI:** Ligand A (62.35) has a slightly higher DILI risk than Ligand B (53.97), but both are acceptable (<60 is good).

**BBB:** Ligand A (54.87) has a lower BBB penetration than Ligand B (65.30). Since SRC is not a CNS target, this is less critical.

**Caco-2:** Ligand A (-4.665) and Ligand B (-5.169) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close, so this isn't a major differentiator.

**Solubility:** Ligand A (-4.983) has slightly worse solubility than Ligand B (-3.62), but both are poor. Solubility is a concern for both.

**hERG:** Ligand A (0.591) has a slightly better hERG profile than Ligand B (0.756), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (-2.753) has significantly *lower* (better) microsomal clearance than Ligand A (37.809). This suggests greater metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (43.675) has a significantly longer in vitro half-life than Ligand A (13.349), further supporting its improved metabolic stability.

**P-gp Efflux:** Ligand A (0.263) has lower P-gp efflux than Ligand B (0.518), which is slightly favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.4 kcal/mol). This difference of 1.4 kcal/mol is significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have some ADME liabilities (poor solubility, negative Caco-2), Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2) and *much* stronger binding affinity (-9.8 vs -8.4 kcal/mol) make it the more promising drug candidate for SRC kinase inhibition. The slightly better hERG profile of Ligand A is overshadowed by these factors.

Output:
1
2025-04-17 13:27:00,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.435 and 374.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.52) is better than Ligand B (93.21). Both are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (2.513) is optimal, while Ligand B (1.08) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable.

**QED:** Ligand A (0.848) has a significantly better QED score than Ligand B (0.664), indicating a more drug-like profile.

**DILI:** Ligand B (55.448) has a lower DILI risk than Ligand A (82.241), which is a significant advantage.

**BBB:** Ligand B (83.443) has a higher BBB penetration percentile than Ligand A (55.254), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.464) has a worse Caco-2 permeability than Ligand B (-5.041). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.61) has better aqueous solubility than Ligand B (-2.853).

**hERG Inhibition:** Ligand A (0.23) has a much lower hERG inhibition liability than Ligand B (0.418), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand B (6.575) has a significantly lower microsomal clearance than Ligand A (71.856), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (8.787 and 8.848 hours).

**P-gp Efflux:** Ligand A (0.276) has lower P-gp efflux liability than Ligand B (0.109).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand A has a better QED, solubility, hERG profile, and binding affinity. However, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The hERG risk for Ligand B is concerning, but the improved metabolic stability is valuable for an enzyme target. The slightly better affinity of Ligand A is a plus, but the DILI and metabolic stability of Ligand B are more important for kinase inhibitors.

Output:
1
2025-04-17 13:27:00,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.539 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is significantly better than Ligand B (89.55). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Ligand A (4.478) is higher than the optimal range of 1-3, potentially causing solubility issues. Ligand B (1.452) is within the optimal 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 reasonable QED scores (0.858 and 0.743), indicating good drug-like properties.

**DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (57.697), which is a significant advantage. Both are below the concerning threshold of 60, but lower is better.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (90.733) has a higher BBB percentile than Ligand B (49.981).

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

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Ligand A (0.925) has a lower hERG risk than Ligand B (0.199), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (40.292) has lower microsomal clearance than Ligand B (49.926), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (65.999 hours) has a much longer half-life than Ligand B (-15.895 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.406) has lower P-gp efflux than Ligand B (0.031), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-6.8 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite the better ADME profile of Ligand A, the significantly stronger binding affinity of Ligand B (-7.8 vs -6.8 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. While the solubility and permeability are concerning for both, potency is paramount. The improved metabolic stability and lower hERG risk of Ligand A are attractive, but the 1.0 kcal/mol difference in binding is likely to have a larger impact on efficacy.

Output:
1
2025-04-17 13:27:00,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.479 Da) is slightly better positioned than Ligand B (387.571 Da).

**TPSA:** Ligand A (64.17) is excellent, well below the 140 threshold for oral absorption. Ligand B (101.29) is still acceptable but less favorable.

**logP:** Ligand A (0.112) is quite low, potentially hindering permeability. Ligand B (1.302) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**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:** Ligand A (0.659) is good, indicating drug-likeness. Ligand B (0.491) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (7.716) has a very low DILI risk, which is excellent. Ligand B (25.165) is still relatively low, but higher than Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (79.411) is higher than Ligand B (57.58).

**Caco-2 Permeability:** Ligand A (-4.586) is poor, consistent with its low logP. Ligand B (-5.732) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.318) is poor. Ligand B (-3.108) is even worse. Both have solubility issues.

**hERG Inhibition:** Ligand A (0.221) has a very low risk of hERG inhibition, a major advantage. Ligand B (0.086) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (0.036) has very low clearance, indicating high metabolic stability. Ligand B (39.016) has significantly higher clearance, suggesting faster metabolism. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-28.879) has a very long half-life, consistent with low clearance. Ligand B (-18.157) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.033, respectively).

**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 excels in potency (binding affinity), metabolic stability (low Cl_mic, long t1/2), and DILI risk. Its main weaknesses are low logP and poor solubility/Caco-2 permeability. However, the strong binding affinity and favorable safety profile are compelling. Ligand B has a better logP but suffers from higher DILI risk, poorer metabolic stability, and a weaker binding affinity.

Given the enzyme-kinase focus, the strong binding affinity and metabolic stability of Ligand A are crucial. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The substantial difference in binding affinity (-1.3 kcal/mol) is a major factor.

Output:
1
2025-04-17 13:27:00,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight:** Both ligands (353.422 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.78) is well below the 140 threshold and suitable for oral absorption. Ligand B (78.43) is also below the threshold, but higher than A.

**3. logP:** Ligand A (4.198) is slightly above the optimal 1-3 range, potentially leading to solubility issues. Ligand B (2.509) is within the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have good QED scores (A: 0.578, B: 0.696), indicating drug-likeness.

**7. DILI:** Ligand A (81.815) has a high DILI risk (above 60), which is a significant concern. Ligand B (29.43) has a low DILI risk, which is very favorable.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (78.209) and Ligand B (41.14) are both moderate, but not a deciding factor.

**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 their relative comparison is important. A value of -5.366 (Ligand A) is better than -5.151 (Ligand B).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-2.477) is slightly better than Ligand A (-4.12).

**11. hERG Inhibition:** Ligand A (0.898) has a slightly higher hERG risk than Ligand B (0.25). Lower is better here.

**12. Microsomal Clearance:** Ligand A (66.814) has a higher Cl_mic than Ligand B (42.978). Lower is better for metabolic stability.

**13. In vitro Half-Life:** Ligand A (39.546) has a longer half-life than Ligand B (13.695). Longer is generally better.

**14. P-gp Efflux:** Ligand A (0.668) has a higher P-gp efflux liability than Ligand B (0.328). Lower is better.

**15. 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 substantial and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and has significantly better DILI and hERG profiles. While Ligand A has a longer half-life and slightly better Caco-2 permeability, the high DILI risk and weaker affinity of Ligand A are major drawbacks. The better metabolic stability of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 13:27:00,400 - INFO - Batch 214 complete. Total preferences: 3424
2025-04-17 13:27:00,400 - INFO - Processing batch 215/512...
2025-04-17 13:27:41,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (368.441 Da) is also good.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (100.94). A TPSA under 140 is desirable for oral absorption, but lower is generally better. Ligand A is much closer to the ideal range for good absorption.

**logP:** Both ligands have acceptable logP values (A: 1.883, B: 1.375), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=8). Lower values are generally preferred to balance solubility and permeability.

**QED:** Ligand A (0.909) has a much higher QED score than Ligand B (0.625), indicating a more drug-like profile.

**DILI:** Ligand B (39.356) has a better DILI score than Ligand A (20.9), indicating a lower risk of drug-induced liver injury. This is a significant advantage for Ligand B.

**BBB:** Ligand A (71.539) has a better BBB score than Ligand B (58.55). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.717) has a better Caco-2 permeability than Ligand B (-5.395).

**Aqueous Solubility:** Ligand A (-1.216) has better aqueous solubility than Ligand B (-2.224).

**hERG Inhibition:** Ligand A (0.228) has a much lower hERG inhibition liability than Ligand B (0.925), which is a critical advantage, reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (0.421) has significantly lower microsomal clearance than Ligand A (46.94), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (11.663) has a longer in vitro half-life than Ligand A (-3.203), which is also favorable.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux liability than Ligand B (0.136).

**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 small (0.4 kcal/mol), it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in metabolic stability (Cl_mic, t1/2), has a slightly better binding affinity, and a lower DILI risk. These are high priorities for an enzyme inhibitor. Ligand A has better solubility, permeability, and a much lower hERG risk. However, the metabolic stability and DILI profile of Ligand B are more critical for an enzyme target. The slightly better binding affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 13:27:41,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.386 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.81) is better than Ligand B (58.64) as both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.447 and 2.433), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 2 HBA) is slightly better than Ligand B (1 HBD, 3 HBA) in terms of balancing solubility and permeability. Both are well within acceptable limits.

**QED:** Both ligands have good QED scores (0.682 and 0.778), indicating a drug-like profile.

**DILI:** Ligand A (61.884) has a higher DILI risk than Ligand B (24.738). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (81 and 78.364), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.93) is significantly worse than Ligand B (-4.415), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.315) is worse than Ligand B (-2.915), which is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.802) has a slightly higher hERG risk than Ligand B (0.253).

**Microsomal Clearance:** Ligand B (79.614) has a much higher microsomal clearance than Ligand A (-3.29), suggesting lower metabolic stability and faster clearance. This is a significant negative for Ligand B.

**In vitro Half-Life:** Ligand A (20.424) has a significantly longer half-life than Ligand B (-18.467).

**P-gp Efflux:** Ligand A (0.339) has lower P-gp efflux than Ligand B (0.182), which is favorable.

**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 for Ligand A, potentially outweighing some of its ADME liabilities.

**Conclusion:**

Despite Ligand A's higher DILI risk and lower solubility/permeability, its *much* stronger binding affinity (-9.7 vs -6.8 kcal/mol) and better metabolic stability (lower Cl_mic, longer half-life) make it the more promising candidate. The affinity difference is large enough to potentially overcome the ADME issues through further optimization. Ligand B's high clearance is a major concern.

Output:
0
2025-04-17 13:27:41,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.411 and 346.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.08) is slightly higher than Ligand B (50.16). Both are below the 140 threshold for good oral absorption, but ligand B is better.

**logP:** Both ligands have good logP values (3.256 and 4.034), within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility issues, but not critically.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, and Ligand B has 3 HBA. Both are within the acceptable limits (<=10).

**QED:** Both ligands have good QED scores (0.789 and 0.895), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.646, which is higher than Ligand B's 20.279. This is a significant difference, with Ligand B being much safer.

**BBB:** Both have reasonable BBB penetration (73.672 and 78.79). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.343 and -4.546), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.983 and -3.636). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.674 and 0.588).

**Microsomal Clearance:** Ligand A (55.599) and Ligand B (52.683) have similar microsomal clearance values, indicating comparable metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (23.358 and 23.864 hours), which is good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.724 and 0.296). Ligand B is better.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). The difference is 0.8 kcal/mol, which is significant.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better in terms of DILI risk (a crucial factor for oncology drugs) and has slightly better P-gp efflux. The solubility is similar for both, and the metabolic stability is comparable. The binding affinity difference, while present, is likely outweighed by the improved safety profile of Ligand B.

Output:
1
2025-04-17 13:27:41,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.447 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly higher than Ligand B (58.64). Both are acceptable, but Ligand B's lower TPSA is preferable for better absorption.

**logP:** Both ligands have good logP values (1.205 and 2.439), 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 (0.839 and 0.764), indicating good drug-like properties.

**DILI:** Ligand A (29.779) has a significantly lower DILI risk than Ligand B (8.453), which is a major advantage.

**BBB:** Ligand A (62.582) has a lower BBB penetration than Ligand B (92.012). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.237) has a negative Caco-2 value, indicating poor permeability. Ligand B (-4.479) is also negative, but less so. This is a concern for both, but more so for A.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.813 and -2.182), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.072) has a very low hERG inhibition risk, which is excellent. Ligand B (0.578) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (12.094) has a lower microsomal clearance than Ligand B (25.983), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-4.171) has a more negative half-life, indicating a shorter half-life than Ligand B (-2.849). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.047).

**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 some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a much lower DILI risk, and better metabolic stability. However, it has poorer Caco-2 permeability and a shorter half-life. Ligand B has better permeability and half-life, but a higher DILI risk and weaker binding affinity. Given the importance of potency and safety (low DILI) for an oncology target like SRC kinase, and the fact that the affinity difference is substantial, Ligand A is the more promising candidate, despite its permeability and half-life concerns. These can be addressed through further optimization.

Output:
0
2025-04-17 13:27:41,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (355.425 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (39.72) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (66.92) is still under 140, but less optimal than A.

**logP:** Ligand A (4.597) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.866) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 threshold.

**QED:** Both ligands (A: 0.776, B: 0.701) have good drug-likeness scores, exceeding 0.5.

**DILI:** Ligand A (46.685) has a moderate DILI risk, while Ligand B (12.33) has a very low risk, which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (A: 88.29, B: 86.002), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**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. A's value (-4.785) is more negative than B's (-4.397), suggesting slightly worse permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. A's value (-4.799) is slightly worse than B's (-1.152).

**hERG Inhibition:** Ligand A (0.779) has a slightly higher hERG risk than Ligand B (0.201), which is preferable.

**Microsomal Clearance:** Ligand A (54.505) has a higher microsomal clearance than Ligand B (34.66), indicating lower metabolic stability. This is a crucial disadvantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-7.121) has a longer in vitro half-life than Ligand A (17.834). This is a strong advantage for B.

**P-gp Efflux:** Ligand A (0.442) has lower P-gp efflux than Ligand B (0.041), which is slightly better.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). Although the difference is small (0.6 kcal/mol), it's still a positive factor.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity. While Ligand A has a slightly better TPSA and P-gp efflux, these are outweighed by the advantages of Ligand B in terms of safety (DILI, hERG) and pharmacokinetics (Cl_mic, t1/2). The slightly higher logP of Ligand A is a concern, while Ligand B's logP is optimal.

Output:
1
2025-04-17 13:27:41,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.467 and 348.451 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.2) is well below the 140 threshold, and good for oral absorption. Ligand B (112.66) is still within acceptable limits but less optimal.

**logP:** Ligand A (2.878) is optimal (1-3). Ligand B (1.49) is on the lower side, potentially impacting permeability.

**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 reasonable QED scores (0.83 and 0.626), indicating good drug-like properties.

**DILI:** Ligand A (68.282) has a higher DILI risk than Ligand B (49.632), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.699) shows slightly better BBB penetration than Ligand A (54.091).

**Caco-2 Permeability:** Ligand A (-4.839) is better than Ligand B (-5.476), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.704) is better than Ligand B (-2.362), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.314) shows a significantly lower hERG risk than Ligand B (0.051), a crucial factor for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (15.454) has a lower microsomal clearance than Ligand B (26.335), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (70.761) has a much longer in vitro half-life than Ligand B (-12.235), which is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux than Ligand B (0.045), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This 1.5 kcal/mol difference is significant and could potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates a significantly superior ADMET profile. Its lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and lower P-gp efflux are all highly desirable characteristics for a kinase inhibitor. The difference in binding affinity (0.9 kcal/mol) is not large enough to overcome the substantial ADMET advantages of Ligand A.

Output:
1
2025-04-17 13:27:41,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (431.302 Da) is slightly higher, but acceptable. Ligand B (347.39 Da) is also good.

**TPSA:** Ligand A (41.57) is excellent, well below the 140 threshold. Ligand B (69.72) is still reasonable, but higher.

**logP:** Ligand A (4.164) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.942) is quite low, which could hinder permeability.

**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: 0.885), indicating good drug-like properties.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (48.623), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.474) has a slightly better BBB score than Ligand B (66.576).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.656 and -4.562), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-4.555 and -1.916). This is a major drawback.

**hERG Inhibition:** Ligand A (0.656) has a slightly higher hERG risk than Ligand B (0.22), but both are relatively low.

**Microsomal Clearance:** Ligand B (10.254 mL/min/kg) has significantly lower microsomal clearance than Ligand A (62.936 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (0.005 hours) has a very short half-life, while Ligand A (41.696 hours) has a much more desirable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.543 and 0.069), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -9.4 kcal/mol), with Ligand B being slightly better. The affinity difference is small, but could be relevant.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly lower microsomal clearance (better metabolic stability) and lower DILI risk are key advantages for an enzyme target like SRC kinase. While its logP is low and solubility is poor, these issues might be addressed through formulation strategies. Ligand A's higher logP and significantly higher clearance are more problematic. The poor Caco-2 and solubility are concerning for both, but metabolic stability is paramount for kinase inhibitors.

Output:
1
2025-04-17 13:27:41,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.211 Da) is slightly higher than Ligand B (344.346 Da), but both are acceptable.

**TPSA:** Ligand A (80.01) is well below the 140 threshold for oral absorption. Ligand B (110.25) is also acceptable, but closer to the limit.

**logP:** Ligand A (3.525) is within the optimal range (1-3). Ligand B (1.469) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.444, Ligand B: 0.562), indicating moderate drug-likeness. Ligand B is slightly better.

**DILI:** Both have relatively high DILI risk (Ligand A: 85.459, Ligand B: 81.311), but this isn't a dealbreaker at this stage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.064) has better BBB penetration than Ligand B (62.156).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.522 and -4.871), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-5.504 and -3.564), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.842) has a slightly higher hERG risk than Ligand B (0.443), but both are relatively low.

**Microsomal Clearance:** Ligand A (88.867) has a higher microsomal clearance, indicating lower metabolic stability, than Ligand B (41.468). This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-18.619) has a significantly longer in vitro half-life than Ligand A (-4.327), which is a major positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.522, Ligand B: 0.093), which is good.

**Binding Affinity:** Ligand A (-9.5 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's primary advantage is its much stronger binding affinity. However, it suffers from higher microsomal clearance, shorter half-life, and poorer solubility. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, but its binding affinity is considerably weaker. Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity (-9.5 vs -8.2 kcal/mol), the stronger binding of Ligand A is likely to be more impactful. While the solubility and metabolic stability are concerns, these can potentially be addressed through further optimization.

Output:
0
2025-04-17 13:27:41,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.443 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.25) is higher than Ligand B (59.08). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (4.443) is high, potentially leading to solubility issues and off-target effects. Ligand B (1.379) 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 aiding permeability.

**H-Bond Acceptors:** Both ligands have reasonable HBA counts (Ligand A: 3, Ligand B: 4), well below the 10 threshold.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.863, Ligand B: 0.767), indicating good drug-like properties.

**DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (31.02). Ligand B is significantly better here.

**BBB:** Both ligands have high BBB penetration (Ligand A: 83.366, Ligand B: 81.272), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-5.541) has very poor solubility, while Ligand B (-1.65) is slightly better, but still poor. This is a concern for both.

**hERG Inhibition:** Ligand A (0.515) has a slightly higher hERG risk than Ligand B (0.414), but both are relatively low.

**Microsomal Clearance:** Ligand A (79.493) has higher microsomal clearance, suggesting lower metabolic stability compared to Ligand B (2.789). This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-2.487) has a negative half-life, which is not possible. Ligand B (0.158) has a very short half-life, but is still better than a negative value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.394, Ligand B: 0.045), which is favorable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity. However, its high logP, poor solubility, and higher DILI risk are significant drawbacks. Ligand B has better ADME properties (lower logP, lower DILI, better metabolic stability), but its binding affinity is very weak.

Given the enzyme-kinase specific priorities, potency (affinity) is paramount. The >1.5 kcal/mol advantage of Ligand A in binding affinity is substantial enough to outweigh its ADME liabilities, *provided* that solubility can be addressed through formulation strategies. The poor solubility is a major hurdle, but the potency difference is significant.

Output:
1
2025-04-17 13:27:41,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (364.471 Da) is also good.

**TPSA:** Ligand A (57.0) is well below the 140 threshold for oral absorption and is also favorable. Ligand B (84.42) is still acceptable but less optimal.

**logP:** Both ligands have good logP values (A: 2.381, B: 1.109) falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 6 HBA) is also acceptable, but slightly higher counts might affect permeability.

**QED:** Both ligands have reasonable QED values (A: 0.758, B: 0.576), indicating good drug-like properties.

**DILI:** Ligand A (12.253) has a significantly lower DILI risk than Ligand B (57.193), which is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (77.821) is higher than Ligand B (57.231).

**Caco-2 Permeability:** Ligand A (-4.521) is better than Ligand B (-5.2), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.433) is better than Ligand B (-1.689). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.528) has a much lower hERG risk than Ligand B (0.057). This is a critical safety parameter.

**Microsomal Clearance:** Ligand B (32.825) has lower microsomal clearance than Ligand A (46.856), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-26.374) has a longer in vitro half-life than Ligand A (38.252), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.04, B: 0.014).

**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:**

Ligand A is superior due to its significantly better safety profile (lower DILI and hERG risk), better solubility, and permeability. While Ligand B has slightly better metabolic stability and binding affinity, the safety concerns associated with Ligand B outweigh these minor advantages, especially considering the relatively small difference in binding affinity. The improved ADME properties of Ligand A make it a more promising drug candidate.

Output:
0
2025-04-17 13:27:41,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.451 and 351.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (94.22 and 95.67) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (target <90 A^2). This is less critical for a non-CNS target like SRC.

**logP:** Ligand A (0.599) is slightly low, potentially hindering permeation. Ligand B (1.958) is better, 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 (0.813 and 0.783), indicating generally drug-like properties.

**DILI:** Ligand A (29.081) has a significantly lower DILI risk than Ligand B (39.434), which is a major advantage.

**BBB:** This is less important for SRC, but Ligand A (55.797) has slightly better BBB penetration than Ligand B (44.979).

**Caco-2 Permeability:** Ligand A (-5.208) and Ligand B (-4.779) both have negative values, suggesting poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.898 and -2.184) indicating poor solubility, a significant concern.

**hERG Inhibition:** Ligand A (0.128) has a much lower hERG risk than Ligand B (0.372), a critical advantage.

**Microsomal Clearance:** Ligand A (-18.025) has a much lower (better) microsomal clearance than Ligand B (26.043), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.229) has a shorter half-life than Ligand B (-2.958), which is less desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.016 and 0.138).

**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 significant ADME liabilities of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have solubility and permeability issues, Ligand A demonstrates a significantly better safety profile (lower DILI and hERG risk) and improved metabolic stability (lower Cl_mic). The slightly better affinity of Ligand B does not outweigh these critical advantages. Addressing the solubility and permeability issues through formulation or further structural modifications would be the next steps for Ligand A.

Output:
0
2025-04-17 13:27:41,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (360.523 and 368.825 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (124.42). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**3. logP:** Ligand A (3.783) is optimal, while Ligand B (0.327) is quite low, potentially hindering membrane permeability.

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

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

**6. QED:** Both ligands have acceptable QED values (0.839 and 0.71), indicating good drug-like properties.

**7. DILI:** Ligand A (37.999) has a much lower DILI risk than Ligand B (57.348), which is approaching a moderate risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.084) is better than Ligand B (57.193).

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not provided, so it's hard to interpret.

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not provided.

**11. hERG Inhibition:** Ligand A (0.504) has a much lower hERG risk than Ligand B (0.139). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (51.527) has a higher (worse) clearance than Ligand B (-25.392). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-10.636) has a longer half-life than Ligand A (-9.378).

**14. P-gp Efflux:** Both are very low (0.38 and 0.009), suggesting minimal P-gp efflux.

**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 its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, and better metabolic stability and half-life. However, it suffers from poor logP, higher TPSA, and a higher DILI risk. Ligand A has better ADME properties (logP, TPSA, DILI, hERG), but its binding affinity is very weak.

Given that we are targeting a kinase (enzyme class), potency (binding affinity) is paramount. The 1.8 kcal/mol difference in binding affinity is substantial. While Ligand B's ADME properties are less ideal, optimization efforts could focus on improving these while retaining the strong binding affinity. The poor logP and TPSA are the biggest concerns, but these are often addressable through chemical modifications. The DILI risk is moderate but manageable. Ligand A's weak binding affinity makes it unlikely to be a viable candidate, regardless of its better ADME profile.

Output:
1
2025-04-17 13:27:41,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 349.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.42) is better than Ligand B (52.65), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.207) is within the optimal 1-3 range. Ligand B (2.284) is also acceptable.

**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 3. Both are below the 10 threshold.

**QED:** Ligand A (0.866) has a significantly better QED score than Ligand B (0.684), indicating a more drug-like profile.

**DILI:** Ligand A (34.432) has a much lower DILI risk than Ligand B (11.012), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (66.964) is better than Ligand B (54.44).

**Caco-2 Permeability:** Ligand A (-5.109) has a worse Caco-2 permeability than Ligand B (-4.778).

**Aqueous Solubility:** Ligand A (-1.009) has a slightly better solubility than Ligand B (-2.15).

**hERG:** Ligand A (0.076) has a much lower hERG inhibition liability than Ligand B (0.39), which is a major advantage.

**Microsomal Clearance:** Ligand A (-1.218) has a lower (better) microsomal clearance than Ligand B (33.509), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.906) has a better in vitro half-life than Ligand B (10.339).

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.025).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This difference of 2.5 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a better QED score, significantly lower DILI and hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a substantially stronger binding affinity. While Ligand B has slightly better Caco-2 permeability, the overall profile of Ligand A is far more favorable for development as a drug candidate targeting SRC kinase.

Output:
1
2025-04-17 13:27:41,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption, and even favorable. Ligand B (96.97) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.733) is within the optimal 1-3 range. Ligand B (0.757) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 6 HBA) is still acceptable, but higher.

**QED:** Ligand A (0.848) is very good, indicating high drug-likeness. Ligand B (0.492) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (20.318) has a very low DILI risk. Ligand B (27.259) is also relatively low, but higher than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.194) is better than Ligand B (58.007), but not a deciding factor.

**Caco-2:** Ligand A (-4.365) and Ligand B (-5.347) are both negative, which is unusual. Lower (more negative) values suggest poor permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate a complete barrier.

**Solubility:** Ligand A (-3.158) and Ligand B (-1.363) are both negative, which is also unusual. Lower (more negative) values suggest poor solubility.

**hERG:** Both ligands have very low hERG risk (0.397 and 0.279 respectively).

**Microsomal Clearance:** Ligand A (51.863) has moderate clearance. Ligand B (27.8) has significantly lower clearance, indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (10.816 hours) has a reasonable half-life. Ligand B (-24.871 hours) has a negative half-life, which is likely an error in the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.013 respectively).

**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 concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, and much better metabolic stability (lower Cl_mic). While its QED is lower and logP is slightly suboptimal, the strong affinity and metabolic stability are crucial for an enzyme target. The negative half-life for Ligand B is concerning and likely an error. If corrected, it would further strengthen the case for Ligand B. Ligand A has better solubility and a higher QED, but the weaker binding and moderate clearance are drawbacks.

Output:
1
2025-04-17 13:27:41,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (385.848 and 353.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.37) is better than Ligand B (88.91), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (2.939 and 2.064), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 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:** Ligand A (0.802) has a significantly better QED score than Ligand B (0.665), indicating a more drug-like profile.

**DILI:** Ligand B (51.842) has a much lower DILI risk than Ligand A (85.576). This is a significant advantage for Ligand B.

**BBB:** Ligand B (67.468) has a higher BBB percentile than Ligand A (53.47), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.683) and Ligand B (-4.987) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-4.835) and Ligand B (-2.335) both have negative solubility values, which is also concerning. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.422) has a slightly higher hERG risk than Ligand B (0.065). This favors Ligand B.

**Microsomal Clearance:** Ligand B (25.363 mL/min/kg) has significantly lower microsomal clearance than Ligand A (61.444 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (4.578 hours) has a much shorter half-life than Ligand A (45.075 hours). This is a major drawback for Ligand B.

**P-gp Efflux:** Ligand A (0.251) has slightly higher P-gp efflux than Ligand B (0.042), 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 the most important factor, as a >1.5 kcal/mol advantage can outweigh other issues.

**Overall Assessment:**

While Ligand A has a better QED and longer half-life, Ligand B's overwhelmingly stronger binding affinity (-8.2 vs 0.0 kcal/mol) and significantly better metabolic stability (lower Cl_mic) are decisive. The lower DILI and hERG risk are also beneficial. The poor Caco-2 and solubility are concerning, but can potentially be addressed with formulation strategies. The shorter half-life is a drawback, but the potency may allow for more frequent dosing.

Output:
1
2025-04-17 13:27:41,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.345 Da) is slightly higher than Ligand B (335.407 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is significantly better than Ligand B (57.84). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have good logP values (A: 3.214, B: 3.153), 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 counts generally improve permeability.

**QED:** Both ligands have good QED scores (A: 0.597, B: 0.796), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (88.523) has a higher DILI risk than Ligand B (51.648). This is a significant concern, as a lower DILI risk is highly desirable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (77.898) is slightly better than Ligand B (48.662).

**Caco-2 Permeability:** Ligand A (-4.009) is better than Ligand B (-5.222). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-4.419) is better than Ligand B (-2.972). Higher solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.603) has a lower hERG risk than Ligand B (0.371), which is preferable.

**Microsomal Clearance:** Ligand B (18.777) has significantly lower microsomal clearance than Ligand A (96.545). Lower clearance indicates better metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-2.554) has a slightly better (less negative) in vitro half-life than Ligand A (-1.404).

**P-gp Efflux:** Both ligands have similar P-gp efflux values (A: 0.335, B: 0.334).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a crucial advantage, as a 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) and a lower DILI risk, the significantly stronger binding affinity of Ligand A (-9.5 vs -7.4 kcal/mol) is a decisive factor. The improved TPSA, solubility, and Caco-2 permeability of Ligand A also contribute to its favorability. The higher DILI risk of Ligand A is a concern, but could potentially be mitigated through structural modifications in further optimization. The potency advantage is substantial enough to prioritize Ligand A for further development.

Output:
1
2025-04-17 13:27:41,105 - INFO - Batch 215 complete. Total preferences: 3440
2025-04-17 13:27:41,105 - INFO - Processing batch 216/512...
2025-04-17 13:28:22,421 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.447 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.71) is slightly higher than Ligand B (88.32). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is closer to the 90 A^2 threshold for CNS targets, though that's not a primary concern here.

**logP:** Ligand A (0.1) is quite low, potentially hindering permeability. Ligand B (1.96) 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, but lower is generally preferred.

**QED:** Both ligands have good QED scores (0.734 and 0.851), indicating good drug-like properties.

**DILI:** Ligand A (84.141) has a higher DILI risk than Ligand B (41.877). This is a substantial negative for Ligand A.

**BBB:** This is less critical for a non-CNS target. Ligand A (48.779) is lower than Ligand B (89.027).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.755 vs -4.939).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, values are similar (-3.137 vs -2.679).

**hERG Inhibition:** Ligand A (0.234) has a slightly lower hERG risk than Ligand B (0.493), which is favorable.

**Microsomal Clearance:** Ligand A (15.131) has significantly higher microsomal clearance than Ligand B (4.295), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-42.707) has a much shorter in vitro half-life than Ligand B (-16.744), further supporting the lower metabolic stability concern.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.009 and 0.023).

**Binding Affinity:** Ligand A (-10.8 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 liabilities. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its significantly higher DILI risk, higher microsomal clearance, and shorter half-life are major concerns. Ligand B, while having a weaker binding affinity, possesses a much more favorable ADME profile, with lower DILI risk, better metabolic stability, and a longer half-life. The logP value of ligand B is also much more favorable. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The substantial affinity difference *might* be overcome with further optimization of Ligand B, but the liabilities of Ligand A are harder to address.

Output:
1
2025-04-17 13:28:22,421 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.386 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (60.69) is significantly better than Ligand B (78.43). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 3.005, B: 3.495), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=3, HBA=5) as it has fewer HBDs.

**QED:** Both ligands have reasonable QED scores (A: 0.746, B: 0.568), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (35.595) has a much lower DILI risk than Ligand B (71.772). This is a significant advantage.

**BBB:** Ligand A (85.692) has a higher BBB percentile than Ligand B (33.85). While not critical for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.132) has a better Caco-2 permeability than Ligand B (-5.357).

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-3.94 and -3.988). This is a potential concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.564, B: 0.678).

**Microsomal Clearance:** Ligand A (76.176) has a higher microsomal clearance than Ligand B (62.39), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (82.609) has a significantly longer in vitro half-life than Ligand A (4.868), which is a significant advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.424, B: 0.443).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). The difference is 0.8 kcal/mol, which is meaningful.

**Overall Assessment:**

Ligand A has several advantages: better TPSA, lower DILI risk, better Caco-2 permeability, and slightly better binding affinity. However, Ligand B has a significantly longer half-life and better metabolic stability (lower Cl_mic). The binding affinity difference is substantial enough to outweigh the metabolic concerns, especially considering SRC is an intracellular target where sufficient drug concentration can be maintained with appropriate dosing. The lower DILI risk of Ligand A is also a significant factor.

Output:
0
2025-04-17 13:28:22,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.487 Da and 362.861 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (76.02), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.815) is slightly lower than ideal (1-3), but acceptable. Ligand B (2.251) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.719 and 0.707), indicating good drug-likeness.

**DILI:** Ligand A (46.452) has a lower DILI risk than Ligand B (51.144), both are acceptable (<60).

**BBB:** Both ligands have similar BBB values (46.452 and 51.377), which is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.988) has worse Caco-2 permeability than Ligand B (-5.4), but both are very poor.

**Aqueous Solubility:** Ligand A (-2.502) has better solubility than Ligand B (-1.947), both are poor.

**hERG:** Ligand A (0.121) has a significantly lower hERG risk than Ligand B (0.696). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (68.342) has higher microsomal clearance than Ligand B (22.142), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (14.353) has a much longer in vitro half-life than Ligand A (-5.167), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.039) has a lower P-gp efflux liability than Ligand B (0.153).

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better solubility and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-9.4 vs -8.2 kcal/mol), much better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk are more critical for an enzyme target like SRC kinase. The slightly higher logP of Ligand B is also favorable. The Caco-2 and solubility are both poor, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:28:22,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.423 and 345.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.85) is slightly above the preferred <100 for optimal absorption, while Ligand B (95.73) is better, being comfortably below 140 and closer to the ideal.

**logP:** Ligand A (-0.965) is a bit low, potentially hindering permeation. Ligand B (-0.203) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is well within acceptable limits. Ligand B (1 HBD, 7 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.488 and 0.698), suggesting drug-like properties, with Ligand B being slightly better.

**DILI:** Ligand A (29.818) has a significantly lower DILI risk than Ligand B (47.848), which is a major advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.217) has better BBB penetration than Ligand A (49.477), but this isn't a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.486 and -5.123), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.16 and -1.744), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Ligand A (0.089) has a much lower hERG risk than Ligand B (0.215), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-18.737) has a much lower (better) microsomal clearance than Ligand B (43.447), indicating better metabolic stability. This is a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand A (4.558) has a shorter half-life than Ligand B (11.954), which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.022).

**Binding Affinity:** Ligand B (-7.8 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 drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor solubility and permeability, Ligand A exhibits significantly better metabolic stability (lower Cl_mic), lower DILI risk, and lower hERG risk. These are critical factors for an enzyme inhibitor. The slightly better binding affinity of Ligand B is not enough to offset these substantial ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 13:28:22,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.471 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.84) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (106.66) is still acceptable, but less optimal.

**logP:** Ligand A (2.787) is within the optimal 1-3 range. Ligand B (-0.983) is below 1, potentially hindering permeation.

**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 (0.847) has a very strong drug-like profile. Ligand B (0.59) is acceptable but less desirable.

**DILI:** Ligand A (37.728) has a low DILI risk. Ligand B (27.608) also has a low DILI risk, but slightly lower.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.284) is better than Ligand B (43.583).

**Caco-2 Permeability:** Ligand A (-4.791) and Ligand B (-5.288) both have negative 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:** Ligand A (-2.596) and Ligand B (-1.983) both have negative solubility values, suggesting poor solubility. Again, the scale is unknown.

**hERG:** Both ligands have very low hERG risk (0.068 and 0.047), which is excellent.

**Microsomal Clearance:** Ligand A (31.101) has a moderate clearance, while Ligand B (-15.715) has a negative clearance, which is highly favorable, indicating excellent metabolic stability.

**In vitro Half-Life:** Both ligands have similar and negative half-lives (-8.151 and -8.596), which is unusual and requires further investigation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.085 and 0.01).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a major deciding factor.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While both have good potency and low hERG risk, Ligand B exhibits significantly better metabolic stability (negative Cl_mic) and a slightly lower DILI risk. The lower logP of Ligand B is a concern, but the superior metabolic stability outweighs this drawback for an enzyme target like SRC kinase. The negative solubility and Caco-2 values for both are concerning and would need to be investigated further, but the overall profile of Ligand B is more favorable.

Output:
1
2025-04-17 13:28:22,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.34 Da) is slightly better, being closer to the lower end which can aid permeability. Ligand B (427.412 Da) is still acceptable.

**TPSA:** Ligand A (58.56) is significantly better than Ligand B (43.18). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have a logP around 4.0, which is at the upper limit of the optimal range. This could potentially lead to solubility issues or off-target interactions, but it's not a deal-breaker.

**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, but Ligand A's profile is slightly more balanced.

**QED:** Both ligands have reasonable QED scores (0.824 and 0.67), indicating good drug-like properties.

**DILI:** Ligand A (56.146) has a higher DILI risk than Ligand B (35.75). This is a significant concern for Ligand A.

**BBB:** Ligand B (78.79) has a better BBB penetration score than Ligand A (36.952). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.96) shows poor Caco-2 permeability, while Ligand B (-5.173) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.79 and -3.266 respectively). This is a major drawback for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.663) has a slightly higher hERG inhibition risk than Ligand B (0.796). Lower is better here.

**Microsomal Clearance:** Ligand A (27.207 mL/min/kg) has significantly lower microsomal clearance than Ligand B (50.503 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-4.215 hours) has a much longer in vitro half-life than Ligand B (13.803 hours). This is another significant advantage.

**P-gp Efflux:** Ligand A (0.322) has lower P-gp efflux than Ligand B (0.575), which is favorable for bioavailability.

**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 factor.

**Overall Assessment:**

Ligand A has several advantages: better TPSA, lower Cl_mic, longer t1/2, and lower P-gp efflux. However, its higher DILI risk and poor Caco-2 permeability are significant concerns. Ligand B has a slightly better binding affinity and lower DILI risk, but suffers from higher Cl_mic and shorter t1/2.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand A outweighs the slightly better affinity of Ligand B. The DILI risk of Ligand A is concerning, but could potentially be addressed through structural modifications. The poor solubility is a problem for both, but formulation strategies could be explored.

Output:
0
2025-04-17 13:28:22,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.373 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (71.34 and 69.72) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (4.411) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (0.905) is slightly below the optimal range, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <= 5 criteria.

**5. H-Bond Acceptors:** Both ligands (4) are below the HBA <= 10 criteria.

**6. QED:** Both ligands (0.703 and 0.774) have good drug-likeness scores.

**7. DILI:** Ligand A (96.51) has a very high DILI risk, which is a major concern. Ligand B (8.686) has a very low DILI risk, which is excellent.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (44.32) and Ligand B (57.929) are both relatively low.

**9. Caco-2 Permeability:** Ligand A (-4.822) and Ligand B (-5.002) both have negative Caco-2 values, suggesting poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.108) and Ligand B (-0.522) have poor solubility.

**11. hERG Inhibition:** Ligand A (0.89) and Ligand B (0.163) both have relatively low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (33.02) has moderate clearance, while Ligand B (-10.848) has negative clearance, indicating excellent metabolic stability.

**13. In vitro Half-Life:** Ligand A (125.449) has a good half-life. Ligand B (4.59) has a very short half-life, which is a significant drawback.

**14. P-gp Efflux:** Both ligands (0.461 and 0.012) have low P-gp efflux liability.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage.

**Conclusion:**

Despite Ligand B's poor solubility and short half-life, its *significantly* superior binding affinity (-7.9 vs -0.0 kcal/mol) and *extremely* low DILI risk outweigh the drawbacks. The high binding affinity suggests that even with lower bioavailability, it could still achieve therapeutic concentrations. The high DILI risk of Ligand A is a deal-breaker.

Output:
1
2025-04-17 13:28:22,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.471 and 343.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.44) is slightly higher than Ligand B (54.26), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.568 and 2.69), falling within the optimal range of 1-3.

**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:** Both ligands have similar QED scores (0.883 and 0.809), indicating good drug-likeness.

**DILI:** Ligand A (13.649) has a significantly lower DILI risk than Ligand B (48.546). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (73.905 and 79.139), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.723), which is unusual and suggests poor permeability. This is a concerning aspect for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.862 and -2.83), indicating poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.713 and 0.53).

**Microsomal Clearance:** Ligand A (-1.938) has a *much* lower (better) microsomal clearance than Ligand B (87.403). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (35.818) has a longer in vitro half-life than Ligand B (19.68). This is another advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.05) has a much lower P-gp efflux liability than Ligand B (0.344).

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is minimal (0.1 kcal/mol) and likely less important than the ADME differences.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have issues with solubility and Caco-2 permeability, Ligand A exhibits a much more favorable ADME profile: lower DILI risk, significantly lower microsomal clearance, longer half-life, and lower P-gp efflux. The small difference in binding affinity is outweighed by these substantial ADME advantages.

Output:
1
2025-04-17 13:28:22,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.704 Da) is slightly higher than Ligand B (350.467 Da), but both are acceptable.

**2. TPSA:** Ligand A (67.01) is well below the 140 threshold for oral absorption. Ligand B (92.15) is still within range, but less optimal.

**3. logP:** Ligand A (3.835) is at the higher end of the optimal range (1-3), while Ligand B (0.505) 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 3 HBA, and Ligand B has 6. Both are within the acceptable limit of 10, but Ligand B is higher.

**6. QED:** Both ligands have good QED scores (A: 0.609, B: 0.712), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 66.15, which is moderately high. Ligand B has a much lower DILI risk of 18.728, which is excellent.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.529) is higher than Ligand B (37.418).

**9. Caco-2 Permeability:** Ligand A (-4.932) is better than Ligand B (-5.573), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.575) is better than Ligand B (-0.5), suggesting better formulation potential.

**11. hERG Inhibition:** Ligand A (0.566) has a slightly higher hERG risk than Ligand B (0.054), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (24.841) has a higher clearance than Ligand B (-11.19), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-7.354) has a longer half-life than Ligand B (2.623), which is a positive.

**14. P-gp Efflux:** Ligand A (0.386) has lower P-gp efflux than Ligand B (0.002), which is favorable.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and longer half-life. However, it suffers from a higher DILI risk and lower metabolic stability (higher clearance). Ligand B has a much better safety profile (lower DILI) and metabolic stability, but its lower logP and weaker binding affinity are concerning.

Given the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG), the stronger binding affinity of Ligand A is a major advantage that could potentially outweigh its drawbacks. The difference in binding affinity (-8.1 vs -9.0) is substantial. While the DILI risk is a concern, it's not excessively high, and further optimization could address it. The lower metabolic stability is also a concern, but could be mitigated through structural modifications. The solubility of A is also better.

Output:
1
2025-04-17 13:28:22,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.435 Da and 357.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.97) is excellent, well below the 140 threshold for oral absorption. Ligand B (38.13) is also very good.

**logP:** Ligand A (1.207) is optimal. Ligand B (4.124) is approaching the upper limit and could potentially cause solubility issues or off-target effects, but is still within an acceptable range.

**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 good.

**QED:** Both ligands have reasonable QED scores (0.848 and 0.768), indicating good drug-like properties.

**DILI:** Ligand A (56.689) has a moderate DILI risk, but still acceptable. Ligand B (13.3) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (73.827) has moderate BBB penetration. Ligand B (93.835) has excellent BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.249) has poor Caco-2 permeability, which is a concern for oral absorption. Ligand B (-4.301) also has poor Caco-2 permeability, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.291) has poor aqueous solubility. Ligand B (-4.564) also has poor aqueous solubility, but worse than A.

**hERG Inhibition:** Ligand A (0.577) has a low hERG risk. Ligand B (0.868) has a slightly higher hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (15.11) has a moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (49.177) has a high microsomal clearance, indicating poor metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (33.832) has a reasonable in vitro half-life. Ligand B (-13.098) has a very short in vitro half-life, which is a major concern.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, which is favorable. Ligand B (0.554) has slightly higher P-gp efflux, but still reasonable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a very low DILI risk, and excellent BBB penetration. However, it suffers from poor metabolic stability (high Cl_mic, short t1/2) and poor solubility/permeability. Ligand A has better metabolic stability and permeability, but weaker binding affinity and a higher DILI risk.

Given the enzyme-specific priorities, binding affinity is paramount. The 1.8 kcal/mol difference in binding affinity is substantial. While the metabolic stability of Ligand B is a concern, it could potentially be addressed through structural modifications. The poor solubility/permeability could also be improved. The better DILI profile of Ligand B is also a plus.

Output:
1
2025-04-17 13:28:22,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (337.383 and 371.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.12) is better than Ligand B (98.74), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.46) is within the optimal 1-3 range. Ligand B (-0.019) is slightly below 1, which *could* indicate permeability issues, but is not a major concern at this stage.

**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 HBA, both are acceptable (<=10).

**QED:** Ligand A (0.74) has a better QED score than Ligand B (0.529), indicating better overall drug-likeness.

**DILI:** Ligand A (79.333) has a significantly higher DILI risk than Ligand B (13.843). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (53.083) is lower than Ligand B (36.371).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5 and -5.522). This is unusual and suggests poor permeability, but the scale isn't clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.973 and -1.457). Similar to Caco-2, this is concerning, but the scale is unclear.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.411 and 0.109). This is excellent.

**Microsomal Clearance:** Ligand A (-13.927) has *much* lower (better) microsomal clearance than Ligand B (10.528), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-1.823) has a negative half-life, which is not possible. Ligand B (-18.221) also has a negative half-life, which is also not possible. This is a data quality issue.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.063 and 0.008). This is good.

**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 B is the better candidate despite the negative solubility and half-life values. The significantly lower DILI risk is a major advantage. The slightly better binding affinity is a bonus. The negative values for Caco-2 and solubility are concerning, but could be artifacts of the data or scale. Ligand A's high DILI risk is a significant drawback that outweighs its slightly better QED and metabolic stability.

Output:
1
2025-04-17 13:28:22,423 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.315 Da) is slightly lower, which could be beneficial for permeability. Ligand B (366.527 Da) is also good.

**TPSA:** Ligand A (133.51) is borderline, but acceptable for oral absorption. Ligand B (67.43) is excellent, well below the 140 threshold.

**logP:** Ligand A (0.703) is a little low, potentially hindering permeation. Ligand B (3.273) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 9 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also good.

**QED:** Both ligands have similar, good QED values (0.775 and 0.778).

**DILI:** Ligand A has a high DILI risk (87.476), which is a significant concern. Ligand B has a much lower DILI risk (31.02), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (48.972) and Ligand B (56.301) are both low.

**Caco-2 Permeability:** Ligand A (-4.517) is poor, suggesting poor absorption. Ligand B (-5.023) is also poor, but comparable.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.878 and -3.053). This could pose formulation challenges.

**hERG:** Ligand A (0.091) has a slightly higher hERG risk than Ligand B (0.269), but both are relatively low.

**Microsomal Clearance:** Ligand A (92.166) has high microsomal clearance, indicating poor metabolic stability. Ligand B (54.687) has moderate clearance, better than A.

**In vitro Half-Life:** Ligand A (-13.115) has a very short half-life, a significant drawback. Ligand B (23.997) has a better, though not ideal, half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.078).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.9 kcal/mol). The difference is minimal.

**Conclusion:**

Despite similar binding affinities and QED scores, **Ligand B is the more promising candidate.** The primary driver is the significantly lower DILI risk (31.02 vs. 87.476). Additionally, Ligand B demonstrates better metabolic stability (lower Cl_mic, longer t1/2) and a more favorable logP. While both have poor solubility and Caco-2 permeability, the DILI and metabolic stability issues with Ligand A are more critical concerns for an enzyme target.

Output:
1
2025-04-17 13:28:22,423 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties crucial for enzyme-kinase inhibitors (potency, metabolic stability, solubility, and hERG risk).

**Ligand A:**

*   **MW:** 423.292 Da - Within the ideal range (200-500).
*   **TPSA:** 77.75 - Good for oral absorption, below the 140 threshold.
*   **logP:** 3.483 - Optimal (1-3).
*   **HBD:** 1 - Acceptable (<=5).
*   **HBA:** 7 - Acceptable (<=10).
*   **QED:** 0.634 - Good drug-like profile (>0.5).
*   **DILI:** 98.139 - Very high risk (>60). This is a significant concern.
*   **BBB:** 55.021 - Not a priority for a non-CNS target.
*   **Caco-2:** -4.767 - Poor permeability.
*   **Solubility:** -4.874 - Very poor solubility.
*   **hERG:** 0.571 - Low risk.
*   **Cl_mic:** 75.158 - Moderate clearance.
*   **t1/2:** 45.413 - Good in vitro half-life.
*   **Pgp:** 0.639 - Moderate efflux.
*   **Affinity:** -7.2 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 340.387 Da - Within the ideal range (200-500).
*   **TPSA:** 103.87 - Acceptable, but approaching the upper limit for optimal absorption.
*   **logP:** 0.998 - Low, potentially impacting permeability.
*   **HBD:** 2 - Acceptable (<=5).
*   **HBA:** 5 - Acceptable (<=10).
*   **QED:** 0.864 - Excellent drug-like profile (>0.5).
*   **DILI:** 64.521 - Moderate risk, but better than Ligand A.
*   **BBB:** 54.013 - Not a priority for a non-CNS target.
*   **Caco-2:** -5.284 - Poor permeability.
*   **Solubility:** -3.182 - Poor solubility.
*   **hERG:** 0.135 - Very low risk.
*   **Cl_mic:** 15.217 - Low clearance, indicating good metabolic stability.
*   **t1/2:** -10.197 - Very short half-life.
*   **Pgp:** 0.027 - Low efflux.
*   **Affinity:** -8.8 kcal/mol - Exceptional binding affinity, 1.6 kcal/mol better than Ligand A.

**Comparison & Decision:**

Both ligands have poor Caco-2 permeability and solubility, which are significant drawbacks. However, Ligand B possesses a substantially superior binding affinity (-8.8 vs -7.2 kcal/mol) and a much better metabolic stability profile (lower Cl_mic, though with a very short half-life). Ligand A has a very high DILI risk, which is unacceptable. While Ligand B's DILI risk is moderate, it's far preferable to Ligand A. The difference in binding affinity is substantial enough to potentially overcome the permeability and solubility issues with further optimization. The short half-life of Ligand B is a concern, but can be addressed through structural modifications.

Output:
1
2025-04-17 13:28:22,423 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (386.543 and 376.806 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.05) is better than Ligand B (37.49) as it is still within the acceptable range for oral absorption (<140), while Ligand B is quite low.

**logP:** Ligand A (1.482) is optimal (1-3). Ligand B (4.434) is slightly 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=3) both have reasonable numbers of H-bond donors and acceptors, well within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.795, B: 0.838), indicating drug-like properties.

**DILI:** Ligand A (66.382) has a higher DILI risk than Ligand B (47.732), which is preferable.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (90.035) is higher than Ligand A (70.803). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.635) has a lower Caco-2 permeability than Ligand B (-4.631).

**Aqueous Solubility:** Ligand A (-2.769) has better aqueous solubility than Ligand B (-4.765).

**hERG Inhibition:** Ligand A (0.256) has a significantly lower hERG inhibition risk than Ligand B (0.939), a crucial advantage.

**Microsomal Clearance:** Ligand A (3.16 mL/min/kg) has a lower microsomal clearance than Ligand B (29.759 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.948 hours) has a much longer in vitro half-life than Ligand B (-6.38 hours), indicating better duration of action.

**P-gp Efflux:** Ligand A (0.118) has lower P-gp efflux liability than Ligand B (0.754), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.3 vs -6.1 kcal/mol). However, it suffers from a higher logP, a higher hERG risk, and significantly higher microsomal clearance and lower in vitro half-life. Ligand A is better in terms of safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), solubility, and P-gp efflux. The difference in binding affinity is substantial (2.2 kcal/mol), and for an enzyme target, this is often the most critical factor. While Ligand A's ADME properties are better, the potency advantage of Ligand B is likely to outweigh these concerns, especially with potential for optimization of the ADME profile.

Output:
1
2025-04-17 13:28:22,423 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.455 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (94.83 and 91.42) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.213) is optimal, while Ligand B (0.284) is slightly 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 7 HBA, and Ligand B has 5, both are below the 10 limit.

**QED:** Both ligands have good QED scores (0.724 and 0.848), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (49.864 and 51.338, respectively), well below the 60 threshold.

**BBB:** Both have moderate BBB penetration (53.432 and 52.579), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.713 and -5.214). This 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 (-2.311 and -0.917). This is also concerning, suggesting poor solubility.

**hERG:** Both ligands show very low hERG inhibition risk (0.155 and 0.126).

**Microsomal Clearance:** Ligand A has a significantly lower (better) Cl_mic (-7.349) compared to Ligand B (15.245). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (14.92 hours) than Ligand B (-3.571 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.153 and 0.013).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a 0.5 kcal/mol difference, which is significant.

**Conclusion:**

Ligand A is the better candidate. While both ligands have issues with predicted solubility and permeability, Ligand A demonstrates superior binding affinity, significantly better metabolic stability (lower Cl_mic, longer half-life), and a slightly better logP value. The 0.5 kcal/mol difference in binding affinity is substantial enough to outweigh the potential drawbacks of the slightly lower logP and questionable permeability/solubility predictions. Given the enzyme-specific priorities, the stronger binding and improved metabolic stability of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 13:28:22,423 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.5 and 352.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.95) is significantly better than Ligand B (89.87). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (3.99) is optimal, while Ligand B (1.074) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 4 HBA) both are within acceptable limits.

**QED:** Ligand A (0.887) has a better QED score than Ligand B (0.624), indicating a more drug-like profile.

**DILI:** Ligand A (12.214) has a much lower DILI risk than Ligand B (10.237), which is a significant advantage.

**BBB:** Ligand A (78.364) has a better BBB penetration score than Ligand B (49.515), although BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.41) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.939) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.261) and Ligand B (-1.882) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.824) has a slightly higher hERG risk than Ligand B (0.099). This is a concern for Ligand A.

**Microsomal Clearance:** Ligand A (-11.728) has a much lower (better) microsomal clearance than Ligand B (21.571), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (31.07) has a much longer half-life than Ligand B (-9.186), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.28) has a lower P-gp efflux liability than Ligand B (0.006), which is favorable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 1.3 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the poor Caco-2 and solubility of Ligand A, its superior binding affinity, metabolic stability (low Cl_mic and long t1/2), lower DILI risk, and better QED score outweigh the drawbacks. The lower hERG risk of Ligand B is a positive, but the significantly worse metabolic stability and lower affinity are major concerns. The poor permeability of both is a concern that would need to be addressed in further optimization, but the stronger binding and better PK profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 13:28:22,423 - INFO - Batch 216 complete. Total preferences: 3456
2025-04-17 13:28:22,423 - INFO - Processing batch 217/512...
2025-04-17 13:29:08,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (349.362 and 348.374 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.82) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (91.57) is well within the acceptable range.

**3. logP:** Ligand A (0.494) is a bit low, potentially hindering permeation. Ligand B (2.981) is near 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:** 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 above 0.6, indicating good drug-like properties. Ligand A (0.721) is slightly better than Ligand B (0.684).

**7. DILI:** Ligand B (47.926) has a slightly higher DILI risk than Ligand A (36.138), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (48.197) has a better BBB penetration percentile than Ligand B (31.834). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.813) shows poor Caco-2 permeability, which is a significant concern. Ligand B (-5.314) also shows poor Caco-2 permeability, but is slightly better than Ligand A.

**10. Aqueous Solubility:** Ligand A (-1.915) has poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-3.677) also has poor aqueous solubility, but is worse than Ligand A.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.468 and 0.472), which is excellent.

**12. Microsomal Clearance:** Ligand A (-33.166) has a lower (better) microsomal clearance than Ligand B (28.386), indicating better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (37.781 and 37.698 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.09).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -8.8 kcal/mol). Ligand A has a slightly better affinity.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Comparison & Conclusion:**

Ligand A has a slightly better binding affinity and lower DILI risk, and better metabolic stability. However, its significantly lower Caco-2 permeability and aqueous solubility are major drawbacks. Ligand B has slightly worse affinity and metabolic stability, but better Caco-2 permeability and aqueous solubility.

Considering the enzyme-specific priorities, the better metabolic stability and affinity of Ligand A are valuable. However, the poor permeability and solubility of Ligand A are significant concerns that could severely limit its bioavailability. While Ligand B's affinity is slightly lower, its better permeability and solubility make it a more promising starting point for optimization.

Output:
1
2025-04-17 13:29:08,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.229 Da) is slightly higher than Ligand B (345.359 Da), but both are acceptable.

**TPSA:** Ligand A (49.85) is well below the 140 threshold for oral absorption and suitable for kinase inhibitors. Ligand B (110.45) is higher, but still within a reasonable range, though potentially impacting absorption slightly more.

**logP:** Ligand A (2.838) is optimal. Ligand B (0.573) is a bit low, potentially leading to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (1 HBD, 7 HBA) is also acceptable, but the higher HBA count could slightly affect permeability.

**QED:** Both ligands have good QED scores (A: 0.732, B: 0.781), indicating good drug-like properties.

**DILI:** Ligand B (70.143) has a higher DILI risk than Ligand A (56.301), though both are above the preferred <40.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.29) has better BBB penetration than Ligand B (46.491), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.552) has poor Caco-2 permeability, suggesting absorption issues. Ligand B (-5.37) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.363) has poor solubility. Ligand B (-0.631) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.598) has a very low hERG risk, which is excellent. Ligand B (0.1) also has very low hERG risk.

**Microsomal Clearance:** Ligand A (38.082) has moderate clearance. Ligand B (-5.846) has negative clearance, which is excellent and indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (-15.769) has a very long half-life, which is excellent. Ligand B (3.909) has a short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.336, B: 0.003), which is favorable.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has 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 superior binding affinity and a very favorable safety profile (low hERG, acceptable DILI). Its major drawbacks are poor Caco-2 permeability and solubility, and moderate clearance. However, the strong binding affinity is a significant advantage. Ligand B has better metabolic stability and slightly better solubility, but its binding affinity is weaker, and it has a higher DILI risk.

Given the priority for potency in kinase inhibitors, and the substantial difference in binding affinity, Ligand A is the more promising candidate, despite its ADME challenges. Formulation strategies could potentially address the solubility and permeability issues.

Output:
1
2025-04-17 13:29:08,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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.

**TPSA:** Ligand A (72.28) is better than Ligand B (87.66). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range.

**logP:** Both ligands have good logP values (A: 1.363, B: 1.27), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=3, HBA=4). Lower HBD is generally better for permeability.

**QED:** Ligand A (0.908) has a significantly higher QED score than Ligand B (0.661), indicating a more drug-like profile.

**DILI:** Ligand A (32.105) has a lower DILI risk than Ligand B (26.987), both are good.

**BBB:** Ligand B (71.966) has a higher BBB percentile than Ligand A (60.45), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.458) has a worse Caco-2 permeability than Ligand B (-4.645).

**Aqueous Solubility:** Ligand A (-0.551) has a slightly better solubility than Ligand B (-1.79).

**hERG:** Ligand A (0.425) has a lower hERG risk than Ligand B (0.356), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-14.387) has a much lower (better) microsomal clearance than Ligand B (8.265), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (20.798 hours) has a longer half-life than Ligand B (-19.493 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.026, B: 0.017).

**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 less than 1.5 kcal/mol, it contributes to the overall preference.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in QED, DILI, hERG risk, metabolic stability (Cl_mic and t1/2), and binding affinity. While Ligand B has slightly better Caco-2 permeability and BBB, these are less critical for an SRC kinase inhibitor. The superior ADME profile and slightly better potency of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 13:29:08,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.393 and 349.391 Da) are within the ideal range (200-500 Da).

**TPSA:** Ligand A (36.44) is significantly better than Ligand B (110.37). A TPSA below 140 is good for oral absorption, but Ligand B is pushing the limit and could have absorption issues.

**logP:** Both ligands have acceptable logP values (3.016 and 1.239), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is more favorable than Ligand B (1 HBD, 6 HBA). Lower counts generally improve permeability.

**QED:** Ligand A (0.858) has a much better QED score than Ligand B (0.613), indicating a more drug-like profile.

**DILI:** Ligand B (47.421) has a lower DILI risk than Ligand A (35.479), which is a positive.

**BBB:** Both have high BBB penetration, but Ligand A (96.937) is slightly better than Ligand B (87.476). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability. However, the magnitude of the negative value for Ligand A (-4.544) is less severe than for Ligand B (-4.859).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.533) is slightly better than Ligand B (-2.758). This is a significant concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.945 and 0.352), which is excellent.

**Microsomal Clearance:** Ligand B (9.966) has much lower microsomal clearance than Ligand A (55.621), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-24.469) has a longer in vitro half-life than Ligand A (-15.918), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.635 and 0.091), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other significant ADME differences.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. While both have poor solubility and permeability, the metabolic advantage of Ligand B is critical for an enzyme inhibitor. Ligand A has a slightly better QED and TPSA, but these are outweighed by the metabolic concerns.

Output:
1
2025-04-17 13:29:08,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.378 and 351.437 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.22) is better than Ligand B (29.54) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (0.9) is within the optimal range (1-3), while Ligand B (4.299) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (2) are both acceptable, being less than 10.

**QED:** Both ligands have reasonable QED scores (0.845 and 0.733), indicating good drug-like properties.

**DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (15.51). This is a significant drawback for Ligand A.

**BBB:** Ligand A (53.083) has a lower BBB penetration score than Ligand B (97.131). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Ligand A (-4.905) and Ligand B (-4.399) are both negative, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-3.126) and Ligand B (-4.015) are both negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.516) has a slightly higher hERG inhibition liability than Ligand B (0.867), which is favorable for B.

**Microsomal Clearance:** Ligand A (-28.704) has significantly lower (better) microsomal clearance than Ligand B (78.195), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.504) has a slightly lower half-life than Ligand B (-0.165), but both are negative, making interpretation difficult without knowing the scale.

**P-gp Efflux:** Ligand A (0.031) has a much lower P-gp efflux liability than Ligand B (0.586), which is favorable for A.

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

**Conclusion:**

Ligand B is the better candidate. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, Ligand B has significantly lower DILI risk, better BBB penetration, and a slightly better hERG profile. The higher logP of Ligand B is a concern, but the lower DILI risk is a more critical factor for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:29:08,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.471 and 371.497 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is better than Ligand B (45.23). Both are well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands (2.584 and 3.486) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** 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 (0.863 and 0.798), indicating good drug-like properties.

**DILI:** Ligand A (20.706) has a significantly lower DILI risk than Ligand B (26.91). This is a major advantage.

**BBB:** While not a primary concern for a non-CNS target, Ligand B (90.229) has a higher BBB penetration than Ligand A (74.176).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.94 and -4.885), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.723) has better solubility than Ligand B (-3.36).

**hERG Inhibition:** Ligand A (0.39) has a lower hERG inhibition liability than Ligand B (0.764), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (18.796) has a higher microsomal clearance than Ligand B (8.131), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-0.08) has a slightly longer in vitro half-life than Ligand A (-16.736), suggesting better stability.

**P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux than Ligand B (0.234), which is favorable for bioavailability.

**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, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, lower DILI risk, and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-8.9 vs -6.9 kcal/mol) is a critical advantage for an enzyme inhibitor. The difference of 2 kcal/mol is substantial. Although Ligand B has a slightly higher DILI risk and worse hERG, these are often manageable in optimization. The lower metabolic stability of Ligand A is also a concern.

Output:
1
2025-04-17 13:29:08,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.515 and 357.42 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is slightly higher than Ligand B (38.13), but both are well below the 140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (3.522 and 3.89), 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 2 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.774 and 0.695), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (31.563 and 30.748), both well below the concerning threshold of 60.

**8. BBB:** Ligand B (94.61) shows significantly better BBB penetration than Ligand A (74.564). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.767 and -4.202). This is unusual and suggests poor permeability. However, these values are on a log scale, so even negative values can be comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.015 and -3.763). This indicates poor aqueous solubility, which is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.465 and 0.626), which is excellent.

**12. Microsomal Clearance:** Ligand A (64.038) has slightly higher microsomal clearance than Ligand B (60.136). Lower clearance is preferred for metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.97) has a slightly longer in vitro half-life than Ligand A (-17.451). Longer half-life is preferred.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.332 and 0.34).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.4 and -8.9 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering the enzyme-specific priorities, both ligands are quite similar. However, Ligand B has a slightly better in vitro half-life and lower microsomal clearance, indicating better metabolic stability. While both have poor solubility and permeability (as indicated by the negative Caco-2 and solubility values), the slight advantage in metabolic stability makes Ligand B marginally more promising.

Output:
1
2025-04-17 13:29:08,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.46 and 345.45 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (74.33 and 72.61) below the 140 A^2 threshold for good absorption.

**3. logP:** Both ligands have logP values (1.818 and 2.195) within the optimal 1-3 range.

**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:** Ligand A (4 HBA) is preferable to Ligand B (6 HBA).

**6. QED:** Both ligands have good QED scores (0.754 and 0.838), indicating good drug-like properties.

**7. DILI:** Ligand B (38.503 percentile) has a significantly lower DILI risk than Ligand A (49.011 percentile), a substantial advantage.

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand A (76.658%) is slightly better than Ligand B (63.978%). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.762) has a better Caco-2 permeability than Ligand B (-5.079).

**10. Aqueous Solubility:** Ligand A (-3.149) has better aqueous solubility than Ligand B (-2.454), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.653) has a lower hERG inhibition liability than Ligand B (0.096), which is a significant advantage for safety.

**12. Microsomal Clearance:** Ligand B (26.566 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (47.564 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-13.448 hours) has a longer in vitro half-life than Ligand A (17.469 hours), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux liability than Ligand B (0.201).

**15. 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 ADME drawbacks.

**Overall Assessment:**

While Ligand A has slightly better solubility and permeability, Ligand B exhibits a substantially stronger binding affinity (-8.9 vs -7.0 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2). The stronger binding affinity is the most critical factor for an enzyme inhibitor, and the improved safety profile (lower DILI, lower hERG) and metabolic stability of Ligand B are also highly desirable.

Output:
1
2025-04-17 13:29:08,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (348.447 and 369.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (78.53 and 80.76) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (0.993 and 1.86) are 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 4 HBAs, and Ligand B has 6 HBAs, both are below the limit of <=10.

**6. QED:** Both ligands have similar QED values (0.861 and 0.853), indicating good drug-likeness.

**7. DILI:** Ligand A (44.048) has a slightly better DILI score than Ligand B (56.766), indicating lower potential for liver injury. Both are below the concerning threshold of 60.

**8. BBB:** Both ligands have moderate BBB penetration, with Ligand B (75.649) being slightly better than Ligand A (61.225). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a major concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.701 and -4.753). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are not directly interpretable without knowing the scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.666 and -3.617), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.231) has a significantly lower hERG inhibition risk than Ligand B (0.574). This is a crucial advantage.

**12. Microsomal Clearance:** Ligand A (9.774) has a lower microsomal clearance than Ligand B (39.548), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-22.519) has a much longer in vitro half-life than Ligand B (-2.708). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.062).

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). While both are good, the 1 kcal/mol difference is noticeable.

**Enzyme-Specific Prioritization:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in these areas: better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity. While both have poor solubility and permeability, the superior ADME profile of Ligand A outweighs the slight advantage in BBB penetration of Ligand B.

Output:
0
2025-04-17 13:29:08,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (337.375 and 365.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.63) is well below the 140 threshold and favorable for oral absorption. Ligand B (87.3) is still within acceptable limits but higher.

**3. logP:** Both ligands have good logP values (2.831 and 1.85), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (3) are both acceptable, with Ligand A being slightly preferable.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the desirable limit of 10.

**6. QED:** Both ligands have reasonable QED scores (0.852 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A (55.409) has a slightly higher DILI risk than Ligand B (45.444), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.615) has a higher BBB percentile than Ligand B (46.064), but this is not a major factor in this decision.

**9. Caco-2 Permeability:** Ligand A (-4.48) has a worse Caco-2 permeability than Ligand B (-5.168).

**10. Aqueous Solubility:** Ligand A (-4.116) has worse aqueous solubility than Ligand B (-2.724).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.415 and 0.172), which is excellent.

**12. Microsomal Clearance:** Ligand B (33.443) has a lower microsomal clearance than Ligand A (44.343), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (12.712) has a longer in vitro half-life than Ligand A (-15.39), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.178 and 0.095).

**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 >1.4 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B demonstrates superior ADME properties (better solubility, metabolic stability, and half-life), the significantly stronger binding affinity of Ligand A (-8.8 vs -7.4 kcal/mol) is a decisive factor. For an enzyme target like SRC kinase, potency is paramount. The slight drawbacks in ADME for Ligand A are likely manageable through formulation or further optimization, but a substantial potency advantage is harder to achieve later in the drug discovery process.

Output:
1
2025-04-17 13:29:08,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.371 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.69) is better than Ligand B (49.41), being below the 140 A^2 threshold for good absorption. Ligand B is excellent.

**logP:** Ligand A (0.65) is a bit low, potentially hindering permeability. Ligand B (3.521) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**H-Bond Acceptors:** Ligand A (6) is acceptable, while Ligand B (2) is even better.

**QED:** Both ligands have good QED scores (0.646 and 0.8), indicating drug-like properties.

**DILI:** Ligand A (57.154) has a moderate DILI risk, while Ligand B (19.93) has a very low risk, which is a significant advantage.

**BBB:** Ligand A (20.434) has poor BBB penetration, while Ligand B (84.141) has good BBB penetration. Since SRC is not a CNS target, this is less critical but still a positive for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.087) has very poor Caco-2 permeability. Ligand B (-4.867) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.233) has poor solubility, while Ligand B (-4.046) is also poor.

**hERG Inhibition:** Ligand A (0.169) has a slightly elevated hERG risk, while Ligand B (0.575) is better.

**Microsomal Clearance:** Ligand A (13.25) has lower clearance, suggesting better metabolic stability than Ligand B (55.501). This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (32.755) has a longer half-life than Ligand B (23.018), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux, which is good. Ligand B (0.107) is slightly higher.

**Binding Affinity:** Ligand A (-8.6) has significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

While Ligand A has issues with logP, solubility, and Caco-2 permeability, its *much* stronger binding affinity (-8.6 kcal/mol vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are critical for an enzyme target like SRC kinase. The lower DILI risk of Ligand B is attractive, but the lack of binding affinity makes it unlikely to be effective. The affinity difference is so large that optimization of Ligand A's ADME properties is a more promising path than attempting to improve the affinity of Ligand B.

Output:
0
2025-04-17 13:29:08,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.463 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.01) is well below the 140 threshold and excellent for oral absorption. Ligand B (92.84) is still acceptable but less optimal.

**logP:** Ligand A (4.472) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.986) is within the optimal range.

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

**H-Bond Acceptors:** Both ligands (A: 6, B: 6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.587, B: 0.916), indicating drug-likeness. Ligand B is significantly better.

**DILI:** Both ligands have similar DILI risk (A: 81.311, B: 80.962), and are in the moderate range. This is a concern for both, but not a deciding factor.

**BBB:** Both ligands have moderate BBB penetration (A: 50.679, B: 74.719). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.006 and -4.638), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.436 and -2.727). This is a major issue for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.358, B: 0.323), which is positive.

**Microsomal Clearance:** Ligand A (110.419) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (23.806) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.804) has a short half-life, consistent with the high clearance. Ligand B (18.058) has a significantly longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.446, B: 0.055). Ligand B is better.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some of the other drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B's significantly better metabolic stability (lower Cl_mic, longer t1/2) and stronger binding affinity are crucial advantages. The slightly better QED and P-gp efflux also contribute to its favorability. Although the logP is lower, it's within an acceptable range. The DILI risk is similar for both.

Output:
1
2025-04-17 13:29:08,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.359 and 343.358 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.56) is slightly above the preferred <140, but acceptable. Ligand B (84.23) is well within the range.

**logP:** Ligand A (0.442) is quite low, potentially hindering permeability. Ligand B (2.849) is optimal.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.719 and 0.818 respectively), indicating drug-likeness.

**DILI:** Both ligands have similar and relatively high DILI risk (85.498 and 84.374 percentile). This is a concern for both, but not a deciding factor at this stage.

**BBB:** Ligand A (28.344) has very low BBB penetration, while Ligand B (84.451) has good BBB penetration. Since SRC is not a CNS target, this is not a major consideration.

**Caco-2 Permeability:** Ligand A (-5.469) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.613) is also not great, but better than A.

**Aqueous Solubility:** Ligand A (-2.524) has poor solubility, while Ligand B (-4.891) is also poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.13) has very low hERG inhibition risk, which is excellent. Ligand B (0.235) also has low hERG inhibition risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-27.734) has very low microsomal clearance, indicating high metabolic stability. Ligand B (55.179) has moderate clearance, which is less desirable.

**In vitro Half-Life:** Ligand A (1.92) has a short half-life, while Ligand B (34.597) has a long half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.247).

**Binding Affinity:** Ligand B (-7.5 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.

**Conclusion:**

While both ligands have DILI concerns, Ligand B is the more promising candidate. It has a better logP, significantly better binding affinity, a much longer half-life, and better Caco-2 permeability despite similar solubility issues. The superior affinity and metabolic stability outweigh the slightly higher hERG risk and DILI concern. The poor logP and permeability of Ligand A are major drawbacks.

Output:
1
2025-04-17 13:29:08,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.279 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (81.67) is better than Ligand B (65.97). Both are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (1.437) is optimal (1-3). Ligand B (6.057) is significantly higher, raising concerns about solubility and potential off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is better balanced. Ligand B (HBD=0, HBA=6) has fewer donors, which might affect solubility, but the HBA count is acceptable.

**QED:** Ligand A (0.734) is significantly better than Ligand B (0.265), indicating a more drug-like profile.

**DILI:** Ligand A (44.281) has a much lower DILI risk than Ligand B (77.007). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (45.638) is higher than Ligand A (24.855), but it's not a deciding factor.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both, but the lower TPSA and logP of Ligand A might mitigate this somewhat.

**Aqueous Solubility:** Ligand A (-2.723) is better than Ligand B (-6.627), although both are poor. Solubility is a key concern for enzymes, and Ligand A's better logP and H-bonding potential suggest it might be formulated more easily.

**hERG Inhibition:** Ligand A (0.194) has a much lower hERG risk than Ligand B (0.882). This is a critical advantage.

**Microsomal Clearance:** Ligand A (-40.083) has a much lower (better) microsomal clearance than Ligand B (49.848), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (20.145 hours) has a better in vitro half-life than Ligand B (-59.264 hours).

**P-gp Efflux:** Ligand A (0.089) shows lower P-gp efflux than Ligand B (0.984), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). However, the difference (1.6 kcal/mol) is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A is significantly superior. While Ligand B has slightly better binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding DILI risk, hERG inhibition, metabolic stability, solubility, and QED. These factors are crucial for developing a viable drug candidate targeting an enzyme like SRC kinase.

Output:
0
2025-04-17 13:29:08,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (339.439 and 346.446 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.11) is better than Ligand B (49.41) as it is still below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (3.467 and 3.153), 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 4 HBA, and Ligand B has 2. Both are below the acceptable threshold of 10.

**6. QED:** Both ligands have high QED scores (0.906 and 0.89), indicating good drug-like properties.

**7. DILI:** Ligand B (29.236) has a significantly lower DILI risk than Ligand A (48.468). This is a substantial advantage.

**8. BBB:** Ligand B (96.355) has a much higher BBB penetration percentile than Ligand A (72.896). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**9. Caco-2 Permeability:** Ligand A (-4.389) has better Caco-2 permeability than Ligand B (-4.616).

**10. Aqueous Solubility:** Ligand A (-3.734) has better aqueous solubility than Ligand B (-3.46). This is a positive for formulation.

**11. hERG Inhibition:** Ligand B (0.777) has a slightly higher hERG inhibition risk than Ligand A (0.456), but both are reasonably low.

**12. Microsomal Clearance:** Ligand A (28.261) has lower microsomal clearance than Ligand B (36.009), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.913) has a longer in vitro half-life than Ligand A (-2.526). This is a significant advantage for dosing frequency.

**14. P-gp Efflux:** Ligand A (0.14) has lower P-gp efflux than Ligand B (0.34), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.7). While both are excellent, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly lower DILI risk, a longer half-life, and better BBB penetration. While Ligand A has slightly better solubility and lower P-gp efflux, the improvements in safety (DILI) and pharmacokinetics (half-life) offered by Ligand B are more critical for an enzyme target like SRC. The binding affinity difference is minimal.

Output:
1
2025-04-17 13:29:08,600 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [360.38 ,  76.02 ,   2.116,   2.   ,   4.   ,   0.782,  41.605,  83.327, -4.634,  -3.311,   0.452,  30.239, -28.548,   0.069,  -7.6  ]
**Ligand B:** [378.42 ,  71.25 ,   1.3  ,   1.   ,   6.   ,   0.808,  39.046,  82.009, -4.799,  -3.138,   0.217,  -5.029, -19.052,   0.105,  -7.7  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (360.38) is slightly preferred.
2. **TPSA:** Both are good, below 140 A<sup>2</sup>. B (71.25) is slightly better.
3. **logP:** Both are optimal (1-3). A (2.116) is slightly better than B (1.3).
4. **HBD:** Both are acceptable (<=5). A (2) is slightly better than B (1).
5. **HBA:** Both are acceptable (<=10). A (4) is better than B (6).
6. **QED:** Both are good (>0.5). B (0.808) is slightly better than A (0.782).
7. **DILI:** Both are good (<40). A (41.605) is slightly higher, but still acceptable. B (39.046) is slightly preferred.
8. **BBB:** Both are good (high percentile). A (83.327) and B (82.009) are comparable. Not a major factor here as SRC is not a CNS target.
9. **Caco-2:** Both are very poor (negative values). This is a significant concern for oral bioavailability.
10. **Solubility:** Both are very poor (negative values). This is a significant concern for formulation and bioavailability.
11. **hERG:** Both are low risk. A (0.452) is slightly better than B (0.217).
12. **Cl_mic:** A (30.239) has higher clearance than B (-5.029), meaning B has better metabolic stability. This is a key consideration for kinase inhibitors.
13. **t1/2:** A (-28.548) has a negative half-life, which is not possible. B (-19.052) also has a negative half-life, which is not possible. Both are very poor.
14. **Pgp:** Both are low. A (0.069) is slightly better than B (0.105).
15. **Binding Affinity:** B (-7.7) has a slightly better binding affinity than A (-7.6), although the difference is small.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

*   **Affinity:** B has a slightly better affinity.
*   **Metabolic Stability:** B has significantly better metabolic stability (lower Cl_mic).
*   **Solubility:** Both are poor, but this is a formulation challenge that can be addressed.
*   **hERG:** Both are good.
*   **t1/2:** Both are very poor.

**Conclusion:**

Despite the similar binding affinities, **Ligand B** is the more promising candidate due to its superior metabolic stability (lower Cl_mic) and slightly better DILI score. While both have poor solubility and Caco-2 permeability, these are formulation challenges that can potentially be overcome. The negative half-life values are concerning and would require further investigation, but the better metabolic stability of B makes it the more favorable choice.

Output:
1
2025-04-17 13:29:08,600 - INFO - Batch 217 complete. Total preferences: 3472
2025-04-17 13:29:08,600 - INFO - Processing batch 218/512...
2025-04-17 13:29:50,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.32) is slightly higher than Ligand B (359.411), but both are acceptable.

**TPSA:** Ligand A (71.84) is better than Ligand B (121.18) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (4.823) is high, potentially causing solubility issues and off-target effects. Ligand B (0.376) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is better than Ligand B (HBD=3, HBA=6) as it is closer to the ideal range.

**QED:** Both ligands have similar QED values (A: 0.624, B: 0.681), indicating good drug-likeness.

**DILI:** Both ligands have high DILI risk (A: 88.019, B: 83.443), which is a concern. However, this can be addressed in later optimization stages.

**BBB:** Ligand A (76.735) has better BBB penetration than Ligand B (45.909), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a major worry.

**Caco-2 Permeability:** Ligand A (-4.803) has a worse Caco-2 permeability than Ligand B (-5.595).

**Aqueous Solubility:** Ligand A (-5.704) has worse solubility than Ligand B (-3.135).

**hERG Inhibition:** Ligand A (0.521) has a slightly higher hERG risk than Ligand B (0.385), but both are relatively low.

**Microsomal Clearance:** Ligand A (54.794) has a higher microsomal clearance than Ligand B (-6.554). This means Ligand B is more metabolically stable, which is a significant advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (48.082) has a longer half-life than Ligand B (-26.371), which is desirable.

**P-gp Efflux:** Ligand A (0.559) has lower P-gp efflux than Ligand B (0.017), which is better.

**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.

**Conclusion:**

Despite Ligand A's higher logP and lower solubility, its significantly stronger binding affinity (-8.8 kcal/mol vs -7.6 kcal/mol) and better metabolic profile (lower Cl_mic, longer half-life) make it the more promising candidate. The affinity difference is large enough to potentially overcome the solubility and logP issues through formulation or further optimization. Ligand B's poor metabolic stability is a major drawback.

Output:
1
2025-04-17 13:29:50,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.38 Da) is slightly higher than Ligand B (373.825 Da), but both are acceptable.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (92.79). Lower TPSA generally improves cell permeability, which is beneficial. Ligand B's TPSA is quite high.

**logP:** Both ligands have acceptable logP values (A: 4.323, B: 3.411), falling within the 1-3 range. Ligand A is a bit higher, potentially raising concerns about off-target effects, but not dramatically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) has a more favorable profile than Ligand B (HBD=2, HBA=6). Lower HBA is generally preferred for better permeability.

**QED:** Ligand A (0.791) has a significantly better QED score than Ligand B (0.571), indicating a more drug-like profile.

**DILI:** Ligand A (14.618) has a much lower DILI risk than Ligand B (99.147). This is a major advantage for Ligand A.

**BBB:** Ligand A (89.492) has a better BBB penetration score than Ligand B (49.128), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.195 and -5.08), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-3.678 and -4.714), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.918 and 0.652), which is good.

**Microsomal Clearance:** Ligand A (10.413) has a significantly lower microsomal clearance than Ligand B (44.13), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (13.823) has a shorter half-life than Ligand B (21.375), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.411 and 0.496), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-9.4 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the superior candidate. It has a significantly better DILI score, lower TPSA, better QED, and lower microsomal clearance. The binding affinity is identical, so the improved ADME properties of Ligand A outweigh the shared drawbacks. The poor solubility and permeability would need to be addressed through formulation strategies, but the other advantages make Ligand A a more promising starting point.

Output:
0
2025-04-17 13:29:50,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.455 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.57) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (75.19) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.811 and 2.128), falling within the 1-3 range.

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

**QED:** Both ligands have good QED scores (0.648 and 0.927), indicating good drug-like properties. Ligand B is superior here.

**DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (49.399), though both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (57.774) is higher than Ligand A (47.111), but not a deciding factor.

**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 suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Ligand A (0.051) has a very low hERG risk, which is excellent. Ligand B (0.357) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (11.202) has lower microsomal clearance, indicating better metabolic stability, which is a key priority for enzymes. Ligand B (15.426) is higher, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-35.163) has a negative half-life, which is impossible and indicates an issue with the data. Ligand B (6.942) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.03), which is good.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better hERG and potentially better metabolic stability (lower Cl_mic), the significant advantage in binding affinity for Ligand B (-8.4 vs -7.4 kcal/mol) is the most crucial factor for an enzyme inhibitor. The better QED score and more reasonable half-life for Ligand B also contribute to its favorability. 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-stage optimization. The impossible half-life for Ligand A is a red flag.

Output:
1
2025-04-17 13:29:50,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.383 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.71) is slightly above the preferred <140, but acceptable. Ligand B (93.53) is well within the range.

**logP:** Ligand A (2.101) is optimal. Ligand B (0.965) is a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (5) is within the acceptable limit of <=10. Ligand B (6) is also good.

**QED:** Both ligands have similar QED values (0.679 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (36.603) has a lower DILI risk than Ligand B (41.179), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (72.78) has a higher BBB value than Ligand A (43.699), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-5.001) has a very poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.527) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.505) has poor aqueous solubility, while Ligand B (-1.817) is slightly better, but still poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.232 and 0.125), which is excellent.

**Microsomal Clearance:** Ligand A (13.439) has a lower microsomal clearance, indicating better metabolic stability, which is highly desirable for an enzyme target. Ligand B (85.15) has a very high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (38.431) has a longer half-life than Ligand B (-22.437), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.046), which is good.

**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 meaningful.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand A's significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly stronger binding affinity outweigh the slightly higher TPSA and lower Caco-2 permeability. The poor permeability and solubility would need to be addressed in further optimization, but the superior pharmacokinetic profile of A is more critical for an enzyme target like SRC.

Output:
0
2025-04-17 13:29:50,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.439 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (71.34) is better than Ligand B (87.3). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range.

**logP:** Both ligands have good logP values (A: 2.585, B: 1.925), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is slightly better than Ligand B (HBD=3, HBA=4) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.864) has a significantly higher QED score than Ligand B (0.658), indicating a more drug-like profile.

**DILI:** Ligand B (39.511) has a slightly lower DILI risk than Ligand A (46.064), but both are below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (A: 55.099, B: 59.791), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.816) has a worse Caco-2 permeability than Ligand B (-5.289). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-3.893) has a worse aqueous solubility than Ligand B (-2.673). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.184, B: 0.274), which is excellent.

**Microsomal Clearance:** Both have similar and reasonable microsomal clearance values (A: 32.256, B: 29.711), suggesting acceptable metabolic stability.

**In vitro Half-Life:** Ligand A (52.75) has a significantly better in vitro half-life than Ligand B (13.626), indicating better metabolic stability and potentially less frequent dosing.

**P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (A: 0.179, B: 0.076).

**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, especially for an enzyme target.

**Overall Assessment:**

While Ligand A has a better QED, solubility, and half-life, the significantly stronger binding affinity of Ligand B (-7.2 vs -8.0 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. A 1.2 kcal/mol difference in binding is substantial and can often outweigh minor ADME drawbacks. The slightly lower solubility of B is a concern, but potentially addressable through formulation.

Output:
1
2025-04-17 13:29:50,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.833 and 368.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.61) is better than Ligand B (50.6). Both are below 140, suggesting good absorption potential.

**logP:** Ligand B (2.38) is optimal (1-3), while Ligand A (0.475) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.77) is better than Ligand B (0.469). Ligand A is well above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (30.942) is significantly better than Ligand B (12.33), indicating a much lower risk of drug-induced liver injury.

**BBB:** Ligand B (79.411) is better than Ligand A (33.346). However, BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.122) is better than Ligand B (-4.995), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.399) is better than Ligand B (-1.234), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.081) is significantly better than Ligand B (0.682), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-6.818) is *much* better than Ligand B (58.724), suggesting significantly higher metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (13.798) is better than Ligand A (7.713), but both are reasonable.

**P-gp Efflux:** Ligand A (0.004) is much better than Ligand B (0.254), indicating lower efflux and improved bioavailability.

**Binding Affinity:** Ligand B (-8.6) is slightly better than Ligand A (-9.2). However, the difference is relatively small, and other factors are more important.

**Overall Assessment:**

Ligand A is superior due to its significantly better DILI score, lower hERG risk, dramatically improved metabolic stability (Cl_mic), better solubility, and lower P-gp efflux. While Ligand B has a slightly better binding affinity, the ADME/Tox profile of Ligand A is far more favorable. The lower logP of Ligand A is a minor drawback, but can potentially be addressed with further optimization without sacrificing the other crucial properties.

Output:
0
2025-04-17 13:29:50,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (363.443 Da) is also good.

**TPSA:** Ligand A (40.62) is excellent, well below the 140 threshold for oral absorption. Ligand B (95.33) is higher, potentially impacting absorption, though still not prohibitive.

**logP:** Ligand A (3.556) is optimal. Ligand B (1.024) is a bit low, potentially hindering membrane 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.

**QED:** Both ligands have good QED scores (A: 0.779, B: 0.852), indicating drug-likeness.

**DILI:** Ligand A (12.175) has a very low DILI risk, which is excellent. Ligand B (73.09) is higher, suggesting a moderate risk of liver injury.

**BBB:** Ligand A (88.445) has good BBB penetration, while Ligand B (37.146) is low. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.483) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.597) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.707) and Ligand B (-2.033) both have poor solubility. This is a significant drawback for both, but may be less critical if the compound demonstrates excellent potency and stability.

**hERG Inhibition:** Ligand A (0.608) has a low hERG risk, which is very favorable. Ligand B (0.091) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (87.607) has a high microsomal clearance, suggesting poor metabolic stability. Ligand B (40.716) has a significantly lower clearance, indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-8.015) has a very short half-life, consistent with the high clearance. Ligand B (-40.995) has a much longer half-life, a major benefit.

**P-gp Efflux:** Ligand A (0.168) has low P-gp efflux, which is good. Ligand B (0.032) has even lower efflux, potentially improving bioavailability.

**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, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A has better affinity and lower DILI risk, but suffers from poor Caco-2 permeability, high clearance, short half-life, and poor solubility. Ligand B has better metabolic stability (lower clearance, longer half-life), lower P-gp efflux, and a slightly better solubility profile, but its affinity is a bit lower and its TPSA is higher.

Given the enzyme-specific priorities, metabolic stability and half-life are critical. Ligand B's significantly improved metabolic profile outweighs the slightly weaker binding affinity of Ligand B. The solubility issues of both compounds are a concern, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:29:50,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.471 and 353.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (54.34) is well below the 140 threshold, suggesting good absorption. Ligand B (118.37) is still acceptable but higher, potentially slightly hindering absorption.

**logP:** Ligand A (2.294) is optimal (1-3). Ligand B (-0.288) is below 1, which could impede permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but higher.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, potentially impacting permeability.

**QED:** Ligand A (0.834) is excellent, indicating strong drug-likeness. Ligand B (0.532) is acceptable, but lower.

**DILI:** Ligand A (25.94) has a very low DILI risk. Ligand B (52.385) is higher, indicating a moderate risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.833) is higher than Ligand B (52.966).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it's hard to compare directly.

**Aqueous Solubility:** Both are negative, suggesting poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.395) has a very low hERG risk. Ligand B (0.062) also has low risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (44.795) has moderate clearance. Ligand B (19.15) has significantly lower clearance, indicating better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand A (-14.104) has a very short half-life. Ligand B (-4.898) is better, but still relatively short.

**P-gp Efflux:** Ligand A (0.252) has low efflux. Ligand B (0.04) has very low efflux.

**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, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

While Ligand A has better drug-likeness (QED) and lower DILI risk, Ligand B possesses a much stronger binding affinity (-7.5 vs -10.1 kcal/mol) and superior metabolic stability (lower Cl_mic). The lower logP of Ligand B is a concern, but the significantly improved binding affinity is a major advantage for an enzyme target like SRC kinase. The slightly higher DILI risk of Ligand B is manageable, especially given the potency.

Output:
1
2025-04-17 13:29:50,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.463 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.53) is slightly higher than Ligand B (69.72). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have acceptable logP values (0.873 and 0.505), falling within the 1-3 range. Ligand B is slightly lower, which could slightly reduce permeability 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 the acceptable ranges (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.508 and 0.783), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (19.891) has a lower DILI risk than Ligand B (26.406), which is favorable.

**BBB:** Both ligands have relatively low BBB penetration (60.411 and 76.541), which is not a major concern for a non-CNS target like SRC kinase. Ligand B is better here.

**Caco-2 Permeability:** Ligand A (-5.136) has worse Caco-2 permeability than Ligand B (-4.881).

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-1.68 and -1.681). This is a potential issue for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.157 and 0.158), which is excellent.

**Microsomal Clearance:** Ligand A (39.019) has a significantly higher microsomal clearance than Ligand B (8.284). This suggests Ligand B is more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (7.527 hours) has a much longer in vitro half-life than Ligand A (1.225 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.01).

**Binding Affinity:** Both ligands have identical and excellent binding affinity (-7.9 kcal/mol).

**Conclusion:**

While both ligands exhibit excellent binding affinity, Ligand B is the superior candidate due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2), better Caco-2 permeability, and higher QED score. The slightly lower DILI risk of Ligand A is a minor advantage that is outweighed by the more substantial ADME benefits of Ligand B.

Output:
1
2025-04-17 13:29:50,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.359 and 380.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.77) is better than Ligand B (75.19), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.432) is slightly low, potentially hindering permeation. Ligand B (3.101) is optimal.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is excellent.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable range (<=10).

**QED:** Ligand B (0.835) has a significantly better QED score than Ligand A (0.333), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (58.434 and 63.203), falling in the acceptable range (<60 is good).

**BBB:** Both have moderate BBB penetration (45.677 and 50.679). Not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-5.303 and -5.184), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both have negative solubility values (-2.059 and -3.33), also concerning. Poor solubility can hinder bioavailability.

**hERG:** Ligand A (0.018) has a very low hERG risk, while Ligand B (0.511) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (-13.054) has a much lower (better) microsomal clearance than Ligand B (56.583), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (36.274) has a significantly longer half-life than Ligand A (0.293), which is desirable.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, while Ligand B (0.126) is slightly higher.

**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, it is still a factor.

**Overall Assessment:**

Ligand B is superior. While both have issues with Caco-2 and solubility, Ligand B has a much better QED score, longer half-life, and slightly better binding affinity. The better logP and lower HBD count also contribute to its improved profile. Ligand A's main advantage is its lower hERG risk and better metabolic stability, but the other drawbacks outweigh this benefit. The slightly better affinity of Ligand B, combined with its improved drug-like properties, makes it the more promising candidate.

Output:
1
2025-04-17 13:29:50,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 363.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (29.54) as it is closer to the ideal range of <=140. Ligand B is very low, which could indicate poor solubility.

**logP:** Ligand A (1.68) is optimal (1-3), while Ligand B (4.912) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Both ligands (3) are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.46 and 0.624), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (32.842 and 33.307), which is good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.229) has a higher BBB percentile than Ligand A (62.233), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.377) is significantly worse than Ligand B (-4.965).

**Aqueous Solubility:** Ligand A (-2.71) is better than Ligand B (-5.259), which is a significant advantage for *in vivo* activity.

**hERG Inhibition:** Ligand A (0.097) is much lower (better) than Ligand B (0.834), reducing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (26.043) has significantly lower clearance than Ligand B (145.814), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-2.218) has a longer half-life than Ligand B (3.379), which is desirable.

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.839), improving bioavailability.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.6), but the difference is less than 1.5 kcal/mol, so it is not a deciding factor.

**Overall:**

Ligand A is superior due to its better solubility, significantly lower hERG risk, much better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity and Caco-2 permeability, the ADME properties of Ligand A are far more favorable for development as an enzyme inhibitor. The solubility and metabolic stability advantages are particularly important for SRC kinase inhibition.

Output:
0
2025-04-17 13:29:50,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.363 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.07) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (75.44) is excellent, well below 140.

**logP:** Ligand A (-0.449) is a bit low, potentially hindering permeation. Ligand B (2.407) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (8) and Ligand B (4) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.553 and 0.779, respectively), indicating drug-like properties.

**DILI:** Ligand A (68.515) has a higher DILI risk than Ligand B (23.769), which is a significant concern.

**BBB:** BBB is less crucial for a non-CNS target like SRC, but Ligand B (86.817) has a higher percentile than Ligand A (43.273).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.676 and -4.551), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.078 and -2.323), which is also concerning and indicates very poor solubility.

**hERG Inhibition:** Ligand A (0.557) has a slightly higher hERG risk than Ligand B (0.238), but both are relatively low.

**Microsomal Clearance:** Ligand A (13.897) has significantly lower microsomal clearance than Ligand B (33.993), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.197) has a negative half-life, which is impossible and indicates a data error or a very rapidly metabolized compound. Ligand B (15.072) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.088, respectively).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), although both are excellent.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have concerning Caco-2 and solubility values, Ligand A's DILI risk is significantly higher, and its in vitro half-life is nonsensical. Ligand B has better logP, lower DILI, better half-life, and comparable binding affinity. The slightly better metabolic stability of Ligand A is outweighed by its other liabilities.

Output:
1
2025-04-17 13:29:50,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.394 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have similar TPSA values (72.16 and 72.28), below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have optimal logP values (1.347 and 1.406) 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 HBA, and Ligand B has 6. Both are below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.769 and 0.744), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 55.758, while Ligand B has 40.403. Ligand B is preferable here, being below the 40 threshold.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (75.029) is slightly better than Ligand B (64.482), but this is not a major deciding factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.576 and -4.896). This is unusual and suggests poor permeability. However, these values are on a log scale and small differences can be significant.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.019 and -2.007). This is also concerning, indicating poor aqueous solubility. Ligand A is slightly better than Ligand B.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.371 and 0.407), which is excellent.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (33.391) than Ligand B (46.962). This suggests better metabolic stability for Ligand A, a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A has a longer half-life (25.675) than Ligand B (0.34). This is a significant advantage for Ligand A, as it suggests less frequent dosing.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.178 and 0.206).

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-8.9 kcal/mol) compared to Ligand A (-7.3 kcal/mol). This difference of 1.6 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most critical factor for an enzyme inhibitor. While Ligand A has better metabolic stability and half-life, the substantial affinity advantage of Ligand B is likely to be more impactful. The DILI score for Ligand B is also preferable. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:29:50,711 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.503 and 360.393 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (47.61) is well below the 140 threshold and very favorable. Ligand B (90.28) is still under 140, but less optimal than A.

**3. logP:** Ligand A (1.307) is within the optimal range of 1-3. Ligand B (3.62) is at the higher end of the optimal range, potentially raising concerns about 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 6 HBA, both are acceptable (<=10).

**6. QED:** Both ligands have QED values above 0.5 (0.845 and 0.725), indicating good drug-like properties.

**7. DILI:** Ligand A (5.777) has a very low DILI risk, excellent. Ligand B (84.645) has a significantly higher DILI risk, a major concern.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.637) is moderate, while Ligand B (35.324) is low.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and requires further investigation, but we'll proceed with relative comparison. Ligand A (-5.109) is slightly better than Ligand B (-5.038).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.014) is slightly better than Ligand B (-4.975).

**11. hERG Inhibition:** Ligand A (0.773) has a lower hERG risk than Ligand B (0.655), which is preferable.

**12. Microsomal Clearance:** Ligand A (3.19 mL/min/kg) has significantly lower clearance than Ligand B (34.016 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.86 hours) has a better half-life than Ligand B (23.472 hours).

**14. P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, while Ligand B (0.219) is higher.

**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.

**Overall Assessment:**

Ligand B boasts a considerably stronger binding affinity, which is paramount for an enzyme inhibitor. However, its high DILI risk (84.645) is a major red flag. Its metabolic stability is also poor (high Cl_mic). Ligand A, while having a weaker affinity, presents a much more favorable safety profile (very low DILI) and better metabolic stability. The solubility and permeability issues are similar for both, but the difference in DILI and metabolic stability is substantial. For an enzyme target, prioritizing metabolic stability and minimizing toxicity are crucial. While the affinity difference is significant, it might be possible to improve Ligand A's affinity through further optimization without drastically altering its favorable ADME properties. The high DILI risk of Ligand B makes it a less viable starting point.

Output:
0
2025-04-17 13:29:50,711 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.913 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.53) is still under 140, but less optimal than A.

**logP:** Both ligands have good logP values (3.485 and 2.658), falling within the 1-3 range.

**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, acceptable QED values (0.74 and 0.728).

**DILI:** Ligand A (44.009) has a slightly better DILI score than Ligand B (52.346), indicating a lower risk of liver injury. Both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (71.966 and 66.615), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.604 and -4.5), which is unusual and potentially problematic. 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 (-4.389 and -3.377), which is also unusual. Similar to Caco-2, these are on a log scale and negative values are not necessarily indicative of poor solubility.

**hERG:** Both ligands have low hERG risk (0.604 and 0.42).

**Microsomal Clearance:** Ligand A (60.279) has slightly better metabolic stability (lower clearance) than Ligand B (63.931).

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (19.605 and 19.734 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.107 and 0.214).

**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 advantage, which is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. Its stronger binding affinity is the most important factor, given the enzyme target class. It also has slightly better DILI and microsomal clearance profiles, and a more favorable TPSA. While both ligands have unusual negative values for Caco-2 and solubility, the difference in binding affinity is decisive.

Output:
1
2025-04-17 13:29:50,711 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 364.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.36) is slightly higher than Ligand B (58.64), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (4.904) is a bit high, potentially leading to solubility issues, while Ligand B (3.428) is within the optimal 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 (0.753 and 0.814, respectively), indicating drug-like properties.

**DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (33.075). This is a significant concern.

**BBB:** Ligand A (69.407) and Ligand B (90.151). BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires investigation. However, we can still compare them relatively. Ligand A (-4.61) is slightly worse than Ligand B (-4.396).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-6.344) is slightly worse than Ligand B (-4.569).

**hERG:** Both ligands have low hERG inhibition liability (0.684 and 0.622, respectively), which is good.

**Microsomal Clearance:** Ligand A (111.673) has higher microsomal clearance than Ligand B (68.607), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (99.005) has a longer half-life than Ligand B (-4.342). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.554 and 0.21, respectively).

**Binding Affinity:** Ligand B (-7.8 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 very important.

**Conclusion:**

Ligand B is the more promising candidate. While both have solubility issues (negative solubility values), Ligand B has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and a longer half-life (although the negative value is concerning). The higher logP of Ligand A is also a concern. The substantial improvement in binding affinity of Ligand B outweighs the slight drawbacks in other properties.

Output:
1
2025-04-17 13:29:50,711 - INFO - Batch 218 complete. Total preferences: 3488
2025-04-17 13:29:50,711 - INFO - Processing batch 219/512...
2025-04-17 13:30:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.434 and 364.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (91.57). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands have acceptable logP values (1.35 and 1.808), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (3 HBD, 5 HBA). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.779) has a better QED score than Ligand B (0.633), indicating a more drug-like profile.

**DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (33.501). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.827) is better than Ligand B (25.94), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.577) is better than Ligand B (-5.478), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.054) is better than Ligand B (-1.853), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.361 and 0.23), which is excellent.

**Microsomal Clearance:** Ligand A (1.733) has significantly lower microsomal clearance than Ligand B (37.035), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-4.978) has a much longer in vitro half-life than Ligand B (36.56), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.073 and 0.047).

**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 outweighed by the ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A demonstrates superior ADME properties across the board, particularly in DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and solubility. While Ligand B has a slightly better binding affinity, the substantial advantages of Ligand A in key ADME parameters, especially metabolic stability and safety (DILI), make it the more promising drug candidate for SRC kinase inhibition.

Output:
0
2025-04-17 13:30:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 347.306 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (117.51). A TPSA under 90 is preferable, and Ligand A is comfortably within this range, suggesting better permeability. Ligand B is higher and could present absorption challenges.

**logP:** Both ligands have acceptable logP values (2.96 and 1.096), 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=8). The lower HBA count of Ligand A is beneficial for permeability.

**QED:** Ligand A (0.892) has a much higher QED score than Ligand B (0.506), indicating a more drug-like profile.

**DILI:** Ligand B (87.127) has a significantly higher DILI risk than Ligand A (52.423). This is a major concern for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.794) is better than Ligand B (49.05).

**Caco-2 Permeability:** Both are negative, indicating poor permeability, but Ligand A (-4.85) is less negative than Ligand B (-4.922), suggesting slightly better permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility, with Ligand A (-2.395) being slightly better than Ligand B (-2.902).

**hERG:** Both ligands have very low hERG inhibition liability (0.161 and 0.134), which is excellent.

**Microsomal Clearance:** Ligand B (-0.345) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand A (3.503) has a positive clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-6.964) has a much longer in vitro half-life than Ligand B (0.638), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.075 and 0.058), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, QED, lower DILI risk, and significantly longer half-life. While Ligand B has better metabolic stability (lower Cl_mic), the high DILI risk and lower QED are major drawbacks. The slightly better half-life of Ligand A outweighs the small difference in metabolic stability.

Output:
1
2025-04-17 13:30:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.407 and 355.435 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.71) is better than Ligand B (110.18), both are acceptable for oral absorption being under 140.

**logP:** Ligand A (1.607) is within the optimal 1-3 range. Ligand B (-1.254) is below 1, which could hinder permeation.

**H-Bond Donors:** Both ligands have 3 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 (0.645) has a better QED score than Ligand B (0.526), indicating a more drug-like profile.

**DILI:** Ligand A (87.631) has a significantly higher DILI risk than Ligand B (16.906). This is a major concern for Ligand A.

**BBB:** Both are low, not a priority for a non-CNS target like SRC.

**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 (0.13) has a slightly higher hERG risk than Ligand B (0.017), but both are very low and acceptable.

**Microsomal Clearance:** Ligand B (-10.156) has a much lower (better) microsomal clearance than Ligand A (-1.797), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.54) has a much longer in vitro half-life than Ligand A (-9.643), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.127) has slightly lower P-gp efflux than Ligand B (0.004), which is preferable.

**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:**

Ligand A has a better binding affinity and slightly better P-gp efflux. However, its significantly higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter half-life) are major drawbacks. Ligand B, despite slightly weaker binding, presents a much more favorable safety profile (low DILI) and better pharmacokinetic properties (lower Cl_mic, longer half-life). Given the enzyme-specific priorities, metabolic stability and safety are crucial. The 1.3 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 13:30:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 352.431 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.6) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (88.1) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (-0.399) is a bit low, potentially hindering permeation. Ligand B (0.085) is closer to the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (2) is even better, potentially improving permeability.

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

**QED:** Ligand B (0.634) has a better QED score than Ligand A (0.464), indicating a more drug-like profile.

**DILI:** Ligand B (15.743) has a significantly lower DILI risk than Ligand A (22.993), which is a major advantage.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (68.282) is slightly better than Ligand A (46.762).

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

**hERG:** Both ligands have very low hERG inhibition risk (0.038 and 0.213), which is excellent.

**Microsomal Clearance:** Ligand A (-24.383) has a much lower (better) microsomal clearance than Ligand B (26.154), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-4.112) has a slightly better in vitro half-life than Ligand B (-1.37), though both are negative values which is strange.

**P-gp:** Both ligands have very low P-gp efflux liability (0.005 and 0.021).

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

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is superior due to its better QED, significantly lower DILI risk, and slightly better logP and BBB. Ligand A has better metabolic stability (lower Cl_mic) and half-life, but the DILI risk associated with Ligand A is a significant concern. Given the enzyme-specific priorities, the lower DILI risk of Ligand B outweighs the slightly better metabolic stability of Ligand A.

Output:
1
2025-04-17 13:30:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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:** Both ligands have TPSA values around 97, which is acceptable for general absorption but not optimized for CNS penetration (though not a primary concern for SRC).

**logP:** Ligand A (0.2) is quite low, potentially hindering permeability. Ligand B (-0.04) is slightly better but still on the low side. Both are below the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 7 HBA, which is within the acceptable limit of <=10.

**QED:** Ligand A (0.835) has a significantly better QED score than Ligand B (0.715), indicating a more drug-like profile.

**DILI:** Ligand B (78.054) has a higher DILI risk than Ligand A (57.154). This is a significant concern.

**BBB:** Both have reasonable BBB penetration, but this isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is concerning, but the low logP values likely contribute to this.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.081) has a much lower hERG inhibition risk than Ligand B (0.274). This is a critical advantage.

**Microsomal Clearance:** Ligand A (2.683) has significantly lower microsomal clearance than Ligand B (5.063), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.412 hours) has a better in vitro half-life than Ligand B (-8.167 hours - a negative value is unusual and suggests very rapid degradation).

**P-gp Efflux:** Both have low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand A is significantly better overall. While both have issues with logP and solubility, Ligand A excels in crucial areas: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and a better QED score. The slightly better binding affinity further supports its selection. The poor solubility and permeability of both compounds would need to be addressed through formulation or further structural modification, but Ligand A provides a much stronger starting point.

Output:
0
2025-04-17 13:30:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.455 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.69) is better than Ligand B (92.35). Lower TPSA generally indicates better cell permeability. Both are below 140, so acceptable for oral absorption.

**logP:** Both ligands have good logP values (2.41 and 2.688), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability. Both are well within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have 7 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.669 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (51.26) has a slightly better DILI score than Ligand B (55.448), both are acceptable (<60).

**BBB:** Ligand A (83.133) has a better BBB score than Ligand B (76.192), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.623) is slightly better than Ligand B (-4.805) but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.875) is significantly better than Ligand B (-4.179). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.147) is much better than Ligand B (0.253). Lower hERG inhibition is highly desirable to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand B (56.019) has a lower microsomal clearance than Ligand A (83.27), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (17.989) has a significantly longer half-life than Ligand A (-14.399). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.164) is better than Ligand B (0.291). Lower P-gp efflux is preferred.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.7). While both are excellent, the 0.2 kcal/mol difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has a better half-life and slightly better binding affinity, but Ligand A excels in solubility, hERG inhibition, and DILI risk. Given the enzyme-specific priorities, the better solubility and lower hERG risk of Ligand A are more critical than the slightly improved metabolic stability and affinity of Ligand B. The poor Caco-2 permeability is a concern for both, but the other advantages of A make it the better candidate.

Output:
0
2025-04-17 13:30:33,140 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.487 Da and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (74.07 and 78.51) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.242 and 0.853), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 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:** Both ligands have similar QED scores (0.781 and 0.747), indicating good drug-likeness.

**DILI:** Ligand A (34.82 percentile) has a significantly lower DILI risk than Ligand B (8.453 percentile). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (82.513) has a higher BBB penetration than Ligand B (64.87), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.735) has a lower Caco-2 permeability than Ligand B (-5.394), suggesting potentially lower intestinal absorption. This is a slight negative for Ligand A.

**Aqueous Solubility:** Ligand A (-2.039) has better solubility than Ligand B (-1.235). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.773) has a lower hERG inhibition liability than Ligand B (0.176), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (20.438 mL/min/kg) has a higher microsomal clearance than Ligand B (-15.698 mL/min/kg), meaning Ligand B is more metabolically stable. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-29.185 hours) has a much longer in vitro half-life than Ligand B (-3.734 hours). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.129 and 0.007).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better metabolic stability. However, Ligand A demonstrates significantly better safety profiles with lower DILI and hERG risk, and a longer half-life. The difference in binding affinity, while notable, is potentially surmountable with further optimization. Given the importance of safety and PK properties for kinase inhibitors, and the longer half-life of Ligand A, I would favor Ligand A.

Output:
0
2025-04-17 13:30:33,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which could be favorable for permeability, while Ligand B (397.993 Da) is still well within the range.

**TPSA:** Ligand A (43.86) is better than Ligand B (37.38) as it is closer to the ideal threshold of <=140.

**logP:** Ligand A (1.908) is optimal, while Ligand B (4.417) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (0) and HBA (3 & 4 respectively), falling within the acceptable limits.

**QED:** Both ligands have similar QED values (0.691 and 0.66), indicating good drug-likeness.

**DILI:** Ligand A (13.571) has a significantly lower DILI risk than Ligand B (52.307), which is a major advantage.

**BBB:** Both have good BBB penetration (71.229 and 76.115), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.69) has a worse Caco-2 permeability than Ligand B (-5.102).

**Aqueous Solubility:** Ligand A (-2.127) has a better aqueous solubility than Ligand B (-4.492).

**hERG Inhibition:** Ligand A (0.462) has a lower hERG inhibition liability than Ligand B (0.961), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (51.776) has a lower microsomal clearance than Ligand B (62.763), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (66.904) has a significantly longer in vitro half-life than Ligand A (2.08). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.096 and 0.739).

**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 excels in key areas for an enzyme inhibitor: lower DILI risk, lower hERG inhibition, better solubility, and better metabolic stability (lower Cl_mic). While Ligand B has a longer half-life, the superior safety profile and ADME properties of Ligand A outweigh this advantage. The slightly lower Caco-2 permeability of Ligand A is a minor concern, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 13:30:33,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.479 and 372.893 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 (78.87) is well within the range.

**logP:** Ligand A (0.127) is quite low, potentially hindering permeation. Ligand B (2.379) is within the optimal 1-3 range.

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

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

**QED:** Both ligands have similar QED values (0.576 and 0.506), indicating good drug-likeness.

**DILI:** Ligand A (4.382) has a very low DILI risk, which is excellent. Ligand B (33.424) is also low, but higher than A.

**BBB:** Ligand A (56.495) has a moderate BBB penetration, while Ligand B (67.817) is better. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.208 and -5.058), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.627 and -2.457), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.19) has a very low hERG risk, which is excellent. Ligand B (0.402) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (-22.15) has a very negative clearance, indicating high metabolic stability. Ligand B (6.816) has a positive clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (0.954) has a very short half-life, which is a concern. Ligand B (1.585) is slightly better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.125).

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.8). This 0.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its superior binding affinity (-9.0 vs -8.8 kcal/mol) is a significant advantage for an enzyme target like SRC. Furthermore, Ligand B has better logP, BBB, and microsomal clearance compared to Ligand A. While Ligand A has a slightly better DILI profile and hERG risk, the potency advantage of Ligand B is more critical in this context. Addressing the solubility and permeability issues through formulation strategies might be possible, but a weaker binder is less likely to be salvaged.

Output:
1
2025-04-17 13:30:33,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.356 and 354.382 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (85.69) is still under 140, but less favorable than A.

**logP:** Ligand A (2.653) is optimal (1-3). Ligand B (-0.109) is below 1, which may impede permeation.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 6. Both are within the acceptable limit of 10, but B is higher.

**QED:** Ligand A (0.909) has a very strong drug-like profile. Ligand B (0.704) is still acceptable, but less ideal.

**DILI:** Both ligands have acceptable DILI risk (A: 45.328, B: 48.313), below the 60 threshold.

**BBB:** Both have high BBB penetration, but A is better (93.098 vs 83.831). This isn't a primary concern for a kinase inhibitor, but is a bonus.

**Caco-2 Permeability:** Ligand A (-4.618) and Ligand B (-4.493) both have negative values, indicating poor permeability. This is concerning.

**Aqueous Solubility:** Ligand A (-3.7) and Ligand B (-1.76) both have negative values, indicating poor solubility. This is also concerning.

**hERG Inhibition:** Ligand A (0.511) has a low hERG risk. Ligand B (0.151) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (6.498) has a higher Cl_mic than Ligand B (3.259), suggesting lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (-19.638) has a much longer in vitro half-life than Ligand A (-8.689), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.102, B: 0.031).

**Binding Affinity:** Ligand A (-8.5 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 A.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a significantly better metabolic stability profile (lower Cl_mic, longer half-life) and a more optimal logP. The slightly weaker binding affinity of B is outweighed by its superior ADME properties, which are crucial for *in vivo* efficacy as an enzyme inhibitor.

Output:
1
2025-04-17 13:30:33,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (374.369 Da) is also acceptable.

**TPSA:** Ligand A (62.3) is well below the 140 threshold for good oral absorption, and suitable for kinase inhibitors. Ligand B (113.18) is higher, but still within a reasonable range, though potentially impacting absorption slightly.

**logP:** Ligand A (3.246) is optimal. Ligand B (0.45) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 3), well below the limit of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 5), below the limit of 10.

**QED:** Both ligands have good QED scores (Ligand A: 0.787, Ligand B: 0.679), indicating drug-like properties.

**DILI:** Ligand A (21.985) has a significantly lower DILI risk than Ligand B (87.282). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.627) shows better potential for BBB penetration than Ligand B (55.37).

**Caco-2 Permeability:** Ligand A (-4.304) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.432) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.286 and -3.18), indicating very poor aqueous solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.545) has a lower hERG risk than Ligand B (0.64), which is preferable.

**Microsomal Clearance:** Ligand A (72.402) has a moderate clearance, while Ligand B (-16.05) has a negative clearance, which is not physically possible and likely indicates a very stable compound *in vitro*. This is a substantial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (29.97 hours) has a reasonable half-life. Ligand B (-12.06 hours) is not physically possible and suggests a very long half-life *in vitro*.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.096, Ligand B: 0.012).

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8 kcal/mol, Ligand B: -9.4 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and *in vitro* stability (as indicated by the negative, and therefore extremely low, microsomal clearance and half-life). However, its low logP and high DILI risk are major drawbacks. Ligand A has a better logP, lower DILI, and a reasonable half-life, but suffers from poor Caco-2 permeability and solubility. The negative Caco-2 and solubility for both are concerning, but the DILI risk for Ligand B is particularly worrisome. Given the enzyme class, metabolic stability is highly valued. The very high stability of Ligand B, coupled with its superior binding affinity, outweighs the logP and DILI concerns, *assuming* the negative clearance/half-life values are not artifacts of the prediction method.

Output:
1
2025-04-17 13:30:33,141 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 353.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.25) is slightly above the preferred <140 for good oral absorption, while Ligand B (89.35) is well within the range.

**logP:** Both ligands have acceptable logP values (1.318 and 0.595), falling within the 1-3 range. Ligand A is slightly better here.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2 and 1 respectively) and HBA (6 each) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.65 and 0.775), indicating drug-likeness.

**DILI:** Ligand A (41.838) has a lower DILI risk than Ligand B (68.98), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (70.997 and 79.798), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.893 and -4.895), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2 and -2.342), which is also concerning and suggests very poor solubility.

**hERG:** Both ligands have low hERG risk (0.253 and 0.08), which is excellent.

**Microsomal Clearance:** Ligand A (34.957) has a lower Cl_mic than Ligand B (18.274), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.714) has a significantly longer in vitro half-life than Ligand A (-11.208), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.025).

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.1), a 0.3 kcal/mol difference. While a 1.5 kcal/mol advantage is usually significant, 0.3 kcal/mol is less impactful, especially considering the other ADME properties.

**Overall Assessment:**

Ligand A has advantages in DILI risk and microsomal clearance, suggesting better safety and metabolic stability. However, Ligand B has a significantly longer half-life and slightly better binding affinity. Both have poor predicted permeability and solubility.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and potency (affinity) are key. While Ligand A has better metabolic stability, the longer half-life of Ligand B is a substantial benefit, potentially allowing for less frequent dosing. The slight affinity difference is less important than the half-life. The poor solubility and permeability are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:30:33,142 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.375 Da) is slightly higher than Ligand B (351.403 Da), but both are acceptable.

**TPSA:** Ligand A (120.62) is better than Ligand B (132.96) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (2.204) is optimal (1-3). Ligand B (-1.511) is too low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=9) is better than Ligand B (HBD=4, HBA=5) as it is closer to the ideal thresholds.

**QED:** Ligand A (0.685) is better than Ligand B (0.489), indicating a more drug-like profile.

**DILI:** Ligand B (23.071) is significantly better than Ligand A (99.496), indicating a much lower risk of drug-induced liver injury. This is a major advantage for Ligand B.

**BBB:** Ligand A (61.691) is better than Ligand B (22.063), but BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.97) is better than Ligand B (-6.02), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.009) is better than Ligand B (-1.644), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG risk (0.335 and 0.041, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (-27.031) has significantly lower (better) microsomal clearance than Ligand A (29.753), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (45.942) has a much longer half-life than Ligand B (4.9), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.239 and 0.003, respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -8.9 kcal/mol), with Ligand A being slightly better. However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B has a significant advantage in DILI risk and metabolic stability (Cl_mic). Ligand A has better solubility, Caco-2 permeability, and half-life, and slightly better affinity. However, the low logP of Ligand B is a concern. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, hERG), the lower DILI risk and better metabolic stability of Ligand B outweigh the slightly lower logP and half-life. The affinity difference is minimal.

Output:
1
2025-04-17 13:30:33,142 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.403 and 352.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.01) is slightly above the optimal <90 for CNS penetration, but acceptable. Ligand B (88.1) is within the desired range.

**logP:** Ligand A (1.309) is within the optimal 1-3 range. Ligand B (0.228) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 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 (0.904) has a very high QED score, indicating excellent drug-likeness. Ligand B (0.641) is still good, exceeding the 0.5 threshold.

**DILI:** Ligand A (65.103) has a moderate DILI risk, while Ligand B (17.642) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.76) and Ligand B (45.638) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.073) and Ligand B (-4.966) have similar, negative Caco-2 values, suggesting poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.601) and Ligand B (-0.931) both have negative solubility values, indicating poor aqueous solubility. Ligand B is better in this regard.

**hERG Inhibition:** Ligand A (0.069) has a very low hERG risk, excellent. Ligand B (0.141) is also low, but slightly higher than A.

**Microsomal Clearance:** Ligand A (0.405) has very low microsomal clearance, suggesting high metabolic stability, a major advantage. Ligand B (10.388) has significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-5.985) has a very long in vitro half-life, consistent with low clearance. Ligand B (9.051) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 and 0.055 respectively).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a substantially better binding affinity than Ligand A (-7.2 kcal/mol), a difference of 1.2 kcal/mol. This is a significant advantage that can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better hERG profile, Ligand B's significantly stronger binding affinity (-8.4 vs -7.2 kcal/mol) is a crucial advantage for an enzyme inhibitor. The lower DILI risk for Ligand B is also a positive factor. Although Ligand B has slightly lower solubility and higher clearance, the potency difference is substantial enough to make it the more promising candidate.

Output:
1
2025-04-17 13:30:33,142 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.527 Da) is slightly higher than Ligand B (346.515 Da), but both are acceptable.

**TPSA:** Ligand A (66.22) is higher than Ligand B (41.57). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better, suggesting potentially improved absorption.

**logP:** Both ligands have good logP values (A: 4.102, B: 3.777), falling within the optimal range of 1-3, although A is a bit high.

**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 (A: 0.697, B: 0.852), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (39.705) has a slightly higher DILI risk than Ligand B (27.608), but both are below the 40 threshold, indicating low risk.

**BBB:** Both ligands have similar BBB penetration (A: 76.309, B: 77.433), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.483 and -4.537), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.486 and -4.389), also unusual and indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show a low risk of hERG inhibition (A: 0.693, B: 0.831).

**Microsomal Clearance:** Ligand A (105.179) has higher microsomal clearance than Ligand B (85.567), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (42.004) has a significantly longer in vitro half-life than Ligand A (-14.877), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.402, B: 0.497).

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.5 kcal/mol, B: -8.6 kcal/mol). The difference is minimal.

**Conclusion:**

While both ligands have strong binding affinity, Ligand B is the more promising candidate. It has a lower TPSA, a better QED score, lower DILI risk, significantly better in vitro half-life (metabolic stability), and slightly better P-gp efflux. The major drawbacks of poor Caco-2 permeability and aqueous solubility are shared by both, but the improved ADME properties of Ligand B outweigh the slight differences in other parameters.

Output:
1
2025-04-17 13:30:33,142 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 344.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (103.95 and 98.22) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.46 and 1.444), falling within the optimal range of 1-3.

**H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.725 and 0.763), indicating drug-like properties.

**DILI:** Ligand A (37.379) has a lower DILI risk than Ligand B (43.66), both are acceptable (<40 is good, >60 is high risk).

**BBB:** Both ligands have similar BBB penetration (52.617 and 56.029). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.324 and -4.781). This is unusual and suggests poor permeability. However, these values are on a log scale and need to be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.498 and -3.907). This also suggests poor solubility.

**hERG Inhibition:** Ligand A (0.025) has a significantly lower hERG inhibition risk than Ligand B (0.333). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (-4.9) has a much lower (better) microsomal clearance than Ligand B (-11.523). This indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.161) has a more negative value, suggesting a longer half-life than Ligand B (12.912).

**P-gp Efflux:** Ligand A (0.024) has a lower P-gp efflux liability than Ligand B (0.102).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). While the difference is less than the 1.5kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand A is the better candidate. It demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, lower P-gp efflux, and slightly better binding affinity. While both ligands have concerningly low solubility and permeability, the ADME properties of Ligand A are significantly more favorable, particularly the hERG and metabolic stability profiles, which are critical for kinase inhibitors.

Output:
0
2025-04-17 13:30:33,142 - INFO - Batch 219 complete. Total preferences: 3504
2025-04-17 13:30:33,142 - INFO - Processing batch 220/512...
2025-04-17 13:31:11,825 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.555 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (86.88). A TPSA under 140 is good for oral absorption, and both are under, but A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.521) is optimal, while Ligand B (1.565) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.709 and 0.872), indicating drug-like properties.

**DILI:** Both have low DILI risk (28.073 and 22.722), which is excellent.

**BBB:** Both have reasonably high BBB penetration (89.259 and 73.827), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.814 and -4.844) which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-4.553 and -1.015). This is a major drawback for both compounds and could severely limit bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.929 and 0.166), which is excellent.

**Microsomal Clearance:** Ligand A (72.189) has higher clearance than Ligand B (27.207). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand B (-13.312) has a significantly longer half-life than Ligand A (-41.296). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.486 and 0.087).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While both compounds have excellent binding affinity and low hERG/DILI risk, the poor solubility and Caco-2 permeability are major concerns. Ligand B is slightly favored due to its better metabolic stability (lower Cl_mic) and longer half-life. However, the solubility issue is critical. Given the equal affinity, the ADME properties are the deciding factor.

Output:
1
2025-04-17 13:31:11,825 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.889 Da and 354.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (81.51), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.361) is slightly higher than Ligand B (2.33), both within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Ligand A is better here, as fewer HBA generally improves permeability.

**QED:** Both ligands have similar QED values (0.722 and 0.697), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (35.828 and 37.456), which is good.

**BBB:** Both have moderate BBB penetration (67.623 and 65.025). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.762 and -4.918), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-4.052 and -3.156), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.35) has a significantly lower hERG risk than Ligand B (0.826). This is a critical advantage.

**Microsomal Clearance:** Ligand B (24.725) has lower microsomal clearance than Ligand A (32.911), suggesting better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (34.516) has a shorter half-life than Ligand A (44.435). This is a negative for Ligand B.

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux than Ligand B (0.266), suggesting better bioavailability.

**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 ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, and better metabolic stability. However, it has a shorter half-life. Both ligands have poor solubility and permeability. Ligand A has a much better hERG profile and lower P-gp efflux. Given the priority for potency in kinase inhibitors, and the substantial difference in binding affinity (-8.4 vs -6.7 kcal/mol), Ligand B is the more promising candidate *despite* the solubility and permeability concerns. These can be addressed through formulation strategies. The improved binding affinity is likely to have a greater impact on efficacy.

Output:
1
2025-04-17 13:31:11,825 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.435 and 385.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.87 and 73.74) are below 140, suggesting good oral absorption potential.

**logP:** Both ligands have logP values within the optimal range (3.048 and 2.411).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable H-bond characteristics, well within the acceptable limits.

**QED:** Both ligands have good QED scores (0.682 and 0.867), indicating drug-like properties.

**DILI:** Ligand A (68.166) has a slightly higher DILI risk than Ligand B (50.795), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.143) has a slightly better BBB score than Ligand B (49.864).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.036 and -4.713), which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.201 and -3.243). This is a major drawback.

**hERG:** Both ligands have very low hERG inhibition liability (0.338 and 0.384), which is excellent.

**Microsomal Clearance:** Ligand B (18.256 mL/min/kg) has significantly lower microsomal clearance than Ligand A (40.857 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (8.607 hours) has a longer in vitro half-life than Ligand A (3.548 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.121 and 0.371).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.4 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and BBB score, Ligand B is significantly better regarding metabolic stability (lower Cl_mic and longer t1/2). Both have poor solubility and permeability, which are major issues. However, for an enzyme target, metabolic stability is paramount. The slightly higher potency of Ligand A is unlikely to overcome the substantial metabolic liabilities.

Output:
1
2025-04-17 13:31:11,825 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.455 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is well below the 140 threshold, while Ligand B (67.87) is also acceptable.

**logP:** Ligand A (3.135) is optimal, while Ligand B (1.039) is a bit low, potentially hindering permeability.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.878) has a significantly better QED score than Ligand B (0.694), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (32.959 and 30.903), which is favorable.

**BBB:** Both have similar BBB penetration (73.788 and 73.129), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.07) has poor Caco-2 permeability, while Ligand B (-4.547) is also low but slightly better.

**Aqueous Solubility:** Ligand A (-3.27) and Ligand B (-1.64) both have poor solubility.

**hERG Inhibition:** Ligand A (0.642) has a slightly higher hERG risk than Ligand B (0.283), but both are relatively low.

**Microsomal Clearance:** Ligand A (81.283) has a significantly higher microsomal clearance than Ligand B (16.693), suggesting lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (13.494) has a longer half-life than Ligand B (-11.384), but the negative value for B is concerning and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.574) has a slightly higher P-gp efflux liability than Ligand B (0.051), which is less desirable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1 kcal/mol difference is significant and could outweigh some ADME concerns.

**Overall Assessment:**

Ligand A possesses a much stronger binding affinity, a better QED score, and a longer half-life. However, it suffers from poor Caco-2 permeability, higher microsomal clearance, and slightly higher P-gp efflux. Ligand B has better permeability and metabolic stability, but significantly weaker binding affinity and a concerning negative in vitro half-life.

Given that SRC is a kinase (enzyme target), potency and metabolic stability are paramount. The 1 kcal/mol difference in binding affinity is substantial. While Ligand A's metabolic stability is a concern, it might be addressable through structural modifications. The poor permeability and efflux are also potential issues, but the strong binding could compensate. Ligand B's weak binding affinity is a more fundamental issue that is harder to overcome.

Output:
0
2025-04-17 13:31:11,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.535 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Ligand A (69.73) is better than Ligand B (83.56) as it's closer to the threshold for good oral absorption (<=140).

**logP:** Both ligands have good logP values (A: 1.205, B: 2.036), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand A has 7 HBAs, while Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (A: 0.604, B: 0.875), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (35.169) has a significantly lower DILI risk than Ligand B (49.632), placing it in a more favorable range.

**BBB:** Both have reasonable BBB penetration (A: 78.209, B: 70.841), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.913, B: 0.666), which is excellent.

**Microsomal Clearance:** Ligand A (14.96) has a lower microsomal clearance than Ligand B (34.54), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (29.019) has a longer in vitro half-life than Ligand B (7.565), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux (A: 0.058, B: 0.043), which is good.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a substantially better binding affinity than Ligand A (-6.8 kcal/mol). This 0.8 kcal/mol difference is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better DILI, metabolic stability (lower Cl_mic, longer t1/2), and TPSA, the significantly stronger binding affinity of Ligand B (-7.6 vs -6.8 kcal/mol) is the most critical factor for an enzyme inhibitor. The potency advantage is likely to be more impactful than the slightly less favorable ADME properties of Ligand B.

Output:
1
2025-04-17 13:31:11,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.375 and 360.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.0) is higher than Ligand B (76.02). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (0.461) is quite low, potentially hindering permeability. Ligand B (2.919) 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, though Ligand B has a slightly more favorable balance.

**QED:** Both ligands have good QED scores (0.84 and 0.88), indicating good drug-like properties.

**DILI:** Ligand A (57.929) has a lower DILI risk than Ligand B (71.694), which is preferable.

**BBB:** Both have similar BBB penetration (62.466 and 62.311), which isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.844 and -4.869), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.606) has better solubility than Ligand B (-3.99). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.018) has a much lower hERG risk than Ligand B (0.21). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (3.514 mL/min/kg) has significantly lower microsomal clearance than Ligand B (27.573 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.175 hours) has a shorter half-life than Ligand B (38.686 hours). The longer half-life of Ligand B is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032 and 0.064).

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower microsomal clearance, which are critical for an enzyme inhibitor. It also has a much lower hERG risk. While Ligand B has a better logP and half-life, the superior potency and safety profile of Ligand A make it the more promising candidate. The solubility of Ligand A is also better than that of Ligand B. The negative Caco-2 values are concerning for both, but the strong binding affinity of A suggests it might overcome this issue.

Output:
0
2025-04-17 13:31:11,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.402 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.91) is slightly higher than Ligand B (58.64), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (2.857 and 2.346, respectively), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.795 and 0.75), indicating drug-like properties.

**DILI:** Ligand A (55.991) has a higher DILI risk than Ligand B (13.339). This is a significant concern.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (80.496) is better than Ligand A (69.523). However, BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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, which is also unusual. Again, interpretation is difficult without knowing the scale.

**hERG:** Both ligands have very low hERG inhibition risk (0.236 and 0.244), which is excellent.

**Microsomal Clearance:** Ligand B (72.09) has a significantly higher microsomal clearance than Ligand A (8.046), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (14.585) has a longer in vitro half-life than Ligand B (4.848), supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.051 and 0.104).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Conclusion:**

While Ligand B has a superior binding affinity, the significantly higher DILI risk associated with Ligand A is a major concern. The lower metabolic stability of Ligand B (higher Cl_mic, shorter t1/2) is also a drawback, but the strong binding affinity might compensate. However, the DILI risk for Ligand A is too high to ignore. Therefore, despite the slightly better metabolic profile of Ligand A, the superior binding affinity of Ligand B makes it the more promising candidate, assuming the DILI risk can be mitigated through structural modifications.

Output:
1
2025-04-17 13:31:11,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.38 and 362.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is higher than Ligand B (58.2). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (0.718) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (3.755) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are acceptable, but Ligand B has fewer, potentially improving permeability.

**QED:** Both ligands have good QED scores (0.534 and 0.776), indicating drug-like properties.

**DILI:** Ligand A (25.4%) has a significantly lower DILI risk than Ligand B (36.6%), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (70.4%) is slightly better. However, BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.032) has a negative Caco-2 value, which is concerning for intestinal absorption. Ligand B (-4.826) is also negative, but less so.

**Solubility:** Ligand A (-1.7) has slightly better solubility than Ligand B (-4.091).

**hERG:** Ligand A (0.313) has a much lower hERG risk than Ligand B (0.622), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-9.919) has a much lower (better) microsomal clearance than Ligand B (82.547), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.764) has a longer in vitro half-life than Ligand B (40.479), which is desirable.

**P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.451), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is relatively small and can be outweighed by other factors.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile with significantly lower DILI, hERG, and P-gp efflux, and better metabolic stability (lower Cl_mic and longer t1/2). While Ligand B has a slightly better binding affinity and logP, the ADME advantages of Ligand A are more critical for overall drug development success, especially considering the enzyme class. The negative 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 13:31:11,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.748 and 373.791 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.36) is better than Ligand B (99.12), both are below the 140 threshold for oral absorption, but closer to the 90 threshold is better.

**logP:** Ligand A (3.723) is within the optimal 1-3 range, while Ligand B (4.79) is slightly higher, potentially leading to solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=2, HBA=3) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.478 and 0.408), indicating moderate drug-likeness.

**DILI:** Ligand A (87.864) has a higher DILI risk than Ligand B (59.403). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (76.309 and 78.868), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is not useful.

**Aqueous Solubility:** Both ligands have negative solubility values which is not useful.

**hERG Inhibition:** Ligand A (0.22) shows lower hERG inhibition risk than Ligand B (0.691), which is a positive attribute.

**Microsomal Clearance:** Ligand B (40.583) has lower microsomal clearance than Ligand A (63.682), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (30.546) has a significantly longer in vitro half-life than Ligand A (1.818), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.19) has slightly lower P-gp efflux than Ligand B (0.229).

**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, but needs to be weighed against the other factors.

**Overall Assessment:**

While Ligand A boasts a slightly better binding affinity, Ligand B is superior in several critical aspects for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and a more favorable logP. The affinity difference, while noticeable, might be overcome with further optimization of Ligand B. The higher DILI risk for Ligand A is a major concern.

Output:
1
2025-04-17 13:31:11,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (387.531 and 384.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.45) is better than Ligand B (105.39) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.45 and 1.419), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.656 and 0.818), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have similar DILI risk (51.493 and 51.105), which is acceptable (below 60).

**BBB:** Ligand A (80.574) has a significantly higher BBB penetration percentile than Ligand B (54.13). While not a primary concern for a non-CNS target, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.298) has slightly better Caco-2 permeability than Ligand B (-5.282), suggesting better absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.804 and -2.83). This is a significant concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.218 and 0.102), which is excellent. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (23.109) has a higher microsomal clearance than Ligand B (-8.168). This means Ligand B is predicted to have better metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-22.783) has a much longer predicted in vitro half-life than Ligand A (3.947), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.032).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity and acceptable safety profiles, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic and longer t1/2). The solubility is a concern for both, but metabolic stability is a higher priority for kinase inhibitors. The slightly better QED and hERG profile of Ligand B are also beneficial.

Output:
1
2025-04-17 13:31:11,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (382.551 and 359.417 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.27) is slightly higher than Ligand B (67.59), but both are below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (3.059 and 2.725) 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 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.679 and 0.775), indicating drug-like properties.

**7. DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (39.046). This is a significant concern, as we want to minimize liver injury potential.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (87.01) has a higher BBB percentile than Ligand A (64.676), but this is less critical here.

**9. Caco-2 Permeability:** Ligand A (-5.147) has a worse Caco-2 permeability than Ligand B (-4.6).

**10. Aqueous Solubility:** Ligand A (-3.274) has worse aqueous solubility than Ligand B (-2.028). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.113 and 0.358), which is good.

**12. Microsomal Clearance:** Ligand A (61.901) has a higher microsomal clearance than Ligand B (33.548). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-15.282) has a better in vitro half-life than Ligand A (-18.462).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.355 and 0.089).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.4). However, the difference is only 0.4 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior in almost all ADME-Tox properties. Specifically, it has a significantly lower DILI risk, better solubility, better Caco-2 permeability, and improved metabolic stability (lower Cl_mic and better half-life). The 0.4 kcal/mol difference in binding affinity is unlikely to outweigh these substantial advantages in drug-like properties for an enzyme target like SRC.

Output:
1
2025-04-17 13:31:11,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.3 and 78.87) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.169 and 1.019), falling within the 1-3 range. Ligand B is slightly lower, which *could* indicate a slight solubility advantage, but isn't a major concern.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.84 and 0.788), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (20.396 and 23.769), well below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (73.788 and 74.176), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.608 and -4.705). This is unusual and suggests poor permeability. However, Caco-2 values can be unreliable and are less important than other factors for kinase inhibitors.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.391 and -1.63). This is concerning, as poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.613 and 0.315), which is excellent.

**Microsomal Clearance:** Ligand A has a Cl_mic of 6.233 mL/min/kg, while Ligand B has a negative value of -6.212 mL/min/kg. A negative value for Cl_mic is not physically meaningful and suggests a potential issue with the data or model. Assuming the positive value is more reliable, Ligand A has a better metabolic stability profile.

**In vitro Half-Life:** Ligand A has a negative half-life (-1.026 hours), which is impossible. Ligand B has a half-life of 7.505 hours, which is a good sign. Again, the negative value for Ligand A is a red flag.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.042).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-8.5 kcal/mol) compared to Ligand A (-7.6 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh minor ADME drawbacks.

**Conclusion:**

Despite the questionable solubility and Caco-2 values for both, Ligand B is the superior candidate. Its significantly stronger binding affinity (-8.5 vs -7.6 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, the negative and unrealistic values for half-life and clearance for Ligand A raise concerns about the reliability of its predicted ADME properties. Ligand B's positive half-life is a strong indicator of better metabolic stability.

Output:
1
2025-04-17 13:31:11,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (356.466 and 364.383 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (33.2) is significantly better than Ligand B (49.41). Lower TPSA generally favors better absorption.

**logP:** Ligand A (4.805) is higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (2.536) is within the optimal range.

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

**H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (2).

**QED:** Both ligands have similar QED values (0.74 and 0.602), indicating good drug-likeness.

**DILI:** Ligand B (32.261) has a much lower DILI risk than Ligand A (56.883), which is a significant advantage.

**BBB:** Ligand A (91.702) has a higher BBB penetration percentile than Ligand B (70.376). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.542 and -4.666), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.581 and -3.407), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.75) has a slightly higher hERG inhibition risk than Ligand B (0.56). Lower is better here.

**Microsomal Clearance:** Ligand B (-0.197) has significantly lower (better) microsomal clearance than Ligand A (102.08). 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 (33.97), which is a major advantage.

**P-gp Efflux:** Ligand A (0.631) has a slightly lower P-gp efflux liability than Ligand B (0.052). Lower is better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -7.9 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for an enzyme target (SRC kinase), Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The slightly better logP of Ligand B is also beneficial. The similar binding affinities make the ADME properties the deciding factors.

Output:
1
2025-04-17 13:31:11,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 140, indicating good potential for oral absorption. Ligand B (63.91) is significantly lower than Ligand A (87.3), which is favorable.

**logP:** Ligand A (0.636) is a bit low, potentially hindering permeation. Ligand B (3.079) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores, with Ligand B (0.78) being better than Ligand A (0.376), suggesting a more drug-like profile.

**DILI:** Ligand A (27.608) has a much lower DILI risk than Ligand B (59.054), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (88.639) has a higher BBB score than Ligand A (30.128), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, this is a scale and the negative values could be relative to a standard.

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

**hERG:** Ligand A (0.031) has a very low hERG risk, while Ligand B (0.372) is slightly higher. This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (22.291 mL/min/kg) has a lower microsomal clearance than Ligand B (51.309 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.036 hours) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (-22.791 hours) also has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**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 minimal.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and a more favorable QED, Ligand A excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and a much lower hERG risk. The negative values for Caco-2 and Solubility are concerning for both, but the other advantages of Ligand A outweigh this. The negative half-life values are suspect for both compounds.

Output:
0
2025-04-17 13:31:11,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (388.6 and 358.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is better than Ligand B (75.62). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**logP:** Both ligands have acceptable logP values (2.03 and 3.63, respectively), 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 (1 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 7 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.783) has a significantly better QED score than Ligand B (0.499), indicating a more drug-like profile.

**DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (69.639). This is a significant advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (74.021) is slightly better, but this isn't a deciding factor.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both compounds. However, the scale is not specified, so it's difficult to interpret the absolute impact.

**Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both compounds, but could be mitigated by formulation strategies.

**hERG:** Ligand A (0.148) has a much lower hERG inhibition liability than Ligand B (0.627), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (37.383) has a lower microsomal clearance than Ligand B (74.782), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (50.948) has a significantly longer in vitro half-life than Ligand A (-3.373). This is a key advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.052 and 0.474, respectively), which is good.

**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 A is superior in most critical ADME properties: QED, DILI risk, hERG risk, and metabolic stability. It also has a better TPSA and HBD/HBA profile. The primary advantage of Ligand B is its longer in vitro half-life and slightly better binding affinity. However, the significantly better safety profile (DILI, hERG) and drug-likeness (QED) of Ligand A outweigh the modest advantage in half-life and affinity. The poor Caco-2 and solubility for both are concerning, but potentially addressable.

Output:
0
2025-04-17 13:31:11,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (356.438 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is well below the 140 threshold, and quite favorable. Ligand B (102.42) is still under 140 but less optimal than A.

**3. logP:** Ligand A (2.002) is within the optimal 1-3 range. Ligand B (0.953) 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 (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.56 and 0.824, respectively), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (40.52 and 43.622), being below the 60 threshold.

**8. BBB:** This is less critical for an oncology target, but Ligand A (91.663) has a significantly higher BBB percentile than Ligand B (38.348).

**9. Caco-2 Permeability:** Ligand A (-4.676) and Ligand B (-5.271) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.817 and -2.167), suggesting poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.465 and 0.208), which is excellent.

**12. Microsomal Clearance:** Ligand A (19.881) has a higher (worse) microsomal clearance than Ligand B (-6.068). A negative value for B indicates high metabolic stability, which is highly desirable for a kinase inhibitor.

**13. In vitro Half-Life:** Ligand A (-8.738) has a negative half-life, suggesting very rapid metabolism. Ligand B (8.022) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.267 and 0.083), which is favorable.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B demonstrates significantly better ADME properties, particularly regarding metabolic stability (Cl_mic and t1/2). The poor solubility and permeability are concerns for both, but the superior metabolic stability of Ligand B is crucial for a kinase inhibitor, as these often require sustained exposure. The significantly better half-life and lower clearance of Ligand B outweigh the slight advantage in binding affinity of Ligand A.

Output:
1
2025-04-17 13:31:11,827 - INFO - Batch 220 complete. Total preferences: 3520
2025-04-17 13:31:11,827 - INFO - Processing batch 221/512...
2025-04-17 13:31:51,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.423 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is higher than Ligand B (43.86). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (1.422) and Ligand B (2.524) are both 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 (0.844) has a significantly higher QED score than Ligand B (0.633), indicating better overall drug-likeness.

**DILI:** Ligand A (30.516) has a much lower DILI risk than Ligand B (6.979), which is a significant advantage.

**BBB:** Ligand A (52.268) has a lower BBB penetration percentile than Ligand B (83.831). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.302) and Ligand B (-4.903) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.334) and Ligand B (-1.377) both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.239) has a lower hERG inhibition liability than Ligand B (0.735), which is a significant advantage.

**Microsomal Clearance:** Ligand A (24.422) has a lower microsomal clearance than Ligand B (45.185), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (16.027) has a longer in vitro half-life than Ligand B (-1.891), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.051) has a lower P-gp efflux liability than Ligand B (0.105), which is a slight advantage.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.0 and -7.9 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have issues with Caco-2 permeability and solubility, Ligand A demonstrates superior drug-likeness (QED), significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The binding affinity is comparable between the two. The enzyme-specific priorities clearly favor Ligand A due to its improved ADME-Tox profile.

Output:
0
2025-04-17 13:31:51,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (354.491 and 358.551 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is better than Ligand B (36.36) as it is closer to the threshold of 140 for good oral absorption.

**3. logP:** Ligand A (2.112) is optimal (1-3), while Ligand B (4.727) is slightly high, potentially leading to solubility issues or 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):** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.689 and 0.777, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (25.126) has a significantly lower DILI risk than Ligand B (9.965), which is a major advantage.

**8. BBB:** Both ligands have good BBB penetration (76.154 and 78.519), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.578 and -4.847). This is unusual and suggests poor permeability. However, the absolute values are similar.

**10. Aqueous Solubility:** Ligand A (-1.854) has better solubility than Ligand B (-4.322).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.425 and 0.827).

**12. Microsomal Clearance (Cl_mic):** Both ligands have similar microsomal clearance rates (44.187 and 44.528 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.574) has a longer in vitro half-life than Ligand A (-1.982), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.567).

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has a higher logP and slightly lower solubility, its significantly improved binding affinity (-9.3 vs -6.4 kcal/mol) and longer half-life are crucial advantages. The lower DILI risk of Ligand A is also a positive, but the potency difference is more significant.

Output:
1
2025-04-17 13:31:51,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.491 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.97 and 98.66) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have acceptable logP values (1.455 and 0.811), falling within the optimal 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for cell permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (4 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED scores (0.754 and 0.545), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (42.846) has a slightly higher DILI risk than Ligand B (16.479), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.76) is higher than Ligand B (30.554).

**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 concerning. This could lead to formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.172 and 0.216), which is excellent.

**Microsomal Clearance:** Ligand A (19.722) has a higher microsomal clearance than Ligand B (4.492). This suggests Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (16.311 hours) has a significantly longer in vitro half-life than Ligand A (-25.402 hours - negative value is concerning). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.049).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.0 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have good potency, Ligand B is the more promising candidate due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and acceptable QED. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The slight advantage in potency of Ligand A is outweighed by the superior ADME properties of Ligand B.

Output:
1
2025-04-17 13:31:51,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.26) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for good absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (1.487 and 2.127), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.856 and 0.822), indicating good drug-likeness.

**DILI:** Ligand A (54.634) has a higher DILI risk than Ligand B (37.767). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (68.282) and Ligand B (45.56) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.055) has a worse Caco-2 permeability compared to Ligand B (-4.603), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.788 and -2.468). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.084) has a slightly lower hERG inhibition risk than Ligand B (0.559), which is favorable.

**Microsomal Clearance:** Ligand A (48.946) has a higher microsomal clearance than Ligand B (31.461), suggesting lower metabolic stability. This is a key disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (5.119) has a significantly longer in vitro half-life than Ligand A (-23.603), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.057) has lower P-gp efflux than Ligand B (0.171), which is favorable.

**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 the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), **Ligand B** is the more promising candidate. While both have good potency, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and better Caco-2 permeability. The slightly higher hERG risk for Ligand B is a minor concern compared to the metabolic liabilities of Ligand A.



Output:
1
2025-04-17 13:31:51,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.801 and 373.425 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (116.36) is slightly above the preferred <140 for good oral absorption, while Ligand B (71.53) is well within the range.

**logP:** Both ligands have good logP values (2.335 and 1.812), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, acceptable, while Ligand B has 5 HBA, also acceptable.

**QED:** Ligand B (0.826) has a significantly better QED score than Ligand A (0.48), suggesting a more drug-like profile.

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a major concern. Ligand B has a much lower, and acceptable, DILI risk (43.622%).

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (85.498) than Ligand A (45.095), but this is not a primary factor.

**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 (0.262) has a slightly higher hERG risk than Ligand B (0.165), but both are relatively low.

**Microsomal Clearance:** Ligand B (-3.967) has a *much* lower (better) microsomal clearance than Ligand A (21.634), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-1.731) has a longer in vitro half-life than Ligand A (29.022), indicating greater stability.

**P-gp Efflux:** Ligand A (0.256) has slightly higher P-gp efflux liability than Ligand B (0.042).

**Binding Affinity:** Ligand B (-9.0 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.

**Conclusion:**

Ligand B is significantly more promising. While both have unusual solubility and permeability values, Ligand B excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly improved metabolic stability (lower Cl_mic, longer t1/2), a better QED score, and slightly better binding affinity. The high DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 13:31:51,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.463) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both are acceptable. Ligand B (82.27) is better than Ligand A (99.1) as it is closer to the <140 threshold for good absorption.

**logP:** Ligand B (1.713) is optimal (1-3), while Ligand A (0.147) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

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

**QED:** Both ligands have acceptable QED values (Ligand A: 0.484, Ligand B: 0.599), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand B (38.154) has a much lower DILI risk than Ligand A (5.777), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (44.94) is slightly better than Ligand B (26.134).

**Caco-2 Permeability:** Ligand A (-4.99) has a better Caco-2 permeability than Ligand B (-5.752), though both are poor.

**Aqueous Solubility:** Ligand A (-0.368) has better solubility than Ligand B (-2.407).

**hERG Inhibition:** Ligand A (0.331) shows a lower hERG inhibition risk than Ligand B (0.204), which is a positive.

**Microsomal Clearance:** Ligand A (-5.929) has significantly lower microsomal clearance than Ligand B (39.118), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (24.472) has a much longer half-life than Ligand A (1.822), which is desirable.

**P-gp Efflux:** Ligand A (0.02) has lower P-gp efflux than Ligand B (0.083), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-5.8 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 solubility and lower hERG risk, Ligand B's superior binding affinity (-8.4 vs -5.8 kcal/mol) and significantly lower DILI risk are critical advantages. The longer half-life of Ligand B is also beneficial. The lower logP of Ligand A is a concern for permeability. The improved metabolic stability of Ligand A is good, but the potency difference is more important for an enzyme target.

Output:
1
2025-04-17 13:31:51,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.334 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (39.68) is significantly better than Ligand B (82.53). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target. Ligand B's TPSA is relatively high.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.928, Ligand B: 1.582), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) has a more favorable profile than Ligand B (HBD=2, HBA=4). Fewer hydrogen bonds can improve membrane permeability.

**QED:** Both ligands have similar QED values (Ligand A: 0.773, Ligand B: 0.631), indicating good drug-like properties.

**DILI:** Ligand A (38.93) has a significantly lower DILI risk than Ligand B (48.197), which is a crucial advantage.

**BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (88.445) has a higher BBB percentile than Ligand B (28.848).

**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 similar (-4.499 vs -4.539).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility. Ligand A (-2.879) is slightly better than Ligand B (-3.468).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.485, Ligand B: 0.461).

**Microsomal Clearance:** Ligand A (29.915) has a significantly lower microsomal clearance than Ligand B (55.066), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (11.297 hours) has a much longer half-life than Ligand B (3.51 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.064, Ligand B: 0.191).

**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 only 0.3 kcal/mol, which is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, **Ligand A** is the more promising drug candidate. It exhibits lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a more favorable TPSA and H-bonding profile, despite a slightly weaker binding affinity. The 0.3 kcal/mol difference in binding affinity is likely surmountable through further optimization, while the ADME advantages of Ligand A are more difficult to improve post-hoc.

Output:
0
2025-04-17 13:31:51,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.407 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (95.5) is significantly better than Ligand A (133.21), falling well below the 140 threshold for good oral absorption.

**logP:** Ligand B (2.275) is within the optimal range (1-3), while Ligand A (-0.249) is below 1, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both have similar HBD (3/4) and HBA (4/4) counts, which are acceptable.

**QED:** Both ligands have good QED scores (0.541 and 0.671), indicating drug-like properties.

**DILI:** Ligand A (39.667) has a much lower DILI risk than Ligand B (67.429), which is a considerable advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (62.117) is better than Ligand B (34.122).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.111) shows a much lower hERG inhibition liability than Ligand B (0.347), which is a major advantage.

**Microsomal Clearance:** Ligand A (-3.278) has significantly lower (better) microsomal clearance than Ligand B (23.014), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.753) has a very short half-life, while Ligand B (-36.902) is also poor.

**P-gp Efflux:** Ligand A (0.005) has lower P-gp efflux liability than Ligand B (0.033), which is a slight advantage.

**Binding Affinity:** Ligand B (-10.2 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. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. While it has some ADME liabilities (higher DILI, higher Cl_mic, lower solubility, and lower BBB), the strong binding affinity is a significant advantage. Ligand A has better DILI, hERG, and metabolic stability, but its poor logP and weak binding affinity are major concerns. Given the importance of potency for enzyme inhibition, the stronger binding of Ligand B is likely to be more impactful, even with the ADME challenges. These could be addressed through further optimization.

Output:
1
2025-04-17 13:31:51,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (376.4 and 350.4) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is significantly better than Ligand B (102.32). TPSA < 140 is good for oral absorption, and A is much closer to the ideal.

**logP:** Ligand A (2.384) is optimal (1-3), while Ligand B (0.266) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), both are below the threshold of 10.

**QED:** Both ligands have reasonable QED scores (0.881 and 0.655), indicating good drug-like properties.

**DILI:** Ligand A (51.221) has a slightly higher DILI risk than Ligand B (38.503), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (80.031) is better than Ligand B (50.795).

**Caco-2 Permeability:** Both have negative values (-4.734 and -4.792), which is unusual and difficult to interpret without more context. However, the values are similar.

**Aqueous Solubility:** Both have negative values (-3.408 and -2.003), which is also unusual and difficult to interpret without more context. However, the values are similar.

**hERG Inhibition:** Ligand A (0.432) has a much lower hERG risk than Ligand B (0.036), which is a significant advantage.

**Microsomal Clearance:** Ligand A (1.865) has significantly lower microsomal clearance than Ligand B (57.194), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-9.863) has a much longer in vitro half-life than Ligand B (-7.967).

**P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux than Ligand B (0.015).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -7.6 kcal/mol), with Ligand A being slightly better. The 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the slightly higher DILI risk, Ligand A is the superior candidate. Its significantly better logP, lower hERG risk, much improved metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity outweigh the minor DILI difference. The better TPSA and HBA/HBD profiles also contribute to its favorability.

Output:
1
2025-04-17 13:31:51,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.475 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.01) is slightly higher than Ligand B (80.12), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.283 and 1.768), falling within the 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 within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.641 and 0.777), indicating drug-like properties.

**DILI:** Ligand A (49.67) has a slightly better DILI score than Ligand B (53.509), both are acceptable.

**BBB:** Both are low, which is fine for an oncology target. Ligand B (59.403) is slightly higher than Ligand A (41.218).

**Caco-2:** Both have negative Caco-2 values, which is unusual. However, we'll assume these represent percentile scores and interpret them accordingly. Ligand A (-5.719) is worse than Ligand B (-5.11).

**Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-0.464) is slightly better than Ligand B (-1.94).

**hERG:** Both have very low hERG inhibition liability (0.254 and 0.195), which is excellent.

**Microsomal Clearance:** Ligand A (24.75 mL/min/kg) has significantly lower microsomal clearance than Ligand B (51.636 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.029 hours) has a longer half-life than Ligand B (-0.07 hours). The negative value for Ligand B is concerning and likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.189).

**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 difference (>1.5 kcal/mol) and a major advantage.

**Conclusion:**

Ligand A is the superior candidate. Its significantly stronger binding affinity, lower microsomal clearance (better metabolic stability), and longer half-life outweigh the slightly worse Caco-2 and solubility values. Both ligands have acceptable ADME properties overall, but the potency advantage of Ligand A is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:31:51,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.483 and 360.351 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.56) is higher than Ligand B (41.57). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Both ligands have good logP values (2.198 and 2.486), 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 3. Ligand B is preferable here, minimizing potential issues with permeability.

**QED:** Ligand A (0.889) has a significantly higher QED score than Ligand B (0.482), indicating a more drug-like profile overall.

**DILI:** Ligand A (60.062) has a higher DILI risk than Ligand B (31.02), which is a significant concern.

**BBB:** Ligand A (64.986) has a lower BBB penetration percentile than Ligand B (96.355). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Ligand A (-4.889) has worse Caco-2 permeability than Ligand B (-4.451), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.621) has worse aqueous solubility than Ligand B (-3.071). Solubility is important for bioavailability, favoring B.

**hERG:** Ligand A (0.507) has a slightly higher hERG risk than Ligand B (0.728), but both are reasonably low.

**Microsomal Clearance:** Ligand A (58.386) has a higher microsomal clearance than Ligand B (24.947). This means Ligand B is more metabolically stable, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (10.314) has a slightly longer half-life than Ligand B (8.592), which is a minor advantage.

**P-gp Efflux:** Ligand A (0.333) has higher P-gp efflux than Ligand B (0.098), meaning B will have better bioavailability.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a crucial advantage, and can outweigh some of the other differences.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED score and slightly longer half-life, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic), better solubility, lower DILI risk, and a substantially improved binding affinity. The lower TPSA and P-gp efflux of Ligand B are also beneficial.

Output:
1
2025-04-17 13:31:51,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.259 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.79 and 67.87) are reasonably low, suggesting good potential for cell permeability, though not optimized for CNS penetration.

**logP:** Ligand A (3.23) is optimal, while Ligand B (1.108) is a bit low, potentially hindering permeation.

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

**H-Bond Acceptors:** Both ligands (4) are well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.769 and 0.73), indicating drug-like properties.

**DILI:** Ligand A (58.24) has a moderate DILI risk, while Ligand B (21.481) has a low DILI risk. This favors Ligand B.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand B (80.613) has better BBB penetration than Ligand A (34.626), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.854 and -4.684), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.887 and -2.96), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.762) has a slightly higher hERG risk than Ligand B (0.213), favoring Ligand B.

**Microsomal Clearance:** Ligand B (8.139 mL/min/kg) has significantly lower microsomal clearance than Ligand A (41.262 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (5.08 hours) has a much shorter half-life than Ligand A (23.258 hours). While a longer half-life is generally preferred, the significant difference in clearance is more impactful.

**P-gp Efflux:** Ligand A (0.605) has higher P-gp efflux than Ligand B (0.055), which is unfavorable.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly improved metabolic stability (lower Cl_mic), stronger binding affinity, lower DILI risk, lower hERG risk, and lower P-gp efflux outweigh the shorter half-life. The stronger binding affinity is particularly important for an enzyme target like SRC kinase. Addressing the solubility and permeability issues would be critical in further development, but Ligand B provides a better starting point.

Output:
1
2025-04-17 13:31:51,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.483 Da and 374.522 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is slightly higher than Ligand B (58.64), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.407 and 2.39), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4-5 HBA, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.858 and 0.709), indicating good drug-likeness.

**DILI:** Ligand B (26.095) has a significantly lower DILI risk than Ligand A (56.223). This is a major advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration, but Ligand B (93.68) is higher than Ligand A (80.574). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It suggests poor permeability. Ligand A (-5.074) is slightly worse than Ligand B (-4.814).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.639) is slightly worse than Ligand B (-2.969).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.651 and 0.642).

**Microsomal Clearance:** Ligand A (38.468) has a lower microsomal clearance than Ligand B (41.811), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.082) has a longer half-life than Ligand B (-7.43). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.477 and 0.291).

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2). While the difference is small (0.2 kcal/mol), it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a slight advantage in binding affinity and a better half-life, while Ligand B excels in DILI risk and BBB penetration. However, the significantly lower DILI risk for Ligand B is a critical factor, especially in oncology where toxicity is a major concern. The slightly better half-life of Ligand A is outweighed by the higher DILI risk. The solubility and permeability are poor for both, but similar.

Output:
1
2025-04-17 13:31:51,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.391 and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.23) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (76.66) is excellent, well below 140.

**logP:** Both ligands (1.641 and 1.586) 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 4. Both are within the acceptable range (<=10).

**QED:** Ligand B (0.676) has a better QED score than Ligand A (0.459), indicating a more drug-like profile.

**DILI:** Ligand A (63.94) has a higher DILI risk than Ligand B (22.024). This is a significant concern.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand B (92.168) has a higher BBB percentile than Ligand A (71.268).

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude suggests Ligand B (-4.706) has better permeability than Ligand A (-5.017).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-2.179) is slightly better than Ligand A (-3.423).

**hERG:** Both ligands have low hERG inhibition liability (0.27 and 0.239), which is good.

**Microsomal Clearance:** Ligand A (8.305) has a significantly lower microsomal clearance than Ligand B (20.57), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (4.344) has a longer half-life than Ligand A (-25.044). The negative value for Ligand A is concerning and likely indicates rapid degradation.

**P-gp Efflux:** Both have low P-gp efflux liability (0.118 and 0.034), which is favorable.

**Binding Affinity:** Ligand B (-7.9 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:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B excels in key areas: significantly better binding affinity, lower DILI risk, better QED, and a longer half-life. The improved metabolic stability of Ligand A is a plus, but the much stronger binding of Ligand B, coupled with the lower toxicity risk, makes it the preferred choice.

Output:
1
2025-04-17 13:31:51,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.45 and 353.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (62.73). A TPSA under 140 is good for oral absorption, both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (3.32 and 4.75), but Ligand B is pushing the upper limit, potentially leading to solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.82 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (31.60) has a much lower DILI risk than Ligand B (83.64), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (94.38) is better than Ligand B (67.16).

**Caco-2 Permeability:** Ligand A (-4.26) is better than Ligand B (-5.05), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.32) is significantly better than Ligand B (-5.02), a crucial factor for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.60 and 0.64).

**Microsomal Clearance:** Ligand A (57.67) has lower microsomal clearance than Ligand B (83.61), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (55.22) has a longer half-life than Ligand A (6.02), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.25 and 0.31).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While a 0.3 kcal/mol difference is not huge, it's a factor.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in crucial ADME properties like DILI risk, solubility, and metabolic stability. While Ligand B has a slightly better binding affinity and half-life, the substantial advantages of Ligand A in ADME properties, particularly the lower DILI and better solubility, outweigh the small difference in binding. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity are paramount.

Output:
0
2025-04-17 13:31:51,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.841 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.4) is significantly better than Ligand B (94.31). A TPSA under 140 is good for oral absorption, and both are under, but A is preferable.

**logP:** Both ligands have acceptable logP values (3.355 and 2.519, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is slightly better than Ligand B (HBD=2, HBA=5) in terms of maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.893 and 0.755), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (65.413 and 69.019), placing them in a moderate risk category. This isn't a major differentiating factor.

**BBB:** Both ligands have similar BBB penetration (74.564 and 73.401). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.742 and -4.884). This is unusual and suggests poor permeability. However, the values are very close.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.283 and -4.041), indicating poor aqueous solubility. This is a concern, but again, similar for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.617 and 0.593), which is excellent.

**Microsomal Clearance:** Ligand A (19.057 mL/min/kg) has significantly lower microsomal clearance than Ligand B (68.558 mL/min/kg). This suggests better metabolic stability for Ligand A, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (34.694 hours) has a much longer half-life than Ligand B (-15.523 hours). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.259 and 0.166).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol). The difference is minimal.

**Conclusion:**

Ligand A is the more promising candidate. While both ligands have good binding affinity and acceptable physicochemical properties, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic) and a longer half-life. These factors are crucial for kinase inhibitors, as they directly impact drug exposure and dosing frequency. The slightly better TPSA and H-bond profile of Ligand A further support this conclusion. The solubility and Caco-2 values are poor for both, but the metabolic advantages of A outweigh these concerns.

Output:
1
2025-04-17 13:31:51,191 - INFO - Batch 221 complete. Total preferences: 3536
2025-04-17 13:31:51,191 - INFO - Processing batch 222/512...
2025-04-17 13:32:31,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands have similar TPSA values (62.55 and 62.74), well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.395) is slightly higher than Ligand B (1.666). Both are within the optimal 1-3 range, but Ligand B is closer to the lower bound, which *could* indicate potential permeability issues.

**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 (0.609 and 0.753), indicating drug-like properties.

**DILI:** Ligand A (45.328) has a moderate DILI risk, while Ligand B (8.569) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (64.482) and Ligand B (84.839) both have reasonable BBB penetration, but Ligand B is better. This is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.711 and -4.527), which is unusual and suggests poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.486 and -0.334), indicating poor aqueous solubility. This is a significant drawback for both. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.681) has a slightly higher hERG risk than Ligand B (0.242). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (79.926) has a higher microsomal clearance than Ligand B (12.865). Lower clearance is preferred for better metabolic stability, giving Ligand B a substantial advantage.

**In vitro Half-Life:** Ligand A (40.012) has a longer in vitro half-life than Ligand B (-0.553). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.764) has higher P-gp efflux than Ligand B (0.032). Lower efflux is better, favoring Ligand B.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B demonstrates significantly better ADME properties: lower DILI risk, lower hERG risk, much lower microsomal clearance (better metabolic stability), and lower P-gp efflux. The slightly better BBB penetration is a bonus. The in vitro half-life is less favorable for Ligand B, but the other ADME advantages outweigh this. The binding affinity is essentially the same for both.

Output:
1
2025-04-17 13:32:31,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.4 and 360.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.62) is better than Ligand B (134.19).  TPSA < 140 is good for oral absorption, and both are within this limit, but A is closer to the ideal.

**logP:** Ligand A (0.586) is slightly lower than ideal (1-3), but still acceptable. Ligand B (-0.596) is below 1, which could hinder permeation. This favors A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is preferable to Ligand B (4 HBD, 7 HBA). Lower HBDs are generally better for permeability. Both are within acceptable limits.

**QED:** Ligand A (0.729) has a significantly better QED score than Ligand B (0.258), indicating a more drug-like profile.

**DILI:** Ligand A (87.13) has a higher DILI risk than Ligand B (42.89), which is a significant drawback for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (61.96) is better than Ligand B (20.74).

**Caco-2 Permeability:** Ligand A (-4.355) is significantly better than Ligand B (-5.616), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.375) is better than Ligand B (-1.325), which is crucial for formulation and bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.116 and 0.1, respectively).

**Microsomal Clearance:** Ligand A (119.64) is significantly *higher* than Ligand B (-14.72), indicating *lower* metabolic stability. This is a major concern for A.

**In vitro Half-Life:** Ligand A (-50.56) is significantly *lower* than Ligand B (-10.09), indicating a shorter half-life and potentially requiring more frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.094 and 0.019).

**Binding Affinity:** Both ligands have comparable binding affinities (-9.7 and -8.3 kcal/mol). The difference of 1.4 kcal/mol is not substantial enough to outweigh other ADME concerns.

**Conclusion:**

Despite the higher DILI risk, Ligand A is the more promising candidate. Its superior QED, logP, Caco-2 permeability, and solubility outweigh the DILI concern. Ligand B has a much lower QED, a problematic logP, and worse permeability/solubility. The metabolic stability and half-life of Ligand A are concerning, but these can potentially be addressed through structural modifications. The binding affinity difference is not large enough to favor Ligand B.

Output:
0
2025-04-17 13:32:31,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (334.379 and 365.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (79.9 and 71.53) below 140, suggesting reasonable absorption potential.

**3. logP:** Both ligands have logP values (2.598 and 2.317) 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 (4) and Ligand B (5) both meet the HBA <= 10 criteria.

**6. QED:** Both ligands have good QED scores (0.536 and 0.805), indicating drug-likeness. Ligand B is better here.

**7. DILI:** Ligand A (75.96) has a higher DILI risk than Ligand B (35.13). This is a significant drawback for Ligand A.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (70.531) shows better penetration than Ligand A (42.148).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.074 and -4.844), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.906 and -2.017), also unusual. Again, absolute values are similar.

**11. hERG Inhibition:** Ligand A (0.76) has a slightly higher hERG risk than Ligand B (0.408), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (26.209) has a slightly higher microsomal clearance than Ligand B (24.811), indicating potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.645) has a significantly longer in vitro half-life than Ligand A (-12.49). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.236 and 0.118).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 2.1 kcal/mol difference is substantial and outweighs minor ADME concerns.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have some concerning permeability/solubility values, Ligand B's significantly better binding affinity, lower DILI risk, and longer half-life make it a more promising starting point for drug development. The stronger binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:32:31,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (363.805 Da) is also good.

**TPSA:** Ligand A (80.05) is excellent, well below the 140 threshold for oral absorption. Ligand B (105.21) is still acceptable, but less ideal.

**logP:** Ligand A (3.34) is within the optimal range (1-3). Ligand B (1.346) is on the lower end, potentially impacting permeability.

**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 reasonable QED values (A: 0.723, B: 0.585), indicating drug-like properties.

**DILI:** Ligand A (64.521) has a lower DILI risk than Ligand B (77.782), which is a significant advantage.

**BBB:** Both have moderate BBB penetration (A: 50.679, B: 43.893), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is significant. Ligand A (-4.994) is better than Ligand B (-5.483).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.971) is slightly better than Ligand B (-2.752).

**hERG:** Both ligands have very low hERG risk (A: 0.425, B: 0.331), which is excellent.

**Microsomal Clearance:** Ligand A (34.23) has a higher clearance than Ligand B (28.641), meaning Ligand B is more metabolically stable. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (104.27) has a significantly longer half-life than Ligand A (43.995), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.042, B: 0.06), which is good.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference (1.6 kcal/mol) is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a clear advantage in binding affinity and metabolic stability (lower Cl_mic and longer t1/2). While Ligand A has a slightly better TPSA and DILI score, the superior potency and metabolic profile of Ligand B are more critical for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor concern, but the strong binding affinity is likely to compensate.

Output:
1
2025-04-17 13:32:31,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.358 Da and 348.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.43) is better than Ligand B (49.41), being closer to the upper limit of 140 for good absorption.

**logP:** Both ligands have good logP values (1.623 and 2.524), 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 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar, good QED scores (0.85 and 0.852).

**DILI:** Ligand A has a significantly higher DILI risk (67.778%) compared to Ligand B (30.826%). This is a major concern for Ligand A.

**BBB:** Ligand A has a higher BBB penetration (91.625%) than Ligand B (74.564%), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.161) is worse than Ligand B (-4.812). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-3.246) is slightly better than Ligand B (-3.658), but both are poor.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.606 and 0.504).

**Microsomal Clearance:** Ligand B has a much lower (better) microsomal clearance (-3.858 mL/min/kg) than Ligand A (18.438 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (1.963 hours) than Ligand A (-16.919 hours). Note the negative value for ligand A is concerning.

**P-gp Efflux:** Both have low P-gp efflux liability (0.102 and 0.131).

**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.

**Conclusion:**

Ligand B is the superior candidate. While both have acceptable MW, logP, QED, and P-gp efflux, Ligand B excels in the critical areas for kinase inhibitors: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and a substantially stronger binding affinity. Ligand A's high DILI risk and poor metabolic stability are major drawbacks that outweigh its slightly better solubility and BBB penetration.

Output:
1
2025-04-17 13:32:31,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.445 and 357.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (108.41) is still acceptable but less optimal.

**logP:** Ligand A (2.387) is within the optimal 1-3 range. Ligand B (-1.797) is below 1, which could hinder permeability.

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

**QED:** Both ligands have reasonable QED scores (0.687 and 0.543, respectively), indicating generally drug-like properties.

**DILI:** Both ligands have low DILI risk (30.748 and 34.432), which is positive.

**BBB:** Ligand A (87.088) has a good BBB score, although SRC is not a CNS target, it's not detrimental. Ligand B (18.147) is very low, which is not a concern here.

**Caco-2 Permeability:** Ligand A (-4.567) is poor, while Ligand B (-5.035) is also poor. This is a potential issue for both, but less critical for a kinase inhibitor that might be developed for IV administration.

**Aqueous Solubility:** Ligand A (-2.425) is poor, while Ligand B (-0.772) is also poor. This is a concern for both, potentially impacting bioavailability if oral administration is desired.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.656 and 0.096), which is excellent.

**Microsomal Clearance:** Ligand A (20.315) is moderate, while Ligand B (-0.365) is very low, suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (6.965) is reasonable, while Ligand B (-14.641) is very long, further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.294 and 0.011).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.6 kcal/mol). Ligand B is slightly better (-8.6 vs -8.0), but the difference is small.

**Conclusion:**

While both ligands have good potency, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The lower logP and Caco-2 permeability of Ligand B are drawbacks, but less critical for a kinase inhibitor, and could potentially be addressed through formulation strategies or prodrug approaches. The solubility is also a concern for both, but Ligand B is slightly better.

Output:
1
2025-04-17 13:32:31,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.471 and 367.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.29) is slightly above the optimal <140, while Ligand B (100.99) is closer to the ideal. This suggests slightly better absorption potential for Ligand B.

**logP:** Ligand A (1.829) is within the optimal 1-3 range. Ligand B (-0.022) is slightly below 1, which *could* indicate permeability issues, though not drastically.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.613) has a better QED score than Ligand B (0.47), indicating a more drug-like profile.

**DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (39.473), but both are acceptable (<60).

**BBB:** Both ligands have low BBB penetration (47.654 and 40.403 respectively), which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.934) has significantly worse Caco-2 permeability than Ligand B (-5.299). Both are negative, suggesting poor permeability, but Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-3.401) has slightly better aqueous solubility than Ligand B (-2.001).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.482 and 0.132 respectively).

**Microsomal Clearance:** Ligand B (-8.277) has *much* lower microsomal clearance than Ligand A (30.508), indicating significantly better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-3.921) has a longer in vitro half-life than Ligand A (-1.92), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.032 respectively).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has slightly better binding affinity than Ligand B (-7.9 kcal/mol). This is a 0.8 kcal/mol difference, which is significant but not overwhelming.

**Conclusion:**

While Ligand A has a slightly better binding affinity and QED score, Ligand B is significantly superior in terms of metabolic stability (lower Cl_mic and longer t1/2) and has a lower DILI risk. The slightly lower logP of Ligand B is a minor concern, but the substantial improvement in metabolic stability outweighs this drawback, especially for a kinase inhibitor where maintaining therapeutic concentrations is critical. The Caco-2 permeability is poor for both, but the difference isn't enough to favor A given the other advantages of B.

Output:
1
2025-04-17 13:32:31,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.769 Da) is slightly higher than Ligand B (344.503 Da), but both are acceptable.

**TPSA:** Ligand A (94.95) is acceptable for oral absorption, while Ligand B (47.61) is excellent.

**logP:** Both ligands have good logP values (A: 2.568, B: 1.307), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of hydrogen bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.813, B: 0.845), indicating good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (82.241), while Ligand B has a very low risk (5.777). This is a significant advantage for Ligand B.

**BBB:** Both have moderate BBB penetration (A: 66.576, B: 64.637), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.165) shows poor permeability, while Ligand B (-5.109) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.128) has poor solubility, while Ligand B (-1.014) is slightly better. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.278) has a slightly elevated hERG risk, while Ligand B (0.773) is better.

**Microsomal Clearance:** Ligand A (76.635) has higher clearance, indicating lower metabolic stability, compared to Ligand B (3.19). This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (1.388 hours) has a short half-life, while Ligand B (7.86 hours) has a much longer half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.153) has low P-gp efflux, while Ligand B (0.016) has very low P-gp efflux. Both are good.

**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 for Ligand A.

**Overall Assessment:**

Ligand A boasts a superior binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from significant drawbacks: high DILI risk, poor solubility, high microsomal clearance (low metabolic stability), and a short half-life. Ligand B, while having a weaker binding affinity, presents a much more favorable ADMET profile, with low DILI risk, better solubility, excellent metabolic stability (low clearance, long half-life), and low P-gp efflux.

Considering the enzyme-specific priorities, metabolic stability and solubility are crucial. The substantial difference in DILI risk also heavily favors Ligand B. While the affinity difference is significant (2 kcal/mol), it may be possible to optimize Ligand B's affinity through further medicinal chemistry efforts, while mitigating the severe liabilities of Ligand A would be far more challenging.

Output:
1
2025-04-17 13:32:31,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (349.37 and 342.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.59) is better than Ligand B (40.62) as it is closer to the threshold of 140 for good oral absorption.

**3. logP:** Ligand B (2.987) is optimal (1-3), while Ligand A (0.387) is below 1, potentially hindering permeation.

**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, while Ligand B (2) is also good.

**6. QED:** Both ligands have similar QED values (0.637 and 0.582), indicating reasonable drug-likeness.

**7. DILI:** Ligand B (21.055) has a significantly lower DILI risk than Ligand A (57.852), making it safer.

**8. BBB:** Ligand B (71.927) shows better BBB penetration than Ligand A (59.597), but this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.432) has a worse Caco-2 permeability than Ligand B (-4.71).

**10. Aqueous Solubility:** Ligand A (-2.586) has a worse aqueous solubility than Ligand B (-2.809).

**11. hERG Inhibition:** Ligand A (0.113) has a lower hERG inhibition risk than Ligand B (0.415).

**12. Microsomal Clearance:** Ligand A (-1.132) has a lower (better) microsomal clearance than Ligand B (68.039), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-26.275) has a longer in vitro half-life than Ligand B (-32.506).

**14. P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux than Ligand B (0.239).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.9 kcal/mol). This is a critical parameter, and the difference is negligible.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison:** Ligand B excels in DILI risk and has a good logP. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. While Ligand A's logP is suboptimal, its superior metabolic stability and lower P-gp efflux are more critical for an enzyme target. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 13:32:31,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 better than Ligand B (36.66). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have good logP values (3.242 and 3.358), 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 5 HBA. Ligand A is slightly better, as having some HBD can improve solubility.

**QED:** Both ligands have good QED scores (0.738 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A (41.838) has a slightly higher DILI risk than Ligand B (30.826), but both are below the concerning threshold of 60.

**BBB:** Both have acceptable BBB penetration, but it's less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.638) has a worse Caco-2 permeability than Ligand B (-5.087).

**Aqueous Solubility:** Ligand A (-3.928) has a worse solubility than Ligand B (-3.121).

**hERG:** Both ligands have relatively low hERG inhibition risk (0.695 and 0.843).

**Microsomal Clearance:** Ligand A (63.267) has a lower microsomal clearance than Ligand B (68.076), indicating better metabolic stability, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-41.07) has a significantly longer in vitro half-life than Ligand A (5.202), which is a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.426 and 0.667).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall:** While Ligand A has better TPSA and slightly better DILI, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity and a much longer half-life. The slightly worse solubility of Ligand B is a manageable concern, and its metabolic stability is acceptable. The superior potency of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 13:32:31,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.4 and 362.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.08) is higher than Ligand B (75.71). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (0.87) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (1.83) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 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 (0.699 and 0.732), indicating drug-like properties.

**DILI:** Ligand A (74.021) has a higher DILI risk than Ligand B (31.175). This is a significant concern, as lower DILI is preferred.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (82.047) has a higher BBB percentile, but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.283) shows poor permeability, while Ligand B (-4.611) is slightly better, but still suboptimal.

**Aqueous Solubility:** Ligand A (-3.047) has poor solubility, which is a major drawback. Ligand B (-2.361) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.024) has very low hERG inhibition risk, which is excellent. Ligand B (0.376) is a bit higher, but still relatively low.

**Microsomal Clearance:** Ligand A (37.371) has lower microsomal clearance than Ligand B (46.346), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.89 hours) has a shorter half-life than Ligand B (-34.69 hours - likely an error, indicating very long half-life). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.055).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.5 and -7.6 kcal/mol), which are comparable and strong enough to be considered good.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better hERG profile and lower clearance, its significantly higher DILI risk and poor solubility are major liabilities. Ligand B has a much lower DILI risk, better solubility, and a potentially much longer half-life (assuming the -34.69 is not an error). The slightly higher logP and lower TPSA of Ligand B are also favorable. The comparable binding affinities mean the ADME properties are the deciding factors.

Output:
1
2025-04-17 13:32:31,627 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443 Da) is slightly lower than Ligand B (377.432 Da), which is acceptable.

**TPSA:** Ligand A (75.19) is higher than Ligand B (45.55). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have optimal logP values (around 2), indicating good balance between hydrophobicity and hydrophilicity. Ligand A (2.024) and Ligand B (1.919) are very similar.

**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.

**QED:** Both ligands have reasonable QED scores (0.888 and 0.76), suggesting good drug-like properties.

**DILI:** Ligand A (36.06) has a slightly higher DILI risk than Ligand B (22.218), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (85.653 and 87.088), but this is less crucial for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.952 and -4.766), which is unusual and potentially problematic. It suggests low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.172 and -1.851), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.553 and 0.67), which is good.

**Microsomal Clearance:** Ligand B (7.901) has significantly lower microsomal clearance than Ligand A (44.943), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-26.107) has a longer in vitro half-life than Ligand A (-16.108), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.055 and 0.095), which is favorable.

**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 outweighs most other concerns.

**Conclusion:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2) and substantially stronger binding affinity make it much more likely to be a viable drug candidate for SRC kinase. The lower DILI risk is also a bonus.

Output:
1
2025-04-17 13:32:31,627 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.519 Da and 369.546 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (40.54), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.477) is optimal (1-3), while Ligand B (4.629) is slightly high, potentially leading to solubility issues or off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (3) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.628 and 0.689, respectively), indicating drug-likeness.

**DILI:** Ligand A (14.851) has a significantly lower DILI risk than Ligand B (21.83), which is a crucial advantage.

**BBB:** Ligand B (91.392) has a much higher BBB penetration percentile than Ligand A (43.273). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.846) is slightly better than Ligand B (-4.537).

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and suggests poor solubility. Ligand A (-3.112) is slightly better than Ligand B (-4.554).

**hERG:** Ligand A (0.365) has a lower hERG inhibition liability than Ligand B (0.847), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (37.445) has a lower microsomal clearance than Ligand B (70.503), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (33.511) has a longer in vitro half-life than Ligand A (20.226), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux liability than Ligand B (0.903), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), and lower P-gp efflux. While Ligand B has a longer half-life and better BBB penetration (irrelevant for this target), the superior safety and ADME profile of Ligand A make it the preferred choice.

Output:
0
2025-04-17 13:32:31,627 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.409 and 355.345 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.78) is excellent, well below the 140 threshold for good absorption. Ligand B (96.33) is higher, but still acceptable, though potentially impacting permeability.

**logP:** Ligand A (2.392) is optimal (1-3). Ligand B (-0.493) is below 1, which could hinder permeation.

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

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.839 and 0.765), indicating good drug-like properties.

**DILI:** Ligand A (8.763) has a very low DILI risk, which is excellent. Ligand B (60.682) is higher, indicating a moderate risk of liver injury.

**BBB:** Ligand A (91.508) has excellent BBB penetration, although this isn't a primary concern for a non-CNS target like SRC. Ligand B (73.478) is lower.

**Caco-2 Permeability:** Ligand A (-4.264) is poor, suggesting limited intestinal absorption. Ligand B (-5.168) is also poor.

**Aqueous Solubility:** Ligand A (-1.602) is poor. Ligand B (-2.473) is even worse.

**hERG Inhibition:** Ligand A (0.675) has a low hERG risk. Ligand B (0.197) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (12.539) has moderate clearance. Ligand B (-17.191) 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 (-4.906) has a negative half-life, which is not possible and likely an error in the data. Ligand B (-5.753) also has a negative half-life, which is also an error.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.049 and 0.022), which is favorable.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the solubility and permeability issues for both compounds, Ligand B is the better candidate. The significantly stronger binding affinity (-9.9 vs -8.2 kcal/mol) is the deciding factor for an enzyme target. The lower P-gp efflux is also beneficial. The DILI risk for Ligand B is higher, but not critically so, and could be addressed with further optimization. The negative values for clearance and half-life are concerning and likely data errors, but the overall profile of ligand B still makes it more promising.

Output:
1
2025-04-17 13:32:31,627 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.393 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (67.87). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (3.606) is optimal, while Ligand B (1.401) is a bit low. A logP below 1 can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 for A, 4 for B) counts, well within the recommended limits.

**QED:** Ligand B (0.815) has a higher QED score than Ligand A (0.512), suggesting a more generally drug-like profile. However, QED is less critical than other factors here.

**DILI:** Ligand A (60.954) has a higher DILI risk than Ligand B (12.292). This is a significant concern, as liver toxicity is a major cause of drug failure.

**BBB:** This is less important for a non-CNS target like SRC. Ligand A (90.617) has better BBB penetration than Ligand B (71.772), but it's not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.081) has better Caco-2 permeability than Ligand B (-4.733), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.829) has better aqueous solubility than Ligand A (-4.54). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.445) has a lower hERG inhibition liability than Ligand B (0.267), which is favorable.

**Microsomal Clearance:** Ligand A (95.92) has significantly higher microsomal clearance than Ligand B (16.688). This means Ligand A is metabolized much faster, leading to lower exposure.

**In vitro Half-Life:** Ligand B (11.497) has a longer in vitro half-life than Ligand A (-9.888). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.329) has lower P-gp efflux than Ligand B (0.014). Lower efflux is generally better.

**Binding Affinity:** Ligand B (-8.2) has a stronger binding affinity than Ligand A (-7.3). A 1.5 kcal/mol difference in binding is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better Caco-2 permeability and P-gp efflux, Ligand B's significantly stronger binding affinity (-8.2 vs -7.3 kcal/mol), much lower DILI risk (12.292 vs 60.954), and longer half-life (11.497 vs -9.888) are more critical for an enzyme target like SRC. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization. The higher QED of Ligand B is also a positive.



Output:
1
2025-04-17 13:32:31,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.467 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.05) is well below the 140 threshold, and even better, below the 90 for CNS targets. Ligand B (89.87) is still within the acceptable range for oral absorption (<140), but less optimal than A.

**logP:** Ligand A (4.22) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.6) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 4 HBA) both meet the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.532 and 0.707), indicating drug-like properties.

**DILI:** Ligand A (83.598) has a higher DILI risk than Ligand B (39.473). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.078) has a slightly higher BBB penetration than Ligand B (42.226), but it's not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.918 and -4.865), which is unusual and suggests poor permeability. This needs further investigation, but is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.8 and -2.355), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.796) has a slightly higher hERG risk than Ligand B (0.347), but both are relatively low.

**Microsomal Clearance:** Ligand A (124.331) has a higher microsomal clearance, suggesting lower metabolic stability, compared to Ligand B (20.475). This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-5.106) has a longer in vitro half-life than Ligand A (22.796), which is desirable.

**P-gp Efflux:** Ligand A (0.638) has slightly lower P-gp efflux than Ligand B (0.273), which is preferable.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-10.1 vs -8.6 kcal/mol), lower DILI risk (39.473 vs 83.598), and better metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher logP and lower P-gp efflux. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the superior potency and safety profile of Ligand B make it the better starting point.

Output:
1
2025-04-17 13:32:31,628 - INFO - Batch 222 complete. Total preferences: 3552
2025-04-17 13:32:31,628 - INFO - Processing batch 223/512...
2025-04-17 13:33:11,159 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.439 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.42) is better than Ligand B (96.02), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (1.996) is optimal (1-3), while Ligand B (-0.411) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Lower HBD generally improves permeability.

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

**QED:** Both ligands have similar QED values (0.713 and 0.696), indicating good drug-likeness.

**DILI:** Ligand A (69.639) has a higher DILI risk than Ligand B (41.799). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (76.696) is better than Ligand B (46.297).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.581) is slightly better than Ligand B (-4.91).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.013) is slightly better than Ligand B (-1.219).

**hERG Inhibition:** Ligand A (0.315) has a much lower hERG risk than Ligand B (0.058). This is a major advantage for Ligand A.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (10.129 and 10.469 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (8.585) has a longer half-life than Ligand B (3.66), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.22 and 0.005).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). The 0.9 kcal/mol difference is significant and could outweigh some ADME liabilities.

**Overall Assessment:**

Ligand A is the better candidate. While it has a higher DILI risk, its superior binding affinity, lower hERG risk, longer half-life, and slightly better permeability/solubility outweigh this concern. The stronger binding affinity is particularly important for an enzyme inhibitor. Ligand B's low logP is a significant concern, potentially leading to poor absorption.

Output:
1
2025-04-17 13:33:11,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.487) is slightly higher than Ligand B (351.422), but both are acceptable.

**TPSA:** Ligand A (127.55) is borderline for good oral absorption (<=140), while Ligand B (69.72) is well within the acceptable range.

**logP:** Ligand A (-0.821) is a bit low, potentially hindering permeation. Ligand B (0.505) is also on the lower side, but better than Ligand A. Both could benefit from increased lipophilicity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=8) 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 (A: 0.679, B: 0.783), indicating drug-like properties.

**DILI:** Ligand A (39.511) has a slightly higher DILI risk than Ligand B (26.406), but both are below the concerning threshold of 60.

**BBB:** Ligand A (23.73) has poor BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (76.541) has better BBB penetration, but again, this is less critical here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.826 and -4.881), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.428 and -1.681), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.027, B: 0.158), which is excellent.

**Microsomal Clearance:** Ligand A (-22.437) has significantly lower (better) microsomal clearance than Ligand B (8.284), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (33.447) has a longer half-life than Ligand B (7.527), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.007, B: 0.01), which is favorable.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.5), but the difference is less than 1.5 kcal/mol.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The significantly improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand A is crucial for an enzyme target like SRC kinase. While both have poor solubility and permeability, the metabolic advantages of Ligand A outweigh the minor affinity difference. Addressing the solubility and permeability issues through formulation or further chemical modifications would be the next step for Ligand A.

Output:
0
2025-04-17 13:33:11,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.39) is slightly above the preferred <140, but acceptable. Ligand B (66.4) is well within the range.

**logP:** Both ligands have good logP values (1.596 and 2.286), falling 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 4 HBA, also acceptable.

**QED:** Both ligands have similar and good QED scores (0.843 and 0.825), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 59.636, which is approaching the higher risk threshold (>60). Ligand B has a significantly lower DILI risk (35.789), making it more favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (80.574) than Ligand A (55.642), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. This suggests poor permeability.

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

**hERG:** Ligand A (0.301) has a slightly better hERG profile (lower risk) than Ligand B (0.436).

**Microsomal Clearance (Cl_mic):** Ligand A (-2.256) shows significantly lower (better) microsomal clearance than Ligand B (39.753). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-27.428) has a significantly longer half-life than Ligand B (-0.653). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux liability than Ligand B (0.196), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.0 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is substantial.

**Conclusion:**

While Ligand B has a better DILI score, Ligand A is superior overall. The significantly better metabolic stability (lower Cl_mic, longer half-life), lower P-gp efflux, and slightly better binding affinity of Ligand A outweigh the slightly higher DILI risk. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. Given the enzyme-specific priorities, the superior potency and pharmacokinetic properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 13:33:11,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.4 and 339.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.9) is better than Ligand B (38.3). Both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.33) is optimal, while Ligand B (4.77) is high, potentially leading to solubility issues and off-target effects.

**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 (5 and 2 respectively), well below the limit of 10.

**QED:** Both ligands have reasonable QED scores (0.758 and 0.668), indicating good drug-likeness.

**DILI:** Ligand A (65.9) has a higher DILI risk than Ligand B (37.0), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.5) is slightly better than Ligand B (55.0).

**Caco-2:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Solubility:** Ligand A (-2.33) is better than Ligand B (-4.99), indicating better aqueous solubility.

**hERG:** Ligand A (0.101) has a much lower hERG risk than Ligand B (0.871), a significant advantage.

**Microsomal Clearance:** Ligand A (-2.48) has a lower (better) microsomal clearance than Ligand B (107.0), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.8) has a longer half-life than Ligand B (-3.49), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.037) has a lower P-gp efflux liability than Ligand B (0.799), which is favorable.

**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.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the highest priority for an enzyme inhibitor. However, it suffers from a high logP, poor solubility, higher hERG risk, and poorer metabolic stability. Ligand A is more balanced, with better solubility, lower hERG risk, better metabolic stability, and lower P-gp efflux. The difference in binding affinity (1.4 kcal/mol) is significant, but the ADME liabilities of Ligand B are concerning. Given the enzyme class, metabolic stability and safety (hERG) are also important. While Ligand B's affinity is tempting, the ADME profile of Ligand A is more promising.

Output:
0
2025-04-17 13:33:11,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 365.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.79) is significantly better than Ligand B (101.22). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (1.705 and 1.608), 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 HBAs, while Ligand B has 7. Ligand A is better here, being closer to the preferred limit of <=10.

**QED:** Both ligands have acceptable QED scores (0.797 and 0.724), indicating good drug-like properties.

**DILI:** Ligand A (30.942) has a much lower DILI risk than Ligand B (63.823). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.252) is better than Ligand B (47.189), but this isn't a major deciding factor.

**Caco-2:** Both have negative Caco-2 values (-5.022 and -5.126). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**Solubility:** Ligand A (-0.86) is better than Ligand B (-2.523), indicating better aqueous solubility. Solubility is important for bioavailability.

**hERG:** Ligand A (0.614) has a lower hERG risk than Ligand B (0.143). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (43.168) has lower microsomal clearance than Ligand B (64.491), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (38.387) has a slightly longer half-life than Ligand A (33.507), but the difference is not substantial.

**P-gp:** Both have very low P-gp efflux liability (0.134 and 0.128).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a better safety profile (lower DILI, lower hERG), better solubility, better metabolic stability (lower Cl_mic), and, most importantly, significantly stronger binding affinity. While both have poor Caco-2 permeability, the superior potency and safety profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 13:33:11,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.422 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.23) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Ligand A (1.263) is within the optimal range, while Ligand B (3.355) is approaching the upper limit. This could potentially lead to solubility issues with Ligand B.

**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.

**QED:** Both ligands have similar QED values (0.724 and 0.711), indicating good drug-likeness.

**DILI:** Ligand A (34.626) has a significantly lower DILI risk than Ligand B (16.208). This is a major advantage for Ligand A.

**BBB:** Ligand A (76.735) has a good BBB percentile, while Ligand B (91.198) is even better. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.384) has a negative Caco-2 value, which is concerning, indicating poor permeability. Ligand B (-4.484) is also negative, but less so.

**Aqueous Solubility:** Ligand A (-2.592) has slightly better solubility than Ligand B (-3.961), although both are poor.

**hERG Inhibition:** Ligand A (0.603) has a slightly higher hERG risk than Ligand B (0.751), but both are relatively low.

**Microsomal Clearance:** Ligand A (-10.32) has a *much* lower (better) microsomal clearance than Ligand B (57.782). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (16.819) has a longer half-life than Ligand B (9.186). This is favorable.

**P-gp Efflux:** Ligand A (0.029) has much lower P-gp efflux than Ligand B (0.252), indicating better bioavailability.

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.6). However, the difference is only 0.4 kcal/mol, which is not substantial enough to outweigh the other significant advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, better P-gp efflux, and comparable solubility and hERG risk. The poor Caco-2 permeability of Ligand A is a concern, but could potentially be addressed through formulation strategies. The substantial differences in metabolic stability and safety (DILI) outweigh the minor affinity difference.

Output:
0
2025-04-17 13:33:11,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 and 365.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (47.36), both are well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.65 and 3.718, respectively), falling within the 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:** 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 (0.628 and 0.722), indicating drug-like properties.

**DILI:** Ligand A (15.394) has a significantly lower DILI risk than Ligand B (23.769), which is a major advantage.

**BBB:** Ligand B (89.027) has a higher BBB penetration percentile than Ligand A (51.066). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.743 and -4.793), indicating poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.218 and -3.008), indicating poor solubility. This is a significant concern for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.465 and 0.539), which is excellent.

**Microsomal Clearance:** Ligand A (35.3 mL/min/kg) has significantly better metabolic stability (lower clearance) than Ligand B (68.353 mL/min/kg). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (8.616) has a longer half-life than Ligand B (-4.936). This is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.305 and 0.301).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.7 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have poor Caco-2 and solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and slightly better binding affinity. These factors are more critical for an enzyme target like SRC kinase than BBB penetration.

Output:
0
2025-04-17 13:33:11,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.5 & 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.95).  A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**logP:** Ligand A (2.335) is optimal (1-3), while Ligand B (0.453) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Ligand A (0.894) has a better QED score than Ligand B (0.731), indicating a more drug-like profile.

**DILI:** Ligand A (27.3) has a significantly lower DILI risk than Ligand B (19.7). Both are good, but A is preferable.

**BBB:** Both have reasonable BBB penetration, but Ligand A (81.7) is better than Ligand B (71.4). While not a primary concern for a non-CNS target like SRC, higher BBB is rarely detrimental.

**Caco-2:** Ligand A (-5.061) is better than Ligand B (-4.797), indicating better intestinal absorption.

**Solubility:** Ligand A (-2.771) is better than Ligand B (-0.711), which is crucial for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.385 and 0.192, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (26.383) has a higher Cl_mic than Ligand B (20.078), meaning it is cleared faster and has lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-14.937) has a significantly longer in vitro half-life than Ligand A (9.81), indicating better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux (0.191 and 0.024), which is good.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a substantially better binding affinity than Ligand B (-7.8 kcal/mol). This 1.4 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher metabolic clearance, its significantly superior binding affinity (-9.2 vs -7.8 kcal/mol) and better overall drug-like properties (QED, solubility, DILI) make it the more promising candidate. The affinity difference is large enough to compensate for the slightly less favorable clearance.

Output:
1
2025-04-17 13:33:11,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.917 Da) is slightly higher than Ligand B (342.403 Da), but both are acceptable.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (122.89). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.512, B: 1.172) falling 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=6) as it has fewer hydrogen bond donors and acceptors, which can improve permeability.

**QED:** Both ligands have acceptable QED values (A: 0.858, B: 0.649), indicating good drug-like properties.

**DILI:** Ligand A (40.054) has a much lower DILI risk than Ligand B (66.964). This is a significant advantage.

**BBB:** Both have similar, relatively low BBB penetration (A: 53.897, B: 50.523). This isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.034 and -5.603), which is unusual and suggests poor permeability. However, these values are on a log scale and the absolute value matters more.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.975 and -3.038). This is a significant drawback and would require formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.642, B: 0.645), which is good.

**Microsomal Clearance:** Ligand A (9.588) has a higher microsomal clearance than Ligand B (1.159), indicating potentially lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (9.947) has a much longer in vitro half-life than Ligand A (-1.046), which is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.161, B: 0.026), which is favorable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage and can potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, lower DILI risk, and better TPSA, HBD/HBA counts. However, it has higher microsomal clearance and a shorter half-life, and poor solubility. Ligand B has better metabolic stability and half-life, but significantly weaker binding affinity and a higher DILI risk.

Given that potency is a primary concern for enzyme inhibitors, and the difference in binding affinity is substantial (8.6 vs 0.0 kcal/mol), Ligand A is the more promising candidate *despite* its ADME liabilities. The poor solubility and metabolic stability could be addressed through medicinal chemistry optimization. The large binding affinity advantage is likely to be more impactful than the ADME concerns.

Output:
1
2025-04-17 13:33:11,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.419 and 371.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.55) is better than Ligand B (125.2), being closer to the <140 threshold for good oral absorption.

**3. logP:** Ligand A (0.121) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (-0.247) is even lower, raising more concern for permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

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

**6. QED:** Ligand A (0.675) has a better QED score than Ligand B (0.523), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 52.113, Ligand B: 49.632), below the 60 threshold.

**8. BBB:** Both ligands have low BBB penetration (Ligand A: 36.371, Ligand B: 33.23), which is not a major concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.737 and -5.993), which is unusual and suggests very poor permeability. This is a significant issue.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.614 and -1.527). This is a critical drawback.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.177, Ligand B: 0.073), which is excellent.

**12. Microsomal Clearance:** Ligand A (2.877) has significantly lower microsomal clearance than Ligand B (5.057), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.748 hours) has a longer in vitro half-life than Ligand B (17.527 hours), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.015, Ligand B: 0.056).

**15. Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), although the difference is small.

**Overall Assessment:**

Both ligands have significant issues with solubility and permeability. However, Ligand A is superior due to its better QED, lower microsomal clearance, longer half-life, and slightly better binding affinity. The small affinity difference is less important than the ADME advantages of Ligand A. While both are problematic, Ligand A has a slightly more favorable profile for further optimization.

Output:
0
2025-04-17 13:33:11,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.69) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (104.45) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (3.075) is optimal (1-3). Ligand B (-0.829) is below 1, which may impede permeation. This is a significant drawback for B.

**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 slightly better.

**QED:** Both ligands have reasonable QED scores (0.802 and 0.673), indicating good drug-like properties.

**DILI:** Ligand A (19.271) has a much lower DILI risk than Ligand B (39.279). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (85.459) is better than Ligand B (27.646).

**Caco-2 Permeability:** Ligand A (-4.36) is better than Ligand B (-4.968), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.434) is better than Ligand B (-0.686). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.614) has a lower hERG risk than Ligand B (0.03). This is a crucial advantage for A, minimizing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (33.574) has higher metabolic stability (lower clearance) than Ligand B (9.534). This is a key advantage for A.

**In vitro Half-Life:** Ligand A (3.091) has a better half-life than Ligand B (-17.125).

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.02).

**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 the other significant advantages of Ligand A.

**Conclusion:**

Ligand A is significantly better than Ligand B across multiple crucial ADME-Tox properties (DILI, hERG, solubility, metabolic stability, permeability). While both have good potency, Ligand A's superior profile makes it a much more viable drug candidate.

Output:
0
2025-04-17 13:33:11,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.885 and 378.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for absorption. Ligand B (111.24) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.118) is optimal (1-3). Ligand B (-0.879) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is excellent. Ligand B (1 HBD, 7 HBA) is acceptable, but the higher HBA count could slightly affect permeability.

**QED:** Both ligands (0.579 and 0.546) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (35.905) has a lower DILI risk than Ligand B (45.677), both being acceptable (<60).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.003) is higher than Ligand B (42.226).

**Caco-2 Permeability:** Both are negative (-5.07 and -5.035), indicating poor permeability. This is concerning and needs further investigation, but the scale is not clear, so we cannot definitively rule out either.

**Aqueous Solubility:** Both are negative (-3.637 and -1.252), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.384) has a much lower hERG risk than Ligand B (0.104), which is a critical advantage.

**Microsomal Clearance:** Ligand A (32.485) has higher clearance than Ligand B (17.555), suggesting lower metabolic stability. Ligand B is preferred here.

**In vitro Half-Life:** Ligand A (-2.415) has a shorter half-life than Ligand B (-41.572), which is undesirable. Ligand B is preferred.

**P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux than Ligand B (0.009), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 1.5 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a better balance of properties. Its superior binding affinity, lower hERG risk, and more favorable TPSA and logP values are significant advantages. While both compounds have poor solubility and Caco-2 permeability, the stronger binding of Ligand A and its better safety profile make it the more promising candidate. The lower metabolic stability and half-life of Ligand A are concerns, but can be addressed through structural modifications. Ligand B's poor logP is a major drawback.

Output:
1
2025-04-17 13:33:11,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.423 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is better than Ligand B (49.41), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (-0.291) is slightly low, potentially hindering permeation, while Ligand B (3.127) 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 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.561 and 0.836), indicating drug-like properties.

**DILI:** Ligand A (50.174) has a slightly higher DILI risk than Ligand B (31.059), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (76.89) has a higher BBB percentile than Ligand A (51.183).

**Caco-2 Permeability:** Ligand A (-4.914) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.142) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.631) has poor aqueous solubility, while Ligand B (-3.669) is even worse.

**hERG Inhibition:** Ligand A (0.084) has a very low hERG risk, which is excellent. Ligand B (0.55) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (24.613) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (84.212). This is a significant advantage.

**In vitro Half-Life:** Ligand A (-13.278) has a negative half-life, which is not possible. This is a major red flag and indicates an issue with the data or the molecule's stability. Ligand B (6.619) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable. Ligand B (0.275) is slightly higher.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), but both are good.

**Conclusion:**

Despite Ligand B's better logP and slightly better affinity, Ligand A is severely hampered by its negative in vitro half-life and poor Caco-2 permeability. The negative half-life is a critical issue. While Ligand B has solubility and clearance concerns, these can potentially be addressed through formulation or structural modifications. Ligand A's issues are more fundamental and suggest instability. Therefore, Ligand B is the more viable candidate.

Output:
1
2025-04-17 13:33:11,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.49 Da) is slightly higher than Ligand B (364.471 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (A: 89.26, B: 87.32), indicating good potential for oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.167) is slightly higher than Ligand B (2.078), but both are acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within the desirable limits.

**QED:** Both ligands have QED values above 0.5 (A: 0.713, B: 0.751), suggesting good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (91.314 percentile) than Ligand B (57.387 percentile). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.609) is better than Ligand B (41.218), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close (-5.242 for A, -5.375 for B), so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are similar (-3.736 for A, -2.746 for B).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.604, B: 0.388).

**Microsomal Clearance:** Ligand B has a much higher microsomal clearance (55.475 mL/min/kg) than Ligand A (17.668 mL/min/kg). Lower clearance is preferred for better metabolic stability, giving an advantage to Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (42.102 hours) than Ligand B (-31.36 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.387, B: 0.099).

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.8 kcal/mol) than Ligand B (-6.7 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) than Ligand B. However, its major drawback is the high DILI risk. Ligand B has a lower DILI risk, but significantly weaker binding affinity and poorer metabolic stability. Given the priorities for enzyme inhibitors, the strong binding 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 weaker affinity of Ligand B is a more fundamental issue that is harder to overcome.

Output:
1
2025-04-17 13:33:11,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (365.459 Da) is also good.

**TPSA:** Ligand A (49.85) is excellent, well below the 140 threshold for oral absorption. Ligand B (110.16) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (2.481) is optimal. Ligand B (0.963) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (A: 0.773, B: 0.854), indicating good drug-like properties.

**DILI:** Ligand A (21.055) has a significantly lower DILI risk than Ligand B (50.136), which is a major advantage.

**BBB:** Ligand A (97.751) shows excellent BBB penetration, while Ligand B (49.942) is much lower. While SRC isn't a CNS target, good BBB penetration often correlates with better overall drug distribution.

**Caco-2 Permeability:** Ligand A (-4.272) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.067) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.456) has poor aqueous solubility, potentially causing formulation issues. Ligand B (-3.5) is also poor.

**hERG Inhibition:** Ligand A (0.556) has a low hERG risk, which is excellent. Ligand B (0.335) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (46.5) has moderate clearance. Ligand B (21.192) has lower clearance, indicating better metabolic stability, a key consideration for kinases.

**In vitro Half-Life:** Ligand A (-6.632) has a very short half-life. Ligand B (-45.489) has a much longer half-life, a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.124, B: 0.026), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -9.0 kcal/mol, B: -8.4 kcal/mol). Ligand A has a slight advantage, but it's not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor Caco-2 and solubility, Ligand B's significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and comparable binding affinity outweigh Ligand A's slightly better logP and TPSA. The poor Caco-2 and solubility of both compounds would need to be addressed during lead optimization, but the metabolic stability and safety profile of Ligand B make it a better starting point.

Output:
1
2025-04-17 13:33:11,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (45.55), being under the 140 threshold, but both are acceptable.

**logP:** Ligand A (0.692) is a bit low, potentially hindering permeability. Ligand B (2.741) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5.

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

**QED:** Both ligands have good QED scores (0.843 and 0.794), indicating good drug-like properties.

**DILI:** Ligand A (37.069) has a lower DILI risk than Ligand B (43.234), both being under the 40 threshold.

**BBB:** Ligand A (27.879) has a lower BBB penetration than Ligand B (71.229). Since SRC is not a CNS target, this is less crucial.

**Caco-2:** Both ligands have negative Caco-2 values (-4.972 and -4.796), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have negative solubility values (-1.34 and -2.986), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Both ligands have low hERG risk (0.316 and 0.392), which is positive.

**Microsomal Clearance:** Ligand A (-0.249) has significantly *lower* (better) microsomal clearance than Ligand B (71.535). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (2.641) has a shorter half-life than Ligand B (38.533). This is a drawback for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.025 and 0.413), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -8.3 kcal/mol). Ligand A is slightly better (-8.9 vs -8.3).

**Overall Assessment:**

Ligand A has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic). However, it has a lower half-life and a lower logP. Ligand B has better solubility, BBB penetration (irrelevant here), and half-life, but has a higher DILI risk and significantly worse metabolic stability.

Given the enzyme-specific priorities, metabolic stability is crucial. The substantial difference in Cl_mic favors Ligand A. While the solubility and Caco-2 values are concerning for both, the superior binding affinity and metabolic stability of Ligand A outweigh the drawbacks.

Output:
0
2025-04-17 13:33:11,161 - INFO - Batch 223 complete. Total preferences: 3568
2025-04-17 13:33:11,161 - INFO - Processing batch 224/512...
2025-04-17 13:33:55,890 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 346.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is well below the 140 threshold for good absorption, and favorable for kinase inhibitors. Ligand B (126.8) is still acceptable, but less optimal.

**logP:** Ligand A (2.165) is within the optimal 1-3 range. Ligand B (0.723) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is excellent. Ligand B (4 HBD, 9 HBA) is acceptable but approaching the upper limits.

**QED:** Ligand A (0.718) is very good, indicating strong drug-likeness. Ligand B (0.578) is acceptable, but lower than A.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 40.364, Ligand B: 48.623), below the 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.554) is higher than Ligand B (54.634).

**Caco-2 Permeability:** Ligand A (-4.844) and Ligand B (-5.589) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.089) and Ligand B (-2.103) both have negative values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.112) has a very low hERG risk, which is excellent. Ligand B (0.343) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (25.033 mL/min/kg) is better than Ligand B (14.482 mL/min/kg), indicating better metabolic stability. Lower is better.

**In vitro Half-Life:** Ligand A (-4.872 hours) is significantly better than Ligand B (16.983 hours). A negative value suggests a long half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.042, Ligand B: 0.011).

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-10.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is superior. While both have issues with Caco-2 permeability and solubility, Ligand A has a significantly better binding affinity, better metabolic stability (lower Cl_mic, longer half-life), lower hERG risk, and a better QED score. The strong binding affinity of Ligand A (-9.0 kcal/mol) is a major advantage that can potentially offset the permeability/solubility concerns.

Output:
0
2025-04-17 13:33:55,890 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.438 and 341.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (71.76) as both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands (2.267 and 2.43) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBAs, while Ligand B has 7. Ligand A is better here, as lower HBA counts are generally preferred for permeability.

**QED:** Ligand B (0.924) has a significantly better QED score than Ligand A (0.644), indicating a more drug-like profile.

**DILI:** Ligand A (22.838) has a much lower DILI risk than Ligand B (61.419). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (90.074) is better than Ligand B (70.027). While not a primary concern for a kinase inhibitor, higher BBB is never a detriment.

**Caco-2:** 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.

**Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition risk (0.364 and 0.467 respectively).

**Microsomal Clearance:** Ligand A (2.619) has significantly lower microsomal clearance than Ligand B (46.186), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (20.516) has a slightly longer half-life than Ligand A (19.79), but the difference is minor.

**P-gp efflux:** Both have low P-gp efflux liability (0.07 and 0.073).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage for Ligand B. The difference of 2.3 kcal/mol is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and QED score. However, Ligand A has a much lower DILI risk and better metabolic stability (lower Cl_mic). Considering the enzyme-specific priorities, metabolic stability and safety (DILI) are very important. The substantial difference in binding affinity (-7.4 vs -9.7) is a significant factor, and the improved QED of Ligand B is also beneficial. While Ligand A's lower DILI is attractive, the potency advantage of Ligand B is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 13:33:55,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.419 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (391.27 Da) is still well within acceptable limits.

**2. TPSA:** Ligand A (66.4) is higher than Ligand B (53.76). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is closer to the ideal range.

**3. logP:** Both ligands have good logP values (A: 4.236, B: 3.48), falling within the optimal 1-3 range. Ligand A is slightly higher, potentially raising concerns about solubility and off-target effects, but not dramatically.

**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 2 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Ligand A (0.858) has a significantly higher QED score than Ligand B (0.723), indicating a more drug-like profile.

**7. DILI:** Ligand A (70.531) has a higher DILI risk than Ligand B (53.276). This is a significant concern for Ligand A.

**8. BBB:** Ligand A (22.412) has a very low BBB penetration percentile, while Ligand B (85.964) has a high BBB penetration percentile. This is not a primary concern for SRC kinase inhibitors as it is not a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.782 and -4.423). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.868 and -3.617), indicating poor aqueous solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.061) has a lower hERG inhibition liability than Ligand B (0.669), which is favorable.

**12. Microsomal Clearance:** Ligand A (34.657) has lower microsomal clearance than Ligand B (56.949), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.057) has a negative half-life, which is not possible, and indicates a very short half-life. Ligand B (32.616) has a much longer half-life.

**14. P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.507), which is favorable.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has slightly lower QED and solubility than Ligand A, its significantly stronger binding affinity (-7.8 vs -9.1 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B has a much better in vitro half-life, lower DILI risk, and higher BBB penetration (though not crucial here). Ligand A's high DILI risk and extremely short half-life are significant liabilities. The negative Caco-2 and solubility values for both are concerning and would require further investigation (e.g., salt formation, formulation strategies).

Output:
1
2025-04-17 13:33:55,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.53 Da and 353.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly higher than Ligand B (64.86), both are acceptable for oral absorption (<140).

**logP:** Both ligands have good logP values (3.37 and 2.84), 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 excellent QED scores (0.814 and 0.816), indicating strong drug-like properties.

**DILI:** Ligand A (47.73) has a slightly higher DILI risk than Ligand B (39.67), but both are below the concerning threshold of 60.

**BBB:** Ligand A (74.95) and Ligand B (93.68) both have good BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.894) has poor Caco-2 permeability, while Ligand B (-5.017) is also poor. This suggests potential absorption issues for both.

**Aqueous Solubility:** Ligand B (-2.701) has better aqueous solubility than Ligand A (-5.068). Solubility is important for formulation and bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.356 and 0.426), which is favorable.

**Microsomal Clearance:** Ligand B (33.40) has significantly lower microsomal clearance than Ligand A (73.66), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-3.06) has a longer in vitro half-life than Ligand A (9.87), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux than Ligand B (0.515), which could lead to better bioavailability.

**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, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand B's better solubility and metabolic stability, the significantly stronger binding affinity of Ligand A (-8.1 vs -7.1 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. While Ligand A has some ADME concerns (lower Caco-2 permeability), these can potentially be addressed through formulation strategies. The substantial binding advantage makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 13:33:55,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.354 Da and 356.857 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.03) is better than Ligand B (51.02) as it is still within the acceptable range for oral absorption, while Ligand B is excellent.

**logP:** Ligand A (0.446) is a bit low, potentially hindering permeability. Ligand B (3.061) is optimal.

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

**H-Bond Acceptors:** Ligand A (7) is good. Ligand B (4) is also good.

**QED:** Both ligands have acceptable QED scores (0.669 and 0.59), indicating reasonable drug-likeness.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (56.34), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (60.76) is slightly better than Ligand A (51.725).

**Caco-2 Permeability:** Ligand A (-5.268) is poor, indicating very low permeability. Ligand B (-4.673) is also poor but better than A.

**Aqueous Solubility:** Ligand A (-1.883) is poor. Ligand B (-3.341) is also poor.

**hERG Inhibition:** Ligand A (0.103) has a very low hERG risk, which is excellent. Ligand B (0.588) is also low, but higher than A.

**Microsomal Clearance:** Ligand A (-0.517) suggests good metabolic stability. Ligand B (77.605) indicates high metabolic clearance, a significant drawback.

**In vitro Half-Life:** Ligand A (13.896) has a reasonable half-life. Ligand B (-26.468) has a very short half-life, which is problematic.

**P-gp Efflux:** Ligand A (0.042) shows low P-gp efflux, which is favorable. Ligand B (0.521) is slightly higher, but still acceptable.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.0 kcal/mol and -7.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

While Ligand A has a better hERG profile and slightly better metabolic stability, Ligand B has a significantly better logP, Caco-2 permeability, and a much longer in vitro half-life. The poor permeability and solubility of Ligand A are major concerns. Considering the enzyme-specific priorities, the improved metabolic stability and permeability of Ligand B outweigh the slightly higher hERG risk and DILI.

Output:
1
2025-04-17 13:33:55,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (408.252 and 374.819 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands are below the 140 A^2 threshold (89.55 and 76.02), suggesting good oral absorption potential.

**logP:** Both ligands have logP values within the optimal 1-3 range (3.106 and 2.056), indicating good partitioning properties.

**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 (0.717 and 0.513), indicating a drug-like profile.

**DILI:** Ligand A has a DILI risk of 84.18, which is high. Ligand B has a significantly lower DILI risk of 48.468, which is much more favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (83.443) has a higher BBB value than Ligand A (66.886).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.015 and -4.916), which 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.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.063 and -3.188), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.233 and 0.26), which is excellent.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (71.462) than Ligand B (32.541), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (4.079 hours) compared to Ligand A (-11.99 hours). The negative value for Ligand A is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.102 and 0.123).

**Binding Affinity:** Ligand B has a better binding affinity (-9.7 kcal/mol) than Ligand A (-8.1 kcal/mol). This 1.6 kcal/mol difference is substantial and outweighs minor ADME concerns.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have issues with solubility and Caco-2 permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer half-life), a much lower DILI risk, and a substantially stronger binding affinity. The improved binding affinity is a key advantage for an enzyme inhibitor.

Output:
1
2025-04-17 13:33:55,891 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [388.471, 130.39 ,  -0.115,   3.   ,   7.   ,   0.633,  79.953,  36.371, -5.319,  -2.769,   0.312,  30.708, -12.807,   0.042,  -7.5  ]
**Ligand B:** [370.387,  78.43 ,   2.231,   3.   ,   3.   ,   0.545,  22.8  ,  70.415, -5.001,  -2.868,   0.448,  21.071,   7.792,   0.109,  -9.3  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (388.471) is slightly higher than B (370.387).
2. **TPSA:** A (130.39) is borderline for good oral absorption, while B (78.43) is well within the ideal range.
3. **logP:** A (-0.115) is quite low, potentially hindering permeability. B (2.231) is optimal.
4. **HBD:** Both have 3 HBD, which is acceptable.
5. **HBA:** A has 7 HBA, acceptable. B has 3 HBA, which is excellent.
6. **QED:** Both have good QED scores (A: 0.633, B: 0.545), indicating drug-like properties.
7. **DILI:** A (79.953) has a significantly higher DILI risk than B (22.8). This is a major concern.
8. **BBB:** A (36.371) has poor BBB penetration, while B (70.415) is reasonably good. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for B.
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. Again, the scale is unknown.
11. **hERG:** Both have low hERG risk (A: 0.312, B: 0.448).
12. **Cl_mic:** A (30.708) has a higher microsomal clearance than B (21.071), indicating lower metabolic stability.
13. **t1/2:** A (-12.807) has a negative in vitro half-life, which is not possible. B (7.792) has a reasonable half-life.
14. **Pgp:** A (0.042) has lower P-gp efflux liability than B (0.109), which is favorable.
15. **Affinity:** B (-9.3 kcal/mol) has a significantly stronger binding affinity than A (-7.5 kcal/mol). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. B excels in affinity and has better metabolic stability and a positive half-life. A has a concerningly high DILI risk and a negative half-life. Although A has lower Pgp efflux, the other factors heavily favor B.

**Conclusion:**

Ligand B is the more promising drug candidate due to its superior binding affinity, lower DILI risk, better metabolic stability, and acceptable physicochemical properties. The negative values for Caco-2 and solubility are concerning, but the large difference in binding affinity and the DILI risk of A outweigh these concerns.

Output:
1
2025-04-17 13:33:55,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.355 and 353.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.48) is better than Ligand B (105.98), both being reasonably good for oral absorption (<=140).

**logP:** Ligand A (1.925) is optimal, while Ligand B (0.518) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (7) is better than Ligand B (6), both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.729 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (98.488) has a significantly higher DILI risk than Ligand B (50.097). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, with Ligand A at 72.237 and Ligand B at 74.564. Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.967) is worse than Ligand B (-5.237), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.819) is worse than Ligand B (-1.925), indicating lower solubility.

**hERG:** Ligand A (0.231) has a slightly higher hERG risk than Ligand B (0.018), but both are very low and acceptable.

**Microsomal Clearance:** Ligand A (95.155) has a higher microsomal clearance than Ligand B (8.836), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (4.219) has a shorter half-life than Ligand B (1.994), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.181) has lower P-gp efflux than Ligand B (0.012), which is slightly favorable.

**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 could outweigh some ADME concerns.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its significantly higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2) are major concerns. Ligand B, while having a weaker binding affinity, exhibits a much better safety profile (lower DILI) and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and safety are crucial. The affinity difference, while notable, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 13:33:55,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.381 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.42) is better than Ligand B (49.41), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.528 and 3.575), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but not a major one.

**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:** Ligand A (0.874) has a significantly better QED score than Ligand B (0.612), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (39.201 and 31.601), both well below the 40 threshold.

**BBB:** Ligand A (77.743) has a better BBB penetration score than Ligand B (54.75). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.493) has worse Caco-2 permeability than Ligand B (-4.89).

**Aqueous Solubility:** Ligand A (-3.579) has worse aqueous solubility than Ligand B (-2.727). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.464 and 0.432), which is excellent.

**Microsomal Clearance:** Ligand A (27.411) has higher microsomal clearance than Ligand B (23.566). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.214) has a longer in vitro half-life than Ligand A (5.748). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand B (0.283) has slightly lower P-gp efflux than Ligand A (0.089), which is better.

**Binding Affinity:** Ligand A (-9.4 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 outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand A having better QED and BBB penetration, the dramatically superior binding affinity of Ligand A (-9.4 kcal/mol vs -0.0 kcal/mol) is the most important factor. The slightly worse solubility and higher clearance of Ligand A are less concerning given its significantly stronger potency. The longer half-life of Ligand B is a plus, but the potency difference is too large to ignore.

Output:
1
2025-04-17 13:33:55,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.359 Da and 357.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (113.24 and 110.0) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.323) is slightly low, potentially hindering permeation. Ligand B (1.458) is within the optimal 1-3 range. This favors Ligand B.

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

**H-Bond Acceptors:** Ligand A (7) and Ligand B (6) are both below the 10 limit.

**QED:** Both ligands have good QED scores (0.831 and 0.678), indicating drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (72.392 and 74.719), which is a concern. However, this is a predictive score and needs further investigation.

**BBB:** Both ligands have moderate BBB penetration (60.915 and 63.009), which is not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values (-5.009 and -5.901), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.325 and -3.121). This is a major issue for bioavailability and formulation.

**hERG:** Both ligands have low hERG inhibition liability (0.119 and 0.417), which is positive.

**Microsomal Clearance:** Ligand A (-3.893) has a much lower (better) microsomal clearance than Ligand B (5.286), indicating greater metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-7.551) has a longer (better) in vitro half-life than Ligand B (-5.897). This further supports the better metabolic stability of Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.066).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a >1.3 kcal/mol advantage, which is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both compounds, Ligand B's significantly superior binding affinity (-9.2 vs -7.9 kcal/mol) is a decisive factor. The improved logP of Ligand B is also favorable. While Ligand A has better metabolic stability, the potency advantage of Ligand B is more critical for an enzyme target like SRC kinase. The DILI risk is similar for both, and the hERG risk is low. Addressing the solubility issues through formulation strategies would be a priority for Ligand B.

Output:
1
2025-04-17 13:33:55,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as befits an enzyme target.

**Molecular Weight:** Both ligands (353.419 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.39) is slightly higher than Ligand B (76.02), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (-0.911) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.449) 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 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.638) has a better QED score than Ligand A (0.493), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (28.965 and 29.779, respectively).

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (46.84) is slightly better than Ligand A (35.052).

**Caco-2 Permeability:** Ligand A (-4.664) has poor Caco-2 permeability, while Ligand B (-5.05) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.511) has slightly better solubility than Ligand B (-2.685).

**hERG:** Both ligands have very low hERG risk (0.076 and 0.19, respectively). This is excellent.

**Microsomal Clearance:** Ligand A (13.722) has significantly lower microsomal clearance than Ligand B (44.126), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-10.655) has a longer in vitro half-life than Ligand B (27.491). This is a strong positive for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.008 and 0.051, respectively).

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.7). However, the difference is only 0.6 kcal/mol, which is not substantial enough to outweigh other significant differences.

**Conclusion:**

While Ligand B has a better logP and QED score and slightly better binding affinity, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility. Given the priority for metabolic stability in enzyme inhibitors, and the relatively small difference in binding affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 13:33:55,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.451 Da and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.36) is acceptable, being under the 140 threshold, but higher than ideal for CNS penetration. Ligand B (32.34) is excellent, well below 90, indicating good permeability.

**logP:** Ligand A (1.098) is within the optimal range (1-3). Ligand B (4.253) is slightly above, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 1 HBD and 2 HBA, also good. Both are within the recommended limits.

**QED:** Both ligands have good QED scores (0.711 and 0.867, respectively), indicating drug-like properties.

**DILI:** Ligand A (18.224) has a very low DILI risk, which is excellent. Ligand B (22.8) also has a low DILI risk, but slightly higher than A.

**BBB:** Ligand A (57.154) has a moderate BBB penetration potential. Ligand B (90.035) has excellent BBB penetration. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.332) has poor Caco-2 permeability, which is a significant concern. Ligand B (-4.7) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.388) has poor aqueous solubility. Ligand B (-4.402) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.569) has a low hERG inhibition risk, which is excellent. Ligand B (0.768) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-24.777) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (85.965) has high microsomal clearance, suggesting rapid metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-15.544) has a long *in vitro* half-life, consistent with its low clearance. Ligand B (34.601) has a moderate half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.011 and 0.581, respectively).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B's slightly higher logP and lower solubility/permeability, its significantly superior binding affinity (-7.9 vs -6.6 kcal/mol) and excellent metabolic stability (low Cl_mic) make it the more promising candidate. The lower DILI risk and good QED further support this. While Ligand A has better solubility and lower DILI, the potency advantage of Ligand B is critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:33:55,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is slightly higher than Ligand B (75.71), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.483 and 2.428), 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.

**QED:** Both ligands have reasonable QED scores (0.743 and 0.609), indicating good drug-likeness.

**DILI:** Ligand A (35.285) has a lower DILI risk than Ligand B (29.236), suggesting a safer profile regarding liver toxicity.

**BBB:** Ligand A (66.227) has a higher BBB penetration score than Ligand B (51.725), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.945) shows better Caco-2 permeability than Ligand B (-4.434).

**Aqueous Solubility:** Ligand A (-1.849) has better aqueous solubility than Ligand B (-3.154). This is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.259 and 0.153), which is excellent.

**Microsomal Clearance:** Ligand A (23.124) has significantly lower microsomal clearance than Ligand B (83.602). This indicates better metabolic stability for Ligand A, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-5.478) has a significantly longer in vitro half-life than Ligand B (-13.563). This is also a strong advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.032).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). The difference of 1.8 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It exhibits better metabolic stability (lower Cl_mic, longer t1/2), better solubility, better Caco-2 permeability, a lower DILI risk, and a significantly stronger binding affinity. While Ligand B has a slightly lower TPSA, the advantages of Ligand A in potency and ADME properties are more critical for an enzyme inhibitor targeting oncology.

Output:
1
2025-04-17 13:33:55,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (361.427 and 366.571 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (120.91) is better than Ligand B (49.41) as it is closer to the threshold of 140 for good oral absorption.

**3. logP:** Ligand A (0.832) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (3.621) is within 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 (7) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.749 and 0.501), indicating drug-like properties.

**7. DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (16.053). This is a significant concern.

**8. BBB:** Both ligands have similar BBB penetration (48.003 and 67.235). BBB is not a high priority for a kinase inhibitor unless CNS exposure is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.488 and -5.262), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.946 and -3.463), 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 (0.475 and 0.572), which is good.

**12. Microsomal Clearance:** Ligand A (15.127) has significantly lower microsomal clearance than Ligand B (83.04), indicating better metabolic stability. This is a major advantage.

**13. In vitro Half-Life:** Ligand A (-10.011) has a negative half-life, which is not possible. Ligand B (2.807) has a short half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.218).

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-9.0 and -8.5 kcal/mol).

**Overall Assessment:**

Ligand A has a better TPSA and significantly better metabolic stability (lower Cl_mic) than Ligand B. However, it has a higher DILI risk and an impossible half-life value. Ligand B has a better logP and lower DILI risk. Both compounds have poor Caco-2 permeability and aqueous solubility.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the lower clearance of Ligand A is a strong advantage. The negative half-life is a data error that needs to be addressed, but the other properties suggest it might be a better starting point for optimization. The DILI risk is a concern, but can potentially be mitigated through structural modifications.

Output:
0
2025-04-17 13:33:55,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.479 and 334.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.09 and 75.19) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have acceptable logP values (2.13 and 1.183), falling within the 1-3 range. Ligand A is slightly more favorable.

**H-Bond Donors:** Both ligands have reasonable HBD counts (2 and 1), well below the 5 limit.

**H-Bond Acceptors:** Both ligands have reasonable HBA counts (4), well below the 10 limit.

**QED:** Both ligands have good QED scores (0.588 and 0.833), indicating good drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (66.731) has a higher DILI risk than Ligand B (54.556). This is a negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (46.801) has a slightly higher value than Ligand B (36.409).

**Caco-2 Permeability:** Both have negative 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, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.335 and 0.105), which is excellent.

**Microsomal Clearance:** Ligand A (74.562) has a significantly higher microsomal clearance than Ligand B (-15.938). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (11.299) has a shorter half-life than Ligand B (-13.844). Again, this supports better metabolic stability for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.131 and 0.009).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.1 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B is the better candidate. While both ligands have good potency and drug-like properties, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The slightly better binding affinity of Ligand B is a bonus. The unusual negative solubility and Caco-2 values are concerning, but the other ADME properties of Ligand B are significantly more favorable.

Output:
1
2025-04-17 13:33:55,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is slightly higher than Ligand B (67.87). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands (1.364 and 1.503) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.713 and 0.763), indicating good drug-likeness.

**DILI:** Ligand A (35.285) has a slightly higher DILI risk than Ligand B (31.718), but both are below the concerning threshold of 60.

**BBB:** Ligand A (39.395) has a lower BBB penetration than Ligand B (63.358). BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.056) has worse Caco-2 permeability than Ligand B (-4.752). Both are negative, indicating low permeability, but B is better.

**Aqueous Solubility:** Ligand A (-2.414) has worse aqueous solubility than Ligand B (-1.935). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.172 and 0.232).

**Microsomal Clearance:** Ligand A (27.595) has significantly lower microsomal clearance than Ligand B (45.418), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (8.634) has a slightly shorter half-life than Ligand B (9.839).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.087 and 0.05).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability, Ligand B's superior binding affinity (-9.4 vs -8.5 kcal/mol) is a critical advantage for an enzyme inhibitor. The difference in affinity is large enough to compensate for the slightly higher clearance and lower solubility. Ligand B also has better Caco-2 permeability and BBB penetration. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 13:33:55,896 - INFO - Batch 224 complete. Total preferences: 3584
2025-04-17 13:33:55,896 - INFO - Processing batch 225/512...
2025-04-17 13:34:36,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.817 and 367.456 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.17) is slightly higher than Ligand B (61.44). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better positioned for potential CNS penetration if desired.

**3. logP:** Both ligands have good logP values (3.235 and 2.562), 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 (6) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.776 and 0.624), indicating good drug-like properties.

**7. DILI:** Ligand A (85.459) has a significantly higher DILI risk than Ligand B (14.889). This is a major concern for Ligand A.

**8. BBB:** Ligand A (72.896) has better BBB penetration potential than Ligand B (61.807), but this is less crucial for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.121 and -5.067), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.214 and -2.165), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Ligand A (0.284) has a slightly higher hERG risk than Ligand B (0.685), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (29.082) has a higher microsomal clearance than Ligand A (23.668), meaning Ligand A is likely more metabolically stable.

**13. In vitro Half-Life:** Ligand A (43.273) has a significantly longer in vitro half-life than Ligand B (20.107), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.073) has lower P-gp efflux than Ligand B (0.022), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-7.0) 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:**

Despite the poor Caco-2 and solubility for both, Ligand B is the superior candidate due to its significantly stronger binding affinity (-7.0 kcal/mol vs 0.0 kcal/mol) and much lower DILI risk (14.889 vs 85.459). The improved binding affinity is likely to be a critical factor in achieving efficacy, and the lower DILI risk is essential for safety. While Ligand A has better metabolic stability and half-life, the substantial affinity difference and DILI concern make Ligand B the more promising candidate.

Output:
1
2025-04-17 13:34:36,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (45.67) is significantly better than Ligand B (105.34). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is higher, potentially hindering absorption.

**logP:** Ligand A (2.46) is optimal (1-3). Ligand B (0.632) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.862, B: 0.662), indicating good drug-like properties.

**DILI:** Ligand A (47.421) has a much lower DILI risk than Ligand B (69.872). This is a significant advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (81.815) has a better BBB percentile than Ligand B (59.984).

**Caco-2 Permeability:** Ligand A (-4.326) is significantly better than Ligand B (-5.19). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-1.293) is better than Ligand B (-2.717). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.632) has a lower hERG risk than Ligand B (0.361), which is preferable.

**Microsomal Clearance:** Ligand A (23.548) has a higher (worse) microsomal clearance than Ligand B (2.579). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (36.545) has a longer half-life than Ligand B (-12.197). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.187) has lower P-gp efflux liability than Ligand B (0.019). Lower efflux is generally desirable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall:**

Ligand A demonstrates a superior overall profile. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A excels in crucial areas like DILI risk, solubility, permeability, and hERG inhibition. The combination of these factors makes Ligand A a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 13:34:36,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (67.23) is excellent, well below 140.

**logP:** Ligand A (-0.247) is a bit low, potentially hindering permeation. Ligand B (2.84) 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 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.647 and 0.771), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (36.177 and 35.014), which is positive.

**BBB:** Ligand A (30.128) has low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (74.68) has moderate BBB penetration, also not critical here.

**Caco-2 Permeability:** Ligand A (-5.203) has very poor Caco-2 permeability, a significant drawback. Ligand B (-4.62) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.141) has poor aqueous solubility. Ligand B (-3.126) has even poorer aqueous solubility.

**hERG Inhibition:** Ligand A (0.062) has very low hERG inhibition risk, which is excellent. Ligand B (0.474) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-52.282) has very low microsomal clearance, indicating high metabolic stability. This is a major advantage. Ligand B (67.479) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (0.703) has a very short half-life. Ligand B (12.257) has a much longer half-life, a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.005 and 0.367), which is favorable.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has excellent metabolic stability and very low hERG risk, its poor Caco-2 permeability, low logP, and poor solubility are major concerns. Ligand B, despite slightly higher clearance and lower solubility, has a significantly better binding affinity, a more favorable logP, and a much longer half-life. The stronger binding affinity of Ligand B is a critical factor for an enzyme inhibitor, and the improved half-life is also highly desirable.

Output:
1
2025-04-17 13:34:36,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.479 and 368.865 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is slightly higher than Ligand B (81.75), but both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (0.989 and 0.896) 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 within acceptable limits.

**QED:** Ligand B (0.756) has a better QED score than Ligand A (0.541), indicating a more drug-like profile.

**DILI:** Ligand B (23.575) has a significantly lower DILI risk than Ligand A (36.681), which is a major advantage.

**BBB:** Ligand B (77.549) has a higher BBB penetration score than Ligand A (37.805), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.096 and -4.901), 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 ligands have negative solubility values (-1.695 and -2.471), indicating poor aqueous solubility, which is a concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.257 and 0.245).

**Microsomal Clearance:** Ligand B (-4.157) has *much* lower (better) microsomal clearance than Ligand A (36.719), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand B (6.046 hours) has a longer half-life than Ligand A (9.257 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.011).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Conclusion:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly lower DILI risk, dramatically improved metabolic stability (lower Cl_mic, longer half-life), and stronger binding affinity outweigh the slightly lower QED and BBB scores. The affinity difference is substantial and is the primary driver of this decision.

Output:
1
2025-04-17 13:34:36,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.39 and 365.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.62) is better than Ligand B (73.74), both are under the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.453) is slightly low, potentially hindering permeation. Ligand B (1.71) is within the optimal 1-3 range. This favors Ligand B.

**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 similar QED values (0.717 and 0.712), indicating good drug-likeness.

**DILI:** Ligand A (43.66) has a better DILI score than Ligand B (16.21), indicating lower liver injury risk. This is a significant advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (68.21 and 65.84), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar negative Caco-2 values (-5.12 and -5.03), which is not ideal.

**Aqueous Solubility:** Both ligands have similar negative solubility values (-2.36 and -1.50), which is not ideal.

**hERG Inhibition:** Ligand A (0.061) has a much lower hERG inhibition risk than Ligand B (0.345). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-4.914) has significantly lower microsomal clearance than Ligand B (20.552), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.316) has a longer half-life than Ligand B (-2.903). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux values (0.019 and 0.122).

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.0), a difference of 1.2 kcal/mol. While affinity is a priority, the other ADME properties of Ligand A are much more favorable.

**Overall Assessment:**

Ligand A demonstrates superior ADME properties, particularly regarding DILI risk, hERG inhibition, metabolic stability (lower Cl_mic, longer t1/2), and solubility. While Ligand B has a slightly better binding affinity, the substantial improvements in safety and pharmacokinetic properties of Ligand A outweigh this difference. Given the enzyme-specific priorities, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 13:34:36,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.379 Da and 347.459 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (118.45) is slightly higher than Ligand B (78.51). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (-0.833) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (1.2) 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 3 HBA. Both are within the acceptable limit of <=10, with Ligand B being preferable.

**QED:** Both ligands have good QED scores (0.662 and 0.784, respectively), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 64.754, which is borderline high. Ligand B has a much lower DILI risk of 11.283, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (66.886 and 64.599, respectively). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.437 and -5.065). These values are unusual and suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.722 and -1.741). These values are also unusual and suggest poor solubility.

**hERG Inhibition:** Ligand A (0.023) has a very low hERG risk, which is excellent. Ligand B (0.116) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-21.152) has a much lower (better) microsomal clearance than Ligand B (-2.237). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.807) has a very short half-life, while Ligand B (8.046) has a much longer half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.013, respectively).

**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 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 poor solubility, permeability, and a borderline high DILI risk. Ligand B has better solubility, permeability, a much lower DILI risk, and a longer half-life, but its binding affinity is weaker.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the significantly stronger binding affinity of Ligand A is a major advantage. While its ADME properties are not ideal, optimization could potentially address these issues. The lower DILI risk of Ligand B is appealing, but the weaker affinity is a significant drawback.

Output:
0
2025-04-17 13:34:36,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.418 and 342.439 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 62.55, which is well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.541) is slightly higher than Ligand B (2.679), both 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 3 HBA, which is acceptable (<=10).

**6. QED:** Ligand B (0.915) has a significantly higher QED score than Ligand A (0.668), indicating better overall drug-likeness.

**7. DILI:** Ligand B (30.826) has a much lower DILI risk than Ligand A (53.005). This is a significant advantage.

**8. BBB:** Ligand A (89.88) has better BBB penetration than Ligand B (62.97), but BBB is not a primary concern for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Ligand A (-4.823) has worse Caco-2 permeability than Ligand B (-5.078). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.392) has worse aqueous solubility than Ligand B (-2.994). Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand B (0.204) has a much lower hERG inhibition liability than Ligand A (0.966). This is a critical advantage, reducing the risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (19.815 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (69.921 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (38.197 hours) has a much longer in vitro half-life than Ligand A (89.388 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.721) has higher P-gp efflux than Ligand B (0.2). Lower efflux is preferable.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a considerably stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is significantly better across multiple crucial parameters. It has a higher QED, lower DILI risk, much lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and, most importantly, a substantially stronger binding affinity. While both have poor Caco-2 and solubility, the superior potency and safety profile of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 13:34:36,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.5 and 360.8 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (82.5 and 78.4) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands (1.51 and 2.47) are within the optimal 1-3 range. Ligand B is slightly higher, potentially improving membrane permeability.

**4. H-Bond Donors:** Both have 2 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 (0.801 and 0.875), indicating good drug-like properties.

**7. DILI:** Ligand A (22.7) has a significantly lower DILI risk than Ligand B (55.7), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.6) is higher than Ligand B (35.1).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.28 and -5.28), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.95 and -3.87), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.241) has a lower hERG inhibition liability than Ligand B (0.412), which is preferable.

**12. Microsomal Clearance:** Ligand B (63.6) has a higher microsomal clearance than Ligand A (25.1), suggesting lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (-7.6) has a longer in vitro half-life than Ligand A (-14.1), which is a positive for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux values (0.191 and 0.055), which is good.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-10 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity, a longer half-life, and a slightly better logP. However, it suffers from significantly higher DILI risk, higher microsomal clearance, and poorer hERG profile. Ligand A has a much better safety profile (lower DILI, lower hERG), better metabolic stability, but a weaker binding affinity.

Given that SRC kinases are enzymes, potency (affinity) is paramount. The 1.8 kcal/mol difference in binding affinity is substantial. While the ADME properties of Ligand B are concerning, they might be addressable through further optimization. The DILI risk is the biggest concern, but could potentially be mitigated with structural modifications. The improved affinity of Ligand B is likely to translate to greater efficacy *in vivo*, making it the more promising candidate despite its drawbacks.

Output:
1
2025-04-17 13:34:36,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.252 Da) is slightly higher than Ligand B (363.527 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (61.44) is significantly lower than Ligand A (89.55), which is favorable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.106) is slightly higher than Ligand B (2.129), but both are acceptable.

**H-Bond Donors & Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, and Ligand B has 4. Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (A: 0.717, B: 0.842), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 84.18, which is high. Ligand B has a DILI risk of 13.3, which is very good. This is a major advantage for Ligand B.

**BBB:** Both have moderate BBB penetration (A: 66.886, B: 59.364). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.233, B: 0.205). This is good.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (71.462) than Ligand B (0.611), indicating faster metabolism and lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (-3.341 hours) than Ligand A (-11.99 hours), indicating better stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.102, B: 0.027), which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.1 kcal/mol, B: -8.5 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B is significantly better due to its much lower DILI risk, better metabolic stability (lower Cl_mic, longer half-life), and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the DILI and metabolic stability issues with Ligand A are more critical concerns. The slightly better potency of Ligand B further strengthens its position.

Output:
1
2025-04-17 13:34:36,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.451 and 359.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (94.22 and 91.32) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.599) is a bit low, potentially hindering permeation. Ligand B (2.11) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands (5) are below the 10 threshold.

**QED:** Ligand A (0.813) has a better QED score than Ligand B (0.66), indicating a more drug-like profile.

**DILI:** Ligand A (29.081) has a significantly lower DILI risk than Ligand B (55.797). This is a major advantage.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability, but we can't directly compare without knowing the scale.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and suggests poor solubility, but we can't directly compare without knowing the scale.

**hERG:** Both ligands have low hERG inhibition risk (0.128 and 0.247).

**Microsomal Clearance:** Ligand A (-18.025) has *much* lower (better) microsomal clearance than Ligand B (39.862), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (1.229) has a shorter half-life than Ligand B (-14.991), but the negative value for B is suspect.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.067).

**Binding Affinity:** Ligand B (0.0) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), but the difference is not substantial enough to overcome the other drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A exhibits significantly better metabolic stability (lower Cl_mic), a much lower DILI risk, and a better QED score. The slightly lower logP of Ligand A is a concern, but the substantial advantages in safety and metabolic stability outweigh this drawback.

Output:
0
2025-04-17 13:34:36,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.479 and 363.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.11) is better than Ligand B (63.17), both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.223) is quite low, potentially hindering permeation. Ligand B (2.579) 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 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.683 and 0.717), indicating good drug-like properties.

**DILI:** Ligand A (7.445) has a very low DILI risk, significantly better than Ligand B (51.493).

**BBB:** Ligand A (29.508) has poor BBB penetration, while Ligand B (94.649) has excellent penetration. However, since SRC is not a CNS target, BBB is not a major concern.

**Caco-2 Permeability:** Ligand A (-5.117) has very poor Caco-2 permeability, a major red flag. Ligand B (-4.778) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.094) has slightly better solubility than Ligand B (-4.082).

**hERG Inhibition:** Ligand A (0.231) has a lower hERG risk than Ligand B (0.694), which is preferable.

**Microsomal Clearance:** Ligand A (-2.141) has a negative clearance, indicating excellent metabolic stability. Ligand B (42.402) has high clearance, suggesting rapid metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.658) has a good half-life, while Ligand B (-2.012) has a very short half-life.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is good. Ligand B (0.041) also has low P-gp efflux.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Despite Ligand B having a better logP, the significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better Caco-2 permeability of Ligand A outweigh this advantage. The similar binding affinities mean potency is not a differentiating factor. The poor Caco-2 permeability of both is a concern, but the superior metabolic properties of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 13:34:36,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.438 and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (40.62). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.006) is within the optimal 1-3 range, while Ligand B (3.402) is at the higher end, potentially leading to solubility issues.

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

**H-Bond Acceptors:** Ligand A (3) is good, and Ligand B (2) is also good.

**QED:** Ligand A (0.792) is better than Ligand B (0.659), indicating a more drug-like profile.

**DILI:** Ligand A (14.269) has a significantly lower DILI risk than Ligand B (8.181), which is a major advantage.

**BBB:** Ligand A (83.831) has a good BBB penetration, while Ligand B (96.161) is even better. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.979) and Ligand B (-4.669) both have negative values, which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Ligand A (-2.277) and Ligand B (-3.324) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.245) has a lower hERG inhibition liability than Ligand B (0.909), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-4.431) has a much lower (better) microsomal clearance than Ligand B (61.996), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.475) has a very short half-life, while Ligand B (-17.794) has a negative half-life, which is not possible. This suggests that Ligand B is rapidly metabolized.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is favorable. Ligand B (0.681) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), although both are good.

**Conclusion:**

Ligand A is the superior candidate. It has a lower DILI risk, lower hERG inhibition, significantly better metabolic stability (lower Cl_mic and a reasonable, though short, half-life), better QED, and slightly better binding affinity. While both ligands have poor solubility and permeability, the ADME-Tox profile of Ligand A is much more favorable, making it a more viable drug candidate for SRC kinase inhibition.

Output:
0
2025-04-17 13:34:36,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.288 Da) is slightly higher than Ligand B (341.371 Da), but both are acceptable.

**TPSA:** Ligand A (47.56) is significantly better than Ligand B (120.91). Lower TPSA generally improves permeability, which is beneficial.

**logP:** Ligand A (4.173) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.419) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=6) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.82, B: 0.819), indicating good drug-likeness.

**DILI:** Ligand A (62.854) and Ligand B (72.974) both have DILI risks that are moderately high, but Ligand A is slightly better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.307) is better than Ligand B (47.964).

**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 (0.776) is better than Ligand B (0.112), indicating a lower risk of cardiotoxicity. This is a crucial factor for kinase inhibitors.

**Microsomal Clearance:** Ligand A (60.937) is higher than Ligand B (49.23), meaning Ligand B is likely to have better metabolic stability. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand A (82.538) has a longer half-life than Ligand B (0.648), which is desirable.

**P-gp Efflux:** Ligand A (0.878) is better than Ligand B (0.058), meaning less efflux and potentially better bioavailability.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This 1.7 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), and a more optimal logP. However, it has a lower hERG score and a lower BBB score. Ligand A has a better hERG score, BBB, P-gp efflux, and in vitro half-life, but suffers from a higher logP and higher microsomal clearance. The binding affinity difference is the most significant factor. Given the enzyme-specific priorities, the stronger binding affinity of Ligand B is the most important factor. While the hERG score is a concern, it's not insurmountable during lead optimization.

Output:
1
2025-04-17 13:34:36,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.459 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.08) is better than Ligand B (100.27). Both are under 140, but lower TPSA generally favors absorption.

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

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (6). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.703) is better than Ligand B (0.585), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.339) has a significantly lower DILI risk than Ligand B (19.504). This is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.876) is lower than Ligand B (49.787).

**9. Caco-2:** Ligand A (-4.689) and Ligand B (-4.987) are similar and both are negative, suggesting poor permeability.

**10. Solubility:** Ligand A (-1.628) is slightly better than Ligand B (-1.92), but both are poor.

**11. hERG:** Ligand A (0.279) has a much lower hERG risk than Ligand B (0.083). This is a significant advantage.

**12. Cl_mic:** Ligand B (-7.353) has a *much* lower (better) microsomal clearance than Ligand A (15.938). This suggests better metabolic stability.

**13. t1/2:** Ligand B (23.154) has a significantly longer in vitro half-life than Ligand A (-11.504). This is a major advantage.

**14. Pgp:** Ligand A (0.135) has lower Pgp efflux than Ligand B (0.024), which is preferable.

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-10.6). However, the difference is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and metabolic stability (lower Cl_mic and longer t1/2), Ligand A demonstrates significantly better safety profiles (lower DILI and hERG risk) and a better QED score. The poor Caco-2 and solubility for both compounds are concerning, but can be addressed with formulation strategies. The lower TPSA, HBD, and HBA of Ligand A also contribute to a more favorable profile. The substantial difference in DILI and hERG risk makes Ligand A the more viable starting point for further optimization.

Output:
0
2025-04-17 13:34:36,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.423 and 361.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.39) is slightly higher than Ligand B (72.91). Both are below the 140 threshold for good absorption, but Ligand B is preferable.

**logP:** Ligand A (2.001) is within the optimal 1-3 range. Ligand B (3.268) is at the higher end but still acceptable.

**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 6 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.627 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (81.039) has a higher DILI risk than Ligand B (77.627), though both are reasonably low.

**BBB:** Both ligands have good BBB penetration (69.794 and 86.739). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.559 and -4.494), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.592 and -4.65), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.223 and 0.224). This is excellent.

**Microsomal Clearance:** Ligand A (61.365) has significantly lower microsomal clearance than Ligand B (106.636), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (14.987 hours) has a longer half-life than Ligand B (-17.961 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 (0.16 and 0.604).

**Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (0.0). 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 substantially higher binding affinity (-7.0 kcal/mol vs 0.0 kcal/mol) is a major advantage for an enzyme inhibitor. The better metabolic stability of Ligand A is appealing, but the difference in binding affinity is so large that it likely outweighs this benefit. The negative half-life for Ligand B is a major concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 13:34:36,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.415 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (77.1) is better than Ligand B (48). While both are acceptable, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.076) is optimal, while Ligand B (3.774) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (0 HBD, 4 HBA). Both are within acceptable limits, but a slight balance of HBDs can improve solubility.

**QED:** Ligand A (0.796) is significantly better than Ligand B (0.64), indicating a more drug-like profile.

**DILI:** Ligand B (30.671) has a much lower DILI risk than Ligand A (50.911), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (86.274) is better than Ligand A (76.076). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.607) is slightly better than Ligand B (-4.728).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand B (-3.49) is slightly better than Ligand A (-1.473).

**hERG Inhibition:** Ligand A (0.151) has a much lower hERG risk than Ligand B (0.67), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (21.372) has significantly lower microsomal clearance than Ligand B (92.13), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.403 hours) is better than Ligand B (-5.541 hours).

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.522), which is favorable for bioavailability.

**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 ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor for an enzyme inhibitor. While it has some ADME liabilities (higher logP, higher hERG, higher Cl_mic, lower solubility), the substantial difference in binding affinity (-9.2 vs -7.9 kcal/mol) is a >1.5 kcal/mol advantage and likely outweighs these concerns. Ligand A has better ADME properties overall (lower DILI, lower Cl_mic, better hERG), but its weaker binding affinity makes it less likely to be effective.

Output:
1
2025-04-17 13:34:36,497 - INFO - Batch 225 complete. Total preferences: 3600
2025-04-17 13:34:36,497 - INFO - Processing batch 226/512...
2025-04-17 13:35:15,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.531 and 344.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.34) is better than Ligand B (110.83), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold if CNS penetration were a consideration.

**logP:** Ligand A (1.648) is within the optimal 1-3 range. Ligand B (-0.059) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 8 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.61 and 0.672, respectively), indicating good drug-like properties.

**DILI:** Ligand A (34.626) has a significantly lower DILI risk than Ligand B (65.723). This is a major advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC kinase.

**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 are likely indicating very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a potential issue that would need to be addressed during formulation.

**hERG Inhibition:** Ligand A (0.319) has a lower hERG inhibition liability than Ligand B (0.07), which is favorable.

**Microsomal Clearance:** Ligand A (37.39 mL/min/kg) has a lower microsomal clearance than Ligand B (40.492 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.234 hours) has a longer half-life than Ligand B (-4.116 hours). The negative value for B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.7 kcal/mol), but the difference is small (0.2 kcal/mol) and may not be enough to overcome the other ADME deficiencies.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has a marginally better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG inhibition. The solubility and permeability issues are present in both, but the superior safety and stability profile of Ligand A make it the preferred choice for further optimization.

Output:
0
2025-04-17 13:35:15,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (354.426 and 348.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.32) is slightly higher than Ligand B (75.19), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (1.129) is within the optimal range of 1-3. Ligand B (2.329) is also within range, but closer to the upper limit.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the HBA <=10 threshold.

**6. QED:** Both ligands have good QED scores (A: 0.802, B: 0.829), indicating drug-like properties.

**7. DILI:** Ligand A (45.677) has a lower DILI risk than Ligand B (54.401), both being acceptable (<60).

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (85.653) has a higher BBB percentile than Ligand A (51.842), but this is not a major factor in this case.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-4.972 vs -4.421).

**10. Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.925) is slightly better than Ligand B (-2.687).

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.292, B: 0.276), which is excellent.

**12. Cl_mic:** Ligand A (2.17) has significantly lower microsomal clearance than Ligand B (39.051), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. t1/2:** Ligand A (-35.655) has a much longer in vitro half-life than Ligand B (-10.98), further supporting its better metabolic stability. Note that negative values are unusual, but we are comparing relative values.

**14. Pgp:** Both ligands have very low P-gp efflux liability (A: 0.034, B: 0.033).

**15. Binding Affinity:** Ligand A (-8.9 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:**

Ligand A is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A's significantly improved metabolic stability (lower Cl_mic, longer t1/2) and substantially stronger binding affinity make it a much more promising drug candidate for SRC kinase inhibition. The lower DILI risk is also a positive factor.

Output:
0
2025-04-17 13:35:15,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good absorption, while Ligand B (99.57) is still acceptable but closer to the limit.

**logP:** Ligand A (1.441) is within the optimal 1-3 range. Ligand B (-0.546) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 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 (0.504 and 0.746, respectively), indicating drug-like properties.

**DILI:** Ligand A (29.74) has a significantly lower DILI risk than Ligand B (39.938), which is a major advantage. Both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (63.125) shows slightly better BBB penetration than Ligand A (54.634).

**Caco-2 Permeability:** Ligand A (-4.402) has a *very* poor Caco-2 permeability score. This is a significant red flag. Ligand B (-5.22) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.737 and -1.073 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.397 and 0.092, respectively).

**Microsomal Clearance:** Ligand A (13.282) has slightly lower microsomal clearance than Ligand B (14.292), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.564) has a significantly longer in vitro half-life than Ligand A (-3.623), which is a substantial benefit.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.089 and 0.008, respectively).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a substantially 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:**

While Ligand B has a slightly higher DILI risk and lower logP, its significantly stronger binding affinity (-7.7 vs -9.0 kcal/mol) and substantially longer half-life (11.564 vs -3.623) outweigh these drawbacks. The poor Caco-2 permeability of both is concerning, but the superior potency and metabolic stability of Ligand B make it the more promising candidate. Ligand A's extremely poor Caco-2 permeability is a major issue.

Output:
1
2025-04-17 13:35:15,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (333.439 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.63) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (97.56) is still acceptable, but less optimal.

**logP:** Ligand A (3.007) is optimal. Ligand B (1.115) is a bit low, 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.

**QED:** Both ligands have good QED scores (0.78 and 0.856), indicating good drug-like properties.

**DILI:** Ligand A (35.983) has a lower DILI risk than Ligand B (52.423), which is preferable. Both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.676) is higher than Ligand A (69.833), but this is not a major factor here.

**Caco-2 Permeability:** Ligand A (-5.224) is significantly worse than Ligand B (-4.701), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.943) is slightly better than Ligand B (-2.348), but both are poor.

**hERG:** Ligand A (0.773) has a lower hERG risk than Ligand B (0.074). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (6.342) has a much lower Cl_mic, indicating better metabolic stability, which is crucial for kinase inhibitors. Ligand B (16.687) is considerably higher.

**In vitro Half-Life:** Ligand A (30.323) has a much longer half-life than Ligand B (-1.244), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux liability than Ligand B (0.026), which is favorable.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While the difference is not huge, it's enough to consider given the other favorable properties of Ligand A.

**Overall:**

Ligand A is the stronger candidate. It has a better safety profile (lower DILI, lower hERG), superior metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While Ligand A has poorer Caco-2 permeability and solubility, the benefits in safety and stability outweigh these drawbacks, especially for a kinase inhibitor where potency is already good.

Output:
0
2025-04-17 13:35:15,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.363 and 379.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.89) is slightly above the optimal <140 for good oral absorption, but acceptable. Ligand B (88.16) is well within the optimal range.

**logP:** Both ligands (2.011 and 2.357) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, both acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.621 and 0.835), indicating drug-like properties.

**DILI:** Both ligands have high DILI risk (89.376 and 82.435), which is a concern. However, this can sometimes be mitigated with structural modifications.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (64.831) has a higher BBB percentile than Ligand A (38.465), but this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.888 and -4.924). This is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.514 and -3.721), indicating very poor aqueous solubility. This is a major issue for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.629) has a slightly higher hERG risk than Ligand B (0.323), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (34.456) has a lower microsomal clearance than Ligand B (45.624), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (28.962) has a significantly longer half-life than Ligand A (-9.321). A negative half-life is not physically possible, and indicates a very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.161 and 0.48).

**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, potentially outweighing some ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -9.3 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Additionally, Ligand B has a longer *in vitro* half-life and lower hERG risk. While the DILI risk is high for both, the superior potency and stability of Ligand B make it the better starting point for optimization.

Output:
1
2025-04-17 13:35:15,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.343 Da) is slightly better positioned.

**TPSA:** Both are reasonably good, below the 140 A^2 threshold for oral absorption. Ligand B (102.88 A^2) is better than Ligand A (125.8 A^2).

**logP:** Ligand A (1.212) is optimal (1-3), while Ligand B (0.273) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (1 HBD, 8 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.619, B: 0.68), indicating drug-like properties.

**DILI:** Ligand A (84.917) has a higher DILI risk than Ligand B (70.182), which is preferable.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand B (68.748) shows slightly better penetration than Ligand A (46.568).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.801) is slightly better than Ligand B (-4.82).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.86) is slightly better than Ligand B (-2.651).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.453, B: 0.103), which is excellent. Ligand B is better.

**Microsomal Clearance:** Ligand A (25.107 mL/min/kg) has significantly lower clearance than Ligand B (67.119 mL/min/kg), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (15.921 hours) has a longer half-life than Ligand B (12.689 hours), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.028, B: 0.015), which is good.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). However, the difference is small and may not be significant.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better permeability and solubility, despite the higher DILI risk. Ligand B has better logP, DILI, hERG, and binding affinity. Considering the priorities for an enzyme target (potency, metabolic stability, solubility, hERG), the metabolic stability advantage of Ligand A is crucial. The small difference in binding affinity (-8.6 vs -9.4 kcal/mol) is unlikely to outweigh the substantial difference in metabolic stability.

Output:
0
2025-04-17 13:35:15,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.53 and 353.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (61.88), being well below the 140 threshold for good absorption.

**logP:** Ligand A (3.94) is optimal, while Ligand B (0.57) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.75) is significantly better than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand A (9.23) has a much lower DILI risk than Ligand B (16.13). Both are below the 40 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (94.03) is better than Ligand B (70.88).

**Caco-2:** Both have negative values (-4.50 and -4.44), which is unusual and requires further investigation. However, the absolute values are similar.

**Solubility:** Ligand A (-4.02) is better than Ligand B (-1.18), indicating better aqueous solubility.

**hERG:** Ligand A (0.88) is better than Ligand B (0.37), indicating lower hERG inhibition risk.

**Microsomal Clearance:** Ligand A (51.48) has higher clearance than Ligand B (10.27), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-28.1) has a much longer half-life than Ligand A (-1.32), indicating better *in vitro* stability.

**P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.03), which is favorable.

**Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-7.0). This 1.4 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A having better TPSA, logP, QED, DILI, solubility, hERG, and P-gp efflux, Ligand B's significantly superior binding affinity (-8.4 vs -7.0 kcal/mol) and substantially longer *in vitro* half-life are crucial for an enzyme target like SRC kinase. While Ligand A has a better metabolic profile (lower Cl_mic), the longer half-life of Ligand B mitigates the higher clearance to a degree. The lower logP of Ligand B is a concern, but the strong binding affinity may compensate.

Output:
1
2025-04-17 13:35:15,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.423 and 380.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.63) is slightly above the optimal <140 for oral absorption, while Ligand B (105.31) is well within.

**logP:** Ligand A (0.828) is a bit low, potentially hindering permeation. Ligand B (1.546) is better, falling within the 1-3 range.

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

**QED:** Ligand B (0.847) has a significantly better QED score than Ligand A (0.38), indicating a more drug-like profile.

**DILI:** Ligand A (12.059) has a much lower DILI risk than Ligand B (84.141). This is a significant advantage for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration (53.974 and 58.821 respectively), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.952) is slightly better than Ligand B (-5.125).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand A (-1.035) is slightly better than Ligand B (-2.682).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.097 and 0.194 respectively).

**Microsomal Clearance:** Ligand A (-14.561) has significantly lower (better) microsomal clearance than Ligand B (-0.058), suggesting much greater metabolic stability.

**In vitro Half-Life:** Ligand A (1.998 hours) has a slightly better in vitro half-life than Ligand B (-0.416 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.04 respectively).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity and QED score, which are key for an enzyme inhibitor. However, it has a very high DILI risk and poor metabolic stability (high Cl_mic). Ligand A has a much lower DILI risk and significantly better metabolic stability, but its binding affinity is weaker and QED is low.

The difference in binding affinity (-9.9 vs -8.4 kcal/mol) is 1.5 kcal/mol, which, according to the guidelines, can outweigh minor ADME drawbacks. The high DILI risk of Ligand B is a major concern, and poor metabolic stability can lead to low exposure *in vivo*. While Ligand A's affinity isn't ideal, the significantly improved safety profile and metabolic stability make it the more promising candidate, especially considering optimization could potentially improve its binding.

Output:
0
2025-04-17 13:35:15,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (382.404 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is slightly higher than Ligand B (66.65), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have similar logP values (2.019 and 2.028), 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:** Both ligands have good QED scores (0.745 and 0.839), indicating drug-like properties.

**7. DILI:** Ligand B (27.608) has a significantly lower DILI risk than Ligand A (56.65), placing it in a much more favorable category. This is a substantial advantage.

**8. BBB:** Both have reasonable BBB penetration (82.784 and 76.541). Not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, making it 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 (0.747) has a slightly higher hERG risk than Ligand B (0.099). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand B (31.759) has lower microsomal clearance than Ligand A (38.837), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-12.148) has a negative half-life, which is impossible. This is a major red flag. Ligand A has a half-life of 2.897.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.147 and 0.067).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.7 kcal/mol), which is excellent.

**Conclusion:**

Despite the strange negative values for Caco-2 and solubility, the key differences lie in DILI and metabolic stability. Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). However, the negative in vitro half-life for Ligand B is a critical issue. A negative half-life is not physically possible and suggests a problem with the data or the compound itself. Therefore, despite the advantages of Ligand B in other areas, the data issue makes Ligand A the more viable candidate.

Output:
0
2025-04-17 13:35:15,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.389 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (52.65), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.415 and 1.765), 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 (0.738 and 0.826), indicating good drug-likeness.

**DILI:** Ligand A (56.727) has a higher DILI risk than Ligand B (15.936). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (74.486 and 71.733). This isn't a primary concern for a kinase inhibitor, but it's not detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.14 and -4.904).

**Aqueous Solubility:** Both ligands have negative solubility values (-2.865 and -2.127), which is concerning. Solubility is a key factor for oral bioavailability.

**hERG Inhibition:** Ligand A (0.093) has a slightly lower hERG risk than Ligand B (0.381), which is favorable.

**Microsomal Clearance:** Ligand A (0.019) has significantly lower microsomal clearance than Ligand B (4.303). This suggests much better metabolic stability for Ligand A, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-7.003) has a much longer in vitro half-life than Ligand B (23.125). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.018) has lower P-gp efflux than Ligand B (0.094), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.1) has slightly better binding affinity than Ligand A (-8.1). While a 1.5 kcal/mol difference can be important, the other factors weigh more heavily in this case.

**Conclusion:**

Despite slightly weaker binding affinity, Ligand A is the superior candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux outweigh the minor difference in binding affinity. Both ligands have solubility and permeability issues, but these are less critical than metabolic stability and safety for an enzyme inhibitor.

Output:
0
2025-04-17 13:35:15,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.535 and 362.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (83.04). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal range for permeability.

**logP:** Both ligands have good logP values (2.649 and 2.234), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.8 and 0.749), indicating good drug-likeness.

**DILI:** Ligand A (11.09) has a much lower DILI risk than Ligand B (60.372). This is a significant advantage for Ligand A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (68.592) is slightly better than Ligand B (56.495).

**Caco-2 Permeability:** Ligand A (-4.621) is better than Ligand B (-5.287), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.202) is better than Ligand B (-2.451). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.364) has a lower hERG risk than Ligand B (0.591), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (43.532) has significantly lower microsomal clearance than Ligand B (63.406), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (46.503) has a longer in vitro half-life than Ligand A (4.964). This is a positive for Ligand B, but can be offset by its other weaknesses.

**P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux than Ligand B (0.076), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). This 1.1 kcal/mol difference is notable, but not overwhelming given the other factors.

**Overall Assessment:**

Ligand A demonstrates a superior ADMET profile with lower DILI risk, better solubility, lower hERG risk, and better metabolic stability. While Ligand B has a slightly better binding affinity, the significant advantages of Ligand A in terms of safety and pharmacokinetic properties outweigh this difference.

Output:
0
2025-04-17 13:35:15,590 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (347.5 and 346.5 Da) fall comfortably within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (52.65) is significantly better than Ligand B (67.43).  TPSA < 140 is good for oral absorption, both are under, but A is preferable.

3. **logP:** Both ligands (1.733 and 1.864) are within the optimal 1-3 range. Again, no significant difference.

4. **HBD:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

5. **HBA:** Both ligands have 3 HBA, which is acceptable.

6. **QED:** Both ligands have good QED scores (0.51 and 0.546), indicating drug-like properties.

7. **DILI:** Ligand A (4.886) has a much lower DILI risk than Ligand B (12.485). This is a significant advantage for Ligand A.  A DILI percentile <40 is good, and A is closer to that.

8. **BBB:** Ligand A (79.992) has a better BBB percentile than Ligand B (53.703). While SRC is not necessarily a CNS target, higher BBB is rarely a detriment.

9. **Caco-2:** Both ligands have negative Caco-2 values (-4.87 and -4.905). This is unusual and suggests poor permeability. However, the values are very similar.

10. **Solubility:** Ligand A (-1.131) has better solubility than Ligand B (-2.733). Better solubility is crucial for bioavailability.

11. **hERG:** Ligand A (0.702) has a lower hERG risk than Ligand B (0.336). Lower hERG is preferred.

12. **Cl_mic:** Ligand A (1.6) has significantly lower microsomal clearance than Ligand B (10.277). This indicates better metabolic stability for Ligand A, a key factor for kinase inhibitors.

13. **t1/2:** Ligand A (6.365) has a shorter half-life than Ligand B (22.101). Longer half-life is generally preferred, giving B an advantage here.

14. **Pgp:** Ligand A (0.028) has lower P-gp efflux than Ligand B (0.061). Lower P-gp efflux is favorable for bioavailability.

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, exceeding the 1.5 kcal/mol threshold.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in affinity, DILI, Cl_mic, solubility, and hERG. While Ligand B has a longer half-life, the superior affinity and ADME properties of Ligand A outweigh this single advantage. The negative Caco-2 values are concerning for both, but the overall profile of A is much more promising.

**Conclusion:**

Ligand A is the more viable drug candidate.

1
2025-04-17 13:35:15,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.43 and 359.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.14) is well below the 140 threshold, suggesting good absorption. Ligand B (116.8) is higher but still within an acceptable range, though potentially less favorable.

**logP:** Ligand A (4.89) is high, potentially leading to solubility issues and off-target effects. Ligand B (0.30) is very low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. 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 (0.636 and 0.793), indicating generally drug-like properties.

**DILI:** Ligand A (89.84) has a higher DILI risk than Ligand B (67.00), which is better.

**BBB:** Both have moderate BBB penetration (45.68 and 48.35), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.86) has a very poor Caco-2 permeability. Ligand B (-5.599) is also poor, but slightly better.

**Solubility:** Ligand A (-6.452) has very poor aqueous solubility, a significant drawback. Ligand B (-2.982) is also poor, but better than A.

**hERG:** Ligand A (0.744) has a slightly elevated hERG risk, while Ligand B (0.071) has a very low risk, which is highly desirable.

**Microsomal Clearance:** Ligand A (84.61) has high microsomal clearance, indicating poor metabolic stability. Ligand B (6.80) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (-12.88) has a very short half-life. Ligand B (-0.41) is slightly better, but still short.

**P-gp Efflux:** Ligand A (0.825) has moderate P-gp efflux. Ligand B (0.031) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-9.3) has significantly stronger binding affinity than Ligand B (0.0). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most critical factor for an enzyme inhibitor. However, it suffers from poor solubility, high logP, poor Caco-2 permeability, high DILI risk, high metabolic clearance, and short half-life. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower hERG, lower P-gp efflux, slightly better solubility and permeability) but extremely weak binding affinity.

Despite the ADME concerns, the substantial binding affinity advantage of Ligand A is likely to be more impactful in the early stages of drug development. Optimization efforts could focus on improving its solubility and metabolic stability without sacrificing potency. The weak binding of Ligand B makes it unlikely to be a viable starting point, even with better ADME properties.

Output:
1
2025-04-17 13:35:15,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.47 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold and favorable. Ligand B (76.46) is still under 140, but less optimal than A.

**logP:** Ligand A (3.0) is at the upper end of the optimal range (1-3). Ligand B (1.405) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (1 HBD, 5 HBA) is acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have good QED scores (0.773 and 0.874), indicating good drug-like properties.

**DILI:** Ligand A (36.293) has a lower DILI risk than Ligand B (44.126), which is a significant advantage. Both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a kinase inhibitor, but Ligand A (84.451) has better BBB penetration than Ligand B (71.772).

**Caco-2 Permeability:** Ligand A (-4.579) and Ligand B (-4.83) both have negative values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-4.18) and Ligand B (-2.171) both have negative values, indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.719) has a considerably lower hERG risk than Ligand B (0.152), which is a critical advantage.

**Microsomal Clearance:** Ligand A (34.941) has a higher microsomal clearance than Ligand B (9.82), meaning Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand A (6.359) has a shorter half-life than Ligand B (-10.331), indicating Ligand B is more stable.

**P-gp Efflux:** Ligand A (0.586) has lower P-gp efflux than Ligand B (0.079), which is favorable.

**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 that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has some ADME liabilities (lower solubility, higher P-gp efflux, lower metabolic stability), the potency advantage is significant. Ligand A has better solubility, lower DILI, and lower hERG risk, but its binding affinity is very weak. Given the priority for potency in kinase inhibitors, Ligand B is the more promising candidate, despite its ADME challenges, which can be addressed through further optimization.

Output:
1
2025-04-17 13:35:15,591 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.288 Da and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.93) is better than Ligand B (105.64). Both are acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.924) is optimal, while Ligand B (0.831) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.561 and 0.645), indicating drug-like properties.

**DILI:** Ligand A (75.456) has a significantly higher DILI risk than Ligand B (11.322). This is a major concern for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand A (89.104) is higher than Ligand B (66.344), but this is less important.

**Caco-2 Permeability:** Ligand A (-4.942) is better than Ligand B (-5.747), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.96) is better than Ligand B (-1.461), which is a significant advantage for bioavailability.

**hERG:** Ligand A (0.67) has a lower hERG risk than Ligand B (0.263), which is desirable.

**Microsomal Clearance:** Ligand B (-10.23) has a much lower (better) microsomal clearance than Ligand A (58.136), indicating better metabolic stability. This is a critical advantage.

**In vitro Half-Life:** Ligand B (-5.218) has a longer half-life than Ligand A (-2.173), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.26 and 0.015).

**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.

**Conclusion:**

Despite Ligand A having slightly better Caco-2 permeability and solubility, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.3 vs -7.8 kcal/mol), much lower DILI risk (11.322 vs 75.456), and improved metabolic stability (lower Cl_mic and longer half-life) outweigh the minor advantages of Ligand A. The slightly lower logP of Ligand B is a minor concern compared to the other benefits.

Output:
1
2025-04-17 13:35:15,591 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.491 and 347.434 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (74.33) is higher than Ligand B (54.46). Both are acceptable, but B is better for permeability.

**logP:** Both ligands (2.053 and 2.099) are within the optimal range of 1-3.

**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 (4) are well below the limit of <=10.

**QED:** Both ligands have good QED scores (0.716 and 0.801), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (21.908) has a significantly higher DILI risk than Ligand B (6.669). This is a major concern for Ligand A.

**BBB:** Ligand A (52.036) has a lower BBB penetration percentile than Ligand B (96.743). While not critical for a non-CNS target like SRC, higher BBB is generally a positive attribute.

**Caco-2 Permeability:** Ligand A (-5.107) has worse Caco-2 permeability than Ligand B (-4.705). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.346) has slightly better aqueous solubility than Ligand B (-2.575).

**hERG Inhibition:** Ligand A (0.47) has a lower hERG inhibition liability than Ligand B (0.723), which is favorable.

**Microsomal Clearance:** Ligand A (19.449) and Ligand B (19.805) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand A (59.219) has a significantly longer in vitro half-life than Ligand B (-14.276). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.017) has much lower P-gp efflux liability than Ligand B (0.109), which is favorable.

**Binding Affinity:** Ligand B (-9.2) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B has better overall ADME properties, particularly regarding DILI risk and BBB penetration. However, Ligand A has a significantly longer half-life and lower P-gp efflux. The DILI risk for Ligand A is concerning. While the difference in binding affinity is not substantial, the longer half-life and lower P-gp efflux of Ligand A are attractive. Considering the enzyme-specific priorities, metabolic stability (half-life) and minimizing off-target effects (DILI, hERG) are important.

Despite the slightly better affinity of Ligand B, the significantly lower DILI risk and improved half-life/P-gp profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 13:35:15,591 - INFO - Batch 226 complete. Total preferences: 3616
2025-04-17 13:35:15,591 - INFO - Processing batch 227/512...
2025-04-17 13:35:56,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (373.509 and 363.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (46.61). A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**logP:** Both ligands have similar logP values (4.476 and 4.225), slightly above the optimal 1-3 range, but not drastically so. This could potentially lead to some solubility issues, but is not a major concern.

**H-Bond Donors & Acceptors:** Both have a reasonable number of HBDs (0) and HBAs (3 and 4 respectively), falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.617 and 0.736), indicating good drug-like properties.

**DILI:** Ligand A (11.245) has a much lower DILI risk than Ligand B (48.623). This is a significant advantage for Ligand A.

**BBB:** Both have high BBB penetration (95.308 and 83.482), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.625 and -4.822). This is unusual and suggests poor permeability. However, in this context, it's less critical than other factors.

**Aqueous Solubility:** Both have negative solubility values (-4.913 and -4.663), indicating poor aqueous solubility. This is a potential issue, but can be addressed through formulation.

**hERG Inhibition:** Ligand A (0.734) has a slightly higher hERG risk than Ligand B (0.404), but both are relatively low.

**Microsomal Clearance:** Ligand A (89.184) has a higher microsomal clearance than Ligand B (79.603), meaning it is metabolized faster. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (12.127) has a significantly longer in vitro half-life than Ligand A (-6.118). This is a major advantage for Ligand B, indicating better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.561 and 0.844).

**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 outweighs many of the other drawbacks.

**Conclusion:**

While Ligand A has a better DILI profile and slightly better TPSA, Ligand B's significantly stronger binding affinity (-8.2 vs -7.1 kcal/mol) and longer half-life are critical advantages for an enzyme inhibitor. The lower DILI risk of Ligand A is appealing, but the potency difference is more important. The solubility issues are present in both and can be addressed during formulation.

Output:
1
2025-04-17 13:35:56,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.443 and 371.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.87 and 73.14) below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have logP values (2.694 and 2.507) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2 HBD) and Ligand B (0 HBD) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4 HBA) and Ligand B (7 HBA) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.559 and 0.713), indicating drug-like properties.

**7. DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (41.295). This is a major advantage for Ligand A.

**8. BBB:** While not a primary concern for a non-CNS target like SRC, Ligand B (93.486) has a higher BBB penetration score than Ligand A (66.537).

**9. Caco-2 Permeability:** Ligand A (-5.079) and Ligand B (-4.36) have negative values, which is unusual. Lower (more negative) values indicate poorer permeability. However, the difference isn't substantial.

**10. Aqueous Solubility:** Ligand A (-2.869) and Ligand B (-3.922) have negative values, indicating poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.667 and 0.489), which is favorable.

**12. Microsomal Clearance:** Ligand A (20.652) has a significantly lower microsomal clearance than Ligand B (48.668), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-4.069) has a slightly longer in vitro half-life than Ligand B (-3.597).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.154 and 0.218).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This difference is 0.4 kcal/mol, which is not a huge difference.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in critical ADME properties. Specifically, its significantly lower DILI risk and lower microsomal clearance (better metabolic stability) are major advantages for an enzyme target like SRC kinase. The slightly longer half-life also contributes to its favorability. The solubility is a concern for both, but the other advantages of Ligand A outweigh the small affinity difference.

Output:
0
2025-04-17 13:35:56,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (384.523 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.55) is slightly higher than Ligand B (67.87), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (1.907 and 1.87) within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.786 and 0.688), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (59.48%) compared to Ligand B (10.237%). This is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (70.027%) has better BBB penetration than Ligand A (55.138%).

**Caco-2 Permeability:** Ligand A (-5.382) has worse Caco-2 permeability than Ligand B (-4.782), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.377) has worse aqueous solubility than Ligand B (-1.411). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.205 and 0.237), which is excellent.

**Microsomal Clearance:** Ligand A (15.753) has a higher microsomal clearance than Ligand B (22.613), meaning it's likely less metabolically stable.

**In vitro Half-Life:** Ligand B (4.755) has a significantly shorter in vitro half-life than Ligand A (35.388). While a longer half-life is generally preferred, the metabolic stability issue with Ligand A is more concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.207 and 0.044).

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a slightly better binding affinity than Ligand B (-9.1 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand A, its significantly higher DILI risk, lower solubility, and higher microsomal clearance make it a less desirable candidate. Ligand B, while having a slightly weaker binding affinity, exhibits a much more favorable safety profile (lower DILI), better solubility, and potentially better metabolic stability. For an oncology target, a manageable safety profile is crucial.

Output:
1
2025-04-17 13:35:56,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.423 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.58) is better than Ligand B (89.43). Both are below the 140 threshold for oral absorption, but lower TPSA is generally preferred.

**logP:** Ligand A (2.848) is within the optimal 1-3 range. Ligand B (0.827) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**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. Both are within the acceptable range (<=10).

**QED:** Both ligands have similar QED values (0.775 and 0.763), indicating good drug-likeness.

**DILI:** Ligand A (30.012) has a slightly higher DILI risk than Ligand B (25.165), but both are well below the concerning threshold of 60.

**BBB:** Ligand A (70.997) has a better BBB percentile than Ligand B (67.158), but BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.115) has significantly worse Caco-2 permeability than Ligand B (-4.59). This suggests Ligand A may have poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.539) has slightly better aqueous solubility than Ligand B (-1.93), which is a positive.

**hERG Inhibition:** Ligand A (0.683) has a lower hERG inhibition risk than Ligand B (0.118), a significant advantage.

**Microsomal Clearance:** Ligand A (-10.377) has *much* lower microsomal clearance than Ligand B (29.46). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (36.299) has a longer in vitro half-life than Ligand B (-2.105), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.14) has lower P-gp efflux than Ligand B (0.014), which is favorable.

**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.

**Conclusion:**

Despite Ligand A's slightly worse Caco-2 permeability, its significantly superior binding affinity, metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and lower P-gp efflux make it the more promising drug candidate. The difference in binding affinity is large enough to compensate for the permeability concern.

Output:
1
2025-04-17 13:35:56,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (348.407 and 353.423 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.07) is slightly higher than Ligand B (107.37). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable due to its lower TPSA.

**logP:** Both ligands (-0.415 and -0.125) are relatively low. While not ideal, they are not excessively low that would preclude permeability.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.549 and 0.599), indicating good drug-like properties.

**DILI:** Ligand A (45.25) has a slightly better DILI score than Ligand B (55.176), suggesting a lower risk of liver injury.

**BBB:** Both ligands have similar BBB penetration (54.866 and 51.299), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-6.273) has slightly better Caco-2 permeability than Ligand B (-5.409), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.582) has slightly better aqueous solubility than Ligand B (-1.091).

**hERG:** Both ligands have very low hERG inhibition liability (0.041 and 0.069), which is excellent.

**Microsomal Clearance:** Ligand A (-24.459) has significantly lower (better) microsomal clearance than Ligand B (-3.026), indicating much greater metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-10.896) has a shorter in vitro half-life than Ligand B (22.03). This is a drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.018).

**Binding Affinity:** Both ligands have identical binding affinity (-8.1 kcal/mol), which is excellent and the most important factor.

**Conclusion:**

Despite Ligand B having a slightly better TPSA and in vitro half-life, Ligand A is the superior candidate. The significantly lower microsomal clearance of Ligand A is a major advantage for an enzyme target like SRC kinase, indicating greater metabolic stability and potentially longer duration of action. The slightly better solubility and Caco-2 permeability also contribute to its favorability. The binding affinity is identical, so the ADME properties are the deciding factors.

Output:
1
2025-04-17 13:35:56,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (355.463 Da) is within the ideal range (200-500 Da). Ligand B (557.054 Da) is above this range, which could impact permeability.

**TPSA:** Ligand A (62.3) is well below the 140 threshold for oral absorption. Ligand B (112.4) is still acceptable, but less optimal.

**logP:** Ligand A (2.884) is within the optimal range (1-3). Ligand B (5.932) is significantly higher, potentially causing solubility issues and off-target interactions.

**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 could slightly reduce permeability.

**QED:** Ligand A (0.839) is excellent, indicating high drug-likeness. Ligand B (0.218) is poor, suggesting significant issues with its overall drug-like properties.

**DILI:** Ligand A (72.586) has a moderate DILI risk, but is acceptable. Ligand B (85.925) has a higher DILI risk, which is concerning.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.462) is decent, while Ligand B (19.814) is low.

**Caco-2 Permeability:** Ligand A (-4.926) is poor. Ligand B (-5.386) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.332) is poor. Ligand B (-5.551) is even worse. Solubility is a significant concern for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.338) has very low hERG risk, which is excellent. Ligand B (0.893) has a slightly elevated hERG risk, but is still acceptable.

**Microsomal Clearance:** Ligand A (56.254) is good, indicating reasonable metabolic stability. Ligand B (78.436) is higher, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (9.588 hours) is good. Ligand B (156.03 hours) is excellent.

**P-gp Efflux:** Ligand A (0.287) has low P-gp efflux, which is favorable. Ligand B (0.945) has higher P-gp efflux, potentially reducing bioavailability.

**Binding Affinity:** Ligand B (-8.9 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 the most important factor for an enzyme inhibitor. However, it suffers from a high molecular weight, poor solubility, high logP, and higher DILI risk. Ligand A has better ADME properties (MW, TPSA, logP, solubility, DILI, P-gp), but its binding affinity is very weak.

Despite the ADME concerns with Ligand B, the substantial difference in binding affinity (-8.9 vs -0.0 kcal/mol) is likely to outweigh the drawbacks, *provided* the solubility issues can be addressed through formulation strategies. The poor Caco-2 permeability is also a concern, but less critical than the binding affinity. Ligand A's weak binding affinity makes it unlikely to be a viable candidate, even with better ADME properties.

Output:
1
2025-04-17 13:35:56,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (337.47 and 346.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (28.6) is significantly better than Ligand B (132.75). A TPSA under 140 is good for oral absorption, but Ligand B's value is quite high, potentially hindering absorption.

**logP:** Ligand A (3.382) is optimal (1-3). Ligand B (0.234) is quite low, potentially causing permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 8 HBA). Both are within acceptable ranges, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.858) has a better QED score than Ligand B (0.657), indicating a more drug-like profile.

**DILI:** Ligand A (14.39) has a much lower DILI risk than Ligand B (63.75), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (97.67) is higher than Ligand B (58.12), but this is not a major factor in this case.

**Caco-2 Permeability:** Ligand A (-4.504) is better than Ligand B (-5.785), indicating better intestinal absorption.

**Aqueous Solubility:** Both are very poor (-2.341 and -2.709). This is a concern for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.949) has a lower hERG risk than Ligand B (0.037), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (47.98) is higher than Ligand B (11.53), indicating faster clearance and lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-13.46) has a longer half-life than Ligand A (-26.42), a significant advantage.

**P-gp Efflux:** Ligand A (0.338) has lower P-gp efflux than Ligand B (0.015), which is favorable.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks of Ligand A. The difference of 2.6 kcal/mol is substantial.

**Conclusion:**

Despite Ligand A's higher microsomal clearance, its significantly better binding affinity (-9.3 vs -6.7 kcal/mol), lower DILI risk, lower hERG risk, and better QED score make it the more promising drug candidate. The strong binding affinity is a key driver, and the other advantages mitigate the metabolic stability concern.

Output:
1
2025-04-17 13:35:56,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.383 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.86) is well below the 140 threshold, while Ligand B (104.81) is still acceptable but closer to the limit.

**logP:** Ligand A (2.21) is optimal (1-3). Ligand B (-0.038) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (5) meet the <=10 criteria.

**QED:** Ligand A (0.859) has a significantly better QED score than Ligand B (0.533), indicating a more drug-like profile.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (35.673). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.758) is slightly better than Ligand B (53.276).

**Caco-2:** Ligand A (-4.471) and Ligand B (-5.091) 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 (-4.036) and Ligand B (-1.543) both have negative solubility values, suggesting poor aqueous solubility. Again, the scale is unclear.

**hERG:** Ligand A (0.69) has a lower hERG risk than Ligand B (0.129), which is a significant advantage.

**Microsomal Clearance:** Ligand A (35.665) has a higher microsomal clearance than Ligand B (16.967), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-14.164) has a negative half-life, which is impossible and likely indicates an issue with the data. Ligand B (-16.966) also has a negative half-life.

**P-gp Efflux:** Both ligands (0.151 and 0.018) have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-10.7 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.

**Conclusion:**

Despite Ligand A's better QED and lower hERG risk, Ligand B is the more promising candidate due to its *much* stronger binding affinity (-10.7 vs -7.8 kcal/mol). The difference in affinity is likely to outweigh the slightly higher DILI risk and lower QED. The negative half-life values for both compounds are concerning and require further investigation, but the affinity difference is the most critical factor in this initial comparison.

Output:
1
2025-04-17 13:35:56,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.455 and 354.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (99.5 and 93.22) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.544) is within the optimal 1-3 range. Ligand B (0.198) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern at this stage.

**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 (0.824) has a significantly higher QED score than Ligand B (0.517), indicating better overall drug-likeness.

**DILI:** Ligand A (53.858) has a slightly higher DILI risk than Ligand B (42.536), but both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (75.301) is higher than Ligand B (39.511), but this is less important.

**Caco-2 Permeability:** Both are negative (-4.589 and -4.409), which is unusual and requires further investigation. It's difficult to interpret these values without knowing the scale.

**Aqueous Solubility:** Both are negative (-2.159 and -1.094), again, unusual and requiring further investigation.

**hERG Inhibition:** Ligand A (0.559) has a slightly higher hERG risk than Ligand B (0.052). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (-5.85) has a *much* lower (better) microsomal clearance than Ligand B (20.029). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (23.046) has a much longer half-life than Ligand B (-9.103). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux than Ligand B (0.033), which is favorable.

**Binding Affinity:** Ligand A (-8.0) has a stronger binding affinity than Ligand B (-6.6). This is a crucial advantage, as a 1.4 kcal/mol difference can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand B having a slightly lower hERG risk, Ligand A is the superior candidate. The significantly stronger binding affinity (-8.0 vs -6.6 kcal/mol), much better metabolic stability (lower Cl_mic and longer t1/2), and higher QED score outweigh the slightly higher DILI and hERG risk. The negative Caco-2 and Solubility values are concerning for both, but the potency and metabolic stability of Ligand A are more critical for an enzyme target like SRC.

Output:
1
2025-04-17 13:35:56,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.395 and 344.411 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.23) is better than Ligand B (66.92) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.993 and 1.589), falling within the 1-3 optimal range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 0 HBDs, which is good. Ligand A has 5 HBAs and Ligand B has 4 HBAs, both are acceptable.

**QED:** Both ligands have similar QED values (0.772 and 0.778), indicating good drug-likeness.

**DILI:** Ligand B (34.393) has a significantly lower DILI risk than Ligand A (60.178). This is a major advantage for Ligand B.

**BBB:** Ligand B (86.002) has better BBB penetration than Ligand A (61.768), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.368 and -4.353), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.079 and -2.211), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.662) has a slightly higher hERG inhibition liability than Ligand B (0.368), making Ligand B preferable.

**Microsomal Clearance:** Ligand B (30.946) has a significantly lower microsomal clearance than Ligand A (60.958), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-10.692) has a longer in vitro half-life than Ligand A (-9.433), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.32) has lower P-gp efflux liability than Ligand B (0.12), which is slightly better.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and P-gp efflux, Ligand B demonstrates significantly better ADMET properties: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG inhibition, and better BBB penetration. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are critical. The small difference in binding affinity is outweighed by the substantial improvements in ADMET properties for Ligand B. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:35:56,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.706 and 387.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (99.81 and 91.76) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.888 and 1.229), falling within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7 HBA. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.805) has a significantly better QED score than Ligand B (0.684), indicating a more drug-like profile.

**DILI:** Ligand A (87.864) has a higher DILI risk than Ligand B (66.421), which is a concern. However, Ligand B is still above the 60 threshold, indicating a moderate risk.

**BBB:** Ligand A (48.391) has a lower BBB penetration percentile than Ligand B (17.72). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Ligand A (-4.83) has a worse Caco-2 permeability than Ligand B (-5.067). Both are poor.

**Aqueous Solubility:** Ligand A (-4.387) has a worse aqueous solubility than Ligand B (-2.833). Both are poor.

**hERG Inhibition:** Ligand A (0.157) has a lower hERG inhibition risk than Ligand B (0.328), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-2.315) has a much lower (better) microsomal clearance than Ligand B (16.161), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.25 hours) has a better in vitro half-life than Ligand B (-6.101 hours).

**P-gp Efflux:** Ligand A (0.098) has a lower P-gp efflux liability than Ligand B (0.142), which is favorable.

**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, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a higher DILI risk, its significantly superior binding affinity (-8.7 vs 0 kcal/mol), better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better QED outweigh the DILI concern. The difference in binding affinity is substantial and likely to be critical for efficacy. The solubility and Caco-2 permeability are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:35:56,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (388.6 and 362.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is slightly higher than Ligand B (56.75). Both are below the 140 threshold for oral absorption, but not particularly optimized for CNS penetration (which requires <90). This isn't a primary concern for a non-CNS target like SRC.

**logP:** Both ligands have similar logP values (2.028 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 good QED scores (0.783 and 0.826), indicating good drug-like properties.

**DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (57.348). This is a major advantage for Ligand A.

**BBB:** Ligand B (85.731) has a higher BBB penetration percentile than Ligand A (45.909). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.963 and -4.625), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.57 and -2.879), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Ligand A (0.148) has a much lower hERG inhibition liability than Ligand B (0.568), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (59.507) has a higher microsomal clearance than Ligand A (37.383), meaning Ligand A is likely more metabolically stable. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-3.373) has a slightly longer in vitro half-life than Ligand B (-0.72).

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux liability than Ligand B (0.245), suggesting better oral bioavailability.

**Binding Affinity:** Ligand A (-7.6) has a better binding affinity than Ligand B (0.0). The difference in binding affinity is substantial.

**Overall Assessment:**

Ligand A is the superior 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, lower hERG risk, lower P-gp efflux, and *much* stronger binding affinity. The substantial difference in binding affinity (-7.6 vs 0.0 kcal/mol) is the most critical factor, and can potentially compensate for the solubility and permeability issues.

Output:
1
2025-04-17 13:35:56,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (448.308 Da) is higher, but still acceptable. Ligand B (337.471 Da) is lower, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values (51.02 and 57.74) well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have logP values 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 isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have low HBD counts (0) and acceptable HBA counts (4 and 5 respectively), suggesting good permeability potential.

**QED:** Both ligands have good QED scores (0.565 and 0.791), indicating a generally drug-like profile.

**DILI:** Ligand A has a significantly higher DILI risk (59.17%) than Ligand B (32.183%). This is a major concern for Ligand A.

**BBB:** Both have acceptable BBB penetration scores (79.217 and 74.292), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.889 and -4.874), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.085 and -4.917), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both have low hERG inhibition liability (0.847 and 0.695), which is positive.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (98.355) than Ligand B (56.796), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a negative in vitro half-life (-2.915), which is concerning. Ligand A has a much better half-life (103.49).

**P-gp Efflux:** Both have low P-gp efflux liability (0.571 and 0.335).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-7.1 kcal/mol) compared to Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly better binding affinity outweighs the slightly higher logP and the negative half-life. Ligand A's high DILI risk and higher microsomal clearance are major drawbacks. The improved potency of Ligand B is crucial for an enzyme target like SRC.

Output:
1
2025-04-17 13:35:56,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.419 and 362.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.23) is slightly above the preferred <90 for CNS penetration, but acceptable for a non-CNS target. Ligand B (78.43) is well within the ideal range.

**logP:** Both ligands have good logP values (0.916 and 1.748), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (3 HBD, 3 HBA) both have acceptable numbers of hydrogen bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have similar QED values (0.643 and 0.646), indicating good drug-likeness.

**DILI:** Ligand A (60.217) has a higher DILI risk than Ligand B (13.416). This is a significant concern.

**BBB:** Both ligands have good BBB penetration (79.488 and 70.997), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.763 and -4.983), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.135 and -2.518), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.057) has a very low hERG inhibition risk, which is excellent. Ligand B (0.398) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-11.531) exhibits significantly lower microsomal clearance than Ligand B (13.43), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (8.575) has a slightly longer in vitro half-life than Ligand B (-11.256).

**P-gp Efflux:** Ligand A (0.08) has lower P-gp efflux liability than Ligand B (0.032), which is favorable.

**Binding Affinity:** Ligand B (-9.1 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 concerns.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. The substantially stronger binding affinity (-9.1 vs -6.9 kcal/mol) is a major advantage for an enzyme target. While Ligand A has better metabolic stability (lower Cl_mic) and lower DILI risk, the affinity difference is too significant to ignore. The slightly higher DILI risk of Ligand B could be addressed with further structural modifications. The solubility and permeability issues of both compounds would need to be addressed during lead optimization.

Output:
1
2025-04-17 13:35:56,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.357 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.01) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.601) is within the optimal 1-3 range, while Ligand B (3.276) is at the higher end, potentially leading to solubility issues.

**H-Bond Donors:** Both 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.

**QED:** Both ligands have similar QED values (0.712 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (31.485) has a significantly lower DILI risk than Ligand B (14.889), which is a major advantage.

**BBB:** Ligand A (94.455) shows better BBB penetration than Ligand B (73.401), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.676) has a worse Caco-2 permeability than Ligand B (-4.825), but both are poor.

**Aqueous Solubility:** Ligand A (-2.39) has better solubility than Ligand B (-4.098).

**hERG Inhibition:** Ligand A (0.689) has a lower hERG risk than Ligand B (0.46), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-1.494) has a lower (better) microsomal clearance than Ligand B (69.006), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.06) has a longer half-life than Ligand B (0.883).

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux than Ligand B (0.318), which is favorable.

**Binding Affinity:** Ligand B (-8.7) 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 is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties, particularly regarding DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and solubility. These factors are crucial for developing a viable drug candidate, especially for an enzyme target where metabolic stability and minimizing off-target effects are paramount. The small difference in binding affinity is outweighed by the substantial improvements in safety and pharmacokinetic properties of Ligand A.

Output:
1
2025-04-17 13:35:56,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.503 and 352.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.18) is better than Ligand B (111.47). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (2.557) is within the optimal 1-3 range. Ligand B (-1.168) is significantly lower, potentially hindering permeability.

**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 (6 and 8, respectively), below the threshold of 10.

**QED:** Both ligands have good QED values (0.439 and 0.627), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have similar DILI risk (59.364 and 57.154), both are acceptable.

**BBB:** Both ligands have moderate BBB penetration (51.066 and 61.535). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.116 and -5.394). This is unusual and suggests poor permeability *in vitro*, but could be due to experimental artifacts.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.702 and -1.251). This is also concerning, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.213 and 0.023), which is excellent.

**Microsomal Clearance:** Ligand A (57.584) has higher clearance than Ligand B (-1.951). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-3.214) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (22.964) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.214 and 0.024).

**Binding Affinity:** Both ligands have strong binding affinities (-7.8 and -7.6 kcal/mol), both are good. Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and TPSA, but suffers from a nonsensical negative half-life and higher microsomal clearance. Ligand B has a better logP, QED, and significantly better metabolic stability (lower Cl_mic, positive t1/2). The solubility is poor for both, but can be addressed with formulation strategies. Given the importance of metabolic stability for kinase inhibitors, and the questionable half-life of Ligand A, Ligand B is the more promising candidate.

Output:
1
2025-04-17 13:35:56,810 - INFO - Batch 227 complete. Total preferences: 3632
2025-04-17 13:35:56,810 - INFO - Processing batch 228/512...
2025-04-17 13:36:39,655 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (347.434 and 376.551 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.3) is better than Ligand B (47.09) as it is closer to the threshold of 140, indicating better potential for oral absorption.

**3. logP:** Ligand A (2.71) is optimal, while Ligand B (4.053) is approaching the upper limit and could potentially cause solubility issues or off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0) as it strikes a better balance between solubility and permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (7), as it is closer to the ideal threshold of 10.

**6. QED:** Ligand A (0.833) is significantly better than Ligand B (0.555), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (42.071 and 45.328, both < 60).

**8. BBB:** This is less critical for an oncology target. Ligand A (83.831) is better than Ligand B (74.874).

**9. Caco-2 Permeability:** Ligand A (-4.542) is better than Ligand B (-5.551), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.051) is better than Ligand B (-3.656).

**11. hERG Inhibition:** Ligand A (0.477) is better than Ligand B (0.79), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (55.853) is better than Ligand B (64.605), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.934) is better than Ligand B (35.838), indicating a longer half-life.

**14. P-gp Efflux:** Ligand A (0.12) is better than Ligand B (0.625), indicating lower P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-9.1). 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 across most critical ADME properties, including QED, solubility, metabolic stability, and efflux. While Ligand B has a slightly better binding affinity, the superior overall profile of Ligand A makes it the more promising drug candidate for an enzyme target in oncology.

Output:
0
2025-04-17 13:36:39,655 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.343 and 354.416 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.79) is well within the desirable range for oral absorption (<140). Ligand B (33.2) is excellent, suggesting good absorption.

**logP:** Ligand A (0.241) is quite low, potentially hindering membrane permeability. Ligand B (4.671) is slightly high, 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, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.769 and 0.667), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.397, which is moderately high. Ligand B has a much lower DILI risk (24.544), a significant advantage.

**BBB:** Ligand A has a BBB penetration of 36.293, which is low. Ligand B has a high BBB penetration (92.051), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.284), indicating very poor permeability. Ligand B has a negative value as well (-4.511), but slightly better than A.

**Aqueous Solubility:** Ligand A has very poor solubility (-1.957). Ligand B also has poor solubility (-4.698), but is still better than A.

**hERG Inhibition:** Ligand A has a low hERG risk (0.093), which is excellent. Ligand B has a slightly higher hERG risk (0.712), but it's still relatively low.

**Microsomal Clearance:** Ligand A has a low Cl_mic (2.766 mL/min/kg), indicating good metabolic stability. Ligand B has a significantly higher Cl_mic (64.995 mL/min/kg), suggesting rapid metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A has a very short half-life (-26.7 hours), which is concerning. Ligand B has a short half-life (3.649 hours), but is better than A.

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.01), which is favorable. Ligand B has a moderate P-gp efflux (0.493).

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a major advantage, and could potentially overcome some of its ADME liabilities.

**Conclusion:**

Despite Ligand B's higher logP and faster clearance, its *much* stronger binding affinity (-7.0 vs -9.1 kcal/mol) and significantly lower DILI risk are decisive. The improved binding affinity is a substantial advantage for an enzyme inhibitor. While Ligand A has better hERG and P-gp properties, the poor solubility, permeability, and half-life are major drawbacks.

Output:
1
2025-04-17 13:36:39,655 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.419 and 341.415 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.27) is slightly higher than Ligand B (91.81), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.004 and 1.384), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 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 (0.808 and 0.784), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (51.648 and 50.136 percentile).

**BBB:** Ligand A (57.425) has a higher BBB penetration score than Ligand B (29.934). However, BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.472 and -5.302). This is unusual and suggests poor permeability. However, these values are on the same scale, so this isn't a differentiating factor.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.415 and -3.199). This is also unusual and suggests poor solubility. Again, similar for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.249 and 0.284), which is excellent.

**Microsomal Clearance:** This is a key difference. Ligand A has a Cl_mic of 29.506 mL/min/kg, while Ligand B has a significantly lower Cl_mic of -16.394 mL/min/kg. Lower Cl_mic indicates better metabolic stability, which is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand B (20.208 hours) has a much longer half-life than Ligand A (5.132 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.044).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While both are good, the 0.6 kcal/mol difference is significant and could outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While both ligands have similar molecular properties in many areas, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic, longer half-life) and slightly better binding affinity. These are critical factors for kinase inhibitors. The negative Caco-2 and solubility values are concerning for both, but the improved metabolic profile of Ligand B makes it the better choice for further optimization.

Output:
1
2025-04-17 13:36:39,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (73.74), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.486 and 1.849), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.852 and 0.799), indicating good drug-likeness.

**DILI:** Ligand A (22.257) has a significantly lower DILI risk than Ligand B (16.014). This is a major advantage.

**BBB:** Ligand A (76.347) has a higher BBB percentile than Ligand B (55.06), but BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.365) has a worse Caco-2 permeability than Ligand B (-4.848). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.274) has a better aqueous solubility than Ligand B (-1.643).

**hERG:** Both ligands have very low hERG inhibition liability (0.166 and 0.104), which is excellent.

**Microsomal Clearance:** Ligand A (35.731) has a higher microsomal clearance than Ligand B (20.465), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-8.749) has a significantly longer in vitro half-life than Ligand A (17.669). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.121 and 0.037).

**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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a substantially better binding affinity and lower DILI risk, and better solubility. However, it has a higher microsomal clearance and shorter half-life, and lower Caco-2 permeability. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, but a higher DILI risk and significantly weaker binding affinity.

Given the enzyme-kinase focus, potency (binding affinity) is paramount. The 2.1 kcal/mol difference in binding affinity is significant. While Ligand B's improved metabolic stability is desirable, the superior potency of Ligand A is likely to be more impactful, especially in early stages of development where optimization can address the metabolic stability issues. The lower DILI risk of Ligand A is also a significant benefit.

Output:
1
2025-04-17 13:36:39,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.402 and 364.486 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.992 and 2.007) within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.614 and 0.78), indicating good drug-like properties.

**DILI:** Ligand B (27.22) has a significantly lower DILI risk than Ligand A (35.13). This is a major advantage for Ligand B.

**BBB:** Ligand B (86.119) has a much higher BBB penetration percentile than Ligand A (59.248). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.757) and Ligand B (-5.067) both have negative Caco-2 values, 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 very poor aqueous solubility (-4.015 and -3.302). This is a significant concern for both, but slightly better for Ligand B.

**hERG Inhibition:** Ligand A (0.239) has a slightly higher hERG inhibition liability than Ligand B (0.431), meaning Ligand B is slightly safer regarding cardiotoxicity.

**Microsomal Clearance:** Ligand B (26.083) has a much lower microsomal clearance than Ligand A (63.451), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-6.9) has a significantly longer in vitro half-life than Ligand A (-4.263). This is another significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.133), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a decisive advantage, as potency is a primary concern for enzyme inhibitors. The difference of 1 kcal/mol is substantial.

**Conclusion:**

Ligand B is the superior candidate. While both have poor solubility and permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and, most importantly, a substantially stronger binding affinity. The binding affinity difference outweighs the slight disadvantage in P-gp efflux.

Output:
1
2025-04-17 13:36:39,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.348 and 376.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.51 and 75.19) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.025) is slightly lower than optimal (1-3), while Ligand B (2.902) is well within the optimal range.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 1 HBD, also good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.736 and 0.841), suggesting good drug-like properties.

**DILI:** Ligand A (37.611) has a lower DILI risk than Ligand B (72.819), which is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**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 should be interpreted with caution.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, caution is needed with this scale.

**hERG:** Ligand A (0.069) has a much lower hERG risk than Ligand B (0.299), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-1.499) has a *negative* microsomal clearance, which is highly unusual and suggests exceptional metabolic stability. Ligand B (31.465) has a high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (-29.36) has a negative half-life, which is also unusual, but consistent with the negative clearance. Ligand B (10.411) has a moderate half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.012 and 0.177).

**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.

**Overall Assessment:**

Ligand B has a better logP and significantly higher binding affinity. However, Ligand A exhibits far superior ADMET properties: much lower DILI risk, significantly lower hERG risk, and exceptionally high metabolic stability (negative clearance and half-life). The negative values for clearance and half-life are concerning and require further investigation, but they strongly suggest a very stable molecule. The lower affinity of Ligand A is a drawback, but the ADMET advantages are substantial, especially the hERG and DILI profiles. Given the enzyme-specific priorities, the metabolic stability and safety profile of Ligand A are highly attractive. The difference in binding affinity (2.4 kcal/mol) is significant, but not insurmountable with further optimization, and could be offset by the improved pharmacokinetic properties.

Output:
0
2025-04-17 13:36:39,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.455 and 382.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.97) is slightly above the preferred <140, but acceptable. Ligand B (49.41) is well within the ideal range.

**logP:** Ligand A (1.704) is optimal. Ligand B (4.664) is a bit high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is good. Ligand B (1 HBD, 3 HBA) is also good. Both are within the recommended limits.

**QED:** Both ligands have similar QED scores (0.494 and 0.424), indicating moderate drug-likeness.

**DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (28.383), which is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (79.294) has a higher score than Ligand A (63.009).

**Caco-2 Permeability:** Both ligands have very similar, and poor, Caco-2 permeability scores (-4.972 and -4.961).

**Aqueous Solubility:** Both ligands have poor aqueous solubility scores (-2.387 and -3.569).

**hERG:** Both ligands have similar, and acceptable, hERG inhibition liability scores (0.619 and 0.838).

**Microsomal Clearance:** Ligand A (27.366) has significantly lower microsomal clearance than Ligand B (52.864), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (52.262) has a longer in vitro half-life than Ligand B (-2.668), further supporting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.728).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-10.6 and -10.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. While both have poor solubility and permeability, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The slightly higher logP of Ligand B is a concern. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity (DILI) are crucial.

Output:
0
2025-04-17 13:36:39,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.438 Da and 384.933 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.12) is slightly higher than Ligand B (67.23), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (2.275 and 2.26), 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 (0.672 and 0.764), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (49.864 and 47.693 percentiles), which is favorable.

**BBB:** Ligand A has a significantly higher BBB penetration percentile (77.976) compared to Ligand B (31.912). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.925 and -5.025). This is unusual and suggests poor permeability. However, these values are on a log scale and could represent very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.277 and -3.697), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.526 and 0.089 percentiles), which is excellent.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (13.962 mL/min/kg) than Ligand B (56.629 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (11.506 hours) than Ligand B (8.653 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.074 percentiles), which is favorable.

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.7 kcal/mol) compared to Ligand A (-8.4 kcal/mol). While the difference is small (0.3 kcal/mol), it's within the range where it could outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand B** is slightly more promising. The marginal improvement in binding affinity (-8.7 vs -8.4 kcal/mol) is a significant advantage for an enzyme target like SRC kinase. While both ligands have poor solubility and permeability, the better metabolic stability (lower Cl_mic and longer t1/2) of Ligand A is appealing. However, the slightly stronger binding of Ligand B tips the balance. Further optimization would be needed to address the solubility and permeability issues for either compound.

Output:
1
2025-04-17 13:36:39,657 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.379 Da and 335.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.25) is higher than Ligand B (27.3). While both are reasonably low, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have good logP values (3.39 and 3.799), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.666 and 0.806), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 77.045, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 11.594, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (97.945) has a higher BBB score than Ligand A (65.452), but this is not a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates poor permeability.

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

**hERG:** Ligand A (0.576) has a slightly better hERG profile than Ligand B (0.981), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (128.705) has a higher microsomal clearance than Ligand B (23.766). This suggests Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (54.755) has a significantly longer in vitro half-life than Ligand A (-11.554), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.46) has lower P-gp efflux than Ligand B (0.217), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.5 kcal/mol). Ligand B is slightly better, but the difference is small.

**Conclusion:**

Despite similar binding affinities, Ligand B is the superior candidate. Its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and improved TPSA outweigh the slightly better hERG and P-gp efflux profiles of Ligand A. The poor solubility and permeability of both compounds are concerns that would need to be addressed in subsequent optimization, but the ADME profile of Ligand B is far more promising.

Output:
1
2025-04-17 13:36:39,657 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.297 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.59) is higher than Ligand B (58.2). While both are below 140, Ligand B's lower TPSA is preferable for absorption.

**logP:** Ligand A (2.85) is within the optimal 1-3 range. Ligand B (4.103) is slightly higher, potentially leading to solubility issues and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA). Ligand B's lower count is slightly more favorable for permeability.

**QED:** Both ligands have good QED scores (0.543 and 0.71), 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 (26.948), making it much more attractive from a safety perspective.

**BBB:** Both have reasonable BBB penetration (75.998 and 72.625), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.703 and -4.54). This 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 (-5.311 and -5.001), indicating poor solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.8) has a slightly higher hERG risk than Ligand B (0.306), which is preferable.

**Microsomal Clearance:** Ligand A (62.612) has lower microsomal clearance than Ligand B (72.962), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.536 hours) has a significantly longer half-life than Ligand A (9.198 hours), which is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.461 and 0.171), which is good.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.6 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and permeability, Ligand B has a significantly lower DILI risk, a longer half-life, and slightly better binding affinity. The lower DILI risk is a critical factor, and the improved half-life is a substantial benefit. The slightly higher logP of Ligand B is a minor concern compared to the significant safety advantage.

Output:
1
2025-04-17 13:36:39,657 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.435 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (71.87 and 70.08) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.048) is optimal, while Ligand B (1.127) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands are acceptable. Ligand A has 0 HBD, and Ligand B has 1 HBD, both are within the limit of 5.

**5. H-Bond Acceptors:** Both ligands are acceptable. Ligand A has 6 HBA, and Ligand B has 4 HBA, both are within the limit of 10.

**6. QED:** Both ligands have good QED scores (0.682 and 0.827), indicating drug-like properties.

**7. DILI:** Ligand A (68.166) has a higher DILI risk than Ligand B (20.706). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (81.698) is significantly better than Ligand A (70.143). While not a primary concern for a kinase inhibitor, better BBB penetration could be beneficial.

**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. Again, the scale is undefined.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.338 and 0.383), which is excellent.

**12. Microsomal Clearance:** Ligand B (35.958) has lower microsomal clearance than Ligand A (40.857), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (-6.896) has a longer in vitro half-life than Ligand A (3.548), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.121 and 0.111).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand B is the more promising candidate. It exhibits significantly lower DILI risk and better metabolic stability (lower Cl_mic and longer t1/2) compared to Ligand A. While Ligand A has a slightly better logP, the lower DILI and improved metabolic properties of Ligand B are more critical for a kinase inhibitor. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B make it preferable.

Output:
1
2025-04-17 13:36:39,657 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 Da and 364.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.61) is higher than Ligand B (72.87). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Ligand A (-0.522) is quite low, potentially hindering permeability. Ligand B (2.753) 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 even better, potentially improving permeability.

**H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (8) is also within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.403 and 0.826 respectively), with Ligand B being significantly better.

**DILI:** Ligand A (22.838) has a much lower DILI risk than Ligand B (55.68). This is a strong positive for Ligand A.

**BBB:** Both ligands have similar BBB penetration (66.809 and 66.499). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.928 and -5.456), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without more context.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.344 and -4.044), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.037) shows very low hERG inhibition risk, which is excellent. Ligand B (0.277) has a slightly higher, but still relatively low, risk.

**Microsomal Clearance:** Ligand A (-20.589) has a much lower (better) microsomal clearance than Ligand B (75.719), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-12.743) has a negative half-life, which is not possible. This is a data error. Ligand B (0.951) has a very short half-life, which is undesirable.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is favorable. Ligand B (0.348) has slightly higher efflux.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-6.5). The difference is 1.5 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. However, its logP is very low, potentially causing permeability issues. Its half-life is also an impossible value. Ligand B has a better logP and QED, but suffers from higher DILI risk, poor metabolic stability, and a very short half-life.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), and the significant advantage in binding affinity for Ligand A, I would initially favor Ligand A *if* the half-life value is corrected. The low logP is a concern, but could potentially be addressed with formulation strategies. The DILI risk is also low. The erroneous half-life is a significant red flag, however. Assuming the half-life is a data error, and can be corrected, Ligand A is the better candidate.

Output:
1
2025-04-17 13:36:39,658 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.359 Da and 370.425 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (63.17) is better than Ligand B (66.71), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.579 and 1.209 respectively), falling within the optimal 1-3 range. Ligand A is slightly higher, which might be beneficial for membrane permeability, but not excessively high.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. 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 scores (0.717 and 0.859), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (51.493 and 50.989), both are below the 60 threshold and are considered good.

**BBB:** Ligand A has a significantly higher BBB penetration percentile (94.649) compared to Ligand B (78.558). While not a primary concern for a kinase inhibitor, higher BBB penetration could be advantageous if off-target effects in the CNS are a concern.

**Caco-2 Permeability:** Ligand A (-4.778) has worse Caco-2 permeability than Ligand B (-5.004). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.082) has worse solubility than Ligand B (-1.751). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.694 and 0.602), which is excellent.

**Microsomal Clearance:** Ligand B (16.155) has significantly lower microsomal clearance than Ligand A (42.402). Lower clearance indicates better metabolic stability, a critical factor for enzyme inhibitors.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (-2.012 and -1.827).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.039).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand B is more promising. While Ligand A has slightly better TPSA and BBB, Ligand B has significantly better solubility and, crucially, much better metabolic stability (lower Cl_mic). For an enzyme inhibitor, metabolic stability is paramount. The slightly lower Caco-2 permeability of Ligand B is less concerning than the higher clearance of Ligand A. The binding affinities are essentially the same.

Output:
1
2025-04-17 13:36:39,658 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.523 and 366.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (111.95). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand A is much more favorable.

**logP:** Ligand A (3.783) is optimal, while Ligand B (0.942) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but lower counts are generally preferred for better permeability.

**QED:** Both ligands have reasonable QED scores (0.839 and 0.778), indicating good drug-like properties.

**DILI:** Ligand A (37.999) has a lower DILI risk than Ligand B (64.599), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.084) is better than Ligand B (60.644).

**Caco-2 Permeability:** Both are negative (-5.072 and -5.025), which is unusual and suggests poor permeability. However, this is a scale and the meaning of negative values isn't clear without more context.

**Aqueous Solubility:** Both are negative (-4.318 and -3.709), again suggesting poor solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.504) has a much lower hERG risk than Ligand B (0.272), which is a critical safety parameter.

**Microsomal Clearance:** Ligand A (51.527) has a higher Cl_mic than Ligand B (2.585), meaning it's cleared more quickly. This is a disadvantage.

**In vitro Half-Life:** Ligand A (-9.378) has a negative half-life, which is concerning. Ligand B (0.759) is better, but still relatively low.

**P-gp Efflux:** Ligand A (0.38) is better than Ligand B (0.038), indicating less efflux and potentially better bioavailability.

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having better TPSA, logP, DILI, hERG, and P-gp efflux properties, the significantly superior binding affinity of Ligand B (-8.6 vs 0.0 kcal/mol) is the deciding factor for an enzyme target like SRC kinase. The potency advantage is substantial. While Ligand B has some ADME liabilities (higher DILI, lower half-life, lower solubility), these can potentially be addressed through further optimization. The strong binding affinity provides a solid foundation for a viable drug candidate.

Output:
1
2025-04-17 13:36:39,658 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.5 and 351.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is well below the 140 threshold for good absorption. Ligand B (118.06) is still acceptable, but less optimal.

**logP:** Ligand A (3.39) is within the optimal 1-3 range. Ligand B (0.294) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable range (<=10).

**QED:** Both ligands have similar QED scores (0.765 and 0.756), indicating good drug-likeness.

**DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (77.976). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.574) has a higher BBB score than Ligand B (39.977).

**Caco-2 Permeability:** Ligand A (-4.269) and Ligand B (-5.358) both have negative values, indicating poor permeability. However, the scale is not defined, so it's hard to interpret the magnitude of the difference.

**Aqueous Solubility:** Ligand A (-4.1) and Ligand B (-1.751) both have negative values, indicating poor solubility. Again, the scale is not defined.

**hERG Inhibition:** Ligand A (0.291) has a much lower hERG risk than Ligand B (0.017). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (82.763) has higher microsomal clearance, suggesting faster metabolism and lower metabolic stability, while Ligand B (-28.473) has negative clearance, which is unusual and potentially indicates very high stability.

**In vitro Half-Life:** Ligand A (-21.31) has a negative half-life, which is not possible. This is a red flag. Ligand B (-12.909) also has a negative half-life, also a red flag.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.006).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), but the difference is less than the 1.5 kcal/mol threshold that would strongly favor it.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. Ligand A has a significantly lower DILI risk and hERG inhibition liability, both crucial for drug development. While both have issues with solubility and permeability, the metabolic stability concern with Ligand A (positive Cl_mic) and the negative half-life values for both are concerning. However, the negative half-life values are likely data errors. The lower DILI and hERG risk for Ligand A outweigh the slight affinity difference.

Output:
1
2025-04-17 13:36:39,658 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.443 and 353.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (87.74), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have similar logP values (0.544 and 0.591), which are slightly low but acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, meeting the criteria of <=5 and <=10 respectively.

**QED:** Both ligands have good QED scores (0.711 and 0.684), indicating drug-likeness.

**DILI:** Ligand A (33.075) has a significantly lower DILI risk than Ligand B (42.846), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand B (77.898) has a higher BBB penetration score than Ligand A (51.57), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.612 and -4.606). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.524 and -2.14). This is a significant drawback.

**hERG:** Both ligands have low hERG inhibition liability (0.37 and 0.227), which is positive.

**Microsomal Clearance:** Ligand A (24.819) has a higher microsomal clearance than Ligand B (22.117). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-38.071) has a much longer in vitro half-life than Ligand A (9.18), indicating greater stability. This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.03).

**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 overcome other deficiencies.

**Conclusion:**

While both compounds have good binding affinity, Ligand A is preferable due to its significantly lower DILI risk. Ligand B has better metabolic stability and half-life, but the higher DILI risk is a major concern. The poor solubility and Caco-2 permeability are drawbacks for both, but these can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, minimizing toxicity (DILI) is crucial.

Output:
0
2025-04-17 13:36:39,658 - INFO - Batch 228 complete. Total preferences: 3648
2025-04-17 13:36:39,658 - INFO - Processing batch 229/512...
2025-04-17 13:37:29,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.434 and 365.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is better than Ligand B (38.77), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.451) is within the optimal 1-3 range. Ligand B (4.373) is slightly higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.891) has a significantly better QED score than Ligand B (0.618), indicating a more drug-like profile.

**DILI:** Ligand A (47.538) has a slightly higher DILI risk than Ligand B (22.451), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (Ligand A: 83.831, Ligand B: 89.492), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.568 and -4.752), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.47 and -4.587). This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.491) has a lower hERG inhibition risk than Ligand B (0.748), which is favorable.

**Microsomal Clearance:** Ligand A (36.606 mL/min/kg) has a lower microsomal clearance than Ligand B (94.802 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-1.605 hours) has a shorter half-life than Ligand B (30.425 hours). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux than Ligand B (0.788), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). The 0.9 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is better overall. Despite the poor solubility and permeability (shared by both), it has a superior QED score, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The longer half-life of Ligand B is a benefit, but the significantly worse metabolic stability and slightly worse affinity are more concerning for an enzyme target. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the core properties of Ligand A are more promising.

Output:
0
2025-04-17 13:37:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.451 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (97.35 and 95.57) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.746) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (1.709) is within the optimal range.

**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 (0.847 and 0.792), indicating good drug-like properties.

**DILI:** Ligand A (35.595) has a significantly lower DILI risk than Ligand B (49.011), which is a major advantage. Both are below the concerning threshold of 60.

**BBB:** Both have moderate BBB penetration, but Ligand A (71.733) is higher than Ligand B (60.838). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired/undesired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.125) is slightly better than Ligand B (-4.458).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.339) is slightly better than Ligand B (-3.592).

**hERG Inhibition:** Ligand A (0.088) has a much lower hERG risk than Ligand B (0.568). This is a critical advantage.

**Microsomal Clearance:** Ligand A (16.536) has a higher microsomal clearance than Ligand B (3.209), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (27.674) has a significantly longer in vitro half-life than Ligand A (-13.345), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.035 and 0.195).

**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 of the ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk and slightly better solubility, Ligand B's significantly stronger binding affinity (-9.1 vs -7.0 kcal/mol) and longer half-life are crucial for an enzyme inhibitor. The improved binding affinity is likely to overcome the slightly higher DILI and lower solubility. The difference in half-life is also substantial.

Output:
1
2025-04-17 13:37:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (424.32 Da) is slightly higher than Ligand B (366.447 Da), but both are acceptable.

**TPSA:** Ligand A (88.16) is better than Ligand B (110.91). TPSA is important for oral absorption, and lower is generally better. Ligand A is closer to the preferred threshold of <=140.

**logP:** Ligand A (2.752) is optimal, while Ligand B (0.038) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for Ligand A.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 5 HBAs, acceptable. Ligand B has 8 HBAs, which is getting towards the upper limit and could potentially impact permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.745, B: 0.685), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 73.439, B: 70.531), and are within an acceptable range (<80).

**BBB:** Ligand A (71.733) has better BBB penetration than Ligand B (51.958), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted with caution.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, these should be interpreted cautiously.

**hERG Inhibition:** Ligand A (0.379) has a much lower hERG risk than Ligand B (0.161), which is a significant advantage. Avoiding hERG inhibition is crucial for cardiac safety.

**Microsomal Clearance:** Ligand A (19.447 mL/min/kg) has significantly lower microsomal clearance than Ligand B (41.629 mL/min/kg). Lower clearance indicates better metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (88.196 hours) has a substantially longer half-life than Ligand B (14.824 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.305) has lower P-gp efflux than Ligand B (0.06). Lower efflux is generally better for bioavailability.

**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 meaningful and can outweigh some minor ADME drawbacks.

**Overall:**

Ligand A is superior to Ligand B. It has a more optimal logP, better TPSA, significantly lower hERG risk, improved metabolic stability (lower Cl_mic and 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 make it the more promising drug candidate.

Output:
1
2025-04-17 13:37:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.411 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (88.1), being well below the 140 threshold for good absorption.

**logP:** Both ligands (0.591 and 0.698) are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as lower HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand B (5) is preferable to Ligand A (4), but both are acceptable.

**QED:** Both ligands have similar, good QED values (0.735 and 0.701).

**DILI:** Ligand B (7.29) has a much lower DILI risk than Ligand A (49.399), which is a significant advantage.

**BBB:** Ligand A (64.25) has better BBB penetration than Ligand B (39.667), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.532) and Ligand B (-4.722) are both very poor.

**Aqueous Solubility:** Ligand A (-2.146) is better than Ligand B (-0.78), which is important for formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.15 and 0.261).

**Microsomal Clearance:** Ligand A (8.449) has significantly lower microsomal clearance than Ligand B (17.751), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.551) has a shorter half-life than Ligand B (11.147), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.031).

**Binding Affinity:** Ligand A (-7.8) has a substantially stronger binding affinity than Ligand B (-6.5), a difference of 1.3 kcal/mol. This is a major advantage that can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B's lower DILI risk, Ligand A's significantly superior binding affinity (-7.8 vs -6.5 kcal/mol) and better metabolic stability (lower Cl_mic) make it the more promising drug candidate. The slightly lower solubility and higher DILI risk of Ligand A are less concerning given the strong potency and metabolic profile.

Output:
1
2025-04-17 13:37:29,183 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as drug candidates targeting SRC, a kinase. I'll follow the provided guidelines and protein-class-specific priorities (enzymes: potency, metabolic stability, solubility, and hERG risk).

**Ligand A:** [363.439, 100.55 ,   2.472,   3.   ,   6.   ,   0.685,  84.102,  49.903, -4.821,  -3.567,   0.298,  77.238,  24.208,   0.415,  -9.4  ]
**Ligand B:** [366.477,  33.2  ,   4.623,   0.   ,   3.   ,   0.716,  32.299,  86.817, -4.769,  -3.942,   0.834,  68.914,  11.306,   0.441,  -8.6  ]

**Step-by-step comparison:**

1. **MW:** Both ligands (363.439 & 366.477 Da) are within the ideal range (200-500 Da). No significant difference here.
2. **TPSA:** Ligand A (100.55) is slightly higher than Ligand B (33.2). While both are reasonably low, B is much better positioned for good oral absorption.
3. **logP:** Ligand A (2.472) is optimal. Ligand B (4.623) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.
4. **HBD:** Ligand A (3) is acceptable. Ligand B (0) is also fine, but a lack of HBDs can sometimes hinder solubility.
5. **HBA:** Both ligands (A: 6, B: 3) are within the acceptable range (<=10).
6. **QED:** Both ligands (A: 0.685, B: 0.716) have good drug-likeness scores (>0.5).
7. **DILI:** Ligand A (84.102) has a significantly higher DILI risk than Ligand B (32.299). This is a major concern for Ligand A.
8. **BBB:** Ligand B (86.817) has a higher BBB penetration score than Ligand A (49.903). While not crucial for a non-CNS target like SRC, it's a slight advantage.
9. **Caco-2:** Both are negative values, indicating poor permeability.
10. **Solubility:** Both ligands have very poor solubility scores (-3.567 and -3.942). This is a significant drawback for both, but slightly worse for B.
11. **hERG:** Both ligands have low hERG inhibition liability (0.298 and 0.834), which is good.
12. **Cl_mic:** Ligand B (68.914) has a lower microsomal clearance than Ligand A (77.238), suggesting better metabolic stability. This is a key advantage for an enzyme target.
13. **t1/2:** Ligand B (11.306) has a longer in vitro half-life than Ligand A (24.208). This is also a positive for metabolic stability and dosing frequency.
14. **Pgp:** Both ligands have low Pgp efflux liability (0.415 and 0.441).
15. **Binding Affinity:** Ligand A (-9.4) has a significantly stronger binding affinity than Ligand B (-8.6). This is a substantial advantage (1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, its significantly higher DILI risk is a major red flag. Ligand B, while having a weaker affinity, exhibits a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better TPSA. The solubility is poor for both, but this can be addressed with formulation strategies.

Given the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG), and the substantial difference in DILI risk, I believe **Ligand B** is the more viable drug candidate, despite its slightly lower binding affinity. The improved safety and metabolic stability outweigh the affinity difference, especially considering that further optimization of Ligand B could potentially improve its binding.

1
2025-04-17 13:37:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.415 and 359.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is slightly higher than Ligand B (71.11), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.746) is optimal, while Ligand B (0.596) is a bit low, potentially hindering permeation.

**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 (0.787 and 0.752), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (81.078%) compared to Ligand B (25.165%). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (65.374% and 78.907%), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating 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:** Both ligands have low hERG inhibition risk (0.355 and 0.527).

**Microsomal Clearance:** Ligand A has a moderate clearance (108.935), while Ligand B has a negative clearance (-18.569), suggesting very high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A has a half-life of 16.965 hours, while Ligand B has a negative half-life (-11.463). This is a concern for both, but the negative value for B is suspect.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.199 and 0.031).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.5 kcal/mol), with Ligand B being slightly better. The difference is less than 1.5 kcal/mol, so this is not a decisive factor.

**Conclusion:**

Despite similar binding affinities and good QED scores, Ligand B is the more promising candidate. Its significantly lower DILI risk and much better predicted metabolic stability (negative Cl_mic) outweigh the slightly lower logP. While both have poor predicted permeability and solubility, these can be addressed through formulation strategies. The high DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 13:37:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.519 Da) is slightly higher than Ligand B (351.491 Da), but both are acceptable.

**TPSA:** Ligand A (109.41) is higher than Ligand B (61.88). While <140 is generally good for oral absorption, Ligand A is approaching the upper limit. Ligand B's TPSA is excellent.

**logP:** Both ligands have good logP values (A: 2.014, B: 1.535), 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 reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar and acceptable QED values (A: 0.768, B: 0.756), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (96.045) compared to Ligand B (6.747). This is a major red flag for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (68.941) has a higher BBB value than Ligand A (39.046), but this isn't decisive here.

**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 and suggesting poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.229) has a slightly higher hERG risk than Ligand B (0.325), but both are relatively low.

**Microsomal Clearance:** Ligand B (14.559) has a much higher microsomal clearance than Ligand A (-4.102). The negative value for Ligand A is highly unusual and suggests *very* high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand B has a very short in vitro half-life (12.687 hours) compared to Ligand A (89.177 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.207, B: 0.018).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand B has a much better binding affinity, lower DILI risk, and a better TPSA. However, it has a short half-life and higher metabolic clearance. Ligand A has excellent metabolic stability and half-life, but suffers from a very high DILI risk and significantly weaker binding affinity.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the strong binding affinity of Ligand B outweighs its metabolic liabilities *if* those can be addressed through structural modifications. The high DILI risk of Ligand A is a major concern and is unlikely to be overcome easily.

Output:
1
2025-04-17 13:37:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.391 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (138.68) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (122.03) is well within the acceptable range.

**logP:** Ligand A (0.774) is a bit low, potentially impacting permeability. Ligand B (0.043) is even lower, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, both within reasonable limits. Ligand B has 3 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have QED values (0.632 and 0.581) above the 0.5 threshold, indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 83.908, which is high and concerning. Ligand B has a significantly lower DILI risk of 52.772, which is much more favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (64.211) and Ligand B (25.242) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.732 and -5.525), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.097 and -2.144), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.217 and 0.028), which is excellent.

**Microsomal Clearance:** Ligand A (8.203) has a slightly higher, but still reasonable, microsomal clearance than Ligand B (5.483). Lower is better for metabolic stability.

**In vitro Half-Life:** Ligand B (-8.822) has a significantly longer in vitro half-life than Ligand A (-7.142), which is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.013), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent and strong.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B has a significantly lower DILI risk and a substantially longer in vitro half-life. The high DILI risk associated with Ligand A is a major red flag. The slightly better metabolic stability of Ligand A is outweighed by the DILI concern.

Output:
1
2025-04-17 13:37:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.419 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is slightly above the preferred <140, but acceptable. Ligand B (84.67) is excellent, well below 140.

**logP:** Ligand A (-0.839) is a bit low, potentially hindering permeability. Ligand B (1.819) 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 (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.597, B: 0.759), indicating drug-likeness.

**DILI:** Ligand A (23.846) has a much lower DILI risk than Ligand B (34.626), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (75.378) has a higher BBB score, but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative 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 values, indicating poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.105, B: 0.134), which is good.

**Microsomal Clearance:** Ligand A (-37.566) has significantly lower (better) microsomal clearance than Ligand B (49.418), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (22.693) has a longer half-life than Ligand B (-19.824), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.005, B: 0.093).

**Binding Affinity:** Ligand A (-9.9) has a substantially stronger binding affinity than Ligand B (-7.5). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.9 kcal/mol vs -7.5 kcal/mol) is a major advantage for an enzyme target. Furthermore, it has lower DILI risk, better metabolic stability (lower Cl_mic), and a longer half-life. While Ligand B has a slightly better logP and TPSA, the potency and ADME advantages of Ligand A are more critical for an enzyme inhibitor. The solubility issue would need to be addressed through formulation strategies.

Output:
1
2025-04-17 13:37:29,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (361.511 and 360.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is excellent, well below the 140 threshold for oral absorption. Ligand B (104.02) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (3.199) is optimal. Ligand B (0.613) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 10 HBA) is at the higher end of acceptable ranges, potentially affecting permeability.

**QED:** Both ligands have reasonable QED scores (0.777 and 0.563), indicating good drug-like properties.

**DILI:** Ligand A (54.634) has a lower DILI risk than Ligand B (83.753), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (81.776) has a higher BBB percentile than Ligand B (32.416).

**Caco-2 Permeability:** Ligand A (-4.697) shows poor permeability, while Ligand B (-5.587) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.606) is better than Ligand B (-2.463), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG risk (0.396 and 0.471), which is excellent.

**Microsomal Clearance:** Ligand A (96.521) has high microsomal clearance, suggesting rapid metabolism and potentially low in vivo exposure. Ligand B (20.261) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (53.795) has a significantly longer half-life than Ligand A (-32.438), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.317 and 0.006), which is good.

**Binding Affinity:** Ligand A (-9.0) has a substantially stronger binding affinity than Ligand B (-8.3). This is a difference of 0.7 kcal/mol, which is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's superior binding affinity, the combination of Ligand B's significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and acceptable solubility makes it the more promising drug candidate. The lower logP and Caco-2 permeability of Ligand B are concerns, but the strong binding affinity of Ligand A is not enough to overcome the poor metabolic profile.

Output:
1
2025-04-17 13:37:29,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.419 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.34) is slightly higher than Ligand B (75.16), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.87) is at the upper end of the optimal range (1-3), while Ligand B (2.072) 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 (2 HBD, 6 HBA) and Ligand B (3 HBD, 3 HBA) both have reasonable numbers of H-bonds, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.726 and 0.748), indicating generally drug-like properties.

**DILI:** Ligand A (94.649) has a significantly higher DILI risk than Ligand B (47.732). This is a major red flag for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (73.866) shows better BBB penetration than Ligand A (19.542).

**Caco-2 Permeability:** Ligand A (-5.035) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.743) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.699) has very poor aqueous solubility, which is concerning. Ligand B (-2.486) is better, but still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.442 and 0.402), which is good.

**Microsomal Clearance:** Ligand B (26.736) has significantly lower microsomal clearance than Ligand A (57.181), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (86.693) has a much longer in vitro half-life than Ligand A (-4.395), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.45 and 0.091), which is favorable.

**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 advantage. However, the other ADME properties of Ligand A are significantly worse.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its extremely poor solubility, poor Caco-2 permeability, high DILI risk, and faster clearance make it a less viable candidate. The difference in binding affinity (2.5 kcal/mol) is substantial, but can be overcome with further optimization. Ligand B, despite its weaker binding, has a much more favorable ADME profile, particularly regarding metabolic stability (lower Cl_mic and higher t1/2) and safety (lower DILI). For an enzyme target like SRC kinase, metabolic stability and safety are paramount.

Output:
1
2025-04-17 13:37:29,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.378 and 351.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (90.98 and 87.3) below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have logP values (1.468 and 1.737) within the optimal range of 1-3.

**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 (3) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.829) has a higher QED score than Ligand B (0.681), indicating a more drug-like profile.

**7. DILI:** Ligand A (51.221) has a higher DILI risk than Ligand B (24.893). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.979 and -4.996), which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.105 and -3.157), also unusual and suggesting poor solubility. This is a potential issue for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.415 and 0.072). This is excellent for both.

**12. Microsomal Clearance:** Ligand A (-11.972) has a much lower (better) microsomal clearance than Ligand B (42.132). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-32.295) has a much longer (better) in vitro half-life than Ligand B (-5.997). This further supports better metabolic stability for Ligand A.

**14. P-gp Efflux:** Both ligands exhibit very low P-gp efflux liability (0.025 and 0.027).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good potency, Ligand B is superior in terms of DILI risk and has acceptable ADME properties. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a higher QED score, but its DILI risk is considerably higher. Given that SRC is an enzyme target, metabolic stability and safety (DILI) are crucial. The difference in DILI risk is substantial enough to outweigh the slightly better QED and metabolic stability of Ligand A.

Output:
1
2025-04-17 13:37:29,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (400.28 and 476.115 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.91) is higher than Ligand B (42.43). While both are reasonably low, Ligand B is better positioned for good absorption.

**3. logP:** Both ligands have logP values (3.146 and 4.568) within the optimal 1-3 range, but Ligand B is slightly higher, potentially raising concerns about solubility and off-target effects.

**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 QED values (0.663 and 0.611), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (76.386 and 75.029), indicating a moderate risk. This isn't a major differentiator.

**8. BBB:** Both ligands have high BBB penetration (92.323 and 89.298), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-5.326) has a lower Caco-2 permeability than Ligand B (-4.604), suggesting potentially poorer absorption.

**10. Aqueous Solubility:** Ligand A (-2.621) has better aqueous solubility than Ligand B (-5.208). This is a significant advantage for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.69 and 0.666), which is good.

**12. Microsomal Clearance:** Ligand A (27.945) has significantly lower microsomal clearance than Ligand B (47.804), indicating better metabolic stability. This is crucial for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (20.969) has a longer in vitro half-life than Ligand B (-4.948), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.663 and 0.49).

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.2). 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, which is the most important factor for an enzyme inhibitor. Although its logP is slightly higher and solubility is lower than Ligand A, the difference in binding affinity is significant. The metabolic stability of Ligand A is better, but the potency of Ligand B is likely to drive efficacy.

Output:
1
2025-04-17 13:37:29,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (372.921 Da) is also well within range.

**TPSA:** Ligand A (123.71) is better than Ligand B (41.13) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (1.282) is optimal, while Ligand B (4.675) is high. High logP can lead to solubility issues and off-target effects.

**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 B (0.819) has a significantly better QED score than Ligand A (0.462), indicating a more drug-like profile.

**DILI:** Ligand A (83.172) has a higher DILI risk than Ligand B (60.682), which is undesirable.

**BBB:** Both have relatively low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (80.419) 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 difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.511) has a slightly lower hERG inhibition risk than Ligand B (0.809), which is preferable.

**Microsomal Clearance:** Ligand A (16.359) has a higher microsomal clearance than Ligand B (6.687), suggesting lower metabolic stability. This is a significant disadvantage.

**In vitro Half-Life:** Ligand B (41.686) has a better in vitro half-life than Ligand A (46.784).

**P-gp Efflux:** Both have low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a crucial advantage, potentially outweighing some of its ADME drawbacks. The difference of 1.2 kcal/mol is substantial.

**Conclusion:**

Despite Ligand B's higher logP and lower solubility, its significantly superior binding affinity (-9.8 vs -8.6 kcal/mol) and better QED, lower DILI risk, and improved metabolic stability (lower Cl_mic, better t1/2) make it the more promising drug candidate. The potency advantage is substantial enough to warrant further optimization to address the solubility and logP issues.

Output:
1
2025-04-17 13:37:29,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**
*   **MW:** 382.957 Da - Within the ideal range (200-500).
*   **TPSA:** 41.57 A<sup>2</sup> - Good for oral absorption (<140).
*   **logP:** 4.653 - Slightly high, potential solubility issues, but acceptable.
*   **HBD:** 1 - Good.
*   **HBA:** 3 - Good.
*   **QED:** 0.823 - Excellent drug-likeness.
*   **DILI:** 50.136 - Acceptable risk.
*   **BBB:** 88.91 - High, but less critical for a non-CNS target like SRC.
*   **Caco-2:** -4.835 - Very poor permeability. A major concern.
*   **Solubility:** -4.825 - Very poor solubility. A major concern.
*   **hERG:** 0.829 - Low risk.
*   **Cl_mic:** 75.869 mL/min/kg - Moderate clearance, could be better.
*   **t1/2:** 45.882 hours - Good in vitro half-life.
*   **Pgp:** 0.487 - Low efflux, good.
*   **Affinity:** -9.0 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 356.423 Da - Within the ideal range.
*   **TPSA:** 117.79 A<sup>2</sup> - Higher, potentially impacting absorption, but still within a reasonable range.
*   **logP:** 1.11 - Good.
*   **HBD:** 2 - Good.
*   **HBA:** 7 - Acceptable.
*   **QED:** 0.603 - Good drug-likeness.
*   **DILI:** 49.864 - Acceptable risk.
*   **BBB:** 58.278 - Lower, not a major concern.
*   **Caco-2:** -5.058 - Very poor permeability. A major concern.
*   **Solubility:** -1.721 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.089 - Very low risk.
*   **Cl_mic:** 45.559 mL/min/kg - Good metabolic stability.
*   **t1/2:** -7.989 hours - Poor in vitro half-life.
*   **Pgp:** 0.069 - Low efflux, good.
*   **Affinity:** -7.9 kcal/mol - Good binding affinity, though significantly weaker than Ligand A.

**Comparison and Decision:**

Both compounds suffer from very poor Caco-2 permeability and suboptimal solubility. However, Ligand A has a *much* stronger binding affinity (-9.0 kcal/mol vs -7.9 kcal/mol). The difference in affinity (1.1 kcal/mol) is substantial and could outweigh the permeability/solubility issues, *if* formulation strategies can be developed to address those. Ligand B has a better metabolic stability profile (lower Cl_mic) and a lower hERG risk, but the significantly weaker binding affinity is a major drawback for an enzyme target like SRC kinase. The poor half-life of Ligand B is also a concern.

Given the priority for potency in enzyme inhibition, and the potential to mitigate solubility/permeability issues through formulation, Ligand A is the more promising candidate.

Output:
1
2025-04-17 13:37:29,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.487 and 352.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 58.64, well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values within the optimal range (2.348 and 2.837).

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, also acceptable.

**6. QED:** Ligand A (0.541) has a slightly better QED score than Ligand B (0.8), indicating a more drug-like profile.

**7. DILI:** Ligand A (10.896) has a significantly lower DILI risk than Ligand B (26.095). This is a crucial advantage.

**8. BBB:** Both ligands have acceptable BBB penetration, but Ligand B (80.884) is higher than Ligand A (70.609). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.414 and -4.442). This is unusual and suggests poor permeability. It is difficult to interpret these values without knowing the scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.9 and -2.482). Again, this is unusual and suggests poor solubility. It is difficult to interpret these values without knowing the scale.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.403 and 0.339).

**12. Microsomal Clearance:** Ligand A (36.514) has lower microsomal clearance than Ligand B (54.549), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.402) has a longer in vitro half-life than Ligand B (-9.482).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.063 and 0.088).

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.5). However, the difference is only 0.5 kcal/mol, which is not substantial enough to outweigh other significant differences.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better QED score. While Ligand B has a marginally better binding affinity, the advantages of Ligand A in ADME-Tox properties are more critical for overall drug development success. The negative values for Caco-2 and solubility are concerning for both, but the other differences favor Ligand A.

Output:
0
2025-04-17 13:37:29,185 - INFO - Batch 229 complete. Total preferences: 3664
2025-04-17 13:37:29,185 - INFO - Processing batch 230/512...
2025-04-17 13:38:18,511 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (352.431 Da) is also good.

**TPSA:** Ligand A (39.08) is excellent, well below the 140 threshold for oral absorption. Ligand B (95.94) is higher, but still within a reasonable range, though potentially impacting absorption slightly.

**logP:** Ligand A (3.779) is optimal. Ligand B (0.105) is very low, raising concerns about permeability and potentially requiring formulation strategies to enhance absorption.

**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 good QED scores (A: 0.503, B: 0.646), indicating generally drug-like properties.

**DILI:** Ligand A (38.503) has a slightly higher DILI risk than Ligand B (23.846), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.474) is higher than Ligand B (42.226).

**Caco-2 Permeability:** Ligand A (-5.118) has poor Caco-2 permeability, while Ligand B (-4.989) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.987) has poor aqueous solubility, while Ligand B (-0.927) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.976) has a very low hERG risk, which is excellent. Ligand B (0.042) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (41.894) has moderate clearance, while Ligand B (7.87) has very low clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-8.931) has a long half-life, which is good. Ligand B (1.601) has a short half-life, which is a concern.

**P-gp Efflux:** Ligand A (0.935) has moderate P-gp efflux, while Ligand B (0.04) has very low P-gp efflux.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has 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 is the stronger candidate. While it has a lower logP and shorter half-life, its significantly improved binding affinity (-10.1 vs -8.2 kcal/mol) and superior metabolic stability (lower Cl_mic) are crucial for an enzyme target. The lower P-gp efflux is also beneficial. The slightly lower solubility and permeability are concerns, but potentially addressable through formulation. Ligand A's better solubility and permeability are offset by its weaker binding and moderate metabolic clearance.

Output:
1
2025-04-17 13:38:18,511 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [346.431, 87.32, 1.641, 2, 4, 0.794, 40.287, 52.966, -4.789, -3.089, 0.254, -10.973, -20.561, 0.034, -5.9]
**Ligand B:** [342.403, 93.01, 1.247, 1, 6, 0.853, 58.627, 60.838, -5.033, -2.689, 0.078, 33.401, 1.624, 0.047, -7.4]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (346.431) and B (342.403) are very similar.
2. **TPSA:** Both are below the 140 A^2 threshold for oral absorption. A (87.32) is slightly better than B (93.01).
3. **logP:** Both are within the optimal range (1-3). A (1.641) is slightly higher than B (1.247), which is good.
4. **HBD:** A (2) and B (1) both meet the <=5 criteria. B is slightly better.
5. **HBA:** A (4) is better than B (6), both are under the 10 threshold.
6. **QED:** Both are above 0.5, indicating good drug-likeness. A (0.794) is slightly better than B (0.853).
7. **DILI:** A (40.287) is significantly better than B (58.627). This is a crucial advantage, as lower DILI risk is highly desirable.
8. **BBB:** Both are relatively low, which is acceptable for a non-CNS target like SRC. B (60.838) is slightly better than A (52.966), but this isn't a primary concern.
9. **Caco-2:** Both have negative values, indicating poor permeability. A (-4.789) is slightly better than B (-5.033), but both are concerning.
10. **Solubility:** Both have negative values, indicating poor solubility. A (-3.089) is slightly better than B (-2.689).
11. **hERG:** Both are very low, indicating low hERG inhibition risk. A (0.254) is better than B (0.078).
12. **Cl_mic:** A (-10.973) is *much* better than B (33.401). Lower clearance indicates greater metabolic stability, a key consideration for kinase inhibitors.
13. **t1/2:** A (-20.561) is *much* better than B (1.624). A longer half-life is generally preferred.
14. **Pgp:** Both are very low, indicating low P-gp efflux. A (0.034) is slightly better than B (0.047).
15. **Binding Affinity:** B (-7.4) is significantly better than A (-5.9). This is a substantial advantage (1.5 kcal/mol difference).

**Enzyme-Kinase Specific Priorities:**

For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. While B has a significantly better binding affinity, A has much better metabolic stability (Cl_mic and t1/2) and a lower DILI risk. Solubility is poor for both, but A is slightly better. hERG risk is low for both.

**Conclusion:**

Despite the superior binding affinity of Ligand B, the significantly better metabolic stability (Cl_mic, t1/2) and lower DILI risk of Ligand A are more critical for a kinase inhibitor. The difference in binding affinity, while substantial, can potentially be overcome with further optimization, whereas improving metabolic stability and reducing toxicity are often more challenging. The poor Caco-2 and solubility are concerns for both, but can be addressed through formulation strategies.

Therefore, I would select **Ligand A** as the more viable drug candidate.

1
2025-04-17 13:38:18,511 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.355 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.52) is better than Ligand B (132.89) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (1.294) is within the optimal 1-3 range. Ligand B (-0.265) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors:** Both have 4 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 preferable.

**QED:** Ligand A (0.713) has a better QED score than Ligand B (0.547), suggesting a more drug-like profile.

**DILI:** Ligand B (69.872) has a lower DILI risk than Ligand A (87.01), which is a significant advantage.

**BBB:** Ligand A (67.584) has a higher BBB penetration than Ligand B (28.073). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.114) has worse Caco-2 permeability than Ligand B (-5.655), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.375) has better aqueous solubility than Ligand B (-2.357). Solubility is important for formulation and bioavailability.

**hERG:** Ligand A (0.422) has a lower hERG risk than Ligand B (0.112), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-17.801) has a much lower (better) microsomal clearance than Ligand B (-13.214), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (8.95) has a longer in vitro half-life than Ligand A (-12.252), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.017) has lower P-gp efflux than Ligand B (0.008), which is preferable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a >1.5 kcal/mol advantage, and is a major deciding factor.

**Overall:**

Ligand A has a better binding affinity, QED, solubility, hERG risk, and metabolic stability. While Ligand B has a lower DILI risk and longer half-life, the substantial advantage in binding affinity and the better overall ADME profile of Ligand A outweigh these benefits. The slightly lower Caco-2 permeability of A is a concern, but can be addressed through formulation strategies.

Output:
1
2025-04-17 13:38:18,511 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.447 and 367.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.89) is slightly higher than Ligand B (74.43), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.618) is a bit low, potentially hindering permeation. Ligand B (2.616) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**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 similar QED values (0.73 and 0.727), indicating good drug-likeness.

**DILI:** Ligand A (37.185) has a lower DILI risk than Ligand B (46.297), which is preferable.

**BBB:** Ligand A (71.733) has a higher BBB penetration percentile than Ligand B (66.615), but BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.89 and -4.911). This is unusual and suggests poor permeability. It's difficult to interpret without further context, but it's a potential concern for both.

**Aqueous Solubility:** Ligand A (-1.359) has better solubility than Ligand B (-4.03). This is a significant advantage for Ligand B.

**hERG Inhibition:** Ligand A (0.176) has a lower hERG inhibition liability than Ligand B (0.416), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (2.306) has significantly lower microsomal clearance than Ligand B (10.469), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (15.665) has a longer in vitro half-life than Ligand B (10.461), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.027) shows lower P-gp efflux liability than Ligand B (0.164), which is favorable.

**Binding Affinity:** Ligand B (-0.0) has a much better binding affinity than Ligand A (-8.4). This is the most important factor for an enzyme inhibitor. The difference of 8.4 kcal/mol is substantial and likely outweighs most of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A's advantages in DILI, solubility, metabolic stability, and hERG risk, the significantly superior binding affinity of Ligand B (-0.0 kcal/mol vs -8.4 kcal/mol) makes it the more promising drug candidate. A binding affinity difference of this magnitude is likely to overcome the ADME liabilities of Ligand B, especially given that the issues aren't catastrophic.



Output:
1
2025-04-17 13:38:18,511 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (352.406 and 354.441 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (49.41). Both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.183) is within the optimal 1-3 range, while Ligand B (3.111) is at the higher end of the 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 (2) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.752) has a better QED score than Ligand B (0.538), indicating a more drug-like profile.

**7. DILI:** Ligand A (40.132) has a slightly higher DILI risk than Ligand B (18.651), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (65.607) has a lower BBB penetration than Ligand B (86.274). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.755) and Ligand B (-4.495) are similar, and both are negative, meaning low permeability.

**10. Aqueous Solubility:** Ligand A (-1.528) is better than Ligand B (-3.486).

**11. hERG Inhibition:** Ligand A (0.338) has a lower hERG inhibition risk than Ligand B (0.557), which is preferable.

**12. Microsomal Clearance:** Ligand A (20.527) and Ligand B (19.962) are similar.

**13. In vitro Half-Life:** Ligand A (-4.983) has a significantly longer half-life than Ligand B (-16.44). This is a major advantage for dosing considerations.

**14. P-gp Efflux:** Ligand A (0.025) has a lower P-gp efflux liability than Ligand B (0.096).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.5 kcal/mol). The difference is not substantial enough to be a deciding factor.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a better half-life, better solubility, and lower hERG risk. While Ligand B has slightly better Caco-2 permeability, the negative values for both are concerning. The QED score is also better for Ligand A.

Output:
0
2025-04-17 13:38:18,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.423 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is better than Ligand B (71.53), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands (2.264 and 1.944) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Ligand B (0.907) has a significantly higher QED score than Ligand A (0.623), suggesting a more drug-like profile.

**DILI:** Ligand A (42.769) has a slightly better DILI score than Ligand B (53.625), both are reasonably low risk.

**BBB:** Both ligands have similar BBB penetration (67.197 and 66.886), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.729) has slightly better Caco-2 permeability than Ligand B (-4.501).

**Aqueous Solubility:** Ligand A (-2.898) has slightly better aqueous solubility than Ligand B (-2.277).

**hERG:** Both ligands have very low hERG inhibition liability (0.296 and 0.264), which is excellent.

**Microsomal Clearance:** Ligand A (70.3) has higher microsomal clearance than Ligand B (29.178), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-18.57) has a much longer in vitro half-life than Ligand A (-10.732), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.076).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -8.1 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has a better QED score and significantly better metabolic stability (lower Cl_mic, longer t1/2), Ligand A has slightly better solubility and Caco-2 permeability. Given the priority for metabolic stability in enzyme inhibitors, and the fact that both have excellent binding affinity and acceptable safety profiles, Ligand B is the more promising candidate.

Output:
1
2025-04-17 13:38:18,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.471 and 352.312 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.86) is slightly higher than Ligand B (68.29). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands (2.152 and 2.767) 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.

**QED:** Both ligands have good QED scores (0.797 and 0.863), indicating good drug-like properties.

**DILI:** Ligand A (75.378) has a lower DILI risk than Ligand B (81.427), which is preferable.

**BBB:** Ligand A (48.74) has a lower BBB penetration than Ligand B (94.455). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.742) has a lower Caco-2 permeability than Ligand B (-4.231). Both are negative, suggesting poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.043) has slightly better aqueous solubility than Ligand B (-4.156), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.17) shows a lower hERG inhibition risk than Ligand B (0.582), a significant advantage.

**Microsomal Clearance:** Ligand A (4.652) has a lower microsomal clearance than Ligand B (82.314), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (3.143) has a slightly longer half-life than Ligand B (0.072), which is desirable.

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux liability than Ligand B (0.161), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.2 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 minor ADME drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has better BBB penetration (irrelevant here) and slightly better Caco-2 permeability, Ligand A excels in the most important parameters for an enzyme inhibitor: significantly stronger binding affinity, lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and lower P-gp efflux. The slightly better solubility of A is also a plus.

Output:
1
2025-04-17 13:38:18,512 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, following the provided guidelines.

**Ligand A:** [381.234, 58.2, 4.185, 2, 3, 0.781, 76.076, 74.098, -4.421, -5.604, 0.296, 47.207, 39.759, 0.256, -8.3]
**Ligand B:** [351.407, 120.58, -1.072, 3, 7, 0.575, 33.812, 51.803, -5.371, -1.442, 0.122, 0.321, -7.491, 0.006, -8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (381.234) is slightly higher, but acceptable. B (351.407) is also good.
2. **TPSA:** A (58.2) is excellent, well below 140 and favorable for absorption. B (120.58) is higher, but still within a reasonable range for many kinase inhibitors.
3. **logP:** A (4.185) is a bit high, potentially leading to solubility issues and off-target interactions. B (-1.072) is quite low, which could hinder membrane permeability.
4. **HBD:** Both have acceptable HBD counts (A: 2, B: 3), below the threshold of 5.
5. **HBA:** A (3) is good, B (7) is higher but still within the acceptable limit of 10.
6. **QED:** A (0.781) is strong, indicating good drug-like properties. B (0.575) is acceptable, but less ideal.
7. **DILI:** A (76.076) has a significantly higher DILI risk than B (33.812). This is a major concern for A.
8. **BBB:** Both have reasonable BBB penetration, but A (74.098) is better than B (51.803). However, BBB is less critical for a non-CNS target like SRC.
9. **Caco-2:** A (-4.421) is poor, suggesting poor intestinal absorption. B (-5.371) is also poor, but slightly better than A.
10. **Solubility:** A (-5.604) is very poor, consistent with the high logP. B (-1.442) is better, but still indicates low solubility.
11. **hERG:** A (0.296) has a slightly higher hERG risk than B (0.122), but both are relatively low.
12. **Cl_mic:** A (47.207) has a moderate microsomal clearance, suggesting moderate metabolic stability. B (0.321) has very low clearance, indicating excellent metabolic stability. This is a significant advantage for B.
13. **t1/2:** A (39.759) has a good in vitro half-life. B (-7.491) has a very poor in vitro half-life.
14. **Pgp:** A (0.256) has low P-gp efflux, which is favorable. B (0.006) has very low P-gp efflux, even more favorable.
15. **Affinity:** Both have excellent binding affinity (A: -8.3 kcal/mol, B: -8.0 kcal/mol). The difference is minimal.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

While Ligand A has a slightly better BBB penetration and comparable binding affinity, its significantly higher DILI risk, poor solubility, and poor Caco-2 permeability are major drawbacks. Ligand B, despite its lower logP and poor half-life, exhibits *much* better metabolic stability (Cl_mic) and a significantly lower DILI risk. The improved metabolic stability is a critical factor for kinase inhibitors, and the lower DILI risk is essential for clinical development. The poor half-life of B can be addressed through structural modifications. The poor solubility of both compounds is concerning, but can also be addressed through formulation strategies.

Therefore, **Ligand B** is the more promising drug candidate.

1
2025-04-17 13:38:18,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (66.92) is significantly better than Ligand B (78.87). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.035, Ligand B: 0.879), falling within the 1-3 range. Ligand A is slightly preferred.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA) as it has fewer hydrogen bond donors, which can improve membrane permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.507, Ligand B: 0.726), indicating drug-likeness. Ligand B is slightly better here.

**DILI:** Both ligands have low DILI risk (Ligand A: 37.999, Ligand B: 35.285), below the 40 threshold, which is excellent.

**BBB:** Ligand A (75.533) has a better BBB percentile than Ligand B (35.828), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**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 have low hERG risk (Ligand A: 0.566, Ligand B: 0.249), which is crucial for avoiding cardiotoxicity. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (114.395) has a higher microsomal clearance than Ligand B (39.572). Lower clearance is preferred for better metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand A (-35.496) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (-2.345) also has a negative half-life, but is closer to zero. This is a major concern for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.143, Ligand B: 0.058), which is favorable.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a critical advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Despite the issues with Caco-2, solubility, and half-life values, the significantly stronger binding affinity of Ligand A (-7.9 kcal/mol vs -0.0 kcal/mol) is the deciding factor. The better TPSA and logP of Ligand A also contribute to its favorability. While Ligand B has better metabolic stability (lower Cl_mic) and slightly better hERG, the potency difference is substantial. The negative half-life for Ligand A is concerning, but could be addressed through structural modifications.

Output:
1
2025-04-17 13:38:18,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.439 and 362.496 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.0) is better than Ligand B (41.13). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.297 and 3.27), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is not a major concern.

**H-Bond Donors & Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 1 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.394 and 0.761), with Ligand B being significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (83.288) has a significantly higher DILI risk than Ligand B (53.936). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (70.027 and 70.26), which is acceptable, but not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.196) has a worse Caco-2 permeability than Ligand B (-4.59).

**Aqueous Solubility:** Ligand A (-4.264) has a worse aqueous solubility than Ligand B (-5.071).

**hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.755 and 0.902).

**Microsomal Clearance:** Ligand A (116.822) has a higher microsomal clearance than Ligand B (75.334), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (60.895) has a significantly longer in vitro half-life than Ligand A (-12.739), which is a significant advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.63 and 0.582).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.4 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have acceptable potency and physicochemical properties, Ligand B demonstrates significantly better ADME-Tox properties. Specifically, the lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better solubility make it a much more promising drug candidate. The slightly higher QED score further supports this conclusion.

Output:
1
2025-04-17 13:38:18,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.49 and 339.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.29) is better than Ligand B (69.72) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.93 and 0.75), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar and good QED scores (0.826 and 0.823), indicating good drug-likeness.

**DILI:** Ligand B (70.18) has a higher DILI risk than Ligand A (62.23), making A preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (84.8) has a better BBB percentile than Ligand B (59.4).

**Caco-2:** Ligand A (-5.072) has a more negative Caco-2 value, which is not ideal. Ligand B (-4.47) is also not ideal, but slightly better.

**Solubility:** Ligand A (-3.384) has a more negative solubility value, which is not ideal. Ligand B (-2.901) is better.

**hERG:** Ligand A (0.769) has a slightly higher hERG risk than Ligand B (0.252), making B preferable.

**Microsomal Clearance:** Ligand A (50.75) has significantly lower microsomal clearance than Ligand B (14.55), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-1.883) has a negative half-life, which is not ideal. Ligand B (-35.801) is even worse.

**P-gp Efflux:** Ligand A (0.359) has lower P-gp efflux than Ligand B (0.059), which is preferable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a better binding affinity than Ligand B (-7.5 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has some less-than-ideal solubility and Caco-2 values, its superior binding affinity (-8.3 vs -7.5 kcal/mol) and significantly better metabolic stability (lower Cl_mic) are critical advantages for an enzyme target like SRC kinase. The lower DILI risk is also a positive factor. The slightly higher hERG risk is a concern but potentially manageable. Ligand B's lower hERG is offset by its poor metabolic stability.

Output:
1
2025-04-17 13:38:18,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.76) is well below the 140 threshold for good absorption, while Ligand B (83.56) is still acceptable but higher.

**logP:** Ligand A (3.481) is optimal, while Ligand B (1.412) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable counts, within the suggested limits.

**QED:** Both ligands have good QED scores (0.769 and 0.842), indicating drug-likeness.

**DILI:** Ligand A (34.161) has a lower DILI risk than Ligand B (55.642), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (64.986 and 68.127), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.668 and -4.758), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.769 and -2.69), which is also a concern.

**hERG:** Both ligands have low hERG inhibition liability (0.494 and 0.241), which is excellent.

**Microsomal Clearance:** Ligand A (71.254) has significantly higher microsomal clearance than Ligand B (3.741), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (18.541) has a longer in vitro half-life than Ligand A (37.445), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.399 and 0.012), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.3 kcal/mol). This difference of 1.8 kcal/mol is significant and can outweigh some ADME concerns.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.1 vs -7.3 kcal/mol) and much better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly lower logP and higher DILI risk. The lower DILI risk of Ligand A is attractive, but the poor metabolic stability is a critical issue for an enzyme inhibitor.

Output:
1
2025-04-17 13:38:18,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.483 and 369.418 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (70.08) is well below the 140 threshold, and even preferable for oral absorption. Ligand B (96.44) is still acceptable but less optimal.

**logP:** Ligand A (1.198) is within the optimal range of 1-3. Ligand B (0.134) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.85 and 0.814), indicating good drug-likeness.

**DILI:** Ligand A (40.442) has a better DILI score than Ligand B (59.636), indicating lower liver injury risk.

**BBB:** Both ligands have reasonable BBB penetration (60.838 and 71.268), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.675 and -4.828), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.621 and -1.887), which is also a concern, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.267 and 0.152), which is excellent.

**Microsomal Clearance:** Ligand A (26.75) has significantly better microsomal clearance than Ligand B (-12.451). Lower clearance indicates greater metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand A (26.701) has a much longer in vitro half-life than Ligand B (-0.568), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.213 and 0.025).

**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:**

Ligand B has a much better binding affinity, which is the most crucial factor for an enzyme inhibitor. However, it suffers from significantly worse metabolic stability (higher clearance, shorter half-life) and slightly lower solubility. Ligand A has better ADME properties, but a weaker binding affinity. Given the importance of potency for enzyme inhibition, the 1.7 kcal/mol difference in binding affinity is substantial. While the ADME properties of Ligand B are concerning, they might be addressable through further optimization. The strong binding affinity provides a solid starting point.

Output:
1
2025-04-17 13:38:18,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.475 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is better than Ligand B (73.74). Both are below 140, but lower is generally preferred for absorption.

**3. logP:** Both ligands have similar logP values (1.866 and 1.969), 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 (0.787 and 0.855), indicating drug-likeness.

**7. DILI:** Ligand A (50.291) has a significantly lower DILI risk than Ligand B (8.453). This is a major advantage for Ligand A.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (78.131) is better than Ligand A (67.546). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This suggests poor permeability. Ligand A (-4.626) is slightly better than Ligand B (-4.884).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests very poor solubility. Ligand A (-2.622) is slightly better than Ligand B (-1.825).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.465 and 0.167), which is excellent.

**12. Microsomal Clearance:** Ligand B (23.727) has significantly lower microsomal clearance than Ligand A (41.238), indicating better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-30.25) has a negative half-life, which is impossible. This is a major red flag. Ligand A (7.134) has a reasonable half-life.

**14. P-gp Efflux:** Both have very low P-gp efflux (0.091 and 0.027), which is good.

**15. 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 is superior due to its significantly lower DILI risk and reasonable in vitro half-life. While Ligand B has better metabolic stability, the impossibly negative in vitro half-life is a critical flaw. The solubility and permeability issues are concerning for both, but the DILI risk is a more immediate concern for drug development.

Output:
0
2025-04-17 13:38:18,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.53 and 353.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.49) is well below the 140 threshold for good absorption, while Ligand B (82.27) is still acceptable but higher.

**logP:** Both ligands have good logP values (2.77 and 1.53), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, well within acceptable limits. Ligand B has 2 HBD and 3 HBA, also good.

**QED:** Both ligands have high QED scores (0.909 and 0.861), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 60.45, which is borderline high. Ligand B has a much lower DILI risk of 36.45, which is good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have high BBB penetration (90.62 and 80.42), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data. However, we'll proceed assuming these represent low permeability.

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

**hERG Inhibition:** Ligand A (0.887) shows a slightly higher hERG risk than Ligand B (0.389).

**Microsomal Clearance:** Ligand A has a Cl_mic of 14.74 mL/min/kg, which is moderate. Ligand B has a significantly lower Cl_mic of -11.05 mL/min/kg, suggesting much better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A has a half-life of 63.04 hours, which is good. Ligand B has a very short half-life of -34.88 hours, which is a significant drawback.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.61, while Ligand B has a very low efflux of 0.019. This is a benefit for Ligand B.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life, Ligand B excels in key areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. The solubility and Caco-2 values are concerning for both, but the ADME advantages of Ligand B outweigh the longer half-life of Ligand A.

Output:
1
2025-04-17 13:38:18,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (373.337 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (87.47). A TPSA under 140 is good for oral absorption, and A is well within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.576) is optimal, while Ligand B (1.729) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.693 and 0.848), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (41.218 and 37.65), below the 60 threshold.

**BBB:** Both ligands have high BBB penetration (98.139 and 88.329), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the relative values suggest similar permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the relative values suggest similar solubility.

**hERG:** Both ligands show low hERG inhibition risk (0.687 and 0.562), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (30.079 and 29.517 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (14.055 hours) has a significantly longer half-life than Ligand B (-18.949 hours). A negative half-life is not physically possible and indicates a serious issue with the data for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.206 and 0.027).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -9.1 kcal/mol).

**Conclusion:**

Ligand A is the superior candidate. While both have good affinity and acceptable safety profiles, Ligand A has a better TPSA, logP, H-bond characteristics, and a *realistic* half-life. The negative half-life for Ligand B is a critical flaw, suggesting a problem with the data or the molecule's inherent instability. The slightly better logP and TPSA of Ligand A also contribute to its improved predicted pharmacokinetic properties.

Output:
1
2025-04-17 13:38:18,513 - INFO - Batch 230 complete. Total preferences: 3680
2025-04-17 13:38:18,513 - INFO - Processing batch 231/512...
2025-04-17 13:39:00,199 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.443 and 345.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.86) is slightly above the preferred <140, while Ligand B (71.53) is well within the range.

**logP:** Both ligands have good logP values (2.242 and 1.995), falling within the optimal 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, which is within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.601 and 0.886), indicating good drug-like properties.

**DILI:** Ligand A (34.742) has a slightly higher DILI risk than Ligand B (26.018), but both are below the concerning threshold of 60.

**BBB:** Ligand A (25.746) has a low BBB penetration, which isn't critical for a non-CNS target like SRC kinase. Ligand B (84.684) has high BBB penetration, which is irrelevant here.

**Caco-2:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the values are on a different scale, and direct comparison is difficult.

**Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, scale differences make direct comparison difficult.

**hERG:** Both ligands have very low hERG inhibition risk (0.046 and 0.435), which is excellent.

**Microsomal Clearance:** Ligand A (15.071) has lower microsomal clearance than Ligand B (25.133), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.274) has a significantly longer in vitro half-life than Ligand B (-6.274), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.025).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol), with Ligand A being slightly better. The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is slightly more promising. It has a slightly better binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), and a lower DILI risk, despite a slightly higher TPSA. The solubility and Caco-2 values are concerning for both, but the superior metabolic stability and half-life of Ligand A are crucial for *in vivo* efficacy.

Output:
1
2025-04-17 13:39:00,201 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.22) is slightly higher than Ligand B (98.57), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.291 and 1.689 respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.811 and 0.785), indicating drug-likeness.

**DILI:** Ligand A (54.207) has a slightly higher DILI risk than Ligand B (46.801), but both are below the concerning threshold of 60.

**BBB:** Ligand A (64.25) has a higher BBB penetration percentile than Ligand B (25.475). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.024) has a more negative Caco-2 value, suggesting lower permeability than Ligand B (-5.242). This is a slight negative for Ligand A.

**Aqueous Solubility:** Ligand A (-0.868) has slightly better aqueous solubility than Ligand B (-2.729). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.124) shows a significantly lower hERG inhibition liability than Ligand B (0.353). This is a crucial advantage for Ligand A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (-22.433) has a significantly lower (better) microsomal clearance than Ligand A (41.66). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (4.943) has a longer in vitro half-life than Ligand A (-27.591), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.024) has a lower P-gp efflux liability than Ligand B (0.105), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -8.9 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) which is a key consideration for kinase inhibitors. However, Ligand A has a significantly better hERG profile and slightly better solubility. Given the importance of minimizing off-target effects like hERG inhibition for kinase inhibitors, and the similar binding affinities, the lower hERG risk of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 13:39:00,201 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.491 and 358.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (81.67 and 87.66) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.89) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.39) is well within the optimal range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, satisfying the <5 and <10 rules, respectively.

**QED:** Both ligands have acceptable QED scores (0.607 and 0.523), indicating good drug-like properties.

**DILI:** Ligand A (6.669 percentile) has a significantly lower DILI risk than Ligand B (12.796 percentile). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (68.321 and 64.095 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.454) has worse Caco-2 permeability than Ligand B (-4.614), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.382) has better aqueous solubility than Ligand B (-2.518). This is a positive for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.416 and 0.507).

**Microsomal Clearance:** Ligand A (-9.024 mL/min/kg) exhibits significantly lower microsomal clearance than Ligand B (58.533 mL/min/kg), suggesting much better metabolic stability.

**In vitro Half-Life:** Ligand A (7.072 hours) has a longer half-life than Ligand B (0.508 hours), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.056).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a stronger binding affinity than Ligand B (-6.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Despite slightly lower logP and Caco-2 permeability, its significantly better DILI score, dramatically improved metabolic stability (lower Cl_mic and longer t1/2), and superior binding affinity outweigh these concerns. The stronger binding affinity is particularly important for an enzyme target like SRC kinase. The better solubility is also a plus.

Output:
1
2025-04-17 13:39:00,202 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which can be advantageous for permeability. Ligand B (366.615 Da) is also good.

**TPSA:** Ligand A (118.53) is better than Ligand B (32.34) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (0.64) is a bit low, potentially hindering permeation. Ligand B (4.458) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 3 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.714, B: 0.78), indicating good drug-like properties.

**DILI:** Ligand A (44.126) has a slightly higher DILI risk than Ligand B (32.842), but both are below the concerning threshold of 60.

**BBB:** Ligand A (67.08) and Ligand B (85.072) both have acceptable BBB penetration, but this is less critical for a non-CNS target like SRC.

**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 the relative values. Ligand A (-5.191) is slightly better than Ligand B (-5.206).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.183) is slightly better than Ligand B (-4.773).

**hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, which is excellent. Ligand B (0.683) has a moderate hERG risk, which is a concern.

**Microsomal Clearance:** Ligand A (19.043) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (100.475) has a very high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-28.357) has a negative half-life, which is problematic. Ligand B (14.005) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is favorable. Ligand B (0.532) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has some ADME liabilities (high logP, high Cl_mic, moderate Pgp efflux, and moderate hERG risk), the significantly improved potency could make it a viable candidate, especially if these liabilities can be addressed through further optimization. Ligand A has better ADME properties overall (lower logP, lower Cl_mic, lower Pgp efflux, very low hERG risk), but its weaker binding affinity is a major drawback. The negative half-life for Ligand A is also a significant concern.

Output:
1
2025-04-17 13:39:00,202 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.53 and 352.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (36.36) as it is closer to the ideal range for oral absorption (<140).

**logP:** Ligand A (2.362) is optimal (1-3), while Ligand B (4.851) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4/3) counts, well within the recommended limits.

**QED:** Both ligands have similar QED values (0.784 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (25.902) has a significantly lower DILI risk than Ligand B (19.426), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (91.857) is better than Ligand A (76.813). However, BBB is not a primary concern for a kinase inhibitor unless CNS effects are specifically desired.

**Caco-2 Permeability:** Ligand A (-5.124) is worse than Ligand B (-4.547), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.334) is worse than Ligand B (-4.085). Solubility is important for bioavailability.

**hERG:** Ligand A (0.385) has a lower hERG risk than Ligand B (0.897), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (54.839) has lower microsomal clearance than Ligand B (57.113), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.566) has a much longer in vitro half-life than Ligand B (-16.289), indicating better duration of action.

**P-gp Efflux:** Ligand A (0.279) has lower P-gp efflux than Ligand B (0.539), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-9.2). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall:**

Ligand A is the more promising candidate. It has a lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity and Caco-2 permeability, the advantages of Ligand A in terms of safety and pharmacokinetic properties are more critical for an enzyme inhibitor. The logP of Ligand B is also a concern.

Output:
0
2025-04-17 13:39:00,202 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.436 and 348.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (89.07) is still under 140, but less favorable than A.

**logP:** Both ligands (3.017 and 2.303) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 7 HBA.  Ligand A is better here, as higher HBA can sometimes negatively impact permeability.

**QED:** Ligand A (0.79) has a higher QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand A (23.924) has a significantly lower DILI risk than Ligand B (57.425). This is a major advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (91.159) has better BBB penetration than Ligand B (57.193).

**Caco-2 Permeability:** Ligand A (-4.477) has a more favorable (higher) Caco-2 permeability than Ligand B (-5.425).

**Aqueous Solubility:** Ligand A (-3.443) has better aqueous solubility than Ligand B (-2.159).

**hERG:** Ligand A (0.618) has a lower hERG risk than Ligand B (0.198), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (31.024) has lower microsomal clearance than Ligand A (43.835), suggesting better metabolic stability. This is a point in favor of Ligand B.

**In vitro Half-Life:** Ligand B (12.452) has a longer in vitro half-life than Ligand A (-40.154). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux than Ligand B (0.105), which is favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). The difference is 0.6 kcal/mol, which is a moderate advantage.

**Overall Assessment:**

Ligand A excels in most ADME properties (DILI, solubility, permeability, hERG, P-gp efflux) and has a good QED score. While its affinity is slightly lower, its superior ADME profile and safety characteristics are compelling. Ligand B has better metabolic stability and half-life, and slightly better affinity, but suffers from higher DILI risk, lower solubility, and a more concerning hERG profile. For an enzyme target like SRC kinase, a balance of potency and favorable ADME/Tox properties is crucial. Given the significant advantages of Ligand A in safety and key ADME parameters, it is the more promising drug candidate.

Output:
0
2025-04-17 13:39:00,202 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (361.551 Da) is also well within the range.

**TPSA:** Ligand A (96.78) is better than Ligand B (29.54). Lower TPSA generally correlates with better cell permeability, and both are acceptable, but B is significantly better.

**logP:** Ligand A (0.803) is slightly low, potentially hindering permeation. Ligand B (4.56) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which is reasonable. Ligand B has 0 HBD and 3 HBA, also reasonable.

**QED:** Both ligands have acceptable QED values (A: 0.629, B: 0.568), indicating reasonable drug-likeness.

**DILI:** Ligand A (50.368) has a slightly higher DILI risk than Ligand B (33.618), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.552) has a lower BBB penetration than Ligand B (85.149). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.39) has poor Caco-2 permeability, while Ligand B (-4.545) is better, but still low.

**Aqueous Solubility:** Ligand A (-1.555) has poor aqueous solubility, while Ligand B (-5.333) is even worse. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.087) has very low hERG inhibition risk, which is excellent. Ligand B (0.65) has a slightly higher risk, but still relatively low.

**Microsomal Clearance:** Ligand A (21.722) has much lower microsomal clearance than Ligand B (115.692), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (25.044) has a slightly shorter half-life than Ligand B (28.923), but both are reasonable.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is favorable for bioavailability. Ligand B (0.851) has higher P-gp efflux, potentially reducing bioavailability.

**Binding Affinity:** Ligand A (-7.4) has a stronger binding affinity than Ligand B (-6.9). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While its solubility and Caco-2 permeability are poor, the strong binding affinity and metabolic stability are crucial for an enzyme inhibitor. The lower hERG risk is also a significant advantage. Ligand B's high logP and poor solubility are concerning, and its weaker affinity is a major drawback.

Output:
0
2025-04-17 13:39:00,203 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.805 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.49) is slightly above the preferred <140, but acceptable. Ligand B (53.33) is excellent, well below 140.

**logP:** Ligand A (2.334) is within the optimal 1-3 range. Ligand B (4.315) is a bit high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable.

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

**QED:** Both ligands have good QED scores (0.652 and 0.728), indicating good drug-like properties.

**DILI:** Ligand A (80.574) has a higher DILI risk than Ligand B (28.383). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (76.309 and 79.527). This isn't a primary concern for a kinase inhibitor, but isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.906 and -4.794). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute permeability could still be reasonable.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.148 and -5.523). This is concerning, as solubility is a key factor for bioavailability.

**hERG Inhibition:** Ligand A (0.282) has a lower hERG risk than Ligand B (0.91). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (47.216) has lower microsomal clearance than Ligand B (95.472), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (36.247 and 35.312 hours).

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux than Ligand B (0.784), suggesting better oral bioavailability.

**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 for Ligand B, potentially outweighing some of its ADME drawbacks. A 1.8 kcal/mol difference is quite large.

**Conclusion:**

Despite Ligand A having better metabolic stability (lower Cl_mic), lower P-gp efflux, and lower hERG risk, the significantly stronger binding affinity of Ligand B (-8.9 vs -7.1 kcal/mol) is the most important factor for an enzyme inhibitor. While Ligand B has a higher logP and DILI risk, the potency advantage is likely to be decisive. The solubility issues are concerning, but could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:39:00,203 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.434 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (64.41) is significantly better than Ligand B (101.8). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (A: 2.783, B: 1.233), falling within the 1-3 range. Ligand A is slightly better, being closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) is better than Ligand B (HBD=2, HBA=8). Lower HBA is generally preferred for better permeability.

**QED:** Both ligands have similar QED values (A: 0.718, B: 0.688), indicating good drug-likeness.

**DILI:** Ligand A (44.436) has a significantly lower DILI risk than Ligand B (59.713), making it safer from a liver toxicity perspective.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (93.253) has a much higher BBB percentile than Ligand B (53.083).

**Caco-2 Permeability:** Ligand A (-4.202) is better than Ligand B (-5.785), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.173) is better than Ligand B (-2.407), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.665) is significantly better than Ligand B (0.075), indicating a lower risk of cardiotoxicity. This is a critical factor.

**Microsomal Clearance:** Ligand B (30.714) has lower microsomal clearance than Ligand A (50.996), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Both ligands have negative half-lives (-21.213 for A, -23.266 for B), which is unusual and suggests rapid degradation. However, the values are similar.

**P-gp Efflux:** Ligand A (0.267) is better than Ligand B (0.045), indicating lower P-gp efflux and potentially better bioavailability.

**Binding Affinity:** Ligand B (-7.0) has a significantly better binding affinity than Ligand A (0.0). This is a major advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, DILI, BBB, Caco-2, Solubility, hERG, P-gp) and has a reasonable QED. However, its binding affinity is very weak.

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While its ADME properties are generally worse than Ligand A's (higher TPSA, DILI, lower solubility, worse hERG), the substantial improvement in binding affinity (-7.0 kcal/mol vs 0.0 kcal/mol) likely outweighs these drawbacks. The lower clearance of Ligand B is also a positive.

Given the priorities for kinase inhibitors, the significantly improved binding affinity of Ligand B makes it the more promising drug candidate, despite its less favorable ADME profile. Optimization of Ligand B's ADME properties could be pursued in subsequent iterations.

Output:
1
2025-04-17 13:39:00,203 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.399 and 347.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is slightly higher than Ligand B (91.94), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.569) is within the optimal 1-3 range, while Ligand B (3.28) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.639) has a better QED score than Ligand B (0.448), indicating a more drug-like profile.

**DILI:** Ligand B (29.779) has a significantly lower DILI risk than Ligand A (56.921), which is a major advantage.

**BBB:** Ligand B (82.125) shows better BBB penetration than Ligand A (53.587), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.202 and -5.014), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.855 and -2.75), indicating very poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.045) has a slightly lower hERG inhibition liability than Ligand B (0.533), which is preferable.

**Microsomal Clearance:** Ligand A (-29.308) has a much lower (better) microsomal clearance than Ligand B (23.687), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (23.497) has a significantly longer in vitro half-life than Ligand A (-8.923), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.02) has a lower P-gp efflux liability than Ligand B (0.16), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.1), although the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand B has a better binding affinity, lower DILI risk, and a longer half-life. However, Ligand A has better metabolic stability (lower Cl_mic), lower P-gp efflux, and a better QED score. Both have very poor solubility and permeability. Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG), the slightly better binding affinity and significantly lower DILI risk of Ligand B outweigh the advantages of Ligand A, *despite* the solubility and permeability issues. The metabolic stability difference is not large enough to overcome the DILI concern. Addressing the solubility and permeability would be crucial for either compound.

Output:
1
2025-04-17 13:39:00,203 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.443 and 346.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.66) is better than Ligand B (106.66), both are below the 140 A^2 threshold for oral absorption, but A is closer to the preferred <90 A^2 for CNS targets (though this is less critical for a non-CNS target like SRC).

**logP:** Ligand A (1.485) is within the optimal range (1-3), while Ligand B (-0.983) is slightly below, potentially impacting permeability.

**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 similar QED values (0.631 and 0.59), indicating good drug-like properties.

**DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (27.608), which is a major advantage. Both are below the 40 threshold.

**BBB:** This is less critical for SRC, but Ligand A (56.378) has a better BBB percentile than Ligand B (43.583).

**Caco-2 Permeability:** Ligand A (-4.639) has worse Caco-2 permeability than Ligand B (-5.288), but both are poor.

**Aqueous Solubility:** Ligand A (-2.042) has slightly better aqueous solubility than Ligand B (-1.983), but both are poor.

**hERG Inhibition:** Ligand A (0.301) has a lower hERG inhibition liability than Ligand B (0.047), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (-15.715) has significantly lower microsomal clearance than Ligand A (28.41), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-8.596) has a longer in vitro half-life than Ligand A (-11.733), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.1 and 0.01).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. However, Ligand A has a significantly lower DILI risk and lower hERG inhibition liability, which are critical safety parameters. While the affinity difference is not large, the safety profile of Ligand A is considerably better. Given the enzyme-specific priorities, the improved safety profile of Ligand A outweighs the slightly better metabolic stability and affinity of Ligand B.

Output:
1
2025-04-17 13:39:00,203 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.289 and 362.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.63) is well below the 140 threshold for good absorption, while Ligand B (97.11) is approaching it but still acceptable.

**3. logP:** Both ligands (2.533 and 2.24) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is excellent, while Ligand B (3) is still within the acceptable limit of <=5.

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

**6. QED:** Both ligands have good QED scores (0.623 and 0.718), indicating drug-like properties.

**7. DILI:** Ligand A (84.762) has a higher DILI risk than Ligand B (62.466), which is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (85.731) has slightly better BBB penetration than Ligand B (61.923).

**9. Caco-2 Permeability:** Ligand A (-3.871) and Ligand B (-4.989) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-4.29) and Ligand B (-3.786) both have poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.275) has a much lower hERG inhibition liability than Ligand B (0.507), which is a major advantage.

**12. Microsomal Clearance:** Ligand A (118.049) has a higher microsomal clearance than Ligand B (-0.848), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-34.453) has a negative half-life, which is not possible and indicates a very short half-life. Ligand B (22.619) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.426) has slightly lower P-gp efflux than Ligand B (0.078), which is preferable.

**15. Binding Affinity:** Ligand B (-8.8 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.

**Conclusion:**

Despite Ligand B having a slightly higher DILI risk and poorer Caco-2 permeability, its significantly stronger binding affinity (-8.8 vs -7.9 kcal/mol) and much better in vitro half-life (22.619 vs -34.453) make it the more promising candidate. The lower hERG risk of Ligand A is attractive, but the extremely poor half-life is a dealbreaker. The stronger binding of Ligand B is a critical advantage for an enzyme inhibitor.

Output:
1
2025-04-17 13:39:00,203 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.447 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (119.39) is better than Ligand B (40.62) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (-0.833) is a bit low, potentially hindering permeation. Ligand B (3.423) is within the optimal range (1-3).

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

**H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (2) is also good.

**QED:** Both ligands have good QED scores (A: 0.644, B: 0.725), indicating drug-like properties.

**DILI:** Ligand A (62.233) has a moderate DILI risk, but is still acceptable. Ligand B (14.036) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.717) has a higher BBB penetration than Ligand A (48.895), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-5.342) has poor Caco-2 permeability. Ligand B (-4.319) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.765, B: -2.595). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.117) has a very low hERG risk, which is excellent. Ligand B (0.558) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (6.787) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (84.974) has a very high clearance, which is a significant drawback.

**In vitro Half-Life:** Ligand A (45.599) has a better in vitro half-life than Ligand B (-7.445).

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is favorable. Ligand B (0.4) has a slightly higher P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.6 kcal/mol, B: -9.2 kcal/mol). Ligand B is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand B has a better logP, lower DILI risk, and slightly better binding affinity. However, it suffers from very high microsomal clearance and poor in vitro half-life, which are critical drawbacks for an enzyme inhibitor. Ligand A has a lower logP and higher DILI, but its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux make it a more promising candidate. The slightly better affinity of Ligand B is unlikely to outweigh the significant pharmacokinetic liabilities.

Output:
0
2025-04-17 13:39:00,204 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.428 Da) is slightly higher than Ligand B (341.371 Da), but both are acceptable.

**TPSA:** Ligand A (53.4) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (109.8) is still under 140, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (3.333) is optimal. Ligand B (0.095) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (A: 0.771, B: 0.726), indicating good drug-likeness.

**DILI:** Ligand A (29.003) has a significantly lower DILI risk than Ligand B (58.86). This is a substantial advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (91.392) has a better BBB score than Ligand B (44.901).

**Caco-2 Permeability:** Ligand A (-4.815) has a better (less negative) Caco-2 value than Ligand B (-5.569), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.113 and -2.387 respectively). This is a concern for both, but might be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.906) has a lower hERG risk than Ligand B (0.121), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (40.412) has a higher (worse) microsomal clearance than Ligand B (-19.148). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (53.976) has a longer half-life than Ligand B (-0.865).

**P-gp Efflux:** Ligand A (0.247) has lower P-gp efflux liability than Ligand B (0.012), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -7.8 kcal/mol), with Ligand B being slightly better. However, the difference is small and likely less important than the ADME differences.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A excels in crucial areas like DILI risk, hERG inhibition, Caco-2 permeability, and P-gp efflux. The low logP of Ligand B is a major concern, potentially leading to poor bioavailability. The significantly lower DILI and hERG risks associated with Ligand A make it a much safer and more promising starting point for drug development. The slightly higher clearance of Ligand A can be addressed through structural modifications during optimization.

Output:
1
2025-04-17 13:39:00,204 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.43 and 347.46 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.44) is slightly higher than Ligand B (61.68), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (1.449 and 1.06), 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.889 and 0.82), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (36.45 and 34.16), well below the concerning threshold of 60.

**BBB:** Ligand B (70.03) shows better BBB penetration than Ligand A (63.78), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.08) has worse Caco-2 permeability than Ligand B (-4.72), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.767) has worse aqueous solubility than Ligand B (-0.78), which could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.612 and 0.303), which is excellent.

**Microsomal Clearance:** Ligand A (-18.61) has significantly lower microsomal clearance than Ligand B (17.45). This indicates better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (20.28 hours) has a much longer in vitro half-life than Ligand A (-0.239 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 (0.068 and 0.081).

**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 less than the 1.5 kcal/mol threshold, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic). However, Ligand B exhibits superior solubility, Caco-2 permeability, and a much longer half-life. Considering SRC is a kinase, metabolic stability and half-life are crucial. The slightly better affinity of Ligand A is somewhat offset by its poor half-life and solubility. The longer half-life of Ligand B is a significant advantage, potentially outweighing the minor difference in binding affinity.

Output:
1
2025-04-17 13:39:00,204 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.415 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is slightly higher than Ligand B (84.67). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand B (1.767) is within the optimal 1-3 range, while Ligand A (0.9) is slightly below, potentially impacting permeability. Ligand B is better here.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.662 and 0.839, respectively), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (14.114) has a significantly lower DILI risk than Ligand B (56.572). This is a major advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but the values are similar.

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

**hERG:** Both ligands have very low hERG inhibition liability (0.276 and 0.23), which is excellent.

**Microsomal Clearance:** Ligand A (-14.208) has *much* lower (better) microsomal clearance than Ligand B (47.77). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-7.713) has a much longer in vitro half-life than Ligand B (-16.948), again indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03 and 0.138).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). This is a 1.6 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and logP, Ligand A demonstrates superior ADMET properties, particularly regarding DILI risk and metabolic stability (lower Cl_mic and longer t1/2). The difference in binding affinity (1.6 kcal/mol) is outweighed by the substantial improvements in safety (DILI) and pharmacokinetics (Cl_mic, t1/2). For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (DILI) are crucial.

Output:
0
2025-04-17 13:39:00,204 - INFO - Batch 231 complete. Total preferences: 3696
2025-04-17 13:39:00,205 - INFO - Processing batch 232/512...
2025-04-17 13:39:44,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.869 and 345.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have similar TPSA values (64.35 and 64.41), which are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values within the optimal range (4.375 and 3.266). Ligand B is slightly better here, being closer to the ideal 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, well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.805) has a significantly better QED score than Ligand B (0.567), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.891) has a slightly higher DILI risk than Ligand B (28.965), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (70.88 and 76.037), but this is less critical for a non-CNS target like SRC.

**9. Caco-2:** Both have negative Caco-2 values which is unusual. Assuming these are logP values, they are very poor.

**10. Solubility:** Both ligands have negative solubility values which is unusual. Assuming these are logS values, they are very poor.

**11. hERG:** Both ligands have similar, low hERG inhibition liability (0.751 and 0.794), which is good.

**12. Cl_mic:** Ligand A (26.014 mL/min/kg) has significantly lower microsomal clearance than Ligand B (46.067 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. t1/2:** Ligand A (53.316 hours) has a much longer in vitro half-life than Ligand B (-22.087 hours). The negative value for Ligand B is concerning and likely an error, but even if it were positive, Ligand A's half-life is substantially better.

**14. Pgp:** Both ligands have similar Pgp efflux liability (0.382 and 0.506), which is acceptable.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.4 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A is the superior candidate. While both ligands have good potency and acceptable safety profiles, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a higher QED score. These factors are crucial for an enzyme inhibitor, as they contribute to sustained target engagement and favorable pharmacokinetic properties. The slight advantage in binding affinity further supports the selection of Ligand A. 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 13:39:44,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 359.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.69) is slightly higher than Ligand B (78.51), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.37) is quite low, potentially hindering permeability. Ligand B (1.303) is better, 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.796 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (46.297) has a slightly higher DILI risk than Ligand B (31.795), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (76.231 and 82.706), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is also a significant concern.

**hERG:** Ligand A (0.07) has a slightly better hERG profile than Ligand B (0.323), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (0.897) has significantly *lower* microsomal clearance than Ligand B (-4.001), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (17.908) has a longer half-life than Ligand B (-8.102), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.028 and 0.027).

**Binding Affinity:** Ligand A (-10.4 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.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-10.4 vs -7.4 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target like SRC kinase. While Ligand B has a slightly better logP, the potency and stability advantages of Ligand A are more important. Further optimization would focus on improving the solubility and permeability of Ligand A, but the core structure appears more promising.

Output:
0
2025-04-17 13:39:44,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.515 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.29) is better than Ligand B (67.87), both are under the 140 threshold for oral absorption, but Ligand B is closer to the 90 threshold for CNS targets (though that's not a priority here).

**logP:** Both ligands (1.186 and 2.116) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), both are within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands (4) are well below the 10 limit.

**QED:** Both ligands (0.57 and 0.61) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (14.696) has a significantly lower DILI risk than Ligand B (17.138), both are good (<40).

**BBB:** Ligand A (61.419) has a lower BBB penetration than Ligand B (88.29), but BBB isn't a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-5.685) has worse Caco-2 permeability than Ligand B (-4.569).

**Aqueous Solubility:** Ligand A (-2.919) has worse aqueous solubility than Ligand B (-1.578).

**hERG Inhibition:** Ligand A (0.165) has a lower hERG risk than Ligand B (0.479), which is a significant advantage.

**Microsomal Clearance:** Ligand A (43.265) has lower microsomal clearance than Ligand B (58.358), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.127) has a much shorter half-life than Ligand B (12.155). This is a major drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.011) has lower P-gp efflux than Ligand B (0.065), which is favorable.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.3). The difference is 0.4 kcal/mol, which is not substantial enough to overcome the other deficiencies.

**Conclusion:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, its significantly shorter half-life (0.127 vs 12.155) and worse solubility are major concerns. Ligand B has a much better half-life and solubility, and acceptable values for all other parameters. The 0.4 kcal/mol difference in binding affinity is not enough to overcome the ADME deficiencies of Ligand A. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 13:39:44,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.45 & 351.54 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.29) is higher than Ligand B (43.86). While both are acceptable, Ligand B's lower TPSA is preferable for permeability.

**logP:** Both ligands have similar logP values (2.82 & 2.77), 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.

**QED:** Both ligands have similar QED values (0.737 & 0.6), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 69.68%, which is considered high. Ligand B has a much lower DILI risk of 5.97%, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 34.32%, while Ligand B has 87.09%. Since SRC is not a CNS target, BBB is less critical, but higher BBB is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.184) and Ligand B (-4.5) 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:** Ligand A (-4.179) has worse solubility than Ligand B (-1.262). Solubility is important for bioavailability, so Ligand B is favored.

**hERG Inhibition:** Ligand A (0.563) has a slightly higher hERG risk than Ligand B (0.761), but both are relatively low.

**Microsomal Clearance:** Ligand A (82.53 mL/min/kg) has significantly higher microsomal clearance than Ligand B (33.10 mL/min/kg). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (17.09 hours) has a longer half-life than Ligand B (-0.101 hours). However, the negative half-life for Ligand B is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux than Ligand B (0.091), which is preferable.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A, and could potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a high DILI risk and higher metabolic clearance. Ligand B has a much better safety profile (DILI) and metabolic stability, but significantly weaker binding affinity. Given the substantial difference in binding affinity (-9.9 vs 0.0 kcal/mol), the potency advantage of Ligand A is likely to outweigh its ADME liabilities, *assuming* the binding affinity measurement is reliable. The negative half-life for Ligand B is a red flag.

Output:
1
2025-04-17 13:39:44,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.439 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is better than Ligand B (61.36), both are below the 140 threshold for good absorption.

**logP:** Both ligands (2.761 and 2.918) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Ligand A (0.879) has a higher QED score than Ligand B (0.77), indicating better overall drug-likeness.

**DILI:** Ligand A (14.928) has a significantly lower DILI risk than Ligand B (37.224). This is a crucial advantage.

**BBB:** Both have reasonable BBB penetration, with Ligand A at 77.705 and Ligand B at 90.229. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.894 and -4.931). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both have negative solubility values (-3.013 and -2.916), indicating poor aqueous solubility. This is a concern, but similar for both.

**hERG Inhibition:** Ligand A (0.774) has a lower hERG inhibition liability than Ligand B (0.902), which is preferable.

**Microsomal Clearance:** Ligand A (32.652) has a lower microsomal clearance than Ligand B (62.809), suggesting better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (0.698) has a lower half-life than Ligand B (-0.058). This is a disadvantage for ligand A.

**P-gp Efflux:** Ligand A (0.13) has lower P-gp efflux than Ligand B (0.268), which is preferable.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). While both are good, the 0.7 kcal/mol difference is noteworthy.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic), lower hERG inhibition, better QED, and slightly better binding affinity. While both have poor solubility and permeability, the ADME properties of Ligand A are more favorable, making it a more promising drug candidate for SRC kinase inhibition.

Output:
0
2025-04-17 13:39:44,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.841 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (76.02) is lower than Ligand A (90.41), which is slightly preferable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.083) is at the upper end, while Ligand B (1.813) is closer to 2. This favors Ligand B slightly.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 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 scores (A: 0.796, B: 0.706), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (89.686%) compared to Ligand B (21.908%). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (68.786%) is slightly better than Ligand B (53.276%), but this is not a deciding factor.

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the scale is undefined.

**hERG:** Ligand A (0.209) has a slightly better hERG profile (lower risk) than Ligand B (0.057).

**Microsomal Clearance:** Ligand A (89.737) has a much higher microsomal clearance than Ligand B (30.013), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-16.095) has a negative half-life, which is not possible and suggests a very rapid degradation. Ligand A (71.831) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.506) has a lower P-gp efflux liability than Ligand B (0.024), which is preferable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate despite the negative half-life and solubility values. Ligand A has a high DILI risk and poor metabolic stability (high Cl_mic), which are major concerns. The slight advantage of Ligand A in hERG and BBB is outweighed by these significant liabilities. 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 13:39:44,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.925 Da) is slightly higher, but acceptable. Ligand B (365.459 Da) is also good.

**TPSA:** Ligand A (70.4) is well below the 140 threshold for oral absorption. Ligand B (111.18) is still under 140, but getting closer to the limit, potentially impacting absorption.

**logP:** Ligand A (3.78) is within the optimal range (1-3). Ligand B (0.466) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both within acceptable limits. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.769, B: 0.731), indicating good drug-likeness.

**DILI:** Ligand A (82.396) has a higher DILI risk than Ligand B (59.984). While both are above the preferred <40, Ligand B is significantly better.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (57.193) is slightly better than Ligand B (47.615).

**Caco-2 Permeability:** Ligand A (-4.943) shows better predicted permeability than Ligand B (-5.553).

**Aqueous Solubility:** Ligand A (-4.863) has better predicted solubility than Ligand B (-1.484). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.477) has a much lower hERG risk than Ligand B (0.085). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (55.335) has higher microsomal clearance than Ligand B (23.277), indicating lower metabolic stability. Ligand B is much better here.

**In vitro Half-Life:** Ligand A (55.096) has a positive half-life, while Ligand B (-21.638) has a negative half-life, suggesting very rapid metabolism. This is a major drawback for Ligand B.

**P-gp Efflux:** Ligand A (0.73) has slightly higher P-gp efflux than Ligand B (0.042), but both are relatively low.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8 kcal/mol, B: -9 kcal/mol), with Ligand B being slightly better. However, the difference in affinity is likely less important than the ADME differences.

**Overall Assessment:**

Ligand B has a better binding affinity and lower DILI risk, and significantly better metabolic stability (lower Cl_mic, positive t1/2). However, it suffers from very low logP, potentially impacting absorption, and a concerningly low solubility. Ligand A has a slightly higher DILI risk and faster metabolism, but its logP and solubility are much more favorable, and its hERG risk is significantly lower. Given the enzyme-specific priorities, the better metabolic stability and slightly better binding affinity of Ligand B are attractive. However, the poor logP and solubility of Ligand B are major concerns that could severely limit its bioavailability. The more balanced profile of Ligand A, with acceptable ADME properties and a strong binding affinity, makes it the more promising candidate.

Output:
1
2025-04-17 13:39:44,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.381 and 382.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is better than Ligand B (49.41) as it is closer to the threshold of 140.

**logP:** Both ligands have logP values (4.092 and 4.664) that are slightly high, potentially leading to solubility issues or off-target effects. Ligand B is a bit higher.

**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 3 HBA, well within the acceptable limit of <=10.

**QED:** Ligand A (0.74) has a significantly better QED score than Ligand B (0.424), indicating a more drug-like profile.

**DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (28.383). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonably high BBB penetration (82.513 and 79.294), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.689 and -4.961). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.998 and -3.569). This is a major concern.

**hERG Inhibition:** Ligand A (0.804) has slightly higher hERG inhibition risk than Ligand B (0.838), but both are relatively low.

**Microsomal Clearance:** Ligand A (85.834) has a significantly higher microsomal clearance than Ligand B (52.864), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.668) has a slightly better (less negative) in vitro half-life than Ligand A (-24.41).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.271 and 0.728).

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a substantially better binding affinity than Ligand A (-8.5 kcal/mol). This difference of 1.7 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having a better QED and TPSA, Ligand B is the more promising candidate. The significantly stronger binding affinity (-10.2 vs -8.5 kcal/mol) of Ligand B is a major advantage for an enzyme inhibitor. While both have poor solubility and permeability, the lower DILI risk and better metabolic stability (lower Cl_mic, better t1/2) of Ligand B are also favorable. The slightly higher logP of Ligand B is a minor concern compared to the substantial affinity difference.

Output:
1
2025-04-17 13:39:44,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.909 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.36) is significantly better than Ligand B (88.58).  A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have good logP values (2.536 and 2.318), 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 (0.785 and 0.898), indicating good drug-likeness.

**DILI:** Ligand A (22.838) has a much lower DILI risk than Ligand B (44.591). This is a significant advantage for Ligand A.

**BBB:** Ligand A (92.943) shows better BBB penetration than Ligand B (69.95), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.099 and -5.104), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.577 and -2.584). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.577) has a slightly higher hERG risk than Ligand B (0.222), but both are relatively low.

**Microsomal Clearance:** Ligand A (11.407) and Ligand B (10.953) have similar, relatively low, microsomal clearance values, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (26.538) has a longer half-life than Ligand B (16.643), which is desirable.

**P-gp Efflux:** Ligand A (0.034) has very low P-gp efflux liability, while Ligand B (0.124) is slightly higher. Lower is better.

**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, and could potentially outweigh some of the ADME deficiencies.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.3 vs 0 kcal/mol) is a major advantage. While both ligands have poor solubility and Caco-2 permeability, the potency difference is substantial. Ligand A has a better safety profile (lower DILI) and better pharmacokinetic properties (longer half-life, lower P-gp efflux), but the binding affinity is a critical factor for enzyme inhibitors. Given the importance of potency for kinase inhibitors, and the fact that the other ADME properties are only moderately different, the stronger binding of Ligand B is the deciding factor.

Output:
1
2025-04-17 13:39:44,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.268 Da) is slightly higher than Ligand B (342.359 Da), but both are acceptable.

**TPSA:** Ligand A (86.36) is better than Ligand B (104.19) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (2.584) is optimal (1-3), while Ligand B (-0.827) is below 1, potentially hindering permeation. This is a significant negative for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=1, HBA=6) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.684, B: 0.784), indicating good drug-like properties.

**DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (61.807), which is concerning. However, DILI prediction is not perfect.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (61.613) and Ligand B (33.385) are both relatively low, which is fine.

**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 very low hERG inhibition liability (A: 0.248, B: 0.202), which is excellent.

**Microsomal Clearance:** Ligand B (-4.604) has a *negative* microsomal clearance, which is impossible. This is a major red flag and indicates a problem with the data or the prediction method. Ligand A (18.264) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (-4.228) has a negative half-life, which is impossible and further reinforces the data quality concerns. Ligand A (37.039) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.051, B: 0.009), which is good.

**Binding Affinity:** Both ligands have strong binding affinities (A: -9.6 kcal/mol, B: -8.9 kcal/mol). Ligand A is slightly better (-9.6 vs -8.9).

**Conclusion:**

Despite Ligand A's higher DILI risk, the impossible values for Ligand B's clearance and half-life make it a non-starter. The negative values strongly suggest a data error or a flawed prediction. Ligand A, while not perfect, has more plausible ADME properties and a slightly better binding affinity. Therefore, Ligand A is the more viable drug candidate.

Output:
1
2025-04-17 13:39:44,355 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [358.869, 41.57, 3.669, 1, 3, 0.906, 54.711, 57.736, -4.885, -3.981, 0.914, 17.93, 1.155, 0.681, -8.6]
**Ligand B:** [345.487, 43.86, 1.437, 0, 3, 0.684, 6.747, 75.805, -4.487, -1.519, 0.347, 28.499, -6.384, 0.025, -7.8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (358.869) is slightly higher than B (345.487), but both are acceptable.
2. **TPSA:** Both are above the ideal <140 for good oral absorption, but not dramatically so. A (41.57) is slightly better than B (43.86).
3. **logP:** A (3.669) is optimal (1-3), while B (1.437) is on the lower side, potentially impacting permeability.
4. **HBD:** A (1) is good, B (0) is also acceptable.
5. **HBA:** Both have 3 HBA, which is within the acceptable range.
6. **QED:** A (0.906) is excellent, indicating high drug-likeness. B (0.684) is still reasonable, but less optimal.
7. **DILI:** A (54.711) is better than B (6.747) - both are below 60, indicating low risk.
8. **BBB:** A (57.736) is lower than B (75.805). Since SRC is not a CNS target, this is less critical, but B has an advantage.
9. **Caco-2:** Both have negative values, indicating poor permeability. A (-4.885) is worse than B (-4.487).
10. **Solubility:** Both have negative values, indicating poor solubility. A (-3.981) is worse than B (-1.519).
11. **hERG:** A (0.914) is better than B (0.347) - lower is better, minimizing cardiotoxicity risk.
12. **Cl_mic:** A (17.93) is significantly better than B (28.499) - lower clearance means greater metabolic stability.
13. **t1/2:** A (1.155) is better than B (-6.384) - longer half-life is generally preferred.
14. **Pgp:** A (0.681) is better than B (0.025) - lower efflux is preferred.
15. **Affinity:** A (-8.6 kcal/mol) is slightly better than B (-7.8 kcal/mol), representing a stronger binding affinity.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in affinity, Cl_mic, t1/2, and hERG. While both have poor solubility and Caco-2 permeability, A is still better in this regard. The slightly better affinity of A is also significant.

**Conclusion:**

Considering the enzyme-specific priorities and the overall profile, **Ligand A** is the more promising drug candidate. Its superior metabolic stability, better hERG profile, and slightly stronger binding affinity outweigh the slightly lower BBB and poorer permeability compared to Ligand B.

Output:
1
2025-04-17 13:39:44,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (383.445 Da) is also good.

**TPSA:** Ligand A (73.47) is higher than Ligand B (53.51). While both are acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Both ligands have good logP values (A: 1.641, B: 2.688), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA. Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.703, B: 0.819), indicating good drug-like properties.

**DILI:** Ligand B (62.233) has a higher DILI risk than Ligand A (13.571). This is a significant concern for Ligand B.

**BBB:** Both have reasonable BBB penetration, but Ligand B (88.872) is better than Ligand A (70.88). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-5.032) has a significantly *better* Caco-2 permeability than Ligand B (-4.496).

**Aqueous Solubility:** Ligand A (-1.2) has better aqueous solubility than Ligand B (-3.443). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.419) has a lower hERG risk than Ligand B (0.607), which is desirable.

**Microsomal Clearance:** Ligand A (9.287) has a *much* lower microsomal clearance than Ligand B (32.718). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (7.45) has a longer half-life than Ligand A (2.327). This is a positive for Ligand B, but the difference might be overcome by better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.02, B: 0.163).

**Binding Affinity:** Both ligands have very good binding affinities (A: -8.9 kcal/mol, B: -8.5 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.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a slightly longer half-life and better BBB penetration, Ligand A excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, better solubility, much better metabolic stability (lower Cl_mic), and better Caco-2 permeability. The slightly better binding affinity of Ligand A further supports this conclusion. The lower DILI risk is particularly important, as liver toxicity is a common issue in drug development.

Output:
0
2025-04-17 13:39:44,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.463 and 363.502 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (54.34) is higher than Ligand B (36.44). While both are reasonably low, Ligand B is better positioned for good absorption.

**3. logP:** Both ligands have good logP values (3.034 and 3.713), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for off-target effects, but not critically 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:** Both ligands have 4 HBAs, well within the limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.839 and 0.752), indicating good drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (68.437%) compared to Ligand B (21.946%). This is a major concern for Ligand A.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (94.029%) is considerably better than Ligand A (77.627%). While not a primary concern for a kinase inhibitor, higher BBB penetration isn't detrimental.

**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. We will assume these are percentile scores and interpret lower values as lower permeability. Ligand A (-5.063) is worse than Ligand B (-4.501).

**10. Aqueous Solubility:** Both have negative solubility values, again unusual and suggesting poor solubility. Ligand A (-4.558) is slightly worse than Ligand B (-3.395).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.671 and 0.793), which is good.

**12. Microsomal Clearance:** Ligand B (53.901) has lower microsomal clearance than Ligand A (68.387), indicating better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (43.752 and 44.095 hours).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.234 and 0.364).

**15. Binding Affinity:** Ligand B (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better TPSA and solubility outweigh the slightly higher logP. While both have issues with Caco-2 and solubility, the potency and safety profile of Ligand B make it a much more promising starting point for further optimization.

Output:
1
2025-04-17 13:39:44,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as guidelines for enzyme targets suggest.

**Molecular Weight:** Both ligands (349.381 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is significantly better than Ligand B (62.74), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.754 and 1.178), 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:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.846 and 0.776), indicating good drug-likeness.

**DILI:** Both ligands have very similar and acceptable DILI risk (31.989 and 31.679 percentile).

**BBB:** Ligand A (78.829) has a better BBB penetration score than Ligand B (43.893), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.263) shows better Caco-2 permeability than Ligand B (-4.33), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.319) is slightly better than Ligand B (-2.608) in terms of aqueous solubility, though both are negative values which suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.407 and 0.207), which is excellent.

**Microsomal Clearance:** Ligand A (-5.546) has significantly *lower* (better) microsomal clearance than Ligand B (23.715). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-12.838) has a longer in vitro half-life than Ligand B (-14.327), further supporting better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.025).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 and -7.5 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good binding affinity and acceptable ADME properties, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), slightly better Caco-2 permeability, and better TPSA. These factors are crucial for an enzyme target like SRC, as they contribute to higher exposure and efficacy.

Output:
1
2025-04-17 13:39:44,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.495 and 358.454 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.51) is well below the 140 threshold, and even below 90, suggesting good permeability. Ligand B (76.66) is still under 140, but higher than A.

**3. logP:** Ligand A (3.896) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (1.72) is lower, potentially impacting 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 similar QED values (0.768 and 0.727), indicating good drug-likeness.

**7. DILI:** Ligand A (67.507) has a higher DILI risk than Ligand B (38.116). This is a significant concern for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (75.921) is slightly better than Ligand A (68.127). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**9. Caco-2 Permeability:** Ligand A (-5.252) has poor Caco-2 permeability, while Ligand B (-4.873) is slightly better, but still not great.

**10. Aqueous Solubility:** Ligand A (-4.134) has very poor aqueous solubility. Ligand B (-2.089) is better, but still low.

**11. hERG Inhibition:** Ligand A (0.817) has a higher hERG risk than Ligand B (0.407), which is preferable.

**12. Microsomal Clearance:** Ligand A (64.731) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (18.141). This is a major drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (68.805) has a longer half-life than Ligand B (4.303). This is a positive for Ligand A, but is outweighed by the poor metabolic stability.

**14. P-gp Efflux:** Ligand A (0.438) has moderate P-gp efflux, while Ligand B (0.035) has very low efflux. This is a benefit for Ligand B.

**15. Binding Affinity:** Ligand A (-8.7 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, its significantly higher DILI risk, poor solubility, and higher microsomal clearance are major concerns. Ligand B, while having weaker affinity, presents a much more favorable ADME-Tox profile, with lower DILI, better metabolic stability (lower Cl_mic, longer half-life), and lower P-gp efflux. The difference in binding affinity is substantial, but the ADME properties of Ligand A are too problematic. While the affinity of Ligand B is not great, it is a starting point for optimization.

Output:
1
2025-04-17 13:39:44,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.435 Da and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (88.18 and 84.42) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.176) is quite low, potentially hindering permeation. Ligand B (1.157) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**QED:** Ligand B (0.866) has a significantly higher QED score than Ligand A (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (37.999) has a lower DILI risk than Ligand B (50.291), which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (84.025) has better BBB penetration than Ligand A (62.97), but it's not a deciding factor here.

**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. Ligand A (-0.962) is slightly better than Ligand B (-2.504).

**hERG Inhibition:** Ligand A (0.177) has a lower hERG risk than Ligand B (0.235), which is a significant advantage.

**Microsomal Clearance:** Ligand A (13.76 mL/min/kg) has a lower microsomal clearance than Ligand B (20.587 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (6.506 hours) has a longer half-life than Ligand A (-4.05 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). The difference is 0.6 kcal/mol, which is not a huge difference, but still noticeable.

**Overall Assessment:**

Ligand B has a better QED score, longer half-life, and slightly better binding affinity. However, Ligand A has a lower DILI risk, lower hERG risk, and better metabolic stability (lower Cl_mic). The low logP of Ligand A is a concern, but the slightly better affinity of Ligand B might compensate. Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG), the lower hERG and DILI risks of Ligand A, combined with its better metabolic stability, make it a slightly more promising candidate.

Output:
0
2025-04-17 13:39:44,356 - INFO - Batch 232 complete. Total preferences: 3712
2025-04-17 13:39:44,356 - INFO - Processing batch 233/512...
2025-04-17 13:40:35,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.439 Da) is slightly lower than Ligand B (386.25 Da), which is acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (48.0) is slightly higher than Ligand B (42.68), but both are favorable.

**logP:** Ligand A (2.413) is within the optimal range (1-3), while Ligand B (4.937) is higher. A logP of 4.937 is approaching the upper limit and could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD and HBA counts. Ligand A (0 HBD, 5 HBA) and Ligand B (0 HBD, 3 HBA) are both within the recommended limits.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.788, Ligand B: 0.707), indicating good drug-like properties.

**DILI:** Ligand A (9.926%) has a significantly lower DILI risk than Ligand B (37.611%). This is a major advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (94.649%) shows higher BBB penetration potential than Ligand B (84.529%).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, assuming lower values indicate lower permeability, both are concerning.

**Aqueous Solubility:** Ligand A (-2.762) has better solubility than Ligand B (-5.325). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.884) has a lower hERG inhibition liability than Ligand B (0.778), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (55.438 mL/min/kg) has lower microsomal clearance than Ligand B (88.798 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (65.181 hours) has a much longer in vitro half-life than Ligand A (-1.464 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.327, Ligand B: 0.46).

**Binding Affinity:** Both ligands have comparable binding affinities (Ligand A: -7.8 kcal/mol, Ligand B: -7.0 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Ligand A is preferable. While Ligand B has a longer half-life, Ligand A demonstrates superior properties in several critical areas: lower DILI risk, better solubility, lower hERG inhibition, and better metabolic stability (lower Cl_mic). The slightly better binding affinity of Ligand A further supports this conclusion. The negative Caco-2 values are a concern for both, but the other advantages of Ligand A outweigh this drawback.

Output:
0
2025-04-17 13:40:35,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.405 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is slightly higher than Ligand B (49.85). Both are acceptable, but Ligand B is preferable as lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (2.269 and 2.607), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have low HBD counts (0) and acceptable HBA counts (5 and 3 respectively), indicating good potential for permeability.

**QED:** Both ligands have similar QED values (0.78 and 0.718), indicating good drug-likeness.

**DILI:** Ligand B (28.112) has a significantly lower DILI risk than Ligand A (35.324). This is a substantial advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (84.49) is better than Ligand A (76.851). While not a primary concern for a non-CNS target like SRC, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Ligand A (-4.174) and Ligand B (-4.332) have similar, very poor Caco-2 permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-1.011) is slightly better than Ligand B (-2.695) in terms of aqueous solubility.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.519 and 0.525).

**Microsomal Clearance:** Ligand B (87.408) has significantly higher microsomal clearance than Ligand A (63.769), suggesting faster metabolism and lower metabolic stability. This is a disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-15.925) has a longer in vitro half-life than Ligand B (-8.081). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.079 and 0.495).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.9 kcal/mol). This difference of 1.5 kcal/mol is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and lower DILI risk, which are high priorities for an enzyme inhibitor. While it has higher microsomal clearance and lower solubility than Ligand A, the potency advantage is substantial. The poor Caco-2 permeability is a concern for both, but can potentially be addressed through formulation strategies. The longer half-life of Ligand A is a plus, but the potency difference is more critical.

Output:
1
2025-04-17 13:40:35,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 405.292 Da - Within the ideal range (200-500 Da).
* Ligand B: 343.387 Da - Also within the ideal range.
* *Comment:* Both are acceptable.

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 68.29  - Good for oral absorption (<140).
* Ligand B: 108.62 - Still acceptable for oral absorption, but approaching the upper limit.
* *Comment:* Ligand A is better here.

**3. Lipophilicity (logP):**
* Ligand A: 3.342 - Optimal (1-3).
* Ligand B: 0.292 - Below optimal, potentially hindering permeation.
* *Comment:* Ligand A is significantly better.

**4. H-Bond Donors (HBD):**
* Ligand A: 1 -  Good.
* Ligand B: 3 - Acceptable, but higher than Ligand A.
* *Comment:* Ligand A is better.

**5. H-Bond Acceptors (HBA):**
* Ligand A: 4 - Good.
* Ligand B: 6 - Acceptable, but higher than Ligand A.
* *Comment:* Ligand A is better.

**6. QED:**
* Ligand A: 0.775 - Excellent drug-like profile.
* Ligand B: 0.626 - Good drug-like profile, but lower than Ligand A.
* *Comment:* Ligand A is better.

**7. DILI:**
* Ligand A: 64.948 - Moderate risk.
* Ligand B: 65.684 - Moderate risk, similar to Ligand A.
* *Comment:* Similar risk for both.

**8. BBB:**
* Ligand A: 61.38 - Not a priority for an oncology target.
* Ligand B: 45.56 - Not a priority for an oncology target.
* *Comment:* Not relevant for this target.

**9. Caco-2 Permeability:**
* Ligand A: -4.803 - Poor permeability.
* Ligand B: -5.392 - Poor permeability.
* *Comment:* Both are poor, but Ligand B is slightly worse.

**10. Aqueous Solubility:**
* Ligand A: -4.303 - Poor solubility.
* Ligand B: -2.519 - Better solubility than Ligand A.
* *Comment:* Ligand B is better.

**11. hERG Inhibition:**
* Ligand A: 0.196 - Low risk.
* Ligand B: 0.236 - Low risk, similar to Ligand A.
* *Comment:* Similar risk for both.

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 110.471 - High clearance, suggesting poor metabolic stability.
* Ligand B: 11.337 - Low clearance, suggesting good metabolic stability.
* *Comment:* Ligand B is significantly better.

**13. In vitro Half-Life (t1/2):**
* Ligand A: 3.566 - Short half-life.
* Ligand B: 8.431 - Longer half-life.
* *Comment:* Ligand B is better.

**14. P-gp Efflux:**
* Ligand A: 0.185 - Low efflux.
* Ligand B: 0.06 - Very low efflux.
* *Comment:* Ligand B is better.

**15. Binding Affinity:**
* Ligand A: -8.8 kcal/mol - Excellent.
* Ligand B: -8.1 kcal/mol - Very good, but less potent than Ligand A.
* *Comment:* Ligand A has a significant advantage in binding affinity.

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both compounds have moderate DILI and low hERG risk, Ligand A boasts a significantly stronger binding affinity (-8.8 vs -8.1 kcal/mol). However, Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and solubility. Ligand A suffers from poor permeability and solubility, while Ligand B has poor permeability. The affinity difference is substantial (0.7 kcal/mol), and for an enzyme target, this is often a deciding factor. The improved metabolic stability of Ligand B is valuable, but the potency advantage of Ligand A is likely to be more impactful, especially considering optimization potential to address its permeability and solubility issues.

Output:
1
2025-04-17 13:40:35,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.403 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.52) is better than Ligand B (104.08), both are acceptable for oral absorption (<140).

**logP:** Ligand A (1.469) is within the optimal 1-3 range. Ligand B (-0.138) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7, and Ligand B has 6, both are below the 10 threshold.

**QED:** Both have good QED scores (0.615 and 0.747, respectively), indicating drug-likeness.

**DILI:** Both have similar DILI risk (60.915 and 61.38), placing them in the moderate risk category. This isn't ideal, but not disqualifying.

**BBB:** Ligand A (68.554) has a better BBB percentile than Ligand B (38.426). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.421) is better than Ligand B (-4.928), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.19) is better than Ligand B (-1.818), indicating better solubility. This is important for bioavailability.

**hERG Inhibition:** Both have very low hERG risk (0.156 and 0.108), which is excellent.

**Microsomal Clearance:** Ligand A (51.704) has higher clearance than Ligand B (-2.545). This means Ligand B is predicted to have better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (3.923) has a longer half-life than Ligand B (0.0). This is a positive for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux (0.13 and 0.018), which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small (0.3 kcal/mol), it's within the range where it could outweigh other factors.

**Overall Assessment:**

Ligand B has a superior binding affinity and significantly better metabolic stability (lower Cl_mic, longer half-life). While Ligand A has better solubility and Caco-2 permeability, the improved potency and metabolic profile of Ligand B are more critical for an enzyme target like SRC kinase. The slight decrease in solubility is a manageable concern.

Output:
1
2025-04-17 13:40:35,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.43 and 378.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.69) is well below the 140 threshold, suggesting good absorption. Ligand B (139.8) is approaching the upper limit but still acceptable.

**logP:** Both ligands have good logP values (2.03 and 1.66), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has 9 HBA, which is higher but not drastically concerning.

**QED:** Ligand A (0.869) has a significantly better QED score than Ligand B (0.516), indicating better overall drug-likeness.

**DILI:** Ligand A (45.52) has a much lower DILI risk than Ligand B (99.07), which is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (66.65) is higher than Ligand B (23.15).

**Caco-2 Permeability:** Ligand A (-4.689) and Ligand B (-5.774) both have negative values, indicating poor permeability. This is a potential issue for both, but the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.651 and -3.191), indicating poor aqueous solubility. This is a drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.807) has a lower hERG risk than Ligand B (0.347), which is preferable.

**Microsomal Clearance:** Ligand A (14.84) has a lower microsomal clearance than Ligand B (19.39), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.223) has a slightly longer half-life than Ligand B (14.009).

**P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux than Ligand B (0.089), which is favorable.

**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 can outweigh some ADME concerns.

**Conclusion:**

Ligand A is the superior candidate. While both have solubility and permeability issues, Ligand A demonstrates significantly better drug-likeness (QED), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and, crucially, a much stronger binding affinity. The improved potency and safety profile of Ligand A make it the more promising starting point for further optimization.

Output:
0
2025-04-17 13:40:35,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.487 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.44) is still acceptable, but less favorable.

**logP:** Ligand A (2.302) is optimal (1-3). Ligand B (0.623) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very good. Ligand B (3 HBD, 6 HBA) is also acceptable, but higher.

**QED:** Both ligands have similar and good QED values (0.633 and 0.666, respectively), indicating good drug-like properties.

**DILI:** Ligand A (6.669 percentile) has a significantly lower DILI risk than Ligand B (34.548 percentile). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.849) has a higher BBB penetration than Ligand B (42.924), but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.325) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.058) is also poor, but similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.253 and -2.624). This is a concern for both, but might be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.51 and 0.085, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (52.924 mL/min/kg) has a higher clearance than Ligand B (6.408 mL/min/kg). This suggests Ligand B is more metabolically stable, which is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (8.935 hours) has a slightly longer half-life than Ligand A (7.579 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.059 and 0.006, respectively).

**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 of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 permeability and solubility of both compounds, Ligand A is the more promising candidate. The significantly stronger binding affinity (-7.9 vs -6.9 kcal/mol) is a major advantage. Furthermore, the lower DILI risk of Ligand A is a critical factor. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the potency difference is likely to be more impactful for an enzyme inhibitor. The solubility and permeability issues could be addressed through formulation strategies.

Output:
1
2025-04-17 13:40:35,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (354.447 Da and 362.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.31) is well below the 140 threshold for good oral absorption. Ligand B (97.12) is still acceptable but closer to the limit.

**3. logP:** Ligand A (0.57) is a bit low, potentially hindering permeation. Ligand B (2.501) is 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 (5) and Ligand B (6) both meet the HBA <=10 criteria.

**6. QED:** Ligand A (0.509) is just above the 0.5 threshold, indicating reasonable drug-likeness. Ligand B (0.823) has a significantly better QED score.

**7. DILI:** Ligand A (14.851) has a very favorable DILI risk, well below the 40 threshold. Ligand B (65.103) is higher, indicating a moderate risk of liver injury.

**8. BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (50.679) and Ligand B (54.478) are both relatively low.

**9. Caco-2 Permeability:** Ligand A (-4.644) and Ligand B (-5.117) both have negative Caco-2 values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Ligand A (-0.215) and Ligand B (-3.905) both have negative solubility values, indicating poor aqueous solubility. Ligand B is worse.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.209 and 0.22, respectively).

**12. Microsomal Clearance:** Ligand A (24.657) has a lower microsomal clearance than Ligand B (30.98), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.682) has a shorter half-life than Ligand B (35.233), which is less desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.23, respectively).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1 kcal/mol difference is substantial.

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity, has a longer half-life, but suffers from higher DILI risk and lower solubility. Ligand A has better DILI and metabolic stability, but weaker affinity and a shorter half-life. The affinity difference is significant. Given the importance of potency for an enzyme target, and the fact that the DILI risk for Ligand B is moderate rather than high, the stronger binding of Ligand B outweighs its drawbacks.

Output:
1
2025-04-17 13:40:35,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.523 Da) is slightly higher than Ligand B (344.419 Da), but both are acceptable.

**TPSA:** Ligand A (76.14) is well below the 140 threshold for oral absorption. Ligand B (103.87) is also below, but closer to the limit.

**logP:** Ligand A (3.864) is at the higher end of the optimal range (1-3), potentially raising concerns about off-target effects, but still acceptable. Ligand B (1.41) is lower, which could impact permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5-6 HBA, which are within the acceptable limits.

**QED:** Both ligands have good QED scores (0.682 and 0.79), indicating generally drug-like properties.

**DILI:** Ligand A (80.807) has a higher DILI risk than Ligand B (57.425). This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (82.086) has a slightly better score than Ligand B (44.591).

**Caco-2 Permeability:** Ligand A (-4.664) has a worse Caco-2 permeability than Ligand B (-5.583), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.366) has worse aqueous solubility than Ligand B (-1.683). This is a concern for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.292) has a slightly higher hERG inhibition risk than Ligand B (0.133), but both are relatively low.

**Microsomal Clearance:** Ligand A (88.467) has significantly higher microsomal clearance than Ligand B (21.145). This suggests Ligand A will be metabolized more quickly, leading to lower exposure.

**In vitro Half-Life:** Ligand A (30.75 hours) has a longer half-life than Ligand B (-14.737 hours). However, the negative value for Ligand B is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.568 and 0.025), which is favorable.

**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 a positive point for 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 lower DILI risk, better solubility, and much lower microsomal clearance, indicating improved metabolic stability. Ligand A's higher DILI risk and clearance are major concerns that would likely lead to its rejection during drug development. The slightly better affinity of Ligand A is unlikely to outweigh these significant ADME liabilities.

Output:
1
2025-04-17 13:40:35,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.371 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.09) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (78.87) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (0.62) is a bit low, potentially hindering permeation. Ligand B (1.629) 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 2 HBD and 4 HBA, also good.

**QED:** Both ligands have similar QED values (0.71 and 0.651), indicating good drug-likeness.

**DILI:** Ligand A (58.55) has a moderate DILI risk, while Ligand B (8.453) has a very low risk, which is a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand B (65.607) has a higher BBB percentile than Ligand A (39.279).

**Caco-2 Permeability:** Ligand A (-5.398) shows poor permeability, while Ligand B (-4.724) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.189) has poor solubility, a major concern. Ligand B (-1.639) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.099) has a very low hERG risk, which is excellent. Ligand B (0.286) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (1.851) has a low microsomal clearance, indicating good metabolic stability. Ligand B (11.369) has a significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-38.368) has a very long half-life, which is highly desirable. Ligand B (-4.318) has a shorter half-life, though still reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.056).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -8.0 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a slight edge in binding affinity and a much better safety profile (DILI). However, Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2) and a much lower hERG risk. The poor solubility and permeability of Ligand A are significant drawbacks, potentially limiting bioavailability. Ligand B's higher metabolic clearance is a concern, but could be addressed with structural modifications. Given the importance of metabolic stability and solubility for kinase inhibitors, and the slight advantage in affinity, I would lean towards Ligand A, but with the caveat that solubility/permeability need to be addressed. However, the low DILI risk of Ligand B is very attractive. Considering the balance, and the fact that metabolic stability can be improved with medicinal chemistry, I choose Ligand B.

Output:
1
2025-04-17 13:40:35,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.571 and 348.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.16) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (79.62) is still under 140, but less optimal than A.

**logP:** Both ligands have acceptable logP values (3.429 and 2.007), 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.695 and 0.826), indicating drug-like properties.

**DILI:** Ligand A (18.418) has a significantly lower DILI risk than Ligand B (44.63). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (85.421) is slightly higher than Ligand A (77.898). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.343) has a worse Caco-2 permeability score than Ligand B (-4.604), indicating lower intestinal absorption.

**Aqueous Solubility:** Both have negative solubility scores (-2.485 and -3.136), indicating poor aqueous solubility. This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Ligand A (0.742) has a slightly higher hERG risk than Ligand B (0.145). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (29.175) has a higher microsomal clearance than Ligand B (27.584), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.748) has a significantly longer in vitro half-life than Ligand A (44.099), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.139 and 0.072).

**Binding Affinity:** Both ligands have excellent binding affinity (-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 has a significant advantage in terms of DILI risk. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a lower hERG risk. Solubility is a concern for both, but the metabolic stability and safety profile of Ligand B are more critical for an enzyme target like SRC. The slightly better Caco-2 permeability of Ligand B is also a plus. While Ligand A has slightly better TPSA, the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 13:40:35,953 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both A (345.4) and B (346.4) are within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Both are below the 140 A^2 threshold for good oral absorption. A (93.45) is slightly higher than B (89.87), but both are acceptable.

3. **logP:** Both A (1.446) and B (1.6) fall within the optimal 1-3 range. Again, no significant difference.

4. **HBD:** A (2) and B (3). Both are within the acceptable limit of <=5.

5. **HBA:** A (5) and B (4). Both are within the acceptable limit of <=10.

6. **QED:** Both A (0.755) and B (0.707) are above 0.5, indicating good drug-likeness. A is slightly better.

7. **DILI:** A (56.262) is higher than B (39.473). B has a significantly lower DILI risk, which is a major advantage.

8. **BBB:** A (33.23) is lower than B (42.226). Since SRC is not a CNS target, this is less critical, but B is still better.

9. **Caco-2:** A (-5.527) is worse than B (-4.865). Lower values indicate poorer permeability. B is better.

10. **Solubility:** A (-1.522) is better than B (-2.355). Solubility is important for bioavailability, giving a slight edge to A.

11. **hERG:** A (0.028) is much lower than B (0.347). This is a significant advantage for A, indicating lower cardiotoxicity risk.

12. **Cl_mic:** A (-5.14) is much lower than B (20.475). This is a *major* advantage for A, indicating much better metabolic stability.

13. **t1/2:** A (-11.785) is much better than B (-5.106). A has a significantly longer in vitro half-life, which is desirable.

14. **Pgp:** A (0.013) is much lower than B (0.273). Lower Pgp efflux is better, giving a significant advantage to A.

15. **Binding Affinity:** A (-9.2) is slightly better than B (-10.1). While both are excellent, A's affinity is still superior.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Both are good, but A is slightly better.
*   **Metabolic Stability:** A is *significantly* better (lower Cl_mic, longer t1/2).
*   **Solubility:** A is slightly better.
*   **hERG Risk:** A is *significantly* better.
*   **DILI:** B is better.

**Conclusion:**

While ligand B has a lower DILI risk, ligand A overwhelmingly outperforms it in the critical parameters for an enzyme inhibitor: metabolic stability, hERG risk, Pgp efflux, and in vitro half-life. The slightly better affinity of A further solidifies its advantage. The DILI risk for A is still within an acceptable range.

Output:
1
2025-04-17 13:40:35,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.447 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.6) is slightly above the preferred <140, while Ligand B (96.11) is well within the range.

**logP:** Ligand A (-0.191) is a bit low, potentially hindering permeation. Ligand B (1.188) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, both acceptable. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.717 and 0.746), indicating good drug-likeness.

**DILI:** Ligand A (40.946) has a slightly higher DILI risk than Ligand B (32.028), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.482) and Ligand B (46.336) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a significant concern.

**hERG:** Both ligands have very low hERG inhibition risk (0.151 and 0.134), which is excellent.

**Microsomal Clearance:** Ligand A (43.07 mL/min/kg) has higher clearance than Ligand B (4.777 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-19.003) has a much longer in vitro half-life than Ligand A (-32.78).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.027).

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference.

**Conclusion:**

Despite Ligand A's superior binding affinity, Ligand B is the more promising candidate. The significantly better metabolic stability (lower Cl_mic, longer t1/2), better logP, and lower DILI risk of Ligand B outweigh the slightly weaker binding. The poor Caco-2 and solubility for both compounds are concerning and would require attention during lead optimization (e.g., salt formation, prodrug strategies). However, the metabolic stability and safety profile of Ligand B make it a better starting point.

Output:
1
2025-04-17 13:40:35,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.435 Da and 384.267 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.91) is well below the 140 threshold for oral absorption and even below 90 for potential CNS penetration, while Ligand B (110) is still acceptable but less favorable.

**logP:** Ligand A (3.554) is at the higher end of the optimal range (1-3), while Ligand B (1.949) is closer to the lower end. While higher logP can sometimes cause issues, it's less concerning than a very low logP.

**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:** Ligand A (0.778) has a significantly better QED score than Ligand B (0.492), indicating a more drug-like profile.

**DILI:** Ligand A (76.89) has a higher DILI risk than Ligand B (64.599), but both are reasonably acceptable.

**BBB:** Both ligands have good BBB penetration (Ligand A: 69.407, Ligand B: 74.758), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. 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, which is also unusual. This suggests poor predicted solubility, a significant concern for oral bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.308, Ligand B: 0.438).

**Microsomal Clearance:** Ligand A (29.737) has a higher microsomal clearance than Ligand B (17.368), meaning Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand A (12.633) has a longer half-life than Ligand B (5.878), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.437, Ligand B: 0.064), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.4 kcal/mol, Ligand B: -8.7 kcal/mol). Ligand B is slightly better in this regard, but the difference is small.

**Overall Assessment:**

Ligand B has a slight edge in binding affinity and significantly better metabolic stability (lower Cl_mic) and a longer half-life. However, Ligand A has a much better QED score and a more favorable TPSA. The solubility and Caco-2 permeability are concerning for both, but the QED score of Ligand A is a strong indicator of overall drug-likeness. Considering the importance of metabolic stability for kinase inhibitors, and the slightly better affinity of Ligand B, it is the slightly more promising candidate.

Output:
1
2025-04-17 13:40:35,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.451 Da) is slightly lower, which could be advantageous for permeability. Ligand B (387.483 Da) is still acceptable.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption. Ligand A (107.7) is better than Ligand B (114.46).

**logP:** Both ligands have low logP values (A: 0.102, B: -0.101), which is less than ideal. Low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 7 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.55, B: 0.659), indicating drug-like properties.

**DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (80.574). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (13.765) is lower than Ligand B (49.011), but this is not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating 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:** Both ligands have very low hERG inhibition liability (A: 0.046, B: 0.049), which is excellent.

**Microsomal Clearance:** Ligand A (20.86 mL/min/kg) has a higher microsomal clearance than Ligand B (-6.114 mL/min/kg). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (19.955 hours) has a longer half-life than Ligand B (9.646 hours), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.024, B: 0.066), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.6 kcal/mol, B: -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

While both ligands have good binding affinity and acceptable QED scores, Ligand A is the better candidate due to its significantly lower DILI risk (13.067 vs 80.574) and longer in vitro half-life (19.955 vs 9.646). Although both have poor predicted permeability and solubility, the lower DILI risk is a critical advantage, especially for an oncology target where chronic administration is often required. The slightly better TPSA of Ligand A is also a minor positive. The improved metabolic stability of Ligand B is a plus, but the high DILI risk outweighs this benefit.

Output:
0
2025-04-17 13:40:35,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.53 and 357.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.27) is better than Ligand B (92.18). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Both ligands have good logP values (2.35 and 2.97), falling within the 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Ligand A is preferable here, as lower HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.679 and 0.732), indicating good drug-likeness.

**DILI:** Ligand A (31.56) has a significantly lower DILI risk than Ligand B (98.37). This is a major advantage for Ligand A.

**BBB:** Ligand A (63.75) has better BBB penetration than Ligand B (23.30), but BBB is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.852) and Ligand B (-5.148) both show poor Caco-2 permeability. This is a concern for oral bioavailability for both.

**Solubility:** Both ligands have similar poor solubility (-3.63 and -3.75). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG risk (0.176 and 0.115). This is excellent.

**Microsomal Clearance:** Ligand A (67.87) has significantly higher microsomal clearance than Ligand B (1.57). This indicates Ligand B is much more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-3.25) has a longer in vitro half-life than Ligand A (-23.95). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.096 and 0.022).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.4 kcal/mol). This 2.3 kcal/mol difference is very significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better TPSA, DILI, and BBB, Ligand B's superior binding affinity (-9.7 vs -7.4 kcal/mol), significantly better metabolic stability (lower Cl_mic, longer t1/2), and acceptable other properties make it the more promising drug candidate. The strong binding affinity is a critical advantage for an enzyme inhibitor, and the improved metabolic stability will likely translate to better *in vivo* exposure. The poor Caco-2 and solubility are concerns, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 13:40:35,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (349.391 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is slightly above the optimal <140, while Ligand B (105.76) is well within. This favors B for absorption.

**logP:** Ligand A (0.583) is a bit low, potentially hindering permeation. Ligand B (-0.647) is even lower, raising similar concerns. Both are suboptimal, but neither is drastically outside the acceptable range.

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

**H-Bond Acceptors:** Ligand A has 7 HBA, within the limit. Ligand B has 5 HBA, also good.

**QED:** Ligand A (0.687) has a better QED score than Ligand B (0.478), indicating a more drug-like profile.

**DILI:** Ligand A (65.917) has a significantly higher DILI risk than Ligand B (26.173). This is a major concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (63.862 and 60.644), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.877) and Ligand B (-5.368) both have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-2.789) and Ligand B (-1.297) both have negative solubility values, indicating poor solubility. This is a significant drawback for both.

**hERG:** Both ligands have very low hERG risk (0.098 and 0.06), which is excellent.

**Microsomal Clearance:** Ligand B (20.886 mL/min/kg) has a lower microsomal clearance than Ligand A (42.656 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (1.426 hours) has a slightly lower half-life than Ligand A (21.546 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.003).

**Binding Affinity:** Ligand B (-7.3 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 B.

**Overall Assessment:**

Ligand A has a better QED and in vitro half-life, but suffers from a significantly higher DILI risk and higher microsomal clearance. Ligand B has a better DILI profile, lower clearance, and slightly better binding affinity. Both have poor Caco-2 permeability and aqueous solubility. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), Ligand B is the more promising candidate despite the slightly lower QED and half-life. The lower DILI risk and improved metabolic stability are crucial advantages.

Output:
1
2025-04-17 13:40:35,954 - INFO - Batch 233 complete. Total preferences: 3728
2025-04-17 13:40:35,954 - INFO - Processing batch 234/512...
2025-04-17 13:41:15,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing enzyme-specific properties.

**1. Molecular Weight:** Both ligands (358.429 and 358.427 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is well below the 140 threshold and favorable for oral absorption. Ligand B (86.03) is also below the threshold, but closer to it.

**3. logP:** Ligand A (3.236) is within the optimal range of 1-3. Ligand B (1.506) is at the lower end, potentially impacting permeability.

**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 (8) is also within the limit.

**6. QED:** Both ligands have good QED scores (0.542 and 0.636, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (42.071) has a lower DILI risk than Ligand B (75.184), which is a significant advantage.

**8. BBB:** This is less critical for a kinase inhibitor, but Ligand A (89.492) has a better BBB percentile than Ligand B (47.15).

**9. Caco-2 Permeability:** Ligand A (-4.106) has a worse Caco-2 permeability than Ligand B (-4.82).

**10. Aqueous Solubility:** Ligand A (-3.785) has a worse aqueous solubility than Ligand B (-1.434).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.724 and 0.113, respectively). Ligand B is better.

**12. Microsomal Clearance:** Ligand A (62.115) has a higher microsomal clearance than Ligand B (54.437), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-15.491) has a longer in vitro half-life than Ligand A (-11.834), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.203 and 0.065, respectively). Ligand B is better.

**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:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B appears to be the more promising candidate. While Ligand A has a slightly better BBB score, Ligand B excels in crucial areas: lower DILI risk, better solubility, longer half-life, lower P-gp efflux, and slightly better hERG inhibition. The binding affinity is comparable. The slightly lower logP of Ligand B is a minor concern, but can potentially be addressed through further optimization.

Output:
1
2025-04-17 13:41:15,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.47 and 342.33 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.27) is significantly better than Ligand B (80.34). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's higher TPSA could hinder cell permeability.

**logP:** Ligand A (3.78) is slightly higher than Ligand B (2.14), both within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**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.

**QED:** Ligand A (0.925) has a substantially better QED score than Ligand B (0.772), indicating a more drug-like profile.

**DILI:** Ligand B (93.835) has a much higher DILI risk than Ligand A (43.117). This is a major concern for Ligand B.

**BBB:** Ligand A (83.055) has better BBB penetration than Ligand B (66.886), though this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.065) shows better Caco-2 permeability than Ligand B (-4.405).

**Aqueous Solubility:** Ligand A (-3.304) has better aqueous solubility than Ligand B (-4.108). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.789) has a slightly higher hERG risk than Ligand B (0.565), but both are reasonably low.

**Microsomal Clearance:** Ligand A (32.683) and Ligand B (33.071) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (38.492) has a significantly longer in vitro half-life than Ligand B (-14.399). This is a significant advantage for Ligand A, as it suggests less frequent dosing.

**P-gp Efflux:** Ligand A (0.702) has lower P-gp efflux than Ligand B (0.287), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very strong binding affinities (-9.5 and -8.6 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A is clearly superior. It has a better QED score, lower DILI risk, better solubility, better Caco-2 permeability, longer half-life, lower P-gp efflux, and slightly better binding affinity. While Ligand B has a slightly lower hERG risk, the other advantages of Ligand A outweigh this minor benefit. The high DILI risk for Ligand B is a significant red flag.

Output:
1
2025-04-17 13:41:15,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as befits an enzyme target.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.319 Da) is slightly lower than Ligand B (355.435 Da), which is not a significant difference.

**TPSA:** Ligand A (91.52) is better than Ligand B (110.01) as it is closer to the desirable threshold of <=140 for oral absorption.

**logP:** Ligand A (3.21) is optimal, while Ligand B (-0.055) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is better than Ligand B (1 HBD, 5 HBA) as it strikes a better balance.

**QED:** Both ligands have good QED scores (Ligand A: 0.503, Ligand B: 0.623), indicating good drug-like properties.

**DILI:** Ligand A (90.5) has a significantly higher DILI risk than Ligand B (34.277). This is a major concern for Ligand A.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.412) is poor, while Ligand B (-5.347) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-4.351) is poor, while Ligand B (-1.037) is also poor. Both are problematic.

**hERG Inhibition:** Ligand A (0.088) is very low risk, while Ligand B (0.104) is also low risk.

**Microsomal Clearance:** Ligand A (124.061) has higher clearance than Ligand B (25.767), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-57.823) has a very short half-life, while Ligand B (-3.472) has a slightly better, but still short, half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 kcal/mol and -7.6 kcal/mol respectively). The difference of 0.4 kcal/mol is not substantial enough to overcome the ADME deficiencies of Ligand A.

**Conclusion:**

Despite having comparable binding affinity, Ligand B is the more promising candidate. Ligand A has unacceptable DILI risk, poor solubility, poor Caco-2 permeability, and a short half-life. Ligand B, while not perfect, has a much lower DILI risk and better metabolic stability. The low logP and solubility of Ligand B are concerns, but these are potentially addressable through further optimization, whereas the high DILI risk of Ligand A is a more fundamental issue.

Output:
1
2025-04-17 13:41:15,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (468.145 Da) is at the higher end, while Ligand B (349.479 Da) is more favorably positioned.

**TPSA:** Both ligands have TPSA values (A: 67.43, B: 71.54) that are acceptable for oral absorption (<140).

**logP:** Ligand A (4.735) is higher than optimal (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.839) is within the ideal range.

**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 still within the acceptable limit of 10.

**QED:** Both ligands have similar and acceptable QED values (A: 0.641, B: 0.659), indicating good drug-like properties.

**DILI:** Ligand A (77.782) has a significantly higher DILI risk than Ligand B (26.095). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired. Both are reasonably high, but not critical for this target.

**Caco-2 Permeability:** Ligand A (-4.788) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.104) also has poor Caco-2 permeability, but is slightly better than A.

**Aqueous Solubility:** Ligand A (-5.265) has very poor aqueous solubility, which is a significant drawback. Ligand B (-1.905) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.749) has a slightly higher hERG risk than Ligand B (0.905), but both are reasonably acceptable.

**Microsomal Clearance:** Ligand A (61.127) has a higher microsomal clearance than Ligand B (34.4), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (95.055) has a much longer in vitro half-life than Ligand B (24.734), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.503) shows lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a crucial advantage, as a 1.9 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's longer half-life and lower P-gp efflux, its significantly higher DILI risk, poor solubility, and lower binding affinity make it a less desirable candidate. Ligand B, while having some ADME liabilities (Caco-2, solubility), has a much better safety profile (DILI), superior binding affinity, and acceptable metabolic stability. The strong binding affinity of Ligand B is a critical factor for an enzyme inhibitor.

Output:
1
2025-04-17 13:41:15,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 380.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (81.34), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.712) is optimal, while Ligand B (3.231) is approaching the upper limit.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (1), both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.753 and 0.861), indicating good drug-like properties.

**DILI:** Ligand A (42.497) has a significantly lower DILI risk than Ligand B (63.746). This is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.992) is better than Ligand A (59.946).

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.003) is smaller than that of Ligand B (-4.947), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is concerning. Ligand B (-3.596) is slightly better than Ligand A (-2.602).

**hERG Inhibition:** Ligand A (0.207) has a much lower hERG risk than Ligand B (0.569). This is a significant advantage.

**Microsomal Clearance:** Ligand A (-4.434) has a much lower (better) microsomal clearance than Ligand B (56.297), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.588) has a slightly longer half-life than Ligand B (6.633).

**P-gp Efflux:** Ligand A (0.038) has a much lower P-gp efflux liability than Ligand B (0.117).

**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 1.6 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have solubility issues, Ligand A is slightly better. The superior ADME-Tox profile of Ligand A, combined with its slightly better potency, makes it the more promising drug candidate.

Output:
0
2025-04-17 13:41:15,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.375 and 348.359 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.58) is slightly above the preferred <140, but acceptable. Ligand B (101.93) is well within the range.

**3. logP:** Both ligands (-0.346 and -0.136) are a bit low. While not a hard cutoff, values below 1 can sometimes hinder permeability.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 7 HBA, which is within the acceptable range of <=10.

**6. QED:** Ligand B (0.683) has a better QED score than Ligand A (0.438), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.146) has a lower DILI risk than Ligand B (76.192), which is a significant advantage.

**8. BBB:** Both have reasonable BBB penetration, around 69-70%, which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.947 and -4.217), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.196 and -1.928), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.04 and 0.032), which is excellent.

**12. Microsomal Clearance:** Ligand A (11.523) has significantly lower microsomal clearance than Ligand B (41.727), suggesting better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-19.095) has a longer in vitro half-life than Ligand B (-16.639), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.009).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.5), although the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

While both ligands have issues with solubility and permeability, Ligand A appears to be the more promising candidate. Its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and longer t1/2) are crucial advantages for an enzyme inhibitor. The slightly better binding affinity is a bonus. The solubility/permeability issues would need to be addressed through formulation or further chemical modifications, but the ADME profile of Ligand A is more favorable.

Output:
0
2025-04-17 13:41:15,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.402 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Ligand A (1.697) is within the optimal 1-3 range. Ligand B (3.371) 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 3 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.632 and 0.721), indicating good drug-like properties.

**DILI:** Both have low DILI risk (29.159 and 32.183), which is excellent.

**BBB:** Both have moderate BBB penetration (67.041 and 65.607). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.634 and -4.746). 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 (-2.67 and -3.537), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.176 and 0.402), which is highly desirable.

**Microsomal Clearance:** Ligand A (13.042 mL/min/kg) has significantly lower clearance than Ligand B (54.685 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-15.336 hours) has a negative half-life, which is not possible. Ligand B (-6.805 hours) also has a negative half-life. These values are likely errors or represent a very rapid degradation.

**P-gp Efflux:** Both have low P-gp efflux liability (0.034 and 0.364), which is favorable.

**Binding Affinity:** Ligand B (-7.3 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 other drawbacks.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A appears to be the more promising candidate. The primary reason is its significantly lower microsomal clearance, suggesting better metabolic stability. Both compounds have poor solubility and permeability, which are major liabilities. The negative half-life values are concerning and need further investigation. However, given the choice between the two, the improved metabolic stability of Ligand A is more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:41:15,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as guidelines for enzyme targets suggest.

**Molecular Weight:** Both ligands (354.447 and 336.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is slightly higher than Ligand B (58.87). Both are below the 140 threshold for oral absorption, but ligand B is better.

**logP:** Ligand A (0.716) is a bit low, potentially hindering permeation. Ligand B (2.464) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable, below the 10 threshold.

**QED:** Both ligands have good QED scores (0.682 and 0.749), indicating drug-like properties.

**DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (54.478). This is a major advantage for Ligand A.

**BBB:** Ligand A (72.431) and Ligand B (82.513) both have good BBB penetration, but Ligand B is slightly better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.732) has worse Caco-2 permeability than Ligand B (-5.305). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.02) has better aqueous solubility than Ligand B (-2.681). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.309) has a lower hERG inhibition liability than Ligand B (0.569), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (29.031) has lower microsomal clearance than Ligand B (52.365), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-4.89) has a longer in vitro half-life than Ligand B (4.939). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux than Ligand B (0.513), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have similar binding affinities (-8.5 and -8.6 kcal/mol), which are excellent. The difference is negligible.

**Overall Assessment:**

Ligand A excels in key areas for an enzyme inhibitor: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG inhibition, lower P-gp efflux, and better solubility. While Ligand B has a slightly better logP and Caco-2 permeability, the ADME-Tox profile of Ligand A is significantly more favorable. The binding affinity is comparable. Therefore, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 13:41:15,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.37 and 351.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.83) is slightly higher than Ligand B (75.87). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (1.87 and 1.93), 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 3 HBA. Ligand B is preferable here, with lower counts, potentially improving permeability.

**QED:** Ligand B (0.761) has a higher QED score than Ligand A (0.53), indicating a more drug-like profile.

**DILI:** Ligand A has a significantly higher DILI risk (82.241) compared to Ligand B (11.4). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a general oncology target like SRC. Ligand B has a higher BBB score (93.37) than Ligand A (20.124), but this is less critical.

**Caco-2 Permeability:** Ligand A (-5.653) has poor Caco-2 permeability, while Ligand B (-4.459) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-3.93) and Ligand B (-2.286) both have poor aqueous solubility.

**hERG:** Both ligands have low hERG risk (0.607 and 0.666), which is good.

**Microsomal Clearance:** Ligand A (18.877) has lower microsomal clearance than Ligand B (63.402), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (70.631 hours) has a significantly longer half-life than Ligand B (-11.076 hours). This is a substantial advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.316 and 0.118).

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity, lower clearance, and a significantly longer half-life. However, its major drawback is the high DILI risk and poor Caco-2 permeability. Ligand B has a better QED, lower DILI risk, and slightly better Caco-2 permeability, but suffers from poor metabolic stability (high clearance) and a shorter half-life.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), and the significant DILI risk associated with Ligand A, **Ligand B is the more viable drug candidate.** While its metabolic stability is a concern, this can potentially be addressed through structural modifications during lead optimization. The high DILI risk of Ligand A is a more difficult issue to resolve.

Output:
1
2025-04-17 13:41:15,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.387 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (95.08) is better than Ligand B (38.13). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (0.676) is lower than the optimal range (1-3), potentially hindering permeability. Ligand B (3.835) is within the optimal 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 A (0.886) has a higher QED score than Ligand B (0.687), indicating better overall drug-likeness.

**DILI:** Ligand B (14.696) has a significantly lower DILI risk than Ligand A (63.125). This is a major advantage for Ligand B.

**BBB:** Ligand B (93.563) has a much higher BBB penetration percentile than Ligand A (23.536). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-5.201) has worse Caco-2 permeability than Ligand B (-4.264).

**Aqueous Solubility:** Ligand A (-1.882) has slightly better aqueous solubility than Ligand B (-4.569).

**hERG Inhibition:** Ligand A (0.134) has a lower hERG inhibition liability than Ligand B (0.711), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-10.264) has a much lower microsomal clearance than Ligand B (52.664), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-9.881) has a longer in vitro half-life than Ligand B (-11.161), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.013) has lower P-gp efflux liability than Ligand B (0.339), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.9) 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 has a significantly better safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic, longer t1/2). It also has a slightly better binding affinity and logP. Ligand A has better solubility and P-gp efflux, but the DILI and metabolic stability concerns are more critical for an enzyme target like SRC. The slightly better affinity of Ligand B, combined with its superior ADME properties, makes it the more promising candidate.

Output:
1
2025-04-17 13:41:15,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.451 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.99) is well below the 140 threshold for good absorption, and even better for potential CNS penetration (though not a priority here). Ligand B (107.97) is still acceptable but less optimal.

**logP:** Ligand A (0.302) is a bit low, potentially hindering permeability. Ligand B (-0.839) is even lower, raising more concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 5 HBA) both are within acceptable ranges (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.75 and 0.597), indicating good drug-like properties.

**DILI:** Ligand A (32.571) has a much lower DILI risk than Ligand B (23.846), which is a significant advantage.

**BBB:** BBB is not a high priority for a non-CNS target, but Ligand A (60.527) has a better score than Ligand B (42.497).

**Caco-2 Permeability:** Ligand A (-4.713) and Ligand B (-5.333) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is concerning, but the low logP values likely contribute to this.

**Aqueous Solubility:** Ligand A (-1.629) and Ligand B (-0.946) both have negative solubility values, indicating poor solubility. This is a drawback for both.

**hERG:** Ligand A (0.325) has a lower hERG risk than Ligand B (0.105), which is preferable.

**Microsomal Clearance:** Ligand A (-14.638) has significantly lower (better) microsomal clearance than Ligand B (-37.566), indicating much better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-14.299) has a negative half-life, which is unusual. Ligand B (22.693) has a positive and more reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.005).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is paramount for an enzyme inhibitor. While it has some ADME drawbacks (lower logP, solubility, and higher DILI), the substantial potency advantage is likely to be the deciding factor. The better metabolic stability of Ligand A is appealing, but the difference in binding affinity is too large to ignore.

Output:
1
2025-04-17 13:41:15,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.459 Da and 347.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (79.04) is better than Ligand B (107.19). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.152) is optimal (1-3), while Ligand B (-0.026) is significantly lower, potentially hindering permeation. This is a major drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBD, which is acceptable. Ligand A has 3 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.611 and 0.602), indicating good drug-likeness.

**DILI:** Both have low DILI risk (38.736 and 34.781, respectively), which is positive.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.083) is slightly better than Ligand B (40.016).

**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 (-5.194) is slightly better than Ligand B (-5.652).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates very low solubility. Ligand A (-2.974) is slightly better than Ligand B (-1.691).

**hERG Inhibition:** Ligand A (0.822) has a lower hERG risk than Ligand B (0.059), which is a significant advantage.

**Microsomal Clearance:** Ligand A (35.311) has higher clearance than Ligand B (-26.871), meaning Ligand B is more metabolically stable. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (-24.575) has a longer half-life than Ligand A (-29.534), which is a positive for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.494 and 0.007), which is good.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Conclusion:**

Despite Ligand B having better metabolic stability and half-life, Ligand A is the superior candidate. The significantly stronger binding affinity (-8.7 vs -6.8 kcal/mol) is a critical advantage for an enzyme inhibitor. Additionally, Ligand A has a better logP, TPSA, and hERG risk profile. The solubility and Caco-2 values are poor for both, but the potency advantage of A is substantial.

Output:
1
2025-04-17 13:41:15,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.407 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.62 and 98.14) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (0.99 and 1.035) 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 7 HBA, and Ligand B has 6. Both are below the 10 limit.

**QED:** Both ligands have the same QED score of 0.692, indicating good drug-likeness.

**DILI:** Ligand A (58.24) has a slightly higher DILI risk than Ligand B (56.883), but both are reasonably acceptable.

**BBB:** Ligand A (28.461) has a significantly lower BBB penetration percentile than Ligand B (72.741). Since SRC is not a CNS target, this is less critical, but a higher value is generally preferred.

**Caco-2 Permeability:** Ligand A (-5.746) has worse Caco-2 permeability than Ligand B (-4.826). Both are negative, indicating poor permeability, but B is better.

**Aqueous Solubility:** Ligand A (-2.467) has slightly worse aqueous solubility than Ligand B (-3.168). Both are negative, indicating poor solubility, but B is better.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.272 and 0.142), which is excellent.

**Microsomal Clearance:** Ligand A (-5.452) has significantly lower (better) microsomal clearance than Ligand B (48.052). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (38.84) has a significantly shorter half-life than Ligand B (7.61). This is a substantial drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.199).

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is preferable. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B demonstrates superior Caco-2 permeability, aqueous solubility, and a much longer in vitro half-life. The longer half-life is a significant advantage for kinase inhibitors, allowing for less frequent dosing. The difference in BBB is not critical for a non-CNS target. The slightly higher DILI risk for Ligand A is also a concern. The binding affinity is identical, so the ADME properties are the deciding factors.

Output:
1
2025-04-17 13:41:15,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.415 and 342.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (70.31), both are below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands (2.064 and 1.73) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1), both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand B (7) is better than Ligand A (5), both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.767 and 0.892), indicating good drug-like properties.

**DILI:** Ligand A (16.557) has a significantly lower DILI risk than Ligand B (35.789). This is a major advantage.

**BBB:** Both ligands have good BBB penetration (70.143 and 73.672). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.073 and -4.972). These values are unusual and suggest poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.675 and -2.496). Similar to Caco-2, the scale is not specified.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.464 and 0.689).

**Microsomal Clearance:** Ligand A (22.514) has significantly lower microsomal clearance than Ligand B (58.857), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-17.275) has a negative half-life, which is not possible. Ligand B (25.017) has a reasonable half-life. The negative value for Ligand A is a significant red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 and 0.048).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.7 and -8.7 kcal/mol). The difference of 1 kcal/mol is not enough to outweigh other factors.

**Conclusion:**

Ligand B is more promising due to the positive half-life value, despite the higher DILI and clearance. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 13:41:15,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.463 and 366.933 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.04) is preferable to Ligand B (45.59) as it is closer to the 140 A^2 threshold for good oral absorption. Ligand B is quite low, which *could* indicate poor solubility.

**logP:** Ligand A (-1.61) is within the optimal range (1-3), but on the lower side. Ligand B (4.287) is slightly above the optimal range, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is better than Ligand B (1 HBD, 4 HBA) as it is closer to the ideal range of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.532 and 0.745), indicating drug-likeness.

**DILI:** Ligand A (30.826) has a significantly lower DILI risk than Ligand B (8.414), which is a major advantage.

**BBB:** BBB is not a primary concern for a kinase inhibitor, but Ligand B (82.435) has a higher BBB percentile than Ligand A (41.218).

**Caco-2 Permeability:** Ligand A (-5.644) has a negative Caco-2 value, which is concerning. Ligand B (-4.54) is also negative, but less so. Both suggest poor permeability.

**Aqueous Solubility:** Ligand A (-1.422) has slightly better solubility than Ligand B (-3.752).

**hERG Inhibition:** Ligand A (0.106) has a much lower hERG inhibition liability than Ligand B (0.844), a critical advantage for safety.

**Microsomal Clearance:** Ligand A (-16.389) exhibits significantly lower microsomal clearance, indicating better metabolic stability, a key priority for kinase inhibitors. Ligand B (65.163) has high clearance.

**In vitro Half-Life:** Ligand A (6.543) has a shorter half-life than Ligand B (23.06), but the difference isn't dramatic.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux liability, while Ligand B (0.721) is higher.

**Binding Affinity:** Ligand B (-8.1) has a significantly stronger binding affinity than Ligand A (-6.6). This is a substantial advantage, potentially outweighing some of the ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it has concerning properties regarding DILI risk, hERG inhibition, and metabolic stability. Ligand A has a much better safety profile (DILI, hERG) and metabolic stability, but suffers from weaker binding and potentially poor permeability.

Despite the affinity advantage of Ligand B, the combination of significantly better safety (DILI, hERG) and metabolic stability of Ligand A makes it the more promising candidate for further optimization. The permeability issues with Ligand A could potentially be addressed through structural modifications. The safety concerns with Ligand B are harder to fix without significantly impacting binding.

Output:
0
2025-04-17 13:41:15,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 352.381 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.87) is better than Ligand B (58.64). Both are below 140, suggesting good absorption potential.

**logP:** Ligand A (1.157) is within the optimal range (1-3), while Ligand B (3.146) is at the higher end, potentially raising solubility concerns.

**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 (0.706 and 0.856), indicating good drug-likeness.

**DILI:** Ligand A (25.281) has a significantly lower DILI risk than Ligand B (64.599). This is a major advantage for Ligand A.

**BBB:** Ligand B (81.698) has better BBB penetration than Ligand A (58.007), but BBB is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.874) is better than Ligand B (-4.481). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.035) has better solubility than Ligand B (-3.856).

**hERG Inhibition:** Ligand A (0.18) has a much lower hERG risk than Ligand B (0.784). This is a critical advantage for Ligand A, minimizing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (39.082) has lower microsomal clearance than Ligand B (68.315), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.974) has a better (longer) half-life than Ligand B (-33.248).

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.294), suggesting better bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Conclusion:**

Ligand A is the superior candidate. While both have excellent binding affinity, Ligand A demonstrates significantly better ADMET properties, specifically lower DILI risk, lower hERG inhibition, better solubility, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. These factors are crucial for developing a safe and effective enzyme inhibitor.

Output:
0
2025-04-17 13:41:15,710 - INFO - Batch 234 complete. Total preferences: 3744
2025-04-17 13:41:15,710 - INFO - Processing batch 235/512...
2025-04-17 13:42:03,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.304 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.04) is better than Ligand B (43.86) as it is still within the acceptable range for oral absorption, while ligand B is significantly lower.

**logP:** Both ligands have good logP values (1.92 and 2.3), falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.838) has a significantly higher QED score than Ligand B (0.524), indicating a more drug-like profile.

**DILI:** Ligand A (72.703) has a higher DILI risk than Ligand B (14.23). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration (83.443 and 71.888). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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:** Ligand A (-3.531) has significantly worse solubility than Ligand B (-1.51). This is a major concern for Ligand A.

**hERG Inhibition:** Ligand A (0.201) has a slightly higher hERG risk than Ligand B (0.542), but both are relatively low.

**Microsomal Clearance:** Ligand B (37.22) has a lower microsomal clearance than Ligand A (63.809), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-10.607) has a significantly longer in vitro half-life than Ligand A (-6.238), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.374) has lower P-gp efflux than Ligand B (0.103), which is slightly better.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). This is a 2.2 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better in terms of critical ADME properties for an enzyme inhibitor. Specifically, Ligand B has much lower DILI risk, better solubility, and significantly improved metabolic stability (lower Cl_mic and longer t1/2). The higher QED score of Ligand A is also a positive, but the solubility and DILI issues are major concerns. The affinity difference, while notable, is likely surmountable with further optimization of Ligand B.

Output:
1
2025-04-17 13:42:03,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.438 Da and 374.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is better than Ligand B (51.02), being under 140, but both are good.

**logP:** Ligand A (1.84) is optimal (1-3). Ligand B (4.062) is pushing the upper limit and could present solubility issues.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.703 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (32.687) has a significantly lower DILI risk than Ligand B (61.225). This is a major advantage for Ligand A.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (76.696) is better than Ligand B (52.191).

**Caco-2 Permeability:** Ligand A (-4.951) and Ligand B (-5.193) are both poor.

**Aqueous Solubility:** Ligand A (-1.986) is better than Ligand B (-3.226), but both are poor.

**hERG Inhibition:** Ligand A (0.229) is much better than Ligand B (0.343), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (20.768) has a lower clearance than Ligand B (68.15), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.339) has a longer half-life than Ligand B (21.328).

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.264).

**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.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, the substantial drawbacks in DILI risk, hERG inhibition, metabolic stability (high Cl_mic, short half-life), and solubility are concerning. Ligand A, despite its weaker binding, presents a much more favorable ADMET profile. The difference in binding affinity (-8.0 vs -0.0) is significant, but the ADMET issues with Ligand B are likely to be insurmountable. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are critical.

Output:
0
2025-04-17 13:42:03,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.427 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.22) is slightly higher than Ligand B (72.8). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (2.471 and 1.835), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the limit of 10.

**QED:** Ligand A (0.709) has a significantly better QED score than Ligand B (0.461), indicating a more drug-like profile.

**DILI:** Ligand B (3.18) has a much lower DILI risk than Ligand A (44.126), a substantial advantage.

**BBB:** Both ligands have reasonable BBB penetration (64.056 and 74.098). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.751) has poor Caco-2 permeability, while Ligand B (-5.027) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.925) has slightly better aqueous solubility than Ligand B (-2.642).

**hERG:** Both ligands have relatively low hERG inhibition risk (0.588 and 0.622).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (29.91 and 28.781 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-0.877) has a slightly longer in vitro half-life than Ligand B (0.642).

**P-gp Efflux:** Both ligands exhibit similar P-gp efflux liability (0.049 and 0.066).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

While Ligand A has a better QED and slightly better solubility and half-life, Ligand B's significantly stronger binding affinity (-8.2 vs -9.7 kcal/mol) and dramatically lower DILI risk (3.18 vs 44.126) outweigh the minor drawbacks in QED and solubility. The slightly better Caco-2 permeability of Ligand B is also a minor benefit. Given the enzyme-kinase target class priority, potency and safety (DILI) are paramount.

Output:
1
2025-04-17 13:42:03,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.366 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.5 and 93.46) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.234) is slightly low, potentially hindering permeation. Ligand B (2.443) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the 5 threshold.

**H-Bond Acceptors:** Both ligands (5) meet the criteria of being less than or equal to 10.

**QED:** Both ligands (0.813 and 0.703) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (64.793) has a higher DILI risk than Ligand B (42.73). This favors Ligand B.

**BBB:** Both ligands have moderate BBB penetration (60.295 and 56.572), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.803 and -4.367) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.518 and -3.345) which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.146 and 0.105).

**Microsomal Clearance:** Ligand A (-4.144) has a significantly *lower* (better) microsomal clearance than Ligand B (64.353), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.551) has a lower in vitro half-life than Ligand B (-23.708).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.067).

**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 advantage.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B has a better logP, lower DILI risk, and a *much* stronger binding affinity (-7.2 vs 0.0 kcal/mol). The substantial difference in binding affinity outweighs the slightly worse metabolic stability (higher Cl_mic) and half-life. The poor solubility and permeability are significant drawbacks for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:42:03,823 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.39 and 365.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.65) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.43) is excellent, well below 140.

**logP:** Ligand A (-0.528) is a bit low, potentially hindering permeability. Ligand B (1.237) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, contributing to improved permeability.

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

**QED:** Both ligands have good QED scores (0.678 and 0.712), indicating drug-like properties.

**DILI:** Ligand A (56.96) has a moderate DILI risk, while Ligand B (22.102) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.027) shows reasonable BBB penetration, while Ligand A (18.34) is low.

**Caco-2:** Both ligands have negative Caco-2 values (-5.363 and -5.28), which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Both ligands have negative solubility values (-1.312 and -1.672), which is also unusual and suggests poor aqueous solubility. This is a concern for both.

**hERG:** Ligand A (0.094) has a very low hERG risk, a major advantage. Ligand B (0.31) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-14.299) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (18.506) has a moderate clearance.

**In vitro Half-Life:** Ligand A (13.904) has a reasonable half-life, while Ligand B (15.005) is slightly better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.071).

**Binding Affinity:** Ligand B (-7.1 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.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly stronger binding affinity (-7.1 vs -10.2 kcal/mol) and lower DILI risk are critical advantages for an enzyme target like SRC. The better logP and lower HBD also contribute to its favorability. The slightly better metabolic stability and half-life are also beneficial. Ligand A's primary advantage is the very low hERG risk, but the weaker binding and higher DILI risk are more concerning.

Output:
1
2025-04-17 13:42:03,823 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.467 and 355.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.34) is better than Ligand B (92.5). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (3.206) is optimal, while Ligand B (1.379) is a bit low, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 3 HBA. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.752 and 0.705), indicating good drug-likeness.

**DILI:** Ligand B (23.691) has a significantly lower DILI risk than Ligand A (59.403). This is a major advantage for Ligand B.

**BBB:** Ligand B (80.07) has a higher BBB penetration percentile than Ligand A (47.228). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.964) has a more negative Caco-2 value than Ligand B (-5.226). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.252) has a more negative solubility value than Ligand B (-2.46). Lower values indicate lower solubility.

**hERG Inhibition:** Ligand A (0.629) has a slightly higher hERG inhibition liability than Ligand B (0.249). Lower is better here.

**Microsomal Clearance:** Ligand B (3.515) has significantly lower microsomal clearance than Ligand A (25.376), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-11.906) has a longer in vitro half-life than Ligand A (-24.505), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.023), which is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.0 kcal/mol). Ligand A has a 1.5 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and slightly lower P-gp efflux. However, Ligand B excels in crucial ADME properties: significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. While Ligand A's affinity is better, the ADME profile of Ligand B is far more favorable for development as a kinase inhibitor. The substantial difference in metabolic stability and DILI risk outweighs the affinity difference.

Output:
1
2025-04-17 13:42:03,823 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly preferred due to being lower in MW.

**TPSA:** Ligand A (61.44) is better than Ligand B (75.27), being closer to the desirable threshold of <=140 for oral absorption.

**logP:** Both ligands have good logP values (A: 3.975, B: 3.09), falling within the optimal 1-3 range.

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

**QED:** Both ligands have similar QED scores (A: 0.783, B: 0.735), indicating good drug-likeness.

**DILI:** Ligand A (69.717) has a higher DILI risk than Ligand B (43.66). This is a significant drawback for Ligand A.

**BBB:** Both have good BBB penetration, but Ligand B (85.072) is slightly better than Ligand A (79.721). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.691 for A, -4.871 for B), so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-3.782) is slightly better than Ligand A (-5.19).

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.736, B: 0.716), which is good.

**Microsomal Clearance:** Ligand B (5.089) has significantly lower microsomal clearance than Ligand A (73.957). This indicates better metabolic stability for Ligand B, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (57.348) has a longer in vitro half-life than Ligand A (35.137), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.582, B: 0.326), which is favorable.

**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 enough to be considered, especially given the other advantages of Ligand B.

**Overall:**

Ligand B is the more promising candidate. While Ligand A has a slightly lower molecular weight, Ligand B excels in critical areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The solubility and permeability issues are shared by both, and would need to be addressed in further optimization, but the ADME profile of Ligand B is clearly superior.

Output:
1
2025-04-17 13:42:03,823 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.21 and 96.25) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (target <90).

**logP:** Ligand A (1.391) is optimal, while Ligand B (0.393) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.548 and 0.662), indicating drug-like properties.

**DILI:** Ligand A (52.423) has a slightly higher DILI risk than Ligand B (38.503), but both are below the concerning threshold of 60.

**BBB:** Ligand B (69.833) has a better BBB penetration score than Ligand A (42.303), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.353 and -5.197), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.708 and -2.124), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.26 and 0.105), which is excellent.

**Microsomal Clearance:** Ligand A (8.744) has a higher microsomal clearance than Ligand B (-12.193). A negative value for Ligand B suggests *very* high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (8.289) has a reasonable half-life, while Ligand B (1.116) has a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.079 and 0.02).

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), though the difference is small.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. The primary driver is its significantly better metabolic stability (indicated by the negative Cl_mic value) and lower DILI risk. While both have poor solubility and permeability, the improved stability profile of Ligand B is crucial for an enzyme target like SRC kinase. The slightly better BBB penetration of Ligand B is a minor benefit but not a deciding factor. The small advantage in binding affinity of Ligand A is outweighed by the superior metabolic properties of Ligand B.

Output:
1
2025-04-17 13:42:03,823 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.406 and 349.45 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (43.86) as it is still within the acceptable range for oral absorption (<=140), while ligand B is significantly lower, which could indicate issues with solubility.

**logP:** Both ligands (1.518 and 1.654) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as it provides better solubility.

**H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3) as it provides better solubility.

**QED:** Ligand A (0.816) has a significantly better QED score than Ligand B (0.519), suggesting a more drug-like profile.

**DILI:** Ligand B (14.541) has a much lower DILI risk than Ligand A (44.397), a significant advantage.

**BBB:** Both ligands have high BBB penetration (87.553 and 86.545), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.779) has a slightly better Caco-2 permeability than Ligand B (-4.301), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-2.113) has a slightly better aqueous solubility than Ligand B (-1.459).

**hERG:** Both ligands have low hERG inhibition risk (0.341 and 0.42), which is good.

**Microsomal Clearance:** Ligand B (10.02) has a lower microsomal clearance than Ligand A (16.96), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.031) has a significantly longer in vitro half-life than Ligand A (-1.93), a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.044 and 0.058).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol), which is a significant advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 and solubility, Ligand B excels in critical areas for kinase inhibitors: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and superior binding affinity. The higher QED of Ligand A is positive, but the benefits of Ligand B's ADME profile and potency outweigh this.

Output:
1
2025-04-17 13:42:03,823 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (414.296 Da) is slightly higher than Ligand B (342.439 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (81.7) is higher than Ligand B (71.34), but both are reasonable.

**3. logP:** Both ligands have logP values between 1-3 (Ligand A: 3.932, Ligand B: 3.315), which is optimal. Ligand A is slightly higher, potentially increasing off-target interactions, 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 (5) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.714, Ligand B: 0.779), indicating drug-like properties.

**7. DILI Risk:** Ligand A (64.521) has a higher DILI risk than Ligand B (38.697). This is a significant concern, as lower DILI is preferred.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (68.941) and Ligand B (53.587) are both relatively low.

**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, suggesting poor aqueous solubility. Again, the scale is not specified, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.505, Ligand B: 0.239). Ligand B is slightly better here.

**12. Microsomal Clearance:** Ligand A (102.18) has a higher microsomal clearance than Ligand B (41.119), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (37.394) has a longer half-life than Ligand B (27.3), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.14, Ligand B: 0.238).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.3 kcal/mol, Ligand B: -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have similar binding affinities, Ligand B demonstrates a significantly lower DILI risk and better metabolic stability (lower Cl_mic). Although both have issues with Caco-2 and solubility, the lower DILI and better metabolic stability of Ligand B outweigh the slight advantage of Ligand A's longer half-life. The enzyme-specific priorities of metabolic stability and low toxicity make Ligand B the better choice.

Output:
1
2025-04-17 13:42:03,823 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [365.401, 46.61, 3.208, 0, 3, 0.821, 72.043, 76.231, -4.411, -5.257, 0.72, 80.369, -3.484, 0.388, -8.8]
**Ligand B:** [358.467, 74.33, 2.109, 2, 4, 0.86, 77.472, 62.97, -4.774, -2.666, 0.143, 34.127, 19.749, 0.117, -7.7]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (365.4) is slightly higher than B (358.5), but both are acceptable.
2. **TPSA:** A (46.61) is good, well below the 140 threshold. B (74.33) is higher, but still within a reasonable range for kinase inhibitors.
3. **logP:** A (3.208) is optimal. B (2.109) is slightly lower, but still acceptable.
4. **HBD:** A (0) is good, minimizing potential issues with hydrogen bonding. B (2) is acceptable.
5. **HBA:** A (3) is good. B (4) is acceptable.
6. **QED:** Both A (0.821) and B (0.86) have excellent drug-likeness scores.
7. **DILI:** Both A (72.043) and B (77.472) have acceptable DILI risk, below the concerning 60 threshold.
8. **BBB:** A (76.231) is better than B (62.97), but BBB is not a primary concern for SRC kinase, as it's not a CNS target.
9. **Caco-2:** A (-4.411) is very poor. B (-4.774) is also poor. This suggests potential absorption issues for both, but this is less critical for a kinase inhibitor where IV dosing is possible.
10. **Solubility:** A (-5.257) is poor. B (-2.666) is better, but still poor. Solubility is important for kinases, so B has an advantage here.
11. **hERG:** A (0.72) is better than B (0.143), indicating lower cardiotoxicity risk. This is a significant advantage for A.
12. **Cl_mic:** A (80.369) is higher than B (34.127), meaning faster metabolic clearance and lower metabolic stability. B is significantly better here.
13. **t1/2:** A (-3.484) is poor. B (19.749) is good. This reinforces the advantage of B in terms of metabolic stability.
14. **Pgp:** A (0.388) is better than B (0.117), suggesting lower P-gp efflux and potentially better bioavailability.
15. **Binding Affinity:** A (-8.8) is significantly better than B (-7.7), a difference of 1.1 kcal/mol. This is a substantial advantage, and often outweighs minor ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A has a much stronger binding affinity.
*   **Metabolic Stability:** B is significantly better (lower Cl_mic, longer t1/2).
*   **Solubility:** B is better, though both are poor.
*   **hERG:** A is better.

**Conclusion:**

While Ligand B has better metabolic stability and solubility, the significantly stronger binding affinity of Ligand A (-8.8 kcal/mol vs -7.7 kcal/mol) is a decisive factor. A 1.1 kcal/mol difference is substantial and can often overcome moderate ADME liabilities, especially considering kinases are often amenable to IV administration if oral bioavailability is limited. The better hERG profile of A is also a positive.

Output:
1
2025-04-17 13:42:03,824 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.411 and 335.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.43) is well below the 140 threshold for good absorption, while Ligand B (98.81) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (2.109 and 2.751), 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:** Both ligands have similar QED scores (0.797 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A (66.964) has a slightly higher DILI risk than Ligand B (82.513), but both are above the ideal <40, suggesting potential liver toxicity concerns.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.135) shows better BBB penetration than Ligand B (64.754).

**Caco-2 Permeability:** Ligand A (-4.433) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.148) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.102 and -3.824) which is very concerning. Poor solubility will severely limit bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.552 and 0.453), which is excellent.

**Microsomal Clearance:** Ligand A (44.641) has a higher microsomal clearance than Ligand B (25.01), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (6.391) has a slightly longer half-life than Ligand A (7.285).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.5 and 0.189).

**Binding Affinity:** Ligand B (-7.7 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 issues.

**Conclusion:**

Despite the solubility issues for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.7 vs -0.0 kcal/mol) is a major advantage for an enzyme inhibitor. While Ligand A has slightly better metabolic stability, the difference isn't substantial enough to overcome the huge potency gap. The DILI risk is higher for both, but can potentially be addressed through structural modifications. The poor Caco-2 and solubility are concerning and would need to be addressed, but the potency of Ligand B makes it a better starting point for optimization.

Output:
1
2025-04-17 13:42:03,824 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (374.418 Da and 383.279 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.94 and 83.06) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.711) is optimal, while Ligand B (4.07) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Ligand A (0.589) is better than Ligand B (0.384), indicating a more drug-like profile.

**DILI:** Ligand A (22.257) has a significantly lower DILI risk than Ligand B (33.463), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (88.329) is slightly better than Ligand A (74.292). However, BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.962 and -4.922), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.779) is better than Ligand B (-4.808), indicating better solubility.

**hERG Inhibition:** Ligand A (0.277) has a much lower hERG risk than Ligand B (0.892), a critical advantage.

**Microsomal Clearance:** Ligand A (44.595) has higher microsomal clearance than Ligand B (21.015), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (10.175) has a slightly longer half-life than Ligand A (9.5), which is preferable.

**P-gp Efflux:** Ligand A (0.037) has significantly lower P-gp efflux than Ligand B (0.332), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.7 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:**

Ligand B has a significantly better binding affinity (-9.7 vs -7.3 kcal/mol). However, it has a higher logP, a higher DILI risk, a higher hERG risk, and a higher P-gp efflux. Ligand A has better solubility, lower DILI and hERG risk, and lower P-gp efflux, but suffers from higher microsomal clearance.

Given the priority for potency in enzyme inhibitors, the substantial difference in binding affinity (-2.4 kcal/mol) is a significant factor. While Ligand B's ADME properties are less ideal, the increased potency could be optimized through further medicinal chemistry efforts. The higher hERG and DILI risks are manageable concerns that can be addressed in subsequent iterations.

Output:
1
2025-04-17 13:42:03,824 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.466 and 354.51 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is slightly higher than Ligand B (49.41). Both are acceptable, but B is better for permeability.

**logP:** Both ligands have good logP values (2.508 and 3.86), falling within the optimal 1-3 range. Ligand B is a bit higher, potentially leading to slight solubility concerns, 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 well within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.593 and 0.639), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 22.8%, while Ligand B has 12.136%. Both are low risk, but Ligand B is preferable.

**BBB:** Both ligands have high BBB penetration (87.941 and 85.576). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.597 and -4.388). This is unusual and suggests poor permeability, but the scale isn't clearly defined. We'll need to consider other factors.

**Aqueous Solubility:** Both have negative solubility values (-3.18 and -3.712) which is also unusual. Again, the scale isn't clear, but suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.533 and 0.651), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand A has a Cl_mic of 55.247, while Ligand B has 58.704. Lower is better, so Ligand A is slightly preferable.

**In vitro Half-Life (t1/2):** Ligand A has a half-life of -4.367 hours, while Ligand B has -5.292 hours. Both are negative, which is strange. However, the more negative value for B suggests a shorter half-life, making A preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.243 and 0.266), which is good.

**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.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the significantly stronger binding affinity of Ligand B (-8.0 kcal/mol vs -7.5 kcal/mol) is the most important factor for an enzyme inhibitor. Ligand B also has a lower DILI risk. While Ligand A has slightly better metabolic stability (lower Cl_mic and longer half-life), the potency advantage of Ligand B is more critical.

Output:
1
2025-04-17 13:42:03,824 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.459 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.35) is significantly better than Ligand B (102.88). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (2.015) is optimal (1-3), while Ligand B (0.468) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 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.

**QED:** Ligand A (0.908) has a much better QED score than Ligand B (0.611), indicating a more drug-like profile.

**DILI:** Ligand A (26.173) has a significantly lower DILI risk than Ligand B (64.056). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration (A: 77.627, B: 70.88), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.947 and -4.964). This is unusual and suggests poor permeability *in vitro*. However, this is less concerning if the binding affinity is high.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.33 and -1.579), indicating poor aqueous solubility. This is a drawback for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.326) has a much lower hERG risk than Ligand B (0.19). This is a significant advantage.

**Microsomal Clearance:** Ligand A (11.141) has slightly higher microsomal clearance than Ligand B (10.476), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-17.268) has a very poor in vitro half-life, indicating rapid metabolism. Ligand A (4.195) is much better.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.053 and 0.008).

**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 of the ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. Its significantly better binding affinity, lower DILI risk, lower hERG risk, and better in vitro half-life outweigh its slightly higher microsomal clearance and poor solubility (which can be addressed with formulation). While both have poor Caco-2 permeability, the stronger binding of Ligand A makes it more likely to achieve efficacy *in vivo*.

Output:
1
2025-04-17 13:42:03,825 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.435 Da) and Ligand B (346.471 Da) are both acceptable.

**TPSA:** Ligand A (87.3) is better than Ligand B (53.76). Both are below 140, indicating good oral absorption potential.

**logP:** Both ligands have good logP values (Ligand A: 1.67, Ligand B: 3.159), falling 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 3-5 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (Ligand A: 0.778, Ligand B: 0.762), indicating good drug-like properties.

**DILI:** Ligand A (72.276) has a higher DILI risk than Ligand B (11.361). This is a significant concern for Ligand A.

**BBB:** Ligand B (81.078) has better BBB penetration than Ligand A (54.13). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.614) has worse Caco-2 permeability than Ligand B (-4.494).

**Aqueous Solubility:** Ligand A (-3.114) has worse aqueous solubility than Ligand B (-2.779). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.292) has a slightly higher hERG inhibition liability than Ligand B (0.561). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (-3.781) has significantly better microsomal clearance (more negative, indicating lower clearance and thus better metabolic stability) than Ligand B (73.996). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (105.964) has a much longer in vitro half-life than Ligand B (25.689). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux than Ligand B (0.094), which is preferable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (Ligand A: -9.4 kcal/mol, Ligand B: -8.4 kcal/mol). Ligand A has a 1 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a significant advantage in binding affinity, metabolic stability (Cl_mic and t1/2), and P-gp efflux. However, it suffers from higher DILI risk, lower solubility, and lower Caco-2 permeability. Ligand B has better solubility, lower DILI risk, and better Caco-2 permeability, but its metabolic stability is a concern.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), the superior binding affinity and metabolic stability of Ligand A outweigh its drawbacks. The 1 kcal/mol difference in binding is substantial. While the DILI risk is a concern, it can be addressed through further structural modifications.

Output:
0
2025-04-17 13:42:03,825 - INFO - Batch 235 complete. Total preferences: 3760
2025-04-17 13:42:03,825 - INFO - Processing batch 236/512...
2025-04-17 13:42:46,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (352.425 and 351.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (42.43) is better than Ligand B (51.91), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (3.938 and 3.065), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBDs, 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 (0.632 and 0.722), indicating good drug-likeness.

**7. DILI:** Ligand A (15.975) has a significantly lower DILI risk than Ligand B (29.391). This is a major advantage for Ligand A.

**8. BBB:** Both have high BBB penetration (94.067 and 96.161). While not crucial for a non-CNS target like SRC, it doesn't detract from their potential.

**9. Caco-2 Permeability:** Ligand A (-3.763) is worse than Ligand B (-4.316), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.54) is worse than Ligand B (-3.855), indicating lower aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.713) has a slightly higher hERG risk than Ligand B (0.582), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (83.91) has a higher microsomal clearance than Ligand B (44.171), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (44.402) has a much longer in vitro half-life than Ligand A (-2.234), suggesting better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.425) has lower P-gp efflux than Ligand B (0.19), which is favorable.

**15. Binding Affinity:** Ligand A (-9.2) has a significantly stronger binding affinity than Ligand B (-6.6). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a lower DILI risk, and lower P-gp efflux. However, it suffers from lower Caco-2 permeability, lower solubility, and higher microsomal clearance (shorter half-life). Ligand B has better ADME properties (solubility, permeability, metabolic stability), but a weaker binding affinity.

Given that we are targeting a kinase (enzyme class), potency (binding affinity) is paramount. The 2.6 kcal/mol difference in binding affinity is substantial. While the ADME properties of Ligand A are less ideal, they are not catastrophic, and optimization could potentially address these issues. The stronger binding of Ligand A is likely to translate to greater efficacy *in vivo*.

Output:
1
2025-04-17 13:42:46,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.406 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (87.39), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (2.153 and 3.246), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 3) and HBA (4 and 4) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.855 and 0.685), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (44.203 and 47.732), both are below the 60 threshold, indicating low risk.

**BBB:** Ligand B (64.831) has a higher BBB penetration score than Ligand A (53.432), but BBB isn't a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.225 and -4.764), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.073 and -3.473), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.644 and 0.554), which is good.

**Microsomal Clearance:** Ligand A (26.434 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (35.609 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (71.482 hours) has a much longer in vitro half-life than Ligand A (-17.278 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 (0.279 and 0.458).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-9.1 kcal/mol). A 1.9 kcal/mol difference is substantial and can often outweigh other ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate despite the poor permeability and solubility. The significantly stronger binding affinity (-7.2 vs -9.1 kcal/mol) is a major advantage for an enzyme inhibitor. The longer half-life of Ligand B is also a significant benefit. While both have poor solubility and permeability, these can potentially be addressed through formulation strategies. The lower metabolic stability of Ligand A is a more difficult problem to overcome.

Output:
1
2025-04-17 13:42:46,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.387 and 347.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (100.21 and 100.55) slightly above the optimal <140 for oral absorption, but not drastically so.

**3. logP:** Ligand A (0.259) is quite low, potentially hindering permeation. Ligand B (0.797) is better, but still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (5) meet the HBA <=10 criteria.

**6. QED:** Ligand A (0.811) has a significantly better QED score than Ligand B (0.604), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.374) has a higher DILI risk than Ligand B (41.915), which is a concern. However, both are still within acceptable ranges.

**8. BBB:** Both ligands have low BBB penetration (47.499 and 43.505), which isn't crucial for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.362 and -4.901), which is unusual and suggests poor permeability. This is a significant drawback.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.181 and -2.111). This is a major issue for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.02 and 0.047), which is excellent.

**12. Microsomal Clearance:** Ligand A (-16.6) has a much lower (better) microsomal clearance than Ligand B (3.904), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.432) has a shorter half-life than Ligand B (-32.27). The negative value for Ligand B is unusual and likely indicates a very long half-life, which is a positive.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.029 and 0.046), which is favorable.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol), though both are good.

**Overall Assessment:**

Ligand A has a better QED, binding affinity, and *significantly* better metabolic stability (lower Cl_mic). However, it has a higher DILI risk and poorer solubility. Ligand B has better solubility and a potentially longer half-life, but lower QED, weaker binding, and worse metabolic stability.

The poor solubility and Caco-2 permeability of both compounds are major concerns. However, for an enzyme target like SRC kinase, metabolic stability is paramount. The substantial difference in Cl_mic favors Ligand A. The slightly better binding affinity of Ligand A further strengthens its position. While the DILI risk is higher, it's still within a manageable range.

Output:
0
2025-04-17 13:42:46,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (374.388 Da and 350.375 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.35) is well below the 140 threshold and favorable for oral absorption. Ligand B (115.89) is still within acceptable limits, but less optimal.

**3. logP:** Ligand A (3.174) is within the optimal range of 1-3. Ligand B (-1.601) is significantly below 1, which could hinder permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are well below the 10 HBA threshold.

**6. QED:** Ligand A (0.873) has a very good QED score, indicating high drug-likeness. Ligand B (0.458) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (69.639) has a higher DILI risk than Ligand B (49.632), but both are below the concerning 60 percentile.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.664) is slightly better than Ligand B (52.889).

**9. Caco-2:** Ligand A (-4.895) and Ligand B (-5.46) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability. Ligand B is slightly worse.

**10. Solubility:** Ligand A (-3.9) and Ligand B (-2.349) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poorer solubility. Ligand A is slightly worse.

**11. hERG:** Ligand A (0.562) has a much lower hERG risk than Ligand B (0.017), which is a significant advantage.

**12. Cl_mic:** Ligand A (19.877) has a higher microsomal clearance than Ligand B (-21.892).  A negative value for Cl_mic suggests very high metabolic stability, making Ligand B preferable in this regard.

**13. t1/2:** Ligand A (58.524) has a longer in vitro half-life than Ligand B (-6.836). A negative value for t1/2 is unusual and suggests very rapid metabolism. Ligand A is preferable.

**14. Pgp:** Ligand A (0.304) has lower P-gp efflux liability than Ligand B (0.004), which is favorable.

**15. 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.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Overall Assessment:**

Ligand A has a superior binding affinity, better QED, lower hERG risk, and a longer half-life. While Ligand B has better metabolic stability (Cl_mic), the significantly stronger binding of Ligand A, coupled with its more favorable drug-like properties, makes it the more promising candidate. The lower logP and Caco-2/Solubility scores of Ligand B are concerning for oral bioavailability.

Output:
1
2025-04-17 13:42:46,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.411 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.71 and 78.66) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.31 and 2.443) 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=5) in terms of H-bonding potential, being closer to the ideal thresholds.

**QED:** Ligand A (0.913) has a significantly better QED score than Ligand B (0.787), indicating a more drug-like profile.

**DILI:** Ligand A (56.921) has a higher DILI risk than Ligand B (46.297), but both are reasonably acceptable.

**BBB:** Ligand A (80.496) has a better BBB penetration percentile than Ligand B (57.619). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.548 and -4.885), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.383 and -2.771), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.21) shows a lower hERG inhibition liability than Ligand B (0.443), which is a positive attribute.

**Microsomal Clearance:** Ligand B (-10.522) has a significantly lower (better) microsomal clearance than Ligand A (28.983), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (37.163) has a longer in vitro half-life than Ligand A (-4.438), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.203) has a lower P-gp efflux liability than Ligand B (0.235), which is slightly favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.8 and -8.5 kcal/mol). Ligand A has a 1.3 kcal/mol advantage, which is substantial and can potentially outweigh some of its ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability for both compounds, Ligand A is the better candidate. The significantly better QED score, lower hERG risk, and, most importantly, the stronger binding affinity (-9.8 kcal/mol vs -8.5 kcal/mol) outweigh the slightly higher DILI risk and worse metabolic stability compared to Ligand B. The 1.3 kcal/mol difference in binding affinity is a significant advantage for an enzyme target like SRC kinase. Addressing the solubility and permeability issues would be critical in further development, but the potency and drug-like properties of Ligand A make it the more promising starting point.

Output:
0
2025-04-17 13:42:46,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.399 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.37 and 89.35) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.137) is optimal, while Ligand B (1.673) is slightly lower but still acceptable.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1, both 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:** Ligand A (0.872) has a better QED score than Ligand B (0.685), indicating a more drug-like profile.

**DILI:** Ligand A (83.598) has a higher DILI risk than Ligand B (66.693). This is a significant negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (75.843 and 79.488), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.77 and -5.378), 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 ligands have negative solubility values (-4.509 and -2.376), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.34 and 0.325), which is excellent.

**Microsomal Clearance:** Ligand B (40.526 mL/min/kg) has significantly lower microsomal clearance than Ligand A (60.953 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (2.455 hours) has a slightly longer half-life than Ligand A (24.342 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.334 and 0.093).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.8 vs -9.6 kcal/mol) and improved metabolic stability (lower Cl_mic and longer half-life) are crucial for an enzyme inhibitor. While Ligand A has a better QED, the higher DILI risk is a serious concern. The affinity difference is large enough to compensate for the slightly lower QED and solubility issues.

Output:
1
2025-04-17 13:42:46,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.5 and 353.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.2) is significantly better than Ligand B (113.2).  A TPSA under 140 is preferred for oral absorption, but lower is generally better for kinases. Ligand B's TPSA is quite high.

**logP:** Ligand A (4.2) is higher than Ligand B (1.05). While 4.2 is approaching the upper limit, it's still acceptable. Ligand B's logP is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Lower HBD counts are generally better for permeability.

**QED:** Both ligands have similar QED values (0.595 and 0.582), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (53.6% and 53.7%), which is acceptable (below 60).

**BBB:** Ligand A (72.9%) has slightly better BBB penetration than Ligand B (65.0%), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.115 and -5.524). This is unusual and suggests poor permeability *in vitro*. However, this is a relative metric and doesn't necessarily disqualify a candidate.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.096 and -2.495). This is also concerning, as solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.257) has a much lower hERG risk than Ligand B (0.47). This is a significant advantage.

**Microsomal Clearance:** Ligand A (63.6) has higher microsomal clearance than Ligand B (9.1). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (9.89 hours) has a significantly longer half-life than Ligand A (-9.342 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.619) has lower P-gp efflux than Ligand B (0.08). Lower efflux is preferred.

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

**Overall Assessment:**

Ligand A excels in logP, TPSA, hERG risk, and P-gp efflux. Ligand B has a much better in vitro half-life and lower microsomal clearance. Solubility and Caco-2 permeability are poor for both. Given the enzyme-specific priorities, metabolic stability (half-life and clearance) is crucial. While Ligand A has better ADME properties overall (except for half-life), the significantly longer half-life of Ligand B is a strong advantage. The equal binding affinity makes this the deciding factor.

Output:
1
2025-04-17 13:42:46,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 362.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.6) is better than Ligand B (97.11), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (though that's not a priority here).

**logP:** Ligand A (0.025) is very low, potentially hindering permeability. Ligand B (2.03) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Both have 3 HBDs and 5 HBAs, which are acceptable.

**QED:** Both ligands have a QED of 0.7, indicating good drug-likeness.

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (66.886). This is a major advantage for A.

**BBB:** Ligand A (38.736) has a lower BBB penetration than Ligand B (75.843), but BBB is not a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Both ligands have very negative Caco-2 values (-5.228 and -5.219), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.327) is slightly better than Ligand B (-3.142), but both are very poor. Solubility is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.186 and 0.535).

**Microsomal Clearance:** Ligand A (-25.604) has significantly lower (better) microsomal clearance than Ligand B (9.203). This indicates better metabolic stability for A.

**In vitro Half-Life:** Ligand A (9.154) has a shorter half-life than Ligand B (29.477). This is a disadvantage for A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.12).

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has advantages in DILI risk and microsomal clearance, suggesting a better safety and metabolic profile. However, its very low logP and poor solubility are significant drawbacks. Ligand B has a better logP, which is crucial for permeability, and a longer half-life. While its DILI risk is higher, the superior logP and half-life outweigh this concern, especially given the excellent binding affinity shared by both. The Caco-2 values are concerning for both, but the better logP of B suggests it might overcome this issue more readily.

Output:
1
2025-04-17 13:42:46,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.47 & 348.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is significantly better than Ligand B (67.43).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.61 & 2.56), 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 maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.841) has a much higher QED score than Ligand B (0.629), indicating a more drug-like profile.

**DILI:** Ligand A (23.65) has a much lower DILI risk than Ligand B (14.89), suggesting better liver safety. Both are below the 40 threshold.

**BBB:** Ligand A (78.79) has a better BBB percentile than Ligand B (56.53), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.5) has a better Caco-2 permeability than Ligand B (-5.11), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.53) has better aqueous solubility than Ligand B (-2.49). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.553) has a lower hERG inhibition liability than Ligand B (0.252), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (82.16) has a higher microsomal clearance than Ligand B (32.14). This indicates lower metabolic stability for Ligand A. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-15.48) has a longer in vitro half-life than Ligand A (-11.64), indicating better stability.

**P-gp Efflux:** Ligand A (0.48) has a lower P-gp efflux liability than Ligand B (0.066), which could improve bioavailability.

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

**Overall Assessment:**

Ligand A excels in nearly all ADME properties (QED, DILI, solubility, hERG, P-gp) and has a significantly better binding affinity. However, its higher microsomal clearance is a concern. Ligand B has a better half-life and lower clearance, but suffers from poorer ADME properties across the board and a significantly weaker binding affinity. The difference in binding affinity (-7.4 vs 0) is large enough to potentially overcome the metabolic stability issue of Ligand A, especially with potential optimization strategies to reduce its clearance.

Output:
1
2025-04-17 13:42:46,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.402 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold for good absorption. Ligand B (107.26) is still acceptable but less favorable.

**logP:** Ligand A (2.689) is optimal (1-3). Ligand B (-1.074) is too low, potentially hindering permeation.

**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 4, both within the acceptable limit of 10.

**QED:** Ligand A (0.892) has a very strong drug-like profile. Ligand B (0.694) is still acceptable, but less ideal.

**DILI:** Ligand A (30.826) has a low DILI risk. Ligand B (21.908) also has a low DILI risk, but slightly lower.

**BBB:** Ligand A (95.308) shows excellent BBB penetration, though this isn't a primary concern for a non-CNS target like SRC. Ligand B (68.67) is lower.

**Caco-2 Permeability:** Ligand A (-4.467) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.126) is also low, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.067) is also concerningly low, indicating potential formulation issues. Ligand B (-1.067) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.592) has a low hERG risk. Ligand B (0.089) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (25.054) has moderate clearance. Ligand B (-7.818) has negative clearance which is not possible and indicates a potential error in the data.

**In vitro Half-Life:** Ligand A (12.119) has a reasonable half-life. Ligand B (-12.583) has a negative half-life which is not possible and indicates a potential error in the data.

**P-gp Efflux:** Ligand A (0.158) has low P-gp efflux, which is favorable. Ligand B (0.001) has very low 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 (-7.8 kcal/mol). This 1.0 kcal/mol difference is substantial.

**Conclusion:**

Despite the concerning Caco-2 and solubility values for Ligand A, its significantly superior binding affinity (-8.8 vs -7.8 kcal/mol) and acceptable ADME properties (low DILI, low hERG, good QED) make it the more promising candidate. The negative values for clearance and half-life of Ligand B are impossible and indicate a data error. While Ligand B has slightly better P-gp efflux and hERG, the binding affinity difference is crucial for an enzyme target like SRC. Optimization efforts on Ligand A could focus on improving its solubility and permeability.

Output:
1
2025-04-17 13:42:46,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.371 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (87.76) is good for oral absorption, while Ligand B (19.37) is excellent.

**logP:** Ligand A (1.025) is optimal. Ligand B (4.913) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable.

**QED:** Ligand A (0.895) is excellent, indicating strong drug-likeness. Ligand B (0.703) is still good, but less favorable than A.

**DILI:** Ligand A (86.778) has a high DILI risk. Ligand B (33.695) has a low DILI risk, a significant advantage.

**BBB:** Ligand A (39.24) is low, not a major concern for a non-CNS target. Ligand B (98.333) is very high, but irrelevant for SRC kinase as it's not a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.714 and -4.784), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.111 and -4.568), which is also unusual and concerning. This suggests poor solubility.

**hERG Inhibition:** Ligand A (0.362) has a low hERG risk. Ligand B (0.963) has a higher hERG risk, which is undesirable.

**Microsomal Clearance:** Ligand A (7.645) has a lower clearance, indicating better metabolic stability. Ligand B (39.123) has a much higher clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-9.515) has a very negative half-life, which is unusual and suggests very rapid degradation. Ligand B (28.418) has a positive half-life, indicating better stability.

**P-gp Efflux:** Ligand A (0.033) has low P-gp efflux, which is good. Ligand B (0.76) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.2 kcal/mol difference is substantial and a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, better half-life), and lower P-gp efflux. However, it has a high DILI risk and poor solubility/permeability. Ligand B has a low DILI risk and better solubility/permeability, but weaker binding affinity and poor metabolic stability.

Given the enzyme-specific priorities, binding affinity and metabolic stability are paramount. The 1.2 kcal/mol difference in binding affinity is a significant advantage for Ligand A, and while its metabolic stability is worse than B, it's still acceptable. The poor solubility/permeability of A is a concern, but potentially addressable through formulation strategies. The high DILI risk of A is a concern, but could be mitigated through structural modifications. The weaker binding of B is a more difficult issue to resolve.

Output:
0
2025-04-17 13:42:46,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.46 and 342.48 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is slightly higher than Ligand B (49.41). Both are below 140, suggesting reasonable absorption potential.

**logP:** Both ligands have good logP values (2.11 and 3.03), 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 2. Both are within acceptable limits (<=10).

**QED:** Both ligands have similar QED scores (0.859 and 0.806), indicating good drug-likeness.

**DILI:** Ligand A (34.39) has a slightly higher DILI risk than Ligand B (28.23), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.78) has lower BBB penetration than Ligand B (75.11). This is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.848 and -4.797). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are relative to a reference. It's difficult to interpret without knowing the experimental setup.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.675 and -3.756). Similar to Caco-2, these are relative values and indicate poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.433 and 0.39), which is excellent.

**Microsomal Clearance:** Ligand A (41.36) has significantly lower microsomal clearance than Ligand B (56.86), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-7.362) has a longer in vitro half-life than Ligand A (-6.03), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.214 and 0.27).

**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 factor.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and a longer half-life. However, Ligand A exhibits significantly better metabolic stability (lower Cl_mic), which is crucial for kinase inhibitors. The solubility and permeability data are concerning for both, but the metabolic stability advantage of Ligand A is more critical for an enzyme target like SRC. The small difference in binding affinity is likely outweighed by the improved metabolic stability.

Output:
1
2025-04-17 13:42:46,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.383 and 365.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly higher than Ligand B (61.44). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (1.31) is within the optimal range, while Ligand B (3.236) is towards the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and 5/3 HBAs respectively, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.784 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A (54.207) has a slightly higher DILI risk than Ligand B (43.738), but both are below the concerning threshold of 60.

**BBB:** Ligand B (70.997) has a better BBB penetration score than Ligand A (52.074), but BBB is less critical for a non-CNS target like SRC.

**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:** Ligand A (0.18) has a significantly lower hERG inhibition liability than Ligand B (0.533), which is a major advantage.

**Microsomal Clearance:** Ligand B (52.862) has a higher microsomal clearance than Ligand A (40.01), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (77.955) has a substantially longer in vitro half-life than Ligand A (-16.251), which is a significant positive.

**P-gp Efflux:** Ligand A (0.023) has much lower P-gp efflux liability than Ligand B (0.323), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This difference of 2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has advantages in hERG and P-gp efflux, the significantly stronger binding affinity of Ligand B (-10.2 vs -8.2 kcal/mol) is the most critical factor for an enzyme inhibitor. The longer half-life of Ligand B is also a significant benefit. The slightly higher DILI and clearance are less concerning given the potency advantage. The negative solubility and Caco-2 values are concerning and would need to be investigated further, but the binding affinity difference is likely to be decisive.

Output:
1
2025-04-17 13:42:46,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (95.6), both are below 140, suggesting good absorption potential.

**logP:** Ligand A (2.612) is optimal (1-3), while Ligand B (0.383) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands are acceptable (2 and 1 respectively, both <=5).

**H-Bond Acceptors:** Both ligands are acceptable (4 and 5 respectively, both <=10).

**QED:** Both ligands have good QED scores (0.503 and 0.632 respectively, both >=0.5).

**DILI:** Ligand A (18.224) has a significantly lower DILI risk than Ligand B (74.603), which is a major advantage. Ligand B is in the high-risk category.

**BBB:** Ligand A (67.468) has better BBB penetration than Ligand B (43.117), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.969) is slightly better than Ligand B (-4.886).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.844) is slightly better than Ligand B (-3.319).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.14 and 0.064 respectively).

**Microsomal Clearance:** Ligand B (12.595) has significantly lower microsomal clearance than Ligand A (59.619), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-35.421) has a much longer in vitro half-life than Ligand A (-18.614), which is a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.027 and 0.037 respectively).

**Binding Affinity:** Ligand B (-9) has a significantly stronger binding affinity than Ligand A (-6), a difference of 3 kcal/mol. This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand B has superior binding affinity and metabolic stability, its high DILI risk is a major concern. Ligand A has a much better safety profile (lower DILI) and slightly better permeability and solubility, but weaker binding. Considering the enzyme class (kinase) and prioritizing potency, metabolic stability, solubility, and safety, the stronger binding affinity of Ligand B is a significant advantage. However, the high DILI risk of Ligand B is a serious drawback that would require further investigation and potentially lead to its rejection. The slightly better overall profile of Ligand A, particularly the significantly lower DILI risk, makes it the more viable candidate at this stage.

Output:
1
2025-04-17 13:42:46,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.5 and 356.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (104.73). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (2.55 and 1.14), falling within the 1-3 optimal range. Ligand A is slightly better.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=5). Lower values are generally preferred for better permeability.

**QED:** Ligand A (0.802) has a significantly higher QED score than Ligand B (0.537), indicating a more drug-like profile.

**DILI:** Both ligands have a low DILI risk (around 10%), which is good.

**BBB:** Ligand A (70.9%) has a better BBB penetration score than Ligand B (60.6%). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.82 and -4.74). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.65 and -1.85). This is also unusual and indicates poor aqueous solubility. Again, the values are comparable.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.36 and 0.10). This is excellent.

**Microsomal Clearance:** Ligand A (19.1 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (56.9 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.087 hours) has a very short half-life, while Ligand B (-31.73 hours) is negative. This is a major concern for both, but the negative value for Ligand B is particularly problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.08 and 0.01). This is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is superior due to its better TPSA, QED, lower microsomal clearance, and better BBB penetration. While both have poor solubility and permeability (indicated by negative Caco-2 and solubility values), and short half-lives, Ligand A's superior ADME properties and drug-likeness outweigh the slightly weaker binding affinity. The negative half-life for Ligand B is a significant red flag.

Output:
0
2025-04-17 13:42:46,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.33 and 363.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (67.6), being well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have good logP values (3.019 and 3.754), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not critically.

**H-Bond Donors/Acceptors:** Ligand A (2 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 (0.787 and 0.876), indicating drug-like properties.

**DILI:** Ligand A (42.691) has a much lower DILI risk than Ligand B (72.043). This is a significant advantage.

**BBB:** Both have moderate BBB penetration, but Ligand B (77.007) is higher than Ligand A (64.715). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.613 and -4.664), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.987 and -4.711), which is also unusual and indicates very poor solubility. This is a major concern for both.

**hERG Inhibition:** Both have low hERG inhibition risk (0.569 and 0.608), which is good.

**Microsomal Clearance:** Ligand A (38.592) has lower microsomal clearance than Ligand B (46.795), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (16.167 hours) has a longer half-life than Ligand B (10.936 hours), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.034 and 0.504).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.9 kcal/mol). Ligand B is slightly better, with a 0.9 kcal/mol advantage.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better TPSA/H-bond profile outweigh the slightly better BBB penetration and binding affinity of Ligand B. The poor Caco-2 and solubility are concerning for both, and would need to be addressed through formulation or structural modifications, but the safety profile of Ligand A makes it the preferred starting point.

Output:
0
2025-04-17 13:42:46,032 - INFO - Batch 236 complete. Total preferences: 3776
2025-04-17 13:42:46,032 - INFO - Processing batch 237/512...
2025-04-17 13:43:26,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.39 and 344.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.23) is better than Ligand B (91.23), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have a logP around 2 (2.0 and 2.215), which is optimal.

**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 good QED scores (0.765 and 0.87), indicating good drug-like properties.

**7. DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (60.644). This is a major advantage for Ligand A. Ligand B is approaching a concerning DILI percentile.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (46.724) and Ligand B (61.962) are both relatively low.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.034 and -4.954). 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 have negative solubility values (-2.243 and -3.063), indicating poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.25 and 0.186), which is excellent.

**12. Microsomal Clearance:** Ligand B (19.764) has a lower microsomal clearance than Ligand A (26.651), suggesting better metabolic stability. This is a positive for Ligand B.

**13. In vitro Half-Life:** Ligand B (23.79) has a shorter half-life than Ligand A (36.357). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.096).

**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 substantial advantage (1.1 kcal/mol difference) 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, it has a significantly higher DILI risk and a shorter half-life. Ligand A has a lower DILI risk and a longer half-life, but its binding affinity is weaker.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the stronger binding affinity of Ligand B is a significant advantage. While the DILI risk is a concern, it's not prohibitive at 60.644, and further optimization could potentially mitigate this. The lower half-life can be addressed through formulation or structural modifications. The solubility issues are similar for both.

Output:
1
2025-04-17 13:43:26,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.825 Da and 350.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.99) is excellent, well below the 140 threshold for good absorption. Ligand B (112.38) is still acceptable, but less optimal.

**logP:** Ligand A (3.392) is within the optimal 1-3 range. Ligand B (-1.566) is significantly lower, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.727) has a strong drug-like profile. Ligand B (0.572) is still reasonable, but less desirable.

**DILI:** Ligand A (52.385) has a low DILI risk. Ligand B (25.165) has an even lower DILI risk, which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (30.981) and Ligand B (11.943) are both low, as expected.

**Caco-2 Permeability:** Ligand A (-4.563) is poor, indicating low intestinal absorption. Ligand B (-5.539) is even worse.

**Aqueous Solubility:** Ligand A (-4.445) is poor. Ligand B (-0.353) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.677) has a low hERG risk. Ligand B (0.016) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (93.639) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-13.365) has negative clearance, which is excellent and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (13.417 hours) is reasonable. Ligand B (-4.078 hours) is negative, which is not realistic. This value is likely an error or outlier.

**P-gp Efflux:** Ligand A (0.531) has moderate P-gp efflux. Ligand B (0.004) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has excellent binding affinity. Ligand B (-5.9 kcal/mol) also has good binding affinity, but is 1.6 kcal/mol weaker.

**Overall Assessment:**

Ligand A has a better QED score and a significantly stronger binding affinity. However, it suffers from poor Caco-2 permeability, poor solubility, and high microsomal clearance. Ligand B has a lower binding affinity, but exhibits excellent metabolic stability (negative Cl_mic), very low hERG risk, and low P-gp efflux. The negative half-life for Ligand B is concerning and likely an error.

Given the enzyme-kinase target class, metabolic stability is crucial. The substantial difference in Cl_mic and the lower hERG risk of Ligand B outweigh the slightly weaker binding affinity. While the solubility and permeability are both poor, these can be addressed through formulation strategies. The negative half-life is a red flag, but assuming it's an error, Ligand B is the more promising candidate.

Output:
1
2025-04-17 13:43:26,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 348.487 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (69.64). A TPSA under 140 is good for oral absorption, and both are well within this limit, but A is preferable.

**logP:** Both ligands (2.712 and 2.546) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.692) is better than Ligand B (0.402). A higher QED indicates a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (16.479 and 15.626), both below the 40 threshold.

**BBB:** Ligand A (78.48) is better than Ligand B (52.811). While not a primary concern for a non-CNS target, higher BBB penetration can sometimes correlate with better overall drug distribution.

**Caco-2 Permeability:** Ligand A (-4.287) is better than Ligand B (-4.681). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.925) is better than Ligand B (-1.81). Higher solubility is generally preferred.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.393 and 0.348), which is excellent.

**Microsomal Clearance:** Ligand A (47.212) is worse than Ligand B (26.624). Lower clearance is preferred for metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-11.62) is worse than Ligand B (-7.386). A more positive value (longer half-life) is preferred. This is another advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.058 and 0.2).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent and the most important factor.

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic and longer t1/2). Ligand A has advantages in TPSA, QED, Caco-2 permeability, and solubility. However, the metabolic stability advantages of Ligand B are more critical for an enzyme target like SRC kinase. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 13:43:26,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.47 & 348.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.56) is significantly better than Ligand B (58.64).  A TPSA under 140 is good for oral absorption, and both are well below this, but lower is generally preferred.

**logP:** Both ligands have good logP values (4.06 & 2.35), falling within the 1-3 range. Ligand B is slightly better, being closer to 1-3.

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

**QED:** Both ligands have good QED scores (0.60 & 0.78), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (17.45) has a lower DILI risk than Ligand B (20.82), which is preferable. Both are below the 40 threshold.

**BBB:** Both have reasonable BBB penetration (68.55% & 62.74%). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.23) is significantly worse than Ligand B (-4.55), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.15 & -2.86). This is a concern and may require formulation strategies.

**hERG Inhibition:** Ligand A (0.98) has a slightly better hERG profile than Ligand B (0.19), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (26.64) has significantly better metabolic stability (lower clearance) than Ligand B (39.41). This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (29.77) has a longer half-life than Ligand B (14.61), which is desirable.

**P-gp Efflux:** Ligand A (0.72) has slightly better P-gp efflux properties than Ligand B (0.08).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly better binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.1 vs -8.6 kcal/mol). While Ligand A has better metabolic stability and DILI, the potency advantage of Ligand B is substantial. The slightly worse solubility and clearance of Ligand B are manageable with formulation and potentially structural modifications. The Caco-2 permeability is also slightly better for Ligand B. Considering the enzyme-specific priorities, potency is paramount, and Ligand B's superior binding affinity makes it the more promising candidate.

Output:
1
2025-04-17 13:43:26,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.359 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.53) is slightly higher than Ligand B (87.66). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (-0.191) is quite low, potentially hindering membrane permeability. Ligand B (1.506) 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 the acceptable range. Ligand A has 6 HBA, while Ligand B has 4. Both are under the 10 HBA limit.

**QED:** Both ligands have similar QED values (0.664 and 0.648), indicating good drug-likeness.

**DILI:** Ligand A (69.756) has a higher DILI risk than Ligand B (16.44). This is a substantial difference, favoring Ligand B.

**BBB:** Ligand A (8.181) has very low BBB penetration, while Ligand B (25.94) is also low, but better than A. BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.633) has poor Caco-2 permeability, while Ligand B (-4.901) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.954 and -1.702). This is a concern for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.135 and 0.151). This is excellent.

**Microsomal Clearance:** Ligand A (16.49) has higher microsomal clearance than Ligand B (10.518), suggesting lower metabolic stability. Ligand B is preferred here.

**In vitro Half-Life:** Both have similar in vitro half-lives (11.153 and 11.617 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.024).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.9 and -8.9 kcal/mol). Ligand A is slightly better (-9.9 kcal/mol), with a 1.0 kcal/mol advantage.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, its significantly lower logP, higher DILI risk, and higher microsomal clearance are major drawbacks. Ligand B has a more balanced profile with a good logP, much lower DILI risk, and better metabolic stability. The 1.0 kcal/mol difference in binding affinity is unlikely to outweigh these ADME/Tox concerns. For an enzyme target like SRC kinase, metabolic stability, solubility, and safety (DILI, hERG) are critical.

Output:
1
2025-04-17 13:43:26,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.45 & 354.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.72 & 78.87) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.399 & 1.421), falling within the 1-3 range. Ligand B is slightly more hydrophilic.

**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 reasonable QED scores (0.465 & 0.725), with Ligand B being more drug-like.

**DILI:** Ligand A (35.014) has a significantly lower DILI risk than Ligand B (7.871), indicating a better safety profile.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.513) has better BBB penetration than Ligand B (56.572).

**Caco-2 Permeability:** Ligand A (-5.004) has worse Caco-2 permeability than Ligand B (-4.712), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.866 & -1.565). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.887) has a slightly better hERG profile than Ligand B (0.298), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-6.786) has *much* lower microsomal clearance than Ligand B (41.551). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-4.128) has a better in vitro half-life than Ligand B (8.599).

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux than Ligand B (0.012), potentially leading to better oral bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a 1.5 kcal/mol difference, which is significant.

**Conclusion:**

While Ligand B boasts a slightly better binding affinity, Ligand A demonstrates a significantly superior ADMET profile. The lower DILI risk, dramatically improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux are crucial advantages for an enzyme target like SRC kinase. The solubility is poor for both, but the other benefits of Ligand A outweigh the slightly weaker binding.

Output:
0
2025-04-17 13:43:26,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.454 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.81) is better than Ligand B (63.94), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.426 and 1.166), falling within the optimal 1-3 range. Ligand A is slightly better.

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

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

**QED:** Both ligands have good QED scores (0.603 and 0.813), indicating good drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (11.206) has a significantly lower DILI risk than Ligand B (28.655), which is a major advantage.

**BBB:** Ligand A (92.827) shows better BBB penetration than Ligand B (53.625), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.463) has better Caco-2 permeability than Ligand B (-4.846), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.994) has better aqueous solubility than Ligand B (-2.259).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.628 and 0.29), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (43.684) has higher microsomal clearance than Ligand B (-1.264), meaning Ligand B is more metabolically stable. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (34.555) has a much longer in vitro half-life than Ligand A (-2.301), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.136) has lower P-gp efflux than Ligand B (0.041), which is preferable.

**Binding Affinity:** Ligand B (-7.9) has a significantly stronger binding affinity than Ligand A (-9.3). This is a crucial factor, and the 1.4 kcal/mol difference is substantial enough to potentially outweigh some ADME drawbacks.

**Overall:**

Ligand B demonstrates a significantly stronger binding affinity and superior metabolic stability (lower Cl_mic and longer t1/2). While Ligand A has better solubility and lower DILI, the potency and metabolic stability advantages of Ligand B are more critical for an enzyme target like SRC kinase. The higher affinity of Ligand B is likely to translate to greater efficacy.

Output:
1
2025-04-17 13:43:26,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.447 and 346.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.02) is well below the 140 threshold for good absorption, while Ligand B (96.17) is still acceptable but less optimal.

**logP:** Ligand A (4.161) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.324) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 7 HBA) both have reasonable counts, staying within the guidelines.

**QED:** Both ligands have similar QED values (0.674 and 0.665), indicating good drug-likeness.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (59.907), which is preferable.

**BBB:** Both ligands have low BBB penetration (41.566 and 40.946), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.286 and -5.164), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.223 and -1.345). This is a major drawback.

**hERG Inhibition:** Ligand A (0.342) has a slightly higher hERG risk than Ligand B (0.178), but both are relatively low.

**Microsomal Clearance:** Ligand B (-2.176) exhibits *negative* microsomal clearance, which is physiologically impossible and indicates a potential issue with the data or model. Ligand A (59.972) has a moderate clearance.

**In vitro Half-Life:** Ligand B (30.197) has a slightly longer half-life than Ligand A (28.419).

**P-gp Efflux:** Ligand A (0.211) shows low P-gp efflux, which is good. Ligand B (0.045) is even lower.

**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.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.2 vs 0 kcal/mol) outweighs the slightly higher logP and DILI risk of Ligand A. The negative microsomal clearance for Ligand B is a red flag and requires further investigation, but the binding affinity difference is so large that it warrants prioritizing Ligand B for further optimization, assuming the clearance data can be resolved.

Output:
1
2025-04-17 13:43:26,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (385.222 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (110) is still under 140, but less optimal than A.

**logP:** Ligand A (3.919) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.533) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 5 HBA) both have reasonable counts, staying within the guidelines.

**QED:** Both ligands have acceptable QED values (0.767 and 0.588, respectively), indicating good drug-like properties.

**DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (46.258). This is a significant drawback for A.

**BBB:** Both have good BBB penetration (70.027 and 76.347), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.461) has poor Caco-2 permeability, while Ligand B (-5.052) is also poor. This suggests potential absorption issues for both, but A is slightly better.

**Aqueous Solubility:** Ligand A (-5.547) has very poor aqueous solubility, which is a major concern. Ligand B (-3.058) is better, but still not ideal.

**hERG:** Ligand A (0.61) has a slightly higher hERG risk than Ligand B (0.325), though both are relatively low.

**Microsomal Clearance:** Ligand A (85.787) has higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (34.85). This is a significant negative for A.

**In vitro Half-Life:** Ligand A (47.034) has a shorter half-life than Ligand B (-27.489, which is a very long half-life). This favors B.

**P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux than Ligand B (0.041), which is favorable.

**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 could outweigh some of the ADME drawbacks of Ligand A *if* those drawbacks aren't insurmountable.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the highest priority. However, it suffers from poor solubility, higher DILI risk, and higher metabolic clearance. Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life, lower P-gp efflux), but weaker binding affinity.

Considering the enzyme-specific priorities, the substantial affinity advantage of Ligand A is compelling. While the solubility and metabolic stability are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The DILI risk is moderate, but not prohibitive. The slightly higher hERG risk is also manageable.

Output:
1
2025-04-17 13:43:26,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.386 and 355.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.81) is better than Ligand B (53.09), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (3.447) is slightly higher than Ligand B (1.839). Both are within the optimal 1-3 range, but Ligand A is approaching the upper limit.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (0). This could slightly impact permeability, but isn't a major concern.

**H-Bond Acceptors:** Ligand A (2) is lower than Ligand B (4). Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.682 and 0.633), indicating good drug-like properties.

**DILI:** Ligand A (61.884) has a higher DILI risk than Ligand B (25.514). This is a significant negative for Ligand A.

**BBB:** Both have good BBB penetration, but Ligand A (81) is slightly better than Ligand B (76.037). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.93) is better than Ligand B (-4.233), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.315) is worse than Ligand B (-1.323), meaning Ligand B has better solubility. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.802) has a higher hERG risk than Ligand B (0.537). This is a concern for Ligand A.

**Microsomal Clearance:** Ligand A (-3.29) has significantly *lower* (better) microsomal clearance than Ligand B (56.964). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (20.424) has a longer half-life than Ligand B (-2.603). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.339) has lower P-gp efflux than Ligand B (0.174), which is favorable.

**Binding Affinity:** Ligand B (-7.4) has a significantly better binding affinity than Ligand A (-9.7). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

While Ligand A has advantages in metabolic stability (Cl_mic, t1/2), Caco-2 permeability, and P-gp efflux, its higher DILI risk, hERG inhibition liability, and significantly weaker binding affinity are major drawbacks. Ligand B, despite slightly lower metabolic stability and solubility, possesses a much stronger binding affinity and a significantly better safety profile (lower DILI and hERG). For an enzyme target like SRC kinase, potency and safety are paramount.

Output:
1
2025-04-17 13:43:26,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.37 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.89) is higher than Ligand B (61.44). While both are below 140, the lower TPSA of Ligand B is preferable for better absorption.

**logP:** Ligand A (0.245) is quite low, potentially hindering permeability. Ligand B (2.452) 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 7 HBA, while Ligand B has 3. Ligand B's lower HBA count is favorable for permeability.

**QED:** Ligand A (0.806) has a higher QED score than Ligand B (0.637), suggesting a more drug-like profile overall.

**DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (9.306). This is a major concern for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand B (69.407) is slightly better. This isn't a primary concern for a kinase inhibitor, but a slight advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are very close, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, values are similar.

**hERG:** Ligand A (0.546) has a slightly higher hERG risk than Ligand B (0.418), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (38.046) has a significantly lower microsomal clearance than Ligand A (1.464), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (9.358) has a longer in vitro half-life than Ligand A (39.391). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a very important advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better QED score, Ligand B excels in the most critical areas for an enzyme inhibitor: binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. Ligand B also has a more favorable logP and TPSA. The slightly lower QED of Ligand B is a minor concern compared to the significant advantages it offers.

Output:
1
2025-04-17 13:43:26,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (1.47 and 2.296), 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 3 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.651 and 0.728), indicating good drug-like properties.

**DILI:** Ligand A (14.773) has a significantly lower DILI risk than Ligand B (17.798). Both are below the 40 threshold, which is good.

**BBB:** Ligand B (96.937) has a much higher BBB penetration percentile than Ligand A (64.87). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.039) has worse Caco-2 permeability than Ligand B (-4.311). Both are negative values, which is unusual and indicates poor permeability.

**Aqueous Solubility:** Ligand A (-2.109) has slightly better solubility than Ligand B (-3.022). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.195) has a lower hERG inhibition liability than Ligand B (0.655), which is preferable.

**Microsomal Clearance:** Ligand A (29.276) has significantly lower microsomal clearance than Ligand B (49.907), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Both ligands have negative half-lives (-13.612 and -14.063), which is not physically meaningful and likely an error in the data. We cannot use this parameter for comparison.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux liability than Ligand B (0.179), which is favorable.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is relatively small (0.9 kcal/mol).

**Overall Assessment:**

Ligand A is better overall. It has a lower DILI risk, lower hERG inhibition, significantly lower microsomal clearance (better metabolic stability), lower P-gp efflux, and comparable binding affinity. While Ligand B has better Caco-2 permeability and BBB penetration, these are less important for a non-CNS enzyme target like SRC. The solubility is slightly better for A, but both are poor. The most important factor is the metabolic stability, and A is superior in that regard.

Output:
0
2025-04-17 13:43:26,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 346.402 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.45) is slightly higher than Ligand B (49.85). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (2.05 and 1.977), 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.846 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A (57.387) has a higher DILI risk than Ligand B (42.846). Both are below the concerning 60 threshold, but B is preferable.

**BBB:** Both ligands have good BBB penetration (75.378 and 83.288). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.348 and -4.091). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.983 and -2.422). Again, these values are on a log scale and indicate poor solubility.

**hERG Inhibition:** Ligand A (0.193) has a slightly higher hERG risk than Ligand B (0.603). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (77.298) has a higher microsomal clearance than Ligand B (35.213). Lower clearance is preferred for better metabolic stability, so Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-31.614) has a much longer in vitro half-life than Ligand A (-12.97). This is a major advantage for Ligand B, suggesting less frequent dosing could be possible.

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux than Ligand B (0.381), which is favorable.

**Binding Affinity:** Ligand B (-7.2 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 the other ADME differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity and P-gp efflux, Ligand B excels in critical ADME properties for an enzyme inhibitor: lower DILI risk, significantly lower microsomal clearance (better metabolic stability), and a much longer in vitro half-life. The TPSA is also significantly better for Ligand B. The solubility and Caco-2 values are poor for both, but the other advantages of Ligand B make it the better choice.

Output:
1
2025-04-17 13:43:26,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.382 and 358.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.51) is well below the 140 threshold, suggesting good absorption. Ligand B (108.05) is still acceptable, but less optimal.

**logP:** Ligand A (2.995) is within the optimal 1-3 range. Ligand B (-1.122) is significantly below this, which could hinder permeability despite potentially improving solubility.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (2 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.571 and 0.561), indicating good drug-likeness.

**DILI:** Ligand A (97.131) has a high DILI risk, a significant concern. Ligand B (51.842) has a much lower, and acceptable, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (81.233) has a higher BBB score than Ligand A (45.677), but this is not a major factor here.

**Caco-2 Permeability:** Ligand A (-4.431) has poor predicted permeability. Ligand B (-5.188) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.203) has poor solubility. Ligand B (-1.798) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.57) has a slightly higher hERG risk than Ligand B (0.101), which is preferable.

**Microsomal Clearance:** Ligand B (-11.98) has significantly lower (better) microsomal clearance than Ligand A (62.43), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-4.448) has a longer predicted half-life than Ligand A (-25.239), which is desirable.

**P-gp Efflux:** Ligand A (0.417) has lower P-gp efflux than Ligand B (0.004), which is preferable.

**Binding Affinity:** Ligand B (-8.6 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 consider, especially given the other factors.

**Overall Assessment:**

Ligand A suffers from high DILI risk, poor permeability, and poor solubility. While it has slightly better P-gp efflux, the other drawbacks are substantial. Ligand B, despite having lower logP and permeability, has a much more favorable safety profile (DILI), better metabolic stability (Cl_mic, t1/2), and slightly better binding affinity. For an enzyme target like SRC kinase, metabolic stability and safety are paramount. The slightly lower logP of Ligand B can be addressed through further optimization, but the high DILI risk of Ligand A is a more difficult problem to solve.

Output:
1
2025-04-17 13:43:26,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.46 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (107.11). A TPSA under 140 is good for oral absorption, and both are under, but A is much closer to the ideal for better absorption.

**logP:** Both ligands have acceptable logP values (2.43 and 1.54), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=4, HBA=4) as it has fewer hydrogen bond donors, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.629 and 0.542), indicating good drug-like properties.

**DILI:** Ligand A (23.85) has a much lower DILI risk than Ligand B (38.47), a significant advantage. Lower is better, and A is well below the 40% threshold.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (82.05) has a better BBB percentile than Ligand B (40.40).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.199 and -5.193), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.338 and -2.585), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.298) has a lower hERG inhibition liability than Ligand B (0.384), which is desirable.

**Microsomal Clearance:** Ligand B (21.04) has a slightly lower microsomal clearance than Ligand A (24.40), suggesting better metabolic stability. However, both are reasonably low.

**In vitro Half-Life:** Ligand A (-3.219) has a longer in vitro half-life than Ligand B (-26.02), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.09) has a lower P-gp efflux liability than Ligand B (0.283), which is preferable.

**Binding Affinity:** Ligand A (-10.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. The difference of 2.1 kcal/mol is substantial.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. Its superior binding affinity, lower DILI risk, better BBB penetration, lower hERG inhibition, longer half-life, and lower P-gp efflux outweigh the slightly higher microsomal clearance. While both ligands have concerning Caco-2 and solubility values, the strong binding affinity of Ligand A suggests it may still be viable with appropriate formulation strategies.

Output:
0
2025-04-17 13:43:26,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (356.535 and 349.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (99.6). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching a concerning level.

**logP:** Ligand A (4.594) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.822) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but lower counts generally favor permeability.

**QED:** Both ligands have similar QED values (0.869 and 0.82), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (46.103 and 49.283), and are both below the 60 threshold, indicating acceptable risk.

**BBB:** Ligand A (83.986) has a better BBB percentile than Ligand B (65.801), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.236) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.987) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.031 and -2.239). This is a concern for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.917) has a slightly higher hERG risk than Ligand B (0.051). B is significantly better here, a major advantage.

**Microsomal Clearance:** Ligand B (-6.088) has a much lower (better) microsomal clearance than Ligand A (8.446), indicating greater metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (-0.814) has a negative half-life, which is unusual and suggests very rapid metabolism. Ligand A (46.898) has a much better half-life.

**P-gp Efflux:** Ligand A (0.772) has a lower P-gp efflux liability than Ligand B (0.009), meaning A is less likely to be pumped out of cells.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This ~1.1 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic). Its hERG risk is also much lower. While its logP is low and Caco-2 permeability is poor, the strong binding affinity and metabolic stability are critical for an enzyme inhibitor. Ligand A has better P-gp efflux, but its poor permeability and higher clearance are significant drawbacks. The negative half-life for ligand B is a concern, but could be addressed through structural modifications.

Output:
1
2025-04-17 13:43:26,639 - INFO - Batch 237 complete. Total preferences: 3792
2025-04-17 13:43:26,639 - INFO - Processing batch 238/512...
2025-04-17 13:44:19,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (345.447 and 369.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (82.23 and 84.67) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.68 and 1.401) are within the optimal range of 1-3.

**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, though both are acceptable.

**QED:** Both ligands have reasonable QED scores (0.813 and 0.708), indicating good drug-like properties.

**DILI:** Ligand A (42.924) has a slightly higher DILI risk than Ligand B (36.293), but both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a kinase inhibitor, but Ligand A (69.484) has a better BBB score than Ligand B (55.642).

**Caco-2 Permeability:** Ligand A (-4.491) has a slightly better Caco-2 permeability than Ligand B (-5.195), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.274) has a slightly better aqueous solubility than Ligand B (-2.501).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.251 and 0.211), which is excellent.

**Microsomal Clearance:** Ligand A (25.827 mL/min/kg) has significantly lower microsomal clearance than Ligand B (44.692 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (4.636 hours) has a longer in vitro half-life than Ligand A (1.588 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.154 and 0.046).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand A has advantages in solubility, permeability, and metabolic stability, the slightly stronger binding affinity of Ligand B (-8.7 vs -8.0 kcal/mol) is a crucial factor for an enzyme inhibitor. The difference in binding affinity is likely to outweigh the minor drawbacks of Ligand B in terms of metabolic stability and half-life. The half-life of 4.636 hours is still reasonable.

Output:
1
2025-04-17 13:44:19,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.5 & 363.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.09) is well below the 140 threshold, while Ligand B (80.32) is still acceptable but closer to the limit.

**logP:** Ligand A (1.185) is within the optimal 1-3 range. Ligand B (2.161) is also good, though slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 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 (0.676 and 0.769, respectively), indicating drug-likeness.

**DILI:** Ligand A (4.924) has a very favorable DILI score, significantly lower than Ligand B (80.807), which is a high risk. This is a major concern for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (83.094) shows higher penetration than Ligand A (57.193).

**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 unusual and suggesting poor solubility. This is a concern for both, but Ligand B's value (-3.434) is worse than Ligand A (-0.767).

**hERG:** Both ligands have low hERG inhibition liability (0.458 and 0.577), which is good.

**Microsomal Clearance:** Ligand A (38.316) has lower microsomal clearance than Ligand B (57.472), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.338 hours) has a shorter half-life than Ligand B (41.597 hours), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.028 and 0.263), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -6.9 kcal/mol), with Ligand A being slightly better. The difference is less than the 1.5 kcal/mol threshold that could outweigh other ADME issues.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** While both have similar binding affinities, Ligand A has a significantly better DILI score and better metabolic stability (lower Cl_mic). The solubility and permeability concerns are present in both, but Ligand B's values are worse. The lower DILI risk is a critical advantage, as liver toxicity is a major cause of drug failure.

Output:
0
2025-04-17 13:44:19,104 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (454.316 Da) is within the ideal range (200-500 Da). Ligand B (364.837 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (66.29) is good, below the 140 threshold for oral absorption. Ligand B (112.66) is also below 140, but closer to the limit. A favors better absorption.

3. **logP:** Both ligands (A: 1.884, B: 1.357) fall within the optimal 1-3 range. No significant difference.

4. **HBD:** Ligand A (1) is excellent, while Ligand B (3) is acceptable but slightly higher. Lower is generally preferred for permeability. A is better.

5. **HBA:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10. No difference.

6. **QED:** Both ligands have good QED scores (A: 0.554, B: 0.654), indicating drug-like properties. B is slightly better.

7. **DILI:** Ligand A (55.448) is better than Ligand B (64.831) as it has a lower DILI risk percentile.

8. **BBB:** Ligand A (66.886) has a better BBB percentile than Ligand B (20.512). However, since SRC is not a CNS target, this is less critical.

9. **Caco-2:** Both ligands have negative Caco-2 values (-5.125 and -5.743). This is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method and should be interpreted cautiously.

10. **Solubility:** Both ligands have negative solubility values (-2.521 and -2.064), also suggesting poor solubility. Similar caution applies as with Caco-2.

11. **hERG:** Ligand A (0.752) has a slightly higher hERG risk than Ligand B (0.379), meaning B is safer regarding cardiotoxicity.

12. **Cl_mic:** Ligand A (40.816) has a higher microsomal clearance than Ligand B (3.195). This suggests Ligand B is more metabolically stable, a key consideration for kinases.

13. **t1/2:** Ligand B (-1.893) has a negative in vitro half-life, which is not physically possible. This is likely an artifact of the prediction. Ligand A (12.06) has a reasonable half-life.

14. **Pgp:** Ligand A (0.227) has lower P-gp efflux liability than Ligand B (0.045), which is favorable for bioavailability.

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, potentially outweighing some ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B excels in binding affinity and has significantly better metabolic stability (lower Cl_mic). While its half-life prediction is suspect, the lower Cl_mic is a strong indicator. Ligand A has better DILI and Pgp profiles, but the affinity difference is too large to ignore.

**Conclusion:**

Despite some ADME concerns with Ligand B (negative solubility/Caco-2, questionable half-life), the significantly stronger binding affinity (-7.9 vs -10.2 kcal/mol) and improved metabolic stability make it the more promising candidate. Further optimization could address the solubility issues.

Output:
1

2025-04-17 13:44:19,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, excellent for absorption. Ligand B (129.37) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (2.346) is optimal (1-3). Ligand B (-0.162) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (4 HBD, 7 HBA) is acceptable, but higher counts could affect permeability.

**QED:** Ligand A (0.83) is very good, indicating high drug-likeness. Ligand B (0.574) is acceptable, but less optimal.

**DILI:** Ligand A (6.049) has a very low DILI risk. Ligand B (42.536) is higher, indicating a moderate risk.

**BBB:** Ligand A (87.864) shows good BBB penetration, though SRC isn't a CNS target, it's not detrimental. Ligand B (9.306) is very low.

**Caco-2 Permeability:** Ligand A (-4.563) is poor, suggesting low intestinal absorption. Ligand B (-5.639) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.753) is poor. Ligand B (-1.841) is also poor, but slightly better.

**hERG Inhibition:** Both ligands (0.487 and 0.036) have low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (38.614) has moderate clearance. Ligand B (-0.282) has *very* low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (11.499 hours) is reasonable. Ligand B (14.382 hours) is better, suggesting a longer duration of action.

**P-gp Efflux:** Both ligands (0.032 and 0.005) show minimal P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (0.0) is significantly weaker than Ligand B (-8.4 kcal/mol). This is a major difference.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity (-8.4 kcal/mol vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2). While Ligand B has a lower logP and higher DILI risk, the substantial advantage in binding affinity outweighs these drawbacks for an enzyme target like SRC kinase. The poor Caco-2 and solubility of both are concerning, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 13:44:19,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.387 Da and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.81) is better than Ligand B (88.1). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.51) is optimal, while Ligand B (0.474) 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 (0.879) has a significantly better QED score than Ligand B (0.489), indicating a more drug-like profile.

**DILI:** Ligand B (25.553) has a much lower DILI risk than Ligand A (70.919). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 50.679, Ligand B: 56.805). BBB is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.927 and -4.714), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand B (-1.034) has slightly better solubility than Ligand A (-4.427), although both are poor.

**hERG:** Ligand A (0.491) has a slightly better hERG profile than Ligand B (0.332), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (2.759) has significantly lower microsomal clearance than Ligand B (9.904), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.401 hours) has a longer half-life than Ligand B (8.8 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.054 and 0.038), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 kcal/mol and -7.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is superior in terms of QED, metabolic stability (Cl_mic and t1/2), and has a slightly better hERG profile. However, Ligand B has a significantly lower DILI risk, which is a crucial factor. While both have poor Caco-2 permeability and solubility, the lower DILI risk of Ligand B, combined with comparable binding affinity, makes it the more promising candidate. The metabolic stability of Ligand A is attractive, but DILI is a major concern in drug development.

Output:
1
2025-04-17 13:44:19,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.296 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.57) is higher than Ligand B (43.86). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have good logP values (3.383 and 2.356), 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 3 HBA. Both are acceptable, but Ligand B's lower HBD count might slightly favor permeability.

**QED:** Both ligands have similar QED values (0.764 and 0.765), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 86.855, which is high. Ligand B has a much lower DILI risk of 11.4, a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (64.056 and 84.878), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.863) has poor Caco-2 permeability, while Ligand B (-4.368) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-5.153) has very poor aqueous solubility, a major concern. Ligand B (-1.587) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.803) has a slightly higher hERG risk than Ligand B (0.684), but both are reasonably low.

**Microsomal Clearance:** Ligand A (10.782) has lower microsomal clearance, indicating better metabolic stability, which is crucial for an enzyme target. Ligand B (36.998) has significantly higher clearance.

**In vitro Half-Life:** Ligand A (26.064) has a longer half-life than Ligand B (-2.535), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.197 and 0.219).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's poor solubility and Caco-2 permeability, and high DILI risk, its *much* stronger binding affinity (-9.7 kcal/mol vs -7.8 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) make it the more promising candidate. The potency advantage is significant for an enzyme target like SRC kinase. While solubility is a concern, formulation strategies can sometimes mitigate this. The DILI risk is a concern, but could be investigated further.

Output:
1
2025-04-17 13:44:19,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 340.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 95.42, which is slightly above the optimal <140 for good oral absorption, but not a major concern.

**logP:** Both ligands have logP values within the optimal range (1.055 and 1.412).

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.831 and 0.877), indicating good drug-like properties.

**DILI:** Ligand A (44.513) has a significantly lower DILI risk than Ligand B (63.746). This is a substantial advantage.

**BBB:** Ligand A (52.811) has a better BBB percentile than Ligand B (23.924), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.984) has a worse Caco-2 permeability than Ligand B (-5.145), but both are quite poor.

**Aqueous Solubility:** Ligand A (-1.798) has better aqueous solubility than Ligand B (-2.954). This is a significant advantage for an enzyme inhibitor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.174 and 0.093).

**Microsomal Clearance:** Ligand A (15.793 mL/min/kg) has a higher microsomal clearance than Ligand B (2.699 mL/min/kg). This indicates Ligand B is more metabolically stable, a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-23.929 hours) has a significantly longer in vitro half-life than Ligand A (-4.651 hours). This is a major advantage, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.01).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially better binding affinity than Ligand A (-7.3 kcal/mol). This 1.7 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and lower DILI risk, Ligand B's superior binding affinity (-9.0 vs -7.3 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme inhibitor. The difference in binding affinity is substantial enough to compensate for the slightly higher DILI risk and lower solubility.

Output:
1
2025-04-17 13:44:19,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.447 and 355.479 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.74) is excellent, well below the 140 threshold for oral absorption. Ligand B (118.36) is still acceptable but less optimal.

**logP:** Ligand A (0.599) is a bit low, potentially hindering permeation. Ligand B (1.15) is better, 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 similar QED scores (0.596 and 0.509), indicating reasonable drug-likeness.

**DILI:** Ligand A (21.791) has a significantly lower DILI risk than Ligand B (27.104), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (61.535) has a slightly better BBB score than Ligand B (50.795).

**Caco-2 Permeability:** Ligand A (-4.934) has a much better Caco-2 permeability than Ligand B (-5.278), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.138) has better solubility than Ligand B (-2.856). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.045) has a much lower hERG inhibition liability than Ligand B (0.116), a crucial safety factor.

**Microsomal Clearance:** Ligand A (4.29) has a significantly lower microsomal clearance than Ligand B (42.959), indicating much better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-0.204) has a better in vitro half-life than Ligand B (-30.48), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.006).

**Binding Affinity:** Ligand A (-8.7 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 Ligand A.

**Overall:** Ligand A is significantly better than Ligand B. It has a lower DILI risk, better solubility, much better metabolic stability (lower Cl_mic and better t1/2), lower hERG inhibition, and slightly better binding affinity. While Ligand B has a slightly better logP, the ADME-Tox advantages of Ligand A outweigh this minor difference.

Output:
0
2025-04-17 13:44:19,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.439 Da and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.55) is better than Ligand B (96.11), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have a logP of approximately 1.77, which is optimal.

**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.

**QED:** Ligand A (0.746) has a slightly better QED score than Ligand B (0.683), indicating a more drug-like profile.

**DILI:** Ligand B (52.423) has a significantly lower DILI risk than Ligand A (72.354). This is a substantial advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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 significant drawback for both.

**hERG Inhibition:** Ligand A (0.287) has a slightly higher hERG inhibition liability than Ligand B (0.153), meaning Ligand B is safer in terms of cardiotoxicity.

**Microsomal Clearance:** Ligand B (9.063) has a lower microsomal clearance than Ligand A (65.363), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-10.821) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound's stability. Ligand A (6.542) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.7). This 1.3 kcal/mol difference is significant and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has several advantages: lower DILI risk, better metabolic stability (lower Cl_mic), and lower hERG inhibition. However, its negative in vitro half-life is a major red flag. Ligand A has a better half-life and stronger binding affinity, but suffers from higher DILI risk and worse metabolic stability. Given the importance of metabolic stability for kinase inhibitors, and the problematic half-life of Ligand B, I would lean towards Ligand A despite its drawbacks. The binding affinity difference is substantial enough to warrant further investigation and optimization of Ligand A to address its DILI and metabolic stability issues.

Output:
1
2025-04-17 13:44:19,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.435 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (70.67), both are below the 140 threshold for oral absorption, and suitable for kinase inhibitors.

**logP:** Ligand A (0.741) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.544) is within the ideal 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.

**QED:** Ligand A (0.748) has a slightly better QED score than Ligand B (0.694), indicating a more drug-like profile.

**DILI:** Ligand A (42.613) has a significantly lower DILI risk than Ligand B (8.104), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (Ligand A: 82.513, Ligand B: 80.186), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.021) has worse Caco-2 permeability than Ligand B (-4.768), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.234) has worse aqueous solubility than Ligand B (-1.741). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.2, Ligand B: 0.387).

**Microsomal Clearance:** Ligand A (20.918 mL/min/kg) has a lower microsomal clearance than Ligand B (37.66 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.225 hours) has a slightly longer half-life than Ligand B (2.117 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.06, Ligand B: 0.006).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While both are good, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B has a better logP, Caco-2 permeability, and binding affinity. However, Ligand A excels in DILI risk and has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED score. The significantly lower DILI risk for Ligand A is a crucial advantage, as liver toxicity is a common issue in drug development. The slightly better affinity of Ligand B might be outweighed by the higher DILI risk. Considering the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 13:44:19,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.5 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (109.6), being well below the 140 threshold for good absorption. Ligand B is approaching the upper limit, potentially hindering absorption.

**logP:** Ligand A (2.015) is optimal (1-3). Ligand B (0.009) is very low, which could significantly impair permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.874) has a much better drug-likeness score than Ligand B (0.64), indicating a more favorable overall profile.

**DILI:** Ligand A (27.9) has a significantly lower DILI risk than Ligand B (35.8), both are good, but A is better.

**BBB:** Both have reasonable BBB penetration, but Ligand B (71.8) is slightly better than Ligand A (67.2). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.318) is better than Ligand B (-5.544), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.175) is better than Ligand B (-1.928), indicating better solubility.

**hERG:** Ligand A (0.159) shows lower hERG inhibition risk than Ligand B (0.449), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (21.8 mL/min/kg) is much better than Ligand B (-23.6 mL/min/kg). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-7.503) is much better than Ligand B (0.13), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.039) is much better than Ligand B (0.004), indicating less P-gp efflux.

**Binding Affinity:** Ligand B (-8.2 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 numerous ADME advantages of Ligand A.

**Overall:** Ligand A is a significantly more promising drug candidate. It excels in almost all ADME properties (solubility, permeability, metabolic stability, efflux, hERG risk, DILI) and has a very good binding affinity. While Ligand B has slightly better binding affinity, its poor logP, solubility, and metabolic stability are major drawbacks.



Output:
0
2025-04-17 13:44:19,105 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A: [353.419, 96.97, 0.529, 2, 5, 0.59, 37.146, 54.44, -5.625, -1.72, 0.152, -6.323, -3.766, 0.023, -6.4]**
**Ligand B: [350.463, 96.11, 1.971, 3, 4, 0.731, 50.795, 73.672, -4.651, -3.841, 0.266, 56.139, -49.717, 0.057, -9]**

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A: 353.419, B: 350.463.  No significant difference.
2. **TPSA:** Both are good, below the 140 A^2 threshold for oral absorption. A: 96.97, B: 96.11. Very similar.
3. **logP:** Ligand A (0.529) is a bit low, potentially hindering permeability. Ligand B (1.971) is much better, falling within the optimal 1-3 range. This is a significant advantage for B.
4. **HBD:** Both are acceptable (<=5). A: 2, B: 3. No major concern.
5. **HBA:** Both are acceptable (<=10). A: 5, B: 4. No major concern.
6. **QED:** Both are above 0.5, indicating good drug-like properties. A: 0.59, B: 0.731. B is slightly better.
7. **DILI:** Ligand A (37.146) has a lower DILI risk than Ligand B (50.795). This is a positive for A.
8. **BBB:**  Not a primary concern for SRC kinase (an enzyme). A: 54.44, B: 73.672. B is better, but not crucial.
9. **Caco-2:** Both are negative, indicating poor permeability. A: -5.625, B: -4.651. B is slightly better.
10. **Solubility:** Both are negative, indicating poor solubility. A: -1.72, B: -3.841. A is slightly better.
11. **hERG:** Both have low hERG risk. A: 0.152, B: 0.266. A is slightly better.
12. **Cl_mic:** Ligand A (-6.323) has a *much* lower (better) microsomal clearance than Ligand B (56.139), suggesting greater metabolic stability. This is a major advantage for A.
13. **t1/2:** Ligand A (-3.766) has a negative half-life, which is concerning. Ligand B (-49.717) is also negative, but more negative, indicating very rapid clearance. Both are poor, but A is slightly better.
14. **Pgp:** Both have low Pgp efflux. A: 0.023, B: 0.057. A is slightly better.
15. **Binding Affinity:** Ligand B (-9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This is a substantial advantage for B, potentially outweighing some ADME drawbacks.

**Prioritization for Enzyme (Kinase) Targets:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B is significantly better (-9 vs -6.4 kcal/mol).
*   **Metabolic Stability:** A is *much* better (Cl_mic of -6.323 vs 56.139).
*   **Solubility:** A is slightly better.
*   **hERG:** A is slightly better.
*   **logP:** B is much better.

**Conclusion:**

While Ligand A has better metabolic stability, DILI, hERG, and solubility, the *substantial* difference in binding affinity for Ligand B is a critical factor. A 2.6 kcal/mol difference in binding affinity is significant. The better logP of ligand B also contributes to its potential for better absorption. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The poor half-life of both is also a concern, but can be addressed with structural modifications.

Therefore, I would select **Ligand B** as the more promising drug candidate.

1
2025-04-17 13:44:19,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 346.402 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (104.39) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (60.85) is excellent, well below 140.

**logP:** Both ligands (1.297 and 1.865) 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 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand B (0.909) has a much better QED score than Ligand A (0.398), indicating a more drug-like profile.

**DILI:** Ligand B (35.673) has a significantly lower DILI risk than Ligand A (67.468). This is a major advantage for Ligand B.

**BBB:** While not critical for a non-CNS target like SRC, Ligand B (91.508) has a higher BBB percentile than Ligand A (56.689).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.066) is worse than Ligand B (-4.379).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.831) is worse than Ligand B (-2.016).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.288 and 0.592 respectively).

**Microsomal Clearance:** Ligand B (33.88) has significantly lower microsomal clearance than Ligand A (92.561), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.829) has a longer in vitro half-life than Ligand A (-26.92).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.153 and 0.228 respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-8.3 and -8.6 kcal/mol), which are both excellent. The difference is minimal.

**Conclusion:**

While both ligands have good binding affinity, Ligand B is significantly better overall. It has a much better QED score, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. Although both have poor Caco-2 permeability, the other advantages of Ligand B outweigh this drawback, especially given that SRC is not a CNS target.

Output:
1
2025-04-17 13:44:19,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (387.571 Da) is still well within the acceptable range.

**TPSA:** Ligand B (87.3) is significantly better than Ligand A (116.12). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand B (1.642) is within the optimal range (1-3), while Ligand A (0.478) is a bit low, potentially hindering membrane permeability.

**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 limits.

**QED:** Both ligands have reasonable QED values (A: 0.666, B: 0.589), indicating good drug-like properties.

**DILI:** Ligand B (39.201) has a lower DILI risk than Ligand A (54.168), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (45.25) shows slightly better BBB penetration than Ligand A (32.648).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.649 and -5.513), which 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 (-1.883 and -2.143), indicating poor solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.065, B: 0.042), which is excellent.

**Microsomal Clearance:** Ligand A (-6.776) has a much lower (better) microsomal clearance than Ligand B (16.428). This suggests that Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (24.236 hours) has a significantly longer half-life than Ligand B (15.422 hours), which is desirable for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.007, B: 0.015).

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and significantly better metabolic stability (lower Cl_mic and longer t1/2). However, Ligand B has a lower DILI risk and a more favorable TPSA and logP, which are important for permeability. Both have poor solubility and Caco-2 permeability. Considering the enzyme-specific priorities, metabolic stability is crucial for kinase inhibitors. The slightly better affinity of Ligand A is a bonus, but the difference isn't large enough to outweigh the better ADME profile of Ligand B. The lower DILI risk of Ligand B is also a significant advantage.

Output:
1

2025-04-17 13:44:19,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.455 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.37) is better than Ligand B (99.18) as it is closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.418) is optimal (1-3), while Ligand B (-0.968) is below 1, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors:** Both 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:** Ligand A (0.851) has a better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Ligand A (85.459) has a higher DILI risk than Ligand B (18.728). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.874) is better than Ligand B (28.073).

**Caco-2 Permeability:** Both have negative values (-5.022 and -5.048), which is unusual and difficult to interpret without knowing the scale. However, they are very similar.

**Aqueous Solubility:** Both have negative values (-4.329 and -0.91), which is also unusual and difficult to interpret. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.22) has a slightly higher hERG risk than Ligand B (0.047), but both are relatively low.

**Microsomal Clearance:** Ligand A (76.1) has significantly higher microsomal clearance than Ligand B (2.747), indicating lower metabolic stability. This is a major disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-7.182) has a much longer in vitro half-life than Ligand A (-1.502), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux than Ligand B (0.008), which is slightly favorable.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-9.4). While A has a stronger binding affinity, the difference is not substantial enough to overcome the other significant ADME issues.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is low, its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and comparable binding affinity outweigh the drawbacks. Ligand A's high DILI risk and poor metabolic stability are major concerns. The slightly better affinity of Ligand A is not enough to overcome these issues.

Output:
1
2025-04-17 13:44:19,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.308 Da) is slightly higher, but acceptable. Ligand B (358.439 Da) is also good.

**TPSA:** Ligand A (64.35) is excellent, well below the 140 threshold. Ligand B (100.21) is still reasonable, but less optimal for absorption.

**logP:** Ligand A (3.831) is within the optimal range (1-3). Ligand B (-1.569) is significantly below, which could hinder 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 scores (A: 0.74, B: 0.517), indicating decent drug-likeness.

**DILI:** Ligand A (63.513) has a higher DILI risk than Ligand B (21.946). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.292) is better than Ligand B (45.715).

**Caco-2 Permeability:** Ligand A (-4.576) is poor, suggesting poor absorption. Ligand B (-5.31) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.72) is poor. Ligand B (-0.428) is also poor, but better than A.

**hERG:** Ligand A (0.535) has a slightly higher hERG risk than Ligand B (0.041). B is much better here.

**Microsomal Clearance:** Ligand A (91.347) has a higher clearance, indicating lower metabolic stability. Ligand B (5.641) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (68.198) has a longer half-life than Ligand B (-9.381). However, the negative value for B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.749) has moderate P-gp efflux. Ligand B (0.002) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly better 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 primary driver for enzyme inhibitors. However, it suffers from poor Caco-2 permeability, solubility, higher DILI risk, and higher metabolic clearance. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux, better hERG), but its significantly weaker binding affinity is a major drawback.

The difference in binding affinity (1.9 kcal/mol) is substantial and likely outweighs the ADME concerns of Ligand A, *provided* formulation strategies can address the solubility and permeability issues. The DILI risk is a concern, but could be mitigated with further structural modifications. The better metabolic stability of Ligand B is appealing, but the weak binding makes it less likely to be effective *in vivo*.

Output:
1
2025-04-17 13:44:19,106 - INFO - Batch 238 complete. Total preferences: 3808
2025-04-17 13:44:19,106 - INFO - Processing batch 239/512...
2025-04-17 13:44:59,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (348.447 and 352.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.25) is significantly better than Ligand B (131.52). TPSA < 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (0.732) is within the optimal 1-3 range, while Ligand B (-1.461) is slightly below 1, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=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 similar QED values (0.543 and 0.514), indicating good drug-likeness.

**DILI:** Ligand A (25.359) has a much lower DILI risk than Ligand B (55.176). A DILI score <40 is preferred, and A is well within that range, while B is moderately concerning.

**BBB:** Both ligands have low BBB penetration (16.479 and 20.396), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.203 and -5.653), 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 (-0.988 and -1.088), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.199 and 0.096), which is excellent.

**Microsomal Clearance:** Ligand B (-3.732) has a negative clearance, which is highly favorable, suggesting excellent metabolic stability. Ligand A (0.809) has a positive clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand B (1.317) has a slightly longer half-life than Ligand A (-18.314), but both values are problematic. A positive half-life is desired.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.024), which is favorable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its lower DILI risk, better TPSA, and more favorable logP outweigh the slightly higher microsomal clearance and problematic half-life value. The solubility issues are a concern for both, but the lower DILI risk is a critical advantage for A. The negative half-life for A is concerning, but could be an artifact of the prediction method.

Output:
0
2025-04-17 13:44:59,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight (MW):** Both ligands (348.418 and 364.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (69.64 and 66.4) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.016 and 1.993) are within the optimal 1-3 range.

**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 (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.878 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A (38.697) has a lower DILI risk than Ligand B (72.005). This is a significant advantage.

**8. BBB:** Both ligands have acceptable BBB penetration, but Ligand B (91.198) is significantly higher than Ligand A (66.731). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.581 and -4.738). This 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 (-2.45 and -3.123). Again, this is unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.554 and 0.751).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-1.661 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (73.309 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (2.551 hours) has a shorter half-life than Ligand B (5.605 hours). While a longer half-life is generally preferred, the difference isn't drastic.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.151 and 0.268).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a significantly lower DILI risk and much better metabolic stability (lower Cl_mic) than Ligand B. While both have poor predicted solubility and permeability, the improved safety and pharmacokinetic profile of Ligand A outweigh the slight advantage of Ligand B's longer half-life and higher BBB penetration (which isn't relevant for this target).

Output:
0
2025-04-17 13:44:59,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.502 and 346.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is well below the 140 threshold, and even below 90, suggesting good permeability. Ligand B (49.41) is still acceptable, but less optimal.

**logP:** Both ligands (3.685 and 3.24) are 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.718 and 0.771), indicating drug-likeness.

**DILI:** Ligand A (36.293) has a slightly higher DILI risk than Ligand B (28.887), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (87.553 and 86.817), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.403 and -4.659). This is unusual and suggests poor permeability. However, these values are often predicted and can be inaccurate.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.048 and -3.518), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.91 and 0.807), which is excellent.

**Microsomal Clearance:** Ligand A (43.873) has considerably lower microsomal clearance than Ligand B (62.309), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (55.17) has a much longer half-life than Ligand B (7.416), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.665 and 0.227).

**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 small, it's a factor.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The significantly improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand A is crucial for an enzyme inhibitor. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies. The negative Caco-2 and solubility values are the biggest weaknesses, but the metabolic advantage of Ligand A outweighs the small affinity difference.

Output:
1
2025-04-17 13:44:59,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 363.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is better than Ligand B (41.93). While both are acceptable, Ligand B's lower TPSA is advantageous for cell permeability.

**logP:** Ligand A (0.21) is quite low, potentially hindering permeability. Ligand B (4.588) is high, potentially causing solubility and off-target issues.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is excellent.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.568 and 0.708), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (11.206 and 12.059), which is good.

**BBB:** Ligand A (29.508) has very low BBB penetration, while Ligand B (74.37) is much better. However, BBB is not a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.036) has poor Caco-2 permeability, while Ligand B (-5.103) is also poor.

**Aqueous Solubility:** Ligand A (-0.644) has poor solubility, while Ligand B (-4.314) is even worse. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.08) has very low hERG risk, which is excellent. Ligand B (0.947) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (3.993) has lower clearance, suggesting better metabolic stability than Ligand B (118.825). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (3.199) has a shorter half-life than Ligand B (31.267), which is a disadvantage.

**P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, which is favorable. Ligand B (0.578) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9) has a significantly stronger binding affinity than Ligand B (-8.4). This is a crucial advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's poor logP, solubility, and Caco-2 permeability, its *significantly* stronger binding affinity (-9 vs -8.4 kcal/mol) and much better metabolic stability (lower Cl_mic) make it the more promising candidate. The lower hERG risk is also a plus. While solubility is a concern, formulation strategies can sometimes mitigate this. The difference in binding affinity is substantial enough to prioritize Ligand A for further optimization.

Output:
0
2025-04-17 13:44:59,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase properties (potency, metabolic stability, solubility, and hERG risk).

**Ligand A:**
*   **MW:** 353.375 Da - Within the ideal range (200-500).
*   **TPSA:** 121.11 - Acceptable, but approaching the upper limit for good oral absorption.
*   **logP:** 0.166 - Low, potentially hindering permeation.
*   **HBD:** 3 - Acceptable.
*   **HBA:** 6 - Acceptable.
*   **QED:** 0.544 - Good drug-likeness.
*   **DILI:** 47.732 - Low risk.
*   **BBB:** 24.777 - Low, not a concern for a non-CNS target.
*   **Caco-2:** -5.43 - Very poor permeability.
*   **Solubility:** -0.886 - Poor solubility.
*   **hERG:** 0.16 - Low risk.
*   **Cl_mic:** -31.563 - Excellent metabolic stability (negative value suggests very low clearance).
*   **t1/2:** 13.725 - Good in vitro half-life.
*   **Pgp:** 0.02 - Low efflux.
*   **Affinity:** -7.7 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 348.487 Da - Within the ideal range.
*   **TPSA:** 58.64 - Excellent, promotes good absorption.
*   **logP:** 2.798 - Optimal.
*   **HBD:** 1 - Acceptable.
*   **HBA:** 3 - Acceptable.
*   **QED:** 0.751 - Very good drug-likeness.
*   **DILI:** 16.751 - Very low risk.
*   **BBB:** 82.241 - High, not a primary concern for a non-CNS target.
*   **Caco-2:** -4.806 - Poor permeability.
*   **Solubility:** -3.045 - Very poor solubility.
*   **hERG:** 0.319 - Low risk.
*   **Cl_mic:** 39.728 - Moderate metabolic clearance.
*   **t1/2:** -1.782 - Very short half-life.
*   **Pgp:** 0.24 - Low efflux.
*   **Affinity:** -8.5 kcal/mol - Excellent binding affinity, slightly better than Ligand A.

**Comparison & Decision:**

Both compounds have excellent binding affinity. However, Ligand A and B both have poor Caco-2 permeability and solubility. Ligand B has a better logP, QED, and DILI score. However, Ligand A has superior metabolic stability (Cl_mic) and a longer half-life. For an enzyme target like SRC kinase, metabolic stability and half-life are crucial. While Ligand B's affinity is marginally better, the significantly better metabolic profile of Ligand A outweighs this difference. The poor solubility of both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:44:59,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.471 and 364.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.15) is better than Ligand B (49.41). Both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.797 and 3.375), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.843) has a significantly better QED score than Ligand B (0.556), indicating a more drug-like profile.

**DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (16.053), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (77.511 and 81.776), but this is less critical for a non-CNS target like SRC.

**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.

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale isn't specified.

**hERG:** Ligand A (0.54) has a lower hERG risk than Ligand B (0.736), which is favorable.

**Microsomal Clearance:** Ligand B (93.888) has a much higher microsomal clearance than Ligand A (15.253), indicating poorer metabolic stability. This is a critical disadvantage for an enzyme target.

**In vitro Half-Life:** Ligand A (0.26) has a very short half-life, while Ligand B (-2.238) is even worse. Both are very poor.

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux than Ligand B (0.299), which is slightly better.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly better binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand B has a superior binding affinity, Ligand A is the more promising candidate overall. The significantly better QED, much lower DILI risk, and substantially improved metabolic stability (lower Cl_mic) of Ligand A are crucial for enzyme targets. The poor solubility and permeability are concerning for both, but can potentially be addressed through formulation strategies. The difference in binding affinity (-1.5 kcal/mol) is significant, but the ADME profile of Ligand A is far more favorable, increasing the likelihood of *in vivo* efficacy and a safer profile.

Output:
0
2025-04-17 13:44:59,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.383 and 344.375 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.71) is better than Ligand B (112.33), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (2.101) is optimal (1-3), while Ligand B (0.684) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

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

**QED:** Ligand A (0.679) is significantly better than Ligand B (0.258), indicating a more drug-like profile.

**DILI:** Ligand A (36.603) has a much lower DILI risk than Ligand B (51.338), which is approaching a moderate risk level.

**BBB:** Both ligands have similar BBB penetration (43.699 vs 46.84), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.001) is slightly better than Ligand B (-4.793), indicating potentially better intestinal absorption, but both are negative values which are difficult to interpret without knowing the scale.

**Aqueous Solubility:** Ligand A (-2.505) is better than Ligand B (-1.128), indicating better solubility.

**hERG Inhibition:** Ligand A (0.232) has a lower hERG risk than Ligand B (0.178), both are very low and acceptable.

**Microsomal Clearance:** Ligand A (13.439) has higher, and therefore worse, clearance than Ligand B (-3.67). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (38.431) has a longer half-life than Ligand B (-5.159), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.018), which is favorable.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a >1.5 kcal/mol advantage, and is a very important factor.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, and better metabolic stability. However, it has a lower logP and QED score, and a higher DILI risk. Ligand A has better solubility, a lower DILI risk, and a better QED score. The difference in binding affinity is substantial, and outweighs the other drawbacks of Ligand B.

Output:
1
2025-04-17 13:44:59,097 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.523 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (81.99). Both are below the 140 A^2 threshold for good oral absorption, but lower is generally preferred.

**logP:** Ligand A (1.479) is optimal (1-3), while Ligand B (3.547) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have similar QED values (0.657 and 0.627), indicating good drug-likeness.

**DILI:** Ligand A (3.218) has a significantly lower DILI risk than Ligand B (53.509). This is a major advantage for Ligand A.

**BBB:** Ligand A (52.811) has a slightly better BBB penetration than Ligand B (47.615), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.926 and -4.991), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.676) is better than Ligand B (-4.782), indicating better solubility.

**hERG:** Ligand A (0.427) has a lower hERG risk than Ligand B (0.68), which is favorable.

**Microsomal Clearance:** Ligand A (18.191) has significantly lower microsomal clearance than Ligand B (81.709), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-0.157) has a slightly better half-life than Ligand B (37.709).

**P-gp Efflux:** Ligand A (0.019) has a lower P-gp efflux liability than Ligand B (0.338), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have similar potency, Ligand A demonstrates significantly better ADMET properties, specifically lower DILI risk, lower microsomal clearance (better metabolic stability), better solubility, lower hERG risk, and lower P-gp efflux. These factors are critical for a viable enzyme inhibitor. The Caco-2 permeability is a concern for both, but the superior ADMET profile of Ligand A outweighs this drawback.

Output:
0
2025-04-17 13:44:59,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.495 and 383.187 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (81.91). A TPSA under 140 is good for oral absorption, both are, but lower is preferred.

**logP:** Ligand A (2.336) is within the optimal 1-3 range. Ligand B (3.789) is pushing the upper limit, potentially leading to solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (0 HBD, 5 HBA). Both are within acceptable limits, but more balanced H-bonding is generally favorable.

**QED:** Ligand A (0.845) has a much better QED score than Ligand B (0.431), indicating a more drug-like profile.

**DILI:** Ligand B (81.039) has a significantly higher DILI risk than Ligand A (19.969). This is a major concern for Ligand B.

**BBB:** Both have reasonable BBB penetration (Ligand A: 81.698, Ligand B: 78.79). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.88) is slightly better than Ligand B (-4.559).

**Aqueous Solubility:** Ligand A (-2.684) is better than Ligand B (-5.755), although both are poor. Solubility is a critical factor for bioavailability.

**hERG:** Ligand A (0.346) has a much lower hERG risk than Ligand B (0.71). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (47.884) has lower microsomal clearance than Ligand B (55.274), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (8.714) has a longer half-life than Ligand A (3.848). This is a positive for Ligand B, but other factors are more important.

**P-gp Efflux:** Ligand A (0.13) has lower P-gp efflux than Ligand B (0.503), suggesting better oral bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While a 1.2 kcal/mol difference is good, it's not enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, lower hERG risk, better solubility, better QED, and better P-gp efflux. The solubility and DILI issues with Ligand B are major red flags. The slightly longer half-life of Ligand B is not enough to compensate for these drawbacks.

Output:
0
2025-04-17 13:44:59,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.46 and 345.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (78.09 and 73.2) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.70 and 3.03) 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 A (0.779) has a significantly better QED score than Ligand B (0.594), indicating a more drug-like profile.

**DILI:** Ligand A (40.40) has a slightly higher DILI risk than Ligand B (8.92), but both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (67.12 and 76.00), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.98 and -4.81), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.9 and -2.17), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.17 and 0.47), which is excellent.

**Microsomal Clearance:** Ligand A (59.79 mL/min/kg) has a higher microsomal clearance than Ligand B (12.26 mL/min/kg). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-16.13 hours) has a longer in vitro half-life than Ligand A (-28.73 hours). This is another point in favor of Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.10 and 0.11).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -9.0 kcal/mol). Ligand B has a 0.8 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and permeability, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity outweigh Ligand A's better QED score. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the improved pharmacokinetic profile of Ligand B provides a stronger starting point.

Output:
1
2025-04-17 13:44:59,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.415 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.9) is better than Ligand B (82.08), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Both ligands have good logP values (1.063 and 0.77), 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:** Both ligands have the same number of H-bond acceptors (4), well below the 10 limit.

**6. QED:** Ligand A (0.854) has a significantly better QED score than Ligand B (0.721), indicating a more drug-like profile.

**7. DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (32.842). This is a negative for Ligand A.

**8. BBB:** Ligand A (71.462) has a better BBB penetration score than Ligand B (57.736), but this is less important for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, lower is worse. Ligand A (-4.927) is worse than Ligand B (-5.039).

**10. Solubility:** Both have negative solubility values, which is also unusual. Assuming these are percentile scores, lower is worse. Ligand A (-1.957) is better than Ligand B (-2.049).

**11. hERG:** Ligand A (0.209) has a significantly lower hERG inhibition liability than Ligand B (0.102), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**12. Cl_mic:** Ligand A (8.341) has lower microsomal clearance than Ligand B (10.339), suggesting better metabolic stability.

**13. t1/2:** Ligand A (27.095) has a much longer in vitro half-life than Ligand B (-12.301). This is a major advantage for Ligand A, suggesting less frequent dosing.

**14. Pgp:** Ligand A (0.021) has lower P-gp efflux liability than Ligand B (0.01), which is a slight advantage.

**15. Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-7.9). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. The 2.1 kcal/mol difference is substantial.

**Overall Assessment:**

Despite Ligand A's higher DILI risk, its significantly superior binding affinity, metabolic stability (lower Cl_mic, longer t1/2), better QED, and lower hERG risk outweigh this concern. The substantial difference in binding affinity (-10.0 vs -7.9 kcal/mol) is a key driver in this decision. While both have issues with Caco-2 and solubility, the overall profile of Ligand A is more promising for development as a kinase inhibitor.

Output:
1
2025-04-17 13:44:59,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.755 and 364.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (84.27 and 88.33) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (3.947) is at the higher end of the optimal range (1-3), while Ligand B (2.669) is well within it. Ligand A's 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 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 (0.617 and 0.778), indicating good drug-like properties.

**DILI:** Ligand A (84.645) has a higher DILI risk than Ligand B (55.991). This is a significant negative for Ligand A.

**BBB:** Both have low BBB penetration, which isn't a major concern for an oncology 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 unusual and suggests poor solubility. This is a concern for both.

**hERG:** Both ligands have low hERG inhibition liability (0.587 and 0.418), which is excellent.

**Microsomal Clearance:** Ligand A (55.421) has lower microsomal clearance than Ligand B (86.155), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (66.388) has a longer half-life than Ligand B (-21.729). The negative value for ligand B is concerning and suggests very rapid degradation. This is a major advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.171 and 0.112), which is good.

**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 still a positive for Ligand A.

**Overall:**

Ligand A has a better binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. However, it has a higher DILI risk and a slightly higher logP. Ligand B has a lower DILI risk but significantly worse metabolic stability (very short half-life) and a slightly lower binding affinity.

Given the priorities for enzyme inhibitors, metabolic stability and potency are crucial. The significantly better half-life and slightly better affinity of Ligand A outweigh its higher DILI risk, especially since the DILI risk is still below the 60% threshold considered high risk. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:44:59,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.53 and 347.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, suggesting good absorption. Ligand B (78.51) is also below the threshold, but higher than A.

**logP:** Ligand A (4.812) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.197) is at the lower end of optimal, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which is acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.832 and 0.805), indicating good drug-likeness.

**DILI:** Ligand A (41.26) has a slightly higher DILI risk than Ligand B (27.45), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.51) has a higher BBB percentile than Ligand B (45.91).

**Caco-2 Permeability:** Ligand A (-4.583) and Ligand B (-5.107) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.463) and Ligand B (-3.238) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.636) has a higher hERG risk than Ligand B (0.066). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (79 mL/min/kg) has a higher clearance than Ligand B (12.56 mL/min/kg), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (14.76 hours) has a longer half-life than Ligand B (7.31 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.313) has lower P-gp efflux than Ligand B (0.03), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol) - a difference of 0.5 kcal/mol. This is a substantial advantage.

**Conclusion:**

While Ligand A has a longer half-life and slightly better P-gp efflux, Ligand B is superior overall. The most important factors for an enzyme inhibitor are potency and metabolic stability. Ligand B's significantly stronger binding affinity (-7.9 vs -7.4 kcal/mol) and much lower microsomal clearance (12.56 vs 79 mL/min/kg) outweigh the slightly shorter half-life and lower P-gp. Furthermore, Ligand B has a much lower hERG risk. The solubility and permeability are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:44:59,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 342.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.58) is better than Ligand B (41.05) as it is closer to the optimal threshold of 140 for oral absorption. Ligand B is very low, which could indicate issues with solubility.

**logP:** Ligand A (-1.072) is slightly low, potentially hindering permeation, but not drastically. Ligand B (4.792) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is better balanced than Ligand B (1 HBD, 4 HBA). Both are within acceptable limits, but A is closer to ideal.

**QED:** Both ligands have good QED scores (0.575 and 0.835), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (33.812 and 36.409), which is favorable.

**BBB:** Ligand B (93.912) has a significantly higher BBB penetration percentile than Ligand A (51.803). However, since SRC is not a CNS target, this is less crucial.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.371 and -5.069), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.442) is better than Ligand B (-4.846), indicating better solubility.

**hERG Inhibition:** Ligand A (0.122) has a much lower hERG inhibition liability than Ligand B (0.898), which is a critical advantage.

**Microsomal Clearance:** Ligand A (0.321) has much lower microsomal clearance than Ligand B (81.996), indicating better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-7.491) has a much longer in vitro half-life than Ligand B (26.037), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (-8) has lower P-gp efflux liability than Ligand B (0.579), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-7.491), a difference of 1.61 kcal/mol. This is a substantial difference and could potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better in terms of ADME properties crucial for an enzyme target. Specifically, Ligand A has much better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better solubility. The Caco-2 permeability is poor for both, but the other advantages of Ligand A make it the more promising candidate. The affinity difference, while significant, is likely surmountable through further optimization of Ligand A.

Output:
0
2025-04-17 13:44:59,098 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.378 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (95.25) is better than Ligand B (29.54). Lower TPSA generally improves oral absorption.

**logP:** Ligand A (1.749) is optimal, while Ligand B (4.205) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, which are both good. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have acceptable QED scores (Ligand A: 0.49, Ligand B: 0.646). Ligand B is slightly better.

**DILI:** Ligand A (83.172) has a higher DILI risk than Ligand B (24.04). This is a significant concern for Ligand A.

**BBB:** Both have good BBB penetration, but Ligand B (98.294) is superior to Ligand A (81.776). While not critical for a non-CNS target like SRC, it's a minor positive for B.

**Caco-2 Permeability:** Ligand A (-5.138) has poor Caco-2 permeability, while Ligand B (-4.029) is better, though still not great.

**Aqueous Solubility:** Ligand A (-3.553) has poor aqueous solubility, while Ligand B (-4.319) is also poor. Both are problematic.

**hERG Inhibition:** Ligand A (0.48) has a lower hERG risk than Ligand B (0.866). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-0.393) has a lower (better) microsomal clearance than Ligand B (73.596), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (28.192) has a shorter half-life than Ligand B (4.472). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux than Ligand B (0.272), which is favorable.

**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 has a better QED, BBB, and Caco-2 permeability, but suffers from a higher DILI risk, higher logP, and significantly worse metabolic stability (high Cl_mic and low t1/2). Ligand A has a lower DILI risk and much better metabolic stability, lower P-gp efflux, and a lower hERG risk, but has poor solubility and permeability.

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, hERG), Ligand A is the better candidate. The significantly improved metabolic stability (lower Cl_mic) and lower DILI risk outweigh the solubility and permeability concerns, especially given the strong binding affinity. Solubility and permeability can be addressed with formulation strategies. The hERG risk is also lower with Ligand A.

Output:
0
2025-04-17 13:44:59,099 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.423 and 343.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.0) is slightly above the preferred <140 for good oral absorption, but still acceptable. Ligand B (79.18) is well within the optimal range.

**logP:** Ligand A (-1.331) is a bit low, potentially hindering permeation. Ligand B (1.152) 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 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.408 and 0.793, respectively), indicating reasonable drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (15.626 and 59.946), but Ligand B is significantly higher and therefore more concerning.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.088) has a very low hERG risk, which is excellent. Ligand B (0.47) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-4.35 mL/min/kg) suggests good metabolic stability. Ligand B (50.438 mL/min/kg) indicates high metabolic clearance and poor stability.

**In vitro Half-Life:** Ligand A (-6.131 hours) is a negative value, which is not interpretable. Ligand B (2.986 hours) is a short half-life, which is undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much better binding affinity, a more favorable logP, and a better QED score. However, it has a significantly higher DILI risk, a shorter half-life, and higher microsomal clearance. Ligand A has a much better hERG profile and better metabolic stability, but suffers from a lower logP, negative solubility and half-life values, and a weaker binding affinity.

Despite the solubility issues, the significantly stronger binding affinity of Ligand B (-8.2 kcal/mol vs -10.7 kcal/mol) is a major advantage for an enzyme target. The difference in binding affinity is likely to outweigh the ADME liabilities, especially considering the potential for optimization of solubility and metabolic stability through medicinal chemistry efforts. The DILI risk is concerning but could be addressed through structural modifications.

Output:
1
2025-04-17 13:44:59,099 - INFO - Batch 239 complete. Total preferences: 3824
2025-04-17 13:44:59,099 - INFO - Processing batch 240/512...
2025-04-17 13:45:41,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.419 and 360.567 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (94.17) is better than Ligand B (44.1). Both are below the 140 threshold for good absorption, but Ligand B is significantly lower, which could be advantageous.

**logP:** Ligand A (-0.046) is suboptimal, being close to 1, which might hinder permeation. Ligand B (4.811) is too high, potentially causing solubility and off-target issues.

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

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (3) is also good.

**QED:** Ligand A (0.643) is better than Ligand B (0.438), indicating a more drug-like profile.

**DILI:** Ligand A (38.62) is significantly better than Ligand B (10.857), indicating a much lower risk of drug-induced liver injury.

**BBB:** Ligand A (51.415) is lower than Ligand B (83.249). While BBB isn't a primary concern for a kinase inhibitor, higher is generally better.

**Caco-2 Permeability:** Both ligands have negative values (-4.643 and -4.798), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.528) is better than Ligand B (-4.957), indicating slightly better solubility.

**hERG Inhibition:** Ligand A (0.164) is much better than Ligand B (0.842), posing a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (28.969) is significantly better than Ligand B (119.85), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.163) is better than Ligand B (-12.708), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.021) is much better than Ligand B (0.599), suggesting less efflux and potentially better bioavailability.

**Binding Affinity:** Ligand A (-8.8) is significantly better than Ligand B (-6.9). This is a crucial advantage, as a 1.9 kcal/mol difference can outweigh many ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both have poor Caco-2 permeability, Ligand A excels in critical areas: significantly better binding affinity, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and better t1/2), lower P-gp efflux, and a higher QED score. The slightly better solubility also contributes. Ligand B's high logP is a significant drawback. The substantial affinity advantage of Ligand A makes it the more promising drug candidate despite the permeability concerns.

Output:
0
2025-04-17 13:45:41,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (356.413 and 358.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (81.59) is better than Ligand B (91.57), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands (2.093 and 2.841) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is slightly higher than Ligand B (3), but both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (5), both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.547 and 0.654, respectively), indicating drug-likeness.

**DILI:** Ligand A (27.685) has a significantly lower DILI risk than Ligand B (81.504). This is a major advantage for Ligand A.

**BBB:** Ligand A (72.896) has a better BBB score than Ligand B (53.044), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.748) is better than Ligand B (-5.192), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.344) is better than Ligand B (-3.696), indicating better solubility.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.618 and 0.675), and are within acceptable ranges.

**Microsomal Clearance:** Ligand A (29.119) has significantly lower microsomal clearance than Ligand B (52.378), suggesting better metabolic stability. This is a key advantage for a kinase inhibitor.

**In vitro Half-Life:** Ligand A (-5.925) has a much longer in vitro half-life than Ligand B (104.781), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.285 and 0.585).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.5 kcal/mol), with Ligand A being slightly better. The difference is small, and both are well below the -7.0 kcal/mol threshold.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. It demonstrates superior ADME properties, particularly lower DILI risk, better solubility, and significantly improved metabolic stability (lower Cl_mic and longer t1/2). While both ligands have excellent binding affinity, the ADME advantages of Ligand A outweigh the minor difference in potency.

Output:
1
2025-04-17 13:45:41,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.829 Da and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.53 and 72.88) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.233) is optimal, while Ligand B (1.98) is slightly lower, potentially impacting permeability.

**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.

**QED:** Both ligands have similar QED values (0.857 and 0.826), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 77.588, which is concerning (high risk). Ligand B has a much lower DILI risk of 13.3, which is excellent.

**BBB:** Both ligands have reasonable BBB penetration (53.276 and 72.431), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.572 and -4.823). This is a significant drawback for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.97 and -1.541). This is a major concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.34 and 0.425), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (78.046) than Ligand B (-4.79). This indicates that Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B has a slightly longer in vitro half-life (-0.436) than Ligand A (38.959).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.024).

**Binding Affinity:** Ligand A has a significantly better binding affinity (-7.6 kcal/mol) than Ligand B (-6.4 kcal/mol). This is a substantial advantage.

**Conclusion:**

While Ligand A boasts a superior binding affinity, its high DILI risk and poor solubility are major liabilities. Ligand B, despite its slightly weaker binding affinity, exhibits a much more favorable safety profile (low DILI) and better metabolic stability. The poor Caco-2 and solubility are concerning for both, but the DILI risk for Ligand A is a dealbreaker. Considering the enzyme-specific priorities, I would favor Ligand B as a starting point for further optimization, as the solubility and permeability issues are more readily addressed through medicinal chemistry than a high DILI risk.

Output:
1
2025-04-17 13:45:41,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (374.415 and 335.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (131.03) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (73.2) is excellent, well below 140.

**logP:** Ligand A (-0.694) is a bit low, potentially hindering permeation. Ligand B (2.244) 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 3 HBA, also good.

**QED:** Both ligands have good QED scores (0.521 and 0.861), indicating drug-like properties.

**DILI:** Both ligands have the same DILI risk (47.732), which is good (below 60).

**BBB:** Ligand A (35.789) has low BBB penetration, as expected for a non-CNS target. Ligand B (78.519) shows moderate BBB penetration, which isn't a major concern for an oncology target.

**Caco-2 Permeability:** Ligand A (-6.124) has poor Caco-2 permeability, a significant drawback. Ligand B (-4.943) is also not great, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-2.026) has poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-4.156) also has poor solubility, but slightly better than A.

**hERG:** Both ligands have low hERG risk (0.217 and 0.498), which is positive.

**Microsomal Clearance:** Ligand A (11.248 mL/min/kg) has lower clearance, suggesting better metabolic stability than Ligand B (18.796 mL/min/kg).

**In vitro Half-Life:** Ligand A (-14.304 hours) has a negative half-life, which is unusual and likely an error or indicates very rapid metabolism. Ligand B (3.829 hours) has a short but positive half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.044 and 0.107), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.7 and -8.5 kcal/mol), both being excellent. The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. While both have solubility issues, Ligand A's extremely poor Caco-2 permeability and negative in vitro half-life are major red flags. Ligand B has better logP, TPSA, and a positive half-life, making it more likely to be a viable drug candidate.

Output:
1
2025-04-17 13:45:41,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.487 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is slightly higher than Ligand B (53.51), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.119) is slightly lower than the optimal 1-3 range, while Ligand B (2.786) is well within the range.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both below the 10 threshold.

**QED:** Both ligands have good QED scores (0.799 and 0.831, respectively), indicating drug-likeness.

**DILI:** Ligand A (44.591) has a slightly higher DILI risk than Ligand B (20.396). Both are acceptable (<60).

**BBB:** Ligand A (63.94) has a lower BBB penetration than Ligand B (84.917). This isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close enough that this is unlikely to be a deciding factor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the values are close enough that this is unlikely to be a deciding factor.

**hERG Inhibition:** Ligand A (0.122) has a slightly higher hERG risk than Ligand B (0.341). Both are relatively low risk.

**Microsomal Clearance:** Ligand A (35.263) has higher microsomal clearance than Ligand B (25.606), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-14.813) has a *negative* half-life, which is impossible and indicates a significant issue with the data or the compound itself. Ligand A (2.12) has a short half-life, but it's a realistic value.

**P-gp Efflux:** Ligand A (0.046) has a lower P-gp efflux liability than Ligand B (0.143), which is favorable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the superior binding affinity of Ligand B (-8.9 kcal/mol vs -7.6 kcal/mol) and its better metabolic stability (lower Cl_mic) outweigh the slightly higher logP and P-gp efflux. The negative half-life for Ligand B is a major red flag, making Ligand A the more viable candidate despite its lower affinity and metabolic stability.

Output:
0
2025-04-17 13:45:41,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (87.47) is better than Ligand B (102.76), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (A: 1.729, B: 0.991) 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 balancing solubility and permeability.

**QED:** Ligand A (0.848) has a significantly better QED score than Ligand B (0.642), indicating a more drug-like profile.

**DILI:** Ligand A (37.65) has a much lower DILI risk than Ligand B (65.413). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.329) is better than Ligand B (26.406).

**Caco-2 Permeability:** Ligand A (-4.795) is slightly better than Ligand B (-5.298), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.148 and -3.057 respectively). This is a concern for both, but needs to be balanced against other factors.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.562, B: 0.332), which is good.

**Microsomal Clearance:** Ligand A (29.517 mL/min/kg) has a higher microsomal clearance than Ligand B (13.093 mL/min/kg), meaning Ligand B is likely to have better metabolic stability.

**In vitro Half-Life:** Ligand B (8.68 hours) has a better in vitro half-life than Ligand A (-18.949 hours). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.027, B: 0.093).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.1 and -9.6 kcal/mol respectively). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has a superior drug-like profile (higher QED, lower DILI) and better permeability characteristics (TPSA, Caco-2). However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2). The affinity difference is minimal. Given the importance of metabolic stability for kinase inhibitors, and the relatively small difference in affinity, Ligand B is slightly favored. However, the significantly lower DILI risk of Ligand A is a strong point in its favor. Considering the overall balance, the better QED and DILI profile of Ligand A outweigh the slightly better metabolic stability of Ligand B.

Output:
0
2025-04-17 13:45:41,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.475 and 374.35 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.65) is slightly above the optimal <140, but acceptable. Ligand B (58.64) is well within the ideal range.

**logP:** Both ligands have good logP values (1.531 and 2.846), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Ligand A (0.79) has a better QED score than Ligand B (0.525), indicating a more drug-like profile.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (35.285). This is a significant negative for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (90.772) has a higher percentile than Ligand A (66.344).

**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, also unusual. Again, the magnitude is similar.

**hERG:** Ligand A (0.05) has a much lower hERG inhibition liability than Ligand B (0.756), which is a significant advantage.

**Microsomal Clearance:** Ligand A (50.793) has higher microsomal clearance than Ligand B (23.579), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.166) has a longer in vitro half-life than Ligand A (-28.841), suggesting better metabolic stability.

**P-gp Efflux:** Ligand A (0.035) has lower P-gp efflux liability than Ligand B (0.295), which is favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a better binding affinity than Ligand A (-8.7 kcal/mol). While A is slightly better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better binding affinity and P-gp efflux, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a better QED score. The lower hERG risk of Ligand A is a positive, but the DILI risk of Ligand A is concerning. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 13:45:41,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.22) is slightly higher than Ligand B (66.65). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.295 and 3.128), 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 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and acceptable QED values (0.675 and 0.723), indicating good drug-likeness.

**DILI:** Both ligands have very similar and low DILI risk (29.973 and 29.43 percentile), which is excellent.

**BBB:** Ligand A (60.876) has a lower BBB penetration percentile than Ligand B (85.925). Since SRC is not a CNS target, this is less critical, but a higher value is generally preferable.

**Caco-2 Permeability:** Ligand A (-4.861) has worse Caco-2 permeability than Ligand B (-4.466). Both are negative, indicating poor permeability, but B is better.

**Aqueous Solubility:** Ligand A (-3.414) has worse aqueous solubility than Ligand B (-2.489). Solubility is important for bioavailability, so Ligand B is favored.

**hERG Inhibition:** Ligand A (0.39) shows a slightly lower hERG inhibition liability than Ligand B (0.503), which is better.

**Microsomal Clearance:** Ligand A (29.609) has a lower microsomal clearance than Ligand B (97.098). Lower clearance indicates better metabolic stability, making Ligand A more favorable.

**In vitro Half-Life:** Ligand A (-14.695) has a shorter in vitro half-life than Ligand B (-25.151). A longer half-life is generally preferred, so Ligand B is favored.

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux liability than Ligand B (0.509), which is 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 in affinity is a major advantage and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, better Caco-2 permeability, better solubility, and better BBB penetration. While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, the substantial improvement in binding affinity of Ligand B is the most critical factor for an enzyme target like SRC kinase. The differences in solubility and permeability, while not ideal, are less concerning than a weaker binding interaction.

Output:
1
2025-04-17 13:45:41,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (452.227 Da) is higher, but still acceptable. Ligand B (357.357 Da) is slightly preferred.

**TPSA:** Ligand A (80.05) is good, below the 140 threshold for oral absorption. Ligand B (93.46) is also acceptable, but closer to the limit.

**logP:** Ligand A (3.322) is optimal. Ligand B (1.657) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.443, B: 0.656), with B being slightly more drug-like.

**DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (49.942). This is a significant concern for A.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (85.731) has better BBB penetration than A (63.862).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.32) is worse than Ligand B (-4.417).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.054) is worse than Ligand B (-2.898).

**hERG Inhibition:** Ligand A (0.819) has a slightly higher hERG risk than Ligand B (0.179). B is much preferred.

**Microsomal Clearance:** Ligand B (34.347 mL/min/kg) has lower clearance and therefore better metabolic stability than Ligand A (53.504 mL/min/kg).

**In vitro Half-Life:** Ligand A (72.197 hours) has a significantly longer half-life than Ligand B (-10.603 hours). This is a major advantage for A.

**P-gp Efflux:** Ligand A (0.549) has lower P-gp efflux than Ligand B (0.038), which is favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a longer half-life, which are critical for an enzyme inhibitor. However, it suffers from higher DILI risk, worse solubility, worse permeability, and a slightly higher hERG risk. Ligand B has better ADME properties (lower DILI, better solubility, better permeability, lower hERG, better metabolic stability), but its binding affinity is significantly weaker.

The difference in binding affinity (1.1 kcal/mol) between A and B is substantial. Given that SRC is a kinase, potency is paramount. The longer half-life of A is also a significant benefit. While the ADME properties of A are not ideal, they may be addressable through further optimization. The weaker binding of B is a more difficult issue to resolve.

Output:
1
2025-04-17 13:45:41,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (352.425 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is well below the 140 threshold and favorable for oral absorption. Ligand B (61.88) is still within acceptable limits, but less optimal than A.

**3. logP:** Ligand A (2.671) is within the optimal 1-3 range. Ligand B (0.781) is slightly below 1, which *could* indicate potential permeability issues, although not drastically.

**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):** Both ligands have acceptable HBA counts (2 for A, 4 for B), below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.78 and 0.764), indicating good drug-like properties.

**7. DILI:** Ligand A (23.149) has a significantly lower DILI risk than Ligand B (12.757), which is a major advantage.

**8. BBB:** Ligand A (95.425) shows excellent BBB penetration, while Ligand B (61.031) is considerably lower. While SRC isn't a CNS target, good BBB penetration generally correlates with better overall bioavailability.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.477 and -4.578). This is unusual and suggests a potential issue with the data or the model used to predict this value. We'll proceed cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.28 and -1.617). Again, this is concerning and suggests the model may be flagging a potential solubility issue.

**11. hERG Inhibition:** Ligand A (0.606) shows lower hERG inhibition risk than Ligand B (0.238), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (29.09) has a higher Cl_mic than Ligand B (1.985), suggesting faster metabolism and lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (7.402) has a longer half-life than Ligand B (3.245), which is a positive.

**14. P-gp Efflux:** Ligand A (0.108) has lower P-gp efflux than Ligand B (0.009), suggesting better bioavailability.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower DILI risk, better BBB penetration, and lower hERG inhibition. However, it has higher microsomal clearance. Ligand B has better metabolic stability, but weaker binding affinity, higher DILI risk, and lower BBB penetration. The substantial difference in binding affinity of Ligand A is a significant advantage. The negative Caco-2 and solubility values for both are concerning, but the superior potency and safety profile of Ligand A make it the more promising candidate, assuming these solubility/permeability issues can be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 13:45:41,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.361 and 346.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.69) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (-0.532) is quite low, potentially hindering membrane permeability. Ligand B (3.524) 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 6 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits, but Ligand B is more favorable due to fewer hydrogen bonding groups, potentially improving permeability.

**QED:** Both ligands have similar QED values (0.606 and 0.513), indicating good drug-likeness.

**DILI:** Ligand A (45.483) has a slightly higher DILI risk than Ligand B (6.824). Ligand B is much preferred here.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.139) shows better BBB penetration, but it's not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.18) shows poor permeability, while Ligand B (-4.761) is also not great, but better than A.

**Aqueous Solubility:** Ligand A (-1.205) has poor solubility, while Ligand B (-3.515) is also poor. This is a potential issue for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.312) has a slightly lower hERG risk than Ligand B (0.594), but both are reasonably low.

**Microsomal Clearance:** Ligand A (-3.359) has a lower (better) microsomal clearance than Ligand B (77.552), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-13.791) has a shorter half-life than Ligand B (-5.838). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.02) has lower P-gp efflux than Ligand B (0.106), which is favorable.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.5). While both are good, the difference is approximately 0.8 kcal/mol, which is meaningful.

**Overall Assessment:**

Ligand B excels in several key areas: logP, TPSA, DILI risk, and binding affinity. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, the poor logP and solubility of Ligand A, coupled with the higher DILI risk, are significant drawbacks. The slightly better binding affinity of Ligand B, combined with its superior ADME properties, makes it the more promising candidate. The difference in binding affinity is not large enough to overcome the ADME issues of Ligand A.

Output:
1
2025-04-17 13:45:41,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (370.896 and 390.315 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.57) is significantly better than Ligand B (74.09). A TPSA under 90 is generally acceptable, but lower is preferable for good absorption. Ligand A is much closer to the optimal range.

**3. logP:** Ligand A (4.428) is slightly higher than optimal (1-3), but still potentially manageable. Ligand B (2.692) is within the optimal range. However, for a kinase inhibitor, a slightly higher logP isn't a major concern 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, while Ligand B has 7. Ligand A is preferable here, as higher HBA counts can sometimes hinder permeability.

**6. QED:** Both ligands have similar QED values (0.833 and 0.797), indicating good drug-like properties.

**7. DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (52.772). This is a crucial advantage, as minimizing liver toxicity is paramount.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (83.249) is better than Ligand A (69.407). However, BBB penetration is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Ligand A (-4.499) has a worse Caco-2 permeability than Ligand B (-5.338). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-4.006) has better aqueous solubility than Ligand B (-3.421). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.908) has a lower hERG inhibition risk than Ligand B (0.12). This is a significant advantage, as hERG inhibition can lead to cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (36.921) has higher microsomal clearance than Ligand B (10.862), indicating faster metabolism and potentially lower *in vivo* exposure. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (39.193) has a much longer half-life than Ligand B (7.82). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux than Ligand B (0.099), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). This is a 1.5 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand B has a better binding affinity and slightly better Caco-2 permeability. However, Ligand A demonstrates a significantly better safety profile (lower DILI and hERG risk), better solubility, and a longer half-life, despite having a slightly higher logP and higher clearance. The improved safety profile and half-life of Ligand A outweigh the slightly better affinity of Ligand B, especially considering the 1.5 kcal/mol difference isn't enormous.

Output:
0
2025-04-17 13:45:41,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.447 and 366.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (110.1 and 104.12) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.22) is slightly low, potentially hindering permeation. Ligand B (0.586) is better, falling within the 1-3 range.

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

**H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (7) is also within the limit.

**QED:** Both ligands have reasonable QED scores (0.482 and 0.735), with Ligand B being significantly better.

**DILI:** Ligand A (14.308) has a very favorable DILI score, indicating low liver injury risk. Ligand B (62.001) is higher, suggesting a moderate risk.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.214 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 (-1.165 and -2.082), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.183 and 0.148).

**Microsomal Clearance:** Ligand A (0.606) has significantly lower microsomal clearance, indicating better metabolic stability. Ligand B (21.464) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (13.569) has a longer half-life, which is desirable. Ligand B (7.81) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.008 and 0.029).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is preferable despite the slightly lower binding affinity. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic and longer t1/2) are crucial advantages for an enzyme inhibitor. While both have poor solubility and permeability, the metabolic profile of Ligand A is more promising. The small difference in binding affinity is outweighed by the ADME benefits.

Output:
0
2025-04-17 13:45:41,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.431 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.16) is slightly higher than Ligand B (54.46). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Ligand A (1.388) is within the optimal range (1-3), while Ligand B (3.019) is at the higher end, but still acceptable.

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

**QED:** Both ligands have similar QED values (0.719 and 0.684), indicating good drug-likeness.

**DILI:** Ligand A (38.581) has a lower DILI risk than Ligand B (11.4), which is a significant advantage.

**BBB:** Ligand A (67.662) has a lower BBB penetration than Ligand B (79.566). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.589) has a negative Caco-2 value, which is concerning. Ligand B (-5.065) is also negative, and similarly concerning. This suggests poor intestinal absorption for both.

**Aqueous Solubility:** Ligand A (-1.611) has slightly better solubility than Ligand B (-3.481), but both are quite poor.

**hERG:** Ligand A (0.205) has a much lower hERG inhibition liability than Ligand B (0.708), which is a crucial advantage.

**Microsomal Clearance:** Ligand B (71.506) has a significantly higher microsomal clearance than Ligand A (14.703), indicating poorer metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-2.998) has a slightly longer in vitro half-life than Ligand B (-3.878).

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux liability than Ligand B (0.093).

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.4), although both are very good. The 1.5 kcal/mol difference is meaningful.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have poor Caco-2 permeability and solubility, Ligand A demonstrates significantly lower DILI and hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. These factors are particularly important for an enzyme target like SRC kinase. The slightly better binding affinity of A, combined with the significantly improved safety and pharmacokinetic profiles, outweigh the slightly lower BBB penetration (which isn't critical for this target) and TPSA.

Output:
0
2025-04-17 13:45:41,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.375 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.07) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (67.43) is well within the ideal range.

**logP:** Ligand A (0.754) is a bit low, potentially hindering permeation. Ligand B (2.703) is optimal.

**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 scores (0.63 and 0.725), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (77.743), which is a significant concern. Ligand B has a much lower DILI risk (19.426), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (63.319) than Ligand A (11.245).

**Caco-2 Permeability:** Ligand A (-6.231) shows poor permeability, while Ligand B (-5.064) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.664 and -2.87). This is a concern, but can be addressed through formulation.

**hERG Inhibition:** Ligand A (0.01) has very low hERG inhibition risk, a strong positive. Ligand B (0.251) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A has a low Cl_mic (-16.081), indicating good metabolic stability. Ligand B has a significantly higher Cl_mic (33.985), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a short half-life (-3.744), while Ligand B has a longer half-life (28.538), a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.002 and 0.061).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, its high DILI risk and poor Caco-2 permeability are major concerns. Ligand B has a better safety profile (lower DILI), better metabolic stability (longer half-life), and better logP, but its binding affinity is considerably weaker.

Given the importance of potency for kinase inhibitors, the superior binding affinity of Ligand A is a strong argument in its favor. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The poor permeability is also a drawback, but potentially addressable.

Output:
1
2025-04-17 13:45:41,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (381.969 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.38) is well below the 140 threshold, suggesting good absorption. Ligand B (67.43) is still within acceptable limits but higher.

**logP:** Ligand A (4.703) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.537) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) and Ligand B (2 HBD, 3 HBA) both have reasonable counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar QED values (0.669 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (13.61). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (87.088 and 71.811), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.04) shows poor permeability, while Ligand B (-4.66) is slightly better, but both are negative values which isn't ideal.

**Aqueous Solubility:** Ligand A (-6.144) has very poor solubility, a significant drawback. Ligand B (-2.633) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.876) has a lower hERG risk than Ligand B (0.351), which is preferable.

**Microsomal Clearance:** Ligand A (75.747) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (40.337) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.228) has a very short half-life, which is a major concern. Ligand B (3.395) has a slightly better, but still short, half-life.

**P-gp Efflux:** Ligand A (0.521) has lower P-gp efflux, which is beneficial. Ligand B (0.044) has very low P-gp efflux, which is even better.

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and better metabolic stability (lower Cl_mic). While its solubility is still not ideal, it's better than Ligand A's. Ligand A suffers from very poor solubility, short half-life, and higher clearance. The lower DILI risk and P-gp efflux for Ligand A are positives, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 13:45:41,694 - INFO - Batch 240 complete. Total preferences: 3840
2025-04-17 13:45:41,694 - INFO - Processing batch 241/512...
2025-04-17 13:46:22,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.359 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.24) is better than Ligand B (53.51), being below the 140 threshold for good absorption. Ligand B is very low, which *could* indicate issues with solubility.

**logP:** Ligand A (0.143) is quite low, potentially hindering permeability. Ligand B (3.032) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (7) is reasonable. Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.791 and 0.826), indicating good drug-like properties.

**DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (26.871). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (87.01) has better BBB penetration, but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-5.186) has poor Caco-2 permeability, which aligns with its low logP. Ligand B (-4.587) is also not great, but better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.184 and -2.8). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.039) has very low hERG inhibition risk, which is excellent. Ligand B (0.447) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (11.865) has lower microsomal clearance, indicating better metabolic stability. Ligand B (53.529) has significantly higher clearance.

**In vitro Half-Life:** Ligand A (6.284) has a shorter half-life than Ligand B (-7.763, which is likely an error and should be interpreted as a very long half-life).

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.138) is slightly higher.

**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.

**Overall Assessment:**

Ligand B is the better candidate. While both have solubility issues, Ligand B has a much better logP, lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. Ligand A's low logP and high DILI risk are major drawbacks. The solubility issues for both would need to be addressed through formulation strategies, but the other ADME properties of Ligand B are more favorable for development.

Output:
1
2025-04-17 13:46:22,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.49) is slightly higher than Ligand B (350.46), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (83.56) is slightly higher than Ligand B (78.87).

**logP:** Ligand A (1.261) is within the optimal range (1-3), while Ligand B (3.149) is at the higher end. This could potentially lead to solubility issues for Ligand B.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBDs and acceptable HBA counts (6 and 4 respectively).

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (31.291) has a significantly lower DILI risk than Ligand B (18.922), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.113) has a worse Caco-2 permeability than Ligand B (-4.708), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.843) has better aqueous solubility than Ligand B (-3.672). This is a positive attribute, especially given Ligand B's higher logP.

**hERG Inhibition:** Ligand A (0.212) has a lower hERG inhibition liability than Ligand B (0.713), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-13.349) has a much lower (better) microsomal clearance than Ligand B (107.093). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (-13.817) has a slightly worse in vitro half-life than Ligand A (11.153).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While its Caco-2 permeability is slightly worse, it has significantly better DILI risk, hERG inhibition liability, and metabolic stability (lower Cl_mic). The stronger binding affinity further solidifies its advantage. Ligand B's higher logP and DILI risk are concerning.

Output:
0
2025-04-17 13:46:22,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.59) is better than Ligand B (67.43), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.178 and 2.202) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

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

**QED:** Ligand A (0.745) has a better QED score than Ligand B (0.62), indicating a more drug-like profile.

**DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (23.187), which is a major advantage.

**BBB:** Both have reasonable BBB penetration (69.523 and 62.233), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.051) and Ligand B (-5.29) have negative values, which is not ideal. However, the values are similar.

**Solubility:** Ligand A (-2.339) has slightly better solubility than Ligand B (-3.34).

**hERG:** Ligand A (0.474) has a lower hERG risk than Ligand B (0.334), which is a positive.

**Microsomal Clearance:** Ligand A (39.684) has a lower microsomal clearance than Ligand B (67.403), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (22.944) has a much longer half-life than Ligand B (-0.016). This is a significant advantage, suggesting less frequent dosing potential.

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux than Ligand B (0.09), which is favorable.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-9.8). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall:**

Ligand A demonstrates superior ADME properties (lower DILI, better metabolic stability, longer half-life, better solubility, lower hERG risk) and a good QED score. While Ligand B has slightly better binding affinity, the overall profile of Ligand A is more favorable for development as a drug candidate targeting SRC kinase.

Output:
0
2025-04-17 13:46:22,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (408.231 and 371.453 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.97) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (62.3) is well within the ideal range.

**logP:** Both ligands (2.063 and 2.127) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.812 and 0.863), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 80.807, which is high and concerning. Ligand B has a much lower DILI risk of 35.014, which is good.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (78.79) has a higher BBB score than Ligand A (53.432), but this is less critical.

**Caco-2 Permeability:** Ligand A (-4.941) and Ligand B (-4.961) have similar, very poor Caco-2 permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-3.881) and Ligand B (-2.662) have poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.824) has a slightly higher hERG risk than Ligand B (0.375), but both are relatively low.

**Microsomal Clearance:** Ligand A (14.782) has a higher microsomal clearance than Ligand B (-1.83). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (60.881) has a longer half-life than Ligand B (-3.561). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.377) has lower P-gp efflux than Ligand B (0.132), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.9 kcal/mol), with Ligand A being slightly more potent. The difference is less than 1.5 kcal/mol, so it doesn't overwhelmingly favor Ligand A.

**Conclusion:**

Despite Ligand A's slightly better potency and half-life, the significantly higher DILI risk and lower metabolic stability make it a less desirable candidate. Ligand B has a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic), and acceptable drug-like properties. While both have poor Caco-2 permeability and solubility, the safety and metabolic advantages of Ligand B outweigh the slight potency difference.

Output:
1
2025-04-17 13:46:22,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.354 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.55) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (95.71) is excellent, well below 140.

**logP:** Ligand A (0.55) is a bit low, potentially hindering permeation. Ligand B (2.775) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also good.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.701 and 0.568, respectively), indicating drug-likeness.

**DILI:** Ligand A (83.87) has a higher DILI risk than Ligand B (56.805). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (65.413) and Ligand B (57.154) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.888) has poor Caco-2 permeability, which is concerning. Ligand B (-5.56) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.329 and -4.216). This is a major drawback that would require formulation strategies.

**hERG Inhibition:** Ligand A (0.158) has a slightly higher hERG risk than Ligand B (0.534), but both are relatively low.

**Microsomal Clearance:** Ligand A (25.757) has significantly lower microsomal clearance than Ligand B (51.054), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.915) has a longer in vitro half-life than Ligand B (-29.522), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.005 and 0.199 respectively).

**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 its ADME liabilities.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, it has a higher DILI risk and significantly poorer Caco-2 permeability. Ligand B has better ADME properties (lower DILI, better logP, better TPSA), but its binding affinity is considerably weaker. Given the importance of potency for kinase inhibitors, the superior binding affinity of Ligand A is likely to be more impactful, *provided* the solubility and permeability issues can be addressed through formulation. The lower metabolic clearance of Ligand A is also a plus.

Output:
1
2025-04-17 13:46:22,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (351.407 and 363.502 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.06) is well below the 140 threshold for good oral absorption, while Ligand B (35.58) is even better.

**3. logP:** Ligand A (-1.547) is slightly low, potentially hindering permeation. Ligand B (1.965) is 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 each), below the limit of 10.

**6. QED:** Both ligands have similar and good QED scores (0.605 and 0.619).

**7. DILI:** Both ligands have low DILI risk (29.042 and 30.787), indicating good safety profiles.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.85) has a higher BBB percentile than Ligand A (56.572), but this is not a major factor in this case.

**9. Caco-2 Permeability:** Ligand A (-5.099) shows poor permeability, while Ligand B (-4.843) is slightly better but still low.

**10. Aqueous Solubility:** Ligand A (-1.246) has slightly better solubility than Ligand B (-2.428).

**11. hERG Inhibition:** Ligand A (0.085) shows very low hERG inhibition risk, which is excellent. Ligand B (0.832) is slightly higher, but still relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-9.761) has significantly lower (better) microsomal clearance than Ligand B (22.082), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.544) has a much longer half-life than Ligand A (5.721).

**14. P-gp Efflux:** Ligand A (0.001) shows very low P-gp efflux, while Ligand B (0.118) is slightly higher.

**15. Binding Affinity:** Ligand A (-6.7 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference, and a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in affinity and metabolic stability (low Cl_mic), and has a very favorable hERG profile. While its logP is slightly low and Caco-2 permeability is poor, the strong binding affinity and metabolic stability are crucial for an enzyme inhibitor. Ligand B has a longer half-life, but its significantly worse affinity and higher Cl_mic are major drawbacks.

Output:
0
2025-04-17 13:46:22,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.342 and 357.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.73 and 73.74) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.687 and 1.622) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 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 high QED scores (0.926 and 0.906), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 87.01, which is high. Ligand B has a much lower DILI risk of 39.899, which is good. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (51.493) and Ligand B (61.535) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.457 and -4.843), 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 (-3.832 and -2.202), indicating poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.072) has a very low hERG risk, while Ligand B (0.327) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (26.646) has a higher microsomal clearance than Ligand B (1.458), suggesting lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-19.931) has a negative half-life, which is not physically possible and indicates a problem with the data or the prediction method. Ligand B (-1.095) also has a negative half-life, but is closer to zero. Both are concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.096).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a >1 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite both ligands having issues with predicted permeability and solubility, Ligand B is the more promising candidate. It has a significantly better binding affinity, a much lower DILI risk, and better metabolic stability (lower Cl_mic). The half-life values are concerning for both, but the negative value for Ligand A is particularly problematic. The stronger binding affinity of Ligand B is a key advantage for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:46:22,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.443 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.84) is better than Ligand B (82.43), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.891 and 1.792), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

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

**QED:** Both ligands have high QED scores (0.9 and 0.815), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (43.622 and 48.623), both below the 60 threshold.

**BBB:** Both ligands have high BBB penetration (81.66 and 85.653), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.641 and -4.731), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.712 and -3.064). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.318 and 0.615), which is excellent.

**Microsomal Clearance:** Ligand B (1.348) has significantly lower microsomal clearance than Ligand A (24.586), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (24.382) has a longer in vitro half-life than Ligand A (-9.64), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.04 and 0.101), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.7 kcal/mol). Ligand B is slightly better, but the difference is small.

**Conclusion:**

While both ligands have excellent binding affinity and acceptable safety profiles, Ligand B is the more promising candidate due to its significantly improved metabolic stability (lower Cl_mic and longer t1/2). The poor solubility and Caco-2 permeability are concerns for both, but metabolic stability is a higher priority for kinase inhibitors.

Output:
1
2025-04-17 13:46:22,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.5 and 364.8 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (96.26). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands have acceptable logP values (1.687 and 2.698, respectively), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 5 HBA) in terms of maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.697 and 0.669), indicating good drug-likeness.

**DILI:** Ligand B (68.592) has a higher DILI risk than Ligand A (6.398). This is a significant concern, as lower DILI is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.582) is better than Ligand B (35.595).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.254 and -5.182), which is unusual and suggests poor permeability. However, these values are on the same scale, so this isn't a differentiating factor.

**Aqueous Solubility:** Ligand A (-0.949) is better than Ligand B (-3.655), indicating better solubility. Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.31 and 0.355), which is good.

**Microsomal Clearance:** Ligand A (11.513 mL/min/kg) has significantly lower microsomal clearance than Ligand B (30.699 mL/min/kg). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (136.244 hours) has a much longer half-life than Ligand A (4.748 hours). This is a positive for Ligand B, potentially allowing for less frequent dosing.

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

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a substantially better binding affinity than Ligand A (-6.2 kcal/mol). This difference of 1.8 kcal/mol is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has superior ADME properties (lower DILI, better solubility, better metabolic stability), but Ligand B has a much stronger binding affinity. The difference in binding affinity is substantial. Given that we are targeting an enzyme, potency is paramount. While the longer half-life of Ligand B is a benefit, the higher DILI risk is a concern, but the potency advantage is likely to outweigh this risk, especially in early stages of development where optimization can address the DILI.

Output:
1
2025-04-17 13:46:22,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.491 Da) is slightly higher than Ligand B (341.455 Da), but both are acceptable.

**TPSA:** Ligand A (111.21) is higher than Ligand B (62.3). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.126) is quite low, potentially hindering membrane permeability. Ligand B (2.608) 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 1 HBD and 3 HBA. Both are within acceptable limits, but Ligand B has fewer, which generally favors permeability.

**QED:** Ligand B (0.916) has a much higher QED score than Ligand A (0.506), indicating a more drug-like profile.

**DILI:** Ligand A (26.095) has a lower DILI risk than Ligand B (38.93), which is favorable.

**BBB:** Ligand A (15.432) has very low BBB penetration, while Ligand B (78.015) has good penetration. Since SRC is not a CNS target, this is less critical, but still a point for Ligand B.

**Caco-2 Permeability:** Ligand A (-6.079) has poor Caco-2 permeability, while Ligand B (-4.896) is better, though still not great.

**Aqueous Solubility:** Ligand A (-0.996) has poor solubility, while Ligand B (-2.962) is even worse. This is a significant concern for both, but slightly more so for Ligand B.

**hERG Inhibition:** Ligand A (0.155) has a very low hERG risk, which is excellent. Ligand B (0.294) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-14.797) has very low microsomal clearance, indicating high metabolic stability, which is a major advantage. Ligand B (37.691) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (4.979) has a longer half-life than Ligand B (2.189). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, while Ligand B (0.231) has slightly higher efflux.

**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 many ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a more favorable logP and QED score. However, it suffers from higher microsomal clearance and lower metabolic stability, and worse solubility. Ligand A has excellent metabolic stability and low hERG risk, but its low logP and poor solubility are major concerns. The superior binding affinity of Ligand B is a critical factor for an enzyme inhibitor, and its better permeability profile (lower TPSA, fewer H-bonds) is also beneficial. While the solubility and metabolic stability are concerns for Ligand B, these can potentially be addressed through further optimization. The poor logP of Ligand A is a more fundamental issue that would be harder to fix.

Output:
1
2025-04-17 13:46:22,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 373.875 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.56) is better than Ligand B (38.13) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (1.072) is optimal (1-3), while Ligand B (4.446) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (0 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.705) has a better QED score than Ligand B (0.523), indicating a more drug-like profile.

**DILI:** Ligand A (35.867) has a lower DILI risk than Ligand B (19.698), which is preferable.

**BBB:** Both have acceptable BBB penetration, but Ligand B (87.864) is slightly better than Ligand A (77.2). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.802) has a better Caco-2 permeability than Ligand B (-4.385), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.629) has better aqueous solubility than Ligand B (-5.561). This is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.1 and 0.511 respectively), which is good.

**Microsomal Clearance:** Ligand A (59.023) has lower microsomal clearance than Ligand B (72.131), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.847) has a longer in vitro half-life than Ligand B (-1.625), which is desirable for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.049 and 0.314 respectively).

**Binding Affinity:** Ligand A (-8.6 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 factor.

**Overall:** Considering all factors, Ligand A is the more promising candidate. It has better physicochemical properties (logP, TPSA, solubility, QED), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. Ligand B's higher logP and lower solubility are concerning, despite its slightly better BBB penetration (which isn't a primary concern for SRC).

Output:
0
2025-04-17 13:46:22,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.463 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.23) is slightly higher than Ligand B (61.88). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**3. logP:** Both ligands have good logP values (2.739 and 1.189), 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 6 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both have acceptable QED values (0.632 and 0.599), indicating good drug-likeness.

**7. DILI:** Both have relatively low DILI risk (20.9 and 22.761), well below the concerning threshold of 60.

**8. BBB:** Ligand A (79.682) has better BBB penetration than Ligand B (67.584), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.439) has worse Caco-2 permeability than Ligand B (-5.212).

**10. Aqueous Solubility:** Ligand A (-2.686) has worse aqueous solubility than Ligand B (-1.65). Solubility is important for enzyme inhibitors.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.865 and 0.185), which is excellent.

**12. Microsomal Clearance:** Ligand A (-14.24) has significantly *lower* (better) microsomal clearance than Ligand B (7.73). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (25.036) has a much longer in vitro half-life than Ligand B (-0.797). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.162 and 0.045).

**15. 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.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and better solubility. These factors are crucial for an enzyme inhibitor, ensuring sufficient exposure and duration of action. The slightly lower Caco-2 permeability and TPSA of Ligand A are less concerning given the other advantages.

Output:
1
2025-04-17 13:46:22,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.367 Da) is slightly higher than Ligand B (357.357 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (80.76) is also below the threshold, but higher than A.

**logP:** Ligand A (4.755) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.183) 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, falling within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.636, B: 0.756), indicating drug-like properties.

**DILI:** Ligand A has a higher DILI risk (67.739%) than Ligand B (39.201%). This is a significant concern for A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (78.48%) has a higher BBB penetration than Ligand A (52.617%), but this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, the magnitude is similar.

**Aqueous Solubility:** Ligand A (-6.494) has very poor predicted aqueous solubility, a major drawback. Ligand B (-1.684) has better, though still low, solubility.

**hERG Inhibition:** Ligand A (0.644) has a slightly elevated hERG risk, while Ligand B (0.29) is very low, a significant advantage for B.

**Microsomal Clearance:** Ligand A (93.182) has high microsomal clearance, indicating poor metabolic stability. Ligand B (16.754) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (28.305 hours) has a reasonable half-life. Ligand B (-17.563 hours) has a negative half-life, which is not possible and indicates a problem with the prediction.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.65, B: 0.016), which is favorable.

**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 advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk, poor aqueous solubility, and high microsomal clearance are major concerns. Ligand B, despite a weaker affinity, presents a much more favorable ADME profile with lower DILI and hERG risk, and better metabolic stability. The negative half-life for Ligand B is a red flag, but the other ADME properties are more compelling. The difference in binding affinity (1.2 kcal/mol) might be overcome with further optimization of Ligand B. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 13:46:22,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.291 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is well below the 140 threshold, and even below 90, suggesting good permeability. Ligand B (70.08) is also below 140, but higher than A.

**logP:** Ligand A (3.693) is within the optimal 1-3 range. Ligand B (0.265) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.732 and 0.793), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 91.314, which is high and concerning. Ligand B has a much lower DILI risk of 34.587, which is good.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (85.498) has better BBB penetration than Ligand B (61.535).

**Caco-2 Permeability:** Ligand A (-4.636) and Ligand B (-4.522) have similar, very poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.818) and Ligand B (-1.732) both have poor aqueous solubility. B is better than A.

**hERG Inhibition:** Ligand A (0.751) has a moderate hERG risk, while Ligand B (0.178) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (68.571) has higher clearance than Ligand B (32.703), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (43.791) has a longer half-life than Ligand B (13.537).

**P-gp Efflux:** Ligand A (0.434) has lower P-gp efflux than Ligand B (0.132), which is favorable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity and acceptable metabolic stability (half-life), but suffers from a high DILI risk, poor Caco-2 permeability, and moderate hERG risk. Ligand B has a much better safety profile (low DILI, low hERG) and better metabolic stability, but its binding affinity is weaker and logP is very low, which could affect absorption.

Given that SRC is an enzyme, potency (binding affinity) is paramount. The 1.8 kcal/mol difference in binding affinity is significant. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications in later optimization stages. The poor permeability of both compounds is also a concern, but can be addressed. The low logP of Ligand B is a more difficult issue to resolve.

Output:
1
2025-04-17 13:46:22,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.383 and 356.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.79) is better than Ligand B (69.64), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.114 and 2.588), 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 3. Both are below the 10 threshold.

**QED:** Both ligands have acceptable QED scores (0.834 and 0.591), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.723, which is higher than Ligand B's 12.524. This is a significant concern for Ligand A.

**BBB:** Both have reasonable BBB penetration (47.15 and 64.948), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.738 and -4.681), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.183 and -2.118), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.547 and 0.521).

**Microsomal Clearance:** Ligand B (19.697 mL/min/kg) has significantly lower microsomal clearance than Ligand A (50.99 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (24.753 hours) has a much longer in vitro half-life than Ligand A (-20.58 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.288 and 0.094).

**Binding Affinity:** Ligand B (-8.3 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 significantly better due to its much lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both ligands suffer from poor predicted solubility and permeability, the lower toxicity and improved PK properties of Ligand B make it the more promising candidate. The negative Caco-2 and solubility values for both would require significant medicinal chemistry effort to address.

Output:
1
2025-04-17 13:46:22,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.467 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.2) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (60.25) is excellent, well below 140.

**logP:** Both ligands (2.103 and 2.527) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good.

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

**QED:** Ligand B (0.822) has a significantly better QED score than Ligand A (0.397), indicating a more drug-like profile.

**DILI:** Ligand A (16.673) has a much lower DILI risk than Ligand B (32.571), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (83.831) has a higher BBB penetration than Ligand A (46.879), but this is not a major factor in this case.

**Caco-2 Permeability:** Ligand A (-5.248) has a worse Caco-2 permeability than Ligand B (-4.916), suggesting slightly poorer absorption.

**Aqueous Solubility:** Ligand A (-1.087) has better aqueous solubility than Ligand B (-2.735). This is a positive for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.103) has a much lower hERG inhibition risk than Ligand B (0.242), a critical safety parameter.

**Microsomal Clearance:** Ligand A (8.288) has a significantly lower microsomal clearance than Ligand B (67.887), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.068) has a longer in vitro half-life than Ligand B (-9.123), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.007) has a lower P-gp efflux liability than Ligand B (0.336), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better 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 of Ligand B.

**Overall Assessment:**

Ligand A has a more favorable ADME profile overall, with lower DILI, hERG, Cl_mic, and Pgp efflux, and better solubility and half-life. Ligand B has a slightly better binding affinity and QED, but its higher DILI, hERG, and Cl_mic are concerning. Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and safety (DILI and hERG) are crucial. The affinity difference, while significant, is not enough to overcome the substantial ADME liabilities of Ligand B.

Output:
0
2025-04-17 13:46:22,970 - INFO - Batch 241 complete. Total preferences: 3856
2025-04-17 13:46:22,970 - INFO - Processing batch 242/512...
2025-04-17 13:47:03,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (53.09) is slightly higher than Ligand B (49.41), but both are good.

**logP:** Ligand A (0.568) is a bit low, potentially hindering permeation. Ligand B (2.863) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.521, Ligand B: 0.807), indicating drug-like properties. Ligand B's score is notably higher.

**DILI:** Ligand A (3.8%) has a very favorable DILI risk profile. Ligand B (18.069%) is higher, but still relatively low.

**BBB:** Ligand A (69.407%) shows moderate BBB penetration, while Ligand B (59.946%) is lower. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a problem with the prediction method or the compounds themselves. It's difficult to interpret this data without further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and problematic. Again, difficult to interpret.

**hERG Inhibition:** Ligand A (0.335) has a very low hERG risk, which is excellent. Ligand B (0.596) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (5.608 mL/min/kg) has a lower clearance than Ligand B (36.94 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (6.975 hours) has a longer half-life than Ligand B (-1.822 hours). The negative value for B is concerning and likely an artifact of the prediction. This strongly favors Ligand A.

**P-gp Efflux:** Ligand A (0.026) has very low P-gp efflux, while Ligand B (0.111) is slightly higher. This is a minor advantage for Ligand A.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While a 1.5 kcal/mol difference is usually significant, the ADME profile of Ligand A is much more favorable.

**Overall Assessment:**

Ligand A demonstrates a significantly better ADME profile, particularly regarding metabolic stability (lower Cl_mic, longer t1/2), hERG risk, and P-gp efflux. While Ligand B has slightly better binding affinity and logP, the poor predicted half-life and higher clearance are major drawbacks for an enzyme target. The negative solubility and Caco-2 values for both compounds are concerning and would require experimental validation. However, based on the available data, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 13:47:03,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.248 Da) is slightly higher than Ligand B (339.395 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (72.7 and 70.15) well below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.13 and 3.556) within the optimal range of 1-3. Ligand B is slightly higher, potentially increasing off-target interactions, but not drastically.

**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:** Both ligands have similar QED values (0.666 and 0.642), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 82.745, which is concerningly high (>60). Ligand B has a significantly lower DILI risk of 57.348, still above the ideal <40, but much better than A.

**BBB:** Both have reasonable BBB penetration, but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a major concern.

**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, which is also unusual and suggests poor solubility. This is a potential issue for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.658 and 0.629), which is good.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (95.368), indicating poor metabolic stability. Ligand B has a much lower clearance (69.036), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 42.837 hours, which is good. Ligand B has a negative half-life (-33.472), which is problematic and likely indicates rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.479 and 0.738), which is favorable.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-7.7 kcal/mol) compared to Ligand A (-6.8 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the significantly better binding affinity of Ligand B (-7.7 kcal/mol vs -6.8 kcal/mol) and its much lower DILI risk (57.348 vs 82.745) and better metabolic stability (lower Cl_mic) make it the more promising candidate. While the negative half-life is a concern, it might be addressable through structural modifications. The higher affinity is a critical advantage for an enzyme inhibitor.

Output:
1
2025-04-17 13:47:03,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.455 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.65) is better than Ligand B (105.48), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.392) is slightly better than Ligand B (-0.221), both are a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (6), staying within the preferred range.

**QED:** Both ligands have acceptable QED values (0.753 and 0.63, respectively), indicating good drug-likeness.

**DILI:** Both ligands have similar, low DILI risk (42.846 and 42.536 percentile), which is good.

**BBB:** Ligand A (83.831) has a significantly higher BBB penetration score than Ligand B (47.111). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.986) has a slightly better (less negative) Caco-2 value than Ligand B (-5.474), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.549 and -1.426). This is a significant concern for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.107 and 0.07), which is excellent.

**Microsomal Clearance:** Ligand A (13.922) has a slightly higher microsomal clearance than Ligand B (12.029). Lower is better, so Ligand B is slightly preferable here.

**In vitro Half-Life:** Ligand B (17.108) has a significantly longer half-life than Ligand A (8.854), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.012), which is good.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.4 kcal/mol). This difference of 2.1 kcal/mol is very significant and likely outweighs the slight ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A having slightly better TPSA, logP, and Caco-2 permeability, the significantly stronger binding affinity of Ligand B (-9.5 vs -7.4 kcal/mol) and its longer half-life are decisive. The solubility is a concern for both, but can be addressed with formulation strategies. The slightly higher clearance of Ligand A is less concerning than the affinity difference.

Output:
1
2025-04-17 13:47:03,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (347.415 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.46) is slightly higher than Ligand B (96.25). Both are below the 140 A^2 threshold for good oral absorption, but closer to the 90 A^2 threshold for CNS targets (less relevant here).

**3. logP:** Both ligands have optimal logP values (1.251 and 1.116), 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:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.672 and 0.718), indicating a drug-like profile.

**7. DILI:** Both ligands have low DILI risk (40.054 and 38.736), which is favorable.

**8. BBB:** Ligand B (59.442) has a higher BBB percentile than Ligand A (46.762), but this isn't a primary concern for a non-CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.988 and -4.864). This is unusual and suggests poor permeability. However, these values are on a log scale and need careful interpretation. A negative value indicates permeability less than 1%, which is poor.

**10. Aqueous Solubility:** Both have negative solubility values (-2.165 and -2.706). Again, these are on a log scale and indicate very poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.121 and 0.089), which is excellent.

**12. Microsomal Clearance:** Ligand B (32.423) has significantly lower microsomal clearance than Ligand A (8.921). This suggests better metabolic stability for Ligand B, a key priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand B (1.23 hours) has a slightly longer half-life than Ligand A (6.69 hours). This is a positive attribute for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.057), which is favorable.

**15. 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.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly lower microsomal clearance and slightly longer half-life are crucial advantages for an enzyme inhibitor like an SRC kinase inhibitor. While both have similar potency and safety profiles, metabolic stability is a critical factor for *in vivo* efficacy.

Output:
1
2025-04-17 13:47:03,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.271 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.56) is well below the 140 threshold, while Ligand B (105.9) is still acceptable but higher.

**logP:** Ligand A (3.109) is optimal. Ligand B (0.186) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is also within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.805 and 0.83), indicating good drug-likeness.

**DILI:** Ligand A (53.742) has a lower DILI risk than Ligand B (80.07). Both are below the concerning 60 threshold, but A is preferable.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand B (41.024) is slightly better than Ligand A (37.456).

**Caco-2 Permeability:** Ligand A (-4.595) is better than Ligand B (-5.502), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.636) is better than Ligand B (-1.509). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.732 and 0.101, respectively).

**Microsomal Clearance:** Ligand A (9.478) has a higher microsomal clearance than Ligand B (3.343), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (4.695) has a significantly longer half-life than Ligand A (26.551). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.503 and 0.009).

**Binding Affinity:** Ligand B (-8.4) has a stronger binding affinity than Ligand A (-8.0). While both are excellent, the 0.4 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better solubility and Caco-2 permeability, Ligand B excels in crucial areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), a slightly stronger binding affinity, and a lower DILI risk. The low logP of Ligand B is a concern, but the strong binding affinity might compensate for this. The difference in metabolic stability and half-life is substantial enough to outweigh the minor advantages of Ligand A.

Output:
1
2025-04-17 13:47:03,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.447 and 347.386 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.89) is slightly higher than Ligand B (59.95). Both are below 140, acceptable for oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (1.746) is within the optimal 1-3 range. Ligand B (3.165) is at the higher end, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.68 and 0.806), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (28.577) has a considerably lower DILI risk than Ligand B (44.591). This is a significant advantage for Ligand A.

**BBB:** Ligand A (85.343) has a higher BBB penetration percentile than Ligand B (63.086). While not a primary concern for a kinase inhibitor, it's a slight positive for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.663 and -4.833), which is unusual and suggests poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.07 and -2.893), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.267) has a much lower hERG inhibition liability than Ligand B (0.932). This is a crucial advantage for Ligand A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (38.651 and 38.504 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (12.332 hours) has a longer half-life than Ligand A (6.384 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.011) shows very low P-gp efflux liability, while Ligand B (0.509) is higher. This is a positive for Ligand A.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. It has a significantly lower DILI risk, lower hERG inhibition, and lower P-gp efflux. While Ligand B has a slightly longer half-life, the safety advantages of Ligand A outweigh this benefit, especially for an oncology target where chronic administration is likely.

Output:
0
2025-04-17 13:47:03,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.435 and 362.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.69 and 89.87) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.692) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.052) is closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (3 HBD, 4 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED scores (0.696 and 0.602), indicating reasonable drug-likeness.

**DILI:** Ligand A (31.02) has a slightly higher DILI risk than Ligand B (25.165), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.182) has a higher BBB score than Ligand A (64.831).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.848 and -4.826), which 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 (-0.933 and -1.876), which is also unusual and suggests poor solubility. Ligand B is worse than Ligand A.

**hERG Inhibition:** Ligand A (0.133) shows a lower hERG inhibition liability than Ligand B (0.451), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-10.196) has a significantly lower (better) microsomal clearance than Ligand A (42.585), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (5.724) has a longer in vitro half-life than Ligand A (-2.395), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.037).

**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 small, and A is already very potent.

**Overall Assessment:**

Ligand B is preferable due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. While Ligand A has a lower hERG risk, the metabolic stability of Ligand B is a more critical factor for an enzyme target like SRC kinase. The solubility and permeability issues are similar for both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 13:47:03,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.386 and 348.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (89.19). TPSA <140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have good logP values (2.736 and 2.697), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 7 HBA) regarding the number of hydrogen bond donors and acceptors. Lower values generally improve permeability.

**QED:** Both ligands have acceptable QED values (0.863 and 0.709), indicating good drug-like properties.

**DILI:** Ligand A (51.493) has a slightly higher DILI risk than Ligand B (39.899), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (94.184 and 94.455), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.524 and -5.173). 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 ligands have negative solubility values (-3.093 and -3.733). This is also unusual and suggests very poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.717 and 0.797), which is excellent.

**Microsomal Clearance:** Ligand A (25.547 mL/min/kg) has significantly lower microsomal clearance than Ligand B (76.376 mL/min/kg). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-17.532 hours) has a negative half-life, which is impossible. Ligand B (14.136 hours) has a reasonable half-life. The negative value for A is a major red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.172 and 0.109).

**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.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.7 vs -7.6 kcal/mol) and much lower microsomal clearance (25.547 vs 76.376) are major advantages. The negative half-life for ligand A is a critical issue, but the superior binding could potentially be optimized to overcome this. Ligand B's half-life is reasonable, but its weaker binding and higher clearance make it less attractive.

Output:
0
2025-04-17 13:47:03,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.394 and 350.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.76) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (52.41) is well within the acceptable range.

**3. logP:** Both ligands have logP values within the optimal range (1-3): Ligand A (1.32) and Ligand B (2.732).

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than or equal to 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being less than or equal to 10.

**6. QED:** Ligand A (0.805) has a significantly better QED score than Ligand B (0.685), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.285) has a much lower DILI risk than Ligand B (10.896), which is a significant advantage. Both are below the 40 threshold.

**8. BBB:** Ligand A (57.968) has a lower BBB penetration than Ligand B (82.047). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.356) has a worse Caco-2 permeability than Ligand B (-4.892). Both are negative, indicating poor permeability, but B is slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.295 and -2.399). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.209) has a much lower hERG inhibition risk than Ligand B (0.702), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (15.881) has a considerably lower microsomal clearance than Ligand B (43.713), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.023) has a worse in vitro half-life than Ligand B (12.994).

**14. P-gp Efflux:** Ligand A (0.011) has a much lower P-gp efflux liability than Ligand B (0.447), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.4), but the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A demonstrates significantly better DILI risk, hERG inhibition, metabolic stability (lower Cl_mic), and P-gp efflux. The QED score is also significantly higher for Ligand A. The solubility is poor for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:47:03,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.324 and 367.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.55) is slightly higher than Ligand B (90.73). Both are acceptable for oral absorption (<140), but Ligand B is better.

**logP:** Both ligands have good logP values (1.182 and 1.657), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 0. Both are 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:** Ligand A (0.744) has a higher QED score than Ligand B (0.546), indicating better overall drug-likeness.

**DILI:** Ligand B (71.811) has a significantly higher DILI risk than Ligand A (51.881). This is a major concern.

**BBB:** Ligand A (52.656) has better BBB penetration than Ligand B (29.12), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.735) has slightly better Caco-2 permeability than Ligand B (-4.821).

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.768 and -2.757). This could present formulation challenges.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.401 and 0.394), which is relatively low and acceptable.

**Microsomal Clearance:** Ligand A (7.567) has significantly lower microsomal clearance than Ligand B (57.535), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-35.032) has a longer in vitro half-life than Ligand B (-27.877). This is another advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.14).

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Conclusion:**

Despite similar binding affinities and acceptable physicochemical properties, Ligand A is the more promising candidate. Its significantly lower DILI risk and improved metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly lower QED and TPSA. Solubility is a concern for both, but can be addressed through formulation strategies. The lower DILI risk is particularly important for oncology drugs, where chronic administration is often required.

Output:
0
2025-04-17 13:47:03,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (335.403 Da) is slightly better, being closer to the ideal range.

**TPSA:** Ligand A (59.32) is significantly better than Ligand B (134.46). Lower TPSA generally correlates with better cell permeability. Ligand B's TPSA is quite high, potentially hindering absorption.

**logP:** Ligand A (4.146) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.499) is too low, which could impede membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer hydrogen bonds generally improve permeability.

**QED:** Ligand A (0.537) is better than Ligand B (0.393), indicating a more drug-like profile.

**DILI:** Both ligands have concerning DILI risk (Ligand A: 60.101, Ligand B: 65.491). Ligand A is slightly better, but both are above the 60 percentile, indicating a potential liver toxicity risk.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (55.254) is better than Ligand B (43.815).

**Caco-2 Permeability:** Ligand A (-4.431) is better than Ligand B (-5.323), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-6.369) is better than Ligand B (-3.185), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.851) is much better than Ligand B (0.073). Lower hERG inhibition is critical to avoid cardiotoxicity. Ligand B poses a significant hERG risk.

**Microsomal Clearance:** Ligand A (115.544) is worse than Ligand B (-25.201). Lower clearance indicates better metabolic stability, making Ligand B preferable.

**In vitro Half-Life:** Ligand A (-17.357) is worse than Ligand B (6.734).  A longer half-life is generally desirable, favoring Ligand B.

**P-gp Efflux:** Ligand A (0.609) is better than Ligand B (0.035). Lower P-gp efflux is preferable for better bioavailability.

**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 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 a slightly better solubility profile. However, it suffers from a high TPSA, low logP, and a concerning hERG risk. Ligand A has a better overall ADME profile (TPSA, logP, solubility, hERG, P-gp), but its binding affinity is weaker.

Given the enzyme-specific priorities, the strong binding affinity of Ligand B is a critical factor. While the hERG risk is concerning, it might be mitigated through structural modifications during lead optimization. The metabolic stability is also a significant advantage. The lower logP and high TPSA are more readily addressed through chemical modifications than significantly improving the binding affinity of Ligand A.

Output:
1
2025-04-17 13:47:03,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing enzyme characteristics.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.769 Da) is slightly higher than Ligand B (356.495 Da), but both are acceptable.

**2. TPSA:** Ligand A (63.24) is well below the 140 threshold for oral absorption. Ligand B (70.67) is also acceptable.

**3. logP:** Both ligands have logP values within the optimal range (1-3): Ligand A (4.408) is a bit high, potentially leading to solubility issues, while Ligand B (3.469) is better.

**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 (Ligand A: 0.758, Ligand B: 0.832), indicating drug-like properties.

**7. DILI:** Ligand A (88.484) has a significantly higher DILI risk than Ligand B (47.77). This is a major concern.

**8. BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (61.38) has a higher BBB score than Ligand A (36.448).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.827) is slightly better than Ligand B (-5.22).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.192) is slightly better than Ligand B (-4.057).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.671, Ligand B: 0.539).

**12. Microsomal Clearance:** Ligand A (12.715) has a lower (better) microsomal clearance than Ligand B (33.802), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (78.462) has a significantly longer half-life than Ligand B (-14.953). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.595, Ligand B: 0.21).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a 0.6 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a better binding affinity and lower DILI risk, Ligand A possesses superior metabolic stability (lower Cl_mic, longer t1/2). However, the high DILI risk associated with Ligand A is a major red flag. The slightly better affinity of Ligand B, combined with the much lower DILI risk, outweighs the better metabolic stability of Ligand A. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 13:47:03,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.386 and 357.845 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.3) is well below the 140 threshold, and even below 90, suggesting good permeability. Ligand B (76.73) is still under 140, but higher than A.

**logP:** Both ligands (2.505 and 3.306) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are under the 10 threshold, but B is higher.

**QED:** Ligand A (0.933) has a much better QED score than Ligand B (0.699), indicating a more drug-like profile.

**DILI:** Ligand B (70.492) has a higher DILI risk than Ligand A (60.644), though both are above the preferred <40.

**BBB:** Ligand A (93.68) has significantly better BBB penetration potential than Ligand B (57.852). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.75) has better Caco-2 permeability than Ligand B (-5.592).

**Aqueous Solubility:** Ligand A (-3.564) has better aqueous solubility than Ligand B (-3.198).

**hERG Inhibition:** Ligand A (0.635) shows a lower hERG inhibition liability than Ligand B (0.261), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (4.919) has a significantly lower microsomal clearance than Ligand B (35.967), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.799) has a much longer in vitro half-life than Ligand B (35.941).

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux liability than Ligand B (0.138).

**Binding Affinity:** Ligand B (-7.3) 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.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, **Ligand A is the more promising drug candidate**. While Ligand B has slightly better binding affinity, Ligand A excels in almost all other critical ADMET properties: better QED, lower DILI, better solubility, significantly lower hERG risk, much better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. These factors are crucial for developing a viable drug, and the small difference in binding affinity is unlikely to outweigh these substantial advantages.

Output:
0
2025-04-17 13:47:03,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.4 and 367.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.46) is better than Ligand B (100.73), both are acceptable but closer to the upper limit for good oral absorption.

**logP:** Ligand A (1.958) is optimal, while Ligand B (0.104) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both are acceptable.

**QED:** Both ligands have similar QED scores (0.713 and 0.769), indicating good drug-likeness.

**DILI:** Ligand A (75.03) has a higher DILI risk than Ligand B (62.20), but both are within an acceptable range.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (40.09) is lower than Ligand B (23.19).

**Caco-2:** Ligand A (-4.834) is better than Ligand B (-5.346), indicating better intestinal absorption.

**Solubility:** Ligand A (-3.222) is better than Ligand B (-2.795), which is crucial for bioavailability.

**hERG:** Both ligands show very low hERG inhibition risk (0.093 and 0.165).

**Microsomal Clearance:** Ligand B (-20.93) has significantly lower (better) microsomal clearance than Ligand A (92.361), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (19.515) has a much longer in vitro half-life than Ligand A (-21.69), further supporting its improved metabolic stability.

**P-gp efflux:** Both ligands have low P-gp efflux liability (0.096 and 0.015).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.7 and -8.7 kcal/mol). The difference of 1 kcal/mol is not enough to overcome the other ADME differences.

**Conclusion:**

While both ligands exhibit good binding affinity, Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic, longer t1/2) and solubility. The lower logP of Ligand B is a concern, but the strong binding affinity and other favorable properties likely outweigh this drawback. Ligand A's high microsomal clearance is a significant negative.

Output:
1
2025-04-17 13:47:03,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.361 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.56) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (52.65) is well within the acceptable range.

**logP:** Ligand A (4.035) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.624) is well within the optimal 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:** Both ligands have good QED scores (0.73 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 69.252, which is concerning (high risk >60). Ligand B has a significantly lower DILI risk of 5.273, which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (71.888) than Ligand A (32.92), but this is less critical here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. Again, difficult to interpret without knowing the scale.

**hERG:** Ligand A has a hERG risk of 0.235, which is low and favorable. Ligand B has a slightly higher hERG risk of 0.529, still acceptable.

**Microsomal Clearance:** Ligand A has a Cl_mic of 9.999, which is relatively high, suggesting faster metabolism. Ligand B has a negative Cl_mic (-7.854), indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 45.64 hours, which is good. Ligand B has a very short t1/2 of 5.364 hours, which is a significant drawback.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.277, which is acceptable. Ligand B has a very low Pgp efflux liability of 0.017, which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). The difference of 0.4 kcal/mol is substantial enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its in vitro half-life is a concern, its significantly lower DILI risk, excellent metabolic stability (negative Cl_mic), strong binding affinity, and low P-gp efflux liability outweigh the drawbacks. Ligand A's high DILI risk is a major red flag. The unusual negative values for Caco-2 and solubility for both compounds need to be investigated, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 13:47:03,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.447 and 349.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (1.739 and 2.82), 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:** Ligand A (0.869) has a better QED score than Ligand B (0.734), indicating a more drug-like profile.

**DILI:** Ligand B (30.361) has a significantly lower DILI risk than Ligand A (54.556). This is a major advantage for Ligand B.

**BBB:** Ligand B (91.198) has a higher BBB percentile than Ligand A (73.943), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.393) has worse Caco-2 permeability than Ligand B (-4.294).

**Aqueous Solubility:** Ligand A (-3.395) has worse aqueous solubility than Ligand B (-2.948).

**hERG:** Ligand A (0.157) has a slightly lower hERG risk than Ligand B (0.326), which is favorable.

**Microsomal Clearance:** Ligand A (19.106) has a significantly lower microsomal clearance than Ligand B (83.283), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-11.874) has a much longer in vitro half-life than Ligand B (6.594), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux than Ligand B (0.102).

**Binding Affinity:** Ligand B (-8.7) has a significantly stronger binding affinity than Ligand A (-7.1). This is a substantial advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a superior binding affinity and lower DILI risk. However, Ligand A exhibits much better metabolic stability (lower Cl_mic and longer t1/2) and slightly better hERG risk. The difference in binding affinity is significant, and for an enzyme target like SRC kinase, potency is paramount. While metabolic stability is important, a strong binder like Ligand B is more likely to be effective even with faster clearance, especially if formulation strategies can mitigate this. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 13:47:03,501 - INFO - Batch 242 complete. Total preferences: 3872
2025-04-17 13:47:03,501 - INFO - Processing batch 243/512...
2025-04-17 13:47:41,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.391 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.36) is slightly above the preferred <140, but acceptable. Ligand B (87.46) is excellent, well below 140.

**logP:** Ligand A (0.217) is quite low, potentially hindering permeability. Ligand B (0.57) is also low, but better than A. 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 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.724 and 0.796, respectively), indicating drug-like properties.

**DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (53.936), though both are moderately risky.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (56.378) is slightly better than Ligand B (27.84).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.21 and -5.268), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.17 and -2.367), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG:** Ligand A (0.04) has a slightly lower hERG risk than Ligand B (0.114), which is favorable.

**Microsomal Clearance:** Ligand A (-14.955) has a much lower (better) microsomal clearance than Ligand B (19.428), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (30.961 hours) has a significantly longer half-life than Ligand B (4.097 hours), which is a substantial advantage.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.004 and 0.044).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite the poor permeability and solubility of both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.5 vs -8.0 kcal/mol) is a critical advantage for an enzyme inhibitor. While Ligand A has better metabolic stability and half-life, the potency difference is more important in this case. The slightly lower DILI and hERG risks of Ligand B are also beneficial. The poor solubility and permeability would need to be addressed through formulation or further chemical modifications, but the strong binding affinity provides a solid foundation for optimization.

Output:
1
2025-04-17 13:47:41,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 362.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (42.43). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.04 and 4.03), within the optimal 1-3 range, though Ligand B is slightly higher.

**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 and <=10 HBA).

**QED:** Both have good QED scores (0.665 and 0.735), indicating drug-like properties.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (20.59), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand B (89.96) has a higher BBB penetration than Ligand A (70.42), but BBB is less critical for a non-CNS target like SRC kinase.

**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 have negative solubility values, which is also unusual. Again, the values are close, and this isn't a major differentiator.

**hERG Inhibition:** Ligand A (0.367) has a lower hERG risk than Ligand B (0.585). This is a significant advantage.

**Microsomal Clearance:** Ligand A (52.07) has a lower microsomal clearance than Ligand B (93.95), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (5.734) has a slightly longer half-life than Ligand A (4.763), but the difference isn't substantial.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.613), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.0). While both are excellent, the 0.6 kcal/mol difference is meaningful.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a significantly lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. While Ligand B has better BBB penetration and half-life, these are less critical for a non-CNS enzyme target like SRC kinase. The combination of improved safety (DILI, hERG) and metabolic stability makes Ligand A the preferred choice.

Output:
1
2025-04-17 13:47:41,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.539 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is well below 140, and Ligand B (58.64) is also below 140. Both are acceptable for oral absorption.

**logP:** Ligand A (4.478) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.348) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.858) has a very good QED score, indicating high drug-likeness. Ligand B (0.541) is acceptable, but less ideal.

**DILI:** Ligand A (39.201) has a low DILI risk. Ligand B (10.896) has a very low DILI risk, which is excellent.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (70.609) is better than Ligand A (90.733). This is less important for a kinase inhibitor unless CNS penetration is specifically desired.

**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.

**hERG Inhibition:** Ligand A (0.925) has a slightly higher hERG risk than Ligand B (0.403), but both are relatively low.

**Microsomal Clearance:** Ligand A (40.292) has a moderate clearance. Ligand B (36.514) has a lower clearance, suggesting better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand A (65.999) has a reasonable half-life. Ligand B (-15.402) has a negative half-life, which is impossible and indicates a significant issue with the data or the compound's stability.

**P-gp Efflux:** Ligand A (0.406) has low P-gp efflux. Ligand B (0.063) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-6.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand B appears to be the better candidate despite the negative Caco-2 and solubility values. Its lower logP, lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux are all advantages. The negative half-life for Ligand B is a critical issue that needs investigation, but assuming it's a data error, the other properties make it preferable. Ligand A's higher logP and slightly lower metabolic stability are less desirable. The small difference in binding affinity is unlikely to outweigh the ADME advantages of Ligand B. The poor solubility and permeability of both compounds are significant hurdles that would need to be addressed through formulation or structural modification.

Output:
1
2025-04-17 13:47:41,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.483 Da and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is slightly higher than Ligand B (58.64), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.694 and 2.241, respectively), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have high QED scores (0.808 and 0.849), indicating good drug-like properties.

**DILI:** Ligand A (47.926) has a slightly higher DILI risk than Ligand B (35.595), but both are below the concerning threshold of 60.

**BBB:** Ligand A (55.332) has a lower BBB penetration than Ligand B (71.384). This is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.005 and -4.876). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development.

**Aqueous Solubility:** Ligand A (-1.713) has slightly better solubility than Ligand B (-3.401), although both are quite poor. This is a potential concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.121 and 0.261). This is excellent.

**Microsomal Clearance:** Ligand A (32.663) has lower microsomal clearance than Ligand B (38.762), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.548 hours) has a significantly longer half-life than Ligand B (6.835 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.055 and 0.155).

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand A is the better candidate. While both have some issues with solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-9.1 vs -7.5 kcal/mol) and longer half-life (18.5 vs 6.8 hours) outweigh its slightly higher DILI risk and lower BBB penetration. The improved metabolic stability (lower Cl_mic) is also a significant benefit for an enzyme target. The difference in binding affinity is substantial enough to potentially overcome the solubility issues through formulation strategies.

Output:
1
2025-04-17 13:47:41,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 352.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is better than Ligand B (100.6). Both are under 140, but lower TPSA generally favors absorption.

**logP:** Ligand A (2.893) is optimal (1-3). Ligand B (0.237) is quite low, potentially hindering permeability.

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

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**QED:** Both ligands have similar good QED values (0.635 and 0.673, both >=0.5).

**DILI:** Both ligands have acceptable DILI risk (56.65 and 54.556, both <60).

**BBB:** Ligand A (65.529) is better than Ligand B (30.361), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative values (-5.012 and -5.211), which is unusual and hard to interpret without knowing the scale. However, the values are similar.

**Solubility:** Ligand A (-2.93) is better than Ligand B (-1.25). Higher solubility is preferred.

**hERG:** Ligand A (0.104) has a significantly lower hERG risk than Ligand B (0.253). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (74.608) has higher clearance than Ligand B (13.472). Lower clearance is preferred for metabolic stability. Ligand B is much better here.

**In vitro Half-Life:** Ligand A (-39.813) has a negative half-life, which is impossible. This is a major red flag. Ligand B (34.235) is acceptable.

**P-gp Efflux:** Ligand A (0.325) is better than Ligand B (0.031). Lower efflux 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, potentially outweighing some ADME concerns.

**Conclusion:**

Despite Ligand B's lower logP and higher P-gp efflux, its significantly superior binding affinity (-8.6 vs -7.3 kcal/mol) and much better metabolic stability (lower Cl_mic, positive t1/2) are critical for an enzyme target like SRC kinase. Ligand A's negative in vitro half-life is a dealbreaker. While Ligand A has better hERG, the affinity and metabolic stability of Ligand B are more important.

Output:
1
2025-04-17 13:47:41,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.27 Da) is slightly better positioned than Ligand B (428.766 Da).

**TPSA:** Ligand A (63.41) is better than Ligand B (76.1), falling well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.595) is optimal, while Ligand B (1.256) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands are acceptable (Ligand A: 2, Ligand B: 1), well below the 5 limit.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (7), both are below the 10 limit.

**QED:** Both ligands have reasonable QED scores, but Ligand A (0.824) is significantly better than Ligand B (0.669), indicating a more drug-like profile.

**DILI:** Ligand A (61.691) has a higher DILI risk than Ligand B (33.773), which is a concern. However, the difference isn't massive.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.805) is better than Ligand B (47.848).

**Caco-2 Permeability:** Ligand A (-4.878) is better than Ligand B (-5.648), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.225) is better than Ligand B (-1.693), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.876) is better than Ligand B (0.586), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-9.508) has a *much* better (lower) microsomal clearance than Ligand A (13.967), suggesting significantly improved metabolic stability.

**In vitro Half-Life:** Ligand B (-2.688) has a better (longer) half-life than Ligand A (57.687).

**P-gp Efflux:** Ligand A (0.291) is better than Ligand B (0.016), indicating lower efflux.

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

**Overall Assessment:**

While Ligand A has better solubility and a higher QED score, Ligand B's significantly superior binding affinity (-9.2 vs 0 kcal/mol) and dramatically improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the drawbacks of its slightly lower solubility and higher TPSA. The lower DILI risk for Ligand B is also a plus. The binding affinity difference is large enough to overcome the other minor issues.

Output:
1
2025-04-17 13:47:41,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.407 and 370.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.78) is better than Ligand B (137.76), both being below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.586) is within the optimal 1-3 range. Ligand B (-0.685) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is preferable to Ligand B (HBD=3, HBA=7) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand B (0.523) has a better QED score than Ligand A (0.22), indicating a more drug-like profile.

**DILI:** Ligand A (47.693) has a much lower DILI risk than Ligand B (81), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (38.271) is lower than Ligand B (17.604).

**Caco-2 Permeability:** Both are negative (-5.22 and -5.754), which is unusual. It suggests very poor permeability. This is a serious concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.173 and -2.788), which is highly problematic. Poor solubility will severely limit bioavailability.

**hERG Inhibition:** Ligand A (0.088) has a much lower hERG risk than Ligand B (0.237), a crucial factor for safety.

**Microsomal Clearance:** Ligand A (26.735) has a higher microsomal clearance than Ligand B (21.619), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-11.98) has a significantly longer in vitro half-life than Ligand A (-3.355), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.017).

**Binding Affinity:** Ligand B (-10.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a very large difference and a major driver for selection.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, the significantly stronger binding affinity of Ligand B (-10.8 vs -6.6 kcal/mol) and its better in vitro half-life outweigh the other drawbacks. The lower DILI risk and hERG inhibition of Ligand A are attractive, but the potency difference is too large to ignore. The solubility and permeability issues would need to be addressed through formulation or further chemical modification for either compound.

Output:
1
2025-04-17 13:47:41,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.55 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (75.35) is still under 140, but less optimal than A.

**logP:** Both ligands have good logP values (3.35 and 2.328), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (0 for both). Ligand A (3 HBA) is better than Ligand B (7 HBA).

**QED:** Both ligands have good QED scores (0.656 and 0.778), indicating drug-likeness.

**DILI:** Ligand A (25.359) has a significantly lower DILI risk than Ligand B (59.054), which is a substantial advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (91.314) is better than Ligand B (68.554).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.68) is slightly better than Ligand B (-4.547).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.436) is slightly better than Ligand B (-3.335).

**hERG:** Ligand A (0.671) has a lower hERG risk than Ligand B (0.248), which is favorable.

**Microsomal Clearance:** Ligand A (67.752) has a higher microsomal clearance than Ligand B (39.805), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-5.348) has a longer in vitro half-life than Ligand A (-9.226), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.315) has lower P-gp efflux than Ligand B (0.26), which is favorable.

**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:**

Ligand A has a much stronger binding affinity, lower DILI risk, and lower hERG risk. While it has higher microsomal clearance and lower half-life, the significantly better binding affinity (-7.8 vs 0.0) and safety profile make it the more promising candidate. The slightly better TPSA and logP also contribute to its favorability. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:47:41,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.471 and 352.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.84) is significantly better than Ligand B (110.26).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.787 and 1.35), 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=6). Lower counts are generally better for permeability.

**QED:** Both ligands have reasonable QED scores (0.847 and 0.742), indicating good drug-likeness.

**DILI:** Ligand A (37.728) has a much lower DILI risk than Ligand B (57.154). This is a significant advantage for A.

**BBB:** Both ligands have good BBB penetration (73.284 and 70.764), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-4.791 and -4.966).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. Again, the values are similar (-2.596 and -3.047).

**hERG:** Ligand A (0.068) has a much lower hERG risk than Ligand B (0.248). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (31.101) has significantly lower microsomal clearance than Ligand B (58.044), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.151) has a more negative in vitro half-life, which is better (longer half-life). Ligand B (8.657) is positive, indicating a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.074).

**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 is clearly superior. While both have similar binding affinities, Ligand A excels in crucial ADME properties: lower DILI risk, lower hERG risk, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. It also has better TPSA and H-bond characteristics. The solubility and Caco-2 values are concerning for both, but the other advantages of A outweigh these drawbacks.

Output:
0
2025-04-17 13:47:41,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.293 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (80.34) is well below the 140 threshold for oral absorption and is favorable. Ligand B (111.95) is still acceptable but less optimal.

**logP:** Ligand A (2.552) is within the optimal range (1-3). Ligand B (0.942) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2 respectively) and HBA (5 each) counts.

**QED:** Both ligands have similar and good QED scores (0.788 and 0.778).

**DILI:** Ligand A (85.072) has a higher DILI risk than Ligand B (64.599). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (74.874) is slightly better than Ligand B (60.644).

**Caco-2 Permeability:** Ligand A (-4.414) has better Caco-2 permeability than Ligand B (-5.025).

**Aqueous Solubility:** Ligand A (-4.116) has slightly better solubility than Ligand B (-3.709).

**hERG:** Both ligands have low hERG inhibition risk (0.533 and 0.272).

**Microsomal Clearance:** Ligand B (2.585) has significantly lower microsomal clearance than Ligand A (26.833), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (0.759) has a longer in vitro half-life than Ligand A (-14.581), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.17 and 0.038).

**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:**

Ligand B is the more promising candidate. While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B excels in metabolic stability (lower Cl_mic and longer t1/2), has a lower DILI risk, and a slightly better binding affinity. The lower logP of Ligand A is a concern for permeability. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity (DILI) are crucial, making Ligand B the preferred choice.

Output:
1
2025-04-17 13:47:41,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.27 Da) is slightly higher than Ligand B (346.383 Da), but both are acceptable.

**TPSA:** Ligand A (61.19) is significantly better than Ligand B (104.73). Lower TPSA generally indicates better permeability, which is important for oral absorption.

**logP:** Ligand A (3.068) is optimal, while Ligand B (1.194) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (3 HBD, 5 HBA). Lower HBDs are generally preferred.

**QED:** Both ligands have good QED scores (Ligand A: 0.465, Ligand B: 0.671), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (68.205) has a higher DILI risk than Ligand B (54.556), but both are acceptable (below 60).

**BBB:** Both have high BBB penetration, but Ligand A (96.2) is better than Ligand B (68.592). However, BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.452) shows better Caco-2 permeability than Ligand B (-4.948), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.147) is better than Ligand B (-2.961), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.706) has a slightly higher hERG risk than Ligand B (0.281), which is a concern.

**Microsomal Clearance:** Ligand B (35.717) has significantly lower microsomal clearance than Ligand A (86.382), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-6.364) has a longer in vitro half-life than Ligand A (7.255), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.554) has lower P-gp efflux than Ligand B (0.199), which is favorable.

**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:**

Ligand B is the more promising candidate. While Ligand A has better TPSA, Caco-2 permeability, solubility, and P-gp efflux, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. For a kinase inhibitor, metabolic stability is paramount. The slightly lower logP of Ligand B is a minor drawback that could be addressed through further optimization, while the higher hERG risk of Ligand A is a more significant concern.



Output:
1
2025-04-17 13:47:41,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.793 and 345.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (99.87) is still under 140, but less optimal than A.

**logP:** Ligand A (3.723) is at the higher end of the optimal 1-3 range, while Ligand B (0.358) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is within the ideal ranges. Ligand B (1 HBD, 9 HBA) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.543 and 0.695, respectively), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.82 percentile), which is a significant concern. Ligand B has a much lower DILI risk (55.176 percentile), which is preferable.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (75.107) has a higher BBB score than A (55.487), but this is less critical here.

**Caco-2 Permeability:** Ligand A (-4.864) has poor Caco-2 permeability, while Ligand B (-5.675) is also poor.

**Aqueous Solubility:** Ligand A (-5.877) has poor solubility, while Ligand B (-1.668) has slightly better solubility.

**hERG Inhibition:** Ligand A (0.279) has a slightly higher hERG risk than Ligand B (0.099), but both are relatively low.

**Microsomal Clearance:** Ligand A (34.48 mL/min/kg) has a higher clearance than Ligand B (13.324 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (101.147 hours) has a significantly longer half-life than Ligand B (12.404 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.289) has lower P-gp efflux than Ligand B (0.072), suggesting better bioavailability.

**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 difference and a strong driver for selecting Ligand B.

**Overall Assessment:**

Ligand B is the better candidate despite its lower half-life. The significantly improved binding affinity (-7.5 vs -9.0 kcal/mol) outweighs the shorter half-life, especially for a kinase inhibitor where potency is paramount. Furthermore, Ligand B has a much lower DILI risk, better solubility, and lower logP, all of which are favorable. Ligand A's high DILI risk and poor Caco-2 permeability are significant drawbacks.

Output:
1
2025-04-17 13:47:41,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (340.427 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.19) is slightly higher than Ligand B (67.87), but both are below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have optimal logP values (1.718 and 1.501), falling within the 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, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.828) has a slightly better QED score than Ligand B (0.737), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand A (53.044) has a higher DILI risk than Ligand B (21.636). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (76.735) is slightly better than Ligand B (65.801). However, BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.064 and -4.662). This is unusual and suggests poor permeability. However, negative values can sometimes be artifacts of the prediction method.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.331 and -1.925), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.286 and 0.129), which is excellent.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (43.535 and 45.253 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.288 hours) has a significantly longer in vitro half-life than Ligand A (-1.416 hours). This is a major advantage for Ligand B, as it suggests less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.121 and 0.03).

**15. 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 small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B has a significantly better DILI score and a much longer in vitro half-life. The slightly better binding affinity also contributes to its favorability. The DILI risk associated with Ligand A is a substantial concern, outweighing its slightly better QED and BBB values.

Output:
1
2025-04-17 13:47:41,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.459 and 382.291 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is slightly higher than Ligand B (62.61), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.641 and 3.066), 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 (0.609 and 0.781), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (41.877 and 47.421, both <60).

**BBB:** Ligand A (70.88) has a slightly better BBB penetration percentile than Ligand B (66.499), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.08) has a worse Caco-2 permeability than Ligand B (-4.9).

**Aqueous Solubility:** Ligand A (-2.149) has slightly better aqueous solubility than Ligand B (-4.175). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.342 and 0.365).

**Microsomal Clearance:** Ligand B (27.474 mL/min/kg) has significantly lower microsomal clearance than Ligand A (37.09 mL/min/kg), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (33.252 hours) has a much longer in vitro half-life than Ligand A (-13.804 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.154 and 0.095).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has slightly better solubility and BBB penetration, Ligand B boasts a significantly stronger binding affinity, lower microsomal clearance, and a much longer half-life. These latter properties are crucial for an enzyme inhibitor, suggesting better efficacy and potentially improved pharmacokinetics. The difference in binding affinity is the most decisive factor.

Output:
1
2025-04-17 13:47:41,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.495 and 351.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.3) is significantly better than Ligand B (115.3). A TPSA under 140 is good for oral absorption, and A is much closer to the ideal for CNS penetration (under 90) even though that's not a primary concern here.

**logP:** Ligand A (2.35) is optimal, while Ligand B (0.908) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is preferable to Ligand B (4 HBD, 7 HBA). While both are within acceptable limits, fewer HBDs generally improve membrane permeability.

**QED:** Ligand A (0.725) has a better QED score than Ligand B (0.489), indicating a more drug-like profile.

**DILI:** Ligand A (23.187) has a much lower DILI risk than Ligand B (47.654), a significant advantage.

**BBB:** Both ligands have similar BBB penetration (67.662 and 67.352), which isn't a major factor for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.188 and -5.194). This is unusual and suggests poor permeability *in vitro*. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.081 and -2.592). This is also unusual and suggests poor solubility *in vitro*. Again, the values are very similar.

**hERG:** Both ligands have low hERG risk (0.548 and 0.559).

**Microsomal Clearance:** Ligand A (19.466 mL/min/kg) has significantly lower microsomal clearance than Ligand B (31.99 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.097 hours) has a longer half-life than Ligand B (20.803 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.509 and 0.011).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.2 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Ligand A is the superior candidate. It has a better QED score, lower DILI risk, lower microsomal clearance (better metabolic stability), and, crucially, significantly stronger binding affinity. While both ligands have issues with *in vitro* permeability and solubility, the substantial improvement in binding affinity and the favorable ADME properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 13:47:41,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.467 and 373.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.03) is better than Ligand B (76.29). Lower TPSA generally correlates with better cell permeability, important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have good logP values (2.962 and 2.776), 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 (<=10).

**QED:** Both ligands have good QED scores (0.653 and 0.715), indicating good drug-like properties.

**DILI:** Ligand A (55.525) has a lower DILI risk than Ligand B (81.466). This is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (88.29) has a better BBB percentile than Ligand B (74.796).

**Caco-2 Permeability:** Ligand A (-4.602) is better than Ligand B (-4.881), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.316) is better than Ligand B (-3.131), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.699 and 0.748), and are relatively low risk.

**Microsomal Clearance:** Ligand A (55.474) has higher microsomal clearance than Ligand B (13.645). This means Ligand B is more metabolically stable, a key advantage for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-10.502) has a significantly longer in vitro half-life than Ligand A (18.535). This is a major positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.455 and 0.324).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 2.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much longer half-life, which are highly desirable for a kinase inhibitor. While Ligand A has better solubility and lower DILI risk, the potency and metabolic stability advantages of Ligand B are more critical in this case. The higher DILI risk of Ligand B is a concern, but could be mitigated with further structural modifications.

Output:
1
2025-04-17 13:47:41,799 - INFO - Batch 243 complete. Total preferences: 3888
2025-04-17 13:47:41,799 - INFO - Processing batch 244/512...
2025-04-17 13:48:29,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.399 Da) is slightly lower, which could be beneficial for permeability. Ligand B (362.539 Da) is also good.

**TPSA:** Ligand A (93.73) is better than Ligand B (46.34) as it is closer to the 140 threshold.

**logP:** Ligand A (0.491) is a bit low, potentially hindering permeability. Ligand B (4.108) is high, potentially causing solubility issues and off-target effects.

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

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

**QED:** Both ligands have good QED scores (A: 0.527, B: 0.653), indicating generally drug-like properties.

**DILI:** Ligand A (49.632) has a slightly higher DILI risk than Ligand B (27.453), but both are below the concerning threshold of 60.

**BBB:** Ligand A (29.779) has low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (85.537) has high BBB penetration, which is irrelevant here and could even be a negative if off-target effects in the CNS are a concern.

**Caco-2:** Both have negative Caco-2 values which is unusual. Assuming these are percentile scores, Ligand A (-5.259) is worse than Ligand B (-4.999).

**Solubility:** Ligand A (-1.579) has slightly better solubility than Ligand B (-4.417).

**hERG:** Ligand A (0.137) has a much lower hERG risk than Ligand B (0.531), which is a significant advantage.

**Cl_mic:** Ligand A (17.94) has much lower microsomal clearance than Ligand B (119.565), indicating better metabolic stability. This is a key advantage for an enzyme target.

**t1/2:** Ligand A (-4.298) has a negative half-life, which is unusual. Ligand B (10.26) has a reasonable half-life.

**Pgp:** Ligand A (0.037) has lower P-gp efflux than Ligand B (0.707), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.5) 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 is the better candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties: lower hERG risk, significantly lower microsomal clearance (better metabolic stability), lower P-gp efflux, and better solubility. The slightly lower logP of Ligand A is a minor concern that could potentially be addressed through further optimization, but the ADME advantages are more critical for an enzyme inhibitor.

Output:
0
2025-04-17 13:48:29,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.519 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is significantly better than Ligand B (82.11). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands (3.23 and 2.985) 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, while Ligand B has 5. Both are under the limit of 10, but A is better.

**QED:** Both ligands have good QED scores (0.831 and 0.857), indicating good drug-like properties.

**DILI:** Ligand A (8.104) has a much lower DILI risk than Ligand B (28.306). This is a significant advantage for Ligand A.

**BBB:** Ligand A (82.668) has a better BBB penetration score than Ligand B (48.042), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.631) has a worse Caco-2 permeability than Ligand B (-5.164).

**Aqueous Solubility:** Ligand A (-1.745) has a better aqueous solubility than Ligand B (-3.209). This is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.512 and 0.675), which is excellent.

**Microsomal Clearance:** Ligand A (16.199) has a lower microsomal clearance than Ligand B (18.161), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (50.895) has a significantly longer in vitro half-life than Ligand B (-21.01). This is a major advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.036) has a much lower P-gp efflux liability than Ligand B (0.302), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A is superior to Ligand B. It has a lower DILI risk, better solubility, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a significantly stronger binding affinity. While Ligand B has slightly better Caco-2 permeability, the other advantages of Ligand A are more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:48:29,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 333.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (49.94), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.243) is optimal (1-3), while Ligand B (4.786) is slightly high, potentially leading to solubility issues and off-target effects.

**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 within the acceptable limit of <=10.

**QED:** Ligand A (0.741) has a better QED score than Ligand B (0.654), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 57.193, Ligand B: 54.556), below the concerning threshold of 60.

**BBB:** Ligand A (71.656) has a better BBB penetration percentile than Ligand B (57.852), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.705) is slightly better than Ligand B (-4.926).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.017) is slightly better than Ligand B (-4.984).

**hERG Inhibition:** Ligand A (0.433) has a significantly lower hERG inhibition risk than Ligand B (0.935), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (35.93) has a lower microsomal clearance than Ligand B (47.052), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.436) has a better in vitro half-life than Ligand B (-20.458).

**P-gp Efflux:** Ligand A (0.015) has a much lower P-gp efflux liability than Ligand B (0.81), indicating better bioavailability.

**Binding Affinity:** Ligand B (-9.6 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 has a much better binding affinity. However, it suffers from higher logP, higher hERG risk, higher P-gp efflux, and poorer metabolic stability (higher Cl_mic, lower t1/2). Ligand A has a more balanced profile with better ADME properties (lower logP, lower hERG, lower P-gp, better metabolic stability) and a good QED score. The difference in binding affinity (2.1 kcal/mol) is significant, but the ADME liabilities of Ligand B are concerning. Given the enzyme-specific priorities, metabolic stability and safety (hERG) are important.

Output:
0
2025-04-17 13:48:29,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.419 Da and 362.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.48) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (51.02) is excellent, well below 140.

**3. logP:** Ligand A (1.366) is within the optimal 1-3 range. Ligand B (3.257) is also within the optimal range, but closer to the upper limit.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, and potentially beneficial for permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.744 and 0.747), indicating good drug-like properties.

**7. DILI:** Ligand A (52.734) has a moderate DILI risk, but is still acceptable. Ligand B (22.489) has a significantly lower DILI risk, which is a major advantage.

**8. BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (80.845) has a higher BBB penetration than Ligand A (53.587), but this is less important here.

**9. Caco-2 Permeability:** Ligand A (-4.633) has poor Caco-2 permeability. Ligand B (-5.108) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-2.411) has poor aqueous solubility. Ligand B (-3.581) also has poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.068) has a very low hERG risk, which is excellent. Ligand B (0.452) has a slightly higher hERG risk, but still relatively low.

**12. Microsomal Clearance:** Ligand A (11.583) has a relatively low microsomal clearance, suggesting better metabolic stability. Ligand B (90.353) has a very high microsomal clearance, indicating poor metabolic stability.

**13. In vitro Half-Life:** Ligand A (-20.127) has a very long in vitro half-life, which is highly desirable. Ligand B (23.433) has a shorter half-life, which is less favorable.

**14. P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is excellent. Ligand B (0.334) has a slightly higher P-gp efflux, but still relatively low.

**15. Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-8.6). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, a much lower DILI risk, and a higher BBB score, despite having a higher logP and poorer metabolic stability. However, the difference in binding affinity is substantial. The poor metabolic stability of Ligand B could be addressed through structural modifications. The poor solubility and permeability of both compounds are concerning, but can also be addressed through prodrug strategies or formulation. Given the importance of potency for kinase inhibitors, and the significant advantage in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 13:48:29,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.219 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (54.88) is significantly better than Ligand B (82.43). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (4.937) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.421) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 & 4) counts, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.523 and 0.66), indicating drug-like properties.

**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 (31.524%).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.168) is higher than Ligand B (52.191), but this is not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.836 and -4.719), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.713 and -2.096), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG:** Both ligands have low hERG inhibition liability (0.739 and 0.763), which is good.

**Microsomal Clearance:** Ligand A (81.086) has higher microsomal clearance than Ligand B (60.895), suggesting lower metabolic stability. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand A (124.989) has a much longer half-life than Ligand B (6.461), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.555 and 0.235), which is favorable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has 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:**

Despite the slightly better binding affinity of Ligand A, the extremely high DILI risk is a deal-breaker. The poor solubility of both compounds is a concern, but potentially addressable. Ligand B has a much more favorable safety profile (DILI), acceptable logP, and reasonable metabolic stability, making it the more promising candidate despite the slightly weaker binding affinity and lower half-life.

Output:
1
2025-04-17 13:48:29,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (87.91) is excellent, well below the 140 threshold for oral absorption. Ligand B (105.39) is still acceptable but less ideal.

**logP:** Ligand A (-0.486) is a bit low, potentially hindering permeation. Ligand B (1.254) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) 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: 0.638, B: 0.812), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (19.504) has a very favorable DILI score, indicating low liver injury risk. Ligand B (65.413) is significantly higher, raising a concern.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (53.974) is higher than Ligand A (36.526), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales where lower values indicate lower permeability, both are poor.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.016) is slightly better than Ligand B (-2.917).

**hERG Inhibition:** Ligand A (0.065) has a very low hERG risk, which is excellent. Ligand B (0.232) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-6.09) indicates very low clearance and excellent metabolic stability. Ligand B (31.013) has significantly higher clearance, suggesting faster metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-0.091) suggests a very long half-life, which is desirable. Ligand B (-15.854) indicates a very short half-life, which is a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.006, B: 0.027).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising drug candidate. Its superior DILI score, significantly better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk are critical advantages for an enzyme inhibitor. While Ligand A's logP and solubility are less ideal, these can potentially be addressed through formulation or further chemical modifications. The substantial ADME benefits of Ligand A outweigh the modest difference in binding affinity.

Output:
0
2025-04-17 13:48:29,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.36 and 354.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold and favorable. Ligand B (85.89) is still acceptable, but less optimal.

**logP:** Ligand A (2.535) is within the optimal 1-3 range. Ligand B (0.618) is a bit low, potentially impacting permeability.

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

**QED:** Both ligands have similar QED values (0.761 and 0.73), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (38.66 and 37.19), which is excellent.

**BBB:** Ligand A has a higher BBB penetration percentile (83.99) than Ligand B (71.73). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.468) has a worse Caco-2 permeability than Ligand B (-4.89), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.886) has better aqueous solubility than Ligand B (-1.359). This is a positive for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.533) has a slightly higher hERG risk than Ligand B (0.176), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.864) has significantly higher microsomal clearance than Ligand B (2.306), suggesting lower metabolic stability. This is a major drawback.

**In vitro Half-Life:** Ligand A (-13.289) has a shorter in vitro half-life than Ligand B (15.665), further supporting the lower metabolic stability concern.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.027).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This 2.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having better solubility and BBB penetration, Ligand B is the superior candidate. The significantly stronger binding affinity (-8.4 vs -6.3 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, Ligand B exhibits much better metabolic stability (lower Cl_mic and longer t1/2) which is a key priority for kinase inhibitors. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization.

Output:
1
2025-04-17 13:48:29,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.355 and 368.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.47) is slightly above the preferred <140, while Ligand B (97.64) is well within. This favors Ligand B for absorption.

**logP:** Both ligands (1.723 and 1.193) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 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 similar QED scores (0.86 and 0.814), indicating good drug-likeness.

**DILI:** Ligand A (84.645) has a higher DILI risk than Ligand B (64.831). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonably high BBB penetration (78.286 and 70.648). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.858) has poorer Caco-2 permeability than Ligand B (-5.25). Lower values are worse.

**Aqueous Solubility:** Ligand A (-4.958) has poorer aqueous solubility than Ligand B (-2.679). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.453 and 0.543).

**Microsomal Clearance:** Ligand A (42.619) has significantly lower microsomal clearance than Ligand B (11.744). Lower clearance indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (8.731) has a longer in vitro half-life than Ligand B (33.289). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.311) has lower P-gp efflux than Ligand B (0.092). Lower efflux is better.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.5). While a 0.2 kcal/mol difference isn't huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2, lower Pgp efflux), but suffers from higher DILI risk and poorer solubility and Caco-2 permeability. Ligand B has better solubility, permeability, and a lower DILI risk. Considering the enzyme-specific priorities, metabolic stability is crucial, but the higher DILI risk of Ligand A is a significant concern. The difference in binding affinity is small enough to be outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 13:48:29,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.29 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.95) is slightly higher than Ligand B (61.44). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands (1.705 and 2.053) are within the optimal 1-3 range.

**H-Bond Donors:** Both 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 B (0.797) has a significantly better QED score than Ligand A (0.201), indicating better overall drug-likeness.

**DILI:** Ligand B (12.524) has a much lower DILI risk than Ligand A (51.687). This is a significant advantage.

**BBB:** Ligand A (82.047) has a higher BBB penetration percentile than Ligand B (62.35). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-5.142) is slightly better than Ligand B (-5.206).

**Aqueous Solubility:** Both have negative solubility values which is unusual and suggests poor solubility. Ligand A (-1.818) is slightly better than Ligand B (-2.029).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.827 and 0.35). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (-4.826) has a lower (better) microsomal clearance than Ligand B (-2.435), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-20.383) has a significantly longer in vitro half-life than Ligand B (-4.343), which is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.133 and 0.021). Ligand B is slightly better.

**Binding Affinity:** Both ligands have very similar binding affinities (-9.0 and -8.3 kcal/mol). The difference is less than 1.5 kcal/mol and therefore not decisive.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. It has a significantly better QED score and a much lower DILI risk. While Ligand A has better metabolic stability and half-life, the lower DILI risk and better QED of Ligand B are more important for initial drug development. The binding affinity is comparable.

Output:
1
2025-04-17 13:48:29,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.431 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than Ligand B (80.56), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.078 and 1.192), 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 within acceptable limits.

**QED:** Ligand B (0.798) has a significantly better QED score than Ligand A (0.478), indicating a more drug-like profile.

**DILI:** Ligand A (27.142) has a much lower DILI risk than Ligand B (42.924), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (68.748 and 70.88), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands 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 negative solubility values, which is also unusual and suggests poor solubility. Again, the values are close.

**hERG:** Both ligands have very low hERG risk (0.082 and 0.089), which is excellent.

**Microsomal Clearance:** Ligand A (66.165) has significantly higher microsomal clearance than Ligand B (20.37), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (1.019 hours) has a slightly better in vitro half-life than Ligand A (-8.064 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.045).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.4 kcal/mol difference is substantial and outweighs many minor ADME concerns.

**Conclusion:**

Ligand B is the more promising drug candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly better QED score, lower microsomal clearance (better metabolic stability), a stronger binding affinity, and a slightly better half-life. The lower DILI risk of Ligand A is appealing, but the superior potency and metabolic stability of Ligand B are more critical for an enzyme target like SRC.

Output:
1
2025-04-17 13:48:29,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.461 Da) is slightly higher than Ligand B (344.419 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (113.96).  A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's TPSA is pushing the upper limit.

**logP:** Both ligands have good logP values (A: 2.979, B: 1.999), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (A: 1, B: 2) and HBA (A: 3, B: 3) counts, well within the guidelines.

**QED:** Ligand A (0.686) has a better QED score than Ligand B (0.467), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 38.542, B: 32.687), which is excellent.

**BBB:**  BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (88.29) has a higher BBB percentile than Ligand B (46.336), but this isn't a deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.362) has a worse Caco-2 permeability than Ligand B (-5.251). This suggests that ligand B might have slightly better absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.766, B: -2.134). Solubility is a concern for both, but ligand B is slightly better.

**hERG:** Ligand A (0.696) has a slightly higher hERG risk than Ligand B (0.123). Lower hERG is preferred, giving a slight edge to Ligand B.

**Microsomal Clearance:** Ligand A (43.78) has a significantly higher microsomal clearance than Ligand B (2.696). Lower clearance is better for metabolic stability, making Ligand B much more favorable.

**In vitro Half-Life:** Ligand A (1.677) has a shorter half-life than Ligand B (-24.213). A longer half-life is generally preferred, strongly favoring Ligand B.

**P-gp Efflux:** Ligand A (0.22) has lower P-gp efflux than Ligand B (0.022). Lower efflux is better, giving a slight edge to Ligand A.

**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, potentially outweighing some of the ADME drawbacks. A difference of 1.3 kcal/mol is significant.

**Overall Assessment:**

Ligand B has better ADME properties (lower Cl_mic, longer t1/2, lower hERG) and slightly better solubility and Caco-2 permeability. However, Ligand A boasts a significantly stronger binding affinity (-8.8 vs -7.5 kcal/mol). For a kinase inhibitor, potency is paramount. The 1.3 kcal/mol difference is large enough to potentially overcome the slightly less favorable ADME profile of Ligand A, especially considering both ligands have acceptable DILI risk.

Output:
1
2025-04-17 13:48:29,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (384.431 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.97 and 93.46) are below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have logP values (2.095 and 2.305) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 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 (0.71) has a better QED score than Ligand A (0.41), indicating a more drug-like profile.

**DILI:** Ligand A has a very high DILI risk (97.945 percentile), which is a major concern. Ligand B has a much lower DILI risk (37.611 percentile), a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (62.737) and Ligand B (59.791) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.844 and -4.688), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.239 and -2.375), indicating poor aqueous solubility. This could hinder formulation and bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.178 and 0.295), which is positive.

**Microsomal Clearance:** Ligand A (64.554 mL/min/kg) has a higher microsomal clearance than Ligand B (46.593 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (14.749 hours) compared to Ligand A (49.261 hours). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.454 and 0.05).

**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 significant ADME concerns with Ligand A.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, the extremely high DILI risk and higher microsomal clearance make it a significantly less desirable candidate. Ligand B, while having slightly weaker binding, demonstrates a much more favorable safety profile (lower DILI) and better metabolic stability (lower Cl_mic, longer t1/2). The solubility and permeability are problematic for both, but the DILI risk is a critical factor that disqualifies Ligand A.

Output:
1
2025-04-17 13:48:29,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.343 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.08) is slightly above the preferred <140, but acceptable. Ligand B (91.76) is well within the range.

**logP:** Ligand A (-1.454) is quite low, potentially hindering permeability. Ligand B (1.325) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable, being less than 10.

**QED:** Both ligands have good QED scores (0.709 and 0.776), indicating good drug-like properties.

**DILI:** Ligand A (59.131) has a moderate DILI risk, while Ligand B (28.655) has a low DILI risk. This favors Ligand B.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**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:** Both ligands show very low hERG inhibition risk (0.192 and 0.145), which is excellent.

**Microsomal Clearance:** Ligand A (-1.882) has negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (2.942) has a reasonable clearance. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (25.793) has a moderate half-life. Ligand B (0.068) has a very short half-life, which is undesirable. This favors Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.011), which is good.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive advantage for Ligand B.

**Overall:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B possesses a much better logP, lower DILI risk, more reasonable microsomal clearance, and, most importantly, a dramatically higher binding affinity. The short half-life of Ligand B is a drawback, but the potency advantage is likely to outweigh this, as optimization can address metabolic stability. The negative clearance value for Ligand A is a red flag and suggests data quality issues.

Output:
1
2025-04-17 13:48:29,168 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [366.447, 124.1, 0.143, 3, 7, 0.549, 63.397, 11.865, -6.062, -1.477, 0.128, 1.158, 20.325, 0.031, -10.6]
**Ligand B:** [371.409, 91.22, 2.609, 2, 5, 0.487, 68.98, 54.246, -5.208, -4.144, 0.794, 46.579, -7.609, 0.222, -9]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (366.447) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** A (124.1) is slightly above the preferred <140 for good oral absorption, but acceptable. B (91.22) is excellent, well below 140.
3. **logP:** A (0.143) is quite low, potentially hindering membrane permeability. B (2.609) is optimal.
4. **HBD:** A (3) is acceptable. B (2) is also good.
5. **HBA:** A (7) is acceptable. B (5) is also good.
6. **QED:** A (0.549) is good, indicating drug-likeness. B (0.487) is acceptable, but slightly lower.
7. **DILI:** Both have elevated DILI risk (A: 63.397, B: 68.98). B is slightly higher, which is a concern.
8. **BBB:** A (11.865) is very low, meaning poor brain penetration. B (54.246) is also low, but significantly better than A. Since SRC is not a CNS target, this is less critical.
9. **Caco-2:** A (-6.062) is very poor permeability. B (-5.208) is also poor, but better than A.
10. **Solubility:** A (-1.477) is very poor. B (-4.144) is also poor. Both have solubility issues.
11. **hERG:** A (0.128) is very low risk, excellent. B (0.794) is moderate risk, a concern.
12. **Cl_mic:** A (1.158) is very low, indicating high metabolic stability. B (46.579) is high, indicating rapid metabolism. This is a significant advantage for A.
13. **t1/2:** A (20.325) is good. B (-7.609) is very poor, suggesting rapid clearance. This further emphasizes A's metabolic stability.
14. **Pgp:** A (0.031) is very low efflux, excellent. B (0.222) is also low, but higher than A.
15. **Affinity:** A (-10.6) is significantly stronger than B (-9). This is a substantial advantage for A.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

*   **Affinity:** A is significantly better.
*   **Metabolic Stability:** A is *much* better (lower Cl_mic, longer t1/2).
*   **Solubility:** Both are poor, but this can be addressed with formulation strategies.
*   **hERG:** A is better.
*   **LogP:** B is better, but A's low logP is a bigger issue.

**Conclusion:**

Despite the poor solubility of both compounds, **Ligand A** is the more promising candidate. Its significantly stronger binding affinity, excellent metabolic stability, and low hERG risk outweigh the concerns about its low logP and solubility. The poor logP could potentially be addressed through structural modifications, but the strong binding and metabolic stability are harder to achieve.

1
2025-04-17 13:48:29,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.39 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Ligand A (0.645) is a bit low, potentially hindering permeation. Ligand B (3.358) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 2 HBA, which is even more favorable for permeability.

**QED:** Both ligands have good QED scores (0.605 and 0.768, respectively), indicating drug-like properties.

**DILI:** Ligand A (36.758) has a moderate DILI risk, while Ligand B (11.206) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (61.923) and Ligand B (87.941). While SRC is not a CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability. Ligand B is better here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.946 and -4.824). This is unusual and suggests a potential issue with the assay or the compounds themselves. However, the values are similar, so it doesn't strongly differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-1.971 and -3.673). This is concerning, but again, similar for both.

**hERG:** Ligand A (0.329) has a slightly higher hERG risk than Ligand B (0.729), though both are relatively low.

**Microsomal Clearance:** Ligand A (-4.474) has a negative clearance, which is highly favorable, indicating excellent metabolic stability. Ligand B (69.209) has a high clearance, suggesting rapid metabolism. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (13.975 hours) has a good half-life. Ligand B (3.823 hours) has a short half-life, consistent with its high clearance.

**P-gp Efflux:** Ligand A (0.049) has very low P-gp efflux, which is good. Ligand B (0.139) is slightly higher, but still acceptable.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand A's slightly lower logP and moderate DILI risk, its *much* stronger binding affinity (-9.8 vs -8.2 kcal/mol) and excellent metabolic stability (negative Cl_mic) are critical for an enzyme target like SRC kinase. The difference in binding affinity is a significant advantage. While Ligand B has better TPSA, logP, and DILI, the weaker binding and poor metabolic stability are major concerns.

Output:
0
2025-04-17 13:48:29,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (336.4 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.24) is better than Ligand B (116.56), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.062) is optimal (1-3). Ligand B (-1.279) is significantly lower, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3), as lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (6), staying within the desirable range.

**QED:** Ligand A (0.922) is excellent, indicating high drug-likeness. Ligand B (0.612) is acceptable but lower.

**DILI:** Ligand B (32.571) has a much lower DILI risk than Ligand A (58.627), a significant advantage.

**BBB:** Ligand A (70.88) shows reasonable BBB penetration, while Ligand B (13.92) is very low. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.954) is better than Ligand B (-5.578), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.856) is better than Ligand B (-1.289), which is a crucial factor for bioavailability.

**hERG Inhibition:** Ligand A (0.824) is better than Ligand B (0.016), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (58.29) is higher than Ligand B (-1.272), suggesting lower metabolic stability for Ligand A. Ligand B is significantly more stable.

**In vitro Half-Life:** Ligand A (9.341) has a longer half-life than Ligand B (-5.281).

**P-gp Efflux:** Ligand A (0.312) is better than Ligand B (0.002), suggesting lower P-gp efflux.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 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 solubility, permeability, and P-gp efflux. However, Ligand B has a significantly better safety profile (lower DILI) and metabolic stability (lower Cl_mic, longer half-life). The strong affinity of Ligand A is a major factor. While the slightly higher DILI risk for Ligand A is a concern, the substantial improvement in binding affinity (-9.7 vs -8.1) is likely to be more impactful for efficacy, especially for an enzyme target where potency is paramount.

Output:
1
2025-04-17 13:48:29,169 - INFO - Batch 244 complete. Total preferences: 3904
2025-04-17 13:48:29,169 - INFO - Processing batch 245/512...
2025-04-17 13:49:07,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.422 and 355.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is well below the 140 threshold for good absorption, and favorable. Ligand B (119.21) is still acceptable but less optimal.

**logP:** Ligand A (2.147) is within the optimal 1-3 range. Ligand B (-1.583) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Ligand A (0.852) has a very good drug-likeness score. Ligand B (0.531) is acceptable but less ideal.

**DILI:** Ligand A (35.595) has a low DILI risk. Ligand B (9.228) also has a low DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.01) is higher than Ligand B (45.522).

**Caco-2 Permeability:** Ligand A (-4.871) is poor. Ligand B (-5.717) is also poor.

**Aqueous Solubility:** Ligand A (-2.051) is poor. Ligand B (-0.653) is slightly better, but still poor.

**hERG Inhibition:** Both ligands (0.205 and 0.118) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (19.974) has moderate clearance. Ligand B (-39.053) has negative clearance, which is excellent and indicates high metabolic stability.

**In vitro Half-Life:** Ligand A (-21.574) has a long half-life. Ligand B (-19.829) also has a long half-life.

**P-gp Efflux:** Both ligands (0.085 and 0.001) show low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good binding affinity and low hERG risk, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic and longer half-life) and slightly better solubility. Although its logP is lower, the strong affinity and excellent metabolic profile outweigh this concern. The Caco-2 permeability is poor for both, but can be addressed during formulation.

Output:
1
2025-04-17 13:49:07,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.382 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.44) is slightly higher than Ligand B (49.41). Both are acceptable, but Ligand B's lower TPSA is preferable for permeability.

**logP:** Ligand A (0.311) 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.

**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, but Ligand B's lower counts are generally better for permeability.

**QED:** Both ligands have good QED scores (0.802 and 0.854), indicating good drug-like properties.

**DILI:** Ligand A (60.062) is at the upper limit of acceptable DILI risk, while Ligand B (40.054) is comfortably below. This favors Ligand B.

**BBB:** Both have reasonable BBB penetration (72.005 and 69.523), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.956 and -4.996), which is unusual and suggests poor permeability. This is a concern for both, but similar for both.

**Aqueous Solubility:** Both have negative solubility values (-2.812 and -4.541), indicating very poor aqueous solubility. This is a significant drawback for both compounds, potentially hindering bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.267 and 0.294), which is excellent.

**Microsomal Clearance:** Ligand A (-32.769) has significantly lower (better) microsomal clearance than Ligand B (51.015), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.382) has a longer half-life than Ligand B (5.24), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.029 and 0.408), which is good.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.7), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B has several advantages: a more optimal logP, lower TPSA, lower DILI risk, and fewer H-bonds. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The poor solubility and Caco-2 permeability are significant concerns for both. Considering the enzyme-specific priorities, metabolic stability is crucial. The 0.2 kcal/mol difference in binding affinity is unlikely to overcome the substantial advantage of Ligand A's improved metabolic profile.

Output:
0
2025-04-17 13:49:07,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.403 and 345.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.19) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (84.23) is well within the ideal range.

**3. logP:** Ligand A (0.308) is quite low, potentially hindering permeability. Ligand B (2.504) 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 (2) is also good.

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

**6. QED:** Both ligands have good QED scores (0.712 and 0.795), indicating drug-like properties.

**7. DILI:** Ligand A (51.609) has a moderate DILI risk. Ligand B (35.983) has a lower, more favorable DILI risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.811) has a higher BBB score than Ligand A (25.94), but it's not a primary concern here.

**9. Caco-2 Permeability:** Ligand A (-5.668) shows poor permeability. Ligand B (-4.943) is slightly better, but still indicates poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.023 and -2.849). This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.069) has a very low hERG risk. Ligand B (0.34) has a slightly higher, but still acceptable, hERG risk.

**12. Microsomal Clearance:** Ligand A (-12.383) has a lower (better) microsomal clearance, indicating greater metabolic stability. Ligand B (50.28) has a high clearance, suggesting rapid metabolism. This is a major advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-31.369) has a very long half-life, which is excellent. Ligand B (-12.603) has a shorter half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.01 and 0.157), which is favorable.

**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.

**Conclusion:**

While both ligands have good binding affinity and acceptable QED scores, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. Although Ligand A has a lower logP and poorer Caco-2 permeability, the improved metabolic stability and safety profile are more critical for an enzyme target like SRC kinase. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:49:07,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.885 and 364.364 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.25) is well below the 140 threshold, while Ligand B (70.08) is also acceptable but higher.

**logP:** Ligand A (3.842) is at the upper end of the optimal range (1-3), while Ligand B (0.784) is below the ideal range. This could indicate potential permeability issues for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values (0.887 and 0.786) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (50.795) has a slightly higher DILI risk than Ligand B (32.028), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (90.074) has better BBB penetration than Ligand B (77.084).

**Caco-2 Permeability:** Ligand A (-4.852) and Ligand B (-4.362) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-4.773) and Ligand B (-1.871) both have negative values, indicating poor solubility. Ligand B is better than Ligand A.

**hERG Inhibition:** Ligand A (0.713) has a slightly higher hERG risk than Ligand B (0.461), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.543) has higher microsomal clearance than Ligand B (26.982), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-33.995) has a significantly longer in vitro half-life than Ligand A (27.909), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.811) has slightly higher P-gp efflux than Ligand B (0.021), which is less desirable.

**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 for Ligand B, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better TPSA and BBB, Ligand B is the superior candidate. Its significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and lower P-gp efflux outweigh the slightly higher TPSA and lower logP. The difference in binding affinity is substantial and crucial for an enzyme inhibitor.

Output:
1
2025-04-17 13:49:07,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.349 Da and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.03) is slightly above the optimal <140 for oral absorption, but still acceptable. Ligand B (88.47) is excellent, well below 140.

**logP:** Ligand A (1.023) is within the optimal 1-3 range. Ligand B (0.311) is a bit low, potentially hindering permeation.

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

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

**QED:** Both ligands have good QED scores (0.605 and 0.756, respectively), suggesting good drug-like properties.

**DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (37.999). This is a significant drawback for Ligand A.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (81.039) is higher than Ligand B (54.13).

**Caco-2 Permeability:** Ligand A (-4.982) and Ligand B (-5.006) are both very poor, indicating poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.774) and Ligand B (-2.278) are both poor, but Ligand B is slightly better.

**hERG:** Ligand A (0.166) has a slightly higher hERG risk than Ligand B (0.678).

**Microsomal Clearance:** Ligand A (4.765) has a much lower (better) microsomal clearance than Ligand B (-47.418). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (4.165) has a shorter half-life than Ligand B (13.349).

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux than Ligand B (0.003), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-8.4 vs -7.8 kcal/mol) and lower DILI risk are critical advantages for an enzyme target like SRC kinase. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The slightly lower logP of Ligand B is a minor concern compared to the other factors.

Output:
1
2025-04-17 13:49:07,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.491 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (84.67), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands (1.85 and 2.186) 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 (4) is lower than Ligand B (5), both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.62 and 0.776, respectively), indicating drug-likeness.

**DILI:** Ligand B (40.675) has a significantly lower DILI risk than Ligand A (11.206), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, with Ligand B (76.541) being slightly better than Ligand A (65.723). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.435 and -4.647), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-0.995) is better than Ligand B (-2.131), indicating better solubility. Solubility is important for kinases.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.281 and 0.247), which is excellent.

**Microsomal Clearance:** Ligand B (41.769) has slightly lower microsomal clearance than Ligand A (45.064), suggesting better metabolic stability, which is important for kinases.

**In vitro Half-Life:** Ligand B (-15.714) has a significantly longer in vitro half-life than Ligand A (1.9), a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.167 and 0.045).

**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.

**Conclusion:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand B is the better candidate. Its significantly lower DILI risk, longer half-life, and slightly better metabolic stability outweigh the slightly lower solubility and Caco-2 permeability. The negative Caco-2 values are concerning for both, but the other advantages of Ligand B make it more promising.

Output:
1
2025-04-17 13:49:07,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is better than Ligand B (71.11), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.152) is optimal (1-3), while Ligand B (0.095) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), below the threshold of 5.

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

**QED:** Both ligands have good QED scores (0.744 and 0.776), indicating drug-like properties.

**DILI:** Ligand B (29.236) has a significantly lower DILI risk than Ligand A (41.838), which is a major advantage.

**BBB:** Ligand A (67.701) has a higher BBB penetration score than Ligand B (55.293), but BBB isn't a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.159) has a negative Caco-2 value, which is concerning. Ligand B (-4.598) is also negative, but less so.

**Aqueous Solubility:** Ligand A (-2.427) has slightly better solubility than Ligand B (-1.164), but both are negative, suggesting poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.147 and 0.213 respectively).

**Microsomal Clearance:** Ligand B (-21.594) has a much lower (better) microsomal clearance than Ligand A (38.374), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (17.748) has a significantly longer in vitro half-life than Ligand A (-9.488), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.046 respectively).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.0 and -7.4 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have good binding affinity and acceptable QED scores, Ligand B is the superior candidate. It demonstrates a significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better logP value. Although both have negative Caco-2 and solubility values, the improvements in safety and PK properties for Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 13:49:07,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.519 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (88.05). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.979 and 2.07), falling 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 maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.827) has a substantially higher QED score than Ligand B (0.628), indicating a more drug-like profile.

**DILI:** Ligand A (20.396) has a much lower DILI risk than Ligand B (62.621). This is a significant advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (74.254) shows better BBB penetration than Ligand B (60.838).

**Caco-2 Permeability:** Ligand A (-4.456) has a better Caco-2 permeability than Ligand B (-5.218).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.127 and -3.16). This is a concern for both, but doesn't differentiate them.

**hERG Inhibition:** Ligand A (0.203) has a slightly better hERG profile than Ligand B (0.548), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (52.924) has a lower microsomal clearance than Ligand B (75.629), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (51.388) has a significantly longer in vitro half-life than Ligand A (-2.273). This is a notable advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.016) exhibits lower P-gp efflux than Ligand B (0.204), which is favorable for bioavailability.

**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 is noticeable.

**Overall Assessment:**

Ligand A is superior overall. While Ligand B has a slightly better binding affinity and a longer half-life, Ligand A excels in crucial areas like DILI risk, QED, metabolic stability (lower Cl_mic), P-gp efflux, and TPSA. The lower DILI risk and higher QED are particularly important. The solubility is poor for both, but this can be addressed with formulation strategies. The slightly weaker binding affinity of Ligand A is likely outweighed by its superior ADME properties, especially considering it is still a strong binding affinity.

Output:
1
2025-04-17 13:49:07,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.37 and 373.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.99) is well below the 140 threshold for oral absorption. Ligand B (117.09) is also below, but closer to the limit.

**logP:** Ligand A (1.63) is optimal. Ligand B (0.126) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, but higher than ideal.

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also acceptable.

**QED:** Ligand A (0.778) is excellent, indicating good drug-likeness. Ligand B (0.523) is acceptable, but lower.

**DILI:** Ligand A (59.364) is better than Ligand B (43.66), both are acceptable.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (65.374) and Ligand B (43.273) are not particularly relevant here.

**Caco-2 Permeability:** Ligand A (-4.72) is poor, while Ligand B (-5.409) is even worse. Both are concerning.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.696 and -1.83), indicating very poor solubility, a significant drawback.

**hERG Inhibition:** Ligand A (0.421) has a lower hERG risk than Ligand B (0.379), both are acceptable.

**Microsomal Clearance:** Ligand A (29.098) has a higher clearance than Ligand B (10.059), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-6.947) has a longer half-life than Ligand B (5.639).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.201 and 0.064).

**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:**

Ligand B's significantly stronger binding affinity (-8.1 vs 0 kcal/mol) is the most important factor, outweighing some of its drawbacks. While its logP is low and Caco-2 permeability is poor, the potency advantage is substantial. Ligand B also has better metabolic stability (lower Cl_mic) and a longer half-life. Ligand A has better solubility and QED, but the binding affinity is a critical deficiency. The solubility issues for both are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:49:07,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.423 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (113.53) is better than Ligand B (58.22), falling well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.386) is optimal (1-3), while Ligand B (4.391) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors & Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=1, HBA=5) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.539, B: 0.666), indicating drug-like properties.

**DILI:** Ligand A (54.401) has a lower DILI risk than Ligand B (75.998), which is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (56.029) is slightly better than Ligand B (44.785).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.127) is slightly better than Ligand B (-5.309), but both are concerning.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.545 and -4.482 respectively). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.587 and 0.568 respectively), which is good.

**Microsomal Clearance:** Ligand A (45.353) has significantly lower microsomal clearance than Ligand B (113.255), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-5.132) has a negative half-life, which is concerning, while Ligand B (-15.561) is even worse. Both are very poor.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.278 and 0.488 respectively), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the better candidate despite the poor solubility and permeability. Its lower DILI risk, significantly better metabolic stability (lower Cl_mic), and acceptable logP outweigh the slightly weaker binding affinity compared to Ligand B. Ligand B's high DILI risk and poor metabolic stability are major red flags. While both have solubility and permeability issues, these can potentially be addressed through formulation strategies. The metabolic stability is harder to fix.

Output:
0
2025-04-17 13:49:07,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 380.432 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.32) is slightly above the preferred <140, while Ligand B (78.43) is well within the range.

**logP:** Both ligands have good logP values (1.636 and 1.454), 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 similar QED scores (0.668 and 0.625), indicating good drug-likeness.

**DILI:** Both ligands have very similar, and acceptable, DILI risk (18.418 and 18.728 percentile).

**BBB:** Ligand B (69.252) has a slightly better BBB penetration score than Ligand A (51.609), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.796) has a worse Caco-2 permeability than Ligand B (-5.474).

**Aqueous Solubility:** Ligand A (-2.727) has a slightly better aqueous solubility than Ligand B (-2.457).

**hERG:** Both ligands have very similar hERG inhibition liability (0.231 and 0.289), indicating low risk.

**Microsomal Clearance:** Ligand B (3.857) has significantly lower microsomal clearance than Ligand A (39.12), indicating much better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-8.323) has a significantly longer in vitro half-life than Ligand A (-29.11), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very similar P-gp efflux liability (0.017 and 0.072).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). However, the difference is less than 1.5 kcal/mol, and the substantial improvements in metabolic stability (Cl_mic and t1/2) for Ligand B outweigh this minor difference in binding.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B exhibits significantly improved metabolic stability (lower Cl_mic, longer t1/2) and comparable safety profiles. The improved metabolic stability will likely translate to better *in vivo* exposure and efficacy.

Output:
1
2025-04-17 13:49:07,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (349.479 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.36) is slightly higher than Ligand B (69.72). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable due to the lower TPSA.

**3. logP:** Both ligands have good logP values (1.231 and 0.869), 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 (3) are both below the 10 threshold. Ligand B is preferable.

**6. QED:** Both ligands have reasonable QED scores (0.835 and 0.75), indicating good drug-like properties.

**7. DILI:** Ligand A (28.461) has a significantly lower DILI risk than Ligand B (51.377). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (72.896) has better BBB penetration than Ligand B (62.466), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2:** Ligand A (-5.117) has a worse Caco-2 permeability than Ligand B (-4.492).

**10. Solubility:** Ligand A (-2.981) has worse solubility than Ligand B (-1.929). Solubility is important for bioavailability, favoring Ligand B.

**11. hERG:** Both ligands have similar hERG inhibition liability (0.872 and 0.32), both are acceptable.

**12. Cl_mic:** Ligand A (-22.443) has a significantly *lower* (better) microsomal clearance than Ligand B (28.674), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. t1/2:** Ligand A (-16.866) has a worse in vitro half-life than Ligand B (-26.777). This favors Ligand B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.095 and 0.06).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in DILI risk and metabolic stability (Cl_mic), which are crucial for kinase inhibitors. While it has slightly worse solubility and Caco-2 permeability, the strong binding affinity and favorable safety/stability profile outweigh these drawbacks. Ligand B has better solubility and Caco-2 permeability, but the higher DILI risk and lower metabolic stability are significant concerns.

Output:
0
2025-04-17 13:49:07,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.447 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.94 and 78.95) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.109 and 0.761), falling within the 1-3 range.

**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 criteria.

**QED:** Both ligands have good QED scores (0.692 and 0.745), indicating drug-like properties.

**DILI:** Ligand A (23.575) has a significantly lower DILI risk than Ligand B (40.054). This is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (61.923) has a higher BBB score than Ligand A (46.336), but this is less important here.

**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 risk (0.137 and 0.233).

**Microsomal Clearance:** Ligand A (15.647) has lower microsomal clearance than Ligand B (24.14), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-38.901) has a significantly longer in vitro half-life than Ligand A (-1.948). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.025).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.0 and -7.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has a better half-life, Ligand A has a substantially lower DILI risk and better metabolic stability (lower Cl_mic). Given that SRC is an enzyme, prioritizing metabolic stability and minimizing toxicity (DILI) are crucial. The similar binding affinities make the ADME/Tox differences the deciding factors.

Output:
0
2025-04-17 13:49:07,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.43 and 366.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.22) is better than Ligand B (97.55), both are acceptable for oral absorption (<140).

**logP:** Both ligands have good logP values (2.79 and 1.46), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<10).

**QED:** Both ligands have similar QED scores (0.80 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (44.59) has a significantly lower DILI risk than Ligand B (59.40), which is a major advantage.

**BBB:** Ligand A (69.91) has a lower BBB penetration than Ligand B (80.26). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.396) has better Caco-2 permeability than Ligand B (-5.083).

**Aqueous Solubility:** Ligand A (-3.663) has better aqueous solubility than Ligand B (-3.226).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.38 and 0.41).

**Microsomal Clearance:** Ligand A (49.76) has higher microsomal clearance than Ligand B (-0.66). This means Ligand B is more metabolically stable, a key consideration for kinases.

**In vitro Half-Life:** Ligand A (23.49) has a longer half-life than Ligand B (2.22). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.07 and 0.03).

**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:**

While Ligand B has better metabolic stability (lower Cl_mic) and BBB penetration, Ligand A excels in several critical areas: significantly lower DILI risk, better solubility, better Caco-2 permeability, and, most importantly, *much* stronger binding affinity. The stronger binding affinity of Ligand A is a significant advantage for an enzyme target like SRC kinase, and the lower DILI risk is a crucial safety factor. The slightly higher clearance of Ligand A is a manageable concern compared to the benefits.

Output:
1
2025-04-17 13:49:07,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.419 and 338.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.53) is slightly higher than the ideal <140, but acceptable. Ligand B (62.98) is excellent, well below 90.

**logP:** Ligand A (0.965) is at the lower end of optimal, potentially impacting permeability. Ligand B (4.586) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), well below the limit of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 and 5 respectively), well below the limit of 10.

**QED:** Both ligands have good QED scores (0.74 and 0.755), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (42.885 and 51.028), both are good (below 60).

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (69.484) is better than Ligand A (56.34).

**Caco-2 Permeability:** Ligand A (-4.889) is very poor, indicating very low intestinal absorption. Ligand B (-5.097) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.539) is poor, while Ligand B (-4.885) is even worse.

**hERG Inhibition:** Ligand A (0.253) has a very low hERG risk, which is excellent. Ligand B (0.696) is higher, but still relatively low.

**Microsomal Clearance:** Ligand A (50.881) has a moderate clearance. Ligand B (69.34) has a higher clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-12.815) has a negative half-life, indicating very rapid metabolism. Ligand B (68.399) has a good half-life.

**P-gp Efflux:** Ligand A (0.088) has low P-gp efflux, which is good. Ligand B (0.237) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-7.8) has significantly better binding affinity than Ligand B (-0.0). This is a crucial advantage for an enzyme target. The difference of 7.8 kcal/mol is substantial.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, and a much lower hERG risk. However, it suffers from poor Caco-2 permeability, solubility, and a very short half-life. Ligand B has better solubility and a longer half-life, but its binding affinity is extremely weak, and its logP is high.

Given the importance of potency for enzyme inhibition, the superior binding affinity of Ligand A is a decisive factor. While its ADME properties are concerning, they can potentially be addressed through further optimization. The extremely weak binding of Ligand B makes it a less promising starting point.

Output:
0
2025-04-17 13:49:07,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.39 and 344.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.66) is slightly above the preferred <140, while Ligand B (96.25) is well within. This favors B.

**logP:** Ligand A (0.386) is quite low, potentially hindering permeation. Ligand B (1.32) is better, falling within the optimal 1-3 range. This favors B.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.685 and 0.75), indicating drug-likeness.

**DILI:** Ligand A (42.46) is slightly higher than Ligand B (36.95), but both are below the concerning threshold of 60, indicating low risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (59.79) is lower than Ligand B (48.78), but neither is particularly high.

**Caco-2 Permeability:** Ligand A (-5.75) and Ligand B (-4.91) both have negative 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 (-2.55 and -3.10), which is concerning. Solubility is a key factor for enzyme inhibitors, as it impacts bioavailability.

**hERG Inhibition:** Ligand A (0.022) has a very low hERG risk, which is excellent. Ligand B (0.238) is slightly higher, but still relatively low. This favors A.

**Microsomal Clearance:** Ligand A (-0.033) has a very low (and likely favorable) clearance, suggesting good metabolic stability. Ligand B (23.93) has a significantly higher clearance, indicating faster metabolism. This strongly favors A.

**In vitro Half-Life:** Ligand A (17.36) has a reasonable half-life, while Ligand B (-1.26) has a very short half-life, suggesting rapid degradation. This strongly favors A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.032), which is good.

**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 only 0.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and TPSA, Ligand A is significantly better in terms of metabolic stability (Cl_mic and t1/2), hERG risk, and has a more favorable logP. The solubility issue is present in both, but the superior ADME properties of Ligand A, particularly its metabolic stability, are crucial for an enzyme inhibitor. The small affinity difference is outweighed by these factors.

Output:
0
2025-04-17 13:49:07,663 - INFO - Batch 245 complete. Total preferences: 3920
2025-04-17 13:49:07,664 - INFO - Processing batch 246/512...
2025-04-17 13:49:48,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.451 and 386.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.13 and 101.41) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (-0.883) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (1.183) is within the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, suggesting improved permeability.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Ligand A (0.522) is slightly better than Ligand B (0.402), indicating a more drug-like profile.

**DILI:** Ligand A (4.343) has a significantly lower DILI risk than Ligand B (39.511), a major advantage.

**BBB:** Both ligands have similar low BBB penetration (43.35 and 43.815), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.391 and -5.449) which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.753 and -1.508), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG risk (0.23 and 0.115), which is excellent.

**Microsomal Clearance:** Ligand A (-30.881) has much lower (better) microsomal clearance than Ligand B (17.623), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (21.605) has a longer half-life than Ligand B (-1.098), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.015 and 0.009), which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-9.3 and -8.8 kcal/mol), with Ligand A being slightly better. The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its significantly lower DILI risk and superior metabolic stability (lower Cl_mic and longer t1/2) are crucial advantages for an enzyme target. While both have poor solubility and permeability, the lower DILI and better metabolic profile of Ligand A make it a better starting point for optimization.

Output:
0
2025-04-17 13:49:48,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.419 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.12) is significantly better than Ligand B (78.87). TPSA < 140 is good for oral absorption, both are under this threshold, but lower is preferred.

**logP:** Ligand A (3.853) is optimal (1-3), while Ligand B (1.601) is at the lower end, 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 2 HBA, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.719 and 0.786, respectively), indicating good drug-like properties.

**DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (36.758). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (40.481 and 40.52), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.967) is slightly worse than Ligand B (-4.572).

**Aqueous Solubility:** Ligand A (-6.207) has significantly worse solubility than Ligand B (-2.007). Solubility is a key factor for enzyme inhibitors.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.805 and 0.532).

**Microsomal Clearance:** Ligand A (69.351) has higher microsomal clearance than Ligand B (37.604), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-22.865) has a slightly better (less negative) in vitro half-life than Ligand A (-29.618).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.617 and 0.227).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.9 and -9.0 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to override the ADME differences.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising candidate. Ligand B exhibits significantly better solubility, lower DILI risk, and better metabolic stability (lower Cl_mic, better t1/2). While both have poor Caco-2 permeability, the other ADME properties of Ligand B are more favorable for development as an enzyme inhibitor.

Output:
1
2025-04-17 13:49:48,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.402 and 351.411 Da) are within the ideal range (200-500 Da).

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (126.45). A TPSA under 90 is preferred, and A is well within that, while B is approaching the upper limit for good oral absorption (140).

**logP:** Ligand A (2.202) is optimal (1-3), while Ligand B (-0.696) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (3) is good, while Ligand B (6) is also acceptable, being under the 10 threshold.

**QED:** Both ligands have similar and good QED values (0.635 and 0.701, respectively), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (37.96 and 37.611, both <40).

**BBB:** Ligand A (84.529) shows better BBB penetration potential than Ligand B (56.65). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.646) is significantly worse than Ligand B (-5.637) - lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.486) is better than Ligand B (-1.117), indicating better solubility.

**hERG:** Ligand A (0.769) has a lower hERG risk than Ligand B (0.017), which is a significant advantage.

**Microsomal Clearance:** Ligand A (31.456) has a higher microsomal clearance than Ligand B (-16.408). This means Ligand B is more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-0.624) has a shorter half-life than Ligand B (14.286). This further supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Ligand A (0.299) has lower P-gp efflux than Ligand B (0.003), which is favorable.

**Binding Affinity:** Ligand A (-8.8 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:**

Despite Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, Ligand A's significantly stronger binding affinity (-8.8 vs -7.8 kcal/mol) and better hERG risk profile are decisive. The potency advantage is substantial for a kinase inhibitor, and the lower hERG risk is critical for safety. While Ligand A's solubility is better, the metabolic stability of B is a concern.

Output:
1
2025-04-17 13:49:48,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 360.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is slightly higher than Ligand B (51.02), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.202) is within the optimal 1-3 range, while Ligand B (3.764) is approaching the upper limit.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable.

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

**QED:** Both ligands have good QED scores (0.718 and 0.755, respectively), indicating drug-like properties.

**DILI:** Ligand A (7.949) has a significantly lower DILI risk than Ligand B (47.693). This is a major advantage for Ligand A.

**BBB:** Ligand A (64.482) has a lower BBB penetration than Ligand B (81.233). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.669 and -4.902), 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 (-2.031 and -4.244), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.368 and 0.415, respectively).

**Microsomal Clearance:** Ligand A (41.563) has a lower microsomal clearance than Ligand B (82.646), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-11.567) has a negative half-life, which is not physically possible. This is likely an error in the data. Ligand B (14.92) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.043 and 0.479, respectively).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B has a better binding affinity and a more reasonable half-life. However, Ligand A has a much lower DILI risk and better metabolic stability (lower Cl_mic). The negative half-life for Ligand A is a major red flag and suggests a data error. Considering the enzyme-kinase focus, metabolic stability and safety (DILI) are crucial. While the affinity difference is notable, the lower DILI and Cl_mic of Ligand A, *assuming the half-life is corrected*, make it a more promising starting point. Given the negative half-life for Ligand A, I am going to select Ligand B.

Output:
1
2025-04-17 13:49:48,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.491 and 345.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (76.66 and 75.44) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.57 and 2.709) are within the optimal range of 1-3.

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

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

**QED:** Ligand B (0.824) has a significantly better QED score than Ligand A (0.591), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (42.458 and 40.713 percentile), which is good.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (88.833) is significantly better than Ligand A (71.811). While not a primary concern for a non-CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.175 and -4.875), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.908 and -3.311), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.343 and 0.497), which is excellent.

**Microsomal Clearance:** Ligand A (32.382 mL/min/kg) has a lower microsomal clearance than Ligand B (48.521 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (11.275 hours) has a longer half-life than Ligand B (-19.32 hours). The negative value for Ligand B is concerning and likely indicates rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.107), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.4 kcal/mol). Ligand B has a slightly better affinity, but the difference is small (0.3 kcal/mol) and may not be decisive.

**Conclusion:**

While both ligands have excellent binding affinity and acceptable safety profiles (DILI, hERG), Ligand A is the more promising candidate. Its lower microsomal clearance and longer half-life are critical advantages for an enzyme target like SRC kinase. Although both have poor solubility and permeability, the metabolic stability advantage of Ligand A outweighs the slightly better QED and BBB of Ligand B. The negative half-life value for Ligand B is a red flag.

Output:
0
2025-04-17 13:49:48,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.447 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.02) is slightly higher than Ligand B (70.47). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (1.728 and 0.957), 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 QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (42.536) has a slightly higher DILI risk than Ligand B (36.681), but both are below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (63.125 and 62.544), which isn't a primary concern for a non-CNS target like SRC.

**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 don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a significant drawback. Ligand B (-1.044) is slightly better than Ligand A (-2.923).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.367 and 0.345), which is excellent.

**Microsomal Clearance:** Ligand A (21.618) has lower microsomal clearance than Ligand B (27.37), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-1.629) has a negative half-life, which is unusual. Ligand B (3.935) has a positive half-life, indicating better stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.09 and 0.027), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is slightly more favorable. While both have poor solubility, Ligand B has a better solubility score than Ligand A. More importantly, Ligand B has a positive in vitro half-life, while Ligand A has a negative one, suggesting better stability. The slight advantage in metabolic stability (lower Cl_mic) for Ligand A is offset by the more reasonable half-life of Ligand B. The binding affinities are essentially the same.

Output:
1
2025-04-17 13:49:48,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.853 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.4) is significantly better than Ligand B (83.98). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (4.066) is higher than Ligand B (1.523). While 4.066 is approaching the upper limit, it's still acceptable. Ligand B's 1.523 is quite low and might hinder 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.

**QED:** Both ligands have similar QED values (0.768 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (49.477) has a slightly higher DILI risk than Ligand B (44.552), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.517) is better than Ligand B (48.662).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.761 and -4.886), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't massive.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.789 and -2.623), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.827) has a considerably lower hERG risk than Ligand B (0.155). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (61.161) has a higher microsomal clearance than Ligand B (15.243), suggesting lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-18.296) has a negative half-life, which is not physically possible and indicates a very short half-life or a problem with the assay. Ligand A (59.567) has a much more reasonable half-life.

**P-gp Efflux:** Ligand A (0.45) has lower P-gp efflux than Ligand B (0.024), which is favorable.

**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).

**Overall Assessment:**

Ligand B has a slightly better binding affinity and a lower DILI risk, but suffers from extremely poor predicted half-life and very low P-gp efflux. Ligand A has a higher logP and clearance, but a much better hERG profile and a reasonable half-life. The poor solubility of both is a major concern. However, the hERG risk is a critical factor for kinase inhibitors, and Ligand A's significantly lower hERG liability, combined with a reasonable half-life, makes it the more promising candidate despite its higher clearance and logP. The negative Caco-2 and solubility values for both are concerning and would require significant optimization, but the hERG risk is a more immediate safety concern.

Output:
1
2025-04-17 13:49:48,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.539 Da and 357.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is slightly better than Ligand B (43.86), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.646 and 1.965, respectively) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.706 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (13.532) has a significantly lower DILI risk than Ligand B (23.575). This is a major advantage.

**BBB:** Both ligands have high BBB penetration (86.08 and 89.802), but this is less critical for a non-CNS target like SRC.

**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 (-4.962 and -4.369).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.043) is slightly better than Ligand A (-3.419).

**hERG Inhibition:** Ligand A (0.511) has a slightly lower hERG inhibition liability than Ligand B (0.806), which is preferable.

**Microsomal Clearance:** Ligand A (54.352) has a higher microsomal clearance than Ligand B (38.67), meaning it's less metabolically stable. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Both ligands have negative half-life values (-10.067 and -10.425), which is unrealistic. This suggests issues with the in vitro assay or prediction method.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.151 and 0.097).

**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 has a significantly better binding affinity and a much lower DILI risk, which are the most important factors for an enzyme target like SRC. While Ligand A has a higher microsomal clearance, the strong binding affinity is likely to compensate for this. The negative solubility and half-life values are concerning but could be artifacts of the prediction methods. Ligand B has slightly better solubility and metabolic stability, but the weaker binding affinity and higher DILI risk make it less attractive.

Output:
1
2025-04-17 13:49:48,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 well within the acceptable range for oral absorption (<140). Ligand B (38.77) is also good, potentially indicating better cell permeability.

**logP:** Ligand A (-0.205) is a bit low, potentially hindering permeation. Ligand B (4.707) is high, which could lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is within the ideal range. Ligand B (0 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.65 and 0.59), indicating reasonable drug-likeness.

**DILI:** Ligand A (21.869) has a significantly lower DILI risk than Ligand B (50.33), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (66.886) has a higher BBB value, but this is less relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.961 and -4.735). 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 (-1.084 and -4.617), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.108) has a much lower hERG inhibition risk than Ligand B (0.65), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-7.273) has a much lower (better) microsomal clearance than Ligand B (116.327), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (37.83) has a shorter half-life than Ligand B (47.58), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.005 and 0.809).

**Binding Affinity:** Ligand A (-6.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). The difference is substantial (1.7 kcal/mol), and this is a key factor.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand A has a significantly better safety profile (lower DILI and hERG risk), better metabolic stability (lower Cl_mic), and a strong binding affinity. Ligand B's high logP and DILI risk are major drawbacks. The substantial affinity difference between Ligand A and B further reinforces the preference for Ligand A.

Output:
0
2025-04-17 13:49:48,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (377.38 and 354.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (21.26) is excellent, well below the 140 threshold for absorption. Ligand B (102.75) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.788) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.949) is quite low, which could hinder membrane permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.406 and 0.663), indicating reasonable drug-likeness.

**DILI:** Both ligands have similar DILI risk (51.03 and 56.22), both are acceptable.

**BBB:** Ligand A (73.67) has a better BBB penetration score than Ligand B (38.89). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.829 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 (-4.951 and -0.617), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.961) has a slightly higher hERG risk than Ligand B (0.066). Lower is better, so Ligand B is preferable here.

**Microsomal Clearance:** Ligand A (49.99) has a higher microsomal clearance than Ligand B (-1.929), indicating faster metabolism and lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand A (28.23) has a longer half-life than Ligand B (-19.57), which is favorable.

**P-gp Efflux:** Ligand A (0.738) has lower P-gp efflux than Ligand B (0.015), which is preferable.

**Binding Affinity:** Ligand B (-8.8 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.

**Conclusion:**

Despite the poor solubility and permeability for both, Ligand B is the more promising candidate. Its significantly superior binding affinity (-8.8 vs -7.0 kcal/mol) outweighs the slightly higher hERG risk and lower BBB penetration. Furthermore, Ligand B exhibits much better metabolic stability (lower Cl_mic, more negative Cl_mic value) and lower P-gp efflux. The poor solubility and permeability would need to be addressed through formulation strategies, but the strong binding and metabolic stability make Ligand B the better starting point for optimization.

Output:
1
2025-04-17 13:49:48,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.431 and 340.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.44) is well below the 140 threshold for good absorption, while Ligand B (95.08) is closer to the limit but still acceptable.

**logP:** Both ligands have good logP values (0.887 and 0.676), 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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (0.61 and 0.886), indicating good drug-like properties.

**DILI:** Ligand A (35.712) has a significantly lower DILI risk than Ligand B (63.125). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (73.866) has a better BBB percentile than Ligand B (23.536).

**Caco-2 Permeability:** Ligand A (-4.492) shows poor permeability, while Ligand B (-5.201) is also poor. Both are significantly negative, suggesting a challenge for intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.258) has slightly better solubility than Ligand B (-1.882), although both are quite poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.363 and 0.134), which is excellent.

**Microsomal Clearance:** Ligand A (40.201) has a higher microsomal clearance than Ligand B (-10.264). This suggests Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-9.881) has a significantly longer in vitro half-life than Ligand A (-4.036). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.163 and 0.013), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent and meets the criteria.

**Conclusion:**

While both ligands have excellent binding affinity and low hERG risk, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. Although Caco-2 permeability is poor for both, metabolic stability is more critical for kinase inhibitors. The slightly better solubility of Ligand A is not enough to overcome the metabolic and DILI concerns.

Output:
1
2025-04-17 13:49:48,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.435 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.29) is slightly higher than Ligand B (89.95). Both are acceptable, but Ligand B is preferable as it's closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.524) is a bit low, potentially hindering permeation. Ligand B (0.756) is also on the lower side, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable limit of <=5. 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 (0.712 and 0.705), indicating good drug-likeness.

**DILI:** Ligand A (39.589) has a slightly higher DILI risk than Ligand B (12.524), but both are below the concerning threshold of 60. Ligand B is significantly better here.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC kinase. Ligand A (43.389) is slightly higher than Ligand B (18.457).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.408 and -5.144), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.077 and -0.811), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Both ligands show very low hERG inhibition liability (0.167 and 0.114), which is excellent.

**Microsomal Clearance:** Ligand A (14.74 mL/min/kg) has a higher microsomal clearance than Ligand B (12.406 mL/min/kg), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (-9.162 hours) has a significantly longer in vitro half-life than Ligand A (20.615 hours). This is a major advantage for Ligand B, as it suggests less frequent dosing.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.014 and 0.021).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), although the difference is small.

**Overall:**

Ligand B is superior. While both ligands have concerning permeability and solubility issues, Ligand B demonstrates better metabolic stability (lower Cl_mic, longer half-life), lower DILI risk, and slightly better binding affinity. The small advantage in binding affinity, coupled with the improved ADME properties, makes Ligand B the more promising candidate. The negative Caco-2 and solubility values would need to be addressed through formulation or structural modifications, but Ligand B provides a better starting point.

Output:
1
2025-04-17 13:49:48,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.5) is slightly higher than Ligand B (86.09), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.041) is within the optimal 1-3 range, while Ligand B (1.908) is also good, but edging towards the higher end.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.778 and 0.907), indicating good drug-like properties.

**DILI:** Ligand A (12.369) has a significantly lower DILI risk than Ligand B (39.085). This is a major advantage.

**BBB:** Both have good BBB penetration (70.027 and 78.907), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.421) is worse than Ligand B (-4.736).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.937) is slightly worse than Ligand B (-3.107).

**hERG Inhibition:** Ligand A (0.138) has a much lower hERG inhibition liability than Ligand B (0.547), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-0.958) has a lower (better) microsomal clearance than Ligand B (23.258), suggesting better metabolic stability.

**In vitro Half-Life:** Both have very short in vitro half-lives (-14.358 and -15.783 hours). This is a concern for both, but not a deciding factor between them.

**P-gp Efflux:** Both have low P-gp efflux liability (0.03 and 0.04).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol), although the difference is relatively small.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is the more promising candidate. While both have poor permeability and solubility, Ligand A exhibits significantly lower DILI and hERG risk, and better metabolic stability (lower Cl_mic). The slightly better binding affinity of Ligand A further reinforces this conclusion. The lower DILI and hERG are critical safety factors.

Output:
0
2025-04-17 13:49:48,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values around 96, which is acceptable for oral absorption but not ideal for CNS penetration (not a priority here).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (1.349) is slightly higher, which could potentially lead to better 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 good QED scores (A: 0.543, B: 0.748), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (25.359) has a significantly lower DILI risk than Ligand B (67.313). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (41.14) than Ligand A (16.479), but this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.203) is slightly better than Ligand B (-5.646).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand A (-0.988) is slightly better than Ligand B (-2.184).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.199, B: 0.087). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (0.809) has significantly lower microsomal clearance than Ligand B (12.773), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.314) has a much longer in vitro half-life than Ligand B (13.878). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.036, B: 0.024).

**Binding Affinity:** Both ligands have similar and strong 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 A is significantly better due to its much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and Caco-2 permeability. While Ligand B has a slightly better QED and binding affinity, the ADME properties of Ligand A are far more favorable for drug development. The small affinity difference is easily outweighed by the substantial improvements in safety and pharmacokinetics.

Output:
0
2025-04-17 13:49:48,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Ligand A (1.239) is within the optimal range (1-3). Ligand B (3.228) is at the higher end, but still acceptable.

**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.

**QED:** Both ligands have similar QED values (0.647 and 0.665), indicating good drug-likeness.

**DILI:** Ligand A (9.345) has a much lower DILI risk than Ligand B (15.2). This is a significant advantage for Ligand A.

**BBB:** Ligand B (82.823) shows better BBB penetration than Ligand A (36.681), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.171) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.762) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.027) has slightly better solubility than Ligand B (-3.245), though both are quite poor.

**hERG:** Ligand A (0.172) has a lower hERG risk than Ligand B (0.524), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (-16.297) has a *much* lower (better) microsomal clearance than Ligand B (68.413). This indicates significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (2.871) has a shorter half-life than Ligand B (-14.219), but the negative value for B is suspect and likely an error.

**P-gp Efflux:** Ligand A (0.009) has a much lower P-gp efflux liability than Ligand B (0.47), suggesting better bioavailability.

**Binding Affinity:** Both ligands have similar binding affinities (-10 kcal/mol and -8.3 kcal/mol). Ligand A has a 1.7 kcal/mol advantage, which is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is the more promising candidate. While Ligand B has slightly better TPSA and BBB penetration, Ligand A excels in critical areas: significantly lower DILI risk, much lower microsomal clearance (better metabolic stability), lower hERG risk, lower P-gp efflux, and a superior binding affinity. The poor Caco-2 permeability of Ligand A is a concern, but the strong binding affinity and improved safety/stability profile make it the better choice for further optimization.

Output:
0
2025-04-17 13:49:48,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.36) is slightly above the preferred <140 for good absorption, while Ligand B (100.21) is well within the range.

**logP:** Both ligands have good logP values (1.948 and 1.106) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.57 and 0.767), indicating drug-like properties.

**DILI:** Ligand A (62.35) and Ligand B (67.739) both have DILI risk above the preferred <40, indicating moderate risk. Ligand B is slightly higher.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.411) is slightly better than Ligand B (29.934).

**Caco-2 Permeability:** Both are negative (-5.528 and -5.648), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both are negative (-2.556 and -2.359), indicating poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.015) has a very low hERG risk, which is excellent. Ligand B (0.226) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-3.667) has a much lower (better) microsomal clearance than Ligand B (28.573), suggesting significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (1.462 hours) has a shorter half-life than Ligand B (18.901 hours). This is a clear advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.041).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.2 kcal/mol). While the difference is not huge, it's a notable advantage.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic), and a much lower hERG risk. However, Ligand B has a longer half-life. Both have poor solubility and permeability. Given the enzyme-specific priorities, metabolic stability and potency are key. The superior metabolic stability and slightly better affinity of Ligand A, combined with its excellent hERG profile, outweigh the longer half-life of Ligand B. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:49:48,080 - INFO - Batch 246 complete. Total preferences: 3936
2025-04-17 13:49:48,080 - INFO - Processing batch 247/512...
2025-04-17 13:50:32,035 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.399 and 363.527 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.32) is better than Ligand B (53.51) as it is closer to the 90 A^2 threshold.

**logP:** Ligand A (0.943) is slightly below the optimal range of 1-3, while Ligand B (3.102) is within the optimal range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0) as it is within the ideal range.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4) as it is within the ideal range.

**QED:** Ligand A (0.897) is better than Ligand B (0.713), indicating a more drug-like profile.

**DILI:** Ligand A (60.644) has a higher DILI risk than Ligand B (28.344), which is a significant concern.

**BBB:** Ligand A (66.925) is lower than Ligand B (86.429). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.877 and -4.901), which is unusual and suggests poor permeability. This is a major red flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.038 and -3.024), which is also a major red flag.

**hERG Inhibition:** Ligand A (0.21) has a lower hERG inhibition liability than Ligand B (0.398), which is preferable.

**Microsomal Clearance:** Ligand B (60.124) has a higher microsomal clearance than Ligand A (25.149), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-13.662) has a longer in vitro half-life than Ligand B (-8.44), which is preferable.

**P-gp Efflux:** Ligand A (0.22) has lower P-gp efflux than Ligand B (0.293), which is preferable.

**Binding Affinity:** Ligand A (-7.9) has slightly better binding affinity than Ligand B (-7.6), but the difference is small.

**Overall Assessment:**

Despite Ligand A having slightly better affinity, QED, hERG, P-gp efflux, and half-life, the significantly lower DILI risk and better metabolic stability of Ligand B are more important for an enzyme inhibitor. The negative Caco-2 and solubility values for both are concerning and would require further investigation (e.g., salt formation, formulation strategies). However, the lower DILI risk makes Ligand B the more promising candidate.

Output:
1
2025-04-17 13:50:32,035 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.45 and 369.45 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.31) is well below the 140 threshold, and even below 90, suggesting good permeability. Ligand B (116.68) is still under 140, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (0.831) is a bit low, potentially hindering permeation, but not drastically. Ligand B (-1.259) is lower and more concerning for permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 8 HBA) is acceptable, but slightly higher counts could affect permeability.

**QED:** Ligand A (0.661) is good, indicating drug-likeness. Ligand B (0.52) is still reasonable, but lower.

**DILI:** Ligand A (46.064) has a lower DILI risk than Ligand B (63.397), which is approaching a higher risk category.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (58.782) is lower than Ligand B (26.561).

**Caco-2 Permeability:** Ligand A (-4.446) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.61) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-0.968) is poor. Ligand B (-1.857) is even worse.

**hERG:** Both ligands have very low hERG risk (0.132 and 0.089 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (31.117) has a moderate clearance, while Ligand B (7.26) has a significantly lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.058 hours) has a short half-life. Ligand B (-20.59 hours) has a negative value, which is impossible and indicates a data error or a very unusual result.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.049 and 0.003 respectively), which is good.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), although both are strong binders. The 0.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has better DILI risk, slightly better affinity, and better H-bonding characteristics. However, its solubility and Caco-2 permeability are very poor. Ligand B has significantly better metabolic stability (lower Cl_mic) but suffers from lower logP, higher DILI risk, and very poor solubility. The negative half-life for Ligand B is a major red flag.

Considering the enzyme-specific priorities, metabolic stability is crucial. However, the extremely poor solubility and permeability of both compounds are major drawbacks. Given the slightly better overall profile (better affinity, DILI, and H-bonding), and the questionable half-life of B, I would lean towards Ligand A as a starting point, *but* significant medicinal chemistry effort would be required to improve its solubility and permeability.

Output:
0
2025-04-17 13:50:32,035 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.405 and 365.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (98.17) is better than Ligand B (108.09), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (2.864) is optimal, while Ligand B (0.487) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Ligand A is preferable here.

**QED:** Ligand B (0.817) has a better QED score than Ligand A (0.41), indicating a more drug-like profile overall.

**DILI:** Ligand A (29.236) has a significantly lower DILI risk than Ligand B (51.609), a major advantage.

**BBB:** Ligand A (84.451) has better BBB penetration than Ligand B (66.925), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.738) has a slightly better Caco-2 permeability than Ligand B (-5.067).

**Aqueous Solubility:** Ligand A (-2.602) has better aqueous solubility than Ligand B (-3.281), which is important for bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.426 and 0.454).

**Microsomal Clearance:** Ligand A (5.607) has significantly lower microsomal clearance than Ligand B (28.044), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.337) has a much longer in vitro half-life than Ligand B (-28.733), which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.044).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and QED, Ligand A excels in critical ADME properties for an enzyme target: lower DILI risk, better solubility, significantly better metabolic stability (lower Cl_mic and longer t1/2). The small difference in binding affinity is likely outweighed by these substantial ADME advantages.

Output:
0
2025-04-17 13:50:32,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.507 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (87.66). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range for oral bioavailability.

**logP:** Ligand A (1.518) is slightly higher than Ligand B (0.979), both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (3), keeping within the preferred limit of <=5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is good.

**QED:** Ligand A (0.759) has a higher QED score than Ligand B (0.597), indicating better overall drug-likeness.

**DILI:** Ligand A (8.104) has a significantly lower DILI risk than Ligand B (35.285). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (36.371) is slightly better than Ligand A (27.801), but this is not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.115) is better than Ligand B (-4.816), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.754) is better than Ligand B (-1.905), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.318 and 0.22 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-5.844) has a much lower (better) microsomal clearance than Ligand B (18.944), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (20.74) has a longer half-life than Ligand B (-8.172), which is desirable for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.042 respectively), which is good.

**Binding Affinity:** Both ligands have equally strong binding affinity (-8.5 and -8.9 kcal/mol).

**Conclusion:**

Ligand A is superior to Ligand B. It has a better QED score, significantly lower DILI risk, better solubility, better Caco-2 permeability, and significantly better metabolic stability (lower Cl_mic and longer half-life). While both ligands have excellent binding affinity and low hERG risk, the ADME properties of Ligand A make it a much more promising drug candidate.

Output:
1
2025-04-17 13:50:32,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.43 and 344.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.53) is better than Ligand B (122.03). Both are below 140, but A is closer to the desirable threshold for good absorption.

**logP:** Ligand A (0.489) is slightly lower than optimal (1-3), but still acceptable. Ligand B (-0.049) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 7 HBA). Both are within acceptable ranges, but lower counts generally favor permeability.

**QED:** Both ligands have good QED scores (0.722 and 0.606, respectively), indicating generally drug-like properties.

**DILI:** Ligand A (73.83) has a higher DILI risk than Ligand B (60.22), but both are reasonably acceptable.

**BBB:** Ligand A (59.33) has a better BBB percentile than Ligand B (24.62). However, BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.816) is significantly better than Ligand B (-5.555), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.562) is better than Ligand B (-2.056). Both are poor, but A is less poor.

**hERG Inhibition:** Ligand A (0.706) has a lower hERG risk than Ligand B (0.1). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (48.44) has a much better microsomal clearance than Ligand B (15.07). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-18.4) has a much longer in vitro half-life than Ligand B (3.479). This is a major advantage for Ligand A, suggesting less frequent dosing.

**P-gp Efflux:** Ligand A (0.101) has a lower P-gp efflux liability than Ligand B (0.02). This is a slight advantage for Ligand A.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -8.4 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 binding affinity, Ligand A excels in crucial ADME properties: better Caco-2 permeability, solubility, significantly lower hERG risk, much better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. These factors are particularly important for an enzyme target like SRC kinase. The slightly higher DILI risk for Ligand A is less concerning than the poor ADME profile of Ligand B.

Output:
1
2025-04-17 13:50:32,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Ligand A:**
*   **MW:** 360.365 Da - Within the ideal range (200-500).
*   **TPSA:** 126.37 - Acceptable, but approaching the upper limit for good oral absorption.
*   **logP:** -0.77 - Low, potentially hindering permeation.
*   **HBD:** 3 - Acceptable.
*   **HBA:** 7 - Acceptable.
*   **QED:** 0.586 - Good drug-like properties.
*   **DILI:** 43.622 - Low risk.
*   **BBB:** 64.986 - Not a priority for a non-CNS target like SRC.
*   **Caco-2:** -5.688 - Very poor permeability.
*   **Solubility:** -1.478 - Poor solubility.
*   **hERG:** 0.089 - Very low risk.
*   **Cl_mic:** -6.604 - Excellent metabolic stability (negative value suggests very low clearance).
*   **t1/2:** -12.275 - Excellent in vitro half-life (negative value suggests very long half-life).
*   **Pgp:** 0.003 - Very low efflux.
*   **Affinity:** -8.2 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 350.438 Da - Within the ideal range (200-500).
*   **TPSA:** 64.16 - Excellent, well below the 140 threshold.
*   **logP:** 3.37 - Optimal.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.651 - Good drug-like properties.
*   **DILI:** 30.399 - Low risk.
*   **BBB:** 95.657 - Not a priority for a non-CNS target like SRC.
*   **Caco-2:** -4.679 - Poor permeability, but better than Ligand A.
*   **Solubility:** -3.02 - Poor solubility, worse than Ligand A.
*   **hERG:** 0.882 - Moderate risk.
*   **Cl_mic:** 52.996 - Moderate metabolic clearance.
*   **t1/2:** 29.334 - Good in vitro half-life.
*   **Pgp:** 0.823 - Moderate efflux.
*   **Affinity:** -7.2 kcal/mol - Good binding affinity, but 1.0 kcal/mol weaker than Ligand A.

**Comparison and Decision:**

While Ligand B has better physicochemical properties (logP, TPSA) and a slightly better QED score, Ligand A significantly outperforms it in key areas for an enzyme target: **binding affinity** (-8.2 vs -7.2 kcal/mol) and **metabolic stability** (much lower Cl_mic and longer t1/2). Ligand A also has a lower hERG risk and negligible Pgp efflux. The poor solubility and Caco-2 permeability of Ligand A are concerning, but these can potentially be addressed through formulation strategies. The 1.0 kcal/mol difference in binding affinity is substantial and likely outweighs the ADME drawbacks of Ligand A. Ligand B's moderate hERG risk is also a concern.

Therefore, Ligand A is the more promising drug candidate.

Output:
1
2025-04-17 13:50:32,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.309 Da and 336.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.02) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (83.81) is still under 140, but less favorable than A.

**logP:** Both ligands have logP values (4.051 and 3.227) within the optimal 1-3 range, though Ligand A is slightly higher.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3-4 HBA, satisfying the <5 and <10 rules respectively.

**QED:** Both ligands have similar QED scores (0.788 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A (58.976) has a higher DILI risk than Ligand B (71.19), which is concerning.

**BBB:** Both ligands have relatively high BBB penetration (80.729 and 72.237), but this is less crucial for a kinase inhibitor unless CNS effects are specifically desired.

**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 (0.665) has a slightly higher hERG risk than Ligand B (0.491), but both are relatively low.

**Microsomal Clearance:** Ligand A (15.577) has significantly lower microsomal clearance than Ligand B (32.751), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (24.265) has a longer half-life than Ligand B (18.021), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.094 and 0.253).

**Binding Affinity:** This is the most critical factor. Ligand B (-7.8 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, and this difference is massive.

**Overall Assessment:**

Despite Ligand A's better TPSA and metabolic stability, the vastly superior binding affinity of Ligand B (-7.8 kcal/mol vs 0.0 kcal/mol) overrides these advantages. The binding affinity difference is so large that it is likely to compensate for the slightly higher DILI risk and lower metabolic stability. The poor solubility and permeability of both compounds are concerning and would need to be addressed in further optimization, but potency is paramount at this stage.

Output:
1
2025-04-17 13:50:32,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.289 Da and 367.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.41) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (83.71) is well within the acceptable range.

**logP:** Both ligands have good logP values (2.562 and 1.604), falling within the 1-3 optimal range.

**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:** Both ligands have good QED scores (0.674 and 0.858), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.957, which is high and concerning. Ligand B has a much lower DILI risk of 37.456, which is favorable.

**BBB:** Both ligands have reasonably high BBB penetration (58.976 and 88.329), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.311 and -4.969). This is unusual and suggests poor permeability, but the scale isn't clearly defined. We'll consider this a potential drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.683 and -2.555). Again, the scale is unclear, but indicates poor solubility. This is a significant concern.

**hERG Inhibition:** Ligand A has a hERG risk of 0.718, which is acceptable. Ligand B has a very low hERG risk of 0.298, which is excellent.

**Microsomal Clearance:** Ligand A has a Cl_mic of 67.794, which is relatively high, suggesting faster metabolism. Ligand B has a negative Cl_mic (-0.927), which is highly desirable, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 34.787 hours, which is reasonable. Ligand B has a very short t1/2 of -6.193 hours, which is a major concern.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.184 and 0.045).

**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 crucial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the questionable Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.9 vs -0.0 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, it has a much lower DILI risk (37.456 vs 89.957) and excellent metabolic stability (negative Cl_mic). The short half-life is a concern, but could potentially be addressed through structural modifications. Ligand A's high DILI risk and weak binding affinity make it a less attractive candidate.

Output:
1
2025-04-17 13:50:32,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**

*   **MW:** 355.45 Da - Within the ideal range (200-500).
*   **TPSA:** 55.84 - Good for oral absorption (<140).
*   **logP:** 4.015 - Slightly high, potential for off-target effects, but manageable.
*   **HBD:** 0 - Low, good for permeability.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.41 - Below the preferred threshold of 0.5, indicating a less drug-like profile.
*   **DILI:** 28.655 - Very good, low risk of liver injury.
*   **BBB:** 94.184 - High, suggesting potential CNS penetration (less relevant for SRC unless CNS effects are desired).
*   **Caco-2:** -4.422 - Very poor permeability. A significant drawback.
*   **Solubility:** -4.924 - Very poor solubility. A major issue for bioavailability.
*   **hERG:** 0.697 - Low risk of hERG inhibition.
*   **Cl_mic:** 99.737 - Very high, indicating rapid metabolism and poor metabolic stability.
*   **t1/2:** -3.102 - Very short half-life.
*   **Pgp:** 0.278 - Low efflux, good.
*   **Affinity:** -8.8 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 345.403 Da - Within the ideal range.
*   **TPSA:** 89.35 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** -0.543 - Low, potentially hindering permeation.
*   **HBD:** 1 - Low, good for permeability.
*   **HBA:** 6 - Acceptable.
*   **QED:** 0.575 - Good, indicates a more drug-like profile.
*   **DILI:** 44.242 - Good, low risk of liver injury.
*   **BBB:** 46.219 - Low, minimal CNS penetration.
*   **Caco-2:** -4.714 - Very poor permeability. A significant drawback.
*   **Solubility:** -1.588 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.047 - Very low risk of hERG inhibition.
*   **Cl_mic:** 31.09 - Moderate, better metabolic stability than Ligand A.
*   **t1/2:** -22.69 - Very short half-life.
*   **Pgp:** 0.024 - Low efflux, good.
*   **Affinity:** -7.7 kcal/mol - Good binding affinity, though not as strong as Ligand A.

**Comparison and Conclusion:**

Ligand A has a significantly better binding affinity (-8.8 kcal/mol vs -7.7 kcal/mol), which is a primary consideration for enzyme inhibitors. However, it suffers from extremely poor solubility and Caco-2 permeability, coupled with very high metabolic clearance and a short half-life. These ADME properties are major liabilities.

Ligand B, while having a slightly weaker affinity, exhibits better solubility (though still poor), lower DILI risk, and better metabolic stability (lower Cl_mic). Its permeability is also very poor, similar to Ligand A.

Despite the superior binding affinity of Ligand A, the severe ADME issues make it a less viable drug candidate. The poor solubility and permeability will likely result in extremely low bioavailability. Ligand B, while not ideal, presents a slightly more balanced profile with better metabolic stability and lower toxicity risk.

Therefore, I would select **Ligand B** as the more promising candidate, recognizing that substantial medicinal chemistry efforts would be needed to improve its permeability and solubility.

Output:
1
2025-04-17 13:50:32,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.483 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (112.81). A TPSA under 140 is good for oral absorption, but lower is generally better, and Ligand A is much closer to the ideal for CNS penetration as well (though that's not a primary concern here).

**logP:** Ligand A (4.015) is at the upper end of the optimal range (1-3), while Ligand B (-0.795) is below 1, which could hinder permeation. Ligand A is preferred here.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 2 HBA) is better than Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Both ligands have acceptable QED values (A: 0.904, B: 0.651), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (32.261) has a much lower DILI risk than Ligand B (44.668), which is a significant advantage.

**BBB:** Ligand A (91.392) has better BBB penetration than Ligand B (66.033), though this isn't a high priority for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-4.659) is worse than Ligand B (-5.477), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.021) is worse than Ligand B (-1.564). Solubility is important, and Ligand B is better in this regard.

**hERG Inhibition:** Ligand A (0.682) has a lower hERG risk than Ligand B (0.283), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (73.251) has higher microsomal clearance than Ligand B (-3.031). This means Ligand B is more metabolically stable, a key priority for enzymes.

**In vitro Half-Life:** Ligand A (18.422) has a shorter half-life than Ligand B (-26.171), indicating faster metabolism. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.561) has lower P-gp efflux than Ligand B (0.041), which is better for bioavailability.

**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 A excels in most ADME properties (TPSA, logP, DILI, hERG, P-gp efflux) and has a comparable binding affinity. However, it suffers from poor Caco-2 permeability, solubility, and metabolic stability (higher Cl_mic, shorter t1/2).

Ligand B has better solubility, metabolic stability, and half-life, but is penalized by a higher logP (potentially impacting permeability), higher DILI risk, and lower BBB penetration.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the better metabolic stability and solubility of Ligand B, coupled with acceptable (though not ideal) DILI and hERG, outweigh the slightly better ADME profile of Ligand A. The similar binding affinities make the ADME differences the deciding factor.

Output:
1
2025-04-17 13:50:32,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.487 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.36) is significantly better than Ligand B (74.43). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (3.464 and 2.19), falling within the 1-3 range. Ligand A is slightly higher, which *could* present a minor solubility concern, but is still acceptable.

**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 (0.912) has a significantly higher QED score than Ligand B (0.794), indicating a more drug-like profile.

**DILI:** Ligand A (21.442) has a much lower DILI risk than Ligand B (9.965), which is a crucial advantage.

**BBB:** Both ligands have good BBB penetration (73.866 and 76.309), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.641 and -4.668), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.851 and -2.954), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.493 and 0.528), which is excellent.

**Microsomal Clearance:** Ligand A (21.969) has a higher microsomal clearance than Ligand B (12.322), indicating faster metabolism and potentially lower *in vivo* exposure. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-19.624) has a *negative* half-life, which is impossible and likely indicates a data error or a very rapidly degrading compound. This is a major red flag for Ligand B. Ligand A has a reasonable half-life (5.977).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.557 and 0.023).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 and -7.5 kcal/mol), making this parameter less decisive.

**Overall Assessment:**

Ligand A is superior despite the slightly higher Cl_mic. Its significantly better QED score, much lower DILI risk, and reasonable half-life outweigh the slightly higher metabolic clearance. Ligand B's negative half-life is a critical flaw, rendering it a highly unlikely drug candidate. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 13:50:32,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.348 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.04 and 70.47) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.009) is optimal (1-3), while Ligand B (0.454) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.916) has a significantly better QED score than Ligand B (0.787), indicating a more drug-like profile.

**DILI:** Ligand A (56.572) has a higher DILI risk than Ligand B (31.563), but both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a non-CNS target like SRC kinase, but Ligand A (87.088) has better BBB penetration than Ligand B (51.221).

**Caco-2 Permeability:** Ligand A (-4.888) has better Caco-2 permeability than Ligand B (-5.149).

**Aqueous Solubility:** Ligand A (-2.695) has better aqueous solubility than Ligand B (-1.152).

**hERG Inhibition:** Ligand A (0.638) has a slightly higher hERG risk than Ligand B (0.131), but both are relatively low.

**Microsomal Clearance:** Ligand A (-33.474) has a significantly lower (better) microsomal clearance than Ligand B (11.376), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.713) has a slightly shorter half-life than Ligand B (3.441).

**P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its superior binding affinity, better QED, improved solubility, and significantly better metabolic stability (lower Cl_mic) are key advantages. While Ligand A has a slightly higher DILI risk and hERG inhibition, these are within acceptable ranges, and are outweighed by its potency and pharmacokinetic properties. The lower logP of Ligand B is a concern for permeability.

Output:
1
2025-04-17 13:50:32,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.38 and 361.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.1) is significantly better than Ligand B (43.86). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Ligand A (4.403) is higher than Ligand B (1.588). While 1-3 is optimal, Ligand A is pushing the upper limit, potentially leading to solubility issues. Ligand B is a bit low, which could affect permeability.

**H-Bond Donors & Acceptors:** Ligand A has 1 HBD and 1 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 scores (0.816 and 0.747), indicating good drug-like properties.

**DILI:** Ligand A (50.601) has a higher DILI risk than Ligand B (21.404). This is a significant advantage for Ligand B.

**BBB:** Both ligands have high BBB penetration (91.663 and 95.076), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.503 and -4.393). This is unusual and suggests poor permeability *in vitro*. It's difficult to interpret without more context, but it's a potential concern for both.

**Aqueous Solubility:** Ligand A (-4.897) has worse solubility than Ligand B (-2.093). This is consistent with its higher logP.

**hERG Inhibition:** Ligand A (0.883) has a slightly higher hERG risk than Ligand B (0.653), but both are reasonably low.

**Microsomal Clearance:** Ligand B (33.853) has significantly lower microsomal clearance than Ligand A (74.413), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-23.527) has a negative half-life, which is not physically possible. This is a major red flag and suggests a significant issue with the data or the compound itself. Ligand A (24.337) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.659 and 0.069), which is favorable.

**Binding Affinity:** Ligand B (-9) has a significantly stronger binding affinity than Ligand A (-8). This 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better QED and half-life, Ligand B is the stronger candidate. The significantly improved binding affinity (-9 vs -8 kcal/mol), lower DILI risk, and much better metabolic stability (lower Cl_mic) are critical advantages for an enzyme target like SRC kinase. The negative half-life for Ligand A is a major concern. The solubility of Ligand A is also worse. The Caco-2 values are concerning for both, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 13:50:32,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.491 Da) is slightly lower than Ligand B (383.861 Da), which is acceptable.

**TPSA:** Ligand A (81.67) is better than Ligand B (100.35) as it is closer to the ideal threshold of 140 for oral absorption.

**logP:** Both ligands have acceptable logP values (A: 1.033, B: 0.551), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is slightly better than Ligand B (HBD=2, HBA=7) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.61, B: 0.785), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (12.641) has a significantly lower DILI risk than Ligand B (70.841). This is a major advantage for Ligand A.

**BBB:** Ligand A (40.558) has a lower BBB penetration than Ligand B (16.673). However, since SRC is not a CNS target, this is not a critical factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.119 for A, -5.392 for B).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the values are similar (-2.305 for A, -2.417 for B).

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.152, B: 0.167). This is excellent.

**Microsomal Clearance:** Ligand A (33.452) has a higher microsomal clearance than Ligand B (-2.591). This suggests that Ligand B is more metabolically stable, which is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (4.324) has a longer in vitro half-life than Ligand A (-1.626), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.044, B: 0.123).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). This 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a much lower DILI risk. Considering the priorities for enzyme inhibitors, metabolic stability is crucial. The slightly better affinity of Ligand B, combined with its improved metabolic profile, outweighs the higher DILI risk compared to Ligand A. The solubility and permeability issues are similar for both, and can be addressed through formulation strategies.

Output:
1
2025-04-17 13:50:32,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.371 and 344.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.4) is better than Ligand B (113.86). Both are below 140, but A is closer to the optimal value for good absorption.

**logP:** Ligand A (0.49) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (0.609) is also on the lower side.

**H-Bond Donors:** Ligand A (0) is preferred as it minimizes potential issues with permeability. Ligand B has 4 HBD, which is acceptable but less ideal.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both within the acceptable range of <=10.

**QED:** Both ligands have reasonable QED values (0.758 and 0.651), indicating good drug-like properties.

**DILI:** Ligand B (56.456) has a lower DILI risk than Ligand A (67.429), which is a significant advantage.

**BBB:** Ligand A (79.566) has a much higher BBB penetration potential than Ligand B (21.326). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.194 and -5.521), which is unusual and suggests poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.394 and -2.441), indicating very poor aqueous solubility, a substantial drawback.

**hERG:** Both ligands have very low hERG inhibition liability (0.038 and 0.065), which is excellent.

**Microsomal Clearance:** Ligand B (-37.743) has significantly lower (better) microsomal clearance than Ligand A (28.841), indicating greater metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-10.838) has a longer (better) in vitro half-life than Ligand A (-28.309), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.002), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -8.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't strongly favor either.

**Conclusion:**

Despite similar binding affinities, Ligand B is the better candidate. Its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk are critical advantages for an enzyme target like SRC kinase. While both have poor solubility and permeability, the metabolic properties of Ligand B outweigh the slightly better TPSA and BBB of Ligand A.

Output:
1
2025-04-17 13:50:32,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.434 Da and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the preferred <140, while Ligand B (76.02) is well within. This favors B for absorption.

**logP:** Both ligands have acceptable logP values (1.132 and 2.566, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within the recommended limits.

**QED:** Both ligands have good QED scores (0.533 and 0.797), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 60.915, which is approaching the higher risk threshold (>60). Ligand B has a significantly lower DILI risk (34.781), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.937) has a higher BBB percentile than Ligand A (52.889), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.263 and -5.171), 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 (-2.161 and -2.659), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.151) has a slightly lower hERG risk than Ligand B (0.321), which is preferable.

**Microsomal Clearance:** Ligand A has a significantly lower (better) microsomal clearance (-24.082) compared to Ligand B (36.185), indicating greater metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (34.568 hours) than Ligand A (8.705 hours), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.058), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.0 kcal/mol). Ligand A is slightly better (-8.9 kcal/mol), but the difference is less than 1.5 kcal/mol, so it's not a decisive factor given the other ADME considerations.

**Conclusion:**

While Ligand A has a slightly better binding affinity and lower hERG risk, Ligand B is the more promising candidate overall. Its significantly lower DILI risk, longer half-life, and better TPSA outweigh the minor advantage in binding affinity and hERG. The metabolic stability of Ligand A is good, but the longer half-life of Ligand B is more valuable for an enzyme target. The solubility issues are present in both, but can be addressed.

Output:
1
2025-04-17 13:50:32,038 - INFO - Batch 247 complete. Total preferences: 3952
2025-04-17 13:50:32,038 - INFO - Processing batch 248/512...
2025-04-17 13:51:14,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.471 and 346.337 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the preferred <90 for CNS penetration, but acceptable for a non-CNS target. Ligand B (83.98) is well within the acceptable range.

**logP:** Ligand A (0.899) is a bit low, potentially hindering permeability. Ligand B (1.618) is better, falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (6 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.807 and 0.862), indicating good drug-likeness.

**DILI:** Ligand A (54.168) has a moderate DILI risk, while Ligand B (79.333) has a higher DILI risk. This is a concern for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (71.035) has better penetration than Ligand A (33.54).

**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. This is a significant concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.269 and 0.224), which is good.

**Microsomal Clearance:** Ligand A (4.352) has a lower microsomal clearance, indicating better metabolic stability compared to Ligand B (17.865).

**In vitro Half-Life:** Ligand A (19.612) has a longer in vitro half-life than Ligand B (7.671), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.168 and 0.033), which is favorable.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks. The difference of 2.3 kcal/mol is quite significant.

**Conclusion:**

Despite Ligand A's slightly lower logP and negative solubility/permeability values, its *much* stronger binding affinity (-9.9 vs -7.6 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The higher DILI risk for Ligand B is also a concern. The affinity difference is large enough to prioritize over the solubility/permeability issues, which can be addressed with formulation strategies.

Output:
1
2025-04-17 13:51:14,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (366.447 Da) is also good.

**TPSA:** Ligand A (54.78) is significantly better than Ligand B (95.26). A TPSA under 140 is good for oral absorption, but lower is generally better. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Ligand A (0.853) is borderline, potentially slightly low for optimal permeation. Ligand B (0.135) is quite low, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA counts (4 for A, 9 for B), falling within the recommended limits.

**QED:** Both ligands have good QED scores (0.589 and 0.623), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (38.813 and 55.176), with Ligand A being slightly preferable.

**BBB:** Both ligands have moderate BBB penetration (56.805 and 65.995). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Ligand A (-4.293) has a much better Caco-2 permeability than Ligand B (-5.123), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.896) has better aqueous solubility than Ligand B (-1.081). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.232 and 0.05), which is excellent.

**Microsomal Clearance:** Ligand A (9.406) has significantly lower microsomal clearance than Ligand B (40.269). This indicates better metabolic stability for Ligand A, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (3.666 hours) has a shorter half-life than Ligand B (18.537 hours). While a longer half-life is generally preferred, the substantial difference in metabolic stability (Cl_mic) for Ligand A may compensate for this.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.062 and 0.065).

**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 enough to be a deciding factor given the other ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. It has superior TPSA, Caco-2 permeability, aqueous solubility, and, most importantly, much better metabolic stability (lower Cl_mic). The slightly better binding affinity further strengthens its position. While Ligand B has a longer half-life, the substantial difference in metabolic clearance for Ligand A makes it a more promising candidate. Ligand B's low logP is a significant concern.

Output:
0
2025-04-17 13:51:14,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.455 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is higher than Ligand B (74.57). While both are reasonably good, Ligand B is better positioned for oral absorption.

**logP:** Both ligands (2.23 and 1.944) are 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 acceptable, but Ligand B has a slight advantage with fewer HBDs, potentially improving permeability.

**QED:** Both ligands have good QED scores (0.612 and 0.753), indicating good drug-like properties.

**DILI:** Ligand A (75.533) has a significantly higher DILI risk than Ligand B (24.467). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (47.732) has a higher BBB value than Ligand A (26.483), but this isn't a primary deciding factor.

**Caco-2 Permeability:** Ligand A (-5.418) shows poor Caco-2 permeability, while Ligand B (-4.737) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-3.676) has poorer solubility than Ligand B (-1.715). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.203) has a slightly higher hERG risk than Ligand B (0.343), but both are relatively low.

**Microsomal Clearance:** Ligand A (-10.552) exhibits much better metabolic stability (lower clearance) than Ligand B (23.067). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-6.852) has a longer half-life than Ligand B (4.414), which is desirable.

**P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux than Ligand B (0.164), which is favorable.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is not substantial enough to overcome the other significant drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has superior metabolic stability (Cl_mic, t1/2) and P-gp efflux, but suffers from a high DILI risk, poor solubility, and poor Caco-2 permeability. Ligand B has a better safety profile (lower DILI), better solubility, and slightly better Caco-2 permeability, but has poorer metabolic stability and a slightly weaker binding affinity.

Considering the enzyme-specific priorities, metabolic stability is crucial. However, the high DILI risk associated with Ligand A is a major red flag. While the affinity of Ligand A is slightly better, the safety concerns outweigh this benefit. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 13:51:14,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.41 and 353.507 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.53) is slightly higher than Ligand B (72.88). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have similar logP values (1.331 and 1.399), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.6 and 0.615), indicating good drug-likeness.

**DILI:** Ligand A (48.507) has a higher DILI risk than Ligand B (4.382). This is a significant advantage for Ligand B.

**BBB:** Ligand A (65.917) has a better BBB penetration score than Ligand B (54.013). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.164) shows poorer Caco-2 permeability compared to Ligand B (-4.939). While both are negative, B is better.

**Aqueous Solubility:** Ligand A (-2.329) has lower aqueous solubility than Ligand B (-1.23). Solubility is important for bioavailability, favoring Ligand B.

**hERG Inhibition:** Ligand A (0.087) has a slightly lower hERG inhibition risk than Ligand B (0.298), which is preferable.

**Microsomal Clearance:** Ligand A (-2.441) has significantly lower microsomal clearance than Ligand B (11.272). Lower clearance indicates better metabolic stability, a key consideration for enzymes. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-6.03) has a shorter in vitro half-life than Ligand B (11.969). This reinforces the advantage of Ligand A regarding metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.037), which is good.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-6.5). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a clear advantage in binding affinity (-7.3 vs -6.5 kcal/mol). However, Ligand A exhibits superior metabolic stability (lower Cl_mic and longer t1/2) and a lower DILI risk. Solubility is also better for Ligand B. Considering SRC is a kinase (enzyme), metabolic stability and safety (DILI) are paramount. While the affinity difference is notable, the improved ADME profile of Ligand A, particularly the lower clearance and DILI, make it a more promising candidate.

Output:
0
2025-04-17 13:51:14,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.483 and 372.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (84.5), both are below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands (1.666 and 1.33) are within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 4 HBA, which are acceptable.

**QED:** Ligand A (0.755) has a better QED score than Ligand B (0.649), indicating higher drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (36.681 and 39.667, both <40).

**BBB:** Ligand B (71.501) has a better BBB penetration score than Ligand A (56.689), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.393) has worse Caco-2 permeability than Ligand B (-4.599), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.85) has better aqueous solubility than Ligand B (-3.52).

**hERG Inhibition:** Ligand A (0.196) has a much lower hERG inhibition liability than Ligand B (0.567), which is a significant advantage.

**Microsomal Clearance:** Ligand A (52.858) has lower microsomal clearance than Ligand B (69.759), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.953) has a longer in vitro half-life than Ligand B (-51.427), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux liability than Ligand B (0.154).

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.9 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, **Ligand A** is the more promising drug candidate. It has a better QED score, significantly lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly stronger binding affinity. While Ligand B has better Caco-2 permeability and BBB, these are less critical for a non-CNS enzyme target like SRC.

Output:
1
2025-04-17 13:51:14,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 354.382 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.54 and 85.69) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (1.331) is within the optimal 1-3 range. Ligand B (-0.109) is slightly below 1, which *could* indicate potential permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (7/6) counts, well within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.816 and 0.704), suggesting good drug-like properties.

**DILI:** Ligand A (36.448) has a lower DILI risk than Ligand B (48.313), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand B (83.831) has a higher BBB percentile than Ligand A (52.074).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.678 and -4.493), 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 (-1.597 and -1.76), which is also unusual and indicates poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.924) has a slightly higher hERG risk than Ligand B (0.151), which is a negative for Ligand A.

**Microsomal Clearance:** Ligand A (15.321) has a significantly higher microsomal clearance than Ligand B (3.259). This suggests that Ligand B is more metabolically stable, a crucial factor for enzymes.

**In vitro Half-Life:** Ligand B (-19.638) has a much longer in vitro half-life than Ligand A (19.387). This is a major advantage for Ligand B, as it suggests less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.347 and 0.031), which is favorable.

**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 only 0.4 kcal/mol, which may not be enough to overcome the ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2), has a lower DILI risk, and a significantly lower hERG risk. The slightly weaker binding affinity of Ligand B is likely outweighed by its superior ADME properties, especially given the relatively small difference in affinity. The poor solubility and permeability would need to be addressed through formulation or further structural modifications, but these are more tractable problems than poor metabolic stability or high toxicity risk.

Output:
1
2025-04-17 13:51:14,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.479 and 351.451 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.12) is significantly better than Ligand B (110.35). A TPSA under 140 is good for oral absorption, and A is much closer to the optimal <90 for CNS penetration (though that's not a priority here). B's TPSA is higher and may hinder absorption.

**logP:** Both ligands have similar logP values (-0.069 and -0.089), both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 5 HBA). Lower HBD counts generally improve permeability.

**QED:** Ligand A (0.695) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand A (12.641) has a much lower DILI risk than Ligand B (21.442). This is a significant advantage for A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (56.417) is better than Ligand B (16.363), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.848) is better than Ligand B (-5.676) indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.318) is better than Ligand B (-1.525), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.282 and 0.235), which is good.

**Microsomal Clearance:** Ligand A (0.034) has a much lower Cl_mic than Ligand B (-9.908). This suggests significantly better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (17.386) has a longer half-life than Ligand A (-3.526). However, the negative value for A is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.006).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While a 1 kcal/mol difference is noticeable, the substantial advantages of Ligand A in other ADME properties outweigh this.

**Overall:** Ligand A is the superior candidate. It has better TPSA, QED, DILI risk, solubility, and *significantly* better metabolic stability (Cl_mic). While Ligand B has slightly better binding affinity and half-life, the metabolic instability of A is a major concern, but the superior ADME profile of Ligand A makes it the more viable drug candidate.

Output:
0
2025-04-17 13:51:14,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.463 and 354.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.31) is better than Ligand B (58.2). Both are below the 140 threshold for oral absorption, but lower TPSA is generally preferred.

**logP:** Ligand A (0.652) is suboptimal, being slightly below the preferred 1-3 range. Ligand B (3.741) is within the optimal range. This favors Ligand B.

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

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (2) is also good.

**QED:** Both ligands have good QED scores (0.614 and 0.732, respectively), indicating drug-likeness.

**DILI:** Ligand A (4.731) has a very low DILI risk, which is excellent. Ligand B (38.891) is also reasonably low, but higher than A.

**BBB:** Ligand A (70.105) has moderate BBB penetration. Ligand B (83.249) has better BBB penetration. Since SRC is not a CNS target, this is a minor advantage for B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.467 and -4.558), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.548 and -4.543), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.31) has a very low hERG risk, which is excellent. Ligand B (0.58) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (21.336) has lower microsomal clearance than Ligand B (50.603), suggesting better metabolic stability. This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (11.843) has a shorter half-life than Ligand B (23.084). This favors B.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is excellent. Ligand B (0.342) has moderate P-gp efflux. This is a significant advantage for A.

**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 concerns.

**Overall Assessment:**

Ligand B has a better binding affinity and logP, and a longer half-life. However, Ligand A has significantly better DILI, hERG, and P-gp efflux profiles, and better metabolic stability (lower Cl_mic). Both have poor solubility and Caco-2 permeability, which are major concerns. The superior binding affinity of Ligand B is a critical factor for an enzyme inhibitor, and the difference is large enough to potentially overcome the slight ADME disadvantages.

Output:
1
2025-04-17 13:51:14,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.361 and 381.925 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.7) is slightly above the optimal <140, but acceptable. Ligand B (63.24) is well within the ideal range.

**logP:** Both ligands have logP values (2.578 and 3.605) within the optimal 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not drastically.

**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 (0.762 and 0.813), indicating good drug-like properties.

**DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (45.095). This is a significant concern.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (70.997) has a better BBB score than Ligand A (33.734), but this is less critical here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.359 and -4.947), which is unusual and suggests poor permeability. This is a major red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.62 and -3.399), indicating very poor aqueous solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.658) shows slightly higher hERG inhibition risk than Ligand B (0.31).

**Microsomal Clearance:** Ligand A (17.297) has lower microsomal clearance than Ligand B (26.845), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (37.208) has a slightly longer half-life than Ligand A (33.149).

**P-gp Efflux:** Ligand A (0.136) has lower P-gp efflux than Ligand B (0.414), which is beneficial for bioavailability.

**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.

**Conclusion:**

Despite both ligands having poor Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.5 kcal/mol) is a major advantage for an enzyme inhibitor. It also has a lower DILI risk, lower hERG risk, and a slightly longer half-life. While the higher logP and P-gp efflux are minor concerns, the superior potency and safety profile make Ligand B the better choice. The permeability and solubility issues would need to be addressed through formulation or further chemical modifications, but the strong binding affinity provides a solid foundation for optimization.

Output:
1
2025-04-17 13:51:14,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.459 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (43.86) as it is closer to the 140 threshold.

**logP:** Both ligands have good logP values (2.157 and 2.07), 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 3 HBA. Both are acceptable, but Ligand A's HBD count might slightly improve solubility.

**QED:** Ligand B (0.737) has a higher QED score than Ligand A (0.523), indicating a more drug-like profile.

**DILI:** Ligand B (5.816) has a significantly lower DILI risk than Ligand A (34.742), which is a major advantage.

**BBB:** Ligand B (81.311) shows better BBB penetration than Ligand A (62.233), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.656) has a worse Caco-2 permeability than Ligand B (-4.514).

**Aqueous Solubility:** Ligand A (-2.013) has a worse aqueous solubility than Ligand B (-0.953).

**hERG:** Both ligands have very low hERG risk (0.311 and 0.519), which is excellent.

**Microsomal Clearance:** Ligand A (29.615) has lower microsomal clearance than Ligand B (32.623), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.722) has a slightly longer in vitro half-life than Ligand A (6.423).

**P-gp Efflux:** Ligand A (0.248) has a lower P-gp efflux liability than Ligand B (0.041), which is a positive.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is highly significant.

**Conclusion:**

While Ligand A has slightly better metabolic stability and P-gp efflux, Ligand B overwhelmingly wins due to its significantly superior binding affinity (-7.4 vs 0.0 kcal/mol), lower DILI risk, better QED, and better solubility. The strong binding affinity is likely to outweigh any minor drawbacks in metabolic stability or P-gp efflux.

Output:
1
2025-04-17 13:51:14,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.463 and 350.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.31) is slightly higher than Ligand B (67.43), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (0.674) is a bit low, potentially hindering permeation. Ligand B (2.894) 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 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.858) has a significantly higher QED score than Ligand A (0.647), indicating better overall drug-likeness.

**DILI:** Ligand A (20.512) has a much lower DILI risk than Ligand B (43.079). This is a significant advantage for Ligand A.

**BBB:** Ligand B (75.029) shows better BBB penetration than Ligand A (53.548), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.45 and -4.231), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.594) has slightly better solubility than Ligand B (-3.77), though both are poor. Solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.26) has a much lower hERG risk than Ligand B (0.497). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (45.649) has lower microsomal clearance than Ligand B (49.9), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.422) has a slightly longer in vitro half-life than Ligand A (15.83), but the negative value for Ligand B is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.032) has a much lower P-gp efflux liability than Ligand B (0.109), indicating better bioavailability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a better QED and logP, Ligand A is significantly better regarding safety (DILI, hERG) and metabolic stability (Cl_mic). The similar binding affinities mean the ADME/Tox profile becomes the deciding factor. The lower DILI and hERG risks for Ligand A are crucial for a drug candidate, outweighing the slightly better QED and logP of Ligand B. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:51:14,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.362 and 359.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is better than Ligand B (96.97), both are below the 140 threshold for oral absorption, but A is closer to the ideal for better absorption.

**logP:** Ligand A (0.899) is slightly better than Ligand B (-0.628), both are within the optimal 1-3 range, but B is getting close to the lower limit which could impact permeability.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

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

**QED:** Ligand A (0.837) has a higher QED score than Ligand B (0.631), indicating a more drug-like profile.

**DILI:** Ligand B (35.634) has a significantly lower DILI risk than Ligand A (54.517), making it safer from a liver toxicity perspective.

**BBB:** Ligand B (78.519) has a higher BBB penetration percentile than Ligand A (57.968), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.893) has a worse Caco-2 permeability than Ligand B (-5.077), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.74) has a better aqueous solubility than Ligand B (-1.597), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.209 and 0.206), which is excellent.

**Microsomal Clearance:** Ligand B (-14.419) has a significantly lower microsomal clearance than Ligand A (19.291), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (4.337) has a positive half-life, while Ligand A (-19.095) has a negative half-life, indicating a much shorter half-life and faster metabolism. This is a significant drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.015).

**Binding Affinity:** Both ligands have similar binding affinities (-8.9 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so ADME properties become more important.

**Overall:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, positive t1/2), lower DILI risk, and comparable binding affinity. While Ligand A has slightly better solubility and TPSA, the metabolic liabilities of Ligand A are too significant to ignore for an enzyme target.

Output:
1
2025-04-17 13:51:14,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (334.354 Da and 372.881 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (80.71 and 72.78) well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (4.005 and 3.922) that are 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.

**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 (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.674 and 0.711), indicating good drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (97.325%) compared to Ligand B (73.982%). This is a major red flag for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (61.419% and 61.38%), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.72) shows poor Caco-2 permeability, while Ligand B (-5.169) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-6.799) has very poor aqueous solubility, while Ligand B (-5.148) is also poor, but better than A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.851 and 0.899), which is good.

**12. Microsomal Clearance:** Ligand B (41.964 mL/min/kg) has significantly lower microsomal clearance than Ligand A (11.056 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (41.298 hours) has a much longer in vitro half-life than Ligand A (90.772 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.329 and 0.606).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). The difference is 1.1 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, its significantly higher DILI risk, poor solubility, and poor Caco-2 permeability are major drawbacks. Ligand B, despite a slightly weaker binding affinity, demonstrates much better ADME properties, particularly lower DILI risk and improved metabolic stability (lower Cl_mic and longer t1/2). For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are crucial. The 1.1 kcal/mol difference in binding affinity can likely be overcome with further optimization of Ligand B, while mitigating the serious liabilities of Ligand A would be far more challenging.

Output:
1
2025-04-17 13:51:14,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (360.523 and 351.407 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is well below the 140 threshold, and favorable for oral absorption. Ligand B (129.37) is also below the threshold, but higher than A.

**3. logP:** Ligand A (3.334) is within the optimal range of 1-3. Ligand B (-1.015) is significantly below this range, which could hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is within the acceptable limit of <=5. Ligand B (4) is also within the limit, but higher than A.

**5. H-Bond Acceptors:** Ligand A (3) is within the acceptable limit of <=10. Ligand B (7) is also within the limit, but higher than A.

**6. QED:** Ligand A (0.571) is above the 0.5 threshold, indicating good drug-likeness. Ligand B (0.451) is below the threshold, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (46.995) has a lower DILI risk than Ligand B (27.801), both are good.

**8. BBB:** Ligand A (63.086) has a moderate BBB penetration, while Ligand B (23.769) has low BBB penetration. Since SRC is not a CNS target, this is less critical, but still a point for A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.222 and -5.659). This is unusual and suggests potential issues with intestinal absorption. However, negative values can sometimes occur in modeling and don't necessarily preclude activity.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.698 and -1.033). This is also concerning and suggests poor aqueous solubility, potentially impacting bioavailability.

**11. hERG Inhibition:** Ligand A (0.825) has a lower hERG risk than Ligand B (0.034).

**12. Microsomal Clearance:** Ligand A (94.58) has a higher microsomal clearance than Ligand B (-5.026), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.953) has a longer half-life than Ligand B (6.536).

**14. P-gp Efflux:** Ligand A (0.693) has lower P-gp efflux than Ligand B (0.002).

**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 substantial advantage.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from a very low logP, lower QED, and a significantly better hERG risk profile. Ligand A has better ADME properties (logP, QED, P-gp efflux, half-life) and a better DILI score, but weaker binding affinity.

Despite the solubility concerns for both, the significantly higher binding affinity of Ligand B is likely to outweigh the ADME drawbacks, especially if formulation strategies can address the solubility issue. The difference in binding affinity (>1.5 kcal/mol) is substantial enough to favor Ligand B.

Output:
1
2025-04-17 13:51:14,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 Da and 338.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.69) is better than Ligand B (70.07), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.009) is suboptimal, potentially hindering permeation. Ligand B (3.727) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

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

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

**QED:** Ligand A (0.796) is better than Ligand B (0.53), indicating a more drug-like profile.

**DILI:** Ligand A (31.02) is significantly better than Ligand B (56.727), suggesting a lower risk of drug-induced liver injury.

**BBB:** Ligand A (44.746) is lower than Ligand B (80.031). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.96 and -5.051) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-1.235) is slightly better than Ligand B (-4.03), both are poor.

**hERG:** Ligand A (0.235) is much better than Ligand B (0.919), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-8.848) is significantly better than Ligand B (69.218), indicating much better metabolic stability.

**In vitro Half-Life:** Ligand A (5.147) is much better than Ligand B (34.465), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.03) is much better than Ligand B (0.409), suggesting lower P-gp efflux.

**Binding Affinity:** Ligand A (-8.2) is significantly better than Ligand B (0.0), indicating much stronger binding.

**Overall Assessment:**

Ligand A excels in binding affinity, metabolic stability (Cl_mic and t1/2), DILI risk, hERG risk, and P-gp efflux. While its logP and solubility are suboptimal, the significantly stronger binding affinity (-8.2 kcal/mol vs 0.0 kcal/mol) and superior ADME properties outweigh these drawbacks. Ligand B has a better logP, but suffers from poor metabolic stability, higher DILI and hERG risk, and significantly weaker binding.

Output:
1
2025-04-17 13:51:14,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly preferred due to being lower in MW.

**TPSA:** Ligand A (53.51) is better than Ligand B (62.3), both are acceptable but lower TPSA generally aids absorption.

**logP:** Ligand A (1.79) is optimal, while Ligand B (3.713) is approaching the upper limit. This favors Ligand A.

**H-Bond Donors:** Both are acceptable (Ligand A: 0, Ligand B: 1).

**H-Bond Acceptors:** Both are acceptable (Ligand A: 3, Ligand B: 5).

**QED:** Both ligands have good QED scores (A: 0.844, B: 0.809), indicating good drug-like properties.

**DILI:** Ligand A (19.232) has a much lower DILI risk than Ligand B (67.817). This is a significant advantage for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (86.274) is better than Ligand B (68.088).

**Caco-2 Permeability:** Ligand A (-4.89) and Ligand B (-5.193) are similar and both show poor permeability.

**Aqueous Solubility:** Ligand A (-1.842) is better than Ligand B (-4.692). Solubility is important for bioavailability.

**hERG:** Ligand A (0.169) has a much lower hERG risk than Ligand B (0.335). This is a critical advantage.

**Microsomal Clearance:** Ligand A (49.307) has lower clearance than Ligand B (71.893), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.568) has a longer half-life than Ligand B (14.983). This is a significant advantage.

**P-gp Efflux:** Both are low, indicating minimal P-gp efflux.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a 1.5kcal/mol advantage, which is significant.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates significantly better ADMET properties. Specifically, the lower DILI risk, lower hERG inhibition, better solubility, and improved metabolic stability (lower Cl_mic and longer t1/2) are crucial for a viable drug candidate, especially for an enzyme target. The slightly lower affinity of Ligand A can potentially be optimized in subsequent iterations, but mitigating the risks associated with Ligand B's ADMET profile would be more challenging.

Output:
0
2025-04-17 13:51:14,458 - INFO - Batch 248 complete. Total preferences: 3968
2025-04-17 13:51:14,458 - INFO - Processing batch 249/512...
2025-04-17 13:51:58,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.267 Da) is slightly higher than Ligand B (355.435 Da), but both are acceptable.

**TPSA:** Ligand A (49.5) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (96.97) is higher, but still within a reasonable range, though potentially impacting absorption slightly.

**logP:** Ligand A (4.238) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (-0.188) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 5 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.639 and 0.629), indicating good drug-like properties.

**DILI:** Ligand A (52.074) has a slightly higher DILI risk than Ligand B (41.644), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.79) has a better BBB score than Ligand B (58.085), but it's not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.931 and -4.938), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.357 and -1.481), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.967) has a slightly higher hERG risk than Ligand B (0.062). Ligand B is much preferred here.

**Microsomal Clearance:** Ligand B (-2.885) has a significantly *lower* (better) microsomal clearance than Ligand A (59.082), indicating greater metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (75.157) has a much longer in vitro half-life than Ligand B (3.165), which is desirable.

**P-gp Efflux:** Ligand A (0.96) has a slightly higher P-gp efflux liability than Ligand B (0.008), meaning B is less likely to be pumped out of cells.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (0 kcal/mol). This is a decisive factor. The >1.5 kcal/mol advantage of B outweighs most of its drawbacks.

**Overall:** While both ligands have significant drawbacks (poor solubility and permeability), Ligand B is the stronger candidate. Its dramatically superior binding affinity (-8.5 vs 0 kcal/mol) and significantly better metabolic stability (lower Cl_mic) are critical advantages for an enzyme inhibitor. The lower hERG risk is also a positive. Although its logP is low, the high binding affinity may overcome this.



Output:
1
2025-04-17 13:51:58,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.515 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (61.88). A TPSA under 140 is good for oral absorption, and both are well below this, but A is preferable.

**logP:** Ligand A (3.666) is optimal, while Ligand B (1.169) is a bit low. A logP between 1-3 is preferred, and B is closer to the lower limit, potentially impacting permeability.

**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 range (<=10), but A is slightly better.

**QED:** Ligand B (0.809) has a better QED score than Ligand A (0.538), indicating a more drug-like profile overall.

**DILI:** Ligand A (10.198) has a much lower DILI risk than Ligand B (23.575). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (93.757) has a higher BBB percentile than Ligand B (65.839).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, A (-4.883) is slightly less negative than B (-4.642).

**Aqueous Solubility:** Ligand A (-3.95) has better solubility than Ligand B (-1.483). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.689 and 0.252 respectively), which is excellent.

**Microsomal Clearance:** Ligand B (7.298) has a significantly lower microsomal clearance than Ligand A (54.556). Lower clearance indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (15.755) has a much longer in vitro half-life than Ligand A (-3.649). This is a major advantage for B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.173 and 0.064).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a better QED score. However, Ligand A has a much lower DILI risk, better solubility, and a slightly better TPSA and logP. The binding affinity is comparable. Given the enzyme-specific priorities, metabolic stability is crucial. While the DILI risk for Ligand A is good, the significantly better metabolic profile of Ligand B outweighs this concern.

Output:
1
2025-04-17 13:51:58,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (53.33), being below the 140 threshold for good absorption. Ligand B is excellent.

**logP:** Ligand A (1.347) is optimal, while Ligand B (4.315) is slightly high. This could potentially lead to solubility issues and off-target interactions, but is not a dealbreaker.

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

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

**QED:** Both ligands have similar QED values (0.779 and 0.728), indicating good drug-likeness.

**DILI:** Ligand A (37.922) has a slightly higher DILI risk than Ligand B (28.383), but both are below the concerning threshold of 60.

**BBB:** Ligand A (53.858) has lower BBB penetration than Ligand B (79.527). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.928 and -4.794), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-2.361) has slightly better solubility than Ligand B (-5.523), but both are very poor. This is a major drawback.

**hERG Inhibition:** Ligand A (0.241) has a much lower hERG risk than Ligand B (0.91). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (18.371) has significantly lower microsomal clearance than Ligand B (95.472), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (15.906) has a lower half-life than Ligand B (35.312), but both are acceptable.

**P-gp Efflux:** Ligand A (0.026) has very low P-gp efflux, while Ligand B (0.784) has moderate efflux. This favors Ligand A.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a very significant advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B's significantly stronger binding affinity (-8.9 kcal/mol vs 0.0 kcal/mol) is a decisive factor. The improved metabolic stability (lower Cl_mic) and longer half-life of Ligand A are attractive, but the potency difference is too large to ignore for an enzyme target like SRC kinase. The higher hERG risk and P-gp efflux of Ligand B are concerns, but can be addressed with further optimization.

Output:
1
2025-04-17 13:51:58,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 352.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (65.87), both are under the 140 threshold for oral absorption.

**logP:** Ligand A (3.432) is optimal, while Ligand B (1.019) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Ligand A is preferable.

**QED:** Both ligands have similar QED scores (0.793 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (29.779) has a significantly lower DILI risk than Ligand B (20.047), a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (87.01) is better than Ligand B (69.833). While not a primary concern for a kinase inhibitor, it's a slight positive.

**Caco-2:** Ligand A (-4.385) is better than Ligand B (-5.025).

**Solubility:** Ligand A (-3.5) is better than Ligand B (-0.254). Solubility is important for bioavailability.

**hERG:** Ligand A (0.537) has a lower hERG risk than Ligand B (0.458), which is preferable.

**Microsomal Clearance:** Ligand A (69.711) has higher clearance than Ligand B (-6.869). Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A (-3.059) has a longer half-life than Ligand B (25.25).

**P-gp efflux:** Ligand A (0.239) has lower P-gp efflux than Ligand B (0.002).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-9.1 vs -7.5 kcal/mol). This is a crucial factor for an enzyme inhibitor. While Ligand B has a lower solubility and higher DILI risk, the potency advantage is substantial. Ligand B also has better metabolic stability. Ligand A has better solubility and lower DILI, but a weaker binding affinity. Given the priority for potency in enzyme inhibition, Ligand B is the more promising candidate.

Output:
1
2025-04-17 13:51:58,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (357.801 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (399.336 Da) is still well within the acceptable range.

**2. TPSA:** Ligand A (77.05) is higher than Ligand B (44.85). For an enzyme, TPSA is less critical than for CNS targets, but lower TPSA generally favors better cell permeability. Ligand B is significantly better here.

**3. logP:** Ligand A (2.48) is optimal, while Ligand B (4.217) is pushing the upper limit. High logP can lead to solubility issues and off-target interactions. Ligand A is preferable.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable and avoids potential issues with metabolic lability.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED scores (A: 0.719, B: 0.655), indicating good drug-like properties.

**7. DILI Risk:** Ligand A (72.392) has a higher DILI risk than Ligand B (25.165). This is a significant concern, as liver toxicity is a major cause of drug failure. Ligand B is much better here.

**8. BBB:** Both have good BBB penetration, but Ligand B (74.254) is slightly better than Ligand A (70.997). This isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.156 and -5.179). This is unusual and suggests very poor permeability. It's difficult to interpret without further information, but it's a negative for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.417 and -4.252). This is also a significant concern, as poor solubility can hinder absorption and bioavailability. Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.068) has a very low hERG risk, while Ligand B (0.929) has a moderate risk. This is a crucial factor, as hERG inhibition can cause cardiotoxicity. Ligand A is significantly better.

**12. Microsomal Clearance:** Ligand A (30.632) has lower microsomal clearance than Ligand B (42.607), indicating better metabolic stability. This is a key priority for enzymes.

**13. In vitro Half-Life:** Ligand A (-0.192) has a very short half-life, while Ligand B (28.524) has a much longer half-life. This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.356) has lower P-gp efflux than Ligand B (0.789), suggesting better oral bioavailability.

**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 decisive advantage, as potency is paramount for enzyme inhibitors. A difference of >7 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has better logP, hERG, and P-gp properties, Ligand B's significantly stronger binding affinity (-8.5 vs 0.0 kcal/mol) and substantially lower DILI risk are overriding advantages. The longer half-life of Ligand B is also a significant benefit. The poor Caco-2 and solubility values are concerning for both, but the potency and safety profile of Ligand B are more promising.

Output:
1
2025-04-17 13:51:58,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (475.71 Da) is higher, but still acceptable. Ligand B (360.523 Da) is lower, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values (A: 48, B: 46.34) well below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (A: 4.243, B: 4.513) slightly above the optimal range of 1-3, but not excessively so. This could lead to some solubility issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 4 HBA, which is favorable for permeability.

**QED:** Both ligands have similar QED scores (A: 0.587, B: 0.585), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (68.825%) than Ligand B (29.663%). This is a major concern.

**BBB:** Both ligands have reasonable BBB penetration (A: 60.101%, B: 64.793%), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands exhibit negative Caco-2 permeability values (A: -4.681, B: -5.206). This is unusual and suggests poor intestinal absorption. However, these values are often predictions and can be inaccurate.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -5.185, B: -3.909). This could limit bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.707, B: 0.764).

**Microsomal Clearance:** Ligand B has a much higher microsomal clearance (147.567 mL/min/kg) than Ligand A (78.689 mL/min/kg), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B has a shorter in vitro half-life (16.094 hours) than Ligand A (31.272 hours), consistent with the higher clearance.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.512, B: 0.744).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.1 kcal/mol) than Ligand A (-9.8 kcal/mol). While a difference of 1.7 kcal/mol is good, it needs to be weighed against other factors.

**Conclusion:**

Considering all factors, **Ligand A is the more promising candidate**. While it has a higher DILI risk, the difference in binding affinity is not substantial enough to overcome Ligand B's significantly worse metabolic stability (higher Cl_mic and shorter half-life) and potentially lower bioavailability (negative Caco-2). The DILI risk can be investigated further through structural modifications. The metabolic instability of Ligand B is more difficult to address without significantly altering its binding affinity.

Output:
0
2025-04-17 13:51:58,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.359 Da and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.04) is better than Ligand B (67.87), both are below 140, suggesting good absorption potential.

**logP:** Ligand A (-0.23) is a bit low, potentially hindering permeation. Ligand B (1.153) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

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

**QED:** Both ligands have good QED scores (0.541 and 0.799), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (68.011) and Ligand B (44.707) both have acceptable DILI risk, below 60. Ligand B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (47.926) and Ligand B (87.01) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.119) and Ligand B (-4.479) are both negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.878 and -1.994). This is a concern for both, but needs to be balanced against other factors.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.133 and 0.384), which is excellent.

**Microsomal Clearance:** Ligand A (49.385) has a higher microsomal clearance than Ligand B (15.651), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-18.425) has a shorter half-life than Ligand B (-9.489), further supporting Ligand B's better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.035).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.6 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't override other ADME considerations.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. While both have similar binding affinities and low hERG risk, Ligand B has a more favorable logP, lower DILI risk, significantly lower microsomal clearance and longer half-life, and a better QED score. The lower logP of Ligand A is a concern for permeability, and its higher clearance is a major drawback.

Output:
1
2025-04-17 13:51:58,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.36) is slightly higher than Ligand B (58.44). Both are below the 140 threshold for oral absorption, but B is significantly better.

**logP:** Both ligands have good logP values (1.52 and 1.16), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also good.

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

**QED:** Ligand B (0.82) has a higher QED score than Ligand A (0.599), indicating a more drug-like profile.

**DILI:** Ligand A (15.626) has a lower DILI risk than Ligand B (20.783), which is preferable.

**BBB:** Ligand B (86.894) shows better BBB penetration than Ligand A (50.872), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.997) and Ligand B (-4.752) have similar, very poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.277) has slightly better solubility than Ligand B (-0.566), though both are quite poor.

**hERG Inhibition:** Ligand A (0.121) has a lower hERG risk than Ligand B (0.287), which is a significant advantage.

**Microsomal Clearance:** Ligand B (11.412) has a lower microsomal clearance than Ligand A (15.122), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.317) has a *negative* half-life, which is impossible and suggests an issue with the data or the compound itself. Ligand A (12.95) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032 and 0.061).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.3), a difference of 0.7 kcal/mol.

**Conclusion:**

While Ligand B has a slightly better binding affinity and metabolic stability, the negative in vitro half-life is a major red flag. This indicates a significant problem with the compound's stability or the experimental data. Ligand A, while having slightly weaker binding and poorer metabolic stability, has a reasonable half-life, lower DILI risk, and lower hERG risk. Given the enzyme-specific priorities, and the critical importance of a plausible half-life, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 13:51:58,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.4 and 366.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is slightly higher than Ligand B (85.77), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.777) is slightly higher than Ligand B (0.568), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (2), both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), both are within the acceptable limit of <=10.

**QED:** Both ligands have similar, good QED values (0.709 and 0.737, respectively), indicating good drug-like properties.

**DILI:** Ligand A (32.261) has a lower DILI risk than Ligand B (25.708), which is preferable.

**BBB:** Ligand A (63.629) has a higher BBB penetration than Ligand B (21.675), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.22 and -5.283), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.394 and -1.048), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.126) has a lower hERG inhibition liability than Ligand B (0.446), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-22.081) has a much lower (better) microsomal clearance than Ligand B (-1.259), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (15.313) has a longer half-life than Ligand B (6.879), which is desirable.

**P-gp Efflux:** Ligand A (0.016) has a lower P-gp efflux liability than Ligand B (0.054), which is preferable.

**Binding Affinity:** Ligand B (-9.8) has a significantly stronger binding affinity than Ligand A (-8.8), a difference of 1.0 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-9.8 vs -8.8 kcal/mol). However, both ligands suffer from very poor solubility and permeability (negative Caco-2 and solubility values). Ligand A has better ADME properties across the board (lower DILI, better BBB, lower hERG, lower Cl_mic, longer t1/2, lower Pgp efflux). The affinity difference is substantial, but the ADME profile of Ligand A is considerably more favorable. Given the enzyme target class, metabolic stability (Cl_mic) and hERG risk are critical. Ligand A's superior metabolic stability and lower hERG risk, coupled with acceptable (though not ideal) ADME properties, make it a more promising starting point for optimization, despite the weaker binding.

Output:
0
2025-04-17 13:51:58,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.358 Da and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.24) is well below the 140 threshold, suggesting good absorption. Ligand B (104.54) is still acceptable but closer to the limit.

**logP:** Ligand A (2.544) is optimal (1-3). Ligand B (0.608) is a bit 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 4 HBA, and Ligand B has 5, both within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.5 (0.691 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 76.192, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 32.377, which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.974) and Ligand B (61.535) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.777) and Ligand B (-5.38) both show poor permeability.

**Aqueous Solubility:** Ligand A (-3.983) and Ligand B (-0.355) both show poor solubility.

**hERG Inhibition:** Ligand A (0.834) has a slightly higher hERG risk than Ligand B (0.034), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (43.452) has a higher clearance than Ligand B (14.424), indicating lower metabolic stability. This is a key negative for Ligand A.

**In vitro Half-Life:** Ligand A (-10.421) has a negative half-life, which is very poor. Ligand B (-14.451) is also poor, but slightly better than A.

**P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux than Ligand B (0.011), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 kcal/mol and -8.0 kcal/mol), with Ligand A being slightly better. However, the difference is less than 1.5 kcal/mol, so it's unlikely to outweigh other significant ADME issues.

**Conclusion:**

Despite Ligand A having slightly better binding affinity, Ligand B is the more promising candidate. Ligand A has a high DILI risk, poor metabolic stability (high Cl_mic, poor half-life), and poor solubility. Ligand B has a much better safety profile (lower DILI, lower hERG), better metabolic stability, and while permeability and solubility are both poor, they are similar between the two. The superior ADME profile of Ligand B outweighs the slightly better binding affinity of Ligand A.

Output:
1
2025-04-17 13:51:58,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.332 and 386.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.6) is slightly higher than Ligand B (67.87), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.987 and 2.34), 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:** Both ligands have similar and good QED scores (0.742 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (84.645) has a higher DILI risk than Ligand B (68.205). This is a significant concern.

**BBB:** Both ligands have moderate BBB penetration (62.97 and 59.984). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.353) has slightly better Caco-2 permeability than Ligand B (-4.784), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.867) has better aqueous solubility than Ligand B (-2.973). This is a positive attribute for bioavailability.

**hERG Inhibition:** Ligand A (0.612) has a slightly higher hERG inhibition risk than Ligand B (0.31), but both are reasonably low.

**Microsomal Clearance:** Ligand B (20.432) has a significantly higher microsomal clearance than Ligand A (3.713). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (24.969) has a longer in vitro half-life than Ligand B (16.874), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.262 and 0.137).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a substantially better binding affinity than Ligand B (-6.8 kcal/mol). This is a 1.8 kcal/mol difference, which is a significant advantage and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk, its significantly superior binding affinity (-8.6 vs -6.8 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The affinity difference is substantial enough to prioritize over the DILI concern, which can potentially be addressed through structural modifications in later optimization stages. Solubility is also better for Ligand A.

Output:
1
2025-04-17 13:51:58,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.387 and 341.411 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (102.05) is slightly higher than Ligand B (66.24). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have good logP values (1.991 and 2.968), 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 6 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.8) has a significantly better QED score than Ligand B (0.419), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (68.592 and 64.637), but are still below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (76.813 and 70.648). This isn't a primary concern for a kinase inhibitor, but isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.9 and -4.515). These values are unusual and suggest very poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.043 and -3.699), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.283 and 0.105), which is excellent.

**Microsomal Clearance:** Ligand A (43.339) has a lower microsomal clearance than Ligand B (56.164), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (17.084) has a longer in vitro half-life than Ligand B (-14.602). The negative value for Ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.482), which is favorable.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.6 vs -8.8 kcal/mol) is a major advantage for an enzyme inhibitor. It also has better metabolic stability (lower Cl_mic, longer t1/2) and a higher QED score. While both have concerning DILI scores, the difference isn't substantial enough to favor Ligand B. The negative solubility and permeability values would need to be addressed through formulation or structural modification, but the potency advantage of Ligand A makes it the better starting point.

Output:
0
2025-04-17 13:51:58,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.5 and 367.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is better than Ligand B (87.3), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.665 and 3.245), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* pose a minor solubility issue, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=3, HBA=3). Lower HBDs are generally favored for better permeability.

**QED:** Ligand A (0.871) has a significantly better QED score than Ligand B (0.721), indicating a more drug-like profile.

**DILI:** Ligand A (55.1) has a slightly higher DILI risk than Ligand B (44.6), but both are acceptable (<60).

**BBB:** Both have similar BBB penetration (79.1 and 77.9), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.868 and -4.774). This is unusual and suggests poor permeability. However, these values are on a log scale, so the difference is minimal.

**Aqueous Solubility:** Both have negative solubility values (-2.845 and -3.882), indicating poor solubility. Ligand B is slightly worse.

**hERG:** Ligand A (0.188) has a substantially lower hERG risk than Ligand B (0.354), which is a significant advantage.

**Microsomal Clearance:** Ligand A (32.93) has a higher microsomal clearance than Ligand B (28.93), meaning it is less metabolically stable. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-0.851) has a longer half-life than Ligand A (14.45). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.166) has lower P-gp efflux than Ligand B (0.095), which is favorable.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly better binding affinity than Ligand A (-8.2 kcal/mol). This 1 kcal/mol difference is substantial and likely outweighs many of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A's better QED, lower hERG risk, and lower P-gp efflux, Ligand B emerges as the more promising candidate. The significantly stronger binding affinity (-9.2 vs -8.2 kcal/mol) is the most critical factor for an enzyme inhibitor. The longer half-life of Ligand B also contributes to its favorability. While both have poor solubility and permeability, the potency advantage of Ligand B is likely to be more readily addressed through formulation strategies than improving the affinity of Ligand A.

Output:
1
2025-04-17 13:51:58,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.23 and 82.78) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.444 and 2.405) are within the optimal 1-3 range.

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

**QED:** Ligand A (0.756) has a better QED score than Ligand B (0.53), indicating a more drug-like profile.

**DILI:** Ligand A (24.118) has a significantly lower DILI risk than Ligand B (17.836), which is a major advantage.

**BBB:** Ligand A (65.801) has a higher BBB penetration percentile than Ligand B (48.003), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.251) has worse Caco-2 permeability than Ligand B (-4.663), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.724) has slightly worse solubility than Ligand B (-1.805), but both are negative, indicating poor solubility.

**hERG:** Ligand A (0.185) has a lower hERG risk than Ligand B (0.512), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (48.238) has higher microsomal clearance than Ligand B (29.924), meaning faster metabolism and potentially lower *in vivo* exposure. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (34.452) has a significantly longer in vitro half-life than Ligand A (-15.461), indicating better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.167), which is slightly favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates a significantly stronger binding affinity (-7.2 vs -9.0 kcal/mol) and a much better in vitro half-life (34.452 vs -15.461), which are critical for an enzyme inhibitor. While Ligand A has a better QED, lower DILI, and lower hERG risk, the superior potency and metabolic stability of Ligand B are more important for this target class. The slightly worse solubility and permeability of Ligand B can be addressed through formulation strategies.

Output:
1
2025-04-17 13:51:58,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.503 and 382.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (82.89). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (2.712 and 1.812), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is more favorable than Ligand B (2 HBD, 6 HBA). Lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.786 and 0.717), indicating good drug-likeness.

**DILI:** Ligand A (31.563) has a lower DILI risk than Ligand B (27.608), suggesting a better safety profile.

**BBB:** Both ligands have high BBB penetration (76.851 and 80.419), but this is less critical for a non-CNS target like SRC.

**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. This suggests very poor solubility, a significant drawback.

**hERG Inhibition:** Ligand A (0.658) has a lower hERG risk than Ligand B (0.453), which is desirable.

**Microsomal Clearance:** Ligand B (35.093) has significantly lower microsomal clearance than Ligand A (63.964), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-32.23) has a negative half-life, which is impossible. Ligand A has a half-life of 9.032 hours. This is a major issue for Ligand B.

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux than Ligand B (0.077), which is preferable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.0 and -7.7 kcal/mol).

**Overall Assessment:**

While both ligands have good binding affinity, Ligand B's negative half-life is a critical flaw. The significantly better metabolic stability (lower Cl_mic) of Ligand B is appealing, but the negative half-life overrides this benefit. Ligand A has a more reasonable half-life, lower DILI risk, and lower hERG risk, despite its higher clearance. The solubility and Caco-2 values are concerning for both, but the half-life issue for B is a dealbreaker.

Output:
1
2025-04-17 13:51:58,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (99.24) is higher than Ligand B (79.37), but both are reasonable.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 1.225, Ligand B: 1.803), which is optimal.

**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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (Ligand A: 0.702, Ligand B: 0.814), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 43.04, Ligand B: 49.515), below the 60 threshold.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 77.821, Ligand B: 70.415), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.262 and -5.328). This is unusual and suggests poor permeability, but the scale isn't clearly defined. It's hard to interpret without knowing the units.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.69 and -4.132). Similar to Caco-2, the scale is unclear, making interpretation difficult. Poor solubility could be a significant issue.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.453, Ligand B: 0.442), which is excellent.

**Microsomal Clearance:** Ligand B has a significantly lower microsomal clearance (26.74 mL/min/kg) compared to Ligand A (46.033 mL/min/kg). This suggests better metabolic stability for Ligand B, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (-22.124 hours) than Ligand A (-9.658 hours), further supporting its superior metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.091, Ligand B: 0.108), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -7.9 kcal/mol, Ligand B: -9.5 kcal/mol). Ligand B is slightly better (-1.6 kcal/mol advantage), but this difference is less critical given the other factors.

**Conclusion:**

Ligand B is the more promising candidate. While both ligands have good potency and acceptable safety profiles, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic and longer t1/2). This is a crucial advantage for a kinase inhibitor, as it suggests a potentially longer duration of action and reduced dosing frequency. The slightly better binding affinity of Ligand B is a bonus. The negative Caco-2 and solubility values are concerning for both, but the improved metabolic stability of Ligand B outweighs this concern.

Output:
1
2025-04-17 13:51:58,519 - INFO - Batch 249 complete. Total preferences: 3984
2025-04-17 13:51:58,519 - INFO - Processing batch 250/512...
2025-04-17 13:52:45,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.362 and 348.359 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.46) is better than Ligand B (101.93), both are acceptable but A is closer to the desirable <140 for oral absorption.

**logP:** Ligand A (1.826) is within the optimal range (1-3), while Ligand B (-0.136) is slightly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly better balanced than Ligand B (0 HBD, 7 HBA). Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.532 and 0.683), indicating drug-like properties.

**DILI:** Ligand A (56.417) has a significantly lower DILI risk than Ligand B (76.192), which is a major advantage.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.109) has worse Caco-2 permeability than Ligand B (-4.217), but both are negative values which is concerning.

**Aqueous Solubility:** Ligand A (-2.45) has slightly better solubility than Ligand B (-1.928), but both are poor.

**hERG:** Ligand A (0.407) has a much lower hERG risk than Ligand B (0.032), which is a critical advantage for safety.

**Microsomal Clearance:** Ligand B (41.727) has lower microsomal clearance than Ligand A (45.447), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (46.877) has a longer in vitro half-life than Ligand B (-16.639), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux than Ligand B (0.009), which is favorable.

**Binding Affinity:** Ligand A (-9.6 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.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better metabolic stability, Ligand A excels in crucial areas: significantly higher binding affinity, lower DILI risk, and lower hERG risk. The stronger binding affinity is particularly important for an enzyme target like SRC kinase. Although both have poor solubility and Caco-2 permeability, the superior potency and safety profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 13:52:45,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.58) is slightly higher than Ligand B (61.88), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.318) is optimal, while Ligand B (0.427) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Ligand A (0.707) has a better QED score than Ligand B (0.498), indicating better overall drug-likeness.

**DILI:** Ligand B (21.598) has a significantly lower DILI risk than Ligand A (31.563), which is a substantial advantage.

**BBB:** Ligand A (85.459) has a higher BBB percentile than Ligand B (42.924), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.434) has a slightly better Caco-2 permeability than Ligand B (-4.964), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.105) has better aqueous solubility than Ligand B (-1.254). Solubility is important for bioavailability.

**hERG:** Ligand A (0.785) has a lower hERG risk than Ligand B (0.205), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-11.807) exhibits significantly lower microsomal clearance (better metabolic stability) than Ligand A (65.498). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (43.144) has a longer half-life than Ligand B (2.622), which is desirable.

**P-gp Efflux:** Ligand A (0.451) has lower P-gp efflux than Ligand B (0.063), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). The difference is 0.6 kcal/mol, which is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B has a superior DILI profile and significantly better metabolic stability (lower Cl_mic). While Ligand A has better solubility and half-life, the lower logP of Ligand B is a concern, but the superior binding affinity and metabolic stability are more critical for an enzyme target like SRC. The slightly better affinity of B, combined with its improved metabolic profile, makes it the more promising candidate.

Output:
1
2025-04-17 13:52:45,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.403 and 361.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.69) is better than Ligand B (47.59), being closer to the threshold for good oral absorption (<=140).

**logP:** Ligand B (3.068) is optimal (1-3), while Ligand A (0.171) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it strikes a balance between solubility and permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.838) has a significantly higher QED score than Ligand B (0.578), indicating a more drug-like profile.

**DILI:** Ligand B (37.728) has a much lower DILI risk than Ligand A (55.719), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (74.913 and 78.209, respectively), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.589 and -5.158).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.982 and -1.854).

**hERG Inhibition:** Ligand A (0.136) shows a lower hERG inhibition risk than Ligand B (0.925), which is a positive.

**Microsomal Clearance:** Ligand B (58.427) has a lower microsomal clearance than Ligand A (16.543), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (50.835) has a shorter half-life than Ligand A (64.516), but both are acceptable.

**P-gp Efflux:** Ligand A (0.014) shows lower P-gp efflux than Ligand B (0.531), which is a positive.

**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 factor.

**Overall Assessment:**

Ligand B is preferable due to its better logP, lower DILI risk, and better metabolic stability (lower Cl_mic). The slightly better binding affinity of Ligand B also contributes. While Ligand A has a higher QED and lower hERG risk, the poor logP and higher DILI risk are significant drawbacks. The poor Caco-2 and solubility for both ligands are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:52:45,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.342 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.86) is better than Ligand B (78.87), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.178) is slightly better than Ligand B (1.629). Ligand B is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as it has fewer hydrogen bond donors and acceptors, which generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.776 and 0.651), indicating good drug-likeness.

**DILI:** Ligand B (8.453) has a significantly lower DILI risk than Ligand A (89.686). This is a major advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (64.521 and 65.607), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.361) has better Caco-2 permeability than Ligand B (-4.724).

**Aqueous Solubility:** Ligand B (-1.639) has better aqueous solubility than Ligand A (-5.64). This is beneficial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.651) has a lower hERG risk than Ligand B (0.286). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (99.72) has much higher microsomal clearance than Ligand B (11.369). This means Ligand B is much more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-4.318) has a longer in vitro half-life than Ligand A (-18.235), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux than Ligand B (0.056).

**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 stronger candidate. While Ligand A has slightly better Caco-2 permeability and P-gp efflux, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The improved solubility of Ligand B is also a plus. The slightly lower logP of Ligand B is a minor drawback, but the benefits outweigh this.

Output:
1
2025-04-17 13:52:45,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (383.945 Da and 364.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (58.36 and 58.73) well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.769) is within the optimal 1-3 range, while Ligand B (4.539) is slightly higher. While still acceptable, the higher logP of B could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, meeting the criteria of <=5 and <=10 respectively.

**QED:** Both ligands have acceptable QED scores (0.754 and 0.627), indicating good drug-like properties.

**DILI:** Ligand A (35.789) has a lower DILI risk than Ligand B (16.867), which is a significant advantage. Lower DILI is always preferred.

**BBB:** Both ligands have moderate BBB penetration (60.644 and 58.24). Since SRC is not a CNS target, this isn't a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.952 and -5.063). 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 ligands have negative solubility values (-3.409 and -4.237), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.848 and 0.808), which is excellent.

**Microsomal Clearance:** Ligand A (53.227) has significantly lower microsomal clearance than Ligand B (85.781). This suggests better metabolic stability for Ligand A, a key consideration for enzymes.

**In vitro Half-Life:** Ligand B (38.714) has a longer in vitro half-life than Ligand A (26.53), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.824 and 0.458).

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent and strong.

**Conclusion:**

While both ligands have strong binding affinity, Ligand A is the more promising candidate. It has a lower DILI risk and significantly better metabolic stability (lower Cl_mic). Although both have poor solubility and permeability, the lower DILI and improved metabolic stability of Ligand A outweigh the slightly longer half-life of Ligand B. The metabolic stability is particularly important for kinase inhibitors as they often require sustained exposure.

Output:
0
2025-04-17 13:52:45,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.483 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (99.61), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (2.925 and 1.622), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) 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 reasonable QED scores (0.755 and 0.612), indicating good drug-like properties.

**DILI:** Ligand A (63.978) has a higher DILI risk than Ligand B (39.473). This is a significant drawback for Ligand A.

**BBB:** BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (72.547) has a higher BBB percentile than Ligand A (42.032).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.224) is worse than Ligand B (-4.982), indicating lower intestinal absorption.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Assuming these are percentile scores, Ligand A (-2.863) is slightly worse than Ligand B (-2.685).

**hERG:** Ligand A (0.291) has a lower hERG risk than Ligand B (0.806), which is a positive attribute.

**Microsomal Clearance:** Ligand B (36.855) has significantly lower microsomal clearance than Ligand A (67.971), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (37.492) has a longer half-life than Ligand B (2.091), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.148) has lower P-gp efflux than Ligand B (0.069), indicating better bioavailability.

**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 still a benefit.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life and lower P-gp efflux, Ligand B exhibits significantly better metabolic stability (lower Cl_mic), a lower DILI risk, and slightly better binding affinity. The lower DILI risk and improved metabolic stability are crucial for kinase inhibitors, outweighing the benefits of Ligand A's longer half-life.

Output:
1
2025-04-17 13:52:45,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 Da and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is well below the 140 threshold for oral absorption, while Ligand B (116.76) is still acceptable but closer to the limit.

**logP:** Ligand A (2.279) is optimal (1-3). Ligand B (-0.277) is below 1, which could hinder permeation.

**H-Bond Donors & Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=4, HBA=5) both are within acceptable limits.

**QED:** Ligand A (0.672) has a better QED score than Ligand B (0.448), indicating better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (Ligand A: 20.706, Ligand B: 22.373), which is good.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (66.537) has a higher BBB percentile than Ligand B (47.654).

**Caco-2 Permeability:** Ligand A (-4.756) and Ligand B (-5.321) 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 (-1.828) and Ligand B (-0.561) both have negative values, which suggests poor solubility.

**hERG:** Both ligands have very low hERG risk (Ligand A: 0.159, Ligand B: 0.073), which is excellent.

**Microsomal Clearance:** Ligand A (37.646) has a higher microsomal clearance than Ligand B (16.514), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-17.232) has a negative half-life, which is impossible. This is a major red flag. Ligand A (5.394) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.028, Ligand B: 0.015).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). The difference is 0.8 kcal/mol, which is not substantial enough to overcome other significant drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, its negative in vitro half-life is a critical flaw. Ligand A has better QED, a positive half-life, and acceptable values for most other parameters. The solubility and Caco-2 permeability are concerns for both, but Ligand A is preferable overall.

Output:
0
2025-04-17 13:52:45,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.451 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.99) is better than Ligand B (49.41) as it is closer to the upper limit of 140, suggesting good oral absorption potential.

**logP:** Ligand B (3.42) is slightly higher than Ligand A (0.302). While 3.42 is approaching the upper limit, 0.302 is quite low and could indicate poor membrane permeability.

**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 (0.75 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (32.571) has a significantly lower DILI risk than Ligand B (17.449), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (60.527 and 68.282). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.713 and -4.884). This is unusual and suggests poor permeability, but the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-1.629) has better solubility than Ligand B (-3.813). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.325 and 0.355).

**Microsomal Clearance:** Ligand A (-14.638) has significantly lower microsomal clearance than Ligand B (53.011), indicating better metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-14.299) has a longer in vitro half-life than Ligand B (-4.605), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.009 and 0.272).

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage (2 kcal/mol difference).

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk and significantly higher microsomal clearance, leading to a shorter half-life. Ligand A has better ADME properties (lower DILI, better solubility, better metabolic stability), but its binding affinity is weaker.

Given the substantial difference in binding affinity (-10.1 vs -8.1 kcal/mol), the advantage of Ligand B outweighs its ADME drawbacks. Optimization of Ligand B could address the DILI and metabolic stability issues, while retaining the strong potency.

Output:
1
2025-04-17 13:52:45,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.359 Da and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.71) is better than Ligand B (67.43), both are below the 140 threshold for oral absorption, and Ligand B is particularly good.

**logP:** Ligand A (-0.114) is quite low, potentially hindering permeability. Ligand B (2.656) is within the optimal 1-3 range. 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 6 HBA, and Ligand B has 4 HBA, both are within the acceptable range (<=10).

**QED:** Ligand A (0.73) has a slightly better QED score than Ligand B (0.582), indicating a more drug-like profile.

**DILI:** Ligand A (69.058) has a higher DILI risk than Ligand B (23.885). This is a significant advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (71.772) is better than Ligand A (19.814).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.062) is slightly better than Ligand B (-4.977).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.115) is slightly better than Ligand B (-3.174).

**hERG Inhibition:** Ligand A (0.046) has a slightly lower hERG risk than Ligand B (0.194), which is preferable.

**Microsomal Clearance:** Ligand A (-15.551) has a much lower (better) microsomal clearance than Ligand B (76.35). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-34.443) has a much longer in vitro half-life than Ligand B (12.05). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.106, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B has advantages in logP, DILI, BBB, and TPSA. However, Ligand A excels in metabolic stability (Cl_mic and t1/2), and has slightly better hERG risk. Given that SRC is an enzyme, metabolic stability and minimizing off-target effects (hERG) are crucial. The similar binding affinity makes these factors the deciding ones. While the solubility and permeability are poor for both, the metabolic advantages of Ligand A are more critical for kinase inhibitors, which often require sustained exposure.

Output:
0
2025-04-17 13:52:45,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.483 and 351.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is better than Ligand B (73.91), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (3.437) is higher than Ligand A (0.707). While 0.707 is on the low side and could hinder permeation, 3.437 is approaching the upper limit and could lead to solubility issues.

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

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

**QED:** Ligand A (0.801) has a higher QED score than Ligand B (0.677), indicating better overall drug-likeness.

**DILI:** Ligand A (9.616%) has a significantly lower DILI risk than Ligand B (11.322%). This is a substantial advantage.

**BBB:** Both ligands have moderate BBB penetration (54.478% and 62.233% respectively). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.383) has worse Caco-2 permeability than Ligand B (-4.476).

**Aqueous Solubility:** Ligand A (-1.675) has better aqueous solubility than Ligand B (-3.357). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.28) has a much lower hERG inhibition liability than Ligand B (0.821). This is a critical advantage, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-9.849) has *much* lower microsomal clearance than Ligand B (58.417), indicating significantly better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (6.539) has a shorter half-life than Ligand B (40.524). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.871), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.9 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.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better Caco-2 permeability and a longer half-life, Ligand A excels in crucial areas: significantly lower DILI risk, much lower hERG inhibition, dramatically improved metabolic stability (lower Cl_mic), better solubility, and slightly better binding affinity. The lower logP of Ligand A is a minor concern, but the other advantages outweigh this. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 13:52:45,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (354.43 and 364.51 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.29) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (58.64) is well within the optimal range.

**3. logP:** Ligand A (0.741) is a bit low, potentially hindering permeation. Ligand B (3.125) is optimal.

**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 each), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.668 and 0.873), indicating drug-like properties.

**7. DILI:** Ligand A (31.291) has a significantly lower DILI risk than Ligand B (47.15), placing it in the preferred <40 range. Ligand B is still acceptable, but higher.

**8. BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (83.831) is higher than Ligand B (63.009).

**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 show low hERG inhibition risk (0.271 and 0.445).

**12. Microsomal Clearance (Cl_mic):** Ligand B (37.291) has lower microsomal clearance than Ligand A (45.586), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (20.654) has a significantly longer in vitro half-life than Ligand A (-32.051), which is a major advantage.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.01 and 0.376).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a crucial advantage for an enzyme inhibitor.

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and half-life. While both have issues with solubility and Caco-2 permeability, the significantly better binding affinity and metabolic stability of Ligand B outweigh these concerns. The lower DILI risk of Ligand A is a positive, but the affinity difference is substantial.

Output:
1
2025-04-17 13:52:45,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.379 and 355.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.58) is higher than Ligand B (61.44). While both are acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Both ligands (1.454 and 1.551) are 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 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.86) has a significantly higher QED score than Ligand B (0.681), indicating a more drug-like profile.

**DILI:** Ligand A (41.024) has a slightly higher DILI risk than Ligand B (17.449), but both are below the concerning threshold of 60.

**BBB:** Ligand A (24.661) has a very low BBB penetration, while Ligand B (91.237) has excellent BBB penetration. Since SRC is not a CNS target, this is less important, but still a point in favor of B.

**Caco-2 Permeability:** Ligand A (-4.808) has poor Caco-2 permeability, while Ligand B (-5.234) is also poor.

**Aqueous Solubility:** Ligand A (-2.682) has slightly better solubility than Ligand B (-2.335), but both are poor.

**hERG Inhibition:** Both ligands (0.773 and 0.65) have low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (-35.893) has significantly lower (better) microsomal clearance than Ligand B (-1.617), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.891 hours) has a much longer half-life than Ligand B (4.946 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands (0.144 and 0.039) have low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in QED, metabolic stability (Cl_mic), and half-life. Ligand B has better TPSA and a slightly better binding affinity, and significantly better BBB penetration. However, the superior metabolic stability and half-life of Ligand A, combined with its good QED score, outweigh the small binding affinity advantage of Ligand B. Both have poor solubility and Caco-2 permeability, which would need to be addressed in further optimization, but the metabolic profile of A is more promising for an enzyme target.

Output:
1
2025-04-17 13:52:45,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (344.37 and 368.40 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.63) is slightly higher than Ligand B (67.87), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have acceptable logP values (1.01 and 1.59), 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 6 HBAs, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have reasonable QED scores (0.46 and 0.64), with Ligand B being slightly more drug-like.

**7. DILI:** Ligand A has a DILI risk of 68.86, which is moderately high. Ligand B has a much lower DILI risk (21.87), which is a significant advantage.

**8. BBB:** Both ligands have reasonable BBB penetration, with Ligand B (89.84) being higher than Ligand A (74.76). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.74 and -4.65), which is unusual and suggests poor permeability. This is a potential red flag for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.16 and -1.68), indicating very poor aqueous solubility. This is a significant concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.34) has a slightly lower hERG risk than Ligand B (0.53), which is preferable.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (74.12) than Ligand B (32.33), indicating lower metabolic stability. This is a major drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B has a much longer in vitro half-life (-7.78 hours) than Ligand A (17.65 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.44) has a slightly lower P-gp efflux liability than Ligand B (0.04).

**15. Binding Affinity:** Ligand A has a better binding affinity (-8.9 kcal/mol) than Ligand B (-7.6 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a shorter half-life. Ligand B has a lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better BBB penetration. The poor solubility and permeability are concerns for both, but the superior affinity of Ligand A might be able to overcome these issues with appropriate formulation strategies.

Considering the enzyme-specific priorities, the metabolic stability and lower toxicity profile of Ligand B are very important. The 1.3 kcal/mol difference in binding affinity, while substantial, might be addressable through further optimization of Ligand B. The poor solubility and permeability are shared issues that would need to be addressed regardless of which lead is chosen.

Output:
1
2025-04-17 13:52:45,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.5 and 371.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (69.72). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target. Ligand A is well below the 140 threshold, while Ligand B is approaching it.

**logP:** Both ligands have acceptable logP values (2.236 and 1.741), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is more favorable than Ligand B (1 HBD, 4 HBA). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have good QED scores (0.449 and 0.635), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (3.994) has a much lower DILI risk than Ligand B (25.165). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.615) has better BBB penetration than Ligand B (61.225), but this isn't a primary concern.

**Caco-2 Permeability:** Ligand A (-4.651) has a much better Caco-2 permeability than Ligand B (-5.148). This suggests better intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-1.023) has better aqueous solubility than Ligand B (-2.44). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.622 and 0.404), which is good.

**Microsomal Clearance:** Ligand A (16.121) has significantly lower microsomal clearance than Ligand B (56.11). This indicates better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (5.974) has a slightly better in vitro half-life than Ligand B (2.529).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.09).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is relatively small (0.9 kcal/mol), and the other ADME properties of Ligand A are considerably better.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties: lower DILI risk, better Caco-2 permeability, better aqueous solubility, and significantly improved metabolic stability (lower Cl_mic and better t1/2). These factors are crucial for a successful kinase inhibitor, outweighing the minor difference in binding affinity.

Output:
0
2025-04-17 13:52:45,442 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [370.471, 92.01, 1.367, 2, 6, 0.672, 41.411, 37.96, -5.071, -2.552, 0.285, 37.518, 38.469, 0.086, -8.1]
**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, -9.2]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (349.475) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.
2. **TPSA:** Both are below 140, good for oral absorption. Ligand B (84.23) is better than Ligand A (92.01).
3. **logP:** Ligand A (1.367) is optimal, while Ligand B (3.078) is at the higher end of optimal.
4. **HBD:** Both have 2 HBD, which is good.
5. **HBA:** Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable, with Ligand B being slightly better.
6. **QED:** Both have good QED scores (>0.5), Ligand B (0.792) is slightly better.
7. **DILI:** Both have acceptable DILI risk (<40 is good). Ligand A (41.411) is slightly higher, but still within a reasonable range. Ligand B (35.091) is better.
8. **BBB:** Ligand B (80.419) has a significantly higher BBB penetration score than Ligand A (37.96). However, SRC is not a CNS target, so this is less critical.
9. **Caco-2:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability. Ligand A (-5.071) is worse than Ligand B (-4.745).
10. **Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.552) is slightly better than Ligand B (-3.593).
11. **hERG:** Both have low hERG inhibition liability, which is good. Ligand A (0.285) is slightly better.
12. **Cl_mic:** Ligand A (37.518) has a lower microsomal clearance than Ligand B (76.391), indicating better metabolic stability. This is a key consideration for enzymes.
13. **t1/2:** Ligand A (38.469) has a longer in vitro half-life than Ligand B (-23.047). This is a significant advantage for dosing frequency.
14. **Pgp:** Both have low P-gp efflux liability. Ligand B (0.166) is slightly better.
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 >1 kcal/mol advantage, which is substantial.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B has a much better binding affinity. Ligand A has better metabolic stability and half-life, but the difference in binding affinity is substantial enough to outweigh these benefits. Solubility is poor for both, but Ligand A is slightly better.

**Conclusion:**

Despite Ligand A's slightly better metabolic stability and solubility, the significantly stronger binding affinity of Ligand B makes it the more promising drug candidate. The difference in binding affinity is likely to have a greater impact on efficacy than the modest differences in ADME properties.

1
2025-04-17 13:52:45,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.427 and 347.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.78) is higher than Ligand B (52.65). Both are below the 140 threshold for oral absorption, but lower is generally better. Ligand B is preferable here.

**3. logP:** Ligand A (1.123) is within the optimal range (1-3), while Ligand B (2.492) is closer to the upper limit. Both are acceptable, but A is slightly better.

**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:** Both ligands have good QED scores (0.596 and 0.72), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (22.761) has a significantly lower DILI risk than Ligand B (13.61). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (55.138) has a lower BBB penetration percentile than Ligand B (76.658). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.565 and -4.925). This 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 ligands have negative solubility values (-1.215 and -1.245). Similar to Caco-2, these are on a log scale and suggest poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.347 and 0.33), which is excellent.

**12. Microsomal Clearance:** Ligand A (3.441) has significantly lower microsomal clearance than Ligand B (31.393). This indicates better metabolic stability for Ligand A, a key priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (0.171) has a very short in vitro half-life, while Ligand B (-1.288) has a negative value, which is also problematic. Both are poor, but the negative value for B is more concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.077 and 0.107).

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). This 0.8 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, and slightly better binding affinity. The better binding affinity is crucial for an enzyme inhibitor. The short half-life is a concern, but can be addressed through structural modifications. Ligand B's higher DILI risk and significantly higher clearance are major drawbacks.

Output:
0
2025-04-17 13:52:45,443 - INFO - Batch 250 complete. Total preferences: 4000
2025-04-17 13:52:45,443 - INFO - Processing batch 251/512...
2025-04-17 13:53:25,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.503 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.15 and 86.78) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.133 and 1.581) 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:** Both ligands have 5 HBAs, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.729 and 0.83), indicating drug-like properties.

**DILI:** Ligand A (14.036) has a significantly lower DILI risk than Ligand B (37.03). This is a major advantage.

**BBB:** Both ligands have good BBB penetration (74.564 and 78.907), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.635 and -4.256). 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 (-2.368 and -2.065). Similar to Caco-2, the scale is unclear, but negative values suggest poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.706 and 0.521).

**Microsomal Clearance:** Ligand A (46.194) has a higher microsomal clearance than Ligand B (-0.132). This suggests Ligand B is more metabolically stable, which is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-3.138) has a negative half-life, which is problematic. Ligand B (34.184) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.174).

**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 less than the 1.5 kcal/mol threshold to outweigh other issues, it's still a positive.

**Conclusion:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk, Ligand B has a significantly better in vitro half-life and a slightly better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the improved metabolic stability (lower Cl_mic and positive t1/2) of Ligand B is more critical for an enzyme inhibitor.

Output:
1
2025-04-17 13:53:25,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.429 and 365.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (104.36) is still under 140, but less favorable than A.

**3. logP:** Both ligands have good logP values (2.417 and 1.63), 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 6. Both are within the acceptable limit of 10, but A is preferable.

**6. QED:** Ligand A (0.622) has a better QED score than Ligand B (0.482), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (49.128), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.066) is better than Ligand B (36.448), but not a deciding factor.

**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 low hERG risk (0.419 and 0.568).

**12. Cl_mic:** Ligand A has a lower microsomal clearance (24.161) than Ligand B (57.164), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. t1/2:** Ligand B has a much longer in vitro half-life (22.289 hours) compared to Ligand A (2.168 hours). This is a significant advantage for dosing convenience.

**14. Pgp:** Both have low Pgp efflux liability (0.03 and 0.099).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is already very good, the 1.2 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in DILI risk, TPSA, QED, and metabolic stability. Ligand B shines with its significantly longer half-life and slightly improved binding affinity. The poor solubility and Caco-2 values for both are concerning, but the difference in metabolic stability is crucial for an enzyme target. However, the superior binding affinity of Ligand B is a strong argument in its favor. Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity (-7.2 vs -8.4), I would prioritize Ligand B, assuming the solubility and permeability issues can be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 13:53:25,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 370.603 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (49.41) as it is closer to the threshold of 140.

**logP:** Both ligands have logP values within the optimal range (2.156 and 3.947). Ligand B is slightly higher, which *could* present solubility challenges, but isn't a major concern.

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

**DILI:** Ligand A (45.677) has a slightly higher DILI risk than Ligand B (9.926), but both are below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated. Ligand B (84.257) is better than Ligand A (62.621).

**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 (0.187) has a lower hERG risk than Ligand B (0.862), which is a significant advantage.

**Microsomal Clearance:** Ligand B (88.598) has a higher microsomal clearance than Ligand A (81.155), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-21.582) has a negative half-life, which is unusual. Ligand B (15.116) has a positive half-life.

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux than Ligand B (0.3), which is favorable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol) - a difference of 1.9 kcal/mol. This is a substantial advantage that can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better QED, lower DILI, lower hERG, and lower P-gp efflux, the substantially stronger binding affinity of Ligand B (-8.7 vs -6.8 kcal/mol) is the most critical factor for an enzyme inhibitor. The difference in affinity is large enough to compensate for the slightly higher DILI and hERG risk, and the higher clearance. The negative solubility and Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 13:53:25,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.414 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is well below the 140 threshold, suggesting good absorption. Ligand B (95.74) is higher but still within a reasonable range for an enzyme inhibitor, though potentially less optimal for oral absorption.

**logP:** Ligand A (3.479) is at the upper end of the optimal range (1-3), while Ligand B (1.055) is at the lower end. While Ligand B's logP is acceptable, it's closer to the threshold where permeability might be compromised.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 HBA, which is favorable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.771 and 0.833), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 58.123, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (23.769), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (92.943) has better BBB penetration than Ligand B (79.992).

**Caco-2 Permeability:** Ligand A (-4.239) shows poor Caco-2 permeability, which is a concern. Ligand B (-5.337) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.7) has very poor aqueous solubility, a major drawback. Ligand B (-2.421) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.53) has a slightly higher hERG risk than Ligand B (0.352), but both are relatively low.

**Microsomal Clearance:** Ligand A (43.866) has moderate clearance. Ligand B (-36.291) has *negative* clearance, which is highly unusual and suggests excellent metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (5.65 hours) has a moderate half-life. Ligand B (-7.031 hours) also has a negative half-life, which is impossible and likely indicates an error in the data or a very stable compound.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.646 and 0.011), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -8.6 kcal/mol). Ligand A is slightly better (-9.7 kcal/mol), 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 and BBB penetration, Ligand B has a significantly lower DILI risk, far superior metabolic stability (negative clearance and half-life), and better aqueous solubility. The poor Caco-2 permeability of both is a concern, but can potentially be addressed through formulation strategies. The combination of low DILI and high metabolic stability outweighs the slight affinity difference.

Output:
1
2025-04-17 13:53:25,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.5) is slightly higher than Ligand B (345.4).

**TPSA:** Ligand A (97.82) is better than Ligand B (112.91), falling comfortably under the 140 Angstrom threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (A: 0.986, B: 1.902), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 5 HBA) as fewer H-bond donors generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.509, B: 0.633), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (69.523), but both are reasonably low and below the concerning 60 threshold.

**BBB:** Ligand A (71.229) has a significantly better BBB penetration score than Ligand B (34.858). While SRC is not a CNS target, better BBB penetration can sometimes correlate with better overall permeability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.135 and -5.385). This is unusual and suggests poor permeability. However, these values are on a log scale and require careful interpretation.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.905 and -3.216). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.711) has a slightly higher hERG inhibition risk than Ligand B (0.15). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (78.551) has a higher microsomal clearance than Ligand B (38.832), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-11.691) has a significantly longer in vitro half-life than Ligand A (0.068). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.259) has lower P-gp efflux liability than Ligand B (0.037), which is preferable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior binding affinity (-7.6 vs -6.6 kcal/mol) is the most important factor, outweighing its slightly less favorable TPSA and logP. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and a better QED score. While both have poor predicted solubility and permeability, the potency and ADME advantages of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 13:53:25,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 364.486 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (60.85 and 58.2) below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (2.404 and 3.804) within the optimal range of 1-3, though Ligand B is approaching the upper limit.

**4. H-Bond Donors:** Ligand A (1 HBD) and Ligand B (2 HBDs) are both acceptable, staying below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands (3 HBAs) are well below the 10 threshold.

**6. QED:** Both ligands have QED values (0.72 and 0.689) above 0.5, indicating good drug-likeness.

**7. DILI:** Both ligands have similar low DILI risk (34.82 and 34.781 percentile), which is good.

**8. BBB:** Both ligands have reasonable BBB penetration (71.811 and 83.676 percentile), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.704 and -4.949), which is unusual and problematic. This suggests very poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.57 and -3.86), which is also problematic and suggests very poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.35 and 0.277), which is excellent.

**12. Microsomal Clearance:** Ligand A (60.893 mL/min/kg) has higher clearance than Ligand B (55.674 mL/min/kg), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (29.194 hours) has a significantly longer half-life than Ligand A (18.721 hours), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.183 and 0.249), which is favorable.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol), by a margin of 0.7 kcal/mol. This is a substantial difference and outweighs some of the minor ADME concerns.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.1 vs -7.4 kcal/mol) and longer half-life (29.194 vs 18.721 hours) are critical advantages for an enzyme inhibitor. While both have poor predicted permeability and solubility, the potency and stability of Ligand B make it the better starting point for optimization. Addressing the solubility and permeability issues will be crucial, but a strong starting point in potency is vital.

Output:
1
2025-04-17 13:53:25,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.451 and 335.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.57) is slightly above the optimal <140, but acceptable. Ligand B (78.86) is excellent, well below 140.

**logP:** Ligand A (-0.447) is a bit low, potentially hindering permeability. Ligand B (2.557) is within the optimal 1-3 range.

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

**QED:** Both ligands have good QED scores (0.551 and 0.687, respectively), indicating drug-likeness.

**DILI:** Ligand A (11.322) has a very favorable DILI score, indicating low liver injury risk. Ligand B (63.086) is significantly higher, raising a concern.

**BBB:** Both have similar, moderate BBB penetration (around 40). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.674 and -5.358) which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.211 and -3.062) which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.087) has a very low hERG risk, which is excellent. Ligand B (0.729) is higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-53.786) has a very favorable, low microsomal clearance, indicating good metabolic stability. Ligand B (67.547) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (8.451 hours) has a reasonable half-life. Ligand B (45.932 hours) has a significantly longer half-life, a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.001 and 0.014), which is good.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.4 and -8.3 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in DILI risk and metabolic stability (Cl_mic), and has a slightly better binding affinity and hERG risk. However, its logP is suboptimal and both ligands have poor Caco-2 and solubility. Ligand B has a much longer half-life, which is a significant benefit, and a better logP. However, its DILI risk is considerably higher.

Considering the enzyme-specific priorities, metabolic stability (Ligand A) and low toxicity (Ligand A) are crucial. The slightly better affinity of Ligand A is a bonus. While the poor solubility and permeability are concerning for both, these can potentially be addressed through formulation strategies. The higher DILI risk of Ligand B is a more difficult issue to overcome.

Output:
0
2025-04-17 13:53:25,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.403 and 348.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.16) is better than Ligand B (137.58). Lower TPSA generally favors better absorption.

**logP:** Ligand A (0.154) is slightly better than Ligand B (-0.203), both are a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is preferable to Ligand B (4 HBD, 7 HBA). Lower counts are generally better for permeability.

**QED:** Ligand A (0.729) has a significantly better QED score than Ligand B (0.543), indicating a more drug-like profile.

**DILI:** Ligand A (43.66) has a much lower DILI risk than Ligand B (63.086), a significant advantage.

**BBB:** Ligand A (31.834) has a lower BBB penetration than Ligand B (16.945), but BBB is not a high priority for a kinase inhibitor unless CNS activity is desired.

**Caco-2:** Both ligands have poor Caco-2 permeability (-5.697 and -5.611). This is a concern for oral bioavailability.

**Solubility:** Both ligands have poor aqueous solubility (-1.579 and -1.407). This is a concern for formulation and bioavailability.

**hERG:** Ligand A (0.145) has a much lower hERG risk than Ligand B (0.062), a critical advantage.

**Microsomal Clearance:** Ligand A (-25.255) has significantly lower (better) microsomal clearance than Ligand B (23.007), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (29.14) has a much longer in vitro half-life than Ligand B (3.236), a significant advantage.

**P-gp Efflux:** Ligand A (0.006) has a lower P-gp efflux liability than Ligand B (0.023), which is beneficial.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While affinity is crucial, the other ADME properties of Ligand A are considerably better. The difference in affinity (0.8 kcal/mol) is not substantial enough to outweigh the significant improvements in other parameters.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more viable drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly improved DILI risk, hERG inhibition, metabolic stability (lower Cl_mic and longer t1/2), P-gp efflux, QED, and solubility. The poor Caco-2 and aqueous solubility are concerns for both, but can be addressed through formulation strategies. The superior ADME profile of Ligand A makes it a more promising starting point for further optimization.

Output:
0
2025-04-17 13:53:25,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.4 and 347.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is slightly higher than Ligand B (75.88), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.443) is a bit low, potentially hindering permeation. Ligand B (1.152) is better, 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 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.83 and 0.82), indicating good drug-likeness.

**DILI:** Ligand A (62.001) has a higher DILI risk than Ligand B (38.581). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the model or data.

**Aqueous Solubility:** Both have negative solubility values which is unusual and suggests issues with the model or data.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.138 and 0.105).

**Microsomal Clearance:** Ligand A (13.348 mL/min/kg) has significantly lower microsomal clearance than Ligand B (52.031 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-30.228 hours) has a much longer half-life than Ligand A (-2.423 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.096).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol), but the difference is less than the 1.5 kcal/mol threshold that would strongly favor it.

**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, a much longer in vitro half-life, and a better logP value. The lower metabolic clearance of Ligand A is positive, but the substantial improvement in half-life with Ligand B outweighs this benefit. The unusual negative values for Caco-2 and solubility are concerning for both, but the other factors point more strongly towards Ligand B.

Output:
1
2025-04-17 13:53:25,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (371.478 and 357.485 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.72) is better than Ligand B (29.54). While both are reasonably low, Ligand B is particularly favorable for cell permeability.

**3. logP:** Ligand A (2.837) is within the optimal range (1-3). Ligand B (4.503) is slightly above, potentially leading to solubility issues or off-target interactions, but not drastically so.

**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 reasonable QED values (0.885 and 0.7), indicating good drug-like properties.

**7. DILI:** Ligand A (46.801) has a moderate DILI risk, while Ligand B (11.516) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (83.094) and Ligand B (96.084) are both high, but not critical for an oncology target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.522 and -4.507), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.92 and -4.294), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.637) and Ligand B (0.892) are both relatively low, suggesting a low risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (34.382) has a lower clearance than Ligand B (72.939), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (-28.922) has a negative half-life, which is not possible, and suggests an issue with the data. Ligand B (-2.97) also has a negative half-life, which is also problematic.

**14. P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux than Ligand B (0.577), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.1). While both are excellent, the 0.8 kcal/mol difference is noteworthy.

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Comparison and Conclusion:**

Ligand A has a better binding affinity and metabolic stability. However, Ligand B has a significantly lower DILI risk, and slightly better P-gp efflux. Both compounds have problematic solubility and permeability. The negative half-life values are concerning for both. The slightly better affinity of Ligand A, combined with its better metabolic stability, outweighs the DILI risk, *assuming the negative half-life can be resolved*.

Output:
0
2025-04-17 13:53:25,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.479 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.36) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (104.73) is well within the acceptable range.

**logP:** Both ligands have good logP values (1.15 and 0.914), falling within the 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 (<=10).

**QED:** Ligand A (0.509) is slightly better than Ligand B (0.422), indicating a more drug-like profile.

**DILI:** Ligand A (27.104) has a significantly lower DILI risk than Ligand B (17.41). Both are good, but A is preferable.

**BBB:** Both ligands have similar BBB penetration (50.795 and 47.964), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.278) has slightly better Caco-2 permeability than Ligand B (-4.865).

**Aqueous Solubility:** Ligand A (-2.856) has slightly worse solubility than Ligand B (-1.353). Solubility is important, so this is a slight negative for A.

**hERG:** Both ligands have very low hERG inhibition risk (0.116 and 0.056), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (42.959 and 42.808 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-34.096) has a longer in vitro half-life than Ligand A (-30.48), which is a positive for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.046).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.7). This 0.3 kcal/mol difference is significant, and could outweigh some of the ADME drawbacks of B.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and a longer half-life. However, Ligand A has a significantly lower DILI risk and slightly better Caco-2 permeability. Considering the enzyme-specific priorities, the slightly better affinity of Ligand B is the most important factor. The DILI risk of Ligand A is good, but the lower risk of Ligand B is preferable. The solubility difference is minor.

Output:
1
2025-04-17 13:53:25,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.422 Da and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (99).  A TPSA under 140 is desirable for oral absorption, and both meet this, but A is much closer to the optimal range for permeability.

**logP:** Both ligands have acceptable logP values (1.18 and 1.851, respectively), falling within the 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 A is preferable.

**QED:** Both have reasonable QED scores (0.778 and 0.674), indicating good drug-like properties.

**DILI:** Ligand A (29.042) has a much lower DILI risk than Ligand B (83.792). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.831) is better than Ligand B (67.701).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.592 and -4.912), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values (-1.756 and -3.018), indicating poor aqueous solubility. This is a concern for both, but B is worse.

**hERG:** Ligand A (0.374) has a much lower hERG inhibition liability than Ligand B (0.034). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (-5.537) has a significantly *lower* (better) microsomal clearance than Ligand B (42.609). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (12.451) has a longer in vitro half-life than Ligand B (2.554). This is a positive attribute for Ligand A, suggesting less frequent dosing potential.

**P-gp Efflux:** Both have low P-gp efflux liability (0.035 and 0.193).

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-8.9). However, the difference is relatively small (0.7 kcal/mol), and other factors are more important.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties: lower DILI risk, significantly lower microsomal clearance (better metabolic stability), longer half-life, and lower hERG inhibition. The TPSA and HBA values are also more favorable for Ligand A. The poor Caco-2 and solubility values are concerns for both, but the advantages of Ligand A in safety and PK outweigh the slight potency difference.



Output:
0
2025-04-17 13:53:25,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.459 and 367.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.63) is better than Ligand B (29.54) as it is still within the acceptable range for oral absorption (<140), while Ligand B is very low and may indicate issues with solubility.

**logP:** Ligand A (-0.024) is suboptimal, being close to 0 and potentially hindering permeation. Ligand B (4.564) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (6) is acceptable, while Ligand B (3) is also good.

**QED:** Both ligands (0.676 and 0.641) have good drug-likeness scores, being above 0.5.

**DILI:** Ligand A (48.313) has a better DILI score than Ligand B (12.485), indicating a lower risk of liver injury.

**BBB:** Ligand A (5.855) has a very low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (94.998) has very high BBB penetration, which is irrelevant here and could even be a negative if off-target effects in the CNS are a concern.

**Caco-2 Permeability:** Ligand A (-5.377) is very poor, while Ligand B (-4.329) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.892) is poor, while Ligand B (-4.74) is very poor.

**hERG Inhibition:** Ligand A (0.095) has a very low hERG risk, which is excellent. Ligand B (0.916) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-7.33) has a very low (and thus favorable) microsomal clearance, indicating good metabolic stability. Ligand B (119.008) has a very high clearance, suggesting rapid metabolism and potentially poor *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-14.341) has a very long half-life, which is desirable. Ligand B (25.2) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.028) has low P-gp efflux, which is good. Ligand B (0.467) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.6 and -7.8 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, very low hERG) and metabolic stability (very low Cl_mic, long t1/2) despite its suboptimal logP and solubility. Ligand B has a better binding affinity, but its high logP, poor solubility, high clearance, and moderate hERG risk are substantial drawbacks. Given the enzyme-specific priorities, the superior ADMET properties of Ligand A outweigh the slightly better affinity of Ligand B.

Output:
0
2025-04-17 13:53:25,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.447 and 365.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (61.44) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (2.603) is optimal (1-3), while Ligand A (0.241) is quite low, potentially hindering permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.787 and 0.695, both > 0.5).

**DILI:** Ligand B (9.19) has a much lower DILI risk than Ligand A (29.236), which is a substantial advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (79.217) is better than Ligand A (68.748).

**Caco-2 Permeability:** Ligand A (-4.57) is significantly worse than Ligand B (-5.084), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.271 and -2.187). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.106) has a slightly lower hERG risk than Ligand B (0.659), which is a positive.

**Microsomal Clearance:** Ligand B (-9.043) has a much lower (better) microsomal clearance than Ligand A (17.126), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-14.837) has a significantly longer in vitro half-life than Ligand A (10.591), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.019).

**Binding Affinity:** Ligand B (-7.5 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:**

Ligand B is the superior candidate. While Ligand A has a slightly better binding affinity and lower hERG risk, Ligand B excels in critical ADME properties for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. The low logP of Ligand A is a major concern, potentially leading to poor absorption.



Output:
1
2025-04-17 13:53:25,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.442 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (70.67). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (4.117) is slightly high, potentially leading to solubility issues, but still within a manageable range. Ligand B (1.546) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable values, within the suggested limits.

**QED:** Both ligands have similar QED values (0.597 and 0.585), indicating good drug-likeness.

**DILI:** Ligand A (24.855) has a much lower DILI risk than Ligand B (5.118), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (87.67 and 71.229), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.641) has a negative Caco-2 value, which is concerning, suggesting poor permeability. Ligand B (-5.183) is also negative, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.377) has poor solubility, consistent with its higher logP. Ligand B (-1.457) has better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.752 and 0.678).

**Microsomal Clearance:** Ligand A (69.112) has a higher microsomal clearance than Ligand B (17.411), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-3.102) has a longer in vitro half-life than Ligand A (2.353), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.721 and 0.035).

**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 override other ADME concerns.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the better candidate. While its logP is low, its significantly better solubility, lower microsomal clearance (better metabolic stability), longer half-life, and lower DILI risk outweigh the slightly lower BBB and Caco-2 permeability. Ligand A suffers from poor solubility and metabolic stability, making it less likely to succeed as a drug candidate.

Output:
1
2025-04-17 13:53:25,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.526 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is slightly higher than Ligand B (40.62), but both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have a logP of approximately 3.93, which is optimal.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands have 2 HBAs, well within the acceptable limit of 10.

**QED:** Ligand A (0.716) has a significantly better QED score than Ligand B (0.379), indicating a more drug-like profile.

**DILI:** Ligand A (30.942) has a much lower DILI risk than Ligand B (8.104), which is a crucial advantage.

**BBB:** Both ligands have high BBB penetration (93.525 and 88.484), but this is less critical for a kinase inhibitor unless CNS activity is desired.

**Caco-2 Permeability:** Ligand A (-4.306) has a worse Caco-2 permeability than Ligand B (-4.672). Lower values here indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.389) has worse solubility than Ligand B (-2.829).

**hERG:** Both ligands show low hERG inhibition risk (0.692 and 0.651).

**Microsomal Clearance:** Ligand A (81.244) has a higher microsomal clearance than Ligand B (71.769), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-19.566) has a significantly longer in vitro half-life than Ligand A (-11.913), which is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.452 and 0.336).

**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, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has a better QED and lower DILI risk, Ligand B's significantly stronger binding affinity (-7.7 vs 0.0 kcal/mol) and longer half-life are critical for an enzyme inhibitor. The slightly lower solubility and higher DILI risk of Ligand B are less concerning given the potency advantage.

Output:
1
2025-04-17 13:53:25,622 - INFO - Batch 251 complete. Total preferences: 4016
2025-04-17 13:53:25,622 - INFO - Processing batch 252/512...
2025-04-17 13:54:10,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.344 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (80.56) is still under 140, but less optimal than A.

**logP:** Ligand A (2.367) is within the optimal 1-3 range. Ligand B (0.082) is quite low, potentially hindering permeation and absorption.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (0 HBD, 6 HBA) is acceptable, but the higher HBA count might slightly impact permeability.

**QED:** Both ligands have good QED scores (0.603 and 0.758), indicating drug-like properties.

**DILI:** Ligand A (41.838) has a lower DILI risk than Ligand B (50.33), both being acceptable but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (98.682) shows excellent BBB penetration, while Ligand B (65.995) is moderate.

**Caco-2 Permeability:** Ligand A (-4.837) and Ligand B (-4.619) are both negative, indicating low permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.51 and -1.26). This is a significant concern.

**hERG Inhibition:** Ligand A (0.751) has a lower hERG risk than Ligand B (0.187), which is a major advantage.

**Microsomal Clearance:** Ligand A (-11.752) demonstrates much better metabolic stability (lower clearance) than Ligand B (26.296).

**In vitro Half-Life:** Ligand A (-0.218) has a slightly better half-life than Ligand B (8.246).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.179 and 0.104).

**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.

**Overall Assessment:**

While Ligand A has better ADME properties (TPSA, logP, DILI, hERG, Cl_mic, t1/2), the binding affinity of Ligand B is far superior. The difference in binding affinity (-8.9 vs 0.0 kcal/mol) is substantial and likely outweighs the ADME concerns, especially considering the potential for optimization of solubility and permeability. The poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 13:54:10,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (380.861 and 402.969 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.31) is slightly above the preferred <140, while Ligand B (78.43) is well within the range.

**logP:** Ligand A (1.546) is optimal, while Ligand B (3.495) is approaching the upper limit but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, both within acceptable limits. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.847) has a very good drug-likeness score, significantly better than Ligand B (0.568).

**DILI:** Ligand A (84.141) has a higher DILI risk than Ligand B (71.772), which is concerning.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (58.821) is lower than Ligand B (33.85).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.125 and -5.357), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.682 and -3.988), indicating very poor aqueous solubility, a major issue for bioavailability.

**hERG:** Ligand A (0.194) has a much lower hERG risk than Ligand B (0.678), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-0.058) has a lower (better) microsomal clearance than Ligand B (62.39), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.416) has a negative half-life, which is not realistic. Ligand B (82.609) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux liability than Ligand B (0.443).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly better binding affinity than Ligand A (-9.9 kcal/mol). This ~1.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a better half-life, and a lower DILI risk. However, it has a higher logP, and a higher P-gp efflux liability. Ligand A has a better QED, lower hERG risk, lower P-gp efflux, and better metabolic stability, but its binding affinity is weaker, and it has a concerningly high DILI risk and unrealistic half-life. The poor solubility and permeability are problematic for both.

Despite the solubility issues, the significantly improved binding affinity of Ligand B is a critical factor for an enzyme inhibitor. The better half-life is also a significant advantage. While the DILI risk is higher, it's still within a manageable range, and could be addressed with further optimization. The solubility and permeability issues are more challenging, but potentially addressable through formulation strategies or prodrug approaches.

Output:
1
2025-04-17 13:54:10,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 351.407 Da) are within the ideal range (200-500 Da).

**TPSA:** Ligand A (76.46) is well below the 140 threshold, suggesting good absorption. Ligand B (114.35) is still within acceptable limits, but less favorable.

**logP:** Ligand A (0.835) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.095) is quite low, raising concerns about permeability.

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

**QED:** Both ligands have good QED scores (A: 0.56, B: 0.672), indicating drug-like properties.

**DILI:** Ligand A (39.434) has a lower DILI risk than Ligand B (55.448), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.452) is slightly better than Ligand B (59.093).

**Caco-2 Permeability:** Ligand A (-4.652) is better than Ligand B (-5.041), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.209 and -2.18 respectively), which could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.219) has a much lower hERG risk than Ligand B (0.081), a significant advantage.

**Microsomal Clearance:** Ligand A (0.421) has significantly lower microsomal clearance than Ligand B (14.285), indicating better metabolic stability. This is a crucial factor for enzymes.

**In vitro Half-Life:** Ligand A (-0.787) has a longer in vitro half-life than Ligand B (2.055), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux than Ligand B (0.006), which is preferable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While a 0.3 kcal/mol difference is noticeable, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and better Caco-2 permeability. The slightly lower logP of Ligand A is a minor concern compared to the significant liabilities of Ligand B. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are paramount, making Ligand A the more promising candidate.



Output:
0
2025-04-17 13:54:10,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.439 Da and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.38) is slightly higher than Ligand B (76.66). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands have good logP values (1.365 and 1.586), falling within the 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:** Ligand A (0.833) has a higher QED score than Ligand B (0.676), indicating better overall drug-likeness.

**DILI:** Ligand B (22.024) has a significantly lower DILI risk than Ligand A (55.176), which is a major advantage.

**BBB:** Ligand B (92.168) shows much better BBB penetration than Ligand A (54.634). While SRC is not necessarily a CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.996 and -4.706), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.926 and -2.179), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.115) has a slightly lower hERG inhibition risk than Ligand B (0.239), which is preferable.

**Microsomal Clearance:** Ligand B (20.57) has a significantly higher microsomal clearance than Ligand A (6.679), meaning it's metabolized faster and has lower metabolic stability. This is a major disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-3.144) has a longer in vitro half-life than Ligand B (4.344), which is a positive.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, while Ligand B (0.034) is slightly higher.

**Binding Affinity:** Ligand B (-7.9) has a significantly stronger binding affinity than Ligand A (-6.8). This 1.1 kcal/mol difference is substantial and could outweigh some other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.9 kcal/mol vs -6.8 kcal/mol) is a major advantage for an enzyme target like SRC. The lower DILI risk is also a significant benefit. While Ligand B has higher microsomal clearance, the potency advantage is likely to be more impactful in this case, and metabolic stability can be improved through structural modifications. Ligand A's slightly better hERG and half-life are not enough to offset the substantial difference in binding affinity.

Output:
1
2025-04-17 13:54:10,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.451 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.77) is slightly higher than Ligand B (78.67). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (0.229) is quite low, potentially hindering permeation. Ligand B (0.685) is better, though still on the lower side of the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are 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:** Ligand B (0.845) has a significantly higher QED score than Ligand A (0.57), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 29.624, Ligand B: 32.299), well below the 60 threshold.

**BBB:** Both ligands have good BBB penetration (Ligand A: 73.672, Ligand B: 81.698), but Ligand B is better. This is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.866 and -4.689). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.04 and -1.362). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.269, Ligand B: 0.224), which is excellent.

**Microsomal Clearance:** Ligand A (-11.81) has a much lower (better) microsomal clearance than Ligand B (-5.943), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (3.144) has a longer half-life than Ligand B (-1.684).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.008, Ligand B: 0.031).

**Binding Affinity:** Ligand B (0.0) has a significantly better binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the unusual negative Caco-2 and solubility values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.5 kcal/mol vs 0.0 kcal/mol) outweighs the slightly less favorable TPSA and logP. Ligand B also has a better QED score and slightly better BBB penetration. While Ligand A has better metabolic stability and half-life, the potency difference is more critical for an enzyme target like SRC.

Output:
1
2025-04-17 13:54:10,607 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [345.443, 69.72, 1.503, 1, 3, 0.814, 31.33, 74.796, -4.52, -2.05, 0.211, 60.726, -16.086, 0.026, -7.9]
**Ligand B:** [364.417, 53.33, 4.123, 0, 5, 0.661, 47.654, 80.574, -4.508, -4.462, 0.885, 105.97, 5.715, 0.361, -8.3]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (345.443) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** Both are acceptable, below 140. B (53.33) is better than A (69.72) as lower TPSA generally correlates with better cell permeability.
3. **logP:** A (1.503) is optimal. B (4.123) is pushing the upper limit and could lead to solubility issues or off-target interactions.
4. **HBD:** A (1) is good. B (0) is also acceptable, but having one donor can sometimes improve solubility.
5. **HBA:** A (3) is good. B (5) is acceptable, but higher HBA can sometimes hinder permeability.
6. **QED:** A (0.814) is excellent, indicating high drug-likeness. B (0.661) is still reasonable, but less ideal.
7. **DILI:** A (31.33) is very good, indicating low liver injury risk. B (47.654) is higher, representing a moderate risk.
8. **BBB:** Both are reasonable, but B (80.574) is better than A (74.796). However, SRC is not a CNS target, so this is less critical.
9. **Caco-2:** Both are negative, indicating poor permeability. This is a concern for both.
10. **Solubility:** A (-2.05) is better than B (-4.462), indicating better aqueous solubility.
11. **hERG:** A (0.211) is very low risk. B (0.885) is higher, indicating a greater potential for cardiotoxicity.
12. **Cl_mic:** A (60.726) is better than B (105.97), indicating better metabolic stability. Lower clearance is preferred for enzymes.
13. **t1/2:** A (-16.086) is better than B (5.715), indicating a longer half-life.
14. **Pgp:** A (0.026) is much lower than B (0.361), indicating less P-gp efflux and potentially better bioavailability.
15. **Binding Affinity:** B (-8.3) is 1.5 kcal/mol stronger than A (-7.9). This is a significant advantage.

**Enzyme-Kinase Specific Priorities:**

For SRC (a kinase), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While B has a significantly better binding affinity, A has superior metabolic stability, solubility, lower DILI risk, and a much better hERG profile. The Caco-2 values are poor for both, but can be addressed with formulation strategies.

**Decision:**

Despite the affinity advantage of Ligand B, the superior ADME properties of Ligand A, particularly its lower DILI and hERG risk, and better metabolic stability, make it the more promising drug candidate. The 0.4 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 13:54:10,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.471 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.53) is slightly above the preferred <140, while Ligand B (91.22) is well within. This favors Ligand B for absorption.

**logP:** Ligand A (1.245) is optimal, while Ligand B (2.463) is also good.

**H-Bond Donors:** Ligand A (3) is acceptable, and Ligand B (2) is even better.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range.

**QED:** Ligand B (0.827) has a significantly better QED score than Ligand A (0.54), indicating a more drug-like profile.

**DILI:** Ligand A (40.287) is slightly better than Ligand B (53.781), but both are reasonably low risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (72.237) is higher, but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.359) is significantly worse than Ligand B (-4.468), suggesting poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.389) is better than Ligand B (-4.076). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.067) has a much lower hERG risk than Ligand B (0.524), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-1.016) has a lower (better) microsomal clearance than Ligand B (55.153), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-3.029) has a longer half-life than Ligand B (-0.23).

**P-gp Efflux:** Both are very low, so this is not a differentiating factor.

**Binding Affinity:** Ligand B (-7.2) has a substantially better binding affinity than Ligand A (0). This is the most crucial factor for an enzyme target. The 1.5 kcal/mol advantage is far exceeded.

**Overall Assessment:**

Ligand B demonstrates superior binding affinity, a better QED score, and better Caco-2 permeability. While Ligand A has a slight edge in DILI and hERG, the significantly stronger binding affinity of Ligand B outweighs these minor drawbacks. The improved metabolic stability (lower Cl_mic and longer half-life) of Ligand A is also a plus, but the potency difference is more important.

Output:
1
2025-04-17 13:54:10,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.394 and 355.366 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (100.55) is better than Ligand B (111.88), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.692) is within the optimal range (1-3), while Ligand B (-0.116) is slightly below, which could potentially hinder permeation.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

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

**6. QED:** Both ligands have similar QED values (0.67 and 0.659), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (55.68 and 54.517), which is acceptable (below 60).

**8. BBB:** Ligand A (58.317) has a better BBB penetration percentile than Ligand B (36.371), but BBB is not a high priority for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.725) has a better Caco-2 permeability than Ligand B (-5.194), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.462) has better aqueous solubility than Ligand B (-1.015), which is crucial for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.165 and 0.218), which is excellent.

**12. Microsomal Clearance:** Ligand B (0.352) has significantly lower microsomal clearance than Ligand A (0.832), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (27.972) has a much longer in vitro half-life than Ligand A (6.995), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.016 and 0.021).

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.2 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity and acceptable safety profiles, Ligand B is more favorable due to its significantly improved metabolic stability (lower Cl_mic and longer t1/2) and slightly better solubility. These factors are particularly important for an enzyme inhibitor like an SRC kinase inhibitor, as they contribute to a longer duration of action and better bioavailability. The slightly lower logP of Ligand B is a minor drawback that is outweighed by its metabolic advantages.

Output:
1
2025-04-17 13:54:10,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.335 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly above the optimal <140, but acceptable. Ligand B (78.43) is well within the acceptable range.

**logP:** Both ligands (1.734 and 2.231) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.809) has a very good QED score, indicating high drug-likeness. Ligand B (0.628) is still acceptable, but lower.

**DILI:** Ligand A (94.649) has a high DILI risk, which is a significant concern. Ligand B (12.524) has a very low DILI risk, a major advantage.

**BBB:** Both ligands have moderate BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.666) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.814) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.849 and -3.23 respectively). This could pose formulation challenges.

**hERG:** Ligand A (0.528) has a slightly elevated hERG risk, but not alarming. Ligand B (0.292) has a very low hERG risk, which is preferable.

**Microsomal Clearance:** Ligand A (47.46) has moderate clearance. Ligand B (29.118) has lower clearance, indicating better metabolic stability, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (1.409) has a short half-life. Ligand B (1.293) also has a short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol) - a difference of 1.9 kcal/mol. This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both compounds having poor solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.7 vs -7.8 kcal/mol) is a major advantage for an enzyme inhibitor. Crucially, it also has a much lower DILI risk (12.524 vs 94.649) and better metabolic stability (lower Cl_mic). While solubility is a concern, it might be addressed through formulation strategies. The higher DILI risk associated with Ligand A is a dealbreaker.

Output:
1
2025-04-17 13:54:10,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.5 and 349.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is significantly better than Ligand B (52.65).  A TPSA under 140 is desirable for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (3.58 and 2.43), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.892 and 0.718), indicating good drug-likeness.

**DILI:** Both ligands have very similar, and low, DILI risk (11.2 and 11.1), which is excellent.

**BBB:** Ligand A (85.033) has a better BBB penetration percentile than Ligand B (78.868), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.577) is slightly better than Ligand B (-4.96), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.558 and -2.622). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.77) has a significantly lower hERG risk than Ligand B (0.552), which is a major advantage.

**Microsomal Clearance:** Both have similar, and relatively low, microsomal clearance (-2.225 and -37.43).

**In vitro Half-Life:** Ligand A (38.77) has a better in vitro half-life than Ligand B (4.425). This suggests better metabolic stability.

**P-gp Efflux:** Ligand A (0.102) has a lower P-gp efflux liability than Ligand B (0.092).

**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 difference and a major factor.

**Overall Assessment:**

While Ligand A has advantages in TPSA, BBB, Caco-2, hERG, and half-life, the significantly superior binding affinity of Ligand B (-8.3 vs 0.0 kcal/mol) is the deciding factor. A binding affinity difference of this magnitude can often outweigh minor ADME drawbacks, especially if the solubility issues can be addressed through formulation. The similar DILI and acceptable logP values for both compounds are also positive.

Output:
1
2025-04-17 13:54:10,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.438 and 346.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is well below the 140 threshold for good absorption. Ligand B (80.79) is also acceptable, but higher.

**logP:** Both ligands (1.598 and 1.898) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (7) are both below the threshold of 10.

**QED:** Ligand A (0.897) has a better QED score than Ligand B (0.725), indicating a more drug-like profile.

**DILI:** Ligand A (25.902) has a significantly lower DILI risk than Ligand B (20.861), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.443) has a better BBB score than Ligand B (53.625).

**Caco-2 Permeability:** Ligand A (-5.013) and Ligand B (-5.427) are both negative, suggesting poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.888 and -1.605), indicating poor solubility. This is a concern.

**hERG Inhibition:** Ligand A (0.292) has a much lower hERG inhibition liability than Ligand B (0.169), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-4.382) has a much lower (better) microsomal clearance than Ligand B (11.737), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.86) has a longer half-life than Ligand B (19.425), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.071).

**Binding Affinity:** Ligand B (-9.4 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 ADME advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG inhibition liability. The solubility and permeability are poor for both, but these can potentially be addressed through formulation strategies. The superior safety profile and metabolic stability of Ligand A make it the preferred choice.

Output:
0
2025-04-17 13:54:10,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.43 and 350.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is better than Ligand B (111.53), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.03) is optimal (1-3), while Ligand B (-0.06) is slightly below 1, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the limit of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5), staying lower than the 10 limit.

**QED:** Both ligands have similar and good QED scores (0.637 and 0.668, both > 0.5).

**DILI:** Ligand A (41.14) has a slightly higher DILI risk than Ligand B (21.91), but both are below the concerning threshold of 60.

**BBB:** Ligand B (58.28) has a better BBB penetration score than Ligand A (37.30), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.95) has a worse Caco-2 permeability than Ligand B (-4.97), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.18) has a slightly better aqueous solubility than Ligand B (-1.36), which is beneficial for formulation.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.03 and 0.073, respectively).

**Microsomal Clearance:** Ligand A (-7.90) has significantly lower (better) microsomal clearance than Ligand B (-6.49), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (17.3) has a slightly longer half-life than Ligand A (15.78), which is a minor advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.009, respectively).

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-8.3), exceeding the >1.5 kcal/mol advantage threshold.

**Conclusion:**

Despite Ligand B having slightly better BBB penetration and half-life, Ligand A is significantly more promising. The substantially stronger binding affinity (-9.0 vs -8.3 kcal/mol) outweighs the minor drawbacks in Caco-2 permeability and DILI risk. Furthermore, Ligand A's superior metabolic stability (lower Cl_mic) is a crucial advantage for an enzyme target. The logP value for ligand A is also more favorable.

Output:
1
2025-04-17 13:54:10,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.443 and 376.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.82) is significantly better than Ligand B (121.8), being well below the 140 threshold for good absorption. Ligand B is approaching the upper limit.

**logP:** Ligand A (2.469) is optimal (1-3). Ligand B (-0.638) is below 1, which may impede permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3, respectively), well within the limit of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 6, respectively), within the limit of 10.

**QED:** Both ligands have reasonable QED scores (0.794 and 0.492), with Ligand A being superior.

**DILI:** Both ligands have low DILI risk (35.285 and 39.046), below the 40 threshold.

**BBB:** Ligand A (74.37) shows better BBB penetration than Ligand B (48.585), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.716) has a worse Caco-2 permeability than Ligand B (-5.377), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.269) has better aqueous solubility than Ligand B (-1.071), though both are negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.409 and 0.067), which is excellent.

**Microsomal Clearance:** Ligand A (10.208) has slightly higher microsomal clearance than Ligand B (9.906), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (24.994 and 23.539 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.034).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol), exceeding the >1.5 kcal/mol advantage threshold.

**Conclusion:**

Ligand A is the more promising candidate. While both ligands have acceptable DILI and hERG profiles, Ligand A excels in TPSA, logP, QED, and crucially, binding affinity. The slightly better affinity of Ligand A could outweigh the slightly higher clearance and worse Caco-2 permeability. The poor Caco-2 and solubility of both compounds would require further optimization, but the stronger binding of A makes it a better starting point.

Output:
1
2025-04-17 13:54:10,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.41 and 357.523 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.55) is better than Ligand B (56.99) as it is still within the acceptable range for oral absorption, while Ligand B is significantly lower, potentially indicating a lack of necessary interactions.

**logP:** Ligand A (1.348) is optimal, while Ligand B (4.02) is pushing the upper limit. Higher logP can lead to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (0) is very low. While fewer HBDs can improve permeability, it might compromise solubility and binding.

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

**QED:** Both ligands have good QED scores (0.534 and 0.772), suggesting good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (45.483 and 38.697), below the 60 threshold.

**BBB:** Ligand A (33.656) has a low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (77.821) has higher BBB penetration, but this is not a priority for this target.

**Caco-2:** Both ligands have negative Caco-2 values (-5.024 and -4.77), which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon.

**Solubility:** Both ligands have negative solubility values (-2.202 and -4.97), indicating poor aqueous solubility. This is a significant drawback.

**hERG:** Ligand A (0.247) has a much lower hERG risk than Ligand B (0.549), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (21.488) has significantly lower microsomal clearance than Ligand B (74.33), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (3.899) has a shorter half-life than Ligand B (-2.774), but the negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux than Ligand B (0.401), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADMET properties, particularly in terms of metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. The solubility of both is poor, but this can be addressed through formulation strategies. The slightly better affinity of Ligand B does not outweigh the significant advantages of Ligand A in terms of safety and pharmacokinetic properties.

Output:
0
2025-04-17 13:54:10,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.391 and 348.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (88.41 and 87.66) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (0.866 and 0.754) are within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.87) has a better QED score than Ligand B (0.517), indicating a more drug-like profile.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (33.23). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (73.672) has a slightly better BBB score than Ligand B (53.625).

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.826 and -4.8). This is a major concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.349 and -1.615). This could present formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.198 and 0.166), which is excellent.

**Microsomal Clearance:** Ligand B (12.741 mL/min/kg) has significantly lower microsomal clearance than Ligand A (22.531 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.067 hours) has a negative half-life, which is a significant drawback. Ligand A (14.822 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.088).

**Binding Affinity:** Ligand A (-9.1 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 a better QED score and half-life, but suffers from a higher DILI risk. Ligand B has a lower DILI risk and better metabolic stability, but a weaker binding affinity and a negative half-life.

Given the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG), the significantly stronger binding affinity of Ligand A (-9.1 vs -7.4 kcal/mol) is a major advantage that likely outweighs its higher DILI risk and slightly worse metabolic stability. The DILI risk, while elevated, is still below the critical 60% threshold. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 13:54:10,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.515 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.43) is slightly higher than Ligand B (71.11), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (1.802) is optimal, while Ligand B (0.238) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.596 and 0.741), indicating good drug-likeness.

**DILI:** Both have low DILI risk (27.724 and 28.073, respectively), which is favorable.

**BBB:** Both have moderate BBB penetration (64.793 and 68.67), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.017) has worse Caco-2 permeability than Ligand B (-4.543), but both are negative values which are difficult to interpret without knowing the scale.

**Aqueous Solubility:** Ligand A (-2.422) has slightly better solubility than Ligand B (-1.241), though both are negative values, indicating poor solubility.

**hERG:** Both ligands have very low hERG risk (0.588 and 0.121), which is excellent.

**Microsomal Clearance:** Ligand A (29.66) has significantly lower microsomal clearance than Ligand B (44.564), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.541) has a slightly longer half-life than Ligand B (-2.394), which is beneficial.

**P-gp Efflux:** Both have low P-gp efflux liability (0.137 and 0.019).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol) - a difference of 1.9 kcal/mol. This is a substantial advantage.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic) and slightly better solubility, the significantly stronger binding affinity of Ligand B (-8.4 vs -6.5 kcal/mol) outweighs the minor ADME drawbacks. The low logP of Ligand B is a concern, but the substantial potency advantage is likely to be more important for an enzyme target.

Output:
1
2025-04-17 13:54:10,609 - INFO - Batch 252 complete. Total preferences: 4032
2025-04-17 13:54:10,609 - INFO - Processing batch 253/512...
2025-04-17 13:54:50,875 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.5 and 364.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.74) is higher than Ligand B (58.2). Both are acceptable, but B is better for absorption.

**logP:** Ligand A (2.066) and Ligand B (3.804) are both within the optimal 1-3 range, but B is approaching the upper limit.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2).

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3).

**QED:** Ligand A (0.89) is significantly better than Ligand B (0.689), indicating a more drug-like profile.

**DILI:** Ligand A (41.9) and Ligand B (34.8) are both good, with low DILI risk. B is slightly better.

**BBB:** Ligand A (63.8) is lower than Ligand B (83.7). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

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

**Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Both ligands have low hERG inhibition liability (0.37 and 0.277), which is excellent.

**Cl_mic:** Ligand A (19.3) has significantly lower microsomal clearance than Ligand B (55.7), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**t1/2:** Ligand A (-5.551) has a negative in vitro half-life, which is problematic. Ligand B (29.194) has a much better half-life.

**Pgp:** Both ligands have low Pgp efflux liability (0.189 and 0.249), which is good.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand B has a slightly better binding affinity and half-life, and a slightly lower DILI risk. However, Ligand A has a significantly better QED score and, critically, much lower microsomal clearance, indicating better metabolic stability. Both ligands suffer from poor solubility and permeability, which are major concerns. Considering the enzyme-specific priorities, metabolic stability (Cl_mic) is very important. While the affinity difference is small, the improved metabolic stability of Ligand A is a significant advantage.

Output:
0
2025-04-17 13:54:50,876 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.511 and 374.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.68) is significantly better than Ligand B (119.81). A TPSA under 140 is good for oral absorption, and A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.803) is optimal (1-3), while Ligand B (-0.747) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=6), both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.804 and 0.515), indicating drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (37.301 and 37.611 percentile).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.633) is slightly better than Ligand B (63.746).

**Caco-2 Permeability:** Ligand A (-4.425) is significantly better than Ligand B (-5.503), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.969) is better than Ligand B (-0.654), which is a crucial factor for bioavailability.

**hERG Inhibition:** Ligand A (0.544) is much lower than Ligand B (0.244), indicating a lower risk of cardiotoxicity. This is a critical advantage.

**Microsomal Clearance:** Ligand B (-10.377) has a *negative* clearance, which is not physically possible and likely an error in the data. Ligand A (62.928) is reasonable. This makes Ligand B highly suspect.

**In vitro Half-Life:** Ligand A (31.501 hours) is much better than Ligand B (-5.77 hours), indicating better metabolic stability. Again, a negative half-life for Ligand B is impossible.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.753 and 0.007), which is good.

**Binding Affinity:** Both ligands have similar strong binding affinities (-9.0 and -8.5 kcal/mol). The difference is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Conclusion:**

Ligand A is significantly superior to Ligand B. Ligand B has several problematic ADME properties, including a negative Caco-2 permeability and a negative in vitro half-life, which are physically impossible and indicate data errors or a fundamentally flawed molecule. Ligand A has better TPSA, logP, solubility, hERG risk, and metabolic stability. While both have good binding affinity, Ligand A's overall profile makes it a much more viable drug candidate.

Output:
0
2025-04-17 13:54:50,876 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.555 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**TPSA:** Ligand A (80.32) is better than Ligand B (49.85). Lower TPSA generally favors better absorption, and both are well below the 140 A^2 threshold.

**logP:** Both ligands have good logP values (Ligand A: 2.302, Ligand B: 2.894), 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 (0.682) has a better QED score than Ligand B (0.475), indicating a more drug-like profile.

**DILI:** Ligand A (55.874) has a higher DILI risk than Ligand B (17.798). This is a significant drawback for Ligand A.

**BBB:** Ligand A (57.619) has lower BBB penetration than Ligand B (90.655). While not critical for a non-CNS target like SRC, better BBB penetration is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.078) has worse Caco-2 permeability than Ligand B (-4.579). Both are negative, indicating poor permeability, but B is better.

**Aqueous Solubility:** Ligand A (-3.393) has worse aqueous solubility than Ligand B (-2.044). Solubility is crucial for bioavailability, making Ligand B more favorable.

**hERG Inhibition:** Ligand A (0.392) has a slightly higher hERG inhibition risk than Ligand B (0.602). Lower is better, so Ligand B is preferred.

**Microsomal Clearance:** Ligand A (45.147) has lower microsomal clearance than Ligand B (67.201), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (10.65) has a shorter half-life than Ligand B (-8.732). A negative half-life is not possible, so this is likely an error in the data, but it suggests that Ligand B is more stable.

**P-gp Efflux:** Ligand A (0.121) has lower P-gp efflux than Ligand B (0.304), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -7.3 kcal/mol, Ligand B: -7.1 kcal/mol). Ligand A has a slightly better affinity, but the difference is small.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and metabolic stability, and lower P-gp efflux. However, it suffers from significantly higher DILI risk, poorer solubility, and worse Caco-2 permeability. Ligand B has a better safety profile (lower DILI, hERG), better solubility, and permeability, and a good BBB score. Considering the enzyme-specific priorities, metabolic stability is important, but a high DILI risk is a major concern. The small difference in binding affinity is outweighed by the substantial ADME/Tox advantages of Ligand B.

Output:
1
2025-04-17 13:54:50,876 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.559 Da) is slightly higher than Ligand B (367.471 Da), but both are acceptable.

**TPSA:** Ligand A (83.47) is better than Ligand B (111.45). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.566, B: 1.61), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (A: 2, B: 3) and HBA (A: 6, B: 6) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have reasonable QED scores (A: 0.633, B: 0.542), indicating good drug-like properties.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (58.511), but both are below the concerning threshold of 60.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (46.219) is lower than Ligand B (15.2), but this is not a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed assuming these represent low permeability.

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

**hERG:** Ligand A (0.465) has a slightly higher hERG risk than Ligand B (0.496), but both are low.

**Microsomal Clearance (Cl_mic):** Ligand A (28.382) has a higher Cl_mic than Ligand B (20.188), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life (t1/2):** Ligand A (26.014) has a longer half-life than Ligand B (9.55), which is desirable. However, this benefit is likely offset by the higher Cl_mic.

**P-gp Efflux:** Ligand A (0.465) has lower P-gp efflux than Ligand B (0.076), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better half-life and P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.8 vs -6.3 kcal/mol) is the most important factor for an enzyme inhibitor. While both have issues with predicted permeability and solubility, the superior potency of Ligand B makes it more likely to be successful, as potency can sometimes compensate for suboptimal ADME properties. The lower Cl_mic of Ligand B also contributes to its better profile.

Output:
1
2025-04-17 13:54:50,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 381.523 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.72) is better than Ligand B (92.5), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.125 and 1.136), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both 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 are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (53.432) has a higher DILI risk than Ligand B (36.293). This is a significant negative for Ligand A.

**BBB:** Both have similar BBB penetration (73.943 and 74.486). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.201 and 0.189). This is excellent.

**Microsomal Clearance:** Ligand A (17.786) has significantly lower microsomal clearance than Ligand B (24.107), indicating better metabolic stability. This is a strong positive for Ligand A.

**In vitro Half-Life:** Ligand A (51.069) has a much longer in vitro half-life than Ligand B (-19.648). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.019 and 0.097).

**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 better metabolic stability (lower Cl_mic, longer t1/2) and slightly better TPSA and logP. The biggest drawback for Ligand A is the higher DILI risk. However, the significant improvements in metabolic stability and half-life outweigh this risk, especially given the identical binding affinity. The solubility and permeability are poor for both, but that can be addressed with formulation strategies.

Output:
1
2025-04-17 13:54:50,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (85.77). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is more favorable.

**logP:** Ligand A (3.099) is optimal, while Ligand B (1.238) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.771 and 0.738), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (21.908 and 23.536), which is positive.

**BBB:** Ligand A (73.827) has a better BBB percentile than Ligand B (42.342), although BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.754) is better than Ligand B (-5.263), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.852) is better than Ligand B (-1.452), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.8) has a lower hERG inhibition liability than Ligand B (0.176), a critical advantage for safety.

**Microsomal Clearance:** Ligand A (30.212) has a higher (worse) microsomal clearance than Ligand B (-14.56). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-6.525) has a longer half-life than Ligand B (-7.773).

**P-gp Efflux:** Ligand A (0.236) has lower P-gp efflux liability than Ligand B (0.015), which is favorable.

**Binding Affinity:** Ligand A (-6.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall assessment.

**Overall Assessment:**

Ligand A is superior due to its better logP, TPSA, solubility, hERG risk, Caco-2 permeability, and P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic), the other advantages of Ligand A, especially the lower hERG risk, outweigh this drawback. The affinity difference is minor.

Output:
1
2025-04-17 13:54:50,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.46 and 350.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.44) is significantly better than Ligand B (95.86). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (1.643) is optimal, while Ligand B (0.282) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better than Ligand B (1 HBD, 6 HBA). Both are within acceptable limits, but B has a higher number of HBA which could affect permeability.

**QED:** Both ligands have good QED scores (0.609 and 0.792), indicating good drug-like properties.

**DILI:** Ligand A (21.95) has a much lower DILI risk than Ligand B (55.80). This is a significant advantage for A.

**BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.609) has significantly worse Caco-2 permeability than Ligand B (-4.629). This is a negative for A.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.27) is slightly better than Ligand B (-0.817).

**hERG:** Ligand A (0.182) has a much lower hERG risk than Ligand B (0.227). This is a crucial advantage for A, as kinase inhibitors can sometimes have cardiotoxicity issues.

**Microsomal Clearance:** Ligand A (-5.954) has a much lower (better) microsomal clearance than Ligand B (35.48). This indicates better metabolic stability for A.

**In vitro Half-Life:** Ligand A (-0.1) has a very short half-life, while Ligand B (0.75) has a slightly better half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for B.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher HBA count, lower logP, and higher microsomal clearance. Ligand A has better ADME properties (lower DILI, hERG, Cl_mic, and better logP), but its binding affinity is very weak.

The difference in binding affinity (-6.7 vs 0.0 kcal/mol) is substantial. While the ADME profile of Ligand A is more favorable, the lack of potency is a major drawback. It's unlikely that A would be effective *in vivo* with such weak binding. Ligand B's issues could potentially be addressed through further optimization, but the strong initial binding is a solid foundation.

Output:
1
2025-04-17 13:54:50,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is well below the 140 threshold for good absorption, while Ligand B (98.74) is still acceptable but closer to the limit.

**logP:** Ligand A (1.346) is within the optimal 1-3 range. Ligand B (0.561) is slightly below 1, which *could* indicate potential permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, both within acceptable limits. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.807) has a higher QED score than Ligand B (0.623), indicating a more drug-like profile.

**DILI:** Ligand A (34.471) has a significantly lower DILI risk than Ligand B (14.114), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (73.866) shows better BBB penetration than Ligand B (28.189).

**Caco-2 Permeability:** Ligand A (-4.774) has a worse Caco-2 permeability score than Ligand B (-5.291), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.969) has better aqueous solubility than Ligand B (-1.153).

**hERG Inhibition:** Ligand A (0.352) has a much lower hERG risk than Ligand B (0.079), a critical safety parameter.

**Microsomal Clearance:** Ligand A (25.866) has a higher microsomal clearance than Ligand B (-6.167), meaning Ligand B is more metabolically stable. This is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (17.147) has a longer half-life than Ligand B (3.822), which is desirable.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.011), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a difference of 0.9 kcal/mol is noticeable, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, and better metabolic stability. However, Ligand A has a significantly better safety profile (lower DILI and hERG risk), better solubility, a higher QED score, and a longer half-life. The lower Caco-2 permeability of Ligand A is a concern, but can potentially be addressed through formulation strategies. The combination of improved safety and drug-likeness outweighs the modest affinity difference.

Output:
0
2025-04-17 13:54:50,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (358.467 and 340.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (76.14 and 74.33) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.423 and 1.48) are 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 6 HBA and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.878 and 0.865), indicating good drug-likeness.

**7. DILI:** Ligand A (72.082) has a higher DILI risk than Ligand B (55.448). This is a concern for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (75.611 and 63.862), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.273 and -5.029), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.141 and -2.758), indicating poor aqueous solubility. This is a major concern for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.507 and 0.428), which is positive.

**12. Microsomal Clearance:** Ligand A (41.276) has a higher microsomal clearance than Ligand B (32.957), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.126 hours) has a significantly longer in vitro half-life than Ligand A (12.674 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.058 and 0.039).

**15. 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 Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its higher DILI risk and lower metabolic stability are concerning. Ligand B, despite its weaker binding, has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and comparable permeability and solubility issues. The difference in binding affinity (-9.7 vs -7.6) is significant (2.1 kcal/mol), and could be overcome with further optimization, while fixing the solubility and permeability issues is more challenging. Given the enzyme-kinase focus, metabolic stability and safety are crucial.

Output:
1
2025-04-17 13:54:50,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 348.418 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.5) is better than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.534 and 2.388), 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 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.734) has a significantly better QED score than Ligand A (0.376), indicating a more drug-like profile.

**DILI:** Ligand A (22.8) has a much lower DILI risk than Ligand B (51.338), which is a significant advantage.

**BBB:** Ligand B (88.29) has a higher BBB penetration percentile than Ligand A (54.905). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.66) has a worse Caco-2 permeability than Ligand B (-4.585).

**Aqueous Solubility:** Ligand A (-2.723) has a worse aqueous solubility than Ligand B (-2.122).

**hERG:** Ligand A (0.091) has a slightly better hERG profile than Ligand B (0.543), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (37.371) has a significantly lower microsomal clearance than Ligand A (55.404), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (42.171) has a much longer in vitro half-life than Ligand A (-21.16), which is a major advantage.

**P-gp Efflux:** Ligand A (0.024) has a lower P-gp efflux liability than Ligand B (0.142).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. While Ligand A has a lower DILI risk and P-gp efflux, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2), better QED score, and slightly better solubility outweigh these advantages. The binding affinity is essentially the same for both. The improved ADME properties of Ligand B suggest it is more likely to be a viable drug candidate.

Output:
1
2025-04-17 13:54:50,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.483 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is slightly higher than Ligand B (67.87), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.549 and 1.865), falling within the optimal 1-3 range.

**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 QED values above 0.5 (0.696 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 60.062, placing it at a moderate risk. Ligand B has a significantly lower DILI risk (32.377), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (78.364) has a slightly higher BBB percentile than Ligand B (65.801).

**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:** Both ligands have low hERG inhibition liability (0.56 and 0.34), which is excellent.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (75.506) than Ligand B (33.065), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (34.217 hours) compared to Ligand A (-5.976 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.277 and 0.066).

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.5 kcal/mol) than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate**. While both ligands have acceptable physicochemical properties, Ligand B excels in key areas for an enzyme target: significantly better binding affinity, lower DILI risk, and much improved metabolic stability (lower Cl_mic and longer t1/2). The negative solubility and Caco-2 values are concerning for both, but the substantial advantage in affinity and safety profile of Ligand B outweighs these concerns.

Output:
1
2025-04-17 13:54:50,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.31 and 344.386 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (62.55). A TPSA under 140 is good for oral absorption, and A is well within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (3.919 and 3.358), falling 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). Lower HBD/HBA generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.748 and 0.925), indicating good drug-like properties.

**DILI:** Ligand A (48.313) has a slightly better DILI score than Ligand B (55.952), both are acceptable, but lower is better.

**BBB:** Ligand A (98.022) has a much higher BBB penetration score than Ligand B (89.531). While not a primary concern for a non-CNS target like SRC, higher BBB is generally not detrimental.

**Caco-2 Permeability:** Ligand A (-4.306) is significantly better than Ligand B (-4.797). Higher Caco-2 values indicate better absorption.

**Aqueous Solubility:** Ligand A (-4.708) is slightly better than Ligand B (-4.001). Both are poor, but A is less poor.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.821 and 0.666), which is good.

**Microsomal Clearance:** Ligand A (38.317 mL/min/kg) is significantly better than Ligand B (9.261 mL/min/kg). Lower clearance indicates better metabolic stability, a key consideration for kinases.

**In vitro Half-Life:** Ligand B (58.718 hours) has a much longer half-life than Ligand A (0.565 hours). This is a significant advantage for B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.329 and 0.166), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA, Caco-2 permeability, microsomal clearance, and has a slightly better DILI score and solubility. Ligand B has a much longer half-life. Given the priority for metabolic stability in kinase inhibitors, and the substantial difference in Cl_mic, Ligand A is the more promising candidate. While the half-life of Ligand B is attractive, the poor metabolic stability could lead to rapid clearance *in vivo*, negating the benefit of the longer half-life observed *in vitro*. The better permeability and lower clearance of Ligand A suggest it will achieve higher concentrations at the target.

Output:
0
2025-04-17 13:54:50,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.42 Da) is slightly higher than Ligand B (361.511 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (59.06 and 61.44 respectively) well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.547) is higher than Ligand B (2.346). While 4.547 is approaching the upper limit of the optimal range (1-3), it's not drastically outside. Ligand B's logP is very good.

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

**QED:** Both ligands have good QED scores (0.675 and 0.747), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (95.347%) compared to Ligand B (36.681%). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (67.701% and 67.003%), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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 a negative value doesn't necessarily mean zero permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility, which could be a formulation challenge. Ligand B (-2.588) is slightly better than Ligand A (-4.534).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.69 and 0.517), which is good.

**Microsomal Clearance:** Ligand B (11.912 mL/min/kg) has a much lower microsomal clearance than Ligand A (42.26 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (8.291 hours) has a longer in vitro half-life than Ligand A (74.994 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.622 and 0.094), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 kcal/mol and -8.4 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility outweigh the slightly higher logP of Ligand A. The poor Caco-2 and solubility values for both are concerning and would require further investigation, but are less critical than the DILI risk associated with Ligand A.

Output:
1
2025-04-17 13:54:50,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (357.384 and 342.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.31) is slightly higher than Ligand B (68.87), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.153 and 3.168), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is not a major concern.

**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 limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.793 and 0.752), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (51.842 and 51.26), which is acceptable (below 60).

**BBB:** Ligand B (89.066) has a higher BBB penetration percentile than Ligand A (72.741). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.226 and -5.44). 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 very poor aqueous solubility (-3.033 and -3.001). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.185) has a lower hERG inhibition liability than Ligand B (0.933), which is favorable.

**Microsomal Clearance:** Ligand A (-10.638) has a significantly lower (better) microsomal clearance than Ligand B (31.617). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-16.209) has a longer in vitro half-life than Ligand B (15.323), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux liability than Ligand B (0.167), which is slightly better for oral bioavailability.

**Binding Affinity:** Ligand A (-8.6 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 minor ADME drawbacks.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.6 vs -6.5 kcal/mol) is a major advantage. Furthermore, it exhibits better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and lower P-gp efflux. While the solubility and permeability issues need to be addressed through formulation or structural modifications, the superior potency and pharmacokinetic properties of Ligand A make it the preferred choice.

Output:
0
2025-04-17 13:54:50,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.407 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.92) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (75.44) is excellent, well below 140.

**logP:** Ligand A (-0.63) is a bit low, potentially hindering permeation. Ligand B (2.953) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.586 and 0.782), indicating drug-like properties.

**DILI:** Ligand A (36.216) has a lower DILI risk than Ligand B (50.446), both are acceptable but A is better.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (71.19) has a higher BBB percentile than Ligand A (43.815), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.291 and -5.103), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.439 and -2.403), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.165) has a lower hERG risk than Ligand B (0.528), which is preferable.

**Microsomal Clearance:** Ligand A (-16.813) has significantly lower (better) microsomal clearance than Ligand B (87.92), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.811) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (8.008) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.272).

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-9.4 and -9.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both compounds have excellent binding affinity, Ligand A appears more promising due to its lower DILI risk, significantly better metabolic stability (lower Cl_mic), and lower hERG risk. However, the negative Caco-2 and solubility values are concerning for both. The negative half-life for Ligand A is also a major red flag. Ligand B has a better half-life and TPSA, but higher DILI, hERG, and Cl_mic. Given the importance of metabolic stability for kinase inhibitors, and the slightly better safety profile, Ligand A is the marginally better candidate, *assuming* the negative half-life can be addressed through structural modifications.

Output:
0
2025-04-17 13:54:50,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.371 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold for good absorption, while Ligand B (86.88) is also acceptable.

**logP:** Both ligands have logP values (1.959 and 2.632) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (2 and 3) and HBA (3 and 3) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.508 and 0.641), indicating drug-like properties.

**DILI:** Ligand A (33.695) has a significantly lower DILI risk than Ligand B (12.369), which is a substantial advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (67.701) shows slightly better penetration than Ligand A (54.478).

**Caco-2 Permeability:** Ligand A (-4.833) shows better Caco-2 permeability than Ligand B (-5.221), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.505) has better aqueous solubility than Ligand B (-2.42), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.499 and 0.302).

**Microsomal Clearance:** Ligand A (0.544) has significantly lower microsomal clearance than Ligand B (30.212), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.894) has a much longer in vitro half-life than Ligand B (-32.846), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.066 and 0.046).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). The difference is 1 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, but Ligand A excels in almost all other crucial ADMET properties. Specifically, Ligand A's significantly lower DILI risk, better solubility, much better metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability make it a much more promising drug candidate. The 1 kcal/mol difference in binding affinity can likely be optimized in subsequent rounds of medicinal chemistry, while fixing the poor ADMET profile of Ligand B would be far more challenging.

Output:
0
2025-04-17 13:54:50,880 - INFO - Batch 253 complete. Total preferences: 4048
2025-04-17 13:54:50,880 - INFO - Processing batch 254/512...
2025-04-17 13:55:33,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (359.86 & 364.51 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.37) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.43) is also under 140, but less optimal than A.

**3. logP:** Ligand A (4.29) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.57) is within the optimal range (1-3).

**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 (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have reasonable QED scores (0.889 and 0.702), indicating good drug-like properties.

**7. DILI:** Ligand A (62.47) has a higher DILI risk than Ligand B (33.35). This is a significant concern.

**8. BBB:** Ligand A (88.29) shows better BBB penetration than Ligand B (54.48), but this is less critical for a kinase inhibitor unless CNS off-target effects are a major concern.

**9. Caco-2 Permeability:** Ligand A (-4.753) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.232) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-4.478) and Ligand B (-3.272) both have very poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.709) has a slightly higher hERG risk than Ligand B (0.222). Lower is better here.

**12. Microsomal Clearance:** Ligand A (76.73) has a higher microsomal clearance than Ligand B (30.15), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (74.55) has a longer half-life than Ligand B (19.57), which is desirable.

**14. P-gp Efflux:** Ligand A (0.678) has a higher P-gp efflux liability than Ligand B (0.084). Lower is better.

**15. 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 relatively small.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B has significantly lower DILI risk, better metabolic stability (lower Cl_mic), a longer half-life, and lower P-gp efflux. The slightly better affinity of Ligand B is a bonus. Ligand A's higher DILI risk and poor permeability are major drawbacks. The high logP of Ligand A is also concerning.

Output:
1
2025-04-17 13:55:33,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.479 and 383.587 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (79.9) is better than Ligand B (63.05) as it is closer to the 90 A^2 threshold for CNS targets, although SRC is not a CNS target, lower TPSA generally correlates with better permeability.

**logP:** Ligand B (2.83) is optimal (1-3), while Ligand A (0.248) is quite low, potentially hindering permeation.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.62 and 0.844, respectively), indicating good drug-like properties.

**DILI:** Ligand B (42.846) has a significantly lower DILI risk than Ligand A (11.206), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.854) is lower than Ligand B (52.036).

**Caco-2 Permeability:** Ligand A (-4.867) has a worse Caco-2 permeability than Ligand B (-5.299), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.889) has better aqueous solubility than Ligand B (-3.556).

**hERG Inhibition:** Ligand A (0.352) has a slightly better hERG profile than Ligand B (0.14), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (37.578) has significantly lower microsomal clearance than Ligand B (81.6), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.98) has a much longer in vitro half-life than Ligand B (0.821), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.003) has much lower P-gp efflux than Ligand B (0.085), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.6) has a stronger binding affinity than Ligand A (-7.9), with a 0.7 kcal/mol difference. This is a substantial advantage that could outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much better DILI score. While Ligand A has better solubility, permeability, metabolic stability and P-gp efflux, the potency advantage of Ligand B is significant. Given the enzyme-kinase specific priorities, potency is paramount. The DILI risk of Ligand A is concerning. The lower logP of Ligand A is a drawback, but the potency difference is large enough to compensate.

Output:
1
2025-04-17 13:55:33,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (343.427 and 366.418 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.44) is better than Ligand B (111.95). Lower TPSA generally favors better absorption.

**logP:** Ligand A (2.15) is optimal, while Ligand B (0.942) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds can improve membrane permeability.

**QED:** Both ligands have similar QED values (0.831 and 0.778), indicating good drug-likeness.

**DILI:** Ligand A (31.136) has a significantly lower DILI risk than Ligand B (64.599), which is a major advantage.

**BBB:** Both have moderate BBB penetration, but Ligand A is slightly better (67.235 vs 60.644). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.664) and Ligand B (-5.025) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.081) is slightly better than Ligand B (-3.709), though both are poor.

**hERG Inhibition:** Ligand A (0.093) shows a much lower hERG inhibition liability than Ligand B (0.272), a critical safety parameter.

**Microsomal Clearance:** Ligand A (5.664) has a higher (worse) microsomal clearance than Ligand B (2.585), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-2.317) has a longer half-life than Ligand B (0.759), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.057) has lower P-gp efflux liability than Ligand B (0.038), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Conclusion:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The significantly lower DILI risk and hERG inhibition liability of Ligand A are crucial safety advantages. While Ligand B has better metabolic stability, Ligand A has a longer half-life. The slightly better TPSA, logP, solubility, and P-gp efflux of Ligand A also contribute to its overall better profile. The affinity difference, while significant, is not enough to overcome the safety concerns associated with Ligand B.

Output:
0
2025-04-17 13:55:33,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.5 and 357.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is higher than Ligand B (55.32). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Ligand A (2.346) is within the optimal 1-3 range. Ligand B (3.535) is slightly higher, potentially increasing off-target effects, but still acceptable.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Lower HBD generally improves permeability.

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

**QED:** Both ligands have good QED scores (0.805 and 0.84), indicating good drug-like properties.

**DILI:** Ligand A (33.773) has a significantly lower DILI risk than Ligand B (61.07), which is a major advantage.

**BBB:** Ligand A (64.482) has a lower BBB penetration than Ligand B (78.519). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.06) has worse Caco-2 permeability than Ligand B (-4.523), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.039) has better aqueous solubility than Ligand B (-4.068), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.221) has a lower hERG inhibition risk than Ligand B (0.428), a significant safety advantage.

**Microsomal Clearance:** Ligand A (49.022) has lower microsomal clearance than Ligand B (85.163), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.447) has a shorter half-life than Ligand B (-41.276), which is a disadvantage.

**P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux than Ligand B (0.401), which is a positive.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). The difference is 1.6 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better Caco-2 permeability and BBB penetration, Ligand A excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The improved solubility of Ligand A is also beneficial. The shorter half-life of Ligand A is a concern, but can potentially be addressed through structural modifications.

Output:
0
2025-04-17 13:55:33,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.471 and 350.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (92.78) is slightly higher than the preferred <140, but acceptable. Ligand B (58.64) is well within the range.

**logP:** Ligand A (1.079) is at the lower end of optimal, potentially impacting permeability. Ligand B (3.045) is near the upper end, but still within 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 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.802 and 0.732), indicating good drug-like properties.

**DILI:** Ligand A (38.581) has a lower DILI risk than Ligand B (18.922), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.443) is higher than Ligand B (78.519).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.485 and -4.508), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.165 and -2.308), indicating very poor aqueous solubility, a major drawback.

**hERG:** Both ligands have low hERG risk (0.193 and 0.246), which is positive.

**Microsomal Clearance:** Ligand A (14.375) has significantly lower microsomal clearance than Ligand B (66.411), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (16.099) has a longer half-life than Ligand B (0.532), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.021 and 0.166).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.0 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Conclusion:**

Despite the poor permeability and solubility of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.4 vs -6.0 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher TPSA and lower logP. The lower DILI risk is also a positive. Addressing the solubility and permeability issues through formulation or further chemical modification would be crucial for Ligand A.

Output:
1
2025-04-17 13:55:33,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.423 and 362.836 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (134.82) is better than Ligand B (51.02), being closer to the <140 threshold for good absorption. Ligand B is very low, which *could* be beneficial for cell permeability but might sacrifice some necessary interactions.

**3. logP:** Ligand A (-0.45) is a bit low, potentially hindering permeability. Ligand B (3.417) is excellent, falling right within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) 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 (0.49 and 0.766 respectively), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (63.629). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (29.12) has a low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (84.451) has high BBB penetration, which is irrelevant here and could even be a negative if off-target effects are a concern.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.649 and -4.614). This is unusual and suggests poor permeability. However, these values are on different scales and hard to interpret directly.

**10. Solubility:** Ligand A (-1.192) has slightly better solubility than Ligand B (-3.449), although both are quite poor.

**11. hERG:** Ligand A (0.038) has a very low hERG risk, a significant advantage. Ligand B (0.309) is slightly higher but still relatively low.

**12. Cl_mic:** Ligand A (-11.859) has much lower microsomal clearance, indicating better metabolic stability. This is a crucial factor for kinase inhibitors. Ligand B (48.497) has high clearance.

**13. t1/2:** Ligand A (3.962) has a shorter half-life than Ligand B (-27.301). However, the negative value for Ligand B is suspect and likely an error. Assuming positive values are better, Ligand A is less desirable here.

**14. Pgp:** Both ligands have very low Pgp efflux (0.003 and 0.527), which is favorable.

**15. Binding Affinity:** Both ligands have similar, strong 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 the better candidate. While its logP and solubility are suboptimal, its significantly lower DILI risk, much better metabolic stability (lower Cl_mic), and very low hERG risk outweigh these drawbacks. The binding affinity is comparable to Ligand B. The negative Caco-2 values are concerning for both, but the other ADME properties of Ligand A are more favorable for development as an SRC kinase inhibitor.

Output:
0
2025-04-17 13:55:33,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.435 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.91) is better than Ligand B (71.09), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.559) is a bit low, potentially hindering permeation, while Ligand B (3.067) is within the optimal 1-3 range.

**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.

**QED:** Both ligands have good QED scores (0.735 and 0.807 respectively), indicating good drug-like properties.

**DILI:** Ligand A (29.236) has a significantly lower DILI risk than Ligand B (39.667), which is a major advantage. Both are below the 40 threshold.

**BBB:** Both ligands have similar BBB penetration (61.497 and 68.399), which isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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:** Ligand A (-0.267) has slightly better solubility than Ligand B (-3.783), which is a positive.

**hERG Inhibition:** Ligand A (0.188) shows a lower hERG inhibition risk than Ligand B (0.403), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (34.139) has a lower microsomal clearance than Ligand B (45.039), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.389) has a worse in vitro half-life than Ligand B (-6.5), but both are negative and difficult to interpret without knowing the scale.

**P-gp Efflux:** Ligand A (0.005) has much lower P-gp efflux liability than Ligand B (0.22), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability (lower Cl_mic). While Ligand B has a slightly better binding affinity and logP, the ADME-Tox profile of Ligand A is much more favorable, especially the lower DILI and hERG. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity are paramount.

Output:
0
2025-04-17 13:55:33,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**

*   **MW:** 351.491 Da - Good (within 200-500 range)
*   **TPSA:** 53.09 A^2 - Excellent (well below 140)
*   **logP:** 1.225 - Good (within 1-3)
*   **HBD:** 0 - Acceptable
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.699 - Excellent (>=0.5)
*   **DILI:** 15.587 - Excellent (low risk, <40)
*   **BBB:** 82.047 - Good
*   **Caco-2:** -4.223 - Poor (negative value indicates very low permeability)
*   **Solubility:** -1.148 - Poor (negative value indicates very low solubility)
*   **hERG:** 0.457 - Excellent (low risk)
*   **Cl_mic:** 21.85 mL/min/kg - Moderate (could be better, but not terrible)
*   **t1/2:** -26.547 hours - Very Poor (negative value indicates very short half-life)
*   **Pgp:** 0.14 - Excellent (low efflux)
*   **Affinity:** -7.0 kcal/mol - Excellent (strong binding)

**Ligand B:**

*   **MW:** 371.459 Da - Good (within 200-500 range)
*   **TPSA:** 85.11 A^2 - Acceptable (below 140)
*   **logP:** 0.662 - Acceptable (slightly below optimal, but ok)
*   **HBD:** 0 - Acceptable
*   **HBA:** 7 - Good (<=10)
*   **QED:** 0.621 - Good (>=0.5)
*   **DILI:** 61.109 - Moderate (slightly elevated risk, but not alarming)
*   **BBB:** 74.874 - Good
*   **Caco-2:** -4.826 - Poor (negative value indicates very low permeability)
*   **Solubility:** -1.506 - Poor (negative value indicates very low solubility)
*   **hERG:** 0.198 - Excellent (low risk)
*   **Cl_mic:** 56.063 mL/min/kg - Poor (high clearance, low metabolic stability)
*   **t1/2:** -35.233 hours - Very Poor (negative value indicates very short half-life)
*   **Pgp:** 0.074 - Excellent (low efflux)
*   **Affinity:** 0.0 kcal/mol - Very Poor (no binding affinity)

**Comparison and Decision:**

Both ligands suffer from extremely poor Caco-2 permeability and aqueous solubility (negative values). They also both have very short in vitro half-lives. However, Ligand A has a significantly better binding affinity (-7.0 kcal/mol vs 0.0 kcal/mol for Ligand B). Ligand A also has a lower DILI risk. While Ligand A's metabolic clearance is moderate, it's far better than Ligand B's high clearance.

Given that we are targeting a kinase (enzyme), potency (affinity) is paramount. Ligand A's strong binding affinity outweighs its moderate metabolic clearance and poor permeability/solubility. Ligand B's complete lack of binding affinity makes it a non-starter, regardless of its other properties.

Therefore, Ligand A is the more viable drug candidate, despite its drawbacks, because it actually binds to the target. Further optimization would focus on improving its solubility, permeability, and metabolic stability.

Output:
0
2025-04-17 13:55:33,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.379 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is slightly higher than Ligand B (78.95), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.037) is optimal, while Ligand B (0.241) is quite low. A low logP can hinder membrane permeability and potentially reduce binding affinity. This is a significant drawback for 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 reasonable QED scores (0.876 and 0.787), indicating good drug-like properties.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (29.236). This is a concern for Ligand A.

**BBB:** Ligand A (28.81) has a low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (68.748) has better BBB penetration, but again, this is less critical here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.859 and -4.57), which is unusual and suggests poor permeability. This needs further investigation, but it's a flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.813 and -2.271), which is also unusual and suggests poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.125 and 0.106), which is excellent.

**Microsomal Clearance:** Ligand A (5.453) has significantly lower microsomal clearance than Ligand B (17.126), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.497) has a shorter half-life than Ligand B (10.591), but both are reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent and strongly suggests good potency.

**Overall Assessment:**

While Ligand A has a higher DILI risk, its significantly better metabolic stability (lower Cl_mic) and optimal logP outweigh this concern, especially given the equal binding affinity. The poor Caco-2 and solubility for both are concerning and would require formulation strategies, but the metabolic stability is a crucial factor for kinase inhibitors. Ligand B's very low logP is a major disadvantage, likely impacting its ability to reach the target effectively.

Output:
0
2025-04-17 13:55:33,832 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.442 and 359.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (109.04).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (0.584) is low, potentially hindering permeation. Ligand B (3.198) is within the optimal 1-3 range. This favors B.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**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.

**QED:** Ligand B (0.813) has a better QED score than Ligand A (0.483), indicating a more drug-like profile.

**DILI:** Ligand A (13.881) has a much lower DILI risk than Ligand B (49.128). This is a significant advantage for A.

**BBB:** Both have reasonably high BBB penetration, but Ligand A (91.663) is better than Ligand B (82.513). While not a primary concern for a kinase inhibitor, higher BBB is never detrimental.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of negativity is similar (-4.709 for A, -4.971 for B).

**Aqueous Solubility:** Ligand A (-1.367) is better than Ligand B (-5.134), indicating better solubility.

**hERG:** Ligand A (0.392) has a much lower hERG inhibition liability than Ligand B (0.854). This is a crucial advantage for A, as kinase inhibitors can sometimes have cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (0.83) has significantly lower microsomal clearance than Ligand B (60.738), indicating better metabolic stability. This is a key factor for kinases.

**In vitro Half-Life:** Ligand A (-9.6) has a much longer in vitro half-life than Ligand B (14.593). This is another significant advantage for A.

**P-gp Efflux:** Ligand A (0.034) has much lower P-gp efflux than Ligand B (0.21), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-6.8). While a 1.5 kcal/mol difference is usually significant, the other ADME properties of A are far superior.



Considering all factors, Ligand A is the more promising drug candidate. While Ligand B has slightly better affinity and QED, Ligand A excels in crucial areas for kinase inhibitors: lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG inhibition, better solubility, and lower P-gp efflux. The lower logP of A is a concern, but its superior ADME profile outweighs this drawback.

Output:
0
2025-04-17 13:55:33,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.343 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.03) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (49.41) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (0.039) is quite low, potentially hindering permeability. Ligand B (3.562) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are reasonable. Ligand B has 1 HBD and 2 HBA, also good.

**QED:** Both ligands have good QED scores (0.504 and 0.796), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 61.031, which is moderately high. Ligand B has a significantly lower DILI risk of 22.179, a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.164) and Ligand B (90.306) are both reasonable.

**Caco-2 Permeability:** Ligand A (-5.349) shows poor permeability. Ligand B (-4.547) is better, but still suggests limited permeability.

**Aqueous Solubility:** Ligand A (-3.129) and Ligand B (-4.26) both indicate poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.179) has a low hERG risk, which is excellent. Ligand B (0.738) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (8.046) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (91.927) has very high clearance, indicating rapid metabolism and a potential issue with dosing frequency.

**In vitro Half-Life:** Ligand A (-17.01) has a negative half-life, which is nonsensical and indicates a problem with the data or the molecule itself. Ligand B (1.719) has a very short half-life, which is not ideal.

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is favorable. Ligand B (0.255) has a slightly higher, but still acceptable, P-gp efflux.

**Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (-8.1). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate despite its higher Caco-2 and lower half-life. The significantly stronger binding affinity (-7.0 vs -8.1 kcal/mol) is a major driver. The lower DILI risk (22.179 vs 61.031) is also a critical advantage. While Ligand A has better metabolic stability and lower P-gp efflux, the poor solubility, low logP, and the nonsensical half-life value raise significant concerns. The binding affinity difference is large enough to outweigh the metabolic stability advantage of Ligand A.

Output:
1
2025-04-17 13:55:33,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.391 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (375.925 Da) is still well within the acceptable range.

**TPSA:** Ligand A (63.25) is significantly better than Ligand B (42.16). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**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. However, for kinases, this isn't as critical as for CNS targets.

**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, but Ligand A's profile is slightly more balanced.

**QED:** Ligand A (0.664) has a better QED score than Ligand B (0.412), indicating a more drug-like profile.

**DILI:** Ligand B (52.385) has a significantly lower DILI risk than Ligand A (86.002). This is a major advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (76.425 and 78.247), but this is less crucial for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.849) has very poor Caco-2 permeability, while Ligand B (-5.564) is also poor but slightly better. This suggests potential absorption issues for both, but more significantly for Ligand A.

**Aqueous Solubility:** Ligand A (-5.887) has very poor aqueous solubility, while Ligand B (-3.335) is better. Solubility is a key factor for bioavailability, making Ligand B more favorable.

**hERG Inhibition:** Ligand A (0.748) has a slightly higher hERG risk than Ligand B (0.961), but both are reasonably safe.

**Microsomal Clearance:** Ligand B (75.562) has lower microsomal clearance than Ligand A (93.479), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (154.008) has a significantly longer in vitro half-life than Ligand A (58.112), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.568) has lower P-gp efflux than Ligand B (0.817), which could lead to better bioavailability.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While this is a positive for Ligand A, the difference is relatively small (0.2 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 crucial ADME properties: lower DILI risk, better solubility, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better P-gp efflux. The poor Caco-2 permeability of both is a concern, but Ligand B's better solubility might mitigate this to some extent. The enzyme-specific priorities clearly favor Ligand B.

Output:
1
2025-04-17 13:55:33,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 and 351.495 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (106.96).  A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (1.237) is optimal, while Ligand B (3.691) is approaching the upper limit. While 3.691 isn't terrible, it raises concerns about potential off-target effects and solubility.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range. Ligand A has 4 HBA, and Ligand B has 3 HBA, both are acceptable.

**QED:** Ligand A (0.707) has a much better drug-likeness score than Ligand B (0.375).

**DILI:** Ligand B (27.142) has a considerably higher DILI risk than Ligand A (13.067). This is a significant negative for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (68.864) is better than Ligand B (58.821).

**Caco-2 Permeability:** Ligand A (-4.517) is better than Ligand B (-4.781), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.759) is significantly better than Ligand B (-4.022). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.214) has a much lower hERG risk than Ligand B (0.329). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (27.105) has a lower clearance than Ligand B (62.31), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.495) has a shorter half-life than Ligand B (-2.752). However, the negative value for B is concerning and might indicate an issue with the assay or prediction.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux than Ligand B (0.141), which is favorable.

**Binding Affinity:** Ligand B (-7.6) has slightly better binding affinity than Ligand A (-7.4), but the difference is only 0.2 kcal/mol. Given the substantial ADME advantages of Ligand A, this small difference in affinity is unlikely to be decisive.

**Conclusion:**

Ligand A is the superior candidate. It demonstrates better drug-likeness (QED), lower toxicity (DILI, hERG), improved solubility and permeability (Caco-2, Solubility), and better metabolic stability (Cl_mic). While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A across multiple critical ADME properties outweigh this minor difference.

Output:
0
2025-04-17 13:55:33,833 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.454 and 353.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is higher than Ligand B (53.74). Both are acceptable, but Ligand B is preferable as lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (2.274 and 2.511), 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.71) has a better QED score than Ligand A (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (31.601) has a significantly lower DILI risk than Ligand B (88.406). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (84.529) is better than Ligand B (78.907). While not a primary concern for a kinase inhibitor, it's a slight positive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.935 and -4.938), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.928 and -3.623), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.513) has a slightly better hERG profile than Ligand B (0.738), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (37.016) has lower microsomal clearance than Ligand B (75.083), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-10.856) has a worse in vitro half-life than Ligand B (-16.603), indicating faster metabolism. This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux than Ligand B (0.519), suggesting better bioavailability.

**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 of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.5 vs -6.8 kcal/mol) and lower DILI risk are major advantages. The lower microsomal clearance and P-gp efflux also contribute to its favorability. While the half-life is worse, the potency advantage is likely to be more impactful for an enzyme inhibitor.

Output:
0
2025-04-17 13:55:33,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.45 and 356.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly above the preferred <60 for optimal permeability, but still reasonable. Ligand B (54.18) is excellent.

**logP:** Both ligands (3.119 and 3.618) are 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:** Ligand A (3) and Ligand B (6) are both acceptable, below the threshold of 10.

**QED:** Both ligands (0.757 and 0.67) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (35.673) has a lower DILI risk than Ligand B (44.242), both are below the concerning threshold of 60.

**BBB:** Ligand A (73.245) has better BBB penetration than Ligand B (55.603), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.74) has significantly better Caco-2 permeability than Ligand B (-5.47). Higher values are better.

**Aqueous Solubility:** Ligand A (-2.715) has better aqueous solubility than Ligand B (-3.184). Higher values are better.

**hERG Inhibition:** Ligand A (0.288) has a lower hERG inhibition risk than Ligand B (0.75). Lower values are better.

**Microsomal Clearance:** Ligand A (19.981) has significantly lower microsomal clearance than Ligand B (74.286), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.671) has a much longer in vitro half-life than Ligand B (-4.583).

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.205).

**Binding Affinity:** Ligand A (-7.8) has slightly better binding affinity than Ligand B (-7.0). While both are good, the 0.8 kcal/mol difference is notable.

**Conclusion:**

Ligand A is superior to Ligand B. It demonstrates better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, better solubility, better Caco-2 permeability, and slightly better binding affinity. While Ligand B has a lower TPSA, the advantages of Ligand A in key ADME/Tox properties and potency outweigh this single benefit.

Output:
1
2025-04-17 13:55:33,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.395 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.2) is slightly above the preferred <140 for good absorption, while Ligand B (91.57) is well within the range.

**logP:** Ligand A (0.16) is quite low, potentially hindering permeability. Ligand B (1.694) is within the optimal 1-3 range.

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

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

**QED:** Both ligands have similar QED values (0.656 and 0.668), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 91.043, which is high and concerning. Ligand B has a much lower DILI risk of 31.369, which is very favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (52.268) is lower than Ligand B (33.54).

**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:** Ligand A (0.165) has a slightly higher hERG risk than Ligand B (0.1). Both are relatively low.

**Microsomal Clearance:** Ligand A (-12.543) has a *much* lower (better) microsomal clearance than Ligand B (23.961), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (50.369) has a longer half-life than Ligand B (32.812), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.098).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.0 and -8.9 kcal/mol). The difference is negligible.

**Conclusion:**

Despite Ligand A's better metabolic stability and half-life, its significantly higher DILI risk and low logP are major drawbacks. Ligand B, while having slightly worse metabolic stability, has a much more favorable safety profile (DILI) and better logP, which is crucial for permeability. Given the enzyme-specific priorities, the lower DILI risk of Ligand B outweighs the slightly better metabolic stability of Ligand A.

Output:
1
2025-04-17 13:55:33,834 - INFO - Batch 254 complete. Total preferences: 4064
2025-04-17 13:55:33,834 - INFO - Processing batch 255/512...
2025-04-17 13:56:23,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.348 and 390.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is slightly higher than Ligand B (52.65), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (1.263) is within the optimal 1-3 range, while Ligand B (2.408) is also acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 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 similar QED values (0.747 and 0.734), indicating good drug-likeness.

**DILI:** Ligand A (48.623) has a slightly higher DILI risk than Ligand B (12.834), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.396) has a higher BBB penetration than Ligand B (66.111).

**Caco-2 Permeability:** Ligand A (-4.658) has a worse Caco-2 permeability than Ligand B (-5.122), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.835) has slightly better solubility than Ligand B (-2.404). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.29) has a lower hERG inhibition risk than Ligand B (0.531), which is a significant advantage.

**Microsomal Clearance:** Ligand A (10.478) has a higher microsomal clearance than Ligand B (6.437), indicating lower metabolic stability. This is a key concern for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-6.187) has a shorter half-life than Ligand B (9.5), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.022) has lower P-gp efflux than Ligand B (0.059), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

While both ligands have good binding affinity and drug-like properties, Ligand B is more favorable due to its significantly better metabolic stability (lower Cl_mic and longer t1/2) and lower hERG risk. Although Ligand A has slightly better solubility and lower P-gp efflux, the metabolic stability and safety profile of Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 13:56:23,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.543 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (71.09 and 73.74) are slightly above the optimal <140, but acceptable.

**3. logP:** Both ligands (3.015 and 2.216) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands (4) are well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.744 and 0.821), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (32.881 and 35.479), both well below the 40 threshold.

**8. BBB:** Ligand A (63.048) is better than Ligand B (51.221), but BBB isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative values (-4.922 and -4.743), which is unusual and suggests poor permeability. However, Caco-2 values can be unreliable and are less critical than other factors for kinase inhibitors.

**10. Aqueous Solubility:** Both have negative values (-3.829 and -1.884), indicating poor solubility. This is a significant concern for kinase inhibitors, as good solubility is needed for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.219 and 0.374).

**12. Microsomal Clearance:** Ligand A (71.371) has higher clearance than Ligand B (47.327). Higher clearance means faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (8.817) has a significantly longer half-life than Ligand A (-5.97). This is a major advantage for Ligand B, as it suggests less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.1 and 0.09).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and comparable scores on other crucial ADME properties. The poor solubility of both is a concern, but the longer half-life of Ligand B is a significant advantage for an enzyme inhibitor. The slightly better affinity of Ligand A is not enough to overcome the metabolic liabilities.

Output:
1
2025-04-17 13:56:23,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.479 and 365.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.11 and 82.68) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.225) is quite low, potentially hindering permeation. Ligand B (1.359) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 threshold.

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (9) is approaching the upper limit of 10, but still acceptable.

**QED:** Both ligands have good QED scores (0.651 and 0.756), indicating drug-like properties.

**DILI:** Ligand A (7.135) has a very favorable DILI score, indicating low liver injury risk. Ligand B (59.829) is higher, indicating a moderate risk. This is a significant advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration (45.909 and 54.711), which isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.977 and -5.819). These values are unusual and suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.595 and -1.783), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.277) has a very low hERG risk, which is excellent. Ligand B (0.084) also has low hERG risk.

**Microsomal Clearance:** Ligand A (2.335) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (20.555) has higher clearance. This favors Ligand A.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (22.748 and 22.518 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.019 and 0.106).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This is a 0.4 kcal/mol difference, which is not a huge advantage, but is noticeable.

**Overall Assessment:**

Ligand A has a significantly better safety profile (DILI and hERG) and better metabolic stability (lower Cl_mic). While Ligand B has slightly better binding affinity, the differences in ADME/Tox are substantial. The low logP and solubility of both compounds are concerning, but the superior safety and metabolic stability of Ligand A make it the more promising candidate, especially considering the potential for optimization of solubility and permeability.

Output:
0
2025-04-17 13:56:23,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.4 and 343.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.91) is significantly better than Ligand B (112.91). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.89 and 1.57), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=3, HBA=5). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.88) has a superior QED score compared to Ligand B (0.63), indicating a more drug-like profile.

**DILI:** Ligand A (39.9%) has a much lower DILI risk than Ligand B (67.5%). This is a significant advantage for A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (70.7%) is better than Ligand B (42.5%).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or the model. However, A (-5.051) is less negative than B (-5.379).

**Aqueous Solubility:** Both have negative solubility values, again suggesting potential data/model issues. A (-3.324) is slightly better than B (-3.15).

**hERG:** Ligand A (0.865) has a much lower hERG risk than Ligand B (0.05). This is a critical advantage for A.

**Microsomal Clearance:** Ligand A (5.94 mL/min/kg) has a much lower microsomal clearance than Ligand B (28.36 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.61 hours) has a significantly longer half-life than Ligand B (-34.999 hours). The negative value for B is concerning and likely an artifact.

**P-gp Efflux:** Ligand A (0.454) has lower P-gp efflux liability than Ligand B (0.045).

**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 threshold.

**Conclusion:**

Ligand A is clearly superior to Ligand B. It has a better QED score, lower DILI and hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and significantly stronger binding affinity. While both have issues with predicted solubility and Caco-2 permeability, A is better in both regards. The substantial difference in binding affinity and the favorable ADME properties make Ligand A the much more promising drug candidate.

Output:
1
2025-04-17 13:56:23,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.515 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.32) is better than Ligand B (58.64), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.162 and 1.96), 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 similar QED scores (0.807 and 0.795), indicating good drug-likeness.

**DILI:** Ligand A (50.291) has a slightly higher DILI risk than Ligand B (32.377), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (73.866 and 71.694). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-5.419) has worse Caco-2 permeability than Ligand B (-4.602), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.972) has slightly worse solubility than Ligand B (-2.652). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.584) has a slightly higher hERG risk than Ligand B (0.397), but both are relatively low.

**Microsomal Clearance:** This is a key parameter for kinases. Ligand A (-1.182) has *much* better metabolic stability (lower clearance) than Ligand B (48.697). This is a significant advantage.

**In vitro Half-Life:** Ligand A (-7.317) has a significantly longer half-life than Ligand B (-11.756). This is also a significant advantage.

**P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.115), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-6.8 kcal/mol) has slightly better binding affinity than Ligand B (-6.1 kcal/mol). While both are good, the 0.7 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability and solubility, Ligand A's significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity outweigh these minor drawbacks. For an enzyme target like SRC kinase, metabolic stability and potency are paramount. The small difference in DILI and hERG are not concerning.

Output:
1
2025-04-17 13:56:23,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.519 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (111.53). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Ligand A (2.837) is optimal (1-3). Ligand B (-0.961) is below 1, which might impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=6). Both are within acceptable limits, but Ligand A has a more favorable balance.

**QED:** Both ligands have reasonable QED values (0.8 and 0.686), indicating good drug-like properties.

**DILI:** Ligand A (11.71) has a much lower DILI risk than Ligand B (35.75). This is a significant advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (77.007) is higher than Ligand B (23.342), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.484) is better than Ligand B (-5.171), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.334) is better than Ligand B (-1.009). Solubility is important for bioavailability, and Ligand A has a clear advantage.

**hERG Inhibition:** Ligand A (0.516) has a much lower hERG risk than Ligand B (0.037). This is a critical advantage.

**Microsomal Clearance:** Ligand A (53.098) is higher than Ligand B (-9.268). Lower clearance is better, suggesting Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (5.238) has a shorter half-life than Ligand B (-31.006). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.071) is better than Ligand B (0.007), indicating less P-gp efflux and potentially better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -9.0 kcal/mol). Ligand B is slightly better, but the difference is likely not enough to overcome its ADME liabilities.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and metabolic stability, but it suffers from poor logP, high DILI risk, a high TPSA, and a very high risk of hERG inhibition. Ligand A has a more balanced profile with better solubility, lower DILI and hERG risk, and a more favorable logP and TPSA. While its half-life is shorter, the other advantages outweigh this drawback, especially considering optimization can address metabolic stability.

Output:
1
2025-04-17 13:56:23,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.443 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.43) is slightly higher than Ligand B (78.67), both are below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (1.677 and 1.299), falling within the optimal 1-3 range.

**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 (3) is lower than Ligand B (5), both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.776 and 0.84), indicating good drug-like properties.

**7. DILI:** Ligand A (33.773) has a slightly higher DILI risk than Ligand B (25.359), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand B (73.401) has a better BBB penetration score than Ligand A (47.111), but BBB is not a primary concern for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Ligand A (-5.004) has a worse Caco-2 permeability than Ligand B (-4.64), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.333) has a worse aqueous solubility than Ligand B (-1.443), which could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.312 and 0.355).

**12. Microsomal Clearance:** Ligand B (3.611) has significantly lower microsomal clearance than Ligand A (18.729), indicating better metabolic stability. This is a critical factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (3.981) has a much longer in vitro half-life than Ligand A (-18.025), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.044 and 0.103).

**15. 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 outweighs minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has acceptable properties, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a substantially stronger binding affinity. These factors are paramount for kinase inhibitors. The slightly better solubility of Ligand B is also a plus.

Output:
1
2025-04-17 13:56:23,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.447 and 368.587 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is better than Ligand B (49.41) as it is still within the acceptable range for oral absorption.

**logP:** Ligand A (1.179) is optimal, while Ligand B (3.699) is approaching the upper limit. Higher logP can sometimes lead to off-target effects.

**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 (0.675) has a better QED score than Ligand A (0.454), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A at 21.869 and Ligand B at 24.234.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.249) is higher than Ligand A (61.691).

**Caco-2 Permeability:** Ligand A (-4.642) and Ligand B (-4.903) both have negative values, which is unusual. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.941 and -3.899 respectively). This is a significant concern.

**hERG:** Ligand A (0.162) has a much lower hERG risk than Ligand B (0.617), which is a major advantage.

**Microsomal Clearance:** Ligand B (101.952) has a higher microsomal clearance than Ligand A (75.412), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-26.67) has a negative half-life, which is not possible. This is a red flag. Ligand B (-10.27) is also negative, indicating a problem with the data.

**P-gp Efflux:** Ligand A (0.039) has very low P-gp efflux, while Ligand B (0.303) has slightly higher efflux.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial difference.

**Conclusion:**

Despite the poor solubility and questionable half-life values, Ligand B is the more promising candidate due to its significantly superior binding affinity (-8.1 vs 0 kcal/mol). The stronger binding is likely to outweigh the drawbacks, especially if solubility can be improved through formulation strategies. The better QED score also supports this choice. The hERG risk is higher for Ligand B, but manageable. The negative half-life values for both compounds raise concerns about data quality.

Output:
1
2025-04-17 13:56:23,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.345 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.8) is better than Ligand B (123.4), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (0.147) is low, potentially hindering permeability. Ligand B (-0.253) is even lower, raising concerns about absorption. Both are below the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (4) is slightly higher, but still acceptable.

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (4) is also good.

**QED:** Ligand A (0.564) is good, indicating drug-like properties. Ligand B (0.363) is lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (48.623) has a lower DILI risk than Ligand B (66.77). Both are acceptable, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.682) is slightly better than Ligand B (69.484).

**Caco-2 Permeability:** Ligand A (-4.764) is better than Ligand B (-5.492), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.489) is better than Ligand B (-2.807), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.187) has a lower hERG risk than Ligand B (0.057). This is a significant advantage.

**Microsomal Clearance:** Ligand A (50.818) is significantly better than Ligand B (0.019). A higher value for B indicates very rapid clearance and poor metabolic stability.

**In vitro Half-Life:** Ligand A (-25.003) is much better than Ligand B (-0.884). A more negative value indicates a longer half-life.

**P-gp Efflux:** Ligand A (0.034) is better than Ligand B (0.01). Lower efflux is preferable.

**Binding Affinity:** Ligand A (-7.9) has a significantly stronger binding affinity than Ligand B (0.0). This is a crucial factor, and the 1.9 kcal/mol difference is substantial.

**Conclusion:**

Ligand A is clearly superior. While both have suboptimal logP values, Ligand A excels in almost every other critical parameter, especially binding affinity, metabolic stability (Cl_mic and t1/2), hERG risk, solubility, and DILI. The substantially stronger binding affinity of Ligand A (-7.9 kcal/mol) outweighs the minor drawbacks of its logP. Ligand B's extremely low microsomal clearance and half-life are major red flags.

Output:
1
2025-04-17 13:56:23,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.531 and 352.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.46 and 76.66) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.529) is at the upper end of the optimal range (1-3), while Ligand B (2.085) is closer to the lower end. This slightly favors A, but both are acceptable.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands (4) are well below the limit of <=10.

**QED:** Both ligands have similar QED values (0.656 and 0.632), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (45.715 and 40.946), both well below the 60 threshold.

**BBB:** Ligand B (88.29) has a higher BBB penetration percentile than Ligand A (71.229), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.84) and Ligand B (-4.76) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.531 and -2.764). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.644 and 0.422), which is positive.

**Microsomal Clearance:** Ligand B (28.219 mL/min/kg) has significantly lower microsomal clearance than Ligand A (69.055 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (11.273 hours) has a longer in vitro half-life than Ligand A (42.587 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.147 and 0.107).

**Binding Affinity:** Ligand A (-6.9 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:**

Despite the superior binding affinity of Ligand A, the significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility of Ligand B are compelling. Both compounds suffer from poor Caco-2 permeability and aqueous solubility, which would need to be addressed through formulation or structural modifications. However, the improved pharmacokinetic profile of Ligand B makes it a more promising starting point for optimization. The large difference in binding affinity is concerning, but could be addressed during lead optimization.

Output:
1
2025-04-17 13:56:23,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (414.296 Da) is slightly higher than Ligand B (372.531 Da), but both are acceptable.

**TPSA:** Ligand A (81.7) is higher than Ligand B (59.08). Both are below 140, suggesting good oral absorption potential, but Ligand B is preferable.

**logP:** Ligand A (3.932) is at the upper end of the optimal range (1-3), while Ligand B (1.632) is closer to the lower end. Ligand B is better here, reducing potential off-target effects.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is within the acceptable range (<=10).

**QED:** Both ligands have similar QED values (0.714 and 0.606), indicating good drug-likeness.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (15.51). This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (76.696) is better than Ligand A (68.941). While not a primary concern for a kinase inhibitor, it's a slight benefit.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.467 and -4.632) and don't strongly differentiate the two.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.125) is slightly better than Ligand A (-4.935).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.505 and 0.561), which is good.

**Microsomal Clearance:** Ligand B (50.762) has significantly lower microsomal clearance than Ligand A (102.18). This indicates better metabolic stability for Ligand B, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-3.175) has a longer in vitro half-life than Ligand A (37.394). Again, this favors Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.14 and 0.072).

**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 for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand A's superior binding affinity, Ligand B demonstrates a significantly better ADME profile, particularly in terms of DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. The difference in binding affinity, while substantial, may be overcome with further optimization of Ligand B. Given the enzyme-specific priorities, the improved ADME properties of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 13:56:23,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.43 and 348.49 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is slightly higher than Ligand B (75.27), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.52) is within the optimal range (1-3), while Ligand B (2.75) is approaching the upper limit.

**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.

**QED:** Ligand A (0.754) has a better QED score than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (20.71) has a significantly lower DILI risk than Ligand B (12.52), which is a major advantage.

**BBB:** Ligand A (18.15) has a lower BBB penetration percentile than Ligand B (67.93). However, since SRC is not a CNS target, this is less critical.

**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. This is a concern for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.285 and 0.111), which is excellent.

**Microsomal Clearance:** Ligand A (5.86) has a much lower microsomal clearance than Ligand B (55.53), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.28) has a more negative half-life, suggesting a longer half-life than Ligand B (-23.43).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.017).

**Binding Affinity:** Both ligands have similar binding affinities (-8.3 and -8.4 kcal/mol), which are both excellent and well below the -7.0 threshold.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have similar potency, Ligand A has a significantly lower DILI risk, better QED, and much better metabolic stability (lower Cl_mic and more negative half-life). The solubility and Caco-2 values are concerning for both, but the ADME advantages of Ligand A outweigh these concerns.

Output:
0
2025-04-17 13:56:23,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.366 and 351.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (110.32) is slightly above the preferred <140, while Ligand B (87.74) is well within the range.

**logP:** Both ligands (0.507 and 0.599) are a bit low, potentially hindering permeation, but not drastically.

**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 good QED scores (0.772 and 0.658), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 66.693, which is moderately high. Ligand B has a much lower DILI risk of 22.838, which is excellent. This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (78.79) and Ligand B (53.083) are both relatively low, which is expected.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.116 and -4.919) which is unusual and problematic. This suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.614 and -1.156), which is also concerning. Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.2 and 0.061), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (7.648) than Ligand B (22.6), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (0.916) has a very short half-life, while Ligand B (3.223) is slightly better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.016), which is favorable.

**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 of the ADME drawbacks. The difference of 1.3 kcal/mol is quite significant.

**Conclusion:**

While Ligand A has better metabolic stability, Ligand B has a much lower DILI risk and significantly better binding affinity. The strong binding affinity of Ligand B is a major advantage for an enzyme target like SRC. The DILI risk associated with Ligand A is concerning. The poor Caco-2 and solubility for both are problematic, but can potentially be addressed with formulation strategies. Given the priorities for enzyme inhibitors, the superior potency and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 13:56:23,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.47 and 378.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (90.98 and 86.71) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.138) is quite low, potentially hindering permeation. Ligand B (1.444) is within the optimal 1-3 range. This favors Ligand B.

**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:** Ligand B (0.669) has a better QED score than Ligand A (0.429), indicating a more drug-like profile.

**DILI:** Ligand A (18.651) has a significantly lower DILI risk than Ligand B (30.554). This is a strong point in favor of Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (74.796) is better than Ligand A (63.862). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.173 and -5.102), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.851 and -2.765), indicating very poor aqueous solubility. This is a major drawback for both, but worse for Ligand B.

**hERG Inhibition:** Ligand A (0.13) has a much lower hERG risk than Ligand B (0.633). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (22.737 mL/min/kg) has a lower microsomal clearance than Ligand B (44.622 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.905 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (-35.124 hours) also has a negative half-life, indicating a similar issue.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.002 and 0.093).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better QED and BBB penetration. However, it has a higher DILI risk, worse solubility, and higher clearance. Ligand A has a lower DILI risk and better metabolic stability, but its logP is very low and its binding affinity is weaker. The negative half-life values for both are concerning.

Given the priority for potency in enzyme inhibition, the significantly stronger binding affinity of Ligand B (-8.3 vs -6.2 kcal/mol) is a decisive factor. While the ADME properties of Ligand B are not ideal, the potency advantage is likely to be more impactful in early stages of drug development, and optimization can be focused on improving its ADME profile. The negative half-life values are a data quality issue that needs to be investigated, but the binding affinity difference is too large to ignore.

Output:
1
2025-04-17 13:56:23,841 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [351.363, 114.79 ,  -1.127,   2.   ,   7.   ,   0.71 ,  79.837,  54.052, -5.036,  -1.93 ,   0.06 , -14.665, -10.098,   0.008,  -8.7  ]
**Ligand B:** [343.471,  43.86 ,   1.338,   0.   ,   3.   ,   0.518,  18.185,  55.874, -4.559,  -1.006,   0.699,  23.663,  -9.377,   0.065,  -6.2  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (351.363) and B (343.471) are comparable.
2. **TPSA:** A (114.79) is better than B (43.86), falling comfortably under the 140 A^2 threshold for oral absorption. B is also good.
3. **logP:** A (-1.127) is slightly lower than optimal (1-3), potentially impacting permeability. B (1.338) is within the ideal range.
4. **HBD:** A (2) and B (0) are both acceptable, below the limit of 5.
5. **HBA:** A (7) and B (3) are both acceptable, below the limit of 10.
6. **QED:** Both A (0.71) and B (0.518) are above the 0.5 threshold, indicating good drug-likeness.
7. **DILI:** A (79.837) has a significantly higher DILI risk than B (18.185). This is a major concern for A.
8. **BBB:** Both are similar, with A (54.052) and B (55.874) being moderate. Not a primary concern for SRC kinase, which is not a CNS target.
9. **Caco-2:** A (-5.036) and B (-4.559) are both negative, indicating poor permeability.
10. **Solubility:** A (-1.93) and B (-1.006) are both negative, indicating poor solubility.
11. **hERG:** A (0.06) is very low, indicating minimal hERG inhibition risk. B (0.699) is slightly higher, but still relatively low.
12. **Cl_mic:** A (-14.665) is much lower (better) than B (23.663), suggesting better metabolic stability.
13. **t1/2:** A (-10.098) is much lower (worse) than B (-9.377), suggesting a shorter half-life.
14. **Pgp:** A (0.008) is very low, indicating minimal P-gp efflux. B (0.065) is slightly higher, but still low.
15. **Affinity:** A (-8.7) is significantly better than B (-6.2), representing a substantial advantage in binding potency (a difference of 2.5 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A has a much stronger binding affinity.
*   **Metabolic Stability:** A has better metabolic stability (lower Cl_mic).
*   **Solubility:** Both are poor, but not a dealbreaker if other properties are favorable.
*   **hERG:** A has a better hERG profile.
*   **DILI:** A has a significantly higher DILI risk, which is a major concern.
*   **Half-life:** B has a slightly better half-life.

**Conclusion:**

Despite the significantly better binding affinity and metabolic stability of Ligand A, the very high DILI risk is a major red flag. While a strong affinity can sometimes outweigh other issues, a high DILI risk is difficult to overcome and would likely lead to attrition during development. Ligand B, while having a weaker affinity, presents a much more favorable safety profile (lower DILI) and acceptable ADME properties.

Therefore, I recommend **Ligand B** as the more viable drug candidate.

1
2025-04-17 13:56:23,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.439 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.33) is better than Ligand B (101.49), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (1.89) is optimal, while Ligand B (0.336) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Both have 6 HBA, also good.

**QED:** Ligand A (0.903) is excellent, indicating high drug-likeness. Ligand B (0.764) is also good, but lower.

**DILI:** Ligand B (56.029) has a lower DILI risk than Ligand A (66.421), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.756) is slightly better than Ligand B (59.325).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.198) is slightly better than Ligand B (-4.891).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.541) is slightly better than Ligand B (-1.497).

**hERG Inhibition:** Both are very low (0.283 and 0.077), indicating minimal cardiotoxicity risk. Ligand B is slightly better.

**Microsomal Clearance:** Ligand B (8.488) has significantly lower clearance than Ligand A (22.169), suggesting better metabolic stability. This is a major advantage for an enzyme inhibitor.

**In vitro Half-Life:** Both have negative half-lives (-5.73 and -5.64), which is unusual and suggests rapid degradation. They are comparable.

**P-gp Efflux:** Both are very low (0.166 and 0.012), indicating minimal P-gp efflux. Ligand B is slightly better.

**Binding Affinity:** Both have excellent binding affinities (-9.1 and -8.3 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is significant.

**Conclusion:**

While Ligand A has a slightly better binding affinity and QED score, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and a lower DILI risk. Given the enzyme-specific priorities, metabolic stability is crucial for maintaining therapeutic concentrations. The affinity difference, while notable, might be overcome with further optimization. The slightly better DILI profile of Ligand B is also a significant advantage.

Output:
1
2025-04-17 13:56:23,842 - INFO - Batch 255 complete. Total preferences: 4080
2025-04-17 13:56:23,842 - INFO - Processing batch 256/512...
2025-04-17 13:57:03,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.47 and 351.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is better than Ligand B (120.67). TPSA < 140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (1.785 and 1.136), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (3 HBD, 4 HBA) is slightly better than Ligand B (4 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are acceptable.

**QED:** Ligand A (0.665) has a significantly better QED score than Ligand B (0.393), indicating a more drug-like profile.

**DILI:** Ligand B (46.762) has a lower DILI risk than Ligand A (59.907), which is a positive for B.

**BBB:** Ligand B (61.807) has a higher BBB penetration percentile than Ligand A (30.826). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.335 and -5.403) which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.574 and -2.101), which is also a major concern. Poor solubility can severely limit bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.355 and 0.274), which is good.

**Microsomal Clearance:** Ligand B (18.561 mL/min/kg) has significantly lower microsomal clearance than Ligand A (74.807 mL/min/kg). This indicates better metabolic stability for Ligand B, a key consideration for kinases.

**In vitro Half-Life:** Ligand B (13.527 hours) has a longer in vitro half-life than Ligand A (7.137 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.133 and 0.061).

**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 notable.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor Caco-2 and solubility, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and a lower DILI risk. The higher QED score of Ligand A is offset by its poorer metabolic profile. For an enzyme target like SRC kinase, metabolic stability and potency are paramount.

Output:
1
2025-04-17 13:57:03,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.511 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is significantly better than Ligand B (97.12). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (2.976 and 1.775, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 8 HBA). Lower counts are generally better for permeability.

**QED:** Ligand A (0.734) has a higher QED score than Ligand B (0.563), indicating a more drug-like profile.

**DILI:** Ligand A (37.999) has a significantly lower DILI risk than Ligand B (60.489). This is a major advantage.

**BBB:** While not a primary concern for a non-CNS target, Ligand B (75.107) has a higher BBB percentile than Ligand A (52.656).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-5.233 and -5.068).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Again, the values are similar (-2.224 and -2.249).

**hERG Inhibition:** Ligand A (0.155) shows a much lower hERG inhibition liability than Ligand B (0.885). This is a critical advantage.

**Microsomal Clearance:** Ligand A (20.299) has a lower microsomal clearance than Ligand B (43.611), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (65.641) has a significantly longer in vitro half-life than Ligand A (4.623). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.249) has lower P-gp efflux liability than Ligand B (0.18).

**Binding Affinity:** Ligand A (-8.6 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 contributes to the overall preference.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a lower DILI risk, lower hERG inhibition, lower microsomal clearance (better metabolic stability), a higher QED score, and a slightly better binding affinity. While Ligand B has a longer half-life, the superior ADME-Tox profile of Ligand A outweighs this benefit. The poor solubility and Caco-2 permeability are concerning for both, but the other advantages of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 13:57:03,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (343.475 and 340.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.04) is higher than Ligand B (51.02). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better.

**3. logP:** Ligand A (2.502) and Ligand B (3.573) are both within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

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

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), both are within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.909 and 0.855), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (41.411 and 40.403 percentile), which is favorable.

**8. BBB:** Ligand A (89.957) has a better BBB penetration percentile than Ligand B (70.919), but BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.988) has better Caco-2 permeability than Ligand B (-4.815).

**10. Aqueous Solubility:** Ligand A (-2.178) has better aqueous solubility than Ligand B (-4.021). This is a significant advantage for an enzyme inhibitor, aiding in formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.868) has a slightly higher hERG inhibition risk than Ligand B (0.554), but both are reasonably low.

**12. Microsomal Clearance:** Ligand A (11.647 mL/min/kg) has significantly lower microsomal clearance than Ligand B (73.42 mL/min/kg). This suggests better metabolic stability for Ligand A, a crucial factor for enzymes.

**13. In vitro Half-Life:** Ligand A (5.527 hours) has a much shorter in vitro half-life than Ligand B (-22.034 hours). The negative value for Ligand B suggests a very long half-life, which is highly desirable.

**14. P-gp Efflux:** Ligand A (0.407) shows lower P-gp efflux than Ligand B (0.509).

**15. Binding Affinity:** Ligand B (-8.9 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, permeability, and metabolic stability, the significantly stronger binding affinity of Ligand B (-8.9 vs -6.9 kcal/mol) is the most critical factor for an enzyme inhibitor. The longer half-life of Ligand B is also a major advantage. The slightly higher logP and lower solubility of Ligand B are acceptable trade-offs for the improved potency and stability.

Output:
1
2025-04-17 13:57:03,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.523 Da) is slightly higher than Ligand B (338.375 Da), but both are acceptable.

**TPSA:** Ligand A (82.78) is well below the 140 threshold for oral absorption, and suitable. Ligand B (134.5) is approaching the upper limit, potentially impacting absorption, but still acceptable.

**logP:** Both ligands have good logP values (A: 1.805, B: 1.479), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is better than Ligand B (HBD=4, HBA=7) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.806) has a significantly better QED score than Ligand B (0.512), indicating a more drug-like profile.

**DILI:** Ligand A (45.25) has a much lower DILI risk than Ligand B (68.282). This is a significant advantage.

**BBB:** BBB is not a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired. Both are relatively low (A: 36.216, B: 30.748).

**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 (-5.163) is slightly better than Ligand B (-6.081).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.438) is slightly better than Ligand B (-2.76).

**hERG:** Ligand A (0.167) has a much lower hERG risk than Ligand B (0.517). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (23.872) has higher microsomal clearance than Ligand B (-4.781). This suggests Ligand B is more metabolically stable, which is highly desirable for an enzyme target.

**In vitro Half-Life:** Ligand A (10.306 hours) has a longer half-life than Ligand B (3.344 hours). This is a positive attribute.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.038, B: 0.01).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.7 kcal/mol, B: -8.7 kcal/mol). Ligand A is slightly more potent. The 1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly better QED, lower DILI risk, lower hERG risk, longer half-life, and slightly better binding affinity. While Ligand B has better metabolic stability (lower Cl_mic), the other advantages of Ligand A are more critical for an enzyme inhibitor. The slightly better permeability and solubility predictions for Ligand A are also beneficial.

Output:
1
2025-04-17 13:57:03,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 369.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (100.55). A TPSA under 90 is preferred, and A is closer to that threshold.

**logP:** Both ligands have good logP values (1.835 and 1.316), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have similar and acceptable QED values (0.63 and 0.642), indicating good drug-likeness.

**DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (57.619). This is a significant advantage.

**BBB:** Ligand A (67.158) has a better BBB percentile than Ligand B (34.122), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.733) has a better Caco-2 permeability than Ligand B (-5.237), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.335) has better aqueous solubility than Ligand B (-1.732). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.191 and 0.267), which is good.

**Microsomal Clearance:** Ligand A (43.554) has higher microsomal clearance than Ligand B (29.939), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (14.826) has a significantly longer in vitro half-life than Ligand A (-1.432), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.213).

**Binding Affinity:** Ligand B (-9.6 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. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. While Ligand A has better TPSA, solubility, and a much lower DILI risk, the superior potency and metabolic stability of Ligand B are more important in this context. The difference in binding affinity is substantial.

Output:
1
2025-04-17 13:57:03,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.423 and 362.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (131.36) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (89.87) is well within the optimal range.

**logP:** Ligand A (-2.427) is a bit low, potentially hindering permeation. Ligand B (0.764) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 7 HBA, acceptable. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.342 and 0.595), with Ligand B being better.

**DILI:** Ligand A (12.136) has a very low DILI risk, which is excellent. Ligand B (16.479) is slightly higher but still relatively low.

**BBB:** Ligand A (18.534) has a low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (64.637) has moderate BBB penetration, also not a key factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.737 and -4.961), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (0.046) has very poor solubility, a major drawback. Ligand B (-1.356) also has poor solubility, though slightly better than A.

**hERG Inhibition:** Ligand A (0.034) shows very low hERG inhibition risk, a significant advantage. Ligand B (0.338) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (2.322) has low microsomal clearance, indicating good metabolic stability. Ligand B (11.863) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-7.161) has a very long in vitro half-life, highly desirable. Ligand B (-30.073) has a very short half-life, a major disadvantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.002 and 0.023).

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-6.9). The difference is 0.9 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, excellent DILI profile, very low hERG risk, and long half-life. While its solubility and Caco-2 permeability are poor, the strong binding and favorable safety/stability profiles outweigh these concerns. Ligand B suffers from a shorter half-life and higher clearance, despite having slightly better logP and TPSA. The solubility issues are also a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:57:03,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.455 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is well below the 140 threshold for good absorption, while Ligand B (132.81) is approaching the limit but still acceptable.

**logP:** Ligand A (2.606) is within the optimal 1-3 range. Ligand B (-1.131) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both within acceptable limits. Ligand B has 5 HBD and 7 HBA, still within the guidelines but edging towards potentially less favorable permeability.

**QED:** Ligand A (0.617) has a better QED score than Ligand B (0.419), indicating a more drug-like profile.

**DILI:** Ligand A (43.117) has a lower DILI risk than Ligand B (62.466), suggesting better liver safety.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (56.223) has a better BBB score than Ligand B (35.595).

**Caco-2 Permeability:** Ligand A (-4.576) and Ligand B (-5.544) 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.

**Aqueous Solubility:** Ligand A (-3.283) and Ligand B (-1.181) both have negative solubility values, which is also unusual. Higher solubility is preferred.

**hERG:** Ligand A (0.374) has a significantly lower hERG risk than Ligand B (0.154), which is a major advantage.

**Microsomal Clearance:** Ligand A (53.225) has a higher microsomal clearance than Ligand B (-13.906). This indicates that Ligand B is likely to have better metabolic stability.

**In vitro Half-Life:** Ligand B (7.88) has a longer in vitro half-life than Ligand A (-7.053), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.156 and 0.004 respectively).

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.053), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, lower hERG) and better drug-like properties (higher QED). While Ligand B has better metabolic stability and slightly better binding affinity, the concerns around its logP, DILI, and hERG risk are substantial. For an enzyme target like SRC kinase, metabolic stability and potency are important, but safety is paramount. The modest improvement in binding affinity of Ligand B does not outweigh the significant liabilities.

Output:
0
2025-04-17 13:57:03,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.474 and 366.487 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.25) is significantly better than Ligand B (79.74). Lower TPSA generally favors better absorption.

**3. logP:** Ligand A (3.643) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (1.402) is on the lower side, 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, 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 (0.701 and 0.81), indicating good drug-like properties.

**7. DILI:** Ligand A (69.911) has a slightly higher DILI risk than Ligand B (60.217), but both are reasonably acceptable.

**8. BBB:** Both have reasonable BBB penetration, but Ligand A (77.821) is better than Ligand B (69.678). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2:** Ligand A (-4.821) has a worse Caco-2 permeability than Ligand B (-5.095), indicating lower intestinal absorption.

**10. Solubility:** Ligand A (-3.842) has worse solubility than Ligand B (-2.719). Solubility is important for bioavailability.

**11. hERG:** Ligand A (0.761) has a slightly higher hERG risk than Ligand B (0.598). Lower hERG is preferred.

**12. Cl_mic:** Ligand A (114.159) has higher microsomal clearance than Ligand B (47.701), indicating lower metabolic stability. This is a significant drawback.

**13. t1/2:** Ligand A (114.358) has a longer in vitro half-life than Ligand B (43.011), which is a positive.

**14. Pgp:** Ligand A (0.772) has higher P-gp efflux than Ligand B (0.045). Lower P-gp efflux is preferred.

**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 ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is the most critical factor for an enzyme inhibitor. However, it suffers from higher Cl_mic (lower metabolic stability), lower solubility, and higher P-gp efflux. Ligand B has better ADME properties (solubility, metabolic stability, P-gp efflux) but weaker binding affinity. The difference in binding affinity (1.1 kcal/mol) is substantial enough to favor Ligand A, *provided* that the metabolic stability issues can be addressed through further optimization. The longer half-life of Ligand A is also a positive.

Output:
1
2025-04-17 13:57:03,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.411 and 348.311 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.43) is significantly better than Ligand B (117.07). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B is approaching a level that could hinder absorption.

**logP:** Both ligands have acceptable logP values (2.109 and 1.248), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (1 HBD, 9 HBA). Lower HBD and HBA generally improve permeability.

**QED:** Ligand A (0.797) has a higher QED score than Ligand B (0.582), indicating better overall drug-likeness.

**DILI:** Ligand B (96.704) has a significantly higher DILI risk than Ligand A (66.964). This is a major concern.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (88.135) has better BBB penetration than Ligand B (46.336).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, Ligand A (-4.433) is slightly better than Ligand B (-4.531).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-3.102) is slightly better than Ligand B (-2.988).

**hERG Inhibition:** Ligand A (0.552) has a much lower hERG inhibition risk than Ligand B (0.076). This is a critical advantage.

**Microsomal Clearance:** Ligand A (44.641) has a lower microsomal clearance than Ligand B (72.669), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.285 hours) has a positive half-life, while Ligand B (-26.263 hours) has a negative half-life, which is not physically possible and indicates a significant issue with the data.

**P-gp Efflux:** Ligand A (0.5) has lower P-gp efflux than Ligand B (0.154), suggesting better bioavailability.

**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:**

Ligand B has a much stronger binding affinity, which is a major plus. However, it suffers from a very high DILI risk, a negative in vitro half-life, and a higher hERG risk. Ligand A, while having weaker binding, presents a much more favorable ADMET profile, with lower DILI and hERG risks, better metabolic stability, and a more reasonable half-life. Given the enzyme-specific priorities, the significantly better ADMET profile of Ligand A outweighs the binding affinity difference, especially considering optimization can potentially improve the affinity of Ligand A. The negative half-life for Ligand B is a showstopper.

Output:
0
2025-04-17 13:57:03,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.487 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is excellent, well below the 140 threshold, suggesting good absorption. Ligand B (85.17) is still acceptable, but less optimal.

**logP:** Ligand A (3.842) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.3) is a bit low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=1, HBA=8) is acceptable, but the higher HBA count could slightly reduce permeability.

**QED:** Ligand A (0.904) is excellent, indicating a highly drug-like profile. Ligand B (0.713) is still good, but not as strong.

**DILI:** Ligand A (33.501) has a very low DILI risk, which is excellent. Ligand B (52.307) is higher, but still within an acceptable range.

**BBB:** Ligand A (95.502) shows excellent BBB penetration, though this is less critical for a non-CNS target like SRC. Ligand B (77.627) is reasonable.

**Caco-2 Permeability:** Ligand A (-4.548) has poor Caco-2 permeability. Ligand B (-5.407) is even worse. Both are concerning.

**Aqueous Solubility:** Ligand A (-4.004) has poor aqueous solubility. Ligand B (-2.167) is better, but still not ideal.

**hERG Inhibition:** Both ligands (0.381 and 0.405) show very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (52.54) has moderate clearance, suggesting moderate metabolic stability. Ligand B (46.53) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.801) has a moderate half-life. Ligand B (10.96) has a shorter half-life, which is less desirable.

**P-gp Efflux:** Both ligands (0.146 and 0.06) show low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This ~2.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B's significantly superior binding affinity (-9.6 vs -7.3 kcal/mol) is the most critical factor. While Ligand B has slightly worse solubility and Caco-2 permeability, the strong binding is likely to compensate. Ligand A has better TPSA, QED, and DILI, but the weaker binding affinity is a major drawback for an enzyme target. The better metabolic stability of Ligand B is also a positive.

Output:
1
2025-04-17 13:57:03,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.442 and 346.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (70.07) is well within the range.

**logP:** Ligand A (1.749) is optimal. Ligand B (3.671) is towards 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 (2 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.781 and 0.68), indicating good drug-like properties.

**DILI:** Ligand A (38.969) has a significantly lower DILI risk than Ligand B (71.152), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (73.827 and 77.588), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.365) has poor Caco-2 permeability, while Ligand B (-4.794) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.045) has better solubility than Ligand B (-4.1). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.149) has a much lower hERG risk than Ligand B (0.879), a critical safety parameter.

**Microsomal Clearance:** Ligand A (-0.155) shows excellent metabolic stability (negative value indicates low clearance), while Ligand B (51.302) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-23.113) has a very long half-life, which is highly desirable. Ligand B (97.71) also has a long half-life, but not as impressive as Ligand A.

**P-gp Efflux:** Ligand A (0.042) has low P-gp efflux, while Ligand B (0.478) has moderate efflux.

**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 noteworthy.

**Overall Assessment:**

Ligand A is significantly better due to its superior safety profile (lower DILI and hERG), excellent metabolic stability (low Cl_mic and long t1/2), and slightly better binding affinity. While Ligand A has poorer Caco-2 permeability and solubility, the advantages in safety and pharmacokinetics outweigh these drawbacks, especially for an enzyme target where potency is already good. Ligand B's higher DILI and hERG risk are concerning.

Output:
0
2025-04-17 13:57:03,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.43 and 368.46 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.87) is better than Ligand B (104.73), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.52) is optimal, while Ligand B (0.323) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 3 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:** Ligand A (0.754) is slightly better than Ligand B (0.643), both are above the 0.5 threshold.

**DILI:** Ligand A (20.71) has a significantly lower DILI risk than Ligand B (46.61). This is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (18.15) is lower than Ligand B (43.70).

**Caco-2:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.285 and 0.227 respectively).

**Microsomal Clearance:** Ligand A (5.86) has a higher (worse) microsomal clearance than Ligand B (3.08), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-21.28) has a significantly worse in vitro half-life than Ligand B (-0.83).

**P-gp efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.027 respectively).

**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 the better candidate. While it has a higher microsomal clearance and a shorter half-life, its significantly stronger binding affinity (-8.3 vs -7.6 kcal/mol) and dramatically lower DILI risk (20.7 vs 46.6) are decisive advantages. The slightly better logP and TPSA values also favor Ligand A. The poor Caco-2 and solubility are concerns for both, but can be addressed through formulation strategies. The affinity difference is large enough to potentially overcome the metabolic stability issues with Ligand A, especially given that SRC is an intracellular target where maintaining high local concentrations is possible.

Output:
1
2025-04-17 13:57:03,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.443 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (34.59) is significantly better than Ligand A (63.05). Lower TPSA generally improves oral absorption.

**logP:** Ligand A (2.629) is optimal, while Ligand B (4.516) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides some hydrogen bonding potential for target interaction.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.93, Ligand B: 0.636), indicating good drug-like properties.

**DILI:** Ligand B (30.438) has a much lower DILI risk than Ligand A (53.315), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (Ligand A: 82.125, Ligand B: 88.872), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.089) shows poor permeability, while Ligand B (-4.389) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.801) has slightly better solubility than Ligand B (-4.66), which is a positive.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.619, Ligand B: 0.807).

**Microsomal Clearance:** Ligand A (29.469 mL/min/kg) has significantly lower microsomal clearance than Ligand B (104.659 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (13.806 hours) has a longer half-life than Ligand A (8.765 hours), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.121, Ligand B: 0.502).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B's better DILI and half-life, Ligand A's substantially superior binding affinity (-9.5 vs -8.6 kcal/mol) and better metabolic stability (lower Cl_mic) are crucial for an enzyme target like SRC kinase. While Ligand A has poorer Caco-2 permeability, the potency advantage is likely to be more impactful in driving efficacy. The slightly better solubility of Ligand A is also a plus.

Output:
1
2025-04-17 13:57:03,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (336.355 and 354.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.28) is slightly above the preferred <140, but acceptable. Ligand B (71.45) is excellent, well below 140.

**logP:** Ligand A (0.617) is a bit low, potentially hindering permeability. Ligand B (4.014) is at the upper end of the optimal range, potentially causing solubility issues but acceptable.

**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 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.683 and 0.726, respectively), indicating drug-like properties.

**DILI:** Both ligands have high DILI risk (85.072 and 82.396), which is a concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (43.117) is slightly better than Ligand A (39.473), but both are low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.322 and -5.213), indicating poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.687 and -5.188), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.124) has a very low hERG risk, which is excellent. Ligand B (0.622) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (9.187) has a lower Cl_mic, suggesting better metabolic stability. Ligand B (99.951) has a very high Cl_mic, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (9.273) has a longer half-life, which is favorable. Ligand B (-23.145) has a negative half-life, indicating very rapid degradation.

**P-gp Efflux:** Ligand A (0.078) has low P-gp efflux, which is good. Ligand B (0.79) 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 major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most critical factor for an enzyme inhibitor. However, it suffers from very high metabolic clearance, poor half-life, and moderate P-gp efflux. Ligand A has better ADME properties (lower Cl_mic, longer half-life, lower P-gp efflux, and very low hERG risk), but its binding affinity is extremely weak.

Despite the ADME concerns with Ligand B, the substantial difference in binding affinity (-8.0 kcal/mol vs 0.0 kcal/mol) is a decisive factor. Optimization efforts could focus on improving the metabolic stability of Ligand B.

Output:
1
2025-04-17 13:57:03,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.415 and 348.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (61.28), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (2.934) is optimal (1-3), while Ligand A (0.678) 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:** Both ligands have 5 HBA, also within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.79 and 0.857), indicating good drug-likeness.

**DILI:** Ligand B (30.942) has a significantly lower DILI risk than Ligand A (44.048), making it more favorable.

**BBB:** Ligand B (85.498) has a much higher BBB penetration percentile than Ligand A (62.04), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.891) has worse Caco-2 permeability than Ligand B (-5.066), both are poor.

**Aqueous Solubility:** Ligand A (-2.652) has better solubility than Ligand B (-3.797).

**hERG Inhibition:** Ligand A (0.114) has a lower hERG inhibition liability than Ligand B (0.947), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-13.278) has significantly lower microsomal clearance than Ligand B (65.717), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (24.946) has a much longer in vitro half-life than Ligand A (-3.018), which is a major advantage.

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux liability than Ligand B (0.459).

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-9.4). However, the difference is relatively small.

**Overall Assessment:**

Ligand B has a better overall profile. While Ligand A has better solubility and lower hERG risk, Ligand B excels in critical areas for an enzyme inhibitor: lower DILI risk, significantly longer half-life, and better metabolic stability (lower Cl_mic). The slightly better binding affinity of Ligand B further supports its selection. The lower logP of Ligand A is a concern, and the higher DILI risk is undesirable.

Output:
1
2025-04-17 13:57:03,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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.

**TPSA:** Ligand A (106.1) is higher than Ligand B (67.43). While both are reasonably low, Ligand B is preferable for potentially better absorption.

**logP:** Both ligands have good logP values (A: 1.949, B: 3.59), 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:** Both ligands have 2 HBD and a reasonable number of HBA (A: 6, B: 3). This is favorable for both.

**QED:** Both ligands have good QED scores (A: 0.555, B: 0.717), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (81.776) has a significantly higher DILI risk than Ligand B (36.099). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (A: 69.678, B: 73.827). This isn't a primary concern for a kinase inhibitor, but higher 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 we can't interpret this value accurately.

**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 very low hERG inhibition risk (A: 0.095, B: 0.736), which is excellent.

**Microsomal Clearance:** Ligand A (82.006) has higher microsomal clearance than Ligand B (57.942), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 26.51, B: 25.831).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.022, B: 0.228), which is favorable.

**Binding Affinity:** Both ligands have identical binding affinities (-7.6 kcal/mol), which is excellent and a major positive for both.

**Conclusion:**

Despite having identical binding affinities, Ligand B is the more promising candidate. The significantly lower DILI risk and better QED score are major advantages. While both have questionable Caco-2 and solubility values, the lower clearance of Ligand B suggests better metabolic stability. The slightly lower TPSA is also a plus.

Output:
1
2025-04-17 13:57:03,053 - INFO - Batch 256 complete. Total preferences: 4096
2025-04-17 13:57:03,053 - INFO - Processing batch 257/512...
2025-04-17 13:57:44,700 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.86 and 368.79 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.59) is well below the 140 threshold for oral absorption, while Ligand B (138.11) is approaching the upper limit. This favors Ligand A.

**logP:** Ligand A (3.23) is optimal, while Ligand B (0.44) is quite low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, both within acceptable limits. Ligand B has 1 HBD and 7 HBA, also acceptable, but the higher HBA count might slightly impact permeability.

**QED:** Ligand A (0.71) has a strong drug-like profile, while Ligand B (0.32) is considerably lower, suggesting potential issues.

**DILI:** Ligand B (68.94) has a higher DILI risk than Ligand A (52.15), although both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (56.22) is slightly better than Ligand B (48.08).

**Caco-2 Permeability:** Ligand A (-4.68) has a much better (more positive) Caco-2 value than Ligand B (-5.57), indicating superior intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.51) has better solubility than Ligand B (-1.68). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.80) has a slightly higher hERG risk than Ligand B (0.03), but both are relatively low.

**Microsomal Clearance:** Ligand A (69.31) has a higher (worse) microsomal clearance than Ligand B (-1.08). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (8.95) has a longer half-life than Ligand A (19.80), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.56) has better P-gp efflux profile than Ligand B (0.02).

**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 minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its optimal logP, better TPSA, higher QED, better Caco-2 permeability, and significantly stronger binding affinity. While Ligand B has better metabolic stability (lower Cl_mic) and half-life, the potency advantage of Ligand A is critical for an enzyme inhibitor. The slightly higher hERG risk for Ligand A is manageable given the overall profile.

Output:
1
2025-04-17 13:57:44,700 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (356.438 and 361.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (62.3). Both are below 140, suggesting good absorption potential.

**3. logP:** Both ligands have acceptable logP values (1.165 and 2.928, respectively), falling within the optimal range of 1-3.

**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 each), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.775 and 0.847), indicating a drug-like profile.

**7. DILI:** Ligand A (20.24) has a significantly lower DILI risk than Ligand B (42.846). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (82.823) has a higher BBB percentile than Ligand B (61.923), but it's not a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-4.626) has a better Caco-2 permeability than Ligand B (-5.055).

**10. Aqueous Solubility:** Ligand A (-1.35) has better aqueous solubility than Ligand B (-2.609).

**11. hERG Inhibition:** Ligand A (0.427) has a lower hERG inhibition liability than Ligand B (0.27), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-6.176) has a significantly lower (better) microsomal clearance than Ligand B (42.96). This indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.231) has a longer in vitro half-life than Ligand B (-5.297).

**14. P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux liability than Ligand B (0.201).

**15. Binding Affinity:** Ligand B (0.0) has a slightly better binding affinity than Ligand A (-6.7). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in metabolic stability (Cl_mic, t1/2), solubility, DILI, and hERG risk, while Ligand B has a marginally better binding affinity. The substantial improvements in ADME properties for Ligand A are more important for overall drug development success.

Output:
0
2025-04-17 13:57:44,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.233 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**TPSA:** Ligand A (67.77) is well below the 140 threshold for oral absorption. Ligand B (102.16) is also below the threshold, but closer to it.

**logP:** Ligand A (4.885) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.673) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=7) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.715, B: 0.826), indicating good drug-like properties.

**DILI:** Ligand A (84.219) has a higher DILI risk than Ligand B (70.26), suggesting potential liver toxicity concerns.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.431) and Ligand B (62.699) are comparable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.754 and -4.726), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-5.675 and -3.316), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.486) has a slightly higher hERG risk than Ligand B (0.237), but both are relatively low.

**Microsomal Clearance:** Ligand A (63.54 mL/min/kg) has a higher clearance than Ligand B (26.409 mL/min/kg), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-28.563 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound's stability. Ligand A (88.654 hours) has a good in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.399, B: 0.176).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.4 kcal/mol), which is the most important factor. The difference is negligible.

**Overall Assessment:**

Ligand B initially appears better due to its lower logP, lower DILI risk, and significantly better metabolic stability (lower Cl_mic). However, the negative in vitro half-life is a critical flaw. It suggests either a data error or an extremely unstable compound. Ligand A has a higher logP and DILI risk, but its metabolic stability and in vitro half-life are much better. The solubility issues are concerning for both. Given the choice, and assuming the negative half-life for B is an error, B is preferable. However, the negative half-life is a showstopper. Therefore, I will choose A.

Output:
0
2025-04-17 13:57:44,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.301 Da) is slightly higher than Ligand B (350.415 Da), but both are acceptable.

**2. TPSA:** Ligand A (54.88) is well below the 140 A^2 threshold for good oral absorption. Ligand B (89.8) is still under the threshold but closer to it.

**3. logP:** Ligand A (4.618) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.261) is within the optimal range.

**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: 4, Ligand B: 5), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.624, Ligand B: 0.737), indicating drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (86.933%) compared to Ligand B (32.842%). This is a major concern.

**8. BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (87.321%) has a higher BBB percentile than Ligand B (62.97%).

**9. Caco-2 Permeability:** Ligand A (-4.853) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.086) is also poor, but similar to A.

**10. Aqueous Solubility:** Ligand A (-4.841) has very poor aqueous solubility, consistent with its high logP. Ligand B (-1.596) has better solubility, though still not ideal.

**11. hERG Inhibition:** Ligand A (0.484) has a slightly higher hERG risk than Ligand B (0.153), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (49.401) has higher microsomal clearance than Ligand B (7.079), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.404) has a slightly longer half-life than Ligand B (31.267).

**14. P-gp Efflux:** Ligand A (0.429) has a lower P-gp efflux liability than Ligand B (0.022), which is favorable.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a much better affinity, but suffers from poor solubility, high DILI risk, and higher clearance. Ligand B has better solubility, lower DILI, and better metabolic stability, but a weaker binding affinity. The difference in affinity is >1.5 kcal/mol, which is a significant advantage. However, the high DILI risk for Ligand A is a major red flag.

Considering the balance, despite the superior affinity of Ligand A, the significantly higher DILI risk and poor solubility make it a less viable candidate. Ligand B, while having a weaker affinity, presents a much more favorable safety and ADME profile.

Output:
1
2025-04-17 13:57:44,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.397 and 348.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.79) is better than Ligand B (58.2), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.027 and 2.426), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand B (2 HBD, 2 HBA) is slightly better than Ligand A (3 HBD, 4 HBA) in terms of balancing solubility and permeability, but both are within reasonable limits.

**QED:** Both ligands have good QED scores (0.754 and 0.802), indicating drug-like properties.

**DILI:** Ligand A (10.585 percentile) has a significantly lower DILI risk than Ligand B (25.979 percentile). This is a major advantage.

**BBB:** Both have good BBB penetration, but Ligand B (83.482) is slightly better than Ligand A (77.937). This is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.194) and Ligand B (-4.758) have negative values, indicating poor permeability.

**Solubility:** Ligand A (-1.626) has better solubility than Ligand B (-3.914). Solubility is important for bioavailability.

**hERG:** Ligand A (0.652) has a lower hERG risk than Ligand B (0.416). Lower is better.

**Microsomal Clearance:** Ligand A (-35.099) has *much* lower microsomal clearance than Ligand B (5.519). This suggests significantly better metabolic stability for Ligand A, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-5.196) has a longer half-life than Ligand B (15.2).

**P-gp Efflux:** Ligand A (0.018) has lower P-gp efflux than Ligand B (0.184), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A is superior due to its significantly better DILI score, lower microsomal clearance (better metabolic stability), longer half-life, lower P-gp efflux, better solubility, lower hERG risk, and slightly better binding affinity. While Ligand B has slightly better BBB penetration and Caco-2 permeability, these are less critical for a non-CNS kinase target, and the ADME advantages of Ligand A are more important.

Output:
1
2025-04-17 13:57:44,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.451 and 349.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.25) is well below the 140 threshold for oral absorption, and even below 90 for potential CNS penetration (though that's not our primary goal here). Ligand B (71.53) is also acceptable, though slightly higher.

**logP:** Ligand A (3.952) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.317) is well within the optimal range.

**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 below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.697 and 0.786), indicating generally drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (83.831) compared to Ligand B (30.748). This is a major concern for Ligand A.

**BBB:** Both have similar BBB penetration (68.592 and 71.539), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.489 and -4.399) which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both have negative solubility values (-4.438 and -1.98) which is also unusual and suggests poor solubility. This is a potential issue for both.

**hERG Inhibition:** Ligand A (0.508) has a slightly higher hERG risk than Ligand B (0.181), but both are reasonably low.

**Microsomal Clearance:** Ligand A (71.041) has a higher microsomal clearance than Ligand B (9.059), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-10.415) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (-0.087) is also negative, but closer to zero. Both are problematic.

**P-gp Efflux:** Both have low P-gp efflux liability (0.38 and 0.037).

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage for Ligand A.

**Conclusion:**

Despite the significantly better binding affinity of Ligand A, its high DILI risk, higher microsomal clearance (lower metabolic stability), and the impossible half-life value make it a less desirable candidate. Ligand B, while having a weaker binding affinity, has a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic), and a more reasonable P-gp efflux profile. The negative Caco-2 and solubility values are concerning for both, but the other issues with Ligand A are more critical. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 13:57:44,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.415 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.53) is better than Ligand B (100.35), both are under the 140 threshold for oral absorption.

**logP:** Ligand A (1.443) is optimal, while Ligand B (0.349) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, and Ligand B (2) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable, and Ligand B (6) is also within the limit.

**QED:** Ligand A (0.663) is better than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 39.201, Ligand B: 37.844), both are below 40.

**BBB:** Ligand A (70.648) has better BBB penetration than Ligand B (34.742), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.8) is better than Ligand B (-5.376), indicating better intestinal absorption.

**Solubility:** Ligand A (-3.174) is better than Ligand B (-1.285).

**hERG:** Both ligands have very low hERG risk (Ligand A: 0.13, Ligand B: 0.091).

**Microsomal Clearance:** Ligand A (40.393) has significantly higher clearance than Ligand B (13.271), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-6.383) has a better half-life than Ligand A (-19.967).

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.025, Ligand B: 0.017).

**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.

**Conclusion:**

Despite Ligand A's superior binding affinity, Ligand B is the more promising candidate. The significantly lower microsomal clearance and better in vitro half-life of Ligand B outweigh the affinity difference. SRC kinases are enzymes, and metabolic stability is crucial for maintaining therapeutic concentrations. While the affinity difference is notable, a 1.5 kcal/mol advantage isn't enough to overcome the substantial metabolic liability of Ligand A. Ligand B also has better solubility and Caco-2 permeability.

Output:
1
2025-04-17 13:57:44,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.852 Da) is slightly higher than Ligand B (348.399 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 83.76, Ligand B: 81.01), suggesting good oral absorption potential.

**logP:** Ligand A (2.448) is within the optimal range (1-3). Ligand B (0.887) is slightly below, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD/HBA counts (A: 0/5, B: 1/5), balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.568, B: 0.772), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (83.211) has a higher DILI risk than Ligand B (60.101), which is concerning. While 83.211 isn't extremely high, it's significantly higher than Ligand B and a potential red flag.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.498) has a higher BBB percentile than Ligand B (46.413), but this isn't a major factor in this decision.

**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 might not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is unclear, but it suggests potential formulation challenges.

**hERG:** Ligand A (0.788) has a slightly higher hERG risk than Ligand B (0.158), which is preferable for B.

**Microsomal Clearance:** Ligand B (0.757) has significantly lower microsomal clearance than Ligand A (41.365), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (21.185) has a much longer in vitro half-life than Ligand A (-25.146). The negative value for A is concerning and suggests rapid degradation. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.283) has lower P-gp efflux than Ligand B (0.072), which is slightly favorable.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a crucial advantage, as a 1.8 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the superior candidate. Its significantly stronger binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG risk outweigh the slightly lower logP and P-gp efflux. The unusual solubility and Caco-2 values are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 13:57:44,701 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.829 Da and 368.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.53 and 83.37) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.137 and 2.582) 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.791 and 0.804), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 84.374, which is high. Ligand B has a much lower DILI risk of 43.117, which is good. This is a significant advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 38.852, while Ligand B has 93.408. While SRC is not a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.281 and -4.9). This is unusual and suggests poor permeability, but the scale is not specified.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.505 and -3.399). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A has a very low hERG inhibition risk (0.046), which is excellent. Ligand B has a slightly higher risk (0.801), but still relatively low.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (18.919 mL/min/kg) than Ligand B (69.847 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 11.978 hours, while Ligand B has a negative half-life (-3.028 hours). A negative half-life is not physically possible and indicates a problem with the data or the compound's stability.

**P-gp Efflux:** Ligand A has a very low P-gp efflux liability (0.038), while Ligand B has a moderate efflux liability (0.205).

**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.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability, and lower P-gp efflux. However, it exhibits a high DILI risk. Ligand B has a much lower DILI risk, better BBB penetration, and a reasonable hERG risk. The negative half-life for Ligand B is a major red flag. The negative Caco-2 and solubility values for both are concerning.

Given the enzyme-specific priorities, potency (affinity) and metabolic stability are crucial. Ligand A's superior affinity and stability are very attractive. While the high DILI risk is a concern, it might be mitigated through structural modifications. The negative half-life of Ligand B is a dealbreaker.

Output:
0
2025-04-17 13:57:44,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.897 Da) is slightly higher than Ligand B (346.494 Da), but both are acceptable.

**TPSA:** Ligand A (56.15) is higher than Ligand B (41.05). Both are below the 140 A^2 threshold for good oral absorption, but lower is generally better. Ligand B has a more favorable TPSA.

**logP:** Ligand A (3.12) is within the optimal range (1-3). Ligand B (4.452) is slightly above, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and are within acceptable limits (<=5 HBD, <=10 HBA). Ligand B has 4 HBA, slightly lower than Ligand A's 5, which is slightly favorable.

**QED:** Ligand A (0.889) has a significantly better QED score than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (50.95), which is a concern.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (92.323) is better than Ligand A (75.107). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**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 concerning.

**hERG Inhibition:** Ligand A (0.531) has a lower hERG inhibition risk than Ligand B (0.933), which is a significant advantage.

**Microsomal Clearance:** Ligand A (73.388) has lower microsomal clearance than Ligand B (98.631), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (47.512) has a longer half-life than Ligand B (21.75), which is desirable.

**P-gp Efflux:** Ligand A (0.594) has lower P-gp efflux than Ligand B (0.835), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is the most important factor for an enzyme inhibitor. While it has some ADME liabilities (higher logP, higher P-gp efflux, lower QED, and lower metabolic stability), the strong binding affinity (-7.6 kcal/mol vs -10.2 kcal/mol) is a significant advantage. The DILI risk is lower for Ligand B. The solubility and Caco-2 permeability are poor for both, but the affinity difference is substantial enough to favor Ligand B.

Output:
1
2025-04-17 13:57:44,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 345.491 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (54.26), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.108) is within the optimal 1-3 range, while Ligand B (2.64) is also good, 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.73 and 0.646), indicating good drug-likeness.

**DILI:** Ligand A (21.481) has a significantly lower DILI risk than Ligand B (12.796). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (80.613 and 82.164), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.684) has worse Caco-2 permeability than Ligand B (-5.082), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.96) has slightly better aqueous solubility than Ligand B (-1.265).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.213 and 0.299).

**Microsomal Clearance (Cl_mic):** Ligand A (8.139) has significantly lower microsomal clearance than Ligand B (23.043), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (5.08) has a longer in vitro half-life than Ligand B (3.222). This further supports its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.055 and 0.153).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This 1.3 kcal/mol difference 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 critical areas for an enzyme inhibitor: significantly stronger binding affinity, lower DILI risk, and much better metabolic stability (lower Cl_mic and longer t1/2). The improved solubility is also a plus.

Output:
1
2025-04-17 13:57:44,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase properties (potency, metabolic stability, solubility, and hERG risk).

**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, but both are acceptable.

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand B (82.53 A^2) is better than Ligand A (95.58 A^2).

**logP:** Ligand A (0.193) is quite low, potentially hindering permeation. Ligand B (1.923) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (4/5) counts.

**QED:** Both have good QED scores (0.671 and 0.813), indicating drug-likeness.

**DILI:** Ligand A (27.104) has a much lower DILI risk than Ligand B (51.338), which is a positive.

**BBB:** BBB is not a primary concern for a general oncology target, but Ligand A (69.756) is better than Ligand B (33.656).

**Caco-2 Permeability:** Ligand A (-5.449) and Ligand B (-4.924) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.257 and -3.415).

**hERG:** Ligand A (0.045) has a very low hERG risk, significantly better than Ligand B (0.159).

**Microsomal Clearance:** Ligand A (3.92 mL/min/kg) has a lower Cl_mic, suggesting better metabolic stability, than Ligand B (-1.814 mL/min/kg).

**In vitro Half-Life:** Ligand B (40.18 hours) has a much longer half-life than Ligand A (-1.835 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.016 and 0.125).

**Binding Affinity:** Ligand B (-9.5 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 concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and a longer half-life, which are critical for an enzyme inhibitor. Its logP is also much better, improving permeability. While its DILI risk is higher and solubility is poor, the strong binding and improved metabolic stability are more important for an oncology kinase target. Ligand A has a better DILI and hERG profile, but its weak binding affinity and poor half-life are major drawbacks.

Output:
1
2025-04-17 13:57:44,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.439 Da and 348.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.42) is better than Ligand B (40.62) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.529 and 2.791), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 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 (0.35 and 0.524), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (18.418) has a significantly lower DILI risk than Ligand B (13.843), indicating a better safety profile.

**BBB:** Ligand A (43.311) has a lower BBB penetration than Ligand B (82.125). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.871) has worse Caco-2 permeability than Ligand B (-4.362).

**Aqueous Solubility:** Ligand A (-1.271) has better aqueous solubility than Ligand B (-3.418), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.125) has a much lower hERG inhibition liability than Ligand B (0.516), a crucial advantage for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (26.693) has a lower microsomal clearance than Ligand B (46.359), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.321) has a positive half-life, while Ligand B (-12.978) has a negative half-life. This suggests that Ligand A has a longer half-life and better stability.

**P-gp Efflux:** Ligand A (0.004) has lower P-gp efflux liability than Ligand B (0.141), potentially leading to improved oral bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-6.9 kcal/mol), which is a good value.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, lower hERG inhibition, better solubility, lower microsomal clearance, longer half-life, and lower P-gp efflux. While Ligand B has slightly better Caco-2 permeability and BBB penetration (which is irrelevant for this target), the ADME-Tox advantages of Ligand A outweigh these minor differences. Both ligands have the same binding affinity, so the ADME properties are the deciding factor.

Output:
1
2025-04-17 13:57:44,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.471 and 350.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (67.43), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.841 and 1.852, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 3 HBA) as lower HBD/HBA generally leads to better permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.713 and 0.519), indicating drug-like properties, with A being slightly better.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (16.557), which is a significant advantage. Both are below the 40 threshold.

**BBB:** Both have similar BBB penetration (86.274 and 83.443), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.041) is better than Ligand B (-4.652), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.491) is better than Ligand B (-2.816), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.571 and 0.325), which is good.

**Microsomal Clearance:** Ligand A (98.882) has a much higher microsomal clearance than Ligand B (15.093). This indicates that Ligand B is much more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (14.946) has a significantly longer in vitro half-life than Ligand A (1.191), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.057).

**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 drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand B exhibits superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, Ligand A's significantly stronger binding affinity (-9.4 vs -7.4 kcal/mol) is a decisive factor, especially for an enzyme target like SRC kinase. The difference in binding affinity is substantial enough to compensate for the slightly higher clearance of Ligand A. The lower DILI risk for Ligand A is also a bonus.

Output:
0
2025-04-17 13:57:44,702 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is well below the 140 threshold for good absorption, while Ligand B (98.74) is still acceptable but approaching the limit.

**logP:** Ligand A (1.936) is optimal (1-3). Ligand B (0.561) is slightly low, potentially hindering permeation.

**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 (0.744 and 0.623, both > 0.5).

**DILI:** Ligand A (25.204) has a much lower DILI risk than Ligand B (10.508), which is a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (78.868) has a better BBB percentile than Ligand B (38.387).

**Caco-2 Permeability:** Ligand A (-4.445) shows poor permeability, while Ligand B (-5.171) is also poor.

**Aqueous Solubility:** Ligand A (-2.465) is better than Ligand B (-1.411), although both are quite poor.

**hERG:** Both ligands have very low hERG inhibition liability (0.126 and 0.097), which is excellent.

**Microsomal Clearance:** Ligand B (-15.822) has a significantly lower (better) microsomal clearance than Ligand A (61.28), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (0.885) has a slightly better in vitro half-life than Ligand A (-20.17).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.008).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to outweigh the other factors.

**Conclusion:**

Considering the priorities for an enzyme target, Ligand B's superior metabolic stability (lower Cl_mic, better t1/2) and slightly improved binding affinity are attractive. However, Ligand A has a much lower DILI risk and better solubility, which are crucial for drug development. The poor Caco-2 permeability for both is a concern, but could potentially be addressed through formulation strategies. Given the significantly lower DILI risk of Ligand A, and the fact that the affinity difference isn't large enough to overcome the other issues with Ligand B, I would select Ligand A as the more promising candidate.

Output:
0
2025-04-17 13:57:44,703 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 348.495 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is slightly higher than Ligand B (77.15), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.606) is optimal, while Ligand B (1.631) is a bit low, potentially impacting 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 5, both acceptable (<=10).

**QED:** Both ligands have good QED scores (0.674 and 0.817 respectively), indicating good drug-like properties.

**DILI:** Ligand A (47.887) has a slightly higher DILI risk than Ligand B (8.414). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.38) is lower than Ligand B (58.278).

**Caco-2 Permeability:** Ligand A (-4.872) has better Caco-2 permeability than Ligand B (-5.522).

**Aqueous Solubility:** Ligand A (-4.147) has better aqueous solubility than Ligand B (-1.324). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.101) has a much lower hERG risk than Ligand B (0.33). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (47.913) has higher microsomal clearance than Ligand B (-8.728). This means Ligand B is likely more metabolically stable, which is highly desirable for an enzyme target.

**In vitro Half-Life:** Ligand A (3.62) has a shorter half-life than Ligand B (-0.487). This is another advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.277) has lower P-gp efflux liability than Ligand B (0.02), which is a slight advantage.

**Binding Affinity:** Ligand A (-7.8) has a slightly stronger binding affinity than Ligand B (-7.3). While a 1.5 kcal/mol difference is usually significant, the ADME advantages of Ligand B are substantial.

**Overall Assessment:**

Ligand B demonstrates a superior ADME profile, particularly regarding DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and solubility. While Ligand A has a slightly better binding affinity and Caco-2 permeability, the safety and pharmacokinetic advantages of Ligand B outweigh this difference. The lower hERG risk of Ligand A is a benefit, but the significantly lower DILI risk of Ligand B is more impactful. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (like liver toxicity) are paramount.

Output:
1
2025-04-17 13:57:44,703 - INFO - Batch 257 complete. Total preferences: 4112
2025-04-17 13:57:44,703 - INFO - Processing batch 258/512...
2025-04-17 13:58:31,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.439 Da and 363.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.19) is well below the 140 threshold for oral absorption. Ligand B (137.08) is also acceptable, but closer to the upper limit.

**logP:** Ligand A (3.953) is at the higher end of the optimal range (1-3), while Ligand B (1.699) is towards the lower end. While Ligand A's logP could potentially cause off-target effects, it's not drastically high.

**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, well within the guidelines.

**QED:** Ligand A (0.843) has a significantly better QED score than Ligand B (0.467), indicating a more drug-like profile.

**DILI:** Ligand B (68.437) has a slightly higher DILI risk than Ligand A (59.984), but both are acceptable.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 68.748, Ligand B: 67.623). BBB is not a primary concern for SRC kinase, as it's not a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. This is a significant drawback 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 very low hERG inhibition risk (0.395 and 0.394), which is excellent.

**Microsomal Clearance:** Ligand A (92.721) has a higher microsomal clearance than Ligand B (9.975), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-8.257) has a significantly longer in vitro half-life than Ligand A (23.985), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.136 and 0.054), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.6 kcal/mol and -9.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. While both have poor Caco-2 and solubility, Ligand B's significantly better in vitro half-life (lower Cl_mic) and higher QED score outweigh the slightly higher DILI risk and lower logP. The improved metabolic stability is crucial for an enzyme inhibitor.

Output:
1
2025-04-17 13:58:31,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.511 and 370.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.13) is well below the 140 threshold, while Ligand B (84.3) is still acceptable but higher.

**logP:** Ligand A (3.727) is at the upper end of the optimal range (1-3), while Ligand B (1.682) is towards the lower end.

**H-Bond Donors:** Both have 1 HBD, which is good.

**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 (0.714 and 0.824, respectively), indicating good drug-like properties.

**DILI:** Ligand A (23.032) has a significantly lower DILI risk than Ligand B (35.479), which is a major advantage.

**BBB:** Ligand A (50.407) has a lower BBB penetration percentile than Ligand B (75.107). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.908) is worse than Ligand B (-5.088).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.883) is slightly better than Ligand B (-2.045).

**hERG:** Ligand A (0.84) has a slightly higher hERG risk than Ligand B (0.395), but both are relatively low.

**Microsomal Clearance:** Ligand A (99.354) has much higher microsomal clearance than Ligand B (1.163), indicating poorer metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (9.942) has a shorter half-life than Ligand B (22.937), consistent with the higher clearance.

**P-gp Efflux:** Ligand A (0.522) has lower P-gp efflux than Ligand B (0.088), which is favorable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), but the difference is not substantial.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and a lower hERG risk. The Caco-2 and solubility values are concerning for both, but the metabolic stability and safety profile of Ligand B outweigh the slightly weaker binding affinity.

Output:
1
2025-04-17 13:58:31,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (378.885 Da) is also good.

**TPSA:** Ligand A (62.13) is significantly better than Ligand B (75.19). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have similar logP values around 2.5, falling within the optimal range of 1-3.

**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:** Both ligands have good QED scores (0.893 and 0.867), indicating good overall drug-likeness.

**DILI:** Ligand A (19.659) has a much lower DILI risk than Ligand B (60.101). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.94) is slightly better than Ligand B (51.532).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.776) is slightly better than Ligand B (-5.093), but both are concerning.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.121) is slightly better than Ligand B (-3.312).

**hERG:** Ligand A (0.718) has a lower hERG risk than Ligand B (0.156), which is a positive.

**Microsomal Clearance:** Ligand A (50.555) has a higher microsomal clearance than Ligand B (28.961), meaning Ligand B is more metabolically stable. This is a crucial advantage for kinase inhibitors.

**In vitro Half-Life:** Ligand B (8.549 hours) has a significantly longer half-life than Ligand A (23.523 hours). This is a substantial benefit for Ligand B.

**P-gp Efflux:** Ligand A (0.705) has slightly lower P-gp efflux than Ligand B (0.065), which is preferable.

**Binding Affinity:** Ligand A (-6.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A has advantages in binding affinity, DILI risk, hERG, and TPSA. However, Ligand B has a significant advantage in metabolic stability (lower Cl_mic and longer half-life), which is crucial for kinase inhibitors. Both have poor solubility and permeability. The DILI risk for Ligand B is concerning. Given the importance of metabolic stability for kinases, and the relatively small difference in binding affinity, **Ligand B is the more promising candidate**, despite its higher DILI risk. Further optimization could address the solubility and permeability issues, and potentially mitigate the DILI risk.

Output:
1
2025-04-17 13:58:31,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (351.491 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (56.59 and 58.64) are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (3.028 and 3.38) 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 5 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have high QED scores (0.837 and 0.805), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (32.105 and 34.703 percentiles), which is favorable.

**8. BBB:** Both ligands have good BBB penetration (87.553 and 92.594 percentiles), although this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.117 and -4.373), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.606 and -3.861), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.591 and 0.687), which is excellent.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (64.125 mL/min/kg) than Ligand B (89.152 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer half-life (27.407 hours) than Ligand B (-13.806 hours). The negative value for Ligand B is concerning and likely an artifact or error.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.378 and 0.357).

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.3 kcal/mol) compared to Ligand A (-7.8 kcal/mol). This is a >1.5 kcal/mol difference, a substantial advantage.

**Conclusion:**

Despite the poor Caco-2 permeability and aqueous solubility for both compounds, Ligand B's significantly superior binding affinity (-9.3 kcal/mol vs -7.8 kcal/mol) and better metabolic stability (lower Cl_mic) outweigh the drawbacks. The negative half-life for Ligand B is a red flag, but the binding affinity is so much stronger that it is still the better candidate. Addressing the solubility and permeability issues through formulation or structural modifications would be crucial for further development, but the potency advantage of Ligand B makes it the more promising starting point.

Output:
1
2025-04-17 13:58:31,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.308 Da) is slightly higher, but acceptable. Ligand B (350.306 Da) is also good.

**TPSA:** Ligand A (68.29) is excellent, well below the 140 threshold for oral absorption. Ligand B (115.58) is higher, but still within a reasonable range, though potentially impacting absorption slightly.

**logP:** Ligand A (4.239) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.493) is quite low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=2, HBA=7) is also acceptable, though slightly higher HBA could be a minor concern.

**QED:** Both ligands have good QED scores (A: 0.575, B: 0.754), indicating good drug-like properties.

**DILI:** Ligand A (65.452) is approaching a concerning DILI risk, while Ligand B (90.655) is significantly higher and represents a substantial liver toxicity risk.

**BBB:** Both have moderate BBB penetration (A: 70.027, B: 68.67). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.95) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.177) is also poor.

**Aqueous Solubility:** Both have very poor aqueous solubility (A: -4.927, B: -3.022). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.746) has a low hERG risk, which is excellent. Ligand B (0.173) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (113.618) has moderate clearance, suggesting moderate metabolic stability. Ligand B (-3.054) has *very* low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (77.953) has a reasonable half-life. Ligand B (34.287) has a shorter half-life, but still potentially acceptable.

**P-gp Efflux:** Ligand A (0.413) 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 (-9.0 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. Its significantly superior binding affinity (-9.0 vs -7.6 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, its excellent metabolic stability (very low Cl_mic) and very low P-gp efflux are highly desirable. The major drawback is the high DILI risk, but this might be mitigated through structural modifications. Ligand A's higher DILI risk and lower affinity make it less attractive.

Output:
1
2025-04-17 13:58:31,506 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, applying the provided guidelines and priorities.

**Step-by-step comparison:**

1. **MW:** Both A (358.463 Da) and B (351.447 Da) are within the ideal range of 200-500 Da. No clear advantage here.

2. **TPSA:** Ligand A (69.64) is well below the 140 threshold and good for oral absorption. Ligand B (78.95) is also acceptable, but slightly higher.

3. **logP:** Ligand A (2.513) is optimal (1-3). Ligand B (0.387) is a bit low, potentially hindering permeation. This is a strike against B.

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

5. **HBA:** Both A (4) and B (4) are within the acceptable limit of <=10.

6. **QED:** Both A (0.834) and B (0.795) are excellent, indicating good drug-like properties.

7. **DILI:** Ligand A (54.556) is moderate, but acceptable. Ligand B (19.426) is very good, indicating low liver injury risk. This is a point for B.

8. **BBB:** Both A (64.793) and B (57.852) are not particularly high, which is fine since SRC is not a CNS target.

9. **Caco-2:** Both A (-5.083) and B (-4.867) are negative, which is unusual. Lower values suggest poor permeability. It's hard to interpret these values without knowing the scale, but they are both similarly problematic.

10. **Solubility:** Ligand A (-3.277) and B (-1.409) are both negative, suggesting poor aqueous solubility. B is slightly better, but both are a concern.

11. **hERG:** Ligand A (0.579) is low risk. Ligand B (0.119) is *very* low risk, a significant advantage.

12. **Cl_mic:** Ligand A (43.617) is moderate. Ligand B (-3.143) is *very* low, indicating excellent metabolic stability. This is a major advantage for B.

13. **t1/2:** Ligand A (34.829) is reasonable. Ligand B (-2.019) is very short, a significant drawback.

14. **Pgp:** Ligand A (0.54) is low efflux. Ligand B (0.015) is *extremely* low efflux, a substantial advantage.

15. **Affinity:** Ligand A (-8.2 kcal/mol) is slightly better than Ligand B (-8.6 kcal/mol). While the difference is small, it's a point for A.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A has a slightly better affinity.
*   **Metabolic Stability:** B is *significantly* more metabolically stable (much lower Cl_mic).
*   **Solubility:** Both are poor, but B is slightly better.
*   **hERG Risk:** B has a much lower hERG risk.
*   **Pgp Efflux:** B has significantly lower Pgp efflux.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising drug candidate. Its superior metabolic stability, lower hERG risk, and lower Pgp efflux outweigh the small difference in binding affinity. The lower logP of B is a concern, but could potentially be addressed with further optimization. The poor solubility of both is a concern that would need to be addressed.

Output:
1
2025-04-17 13:58:31,506 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [377.897, 59.23, 3.912, 1, 5, 0.824, 66.615, 74.176, -4.969, -4.352, 0.265, 34.741, 15.876, 0.637, -9.3]
**Ligand B:** [365.861, 78.45, 1.759, 2, 4, 0.753, 52.889, 48.352, -4.835, -3.102, 0.439, 18.244, 8.77, 0.268, -8.8]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). Ligand B (365.861 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.
2. **TPSA:** Ligand A (59.23) is better than Ligand B (78.45).  TPSA <140 is good for oral absorption, and both are under this threshold, but A is closer to the optimal range.
3. **logP:** Ligand A (3.912) is slightly higher than Ligand B (1.759). Both are within the optimal range of 1-3, but A is closer to the upper limit.
4. **HBD:** Ligand A (1) is better than Ligand B (2). Lower is preferred.
5. **HBA:** Ligand A (5) is better than Ligand B (4). Lower is preferred.
6. **QED:** Ligand A (0.824) is better than Ligand B (0.753). Both are above 0.5, indicating good drug-likeness, but A is higher.
7. **DILI:** Ligand A (66.615) is worse than Ligand B (52.889). Both are acceptable (<60 is good), but B is significantly better.
8. **BBB:** Ligand A (74.176) is better than Ligand B (48.352). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.
9. **Caco-2:** Both ligands have negative values, which is unusual. Assuming these are log scale values, higher is better. Ligand A (-4.969) is better than Ligand B (-4.835).
10. **Solubility:** Ligand A (-4.352) is better than Ligand B (-3.102). Higher is better.
11. **hERG:** Ligand A (0.265) is better than Ligand B (0.439). Lower is preferred.
12. **Cl_mic:** Ligand A (34.741) is better than Ligand B (18.244). Lower is preferred for metabolic stability.
13. **t1/2:** Ligand A (15.876) is better than Ligand B (8.77). Longer is preferred.
14. **Pgp:** Ligand A (0.637) is better than Ligand B (0.268). Lower is preferred.
15. **Binding Affinity:** Ligand A (-9.3) is significantly better than Ligand B (-8.8). A difference of 0.5 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in all these areas, especially binding affinity and metabolic stability. While Ligand B has a better DILI score, the substantial advantage in binding affinity and metabolic stability of Ligand A is more critical.

**Conclusion:**

Ligand A is the more promising drug candidate due to its superior binding affinity, metabolic stability, solubility, and overall drug-like properties. The slightly higher DILI risk is outweighed by the significant potency and pharmacokinetic advantages.

Output:
1

2025-04-17 13:58:31,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (451.676 Da) is slightly higher, but acceptable. Ligand B (347.379 Da) is also good.

**TPSA:** Ligand A (60.67) is excellent, well below the 140 threshold. Ligand B (126.82) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (4.764) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.555) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have good QED scores (A: 0.537, B: 0.628), indicating generally drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (A: 84.374, B: 76.386).

**BBB:** Ligand A (75.727) shows better BBB penetration potential than Ligand B (59.325), although this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.398) has poor Caco-2 permeability, a significant concern. Ligand B (-5.204) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-6.253) has very poor solubility, likely due to its high logP. Ligand B (-2.494) has better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.777) has a slightly higher hERG risk than Ligand B (0.065), which is a significant advantage for B.

**Microsomal Clearance:** Both ligands have similar, relatively low microsomal clearance (A: 24.808, B: 23.42), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 76.571, B: 0.796).

**P-gp Efflux:** Ligand A (0.752) has slightly higher P-gp efflux liability than Ligand B (0.021), which is better for B.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.0 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Conclusion:**

Despite Ligand A's high logP, poor solubility, and Caco-2 permeability, its *much* stronger binding affinity (-8.3 vs -6.0 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. The potency difference is likely to be more impactful than the ADME liabilities, especially considering the reasonable metabolic stability and acceptable DILI risk. Ligand B's better ADME properties are overshadowed by its weaker binding.

Output:
1
2025-04-17 13:58:31,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.68) is slightly higher than Ligand B (87.66), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.28 and 0.94), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 5 HBAs, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.719) has a significantly better QED score than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Ligand B (23.187) has a much lower DILI risk than Ligand A (60.45), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (71.501) is better than Ligand A (64.599). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.241 and -5.264), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.263 and -2.557), also unusual and concerning.

**hERG Inhibition:** Ligand A (0.387) has a slightly higher hERG risk than Ligand B (0.27), but both are relatively low.

**Microsomal Clearance:** Ligand B (-18.924) has a significantly lower (better) microsomal clearance than Ligand A (-26.375), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.629 hours) has a longer half-life than Ligand B (4.381 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.062).

**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 threshold.

**Overall Assessment:**

Ligand A has a better QED, longer half-life, and *much* stronger binding affinity. However, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). Both have poor predicted permeability and solubility. The strong binding affinity of Ligand A is a major advantage for an enzyme inhibitor, and could potentially outweigh the slightly higher DILI risk and shorter half-life, *especially* if the DILI risk can be mitigated through structural modifications. The permeability and solubility issues are shared by both and would need to be addressed in further optimization.

Output:
1
2025-04-17 13:58:31,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.41 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is better than Ligand B (87.3), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand B (1.126) is better than Ligand A (0.415). Ligand A is slightly low, potentially hindering permeability. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3). Both are within the acceptable range.

**QED:** Ligand A (0.788) is significantly better than Ligand B (0.629), indicating a more drug-like profile.

**DILI:** Ligand B (29.43) is significantly better than Ligand A (49.011). Lower DILI is crucial.

**BBB:** Ligand A (83.404) is better than Ligand B (54.207), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.489) is better than Ligand B (-5.06). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-1.633) is better than Ligand B (-2.961). Better solubility is important for bioavailability.

**hERG Inhibition:** Ligand B (0.074) is significantly better than Ligand A (0.249). Lower hERG risk is critical.

**Microsomal Clearance:** Ligand A (2.057) is much better than Ligand B (49.566). Lower clearance indicates better metabolic stability, a key factor for kinases.

**In vitro Half-Life:** Ligand A (0.469) is better than Ligand B (-1.277).

**P-gp Efflux:** Ligand A (0.056) is better than Ligand B (0.058).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) is significantly better than Ligand A (-7.6 kcal/mol). This is a substantial difference in potency, and for an enzyme, affinity is paramount. The 1.5 kcal/mol advantage outweighs most other concerns.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity (-9.1 vs -7.6 kcal/mol), which is the most important factor for an enzyme inhibitor. While Ligand A has better QED, solubility, and metabolic stability, Ligand B's superior potency and lower hERG risk are more critical. The lower DILI score for Ligand B is also a significant advantage. The slightly higher logP of Ligand B is also preferable.

Output:
1
2025-04-17 13:58:31,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.523 Da) is slightly higher than Ligand B (345.447 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for oral absorption and is quite favorable. Ligand B (80.12) is still under 140, but less optimal than A.

**logP:** Ligand A (3.815) is at the upper end of the optimal range (1-3), while Ligand B (1.483) is at the lower end. While both are within range, a higher logP can sometimes be beneficial for kinase inhibitors, but needs to be balanced with solubility.

**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, but A is slightly better.

**QED:** Both ligands have similar, good QED values (0.838 and 0.847).

**DILI:** Ligand A (36.06) has a slightly better DILI percentile than Ligand B (41.411), indicating lower potential for liver injury. Both are below the concerning threshold of 60.

**BBB:** Ligand A (80.419) has a better BBB percentile than Ligand B (69.756), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.013 and -5.026), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.114 and -2.828), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.511) has a slightly better hERG profile than Ligand B (0.179), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (46.16 mL/min/kg) has a lower microsomal clearance than Ligand A (43.184 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-19.498 hours) has a significantly *longer* in vitro half-life than Ligand A (2.015 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux than Ligand B (0.1), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have significant ADME liabilities (poor solubility and permeability), Ligand B demonstrates a stronger binding affinity and a significantly longer half-life. The improved metabolic stability is a key advantage for an enzyme inhibitor. The slightly lower P-gp efflux of Ligand A is a minor benefit, but doesn't outweigh the substantial difference in half-life and binding affinity.

Output:
1
2025-04-17 13:58:31,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B, keeping in mind we're targeting an enzyme (kinase) in oncology, so potency, metabolic stability, solubility, and hERG risk are key.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (467.136 Da) is higher, but still acceptable. Ligand B (352.825 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (46.92) is well below the 140 threshold for oral absorption. Ligand B (62.14) is also below, but higher than A.

**logP:** Both ligands have good logP values (A: 4.504, B: 3.247), falling within the 1-3 range. Ligand A is slightly higher, which *could* raise solubility concerns, but isn't a major issue.

**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 B is closer to the upper limit.

**QED:** Both ligands have good QED scores (A: 0.617, B: 0.733), indicating good drug-like properties.

**DILI:** Both have relatively high DILI risk (A: 71.694, B: 79.333). This is a concern for both, but B is slightly worse.

**BBB:** BBB isn't a primary concern for an oncology target, but A (84.219) has better penetration than B (62.931).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. A (-5.01) is slightly worse than B (-4.998).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. A (-4.714) is slightly worse than B (-4.039).

**hERG:** Both have low hERG risk (A: 0.786, B: 0.704), which is excellent.

**Microsomal Clearance:** Ligand A (64.827) has a higher clearance than Ligand B (57.044), indicating lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand A (110.702) has a longer half-life than Ligand B (65.031), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux (A: 0.814, B: 0.665), which is good.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has *significantly* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a massive advantage for A, potentially outweighing its ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability predictions (negative Caco-2 and solubility values, which are suspect and would need experimental verification), Ligand A is the more promising candidate due to its *much* stronger binding affinity (-8.7 kcal/mol vs -0.0 kcal/mol). The longer half-life is also a plus. While the higher DILI and clearance are concerns, the potency difference is substantial enough to prioritize A for further investigation, assuming the solubility/permeability issues can be addressed through formulation or structural modifications.

Output:
1
2025-04-17 13:58:31,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.65) is well below the 140 threshold for oral absorption, and even better for kinase inhibitors. Ligand B (101.21) is still acceptable, but less optimal.

**logP:** Ligand A (0.265) is quite low, potentially hindering permeability. Ligand B (1.308) 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 is good. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.613 and 0.806), indicating drug-like properties.

**DILI:** Ligand A (32.959) has a lower DILI risk than Ligand B (49.283), which is favorable.

**BBB:** Both are not CNS focused, so this is less important. Ligand B (90.772) has better BBB penetration than Ligand A (58.782).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental setup or the compounds themselves. However, the values are similar (-4.913 and -5.172).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and concerning. Ligand A (-1.01) is slightly better than Ligand B (-2.912).

**hERG Inhibition:** Both ligands have very low hERG risk (0.071 and 0.377), which is excellent.

**Microsomal Clearance:** Ligand A (10.736) has higher microsomal clearance than Ligand B (2.823), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-20.936) has a much longer in vitro half-life than Ligand A (-12.362), which is highly desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.017 and 0.023).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.5 and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't heavily favor one over the other.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the better candidate. While Ligand A has a slightly lower DILI risk, Ligand B has a much better logP, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a better aqueous solubility. The binding affinity is comparable. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this issue.

Output:
1
2025-04-17 13:58:31,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.407 and 349.362 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have a TPSA of approximately 102.75-102.76, which is acceptable for oral absorption (<=140).

**logP:** Ligand A (-0.949) is slightly below the optimal range (1-3), potentially impacting permeability. Ligand B (-0.312) is closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.663 and 0.586), indicating good drug-like properties.

**DILI:** Ligand A (56.223) has a higher DILI risk than Ligand B (40.054), but both are below the concerning threshold of 60.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.957 and -4.847), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-0.617 and -1.242), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.066 and 0.151), which is excellent.

**Microsomal Clearance:** Ligand A (-1.929 mL/min/kg) has significantly lower (better) microsomal clearance than Ligand B (-26.971 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.573 hours) has a longer half-life than Ligand B (-3.082 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.008).

**Binding Affinity:** Ligand A (-8.8 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:**

Despite the shared issues of poor Caco-2 permeability and aqueous solubility, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.8 vs -6.6 kcal/mol) and improved metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly higher DILI risk and lower logP. The improved metabolic stability and binding affinity are critical for an enzyme target like SRC kinase. Addressing the solubility and permeability issues through formulation or structural modifications would be the next steps.

Output:
1
2025-04-17 13:58:31,508 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.479 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (65.18), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.585 and 2.116) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0), as some H-bond donors can aid solubility.

**H-Bond Acceptors:** Ligand B (6) is slightly better than Ligand A (5) but both are within the acceptable range.

**QED:** Both ligands have good QED scores (0.708 and 0.832), indicating good drug-like properties.

**DILI:** Ligand A (27.995) has a significantly lower DILI risk than Ligand B (42.846), which is a major advantage.

**BBB:** Both are moderate, but Ligand A (70.57) is better than Ligand B (66.344). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.971) is slightly better than Ligand B (-4.774), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.012) is slightly better than Ligand B (-1.838).

**hERG:** Both ligands have very low hERG inhibition liability (0.048 and 0.26), which is excellent.

**Microsomal Clearance:** Ligand A (34.637) has a lower microsomal clearance than Ligand B (42.994), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.41) has a significantly longer in vitro half-life than Ligand B (4.868), a crucial advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.025 and 0.148).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.4 and -9.2 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have excellent binding affinity and acceptable physicochemical properties, Ligand A demonstrates a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and Caco-2 permeability. These factors are particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:58:31,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.248 Da) is slightly higher than Ligand B (348.443 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (77.25) is slightly higher than Ligand B (71.78), but both are good.

**logP:** Ligand A (4.132) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.544) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.667 and 0.696), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (96.782%) compared to Ligand B (32.881%). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (80.031%) is higher than Ligand B (61.497%), but this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. However, these values are on a different scale and are difficult to interpret directly without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Again, the scale is unknown, making direct comparison difficult.

**hERG:** Both ligands have very low hERG inhibition liability (0.395 and 0.562), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand B (46.104 mL/min/kg) has lower microsomal clearance than Ligand A (60.612 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life (t1/2):** Ligand B (30.809 hours) has a longer half-life than Ligand A (73.952 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.307 and 0.379), which is favorable.

**Binding Affinity:** Ligand A (0 kcal/mol) has a similar binding affinity to Ligand B (0 kcal/mol).

**Overall Assessment:**

Ligand B is significantly better due to its lower DILI risk, better logP, and improved metabolic stability (lower Cl_mic and longer t1/2). While both have poor solubility and permeability based on the provided values, the lower DILI risk of Ligand B is a critical advantage, especially for an oncology target where chronic administration is often required. The similar binding affinities mean the ADME properties are the deciding factor.

Output:
1
2025-04-17 13:58:31,508 - INFO - Batch 258 complete. Total preferences: 4128
2025-04-17 13:58:31,508 - INFO - Processing batch 259/512...
2025-04-17 13:59:12,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.714 Da) is slightly higher than Ligand B (351.403 Da), but both are acceptable.

**TPSA:** Ligand A (64.74) is significantly better than Ligand B (104.81). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.695) is within the optimal range (1-3), while Ligand B (-0.429) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD/HBA counts (Ligand A: 1/5, Ligand B: 2/5).

**QED:** Both ligands have good QED scores (Ligand A: 0.591, Ligand B: 0.606), indicating drug-like properties.

**DILI:** Ligand A (77.743) has a higher DILI risk than Ligand B (26.444). This is a significant concern for Ligand A.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**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 (0.846) has a slightly higher hERG risk than Ligand B (0.044), but both are relatively low.

**Microsomal Clearance:** Ligand A (61.007) has a higher microsomal clearance than Ligand B (-3.09). This suggests Ligand A is less metabolically stable.

**In vitro Half-Life:** Ligand A (43.874) has a longer half-life than Ligand B (-1.522), which is a positive.

**P-gp Efflux:** Ligand A (0.738) has a lower P-gp efflux than Ligand B (0.006), which is favorable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This difference of 1.6 kcal/mol is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A having a longer half-life and lower P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.5 vs -10.1 kcal/mol) is a major advantage for an enzyme inhibitor. While Ligand B has a lower logP and a slightly higher risk of poor permeability based on the Caco-2 and solubility values, the potency advantage is likely to be more critical. The lower DILI risk for Ligand B is also a significant benefit.

Output:
1
2025-04-17 13:59:12,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 342.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (60.85) is slightly higher than Ligand B (49.41). Both are below the 140 threshold for good oral absorption, but ligand B is better.

**logP:** Both ligands have good logP values (2.509 and 3.184), 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 3 HBAs, and Ligand B has 2. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.613 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A (13.959) has a lower DILI risk than Ligand B (15.083), both are good (<40).

**BBB:** Ligand A (68.127) has a lower BBB penetration than Ligand B (83.404). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.924) is slightly worse than Ligand A (-4.54).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand B (-3.767) is worse than Ligand A (-1.571). This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.22 and 0.263), which is excellent.

**Microsomal Clearance:** Ligand A (22.628 mL/min/kg) has a lower microsomal clearance than Ligand B (28.438 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.252) has a longer in vitro half-life than Ligand A (-4.157), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.13 and 0.108), which is good.

**Binding Affinity:** Ligand B (-8.252 kcal/mol) has a significantly better binding affinity than Ligand A (-8.6 kcal/mol). This is a crucial advantage for an enzyme inhibitor. The difference of 0.35 kcal/mol is substantial.

**Conclusion:**

While both compounds have issues with Caco-2 permeability and aqueous solubility, Ligand B's significantly stronger binding affinity (-8.252 vs -8.6 kcal/mol) and longer half-life outweigh the slightly higher DILI risk and lower solubility. The better metabolic stability (lower Cl_mic) also favors Ligand B. The solubility issue would need to be addressed through formulation, but the potency advantage is critical for an enzyme inhibitor.

Output:
1
2025-04-17 13:59:12,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.447 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 (59.08). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better positioned.

**3. logP:** Both ligands have good logP values (1.357 and 0.919), 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:** Both ligands have reasonable QED scores (0.807 and 0.709), indicating good drug-like properties.

**7. DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (23.149), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have reasonable BBB penetration (76.813 and 68.166), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.584 and -4.636). This is unusual and suggests poor permeability, but the scale isn't specified. We'll need to consider this cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.28 and -1.425). Again, the scale is unspecified, but negative values suggest poor solubility. This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.172 and 0.389), which is excellent.

**12. Microsomal Clearance:** Ligand A (21.024) has lower microsomal clearance than Ligand B (33.596), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (5.931) has a slightly longer in vitro half-life than Ligand A (5.294), but the difference is minimal.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.046 and 0.098), which is favorable.

**15. 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 override other ADME considerations.

**Overall Assessment:**

While both ligands have good potency, Ligand A is slightly better overall. It has a lower DILI risk and, crucially, significantly lower microsomal clearance, suggesting better metabolic stability. The negative Caco-2 and solubility values are concerning for both, but the metabolic stability advantage of Ligand A is more important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:59:12,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.909 Da) is slightly higher than Ligand B (363.483 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 84.23, Ligand B: 72.88), suggesting good oral absorption potential.

**logP:** Ligand A (3.773) is at the upper end of the optimal range (1-3), while Ligand B (1.516) is towards 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:** Both have 2 HBD and 5-6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.684, Ligand B: 0.851), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A has a significantly higher DILI risk (94.843%) compared to Ligand B (25.281%). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (69.833%) is higher than Ligand B (55.021%), but this isn't a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.21 and -5.166), which is unusual and suggests poor permeability. This is a red flag for both, but needs further investigation (these values might be errors or indicate active efflux).

**Aqueous Solubility:** Both ligands have negative solubility values (-4.461 and -2.138), also unusual and concerning. Similar to Caco-2, this needs further investigation.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.595 and 0.522), which is positive.

**Microsomal Clearance:** Ligand B has a much lower microsomal clearance (1.477 mL/min/kg) than Ligand A (53.162 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (10.65 hours) compared to Ligand A (37.504 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.265 and 0.035), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better QED outweigh the slightly lower logP. The negative Caco-2 and solubility values are concerning for both, but the ADME profile of Ligand B is substantially better overall.

Output:
1
2025-04-17 13:59:12,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 and 355.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.49) is better than Ligand B (133.7). Lower TPSA generally indicates better permeability. Ligand A is well below the 140 threshold. Ligand B is approaching it.

**logP:** Ligand A (2.019) is optimal, while Ligand B (0.618) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

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

**QED:** Ligand A (0.357) is lower than Ligand B (0.224), but both are below the desirable threshold of 0.5. This indicates both have room for improvement in drug-likeness.

**DILI:** Ligand A (64.715) has a higher DILI risk than Ligand B (33.346). This is a significant drawback for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand A (71.656) is slightly better than Ligand B (41.993).

**Caco-2 Permeability:** Ligand A (-5.229) has worse Caco-2 permeability than Ligand B (-4.944). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.71) has worse solubility than Ligand B (-0.914). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.582) has a slightly higher hERG risk than Ligand B (0.107). Lower is better here.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (39.398 and 39.263 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-1.816 hours) has a very short half-life, while Ligand B (-18.39 hours) has a longer half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.103 and 0.009).

**Binding Affinity:** Ligand B (-8.2 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 for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. It has better solubility, a significantly longer half-life, lower DILI risk, and slightly better binding affinity. While its logP is a bit low, the other advantages outweigh this drawback. Ligand A suffers from poor solubility, a short half-life, and higher DILI risk.

Output:
1
2025-04-17 13:59:12,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.387 and 344.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.95) is better than Ligand B (32.34) as it is still within the acceptable range for oral absorption (<140), while Ligand B is significantly lower.

**logP:** Ligand A (0.58) is suboptimal, potentially hindering permeation. Ligand B (4.311) is high, potentially causing solubility or off-target issues, but is closer to the ideal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have similar, good QED scores (0.737 and 0.748).

**DILI:** Ligand A (50.523) has a moderate DILI risk, while Ligand B (14.036) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (19.814) has very low BBB penetration, while Ligand B (95.192) has excellent BBB penetration. While SRC is not a CNS target, higher BBB penetration generally correlates with fewer off-target effects.

**Caco-2 Permeability:** Ligand A (-5.501) has poor Caco-2 permeability, which is a concern for oral absorption. Ligand B (-4.769) is slightly better but still not ideal.

**Aqueous Solubility:** Ligand A (-2.318) has poor aqueous solubility, while Ligand B (-4.406) also has poor aqueous solubility.

**hERG:** Ligand A (0.087) has a very low hERG risk, which is excellent. Ligand B (0.792) has a slightly elevated hERG risk, but still within a reasonable range.

**Microsomal Clearance:** Ligand A (-18.611) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (63.346) has high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-25.237) has a very long in vitro half-life, consistent with its low clearance. Ligand B (14.428) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.231).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.5 and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Conclusion:**

Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2) and a significantly lower hERG risk, which are crucial for enzyme inhibitors. However, it suffers from poor solubility and permeability. Ligand B has a much better DILI profile, better BBB penetration, and slightly better Caco-2 permeability, but is metabolically less stable and has a slightly higher hERG risk.

Considering the priorities for kinase inhibitors, the excellent metabolic stability and very low hERG risk of Ligand A outweigh its solubility and permeability concerns, especially given its strong binding affinity. While solubility/permeability can be addressed through formulation strategies, mitigating potential toxicity (hERG) and ensuring sufficient exposure (metabolic stability) are more challenging.

Output:
0
2025-04-17 13:59:12,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.379 and 355.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.25 and 75.88) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.39) is slightly higher than optimal (1-3), but acceptable. Ligand B (2.13) is well within the optimal range.

**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:** Both ligands have good QED scores (0.666 and 0.781), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 77.045, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 41.915, which is good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (92.71) has better BBB penetration than Ligand A (65.452), but it's not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.869 and -4.041). This is unusual and suggests poor permeability, but these values are often predictions and can be inaccurate.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.992 and -2.473), which is also unusual and suggests poor solubility. Again, these are predictions.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.576 and 0.365).

**Microsomal Clearance:** Ligand A has a high microsomal clearance (128.705 mL/min/kg), indicating poor metabolic stability. Ligand B has a much lower clearance (39.027 mL/min/kg), suggesting better stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-11.554 hours), which is not physically possible and likely an artifact of the prediction. Ligand B has a negative half-life as well (-28.382 hours), also likely an artifact.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.46 and 0.145).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand B is the more promising candidate. Its significantly lower DILI risk and lower microsomal clearance (better metabolic stability) outweigh the slightly better logP of Ligand A. The negative Caco-2 and solubility predictions are concerning for both, but these are predictions and may not reflect the true *in vitro* or *in vivo* properties. The unrealistic half-life predictions are also concerning, but don't necessarily disqualify the compounds. The lower DILI and better metabolic stability of Ligand B make it the better choice for further investigation.

Output:
1
2025-04-17 13:59:12,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.435 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.77) is better than Ligand B (137.31), being comfortably under the 140 threshold for good absorption.

**logP:** Ligand A (1.44) is optimal, while Ligand B (0.004) is very low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is good, while Ligand B (5) is at the upper limit.

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

**QED:** Ligand A (0.775) is significantly better than Ligand B (0.406), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (25.785 and 29.159, respectively), below the 40 threshold.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values (-5.55 and -5.711), which is unusual and suggests poor permeability. However, this metric can be unreliable and is less critical than other factors.

**Aqueous Solubility:** Both have negative values (-1.622 and -2.929), which is also unusual. Solubility is important for enzymes, and this is a potential concern for both.

**hERG:** Both ligands have very low hERG risk (0.134 and 0.144).

**Microsomal Clearance:** Ligand A (-19.507) has significantly lower (better) microsomal clearance than Ligand B (0.912), suggesting much better metabolic stability.

**In vitro Half-Life:** Ligand A (5.969) has a better in vitro half-life than Ligand B (-10.792).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.006 and 0.017).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Conclusion:**

Ligand A is significantly better than Ligand B. The most critical factor is the much stronger binding affinity (-9.1 vs -0.0 kcal/mol). Additionally, Ligand A has better logP, TPSA, QED, metabolic stability (Cl_mic and t1/2), and a slightly better DILI score. While both have issues with predicted solubility and Caco-2 permeability, the superior potency and metabolic stability of Ligand A outweigh these concerns.

Output:
1
2025-04-17 13:59:12,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (380.206 and 358.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.02) is better than Ligand B (76.66), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (4.125) is slightly high, potentially leading to solubility issues, while Ligand B (2.276) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 threshold.

**QED:** Ligand A (0.676) has a better QED score than Ligand B (0.464), indicating a more drug-like profile.

**DILI:** Ligand B (14.036) has a significantly lower DILI risk than Ligand A (90.384), which is a major concern.

**BBB:** Both ligands have good BBB penetration (A: 77.627, B: 81.582), but this is less crucial for a non-CNS target like SRC.

**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 (0.447) has a slightly lower hERG risk than Ligand B (0.525), which is preferable.

**Microsomal Clearance:** Ligand B (19.013) has a significantly lower microsomal clearance than Ligand A (59.647), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (16.826) has a longer in vitro half-life than Ligand A (5.094), which is desirable.

**P-gp Efflux:** Ligand A (0.3) has lower P-gp efflux than Ligand B (0.077), which is favorable.

**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 (1.4 kcal/mol difference).

**Conclusion:**

Despite Ligand A's superior binding affinity, the extremely high DILI risk (90.384) is a major red flag. Ligand B, while having a slightly weaker binding affinity, exhibits a much more favorable safety profile (low DILI), better metabolic stability (lower Cl_mic, longer t1/2), and acceptable drug-like properties. The binding affinity difference, while significant, may be overcome with further optimization of Ligand B. Given the enzyme-specific priorities, the lower toxicity and better metabolic profile of Ligand B make it the more viable drug candidate.

Output:
1
2025-04-17 13:59:12,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.439 and 347.434 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (81.5) is slightly higher than Ligand B (64.41). Both are below the 140 threshold for good oral absorption, but ligand B is preferable.

**logP:** Both ligands have good logP values (1.258 and 2.471, respectively) within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA and Ligand B has 3 HBA. Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.799 and 0.726), indicating good drug-likeness.

**DILI:** Ligand A (54.789) has a higher DILI risk than Ligand B (31.252). This is a significant advantage for Ligand B.

**BBB:** Ligand A (58.123) and Ligand B (77.084). BBB is not a primary concern for a kinase inhibitor, but higher is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.874 and -4.246). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.715 and -2.103). This is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.301 and 0.785).

**Microsomal Clearance:** Ligand A (-22.446) has significantly lower (better) microsomal clearance than Ligand B (66.511). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-1.601) has a shorter half-life than Ligand B (13.974). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have similar low P-gp efflux liability (0.27 and 0.267).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol).

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is more promising. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B has a significantly lower DILI risk, which is crucial. The similar binding affinity makes the ADME properties the deciding factor. The poor Caco-2 and solubility are concerns for both, but the lower DILI risk of Ligand B outweighs the better metabolic stability of Ligand A.

Output:
1
2025-04-17 13:59:12,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.65) is slightly higher than Ligand B (59.39), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.791 and 2.251), 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.

**QED:** Both ligands have good QED scores (0.773 and 0.837), indicating a drug-like profile.

**DILI:** Ligand B (28.267) has a significantly lower DILI risk than Ligand A (58.395). This is a major advantage.

**BBB:** Both ligands have high BBB penetration (83.172 and 89.298), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.517 and -4.584). This is unusual and suggests a potential issue with permeability prediction or data quality. However, since both are similarly affected, it doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-2.884 and -1.887). Similar to Caco-2 permeability, this is concerning, but consistent between the two.

**hERG:** Both ligands have similar, low hERG risk (0.437 and 0.468).

**Microsomal Clearance:** Ligand B (63.85) has a lower microsomal clearance than Ligand A (78.155), indicating better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (60.123) has a much longer in vitro half-life than Ligand A (-38.506). This is a major advantage, potentially leading to less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.53 and 0.222).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has slightly better binding affinity than Ligand A (-7.4 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands have acceptable properties, Ligand B demonstrates a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The negative solubility and Caco-2 values are concerning for both, but don't differentiate them. Given the enzyme-specific priorities, the improved metabolic stability and reduced toxicity risk of Ligand B are decisive.

Output:
1
2025-04-17 13:59:12,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.389 and 356.329 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.91) is better than Ligand B (100.63), both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.415) is within the optimal 1-3 range. Ligand B (-0.238) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.738) has a higher QED score than Ligand B (0.573), suggesting better overall drug-likeness.

**DILI:** Ligand B (64.521) has a higher DILI risk than Ligand A (56.727), although both are reasonably acceptable.

**BBB:** Ligand A (74.486) has a better BBB penetration score than Ligand B (60.682), but BBB isn't a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.14 and -5.131). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.865 and -2.061). This is also a significant concern for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.093) has a slightly lower hERG risk than Ligand B (0.086), which is preferable.

**Microsomal Clearance:** Ligand A (0.019) has *much* lower microsomal clearance than Ligand B (3.61). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-7.003) has a much longer half-life than Ligand B (-31.504). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.018) has lower P-gp efflux than Ligand B (0.009), which is preferable.

**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 where other issues can be overlooked.

**Conclusion:**

Ligand A is the superior candidate. While both have poor Caco-2 permeability and solubility, Ligand A's significantly stronger binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), better QED, and lower DILI risk outweigh the shared issues. The difference in binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 13:59:12,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (85.25) is preferable as it is lower than Ligand A (100.35).

**logP:** Ligand A (0.344) is a bit low, potentially hindering permeation. Ligand B (0.879) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.693, B: 0.783), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (50.136) has a lower DILI risk than Ligand B (63.746), which is a significant advantage.

**BBB:** Both have similar BBB penetration (A: 53.703, B: 52.036), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG:** Ligand A (0.038) has a much lower hERG risk than Ligand B (0.449), a critical advantage.

**Microsomal Clearance:** Ligand A (15.15 mL/min/kg) has significantly lower microsomal clearance than Ligand B (28.671 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (21.702 hours) has a longer half-life than Ligand A (-1.277 hours), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Both have similar, strong binding affinities (A: -8.4 kcal/mol, B: -8.1 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 DILI risk (50.136 vs 63.746) and hERG risk (0.038 vs 0.449) and lower microsomal clearance (15.15 vs 28.671). While Ligand B has a slightly better QED and longer half-life, the safety profiles of Ligand A are more favorable, and the binding affinity difference is minimal. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 13:59:12,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (337.379 and 341.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (75.29 and 73.99) are below the 140 A^2 threshold for good oral absorption, which is good.

**3. logP:** Ligand A (2.211) is within the optimal 1-3 range. Ligand B (3.75) is slightly higher, but still acceptable.

**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 (4) is good. Ligand B (2) is good.

**6. QED:** Both ligands (0.688 and 0.684) are above 0.5, indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (64.444 and 65.917), placing them in a moderate risk category, but not excessively high.

**8. BBB:** Both ligands have similar BBB penetration (67.08 and 68.748), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.677 and -4.983). 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 negative solubility values (-3.607 and -5.168). Again, these are on a log scale, indicating very poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Ligand A (0.265) has a lower hERG risk than Ligand B (0.738), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (78.716) has higher microsomal clearance than Ligand B (55.85). This suggests Ligand B is more metabolically stable, which is desirable for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-32.054) has a negative half-life, which is not physically possible and indicates a very short half-life. Ligand B (24.074) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.225 and 0.44).

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). This 0.7 kcal/mol difference is substantial enough to be a key factor.

**Overall Assessment:**

Ligand A has a better binding affinity and lower hERG risk. However, its extremely short in vitro half-life and poor solubility are major drawbacks. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, but its hERG risk is higher and binding affinity is slightly lower.

Considering the priorities for enzyme inhibitors, metabolic stability and solubility are crucial. While Ligand A's affinity is better, its poor half-life and solubility are likely to lead to poor *in vivo* exposure. Ligand B, despite the slightly lower affinity, has a more favorable ADME profile, particularly regarding metabolic stability and half-life.

Output:
1
2025-04-17 13:59:12,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.797 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.08) is slightly higher than the ideal <140, but acceptable. Ligand B (66.4) is excellent, well below 90, suggesting good absorption.

**logP:** Both ligands (2.214 and 2.286) 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 good.

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

**QED:** Both ligands have good QED scores (0.667 and 0.825), indicating drug-like properties.

**DILI:** Ligand A (79.062) has a higher DILI risk than Ligand B (35.789). This is a significant concern, as a lower DILI percentile is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (80.574) has a higher BBB score than Ligand A (32.299), but this isn't a primary driver in this case.

**Caco-2 Permeability:** Ligand A (-5.323) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.692) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.41) has poor aqueous solubility. Ligand B (-2.035) is better, but still not ideal.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.322 and 0.436), which is excellent.

**Microsomal Clearance:** Ligand A (2.187) has significantly lower microsomal clearance than Ligand B (39.753), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (48.668) has a much longer in vitro half-life than Ligand B (-0.653), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.142 and 0.196).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.0 kcal/mol). This difference of 1.4 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk and poorer solubility/permeability, its significantly superior binding affinity and much better metabolic stability (lower Cl_mic and longer t1/2) make it the more promising candidate. The strong binding affinity is a key advantage for an enzyme inhibitor, and the improved metabolic stability suggests a potentially longer duration of action. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. Ligand B's better ADME properties are overshadowed by its weaker binding.

Output:
1
2025-04-17 13:59:12,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (377.455 Da) is also good.

**TPSA:** Ligand A (57.0) is excellent, well below the 140 threshold for oral absorption. Ligand B (135.25) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (2.381) is optimal. Ligand B (0.475) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 9 HBA) is also acceptable, though slightly higher counts might affect permeability.

**QED:** Both ligands have reasonable QED values (A: 0.758, B: 0.593), suggesting good drug-like properties.

**DILI:** Ligand A (12.253) has a very low DILI risk, which is excellent. Ligand B (86.39) has a significantly higher DILI risk, which is a major concern.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (77.821) is decent, while Ligand B (58.007) is lower.

**Caco-2 Permeability:** Ligand A (-4.521) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-6.11) is even worse.

**Aqueous Solubility:** Ligand A (-0.433) has poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-2.225) is even worse.

**hERG Inhibition:** Ligand A (0.528) has a low hERG risk, which is good. Ligand B (0.443) is also low.

**Microsomal Clearance:** Ligand A (46.856) has moderate clearance, suggesting moderate metabolic stability. Ligand B (9.813) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (38.252) has a reasonable half-life. Ligand B (-16.287) has a very short half-life, which is a significant issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.04, B: 0.255), which is favorable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and excellent metabolic stability, but suffers from higher DILI risk, poor solubility, poor permeability, and a very short half-life. Ligand A has a better safety profile (DILI, hERG) and acceptable metabolic stability, but has poor solubility and permeability.

Despite the strong affinity of Ligand B, the high DILI risk and very short half-life are major red flags. While solubility and permeability can sometimes be improved through formulation, a high DILI risk is harder to mitigate. The poor half-life would necessitate very frequent dosing.

Considering the enzyme-specific priorities and the significant safety concerns with Ligand B, Ligand A is the more viable candidate, despite its lower affinity and permeability issues. Formulation strategies could be explored to address the solubility and permeability.

Output:
0
2025-04-17 13:59:12,633 - INFO - Batch 259 complete. Total preferences: 4144
2025-04-17 13:59:12,633 - INFO - Processing batch 260/512...
2025-04-17 14:00:01,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which can be favorable for permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (94.66) is slightly higher than Ligand B (86.88).

**logP:** Ligand A (0.06) is quite low, potentially hindering membrane permeability and absorption. Ligand B (3.133) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors & Acceptors:** Both have acceptable HBD (3) and HBA (4/3) counts.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.718) is slightly better than Ligand B (0.618).

**DILI:** Ligand A (17.138) has a much lower DILI risk than Ligand B (42.885), which is a strong positive for Ligand A.

**BBB:** Ligand A (40.403) has a lower BBB penetration percentile than Ligand B (52.268). Since SRC is not a CNS target, this is less critical.

**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 (-5.356) is more negative than Ligand B (-5.04), suggesting potentially worse permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and warrants further investigation. Ligand A (-1.627) is slightly better than Ligand B (-4.097).

**hERG Inhibition:** Ligand A (0.135) has a very low hERG risk, which is excellent. Ligand B (0.298) is also low, but higher than Ligand A.

**Microsomal Clearance:** Ligand A (-31.512) has a much lower (better) microsomal clearance than Ligand B (39.269), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand B (10.649) has a significantly longer in vitro half-life than Ligand A (1.456), which is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux liability, which is favorable. Ligand B (0.104) is slightly higher.

**Binding Affinity:** Ligand B (-9.2 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 A excels in safety (low DILI, low hERG) and metabolic stability (low Cl_mic, low P-gp efflux). However, its low logP and weak binding affinity are major concerns. Ligand B has a much stronger binding affinity and a better logP, but suffers from higher DILI risk and a shorter half-life.

Given that we are targeting a kinase (enzyme), potency (binding affinity) and metabolic stability are paramount. The substantial difference in binding affinity (-9.2 vs 0.0 kcal/mol) is the deciding factor. While Ligand B's DILI and half-life are not ideal, these can potentially be addressed through further optimization. The lack of significant binding from Ligand A makes it unlikely to be a viable candidate, regardless of its favorable ADME properties.

Output:
1
2025-04-17 14:00:01,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.519 Da and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is well below the 140 threshold and favorable for oral absorption. Ligand B (95.75) is higher, but still within an acceptable range, though less optimal.

**logP:** Ligand A (2.669) is within the optimal 1-3 range. Ligand B (0.572) is slightly below 1, which *could* indicate potential permeability issues, but isn't a hard disqualifier.

**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, being under the 10 HBA limit.

**QED:** Both ligands have high QED scores (0.827 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (12.33) has a significantly lower DILI risk than Ligand B (35.014). This is a major advantage for Ligand A.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (58.085) is lower than Ligand B (48.158).

**Caco-2 Permeability:** Ligand A (-4.403) is better than Ligand B (-5.016), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.547) is better than Ligand B (-1.719), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.68 and 0.116), which is excellent.

**Microsomal Clearance:** Ligand A (38.762) has a higher (worse) microsomal clearance than Ligand B (9.51). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (12.427) has a significantly longer half-life than Ligand A (2.421). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.204 and 0.01).

**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 overcome other ADME differences.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, Ligand A has a much lower DILI risk and better solubility. Given the enzyme-specific priorities, the lower DILI risk and better solubility of Ligand A are more critical. The binding affinity difference is minimal. Therefore, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 14:00:01,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (387.845 Da) and Ligand B (341.386 Da) are both acceptable.

**2. TPSA:** Ligand A (113.51) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (56.15) is excellent, well below 140.

**3. logP:** Ligand A (1.649) is within the optimal range (1-3). Ligand B (3.002) is at the higher end of optimal, but still acceptable.

**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 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (A: 0.722, B: 0.776), indicating good drug-like properties.

**7. DILI:** Ligand A (85.653) has a higher DILI risk than Ligand B (75.378). Both are above the preferred <40, but Ligand B is better.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (41.218) and Ligand B (74.37) are both relatively low, but not a major concern.

**9. Caco-2 Permeability:** Ligand A (-5.117) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.578) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-2.826) and Ligand B (-4.23) both have poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.044) has very low hERG inhibition risk, which is excellent. Ligand B (0.851) has a slightly higher, but still acceptable, risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (16.927) has lower clearance than Ligand B (84.265), indicating better metabolic stability. This is a key priority for enzymes.

**13. In vitro Half-Life:** Ligand A (3.585) has a shorter half-life than Ligand B (22.846). Longer half-life is preferable.

**14. P-gp Efflux:** Ligand A (0.412) has lower P-gp efflux than Ligand B (0.657), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand A (-8.0 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 hERG profile and lower P-gp efflux, Ligand B excels in several critical areas for an enzyme inhibitor: significantly stronger binding affinity, better metabolic stability (lower Cl_mic), and a longer half-life. The slightly higher DILI risk and poorer solubility of Ligand B are potential concerns, but the substantial improvement in binding affinity is likely to outweigh these drawbacks. The TPSA is also much more favorable for Ligand B.

Output:
1
2025-04-17 14:00:01,324 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [349.402, 48.0, 2.173, 0.0, 5.0, 0.763, 29.818, 95.308, -4.231, -2.37, 0.746, 57.916, -6.69, 0.28, -8.7]
**Ligand B:** [367.559, 61.44, 2.767, 2.0, 4.0, 0.705, 33.501, 54.052, -4.953, -2.582, 0.56, 60.421, 59.068, 0.221, -7.2]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (349.4) is slightly preferred due to being a bit lower.
2. **TPSA:** A (48.0) is better than B (61.44).  Both are below 140, but A is closer to the optimal for oral absorption.
3. **logP:** Both are within the optimal range (1-3). B (2.767) is slightly higher, which might present a minor solubility concern, but is still acceptable.
4. **HBD:** A (0) is better than B (2). Fewer HBDs generally improve permeability.
5. **HBA:** A (5) is better than B (4). Both are within the acceptable range.
6. **QED:** Both are good (A: 0.763, B: 0.705), indicating good drug-like properties.
7. **DILI:** A (29.8) is significantly better than B (33.5). Lower DILI risk is crucial.
8. **BBB:** A (95.3) is much better than B (54.1). While SRC is not a CNS target, higher BBB penetration can sometimes correlate with better overall drug distribution.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.231) is slightly better than B (-4.953).
10. **Solubility:** Both are negative, indicating poor solubility. A (-2.37) is slightly better than B (-2.582).
11. **hERG:** A (0.746) is better than B (0.56). Lower hERG risk is essential.
12. **Cl_mic:** A (57.9) is better than B (60.4). Lower clearance is preferred for metabolic stability.
13. **t1/2:** B (59.1) is significantly better than A (-6.69). This is a major advantage for B.
14. **Pgp:** A (0.28) is better than B (0.221). Lower Pgp efflux is preferred.
15. **Affinity:** A (-8.7) is *significantly* better than B (-7.2). A 1.5 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A is a clear winner.
*   **Metabolic Stability:** B has a much better *in vitro* half-life. A has a negative half-life, which is concerning.
*   **Solubility:** Both are poor, but A is slightly better.
*   **hERG:** A has a lower hERG risk.
*   **DILI:** A has a lower DILI risk.

**Overall Assessment:**

While ligand B has a superior *in vitro* half-life, the significantly stronger binding affinity of ligand A (-8.7 vs -7.2 kcal/mol) is a critical advantage for an enzyme inhibitor. The better DILI, hERG, and BBB profiles of A are also beneficial. The poor Caco-2 and solubility of both are concerns, but these can potentially be addressed through formulation strategies. The negative half-life of A is a serious concern, but the strong binding affinity might allow for a lower dose, potentially mitigating the rapid clearance.

Considering the priorities for an enzyme inhibitor, the substantial binding affinity advantage of ligand A outweighs the drawbacks.

Output:
1
2025-04-17 14:00:01,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (67.23). A TPSA under 140 is good for oral absorption, and both are well within this limit, but A is preferable.

**logP:** Both ligands have good logP values (3.641 and 2.709), 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 4. Both are acceptable (<=10), but A is slightly better.

**QED:** Ligand A (0.845) has a much higher QED score than Ligand B (0.66), indicating a more drug-like profile.

**DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (41.024), which is a major advantage. Both are below the 40 threshold, but A is much better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.174) is better than Ligand B (69.794).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.985) is slightly better than Ligand B (-4.836), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-4.499) is slightly better than Ligand B (-2.745).

**hERG:** Both ligands have low hERG inhibition liability (0.475 and 0.255), which is excellent.

**Microsomal Clearance:** Ligand A (41.577) and Ligand B (39.648) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (5.88 hours) has a longer half-life than Ligand B (-0.647 hours). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.232) has lower P-gp efflux than Ligand B (0.09), which is preferable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Conclusion:**

Ligand A is clearly superior to Ligand B. Its significantly stronger binding affinity, better QED score, lower DILI risk, longer half-life, and lower P-gp efflux outweigh the slightly worse Caco-2 and solubility values. The negative Caco-2 and solubility values are concerning and would require further investigation (formulation studies, prodrug approaches), but the potency advantage of Ligand A is substantial enough to make it the more promising candidate.

Output:
1
2025-04-17 14:00:01,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.439 and 347.415 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.75) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (91.65) is still within acceptable limits for oral absorption (<140), but less optimal than A.

**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 (1.163) is slightly below 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 reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.711, B: 0.855), indicating generally drug-like properties.

**DILI:** Ligand A (55.913) has a moderate DILI risk, while Ligand B (43.389) has a lower, more favorable DILI risk.

**BBB:** BBB is not a primary concern for a kinase inhibitor, but Ligand A (77.898) shows better potential for CNS penetration than Ligand B (50.872).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, given the TPSA values, we can assume they are permeable.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This is a concern, but we can consider other factors.

**hERG Inhibition:** Ligand A (0.878) has a slightly higher hERG risk than Ligand B (0.127), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (112.013) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (29.111), which is excellent.

**In vitro Half-Life:** Ligand A (107.051) has a longer half-life than Ligand B (18.47), which is desirable.

**P-gp Efflux:** Ligand A (0.737) has moderate P-gp efflux, while Ligand B (0.025) has very low efflux, which is favorable.

**Binding Affinity:** Ligand B (-9.2 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 of Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better half-life and BBB, Ligand B's superior binding affinity, lower DILI risk, significantly lower microsomal clearance (better metabolic stability), and lower hERG risk are more critical for an enzyme inhibitor. The slightly lower logP and higher TPSA are less concerning given the strong binding affinity. The unusual solubility and Caco-2 values would need further investigation, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 14:00:01,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.507 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (55.89) is better than Ligand B (63.25) as it is closer to the ideal range for good oral absorption (<=140).

**logP:** Ligand A (0.943) is slightly lower than optimal (1-3), but still acceptable. Ligand B (3.463) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA), as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Ligand B (0.73) has a better QED score than Ligand A (0.497), suggesting a more drug-like profile.

**DILI:** Ligand A (4.382) has a significantly lower DILI risk than Ligand B (52.152), which is a major advantage.

**BBB:** Ligand B (83.249) has a higher BBB penetration score than Ligand A (62.233), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.223) has a much worse Caco-2 permeability than Ligand B (-4.522).

**Aqueous Solubility:** Ligand A (0.103) has significantly worse aqueous solubility than Ligand B (-4.711). This is a significant drawback for Ligand A.

**hERG Inhibition:** Ligand A (0.452) has a lower hERG inhibition liability than Ligand B (0.564), which is favorable.

**Microsomal Clearance:** Ligand A (-19.859) has a much lower microsomal clearance than Ligand B (53.182), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (33.907) has a longer in vitro half-life than Ligand A (-5.788), which is desirable.

**P-gp Efflux:** Ligand A (0.009) has a much lower P-gp efflux liability than Ligand B (0.277), which is favorable.

**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 concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic) and lower DILI risk. However, it suffers from poor solubility and Caco-2 permeability. Ligand B has better solubility, permeability, QED, and half-life, but weaker binding affinity and a higher DILI risk.

Given the enzyme-specific priorities, the strong binding affinity and metabolic stability of Ligand A are crucial. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The significantly lower DILI risk is also a major benefit. The difference in binding affinity (-8.9 vs -7.7 kcal/mol) is substantial and likely to be more impactful than the ADME differences.

Output:
0
2025-04-17 14:00:01,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.451 and 362.348 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.29 and 78.87) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (2.631 and 1.78) are within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility but also potentially reduced permeability.

**H-Bond Donors:** Both have 2 HBD, well within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the 10 limit.

**QED:** Both ligands have good QED scores (0.68 and 0.739), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 57.038, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 31.02, which is significantly better. This is a major advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.609) has a better BBB score than Ligand A (19.116), but this is not a primary concern here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.362 and -5.141). These values are unusual and suggest poor permeability. However, the scale is not specified and these values may be relative to a control.

**Aqueous Solubility:** Both have negative solubility values (-1.875 and -2.246). Similar to Caco-2, the scale is not specified. Negative values suggest poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.661 and 0.595), which is excellent.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (13.22 mL/min/kg) than Ligand B (43.044 mL/min/kg). Lower clearance indicates better metabolic stability, favoring Ligand A.

**In vitro Half-Life:** Ligand A has a positive half-life (31.456 hours), while Ligand B has a negative half-life (-31.417 hours). This is highly unusual and suggests a significant issue with the experimental setup or the ligand's stability. The negative value is concerning.

**P-gp Efflux:** Both have low P-gp efflux liability (0.356 and 0.062), which is good.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-7.7 kcal/mol) than Ligand B (-6.6 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has superior binding affinity and better metabolic stability, Ligand B has a much lower DILI risk and a more reasonable (though still concerning) in vitro half-life. The negative half-life for Ligand B is a major red flag. Given the enzyme-specific priorities, the substantial binding affinity advantage of Ligand A, combined with acceptable (though not ideal) ADME properties, makes it the more promising candidate despite the slightly elevated DILI risk. The negative half-life of Ligand B is a critical flaw.

Output:
0
2025-04-17 14:00:01,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.423 and 368.821 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.23 and 93.62) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Both ligands (1.492 and 1.623) 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.764 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A (71.19) has a higher DILI risk than Ligand B (35.789). This is a significant negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (28.461 and 70.182). BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.218) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.59) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.483) has poor aqueous solubility, while Ligand B (-2.723) is slightly better. Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.303 and 0.345).

**Microsomal Clearance:** Ligand A (-0.565) has a much lower (better) microsomal clearance than Ligand B (31.839). This indicates greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (13.129) has a shorter half-life than Ligand B (52.438). This is a negative for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.195).

**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 positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While both have acceptable MW, logP, QED, and hERG, Ligand B significantly outperforms Ligand A in several critical areas: lower DILI risk, better Caco-2 permeability, and better aqueous solubility. The slightly better binding affinity of Ligand B further supports this conclusion. Ligand A's poor solubility, permeability, and higher DILI risk are significant drawbacks. Although Ligand A has better metabolic stability, the other factors outweigh this advantage.

Output:
1
2025-04-17 14:00:01,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.523 Da) and Ligand B (350.503 Da) are both acceptable.

**TPSA:** Ligand A (87.14) is better than Ligand B (49.85). While both are reasonably low, Ligand B is closer to the ideal for good oral absorption (<=140).

**logP:** Ligand A (4.133) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.972) is within the optimal range (1-3).

**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:** Both ligands have good QED scores (Ligand A: 0.623, Ligand B: 0.786), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 77.549, which is high and concerning. Ligand B has a much lower DILI risk (24.312), a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 60.566, Ligand B: 77.821). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.732 and -4.421). This is unusual and suggests poor permeability. However, these values are on a log scale, so even negative values can indicate some permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.313 and -3.227). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.614, Ligand B: 0.554).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (Ligand A: 36.574, Ligand B: 36.577). This suggests similar metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (14.257 hours) compared to Ligand A (66.137 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.671, Ligand B: 0.295). Ligand B is better.

**Binding Affinity:** Ligand B (-9.6 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 minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have some solubility/permeability concerns (negative Caco-2 and solubility values), Ligand B's significantly stronger binding affinity, lower DILI risk, and longer half-life outweigh the slightly higher TPSA and logP. The difference in binding affinity is substantial and a key driver for selection. The improved DILI profile is also critical.

Output:
1
2025-04-17 14:00:01,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.53 and 367.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is significantly better than Ligand B (97.39). A TPSA under 140 is good for oral absorption, and both meet this, but A is preferable.

**logP:** Ligand A (2.85) is optimal, while Ligand B (0.773) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.807) has a higher QED score than Ligand B (0.596), indicating better overall drug-likeness.

**DILI:** Ligand B (56.15) has a lower DILI risk than Ligand A (38.19), which is a positive.

**BBB:** Ligand A (78.21) has better BBB penetration than Ligand B (35.05). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.441) is better than Ligand B (-4.886), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.37) is better than Ligand B (-2.834), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.711) has a lower hERG risk than Ligand B (0.291), a significant advantage for safety.

**Microsomal Clearance:** Ligand B (10.49) has significantly lower microsomal clearance than Ligand A (29.65), indicating better metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-28.94) has a significantly longer in vitro half-life than Ligand A (38.64), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.308) has lower P-gp efflux than Ligand B (0.049), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.5). While a 1.5 kcal/mol difference is significant, the other ADME properties of Ligand B are concerning.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic and longer t1/2). However, it suffers from a low logP, higher TPSA, and a concerningly low hERG inhibition score. Ligand A, while having slightly weaker binding, has superior drug-like properties (QED, solubility, TPSA, logP, hERG) and acceptable metabolic stability. The lower hERG risk for Ligand A is a major advantage. Given the enzyme-kinase focus, metabolic stability is important, but not at the expense of safety.

Output:
0
2025-04-17 14:00:01,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.425 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (67.43). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is closer to the ideal for better absorption.

**logP:** Both ligands have good logP values (2.671 and 2.009), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (2 HBD, 3 HBA) in terms of balancing solubility and permeability. Fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED scores (0.78 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (23.149) has a lower DILI risk than Ligand B (20.279), suggesting a safer profile. Both are good, but A is slightly better.

**BBB:** Ligand A (95.425) has a much higher BBB penetration percentile than Ligand B (50.523). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.477) has a better Caco-2 permeability score than Ligand B (-4.507), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility scores (-3.28 and -3.173). This is a potential concern for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.606) has a lower hERG inhibition liability than Ligand B (0.238), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (29.09) has a lower microsomal clearance than Ligand B (33.92), suggesting better metabolic stability. This is important for maintaining therapeutic concentrations.

**In vitro Half-Life:** Ligand A (7.402) has a longer in vitro half-life than Ligand B (-5.579), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.108) has lower P-gp efflux liability than Ligand B (0.032), indicating better bioavailability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is the superior candidate. It demonstrates better ADME properties across multiple parameters (TPSA, H-bonds, DILI, BBB, Caco-2, hERG, Cl_mic, t1/2, Pgp) while maintaining comparable binding affinity to Ligand B. The lower hERG risk and improved metabolic stability are particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:00:01,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.475 and 347.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.23) is better than Ligand B (93.25), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands (1.277 and 1.471) are 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 4 HBA, and Ligand B has 5. Both are acceptable, below the 10 threshold.

**6. QED:** Ligand A (0.759) has a better QED score than Ligand B (0.522), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.292) has a significantly lower DILI risk than Ligand B (34.083). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (61.923) is slightly better than Ligand A (50.679).

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.337 and -5.084), 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. Solubility:** Both ligands have negative solubility values (-1.926 and -1.878), which is also unusual and suggests poor solubility.

**11. hERG:** Ligand A (0.496) has a lower hERG inhibition liability than Ligand B (0.641), which is preferable.

**12. Cl_mic:** Ligand A (-17.114) has a much lower (better) microsomal clearance than Ligand B (5.936), suggesting better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**13. t1/2:** Ligand A (26.739 hours) has a significantly longer in vitro half-life than Ligand B (2.94 hours). This is a major advantage, potentially allowing for less frequent dosing.

**14. Pgp:** Ligand B (0.144) has slightly lower P-gp efflux liability than Ligand A (0.035), which is a minor advantage.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-9.4 and -8.4 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a better QED score, much lower DILI risk, lower hERG liability, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have poor Caco-2 and solubility values, the superior ADME properties of Ligand A, particularly its metabolic stability and safety profile, outweigh the small differences in permeability/solubility.

Output:
0
2025-04-17 14:00:01,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (397.232 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.63) is better than Ligand B (78.87), both are acceptable, but lower is generally preferred for absorption.

**logP:** Ligand A (3.003) is optimal, while Ligand B (1.631) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as it has fewer HBDs. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.633 and 0.618), indicating good drug-likeness.

**DILI:** Ligand B (5.7) has a significantly lower DILI risk than Ligand A (83.637), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (59.791 and 60.682), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.674), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.828 and -1.317), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.858) has a slightly higher hERG risk than Ligand B (0.518), but both are within acceptable limits.

**Microsomal Clearance:** Ligand B (48.748) has a much lower microsomal clearance than Ligand A (80.85), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (11.163) has a longer half-life than Ligand B (0.735), which is desirable.

**P-gp Efflux:** Ligand A (0.693) has lower P-gp efflux than Ligand B (0.045), which is preferable.

**Binding Affinity:** Ligand B (-8.1 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 better candidate despite its lower logP and solubility. The significantly improved metabolic stability (lower Cl_mic, longer t1/2), much lower DILI risk, and substantially stronger binding affinity (-8.1 vs -9.9 kcal/mol) outweigh the concerns about permeability and solubility. While both have poor permeability and solubility, the potency and safety profile of Ligand B are more favorable for further development as an SRC kinase inhibitor.

Output:
1
2025-04-17 14:00:01,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (351.403 and 351.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.66) is slightly higher than Ligand B (87.74). Both are acceptable, but Ligand B is preferable as it's closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.133) is quite low, potentially hindering permeation. Ligand B (-0.269) 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, 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 (0.647 and 0.539), indicating good drug-like properties.

**DILI:** Ligand A (54.827) has a lower DILI risk than Ligand B (71.19), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (71.268) has a higher BBB percentile than Ligand A (45.909), but this is less critical.

**Caco-2 Permeability:** Ligand A (-5.169) has significantly worse Caco-2 permeability than Ligand B (-4.652), suggesting poorer absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.589 and -1.626). This is a major concern for both.

**hERG:** Both ligands have low hERG inhibition liability (0.124 and 0.26), which is excellent.

**Microsomal Clearance:** Ligand A (-2.645) has a much lower (better) microsomal clearance than Ligand B (13.935), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (15.408 hours) has a longer half-life than Ligand B (-10.61 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.106).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This 0.5 kcal/mol difference is meaningful, and could outweigh some of the ADME drawbacks.

**Overall:**

Ligand A has a better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and longer half-life. However, it suffers from poor Caco-2 permeability and very low logP. Ligand B has better TPSA and Caco-2 permeability, but has a higher DILI risk, worse metabolic stability, and a shorter half-life.

Considering the priorities for an enzyme target, the improved potency (binding affinity) and metabolic stability of Ligand A are crucial. While the solubility and logP are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 14:00:01,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.428 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.02) is significantly better than Ligand B (70.39). TPSA < 140 is good for oral absorption, both are within this range, but lower is preferable.

**logP:** Ligand A (4.701) is slightly higher than the optimal range (1-3), while Ligand B (2.606) is within the optimal range. High logP can cause solubility issues, a potential concern for Ligand A.

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

**QED:** Both ligands have similar QED values (0.693 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (38.503). Ligand B is well below the 40% threshold, indicating low liver injury risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.427) has better BBB penetration than Ligand B (54.052).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.994 and -4.817), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.897 and -2.232), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Both ligands have similar hERG values (0.803 and 0.552), indicating a potential for hERG inhibition, but not excessively high.

**Microsomal Clearance:** Ligand A (59.417) has a higher microsomal clearance than Ligand B (38.356), suggesting lower metabolic stability. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand B (12.318 hours) has a longer in vitro half-life than Ligand A (22.849 hours). Longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have similar P-gp efflux values (0.553 and 0.314), indicating moderate efflux potential.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While both are strong binders, the difference is meaningful.

**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 metabolic stability (lower Cl_mic), a longer half-life, and slightly better binding affinity. Ligand A's higher logP and DILI risk are concerning. The slightly better binding affinity of Ligand B, coupled with the improved ADME properties, makes it the preferred choice.

Output:
1
2025-04-17 14:00:01,325 - INFO - Batch 260 complete. Total preferences: 4160
2025-04-17 14:00:01,325 - INFO - Processing batch 261/512...
2025-04-17 14:00:48,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.387 and 362.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.21) is slightly higher than Ligand B (60.85). Both are acceptable, but Ligand B's lower TPSA is preferable for permeability.

**logP:** Both ligands have good logP values (1.256 and 1.615), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.759 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 57.038, which is moderate. Ligand B has a much lower DILI risk of 19.193, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 85.459, while Ligand B has 77.433. While not a primary concern for a non-CNS target like SRC, the higher BBB value for A isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.924 and -4.592), which is unusual and indicates 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 (-1.127 and -1.64). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A has a very low hERG risk (0.093), which is excellent. Ligand B has a slightly higher, but still acceptable, hERG risk (0.667).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (47.319) than Ligand B (6.443), suggesting lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand A has a negative half-life (-12.539), which is not physically possible and indicates a problem with the data or the molecule's stability. Ligand B has a half-life of -3.107, also problematic, but less severe.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.043 and 0.102).

**Binding Affinity:** Ligand A has a binding affinity of -8.3 kcal/mol, which is excellent. Ligand B has a binding affinity of -7.1 kcal/mol, which is also good, but 1.2 kcal/mol weaker.

**Conclusion:**

Despite the poor solubility and permeability for both compounds, Ligand A's significantly stronger binding affinity (-8.3 vs -7.1 kcal/mol) is a major advantage. However, the negative and problematic half-life for Ligand A is a serious concern. Ligand B has a better DILI profile, significantly better metabolic stability (lower Cl_mic), and a less problematic (though still negative) half-life. The 1.2 kcal/mol difference in binding affinity can often be overcome with further optimization, while fixing the stability issues of Ligand A might be more challenging.

Output:
1
2025-04-17 14:00:48,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.423 and 365.817 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.23 and 93.46) are reasonably close to the 140 A^2 threshold for oral absorption, though not optimal.

**logP:** Both ligands (1.492 and 1.525) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable.

**QED:** Both have good QED scores (0.764 and 0.792), indicating drug-likeness.

**DILI:** Ligand A (71.19) has a slightly better DILI score than Ligand B (75.766), indicating a lower risk of liver injury, but both are acceptable.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (52.617) has a higher percentile than Ligand A (28.461).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.218 and -4.994), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.483 and -3.484), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both have low hERG inhibition risk (0.303 and 0.201), which is positive.

**Microsomal Clearance:** Ligand A (-0.565) has a lower (better) microsomal clearance than Ligand B (-1.508), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.129 hours) has a longer half-life than Ligand B (7.769 hours), which is preferable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.128 and 0.197).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having poor Caco-2 permeability and aqueous solubility, Ligand A is the better candidate. Its significantly stronger binding affinity (-8.1 vs -7.1 kcal/mol), lower microsomal clearance, and longer half-life outweigh the slightly higher DILI risk and lower BBB penetration. Improving solubility and permeability would be crucial for further development, but the potency advantage of Ligand A makes it the more promising starting point.

Output:
0
2025-04-17 14:00:48,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.547 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (110) is still within acceptable limits, but higher than A.

**logP:** Ligand A (4.138) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.819) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, unlikely to cause major issues.

**QED:** Both ligands have similar QED values (0.732 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A (22.722) has a much lower DILI risk than Ligand B (70.958), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.474) has a higher BBB percentile than Ligand B (27.646).

**Caco-2 Permeability:** Ligand A (-4.688) shows poor permeability, while Ligand B (-5.41) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.374) has slightly better solubility than Ligand B (-2.026), but both are quite poor.

**hERG Inhibition:** Ligand A (0.699) has a lower hERG risk than Ligand B (0.008), which is a significant advantage.

**Microsomal Clearance:** Ligand A (67.607) has a higher microsomal clearance than Ligand B (20.948), indicating lower metabolic stability. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (-30.843) has a significantly longer in vitro half-life than Ligand A (-12.669), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.503 and 0.023).

**Binding Affinity:** Both ligands have very similar binding affinities (-9.0 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is better overall. While Ligand A has a lower DILI and hERG risk, the significantly better metabolic stability (longer half-life, lower Cl_mic) of Ligand B is crucial for an enzyme target. The slightly better logP and Caco-2 permeability of Ligand B are also beneficial. The similar binding affinities mean that the ADME properties are the deciding factor.

Output:
1
2025-04-17 14:00:48,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.519 Da and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.43 and 75.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.622 and 3.146) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3 and 2) and HBA (3 and 3) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have QED scores (0.529 and 0.561) above 0.5, indicating good drug-likeness.

**DILI:** Ligand B (30.826) has a significantly lower DILI risk than Ligand A (13.92). This is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (71.772) has a higher BBB percentile than Ligand A (48.003).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.803) is slightly better than Ligand B (-4.988), but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.129) is slightly better than Ligand B (-3.625).

**hERG Inhibition:** Ligand A (0.515) has a lower hERG inhibition liability than Ligand B (0.771), which is favorable.

**Microsomal Clearance:** Ligand B (53.532) has a lower microsomal clearance than Ligand A (58.264), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (10.05) has a longer in vitro half-life than Ligand A (-8.173). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.403) has lower P-gp efflux liability than Ligand B (0.107).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). The 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 and solubility, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and substantially stronger binding affinity. The higher BBB value is a bonus. The slightly higher hERG and P-gp efflux are less concerning given the overall profile and the importance of potency and metabolic stability for kinase inhibitors.

Output:
1
2025-04-17 14:00:48,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.646 Da) is towards the higher end, while Ligand B (337.383 Da) is more optimal.

**TPSA:** Ligand A (113.41) is acceptable for oral absorption, though nearing the upper limit. Ligand B (76.19) is excellent, well below the 140 threshold.

**logP:** Both ligands have good logP values (A: 2.412, B: 2.735), 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 1 HBD and 5 HBA, also acceptable and potentially better for permeability.

**QED:** Both have reasonable QED scores, with Ligand B (0.75) being better than Ligand A (0.438).

**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 (75.339%).

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (64.948%) has a higher BBB value than Ligand A (40.791%), but this isn't a deciding factor.

**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 low hERG inhibition liability (A: 0.396, B: 0.356), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (2.602) than Ligand B (29.688), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A has a longer half-life (108.187 hours) than Ligand B (32.979 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.222, B: 0.029).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.8 kcal/mol, B: -9.1 kcal/mol). Ligand A is slightly better (-9.8 vs -9.1), but the difference is less than 1.5 kcal/mol and therefore doesn't outweigh other factors.

**Overall Assessment:**

Ligand A has better potency and metabolic stability, but its extremely high DILI risk is a major red flag. Ligand B has a much better safety profile (lower DILI), better TPSA and QED, and acceptable metabolic stability. While Ligand A's affinity is slightly better, the DILI risk associated with Ligand A makes it a less viable candidate.

Output:
1
2025-04-17 14:00:48,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, suggesting good absorption. Ligand B (85.77) is also below the threshold, but closer to it.

**logP:** Ligand A (2.759) is optimal (1-3). Ligand B (0.791) is a bit low, potentially hindering permeation.

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

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

**QED:** Both ligands have good QED scores (0.685 and 0.845), indicating drug-likeness.

**DILI:** Ligand A (17.255) has a significantly lower DILI risk than Ligand B (47.421). This is a major advantage.

**BBB:** Ligand A (75.921) has better BBB penetration than Ligand B (24.506), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.37) and Ligand B (-4.815) 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 (-2.798) and Ligand B (-1.073) both have negative solubility values, suggesting poor solubility. Again, the scale is unclear.

**hERG:** Ligand A (0.445) has a lower hERG risk than Ligand B (0.261), which is preferable.

**Microsomal Clearance:** Ligand A (76.671) has a higher microsomal clearance than Ligand B (-7.542). This indicates Ligand B is more metabolically stable, a key consideration for kinases.

**In vitro Half-Life:** Ligand A (3.863) has a longer half-life than Ligand B (1.351). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux than Ligand B (0.018), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.0 and -7.7 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

While both ligands exhibit good binding affinity, Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Ligand A has better BBB penetration and P-gp efflux. Given the enzyme-kinase specific priorities, metabolic stability is crucial. The lower DILI risk of Ligand B is also a significant advantage. Although both have poor solubility and permeability, the metabolic advantage of Ligand B outweighs the slight benefits of Ligand A.

Output:
1
2025-04-17 14:00:48,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.331 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.51) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (83.22) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.396 and 2.562), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, both within acceptable limits. Ligand B has 3 HBD and 4 HBA, also within limits.

**QED:** Both ligands have good QED scores (0.568 and 0.73), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 94.649, which is *very high* and a significant concern. Ligand B has a much lower DILI risk of 46.297, which is still not ideal, but significantly better.

**BBB:** Both have moderate BBB penetration (57.852 and 54.556), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.687) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.104) also has poor Caco-2 permeability, but is slightly better than A.

**Aqueous Solubility:** Ligand A (-3.667) has poor aqueous solubility. Ligand B (-2.407) has better aqueous solubility than A, but still not great.

**hERG Inhibition:** Ligand A (0.181) has a very low hERG inhibition risk, which is excellent. Ligand B (0.617) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (44.741) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (22.973) has *much* lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-31.758) has a very short in vitro half-life, a significant drawback. Ligand B (13.555) has a better, though still not ideal, half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.042 and 0.061), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-10 and -8 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its *extremely high* DILI risk, poor Caco-2 permeability, and short half-life are major liabilities. Ligand B, while having slightly weaker affinity, presents a much more favorable ADME-Tox profile, with significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The difference in binding affinity (2 kcal/mol) is likely surmountable with further optimization, whereas mitigating the severe liabilities of Ligand A would be much more challenging.

Output:
1
2025-04-17 14:00:48,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 358.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.7) is better than Ligand B (113.96). Both are under 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (1.663) is within the optimal 1-3 range. Ligand B (-0.16) is below 1, which might hinder permeation.

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

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Both are under 10.

**QED:** Both ligands have reasonable QED scores (0.624 and 0.494), indicating drug-likeness, but A is better.

**DILI:** Ligand A (32.61) has a significantly lower DILI risk than Ligand B (25.708), placing it in the good category.

**BBB:** Ligand A (68.748) has better BBB penetration than Ligand B (53.121), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.244) has worse Caco-2 permeability than Ligand B (-4.942).

**Aqueous Solubility:** Ligand A (-2.545) has worse aqueous solubility than Ligand B (-1.564).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.421 and 0.118).

**Microsomal Clearance:** Ligand A (-12.785) has significantly lower microsomal clearance than Ligand B (54.352), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-5.276) has a worse in vitro half-life than Ligand B (-50.805).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.041).

**Binding Affinity:** Both ligands have strong binding affinities (-9.6 and -8 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, logP, QED, significantly lower DILI risk, and, crucially, much better metabolic stability (lower Cl_mic). While Ligand B has better Caco-2 permeability, solubility and half-life, the metabolic stability advantage of Ligand A is more important for an enzyme target like SRC. The slightly better binding affinity of Ligand A further solidifies its position.

Output:
1
2025-04-17 14:00:48,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.407 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.78) is slightly above the optimal <140, but acceptable. Ligand B (110.01) is well within the range.

**logP:** Both ligands have a logP around 1.6, which is optimal.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**QED:** Ligand A (0.22) is quite low, indicating poor drug-likeness. Ligand B (0.704) is excellent, indicating strong drug-like properties.

**DILI:** Ligand A (47.693) has a moderate DILI risk, while Ligand B (68.166) has a higher DILI risk.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**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 very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Ligand A (0.088) has a very low hERG risk, which is excellent. Ligand B (0.241) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (26.735) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (31.213).

**In vitro Half-Life:** Ligand A (-3.355) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (6.758) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**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 outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.8 vs -6.6 kcal/mol) is a major advantage for an enzyme inhibitor. While Ligand B has a higher DILI risk, the better QED score and more reasonable half-life make it preferable. The negative half-life for Ligand A is a red flag. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the potency advantage of Ligand B is compelling.

Output:
1
2025-04-17 14:00:48,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.36 & 360.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.8) is significantly better than Ligand B (86.88). A TPSA under 90 is preferred, and A is closer to the optimal range for good absorption.

**3. logP:** Both ligands have acceptable logP values (2.553 & 3.181), falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands are acceptable (2 & 3).

**5. H-Bond Acceptors:** Both ligands are acceptable (3 & 4).

**6. QED:** Ligand A (0.87) has a much better QED score than Ligand B (0.6), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.285) has a significantly lower DILI risk than Ligand B (53.625). Both are below the 60 threshold, but A is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.843) is better than Ligand B (32.726).

**9. Caco-2 Permeability:** Ligand A (-4.491) is better than Ligand B (-5.738), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.646) is better than Ligand B (-2.396), though both are quite poor. Solubility is a concern for both.

**11. hERG Inhibition:** Ligand A (0.734) has a lower hERG risk than Ligand B (0.593), which is crucial for avoiding cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-7.629) has a *much* better (lower) microsomal clearance than Ligand B (25.614), indicating significantly improved metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (13.538) has a better half-life than Ligand B (-8.444).

**14. P-gp Efflux:** Ligand A (0.124) has a lower P-gp efflux liability than Ligand B (0.186).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.3 & -7.9 kcal/mol). Ligand A is 1.4 kcal/mol better, which is a substantial advantage and can outweigh some of the other drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B across most critical parameters. While both have good binding affinity, Ligand A excels in predicted metabolic stability (Cl_mic), DILI risk, QED, TPSA, and hERG inhibition. The improved metabolic stability is particularly important for a kinase inhibitor, as it suggests a longer duration of action and potentially lower dosing requirements. The better solubility and permeability profiles of Ligand A also contribute to its higher potential.

Output:
1
2025-04-17 14:00:48,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.443 and 379.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (59.39 and 63.25) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.18 and 3.964) 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 (1 HBD, 4 HBA) and Ligand B (2 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.877) has a significantly higher QED score than Ligand B (0.636), indicating better overall drug-likeness.

**DILI:** Ligand A (36.293) has a much lower DILI risk than Ligand B (88.329). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration percentiles (72.237 and 70.027). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.735 and -4.812), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.821 and -4.136), indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.881 and 0.864), which is good.

**Microsomal Clearance:** Ligand B (98.502) has a higher microsomal clearance than Ligand A (76.184), suggesting Ligand B will be metabolized more quickly and have lower metabolic stability.

**In vitro Half-Life:** Ligand B (54.026 hours) has a significantly longer in vitro half-life than Ligand A (8.195 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.526 and 0.849).

**Binding Affinity:** Both ligands have excellent binding affinity (-10.0 and -9.7 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a much better safety profile (lower DILI) and better drug-likeness (higher QED). However, Ligand B has a significantly longer half-life. Both have poor solubility and permeability. Given the enzyme-specific priorities, metabolic stability is important, but the DILI risk of Ligand B is concerning. The longer half-life of Ligand B *could* be improved through prodrug strategies, but the DILI risk is harder to address. The superior overall profile of Ligand A, particularly the much lower DILI risk, makes it the more promising candidate.

Output:
0
2025-04-17 14:00:48,502 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, following the provided guidelines.

**Ligand A:** [385.819, 55.4, 4.854, 1, 4, 0.748, 84.064, 77.472, -4.538, -6.128, 0.37, 85.406, 20.323, 0.18, -10.1]
**Ligand B:** [386.905, 74.77, 1.236, 1, 6, 0.796, 51.881, 43.699, -5.011, -2.391, 0.367, -4.425, 33.411, 0.126, -7.7]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da).  A: 385.819, B: 386.905 - Similar.
2. **TPSA:** A (55.4) is better than B (74.77).  A is well below the 140 threshold for oral absorption. B is still acceptable, but less optimal.
3. **logP:** A (4.854) is higher than B (1.236). A is approaching the upper limit where solubility issues might arise, while B is quite low and may have permeability issues.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A (4) is better than B (6). Lower HBA generally favors permeability.
6. **QED:** Both are good (A: 0.748, B: 0.796), indicating drug-like properties. B is slightly better.
7. **DILI:** A (84.064) is significantly higher than B (51.881). This is a major concern for ligand A. B is within an acceptable range.
8. **BBB:** A (77.472) is better than B (43.699), but BBB is less critical for a non-CNS target like SRC.
9. **Caco-2:** A (-4.538) is worse than B (-5.011). Lower values indicate poorer permeability.
10. **Solubility:** A (-6.128) is worse than B (-2.391). Solubility is a concern for A.
11. **hERG:** Both are low (A: 0.37, B: 0.367), indicating low cardiotoxicity risk. Similar.
12. **Cl_mic:** A (85.406) is much higher than B (-4.425). This means A has significantly faster metabolic clearance and lower metabolic stability, a major drawback.
13. **t1/2:** A (20.323) is lower than B (33.411). B has a better in vitro half-life.
14. **Pgp:** Both are low (A: 0.18, B: 0.126), indicating minimal P-gp efflux. B is slightly better.
15. **Binding Affinity:** A (-10.1) is *significantly* better than B (-7.7). This is a 2.4 kcal/mol difference, which is substantial.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While A has a much better binding affinity, it is severely hampered by its high DILI risk, poor solubility, and high microsomal clearance. B, while having a weaker affinity, has a much better safety profile (DILI), better metabolic stability, and better solubility.

**Conclusion:**

Despite the significantly stronger binding affinity of Ligand A, its poor ADME properties (especially DILI and metabolic stability) make it a less viable drug candidate. Ligand B, with its better safety profile and metabolic stability, is the more promising starting point for further optimization, even though its initial affinity is lower. The affinity gap can be addressed through medicinal chemistry efforts, while fixing the ADME liabilities of Ligand A would be far more challenging.

Output:
1
2025-04-17 14:00:48,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.419 and 347.434 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.05) is higher than Ligand B (62.3). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have logP values within the optimal range (1.856 and 2.936). Ligand B is slightly higher, potentially improving membrane permeability.

**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 (0.759 and 0.805), indicating good drug-like properties.

**DILI:** Ligand A (48.468) has a slightly higher DILI risk than Ligand B (35.091), but both are below the concerning threshold of 60.

**BBB:** Ligand A (55.254) has a lower BBB penetration percentile than Ligand B (84.374). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.264) has worse Caco-2 permeability than Ligand B (-4.528). Both are negative, which is unusual and requires further investigation, but B is better.

**Aqueous Solubility:** Ligand A (-2.934) has worse aqueous solubility than Ligand B (-2.541). Both are negative, which is concerning.

**hERG:** Ligand A (0.505) has a slightly higher hERG risk than Ligand B (0.638). Lower is better, so B is preferable.

**Microsomal Clearance:** Ligand A (19.577) has lower microsomal clearance than Ligand B (28.884), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (29.215) has a longer in vitro half-life than Ligand B (-6.226). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux than Ligand B (0.194), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, better TPSA, better BBB, better Caco-2 permeability, better hERG, and a lower DILI risk. While Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, the substantial difference in binding affinity of Ligand B is the most critical factor for an enzyme inhibitor. The improved ADME properties of Ligand B further support its selection.



Output:
1
2025-04-17 14:00:48,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.422 and 383.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good absorption. Ligand B (105.98) is also acceptable, but higher.

**logP:** Both ligands (1.039 and 1.146) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (7) are both below the threshold of 10.

**QED:** Both ligands have similar QED values (0.694 and 0.665), indicating good drug-likeness.

**DILI:** Ligand A (30.903) has a significantly lower DILI risk than Ligand B (67.39), placing it in the preferable <40 percentile. Ligand B is approaching the higher risk threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.129) is higher than Ligand B (37.65).

**Caco-2 Permeability:** Ligand A (-4.547) and Ligand B (-5.641) are both negative, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.64) is better than Ligand B (-2.304), though both are still relatively poor.

**hERG Inhibition:** Ligand A (0.283) has a much lower hERG risk than Ligand B (0.195), which is a significant advantage.

**Microsomal Clearance:** Ligand A (16.693) has lower microsomal clearance than Ligand B (24.019), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.384) has a longer in vitro half-life than Ligand B (-3), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux than Ligand B (0.238), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.3), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The solubility and Caco-2 permeability are poor for both, but the other advantages of Ligand A outweigh the small affinity difference.

Output:
0
2025-04-17 14:00:48,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 354.466 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.55) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (58.64) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.719) is a bit low, potentially hindering permeation. Ligand B (2.294) 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 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand B (0.843) has a significantly better QED score than Ligand A (0.41), indicating a more drug-like profile.

**DILI:** Ligand A (51.028) has a slightly higher DILI risk than Ligand B (34.277), though both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.135) has a higher BBB value than Ligand A (42.924).

**Caco-2 Permeability:** Ligand A (-5.181) has a very poor Caco-2 permeability score, indicating poor absorption. Ligand B (-4.401) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.371) and Ligand B (-3.707) both have poor solubility, which is a concern.

**hERG Inhibition:** Ligand A (0.269) shows a lower hERG risk than Ligand B (0.477), which is favorable.

**Microsomal Clearance:** Ligand A (-22.881) has a much lower (better) microsomal clearance than Ligand B (61.379), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.838) has a better in vitro half-life than Ligand B (-15.128).

**P-gp Efflux:** Ligand A (0.042) has a lower P-gp efflux liability than Ligand B (0.206), which is better.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), though both are good. The 0.8 kcal/mol difference is not huge, but is a factor.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand B is the better candidate despite its slightly higher hERG risk. The significantly better QED, metabolic stability (lower Cl_mic, better t1/2), and slightly better binding affinity outweigh the slightly higher hERG and DILI risks. Ligand A's very poor Caco-2 permeability and lower QED are significant drawbacks. While solubility is a concern for both, it can be addressed with formulation strategies.

Output:
1
2025-04-17 14:00:48,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.515 and 344.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.33) is better than Ligand B (86.34), both are below the 140 threshold for oral absorption, but A is closer to the <90 threshold for CNS penetration (though that's not a priority here).

**logP:** Both ligands have good logP values (1.633 and 2.075), 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=8) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.735 and 0.789), indicating good drug-like properties.

**DILI:** Ligand A (22.722) has a significantly lower DILI risk than Ligand B (54.401). This is a major advantage.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand B (63.862) has a higher value than Ligand A (41.644).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.56 and -5.702). This is unusual and suggests poor permeability. However, these values are on a log scale, so the difference isn't huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.799 and -2.326), indicating poor aqueous solubility. Ligand A is slightly better.

**hERG Inhibition:** Ligand A (0.207) has a much lower hERG inhibition liability than Ligand B (0.098), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-17.009) has a much lower (better) microsomal clearance than Ligand B (7.816). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (8.126) has a slightly longer in vitro half-life than Ligand A (6.069).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.096).

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.8). While the difference is small, it's still a positive.

**Overall:**

Ligand A is significantly better due to its lower DILI risk, lower hERG inhibition, and better metabolic stability (lower Cl_mic). The slightly better binding affinity and TPSA are also beneficial. While both have poor solubility and Caco-2 permeability, the safety and metabolic stability advantages of Ligand A outweigh these drawbacks, especially for an enzyme target where potency can be optimized further.

Output:
1
2025-04-17 14:00:48,503 - INFO - Batch 261 complete. Total preferences: 4176
2025-04-17 14:00:48,503 - INFO - Processing batch 262/512...
2025-04-17 14:01:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.462 and 343.343 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (124.75). A TPSA under 90 is not crucial for a non-CNS target like SRC, but lower TPSA generally correlates with better permeability.

**logP:** Ligand A (3.226) is optimal, while Ligand B (1.37) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=8). Ligand B has a higher number of HBA, which could impact permeability.

**QED:** Both ligands have similar QED scores (0.734 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (11.09) has a much lower DILI risk than Ligand B (83.637), a significant advantage.

**BBB:** This isn't a primary concern for SRC, but Ligand A (93.331) shows better potential for BBB penetration than Ligand B (57.619).

**Caco-2 Permeability:** Ligand A (-4.649) is better than Ligand B (-4.973), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar poor solubility (-3.278 and -3.433). This is a potential issue for both, requiring formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.911 and 0.48).

**Microsomal Clearance:** Ligand A (34.626) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (48.039).

**In vitro Half-Life:** Ligand A (5.014 hours) has a significantly longer half-life than Ligand B (-18.357 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.426 and 0.159).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.3 kcal/mol), with Ligand B being slightly better. However, the difference of 0.3 kcal/mol is unlikely to overcome the substantial ADME deficiencies of Ligand B.

**Conclusion:**

Ligand A is the superior candidate. While both ligands exhibit strong binding affinity, Ligand A demonstrates significantly better ADME properties, including lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), better permeability (lower TPSA, better Caco-2), and a more optimal logP. The slightly better affinity of Ligand B is overshadowed by its poorer ADME profile.

Output:
1
2025-04-17 14:01:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 344.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (59.07), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.557 and 3.496), 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:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Ligand B (0.805) has a significantly better QED score than Ligand A (0.492), indicating a more drug-like profile.

**DILI:** Ligand A (17.875) has a much lower DILI risk than Ligand B (57.348). This is a significant advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (70.609 and 73.943), but this is less critical for a non-CNS target like SRC.

**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 (0.398 and 0.9), which is favorable.

**Microsomal Clearance:** Ligand B (61.186) has a higher microsomal clearance than Ligand A (83.401), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-20.593) has a longer in vitro half-life than Ligand B (32.646), which is a substantial advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.153 and 0.397).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). This 0.6 kcal/mol difference is notable, but not overwhelmingly large.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, better metabolic stability, longer half-life) and comparable binding affinity. While Ligand B has a slightly better QED and binding affinity, the higher DILI risk and poorer metabolic stability are major concerns. Given the enzyme-kinase target class, metabolic stability and safety are paramount.

Output:
0
2025-04-17 14:01:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight:** Both ligands (349.475 and 343.387 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (99).  A TPSA under 140 is good for oral absorption, and Ligand A is well within that, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (0.718 and 1.851), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to minor solubility issues, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the desired 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 Ligand A is preferable.

**6. QED:** Both ligands have similar and good QED values (0.656 and 0.674), indicating good drug-likeness.

**7. DILI:** Ligand B (83.792) has a considerably higher DILI risk than Ligand A (5.118). This is a significant concern.

**8. BBB:** Ligand A (77.937) shows better BBB penetration potential than Ligand B (67.701), although this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.927 and -4.912). This indicates poor intestinal absorption for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.114 and -3.018). This is a concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.608) has a lower hERG inhibition risk than Ligand B (0.034), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (17.265) has significantly lower microsomal clearance than Ligand B (42.609), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.288) has a longer in vitro half-life than Ligand B (2.554), which is desirable.

**14. P-gp Efflux:** Ligand A (0.029) shows lower P-gp efflux than Ligand B (0.193), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-9.3). However, the difference is only 1.1 kcal/mol, and is likely outweighed by the other factors.

**Enzyme-Kinase Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. While Ligand B has slightly better affinity, Ligand A excels in metabolic stability, hERG risk, DILI risk, and P-gp efflux. The poor solubility and Caco-2 permeability are concerns for both, but the superior safety and pharmacokinetic profile of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 14:01:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (356.463 and 350.459 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (77.1 and 75.8) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.452) is optimal, while Ligand B (2.543) is also within the acceptable range (1-3), but closer to the upper limit.

**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 good QED scores (0.633 and 0.741), indicating drug-like properties.

**7. DILI:** Ligand A (19.504) has a significantly lower DILI risk than Ligand B (23.885), which is a substantial advantage.

**8. BBB:** Both have good BBB penetration (71.811 and 73.827), although this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.667 and -4.855). These are unusual and suggest poor permeability. However, these values are on a log scale and may not be directly comparable without knowing the units.

**10. Aqueous Solubility:** Both have negative solubility values (-1.642 and -2.151). Similar to Caco-2, these values are unusual and suggest poor solubility.

**11. hERG Inhibition:** Both have very low hERG risk (0.216 and 0.375).

**12. Microsomal Clearance:** Ligand A (9.416) has significantly lower microsomal clearance than Ligand B (73.792), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-7.106) has a much longer in vitro half-life than Ligand B (-6.442), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.024 and 0.388).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.3 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh the other significant advantages of Ligand A.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have good potency, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and comparable permeability and solubility. These factors are particularly important for an enzyme target like SRC kinase.

Output:
0
2025-04-17 14:01:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (360.483 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is slightly higher than Ligand B (59.08). Both are below the 140 threshold for good oral absorption, but neither are optimized for CNS penetration (below 90).

**3. logP:** Both ligands have good logP values (1.745 and 1.923), 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 below the 10 threshold.

**6. QED:** Ligand A (0.821) has a better QED score than Ligand B (0.701), indicating a more drug-like profile.

**7. DILI:** Ligand B (28.616) has a significantly lower DILI risk than Ligand A (49.011). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (77.239) has a higher BBB percentile than Ligand A (56.611), but this is less critical for a non-CNS target like SRC.

**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 aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.211) has a slightly lower hERG inhibition liability than Ligand B (0.422), which is favorable.

**12. Microsomal Clearance:** Ligand A (52.619) has lower microsomal clearance than Ligand B (54.615), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.605) has a significantly longer in vitro half-life than Ligand A (-4.095). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux liability than Ligand B (0.169), which is favorable.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-6.7 kcal/mol). The 1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand B's superior binding affinity (-7.7 vs -6.7 kcal/mol), significantly lower DILI risk (28.6 vs 49.0), and longer half-life (-10.6 vs -4.1) outweigh the slightly higher P-gp efflux and hERG risk. The stronger binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:01:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.383 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.85) is slightly above the optimal <140 for good absorption, while Ligand B (119.23) is well within this range.

**logP:** Ligand A (0.305) is quite low, potentially hindering permeability. Ligand B (1.615) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 9 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 scores (0.793 and 0.673), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (79.837 and 64.327), below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (60.527 and 62.97), which isn't a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.031 and -5.36), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-1.989 and -2.46), also unusual and indicating very poor solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.007 and 0.135), which is excellent.

**Microsomal Clearance:** Ligand A (31.639) has a higher microsomal clearance than Ligand B (14.713), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (1.812) has a longer in vitro half-life than Ligand A (0.631), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.024).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol), although the difference is small.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. It has a better logP, slightly better solubility (though still poor), a significantly lower microsomal clearance (better metabolic stability), and a longer half-life. The biggest concern for both is the poor Caco-2 permeability and solubility. However, given the enzyme-specific priorities, metabolic stability is crucial. Ligand B's superior metabolic stability and slightly better logP outweigh the minimal difference in binding affinity.

Output:
1
2025-04-17 14:01:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.411 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.04) is slightly higher than Ligand B (61.44), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.527) is slightly higher than Ligand B (2.186), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2), keeping within the desirable limit of <=5.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3), keeping within the desirable limit of <=10.

**QED:** Both ligands have similar and good QED values (0.793 and 0.798, respectively), indicating good drug-like properties.

**DILI:** Ligand B (21.869) has a significantly lower DILI risk than Ligand A (74.409). This is a major advantage for Ligand B.

**BBB:** Ligand B (62.233) has a higher BBB penetration score than Ligand A (52.385), but BBB is not a high priority for a kinase inhibitor unless CNS activity is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.564 and -4.825), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand B (-2.31) is better than Ligand A (-4.494), indicating better solubility. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand B (0.49) has a lower hERG inhibition liability than Ligand A (0.848), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (17.456) has a much lower microsomal clearance than Ligand A (80.36), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (7.995) has a longer in vitro half-life than Ligand A (22.613), which is a positive attribute.

**P-gp Efflux:** Ligand B (0.089) has lower P-gp efflux liability than Ligand A (0.61), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage, and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates superior ADMET properties (lower DILI, better solubility, lower hERG, lower clearance, longer half-life, lower P-gp efflux). However, Ligand A has a *much* stronger binding affinity. The difference in affinity is very large (8.9 vs 0.0 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. While the ADMET profile of Ligand B is preferable, the significantly weaker binding of Ligand B makes it less likely to be a viable drug candidate. The strong binding of Ligand A suggests it could be effective at lower doses, potentially mitigating some of the ADMET concerns.

Output:
0
2025-04-17 14:01:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.431 and 355.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.42) is slightly above the preferred <140 for good absorption, while Ligand B (91.32) is well within the range.

**logP:** Ligand A (0.023) is quite low, potentially hindering permeation. Ligand B (2.056) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and are within the acceptable limits. Ligand A has 5 HBA, while Ligand B has 4, both acceptable.

**QED:** Both ligands have similar QED values (0.689 and 0.698), indicating good drug-likeness.

**DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (45.25). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.554) has a higher BBB percentile than Ligand A (52.85).

**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, making interpretation difficult.

**hERG:** Ligand A (0.139) has a slightly lower hERG inhibition liability than Ligand B (0.306), which is preferable.

**Microsomal Clearance:** Ligand A (-5.935) has significantly lower (better) microsomal clearance than Ligand B (14.553), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-49.152) has a much longer in vitro half-life than Ligand B (-13.84), which is a major advantage.

**P-gp Efflux:** Ligand A (0.004) has much lower P-gp efflux liability than Ligand B (0.038), suggesting better bioavailability.

**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 concerns.

**Conclusion:**

Despite Ligand A's low logP and slightly higher TPSA, its significantly superior binding affinity (-8.4 vs -7.3 kcal/mol), much better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux outweigh the drawbacks. The lower DILI risk of Ligand B is a consideration, but the potency advantage of Ligand A is crucial for an enzyme target like SRC kinase. The negative solubility and Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 14:01:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.5 and 341.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.53 and 68.39) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.317) is within the optimal 1-3 range. Ligand B (3.673) is slightly higher, potentially increasing off-target effects but still acceptable.

**H-Bond Donors:** Both have 1 HBD, well within the limit of 5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4, both below the limit of 10.

**QED:** Both ligands have good QED scores (0.805 and 0.865), indicating drug-likeness.

**DILI:** Ligand A (35.13) has a significantly lower DILI risk than Ligand B (57.154). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration (70.531 and 76.386), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.844 and -4.393), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.017 and -4.567), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.408 and 0.625), which is good.

**Microsomal Clearance:** Ligand A (24.811) has significantly lower microsomal clearance than Ligand B (80.62). This suggests better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (5.645) has a slightly longer half-life than Ligand B (0.289), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.118 and 0.383), which is favorable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference isn't huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is the better candidate. It has a lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both compounds suffer from poor predicted solubility and permeability, the ADME advantages of Ligand A outweigh the slightly better logP of Ligand B. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but starting with a compound with better inherent metabolic stability and safety is preferable.

Output:
0
2025-04-17 14:01:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.419 Da and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.81) is better than Ligand B (58.2). While both are acceptable, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (-0.183) is a bit low, potentially hindering permeability. Ligand B (3.592) is excellent, falling right in the optimal range of 1-3. This is a significant advantage for Ligand B.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.509 and 0.521), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (36.758 and 37.728), and are both below the 40 threshold, indicating low risk.

**BBB:** Ligand A (36.603) and Ligand B (60.915). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.013) and Ligand B (-4.865). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.721) and Ligand B (-4.874). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.058) and Ligand B (0.253). Both are very low, indicating minimal risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (32.488) is significantly better than Ligand B (81.91). Lower clearance indicates better metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-3.357) is better than Ligand B (3.682). A negative value suggests a longer half-life.

**P-gp Efflux:** Ligand A (0.018) is much better than Ligand B (0.452). Lower P-gp efflux is preferable for better bioavailability.

**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 has a significantly better logP, which is crucial for permeability and absorption. It also has a slightly better binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic), better half-life, and lower P-gp efflux. The difference in binding affinity is small, and the improved ADME properties of Ligand A are very important for an enzyme inhibitor.

Output:
0
2025-04-17 14:01:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.435 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.33) is slightly higher than Ligand B (107.97), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.987) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (-0.593) is closer to the optimal 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 similar QED values (0.501 and 0.485), indicating reasonable drug-likeness.

**DILI:** Ligand A (14.114) has a significantly lower DILI risk than Ligand B (17.216), which is a major advantage.

**BBB:** Ligand A (19.581) has a much lower BBB penetration than Ligand B (45.87). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-5.254 and -5.249). This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-0.738 and -1.033). This is a significant drawback.

**hERG:** Both ligands have similar, very low hERG inhibition risk (0.14 and 0.143), which is good.

**Microsomal Clearance:** Ligand A (-20.099) has a much lower (better) microsomal clearance than Ligand B (18.072), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (19.178) has a longer in vitro half-life than Ligand A (-15.166), which is favorable.

**P-gp Efflux:** Both ligands have similar, very low P-gp efflux liability (0.012 and 0.014).

**Binding Affinity:** Ligand B (-7.1 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.

**Conclusion:**

While Ligand A has better DILI and metabolic stability, the significantly stronger binding affinity of Ligand B (-7.1 vs -9.5 kcal/mol) is a critical factor for an enzyme inhibitor. The difference of 2.4 kcal/mol is substantial. Although both have poor solubility and permeability, the potency advantage of Ligand B is likely to be more impactful in driving forward development, and formulation strategies can be explored to address the solubility/permeability issues.

Output:
1
2025-04-17 14:01:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.459 Da and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.32) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (66.65) is excellent, well below 140.

**logP:** Ligand A (0.286) is quite low, potentially hindering permeability. Ligand B (2.73) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.605 and 0.84), indicating drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (43.622 and 45.444, both <60).

**BBB:** Ligand A (55.448) has a lower BBB penetration percentile than Ligand B (88.329). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.893) shows poor permeability. Ligand B (-4.772) is better, but still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.752 and -2.725). This is a significant concern for both.

**hERG:** Ligand A (0.029) has a very low hERG risk, which is excellent. Ligand B (0.501) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (21.061) has a lower microsomal clearance than Ligand B (71.678), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (17.764) has a longer half-life than Ligand B (1.224), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, indicating good bioavailability. Ligand B (0.593) is higher, which could reduce bioavailability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and hERG risk, its poor logP and Caco-2 permeability are major drawbacks. Ligand B's significantly higher binding affinity (-9.0 vs -7.2 kcal/mol) is a compelling advantage for an enzyme inhibitor, and its logP is within the optimal range. The solubility is a concern for both, but the potency advantage of Ligand B outweighs the other issues, especially considering that solubility can be addressed with formulation strategies.

Output:
1
2025-04-17 14:01:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.336 Da) is slightly higher than Ligand B (370.797 Da), but both are acceptable.

**TPSA:** Ligand A (75.19) is significantly better than Ligand B (137.3). A TPSA under 140 is good for oral absorption, and A is comfortably within that range while B is approaching the upper limit.

**logP:** Ligand A (2.625) is optimal, while Ligand B (0.097) is quite low. Low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=3, HBA=8). Lower counts generally improve permeability.

**QED:** Ligand A (0.771) has a better QED score than Ligand B (0.532), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (A: 72.005, B: 63.009), below the concerning threshold of 60.

**BBB:** Both have reasonable BBB penetration, but Ligand B (74.952) is slightly better than Ligand A (68.127). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability & Solubility:** Both have negative Caco-2 values (-5.1 and -5.849) and negative solubility values (-3.092 and -2.738). These scales are not intuitive, but lower values generally indicate poorer permeability and solubility.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.151, B: 0.344), which is excellent.

**Microsomal Clearance & Half-Life:** Ligand A (Cl_mic=63.88, t1/2=17.734) shows better metabolic stability (lower clearance) and a longer half-life than Ligand B (Cl_mic=19.168, t1/2=22.994). While B has a longer half-life, the significantly lower clearance is a major advantage for A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.201, B: 0.096).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.4 kcal/mol, B: -8.1 kcal/mol). The difference is 0.3 kcal/mol, which isn't substantial enough to override other significant ADME differences.

**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, logP, QED, and importantly, *microsomal clearance*. The lower clearance of Ligand A suggests better metabolic stability, a critical factor for kinase inhibitors. The slightly better binding affinity of A is a bonus. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of A outweigh this.

Output:
1
2025-04-17 14:01:27,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.378 and 363.849 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is slightly higher than Ligand B (85.09), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.449) is a bit low, potentially hindering permeation. Ligand B (1.594) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 2 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 high QED scores (0.824 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A (56.689) has a slightly higher DILI risk than Ligand B (53.083), but both are reasonably low.

**BBB:** Ligand A (77.588) shows better BBB penetration than Ligand B (62.699), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.999) has significantly worse Caco-2 permeability than Ligand B (-5.512). Both are negative, indicating poor permeability, but Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-2.486) has slightly better aqueous solubility than Ligand B (-2.254).

**hERG:** Both ligands have very low hERG inhibition risk (0.158 and 0.129).

**Microsomal Clearance:** Ligand A (-28.588) exhibits significantly lower microsomal clearance than Ligand B (9.108), suggesting much better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (6.328 hours) has a shorter half-life than Ligand B (14.638 hours). This further supports the better metabolic stability of Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.294).

**Binding Affinity:** Both ligands have excellent binding affinity (-10.2 and -9.3 kcal/mol). Ligand A is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and solubility, but its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability are key advantages for an enzyme inhibitor. Ligand B has a better logP, but the difference isn't substantial enough to outweigh the metabolic benefits of Ligand A. The DILI risk is similar for both.

Output:
0
2025-04-17 14:01:27,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (375.491 and 358.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.8) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (87.66) is excellent, well below 140.

**logP:** Ligand A (-0.575) is a bit low, potentially hindering permeation. Ligand B (1.027) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.637 and 0.574), indicating good drug-like properties.

**DILI:** Ligand A (33.307) has a low DILI risk. Ligand B (12.214) has an even lower DILI risk, which is highly favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (72.819) has a higher BBB percentile than Ligand A (34.781), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.634) has poor Caco-2 permeability. Ligand B (-4.83) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-0.746) has poor solubility. Ligand B (-3.064) has even worse solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.092) has a very low hERG risk, which is excellent. Ligand B (0.318) also has a low hERG risk, but slightly higher than Ligand A.

**Microsomal Clearance:** Ligand A (-16.932) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (47.415) has a significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (29.343) has a reasonable half-life. Ligand B (-16.102) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.015).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent and a key factor.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is the better candidate. Ligand B has poor solubility and a significantly higher microsomal clearance leading to a very short half-life. Although Ligand B has slightly better TPSA and DILI, the metabolic instability and poor half-life are major concerns for *in vivo* efficacy. Ligand A, despite its slightly lower logP and Caco-2 permeability, has superior metabolic stability and a reasonable half-life, making it more likely to be a viable drug candidate.

Output:
0
2025-04-17 14:01:27,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.515 and 377.868 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.06) is better than Ligand B (46.17), being below 140, but both are acceptable.

**logP:** Ligand A (2.46) is optimal (1-3). Ligand B (4.846) is slightly high, potentially leading to solubility issues and off-target effects.

**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 2. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.886) has a significantly better QED score than Ligand B (0.706), indicating a more drug-like profile.

**DILI:** Ligand A (60.45) is borderline, but acceptable. Ligand B (87.01) is significantly higher, indicating a higher risk of drug-induced liver injury.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (72.78) is better than Ligand B (46.491).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.781 and -4.674), which is unusual and suggests poor permeability. However, negative values aren't directly comparable and require further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.025 and -5.536), indicating poor aqueous solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.319) has a lower hERG risk than Ligand B (0.676), which is a significant advantage.

**Microsomal Clearance:** Ligand A (27.197 mL/min/kg) has lower clearance and therefore better metabolic stability than Ligand B (42.301 mL/min/kg).

**In vitro Half-Life:** Ligand A (39.196 hours) has a better in vitro half-life than Ligand B (70.75 hours).

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux liability than Ligand B (0.295), which is favorable.

**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 is superior to Ligand B. While both have good binding affinity, Ligand A demonstrates a significantly better drug-like profile (higher QED), lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. The slightly better solubility and BBB penetration further support choosing Ligand A. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh these drawbacks.

Output:
0
2025-04-17 14:01:27,276 - INFO - Batch 262 complete. Total preferences: 4192
2025-04-17 14:01:27,276 - INFO - Processing batch 263/512...
2025-04-17 14:02:10,665 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (74.59 and 73.74) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.295) is optimal, while Ligand B (0.768) 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 (0.801 and 0.854), indicating drug-likeness.

**DILI:** Ligand A (58.589) has a moderate DILI risk, while Ligand B (26.599) has a low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Both have high BBB penetration (82.164 and 84.257), which isn't crucial for a non-CNS target like SRC, but isn't detrimental.

**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 caution and consider other factors.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data.

**hERG Inhibition:** Ligand A (0.703) has a slightly higher hERG risk than Ligand B (0.445), although both are relatively low.

**Microsomal Clearance:** Ligand A (26.325 mL/min/kg) has a moderate clearance, while Ligand B (-22.476 mL/min/kg) has a *negative* clearance, which is impossible. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (27.568 hours) has a good half-life, while Ligand B (8.328 hours) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.204) has low P-gp efflux, while Ligand B (0.054) has very low P-gp efflux.

**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.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the most critical factor is the binding affinity. Ligand B's significantly stronger binding affinity (-8.7 kcal/mol vs -7.1 kcal/mol) is a major advantage that likely outweighs the slightly lower logP and the better DILI profile. However, the negative microsomal clearance for Ligand B is a serious concern, suggesting a data error or an unphysical property. Given the importance of metabolic stability for an enzyme inhibitor, and the fact that Ligand A has a reasonable clearance, Ligand A is the more viable candidate.

Output:
0
2025-04-17 14:02:10,665 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.381 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.2 and 76.66) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.021 and 1.324), falling within the optimal 1-3 range.

**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 below the limits of 5 and 10 respectively.

**QED:** Both ligands have acceptable QED scores (0.772 and 0.681), indicating good drug-like properties.

**DILI:** Ligand A (27.414 percentile) has a significantly lower DILI risk than Ligand B (37.263 percentile). This is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.555) has a higher BBB penetration than Ligand B (68.205), but this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.952 and -4.874), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.226 and -2.187), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.615) has a slightly higher hERG inhibition risk than Ligand B (0.1), which is unfavorable.

**Microsomal Clearance:** Ligand A (2.927 mL/min/kg) has a much lower microsomal clearance than Ligand B (26.941 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-10.68 hours) has a negative half-life, which is not physically possible. Ligand B (6.549 hours) has a reasonable half-life. The negative value for Ligand A is a major red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.109 and 0.07), which is good.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), a difference of 0.8 kcal/mol. While a difference of >1.5 kcal/mol is considered significant, 0.8 kcal/mol is not enough to overcome the other substantial drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is preferable despite the negative half-life and solubility. The significantly lower DILI risk and much better metabolic stability (lower Cl_mic) are critical advantages for an enzyme inhibitor. The slightly weaker binding affinity is less concerning than the potential for liver toxicity and rapid metabolism. The negative half-life is a data error that would need to be resolved, but even without that, the other factors favor Ligand A. Ligand B's higher DILI risk and significantly higher clearance are major liabilities. The slightly better affinity isn't enough to compensate for these.

Output:
0
2025-04-17 14:02:10,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.459 and 358.869 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.71) is slightly higher than the ideal <140, but acceptable. Ligand B (66.56) is excellent, well below 140.

**logP:** Ligand A (1.366) is within the optimal 1-3 range. Ligand B (4.235) is a bit high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both within acceptable limits. Ligand B has 2 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (0.706 and 0.786), indicating drug-like properties.

**DILI:** Ligand A (66.576) has a higher DILI risk than Ligand B (32.842). This is a significant concern.

**BBB:** This is less important for a non-CNS target like SRC. Ligand B (64.87) is slightly higher, but not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.329) has very poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.922) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.607 and -5.138). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.269) has a lower hERG risk than Ligand B (0.883), which is a positive.

**Microsomal Clearance:** Ligand A (11.491) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (76.145) has high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (42.336) has a longer half-life than Ligand B (-0.86), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.069 and 0.389), which is good.

**Binding Affinity:** Both ligands have comparable and excellent binding affinity (-9.0 and -8.6 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Despite similar binding affinities, Ligand A is the more promising candidate. While both have poor solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Its hERG risk is also lower. Although Caco-2 permeability is poor for both, the other advantages of Ligand A outweigh this drawback, especially considering the importance of metabolic stability for an enzyme inhibitor.

Output:
0
2025-04-17 14:02:10,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is excellent, well below the 140 threshold for oral absorption. Ligand B (124.1) is still acceptable, but less optimal.

**logP:** Ligand A (1.291) is within the optimal 1-3 range. Ligand B (0.496) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but higher counts can sometimes affect permeability.

**QED:** Both ligands have good QED scores (0.489 and 0.701), suggesting reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (14.851) has a very low DILI risk, which is excellent. Ligand B (43.389) is higher but still within an acceptable range.

**BBB:** Ligand A (66.344) has moderate BBB penetration. Ligand B (43.583) is lower. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.482) has poor Caco-2 permeability, a significant concern. Ligand B (-5.145) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.541) has poor solubility, which is a major drawback. Ligand B (-3.118) is even worse.

**hERG Inhibition:** Both ligands have very low hERG risk (0.404 and 0.249), which is excellent.

**Microsomal Clearance:** Ligand A (27.458) has moderate clearance, suggesting moderate metabolic stability. Ligand B (6.638) has very low clearance, indicating good metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (9.716 hours) has a reasonable half-life. Ligand B (-13.479 hours) has a negative half-life which is not possible. This is a major issue for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.094 and 0.006), which is favorable.

**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.

**Overall Assessment:**

Ligand A suffers from poor Caco-2 permeability and solubility, which are critical for oral bioavailability. While its DILI risk is very low, the absorption issues are substantial. Ligand B has a superior binding affinity and better metabolic stability, but its solubility is very poor and the half-life is not possible. Given the enzyme-specific priorities, binding affinity and metabolic stability are key.

Despite the solubility and half-life issues, the significantly stronger binding affinity of Ligand B is a major advantage that could potentially be overcome with formulation strategies. The negative half-life for Ligand B is a critical flaw.

Output:
0
2025-04-17 14:02:10,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.443 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (90.03). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range for oral bioavailability.

**logP:** Ligand A (1.163) is better than Ligand B (0.382). Both are within the 1-3 range, but B is quite 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 4 HBA, while Ligand B has 5. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.535 and 0.574, respectively), indicating drug-like properties.

**DILI:** Ligand A (47.693) has a slightly higher DILI risk than Ligand B (25.902), but both are below the concerning threshold of 60.

**BBB:** Ligand A (50.523) has a slightly better BBB penetration than Ligand B (40.713). However, BBB is not a primary concern for SRC kinase inhibitors as it is not a CNS target.

**Caco-2 Permeability:** Ligand A (-4.892) has a worse Caco-2 permeability than Ligand B (-5.167). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-2.699) has a better aqueous solubility than Ligand B (-1.388). Both are negative, indicating poor solubility, but A is better.

**hERG Inhibition:** Ligand A (0.154) has a lower hERG inhibition liability than Ligand B (0.33). This is a significant advantage for A, reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-17.931) has a significantly lower (better) microsomal clearance than Ligand A (21.979). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (9.699) has a significantly longer in vitro half-life than Ligand A (-1.881). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.118) has a lower P-gp efflux liability than Ligand B (0.063). This is a slight advantage for A.

**Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-7.3). While both are excellent, the 0.2 kcal/mol difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability. These are critical factors for an enzyme inhibitor. While Ligand A has a slightly better binding affinity and lower hERG risk, the metabolic advantages of Ligand B are more impactful for overall drug development. The slightly lower logP of Ligand B is a concern, but the better metabolic profile is more important.

Output:
1
2025-04-17 14:02:10,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.772 and 358.324 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.35) is well below the 140 threshold for oral absorption. Ligand B (93.84) is still acceptable but closer to the limit.

**logP:** Ligand A (3.015) is optimal. Ligand B (0.993) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 6 HBA) both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.909 and 0.805), indicating good drug-likeness.

**DILI:** Ligand A (89.221) has a higher DILI risk than Ligand B (73.982), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (72.78) has a slightly higher BBB score, but this is not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.571) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-5.013) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.005) has poor solubility. Ligand B (-2.681) is better, though still not ideal.

**hERG Inhibition:** Ligand A (0.677) has a slightly higher hERG risk than Ligand B (0.288), which is preferable.

**Microsomal Clearance:** Ligand A (21.756) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (37.081) has higher clearance.

**In vitro Half-Life:** Ligand A (43.279) has a longer half-life than Ligand B (-9.65), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.337) has lower P-gp efflux, indicating better bioavailability. Ligand B (0.038) has very low P-gp efflux.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-6.9). This difference of 0.7 kcal/mol is significant.

**Overall Assessment:**

Ligand A has a better binding affinity, lower microsomal clearance, longer half-life, and lower P-gp efflux. However, it suffers from very poor Caco-2 permeability and solubility, and higher DILI risk. Ligand B has better solubility, lower DILI, and lower hERG risk, but weaker binding affinity, higher clearance, and shorter half-life.

Considering the priorities for enzyme inhibitors, the binding affinity is crucial. The 0.7 kcal/mol difference in binding affinity for Ligand A is substantial enough to potentially outweigh its ADME liabilities, *provided* formulation strategies can address the solubility and permeability issues. The better metabolic stability and longer half-life of Ligand A are also beneficial.

Output:
1
2025-04-17 14:02:10,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (346.43 and 359.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (87.66 and 87.74) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (1.652) is optimal, while Ligand B (0.476) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands (4) are well within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.668 and 0.533), indicating drug-like properties.

**DILI:** Ligand A (35.29%) has a better DILI score than Ligand B (41.92%), indicating lower potential for liver injury. Both are below the 40% threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (80.96%) has a higher BBB score than Ligand A (65.84%).

**Caco-2 Permeability:** Ligand A (-4.756) has a worse Caco-2 permeability score than Ligand B (-5.207), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.694 and -2.022), indicating poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.283 and 0.119), which is excellent.

**Microsomal Clearance:** Ligand B (-8.345) has significantly lower (better) microsomal clearance than Ligand A (17.643), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-30.239) has a much longer in vitro half-life than Ligand A (16.216), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.211 and 0.01), which is favorable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), a difference of 0.6 kcal/mol. While a 1.5 kcal/mol advantage is considered significant, 0.6 kcal/mol is less compelling.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic, longer t1/2), a better DILI score, and a slightly better solubility. The lower logP of Ligand B is a minor concern, but the substantial improvements in metabolic stability and safety outweigh this drawback, especially for a kinase inhibitor where chronic dosing is often anticipated.

Output:
1
2025-04-17 14:02:10,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.885 Da) is slightly higher than Ligand B (345.399 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 83.98, Ligand B: 80.76), indicating good potential for oral absorption.

**logP:** Ligand A (2.537) is within the optimal range (1-3). Ligand B (0.305) is slightly below 1, which *could* indicate potential permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (Ligand A: 2, Ligand B: 1) and HBA (both 5) counts.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.474, Ligand B: 0.593), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (75.107) has a higher DILI risk than Ligand B (52.152). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (66.615) has a slightly higher BBB value than Ligand A (52.191).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.41) is worse than Ligand B (-4.485).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.614) is worse than Ligand B (-1.791).

**hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.096, Ligand B: 0.216), which is excellent.

**Microsomal Clearance:** Ligand A (46.049 mL/min/kg) has a moderate clearance, while Ligand B (-0.126 mL/min/kg) has *very* low clearance (and is likely an outlier, potentially indicating high metabolic stability). This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (15.262 hours) has a reasonable half-life. Ligand B (-19.811 hours) is also an outlier, and likely indicates a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.114, Ligand B: 0.047).

**Binding Affinity:** Ligand A (-11.1 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 threshold.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, the combination of its higher DILI risk, worse solubility, and worse Caco-2 permeability makes it a less attractive candidate. Ligand B, while having a weaker binding affinity, demonstrates significantly better ADME properties, particularly its extremely low microsomal clearance and potentially very long half-life. The negative values for Caco-2 and solubility are concerning, but the extremely low clearance and DILI risk are compelling. The affinity difference, while substantial, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 14:02:10,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.439 and 376.444 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.71) is slightly higher than Ligand B (49.41), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.226 and 3.091), 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 3. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.876) has a higher QED score than Ligand B (0.75), indicating better overall drug-likeness.

**DILI:** Ligand A (8.492) has a significantly lower DILI risk than Ligand B (21.598), which is a major advantage.

**BBB:** Ligand B (92.555) has a higher BBB penetration percentile than Ligand A (74.564), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.791 and -4.885), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.157 and -4.626), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.854) has a slightly higher hERG inhibition risk than Ligand B (0.499), but both are relatively low.

**Microsomal Clearance:** Ligand A (-5.222) has a *much* lower (better) microsomal clearance than Ligand B (32.169), suggesting significantly improved metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (34.623) has a longer in vitro half-life than Ligand B (-9.648), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.187 and 0.169).

**Binding Affinity:** Ligand A (-7.8 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.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a better QED score, significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both have poor solubility and permeability, the metabolic advantages of Ligand A outweigh these drawbacks, especially for a kinase inhibitor where maintaining therapeutic concentrations is crucial.

Output:
0
2025-04-17 14:02:10,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.35) is slightly higher than Ligand B (88.91). Both are below the 140 threshold for good absorption, but Ligand B is closer to the preferred <90 for potential CNS activity (though this isn't a primary concern for SRC).

**logP:** Ligand A (2.511) and Ligand B (1.033) are both within the optimal 1-3 range. Ligand B is closer to the lower bound, which *could* slightly impact permeability, but is still acceptable.

**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 good QED scores (0.764 and 0.804, respectively), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (69.135 and 69.678), placing them in a moderate risk category. This isn't ideal, but not immediately disqualifying.

**BBB:** Ligand A (75.301) has better BBB penetration potential than Ligand B (45.638), but this is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.245 and -5.643), which is unusual and suggests poor permeability. This is a significant concern for both compounds.

**Aqueous Solubility:** Both have negative solubility values (-2.98 and -2.604), also unusual and indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.275 and 0.139), which is excellent.

**Microsomal Clearance:** Ligand A (21.704) has slightly higher microsomal clearance than Ligand B (20.556), meaning it might be metabolized faster.

**In vitro Half-Life:** Ligand B (9.467) has a significantly longer in vitro half-life than Ligand A (31.201). This is a major advantage for Ligand B, suggesting less frequent dosing could be possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.166 and 0.017).

**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 outweigh minor ADME drawbacks.

**Overall Assessment:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility. However, Ligand B has a substantially better in vitro half-life, which is crucial for an enzyme inhibitor. The slightly better affinity of Ligand A is not enough to overcome the significantly better metabolic stability of Ligand B. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, hERG), Ligand B is the more promising candidate, despite the similar DILI risk. The poor solubility and permeability would need to be addressed through formulation or further chemical modification, but the improved half-life provides a better starting point.

Output:
1
2025-04-17 14:02:10,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.5 and 356.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.34) is slightly higher than the preferred <140, but acceptable. Ligand B (43.18) is excellent, well below 90, suggesting good absorption.

**logP:** Both ligands (2.868 and 3.52) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good.

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

**QED:** Ligand A (0.853) has a significantly better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Ligand A (44.862) has a slightly higher DILI risk than Ligand B (38.309), but both are below the concerning threshold of 60.

**BBB:** Ligand A (69.794) has a better BBB penetration score than Ligand B (59.325), though this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.043) and Ligand B (-5.378) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have very poor aqueous solubility (-3.012 and -2.33 respectively). This is a major drawback.

**hERG:** Ligand A (0.692) has a lower hERG risk than Ligand B (0.919), which is favorable.

**Microsomal Clearance:** Ligand A (42.659) has a lower microsomal clearance than Ligand B (58.049), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.3) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (6.92) has a reasonable half-life.

**P-gp:** Ligand A (0.19) has a lower P-gp efflux liability than Ligand B (0.483), which is better.

**Binding Affinity:** Ligand A (-8.3) has a significantly stronger binding affinity than Ligand B (-7.0). This is a substantial advantage.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.3 vs -7.0 kcal/mol) is a major advantage that could outweigh some of the ADME liabilities. Furthermore, Ligand A has a better QED score, lower hERG risk, lower microsomal clearance, and lower P-gp efflux. The negative half-life for Ligand A is a red flag and needs investigation, but the overall profile is superior to Ligand B. The solubility issue would need to be addressed through formulation strategies.

Output:
0
2025-04-17 14:02:10,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (368.411 and 368.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.82) is slightly higher than Ligand B (78.67). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable due to its lower TPSA.

**3. logP:** Ligand A (1.424) and Ligand B (0.673) are both within the optimal 1-3 range. Ligand A is slightly better.

**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 good QED scores (0.703 and 0.799 respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 89.957, which is high. Ligand B has a much lower DILI risk of 43.428, which is good. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 74.913, while Ligand B has 25.126. While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Ligand A (-4.881) and Ligand B (-5.157) both have negative Caco-2 values, indicating poor permeability. Ligand B is slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.409) and Ligand B (-1.621) both have negative solubility values, indicating poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.389) and Ligand B (0.16) both have low hERG inhibition risk, which is good. Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (70.576) has higher microsomal clearance than Ligand B (35.97). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**13. In vitro Half-Life:** Ligand A (23.642) has a shorter half-life than Ligand B (-7.573). A negative value for half-life is unusual and likely indicates a very long half-life, which is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.09) and Ligand B (0.067) both have low P-gp efflux, which is good. Ligand B is slightly better.

**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 major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a high DILI risk. Ligand B has a much better safety profile (lower DILI, hERG, and P-gp efflux), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and TPSA. The substantial difference in binding affinity (-8.7 vs -0.0) is a major advantage for Ligand A. While the DILI risk is concerning, it might be mitigated through structural modifications. Given the significant potency advantage of Ligand A, it is the more promising candidate, *assuming* the DILI risk can be addressed through further optimization.

Output:
0
2025-04-17 14:02:10,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (356.482 and 351.363 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.64) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (114.79) is still under 140, but less optimal than A.

**logP:** Ligand A (2.588) is within the optimal 1-3 range. Ligand B (-1.127) is below 1, which might impede 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 within the acceptable range, but ligand A is preferable.

**QED:** Both ligands have good QED scores (0.591 and 0.71), indicating drug-like properties.

**DILI:** Ligand A (12.524) has a significantly lower DILI risk than Ligand B (79.837), a major advantage.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (64.948) is slightly better than Ligand B (54.052).

**Caco-2 Permeability:** Ligand A (-4.681) and Ligand B (-5.036) both have negative values, indicating low permeability. This is a concern for both, but not a deciding factor.

**Aqueous Solubility:** Ligand A (-2.118) and Ligand B (-1.93) both have negative values, indicating low solubility. This is a concern for both, but not a deciding factor.

**hERG:** Both ligands have very low hERG inhibition risk (0.521 and 0.06).

**Microsomal Clearance:** Ligand A (19.697) has a higher microsomal clearance than Ligand B (-14.665). This means Ligand B is more metabolically stable, which is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (24.753) has a longer half-life than Ligand B (-10.098). This is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.094 and 0.008).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.7 kcal/mol). Ligand B is slightly better (-8.7 vs -8.3), but the difference is small.

**Conclusion:**

While Ligand B has slightly better binding affinity and metabolic stability, Ligand A is significantly better regarding DILI risk and has a longer half-life. The lower DILI risk is a crucial advantage, and the slightly lower affinity of Ligand A can potentially be optimized in later stages of drug development. The logP value of Ligand B is a concern.

Output:
0
2025-04-17 14:02:10,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.439 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (81.5) is higher than Ligand B (65.55). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (Ligand A: 1.258, Ligand B: 2.99), falling within the optimal 1-3 range. Ligand B is closer to the upper end of the range, which could potentially lead to off-target effects, but is still acceptable.

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

**H-Bond Acceptors:** Both are within the acceptable range (Ligand A: 6, Ligand B: 7).

**QED:** Ligand A (0.799) has a higher QED score than Ligand B (0.556), indicating a more drug-like profile.

**DILI:** Ligand A (54.789) has a higher DILI risk than Ligand B (32.959). This is a significant advantage for Ligand B.

**BBB:** Ligand A (58.123) has a lower BBB penetration than Ligand B (77.821). While not critical for a non-CNS target like SRC, higher BBB is generally preferable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, the values are similar (-4.874 vs -4.975).

**Aqueous Solubility:** Both have negative solubility values, also unusual. Ligand B (-3.08) is slightly worse than Ligand A (-1.715).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.301, Ligand B: 0.772).

**Microsomal Clearance:** Ligand A (-22.446) has *much* lower microsomal clearance than Ligand B (58.479). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (73.73) has a significantly longer in vitro half-life than Ligand A (-1.601). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (Ligand A: 0.27, Ligand B: 0.48).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol).

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic) and QED, while Ligand B has better DILI risk, BBB penetration, and in vitro half-life. The binding affinity is identical. Given that SRC is an enzyme, metabolic stability and potency are key. The significantly lower Cl_mic for Ligand A is a substantial advantage. However, the longer half-life of Ligand B is also very attractive. The DILI risk for Ligand B is also significantly lower. Considering the balance, the longer half-life and lower DILI risk of Ligand B outweigh the better metabolic stability of Ligand A.

Output:
1

2025-04-17 14:02:10,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.467 and 353.423 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.27) is better than Ligand B (101.74). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred <90 for CNS targets (though this isn't a CNS target).

**3. logP:** Ligand A (-0.202) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (0.138) is also on the lower side but 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 6 HBA, and Ligand B has 8. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.631 and 0.776, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (7.949) has a significantly lower DILI risk than Ligand B (43.234). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (38.736) has a lower BBB percentile than Ligand B (27.026). This is not a primary concern for a non-CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.54 and -5.009). These values are unusual and suggest poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.409 and -0.968). Again, the scale is not specified, but these values suggest poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.106 and 0.071). This is excellent.

**12. Microsomal Clearance:** Ligand A (-17.11) has a much lower (better) microsomal clearance than Ligand B (-25.31), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.736) has a longer in vitro half-life than Ligand B (-4.306). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.001 and 0.007).

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.5 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the superior candidate. While both have similar binding affinities, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better TPSA. The solubility and permeability issues are shared by both, but the improvements in safety and stability with Ligand A outweigh the similar issues with both.

Output:
1
2025-04-17 14:02:10,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.535 and 358.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is better than Ligand B (58.64), both being reasonably low for good absorption.

**logP:** Both ligands have acceptable logP values (2.77 and 1.998), falling within the 1-3 range. Ligand B is slightly lower, which could slightly hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 3 HBA) both have favorable counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.569 and 0.642), indicating drug-like properties.

**DILI:** Ligand A (11.632) has a significantly lower DILI risk than Ligand B (18.728). This is a major advantage.

**BBB:** Both have reasonable BBB penetration (75.727 and 81.776), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.607 and -4.576) which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.397 and -2.809), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG:** Ligand A (0.765) has a slightly better hERG profile than Ligand B (0.453), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (48.438) has a higher microsomal clearance than Ligand B (10.79). This means Ligand B is more metabolically stable, a key consideration for kinases.

**In vitro Half-Life:** Ligand B (-11.551) has a negative half-life, which is not physically possible and indicates a major issue with the data or the compound itself. Ligand A (20.593) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux than Ligand B (0.075), which is preferable.

**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 relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand B has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic). However, it has a *completely unrealistic* negative in vitro half-life, a higher DILI risk, and worse P-gp efflux. Ligand A has a more reasonable half-life, lower DILI, better P-gp efflux, and a slightly better hERG profile. Both compounds suffer from very poor solubility and permeability.

Given the critical importance of metabolic stability for kinase inhibitors, and the unrealistic half-life of Ligand B, I would prioritize Ligand A despite its slightly weaker binding affinity. The DILI risk is also a significant advantage. The poor solubility and permeability of both compounds would need to be addressed through formulation or further chemical modification, but these are fixable issues. The negative half-life of Ligand B is not.

Output:
0
2025-04-17 14:02:10,667 - INFO - Batch 263 complete. Total preferences: 4208
2025-04-17 14:02:10,667 - INFO - Processing batch 264/512...
2025-04-17 14:02:58,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (74.57 and 71.53) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (2.077 and 1.464) 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.706 and 0.86), indicating drug-like properties.

**DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (38.348). This is a major advantage for Ligand A.

**BBB:** Both have similar BBB penetration (57.193 and 58.007). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.754 and -5.031), 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 have negative solubility values (-1.296 and -1.837), again suggesting poor solubility. Similar to Caco-2, these values are on a log scale and hard to interpret without knowing the base of the log.

**hERG Inhibition:** Ligand A (0.423) has a slightly higher hERG risk than Ligand B (0.16), but both are relatively low.

**Microsomal Clearance:** Ligand B (16.142) has a significantly lower microsomal clearance than Ligand A (22.754), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (9.751) has a longer in vitro half-life than Ligand B (-2.422). This is a positive for Ligand A.

**P-gp Efflux:** Ligand B (0.077) has a much lower P-gp efflux liability than Ligand A (0.298), suggesting better bioavailability.

**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, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a longer half-life, and a lower DILI risk. However, Ligand B has better metabolic stability and lower P-gp efflux. The difference in binding affinity is substantial (-8.7 vs 0.0 kcal/mol), which is the most important factor for an enzyme inhibitor. While Ligand B's metabolic stability is better, the superior potency of Ligand A is likely to be more impactful, especially considering the potential for further optimization of its metabolic properties. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 14:02:58,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.478 Da and 361.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (134.92) is still acceptable but approaching the upper limit for good absorption.

**logP:** Ligand A (2.964) is optimal (1-3). Ligand B (0.593) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is ideal. Ligand B (4 HBD, 8 HBA) is acceptable, but higher values could impact permeability.

**QED:** Both ligands have similar QED values (0.742 and 0.54), indicating reasonable drug-likeness.

**DILI:** Ligand A (16.479) has a significantly lower DILI risk than Ligand B (65.103), which is a major concern.

**BBB:** BBB isn't a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired. Ligand A (84.141) is better than Ligand B (59.442), but neither is exceptionally high.

**Caco-2 Permeability:** Ligand A (-4.688) has poor Caco-2 permeability, while Ligand B (-5.768) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.747) and Ligand B (-2.71) both have poor aqueous solubility.

**hERG:** Ligand A (0.567) has a lower hERG risk than Ligand B (0.198), which is preferable.

**Microsomal Clearance:** Ligand A (24.756) has higher microsomal clearance than Ligand B (-4.226). This means Ligand B is more metabolically stable, which is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (12.124 hours) has a longer half-life than Ligand A (10.281 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux than Ligand B (0.025), which is preferable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 kcal/mol and -8.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Overall Assessment:**

Ligand B is superior in terms of metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better half-life. However, Ligand A has a significantly lower DILI risk, better TPSA, and better P-gp efflux. The poor Caco-2 and solubility of both are concerning, but can potentially be addressed with formulation strategies. Given the importance of minimizing toxicity (DILI) and maximizing metabolic stability for kinase inhibitors, and the similar binding affinities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 14:02:58,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.38 and 354.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.46) is significantly better than Ligand B (90.98). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (2.793) is optimal (1-3), while Ligand B (0.037) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and acceptable HBA counts (3 and 5 respectively).

**QED:** Ligand A (0.871) has a much better QED score than Ligand B (0.657), indicating a more drug-like profile.

**DILI:** Ligand A (15.9%) has a significantly lower DILI risk than Ligand B (29.0%). Both are acceptable, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (82%) is better than Ligand B (74.3%).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the magnitude of the negative value for Ligand A (-4.614) is smaller than for Ligand B (-4.661), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also problematic. Ligand B (-0.917) is slightly better than Ligand A (-2.815).

**hERG:** Ligand A (0.488) has a much lower hERG risk than Ligand B (0.376). Lower is better here.

**Microsomal Clearance:** Ligand A (5.085) has significantly lower microsomal clearance than Ligand B (31.2), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-0.948) has a better (longer) half-life than Ligand B (-30.573).

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux than Ligand B (0.016), suggesting better bioavailability.

**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 of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B boasts superior binding affinity, Ligand A has a much more favorable ADME profile. Specifically, its lower DILI risk, better metabolic stability (lower Cl_mic and better half-life), lower hERG risk, and better QED score are significant advantages. The lower logP of Ligand B is a major concern, potentially limiting its absorption. The affinity difference is substantial, but the ADME profile of Ligand A is much more promising for development. Considering the enzyme-specific priorities, the improved metabolic stability and reduced toxicity risk of Ligand A are compelling.

Output:
0
2025-04-17 14:02:58,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.423 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.9) is better than Ligand B (79.79), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (2.667) is optimal (1-3), while Ligand A (0.253) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

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

**H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**QED:** Both ligands have similar and good QED values (0.715 and 0.741, respectively).

**DILI:** Ligand B (31.02) has a much lower DILI risk than Ligand A (50.756), which is a significant advantage.

**BBB:** Ligand A (81.388) has better BBB penetration than Ligand B (56.534), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.046) has worse Caco-2 permeability than Ligand B (-4.895), but both are quite poor.

**Aqueous Solubility:** Ligand A (-1.805) has better aqueous solubility than Ligand B (-3.374).

**hERG Inhibition:** Ligand A (0.196) has a lower hERG inhibition risk than Ligand B (0.351), which is a positive.

**Microsomal Clearance:** Ligand A (-2.326) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (29.284). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (12.936 hours) has a better in vitro half-life than Ligand B (29.711 hours).

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.078), which is favorable.

**Binding Affinity:** Ligand A (-7.9 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 to outweigh major ADME issues, it contributes to the overall assessment.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and better solubility. However, its major drawback is the very low logP, which could severely limit its permeability and bioavailability. Ligand B has a more favorable logP but suffers from higher DILI, worse metabolic stability, and higher P-gp efflux.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), Ligand A's superior metabolic stability and lower DILI risk are significant advantages. While the low logP is concerning, it might be addressable through formulation strategies. The slightly better binding affinity also supports choosing Ligand A.

Output:
0
2025-04-17 14:02:58,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.455 and 360.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.37) is significantly better than Ligand B (77.81), being well below the 140 threshold for good absorption.

**logP:** Both ligands have logP values (3.92 and 4.103) that are slightly above the optimal 1-3 range, but still acceptable.

**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.

**QED:** Ligand A (0.916) has a substantially higher QED score than Ligand B (0.779), indicating better overall drug-likeness.

**DILI:** Ligand B (72.858) has a higher DILI risk than Ligand A (44.513), though both are acceptable.

**BBB:** Ligand A (95.967) shows much better BBB penetration potential than Ligand B (51.415). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.582) has a higher Caco-2 permeability than Ligand B (-4.762), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.745) has better aqueous solubility than Ligand B (-5.705).

**hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.821 and 0.724).

**Microsomal Clearance:** Ligand A (100.565) has a higher microsomal clearance than Ligand B (56.004), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (89.973) has a longer in vitro half-life than Ligand A (65.356), which is a positive attribute.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.622 and 0.571).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Despite Ligand A having a higher microsomal clearance, its significantly superior binding affinity (-8.2 vs -6.5 kcal/mol), higher QED, better solubility, and lower DILI risk outweigh this drawback. The substantial difference in binding affinity is particularly important for an enzyme target like SRC kinase. Ligand B's longer half-life is a benefit, but not enough to overcome the potency difference.

Output:
0
2025-04-17 14:02:58,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.491 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is well below the 140 threshold and favorable for absorption. Ligand B (114.39) is still within acceptable limits, but less optimal than A.

**logP:** Both ligands (1.848 and 1.256) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which is good. Ligand B has 1 HBD and 7 HBA, still acceptable but slightly higher HBA count.

**QED:** Both ligands have QED values (0.697 and 0.595) above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (6.592) has a significantly lower DILI risk than Ligand B (71.656), which is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (40.093) is lower than Ligand B (51.803).

**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 ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is undefined.

**hERG:** Both ligands have low hERG inhibition liability (0.243 and 0.224), which is excellent.

**Microsomal Clearance:** Ligand A (19.334) has a lower microsomal clearance than Ligand B (34.301), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.822) has a positive half-life, while Ligand B (-6.775) has a negative half-life, which is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.318).

**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 significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from a very high DILI risk and a negative in vitro half-life, indicating poor metabolic stability. Ligand A has a much better safety profile (lower DILI) and better metabolic stability (lower Cl_mic, positive t1/2), but its binding affinity is very weak.

Despite the superior affinity of Ligand B, the high DILI risk and poor stability are major red flags. While affinity is crucial, a compound with significant toxicity or rapid metabolism is unlikely to be a viable drug candidate. Ligand A, while weaker in binding, presents a much more favorable starting point for optimization, as the safety and stability issues are less severe.

Output:
0
2025-04-17 14:02:58,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.423 and 349.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (99.5 and 93.11) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.316 and 1.189) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Both have 6 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.608 and 0.837), indicating good drug-likeness.

**DILI:** Both ligands have DILI risk around 60, which is borderline. Ligand B is slightly better (59.713 vs 61.807).

**BBB:** Ligand B (81.194) has a significantly higher BBB penetration percentile than Ligand A (56.65). However, since SRC is not a CNS target, this is less critical.

**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 Inhibition:** Ligand B (0.104) has a much lower hERG inhibition liability than Ligand A (0.44), which is a significant advantage.

**Microsomal Clearance:** Ligand B (39.28) has a lower microsomal clearance than Ligand A (42.299), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-34.968) has a much longer in vitro half-life than Ligand A (20.832), which is a major advantage.

**P-gp Efflux:** Ligand B (0.046) has a lower P-gp efflux liability than Ligand A (0.169), potentially leading to better bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). The difference is 0.7 kcal/mol, which is not substantial enough to outweigh the ADME advantages of Ligand B.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. These factors are crucial for developing a viable drug candidate.

Output:
1
2025-04-17 14:02:58,668 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (353.507 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is slightly higher than Ligand B (53.51), but both are well below the 140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (3.75 and 3.025, respectively), 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 3 HBAs, well within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.819 and 0.715), indicating good drug-like properties.

**7. DILI:** Ligand A (21.52) has a significantly lower DILI risk than Ligand B (16.44). This is a substantial advantage.

**8. BBB:** Ligand A (93.253) has higher BBB penetration than Ligand B (75.107). While not a primary concern for a kinase inhibitor (unless CNS effects are desired), it's a positive attribute.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with permeability prediction. However, the values are similar (-4.304 and -4.433) and don't strongly differentiate the two.

**10. Aqueous Solubility:** Ligand A (-3.269) and Ligand B (-1.712) both have negative solubility values, indicating poor solubility. Ligand B is slightly better, but both are concerning.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.483 and 0.42).

**12. Microsomal Clearance:** Ligand A (52.85) has lower microsomal clearance than Ligand B (66.022), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.399) has a negative half-life, which is not physically possible and indicates a prediction error. Ligand A (3.191) has a reasonable half-life. This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have similar low P-gp efflux liability (0.076 and 0.084).

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.1), a difference of 0.3 kcal/mol. While affinity is crucial, the difference is not substantial enough to outweigh other significant factors.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, positive t1/2), lower DILI risk, and better BBB penetration. The solubility of both is poor, but the other advantages of Ligand A make it the preferred choice.

Output:
1
2025-04-17 14:02:58,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (341.455 and 349.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.41) is better than Ligand B (64.86), both are below the 140 threshold for good absorption.

**3. logP:** Ligand A (2.22) is optimal, while Ligand B (3.163) is towards the higher end of the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (6), as lower HBA is generally preferable.

**6. QED:** Ligand A (0.835) has a significantly better QED score than Ligand B (0.73), indicating a more drug-like profile.

**7. DILI:** Ligand A (16.169) has a much lower DILI risk than Ligand B (23.187), which is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (76.619 and 72.005), but Ligand A is slightly better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG:** Both ligands have low hERG inhibition risk (0.374 and 0.264), which is good.

**12. Cl_mic:** Ligand A (31.256) has a lower microsomal clearance than Ligand B (40.495), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-38.361) has a much longer in vitro half-life than Ligand B (-4.409), indicating better stability.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.197 and 0.043).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol) by 1.6 kcal/mol. This is a substantial difference and a major advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of DILI risk, metabolic stability (Cl_mic and t1/2), and QED. Both have poor solubility and Caco-2 permeability, which are serious issues. However, the strong affinity of Ligand B might outweigh the ADME concerns, *if* solubility and permeability can be improved through formulation or structural modifications. The lower DILI risk of Ligand A is also a significant advantage. Given the enzyme-kinase focus, metabolic stability and potency are key. The 1.6 kcal/mol difference in binding is substantial.

Output:
1
2025-04-17 14:02:58,669 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.368 Da and 347.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.01) is better than Ligand B (64.41), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.968) is at the upper end of the optimal range (1-3), while Ligand B (2.471) is well within it. Ligand A's higher logP *could* lead to off-target effects, but it's not a severe concern at this stage.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (6/3) counts, well below the thresholds.

**QED:** Both ligands have good QED scores (0.653 and 0.726), indicating drug-likeness.

**DILI:** Ligand A (81.078) has a significantly higher DILI risk than Ligand B (31.252). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (89.027) is better than Ligand B (77.084).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Similar to Caco-2, these values should be interpreted cautiously.

**hERG:** Ligand A (0.444) has a lower hERG risk than Ligand B (0.785), which is favorable.

**Microsomal Clearance:** Ligand B (66.511) has a significantly lower microsomal clearance than Ligand A (83.104), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (13.974) has a longer half-life than Ligand A (34.106). This is another significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.703) has a lower P-gp efflux liability than Ligand B (0.267), which is favorable.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better P-gp efflux and hERG profile, Ligand B excels in critical areas for kinase inhibitors: significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly improved binding affinity. The solubility and permeability issues are present in both, and would need to be addressed during optimization, but the ADME profile of Ligand B is considerably more promising.

Output:
1
2025-04-17 14:02:58,669 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.347 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (131.04) is borderline, but acceptable for oral absorption. Ligand B (71.44) is excellent, well below the 140 threshold.

**logP:** Ligand A (-0.347) is a bit low, potentially hindering permeation. Ligand B (0.887) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.545 and 0.61), indicating drug-likeness.

**DILI:** Ligand A (79.682) has a higher DILI risk than Ligand B (35.712), which is a significant concern.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**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.

**Solubility:** Both ligands have negative solubility values, which is also unusual. Again, without knowing the scale, it's hard to assess.

**hERG:** Ligand A (0.027) has a very low hERG risk, which is excellent. Ligand B (0.363) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-28.252) has excellent metabolic stability (negative clearance). Ligand B (40.201) has moderate clearance, which is less desirable.

**In vitro Half-Life:** Ligand A (16.714 hours) has a good half-life. Ligand B (-4.036 hours) has a negative half-life, which is impossible and suggests an issue with the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.6 and -7.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A has a better hERG profile and significantly better metabolic stability (lower Cl_mic, longer t1/2). However, its DILI risk is considerably higher, and its logP is suboptimal. Ligand B has a better logP and lower DILI risk, but its half-life is impossible. Given the data quality issues with Ligand B (negative half-life), and the importance of metabolic stability for kinase inhibitors, I would choose Ligand A, but with a strong caveat that the DILI risk needs to be addressed through further structural modifications.

Output:
1
2025-04-17 14:02:58,669 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.4) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (88.08) is excellent, well below the 140 cutoff for good absorption. Ligand B (121.01) is still acceptable, but less ideal.

**logP:** Ligand A (1.429) is optimal. Ligand B (-0.479) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD/HBA counts (A: 1/5, B: 2/5), falling within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.91, B: 0.64), indicating drug-like properties. Ligand A is superior.

**DILI:** Ligand A (57.658) has a moderate DILI risk, while Ligand B (39.628) is better with a lower risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (64.211) is higher, but not a deciding factor.

**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. We'll assume these indicate low solubility.

**hERG:** Both ligands have very low hERG risk (A: 0.106, B: 0.25), which is excellent.

**Microsomal Clearance:** Ligand A (-3.223) has a *much* lower (better) microsomal clearance than Ligand B (-21.848), indicating significantly better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-5.941) has a better (longer) in vitro half-life than Ligand B (-27.126). This further supports its improved metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.003, B: 0.024).

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.8), a difference of 0.4 kcal/mol. While affinity is paramount, the difference isn't large enough to overcome the substantial ADME advantages of Ligand A.

**Overall:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in key ADME properties crucial for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), better logP, and a higher QED score. The negative solubility and Caco-2 values are concerning for both, but the metabolic advantages of A outweigh the small affinity difference.

Output:
0
2025-04-17 14:02:58,669 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.571 and 351.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (61.44), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands (3.021 and 2.844) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.718 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (16.402) is significantly better than Ligand B (5.584) with respect to DILI risk. Lower is better, and Ligand A is well below the 40 threshold. Ligand B is also below, but closer to the threshold.

**BBB:** Both ligands have similar BBB penetration (76.658 and 71.966), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.926) and Ligand B (-5.011) are both negative, which is unusual. A higher value is desired, but the values are similar.

**Solubility:** Ligand A (-3.933) is better than Ligand B (-2.479). Higher solubility is preferred.

**hERG:** Both ligands have low hERG inhibition risk (0.677 and 0.639).

**Microsomal Clearance:** Ligand A (75.44) has a higher microsomal clearance than Ligand B (17.703). Lower clearance is preferred for better metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand A (12.266) has a longer half-life than Ligand B (-4.231). Longer half-life is preferred.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.141 and 0.062).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -7.9 kcal/mol). The difference of 0.1 kcal/mol is not substantial enough to be a deciding factor.

**Overall Assessment:**

Ligand A has advantages in DILI risk, solubility, and in vitro half-life. Ligand B has a significant advantage in microsomal clearance. Considering the enzyme-specific priorities, metabolic stability (Cl_mic) is crucial. While Ligand A has a longer half-life, the significantly lower Cl_mic of Ligand B suggests it will be more metabolically stable *in vivo*. The better DILI and solubility of Ligand A are also important, but the difference in Cl_mic is more impactful for an enzyme target.

Output:
1
2025-04-17 14:02:58,670 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight (MW):**
* Ligand A: 349.431 Da - Within the ideal range (200-500).
* Ligand B: 412.284 Da - Still within the ideal range, but approaching the upper limit.
* *Advantage: Ligand A*

**2. TPSA:**
* Ligand A: 82.45 - Good for oral absorption (<140).
* Ligand B: 82.11 - Also good for oral absorption.
* *No significant difference.*

**3. logP:**
* Ligand A: 2.088 - Optimal (1-3).
* Ligand B: 1.91 - Optimal (1-3).
* *No significant difference.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Meets the criteria (<=5).
* Ligand B: 2 - Meets the criteria (<=5).
* *No significant difference.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 6 - Meets the criteria (<=10).
* Ligand B: 4 - Meets the criteria (<=10).
* *No significant difference.*

**6. QED:**
* Ligand A: 0.795 - Excellent drug-like profile.
* Ligand B: 0.795 - Excellent drug-like profile.
* *No significant difference.*

**7. DILI:**
* Ligand A: 64.211 - Moderate risk, but acceptable.
* Ligand B: 56.689 - Lower risk, better.
* *Advantage: Ligand B*

**8. BBB:**
* Ligand A: 82.086 - Not a priority for this target.
* Ligand B: 56.805 - Not a priority for this target.
* *No significant difference.*

**9. Caco-2 Permeability:**
* Ligand A: -4.832 - Suggests poor permeability.
* Ligand B: -4.648 - Suggests poor permeability, but slightly better than A.
* *Advantage: Ligand B*

**10. Aqueous Solubility:**
* Ligand A: -3.3 - Poor solubility.
* Ligand B: -2.863 - Better solubility than A, but still poor.
* *Advantage: Ligand B*

**11. hERG Inhibition:**
* Ligand A: 0.181 - Low risk.
* Ligand B: 0.439 - Higher risk than A.
* *Advantage: Ligand A*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 64.098 - Moderate clearance.
* Ligand B: -18.534 - Negative clearance is unusual and likely an error, but assuming it represents very low clearance, this is a significant advantage.
* *Advantage: Ligand B*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -10.408 - Negative half-life is unusual and likely an error, but assuming it represents a very short half-life, this is a disadvantage.
* Ligand B: 20.97 - Good half-life.
* *Advantage: Ligand B*

**14. P-gp Efflux:**
* Ligand A: 0.187 - Low efflux, good.
* Ligand B: 0.028 - Very low efflux, excellent.
* *Advantage: Ligand B*

**15. Binding Affinity:**
* Ligand A: -9.1 kcal/mol - Excellent.
* Ligand B: -9.3 kcal/mol - Slightly better than A.
* *Advantage: Ligand B*

**Overall Assessment (Enzyme-Kinase Specific):**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand A has a slightly better hERG profile and comparable affinity, Ligand B demonstrates significantly better metabolic stability (Cl_mic and t1/2), solubility, and P-gp efflux. The small advantage in binding affinity of Ligand B further supports its selection. The poor Caco-2 permeability of both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:02:58,670 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 and 338.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.64 and 63.42) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.247) is optimal, while Ligand B (3.621) is approaching the higher end of the preferred range, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 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 (0.723 and 0.766), indicating drug-like properties.

**DILI:** Ligand A (15.01) has a significantly lower DILI risk than Ligand B (77.55). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (70.76) has a higher BBB penetration, but this is less relevant here.

**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, suggesting poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.266) has a much lower hERG inhibition liability than Ligand B (0.936), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (85.20) has a higher microsomal clearance than Ligand A (38.46), indicating lower metabolic stability. This is a critical drawback for Ligand B.

**In vitro Half-Life:** Ligand B (74.72) has a much longer in vitro half-life than Ligand A (4.96). This is a positive for Ligand B, but may not outweigh the metabolic instability.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux liability than Ligand B (0.189), which is favorable.

**Binding Affinity:** Both ligands have similar 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 priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has a longer half-life, Ligand A exhibits significantly better safety profiles (lower DILI and hERG) and better metabolic stability (lower Cl_mic). The similar binding affinities make the ADME/Tox advantages of Ligand A decisive.

Output:
0
2025-04-17 14:02:58,670 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.337, 67.87, 2.259, 1, 4, 0.848, 68.98, 89.957, -4.465, -3.918, 0.602, 21.473, 12.993, 0.156, -8]
**Ligand B:** [334.394, 26.71, 4.69, 1, 3, 0.753, 68.088, 66.344, -4.888, -5.186, 0.959, 92.685, -28.383, 0.767, 0]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). Ligand B (334.394 Da) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** Ligand A (67.87) is higher than Ligand B (26.71).  Both are below the 140 threshold for oral absorption, but Ligand B is significantly lower, suggesting better absorption.
3. **logP:** Ligand A (2.259) is within the optimal range (1-3). Ligand B (4.69) is a bit high, potentially leading to solubility issues or off-target interactions.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable range.
6. **QED:** Ligand A (0.848) has a better QED score than Ligand B (0.753), indicating a more drug-like profile.
7. **DILI:** Both ligands have similar DILI risk (68.98 and 68.088), indicating moderate risk. This isn't a major differentiator.
8. **BBB:** Ligand A (89.957) has a significantly higher BBB percentile than Ligand B (66.344). While SRC isn't a CNS target, higher BBB can sometimes correlate with better overall bioavailability.
9. **Caco-2:** Ligand A (-4.465) and Ligand B (-4.888) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.
10. **Solubility:** Ligand A (-3.918) has slightly better solubility than Ligand B (-5.186), but both are very poor.
11. **hERG:** Ligand A (0.602) has a lower hERG risk than Ligand B (0.959), which is preferable.
12. **Cl_mic:** Ligand A (21.473) has a much lower microsomal clearance than Ligand B (92.685), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.
13. **t1/2:** Ligand A (12.993) has a longer in vitro half-life than Ligand B (-28.383). The negative value for Ligand B is concerning and suggests very rapid degradation.
14. **Pgp:** Ligand A (0.156) has lower P-gp efflux than Ligand B (0.767), which is favorable for bioavailability.
15. **Binding Affinity:** Ligand A (-8) has a significantly stronger binding affinity than Ligand B (0). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in these areas. Its significantly stronger binding affinity (-8 kcal/mol vs 0 kcal/mol) and much better metabolic stability (lower Cl_mic, longer t1/2) are major advantages. While both have poor Caco-2 and solubility, the superior binding and metabolic properties of Ligand A outweigh these drawbacks.

**Conclusion:**

Ligand A is the more promising drug candidate.

1
2025-04-17 14:02:58,670 - INFO - Batch 264 complete. Total preferences: 4224
2025-04-17 14:02:58,670 - INFO - Processing batch 265/512...
2025-04-17 14:03:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.539 Da and 352.469 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is slightly higher than Ligand B (36.36), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (3.534) is within the optimal 1-3 range, while Ligand B (4.851) is slightly higher. This could potentially lead to solubility issues for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.769 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (17.371) has a significantly lower DILI risk than Ligand B (19.426), which is a major advantage.

**BBB:** Both ligands exhibit good BBB penetration (79.294 and 91.857), though this is less critical for a non-CNS target like SRC.

**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 negative solubility values, which is concerning. Ligand B (-4.085) is slightly worse than Ligand A (-3.325).

**hERG Inhibition:** Ligand A (0.609) has a lower hERG inhibition liability than Ligand B (0.897), which is a positive.

**Microsomal Clearance:** Ligand A (93.874) has a higher microsomal clearance than Ligand B (57.113), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-16.289) has a negative half-life which is not possible. This is a major red flag. Ligand A (13.809) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.404 and 0.539).

**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 could outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower DILI/hERG risk, but suffers from higher microsomal clearance. Ligand B has better metabolic stability but weaker binding affinity and a higher DILI risk. The negative half-life for Ligand B is a critical issue. Given the importance of potency for kinase inhibitors, and the significant difference in binding affinity, Ligand A is the more promising candidate *despite* its lower metabolic stability. Further optimization could address the clearance issue.

Output:
1
2025-04-17 14:03:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 386.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.86) is better than Ligand B (101.41), both are acceptable, but closer to the upper limit for good oral absorption.

**logP:** Ligand B (1.183) is better than Ligand A (0.319). Ligand A is quite low, potentially hindering permeation. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Both have 6 HBA, which is also good.

**QED:** Ligand A (0.845) has a significantly better QED score than Ligand B (0.402), indicating a more drug-like profile.

**DILI:** Ligand B (39.511) has a much lower DILI risk than Ligand A (61.807). This is a significant advantage for Ligand B.

**BBB:** Ligand A (51.066) and Ligand B (43.815) are both low, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.406) is significantly worse than Ligand B (-5.449), indicating lower intestinal absorption.

**Aqueous Solubility:** Both are very poor (-1.532 and -1.508), which is a concern. However, SRC is an intracellular target, so solubility is less critical than for some other targets.

**hERG Inhibition:** Ligand A (0.237) has a slightly better hERG profile than Ligand B (0.115), but both are very low risk.

**Microsomal Clearance:** Ligand B (17.623) has a slightly better microsomal clearance than Ligand A (19.066), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.602) has a much better in vitro half-life than Ligand B (-1.098). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.135) has a slightly better P-gp efflux profile than Ligand B (0.009).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This ~1.3 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and a lower DILI risk. While its QED and solubility are less favorable, the strong binding affinity is crucial for an enzyme inhibitor. The slightly better metabolic stability of Ligand B is also a plus. Ligand A's better half-life and QED are offset by its poor logP, Caco-2 permeability, and higher DILI risk. The affinity difference is the deciding factor here.

Output:
1
2025-04-17 14:03:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 361.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.36) is well below the 140 threshold, while Ligand B (106.1) is still acceptable but higher. This favors Ligand A for better absorption.

**logP:** Ligand A (3.42) is optimal, while Ligand B (1.088) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2-3) and HBA (2-7) counts.

**QED:** Both ligands have good QED scores (0.733 and 0.765), indicating drug-likeness.

**DILI:** Ligand A (28.693) has a significantly lower DILI risk than Ligand B (68.903). This is a major advantage for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand A (81.233) has better BBB penetration than Ligand B (38.542).

**Caco-2 Permeability:** Ligand A (-4.43) has a worse Caco-2 permeability than Ligand B (-5.627), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.275) has worse solubility than Ligand B (-2.088).

**hERG:** Ligand A (0.581) has a higher hERG risk than Ligand B (0.047). This is a significant concern for Ligand A.

**Microsomal Clearance:** Ligand B (-8.849) has significantly lower (better) microsomal clearance than Ligand A (41.62). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (17.878) has a longer half-life than Ligand A (22.941).

**P-gp Efflux:** Ligand A (0.435) has a lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -8.7 kcal/mol), with Ligand B being slightly better. The difference is within the acceptable range where other factors can be decisive.

**Overall Assessment:**

Ligand B is preferable. While Ligand A has better TPSA and P-gp efflux, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a slightly better binding affinity. The hERG risk for Ligand A is a significant red flag. The lower logP and Caco-2 permeability of Ligand B are less concerning given the overall profile and the fact that SRC kinase is not a CNS target.

Output:
1
2025-04-17 14:03:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.5 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.33) is better than Ligand B (101.21). TPSA < 140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Both ligands have similar logP values (1.42 and 1.308), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable.

**QED:** Ligand B (0.806) has a higher QED score than Ligand A (0.652), indicating a more drug-like profile.

**DILI:** Ligand A (33.3) has a significantly lower DILI risk than Ligand B (49.3), which is a major advantage. Lower DILI is crucial.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (90.8) has better BBB penetration than Ligand A (55.9). This is not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.1 and -5.172), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.239 and -2.912), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.212) has a lower hERG inhibition liability than Ligand B (0.377), which is desirable.

**Microsomal Clearance:** Ligand A (-1.788) has a lower (better) microsomal clearance than Ligand B (2.823), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.341 hours) has a much longer in vitro half-life than Ligand B (-20.936 hours - a negative value is concerning). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.045 and 0.023).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand B has a better binding affinity and QED, Ligand A demonstrates superior ADMET properties, particularly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. The poor solubility and permeability are concerning for both, but the significant advantage in binding affinity for Ligand B is compelling. Given that SRC is an enzyme, potency is paramount. The improved ADMET profile of Ligand A is valuable, but the 1.3 kcal/mol difference in binding affinity is substantial enough to favor Ligand B, assuming solubility/permeability can be addressed through formulation or further optimization.

Output:
1
2025-04-17 14:03:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.419 and 391.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.94) is better than Ligand B (110.53), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.072) is optimal (1-3), while Ligand B (1.243) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**QED:** Both ligands have acceptable QED scores (0.419 and 0.754, respectively), with Ligand B being better.

**DILI:** Ligand A (40.481) has a much lower DILI risk than Ligand B (86.933). This is a significant advantage.

**BBB:** Ligand A (80.496) has better BBB penetration than Ligand B (55.913), although this isn't a primary concern for a non-CNS target like SRC.

**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, also unusual and suggesting poor solubility. Again, the scale is unspecified.

**hERG:** Ligand A (0.596) has a lower hERG risk than Ligand B (0.224), which is preferable.

**Microsomal Clearance:** Ligand A (30.452) has a lower Cl_mic, indicating better metabolic stability than Ligand B (41.477).

**In vitro Half-Life:** Ligand A (18.505) has a longer half-life than Ligand B (-16.471). The negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.311) has lower P-gp efflux liability than Ligand B (0.207).

**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 some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.6 vs -7.4 kcal/mol). However, it suffers from a higher DILI risk, lower BBB penetration, a potentially problematic negative in vitro half-life, and a lower logP. Ligand A is generally better across most ADME properties (DILI, metabolic stability, hERG, P-gp efflux), but its affinity is weaker.

Given that SRC is an enzyme, potency (affinity) is paramount. The 1.2 kcal/mol difference in binding affinity is substantial. While Ligand B's ADME profile is less ideal, the strong binding could be optimized through further medicinal chemistry efforts. The DILI risk is a concern, but not insurmountable.

Output:
1
2025-04-17 14:03:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 366.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.87) is better than Ligand B (60.85), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (0.928 and 1.355), 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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.828 and 0.751), indicating good drug-likeness.

**DILI:** Ligand A (40.83) has a slightly higher DILI risk than Ligand B (24.506), but both are below the concerning threshold of 60.

**BBB:** Ligand A (29.74) has a low BBB penetration, while Ligand B (86.584) has excellent BBB penetration. However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.847 and -4.667), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.562 and -2.439), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.269) has a lower hERG risk than Ligand B (0.407), which is preferable.

**Microsomal Clearance:** Ligand A (-2.941) has a much lower (better) microsomal clearance than Ligand B (8.734), indicating greater metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.941) has a much longer in vitro half-life than Ligand B (-43.248), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.026).

**Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-7.9). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-10.0 kcal/mol vs -7.9 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target like SRC kinase. The lower hERG risk is also a benefit. While the solubility and permeability issues need to be addressed through formulation or structural modifications, the potency and metabolic properties of Ligand A make it a better starting point for optimization.

Output:
1
2025-04-17 14:03:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.5 and 341.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (90.38). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.39) is optimal, while Ligand B (1.787) is on the lower side, potentially hindering permeation.

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

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

**QED:** Both ligands have similar QED values (0.765 and 0.697), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (29.042 and 27.336), which is favorable.

**BBB:** Ligand A (80.574) has a better BBB percentile than Ligand B (64.676), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.269) and Ligand B (-5.468) both have negative values, indicating poor permeability. This is a concern for both.

**Solubility:** Ligand A (-4.1) has better solubility than Ligand B (-2.551), which is important for bioavailability.

**hERG:** Ligand A (0.291) shows a significantly lower hERG risk than Ligand B (0.577), a crucial advantage.

**Microsomal Clearance:** Ligand A (82.763) has higher microsomal clearance than Ligand B (15.17), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-6.522) has a longer half-life than Ligand A (-21.31), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.023).

**Binding Affinity:** Ligand B (-7.9 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 has a better binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has better solubility and a much lower hERG risk. Considering the priorities for kinase inhibitors, metabolic stability and potency are key. While Ligand A's hERG profile is excellent, the significantly worse metabolic stability and slightly lower affinity make it less attractive. The slightly lower logP of Ligand B is a minor concern, but the superior affinity and metabolic properties outweigh this.

Output:
1
2025-04-17 14:03:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (382.404 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.71) is slightly higher than Ligand B (67.43), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.019 and 2.973), falling within the optimal 1-3 range.

**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: 5, Ligand B: 3).

**6. QED:** Ligand A (0.745) has a better QED score than Ligand B (0.496), indicating a more drug-like profile.

**7. DILI:** Ligand B (19.736) has a significantly lower DILI risk than Ligand A (56.65), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.784) has a higher BBB percentile than Ligand B (64.986), but this is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.887 and -4.871), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.472 and -2.677), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.747) has a slightly higher hERG inhibition risk than Ligand B (0.28), but both are relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (38.837) has a lower microsomal clearance than Ligand B (46.966), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.021) has a significantly longer in vitro half-life than Ligand A (2.897), which is a major advantage for dosing convenience.

**14. P-gp Efflux:** Ligand A (0.147) has lower P-gp efflux than Ligand B (0.042), which is preferable.

**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 substantial advantage, potentially outweighing some of the ADME concerns.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has superior affinity and better metabolic stability. However, Ligand B has a much better DILI score and a significantly longer half-life. The poor Caco-2 and solubility for both are concerning.

**Overall Assessment:** The significantly stronger binding affinity of Ligand A is a major advantage. While Ligand B has better safety (DILI) and PK (half-life), the difference in binding affinity is substantial. Given that we can potentially address solubility and permeability issues through formulation strategies, the higher potency of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 14:03:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (369.4 and 344.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (122.74) is slightly above the preferred <140, but acceptable. Ligand B (69.64) is well within the range, indicating potentially better absorption.

**3. logP:** Ligand A (0.702) is a bit low, potentially hindering permeability. Ligand B (1.943) is closer to 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 (8) is good. Ligand B (3) is excellent.

**6. QED:** Both ligands have good QED scores (0.537 and 0.694), suggesting drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (87.01) has a significantly higher DILI risk than Ligand B (13.42). This is a major concern for Ligand A.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (61.54) and Ligand B (53.59) are both relatively low.

**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 difficult to interpret without more context.

**10. Solubility:** Both ligands have negative solubility values, also unusual. Again, difficult to interpret.

**11. hERG:** Both ligands have very low hERG risk (0.166 and 0.152), which is excellent.

**12. Cl_mic:** Ligand A (39.69) has lower microsomal clearance than Ligand B (50.33), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-32.57) has a more negative in vitro half-life, which is not possible. This is a red flag. Ligand B (-28.43) is also negative, but less so. These values are likely errors.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.336 and 0.118), which is favorable.

**15. 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 minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility values, Ligand B has a significantly better DILI profile, a stronger binding affinity, and a better logP value. Ligand A's high DILI risk and questionable half-life value are major drawbacks. The stronger binding affinity of Ligand B is a critical advantage for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:03:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.833 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (58.2), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.275) is optimal, while Ligand B (3.937) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, Ligand B has 2. Both are within the acceptable range.

**QED:** Ligand A (0.811) has a significantly better QED score than Ligand B (0.698), indicating better overall drug-likeness.

**DILI:** Ligand A (70.57) has a higher DILI risk than Ligand B (15.471). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (64.599 and 64.948), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.244 and -4.749).

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, values are similar (-3.381 and -4.368).

**hERG:** Ligand A (0.201) has a slightly better hERG profile than Ligand B (0.385), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (37.16 mL/min/kg) has significantly lower microsomal clearance than Ligand B (57.72 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (34.163 hours) has a much longer half-life than Ligand B (0.487 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.195) has lower P-gp efflux than Ligand B (0.151), which is favorable.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a 0.5 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B has a much better binding affinity (-9.0 vs -8.5 kcal/mol) and a significantly lower DILI risk (15.471 vs 70.57). While Ligand A has advantages in QED, metabolic stability (Cl_mic and t1/2), and P-gp efflux, the strong binding affinity and lower toxicity of Ligand B outweigh these benefits. The similar Caco-2 and solubility values are concerning for both, but can be addressed during lead optimization. The difference in binding affinity is large enough to overcome the other minor drawbacks of Ligand B.

Output:
1
2025-04-17 14:03:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.54) is well below the 140 threshold, and even preferable for oral absorption. Ligand B (81.75) is still acceptable, but less optimal.

**logP:** Ligand A (2.297) is within the optimal 1-3 range. Ligand B (0.374) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 and 2 respectively) and HBA (4 each) counts.

**QED:** Ligand A (0.834) has a significantly higher QED score than Ligand B (0.588), indicating better overall drug-likeness.

**DILI:** Ligand A (46.142) has a much lower DILI risk than Ligand B (13.3), which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (73.401) is better than Ligand B (38.813).

**Caco-2 Permeability:** Ligand A (-4.706) is better than Ligand B (-5.095), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.596) is better than Ligand B (-0.696). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.398 and 0.094 respectively), which is positive.

**Microsomal Clearance:** Ligand A (32.289) has a higher (worse) microsomal clearance than Ligand B (7.384), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-13.451) has a significantly longer in vitro half-life than Ligand A (9.855), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.081 and 0.003 respectively).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Ligand A excels in most ADME properties (QED, DILI, solubility, permeability, TPSA) and has good potency. However, its metabolic stability (higher Cl_mic, shorter t1/2) is a concern.

Ligand B has slightly weaker ADME properties overall, but shines in metabolic stability (lower Cl_mic, longer t1/2) and has a marginally better binding affinity.

Considering the priorities for enzyme inhibitors, the improved metabolic stability of Ligand B is a significant advantage. While Ligand A has better overall drug-likeness scores, the longer half-life of Ligand B could translate to a more favorable dosing regimen and potentially better *in vivo* efficacy. The slight affinity difference is less important than the metabolic stability.

Output:
1
2025-04-17 14:03:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.869 and 349.337 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (85.43) is still under 140, but less optimal than A.

**logP:** Ligand A (4.767) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.43) is within the optimal 1-3 range.

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

**QED:** Both ligands have similar QED values (0.804 and 0.781), indicating good drug-likeness.

**DILI:** Ligand A (64.948) has a higher DILI risk than Ligand B (56.34), though both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.474) has a better BBB score than Ligand B (43.699).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.768 and -4.753). This is unusual and suggests poor permeability, but the scale is not specified. We'll need to consider this cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.555 and -2.716). Similar to Caco-2, this is concerning and suggests poor solubility.

**hERG:** Ligand A (0.736) has a slightly higher hERG risk than Ligand B (0.529), but both are relatively low.

**Microsomal Clearance:** Ligand B (-17.779) has significantly lower (better) microsomal clearance than Ligand A (61.482), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand B (-13.164) has a longer half-life than Ligand A (68.489), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.642) has a lower P-gp efflux liability than Ligand B (0.045), which is favorable.

**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 is the more promising candidate. While Ligand A has slightly better TPSA and P-gp efflux, Ligand B excels in critical areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and a lower DILI risk. The solubility and permeability concerns are present in both, but the metabolic advantages of Ligand B are more important for an enzyme target.

Output:
1
2025-04-17 14:03:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.841 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.41) is better than Ligand B (95.66), both are acceptable but closer to the upper limit for good oral absorption (<=140).

**logP:** Ligand A (3.083) is optimal, while Ligand B (1.909) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=8) is preferable to Ligand B (HBD=3, HBA=4) as it has fewer HBDs. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.796 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (89.686) has a significantly higher DILI risk than Ligand B (31.563). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (68.786) and Ligand B (40.791) are both low.

**Caco-2 Permeability:** Ligand A (-4.694) is better than Ligand B (-5.325), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.753) is better than Ligand B (-2.195), suggesting better formulation potential.

**hERG:** Ligand A (0.209) has a lower hERG risk than Ligand B (0.647), which is a positive attribute.

**Microsomal Clearance:** Ligand A (89.737) has a higher microsomal clearance than Ligand B (-28.65). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (71.831) has a longer half-life than Ligand B (31.918), which is desirable.

**P-gp Efflux:** Ligand A (0.506) has lower P-gp efflux than Ligand B (0.084), suggesting better bioavailability.

**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, solubility, hERG risk, half-life, and P-gp efflux, its significantly higher DILI risk is a major drawback. Ligand B, despite having a slightly lower logP and higher P-gp efflux, has a much lower DILI risk and better metabolic stability (lower Cl_mic). Given the enzyme-specific priorities, metabolic stability and minimizing toxicity (DILI) are crucial. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 14:03:39,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.369 and 358.829 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.82) is better than Ligand B (85.92), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.811) is slightly lower than optimal (1-3), but acceptable. Ligand B (3.401) is within the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better.

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

**QED:** Ligand B (0.857) has a significantly higher QED score than Ligand A (0.451), indicating better overall drug-likeness.

**DILI:** Ligand B (40.054) has a lower DILI risk than Ligand A (48.042), both are acceptable.

**BBB:** Ligand A (71.501) shows better BBB penetration than Ligand B (48.391), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.157) and Ligand B (-4.951) are both poor.

**Aqueous Solubility:** Ligand A (-1.275) is better than Ligand B (-4.309).

**hERG Inhibition:** Ligand A (0.709) has a lower hERG risk than Ligand B (0.447), which is a significant advantage.

**Microsomal Clearance:** Ligand A (0.484) has significantly lower microsomal clearance than Ligand B (40.94), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.651) has a much longer in vitro half-life than Ligand B (3.543), a major advantage.

**P-gp Efflux:** Ligand A (0.1) has lower P-gp efflux than Ligand B (0.124).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has advantages in solubility, metabolic stability, and hERG risk, the significantly stronger binding affinity of Ligand B (-9.1 vs -7.6 kcal/mol) is the most critical factor for an enzyme inhibitor. The better QED score of Ligand B also supports its potential. The slightly higher logP of Ligand B is acceptable. The lower half-life and higher clearance of Ligand B could potentially be addressed through structural modifications in later optimization stages.

Output:
1
2025-04-17 14:03:39,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.475 and 357.401 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (78.87 and 80.32) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**3. logP:** Both ligands have logP values within the optimal range (1.485 and 2.396).

**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 QED values above 0.5 (0.616 and 0.711), indicating good drug-likeness.

**7. DILI:** Ligand A (5.312) has a significantly lower DILI risk than Ligand B (48.468). This is a major advantage for Ligand A.

**8. BBB:** Both have reasonable BBB penetration (68.864 and 70.531), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both show negative Caco-2 values (-4.746 and -4.609). 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 (-1.402 and -2.989). This is concerning, as poor solubility can hinder bioavailability. Ligand B has worse solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.356 and 0.585).

**12. Microsomal Clearance:** Ligand A (10.362) has a much lower microsomal clearance than Ligand B (43.218), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-12.318) has a longer in vitro half-life than Ligand B (-17.681). This is another advantage for Ligand A.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.083 and 0.093).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). However, the difference is only 0.5 kcal/mol, which is less significant than the ADME advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A exhibits significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The small difference in binding affinity is outweighed by these crucial ADME properties.

Output:
0
2025-04-17 14:03:39,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.441 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is well below the 140 threshold for oral absorption, and favorable. Ligand B (60.85) is still acceptable, but less optimal.

**logP:** Ligand A (4.086) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.094) is well within the optimal range.

**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 below the limits of 5 and 10 respectively.

**QED:** Both ligands have acceptable QED scores (0.858 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A (22.334) has a significantly lower DILI risk than Ligand B (13.843), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (92.943) shows better BBB penetration than Ligand B (69.058).

**Caco-2 Permeability:** Ligand A (-4.591) and Ligand B (-4.898) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.588) and Ligand B (-1.981) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both, but less severe for Ligand B.

**hERG Inhibition:** Ligand A (0.906) has a slightly higher hERG risk than Ligand B (0.235), which is preferable for Ligand B.

**Microsomal Clearance:** Ligand A (-2.785) has a more negative value, indicating lower clearance and better metabolic stability than Ligand B (21.234). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (37.761 hours) has a much longer half-life than Ligand B (9.322 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux liability than Ligand B (0.093), which is beneficial.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the primary driver for enzyme inhibitors. While it has some ADME liabilities (slightly higher hERG, lower metabolic stability, and solubility), the potency advantage is substantial. Ligand A has better metabolic stability, DILI risk, and half-life, but its significantly weaker binding affinity is a major drawback. The solubility and permeability issues are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 14:03:39,357 - INFO - Batch 265 complete. Total preferences: 4240
2025-04-17 14:03:39,358 - INFO - Processing batch 266/512...
2025-04-17 14:04:26,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.483 Da and 346.366 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.88) is well below the 140 threshold for good absorption, while Ligand B (97.98) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (1.516 and 0.916) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable limits. Ligand A has 5 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.851 and 0.787), indicating good drug-like properties.

**DILI:** Ligand A (25.281) has a significantly lower DILI risk than Ligand B (70.958), which is a substantial advantage.

**BBB:** BBB is not a primary concern for SRC kinase inhibitors, as it's not a CNS target. Ligand A (55.021) is lower than Ligand B (45.754), but this is not a major factor.

**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 indicates poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.522) has a slightly higher hERG risk than Ligand B (0.322), but both are relatively low.

**Microsomal Clearance:** Ligand B (-17.587) has a *much* lower (better) microsomal clearance than Ligand A (1.477), suggesting significantly better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (-18.103) has a substantially longer in vitro half-life than Ligand A (10.65), further reinforcing its superior metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.035 and 0.021).

**Binding Affinity:** Ligand B (-8.3) has a slightly better (more negative) binding affinity than Ligand A (-7.8), though the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk are crucial advantages for an enzyme inhibitor. The slightly better binding affinity is a bonus. The lower DILI risk is a major factor, and the improved metabolic stability suggests a potentially more favorable pharmacokinetic profile.

Output:
1
2025-04-17 14:04:26,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 360.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (136.59) is borderline, but acceptable for oral absorption. Ligand B (57.69) is excellent, well below the 140 threshold.

**logP:** Both ligands (2.21 and 2.457) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also good.

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4, also good.

**QED:** Ligand B (0.81) has a significantly better QED score than Ligand A (0.408), suggesting a more drug-like profile.

**DILI:** Ligand B (27.336) has a much lower DILI risk than Ligand A (69.911). This is a significant advantage.

**BBB:** Ligand B (78.79) has better BBB penetration than Ligand A (57.154), though this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 ligands have negative solubility values, also unusual. Again, the magnitude is similar.

**hERG Inhibition:** Ligand A (0.494) has a slightly higher hERG risk than Ligand B (0.076), which is preferable.

**Microsomal Clearance:** Ligand B (32.128) has a lower microsomal clearance than Ligand A (62.701), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have similar negative half-life values (-8.697 and -8.765), which is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.112).

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent and removes this as a differentiating factor.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While both have similar binding affinity, Ligand B demonstrates significantly better drug-like properties (higher QED), lower DILI risk, better metabolic stability (lower Cl_mic), and lower hERG risk. 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 14:04:26,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.362 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is slightly above the preferred <140 for good absorption, while Ligand B (94.56) is well within this range.

**logP:** Ligand A (1.468) is optimal, while Ligand B (-0.302) is slightly 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 within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.553 and 0.586, respectively), indicating drug-like properties.

**DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (20.279). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (60.14) and Ligand B (37.573) are both relatively low.

**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 is unspecified.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.08 and 0.136), which is excellent.

**Microsomal Clearance:** Ligand B (-16.365) has significantly lower (better) microsomal clearance than Ligand A (15.406), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.777) has a longer in vitro half-life than Ligand A (-29.74), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.005).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.6 and -8.4 kcal/mol). The difference is 1.2 kcal/mol, which isn't substantial enough to override other ADME concerns.

**Conclusion:**

While both ligands have good binding affinity and acceptable QED, Ligand B is significantly better due to its much lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better TPSA. The lower logP of Ligand B is a minor concern, but the substantial advantage in safety and metabolic properties outweighs this. The negative Caco-2 and solubility values are concerning for both, but without knowing the scale, it's hard to assess their impact.

Output:
1
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.416 Da) is slightly higher than Ligand B (349.475 Da), but both are acceptable.

**TPSA:** Ligand A (59.17) is significantly better than Ligand B (85.43). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**logP:** Both ligands have good logP values (A: 3.166, B: 2.095), 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). Both are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.786, B: 0.705), indicating good drug-likeness.

**DILI:** Ligand A has a higher DILI risk (63.086) compared to Ligand B (29.081). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.096) is better than Ligand B (36.06), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-5.065) shows poor permeability, while Ligand B (-4.993) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-4.193) is slightly better than Ligand B (-2.25), but both are quite poor.

**hERG Inhibition:** Ligand A (0.715) has a slightly higher hERG risk than Ligand B (0.307), but both are reasonably low.

**Microsomal Clearance:** Ligand B (9.604) has significantly lower microsomal clearance than Ligand A (34.135), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (9.163) has a longer half-life than Ligand A (23.623), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.443) has slightly lower P-gp efflux than Ligand B (0.145), which is favorable.

**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 small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a significantly lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has slightly better P-gp efflux and binding affinity, the DILI and metabolic stability concerns are more critical for an enzyme inhibitor. The slightly better TPSA of Ligand A is also a positive, but not enough to overcome the other drawbacks. Solubility is poor for both, which would need to be addressed in formulation.



Output:
1
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly better positioned.

**TPSA:** Both are below the 140 A^2 threshold for good absorption. Ligand B (79.38) is slightly better than Ligand A (87.66).

**logP:** Ligand A (1.221) is optimal, while Ligand B (5.155) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is better balanced. Ligand B (HBD=2, HBA=6) is acceptable but slightly higher in HBA.

**QED:** Ligand A (0.643) has a better drug-likeness score than Ligand B (0.465).

**DILI:** Ligand A (21.287) has a significantly lower DILI risk than Ligand B (80.458), a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (65.219) has a higher BBB value, but it's not relevant here.

**Caco-2 Permeability:** Both have negative values, which is unusual. It's difficult to interpret without knowing the scale. However, the magnitude of the negative value is similar.

**Aqueous Solubility:** Ligand A (-1.89) has better solubility than Ligand B (-4.602).

**hERG Inhibition:** Ligand A (0.155) has a much lower hERG risk than Ligand B (0.897), a critical safety factor.

**Microsomal Clearance:** Ligand A (20.671) has a lower Cl_mic, indicating better metabolic stability than Ligand B (48.307).

**In vitro Half-Life:** Ligand B (47.53) has a longer half-life than Ligand A (11.672). This is a positive for Ligand B, but can be compensated for by other factors.

**P-gp Efflux:** Both have low P-gp efflux liability. Ligand A (0.055) is marginally lower.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 kcal/mol and -8.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall:**

Ligand A is significantly better due to its superior drug-likeness (QED), lower DILI risk, lower hERG risk, better solubility, and improved metabolic stability. While Ligand B has a longer half-life, the other advantages of Ligand A outweigh this benefit, especially considering the importance of safety and ADME properties for an enzyme target. The slightly higher logP of Ligand B is a concern.

Output:
0
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (480.736 Da) is within the ideal range, while Ligand B (347.419 Da) is on the lower side but still acceptable.

**TPSA:** Ligand A (97.38) is good for oral absorption. Ligand B (112.13) is slightly higher, but still reasonable.

**logP:** Both ligands have good logP values (A: 2.4, B: 1.521), falling 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 hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.527, B: 0.81), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a very high DILI risk (96.394), which is a major concern. Ligand B has a much lower, and acceptable, DILI risk (33.23).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (58.782) and Ligand B (69.019) are both relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so the magnitude matters. Ligand A (-4.939) is better than Ligand B (-5.068).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-2.667) is slightly better than Ligand A (-3.471).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.157, B: 0.078), which is excellent.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-9.58), indicating very high metabolic stability, which is excellent. Ligand B has a positive Cl_mic (25.245), indicating faster clearance and lower metabolic stability.

**In vitro Half-Life:** Ligand A has a good half-life (72.926 hours), while Ligand B has a very short half-life (-22.722 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.379, B: 0.034), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.6 kcal/mol, B: -9.0 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand A has excellent potency, metabolic stability, and a low hERG risk, but its extremely high DILI risk is a deal-breaker. Ligand B has slightly better potency, a much lower DILI risk, and low P-gp efflux, but suffers from poor metabolic stability and a short half-life.

Despite Ligand B's slightly lower metabolic stability, the significantly lower DILI risk outweighs this drawback. DILI is a common reason for drug failure, and a high DILI risk is almost always disqualifying. While metabolic stability can sometimes be improved through structural modifications, mitigating a high DILI risk is often much more challenging.

Output:
1
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.507 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is significantly better than Ligand B (74.33).  A TPSA under 90 is generally good, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.617 and 1.48), 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=4) as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.792 and 0.865), indicating good drug-like properties.

**DILI:** Ligand A (7.871) has a much lower DILI risk than Ligand B (55.448). This is a significant advantage for A.  B's DILI is moderately high.

**BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (81.155) is better than Ligand B (63.862), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.719) is better than Ligand B (-5.029), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.316) is better than Ligand B (-2.758), indicating better solubility. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.615) has a lower hERG risk than Ligand B (0.428), which is a significant advantage. Lower is better here.

**Microsomal Clearance:** Ligand A (-7.889) has *much* better metabolic stability than Ligand B (32.957). A negative value indicates very low clearance, which is highly desirable.

**In vitro Half-Life:** Ligand A (2.586) is better than Ligand B (5.126), indicating a longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.039).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 1 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is significantly better than Ligand B. It has superior DILI risk, metabolic stability (Cl_mic), solubility, hERG risk, and a slightly better binding affinity. While both ligands have acceptable properties overall, Ligand A's profile is much more favorable for development as a drug candidate targeting SRC kinase.

Output:
1
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (374.853 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.44) is still acceptable, but less optimal.

**logP:** Ligand A (3.074) is optimal (1-3). Ligand B (-0.262) is significantly below 1, potentially hindering permeability.

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

**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 reasonable QED scores (0.641 and 0.53), indicating good drug-like properties.

**DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (47.964), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (63.707) has a higher BBB value than Ligand A (44.824), but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.49 and -5.333), 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 (-4.411 and -1.015), indicating poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.338) shows a lower hERG inhibition risk than Ligand B (0.028), which is highly desirable.

**Microsomal Clearance:** Ligand A (4.739) has significantly lower microsomal clearance than Ligand B (15.482), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.919) has a longer in vitro half-life than Ligand B (0.384), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux liability than Ligand B (0.006), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). However, the difference is only 0.5 kcal/mol, which is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both ligands have poor solubility and permeability, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. The slightly better binding affinity of Ligand B is outweighed by its significantly worse ADME profile.

Output:
0
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.443 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.83) is higher than Ligand B (74.09). While both are reasonably low, Ligand B is better positioned for good oral absorption.

**logP:** Ligand A (0.604) is slightly low, potentially hindering permeation. Ligand B (2.586) 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: 7, B: 7) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.617, B: 0.712), indicating drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (A: 44.048, B: 43.738), below the 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (47.111) has a higher BBB score than Ligand A (28.655), but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.123 and -5.142), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.333 and -2.243), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.179, B: 0.301), which is positive.

**Microsomal Clearance:** Ligand A (15.669 mL/min/kg) has significantly lower microsomal clearance than Ligand B (35.612 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-34.506 hours) has a negative half-life, which is not physically possible and indicates an issue with the data or the model. Ligand B (-1.861 hours) also has a negative half-life, which is concerning.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.076, B: 0.122).

**Binding Affinity:** Both ligands have very strong binding affinities (A: -9.0 kcal/mol, B: -9.1 kcal/mol). The difference is minimal.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is slightly favored due to its significantly lower microsomal clearance (better metabolic stability) and a slightly better (though still problematic) in vitro half-life. The binding affinity is comparable. The negative half-life values are concerning and would need to be investigated further, but the other ADME properties lean slightly towards A.

Output:
0
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.507 and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is significantly better than Ligand B (80.23). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (0.776 and 1.455), falling within the 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 acceptable, but Ligand A is slightly preferred.

**QED:** Both ligands have good QED scores (0.769 and 0.857), indicating good drug-like properties.

**DILI:** Ligand A (1.473) has a much lower DILI risk than Ligand B (49.128). This is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (83.87) has better BBB penetration than Ligand B (68.127).

**Caco-2 Permeability:** Ligand A (-5.16) shows better Caco-2 permeability than Ligand B (-4.827).

**Aqueous Solubility:** Ligand A (-0.836) has better aqueous solubility than Ligand B (-2.439). This is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.55) has a lower hERG inhibition risk than Ligand B (0.244), which is a major advantage.

**Microsomal Clearance:** Ligand A (1.396) has significantly lower microsomal clearance than Ligand B (18.89), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.754) has a much longer in vitro half-life than Ligand B (36.688). This is a major advantage.

**P-gp Efflux:** Ligand A (0.008) has lower P-gp efflux liability than Ligand B (0.174).

**Binding Affinity:** Ligand B (0.0) has a better binding affinity than Ligand A (-8.5). This is a substantial advantage. However, the other ADME properties of Ligand A are significantly better.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a significantly better overall ADME profile. The lower DILI risk, better solubility, lower hERG inhibition, improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux are all critical advantages for a drug candidate. The difference in binding affinity (0.0 vs -8.5) is substantial, but the improvements in ADME properties for Ligand A are likely to translate into better *in vivo* efficacy and safety. Given the enzyme-specific priorities, metabolic stability and safety are crucial, making Ligand A the more promising candidate.

Output:
0
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.503 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.25) is well below the 140 threshold for good absorption, while Ligand B (104.29) is still acceptable but less optimal.

**logP:** Ligand A (3.905) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.492) is significantly lower, which could impede permeability.

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

**QED:** Both ligands have good QED scores (0.613 and 0.675), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 81.66, which is high and concerning. Ligand B has a much lower DILI risk of 35.169, a significant advantage.

**BBB:** Both have moderate BBB penetration (59.946 and 53.974). Since SRC is not a CNS target, this is not a major factor.

**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 ligands have very poor aqueous solubility (-4.408 and -0.839). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.64) has a moderate hERG risk, while Ligand B (0.053) has a very low risk, a substantial advantage.

**Microsomal Clearance:** Ligand A (75.376) has a moderate clearance, while Ligand B (13.906) has a very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (59.899) has a reasonable half-life, but Ligand B (17.779) has a shorter half-life, which is a disadvantage.

**P-gp Efflux:** Ligand A (0.654) has moderate P-gp efflux, while Ligand B (0.002) has very low efflux, which is favorable.

**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 relatively small.

**Overall Assessment:**

Ligand B is the more promising candidate. While its solubility and Caco-2 permeability are concerning, its significantly lower DILI risk, hERG risk, and P-gp efflux, coupled with its superior metabolic stability (lower Cl_mic) and slightly better binding affinity, outweigh the drawbacks. Ligand A's high DILI risk is a major red flag. Solubility issues can potentially be addressed through formulation strategies, but mitigating a high DILI risk is far more challenging.

Output:
1
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.367 Da) is slightly lower than Ligand B (372.334 Da), which isn't a major concern.

**TPSA:** Ligand A (111.55) is better than Ligand B (58.64) as it is closer to the ideal range for oral absorption.

**logP:** Both ligands have good logP values (A: 1.95, B: 1.757), falling within the optimal 1-3 range.

**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, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.664, B: 0.723), indicating good drug-like properties.

**DILI:** Ligand B (35.285) has a significantly lower DILI risk than Ligand A (54.634), making it more favorable.

**BBB:** Ligand B (92.943) has a much higher BBB penetration percentile than Ligand A (37.96). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-5.282) has a worse Caco-2 permeability than Ligand B (-4.583).

**Aqueous Solubility:** Ligand A (-4.242) has a worse aqueous solubility than Ligand B (-2.761).

**hERG:** Both ligands have similar hERG inhibition liability (A: 0.316, B: 0.614), and both are relatively low risk.

**Microsomal Clearance:** Ligand B (1.833) has a much lower microsomal clearance than Ligand A (32.826), indicating better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-17.974) has a better in vitro half-life than Ligand A (-26.819).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.011, B: 0.087).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Conclusion:**

Ligand B is superior to Ligand A. While both have excellent binding affinity, Ligand B demonstrates significantly better ADME properties: lower DILI risk, better BBB penetration, improved Caco-2 permeability, better solubility, and, crucially, much lower microsomal clearance and a longer in vitro half-life. These factors are particularly important for an enzyme target like SRC kinase, where metabolic stability and bioavailability are critical for efficacy.

Output:
1
2025-04-17 14:04:26,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 415.288 Da - Within the ideal range (200-500 Da).
* Ligand B: 348.443 Da - Also within the ideal range.
* *Advantage: Neither is problematic.*

**2. TPSA:**
* Ligand A: 84.00  - Good, below the 140 threshold for oral absorption.
* Ligand B: 78.87 - Excellent, also below 140.
* *Advantage: Both are good, B slightly better.*

**3. logP:**
* Ligand A: 1.737 - Optimal (1-3).
* Ligand B: 1.157 - Optimal (1-3).
* *Advantage: Both are good.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Meets the <=5 criteria.
* Ligand B: 2 - Meets the <=5 criteria.
* *Advantage: Both are good.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 5 - Meets the <=10 criteria.
* Ligand B: 4 - Meets the <=10 criteria.
* *Advantage: Both are good.*

**6. QED:**
* Ligand A: 0.81 - Excellent, well above 0.5.
* Ligand B: 0.706 - Good, above 0.5.
* *Advantage: A is better.*

**7. DILI:**
* Ligand A: 73.052 - Moderate risk.
* Ligand B: 25.281 - Low risk, very good.
* *Advantage: B is significantly better.*

**8. BBB:**
* Ligand A: 68.67 - Not a primary concern for a kinase inhibitor, but moderate.
* Ligand B: 58.007 - Not a primary concern.
* *Advantage: Neither is a strong factor.*

**9. Caco-2 Permeability:**
* Ligand A: -4.399 - Poor permeability.
* Ligand B: -4.874 - Poor permeability.
* *Advantage: Neither is good.*

**10. Aqueous Solubility:**
* Ligand A: -2.453 - Poor solubility.
* Ligand B: -2.035 - Poor solubility.
* *Advantage: Neither is good.*

**11. hERG Inhibition:**
* Ligand A: 0.295 - Low risk.
* Ligand B: 0.18 - Very low risk.
* *Advantage: B is better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 28.646 - Moderate clearance.
* Ligand B: 39.082 - Higher clearance, less desirable.
* *Advantage: A is better.*

**13. In vitro Half-Life:**
* Ligand A: -13.954 - Long half-life.
* Ligand B: -1.974 - Shorter half-life.
* *Advantage: A is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.039 - Low efflux, good.
* Ligand B: 0.114 - Moderate efflux.
* *Advantage: A is better.*

**15. Binding Affinity:**
* Ligand A: -9.6 kcal/mol - Excellent.
* Ligand B: -7.9 kcal/mol - Good.
* *Advantage: A is significantly better (1.7 kcal/mol difference).*

**Overall Assessment:**

For an enzyme (kinase) target, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a *much* stronger binding affinity (-9.6 vs -7.9 kcal/mol), a longer half-life, lower P-gp efflux, and better metabolic stability (lower Cl_mic). While Ligand B has a lower DILI risk, the substantial advantage in affinity and metabolic properties of Ligand A outweighs this concern. Both have poor solubility and permeability, but these can be addressed with formulation strategies.

Output:
1
2025-04-17 14:04:26,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 343.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (70.9) is still acceptable but less favorable.

**logP:** Both ligands have good logP values (3.571 and 2.351), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is more favorable than Ligand B (2 HBD, 7 HBA) as it has fewer hydrogen bond forming groups.

**QED:** Both ligands have acceptable QED values (0.912 and 0.717), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (50.989 and 54.827), both being acceptable.

**BBB:** Ligand A (97.829) has much better BBB penetration potential than Ligand B (85.072), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.356) has a more negative Caco-2 value, indicating *lower* permeability than Ligand B (-5.295). This is a negative for Ligand A.

**Aqueous Solubility:** Ligand A (-4.029) has a more negative solubility value, indicating *lower* solubility than Ligand B (-3.198). This is a negative for Ligand A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.657 and 0.955), which is excellent.

**Microsomal Clearance:** Ligand A (50.249) has lower microsomal clearance than Ligand B (60.109), suggesting better metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (48.595) has a longer in vitro half-life than Ligand A (26.864), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.486 and 0.35), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has advantages in TPSA, metabolic stability (Cl_mic), and BBB penetration. However, it suffers from lower Caco-2 permeability and aqueous solubility. Ligand B has a longer half-life, but is less favorable in TPSA and Cl_mic. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility), the slightly better metabolic stability of Ligand A, combined with its acceptable TPSA and strong binding affinity, gives it a slight edge. The solubility and permeability concerns are moderate and might be addressed through formulation strategies.

Output:
1
2025-04-17 14:04:26,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 374.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (112.23) is still within acceptable limits for oral absorption (<140), but less optimal than A.

**logP:** Ligand A (3.047) is optimal (1-3). Ligand B (0.21) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.65 and 0.739), indicating drug-like properties.

**DILI:** Ligand A (5.777) has a very low DILI risk. Ligand B (63.552) has a significantly higher DILI risk, falling into the high-risk category (>60).

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (83.87) shows better potential for CNS penetration if needed. Ligand B (55.874) is lower.

**Caco-2 Permeability:** Ligand A (-4.633) is poor, while Ligand B (-5.238) is even worse. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.139 and -2.569). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.507) has a low hERG risk, while Ligand B (0.331) is even lower. Both are good.

**Microsomal Clearance:** Ligand A (39.351) has moderate clearance. Ligand B (-6.424) has *negative* clearance, which is highly unusual and likely an artifact of the prediction method, but suggests exceptional metabolic stability.

**In vitro Half-Life:** Ligand A (-13.51) has a negative half-life, which is also likely an artifact of the prediction method. Ligand B (-29.103) is even more negative. Both are problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.126 and 0.048).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage (a >1.9 kcal/mol difference).

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the highest priority for an enzyme inhibitor. However, it suffers from a high DILI risk, very low logP, and poor solubility. Ligand A has better physicochemical properties (logP, TPSA, DILI) but a weaker binding affinity. The negative values for Cl_mic and t1/2 for both are concerning and likely indicate issues with the prediction method.

Despite the DILI risk, the significantly stronger binding affinity of Ligand B is likely to be the deciding factor, *provided* the DILI risk can be mitigated through structural modifications. The potency advantage is large enough to potentially overcome the other drawbacks.

Output:
1
2025-04-17 14:04:26,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.455 and 343.471 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.0) is slightly higher than Ligand B (62.3), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal 1-3 range (2.666 and 2.996 respectively).

**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 QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (4.343) has a significantly lower DILI risk than Ligand B (11.361), which is a major advantage.

**BBB:** Ligand A (68.36) has a lower BBB penetration than Ligand B (76.347). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.871 and -4.8), 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 (-2.301 and -1.705), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.817) has a slightly higher hERG inhibition risk than Ligand B (0.359), but both are relatively low.

**Microsomal Clearance:** Ligand A (36.792 mL/min/kg) has a lower microsomal clearance than Ligand B (49.379 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.959 hours) has a significantly longer in vitro half-life than Ligand B (-14.813 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.138).

**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:**

Ligand B has a slightly better binding affinity, but Ligand A demonstrates superior ADMET properties, particularly regarding DILI risk and metabolic stability (lower Cl_mic, longer t1/2). The difference in binding affinity (1.3 kcal/mol) is not substantial enough to outweigh the significant advantages of Ligand A in terms of safety and pharmacokinetic properties, especially for an enzyme target where metabolic stability is crucial. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 14:04:26,587 - INFO - Batch 266 complete. Total preferences: 4256
2025-04-17 14:04:26,587 - INFO - Processing batch 267/512...
2025-04-17 14:05:08,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (429.38 Da) is within the ideal range (200-500 Da). Ligand B (359.442 Da) is also within the ideal range. No clear advantage here.

**TPSA:** Ligand A (58.64) is good, well below the 140 threshold. Ligand B (87.74) is still acceptable, but higher. A favors absorption.

**logP:** Ligand A (3.948) is at the higher end of optimal, but still acceptable. Ligand B (0.631) is quite low, potentially hindering permeability. A is better.

**H-Bond Donors:** Both ligands have acceptable HBD counts (A: 1, B: 2), below the threshold of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (A: 4, B: 4), below the threshold of 10.

**QED:** Both ligands have reasonable QED values (A: 0.741, B: 0.56), indicating good drug-like properties. A is slightly better.

**DILI:** Ligand A (41.877) has a low DILI risk. Ligand B (22.528) is even lower, indicating a better safety profile regarding liver toxicity. B is better.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (94.223) has a higher BBB percentile than Ligand B (70.803).

**Caco-2 Permeability:** Ligand A (-4.467) has poor Caco-2 permeability. Ligand B (-4.948) also has poor Caco-2 permeability. Both are problematic.

**Aqueous Solubility:** Ligand A (-4.778) has poor aqueous solubility. Ligand B (-1.692) has better aqueous solubility. B is better.

**hERG Inhibition:** Ligand A (0.589) has a low hERG risk. Ligand B (0.346) has an even lower hERG risk. B is better.

**Microsomal Clearance:** Ligand A (117.425) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (16.145) has much lower clearance, indicating better metabolic stability. B is significantly better.

**In vitro Half-Life:** Ligand A (21.555) has a reasonable half-life. Ligand B (-10.872) has a negative half-life, which is not 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 (A: 0.476, B: 0.034). B is better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 kcal/mol and -8.8 kcal/mol). This is not a differentiating factor.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A in several critical areas for an enzyme inhibitor: DILI risk, aqueous solubility, hERG risk, and importantly, metabolic stability (lower Cl_mic). While Ligand A has a slightly better TPSA and QED, these are outweighed by the significant advantages of Ligand B. The negative half-life for Ligand B is concerning and warrants further investigation, but the other properties suggest it's a more promising starting point. The poor Caco-2 permeability is a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 14:05:08,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (366.462 and 363.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (66.4 and 62.74) below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have logP values (1.17 and 1.581) within the optimal 1-3 range.

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

**5. H-Bond Acceptors:** Both have 5 HBAs, which is acceptable.

**6. QED:** Both ligands have QED values (0.8 and 0.795) well above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 60.644, placing it at a moderate risk. Ligand B has a significantly lower DILI risk of 31.756, which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.466) has a higher BBB percentile than Ligand B (57.464).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.988 and -4.973). This is unusual and suggests poor permeability. It's possible these values are errors or represent very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.884 and -1.957), which is also unusual and suggests poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.261 and 0.164), which is excellent.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (17.637 mL/min/kg) than Ligand B (28.68 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer in vitro half-life (-14.979 hours) than Ligand B (-9.149 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.028).

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-9.1 kcal/mol) than Ligand B (-7.4 kcal/mol). This is a 1.7 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the concerning negative values for Caco-2 and solubility, Ligand A appears to be the more promising candidate. The significantly better metabolic stability (lower Cl_mic, longer t1/2) and superior binding affinity outweigh the slightly higher DILI risk. The negative Caco-2 and solubility values would need to be investigated further, but the potency advantage is significant for an enzyme target. Ligand B's lower DILI is attractive, but the weaker binding and poorer metabolic stability are less desirable.

Output:
0
2025-04-17 14:05:08,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.45 and 348.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly higher than Ligand B (58.64). Both are acceptable, but B is better for permeability.

**logP:** Both ligands have good logP values (1.164 and 2.509), 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 acceptable limits.

**QED:** Both ligands have good QED scores (0.558 and 0.686), indicating good drug-likeness.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (17.255). This is a significant concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (78.558 and 75.805). This isn't a primary concern for a kinase inhibitor, but it's good to know.

**Caco-2:** Ligand A (-5.85) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.899) is also poor, but slightly better than A.

**Solubility:** Both ligands have very poor aqueous solubility (-3.077 and -3.035). This is a major drawback for both.

**hERG:** Both ligands have low hERG inhibition risk (0.386 and 0.261).

**Microsomal Clearance:** Ligand A (20.47 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (58.096 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.678 hours) has a negative half-life, which is impossible. This is a red flag and suggests an issue with the data or the compound itself. Ligand B (-11.814 hours) is also negative, but less so. Both are problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.137 and 0.085).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). The difference is 0.6 kcal/mol, which is not enough to overcome the other issues.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its significantly higher DILI risk, very poor Caco-2 permeability, and impossible half-life make it a much less viable candidate. Ligand B, while also having poor solubility and a negative half-life, has a much better safety profile (DILI) and slightly better permeability. Given the enzyme-specific priorities, metabolic stability (Cl_mic) is important, and Ligand A has an edge there, but the other issues are too significant.

Output:
1
2025-04-17 14:05:08,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.471 and 384.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.42 and 83.55) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.411 and 1.907) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5 HBA, both are below the 10 threshold.

**QED:** Ligand A (0.48) is slightly below the desirable 0.5 threshold, while Ligand B (0.786) is above it, suggesting better drug-likeness.

**DILI:** Ligand A (47.77) has a lower DILI risk than Ligand B (59.48), both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.943) has a better BBB penetration than Ligand B (55.138).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.105 and -5.382), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.587 and -2.377), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.25 and 0.205).

**Microsomal Clearance:** Ligand A (81.705) has a higher microsomal clearance than Ligand B (15.753), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (35.388 hours) has a much longer in vitro half-life than Ligand A (-4.26 hours), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.207).

**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 of the ADME concerns.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-10.3 vs -7.7 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target like SRC kinase. The better QED score also contributes to its favorability. While the solubility and permeability issues need to be addressed through formulation or further chemical modifications, the potency and metabolic stability advantages of Ligand B make it the better starting point for drug development.

Output:
1
2025-04-17 14:05:08,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.22) is better than Ligand B (98.17), both are acceptable for oral absorption being under 140.

**logP:** Both ligands have good logP values (2.575 and 3.256), 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:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.593) has a better QED score than Ligand B (0.372), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (26.095 and 22.838, respectively), which is excellent.

**BBB:** Both ligands have acceptable BBB penetration (68.166 and 64.715), but these are not critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.158) is better than Ligand B (-4.642), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.182) is better than Ligand B (-2.432), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.561 and 0.287, respectively). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (20.597 mL/min/kg) has significantly lower microsomal clearance than Ligand B (36.773 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.139 hours) has a shorter half-life than Ligand B (11.551 hours). This is a negative for Ligand A, as a longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.152) has lower P-gp efflux than Ligand B (0.042), meaning better bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is the most important factor for an enzyme inhibitor. A difference of 1.2 kcal/mol is substantial.

**Overall:** While Ligand A has better ADME properties (solubility, permeability, metabolic stability, QED, P-gp efflux), the significantly stronger binding affinity of Ligand B (-7.9 vs -9.1 kcal/mol) outweighs these advantages. The difference in affinity is large enough to compensate for the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 14:05:08,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (354.33 and 354.54 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.66) is significantly better than Ligand B (72.8).  A TPSA under 90 is generally acceptable, and A is much closer to the desirable <60 for good permeability.

**3. logP:** Both ligands have acceptable logP values (3.40 and 2.16), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but not dramatically so.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer H-bond donors generally improve permeability.

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

**6. QED:** Ligand A (0.746) has a higher QED score than Ligand B (0.555), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.09) has a higher DILI risk than Ligand B (9.77). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have reasonably high BBB penetration (83.25 and 73.71). This isn't a primary concern for a kinase inhibitor, but higher is generally better.

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

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is unclear, but both appear to have poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.78 and 0.78).

**12. Microsomal Clearance:** Ligand B (40.05) has lower microsomal clearance than Ligand A (54.09), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-5.26) has a negative half-life, which is not possible. This is a major red flag. Ligand A (5.78) is reasonable.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.41 and 0.45).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.5), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B appears to be the better candidate *despite* the nonsensical negative half-life value. The lower DILI risk and better metabolic stability (lower Cl_mic) are significant advantages. The slightly better binding affinity of Ligand B is a bonus. The negative half-life for Ligand B is a data error that would need to be resolved, but assuming it's corrected to a reasonable value, it would be preferred. Ligand A's high DILI risk is a major concern.

Output:
1
2025-04-17 14:05:08,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.419 and 359.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.69) is higher than Ligand B (73.2). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**3. logP:** Ligand A (0.662) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (3.026) is within the 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 (6) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have high QED scores (0.832 and 0.901), indicating good drug-like properties.

**7. DILI:** Ligand A (42.226) and Ligand B (50.136) both have low DILI risk, below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (60.682) is higher than Ligand A (48.856), but neither is particularly high.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.592 and -4.989), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.899 and -3.464), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.051) has a very low hERG risk, which is excellent. Ligand B (0.604) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (19.186) and Ligand B (21.015) have similar microsomal clearance values. These are moderate, suggesting moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A (-24.706) has a negative half-life, which is not physically possible and likely indicates an issue with the data. Ligand B (1.511) has a very short half-life, which is undesirable.

**14. P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is favorable. Ligand B (0.297) is slightly higher, but still relatively low.

**15. Binding Affinity:** Ligand B (-10.0) has a significantly stronger binding affinity than Ligand A (-8.1). This difference of 1.9 kcal/mol is substantial and can outweigh many other drawbacks.

**Conclusion:**

Despite the poor permeability and solubility for both compounds, Ligand B is the more promising candidate due to its significantly stronger binding affinity (-10.0 kcal/mol vs -8.1 kcal/mol). The better logP and lower TPSA of Ligand B also contribute to its favorability. The negative half-life for Ligand A is a critical flaw. While both need significant improvement in solubility and permeability, the potency advantage of Ligand B makes it the better starting point for optimization.

Output:
1
2025-04-17 14:05:08,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.415 and 374.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.48) is better than Ligand B (75.62), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.281) is optimal, while Ligand B (4.354) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, within acceptable limits. Ligand B has 2 HBD and 8 HBA, also acceptable, but slightly higher HBA could impact permeability.

**QED:** Both ligands (0.591 and 0.64) have good drug-likeness scores.

**DILI:** Ligand A (59.403) has a moderate DILI risk, while Ligand B (74.68) has a higher risk.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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 also unusual and indicates poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.592 and 0.515).

**Microsomal Clearance:** Ligand A (-6.721) has significantly lower (better) microsomal clearance than Ligand B (41.773), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (67.419) has a much longer in vitro half-life than Ligand A (-2.568).

**P-gp Efflux:** Both have very low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol), a difference of 1.1 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B's superior binding affinity (-8.7 vs -7.6 kcal/mol) is a major advantage, potentially outweighing its higher logP and DILI risk. However, the negative values for Caco-2 and solubility are concerning for both. The significantly better metabolic stability of Ligand A is also a positive, but the weaker binding is a drawback. Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity, Ligand B is the more promising candidate *despite* its drawbacks, assuming the solubility and permeability issues can be addressed through formulation or further chemical modifications.

Output:
1
2025-04-17 14:05:08,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.515 and 369.795 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.11) is higher than Ligand B (49.77). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have good logP values (3.546 and 4.238), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not critically.

**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 Ligand B is slightly better.

**QED:** Both ligands have good QED scores (0.7 and 0.828), indicating good drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (37.999 and 37.611 percentile), which is positive.

**BBB:** Ligand A (63.164) has a higher BBB penetration percentile than Ligand B (46.879). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-5.621) has a much worse Caco-2 permeability than Ligand B (-4.613). This suggests Ligand B will have better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.856) has slightly better solubility than Ligand B (-4.544), which is favorable.

**hERG Inhibition:** Ligand A (0.636) has a lower hERG inhibition risk than Ligand B (0.885), which is a significant advantage.

**Microsomal Clearance:** Ligand A (66.555) has lower microsomal clearance than Ligand B (79.66), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (33.575) has a longer in vitro half-life than Ligand B (22.893), which is also favorable.

**P-gp Efflux:** Ligand A (0.481) has lower P-gp efflux liability than Ligand B (0.339), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, metabolic stability, and lower hERG risk, the significantly stronger binding affinity of Ligand B (-8.6 vs -7.6 kcal/mol) is the most critical factor for an enzyme target like SRC kinase. The slightly worse ADME properties of Ligand B are likely manageable given the potency advantage.

Output:
1
2025-04-17 14:05:08,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (355.479 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.11) is slightly higher than the preferred <140, but acceptable. Ligand B (59.08) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (-0.185) is a bit low, potentially hindering permeation. Ligand B (1.701) is 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 (5) is acceptable. Ligand B (4) is also good.

**QED:** Ligand A (0.614) is good, indicating drug-like properties. Ligand B (0.444) is lower, suggesting a less ideal drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (9.035 and 9.461, respectively), which is positive.

**BBB:** Ligand A (23.381) has very low BBB penetration. Ligand B (81.582) has good BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.018) has poor Caco-2 permeability. Ligand B (-4.158) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.783 and -0.667, respectively). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.129 and 0.394, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (21.449) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (67.076) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-4.356) has a longer in vitro half-life, further supporting better metabolic stability. Ligand B (-11.604) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.069, respectively).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 1.1 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a superior binding affinity and a more favorable logP value, which are crucial for an enzyme inhibitor. While its QED is lower and its metabolic stability is worse than Ligand A, the affinity difference is substantial enough to outweigh these drawbacks. The poor solubility of both compounds is a concern, but formulation strategies could potentially address this. The slightly better Caco-2 permeability of Ligand B is also a minor advantage.

Output:
1
2025-04-17 14:05:08,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is slightly higher than Ligand B (87.74), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.492) and Ligand B (0.991) 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.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Both ligands have QED values (0.787 and 0.637) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (45.328) has a slightly higher DILI risk than Ligand B (30.826), but both are below the concerning threshold of 60.

**BBB:** Ligand A (54.556) has a lower BBB penetration percentile than Ligand B (69.523). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.874 and -4.817), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.944 and -1.039), indicating very poor aqueous solubility. This is a major concern for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.203) has a slightly higher hERG risk than Ligand B (0.085), but both are relatively low.

**Microsomal Clearance:** Ligand B (43.238 mL/min/kg) has a lower microsomal clearance than Ligand A (26.861 mL/min/kg), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (-15.487 hours) has a significantly longer in vitro half-life than Ligand A (-31.596 hours). This is a major positive for Ligand B.

**P-gp Efflux:** Ligand A (0.128) has slightly lower P-gp efflux than Ligand B (0.03), which is favorable.

**Binding Affinity:** Ligand A (-8.3 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 concerns. The difference of 1.6 kcal/mol is significant.

**Conclusion:**

Despite the poor Caco-2 and solubility profiles of both compounds, Ligand A's significantly stronger binding affinity (-8.3 kcal/mol vs -6.7 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. The improved metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux of Ligand B are beneficial, but are unlikely to compensate for the large difference in binding affinity. The slightly higher DILI risk for Ligand A is a minor concern compared to the potency difference.

Output:
0
2025-04-17 14:05:08,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.427 and 361.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.6) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (91.32) is still acceptable but less favorable.

**logP:** Both ligands (2.716 and 2.609) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is excellent, while Ligand B (3) is acceptable but slightly less desirable.

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

**QED:** Ligand A (0.924) is significantly better than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand A (40.054) has a much lower DILI risk than Ligand B (75.456), which is a significant advantage.

**BBB:** Ligand A (70.997) shows good BBB penetration, while Ligand B (43.583) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for A.

**Caco-2 Permeability:** Ligand A (-4.82) and Ligand B (-5.399) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.081) and Ligand B (-4.116) both have negative values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands (0.511 and 0.435) have low hERG inhibition risk, which is positive.

**Microsomal Clearance:** Ligand A (27.722) has slightly better metabolic stability (lower clearance) than Ligand B (34.802).

**In vitro Half-Life:** Ligand A (38.899) has a longer half-life than Ligand B (-7.14), which is a significant advantage.

**P-gp Efflux:** Both ligands (0.11 and 0.149) have low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.4). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has superior ADME properties (QED, DILI, BBB, metabolic stability, half-life), Ligand B boasts a significantly stronger binding affinity (-9.0 vs -8.4 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. The 0.6 kcal/mol difference is substantial enough to favor Ligand B, despite its less favorable ADME profile. Further optimization of Ligand B could address the DILI and solubility concerns while retaining its strong binding affinity.

Output:
1
2025-04-17 14:05:08,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.543 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (78.95). Both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Ligand A (2.037) is optimal, while Ligand B (0.835) is slightly low, potentially impacting permeability.

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

**H-Bond Acceptors:** Both ligands (4) are well below the 10 limit.

**QED:** Ligand B (0.819) has a significantly better QED score than Ligand A (0.457), suggesting better overall drug-likeness.

**DILI:** Ligand B (33.346) has a much lower DILI risk than Ligand A (7.057), a significant advantage.

**BBB:** Ligand A (55.099) and Ligand B (65.607) are both relatively low, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.802) is worse than Ligand B (-5.105), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.554 and -2.321). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.298) is slightly higher than Ligand B (0.137), indicating a slightly higher risk of cardiotoxicity, but both are relatively low.

**Microsomal Clearance:** Ligand B (7.818) has a significantly lower microsomal clearance than Ligand A (39.526), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.044) has a significantly longer half-life than Ligand A (-3.618), a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands (0.04 and 0.013) show very low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand A.

**Conclusion:**

Ligand B is the superior candidate. While both have poor solubility, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, a better QED score, and a substantially stronger binding affinity. The slightly lower logP of Ligand B is a minor concern compared to the benefits it offers.

Output:
1
2025-04-17 14:05:08,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.422 and 359.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (29.54), being below 140, but Ligand B is significantly lower and more favorable for cell permeability.

**logP:** Ligand A (1.659) is within the optimal 1-3 range. Ligand B (4.137) is slightly higher, potentially leading to solubility issues and 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 good QED scores (0.783 and 0.803), indicating good drug-like properties.

**DILI:** Ligand A (31.291) has a lower DILI risk than Ligand B (37.611), which is preferable. Both are below the 40 threshold.

**BBB:** Ligand A (71.811) has moderate BBB penetration, while Ligand B (95.696) has very high BBB penetration. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.613 and -4.557). This 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 (-1.927) has better solubility than Ligand B (-4.885), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.485) has a lower hERG risk than Ligand B (0.861), which is a significant advantage.

**Microsomal Clearance:** Ligand A (20.147) has lower microsomal clearance than Ligand B (86.453), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.2) has a shorter half-life than Ligand B (17.471). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux than Ligand B (0.81), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly better binding affinity than Ligand A (-7.2 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A's better solubility, lower DILI risk, and lower P-gp efflux, Ligand B's *much* stronger binding affinity (-8.9 vs -7.2 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are decisive. The slightly higher logP and hERG risk of Ligand B are acceptable trade-offs for the significantly improved potency and metabolic profile. The negative Caco-2 values are concerning for both, but the potency advantage of B is likely to overcome this.

Output:
1
2025-04-17 14:05:08,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (351.514 and 354.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.63) is slightly higher than Ligand B (46.34). Both are below the 140 A^2 threshold for good oral absorption, but lower is generally preferred.

**3. logP:** Both ligands have logP values (4.161 and 4.546) that are slightly above the optimal 1-3 range, but still acceptable. The higher logP of Ligand B could potentially lead to solubility issues.

**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 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.679 and 0.652), indicating good drug-likeness.

**7. DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (57.348). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (88.329) has a higher BBB penetration percentile than Ligand B (72.664). While not a primary concern for a kinase inhibitor, it's a slight positive for Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, suggesting poor permeability. Ligand A (-4.926) is slightly better than Ligand B (-5.059).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-4.379) is slightly better than Ligand B (-4.835).

**11. hERG Inhibition:** Ligand A (0.443) has a lower hERG inhibition liability than Ligand B (0.75). This is a significant advantage for Ligand A, as it reduces the risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (101.629) has a much higher microsomal clearance than Ligand A (31.411). This suggests that Ligand A is more metabolically stable, a crucial factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (8.392) has a shorter in vitro half-life than Ligand B (29.328). This is a drawback for Ligand A, but the significantly better metabolic stability may compensate for it.

**14. P-gp Efflux:** Ligand A (0.533) has a lower P-gp efflux liability than Ligand B (0.805). This is a slight advantage for Ligand A.

**15. 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 for Ligand B. A 1.1 kcal/mol difference is quite significant.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A presents a much more favorable ADMET profile. Specifically, the lower DILI risk, lower hERG inhibition, and significantly improved metabolic stability (lower Cl_mic) are critical advantages for an enzyme inhibitor. The slightly better solubility and permeability of Ligand A are also beneficial. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand A, given its better overall profile.

Output:
0
2025-04-17 14:05:08,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.451 and 364.426 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.25) is better than Ligand B (66.48), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Ligand A (3.952) is slightly higher than Ligand B (2.298). Both are within the optimal 1-3 range, but A is nearing 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 (6) is higher than Ligand B (3). Both are acceptable, but B is better.

**6. QED:** Both ligands have similar QED values (0.697 and 0.601), indicating good drug-like properties.

**7. DILI:** Ligand A (83.831) has a significantly higher DILI risk than Ligand B (15.277). This is a major concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.592) is better than Ligand B (48.313).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.489) is slightly better than Ligand B (-4.891).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.438) is slightly better than Ligand B (-2.337).

**11. hERG Inhibition:** Ligand A (0.508) has a slightly higher hERG risk than Ligand B (0.11). B is much better here.

**12. Microsomal Clearance:** Ligand B (9.419) has significantly lower microsomal clearance than Ligand A (71.041), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.332) has a longer in vitro half-life than Ligand A (-10.415).

**14. P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux than Ligand B (0.062), potentially leading to better bioavailability.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 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 clearly the better candidate. While Ligand A has slightly better Caco-2 permeability and P-gp efflux, its significantly higher DILI risk, higher hERG risk, and much higher microsomal clearance outweigh these benefits. Ligand B demonstrates a much more favorable safety profile (lower DILI and hERG) and better metabolic stability, which are crucial for kinase inhibitors. The similar binding affinities make the ADME/Tox profile the deciding factor.

Output:
1
2025-04-17 14:05:08,334 - INFO - Batch 267 complete. Total preferences: 4272
2025-04-17 14:05:08,334 - INFO - Processing batch 268/512...
2025-04-17 14:05:52,804 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (351.535 and 342.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.44) is higher than Ligand B (40.62). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better permeability.

**3. logP:** Both ligands have good logP values (3.539 and 2.674), 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):** Both ligands have 2 HBA, well below the limit of <=10.

**6. QED:** Both ligands have similar QED values (0.796 and 0.774), indicating good drug-like properties.

**7. DILI:** Ligand A (16.557) has a slightly higher DILI risk than Ligand B (12.253), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (91.508) has a significantly higher BBB penetration percentile than Ligand B (74.098). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.631 and -4.667). This is unusual and suggests either experimental error or a very poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-3.179 and -3.295). This is also unusual and suggests very poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.523 and 0.6), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (37.279) has a lower microsomal clearance than Ligand B (47.035), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-8.332) has a significantly longer in vitro half-life than Ligand B (1.331), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.152 and 0.115).

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial difference (1.6 kcal/mol), and is a major advantage.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand B has a significantly better binding affinity. While both have poor solubility and permeability, the superior affinity of Ligand B is likely to outweigh these drawbacks, especially with potential formulation strategies. Ligand A has better metabolic stability, but the affinity difference is more significant.

Output:
1
2025-04-17 14:05:52,804 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.296 and 386.583 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.58) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (78.43) is well within the acceptable range.

**logP:** Ligand A (0.696) is a bit low, potentially hindering permeability. Ligand B (2.302) 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 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.682 and 0.558), indicating good drug-like properties.

**DILI:** Ligand A (64.444) has a higher DILI risk than Ligand B (38.697). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.419) is better than Ligand B (43.699), but it's not a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and are less impactful than other parameters.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern, but can be addressed with formulation strategies.

**hERG:** Ligand A (0.056) has a very low hERG risk, which is excellent. Ligand B (0.205) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (37.536) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (41.84).

**In vitro Half-Life:** Ligand A (-11.332) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (-2.444) also has a negative half-life, also indicating an issue with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.162), which is favorable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a significantly lower DILI risk, a more favorable logP, and a slightly better binding affinity. The negative half-life values are concerning for both, and would need to be investigated further. However, the lower DILI risk for Ligand B is a key advantage, as liver toxicity is a major cause of drug failure.

Output:
1
2025-04-17 14:05:52,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.3 and 346.5 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (94.6) is higher than Ligand B (67.2). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have good logP values (2.85 and 1.92), 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. Ligand B is preferable here, as fewer HBA generally improves permeability.

**QED:** Both ligands have acceptable QED scores (0.543 and 0.578), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (95.4%), which is a major concern. Ligand B has a much lower DILI risk (22.5%), making it significantly safer.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (76.0%) is higher than Ligand B (53.1%).

**Caco-2 Permeability:** Ligand A (-4.7) is worse than Ligand B (-5.0), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.3) is worse than Ligand B (-1.7), indicating lower solubility.

**hERG:** Ligand A (0.8) has a higher hERG risk than Ligand B (0.23), which is undesirable.

**Microsomal Clearance:** Ligand A (62.6) has higher clearance than Ligand B (29.1), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (9.2) has a longer half-life than Ligand B (-7.4). However, the negative value for Ligand B is concerning and suggests a very short half-life.

**P-gp Efflux:** Ligand A (0.46) has higher P-gp efflux than Ligand B (0.13), which is unfavorable.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 1.9 kcal/mol difference is significant.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand A, its extremely high DILI risk, higher hERG risk, lower solubility, and higher clearance make it a poor candidate. Ligand B, while having a slightly weaker binding affinity, is significantly better in terms of safety (DILI, hERG), ADME properties (solubility, clearance, P-gp efflux), and permeability. The difference in binding affinity, while notable, can potentially be overcome with further optimization, whereas mitigating the severe liabilities of Ligand A would be far more challenging.

Output:
1
2025-04-17 14:05:52,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.43 and 350.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.74) is slightly higher than Ligand B (64.33), but both are below the 140 A^2 threshold for good absorption.

**3. logP:** Ligand A (0.622) is a bit low, potentially hindering permeation. Ligand B (3.252) 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:** Ligand A has 5 HBA, while Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.591 and 0.743), indicating drug-like properties.

**7. DILI:** Ligand A (61.031) has a higher DILI risk than Ligand B (13.959). This is a significant concern, favoring Ligand B.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (88.29) has a higher BBB score, but this is less important here.

**9. Caco-2 Permeability:** Ligand A (-4.615) has poorer Caco-2 permeability than Ligand B (-4.187).

**10. Aqueous Solubility:** Ligand A (-1.847) has poorer aqueous solubility than Ligand B (-3.501). Solubility is important for enzyme inhibitors, favoring Ligand B.

**11. hERG Inhibition:** Ligand A (0.415) has a slightly lower hERG risk than Ligand B (0.907), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (6.013) has lower microsomal clearance than Ligand B (44.152), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-15.706) has a significantly *longer* in vitro half-life than Ligand B (18.859). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.409), which is favorable.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B has advantages in logP, DILI risk, solubility, and Caco-2 permeability. However, Ligand A exhibits significantly better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a lower DILI risk. Given the enzyme-specific priorities, metabolic stability and reduced efflux are crucial. While the slightly lower logP of Ligand A is a minor concern, the superior pharmacokinetic properties outweigh this drawback.

Output:
1
2025-04-17 14:05:52,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.491 Da and 370.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.33) is better than Ligand B (124.18). TPSA <140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Ligand A (1.239) is within the optimal 1-3 range. Ligand B (-0.418) is slightly below 1, which *could* indicate permeability issues, though not severely.

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

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

**QED:** Ligand A (0.814) is significantly better than Ligand B (0.47). Higher QED indicates better drug-likeness.

**DILI:** Ligand A (33.812) has a much lower DILI risk than Ligand B (43.622). Both are below 40, indicating low risk, but A is more favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.833) is better than Ligand B (26.25).

**Caco-2 Permeability:** Ligand A (-5.365) is significantly better than Ligand B (-6.1). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-1.982) is better than Ligand B (-1.32). Higher solubility is preferred.

**hERG Inhibition:** Ligand A (0.248) has a much lower hERG risk than Ligand B (0.159). Lower is better.

**Microsomal Clearance:** Ligand A (-39.491) has a *much* lower (better) microsomal clearance than Ligand B (7.346). This indicates significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (31.262) has a longer half-life than Ligand B (21.909).

**P-gp Efflux:** Ligand A (0.008) is much lower than Ligand B (0.031), indicating less P-gp efflux.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-6.5). While both are good, A has a 1.1 kcal/mol advantage.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, *and* has a slightly better binding affinity. Its superior metabolic stability (Cl_mic, t1/2), lower DILI and hERG risk, and better solubility make it a significantly more promising drug candidate. The slightly better logP and TPSA also contribute to its advantage. The 1.1 kcal/mol difference in binding affinity, while not huge, reinforces the overall preference for Ligand A.

Output:
1
2025-04-17 14:05:52,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.89) is significantly better than Ligand B (125.42). A TPSA under 140 is good for oral absorption, but A is much closer to the ideal for good permeability.

**logP:** Both ligands have acceptable logP values (0.761 and 1.284, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.805) has a much higher QED score than Ligand B (0.28), indicating a significantly more drug-like profile.

**DILI:** Ligand A (15.471) has a much lower DILI risk than Ligand B (25.514). Both are below the 40 threshold, but A is preferable.

**BBB:** Ligand A (65.529) has a better BBB percentile than Ligand B (48.003), though BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.891) has a worse Caco-2 permeability than Ligand B (-5.444). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-0.725) has slightly better solubility than Ligand B (-0.566).

**hERG Inhibition:** Ligand A (0.186) has a significantly lower hERG risk than Ligand B (0.234). Both are relatively low, but A is preferable.

**Microsomal Clearance:** Ligand A (2.247) has a higher (worse) microsomal clearance than Ligand B (-6.201). This means Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (14.246) has a slightly longer half-life than Ligand B (13.063).

**P-gp Efflux:** Ligand A (0.044) has a lower P-gp efflux liability than Ligand B (0.012), suggesting better oral bioavailability.

**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 difference.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has better metabolic stability (lower Cl_mic) and slightly better Caco-2 permeability, Ligand A's substantially stronger binding affinity (-8.2 vs 0 kcal/mol) outweighs these drawbacks. Furthermore, Ligand A demonstrates a much more favorable drug-like profile (higher QED), lower DILI risk, and lower hERG risk. The difference in binding affinity is so large that it is likely to overcome any permeability issues.

Output:
1
2025-04-17 14:05:52,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (335.382 and 359.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (37.61) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (45.67) is also below 140, but higher than A.

**3. logP:** Ligand A (3.946) is at the upper end of the optimal range (1-3), while Ligand B (2.99) is comfortably within it.  Ligand A's higher logP *could* present solubility issues, but isn't a major concern yet.

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

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.675 and 0.727), indicating drug-like properties.

**7. DILI:** Ligand B (37.999) has a significantly lower DILI risk than Ligand A (68.05). This is a substantial advantage for Ligand B.

**8. BBB:** Both have high BBB penetration, but Ligand A (93.408) is slightly higher than Ligand B (84.141). However, BBB is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Ligand B (-2.422) has better solubility than Ligand A (-4.786). This is a positive for Ligand B, especially considering Ligand A's higher logP.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.821 and 0.86).

**12. Microsomal Clearance:** Ligand B (95.969) has higher microsomal clearance than Ligand A (90.221), meaning A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (57.374) has a significantly longer half-life than Ligand A (39.911). This is a major advantage for B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have similar low P-gp efflux (0.585 and 0.567).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-10.5 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and half-life, and has better solubility and lower DILI risk. While Ligand A has slightly better metabolic stability, the significantly stronger binding of Ligand B outweighs this benefit. The poor Caco-2 permeability is a concern for both, but can be addressed through formulation strategies.



Output:
1
2025-04-17 14:05:52,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (383.231 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is well below the 140 threshold, while Ligand B (99.77) is approaching it. This favors Ligand A for better absorption.

**logP:** Both ligands have acceptable logP values (3.978 and 2.272, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2/3) and HBA (4/4) counts, within the suggested limits.

**QED:** Both ligands have good QED scores (0.791 and 0.543), indicating drug-like properties.

**DILI:** Ligand A has a higher DILI risk (86.972 percentile) than Ligand B (56.883). This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B has a slightly better BBB score (63.397) than Ligand A (57.193).

**Caco-2 Permeability:** Ligand A (-4.711) has a worse Caco-2 permeability than Ligand B (-5.207), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.186) has worse aqueous solubility than Ligand B (-3.732). Solubility is important for bioavailability.

**hERG:** Ligand A (0.51) has a slightly higher hERG risk than Ligand B (0.18). Lower hERG is preferred.

**Microsomal Clearance:** Ligand A (33.826) has significantly lower microsomal clearance than Ligand B (54.159). Lower clearance indicates better metabolic stability, which is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand A (10.103 hours) has a longer half-life than Ligand B (-17.185 hours - negative value is concerning). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.314 and 0.26, respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.2 kcal/mol). The difference (0.6 kcal/mol) is not substantial enough to outweigh other ADME concerns.

**Overall Assessment:**

Ligand A has a better half-life and slightly better binding affinity, but suffers from significantly higher DILI risk, lower solubility, and worse Caco-2 permeability. Ligand B, while having a slightly lower affinity, presents a much more favorable ADME profile with lower DILI, better solubility, and better permeability. Given the importance of metabolic stability and minimizing toxicity for kinase inhibitors, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 14:05:52,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.387 and 374.819 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.47) is slightly higher than ideal (<140), but still acceptable. Ligand B (78.09) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands (2.317 and 2.55) are 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 (0.736 and 0.795), indicating good drug-like properties.

**DILI:** Ligand A (63.164) has a higher DILI risk than Ligand B (53.858), although both are moderately risky.

**BBB:** Both ligands have similar BBB penetration (61.497 and 64.25), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.25) shows poor Caco-2 permeability, while Ligand B (-4.901) is slightly better. Both are negative values which is unusual, and suggests low permeability.

**Aqueous Solubility:** Ligand A (-2.189) has very poor aqueous solubility, a significant drawback. Ligand B (-3.598) is even worse.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.338 and 0.398).

**Microsomal Clearance:** Ligand A (33.745) has a moderate microsomal clearance, while Ligand B (7.842) is significantly lower, indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-25.565) has a significantly longer in vitro half-life than Ligand A (-14.337), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.152 and 0.065).

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a significant advantage for Ligand A. The difference of 1.4 kcal/mol is large enough to potentially overcome some ADME liabilities.

**Conclusion:**

While Ligand B exhibits superior ADME properties (lower clearance, longer half-life, better TPSA, and slightly better DILI), Ligand A's significantly higher binding affinity (-10.1 vs -8.7 kcal/mol) is a crucial factor for an enzyme inhibitor. The potency advantage is substantial. The poor solubility and permeability of Ligand A are concerning, but could potentially be addressed through formulation strategies or further structural modifications. The improved metabolic stability of Ligand B is attractive, but a weaker binding affinity could necessitate higher doses, potentially exacerbating ADME issues. Given the enzyme target class priority, the potency advantage of Ligand A outweighs its ADME liabilities.

Output:
0
2025-04-17 14:05:52,806 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.483 and 355.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.87 and 66.07) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.186 and 2.934) within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (2 HBDs), as fewer donors generally improve permeability.

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

**QED:** Both ligands have good QED scores (0.751 and 0.883), indicating drug-like properties.

**DILI:** Ligand A (56.883 percentile) has a significantly lower DILI risk than Ligand B (85.227 percentile). This is a major advantage.

**BBB:** Both ligands have reasonably high BBB penetration (69.407 and 78.79 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.974 and -4.913). This is unusual and indicates poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Ligand A (-2.014) has better solubility than Ligand B (-4.65), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.225) exhibits a lower hERG inhibition liability than Ligand B (0.898), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (48.578 mL/min/kg) has a higher microsomal clearance than Ligand B (33.723 mL/min/kg), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (28.358 hours) has a longer in vitro half-life than Ligand A (37.236 hours). This is a slight advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.158 and 0.09).

**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 minor.

**Overall Assessment:**

Ligand A is preferable despite the slightly higher Cl_mic. Its significantly lower DILI risk, better solubility, and lower hERG inhibition liability are critical advantages for drug development. The binding affinity difference is small and outweighed by the ADME/Tox benefits of Ligand A.

Output:
0
2025-04-17 14:05:52,806 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.375 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.15) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (58.44) is excellent, well below 140.

**logP:** Ligand A (-0.318) is a bit low, potentially hindering permeation. Ligand B (1.439) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have a QED of 0.77/0.778, indicating good drug-likeness.

**DILI:** Ligand A (63.823) has a moderate DILI risk, while Ligand B (13.959) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.908) has a higher BBB penetration than Ligand A (34.548), but it's not a major deciding factor here.

**Caco-2 Permeability:** Both have negative values (-5.76 and -4.826), 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.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.632 and -1.434). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.02) has a very low hERG risk, which is excellent. Ligand B (0.244) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-20.177) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (33.609) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (28.365) has a reasonable half-life, while Ligand B (-9.188) has a negative half-life, which is not possible and suggests an issue with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.045).

**Binding Affinity:** Both ligands have similar strong binding affinities (-9.0 and -8.8 kcal/mol).

**Conclusion:**

Considering the priorities for an enzyme target, Ligand A is slightly favored due to its superior metabolic stability (much lower Cl_mic) and lower DILI risk. While both have poor solubility and Caco-2 permeability, the metabolic stability and safety profile of Ligand A are more critical for a kinase inhibitor. The negative half-life for Ligand B is also a major red flag.

Output:
0
2025-04-17 14:05:52,806 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (384.929 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.57) is significantly better than Ligand B (72.63). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (4.332) is higher than Ligand B (2.975). While both are within the acceptable range (1-3 is optimal, up to 4 is tolerable), Ligand A is approaching the upper limit, potentially raising concerns about solubility and off-target effects. Ligand B is closer to the ideal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 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 (A: 0.572, B: 0.785), indicating a generally drug-like profile. Ligand B is slightly better.

**DILI:** Ligand A (36.293) has a slightly higher DILI risk than Ligand B (23.653), but both are below the concerning threshold of 60.

**BBB:** Both have acceptable BBB penetration, but Ligand B (83.288) is better than Ligand A (74.874). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can still compare them relatively. Ligand A (-5.09) is worse than Ligand B (-4.782).

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. Ligand A (-2.882) is worse than Ligand B (-3.149).

**hERG Inhibition:** Ligand A (0.671) has a slightly higher hERG risk than Ligand B (0.397), which is preferable.

**Microsomal Clearance:** Ligand A (111.11) has significantly higher microsomal clearance than Ligand B (54.888), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (34.879) has a longer half-life than Ligand B (17.257), which is a positive. However, this benefit is likely outweighed by the higher clearance.

**P-gp Efflux:** Ligand A (0.864) has slightly higher P-gp efflux than Ligand B (0.288), which is less desirable.

**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's enough to be considered, especially in the context of other factors.

**Overall Assessment:**

Ligand B is the better candidate. It has a more favorable logP, lower DILI risk, better Caco-2 permeability and solubility (despite both being negative), lower hERG risk, significantly better metabolic stability (lower Cl_mic), and a slightly better binding affinity. While Ligand A has a longer half-life, its significantly higher clearance undermines this advantage. The lower TPSA of Ligand A is a plus, but the other ADME properties of Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 14:05:52,806 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (377.403 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.17) is significantly better than Ligand B (78.68).  A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is much closer to the ideal for better absorption.

**logP:** Both ligands have acceptable logP values (3.666 and 2.046), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 5.  Ligand A is preferable here, staying closer to the <10 HBA guideline.

**QED:** Both ligands have similar and good QED scores (0.796 and 0.799).

**DILI:** Ligand A (46.84) has a lower DILI risk than Ligand B (54.556), which is a significant advantage. Both are below the 60 threshold, but lower is better.

**BBB:**  BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (88.29) has better BBB penetration than Ligand B (78.48).

**Caco-2 Permeability:** Ligand A (-4.678) has a worse Caco-2 permeability than Ligand B (-4.941), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.984) has better aqueous solubility than Ligand B (-3.08). Solubility is crucial for bioavailability.

**hERG:** Ligand A (0.78) has a much lower hERG risk than Ligand B (0.096).  This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (19.511) has significantly lower microsomal clearance than Ligand B (57.138). Lower clearance indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-19.456) has a much longer in vitro half-life than Ligand B (10.626). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.202) has lower P-gp efflux than Ligand B (0.064), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a much better binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial difference and a major point in favor of Ligand B.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A presents a much more favorable ADMET profile. The lower DILI, hERG, and microsomal clearance, coupled with the longer half-life and better solubility, make it a significantly more promising drug candidate. The difference in binding affinity (-10.3 vs 0.0 kcal/mol) is substantial, but can be addressed through further optimization. The ADMET properties of Ligand B are concerning, particularly the hERG risk and high clearance.

Output:
0
2025-04-17 14:05:52,806 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [344.455, 69.64, 2.36, 2, 3, 0.711, 20.202, 63.164, -4.611, -1.685, 0.293, 33.897, 24.771, 0.073, -8.1]
**Ligand B:** [380.941, 49.41, 3.949, 1, 3, 0.84, 54.556, 77.007, -5.004, -4.831, 0.526, 57.208, -2.334, 0.583, -8.6]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (344.455) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (69.64) is higher than B (49.41). B is better here, being well below the 140 threshold for oral absorption.
3. **logP:** Both are within the optimal range (1-3), but B (3.949) is approaching the upper limit. A (2.36) is better balanced.
4. **HBD:** A (2) and B (1) are both good, well within the limit of 5. B is slightly better.
5. **HBA:** Both A (3) and B (3) are good, under the limit of 10.
6. **QED:** Both are good (A: 0.711, B: 0.84), indicating drug-like properties. B is slightly better.
7. **DILI:** A (20.202) is significantly better than B (54.556). This is a major advantage for A.
8. **BBB:** B (77.007) is better than A (63.164), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.
9. **Caco-2:** A (-4.611) is much better than B (-5.004). Higher values indicate better absorption.
10. **Solubility:** A (-1.685) is better than B (-4.831). Solubility is crucial for bioavailability, making A preferable.
11. **hERG:** A (0.293) is significantly better than B (0.526), indicating a lower risk of cardiotoxicity.
12. **Cl_mic:** A (33.897) is better than B (57.208). Lower clearance suggests better metabolic stability.
13. **t1/2:** A (24.771) is better than B (-2.334). A longer half-life is generally desirable.
14. **Pgp:** A (0.073) is much better than B (0.583). Lower P-gp efflux is favorable for bioavailability.
15. **Binding Affinity:** B (-8.6) is slightly better than A (-8.1), a difference of 0.5 kcal/mol. While affinity is paramount, the difference isn't huge enough to outweigh the ADME advantages of A.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While B has a slightly better binding affinity, A excels in metabolic stability, solubility, DILI risk, hERG inhibition, and P-gp efflux. The difference in binding affinity (0.5 kcal/mol) is not substantial enough to overcome A's superior ADME profile.

**Conclusion:**

Considering the overall profile and the priorities for a kinase inhibitor, **Ligand A** is the more viable drug candidate.

1
2025-04-17 14:05:52,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (380.863 and 373.953 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (21.06), being below the 140 threshold for good absorption. Ligand B is excellent.

**logP:** Ligand A (2.72) is optimal, while Ligand B (4.997) is slightly high, potentially leading to solubility issues and off-target interactions.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.666 and 0.581), indicating good drug-like properties.

**DILI:** Ligand A (29.43) has a lower DILI risk than Ligand B (38.891), which is preferable. Both are below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.088) has a higher BBB penetration than Ligand B (70.609).

**Caco-2 Permeability:** Ligand A (-4.359) has a worse Caco-2 permeability than Ligand B (-5.241).

**Aqueous Solubility:** Ligand A (-2.957) has a worse aqueous solubility than Ligand B (-4.122).

**hERG Inhibition:** Ligand A (0.483) has a lower hERG risk than Ligand B (0.902), which is a significant advantage.

**Microsomal Clearance:** Ligand A (33.486) has a lower microsomal clearance than Ligand B (56.208), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (42.654) has a significantly longer in vitro half-life than Ligand A (10.501), which is desirable.

**P-gp Efflux:** Ligand A (0.193) has lower P-gp efflux than Ligand B (0.809), which is preferable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.3 kcal/mol). This ~1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better solubility, lower DILI risk, lower hERG, and lower P-gp efflux, Ligand B possesses a significantly stronger binding affinity (-9.3 vs -8.3 kcal/mol) and a longer half-life. Given that we are targeting an enzyme, binding affinity and metabolic stability are paramount. The slightly higher logP and P-gp efflux of Ligand B are less concerning than the weaker binding of Ligand A. The difference in binding affinity is substantial enough to favor Ligand B.

Output:
1
2025-04-17 14:05:52,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.463 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is slightly higher than Ligand B (67.87), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (2.431 and 2.002, respectively), falling 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 <5 HBD and <10 HBA criteria.

**QED:** Ligand A (0.8) has a higher QED score than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand B (40.52) has a significantly lower DILI risk than Ligand A (17.681), which is a substantial advantage.

**BBB:** Both ligands have good BBB penetration, but Ligand B (91.663) is slightly better than Ligand A (81.233). This isn't a primary concern for a non-CNS target like SRC.

**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 solubility. Ligand B (-2.817) is slightly better than Ligand A (-1.259).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.494 and 0.465, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (19.881) exhibits lower microsomal clearance than Ligand A (30.337), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-8.738) has a slightly better (less negative) in vitro half-life than Ligand A (-14.031).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.109 and 0.267, respectively).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9 kcal/mol). While A is better, the difference isn't substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and QED, Ligand B demonstrates significantly lower DILI risk and better metabolic stability (lower Cl_mic and better half-life). Solubility is a concern for both, but B is slightly better. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial, making Ligand B the preferred choice.

Output:
1
2025-04-17 14:05:52,807 - INFO - Batch 268 complete. Total preferences: 4288
2025-04-17 14:05:52,807 - INFO - Processing batch 269/512...
2025-04-17 14:06:32,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (349.475 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (70.67 and 67.43) are below the 140 A^2 threshold for good oral absorption, but higher than the 90 A^2 for CNS targets (not a primary concern here).

**3. logP:** Both ligands have optimal logP values (1.89 and 2.396), falling within the 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 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.761) has a significantly better QED score than Ligand B (0.47), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.183) has a much lower DILI risk than Ligand B (28.228), which is a significant advantage.

**8. BBB:** Ligand A (71.384) has a better BBB penetration percentile than Ligand B (63.358), but this is not a major concern for a non-CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 permeability values (-4.863 and -4.851). This is unusual and suggests potential issues with intestinal absorption. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.283 and -3.247). This is concerning, as low solubility can hinder bioavailability. Ligand B has slightly worse solubility.

**11. hERG Inhibition:** Ligand A (0.619) has a lower hERG inhibition risk than Ligand B (0.3), which is preferable.

**12. Microsomal Clearance:** Ligand A (20.283 mL/min/kg) has a lower microsomal clearance than Ligand B (30.947 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.334 hours) has a significantly longer in vitro half-life than Ligand B (8.784 hours), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.152).

**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.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly superior in most other critical ADME-Tox properties. Specifically, Ligand A exhibits a much better QED score, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG inhibition. The solubility issues are present in both, but the other advantages of Ligand A outweigh the small affinity difference. Given the enzyme-kinase target class, metabolic stability and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 14:06:32,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.446 and 362.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.29) is significantly better than Ligand B (69.68). A TPSA under 140 is good for oral absorption, and both are, but lower is preferred.

**logP:** Both ligands have good logP values (3.365 and 3.703), 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 acceptable (<=10), but A is slightly better.

**QED:** Both have good QED scores (0.929 and 0.878), indicating good drug-like properties.

**DILI:** Ligand A (12.679) has a much lower DILI risk than Ligand B (85.227). This is a significant advantage for Ligand A.

**BBB:** Ligand A (86.584) has better BBB penetration than Ligand B (67.468), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.749) has a slightly better Caco-2 permeability than Ligand B (-4.644), but both are poor.

**Aqueous Solubility:** Ligand A (-1.718) has better aqueous solubility than Ligand B (-4.018). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.934) has a lower hERG inhibition risk than Ligand B (0.347), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-7.601) has *much* lower microsomal clearance than Ligand B (49.816). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (13.408 hours) has a much longer half-life than Ligand B (-14.932 hours). This is a major advantage for Ligand A, suggesting less frequent dosing.

**P-gp Efflux:** Ligand A (0.564) has lower P-gp efflux than Ligand B (0.186), which is favorable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While affinity is paramount, the difference of 1.5 kcal/mol is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties, particularly in terms of DILI risk, metabolic stability (Cl_mic and t1/2), hERG inhibition, and solubility. These factors are crucial for developing a viable drug candidate targeting an enzyme like SRC kinase. The improved ADME profile of Ligand A outweighs the small difference in binding affinity.

Output:
0
2025-04-17 14:06:32,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.371 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.43) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (49.85) is excellent, well below 140.

**logP:** Both ligands have good logP values (3.278 and 2.753), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both within acceptable limits. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Both ligands have similar QED scores (0.739 and 0.734), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 85.576, which is high and concerning. Ligand B has a much lower DILI risk of 21.869, a significant advantage.

**BBB:** Both have relatively low BBB penetration (33.114 and 84.335). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.815 and -4.597), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.261 and -2.034), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.28) has a slightly lower hERG risk than Ligand B (0.471), which is preferable.

**Microsomal Clearance:** Ligand A (33.722) has lower microsomal clearance than Ligand B (59.397), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (60.275) has a longer half-life than Ligand B (-13.213), a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.031 and 0.22).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.3 vs -7.1 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, it has better metabolic stability (lower Cl_mic and longer half-life) and a slightly lower hERG risk. The major drawback of Ligand A is its high DILI risk, but this could potentially be mitigated through structural modifications during lead optimization. Ligand B's lower DILI is appealing, but the weaker binding affinity is a significant disadvantage.

Output:
0
2025-04-17 14:06:32,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (406.259 Da and 383.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (64.22 and 62.74) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (3.478 and 2.804).

**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 QED values above 0.5 (0.722 and 0.588), indicating good drug-likeness.

**DILI:** Both ligands have high DILI risk (81.892 and 80.109), which is a concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Both are relatively high (81.039 and 74.758).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.79 and -4.692), which is unusual and suggests poor permeability. This is a significant drawback.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.312 and -4.865), indicating very poor aqueous solubility, a major issue for bioavailability.

**hERG:** Ligand A (0.583) has a slightly higher hERG risk than Ligand B (0.237), but both are relatively low and not a major concern.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (48.124 mL/min/kg) than Ligand B (102.322 mL/min/kg), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A has a longer half-life (42.905 hours) than Ligand B (10.055 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.453 and 0.411).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-7.9 kcal/mol) than Ligand A (-8.6 kcal/mol). This is a good advantage.

**Overall Assessment:**

Despite the similar profiles, Ligand A is favored due to its significantly better metabolic stability (lower Cl_mic and longer half-life). While both have poor solubility and permeability, the improved metabolic profile is more readily addressed through formulation strategies than improving binding affinity. The slightly better binding affinity of Ligand B is not enough to overcome the metabolic concerns. The high DILI risk is a concern for both, but can be investigated further.

Output:
0
2025-04-17 14:06:32,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.467 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.48) is slightly higher than Ligand B (67.87). Both are below the 140 threshold for good oral absorption, but B is better.

**logP:** Ligand A (3.395) is optimal, while Ligand B (2.137) is a bit lower, but still within the acceptable 1-3 range.

**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 similar QED values (0.706 and 0.61), indicating good drug-likeness.

**DILI:** Ligand A (64.56) has a higher DILI risk than Ligand B (20.279). This is a significant negative for Ligand A.

**BBB:** Both ligands have similar BBB penetration (63.358 and 66.344). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.778) is worse than Ligand B (-4.425).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.599) is worse than Ligand B (-1.968).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.367 and 0.296).

**Microsomal Clearance:** Ligand B (49.764) has a significantly lower microsomal clearance than Ligand A (27.109), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (1.779) has a slightly longer half-life than Ligand A (7.165).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.321 and 0.023).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). While the difference is small, it's still favorable.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic and slightly longer t1/2), better solubility, and slightly better binding affinity. While both have poor Caco-2 permeability and solubility, Ligand B is superior in the critical areas of safety (DILI) and pharmacokinetics (metabolic stability). The small difference in binding affinity is less important than these ADME/Tox advantages.

Output:
1
2025-04-17 14:06:32,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.388 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is well below the 140 threshold, suggesting good absorption. Ligand B (111.39) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (4.213) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.454) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is optimal. Ligand B (HBD=2, HBA=8) is acceptable, but the higher HBA count could affect permeability.

**QED:** Both ligands have similar QED values (0.863 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (50.33) has a lower DILI risk than Ligand B (68.903), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (93.331) shows better BBB penetration than Ligand B (27.879), but this isn't a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.203) has a more favorable Caco-2 permeability than Ligand B (-5.451).

**Aqueous Solubility:** Ligand A (-4.417) has a better solubility profile than Ligand B (-2.059).

**hERG Inhibition:** Ligand A (0.683) has a lower hERG risk than Ligand B (0.11), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (54.519) has a higher (worse) microsomal clearance than Ligand B (-14.873), suggesting lower metabolic stability. This is a key drawback for Ligand A.

**In vitro Half-Life:** Ligand A (22.382) has a shorter half-life than Ligand B (30.357), consistent with the higher clearance.

**P-gp Efflux:** Ligand A (0.255) has lower P-gp efflux liability than Ligand B (0.031), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-11.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This >3.8 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A having better solubility, lower DILI risk, and lower P-gp efflux, the significantly stronger binding affinity of Ligand B (-11.4 vs -7.6 kcal/mol) is the deciding factor. While Ligand B has a lower logP and higher DILI risk, the potency advantage is substantial for an enzyme target. The metabolic stability (lower Cl_mic) and half-life of Ligand B are also better than Ligand A. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 14:06:32,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.391 and 343.515 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.59) is better than Ligand B (37.27) as it is closer to the threshold for good oral absorption.

**logP:** Ligand B (3.758) is slightly higher than the optimal range (1-3), but still acceptable. Ligand A (0.533) is quite low, potentially hindering permeation.

**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.

**QED:** Both ligands have good QED scores (0.634 and 0.854), indicating drug-likeness.

**DILI:** Ligand B (11.09) has a significantly lower DILI risk than Ligand A (65.491), which is a major advantage.

**BBB:** Ligand B (91.198) shows much better BBB penetration than Ligand A (36.371). While SRC is not necessarily a CNS target, better BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-5.789) has poor Caco-2 permeability, while Ligand B (-4.655) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.21 and -3.886). This could pose formulation challenges, but is not a deal-breaker if other properties are strong.

**hERG Inhibition:** Ligand A (0.035) has a very low hERG inhibition risk, which is excellent. Ligand B (0.638) is higher, representing a potential safety concern.

**Microsomal Clearance:** Ligand A (-3.415) has much lower microsomal clearance, indicating better metabolic stability. Ligand B (59.149) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand B (43.993) has a longer in vitro half-life than Ligand A (11.932), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.165).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.7 kcal/mol). The difference is minor, and unlikely to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A has a better TPSA, lower clearance, and a significantly lower hERG risk. However, Ligand B has a much lower DILI risk, better BBB penetration, and a longer half-life. The poor Caco-2 permeability and low logP of Ligand A are concerning. The higher DILI risk of Ligand A is also a significant drawback. While the hERG risk is better for Ligand A, the overall profile of Ligand B is more promising, particularly its improved metabolic stability and safety profile (lower DILI).

Output:
1
2025-04-17 14:06:32,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.969 Da and 374.794 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.38) is excellent, well below the 140 threshold for oral absorption. Ligand B (72.94) is still acceptable but higher, potentially impacting absorption.

**logP:** Ligand A (4.703) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (3.402) 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 good QED scores (0.669 and 0.842), indicating good drug-like properties.

**DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (54.634), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (87.088 and 80.419), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.04) shows poor permeability, a significant drawback. Ligand B (-4.705) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-6.144) has very poor solubility, which is concerning. Ligand B (-3.468) is also poor, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.876 and 0.631), which is good.

**Microsomal Clearance:** Ligand A (75.747) has higher clearance, suggesting lower metabolic stability. Ligand B (22.478) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.228) has a negative half-life, indicating very rapid metabolism. Ligand B (8.654) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.521 and 0.357), which is favorable.

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-9.2 and -8.8 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. While both have solubility issues, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and slightly better Caco-2 permeability. Ligand A's extremely poor solubility and rapid metabolism are major liabilities that outweigh its slightly lower TPSA.

Output:
1
2025-04-17 14:06:32,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.255 Da and 368.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.92) is significantly better than Ligand B (88.32).  A TPSA under 140 is good for oral absorption, and both are within this limit, but A is more favorable.

**logP:** Ligand A (4.596) is higher than Ligand B (1.911). While both are within the acceptable range (1-3), A is pushing the upper limit and could potentially have solubility issues. B is closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 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 values (0.731 and 0.848), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (72.819 and 70.531), indicating moderate risk. This isn't a major differentiating factor.

**BBB:** Both have similar BBB penetration (67.197 and 65.839). Not a major concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-4.637) is worse than Ligand B (-5.062). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.713) is worse than Ligand B (-3.629). Lower values indicate lower solubility.

**hERG Inhibition:** Ligand A (0.855) is better than Ligand B (0.402). Lower hERG inhibition is preferred.

**Microsomal Clearance:** Ligand A (44.326) is higher than Ligand B (36.377), indicating faster clearance and lower metabolic stability.

**In vitro Half-Life:** Ligand A (44.56) is significantly better than Ligand B (3.472).

**P-gp Efflux:** Ligand A (0.516) is better than Ligand B (0.047). Lower P-gp efflux is preferred.

**Binding Affinity:** Ligand B (-8.3) has a significantly better binding affinity than Ligand A (-9.0). This is a crucial factor for enzyme inhibitors.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity (-8.3 kcal/mol vs -9.0 kcal/mol), which is the most important factor for an enzyme inhibitor. It also has better solubility, Caco-2 permeability, and P-gp efflux. While Ligand A has better hERG inhibition and in vitro half-life, the superior binding affinity of Ligand B outweighs these advantages. The slightly higher logP of Ligand A is a concern, and its lower solubility and permeability are also drawbacks.

Output:
1
2025-04-17 14:06:32,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.327 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.86) is slightly above the preferred <140 for good absorption, while Ligand B (110.53) is well within the range.

**logP:** Ligand A (1.761) is optimal, while Ligand B (0.88) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.472 and 0.673), suggesting acceptable drug-likeness. Ligand B is better here.

**DILI:** Ligand A has a high DILI risk (96.549%), which is a significant concern. Ligand B has a much lower DILI risk (32.61%), a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (68.476) than Ligand A (31.214), but this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This 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. This is a concern, but can sometimes be overcome with formulation.

**hERG:** Ligand A (0.86) has a slightly higher hERG risk than Ligand B (0.037), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (13.291 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (60.506 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.409 hours) has a significantly longer half-life than Ligand A (0.495 hours), which is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME liabilities of Ligand A.

**Overall Assessment:**

Ligand A has better binding affinity and metabolic stability, but suffers from a very high DILI risk, a slightly higher hERG risk, and a very short half-life. Ligand B, while having slightly weaker binding and poorer metabolic stability, has a much lower DILI risk, significantly better half-life, and a lower hERG risk. Given the enzyme-specific priorities, the lower DILI and hERG risk, and the improved half-life of Ligand B are more important than the slightly better binding affinity of Ligand A. The poor solubility and permeability of both compounds are concerns, but can potentially be addressed through formulation.

Output:
1
2025-04-17 14:06:32,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.491 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (382.961 Da) is also acceptable.

**TPSA:** Ligand A (59.08) is significantly better than Ligand B (41.37). Lower TPSA generally indicates better cell permeability.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.925, Ligand B: 3.702). Ligand B is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but is still within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (0) and HBA (Ligand A: 4, Ligand B: 5), falling within the guidelines.

**QED:** Both ligands have similar QED values (Ligand A: 0.701, Ligand B: 0.699), indicating good drug-likeness.

**DILI:** Ligand A (7.794) has a much lower DILI risk than Ligand B (24.195), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 83.715, Ligand B: 74.292), but Ligand A is better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.256) is slightly better than Ligand B (-4.848).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.318) is slightly better than Ligand B (-2.195).

**hERG Inhibition:** Ligand A (0.406) has a lower hERG risk than Ligand B (0.798), which is a critical advantage for safety.

**Microsomal Clearance:** Ligand A (38.729) has a lower microsomal clearance than Ligand B (59.368), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.163) has a negative half-life, which is concerning. Ligand B (43.815) has a positive half-life, which is preferred.

**P-gp Efflux:** Ligand A (0.032) has very low P-gp efflux, which is favorable. Ligand B (0.212) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-6.8 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial difference, as a 1.5 kcal/mol advantage can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 and solubility, Ligand A excels in critical areas: significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), and superior binding affinity. The negative in vitro half-life for Ligand A is a concern, but the other advantages, particularly the binding affinity and safety profiles, make it the more promising starting point for optimization. Ligand B's higher logP and DILI risk are less desirable.

Output:
0
2025-04-17 14:06:32,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (336.351 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.06) is slightly higher than Ligand B (69.72). Both are acceptable, but Ligand B is better, potentially indicating improved cell permeability.

**logP:** Ligand A (3.595) is at the upper end of the optimal range (1-3), while Ligand B (1.563) is towards the lower end. Ligand A's higher logP could lead to solubility issues or off-target interactions, while B might have permeability issues.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and Ligand A has 6 HBA and Ligand B has 3 HBA, both within the guidelines.

**QED:** Both ligands have reasonable QED values (0.422 and 0.766), with Ligand B being significantly better, suggesting a more drug-like profile.

**DILI:** Ligand A has a high DILI risk (93.37 percentile), which is a major concern. Ligand B has a very low DILI risk (24.622 percentile), a significant advantage.

**BBB:** Both have reasonable BBB penetration (67.701 and 61.497 percentile), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.114) and Ligand B (-4.646) are both negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-5.436) and Ligand B (-2.18) both have poor solubility.

**hERG Inhibition:** Ligand A (0.526) has a slightly higher hERG risk than Ligand B (0.103), which is preferable.

**Microsomal Clearance:** Ligand A (79.151 mL/min/kg) has a higher clearance than Ligand B (37.422 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-3.475 hours) has a shorter half-life than Ligand B (2.56 hours), indicating faster metabolism.

**P-gp Efflux:** Ligand A (0.518) has a higher P-gp efflux liability than Ligand B (0.034), which is not ideal.

**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.

**Conclusion:**

Ligand B is the superior candidate. While both have solubility and permeability concerns, Ligand B exhibits a significantly stronger binding affinity, a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk. The stronger binding affinity is a critical advantage for an enzyme inhibitor, and the lower toxicity profile is paramount.

Output:
1
2025-04-17 14:06:32,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.531 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (102.84) is still acceptable but higher, potentially impacting absorption.

**logP:** Ligand A (4.125) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.451) is quite low, which could hinder membrane permeation.

**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 than A.

**QED:** Both ligands have good QED scores (0.648 and 0.701), indicating drug-like properties.

**DILI:** Ligand A (21.287) has a significantly lower DILI risk than Ligand B (45.25), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.713) has a better BBB score than Ligand B (11.128).

**Caco-2 Permeability:** Ligand A (-4.603) has a negative Caco-2 value, which is concerning and suggests poor permeability. Ligand B (-5.17) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.938) has very poor solubility. Ligand B (-1.139) is also poor, but better than A.

**hERG:** Ligand A (0.336) has a very low hERG risk, which is excellent. Ligand B (0.041) is also very low, and comparable to A.

**Microsomal Clearance:** Ligand A (69.917) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (15.823) has much lower clearance, suggesting better metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-2.287) has a short half-life, while Ligand B (-27.459) has a very long half-life, which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.116 and 0.026).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This 3.3 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a lower logP and slightly higher TPSA, its significantly superior binding affinity (-9.8 vs -6.5 kcal/mol), much better metabolic stability (lower Cl_mic, longer t1/2), and acceptable DILI and hERG profiles outweigh the minor drawbacks. Ligand A's poor solubility and permeability are major concerns, despite its lower DILI risk. The potency advantage of Ligand B is critical for an enzyme target like SRC.

Output:
1
2025-04-17 14:06:32,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.836 and 356.417 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.28) is well below the 140 threshold and is favorable. Ligand B (71.11) is still under 140, but getting closer to the upper limit.

**3. logP:** Both ligands have good logP values (3.525 and 2.94), 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 limit of <=10.

**6. QED:** Ligand A (0.901) has a significantly better QED score than Ligand B (0.654), indicating a more drug-like profile.

**7. DILI:** Ligand A (68.515) has a higher DILI risk than Ligand B (42.924). This is a negative for Ligand A.

**8. BBB:** Both have high BBB penetration, but Ligand B (90.035) is slightly higher than Ligand A (81.039). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2:** Both ligands 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 concern for both.

**11. hERG:** Ligand A (0.893) has a slightly higher hERG risk than Ligand B (0.395). Lower is better, so Ligand B is preferable.

**12. Cl_mic:** Ligand B (35.108) has significantly lower microsomal clearance than Ligand A (69.802), suggesting better metabolic stability. This is a crucial advantage for Ligand B.

**13. t1/2:** Ligand A (39.774) has a longer in vitro half-life than Ligand B (-14.366). This is a positive for Ligand A, but the negative value for B is concerning.

**14. Pgp:** Ligand A (0.27) has lower P-gp efflux than Ligand B (0.051), which is preferable.

**15. Binding Affinity:** Both ligands have very 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:**

Despite Ligand A's better QED and Pgp efflux, Ligand B is the more promising candidate. The key advantages of Ligand B are its significantly lower DILI risk and much better metabolic stability (lower Cl_mic). While both have poor solubility and Caco-2 permeability, metabolic stability is more critical for an enzyme inhibitor. The slightly longer half-life of Ligand A is overshadowed by its higher DILI and clearance. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 14:06:32,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.438 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.64 and 59.08) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.295) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.842) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable, being less than or equal to 5.

**H-Bond Acceptors:** Both ligands (4) are below the 10 threshold.

**QED:** Both ligands (0.612 and 0.685) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (71.152) has a concerningly high DILI risk (above 60). Ligand B (24.855) has a low DILI risk, which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (69.523 and 71.035). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and indicates poor permeability.

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

**hERG Inhibition:** Ligand A (0.624) has a slightly higher hERG risk than Ligand B (0.322), but both are relatively low.

**Microsomal Clearance:** Ligand A (80.834) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (60.236) has better metabolic stability.

**In vitro Half-Life:** Ligand A (0.995) has a very short half-life. Ligand B (6.883) has a substantially longer half-life, a significant advantage.

**P-gp Efflux:** Ligand A (0.885) and Ligand B (0.07) have different P-gp efflux liabilities. Ligand B has a much lower efflux liability.

**Binding Affinity:** Ligand A (-7.8 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 outweighed by other factors.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, Ligand B is the more promising candidate. The significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux liability of Ligand B outweigh the small difference in binding affinity. The poor permeability and solubility of both are concerning and would need to be addressed in further optimization, but the ADME profile of Ligand B is far superior.

Output:
1
2025-04-17 14:06:32,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.403 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.54) is higher than Ligand B (58.64). While both are reasonably good, Ligand B is significantly better, increasing the likelihood of good oral absorption.

**3. logP:** Ligand A (0.303) is quite low, potentially hindering permeability. Ligand B (1.977) 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 (5) and Ligand B (3) are both acceptable.

**6. QED:** Both ligands have similar, good QED values (0.769 and 0.775).

**7. DILI:** Ligand A (37.611) has a slightly higher DILI risk than Ligand B (17.449), but both are below the concerning threshold of 60.

**8. BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (64.482) is slightly better than Ligand A (56.65).

**9. Caco-2 Permeability:** Ligand A (-5.304) has poor Caco-2 permeability, while Ligand B (-4.696) is better, but still not great.

**10. Aqueous Solubility:** Ligand A (-1.468) has better aqueous solubility than Ligand B (-2.873). This is a positive for Ligand A.

**11. hERG Inhibition:** Ligand A (0.069) has a very low hERG risk, which is excellent. Ligand B (0.217) is also low, but slightly higher.

**12. Microsomal Clearance:** Ligand A (12.029) has significantly lower microsomal clearance than Ligand B (25.476), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (9.683) has a longer in vitro half-life than Ligand B (5.521), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.078 respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol). The difference is minimal and unlikely to be decisive.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2), hERG risk (very low), and solubility. However, it suffers from poor logP and Caco-2 permeability. Ligand B has a better logP and TPSA, but worse metabolic stability and slightly higher hERG risk.

Considering the priorities for kinase inhibitors, metabolic stability and minimizing off-target effects (hERG) are paramount. The superior metabolic stability of Ligand A, coupled with its excellent hERG profile, outweighs its slightly lower logP and Caco-2 permeability. While permeability is important, it can be addressed with formulation strategies. The strong binding affinity is similar for both.

Output:
0
2025-04-17 14:06:32,688 - INFO - Batch 269 complete. Total preferences: 4304
2025-04-17 14:06:32,688 - INFO - Processing batch 270/512...
2025-04-17 14:07:12,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (343.467 and 346.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (38.77) is significantly better than Ligand B (62.99).  For good oral absorption, we want TPSA <= 140. Both are well within this range, but lower is generally preferred.

**3. logP:** Ligand A (3.746) is slightly higher than Ligand B (2.084), both are 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 3 HBA, and Ligand B has 4 HBA. Both are below the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.765 and 0.841), indicating drug-like properties.

**7. DILI:** Both ligands have similar, low DILI risk (25.087 and 26.522 percentile).

**8. BBB:** Both ligands have good BBB penetration (80.574 and 78.829 percentile), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.612) is worse than Ligand B (-4.486). Higher values are better, so B is slightly preferable.

**10. Aqueous Solubility:** Ligand A (-3.041) is worse than Ligand B (-2.252). Higher values are better, so B is preferable.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.684 and 0.507 percentile).

**12. Microsomal Clearance (Cl_mic):** Ligand A (74.856) has higher clearance than Ligand B (24.496). Lower clearance is preferred for metabolic stability, so B is significantly better.

**13. In vitro Half-Life (t1/2):** Ligand B (42.179 hours) has a much longer half-life than Ligand A (12.845 hours). Longer half-life is desirable for less frequent dosing, giving B a substantial advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.671 and 0.272 percentile).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). A >1.5 kcal/mol advantage is considered significant and can outweigh minor ADME drawbacks.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in these areas: significantly better affinity, much lower clearance, longer half-life, and better solubility. While Ligand A has a slightly better TPSA, the substantial advantages of Ligand B in the crucial enzyme-specific parameters outweigh this.

Output:
1
2025-04-17 14:07:12,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (366.487 Da and 398.937 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.67) is slightly higher than Ligand B (60.85), but both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.119) is within the optimal range (1-3), while Ligand B (3.116) is at the higher end of optimal.

**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 (6) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.799 and 0.841), indicating drug-like properties.

**7. DILI:** Ligand A (44.591) has a lower DILI risk than Ligand B (51.648), which is favorable.

**8. BBB:** This is less critical for an oncology target, but Ligand A (63.94) has a slightly better BBB percentile than Ligand B (43.273).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.895) is slightly worse than Ligand B (-4.792).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.256) is slightly worse than Ligand B (-3.118).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.122 and 0.392).

**12. Microsomal Clearance:** Ligand A (35.263) has significantly lower microsomal clearance than Ligand B (9.553), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In Vitro Half-Life:** Ligand B (37.857) has a much longer in vitro half-life than Ligand A (2.12). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.046 and 0.436).

**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 ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, a longer half-life, and a slightly better logP. While Ligand A has a lower DILI risk and slightly better BBB penetration, the superior potency and metabolic stability of Ligand B are more critical for a kinase inhibitor in oncology. The solubility and permeability are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:07:12,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.523 and 375.872 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (69.81). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (3.334 and 2.64), 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 5. Both are within the acceptable limit of 10, but A is preferable.

**QED:** Both ligands have good QED scores (0.571 and 0.793), indicating good drug-like properties.

**DILI:** Ligand A (46.995) has a much lower DILI risk than Ligand B (10.585). This is a significant advantage.

**BBB:** Both have high BBB penetration, but Ligand B (91.392) is slightly better than Ligand A (63.086). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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. Again, the scale is unspecified.

**hERG Inhibition:** Ligand A (0.825) has a slightly higher hERG risk than Ligand B (0.719), but both are relatively low.

**Microsomal Clearance:** Ligand A (94.58) has a significantly higher microsomal clearance than Ligand B (6.677). This means Ligand B is much more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (9.271) has a slightly longer half-life than Ligand A (8.953).

**P-gp Efflux:** Ligand A (0.693) has lower P-gp efflux than Ligand B (0.38), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially better binding affinity than Ligand A (-9.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better TPSA and DILI, Ligand B's significantly stronger binding affinity (-7.8 vs -9.0 kcal/mol) and much better metabolic stability (lower Cl_mic) are critical advantages for an enzyme inhibitor. The slightly lower P-gp efflux is a minor drawback. The unusual negative values for Caco-2 and solubility are concerning but difficult to assess without knowing the scale. Given the priorities for kinase inhibitors, the potency and metabolic stability of Ligand B are more important than the slightly better TPSA and DILI of Ligand A.

Output:
1
2025-04-17 14:07:12,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.555 Da) is slightly higher than Ligand B (356.463 Da), but both are acceptable.

**TPSA:** Ligand A (61.36) is significantly better than Ligand B (85.89). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.427, Ligand B: 0.72). Ligand A is slightly more lipophilic, which could aid in membrane permeability, while Ligand B is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=2, HBA=5) as it has fewer hydrogen bond donors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.852) has a significantly better QED score than Ligand B (0.636), indicating a more drug-like profile.

**DILI:** Ligand B (24.777) has a much lower DILI risk than Ligand A (53.005), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 76.619, Ligand B: 69.678), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.064 and -4.92), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.184 and -1.616), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Both ligands have very low hERG risk (Ligand A: 0.314, Ligand B: 0.19), which is excellent.

**Microsomal Clearance:** Ligand B (28.889) has a slightly lower microsomal clearance than Ligand A (35.847), suggesting better metabolic stability, which is important for kinase inhibitors.

**In vitro Half-Life:** Ligand A (0.232) has a slightly longer half-life than Ligand B (-0.912), but both are very short and problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.029, Ligand B: 0.018), which is favorable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This 0.4 kcal/mol difference is significant, and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and QED score, and slightly better half-life. However, Ligand B has a much lower DILI risk and slightly better metabolic stability. Both have poor predicted solubility and permeability. Given the importance of metabolic stability and safety (DILI) for enzyme inhibitors, and the relatively small difference in binding affinity, Ligand B is the slightly more promising candidate. The poor solubility and permeability of both compounds would need to be addressed through further optimization.

Output:
1
2025-04-17 14:07:12,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.4 and 351.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.85) is higher than Ligand B (56.67). While both are acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Both ligands have good logP values (1.53 and 2.17), 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 (0.6 and 0.82), indicating good drug-likeness.

**DILI:** Ligand A (47.03) has a slightly higher DILI risk than Ligand B (4.46), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (92.75) has a higher BBB score than Ligand A (51.80), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-4.95) and Ligand B (-4.66) 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:** Ligand A (-1.95) and Ligand B (-0.997) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.13) shows a slightly lower hERG risk than Ligand B (0.84). Lower is better.

**Microsomal Clearance:** Ligand B (10.67) has a slightly lower microsomal clearance than Ligand A (12.27), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.83) has a significantly longer in vitro half-life than Ligand A (-6.27), which is a major advantage.

**P-gp Efflux:** Ligand A (0.11) has a lower P-gp efflux liability than Ligand B (0.27), meaning it's less likely to be pumped out of cells.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a crucial advantage for an enzyme inhibitor, and the 2.1 kcal/mol difference is substantial enough to outweigh minor ADME concerns.

**Conclusion:**

Ligand B is the more promising candidate. While both have some ADME liabilities (negative Caco-2 and solubility values), Ligand B has a significantly higher binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. The stronger binding affinity is the most important factor for an enzyme inhibitor like an SRC kinase inhibitor.

Output:
1
2025-04-17 14:07:12,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.419 Da and 359.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.94) is better than Ligand B (38.13). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly lower, potentially indicating better absorption.

**logP:** Both ligands have good logP values (3.072 and 3.669), falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have reasonable QED scores (0.419 and 0.753), with Ligand B being significantly better.

**DILI:** Ligand A (40.481) is slightly higher than Ligand B (27.336), indicating a slightly higher risk of drug-induced liver injury. Ligand B is preferable here.

**BBB:** Ligand A (80.496) and Ligand B (91.508) both have good BBB penetration, but Ligand B is better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.225 and -5.288), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.409 and -3.755), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.596) is better than Ligand B (0.849), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (30.452) has lower microsomal clearance than Ligand B (82.034), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (18.505) has a longer half-life than Ligand B (12.11), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.311) has lower P-gp efflux than Ligand B (0.82), suggesting better bioavailability.

**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 of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, a better QED score, lower DILI risk, and better BBB penetration. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk. Both have poor solubility and permeability. The strong binding affinity of Ligand B is a major advantage for an enzyme inhibitor. While the ADME properties of Ligand A are better, the potency difference is likely to be more impactful in driving forward a lead optimization program.

Output:
1
2025-04-17 14:07:12,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.507 and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.87) is also below 140, but less optimal than A.

**logP:** Both ligands have logP values within the optimal range (A: 0.918, B: 1.358).

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.819) has a higher QED score than Ligand B (0.696), indicating better overall drug-likeness.

**DILI:** Ligand A (9.616 percentile) has a significantly lower DILI risk than Ligand B (43.622 percentile). This is a major advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand B (90.617) has a higher BBB penetration than Ligand A (64.25). This is not a deciding factor here.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret these values.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified, making interpretation difficult.

**hERG:** Ligand A (0.406) has a lower hERG risk than Ligand B (0.376), which is preferable.

**Microsomal Clearance:** Ligand A (-5.911) has a much lower (better) microsomal clearance than Ligand B (28.121). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-1.433) has a negative value, which is unusual and potentially problematic. Ligand B (-24.973) is even worse. Without knowing the scale, it's hard to interpret, but both suggest rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.021, B: 0.059), which is good.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a crucial advantage, as a 1.8 kcal/mol difference is substantial.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. Its superior binding affinity, lower DILI risk, and significantly better metabolic stability (lower Cl_mic) outweigh the slightly lower BBB penetration compared to Ligand B. While both have issues with solubility and Caco-2 permeability, the potency and safety profile of Ligand A make it the better choice for further development.

Output:
1
2025-04-17 14:07:12,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.415 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (83.22 and 78.43) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (1.26) and Ligand B (0.785) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values (0.864 and 0.79) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (35.13) has a lower DILI risk than Ligand B (19.698), which is preferable.

**BBB:** Ligand A (50.019) has a lower BBB penetration than Ligand B (75.301). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand B (-4.961) shows better Caco-2 permeability than Ligand A (-4.416), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.164) has slightly better aqueous solubility than Ligand A (-1.755).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.331 and 0.24), which is excellent.

**Microsomal Clearance:** Ligand B (3.133) has significantly lower microsomal clearance than Ligand A (19.009), indicating better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand B (3.23) has a shorter half-life than Ligand A (23.785). However, the large difference in Cl_mic is more important than the absolute half-life value.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.345 and 0.006).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has a slightly lower DILI risk, Ligand B's superior binding affinity, lower microsomal clearance (better metabolic stability), and better Caco-2 permeability outweigh this minor difference. The stronger binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:07:12,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (372.46 and 376.953 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (41.05) is slightly above the preferred <140, but acceptable. Ligand B (25.36) is excellent, well below 90.

**3. logP:** Ligand A (3.97) is near the upper limit of optimal (1-3), but still acceptable. Ligand B (4.842) is slightly higher, potentially leading to solubility issues, but not a dealbreaker given the potency.

**4. H-Bond Donors (HBD):** Ligand A (1) and Ligand B (0) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.847) is very good, indicating high drug-likeness. Ligand B (0.721) is also good, but slightly lower.

**7. DILI:** Ligand A (61.419) is moderate risk, but manageable. Ligand B (14.618) is excellent, indicating very low DILI risk.

**8. BBB:** Both ligands have high BBB penetration (92.71 and 93.292), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.854) and Ligand B (-5.241) both have negative values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-5.672) and Ligand B (-3.946) both have negative values, indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.831 and 0.824).

**12. Microsomal Clearance (Cl_mic):** Ligand A (57.729) has a higher clearance than Ligand B (52.504), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.756) has a longer half-life than Ligand B (-4.789). The negative value for Ligand B is concerning and suggests very rapid degradation.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.271 and 0.582).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much better binding affinity, lower DILI risk, and lower Cl_mic. While both have poor solubility and Caco-2 permeability, the superior affinity and metabolic stability of Ligand B are more critical. The negative half-life for Ligand B is a major concern, but the significantly improved binding affinity suggests it may be optimizable.

Output:
1
2025-04-17 14:07:12,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.443 and 359.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (78.87 and 81.99) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (0.544) is a bit low, potentially hindering permeation. Ligand B (3.547) 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:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have QED values above 0.5 (0.711 and 0.627), indicating good drug-likeness.

**7. DILI:** Ligand A (33.075) has a significantly lower DILI risk than Ligand B (53.509). This is a strong advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Both are relatively low, which is fine.

**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:** Ligand A (-1.524) has better solubility than Ligand B (-4.782). This is a positive for Ligand A.

**11. hERG Inhibition:** Ligand A (0.37) has a lower hERG risk than Ligand B (0.68). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (24.819) has much lower microsomal clearance than Ligand B (81.709), indicating better metabolic stability. This is a major advantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (37.709) has a longer in vitro half-life than Ligand A (9.18). This favors Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.338).

**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 deciding factor.

**Overall Assessment:**

While Ligand B has a better logP and slightly longer half-life, Ligand A demonstrates significantly superior ADMET properties: lower DILI risk, better solubility, lower hERG risk, and much better metabolic stability (lower Cl_mic). Given the enzyme-kinase focus, metabolic stability and safety (DILI, hERG) are crucial. The similar binding affinities make the ADMET advantages of Ligand A decisive.

Output:
0
2025-04-17 14:07:12,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 Da and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (80.37). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Both ligands have good logP values (1.891 and 2.264, respectively) falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are below the threshold of 10.

**QED:** Both ligands have good QED scores (0.767 and 0.882), indicating good drug-like properties.

**DILI:** Ligand A (31.989) has a significantly lower DILI risk than Ligand B (61.846). This is a major advantage for Ligand A.

**BBB:** Ligand A (68.786) has better BBB penetration than Ligand B (46.142), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.682) has a worse Caco-2 permeability than Ligand B (-5.086). Both are quite poor, indicating potential absorption issues.

**Aqueous Solubility:** Ligand A (-1.26) has better aqueous solubility than Ligand B (-3.094). This is a positive for Ligand A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.192 and 0.166), which is excellent.

**Microsomal Clearance:** Ligand A (31.256) has a higher microsomal clearance than Ligand B (18.162). This suggests Ligand B is more metabolically stable, which is a key consideration for enzymes.

**In vitro Half-Life:** Ligand B (34.735) has a significantly longer in vitro half-life than Ligand A (12.691). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.085).

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent and the most important factor.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A has a much better safety profile (lower DILI) and better solubility. However, Ligand B has superior metabolic stability (lower Cl_mic and longer t1/2). The difference in metabolic stability is significant. For an enzyme target like SRC kinase, metabolic stability is crucial for achieving adequate exposure and duration of action. The slightly worse DILI risk of Ligand B is likely manageable, especially given the strong affinity. The Caco-2 values are poor for both, suggesting formulation work would be needed.

Output:
1
2025-04-17 14:07:12,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.274 and 349.312 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.46) is better than Ligand B (56.49) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (1.354) is optimal (1-3), while Ligand B (3.725) is approaching the upper limit. Higher logP can lead to 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 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.486 and 0.659), indicating drug-like properties, with Ligand B being slightly better.

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a significant concern. Ligand B has a much lower, and acceptable, DILI risk (78.247%).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (90.112%) has higher BBB penetration than Ligand A (63.474%), but this is not a major factor in this case.

**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:** Ligand A (0.207) has a lower hERG risk than Ligand B (0.767), which is favorable.

**Microsomal Clearance:** Ligand A (9.355) has a lower microsomal clearance, indicating better metabolic stability, which is a key priority for enzymes. Ligand B (94.643) has a very high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (32.58) has a longer half-life than Ligand B (-5.757), which is a strong advantage.

**P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux, which is favorable for bioavailability. Ligand B (0.73) has higher efflux.

**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 is still a factor.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, the extremely high DILI risk and poor metabolic stability (high Cl_mic, short half-life) make it a significantly less desirable candidate. Ligand A, while having a slightly weaker affinity, exhibits a much better safety profile (lower DILI, lower hERG) and superior metabolic stability (lower Cl_mic, longer half-life). 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 14:07:12,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzyme targets: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.379 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.37) is slightly higher than Ligand B (90.12), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.575) is optimal, while Ligand B (1.595) is a little low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.836) has a significantly higher QED score than Ligand B (0.443), indicating better overall drug-likeness.

**DILI:** Ligand B (32.183) has a much lower DILI risk than Ligand A (77.356), which is a significant advantage.

**BBB:** Ligand A (57.193) has a slightly higher BBB penetration potential than Ligand B (43.815), but this is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.983) has a much better Caco-2 permeability than Ligand B (-5.366).

**Aqueous Solubility:** Ligand B (-2.021) has better aqueous solubility than Ligand A (-5.008).

**hERG Inhibition:** Ligand A (0.899) has a slightly higher hERG inhibition liability than Ligand B (0.369), making Ligand B safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (1.859) has significantly lower microsomal clearance than Ligand A (37.796), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.126) has a longer in vitro half-life than Ligand B (-0.271).

**P-gp Efflux:** Ligand A (0.344) has lower P-gp efflux than Ligand B (0.038), which is preferable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial difference, and a 1.4 kcal/mol advantage in binding is significant.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better Caco-2 permeability and P-gp efflux, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic), and a substantially stronger binding affinity. The slightly lower logP and QED of Ligand B are less concerning given the strong affinity and improved safety profile.

Output:
1
2025-04-17 14:07:12,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.353 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is slightly higher than Ligand B (53.76). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Ligand A (1.331) is within the optimal 1-3 range. Ligand B (3.479) is at the higher end but still acceptable.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.889 and 0.842), indicating good drug-likeness.

**DILI:** Ligand A (39.201) and Ligand B (31.601) both have low DILI risk, below the 40 threshold. Ligand B is slightly better.

**BBB:** Ligand A (68.554) and Ligand B (71.888) both have acceptable BBB penetration, but not exceptionally high. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative values (-4.794 and -4.611), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative values (-2.483 and -2.945), indicating poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.456) has a slightly lower hERG risk than Ligand B (0.704). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (13.77) has significantly lower microsomal clearance than Ligand B (52.272), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-2.114) has a negative half-life, which is not possible. This is a data error. Ligand B (30.377) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux than Ligand B (0.65), which is favorable.

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand B's much stronger binding affinity (-7.8 kcal/mol vs 0.0 kcal/mol) is a decisive factor. The improved metabolic stability of Ligand A is attractive, but the difference in binding affinity is substantial enough to outweigh this benefit. The negative half-life value for Ligand A is also concerning and suggests a data quality issue.

Output:
1
2025-04-17 14:07:12,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.443 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (91.32), both are below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (2.537 and 1.781), falling within the optimal 1-3 range. Ligand A is slightly higher, potentially aiding membrane permeability.

**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 4. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.738) has a significantly better QED score than Ligand B (0.47), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.991) has a slightly higher DILI risk than Ligand B (46.452), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (67.197) has a better BBB penetration score than Ligand B (27.181), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.29 and -4.997), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-2.597 and -2.422), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG:** Both ligands have low hERG inhibition liability (0.452 and 0.379), which is good.

**12. Cl_mic:** Ligand A (-2.89) has a *much* lower (better) microsomal clearance than Ligand B (24.49). This suggests significantly better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (25.983) has a longer in vitro half-life than Ligand B (-28.577). This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.057 and 0.068).

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the superior candidate. The key advantages of Ligand A are its significantly better QED score, substantially lower microsomal clearance (better metabolic stability), and longer in vitro half-life. While both have poor Caco-2 and solubility, the ADME properties of Ligand A are far more favorable, making it more likely to succeed as a drug candidate. The small difference in binding affinity is unlikely to outweigh the substantial improvements in pharmacokinetic properties.

Output:
0
2025-04-17 14:07:12,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (352.435 Da and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (119.52) is better than Ligand B (67.87) as it is closer to the threshold of 140, and both are well below 90, which is important for CNS targets (not relevant here).

**3. logP:** Both ligands (1.303 and 1.745) are 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 (6) is higher than Ligand B (4), but both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.844) has a significantly better QED score than Ligand A (0.431), indicating better overall drug-likeness.

**7. DILI:** Ligand A (21.171) has a much lower DILI risk than Ligand B (32.261), which is a significant advantage.

**8. BBB:** Ligand B (74.758) has a higher BBB percentile than Ligand A (62.466), but BBB is not a primary concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Ligand A (-5.473) has a worse Caco-2 permeability than Ligand B (-4.78), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.956) has a worse aqueous solubility than Ligand B (-2.238).

**11. hERG Inhibition:** Ligand A (0.586) has a lower hERG inhibition risk than Ligand B (0.155), which is a significant advantage.

**12. Microsomal Clearance:** Ligand B (14.79) has a higher microsomal clearance than Ligand A (3.163), indicating lower metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (18.36) has a much longer in vitro half-life than Ligand B (1.832), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.026) has a much lower P-gp efflux liability than Ligand B (0.048), suggesting better oral bioavailability.

**15. Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-7.2). This is a crucial factor, and the 1.2 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand B has a better QED and binding affinity, Ligand A demonstrates superior ADME properties, particularly regarding metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG inhibition. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are paramount. The affinity difference, while significant, might be overcome with further optimization of Ligand A, whereas improving the ADME profile of Ligand B would likely be more challenging.

Output:
0
2025-04-17 14:07:12,364 - INFO - Batch 270 complete. Total preferences: 4320
2025-04-17 14:07:12,364 - INFO - Processing batch 271/512...
2025-04-17 14:07:56,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 355.341 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.78) is excellent, well below the 140 threshold for oral absorption. Ligand B (112.73) is still reasonable but less optimal.

**logP:** Ligand A (2.03) is within the optimal 1-3 range. Ligand B (0.922) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both within acceptable limits. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.809) has a very strong drug-like profile. Ligand B (0.631) is still good, exceeding the 0.5 threshold.

**DILI:** Ligand A (54.207) has a moderate DILI risk, but is acceptable. Ligand B (33.928) has a very low DILI risk, which is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (81.233) is higher than Ligand B (65.801).

**Caco-2 Permeability:** Ligand A (-4.65) is poor, suggesting low intestinal absorption. Ligand B (-5.702) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.102) is poor. Ligand B (-2.67) is also poor, but slightly better.

**hERG Inhibition:** Both ligands (0.197 and 0.369) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (19.006) has moderate clearance. Ligand B (-23.431) has *negative* clearance, which is an anomaly and almost certainly indicates very high metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (53.536 hours) has a good half-life. Ligand B (-28.027 hours) also has a negative value, which is an anomaly and suggests a very long half-life.

**P-gp Efflux:** Both ligands (0.023 and 0.024) have very low P-gp efflux liability, which is ideal.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol) - a difference of 1.1 kcal/mol. This is a substantial advantage that can outweigh some of the ADME concerns.

**Conclusion:**

While Ligand A has a better TPSA and QED, Ligand B's significantly superior binding affinity (-9.0 vs -7.9 kcal/mol) and dramatically improved metabolic stability (negative Cl_mic and t1/2) are critical for an enzyme target like SRC. The slightly lower logP and Caco-2 permeability of Ligand B are less concerning given the strong binding and metabolic profile. The lower DILI risk is also a bonus.

Output:
1
2025-04-17 14:07:56,641 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [387.307, 51.13, 4.989, 0., 4., 0.54, 53.005, 70.841, -4.53, -5.895, 0.57, 54.805, 1.779, 0.5, 0.]
**Ligand B:** [381.395, 62.3, 2.392, 1., 4., 0.738, 46.103, 74.719, -4.86, -2.63, 0.305, 17.899, -28.489, 0.107, -8.2]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand A (387.3) is slightly higher, but both are acceptable.
2. **TPSA:** Ligand A (51.13) is better than Ligand B (62.3), being closer to the <140 threshold for good absorption.
3. **logP:** Ligand A (4.989) is a bit high, potentially leading to solubility issues. Ligand B (2.392) is within the optimal range.
4. **HBD:** Ligand A (0) is preferable to Ligand B (1) as fewer HBDs generally improve permeability.
5. **HBA:** Both have 4 HBA, which is acceptable.
6. **QED:** Ligand B (0.738) has a better QED score than Ligand A (0.54), indicating a more drug-like profile.
7. **DILI:** Ligand B (46.103) has a significantly lower DILI risk than Ligand A (53.005), which is a major advantage.
8. **BBB:** Both have good BBB penetration (Ligand A: 70.841, Ligand B: 74.719), but 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:** Ligand B (-2.63) has better solubility than Ligand A (-5.895).
11. **hERG:** Ligand A (0.57) has a slightly higher hERG risk than Ligand B (0.305).
12. **Cl_mic:** Ligand B (17.899) has much lower microsomal clearance than Ligand A (54.805), indicating better metabolic stability. This is a crucial factor for kinases.
13. **t1/2:** Ligand B (-28.489) has a significantly longer in vitro half-life than Ligand A (1.779), which is highly desirable.
14. **Pgp:** Ligand A (0.5) has higher P-gp efflux than Ligand B (0.107).
15. **Binding Affinity:** Ligand B (-8.2) has a *much* stronger binding affinity than Ligand A (0). This is the most important factor for an enzyme target. A difference of >1.5 kcal/mol is significant.

**Enzyme-Kinase Specific Priorities:**

For a kinase like SRC, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B excels in these areas. The strong binding affinity of Ligand B (-8.2 kcal/mol) is a major advantage that can outweigh some of the minor drawbacks.

**Conclusion:**

Ligand B is the far superior candidate. Its significantly better binding affinity, lower DILI risk, improved metabolic stability, longer half-life, and better solubility outweigh the slightly higher TPSA and logP values.

Output:
1
2025-04-17 14:07:56,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.359 Da and 371.461 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.04) is better than Ligand B (73.45), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (-0.23) is slightly low, potentially hindering permeability. Ligand B (3.145) 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 limit of 5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (8) are both acceptable, below the limit of 10.

**QED:** Both ligands have good QED scores (0.541 and 0.73), indicating drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (68.011 and 63.668), below the 60 threshold.

**BBB:** Ligand A (47.926) and Ligand B (82.862) are both relatively low, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.119 and -4.946), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.878 and -4.51), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG risk (0.133 and 0.125), which is excellent.

**Microsomal Clearance:** Ligand A (49.385) has lower clearance than Ligand B (76.648), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.425) has a negative half-life, which is not possible. Ligand B (-14.85) also has a negative half-life, which is not possible. This is a major concern for both.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.317), which is good.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 1 kcal/mol difference is potentially significant.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability. However, Ligand B has a more favorable logP, which is crucial for permeability. Both ligands have concerning negative values for Caco-2 permeability and aqueous solubility, and negative in vitro half-lives, which are problematic. The slightly better affinity of Ligand A, coupled with its better metabolic stability, gives it a slight edge, *assuming the negative half-life can be addressed through structural modifications*. The logP of Ligand A is a concern, but potentially correctable.

Output:
0
2025-04-17 14:07:56,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 360.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.67) is better than Ligand B (52.08) as it is closer to the 140 A^2 threshold for good oral absorption. Ligand B is very low, which could indicate issues with solubility.

**logP:** Ligand A (-0.249) is a bit low, potentially hindering permeability. Ligand B (4.325) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) is better balanced than Ligand B (HBD=0, HBA=5). Both are within acceptable limits, but A is slightly more favorable.

**QED:** Both ligands have similar QED values (0.62 and 0.502), indicating reasonable drug-likeness.

**DILI:** Ligand A (37.922) has a significantly lower DILI risk than Ligand B (80.729). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.715) has better BBB penetration than Ligand B (65.529).

**Caco-2 Permeability:** Ligand A (-5.241) has very poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.531) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.639) has poor solubility, while Ligand B (-5.407) is even worse. This is a concern for both, but more so for B.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.285 and 0.28), which is good.

**Microsomal Clearance:** Ligand A (1.676) has much lower microsomal clearance than Ligand B (101.592), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.316) has a very short half-life, which is a significant negative. Ligand B (-3.547) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.004 and 0.182), which is favorable.

**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 small.

**Overall Assessment:**

Ligand A has significant drawbacks in Caco-2 permeability and in vitro half-life. However, it excels in DILI risk and microsomal clearance, which are critical for enzyme inhibitors. Ligand B has a better binding affinity and slightly better Caco-2, but suffers from a very high DILI risk and poor metabolic stability. Given the priorities for an enzyme target, the lower DILI and better metabolic stability of Ligand A outweigh its permeability and half-life issues, especially as these can be addressed through further optimization. The binding affinity difference is not substantial enough to favor Ligand B given its ADME liabilities.

Output:
0
2025-04-17 14:07:56,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.403 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.05) is higher than Ligand B (67.23). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**3. logP:** Both ligands have good logP values (1.096 and 1.816), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable.

**6. QED:** Both ligands have high QED scores (0.845 and 0.856), indicating good drug-like properties.

**7. DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (24.467). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (63.125) and Ligand B (70.492). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-5.085) has poor Caco-2 permeability, while Ligand B (-4.884) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-2.092) and Ligand B (-1.77) are both poor.

**11. hERG Inhibition:** Ligand A (0.082) has a very low hERG risk, which is excellent. Ligand B (0.371) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (24.698) has lower microsomal clearance than Ligand B (48.936), suggesting better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-13.31) has a shorter half-life than Ligand B (-21.865). This is a disadvantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable. Ligand B (0.163) is slightly higher.

**15. Binding Affinity:** Ligand B (-8.1) 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 is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B's substantially superior binding affinity (-8.1 vs 0.0 kcal/mol) is the most important factor. The lower DILI risk and better BBB are also positives. Ligand A's lower clearance is beneficial, but the significantly weaker binding and higher DILI risk are major concerns.

Output:
1
2025-04-17 14:07:56,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.479 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.69) is well below the 140 threshold, suggesting good absorption. Ligand B (91.06) is also below, but closer to the limit.

**logP:** Ligand A (2.457) is optimal (1-3). Ligand B (1.059) is slightly low, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (3 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.81) has a higher QED score than Ligand B (0.672), indicating better overall drug-likeness.

**DILI:** Ligand A (27.336) has a significantly lower DILI risk than Ligand B (51.609), which is a major advantage.

**BBB:** Both ligands have reasonably high BBB penetration (Ligand A: 78.79, Ligand B: 73.866), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG Inhibition:** Ligand A (0.076) has a much lower hERG inhibition liability than Ligand B (0.262), a critical safety parameter.

**Microsomal Clearance:** Ligand A (32.128) has higher microsomal clearance than Ligand B (5.992), indicating faster metabolism and potentially lower *in vivo* exposure. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-26.122) has a significantly longer *in vitro* half-life than Ligand A (-8.765), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.112, Ligand B: 0.11).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-6.6 kcal/mol). The difference of 2.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower DILI risk, and lower hERG risk. However, it has higher microsomal clearance and a shorter half-life. Ligand B has better metabolic stability, but weaker binding, higher DILI and hERG risk. Given the importance of potency and safety for kinase inhibitors, the superior binding affinity and safety profile of Ligand A are more critical. The metabolic stability issue could potentially be addressed through structural modifications.

Output:
1
2025-04-17 14:07:56,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (376.538 and 348.382 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is well below the 140 threshold, while Ligand B (93.96) is approaching it. This favors Ligand A for better absorption.

**logP:** Both ligands have acceptable logP values (2.72 and 1.489), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.708 and 0.821), indicating good drug-like properties.

**DILI:** Ligand A (29.779) has a significantly lower DILI risk than Ligand B (76.425). This is a substantial advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (91.508) has a better score than Ligand B (60.45).

**Caco-2 Permeability:** Ligand A (-4.895) has a more negative Caco-2 value, suggesting lower permeability than Ligand B (-5.041). However, this is a minor difference and less important than other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.397 and -2.587), indicating poor aqueous solubility. Ligand B is slightly better, but both are problematic.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.77 and 0.063), which is excellent. Ligand B is preferable here.

**Microsomal Clearance:** Ligand A (51.052) has a higher microsomal clearance than Ligand B (14.79), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-48.63) has a much more negative half-life, indicating a very short half-life. Ligand B (-5.271) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.214 and 0.088).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.7 and -8.1 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has better TPSA and BBB, Ligand B excels in DILI risk, microsomal clearance, and in vitro half-life, all of which are crucial for an enzyme inhibitor. The slight advantage in solubility for Ligand B is also beneficial. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 14:07:56,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.383 and 345.33 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.19) is significantly better than Ligand B (115.36).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is getting higher and could potentially impact absorption.

**logP:** Both ligands have good logP values (2.735 and 1.857), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=5). Lower HBD is generally preferable.

**QED:** Both ligands have similar QED values (0.75 and 0.715), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (75.339 and 74.021), which is moderately high but not alarming.

**BBB:** Ligand A (64.948) has a better BBB percentile than Ligand B (22.528). While SRC isn't a CNS target, better BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.953 and -4.848), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.287 and -3.856), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.356 and 0.442), which is excellent.

**Microsomal Clearance:** Ligand A (29.688) has a higher (worse) microsomal clearance than Ligand B (10.998). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (89.733) has a significantly longer in vitro half-life than Ligand A (32.979), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.069), which is good.

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A's substantially superior binding affinity (-9.1 vs -7.9 kcal/mol) is the deciding factor. The difference in potency is large enough to potentially overcome the ADME liabilities, especially given that formulation strategies can sometimes address solubility issues. Ligand B has better metabolic stability (lower Cl_mic and higher t1/2), but the potency difference is too significant to ignore.

Output:
0
2025-04-17 14:07:56,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.543 Da) is slightly higher than Ligand B (350.503 Da), but both are acceptable.

**TPSA:** Ligand A (47.36) is well below the 140 threshold for oral absorption. Ligand B (72.8) is also below, but closer to the limit.

**logP:** Ligand A (3.182) is within the optimal range (1-3). Ligand B (1.835) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (3 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within acceptable limits.

**QED:** Ligand A (0.664) has a better QED score than Ligand B (0.461), indicating a more drug-like profile.

**DILI:** Ligand B (3.18) has a significantly lower DILI risk than Ligand A (26.638), a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (83.249) is better than Ligand B (74.098). This is less critical for a kinase inhibitor unless CNS effects are specifically desired.

**Caco-2 Permeability:** Ligand A (-4.639) has poor Caco-2 permeability, while Ligand B (-5.027) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.464) has slightly better solubility than Ligand B (-2.642), though both are quite poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.649 and 0.622 respectively).

**Microsomal Clearance:** Ligand B (28.781) has significantly lower microsomal clearance than Ligand A (93.131), suggesting better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (29.854 hours) has a significantly longer half-life than Ligand B (0.642 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.365 and 0.066 respectively).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 1.4 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and significantly better metabolic stability (lower Cl_mic) and lower DILI risk. While Ligand A has a longer half-life and slightly better solubility, the significantly stronger binding of Ligand B and its improved safety profile are more important for an enzyme inhibitor. The lower Caco-2 permeability of both is a concern, but can potentially be addressed through formulation strategies. The difference in binding affinity is substantial enough to overcome the shorter half-life.

Output:
1
2025-04-17 14:07:56,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (414.221 Da) is slightly higher than Ligand B (339.439 Da), but both are acceptable.

**TPSA:** Ligand A (38.33) is excellent, well below the 140 threshold for oral absorption. Ligand B (79.45) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (4.754) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.387) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is excellent. Ligand B (HBD=2, HBA=4) is also good, within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.784, B: 0.88), indicating good drug-like properties.

**DILI:** Ligand A (64.909) has a higher DILI risk than Ligand B (29.779), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.421) has better BBB penetration than Ligand B (54.44), but this isn't a primary factor.

**Caco-2 Permeability:** Ligand A (-4.67) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.18) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.531) has very poor solubility. Ligand B (-1.992) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.812) has a slightly higher hERG risk than Ligand B (0.411), but both are relatively low.

**Microsomal Clearance:** Ligand A (70.057) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (-11.233) has negative clearance (highly stable). This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (38.075) has a moderate half-life. Ligand B (14.677) has a shorter half-life, but the negative clearance suggests it could be more stable *in vivo*.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.45, B: 0.059), which is favorable.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor solubility, poor permeability, higher DILI risk, and lower metabolic stability. Ligand B has better ADME properties (solubility, permeability, metabolic stability, DILI risk) but significantly weaker binding affinity.

The difference in binding affinity (3.2 kcal/mol) is substantial. While the ADME properties of Ligand A are concerning, the potency advantage is likely to be critical. Optimization efforts could focus on improving the solubility and metabolic stability of Ligand A while maintaining its high affinity.

Output:
1
2025-04-17 14:07:56,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.467 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.96 and 81.75) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.729) is within the optimal 1-3 range. Ligand B (-0.425) is slightly below 1, which *could* indicate potential permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, which are acceptable.

**QED:** Both ligands have QED values (0.75 and 0.612) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (52.656) has a moderate DILI risk. Ligand B (24.118) has a significantly lower DILI risk, which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (58.24) and B (41.218) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.451 and -5.063), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.569 and -1.254), indicating poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.49 and 0.089), which is excellent.

**Microsomal Clearance:** Ligand A (36.033 mL/min/kg) has a moderate clearance. Ligand B (2.98 mL/min/kg) has *very* low clearance, indicating excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (5.062 hours) has a reasonable half-life. Ligand B (-18.154 hours) has a negative half-life, which is impossible and suggests an issue with the data or the model.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.133 and 0.008).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility and permeability concerns (negative Caco-2 and solubility values), Ligand B has a substantially better binding affinity, significantly lower DILI risk, and much better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is a data anomaly that needs to be investigated, but the other advantages are compelling. Ligand A's moderate DILI risk and slightly weaker binding are less desirable.

Output:
1
2025-04-17 14:07:56,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 357.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.34) is better than Ligand B (38.13). Both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.556 and 3.89), falling within the 1-3 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, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED scores (0.661 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A (45.095) has a slightly higher DILI risk than Ligand B (30.748), but both are below the concerning threshold of 60.

**BBB:** Ligand A (70.027) has moderate BBB penetration, while Ligand B (94.61) has high BBB penetration. Since SRC is not a CNS target, this is less important, but a slight advantage for B.

**Caco-2 Permeability:** Ligand A (-5.241) has poor Caco-2 permeability, while Ligand B (-4.202) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-2.296) has poor aqueous solubility, while Ligand B (-3.763) is even worse. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.238) has a lower hERG inhibition risk than Ligand B (0.626), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (25.946) has significantly lower microsomal clearance than Ligand B (60.136), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-1.398) has a shorter in vitro half-life than Ligand B (-10.97). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.34), indicating better bioavailability.

**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 for Ligand B, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While it has some ADME liabilities (worse solubility, higher P-gp efflux, higher hERG), the strong binding affinity is likely to compensate for these. Ligand A has better metabolic stability and lower hERG risk, but the weaker binding affinity is a major drawback. Given the priority for potency in enzyme inhibition, Ligand B is the more promising candidate.

Output:
1
2025-04-17 14:07:56,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.507 and 345.374 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (87.3 and 82.27) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (1.986) is within the optimal range (1-3). Ligand B (0.988) is slightly below, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD (3 and 2) and HBA (3) counts.

**QED:** Both ligands have good QED scores (0.561 and 0.854), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (16.324) has a significantly lower DILI risk than Ligand B (37.611). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (64.211 and 69.833). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.864 and -5.061), which is unusual and suggests poor permeability. This is a potential red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.705 and -2.991), indicating very poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.189 and 0.268), which is good.

**Microsomal Clearance:** Ligand B (-21.283) has a *much* lower (better) microsomal clearance than Ligand A (45.518). This suggests significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-15.1) has a longer in vitro half-life than Ligand A (-3.174), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.014).

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-8.6 and -8.9 kcal/mol). The difference is minimal.

**Conclusion:**

While both compounds have excellent binding affinity, Ligand B has a clear advantage in metabolic stability (lower Cl_mic and longer t1/2) and a better QED score. However, Ligand A has a significantly lower DILI risk. The solubility and permeability are poor for both. Given the enzyme-specific priorities, metabolic stability is crucial. The lower DILI risk of Ligand A is valuable, but the substantial difference in Cl_mic and t1/2 for Ligand B outweighs this concern.

Output:
1
2025-04-17 14:07:56,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.47 and 377.87 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.14) is slightly higher than the preferred <140, but still reasonable. Ligand B (49.25) is excellent, well below 140.

**logP:** Ligand A (2.389) is optimal (1-3). Ligand B (4.086) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.629 and 0.747, respectively), indicating good drug-like properties.

**DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (68.98), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.772) and Ligand B (74.06) are both reasonably high.

**Caco-2 Permeability:** Ligand A (-4.849) is poor, indicating low intestinal absorption. Ligand B (-5.036) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.269 and -4.116, respectively). This is a significant concern.

**hERG Inhibition:** Ligand A (0.136) has a very low hERG risk, which is excellent. Ligand B (0.781) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (89.697) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (25.818) has significantly lower clearance, indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-15.861) has a very short half-life, which is undesirable. Ligand B (50.294) has a much longer half-life, which is a significant advantage.

**P-gp Efflux:** Ligand A (0.103) has low P-gp efflux. Ligand B (0.833) has higher P-gp efflux.

**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.

**Conclusion:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the superior candidate. Its significantly stronger binding affinity, much better metabolic stability (lower Cl_mic and longer t1/2), and acceptable hERG risk outweigh the slightly higher P-gp efflux and DILI risk. The poor solubility will need to be addressed through formulation strategies, but the potency and metabolic stability of Ligand B make it a more promising starting point for drug development.

Output:
1
2025-04-17 14:07:56,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 368.331 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is slightly higher than Ligand B (80.49), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.055 and 2.086, respectively), 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5 (0.831 and 0.775), indicating good drug-likeness.

**DILI:** Ligand A (44.513) has a lower DILI risk than Ligand B (58.705), which is preferable. Both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.755) has a higher BBB value than Ligand A (52.811), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.984 and -4.675). This is unusual and suggests poor permeability. However, these values are on a strange scale, and their absolute meaning is unclear without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.798 and -2.928). Similar to Caco-2, this is unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.174) shows a significantly lower hERG risk than Ligand B (0.314), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (15.793) has a lower microsomal clearance than Ligand B (19.595), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.651) has a more negative in vitro half-life, which is unusual and suggests a shorter half-life. Ligand B (-15.881) is even more negative, indicating very poor stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.073).

**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.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates a significantly lower hERG risk, lower DILI risk, and better metabolic stability (lower Cl_mic). The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh the small binding affinity difference. The improved safety profile (hERG, DILI) and metabolic stability are crucial for kinase inhibitors.

Output:
0
2025-04-17 14:07:56,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.479 and 367.599 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.89) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (29.54) is excellent, well below 140.

**3. logP:** Ligand A (0.99) is at the lower end of optimal (1-3), potentially impacting permeability. Ligand B (4.454) is a bit high, potentially leading to solubility issues and off-target effects.

**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 (3) is also good.

**6. QED:** Both ligands (0.601 and 0.603) have good drug-likeness scores, exceeding 0.5.

**7. DILI:** Ligand A (11.4) has a much lower DILI risk than Ligand B (22.102), which is a significant advantage.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (78.674) has a higher BBB score than Ligand A (38.813).

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.138 and -5.033), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-1.231) has slightly better solubility than Ligand B (-5.094), though both are quite poor.

**11. hERG:** Ligand A (0.177) has a much lower hERG risk than Ligand B (0.837), a critical advantage for safety.

**12. Cl_mic:** Ligand A (19.509) has significantly lower microsomal clearance than Ligand B (96.428), indicating better metabolic stability.

**13. t1/2:** Ligand B (30.078) has a longer in vitro half-life than Ligand A (17.203), which is a positive.

**14. Pgp:** Ligand A (0.017) has much lower P-gp efflux liability than Ligand B (0.65), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.4). However, the difference is less than 1.5 kcal/mol, so it doesn't overwhelmingly outweigh other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor Caco-2 permeability and solubility, Ligand A exhibits significantly better safety profiles (lower DILI and hERG risk), better metabolic stability (lower Cl_mic), and lower P-gp efflux. The slightly weaker binding affinity of Ligand A is less concerning given its superior ADME-Tox properties. Ligand B's higher logP and DILI risk are substantial drawbacks.

Output:
0
2025-04-17 14:07:56,645 - INFO - Batch 271 complete. Total preferences: 4336
2025-04-17 14:07:56,645 - INFO - Processing batch 272/512...
2025-04-17 14:08:37,480 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.535 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (43.86) is better than Ligand B (29.54) as it is still within the acceptable range for oral absorption, while ligand B is very low, which might indicate a lack of necessary interactions.

**logP:** Ligand A (2.914) is optimal, while Ligand B (4.551) is pushing the upper limit. Higher logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (0) and HBA (3 & 4 respectively), falling within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.474 and 0.678), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (10.934) has a significantly lower DILI risk than Ligand B (42.691), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (92.555) has a higher BBB score, but this is not a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.406) is better than Ligand B (-5.054), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.501) is better than Ligand B (-4.732), which is crucial for bioavailability.

**hERG:** Both ligands have relatively low hERG risk (0.621 and 0.769), which is good.

**Microsomal Clearance:** Ligand A (79.046) has significantly lower microsomal clearance than Ligand B (107.866), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (39.258) has a much longer half-life than Ligand A (4.61), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.127 and 0.732).

**Binding Affinity:** Ligand B (-9.0 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 2.3 kcal/mol is significant.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. However, it has a higher logP, a higher DILI risk, and lower solubility. Ligand A has better ADME properties (lower DILI, better solubility, better permeability, better metabolic stability), but its binding affinity is considerably weaker.

Given the substantial difference in binding affinity, I believe Ligand B is the more promising candidate, despite its ADME liabilities. The potency advantage is likely to be more impactful than the ADME concerns, which can potentially be addressed through further optimization.

Output:
1
2025-04-17 14:08:37,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (374.463 and 359.461 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (130.13) is borderline, but acceptable for oral absorption. Ligand B (52.65) is excellent, well below the 140 threshold.

**3. logP:** Ligand A (-0.315) is slightly low, potentially hindering permeation. Ligand B (2.137) is optimal.

**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 (3) is also good.

**6. QED:** Both ligands have good QED scores (0.51 and 0.608), indicating drug-like properties.

**7. DILI:** Ligand A (60.295) has a moderate DILI risk, while Ligand B (12.33) has a very low risk, which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (73.943) has better BBB penetration, but it's not a primary concern here. Ligand A (47.809) is lower.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.47 and -4.912), 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 of absorption.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.219 and -1.129), indicating poor aqueous solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Ligand A (0.25) has a slightly higher hERG risk than Ligand B (0.468), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-8.541) has a much lower (better) microsomal clearance than Ligand B (2.091), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (32.565) has a shorter half-life than Ligand B (-9.014), which is a negative.

**14. P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux than Ligand B (0.02), which is favorable.

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-6.6), a difference of 1.2 kcal/mol.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand A has better affinity and significantly better metabolic stability. However, Ligand B has a much lower DILI risk and a better logP. The solubility is poor for both.

**Overall Assessment:** While Ligand A has a better binding affinity and metabolic stability, Ligand B's significantly lower DILI risk and more favorable logP make it a more promising starting point. The 1.2 kcal/mol difference in affinity can potentially be overcome with further optimization, but mitigating the DILI risk early in the process is highly desirable. The poor solubility of both compounds is a concern that would need to be addressed.

Output:
1
2025-04-17 14:08:37,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.41 and 370.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is better than Ligand B (84.94). Both are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (3.524) is slightly higher than Ligand B (1.212). Ligand B is a bit low, potentially hindering permeation. Ligand A is within the optimal range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Both have 5 HBA, also good.

**QED:** Ligand B (0.861) has a higher QED score than Ligand A (0.548), indicating a more drug-like profile overall.

**DILI:** Ligand A (31.718) has a significantly lower DILI risk than Ligand B (68.282). This is a major advantage for Ligand A.

**BBB:** Ligand A (87.127) has better BBB penetration than Ligand B (68.67), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.892) has worse Caco-2 permeability than Ligand B (-4.71). Both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.472) has worse aqueous solubility than Ligand B (-2.932). Solubility is a concern for both, but less so for Ligand B.

**hERG Inhibition:** Ligand A (0.835) has a slightly higher hERG risk than Ligand B (0.23). Ligand B is much better here.

**Microsomal Clearance:** Ligand B (52.239) has lower microsomal clearance than Ligand A (70.983), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.3) has a longer half-life than Ligand B (2.033). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.16), indicating better bioavailability.

**Binding Affinity:** Ligand B (-7.7) has slightly better binding affinity than Ligand A (-7.6). While this is a small difference, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B has a better QED, lower hERG risk, and better metabolic stability. However, Ligand A has a significantly lower DILI risk, longer half-life, and better P-gp efflux. The binding affinity difference is minimal. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is slightly better due to its superior metabolic stability and lower hERG risk, despite the slightly lower QED and higher DILI. The small affinity difference is unlikely to outweigh the ADME advantages of Ligand B.

Output:
1
2025-04-17 14:08:37,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.455 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (76.66) is still within acceptable limits (<140) but less favorable than A.

**logP:** Ligand A (3.248) is optimal. Ligand B (1.192) is a bit low, potentially hindering permeation, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (1 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 (0.733 and 0.671, respectively), indicating drug-like properties.

**DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (39.55), which is a major advantage. Both are below the 40 threshold.

**BBB:** Both have reasonable BBB penetration (70.531 and 69.446), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-3.972) shows better Caco-2 permeability than Ligand B (-5.302).

**Aqueous Solubility:** Ligand A (-3.756) has better aqueous solubility than Ligand B (-2.667).

**hERG:** Both ligands have low hERG inhibition risk (0.335 and 0.281).

**Microsomal Clearance:** Ligand A (90.715) has higher microsomal clearance than Ligand B (31.015), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (11.124 hours) has a substantially longer in vitro half-life than Ligand A (4.88 hours), which is a considerable advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.112).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A having better TPSA, logP, solubility, and lower DILI, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.9 vs -6.2 kcal/mol) and the longer in vitro half-life (11.124 vs 4.88 hours) are critical advantages for an enzyme inhibitor. While Ligand A has better solubility, the difference is not large enough to overcome the potency and stability advantages of Ligand B. The slightly higher DILI risk of Ligand B is acceptable given the overall profile.

Output:
1
2025-04-17 14:08:37,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (374.503 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.94 and 78.53) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (1.203 and 1.391) 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 acceptable (<=10).

**QED:** Ligand B (0.824) has a significantly better QED score than Ligand A (0.457), indicating a more drug-like profile.

**DILI:** Ligand A (38.813) has a much lower DILI risk than Ligand B (68.088), which is a significant advantage.

**BBB:** Both have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 can be misleading.

**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 ligands have very low hERG inhibition risk (0.28 and 0.279), which is excellent.

**Microsomal Clearance:** Ligand B (59.315) has a slightly lower microsomal clearance than Ligand A (61.874), suggesting better metabolic stability, which is desirable.

**In vitro Half-Life:** Ligand B (-13.926) has a significantly longer in vitro half-life than Ligand A (-6.012), which is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.034 and 0.11), which is good.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.6 kcal/mol difference is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk, Ligand B's superior binding affinity (-8.9 vs -7.3 kcal/mol), better QED, and longer half-life are more critical for an enzyme target like SRC kinase. The slightly higher DILI risk of Ligand B is a manageable concern compared to the potency and PK advantages. The poor solubility and permeability of both compounds would need to be addressed during lead optimization.

Output:
1
2025-04-17 14:08:37,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 342.399 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (83.04). Both are below the 140 threshold for oral absorption, but lower TPSA generally favors better cell permeability.

**logP:** Ligand B (2.712) is closer to the optimal 1-3 range than Ligand A (0.6). Ligand A's low logP could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (0 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.689 and 0.614), indicating reasonable drug-likeness.

**DILI:** Ligand A (4.692) has a significantly lower DILI risk than Ligand B (64.056). This is a major advantage for Ligand A.

**BBB:** Ligand B (80.419) has a higher BBB penetration percentile than Ligand A (29.275). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.056) has a worse Caco-2 permeability than Ligand B (-4.817).

**Aqueous Solubility:** Ligand A (-0.408) has a slightly better aqueous solubility than Ligand B (-2.882).

**hERG:** Both ligands have very low hERG inhibition liability (0.365 and 0.29), which is excellent.

**Microsomal Clearance:** Ligand A (-25.518) exhibits significantly lower microsomal clearance than Ligand B (95.923), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-9.877) has a better in vitro half-life than Ligand B (-22.288).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 and 0.624).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.1 and -9.2 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A demonstrates significantly lower DILI risk and microsomal clearance, indicating better safety and metabolic stability. The slightly lower logP of Ligand A is a concern, but its other advantages outweigh this drawback.

Output:
0
2025-04-17 14:08:37,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.374 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.21) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (62.66) is excellent, well below 90.

**logP:** Both ligands (1.616 and 3.517) are within the optimal 1-3 range. Ligand B is closer to the upper end, which could potentially lead to some off-target interactions, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, fitting the <5 and <10 rules. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.693 and 0.684), indicating good drug-like properties.

**DILI:** Ligand A (51.221) has a moderate DILI risk, while Ligand B (11.128) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have good BBB penetration (75.107 and 78.48), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.678 and -4.528). 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 negative solubility values (-3.406 and -2.681). Again, these are on a log scale and indicate poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.269) has a slightly higher hERG risk than Ligand B (0.645), but both are relatively low.

**Microsomal Clearance:** Ligand A (24.569) has significantly lower microsomal clearance than Ligand B (83.809), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-9.072) has a longer in vitro half-life than Ligand B (15.271).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.175).

**Binding Affinity:** Both ligands have identical binding affinities (-8.5 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have strong binding affinity, Ligand A is the more promising candidate. It has significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Although both have poor predicted solubility and permeability, the metabolic stability advantage of Ligand A is more crucial for an enzyme target like SRC kinase. The slightly higher hERG risk of Ligand A is not a major concern given its low value.

Output:
0
2025-04-17 14:08:37,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.455 and 355.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.87) is well below the 140 threshold for oral absorption, and even below 90 for potential CNS penetration (though not a priority here). Ligand B (125.04) is still within acceptable limits for oral absorption, but higher than A.

**logP:** Ligand A (1.909) is optimal. Ligand B (-1.455) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 3 respectively) and HBA (6 each) counts.

**QED:** Ligand A (0.85) has a much better QED score than Ligand B (0.278), indicating a more drug-like profile.

**DILI:** Ligand A (76.076) has a higher DILI risk than Ligand B (21.908). This is a significant drawback for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (59.325) is higher than Ligand A (45.909), but this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the assay or the compounds.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and suggests issues with the assay or the compounds.

**hERG:** Both ligands have very low hERG risk (0.069 and 0.072).

**Microsomal Clearance:** Ligand A (24.909) has a much lower (better) microsomal clearance than Ligand B (-0.393). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (11.16 hours) has a significantly longer half-life than Ligand B (-25.3 hours). Again, this favors Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.002).

**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 a notable advantage.

**Overall Assessment:**

Ligand B has a better binding affinity and significantly lower DILI risk. However, it suffers from a lower logP, a much lower QED score, and a significantly worse microsomal clearance and in vitro half-life. Ligand A has a better QED, logP, metabolic stability, and half-life. The difference in binding affinity (0.9 kcal/mol) is not large enough to overcome the substantial ADME deficiencies of Ligand B, especially the low QED and poor metabolic stability. The higher DILI risk of Ligand A is concerning, but could potentially be mitigated with structural modifications.

Output:
1
2025-04-17 14:08:37,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.371 and 357.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.45) is better than Ligand B (90.98), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands (2.455 and 2.22) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (2), as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (8) is better than Ligand B (5), both are within the acceptable range.

**QED:** Both ligands have good QED scores (0.538 and 0.708), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (76.037) is significantly better than Ligand B (81.349) in terms of DILI risk, indicating a lower potential for liver injury.

**BBB:** Ligand A (43.699) is better than Ligand B (30.477), but BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.42 and -5.45). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is not huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.085 and -2.877), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.816) is better than Ligand B (0.496), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (19.155 mL/min/kg) is significantly better than Ligand B (33.334 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.753 hours) is significantly better than Ligand B (58.214 hours). Note the negative value for A is unusual, but indicates a longer half-life.

**P-gp Efflux:** Ligand A (0.109) is better than Ligand B (0.144), indicating lower P-gp efflux.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) is significantly better than Ligand B (-6.8 kcal/mol). This is a crucial advantage, as a 2.1 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have issues with Caco-2 permeability and solubility, Ligand A excels in the most critical areas for an enzyme inhibitor: binding affinity, metabolic stability (lower Cl_mic and better t1/2), and lower DILI risk. The better hERG profile and lower P-gp efflux further support its selection. The significantly stronger binding affinity of Ligand A can potentially compensate for the permeability and solubility issues, making it a more promising drug candidate.

Output:
0
2025-04-17 14:08:37,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.511 Da) is slightly higher than Ligand B (337.467 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (49.85) is higher than Ligand B (36.44), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.037) and Ligand B (3.474) are both acceptable.

**H-Bond Donors/Acceptors:** Both ligands have low HBD counts (0) and acceptable HBA counts (4 for A, 3 for B), suggesting good permeability.

**QED:** Both ligands have QED values above 0.5 (0.778 and 0.692), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 52.074, which is acceptable (below 60). Ligand B has a significantly lower DILI risk of 24.04, which is preferable.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (74.098) and Ligand B (92.012) are both acceptable, but B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and requires further investigation. The values are similar.

**hERG:** Ligand A (0.35) has a lower hERG risk than Ligand B (0.913), which is a significant advantage.

**Microsomal Clearance:** Ligand A (85.432) has higher microsomal clearance than Ligand B (93.697), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (10.239 hours) has a significantly longer half-life than Ligand A (1.714 hours), which is a major advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.209) has lower P-gp efflux than Ligand B (0.437), which is preferable.

**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, as a 1.5 kcal/mol difference can outweigh other concerns.

**Conclusion:**

While Ligand A has a slightly better hERG profile and P-gp efflux, Ligand B is superior overall. The significantly stronger binding affinity (-7.7 vs -9.7 kcal/mol) and longer half-life (10.239 vs 1.714 hours) are critical advantages for an enzyme inhibitor. The lower DILI risk is also a positive factor. The similar issues with Caco-2 and solubility would need to be addressed in further development, but the potency and PK advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 14:08:37,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (362.813 Da and 352.391 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is well below the 140 threshold, suggesting good absorption. Ligand B (122.55) is also below, but closer to the limit.

**logP:** Ligand A (2.302) is optimal (1-3). Ligand B (-0.502) is below 1, which may impede permeation.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher than ideal.

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

**QED:** Both ligands (0.595 and 0.569) have good drug-likeness scores (>0.5).

**DILI:** Ligand A (64.754) is moderately risky, while Ligand B (54.517) is better, indicating lower potential for liver injury.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (96.161) is higher than Ligand B (48.081).

**Caco-2 Permeability:** Ligand A (-4.711) is poor, while Ligand B (-5.28) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.91) is poor, while Ligand B (-2.107) is also poor. Both are problematic.

**hERG:** Ligand A (0.258) has a very low risk of hERG inhibition, which is excellent. Ligand B (0.037) is even lower, and thus even better.

**Microsomal Clearance:** Ligand A (55.767) is moderate. Ligand B (-0.244) is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (-14.048) is very poor. Ligand B (-5.823) is also poor, but better than Ligand A.

**P-gp Efflux:** Ligand A (0.17) is low, suggesting minimal efflux. Ligand B (0.013) is even lower, suggesting very minimal efflux.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh many ADME concerns.

**Conclusion:**

While Ligand B has a lower logP and poorer Caco-2/solubility, its significantly superior binding affinity (-9.5 vs -8.6 kcal/mol) and excellent metabolic stability (Cl_mic = -0.244) are crucial advantages for an enzyme target. The lower DILI risk and hERG inhibition are also favorable. The lower logP is a concern, but can potentially be addressed through structural modifications. The poor solubility and permeability are also concerns, but the potency advantage of Ligand B is significant enough to warrant further optimization efforts.

Output:
1
2025-04-17 14:08:37,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.364 Da and 352.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.66 and 77.92) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.046) is slightly higher than Ligand B (0.525), both are within the optimal 1-3 range, but Ligand B is a bit low and might have permeability issues.

**H-Bond Donors:** Ligand A (3) 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 acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.637 and 0.725), indicating good drug-like properties.

**DILI:** Ligand B (21.442) has a significantly lower DILI risk than Ligand A (38.736). This is a major advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (80.419 and 79.488), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.065 and -4.861), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar.

**Aqueous Solubility:** Both have negative solubility values (-1.771 and -1.861), indicating poor solubility, which is a concern.

**hERG Inhibition:** Ligand A (0.334) has a slightly better hERG profile than Ligand B (0.176), but both are relatively low risk.

**Microsomal Clearance:** Ligand A has 0 clearance, which is excellent, indicating high metabolic stability. Ligand B has a clearance of 9.29, which is higher and suggests faster metabolism.

**In vitro Half-Life:** Ligand A (-18.091) has a much longer half-life than Ligand B (-8.326), indicating better in vitro stability.

**P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.065), which is favorable.

**Binding Affinity:** Ligand B (-9.4 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 can outweigh other drawbacks.

**Conclusion:**

Despite Ligand B having slightly lower logP and solubility, its significantly stronger binding affinity (-9.4 vs -0.0 kcal/mol) and lower DILI risk (21.442 vs 38.736) outweigh the drawbacks. The superior binding affinity is critical for an enzyme inhibitor. Ligand A has better metabolic stability and P-gp efflux, but the binding affinity is too weak to be a viable candidate.

Output:
1
2025-04-17 14:08:37,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.443 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.87) is also below 140, but slightly higher than A.

**logP:** Both ligands have good logP values (2.727 and 1.973), 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 and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.777 and 0.724), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 46.84, which is good (low risk). Ligand B has a significantly lower DILI risk of 27.104, which is excellent.

**BBB:**  BBB is less critical for a non-CNS target like SRC kinase. Ligand A has 85.964, and Ligand B has 65.529.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.646 and -4.713), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.325 and -1.303). This is also a concern, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.635) has a slightly higher hERG risk than Ligand B (0.339), but both are relatively low.

**Microsomal Clearance:** Ligand A (79.793) has higher microsomal clearance than Ligand B (21.937). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (0.898 hours) has a very short half-life, while Ligand A (17.349 hours) has a much longer half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.173 and 0.043).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial difference (0.8 kcal/mol), and a key factor.

**Overall Assessment:**

Ligand B has a superior binding affinity and significantly better metabolic stability (lower Cl_mic) and lower DILI risk. However, its in vitro half-life is very short. Ligand A has a much better half-life and acceptable metabolic stability, but its binding affinity is weaker. The difference in binding affinity is substantial enough to outweigh the shorter half-life of Ligand B, especially considering that half-life can potentially be improved through structural modifications. The poor Caco-2 and solubility are concerns for both, but can also be addressed in later stages of optimization.

Output:
1
2025-04-17 14:08:37,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.368 Da and 371.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is better than Ligand B (103.86), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.26) is optimal, while Ligand B (-0.685) is slightly below the ideal range, potentially hindering permeation.

**H-Bond Donors:** Both have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Both have acceptable HBA counts (5), below the threshold of 10.

**QED:** Both ligands have similar QED values (0.646 and 0.623), indicating good drug-likeness.

**DILI:** Ligand A (39.434) has a lower DILI risk than Ligand B (47.77), both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.868) is better than Ligand B (50.911).

**Caco-2 Permeability:** Ligand A (-4.909) is better than Ligand B (-5.403), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.502) is better than Ligand B (-1.388), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.686) has a lower hERG risk than Ligand B (0.03), which is a significant advantage.

**Microsomal Clearance:** Ligand A (29.973) has a higher (worse) microsomal clearance than Ligand B (-8.366), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-23.278) has a lower in vitro half-life than Ligand B (12.175), indicating faster metabolism.

**P-gp Efflux:** Ligand A (0.152) has a lower P-gp efflux than Ligand B (0.016), which is favorable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

While Ligand A has better solubility, lower hERG risk, and better permeability, Ligand B's substantially stronger binding affinity (-9.3 vs -7.7 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed with further optimization. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 14:08:37,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (379.5 and 372.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (62.66), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.961) is optimal, while Ligand B (3.417) is approaching the upper limit of the optimal range.

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

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

**QED:** Ligand A (0.851) is significantly better than Ligand B (0.684), indicating a more drug-like profile.

**DILI:** Ligand A (58.976) has a higher DILI risk than Ligand B (31.834), but both are below the concerning threshold of 60.

**BBB:** Ligand A (28.189) has a lower BBB penetration than Ligand B (85.615). This is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.286) has worse Caco-2 permeability than Ligand B (-4.187), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.127) has better solubility than Ligand B (-3.451), both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.382) has a much lower hERG risk than Ligand B (0.685). This is a significant advantage.

**Microsomal Clearance:** Ligand A (6.065) has a much lower microsomal clearance than Ligand B (65.826), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.694) has a much longer in vitro half-life than Ligand B (-20.561). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.146) has lower P-gp efflux than Ligand B (0.501).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has better BBB penetration, the significantly stronger binding affinity (-8.8 vs -0.0 kcal/mol) of Ligand A outweighs all other considerations. Furthermore, Ligand A demonstrates better QED, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The slightly lower Caco-2 and solubility of Ligand A are less concerning than the poor affinity of Ligand B.

Output:
1
2025-04-17 14:08:37,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**
*   **MW:** 366.439 Da - Within the ideal range (200-500).
*   **TPSA:** 89.59 - Good for oral absorption (<140).
*   **logP:** 1.581 - Optimal (1-3).
*   **HBD:** 0 - Acceptable.
*   **HBA:** 6 - Acceptable.
*   **QED:** 0.801 - Excellent drug-likeness.
*   **DILI:** 67.623 - Moderate risk, but not overly concerning.
*   **BBB:** 73.284 - Moderate, not a primary concern for a non-CNS target.
*   **Caco-2:** -4.68 - Very poor permeability. A significant drawback.
*   **Solubility:** -2.36 - Very poor solubility. A major issue for bioavailability.
*   **hERG:** 0.089 - Very low risk of hERG inhibition. Excellent.
*   **Cl_mic:** 53.759 - Moderate clearance, suggesting moderate metabolic stability.
*   **t1/2:** 19.653 - Moderate half-life.
*   **Pgp:** 0.189 - Low efflux, favorable.
*   **Affinity:** -8.6 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 404.279 Da - Within the ideal range (200-500).
*   **TPSA:** 29.54 - Excellent for absorption.
*   **logP:** 4.427 - Slightly high, potentially leading to solubility issues.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 2 - Acceptable.
*   **QED:** 0.704 - Good drug-likeness.
*   **DILI:** 59.636 - Moderate risk, acceptable.
*   **BBB:** 82.474 - Moderate, not a primary concern for a non-CNS target.
*   **Caco-2:** -4.634 - Very poor permeability. A significant drawback.
*   **Solubility:** -4.995 - Very poor solubility. A major issue for bioavailability.
*   **hERG:** 0.861 - Moderate hERG risk, needs consideration.
*   **Cl_mic:** 96.752 - High clearance, suggesting poor metabolic stability. A significant drawback.
*   **t1/2:** 42.097 - Good half-life.
*   **Pgp:** 0.883 - Moderate efflux.
*   **Affinity:** -8.7 kcal/mol - Excellent binding affinity, slightly better than Ligand A.

**Comparison and Decision:**

Both ligands have excellent binding affinity. However, both suffer from very poor Caco-2 permeability and aqueous solubility, which are critical for oral bioavailability. Ligand A has a better hERG profile and slightly better metabolic stability (lower Cl_mic), but its solubility is worse than Ligand B. Ligand B has a higher logP, which could contribute to off-target effects and solubility issues. The higher clearance of Ligand B is a major concern.

Despite the similar issues with permeability and solubility, Ligand A is slightly favored due to its better hERG profile and lower clearance. While both would require significant medicinal chemistry efforts to improve their ADME properties, Ligand A presents a slightly more promising starting point due to the lower risk of cardiotoxicity and better metabolic stability.

Output:
0
2025-04-17 14:08:37,484 - INFO - Batch 272 complete. Total preferences: 4352
2025-04-17 14:08:37,484 - INFO - Processing batch 273/512...
2025-04-17 14:09:28,627 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.451 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.55) is better than Ligand B (49.41) as it is still within the acceptable range for oral absorption, while ligand B is significantly lower, which is not necessarily a benefit.

**logP:** Ligand B (3.889) is closer to the optimal range (1-3) than Ligand A (0.546), which is quite low and could indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.508 and 0.723, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (29.469) has a significantly lower DILI risk than Ligand B (18.418), which is a major advantage.

**BBB:** Ligand A (67.313) has a lower BBB penetration than Ligand B (76.89), but since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.777) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.916) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-1.893) has poor aqueous solubility. Ligand B (-4.248) is even worse.

**hERG Inhibition:** Ligand A (0.075) has a very low hERG risk, a significant advantage. Ligand B (0.633) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (8.312) has a much lower microsomal clearance, suggesting better metabolic stability than Ligand B (66.348).

**In vitro Half-Life:** Ligand A (5.875) has a shorter half-life than Ligand B (-6.101, meaning a longer half-life).

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is favorable. Ligand B (0.44) has moderate P-gp efflux.

**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 small.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, very low hERG, low P-gp efflux) and better metabolic stability (lower Cl_mic). However, it suffers from poor solubility and permeability. Ligand B has better permeability and solubility, but has higher DILI and hERG risk, and higher P-gp efflux. Given the enzyme-kinase target class, metabolic stability and safety are prioritized. The slightly better affinity of Ligand B is unlikely to outweigh the substantial safety concerns.

Output:
0
2025-04-17 14:09:28,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.27 Da) is slightly higher than Ligand B (363.361 Da), but both are acceptable.

**TPSA:** Ligand A (63.41) is better than Ligand B (107.97). TPSA < 140 is good for oral absorption, and both are below this, but A is significantly lower.

**logP:** Ligand A (3.595) is optimal (1-3), while Ligand B (-1.269) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 3 respectively) and HBA (5 each) counts.

**QED:** Ligand A (0.824) has a much better QED score than Ligand B (0.523), indicating a more drug-like profile.

**DILI:** Ligand B (28.461) has a significantly lower DILI risk than Ligand A (61.691), which is a major advantage.

**BBB:** Ligand A (75.805) has better BBB penetration than Ligand B (53.858), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.878) has a negative Caco-2 value, which is concerning. Ligand B (-5.166) is also negative, but similar.

**Aqueous Solubility:** Ligand A (-4.225) has better solubility than Ligand B (-1.417).

**hERG Inhibition:** Ligand A (0.876) has a slightly higher hERG risk than Ligand B (0.165), which is preferable for B.

**Microsomal Clearance:** Ligand B (-19.059) has significantly lower (better) microsomal clearance than Ligand A (13.967), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (57.687) has a longer half-life than Ligand B (4.367), which is desirable.

**P-gp Efflux:** Ligand A (0.291) has lower P-gp efflux than Ligand B (0.004), which is better.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a critical advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, significantly better metabolic stability (lower Cl_mic), and lower DILI risk. While its logP is low and Caco-2 permeability is poor, the strong binding affinity is a major advantage for an enzyme target like SRC. The lower DILI risk is also a significant benefit. Ligand A has better solubility and half-life, but the much weaker binding and higher DILI risk are substantial drawbacks.

Output:
1
2025-04-17 14:09:28,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.405 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (89.26 and 86.88) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.495 and 2.231) 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 acceptable, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.821 and 0.867), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 75.378, which is concerning (high risk). Ligand B has a much lower DILI risk of 36.487, which is favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (61.923) and Ligand B (41.218) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.946 and -4.981), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.753 and -2.25), indicating very poor aqueous solubility, a major issue for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.563 and 0.416), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (26.726) than Ligand B (56.313), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (35.87 hours) than Ligand B (-9.407 hours). The negative value for Ligand B is problematic and suggests rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.44 and 0.074).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-10 kcal/mol) compared to Ligand A (-7.1 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its significantly superior binding affinity (-10 vs -7.1 kcal/mol) outweighs the slightly higher microsomal clearance. Furthermore, Ligand B has a much lower DILI risk (36.487 vs 75.378) and a more reasonable (though still problematic) in vitro half-life compared to Ligand A. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the potency and safety profile of Ligand B make it the better starting point.

Output:
1
2025-04-17 14:09:28,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (458.181 Da) is higher, but still acceptable. Ligand B (342.439 Da) is slightly better.

**TPSA:** Ligand A (66.05) is higher than Ligand B (53.76), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (4.405) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (2.871) is within the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is within the acceptable limit of 10.

**QED:** Ligand B (0.845) has a significantly better QED score than Ligand A (0.236), indicating a more drug-like profile.

**DILI:** Ligand A (98.216) has a very high DILI risk, which is a major concern. Ligand B (30.942) has a low DILI risk.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (83.288) is better than Ligand A (66.576). This is less critical for a kinase inhibitor than for a CNS-targeting drug.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. It suggests poor permeability.

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

**hERG:** Ligand A (0.596) has a slightly higher hERG risk than Ligand B (0.366), but both are relatively low.

**Microsomal Clearance:** Ligand A (37.715) has lower microsomal clearance than Ligand B (55.597), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (123.189) has a longer in vitro half-life than Ligand B (40.595), which is desirable.

**P-gp Efflux:** Ligand A (0.331) has lower P-gp efflux than Ligand B (0.336), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.2 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.

**Conclusion:**

Despite Ligand A's better metabolic stability and half-life, the significantly higher DILI risk, poorer QED score, and *much* weaker binding affinity make it a less desirable candidate. Ligand B has a superior binding affinity, a much better safety profile (DILI), and a more drug-like QED score. The negative solubility and permeability values are concerning for both, but the potency advantage of Ligand B is substantial and could be addressed with formulation strategies.

Output:
1
2025-04-17 14:09:28,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.423 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (96.25) is still acceptable, but less optimal.

**logP:** Ligand A (2.588) is within the optimal 1-3 range. Ligand B (-0.571) is below 1, which could 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 7. Both are within the acceptable limit of 10, but Ligand B is closer to the upper bound.

**QED:** Both ligands have good QED scores (0.677 and 0.782), indicating drug-like properties.

**DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (30.942). This is a concern for Ligand A.

**BBB:** This isn't a primary concern for a kinase inhibitor, but Ligand A (67.313) has a slightly better score than Ligand B (50.795).

**Caco-2 Permeability:** Ligand A (-4.461) has a negative value, indicating poor permeability. Ligand B (-5.376) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.902) has poor solubility, while Ligand B (-0.016) is slightly better, but still not ideal.

**hERG:** Ligand A (0.65) has a higher hERG risk than Ligand B (0.05). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (47.274) has a higher clearance, indicating lower metabolic stability. Ligand B (-3.857) has a negative clearance, which is excellent and suggests high metabolic stability.

**In vitro Half-Life:** Ligand A (-6.669) has a negative half-life, which is unusual and suggests very rapid metabolism. Ligand B (13.329) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.429 and 0.011), which is good.

**Binding Affinity:** Both ligands have similar binding affinities (-9.2 and -6.7 kcal/mol). Ligand A is significantly more potent.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor solubility, poor permeability, higher DILI risk, higher hERG risk, and very poor metabolic stability (high clearance, short half-life).

Ligand B has a weaker binding affinity, but it has significantly better ADME properties: lower DILI risk, lower hERG risk, excellent metabolic stability, and slightly better solubility. While the logP is suboptimal, the other improvements are substantial.

Considering the balance, the improved ADME profile of Ligand B outweighs the potency difference, especially given that further optimization could potentially improve its binding affinity. The poor ADME properties of Ligand A are likely to be insurmountable hurdles in development.

Output:
1
2025-04-17 14:09:28,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (383.86 and 359.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (95.13), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (1.477) is optimal, while Ligand B (3.24) is at the higher end of the optimal range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable.

**QED:** Ligand A (0.824) has a slightly better QED score than Ligand B (0.742), indicating a more drug-like profile.

**DILI:** Ligand B (63.67) has a slightly higher DILI risk than Ligand A (75.69), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (55.49) is better than Ligand B (26.64).

**Caco-2 Permeability:** Ligand A (-4.951) is significantly better than Ligand B (-5.089), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.625) is better than Ligand B (-4.282), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.186) has a much lower hERG risk than Ligand B (0.693). This is a significant advantage.

**Microsomal Clearance:** Ligand A (-17.75) has much lower microsomal clearance than Ligand B (48.304), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.557) has a much longer in vitro half-life than Ligand B (63.942), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.076) has a lower P-gp efflux liability than Ligand B (0.419), improving bioavailability.

**Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.4), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties, particularly in terms of metabolic stability (Cl_mic, t1/2), solubility, and hERG risk. The better QED score and lower P-gp efflux also contribute to its favorability. The small difference in binding affinity is outweighed by the substantial improvements in drug-like properties.

Output:
0
2025-04-17 14:09:28,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.45 and 350.39 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.87). A TPSA under 90 is generally preferred, and A is closer to the optimal range for oral absorption (<140).

**logP:** Both ligands have good logP values (2.211 and 1.459), 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 it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.789) has a higher QED score than Ligand B (0.601), indicating a more drug-like profile.

**DILI:** Both ligands have the same DILI risk (35.285), which is a good, low-risk value (<40).

**BBB:** Ligand A (89.531) has a better BBB penetration percentile than Ligand B (76.619). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.633) has a higher (less negative) Caco-2 permeability than Ligand B (-4.715), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.055) has better aqueous solubility than Ligand B (-1.591). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.307 and 0.358), which is excellent.

**Microsomal Clearance:** Ligand B (3.163) has significantly lower microsomal clearance than Ligand A (40.197), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-17.768) has a much longer in vitro half-life than Ligand A (-7.313), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.135 and 0.058).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 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 TPSA, Caco-2 permeability and solubility, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. Given the enzyme-specific priorities, metabolic stability is paramount.

Output:
1
2025-04-17 14:09:28,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.323 and 363.929 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.81) is better than Ligand B (21.7). Lower TPSA generally improves permeability.

**logP:** Ligand A (3.809) is within the optimal range (1-3), while Ligand B (4.445) is slightly higher, 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:** Ligand A (2) is good, and Ligand B (3) is also acceptable.

**QED:** Both ligands have similar QED values (0.732 and 0.745), indicating good drug-likeness.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (10.857). This is a significant drawback for Ligand A.

**BBB:** Ligand A (78.945) has a better BBB penetration potential than Ligand B (96.161). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.074 and -5.043), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.62 and -4.225), indicating poor aqueous solubility. This is a significant issue for both.

**hERG Inhibition:** Ligand A (0.88) has a slightly higher hERG risk than Ligand B (0.934), but both are relatively low.

**Microsomal Clearance:** Ligand B (39.47) has a higher microsomal clearance than Ligand A (7.764), indicating lower metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (37.099) has a longer half-life than Ligand B (34.999), which is desirable.

**P-gp Efflux:** Ligand A (0.385) has lower P-gp efflux than Ligand B (0.625), which is preferable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). The difference is 0.5 kcal/mol, which is a meaningful advantage.

**Overall Assessment:**

Ligand B has a significantly lower DILI risk and slightly 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 permeability. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), the better binding affinity of Ligand B and its significantly lower DILI risk outweigh the slightly better metabolic stability of Ligand A. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:09:28,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
*   Ligand A: 362.392 Da - Within the ideal range (200-500 Da).
*   Ligand B: 401.539 Da - Also within the ideal range.
*   *No clear advantage here.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 60.85 - Excellent, well below the 140 threshold for oral absorption.
*   Ligand B: 105.15 - Still reasonable, but higher than Ligand A.
*   *Ligand A is better.*

**3. Lipophilicity (logP):**
*   Ligand A: 2.362 - Optimal.
*   Ligand B: 1.361 - Acceptable, but slightly lower.
*   *Ligand A is better.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 1 - Excellent.
*   Ligand B: 2 - Acceptable.
*   *Ligand A is better.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 3 - Excellent.
*   Ligand B: 8 - Higher, approaching the upper limit.
*   *Ligand A is better.*

**6. QED:**
*   Ligand A: 0.837 - Very good, strongly drug-like.
*   Ligand B: 0.393 - Poor, significantly below the 0.5 threshold.
*   *Ligand A is significantly better.*

**7. DILI:**
*   Ligand A: 20.9 - Excellent, very low risk.
*   Ligand B: 81.466 - High risk of liver injury.
*   *Ligand A is significantly better.*

**8. BBB:**
*   Ligand A: 75.727 - Good, but not critical for a non-CNS target like SRC.
*   Ligand B: 38.426 - Low.
*   *Ligand A is better.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.904 - Negative values are unusual and suggest a potential issue with the data or a very poor permeability.
*   Ligand B: -5.638 - Similar to A, also suggesting poor permeability.
*   *Neither is good, but the difference is small.*

**10. Aqueous Solubility:**
*   Ligand A: -2.192 - Poor solubility.
*   Ligand B: -1.881 - Also poor, slightly better than A.
*   *Ligand B is slightly better.*

**11. hERG Inhibition:**
*   Ligand A: 0.348 - Low risk.
*   Ligand B: 0.271 - Very low risk.
*   *Ligand B is slightly better.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: -13.188 - Negative values are unusual and suggest a potential issue with the data or very high metabolic stability.
*   Ligand B: 19.862 - Moderate clearance.
*   *Ligand A is better, assuming the negative value indicates high stability.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: -19.679 - Negative values are unusual and suggest a potential issue with the data or very long half-life.
*   Ligand B: 25.485 - Good half-life.
*   *Ligand B is better.*

**14. P-gp Efflux:**
*   Ligand A: 0.019 - Very low efflux.
*   Ligand B: 0.2 - Low efflux.
*   *Ligand A is better.*

**15. Binding Affinity:**
*   Ligand A: -10.6 kcal/mol - Excellent.
*   Ligand B: 0.0 kcal/mol - Very weak binding.
*   *Ligand A is significantly better.*

**Overall Assessment:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand A is clearly superior. Its much stronger binding affinity (-10.6 vs 0.0 kcal/mol) is a major advantage that outweighs its slightly lower solubility and permeability. The significantly lower DILI risk and better QED score further strengthen its profile. While both have issues with Caco-2 permeability, the overall profile of A is far more promising. The unusual negative values for Cl_mic and t1/2 for Ligand A suggest potentially very high stability and long half-life, which is highly desirable.



Output:
1
2025-04-17 14:09:28,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands have TPSA values around 79, which is acceptable, though ideally below 90 for good absorption.

**logP:** Ligand A (2.182) is within the optimal range (1-3). Ligand B (3.701) is approaching the upper limit, potentially raising concerns about solubility and off-target effects.

**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.

**QED:** Both ligands have reasonable QED scores (A: 0.492, B: 0.733), with Ligand B being significantly better.

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (55.758), a significant advantage.

**BBB:** Both have moderate BBB penetration, but Ligand B (57.154) is slightly better than Ligand A (56.611). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.258) has a much lower hERG inhibition liability than Ligand B (0.65), a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (33.381) has significantly lower microsomal clearance than Ligand B (93.666), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.454) has a more negative half-life, which is not good. Ligand B (-1.51) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux liability than Ligand B (0.417), potentially leading to better oral bioavailability.

**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 major factor favoring Ligand A.

**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 an enzyme inhibitor: significantly better binding affinity, lower DILI risk, lower hERG inhibition, and better metabolic stability (lower Cl_mic). The slightly better QED of Ligand B is outweighed by these factors. The poor half-life of Ligand A is a concern, but could potentially be addressed through structural modifications.

Output:
0
2025-04-17 14:09:28,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.503 and 367.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (82.53).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (4.289) is slightly higher than the optimal range (1-3), while Ligand B (2.609) is within the optimal range. High logP can lead to solubility issues, but is less concerning than a very high TPSA.

**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 (0.813 and 0.836), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (46.801 and 63.513), with Ligand A being slightly better. Both are acceptable, below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (63.784 and 66.033). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.05 and -5.018). This is unusual and suggests poor permeability. However, these values are very close, so it's not a major differentiator.

**Aqueous Solubility:** Ligand A (-5.267) has worse solubility than Ligand B (-3.841). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.8 and 0.724), which is excellent.

**Microsomal Clearance:** Ligand A (117.764) has significantly higher microsomal clearance than Ligand B (24.072). This means Ligand A is likely to be metabolized more quickly, leading to a shorter half-life. This is a significant drawback.

**In vitro Half-Life:** Ligand A (26.868) has a shorter half-life than Ligand B (3.194). This is consistent with the higher clearance.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.706 and 0.281), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -7.8 kcal/mol). The difference is minimal.

**Conclusion:**

While Ligand A has a slightly better logP and DILI score, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic) and longer half-life. The solubility of Ligand A is also worse. For an enzyme target like SRC kinase, metabolic stability is crucial for maintaining therapeutic concentrations. The minimal difference in binding affinity doesn't outweigh the substantial difference in pharmacokinetic properties.

Output:
1
2025-04-17 14:09:28,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.49 and 355.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, while Ligand B (107.97) is still acceptable but higher. Lower TPSA generally favors better absorption.

**logP:** Ligand A (2.703) is optimal (1-3). Ligand B (-0.042) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED scores (0.725 and 0.538), indicating good drug-like properties.

**DILI:** Ligand A (19.43) has a significantly lower DILI risk than Ligand B (29.78), which is favorable. Both are below the 40 threshold.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (63.32) is better than Ligand B (33.23).

**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 (0.251) has a much lower hERG risk than Ligand B (0.109), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-11.704) has a significantly *lower* (better) microsomal clearance than Ligand A (33.985), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.67) has a negative half-life, which is impossible. Ligand A (28.538) is reasonable. This is a major red flag for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.061 and 0.013), which is good.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), although both are strong binders. The difference is 0.8 kcal/mol, which is not huge but still relevant.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has better metabolic stability, Ligand A excels in several critical areas: lower DILI risk, lower hERG risk, a more reasonable half-life, and slightly better binding affinity. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh these issues. The impossible half-life for Ligand B is a dealbreaker.

Output:
0
2025-04-17 14:09:28,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 371.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.15) is better than Ligand B (59). While both are reasonably low, Ligand B is excellent.

**logP:** Ligand A (2.065) is optimal, while Ligand B (4.004) is pushing the upper limit. This could lead to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (6) is acceptable, while Ligand B (4) is also good.

**QED:** Both ligands have similar and acceptable QED values (0.631 and 0.675).

**DILI:** Ligand A (83.288) has a higher DILI risk than Ligand B (16.053). This is a significant concern for Ligand A.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.208) has poor Caco-2 permeability, which is a concern. Ligand B (-4.896) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.509 and -3.69). This is a significant drawback for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.381) has a slightly better hERG profile than Ligand B (0.64).

**Microsomal Clearance:** Ligand A (1.214) has significantly lower microsomal clearance than Ligand B (99.862), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-20.082) has a longer in vitro half-life than Ligand B (52.104), which is a positive.

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux than Ligand B (0.238), which is favorable.

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While its logP is higher and DILI risk is lower, the affinity difference is significant. Ligand A has better metabolic stability and lower P-gp efflux, but its poor Caco-2 permeability and weaker binding affinity are major drawbacks. The higher DILI risk for Ligand A is also concerning. Given the importance of potency for kinase inhibitors, Ligand B is the more promising candidate, despite its slightly less favorable ADME profile.

Output:
1
2025-04-17 14:09:28,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (373.861 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Ligand A (48.3) is significantly better than Ligand B (84.42). Lower TPSA generally favors better absorption.

**logP:** Ligand A (4.35) is higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (1.207) is within the optimal range.

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

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

**QED:** Ligand B (0.866) has a significantly better QED score than Ligand A (0.366), indicating a more drug-like profile.

**DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (34.432). Ligand B is well below the 40% threshold, while Ligand A is approaching a concerning level.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.772) and Ligand B (66.964) are both reasonably good, but not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.843) and Ligand B (-5.109) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret the absolute impact.

**Aqueous Solubility:** Ligand A (-4.589) and Ligand B (-1.009) both have negative values, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.246) has a lower hERG risk than Ligand B (0.076), which is preferable.

**Microsomal Clearance:** Ligand B (-1.218) has a *much* lower (better) microsomal clearance than Ligand A (119.837). This suggests significantly better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (7.906) has a longer half-life than Ligand A (40.739). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.789) has a higher P-gp efflux liability than Ligand B (0.008). Lower efflux is better.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand A having a slightly better hERG profile, Ligand B is the superior candidate. Its significantly better QED, DILI risk, metabolic stability (Cl_mic and t1/2), P-gp efflux, and, most importantly, *much* stronger binding affinity make it a far more promising drug candidate for SRC kinase inhibition. The slightly higher logP of Ligand A is a concern, but the substantial benefits of Ligand B outweigh this drawback.

Output:
1
2025-04-17 14:09:28,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.495 Da) is slightly higher than Ligand B (345.447 Da), but both are acceptable.

**TPSA:** Ligand A (92.26) is slightly above the optimal <140 for oral absorption, while Ligand B (70.47) is well within the range.

**logP:** Ligand A (2.31) is optimal, while Ligand B (0.354) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBAs, within the acceptable limit. Ligand B has 5 HBAs, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.777, B: 0.782), indicating good drug-likeness.

**DILI:** Ligand A (77.821) has a higher DILI risk than Ligand B (14.773). This is a significant concern for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.882) has poor Caco-2 permeability, while Ligand B (-5.309) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.773) has poor aqueous solubility, while Ligand B (-1.142) is also poor, but better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.239, B: 0.146), which is excellent.

**Microsomal Clearance:** Ligand A (45.104) has moderate microsomal clearance, while Ligand B (-23.031) has negative clearance, which is excellent and indicates high metabolic stability.

**In vitro Half-Life:** Ligand A (21.697 hours) has a reasonable half-life, while Ligand B (2.687 hours) has a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.326, B: 0.009), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This 2.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better logP and in vitro half-life, Ligand B is superior overall. The most critical factors are the significantly stronger binding affinity of Ligand B and its much lower DILI risk and superior metabolic stability (negative Cl_mic). Although both have poor solubility and Caco-2 permeability, the potency advantage of Ligand B is substantial enough to make it the more promising candidate, and solubility/permeability can be addressed with formulation strategies.

Output:
1
2025-04-17 14:09:28,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.36 and 349.48 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.94) is better than Ligand B (66.65). Both are below the 140 A^2 threshold for good absorption, but lower TPSA is generally preferred.

**logP:** Ligand A (4.466) is slightly higher than the optimal range (1-3), while Ligand B (2.982) is within the optimal range. High logP can lead to solubility issues and off-target effects, giving a slight edge to Ligand B.

**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 (0.865) has a better QED score than Ligand B (0.792), indicating a more drug-like profile.

**DILI:** Ligand B (33.501) has a significantly lower DILI risk than Ligand A (52.966), which is a major advantage.

**BBB:** Ligand B (81.388) has a higher BBB penetration percentile than Ligand A (61.535). While not a primary concern for a non-CNS target like SRC, it's a neutral benefit.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.472 and -4.28). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**Aqueous Solubility:** Ligand B (-2.796) has better aqueous solubility than Ligand A (-6.039). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.87) has a slightly higher hERG inhibition risk than Ligand B (0.408), which is preferable for Ligand B.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (74.832 and 76.987 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (11.218 hours) has a longer in vitro half-life than Ligand A (23.592 hours). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.602) has slightly lower P-gp efflux liability than Ligand B (0.253), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.3 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 of Ligand A.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better QED and P-gp efflux, Ligand B excels in critical areas: significantly lower DILI risk, better aqueous solubility, a longer half-life, and, most importantly, a substantially stronger binding affinity. The binding affinity difference of 0.8 kcal/mol is significant and likely to translate to greater efficacy. The slightly higher logP of Ligand A is a concern, and the lower solubility is a drawback.

Output:
1
2025-04-17 14:09:28,631 - INFO - Batch 273 complete. Total preferences: 4368
2025-04-17 14:09:28,631 - INFO - Processing batch 274/512...
2025-04-17 14:10:15,163 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.312 Da) is slightly higher than Ligand B (362.539 Da), but both are acceptable.

**TPSA:** Ligand A (76.66) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.598) and Ligand B (3.954) are both acceptable, but Ligand B is approaching the upper limit, which could potentially lead to solubility issues.

**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 (Ligand A: 0.371, Ligand B: 0.737). Ligand B has a significantly higher QED, indicating a more drug-like profile.

**DILI:** Ligand A (64.405) has a higher DILI risk than Ligand B (26.057). Ligand B is well below the 40% threshold, indicating a lower risk of liver injury.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (89.608) has a higher BBB percentile than Ligand A (53.083).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.93 for A, -4.744 for B).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility. The values are similar (-3.486 for A, -3.357 for B).

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.491, Ligand B: 0.626), which is favorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 68.893, Ligand B: 69.741), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand B (7.377 hours) has a significantly shorter half-life than Ligand A (19.514 hours). This is a significant drawback for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.343, Ligand B: 0.61).

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.3 kcal/mol, Ligand B: -8.5 kcal/mol). Ligand B has a slightly better affinity, but the difference is small.

**Overall Assessment:**

Ligand B has a better overall profile. It has a lower DILI risk, a higher QED score, and better TPSA. However, Ligand A has a significantly longer in vitro half-life, which is a crucial factor for kinase inhibitors. The slightly better affinity of Ligand B is unlikely to outweigh the longer half-life of Ligand A. The solubility and Caco-2 values are concerning for both, but are similar.

Output:
1
2025-04-17 14:10:15,163 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (385.251 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.26) is slightly higher than Ligand B (84.42), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.63) is within the optimal range (1-3), while Ligand B (1.411) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.701) has a better QED score than Ligand B (0.48), indicating a more drug-like profile.

**DILI:** Ligand B (47.77) has a significantly lower DILI risk than Ligand A (85.227), which is a major advantage.

**BBB:** Ligand B (73.943) has a better BBB penetration score than Ligand A (61.846), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.822) has a negative Caco-2 value, which is concerning. Ligand B (-5.105) is also negative, suggesting poor permeability for both.

**Aqueous Solubility:** Ligand A (-5.097) has very poor aqueous solubility, while Ligand B (-2.587) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.159) has a slightly higher hERG risk than Ligand B (0.25), but both are relatively low.

**Microsomal Clearance:** Ligand B (81.705) has a significantly higher microsomal clearance than Ligand A (33.7), indicating lower metabolic stability. This is a critical disadvantage.

**In vitro Half-Life:** Ligand A (58.096) has a longer in vitro half-life than Ligand B (-4.26), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.038 respectively).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite Ligand B's lower DILI and better BBB, the significantly stronger binding affinity (-7.7 kcal/mol vs 0.0 kcal/mol) and longer half-life of Ligand B are decisive. While its solubility and permeability are poor, the potency advantage is substantial. The higher metabolic clearance is a concern, but could potentially be addressed with structural modifications during lead optimization. Ligand A's extremely weak binding affinity makes it unlikely to be a viable candidate.

Output:
1
2025-04-17 14:10:15,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (374.547 Da) is still well within the acceptable range.

**TPSA:** Ligand A (101.8) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (75.71) is excellent, well below 140.

**logP:** Both ligands have excellent logP values around 2.0, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also good.

**QED:** Both ligands have QED values > 0.7, indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 90.733, which is high and concerning. Ligand B has a much lower DILI risk of 22.14, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.813) has a higher BBB score than Ligand A (40.403), but this isn't a primary concern here.

**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:** Ligand A (0.349) has a slightly higher hERG risk than Ligand B (0.533), but both are reasonably low.

**Microsomal Clearance:** Ligand A (16.743) has a lower microsomal clearance than Ligand B (66.81), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (32.863) has a longer half-life than Ligand B (-35.058), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.039 respectively).

**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 drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability and half-life, its high DILI risk is a major red flag. Ligand B, despite slightly worse metabolic stability, has a much lower DILI risk and a significantly stronger binding affinity. The improved binding affinity is a critical advantage for an enzyme target like SRC kinase. The solubility and permeability issues are concerning for both, but the superior potency and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 14:10:15,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.391 and 355.389 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (132.47) is slightly above the preferred <140 for good oral absorption, while Ligand B (110) is well within the range.

**3. logP:** Ligand A (0.543) is a bit low, potentially hindering permeation. Ligand B (1.426) is 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 (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Ligand A (0.452) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.715) is above the threshold, suggesting a better drug-like profile.

**7. DILI:** Ligand A (27.453) has a very low DILI risk, which is excellent. Ligand B (54.44) is higher, but still within a reasonable range (below 60).

**8. BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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 concerning and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.058) has a very low hERG risk, which is excellent. Ligand B (0.279) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (3.742 and 3.902 mL/min/kg), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.672 hours) has a short half-life. Ligand B (-10.965 hours) has a negative half-life, which is not physically possible and likely indicates an issue with the data.

**14. P-gp Efflux:** Both have very low P-gp efflux liability.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate despite the questionable negative half-life. The significantly improved binding affinity (-9.3 vs 0 kcal/mol) is a major driver. While Ligand B has a higher DILI risk and slightly higher hERG risk than Ligand A, these are less critical concerns than potency for an enzyme target. The QED score is also better for Ligand B. The negative values for Caco-2 and solubility are concerning for both, but the binding affinity difference is substantial enough to favor Ligand B. The negative half-life for Ligand B is a red flag and would need to be investigated, but the other properties suggest it is still the better starting point.

Output:
1
2025-04-17 14:10:15,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.366 and 333.439 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (55.4) is better than Ligand B (62.73). Both are below the 140 A^2 threshold for good absorption, but lower TPSA is generally preferred.

**logP:** Both ligands have logP values (3.701 and 4.323) within the optimal range of 1-3, although Ligand B is slightly higher.

**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, which can improve permeability.

**QED:** Both ligands have similar QED values (0.667 and 0.63), indicating good drug-likeness.

**DILI:** Ligand A (85.77) has a higher DILI risk than Ligand B (76.464), which is not ideal, but both are below the concerning 60 threshold.

**BBB:** Both ligands have reasonable BBB penetration (73.943 and 68.166), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.422) has better Caco-2 permeability than Ligand B (-5.117).

**Aqueous Solubility:** Ligand A (-5.511) has better aqueous solubility than Ligand B (-4.334). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.551) has a lower hERG inhibition liability than Ligand B (0.861), which is a significant advantage.

**Microsomal Clearance:** Ligand A (102.147) has a lower microsomal clearance than Ligand B (88.532), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (50.318) has a shorter half-life than Ligand B (62.641), which is less desirable.

**P-gp Efflux:** Ligand A (0.808) has lower P-gp efflux than Ligand B (0.753).

**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, potentially outweighing some of the ADME drawbacks of Ligand B. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand A has better solubility, permeability, and a lower hERG risk, Ligand B's significantly stronger binding affinity (-8.5 vs -7.3 kcal/mol) is the most important factor for an enzyme target like SRC kinase. The improved metabolic stability (lower Cl_mic) and longer half-life of Ligand B are also beneficial. The slightly higher logP and DILI risk are acceptable given the potency advantage.

Output:
1
2025-04-17 14:10:15,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.38 and 356.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is higher than Ligand B (53.43). While both are reasonably low, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.405) is quite low, potentially hindering membrane permeability. Ligand B (3.733) 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 (1) is even better, potentially improving permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**QED:** Both ligands have good QED scores (0.638 and 0.769), indicating drug-like properties.

**DILI:** Ligand A (13.416) has a very low DILI risk, significantly better than Ligand B (36.952).

**BBB:** Ligand A (52.268) has a lower BBB penetration than Ligand B (70.027). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.238) has poor Caco-2 permeability, likely due to the low logP. Ligand B (-4.881) is also not ideal, but slightly better.

**Aqueous Solubility:** Ligand A (-1.604) and Ligand B (-3.394) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.425) has a lower hERG risk than Ligand B (0.68). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-25.718) has a much lower (better) microsomal clearance than Ligand B (75.864), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.176) has a shorter half-life than Ligand B (42.988).

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is favorable. Ligand B (0.719) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.5) has a significantly stronger binding affinity than Ligand A (-9). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has a better safety profile (lower DILI, lower hERG, lower P-gp efflux, better metabolic stability), Ligand B possesses a significantly higher binding affinity (-7.5 vs -9 kcal/mol) and a more favorable logP. The stronger binding affinity is paramount for an enzyme inhibitor, and the logP is within the optimal range. The slightly higher DILI and P-gp efflux of Ligand B can be addressed through further optimization. The poor solubility of both compounds is a concern, but can also be addressed with formulation strategies.

Output:
1
2025-04-17 14:10:15,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.419 and 350.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.7) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (55.89) is excellent, well below 140.

**3. logP:** Both ligands (1.162 and 1.617) are 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) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.701 and 0.792), indicating drug-like properties.

**7. DILI:** Ligand A (51.144) has a moderate DILI risk, but is still acceptable. Ligand B (7.871) has a very low DILI risk, which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (81.155) has better BBB penetration, but it's not a primary concern here.

**9. Caco-2 Permeability:** Ligand A (-5.607) has poor Caco-2 permeability, which is a concern. Ligand B (-4.719) is better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.917 and -1.316), which could present formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.454 and 0.615), which is positive.

**12. Microsomal Clearance:** Ligand A (-7.928) has significantly lower (better) microsomal clearance than Ligand B (-7.889), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.662) has a much longer in vitro half-life than Ligand B (2.586), a substantial benefit for dosing frequency.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.026).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2). The poor Caco-2 permeability of Ligand A is a concern, but the substantial advantage in half-life and the acceptable DILI risk outweigh this drawback. Ligand B has a slightly better TPSA and DILI, but the significantly worse metabolic stability is a major disadvantage for an enzyme target.

Output:
0
2025-04-17 14:10:15,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (382.467 Da) is still well within the acceptable range.

**TPSA:** Ligand B (84.74) is significantly better than Ligand A (105.66). Lower TPSA generally correlates with better cell permeability, a crucial factor for kinase inhibitors.

**logP:** Ligand B (0.397) is closer to the optimal range (1-3) than Ligand A (-0.202). A negative logP for Ligand A could indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 0 HBD and 7 HBA. Both are within acceptable limits, but Ligand B's lower HBD count is generally preferred for better permeability.

**QED:** Both ligands have good QED scores (A: 0.592, B: 0.767), indicating generally drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (11.981) has a much lower DILI risk than Ligand B (68.786). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (58.085) has a higher BBB penetration than Ligand A (18.534).

**Caco-2 Permeability:** Both have negative values (-5.481 and -4.991), which is unusual. Assuming these are percentile scores, both have very poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.799 and -2.794). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.136) has a much lower hERG inhibition liability than Ligand B (0.452). This is a critical advantage for Ligand A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-10.259) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (20.604). This is a major advantage for Ligand A, potentially leading to a longer duration of action.

**In vitro Half-Life:** Ligand A (-12.7) has a longer in vitro half-life than Ligand B (3.239), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, while Ligand B (0.082) has slightly higher efflux. Lower is better for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -9.7 kcal/mol). Ligand B is slightly more potent. However, the 1.7 kcal/mol difference in binding affinity might be outweighed by the significant ADME advantages of Ligand A.

**Conclusion:**

While Ligand B has slightly better binding affinity and a better QED score, Ligand A demonstrates superior ADMET properties, particularly regarding DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and P-gp efflux. Given the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising drug candidate. The solubility issue is a concern for both, but can be addressed with formulation strategies. The lower DILI and hERG risks for Ligand A are crucial safety advantages.

Output:
0
2025-04-17 14:10:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.447 Da and 363.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.51) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (71.09) is well within the optimal range.

**logP:** Ligand A (-0.215) is a bit low, potentially hindering permeability. Ligand B (3.309) is excellent, falling right within the 1-3 optimal range.

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

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.714 and 0.707), indicating good drug-likeness.

**DILI:** Ligand A (51.842) and Ligand B (64.831) both have acceptable DILI risk, below the concerning threshold of 60. Ligand A is slightly better.

**BBB:** Both have similar BBB penetration (65.568 and 64.831), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.358 and -4.995), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.337 and -3.457), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.17 and 0.691), which is positive. Ligand A is slightly better.

**Microsomal Clearance:** Ligand A (16.57) has significantly lower microsomal clearance than Ligand B (44.323), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (40.445) has a much longer half-life than Ligand A (-7.198). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.583).

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

**Overall Assessment:**

While both ligands have excellent binding affinity and acceptable safety profiles (DILI, hERG), they both suffer from poor predicted permeability and solubility. However, Ligand A has a significantly lower microsomal clearance, suggesting better metabolic stability, which is a key factor for enzyme inhibitors. Ligand B has a longer half-life, but the higher clearance is a concern. The slightly better DILI and hERG profiles of Ligand A, combined with its superior metabolic stability, make it the more promising candidate, despite the shared solubility and permeability issues. Addressing the solubility and permeability will be critical for either compound.

Output:
0
2025-04-17 14:10:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.371 and 380.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.96) is slightly higher than Ligand B (75.19), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.549 and 2.292), 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.687 and 0.828), indicating a drug-like profile.

**DILI:** Ligand A (84.606) has a higher DILI risk than Ligand B (65.917). This is a significant concern.

**BBB:** Both have moderate BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both compounds, but needs further investigation as negative values can sometimes be artifacts of the prediction method.

**Aqueous Solubility:** Both have negative solubility values, also unusual and concerning. Similar to Caco-2, this requires further investigation.

**hERG:** Ligand A (0.198) has a much lower hERG risk than Ligand B (0.763), which is a major advantage.

**Microsomal Clearance:** Ligand A (35.897) has a lower microsomal clearance than Ligand B (8.127), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (45.928) has a significantly longer in vitro half-life than Ligand A (9.603). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.368) has lower P-gp efflux than Ligand B (0.202). Lower efflux is generally preferred.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has *significantly* better 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:**

Despite the concerning Caco-2 and solubility predictions for both, Ligand B is the stronger candidate. The substantially superior binding affinity (-8.1 vs -0.0 kcal/mol) is the most important factor. While Ligand A has a lower DILI risk and better metabolic stability, the potency difference is too large to ignore. The longer half-life of Ligand B is also beneficial. The hERG risk for Ligand B is a concern, but potentially mitigatable through structural modifications. The poor permeability and solubility would need to be addressed through formulation or further chemical optimization, but the strong binding affinity provides a solid starting point.

Output:
1
2025-04-17 14:10:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (352.41 and 347.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (87.46 and 80.76) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (0.273) is slightly low, potentially hindering permeation. Ligand B (1.115) 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 (5), well below the limit of 10.

**6. QED:** Both ligands have high QED scores (0.796 and 0.807), indicating good drug-like properties.

**7. DILI:** Ligand A (21.675) has a significantly lower DILI risk than Ligand B (30.593). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (62.97 and 60.876), which isn't a primary concern for a non-CNS target like SRC kinase.

**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 (0.227 and 0.307).

**12. Microsomal Clearance:** Ligand A (-13.431) has a much lower (better) microsomal clearance than Ligand B (27.159), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.218) has a negative half-life, which is not possible. Ligand B (6.066) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.011 and 0.014).

**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 substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much better binding affinity. Ligand A has better DILI and Cl_mic, but the affinity difference is substantial. The negative half-life for Ligand A is also a major concern.

Output:
1
2025-04-17 14:10:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.356 and 369.615 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is better than Ligand B (29.54). Lower TPSA generally favors better cell permeability.

**logP:** Ligand B (4.846) is higher than Ligand A (3.485). While both are above the optimal 1-3 range, Ligand B is pushing the upper limit, potentially causing solubility issues.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). A small number of HBDs is generally preferred for permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable range.

**QED:** Both ligands have similar QED values (0.628 and 0.582), indicating reasonable drug-likeness.

**DILI:** Ligand A (49.864) has a significantly lower DILI risk than Ligand B (8.104), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (94.416 and 92.71), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.331) has better Caco-2 permeability than Ligand B (-4.484).

**Aqueous Solubility:** Ligand A (-4.668) has better aqueous solubility than Ligand B (-5.327).

**hERG Inhibition:** Ligand A (0.534) has a lower hERG inhibition risk than Ligand B (0.871), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (72.896) has significantly lower microsomal clearance than Ligand B (145.014), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.703) has a much longer in vitro half-life than Ligand B (15.036), which is highly desirable.

**P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux than Ligand B (0.649), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.1) has slightly better binding affinity than Ligand A (-6.4). However, the difference is only 0.7 kcal/mol, and other factors are more critical.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, **Ligand A is the more viable drug candidate**. It demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG inhibition, better solubility, and lower P-gp efflux, all while maintaining acceptable binding affinity. The slightly weaker binding affinity of Ligand A is outweighed by its superior ADME-Tox profile.

Output:
0
2025-04-17 14:10:15,166 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [381.929, 62.3, 3.488, 1, 4, 0.868, 53.044, 73.75, -5.071, -4.193, 0.405, 37.175, -5.333, 0.529, -9.8]
**Ligand B:** [382.873, 97.12, 2.846, 2, 6, 0.8, 77.2, 50.64, -5.081, -3.453, 0.191, 30.302, 2.784, 0.248, -7.5]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da).
2. **TPSA:** Ligand A (62.3) is significantly better than Ligand B (97.12).  Lower TPSA generally favors oral absorption.
3. **logP:** Ligand A (3.488) is slightly better than Ligand B (2.846), both are within the optimal range of 1-3.
4. **HBD:** Ligand A (1) is preferable to Ligand B (2). Lower HBD can improve permeability.
5. **HBA:** Ligand A (4) is better than Ligand B (6). Lower HBA is generally preferred for permeability.
6. **QED:** Both ligands have similar good QED scores (0.868 and 0.8), indicating good drug-like properties.
7. **DILI:** Ligand A (53.044) is significantly better than Ligand B (77.2). Lower DILI risk is crucial.
8. **BBB:** Ligand A (73.75) is better than Ligand B (50.64), although BBB isn't a primary concern for a non-CNS target like SRC.
9. **Caco-2:** Both have negative values, which is unusual. Assuming these are log scale values, they are similar and indicate poor permeability.
10. **Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.193) is slightly better than Ligand B (-3.453).
11. **hERG:** Ligand A (0.405) is significantly better than Ligand B (0.191). Lower hERG risk is critical.
12. **Cl_mic:** Ligand B (30.302) has lower microsomal clearance than Ligand A (37.175), suggesting better metabolic stability.
13. **t1/2:** Ligand A (-5.333) has a longer in vitro half-life than Ligand B (2.784), which is desirable.
14. **Pgp:** Ligand A (0.529) has lower P-gp efflux than Ligand B (0.248), indicating better absorption.
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 difference.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand A is significantly more potent.
*   **Metabolic Stability:** Ligand B is slightly better in terms of Cl_mic, but Ligand A has a better t1/2.
*   **Solubility:** Both are poor, but A is slightly better.
*   **hERG:** Ligand A has a much lower hERG risk.
*   **DILI:** Ligand A has a much lower DILI risk.

**Conclusion:**

Despite Ligand B having slightly better metabolic stability (Cl_mic), Ligand A is the superior candidate. The significantly stronger binding affinity, lower DILI risk, lower hERG risk, and better Pgp efflux outweigh the slightly less favorable metabolic stability. The better TPSA, HBD/HBA values also contribute to its overall better profile.

Output:
1
2025-04-17 14:10:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.443 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.86) is higher than Ligand B (76.02). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have good logP values (2.981 and 1.281), falling within the 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but both are acceptable.

**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 (0.631 and 0.717), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 65.219, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 36.565, making it significantly safer in this regard.

**BBB:** Both ligands have moderate BBB penetration, but Ligand A is higher at 70.531, while Ligand B is at 48.391. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a major worry.

**Caco-2 Permeability:** Ligand A (-4.379) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.626) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.702) has poor aqueous solubility. Ligand B (-1.515) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.418) has a slightly higher hERG risk than Ligand B (0.182), which is preferable.

**Microsomal Clearance:** Ligand A (49.693) has a moderate microsomal clearance, while Ligand B (14.505) has a much lower clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-10.525) has a very short in vitro half-life, which is undesirable. Ligand B (0.293) has a very short half-life as well, but is still better than Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.35 and 0.053), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is significantly better overall. Its lower DILI risk, better solubility, and much improved metabolic stability (lower Cl_mic, slightly better t1/2) outweigh the slightly lower BBB penetration and Caco-2 permeability. The poor solubility and metabolic stability of Ligand A are major drawbacks.

Output:
1
2025-04-17 14:10:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.503 and 352.435 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is well below the 140 threshold for good oral absorption, and even better for kinase inhibitors. Ligand B (96.69) is still acceptable, but less optimal.

**3. logP:** Ligand A (2.33) is within the optimal 1-3 range. Ligand B (0.992) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is good.

**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 similar QED values (0.547 and 0.537), indicating good drug-like properties.

**7. DILI:** Ligand A (14.114) has a significantly lower DILI risk than Ligand B (47.964). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (45.832) is lower than Ligand B (36.293), but neither are particularly high.

**9. Caco-2:** Ligand A (-4.702) has a worse Caco-2 permeability than Ligand B (-5.255), but both are quite poor.

**10. Solubility:** Ligand A (-2.45) has better solubility than Ligand B (-1.262). Solubility is important for bioavailability.

**11. hERG:** Both ligands have low hERG inhibition risk (0.462 and 0.408), which is excellent.

**12. Cl_mic:** Ligand A (34.29) has a higher microsomal clearance than Ligand B (2.397). This means Ligand B is more metabolically stable, which is a key advantage for kinase inhibitors.

**13. t1/2:** Ligand A (-15.637) has a shorter in vitro half-life than Ligand B (14.657). Again, this favors Ligand B.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.269 and 0.03).

**15. 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 significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has significantly lower DILI risk, better solubility, and a more favorable TPSA. The difference in binding affinity (0.4 kcal/mol) is not large enough to outweigh the substantial advantage of Ligand A's safety profile (DILI) and solubility. The slightly lower Caco-2 permeability of Ligand A is a concern, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 14:10:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.41 and 353.438 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.33) is slightly higher than Ligand B (56.59). Both are acceptable, but B is better for permeability.

**logP:** Ligand A (0.363) is quite low, potentially hindering permeation. Ligand B (1.65) is within the optimal range of 1-3. This is a significant advantage for B.

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

**H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**QED:** Both have reasonable QED scores (0.77 and 0.6), indicating good drug-like properties.

**DILI:** Ligand A (27.918) has a lower DILI risk than Ligand B (11.632), which is favorable.

**BBB:** Both have high BBB penetration (90.694 and 97.247), but this is less critical for a kinase inhibitor unless CNS effects are specifically desired.

**Caco-2:** Ligand A (-4.845) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.43) is slightly better but still not great.

**Solubility:** Ligand A (-0.925) and B (-1.257) have poor aqueous solubility.

**hERG:** Ligand A (0.105) has a lower hERG risk than Ligand B (0.698), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-2.12) has a negative clearance, suggesting excellent metabolic stability. Ligand B (53.442) has high clearance, indicating poor metabolic stability. This is a major drawback for B.

**In vitro Half-Life:** Ligand A (-4.93) has a negative half-life, suggesting excellent stability. Ligand B (22.753) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.032) has low P-gp efflux, while Ligand B (0.185) is slightly higher.

**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 for A, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's low logP and solubility, its *significantly* stronger binding affinity (-8.5 vs 0 kcal/mol) and superior metabolic stability (negative clearance/half-life) make it the more promising candidate. The lower hERG risk is also a plus. While Ligand B has a better logP and TPSA, its poor metabolic stability and weak binding affinity are major concerns for an enzyme inhibitor.

Output:
0
2025-04-17 14:10:15,166 - INFO - Batch 274 complete. Total preferences: 4384
2025-04-17 14:10:15,166 - INFO - Processing batch 275/512...
2025-04-17 14:10:54,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.414 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.09) is significantly better than Ligand B (54.04), being well below the 140 threshold for good absorption.

**logP:** Ligand A (3.951) is at the higher end of the optimal range (1-3), while Ligand B (2.01) is closer to the lower limit.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 4 HBA) as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.828 and 0.885), indicating drug-likeness.

**DILI:** Ligand A (45.677) has a slightly higher DILI risk than Ligand B (21.753), but both are below the concerning threshold of 60.

**BBB:** Both have high BBB penetration, but Ligand A (96.084) is better than Ligand B (83.249). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 values are similarly poor.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or the model's prediction. However, the values are similarly poor.

**hERG Inhibition:** Ligand A (0.657) shows a lower hERG risk than Ligand B (0.68), which is preferable.

**Microsomal Clearance:** Ligand A (62.55) has a higher microsomal clearance than Ligand B (14.636), suggesting lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (33.828) has a much longer in vitro half-life than Ligand A (1.292), which is a major advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.387) has lower P-gp efflux than Ligand B (0.066), which is preferable.

**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 and can potentially outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI and clearance, its *significantly* stronger binding affinity (-8.8 vs -0.0 kcal/mol) is a decisive factor. A >8 kcal/mol difference in binding is substantial and suggests a much higher probability of target engagement and efficacy. The metabolic stability issue could be addressed through structural modifications in later optimization stages. The similar solubility and permeability issues for both ligands are concerning but don't differentiate them.

Output:
1
2025-04-17 14:10:54,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.377 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.76) is slightly above the preferred <140, while Ligand B (103.93) is well within.

**logP:** Ligand A (0.15) is quite low, potentially hindering permeation. Ligand B (1.226) is within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (5) is acceptable, while Ligand B (8) is also within the limit of 10.

**QED:** Ligand B (0.789) has a significantly better QED score than Ligand A (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (20.396) has a much lower DILI risk than Ligand B (80.031), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (62.466) is lower than Ligand B (50.523).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.055 and -4.912), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.63 and -2.413), also unusual and suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.21) has a lower hERG risk than Ligand B (0.083), which is a positive.

**Microsomal Clearance:** Ligand A (19.953) has a lower microsomal clearance than Ligand B (28.094), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-55.539) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (10.085) is reasonable.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, while Ligand B (0.059) is also low.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the stronger binding affinity of Ligand B (-7.8 kcal/mol vs -6.7 kcal/mol) is a major advantage. While Ligand B has a higher DILI risk, the difference in binding affinity is significant enough to prioritize it, assuming further optimization can address the DILI concern. Ligand A's negative half-life is a red flag indicating a data issue.

Output:
1
2025-04-17 14:10:54,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.523 and 371.497 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is higher than Ligand B (45.23). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (1.743) is within the optimal 1-3 range. Ligand B (3.919) is approaching the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.72 and 0.873), indicating good drug-like properties.

**DILI:** Ligand A (11.09) has a significantly lower DILI risk than Ligand B (24.04), which is a major advantage.

**BBB:** Ligand A (57.425) has lower BBB penetration than Ligand B (91.314). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.834 and -4.862), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-0.884) has better solubility than Ligand B (-3.721). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.452) has a lower hERG risk than Ligand B (0.683). This is a crucial factor for safety.

**Microsomal Clearance:** Ligand A (24.383) has a slightly higher microsomal clearance than Ligand B (23.744). Lower is better for metabolic stability, so Ligand B is slightly favored here.

**In vitro Half-Life:** Ligand A (8.442) has a longer half-life than Ligand B (-1.619). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux than Ligand B (0.449), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better solubility, lower hERG risk, lower P-gp efflux, and a longer half-life. The only area where Ligand B is superior is in BBB penetration (irrelevant for this target) and slightly lower microsomal clearance. The poor Caco-2 permeability is a concern for both, but the other advantages of Ligand A outweigh this drawback.

Output:
0
2025-04-17 14:10:54,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.395 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.43) is slightly higher than Ligand B (71.69). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.952 and 1.957), 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:** Ligand A (0.871) has a significantly higher QED score than Ligand B (0.503), indicating better overall drug-likeness.

**DILI:** Both ligands have similar DILI risk (72.819 and 70.686), which is acceptable (below 80).

**BBB:** Ligand B (75.998) has a higher BBB penetration score than Ligand A (44.591). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.931 and -4.942). This is unusual and suggests poor permeability, but the scale is not specified.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.159 and -2.13). This is also unusual and suggests poor solubility, but the scale is not specified.

**hERG Inhibition:** Ligand A (0.015) has a much lower hERG inhibition liability than Ligand B (0.745), which is a significant advantage.

**Microsomal Clearance:** Ligand A (12.439) has a considerably lower microsomal clearance than Ligand B (28.908), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.38) has a negative half-life, which is not possible. Ligand B (4.738) has a short half-life.

**P-gp Efflux:** Ligand A (0.014) has a much lower P-gp efflux liability than Ligand B (0.248).

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is small.

**Overall Assessment:**

Ligand A is superior due to its significantly better QED, lower hERG risk, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While Ligand B has slightly better binding affinity, the ADME properties of Ligand A are much more favorable for drug development, particularly the lower hERG and better metabolic stability. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A outweigh this concern.

Output:
1
2025-04-17 14:10:54,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.494 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (75.44). A TPSA below 140 is desirable for oral absorption, and both meet this. However, lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (3.258 and 2.868, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 4 HBA). Lower numbers are generally better for permeability.

**QED:** Both ligands have good QED scores (0.782 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (12.292) has a much lower DILI risk than Ligand B (38.736). This is a significant advantage.

**BBB:** Both ligands have high BBB penetration (96.743 and 90.772). While not a primary concern for a non-CNS target like SRC, it doesn't detract from their potential.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.533 and -4.262). These values are unusual and suggest poor permeability. However, these are likely reported as log values, and negative values indicate low permeability. Ligand A is slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.671 and -3.336). Again, these are likely log values, and negative values indicate poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.765) has a slightly lower hERG risk than Ligand B (0.463), which is preferable.

**Microsomal Clearance:** Ligand A (56.523) has a lower microsomal clearance than Ligand B (65.912), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.183) has a significantly longer in vitro half-life than Ligand B (0.697). This is a major advantage.

**P-gp Efflux:** Ligand A (0.2) has a lower P-gp efflux liability than Ligand B (0.565), which is preferable.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-9.0). While a 1.5 kcal/mol advantage can be significant, the other ADME properties of Ligand A are more favorable.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better H-bonding characteristics. While Ligand B has slightly better binding affinity, the improvements in ADME properties for Ligand A outweigh this difference, especially considering the enzyme target class. The poor 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 14:10:54,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.334 and 352.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (108.15 and 101.38) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.589) is slightly low, potentially hindering permeation. Ligand B (1.365) is 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 6 HBA, both within the acceptable limit of 10.

**QED:** Both ligands have high QED scores (0.844 and 0.833), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 86.623, which is high. Ligand B has a much lower DILI risk of 55.176, still above the ideal <40, but significantly better than A.

**BBB:** Both have low BBB penetration (59.325 and 54.634), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.656 and -4.996). These values are unusual and suggest poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.036 and -1.926), which is also unusual and suggests very poor solubility.

**hERG Inhibition:** Both have very low hERG inhibition liability (0.145 and 0.115), which is excellent.

**Microsomal Clearance:** Ligand A has a negative clearance (-2.631), indicating very high metabolic stability. Ligand B has a positive clearance (6.679), indicating faster metabolism.

**In vitro Half-Life:** Ligand A has a very long half-life (-40.735), while Ligand B has a shorter half-life (-3.144).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.016 and 0.007).

**Binding Affinity:** Ligand A has a slightly better binding affinity (-7.7 kcal/mol) than Ligand B (-6.8 kcal/mol). The difference is 0.9 kcal/mol, which is significant.

**Conclusion:**

Despite Ligand A's superior binding affinity, its high DILI risk and poor solubility are major drawbacks. Ligand B, while having slightly weaker affinity, exhibits a significantly lower DILI risk and comparable metabolic stability. The negative solubility and Caco-2 values for both are concerning and would require further investigation (perhaps experimental validation as the models may be inaccurate for these properties). However, considering the enzyme-specific priorities, the lower DILI risk of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 14:10:54,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.93) is significantly better than Ligand B (81.67), being well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands (1.147 and 1.201) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3), as fewer HBDs generally improve permeability.

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

**QED:** Ligand A (0.714) has a much better QED score than Ligand B (0.408), indicating a more drug-like profile.

**DILI:** Ligand A (14.928) has a significantly lower DILI risk than Ligand B (5.467), which is a crucial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (70.764) is better than Ligand B (36.06).

**Caco-2 Permeability:** Ligand A (-4.782) and Ligand B (-5.051) are similar and both indicate poor permeability.

**Aqueous Solubility:** Ligand A (-0.626) is better than Ligand B (-1.198), indicating slightly better solubility.

**hERG Inhibition:** Ligand A (0.295) has a much lower hERG risk than Ligand B (0.173), a critical safety parameter.

**Microsomal Clearance:** Ligand A (0.802) has significantly lower microsomal clearance than Ligand B (24.821), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.761) has a much longer in vitro half-life than Ligand B (-0.188), further supporting better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.029 and 0.04 respectively).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.761 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A is significantly better than Ligand B across most crucial ADME-Tox properties. While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A in terms of DILI risk, metabolic stability (lower Cl_mic and longer t1/2), solubility, hERG risk, and QED outweigh this minor difference in potency. The poor Caco-2 permeability is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 14:10:54,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.401 and 342.439 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.08) is better than Ligand B (62.55), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.937) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.82) is within the optimal range.

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

**H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3), as fewer HBAs generally improve permeability.

**QED:** Both ligands have good QED scores (0.634 and 0.837, respectively), indicating good drug-like properties.

**DILI:** Ligand A (19.891) has a significantly lower DILI risk than Ligand B (15.51), which is a major advantage.

**BBB:** Ligand A (95.347) shows excellent BBB penetration, while Ligand B (66.344) is lower. While not a primary concern for a kinase inhibitor, higher BBB penetration isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.45 and -4.89), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.084 and -2.772), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.504) has a lower hERG risk than Ligand B (0.177), which is a positive attribute.

**Microsomal Clearance:** Ligand A (19.091) has a lower microsomal clearance than Ligand B (37.767), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (12.221) has a significantly longer in vitro half-life than Ligand A (1.655). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux than Ligand B (0.102), which is preferable.

**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 has several advantages: lower DILI risk, better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. Ligand B has a longer half-life and slightly better binding affinity. However, the poor Caco-2 and solubility values for both are concerning. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is slightly more promising due to its superior safety profile (DILI, hERG) and metabolic stability, despite the slightly weaker affinity and shorter half-life. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications.

Output:
0
2025-04-17 14:10:54,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.539 Da and 348.407 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (118.01) is still within acceptable limits for oral absorption, but less favorable than A.

**3. logP:** Ligand A (3.989) is optimal. Ligand B (-0.587) is significantly low, potentially hindering membrane permeability and absorption.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 3, respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both below the 10 threshold.

**6. QED:** Both ligands have reasonable QED values (0.832 and 0.657), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (39.201 and 41.062), which is favorable.

**8. BBB:** Ligand A (74.952) shows moderate BBB penetration, while Ligand B (46.84) is lower. This is less critical for a non-CNS target like SRC, but still a consideration.

**9. Caco-2 Permeability:** Ligand A (-4.616) has poor Caco-2 permeability, which is a significant concern. Ligand B (-5.989) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-4.105) and Ligand B (-0.582) both have poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.248) has very low hERG inhibition risk, which is excellent. Ligand B (0.011) is even lower, also excellent.

**12. Microsomal Clearance:** Ligand A (63.311) has moderate clearance, while Ligand B (-35.362) has negative clearance, indicating high metabolic stability. This is a major advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (30.948) has a moderate half-life, while Ligand B (14.237) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.31) shows some P-gp efflux, while Ligand B (0.005) has very low efflux.

**15. Binding Affinity:** Ligand A (-9.0) has significantly stronger binding affinity than Ligand B (0.0). This is a crucial factor.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability and moderate metabolic clearance. Ligand B, while having a much weaker binding affinity, exhibits excellent metabolic stability (negative Cl_mic), very low P-gp efflux, and very low hERG risk. The extremely weak binding affinity of Ligand B is a major drawback, and the difference in affinity (-9.0 vs 0.0 kcal/mol) is substantial. While optimizing ADME properties is important, a compound *must* bind to its target.

Output:
1
2025-04-17 14:10:54,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 and 356.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.78) is well below the 140 threshold, suggesting good absorption. Ligand B (104.21) is still acceptable but less optimal.

**logP:** Both ligands (1.12 and 0.95) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 5 HBA) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.596 and 0.675), indicating drug-like properties.

**DILI:** Ligand A (22.76) has a significantly lower DILI risk than Ligand B (36.64), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (68.36) is slightly better than Ligand A (55.14).

**Caco-2 Permeability:** Ligand A (-4.565) has a much better Caco-2 permeability than Ligand B (-5.179), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.215) has better solubility than Ligand B (-2.404).

**hERG Inhibition:** Ligand A (0.347) has a much lower hERG inhibition liability than Ligand B (0.045), which is a critical safety advantage.

**Microsomal Clearance:** Ligand A (3.441) has a lower microsomal clearance, suggesting better metabolic stability, than Ligand B (5.294).

**In vitro Half-Life:** Ligand A (0.171) has a very short half-life, while Ligand B (-21.4) has a very long half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.007).

**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 A is significantly better overall. It has a much lower DILI risk, better solubility, lower hERG inhibition, and better Caco-2 permeability. While Ligand B has a better half-life and slightly better affinity, the ADME/Tox profile of Ligand A is far superior, making it a more viable drug candidate for SRC kinase inhibition. The improved safety profile (DILI, hERG) and absorption characteristics outweigh the small difference in binding affinity.

Output:
0
2025-04-17 14:10:54,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.479 and 344.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.47) is better than Ligand B (59.39), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.187 and 2.251), falling within the optimal range of 1-3.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are well within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.711 and 0.837), indicating a strong drug-like profile.

**DILI:** Both ligands have low DILI risk (25.553 and 28.267), well below the 40 threshold.

**BBB:** Ligand B (89.298) has a significantly higher BBB penetration percentile than Ligand A (55.215). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.077) has a worse Caco-2 permeability than Ligand B (-4.584).

**Aqueous Solubility:** Ligand A (-1.473) has a worse Aqueous Solubility than Ligand B (-1.887).

**hERG:** Both ligands have low hERG inhibition liability (0.378 and 0.468), which is good.

**Microsomal Clearance:** Ligand A (49.925) has a lower microsomal clearance than Ligand B (63.85), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (60.123) has a longer in vitro half-life than Ligand A (23.732), which is generally desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.222).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). A 0.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better TPSA and Cl_mic, Ligand B's significantly stronger binding affinity (-7.5 vs -6.6 kcal/mol) and longer half-life are more important for an enzyme inhibitor like an SRC kinase inhibitor. The slightly lower metabolic stability of Ligand B is a manageable trade-off for the potency advantage.

Output:
1
2025-04-17 14:10:54,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.377 and 364.486 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.68) is better than Ligand B (49.41), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (4.511) is slightly higher than the optimal range (1-3), while Ligand B (3.844) is within the optimal range. This favors Ligand B.

**H-Bond Donors:** Ligand A (0) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (A: 3, B: 3) are well below the 10 threshold.

**QED:** Both ligands have good QED scores (A: 0.815, B: 0.882), indicating good drug-like properties.

**DILI:** Ligand B (43.622) has a significantly lower DILI risk than Ligand A (56.572), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (A: 86.429, B: 95.735), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or prediction method. However, the values are similar (-4.337 vs -4.927).

**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 (-4.384 vs -4.392).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.8, B: 0.739).

**Microsomal Clearance:** Ligand B (40.922) has significantly lower microsomal clearance than Ligand A (65.884), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (14.888) has a much shorter half-life than Ligand A (50.728). This is a disadvantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.7, B: 0.43).

**Binding Affinity:** Ligand B (-9.3 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 is the preferred candidate. While it has a shorter half-life, its significantly stronger binding affinity (-9.3 vs -7.1 kcal/mol), lower DILI risk, and improved metabolic stability (lower Cl_mic) are critical advantages for an enzyme inhibitor. The slightly better logP also contributes to its favorability. The unusual negative values for Caco-2 and solubility are concerning but similar for both compounds. The substantial affinity difference outweighs the half-life concern, as formulation strategies can often address half-life issues.

Output:
1
2025-04-17 14:10:54,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.407 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.47) is slightly above the optimal <140, but acceptable. Ligand B (84.23) is excellent, well below 140, suggesting better absorption.

**logP:** Both ligands (1.483 and 2.231) are 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.544 and 0.755), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (78.054) has a higher DILI risk than Ligand B (32.299). This is a significant negative for Ligand A.

**BBB:** Both have acceptable BBB penetration (66.188 and 68.864). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.833) has poor Caco-2 permeability, while Ligand B (-5.386) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.119) has poor solubility, while Ligand B (-1.874) is better, but still poor.

**hERG:** Both ligands have very low hERG risk (0.108 and 0.095), which is excellent.

**Microsomal Clearance:** Ligand A (42.129) has lower clearance than Ligand B (46.526), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (16.728) has a longer half-life than Ligand B (-7.689). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.018 and 0.071), which is favorable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). The difference is 1.3 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and longer half-life, which are crucial for an enzyme inhibitor. However, its significantly higher DILI risk and poor Caco-2 permeability are major drawbacks. Ligand B has a lower DILI risk, better solubility, and slightly better Caco-2 permeability, but its binding affinity is weaker and half-life shorter.

Considering the enzyme-specific priorities, the binding affinity advantage of Ligand A (1.3 kcal/mol) is substantial enough to potentially outweigh the DILI risk, *provided* formulation strategies can address the poor solubility and permeability. However, the DILI risk is still concerning. Ligand B, while less potent, presents a safer profile.

Given the balance of factors, and the fact that SRC is not a CNS target, I would lean towards Ligand A due to its superior binding affinity and half-life, but with a strong caveat that further investigation into mitigating the DILI risk and improving solubility/permeability is essential.

Output:
1
2025-04-17 14:10:54,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.415 and 342.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.42) is slightly higher than Ligand B (75.19), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.601 and 1.768), falling within the optimal 1-3 range. Ligand B is slightly lower, which could be beneficial for 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 4. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.673 and 0.819), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 47.421, while Ligand B has a much lower risk of 21.287. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have relatively high BBB penetration (85.343 and 75.805). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.572 and -4.944). 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 have negative solubility values (-2.824 and -2.074), which is also unusual. Similar to Caco-2, these values are on a log scale and require further context.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.122 and 0.123), which is excellent.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (54.131) than Ligand B (36.165). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**13. In vitro Half-Life:** Ligand B has a slightly longer in vitro half-life (-0.069 hours) than Ligand A (-4.254 hours). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.013).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. The difference of 2.3 kcal/mol is substantial.

**Overall Assessment:**

Ligand B is the stronger candidate. While both ligands have acceptable physicochemical properties, Ligand B demonstrates a significantly better safety profile (lower DILI risk), improved metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a much higher binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the superior potency and safety profile of Ligand B outweigh these potential drawbacks.

Output:
1
2025-04-17 14:10:54,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.35 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.43) is slightly higher than Ligand B (71.09). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (0.984) is a bit low, potentially hindering permeation. Ligand B (2.593) is within the optimal 1-3 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 good QED scores (0.819 and 0.865), indicating drug-likeness.

**DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (44.397). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (77.588) has a slightly higher value than Ligand B (43.893).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.52) is slightly better than Ligand B (-4.861).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.124 and -3.25). This is a major drawback.

**hERG:** Ligand A (0.108) has a lower hERG risk than Ligand B (0.191), which is favorable.

**Microsomal Clearance:** Ligand A (27.875) has a higher microsomal clearance than Ligand B (21.077), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-3.074) has a more negative half-life, suggesting a longer half-life and better stability than Ligand A (-23.992).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.117).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite both compounds having solubility issues, Ligand B is the stronger candidate. Its superior binding affinity (-8.2 vs -6.8 kcal/mol) is a decisive factor for an enzyme target. It also exhibits lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), and a more optimal logP. While Ligand A has a slightly lower hERG risk, the benefits of Ligand B's potency and improved ADME profile outweigh this minor advantage.

Output:
1
2025-04-17 14:10:54,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.519 and 365.414 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (80.32), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.787 and 1.919), falling within the optimal 1-3 range. Ligand B is slightly lower, which could slightly improve solubility.

**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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.588 and 0.688), indicating good drug-like properties.

**DILI:** Ligand A (24.506) has a significantly lower DILI risk than Ligand B (39.628). This is a major advantage for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (66.886) is slightly better than Ligand A (53.858).

**Caco-2 Permeability:** Ligand A (-4.68) has worse Caco-2 permeability than Ligand B (-5.252), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.365) has worse aqueous solubility than Ligand B (-2.008). This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.415 and 0.363).

**Microsomal Clearance:** Ligand B (5.796) has significantly lower microsomal clearance than Ligand A (57.453). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (35.038) has a much longer in vitro half-life than Ligand A (17.374). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.256 and 0.029).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.4 kcal/mol). This 0.9 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 a lower DILI risk, Ligand B demonstrates superior potency (binding affinity), metabolic stability (lower Cl_mic, longer t1/2), and slightly improved solubility. The difference in binding affinity is significant. The slightly lower Caco-2 permeability and higher DILI of Ligand B are acceptable trade-offs given its other advantages, especially the potency and metabolic stability.

Output:
1
2025-04-17 14:10:54,773 - INFO - Batch 275 complete. Total preferences: 4400
2025-04-17 14:10:54,773 - INFO - Processing batch 276/512...
2025-04-17 14:11:35,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (355.467 and 362.901 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.84) is higher than Ligand B (52.57). Both are below 140, but B is better positioned for oral absorption.

**3. logP:** Both ligands (4.027 and 3.987) are slightly above the optimal range of 1-3, potentially raising concerns about solubility and off-target effects, but are relatively close.

**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, while Ligand B has 2. Both are within the acceptable limit of <=10. Lower HBA in B is generally favorable for permeability.

**6. QED:** Both ligands have good QED scores (0.741 and 0.778), indicating a generally drug-like profile.

**7. DILI:** Ligand A has a significantly higher DILI risk (83.249%) compared to Ligand B (17.642%). This is a major red flag for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration (61.613% and 69.833%). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-5.129) has worse Caco-2 permeability than Ligand B (-4.596). Lower (more negative) values indicate lower permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.085 and -3.901). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.626) has slightly higher hERG inhibition liability than Ligand B (0.807), but both are reasonably low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (39.772) has a higher microsomal clearance than Ligand B (1.71), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (80.965) has a longer in vitro half-life than Ligand B (20.815). This is a positive for Ligand A, but is outweighed by other factors.

**14. P-gp Efflux:** Ligand A (0.689) has higher P-gp efflux liability than Ligand B (0.441). Lower efflux is better.

**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 for Ligand A.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand A has superior affinity, its significantly higher DILI risk and higher Cl_mic are major drawbacks. Ligand B has a much better safety profile (DILI) and metabolic stability, despite slightly lower affinity. The 1.2 kcal/mol difference in affinity, while noticeable, is less critical than the substantial improvements in safety and metabolic stability offered by Ligand B.

Output:
1
2025-04-17 14:11:35,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.375 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.17) is higher than Ligand B (67.87). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have good logP values (1.513 and 1.786), 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). Ligand B is slightly more favorable due to fewer potential off-target interactions.

**QED:** Both ligands have similar QED scores (0.761 and 0.711), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 90.617, which is high. Ligand B has a much lower DILI risk of 31.059, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (80.962) than Ligand A (59.325).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.892 and -4.367). This is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret definitively.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.894 and -2.124). Again, the scale is unclear, but this suggests potential formulation challenges. Ligand B is slightly better.

**hERG:** Both ligands have very low hERG inhibition liability (0.261 and 0.214), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (45.465) has a higher microsomal clearance than Ligand B (22.759), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (8.214 hours) has a longer in vitro half-life than Ligand A (6.262 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.058), which is favorable.

**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 not huge, it's enough to be considered, especially given the other advantages of Ligand B.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and lower TPSA outweigh the slightly lower Caco-2 and solubility values. The higher BBB value isn't a major factor here, but it doesn't hurt. The higher DILI risk of Ligand A is a major concern.

Output:
1
2025-04-17 14:11:35,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.447 and 355.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (70.16 and 73.32) are below the 140 A^2 threshold for good oral absorption, which is good.

**3. logP:** Ligand A (0.342) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (0.728) is also on the lower side but closer to the preferred range.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (1) 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 (0.542 and 0.711), indicating drug-like properties.

**7. DILI:** Ligand A (9.383) has a significantly lower DILI risk than Ligand B (5.312), which is a major advantage.

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand A (68.592) is lower than Ligand B (56.65). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.643 and -4.998), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.774 and -0.682), indicating poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.45 and 0.338), which is excellent.

**12. Microsomal Clearance:** Ligand A (10.086) has higher microsomal clearance than Ligand B (-6.815). This suggests lower metabolic stability for Ligand A. Ligand B is preferred here.

**13. In vitro Half-Life:** Ligand A (-5.346) has a shorter in vitro half-life than Ligand B (-4.263). This is another point in favor of Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013).

**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 better candidate. While both have issues with Caco-2 permeability and solubility, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and slightly better binding affinity. The lower DILI risk is particularly important. Although Ligand A has a slightly better BBB score, this is not a priority for a non-CNS target like SRC.

Output:
1
2025-04-17 14:11:35,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.833 and 362.539 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (58.2). Both are below 140, suggesting good absorption potential.

**logP:** Ligand A (1.275) is optimal, while Ligand B (4.121) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

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

**QED:** Ligand A (0.811) has a better QED score than Ligand B (0.717), indicating better overall drug-likeness.

**DILI:** Ligand B (30.748) has a significantly lower DILI risk than Ligand A (70.57), which is a substantial advantage.

**BBB:** Both ligands have similar BBB penetration (64.599 and 63.746). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-5.244 and -4.903).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.381 and -3.41). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.201 and 0.401), which is good.

**Microsomal Clearance:** Ligand B (61.361) has a higher microsomal clearance than Ligand A (37.16), meaning it's metabolized faster and has lower metabolic stability. This is a significant disadvantage.

**In vitro Half-Life:** Ligand A (34.163) has a longer in vitro half-life than Ligand B (23.289), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.195 and 0.257).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has a much lower DILI risk, Ligand A is superior in terms of QED, metabolic stability (lower Cl_mic, longer t1/2), and logP. The solubility is poor for both, but the other advantages of Ligand A, particularly the better metabolic stability, outweigh the DILI risk difference. The binding affinity is almost identical. Given the focus on metabolic stability for enzyme inhibitors, Ligand A is the more promising candidate.

Output:
0
2025-04-17 14:11:35,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.471 and 360.351 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.3) is better than Ligand B (42.43), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (1.221) is within the optimal 1-3 range. Ligand B (3.326) is at the higher end, but still acceptable.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.884) has a significantly better QED score than Ligand B (0.278), indicating a more drug-like profile.

**DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (32.997), but both are below the concerning threshold of 60.

**BBB:** Ligand A (75.339) and Ligand B (97.131) both have acceptable BBB penetration, but Ligand B is better.

**Caco-2 Permeability:** Ligand A (-4.867) and Ligand B (-4.271) both have negative values, which is unusual. Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.247) and Ligand B (-3.39) both have negative values, which is unusual. Lower values indicate poorer solubility.

**hERG Inhibition:** Both ligands have similar hERG inhibition liabilities (0.654 and 0.723), which is acceptable.

**Microsomal Clearance:** Ligand A (30.736) has a lower microsomal clearance than Ligand B (55.116), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.206) has a much longer in vitro half-life than Ligand B (-5.791). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.101 and 0.207).

**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.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better QED, metabolic stability, and half-life, the substantial difference in binding affinity outweighs these advantages. The slightly higher logP of Ligand B is not a major concern.

Output:
1
2025-04-17 14:11:35,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (369.546 Da) is also good.

**TPSA:** Ligand A (113.32) is better than Ligand B (40.54) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (0.338) is quite low, potentially hindering permeability. Ligand B (4.629) is high, raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.724, B: 0.689), indicating drug-like properties.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (21.83), which is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (91.392) has a much higher BBB penetration than Ligand A (31.873).

**Caco-2 Permeability:** Ligand A (-5.281) has poor Caco-2 permeability, while Ligand B (-4.537) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-2.89) has poor aqueous solubility, while Ligand B (-4.554) is even worse.

**hERG Inhibition:** Ligand A (0.333) has a lower hERG risk than Ligand B (0.847), which is a positive.

**Microsomal Clearance:** Ligand A (16.561) has lower microsomal clearance, suggesting better metabolic stability, which is crucial for an enzyme target. Ligand B (70.503) has high clearance.

**In vitro Half-Life:** Ligand A (24.121 hours) has a better in vitro half-life than Ligand B (33.511 hours).

**P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux, which is favorable. Ligand B (0.903) has higher efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 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 metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. However, it suffers from poor solubility, permeability, and a higher DILI risk. Ligand B has a higher logP, which is concerning, and significantly worse metabolic stability and solubility. While its DILI risk is lower, the other ADME properties are less favorable.

Given the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG), and the fact that the affinity difference isn't huge, Ligand A is slightly preferable due to its better metabolic stability and lower hERG risk. However, the poor solubility and permeability of Ligand A would require significant formulation work or further chemical modification.

Output:
0
2025-04-17 14:11:35,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.472 and 358.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 140 threshold for oral absorption. Ligand B (61.88) is still reasonable but higher, potentially impacting absorption.

**logP:** Both ligands (4.626 and 4.476) are slightly above the optimal 1-3 range, potentially leading to solubility issues or off-target interactions. However, this isn't a major concern at this stage.

**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 acceptable, under the 10 threshold.

**QED:** Ligand A (0.72) has a better QED score than Ligand B (0.531), indicating a more drug-like profile.

**DILI:** Ligand A (14.696) has a significantly lower DILI risk than Ligand B (53.858), a crucial advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (92.943) has a higher BBB percentile than Ligand B (64.133).

**Caco-2 Permeability:** Ligand A (-4.52) has a lower Caco-2 value than Ligand B (-5.173), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.837) has a lower solubility than Ligand B (-4.099).

**hERG Inhibition:** Both ligands (0.917 and 0.652) have relatively low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (77.06) has a higher microsomal clearance than Ligand B (72.696), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-19.599) has a significantly longer in vitro half-life than Ligand A (4.824), a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands (0.387 and 0.56) have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.0), although the difference is small.

**Overall Assessment:**

Ligand B demonstrates superior metabolic stability (longer half-life) and a slightly better binding affinity. However, Ligand A has a significantly lower DILI risk and a better QED score. Given that DILI is a major concern in drug development, and the affinity difference is small, the lower DILI risk of Ligand A is a strong advantage. The slightly lower solubility and permeability of Ligand A could be addressed through formulation strategies.

Output:
0
2025-04-17 14:11:35,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.825 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, while Ligand B (89.87) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.724) is at the upper end of the optimal range (1-3), while Ligand B (1.053) is slightly below. Ligand B's lower logP could lead to permeability issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both within acceptable limits. Ligand B has 3 HBD and 4 HBA, also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (0.821 and 0.609), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (80.729%) compared to Ligand B (22.722%). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.162%) is higher than Ligand B (58.938%).

**Caco-2 Permeability:** Ligand A (-4.559) and Ligand B (-5.011) both have negative Caco-2 values, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-5.733) and Ligand B (-3.066) both have negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.552) has a slightly higher hERG risk than Ligand B (0.486), but both are relatively low.

**Microsomal Clearance:** Ligand A (89.959) has a higher microsomal clearance than Ligand B (42.078), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (45.248 hours) has a longer half-life than Ligand A (56.704 hours).

**P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.031), which is favorable.

**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 could outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A's superior binding affinity, its significantly higher DILI risk and lower metabolic stability (higher Cl_mic) are major red flags. While the affinity difference is substantial, the potential for liver toxicity and rapid metabolism make Ligand A a less desirable candidate. Ligand B, while having weaker affinity, presents a much better safety profile (lower DILI) and improved metabolic stability. Given the enzyme-specific priorities, I favor Ligand B.

Output:
1
2025-04-17 14:11:35,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (69.3) is significantly better than Ligand B (83.98). Lower TPSA generally translates to better cell permeability, crucial for kinase inhibitors.

**logP:** Both ligands have good logP values (A: 2.122, B: 1.871), 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 hydrogen bond acceptors, which can improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.915) has a significantly higher QED score than Ligand B (0.785), indicating a more drug-like profile.

**DILI:** Ligand A (34.548) has a lower DILI risk than Ligand B (49.864), which is a significant advantage.

**BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-5.113 for A, -5.717 for B), so this doesn't differentiate them significantly.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.092 and -2.945 respectively). This is a major concern for both, but needs to be weighed against other factors.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.388, B: 0.088), which is excellent. Ligand B is slightly better here.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (A: 29.397, B: 30.334). These are moderate, suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-9.619) has a much longer in vitro half-life than Ligand B (4.955), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.072, B: 0.079), which is good.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it may not be enough to overcome the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a better QED score, lower DILI risk, significantly longer half-life, and lower TPSA. While Ligand B has slightly better binding affinity and hERG inhibition, the improvements in ADME properties of Ligand A are more crucial for overall drug development success, especially for an enzyme target where metabolic stability and bioavailability are key. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 14:11:35,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.479 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is slightly higher than Ligand B (49.85). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**3. logP:** Both ligands have good logP values (2.093 and 1.666), 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 3. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.74 and 0.716), indicating good drug-likeness.

**7. DILI:** Ligand A (35.983) has a slightly better DILI score than Ligand B (39.511), both are below the concerning threshold of 60.

**8. BBB:** Both ligands have high BBB penetration (81.737 and 74.292). While not a primary concern for a kinase inhibitor, it doesn't detract from either.

**9. Caco-2 Permeability:** Ligand A (-4.63) has a worse Caco-2 permeability compared to Ligand B (-4.465), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.128) has worse aqueous solubility than Ligand B (-2.815). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.28 and 0.39), which is excellent.

**12. Microsomal Clearance:** Ligand A (78.968) has a significantly higher microsomal clearance than Ligand B (40.836). This indicates Ligand B is more metabolically stable, a critical factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-1.257) has a significantly longer in vitro half-life than Ligand A (-15.933). This further supports better metabolic stability for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.107 and 0.272).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.8 kcal/mol difference is substantial and outweighs minor ADME drawbacks.

**Conclusion:**

Ligand B is the more promising drug candidate. While Ligand A has slightly better DILI, Ligand B excels in key areas for kinase inhibitors: significantly better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a substantially stronger binding affinity. The lower TPSA of Ligand B also suggests improved permeability.

Output:
1
2025-04-17 14:11:35,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.447 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.53) is significantly better than Ligand B (83.73).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is higher and could potentially hinder absorption.

**logP:** Ligand A (4.373) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (2.925) is within the ideal range. However, for a kinase inhibitor, a slightly higher logP isn't a major concern if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (3 HBD, 4 HBA). Lower numbers are generally preferred for better permeability.

**QED:** Both ligands have good QED scores (0.637 and 0.72), indicating generally drug-like properties.

**DILI:** Ligand A (15.083) has a much lower DILI risk than Ligand B (47.421). This is a significant advantage for Ligand A.

**BBB:** Ligand A (68.127) has a better BBB percentile than Ligand B (41.915), although BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.408) has a lower Caco-2 permeability than Ligand B (-4.764), but both are negative values which suggests poor permeability.

**Aqueous Solubility:** Ligand A (-5.589) has better aqueous solubility than Ligand B (-3.029). Solubility is important for formulation and bioavailability.

**hERG:** Both ligands have low hERG risk (0.854 and 0.72).

**Microsomal Clearance:** Ligand A (110.003) has a higher microsomal clearance than Ligand B (46.905), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (55.766) has a significantly longer in vitro half-life than Ligand A (-8.945). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.42 and 0.417).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.6 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has advantages in DILI risk, solubility, TPSA and H-bonding. However, it suffers from significantly higher microsomal clearance and a shorter half-life. Ligand B has a better half-life, lower clearance, and a more favorable logP, but has a higher TPSA and DILI risk. Given the enzyme-specific priorities, metabolic stability (half-life and clearance) are crucial. The longer half-life and lower clearance of Ligand B outweigh its slightly higher TPSA and DILI risk, especially considering the strong binding affinity.

Output:
1
2025-04-17 14:11:35,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.511 and 365.414 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (62.62). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Both ligands (2.366 and 2.427) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 0. Both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.725 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (35.905) has a slightly better DILI score than Ligand B (42.924), both are below the 40 threshold.

**BBB:** Ligand B (71.229) has a better BBB score than Ligand A (59.636), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.995) has worse Caco-2 permeability than Ligand B (-4.527).

**Aqueous Solubility:** Ligand A (-2.795) has worse solubility than Ligand B (-1.935). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.332) has a slightly higher hERG risk than Ligand B (0.167), but both are low risk.

**Microsomal Clearance:** Ligand B (37.126) has better metabolic stability (lower clearance) than Ligand A (41.176). This is a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-9.437) has a significantly longer in vitro half-life than Ligand A (9.844). This is a major advantage.

**P-gp Efflux:** Ligand A (0.25) has slightly lower P-gp efflux than Ligand B (0.153), which is favorable.

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.2). While both are excellent, the 0.4 kcal/mol difference is significant.

**Conclusion:**

Ligand B is the better candidate. It has a slightly better binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and a slightly lower hERG risk. While Ligand A has a slightly better DILI and P-gp efflux, the improvements in metabolic stability and binding affinity for Ligand B outweigh these minor differences, making it a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 14:11:35,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (364.808 Da) is also good.

**TPSA:** Ligand A (73.32) is well below the 140 threshold for oral absorption. Ligand B (86.88) is also acceptable, but slightly higher.

**logP:** Ligand A (-0.047) is a bit low, potentially hindering permeation. Ligand B (2.198) 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) is good. Ligand B (3 HBD, 3 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.65, B: 0.542), indicating good drug-like properties.

**DILI:** Ligand A (13.067) has a very favorable DILI score, indicating low liver injury risk. Ligand B (69.562) is significantly higher, suggesting a higher risk of DILI. This is a major concern for Ligand B.

**BBB:**  BBB isn't a primary concern for a non-CNS target like SRC, but Ligand B (77.007) has a higher score than Ligand A (48.119).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.676) is worse than Ligand B (-5.305).

**Aqueous Solubility:** Ligand A (0.411) has poor solubility. Ligand B (-3.447) has even worse solubility. This is a significant drawback for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.302) has a very low hERG risk. Ligand B (0.489) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-11.077) has a very low (and negative) clearance, indicating excellent metabolic stability. Ligand B (22.169) has a much higher clearance, suggesting faster metabolism. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-1.111) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (25.031) has a good half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.016, B: 0.091).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly better 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:**

Despite the superior binding affinity of Ligand B, the significantly higher DILI risk and faster metabolic clearance (lower stability) are major concerns. Ligand A, while having a slightly lower affinity and poor solubility, exhibits a much better safety profile (low DILI, low hERG) and excellent metabolic stability. The negative half-life for Ligand A is a data quality issue that needs to be investigated, but the other properties strongly favor it. Given the enzyme-specific priorities, metabolic stability and safety are crucial.

Output:
0
2025-04-17 14:11:35,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.419 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (107.97) is better than Ligand B (66.71). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (1.209) is within the optimal range (1-3), while Ligand A (-0.981) is slightly below 1. This could hinder permeation for Ligand A.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). While both are acceptable (<=5), lower is generally preferred.

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

**QED:** Ligand B (0.859) has a significantly higher QED score than Ligand A (0.462), indicating a more drug-like profile.

**DILI:** Ligand A (15.083) has a much lower DILI risk than Ligand B (50.989), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (78.558) has a higher BBB percentile than Ligand A (29.275).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. Ligand A (-4.853) is worse than Ligand B (-5.004).

**Aqueous Solubility:** Both ligands have negative values, suggesting poor solubility. Ligand A (-0.995) is slightly better than Ligand B (-1.751).

**hERG Inhibition:** Ligand A (0.026) has a much lower hERG inhibition liability than Ligand B (0.602), a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (2.775) has significantly lower microsomal clearance than Ligand B (16.155), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.907) has a much longer in vitro half-life than Ligand B (-1.827), a major positive.

**P-gp Efflux:** Ligand A (0.004) has a much lower P-gp efflux liability than Ligand B (0.039), indicating better bioavailability.

**Binding Affinity:** Both ligands have similar binding affinities (-7.8 and -8.6 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to override the significant ADME advantages of Ligand A.

**Overall:**

Ligand A demonstrates superior ADME properties, particularly in terms of DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While Ligand B has a better QED score and logP, the safety and pharmacokinetic advantages of Ligand A are more critical for an enzyme target like SRC. The similar binding affinities make the ADME profile the deciding factor.

Output:
0
2025-04-17 14:11:35,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 362.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.32) is better than Ligand B (51.14), falling below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.161) is optimal, while Ligand B (4.28) is pushing the upper limit and could present solubility issues.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

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

**QED:** Both ligands (0.718 and 0.688) have good drug-likeness scores.

**DILI:** Ligand A (21.753) has a significantly lower DILI risk than Ligand B (29.546). This is a major advantage.

**BBB:** Ligand A (36.642) has a lower BBB penetration than Ligand B (74.758). This is not a major concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.152) has poor Caco-2 permeability, while Ligand B (-4.766) is also poor.

**Aqueous Solubility:** Ligand A (-1.572) has better solubility than Ligand B (-4.126).

**hERG Inhibition:** Ligand A (0.222) has a much lower hERG risk than Ligand B (0.786). This is a critical advantage.

**Microsomal Clearance:** Ligand A (-15.661) has significantly lower (better) microsomal clearance than Ligand B (73.896), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.013) has a longer half-life than Ligand B (21.682).

**P-gp Efflux:** Ligand A (0.012) has lower P-gp efflux than Ligand B (0.312).

**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 not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. These factors are crucial for developing a safe and effective kinase inhibitor. The slightly lower affinity of Ligand A can potentially be optimized in subsequent rounds of drug design.

Output:
0
2025-04-17 14:11:35,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.414 and 380.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is significantly better than Ligand B (43.18), being well below the 140 threshold for oral absorption.

**logP:** Ligand A (1.919) is within the optimal 1-3 range. Ligand B (3.477) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.688 and 0.631), indicating good drug-likeness.

**DILI:** Ligand A (39.628) has a slightly higher DILI risk than Ligand B (10.237), but both are below the concerning threshold of 60.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (77.976) is higher than Ligand A (66.886).

**Caco-2 Permeability:** 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 negative solubility values, which is also unusual and indicates very poor solubility. This is a major concern for both.

**hERG:** Ligand A (0.363) has a much lower hERG risk than Ligand B (0.826), which is a significant advantage.

**Microsomal Clearance:** Ligand A (5.796) has significantly lower microsomal clearance than Ligand B (45.644), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (35.038) has a longer in vitro half-life than Ligand B (4.441), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.029) has much lower P-gp efflux liability than Ligand B (0.279), which is favorable.

**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 of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI, higher hERG risk, higher P-gp efflux, and significantly worse metabolic stability (higher Cl_mic, shorter t1/2) compared to Ligand A. Both compounds have poor solubility and permeability.

Despite the affinity advantage of Ligand B, the significantly better ADME profile of Ligand A, particularly its lower hERG risk and improved metabolic stability, makes it the more promising candidate. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand A. The poor solubility and permeability of both compounds would need to be addressed, but these are formulation challenges that are often easier to tackle than fundamental issues with toxicity or metabolic instability.

Output:
0
2025-04-17 14:11:35,287 - INFO - Batch 276 complete. Total preferences: 4416
2025-04-17 14:11:35,287 - INFO - Processing batch 277/512...
2025-04-17 14:12:16,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.259 Da) is slightly higher than Ligand B (378.372 Da), but both are acceptable.

**TPSA:** Ligand A (65.07) is better than Ligand B (86.71). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.536, B: 1.824), falling within the optimal range of 1-3.

**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:** Both ligands have good QED scores (A: 0.704, B: 0.837), indicating good drug-like properties.

**DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (50.64). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (83.288) is better than Ligand B (66.615).

**Caco-2 Permeability:** Ligand A (-4.116) is significantly worse than Ligand B (-5.113), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.559 and -3.975 respectively), which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.333) has a lower hERG risk than Ligand B (0.794), which is a positive attribute.

**Microsomal Clearance:** Ligand B (21.673) has significantly lower microsomal clearance than Ligand A (72.033), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-22.245) has a slightly better in vitro half-life than Ligand A (-25.032).

**P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux than Ligand B (0.08), which is favorable.

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is the most important factor for an enzyme target, and the 1.9 kcal/mol difference is substantial.

**Conclusion:**

Despite Ligand A having a slightly better BBB and lower hERG risk, Ligand B is the superior candidate. The significantly stronger binding affinity (-10.3 vs -8.4 kcal/mol) and much better metabolic stability (lower Cl_mic) outweigh the slightly higher DILI risk and lower P-gp. The poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:12:16,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.447 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.31) is better than Ligand B (40.62), both are well below the 140 threshold for oral absorption.

**logP:** Ligand B (3.372) is optimal (1-3), while Ligand A (0.57) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0), both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (2), both are within the acceptable limit of <=10.

**QED:** Ligand B (0.737) is better than Ligand A (0.509), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (14.851 vs 15.2), both are good (<40).

**BBB:** Ligand B (91.663) is significantly better than Ligand A (50.679), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have the same Caco-2 permeability (-4.644).

**Aqueous Solubility:** Ligand A (-0.215) is better than Ligand B (-3.21), indicating better solubility.

**hERG Inhibition:** Ligand A (0.209) is better than Ligand B (0.444), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (50.939) is better than Ligand A (24.657), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.682) is better than Ligand B (2.232), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.029) is better than Ligand B (0.277), indicating lower efflux.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8), although the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B has a better QED, logP, metabolic stability (Cl_mic), and binding affinity. However, Ligand A has better solubility, hERG risk, half-life, and P-gp efflux. The slight advantage in binding affinity of Ligand B, combined with its better metabolic stability, is crucial for an enzyme target. The lower logP of Ligand A is a concern, potentially impacting absorption. The better solubility and hERG profile of Ligand A are beneficial, but can potentially be addressed through further optimization.

Output:
1
2025-04-17 14:12:16,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.377 and 354.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is well below the 140 threshold for oral absorption and even below 90 for CNS penetration, while Ligand B (126.46) is still within acceptable limits but less favorable.

**logP:** Ligand A (2.279) is optimal (1-3), while Ligand B (-0.007) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 7 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED scores (0.817 and 0.507), indicating good drug-like properties.

**DILI:** Ligand A (93.835) has a high DILI risk, which is a significant concern. Ligand B (54.634) has a much lower, and acceptable, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (62.233) is better than Ligand B (30.167).

**Caco-2 Permeability:** Ligand A (-4.587) has poor Caco-2 permeability, suggesting absorption issues. Ligand B (-5.396) is similarly poor.

**Aqueous Solubility:** Ligand A (-4.534) has poor solubility, while Ligand B (-1.281) is slightly better, but still not ideal.

**hERG:** Ligand A (0.519) has a slightly elevated hERG risk, but Ligand B (0.049) is very low, a significant advantage.

**Microsomal Clearance:** Ligand A (74.079) has higher clearance, indicating lower metabolic stability. Ligand B (28.316) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.517) has a very short half-life, a major drawback. Ligand B (0.051) has a very short half-life as well.

**P-gp Efflux:** Ligand A (0.209) has lower P-gp efflux, which is favorable. Ligand B (0.08) is even lower, which is even more favorable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.6 kcal/mol) - a difference of 1.7 kcal/mol, which is substantial.

**Conclusion:**

Despite Ligand A's better TPSA and P-gp efflux, its high DILI risk, poor solubility, poor Caco-2 permeability, short half-life, and weaker binding affinity make it a less desirable candidate. Ligand B, while having a slightly lower logP and higher TPSA, exhibits a significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and lower hERG risk. The superior binding affinity and improved safety profile of Ligand B outweigh its slightly less optimal physicochemical properties.

Output:
1
2025-04-17 14:12:16,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.36 and 349.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.24) is well below the 140 threshold for good absorption. Ligand B (104.81) is still acceptable, but less optimal.

**logP:** Ligand A (2.544) is within the optimal 1-3 range. Ligand B (-0.671) is below 1, which could hinder permeation.

**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 are within the acceptable range (<=10).

**QED:** Ligand A (0.691) has a good drug-likeness score, exceeding 0.5. Ligand B (0.389) is below 0.5, indicating a less desirable drug-like profile.

**DILI:** Ligand A (76.192) has a higher DILI risk than Ligand B (42.924), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.974) and Ligand B (20.512) are both relatively low.

**Caco-2:** Both ligands have negative Caco-2 values (-4.777 and -5.124), which is unusual and suggests poor permeability. This is a significant concern.

**Solubility:** Both ligands have negative solubility values (-3.983 and -2.293), also unusual and concerning. This suggests very poor aqueous solubility.

**hERG:** Ligand A (0.834) has a lower hERG risk than Ligand B (0.022), which is a significant advantage.

**Microsomal Clearance:** Ligand A (43.452) has a higher microsomal clearance than Ligand B (-8.94). A negative clearance is not physically possible, so this value for Ligand B is likely an error or an indication of very high stability.

**In vitro Half-Life:** Ligand A (-10.421) has a negative half-life, which is not physically possible. Ligand B (-15.997) also has a negative half-life, indicating an issue with the data.

**P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux than Ligand B (0.024), which is preferable.

**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, while not huge, could be enough to outweigh some of the ADME drawbacks.

**Overall Assessment:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility, indicated by the negative values. The negative half-life and clearance values for Ligand B are particularly concerning and suggest data errors. Ligand A has better QED, hERG risk, and binding affinity. While Ligand A's DILI risk is higher, it's still within an acceptable range. Considering the enzyme-specific priorities, the slightly better affinity of Ligand A, combined with its more favorable hERG profile and QED, makes it the more promising candidate *despite* the permeability and solubility concerns. These concerns would need to be addressed through further optimization, but the starting point is better with Ligand A.

Output:
0
2025-04-17 14:12:16,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (367.398 and 368.449 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (92.7) is slightly above the preferred <140, but acceptable. Ligand B (56.59) is well within the optimal range.

**3. logP:** Ligand A (2.124) is within the optimal 1-3 range. Ligand B (3.456) is slightly higher, but still acceptable.

**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, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.816) has a better QED score than Ligand B (0.749), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.013) has a higher DILI risk than Ligand B (13.843). This is a significant concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.076) has a higher BBB percentile than Ligand A (49.05), but this isn't a major factor here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the value for Ligand A (-4.891) is less negative than Ligand B (-4.994), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.249) is slightly better than Ligand B (-3.818).

**11. hERG Inhibition:** Ligand A (0.698) has a lower hERG inhibition liability than Ligand B (0.856), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (3.412) has a significantly lower Cl_mic than Ligand B (52.564), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life (t1/2):** Ligand A (48.31) has a much longer half-life than Ligand B (2.006), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux liability than Ligand B (0.589), which is favorable for oral bioavailability.

**15. 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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A presents a more favorable ADME profile, particularly regarding metabolic stability (Cl_mic and t1/2) and DILI risk. The substantial difference in binding affinity (-1.1 kcal/mol) is a significant factor. For an enzyme target like SRC kinase, potency is paramount. Although Ligand A has a higher DILI risk, the difference in binding affinity is large enough to potentially overcome this issue through further optimization. The poor solubility and permeability of both compounds would need to be addressed, but these are often easier to improve than potency.

Output:
1
2025-04-17 14:12:16,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzyme targets: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.483 and 350.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (59.39), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.891 and 2.29) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1 each). Ligand B has a slightly higher HBA count (5 vs 2 for A), but both are under the 10 threshold.

**QED:** Both ligands have good QED scores (0.596 and 0.694), indicating good drug-likeness.

**DILI:** Ligand A (16.789) has a much lower DILI risk than Ligand B (8.143). This is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (75.572) is better than Ligand A (65.801). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.776 and -4.808), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.496) is slightly better than Ligand B (-1.413), but both are poor. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.254) shows much lower hERG inhibition liability than Ligand B (0.791). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Both have similar microsomal clearance values (40.554 and 43.118), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-15.106) has a longer in vitro half-life than Ligand B (-5.921), suggesting better metabolic stability.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux liability than Ligand B (0.298).

**Binding Affinity:** Ligand B (0.0) has a better binding affinity than Ligand A (-7.5). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme target. However, Ligand A has a much better safety profile (lower DILI and hERG) and slightly better metabolic stability and permeability. The poor solubility of both is a concern, but can potentially be addressed through formulation strategies. Given the substantial binding affinity advantage of Ligand B, I would prioritize it despite the slightly higher risk profile.

Output:
1
2025-04-17 14:12:16,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.845 Da and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.86) is better than Ligand B (79.54), both are acceptable but lower is better for absorption.

**logP:** Both ligands have good logP values (2.892 and 1.682), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while 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 (0.591 and 0.777), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 67.119, which is moderately high. Ligand B has a much lower DILI risk of 35.479, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Ligand A (68.282) and Ligand B (90.151). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B is better here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.605 and -4.968). 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:** Ligand A (-4.235) and Ligand B (-1.831). Both have poor solubility. Ligand B is better.

**hERG Inhibition:** Ligand A (0.413) is better than Ligand B (0.077), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (66.094) has a higher microsomal clearance than Ligand B (24.249), suggesting lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (19.032) has a longer half-life than Ligand B (10.028), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.432 and 0.079).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.3 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B is the superior candidate. While both have excellent binding affinity, Ligand B demonstrates significantly better ADME properties. Specifically, its much lower DILI risk and lower microsomal clearance are crucial advantages for an enzyme inhibitor. Although both have poor solubility and permeability, the lower clearance and DILI risk of Ligand B outweigh the slightly longer half-life of Ligand A. The slightly better hERG profile of Ligand A is not enough to compensate for the ADME advantages of Ligand B.

Output:
1
2025-04-17 14:12:16,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.397 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold for good absorption, and even favorable for potential CNS penetration. Ligand B (78.87) is still acceptable, but less optimal.

**logP:** Both ligands have good logP values (2.042 and 1.433), 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 good QED scores (0.621 and 0.728), indicating drug-like properties.

**DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (23.342), which is a major advantage.

**BBB:** Ligand A (91.47) shows good BBB penetration, while Ligand B (43.311) does not. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.598) has a lower Caco-2 permeability than Ligand B (-5.016). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.462) has better aqueous solubility than Ligand B (-1.382).

**hERG:** Both ligands have low hERG inhibition liability (0.367 and 0.304), which is excellent.

**Microsomal Clearance:** Ligand A (22.188) has lower microsomal clearance than Ligand B (33.628), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.787) has a longer in vitro half-life than Ligand B (15.185), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.04 and 0.098).

**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.

**Overall Assessment:**

Ligand A is superior due to its lower DILI risk, better solubility, lower microsomal clearance, longer half-life, and better BBB penetration. While Caco-2 permeability is poor for both, the other advantages of Ligand A outweigh this drawback, particularly the improved safety profile (DILI) and metabolic stability. The binding affinity difference is minimal.

Output:
1
2025-04-17 14:12:16,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.463 and 343.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is better than Ligand B (58.56), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.034 and 3.741), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for off-target effects, but isn't a major issue.

**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:** Both ligands have excellent QED scores (0.839 and 0.868), indicating good drug-like properties.

**DILI:** Ligand A (68.437) has a higher DILI risk than Ligand B (61.031), but both are acceptable.

**BBB:** Ligand A (77.627) has better BBB penetration than Ligand B (45.56), but BBB isn't a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.063) has worse Caco-2 permeability than Ligand B (-4.888), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.558 and -4.345). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.671) has a slightly higher hERG risk than Ligand B (0.495), but both are relatively low.

**Microsomal Clearance:** Ligand B (22.026 mL/min/kg) has significantly lower microsomal clearance than Ligand A (68.387 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (20.328 hours) has a longer in vitro half-life than Ligand A (43.752 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.234 and 0.186).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol, so it doesn't outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has slightly better binding affinity and BBB penetration, Ligand B exhibits significantly better metabolic stability (lower Cl_mic) and a longer half-life. The solubility is poor for both, but metabolic stability is a critical factor for kinase inhibitors. The slightly lower DILI risk for Ligand B is also a positive.

Output:
1
2025-04-17 14:12:16,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 and 348.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.66) is better than Ligand B (59.08), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (1.557) is better than Ligand A (0.692). Ligand A is a bit low, potentially hindering permeation. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While both are acceptable, a small number of HBDs can sometimes improve permeability.

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

**QED:** Both ligands have acceptable QED values (0.827 and 0.774, both > 0.5).

**DILI:** Both ligands have very similar, and acceptable, DILI risk (21.91 and 21.17, both < 40).

**BBB:** Ligand A (88.29) has a significantly better BBB penetration percentile than Ligand B (64.72). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.437) has worse Caco-2 permeability than Ligand B (-4.392). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.892) has better aqueous solubility than Ligand B (-2.069). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.463 and 0.268, both low risk).

**Microsomal Clearance:** Ligand A (-6.025) has significantly better metabolic stability (lower clearance) than Ligand B (57.924). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (17.951 hours) has a better in vitro half-life than Ligand B (8.58 hours). This is also a strong advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.037).

**Binding Affinity:** Ligand A (-9.4 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.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has a slightly better logP and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-9.4 vs -7.9 kcal/mol), better metabolic stability (lower Cl_mic), and longer half-life are critical advantages for an enzyme target like SRC kinase. The slightly lower logP of Ligand A is a manageable concern, especially given the substantial potency gain.

Output:
1
2025-04-17 14:12:16,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.422 and 349.395 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (118.03). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (1.568) is optimal, while Ligand B (0.312) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.822 and 0.673), indicating good drug-like properties.

**DILI:** Ligand A (51.648) has a much lower DILI risk than Ligand B (72.703). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (82.435) has a better BBB percentile than Ligand B (30.787).

**Caco-2 Permeability:** Ligand A (-4.761) 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.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.581 and -2.369). This is a concern, but formulation strategies might mitigate it.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.41 and 0.13), which is excellent.

**Microsomal Clearance:** Ligand A (22.258) has significantly lower microsomal clearance than Ligand B (58.4), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-7.667) has a much longer in vitro half-life than Ligand B (-26.847), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.128 and 0.046).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is significantly better due to its superior TPSA, logP, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better BBB penetration. While both have poor solubility and Caco-2 permeability, the ADME advantages of Ligand A, particularly its metabolic stability, outweigh these concerns. The binding affinity is comparable.

Output:
1
2025-04-17 14:12:16,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (389.503 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.36) is slightly above the preferred <140 for good absorption, while Ligand B (87.32) is well within the range.

**logP:** Ligand A (-0.625) is a bit low, potentially hindering permeation. Ligand B (1.641) is closer to 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, but Ligand B is slightly better.

**QED:** Both ligands have good QED scores (0.543 and 0.794), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (52.074 and 40.287), below the 60 threshold.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (52.966) is slightly better than Ligand A (41.334).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.841 and -4.789), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.32 and -3.089), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.08 and 0.254), which is excellent.

**Microsomal Clearance:** Ligand B (-10.973) has significantly lower (better) microsomal clearance than Ligand A (14.951), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-20.561) has a longer in vitro half-life than Ligand A (-18.341), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.017 and 0.034).

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-5.9), a difference of 1.5 kcal/mol. This is a significant advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B has superior ADME properties, particularly regarding metabolic stability (lower Cl_mic, longer t1/2) and a more favorable logP. The poor solubility and permeability of both compounds are major concerns, but the stronger binding of Ligand A might be able to overcome these issues with formulation strategies. However, the metabolic stability of Ligand B is a significant advantage for an enzyme target. Given the enzyme-specific priorities, the improved metabolic stability of Ligand B is more valuable than the slightly better binding affinity of Ligand A.

Output:
1
2025-04-17 14:12:16,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.342 and 345.418 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.52) is higher than Ligand B (43.86). While both are below 140, the lower TPSA of Ligand B is generally more favorable for absorption.

**logP:** Both ligands have good logP values (1.842 and 0.837), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.769) has a significantly better QED score than Ligand B (0.431), indicating a more drug-like profile.

**DILI:** Ligand A (83.792) has a much higher DILI risk than Ligand B (21.055). This is a significant concern for Ligand A.

**BBB:** Ligand A (43.466) and Ligand B (78.79) both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.098) has poor Caco-2 permeability, while Ligand B (-4.681) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-3.047) and Ligand B (-2.102) both have poor aqueous solubility.

**hERG:** Ligand A (0.055) has a very low hERG risk, which is excellent. Ligand B (0.393) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-40.178) has a significantly lower (better) microsomal clearance than Ligand B (9.639), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.785) has a longer in vitro half-life than Ligand B (-30.593), which is desirable.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, while Ligand B (0.086) is slightly higher.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A has a substantially better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. However, it has a significantly higher DILI risk and poorer Caco-2 permeability. Ligand B has a lower DILI risk and slightly better Caco-2 permeability, but weaker binding affinity and poorer metabolic stability.

The difference in binding affinity (-8.6 vs -7.4 kcal/mol) is substantial (1.2 kcal/mol), and this is a primary driver for enzyme inhibitors. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications. The poor solubility and permeability of both compounds are also areas for optimization, but can be addressed with formulation strategies. The superior affinity and metabolic stability of Ligand A outweigh its drawbacks, making it the more promising candidate.

Output:
1
2025-04-17 14:12:16,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.547) is slightly lower, which could be beneficial for permeability. Ligand B (404.363) is also acceptable.

**TPSA:** Ligand A (84.5) is well below the 140 threshold for oral absorption. Ligand B (47.36) is excellent, indicating good potential for absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.591) is slightly better positioned. Ligand B (4.636) is approaching the upper limit and could potentially have solubility issues.

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

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.684, Ligand B: 0.573), indicating good drug-like properties.

**DILI:** Ligand A (18.534) has a significantly lower DILI risk than Ligand B (47.732). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (81.582) is better than Ligand B (71.229). While not a primary concern for a kinase inhibitor, it's a slight positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.369) has a negative value, which is unusual and likely indicates very poor permeability. Ligand B (-5.021) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.155 and -3.635), indicating poor aqueous solubility. This is a concern for both, but potentially more so for Ligand B given its higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.477 and 0.693), which is excellent.

**Microsomal Clearance:** Ligand A (82.02) has a higher microsomal clearance than Ligand B (71.94). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-27.972) has a very short in vitro half-life, indicating rapid metabolism. Ligand B (77.62) has a much longer half-life, a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.048 and 0.851), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent and strong enough to overcome some ADME deficiencies.

**Overall Assessment:**

Ligand A has a significantly lower DILI risk and better BBB penetration, but suffers from very poor Caco-2 permeability and a very short half-life. Ligand B has a longer half-life and better metabolic stability, but a higher DILI risk and slightly worse permeability. Given the importance of metabolic stability for kinase inhibitors, and the equal binding affinity, Ligand B is the more promising candidate despite the higher DILI. The poor permeability of both is a concern, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:12:16,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 Da and 348.399 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (70.08) is significantly better than Ligand B (108.64). A TPSA under 90 is generally preferred, and Ligand A is comfortably within this range, suggesting better permeability. Ligand B is pushing the upper limit.

**logP:** Both ligands have good logP values (1.414 and 1.157), 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 donors and acceptors, which generally improves permeability. Both are within acceptable limits.

**QED:** Ligand A (0.831) has a substantially higher QED score than Ligand B (0.611), indicating a more drug-like profile.

**DILI:** Ligand A (9.616%) has a much lower DILI risk than Ligand B (35.673%). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (54.478%) is slightly better than Ligand B (44.009%).

**Caco-2 Permeability:** Ligand A (-4.508) is better than Ligand B (-5.129), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.965) is better than Ligand B (-1.924), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.385) has a lower hERG risk than Ligand B (0.149), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (14.374) has a higher (worse) microsomal clearance than Ligand B (-2.775). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (16.542) has a longer in vitro half-life than Ligand A (10.521), which is favorable.

**P-gp Efflux:** Ligand A (0.118) has lower P-gp efflux than Ligand B (0.063), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 kcal/mol and -8.2 kcal/mol). The difference of 0.5 kcal/mol is unlikely to outweigh the other significant ADME differences.

**Overall:**

Ligand A is superior in almost all ADME properties (TPSA, QED, DILI, Solubility, hERG, P-gp efflux, Caco-2 permeability) and has comparable binding affinity. While Ligand B has better metabolic stability and half-life, the significant advantages of Ligand A in safety (DILI, hERG) and absorption/distribution outweigh these benefits.

Output:
1
2025-04-17 14:12:16,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.406 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.64) is better than Ligand B (84.23) as it is closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.522 and 2.99 respectively), falling within the 1-3 optimal range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not critically.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.869 and 0.743), indicating good drug-like properties.

**DILI:** Ligand A (36.254) has a significantly lower DILI risk than Ligand B (41.877), making it more favorable. Both are below the 40 threshold.

**BBB:** Both have good BBB penetration (78.48 and 71.074), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.769 and -4.665), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.721 and -3.557) indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.544) has a lower hERG risk than Ligand B (0.133). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (5.875) has a much lower microsomal clearance than Ligand B (68.328). This indicates better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-12.101) has a better (longer) in vitro half-life than Ligand B (-15.859).

**P-gp Efflux:** Ligand A (0.037) has a lower P-gp efflux liability than Ligand B (0.123).

**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. A >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand B's significantly superior binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) is a decisive factor. While Ligand A has better ADME properties (lower DILI, hERG, Cl_mic, Pgp, and better half-life), the potency difference is too large to ignore for an enzyme target like SRC kinase. Improving ADME properties is often achievable through further optimization, but significantly improving binding affinity is much more challenging.

Output:
1
2025-04-17 14:12:16,052 - INFO - Batch 277 complete. Total preferences: 4432
2025-04-17 14:12:16,052 - INFO - Processing batch 278/512...
2025-04-17 14:13:04,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.463 and 364.555 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (79.31) is better than Ligand B (49.41), both are below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (0.674) is a bit low, potentially hindering permeation, while Ligand B (3.392) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.647 and 0.705, respectively), indicating drug-likeness.

**DILI:** Ligand A (20.512) has a significantly lower DILI risk than Ligand B (33.307), which is a major advantage.

**BBB:** Both have moderate BBB penetration (53.548 and 58.24), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.45) and Ligand B (-4.98) have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Solubility:** Ligand A (-0.594) has slightly better solubility than Ligand B (-4.112), although both are quite poor.

**hERG:** Both ligands have low hERG risk (0.26 and 0.32).

**Microsomal Clearance:** Ligand A (45.649) has significantly lower microsomal clearance than Ligand B (75.586), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.83) has a longer half-life than Ligand B (6.893).

**P-gp Efflux:** Both have low P-gp efflux (0.032 and 0.278).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.3 and -8.4 kcal/mol).

**Conclusion:**

While both ligands have good binding affinity, Ligand A is the more promising candidate. Its lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility outweigh the slightly lower logP and Caco-2 permeability. The similar binding affinities mean the ADME properties become the deciding factor.

Output:
0
2025-04-17 14:13:04,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.901 and 384.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.34) is significantly better than Ligand B (75.19). A TPSA under 140 is good for oral absorption, and both are under, but A is preferable.

**logP:** Both ligands have acceptable logP values (3.87 and 2.357), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 6 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar QED scores (0.694 and 0.662), indicating good drug-likeness.

**DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (32.183), which is a significant advantage.

**BBB:** Ligand A (78.092) has better BBB penetration than Ligand B (65.839), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.632) has a worse Caco-2 permeability than Ligand B (-5.428). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.684) has slightly better aqueous solubility than Ligand B (-2.269).

**hERG Inhibition:** Ligand A (0.834) has a lower hERG inhibition liability than Ligand B (0.257), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (37.903) has a lower microsomal clearance than Ligand B (55.055), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (9.941 and 9.23 hours).

**P-gp Efflux:** Ligand A (0.335) has lower P-gp efflux liability than Ligand B (0.225).

**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 difference (1.4 kcal/mol), and a key factor.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic). The difference in binding affinity is significant, but the ADME/Tox advantages of Ligand A are substantial. Given the enzyme-kinase target class, prioritizing metabolic stability and minimizing off-target effects (hERG, DILI) is crucial. The improved ADME properties of Ligand A, coupled with a still-strong binding affinity, make it the more promising candidate.

Output:
0
2025-04-17 14:13:04,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 354.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.0) is better than Ligand B (33.2). While both are reasonably low, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (2.147) is optimal (1-3), while Ligand B (4.861) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.75 and 0.742), indicating good drug-likeness.

**DILI:** Ligand A (33.773) has a slightly higher DILI risk than Ligand B (23.885), but both are below the concerning threshold of 60.

**BBB:** Ligand B (91.508) has a significantly higher BBB penetration percentile than Ligand A (68.67). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.855) and Ligand B (-5.001) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.063 and -4.517). This is a major drawback.

**hERG Inhibition:** Ligand A (0.142) has a much lower hERG inhibition liability than Ligand B (0.785), which is a significant advantage.

**Microsomal Clearance:** Ligand B (89.668) has a much higher microsomal clearance than Ligand A (26.163), indicating poorer metabolic stability. This is a critical disadvantage for Ligand B.

**In vitro Half-Life:** Ligand B (15.592) has a longer in vitro half-life than Ligand A (10.791), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux liability than Ligand B (0.585), which is beneficial.

**Binding Affinity:** Ligand B (-9.9 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 concerns.

**Conclusion:**

Despite the superior binding affinity of Ligand B, the significant drawbacks of high logP, high microsomal clearance, and higher hERG inhibition liability make it a less favorable candidate. Ligand A, while having a weaker binding affinity, exhibits better physicochemical properties regarding logP, metabolic stability, and hERG risk. The poor solubility and Caco-2 permeability are concerning for both, but could potentially be addressed with formulation strategies. Given the enzyme-kinase specific priorities, the improved metabolic stability and reduced toxicity risk of Ligand A are more important than the higher binding affinity of Ligand B.

Output:
0
2025-04-17 14:13:04,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.435 and 345.334 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (106.0 and 108.05) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.535) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.196) is closer to the lower end of the optimal range.

**H-Bond Donors & Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (2 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.522 and 0.823), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (14.696) has a very favorable DILI score, indicating low liver injury risk. Ligand B (69.756) has a significantly higher DILI score, raising a concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (19.077) and Ligand B (55.603) are not particularly relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.441 and -4.913), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (0.006) has extremely poor solubility, a major concern for bioavailability. Ligand B (-2.983) also has poor solubility, but is slightly better than Ligand A.

**hERG:** Both ligands have low hERG inhibition liability (0.21 and 0.29), which is good.

**Microsomal Clearance:** Ligand A (-14.241) has a lower (better) microsomal clearance, suggesting better metabolic stability than Ligand B (-15.203).

**In vitro Half-Life:** Ligand A (22.514) has a longer in vitro half-life than Ligand B (-21.238), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.008).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.3 and -8.6 kcal/mol), which are both excellent.

**Overall Assessment:**

Ligand A has a significantly better DILI score and in vitro half-life, and slightly better metabolic stability. However, its aqueous solubility is extremely poor, and its logP is suboptimal. Ligand B has a higher DILI risk and shorter half-life, but its solubility is slightly better. The binding affinities are comparable. Given the importance of metabolic stability and solubility for an enzyme target, and the very poor solubility of Ligand A, Ligand B is the slightly more promising candidate despite the higher DILI risk. The DILI risk could be addressed with further structural modifications.

Output:
1
2025-04-17 14:13:04,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.571 and 375.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (91.06). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.503) is slightly higher than the optimal range of 1-3, but still acceptable. Ligand B (1.317) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 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 reasonable QED scores (0.459 and 0.575), indicating acceptable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (20.008) has a much lower DILI risk than Ligand B (37.999). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (55.719) and Ligand B (44.785) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.905) shows better Caco-2 permeability than Ligand B (-5.549), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.204) has better aqueous solubility than Ligand B (-2.288). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.391 and 0.199), which is excellent.

**Microsomal Clearance:** Ligand A (47.518) has higher microsomal clearance than Ligand B (9.667). This means Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-1.31) has a negative half-life, which is not physically possible and indicates a problem with the data or the model. Ligand A (33.13) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.28 and 0.055), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.3 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has advantages in TPSA, DILI risk, Caco-2 permeability, solubility, and in vitro half-life. Ligand B has a slight advantage in binding affinity and metabolic stability. However, the negative half-life for Ligand B is a major red flag, suggesting a data quality issue or a fundamentally unstable molecule. The significantly lower DILI risk for Ligand A is also a strong positive. Given the importance of metabolic stability for kinase inhibitors, the difference in Cl_mic is notable, but the negative half-life of B overrides this.

Output:
1
2025-04-17 14:13:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.41 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (90.54 and 93.37) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (though that's not a priority here).

**logP:** Ligand A (0.019) is very low, potentially hindering permeation. Ligand B (0.667) is better, though still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.5 (0.589 and 0.602), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (42.458 and 46.801), below the 60 threshold.

**BBB:** Both have moderate BBB penetration (62.699 and 65.297), which isn't a major concern for a non-CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.051 and -4.817), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-1.89 and -1.027), also concerning, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.116) has a very low hERG risk, which is excellent. Ligand B (0.226) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A has a very low (good) Cl_mic (-18.494 mL/min/kg), suggesting high metabolic stability. Ligand B has a higher Cl_mic (9.806 mL/min/kg), indicating faster metabolism.

**In vitro Half-Life:** Ligand A has a short half-life (-5.959 hours), which is not ideal. Ligand B has a much longer half-life (15.025 hours), a significant advantage.

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.017), which is good. Ligand B has slightly higher efflux (0.051).

**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 difference.

**Overall Assessment:**

Ligand B is the better candidate despite some drawbacks. The primary driver is its significantly stronger binding affinity (-6.5 kcal/mol vs 0.0 kcal/mol). The longer half-life (15.025 hours) is also a major advantage, outweighing the slightly higher Cl_mic and P-gp efflux. While both ligands have poor Caco-2 and solubility, the strong binding and improved metabolic stability of Ligand B make it more likely to be optimized into a viable drug candidate. The low logP of Ligand A is a significant detriment.

Output:
1
2025-04-17 14:13:04,902 - INFO - Okay, let's analyze these two ligands for their potential as drug candidates targeting SRC, a kinase.

**Ligand A:** [349.37 , 117.59 ,   0.387,   3.   ,   6.   ,   0.637,  57.852,  59.597, -5.432,  -2.586,   0.113,  -1.132, -26.275,   0.026,  -7.8  ]
**Ligand B:** [388.53 ,  49.85 ,   2.637,   0.   ,   5.   ,   0.752,  58.434,  88.678, -4.412,  -3.364,   0.605,  76.861,   9.349,   0.519,   0.   ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (349.37) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (117.59) is better than B (49.85). While both are reasonably low, A is closer to the 140 threshold for good oral absorption.
3. **logP:** B (2.637) is optimal (1-3). A (0.387) is quite low, potentially hindering membrane permeability. This is a significant drawback for A.
4. **HBD:** A (3) is acceptable, B (0) is excellent.
5. **HBA:** Both A (6) and B (5) are within the acceptable limit of 10.
6. **QED:** Both A (0.637) and B (0.752) are good, indicating drug-like properties. B is slightly better.
7. **DILI:** Both A (57.852) and B (58.434) are similar and acceptable (below 60).
8. **BBB:** B (88.678) is much higher than A (59.597). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.
9. **Caco-2:** A (-5.432) is very poor, indicating extremely low intestinal absorption. B (-4.412) is also poor, but better than A.
10. **Solubility:** A (-2.586) is poor, while B (-3.364) is also poor. Both are concerning, but B is slightly better.
11. **hERG:** A (0.113) is very low risk, excellent. B (0.605) is higher, but still relatively low risk.
12. **Cl_mic:** A (-1.132) is excellent (negative value indicates low clearance/high stability). B (76.861) is high, suggesting rapid metabolism. This is a major drawback for B.
13. **t1/2:** A (-26.275) is excellent (very long half-life). B (9.349) is reasonable, but significantly shorter than A.
14. **Pgp:** A (0.026) is very low efflux, excellent. B (0.519) is higher, indicating some P-gp efflux.
15. **Affinity:** A (-7.8) is significantly better than B (0.0). A has a strong binding affinity.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and excellent metabolic stability (low Cl_mic, long t1/2), and low Pgp efflux. However, its low logP and poor Caco-2 permeability are major concerns. Ligand B has a better logP and Caco-2, but suffers from high metabolic clearance and a much weaker binding affinity.

The strong binding affinity of Ligand A is a significant advantage that could potentially outweigh its permeability issues, *especially* if formulation strategies can be employed to improve solubility and absorption. The poor metabolic stability of Ligand B is a more difficult hurdle to overcome.

Therefore, despite its permeability concerns, **Ligand A is the more promising candidate.** Further optimization efforts should focus on improving its logP and solubility while maintaining its strong binding affinity.

1
2025-04-17 14:13:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.523 and 364.421 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is better than Ligand B (61.92), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.31) is optimal, while Ligand B (3.528) is approaching the upper limit.

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

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

**QED:** Both ligands have good QED scores (0.68 and 0.788, respectively), indicating drug-likeness.

**DILI:** Ligand A (3.955) has a significantly lower DILI risk than Ligand B (45.25). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (90.112) is higher than Ligand A (70.648). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.148) has poor Caco-2 permeability, while Ligand B (-4.439) is slightly better but still poor.

**Aqueous Solubility:** Ligand A (-0.948) has better solubility than Ligand B (-4.984).

**hERG Inhibition:** Ligand A (0.442) has a lower hERG risk than Ligand B (0.574), which is preferable.

**Microsomal Clearance:** Ligand A (-2.816) has much lower microsomal clearance, indicating better metabolic stability, a crucial factor for kinase inhibitors. Ligand B (45.673) has high clearance.

**In vitro Half-Life:** Ligand A (-11.863) has a longer in vitro half-life than Ligand B (14.986), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, while Ligand B (0.39) has moderate efflux.

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Conclusion:**

Despite similar binding affinities, Ligand A is the superior candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, lower hERG risk, and lower P-gp efflux outweigh Ligand B's slightly better BBB penetration and Caco-2 permeability. The enzyme-specific priorities clearly favor Ligand A.

Output:
0
2025-04-17 14:13:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (392.815 and 359.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.33) is better than Ligand B (29.77) as it is closer to the 140 A^2 threshold.

**logP:** Both ligands have good logP values (3.004 and 3.623), within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to slight solubility issues, but not a major concern.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.697 and 0.788), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 77.2, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 30.826, which is preferable.

**BBB:** Both ligands have high BBB penetration (81.078 and 83.676), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.848) has poor Caco-2 permeability, while Ligand B (-5.293) is also poor.

**Aqueous Solubility:** Ligand A (-3.685) has poor solubility, while Ligand B (-2.953) is also poor.

**hERG Inhibition:** Ligand A (0.595) has a slightly higher hERG risk than Ligand B (0.957), but both are relatively low.

**Microsomal Clearance:** Ligand A (59.301) has a lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (72.926).

**In vitro Half-Life:** Ligand B (27.873) has a slightly longer in vitro half-life than Ligand A (23.512).

**P-gp Efflux:** Ligand A (0.369) has lower P-gp efflux than Ligand B (0.764), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.8 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B is the better candidate. While both ligands have excellent binding affinity, Ligand B has a significantly lower DILI risk, a slightly longer half-life, and lower P-gp efflux. Although both have poor Caco-2 permeability and solubility, the lower DILI risk is a critical advantage. The slightly better metabolic stability of Ligand A is outweighed by its higher DILI risk and worse P-gp efflux.

Output:
1
2025-04-17 14:13:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (382.247 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.22) is better than Ligand B (72.88) as both are below the 140 threshold for good absorption.

**3. logP:** Ligand A (3.035) is optimal (1-3), while Ligand B (0.623) 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:** Ligand A (0.721) has a better QED score than Ligand B (0.473), indicating a more drug-like profile.

**7. DILI:** Ligand B (5.118) has a significantly lower DILI risk than Ligand A (87.786), which is a major concern.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (36.022) and Ligand B (20.357) are both low.

**9. Caco-2 Permeability:** Ligand A (-5.542) and Ligand B (-4.884) are both negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.058) and Ligand B (-0.817) are both negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.029) has a slightly better hERG profile than Ligand B (0.074), but both are very low risk.

**12. Microsomal Clearance:** Ligand B (-7.553) has a significantly *lower* (better) microsomal clearance than Ligand A (17.902), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (0.822) has a slightly better in vitro half-life than Ligand A (-4.287).

**14. P-gp Efflux:** Ligand A (0.052) has a slightly better P-gp efflux profile than Ligand B (0.008).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a slightly better QED and a marginally better hERG profile, Ligand B is the superior candidate. The most critical factors are the significantly lower DILI risk, the much better metabolic stability (lower Cl_mic, longer t1/2), and the stronger binding affinity of Ligand B. The slightly lower logP of Ligand B is a drawback, but the strong affinity can likely compensate for this. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The DILI risk for Ligand A is unacceptably high.

Output:
1
2025-04-17 14:13:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (54.34). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (2.685 and 3.282), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but not drastically.

**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 (0.72 and 0.805), indicating good drug-like properties.

**DILI:** Ligand A (32.299) has a slightly lower DILI risk than Ligand B (38.891), both are below the 40 threshold.

**BBB:** Both have reasonable BBB penetration (77.162 and 71.501), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.365 and -4.669). This is unusual and suggests poor permeability. However, these values are on a log scale and need to be interpreted cautiously.

**Aqueous Solubility:** Both have negative solubility values (-3.741 and -3.628). Again, these are on a log scale and indicate poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.458 and 0.469), which is excellent.

**Microsomal Clearance:** Ligand B (58.594) has a lower microsomal clearance than Ligand A (74.185), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (11.19 hours) has a significantly longer half-life than Ligand A (-27.34 hours). The negative value for Ligand A is concerning and likely indicates very rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.037 and 0.299).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This 0.5 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior in terms of metabolic stability (lower Cl_mic, longer t1/2), and has a better TPSA. Both have poor solubility and permeability (indicated by the negative Caco-2 and solubility values). However, for a kinase inhibitor, metabolic stability and a reasonable half-life are crucial. The 0.5 kcal/mol difference in binding affinity is unlikely to overcome the significant advantage Ligand B has in terms of pharmacokinetic properties.

Output:
1
2025-04-17 14:13:04,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 and 345.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (82.53). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have good logP values (2.296 and 1.383), falling 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:** Both have 1-4 HBD/HBA, which is acceptable.

**QED:** Both ligands have high QED scores (0.831 and 0.845), indicating good drug-like properties.

**DILI:** Ligand A (28.62) has a significantly lower DILI risk than Ligand B (33.70), which is a crucial advantage. Lower DILI is always preferred.

**BBB:** Ligand A (95.43) has much better BBB penetration than Ligand B (52.77). While SRC is not necessarily a CNS target, better BBB penetration can sometimes correlate with better overall distribution.

**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, suggesting poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.489 and 0.209), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance values (19.88 and 20.72), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-1.095) has a slightly worse in vitro half-life than Ligand B (2.634).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.022).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly better binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage, as a 1.9 kcal/mol difference in binding can outweigh minor ADME drawbacks, especially for an enzyme target.

**Conclusion:**

Despite Ligand A having better TPSA, BBB, and DILI, the significantly stronger binding affinity of Ligand B (-7.6 vs -9.5 kcal/mol) is the most important factor for an enzyme inhibitor. The potency advantage outweighs the slightly higher DILI risk and lower BBB penetration. Both have poor solubility and permeability, but this can be addressed with formulation strategies.

Output:
1
2025-04-17 14:13:04,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (359.344 and 349.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (59.0) is significantly better than Ligand B (109.78).  For good oral absorption, we want TPSA <= 140, both are within this range, but lower is preferable.

**3. logP:** Both ligands have acceptable logP values (1.876 and 0.816), falling within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 3 respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (4 and 6 respectively), being less than 10.

**6. QED:** Ligand A (0.895) has a superior QED score compared to Ligand B (0.629), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.077) has a lower DILI risk than Ligand B (49.709), both are below the 60 threshold, but A is preferable.

**8. BBB:** Ligand A (81.698) has a higher BBB penetration percentile than Ligand B (63.203). While not a primary concern for a non-CNS target like SRC, higher BBB is generally not detrimental.

**9. Caco-2 Permeability:** Ligand A (-4.504) has a better Caco-2 permeability than Ligand B (-5.186). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.697) has better aqueous solubility than Ligand B (-2.571). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.766) has lower hERG inhibition liability than Ligand B (0.217), which is a significant advantage.

**12. Microsomal Clearance (Cl_mic):** Both ligands have similar microsomal clearance (14.661 and 15.318 mL/min/kg).

**13. In vitro Half-Life:** Ligand A (-7.455) has a longer in vitro half-life than Ligand B (-7.021).

**14. P-gp Efflux:** Ligand A (0.325) has lower P-gp efflux liability than Ligand B (0.008).

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-5.9 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a key factor.

**Enzyme-Specific Priorities:** For SRC kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand A excels in all these areas. It has a significantly better binding affinity, lower hERG risk, longer half-life, better solubility, and a lower DILI risk.

Output:
1
2025-04-17 14:13:04,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (429.717 Da) is higher, but still acceptable. Ligand B (345.487 Da) is slightly preferred.

**TPSA:** Both ligands have TPSA values (50.36 and 52.65) that are acceptable for oral absorption (<=140). No significant difference here.

**logP:** Ligand A (4.985) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.483) is within the optimal range (1-3). Ligand B is preferred.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (1 HBD, 3 HBA) both fall within the acceptable limits (<=5 HBD, <=10 HBA). No strong preference.

**QED:** Both ligands have good QED scores (0.704 and 0.768), indicating drug-like properties. No significant difference.

**DILI:** Ligand A has a DILI risk of 54.634, which is acceptable (below 60). Ligand B has a very low DILI risk of 6.941, which is excellent. Ligand B is strongly preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (58.085) and Ligand B (69.794) are both moderate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.66 and -4.759), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.717 and -1.466). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.787) has a slightly higher hERG risk than Ligand B (0.244), which is preferable.

**Microsomal Clearance:** Ligand A (78.728 mL/min/kg) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (0.568 mL/min/kg) has excellent metabolic stability. Ligand B is strongly preferred.

**In vitro Half-Life:** Ligand A (37.027 hours) has a reasonable half-life. Ligand B (-0.463 hours) has a very short half-life, which is a major concern. Ligand A is preferred.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.374 and 0.037), which is good. No significant difference.

**Binding Affinity:** Ligand A (-8.3 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 B excels in metabolic stability (low Cl_mic, excellent half-life), DILI risk, and hERG inhibition. However, it has a significantly weaker binding affinity and a very short in vitro half-life. Ligand A has a superior binding affinity and a reasonable half-life, but suffers from higher DILI risk, higher logP, and poorer metabolic stability.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), the stronger binding affinity of Ligand A is a significant advantage. While its ADME properties are less ideal, optimization efforts could potentially address these issues. The very short half-life of Ligand B is a more difficult problem to overcome.

Output:
0
2025-04-17 14:13:04,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.415 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (90.38 and 93.65) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.787 and 1.037) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is slightly better than Ligand B (1 HBD, 7 HBA) in terms of balancing solubility and permeability, although both are acceptable.

**QED:** Both ligands have similar QED scores (0.697 and 0.541), indicating reasonable drug-likeness.

**DILI:** Ligand A (27.336) has a significantly lower DILI risk than Ligand B (56.572). This is a major advantage.

**BBB:** Both ligands have similar BBB penetration (64.676 and 69.717), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.468 and -5.133). 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 (-2.551 and -2.238). Similar to Caco-2, the scale is unclear.

**hERG:** Ligand A (0.577) has a slightly higher hERG risk than Ligand B (0.167), but both are relatively low.

**Microsomal Clearance:** Ligand B (28.685) has a higher microsomal clearance than Ligand A (15.17), suggesting lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (10.282) has a longer in vitro half-life than Ligand A (-6.522). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.023) has slightly lower P-gp efflux than Ligand B (0.022).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor. The difference of 7.9 kcal/mol is huge and likely outweighs any minor ADME concerns.

**Conclusion:**

Ligand A is the superior candidate. Its significantly stronger binding affinity (-7.9 vs 0.0 kcal/mol) is the most important factor. While Ligand B has a slightly better half-life, Ligand A has a much lower DILI risk and acceptable metabolic stability. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of Ligand A is overwhelming.

Output:
1
2025-04-17 14:13:04,903 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (351.466 and 346.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.43) is well below the 140 threshold for good oral absorption, and even better for kinase inhibitors. Ligand B (113.91) is still within acceptable range, but less optimal than A.

**3. logP:** Ligand A (3.119) is within the optimal range of 1-3. Ligand B (-0.028) is significantly below 1, which may hinder permeation.

**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 10 HBA. Ligand A is preferable as it is closer to the optimal limit of <=10.

**6. QED:** Both ligands have good QED values (0.707 and 0.744), indicating good drug-like properties.

**7. DILI:** Ligand A (51.881) has a slightly higher DILI risk than Ligand B (34.393), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.69) is better than Ligand B (65.335), but it's not a major deciding factor.

**9. Caco-2 Permeability:** Ligand A (-4.618) is poor, while Ligand B (-5.577) is even worse. Both are problematic, but A is slightly better.

**10. Aqueous Solubility:** Ligand A (-3.436) is poor, while Ligand B (-1.821) is also poor. Both are problematic, but B is slightly better.

**11. hERG Inhibition:** Ligand A (0.848) has a lower hERG risk than Ligand B (0.422), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (62.359) has higher clearance than Ligand B (5.06). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**13. In vitro Half-Life:** Ligand A (38.394) has a longer half-life than Ligand B (-10.814). Longer half-life is generally preferred, making Ligand A better.

**14. P-gp Efflux:** Ligand A (0.317) has lower P-gp efflux than Ligand B (0.004), indicating better bioavailability.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a crucial factor for enzyme inhibitors.

**Overall Assessment:**

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A emerges as the more promising candidate. While Ligand B has better metabolic stability (lower Cl_mic) and slightly better solubility, Ligand A's significantly stronger binding affinity (-8.4 vs -9.0 kcal/mol) outweighs these drawbacks. The slightly higher DILI risk for A is acceptable given the strong binding. The poor Caco-2 and solubility for both are concerns, but can be addressed through formulation strategies.

Output:
1
2025-04-17 14:13:04,903 - INFO - Batch 278 complete. Total preferences: 4448
2025-04-17 14:13:04,903 - INFO - Processing batch 279/512...
2025-04-17 14:13:52,946 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [361.389, 112.73 ,   0.177,   3.   ,   4.   ,   0.535,  34.82 ,  57.076, -5.228,  -2.163,   0.31 ,  17.033, -17.592,   0.042,  -8.5  ]
**Ligand B:** [338.375, 134.5  ,   1.479,   4.   ,   7.   ,   0.512,  68.282,  30.748, -6.081,  -2.76 ,   0.517,  -4.781,   3.344,   0.01 ,  -8.7  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). Ligand B (338.375) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** Ligand A (112.73) is better than Ligand B (134.5), being closer to the <140 threshold for good oral absorption.
3. **logP:** Ligand B (1.479) is better, falling within the optimal 1-3 range. Ligand A (0.177) is quite low, potentially hindering permeation.
4. **HBD:** Both have 4 HBD, which is acceptable.
5. **HBA:** Ligand A (4) is better than Ligand B (7), as lower HBA generally improves permeability.
6. **QED:** Both are similar and above the 0.5 threshold, indicating good drug-likeness.
7. **DILI:** Ligand A (34.82) has a significantly lower DILI risk than Ligand B (68.282), which is a major advantage.
8. **BBB:** Ligand A (57.076) has better BBB penetration than Ligand B (30.748), but this is less critical for a non-CNS target like SRC.
9. **Caco-2:** Ligand A (-5.228) is better than Ligand B (-6.081), indicating better intestinal absorption.
10. **Solubility:** Ligand A (-2.163) is better than Ligand B (-2.76), which is important for bioavailability.
11. **hERG:** Both are relatively low, but Ligand B (0.517) is slightly higher than Ligand A (0.31).
12. **Cl_mic:** Ligand B (-4.781) has a *much* lower (better) microsomal clearance than Ligand A (17.033), suggesting greater metabolic stability.
13. **t1/2:** Ligand B (3.344) has a longer in vitro half-life than Ligand A (-17.592), which is a positive.
14. **Pgp:** Ligand A (0.042) has lower P-gp efflux than Ligand B (0.01), which is a slight advantage.
15. **Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.5), but the difference is small.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand B has a slightly better affinity, but the difference isn't huge.
*   **Metabolic Stability:** Ligand B is significantly better in terms of Cl_mic and t1/2. This is a crucial advantage.
*   **Solubility:** Ligand A is slightly better.
*   **hERG:** Both are acceptable, but Ligand A is slightly better.
*   **DILI:** Ligand A is significantly better.

**Conclusion:**

While Ligand B has a slightly better binding affinity and significantly better metabolic stability, Ligand A has a much better safety profile (lower DILI) and better solubility. Considering the importance of metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, **Ligand B** appears to be the more promising drug candidate.

Output:
1
2025-04-17 14:13:52,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (381.435 and 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.93) is slightly above the preferred <140, while Ligand B (101.21) is well within.

**logP:** Both ligands have a logP around 1.3, which is optimal.

**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 (0.738 and 0.806), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 86.429, which is high. Ligand B has a much lower DILI risk of 49.283, which is preferable.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (90.772) than Ligand A (14.153), but this is not a major factor in this case.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, Ligand B (-5.172) is slightly better than Ligand A (-5.527).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-2.912) is slightly better than Ligand A (-3.365).

**hERG Inhibition:** Ligand A (0.111) has a slightly lower hERG risk than Ligand B (0.377).

**Microsomal Clearance:** Ligand A (4.685) has a lower microsomal clearance than Ligand B (2.823), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-20.936 hours) compared to Ligand A (32.581 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.1) has lower P-gp efflux than Ligand B (0.023).

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

**Conclusion:**

While Ligand A has slightly better hERG and P-gp profiles, the significantly higher DILI risk and shorter half-life are major drawbacks. Ligand B has a much more favorable safety profile (lower DILI) and improved metabolic stability (longer half-life), making it the more promising drug candidate despite the slightly higher hERG and P-gp efflux. The binding affinity is comparable for both.

Output:
1
2025-04-17 14:13:52,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.515 Da) is slightly higher than Ligand B (338.459 Da), but both are acceptable.

**TPSA:** Ligand A (86.88) is better than Ligand B (66.83), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (A: 2.445, B: 3.429), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* pose a minor solubility issue, but not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is slightly better than Ligand B (HBD=1, HBA=6) in terms of balancing solubility and permeability.

**QED:** Ligand B (0.921) has a significantly higher QED score than Ligand A (0.595), indicating a more drug-like profile overall.

**DILI:** Ligand A (29.624) has a much lower DILI risk than Ligand B (56.805), which is a significant advantage.

**BBB:** Ligand B (69.794) has a higher BBB penetration percentile than Ligand A (53.781), but BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.555 and -5.157 respectively), suggesting potential absorption issues.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.25 and -4.3 respectively).

**hERG Inhibition:** Ligand A (0.33) has a much lower hERG inhibition liability than Ligand B (0.838), which is a crucial advantage for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (24.474) has significantly lower microsomal clearance than Ligand B (77.246), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-3.288) has a negative half-life, which is concerning. Ligand A (2.696) has a positive half-life, indicating better stability.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.103), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a significant advantage, as potency is paramount for enzyme inhibitors.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has a better QED and BBB, Ligand A excels in the critical areas for an enzyme inhibitor: significantly better binding affinity, much lower DILI risk, lower hERG inhibition, and much better metabolic stability (lower Cl_mic and positive t1/2). The solubility and Caco-2 permeability are poor for both, but these can be addressed with formulation strategies. The superior potency and safety profile of Ligand A outweigh the slightly better predicted permeability of Ligand B.

Output:
1
2025-04-17 14:13:52,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.29 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.2) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (88.37) is excellent, well below 140.

**logP:** Ligand A (1.196) is within the optimal 1-3 range. Ligand B (2.622) is also good, falling within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 5. Both are below the 10 limit.

**QED:** Ligand A (0.475) is marginally below the desired 0.5, while Ligand B (0.654) is above it, indicating better drug-likeness.

**DILI:** Ligand A has a DILI risk of 96.976, which is very high and concerning. Ligand B has a much lower DILI risk of 35.867, which is good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (59.519) and Ligand B (76.696) are both relatively low.

**Caco-2:** Both ligands have negative Caco-2 values (-4.612 and -4.975), 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.

**Solubility:** Both ligands have negative solubility values (-3.694 and -2.239), again suggesting poor aqueous solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Ligand A (0.124) has a very low hERG risk, which is excellent. Ligand B (0.65) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (42.077) has moderate clearance, while Ligand B (-32.814) has negative clearance, which is highly favorable, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (16.519) has a moderate half-life. Ligand B (13.424) has a slightly shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.177 and 0.279).

**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 some ADME drawbacks.

**Conclusion:**

Despite both ligands having some issues with predicted permeability and solubility, Ligand B is the superior candidate. Its significantly stronger binding affinity, much lower DILI risk, and excellent metabolic stability (negative Cl_mic) are critical advantages for an enzyme target like SRC kinase. While Ligand A has a very low hERG risk, the high DILI risk is a major red flag.

Output:
1
2025-04-17 14:13:52,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.454 and 363.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is slightly above the preferred <140, but acceptable. Ligand B (70.15) is well within the ideal range.

**logP:** Ligand A (1.049) is at the lower end of optimal, potentially impacting permeability. Ligand B (2.739) is closer to the sweet spot of 1-3.

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

**QED:** Both ligands have good QED scores (0.547 and 0.842), suggesting good drug-like properties.

**DILI:** Ligand A (18.147) has a significantly lower DILI risk than Ligand B (51.26), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B is slightly better (74.835 vs. 66.111). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.217 and 0.27), which is excellent.

**Microsomal Clearance:** Ligand A (29.697) has a higher microsomal clearance than Ligand B (11.626), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (32.629) has a longer in vitro half-life than Ligand A (-24.269), suggesting better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.014 and 0.105).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the poor solubility and permeability for both, Ligand B is slightly favored. While Ligand A has a better DILI score, Ligand B has better logP, metabolic stability (lower Cl_mic, longer t1/2), and slightly better Caco-2 and BBB values. The binding affinity is comparable. Given the enzyme-specific priorities, metabolic stability is crucial, and Ligand B demonstrates superior properties in this regard. The poor solubility and permeability would need to be addressed through formulation or structural modifications, but the underlying pharmacokinetic profile of Ligand B is more promising.

Output:
1
2025-04-17 14:13:52,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.34 Da) is slightly better positioned.

**TPSA:** Ligand A (47.04) is excellent, well below the 140 threshold for oral absorption. Ligand B (104.9) is higher, but still acceptable, though less ideal.

**logP:** Ligand A (4.83) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.063) is very low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is well within the acceptable limits. Ligand B (HBD=2, HBA=7) is also acceptable, but has more HBA.

**QED:** Both ligands have reasonable QED scores (A: 0.734, B: 0.666), indicating good drug-like properties.

**DILI:** Ligand A (88.019) has a higher DILI risk than Ligand B (54.285), which is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (75.107) is better than Ligand B (22.606).

**Caco-2 Permeability:** Ligand A (-4.574) is poor, indicating low intestinal absorption. Ligand B (-5.43) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.524) is very poor, consistent with its high logP. Ligand B (-2.04) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.792) shows a moderate risk of hERG inhibition, while Ligand B (0.085) has a very low risk. This is a major advantage for Ligand B.

**Microsomal Clearance:** Ligand A (76.334) has higher clearance, suggesting lower metabolic stability. Ligand B (16.268) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.49) has a short half-life. Ligand B (-0.828) has an even shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.427, B: 0.02).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage, as potency is a primary consideration for enzyme inhibitors.

**Overall Assessment:**

Ligand B is the more promising candidate despite its low logP and Caco-2 permeability. The significantly stronger binding affinity (-8.6 kcal/mol vs 0.0 kcal/mol) outweighs these drawbacks. Furthermore, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic) and lower hERG risk. While both have poor solubility and permeability, the potency and safety profile of Ligand B make it the preferred choice.

Output:
1
2025-04-17 14:13:52,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.359 Da and 386.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (111.28 and 111.89) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (0.405 and 0.431) are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 7 HBA) is slightly better than Ligand B (1 HBD, 10 HBA) in terms of balancing solubility and permeability. Ligand B has a higher number of HBA which could potentially reduce permeability.

**QED:** Both ligands have acceptable QED scores (0.784 and 0.65), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (75.456 and 77.627), which is a concern. However, this is a predictive score, and further investigation would be needed.

**BBB:** Both ligands have low BBB penetration (56.572 and 58.085), which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.029 and -5.655), which is unusual and suggests poor permeability. This is a significant drawback.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.443 and -1.797). This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.062 and 0.092), which is excellent.

**Microsomal Clearance:** Ligand A (39.296 mL/min/kg) has a significantly better microsomal clearance than Ligand B (6.12 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.305 hours) has a very short half-life, while Ligand B (5.734 hours) has a much more reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.157).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.0 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 more promising candidate. The significantly stronger binding affinity (-8.6 vs -7.6 kcal/mol) and better in vitro half-life (5.734 vs 0.305 hours) are critical advantages for an enzyme inhibitor. While Ligand A has better metabolic stability (lower Cl_mic), the difference in binding affinity is more impactful. The DILI risk is similar for both, and the hERG risk is low for both. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the superior potency of Ligand B makes it the better starting point.

Output:
1
2025-04-17 14:13:52,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (348.403 and 345.418 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.53) is slightly above the preferred <140, but still acceptable. Ligand B (73.2) is well within the ideal range.

**3. logP:** Ligand A (0.289) is quite low, potentially hindering permeability. Ligand B (2.689) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**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 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.746 and 0.861), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (38.387 and 43.195), below the 60 threshold.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (81.698) has a higher BBB score than Ligand A (67.08), but this isn't a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-4.828) has poor Caco-2 permeability, while Ligand B (-4.597) is slightly better, but still poor.

**10. Aqueous Solubility:** Ligand A (-1.678) has poor solubility, while Ligand B (-3.764) is even worse. Both are concerning.

**11. hERG Inhibition:** Ligand A (0.04) has a very low hERG risk, which is excellent. Ligand B (0.848) has a higher, but still acceptable, hERG risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (32.637) has lower clearance than Ligand B (51.88), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand A (-2.109) has a shorter half-life than Ligand B (-3.249), which is less desirable.

**14. P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent. Ligand B (0.234) has a higher, but still relatively low, P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand A (-5.9 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much better binding affinity. While Ligand A has better metabolic stability, the substantial difference in affinity outweighs this benefit. Both have poor solubility, which is a concern for both, but can be addressed with formulation strategies. Ligand A's low logP is a significant drawback for permeability.

Output:
1
2025-04-17 14:13:52,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.327 Da and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.48) is slightly above the optimal <140 for oral absorption, while Ligand B (67.87) is well within the range.

**logP:** Both ligands have good logP values (0.978 and 1.622), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.717 and 0.739), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 79.527, which is concerning (high risk, >60). Ligand B has a much lower DILI risk of 12.136, indicating a significantly better safety profile.

**BBB:** Both ligands show moderate BBB penetration (65.064 and 75.107). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.957 and -4.722), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.035 and -2.046), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.303 and 0.292), which is positive.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (31.915 and 32.467 mL/min/kg), suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (38.007 hours) than Ligand B (13.775 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.034), which is favorable.

**Binding Affinity:** Both ligands have identical binding affinities (-7.3 kcal/mol), which is excellent and removes this as a differentiating factor.

**Conclusion:**

Despite the similar binding affinities and acceptable logP/H-bond properties, Ligand B is the more promising candidate due to its significantly lower DILI risk. The poor Caco-2 and solubility are major drawbacks for both, but the safety profile is paramount. The longer half-life of Ligand A is a plus, but it's outweighed by the high DILI risk. Further optimization would be needed to address the permeability and solubility issues for either compound.

Output:
1
2025-04-17 14:13:52,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.5 & 364.8 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, while Ligand B (95.42) is higher but still acceptable.

**logP:** Ligand A (3.58) is at the upper end of the optimal range (1-3), while Ligand B (1.01) is slightly below, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (0.592 and 0.834), indicating good drug-like properties.

**DILI:** Ligand A (28.5%) has a significantly lower DILI risk than Ligand B (59.8%). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.5%) is high, while Ligand B (45.9%) is lower.

**Caco-2 Permeability:** Ligand A (-4.481) shows poor permeability, while Ligand B (-5.102) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-3.236) and Ligand B (-2.859) both show poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.777) has a lower hERG risk than Ligand B (0.145), which is a significant advantage.

**Microsomal Clearance:** Ligand A (48.04) has a higher clearance than Ligand B (-14.804), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-3.513) has a shorter half-life than Ligand B (-1.366), further supporting Ligand B in terms of metabolic stability.

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.012), which is favorable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-9.6 kcal/mol). While the difference is not huge, it is still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, and lower hERG risk, and lower P-gp efflux. However, it has poor Caco-2 permeability and a higher microsomal clearance, leading to a shorter half-life. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) but suffers from a higher DILI risk, lower hERG safety, and slightly weaker binding.

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), the improved metabolic stability of Ligand B is a significant advantage, and the difference in binding affinity is relatively small. The higher DILI and hERG risk of Ligand B are concerning, but potentially addressable through further optimization. The poor permeability of both compounds is a significant drawback that would need to be addressed regardless.

Output:
1
2025-04-17 14:13:52,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.429 Da and 366.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is slightly higher than Ligand B (58.2). Both are below the 140 threshold for oral absorption, but neither are optimized for CNS penetration (below 90).

**logP:** Both ligands have good logP values (2.414 and 3.522), 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:** Both have 2 HBD and 3 HBA, well within the acceptable limits of 5 and 10 respectively.

**QED:** Both ligands have QED values above 0.5 (0.622 and 0.582), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (20.279 and 21.985), below the concerning threshold of 60.

**BBB:** Ligand A (90.772) has a higher BBB penetration score than Ligand B (67.429), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.545) has a worse Caco-2 permeability score than Ligand B (-5). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.833) has a better solubility score than Ligand B (-4.393). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.451 and 0.406), which is excellent.

**Microsomal Clearance:** Ligand B (87.391) has significantly higher microsomal clearance than Ligand A (43.372). This suggests Ligand A is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (22.809) has a longer half-life than Ligand A (-11.21). However, 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 (0.042 and 0.242), which is favorable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better solubility and lower clearance, the significantly stronger binding affinity of Ligand B (-8.5 vs -6.9 kcal/mol) is the deciding factor. The improved binding is likely to translate to greater efficacy. While Ligand B has a higher clearance and slightly worse solubility, these can potentially be addressed through formulation or structural modifications. The negative half-life of Ligand A is a major red flag.

Output:
1
2025-04-17 14:13:52,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (347.415 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.62) is slightly higher than the preferred <140, but acceptable. Ligand B (69.64) is well below 140 and very good for absorption.

**3. logP:** Both ligands (2.658 and 2.856) are 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 (5) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have a QED of 0.88, indicating excellent drug-like properties.

**7. DILI:** Ligand A (80.535) has a higher DILI risk than Ligand B (30.322). This is a significant concern, as a percentile >60 is considered high risk.

**8. BBB:** Both ligands have similar BBB penetration (60.527 and 60.76), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.734 and -4.822). These values are unusual and suggest 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.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.87 and -4.285), which is also concerning. Similar to Caco-2, these values are on a log scale and require more context.

**11. hERG Inhibition:** Ligand A (0.011) has a very low hERG risk, while Ligand B (0.369) has a slightly elevated, but still relatively low, risk.

**12. Microsomal Clearance:** Ligand A (16.905) has lower microsomal clearance than Ligand B (50.581), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have negative half-life values (-21.112 and -22.067), which is not physically possible. These values are likely errors or represent a different scale.

**14. P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, while Ligand B (0.111) has slightly higher efflux.

**15. 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.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the most critical factor for an enzyme inhibitor is potency. Ligand A's significantly stronger binding affinity (-9.1 kcal/mol vs -7.9 kcal/mol) is a substantial advantage that likely outweighs its higher DILI risk and slightly lower metabolic stability. The lower P-gp efflux and very low hERG risk for Ligand A are also favorable. The DILI risk for Ligand A is concerning, but could potentially be mitigated through structural modifications in further optimization.

Output:
1
2025-04-17 14:13:52,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.385 Da and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is significantly better than Ligand B (94.81). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (1.503) is optimal, while Ligand B (0.656) is slightly low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.577 and 0.701), indicating drug-like properties.

**DILI:** Ligand A (33.346) has a lower DILI risk than Ligand B (42.264), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.094) is better than Ligand B (40.132).

**Caco-2 Permeability:** Ligand A (-4.556) is better than Ligand B (-5.021). Higher values are better, indicating better absorption.

**Aqueous Solubility:** Ligand A (-2.201) is better than Ligand B (-1.938). Higher values are better for formulation.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.265 and 0.242), which is excellent.

**Microsomal Clearance:** Ligand A (32.322) has lower clearance than Ligand B (35.325), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.766) has a much longer half-life than Ligand B (33.941), a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.13).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 kcal/mol and -8.7 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Conclusion:**

Ligand A is superior to Ligand B across most critical ADME properties, including DILI risk, solubility, metabolic stability (lower Cl_mic and longer t1/2), and Caco-2 permeability. While both have good binding affinity and low hERG risk, the overall profile of Ligand A makes it a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 14:13:52,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 and 346.821 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is better than Ligand B (50.7), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (1.314) is optimal, while Ligand B (5.013) is high, potentially leading to solubility issues and off-target effects.

**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 (4 each), well below the threshold of 10.

**QED:** Ligand A (0.677) has a better QED score than Ligand B (0.564), indicating a more drug-like profile.

**DILI:** Ligand A (18.418) has a significantly lower DILI risk than Ligand B (85.964), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (64.017) is higher than Ligand A (43.854).

**Caco-2 Permeability:** Ligand A (-4.698) is better than Ligand B (-5.068), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.386) is significantly better than Ligand B (-5.282), which is a critical factor for bioavailability.

**hERG Inhibition:** Ligand A (0.276) has a much lower hERG risk than Ligand B (0.802), a significant safety advantage.

**Microsomal Clearance:** Ligand B (38.155) has slightly better microsomal clearance than Ligand A (33.052), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (94.309) has a much longer in vitro half-life than Ligand A (-6.151), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux than Ligand B (0.66), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.2 kcal/mol, respectively), with Ligand A being slightly better. The 1.0 kcal/mol difference in affinity is significant, but can be outweighed by other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better half-life, Ligand A excels in critical areas like DILI risk, solubility, hERG inhibition, logP, and Caco-2 permeability. The slightly better affinity of Ligand A, combined with its superior ADME properties and safety profile, makes it the more promising drug candidate. The high logP and DILI risk of Ligand B are major concerns.

Output:
0
2025-04-17 14:13:52,948 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Ligand A:**
*   **MW:** 346.427 Da - Good, within the ideal range.
*   **TPSA:** 98.66 A^2 - Acceptable, though approaching the upper limit for good absorption.
*   **logP:** 0.617 - Low. May have permeability issues.
*   **HBD:** 4 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.554 - Good, drug-like.
*   **DILI:** 29.236 - Excellent, very low risk.
*   **BBB:** 36.216 - Low, not a concern for a non-CNS target.
*   **Caco-2:** -5.036 - Very poor permeability. A significant concern.
*   **Solubility:** -1.96 - Poor solubility. A significant concern.
*   **hERG:** 0.187 - Excellent, very low risk.
*   **Cl_mic:** 8.159 mL/min/kg - Moderate clearance. Not ideal, but not terrible.
*   **t1/2:** 9.44 hours - Good in vitro half-life.
*   **Pgp:** 0.061 - Low efflux, favorable.
*   **Affinity:** -9.9 kcal/mol - Excellent, very strong binding.

**Ligand B:**
*   **MW:** 412.324 Da - Good, within the ideal range.
*   **TPSA:** 48 A^2 - Excellent, very favorable for absorption.
*   **logP:** 3.774 - Good, within the optimal range.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.64 - Good, drug-like.
*   **DILI:** 30.671 - Excellent, very low risk.
*   **BBB:** 86.274 - High, not a primary concern for a non-CNS target but not detrimental.
*   **Caco-2:** -4.728 - Poor permeability, but better than Ligand A.
*   **Solubility:** -3.49 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.67 - Acceptable, low risk.
*   **Cl_mic:** 92.13 mL/min/kg - High clearance, a significant concern for metabolic stability.
*   **t1/2:** -5.541 hours - Very short half-life, a major drawback.
*   **Pgp:** 0.522 - Moderate efflux.
*   **Affinity:** -9.2 kcal/mol - Excellent, strong binding, but slightly weaker than Ligand A.

**Comparison & Decision:**

While Ligand A has a slightly better binding affinity (-9.9 vs -9.2 kcal/mol), its extremely poor Caco-2 permeability and solubility are major liabilities. Ligand B, despite having a shorter half-life and higher clearance, exhibits better permeability and solubility, even if still suboptimal. The difference in binding affinity (0.7 kcal/mol) is unlikely to outweigh the significant ADME deficiencies of Ligand A. The short half-life and high clearance of Ligand B could potentially be addressed through structural modifications, whereas improving the permeability and solubility of Ligand A would likely require more extensive redesign.

Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 14:13:52,948 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.406 and 388.465 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is better than Ligand B (67.35), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (1.492) is within the optimal 1-3 range. Ligand B (3.271) is at the higher end of the optimal range, potentially hinting at some solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 7 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have similar QED values (0.746 and 0.703), indicating good drug-likeness.

**DILI:** Ligand A (46.026) has a significantly lower DILI risk than Ligand B (65.762). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (89.531 and 85.498), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.27) has a more negative Caco-2 value, indicating *lower* permeability than Ligand B (-5.19). This is a negative for Ligand A.

**Aqueous Solubility:** Ligand A (-1.464) has better aqueous solubility than Ligand B (-3.578). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.354) has a lower hERG inhibition liability than Ligand B (0.799), which is a significant advantage.

**Microsomal Clearance:** Ligand A (12.571) has a lower microsomal clearance than Ligand B (43.24), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (4.629) has a lower in vitro half-life than Ligand B (25.658). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux liability than Ligand B (0.254), which is favorable.

**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 for Ligand B, and could potentially outweigh some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity. However, Ligand A demonstrates a superior safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic). The improved solubility of Ligand A is also beneficial. While Ligand A's permeability is lower and half-life is shorter, the stronger binding affinity of Ligand B is a critical factor for an enzyme inhibitor. The difference in binding affinity is substantial enough to overcome the ADME liabilities of Ligand B.

Output:
1
2025-04-17 14:13:52,948 - INFO - Batch 279 complete. Total preferences: 4464
2025-04-17 14:13:52,948 - INFO - Processing batch 280/512...
2025-04-17 14:14:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.45 and 365.474 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (81.99). TPSA < 140 is good for oral absorption, both are under, but A is preferable.

**3. logP:** Both ligands have acceptable logP values (2.357 and 3.495, respectively), falling within the 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, 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 (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.848 and 0.756), indicating good drug-like properties.

**7. DILI:** Ligand A (38.891) has a much lower DILI risk than Ligand B (67.623). This is a significant advantage for Ligand A.

**8. BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand A (89.221) is better than Ligand B (62.117), but this isn't a deciding factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or the prediction method. However, the values are close enough to not be decisive.

**10. Aqueous Solubility:** Ligand A (-2.52) is better than Ligand B (-5.301). Better solubility is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.427) has a lower hERG risk than Ligand B (0.758), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (28.221) has lower microsomal clearance than Ligand B (59.517), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (34.642) has a longer half-life than Ligand A (11.621). This is a positive for Ligand B, but can be mitigated with formulation.

**14. P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux than Ligand B (0.38), which is preferable.

**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 small and likely not enough to overcome its other drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a significantly better safety profile (lower DILI, lower hERG), better solubility, and better metabolic stability (lower Cl_mic). While Ligand B has a slightly longer half-life and marginally better binding affinity, these advantages are outweighed by the superior ADME properties of Ligand A. Given the enzyme-kinase target class, prioritizing metabolic stability, solubility, and safety is crucial.

Output:
0
2025-04-17 14:14:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 351.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.9) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (75.43) is excellent, well below 140.

**logP:** Ligand A (-1.257) is a bit low, potentially hindering permeation. Ligand B (2.124) is within the optimal 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 good QED scores (0.586 and 0.798), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (47.305 and 41.411), which is favorable.

**BBB:** Ligand A (12.369) has very low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (92.904) has high BBB penetration, irrelevant in this case.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.166 and -5.051), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.463 and -3.186), which is also unusual and indicates very poor solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.241) has a very low hERG risk, which is excellent. Ligand B (0.782) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-15.041) has a very low (and negative) microsomal clearance, suggesting excellent metabolic stability. Ligand B (-8.666) also has low clearance, indicating good metabolic stability, though not as good as Ligand A.

**In vitro Half-Life:** Ligand A (9.32) has a relatively short half-life. Ligand B (-14.874) has a very long (and negative) half-life, suggesting exceptional stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.014 and 0.091), which is favorable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). The difference is 0.7 kcal/mol, which is significant.

**Overall Assessment:**

Both compounds have significant issues with solubility and Caco-2 permeability. However, Ligand B has a more optimal logP, better binding affinity, and a significantly longer in vitro half-life. The slightly higher hERG risk of Ligand B is less concerning than the poor logP and weaker binding of Ligand A. The superior metabolic stability and binding affinity of Ligand B outweigh its slightly less favorable solubility and permeability profiles, especially considering the enzyme target class.

Output:
1
2025-04-17 14:14:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.417 Da) is slightly higher than Ligand B (351.506 Da), but both are acceptable.

**TPSA:** Ligand A (114.18) is borderline for good oral absorption, while Ligand B (29.54) is well below the 140 threshold and excellent.

**logP:** Ligand A (0.469) is a bit low, potentially hindering permeability. Ligand B (4.635) is slightly high, potentially causing solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are within acceptable limits. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.644, B: 0.676), indicating drug-like properties.

**DILI:** Ligand A (57.58) has a moderate DILI risk, while Ligand B (20.202) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (61.535) has a moderate BBB penetration, while Ligand B (94.843) has high BBB penetration. Since SRC is not a CNS target, this is less critical, but still a slight advantage for B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.988) is worse than Ligand B (-4.662).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.074) is slightly better than Ligand B (-5.167).

**hERG Inhibition:** Ligand A (0.072) has very low hERG inhibition risk, a significant advantage. Ligand B (0.824) has a moderate risk.

**Microsomal Clearance:** Ligand A (-6.287) has excellent metabolic stability (negative value suggests slow clearance). Ligand B (66.361) has a high clearance, indicating poor metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-8.055) has a very long half-life, consistent with its low clearance. Ligand B (-3.37) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.057) has low P-gp efflux, while Ligand B (0.744) has moderate efflux.

**Binding Affinity:** Ligand A (-7.1) has slightly better binding affinity than Ligand B (-0.0).

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and a *much* better metabolic profile (lower Cl_mic, longer t1/2). It also has a significantly lower hERG risk. While its logP is a bit low and Caco-2 permeability is poor, the strong binding and favorable ADME properties, particularly the metabolic stability, outweigh these concerns for an enzyme target like SRC. Ligand B has better TPSA and lower DILI, but its poor metabolic stability and moderate hERG risk are major liabilities.

Output:
0
2025-04-17 14:14:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (463.012 Da) is towards the upper end, while Ligand B (342.443 Da) is more favorably positioned.

**TPSA:** Both ligands have TPSA values (64.11 and 67.23) that are acceptable for oral absorption (<=140).

**logP:** Ligand A (4.878) is high, potentially leading to solubility issues and off-target effects. Ligand B (1.691) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.658 and 0.606), indicating reasonable drug-likeness.

**DILI:** Ligand A has a very high DILI risk (98.449%), a major red flag. Ligand B has a low DILI risk (10.237%), which is highly desirable.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**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:** Ligand A has very poor aqueous solubility (-6.239), consistent with its high logP. Ligand B has poor solubility (-1), but better than A.

**hERG Inhibition:** Ligand A has a low hERG risk (0.424), which is good. Ligand B also has a low hERG risk (0.345).

**Microsomal Clearance:** Ligand A has a high microsomal clearance (73.34 mL/min/kg), indicating poor metabolic stability. Ligand B has a much lower clearance (15.999 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a relatively short half-life (33.759 hours). Ligand B has a negative half-life (-11.902 hours), which is problematic and likely an error.

**P-gp Efflux:** Both have low P-gp efflux liability (0.311 and 0.037).

**Binding Affinity:** Ligand A has a significantly better binding affinity (-8.4 kcal/mol) than Ligand B (-7.1 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its extremely high DILI risk and poor solubility are major concerns. The high logP and high clearance further detract from its viability. Ligand B, while having a slightly weaker binding affinity, presents a much more favorable ADME-Tox profile, with low DILI risk, better metabolic stability (lower Cl_mic), and a more reasonable logP. The negative half-life for Ligand B is a concern, but the other factors outweigh this issue. The difference in binding affinity (1.3 kcal/mol) is significant, but not insurmountable, and can potentially be addressed through further optimization of Ligand B.

Output:
1
2025-04-17 14:14:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 Da and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is slightly higher than Ligand B (61.44). Both are below the 140 A^2 threshold for good oral absorption, but neither is optimized for CNS penetration (below 90).

**logP:** Both ligands have similar logP values (2.485 and 2.476), 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, <=10 HBA).

**QED:** Ligand A (0.782) has a higher QED score than Ligand B (0.629), indicating a more drug-like profile.

**DILI:** Ligand A (35.052) has a significantly higher DILI risk than Ligand B (14.657). This is a major concern.

**BBB:** Ligand A (55.913) has a lower BBB penetration percentile than Ligand B (71.578). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.409) has worse Caco-2 permeability than Ligand B (-4.95). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.296) has slightly better aqueous solubility than Ligand B (-2.159), but both are quite poor.

**hERG:** Both ligands have very low hERG inhibition liability (0.481 and 0.46), which is excellent.

**Microsomal Clearance:** Ligand A (39.871) and Ligand B (40.611) have similar microsomal clearance values. These are relatively high, indicating moderate metabolic instability.

**In vitro Half-Life:** Ligand A (40.109) has a longer in vitro half-life than Ligand B (-11.008). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.298 and 0.084), which is favorable.

**Binding Affinity:** Both ligands have identical binding affinities (-8.1 kcal/mol), which is excellent and well below the -7.0 kcal/mol threshold.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. While Ligand A has a slightly better QED and in vitro half-life, its significantly higher DILI risk is a major drawback. Ligand B exhibits a much lower DILI risk and better BBB penetration (though not crucial here). Both have poor solubility and permeability, but these can potentially be addressed through formulation strategies. The lower DILI risk of Ligand B outweighs the minor advantages of Ligand A.

Output:
1
2025-04-17 14:14:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.463 and 360.336 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold for oral absorption, while Ligand B (95.42) is approaching the upper limit, but still acceptable.

**logP:** Ligand A (3.241) is within the optimal 1-3 range. Ligand B (1.333) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5 HBAs, both are acceptable.

**QED:** Both ligands have good QED scores (0.561 and 0.826), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 69.407, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 49.593, which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (76.774) than Ligand A (38.387), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-5.202) has poor Caco-2 permeability, while Ligand B (-4.612) is slightly better, but still low.

**Aqueous Solubility:** Ligand A (-3.905) and Ligand B (-2.525) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.637) has a slightly higher hERG risk than Ligand B (0.144), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (67.61) has higher microsomal clearance than Ligand B (36.799), indicating lower metabolic stability. This is a crucial disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-33.941) has a significantly longer in vitro half-life than Ligand A (-3.903), which is a major advantage.

**P-gp Efflux:** Ligand A (0.495) has lower P-gp efflux than Ligand B (0.015), which is better.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.0 kcal/mol). Ligand A has a 0.9 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its significantly higher DILI risk, poor Caco-2 permeability, higher microsomal clearance, and shorter half-life make it a less desirable candidate. Ligand B, while having slightly lower affinity, has a much better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), and acceptable TPSA. The affinity difference, while notable, can potentially be optimized during lead optimization.

Output:
1
2025-04-17 14:14:32,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.423 and 371.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.41) is better than Ligand B (131.44), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.205) is optimal (1-3), while Ligand B (-0.615) is below 1, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (4), staying within the preferred limit of <=5.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (7), remaining closer to the preferred limit of <=10.

**QED:** Ligand A (0.847) is significantly better than Ligand B (0.448), indicating a more drug-like profile.

**DILI:** Ligand B (41.877) is much better than Ligand A (94.649), suggesting a lower risk of drug-induced liver injury. This is a significant advantage for Ligand B.

**BBB:** Ligand A (31.795) and Ligand B (14.541) are both low, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.572) and Ligand B (-6.223) are both negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.036) and Ligand B (-1.657) are both negative, indicating poor solubility.

**hERG:** Both ligands show very low hERG inhibition risk (0.02 and 0.053, respectively).

**Microsomal Clearance:** Ligand B (-9.408) has a lower (better) microsomal clearance than Ligand A (-14.429), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-11.524) has a longer half-life than Ligand A (4.205), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.01).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) is slightly better than Ligand A (-8.1 kcal/mol), though the difference is not huge.

**Overall Assessment:**

Ligand B has a significant advantage in DILI risk and metabolic stability (Cl_mic and t1/2). While Ligand A has better TPSA, logP, HBD, HBA, and QED, the improvements in ADME properties for Ligand B are more crucial for an enzyme target. The slight improvement in binding affinity for Ligand B further supports its selection. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:14:32,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.507 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is slightly higher than Ligand B (59.08). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets (not relevant here). Ligand B is preferable here.

**logP:** Ligand A (3.795) is at the upper end of the optimal 1-3 range, while Ligand B (1.844) is closer to the lower end. Ligand B is preferable.

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

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.808 and 0.732), indicating good drug-like properties.

**DILI:** Ligand A (28.616) has a lower DILI risk than Ligand B (34.238), which is preferable.

**BBB:** Both have high BBB penetration (80.419 and 77.045), but this is less important for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.341 and -4.183). This is unusual and indicates poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.466 and -1.272), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.306 and 0.478), which is excellent.

**Microsomal Clearance:** Ligand A (50.854) has lower microsomal clearance than Ligand B (69.313), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (3.463) has a positive half-life, while Ligand B (-11.356) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.062 and 0.143).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.6 kcal/mol). Ligand A has a 1 kcal/mol advantage.

**Overall Assessment:**

Ligand A is superior due to its better metabolic stability (lower Cl_mic, positive half-life), slightly better DILI risk, and a 1 kcal/mol advantage in binding affinity. While both have poor Caco-2 permeability and solubility, the binding affinity and metabolic stability advantages of Ligand A are more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:14:32,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.206 Da) is slightly higher than Ligand B (367.475 Da), but both are acceptable.

**TPSA:** Ligand A (75.63) is better than Ligand B (89.87) as it is closer to the ideal threshold of 140 for oral absorption.

**logP:** Ligand A (4.465) is higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (-0.085) is below the optimal range, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both within acceptable limits. Ligand B has 1 HBD and 7 HBA, also within limits, but closer to the upper bound for HBA.

**QED:** Both ligands have good QED scores (A: 0.744, B: 0.8), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (97.325%), which is a significant concern. Ligand B has a much lower DILI risk (37.999%), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (64.25) has a higher BBB value than Ligand A (34.936), but this is not a major factor in this case.

**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 (-4.806 and -1.724). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.143) has a slightly higher hERG risk than Ligand B (0.478), but both are relatively low.

**Microsomal Clearance:** Ligand B (26.971 mL/min/kg) has significantly lower microsomal clearance than Ligand A (7.434 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.548 hours) has a negative half-life, which is not possible and indicates a problem with the data. Ligand A (6.276 hours) is acceptable.

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux than Ligand B (0.12), which is slightly better.

**Binding Affinity:** Ligand A (-10.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the strong binding affinity of Ligand A, its extremely high DILI risk and poor solubility are major red flags. Ligand B, while having weaker binding, possesses a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic), and acceptable hERG risk. The negative half-life for Ligand B is concerning and would require further investigation, but the overall profile is more promising. The substantial difference in binding affinity *could* potentially be overcome with further optimization of Ligand B, whereas mitigating the DILI risk of Ligand A would likely require significant structural changes that could compromise its potency.

Output:
1
2025-04-17 14:14:32,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.38 and 349.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.87) is well below the 140 threshold and good for oral absorption. Ligand B (70.47) is also below 140, but higher than A.

**3. logP:** Both ligands have good logP values (2.847 and 1.527), 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 5, both under the limit of 10.

**6. QED:** Ligand A (0.895) has a significantly better QED score than Ligand B (0.695), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.915) has a slightly higher DILI risk than Ligand B (20.434), but both are below the concerning threshold of 60.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (93.447) has better BBB penetration than Ligand B (64.017).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.966 and -4.974), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.446 and -1.146), indicating very poor aqueous solubility, a major concern for bioavailability. Ligand B is slightly better than A.

**11. hERG Inhibition:** Ligand A (0.886) has a slightly higher hERG risk than Ligand B (0.26), which is preferable for B.

**12. Microsomal Clearance:** Ligand A (-3.869) has a much lower (better) microsomal clearance than Ligand B (23.092), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.173) has a very short half-life, while Ligand B (12.582) has a significantly longer half-life, which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.007), which is preferable.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with solubility and permeability, Ligand A stands out due to its significantly superior binding affinity (-8.7 vs -7.5 kcal/mol) and better metabolic stability (lower Cl_mic). The longer half-life of Ligand B is attractive, but the much weaker binding and higher clearance are concerning. The better QED score of Ligand A also supports its selection. The poor solubility and permeability would need to be addressed through formulation or structural modifications, but the potency advantage of A is more critical at this stage.

Output:
1
2025-04-17 14:14:32,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.286 and 332.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.16) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (77.11) is well within the acceptable range.

**logP:** Both ligands have good logP values (2.6 and 1.982), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are acceptable.

**QED:** Ligand B (0.62) has a better QED score than Ligand A (0.433), indicating a more drug-like profile.

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a major concern. Ligand B has a much lower, and acceptable, DILI risk (79.333%).

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (66.576%) has a higher BBB score than Ligand B (39.279%).

**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 (0.421) has a slightly higher hERG risk than Ligand B (0.199), though both are relatively low.

**Microsomal Clearance:** Ligand B (29.57 mL/min/kg) has significantly lower microsomal clearance than Ligand A (62.435 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (31.588 hours) has a longer in vitro half-life than Ligand A (69.034 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.327) has lower P-gp efflux than Ligand B (0.091), which is slightly better.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand B is the far superior candidate. Its significantly stronger binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme target like SRC kinase. The better QED score also supports its drug-likeness. The higher DILI risk for Ligand A is a deal-breaker.

Output:
1
2025-04-17 14:14:32,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.47 and 342.44 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (62.74 and 58.44) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values (1.339 and 1.134) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 0 HBD and acceptable HBA counts (5 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.743 and 0.774), indicating drug-like properties.

**DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (50.33). This is a major advantage for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand B (72.625) is better than Ligand A (61.923). However, BBB is less crucial for a non-CNS target like SRC.

**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, suggesting poor solubility. Again, the scale is unclear.

**hERG:** Both ligands have low hERG inhibition liability (0.125 and 0.242), which is good.

**Microsomal Clearance:** Ligand A (51.286) has a higher microsomal clearance than Ligand B (26.879), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-23.896) has a much longer in vitro half-life than Ligand A (-0.684), indicating better stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.024 and 0.17).

**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 still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a lower DILI risk, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The solubility and permeability issues are shared by both, but the metabolic stability and potency advantages of Ligand B outweigh the slightly higher DILI risk. For an enzyme target like SRC kinase, metabolic stability is crucial for achieving adequate exposure and duration of action.

Output:
1
2025-04-17 14:14:32,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.246 Da) is slightly higher than Ligand B (352.475 Da), but both are acceptable.

**TPSA:** Ligand A (52.57) is well below the 140 threshold for oral absorption and is also favorable. Ligand B (67.87) is still acceptable, but less optimal.

**logP:** Ligand A (3.809) is at the higher end of the optimal range (1-3), while Ligand B (1.87) is towards the lower end. While Ligand A's logP is higher, it's not excessively high, and the increased lipophilicity might aid in cell permeability.

**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 recommended limits.

**QED:** Both ligands have acceptable QED scores (Ligand A: 0.805, Ligand B: 0.688), indicating good drug-like properties.

**DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (10.237). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 69.717, Ligand B: 70.027). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. This is a major concern for both.

**hERG Inhibition:** Ligand A (0.887) has a slightly higher hERG risk than Ligand B (0.237). Lower is better, so Ligand B is preferable here.

**Microsomal Clearance:** Ligand A (25.223) and Ligand B (22.613) have similar, relatively low, microsomal clearance values, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 4.563, Ligand B: 4.755).

**P-gp Efflux:** Ligand A (0.583) has lower P-gp efflux liability than Ligand B (0.044), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -9.4 kcal/mol, Ligand B: -9.1 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 issues with Caco-2 permeability and solubility, Ligand B has a significantly lower DILI risk and hERG inhibition liability. The slight advantage of Ligand A in P-gp efflux is not enough to offset these critical safety concerns. The binding affinities are comparable, making the ADME/Tox profile the deciding factor.

Output:
1
2025-04-17 14:14:32,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is well below the 140 threshold, suggesting good absorption. Ligand B (96.53) is still within acceptable limits, but less favorable.

**logP:** Ligand A (1.435) is optimal. Ligand B (0.906) is slightly low, potentially impacting permeability, but not drastically.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the desirable range (<=10).

**QED:** Both ligands (A: 0.785, B: 0.712) have good drug-likeness scores (>0.5).

**DILI:** Ligand A (30.981) has a significantly lower DILI risk than Ligand B (58.705), which is approaching a moderate risk level.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.399) is slightly better than Ligand A (53.974), but not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.279) is better than Ligand B (-5.102), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.735) is better than Ligand B (-2.775), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (A: 0.474, B: 0.176), which is excellent.

**Microsomal Clearance:** Ligand B (21.976) has a lower microsomal clearance than Ligand A (37.055), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (5.658) has a longer half-life than Ligand A (23.12), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.147, B: 0.06).

**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 a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and lower DILI risk, Ligand B's substantially stronger binding affinity (-8.1 vs -7.0 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2) are more critical for an enzyme target like SRC kinase. The slightly lower logP and higher DILI risk of Ligand B are acceptable trade-offs given the potency and stability advantages.

Output:
1
2025-04-17 14:14:32,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 346.343 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.9) is excellent, well below the 140 threshold for oral absorption. Ligand B (117.79) is still acceptable, but less optimal.

**logP:** Ligand A (0.686) is a bit low, potentially impacting permeability. Ligand B (0.241) is even lower, raising concerns about absorption.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.622 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (27.608) has a much lower DILI risk than Ligand B (63.397), a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (67.08) is better than Ligand B (36.293).

**Caco-2 Permeability:** Ligand A (-4.771) is poor, indicating low permeability. Ligand B (-5.284) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.147) is poor. Ligand B (-1.957) is even worse.

**hERG Inhibition:** Ligand A (0.208) has very low hERG risk, a major plus. Ligand B (0.093) is also very low risk.

**Microsomal Clearance:** Ligand A (22.556) has moderate clearance. Ligand B (2.766) has very low clearance, indicating excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (0.696) has a very short half-life. Ligand B (-26.7) has a very long half-life, a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.029 and 0.01), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.7 kcal/mol). This difference of 2.4 kcal/mol is a very significant advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better TPSA and DILI, Ligand B wins on several crucial parameters for an enzyme inhibitor: significantly better binding affinity, much better metabolic stability (lower Cl_mic and longer t1/2), and acceptable hERG risk. The lower logP and solubility of Ligand B are concerns, but these could potentially be addressed through formulation strategies or further chemical modifications. The substantial improvement in binding affinity and metabolic stability makes Ligand B the more promising candidate.

Output:
1
2025-04-17 14:14:32,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.491 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (58.2), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.709) is optimal, while Ligand B (3.894) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

**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 2. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.586 and 0.628, respectively), indicating drug-likeness.

**DILI:** Ligand A (3.218) has a significantly lower DILI risk than Ligand B (33.307). This is a major advantage for Ligand A.

**BBB:** Ligand A (80.807) has better BBB penetration than Ligand B (67.546), but this isn't a primary concern for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.451) has a worse Caco-2 permeability than Ligand B (-4.687).

**Aqueous Solubility:** Ligand A (-1.369) has better aqueous solubility than Ligand B (-5.032). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.517) has a lower hERG inhibition risk than Ligand B (0.39). Lower is better.

**Microsomal Clearance:** Ligand A (27.931) has significantly lower microsomal clearance than Ligand B (72.73). Lower clearance indicates better metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-26.14) has a much longer in vitro half-life than Ligand B (7.66). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux than Ligand B (0.271), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.1). However, the difference of 1 kcal/mol 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, lower microsomal clearance, longer half-life, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the ADME advantages of Ligand A are more critical for developing a viable drug candidate, especially for a kinase inhibitor where metabolic stability and bioavailability are paramount.

Output:
1
2025-04-17 14:14:32,361 - INFO - Batch 280 complete. Total preferences: 4480
2025-04-17 14:14:32,361 - INFO - Processing batch 281/512...
2025-04-17 14:15:12,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 384.929 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 58.64, well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.759) and Ligand B (3.216) both fall within the optimal 1-3 range.

**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 below the 10 threshold.

**QED:** Both ligands have good QED scores (0.651 and 0.819, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (30.322 and 30.516 percentile), which is favorable.

**BBB:** Both ligands have good BBB penetration (71.772 and 75.572 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.725) and Ligand B (-5.076) both have negative Caco-2 values, indicating poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.646 and -3.165). This is a concern, but can potentially be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.228 and 0.443), which is excellent.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (74.774 mL/min/kg) compared to Ligand B (28.371 mL/min/kg). This suggests Ligand B has better metabolic stability, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A has a significantly longer half-life (-7.044 hours) than Ligand B (32.549 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.241 and 0.216), which is good.

**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 can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better half-life, Ligand B's significantly stronger binding affinity (-8.2 vs -7.4 kcal/mol) is the most important factor for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic) of Ligand B is also a significant advantage. The poor Caco-2 and solubility are concerns for both, but the potency advantage of Ligand B is likely to be more impactful in driving forward development.

Output:
1
2025-04-17 14:15:12,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (341.43 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (45.23) is better than Ligand B (54.56), being closer to the <140 threshold for good absorption.

**3. logP:** Both ligands (3.305 and 3.786) are within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but is not a major concern.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 3 HBA, also good.

**6. QED:** Ligand A (0.911) has a significantly better QED score than Ligand B (0.726), indicating a more drug-like profile.

**7. DILI:** Ligand A (52.695) has a higher DILI risk than Ligand B (20.667). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (78.402 and 78.054), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.705 and -4.686). 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 (-2.816 and -2.948), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.862 and 0.869), which is excellent.

**12. Microsomal Clearance:** Ligand A (29.494) has significantly lower microsomal clearance than Ligand B (40.67), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (21.959) has a much longer in vitro half-life than Ligand A (-1.131). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.408 and 0.496).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -9.6 kcal/mol), with Ligand B being slightly better. The difference is small and likely not decisive.

**Overall Assessment:**

While Ligand A has a better QED and lower Cl_mic, the significantly higher DILI risk is a major concern. Ligand B, despite a lower QED, has a much lower DILI risk and a substantially longer half-life, which are critical for an enzyme inhibitor. The slight improvement in binding affinity for Ligand B is a bonus. The poor Caco-2 and solubility are shared concerns, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:15:12,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.447 and 349.435 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.33) is better than Ligand B (102.06). Both are below 140, but A is closer to the optimal threshold for good absorption.

**3. logP:** Both ligands have good logP values (2.374 and 1.243), 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, while Ligand B has 7. Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.779 and 0.72), indicating good drug-likeness.

**7. DILI:** Ligand A (28.616) has a significantly lower DILI risk than Ligand B (47.77). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (65.413 and 62.04). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.944) has slightly better Caco-2 permeability than Ligand B (-5.073).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.212 and -2.071). This is a concern for both, and formulation strategies would be needed.

**11. hERG Inhibition:** Ligand A (0.078) has a lower hERG inhibition liability than Ligand B (0.211), which is crucial for avoiding cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (42.097) has slightly higher microsomal clearance than Ligand B (39.27), meaning slightly lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.698) has a longer in vitro half-life than Ligand A (4.539), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.088 and 0.08).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This difference, although small, is significant given the enzyme target class.

**Overall Assessment:**

Ligand A is the more promising candidate. While both ligands have similar QED, MW, and logP, Ligand A excels in critical areas: significantly lower DILI risk, lower hERG inhibition, better TPSA and HBA, and slightly better binding affinity. The slightly lower half-life and higher clearance of Ligand A are less concerning than the higher DILI and hERG risks associated with Ligand B. The solubility is a concern for both, but can be addressed through formulation.

Output:
1
2025-04-17 14:15:12,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.4 & 361.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.46) is slightly above the preferred <140 for good oral absorption, while Ligand B (71.84) is well within the range.

**logP:** Ligand A (-0.007) is a bit low, potentially hindering permeation. Ligand B (3.228) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.507 and 0.794, respectively), indicating drug-likeness.

**DILI:** Both ligands have similar DILI risk (54.634 and 55.68), which is acceptable (below 60).

**BBB:** Ligand A (30.167) has low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (70.88) has good BBB penetration, but this isn't a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.396 and -5.017), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.281 and -3.747), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.049) has a very low hERG risk, which is excellent. Ligand B (0.695) has a moderate hERG risk, but still within acceptable limits.

**Microsomal Clearance:** Ligand A (28.316) has lower microsomal clearance than Ligand B (51.813), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.051) has a very short half-life, which is a significant concern. Ligand B (15.915) has a much better half-life.

**P-gp Efflux:** Ligand A (0.08) has low P-gp efflux, which is good. Ligand B (0.545) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A's significantly stronger binding affinity (-9.3 vs -6.6 kcal/mol) and lower microsomal clearance are compelling advantages. The difference in affinity is large enough to potentially overcome the solubility/permeability issues through formulation strategies. Ligand B has a better half-life, but the affinity difference is too significant to ignore.

Output:
0
2025-04-17 14:15:12,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (415.288 Da) is slightly higher than Ligand B (347.39 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (84.0 and 82.43) well below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (1.737 and 1.701), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.81 and 0.849), indicating a strong drug-like profile.

**DILI:** Ligand A has a DILI risk of 73.052, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk (38.581), indicating a better safety profile.

**BBB:** Both have reasonable BBB penetration, but Ligand B (71.268) is slightly better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.399 and -4.351), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.453 and -2.781), also suggesting poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.295) has a slightly lower hERG inhibition risk than Ligand B (0.695), which is preferable.

**Microsomal Clearance:** Ligand B has a significantly lower microsomal clearance (9.114 mL/min/kg) than Ligand A (28.646 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (12.854 hours) than Ligand A (-13.954 hours). The negative value for Ligand A is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.056).

**Binding Affinity:** Both ligands have strong binding affinities (-9.6 and -8.4 kcal/mol). Ligand A has a 1.2 kcal/mol advantage in binding, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity, but its high DILI risk, negative in vitro half-life, and higher microsomal clearance are major concerns. Ligand B, while having slightly weaker binding, exhibits a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and comparable permeability and solubility issues. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The 1.2 kcal/mol difference in binding can potentially be overcome with further optimization, whereas mitigating the safety and metabolic concerns of Ligand A would be far more challenging.

Output:
1
2025-04-17 14:15:12,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (83.89) is better than Ligand B (56.59) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Both ligands have acceptable logP values (A: 1.912, B: 2.316), 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 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.817, B: 0.774), indicating drug-like properties.

**DILI:** Ligand A (34.238) has a significantly lower DILI risk than Ligand B (47.887), which is a major advantage. Both are below the 60 threshold, but A is much closer to 0.

**BBB:** Ligand B (72.082) has a higher BBB penetration score than Ligand A (45.522). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.855 and -4.904). These values are unusual and suggest poor permeability. However, these values are on a log scale, and the absolute values are very close.

**Aqueous Solubility:** Ligand A (-1.294) has better aqueous solubility than Ligand B (-3.276). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.183, B: 0.213).

**Microsomal Clearance:** Ligand A (21.326) has significantly lower microsomal clearance than Ligand B (82.17), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (34.124) has a longer in vitro half-life than Ligand B (-7.418). This is also a positive for metabolic stability and dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.04, B: 0.147).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a lower DILI risk, better solubility, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While Ligand B has better BBB penetration, this is not a priority for a non-CNS target like SRC. The negative Caco-2 values are concerning for both, but the other advantages of Ligand A make it the preferred choice.

Output:
1
2025-04-17 14:15:12,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.752 and 383.901 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.39) is slightly above the preferred <140, but acceptable. Ligand B (83.36) is well within the range, suggesting potentially better absorption.

**3. logP:** Both ligands (2.946 and 3.145) are within the optimal 1-3 range.

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

**5. H-Bond Acceptors:** Both have 5 HBA, also acceptable.

**6. QED:** Both ligands (0.554 and 0.52) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (85.227) has a higher DILI risk than Ligand B (56.572). This is a significant concern, as lower DILI is preferred.

**8. BBB:** Both ligands have similar, moderate BBB penetration (49.981 and 48.662). This isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.949 and -5.081), which is unusual and suggests poor permeability. This is a major red flag.

**10. Solubility:** Both ligands have negative solubility values (-4.131 and -4.296), indicating very poor aqueous solubility. This is a significant issue for bioavailability.

**11. hERG:** Both ligands have very low hERG risk (0.401 and 0.196), which is excellent.

**12. Cl_mic:** Ligand A (20.347) has a significantly lower microsomal clearance than Ligand B (43.814), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. t1/2:** Ligand A (92.005) has a much longer in vitro half-life than Ligand B (4.494), further supporting its better metabolic stability.

**14. Pgp:** Both ligands have low Pgp efflux (0.166 and 0.132).

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.3), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The primary drivers are its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. While both have poor solubility and permeability, metabolic stability is a more critical factor for enzyme inhibitors, as it directly impacts drug exposure. The small difference in binding affinity is unlikely to overcome the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 14:15:12,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.321 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.52) is slightly higher than Ligand B (61.8). Both are below the 140 A^2 threshold for oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (2.726 and 3.049), 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 high QED scores (0.811 and 0.826), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 85.227, which is high. Ligand B has a much lower DILI risk of 13.843, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Ligand A (76.464) has a better BBB penetration percentile than Ligand B (68.282), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.125) has worse Caco-2 permeability than Ligand B (-4.678).

**Aqueous Solubility:** Ligand A (-4.035) has worse aqueous solubility than Ligand B (-2.731).

**hERG:** Ligand A (0.386) has a slightly better hERG profile than Ligand B (0.807).

**Microsomal Clearance:** Ligand A (115.16) has higher microsomal clearance than Ligand B (32.21), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-10.291) has a much shorter half-life than Ligand B (22.616).

**P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux liability than Ligand B (0.142).

**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 noteworthy.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While Ligand A has slightly better BBB penetration and P-gp efflux, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and slightly improved binding affinity. The high DILI risk and poor metabolic stability of Ligand A are major concerns that outweigh its minor advantages.

Output:
1
2025-04-17 14:15:12,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.833 and 353.325 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (88.6) as it's closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.291 and 0.5), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5), both are acceptable.

**QED:** Both ligands have good QED scores (0.813 and 0.779), indicating drug-likeness.

**DILI:** Ligand B (61.07) has a slightly higher DILI risk than Ligand A (76.89), but both are acceptable. Lower is better.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand B (92.323) has better BBB penetration than Ligand A (70.299), but this is not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.483 and -4.321).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and requires further investigation. Ligand A (-3.17) is slightly better than Ligand B (-2.547).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.273 and 0.208).

**Microsomal Clearance:** Ligand A (27.408 mL/min/kg) has lower microsomal clearance than Ligand B (35.031 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-18.814 hours) has a significantly longer in vitro half-life than Ligand A (-10.2 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.142 and 0.013).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly better binding affinity than Ligand A (-6.3 kcal/mol). This is a crucial factor for enzyme inhibitors, and the 1.8 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand A has slightly better TPSA, logP, and solubility, Ligand B's superior binding affinity (-8.1 vs -6.3 kcal/mol) and longer half-life (-18.814 vs -10.2 hours) outweigh these minor advantages. The slightly higher DILI risk for Ligand B is acceptable given the strong potency and improved metabolic stability.

Output:
1
2025-04-17 14:15:12,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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, while Ligand B (358.511 Da) is also well within the range.

**TPSA:** Ligand A (78.25) is better than Ligand B (51.02). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.952, B: 3.821), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* lead to some 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 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.846, B: 0.756), indicating good drug-like properties.

**DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (55.525). This is a significant concern, as a lower DILI percentile is preferred.

**BBB:** Ligand A (64.637) has a lower BBB penetration percentile than Ligand B (78.558). While BBB isn't a primary concern for SRC (an intracellular kinase), it's a slight advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.57) shows poor Caco-2 permeability, while Ligand B (-5.318) also shows poor permeability. Both are quite low.

**Aqueous Solubility:** Ligand A (-5.378) has very poor aqueous solubility, while Ligand B (-3.497) is slightly better, but still poor. Solubility is a concern for both, but more so for Ligand A.

**hERG Inhibition:** Ligand A (0.756) has a slightly higher hERG risk than Ligand B (0.44). Lower hERG is preferred.

**Microsomal Clearance:** Ligand A (103.016) has a lower microsomal clearance than Ligand B (96.015), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (26.246) has a shorter half-life than Ligand B (3.127). This is a significant drawback for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.328, B: 0.664).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a crucial factor, and the 0.4 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the better candidate. While both have solubility and permeability issues, Ligand B has a significantly stronger binding affinity (-7.9 vs -8.3 kcal/mol), a lower DILI risk (55.525 vs 75.184), and a longer in vitro half-life (3.127 vs 26.246). The better binding affinity and lower toxicity risk outweigh the slightly higher logP and lower metabolic stability. Ligand A's poor solubility and short half-life are major drawbacks.

Output:
1
2025-04-17 14:15:12,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (71.53) is significantly better than Ligand B (88.61). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (2.475) is optimal, while Ligand B (4.392) is pushing the upper limit. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 7 HBA). Both are within acceptable ranges, but fewer H-bonds generally improves permeability.

**QED:** Ligand A (0.87) has a much better QED score than Ligand B (0.343), indicating a more drug-like profile.

**DILI:** Ligand B (87.515) has a significantly higher DILI risk than Ligand A (48.081). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.372) has a better BBB score than Ligand B (49.515).

**Caco-2 Permeability:** Ligand A (-4.669) shows better Caco-2 permeability than Ligand B (-4.843).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.867 and -4.175 respectively). This is a significant drawback for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.507) has a lower hERG risk than Ligand B (0.915). This is a crucial advantage.

**Microsomal Clearance:** Ligand B (52.576) has a slightly lower microsomal clearance than Ligand A (60.895), suggesting better metabolic stability. However, the difference isn't huge.

**In vitro Half-Life:** Ligand B (66.864) has a significantly longer in vitro half-life than Ligand A (-18.284). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.326 and 0.82 respectively).

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

**Overall Assessment:**

Ligand A is significantly better overall. While both have poor solubility, Ligand A has a much better safety profile (lower DILI and hERG risk), better drug-likeness (higher QED), and better permeability characteristics (lower TPSA, better Caco-2). The longer half-life of Ligand B is attractive, but the high DILI risk is a major red flag. The slightly better metabolic stability of Ligand B is not enough to overcome the other significant drawbacks.

Output:
1
2025-04-17 14:15:12,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.401 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (76.64), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (0.802) is slightly lower than ideal (1-3), but acceptable. Ligand B (1.25) is better within the optimal range.

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

**QED:** Both ligands have similar QED values (0.812 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (44.087) has a higher DILI risk than Ligand B (18.573). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.233) has a better BBB score than Ligand B (54.789).

**Caco-2 Permeability:** Ligand A (-4.605) has poorer Caco-2 permeability than Ligand B (-5.107), both are poor.

**Aqueous Solubility:** Ligand A (-2.449) has slightly better solubility than Ligand B (-1.564), both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.346 and 0.226).

**Microsomal Clearance:** Ligand B (-3.96) has significantly better metabolic stability (lower clearance) than Ligand A (4.914). This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-34.402) has a much longer in vitro half-life than Ligand A (-11.189). This is a significant benefit for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.054).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 1.6 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, Ligand B is superior overall due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and acceptable solubility. The difference in binding affinity, while notable, is likely surmountable with further optimization, whereas addressing the poor metabolic stability and higher toxicity risk of Ligand A would be more challenging. Given the enzyme-specific priorities, metabolic stability and safety are crucial.

Output:
1
2025-04-17 14:15:12,924 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.832 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (86.71) is slightly higher than Ligand B (74.57), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.365) is slightly higher than Ligand B (1.027).

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

**QED:** Both ligands have QED scores above 0.5, indicating good drug-likeness. Ligand A (0.825) is slightly better than Ligand B (0.573).

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (39.473). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (29.12) has a higher BBB penetration than Ligand A (18.069), but this is not a major factor in this decision.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.045) is worse than Ligand B (-4.837).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.939) is worse than Ligand B (-1.67).

**hERG:** Both ligands have low hERG inhibition liability, which is good. Ligand A (0.456) is slightly higher than Ligand B (0.225).

**Microsomal Clearance:** Ligand B (-13.139) has significantly lower (better) microsomal clearance than Ligand A (51.116). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-0.44) has a slightly better (less negative) in vitro half-life than Ligand A (-21.547).

**P-gp Efflux:** Both ligands have low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly better 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, which is the most important factor for an enzyme inhibitor. However, it has significantly higher DILI risk, worse metabolic stability (higher Cl_mic), and worse solubility and permeability. Ligand B has better ADME properties (lower DILI, better Cl_mic, better solubility), but its binding affinity is very weak.

The difference in binding affinity (7.6 kcal/mol) is substantial and likely outweighs the ADME concerns of Ligand A, *provided* the DILI risk can be mitigated through structural modifications. The poor solubility and permeability are also concerning, but these can often be addressed through formulation strategies. The weak binding of Ligand B is a more fundamental issue that would be difficult to overcome.

Output:
1
2025-04-17 14:15:12,924 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.519 and 370.534 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (43.86 and 42.43) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.5) is optimal, while Ligand B (4.597) is approaching the upper limit and could potentially cause solubility issues or off-target effects.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both are within the acceptable range of <=10.

**QED:** Ligand A (0.766) has a better QED score than Ligand B (0.597), indicating a more drug-like profile.

**DILI:** Ligand A (10.702) has a significantly lower DILI risk than Ligand B (14.657), which is a major advantage.

**BBB:** Both have good BBB penetration, but Ligand B (92.051) is slightly better than Ligand A (83.831). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are relatively close (-4.819 vs -4.375).

**Aqueous Solubility:** Ligand A (-1.302) has better solubility than Ligand B (-4.729), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.708 and 0.683), which is excellent.

**Microsomal Clearance:** Ligand A (44.111) has significantly lower microsomal clearance than Ligand B (103.65), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.012) has a longer in vitro half-life than Ligand B (5.901), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.214 and 0.511).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). The difference is 0.8 kcal/mol, which is not a huge advantage.

**Overall Assessment:**

Ligand A is superior due to its better QED, significantly lower DILI risk, better solubility, and improved metabolic stability (lower Cl_mic and longer t1/2). While Ligand B has a slightly better binding affinity, the ADME advantages of Ligand A outweigh this small difference in potency. The solubility and metabolic stability are particularly important for kinase inhibitors.

Output:
0
2025-04-17 14:15:12,924 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.37 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (20.31) is excellent, well below the 140 threshold, suggesting good absorption. Ligand B (78.87) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.778) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.706) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 1 HBA) is very favorable. Ligand B (2 HBD, 4 HBA) is also good, within the recommended limits.

**QED:** Both ligands have similar QED values (0.69 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A (17.449) has a much lower DILI risk than Ligand B (32.92), a significant advantage.

**BBB:** Ligand A (97.247) shows excellent BBB penetration, while Ligand B (54.75) is lower. This isn't a primary concern for a non-CNS target like SRC, but it could be a benefit if off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.585 and -4.566). This is unusual and suggests poor permeability *in vitro*. However, these values are on a log scale, and the absolute differences are small, so it's not a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.711 and -2.431), indicating poor aqueous solubility. Ligand B is slightly better, but both are problematic.

**hERG Inhibition:** Ligand A (0.952) has a slightly higher hERG risk than Ligand B (0.241). This is a concern for Ligand A.

**Microsomal Clearance:** Ligand A (37.337) has lower microsomal clearance than Ligand B (44.882), indicating better metabolic stability.

**In vitro Half-Life:** Both have negative half-life values (-16.784 and -17.807). These are likely errors or indicate very rapid degradation. The difference is small.

**P-gp Efflux:** Ligand A (0.592) has lower P-gp efflux than Ligand B (0.12), suggesting better bioavailability.

**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 can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower DILI risk, and better metabolic stability. While it has a higher logP and hERG risk, the strong binding affinity is a major advantage for an enzyme target. The solubility issues are a concern for both, but can be addressed with formulation strategies. Ligand B has better logP and hERG, but its weaker binding affinity is a significant drawback.

Output:
0
2025-04-17 14:15:12,924 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 361.32 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (105.64).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is pushing the upper limit, potentially impacting absorption.

**logP:** Both ligands have good logP values (2.662 and 1.298), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (3 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have acceptable QED scores (0.496 and 0.824), with Ligand B being significantly better.

**DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (52.695). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (77.705) is better than Ligand A (68.554). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.928 and -5.102), 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 (-2.614 and -3.516), indicating poor aqueous solubility. Ligand B is slightly worse.

**hERG:** Both have low hERG inhibition risk (0.444 and 0.369).

**Microsomal Clearance:** Ligand B (-10.368) has a much lower (better) microsomal clearance than Ligand A (48.609), indicating better metabolic stability.

**In vitro Half-Life:** Both have negative in vitro half-life values (-9.443 and -9.964), which is also unusual.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.103 and 0.041).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This 0.8 kcal/mol difference is significant, and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in DILI risk and has a slightly better logP. However, it suffers from significantly higher microsomal clearance and a worse TPSA. Ligand B has a superior binding affinity, better QED, better BBB, and significantly improved metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the improved potency and metabolic stability of Ligand B are more critical for an enzyme target like SRC kinase. The 0.8 kcal/mol difference in binding affinity is substantial.

Output:
1
2025-04-17 14:15:12,925 - INFO - Batch 281 complete. Total preferences: 4496
2025-04-17 14:15:12,925 - INFO - Processing batch 282/512...
2025-04-17 14:16:02,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.491 and 353.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.45) is well below the 140 threshold, suggesting good absorption. Ligand B (93.78) is higher, but still within a reasonable range, though potentially slightly less favorable for absorption.

**logP:** Ligand A (4.303) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (-0.101) is quite low, which could hinder membrane permeability.

**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:** Ligand A (0.693) has a good drug-likeness score. Ligand B (0.478) is lower, indicating a less ideal overall drug-like profile.

**DILI:** Ligand A (64.754) has a moderate DILI risk. Ligand B (12.175) has a very low DILI risk, which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (59.364 and 63.784), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.427) has poor Caco-2 permeability. Ligand B (-5.37) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.55) has poor solubility. Ligand B (-0.615) has slightly better solubility, but is still poor.

**hERG Inhibition:** Ligand A (0.631) has a relatively low hERG risk. Ligand B (0.243) has a very low hERG risk, a major advantage.

**Microsomal Clearance:** Ligand A (66.396) has moderate clearance, suggesting moderate metabolic stability. Ligand B (-9.376) has *negative* clearance, which is not physically possible 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 (33.427 hours) has a reasonable half-life. Ligand B (-1.109 hours) has a negative half-life, which is impossible and another indication of data issues.

**P-gp Efflux:** Ligand A (0.699) has moderate P-gp efflux. Ligand B (0.001) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), but the difference is not substantial enough to overcome the severe ADME issues.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, the negative values for microsomal clearance and in vitro half-life are critical flaws. These values are physically impossible and indicate significant issues with the data or the compound's behavior. Ligand A, while having a higher logP and lower solubility, has plausible ADME properties. Therefore, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 14:16:02,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.483 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is slightly higher than Ligand B (43.86), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (4.112) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.382) is 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 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.873) has a significantly better QED score than Ligand B (0.692), indicating a more drug-like profile.

**DILI:** Ligand A (23.226) has a much lower DILI risk than Ligand B (8.918), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (85.498 and 82.047), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values, which is unusual and suggests potential issues with intestinal absorption. However, these values can be unreliable and should be confirmed experimentally.

**Aqueous Solubility:** Ligand A (-5.149) has poorer solubility than Ligand B (-1.278).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.73 and 0.723).

**Microsomal Clearance:** Ligand A (117.498) has significantly higher microsomal clearance than Ligand B (28.297), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-11.262) has a negative half-life, which is not physically possible and indicates a problem with the data or assay. Ligand A (0.59) has a very short half-life.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.736 and 0.149).

**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 its ADME drawbacks.

**Conclusion:**

Despite Ligand A's superior binding affinity, its significantly higher microsomal clearance, lower solubility, and questionable half-life are major concerns. Ligand B, while having a slightly weaker affinity, exhibits much better metabolic stability (lower Cl_mic), better solubility, and a more reasonable (though still problematic) half-life. The difference in binding affinity (1.1 kcal/mol) is substantial, but the ADME profile of Ligand A is too risky. The negative half-life for Ligand B is a data quality issue that needs to be resolved, but even without that, the metabolic stability is a key advantage.

Output:
1
2025-04-17 14:16:02,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.463 and 350.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.84) is better than Ligand B (103.01), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (0.857) is slightly better than Ligand A (0.485). Both are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.677) has a significantly better QED score than Ligand A (0.288), indicating a more drug-like profile.

**DILI:** Ligand A (33.075) has a lower DILI risk than Ligand B (41.101), which is preferable.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (44.746) is slightly higher than Ligand A (30.554).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-5.558) is slightly better than Ligand A (-5.196), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests very poor solubility. Ligand A (-1.327) is slightly better than Ligand B (-2.077).

**hERG:** Ligand A (0.132) has a much lower hERG risk than Ligand B (0.463), a significant advantage.

**Microsomal Clearance:** Ligand B (-6.773) has a significantly lower (better) microsomal clearance than Ligand A (14.37), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.871) has a longer in vitro half-life than Ligand A (-2.362), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.024 and 0.022), which is good.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand B has several advantages: better QED, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. However, Ligand A has a significantly lower hERG risk and DILI risk. The poor Caco-2 and solubility for both are concerning, but the difference in hERG risk is a critical factor for kinase inhibitors. Given the importance of minimizing off-target effects and cardiotoxicity for kinase inhibitors, the lower hERG risk of Ligand A is a major advantage. The slightly better affinity of Ligand B doesn't outweigh the higher hERG risk.

Output:
0
2025-04-17 14:16:02,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.483 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.35) is better than Ligand B (98.66), being comfortably under the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (-1.16) is a bit low, potentially hindering permeation, while Ligand B (1.724) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (6) are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.541 and 0.632), indicating drug-likeness.

**DILI:** Ligand A (5.312) has a significantly lower DILI risk than Ligand B (37.65), which is a substantial advantage.

**BBB:** Ligand A (22.838) has a very low BBB penetration, while Ligand B (83.172) is much better. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.024 and -5.216), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.133 and -2.52), which is also a concern. Ligand B is worse in this regard.

**hERG:** Both ligands have very low hERG inhibition risk (0.217 and 0.165), which is excellent.

**Microsomal Clearance:** Ligand A (30.271) has a much lower microsomal clearance than Ligand B (60.791), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-11.341) has a negative half-life, which is problematic. Ligand B (0.867) is better, but still relatively short.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.208).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a 0.7 kcal/mol stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's better logP and binding affinity, Ligand A exhibits significantly lower DILI risk and better metabolic stability (lower Cl_mic). The negative Caco-2 and solubility values are concerning for both, but the lower DILI and Cl_mic for Ligand A are more critical for an enzyme target like SRC kinase. The binding affinity difference, while notable, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 14:16:02,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values (63.57 and 64.55) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (2.102) being slightly more favorable. Ligand B's logP of 3.209 is still acceptable but closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=0, HBA=6) both have reasonable H-bond properties.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness, but Ligand A (0.829) is significantly better than Ligand B (0.57).

**DILI:** Ligand A (14.114%) has a much lower DILI risk than Ligand B (80.807%). This is a major advantage for Ligand A.

**BBB:** While not a primary concern for a kinase inhibitor, Ligand B (93.486%) shows better BBB penetration than Ligand A (83.676%).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**Aqueous Solubility:** Ligand A (-1.813) has better aqueous solubility than Ligand B (-4.574). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.595 and 0.53), which is good.

**Microsomal Clearance:** Ligand A (61.713 mL/min/kg) has significantly lower microsomal clearance than Ligand B (102.009 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.711 hours) has a slightly better in vitro half-life than Ligand B (-12.273 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.097 and 0.317).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -8.1 kcal/mol). Ligand A is slightly better (-9.0 kcal/mol).

**Overall Assessment:**

Ligand A is the superior candidate. It has a better QED score, significantly lower DILI risk, better solubility, lower microsomal clearance (better metabolic stability), and a slightly better binding affinity. While Ligand B has slightly better BBB penetration, this is less critical for an enzyme target like SRC kinase. The substantial advantages of Ligand A in safety (DILI) and pharmacokinetic properties (clearance, solubility) outweigh the minor difference in BBB penetration.

Output:
0
2025-04-17 14:16:02,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.45 & 359.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (77.05). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have similar logP values (2.89 & 2.99), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=0, HBA=7). Lower HBA is generally preferred for better permeability.

**QED:** Ligand A (0.772) has a higher QED score than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand A (30.83) has a much lower DILI risk than Ligand B (59.17), which is a significant advantage.

**BBB:** Ligand A (93.37) has a much higher BBB penetration percentile than Ligand B (57.15). While SRC is not necessarily a CNS target, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Ligand A (-4.559) has a better Caco-2 permeability than Ligand B (-5.222).

**Aqueous Solubility:** Ligand A (-3.002) has better aqueous solubility than Ligand B (-1.921).

**hERG:** Ligand A (0.849) has a lower hERG inhibition liability than Ligand B (0.585), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (58.60) has a lower microsomal clearance than Ligand B (73.46), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.83) has a significantly longer in vitro half-life than Ligand B (-34.27). This is a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.435) has lower P-gp efflux liability than Ligand B (0.258).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). The difference is 1 kcal/mol, which is significant enough to outweigh some minor ADME drawbacks.

**Overall:** Ligand A consistently outperforms Ligand B across most critical parameters, particularly DILI, hERG, metabolic stability (Cl_mic and t1/2), solubility, and QED. While both have acceptable logP and MW, Ligand A's superior ADMET profile and slightly better binding affinity make it the more promising drug candidate.

Output:
1
2025-04-17 14:16:02,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (347.296 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is well below the 140 threshold, while Ligand B (105.04) is still acceptable but higher. Lower TPSA generally favors better absorption.

**logP:** Ligand A (4.619) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.443) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 7 HBAs. Both are within the acceptable limits, but Ligand A is better.

**QED:** Both ligands have similar QED values (0.724 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (98.022 percentile), which is a major concern. Ligand B has a much lower DILI risk (30.71 percentile), a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (80.264) has better penetration than Ligand B (46.452).

**Caco-2 Permeability:** Ligand A (-4.571) has poor Caco-2 permeability, while Ligand B (-5.751) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-6.055) has very poor solubility, consistent with its high logP. Ligand B (-0.8) is better, but still relatively poor.

**hERG Inhibition:** Ligand A (0.774) has a moderate hERG risk. Ligand B (0.047) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (59.244 mL/min/kg) has moderate clearance, while Ligand B (-18.769 mL/min/kg) has negative clearance, indicating excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (89.403 hours) has a good half-life. Ligand B (16.125 hours) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.358) has low P-gp efflux, while Ligand B (0.008) has very low P-gp efflux. Both are good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.3 kcal/mol), with Ligand B being slightly better. The difference is small enough that it doesn't outweigh other factors.

**Overall Assessment:**

Ligand A suffers from high DILI risk, poor solubility, and poor Caco-2 permeability, despite its good half-life and reasonable BBB. Ligand B, while having lower solubility and permeability than ideal, has a significantly lower DILI risk and *much* better metabolic stability (negative Cl_mic), which is crucial for an enzyme inhibitor. The slightly better affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 14:16:02,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.471 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (96.11). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (2.564 and 1.261), 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=3, HBA=4) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.863) has a significantly higher QED score than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand B (60.14) has a higher DILI risk than Ligand A (17.836). This is a major concern, as a percentile >60 is considered high risk.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (74.758) has a slightly better BBB score than Ligand B (64.637).

**Caco-2 Permeability:** Ligand A (-4.894) is better than Ligand B (-5.569), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.482) is better than Ligand B (-2.526), indicating better solubility.

**hERG Inhibition:** Ligand A (0.309) has a much lower hERG inhibition liability than Ligand B (0.633), which is a significant advantage.

**Microsomal Clearance:** Ligand B (45.688) has slightly better microsomal clearance than Ligand A (42.071), suggesting slightly better metabolic stability. However, the difference is small.

**In vitro Half-Life:** Ligand B (5.684) has a longer half-life than Ligand A (-2.735). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux than Ligand B (0.291).

**Binding Affinity:** Ligand A (-8.2) has a significantly stronger binding affinity than Ligand B (0.0). This is the most crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is very significant.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has a slightly better half-life and microsomal clearance, Ligand A excels in almost every other critical parameter, especially binding affinity (-8.2 vs 0.0 kcal/mol), DILI risk (17.8 vs 60.1), hERG risk (0.3 vs 0.6), solubility, and QED score. The strong binding affinity of Ligand A outweighs the minor advantage of Ligand B's metabolic stability.

Output:
1
2025-04-17 14:16:02,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 357.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.3) is better than Ligand B (53.51). Both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.105 and 2.879), falling 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 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.882 and 0.845), indicating good drug-likeness.

**DILI:** Ligand A (45.483) has a slightly higher DILI risk than Ligand B (37.728), but both are below the concerning threshold of 60.

**BBB:** Ligand A (81.233) has better BBB penetration than Ligand B (72.586), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.812) has slightly better Caco-2 permeability than Ligand B (-4.92), but both are negative values which is not ideal.

**Aqueous Solubility:** Ligand A (-2.914) has slightly better solubility than Ligand B (-2.625), but both are negative values which is not ideal.

**hERG Inhibition:** Ligand A (0.07) has a lower hERG inhibition liability than Ligand B (0.567), which is a significant advantage.

**Microsomal Clearance:** Ligand A (4.219) has significantly lower microsomal clearance than Ligand B (40.285), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (12.731) has a shorter half-life than Ligand B (16.426), but the difference is not substantial.

**P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux liability than Ligand B (0.215), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.8 kcal/mol), with Ligand B being slightly better. However, the difference is small and can be potentially overcome with further optimization.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. These factors are particularly important for an enzyme inhibitor like an SRC kinase inhibitor, as metabolic stability and minimizing off-target effects (like hERG inhibition) are crucial for clinical success. The slight advantage in solubility and TPSA also contribute to its favorability.

Output:
0
2025-04-17 14:16:02,349 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.487, 58.64, 2.35, 1, 3, 0.685, 5.777, 80.574, -4.409, -2.507, 0.37, 25.302, 1.466, 0.033, -7.5]
**Ligand B:** [366.527, 58.64, 3.148, 1, 4, 0.806, 22.257, 77.782, -4.845, -3.061, 0.714, 26.639, 40.368, 0.364, -7.8]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (348.487) is slightly preferred due to being closer to the lower end, potentially aiding permeability.
2. **TPSA:** Both are similar and acceptable (58.64). Both are well below the 140 A^2 threshold for oral absorption.
3. **logP:** A (2.35) is optimal, while B (3.148) is approaching the upper limit. A is slightly preferred.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A has 3 HBA, B has 4. Both are acceptable (<=10).
6. **QED:** Both are reasonable, but B (0.806) is better than A (0.685), indicating a more drug-like profile.
7. **DILI:** A (5.777) is significantly better than B (22.257), indicating a much lower risk of liver injury. This is a major advantage for A.
8. **BBB:** A (80.574) is slightly better than B (77.782), though both are acceptable. Not a primary concern for SRC kinase, but a slight edge to A.
9. **Caco-2:** Both are negative, indicating poor permeability. B (-4.845) is worse than A (-4.409). A is preferred.
10. **Solubility:** Both are negative, indicating poor solubility. B (-3.061) is worse than A (-2.507). A is preferred.
11. **hERG:** A (0.37) is much better than B (0.714), indicating lower cardiotoxicity risk. This is a significant advantage for A.
12. **Cl_mic:** A (25.302) is significantly better than B (26.639), indicating better metabolic stability. This is a key factor for kinase inhibitors.
13. **t1/2:** A (1.466) is much worse than B (40.368). This is a major advantage for B.
14. **Pgp:** A (0.033) is much better than B (0.364), indicating lower efflux and better bioavailability. This is a significant advantage for A.
15. **Binding Affinity:** B (-7.8) is slightly better than A (-7.5), but the difference is relatively small (0.3 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

*   **Affinity:** B has a slightly better affinity, but the difference isn't huge.
*   **Metabolic Stability:** A is better (lower Cl_mic).
*   **Solubility:** A is better.
*   **hERG:** A is significantly better.
*   **t1/2:** B is *much* better.
*   **DILI:** A is significantly better.
*   **Pgp:** A is significantly better.

**Conclusion:**

While ligand B has a slightly better binding affinity and a significantly longer half-life, ligand A demonstrates a superior overall profile, particularly regarding safety (DILI, hERG), metabolic stability (Cl_mic), solubility, and P-gp efflux. The longer half-life of B is attractive, but the significant improvements in safety and ADME properties with A outweigh this benefit. The slightly better affinity of B is unlikely to overcome the substantial ADME/Tox advantages of A.

Therefore, I would select **Ligand A** as the more viable drug candidate.

Output:
0
2025-04-17 14:16:02,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.355 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (41.57) is significantly better than Ligand A (112.91). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.414, Ligand B: 3.668), falling within the 1-3 range. Ligand B is closer to the upper limit, which could potentially lead to solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 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 values (Ligand A: 0.65, Ligand B: 0.742), indicating drug-like properties.

**DILI:** Ligand B (32.803) has a much lower DILI risk than Ligand A (81.621). This is a significant advantage for Ligand B.

**BBB:** Ligand B (71.229) has a better BBB percentile than Ligand A (45.909), although BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.582) has a more negative Caco-2 value, suggesting *lower* permeability than Ligand B (-4.897).

**Aqueous Solubility:** Ligand A (-3.284) has a more negative solubility value, suggesting *lower* solubility than Ligand B (-5.094).

**hERG Inhibition:** Ligand A (0.403) has a lower hERG inhibition liability than Ligand B (0.871), which is favorable.

**Microsomal Clearance:** Ligand A (18.743) has significantly lower microsomal clearance than Ligand B (84.344), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand B (52.133) has a much longer in vitro half-life than Ligand A (-7.151), suggesting better stability.

**P-gp Efflux:** Ligand A (0.177) has lower P-gp efflux liability than Ligand B (0.494), which is preferable.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.5). The difference is 1.5 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability (lower Cl_mic), and lower P-gp efflux. However, Ligand B excels in DILI risk, BBB penetration, solubility, and half-life. The lower DILI risk and better solubility of Ligand B are very important. The significant difference in metabolic stability (Cl_mic) favors Ligand A, but the affinity difference is only 1.5 kcal/mol. Given the importance of metabolic stability for kinase inhibitors, and the acceptable ADME profile of Ligand B, I would choose Ligand B.

Output:
1
2025-04-17 14:16:02,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.451 and 347.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.29) is better than Ligand B (99.77), being comfortably below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.631 and 2.944), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is slightly better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.68 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (57.038) has a significantly lower DILI risk than Ligand B (72.392). This is a crucial advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (65.839) has a higher BBB score than Ligand A (19.116), but this is not a major deciding factor here.

**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:** Ligand A (-1.875) has slightly better solubility than Ligand B (-3.678).

**hERG:** Ligand A (0.661) has a much lower hERG risk than Ligand B (0.134). This is a significant advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (20.725) has a higher microsomal clearance than Ligand A (13.22), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (31.456) has a longer in vitro half-life than Ligand B (16.96), which is desirable.

**P-gp Efflux:** Ligand A (0.356) shows lower P-gp efflux liability than Ligand B (0.138), which is favorable.

**Binding Affinity:** Ligand A (-7.7 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 picture.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It demonstrates a significantly better safety profile (lower DILI and hERG risk), improved metabolic stability (lower Cl_mic, longer t1/2), better solubility, and slightly better binding affinity. While both ligands have issues with Caco-2 permeability, the other advantages of Ligand A outweigh this concern.

Output:
1
2025-04-17 14:16:02,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (381.523 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.5) is slightly higher than Ligand B (67.23). Both are below the 140 threshold for oral absorption, but Ligand B is preferable for potentially better absorption.

**logP:** Both ligands have good logP values (1.136 and 2.142), 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 (0.741 and 0.91), indicating good drug-like properties.

**DILI:** Ligand A (36.293) has a lower DILI risk than Ligand B (18.108), which is favorable.

**BBB:** Ligand A (74.486) has a higher BBB penetration percentile than Ligand B (52.811). While not a primary concern for a kinase inhibitor, higher BBB is generally a plus.

**Caco-2 Permeability:** Ligand A (-5.605) has worse Caco-2 permeability than Ligand B (-4.709).

**Aqueous Solubility:** Ligand A (-2.242) has worse aqueous solubility than Ligand B (-1.447). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.189 and 0.244).

**Microsomal Clearance:** Ligand A (24.107) has lower microsomal clearance than Ligand B (39.303), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-19.648) has a significantly longer in vitro half-life than Ligand B (-5.405), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.097 and 0.038).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). The difference of 1.1 kcal/mol is significant and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic and longer t1/2), and a lower DILI risk. While its solubility and Caco-2 permeability are slightly worse than Ligand B, the improved potency and metabolic stability are more critical for an enzyme inhibitor like an SRC kinase inhibitor. The slightly better BBB penetration is a minor bonus.

Output:
1
2025-04-17 14:16:02,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.603 Da and 363.437 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is slightly higher than Ligand B (45.46), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have logP values around 4 (3.947 and 4.043), which is at the upper limit of the optimal range. This could potentially lead to solubility issues, but is not a major concern at this stage.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 6. While both are within the acceptable range of <=10, Ligand A is preferable due to the lower HBA count.

**QED:** Both ligands have good QED scores (0.593 and 0.743), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (9.926 and 85.072), but Ligand A is significantly lower. This is a major advantage for Ligand A.

**BBB:** Ligand A (84.257) has a much higher BBB penetration percentile than Ligand B (68.631). While not a primary concern for a kinase inhibitor, better BBB penetration could be beneficial.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.977 and -4.696). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.056 and -4.466), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.862 and 0.855), which is good.

**Microsomal Clearance:** Ligand B (44.814) has significantly lower microsomal clearance than Ligand A (88.598), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-3.919) has a negative half-life, which is a concerning outlier. Ligand A has a half-life of 15.116, which is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.3 and 0.672), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 kcal/mol and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic) and a slightly better QED, Ligand A is superior overall. The significantly lower DILI risk and more reasonable in vitro half-life of Ligand A outweigh the benefits of Ligand B's metabolic stability. Both compounds have poor solubility and permeability, which would need to be addressed in further optimization. However, considering the priorities for enzyme inhibitors, the lower DILI risk and more reasonable half-life of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 14:16:02,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.849 and 350.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.67 and 87.66) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.278 and 1.99) 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.561 and 0.685), indicating drug-like properties.

**DILI:** Ligand A (60.721) has a higher DILI risk than Ligand B (47.926), but both are reasonably acceptable.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (71.501) is slightly better than Ligand A (68.67). This is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.834) has worse Caco-2 permeability than Ligand B (-5.39). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.09) has slightly better solubility than Ligand B (-3.343).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.286 and 0.419).

**Microsomal Clearance:** Ligand B (-6.053) has significantly better metabolic stability (lower clearance) than Ligand A (50.7). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-1.997) has a longer predicted half-life than Ligand A (22.227). This is also a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.295 and 0.081).

**Binding Affinity:** Ligand A (0) has a slightly worse binding affinity than Ligand B (0).

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands have acceptable physicochemical properties, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. These factors are critical for an enzyme target like SRC kinase. The slightly better BBB penetration and lower DILI risk of Ligand B are additional benefits. The Caco-2 permeability is poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:16:02,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.397 Da) is slightly higher than Ligand B (336.435 Da), but this isn't a major concern.

**TPSA:** Ligand A (50.8) is better than Ligand B (61.36). Both are acceptable, but lower TPSA generally favors better absorption.

**logP:** Ligand A (3.04) is optimal, while Ligand B (4.065) is pushing the upper limit. Higher logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=2). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.908) is excellent, indicating high drug-likeness. Ligand B (0.774) is still good, but not as strong.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 56.727, Ligand B: 50.291). Ligand B is slightly better.

**BBB:** Ligand A (85.072) has better BBB penetration than Ligand B (61.846), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.15) is better than Ligand B (-5.126). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.972) is better than Ligand B (-4.447). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.397) has a much lower hERG risk than Ligand B (0.715), which is a significant advantage.

**Microsomal Clearance:** Ligand A (42.48) has lower clearance than Ligand B (58.233), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.007) has a much longer half-life than Ligand B (13.802). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.152) has lower P-gp efflux than Ligand B (0.33), indicating better bioavailability.

**Binding Affinity:** Ligand A (-8.4) has significantly stronger binding affinity than Ligand B (-0.0). This is the most important factor for an enzyme inhibitor. A difference of 8.4 kcal/mol is substantial.

**Conclusion:**

Ligand A is clearly superior to Ligand B. It has a better safety profile (lower hERG, lower DILI), better ADME properties (solubility, permeability, metabolic stability, P-gp efflux), and, most importantly, *significantly* higher binding affinity. The superior affinity of Ligand A outweighs any minor drawbacks it might have.

Output:
1
2025-04-17 14:16:02,350 - INFO - Batch 282 complete. Total preferences: 4512
2025-04-17 14:16:02,350 - INFO - Processing batch 283/512...
2025-04-17 14:16:50,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.53 and 345.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (95.57). A TPSA under 140 is good for oral absorption, and both meet this, but A is more favorable.

**logP:** Both ligands have similar logP values (2.055 and 2.096), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBAs, while Ligand B has 6. Both are within the acceptable limit of 10, but A is slightly better.

**QED:** Ligand A (0.635) has a better QED score than Ligand B (0.44), indicating a more drug-like profile.

**DILI:** Ligand A (23.50) has a much lower DILI risk than Ligand B (33.35), which is a significant advantage. Both are below the 40 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (67.47) has a higher BBB penetration than Ligand A (51.96).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Again, similar magnitudes.

**hERG:** Both ligands have a low hERG risk (0.362 and 0.358).

**Microsomal Clearance:** Ligand A (31.47) has significantly lower microsomal clearance than Ligand B (100.08), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (8.92 hours) has a shorter half-life than Ligand B (18.26 hours). While longer is generally preferred, the difference isn't massive.

**P-gp Efflux:** Both have low P-gp efflux liability (0.209 and 0.031).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). This is a 1.1 kcal/mol difference, which is a reasonable advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all other crucial ADME-Tox properties. Specifically, its lower DILI risk and significantly better metabolic stability (lower Cl_mic) are major advantages for an enzyme target like SRC kinase. The better QED score and TPSA also contribute to its overall drug-likeness. The solubility and Caco-2 permeability are poor for both, but this can be addressed through formulation strategies. The binding affinity difference, while present, is unlikely to outweigh the substantial ADME benefits of Ligand A.

Output:
0
2025-04-17 14:16:50,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.479 and 350.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is well below the 140 threshold, while Ligand B (118.58) is still acceptable but higher. Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.368) is optimal (1-3). Ligand B (1.184) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Both ligands 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.

**QED:** Both ligands have reasonable QED scores (0.731 and 0.629), indicating good drug-like properties.

**DILI:** Ligand A (67.507) has a higher DILI risk than Ligand B (49.166). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (59.364) has a higher BBB value than Ligand A (35.905).

**Caco-2 Permeability:** Ligand A (-4.799) and Ligand B (-5.033) 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 (-4.395) and Ligand B (-2.86) both have negative solubility values, suggesting poor solubility. Again, the scale is unspecified.

**hERG:** Ligand A (0.673) has a slightly higher hERG risk than Ligand B (0.107). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand B (8.985) has significantly lower microsomal clearance than Ligand A (81.984), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-4.323) has a longer in vitro half-life than Ligand A (-14.434). This is another advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.474) has lower P-gp efflux than Ligand B (0.069), which is preferable.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 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 demonstrates superior ADME properties: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better P-gp efflux. The slightly lower logP of Ligand B is a minor concern, but the substantial advantages in ADME outweigh this. The poor Caco-2 and solubility values for both are concerning and would require further investigation, but the ADME profile of B is still better.

Output:
1
2025-04-17 14:16:50,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.377 and 360.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (93.01), both are below the 140 threshold for oral absorption, but A is closer to the preferred <90 for CNS targets (though not a primary concern here).

**logP:** Ligand A (2.607) is optimal (1-3), while Ligand B (0.768) 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). Both are within acceptable limits, but A strikes a better balance.

**QED:** Both ligands have good QED scores (0.653 and 0.869), indicating drug-likeness.

**DILI:** Ligand A (36.836) has a significantly lower DILI risk than Ligand B (52.966), which is a major advantage. Both are below the 60 threshold, but A is much safer.

**BBB:** This is less critical for a non-CNS target. Ligand A (71.966) is better than Ligand B (44.979).

**Caco-2 Permeability:** Ligand A (-4.826) is better than Ligand B (-5.129), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.111) is better than Ligand B (-2.306), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.519) is significantly better than Ligand B (0.169), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (28.317) has lower clearance than Ligand A (43.012), suggesting better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand A (39.258) has a better half-life than Ligand B (-4.809).

**P-gp Efflux:** Ligand A (0.138) is better than Ligand B (0.055), indicating lower efflux and potentially better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.3 kcal/mol), with Ligand A being slightly better. The difference is less than 1.5 kcal/mol, so this isn't the deciding factor.

**Overall:** While Ligand B has better metabolic stability (lower Cl_mic), Ligand A excels in almost every other crucial parameter: lower DILI risk, better solubility, lower hERG risk, better permeability, and slightly better binding affinity. The superior safety profile and ADME properties of Ligand A outweigh the slight metabolic advantage of Ligand B.

Output:
1
2025-04-17 14:16:50,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.447 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.98) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (89.87) is still within acceptable limits (<140) but less favorable than A.

**logP:** Ligand A (2.792) is optimal (1-3). Ligand B (0.828) is slightly low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is excellent. Ligand B (3 HBD, 4 HBA) is also acceptable, but slightly higher donor count could be a minor concern.

**QED:** Both ligands have good QED scores (0.912 and 0.619, respectively), indicating drug-like properties.

**DILI:** Ligand A (44.591) has a better DILI score than Ligand B (12.369), indicating lower potential for liver injury.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.012) is higher than Ligand B (47.344), but this is not a primary driver for selection.

**Caco-2 Permeability:** Ligand A (-4.8) is better than Ligand B (-5.07), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.854) is better than Ligand B (-1.97), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.54) has a lower hERG risk than Ligand B (0.173), which is a significant advantage.

**Microsomal Clearance:** Ligand A (22.661) has a higher (worse) clearance than Ligand B (16.113), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.54) has a significantly longer half-life than Ligand A (2.397), which is a major benefit.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux than Ligand B (0.063), which is favorable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (longer half-life). While Ligand A has advantages in solubility, DILI, and hERG, the potency difference is significant. The slightly lower logP of Ligand B is a minor concern, but its strong binding affinity makes it the more promising candidate. The better half-life will also improve dosing.

Output:
1
2025-04-17 14:16:50,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.3) is better than Ligand B (70.08), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.545 and 1.413), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 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 similar QED values (0.791 and 0.752), indicating good drug-likeness.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (10.392), but both are below the concerning threshold of 60. Ligand B is significantly better here.

**BBB:** Ligand A (70.997) has better BBB penetration than Ligand B (63.164), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.313) has worse Caco-2 permeability than Ligand B (-4.427), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.581) has worse aqueous solubility than Ligand B (-1.163). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.416 and 0.322).

**Microsomal Clearance:** Ligand A (15.893) has significantly lower microsomal clearance than Ligand B (44.542), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-30.076) has a much longer in vitro half-life than Ligand B (13.885), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.048 and 0.029).

**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.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has a slightly lower DILI risk and better Caco-2 permeability/solubility, Ligand A's significantly improved metabolic stability (lower Cl_mic and longer t1/2) is crucial for an enzyme inhibitor. The binding affinity is comparable between the two.

Output:
0
2025-04-17 14:16:50,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.853 Da and 361.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have similar TPSA values (88.99 and 88.91), well below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.636) is optimal, while Ligand B (1.695) is slightly lower but still acceptable.

**H-Bond Donors:** Both have 2 HBD, which is within the ideal range.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6 HBA, both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.862 and 0.7), indicating good drug-like properties.

**DILI:** Ligand A (69.833) has a slightly higher DILI risk than Ligand B (62.35), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (54.517) is higher than Ligand B (33.269).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This suggests poor permeability, but the scale is not clearly defined.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests poor solubility, but the scale is not clearly defined.

**hERG:** Ligand A (0.638) has a lower hERG risk than Ligand B (0.259), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-7.575) has *much* lower microsomal clearance than Ligand B (26.911). This indicates significantly better metabolic stability for Ligand A, a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand A (-14.393) has a much longer in vitro half-life than Ligand B (25.08), further supporting its superior metabolic stability.

**P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux than Ligand B (0.074), which is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.8 kcal/mol). Ligand A is slightly better (-9.0 kcal/mol).

**Overall Assessment:**

Ligand A is the superior candidate. While both ligands have good potency and drug-like properties, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower hERG risk. These are critical factors for enzyme inhibitors. The slightly better affinity and lower P-gp efflux further support the selection of Ligand A. The negative solubility and Caco-2 values are concerning for both, but the metabolic advantages of Ligand A outweigh these concerns, as solubility/permeability can be addressed through formulation strategies.

Output:
1
2025-04-17 14:16:50,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (340.427 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (76.02 and 75.88) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (1.014 and 1.544) 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 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.759 and 0.779), indicating good drug-like properties.

**7. DILI:** Ligand A (16.828) has a significantly lower DILI risk than Ligand B (42.807). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (46.413) has a lower BBB penetration than Ligand B (84.257). Since SRC is not a CNS target, this is not a major concern.

**9. Caco-2 Permeability:** Ligand A (-5.161) has worse Caco-2 permeability than Ligand B (-4.463), but both are negative values which is not ideal.

**10. Aqueous Solubility:** Ligand A (-1.826) has worse solubility than Ligand B (-0.774), but both are negative values which is not ideal.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.103 and 0.159).

**12. Microsomal Clearance:** Ligand A (-11.245) has significantly lower (better) microsomal clearance than Ligand B (47.248). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (10.093) has a shorter half-life than Ligand B (-14.564), which is a negative.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.077).

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.3), a 0.5 kcal/mol difference.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and BBB penetration, Ligand A demonstrates significantly better safety profiles with a much lower DILI risk and better metabolic stability (lower Cl_mic). The difference in binding affinity (0.5 kcal/mol) is not substantial enough to outweigh the significant advantages in safety and metabolic stability offered by Ligand A, especially for an enzyme target like SRC kinase where metabolic stability is crucial. The solubility and Caco-2 permeability are not ideal for either, but can be addressed through formulation strategies.

Output:
0
2025-04-17 14:16:50,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (361.877 Da) is also good.

**TPSA:** Ligand A (91.23) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (64.86) is well within the acceptable range.

**logP:** Ligand A (0.667) is a bit low, potentially hindering permeation. Ligand B (3.122) is optimal.

**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 similar QED values (0.763 and 0.767), indicating good drug-likeness.

**DILI:** Ligand A (13.571) has a significantly lower DILI risk than Ligand B (47.383). This is a major advantage for Ligand A.

**BBB:** Ligand A (38.813) has a low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (76.231) has better BBB penetration, but it's not a priority here.

**Caco-2 Permeability:** Ligand A (-5.039) has poor Caco-2 permeability, which is concerning. Ligand B (-4.767) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.219) has poor solubility, which could hinder bioavailability. Ligand B (-4.102) has even worse solubility.

**hERG Inhibition:** Ligand A (0.081) shows very low hERG inhibition risk, a significant advantage. Ligand B (0.139) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (8.291) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (48.982) has high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (22.805) has a longer half-life than Ligand B (-18.437), which is desirable.

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is good. Ligand B (0.247) has higher efflux.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.8 kcal/mol and -8.5 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While both have acceptable MW and QED, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a much lower hERG risk. Although its solubility and Caco-2 permeability are poor, the strong advantage in safety and metabolic stability outweigh these drawbacks, especially given the similar binding affinities.

Output:
0
2025-04-17 14:16:50,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (92.15) is better than Ligand B (36.44). Lower TPSA generally favors better absorption.

**logP:** Ligand A (1.837) is within the optimal range, while Ligand B (3.986) is approaching the upper limit. 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 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.719 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (36.293) has a slightly higher DILI risk than Ligand B (12.641), but both are below the concerning threshold of 60.

**BBB:** Ligand B (88.29) has a significantly higher BBB penetration score than Ligand A (66.77). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.418) has a very poor Caco-2 permeability, while Ligand B (-4.892) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-2.014) has better aqueous solubility than Ligand B (-3.011). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.13) has a much lower hERG inhibition liability than Ligand B (0.822), which is a significant advantage.

**Microsomal Clearance:** Ligand B (71.002) has a much higher microsomal clearance than Ligand A (13.74), indicating lower metabolic stability. This is a critical drawback for Ligand B.

**In vitro Half-Life:** Ligand A (28.104) has a longer in vitro half-life than Ligand B (11.841), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux liability than Ligand B (0.528), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand A (-8.6) has a significantly stronger binding affinity than Ligand B (0.0). This is the most important factor for an enzyme inhibitor. The difference of 8.6 kcal/mol is substantial and likely outweighs minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its significantly superior binding affinity, coupled with acceptable ADME properties (better solubility, lower hERG, lower clearance, lower P-gp efflux, and longer half-life) outweigh its slightly lower Caco-2 permeability and higher DILI risk compared to Ligand B. The strong binding affinity is crucial for an enzyme inhibitor like an SRC kinase inhibitor, and Ligand A has a clear advantage in this regard.

Output:
1
2025-04-17 14:16:50,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 362.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.19) is higher than Ligand B (53.43). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.249) is quite low, potentially hindering membrane permeability. Ligand B (4.011) is at the upper end of the optimal range, which could lead to solubility issues, 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.

**QED:** Both ligands have good QED scores (0.625 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A (51.881) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (86.274) has a higher BBB score than Ligand A (60.876).

**Caco-2 Permeability:** Ligand A (-5.301) has poor predicted Caco-2 permeability, while Ligand B (-4.787) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.259) has very poor predicted solubility, a significant drawback. Ligand B (-4.536) is also poor, but less so than Ligand A.

**hERG Inhibition:** Ligand A (0.268) has a lower hERG risk than Ligand B (0.692), which is a positive attribute.

**Microsomal Clearance:** Ligand A (37.429) has lower microsomal clearance than Ligand B (92.483), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (26.342) has a longer half-life than Ligand B (-9.386), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.045) has significantly lower P-gp efflux than Ligand B (0.447), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.8 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.

**Conclusion:**

Despite Ligand A's poor solubility and Caco-2 permeability, its significantly superior binding affinity (-8.8 vs -6.7 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The lower P-gp efflux is also a benefit. While solubility is a concern, it might be addressed through formulation strategies. The stronger binding is likely to be more impactful for efficacy in an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:16:50,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.808 Da and 351.403 Da) fall within the ideal 200-500 Da range.
**TPSA:** Ligand A (82.74) is well below the 140 threshold for oral absorption, and even below 90 for potential CNS penetration (though not a priority here). Ligand B (113.69) is still under 140, but higher. A favors better absorption.
**logP:** Ligand A (4.615) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.945) is a bit low, potentially hindering permeation.
**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is within acceptable limits. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher.
**QED:** Both ligands have reasonable QED scores (0.837 and 0.601), indicating good drug-like properties.
**DILI:** Ligand A has a higher DILI risk (85.964) than Ligand B (54.207). This is a significant drawback for Ligand A.
**BBB:** BBB is not a major concern for a non-CNS target like SRC kinase, but Ligand A (64.211) is better than Ligand B (41.218).
**Caco-2 Permeability:** Ligand A (-4.397) has poor Caco-2 permeability, indicating poor absorption. Ligand B (-5.236) is also poor, but slightly worse.
**Aqueous Solubility:** Ligand A (-6.554) has very poor aqueous solubility, a major concern. Ligand B (-2.187) is better, but still not great.
**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.402 and 0.134), which is excellent.
**Microsomal Clearance:** Ligand A (54.083) has moderate clearance, while Ligand B (5.669) has very low clearance, suggesting better metabolic stability. This is a significant advantage for Ligand B.
**In vitro Half-Life:** Ligand A (76.45) has a good half-life. Ligand B (45.437) is lower, but still reasonable.
**P-gp Efflux:** Both ligands show low P-gp efflux (0.168 and 0.169), which is good.
**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.

**Conclusion:**

Despite Ligand A's better TPSA and BBB, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.1 vs -7.5 kcal/mol) and much lower DILI risk (54.207 vs 85.964) and better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme target. While solubility and Caco-2 permeability are not ideal for either, the superior potency and safety profile of Ligand B make it the preferred choice.

Output:
1
2025-04-17 14:16:50,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.455 and 355.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.36) is better than Ligand B (41.15). While both are below 140, lower TPSA generally favors better absorption.

**3. logP:** Ligand A (1.63) is optimal, while Ligand B (4.992) is high. High logP can lead to solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable.

**6. QED:** Both ligands have similar QED values (0.482 and 0.411), indicating moderate drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (49.128 and 52.074), and are both acceptable.

**8. BBB:** Ligand A (36.448) has poor BBB penetration, while Ligand B (65.297) is better. However, BBB is not a high priority for a kinase inhibitor unless CNS targets are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It is difficult to interpret these values without knowing the scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. It is difficult to interpret these values without knowing the scale.

**11. hERG Inhibition:** Ligand A (0.568) has a lower hERG risk than Ligand B (0.933), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (57.164) has a lower (better) microsomal clearance than Ligand B (73.432), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (22.289) has a longer half-life than Ligand B (-14.739), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux than Ligand B (0.788), which is favorable for bioavailability.

**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.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all other crucial ADME properties. Specifically, Ligand A has a much better logP, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The slightly weaker binding of Ligand A can potentially be optimized during lead optimization, while fixing the poor ADME properties of Ligand B would be more challenging. Considering the enzyme-specific priorities, Ligand A is the more promising candidate.

Output:
0
2025-04-17 14:16:50,151 - INFO - Okay, let's analyze these two ligands (A and B) as potential drug candidates targeting SRC, a kinase. I'll follow the provided guidelines and prioritize potency, metabolic stability, solubility, and hERG risk, as appropriate for an enzyme target.

**Ligand A:** [361.467, 72.27, 1.904, 0., 5., 0.788, 52.423, 73.129, -5.11, -2.326, 0.266, 24.435, -0.616, 0.273, -9.6]
**Ligand B:** [346.431, 83.89, 1.912, 1., 5., 0.817, 34.238, 45.522, -4.855, -1.294, 0.183, 21.326, 34.124, 0.04, -8.1]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (361.467) and B (346.431) are both acceptable.
2. **TPSA:** A (72.27) is better than B (83.89). Both are below 140, suggesting reasonable absorption.
3. **logP:** Both are very similar and optimal (around 1.9). A (1.904) and B (1.912) are both good.
4. **HBD:** A (0) is preferable to B (1). Fewer HBDs generally improve permeability.
5. **HBA:** Both have 5 HBA, which is acceptable (<=10).
6. **QED:** Both are good, with A (0.788) and B (0.817) both exceeding 0.5.
7. **DILI:** A (52.423) is slightly higher than B (34.238), indicating a somewhat higher potential for liver injury. B is preferable here.
8. **BBB:** A (73.129) is better than B (45.522). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.
9. **Caco-2:** A (-5.11) is worse than B (-4.855). Higher values are better, indicating better absorption. B is preferable.
10. **Solubility:** A (-2.326) is worse than B (-1.294). Higher values are better, indicating better solubility. B is preferable.
11. **hERG:** Both are very low (A: 0.266, B: 0.183), indicating low cardiotoxicity risk. B is slightly better.
12. **Cl_mic:** A (24.435) is better than B (21.326). Lower clearance is preferred for better metabolic stability. A is preferable.
13. **t1/2:** A (-0.616) is worse than B (34.124). Longer half-life is preferred. B is significantly better.
14. **Pgp:** A (0.273) is better than B (0.04). Lower Pgp efflux is preferred. A is preferable.
15. **Binding Affinity:** A (-9.6) is significantly better than B (-8.1). This is a 1.5 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a substantially better binding affinity (-9.6 kcal/mol vs -8.1 kcal/mol). It also has better *in vitro* metabolic stability (lower Cl_mic) and Pgp efflux. However, Ligand B has a lower DILI risk, better solubility, better Caco-2 permeability, and a significantly longer *in vitro* half-life.

Given that we are targeting a kinase (SRC), potency (binding affinity) is paramount. The 1.5 kcal/mol advantage of ligand A is significant. While ligand B has better ADME properties overall, the superior binding affinity of ligand A is likely to be more critical for achieving efficacy. The slightly higher DILI risk of A can be investigated and potentially mitigated during further optimization.

Therefore, I recommend **Ligand A** as the more promising drug candidate.

1
2025-04-17 14:16:50,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 353.522 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.56) is better than Ligand B (29.54) as it is still within the acceptable range for oral absorption (<140), while Ligand B is very low, potentially indicating poor aqueous solubility.

**logP:** Ligand A (0.474) is quite low, potentially hindering permeability. Ligand B (4.596) is slightly high, potentially causing solubility or off-target issues, but closer to the optimal range than Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.698 and 0.567, respectively), indicating drug-like properties.

**DILI:** Ligand A (25.281) has a much lower DILI risk than Ligand B (6.514), which is a significant advantage.

**BBB:** Ligand A (68.941) has a lower BBB penetration than Ligand B (97.712). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.066) has poor Caco-2 permeability, which is concerning. Ligand B (-4.534) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.213) has poor aqueous solubility. Ligand B (-4.396) also has poor solubility.

**hERG Inhibition:** Ligand A (0.497) has a lower hERG inhibition liability than Ligand B (0.964), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-11.619) has a much lower microsomal clearance, indicating better metabolic stability, which is crucial for an enzyme target. Ligand B (86.472) has high clearance.

**In vitro Half-Life:** Ligand A (11.97 hours) has a longer half-life than Ligand B (-4.17 hours), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is good. Ligand B (0.874) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is minimal and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is the better candidate. While its logP and Caco-2 permeability are suboptimal, it excels in critical areas for an enzyme target: low DILI risk, low hERG inhibition, significantly better metabolic stability (lower Cl_mic and longer t1/2), and low P-gp efflux. The slightly weaker binding affinity of Ligand A is less concerning given its superior ADME properties. Ligand B's higher logP and clearance are significant drawbacks.

Output:
0
2025-04-17 14:16:50,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**
*   **MW:** 337.423 Da - Good (within 200-500 range)
*   **TPSA:** 54.46 - Good (<=140)
*   **logP:** 3.819 - Good (1-3 range)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.921 - Excellent (>=0.5)
*   **DILI:** 62.35 - Moderate risk (slightly above 60, but not drastically)
*   **BBB:** 77.239 - Good (though not a primary concern for a non-CNS target)
*   **Caco-2:** -4.403 - Poor (negative value suggests very low permeability)
*   **Solubility:** -5.204 - Very Poor (negative value indicates extremely low solubility)
*   **hERG:** 0.715 - Low risk
*   **Cl_mic:** 76.928 - Moderate (relatively high, suggesting moderate metabolic clearance)
*   **t1/2:** 38.336 - Good (reasonable in vitro half-life)
*   **Pgp:** 0.431 - Low efflux
*   **Affinity:** -7.2 kcal/mol - Excellent

**Ligand B:**
*   **MW:** 349.318 Da - Good (within 200-500 range)
*   **TPSA:** 124.69 - Acceptable (but approaching the upper limit for good absorption)
*   **logP:** 0.702 - Low (may impede permeation)
*   **HBD:** 4 - Good (<=5)
*   **HBA:** 6 - Good (<=10)
*   **QED:** 0.63 - Good (>=0.5)
*   **DILI:** 73.982 - Moderate-High risk (above 60)
*   **BBB:** 35.052 - Poor (not a primary concern here)
*   **Caco-2:** -5 - Poor (negative value suggests very low permeability)
*   **Solubility:** -2.564 - Poor (negative value indicates low solubility)
*   **hERG:** 0.066 - Very Low risk
*   **Cl_mic:** -13.825 - Excellent (negative value indicates very low clearance, high metabolic stability)
*   **t1/2:** 8.578 - Low (short half-life)
*   **Pgp:** 0.007 - Very Low efflux
*   **Affinity:** -9.4 kcal/mol - Excellent (significantly better than Ligand A)

**Comparison and Decision:**

Ligand B has a significantly better binding affinity (-9.4 vs -7.2 kcal/mol). This difference in potency is substantial and can outweigh some of the ADME drawbacks. While both ligands have poor Caco-2 permeability and solubility, Ligand B exhibits *much* better metabolic stability (Cl_mic = -13.825) and very low P-gp efflux. Ligand A has a slightly better DILI score, but Ligand B's hERG risk is exceptionally low. The short half-life of Ligand B is a concern, but can potentially be addressed through formulation or structural modifications.

Given the priority for potency and metabolic stability in enzyme inhibitors, and the significant advantage Ligand B has in these areas, it is the more promising drug candidate.

Output:
1
2025-04-17 14:16:50,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (356.491 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (45.48) is excellent, well below the 140 threshold for oral absorption. Ligand B (127.68) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.927) is at the higher end of the optimal range (1-3), but acceptable. Ligand B (1.419) is a bit low, potentially hindering permeation.

**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 could slightly impact permeability.

**QED:** Ligand A (0.797) is very good, indicating strong drug-likeness. Ligand B (0.442) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (35.75) has a very low DILI risk, which is excellent. Ligand B (98.953) has a very high DILI risk, a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.719) is moderate, while Ligand B (45.134) is lower.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both, but less so for a kinase inhibitor where other routes of access might be relevant.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a concern for both, but can be addressed with formulation strategies.

**hERG:** Ligand A (0.861) has a lower hERG risk than Ligand B (0.3). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (24.164 mL/min/kg) is better (lower clearance) than Ligand B (47.383 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (47.051 hours) has a much longer half-life than Ligand B (21.234 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.413) has lower P-gp efflux than Ligand B (0.171), which is favorable.

**Binding Affinity:** Ligand A (-9.1 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:**

Ligand A is clearly superior. It has a better QED score, significantly lower DILI risk, better hERG profile, improved metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and, most importantly, a much stronger binding affinity. While both have solubility and permeability issues, these are less critical for a kinase inhibitor and can be addressed through formulation. The high DILI risk associated with Ligand B is a major red flag.



Output:
0
2025-04-17 14:16:50,151 - INFO - Batch 283 complete. Total preferences: 4528
2025-04-17 14:16:50,151 - INFO - Processing batch 284/512...
2025-04-17 14:17:32,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.837 and 365.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.29) is better than Ligand B (123.95), being closer to the <140 threshold for good absorption.

**logP:** Ligand B (2.231) is within the optimal 1-3 range, while Ligand A (0.625) is slightly below, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (1) as it is closer to the ideal range of <=5.

**H-Bond Acceptors:** Ligand B (6) is preferable to Ligand A (5) as it is closer to the ideal range of <=10.

**QED:** Ligand A (0.717) has a significantly better QED score than Ligand B (0.431), indicating a more drug-like profile.

**DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (60.45), which is already approaching the higher risk threshold.

**BBB:** Both ligands have moderate BBB penetration, but Ligand A (61.225) is slightly better than Ligand B (57.619). BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.252 and -5.268), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.257 and -2.741), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.285) has a much lower hERG inhibition risk than Ligand B (0.453), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-8.489) exhibits significantly lower (better) microsomal clearance than Ligand B (30.859), suggesting much better metabolic stability.

**In vitro Half-Life:** Ligand B (11.165) has a longer half-life than Ligand A (-2.318), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, while Ligand B (0.11) is slightly higher.

**Binding Affinity:** Ligand B (-9.5 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. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, poorer metabolic stability (higher Cl_mic), and slightly higher P-gp efflux. Ligand A has better ADME properties across the board (QED, DILI, hERG, Cl_mic, Pgp), but its binding affinity is considerably weaker.

Given the substantial affinity difference, the benefits of Ligand B appear to outweigh its drawbacks, *provided* the solubility and permeability issues can be addressed through formulation or structural modifications. The poor solubility and permeability are major concerns, but the potency advantage is significant.

Output:
1
2025-04-17 14:17:32,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.427 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.92) is slightly higher than Ligand B (71.34). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (2.401) and Ligand B (3.322) are both 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 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 scores (0.689 and 0.831, respectively), indicating drug-like properties.

**DILI:** Ligand A (21.869) has a significantly lower DILI risk than Ligand B (25.979), which is a substantial advantage. Both are below the 40 threshold.

**BBB:** Both ligands have relatively low BBB penetration (52.074 and 49.787, respectively). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.512 and -4.82), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.33 and -3.793), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.629) has a slightly higher hERG inhibition risk than Ligand B (0.149). Ligand B is much preferable here.

**Microsomal Clearance:** Ligand A (69.769) has a higher microsomal clearance than Ligand B (49.815), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (28.896 hours) has a significantly longer in vitro half-life than Ligand A (7.086 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.136, respectively), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.4 kcal/mol). Ligand A is slightly better (-8.9 kcal/mol), but the difference is less than 1.5 kcal/mol, so it's not decisive.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity and lower DILI risk, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower hERG risk. The poor solubility and permeability are concerning for both, but the metabolic and safety advantages of Ligand B outweigh the slight affinity difference.

Output:
1
2025-04-17 14:17:32,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.511 and 374.344 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold for good absorption, while Ligand B (98.58) is still acceptable but higher.

**logP:** Both ligands have good logP values (2.305 and 1.834), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better than Ligand B (3 HBD, 7 HBA) regarding the number of hydrogen bond donors and acceptors, which is favorable for permeability.

**QED:** Both ligands have similar QED scores (0.79 and 0.755), indicating good drug-likeness.

**DILI:** Ligand A (60.062) has a moderate DILI risk, while Ligand B (79.604) has a significantly higher risk. This is a major concern for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (62.311) shows slightly better BBB penetration than Ligand B (42.226).

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values, which is unusual and suggests potential issues with absorption prediction. However, the values are similar (-5.089 and -5.111).

**Aqueous Solubility:** Both ligands have negative solubility values (-4.121 and -3.786), which is also unusual and suggests potential formulation challenges. The values are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.447 and 0.438), which is excellent.

**Microsomal Clearance:** Ligand A (47.609) has a considerably lower microsomal clearance than Ligand B (7.614), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (32.531 hours) has a much longer in vitro half-life than Ligand B (-14.648 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.209 and 0.041).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. While both ligands have good potency and acceptable physicochemical properties, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. These are critical factors for enzyme inhibitors. The slightly better TPSA and BBB values also contribute to its favorability. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this issue.

Output:
0
2025-04-17 14:17:32,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.431 and 344.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.57) is better than Ligand B (68.1), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.887) is slightly higher than Ligand B (2.433), both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Lower is generally preferred for kinases.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (7). Lower is generally preferred for kinases.

**QED:** Both ligands have good QED scores (0.63 and 0.793), indicating drug-likeness.

**DILI:** Ligand B (36.332) has a significantly lower DILI risk than Ligand A (69.639). This is a major advantage for Ligand B.

**BBB:** Ligand B (74.176) has a better BBB penetration score than Ligand A (63.784), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.131 and -5.165), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.072 and -2.532), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.643) has a slightly higher hERG risk than Ligand B (0.467), but both are reasonably low.

**Microsomal Clearance:** Ligand B (30.159) has a lower microsomal clearance than Ligand A (95.101), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (25.399) has a slightly longer half-life than Ligand A (29.017), but the difference is not substantial.

**P-gp Efflux:** Ligand A (0.829) has a higher P-gp efflux liability than Ligand B (0.129), meaning B is less likely to be pumped out of cells.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While A is better, the difference is not substantial enough to overcome the other issues.

**Overall Assessment:**

Ligand B is the better candidate. While both ligands have concerning solubility and permeability issues, Ligand B exhibits a much lower DILI risk and better metabolic stability (lower Cl_mic). It also has lower P-gp efflux and a slightly better binding affinity. The slightly better BBB penetration is a minor bonus. Ligand A's higher TPSA, HBD/HBA counts, and higher DILI risk make it less desirable.

Output:
1
2025-04-17 14:17:32,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (396.843 and 367.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is better than Ligand B (72.48) as it is closer to the 90 A^2 threshold, but both are acceptable.

**3. logP:** Both ligands have good logP values (2.735 and 3.729), 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 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 very similar QED values (0.801 and 0.816), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (69.523 and 68.166), and are acceptable.

**8. BBB:** Ligand A (70.648) has better BBB penetration than Ligand B (49.864). However, BBB penetration is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.947 and -4.528). This is concerning, suggesting poor intestinal absorption. However, these values are on a log scale, and the absolute values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.94 and -3.252). This is also concerning, suggesting poor aqueous solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.27 and 0.137), which is excellent.

**12. Microsomal Clearance:** Ligand A has a significantly lower (and better) microsomal clearance (-4.03 mL/min/kg) than Ligand B (49.026 mL/min/kg). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A has a much longer in vitro half-life (26.488 hours) compared to Ligand B (10.538 hours). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.174 and 0.183), which is good.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8 and -9 kcal/mol). Ligand B is slightly better (-9 kcal/mol), but the difference is likely not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A exhibits significantly improved metabolic stability (lower Cl_mic, longer t1/2) and better BBB penetration. The similar solubility and permeability concerns are present in both, but the improved pharmacokinetic properties of Ligand A make it a better starting point for optimization.

Output:
0
2025-04-17 14:17:32,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.403 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.34) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (78.87) is well within the acceptable range.

**logP:** Ligand A (0.767) is a bit low, potentially hindering permeation. Ligand B (1.563) is better, 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 QED values above 0.75, indicating good drug-likeness.

**DILI:** Ligand A (66.731) has a higher DILI risk than Ligand B (7.794). This is a significant concern.

**BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This needs further investigation, but it's a flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.214 and 0.304), which is positive.

**Microsomal Clearance:** Ligand A (-19.076) exhibits significantly *lower* (better) microsomal clearance than Ligand B (38.932). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-17.49) has a longer in vitro half-life than Ligand B (-11.382), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.021).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). The difference of 1.5 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. However, it has a lower logP and negative solubility and Caco-2 values. Ligand B has a better logP and TPSA, but a significantly higher DILI risk and poorer metabolic stability. The negative solubility and Caco-2 values are concerning for both, but the superior binding affinity and metabolic stability of Ligand A, coupled with the lower DILI risk, make it the more promising candidate, *assuming* the solubility and permeability issues can be addressed through formulation or structural modifications.

Output:
1
2025-04-17 14:17:32,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.47 & 356.48 Da) fall within the ideal 200-500 Da range.
**TPSA:** Ligand A (46.34) is better than Ligand B (58.64), both are below the 140 threshold for good absorption.
**logP:** Ligand A (4.375) is slightly higher than optimal (1-3), but still potentially acceptable. Ligand B (2.97) is within the optimal range.
**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1), as fewer donors generally improve permeability.
**H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of 10.
**QED:** Ligand A (0.833) is significantly better than Ligand B (0.612), indicating a more drug-like profile.
**DILI:** Ligand A (34.82) has a lower DILI risk than Ligand B (41.411), both are acceptable.
**BBB:** Both ligands have high BBB penetration (88.872 and 86.933), but this is less critical for a non-CNS target like SRC.
**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.
**Solubility:** Ligand A (-5.23) has worse solubility than Ligand B (-3.218). Solubility is a concern for both, but less so for Ligand B.
**hERG:** Ligand A (0.854) has a slightly higher hERG risk than Ligand B (0.724), but both are relatively low.
**Cl_mic:** Ligand A (102.548) has a higher microsomal clearance than Ligand B (40.663), indicating lower metabolic stability. This is a significant drawback for Ligand A.
**t1/2:** Ligand A (-16.562) has a negative in vitro half-life, which is highly unfavorable. Ligand B (7.958) has a reasonable half-life.
**Pgp:** Ligand A (0.796) has lower P-gp efflux than Ligand B (0.477), which is favorable.
**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and better QED and Pgp properties. However, it suffers from significantly worse metabolic stability (higher Cl_mic, negative t1/2) and solubility. Ligand B has a more favorable ADME profile (better metabolic stability, solubility, and half-life) but weaker binding affinity.

Given that we are targeting a kinase (SRC), potency is crucial. The 0.4 kcal/mol difference in binding affinity is substantial and could outweigh the ADME drawbacks of Ligand A *if* the metabolic instability can be addressed through structural modifications. However, the negative half-life is a major red flag. Ligand B, while less potent, presents a more immediately viable starting point due to its better ADME properties.

Output:
1
2025-04-17 14:17:32,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.849 and 350.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.29) is slightly higher than Ligand B (40.62). Both are below the 140 A^2 threshold for good oral absorption, but ligand B is better.

**logP:** Ligand A (4.287) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (3.298) 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 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.584 and 0.714), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (90.229%) than Ligand B (11.206%). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B is better (85.847 vs 65.374). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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:** Ligand A (0.686) has a slightly higher hERG risk than Ligand B (0.737), but both are relatively low.

**Microsomal Clearance:** Ligand A (72.304) has higher microsomal clearance than Ligand B (62.612), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a negative half-life (-0.133), which is not physically possible and likely an error. Ligand A has a half-life of 51.612 hours, which is good.

**P-gp Efflux:** Ligand A (0.676) has lower P-gp efflux than Ligand B (0.31), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a reasonable half-life, and lower P-gp efflux. However, its high DILI risk and higher logP are significant drawbacks. Ligand B has a better safety profile (much lower DILI), better logP, and better TPSA, but its binding affinity is weaker and its half-life is reported as negative, which is impossible.

Given the priorities for enzyme inhibitors, the strong binding affinity of Ligand A is a major advantage that could potentially outweigh its drawbacks, *provided* the DILI risk can be mitigated through structural modifications. The negative half-life of Ligand B is a showstopper.

Output:
1
2025-04-17 14:17:32,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (347.459 Da and 357.426 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (79.46 and 73.32) below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (3.978) is optimal (1-3), while Ligand B (-0.372) is below 1, which could impede permeation. This is a significant disadvantage for Ligand B.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 1, respectively), well below the limit of 5.

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

**6. QED:** Both ligands have good QED scores (0.698 and 0.73), indicating good drug-like properties.

**7. DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (20.9), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for an oncology target, but Ligand A (64.715) is slightly better than Ligand B (43.583).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the magnitude is similar, and this parameter is less critical than others.

**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 (0.305 and 0.234).

**12. Microsomal Clearance:** Ligand A (18.847) has a higher microsomal clearance than Ligand B (-15.948). A negative value for Ligand B indicates *very* high metabolic stability, which is a major advantage.

**13. In vitro Half-Life:** Ligand A (25.217) has a reasonable half-life, while Ligand B (-17.706) suggests an extremely long half-life, which is highly desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.252 and 0.033).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.4 and -7.6 kcal/mol), with Ligand B being slightly better. However, the difference is small.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A in several critical areas for an enzyme target: logP (better permeability), microsomal clearance (much higher stability), and in vitro half-life (extremely long). While Ligand A has a slightly lower DILI risk, the benefits of Ligand B's improved ADME properties, particularly its metabolic stability and half-life, outweigh this minor drawback. The slightly better affinity of Ligand B is also a plus, though not decisive.

Output:
1
2025-04-17 14:17:32,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 Da and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.76) is slightly above the preferred <140, but acceptable. Ligand B (88.99) is well within the range.

**logP:** Ligand A (0.169) is quite low, potentially hindering permeability. Ligand B (2.048) 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 (0.605 and 0.824), indicating drug-likeness.

**DILI:** Ligand A (32.299) has a lower DILI risk than Ligand B (55.874), which is favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (66.848) is better than Ligand B (54.207).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.075 and -4.893), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.929 and -4.332), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.117) has a very low hERG risk, which is excellent. Ligand B (0.399) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (0.783) has much lower microsomal clearance than Ligand B (11.897), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (-1.071) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (-13.006) also has a negative half-life, indicating a similar issue.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.093), which is good.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity and a more optimal logP. However, both ligands suffer from extremely poor solubility and permeability (negative Caco-2 and solubility values) and negative half-lives, which are critical issues. Ligand A has better metabolic stability (lower Cl_mic) and a significantly lower hERG risk, but its lower affinity and very low logP are concerning.

Despite the poor solubility and permeability, the significantly stronger binding affinity of Ligand B makes it the more promising candidate *if* these solubility/permeability issues can be addressed through formulation or structural modifications. The negative half-lives are a data quality concern that needs investigation.

Output:
1
2025-04-17 14:17:32,289 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.27 and 72.28) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.749) is optimal, while Ligand B (1.294) is slightly below the preferred range, potentially impacting permeability.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 3 HBA, well within the limits. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.725 and 0.84), indicating drug-likeness.

**DILI:** Ligand A (24.157) has a significantly lower DILI risk than Ligand B (18.224), which is a major advantage.

**BBB:** Both have reasonable BBB penetration (67.623 and 71.229), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.776) has poorer Caco-2 permeability compared to Ligand B (-5.058), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.378) has poorer aqueous solubility than Ligand B (-1.679). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.071 and 0.19), which is excellent.

**Microsomal Clearance:** Ligand A (54.965) has higher microsomal clearance than Ligand B (13.475), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (10.894) has a longer in vitro half-life than Ligand A (-27.959), which is favorable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.071 and 0.04).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

While Ligand B has better solubility, permeability, and metabolic stability, the significantly stronger binding affinity of Ligand A (-8.9 vs -7.7 kcal/mol) is a critical advantage for an enzyme target like SRC. The lower DILI risk for Ligand A is also a substantial benefit. The slightly poorer permeability and solubility of Ligand A might be addressable through formulation strategies. The difference in binding affinity is large enough to make Ligand A the more promising candidate.

Output:
1
2025-04-17 14:17:32,289 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.362 Da) is slightly lower, which could be beneficial for permeability. Ligand B (372.491 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140 (A: 93.21, B: 90.98), suggesting good oral absorption potential.

**logP:** Ligand A (2.413) is within the optimal range (1-3). Ligand B (-0.113) is below 1, which could hinder permeation. This is a significant 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 (A: 0.784, B: 0.679), indicating good drug-like properties.

**DILI:** Ligand A (85.576) has a higher DILI risk than Ligand B (40.287). While 85.576 is concerning, it's not drastically high. Ligand B is well below the 60 threshold.

**BBB:** Both ligands have reasonable BBB penetration (A: 69.097, B: 63.203), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.713) and Ligand B (-5.276) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-3.265) and Ligand B (-1.377) both have negative values, indicating very poor solubility. This is a major issue for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.191, B: 0.14). This is a positive attribute for both.

**Microsomal Clearance:** Ligand A (55.117) has a higher microsomal clearance than Ligand B (-6.987). The negative value for Ligand B is unusual and likely indicates very high metabolic stability, which is highly desirable.

**In vitro Half-Life:** Ligand A (20.807 hours) has a reasonable half-life. Ligand B (-21.135 hours) also has a negative value, which is unusual and suggests a very long half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.027, B: 0.004).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). The difference of 1.2 kcal/mol is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A appears to be the more promising candidate. Its superior binding affinity (-8.7 vs -7.5 kcal/mol) is a significant advantage for an enzyme target like SRC kinase. Ligand B's logP is concerningly low, and while it has better DILI and potentially better metabolic stability, the binding affinity difference is crucial. Both compounds would require significant medicinal chemistry effort to improve solubility and permeability, but starting with the more potent ligand is a better strategy.

Output:
0
2025-04-17 14:17:32,289 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (364.917 and 356.535 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is slightly higher than Ligand B (36.36), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.405) is within the optimal range (1-3), while Ligand B (4.481) is slightly above, potentially raising concerns about solubility and off-target effects.

**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 (2) is preferable to Ligand B (4) for the same reason as above.

**6. QED:** Both ligands have similar QED values (0.75 and 0.743), indicating good drug-likeness.

**7. DILI:** Ligand A (12.524) has a significantly lower DILI risk than Ligand B (11.09), which is a crucial advantage.

**8. BBB:** Ligand A (91.508) has significantly higher BBB penetration than Ligand B (69.407). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**9. Caco-2 Permeability:** Ligand A (-4.793) has better Caco-2 permeability than Ligand B (-5.111).

**10. Aqueous Solubility:** Ligand A (-3.946) has better aqueous solubility than Ligand B (-3.243).

**11. hERG Inhibition:** Ligand A (0.508) has a much lower hERG inhibition liability than Ligand B (0.938), a critical safety advantage.

**12. Microsomal Clearance:** Ligand A (44.069) has slightly higher microsomal clearance than Ligand B (41.485), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (32.559) has a significantly longer in vitro half-life than Ligand A (1.184), a substantial advantage for dosing frequency.

**14. P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux liability than Ligand B (0.692), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-10.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). This 1.8 kcal/mol difference is significant and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity and a longer half-life, Ligand A demonstrates a superior safety profile (lower DILI and hERG risk) and better solubility, permeability, and P-gp efflux. The difference in binding affinity, while notable, is not substantial enough to overcome the significant advantages of Ligand A in terms of ADME-Tox properties, especially considering the importance of minimizing off-target effects and ensuring a favorable safety profile for an oncology drug.

Output:
0
2025-04-17 14:17:32,289 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.355 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (404.539 Da) is still acceptable.

**TPSA:** Both ligands have a TPSA of approximately 105, which is slightly above the optimal <140 for good oral absorption, but not a major concern.

**logP:** Ligand A (3.09) is optimal, while Ligand B (1.685) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 8 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.578, B: 0.634), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 86.39, which is high. Ligand B has a DILI risk of 74.641, which is also elevated, but lower than Ligand A. This is a significant concern for both.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (29.818) and Ligand B (16.983) both have low BBB penetration, which is expected and not detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.417 and -5.853), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.709 and -2.378), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.743) has a moderate hERG risk, while Ligand B (0.051) has a very low hERG risk. This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (13.92 mL/min/kg) has a lower clearance than Ligand B (60.853 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.561 hours) has a negative half-life, which is not possible. Ligand B (16.525 hours) has a reasonable half-life. The negative value for Ligand A is a red flag.

**P-gp Efflux:** Ligand A (0.101) has slightly higher P-gp efflux than Ligand B (0.078), but both are relatively low.

**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, which is the most important factor for an enzyme inhibitor. However, it has a very high DILI risk, a negative in vitro half-life (which is impossible), and moderate hERG risk. Ligand B has a lower affinity, but better metabolic stability, lower hERG risk, and a reasonable half-life. Both have poor solubility and permeability.

Despite the strong affinity of Ligand A, the impossible half-life and high DILI risk make it a very poor candidate. The combination of better safety profile (lower DILI and hERG) and reasonable metabolic stability makes Ligand B the more viable candidate, even with its lower affinity. Further optimization of Ligand B to improve its affinity and solubility would be a reasonable next step.

Output:
1
2025-04-17 14:17:32,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.527 and 349.337 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (82.53). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**logP:** Both ligands have good logP values (3.45 and 2.555, respectively), falling within the optimal 1-3 range.

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

**QED:** Both ligands have good QED scores (0.842 and 0.869), indicating good drug-like properties.

**DILI:** Ligand A (47.732) has a lower DILI risk than Ligand B (73.09), which is a significant advantage. Lower DILI is crucial for drug development.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (70.415) has a better BBB percentile than Ligand B (52.191).

**Caco-2 Permeability:** Ligand A (-5.061) has a better Caco-2 permeability than Ligand B (-4.507), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.197 and -3.531). This is a potential issue, but can sometimes be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.427) has a lower hERG inhibition liability than Ligand B (0.194), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (45.927) has a slightly lower Cl_mic than Ligand A (35.484), suggesting better metabolic stability. However, the difference isn't huge.

**In vitro Half-Life:** Ligand A (12.262) has a significantly longer half-life than Ligand B (1.389), which is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.483) has a lower P-gp efflux liability than Ligand B (0.04), indicating better bioavailability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is the most important factor for an enzyme inhibitor. The 1.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Considering all factors, especially the significantly stronger binding affinity, lower DILI risk, lower hERG risk, better Caco-2 permeability, and longer half-life, Ligand A is the more promising drug candidate. While both have solubility issues, the superior potency and safety profile of Ligand A make it a better choice.

Output:
1
2025-04-17 14:17:32,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.391 and 345.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.23) is slightly above the optimal <140 for good absorption, while Ligand B (89.66) is well within the range.

**logP:** Both ligands (1.643 and 1.772) are 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 6. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.835) has a significantly better QED score than Ligand A (0.459), indicating a more drug-like profile.

**DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (56.999), though both are reasonably acceptable.

**BBB:** Both have similar BBB penetration (63.629 and 67.235), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.905 and -5.162). This is unusual and indicates very poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Both have negative solubility values (-3.087 and -2.448), also unusual. Ligand B is slightly better in this regard.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.411 and 0.058). Ligand B is preferable.

**Microsomal Clearance:** Ligand A (14.47) and Ligand B (15.161) have similar microsomal clearance values. These are relatively low, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand B (12.726) has a longer in vitro half-life than Ligand A (-10.19), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.082).

**Binding Affinity:** Ligand B (-9.1 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 factor.

**Conclusion:**

Considering all factors, Ligand B is the more promising drug candidate. It has a better QED score, slightly better solubility, a longer half-life, and a slightly improved binding affinity. While both have poor Caco-2 and solubility values, these are similar. The lower DILI and hERG risk for Ligand B also contribute to its favorability. The slightly better binding affinity, combined with the improved ADME properties, makes Ligand B the preferred choice.

Output:
1
2025-04-17 14:17:32,290 - INFO - Batch 284 complete. Total preferences: 4544
2025-04-17 14:17:32,290 - INFO - Processing batch 285/512...
2025-04-17 14:18:18,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.519 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (113.44) is still within acceptable range, but less favorable than A.

**logP:** Ligand A (3.774) is optimal. Ligand B (0.869) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is acceptable, but A is more favorable.

**QED:** Both ligands (0.708 and 0.609) have good drug-likeness scores.

**DILI:** Ligand A (7.212) has a very low DILI risk. Ligand B (47.732) is higher, but still within an acceptable range.

**BBB:** Ligand A (99.069) has excellent BBB penetration, though this isn't a primary concern for a non-CNS target like SRC. Ligand B (46.762) is lower.

**Caco-2 Permeability:** Ligand A (-4.094) is poor, while Ligand B (-5.126) is even worse. Both are negative values, which is concerning.

**Aqueous Solubility:** Ligand A (-3.758) is poor, and Ligand B (-2.88) is also poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.88) has low hERG risk, which is excellent. Ligand B (0.108) is even lower, and very favorable.

**Microsomal Clearance:** Ligand A (105.127) has a higher clearance, indicating lower metabolic stability. Ligand B (32.267) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.732) has a very short half-life, which is unfavorable. Ligand B (-8.711) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.32) has low P-gp efflux, which is good. Ligand B (0.026) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 0.6 kcal/mol difference is significant, and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better logP, TPSA, H-bond properties, DILI risk, and binding affinity. However, it has significantly worse Caco-2 permeability, aqueous solubility, and *much* worse metabolic stability (higher Cl_mic, shorter half-life) than Ligand B.

Ligand B has better metabolic stability and lower P-gp efflux, but suffers from lower logP, higher TPSA, and weaker binding affinity. The solubility and Caco-2 permeability are poor for both.

Given the priority for potency and metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, Ligand B is the more promising candidate, despite its slightly weaker binding. The improved metabolic stability is a key advantage, and the lower hERG risk is a bonus. The poor solubility and permeability can be addressed through formulation strategies.

Output:
1
2025-04-17 14:18:18,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.439 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (84.72). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is closer to the optimal range.

**logP:** Ligand A (2.206) is optimal, while Ligand B (0.608) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (0 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.892 and 0.749, respectively), indicating good drug-like properties.

**DILI:** Ligand A (35.634) has a lower DILI risk than Ligand B (23.575), which is preferable.

**BBB:** Ligand A (93.874) has a much higher BBB penetration percentile than Ligand B (48.817). While SRC isn't a CNS target, higher BBB penetration can sometimes correlate with better overall distribution.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.627 and -4.617), which is unusual and indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.054 and -2.077), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.571) has a slightly higher hERG risk than Ligand B (0.18), but both are relatively low.

**Microsomal Clearance:** Ligand A (71.346) has a higher microsomal clearance than Ligand B (19.58), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (12.521 hours) has a longer in vitro half-life than Ligand A (22.454 hours). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.349) has lower P-gp efflux liability than Ligand B (0.003), which is preferable.

**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, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.5 vs -7.0 kcal/mol) is a major advantage for an enzyme target like SRC kinase. While Ligand A has higher clearance, the potency difference is substantial. The lower DILI risk and P-gp efflux for Ligand A are also favorable. Ligand B's better half-life and lower hERG are positives, but insufficient to overcome the potency gap.

Output:
1
2025-04-17 14:18:18,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.406 and 349.333 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.62) is still under 140, but less optimal than A.

**logP:** Ligand A (1.343) is within the optimal 1-3 range. Ligand B (3.01) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is favorable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.82) has a very good drug-likeness score. Ligand B (0.641) is still acceptable, but lower than A.

**DILI:** Ligand A (47.77) has a low DILI risk. Ligand B (77.162) has a significantly higher DILI risk, which is concerning.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.072) is higher than Ligand B (73.129).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, and negative values might indicate a percentile below a certain threshold.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.562) has a lower hERG risk than Ligand B (0.789), which is preferable.

**Microsomal Clearance:** Ligand A (3.721) has much lower clearance than Ligand B (85.597), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (0.039) has a very short half-life. Ligand B (17.594) has a significantly longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux than Ligand B (0.398), which is favorable.

**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 and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme target. However, it has a significantly higher DILI risk, higher microsomal clearance (lower metabolic stability), and a shorter half-life. Ligand A has better ADME properties (lower DILI, lower clearance, lower P-gp efflux, better TPSA), but a weaker binding affinity.

The difference in binding affinity (-9.5 vs -7.9 kcal/mol) is a 1.6 kcal/mol difference, which is substantial enough to potentially overcome the ADME liabilities of Ligand B, *provided* the DILI risk can be mitigated through structural modifications. The metabolic instability is also a concern, but could potentially be addressed. The solubility and permeability issues are common and can be addressed through formulation strategies.

Output:
1
2025-04-17 14:18:18,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.479 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.77) is well below the 140 threshold, while Ligand B (85.89) is still acceptable but closer to the limit.

**logP:** Ligand A (3.806) is at the higher end of the optimal range (1-3), while Ligand B (2.197) is comfortably within the optimal range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the HBD <= 5 criteria.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are well below the HBA <= 10 criteria.

**QED:** Ligand A (0.887) has a significantly better QED score than Ligand B (0.539), indicating better overall drug-likeness.

**DILI:** Ligand B (30.748) has a much lower DILI risk than Ligand A (69.252). This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (83.87) is higher than Ligand A (65.297). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**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:** Ligand B (-1.965) has better (less negative) solubility than Ligand A (-4.411).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.13, B: 0.262).

**Microsomal Clearance:** Ligand A (37.418) has significantly lower microsomal clearance than Ligand B (60.598), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand B (9.918) has a slightly longer in vitro half-life than Ligand A (8.591).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.155, B: 0.091).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better QED and metabolic stability, Ligand B has a significantly lower DILI risk, better solubility, and a more potent binding affinity. The binding affinity difference is substantial. Considering the enzyme-specific priorities, the improved potency and reduced toxicity risk of Ligand B outweigh the slightly less favorable metabolic stability and QED.

Output:
1
2025-04-17 14:18:18,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.378 and 343.427 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.01) is slightly higher than Ligand B (71.41). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (1.525 and 1.154), falling within the 1-3 optimal range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

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

**QED:** Both ligands have good QED scores (0.663 and 0.788), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 69.601, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 23.497, which is excellent.

**BBB:** Both ligands show good BBB penetration (70.609 and 75.107), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.191) has a negative Caco-2 value, which is problematic and suggests poor permeability. Ligand B (-4.79) is also negative, but slightly less so.

**Aqueous Solubility:** Ligand A (-3.177) and Ligand B (-2.121) both have negative solubility values, indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.488 and 0.388), which is positive.

**Microsomal Clearance:** Ligand A (20.981) has a lower microsomal clearance than Ligand B (40.467), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.052) has a longer in vitro half-life than Ligand B (-9.133), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.063 and 0.082).

**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 (over 1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability and half-life. However, its high DILI risk and poor Caco-2 permeability are major drawbacks. Ligand B has a much better safety profile (lower DILI) and slightly better Caco-2 permeability, but its binding affinity is considerably weaker.

Given the priorities for enzyme inhibitors, the strong binding affinity of Ligand A is a significant advantage that could potentially outweigh the DILI and permeability concerns, *provided* these can be addressed through further optimization. However, the DILI risk is substantial. Ligand B, while safer, may not be potent enough to be a viable drug candidate.

Considering the balance, and the potential to optimize around the DILI/permeability issues, I would initially favor Ligand A.

Output:
0
2025-04-17 14:18:18,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (373.44 and 352.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (109.59).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is higher, potentially hindering absorption.

**logP:** Ligand A (4.276) is slightly higher than the optimal range (1-3), while Ligand B (2.513) is within the optimal range. High logP can lead to solubility issues, but is less concerning than high TPSA.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.783) has a better QED score than Ligand B (0.571), indicating a more drug-like profile.

**DILI:** Both ligands have high DILI risk (Ligand A: 29.779, Ligand B: 95.502), but Ligand B is considerably worse.

**BBB:** Ligand A (95.657) has excellent BBB penetration, while Ligand B (20.434) has very poor penetration.  While not a primary concern for a kinase inhibitor, it's a bonus.

**Caco-2:** Ligand A (-4.491) and Ligand B (-5.689) 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.

**Solubility:** Ligand A (-5.337) and Ligand B (-3.394) both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.809) has a lower hERG risk than Ligand B (0.26), which is a significant advantage.

**Microsomal Clearance:** Ligand A (67.415) has higher clearance than Ligand B (12.415), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-1.484) has a shorter half-life than Ligand B (0.636), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.474) has lower P-gp efflux than Ligand B (0.073), which is a positive.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While both are excellent, the difference is relatively small.

**Overall Assessment:**

Ligand B has a significantly better profile regarding metabolic stability (lower Cl_mic, longer t1/2) and hERG risk. While its TPSA is higher, the superior binding affinity and lower DILI risk make it a more promising candidate. Ligand A's high logP and clearance are concerning.

Output:
1
2025-04-17 14:18:18,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (374.47 and 368.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.81) is better than Ligand B (97.64), both being below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (1.193) is within the optimal 1-3 range, while Ligand A (-0.747) is slightly below 1, potentially hindering permeability.

**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 (0.814) has a significantly better QED score than Ligand A (0.515), indicating a more drug-like profile.

**DILI:** Both ligands have concerning DILI scores (Ligand A: 37.61, Ligand B: 64.83). Ligand B is higher, indicating a greater potential for liver injury.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.65) is slightly better than Ligand A (63.75).

**Caco-2 Permeability:** Both are negative, suggesting poor permeability.

**Aqueous Solubility:** Both are negative, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.244) shows a much lower hERG inhibition liability than Ligand B (0.543), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-10.38) has a much lower (better) microsomal clearance than Ligand B (11.74), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (33.29 hours) has a significantly longer half-life than Ligand A (-5.77 hours), which is desirable.

**P-gp Efflux:** Both are very low, indicating minimal P-gp efflux.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is not substantial enough to outweigh other significant drawbacks.

**Overall Assessment:**

Ligand A has a better hERG profile and significantly better metabolic stability (lower Cl_mic, though a negative half-life is concerning). Ligand B has a better QED score and a longer half-life. However, Ligand B has a higher DILI risk and a logP closer to the upper limit, and a worse hERG profile. Given the importance of metabolic stability and minimizing off-target effects (hERG) for kinase inhibitors, and the fact that the affinity difference isn't huge, Ligand A appears to be the more promising candidate. The negative half-life for Ligand A is a major concern that would need to be addressed through structural modifications.

Output:
0
2025-04-17 14:18:18,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.411 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.78) is slightly higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but lower is generally preferred. Ligand B is better here.

**logP:** Both ligands have good logP values (2.244 and 1.815), 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 3. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.832) has a significantly higher QED score than Ligand B (0.533), indicating a more drug-like profile.

**DILI:** Ligand A (35.944) has a slightly higher DILI risk than Ligand B (25.553), but both are below the concerning threshold of 60.

**BBB:** Ligand A (78.402) and Ligand B (89.376) both have good BBB penetration, but B is better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired/undesired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.671) is worse than Ligand B (-4.414).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.778) is worse than Ligand B (-2.237).

**hERG:** Ligand A (0.26) has a lower hERG risk than Ligand B (0.571), which is a significant advantage.

**Microsomal Clearance:** Ligand A (31.314) has a higher microsomal clearance than Ligand B (26.547), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (59.244) has a better in vitro half-life than Ligand B (-21.711). This is a significant positive for Ligand A.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux than Ligand B (0.123), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.4 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a better QED score, lower hERG risk, better P-gp efflux, and a longer in vitro half-life. However, it has worse Caco-2 permeability and aqueous solubility, and higher microsomal clearance. Ligand B has better TPSA, BBB penetration, and slightly lower DILI risk.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), the longer half-life and lower hERG risk of Ligand A are crucial advantages. While the solubility and permeability are concerning, these can potentially be addressed through formulation strategies. The metabolic stability of Ligand B is a significant drawback.

Output:
1
2025-04-17 14:18:18,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzyme targets: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.355 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (98.39) is better than Ligand B (45.23). While both are acceptable, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (2.758) is optimal. Ligand B (4.409) 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, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.695, B: 0.821), indicating good drug-like properties.

**DILI:** Ligand A (93.292) has a significantly higher DILI risk than Ligand B (47.964). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (74.952) has a better BBB score than Ligand A (59.674).

**Caco-2 Permeability:** Ligand A (-4.921) is better than Ligand B (-5.219), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.222) is better than Ligand B (-4.496), which is important for formulation and bioavailability.

**hERG:** Ligand A (0.346) has a lower hERG inhibition liability than Ligand B (0.498), which is preferable.

**Microsomal Clearance:** Ligand A (78.593) has a higher microsomal clearance than Ligand B (50.963), meaning it's less metabolically stable. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (11.989) has a significantly longer half-life than Ligand A (112.215), which is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.126) has lower P-gp efflux liability than Ligand B (0.689), which is good.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly better binding affinity than Ligand A (-8.5 kcal/mol). This 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 a slightly higher logP, its significantly better binding affinity, lower DILI risk, and longer half-life outweigh the minor drawbacks. The DILI risk associated with Ligand A is a major red flag. The improved potency of Ligand B is also a key factor for an enzyme target.

Output:
1
2025-04-17 14:18:18,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.402 and 357.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (29.54), being below 140, but both are acceptable.

**logP:** Ligand A (2.496) is optimal (1-3), while Ligand B (4.502) is slightly higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=10.

**QED:** Ligand A (0.861) is significantly better than Ligand B (0.671), indicating a more drug-like profile.

**DILI:** Ligand A (26.599) has a much lower DILI risk than Ligand B (15.238), which is preferable.

**BBB:** Ligand A (70.803) and Ligand B (95.696) are both high, but not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.005) and Ligand B (-4.447) are both negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.246) and Ligand B (-4.147) are both very poor, but Ligand A is slightly better.

**hERG Inhibition:** Ligand A (0.496) and Ligand B (0.828) are both low, indicating a low risk of cardiotoxicity, but Ligand A is better.

**Microsomal Clearance:** Ligand A (32.266) has a lower clearance than Ligand B (55.653), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.672) has a longer half-life than Ligand B (16.887), which is desirable.

**P-gp Efflux:** Ligand A (0.059) has lower P-gp efflux than Ligand B (0.465), which is preferable.

**Binding Affinity:** Both ligands have the same binding affinity (-9.7 kcal/mol), which is excellent.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand A is the superior candidate. It exhibits a better QED score, lower DILI risk, lower microsomal clearance (better metabolic stability), longer in vitro half-life, lower P-gp efflux, and slightly better solubility and hERG inhibition. While both have poor Caco-2 permeability, the other ADME properties of Ligand A make it a more promising starting point for optimization.

Output:
1
2025-04-17 14:18:18,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.435 and 353.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands are below the 140 A^2 threshold (105.91 and 98.4 A^2), indicating good potential for oral absorption.

**logP:** Ligand A (0.974) is slightly better than Ligand B (0.121) as it falls within the optimal 1-3 range. Ligand B is quite low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A has 4 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 good QED scores (0.571 and 0.727), suggesting drug-likeness.

**DILI:** Ligand A (39.55) has a lower DILI risk than Ligand B (43.66), both are acceptable.

**BBB:** Ligand A (18.34) has a very low BBB penetration, while Ligand B (47.499) is better, but still not high. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.874 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 (-1.919 and -1.962), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.269 and 0.246).

**Microsomal Clearance:** Ligand A (-13.393 mL/min/kg) has significantly lower (better) microsomal clearance than Ligand B (12.699 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.827 hours) has a much longer half-life than Ligand B (-28.801 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 (0.01 and 0.02).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. The 1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A's significantly stronger binding affinity, better metabolic stability (lower Cl_mic and longer t1/2), and lower DILI risk outweigh the permeability/solubility concerns. The negative values for Caco-2 and solubility are red flags that would require further investigation (e.g., experimental validation, salt screening, formulation studies), but the potency advantage of Ligand A is compelling. Ligand B's negative half-life is a major concern.

Output:
0
2025-04-17 14:18:18,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.475 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.26) is higher than Ligand B (43.86). While both are reasonably low, Ligand B's lower TPSA is preferable for better absorption.

**3. logP:** Both ligands have good logP values (2.817 and 2.356), 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 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.769 and 0.765), indicating good drug-likeness.

**7. DILI:** Ligand A (14.036) has a slightly higher DILI risk than Ligand B (11.4), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have high BBB penetration (81.698 and 84.878), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-5.206) has significantly worse Caco-2 permeability than Ligand B (-4.368). This suggests Ligand B will be absorbed better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.746 and -1.587). This is a potential concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.191) has a slightly higher hERG risk than Ligand B (0.684), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (21.753) has a significantly lower microsomal clearance than Ligand B (36.998), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (9.046) has a longer in vitro half-life than Ligand B (-2.535). This is a significant advantage, suggesting less frequent dosing may be possible.

**14. P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux than Ligand B (0.219), which is preferable for bioavailability.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.0). While both are excellent, the 0.8 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B has a better balance of properties. It has a lower TPSA, better Caco-2 permeability, and a slightly better binding affinity. While Ligand A has better metabolic stability and half-life, the improved absorption and potency of Ligand B outweigh these advantages. The solubility is a concern for both, but formulation can address this.

Output:
1
2025-04-17 14:18:18,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.423 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than the preferred <140, but acceptable. Ligand B (66.65) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands (2.22 and 2.322) are within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 5 HBA) is good. Ligand B (0 HBD, 4 HBA) is also very good, with fewer H-bonds potentially aiding permeability.

**QED:** Both ligands have good QED scores (0.701 and 0.773), indicating drug-like properties.

**DILI:** Ligand A (83.598) has a higher DILI risk than Ligand B (31.524). This is a significant concern, as a lower DILI score is highly desirable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (91.198) shows better BBB penetration than Ligand A (65.607), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very low 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 or low solubility.

**hERG Inhibition:** Ligand A (0.556) has a slightly higher hERG risk than Ligand B (0.377), but both are reasonably low.

**Microsomal Clearance:** Ligand A (37.616) has lower microsomal clearance than Ligand B (42.148), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.484) has a longer in vitro half-life than Ligand A (-12.319), which is desirable.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux than Ligand B (0.173), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A having slightly better metabolic stability and P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.1 vs -6.5 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. Furthermore, Ligand B exhibits a much lower DILI risk (31.524 vs 83.598), which is a crucial safety parameter. The slightly better half-life of Ligand B also contributes to its favorability. The unusual negative values for Caco-2 and solubility are concerning and would require further investigation, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 14:18:18,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.391 and 366.358 Da) are within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (105.04 and 103.7) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.059) is slightly below the optimal range (1-3), potentially hindering permeation. Ligand B (-0.054) is also low, with similar concerns.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED scores (0.761 and 0.752), indicating good drug-like properties.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (52.423). This is a negative for Ligand A.

**BBB:** Both ligands have low BBB penetration (59.131 and 31.834), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.474 and -5.248), suggesting potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.436 and -0.513). This is a significant concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.222 and 0.05), which is excellent.

**Microsomal Clearance:** Ligand A (-45.013) has significantly lower (better) microsomal clearance than Ligand B (5.24). This suggests much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (24.009 hours) has a longer half-life than Ligand B (0.966 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.013 and 0.012), which is favorable.

**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 relatively small, it's still a factor.

**Overall Assessment:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, despite the slightly weaker binding affinity. The solubility is a concern for both, but the metabolic advantage of A is more crucial for an enzyme target. The slightly better affinity of B is unlikely to overcome the substantial differences in metabolic stability and DILI.

Output:
0
2025-04-17 14:18:18,954 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [367.559, 61.44, 1.872, 2, 4, 0.779, 6.204, 66.344, -5.557, -1.865, 0.385, -7.97, 3.475, 0.011, -8.2]
**Ligand B:** [347.419, 108.95, 2.419, 2, 6, 0.715, 60.682, 70.182, -5.208, -2.998, 0.143, 51.448, -22.705, 0.084, -7.4]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (367.559) is slightly higher than B (347.419), but both are acceptable.
2. **TPSA:** A (61.44) is significantly better than B (108.95).  TPSA < 140 is good for oral absorption, but <90 is preferred for CNS targets. Since SRC is not a CNS target, A is still preferable due to the lower value.
3. **logP:** Both are within the optimal range (1-3). A (1.872) is slightly lower than B (2.419), but both are acceptable.
4. **HBD:** Both have 2 HBD, which is within the ideal range (<=5).
5. **HBA:** A (4) is better than B (6), both are within the ideal range (<=10).
6. **QED:** Both are good (>=0.5), A (0.779) is slightly better than B (0.715).
7. **DILI:** Both are relatively low risk, but A (6.204) is significantly better than B (60.682). This is a major advantage for A.
8. **BBB:** Not a primary concern for SRC. B (70.182) is better than A (66.344), but this is not a deciding factor.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-5.557) is slightly better than B (-5.208), but both are problematic.
10. **Solubility:** Both are negative, indicating poor solubility. A (-1.865) is slightly better than B (-2.998).
11. **hERG:** Both are very low, indicating low cardiotoxicity risk. A (0.385) is better than B (0.143).
12. **Cl_mic:** A (-7.97) is *much* better than B (51.448). Lower clearance is preferred for metabolic stability. This is a significant advantage for A.
13. **t1/2:** A (3.475) is better than B (-22.705). Longer half-life is desirable.
14. **Pgp:** Both are very low, indicating low efflux. A (0.011) is slightly better than B (0.084).
15. **Binding Affinity:** A (-8.2) is significantly better than B (-7.4). A difference of 0.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A is significantly better.
*   **Metabolic Stability:** A is *much* better (lower Cl_mic, better t1/2).
*   **Solubility:** A is slightly better.
*   **hERG:** A is better.
*   **DILI:** A is significantly better.

While both ligands have issues with Caco-2 and solubility, the superior binding affinity, metabolic stability, lower DILI risk, and better overall profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 14:18:18,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.371 Da) is slightly better positioned than Ligand B (373.475 Da).

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption, but Ligand A (113.18) is significantly better than Ligand B (127.59). Lower TPSA generally favors better cell permeability.

**logP:** Ligand A (1.493) is optimal (1-3), while Ligand B (-0.341) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBDs and 5 HBAs, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.543, Ligand B: 0.502), indicating good drug-like properties.

**DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (42.458), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (65.258) is slightly higher than Ligand B (47.15).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.101) is slightly better than Ligand B (-5.919).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.36) is slightly better than Ligand B (-1.68).

**hERG Inhibition:** Both have very low hERG inhibition risk (Ligand A: 0.295, Ligand B: 0.085), which is excellent.

**Microsomal Clearance:** Ligand B (4.571 mL/min/kg) has significantly lower microsomal clearance than Ligand A (18.725 mL/min/kg). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-13.614 hours) has a longer half-life than Ligand A (-11.046 hours).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (Ligand A: 0.041, Ligand B: 0.016).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a significant advantage (1.1 kcal/mol difference).

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better MW and TPSA, Ligand B's superior binding affinity (-8.5 vs -7.4 kcal/mol), lower microsomal clearance, and longer half-life outweigh the minor advantages of Ligand A. The slightly lower logP of Ligand B is a concern, but the significantly improved binding affinity and metabolic stability are more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:18:18,954 - INFO - Batch 285 complete. Total preferences: 4560
2025-04-17 14:18:18,954 - INFO - Processing batch 286/512...
2025-04-17 14:19:07,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.543 and 365.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (101.21). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.728 and 1.966, respectively), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 7 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.745 and 0.869), indicating good drug-like properties.

**DILI:** Ligand A (34.393) has a much lower DILI risk than Ligand B (89.221). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (64.948) is better than Ligand B (43.583).

**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, so it doesn't strongly differentiate them.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the values are similar, so this isn't a major differentiator.

**hERG Inhibition:** Ligand A (0.664) has a slightly higher hERG risk than Ligand B (0.015). This is a point in favor of B, but the value for A is still relatively low.

**Microsomal Clearance:** Ligand A (21.558) has a significantly *lower* (better) microsomal clearance than Ligand B (0.809). This indicates better metabolic stability for A.

**In vitro Half-Life:** Ligand A (26.038 hours) has a significantly longer half-life than Ligand B (-17.5 hours). This is a major advantage for A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.183) has lower P-gp efflux than Ligand B (0.04), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.0 kcal/mol). Ligand A is slightly better (-9.3 kcal/mol), but the difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall:**

Ligand A is the superior candidate. While Ligand B has a slightly lower hERG risk, Ligand A excels in critical areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The TPSA is also much more favorable for absorption. The unusual negative values for Caco-2 and solubility are concerning for both, but don't definitively rule either out without further investigation.



Output:
0
2025-04-17 14:19:07,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.487 and 363.502 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is better than Ligand B (35.58). Both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.246) is slightly higher than Ligand B (1.965), 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 3 HBA, and Ligand B has 4. Both are acceptable, below the 10 threshold.

**QED:** Ligand A (0.787) has a better QED score than Ligand B (0.619), indicating better overall drug-likeness.

**DILI:** Ligand A (21.985) has a significantly lower DILI risk than Ligand B (30.787), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (77.627 and 71.85, respectively), but Ligand A is slightly better. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.304) has worse Caco-2 permeability than Ligand B (-4.843). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-3.286) has worse aqueous solubility than Ligand B (-2.428). Better solubility is preferred.

**hERG Inhibition:** Ligand A (0.545) has a lower hERG inhibition risk than Ligand B (0.832), which is a significant advantage.

**Microsomal Clearance:** Ligand A (72.402) has higher microsomal clearance than Ligand B (22.082), meaning it's less metabolically stable. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (29.97) has a longer half-life than Ligand B (21.544), which is favorable.

**P-gp Efflux:** Ligand A (0.096) has lower P-gp efflux than Ligand B (0.118), which is a slight advantage.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is the most crucial factor for an enzyme inhibitor. The 8 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A's superior binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) is the most important factor. While it has some drawbacks (higher Cl_mic, lower solubility, lower Caco-2), the significantly stronger binding is likely to outweigh these. The lower DILI and hERG risks are also important positives. Ligand B has better solubility and metabolic stability, but its extremely weak binding affinity makes it unlikely to be a viable candidate.

Output:
1
2025-04-17 14:19:07,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.383 Da) is slightly preferred due to being lower in MW.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential (A: 93.56, B: 88.6). Ligand B is slightly better.

**logP:** Both ligands have logP values within the optimal range (1-3). (A: 2.317, B: 2.53). They are comparable.

**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.

**QED:** Both ligands have acceptable QED scores (A: 0.889, B: 0.704), indicating good drug-like properties, with Ligand A being superior.

**DILI:** Both ligands have relatively high DILI risk, but are still acceptable (A: 82.202, B: 79.721). Ligand B is slightly better.

**BBB:** Both ligands have good BBB penetration (A: 72.354, B: 77.2). This isn't a primary concern for a kinase inhibitor, but it's a neutral point.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. This is a significant drawback for both. A: -4.985, B: -4.823. They are comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. This is a significant drawback for both. A: -4.287, B: -3.455. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.204, B: 0.342). This is excellent. Ligand A is slightly better.

**Microsomal Clearance:** Ligand A (14.877 mL/min/kg) has significantly lower microsomal clearance than Ligand B (71.612 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (13.615 hours) has a shorter half-life than Ligand B (18.564 hours), but both are reasonable. Ligand B is slightly better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.141, B: 0.279). Ligand A is slightly better.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). This is a significant advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and half-life, Ligand A demonstrates superior metabolic stability (lower Cl_mic), better QED, and slightly better hERG/P-gp profiles. The poor Caco-2 and solubility for both are concerning, but the metabolic stability is crucial for kinase inhibitors. The higher binding affinity of Ligand B is tempting, but the significantly higher clearance could lead to rapid drug elimination and necessitate higher doses, potentially increasing off-target effects.

Output:
0
2025-04-17 14:19:07,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.881 and 351.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (21.7) is excellent, well below the 140 threshold for absorption. Ligand B (111.88) is higher but still acceptable, though it might slightly hinder absorption compared to A.

**logP:** Ligand A (4.594) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (-0.326) is quite low, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also reasonable, within the guidelines.

**QED:** Both ligands have acceptable QED values (0.781 and 0.594, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (51.493) has a moderate DILI risk, while Ligand B (19.155) has a very low DILI risk, which is a significant advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand A (76.115) is higher than Ligand B (25.475), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.65) is poor, suggesting poor intestinal absorption. Ligand B (-5.781) is even worse.

**Aqueous Solubility:** Ligand A (-4.392) is poor. Ligand B (-0.827) is also poor, but slightly better than A.

**hERG:** Ligand A (0.77) has a slightly elevated hERG risk, while Ligand B (0.08) has a very low risk, a major advantage.

**Microsomal Clearance:** Ligand A (21.666) has moderate clearance. Ligand B (-22.728) has *negative* clearance, which is impossible and indicates a potential data error or unusual metabolic stability. This is a huge positive for B.

**In vitro Half-Life:** Ligand A (44.8) has a reasonable half-life. Ligand B (31.773) is lower, but the negative clearance suggests a longer *in vivo* half-life.

**P-gp Efflux:** Ligand A (0.724) has moderate P-gp efflux. Ligand B (0.007) has very low efflux, which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has significantly better binding affinity than Ligand A (-6.8 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better TPSA, Ligand B is the superior candidate. Its significantly stronger binding affinity, very low DILI and hERG risk, and extremely low P-gp efflux are compelling. The negative microsomal clearance is a flag, but likely indicates exceptional metabolic stability. While both have poor Caco-2 permeability and solubility, the potency and safety profile of Ligand B make it a much more promising starting point for optimization.

Output:
1
2025-04-17 14:19:07,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.415 and 350.591 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is excellent, well below the 140 threshold for oral absorption. Ligand B (23.55) is also very good.

**logP:** Ligand A (1.297) is optimal. Ligand B (4.954) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Ligand A (0.784) has a strong drug-like profile. Ligand B (0.618) is also reasonably good.

**DILI:** Ligand A (36.332) has a low DILI risk. Ligand B (11.594) has a very low DILI risk, which is favorable.

**BBB:** Ligand A (74.37) is decent, but not a primary concern for a non-CNS target like SRC. Ligand B (90.617) is high, but again, less critical here.

**Caco-2 Permeability:** Ligand A (-5.026) is poor, indicating low intestinal absorption. Ligand B (-4.688) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.182) is poor. Ligand B (-4.171) is even worse.

**hERG Inhibition:** Ligand A (0.149) has very low hERG risk. Ligand B (0.937) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (15.035) has low microsomal clearance, suggesting good metabolic stability. Ligand B (89.346) has very high microsomal clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (-3.925) has a negative half-life, which is concerning. Ligand B (6.612) has a positive half-life, indicating better stability.

**P-gp Efflux:** Ligand A (0.089) has low P-gp efflux, which is good. Ligand B (0.775) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's poor Caco-2 permeability and negative in vitro half-life, its significantly superior binding affinity (-9.7 vs -8.5 kcal/mol) and low DILI/hERG risk make it the more promising candidate. The strong binding could potentially overcome the permeability issues, and the metabolic stability (low Cl_mic) is a key advantage. Ligand B's high metabolic clearance is a major drawback, even with a slightly better half-life.

Output:
0
2025-04-17 14:19:07,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.471 Da) is slightly higher than Ligand B (338.499 Da), but both are acceptable.

**TPSA:** Ligand A (93.46) is slightly higher than Ligand B (42.22). Both are below 140, suggesting reasonable absorption, but Ligand B's lower TPSA is preferable.

**logP:** Ligand A (1.377) is within the optimal range (1-3). Ligand B (4.964) 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 has 2 HBD and 6 HBA, fitting well within the guidelines. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.721, Ligand B: 0.546), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (Ligand A: 43.195, Ligand B: 39.628), which is positive.

**BBB:** Both have reasonable BBB penetration, but Ligand B (92.284) is significantly better than Ligand A (68.941). However, BBB is less critical for a non-CNS target like SRC.

**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 aqueous solubility. This is a major concern for both, but potentially more problematic for Ligand B due to its higher logP.

**hERG Inhibition:** Ligand A (0.269) has a very low hERG risk, which is excellent. Ligand B (0.926) has a higher, though still moderate, hERG risk.

**Microsomal Clearance:** Ligand A (44.479) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (62.002). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand B (35.002) has a much longer in vitro half-life than Ligand A (0.562). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.049) has very low P-gp efflux, which is favorable. Ligand B (0.966) has higher P-gp efflux, potentially reducing bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This 0.4 kcal/mol difference is noteworthy, but not overwhelming.

**Overall Assessment:**

Ligand A excels in hERG risk, P-gp efflux, and metabolic stability. Ligand B has a longer half-life and slightly better binding affinity, and better BBB penetration (less relevant here). However, Ligand B's higher logP and associated potential solubility issues, combined with its higher P-gp efflux, are significant drawbacks. Both ligands have poor solubility and Caco-2 permeability. The slightly better binding affinity of Ligand B is unlikely to overcome the ADME liabilities. Given the enzyme-specific priorities, the better metabolic stability and lower toxicity profile of Ligand A make it the more promising candidate, despite the slightly weaker binding.

Output:
0
2025-04-17 14:19:07,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.479 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is excellent, well below the 140 threshold for good absorption. Ligand B (111.39) is still acceptable but less optimal.

**logP:** Ligand A (2.093) is within the optimal 1-3 range. Ligand B (-0.027) is slightly below 1, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), staying within the <5 guideline.

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (9) is at the upper limit of the acceptable range (<10).

**QED:** Both ligands have good QED scores (0.74 and 0.658), indicating generally drug-like properties.

**DILI:** Both ligands have low DILI risk (35.983 and 33.501), which is favorable.

**BBB:** Ligand A (81.737) has a better BBB percentile than Ligand B (62.737), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.63) has poor Caco-2 permeability. Ligand B (-5.165) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.128) has poor aqueous solubility. Ligand B (-1.2) has slightly better aqueous solubility, but still poor.

**hERG Inhibition:** Ligand A (0.28) shows very low hERG inhibition risk, which is excellent. Ligand B (0.07) also shows very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (78.968) has higher microsomal clearance than Ligand B (38.497), suggesting lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (-15.933) has a negative in vitro half-life, which is not possible. This is a red flag and suggests a problem with the data or the molecule. Ligand B (5.343) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.107 and 0.031), which is good.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having better TPSA and a slightly better QED score, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.5 vs -7.6 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Although Ligand B has a slightly higher TPSA and lower solubility, the better affinity and more reasonable metabolic stability (lower Cl_mic, positive t1/2) make it the preferred choice. The negative half-life for Ligand A is a critical issue.

Output:
1
2025-04-17 14:19:07,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.308 Da) is slightly higher than Ligand B (379.555 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (58.64 and 61.36) well below the 140 threshold for oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.514) is slightly higher than Ligand B (2.427), but both are acceptable.

**H-Bond Donors/Acceptors:** Both ligands 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 good QED scores (0.764 and 0.852), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (54.789 and 53.005), and are both below the concerning threshold of 60.

**BBB:** Ligand A has a higher BBB penetration percentile (89.027) than Ligand B (76.619). While not a primary concern for a kinase inhibitor, it's a slight advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.663) has a worse Caco-2 permeability than Ligand B (-5.064). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.493) has worse aqueous solubility than Ligand B (-3.184). Lower values indicate lower solubility.

**hERG Inhibition:** Ligand A (0.77) has a slightly higher hERG inhibition risk than Ligand B (0.314), but both are relatively low.

**Microsomal Clearance:** Ligand B (35.847) has a significantly lower microsomal clearance than Ligand A (104.677), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (36.851) has a longer in vitro half-life than Ligand B (0.232). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.5) has lower P-gp efflux than Ligand B (0.029), which is a slight advantage for Ligand A.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.6 kcal/mol). The difference of 0.1 kcal/mol is negligible.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has a longer half-life and better BBB penetration, Ligand B exhibits significantly better metabolic stability (lower Cl_mic) and better solubility, both critical for an enzyme inhibitor. The slight advantage in half-life for Ligand A is outweighed by the substantial improvement in metabolic stability offered by Ligand B. The binding affinities are essentially identical.

Output:
1
2025-04-17 14:19:07,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.347 Da) is slightly lower, which could be beneficial for permeability. Ligand B (372.853 Da) is also good.

**TPSA:** Ligand A (123.59) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (94.48) is excellent, well below 140, suggesting better absorption potential.

**logP:** Ligand A (0.515) is a bit low, potentially hindering membrane permeability. Ligand B (0.75) is also on the lower side, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, within acceptable limits. Ligand B has 2 HBD and 6 HBA, also within limits.

**QED:** Both ligands have similar QED values (A: 0.8, B: 0.736), indicating good drug-likeness.

**DILI:** Ligand A (71.384) has a higher DILI risk than Ligand B (55.487), which is preferable.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.127 and -5.107), which is unusual and suggests poor permeability *in vitro*. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.968 and -2.446), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.065) has a very low hERG risk, which is excellent. Ligand B (0.136) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (10.329 mL/min/kg) has significantly lower microsomal clearance than Ligand B (29.591 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.422 hours) has a negative half-life, which is not physically possible and indicates an issue with the data or the model. Ligand B (21.912 hours) has a good in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.025 and 0.036), which is favorable.

**Binding Affinity:** Ligand B (-7.2 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 drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B's significantly stronger binding affinity (-7.2 vs -8.6 kcal/mol) is a major advantage for an enzyme target like SRC. It also has a better in vitro half-life and lower DILI risk. The lower metabolic clearance of Ligand A is appealing, but the negative half-life value is a red flag. The superior binding affinity of Ligand B is likely to be more impactful for efficacy.

Output:
1
2025-04-17 14:19:07,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.458 and 355.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.12) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.09) is still acceptable but less optimal.

**logP:** Ligand A (4.162) is slightly above the optimal range (1-3), potentially leading to solubility issues. Ligand B (3.087) is 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 counts, well within the guidelines.

**QED:** Both ligands have similar QED values (0.89 and 0.885), indicating good drug-likeness.

**DILI:** Ligand A (51.26) has a lower DILI risk than Ligand B (63.862), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (85.847) has better BBB penetration than Ligand B (70.958).

**Caco-2 Permeability:** Ligand A (-4.758) has a worse Caco-2 permeability than Ligand B (-5.026). Lower values here indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.301) has worse aqueous solubility than Ligand B (-3.603).

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.239 and 0.339), which is relatively low risk.

**Microsomal Clearance:** Ligand B (28.353) has significantly lower microsomal clearance than Ligand A (34.416), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (36.716) has a much longer in vitro half-life than Ligand A (1.196), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.183 and 0.142).

**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 ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better logP and DILI score, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity, much better metabolic stability (lower Cl_mic and longer t1/2), and better aqueous solubility. The slightly higher DILI risk of Ligand B is a manageable concern given its superior potency and metabolic profile.

Output:
1
2025-04-17 14:19:07,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (378.529 Da and 389.945 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, while Ligand B (59) is also acceptable.

**logP:** Both ligands have logP values around 3.3-3.4, which is optimal for permeability and avoiding solubility issues.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have good QED scores (0.704 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (31.136) has a significantly lower DILI risk than Ligand B (44.591). This is a substantial advantage.

**BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (72.858) has better BBB penetration than Ligand B (57.425).

**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 risk (0.688 and 0.537), which is good.

**Microsomal Clearance:** Ligand A (63.779) has higher microsomal clearance than Ligand B (43.49). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand B (55.021) has a significantly longer in vitro half-life than Ligand A (8.078). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.205 and 0.636), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.4 kcal/mol difference is significant 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 binding affinity (-8.3 vs -6.9 kcal/mol) and longer half-life (55.021 vs 8.078) are critical for an enzyme inhibitor. The lower DILI risk of Ligand A is appealing, but the potency and stability advantages of Ligand B are more important in this case.

Output:
1
2025-04-17 14:19:07,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.387 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.65 and 94.56) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.383) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (0.681) is also on the lower side but better than A.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 5 HBA) as it has fewer HBDs, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.829) has a significantly higher QED score than Ligand B (0.642), indicating a more drug-like profile.

**DILI:** Ligand A (57.813) has a higher DILI risk than Ligand B (19.232), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.117) is slightly better than Ligand B (48.895).

**Caco-2 Permeability:** Ligand A (-4.581) has a much worse Caco-2 permeability than Ligand B (-5.141). Both are very poor.

**Aqueous Solubility:** Ligand A (-1.967) is slightly better than Ligand B (-1.117), but both are poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.103 and 0.079), which is excellent.

**Microsomal Clearance:** Ligand A (12.417 mL/min/kg) has a higher clearance than Ligand B (2.523 mL/min/kg), suggesting lower metabolic stability for A.

**In vitro Half-Life:** Ligand B (1.328 hours) has a longer half-life than Ligand A (-0.412 hours), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.006).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better QED and slightly better solubility, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.4 vs -7.7 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B exhibits a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and comparable hERG risk. While both have poor Caco-2 permeability and solubility, the potency and safety profile of Ligand B make it the better choice.

Output:
1
2025-04-17 14:19:07,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (372.853 Da) is also acceptable.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (87.9). A lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (2.489) is optimal, while Ligand B (0.3) is quite low. A logP below 1 can hinder permeation.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 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.

**QED:** Both ligands have good QED scores (A: 0.719, B: 0.803), indicating drug-like properties.

**DILI:** Ligand B (63.086) has a higher DILI risk than Ligand A (13.416). This is a significant concern.

**BBB:** Ligand A (72.625) has better BBB penetration than Ligand B (32.803), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.831 and -4.769), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.442 and -2.078), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.583) has a slightly higher hERG risk than Ligand B (0.092), but both are relatively low.

**Microsomal Clearance:** Ligand A (36.269) has a higher microsomal clearance than Ligand B (20.086), meaning Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand B (9.101 hours) has a significantly longer half-life than Ligand A (3.616 hours).

**P-gp Efflux:** Ligand A (0.302) has lower P-gp efflux than Ligand B (0.075), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability and longer half-life, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.8 vs -7.1 kcal/mol) is a major advantage for an enzyme inhibitor. While Ligand A has slightly higher clearance and lower half-life, the potency advantage is likely to be more critical. The lower DILI risk for Ligand A is also a significant factor. The poor solubility and permeability indicated by the negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:19:07,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 367.446 Da - Within the ideal range (200-500 Da).
* Ligand B: 415.332 Da - Also within the ideal range.
* *No clear advantage here.*

**2. TPSA:**
* Ligand A: 71.53 A^2 - Good for oral absorption (<=140).
* Ligand B: 65.55 A^2 - Also good for oral absorption.
* *Ligand B is slightly better.*

**3. logP:**
* Ligand A: 2.777 - Optimal (1-3).
* Ligand B: 2.99 - Optimal (1-3).
* *Similar, no significant difference.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Meets the <=5 criteria.
* Ligand B: 0 - Meets the <=5 criteria.
* *Similar, no significant difference.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 5 - Meets the <=10 criteria.
* Ligand B: 7 - Meets the <=10 criteria.
* *Similar, no significant difference.*

**6. QED:**
* Ligand A: 0.813 - Excellent drug-like properties (>=0.5).
* Ligand B: 0.556 - Good drug-like properties (>=0.5).
* *Ligand A is significantly better.*

**7. DILI:**
* Ligand A: 60.062 - Moderate risk.
* Ligand B: 32.959 - Low risk.
* *Ligand B is significantly better.*

**8. BBB:**
* Ligand A: 83.986 - Good, but not critical for a non-CNS target like SRC.
* Ligand B: 77.821 - Acceptable, but lower than A.
* *Ligand A is slightly better, but not a major factor.*

**9. Caco-2 Permeability:**
* Ligand A: -4.729 - Poor permeability.
* Ligand B: -4.975 - Poor permeability.
* *Similar, both are poor.*

**10. Aqueous Solubility:**
* Ligand A: -4.335 - Poor solubility.
* Ligand B: -3.08 - Better solubility than A.
* *Ligand B is better.*

**11. hERG Inhibition:**
* Ligand A: 0.453 - Low risk.
* Ligand B: 0.772 - Moderate risk.
* *Ligand A is better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 59.226 mL/min/kg - Moderate clearance.
* Ligand B: 58.479 mL/min/kg - Moderate clearance.
* *Similar, no significant difference.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -19.23 hours - Very short half-life.
* Ligand B: 73.73 hours - Long half-life.
* *Ligand B is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.134 - Low efflux.
* Ligand B: 0.48 - Moderate efflux.
* *Ligand A is better.*

**15. Binding Affinity:**
* Ligand A: -7.9 kcal/mol - Excellent binding.
* Ligand B: -8.0 kcal/mol - Excellent binding, slightly better than A.
* *Ligand B is slightly better.*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand A has a better QED and lower hERG risk, Ligand B demonstrates a significantly longer half-life, lower DILI risk, and slightly better solubility. The binding affinity is comparable, with Ligand B being marginally better. The poor Caco-2 permeability is a concern for both, but less critical for an intravenously administered oncology drug. Considering the balance, the longer half-life and lower toxicity profile of Ligand B outweigh the slightly better QED and hERG profile of Ligand A.

Output:
1
2025-04-17 14:19:07,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.18) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (107.53) is well within the acceptable range.

**logP:** Ligand A (0.492) is a bit low, potentially hindering permeation. Ligand B (0.161) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is better balanced. Ligand B (4 HBD, 4 HBA) is also acceptable, but has more donors.

**QED:** Ligand A (0.743) has a good drug-likeness score. Ligand B (0.37) is significantly lower, indicating a less drug-like profile.

**DILI:** Ligand A (53.858) has a moderate DILI risk, but is acceptable. Ligand B (25.165) has a very low DILI risk, which is excellent.

**BBB:** Both ligands have low BBB penetration (40.52 and 37.379 respectively), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.291 and -5.336), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.68 and -1.767), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.208 and 0.062), which is positive.

**Microsomal Clearance:** Ligand A (21.82 mL/min/kg) has a higher clearance than Ligand B (14.702 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-10.267 hours) has a negative half-life, which is not possible and indicates a significant issue. Ligand A (20.371 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.017), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), a difference of 0.5 kcal/mol.

**Overall Assessment:**

Despite Ligand B having a slightly better binding affinity and lower DILI risk, its significantly lower QED score, negative in vitro half-life, and very poor solubility are major red flags. Ligand A, while having a lower QED than ideal and poor solubility, has a reasonable half-life and a better overall profile. The negative Caco-2 and solubility values for both are concerning, but the negative half-life for B is a showstopper. Given the enzyme-specific priorities, metabolic stability (half-life) and solubility are crucial.

Output:
0
2025-04-17 14:19:07,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.395 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.99) is significantly better than Ligand B (102.05). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal for good permeability.

**logP:** Ligand A (1.534) is optimal, while Ligand B (0.594) is slightly low, potentially hindering permeation.

**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 (0.531 and 0.693), indicating drug-like properties.

**DILI:** Ligand A (34.277) has a much lower DILI risk than Ligand B (47.15). Both are below the 60 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.284) is better than Ligand B (49.011).

**Caco-2 Permeability:** Ligand A (-4.543) is better than Ligand B (-5.371), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.711) is better than Ligand B (-2.09), suggesting better formulation potential.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.206 and 0.025).

**Microsomal Clearance:** Ligand A (25.61) has slightly higher clearance than Ligand B (22.764). Lower is better for metabolic stability, so Ligand B is slightly favored here.

**In vitro Half-Life:** Ligand B (16.736) has a significantly longer half-life than Ligand A (6.506). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.033).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.2 kcal/mol). This 0.9 kcal/mol difference is a significant advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has a better ADME profile overall (TPSA, logP, solubility, DILI). However, Ligand B's significantly stronger binding affinity (-8.1 vs -7.2 kcal/mol) is a critical factor for an enzyme target. The longer half-life of Ligand B is also a significant advantage. While Ligand B has a slightly higher DILI risk and clearance, the potency difference is substantial enough to make it the more promising candidate.

Output:
1
2025-04-17 14:19:07,239 - INFO - Batch 286 complete. Total preferences: 4576
2025-04-17 14:19:07,239 - INFO - Processing batch 287/512...
2025-04-17 14:19:46,480 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.454 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.88) is well below the 140 threshold for good absorption, and even better for kinases. Ligand B (95.42) is still acceptable but less favorable.

**3. logP:** Ligand A (0.543) is slightly low, potentially hindering permeation. Ligand B (1.762) 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:** 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 (0.772 and 0.67) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (6.863) has a very low DILI risk, which is excellent. Ligand B (32.377) is still acceptable, but higher.

**8. BBB:** Both ligands have low BBB penetration, which is not a major concern for a kinase inhibitor unless CNS off-target effects are a concern. Ligand A (60.915) is slightly better than Ligand B (50.446).

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.131 and -4.876), indicating poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-1.203 and -1.455), indicating poor aqueous solubility. This is also a significant drawback for both.

**11. hERG:** Both ligands have low hERG risk (0.305 and 0.291), which is excellent.

**12. Cl_mic:** Ligand A (-27.249) has a much lower (better) microsomal clearance than Ligand B (36.031), indicating better metabolic stability.

**13. t1/2:** Ligand A (-16.154) has a longer in vitro half-life than Ligand B (19.34), which is favorable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.019 and 0.054), which is good.

**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.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and longer half-life. While both ligands suffer from poor Caco-2 permeability and solubility, the strong binding affinity of Ligand A (-9.8 kcal/mol) is likely to outweigh these ADME drawbacks, especially considering it's an enzyme target. The difference in binding affinity (1.7 kcal/mol) is substantial and could translate to a significant difference in efficacy.

Output:
1
2025-04-17 14:19:46,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.421 and 377.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.16) is slightly higher than Ligand B (84.66). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Ligand A (3.348) is within the optimal 1-3 range. Ligand B (2.028) is also acceptable but closer to the lower bound.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.69 and 0.726), indicating good drug-likeness.

**DILI:** Ligand A (65.568) has a significantly higher DILI risk than Ligand B (20.512). This is a major concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (80.729 and 89.027). While not a primary concern for a non-CNS target like SRC, it doesn't detract from their potential.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.906 and -5.143). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Ligand A (-4.494) has worse solubility than Ligand B (-2.046). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.733) has a slightly higher hERG risk than Ligand B (0.954), but both are reasonably acceptable.

**Microsomal Clearance:** Ligand B (-18.155) has significantly lower (better) microsomal clearance than Ligand A (70.772). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-10.658) has a longer in vitro half-life than Ligand A (-9.572), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.1).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial difference (1.9 kcal/mol), which can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a substantially stronger binding affinity. While both have negative Caco-2 values, the overall profile of Ligand B is far more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 14:19:46,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.397 and 348.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, and Ligand B (67.65) is also acceptable.

**logP:** Both ligands have logP values within the optimal range (2.246 and 1.86).

**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 QED values above 0.5 (0.825 and 0.735), indicating good drug-likeness.

**DILI:** Ligand A (36.293) has a lower DILI risk than Ligand B (6.553), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (89.104 and 87.941), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.351 and -4.65), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.135 and -1.322), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Both ligands have low hERG inhibition liability (0.473 and 0.451), which is good.

**Microsomal Clearance:** Ligand A (27.406) has higher microsomal clearance than Ligand B (11.345). This suggests Ligand B is metabolically more stable.

**In vitro Half-Life:** Ligand B (-12.298) has a negative half-life, which is not possible and indicates an issue with the data or the model. Ligand A (32.588) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.089 and 0.014).

**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.

**Conclusion:**

Despite the slightly better affinity of Ligand B, its negative in vitro half-life is a critical flaw. It suggests a fundamental problem with its stability or the data itself. Ligand A, while having a slightly weaker affinity, has a reasonable half-life and a significantly lower DILI risk. The poor solubility and permeability are concerns for both, but can potentially be addressed with formulation strategies. Given the enzyme-specific priorities, the metabolic stability and lower toxicity risk of Ligand A make it the more viable candidate.

Output:
1
2025-04-17 14:19:46,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 369.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.04) is well below the 140 threshold, suggesting good absorption. Ligand B (88.91) is also acceptable, but slightly higher.

**logP:** Both ligands have logP values within the optimal 1-3 range (1.8 and 2.092 respectively).

**H-Bond Donors/Acceptors:** Ligand A has 0 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 QED values above 0.5 (0.762 and 0.617), indicating good drug-likeness.

**DILI:** Ligand A (45.173) has a lower DILI risk than Ligand B (64.521), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.71) has a higher BBB percentile than Ligand B (54.672).

**Caco-2 Permeability:** Ligand A (-4.337) has a more negative Caco-2 value, which is unusual and suggests *poor* permeability. Ligand B (-5.433) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.233 and -3.033), indicating poor aqueous solubility. This is a concern.

**hERG Inhibition:** Ligand A (0.688) has a lower hERG inhibition risk than Ligand B (0.386), which is a significant advantage.

**Microsomal Clearance:** Ligand A (34.694) has a lower microsomal clearance, indicating better metabolic stability than Ligand B (78.894).

**In vitro Half-Life:** Ligand A (17.267) has a longer half-life than Ligand B (5.342), which is desirable.

**P-gp Efflux:** Ligand A (0.073) has lower P-gp efflux liability than Ligand B (0.176), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-5.9 kcal/mol). This is a crucial difference. The 1.2 kcal/mol advantage is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite the solubility and Caco-2 permeability concerns for both, Ligand B's significantly higher binding affinity (-7.1 vs -5.9 kcal/mol) and acceptable (though not ideal) ADME properties make it the more promising candidate. The stronger binding is likely to be more impactful for efficacy than the moderate ADME drawbacks, which could potentially be addressed through formulation strategies. Ligand A's poor Caco-2 permeability is a significant red flag.

Output:
1
2025-04-17 14:19:46,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.403 and 337.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.63) is better than Ligand B (85.69), both are acceptable for oral absorption (<140).

**logP:** Both ligands have good logP values (3.486 and 2.472), 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 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.495 and 0.739), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a higher DILI risk (94.3 percentile) compared to Ligand B (77.549 percentile). This is a significant concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (60.45 and 59.403 percentile), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.617) shows poor permeability, while Ligand B (-5.125) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.156) has poor solubility, and Ligand B (-3.361) also has poor solubility.

**hERG Inhibition:** Ligand A (0.153) has a slightly higher hERG risk than Ligand B (0.465).

**Microsomal Clearance:** Ligand A (46.601 mL/min/kg) has better metabolic stability (lower clearance) than Ligand B (59.192 mL/min/kg).

**In vitro Half-Life:** Ligand B (-33.534 hours) has a significantly longer half-life than Ligand A (0.87 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.765) has higher P-gp efflux than Ligand B (0.321).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). However, the difference in affinity is less important than the ADME issues with Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity, but suffers from poor solubility, poor permeability, high DILI risk, and a short half-life. Ligand B, while having a weaker binding affinity, demonstrates better metabolic stability (longer half-life), lower DILI risk, and slightly better permeability. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. The substantial difference in half-life and the significantly lower DILI risk make Ligand B the more promising candidate, despite its weaker binding affinity. The affinity difference is not large enough to overcome the ADME liabilities of Ligand A.

Output:
1
2025-04-17 14:19:46,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.447 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.94) is better than Ligand B (78.87), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (1.563) is optimal (1-3), while Ligand A (0.588) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 2 HBDs, well within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 8 HBAs, and Ligand B has 4. Both are below the limit of 10.

**QED:** Both ligands have good QED scores (0.702 and 0.759, respectively), indicating drug-likeness.

**DILI:** Ligand B (7.794) has a significantly lower DILI risk than Ligand A (74.719), which is a major advantage.

**BBB:** Ligand B (65.801) has a higher BBB penetration percentile than Ligand A (47.421), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.78) has a worse Caco-2 permeability than Ligand B (-4.542).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.925 and -1.784, respectively). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.035) has a lower hERG inhibition liability than Ligand B (0.304), which is favorable.

**Microsomal Clearance:** Ligand B (38.932) has a slightly lower microsomal clearance than Ligand A (33.017), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.382) has a significantly longer in vitro half-life than Ligand A (-0.162), a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.021, respectively).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and lower hERG risk, Ligand B is superior overall. The significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly improved Caco-2 permeability outweigh the minor advantages of Ligand A. The similar binding affinities make the ADME properties the deciding factor. The poor solubility is a concern for both, but manageable.

Output:
1
2025-04-17 14:19:46,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (82.44) is significantly better than Ligand B (101.29). Lower TPSA generally correlates with better absorption.

**logP:** Both ligands have acceptable logP values (A: 0.682, B: 1.302), falling within the 1-3 range. Ligand B is slightly better.

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

**H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is within the acceptable limit.

**QED:** Ligand A (0.745) has a better QED score than Ligand B (0.491), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 23.769, B: 25.165), which is good.

**BBB:** Both ligands have similar BBB penetration (A: 57.968, B: 57.58), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.646) has a much better Caco-2 permeability than Ligand B (-5.732).

**Aqueous Solubility:** Ligand A (-1.351) has better aqueous solubility than Ligand B (-3.108).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.077, B: 0.086), which is excellent.

**Microsomal Clearance:** Ligand A (6.813) has significantly lower microsomal clearance than Ligand B (39.016), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (10.852) has a positive in vitro half-life, while Ligand B (-18.157) has a negative one. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.016, B: 0.033).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference (1.3 kcal/mol) is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties like TPSA, solubility, Caco-2 permeability, metabolic stability (Cl_mic and t1/2), and QED. These factors are particularly important for an enzyme target like SRC kinase, where maintaining adequate systemic exposure is crucial for efficacy.

Output:
0
2025-04-17 14:19:46,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (383.86 and 358.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.51) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (49.41) is well within the ideal range.

**logP:** Ligand A (1.995) is optimal (1-3). Ligand B (3.094) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values (0.852 and 0.794) indicating good drug-like properties.

**DILI:** Ligand A (84.34) has a higher DILI risk than Ligand B (57.70). This is a significant concern.

**BBB:** BBB is less important for a non-CNS target like SRC. Ligand B (93.76) has higher BBB penetration, but it's not a deciding factor here.

**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 not uncommon.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.331) has a lower hERG risk than Ligand B (0.916), which is a positive.

**Microsomal Clearance:** Ligand A (69.12) has a higher Cl_mic than Ligand B (30.68). This suggests Ligand B is more metabolically stable, which is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand B (36.12) has a significantly longer half-life than Ligand A (-20.13). This is a major advantage.

**P-gp Efflux:** Ligand A (0.245) shows some P-gp efflux, while Ligand B (0.399) shows more. Both are relatively low.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it has a higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter half-life) compared to Ligand B. Ligand B has better ADME properties overall, but its binding affinity is very weak.

Given the importance of potency for kinase inhibitors, the superior binding affinity of Ligand A is a critical factor. While the DILI risk is concerning, it might be mitigated through structural modifications in subsequent optimization rounds. The poor solubility of both compounds is a concern that needs to be addressed, but is a common starting point for optimization. The difference in binding affinity is so large that it outweighs the ADME concerns for initial selection.

Output:
1
2025-04-17 14:19:46,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 significantly better than Ligand B (49.85). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (Ligand A: 1.375, Ligand B: 2.003), falling within the optimal range of 1-3.

**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 B (0.756) has a better QED score than Ligand A (0.466), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 38.309, Ligand B: 35.595), below the 40 threshold.

**BBB:** Ligand B (90.772) has a much higher BBB penetration percentile than Ligand A (35.673). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction model or the compounds themselves. However, we can still compare the relative values. Ligand A (-4.967) is slightly better than Ligand B (-4.567).

**Aqueous Solubility:** Both ligands have negative solubility values, again indicating potential issues with the prediction. Ligand A (-2.484) is slightly better than Ligand B (-3.121).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.362, Ligand B: 0.449), which is good.

**Microsomal Clearance:** Ligand A (-2.243) has a significantly *lower* (better) microsomal clearance than Ligand B (18.526). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Both have negative half-life values, which is concerning. However, Ligand A (-24.15) is slightly better than Ligand B (-25.399).

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.11, Ligand B: 0.116).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a significant advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a better QED score and binding affinity. However, Ligand A has a significantly better TPSA, lower microsomal clearance (better metabolic stability), and slightly better solubility and Caco-2 permeability. The difference in binding affinity (1 kcal/mol) is not substantial enough to overcome the metabolic stability advantage of Ligand A, especially for a kinase inhibitor where sustained target engagement is crucial. The negative solubility and Caco-2 values are concerning for both, but the other properties of Ligand A are more favorable for overall drug development.

Output:
0
2025-04-17 14:19:46,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.431 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.56) is slightly higher than Ligand B (89.55), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (0.896) is a bit low, potentially impacting permeability. Ligand B (1.279) 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:** Both ligands have 5 H-bond acceptors, which is within the acceptable range (<=10).

**6. QED:** Ligand A (0.711) has a slightly better QED score than Ligand B (0.621), indicating a more drug-like profile.

**7. DILI:** Ligand B (37.611) has a significantly lower DILI risk than Ligand A (21.016), which is a major advantage.

**8. BBB:** Ligand B (71.229) has a higher BBB percentile than Ligand A (39.783), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.441) has worse Caco-2 permeability than Ligand B (-4.857), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.085 and -1.798, respectively). This is a concern, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.32 and 0.343, respectively).

**12. Microsomal Clearance:** Ligand A (-18.393) has a much lower (better) microsomal clearance than Ligand B (25.178), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.257) has a longer in vitro half-life than Ligand A (10.998), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.028, respectively).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-8.8 kcal/mol). This is a crucial advantage for an enzyme target.

**Overall Assessment:**

While Ligand A has a slightly better QED and metabolic stability, Ligand B is the stronger candidate. The significantly improved binding affinity (-7.2 vs -8.8 kcal/mol) is a substantial benefit for an enzyme inhibitor. Additionally, Ligand B has a lower DILI risk and a longer half-life. The slightly lower logP of Ligand A is a concern, and the solubility is poor for both, but the potency advantage of Ligand B outweighs these drawbacks.

Output:
1
2025-04-17 14:19:46,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (424.32 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 88.16, Ligand B: 86.88), suggesting good oral absorption potential.

**logP:** Both ligands have optimal logP values (Ligand A: 2.752, Ligand B: 1.28), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD (Ligand A: 2, Ligand B: 1) and HBA (both: 5) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (Ligand A: 0.745, Ligand B: 0.836), indicating a drug-like profile.

**DILI:** Ligand A has a significantly higher DILI risk (73.439) compared to Ligand B (29.159). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (71.733) and Ligand B (56.029) are both moderate.

**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, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.379) has a slightly higher hERG risk than Ligand B (0.144), but both are relatively low.

**Microsomal Clearance:** Ligand B has a lower microsomal clearance (27.533 mL/min/kg) than Ligand A (19.447 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a significantly longer half-life (88.196 hours) than Ligand B (14.31 hours). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.305) has lower P-gp efflux than Ligand B (0.071), which is favorable.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9 kcal/mol) than Ligand A (-7.8 kcal/mol). This is a crucial advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite the longer half-life and lower P-gp efflux of Ligand A, the significantly higher DILI risk and weaker binding affinity make it a less desirable candidate. Ligand B's superior binding affinity and much lower DILI risk are compelling advantages. The negative Caco-2 and solubility values are concerning for both, but the strong binding affinity of Ligand B suggests it may still be worth pursuing with formulation studies to address these issues.

Output:
1
2025-04-17 14:19:46,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.428 and 375.607 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.4) is better than Ligand B (21.06). While both are reasonably low, Ligand B is exceptionally low, which *could* indicate poor interactions, but isn't a major concern at this stage.

**logP:** Ligand A (3.333) is optimal, while Ligand B (4.987) is slightly high. This could potentially lead to solubility issues and off-target effects 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, but slightly less favorable for oral absorption than Ligand A.

**QED:** Ligand A (0.771) is better than Ligand B (0.649), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (29.003 and 26.173, respectively), which is excellent.

**BBB:** Both have high BBB penetration (91.392 and 84.141), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.815) is better than Ligand B (-5.583), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.113) is significantly better than Ligand B (-3.891). Solubility is a key concern for kinases, and Ligand B's value is concerning.

**hERG Inhibition:** Both ligands have very low hERG risk (0.906 and 0.893), which is excellent.

**Microsomal Clearance:** Ligand A (40.412) is significantly better than Ligand B (64.445). Lower clearance indicates better metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (53.976) is much better than Ligand B (-14.241). A negative half-life is extremely problematic, indicating very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.247 and 0.729), which is good.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.7 kcal/mol).

**Conclusion:**

Ligand A is clearly superior. While both have excellent potency, Ligand A demonstrates significantly better solubility, metabolic stability (lower Cl_mic and a positive, reasonable half-life), and a better QED score. Ligand B's high logP, poor solubility, and extremely poor half-life are major red flags. The slightly lower TPSA of Ligand B is not enough to offset these significant drawbacks.

Output:
0
2025-04-17 14:19:46,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 380.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is significantly better than Ligand B (111.06), being well below the 140 threshold for good absorption.

**logP:** Both ligands (1.541 and 2.466) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.815) has a much higher QED score than Ligand B (0.376), indicating a more drug-like profile.

**DILI:** Ligand A (36.565) has a significantly lower DILI risk than Ligand B (75.301), which is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (54.207) is better than Ligand B (41.722).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and requires further investigation. The values are similar.

**hERG:** Both ligands have low hERG risk (0.115 and 0.261).

**Microsomal Clearance:** Ligand A (7.097) has slightly higher microsomal clearance than Ligand B (6.711), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-14.786) has a longer in vitro half-life than Ligand A (-13.094), which is favorable.

**P-gp Efflux:** Ligand B (0.26) has slightly better P-gp efflux than Ligand A (0.033).

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-0.0).

**Overall Assessment:**

Ligand A is significantly better overall. Its superior QED, much lower DILI risk, lower TPSA, and slightly better binding affinity outweigh the slightly higher clearance and shorter half-life. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A make it the more promising candidate. The large difference in binding affinity (-7.3 vs 0.0) is a major factor.

Output:
1
2025-04-17 14:19:46,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.222 and 366.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.81) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (75.71) is still acceptable but less optimal.

**logP:** Ligand A (4.333) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.585) is 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 HBA, both acceptable.

**QED:** Both ligands have good QED scores (0.734 and 0.785), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 88.019, which is high and concerning. Ligand B has a much lower DILI risk of 46.917, which is preferable.

**BBB:** Both have good BBB penetration (73.827 and 82.474), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.652 and -4.618), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.99 and -2.877). This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.523) has a slightly higher hERG risk than Ligand B (0.368), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (72.129 and 73.848), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (12.707 hours) compared to Ligand A (31.671 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.495 and 0.14).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This difference of 1 kcal/mol is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. It has a significantly better binding affinity, a much lower DILI risk, and a longer half-life. The higher logP of Ligand A is also a concern. The superior binding affinity of Ligand B is a key factor, as it's a primary driver for enzyme inhibitors.

Output:
1
2025-04-17 14:19:46,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 Da and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.53 and 72.72) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.271) is optimal, while Ligand B (0.435) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0, both are within the acceptable limit of <=5.

**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 reasonable QED scores (0.847 and 0.71), indicating good drug-like properties.

**DILI:** Ligand A (47.926) has a slightly higher DILI risk than Ligand B (26.871), but both are below the concerning threshold of 60.

**BBB:** Ligand A (87.166) has better BBB penetration than Ligand B (67.313), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.524) has a worse Caco-2 permeability than Ligand B (-4.919), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.85) has better aqueous solubility than Ligand B (0.034). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.508) has a lower hERG inhibition risk than Ligand B (0.223), which is a significant advantage.

**Microsomal Clearance:** Ligand A (78.62) has a higher microsomal clearance than Ligand B (18.44), indicating lower metabolic stability. This is a critical drawback for an enzyme target.

**In vitro Half-Life:** Ligand A (-6.338) has a longer in vitro half-life than Ligand B (8.296).

**P-gp Efflux:** Ligand A (0.264) has lower P-gp efflux than Ligand B (0.044), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol), which are excellent. The difference is negligible.

**Conclusion:**

Despite Ligand A having a slightly better solubility and lower hERG risk, Ligand B is the more promising candidate due to its significantly better metabolic stability (lower Cl_mic and higher t1/2) and acceptable solubility. The low logP of Ligand B is a concern, but the strong binding affinity and improved metabolic profile outweigh this drawback for an enzyme target.

Output:
1
2025-04-17 14:19:46,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.527 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (95.16). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.722 and 1.022), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (4 and 5 respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.764 and 0.786), indicating good drug-likeness.

**DILI:** Ligand A (25.126) has a much lower DILI risk than Ligand B (65.568). This is a significant advantage for A.

**BBB:** Ligand A (57.154) has a lower BBB penetration than Ligand B (48.391). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value for A (-5.139) is less negative than B (-5.55), potentially indicating slightly better absorption.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. A (-2.082) is slightly better than B (-3.568).

**hERG:** Both ligands have low hERG inhibition risk (0.412 and 0.276), which is good.

**Microsomal Clearance:** Ligand A (26.445) has a lower microsomal clearance than Ligand B (29.079), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (40.054 hours) has a significantly longer half-life than Ligand B (-18.265 hours - which is essentially zero). This is a major advantage for A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.109 and 0.08).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While both are good, the 1.1 kcal/mol difference is noteworthy.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic and significantly longer t1/2), slightly better solubility and permeability, and a slightly stronger binding affinity. While both have poor solubility and permeability, the improvements in safety and PK properties for A outweigh the slight differences in those parameters.

Output:
1
2025-04-17 14:19:46,484 - INFO - Batch 287 complete. Total preferences: 4592
2025-04-17 14:19:46,484 - INFO - Processing batch 288/512...
2025-04-17 14:20:28,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (345.447 and 336.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (0.903) is slightly below the optimal range of 1-3, while Ligand B (2.71) is within the optimal 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 5 HBA, while Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.86 and 0.841), indicating good drug-likeness.

**7. DILI:** Ligand A (19.659) has a significantly lower DILI risk than Ligand B (42.807). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (62.854 and 62.97), which isn't a primary concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.136 and -4.931). 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 critical as the relative comparison.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.29 and -3.83). Similar to Caco-2, these values suggest poor solubility.

**11. hERG Inhibition:** Ligand A (0.07) has a much lower hERG inhibition liability than Ligand B (0.313), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance (Cl_mic):** Ligand A (18.51) has a lower microsomal clearance than Ligand B (39.92), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.468) has a longer in vitro half-life than Ligand B (-5.185).

**14. P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux liability than Ligand B (0.22).

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This 1.1 kcal/mol difference is significant and can outweigh some minor ADME drawbacks.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand A excels in all these areas. It has better affinity, lower DILI, lower hERG, lower Cl_mic, and longer half-life compared to Ligand B. While both have poor solubility and permeability, the superior profile of Ligand A in the critical enzyme-specific parameters makes it the more promising candidate.

Output:
1
2025-04-17 14:20:28,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.351 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (114.93) is better than Ligand B (56.75). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (1.638) is within the optimal range (1-3), while Ligand A (-1.704) is below 1. This is a significant drawback for Ligand A, potentially hindering membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 9 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.652, B: 0.811), indicating a generally drug-like profile.

**DILI:** Ligand A (64.327) has a higher DILI risk than Ligand B (29.779). This is a concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (81.504) is better than Ligand A (74.176). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.659) is worse than Ligand B (-4.777).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.539) is slightly worse than Ligand B (-1.304).

**hERG Inhibition:** Ligand A (0.015) has a very low hERG risk, which is excellent. Ligand B (0.541) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand B (-18.063) has much lower (better) microsomal clearance than Ligand A (24.333), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (1.662) has a longer half-life than Ligand A (-3.713), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.044) shows lower P-gp efflux than Ligand B (0.066), which is favorable.

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 kcal/mol and -6.2 kcal/mol respectively). Ligand A has a 1.8 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux, but suffers from a poor logP, higher DILI risk, poor Caco-2 permeability, and poorer metabolic stability (higher Cl_mic, shorter half-life). Ligand B, while having a slightly weaker binding affinity, exhibits a much more favorable ADME profile, particularly regarding metabolic stability and DILI risk. Given the enzyme-kinase target class priority on metabolic stability and safety, **Ligand B is the more promising drug candidate**. The binding affinity difference, while notable, can potentially be addressed through further optimization, while fixing the severe ADME liabilities of Ligand A would be considerably more challenging.

Output:
1
2025-04-17 14:20:28,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.843 Da) is slightly lower, which could be advantageous for permeability. Ligand B (426.242 Da) is still acceptable.

**TPSA:** Ligand A (37.61) is significantly better than Ligand B (68.02). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have similar logP values around 4.2, which is slightly above the optimal range (1-3) but not drastically so. This could potentially lead to some solubility issues, but is not a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 5 HBA). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have acceptable QED values (A: 0.714, B: 0.634), indicating good drug-like properties.

**DILI:** Ligand A (31.601) has a much lower DILI risk than Ligand B (90.733). This is a significant advantage for Ligand A.

**BBB:** Ligand A (96.782) shows excellent BBB penetration, while Ligand B (70.997) is good, but not as high. Since SRC is not a CNS target, this is less crucial, but still a positive for A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.44 and -4.468). These values are unusual and suggest poor permeability, but are likely reported as logP values and thus are not directly comparable.

**Aqueous Solubility:** Ligand A (-4.217) has better solubility than Ligand B (-5.355). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.848) has a lower hERG risk than Ligand B (0.393). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (35.624) has a lower microsomal clearance than Ligand A (51.714), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (12.191 hours) has a significantly longer half-life than Ligand A (4.421 hours). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.589) has lower P-gp efflux than Ligand B (0.345), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 kcal/mol and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Overall Assessment:**

Ligand A excels in several key areas: DILI risk, hERG inhibition, solubility, and TPSA. Ligand B has a clear advantage in metabolic stability (lower Cl_mic and longer half-life). While metabolic stability is important, the significantly lower DILI and hERG risks associated with Ligand A, coupled with its better solubility and TPSA, make it a more promising candidate. The similar binding affinities mean that the ADME/Tox profile becomes the deciding factor.

Output:
0
2025-04-17 14:20:28,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (401.312 Da) is closer to the upper limit.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (62.15) is lower than Ligand A (69.72), which is slightly better.

**logP:** Ligand A (1.564) is within the optimal range (1-3), while Ligand B (3.382) is at the higher end. While still acceptable, the higher logP of Ligand B could potentially lead to solubility issues or off-target interactions.

**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 QED values above 0.5 (Ligand A: 0.74, Ligand B: 0.609), indicating good drug-like properties.

**DILI:** Ligand A (18.185) has a significantly lower DILI risk than Ligand B (41.915). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 70.609, Ligand B: 71.268), but this is less critical for a non-CNS target like SRC.

**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 poor solubility. This is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.246) has a much lower hERG inhibition liability than Ligand B (0.882). This is a significant advantage for Ligand A, as it minimizes the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (27.799) has a lower microsomal clearance than Ligand B (55.847), indicating better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand B (50.898) has a much longer in vitro half-life than Ligand A (-2.537). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.032) has lower P-gp efflux liability than Ligand B (0.42), which is beneficial for bioavailability.

**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 (0.2 kcal/mol), it's a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in safety parameters (DILI, hERG) and metabolic stability (Cl_mic). Ligand B has a slightly better binding affinity and a significantly longer half-life. However, the higher DILI and hERG risk associated with Ligand B are concerning. The solubility issues are present in both compounds. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and safety), Ligand A is the more promising candidate due to its superior safety profile and metabolic stability, despite the slightly weaker binding affinity and shorter half-life. The small difference in binding affinity can potentially be optimized in subsequent iterations.

Output:
0
2025-04-17 14:20:28,431 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.445 and 366.527 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is better than Ligand B (58.64), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.054 and 2.566), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 4 HBA) as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.623 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (20.861) has a significantly lower DILI risk than Ligand B (33.773). This is a major advantage.

**BBB:** Ligand A (90.074) has a higher BBB penetration score than Ligand B (60.411). While SRC isn't necessarily a CNS target, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Ligand A (-4.398) has a worse Caco-2 permeability than Ligand B (-5.144). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-1.76) has better aqueous solubility than Ligand B (-2.976). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.695) has a lower hERG inhibition liability than Ligand B (0.31). This is a significant advantage, reducing cardiotoxicity risk.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (35.065 and 37.212 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (7.219 hours) has a longer in vitro half-life than Ligand B (3.418 hours). This is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.195) has lower P-gp efflux liability than Ligand B (0.108). Lower efflux is generally preferred.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a crucial advantage for an enzyme target like SRC kinase. The 1.1 kcal/mol difference is substantial.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability, Ligand A excels in almost every other critical parameter: significantly stronger binding affinity, lower DILI risk, better solubility, lower hERG inhibition, longer half-life, lower P-gp efflux, and higher BBB penetration. The superior binding affinity and improved safety profile (DILI, hERG) outweigh the slightly lower permeability.

Output:
1
2025-04-17 14:20:28,431 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.391 and 347.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (127.82) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (110.32) is well within the range.

**3. logP:** Ligand A (0.552) is a bit low, potentially hindering permeation. Ligand B (0.041) is even lower, raising more concerns about permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also good.

**5. H-Bond Acceptors:** Ligand A (7) is within the acceptable limit of 10. Ligand B (5) is also good.

**6. QED:** Both ligands have good QED scores (0.63 and 0.783, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (62.815) has a higher DILI risk than Ligand B (43.66). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have relatively low BBB penetration (61.38 and 55.138, respectively), which isn't critical for a non-CNS target like SRC.

**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, indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.336 and 0.132, respectively).

**12. Microsomal Clearance:** Ligand A (12.583) has a higher microsomal clearance than Ligand B (-1.19). This suggests lower metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (15.254) has a significantly longer in vitro half-life than Ligand A (-2.961). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.012, respectively).

**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 B is the more promising candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better TPSA. Although both have poor predicted permeability and solubility, the metabolic stability and safety profile of Ligand B outweigh these concerns, especially given the equal binding affinity. The low logP values for both are concerning and would need to be addressed in further optimization, but Ligand B is the better starting point.

Output:
1
2025-04-17 14:20:28,431 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.384 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand B (66.4) is significantly better than Ligand A (102.04), being well below the 140 threshold for oral absorption. Ligand A is still acceptable, but B is preferable.

**logP:** Both ligands have good logP values (1.571 and 2.651), falling within the optimal 1-3 range.

**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:** Both ligands have good QED scores (0.669 and 0.761), indicating drug-like properties.

**DILI:** Ligand B (47.034) has a lower DILI risk than Ligand A (36.293), which is favorable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.343) has a higher BBB percentile than Ligand B (57.968), but this is not a major deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and needs further investigation. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.12 and -1.435). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.222 and 0.374), which is excellent.

**Microsomal Clearance:** Ligand A (40.461 mL/min/kg) has a lower microsomal clearance than Ligand B (56.097 mL/min/kg), suggesting better metabolic stability, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand B (29.014 hours) has a significantly longer half-life than Ligand A (-5.97 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.05).

**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 less than the 1.5 kcal/mol threshold to outweigh major ADME issues, it is still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B's significantly longer half-life, lower DILI risk, and slightly better binding affinity outweigh Ligand A's better metabolic stability (lower Cl_mic). The lower TPSA of Ligand B is also beneficial. The negative Caco-2 values are concerning for both and would require further investigation, but the other factors favor Ligand B.

Output:
1
2025-04-17 14:20:28,431 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.402 and 372.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.96) is better than Ligand B (58.12) as it is closer to the 140 threshold.

**logP:** Both ligands have good logP values (3.175 and 3.649), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (1) as it is closer to the 5 threshold.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5) as it is closer to the 10 threshold.

**QED:** Ligand B (0.88) has a significantly better QED score than Ligand A (0.326), indicating a more drug-like profile.

**DILI:** Ligand B (47.15) has a much lower DILI risk than Ligand A (68.244), which is a significant advantage.

**BBB:** Ligand B (94.843) has a much higher BBB penetration percentile than Ligand A (67.778). While not a primary concern for a kinase inhibitor, higher BBB is generally not detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.152 and -4.943). This is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.188 and -4.318). This is also concerning and suggests poor solubility. Similar to Caco-2, these values should be interpreted cautiously.

**hERG Inhibition:** Ligand A (0.62) has a slightly higher hERG inhibition risk than Ligand B (0.49), but both are relatively low.

**Microsomal Clearance:** Ligand B (43.989) has a higher microsomal clearance than Ligand A (32.93), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (34.041) has a longer in vitro half-life than Ligand B (-4.496), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.236) has a lower P-gp efflux liability than Ligand B (0.182), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand B is the superior candidate despite its slightly higher microsomal clearance and P-gp efflux. The substantially stronger binding affinity (-8.6 kcal/mol vs 0.0 kcal/mol) outweighs the minor ADME drawbacks. The better QED and significantly lower DILI risk also favor Ligand B. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B suggests it may still be able to achieve sufficient target engagement *in vivo*.

Output:
1
2025-04-17 14:20:28,431 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.4 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.25) is slightly higher than Ligand B (65.79). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (1.258 and 1.58), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBDs, and Ligand B has 1. Both are within the acceptable limit of 5.

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

**QED:** Both ligands have high QED scores (0.859 and 0.88), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 37.73%, while Ligand B is lower at 24.16%. Both are below the 40% threshold, suggesting low liver injury risk, but Ligand B is preferable.

**BBB:** Ligand A has a BBB penetration of 78.56%, while Ligand B is 58.20%. While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-5.139) is worse than Ligand B (-5.059), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.216) is worse than Ligand B (-0.581), indicating lower solubility. Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.303 and 0.337), which is excellent.

**Microsomal Clearance:** Ligand A (16.41 mL/min/kg) has significantly lower microsomal clearance than Ligand B (9.363 mL/min/kg). Lower clearance indicates better metabolic stability, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-5.927 hours) has a much longer half-life than Ligand B (34.059 hours). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.067).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and longer half-life, which are crucial for an enzyme inhibitor. Ligand B has better TPSA, solubility, DILI, and Caco-2 permeability. However, the superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2) of Ligand A are more critical for a kinase inhibitor. The slight solubility disadvantage of Ligand A can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:20:28,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.345 Da) and Ligand B (339.439 Da) are both acceptable.

**TPSA:** Ligand A (96.33) is better than Ligand B (65.2). Both are below the 140 threshold for oral absorption, but lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (-0.493) is slightly low, potentially hindering permeation. Ligand B (2.151) is within the optimal range (1-3). This favors 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 counts are generally preferred for better permeability, favoring Ligand B.

**QED:** Both ligands have good QED scores (A: 0.765, B: 0.886), indicating drug-like properties.

**DILI:** Ligand A (60.682) is approaching a higher risk level, while Ligand B (43.622) is comfortably below the 60 threshold. This significantly favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (73.478) is better than Ligand B (54.13).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.168) is slightly better than Ligand B (-5.236), but both are concerning.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.473) is slightly better than Ligand B (-3.406).

**hERG:** Both have low hERG inhibition liability (A: 0.197, B: 0.449), which is excellent.

**Microsomal Clearance:** Ligand A (-17.191) shows significantly better metabolic stability (lower clearance) than Ligand B (28.565). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-5.753) has a slightly better (longer) half-life than Ligand B (4.268).

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.022, B: 0.071).

**Binding Affinity:** Both have excellent binding affinity (-9.9 and -9.6 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has advantages in logP, HBA, and DILI risk. However, Ligand A demonstrates superior metabolic stability (Cl_mic and t1/2), slightly better solubility, and a marginally better half-life. Given the enzyme-specific priority on metabolic stability, and the acceptable binding affinity of both, Ligand A is the more promising candidate. The DILI risk of Ligand A is a concern, but potentially mitigable through structural modifications. The poor Caco-2 and solubility for both compounds would need to be addressed during lead optimization.

Output:
0
2025-04-17 14:20:28,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.559 Da and 352.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, while Ligand B (119.54) is still acceptable but higher.

**logP:** Ligand A (2.784) is optimal (1-3). Ligand B (-1.295) is significantly below this range, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.586 and 0.565), indicating good drug-likeness.

**DILI:** Ligand A (22.451) has a much lower DILI risk than Ligand B (49.321), which is a significant advantage. Both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (73.711) is higher than Ligand B (42.032).

**Caco-2 Permeability:** Ligand A (-4.833) is poor, while Ligand B (-5.216) is also poor.

**Aqueous Solubility:** Ligand A (-2.597) is slightly better than Ligand B (-1.746), but both are quite poor.

**hERG Inhibition:** Ligand A (0.636) has a lower hERG risk than Ligand B (0.19), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (68.102) has higher clearance than Ligand B (-13.716), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (10.342) has a longer half-life than Ligand B (3.621), which is a positive.

**P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux than Ligand B (0.009), which is favorable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This difference of 2.8 kcal/mol is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand B's poor logP and solubility, its significantly higher binding affinity (-8.9 vs -6.1 kcal/mol) and lower microsomal clearance are compelling. The lower DILI and hERG risk of Ligand A are attractive, but the substantial affinity difference of Ligand B is likely to be more impactful for efficacy. The lower metabolic stability of Ligand A is also a concern.

Output:
1
2025-04-17 14:20:28,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.4 and 371.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.97) is better than Ligand B (92.5) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand B (1.775) is better than Ligand A (0.528). A logP between 1-3 is optimal, and A 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 (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.861) has a better QED score than Ligand B (0.573), indicating better overall drug-likeness.

**DILI:** Ligand A (35.091) has a significantly lower DILI risk than Ligand B (12.214). This is a major advantage.

**BBB:** Both ligands have moderate BBB penetration (61.691 and 65.374), which isn't a primary concern for a non-CNS target like SRC.

**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 is unclear.

**hERG:** Ligand A (0.163) has a much lower hERG inhibition liability than Ligand B (0.344), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (-4.076) has a *much* lower (better) microsomal clearance than Ligand B (30.433), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (-26.988) has a much longer in vitro half-life than Ligand B (-18.099), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.042).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Ligand A is the superior candidate. While both have issues with Caco-2 and solubility (scale unknown), Ligand A excels in the most critical areas for an enzyme inhibitor: potency (binding affinity), metabolic stability (Cl_mic, t1/2), and safety (DILI, hERG). The significantly stronger binding affinity of Ligand A (-8.8 vs -6.8 kcal/mol) outweighs the slightly lower logP.

Output:
1
2025-04-17 14:20:28,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.5 and 351.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold and excellent for oral absorption. Ligand B (87.74) is still under 140, but less optimal.

**logP:** Ligand A (3.05) is within the optimal 1-3 range. Ligand B (0.433) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 4 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.812 and 0.727, respectively), indicating drug-likeness.

**DILI:** Ligand A (21.946) has a very low DILI risk, which is highly favorable. Ligand B (25.785) is also low, but slightly higher than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.111) is higher than Ligand B (60.876).

**Caco-2 Permeability:** Ligand A (-5.069) is poor, while Ligand B (-4.934) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-3.344) is poor, while Ligand B (-1.617) is also poor, but better than A.

**hERG:** Ligand A (0.344) has a very low hERG risk, excellent. Ligand B (0.122) is also very low, but slightly higher than A.

**Microsomal Clearance:** Ligand A (39.234) has a moderate clearance, while Ligand B (10.669) has a significantly lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.514 hours) has a longer half-life than Ligand A (8.76 hours), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.348 and 0.015, respectively), which is good.

**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 a factor.

**Overall Assessment:**

Ligand A excels in terms of DILI risk, hERG risk, and binding affinity. However, its Caco-2 permeability and aqueous solubility are poor. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, but its logP is concerningly low, and its Caco-2 permeability is also poor. The difference in binding affinity is small enough that it doesn't entirely outweigh the ADME advantages of Ligand B. Given the importance of metabolic stability for kinase inhibitors, and the slightly better solubility of B, I would lean towards Ligand B.

Output:
1
2025-04-17 14:20:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (337.423 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.2) is slightly above the preferred <90 for kinases, while Ligand B (58.44) is well within the range.

**3. logP:** Both ligands have good logP values (2.652 and 2.015) falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, 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:** Both ligands have good QED scores (0.777 and 0.802), indicating good drug-like properties.

**7. DILI:** Ligand A (39.705) has a slightly better DILI risk profile than Ligand B (52.772), both being below the concerning threshold of 60.

**8. BBB:** Both ligands have high BBB penetration (75.107 and 77.2), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.578 and -4.87). 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 have negative solubility values (-4.157 and -2.35). Similar to Caco-2, these are on a log scale and indicate poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.355 and 0.259), which is excellent.

**12. Microsomal Clearance:** Ligand A (50.238) has lower microsomal clearance than Ligand B (77.656), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand B (-7.177) has a longer in vitro half-life than Ligand A (-3.511), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.218 and 0.234).

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is slightly favored. While Ligand B has a longer half-life, Ligand A has better metabolic stability (lower Cl_mic), slightly better binding affinity, and a lower DILI risk. The solubility and permeability issues are similar for both, and could be addressed with formulation strategies. Given the enzyme-specific priorities, the improved metabolic stability and binding affinity of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 14:20:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (374.388 Da and 346.385 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.09) is slightly higher than Ligand B (57.18), but both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.382 and 2.061), 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, being less than 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 values (0.806 and 0.894), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 81.078%, which is high. Ligand B has a DILI risk of 61.303%, which is also elevated, but lower than Ligand A.

**8. BBB:** Both ligands have relatively high BBB penetration (78.48% and 82.164%), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.936 and -4.89), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.813 and -2.994), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.557) has a slightly lower hERG inhibition risk than Ligand B (0.929), which is preferable.

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (24.203 mL/min/kg) than Ligand B (48.272 mL/min/kg), suggesting better metabolic stability. This is a positive attribute for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (-16.47) and Ligand B (-19.478) both have negative in vitro half-life values, which is not physically meaningful and suggests a problem with the data or prediction method.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.182 and 0.082).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.3 kcal/mol and -8.7 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Both ligands have significant issues with solubility and Caco-2 permeability. The high DILI risk for both is also concerning. However, Ligand A has better metabolic stability (lower Cl_mic) and slightly lower hERG risk. Given the enzyme-specific priorities, metabolic stability is crucial. While the DILI risk is high for both, Ligand A is marginally better in this regard. The binding affinity difference is not significant.

Output:
0
2025-04-17 14:20:28,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.373 Da) is slightly lower, which could be advantageous for permeability. Ligand B (360.439 Da) is also good.

**TPSA:** Ligand A (41.99) is well below the 140 threshold and is favorable. Ligand B (75.63) is still reasonably low, but higher than A.

**logP:** Ligand A (4.945) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.653) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 HBA, which are both within acceptable limits. Ligand B has 0 HBD and 6 HBA, also acceptable, but the higher HBA count might slightly impact permeability.

**QED:** Both ligands have similar QED values (0.733 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 84.18, which is concerning (high risk). Ligand B has a much lower DILI risk of 50.136, which is preferable.

**BBB:** Both ligands have reasonably high BBB penetration, but Ligand A (80.574) is better than Ligand B (64.715). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.616) has poor predicted Caco-2 permeability. Ligand B (-5.004) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.326) has poor predicted solubility. Ligand B (-1.658) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.792) has a slightly elevated hERG risk, but not alarming. Ligand B (0.075) has very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (58.811) has moderate clearance, suggesting moderate metabolic stability. Ligand B (22.187) has significantly lower clearance, indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (103.736 hours) has a very long half-life, which is excellent. Ligand B (3.813 hours) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.667) has moderate P-gp efflux. Ligand B (0.092) has very low P-gp efflux, which is beneficial.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.7 kcal/mol), with Ligand B being slightly better. The affinity difference is small and likely less important than the ADME differences.

**Conclusion:**

While Ligand A has a longer half-life and slightly better BBB penetration, its high DILI risk, poor solubility, and poor Caco-2 permeability are significant concerns. Ligand B, despite its shorter half-life, exhibits a much better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), and lower P-gp efflux. The slightly lower solubility and permeability of Ligand B can potentially be addressed through formulation strategies, but mitigating a high DILI risk is far more challenging. Given the priorities for enzyme inhibitors, the improved safety and metabolic stability of Ligand B outweigh the benefits of Ligand A's longer half-life.

Output:
1
2025-04-17 14:20:28,433 - INFO - Batch 288 complete. Total preferences: 4608
2025-04-17 14:20:28,433 - INFO - Processing batch 289/512...
2025-04-17 14:21:09,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (102.05) is still under 140, but less optimal than A.

**3. logP:** Ligand A (3.704) is at the higher end of the optimal range (1-3), while Ligand B (1.374) is at the lower end. This could potentially hinder permeation 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 3 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but B is closer to the upper bound.

**6. QED:** Both ligands have similar QED values (0.825 and 0.789), indicating good drug-likeness.

**7. DILI:** Ligand A (19.504) has a significantly lower DILI risk than Ligand B (56.262). This is a major advantage for A.

**8. BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (76.658) has a higher BBB percentile than Ligand B (55.099).

**9. Caco-2 Permeability:** Ligand A (-4.783) has a more negative Caco-2 value, suggesting *lower* permeability than Ligand B (-5.064). This is unusual and requires careful consideration. However, the scale is not clearly defined, and negative values may indicate a different measurement system.

**10. Aqueous Solubility:** Ligand A (-4.418) has a more negative solubility value, suggesting lower solubility than Ligand B (-3.028). This is a potential drawback for A.

**11. hERG Inhibition:** Ligand A (0.654) has a slightly higher hERG risk than Ligand B (0.073). This is a concern for A, but the value is not extremely high.

**12. Microsomal Clearance:** Ligand A (92.127) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (17.16). This is a significant disadvantage for A.

**13. In vitro Half-Life:** Ligand B (7.659) has a longer in vitro half-life than Ligand A (2.485), indicating better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux than Ligand B (0.03), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.9 kcal/mol). While A has a stronger binding affinity, the difference is not substantial enough to outweigh the ADME concerns.

**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 metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The lower logP of B is a minor concern, but the other advantages outweigh this. The Caco-2 values are difficult to interpret without knowing the scale, but the overall profile of B is more favorable for development as an enzyme inhibitor.

Output:
1
2025-04-17 14:21:09,940 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.487 and 351.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.98) is better than Ligand B (69.22), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.066) is slightly lower than optimal (1-3), but acceptable. Ligand B (2.99) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (2 HBD, 3 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.78 and 0.828, respectively), indicating good drug-like properties.

**DILI:** Ligand A (34.393) has a significantly lower DILI risk than Ligand B (21.481), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (67.041 and 63.746). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.846 and -4.879), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.183 and -2.729), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.165) has a much lower hERG risk than Ligand B (0.621), which is a critical advantage.

**Microsomal Clearance:** Ligand A (3.356) has a significantly lower microsomal clearance than Ligand B (16.066). Lower clearance suggests better metabolic stability, which is crucial for kinases.

**In vitro Half-Life:** Ligand A (3.963) has a slightly lower half-life than Ligand B (4.53), but both are relatively low.

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux liability than Ligand B (0.294), which is favorable.

**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 concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher hERG risk, higher microsomal clearance, and higher P-gp efflux. Ligand A has a better safety profile (lower DILI, hERG, and P-gp) and better metabolic stability (lower Cl_mic), but its affinity is weaker. The poor Caco-2 and solubility are concerning for both.

Despite the affinity difference, the significantly improved safety and metabolic stability profile of Ligand A makes it the more viable starting point for optimization. The affinity can be improved through medicinal chemistry efforts, while addressing safety issues is often more challenging.

Output:
0
2025-04-17 14:21:09,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.467 and 344.327 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.84) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (126.48) is still under 140, but less favorable than A.

**3. logP:** Ligand A (4.027) is at the upper end of the optimal range (1-3), potentially causing solubility issues. Ligand B (0.978) is slightly below the optimal range, 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 6 HBA, and Ligand B has 7 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.741 and 0.717), indicating good drug-likeness.

**7. DILI:** Ligand A (83.249) has a higher DILI risk than Ligand B (79.527), but both are reasonably acceptable.

**8. BBB:** Both ligands have moderate BBB penetration (61.613 and 65.064). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.129 and -4.957). This is unusual and suggests poor permeability *in vitro*. However, these values can be unreliable and require further investigation.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.085 and -4.035), indicating poor aqueous solubility. This is a significant concern, especially with Ligand A's higher logP.

**11. hERG Inhibition:** Ligand A (0.626) has a slightly higher hERG risk than Ligand B (0.303), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (31.915) has significantly lower microsomal clearance than Ligand A (39.772), indicating better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (38.007) has a shorter half-life than Ligand A (80.965), but still reasonable. The longer half-life of Ligand A is a positive.

**14. P-gp Efflux:** Ligand A (0.689) has a slightly higher P-gp efflux liability than Ligand B (0.101), which is unfavorable.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A 1.5 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand A has a longer half-life, its higher logP, DILI risk, P-gp efflux, and *significantly* weaker binding affinity make it less attractive. Ligand B, despite slightly lower metabolic stability and half-life, boasts a much stronger binding affinity, lower P-gp efflux, and a lower DILI risk. The stronger binding affinity is likely to outweigh the minor ADME drawbacks, especially given that solubility can be addressed with formulation strategies.

Output:
1
2025-04-17 14:21:09,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.391 and 362.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand B (62.99) is significantly better than Ligand A (118.37), being well below the 140 threshold for good absorption. Ligand A is approaching the upper limit.

**logP:** Ligand B (3.033) is optimal, while Ligand A (0.583) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is even better, potentially improving permeability.

**H-Bond Acceptors:** Ligand A (7) is acceptable, and Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.687 and 0.842), indicating drug-like properties.

**DILI:** Ligand B (73.672) has a higher DILI risk than Ligand A (65.917), but both are above the 60 threshold and therefore concerning.

**BBB:** Both have relatively low BBB penetration (63.862 and 58.782), which isn't critical for a non-CNS target like SRC.

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

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG:** Ligand A (0.098) has a much lower hERG risk than Ligand B (0.396), which is a significant advantage.

**Microsomal Clearance:** Both have similar microsomal clearance rates (42.656 and 43.285), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (40.343) has a longer half-life than Ligand A (21.546), which is desirable.

**P-gp Efflux:** Ligand A (0.033) has lower P-gp efflux liability than Ligand B (0.553), which is favorable.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), although the difference is small.

**Overall Assessment:**

While both compounds have issues with Caco-2 and solubility, Ligand A is preferable due to its significantly lower hERG risk, better P-gp efflux profile, and slightly better binding affinity. The lower logP of Ligand A is a concern, but the superior safety profile and binding outweigh this drawback. The DILI risk is concerning for both, but can be addressed in later optimization stages.

Output:
0
2025-04-17 14:21:09,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.454 Da and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good oral absorption. Ligand B (86.71) is also acceptable, though slightly higher.

**logP:** Ligand A (1.388) is within the optimal 1-3 range. Ligand B (0.575) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well under the 10 limit.

**QED:** Both ligands have good QED scores (A: 0.666, B: 0.695), indicating drug-like properties.

**DILI:** Ligand A (16.479) has a significantly lower DILI risk than Ligand B (55.952). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.2) has much better BBB penetration than Ligand B (45.366), but it's not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.42 and -4.812), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.872 and -3.11), indicating very poor aqueous solubility. This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.672) has a lower hERG inhibition risk than Ligand B (0.338), which is favorable.

**Microsomal Clearance:** Ligand A (15.057) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (35.167). This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-8.156) has a much longer in vitro half-life than Ligand B (-43.697), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.043, B: 0.121).

**Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-7.9), although the difference is small.

**Conclusion:**

Ligand A is the more promising candidate. While both compounds suffer from poor solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and a slightly better binding affinity. The lower hERG risk is also a positive factor. The small advantage in binding affinity, combined with the substantial improvements in ADME properties, outweighs the slightly lower logP.

Output:
0
2025-04-17 14:21:09,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (390.531 and 364.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.63) is better than Ligand B (42.43) as it is closer to the threshold of 140 for oral absorption.

**logP:** Ligand A (-0.061) is slightly low, potentially hindering permeation, while Ligand B (4.233) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (7) is acceptable, while Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.573 and 0.727, respectively), indicating good drug-like properties.

**DILI:** Ligand A (37.844) has a lower DILI risk than Ligand B (13.106), which is a significant advantage.

**BBB:** Ligand A (27.801) has a low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (89.104) has high BBB penetration, which is not relevant here.

**Caco-2 Permeability:** Ligand A (-5.857) has poor Caco-2 permeability, while Ligand B (-4.461) is also poor.

**Aqueous Solubility:** Ligand A (-1.207) has poor solubility, while Ligand B (-3.987) is even worse.

**hERG Inhibition:** Ligand A (0.232) has a lower hERG risk than Ligand B (0.652), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-12.279) has a significantly *lower* (better) microsomal clearance than Ligand B (95.933), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.019) has a shorter half-life than Ligand B (20.276).

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux than Ligand B (0.617), which is favorable.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly better DILI score, lower hERG risk, and much better metabolic stability (lower Cl_mic). While its solubility and Caco-2 permeability are poor, these can potentially be addressed with formulation strategies. The slightly weaker binding affinity of Ligand A is less concerning given its superior safety and pharmacokinetic properties. Ligand B's high logP and poor solubility are significant drawbacks.

Output:
0
2025-04-17 14:21:09,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.41 and 389.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.47) is better than Ligand B (99.93), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold if CNS penetration were desired (which isn't a primary concern here).

**logP:** Ligand A (3.33) is slightly higher than Ligand B (1.787), both 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 have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.67 and 0.747), indicating good drug-like properties.

**DILI:** Ligand A (62.078) has a higher DILI risk than Ligand B (52.617), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target. Ligand A (62.35) is slightly better than Ligand B (46.607).

**Caco-2 Permeability:** Ligand A (-5.032) is worse than Ligand B (-4.665). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.775) is worse than Ligand B (-2.325). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.335) is slightly higher than Ligand B (0.181), but both are low and pose minimal cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (45.495) has significantly higher microsomal clearance than Ligand B (24.079), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In Vitro Half-Life:** Ligand A (53.958) has a longer half-life than Ligand B (20.442), which is a positive attribute. However, this is somewhat offset by the higher clearance.

**P-gp Efflux:** Ligand A (0.514) has higher P-gp efflux than Ligand B (0.211), which could reduce bioavailability.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly better binding affinity than Ligand A (-8.2 kcal/mol). This is a crucial advantage, especially for an enzyme target.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly longer half-life, Ligand B demonstrates superior binding affinity, better metabolic stability (lower Cl_mic), lower P-gp efflux, and better solubility. The slightly higher DILI risk for Ligand A, coupled with its poorer metabolic stability and lower affinity, makes it less attractive. The binding affinity difference of 0.9 kcal/mol is substantial enough to outweigh the minor drawbacks of Ligand B.

Output:
1
2025-04-17 14:21:09,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 362.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (94.88), both are under the 140 threshold for good absorption.

**logP:** Ligand A (0.906) is within the optimal 1-3 range, while Ligand B (3.208) is at the higher end, potentially leading to solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=4) as it is closer to the ideal ranges.

**QED:** Both ligands have good QED scores (0.622 and 0.728, respectively), indicating drug-likeness.

**DILI:** Ligand A (15.161) has a significantly lower DILI risk than Ligand B (38.658), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (74.176) is slightly better than Ligand A (66.382). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.785) is slightly better than Ligand B (-4.829).

**Aqueous Solubility:** Ligand A (-0.712) has better solubility than Ligand B (-3.987). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.104) has a much lower hERG risk than Ligand B (0.466), which is a critical safety consideration.

**Microsomal Clearance:** Ligand A (13.351) has significantly lower microsomal clearance than Ligand B (35.856), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.934) has a longer in vitro half-life than Ligand B (27.131), which is desirable for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.022 and 0.032 respectively).

**Binding Affinity:** Ligand B (-9.1 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.

**Conclusion:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI, lower hERG) and better ADME properties (lower Cl_mic, longer t1/2, better solubility). Given the enzyme-specific priorities, the improved metabolic stability, solubility, and safety profile of Ligand A are compelling. The affinity difference, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 14:21:09,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.447 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (84.67 and 79.37) below 140, suggesting good oral absorption potential.

**logP:** Both ligands have logP values (2.512 and 2.973) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is acceptable. Ligand A has 6 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.5 (0.626 and 0.908), indicating good drug-like properties. Ligand B is significantly better here.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (59.984), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (94.61) has a significantly higher BBB penetration than Ligand A (71.229).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.772 and -4.366), which is unusual and problematic. These values likely indicate poor permeability. However, we'll need to consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.599 and -3.686), which is also concerning, suggesting poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.408 and 0.42), which is good.

**Microsomal Clearance:** Ligand B (51.487 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (82.125 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (29.681 hours) has a much longer in vitro half-life than Ligand A (-6.876 hours). The negative value for Ligand A is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.27 and 0.117).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. It has a superior QED score, significantly lower microsomal clearance, a longer half-life, and slightly better binding affinity. While both have issues with Caco-2 and solubility, the improved metabolic stability and binding of Ligand B outweigh these concerns, especially for an enzyme target where potency and duration of action are critical.

Output:
1
2025-04-17 14:21:09,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (385.917 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (78.67), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.259 and 1.047), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 4 HBA and Ligand B has 5 HBA, both are within the acceptable range (<=10).

**QED:** Both ligands have similar and good QED values (0.815 and 0.827), indicating good drug-likeness.

**DILI:** Ligand A (48.817) has a lower DILI risk than Ligand B (52.462), both are below the 60 threshold.

**BBB:** Ligand A (78.558) has a better BBB penetration than Ligand B (39.977), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.719 and -4.867). This is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without knowing the units.

**Aqueous Solubility:** Ligand A (-3.989) has better solubility than Ligand B (-1.387), both are negative, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.556) has a lower hERG risk than Ligand B (0.225), which is preferable.

**Microsomal Clearance:** Ligand B (36.921) has a lower microsomal clearance than Ligand A (42.344), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-4.633) has a longer half-life than Ligand B (-0.529).

**P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux than Ligand B (0.229).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly better binding affinity than Ligand B (-6.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability, Ligand A's significantly stronger binding affinity (-8.1 vs -6.8 kcal/mol) is the most crucial factor for an enzyme inhibitor. The better hERG risk, solubility, and P-gp efflux of Ligand A also contribute to its favorability. While both have questionable Caco-2 and solubility values, the potency advantage of Ligand A is compelling.

Output:
1
2025-04-17 14:21:09,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (349.43 and 344.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (77.77 and 78.43) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands (2.74 and 2.93) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 3. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Ligand A (0.727) has a better QED score than Ligand B (0.603), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.13) has a slightly higher DILI risk than Ligand B (20.24), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have reasonable BBB penetration (70.61 and 67.62), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.39 and -4.65), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.31 and -3.12), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.37 and 0.53), which is excellent.

**12. Microsomal Clearance:** Ligand B (48.76) has significantly lower microsomal clearance than Ligand A (73.54), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (8.73 hours) has a much longer in vitro half-life than Ligand A (38.27 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.24 and 0.42).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

While both ligands have strong binding affinities and acceptable safety profiles (DILI, hERG), Ligand B is the more promising candidate due to its significantly improved metabolic stability (lower Cl_mic) and longer half-life. The negative Caco-2 and solubility values are concerning for both, but the superior pharmacokinetic properties of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 14:21:09,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.439 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.25) is slightly higher than Ligand B (78.09). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.737 and 2.521), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.567 and 0.796), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A has a DILI risk of 79.372, which is high. Ligand B has a much lower DILI risk of 35.905, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (60.915 and 69.213). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.199 and -4.952), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.037 and -3.485). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.146 and 0.525), which is excellent.

**Microsomal Clearance:** Ligand A has a very high microsomal clearance (99.973), indicating poor metabolic stability. Ligand B has a better, but still concerning, clearance of 56.7. Lower is better, and Ligand B is preferable.

**In vitro Half-Life:** Both ligands have negative in vitro half-lives (-28.449 and -25.544), which is problematic. This suggests rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.174 and 0.199), which is good.

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

**Conclusion:**

While both ligands have good binding affinity, Ligand B is significantly better due to its much lower DILI risk (35.905 vs 79.372) and better microsomal clearance (56.7 vs 99.973). The solubility and Caco-2 permeability are poor for both, but these can potentially be addressed through formulation strategies. The lower DILI risk is a critical advantage in early drug development.

Output:
1
2025-04-17 14:21:09,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.475 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have similar TPSA values (67.23 and 67.43), which are acceptable for oral absorption (<=140).

**3. logP:** Ligand A (1.754) is slightly better than Ligand B (2.413), both falling 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 (3), again favoring permeability.

**6. QED:** Ligand A (0.818) has a significantly better QED score than Ligand B (0.694), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (25.087), a crucial advantage.

**8. BBB:** Ligand A (80.264) has a better BBB penetration score than Ligand B (62.311), though this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have the same Caco-2 permeability (-5.116), which is not ideal, but not a dealbreaker.

**10. Aqueous Solubility:** Both ligands have the same aqueous solubility (-1.4), which is not ideal.

**11. hERG Inhibition:** Ligand A (0.263) shows a much lower hERG inhibition liability than Ligand B (0.15), a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (15.395) has a lower microsomal clearance than Ligand B (31.457), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.119) has a longer in vitro half-life than Ligand B (-3.4), indicating better stability.

**14. P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux liability than Ligand B (0.064), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.1), though the difference is not huge.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties. It has a better QED score, significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While both have similar MW, TPSA, logP, and Caco-2 permeability, the superior ADME-Tox profile of Ligand A makes it the more promising drug candidate. The slightly better binding affinity further supports this conclusion.

Output:
0
2025-04-17 14:21:09,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (384.42 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.55) is excellent, well below the 140 threshold for oral absorption. Ligand B (111.55) is still acceptable, but less optimal.

**logP:** Both ligands (1.115 and 1.015) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is higher, potentially impacting permeability, but still within the acceptable limit of 5.

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

**QED:** Ligand A (0.79) is strong, indicating good drug-likeness. Ligand B (0.56) is acceptable, but less desirable.

**DILI:** Ligand A (36.681) has a lower DILI risk than Ligand B (21.365), which is a significant advantage.

**BBB:** Ligand A (93.098) shows good BBB penetration, while Ligand B (27.763) is poor. While SRC isn't a CNS target, higher BBB penetration generally correlates with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.54) is poor, while Ligand B (-5.319) is even worse. Both are problematic, suggesting poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.541) is poor, while Ligand B (-2.17) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.36) has a very low hERG risk, a major advantage. Ligand B (0.07) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (1.984) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (22.614) has significantly higher clearance, a major drawback.

**In vitro Half-Life:** Ligand A (-30.619) has a longer in vitro half-life, which is desirable. Ligand B (-29.35) is slightly shorter, but similar.

**P-gp Efflux:** Ligand A (0.036) has low P-gp efflux, which is good. Ligand B (0.037) is also very low.

**Binding Affinity:** Ligand A (-7.5) has a significantly stronger binding affinity than Ligand B (0.0). This is the most important factor for an enzyme target.

**Overall Assessment:**

Ligand A is clearly superior. While both have poor Caco-2 and solubility, Ligand A's significantly stronger binding affinity (-7.5 vs 0.0 kcal/mol) outweighs these drawbacks.  Additionally, Ligand A has better DILI, BBB, QED, and metabolic stability (lower Cl_mic and longer t1/2). The hERG risk is very low for both. The substantial difference in binding affinity makes Ligand A the far more promising candidate.

Output:
1
2025-04-17 14:21:09,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (374.75 and 367.324 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.04) is well below the 140 threshold for good absorption, while Ligand B (96.97) is still acceptable but closer to the limit.

**logP:** Ligand A (2.971) is optimal (1-3). Ligand B (0.191) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (5 & 5) counts, well within the guidelines.

**QED:** Ligand A (0.839) has a strong drug-like profile, significantly better than Ligand B (0.654).

**DILI:** Ligand A (78.402) has a higher DILI risk than Ligand B (40.675), which is good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.176) is slightly better than Ligand B (64.211).

**Caco-2 Permeability:** Ligand A (-4.675) is very poor, while Ligand B (-5.042) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.082) is poor, while Ligand B (-1.505) is also poor, but better than Ligand A.

**hERG Inhibition:** Both ligands (0.207 and 0.155) show very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (45.061) has higher clearance than Ligand B (15.856), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-28.457) has a much longer half-life than Ligand A (-1.932), suggesting better *in vivo* persistence.

**P-gp Efflux:** Both ligands (0.107 and 0.008) have 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 (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite Ligand A's stronger binding affinity, Ligand B is the more promising candidate. The significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility of Ligand B outweigh the affinity difference. The poor Caco-2 and solubility of both are concerning, but can be addressed with formulation strategies. Ligand A's higher clearance is a major concern for *in vivo* efficacy.

Output:
1
2025-04-17 14:21:09,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.459 and 342.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.98) is slightly higher than Ligand B (49.85), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (4.772) is higher than the optimal range (1-3), potentially leading to solubility issues or off-target effects. Ligand B (2.922) 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:** Ligand B (0.858) has a higher QED score than Ligand A (0.531), indicating better overall drug-likeness.

**DILI:** Ligand A (68.864) has a higher DILI risk than Ligand B (77.123), but both are reasonably acceptable.

**BBB:** Not particularly relevant for a non-CNS target like SRC. Ligand B (89.492) has a higher BBB percentile than Ligand A (44.668).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-5.02) is slightly worse than Ligand B (-4.13).

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility. Ligand A (-5.728) is worse than Ligand B (-2.945).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.801 and 0.708, respectively).

**Microsomal Clearance:** Ligand B (33.385) has significantly lower microsomal clearance than Ligand A (129.932), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-23.973) has a longer in vitro half-life than Ligand A (-41.357), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.757 and 0.369, respectively).

**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. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand A's superior binding affinity, Ligand B is the more promising drug candidate. The significant improvements in metabolic stability (lower Cl_mic, longer t1/2), better QED, and more favorable logP outweigh the affinity difference. The poor solubility and permeability of both compounds are concerns that would need to be addressed through formulation or further structural modifications, but the metabolic advantage of Ligand B is more critical for an enzyme target like SRC.

Output:
1
2025-04-17 14:21:09,944 - INFO - Batch 289 complete. Total preferences: 4624
2025-04-17 14:21:09,944 - INFO - Processing batch 290/512...
2025-04-17 14:21:49,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (82.08) is better than Ligand B (105.39), falling well below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (A: 0.77, B: 1.254), falling within the 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 maintaining a balance between solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.721, B: 0.812), indicating drug-like properties.

**DILI:** Ligand A (32.842) has a significantly lower DILI risk than Ligand B (65.413). This is a major advantage.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the lower value for Ligand B (-5.588 vs -5.039) is worse.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both, but the lower value for Ligand B (-2.917 vs -2.049) is worse.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.102, B: 0.232).

**Microsomal Clearance:** Ligand A (10.339) has a significantly lower Cl_mic than Ligand B (31.013), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.301) has a longer in vitro half-life than Ligand B (-15.854), which is more desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.01, B: 0.027).

**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 less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADMET properties, particularly significantly lower DILI risk and better metabolic stability (lower Cl_mic and longer t1/2). The solubility and permeability are poor for both, but Ligand A is better in these aspects. Given the enzyme-kinase target class, metabolic stability and safety (DILI) are crucial, making Ligand A the preferred choice.

Output:
0
2025-04-17 14:21:49,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzyme targets: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.374 and 357.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.7) is slightly higher than Ligand B (53.51). Both are below the 140 A^2 threshold for good oral absorption, but ligand B is better.

**logP:** Both ligands (2.184 and 2.101) are 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:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.773 and 0.779), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.397, categorized as moderate risk. Ligand B has a much lower DILI risk of 26.328, which is a significant advantage.

**BBB:** Ligand A (71.268) and Ligand B (87.088) both have acceptable BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.009 and -4.891), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.81 and -2.934), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.16 and 0.207), which is excellent.

**Microsomal Clearance:** Ligand A (36.586) has lower microsomal clearance than Ligand B (61.37), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.276) has a more negative in vitro half-life than Ligand B (-4.109), indicating a longer half-life and better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.21 and 0.196).

**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, but not overwhelming.

**Conclusion:**

Considering the priorities for enzyme targets, Ligand B is the more promising candidate. While Ligand A has better metabolic stability and half-life, Ligand B has a significantly lower DILI risk, which is a crucial factor for drug development. The slightly better binding affinity of Ligand B further supports its selection. The poor Caco-2 and solubility values are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 14:21:49,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.403 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.05) is slightly higher than Ligand B (72.28). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better positioned.

**logP:** Both ligands (1.074 and 1.316) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 1. 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 scores (0.782 and 0.753), indicating good drug-likeness.

**DILI:** Ligand A (50.291) has a slightly higher DILI risk than Ligand B (33.307). Both are below the concerning threshold of 60, but lower is preferred.

**BBB:** Ligand A (37.96) has a lower BBB penetration percentile than Ligand B (72.043). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.158) has worse Caco-2 permeability than Ligand B (-5.051). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-2.377) has slightly worse aqueous solubility than Ligand B (-1.252). Both are negative, indicating poor solubility, but B is slightly better.

**hERG Inhibition:** Ligand A (0.031) has a slightly lower hERG inhibition risk than Ligand B (0.073). Both are very low risk.

**Microsomal Clearance:** Ligand A (20.046) has a significantly lower microsomal clearance than Ligand B (32.939). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (32.573) has a much longer in vitro half-life than Ligand A (4.543). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.012) has a lower P-gp efflux liability than Ligand B (0.067). This is favorable for Ligand A.

**Binding Affinity:** Ligand A (-8.3 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. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand B has better solubility, permeability, and half-life, the significantly stronger binding affinity of Ligand A (-8.3 vs -6.7 kcal/mol) is the most critical factor for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic) and lower P-gp efflux of Ligand A are also beneficial. The slightly higher DILI risk is a minor concern compared to the potency advantage.

Output:
0
2025-04-17 14:21:49,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.69 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is slightly higher than the preferred <140, but acceptable. Ligand B (69.72) is excellent, well below 140.

**logP:** Both ligands have good logP values (2.732 and 1.787), falling within the optimal 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 similar QED values (0.791 and 0.76), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a major concern. Ligand B has a much lower DILI risk (20.047%), which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (70.919%) is slightly better than Ligand B (65.452%).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.852 and -4.668), 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 (-4.407 and -2.154), indicating poor aqueous solubility. This is a drawback for both.

**hERG:** Ligand A (0.261) has a slightly higher hERG risk than Ligand B (0.122), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (16.876) has lower microsomal clearance than Ligand B (54.122), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (35.083) has a longer half-life than Ligand B (-9.486), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.187 and 0.085).

**Binding Affinity:** Ligand A (-10.2 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.

**Conclusion:**

Despite Ligand A's superior binding affinity and metabolic stability, the extremely high DILI risk (99.147%) is a critical flaw. DILI is a major reason for drug attrition, and a value this high is almost certainly a non-starter. Ligand B, while having a weaker binding affinity, exhibits a much more favorable safety profile (low DILI) and acceptable ADME properties overall. The difference in binding affinity, while significant, may be addressable through further optimization, whereas mitigating a high DILI risk is often far more challenging.

Output:
1
2025-04-17 14:21:49,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 362.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.67) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (77.75) is excellent, well below 140.

**logP:** Ligand A (-0.68) is a bit low, potentially hindering permeation. Ligand B (1.669) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (8) is also acceptable.

**QED:** Both ligands have good QED scores (0.556 and 0.593), indicating drug-like properties.

**DILI:** Ligand A (58.55) is better than Ligand B (77.549) in terms of DILI risk, both are acceptable but A is preferred.

**BBB:** Both ligands have similar BBB penetration (65.335 and 67.623), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.486 and -4.953), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.564 and -3.363), which is also concerning and suggests poor solubility.

**hERG:** Both ligands have very low hERG risk (0.278 and 0.21), which is excellent.

**Microsomal Clearance:** Ligand A (-3.835) has a *negative* clearance, which is not physically possible and indicates a data error or unusual behavior. Ligand B (35.712) has a high clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (-6.945) has a negative half-life, again indicating a data error. Ligand B (11.017) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.005 and 0.124), which is favorable.

**Binding Affinity:** Ligand B (-10.5 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.

**Conclusion:**

Despite the concerning negative values for Caco-2, solubility, clearance and half-life for Ligand A, these are likely data errors. Ligand B is superior due to its much stronger binding affinity (-10.5 vs -7.9 kcal/mol) and better logP. While its metabolic clearance is high, the potency advantage is likely to be more impactful for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:21:49,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.427 Da) is slightly lower, which could be beneficial for permeability. Ligand B (384.464 Da) is also good.

**TPSA:** Ligand A (127.74) is borderline, but acceptable for oral absorption. Ligand B (66.48) is excellent, suggesting good absorption and potentially better cell permeability.

**logP:** Both ligands have good logP values (A: 1.008, B: 2.533), 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 1 HBD and 3 HBA, which is also good and potentially better for permeability.

**QED:** Both ligands have similar QED values (A: 0.605, B: 0.664), both 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 22.993, which is excellent.

**BBB:** Ligand A has a BBB penetration of 34.238, while Ligand B has 91.586. While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-5.613) and Ligand B (-4.681) both have negative Caco-2 values, suggesting poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.613 and -3.801 respectively). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.747, B: 0.813).

**Microsomal Clearance:** Ligand A has a lower Cl_mic (10.359) than Ligand B (60.936), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-46.574) than Ligand A (-23.372), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.062, B: 0.082).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.3 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's slightly better MW and lower Cl_mic, Ligand B is the superior candidate. The most critical factor is the significantly lower DILI risk for Ligand B. The stronger binding affinity (-8.8 vs -7.5 kcal/mol) and longer half-life are also substantial advantages. While both have poor solubility and Caco-2 permeability, the lower DILI risk and improved potency of Ligand B make it the more viable drug candidate.

Output:
1
2025-04-17 14:21:49,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.415 and 386.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.55) is slightly higher than Ligand B (78.43). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have acceptable logP values (1.043 and 2.302, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 5 HBA, which are within the acceptable limits.

**QED:** Ligand A (0.652) has a slightly higher QED score than Ligand B (0.558), indicating better overall drug-likeness.

**DILI:** Ligand B (38.697) has a lower DILI risk than Ligand A (44.552), making it more favorable.

**BBB:** Both have similar BBB penetration (44.281 and 43.699), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.784) shows better Caco-2 permeability than Ligand B (-5.561).

**Aqueous Solubility:** Ligand A (-2.428) has slightly better aqueous solubility than Ligand B (-2.774).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.275 and 0.205, respectively).

**Microsomal Clearance:** Ligand A (38.239) has lower microsomal clearance than Ligand B (41.84), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-33.35) has a significantly longer in vitro half-life than Ligand B (-2.444), a crucial advantage for kinase inhibitors.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.053 and 0.162).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a better binding affinity than Ligand A (-8.3 kcal/mol). The difference is 0.9kcal/mol.

**Overall Assessment:**

Ligand B has a more favorable profile in terms of DILI risk and, crucially, binding affinity. While Ligand A shows better solubility, permeability, and metabolic stability, the 0.9 kcal/mol advantage in binding affinity for Ligand B is substantial enough to outweigh these minor ADME differences, especially for a kinase inhibitor where potency is paramount. The longer half-life of Ligand A is attractive, but the binding affinity difference is more significant.

Output:
1
2025-04-17 14:21:49,050 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (350.459 and 343.402 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (52.65) is well within the acceptable range.

**3. logP:** Both ligands (1.335 and 1.232) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the ideal limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the ideal limit of <=10.

**6. QED:** Both ligands have QED values (0.812 and 0.791) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (36.06). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (77.2 and 78.635). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.771) has slightly worse Caco-2 permeability than Ligand B (-4.41), but both are negative values, indicating relatively poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.831) has slightly better solubility than Ligand B (-2.38).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.228 and 0.352).

**12. Microsomal Clearance (Cl_mic):** Ligand A (21.597) has a higher microsomal clearance than Ligand B (0.284), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand A (19.874) has a longer half-life than Ligand B (-3.15). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.036).

**15. Binding Affinity:** Ligand B (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a substantial advantage for Ligand B, exceeding the 1.5 kcal/mol threshold.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and has much better metabolic stability (lower Cl_mic). While Ligand A has a longer half-life and better solubility, the significantly stronger binding of Ligand B outweighs these benefits. The lower DILI risk of Ligand A is a plus, but the superior affinity of Ligand B is more critical for an enzyme inhibitor.

Output:
1
2025-04-17 14:21:49,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (107.53), being well below the 140 A^2 threshold for good oral absorption.

**logP:** Both are good (1.071 and 0.75), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 4 HBA, which are acceptable.

**QED:** Ligand A (0.798) has a higher QED score than Ligand B (0.516), indicating a more drug-like profile.

**DILI:** Ligand A (12.214) has a much lower DILI risk than Ligand B (15.898), which is a significant advantage.

**BBB:** Ligand A (56.34) has a better BBB percentile than Ligand B (46.568), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.751) is better than Ligand B (-5.325), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.851) is better than Ligand B (-1.396), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.174 and 0.047).

**Microsomal Clearance:** Ligand A (-5.574) has a much lower (better) microsomal clearance than Ligand B (16.955), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (20.412) has a much longer half-life than Ligand B (-2.495), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.006).

**Binding Affinity:** Ligand B (-8.6 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 the other ADME properties of Ligand A are superior.

**Overall:** Considering all factors, Ligand A is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties like DILI risk, metabolic stability (Cl_mic and t1/2), solubility, and Caco-2 permeability. These factors are particularly important for an enzyme target like SRC kinase, where maintaining adequate exposure and minimizing toxicity are critical.

Output:
1
2025-04-17 14:21:49,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (377.897 and 369.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.23) is significantly better than Ligand B (79.8), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.912 and 3.135), 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) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.824 and 0.784), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (66.615 and 70.26), but are still below the high-risk threshold of >60.

**BBB:** Both have high BBB penetration (74.176 and 84.451), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.969 and -4.986), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.352 and -3.519), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.265) has a much lower hERG inhibition liability than Ligand B (0.642), which is a critical advantage.

**Microsomal Clearance:** Ligand B (27.334 mL/min/kg) has lower microsomal clearance than Ligand A (34.741 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.939 hours) has a longer half-life than Ligand A (15.876 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.637) has lower P-gp efflux liability than Ligand B (0.23), indicating potentially better bioavailability.

**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 concerns.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.3 vs -8.1 kcal/mol) is a major advantage for an enzyme target. Furthermore, it exhibits lower hERG inhibition liability, which is crucial for safety. While Ligand B has slightly better metabolic stability and half-life, the affinity difference and reduced hERG risk of Ligand A are more important considerations for initial lead optimization. The solubility and permeability issues would need to be addressed through structural modifications.

Output:
0
2025-04-17 14:21:49,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447 Da) is slightly preferred due to being lower in MW.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (78.43) is better than Ligand A (98.32).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.098) is slightly lower, which *could* be a minor drawback for permeability, but Ligand B (3.495) is approaching the upper limit and could have solubility issues.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (3) and HBA (4 for A, 5 for B) counts.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-likeness.

**DILI:** Ligand A (11.4) has a significantly lower DILI risk than Ligand B (71.772), a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Both are relatively low.

**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 concerning. Ligand A (-1.51) is slightly better than Ligand B (-3.988).

**hERG Inhibition:** Ligand A (0.158) has a much lower hERG inhibition liability than Ligand B (0.678), a crucial safety factor.

**Microsomal Clearance:** Ligand A (-2.479) has a *negative* microsomal clearance, which is highly unusual and suggests exceptional metabolic stability. Ligand B (62.39) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-26.739) has a negative half-life, which is also unusual and suggests a very long half-life. Ligand B (82.609) has a long half-life, but not as extreme.

**P-gp Efflux:** Both have low P-gp efflux liability.

**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 outweigh the significant ADME/Tox advantages of Ligand A.

**Overall:**

Ligand A is significantly better due to its much lower DILI risk, lower hERG inhibition, and exceptional metabolic stability (negative clearance and half-life). While both have poor Caco-2 and solubility, the safety and PK advantages of Ligand A are more critical for initial development. The slightly better affinity of Ligand B is not enough to overcome these drawbacks.

Output:
0
2025-04-17 14:21:49,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 360.361 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.67) is well below the 140 threshold, while Ligand B (94.48) is still acceptable but approaching the upper limit.

**logP:** Ligand A (1.148) is within the optimal range, while Ligand B (0.564) is slightly below, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have similar QED values (0.773 and 0.707), indicating good drug-likeness.

**DILI:** Ligand A (30.632) has a significantly lower DILI risk than Ligand B (61.07), which is approaching a higher risk category.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (74.292) is slightly higher than Ligand A (69.407). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.506 and -4.96), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-0.644) has slightly better solubility than Ligand B (-2.491). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.282 and 0.244).

**Microsomal Clearance:** Ligand A (28.359) has a higher microsomal clearance than Ligand B (5.243), indicating lower metabolic stability. This is a key concern for Ligand A.

**In Vitro Half-Life:** Ligand B (17.818) has a significantly longer in vitro half-life than Ligand A (5.893).

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.026 and 0.031).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite Ligand B having slightly lower logP and a Caco-2 value, its significantly stronger binding affinity (-7.2 vs -0.0 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh these minor drawbacks. The lower DILI risk for Ligand B is also a positive. The poor Caco-2 values for both are concerning, but the potency advantage of Ligand B is substantial enough to prioritize it for further optimization.

Output:
1
2025-04-17 14:21:49,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.434 and 348.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (61.44 and 59.07) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.079) is optimal (1-3), while Ligand B (4.192) is approaching the upper limit and could potentially cause solubility issues or off-target effects.

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

**H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5 HBAs, both are within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED values (0.828 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (25.785) has a significantly lower DILI risk than Ligand B (38.852), which is a major advantage. Both are below the 40 threshold.

**BBB:** Both ligands have good BBB penetration (86.817 and 92.206), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.832 and -4.772), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.436) has better aqueous solubility than Ligand B (-5.205), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.744) has a lower hERG inhibition liability than Ligand B (0.848), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (12.703 mL/min/kg) has significantly lower microsomal clearance than Ligand B (71.591 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.533 hours) has a shorter half-life than Ligand B (47.624 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux liability than Ligand B (0.425), which is favorable for bioavailability.

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite the negative Caco-2 values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -6.2 kcal/mol) and lower DILI risk, lower hERG, lower Cl_mic, and lower Pgp efflux outweigh the shorter half-life and slightly worse solubility compared to Ligand B. The potency advantage is substantial.

Output:
0
2025-04-17 14:21:49,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.443 and 357.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.57) is better than Ligand B (121.02). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (2.316) is within the optimal 1-3 range. Ligand B (-1.657) is significantly lower, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (8). Both are below the threshold of 10, but A is closer to the optimal.

**QED:** Both ligands have similar QED values (0.566 and 0.514), indicating good drug-likeness.

**DILI:** Ligand A (18.651) has a much lower DILI risk than Ligand B (34.781), making it safer.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (48.003) is lower than Ligand B (29.12).

**Caco-2 Permeability:** Ligand A (-4.991) is better than Ligand B (-5.324), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.094) is better than Ligand B (-0.37), which is a significant advantage for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.118 and 0.036, respectively).

**Microsomal Clearance:** Ligand A (36.986) has higher clearance than Ligand B (15.08). This suggests Ligand B has better metabolic stability.

**In vitro Half-Life:** Ligand A (19.997) has a longer half-life than Ligand B (0.897), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.006, respectively).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage (1.8 kcal/mol difference).

**Conclusion:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a significantly better ADME profile, particularly in solubility, DILI risk, and half-life. The lower logP of Ligand B is a concern for permeability. The substantial difference in binding affinity (-8.7 vs -6.9) is significant and could potentially outweigh the ADME concerns with Ligand B, *if* the permeability issues can be addressed through formulation or prodrug strategies. However, given the enzyme-specific priorities, and the substantial improvements in ADME properties with Ligand A, I would predict Ligand A to be the more viable drug candidate.

Output:
0
2025-04-17 14:21:49,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.491 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.23 and 69.72) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (not a priority here).

**logP:** Both ligands (2.746 and 2.034) are 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 3 HBA, both are acceptable (<=10).

**QED:** Both ligands (0.735 and 0.653) have good drug-likeness scores (>0.5).

**DILI:** Ligand A (40.83) has a slightly higher DILI risk than Ligand B (12.524), but both are below the concerning threshold of 60.

**BBB:** BBB is not a high priority for a non-CNS target. Ligand B (73.129) has a slightly higher BBB percentile than Ligand A (67.701).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.9) is slightly worse than Ligand B (-4.486).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.727) is slightly worse than Ligand B (-1.845).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.786 and 0.278), which is excellent.

**Microsomal Clearance:** Ligand A (63.333) has lower microsomal clearance than Ligand B (74.533), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (-14.331) has a significantly longer in vitro half-life than Ligand B (-6.056), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.594 and 0.013), which is good.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -6.0 kcal/mol). Ligand A has a 2 kcal/mol advantage, which is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the better candidate. While both have issues with Caco-2 and solubility, Ligand A's significantly better metabolic stability (lower Cl_mic, longer t1/2) and superior binding affinity outweigh its slightly higher DILI risk and slightly worse Caco-2/solubility. The 2 kcal/mol difference in binding affinity is substantial for an enzyme target.

Output:
1
2025-04-17 14:21:49,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.394 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.67) is better than Ligand B (96.55). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**logP:** Ligand A (0.532) is lower than Ligand B (0.881). Both are within the 1-3 range, but A is on the lower end, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.786 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A (29.081) has a significantly lower DILI risk than Ligand B (52.695). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar, moderate BBB penetration (43.583 and 45.56). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.839) has slightly better Caco-2 permeability than Ligand B (-5.033), though both are negative values which is not ideal.

**Aqueous Solubility:** Ligand A (-0.571) is better than Ligand B (-1.554). Solubility is important for formulation and bioavailability, and A has a better score.

**hERG Inhibition:** Ligand A (0.334) has a lower hERG risk than Ligand B (0.226). Lower is better, making A preferable.

**Microsomal Clearance:** Ligand A (1.474) has significantly lower microsomal clearance than Ligand B (3.612). This indicates better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-16.51) has a longer in vitro half-life than Ligand B (-14.673). This is another advantage for A, suggesting less frequent dosing potential.

**P-gp Efflux:** Ligand A (0.042) has lower P-gp efflux than Ligand B (0.012). Lower efflux is preferable for better oral bioavailability.

**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 ADME concerns.

**Overall Assessment:**

Ligand A excels in ADME properties (DILI, metabolic stability, solubility, hERG) and has acceptable permeability. However, its binding affinity is considerably weaker than Ligand B. Ligand B, while having some ADME liabilities (higher DILI, clearance, and lower solubility), boasts a much stronger binding affinity.

Given that we are targeting a kinase (an enzyme), potency (binding affinity) is the highest priority. The 1.2 kcal/mol difference in binding affinity is significant. While Ligand A has a better safety profile, the superior potency of Ligand B is likely to be more impactful in achieving efficacy.

Output:
1
2025-04-17 14:21:49,051 - INFO - Batch 290 complete. Total preferences: 4640
2025-04-17 14:21:49,051 - INFO - Processing batch 291/512...
2025-04-17 14:22:29,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.39 and 370.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.31) is excellent, well below the 140 threshold for oral absorption. Ligand B (103.45) is still acceptable but less optimal.

**logP:** Ligand A (3.553) is within the optimal 1-3 range. Ligand B (-0.633) is significantly below this, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is very favorable. Ligand B (2 HBD, 7 HBA) is also acceptable, but higher.

**QED:** Both ligands have good QED scores (0.601 and 0.558, respectively), indicating drug-like properties.

**DILI:** Ligand A (53.819) has a slightly higher DILI risk than Ligand B (47.15), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.737) is higher than Ligand B (48.623).

**Caco-2 Permeability:** Ligand A (-4.436) is poor, while Ligand B (-5.653) is even worse. Both are problematic for oral absorption.

**Aqueous Solubility:** Ligand A (-4.227) is poor, but Ligand B (-1.949) is even worse. Both could pose formulation challenges.

**hERG:** Ligand A (0.227) has a very low hERG risk, which is excellent. Ligand B (0.476) is also relatively low, but higher than A.

**Microsomal Clearance:** Ligand A (38.126) has higher clearance than Ligand B (22.765), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-15.773) has a much longer half-life than Ligand A (-0.158), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.268 and 0.015), which is favorable.

**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 relatively small, it's still a factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. It has a significantly better in vitro half-life and lower microsomal clearance, indicating superior metabolic stability. While its logP and solubility are worse than Ligand A, the slightly better binding affinity and substantially improved metabolic stability outweigh these drawbacks. The hERG risk is also slightly lower for Ligand B. The poor Caco-2 and solubility of both compounds are concerns that would need to be addressed in further optimization, but the metabolic stability advantage of B is crucial.

Output:
1
2025-04-17 14:22:29,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.415 and 383.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.29) is better than Ligand B (117.75), being closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.023 and 0.961), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is slightly better than Ligand B (HBD=1, HBA=8) in terms of balancing solubility and permeability. Ligand B has a higher number of HBA, which could potentially affect permeability.

**QED:** Ligand A (0.759) has a significantly better QED score than Ligand B (0.362), indicating a more drug-like profile.

**DILI:** Ligand A (40.83) has a much lower DILI risk than Ligand B (88.057), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (51.066) is slightly better than Ligand B (42.769).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are log values, they are both poor.

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are log values, they are both poor.

**hERG:** Both ligands have very low hERG inhibition liability (0.139 and 0.059), which is excellent.

**Microsomal Clearance:** Ligand A (2.474) has a much lower microsomal clearance than Ligand B (8.595), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.079) has a much longer in vitro half-life than Ligand B (17.902), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.091).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: QED, DILI, metabolic stability (Cl_mic and t1/2), and solubility. These factors are critical for developing a viable drug candidate, especially for a kinase inhibitor where chronic dosing is often required.



Output:
0
2025-04-17 14:22:29,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.206 and 363.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (68.02 and 62.3) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.125) is slightly above the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.882) 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 (0.676 and 0.894), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (90.384 percentile) than Ligand B (30.516 percentile). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (77.627 and 70.841 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.777 and -4.844), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.346 and -3.357). This is a major issue.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.447 and 0.34).

**Microsomal Clearance:** Ligand A has a higher Cl_mic (59.647 mL/min/kg) than Ligand B (32.656 mL/min/kg), indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life ( -13.477 hours) than Ligand A (5.094 hours), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.3 and 0.085), which is favorable.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol), a difference of 0.8 kcal/mol. This is a positive for Ligand A, but may not be enough to overcome its other weaknesses.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its significantly higher DILI risk, faster metabolic clearance, and poor solubility make it a less desirable candidate. Ligand B, while having slightly weaker binding, exhibits a much better safety profile (lower DILI), improved metabolic stability (longer half-life, lower Cl_mic), and similar P-gp and hERG properties. The poor Caco-2 and solubility are concerning for both, but the other factors weigh more heavily in favor of Ligand B.

Output:
1
2025-04-17 14:22:29,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.442 and 360.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly higher than Ligand B (55.57). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (1.998) is within the optimal 1-3 range. Ligand B (3.769) is pushing the upper limit, potentially leading to solubility issues or off-target interactions, but is still acceptable.

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

**QED:** Both ligands have similar QED values (0.784 and 0.736), indicating good drug-likeness.

**DILI:** Ligand A (43.234) has a lower DILI risk than Ligand B (58.744), which is a significant advantage.

**BBB:** Ligand A (85.964) shows better BBB penetration than Ligand B (51.221), but BBB is not a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-4.925) has a worse Caco-2 permeability than Ligand B (-4.631). This suggests Ligand B might have better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.214) has better aqueous solubility than Ligand B (-3.904). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.714) shows a lower hERG inhibition liability than Ligand B (0.416), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (9.376) has a lower microsomal clearance than Ligand B (70.68), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-13.253) has a significantly longer in vitro half-life than Ligand B (30.707), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.192) has lower P-gp efflux liability than Ligand B (0.299), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.2). While a 0.8 kcal/mol difference is noticeable, the ADME properties of Ligand A are superior.

**Overall Assessment:**

Ligand A demonstrates a more favorable balance of properties, particularly regarding safety (lower DILI, lower hERG) and metabolic stability (lower Cl_mic, longer t1/2). While Ligand B has slightly better binding affinity and Caco-2 permeability, the superior ADME profile of Ligand A outweighs this advantage for an enzyme target like SRC kinase.

Output:
0
2025-04-17 14:22:29,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.377 and 361.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.48) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (90.9) is well within the optimal range.

**logP:** Ligand A (0.792) is a bit low, potentially hindering permeation. Ligand B (0.075) is even lower, raising more concern for permeability.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.721) has a better QED score than Ligand B (0.512), indicating a more drug-like profile.

**DILI:** Ligand A (38.697) has a significantly lower DILI risk than Ligand B (5.196), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (66.344) has a higher BBB percentile than Ligand B (53.16).

**Caco-2 Permeability:** Ligand A (-5.017) and Ligand B (-5.087) 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 (-1.508 and -0.7 respectively). This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.141 and 0.247), which is good.

**Microsomal Clearance:** Ligand A (-5.694) has a much lower (better) microsomal clearance than Ligand B (-10.294), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.407) has a longer in vitro half-life than Ligand B (0.514), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 0.8 kcal/mol difference is substantial and could potentially outweigh some of the ADME concerns.

**Conclusion:**

While Ligand B boasts a superior binding affinity, the significantly higher DILI risk, poorer metabolic stability (higher Cl_mic, shorter t1/2), and very poor solubility of Ligand B are major concerns. Ligand A, despite its lower affinity, presents a much more favorable ADME profile with a lower DILI risk, better metabolic stability, and a slightly better QED score. The poor Caco-2 and solubility for both are concerning, but the overall profile of Ligand A is more promising for further optimization.

Output:
0
2025-04-17 14:22:29,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.451 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (113.76) is better than Ligand B (49.41), falling well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.238) is quite low, potentially hindering permeation. Ligand B (3.547) 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 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.614 and 0.616), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (31.524 and 30.361), which is positive.

**BBB:** Ligand A has a higher BBB percentile (76.735) than Ligand B (67.468), but BBB is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.374) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.124) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.609) has poor solubility. Ligand B (-3.535) is even worse. This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.128) has a very low hERG risk, which is excellent. Ligand B (0.63) is slightly higher, but still reasonably low.

**Microsomal Clearance:** Ligand A (29.822) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (77.811) has significantly higher clearance, a major drawback.

**In vitro Half-Life:** Ligand A (3.111 hours) has a longer half-life than Ligand B (0.217 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is favorable. Ligand B (0.456) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This 1.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B's primary advantage is its superior binding affinity (-7.5 kcal/mol vs -6.6 kcal/mol). This is a critical factor for an enzyme inhibitor. While Ligand B has some ADME liabilities (higher logP, higher Cl_mic, lower t1/2, and lower solubility), the strong binding affinity is a significant positive. Ligand A has better ADME properties (lower Cl_mic, longer t1/2, lower P-gp efflux, lower hERG) but significantly weaker binding. Given the enzyme-specific priorities, the potency advantage of Ligand B is likely to be more important than the ADME concerns, especially as the ADME issues aren't catastrophic.

Output:
1
2025-04-17 14:22:29,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.78) is slightly above the preferred <140, while Ligand B (84.94) is well within the range.

**logP:** Ligand A (0.004) is quite low, potentially hindering permeation. Ligand B (1.352) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better.

**H-Bond Acceptors:** Both ligands (A: 6, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.578, B: 0.597), indicating drug-like properties.

**DILI:** Ligand A (54.246) has a moderate DILI risk, while Ligand B (23.769) has a significantly lower and more favorable risk.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (72.431) is higher, but this is less critical here.

**Caco-2 Permeability:** Ligand A (-5.352) has very poor predicted permeability. Ligand B (-4.33) is better, but still relatively low.

**Aqueous Solubility:** Ligand A (-1.329) has poor solubility, while Ligand B (-1.623) is also poor.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.118, B: 0.129).

**Microsomal Clearance:** Ligand A (-3.961) has a negative clearance, indicating excellent metabolic stability. Ligand B (80.838) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (27.827) has a reasonable half-life, while Ligand B (-9.058) has a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.013, B: 0.041).

**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 advantage.

**Conclusion:**

Despite Ligand A's excellent metabolic stability, its poor logP, solubility, Caco-2 permeability, and extremely weak binding affinity are major drawbacks. Ligand B, while having a higher clearance, boasts a significantly stronger binding affinity, a better logP, and a lower DILI risk. The substantial difference in binding affinity (-8.5 vs 0.0 kcal/mol) is likely to outweigh the metabolic stability concerns, especially given that metabolic stability can be further optimized during lead optimization.

Output:
1
2025-04-17 14:22:29,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.45 and 338.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is significantly better than Ligand B (114.77). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.748 and 1.004), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are acceptable.

**QED:** Both ligands have good QED scores (0.726 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A (31.99) has a much lower DILI risk than Ligand B (65.72). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (73.94) is better than Ligand B (23.30).

**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:** Ligand A (-1.78) is better than Ligand B (-3.84). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.216) has a much lower hERG risk than Ligand B (0.369). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (16.16) has a higher (worse) microsomal clearance than Ligand B (0.995). This suggests that Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-8.713) has a longer half-life than Ligand B (8.993). This is a positive for A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.033).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 1.6 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a slightly better binding affinity, Ligand A has significantly better predicted safety profiles (DILI and hERG) and solubility. The improved metabolic stability of Ligand B is a plus, but the longer half-life of Ligand A mitigates some of that concern. Given the enzyme-specific priorities, the lower toxicity risks of Ligand A are more important than the slightly better affinity of Ligand B. The TPSA is also better for Ligand A.

Output:
1
2025-04-17 14:22:29,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.321 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.77) is slightly above the optimal <140 for good absorption, but still reasonable. Ligand B (62.32) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands have good logP values (1.644 and 1.424), falling within the 1-3 range.

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

**QED:** Both ligands have acceptable QED scores (0.876 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 54.634, which is acceptable (below 60). Ligand B has a very low DILI risk of 10.12, which is excellent.

**BBB:** Both ligands have good BBB penetration (82.047 and 89.763), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.585 and -4.284). This is unusual and suggests poor permeability, but these values may be experimental artifacts or indicate a specific transport mechanism.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.13 and -0.333), which is also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.603) has a slightly higher hERG risk than Ligand B (0.736), but both are relatively low.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-1.434), indicating very high metabolic stability, which is excellent. Ligand B has a much higher Cl_mic (27.799), suggesting rapid metabolism and a potential issue.

**In vitro Half-Life:** Ligand A has a very long in vitro half-life (-9.211), further supporting its metabolic stability. Ligand B has a very short half-life (-30.566), which is a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.044).

**Binding Affinity:** Ligand A has a stronger binding affinity (-7.7 kcal/mol) than Ligand B (-6.7 kcal/mol). The 1.0 kcal/mol difference is substantial and can outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand A is significantly more promising. While both have unusual solubility and permeability values, Ligand A's superior binding affinity, exceptional metabolic stability (low Cl_mic and long t1/2), and acceptable DILI risk outweigh the potential issues. Ligand B's rapid metabolism and short half-life are major drawbacks. The negative solubility and permeability values warrant further investigation, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 14:22:29,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.405 Da) is slightly lower, which is generally favorable for permeability. Ligand B (369.418 Da) is also good.

**TPSA:** Ligand A (44.1) is excellent, well below the 140 threshold for oral absorption. Ligand B (98.66) is higher but still acceptable, though it might slightly hinder absorption compared to A.

**logP:** Ligand A (4.492) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (1.453) is within the optimal range (1-3). This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is very favorable. Ligand B (1 HBD, 6 HBA) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have the same QED score (0.793), indicating good drug-likeness.

**DILI:** Ligand A (26.483) has a much lower DILI risk than Ligand B (54.207), which is a substantial advantage.

**BBB:** Ligand A (91.702) shows good BBB penetration, while Ligand B (70.764) is lower. While not a primary concern for a kinase inhibitor, it's a positive attribute for A.

**Caco-2 Permeability:** Ligand A (-4.515) has very poor Caco-2 permeability, a major red flag. Ligand B (-5.243) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.55) has poor aqueous solubility. Ligand B (-2.129) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.826) has a lower hERG risk than Ligand B (0.492), which is a positive.

**Microsomal Clearance:** Ligand A (25.351) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (14.258) has lower clearance, suggesting better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand A (10.103) has a longer half-life than Ligand B (-2.843). This is a positive for A.

**P-gp Efflux:** Ligand A (0.287) has lower P-gp efflux, which is favorable. Ligand B (0.171) has even lower efflux, giving it a slight advantage.

**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's enough to be considered.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has advantages in DILI risk, BBB penetration, and in vitro half-life, its poor Caco-2 permeability and solubility are significant drawbacks. Ligand B has better logP, metabolic stability (lower Cl_mic), and a slightly better binding affinity. The better metabolic stability and solubility of Ligand B are crucial for an enzyme inhibitor. The slightly better binding affinity further solidifies its position.

Output:
1
2025-04-17 14:22:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.379 Da) is slightly lower, which could be beneficial for permeability. Ligand B (369.294 Da) is also acceptable.

**TPSA:** Ligand A (60.25) is significantly better than Ligand B (88.91). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.203, Ligand B: 1.17), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could aid in cell penetration.

**H-Bond Donors/Acceptors:** Both have 5 HBA and are within acceptable limits. Ligand A has 0 HBD, while Ligand B has 2. This isn't a major differentiating factor.

**QED:** Both ligands have good QED scores (Ligand A: 0.684, Ligand B: 0.78), indicating drug-like properties.

**DILI:** Ligand A (74.021) has a higher DILI risk than Ligand B (62.389), but both are still reasonably acceptable.

**BBB:** Both have good BBB penetration (Ligand A: 68.166, Ligand B: 73.517), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.735 and -4.811). These values are unusual and suggest poor permeability. However, these are likely experimental artifacts or indicate a need for further investigation.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.269 and -3.164). This is a significant concern for bioavailability and formulation.

**hERG Inhibition:** Ligand A (0.425) has a slightly higher hERG risk than Ligand B (0.077). This is a crucial factor, and Ligand B is significantly better.

**Microsomal Clearance:** Ligand B (7.558) has a much lower microsomal clearance than Ligand A (48.064), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (30.509) has a longer half-life than Ligand B (-2.922). This is a positive for Ligand A, but the negative value for Ligand B is concerning and potentially an experimental error.

**P-gp Efflux:** Both have very low P-gp efflux (0.145 and 0.029), which is favorable.

**Binding Affinity:** Ligand A (-7.3 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.

**Conclusion:**

While Ligand A has a much better binding affinity, Ligand B has superior metabolic stability (lower Cl_mic) and a significantly lower hERG risk. The poor solubility of both compounds is a major concern, but the difference in binding affinity is substantial. Given the importance of potency for kinase inhibitors, and the relatively manageable DILI risk for Ligand A, the stronger binding affinity of Ligand A is likely to be more impactful. However, the negative half-life for Ligand B is a red flag.

Output:
0
2025-04-17 14:22:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.45 and 369.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold and is favorable. Ligand B (89.38) is still acceptable, but less optimal.

**logP:** Both ligands have logP values (2.211 and 3.302) 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:** Ligand A (0.789) has a significantly better QED score than Ligand B (0.355), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (35.285 and 33.773), both below the 40 threshold.

**BBB:** Ligand A (89.531) has a better BBB penetration score than Ligand B (51.958), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.633) and Ligand B (-4.754) have similar, and poor, Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.055 and -2.58). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.307 and 0.243), which is excellent.

**Microsomal Clearance:** Ligand A (40.197) has a lower microsomal clearance than Ligand B (58.608), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-7.313) has a significantly longer in vitro half-life than Ligand B (9.157), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.068).

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is relatively small, and other factors are more important.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: QED, microsomal clearance, and in vitro half-life. The better QED score suggests a more generally drug-like molecule. The improved metabolic stability (lower Cl_mic, longer t1/2) is particularly important for an enzyme target, as it suggests a longer duration of action and potentially lower dosing requirements. Both have similar solubility and permeability concerns, but the ADME advantages of Ligand A outweigh the slight binding affinity difference.

Output:
1
2025-04-17 14:22:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.419 and 355.341 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.76) is slightly above the optimal <140 for good oral absorption, while Ligand B (95.57) is well within the range.

**logP:** Ligand A (-1.34) is a bit low, potentially hindering permeability. Ligand B (1.4) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (5) is at the upper limit of the preferred range, while Ligand B (1) is excellent.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand B (0.746) has a significantly better QED score than Ligand A (0.311), indicating a more drug-like profile.

**DILI:** Ligand A (9.306) has a very low DILI risk, while Ligand B (52.036) is higher, though still below the concerning 60 threshold.

**BBB:** Ligand A (23.42) has poor BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (84.374) has good BBB penetration, but this is less relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.8 and -4.559), which is unusual and suggests poor permeability. However, these values are on different scales and difficult to directly compare.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.903 and -2.725), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.044) has a very low hERG risk, which is excellent. Ligand B (0.811) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (-34.293) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (-7.885) has a lower, but still acceptable, metabolic stability.

**In vitro Half-Life:** Ligand A (-0.648) has a negative half-life, which is not possible. This is a data error. Ligand B (17.608) has a good in vitro half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.152).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.4 and -7.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the similar binding affinities, Ligand A has a problematic negative half-life and a low logP. Ligand B has a better QED score, better logP, better half-life, and a reasonable DILI score. While both have poor solubility, Ligand B's overall profile is superior, particularly its metabolic stability and drug-likeness. The low hERG risk of Ligand A is attractive, but the other drawbacks outweigh this benefit.

Output:
1
2025-04-17 14:22:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.47 and 370.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.94) is significantly better than Ligand B (97.64). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.368) is optimal, while Ligand B (1.646) is on the lower side. A logP between 1-3 is preferred, so A is better.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.333 and 0.821), with Ligand B being significantly better.

**DILI:** Both ligands have similar, moderately high DILI risk (65.61 and 66.42). This is a concern for both, but not a deciding factor.

**BBB:** Both ligands have moderate BBB penetration (60.84 and 64.83). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.233 and -5.093), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.802 and -2.449). This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.846) has a slightly higher hERG risk than Ligand B (0.403), but both are relatively low.

**Microsomal Clearance:** Ligand A (135.83) has a much higher microsomal clearance than Ligand B (15.93). Lower clearance is desirable for metabolic stability, making Ligand B much better.

**In vitro Half-Life:** Ligand B (31.74) has a significantly longer half-life than Ligand A (-10.61). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.84) has slightly higher P-gp efflux than Ligand B (0.137). Lower efflux is preferred, favoring Ligand B.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While both ligands have significant issues with solubility and Caco-2 permeability, Ligand B is clearly superior. Its significantly stronger binding affinity, lower microsomal clearance, longer half-life, and lower P-gp efflux outweigh the slightly higher DILI risk and lower QED. The poor solubility and permeability would need to be addressed through formulation strategies, but the potency and pharmacokinetic advantages of Ligand B make it a more promising starting point.

Output:
1
2025-04-17 14:22:29,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.395 and 339.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.45) is well below the 140 threshold for good absorption, while Ligand B (99.77) is still acceptable but closer to the limit.

**logP:** Ligand A (3.367) is optimal (1-3). Ligand B (0.604) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable, within the guidelines.

**QED:** Both ligands have similar and good QED scores (0.567 and 0.583, respectively), indicating good drug-like properties.

**DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (40.869). This is a significant concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (81.776) has a higher BBB score than Ligand B (15.704), but this is not a major factor in this case.

**Caco-2 Permeability:** Ligand A (-4.784) has poor Caco-2 permeability, while Ligand B (-5.495) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.029) has poor aqueous solubility, while Ligand B (-1.734) is also poor, but better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.141 and 0.122, respectively).

**Microsomal Clearance:** Ligand A (68.982) has a higher microsomal clearance than Ligand B (-32.593). This suggests Ligand B is more metabolically stable, which is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (-1.216) has a shorter in vitro half-life than Ligand B (-1.949). Again, favoring Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.315 and 0.007, respectively).

**Binding Affinity:** Both ligands have very similar and strong binding affinity (-8.4 and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. It exhibits lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and Caco-2 permeability. While both have poor solubility and permeability, B is better in these areas. The lower DILI risk and improved metabolic stability are particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:22:29,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (358.295 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.25) is significantly better than Ligand B (91.32). A TPSA under 140 is good for oral absorption, and both meet this, but A is preferable.

**logP:** Both ligands have similar and acceptable logP values (1.864 and 1.822), falling within the 1-3 range.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (3). Fewer HBDs generally improve permeability.

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

**QED:** Ligand A (0.766) has a higher QED score than Ligand B (0.582), indicating a more drug-like profile.

**DILI:** Ligand A (61.187) has a higher DILI risk than Ligand B (43.117). This is a negative for Ligand A, but still within a manageable range.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.71) is better than Ligand B (40.675).

**Caco-2 Permeability:** Ligand A (-4.505) is better than Ligand B (-5.132). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.31) is better than Ligand B (-2.123). Higher solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.319) has a much lower hERG inhibition liability than Ligand B (0.19). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (33.171 and 34.167 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-18.804) has a significantly longer in vitro half-life than Ligand B (6.404). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux liability than Ligand B (0.126), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-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.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. It has a better QED score, lower HBD count, better solubility, significantly lower hERG risk, longer half-life, and lower P-gp efflux. While Ligand B has a slightly lower DILI risk, the other advantages of Ligand A are more critical for an enzyme inhibitor. The binding affinity difference is not large enough to overcome the ADME benefits of Ligand A.

Output:
1
2025-04-17 14:22:29,139 - INFO - Batch 291 complete. Total preferences: 4656
2025-04-17 14:22:29,139 - INFO - Processing batch 292/512...
2025-04-17 14:23:10,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.462 and 366.615 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is slightly above the preferred <140, but acceptable. Ligand B (23.55) is excellent, well below 140.

**logP:** Both ligands (4.125 and 4.722) are slightly high, potentially leading to solubility issues or off-target effects, but not drastically so. Ligand B is a bit higher.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.84) has a very good drug-likeness score. Ligand B (0.581) is acceptable, but lower.

**DILI:** Ligand A (18.961) has a low DILI risk, which is excellent. Ligand B (8.802) also has a low DILI risk.

**BBB:** Both ligands have high BBB penetration (94.378 and 88.329), which isn't crucial for a non-CNS target like SRC, but isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.39 and -4.714), which is unusual and suggests poor permeability. This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.547 and -4.24), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.844 and 0.736), which is good.

**Microsomal Clearance:** Ligand A (41.629) has a moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (122.513) has a high clearance, indicating poor metabolic stability. This is a significant negative for Ligand B.

**In vitro Half-Life:** Ligand A (16.627 hours) has a reasonable half-life. Ligand B (35.112 hours) has a longer half-life, which is positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.451 and 0.516), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is the highest priority for an enzyme inhibitor. However, it suffers from higher logP and significantly worse metabolic stability (higher Cl_mic). Both ligands have poor solubility and permeability. While Ligand A has better metabolic stability and a better QED score, the difference in binding affinity is too significant to ignore. The poor solubility and permeability are concerning for both, but could potentially be addressed through formulation strategies. Given the choice, the stronger binding of Ligand B is more likely to translate into efficacy, even with the metabolic liability.

Output:
1
2025-04-17 14:23:10,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.427 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.83) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.232 and 3.034), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 2. Both are below the 10 threshold.

**QED:** Ligand A (0.761) has a better QED score than Ligand B (0.617), indicating a more drug-like profile.

**DILI:** Ligand A (73.439) has a significantly higher DILI risk than Ligand B (18.728). This is a major concern for Ligand A.

**BBB:** Both have similar BBB penetration (56.495 and 73.75). BBB isn't a primary concern for SRC kinase inhibitors unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-5.072) has poor Caco-2 permeability, while Ligand B (-4.82) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.768) has poor aqueous solubility, and Ligand B (-3.069) is also poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.399 and 0.496).

**Microsomal Clearance:** Ligand A (37.116) and Ligand B (34.848) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-16.081) has a significantly longer in vitro half-life than Ligand A (2.057), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.2 and 0.347).

**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 advantage.

**Conclusion:**

Despite the significantly better binding affinity of Ligand A, its high DILI risk and poor Caco-2 permeability are major drawbacks. Ligand B, while having a weaker affinity, exhibits a much lower DILI risk and a better half-life. Given the enzyme-specific priorities, metabolic stability and safety (low DILI) are crucial. The 2.6 kcal/mol difference in binding affinity, while notable, can potentially be overcome with further optimization of Ligand B. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 14:23:10,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.359 Da and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.28) is slightly above the optimal <140 for good absorption, while Ligand B (101.29) is better, closer to the ideal.

**logP:** Ligand A (0.405) is quite low, potentially hindering permeability. Ligand B (1.478) 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, which are acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.784 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A has a concerning DILI risk (75.456), indicating a high potential for liver injury. Ligand B has a much lower and acceptable DILI risk (19.038). This is a major advantage for Ligand B.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**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 (-3.443 and -3.226), which could pose formulation challenges.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.062 and 0.13), which is excellent.

**Microsomal Clearance:** Ligand A (39.296) has higher microsomal clearance than Ligand B (17.222), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (4.188 hours) has a significantly longer half-life than Ligand A (0.305 hours). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.017 and 0.029).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 kcal/mol). This >1.5 kcal/mol difference is a major driver in favor of Ligand B, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is clearly superior. It has a much better logP, significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a substantially stronger binding affinity. The higher binding affinity is the most important factor, and the improved ADME properties further support its selection.

Output:
1
2025-04-17 14:23:10,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.491 and 361.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.25) is significantly better than Ligand B (113.94). Lower TPSA generally correlates with better cell permeability. Ligand A is well below the 140 threshold, while Ligand B is approaching it.

**logP:** Ligand A (3.196) is optimal, while Ligand B (0.615) is quite low. A logP below 1 can hinder 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, and Ligand B has 6. Both are acceptable (<=10), but Ligand A is preferable.

**QED:** Both ligands have similar QED values (0.88 and 0.825), indicating good drug-likeness.

**DILI:** Ligand B (78.054) has a higher DILI risk than Ligand A (7.716). This is a significant concern.

**BBB:** Ligand A (84.374) has better BBB penetration potential than Ligand B (57.231), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.51) has better Caco-2 permeability than Ligand B (-5.145), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.299 and -3.449). This is a significant drawback for both, but needs to be balanced against other properties.

**hERG Inhibition:** Ligand A (0.753) has a slightly higher hERG risk than Ligand B (0.302), but both are relatively low.

**Microsomal Clearance:** Ligand B (33.978) has lower microsomal clearance than Ligand A (42.118), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.418) has a slightly longer in vitro half-life than Ligand A (-15.215).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.045 and 0.046).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly better 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.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has a higher DILI risk and lower logP, the affinity difference is significant. The slightly better metabolic stability and half-life of Ligand B are also beneficial. The solubility is a concern for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:23:10,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.455 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.58) is better than Ligand B (115.98). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred threshold for oral availability.

**logP:** Ligand A (-0.307) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (0.27) is also on the low side, but marginally better.

**H-Bond Donors/Acceptors:** Ligand A (2 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 (0.667) has a better QED score than Ligand B (0.485), indicating a more drug-like profile.

**DILI:** Ligand A (44.436) has a significantly lower DILI risk than Ligand B (16.596), a crucial advantage.

**BBB:** Both ligands have relatively low BBB penetration (27.646 and 45.522 respectively). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.778 and -5.683), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.936 and -1.501), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.028) has a much lower hERG risk than Ligand B (0.112), a critical safety parameter.

**Microsomal Clearance:** Ligand B (-1.052) has a *negative* microsomal clearance, which is not physically possible and suggests an error in the data. Ligand A (7.954) has a reasonable clearance. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand B (-30.512) has a negative half-life, which is impossible and indicates a data error. Ligand A (4.266) has a short half-life, but at least it's a plausible value.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.005).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 0.7 kcal/mol difference is substantial and can overcome some ADME issues.

**Conclusion:**

Despite both ligands having poor permeability and solubility, Ligand A is the far superior candidate. Its significantly better binding affinity, lower DILI risk, lower hERG risk, and plausible (though not ideal) metabolic stability and half-life outweigh the shared permeability and solubility concerns. The impossible values for clearance and half-life of Ligand B disqualify it immediately.



Output:
0
2025-04-17 14:23:10,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.391 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.58) is higher than Ligand B (58.64). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have good logP values (2.042 and 2.76) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 8 HBA, while Ligand B has 3. Ligand B is preferable here, as fewer HBA generally correlate with better permeability.

**QED:** Both ligands have acceptable QED scores (0.785 and 0.651), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (83.443) than Ligand B (16.751). This is a major concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (82.823 and 83.288), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.955 and -4.4) and don't strongly differentiate the two.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.69) is slightly worse than Ligand B (-3.187).

**hERG:** Both ligands have low hERG inhibition risk (0.285 and 0.47), which is good.

**Microsomal Clearance:** Ligand B (95.752) has a significantly higher microsomal clearance than Ligand A (53.683), indicating lower metabolic stability. This is a drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-28.223) has a worse in vitro half-life than Ligand B (-13.421).

**P-gp Efflux:** Both have low P-gp efflux (0.129 and 0.317).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). The difference is 1 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A has better binding affinity and metabolic stability, but suffers from a very high DILI risk and a worse in vitro half-life. Ligand B has a much lower DILI risk, better TPSA and HBA, but worse metabolic stability. Given the importance of avoiding liver toxicity, the lower DILI risk of Ligand B is a critical advantage. While the slightly weaker affinity and higher clearance of Ligand B are concerns, these can potentially be addressed through further optimization. The high DILI risk of Ligand A is a more difficult property to improve.

Output:
1
2025-04-17 14:23:10,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.402 and 346.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (83.89). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (2.202 and 1.912), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**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.

**QED:** Both ligands have good QED scores (0.635 and 0.817), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (37.96 and 34.238), both below the 40 threshold.

**BBB:** Ligand A has a much higher BBB penetration percentile (84.529) than Ligand B (45.522). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.646) is better than Ligand B (-4.855), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.486) is better than Ligand B (-1.294), which is crucial for formulation and bioavailability.

**hERG:** Ligand A (0.769) has a slightly better hERG profile than Ligand B (0.183), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (21.326) has significantly lower microsomal clearance than Ligand A (31.456), suggesting better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand B (34.124) has a much longer in vitro half-life than Ligand A (-0.624), which is highly desirable.

**P-gp Efflux:** Ligand A (0.299) has lower P-gp efflux than Ligand B (0.04), which is preferable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are excellent, the 0.7 kcal/mol difference is significant.

**Overall:**

Ligand A excels in most areas, particularly solubility, permeability, and binding affinity. However, Ligand B has a significant advantage in metabolic stability (lower Cl_mic and longer t1/2). Given that we're targeting an enzyme, metabolic stability is a critical factor. The slightly better binding affinity of Ligand A is valuable, but the improved metabolic profile of Ligand B is more important for *in vivo* efficacy.

Output:
1
2025-04-17 14:23:10,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 347.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (131.54) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (83.6) is well within the ideal range.

**logP:** Ligand A (1.829) is optimal (1-3). Ligand B (3.438) is at the higher end of optimal, potentially raising concerns about off-target effects, but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD criteria (<=5).

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable HBA limit (<=10).

**QED:** Ligand B (0.657) has a better QED score than Ligand A (0.288), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (A: 34.277, B: 41.877, both <40).

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.976) has poor Caco-2 permeability, while Ligand B (-4.877) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-1.009) has slightly better solubility than Ligand B (-4.142).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.172, B: 0.617).

**Microsomal Clearance:** Ligand A (2.406 mL/min/kg) has significantly lower microsomal clearance than Ligand B (81.964 mL/min/kg), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (23.524 hours) has a much longer in vitro half-life than Ligand B (16.529 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.031, B: 0.519).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, the significantly stronger binding affinity of Ligand B (-7.2 vs -8.9 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The difference in affinity is substantial enough to compensate for the slightly higher logP and lower QED of Ligand B. The Caco-2 permeability is poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:23:10,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (409.284 and 386.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.3) is slightly above the preferred <140 for good oral absorption, while Ligand B (89.87) is well within the range.

**logP:** Both ligands have good logP values (1.878 and 1.321), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 6 HBA) both have reasonable numbers of hydrogen bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar QED scores (0.725 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A (64.676) has a higher DILI risk than Ligand B (55.642), though both are acceptable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (51.066) is lower than Ligand B (25.591).

**Caco-2 Permeability:** Ligand A (-4.81) shows poor permeability, while Ligand B (-5.307) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.934 and -3.239). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.511) has a slightly higher hERG risk than Ligand B (0.271), but both are relatively low.

**Microsomal Clearance:** Ligand A (42.751) has a higher microsomal clearance than Ligand B (40.016), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.023 hours) has a significantly longer in vitro half-life than Ligand A (57.175 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.088 and 0.1).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage, as potency is a key priority for enzyme inhibitors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility, Ligand B's significantly stronger binding affinity (-7.4 vs -8.1 kcal/mol) and longer half-life (13.023 vs 57.175 hours) outweigh the slightly higher DILI risk and lower BBB. The better half-life suggests better metabolic stability, which is critical for an enzyme inhibitor. The slightly better Caco-2 permeability and lower hERG risk are also beneficial.



Output:
1
2025-04-17 14:23:10,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.259 Da) is slightly higher than Ligand B (347.375 Da), but both are acceptable.

**2. TPSA:** Ligand A (83.48) is well below the 140 threshold for good absorption. Ligand B (127.49) is also below the threshold, but closer to it.

**3. logP:** Both ligands have optimal logP values (Ligand A: 2.783, Ligand B: 1.498), falling within the 1-3 range.

**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:** Ligand A (4) and Ligand B (7) are both below the limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.653, Ligand B: 0.81), indicating drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (Ligand A: 62.893, Ligand B: 64.288), both are acceptable, but not ideal.

**8. BBB:** Ligand B (78.868) has a better BBB penetration percentile than Ligand A (46.375). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.946 and -4.974), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.945 and -3.963), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.492, Ligand B: 0.276), which is positive.

**12. Microsomal Clearance:** Ligand A (31.93 mL/min/kg) has lower microsomal clearance than Ligand B (41.837 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.759 hours) has a significantly longer in vitro half-life than Ligand B (15.199 hours), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.194, Ligand B: 0.015).

**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 crucial difference.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, the significantly stronger binding affinity of Ligand B (-6.8 kcal/mol vs -0.0 kcal/mol) is a decisive factor. A binding affinity advantage of this magnitude can often outweigh ADME concerns, especially for an enzyme target where potency is paramount. While Ligand A has better metabolic stability and half-life, the lack of significant binding makes it unlikely to be effective. The poor solubility and permeability of both compounds would need to be addressed through formulation or further chemical modifications, but Ligand B represents a better starting point due to its much higher potency.

Output:
1
2025-04-17 14:23:10,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.475 and 345.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (91.76), both are under the 140 threshold for oral absorption, but closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.221 and 1.475), 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) and Ligand B (5) are both within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.613 and 0.807), indicating good drug-likeness. Ligand B is better here.

**7. DILI:** Ligand A (15.665) has a significantly lower DILI risk than Ligand B (48.158). This is a major advantage for Ligand A.

**8. BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (59.597) is slightly better than Ligand A (51.803).

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.084) is slightly better than Ligand B (-4.927).

**10. Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-1.909) is slightly better than Ligand B (-2.842).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.181 and 0.229).

**12. Microsomal Clearance:** Ligand A (18.48) has significantly lower microsomal clearance than Ligand B (27.095), suggesting better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (1.502) has a shorter half-life than Ligand B (-4.176), which is negative and likely an error.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.045 and 0.02).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage for Ligand B. The difference of 1.4 kcal/mol is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better DILI and metabolic stability, the substantial difference in binding affinity makes Ligand B the more promising candidate. The poor solubility and permeability of both are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:23:10,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.575 and 359.857 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (55.32), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.716 and 3.827), 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:** Ligand A has 3 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 good QED scores (0.581 and 0.754), indicating drug-like properties.

**DILI:** Ligand A (29.081) has a significantly lower DILI risk than Ligand B (46.064). This is a major advantage for Ligand A.

**BBB:** Ligand A (44.397) has a lower BBB penetration than Ligand B (79.062). Since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-5.292) has worse Caco-2 permeability than Ligand B (-4.36).

**Aqueous Solubility:** Ligand A (-3.015) has worse aqueous solubility than Ligand B (-4.606). This is a concern for Ligand A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.341 and 0.508).

**Microsomal Clearance:** Ligand A (45.498) has a significantly lower microsomal clearance than Ligand B (112.257), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (16.095) has a positive half-life, while Ligand B (-25.639) has a negative half-life. This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.157).

**Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (0.0). This is the most important factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall:**

Ligand A is the better candidate. While it has slightly worse solubility and Caco-2 permeability, its significantly stronger binding affinity (-8.1 vs 0.0 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic and positive half-life) outweigh these drawbacks. The strong binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:23:10,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.491 Da) is slightly preferred due to being lower in weight.

**TPSA:** Ligand A (47.1) is significantly better than Ligand B (123.95). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (0.482) is suboptimal, being below the preferred 1-3 range. Ligand B (4.009) is at the upper end of the range, potentially causing solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (3 HBD, 7 HBA). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.64, B: 0.495), indicating reasonable drug-likeness. Ligand A is slightly better.

**DILI:** Ligand B (97.286) has a very high DILI risk, which is a major concern. Ligand A (3.296) has a very low DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.074) is higher than Ligand B (52.811), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.912) is better than Ligand B (-5.171), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.576) is better than Ligand B (-5.067). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.621) is better than Ligand B (0.762), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (21.551) has significantly lower clearance than Ligand B (79.667), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.213) has a negative half-life, which is unusual and potentially problematic. Ligand B (25.79) is positive and more reasonable.

**P-gp Efflux:** Ligand A (0.01) is much better than Ligand B (0.633), indicating less efflux and potentially better bioavailability.

**Binding Affinity:** Ligand B (-6.9 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 significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is significantly better overall. It has a much lower DILI risk, better solubility, permeability, metabolic stability, and P-gp efflux profile. While Ligand B has slightly better binding affinity, the substantial ADME liabilities, particularly the high DILI risk, make it a poor candidate. The negative half-life for Ligand A is a concern, but the other advantages are compelling.

Output:
0
2025-04-17 14:23:10,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.379 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.38) is slightly above the preferred <140 for good absorption, while Ligand B (101.65) is well within the range.

**logP:** Ligand A (-0.258) is a bit low, potentially hindering permeation. Ligand B (0.794) is closer to 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 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.704 and 0.866), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (56.456 and 54.362), both considered acceptable.

**BBB:** Ligand A (31.679) has very low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (77.549) has moderate BBB penetration, also not critical here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.23 and -4.834), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.384 and -2.38), indicating very poor aqueous solubility, a major drawback for oral bioavailability.

**hERG Inhibition:** Ligand A (0.096) shows very low hERG inhibition risk, which is excellent. Ligand B (0.416) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (35.195) has a moderate clearance, while Ligand B (20.687) has a lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.669) has a negative half-life, which is not possible and indicates a problem with the data or the molecule's stability. Ligand B (9.158) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.043 and 0.021), which is favorable.

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

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the far superior candidate. Its significantly stronger binding affinity (-9.2 vs 0.0 kcal/mol) outweighs the minor ADME concerns. The better metabolic stability (lower Cl_mic) and reasonable half-life of Ligand B also contribute to its higher potential. The negative half-life for Ligand A is a critical flaw, making it unlikely to be a viable candidate.

Output:
1
2025-04-17 14:23:10,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.308 Da) is higher, but still acceptable. Ligand B (335.451 Da) is slightly better.

**TPSA:** Ligand A (68.29) is better than Ligand B (39.08) as it is still within the acceptable range for oral absorption.

**logP:** Both ligands have similar logP values around 4.2, which is slightly above the optimal range (1-3) but not drastically so. This could potentially lead to some solubility issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within the acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.575, B: 0.7), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (37.611). This is a significant negative for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (70.027) has better BBB penetration than Ligand B (55.176).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.95) is slightly better than Ligand B (-5.135).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.927) is slightly better than Ligand B (-4.187).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.746, B: 0.929), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand B (60.467 mL/min/kg) has significantly lower microsomal clearance than Ligand A (113.618 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-10.368 hours) has a negative half-life, which is concerning. Ligand A (77.953 hours) has a good half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.413, B: 0.806). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a crucial advantage, as a 1.1 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a better half-life, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic). The slight drawbacks in solubility and permeability can be addressed through formulation strategies. The stronger binding affinity of Ligand B is likely to outweigh the minor ADME concerns.

Output:
1
2025-04-17 14:23:10,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.519 Da) is slightly higher than Ligand B (350.354 Da), but both are acceptable.

**TPSA:** Ligand A (109.41) is better than Ligand B (133.15) as it's closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.014, Ligand B: 0.981), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is more favorable than Ligand B (HBD=4, HBA=8) as it has fewer H-bond donors and acceptors, potentially improving permeability.

**QED:** Ligand A (0.768) has a significantly better QED score than Ligand B (0.581), indicating a more drug-like profile.

**DILI:** Ligand B (77.394) has a lower DILI risk than Ligand A (96.045), which is a significant advantage.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (47.15) is slightly better.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

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

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.229, Ligand B: 0.372), which is good.

**Microsomal Clearance:** Ligand A (-4.102) has *much* lower (better) microsomal clearance than Ligand B (31.381). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (89.177) has a much longer in vitro half-life than Ligand B (-15.588), further supporting its improved metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.207, Ligand B: 0.031).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

While Ligand A has better physicochemical properties (QED, TPSA, HBD/HBA, metabolic stability) and a lower DILI risk, the *substantial* difference in binding affinity in favor of Ligand B (-7.7 vs -0.0 kcal/mol) is decisive. A strong binding affinity can often compensate for minor ADME drawbacks, and the difference here is substantial. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies. The improved metabolic stability of Ligand A is a plus, but the potency of Ligand B is paramount.

Output:
1
2025-04-17 14:23:10,073 - INFO - Batch 292 complete. Total preferences: 4672
2025-04-17 14:23:10,073 - INFO - Processing batch 293/512...
2025-04-17 14:23:59,790 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.459 Da and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (64.74 and 67.43) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.513 and 2.64) are 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 (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.929) has a significantly higher QED score than Ligand B (0.672), indicating better overall drug-likeness.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (12.214), but both are still considered good (<40 is ideal, <60 is generally acceptable).

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (86.196) is better than Ligand B (74.06). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired or problematic.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.83 and -4.73), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.014 and -3.25), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.379), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (39.723 mL/min/kg) has a lower microsomal clearance than Ligand B (58.007 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (23.278 hours) has a significantly longer half-life than Ligand B (6.002 hours), which is highly desirable for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.458 and 0.087).

**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.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a superior QED score, better metabolic stability (lower Cl_mic), a longer half-life, and slightly better binding affinity. While both have poor Caco-2 and solubility values, the advantages of Ligand A in terms of metabolic stability and half-life are crucial for an enzyme inhibitor. The slightly higher DILI and hERG risk are not major concerns given the overall profile.

Output:
1
2025-04-17 14:23:59,790 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (347.459 and 343.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.23) is well below the 140 threshold for good absorption, and preferable for kinases. Ligand B (138.68) is approaching the upper limit, potentially impacting absorption.

**3. logP:** Ligand A (2.612) is optimal (1-3). Ligand B (0.774) is slightly low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (4) is acceptable but higher.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is acceptable but higher.

**6. QED:** Both ligands have good QED scores (0.503 and 0.632, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (18.224) has a much lower DILI risk than Ligand B (83.908), which is a significant concern.

**8. BBB:** Both have similar BBB penetration (67.468 and 64.211), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar.

**10. Solubility:** Ligand A (-1.844) is better than Ligand B (-4.097). Solubility is important for kinases.

**11. hERG:** Ligand A (0.14) has a much lower hERG risk than Ligand B (0.217). This is a critical advantage.

**12. Cl_mic:** Ligand A (59.619) has a higher microsomal clearance than Ligand B (8.203), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. t1/2:** Ligand A (-18.614) has a negative in vitro half-life, which is concerning. Ligand B (-7.142) is also negative, but less so. Both need investigation, but A is worse.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.027 and 0.031).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount for an enzyme inhibitor. However, it has a substantially higher DILI risk and slightly worse solubility. Ligand A has better solubility, lower DILI and hERG risk, but poorer binding affinity and metabolic stability.

The difference in binding affinity (-8.3 vs -6.0 kcal/mol) is a 2.3 kcal/mol difference, which is substantial enough to outweigh the moderate ADME concerns of Ligand B, *provided* the DILI risk can be mitigated through structural modifications. The higher metabolic clearance of Ligand A is also a concern.

Output:
1
2025-04-17 14:23:59,790 - INFO - Okay, let's analyze these two ligands for their potential as drug candidates targeting SRC, a kinase.

**Step-by-step comparison:**

1. **MW:** Ligand A (344.371 Da) is within the ideal range (200-500). Ligand B (368.455 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (88.85) is excellent, well below the 140 threshold for oral absorption. Ligand B (97.64) is still acceptable, but slightly higher. A favors absorption.

3. **logP:** Ligand A (0.968) is a little low, potentially impacting permeability. Ligand B (1.637) is better, falling within the optimal 1-3 range. B is favored.

4. **HBD:** Both ligands have 2 HBD, which is good and within the acceptable limit of 5. No difference.

5. **HBA:** Ligand A has 7 HBA, well within the limit of 10. Ligand B has 6 HBA, also good. No significant difference.

6. **QED:** Ligand A (0.859) has a better QED score than Ligand B (0.71), indicating a more drug-like profile. A is favored.

7. **DILI:** Ligand A (57.154) has a lower DILI risk than Ligand B (62.35), both are acceptable, but A is slightly better.

8. **BBB:** Ligand A (70.803) has a better BBB penetration percentile than Ligand B (48.352). While SRC is not a CNS target, better BBB penetration can sometimes correlate with better overall distribution. A is favored.

9. **Caco-2:** Ligand A (-4.756) has a *much* better Caco-2 permeability than Ligand B (-5.35). This suggests significantly better intestinal absorption for A. A is strongly favored.

10. **Solubility:** Ligand A (-2.329) has better aqueous solubility than Ligand B (-3.33). Solubility is important for bioavailability, so A is favored.

11. **hERG:** Ligand A (0.839) has a lower hERG inhibition liability than Ligand B (0.201). Lower hERG is crucial to avoid cardiotoxicity. A is strongly favored.

12. **Cl_mic:** Ligand A (0.271) has *much* lower microsomal clearance than Ligand B (38.095). This indicates significantly better metabolic stability for A. A is strongly favored.

13. **t1/2:** Ligand A (12.255) has a longer in vitro half-life than Ligand B (29.21). This is a positive attribute, suggesting less frequent dosing. A is favored.

14. **Pgp:** Ligand A (0.174) has lower P-gp efflux liability than Ligand B (0.179). A is slightly favored.

15. **Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are good, the difference is not substantial enough to outweigh the many ADME advantages of A.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in all these areas. While Ligand B has acceptable affinity, it is significantly weaker metabolically stable, and has a higher hERG risk.

**Conclusion:**

Ligand A is significantly more likely to be a viable drug candidate than Ligand B. It demonstrates a superior balance of potency, ADME properties, and safety characteristics.

Output:
0
2025-04-17 14:23:59,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 437.344 Da - Within the ideal range (200-500 Da).
* Ligand B: 358.429 Da - Also within the ideal range.
* *Advantage: Neither is problematic.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 94.88 - Good for oral absorption (<=140).
* Ligand B: 58.64 - Excellent for oral absorption.
* *Advantage: Ligand B.*

**3. Lipophilicity (logP):**
* Ligand A: 4.163 - Slightly high, potential for solubility/off-target issues.
* Ligand B: 2.344 - Optimal range (1-3).
* *Advantage: Ligand B.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Acceptable (<=5).
* Ligand B: 1 - Acceptable (<=5).
* *Advantage: Neither is problematic.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 6 - Acceptable (<=10).
* Ligand B: 3 - Acceptable (<=10).
* *Advantage: Ligand B.*

**6. QED:**
* Ligand A: 0.625 - Good drug-like profile (>=0.5).
* Ligand B: 0.76 - Very good drug-like profile.
* *Advantage: Ligand B.*

**7. DILI:**
* Ligand A: 97.518 - High risk of liver injury (>60). This is a significant concern.
* Ligand B: 15.587 - Low risk of liver injury (<40).
* *Advantage: Ligand B.*

**8. BBB:**
* Ligand A: 37.611 - Low BBB penetration. Not a major concern for a non-CNS target.
* Ligand B: 95.269 - High BBB penetration. Not a major concern for a non-CNS target.
* *Advantage: Neither is problematic.*

**9. Caco-2 Permeability:**
* Ligand A: -5.183 - Poor permeability.
* Ligand B: -4.608 - Poor permeability.
* *Advantage: Neither is problematic.*

**10. Aqueous Solubility:**
* Ligand A: -4.394 - Poor solubility.
* Ligand B: -2.388 - Poor solubility.
* *Advantage: Ligand B.*

**11. hERG Inhibition:**
* Ligand A: 0.739 - Acceptable hERG risk.
* Ligand B: 0.583 - Acceptable hERG risk.
* *Advantage: Neither is problematic.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 14.17 mL/min/kg - Moderate clearance.
* Ligand B: 1.156 mL/min/kg - Low clearance, suggesting better metabolic stability.
* *Advantage: Ligand B.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 136.869 hours - Very long half-life.
* Ligand B: -1.095 hours - Very short half-life.
* *Advantage: Ligand A.*

**14. P-gp Efflux:**
* Ligand A: 0.299 - Low efflux, good.
* Ligand B: 0.051 - Very low efflux, excellent.
* *Advantage: Ligand B.*

**15. Binding Affinity:**
* Ligand A: -8.3 kcal/mol
* Ligand B: -8.3 kcal/mol
* *Advantage: Tie.*

**Overall Assessment:**

Both ligands have equivalent binding affinity, which is excellent. However, Ligand A suffers from a very high DILI risk and poor solubility. While it has a longer half-life, the DILI risk is a major red flag. Ligand B, while having a shorter half-life, demonstrates a significantly better overall profile with lower DILI risk, better logP, TPSA, QED, metabolic stability, and P-gp efflux. Given the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate despite the shorter half-life. The half-life could potentially be improved through further optimization.

Output:
1
2025-04-17 14:23:59,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 & 368.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.1) is better than Ligand B (67.87) as it's closer to the <140 threshold for oral absorption.

**logP:** Both ligands (3.13 & 3.06) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, satisfying the <5 and <10 rules, respectively.

**QED:** Both ligands have good QED scores (0.792 & 0.749), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (47.42 & 48.31), well below the concerning threshold of 60.

**BBB:** Both have good BBB penetration (73.59 & 82.63), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.59 & -4.64), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-3.19 & -3.27), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both have low hERG inhibition risk (0.86 & 0.74), which is excellent.

**Microsomal Clearance:** Ligand A (17.12) has significantly lower microsomal clearance than Ligand B (93.42), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (52.89) has a longer half-life than Ligand B (18.53), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux (0.19 & 0.20), which is good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a substantially better binding affinity than Ligand A (-6.8 kcal/mol). This 1.9 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B's significantly stronger binding affinity (-8.7 vs -6.8 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. The improved affinity is likely to translate to greater efficacy, potentially compensating for the solubility and permeability issues. While Ligand A has better metabolic stability, the affinity difference is too large to ignore.

Output:
1
2025-04-17 14:23:59,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.342 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.34) is better than Ligand B (70.47), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.325) is optimal, while Ligand B (0.791) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, below the 10 threshold.

**QED:** Ligand A (0.928) has a significantly better QED score than Ligand B (0.792), indicating better overall drug-likeness.

**DILI:** Ligand B (19.271) has a much lower DILI risk than Ligand A (72.974), a significant advantage.

**BBB:** Ligand B (77.898) shows better BBB penetration than Ligand A (46.762), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.521) has better Caco-2 permeability than Ligand B (-5.095).

**Aqueous Solubility:** Ligand A (-3.813) has better aqueous solubility than Ligand B (-1.162).

**hERG:** Ligand A (0.502) has a better hERG profile than Ligand B (0.459), lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-7.226) has significantly lower microsomal clearance than Ligand B (3.215), suggesting much better metabolic stability.

**In vitro Half-Life:** Ligand A (33.168 hours) has a much longer half-life than Ligand B (8.535 hours), a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux than Ligand B (0.013), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 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.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. It exhibits superior metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a better QED score. While Ligand B has a slightly better binding affinity and lower DILI, the substantial advantages of Ligand A in metabolic stability, solubility, and overall drug-likeness outweigh these benefits.

Output:
1
2025-04-17 14:23:59,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.18) is better than Ligand B (93.46), both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand B (1.639) is better than Ligand A (0.363). Ligand A is quite low, potentially hindering permeability. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.771) is better than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Ligand A (34.161) is significantly better than Ligand B (47.693), indicating a lower risk of drug-induced liver injury. Both are below the 60 threshold, but A is preferable.

**BBB:** Ligand B (71.811) is better than Ligand A (59.636), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.9) is better than Ligand B (-4.461), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.37) is better than Ligand B (-3.143), indicating better solubility.

**hERG:** Ligand A (0.173) is significantly better than Ligand B (0.339), indicating a lower risk of hERG inhibition.

**Microsomal Clearance:** Ligand A (-35.175) is much better than Ligand B (35.07). A negative value for Cl_mic suggests very high metabolic stability, which is highly desirable for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-11.927) is better than Ligand A (-4.699), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.014) is much better than Ligand B (0.242), indicating lower P-gp efflux.

**Binding Affinity:** Ligand B (-6.6) is better than Ligand A (-10.5). This is a substantial difference in potency. A 3.9 kcal/mol difference is significant and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has superior ADME properties (DILI, solubility, hERG, metabolic stability, P-gp efflux) and a better QED score. However, Ligand B has a substantially better binding affinity (-6.6 vs -10.5 kcal/mol). Given that we are targeting a kinase (enzyme), potency is paramount. The difference in binding affinity is large enough to compensate for the slightly less favorable ADME profile of Ligand B. While Ligand A is a very good candidate, the significantly improved potency of Ligand B makes it the more promising drug candidate.

Output:
1
2025-04-17 14:23:59,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.308 Da) is slightly higher, but acceptable. Ligand B (350.379 Da) is also good.

**TPSA:** Ligand A (64.35) is excellent, well below the 140 threshold for oral absorption. Ligand B (133.39) is still acceptable, but closer to the limit.

**logP:** Ligand A (3.831) is optimal. Ligand B (-0.444) is significantly below the 1-3 range, which is a concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is good. Ligand B (HBD=3, HBA=7) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (A: 0.74, B: 0.637), indicating good drug-likeness.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 63.513, B: 62.893).

**BBB:** Ligand A (74.292) has better BBB penetration than Ligand B (58.278), but BBB isn't a high priority for a kinase inhibitor unless CNS targets are considered.

**Caco-2 Permeability:** Ligand A (-4.576) is poor, suggesting low intestinal absorption. Ligand B (-5.516) is even worse.

**Aqueous Solubility:** Ligand A (-4.72) is poor. Ligand B (-1.946) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.535) has a low hERG risk, which is excellent. Ligand B (0.042) also has very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (91.347) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-3.288) has *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**In vitro Half-Life:** Ligand A (68.198) has a reasonable half-life. Ligand B (10.045) has a very short half-life.

**P-gp Efflux:** Ligand A (0.749) has moderate P-gp efflux. Ligand B (0.018) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility of both, Ligand A is the better candidate. Its significantly stronger binding affinity (-9.4 vs -8.3 kcal/mol) is a major advantage for an enzyme inhibitor. While Ligand B has better metabolic stability (negative Cl_mic), the difference in affinity is more critical. The slightly better BBB of A is a minor benefit. The poor permeability and solubility of both would need to be addressed in further optimization, but the potency advantage of A makes it the more promising starting point.

Output:
0
2025-04-17 14:23:59,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (383.5 and 348.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.98) is higher than Ligand B (67.87). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have similar logP values (1.639 and 1.745), falling 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.668 and 0.844), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (94.882 percentile) compared to Ligand B (32.261 percentile). This is a major concern for Ligand A.

**BBB:** Ligand A (54.285) and Ligand B (74.758). BBB is less critical for a non-CNS target like SRC, but higher is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.6) and Ligand B (-4.78). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.117) and Ligand B (-2.238). Both are negative, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.121 and 0.155). This is excellent.

**Microsomal Clearance:** Ligand A (13.779) and Ligand B (14.79). Both have similar microsomal clearance, indicating similar metabolic stability.

**In vitro Half-Life:** Ligand B (1.832) has a significantly lower in vitro half-life compared to Ligand A (55.268). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.163 and 0.048).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). The difference of 1.1 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's longer half-life, the significantly higher DILI risk is a major red flag. The stronger binding affinity of Ligand B, coupled with its lower DILI risk, lower TPSA, and acceptable other properties, makes it the more promising drug candidate. While both have poor solubility and permeability, these can be addressed with formulation strategies. The DILI risk for Ligand A is too high to ignore.

Output:
1
2025-04-17 14:23:59,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.49) is slightly higher than Ligand B (67.23). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (2.834 and 1.84), falling within the optimal 1-3 range. Ligand B is slightly lower, which might slightly improve solubility.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 4. Both are below the 10 limit.

**QED:** Ligand A (0.918) has a significantly better QED score than Ligand B (0.732), indicating a more drug-like profile.

**DILI:** Ligand A (65.413) has a higher DILI risk than Ligand B (26.522). This is a significant negative for Ligand A.

**BBB:** Ligand A (80.264) has better BBB penetration than Ligand B (57.464), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.562) has better Caco-2 permeability than Ligand B (-5.01), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-3.577) has better aqueous solubility than Ligand B (-1.244). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.513) has a slightly higher hERG risk than Ligand B (0.151). This is a negative for Ligand A.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (30.74 and 29.209 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-8.186) has a longer in vitro half-life than Ligand A (-7.233), which is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.183) has lower P-gp efflux than Ligand B (0.039), which is a positive for Ligand A.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has slightly better solubility and Caco-2 permeability, Ligand B has a significantly lower DILI risk and a longer half-life. The lower hERG risk of Ligand B is also a major advantage. The similar binding affinities make the ADME/Tox profile the deciding factor.

Output:
1
2025-04-17 14:23:59,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (85.9) is slightly lower than Ligand B (84.4), a minor advantage.

**logP:** Both ligands have logP values between 1 and 3 (1.331 for A, 1.738 for B), which is optimal.

**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). Ligand B's lower HBD count could slightly improve permeability.

**QED:** Both ligands have QED values above 0.5 (0.758 for A, 0.714 for B), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 65.9%, while Ligand B has 59.1%. Both are acceptable, but Ligand B is slightly better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.2%) has a higher BBB penetration than Ligand A (67.5%), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed with the assumption these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.101 for A, 0.133 for B), which is excellent.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-2.476), indicating very high metabolic stability, which is excellent. Ligand B has a significantly higher Cl_mic (56.019), suggesting faster metabolism and a potential issue.

**In vitro Half-Life:** Ligand A has a half-life of 19.8 hours, which is good. Ligand B has a negative half-life (-26.245), which is not physically possible and suggests a data error or a very rapidly metabolized compound.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 for A, 0.044 for B), which is favorable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most crucial factor for an enzyme inhibitor. However, it suffers from a high microsomal clearance and an impossible half-life value, raising serious concerns about its metabolic stability. Ligand A has excellent metabolic stability and a good half-life, but its binding affinity is weaker. The solubility issues are concerning for both.

Despite the affinity advantage of Ligand B, the metabolic instability and data error regarding half-life are significant red flags. Ligand A, while having a weaker binding affinity, presents a more favorable overall profile with good metabolic stability and a reasonable half-life.

Output:
0
2025-04-17 14:23:59,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (345.414 and 345.359 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (47.56) is well below the 140 threshold, and excellent for oral absorption. Ligand B (116.42) is still within acceptable limits, but less favorable than A.

**3. logP:** Ligand A (4.121) is slightly high, potentially leading to solubility issues or off-target effects, but still within a manageable range. Ligand B (-0.039) is too low, which could hinder membrane permeability and reduce bioavailability.

**4. H-Bond Donors:** Ligand A (1) is ideal. Ligand B (3) is acceptable, but less optimal.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable.

**6. QED:** Ligand A (0.857) has a very strong drug-like profile. Ligand B (0.531) is acceptable, but less desirable.

**7. DILI:** Ligand A (62.001) has a moderate DILI risk, but is still acceptable. Ligand B (82.28) has a higher DILI risk, which is concerning.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.258) is moderate, and Ligand B (39.705) is low.

**9. Caco-2 Permeability:** Ligand A (-4.275) is poor, while Ligand B (-5.436) is even worse. Both are problematic.

**10. Aqueous Solubility:** Ligand A (-4.894) is poor, while Ligand B (-3.415) is slightly better, but still poor.

**11. hERG Inhibition:** Ligand A (0.779) has a low risk of hERG inhibition. Ligand B (0.224) also has a low risk.

**12. Microsomal Clearance:** Ligand A (70.126) has moderate clearance, indicating moderate metabolic stability. Ligand B (-14.808) has negative clearance, which is not possible and indicates an error or outlier in the data. This is a significant red flag.

**13. In vitro Half-Life:** Ligand A (12.71) has a relatively short half-life. Ligand B (1.284) has a very short half-life, which is undesirable.

**14. P-gp Efflux:** Ligand A (0.352) has low P-gp efflux, which is good. Ligand B (0.01) has very low P-gp efflux, also good.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.1 kcal/mol). The difference is negligible.

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both ligands have comparable affinity, Ligand B exhibits a problematic negative microsomal clearance and very short half-life. Ligand A has moderate clearance and half-life, and a better overall profile regarding solubility and DILI risk. The poor Caco-2 and solubility of both are concerns, but the metabolic instability of Ligand B is a more critical issue for an enzyme target.

Output:
0
2025-04-17 14:23:59,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.389 Da and 360.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is higher than Ligand B (49.85). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Ligand A (0.101) is quite low, potentially hindering permeation. Ligand B (2.195) 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:** Ligand B (0.699) has a better QED score than Ligand A (0.441), indicating a more drug-like profile.

**DILI:** Ligand A (23.808) has a slightly higher DILI risk than Ligand B (11.128), though both are relatively low and acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (96.084) has a higher BBB penetration, but this is not a major factor here.

**Caco-2 Permeability:** Ligand A (-4.859) has poor Caco-2 permeability, which is a concern. Ligand B (-4.291) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-0.817) has poor aqueous solubility, while Ligand B (-1.76) is also poor. This is a potential issue for both, but more so for Ligand A.

**hERG Inhibition:** Ligand A (0.253) has a slightly higher hERG risk than Ligand B (0.684), but both are relatively low.

**Microsomal Clearance:** Ligand A (27.502) has lower microsomal clearance than Ligand B (33.714), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.274) has a significantly longer in vitro half-life than Ligand B (-5.148), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.097 respectively).

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

**Conclusion:**

While Ligand A has a longer half-life, its poor logP, Caco-2 permeability, and solubility are significant drawbacks. Ligand B has a better logP, QED, and lower DILI risk, making it more likely to be a viable drug candidate despite the slightly shorter half-life. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 14:23:59,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 370.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold and favorable for oral absorption. Ligand B (88.85) is also below 140, but higher than A.

**logP:** Ligand A (2.401) is within the optimal 1-3 range. Ligand B (1.36) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.782 and 0.813), indicating good drug-like properties.

**DILI:** Ligand A (23.614) has a significantly lower DILI risk than Ligand B (54.052), which is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (83.482) has a higher BBB percentile than Ligand B (68.554).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a problem with the data.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and suggests a problem with the data.

**hERG:** Both ligands have low hERG risk (0.408 and 0.268).

**Microsomal Clearance:** Ligand A (58.235) has a better (lower) microsomal clearance than Ligand B (9.506), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (41.174 hours) has a significantly longer half-life than Ligand A (1.618 hours). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.23 and 0.052).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a 1.5 kcal/mol advantage, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much longer half-life. However, it has a higher DILI risk and a lower logP. Ligand A has better metabolic stability (lower Cl_mic), lower DILI risk, and a better logP, but weaker binding affinity and a shorter half-life.

Given the enzyme-specific priorities, the stronger binding affinity of Ligand B is a critical factor. The longer half-life is also very beneficial. While the higher DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. The lower logP of Ligand B could also be addressed. The questionable solubility and permeability data for both compounds would need to be investigated further.

Output:
1
2025-04-17 14:23:59,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.467 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is well below the 140 threshold, while Ligand B (96.25) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.24) is optimal, while Ligand B (-0.571) is significantly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is within acceptable limits. Ligand B (1 HBD, 7 HBA) is also acceptable, but the higher HBA count might slightly reduce permeability.

**QED:** Both ligands have good QED scores (0.882 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A (56.921) has a moderate DILI risk, while Ligand B (30.942) has a low DILI risk. This favors Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (91.702) has a higher BBB percentile than Ligand B (50.795).

**Caco-2 Permeability:** Ligand A (-4.89) has poor Caco-2 permeability, while Ligand B (-5.376) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.578) has poor solubility, while Ligand B (-0.016) has very poor solubility. This is a concern for both, but slightly less so for Ligand B.

**hERG Inhibition:** Ligand A (0.716) has a moderate hERG risk, while Ligand B (0.05) has very low hERG risk. This strongly favors Ligand B.

**Microsomal Clearance:** Ligand A (51.013) has moderate clearance, while Ligand B (-3.857) has negative clearance, suggesting excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (11.191 hours) has a reasonable half-life, while Ligand B (13.329 hours) has a slightly longer half-life.

**P-gp Efflux:** Ligand A (0.297) has low P-gp efflux, while Ligand B (0.011) has very low P-gp efflux. Both are good.

**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, potentially outweighing some of its ADME drawbacks. The difference of 2.1 kcal/mol is quite large.

**Overall Assessment:**

Ligand B has superior ADME properties (lower DILI, lower hERG, better metabolic stability, lower P-gp efflux). However, Ligand A boasts a much stronger binding affinity (-8.8 vs -6.7 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. While the solubility and permeability of Ligand A are concerning, these can potentially be addressed through formulation strategies or further chemical modifications. The strong binding affinity of Ligand A makes it a more promising starting point for optimization.

Output:
0
2025-04-17 14:23:59,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.395 and 352.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.51) is better than Ligand B (42.43). While both are reasonably low, Ligand B's TPSA is exceptionally good, potentially indicating better cell permeability.

**logP:** Ligand A (0.622) is lower than optimal (1-3), potentially hindering permeability. Ligand B (4.55) is high, potentially causing solubility issues and off-target effects.

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

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

**QED:** Ligand A (0.791) has a better QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Ligand A (76.58) has a higher DILI risk than Ligand B (85.149), which is concerning.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (59.907) is higher than Ligand A (34.548).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.798) is slightly better than Ligand B (-4.58).

**Aqueous Solubility:** Ligand A (-3.955) is better than Ligand B (-5.933), indicating better solubility.

**hERG Inhibition:** Ligand A (0.234) has a lower hERG risk than Ligand B (0.537), which is a significant advantage.

**Microsomal Clearance:** Ligand A (24.464) has a lower Cl_mic, suggesting better metabolic stability, which is crucial for kinase inhibitors. Ligand B (100.973) has a very high Cl_mic, a major drawback.

**In vitro Half-Life:** Ligand A (-36.403) has a negative half-life, which is concerning. Ligand B (26.247) has a positive half-life, indicating better stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.062 and 0.508, respectively).

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, its high logP and high microsomal clearance are significant drawbacks. Ligand A has better ADME properties (solubility, hERG, metabolic stability), but its binding affinity is weaker. Considering the substantial affinity difference, the benefits of Ligand B's potency likely outweigh its ADME liabilities, especially given that optimization can address these issues.

Output:
1
2025-04-17 14:23:59,792 - INFO - Batch 293 complete. Total preferences: 4688
2025-04-17 14:23:59,792 - INFO - Processing batch 294/512...
2025-04-17 14:24:48,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.383 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.34) is slightly above the optimal <140 for oral absorption, while Ligand B (71.44) is well within the range.

**logP:** Ligand A (0.658) is a bit low, potentially hindering permeability. Ligand B (0.887) is also on the lower side but slightly better.

**H-Bond Donors:** Ligand A has 4 HBD, acceptable. Ligand B has 0 HBD, which is also acceptable and may improve permeability.

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

**QED:** Both ligands have similar QED values (0.638 and 0.61), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 61.419%, which is considered high risk. Ligand B has a significantly lower DILI risk of 35.712%, which is good. This is a major advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (73.866%) has a higher BBB value than Ligand A (23.265%), but this is less critical here.

**Caco-2 Permeability:** Ligand A (-5.624) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.492) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.254 and -2.258). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.328 and 0.363).

**Microsomal Clearance:** Ligand A has a much lower (better) microsomal clearance (-32.821) compared to Ligand B (40.201), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (26.708 hours) than Ligand B (-4.036 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.008 and 0.163).

**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 deficiencies.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), but suffers from poor Caco-2 permeability and a high DILI risk. Ligand B has a better DILI profile, slightly better permeability, and a good BBB score (though less important here), but its affinity is weaker and metabolic stability is worse.

Given the enzyme-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 solubility and permeability are also concerns, but could potentially be addressed through formulation strategies. The difference in binding affinity (1.3 kcal/mol) is substantial enough to favor Ligand A despite its drawbacks.

Output:
0
2025-04-17 14:24:48,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.52) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (90.98) is well within the desired range.

**logP:** Ligand A (-0.128) is quite low, potentially hindering permeability. Ligand B (1.834) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are below the 10 threshold.

**QED:** Both ligands have reasonable QED scores (A: 0.664, B: 0.555), indicating good drug-like properties.

**DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (36.758), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.609) has a higher BBB score than Ligand A (53.625).

**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 unknown, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.116, B: 0.218), which is positive.

**Microsomal Clearance:** Ligand A (-6.56) shows *much* better metabolic stability (lower clearance) than Ligand B (41.051). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-0.715) has a negative half-life, which is impossible. Ligand B (-18.082) 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: 0.004, B: 0.211).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). The 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the questionable solubility and permeability data, the key factors for an enzyme inhibitor are potency and metabolic stability. Ligand A has a substantially better binding affinity (-9.2 vs -8.1 kcal/mol) and significantly improved metabolic stability (lower Cl_mic). While Ligand B has a better logP, the difference in affinity and stability is more critical for an enzyme target. The negative half-life values for both are concerning and suggest data quality issues, but the relative difference in Cl_mic remains a strong indicator.

Output:
0
2025-04-17 14:24:48,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.5 and 351.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is higher than Ligand B (47.36). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (2.069) and Ligand B (3.353) are both within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but not drastically.

**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 (0.752) has a slightly better QED score than Ligand B (0.607), indicating a more drug-like profile.

**DILI:** Ligand B (31.524) has a significantly lower DILI risk than Ligand A (66.072). This is a major advantage for Ligand B.

**BBB:** Ligand A (46.219) has a lower BBB penetration percentile than Ligand B (94.804). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.533) has worse Caco-2 permeability than Ligand B (-4.053). Both are negative, indicating poor permeability, but Ligand B is better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.24 and -3.419). This is a significant drawback for both, but needs to be considered alongside other factors.

**hERG Inhibition:** Ligand A (0.112) has a lower hERG inhibition risk than Ligand B (0.778). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (39.62) has lower microsomal clearance than Ligand B (80.583), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-23.945) has a longer in vitro half-life than Ligand B (20.908). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.145) has lower P-gp efflux than Ligand B (0.46). This is a slight advantage for Ligand A.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.2). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B has a substantially lower DILI risk and better Caco-2 permeability, and a much better BBB score. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. Both have poor solubility. The binding affinity difference is minimal. Given the enzyme-kinase focus, metabolic stability and safety (DILI, hERG) are paramount. Although Ligand A has poor solubility, its superior metabolic stability and safety profile outweigh the slightly weaker binding affinity and solubility concerns.

Output:
1
2025-04-17 14:24:48,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.331 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.49) is slightly higher than the ideal <140, but acceptable. Ligand B (89.87) is excellent, well below 140.

**logP:** Ligand A (0.353) is a bit low, potentially hindering permeability. Ligand B (1.074) is better, falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.541 and 0.624), indicating 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 (10.237%), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.374%) is moderate, while Ligand B (49.515%) is lower.

**Caco-2 Permeability:** Ligand A (-5.191) and Ligand B (-4.939) are both negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.914 and -1.882). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.051 and 0.099), which is excellent.

**Microsomal Clearance:** Ligand A (28.872) has a higher clearance than Ligand B (21.571), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (70.138) has a better in vitro half-life than Ligand B (-9.186).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.006).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), a difference of 0.7 kcal/mol. While a difference of >1.5 kcal/mol is usually significant, 0.7 kcal/mol is less impactful, especially when considering other factors.

**Conclusion:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. The significantly lower DILI risk for Ligand B is a major advantage, outweighing the small difference in binding affinity. The better logP and TPSA values of Ligand B also contribute to its improved drug-like properties. While both have poor solubility and Caco-2 permeability, these issues are often addressable during formulation. The lower metabolic stability of Ligand A is also a concern.

Output:
1
2025-04-17 14:24:48,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.547 Da) is slightly better positioned.

**TPSA:** Ligand B (50.36) is significantly better than Ligand A (84.5). Lower TPSA generally favors better absorption, which is beneficial.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.591) is slightly better.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.684) is slightly better.

**DILI:** Ligand A (18.534) has a much lower DILI risk than Ligand B (67.739). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.582) is better than Ligand B (71.229).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.369) is slightly better than Ligand B (-4.765).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.155) is slightly better than Ligand B (-4.731).

**hERG Inhibition:** Ligand A (0.477) has a lower hERG inhibition liability than Ligand B (0.799). This is a crucial advantage.

**Microsomal Clearance:** Ligand B (70.815) has a lower microsomal clearance than Ligand A (82.02), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (41.938) has a longer half-life than Ligand A (-27.972). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability. Ligand A (0.048) is slightly better than Ligand B (0.518).

**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 A excels in DILI risk and hERG inhibition, which are critical for safety. It also has slightly better QED, logP, and P-gp efflux. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer half-life) and slightly better binding affinity. The poor solubility and permeability of both are concerning, but the strong binding affinity of Ligand B, coupled with its improved metabolic profile, makes it the more promising candidate, assuming solubility/permeability can be addressed through formulation or further chemical modifications.

Output:
1
2025-04-17 14:24:48,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.77) is better than Ligand B (116.48), being closer to the <140 threshold for good absorption.

**logP:** Ligand B (-0.03) is slightly better than Ligand A (0.229), being closer to the optimal 1-3 range. However, both are quite low and might present permeability challenges.

**H-Bond Donors:** Both have 4 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand B (6) is slightly better than Ligand A (4), but both are well within the acceptable limit of <=10.

**QED:** Both ligands have similar QED scores (0.57 and 0.549), indicating good drug-likeness.

**DILI:** Ligand B (20.163) has a significantly lower DILI risk than Ligand A (29.624), which is a major advantage.

**BBB:** Ligand A (73.672) has a much better BBB penetration potential than Ligand B (19.426). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.866) has better Caco-2 permeability than Ligand B (-5.529), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.376) has slightly better aqueous solubility than Ligand A (-1.04), but both are poor.

**hERG Inhibition:** Ligand A (0.269) has a lower hERG inhibition liability than Ligand B (0.134), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (-11.81) has significantly lower microsomal clearance than Ligand B (27.372), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (3.144) has a better in vitro half-life than Ligand B (-14.468), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.008) has much lower P-gp efflux liability than Ligand B (0.02), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.5). The difference is 0.9 kcal/mol, which is substantial, but not overwhelmingly so.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all other critical ADMET properties, particularly metabolic stability (Cl_mic, t1/2), DILI risk, and hERG inhibition. The better metabolic stability of Ligand A is especially important for an enzyme inhibitor, as it suggests a longer duration of action and potentially lower dosing requirements. The lower DILI and hERG risks also contribute to a more favorable safety profile. The slight difference in binding affinity is likely surmountable through further optimization of Ligand A.

Output:
0
2025-04-17 14:24:48,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (338.411 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.44) is well below the 140 threshold for good oral absorption and is also favorable. Ligand B (98.06) is still acceptable but less optimal.

**3. logP:** Both ligands have a logP around 1.3, which is within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1) is excellent, while Ligand B (3) is acceptable but slightly higher.

**5. H-Bond Acceptors:** Ligand A (4) is good, and Ligand B (3) is also good. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.793 and 0.72), indicating good drug-likeness.

**7. DILI:** Ligand A (34.742) has a lower DILI risk than Ligand B (44.513), both are below the 40 threshold.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (63.009) is lower than Ligand B (46.181).

**9. Caco-2 Permeability:** Ligand A (-4.678) shows better Caco-2 permeability than Ligand B (-5.069).

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.863 and -2.898), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.553 and 0.21), which is excellent.

**12. Microsomal Clearance:** Ligand A (-18.552) has significantly lower microsomal clearance than Ligand B (-5.066), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (18.413) has a longer in vitro half-life than Ligand B (-12.013), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.03).

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.1 and -8.5 kcal/mol). Ligand B is slightly better (-8.5 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A is preferable. While both ligands have good binding affinity and acceptable drug-like properties, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic and longer t1/2) and a lower DILI risk. The slightly better Caco-2 permeability also contributes to its favorability. The solubility is a concern for both, but metabolic stability is a higher priority for an enzyme target like SRC kinase.

Output:
0
2025-04-17 14:24:48,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.37 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.8) is higher than the preferred <140, but still reasonable. Ligand B (53.51) is excellent, well below 90, suggesting good absorption.

**logP:** Ligand A (-0.037) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (2.929) is almost perfect.

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

**QED:** Both ligands have good QED scores (0.761 and 0.834), indicating drug-like properties.

**DILI:** Ligand A (54.362) has a moderate DILI risk, while Ligand B (35.983) has a lower, more favorable risk.

**BBB:** Both have reasonable BBB penetration, but Ligand B (74.641) is better than Ligand A (64.211). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 unspecified.

**hERG:** Ligand A (0.218) has a slightly higher hERG risk than Ligand B (0.47), but both are relatively low.

**Microsomal Clearance:** Ligand A (-9.087) has a *negative* microsomal clearance, which is impossible. This suggests a data error. Ligand B (45.081) is moderate, indicating reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (-21.189) has a negative half-life, which is impossible. This also indicates a data error. Ligand B (-4.343) is also negative, indicating a data error.

**P-gp Efflux:** Ligand A (0.051) has very low P-gp efflux, which is good. Ligand B (0.245) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-10.4) has significantly better binding affinity than Ligand B (-8.3). This is a substantial advantage (>1.5 kcal/mol difference).

**Conclusion:**

Despite the issues with negative values for clearance and half-life, the significantly stronger binding affinity of Ligand A (-10.4 kcal/mol vs -8.3 kcal/mol) is a major advantage for an enzyme inhibitor. The lower DILI risk and P-gp efflux of Ligand A are also favorable. The slightly lower logP of Ligand A is a minor concern that could potentially be addressed through further optimization. The negative values for clearance and half-life are concerning and would require investigation, but the binding affinity difference is so large that it outweighs these concerns *assuming the negative values are data errors*.

Output:
1
2025-04-17 14:24:48,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (380.863 Da) is also well within range.

**TPSA:** Ligand A (94.34) is slightly higher than Ligand B (49.85). Both are below the 140 threshold for oral absorption, but B is significantly lower, which is generally favorable.

**logP:** Ligand A (3.811) is at the upper end of the optimal range (1-3), while Ligand B (2.72) is well within. 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 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are acceptable, but B's lower count may offer a slight permeability advantage.

**QED:** Both ligands have reasonable QED scores (A: 0.494, B: 0.666), indicating acceptable drug-likeness, but B is better.

**DILI:** Ligand A has a DILI risk of 67.429, which is considered high risk (>60). Ligand B has a much lower DILI risk of 29.43, which is good (<40). This is a significant advantage for Ligand B.

**BBB:** Ligand A (60.876) and Ligand B (87.088). While not a primary concern for a kinase inhibitor, B has better BBB penetration.

**Caco-2 Permeability:** Ligand A (-5.266) has poor Caco-2 permeability, while Ligand B (-4.359) is also poor, but better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.238 and -2.957 respectively). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.904) has a slightly higher hERG inhibition risk than Ligand B (0.483), which is preferable.

**Microsomal Clearance:** Ligand A (41.329) has a moderate clearance, while Ligand B (33.486) has a lower clearance, suggesting better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand A (18.204) has a shorter half-life than Ligand B (10.501).

**P-gp Efflux:** Ligand A (0.601) and Ligand B (0.193) are both acceptable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both have poor solubility, Ligand B demonstrates significantly better safety (lower DILI risk), metabolic stability (lower Cl_mic), and a slightly better overall ADME profile. The comparable binding affinity makes the superior ADME properties of Ligand B the deciding factor.

Output:
1
2025-04-17 14:24:48,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.374 and 346.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.87) is significantly better than Ligand B (85.25).  A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.796 and 1.732), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (1 & 2) and HBA (5 & 5) counts, well within the guidelines.

**QED:** Both ligands have similar QED scores (0.775 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (68.244) has a slightly lower DILI risk than Ligand B (73.517), which is preferable. Both are acceptable, but lower is better.

**BBB:** Ligand A (70.686) has a better BBB penetration score than Ligand B (56.34). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.539) has a worse Caco-2 permeability than Ligand B (-4.744). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.175) has slightly worse solubility than Ligand B (-2.829). Both are negative, indicating poor solubility, but B is slightly better.

**hERG Inhibition:** Ligand A (0.868) has a slightly higher hERG inhibition risk than Ligand B (0.603). Lower is better, so B is preferable.

**Microsomal Clearance:** Ligand A (34.338) has a slightly lower microsomal clearance than Ligand B (35.622), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (12.163 hours) has a significantly longer half-life than Ligand B (-29.065 hours). This is a major advantage for Ligand A, as it suggests less frequent dosing.

**P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux liability than Ligand B (0.14), which is preferable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it's a significant factor.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. Ligand B has slightly better affinity and Caco-2/solubility. However, the longer half-life and better metabolic stability of Ligand A are crucial for an enzyme inhibitor, outweighing the small affinity advantage of Ligand B. The slightly better solubility and permeability of Ligand B are not enough to compensate for its poor metabolic profile.

Output:
0
2025-04-17 14:24:48,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 367.837 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is well below the 140 threshold for good absorption. Ligand B (121.44) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (0.777 and 0.616), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.664 and 0.5), indicating reasonable drug-likeness.

**DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (61.691), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.862) is higher than Ligand B (31.136).

**Caco-2 Permeability:** Ligand A (-4.976) shows poor permeability, while Ligand B (-5.26) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.746) has better solubility than Ligand B (-2.036).

**hERG:** Both ligands have very low hERG risk (0.179 and 0.193), which is excellent.

**Microsomal Clearance:** Ligand A (30.221) has higher microsomal clearance than Ligand B (-6.235), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-6.571) has a longer in vitro half-life than Ligand A (-2.294), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.01 and 0.014).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.2 and -7.3 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good binding affinity, Ligand B is the more promising candidate. Its lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better Caco-2 permeability outweigh the slightly higher TPSA and lower solubility compared to Ligand A. The enzyme-specific priorities of metabolic stability and lower toxicity strongly favor Ligand B.

Output:
1
2025-04-17 14:24:48,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.495 and 360.361 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (105.34) is still under 140, but less optimal than A.

**logP:** Ligand A (3.126) is within the optimal 1-3 range. Ligand B (0.632) is a bit low, potentially hindering permeation.

**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 similar QED values (0.663 and 0.662), indicating good drug-likeness.

**DILI:** Ligand A (42.613) has a better DILI score than Ligand B (69.872), indicating lower liver injury risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.67) is slightly better than Ligand B (59.984).

**Caco-2 Permeability:** Ligand A (-4.802) is better than Ligand B (-5.19), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.992) is better than Ligand B (-2.717), indicating better solubility.

**hERG:** Both ligands have similar hERG values (0.349 and 0.361), suggesting low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (68.335) has a higher (worse) microsomal clearance than Ligand B (2.579), suggesting lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (-12.197) has a better (longer) in vitro half-life than Ligand A (-11.658).

**P-gp Efflux:** Both ligands have similar P-gp efflux values (0.425 and 0.019), suggesting similar efflux liability.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly better binding affinity than Ligand B (-7.1 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has superior binding affinity, better TPSA, logP, solubility, and DILI risk. However, it has a significantly higher microsomal clearance, indicating poorer metabolic stability. Ligand B has better metabolic stability and half-life, but weaker binding affinity and less favorable solubility and logP.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is a major advantage. While the higher clearance is a concern, it might be addressable through structural modifications. The difference in binding affinity is large enough to potentially compensate for the metabolic liability.

Output:
1
2025-04-17 14:24:48,548 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [359.451, 91.32, 2.11, 3, 5, 0.66, 55.797, 33.501, -5.495, -3.16, 0.247, 39.862, -14.991, 0.067, 0]
**Ligand B:** [337.402, 45.46, 3.734, 1, 5, 0.721, 81, 68.437, -4.725, -3.902, 0.918, 50.753, -2.83, 0.691, -8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (337.402) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** Ligand A (91.32) is higher than Ligand B (45.46).  For an enzyme, TPSA is less critical than for CNS targets, but lower is generally preferred for oral absorption. Ligand B is significantly better here.
3. **logP:** Both are within the optimal range (1-3). Ligand B (3.734) is a bit higher, which *could* raise concerns about solubility or off-target effects, but is still acceptable.
4. **HBD:** Ligand A (3) is higher than Ligand B (1). Lower is generally better for permeability. Ligand B is better.
5. **HBA:** Both have 5 HBA, which is acceptable.
6. **QED:** Both have good QED scores (A: 0.66, B: 0.721), indicating drug-like properties. Ligand B is slightly better.
7. **DILI:** Ligand A (55.797) has a lower DILI risk than Ligand B (81). This is a significant advantage for Ligand A.
8. **BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (68.437) has a higher BBB score, but this is less important here.
9. **Caco-2:** Both have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both compounds.
10. **Solubility:** Both have negative solubility values, indicating poor solubility. This is a significant drawback for both compounds.
11. **hERG:** Ligand A (0.247) has a much lower hERG risk than Ligand B (0.918). This is a major advantage for Ligand A.
12. **Cl_mic:** Ligand A (39.862) has lower microsomal clearance than Ligand B (50.753), suggesting better metabolic stability. This is a positive for Ligand A.
13. **t1/2:** Ligand A (-14.991) has a very negative in vitro half-life, indicating very rapid metabolism. Ligand B (-2.83) is still negative, but much better than Ligand A.
14. **Pgp:** Ligand A (0.067) has lower P-gp efflux liability than Ligand B (0.691). This is a positive for Ligand A.
15. **Binding Affinity:** Ligand B (-8) has a significantly stronger binding affinity than Ligand A (0). This is a *major* advantage for Ligand B. A difference of 8 kcal/mol is substantial and can often outweigh other ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much stronger binding affinity, which is the most important factor. While Ligand B has some ADME liabilities (higher DILI, Pgp efflux, and poorer t1/2), the significantly improved potency is likely to be the dominant factor. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies.

**Conclusion:**

Despite Ligand A's better DILI, hERG, Cl_mic and Pgp profiles, the substantially stronger binding affinity of Ligand B makes it the more promising drug candidate. The potency advantage is likely to outweigh the ADME drawbacks, especially given that formulation strategies can be explored to improve solubility and permeability.

1
2025-04-17 14:24:48,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.419 and 358.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.68) is well below the 140 threshold and good for oral absorption. Ligand B (99.1) is still acceptable but closer to the limit.

**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 (0.821) is below the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is within acceptable limits. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.678 and 0.567), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.51), a significant concern. Ligand B has a very low DILI risk (8.841), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.358) and Ligand B (42.962) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.676 and -4.954), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.843 and -0.914), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.685) has a slightly higher hERG risk than Ligand B (0.158), but both are relatively low.

**Microsomal Clearance:** Ligand A (154.848) has a high microsomal clearance, suggesting poor metabolic stability. Ligand B (16.571) has a much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.317 hours) has a short half-life. Ligand B (-7.856 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or the model.

**P-gp Efflux:** Ligand A (0.257) has low P-gp efflux, which is favorable. Ligand B (0.024) has very low P-gp efflux, which is even more favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.2 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux, but its extremely high DILI risk and poor metabolic stability are major drawbacks. The poor solubility and permeability are also concerning. Ligand B has a significantly lower DILI risk and much better metabolic stability. While its logP is lower and solubility is also poor, the lower DILI and better metabolic stability are critical for an enzyme target like SRC. The negative half-life for Ligand B is a data issue that needs to be investigated, but the other properties are more favorable.

Output:
1
2025-04-17 14:24:48,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.455 and 356.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.37) is better than Ligand B (51.22) as both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (3.005 and 4.031). Ligand B is slightly higher, which *could* present a minor solubility issue, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are well within acceptable limits.

**QED:** Ligand A (0.908) has a significantly better QED score than Ligand B (0.69), indicating a more drug-like profile.

**DILI:** Ligand A (14.424) has a much lower DILI risk than Ligand B (58.123), a significant advantage.

**BBB:** Ligand A (72.354) has a better BBB penetration score than Ligand B (52.268), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.094) has a worse Caco-2 permeability than Ligand B (-4.803).

**Aqueous Solubility:** Ligand A (-2.477) has a better aqueous solubility than Ligand B (-4.878).

**hERG:** Both ligands have low hERG inhibition liability (0.67 and 0.565), which is good.

**Microsomal Clearance:** Ligand A (29.452) has a significantly lower microsomal clearance than Ligand B (75.266), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.481) has a shorter half-life than Ligand B (18.349).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.31 and 0.487).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. Its significantly better binding affinity, lower DILI risk, better QED score, and improved metabolic stability (lower Cl_mic) outweigh the slightly worse Caco-2 permeability and shorter half-life. The strong binding affinity is the most important factor for an enzyme inhibitor, and Ligand A's affinity is considerably better.

Output:
1
2025-04-17 14:24:48,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.4 and 350.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.3) is excellent, well below the 140 threshold for oral absorption. Ligand B (116.4) is still acceptable, but less ideal.

**logP:** Ligand A (0.489) is a bit low, potentially hindering permeability. Ligand B (-0.665) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better balanced. Ligand B (4 HBD, 4 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (0.789 and 0.508), indicating drug-like properties.

**DILI:** Ligand A (55.3) has a moderate DILI risk, while Ligand B (35.9) shows a lower risk, which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.0) is higher than Ligand B (29.1).

**Caco-2 Permeability:** Ligand A (-4.816) is quite poor, suggesting very limited intestinal absorption. Ligand B (-5.696) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.44) and Ligand B (-1.614) both have poor aqueous solubility.

**hERG:** Both ligands have very low hERG risk (0.067 and 0.021), which is excellent.

**Microsomal Clearance:** Ligand B (-13.412) has a significantly lower (better) microsomal clearance than Ligand A (25.787), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (25.286) has a much longer in vitro half-life than Ligand A (-13.385), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.004).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), although the difference is small.

**Conclusion:**

While Ligand A has a slightly better TPSA, Ligand B is superior overall. The key advantages of Ligand B are its significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity. The poor Caco-2 and solubility for both are concerning, but the metabolic stability and safety profile of Ligand B are more critical for an enzyme target. The small affinity difference is less important than the ADME improvements.

Output:
1
2025-04-17 14:24:48,548 - INFO - Batch 294 complete. Total preferences: 4704
2025-04-17 14:24:48,548 - INFO - Processing batch 295/512...
2025-04-17 14:25:32,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.458 Da and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.33) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (84.67) is still under 140, but less favorable than A.

**3. logP:** Ligand A (-0.599) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (1.056) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.687 and 0.88), indicating good drug-like properties.

**7. DILI:** Ligand A (6.32) has a very low DILI risk. Ligand B (41.877) is higher, but still within an acceptable range.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.501) has a better BBB score than Ligand A (36.293), but it's not a primary concern here.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.024) has worse permeability than Ligand B (-5.205).

**10. Aqueous Solubility:** Ligand A (0.656) has better aqueous solubility than Ligand B (-0.864). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.245) has a significantly lower hERG risk than Ligand B (0.071). This is a crucial advantage.

**12. Microsomal Clearance:** Ligand A (-19.659) has *much* lower microsomal clearance (more negative value) than Ligand B (26.764), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-31.215) has a longer in vitro half-life than Ligand B (-11.274), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.046).

**15. Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.5 kcal/mol). This 0.5 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand A presents a superior profile for development as an SRC kinase inhibitor. While Ligand B has slightly better binding affinity and logP, Ligand A excels in crucial areas: significantly lower DILI risk, substantially better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and a much lower hERG risk. The slightly lower logP of Ligand A is a minor drawback that could potentially be addressed with further optimization, but the metabolic and safety advantages of Ligand A are more difficult to improve later in development.

Output:
0
2025-04-17 14:25:32,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.69) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (54.78) is excellent, well below 140.

**logP:** Ligand A (0.662) is a bit low, potentially hindering permeation. Ligand B (1.773) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the threshold of 5.

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

**QED:** Both ligands have good QED scores (0.832 and 0.856), indicating drug-like properties.

**DILI:** Ligand A (42.226) has a lower DILI risk than Ligand B (60.682), which is approaching a higher risk category.

**BBB:** Both have similar BBB penetration (48.856 and 49.244), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.592 and -4.27), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.899 and -2.789), indicating poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.051) has a very low hERG risk, while Ligand B (0.352) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (19.186) has lower microsomal clearance than Ligand B (23.041), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.706) has a significantly longer in vitro half-life than Ligand B (-8.983), a substantial advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.011 and 0.209).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.7 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Despite both having similar binding affinities, Ligand A is the better candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a significantly lower hERG risk. While both have poor solubility and permeability, the improved safety and pharmacokinetic profile of Ligand A outweigh the slight disadvantage in logP.

Output:
0
2025-04-17 14:25:32,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.483 Da) is slightly higher than Ligand B (361.471 Da), but both are acceptable.

**TPSA:** Ligand A (103.6) is slightly higher than Ligand B (80.12). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.003) is lower than Ligand B (2.189). Both are within the optimal range of 1-3, but Ligand B is better positioned.

**H-Bond Donors/Acceptors:** Ligand A has 0 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 (Ligand A: 0.713, Ligand B: 0.909), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (74.176) has a higher DILI risk than Ligand B (69.407). Lower is better, so Ligand B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (46.375) is lower than Ligand B (62.97).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.522) is slightly worse than Ligand B (-4.875).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-4.547) is slightly better than Ligand B (-2.137).

**hERG:** Both ligands have low hERG risk (Ligand A: 0.413, Ligand B: 0.171). Ligand B is preferable.

**Microsomal Clearance:** Ligand A (81.662) has significantly higher microsomal clearance than Ligand B (28.799), indicating poorer metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-0.228) has a negative half-life, which is concerning. Ligand B (34.867) has a much more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.084, Ligand B: 0.159).

**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 enough to be considered, especially given the other factors.

**Overall Assessment:**

Ligand B is clearly the better candidate. It has a better logP, lower DILI risk, better metabolic stability (lower Cl_mic and a positive half-life), better hERG risk, and slightly better binding affinity. While both have issues with Caco-2 and solubility, Ligand A's poor metabolic stability and negative half-life are significant drawbacks. The slightly better affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 14:25:32,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 357.495 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good absorption. Ligand B (90.9) is still acceptable, but closer to the limit.

**logP:** Ligand A (1.971) is optimal. Ligand B (0.515) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also good, within the recommended limits.

**QED:** Ligand A (0.759) is strong, indicating good drug-likeness. Ligand B (0.589) is acceptable, but less optimal.

**DILI:** Ligand A (19.542) has a very low DILI risk. Ligand B (9.926) is also low risk, but slightly higher than A.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (65.374) is better than Ligand B (24.002).

**Caco-2 Permeability:** Ligand A (-4.757) has poor Caco-2 permeability. Ligand B (-5.248) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.679) has poor aqueous solubility. Ligand B (-0.724) is better, but still not great.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.321 and 0.216, respectively).

**Microsomal Clearance:** Ligand A (43.727) has moderate clearance. Ligand B (24.74) has lower clearance, indicating better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (9.231) has a moderate half-life. Ligand B (12.048) has a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.042 and 0.01, respectively).

**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 and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's superior binding affinity, the combination of Ligand B's better metabolic stability (lower Cl_mic, longer t1/2), slightly better solubility, and acceptable DILI risk makes it the more promising candidate. While Ligand A has a better affinity, its poor Caco-2 permeability and solubility are significant concerns for oral bioavailability. The affinity difference is large, but SRC is not a target where extremely high potency is absolutely required, and optimizing ADME properties is crucial for a viable drug.

Output:
1
2025-04-17 14:25:32,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.5) is slightly higher than Ligand B (345.4).

**TPSA:** Ligand A (49.85) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (127.94) is higher, but still acceptable.

**logP:** Ligand A (3.58) is optimal. Ligand B (-0.621) is significantly lower, potentially hindering membrane permeability and absorption.

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

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (10) is at the upper limit of acceptability.

**QED:** Both ligands have good QED scores (A: 0.592, B: 0.681), indicating drug-like properties.

**DILI:** Ligand A (28.5) has a much lower DILI risk than Ligand B (65.9). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.5) is higher than Ligand B (54.1).

**Caco-2 Permeability:** Ligand A (-4.481) is poor, while Ligand B (-5.383) is also poor. Both are negative values, which is unusual and suggests low permeability.

**Aqueous Solubility:** Ligand A (-3.236) is poor, while Ligand B (-1.847) is also poor. Both are negative values, which is unusual and suggests low solubility.

**hERG Inhibition:** Ligand A (0.777) has a lower hERG risk than Ligand B (0.029). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (48.04) is higher than Ligand B (23.552), suggesting faster clearance and lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-3.513) is negative, indicating a very short half-life. Ligand B (3.905) is positive, suggesting a longer half-life. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux than Ligand B (0.046). This is a slight advantage for Ligand A.

**Binding Affinity:** Ligand B (-9.3) has a significantly stronger binding affinity than Ligand A (-8.6). This is a crucial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, it has a higher DILI risk, lower logP, and higher HBA count. Ligand A has better DILI and hERG profiles, but its solubility, permeability, and metabolic stability are concerning. The strong affinity of Ligand B is the most important factor for an enzyme inhibitor, and the difference in binding is substantial. While the ADME properties of Ligand B are not ideal, they could potentially be improved through further optimization.

Output:
1
2025-04-17 14:25:32,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.393 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (86.88). A TPSA below 140 is desirable for oral absorption, and both meet this, but A is much closer to the ideal for good permeability.

**logP:** Ligand A (4.724) is slightly higher than the optimal range (1-3), potentially causing solubility issues, while Ligand B (2.786) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.849 and 0.783), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (65.103 and 64.754).

**BBB:** Ligand A (70.415) shows better BBB penetration than Ligand B (44.668), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.343) has a much better Caco-2 permeability than Ligand B (-5.372), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.067) has better aqueous solubility than Ligand B (-3.201).

**hERG:** Ligand A (0.791) has a lower hERG risk than Ligand B (0.535), which is a significant advantage.

**Microsomal Clearance:** Ligand A (100.262) has a higher microsomal clearance than Ligand B (4.756), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (19.095) has a shorter in vitro half-life than Ligand B (-7.076), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.356) shows lower P-gp efflux than Ligand B (0.193), which is favorable.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a significantly better binding affinity than Ligand A (-10.3 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better solubility, permeability, and lower hERG risk, the significantly superior binding affinity of Ligand B (-0.0 kcal/mol vs -10.3 kcal/mol) outweighs the ADME advantages of Ligand A. The lower metabolic stability of Ligand A (higher Cl_mic, shorter t1/2) is also a critical concern. The binding affinity difference is substantial enough to overcome the slightly less favorable logP and TPSA values of Ligand B.

Output:
1
2025-04-17 14:25:32,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.29 and 344.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (111.54) is better than Ligand B (49.41) as it is below the 140 A^2 threshold for good oral absorption. Ligand B is excellent.

**logP:** Ligand A (0.86) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (3.132) is within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBAs, which is acceptable. Ligand B has 2 HBAs, which is excellent.

**QED:** Both ligands have good QED scores (0.419 and 0.855), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A has a DILI risk of 85.77, which is high. Ligand B has a much lower DILI risk of 25.785, which is good.

**BBB:** Both ligands have good BBB penetration (72.237 and 84.606). This is less critical for a non-CNS target like SRC.

**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 (0.214) has a slightly higher hERG risk than Ligand B (0.48), but both are relatively low.

**Microsomal Clearance:** Ligand A (31.671) has lower microsomal clearance than Ligand B (72.056), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.721) has a longer half-life than Ligand B (-4.436), which is desirable.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux than Ligand B (0.22), which is preferable.

**Binding Affinity:** Ligand A (-10 kcal/mol) has significantly better binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage.

**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 and poor solubility/permeability. Ligand B has a better safety profile (lower DILI), better logP, and fewer HBAs, but its binding affinity is considerably weaker.

The difference in binding affinity (-10 vs -6.5 kcal/mol) is a 3.5 kcal/mol advantage for Ligand A, which is substantial enough to potentially outweigh the higher DILI risk and poor solubility/permeability, *provided* formulation strategies can be developed to address the solubility issues. The poor Caco-2 and solubility values are concerning, but the potency advantage is significant.

Output:
1
2025-04-17 14:25:32,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 better than Ligand B (81.34). Lower TPSA generally improves oral absorption.

**logP:** Ligand A (0.969) is slightly lower than the optimal range (1-3), but still acceptable. Ligand B (3.231) is within the optimal range.

**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:** Ligand B (0.861) has a higher QED score than Ligand A (0.574), indicating a more drug-like profile.

**DILI:** Ligand B (63.746) has a higher DILI risk than Ligand A (12.834). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (79.992) has a higher BBB score than Ligand A (61.07).

**Caco-2 Permeability:** Ligand A (-5.136) has a worse Caco-2 permeability than Ligand B (-4.947).

**Aqueous Solubility:** Ligand A (-1.049) has a better solubility than Ligand B (-3.596). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.053) has a much lower hERG inhibition risk than Ligand B (0.569). This is a critical advantage.

**Microsomal Clearance:** Ligand A (-12.565) has a significantly lower (better) microsomal clearance than Ligand B (56.297), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.997) has a much longer half-life than Ligand B (6.633).

**P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux than Ligand B (0.117), which could improve bioavailability.

**Binding Affinity:** Ligand B (-7.5) has a stronger binding affinity than Ligand A (-6.8). This is a 1.7 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and QED, but suffers from higher DILI risk, poorer solubility, higher hERG inhibition, and worse metabolic stability (higher clearance, shorter half-life). Ligand A has a significantly better safety profile (lower DILI, hERG), better metabolic stability, and better solubility. The 1.7 kcal/mol difference in binding affinity is significant, but the ADME/Tox profile of Ligand A is far superior. Given the enzyme-specific priorities, the improved metabolic stability and reduced toxicity of Ligand A are more important than the slightly stronger binding of Ligand B.

Output:
0
2025-04-17 14:25:32,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (367.515 Da and 376.953 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is above the preferred <140 for good oral absorption, but not drastically so. Ligand B (25.36) is excellent, well below 90, suggesting good permeability.

**3. logP:** Ligand A (2.481) is within the optimal 1-3 range. Ligand B (4.842) is slightly high, potentially leading to solubility issues and off-target interactions, but not extreme.

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

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

**6. QED:** Ligand A (0.868) is excellent, indicating a highly drug-like profile. Ligand B (0.721) is also good, but slightly lower than A.

**7. DILI:** Ligand A (47.77) is good, indicating low liver injury risk. Ligand B (14.618) is *very* good, even lower risk.

**8. BBB:** Ligand A (61.535) is moderate. Ligand B (93.292) is excellent, suggesting good potential for CNS penetration, though this is less critical for SRC kinase which is not a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.884) is poor. Ligand B (-5.241) is also poor. Both are negative values, indicating low permeability.

**10. Aqueous Solubility:** Ligand A (-2.262) is poor. Ligand B (-3.946) is even worse. Solubility is a concern for both.

**11. hERG Inhibition:** Ligand A (0.447) is good, low risk. Ligand B (0.824) is slightly higher, indicating a moderate risk, but still acceptable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (64.282) is relatively high, suggesting faster metabolism. Ligand B (52.504) is lower, indicating better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (11.743) is moderate. Ligand B (-4.789) is very poor, indicating rapid degradation.

**14. P-gp Efflux:** Ligand A (0.185) is good, low efflux. Ligand B (0.582) is moderate.

**15. Binding Affinity:** Ligand B (-8.0) is significantly stronger than Ligand A (-0.0). This is a crucial difference.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison & Decision:**

Ligand B has a *much* stronger binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol). This is a decisive advantage that can often outweigh other drawbacks. While Ligand B has poor solubility and a very short half-life, these can be addressed through formulation strategies or further chemical modifications. Ligand A has better solubility and half-life, but its binding affinity is essentially non-existent. The lower DILI risk and better metabolic stability of Ligand B are also favorable.

Output:
1
2025-04-17 14:25:32,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.869 and 347.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (56.33) is significantly better than Ligand B (97.37). A TPSA below 140 is desirable for oral absorption, and both meet this, but A is much closer to the preferred range for good permeability.

**logP:** Both ligands have good logP values (3.979 and 3.061), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 5. Lower HBA is generally preferred for permeability, giving an edge to Ligand A.

**QED:** Both have reasonable QED scores (0.81 and 0.765), indicating good drug-like properties.

**DILI:** Ligand A (39.667) has a much lower DILI risk than Ligand B (60.682).  This is a significant advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (67.352) is better than Ligand B (55.913).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.994 and -4.869), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without more context.

**Aqueous Solubility:** Both have negative solubility values (-4.288 and -3.27). This is concerning and suggests poor solubility, which could hinder bioavailability.

**hERG Inhibition:** Ligand A (0.811) has a lower hERG risk than Ligand B (0.452), which is favorable.

**Microsomal Clearance:** Ligand A (4.097) has significantly lower microsomal clearance than Ligand B (56.604), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (31.206 hours) has a longer half-life than Ligand B (41.61 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.369 and 0.379).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme target. However, Ligand A has significantly better ADME properties: lower DILI risk, lower microsomal clearance (better metabolic stability), and a better TPSA. The solubility and permeability issues are shared by both, and are concerning.

Despite the superior affinity of Ligand B, the poor ADME profile, especially the high DILI risk and high clearance, makes it less likely to be a viable drug candidate. The significantly better ADME profile of Ligand A, despite its weaker binding, makes it a more promising starting point for optimization. Further optimization of Ligand A could potentially improve its binding affinity while maintaining its favorable ADME properties.

Output:
0
2025-04-17 14:25:32,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.5 and 345.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.72 and 70.15) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.861) is slightly low, potentially hindering permeation. Ligand B (3.198) is within the optimal 1-3 range.

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

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

**QED:** Both ligands have good QED scores (0.58 and 0.828), indicating drug-like properties.

**DILI:** Ligand A (18.573) has a significantly lower DILI risk than Ligand B (37.456), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (88.29) has a higher BBB percentile than Ligand A (46.84).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poorer permeability. They are relatively similar.

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. Ligand A (-2.229) is slightly better than Ligand B (-3.586).

**hERG Inhibition:** Ligand A (0.134) has a much lower hERG risk than Ligand B (0.698), a critical safety parameter.

**Microsomal Clearance:** Ligand A (1.839) has significantly lower microsomal clearance than Ligand B (67.375), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.262) has a much longer in vitro half-life than Ligand B (1.212), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux than Ligand B (0.152), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.6 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.

**Overall:**

Ligand A demonstrates superior ADME properties, particularly regarding DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A in safety and pharmacokinetic parameters make it the more promising drug candidate.

Output:
0
2025-04-17 14:25:32,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.4 and 341.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (118.8 and 113.0 A^2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.03 and 0.96), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBDs, which is good. Ligand A has 7 HBAs and Ligand B has 6 HBAs, both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.749 and 0.812), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (60.3 and 58.5), which is acceptable, being below the 60 threshold.

**BBB:** Ligand A has a much higher BBB penetration percentile (91.5) compared to Ligand B (44.4). While not a primary concern for a non-CNS target like SRC, it doesn't detract from Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.054 and -5.058). This is unusual and suggests poor permeability. However, these values might be experimental artifacts or indicate a need for formulation strategies to enhance absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.625 and -3.429). This is also concerning and suggests poor aqueous solubility, potentially hindering bioavailability. Formulation strategies would be crucial.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.091 and 0.111), which is excellent.

**Microsomal Clearance:** Ligand A exhibits significantly lower microsomal clearance (-11.44 mL/min/kg) than Ligand B (12.13 mL/min/kg). This indicates better metabolic stability for Ligand A, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A has a shorter in vitro half-life (4.61 hours) compared to Ligand B (24.60 hours). This is a drawback for Ligand A, as a longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.03).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.3 kcal/mol) than Ligand A (-7.9 kcal/mol). This 0.4 kcal/mol difference is significant, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity and a significantly longer half-life, which are key advantages for an enzyme inhibitor. However, Ligand A has better metabolic stability (lower Cl_mic) and better BBB penetration. Both have poor solubility and permeability. The affinity difference is substantial enough to favor Ligand B, assuming formulation strategies can address the solubility and permeability issues.

Output:
1
2025-04-17 14:25:32,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (339.399 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 A (84.83) is slightly better than Ligand B (87.15).

**logP:** Ligand A (2.643) is optimal (1-3). Ligand B (0.168) is quite low, potentially hindering membrane permeability and absorption. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.763, B: 0.701), indicating good drug-like properties.

**DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (34.277). This is a negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.309) has a higher BBB percentile than Ligand A (57.736), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-5.183) has a more negative Caco-2 value, suggesting *lower* permeability. Ligand B (-4.465) is better in this regard.

**Aqueous Solubility:** Ligand A (-4.462) has a slightly better (less negative) solubility score than Ligand B (-1.052), indicating better solubility.

**hERG Inhibition:** Ligand A (0.756) has a slightly higher hERG risk than Ligand B (0.253). Lower is better, favoring Ligand B.

**Microsomal Clearance:** Ligand A (32.694 mL/min/kg) has a higher clearance than Ligand B (13.717 mL/min/kg), meaning Ligand B is more metabolically stable. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (22.438 hours) has a longer half-life than Ligand B (-32.37 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 (A: 0.082, B: 0.026), which is good.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for Ligand A. The 1.2 kcal/mol difference is large enough to potentially offset some ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and slightly better solubility, but suffers from higher DILI risk, lower Caco-2 permeability, and higher hERG risk. Ligand B has better metabolic stability (lower Cl_mic), lower DILI and hERG risk, and better Caco-2 permeability, but its logP is very low and its half-life is extremely short.

The difference in binding affinity is substantial. Given that we're targeting an enzyme (kinase), potency is paramount. While Ligand B has better ADME properties in some respects, the extremely short half-life is a major issue. Even with good metabolic stability (low Cl_mic), a negative half-life suggests rapid degradation through other pathways. The low logP is also a significant concern for oral bioavailability.

Therefore, I believe Ligand A, despite its drawbacks, is the more promising candidate due to its significantly stronger binding affinity. Further optimization could address the DILI, permeability, and hERG concerns.

Output:
0
2025-04-17 14:25:32,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.39 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (60.23), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.085 and 3.666), 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.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is preferable to Ligand B (0 HBD, 7 HBA). While both are within acceptable limits, a balance is generally desired.

**QED:** Ligand A (0.871) has a significantly higher QED score than Ligand B (0.543), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (35.983 and 35.13 percentile), which is good.

**BBB:** Ligand A (73.75) has a better BBB penetration score than Ligand B (51.687), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.017) has a worse Caco-2 permeability than Ligand B (-5.526).

**Aqueous Solubility:** Ligand A (-3.952) has a better aqueous solubility than Ligand B (-2.936). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.483) has a lower hERG inhibition liability than Ligand B (0.855), which is a significant advantage.

**Microsomal Clearance:** Ligand A (16.745 mL/min/kg) has a much lower microsomal clearance than Ligand B (76.429 mL/min/kg), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (10.658 hours) has a shorter half-life than Ligand B (42.96 hours). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux liability than Ligand B (0.6).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.5 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 half-life, Ligand A excels in critical areas: QED, hERG risk, metabolic stability (lower Cl_mic), solubility, and P-gp efflux. The superior metabolic stability and reduced toxicity risk of Ligand A outweigh the slightly shorter half-life, especially given the strong binding affinity of both compounds.

Output:
1
2025-04-17 14:25:32,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 362.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.09) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (59.07) is well within the ideal range.

**logP:** Ligand A (1.109) is optimal. Ligand B (4.053) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but not critically high.

**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, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.708 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (43.738) has a slightly better DILI risk profile than Ligand B (55.448), both are acceptable.

**BBB:** Ligand A (61.38) has a lower BBB penetration than Ligand B (86.623). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.915) has a worse Caco-2 permeability than Ligand B (-5.209).

**Aqueous Solubility:** Ligand A (-1.535) has a better aqueous solubility than Ligand B (-4.355). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.103) has a significantly lower hERG inhibition risk than Ligand B (0.745). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (44.388) has lower microsomal clearance than Ligand B (78.082), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (43.086) has a longer in vitro half-life than Ligand A (22.293). This is a positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.013) has a significantly lower P-gp efflux liability than Ligand B (0.246), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.6 kcal/mol). The 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 a longer half-life and better BBB penetration (irrelevant here), Ligand A boasts a significantly better binding affinity, lower hERG risk, lower P-gp efflux, and better solubility, and lower microsomal clearance. The superior binding affinity and improved safety profile (hERG, P-gp) are crucial for an enzyme inhibitor, and the slightly lower metabolic stability can potentially be addressed through further optimization.

Output:
0
2025-04-17 14:25:32,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (354.451 and 346.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (105.48 and 105.82) slightly above the optimal <140 for oral absorption, but not drastically so.

**3. logP:** Ligand A (0.236) is quite low, potentially hindering permeation. Ligand B (1.484) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is at the upper limit, while Ligand B (2) is better.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.589 and 0.812), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (27.026) has a much lower DILI risk than Ligand B (50.136), which is a substantial advantage.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (49.787) than Ligand A (29.12), but this is less critical.

**9. Caco-2 Permeability:** Both ligands have similar and very poor Caco-2 permeability (-5.194 and -5.144). This is a concern for oral bioavailability for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.714 and -2.436). This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.082 and 0.062).

**12. Microsomal Clearance:** Ligand B (-14.384) has significantly lower (better) microsomal clearance than Ligand A (36.056), indicating better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (25.431) has a longer in vitro half-life than Ligand A (7.181), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.1 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. Ligand B excels in metabolic stability (Cl_mic and t1/2) and has a slightly better logP. Ligand A has a better DILI score. However, metabolic stability is often more critical than DILI risk, as it directly impacts drug exposure. The poor solubility and Caco-2 permeability are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:25:32,486 - INFO - Batch 295 complete. Total preferences: 4720
2025-04-17 14:25:32,486 - INFO - Processing batch 296/512...
2025-04-17 14:26:12,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.421 and 348.393 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is slightly higher than Ligand B (50.36), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have logP values within the optimal range (2.838 and 3.714). Ligand B is slightly higher, potentially impacting solubility but not drastically.

**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 (0.906) has a significantly better QED score than Ligand B (0.715), indicating a more drug-like profile.

**DILI:** Ligand A (62.001) has a slightly higher DILI risk than Ligand B (51.493), but both are reasonably acceptable, being below the 60 threshold.

**BBB:** Both ligands have good BBB penetration (80.225 and 83.831), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.916 and -4.616), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.11 and -4.432), which is a major drawback.

**hERG Inhibition:** Ligand A (0.314) has a much lower hERG inhibition risk than Ligand B (0.967), which is a significant advantage.

**Microsomal Clearance:** Ligand A (33.348 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (69.969 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (16.609 hours) has a longer half-life than Ligand B (-1.784 hours). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.282) has lower P-gp efflux than Ligand B (0.566), which is favorable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some of the ADME concerns.

**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 QED score, lower hERG risk, lower microsomal clearance (better metabolic stability), and longer half-life. The poor solubility and Caco-2 permeability are concerns for both, but the ADME profile of Ligand A is considerably more favorable overall. Ligand B's negative in vitro half-life is a major red flag. The affinity difference, while notable, is unlikely to overcome the substantial ADME liabilities of Ligand B.

Output:
0
2025-04-17 14:26:12,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.39 and 344.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.08) is higher than Ligand B (67.43). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.676) is slightly low, potentially hindering permeability. Ligand B (2.005) is 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 acceptable.

**QED:** Ligand A (0.886) has a significantly better QED score than Ligand B (0.638), indicating a more drug-like profile overall.

**DILI:** Ligand A (63.13) has a higher DILI risk than Ligand B (23.89). This is a significant drawback for Ligand A.

**BBB:** Ligand A (23.54) has very low BBB penetration, while Ligand B (67.58) is moderately good. This isn't a primary concern for a non-CNS target like SRC, but it's a point in favor of Ligand B.

**Caco-2 Permeability:** Ligand A (-5.201) has poor Caco-2 permeability, while Ligand B (-4.648) is better, though still not ideal.

**Aqueous Solubility:** Ligand A (-1.882) has poor aqueous solubility, while Ligand B (-3.022) is also poor. This is a concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.134) has a slightly lower hERG risk than Ligand B (0.338), which is favorable.

**Microsomal Clearance:** Ligand A (-10.264) has significantly better metabolic stability (lower clearance) than Ligand B (66.721). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-9.881) has a much longer in vitro half-life than Ligand B (-4.481), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, while Ligand B (0.158) has slightly higher efflux.

**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.

**Overall Assessment:**

Ligand A has superior metabolic stability (Cl_mic, t1/2), a better QED score, and lower P-gp efflux. However, it suffers from poor solubility, permeability, and a higher DILI risk. Ligand B has better logP, TPSA, and binding affinity, but its metabolic stability is a major concern.

The binding affinity difference (0.5 kcal/mol) is notable, but the significantly better metabolic stability of Ligand A, coupled with its better QED, makes it the more promising candidate, *provided* the solubility and permeability issues can be addressed through formulation or further structural modifications. The DILI risk is also a concern, but potentially mitigable.

Output:
0
2025-04-17 14:26:12,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 and 368.587 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (40.62), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.495 and 3.65), 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:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 3 HBA, well below the limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.773 and 0.657), indicating good drug-like properties.

**DILI:** Ligand A (10.392) has a significantly lower DILI risk than Ligand B (17.759). This is a substantial advantage.

**BBB:** Ligand B (85.925) has a higher BBB penetration percentile than Ligand A (68.554). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both have negative values (-4.675 and -4.75), which 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 values (-2.602 and -3.347), indicating poor solubility. Ligand B is slightly worse.

**hERG:** Both ligands show low hERG inhibition liability (0.539 and 0.601), which is good.

**Microsomal Clearance:** Ligand A (28.48) has a significantly lower microsomal clearance than Ligand B (82.217). This indicates better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-2.193) has a negative half-life, which is unusual and suggests a very short half-life. Ligand B (1.957) has a positive half-life, indicating a longer duration of action. This is a significant drawback for Ligand A.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.209 and 0.433).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.3 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has better BBB penetration (irrelevant here) and in vitro half-life, Ligand A demonstrates significantly lower DILI risk and microsomal clearance, indicating better safety and metabolic stability. The binding affinities are comparable. The solubility and Caco-2 permeability are poor for both, but the other advantages of Ligand A outweigh these drawbacks.

Output:
0
2025-04-17 14:26:12,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.446 and 370.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.53) is well below the 140 threshold, while Ligand B (107.94) is still acceptable but higher. This favors Ligand A for better absorption.

**logP:** Ligand A (2.777) is optimal (1-3). Ligand B (0.209) is quite low, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (1 & 2) and HBA (5) counts, within the acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.813 and 0.697), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (60.062 and 59.907), placing them in a moderate risk category, but not alarming.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (83.986) has a higher percentile than Ligand B (61.38).

**Caco-2 Permeability:** Ligand A (-4.729) shows poor permeability, while Ligand B (-5.368) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-4.335) and Ligand B (-3.075) have poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.453 and 0.157), which is positive.

**Microsomal Clearance:** Ligand B (33.193) has significantly lower microsomal clearance than Ligand A (59.226), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-16.241) has a slightly longer half-life than Ligand A (-19.23), although both are negative values.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.134 and 0.031), which is favorable.

**Binding Affinity:** Ligand A (-7.9) has a slightly stronger binding affinity than Ligand B (-7.5). While the difference is less than the 1.5 kcal/mol threshold, it's still a factor.

**Conclusion:**

While Ligand A has slightly better binding affinity and TPSA, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and a more reasonable logP value. The poor Caco-2 permeability and solubility are concerning for both, but the lower logP of Ligand B is more problematic for absorption. Considering the enzyme-specific priorities (potency, metabolic stability, solubility, hERG), the improved metabolic stability of Ligand B outweighs the slightly weaker binding affinity.

Output:
1
2025-04-17 14:26:12,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.813 and 360.424 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.39) is slightly higher than Ligand B (50.16). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (2.773 and 3.276), 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.603 and 0.735), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 74.99, which is concerning (high risk). Ligand B has a much lower DILI risk of 23.226 (good). This is a major advantage for Ligand B.

**BBB:** Both ligands have high BBB penetration (91.276 and 91.625), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.727 and -4.656). This is unusual and suggests poor permeability. However, negative values are sometimes artifacts of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.778 and -3.417). This is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.342) has a slightly lower hERG risk than Ligand B (0.476), which is preferable.

**Microsomal Clearance:** Ligand A (90.298) has a higher microsomal clearance than Ligand B (42.926). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (16.81) has a significantly longer in vitro half-life than Ligand A (-4.485). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.085), which is preferable.

**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.

**Conclusion:**

While both ligands have good potency, Ligand B is significantly better due to its much lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The slightly higher hERG risk for Ligand B is a minor concern compared to the significant DILI risk of Ligand A. The Caco-2 and solubility values are concerning for both, but the ADME profile of B is superior overall.

Output:
1
2025-04-17 14:26:12,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (64.68), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.045) is optimal, while Ligand B (1.212) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), keeping within the desired range of <=5.

**H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (5), keeping within the desired range of <=10.

**QED:** Both ligands have good QED scores (0.65 and 0.796, respectively), indicating drug-likeness.

**DILI:** Ligand A (9.965) has a significantly lower DILI risk than Ligand B (13.339), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (75.107 and 74.292), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.518) is better than Ligand B (-5.448), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.306) is better than Ligand B (-2.052), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.361 and 0.498).

**Microsomal Clearance:** Ligand A (56.24) has a significantly lower Cl_mic than Ligand B (13.153), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.02) has a longer half-life than Ligand B (9.013).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.103 and 0.017).

**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 substantially better binding affinity, Ligand A demonstrates superior ADME properties across multiple critical parameters (DILI, Cl_mic, t1/2, solubility, Caco-2). The difference in binding affinity is large enough to overcome the ADME drawbacks of Ligand B. A binding affinity of -7.0 kcal/mol is excellent, and the other properties of Ligand B are not ideal.

Output:
1
2025-04-17 14:26:12,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 356.482 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for good oral absorption, but B is better.

**logP:** Both ligands have good logP values (3.041 and 2.539), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.603 and 0.763), indicating good drug-like properties.

**DILI:** Ligand B (8.414) has a significantly lower DILI risk than Ligand A (24.544). This is a major advantage for Ligand B.

**BBB:** Ligand B (92.71) has a much higher BBB penetration percentile than Ligand A (48.391). While not critical for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-5.046) has worse Caco-2 permeability than Ligand B (-4.397). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.46) has worse aqueous solubility than Ligand B (-2.582). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.617) has slightly higher hERG inhibition liability than Ligand B (0.557). Lower is better, so B is preferable.

**Microsomal Clearance:** Ligand B (27.423) has significantly lower microsomal clearance than Ligand A (74.464). This indicates better metabolic stability for Ligand B, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-22.141) has a longer in vitro half-life than Ligand A (-15.141). This is another advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.154) has slightly higher P-gp efflux liability than Ligand B (0.095). Lower is better, so B is preferable.

**Binding Affinity:** Ligand B (-8.4) has slightly better binding affinity than Ligand A (-7.9). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most crucial ADME-Tox properties. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, lower hERG risk, and slightly better binding affinity. While both have poor Caco-2 permeability, the other advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 14:26:12,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.387 and 363.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.11) is better than Ligand B (113.66), both are acceptable but closer to the upper limit for good absorption.

**3. logP:** Ligand A (-0.03) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (0.216) is also on the lower side, but marginally better.

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

**5. H-Bond Acceptors:** Both ligands (A: 6, B: 6) are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.773, B: 0.692), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (A: 41.76, B: 45.328), below the 60 threshold.

**8. BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (55.603) is better than Ligand B (38.465).

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.817) is slightly better than Ligand B (-5.452).

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-1.496) is slightly better than Ligand B (-2.44).

**11. hERG Inhibition:** Both ligands have very low hERG risk (A: 0.102, B: 0.319), which is excellent.

**12. Microsomal Clearance:** Ligand A (10.649) has significantly lower microsomal clearance than Ligand B (-27.508). This suggests better metabolic stability for Ligand A, a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-12.186) has a negative half-life, which is concerning. Ligand B (14.509) has a positive half-life, indicating better in vitro stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.012, B: 0.071).

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and in vitro half-life, Ligand A demonstrates superior metabolic stability (lower Cl_mic) and slightly better solubility and permeability. The difference in binding affinity is not substantial enough to outweigh the significant advantage in metabolic stability for a kinase inhibitor, where maintaining therapeutic concentrations is crucial. The negative half-life for Ligand A is a major concern.

Output:
1
2025-04-17 14:26:12,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (340.43 and 354.49 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.49) is better than Ligand B (78.87). Both are below 140, supporting oral absorption.

**3. logP:** Both ligands have good logP values (2.496 and 1.563), 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 reasonable QED scores (0.846 and 0.693), indicating good drug-likeness.

**7. DILI:** Ligand A (34.703) has a significantly lower DILI risk than Ligand B (11.361). This is a major advantage.

**8. BBB:** Both ligands have similar BBB penetration (68.09 and 67.66). This isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.336) has worse Caco-2 permeability than Ligand B (-4.608).

**10. Aqueous Solubility:** Ligand A (-1.449) has worse aqueous solubility than Ligand B (-1.786).

**11. hERG Inhibition:** Ligand A (0.673) has a slightly better hERG profile than Ligand B (0.366), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-42.889) has *much* lower microsomal clearance than Ligand B (17.388). This indicates significantly better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (38.069) has a longer in vitro half-life than Ligand B (-5.921). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux than Ligand B (0.077).

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-6.6). While both are good, the 1 kcal/mol difference is notable.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better Caco-2 permeability and solubility, Ligand A excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), slightly better hERG profile, and slightly better binding affinity. The superior metabolic stability and safety profile of Ligand A outweigh the minor drawbacks in permeability and solubility.

Output:
1
2025-04-17 14:26:12,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.434 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (79.53). A TPSA below 140 is desirable for oral absorption, and both meet this, but A is much closer to the optimal range for permeability.

**logP:** Ligand A (3.056) is optimal, while Ligand B (1.876) is a bit low, potentially hindering permeation.

**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 HBA limit.

**QED:** Both ligands have very similar and high QED scores (0.906 and 0.904), indicating good drug-likeness.

**DILI:** Ligand A (49.399) has a higher DILI risk than Ligand B (21.753). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (94.378) shows better BBB penetration than Ligand A (83.249).

**Caco-2 Permeability:** Ligand A (-4.749) has slightly better Caco-2 permeability than Ligand B (-4.894), but both are negative values, which is not ideal.

**Aqueous Solubility:** Ligand A (-3.096) has slightly better aqueous solubility than Ligand B (-2.55), but both are negative values, which is not ideal.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.765 and 0.772), which is positive.

**Microsomal Clearance:** Ligand B (15.792) has significantly lower microsomal clearance than Ligand A (39.861), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (17.975) has a longer half-life than Ligand B (-12.694). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.268 and 0.041).

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better solubility and half-life, Ligand B is superior overall. The significantly stronger binding affinity (-10.2 vs -8.7 kcal/mol) and lower DILI risk are major advantages. The improved metabolic stability (lower Cl_mic) is also critical for an enzyme target. The slightly lower logP of Ligand B is a minor concern, but the potency advantage outweighs this.

Output:
1
2025-04-17 14:26:12,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (399.263 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (34.89) is excellent, well below the 140 threshold for oral absorption. Ligand B (76.46) is still acceptable but higher, potentially impacting absorption.

**3. logP:** Ligand A (4.823) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.49) is optimal.

**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 (3 for A, 5 for B), below the limit of 10.

**6. QED:** Both ligands have good QED values (0.59 and 0.79), indicating drug-like properties.

**7. DILI:** Ligand A (60.915) is approaching a concerning DILI risk, while Ligand B (33.812) is very good. This is a significant advantage for B.

**8. BBB:** Both ligands have high BBB penetration (82.047 and 82.435), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.762 and -4.759), which is unusual and suggests poor permeability. This is a concern for both, but the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.242 and -1.787), indicating poor aqueous solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.814) has a slightly higher hERG risk than Ligand B (0.434), which is preferable.

**12. Microsomal Clearance:** Ligand A (49.193) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (21.324) is significantly better in this regard.

**13. In vitro Half-Life:** Ligand A (27.319) has a longer half-life than Ligand B (16.086), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.967 and 0.115), which is good.

**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 for 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 the primary driver for enzyme inhibitors. However, it has a higher DILI risk, higher microsomal clearance (lower metabolic stability), and a slightly higher hERG risk. Ligand B has better ADME properties (lower DILI, better metabolic stability, better logP) but weaker binding affinity.

Given the substantial affinity difference, the benefit of Ligand A's potency likely outweighs the ADME concerns, *provided* the DILI risk can be mitigated through further structural modifications. The difference in binding affinity is significant enough to prioritize this ligand for further optimization.

Output:
1
2025-04-17 14:26:12,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 349.395 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (109.39) is better than Ligand B (118.03), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.75) is slightly better than Ligand B (0.312), both are a little low, potentially impacting permeability, but not drastically.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2), staying closer to the ideal of <=5.

**H-Bond Acceptors:** Both ligands have 7 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.815) is significantly better than Ligand B (0.673), indicating a more drug-like profile.

**DILI:** Ligand B (72.703) has a higher DILI risk than Ligand A (52.191). Ligand A is comfortably below the 60 threshold, while Ligand B is approaching it.

**BBB:** Ligand A (64.017) has better BBB penetration than Ligand B (30.787), but BBB isn't a primary concern for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.981) has better Caco-2 permeability than Ligand B (-5.141), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.583) has better aqueous solubility than Ligand B (-2.369). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.087) shows significantly lower hERG inhibition liability than Ligand B (0.13). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (9.895) has a much lower microsomal clearance than Ligand B (58.4), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-26.847) has a significantly longer in vitro half-life than Ligand A (2.84). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.01) has lower P-gp efflux than Ligand B (0.046), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.0 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a better in vitro half-life, Ligand A excels in crucial areas like DILI risk, hERG inhibition, metabolic stability (lower Cl_mic), solubility, Caco-2 permeability, QED, and P-gp efflux. These advantages outweigh the slightly shorter half-life of Ligand A, especially given the similar binding affinities.

Output:
1
2025-04-17 14:26:12,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (62.3) is significantly lower than Ligand A (87.15), which is favorable.

**logP:** Ligand A (-0.064) is slightly below the optimal range (1-3), potentially hindering permeation. Ligand B (2.652) is well within the optimal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-likeness. Ligand B (0.647) is slightly better.

**DILI:** Ligand A (36.681) has a lower DILI risk than Ligand B (66.576), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.923) is slightly better than Ligand B (57.852).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.511) is slightly better than Ligand B (-5.429).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a major concern for both.

**hERG:** Ligand A (0.096) has a much lower hERG risk than Ligand B (0.32), which is a critical advantage.

**Microsomal Clearance:** Ligand A (13.631) has a significantly lower microsomal clearance than Ligand B (60.94), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.987) has a longer in vitro half-life than Ligand B (-0.053), which is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is significantly better due to its lower DILI risk, lower hERG risk, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. The slightly better logP and TPSA of Ligand B are outweighed by these critical ADME/Tox advantages of Ligand A. The poor solubility and permeability are concerns for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 14:26:12,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 347.419 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (120.25) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (81.77) is well within the range, suggesting potentially better absorption.

**logP:** Ligand A (1.522) is within the optimal 1-3 range. Ligand B (-0.413) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**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 (0.576 and 0.801), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (41.954) has a slightly higher DILI risk than Ligand B (36.448), but both are below the concerning threshold of 60.

**BBB:** BBB isn't a major concern for a non-CNS target like SRC, but Ligand B (36.448) has a higher percentile than Ligand A (18.961).

**Caco-2 Permeability:** Ligand A (-5.391) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-4.895) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.908) and Ligand B (-0.988) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**hERG:** Ligand A (0.138) has a very low hERG risk, which is excellent. Ligand B (0.494) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (16.727) has higher microsomal clearance than Ligand B (9.657), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand B (-10.83) has a much longer in vitro half-life than Ligand A (-1.188), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.022), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.4 and -7.2 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for an enzyme target, Ligand B is the more promising candidate. While both have poor solubility, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), a slightly better QED score, and a better Caco-2 permeability (though still poor). Ligand A's higher clearance is a major concern. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 14:26:12,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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. Ligand B (382.555 Da) is also acceptable.

**TPSA:** Ligand A (121.23) is borderline acceptable, while Ligand B (58.56) is excellent for oral absorption.

**logP:** Both ligands have good logP values (A: 1.641, B: 2.148), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are within acceptable limits. Ligand B has 0 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.459, B: 0.529), indicating moderate drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 63.94%, considered high risk. Ligand B has a DILI risk of 49.632%, which is better, though still in the moderate range.

**BBB:** Both ligands have reasonable BBB penetration (A: 71.268%, B: 89.725%). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.017 and -5.19), which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.423 and -2.787), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.27) has a very low hERG risk, which is excellent. Ligand B (0.593) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (8.305 mL/min/kg) than Ligand B (67.543 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a negative half-life (-25.044 hours), which is impossible. This is a major red flag. Ligand B has a half-life of 10.391 hours, which is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.118, B: 0.161).

**Binding Affinity:** Ligand B (-8.7 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 concerns.

**Overall Assessment:**

Ligand B is the better candidate despite its moderate DILI risk and poor solubility. Its significantly stronger binding affinity (-8.7 vs -6.4 kcal/mol) is a major advantage for an enzyme inhibitor. While both have poor Caco-2 permeability and solubility, the superior affinity of Ligand B, coupled with its reasonable half-life and lower Cl_mic than what was initially reported for Ligand A, makes it more promising. The negative half-life for Ligand A is a critical flaw. The lower DILI risk for Ligand B is also a positive factor.

Output:
1
2025-04-17 14:26:12,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.27 and 365.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.25) is significantly better than Ligand B (111.21).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.084) is optimal (1-3), while Ligand B (1.509) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both have 3 HBDs, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBAs, while Ligand B has 6.  Ligand A is preferable here.

**QED:** Both ligands have similar QED values (0.733 and 0.689), indicating good drug-likeness.

**DILI:** Ligand A (54.75) is better than Ligand B (59.907), as lower DILI is desired. Both are acceptable, but A is slightly preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (50.368) is better than Ligand B (13.92).

**Caco-2 Permeability:** Ligand A (-5.137) is significantly better than Ligand B (-5.471), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.613) is better than Ligand B (-1.858), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.597) is better than Ligand B (0.356), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (36.497) is worse than Ligand B (-1.688). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand A (12.463) is better than Ligand B (-15.099), indicating a longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.126 and 0.146), which is good.

**Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (0.0). This is a major advantage, and a difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better ADME properties in many respects (TPSA, logP, solubility, hERG, half-life), the large difference in binding affinity (-8.3 vs 0.0 kcal/mol) makes Ligand B the more promising candidate. The slightly lower logP and higher TPSA of Ligand B are less concerning given its superior potency. The negative microsomal clearance is also a positive.

Output:
1
2025-04-17 14:26:12,489 - INFO - Batch 296 complete. Total preferences: 4736
2025-04-17 14:26:12,489 - INFO - Processing batch 297/512...
2025-04-17 14:26:52,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.44) is significantly better than Ligand B (87.32). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands have similar logP values (1.537 and 1.641), 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 4. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have similar QED scores (0.787 and 0.794), indicating good drug-likeness.

**DILI:** Ligand A (7.949) has a much lower DILI risk than Ligand B (40.287). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (49.244) is lower than Ligand B (52.966).

**Caco-2 Permeability:** Ligand A (-5.281) is slightly better than Ligand B (-4.789), indicating potentially better absorption.

**Aqueous Solubility:** Ligand A (-1.181) is significantly better than Ligand B (-3.089). Solubility is crucial for bioavailability, making A more favorable.

**hERG Inhibition:** Ligand A (0.439) has a lower hERG inhibition risk than Ligand B (0.254). Lower is better here, so A is preferable.

**Microsomal Clearance:** Ligand B (-10.973) has a much *lower* (better) microsomal clearance than Ligand A (1.168). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-20.561) has a significantly longer half-life than Ligand A (-5.459), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.034), which is good.

**Binding Affinity:** Ligand A (-8.5 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:**

Ligand A excels in potency (binding affinity), DILI risk, solubility, and hERG inhibition. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. However, the substantial difference in binding affinity (-8.5 vs -5.9 kcal/mol) and the significantly lower DILI risk of Ligand A are critical advantages for an enzyme target like SRC kinase. The improved solubility of A is also a significant benefit. While B's metabolic stability is good, the potency difference is likely to be more impactful in *in vivo* efficacy.

Output:
1
2025-04-17 14:26:52,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (332.367 Da and 349.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.11 and 71.53) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.982 and 1.949), 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 acceptable, being under the 10 HBA limit.

**QED:** Ligand B (0.852) has a significantly higher QED score than Ligand A (0.62), indicating a more drug-like profile.

**DILI:** Ligand B (37.999) has a much lower DILI risk than Ligand A (79.333). This is a significant advantage.

**BBB:** Ligand B (90.384) has a much higher BBB penetration score than Ligand A (39.279). While SRC is not a CNS target, higher BBB is generally better.

**Caco-2 Permeability:** Ligand A (-5.41) has a worse Caco-2 permeability than Ligand B (-4.358), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.737) has worse aqueous solubility than Ligand B (-3.034).

**hERG Inhibition:** Ligand A (0.199) has a slightly lower hERG inhibition risk than Ligand B (0.41), but both are relatively low.

**Microsomal Clearance:** Ligand B (18.713) has a significantly lower microsomal clearance than Ligand A (29.57), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-26.883) has a much longer in vitro half-life than Ligand A (31.588), which is a major advantage.

**P-gp Efflux:** Ligand A (0.091) has slightly lower P-gp efflux than Ligand B (0.07), but both are very low.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). However, the difference is 1.1 kcal/mol, which is not substantial enough to outweigh the significant ADME advantages of Ligand B.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the superior candidate. It demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility and Caco-2 permeability. While Ligand A has slightly better binding affinity, the ADME profile of Ligand B is far more favorable for drug development.

Output:
1
2025-04-17 14:26:52,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.4 and 353.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (71.11) is well within the range.

**logP:** Ligand A (0.491) is a bit low, potentially hindering permeation. Ligand B (0.238) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.527 and 0.741), indicating generally drug-like properties. Ligand B is better here.

**DILI:** Ligand A (49.632) has a moderate DILI risk, while Ligand B (28.073) has a lower, more favorable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.67) has a higher BBB value than Ligand A (29.779), but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.259) and Ligand B (-4.543) 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 (-1.579 and -1.241). This is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.137 and 0.121), which is excellent.

**Microsomal Clearance:** Ligand A (17.94 mL/min/kg) has a significantly lower (better) microsomal clearance than Ligand B (44.564 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.298 hours) has a slightly better half-life than Ligand B (-2.394 hours), though both are negative and therefore problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.019), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.4 kcal/mol). Ligand B is slightly better.

**Conclusion:**

While both compounds have excellent binding affinity, the poor solubility and permeability of both are major concerns. However, Ligand B has a better QED score, lower DILI risk, better BBB penetration (though not crucial here), and slightly better binding affinity. Crucially, Ligand A has a much better microsomal clearance, suggesting better metabolic stability. Given the enzyme-specific priorities, metabolic stability is important. However, the solubility and permeability issues are so severe that they likely outweigh the benefit of better metabolic stability. Considering the overall profile, Ligand B is marginally better due to the lower DILI risk and slightly better binding, but both compounds require significant optimization to address the solubility and permeability issues.

Output:
1
2025-04-17 14:26:52,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.454 and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.5) is slightly above the preferred <140, but acceptable. Ligand B (49.41) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.834 and 3.304), 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.

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

**QED:** Ligand B (0.825) has a significantly better QED score than Ligand A (0.462), indicating a more drug-like profile.

**DILI:** Ligand B (20.706) has a much lower DILI risk than Ligand A (31.563), which is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (92.943) is slightly higher, but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.185) is slightly better than Ligand B (-4.617), but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.177) is slightly better than Ligand B (-4.181), but both are concerning.

**hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.524 and 0.723), which is good.

**Microsomal Clearance:** Ligand A (23.138) has a significantly lower microsomal clearance than Ligand B (52.121), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-11.496) has a longer half-life than Ligand A (-9.18), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.315 and 0.345), which is good.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B possesses a superior drug-like profile (higher QED, lower DILI) and better half-life. However, Ligand A has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic). The metabolic stability is a critical factor for kinase inhibitors, as they often suffer from rapid metabolism. While the solubility and permeability are poor for both, the improved metabolic stability of Ligand A, coupled with its slightly better affinity, outweighs the advantages of Ligand B.

Output:
0
2025-04-17 14:26:52,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.439 Da) is slightly lower, which can be beneficial for permeability. Ligand B (378.519 Da) is still acceptable.

**TPSA:** Both ligands have TPSA values (A: 53.76, B: 51.66) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 2.871, B: 3.763), falling within the optimal range of 1-3. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (0). Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are below the 10 threshold.

**QED:** Both ligands have similar and good QED scores (A: 0.845, B: 0.813), indicating good drug-like properties.

**DILI:** Ligand A (30.942) has a significantly lower DILI risk than Ligand B (66.615). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (A: 83.288, B: 85.77), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (A: -4.424, B: -4.831). These values are unusual and suggest poor permeability. This is a significant drawback for both compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (A: -2.286, B: -3.696), indicating poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.366, B: 0.326), which is excellent.

**Microsomal Clearance:** Ligand A (55.597) has lower microsomal clearance than Ligand B (64.932), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (40.595) has a significantly longer in vitro half-life than Ligand B (4.935). This is a substantial advantage for Ligand A, indicating potentially less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.336, B: 0.442).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly stronger binding affinity than Ligand A (-9.2 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it might not be enough to overcome the ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While both compounds have poor solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The slightly weaker binding affinity of Ligand A compared to Ligand B is likely outweighed by these critical ADME advantages, especially considering the relatively small difference in binding energy. The poor solubility and permeability would need to be addressed through formulation or further chemical modification, but the starting point with Ligand A is more favorable.

Output:
0
2025-04-17 14:26:52,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (382.423 and 357.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is slightly higher than Ligand B (31.92), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (2.79) is within the optimal 1-3 range. Ligand B (4.966) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0/1) and HBA (3/3) counts.

**QED:** Both ligands have good QED scores (0.524 and 0.724), indicating drug-likeness.

**DILI:** Ligand A (49.632) has a moderate DILI risk, while Ligand B (20.9) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.827) has better BBB penetration than Ligand B (78.635), but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.614) has poor Caco-2 permeability, while Ligand B (-5.338) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.221 and -4.647). This is a concern for both, but potentially more problematic for Ligand B given its higher logP.

**hERG Inhibition:** Ligand A (0.569) has a lower hERG inhibition liability than Ligand B (0.938), which is a positive.

**Microsomal Clearance:** Ligand A (44.473) has lower microsomal clearance than Ligand B (66.905), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-44.582) has a significantly longer in vitro half-life than Ligand B (7.944), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux than Ligand B (0.557), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the solubility issues shared by both compounds, Ligand A is the stronger candidate. Its significantly superior binding affinity (-8.9 vs -7.7 kcal/mol), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux outweigh the slightly higher TPSA and poorer Caco-2 permeability. The hERG risk is also lower for Ligand A. While solubility is a concern, formulation strategies can be explored to address this.

Output:
1
2025-04-17 14:26:52,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (368.459 and 339.439 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.84) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (73.99) is well within the acceptable range.

**3. logP:** Ligand A (0.498) is a bit low, potentially hindering permeation. Ligand B (2.885) is optimal.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 1, Ligand B: 3).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (Ligand A: 6, Ligand B: 2).

**6. QED:** Both ligands have good QED scores (A: 0.757, B: 0.783), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (A: 62.001, B: 59.984), below the concerning threshold of 60.

**8. BBB:** Both ligands have similar, moderate BBB penetration (A: 55.254, B: 55.642). BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**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 low hERG risk (A: 0.153, B: 0.51), which is positive.

**12. Microsomal Clearance (Cl_mic):** Both ligands have similar microsomal clearance (A: 26.821, B: 27.528). Lower is better, but these are not excessively high.

**13. In vitro Half-Life (t1/2):** Ligand B (15.328 hours) has a significantly longer half-life than Ligand A (-19.307 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.056, B: 0.302).

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a substantially better binding affinity than Ligand A (-6.3 kcal/mol). This >1.5 kcal/mol difference is a strong indicator of superiority.

**Enzyme-Specific Priorities:** For kinases, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and half-life, while both have acceptable DILI and hERG. The negative Caco-2 and solubility values are concerning for both, but the significantly stronger binding affinity and better half-life of Ligand B outweigh these concerns.

Output:
1
2025-04-17 14:26:52,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.4 and 348.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (135.17). A TPSA under 140 is good for oral absorption, but A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.155) is optimal (1-3), while Ligand B (-0.369) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=8) as it has fewer H-bonds.

**QED:** Ligand A (0.848) is better than Ligand B (0.581), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (57.39 and 59.05), both being acceptable.

**BBB:** Ligand A (83.09) is better than Ligand B (25.32), but BBB is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.64) is worse than Ligand B (-5.479), but both are quite poor.

**Aqueous Solubility:** Ligand A (-2.637) is better than Ligand B (-2.084), both are poor.

**hERG:** Ligand A (0.335) is better than Ligand B (0.023), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (24.841) is higher than Ligand B (13.875), meaning Ligand B has better metabolic stability.

**In vitro Half-Life:** Ligand B (31.684) has a longer half-life than Ligand A (24.124), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.07).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), a difference of 0.3 kcal/mol.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and metabolic stability, Ligand A is superior in almost all other key ADME properties. The significantly better logP, TPSA, QED, solubility, and hERG risk of Ligand A outweigh the small difference in binding affinity. The poor Caco-2 and solubility of both are concerning, but Ligand A is still better. Given the enzyme-specific priorities, the combination of better ADME properties and acceptable potency makes Ligand A the more promising candidate.

Output:
1
2025-04-17 14:26:52,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.435 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.72) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (58.64) is well within the ideal range.

**logP:** Both ligands have good logP values (2.335 and 2.799), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 9 HBAs, acceptable. Ligand B has 3 HBAs, also acceptable.

**QED:** Both ligands have good QED scores (0.662 and 0.72), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.084), which is a significant concern. Ligand B has a very low DILI risk (13.3), a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (77.821) than Ligand A (48.197), but this is less important.

**Caco-2 Permeability:** Ligand A (-5.191) and Ligand B (-4.609) 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:** Ligand A (-4.785) and Ligand B (-2.563) both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.315) has a slightly higher hERG risk than Ligand B (0.419), but both are relatively low.

**Microsomal Clearance:** Ligand A (88.147) has a higher microsomal clearance than Ligand B (43.801), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-4.948) has a negative half-life, which is not possible and suggests an error in the data. Ligand A (0.257) has a very short half-life, which is also undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.35 and 0.153).

**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. While this is a decent advantage, it is likely outweighed by the other factors.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, the significantly higher DILI risk and higher microsomal clearance make it a less desirable candidate. The negative values for Caco-2 and solubility are also concerning. Ligand B, while having a slightly lower affinity, has a much better safety profile (DILI) and metabolic stability (Cl_mic). The negative half-life for Ligand B is a data error that needs to be addressed, but even ignoring that, the overall profile favors Ligand B.

Output:
1
2025-04-17 14:26:52,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.785 and 364.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.68) is better than Ligand B (67.87), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.301) is optimal, while Ligand B (0.943) is slightly low, potentially hindering permeation.

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

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

**QED:** Both ligands have good QED scores (0.669 and 0.814, respectively), indicating drug-likeness.

**DILI:** Ligand B (41.062) has a significantly lower DILI risk than Ligand A (79.062), which is a major advantage.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**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 unusual. This suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.352 and 0.252, respectively).

**Microsomal Clearance:** Ligand A (-22.983) has a much lower (better) microsomal clearance than Ligand B (30.369), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (53.463) has a longer half-life than Ligand B (-6.143), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.065 and 0.051, respectively).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-10.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability and half-life, Ligand B's significantly stronger binding affinity (-7.5 vs -10.8 kcal/mol) and lower DILI risk are crucial advantages for an enzyme inhibitor. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of B is significant.

Output:
1
2025-04-17 14:26:52,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 349.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, suggesting good absorption. Ligand B (118.11) is also below 140, but higher than A.

**logP:** Ligand A (2.974) is optimal (1-3). Ligand B (-0.988) is below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, but higher.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is acceptable, but higher.

**QED:** Ligand A (0.632) is good (>0.5). Ligand B (0.391) is below 0.5, indicating a less drug-like profile.

**DILI:** Ligand A (17.759) has a very low DILI risk. Ligand B (40.403) is still relatively low, but higher than A.

**BBB:** Ligand A (75.107) has reasonable BBB penetration. Ligand B (43.893) has poor BBB penetration.

**Caco-2:** Ligand A (-4.619) is poor. Ligand B (-5.29) is also poor.

**Solubility:** Ligand A (-2.352) is poor. Ligand B (-2.237) is also poor.

**hERG:** Ligand A (0.591) has a low hERG risk. Ligand B (0.031) has a very low hERG risk.

**Cl_mic:** Ligand A (61.382) has moderate clearance. Ligand B (-2.775) has negative clearance, which is not possible and likely indicates a very stable compound.

**t1/2:** Ligand A (-8.673) is negative, which is not possible. Ligand B (-35.057) is also negative, indicating a very long half-life.

**Pgp:** Ligand A (0.489) has low Pgp efflux. Ligand B (0.01) has very low Pgp efflux.

**Binding Affinity:** Ligand A (-6.4) is good. Ligand B (-7.1) is excellent, 1.7 kcal/mol better than A.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.1 vs -6.4 kcal/mol). While its logP is suboptimal, the substantial improvement in binding affinity is a major advantage for an enzyme target like SRC kinase. The negative values for Cl_mic and t1/2 are concerning and likely represent data errors, but assuming these are corrected, the other ADME properties are acceptable. Ligand A has better QED and DILI, but the affinity difference is crucial. Given the enzyme-specific priorities, the stronger binding of Ligand B outweighs the minor drawbacks.

Output:
1
2025-04-17 14:26:52,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.371 Da) is slightly lower, which could be beneficial for permeability. Ligand B (393.227 Da) is also acceptable.

**TPSA:** Ligand A (105.66) is better than Ligand B (117.57), being closer to the desirable threshold of <=140 for oral absorption.

**logP:** Both ligands have good logP values (A: 1.486, B: 1.32), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=7) is preferable to Ligand B (HBD=2, HBA=5) as lower HBD generally improves permeability. Both are within acceptable limits.

**QED:** Ligand A (0.76) has a significantly better QED score than Ligand B (0.392), indicating a more drug-like profile.

**DILI:** Ligand A (47.732) has a lower DILI risk than Ligand B (64.909), which is a significant advantage. Both are below the concerning threshold of 60, but A is better.

**BBB:** Ligand A (87.553) has a better BBB penetration score than Ligand B (70.841). While not a primary concern for a kinase inhibitor (unless CNS off-target effects are a concern), it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.228) has a better Caco-2 permeability than Ligand B (-5.301).

**Aqueous Solubility:** Ligand A (-2.253) has a better aqueous solubility than Ligand B (-3.002).

**hERG Inhibition:** Ligand A (0.19) has a much lower hERG inhibition liability than Ligand B (0.486), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand B (-10.775) has a significantly lower (better) microsomal clearance than Ligand A (41.186), indicating better metabolic stability. This is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (2.639) has a longer in vitro half-life than Ligand A (-18.973). This is also a significant advantage.

**P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux than Ligand B (0.099).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor, and the difference of 8.6 kcal/mol is substantial.

**Overall Assessment:**

Ligand A excels in almost all ADME properties (QED, DILI, BBB, Caco-2, Solubility, hERG, P-gp) and, critically, has *far* superior binding affinity. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, but this is outweighed by the significantly weaker binding affinity and poorer ADME profile. The large difference in binding affinity is likely to overcome any minor drawbacks in metabolic stability.

Output:
1
2025-04-17 14:26:52,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (354.491 and 355.414 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is better than Ligand B (89.35). TPSA < 140 is good for oral absorption, both are within this range, but lower is preferred.

**3. logP:** Ligand A (1.971) is optimal (1-3), while Ligand B (0.23) is a bit low, potentially hindering permeation.

**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 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.759 and 0.721), indicating good drug-like properties.

**7. DILI:** Ligand A (19.542) has a significantly lower DILI risk than Ligand B (36.758). This is a crucial advantage.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (78.79) is slightly better than Ligand A (65.374). However, BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a major concern.

**9. 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 directly.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is not defined, so we can't interpret these values directly.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.321 and 0.129).

**12. Microsomal Clearance (Cl_mic):** Ligand A (43.727) has a higher Cl_mic than Ligand B (7.499), meaning Ligand B is more metabolically stable. This is a significant advantage for an enzyme inhibitor.

**13. In vitro Half-Life (t1/2):** Ligand B (3.418) has a slightly longer half-life than Ligand A (9.231), but the difference is not substantial.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.025).

**15. 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 (0.3 kcal/mol), it is still a positive factor.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a slightly better affinity, significantly better metabolic stability, and comparable hERG risk. Ligand A has a lower DILI risk and better TPSA, but the metabolic stability and affinity advantages of Ligand B are more critical for an enzyme target.

Output:
1
2025-04-17 14:26:52,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (380.495 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.32) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (64.09) is excellent, well below 140.

**3. logP:** Ligand A (0.738) is a bit low, potentially hindering permeation. Ligand B (0.409) is even lower, raising similar concerns.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (4) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.641 and 0.784, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (50.136) has a moderate DILI risk, but is acceptable. Ligand B (15.936) has a very low DILI risk, which is highly favorable.

**8. BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase. Ligand B (36.371) is higher than Ligand A (18.147).

**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, which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.185 and 0.164), which is excellent.

**12. Cl_mic:** Ligand A (12.632) has a moderate microsomal clearance. Ligand B (-3.911) has *negative* clearance, which is impossible and likely an artifact of the prediction method, but suggests very high metabolic stability.

**13. t1/2:** Ligand A (-1.928) has a negative half-life, which is impossible and likely an artifact of the prediction method. Ligand B (-5.718) also has a negative half-life, also likely an artifact.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.034 and 0.018), which is favorable.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial advantage.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison & Decision:**

While both ligands have issues with Caco-2 and solubility, Ligand A's significantly stronger binding affinity (-9.4 vs -6.2 kcal/mol) is a major advantage that could outweigh its slightly higher DILI risk and lower logP. The negative values for Cl_mic and t1/2 are concerning for both, but likely represent prediction errors. Given the importance of potency for enzyme inhibition, and the acceptable safety profile of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 14:26:52,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.386 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is significantly better than Ligand B (79.31). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.358) is optimal, while Ligand B (0.117) is quite low, potentially hindering membrane permeability.

**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.

**QED:** Ligand A (0.925) has a much higher QED score than Ligand B (0.759), indicating better overall drug-likeness.

**DILI:** Ligand A (55.952) has a higher DILI risk than Ligand B (13.843). This is a significant advantage for Ligand B.

**BBB:** Both have moderate BBB penetration (Ligand A: 89.531, Ligand B: 55.874), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**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.

**Solubility:** Ligand A (-4.001) has worse solubility than Ligand B (-1.513).

**hERG:** Ligand A (0.666) has a slightly higher hERG risk than Ligand B (0.304), but both are relatively low.

**Microsomal Clearance:** Ligand A (9.261) has significantly lower microsomal clearance than Ligand B (25.634), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (58.718) has a much longer half-life than Ligand B (2.697), which is a major advantage.

**P-gp Efflux:** Ligand A (0.166) has lower P-gp efflux than Ligand B (0.028), indicating better bioavailability.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.0 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in potency (affinity), metabolic stability (Cl_mic, t1/2), P-gp efflux, and QED. Its logP is optimal. However, it has a higher DILI risk and lower solubility. Ligand B has a lower DILI risk and better solubility, but suffers from poor logP, lower QED, and significantly worse metabolic stability and binding affinity.

Given the priority for potency and metabolic stability for kinase inhibitors, and the substantial difference in binding affinity (1.0 kcal/mol), Ligand A is the more promising candidate despite the slightly higher DILI risk and lower solubility. These issues could potentially be addressed through further optimization.

Output:
1
2025-04-17 14:26:52,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.431 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.57) is better than Ligand B (67.23), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (2.501) is within the optimal 1-3 range, while Ligand A (0.812) is slightly below, 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 (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.891) has a significantly higher QED score than Ligand A (0.63), indicating better overall drug-likeness.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A at 34.432 and Ligand B at 31.059 (both <40).

**BBB:** Both ligands have similar BBB penetration (65.839 and 68.36, respectively), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.876) is significantly worse than Ligand B (-4.603), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.696) is better than Ligand B (-2.923), suggesting better formulation potential.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.042 and 0.492, respectively).

**Microsomal Clearance:** Ligand B (77.314 mL/min/kg) has a higher clearance than Ligand A (51.159 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-21.635 hours) has a significantly longer half-life than Ligand B (-8.893 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.027 and 0.256, respectively).

**Binding Affinity:** Both ligands have similar strong binding affinities (-8.5 and -8.9 kcal/mol). The difference is minimal.

**Conclusion:**

While Ligand B has a better QED score and logP, Ligand A exhibits superior solubility, metabolic stability (lower Cl_mic and longer t1/2), and comparable binding affinity. Given the enzyme-specific priorities, the improved metabolic stability and solubility of Ligand A outweigh the slightly better QED and logP of Ligand B. The longer half-life is a significant advantage for dosing convenience.

Output:
1
2025-04-17 14:26:52,440 - INFO - Batch 297 complete. Total preferences: 4752
2025-04-17 14:26:52,440 - INFO - Processing batch 298/512...
2025-04-17 14:27:39,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 significantly better than Ligand B (74.41).  A TPSA under 140 is good for oral absorption, and both are under this limit, but lower is generally preferred.

**3. logP:** Ligand A (4.135) is slightly higher than the optimal 1-3 range, while Ligand B (2.846) is within the optimal range. This is a slight advantage for Ligand B.

**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), as lower HBA is generally preferred for permeability.

**6. QED:** Both ligands have similar and acceptable QED values (0.602 and 0.667, both > 0.5).

**7. DILI:** Ligand A (30.322) has a much lower DILI risk than Ligand B (19.93). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (85.498) has a better BBB penetration score than Ligand B (32.92), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-5.008) has a worse Caco-2 permeability than Ligand B (-5.406). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-4.487) is slightly better than Ligand B (-2.858), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.752 and 0.632 respectively).

**12. Microsomal Clearance:** Ligand A (82.108) has a higher microsomal clearance than Ligand B (36.242), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (23.716) has a significantly longer in vitro half-life than Ligand A (6.383). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.575 and 0.233 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:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk and slightly better solubility, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a more optimal logP. The similar binding affinities mean these are not differentiating factors. For an enzyme target like SRC kinase, metabolic stability and reasonable solubility are crucial, making Ligand B the more promising drug candidate.

Output:
1
2025-04-17 14:27:39,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.47 and 366.82 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.5) is better than Ligand B (66.71). Both are below the 140 threshold for good absorption, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (1.354 and 2.504, respectively), falling within the 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 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 (0.741 and 0.854), indicating good drug-like properties.

**DILI:** Ligand A (41.45) has a significantly lower DILI risk than Ligand B (67.003). This is a crucial advantage.

**BBB:** Both ligands have relatively low BBB penetration (53.703 and 81.815). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Ligand A (-5.172) has worse Caco-2 permeability than Ligand B (-4.347).

**Aqueous Solubility:** Ligand A (-1.94) has better aqueous solubility than Ligand B (-3.747). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.207 and 0.376). This is excellent.

**Microsomal Clearance:** Ligand A (22.612) has a lower microsomal clearance than Ligand B (52.534), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (34.232) has a shorter half-life than Ligand B (53.133). This is a slight disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.171).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are excellent, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in DILI risk, solubility, and metabolic stability (lower Cl_mic). Ligand B has a slightly better binding affinity and Caco-2 permeability, and a longer half-life. However, the significantly lower DILI risk of Ligand A is a major advantage, and its better solubility is also important. The affinity difference, while noticeable, is not large enough to outweigh the safety and pharmacokinetic benefits of Ligand A.

Output:
0
2025-04-17 14:27:39,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.483 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (353.423 Da) is also good.

**TPSA:** Ligand A (46.06) is excellent, well below the 140 threshold for good absorption. Ligand B (118.37) is higher but still acceptable, though it might slightly hinder absorption compared to A.

**logP:** Ligand A (4.218) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.291) is quite low, which could severely impede membrane permeation and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is optimal. Ligand B (3 HBD, 7 HBA) is acceptable but less ideal, with the higher HBA count potentially impacting permeability.

**QED:** Ligand A (0.729) is very good, indicating strong drug-like properties. Ligand B (0.561) is acceptable but lower, suggesting a less optimal overall drug-likeness profile.

**DILI:** Ligand A (27.918) has a very low DILI risk, which is excellent. Ligand B (50.174) is moderate, representing a higher potential for liver toxicity.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (96.782) shows good BBB penetration, while Ligand B (51.183) is lower.

**Caco-2 Permeability:** Ligand A (-4.675) is poor, indicating very low intestinal absorption. Ligand B (-4.914) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.031) is poor. Ligand B (-1.631) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.902) has a low risk of hERG inhibition, which is favorable. Ligand B (0.084) has a very low risk, which is excellent.

**Microsomal Clearance:** Ligand A (48.357) has moderate clearance, suggesting moderate metabolic stability. Ligand B (24.613) has low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (45.691) has a reasonable half-life. Ligand B (-13.278) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.692) has moderate P-gp efflux. Ligand B (0.016) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands have similar strong binding affinities (-8.0 kcal/mol and -7.3 kcal/mol respectively). The difference of 0.7 kcal/mol is not substantial enough to override other significant ADME concerns.

**Overall Assessment:**

Ligand A has better QED, DILI, and hERG profiles. However, its low Caco-2 permeability and solubility are concerning. Ligand B has better metabolic stability (lower Cl_mic, though a very short half-life is a major issue) and P-gp efflux. However, its low logP is a major red flag for permeability and bioavailability. Considering the importance of metabolic stability and potency for kinase inhibitors, and the severe permeability issues with Ligand B, Ligand A is the slightly more promising candidate, despite its solubility and permeability challenges. These could potentially be addressed through formulation strategies. The very short half-life of Ligand B is a major obstacle.

Output:
0
2025-04-17 14:27:39,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (361.511 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is slightly higher than Ligand B (61.88), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (3.055) is optimal, while Ligand B (0.864) is a bit 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:** Both ligands (A: 4, B: 4) are well below the 10 limit.

**6. QED:** Ligand A (0.818) has a better QED score than Ligand B (0.522), indicating a more drug-like profile.

**7. DILI:** Ligand B (11.09) has a significantly lower DILI risk than Ligand A (41.218), which is a major advantage.

**8. BBB:** Ligand B (66.576) has a higher BBB penetration percentile than Ligand A (55.293), but this is not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.946 and -4.718), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Ligand B (-1.093) has slightly better solubility than Ligand A (-3.86), which is beneficial.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.341 and 0.243, respectively).

**12. Microsomal Clearance:** Ligand B (18.671) has significantly lower microsomal clearance than Ligand A (47.088), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.93) has a slightly longer half-life than Ligand A (25.764), though both are relatively short.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.162 and 0.036).

**15. Binding Affinity:** Ligand B (-6.9) has a slightly better binding affinity than Ligand A (-6.7), though the difference is small (0.2 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, the significant advantages in DILI risk, metabolic stability (lower Cl_mic), solubility, and QED outweigh the slightly lower logP. The poor Caco-2 permeability is a concern for both, but the other ADME properties of Ligand B are more favorable for development. The lower DILI risk is particularly important.

Output:
1
2025-04-17 14:27:39,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.411 and 352.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.48) is better than Ligand B (60.85), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.406 and 2.525), falling within the 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, well within acceptable limits.

**QED:** Both ligands have good QED scores (0.9 and 0.846), indicating good drug-like properties.

**DILI:** Ligand A (28.616) has a significantly lower DILI risk than Ligand B (14.308). This is a major advantage for Ligand A.

**BBB:** Both have similar BBB penetration (61.38 and 64.327), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.796) has slightly better Caco-2 permeability than Ligand B (-4.423).

**Aqueous Solubility:** Ligand A (-2.023) has slightly better aqueous solubility than Ligand B (-2.386).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.208 and 0.467).

**Microsomal Clearance:** Ligand A (6.302) has significantly lower microsomal clearance than Ligand B (46.033). This suggests better metabolic stability for Ligand A, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-27.704) has a much longer in vitro half-life than Ligand B (-18.875). This is another significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.036 and 0.274).

**Binding Affinity:** Both ligands have equivalent binding affinity (-9.0 and -9.1 kcal/mol).

**Conclusion:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand A is the superior candidate. Its significantly lower DILI risk, lower microsomal clearance, and longer half-life outweigh the slightly better logP of Ligand B. These factors are critical for an enzyme inhibitor, as metabolic stability and minimizing toxicity are paramount.

Output:
0
2025-04-17 14:27:39,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (333.355 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.41) is slightly above the preferred <140, while Ligand B (75.44) is well within the range.

**logP:** Both ligands have logP values (3.09 and 2.858) that are optimal (1-3).

**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:** Ligand B (0.912) has a significantly higher QED score than Ligand A (0.578), indicating better overall drug-likeness.

**DILI:** Ligand B (32.377) has a much lower DILI risk than Ligand A (86.39), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (76.309) has a higher BBB percentile than Ligand A (29.818).

**Caco-2 Permeability:** Ligand A (-5.417) has a negative Caco-2 value, which is concerning. Ligand B (-4.873) is also negative, but less so. Both suggest poor intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.709 and -3.16), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.743) has a slightly higher hERG inhibition liability than Ligand B (0.26), which is preferable.

**Microsomal Clearance:** Ligand B (50.191) has a significantly lower microsomal clearance than Ligand A (13.92), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-26.834) has a much longer in vitro half-life than Ligand A (-15.561), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.064).

**Binding Affinity:** Ligand A (-8.5 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's not a decisive factor.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial ADMET properties: significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), higher QED, and lower hERG inhibition. The negative Caco-2 and solubility values are concerns for both, but the other advantages of Ligand B outweigh this drawback. The enzyme-specific priorities clearly favor Ligand B.

Output:
1
2025-04-17 14:27:39,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.467 and 361.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (61.94 and 64.00) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.368 and 3.053) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 7 HBA, which is acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.333 and 0.716), with Ligand B being significantly better.

**DILI:** Ligand A (65.607) has a slightly higher DILI risk than Ligand B (57.968), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (71.035) is slightly better than Ligand A (60.838).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.233 and -5.311), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.802 and -3.288). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.846 and 0.779).

**Microsomal Clearance:** Ligand A (135.832) has a higher microsomal clearance than Ligand B (81.799), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (94.356) has a much longer in vitro half-life than Ligand A (-10.607), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.84 and 0.371).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold that would strongly favor Ligand A.

**Overall Assessment:**

While Ligand A has slightly better binding affinity, Ligand B is superior in several critical ADME properties. Specifically, Ligand B has a significantly better QED score, lower microsomal clearance (better metabolic stability), and a much longer in vitro half-life. The poor solubility and Caco-2 permeability are concerning for both, but the improved metabolic stability and half-life of Ligand B are more valuable for an enzyme target like SRC kinase. The slightly better DILI score for Ligand B is also a plus.

Output:
1
2025-04-17 14:27:39,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.417 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.79) is slightly higher than Ligand B (61.36), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.378 and 2.692), 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:** Both ligands have good QED scores (0.698 and 0.889), indicating drug-like properties.

**DILI:** Ligand A (19.969) has a significantly lower DILI risk than Ligand B (50.33), which is a major advantage. Ligand A is well below the 40 threshold, while Ligand B is approaching a moderate risk.

**BBB:** Both ligands have high BBB penetration (80.574 and 89.027), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.848). These values are unusual and suggest poor permeability. However, Caco-2 values can be unreliable and are less important than other factors here.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.47 and -2.587). Similar to Caco-2, these are unusual and suggest poor solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.242) has a much lower hERG risk than Ligand B (0.639), which is a significant advantage.

**Microsomal Clearance:** Ligand A (13.333 mL/min/kg) has a lower microsomal clearance than Ligand B (71.977 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.4 hours) has a shorter half-life than Ligand B (-1.038 hours). Both are negative, which is unusual and suggests rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.024 and 0.294).

**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.

**Conclusion:**

While Ligand B has a significantly better binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI and hERG) and better metabolic stability (lower Cl_mic). The negative solubility and Caco-2 values are concerning for both, but potentially addressable. Given the importance of minimizing toxicity and maximizing metabolic stability for an enzyme target like SRC kinase, and the substantial difference in DILI and hERG, I would favor Ligand A as the more viable drug candidate *despite* the weaker binding affinity. The affinity difference is large, but optimization of Ligand A could potentially improve its binding while retaining its favorable ADMET properties.

Output:
0
2025-04-17 14:27:39,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.5 and 361.8 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.88) is well below the 140 threshold for good absorption, while Ligand B (104.11) is still acceptable, but less optimal.

**logP:** Both ligands (1.378 and 1.928) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 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 (0.691 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A (8.996) has a significantly lower DILI risk than Ligand B (70.182). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (64.676) has a higher BBB value than Ligand A (42.226), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.953) is slightly better than Ligand B (-5.384).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.662) is slightly better than Ligand B (-3.851).

**hERG:** Ligand A (0.508) has a lower hERG risk than Ligand B (0.719), which is favorable.

**Microsomal Clearance:** Ligand A (18.633) has a higher microsomal clearance than Ligand B (-7.139). This suggests Ligand B is more metabolically stable, a key consideration for enzymes.

**In vitro Half-Life:** Ligand B (1.628) has a longer in vitro half-life than Ligand A (-1.161), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.088 and 0.068).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 2.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better safety profiles (lower DILI, lower hERG) and slightly better solubility and permeability, Ligand B's significantly stronger binding affinity (-8.6 vs -6.4 kcal/mol) and improved metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target like SRC kinase. The potency advantage is likely to be more impactful than the ADME concerns, especially given that the DILI and hERG risks for Ligand B are not extremely high.

Output:
1
2025-04-17 14:27:39,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.382 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (72.7 and 71.09) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.577 and 3.374) are 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:** Both ligands have good QED scores (0.611 and 0.814), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 95.192, which is *very* high. Ligand B has a DILI risk of 47.732, which is acceptable. This is a major red flag for Ligand A.

**BBB:** Both have reasonable BBB penetration (65.839 and 74.952). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.817 and -4.894). This is unusual and suggests poor permeability. However, these values are on a log scale and are often reported as ratios, so the negative values are likely indicating values less than 1.

**Aqueous Solubility:** Both have negative solubility values (-3.804 and -5.068), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.553) has a slightly higher hERG risk than Ligand B (0.356), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (44.226) has significantly lower microsomal clearance than Ligand B (73.655), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (32.341) has a longer half-life than Ligand B (9.873), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.457 and 0.155).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), although the difference is not huge.

**Conclusion:**

Despite Ligand A having better metabolic stability and half-life, the extremely high DILI risk (95.192) is a deal-breaker. The poor solubility of both compounds is also concerning, but can potentially be addressed with formulation strategies. Ligand B, with its significantly lower DILI risk and slightly better binding affinity, is the more promising candidate.

Output:
1
2025-04-17 14:27:39,859 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [343.343, 101.66 ,   0.359,   0.   ,   7.   ,   0.79 ,  73.09 ,  61.807, -4.751,  -1.701,   0.151,   9.684,  -5.228,   0.028,  -8.7  ]
**Ligand B:** [426.242,  68.02 ,   4.258,   1.   ,   5.   ,   0.634,  90.733,  70.997, -4.468,  -5.355,   0.393,  35.624,  12.191,   0.345,  -8.   ]

**Step-by-step comparison:**

1. **MW:** Ligand A (343.343 Da) is within the ideal range (200-500 Da). Ligand B (426.242 Da) is also acceptable, but approaching the upper limit.
2. **TPSA:** Ligand A (101.66) is good for oral absorption (<140). Ligand B (68.02) is excellent.
3. **logP:** Ligand A (0.359) is quite low, potentially hindering permeability. Ligand B (4.258) is slightly high, potentially causing solubility or off-target issues, but still within a reasonable range.
4. **HBD:** Ligand A (0) is ideal. Ligand B (1) is also acceptable.
5. **HBA:** Ligand A (7) is good. Ligand B (5) is also good.
6. **QED:** Both ligands (A: 0.79, B: 0.634) have acceptable drug-likeness scores (>0.5).
7. **DILI:** Ligand A (73.09) is better than Ligand B (90.733) in terms of liver injury risk.
8. **BBB:** Both ligands have good BBB penetration (A: 61.807, B: 70.997), but not critical for SRC kinase which is not a CNS target.
9. **Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. We'll proceed with caution.
10. **Solubility:** Ligand A (-1.701) has poor solubility. Ligand B (-5.355) is even worse. This is a significant concern for both.
11. **hERG:** Ligand A (0.151) has a very low hERG risk. Ligand B (0.393) is also low, but slightly higher.
12. **Cl_mic:** Ligand A (9.684) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (35.624) has higher clearance.
13. **t1/2:** Ligand A (-5.228) has a negative in vitro half-life, which is not possible and suggests a data issue. Ligand B (12.191) has a reasonable half-life.
14. **Pgp:** Ligand A (0.028) has very low P-gp efflux. Ligand B (0.345) is also low.
15. **Affinity:** Both ligands have excellent binding affinity (A: -8.7 kcal/mol, B: -8.0 kcal/mol). Ligand A is slightly better.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Decision:**

Despite the slightly better affinity of Ligand A, the problematic negative half-life and very poor solubility are major red flags. Ligand B, while having a higher DILI risk and slightly higher Cl_mic, has a reasonable half-life and, although still poor, a less problematic solubility profile. The affinity is still excellent. The negative Caco-2 values for both are concerning, but given the other factors, Ligand B appears to be the more viable starting point for optimization.

1
2025-04-17 14:27:39,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.435 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.18) is better than Ligand B (67.23), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.234) is slightly low, potentially hindering permeation. Ligand B (2.515) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**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 good QED scores (0.711 and 0.826), indicating drug-likeness.

**DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (39.938), which is a major advantage.

**BBB:** Ligand A (55.021) has a lower BBB penetration than Ligand B (82.474). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.977 and -4.849), 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 have negative solubility values (-0.682 and -3.877), indicating poor solubility. Ligand B is worse.

**hERG:** Ligand A (0.072) has a much lower hERG inhibition liability than Ligand B (0.359), which is a significant advantage.

**Microsomal Clearance:** Ligand A (3.245) has a lower microsomal clearance than Ligand B (49.317), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-2.888) has a negative half-life, which is problematic. Ligand B (5.257) has a positive half-life, indicating better stability.

**P-gp Efflux:** Ligand A (0.005) has a much lower P-gp efflux liability than Ligand B (0.133), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.8 kcal/mol). Ligand A is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has a better DILI score, lower hERG risk, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While its solubility and half-life are concerning, the improved safety profile and metabolic stability are significant advantages for an enzyme target like SRC kinase. Ligand B has better logP and BBB, but the higher DILI, hERG, and clearance are drawbacks. The negative Caco-2 and solubility values for both are concerning and would need further investigation, but the other factors lean towards Ligand A.

Output:
0
2025-04-17 14:27:39,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.5) is slightly higher than Ligand B (348.5).

**TPSA:** Ligand A (91.93) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (59.07) is well within the acceptable range.

**logP:** Ligand A (1.165) is optimal. Ligand B (4.192) is approaching the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) 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:** Ligand B (0.774) has a better QED score than Ligand A (0.386), indicating a more drug-like profile.

**DILI:** Both ligands have similar, relatively low DILI risk (A: 37.1, B: 38.9), both below the 40 threshold.

**BBB:** Ligand B (92.2) has a much higher BBB penetration percentile than Ligand A (63.8). While SRC isn't a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.753 and -4.772), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.801 and -5.205), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.342) has a lower hERG inhibition risk than Ligand B (0.848), which is preferable.

**Microsomal Clearance:** Ligand A (19.08) has significantly lower microsomal clearance than Ligand B (71.591), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (47.624) has a longer in vitro half-life than Ligand A (12.941), which is desirable.

**P-gp Efflux:** Ligand A (0.023) has much lower P-gp efflux liability than Ligand B (0.425), indicating better bioavailability.

**Binding Affinity:** Ligand A (-7.7 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.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-7.7 vs -6.2 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, it has better metabolic stability (lower Cl_mic) and lower P-gp efflux, and lower hERG risk. While Ligand B has a better QED and longer half-life, the potency and metabolic stability advantages of Ligand A are more critical for kinase inhibitors. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the core potency and stability profile of Ligand A is superior.

Output:
0
2025-04-17 14:27:39,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.248 Da) is slightly higher than Ligand B (351.397 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (A: 73.22, B: 70.23), suggesting good oral absorption potential.

**logP:** Both ligands have logP values within the optimal range (1-3), with A at 3.858 and B at 2.774. Ligand A is at the higher end, potentially raising concerns about off-target effects, but still within acceptable limits.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=2) both have reasonable H-bond characteristics, falling within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.673, B: 0.73), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (98.682) compared to Ligand B (60.682). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 80.962, B: 81.466), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.754 and -4.708), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.72 and -4.274), indicating very poor aqueous solubility. This is a major formulation challenge for both.

**hERG Inhibition:** Ligand A (0.606) has a slightly higher hERG inhibition risk than Ligand B (0.322), but both are relatively low.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (130.734) than Ligand B (23.177), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (95.559) than Ligand B (6.658), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.735) has a slightly higher P-gp efflux liability than Ligand B (0.104).

**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 can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a longer half-life, its high DILI risk and higher microsomal clearance are major concerns. Ligand B, despite its lower half-life, exhibits a significantly better binding affinity, lower DILI risk, and lower P-gp efflux. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. Given the enzyme-specific priorities, the superior binding affinity and improved safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 14:27:39,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (104.21). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (2.811 and 1.794, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is slightly better than Ligand B (HBD=3, HBA=5), as lower counts are generally preferred for permeability.

**QED:** Both ligands have similar QED values (0.76 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (47.926) has a lower DILI risk than Ligand B (51.648), which is favorable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (61.923) is slightly better than Ligand B (51.725).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.948 and -4.795). 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 (-3.903 and -3.043), indicating poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.337) has a much lower hERG inhibition liability than Ligand B (0.117), which is a substantial advantage. Lower hERG is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (37.849) has a lower microsomal clearance than Ligand B (39.04), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.873 hours) has a significantly longer half-life than Ligand B (-28.775 hours). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.187) has lower P-gp efflux liability than Ligand B (0.01), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it may not be enough to overcome the ADME deficiencies of Ligand B.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of hERG risk, metabolic stability (lower Cl_mic and longer t1/2), and DILI risk. Both have poor solubility and permeability, but Ligand A's other advantages outweigh this concern. The negative half-life for Ligand B is a major red flag.

Output:
0
2025-04-17 14:27:39,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.361 and 368.865 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.9) is slightly higher than Ligand B (76.46). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have acceptable logP values (0.925 and 1.583), falling within the 1-3 range. Ligand B is slightly more favorable.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are below the limit of <=10.

**QED:** Both ligands have good QED scores (0.665 and 0.8), indicating good drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (44.862 and 47.421), well below the 60 threshold.

**BBB:** Ligand A (77.821) has a better BBB penetration score than Ligand B (62.854), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.576) and Ligand B (-4.886) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.294) and Ligand B (-2.326) both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.255 and 0.273), which is excellent.

**Microsomal Clearance:** Ligand B (12.282) has significantly lower microsomal clearance than Ligand A (48.755). This indicates better metabolic stability for Ligand B, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-0.948) has a slightly better (less negative) in vitro half-life than Ligand A (-30.409), suggesting better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.046 and 0.03).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While both ligands have some ADME concerns (poor Caco-2 and solubility), Ligand B is the more promising candidate. Its significantly stronger binding affinity, coupled with better metabolic stability (lower Cl_mic and better t1/2), makes it a superior choice despite slightly lower BBB penetration. The improved QED score also contributes to its favorability.

Output:
1
2025-04-17 14:27:39,860 - INFO - Batch 298 complete. Total preferences: 4768
2025-04-17 14:27:39,860 - INFO - Processing batch 299/512...
2025-04-17 14:28:25,730 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (58.81) is slightly higher than Ligand B (49.22), but both are good.

**logP:** Both ligands have logP values between 3 and 4, which is optimal. Ligand A (3.598) and Ligand B (3.865) are both acceptable.

**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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.728) is slightly higher than Ligand B (0.692).

**DILI:** This is a critical parameter. Ligand A has a DILI risk of 94.959, which is *very high*. Ligand B has a DILI risk of 44.281, which is acceptable (below 60). This is a major strike against Ligand A.

**BBB:** BBB is less crucial for a non-CNS target like SRC, but Ligand A (83.831) is slightly better than Ligand B (76.619).

**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, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.758) has a slightly higher hERG risk than Ligand B (0.954), but both are relatively low.

**Microsomal Clearance:** Ligand B (17.778 mL/min/kg) has significantly lower microsomal clearance than Ligand A (65.704 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (4.817 hours) has a longer half-life than Ligand A (19.942 hours). This is a positive for Ligand B, suggesting less frequent dosing may be possible.

**P-gp Efflux:** Ligand A (0.645) has lower P-gp efflux than Ligand B (0.397), which could lead to better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.7 kcal/mol for A and -8.1 kcal/mol for B). Ligand A has a 0.6 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and slightly better BBB penetration, its *extremely high* DILI risk is a deal-breaker. The significantly better metabolic stability (lower Cl_mic, longer t1/2) and acceptable DILI risk of Ligand B make it the far more promising candidate. The slightly lower affinity of Ligand B can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 14:28:25,730 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.431 Da and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.15) is better than Ligand B (84.64), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.673) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.232) is within the optimal range.

**H-Bond Donors:** Ligand A (0) is excellent, while Ligand B (1) is acceptable.

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

**QED:** Both ligands have good QED scores (0.68 and 0.869 respectively), indicating good drug-like properties.

**DILI:** Ligand A (25.475) has a significantly lower DILI risk than Ligand B (41.179), which is a major advantage. Both are below the concerning threshold of 60.

**BBB:** Ligand A (69.562) has a moderate BBB penetration, while Ligand B (53.121) is lower. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.479 and -4.667), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.859 and -2.97), which is also concerning and suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.345 and 0.427), which is positive.

**Microsomal Clearance:** Ligand A (67.792) has higher microsomal clearance than Ligand B (16.365), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (6.146) has a significantly longer in vitro half-life than Ligand A (-1.592), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.097).

**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 significant, and can outweigh some of the ADME drawbacks.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the stronger candidate. It has a significantly better binding affinity, a longer half-life, lower microsomal clearance, and a lower DILI risk. The slightly better logP of Ligand B also contributes to its favorability. The affinity difference is substantial enough to overcome the slightly higher TPSA and DILI risk compared to Ligand A.

Output:
1
2025-04-17 14:28:25,730 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.455 and 354.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.57) is higher than Ligand B (79.53). While both are reasonably good, Ligand B is better positioned for oral absorption being below 90.

**logP:** Ligand A (0.261) is quite low, potentially hindering permeability. Ligand B (2.018) 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:** Both ligands have good QED scores (0.778 and 0.877), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (37.03 and 34.781), which is favorable.

**BBB:** Ligand A (75.184) and Ligand B (94.339) both have acceptable BBB penetration, but Ligand B is better. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.354) has poor Caco-2 permeability, while Ligand B (-4.806) is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.536 and -2.002). This is a potential issue for both, requiring formulation strategies.

**hERG Inhibition:** Ligand A (0.36) has a slightly better hERG profile than Ligand B (0.63), but both are reasonably low risk.

**Microsomal Clearance:** Ligand A (-10.367) has a better (lower) microsomal clearance than Ligand B (-9.971), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (27.679) has a longer half-life than Ligand B (-8.824). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.013) has much lower P-gp efflux than Ligand B (0.042), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >1.8 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better metabolic stability, longer half-life, and lower P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.0 vs -7.2 kcal/mol) is the most critical factor for an enzyme inhibitor. Ligand B also has a more favorable logP and TPSA, improving its potential for permeability and absorption. While solubility is a concern for both, the potency advantage of Ligand B makes it the better choice.

Output:
1
2025-04-17 14:28:25,730 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.438 Da) is slightly preferred due to being lower in MW.

**TPSA:** Ligand A (64.68) is significantly better than Ligand B (96.11). Lower TPSA generally correlates with better cell permeability, important for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (A: 1.488, B: 2.836), 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.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (A: 2, B: 3) and HBA (A: 4, B: 4) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Ligand A (0.816) has a substantially better QED score than Ligand B (0.665), indicating a more drug-like profile.

**DILI:** Ligand A (37.146) has a much lower DILI risk than Ligand B (70.182). This is a significant advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (89.686) is better than Ligand B (64.172).

**Caco-2 Permeability:** Ligand A (-4.858) is better than Ligand B (-5.112), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.254) is better than Ligand B (-3.629), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.803) has a lower hERG risk than Ligand B (0.474). This is a significant advantage.

**Microsomal Clearance:** Ligand A (23.78) has a lower microsomal clearance than Ligand B (47.591), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.024) has a better in vitro half-life than Ligand B (9.417).

**P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux liability than Ligand B (0.223), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While a 0.3 kcal/mol difference is noticeable, the other ADME properties of Ligand A are significantly better.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties (DILI, solubility, metabolic stability, hERG, P-gp efflux, QED, TPSA). While Ligand B has a slightly better binding affinity, the superior ADME profile of Ligand A makes it the more promising drug candidate. The better ADME properties are likely to translate to better *in vivo* efficacy and safety.

Output:
0
2025-04-17 14:28:25,730 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (355.825 Da and 340.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (56.15) is well below the 140 threshold, and even below 90, suggesting good permeability. Ligand B (68.44) is also below 140, but higher than A.

**3. logP:** Ligand A (4.31) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.676) is quite low, which might hinder membrane permeability.

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

**5. H-Bond Acceptors:** Ligand A (4) and B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.758 and 0.792), indicating drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (96.51), which is a significant concern. Ligand B has a very low DILI risk (18.108), a major advantage.

**8. BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (64.831) and B (56.805) are both relatively low.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so we can't interpret these values definitively.

**10. Solubility:** Both ligands have very poor aqueous solubility (-5.567 and -2.61). This is a significant drawback.

**11. hERG:** Ligand A (0.598) has a slightly elevated hERG risk, while Ligand B (0.341) is better.

**12. Cl_mic:** Ligand A (84.584) has a relatively high microsomal clearance, indicating faster metabolism. Ligand B (-27.634) has a *negative* clearance, which is impossible and likely an error in the data. This is a huge red flag.

**13. t1/2:** Ligand A (58.587) has a reasonable in vitro half-life. Ligand B (-9.994) has a negative half-life, which is impossible.

**14. Pgp:** Ligand A (0.625) has moderate P-gp efflux. Ligand B (0.01) has very low P-gp efflux, which is favorable.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.9). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's strong binding affinity, its high DILI risk and relatively high metabolic clearance are major concerns. The solubility is also very poor. Ligand B has a much better safety profile (DILI, hERG, Pgp) but suffers from extremely poor predicted permeability (Caco-2) and impossible values for clearance and half-life.

Given the importance of metabolic stability and safety for kinase inhibitors, and the fact that the negative values for Ligand B's Cl_mic and t1/2 are almost certainly errors, I would cautiously favor Ligand A *if* the DILI risk could be mitigated through structural modifications. However, the data for Ligand B is so flawed that it's essentially unusable.

Output:
1
2025-04-17 14:28:25,730 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.375 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.84) is better than Ligand B (104.9), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (1.986 and 1.052), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=6) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.916) has a significantly better QED score than Ligand B (0.686), indicating a more drug-like profile.

**DILI:** Ligand A (80.962) has a higher DILI risk than Ligand B (20.279). This is a significant drawback for Ligand A.

**BBB:** Ligand A (74.719) has a better BBB penetration score than Ligand B (46.491), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.638 and -4.653), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.727 and -1.403), indicating very poor aqueous solubility. This is a significant issue for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.323) has a lower hERG inhibition risk than Ligand B (0.166), which is favorable.

**Microsomal Clearance:** Ligand A (23.806) has a lower microsomal clearance than Ligand B (34.643), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.058) has a slightly shorter half-life than Ligand B (28.983), but both are acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.055 and 0.066).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic) and QED. However, it has a significantly higher DILI risk and poor solubility. Ligand B has a lower DILI risk but weaker binding affinity and poorer metabolic stability. The large difference in binding affinity (-8.9 vs -6.7 kcal/mol) is a key factor. For an enzyme target like SRC kinase, potency is paramount. While the solubility and DILI of Ligand A are concerning, these can potentially be addressed through formulation strategies or further chemical modifications. The weaker binding of Ligand B is harder to overcome.

Output:
0
2025-04-17 14:28:25,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.375 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is slightly higher than Ligand B (67.67), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (0.602 and 0.787), falling within the 1-3 range.

**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, <=10 HBA).

**QED:** Ligand B (0.764) has a better QED score than Ligand A (0.492), indicating a more drug-like profile.

**DILI:** Ligand B (34.471) has a significantly lower DILI risk than Ligand A (18.457), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (71.074 and 70.105). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.963 and -4.573), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close.

**Aqueous Solubility:** Ligand B (0.031) has slightly better aqueous solubility than Ligand A (-0.658).

**hERG Inhibition:** Ligand A (0.437) has a lower hERG inhibition risk than Ligand B (0.275), which is favorable.

**Microsomal Clearance:** Ligand A (-6.504) has a much lower (better) microsomal clearance than Ligand B (24.008). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-10.242) has a much longer in vitro half-life than Ligand B (3.447), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.065).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.0 kcal/mol), with Ligand A being slightly better. The difference is less than 1.5 kcal/mol, so this isn't a decisive factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has a better QED and lower DILI, Ligand A exhibits significantly improved metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. The improved metabolic stability is crucial for kinase inhibitors, as they often require sustained exposure. The slightly better hERG profile of Ligand A is also a plus. The Caco-2 permeability is a concern for both, but the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 14:28:25,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 347.459 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.32) is well below the 140 threshold for good absorption, and is preferable to Ligand B (78.51).

**logP:** Both ligands (1.156 and 1.366) fall within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (2 HBD, 3 HBA) as it has fewer HBDs and stays within the acceptable range for both.

**QED:** Both ligands have similar QED scores (0.744 and 0.712), indicating good drug-likeness.

**DILI:** Ligand A (16.44) has a significantly lower DILI risk than Ligand B (19.271), which is a major advantage.

**BBB:** Both have acceptable BBB penetration, but Ligand A (69.678) is slightly better than Ligand B (65.374). This is not a primary concern for a kinase inhibitor, but a small benefit.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.939) is slightly better than Ligand B (-5.069).

**Aqueous Solubility:** Ligand A (-0.733) is better than Ligand B (-2.782) in terms of solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.295 and 0.215), which is good.

**Microsomal Clearance:** Ligand A (1.561) has a much lower microsomal clearance than Ligand B (53.958), indicating significantly better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-0.396) has a better in vitro half-life than Ligand B (-9.779).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.085).

**Binding Affinity:** Ligand B (-8.3 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 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 ADME properties: lower DILI risk, better solubility, significantly lower microsomal clearance (better metabolic stability), and a better in vitro half-life. These factors are particularly important for kinase inhibitors, where maintaining therapeutic concentrations is vital. The slightly better TPSA and H-bonding profile of Ligand A also contribute to its favorability.

Output:
0
2025-04-17 14:28:25,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.487 and 389.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is better than Ligand B (97.39). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (1.806 and 2.078), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is slightly better than Ligand B (2 HBD, 6 HBA) regarding HBD count, but both are within acceptable limits.

**QED:** Ligand A (0.815) has a significantly higher QED score than Ligand B (0.63), indicating a more drug-like profile.

**DILI:** Ligand A (47.964) has a much lower DILI risk than Ligand B (65.723), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.682) is better than Ligand B (59.558).

**Caco-2 Permeability:** Both have very poor Caco-2 permeability (-4.734 and -4.763). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.687 and -3.071). This is a significant drawback.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.35 and 0.381), which is good.

**Microsomal Clearance:** Ligand A (43.638) has significantly lower microsomal clearance than Ligand B (61.645), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.402) has a positive half-life, while Ligand B (-45.79) has a negative half-life, indicating very poor stability.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.35 and 0.441).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a higher QED score, lower DILI risk, better metabolic stability (lower Cl_mic and positive t1/2), and slightly better binding affinity. While both compounds have poor solubility and Caco-2 permeability, the ADME profile of Ligand A is far superior, making it a more promising drug candidate. The small advantage in binding affinity further supports this conclusion.

Output:
0
2025-04-17 14:28:25,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.385 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (105.48) is still acceptable but less optimal.

**logP:** Ligand A (2.048) is within the optimal 1-3 range. Ligand B (-0.709) is below 1, potentially hindering permeation.

**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 (A: 0.871, B: 0.565), indicating good drug-like properties.

**DILI:** Ligand A (54.75) has a slightly higher DILI risk than Ligand B (38.581), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.2) is higher than Ligand B (50.407).

**Caco-2 Permeability:** Ligand A (-4.984) and Ligand B (-5.538) both have negative values, indicating poor permeability. This is a concern.

**Aqueous Solubility:** Ligand A (-3.302) has better solubility than Ligand B (-0.597). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (A: 0.479, B: 0.154), which is excellent.

**Microsomal Clearance:** Ligand A (4.88 mL/min/kg) has a lower clearance than Ligand B (-11.273 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-42.239 hours) has a significantly longer half-life than Ligand B (7.554 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.09, B: 0.018).

**Binding Affinity:** Both ligands have the same binding affinity (-9.5 kcal/mol), which is excellent.

**Conclusion:**

While both ligands bind equally well, Ligand A is superior due to its better logP, solubility, metabolic stability (lower Cl_mic, longer t1/2), and slightly lower DILI risk. The lower logP of Ligand B is a significant concern, potentially leading to poor permeability. The longer half-life of Ligand A is also a substantial advantage for dosing considerations.

Output:
1
2025-04-17 14:28:25,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.43 & 343.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is better than Ligand B (114.3), being closer to the <140 threshold for good absorption.

**3. logP:** Both ligands have similar logP values (1.199 & 1.177), falling 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:** Both ligands have the same number of H-bond acceptors (5), which is within the acceptable range (<=10).

**6. QED:** Ligand A (0.588) has a slightly better QED score than Ligand B (0.491), indicating better overall drug-likeness.

**7. DILI:** Ligand B (57.35) has a higher DILI risk than Ligand A (44.55), although both are below the concerning threshold of 60.

**8. BBB:** Both have similar low BBB penetration (59.79 & 59.09), which isn't a major concern for a non-CNS target like SRC.

**9. Caco-2:** Both have very poor Caco-2 permeability (-4.947 & -4.939). This is a significant drawback for oral bioavailability.

**10. Solubility:** Both have poor aqueous solubility (-2.799 & -2.018). This is a concern for formulation and bioavailability.

**11. hERG:** Both ligands show very low hERG inhibition risk (0.144 & 0.145). This is excellent.

**12. Cl_mic:** Ligand B (-4.135) has significantly *lower* (better) microsomal clearance than Ligand A (16.608), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. t1/2:** Ligand B (-2.818) has a longer in vitro half-life than Ligand A (-1.581), further supporting its better metabolic stability.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.043 & 0.008).

**15. Binding Affinity:** Ligand B (-9.8 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.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and substantially stronger binding affinity outweigh the slightly higher DILI risk and lower QED. For an enzyme target like SRC kinase, potency and metabolic stability are paramount.

Output:
1
2025-04-17 14:28:25,732 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [350.415, 87.15, 0.301, 1, 5, 0.737, 14.23, 32.765, -4.657, -0.788, 0.091, 21.795, 3.306, 0.04, -8.6]
**Ligand B:** [346.387, 116.23, 0.768, 4, 4, 0.592, 61.07, 48.662, -5.608, -3.273, 0.18, 6.83, 34.299, 0.024, -8.2]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (350.415) and B (346.387) are very close.
2. **TPSA:** A (87.15) is excellent, well below 140 and good for oral absorption. B (116.23) is still acceptable, but less ideal.
3. **logP:** A (0.301) is quite low, potentially hindering permeability. B (0.768) is better, closer to the optimal 1-3 range.
4. **HBD:** A (1) is good. B (4) is higher, potentially impacting permeability.
5. **HBA:** A (5) is good. B (4) is also good.
6. **QED:** A (0.737) is very good, indicating high drug-likeness. B (0.592) is acceptable but lower.
7. **DILI:** A (14.23) is excellent, very low risk. B (61.07) is moderately high, a concern.
8. **BBB:** A (32.765) is low, not a priority for SRC (not a CNS target). B (48.662) is also low, and not a major factor here.
9. **Caco-2:** A (-4.657) is very poor. B (-5.608) is also poor, but slightly better. Both suggest significant permeability issues.
10. **Solubility:** A (-0.788) is poor. B (-3.273) is even worse. Solubility is a concern for both.
11. **hERG:** A (0.091) is excellent, very low risk of cardiotoxicity. B (0.18) is also good, but slightly higher.
12. **Cl_mic:** A (21.795) is moderate, suggesting reasonable metabolic stability. B (6.83) is very good, indicating higher metabolic stability.
13. **t1/2:** A (3.306) is relatively short. B (34.299) is excellent, suggesting a longer duration of action.
14. **Pgp:** A (0.04) is very low, indicating minimal efflux. B (0.024) is also very low.
15. **Affinity:** A (-8.6) is excellent, significantly stronger binding. B (-8.2) is also good, but weaker. The difference is 1.5 kcal/mol, which is a substantial advantage for A.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

Despite the solubility and Caco-2 issues, **Ligand A** is the more promising candidate. The significantly stronger binding affinity (-8.6 vs -8.2 kcal/mol) is a major advantage that can potentially outweigh the ADME drawbacks. Furthermore, A has a much lower DILI risk and a better QED score. While B has better metabolic stability, the superior potency and safety profile of A make it the better choice for further optimization. The solubility and permeability issues of A can be addressed through formulation strategies or further structural modifications.

Output:
0
2025-04-17 14:28:25,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 358.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (40.62) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (1.563 and 2.682), 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.786 and 0.775), indicating good drug-likeness.

**DILI:** Ligand A (29.624) has a significantly lower DILI risk than Ligand B (19.426), which is a major advantage. Lower DILI is always preferred.

**BBB:** Ligand A (75.107) has a good BBB penetration, while Ligand B (91.663) is even better. However, since SRC is not a CNS target, this is less crucial.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.301 and -4.521), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.55 and -3.82), which is also concerning and suggests poor solubility. This could hinder bioavailability.

**hERG Inhibition:** Ligand A (0.168) has a lower hERG inhibition risk than Ligand B (0.714), which is a significant advantage.

**Microsomal Clearance:** Ligand B (31.913) has a lower microsomal clearance than Ligand A (38.196), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.4) has a longer in vitro half-life than Ligand A (-11.624), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.03) has a lower P-gp efflux liability than Ligand B (0.143), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A exhibits a significantly lower DILI risk and hERG inhibition liability. Both ligands have concerningly poor predicted permeability and solubility. Given the enzyme-specific priorities, the improved potency of Ligand B is a key factor. While the solubility and permeability are problematic for both, these can potentially be addressed through formulation strategies. The lower DILI and hERG risk of Ligand A are valuable, but the potency advantage of Ligand B is more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:28:25,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.415 and 362.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.6) is better than Ligand B (109.76), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.881) is optimal (1-3), while Ligand B (0.338) is slightly low, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.761 and 0.655, both >=0.5).

**DILI:** Ligand A (64.444) has a lower DILI risk than Ligand B (81.892), which is preferable.

**BBB:** Both have similar BBB penetration (59.093 and 64.87), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.448) is better than Ligand B (-5.08), indicating better intestinal absorption.

**Solubility:** Ligand A (-3.382) is better than Ligand B (-2.323), indicating better aqueous solubility.

**hERG:** Both ligands show very low hERG inhibition risk (0.236 and 0.131).

**Microsomal Clearance:** Ligand A (44.758) has a higher Cl_mic than Ligand B (20.295), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-12.539) has a longer half-life than Ligand A (-30.892), which is preferable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.095 and 0.033).

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.4). While the difference is less than the 1.5 kcal/mol threshold to outweigh other factors, it's still a positive.

**Overall:**

Ligand A has advantages in TPSA, logP, DILI, Caco-2, and Solubility, and slightly better affinity. However, Ligand B has a significantly better half-life and lower microsomal clearance, which are critical for an enzyme target. The lower logP of Ligand B is a concern, but the superior metabolic stability and longer half-life are more important for kinase inhibitors. The slightly better affinity of Ligand A isn't enough to overcome the metabolic liability.

Output:
1
2025-04-17 14:28:25,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.459 Da and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.39) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (49.41) is excellent, well below 140.

**logP:** Ligand A (-0.709) is a bit low, potentially hindering permeability. Ligand B (2.85) is optimal.

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

**QED:** Both ligands have good QED scores (0.588 and 0.765, respectively), indicating drug-like properties.

**DILI:** Ligand A (35.595) has a slightly higher DILI risk than Ligand B (29.818), but both are below the concerning threshold of 60.

**BBB:** BBB is not a major concern for a non-CNS target like SRC. Ligand B (76.231) has a higher BBB score, but this is less relevant here. Ligand A (16.324) is lower.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.394 and -5.087), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.462 and -3.775), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.11) has a very low hERG risk, which is excellent. Ligand B (0.399) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (4.302) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (60.52) has a much higher clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-12.806) has a negative half-life, which is not physically possible and suggests an issue with the data or the compound. Ligand B (-15.836) also has a negative half-life, which is also concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.28).

**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 outweigh other significant drawbacks.

**Overall Assessment:**

Both compounds have serious issues with solubility and permeability. The negative Caco-2 and solubility values are major red flags. However, Ligand A has a more favorable metabolic stability profile (lower Cl_mic, though the half-life data is suspect) and a significantly lower hERG risk. Ligand B has a better logP and slightly better affinity, but the high metabolic clearance is a major concern. Given the priorities for enzyme inhibitors, metabolic stability and safety (hERG) are crucial. Although both have issues, Ligand A is slightly more promising due to its better metabolic profile and lower hERG risk. The negative half-life for both needs investigation.

Output:
0
2025-04-17 14:28:25,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.362 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (71.34). A TPSA under 140 is good for oral absorption, and both are well within this limit, but A is preferable.

**logP:** Both ligands have good logP values (3.26 and 3.653), 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 maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar QED values (0.7 and 0.712), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (33.812 and 36.603), well below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (86.584 and 85.459), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.603 and -4.498). This is unusual and suggests a potential issue with permeability prediction. However, the magnitude is similar for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.293 and -3.947). Again, this is unusual and suggests potential formulation challenges. The values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.649 and 0.702), which is excellent.

**Microsomal Clearance:** Ligand A (24.523 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (59.878 mL/min/kg). This suggests better metabolic stability for Ligand A, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-15.846 hours) has a negative half-life, which is not possible. Ligand B (34.018 hours) has a reasonable half-life. This is a major red flag for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.665), which is favorable.

**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.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the primary differentiating factor is the microsomal clearance and in vitro half-life. Ligand A has significantly better metabolic stability (lower Cl_mic) but an impossible half-life value. Ligand B has a reasonable half-life, making it the more viable candidate despite its higher Cl_mic. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 14:28:25,733 - INFO - Batch 299 complete. Total preferences: 4784
2025-04-17 14:28:25,733 - INFO - Processing batch 300/512...
2025-04-17 14:29:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 344.371 Da - Within the ideal range (200-500 Da).
* Ligand B: 372.809 Da - Within the ideal range (200-500 Da).
* *Both are acceptable.*

**2. TPSA:**
* Ligand A: 127.43 A^2 - Acceptable, but approaching the upper limit for good oral absorption.
* Ligand B: 102.88 A^2 - Excellent, well below the 140 A^2 threshold.
* *Ligand B is better.*

**3. logP:**
* Ligand A: 1.47 - Optimal.
* Ligand B: 0.729 - Slightly low, potentially impacting permeability.
* *Ligand A is better.*

**4. H-Bond Donors (HBD):**
* Ligand A: 3 - Acceptable (<=5).
* Ligand B: 1 - Acceptable (<=5).
* *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 7 - Acceptable (<=10).
* Ligand B: 8 - Acceptable (<=10).
* *Both are acceptable.*

**6. QED:**
* Ligand A: 0.677 - Good, above the 0.5 threshold.
* Ligand B: 0.754 - Very good, above the 0.5 threshold.
* *Ligand B is better.*

**7. DILI:**
* Ligand A: 84.684 - Moderate risk.
* Ligand B: 89.492 - Moderate risk.
* *Neither is ideal, but both are within a manageable range.*

**8. BBB:**
* Ligand A: 62.35 - Not a priority for a non-CNS target like SRC.
* Ligand B: 64.482 - Not a priority for a non-CNS target like SRC.
* *Equal.*

**9. Caco-2 Permeability:**
* Ligand A: -5.185 - Poor permeability.
* Ligand B: -4.719 - Poor permeability.
* *Both are poor, but B is slightly better.*

**10. Aqueous Solubility:**
* Ligand A: -3.977 - Poor solubility.
* Ligand B: -3.035 - Poor solubility.
* *Ligand B is slightly better.*

**11. hERG Inhibition:**
* Ligand A: 0.213 - Low risk, excellent.
* Ligand B: 0.124 - Low risk, excellent.
* *Both are excellent.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 43.648 mL/min/kg - Moderate clearance.
* Ligand B: 52.71 mL/min/kg - Moderate clearance.
* *Ligand A is better (lower clearance).*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 15.537 hours - Good.
* Ligand B: -12.374 hours - Very poor.
* *Ligand A is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.11 - Low efflux, good.
* Ligand B: 0.029 - Very low efflux, excellent.
* *Ligand B is better.*

**15. Binding Affinity:**
* Ligand A: -7.3 kcal/mol - Excellent.
* Ligand B: -8.4 kcal/mol - Outstanding, 1.1 kcal/mol stronger.

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a superior binding affinity (-8.4 kcal/mol vs -7.3 kcal/mol), better TPSA, QED, Caco-2 permeability, solubility, and P-gp efflux. However, it has a significantly worse in vitro half-life. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and acceptable solubility. The affinity difference between B and A is substantial. Given the enzyme target, the stronger binding affinity of Ligand B is a major advantage that outweighs the poorer half-life, especially considering optimization strategies can often improve metabolic stability.

Output:
1
2025-04-17 14:29:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.423 and 344.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have similar TPSA values (58.38 and 58.44), which are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.538) is slightly higher than Ligand B (2.005). Both are within the optimal range of 1-3, but Ligand B is closer to the lower limit, which *could* present permeability challenges.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and acceptable HBA counts (5 and 4 respectively), satisfying the criteria for good permeability.

**QED:** Ligand A (0.835) has a better QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand A (65.491) has a significantly higher DILI risk than Ligand B (25.514). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (73.827 and 77.705), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.58 and -4.785). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**Aqueous Solubility:** Ligand A (-5.488) has significantly worse aqueous solubility than Ligand B (-1.003). This is a substantial drawback for Ligand A.

**hERG Inhibition:** Ligand A (0.797) has a slightly higher hERG risk than Ligand B (0.195), but both are relatively low.

**Microsomal Clearance:** Ligand A (86.717) has a much higher microsomal clearance than Ligand B (48.676), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-14.271) has a negative half-life, which is not possible. This is a data error, and makes it difficult to assess its metabolic stability. Ligand A (16.643) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.406 and 0.172).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), but the difference is relatively small (0.3 kcal/mol).

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its significantly higher DILI risk, lower solubility, and higher microsomal clearance make it a less desirable candidate. The negative half-life value for Ligand B is a data quality issue, but the other favorable properties (lower DILI, better solubility, lower clearance) make it the more promising candidate. The difference in binding affinity is not large enough to overcome the ADME deficiencies of Ligand A.

Output:
1
2025-04-17 14:29:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.351 and 382.961 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is higher than Ligand B (41.37). Both are acceptable, but Ligand B is better for permeability.

**logP:** Both ligands have similar logP values (3.699 and 3.702), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.699) has a better QED score than Ligand A (0.414), indicating a more drug-like profile.

**DILI:** Ligand B (24.195) has a significantly lower DILI risk than Ligand A (39.511), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, with Ligand A at 87.088 and Ligand B at 74.292. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.356 and -4.848), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.261 and -2.195), indicating poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.891) has a slightly higher hERG risk than Ligand B (0.798), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (60.666 and 59.368), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (43.815) has a substantially longer in vitro half-life than Ligand A (27.368), which is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.251) has a higher P-gp efflux liability than Ligand B (0.212), meaning Ligand B will likely have better oral bioavailability.

**Binding Affinity:** Ligand A (-9.0) has a much stronger binding affinity than Ligand B (-0.0). This is a very substantial advantage, and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity (-9.0 kcal/mol vs -0.0 kcal/mol). However, Ligand B demonstrates superior drug-like properties in terms of DILI risk, QED, in vitro half-life, and P-gp efflux. Both ligands have poor solubility and permeability. Given the importance of potency for kinase inhibitors, and the large difference in binding affinity, Ligand A is the more promising candidate *despite* its poorer ADME profile. The strong binding affinity could potentially be optimized with further modifications to improve solubility and permeability.

Output:
0
2025-04-17 14:29:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 362.857 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.36) is slightly higher than Ligand B (62.55), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.163 and 2.949), 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 (0.718 and 0.837), indicating good drug-like properties.

**DILI:** Ligand A (26.522) has a significantly lower DILI risk than Ligand B (34.703), which is a major advantage. Both are below the 40 threshold, but A is preferable.

**BBB:** Ligand A (70.803) has a better BBB penetration score than Ligand B (65.025), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.516 and -4.55), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.295) has better solubility than Ligand B (-5.031), which is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.276 and 0.236), which is excellent.

**Microsomal Clearance:** Ligand A (38.698) has a higher microsomal clearance than Ligand B (20.554), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (6.738) has a significantly longer in vitro half-life than Ligand A (29.112). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.06), which is favorable.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a significant advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A boasts superior binding affinity and a much lower DILI risk, and better solubility. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has better metabolic stability and half-life, but weaker binding affinity and a higher DILI risk. Considering the enzyme-specific priorities, the stronger binding affinity of Ligand A is a critical factor. The difference in binding affinity (-7.3 vs -6.4 kcal/mol) is substantial. While the metabolic stability of Ligand B is better, this can potentially be addressed through structural modifications during lead optimization. The lower DILI risk of Ligand A is also a significant benefit.

Output:
1
2025-04-17 14:29:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.43 and 350.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.49) is slightly higher than Ligand B (53.43). Both are below the 140 threshold for good oral absorption, but the lower TPSA of Ligand B is slightly preferable.

**logP:** Ligand A (2.496) and Ligand B (3.684) are both within the optimal 1-3 range. Ligand B is closer to the upper limit, which *could* present solubility issues, but isn't a major concern.

**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). Ligand B is slightly more favorable here.

**QED:** Both ligands have reasonable QED scores (0.846 and 0.691), indicating good drug-like properties.

**DILI:** Ligand A (34.703) has a significantly higher DILI risk than Ligand B (13.649). This is a major red flag for Ligand A.

**BBB:** Ligand A (68.088) and Ligand B (80.574) both have acceptable BBB penetration, but Ligand B is better. This isn't a primary concern for an oncology target, but it's a positive for B.

**Caco-2 Permeability:** Ligand A (-5.336) has poor Caco-2 permeability, while Ligand B (-4.389) is slightly better, but still poor. Both are problematic, suggesting potential absorption issues.

**Aqueous Solubility:** Ligand A (-1.449) has slightly better solubility than Ligand B (-3.651), which is a positive.

**hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.673 and 0.768), and are within acceptable limits.

**Microsomal Clearance:** Ligand A (-42.889) has significantly lower (better) microsomal clearance than Ligand B (66.218). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (38.069) has a much longer half-life than Ligand B (-10.813). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.04 and 0.308), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent. This removes binding affinity as a differentiating factor.

**Overall Assessment:**

Ligand A has advantages in metabolic stability (Cl_mic, t1/2) and solubility, but suffers from a significantly higher DILI risk and poor Caco-2 permeability. Ligand B has a lower DILI risk and slightly better Caco-2 permeability and TPSA, but worse metabolic stability.

Given the enzyme-specific priorities, metabolic stability and DILI risk are crucial. While Ligand A's longer half-life and better solubility are attractive, the high DILI risk is a major concern. Ligand B's lower DILI risk outweighs its slightly worse metabolic stability, especially considering that metabolic stability can be improved through structural modifications.

Output:
1
2025-04-17 14:29:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.419 Da) is slightly better positioned.

**TPSA:** Ligand B (58.2) is significantly better than Ligand A (113.44). Lower TPSA generally improves permeability.

**logP:** Ligand B (3.934) is higher than Ligand A (0.115). While 3.934 is approaching the upper limit, it's still acceptable. Ligand A's logP is very low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits, but Ligand B is slightly more favorable due to having fewer hydrogen bonding groups.

**QED:** Ligand A (0.671) has a better QED score than Ligand B (0.487), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 49.011, Ligand B: 42.148). Ligand B is slightly better.

**BBB:** Ligand B (82.513) has a much higher BBB percentile than Ligand A (43.66). While SRC is not a CNS target, higher BBB is generally not detrimental.

**Caco-2 Permeability:** Ligand A (-5.249) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.925) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.391) has slightly better solubility than Ligand B (-4.26).

**hERG Inhibition:** Ligand A (0.158) has a lower hERG risk than Ligand B (0.425), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-4.236) has a significantly *lower* (better) microsomal clearance than Ligand B (53.171), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.75) has a shorter half-life than Ligand B (18.172).

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.343), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic), lower P-gp efflux, and lower hERG risk. While its logP and Caco-2 permeability are concerning, the strong binding affinity (-9.8 kcal/mol) is a major advantage that can potentially be overcome with formulation strategies. Ligand B has better TPSA and BBB, but its weaker affinity and higher metabolic clearance are significant drawbacks. Considering the priorities for kinase inhibitors, potency and metabolic stability are paramount.

Output:
0
2025-04-17 14:29:15,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.86 and 375.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.59 and 66.32) are slightly above the optimal <140 for good absorption, but not drastically so. This is less critical for a non-CNS target like SRC.

**logP:** Both ligands have good logP values (3.20 and 2.83), falling within the 1-3 range, suggesting good permeability and avoiding solubility issues.

**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.

**QED:** Both ligands have acceptable QED scores (0.879 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A (67.47%) has a higher DILI risk than Ligand B (54.48%), which is a significant concern.

**BBB:** This is less important for SRC, but Ligand A (66.42%) has a higher BBB penetration than Ligand B (29.93%).

**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 (-4.95 and -5.32).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-2.95) is slightly better than Ligand A (-4.12).

**hERG:** Ligand A (0.586) has a slightly better hERG profile than Ligand B (0.323), suggesting lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-5.585) has *much* better metabolic stability (lower clearance) than Ligand B (60.834). This is a major advantage.

**In vitro Half-Life:** Ligand A (39.89 hours) has a significantly longer half-life than Ligand B (11.03 hours). This is highly desirable.

**P-gp Efflux:** Ligand A (0.184) has lower P-gp efflux than Ligand B (0.269), which is favorable for bioavailability.

**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 relatively small (0.6 kcal/mol) and may not outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate despite the slightly weaker binding affinity. Its significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better hERG profile outweigh the small difference in binding affinity. The higher DILI risk for Ligand A is a concern, but could be addressed with further structural modifications. The negative solubility and Caco-2 values are concerning and require further investigation, but are similar for both compounds.

Output:
0
2025-04-17 14:29:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.415 and 369.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.11) is slightly higher than Ligand B (88.52), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (1.614) and Ligand B (0.809) are both within the optimal range of 1-3. Ligand B is a bit lower, which *could* slightly impact permeability, 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 good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 8, which is approaching the upper limit, but still within range.

**6. QED:** Both ligands have similar QED values (0.711 and 0.77), indicating good drug-like properties.

**7. DILI:** Ligand A (56.805) has a lower DILI risk than Ligand B (63.086), which is preferable. Both are below the concerning threshold of 60, but lower is better.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern. Ligand B (84.451) has a higher BBB penetration than Ligand A (51.415).

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-5.367) is significantly worse than Ligand B (-4.649).

**10. Aqueous Solubility:** Both ligands have negative values, which is also unusual. Assuming these are logS values, lower values indicate poorer solubility. Ligand A (-2.687) is slightly worse than Ligand B (-2.616).

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.459 and 0.442), which is excellent.

**12. Microsomal Clearance:** Ligand A (1.758) has significantly lower microsomal clearance than Ligand B (44.085), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (14.813) has a longer half-life than Ligand B (5.467), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04).

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-9.8). However, the difference is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. While Ligand B has slightly better binding affinity and Caco-2 permeability, the ADME profile of Ligand A is far more favorable for development as a kinase inhibitor. The solubility and permeability issues for both are concerning, but the metabolic stability advantage of A is more critical.

Output:
0
2025-04-17 14:29:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (431.664 Da) is slightly higher than Ligand B (373.45 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for oral absorption. Ligand B (93.46) is also below the threshold, but closer to it.

**logP:** Ligand A (4.368) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.333) is within the optimal range (1-3).

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

**QED:** Both ligands have good QED scores (A: 0.523, B: 0.714), indicating a generally drug-like profile. Ligand B is slightly better.

**DILI:** Both ligands have similar DILI risk (A: 73.982, B: 65.568), and are both acceptable.

**BBB:** Both ligands have good BBB penetration (A: 79.178, B: 71.501), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.585) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.266) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.554) has very poor solubility. Ligand B (-3.119) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.84) has a slightly higher hERG risk than Ligand B (0.29), which is preferable.

**Microsomal Clearance:** Ligand A (64.995) has higher clearance, indicating lower metabolic stability. Ligand B (46.625) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (92.792) has a longer half-life than Ligand B (5.027). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.511) has lower P-gp efflux than Ligand B (0.075), which is preferable.

**Binding Affinity:** Ligand B (-8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7 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 permeability, Ligand B has a significantly better binding affinity (-8 vs -7 kcal/mol), better logP, lower hERG risk, and better metabolic stability (lower Cl_mic). The longer half-life of Ligand A is attractive, but the superior potency and ADME profile of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 14:29:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (385.917 and 376.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (80.23 and 76.15) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.009) is optimal, while Ligand B (1.089) is slightly below the preferred range, 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 (0.795 and 0.694), indicating drug-like properties.

**7. DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (38.852). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (86.39 and 82.009), but this is less critical for a non-CNS target like SRC.

**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.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or very poor solubility.

**11. hERG Inhibition:** Ligand A (0.191) has a lower hERG risk than Ligand B (0.507), which is favorable.

**12. Microsomal Clearance:** Ligand A (15.241) has significantly lower microsomal clearance than Ligand B (51.15), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (21.21) has a longer half-life than Ligand B (-56.212), which is a major advantage. The negative value for Ligand B is concerning.

**14. P-gp Efflux:** Ligand A (0.517) has lower P-gp efflux than Ligand B (0.078), suggesting better oral bioavailability.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Despite Ligand A's higher DILI risk, its superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, slightly better affinity, and lower hERG risk make it the more promising candidate. The negative solubility and Caco-2 values are concerning for both, but the ADME properties of Ligand A are generally superior. The difference in binding affinity is not large enough to overcome the significant ADME advantages of Ligand A.

Output:
0
2025-04-17 14:29:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.793 and 353.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is better than Ligand B (78.95), both are under the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Ligand A (3.723) is optimal, while Ligand B (0.492) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, well below the 5 limit.

**H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of 10.

**QED:** Ligand B (0.78) has a better QED score than Ligand A (0.543), suggesting a more drug-like profile.

**DILI:** Ligand A (96.82) has a very high DILI risk, which is a major concern. Ligand B (15.898) has a low DILI risk, a significant advantage.

**BBB:** Both ligands have similar BBB penetration (55.487 and 58.821), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.864 and -4.784), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.877 and -0.881), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.279) has a slightly better hERG profile than Ligand B (0.107), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (12.165) has a lower microsomal clearance than Ligand A (34.48), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (101.147) has a much longer in vitro half-life than Ligand B (-5.489), which is a positive.

**P-gp Efflux:** Ligand A (0.289) has lower P-gp efflux than Ligand B (0.014), which is preferable.

**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 of the ADME concerns.

**Overall Assessment:**

Ligand A has a better half-life and P-gp efflux, but suffers from a very high DILI risk and poor solubility. Ligand B has a significantly better binding affinity, lower DILI, and better metabolic stability, but has a lower logP and poor solubility. The strong binding affinity of Ligand B is a major advantage for an enzyme target. While the solubility and logP are concerning, these could potentially be addressed through formulation or further chemical modifications. The high DILI risk of Ligand A is a more difficult issue to resolve.

Output:
1
2025-04-17 14:29:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.837 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.26) is better than Ligand B (52.65) as it is closer to the <140 threshold for good absorption.

**logP:** Ligand A (4.128) is slightly higher than optimal (1-3), potentially leading to solubility issues, while Ligand B (2.301) is within the ideal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.723 and 0.849), indicating good 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 6.592, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (79.566) is higher than Ligand A (56.34), but this is not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.861 and -4.816), 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 have negative solubility values (-5.23 and -2.85), indicating poor aqueous solubility. Ligand B is better in this regard.

**hERG Inhibition:** Ligand A (0.746) has a higher hERG risk than Ligand B (0.525), which is undesirable.

**Microsomal Clearance:** Ligand B (30.292 mL/min/kg) has significantly lower microsomal clearance than Ligand A (83.119 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (3.734 hours) has a longer half-life than Ligand A (14.222 hours). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.563) has lower P-gp efflux than Ligand B (0.04), which is better.

**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, and a difference of 1.9 kcal/mol is substantial enough to outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having a better P-gp efflux, Ligand B is the superior candidate. Its significantly improved binding affinity, much lower DILI risk, and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly higher logP and lower P-gp efflux of Ligand A. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies. The strong binding affinity of Ligand B is a key driver for its selection.

Output:
1
2025-04-17 14:29:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.825 and 355.523 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.52) is significantly better than Ligand B (81.67). A TPSA below 140 is good for oral absorption, and both are under this limit, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (3.886) is within the optimal 1-3 range, while Ligand B (1.525) is on the lower side. Lower logP can hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Fewer H-bond donors generally improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.696) has a slightly better QED score than Ligand B (0.586), indicating a more drug-like profile. Both are above the 0.5 threshold.

**DILI:** Ligand A (63.668) has a higher DILI risk than Ligand B (5.312). This is a significant drawback for Ligand A.

**BBB:** Ligand A (82.009) has better BBB penetration than Ligand B (30.826), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.935) has significantly better Caco-2 permeability than Ligand B (-5.056). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-4.579) has better aqueous solubility than Ligand B (-0.94). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.91) has a lower hERG inhibition risk than Ligand B (0.15). Lower hERG risk is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (57.882) has a higher microsomal clearance than Ligand B (8.057), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (8.42) has a longer half-life than Ligand B (2.283). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.733) has lower P-gp efflux than Ligand B (0.026), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is the most important factor for an enzyme inhibitor, and the difference of 1.6 kcal/mol is substantial.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME drawbacks. The significantly superior binding affinity (-9.0 vs -7.4 kcal/mol) outweighs the lower logP and slightly worse solubility. The much lower DILI risk and significantly better metabolic stability (lower Cl_mic) are also major advantages. Ligand A has better permeability and solubility, but its higher DILI risk and lower metabolic stability are concerning.

Output:
1
2025-04-17 14:29:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (82.49). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands (2.513 and 2.32) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for better permeability.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5). Lower HBA is generally preferred for better permeability.

**QED:** Both ligands have good QED scores (0.719 and 0.837), indicating good drug-like properties.

**DILI:** Ligand A (21.675) has a considerably lower DILI risk than Ligand B (29.818), which is a significant advantage. Both are below the 40 threshold, but lower is always better.

**BBB:** Ligand A (71.811) has a higher BBB penetration score than Ligand B (43.815). While not a primary concern for a non-CNS target like SRC, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Ligand A (-4.667) is better than Ligand B (-5.145). Higher Caco-2 permeability suggests better absorption.

**Aqueous Solubility:** Ligand A (-2.116) is better than Ligand B (-1.808). Better solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.346 and 0.365).

**Microsomal Clearance:** Ligand B (34.096) has lower microsomal clearance than Ligand A (43.312), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (28.851) has a significantly longer in vitro half-life than Ligand A (-11.696). This is a major advantage, suggesting less frequent dosing potential.

**P-gp Efflux:** Ligand A (0.261) has lower P-gp efflux than Ligand B (0.058). Lower efflux is preferable.

**Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (0). A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

Ligand B wins on binding affinity and metabolic stability (lower Cl_mic and longer t1/2), which are critical for kinase inhibitors. The slightly higher TPSA and H-bond donors/acceptors are less concerning given the strong affinity. While Ligand A has better solubility and lower DILI, the potency and metabolic advantages of Ligand B outweigh these benefits.

Output:
1
2025-04-17 14:29:15,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (341.455 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.99) is slightly higher than Ligand B (64.8). Both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets (not relevant here).

**3. logP:** Both ligands have good logP values (3.75 and 3.31), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 3 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 2 HBA, and Ligand B has 5. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.684 and 0.755), indicating good drug-like properties.

**7. DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (48.468). Ligand B is preferable here.

**8. BBB:** This is less important for a non-CNS target like SRC. Ligand B (84.219) has a higher BBB percentile than Ligand A (68.748).

**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:** Ligand A (-5.168) has worse solubility than Ligand B (-2.735). Ligand B is preferable.

**11. hERG Inhibition:** Ligand A (0.738) has a slightly higher hERG risk than Ligand B (0.337). Ligand B is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (55.85) has lower clearance than Ligand B (85.888), indicating better metabolic stability. This is a key factor for enzymes.

**13. In vitro Half-Life:** Ligand A (24.074) has a much longer half-life than Ligand B (0.003). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.44) has lower P-gp efflux than Ligand B (0.209), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-9.0) has significantly stronger binding affinity than Ligand A (-6.8). A difference of 2.2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-9.0 vs -6.8 kcal/mol). While Ligand A has better metabolic stability (lower Cl_mic and longer half-life), the substantial affinity advantage of Ligand B is likely to be more important. Ligand B also shows better DILI, solubility and hERG profiles. The Caco-2 values are concerning for both, but the superior binding and better ADME properties of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 14:29:15,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.893 and 377.432 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (45.55), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.133) is optimal, while Ligand B (1.919) is slightly lower, but still acceptable.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (3) is acceptable, while Ligand B (5) is also acceptable.

**QED:** Both ligands have good QED scores (0.618 and 0.76), indicating good drug-like properties.

**DILI:** Ligand A (42.885) has a slightly higher DILI risk than Ligand B (22.218), but both are below the concerning threshold of 60.

**BBB:** Ligand A (52.268) has a lower BBB penetration than Ligand B (87.088). However, since SRC is not a CNS target, this is less important.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we will proceed with the comparison based on the other parameters.

**Solubility:** Ligand A (-4.097) has a worse solubility than Ligand B (-1.851). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.298 and 0.67).

**Microsomal Clearance:** Ligand A (39.269) has higher microsomal clearance than Ligand B (7.901), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-26.107) has a much longer in vitro half-life than Ligand A (10.649). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.104 and 0.095).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -9.9 kcal/mol). Ligand B is slightly better.

**Conclusion:**

While both ligands have good potency, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and better solubility. The slightly better BBB penetration of Ligand B is not a major factor for a non-CNS target. The DILI risk is lower for Ligand B.

Output:
1
2025-04-17 14:29:15,167 - INFO - Batch 300 complete. Total preferences: 4800
2025-04-17 14:29:15,167 - INFO - Processing batch 301/512...
2025-04-17 14:29:57,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.446 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (99.77), both being acceptable but closer to the upper limit for good oral absorption (<=140).

**logP:** Both ligands have good logP values (2.459 and 1.742), falling within the 1-3 range. Ligand A is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBD and a reasonable number of HBA (5 and 4 respectively), satisfying the <=5 and <=10 rules.

**QED:** Both ligands have good QED scores (0.509 and 0.561), indicating good drug-likeness.

**DILI:** Ligand B (22.8) has a significantly lower DILI risk than Ligand A (50.33), which is a major advantage.

**BBB:** Ligand B (64.017) has a higher BBB penetration percentile than Ligand A (45.444). While not crucial for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.184 and -5.417), which is unusual and indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.601 and -2.38), indicating poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.234) has a slightly higher hERG risk than Ligand B (0.046), making Ligand B safer in terms of cardiotoxicity.

**Microsomal Clearance:** Ligand B (27.571) has a significantly lower microsomal clearance than Ligand A (52.358), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-19.949) has a much longer in vitro half-life than Ligand A (-3.625), which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.097 and 0.008).

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A's significantly stronger binding affinity (-8.9 kcal/mol vs -7.5 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The improved affinity is likely to be more impactful than the slightly worse ADME properties of Ligand A, especially the DILI risk. Ligand B has better ADME properties, but the weaker binding affinity is a significant drawback.

Output:
1
2025-04-17 14:29:57,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.427 and 345.395 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (75.43 and 72.91) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (1.947 and 1.96) 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 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.921) has a significantly higher QED score than Ligand B (0.763), suggesting a more drug-like profile.

**7. DILI:** Ligand A (58.395) has a higher DILI risk than Ligand B (39.783). This is a negative for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (79.682 and 88.91). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.44 and -4.182). This is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method and should be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.073 and -3.325). Similar to Caco-2, these are likely prediction artifacts and suggest potentially poor solubility.

**11. hERG Inhibition:** Ligand A (0.726) has a slightly higher hERG risk than Ligand B (0.576), but both are reasonably low.

**12. Microsomal Clearance:** Ligand B (75.949) has a lower microsomal clearance than Ligand A (57.664), indicating better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (6.406) has a longer in vitro half-life than Ligand A (13.981). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.593) has lower P-gp efflux than Ligand B (0.298), which is favorable.

**15. Binding Affinity:** Ligand B (-6.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a crucial advantage, as potency is a primary concern for kinase inhibitors.

**Overall Assessment:**

While Ligand A has a better QED and lower P-gp efflux, Ligand B is superior due to its significantly stronger binding affinity, better metabolic stability (lower Cl_mic and longer t1/2), and lower DILI risk. The negative Caco-2 and solubility predictions are concerning for both, but the substantial affinity advantage of Ligand B outweighs these concerns.

Output:
1
2025-04-17 14:29:57,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly lower, which could be advantageous for permeability. Ligand B (399.336 Da) is also acceptable.

**TPSA:** Ligand A (84.5) is significantly better than Ligand B (44.85). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (2.023) being slightly more favorable than Ligand B (4.217). High logP can lead to off-target effects and poor solubility.

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

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range.

**QED:** Both ligands have similar QED values (0.716 and 0.655), indicating good drug-likeness.

**DILI:** Ligand A (19.155) has a much lower DILI risk than Ligand B (25.165), a significant advantage.

**BBB:** Ligand B (74.254) has a higher BBB penetration percentile than Ligand A (49.011). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.446) has a more favorable Caco-2 permeability than Ligand B (-5.179), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.641) has better aqueous solubility than Ligand B (-4.252). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.189 and 0.929), which is excellent.

**Microsomal Clearance:** Ligand A (69.043) has higher microsomal clearance than Ligand B (42.607), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (28.524) has a significantly longer in vitro half-life than Ligand A (-21.907), which is a major advantage. A longer half-life translates to less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.054 and 0.789).

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. While Ligand A has slightly better TPSA, logP, solubility, and Caco-2 permeability, the metabolic stability and safety profile of Ligand B outweigh these minor advantages. The similar binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 14:29:57,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.466 and 363.439 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, while Ligand B (88.6) is still acceptable but higher.

**logP:** Ligand A (2.508) is optimal. Ligand B (0.981) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the limit of 5.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is also acceptable, below the 10 limit.

**QED:** Both ligands have good QED scores (0.658 and 0.788), indicating drug-likeness.

**DILI:** Ligand A (20.744) has a significantly lower DILI risk than Ligand B (41.838), which is a major advantage.

**BBB:** Both have reasonably high BBB penetration (81.892 and 79.411), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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 very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.499 and 0.217).

**Microsomal Clearance:** Ligand A (24.778) has a lower Cl_mic than Ligand B (27.238), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.708) has a negative half-life, which is not possible. This is a critical issue. Ligand A (10.757) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.072 and 0.068), which is 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, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Ligand A is the superior candidate. While both have solubility and permeability issues (negative Caco-2 and solubility values), Ligand A demonstrates a significantly stronger binding affinity, lower DILI risk, and better metabolic stability. The negative half-life for Ligand B is a showstopper. The superior binding affinity of Ligand A can potentially compensate for the solubility/permeability issues, making it a more promising starting point for optimization.

Output:
1
2025-04-17 14:29:57,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.381 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (117.7), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.943 and 2.201), falling within the 1-3 range.

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

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), staying well below the 10 limit.

**QED:** Both ligands have reasonable QED scores (0.851 and 0.728), indicating good drug-like properties.

**DILI:** Ligand A (36.758) has a much lower DILI risk than Ligand B (85.615). This is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (73.827) has better BBB penetration than Ligand B (48.662).

**Caco-2 Permeability:** Ligand A (-4.745) has a slightly better (less negative) Caco-2 permeability than Ligand B (-5.248), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.903) has better aqueous solubility than Ligand B (-3.249).

**hERG Inhibition:** Ligand A (0.331) has a significantly lower hERG inhibition risk than Ligand B (0.133). This is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-6.842) exhibits much lower microsomal clearance, suggesting better metabolic stability, compared to Ligand B (13.265).

**In vitro Half-Life:** Ligand A (-10.771) has a longer in vitro half-life than Ligand B (23.172).

**P-gp Efflux:** Ligand A (0.044) shows lower P-gp efflux than Ligand B (0.153).

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is not substantial enough to offset the ADME advantages of Ligand A.

**Overall:**

Ligand A is clearly superior. While Ligand B has slightly better binding affinity, Ligand A excels in almost all ADME properties, including significantly lower DILI and hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and improved solubility and permeability. These factors are critical for developing a viable drug candidate, especially for an enzyme target like SRC kinase. The small difference in binding affinity is outweighed by the substantial improvements in drug-like properties.

Output:
0
2025-04-17 14:29:57,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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. Ligand B (377.507 Da) is also acceptable.

**TPSA:** Ligand A (47.36) is excellent, well below the 140 threshold for oral absorption. Ligand B (79.39) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (2.744) is optimal (1-3). Ligand B (-0.536) is significantly lower, which is a concern for membrane permeability and could hinder oral absorption.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (4 for A, 6 for B) counts, well within the recommended limits.

**QED:** Both ligands have reasonable QED values (0.86 for A, 0.565 for B), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (29.042 and 27.336), which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.684) has a higher BBB score than Ligand B (63.086), but this isn't a major factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.634 and -4.651), 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 (-2.84 and -1.324), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.486) has a lower hERG risk than Ligand B (0.579), which is preferable.

**Microsomal Clearance:** Ligand A (73.322) has a higher microsomal clearance than Ligand B (32.215), indicating lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand B (-46.56) has a much longer in vitro half-life than Ligand A (-13.481), which is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.47 and 0.007).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better TPSA and hERG profiles. However, it has a higher microsomal clearance and a shorter half-life. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) but suffers from a significantly lower logP, which is a major concern for permeability and bioavailability. The strong binding affinity of Ligand A is a critical factor for kinase inhibitors, and its other properties, while not ideal, might be optimized further. The poor logP of Ligand B is a more difficult property to improve without significantly altering the binding pose.

Output:
0
2025-04-17 14:29:57,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.452 Da) is slightly higher than Ligand B (333.439 Da), but both are acceptable.

**2. TPSA:** Ligand A (42.74) is significantly better than Ligand B (62.73). Lower TPSA generally indicates better cell permeability.

**3. logP:** Both ligands have logP values around 4 (A: 3.968, B: 4.323). This is slightly high, potentially leading to solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (1) 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 (A: 0.679, B: 0.63), indicating good drug-likeness.

**7. DILI:** Ligand A (14.036) has a much lower DILI risk than Ligand B (76.464). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (92.323) has a much higher BBB penetration potential than Ligand B (68.166). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**9. Caco-2 Permeability:** Ligand A (-4.727) is better than Ligand B (-5.117). Higher Caco-2 permeability suggests better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.637) is better than Ligand B (-4.334). Better solubility is crucial for bioavailability.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.829, B: 0.861).

**12. Microsomal Clearance:** Ligand A (8.323) has a significantly lower microsomal clearance than Ligand B (88.532). This indicates greater metabolic stability for Ligand A, a key factor for enzymes.

**13. In vitro Half-Life:** Ligand A (13.751) has a better in vitro half-life than Ligand B (62.641). This also supports greater metabolic stability for Ligand A.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.606, B: 0.753).

**15. Binding Affinity:** Both ligands have very similar binding affinities (A: -8.0, B: -8.5). The difference is negligible.

**Conclusion:**

Ligand A is significantly better than Ligand B. While both have acceptable binding affinity and drug-likeness, Ligand A excels in crucial ADME properties: lower DILI risk, better solubility, significantly lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The lower TPSA, HBD, and HBA also contribute to its favorable profile. These factors are particularly important for an enzyme target like SRC kinase.

Output:
0
2025-04-17 14:29:57,749 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.511 and 376.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands (2.366 and 3.482) are 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:** Ligand A (3) is higher than Ligand B (1), but both are within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.725 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (35.905) has a slightly higher DILI risk than Ligand B (30.826), but both are below the concerning threshold of 60.

**BBB:** Ligand A (59.636) has a lower BBB penetration percentile than Ligand B (71.811). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.995) has worse Caco-2 permeability than Ligand B (-5.365). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.795) has slightly better aqueous solubility than Ligand B (-3.775). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.332) has a slightly higher hERG inhibition liability than Ligand B (0.676), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (41.176) has slightly higher microsomal clearance than Ligand B (39.003). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand A (9.844) has a shorter in vitro half-life than Ligand B (6.273). Longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux than Ligand B (0.52), which is favorable for bioavailability.

**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 difference. A >1.5 kcal/mol advantage in binding affinity can often outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand B having better TPSA, BBB, and P-gp efflux, the dramatically superior binding affinity of Ligand A (-8.2 kcal/mol vs -0.0 kcal/mol) is the deciding factor. This strong binding is critical for a kinase inhibitor. While Ligand A has slightly less favorable metabolic stability and permeability, the potency advantage is substantial enough to make it the more promising candidate.

Output:
1
2025-04-17 14:29:57,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.392 and 363.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (80.12), being well below the 140 threshold for good absorption. Ligand B is higher, potentially impacting absorption.

**logP:** Both ligands (2.061 and 2.013) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 6 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.722 and 0.776), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (41.877 and 43.195), below the concerning threshold of 60.

**BBB:** Ligand A (70.454) has a better BBB percentile than Ligand B (64.793), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.273) has a better Caco-2 permeability than Ligand B (-5.04), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.969) has better solubility than Ligand B (-3.111), which is important for bioavailability.

**hERG:** Both ligands have low hERG risk (0.476 and 0.55), which is good.

**Microsomal Clearance:** Ligand A (11.619) has significantly lower microsomal clearance than Ligand B (53.175), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-22.763) has a better (longer) in vitro half-life than Ligand B (-18.218).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.14).

**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 and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG), **Ligand A is the more promising drug candidate.** It has better TPSA, Caco-2 permeability, solubility, metabolic stability (lower Cl_mic and better half-life), and a slightly stronger binding affinity. While both ligands are generally acceptable, the improvements in ADME properties for Ligand A make it the preferred choice.

Output:
1
2025-04-17 14:29:57,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B, keeping in mind we're targeting an enzyme (kinase) in oncology, so potency, metabolic stability, solubility, and hERG risk are key.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.233 Da) is slightly higher than Ligand B (366.487 Da), but both are acceptable.

**TPSA:** Ligand A (82.26) is better than Ligand B (93.21). Lower TPSA generally favors oral absorption, and both are reasonably good, but A is preferable.

**logP:** Ligand A (3.161) is optimal, while Ligand B (1.318) is on the lower side. A logP between 1-3 is preferred, and A is closer to the ideal range. Lower logP can sometimes hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 2 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 (A: 0.564, B: 0.649), indicating good drug-like properties.

**DILI:** Ligand A (65.374) has a higher DILI risk than Ligand B (42.303). This is a significant drawback for Ligand A. We want a DILI score < 40 if possible.

**BBB:** Both have reasonable BBB penetration, but Ligand A (74.952) is better than Ligand B (61.613). However, BBB isn't a primary concern for an oncology target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.047 and -5.342). This is unusual and suggests poor permeability. However, for a kinase inhibitor, systemic exposure can be achieved through other means, and permeability isn't as critical as for oral absorption.

**Aqueous Solubility:** Both have negative solubility values (-4.126 and -2.224). This is also concerning, but can sometimes be overcome with formulation strategies.

**hERG:** Ligand A (0.347) has a slightly higher hERG risk than Ligand B (0.075). Lower hERG is preferred.

**Microsomal Clearance:** Ligand A (18.726) has significantly lower microsomal clearance than Ligand B (28.098). Lower clearance indicates better metabolic stability, which is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand A (13.037 hours) has a longer half-life than Ligand B (0.168 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.008). Lower efflux is generally preferred.

**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, and a difference of >1.5 kcal/mol can often outweigh other 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 higher DILI risk and slightly higher hERG risk. Ligand B has a better DILI and hERG profile, but significantly weaker binding affinity and poorer metabolic stability.

Given the priorities for a kinase inhibitor (potency, metabolic stability), the significantly stronger binding affinity of Ligand A (-9.9 vs -7.2 kcal/mol) is the most important factor. The improved metabolic stability further supports this choice. While the higher DILI risk is a concern, it might be mitigated through structural modifications in subsequent optimization rounds.

Output:
1
2025-04-17 14:29:57,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 341.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.58) is higher than Ligand B (53.08). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (1.852) is within the optimal 1-3 range. Ligand B (3.216) is at the higher end of optimal, potentially raising concerns about off-target effects, but still acceptable.

**H-Bond Donors:** Both ligands have 2 HBD, which is good.

**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 good QED scores (0.715 and 0.832), indicating good drug-like properties.

**DILI:** Ligand A (9.965) has a very low DILI risk, significantly better than Ligand B (32.842). This is a major advantage for Ligand A.

**BBB:** Ligand A (53.664) has a lower BBB penetration than Ligand B (94.029). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.236 and -5.193), which is unusual and suggests poor permeability. This is a significant concern for both, but the values are very similar.

**Aqueous Solubility:** Ligand A (-0.308) is slightly better than Ligand B (-3.115), though both are poor. Solubility is a concern for both, but Ligand A is marginally better.

**hERG Inhibition:** Ligand A (0.202) has a much lower hERG risk than Ligand B (0.928). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (0.445) has a much lower microsomal clearance than Ligand B (39.101), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (53.643) has a much longer in vitro half-life than Ligand B (27.546), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.017) has a lower P-gp efflux liability than Ligand B (0.081), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.6), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME-Tox properties: significantly lower DILI risk, lower hERG risk, much better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The solubility and Caco-2 permeability are poor for both, but the ADME advantages of Ligand A outweigh the slight binding affinity difference.

Output:
0
2025-04-17 14:29:57,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.423 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.99) is better than Ligand B (131.54). TPSA <140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (1.529 and 1.829), 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=5) regarding the number of hydrogen bond donors and acceptors, both are within acceptable limits.

**QED:** Ligand A (0.878) has a significantly higher QED score than Ligand B (0.288), indicating a much more drug-like profile.

**DILI:** Ligand A (72.664) has a higher DILI risk than Ligand B (34.277), but both are below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.033 and -4.976).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, values are similar (-2.6 and -1.009).

**hERG Inhibition:** Ligand A (0.032) has a very low hERG inhibition risk, significantly lower than Ligand B (0.172). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (26.043 mL/min/kg) has a higher microsomal clearance than Ligand B (2.406 mL/min/kg), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.943 hours) has a negative half-life, which is not possible. Ligand B (23.524 hours) has a reasonable half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.031).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While both are good, the difference of 1.8 kcal/mol is substantial.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a better QED and lower hERG risk, Ligand B has a significantly better binding affinity, a more reasonable in vitro half-life, and a lower DILI risk. The binding affinity difference is large enough to outweigh the advantages of Ligand A. The negative solubility and Caco-2 values for both are concerning and would need to be addressed through formulation or structural modifications, but this is a secondary consideration given the clear advantage in binding affinity for Ligand B.

Output:
1
2025-04-17 14:29:57,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.374 and 356.289 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.74) is significantly better than Ligand B (131.59). A TPSA under 140 is good for oral absorption, but Ligand B is approaching a level that could hinder it.

**logP:** Ligand A (2.219) is optimal, while Ligand B (0.564) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (1 HBD, 8 HBA). Both are within acceptable ranges, but fewer H-bonds generally improves permeability.

**QED:** Both ligands have good QED scores (0.718 and 0.844), indicating good drug-like properties.

**DILI:** Both ligands have high DILI risk (82.629 and 87.01), which is a concern. However, this is a prediction and needs experimental validation.

**BBB:** This is less critical for a non-CNS target like SRC. Both have similar BBB penetration (82.513 and 80.419).

**Caco-2 Permeability:** Both are negative (-4.553 and -4.898). This is unusual and suggests poor permeability. These values are likely errors or indicate very poor absorption.

**Aqueous Solubility:** Both ligands have poor solubility (-2.71 and -3.058). This is a significant drawback, potentially limiting bioavailability.

**hERG Inhibition:** Both ligands have low hERG risk (0.892 and 0.359), which is good.

**Microsomal Clearance:** Ligand B (33.042) has significantly lower microsomal clearance than Ligand A (62.196), suggesting better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-50.854) has a longer in vitro half-life than Ligand A (-35.472), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.334 and 0.034).

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

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand B is the more promising candidate. Its significantly lower microsomal clearance and longer half-life address a key priority for enzyme inhibitors. While both have poor solubility and high DILI risk, metabolic stability is often easier to improve through structural modifications than potency. The lower logP of Ligand B is a minor concern, but the improved metabolic profile outweighs this. The negative Caco-2 values are concerning for both, but may be an artifact of the prediction.

Output:
1
2025-04-17 14:29:57,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.5 and 352.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (58.44), both being under the 140 threshold for oral absorption.

**logP:** Ligand A (3.131) is within the optimal range (1-3), while Ligand B (1.547) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.829) has a significantly better QED score than Ligand A (0.57), suggesting a more drug-like profile.

**DILI:** Ligand A (14.424) has a much lower DILI risk than Ligand B (37.999), a crucial advantage.

**BBB:** Ligand B (92.943) shows excellent BBB penetration, while Ligand A (61.38) is moderate. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.156) has poor Caco-2 permeability, while Ligand B (-4.461) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-3.683) has slightly better solubility than Ligand B (-1.613), both are poor.

**hERG:** Ligand A (0.367) has a lower hERG risk than Ligand B (0.496), which is a positive.

**Microsomal Clearance:** Ligand A (47.406) has higher microsomal clearance than Ligand B (39.83), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-34.931) has a significantly longer in vitro half-life than Ligand A (-6.718), a major advantage.

**P-gp Efflux:** Ligand A (0.246) has lower P-gp efflux liability than Ligand B (0.124), which is better.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a critical factor, and the 2.2 kcal/mol difference is significant, likely outweighing some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A's lower DILI risk and slightly better solubility, Ligand B is the more promising candidate. The significantly stronger binding affinity (-10.2 vs -8.0 kcal/mol) and longer half-life are crucial for an enzyme target like SRC kinase. While Ligand B has a higher DILI risk and lower solubility, these can potentially be addressed through further optimization. The superior affinity is likely to drive efficacy, making Ligand B the better choice.

Output:
1
2025-04-17 14:29:57,750 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.491 and 340.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is higher than Ligand B (51.02). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (1.711) is within the optimal 1-3 range. Ligand B (3.735) is at the higher end, potentially raising solubility concerns, but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well within the acceptable limit of 10.

**QED:** Ligand B (0.833) has a significantly better QED score than Ligand A (0.514), indicating a more drug-like profile.

**DILI:** Ligand A (7.794) has a very low DILI risk, much better than Ligand B (31.912), which is still relatively low but higher.

**BBB:** Ligand A (60.876) has a lower BBB penetration percentile than Ligand B (74.564). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.786 and -4.737), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.305) has slightly better solubility than Ligand B (-4.14), though both are poor.

**hERG Inhibition:** Ligand A (0.521) has a lower hERG risk than Ligand B (0.358), which is preferable.

**Microsomal Clearance:** Ligand A (35.289) has a much lower microsomal clearance than Ligand B (77.589), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (3.558) has a shorter half-life than Ligand B (-10.769). The negative value for B is concerning and likely an error, making A preferable.

**P-gp Efflux:** Ligand A (0.267) has lower P-gp efflux than Ligand B (0.331), which is slightly better.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This 1.1 kcal/mol difference is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and QED, and slightly better BBB penetration. However, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, and a more reasonable in vitro half-life. Both have poor Caco-2 permeability and solubility, which are major concerns. Given the importance of metabolic stability for kinase inhibitors, and the acceptable (though not ideal) affinity of Ligand A, I would select Ligand A for further optimization. The solubility and permeability issues would need to be addressed through structural modifications.

Output:
0
2025-04-17 14:29:57,751 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (358.454 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.87 and 70.08) below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have logP values (1.267 and 0.881) within the optimal 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:** Both ligands (4) meet the HBA criteria of <=10.

**6. QED:** Both ligands have good QED scores (0.641 and 0.772), indicating drug-like properties.

**7. DILI:** Ligand A (5.777) has a much lower DILI risk than Ligand B (11.361). This is a significant advantage.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (88.872) has better BBB penetration than Ligand B (61.535), but this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.466). These values are unusual and likely indicate a problem with the model or data. However, they are similar for both compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.151 and -0.643). Similar to Caco-2, these are unusual and problematic. Again, they are similar between the two.

**11. hERG Inhibition:** Ligand A (0.608) has a slightly higher hERG risk than Ligand B (0.215), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-2.541) has significantly lower (better) microsomal clearance than Ligand B (4.442), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.908) has a significantly longer in vitro half-life than Ligand B (2.997), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.143) has lower P-gp efflux than Ligand B (0.072), which is favorable for bioavailability.

**15. Binding Affinity:** Both ligands have identical binding affinities (-7.4 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands exhibit good binding affinity, Ligand A is the superior candidate due to its significantly lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The solubility and Caco-2 values are concerning for both, but are similar. Given the enzyme-kinase focus, metabolic stability and safety (DILI) are paramount.

Output:
1
2025-04-17 14:29:57,751 - INFO - Batch 301 complete. Total preferences: 4816
2025-04-17 14:29:57,751 - INFO - Processing batch 302/512...
2025-04-17 14:30:37,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (348.487 and 343.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.34) is well below the 140 threshold for good oral absorption. Ligand B (91.32) is still acceptable but closer to the limit.

**3. logP:** Ligand A (3.819) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.342) is slightly below the optimal range, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) both meet the HBD <= 5 criteria.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) both meet the HBA <= 10 criteria.

**6. QED:** Both ligands have similar and acceptable QED values (0.667 and 0.68).

**7. DILI:** Ligand A (29.779) has a significantly lower DILI risk than Ligand B (34.277), indicating a better safety profile. Both are below the 40 threshold.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.446) is higher than Ligand B (36.177), but neither is particularly high.

**9. Caco-2 Permeability:** Ligand A (-4.718) and Ligand B (-5.104) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't fully defined, so this is difficult to interpret.

**10. Aqueous Solubility:** Ligand A (-3.882) and Ligand B (-2.044) both have negative values, suggesting poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.725) has a slightly higher hERG risk than Ligand B (0.114), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (78.366) has higher clearance than Ligand B (-7.361). Ligand B exhibits *negative* clearance, which is not physically possible and likely indicates an issue with the data or model. This is a major red flag.

**13. In vitro Half-Life:** Ligand A (25.808) has a longer half-life than Ligand B (3.859).

**14. P-gp Efflux:** Ligand A (0.768) has a slightly higher P-gp efflux liability than Ligand B (0.038).

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial difference (>1.5 kcal/mol).

**Enzyme-Specific Considerations:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much better binding affinity, but its negative Cl_mic value is a critical flaw. While a strong affinity can sometimes outweigh ADME issues, a negative clearance is not realistic and suggests a problem with the data or the prediction method. Ligand A has acceptable ADME properties, even if its affinity is lower.

Output:
1
2025-04-17 14:30:37,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 361.486 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.64) is slightly above the optimal <140, but acceptable. Ligand B (59.22) is well within the range.

**logP:** Ligand A (2.192) is optimal. Ligand B (3.815) is approaching the upper limit but still acceptable.

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

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.639, B: 0.762), indicating drug-like properties.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (42.962), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (A: 83.094, B: 86.817), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.338) shows poor permeability, while Ligand B (-5.158) is also poor.

**Aqueous Solubility:** Ligand A (-1.75) is better than Ligand B (-3.705).

**hERG Inhibition:** Ligand A (0.507) has a lower hERG risk than Ligand B (0.964), which is a positive.

**Microsomal Clearance:** Ligand A (39.34) has significantly lower microsomal clearance than Ligand B (87.657), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.866) has a shorter half-life than Ligand B (18.576), which is a disadvantage.

**P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux than Ligand B (0.595), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.4 kcal/mol, B: -8.9 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic, lower P-gp efflux). While it has poorer Caco-2 permeability and a shorter half-life, the improved safety and metabolic stability are more crucial for an enzyme inhibitor. Ligand B has slightly better binding affinity and half-life, but the higher DILI and hERG risks are concerning.

Output:
0
2025-04-17 14:30:37,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.479 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.03) is better than Ligand B (58.36), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.286) is within the optimal 1-3 range. Ligand B (3.07) 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:** Both ligands (A: 5, B: 5) are below the 10 threshold.

**QED:** Both ligands have good QED scores (A: 0.509, B: 0.769), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (12.098) has a significantly lower DILI risk than Ligand B (10.896), which is a strong advantage. Both are well below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (A: 65.801, B: 67.274). BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.186) is slightly worse than Ligand B (-4.923).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.864) is slightly better than Ligand B (-3.046).

**hERG Inhibition:** Ligand A (0.454) has a lower hERG risk than Ligand B (0.73), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-0.409) has a negative clearance, which is excellent and indicates high metabolic stability. Ligand B (56.495) has a high clearance, indicating poor metabolic stability. This is a major drawback.

**In vitro Half-Life:** Ligand A (10.112) has a better in vitro half-life than Ligand B (9.247).

**P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, while Ligand B (0.352) has slightly higher efflux.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly better binding affinity than Ligand A (-6.7 kcal/mol). This is a 0.6 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has a superior binding affinity, Ligand A has much better metabolic stability (Cl_mic), lower DILI risk, and lower hERG risk. The poor metabolic stability of Ligand B is a major concern for an enzyme inhibitor, as it will likely be rapidly cleared *in vivo*. The better affinity of Ligand B *could* be overcome with structural modifications, but starting with a molecule that already has good metabolic stability and safety profiles (Ligand A) is a more rational approach. The solubility and permeability issues are shared by both and would need to be addressed in either case.

Output:
0
2025-04-17 14:30:37,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (415.288 Da) is slightly higher than Ligand B (367.921 Da), but both are acceptable.

**TPSA:** Ligand A (96.74) is higher than Ligand B (52.65). While both are below 140, Ligand B's lower TPSA is more favorable for absorption.

**logP:** Both ligands have good logP values (A: 2.837, B: 1.699) 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 within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.527, B: 0.772), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (10.702), but both are below the concerning threshold of 60.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (84.025) is higher than Ligand B (61.884), but this is not a major factor in this case.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are logP values, Ligand B (-5) is worse than Ligand A (-3.023).

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual. Assuming these are logS values, Ligand B (-1.739) is better than Ligand A (-3.023).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.816, B: 0.5), which is excellent.

**Microsomal Clearance:** Ligand A (-19.54) shows significantly *lower* (better) microsomal clearance than Ligand B (2.469), indicating greater metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (23.371) has a longer in vitro half-life than Ligand B (14.294), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.076, B: 0.063).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has a slightly better QED and lower TPSA, Ligand A's significantly stronger binding affinity (-7.7 vs -6.5 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are critical advantages for an enzyme inhibitor. The slightly higher DILI risk of Ligand A is acceptable given the substantial potency benefit.

Output:
1
2025-04-17 14:30:37,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.531 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (86.88). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (3.912 and 3.158), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=3, HBA=4) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have good QED scores (0.676 and 0.74), indicating drug-likeness.

**DILI:** Ligand A (25.785) has a much lower DILI risk than Ligand B (73.943). This is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (80.574) is better than Ligand B (59.403).

**Caco-2 Permeability:** Ligand A (-4.795) is better than Ligand B (-5.522), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.756) is better than Ligand B (-4.056), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liabilities (0.465 and 0.56).

**Microsomal Clearance:** Ligand B (30.262) has significantly lower microsomal clearance than Ligand A (74.539), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (52.195) has a longer in vitro half-life than Ligand A (-22.571). This is a significant advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.396 and 0.303).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a 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:**

While Ligand A has better solubility, lower DILI risk, and slightly better permeability, Ligand B's significantly stronger binding affinity (-8.1 vs -7.2 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target like SRC kinase. The stronger binding is likely to translate to greater efficacy, and the improved metabolic stability will lead to a longer duration of action. The higher DILI risk of Ligand B is a concern, but could be addressed through further optimization.

Output:
1
2025-04-17 14:30:37,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.319 Da) is slightly lower than Ligand B (365.499 Da), which is acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (82.53) is better than Ligand A (91.52).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (1.715) is slightly lower, potentially impacting permeability, but still acceptable. Ligand A (3.21) is towards the higher end but still within range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores, indicating drug-likeness (Ligand A: 0.503, Ligand B: 0.698). Ligand B is better.

**DILI:** Ligand A has a significantly higher DILI risk (90.5 percentile) than Ligand B (29.624 percentile). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.637) and Ligand B (54.052) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.412) is slightly better than Ligand B (-5.041), but both are problematic.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-4.351) is slightly better than Ligand B (-1.843).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.088 and 0.247, respectively).

**Microsomal Clearance:** Ligand B has a much lower microsomal clearance (42.363 mL/min/kg) than Ligand A (124.061 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (19.061 hours) than Ligand A (-57.823 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.275 and 0.224, respectively).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -8.3 kcal/mol, respectively). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is significantly better than Ligand A. While both have issues with Caco-2 permeability and solubility, Ligand B has a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The high DILI risk associated with Ligand A is a major red flag. The slightly better affinity of Ligand B, combined with its superior ADME properties, makes it the more promising candidate.

Output:
1
2025-04-17 14:30:37,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 350.423 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.91) is well below the 140 threshold for oral absorption and even closer to the 90 threshold for CNS penetration (though that's not a primary concern here). Ligand B (128.01) is still under 140, but less favorable than A.

**logP:** Ligand A (0.636) is a bit low, potentially hindering permeation. Ligand B (0.355) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better balanced. Ligand B (5 HBD, 4 HBA) has a higher number of HBDs, which could impact permeability.

**QED:** Ligand A (0.776) has a significantly better QED score than Ligand B (0.455), suggesting a more drug-like profile.

**DILI:** Ligand A (29.934) has a much lower DILI risk than Ligand B (39.473), which is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target, but Ligand A (67.623) is better than Ligand B (39.899).

**Caco-2 Permeability:** Ligand A (-4.904) is better than Ligand B (-5.801), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.893) is better than Ligand B (-1.469), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.187 and 0.068, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (-12.607) has a much lower (better) microsomal clearance than Ligand A (9.711), indicating greater metabolic stability. This is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-3.006) has a longer half-life than Ligand A (8.624), which is also favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.006, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent and removes this as a differentiating factor.

**Conclusion:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2), Ligand A has a better overall profile, particularly regarding drug-likeness (QED), DILI risk, solubility, and permeability (Caco-2). The difference in metabolic stability, while important, is outweighed by the other advantages of Ligand A, especially considering the strong binding affinity shared by both.

Output:
1
2025-04-17 14:30:37,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.455 and 341.43 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.45) is slightly higher than Ligand B (48.99). Both are below the 140 threshold for good absorption, but B is better.

**3. logP:** Both ligands have similar logP values (3.972 and 3.988), 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 2. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.61 and 0.898), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (54.401) has a higher DILI risk than Ligand B (33.773). This is a significant advantage for B.

**8. BBB:** Ligand A (82.9) and Ligand B (96.937) both have acceptable BBB penetration, but B is better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired/undesired.

**9. Caco-2 Permeability:** Ligand A (-4.912) and Ligand B (-5.104) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.319 and -3.418). This is a major concern.

**11. hERG Inhibition:** Ligand A (0.898) has slightly higher hERG inhibition risk than Ligand B (0.929).

**12. Microsomal Clearance:** Ligand A (50.729) has higher microsomal clearance than Ligand B (30.402). This means Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-23.55) has a significantly longer in vitro half-life than Ligand A (62.48). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.389) has lower P-gp efflux than Ligand B (0.661).

**15. Binding Affinity:** Ligand B (-8.8 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 difference threshold.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and, most importantly, a substantially stronger binding affinity. The improved binding affinity is likely to outweigh the solubility and permeability concerns, especially given the potential for formulation strategies to address those issues.

Output:
1
2025-04-17 14:30:37,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.415 and 331.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.78) is better than Ligand B (38.56) as it is closer to the ideal threshold of <140.

**logP:** Both ligands have logP values (4.125 and 4.822) that are slightly above the optimal 1-3 range, but not drastically so. Ligand B is a bit higher, 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.521 and 0.585), indicating good drug-like properties.

**DILI:** Ligand A (75.456) has a lower DILI risk than Ligand B (84.18), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.229) is slightly better than Ligand B (58.085).

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. Ligand A (-5.214) is slightly better than Ligand B (-4.736).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.233 and -6.017). This is a significant concern.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.892 and 0.954), which is good.

**Microsomal Clearance:** Ligand A (60.502) and Ligand B (57.217) have similar microsomal clearance values. Lower is better, so they are both acceptable.

**In vitro Half-Life:** Ligand A (56.825) has a significantly longer half-life than Ligand B (11.997). This is a major advantage as it suggests less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.525 and 0.947), which is good.

**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 difference (over 2 kcal/mol) and is a major factor.

**Conclusion:**

Despite the solubility concerns for both, the significantly stronger binding affinity of Ligand B (-8.9 kcal/mol vs -6.9 kcal/mol) outweighs the slightly higher DILI risk and lower half-life. The potency advantage is substantial enough to prioritize Ligand B, assuming solubility can be addressed through formulation strategies.

Output:
1
2025-04-17 14:30:37,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.515 and 357.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.44) is better than Ligand B (29.54) as it is still within the acceptable range for oral absorption (<140), while Ligand B is very low, which could indicate issues with solubility.

**logP:** Ligand A (1.25) is optimal, while Ligand B (4.503) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, fitting the guidelines. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.718 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (16.712) has a much lower DILI risk than Ligand B (11.516), which is a significant advantage.

**BBB:** Ligand A (57.154) has a lower BBB penetration than Ligand B (96.084). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.227) has a negative value, suggesting poor permeability. Ligand B (-4.507) is also negative, but less so.

**Aqueous Solubility:** Ligand A (-2.247) has poor solubility, while Ligand B (-4.294) is even worse.

**hERG Inhibition:** Ligand A (0.486) has a lower hERG risk than Ligand B (0.892), which is a positive.

**Microsomal Clearance:** Ligand A (34.975) has a lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (72.939).

**In vitro Half-Life:** Ligand A (-1.448) has a negative half-life, which is concerning. Ligand B (-2.97) is even worse.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is good. Ligand B (0.577) has higher efflux.

**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 of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite its poor solubility and half-life. Its significantly stronger binding affinity (-8.6 vs -7.1 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has a much lower DILI risk and better metabolic stability (lower Cl_mic). While the solubility and half-life are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. Ligand B's high logP and worse solubility are significant drawbacks, even with its better BBB penetration (which isn't crucial here).

Output:
1
2025-04-17 14:30:37,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.438 Da) is slightly higher than Ligand B (367.515 Da), but both are acceptable.

**TPSA:** Ligand A (97.38) is higher than Ligand B (69.72). While both are below 140, the lower TPSA of Ligand B is preferable for oral absorption.

**logP:** Both ligands have good logP values (Ligand A: 2.193, Ligand B: 1.246), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (Ligand A: 5, Ligand B: 4), satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.87, Ligand B: 0.794), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (93.059%) compared to Ligand B (26.173%). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (65.801%) and Ligand B (57.968%) are both relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.657) is slightly better than Ligand B (-4.915).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.518) is slightly better than Ligand B (-1.99).

**hERG:** Ligand A (0.574) has a slightly higher hERG risk than Ligand B (0.053). Ligand B is much preferred here.

**Microsomal Clearance:** Ligand B (19.166 mL/min/kg) has a lower microsomal clearance than Ligand A (12.329 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.325 hours) has a negative half-life, which is problematic. Ligand A (176.728 hours) has a very long half-life, which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.514, Ligand B: 0.026).

**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 1.5 kcal/mol, it's still a positive factor for Ligand B.

**Overall Assessment:**

Ligand B is significantly better overall. The major advantage is its much lower DILI risk. While its solubility and Caco-2 permeability are poor, the long half-life of Ligand A is suspect and might indicate issues with the assay or compound stability. The slightly better affinity of Ligand B, combined with its superior safety profile (lower DILI and hERG), makes it the more promising candidate despite the permeability concerns.

Output:
1
2025-04-17 14:30:37,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (335.363 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.91) is excellent, well below the 140 threshold for oral absorption. Ligand B (106.32) is still acceptable, but less optimal.

**3. logP:** Both ligands have good logP values (2.689 and 1.695), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (1 and 2 respectively).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (4 and 5 respectively).

**6. QED:** Both ligands have similar and good QED scores (0.798 and 0.783), indicating good drug-like properties.

**7. DILI:** Ligand A (90.461) has a significantly higher DILI risk than Ligand B (31.02). This is a major concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (65.219) and Ligand B (56.65) are both relatively low.

**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 and suggests poor solubility. However, the scale is not defined, so it is hard to interpret.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.096 and 0.296).

**12. Microsomal Clearance (Cl_mic):** Ligand A (20.526) has a lower (better) Cl_mic than Ligand B (36.832), suggesting greater metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (11.27) has a longer half-life than Ligand B (-13.918). The negative value for Ligand B is concerning.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.088 and 0.013).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite the strong binding affinity of Ligand A, its significantly higher DILI risk is a major drawback. The better metabolic stability and half-life are positives, but the DILI risk outweighs these benefits. Ligand B, while having a slightly weaker affinity, has a much lower DILI risk and acceptable metabolic properties. The negative values for Caco-2 and solubility are concerning for both, but the DILI risk is a more immediate concern.

Output:
1
2025-04-17 14:30:37,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 341.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.71) is better than Ligand B (112.95). Both are acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.154 and 1.192), falling within the 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 6 H-bond acceptors, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.589 and 0.819), indicating good drug-like properties.

**DILI:** Ligand A (11.594) has a significantly lower DILI risk than Ligand B (61.07). This is a major advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC kinase.

**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 very low hERG inhibition risk (0.609 and 0.101).

**Microsomal Clearance:** Ligand A (46.985) has a higher microsomal clearance than Ligand B (3.097). This suggests Ligand B is more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (31.236) has a significantly longer in vitro half-life than Ligand A (-14.541). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.067 and 0.038).

**Binding Affinity:** Both ligands have similar binding affinities (-8.3 kcal/mol).

**Overall Assessment:**

Ligand A has a significant advantage in terms of DILI risk. Ligand B has a better metabolic stability profile (lower Cl_mic, longer t1/2). Solubility and permeability are poor for both, but the negative values make direct comparison difficult. Given the priority for metabolic stability in enzyme inhibitors, and the substantial difference in half-life, Ligand B is more likely to be a viable drug candidate despite the higher DILI risk. The similar binding affinity means potency isn't a differentiating factor.

Output:
1
2025-04-17 14:30:37,553 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (388.251 and 358.829 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.18) is slightly higher than Ligand B (78.09). Both are acceptable, being under 140, but Ligand B is preferable.

**logP:** Both ligands have a logP of approximately 2.1, which is optimal (1-3).

**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). Ligand B is slightly better due to fewer H-bonds.

**QED:** Ligand A (0.696) and Ligand B (0.822) both have good drug-likeness scores (>0.5), with Ligand B being slightly better.

**DILI:** Ligand A (51.028) and Ligand B (59.403) both have acceptable DILI risk, being below 60.

**BBB:** Both have moderate BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.042 and -5.341), indicating potential absorption issues.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.956 and -3.847). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.248) has a lower hERG inhibition risk than Ligand B (0.416), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-14.84) has significantly lower (better) microsomal clearance than Ligand B (15.076). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (57.934) has a longer half-life than Ligand B (-1.966), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux than Ligand B (0.134), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-10.3 kcal/mol). This is the most crucial factor for an enzyme inhibitor. The 2.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While both ligands have some shortcomings (poor solubility and Caco-2 permeability), Ligand A is the superior candidate. Its significantly stronger binding affinity (-8.1 vs -10.3 kcal/mol), coupled with better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG risk, outweigh the slightly higher TPSA. The binding affinity difference is particularly important for an enzyme target.

Output:
0
2025-04-17 14:30:37,553 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 Da and 347.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is excellent, well below the 140 threshold for oral absorption. Ligand B (45.23) is also very good.

**logP:** Ligand A (1.052) is at the low end of optimal, but acceptable. Ligand B (3.278) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, fitting the guidelines. Ligand B has 1 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (0.639 and 0.923, respectively), indicating drug-like properties.

**DILI:** Ligand A (13.804) has a very low DILI risk, which is excellent. Ligand B (54.789) is higher, indicating a moderate risk.

**BBB:** Ligand A (41.062) has a low BBB penetration, which isn't a concern for a non-CNS target like SRC. Ligand B (89.957) has high BBB penetration, irrelevant here.

**Caco-2 Permeability:** Ligand A (-5.093) has poor Caco-2 permeability. Ligand B (-4.466) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.723) has poor aqueous solubility. Ligand B (-3.604) has even worse aqueous solubility.

**hERG Inhibition:** Ligand A (0.289) has a very low hERG risk, which is excellent. Ligand B (0.817) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (12.327 mL/min/kg) has a moderate microsomal clearance. Ligand B (32.669 mL/min/kg) has a higher clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (0.517 hours) has a very short half-life. Ligand B (35.235 hours) has a much longer and desirable half-life.

**P-gp Efflux:** Ligand A (0.138) has low P-gp efflux, which is good. Ligand B (0.466) also has relatively low P-gp efflux.

**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.

**Conclusion:**

Despite Ligand A's poor solubility and permeability, its significantly superior binding affinity (-8.9 vs -6.9 kcal/mol) and very low DILI and hERG risks make it the more promising candidate. The potency advantage is likely to outweigh the ADME liabilities, especially with potential formulation strategies to improve solubility. Ligand B's better half-life is attractive, but the weaker binding and higher DILI risk are significant drawbacks.

Output:
0
2025-04-17 14:30:37,553 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.463 and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.68) is better than Ligand B (49.41) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (1.445) is optimal (1-3), while Ligand B (3.308) is towards the higher end but still acceptable.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.729 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (12.641) has a significantly lower DILI risk than Ligand B (19.155), which is a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand B (83.443) has a higher BBB percentile than Ligand A (61.38).

**Caco-2 Permeability:** Ligand A (-5.168) has a worse Caco-2 permeability than Ligand B (-4.427).

**Aqueous Solubility:** Ligand A (-1.116) has better solubility than Ligand B (-3.703). This is a crucial factor for bioavailability.

**hERG Inhibition:** Ligand A (0.217) has a lower hERG inhibition liability than Ligand B (0.694), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (12.421) has a lower microsomal clearance than Ligand B (24.287), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (17.897) has a longer half-life than Ligand B (-12.917), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.018) has lower P-gp efflux liability than Ligand B (0.181), potentially leading to better bioavailability.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are strong binders, the 1.1 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A is superior due to its lower DILI risk, better solubility, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly stronger binding affinity. While Ligand B has slightly better Caco-2 permeability and BBB penetration, these are less critical for a non-CNS enzyme target like SRC. The combination of favorable ADME properties and strong binding makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 14:30:37,553 - INFO - Batch 302 complete. Total preferences: 4832
2025-04-17 14:30:37,553 - INFO - Processing batch 303/512...
2025-04-17 14:31:22,327 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.403 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.05) is significantly better than Ligand B (114.43). A TPSA under 140 is good for oral absorption, but lower is generally preferred.

**logP:** Both ligands have good logP values (1.235 and 1.192), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=3, HBA=4) as it has fewer HBDs, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.782 and 0.743), indicating good drug-likeness.

**DILI:** Ligand A (59.829) has a slightly higher DILI risk than Ligand B (56.301), but both are below the concerning threshold of 60.

**BBB:** Ligand A (68.554) has a better BBB penetration percentile than Ligand B (41.528), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.864) shows better Caco-2 permeability than Ligand B (-5.4), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.889) has better aqueous solubility than Ligand B (-3.901). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.145) has a much lower hERG inhibition liability than Ligand B (0.212), which is a significant advantage.

**Microsomal Clearance:** Ligand A (43.584) has a higher microsomal clearance than Ligand B (-0.665). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (25.717) has a longer in vitro half-life than Ligand A (16.631), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.124) has a lower P-gp efflux liability than Ligand B (0.044), which is favorable.

**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.

**Conclusion:**

While Ligand A has advantages in TPSA, solubility, hERG, and P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.9 vs -7.8 kcal/mol) and its superior metabolic stability (lower Cl_mic, longer t1/2) are decisive. For an enzyme target like SRC kinase, potency and metabolic stability are paramount. The slightly higher DILI risk of Ligand A is not a major concern given that it's still below the 60 percentile threshold.

Output:
1
2025-04-17 14:31:22,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.459 Da and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.01) is better than Ligand B (110.1), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.01) is within the optimal 1-3 range, while Ligand B (-0.22) is slightly below, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (4 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.578 and 0.482, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (39.473) has a significantly lower DILI risk than Ligand B (14.308), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (46.336) is better than Ligand B (23.187).

**Caco-2 Permeability:** Ligand A (-6.001) and Ligand B (-5.214) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so we can't definitively say how problematic this is.

**Aqueous Solubility:** Ligand A (-2.396) and Ligand B (-1.165) have negative solubility values, which is also unusual. This is a concern for both, but Ligand B is slightly better.

**hERG:** Ligand A (0.437) has a lower hERG risk than Ligand B (0.183), which is favorable.

**Microsomal Clearance:** Ligand A (-4.202) has a much lower (better) microsomal clearance than Ligand B (0.606), indicating greater metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (12.181) and Ligand B (13.569) have comparable in vitro half-lives.

**P-gp Efflux:** Ligand A (0.017) has a lower P-gp efflux liability than Ligand B (0.008), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While a 1.1 kcal/mol difference is noticeable, the other ADME properties of Ligand A are significantly better.

**Overall:** Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. Its significantly lower DILI and microsomal clearance, coupled with a better hERG profile, outweigh the slightly weaker binding affinity compared to Ligand B. The solubility and Caco-2 permeability are concerning for both, but the ADME profile of A is superior.

Output:
0
2025-04-17 14:31:22,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.427 Da) is slightly higher than Ligand B (349.391 Da), but both are acceptable.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (113.49). A TPSA under 140 is good for oral absorption, and Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.888, Ligand B: 0.633), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for cell permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 7 HBAs. Lower HBA counts are generally preferred for better permeability, giving Ligand A an edge.

**QED:** Both ligands have good QED scores (Ligand A: 0.592, Ligand B: 0.676), indicating good drug-like properties.

**DILI:** Ligand B (38.387) has a slightly better DILI score than Ligand A (27.453), indicating a lower risk of liver injury. However, both are below the concerning threshold of 60.

**BBB:** Ligand A (59.364) has a slightly better BBB score than Ligand B (42.264), but neither is particularly high, and BBB isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.991) has a better Caco-2 permeability score than Ligand B (-5.315), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.995) has a better aqueous solubility score than Ligand B (-1.214), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.461, Ligand B: 0.182), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 20.421, Ligand B: 21.784), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (-33.646) has a significantly longer in vitro half-life than Ligand B (-17.429), which is a major advantage for dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.078, Ligand B: 0.061).

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.1 kcal/mol, Ligand B: -8.4 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has advantages in TPSA, HBA, Caco-2 permeability, solubility, and *especially* in vitro half-life. While Ligand B has a slightly better DILI score and binding affinity, the longer half-life of Ligand A is a significant advantage for an enzyme target, potentially allowing for less frequent dosing. The slightly better ADME profile of Ligand A, coupled with a very strong binding affinity, makes it the more promising candidate.

Output:
0
2025-04-17 14:31:22,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.43) is better than Ligand B (69.64), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.18) is within the optimal 1-3 range. Ligand B (2.637) is also acceptable, but slightly higher.

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

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.628) has a better QED score than Ligand A (0.377), indicating a more drug-like profile.

**DILI:** Ligand B (23.769) has a significantly lower DILI risk than Ligand A (51.454), making it more favorable.

**BBB:** Both ligands have similar BBB penetration (62.854 and 65.529), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.041) has a worse Caco-2 permeability than Ligand B (-4.66).

**Aqueous Solubility:** Ligand A (-1.704) has a better aqueous solubility than Ligand B (-3.253). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.209) has a lower hERG inhibition liability than Ligand B (0.338), which is preferable.

**Microsomal Clearance:** Ligand A (17.752) has a significantly lower microsomal clearance than Ligand B (62.565), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (1.993) has a shorter half-life than Ligand B (-29.73). The negative value for Ligand B is unusual and suggests a very long half-life.

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux than Ligand B (0.488), which is favorable.

**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 B has a better QED score and lower DILI risk. However, Ligand A exhibits superior metabolic stability (lower Cl_mic), better solubility, lower hERG risk, and lower P-gp efflux. Considering SRC is an enzyme, metabolic stability and minimizing off-target effects (hERG) are critical. While Ligand B has a potentially longer half-life, the negative value is suspect and requires further investigation. The slight advantage in solubility of Ligand A is also beneficial.

Output:
0
2025-04-17 14:31:22,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (370.299 Da and 398.941 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values below 140 (90.31 and 83.98), suggesting good potential for oral absorption.

**3. logP:** Ligand A (-0.93) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (2.668) 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 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.627 and 0.668), indicating good drug-likeness.

**7. DILI:** Ligand A (35.944) has a significantly lower DILI risk than Ligand B (69.252). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (43.699 and 43.893), which isn't a primary concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.88 and -5.496) which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.242 and -3.924) which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.336 and 0.217).

**12. Microsomal Clearance:** Ligand A (-6.792) has a much lower (better) microsomal clearance than Ligand B (64.776), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.791) has a negative half-life, which is unusual. Ligand B (19.781) has a more reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.077).

**15. 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.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in affinity and metabolic stability (Cl_mic). While its half-life is unusual, the strong binding affinity could compensate. Ligand B has a more reasonable half-life, but its significantly higher DILI risk and lower affinity are drawbacks. The poor solubility and permeability are concerns for both, but the superior binding affinity of Ligand A makes it more likely to overcome these issues with formulation strategies.

Output:
0
2025-04-17 14:31:22,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (347.503 and 358.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is well below the 140 threshold and is favorable. Ligand B (68.09) is also acceptable, though slightly higher.

**3. logP:** Both ligands (2.348 and 2.022) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (1) and Ligand B (0) are both within the acceptable limit of <=5.

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

**6. QED:** Both ligands have good QED scores (0.751 and 0.818), indicating good drug-like properties.

**7. DILI:** Ligand A (19.659) has a significantly lower DILI risk than Ligand B (55.758). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.927) is slightly better than Ligand B (63.358).

**9. Caco-2 Permeability:** Ligand A (-4.672) and Ligand B (-5.307) both have negative values, which is unusual and indicates poor permeability. However, the difference is small.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.891 and -1.982). This is a significant drawback for both, but could be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.488 and 0.256).

**12. Microsomal Clearance (Cl_mic):** Ligand B (41.918) has lower microsomal clearance than Ligand A (51.201), suggesting better metabolic stability. This is a positive for Ligand B.

**13. In vitro Half-Life (t1/2):** Ligand B (-10.359) has a significantly longer half-life than Ligand A (0.891). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.047).

**15. 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 outweigh other factors.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand A is preferable due to its significantly lower DILI risk. Ligand B has better metabolic stability and half-life, but the higher DILI risk is a major concern. Solubility is poor for both, but can be addressed during formulation.

Output:
0
2025-04-17 14:31:22,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.845 and 368.587 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.07) is slightly higher than Ligand B (49.41), but both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (2.674) and Ligand B (3.843) are both within the optimal 1-3 range, though B is approaching the upper limit.

**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:** Ligand A (0.841) has a significantly higher QED score than Ligand B (0.596), indicating better overall drug-likeness.

**DILI:** Ligand A (64.599) has a higher DILI risk than Ligand B (16.673). This is a significant concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 70.648, B: 74.796), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.697 and -4.872). This 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 (-2.075 and -3.835), again unusual and suggesting poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.451) shows slightly lower hERG inhibition risk than Ligand B (0.7).

**Microsomal Clearance:** Ligand A (32.952) has significantly lower microsomal clearance than Ligand B (103.104), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (57.084) has a much longer in vitro half-life than Ligand B (14.808), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.227) has lower P-gp efflux than Ligand B (0.527), which is favorable for bioavailability.

**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 concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and superior metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux. Its QED score is also much higher. However, it has a higher DILI risk and both ligands show poor solubility and permeability. The large difference in binding affinity (-9.1 vs -6.7) is a compelling factor. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications. The poor solubility and permeability are shared issues that would need to be addressed in either case. Given the importance of potency for kinase inhibitors, and the substantial difference in affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 14:31:22,329 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [347.411, 76.07, 2.447, 1, 4, 0.885, 41.179, 61.535, -4.578, -1.993, 0.012, 13.997, -9.436, 0.012, -7.4]
**Ligand B:** [375.491, 118.8, -0.575, 2, 6, 0.637, 33.307, 34.781, -5.634, -0.746, 0.092, -16.932, 29.343, 0.019, -7.8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (347.411) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (76.07) is excellent, well below the 140 threshold for oral absorption. B (118.8) is still acceptable but less ideal.
3. **logP:** A (2.447) is optimal. B (-0.575) is too low, potentially hindering membrane permeability and absorption.
4. **HBD:** Both are acceptable (A: 1, B: 2), within the guideline of <=5.
5. **HBA:** Both are acceptable (A: 4, B: 6), within the guideline of <=10.
6. **QED:** A (0.885) is very good, indicating high drug-likeness. B (0.637) is still reasonable, but less optimal.
7. **DILI:** Both are good, with A (41.179) being slightly better than B (33.307). Both are well below the 60 threshold.
8. **BBB:** A (61.535) is moderate. B (34.781) is low. Not a major concern for a kinase inhibitor (not a CNS target).
9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.578) is slightly better (less negative) than B (-5.634).
10. **Solubility:** Both are negative, indicating poor solubility. A (-1.993) is slightly better than B (-0.746).
11. **hERG:** Both are very low (A: 0.012, B: 0.092), indicating minimal hERG inhibition risk.
12. **Cl_mic:** A (13.997) is better, indicating lower metabolic clearance and thus greater metabolic stability. B (-16.932) suggests rapid clearance.
13. **t1/2:** A (-9.436) is better, indicating a longer in vitro half-life. B (29.343) suggests a shorter half-life.
14. **Pgp:** Both are very low (A: 0.012, B: 0.019), indicating minimal P-gp efflux liability.
15. **Binding Affinity:** B (-7.8) is slightly better than A (-7.4), with a 0.4 kcal/mol difference.

**Enzyme-Kinase Specific Considerations:**

For a kinase inhibitor, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While B has a slightly better binding affinity, A significantly outperforms it in metabolic stability (Cl_mic and t1/2) and has better solubility and QED. The logP of B is a significant concern. The slight affinity advantage of B is unlikely to overcome the substantial ADME deficiencies.

**Conclusion:**

Considering the balance of properties and the priorities for an enzyme inhibitor, **Ligand A** is the more promising drug candidate.

Output:
0
2025-04-17 14:31:22,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.475 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (106.45 and 106.94) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.194) is optimal (1-3). Ligand B (0.52) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both have reasonable H-bond characteristics, within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.422 and 0.56), indicating reasonable drug-likeness.

**DILI:** Ligand A (34.548) has a significantly lower DILI risk than Ligand B (14.928), which is a major advantage.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.966) and Ligand B (-5.209) both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but potentially more so for Ligand B given its lower logP.

**Aqueous Solubility:** Ligand A (-2.43) and Ligand B (-0.432) both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.071 and 0.062).

**Microsomal Clearance:** Ligand A (32.852) has higher microsomal clearance than Ligand B (-7.539), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-20.448) has a longer in vitro half-life than Ligand A (-27.204), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.017).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). This is a 1.6 kcal/mol difference, which is significant enough to potentially offset some ADME liabilities.

**Conclusion:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. The lower DILI risk and significantly better metabolic stability (lower Cl_mic, longer t1/2) of Ligand B are crucial for an enzyme target like SRC kinase. While both have poor solubility and permeability, the metabolic advantages of Ligand B are more readily addressable through formulation strategies than the higher DILI risk of Ligand A.

Output:
1
2025-04-17 14:31:22,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.901 and 332.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.34) is significantly better than Ligand B (62.97), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.87 and 3.002), falling within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5), again favoring permeability.

**QED:** Both ligands have similar and acceptable QED values (0.694 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (79.411), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (78.092) shows better BBB penetration than Ligand B (31.563).

**Caco-2 Permeability:** Ligand A (-4.632) is better than Ligand B (-5.005), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.684) is better than Ligand B (-3.94), indicating better solubility.

**hERG Inhibition:** Both ligands have similar and acceptable hERG inhibition liability (0.834 and 0.771).

**Microsomal Clearance:** Ligand A (37.903) has a higher (worse) microsomal clearance than Ligand B (23.687), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (17.576) has a significantly longer half-life than Ligand A (9.941), which is a substantial advantage.

**P-gp Efflux:** Both ligands show similar P-gp efflux liability (0.335 and 0.425).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.8 kcal/mol), with Ligand B being slightly better.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, HBD, HBA, DILI, Solubility, Caco-2, BBB) and has a comparable binding affinity to Ligand B. However, Ligand B has a significantly longer half-life and slightly better binding affinity, and lower microsomal clearance. The DILI risk for Ligand B is a major concern. Given the enzyme-specific priorities, the lower DILI risk of Ligand A, combined with its favorable ADME profile, outweighs the slight advantage in binding affinity and half-life of Ligand B.

Output:
0
2025-04-17 14:31:22,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.431 and 352.45 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.26 and 69.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.388) is optimal, while Ligand B (1.925) is slightly lower, but 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.

**QED:** Both ligands have good QED scores (0.763 and 0.815), indicating drug-like properties.

**DILI:** Ligand A (36.487) has a lower DILI risk than Ligand B (19.038), which is preferable.

**BBB:** Both ligands have high BBB penetration, but Ligand A is slightly higher (90.539 vs 72.082). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.344) has better Caco-2 permeability than Ligand B (-5.007), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-1.437) has better aqueous solubility than Ligand B (-3.066), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.326 and 0.358).

**Microsomal Clearance:** Ligand A (17.71 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (1.657 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.236 hours) has a much longer in vitro half-life than Ligand B (-3.483 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.042 and 0.079).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial difference (1.1 kcal/mol), and a key factor.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates superior ADME properties, particularly in metabolic stability (lower Cl_mic, longer t1/2) and solubility. The difference in binding affinity (1.1 kcal/mol) is significant, but the improved pharmacokinetic profile of Ligand A is crucial for an enzyme target like SRC. A slightly weaker but more bioavailable drug is often preferable to a potent drug that is rapidly metabolized and has poor solubility. The lower DILI risk for Ligand A also adds to its favorability.

Output:
0
2025-04-17 14:31:22,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.5 and 349.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.34) is better than Ligand B (72.88), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.657) is optimal (1-3 range), while Ligand B (0.905) 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 7 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.724) has a better QED score than Ligand A (0.436), indicating a more drug-like profile.

**DILI:** Ligand B (5.312) has a significantly lower DILI risk than Ligand A (39.318), a major advantage.

**BBB:** Ligand A (71.772) shows better BBB penetration than Ligand B (60.566), but BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.979 and -4.906), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.558 and -1.158), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.45) has a slightly higher hERG risk than Ligand B (0.172), which is preferable for Ligand B.

**Microsomal Clearance:** Ligand B (1.214) has significantly lower microsomal clearance than Ligand A (73.472), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.239) has a much longer in vitro half-life than Ligand A (19.666), a significant advantage.

**P-gp Efflux:** Ligand A (0.191) has lower P-gp efflux than Ligand B (0.033), which is preferable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and P-gp efflux, but Ligand B excels in crucial ADME properties: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and a better QED score. While both have poor solubility and permeability, the ADME profile of Ligand B is far superior, especially considering the enzyme-specific priorities. The 1.1 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, while addressing the solubility/permeability issues.

Output:
1
2025-04-17 14:31:22,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Ligand A (82.53) is better than Ligand B (53.43) as it is closer to the threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.419) is slightly better than Ligand B (3.501), as higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is slightly better than Ligand B (HBD=1, HBA=3) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.776, B: 0.697), indicating good drug-like properties.

**DILI:** Ligand A (41.915) has a slightly higher DILI risk than Ligand B (11.283), but both are below the concerning threshold of 60.

**BBB:** Ligand B (79.062) has a higher BBB penetration percentile than Ligand A (53.742), but BBB is not a primary concern for a kinase inhibitor unless CNS targets are involved.

**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 unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.284) shows a lower hERG inhibition liability than Ligand B (0.61), which is a significant advantage.

**Microsomal Clearance:** Ligand A (30.332) has a lower microsomal clearance than Ligand B (44.853), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-28.455) has a negative half-life, which is not possible. Ligand B (46.898) has a reasonable half-life. This is a major disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.49), which is favorable.

**Binding Affinity:** Ligand B (-7.2 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 drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has a slightly higher logP and hERG risk, the difference in binding affinity (-7.2 vs -8.3 kcal/mol) is substantial. The negative values for Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 14:31:22,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.463 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than Ligand B (79.9). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.403 and 1.067), 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 (0.641 and 0.771), indicating good drug-likeness.

**DILI:** Ligand A (35.983) has a slightly better DILI score than Ligand B (41.45), indicating a lower risk of liver injury. Both are below the concerning threshold of 60.

**BBB:** Ligand B (72.431) has a higher BBB penetration score than Ligand A (53.742), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.981) and Ligand B (-5.034) have similar, and quite poor, Caco-2 permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.018 and -2.091). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.158 and 0.282).

**Microsomal Clearance:** Ligand B (14.483) has significantly lower microsomal clearance than Ligand A (69.07), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (0.183) has a slightly better in vitro half-life than Ligand A (-12.082), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.025).

**Binding Affinity:** Both ligands have identical binding affinities (-7.5 kcal/mol), which is excellent.

**Conclusion:**

While both compounds exhibit excellent binding affinity, Ligand B is the more promising candidate. Its significantly lower microsomal clearance and slightly improved half-life suggest better metabolic stability, a critical factor for enzyme inhibitors. Although both have poor solubility and Caco-2 permeability, the metabolic advantage of Ligand B outweighs these drawbacks, especially given the equal binding affinity.

Output:
1
2025-04-17 14:31:22,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.365 and 355.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.29) is slightly higher than Ligand B (63.91). Both are acceptable, but Ligand B's lower TPSA is preferable for permeability.

**logP:** Both ligands have similar logP values (2.703 and 2.757), falling within the optimal 1-3 range.

**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 6 HBAs, well within the acceptable limit of <=10.

**QED:** Ligand A (0.789) has a higher QED score than Ligand B (0.611), indicating better overall drug-likeness.

**DILI:** Ligand A (79.798) has a significantly higher DILI risk than Ligand B (59.48). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (70.648 and 75.107), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand B (-5.38) shows better Caco-2 permeability than Ligand A (-4.537), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.772) has better aqueous solubility than Ligand A (-4.646). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.118) has a slightly higher hERG inhibition risk than Ligand B (0.363), but both are relatively low.

**Microsomal Clearance:** Ligand A (-0.594) has a *lower* (better) microsomal clearance than Ligand B (39.747). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (6.293) has a longer in vitro half-life than Ligand A (48.266). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux than Ligand B (0.184), which is favorable.

**Binding Affinity:** Ligand B (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having a better QED and lower P-gp efflux, the significantly higher DILI risk and weaker binding affinity make it a less attractive candidate. Ligand B's superior binding affinity, better solubility, Caco-2 permeability, and lower DILI risk outweigh its slightly lower QED and higher P-gp efflux. The longer half-life of Ligand B is also a benefit. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 14:31:22,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.531 Da) is slightly higher than Ligand B (335.407 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (78.09) is slightly higher than Ligand B (73.2), but both are good.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.147, Ligand B: 2.244), which is optimal for permeability and avoiding 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.702, Ligand B: 0.861), indicating a drug-like profile. Ligand B is slightly better.

**DILI:** Ligand A (28.306) has a significantly lower DILI risk than Ligand B (47.732). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (48.352) has a lower BBB penetration than Ligand B (78.519). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.715) is slightly better than Ligand B (-4.943).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.304) is slightly better than Ligand B (-4.156).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.255, Ligand B: 0.498). Ligand A is better.

**Microsomal Clearance:** Ligand A (16.726) has lower microsomal clearance than Ligand B (18.796), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.117) has a longer in vitro half-life than Ligand B (3.829). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.066, Ligand B: 0.107). Ligand A is slightly better.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This difference of 1.4 kcal/mol is substantial and outweighs many of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better ADME properties (lower DILI, better metabolic stability, longer half-life, slightly better solubility, permeability, and P-gp efflux), Ligand B's significantly stronger binding affinity (-8.5 vs -7.1 kcal/mol) is the most critical factor for an enzyme inhibitor. A 1.4 kcal/mol difference in binding affinity is a large advantage that can compensate for the slightly less favorable ADME profile. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 14:31:22,332 - INFO - Batch 303 complete. Total preferences: 4848
2025-04-17 14:31:22,332 - INFO - Processing batch 304/512...
2025-04-17 14:32:03,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 348.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is better than Ligand B (59.08), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (0.666 and 1.375), falling within the 1-3 range. Ligand B is slightly better.

**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:** Ligand A (0.867) has a better QED score than Ligand B (0.72), indicating a more drug-like profile.

**DILI:** Both ligands have similar low DILI risk (32.9% and 33.8%).

**BBB:** Both ligands have similar BBB penetration (62.5% and 60.6%). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.181) has worse Caco-2 permeability than Ligand B (-4.397).

**Aqueous Solubility:** Ligand A (-0.765) has better aqueous solubility than Ligand B (-1.522).

**hERG Inhibition:** Ligand A (0.072) has a significantly lower hERG inhibition risk than Ligand B (0.173), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (0.9) has much lower microsomal clearance than Ligand B (31.681), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-7.178) has a significantly longer in vitro half-life than Ligand B (-11.729).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.028).

**Binding Affinity:** Ligand A (-7.178) has slightly better binding affinity than Ligand B (-9.0). While both are excellent, the difference 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 hERG risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. While Ligand B has slightly better Caco-2 permeability and logP, the advantages of Ligand A in terms of safety (hERG) and pharmacokinetics (Cl_mic, t1/2) are more critical for an enzyme inhibitor targeting SRC.

Output:
0
2025-04-17 14:32:03,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 and 350.478 Da) fall comfortably within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.08) is slightly higher than Ligand B (42.43). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Ligand A (1.677) is within the optimal range (1-3). Ligand B (4.205) is a bit high, potentially leading to solubility issues and off-target interactions.

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

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.699 and 0.705), indicating good drug-likeness.

**DILI:** Ligand A (12.369) has a significantly lower DILI risk than Ligand B (29.042). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (75.107 and 84.878), but this is less critical for a non-CNS target like SRC.

**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 ligands have negative solubility values, indicating poor solubility. Ligand A (-1.026) is slightly better than Ligand B (-2.943).

**hERG Inhibition:** Ligand A (0.306) has a lower hERG inhibition liability than Ligand B (0.817), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (56.262) has lower microsomal clearance than Ligand B (68.096), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (19.5) has a much longer in vitro half-life than Ligand A (-1.907). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.431), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.8). This 0.4 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand A is preferable due to its significantly lower DILI risk and hERG inhibition liability, lower microsomal clearance, and lower P-gp efflux. While Ligand B has a slightly better binding affinity and a longer half-life, the safety and ADME advantages of Ligand A outweigh these benefits. The solubility issues are a concern for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 14:32:03,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.861 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is well below the 140 threshold and suitable for oral absorption. Ligand B (102.05) is still acceptable but less optimal.

**logP:** Both ligands have good logP values (2.893 and 1.203), 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=6) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.568 and 0.785), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (48.43) has a lower DILI risk than Ligand B (64.133), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.997) has a better BBB score than Ligand B (43.699).

**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 (0.357) has a much lower hERG risk than Ligand B (0.092), a significant advantage.

**Microsomal Clearance:** Ligand A (34.141) has a higher (worse) microsomal clearance than Ligand B (13.782), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (29.004 and 28.825 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.132 and 0.008).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol), a difference of 1.2 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability. However, Ligand A has lower DILI risk and hERG liability. The difference in binding affinity is substantial (1.2 kcal/mol) and likely outweighs the slightly higher DILI and hERG risks of Ligand A, especially considering the similar half-lives. The negative solubility and Caco-2 values for both are concerning and would require further investigation, but the binding affinity difference is the most critical factor here.

Output:
1
2025-04-17 14:32:03,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.933 and 368.785 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is well below the 140 threshold, suggesting good absorption. Ligand B (138.11) is approaching the upper limit, but still acceptable.

**logP:** Ligand A (4.877) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.438) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, also good. Ligand B has 7 HBA, which is higher and could impact permeability.

**QED:** Ligand A (0.81) has a strong drug-like profile. Ligand B (0.322) is significantly lower, indicating a less desirable overall profile.

**DILI:** Ligand A (37.224) has a low DILI risk. Ligand B (68.941) has a higher, but still acceptable, DILI risk.

**BBB:** Ligand A (73.943) shows reasonable BBB penetration. Ligand B (48.081) has poor BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.494) has poor Caco-2 permeability, which is concerning. Ligand B (-5.569) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.251) has poor aqueous solubility, likely due to its high logP. Ligand B (-1.677) has better, but still poor, solubility.

**hERG Inhibition:** Ligand A (0.807) has a moderate hERG risk. Ligand B (0.031) has very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (74.378) has moderate clearance. Ligand B (-1.083) has *negative* clearance, which is impossible and likely an error in the data, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (47.927) has a moderate half-life. Ligand B (8.949) has a short half-life.

**P-gp Efflux:** Ligand A (0.217) has low P-gp efflux. Ligand B (0.015) has very low P-gp efflux.

**Binding Affinity:** Ligand A (-9.0) has significantly better binding affinity than Ligand B (-7.5). This is a >1.5 kcal/mol difference, which is substantial.

**Conclusion:**

Despite Ligand A's superior binding affinity, its poor solubility, poor Caco-2 permeability, and moderate hERG risk are major drawbacks. Ligand B, while having weaker affinity, possesses a much better safety profile (very low hERG, low P-gp efflux) and, despite its low logP, has a better solubility profile. The negative microsomal clearance for Ligand B is a data anomaly, but suggests it is highly metabolically stable. The substantial affinity difference is important, but can potentially be addressed through further optimization. Considering the enzyme-specific priorities, I would choose Ligand B as the more viable starting point for drug development due to its superior ADME-Tox properties and potential for optimization.

Output:
1
2025-04-17 14:32:03,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.387 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.35) is slightly higher than Ligand B (76.02), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (1.403) and Ligand B (2.068) are both 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 slightly higher than Ligand B (4), but both are below the 10 threshold.

**6. QED:** Ligand A (0.906) has a significantly better QED score than Ligand B (0.472), indicating a more drug-like profile.

**7. DILI:** Ligand A (83.986) has a higher DILI risk than Ligand B (50.136), which is a concern. However, the difference isn't drastic.

**8. BBB:** Both ligands have similar BBB penetration (57.929 and 57.154), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.967 and -4.742), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.888 and -3.662), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.232 and 0.078). This is excellent.

**12. Microsomal Clearance:** Ligand B (28.896) has lower microsomal clearance than Ligand A (38.571), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (2.13) has a slightly better in vitro half-life than Ligand A (-13.042), though both are quite poor.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.099 and 0.095).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has significantly better binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference of 1.8 kcal/mol is significant.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate due to its significantly stronger binding affinity (-8.5 vs -6.7 kcal/mol) and better QED score (0.906 vs 0.472). While Ligand A has a higher DILI risk, the potency advantage is likely to be more critical for a kinase inhibitor. The improved metabolic stability of Ligand B is a plus, but the difference isn't large enough to overcome the substantial binding affinity gap. Further optimization would be needed to address the solubility and permeability issues for either compound, but Ligand A provides a better starting point.

Output:
0
2025-04-17 14:32:03,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors. Given the target class (enzyme/kinase), potency, metabolic stability, solubility, and hERG risk are prioritized.

**Molecular Weight:** Both ligands (355.391 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.41) is better than Ligand B (129.37). Both are below 140, acceptable for oral absorption.

**logP:** Ligand A (-0.892) is slightly less lipophilic than Ligand B (-1.432). Both are below the optimal 1-3 range, which could potentially hinder permeation, but are not drastically outside.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is better than Ligand B (4 HBD, 7 HBA). Both are within acceptable limits, but A is closer to the ideal.

**QED:** Ligand A (0.619) has a better QED score than Ligand B (0.405), indicating a more drug-like profile.

**DILI:** Ligand A (39.977) has a significantly lower DILI risk than Ligand B (55.797). Both are below 60, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (44.785) is better than Ligand B (27.026).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.018) is slightly better than Ligand B (-5.712).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-0.41) is slightly better than Ligand B (-1.427).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.047 and 0.034).

**Microsomal Clearance:** Ligand B (-20.448) has a much lower (better) microsomal clearance than Ligand A (1.724). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-2.712) has a slightly longer half-life than Ligand A (-11.606).

**P-gp Efflux:** Both are very low (0.008 and 0.006), indicating minimal P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -8.6 kcal/mol). Ligand A is 0.9 kcal/mol better, which is a substantial advantage.

**Conclusion:**

While Ligand B has superior metabolic stability (lower Cl_mic and slightly longer half-life), Ligand A has a better overall profile. The significantly better QED, lower DILI risk, and, crucially, the 0.9 kcal/mol advantage in binding affinity outweigh the slightly worse metabolic stability. For an enzyme target like SRC kinase, potency is paramount, and the improved ADME properties of Ligand A (better TPSA, HBD/HBA, solubility, and QED) make it the more promising candidate.

Output:
0
2025-04-17 14:32:03,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.43 and 364.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (72.11 and 66.57) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.41 and 3.91) are within the optimal 1-3 range, suggesting good permeability. Ligand B is slightly higher, potentially increasing off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5 (0.76 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.72, which is considered high risk. Ligand B has a much lower DILI risk of 39.39, which is good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (79.68 and 67.55), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both 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 have negative solubility values, indicating poor solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.83 and 0.80), which is good.

**Microsomal Clearance:** Ligand A has a Cl_mic of 65.07 mL/min/kg, which is relatively high, suggesting faster metabolism. Ligand B has a Cl_mic of 97.88 mL/min/kg, which is even higher. Both are concerning.

**In vitro Half-Life:** Ligand A has a negative half-life (-1.92 hours), which is not possible. Ligand B has a half-life of 38.92 hours, which is very good. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.37 and 0.92).

**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 for Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a significantly lower DILI risk and a much longer in vitro half-life. The slightly better binding affinity further supports its selection. The higher microsomal clearance is a concern, but the longer half-life suggests it's being metabolized to inactive compounds. Ligand A's high DILI risk is a major drawback.

Output:
1
2025-04-17 14:32:03,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight (MW):** Both ligands (350.463 and 350.438 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (81.75 and 83.98) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (0.945) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (3.056) 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 3 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED scores (0.774 and 0.772), indicating good drug-likeness.

**7. DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (48.119). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (70.143 and 78.48), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.86) has slightly better Caco-2 permeability than Ligand B (-4.505), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.709) has better aqueous solubility than Ligand B (-3.634). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.24 and 0.174).

**12. Microsomal Clearance (Cl_mic):** Ligand A (5.279) has significantly lower microsomal clearance than Ligand B (35.781), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.283) has a longer in vitro half-life compared to Ligand B (-3.916).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.033).

**15. 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 a positive factor.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in these areas: it has slightly better affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and a lower DILI risk. While Ligand B has a better logP, the advantages of Ligand A in the critical ADME/Tox properties outweigh this.

Output:
1
2025-04-17 14:32:03,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (104.73) is better than Ligand B (66.32). While both are below the 140 threshold for oral absorption, Ligand B is significantly lower, potentially indicating better absorption.

**logP:** Ligand A (0.89) is slightly lower than the optimal 1-3 range, potentially causing permeability issues. Ligand B (3.248) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are both acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.533, Ligand B: 0.865), indicating good drug-like properties. Ligand B is superior here.

**DILI:** Ligand A (37.495) has a much lower DILI risk than Ligand B (65.568). This is a significant advantage for Ligand A.

**BBB:** Ligand A (31.834) has a lower BBB penetration than Ligand B (49.787). However, as SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both have negative values (-5.21 and -5.128). These values are unusual and likely indicate poor permeability.

**Aqueous Solubility:** Both have negative values (-1.952 and -3.867), indicating poor solubility.

**hERG Inhibition:** Ligand A (0.076) has a much lower hERG risk than Ligand B (0.396). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-0.617) has a *negative* clearance, which is highly unusual and suggests excellent metabolic stability. Ligand B (54.348) has a high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (-12.316) has a negative half-life, also unusual and indicating exceptional stability. Ligand B (-0.785) has a short half-life.

**P-gp Efflux:** Ligand A (0.092) has low P-gp efflux, while Ligand B (0.207) has slightly higher 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 crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has superior safety profiles (DILI, hERG) and metabolic stability (Cl_mic, t1/2). However, Ligand B has a *much* stronger binding affinity. Given that we are targeting an enzyme (kinase), potency is paramount. While the ADME properties of Ligand B are less favorable, the significant binding affinity advantage likely outweighs these concerns, *provided* that the solubility and permeability issues can be addressed through formulation or further chemical modifications. The negative values for Caco-2 and solubility are concerning and would need investigation.

Output:
1
2025-04-17 14:32:03,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.471 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.8) is slightly higher than Ligand B (64.09). Both are below 140, suggesting reasonable absorption potential.

**logP:** Ligand A (3.143) is optimal, while Ligand B (0.795) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the limit of 5.

**H-Bond Acceptors:** Ligand A (7) and Ligand B (4) are both within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.7 for A, 0.796 for B), indicating drug-like properties.

**DILI:** Ligand A (77.472) has a higher DILI risk than Ligand B (6.786). This is a significant concern for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand A (61.535) is lower than Ligand B (57.193).

**Caco-2 Permeability:** Ligand A (-5.269) has poor Caco-2 permeability, while Ligand B (-4.795) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.146) has poor aqueous solubility, while Ligand B (-0.633) is also poor, but slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.296 and 0.386, respectively).

**Microsomal Clearance:** Ligand A (71.179) has higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (-2.625). This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (32.409) has a shorter half-life than Ligand B (11.17), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.446 and 0.015, respectively).

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

**Conclusion:**

Despite similar binding affinities, Ligand B is the superior candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and Caco-2 permeability outweigh the slightly lower logP. Ligand A's high DILI risk and poor metabolic stability are major liabilities.

Output:
1
2025-04-17 14:32:03,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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.

**TPSA:** Ligand A (52.65) is better than Ligand B (33.2). Lower TPSA generally favors better absorption.

**logP:** Ligand A (1.648) is optimal, while Ligand B (4.192) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**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 (0.745 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (4.033) has a very low DILI risk, significantly better than Ligand B (33.773). This is a major advantage for Ligand A.

**BBB:** Ligand B (93.718) has a higher BBB penetration score than Ligand A (72.082). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.071) has a worse Caco-2 permeability than Ligand B (-4.319), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.463) has better aqueous solubility than Ligand B (-5.039). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.457) has a lower hERG inhibition risk than Ligand B (0.677), which is favorable.

**Microsomal Clearance:** Ligand A (-14.568) has significantly lower microsomal clearance than Ligand B (55.945), indicating much better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-6.109) has a longer in vitro half-life than Ligand B (0.826), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.011) has a lower P-gp efflux liability than Ligand B (0.449), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-10.4 kcal/mol) has a stronger binding affinity than Ligand A (-8.9 kcal/mol). This is a 1.5 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is superior in almost all ADMET properties. Specifically, its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and lower hERG risk are crucial advantages for an enzyme target like SRC kinase. The slightly weaker binding affinity of Ligand A can potentially be optimized through further medicinal chemistry efforts, while the poor ADMET profile of Ligand B is harder to fix.

Output:
0
2025-04-17 14:32:03,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (97.12) is better than Ligand B (40.62). Lower TPSA generally favors better absorption.

**logP:** Ligand A (2.107) is within the optimal range (1-3). Ligand B (3.945) is approaching the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both acceptable, being less than 10.

**QED:** Ligand A (0.643) is better than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand A (52.346) has a higher DILI risk than Ligand B (21.869). This is a significant concern for Ligand A.

**BBB:** Ligand A (48.236) is lower than Ligand B (97.674). BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-5.69) is worse than Ligand B (-4.224), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.423) is better than Ligand B (-3.887), which is a positive attribute.

**hERG Inhibition:** Ligand A (0.324) is better than Ligand B (0.91), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (43.715) is significantly better than Ligand B (74.9), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.787) is significantly better than Ligand B (3.676), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.143) is better than Ligand B (0.445), suggesting lower P-gp efflux.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.6). However, the difference is small (0.7 kcal/mol) and may not be enough to overcome other issues.

**Overall Assessment:**

Ligand A has better solubility, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly better QED score. However, it has a higher DILI risk and lower Caco-2 permeability. Ligand B has a better BBB score (irrelevant here), lower DILI risk, and better Caco-2 permeability, but suffers from worse metabolic stability, solubility, and higher P-gp efflux.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate despite the higher DILI risk. The significantly improved metabolic stability and solubility are crucial for *in vivo* efficacy. The small difference in binding affinity is unlikely to outweigh these ADME advantages. The DILI risk could be investigated further with additional studies.

Output:
0
2025-04-17 14:32:03,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.424 and 391.915 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.17) is slightly higher than Ligand B (41.29), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have logP values (4.905 and 4.16) that are a bit high, potentially leading to solubility issues or off-target effects. Ligand B is slightly better.

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

**QED:** Both ligands have similar QED values (0.766 and 0.77), indicating good drug-likeness.

**DILI:** Ligand A (47.034) has a slightly higher DILI risk than Ligand B (34.626), but both are below the concerning threshold of 60.

**BBB:** Both have high BBB penetration, but Ligand A (93.525) is better than Ligand B (82.784). This is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.6 and -4.721). 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 very poor aqueous solubility (-5.224 and -4.441). This is a significant concern.

**hERG Inhibition:** Ligand A (0.411) has a lower hERG risk than Ligand B (0.882), which is favorable.

**Microsomal Clearance:** Ligand A (50.471) has lower microsomal clearance than Ligand B (57.707), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.475) has a shorter half-life than Ligand B (16.187).

**P-gp Efflux:** Ligand A (0.428) has lower P-gp efflux than Ligand B (0.665), which is preferable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand B is the more promising candidate due to its significantly stronger binding affinity (-7.6 vs -6.9 kcal/mol) and better metabolic stability (lower Cl_mic). The slightly lower hERG risk of Ligand A is a positive, but the affinity difference is more important for an enzyme inhibitor. The solubility issue would need to be addressed through formulation strategies.

Output:
1
2025-04-17 14:32:03,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 349.381 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.9) is slightly above the preferred <90 for CNS, but acceptable for a non-CNS target like SRC. Ligand B (62.3) is well within the ideal range.

**logP:** Ligand A (0.764) is a bit low, potentially hindering permeability. Ligand B (2.679) 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.

**QED:** Ligand A (0.306) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.85) is excellent.

**DILI:** Ligand A (12.524) has a very low DILI risk, which is excellent. Ligand B (52.152) is higher, but still within an acceptable range.

**BBB:** This is less critical for a non-CNS target. Ligand A (39.55) is lower than Ligand B (68.166).

**Caco-2 Permeability:** Ligand A (-5.657) has poor predicted permeability. Ligand B (-4.31) is better, but still not great.

**Aqueous Solubility:** Ligand A (-0.413) has poor predicted solubility. Ligand B (-2.869) is even worse.

**hERG Inhibition:** Ligand A (0.174) has a very low hERG risk, which is excellent. Ligand B (0.383) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-5.505) suggests very low clearance and high metabolic stability, which is excellent. Ligand B (37.8) suggests moderate clearance.

**In vitro Half-Life:** Ligand A (23.026) has a moderate half-life. Ligand B (5.2) has a short half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.009 and 0.083, respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and 0.0 kcal/mol respectively).

**Overall Assessment:**

Ligand A excels in potency (affinity), DILI risk, hERG risk, and metabolic stability. However, it suffers from poor QED, Caco-2 permeability, and aqueous solubility, and a low logP. Ligand B has a better QED, logP and TPSA, but has a higher DILI risk, shorter half-life, and moderate metabolic clearance.

Given the priorities for enzyme inhibitors, metabolic stability and potency are key. Ligand A's significantly better metabolic stability (much lower Cl_mic, longer half-life) and comparable binding affinity outweigh its drawbacks, *provided* the solubility and permeability issues can be addressed through formulation or further structural modifications. The lower QED is also a concern, but less critical than the ADME properties.

Output:
1
2025-04-17 14:32:03,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.382 Da) is slightly lower, which could be beneficial for permeability. Ligand B (355.435 Da) is also good.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (105.76). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit and might have absorption issues.

**logP:** Ligand A (4.723) is high, potentially leading to solubility issues and off-target effects. Ligand B (-0.281) is quite low, which could hinder membrane permeability and bioavailability.

**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 acceptable QED scores (A: 0.732, B: 0.555), indicating reasonable drug-likeness.

**DILI:** Ligand A (93.292) has a high DILI risk, which is a significant concern. Ligand B (28.306) has a very low DILI risk, a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (62.233) is slightly better than Ligand B (50.95).

**Caco-2 Permeability:** Ligand A (-4.617) has poor predicted permeability. Ligand B (-5.468) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.685) has very poor predicted solubility, likely due to its high logP. Ligand B (-1.268) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.696) has a slightly higher hERG risk than Ligand B (0.108), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (113.382) has higher clearance, indicating lower metabolic stability. Ligand B (7.336) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (57.293) has a moderate half-life. Ligand B (17.874) has a shorter half-life, which is a drawback.

**P-gp Efflux:** Ligand A (0.636) has moderate P-gp efflux. Ligand B (0.006) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 0.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a much better binding affinity, but suffers from poor solubility, high DILI risk, and higher metabolic clearance. Ligand B has a significantly lower DILI risk, better metabolic stability, and lower P-gp efflux, but weaker binding affinity and a higher TPSA.

Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. The strong affinity of Ligand A is tempting, but the high DILI risk is a major red flag. While optimization could potentially address the solubility and clearance issues, mitigating a high DILI risk is often very challenging. The slightly weaker affinity of Ligand B is acceptable given its superior safety and metabolic profile.

Output:
1
2025-04-17 14:32:03,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.471 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (59.0) is better than Ligand B (69.72). Both are below the 140 A^2 threshold for good oral absorption, but lower TPSA is generally preferred.

**3. logP:** Both ligands have good logP values (2.857 and 1.564), 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 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.822 and 0.74), indicating drug-like properties.

**7. DILI:** Both ligands have very similar, low DILI risk (18.224 and 18.185 percentile), which is excellent.

**8. BBB:** Both ligands have moderate BBB penetration (41.528 and 70.609 percentile). Since SRC is not a CNS target, this is not a major deciding factor. Ligand B is better here.

**9. Caco-2 Permeability:** Ligand A (-4.422) is better than Ligand B (-4.739). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.676) is better than Ligand B (-2.438). Higher values are preferred.

**11. hERG Inhibition:** Ligand A (0.749) is better than Ligand B (0.246). Lower values indicate lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (27.799) has significantly lower microsomal clearance than Ligand A (70.92). This suggests better metabolic stability for Ligand B, a critical factor for enzymes.

**13. In vitro Half-Life:** Ligand B (-2.537) has a negative half-life, which is concerning and indicates very rapid metabolism. Ligand A (15.195) has a good half-life.

**14. P-gp Efflux:** Ligand A (0.497) is better than Ligand B (0.032). Lower efflux is preferred.

**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 significant.

**Overall Assessment:**

Ligand A has a better binding affinity, solubility, Caco-2 permeability, hERG profile, and half-life. However, Ligand B has significantly better metabolic stability (lower Cl_mic). The difference in binding affinity (0.7 kcal/mol) is substantial and can often outweigh minor ADME drawbacks, especially for an enzyme target where potency is paramount. The significantly better metabolic stability of Ligand B is appealing, but the very short half-life is a major concern. Given the balance, the superior binding affinity and more reasonable half-life of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 14:32:03,858 - INFO - Batch 304 complete. Total preferences: 4864
2025-04-17 14:32:03,858 - INFO - Processing batch 305/512...
2025-04-17 14:32:51,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (352.391 Da) is also good.

**TPSA:** Ligand A (61.44) is excellent, well below the 140 threshold for oral absorption. Ligand B (116.92) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.049) is at the upper end of the optimal range (1-3) and could potentially cause solubility issues or off-target interactions. Ligand B (-0.872) is below the optimal range and may have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is excellent. Ligand B (HBD=3, HBA=7) is acceptable, but the higher HBA count could slightly hinder permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.827, B: 0.613), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (84.025) has a higher DILI risk than Ligand B (60.566), which is a concern.

**BBB:** Ligand A (71.462) has better BBB penetration than Ligand B (12.408), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.624) has poor Caco-2 permeability. Ligand B (-5.166) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.23) has poor aqueous solubility. Ligand B (-1.632) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.724) has a lower hERG risk than Ligand B (0.168), which is a significant advantage.

**Microsomal Clearance:** Ligand A (55.008) has higher microsomal clearance than Ligand B (6.055), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (35.151) has a longer half-life than Ligand B (-3.182), which is a positive.

**P-gp Efflux:** Ligand A (0.23) has lower P-gp efflux than Ligand B (0.016), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.1 kcal/mol, B: -8.6 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, BBB, P-gp efflux, and in vitro half-life. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), poor Caco-2 permeability and poor solubility. Ligand B has better solubility, lower DILI, and better metabolic stability, but lower binding affinity and worse BBB, P-gp efflux and half-life.

Considering the enzyme-specific priorities, metabolic stability and solubility are crucial. While Ligand A has a slightly better binding affinity, the significantly better metabolic stability and solubility of Ligand B, coupled with a lower DILI risk, make it the more promising candidate. The affinity difference of 0.5 kcal/mol is not substantial enough to outweigh the ADME advantages of Ligand B.

Output:
1
2025-04-17 14:32:51,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (343.427 and 352.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.69) is well below the 140 threshold for good oral absorption, and even below 90, which is favorable. Ligand B (95.12) is still under 140, but closer to the limit.

**3. logP:** Ligand A (2.027) is within the optimal range of 1-3. Ligand B (0.461) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**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 (0.869) has a strong drug-like profile, significantly better than Ligand B (0.469).

**7. DILI:** Ligand A (45.522) has a lower DILI risk than Ligand B (38.736), both are good.

**8. BBB:** Ligand A (66.654) and Ligand B (73.401) are both reasonable, but not exceptionally high. BBB isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.689) and Ligand B (-5.069) both have negative values, suggesting poor permeability. This is concerning, but needs to be considered alongside other factors.

**10. Aqueous Solubility:** Ligand A (-2.651) and Ligand B (-1.901) both have negative values, indicating poor solubility. This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.807) has a slightly higher hERG risk than Ligand B (0.277), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (14.84) has a much lower microsomal clearance than Ligand B (29.009), suggesting better metabolic stability. This is a key consideration for an enzyme target.

**13. In vitro Half-Life:** Ligand A (15.223) has a longer in vitro half-life than Ligand B (-1.335), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux than Ligand B (0.016), implying better bioavailability.

**15. Binding Affinity:** Ligand A (-9.7 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.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in affinity and metabolic stability, and has a better half-life and lower P-gp efflux. While both have solubility issues, Ligand A's superior binding and metabolic properties are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 14:32:51,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (385.917 Da) is still well within the range.

**TPSA:** Ligand A (62.55) is significantly better than Ligand B (82.53). Lower TPSA generally indicates better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have good logP values (A: 2.684, B: 2.79), 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 it has fewer hydrogen bond forming groups, which generally improves permeability.

**QED:** Both ligands have acceptable QED values (A: 0.677, B: 0.761), indicating good drug-like properties.

**DILI:** Ligand A (41.76) has a lower DILI risk than Ligand B (67.313), making it more favorable from a safety perspective.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (64.482) is slightly better than Ligand B (52.268).

**Caco-2 Permeability:** Ligand A (-4.87) is better than Ligand B (-5.141), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.515) is better than Ligand B (-4.6), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (A: 0.135, B: 0.442), which is excellent.

**Microsomal Clearance:** Ligand B (33.38) has a lower microsomal clearance than Ligand A (38.416), indicating better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (22.176) has a slightly longer half-life than Ligand B (0.686), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.264, B: 0.21), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -8.4 kcal/mol, B: -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a slightly better metabolic stability (lower Cl_mic), Ligand A is superior in almost all other key parameters, including TPSA, solubility, DILI risk, and Caco-2 permeability. Given the comparable binding affinity, the better ADME profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 14:32:51,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.443 Da) is slightly higher than Ligand B (350.375 Da), but both are acceptable.

**TPSA:** Ligand A (91.84) is better than Ligand B (133.56). TPSA < 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (0.734) is within the optimal range (1-3), while Ligand B (-0.62) is slightly below, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is better than Ligand B (HBD=4, HBA=6). Lower HBD is generally preferred.

**QED:** Both ligands have reasonable QED values (A: 0.83, B: 0.54), indicating good drug-like properties.

**DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (41.45). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (60.566) has a higher BBB value than Ligand A (49.709), but this isn't a major factor here.

**Caco-2:** Ligand A (-4.815) and Ligand B (-5.453) 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:** Ligand A (-2.984) and Ligand B (-1.204) both have negative solubility values, which suggests poor solubility. However, the scale is not specified, so it's hard to interpret.

**hERG:** Both ligands have very low hERG risk (A: 0.372, B: 0.056), which is excellent.

**Microsomal Clearance:** Ligand B (-9.104) has significantly lower (better) microsomal clearance than Ligand A (36.527), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-10.572) has a longer half-life than Ligand A (-14.572), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.114, B: 0.003), which is favorable.

**Binding Affinity:** Both ligands have similar and excellent binding affinities (A: -9.1 kcal/mol, B: -8.7 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Overall:**

Ligand B is the better candidate. While both have similar potency, Ligand B demonstrates superior ADME properties, specifically lower DILI risk and significantly better metabolic stability (lower Cl_mic and longer t1/2). The slightly lower logP of Ligand B is a minor concern, but is outweighed by the benefits of improved metabolic stability and reduced toxicity.

Output:
1
2025-04-17 14:32:51,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (367.515 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is well below the 140 threshold for oral absorption. Ligand B (122.03) is also under the threshold, but closer to it.

**logP:** Ligand A (2.481) is optimal (1-3). Ligand B (0.043) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is excellent. Ligand B (3 HBD, 7 HBA) is acceptable, but higher counts could slightly impact permeability.

**QED:** Ligand A (0.868) is very strong, indicating high drug-likeness. Ligand B (0.581) is acceptable, but lower than A.

**DILI:** Both ligands have acceptable DILI risk (47.77 and 52.772, both <60).

**BBB:** Ligand A (61.535) is moderate. BBB isn't a primary concern for a non-CNS target like SRC. Ligand B (25.242) is low.

**Caco-2 Permeability:** Ligand A (-4.884) is poor, suggesting low intestinal absorption. Ligand B (-5.525) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.262 and -2.144). This is a concern, but can be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.447) has very low hERG risk. Ligand B (0.028) has extremely low hERG risk. Both are excellent.

**Microsomal Clearance:** Ligand A (64.282) has moderate clearance. Ligand B (5.483) has very low clearance, indicating good metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (11.743 hours) is reasonable. Ligand B (-8.822 hours) is extremely short, a major drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.185 and 0.013).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing other drawbacks.

**Conclusion:**

Despite Ligand B's poor Caco-2 permeability, low BBB, and very short half-life, its *much* stronger binding affinity (-8.3 vs 0.0 kcal/mol) and excellent metabolic stability (low Cl_mic) are decisive. The binding affinity difference is substantial enough to prioritize it, assuming formulation strategies can address the solubility and permeability issues. Ligand A's better solubility and permeability are offset by its extremely weak binding.

Output:
1
2025-04-17 14:32:51,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.419 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is better than Ligand B (64.02) as it is still within the acceptable range for oral absorption, while Ligand B is significantly lower.

**logP:** Ligand A (-0.983) is slightly low, potentially hindering permeation, while Ligand B (3.166) is optimal. This favors 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 (6) is also good.

**QED:** Both ligands have similar and acceptable QED values (0.602 and 0.698).

**DILI:** Ligand A (35.246) has a significantly lower DILI risk than Ligand B (51.57), which is a major advantage.

**BBB:** Ligand A (20.085) has a low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (65.064) is better, but not critical here.

**Caco-2 Permeability:** Ligand A (-5.17) is poor, while Ligand B (-4.301) is also poor. Both have negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-1.336) is poor, while Ligand B (-3.977) is even worse. Both are concerning.

**hERG Inhibition:** Ligand A (0.08) has a very low hERG risk, a significant advantage. Ligand B (0.249) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-10.522) has a much lower (better) microsomal clearance than Ligand B (63.459), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (20.118) has a better in vitro half-life than Ligand B (-11.529).

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is favorable. Ligand B (0.301) is higher, but not excessively so.

**Binding Affinity:** Ligand A (-8.3) has a significantly stronger binding affinity than Ligand B (-6.4). This difference of 1.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having a better logP, the significantly superior binding affinity of Ligand A (-8.3 vs -6.4 kcal/mol), combined with its much lower DILI risk, better metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux, makes it the more promising drug candidate. The solubility and Caco-2 permeability are concerns for both, but can be addressed through formulation strategies. The strong binding affinity of Ligand A is a key advantage for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:32:51,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.356 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (103.01).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.485) is optimal, while Ligand B (1.046) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but A is more favorable.

**QED:** Both ligands have similar, good QED values (0.628 and 0.694).

**DILI:** Ligand B (57.387) has a slightly better DILI score than Ligand A (49.864), but both are acceptable (<60).

**BBB:** Ligand A (94.416) has a much higher BBB percentile than Ligand B (36.642). While not a primary concern for a non-CNS target like SRC, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Ligand A (-4.331) is better than Ligand B (-5.314), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.668) is better than Ligand B (-2.735), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.534) has a lower hERG risk than Ligand B (0.441), which is a significant advantage.

**Microsomal Clearance:** Ligand A (72.896) has higher microsomal clearance than Ligand B (38.367), meaning B is more metabolically stable. This is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (19.976) has a significantly longer half-life than Ligand A (-7.703), which is a major advantage.

**P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux than Ligand B (0.011), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-6.4). This is a 1.5 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a longer half-life, which are critical for an enzyme inhibitor. While its logP is lower and TPSA higher than ideal, the substantial binding advantage (-8.4 vs -6.4 kcal/mol) likely compensates for these. Ligand A has better solubility, lower hERG risk, and better Caco-2 permeability, but the weaker binding affinity is a major drawback. The improved metabolic stability of Ligand B is also a significant factor.

Output:
1
2025-04-17 14:32:51,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.774 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.17) is well below the 140 threshold, suggesting good absorption. Ligand B (93.73) is still within acceptable limits, but less optimal.

**logP:** Ligand A (4.988) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.941) is quite low, which might hinder permeation.

**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 the recommended limits.

**QED:** Ligand A (0.574) has a better QED score than Ligand B (0.451), indicating a more drug-like profile.

**DILI:** Ligand A (47.15) has a slightly higher DILI risk than Ligand B (31.291), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.374) and Ligand B (47.15) are both moderate.

**Caco-2 Permeability:** Ligand A (-4.939) and Ligand B (-4.777) both have negative values, which is unusual. This indicates poor permeability.

**Aqueous Solubility:** Ligand A (-5.018) has very poor solubility. Ligand B (-2.486) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.941) has a lower hERG risk than Ligand B (0.071), which is a significant advantage.

**Microsomal Clearance:** Ligand A (14.308) has a much lower Cl_mic, indicating better metabolic stability, which is crucial for kinase inhibitors. Ligand B (63.389) has high clearance.

**In vitro Half-Life:** Ligand A (47.033) has a significantly longer half-life than Ligand B (-23.149), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.499) has lower P-gp efflux liability than Ligand B (0.03), which is desirable.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.1). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 2 kcal/mol is significant.

**Conclusion:**

Despite Ligand A's better QED, metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk, the significantly superior binding affinity of Ligand B (-9.0 vs -7.1 kcal/mol) is the deciding factor. For an enzyme target, potency is paramount. While Ligand B has some ADME liabilities (low logP, moderate solubility, high Cl_mic), these can potentially be addressed through further optimization. Ligand A's poor solubility is a major concern.

Output:
1
2025-04-17 14:32:51,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.463 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.89) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (82.78) is well within the ideal range.

**logP:** Ligand A (-0.893) is a bit low, potentially hindering permeation. Ligand B (1.585) is 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 8 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.711 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (37.999) has a slightly higher DILI risk than Ligand B (19.504), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (43.932 and 46.762), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.102) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.484) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.099 and -2.463), which could pose formulation challenges, but is not a deal-breaker if other properties are favorable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.306 and 0.237), which is excellent.

**Microsomal Clearance:** Ligand A (-18.283) has significantly lower (better) microsomal clearance than Ligand B (37.918), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.471) has a shorter half-life than Ligand B (-4.95), which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.014 and 0.096), which is favorable.

**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 of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's slightly lower logP and poor Caco-2 permeability, its *significantly* stronger binding affinity (-8.2 vs -7.7 kcal/mol) and superior metabolic stability (lower Cl_mic) make it the more promising candidate. The affinity difference is large enough to potentially overcome the permeability issue, and the better metabolic stability is crucial for an enzyme inhibitor.

Output:
1
2025-04-17 14:32:51,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.411 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.33) is significantly better than Ligand B (101.8), being well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.725 and 0.847), falling within the 1-3 optimal range.

**H-Bond Donors:** Both 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:** Both ligands have similar QED values (0.871 and 0.81), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (58.938 and 56.805), which is acceptable (below 60).

**BBB:** Both ligands have low BBB penetration (54.052 and 48.74), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.314 and -5.189), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.501 and -2.12), which is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.544 and 0.408), which is good.

**Microsomal Clearance:** Ligand A (-15.436) has significantly better metabolic stability (lower clearance) than Ligand B (0.2). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (33.958) has a longer half-life than Ligand B (2.509), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.029).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.6 and -8.7 kcal/mol). Ligand A is slightly better (-9.6 kcal/mol).

**Conclusion:**

While both ligands have good binding affinity and acceptable safety profiles (DILI, hERG), Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower TPSA, and slightly better binding affinity. The poor Caco-2 and solubility are concerning for both, but the metabolic advantage of Ligand A is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:32:51,956 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [343.387, 100.21 ,   0.259,   2.   ,   5.   ,   0.811,  65.374,  47.499, -5.362,  -2.181,   0.02 , -16.6  ,   4.432,   0.029,  -7.8  ]
**Ligand B:** [366.527,  58.64 ,   2.362,   1.   ,   4.   ,   0.784,  25.902,  76.813, -5.124,  -3.334,   0.385,  54.839,  -6.566,   0.279,  -9.2  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (343.387) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (100.21) is higher than B (58.64).  Both are below 140, but B is significantly better for oral absorption.
3. **logP:** A (0.259) is quite low, potentially hindering membrane permeability. B (2.362) is within the optimal range (1-3). This is a significant advantage for B.
4. **HBD:** A (2) and B (1) are both acceptable (<=5). B is slightly better.
5. **HBA:** A (5) and B (4) are both acceptable (<=10). B is slightly better.
6. **QED:** Both A (0.811) and B (0.784) are good, indicating drug-like properties.
7. **DILI:** A (65.374) has a higher DILI risk than B (25.902). B is much preferred here.
8. **BBB:** A (47.499) is lower than B (76.813). Not a primary concern for a kinase inhibitor, but B is better.
9. **Caco-2:** A (-5.362) and B (-5.124) are both very low and problematic, suggesting poor intestinal absorption.
10. **Solubility:** A (-2.181) and B (-3.334) are both very low and problematic.
11. **hERG:** A (0.02) is very low, indicating a low risk of hERG inhibition. B (0.385) is slightly higher, but still relatively low.
12. **Cl_mic:** A (-16.6) is much lower (better) than B (54.839), indicating better metabolic stability. This is a key advantage for A.
13. **t1/2:** A (4.432) is shorter than B (-6.566), indicating faster clearance. B is preferred.
14. **Pgp:** A (0.029) is lower (better) than B (0.279), indicating less P-gp efflux. A is preferred.
15. **Binding Affinity:** B (-9.2) has a significantly stronger binding affinity than A (-7.8). This is a substantial advantage for B.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

*   **Affinity:** B is significantly more potent.
*   **Metabolic Stability:** A has a better Cl_mic, but B has a much better t1/2.
*   **Solubility:** Both are very poor.
*   **hERG:** Both are relatively low risk.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and Pgp efflux, the significantly stronger binding affinity of Ligand B (-9.2 vs -7.8 kcal/mol) and its lower DILI risk outweigh these advantages. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies. The substantial difference in binding affinity suggests that B is more likely to be effective *in vivo*, even with potentially lower absolute bioavailability.

Output:
1
2025-04-17 14:32:51,956 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and priorities for enzymes.

**Step-by-step comparison:**

1. **MW:** 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.
2. **TPSA:** Both are below the 140 A<sup>2</sup> threshold for good oral absorption. Ligand A (86.02 A<sup>2</sup>) is slightly higher than Ligand B (78.35 A<sup>2</sup>), but both are good.
3. **logP:** Ligand A (0.651) is a bit low, potentially hindering permeation. Ligand B (3.006) is optimal. This is a significant advantage for B.
4. **HBD:** Both have 2 HBD, which is within the acceptable limit of <=5.
5. **HBA:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.
6. **QED:** Both have good QED scores (A: 0.737, B: 0.775), indicating drug-likeness.
7. **DILI:** Both have acceptable DILI risk (A: 40.132, B: 43.622), below the 60 threshold.
8. **BBB:**  BBB is not a primary concern for a general oncology target like SRC, but Ligand B (78.558) has a much higher percentile than Ligand A (32.144).
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 concerning. Ligand A (-0.671) is slightly better than Ligand B (-3.179), but both are problematic.
11. **hERG:** Both have low hERG inhibition liability (A: 0.281, B: 0.709), which is good.
12. **Cl_mic:** Ligand A (7.05 mL/min/kg) has significantly lower microsomal clearance than Ligand B (47.432 mL/min/kg). This suggests better metabolic stability for A, a key consideration for enzymes.
13. **t1/2:** Ligand A (21.713 hours) has a much longer in vitro half-life than Ligand B (9.973 hours). This is a significant advantage for A.
14. **Pgp:** Both have low Pgp efflux liability (A: 0.164, B: 0.408), which is favorable.
15. **Binding Affinity:** Both have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Enzyme-Specific Prioritization:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While both ligands have excellent binding affinity and acceptable hERG risk, Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and has slightly better solubility. Ligand B has a better logP, but the solubility and metabolic stability issues are more critical for an enzyme target. The negative Caco-2 and solubility values for both are concerning and would require further investigation (salt formation, formulation strategies, etc.).

**Conclusion:**

Considering the enzyme-specific priorities and the overall profile, **Ligand A** is the more promising drug candidate. Its superior metabolic stability and longer half-life outweigh the slightly lower logP and solubility compared to Ligand B.

Output:
0
2025-04-17 14:32:51,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.491 and 356.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.66) is higher than Ligand B (61.88). Both are below the 140 threshold for oral absorption, but lower is generally better. Ligand B has a slight advantage here.

**3. logP:** Ligand A (2.57) and Ligand B (3.549) are both within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility issues, but not drastically.

**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 have 4 H-bond acceptors, well within the acceptable limit of <=10.

**6. QED:** Ligand B (0.735) has a better QED score than Ligand A (0.591), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (Ligand A: 42.458, Ligand B: 44.087), and both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 71.811, Ligand B: 70.027), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests very poor permeability. Ligand A (-5.175) is slightly better than Ligand B (-5.336), but both are problematic.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.908) is slightly better than Ligand B (-3.803).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.343, Ligand B: 0.633).

**12. Microsomal Clearance:** Ligand A (32.382) has significantly lower microsomal clearance than Ligand B (62.91), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (11.275) has a longer in vitro half-life than Ligand B (2.135), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.061, Ligand B: 0.347), which is good.

**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, and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better QED and binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic and longer t1/2). For a kinase inhibitor, metabolic stability is crucial for maintaining therapeutic concentrations. The slightly better affinity of Ligand B is not enough to overcome the significantly worse metabolic profile. The poor Caco-2 and solubility for both ligands are concerning and would need to be addressed in further optimization, but metabolic stability is a more immediate concern.

Output:
0
2025-04-17 14:32:51,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.423 and 347.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.31) is better than Ligand B (52.65), both are under the 140 threshold for good absorption.

**logP:** Ligand A (3.317) is optimal (1-3), while Ligand B (1.941) is on the lower side, potentially impacting permeability.

**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 within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.685 and 0.82), indicating drug-likeness.

**DILI:** Ligand A (40.403) is slightly higher than Ligand B (29.236), but both are below the concerning threshold of 60. Ligand B is preferable here.

**BBB:** Not a high priority for a non-CNS target like SRC. Ligand B (81.815) is higher than Ligand A (57.968).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.878) is worse than Ligand B (-4.719).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.332) is worse than Ligand B (-1.715).

**hERG Inhibition:** Ligand A (0.922) is slightly higher than Ligand B (0.769), indicating a slightly higher risk of cardiotoxicity, though both are relatively low.

**Microsomal Clearance:** Ligand A (38.377) has higher clearance than Ligand B (33.456), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.051) has a significantly longer half-life than Ligand A (-33.482), a major advantage.

**P-gp Efflux:** Ligand A (0.573) has lower efflux than Ligand B (0.067), which is preferable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand B is the better candidate. While Ligand A has a slightly better logP and P-gp efflux, Ligand B excels in key areas for an enzyme inhibitor: significantly better binding affinity, longer half-life, lower DILI risk, and better solubility. The difference in binding affinity is substantial enough to compensate for the slightly lower logP.

Output:
1
2025-04-17 14:32:51,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.459 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (93.44). A TPSA under 140 is good for oral absorption, but lower is preferable. Ligand B's TPSA is getting higher and could potentially impact absorption.

**logP:** Both ligands have acceptable logP values (A: 1.334, B: 2.792) within the 1-3 range. Ligand B is slightly higher, which could lead to some solubility issues, but is still within acceptable limits.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=8). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.831) has a much better QED score than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Ligand A (36.332) has a significantly lower DILI risk than Ligand B (78.402). This is a major advantage for Ligand A.

**BBB:** Ligand A (72.237) has a better BBB penetration score than Ligand B (66.886). While not a primary concern for a kinase inhibitor (unless CNS effects are desired), it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.659) is better than Ligand B (-5.647) indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.523) is better than Ligand B (-3.366) indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.252, B: 0.432).

**Microsomal Clearance:** Ligand A (22.672) has a significantly lower microsomal clearance than Ligand B (53.596), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (49.78) has a much longer in vitro half-life than Ligand A (7.191). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.177, B: 0.273).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -7.8 kcal/mol, B: -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior in almost all ADME properties (QED, DILI, TPSA, solubility, permeability, metabolic stability) and has comparable binding affinity to Ligand B. The only area where Ligand B excels is in vitro half-life. However, the substantial improvements in safety (DILI) and drug-likeness (QED) offered by Ligand A outweigh the slightly shorter half-life. For an enzyme target like SRC kinase, metabolic stability is important, but can be addressed with structural modifications. A lower DILI risk is crucial.

Output:
0
2025-04-17 14:32:51,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.515 and 359.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is higher than Ligand B (29.54). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (1.288) is within the optimal 1-3 range. Ligand B (4.878) is higher, 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 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.731 and 0.678, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (23.575 and 22.024 percentile), which is favorable.

**BBB:** Both ligands have moderate BBB penetration (68.554 and 73.866 percentile). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Ligand A (-4.92) and Ligand B (-4.74) have similar, very poor Caco-2 permeability. This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Ligand A (-2.347) is better than Ligand B (-5.433) in terms of aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.285 and 0.582 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (37.679 mL/min/kg) has significantly lower microsomal clearance than Ligand B (126.031 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.936 hours) has a shorter half-life than Ligand B (10.96 hours), but both are acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.792 percentile), which is favorable.

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has a slightly better binding affinity than Ligand A (-6.3 kcal/mol). The difference is 0.4 kcal/mol, which is not substantial enough to outweigh other significant differences.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A exhibits significantly better metabolic stability (lower Cl_mic) and better aqueous solubility. The Caco-2 permeability is poor for both, but the other advantages of Ligand A make it a better starting point for optimization.

Output:
0
2025-04-17 14:32:51,957 - INFO - Batch 305 complete. Total preferences: 4880
2025-04-17 14:32:51,957 - INFO - Processing batch 306/512...
2025-04-17 14:33:31,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.422 and 368.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (81.75), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.633) is within the optimal range (1-3). Ligand B (-0.621) is slightly below 1, 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 5 HBA, both are acceptable (<=10).

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-likeness. Ligand A (0.711) is slightly better than Ligand B (0.626).

**7. DILI:** Ligand A (45.095) has a much lower DILI risk than Ligand B (12.641). This is a significant advantage for Ligand A.

**8. BBB:** This isn't a primary concern for a non-CNS target like SRC kinase, but Ligand A (85.653) has better BBB penetration than Ligand B (58.821).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.064) is slightly better than Ligand B (-5.624).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.857) is slightly better than Ligand B (-1.856).

**11. hERG Inhibition:** Ligand A (0.425) has a lower hERG risk than Ligand B (0.071). This is a crucial advantage.

**12. Microsomal Clearance:** Ligand A (-2.837) has a significantly *lower* (better) microsomal clearance than Ligand B (-13.614), indicating better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (3.094 and 3.142 hours).

**14. P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux than Ligand B (0.005).

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a major advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Ligand A is the superior candidate. It has a significantly better binding affinity, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), and slightly better solubility and permeability. While both have issues with solubility and permeability, the superior potency and safety profile of Ligand A outweigh these drawbacks.

Output:
1
2025-04-17 14:33:31,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 356.413 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.13) is slightly above the preferred <90 for CNS penetration, but acceptable for a non-CNS target like SRC. Ligand B (53.76) is excellent, well below the 90 threshold.

**logP:** Ligand A (-0.279) is a bit low, potentially hindering permeability. Ligand B (3.332) is near the upper end of the optimal 1-3 range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are both reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.598 and 0.786), indicating good drug-like properties.

**DILI:** Ligand A (34.82) has a slightly higher DILI risk than Ligand B (23.226), but both are below the concerning threshold of 60.

**BBB:** This is less critical for SRC, but Ligand B (93.098) shows better potential for CNS penetration if needed. Ligand A (47.809) is lower.

**Caco-2 Permeability:** Ligand A (-5.159) has poor Caco-2 permeability, a significant drawback. Ligand B (-4.125) is also low, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-0.532) has poor aqueous solubility. Ligand B (-2.497) also has poor solubility, but is still better than Ligand A.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.123 and 0.553), which is excellent.

**Microsomal Clearance:** Ligand A (-12.025) exhibits significantly lower microsomal clearance, suggesting better metabolic stability. Ligand B (44.146) has high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (1.587 hours) has a short half-life, while Ligand B (22.587 hours) has a much longer half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.007 and 0.132).

**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:**

Despite similar binding affinities, Ligand A has a major drawback: very poor Caco-2 permeability and solubility, and a short half-life. While it has better metabolic stability, the absorption issues are likely to severely limit its bioavailability. Ligand B, while having a higher clearance and lower solubility, has better permeability and a significantly longer half-life. For an enzyme target like SRC kinase, metabolic stability and half-life are crucial, and Ligand B has a clear advantage in these areas.

Output:
1
2025-04-17 14:33:31,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.483 Da and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.64) is slightly higher than Ligand B (67.6), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.113) is within the optimal 1-3 range, while Ligand B (2.478) is also acceptable.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 8 HBAs, and Ligand B has 6. Both are below the limit of <=10.

**QED:** Both ligands have good QED scores (0.708 and 0.817, respectively), indicating good drug-like properties.

**DILI:** Ligand A (42.846) has a lower DILI risk than Ligand B (52.423), both are acceptable but A is preferred.

**BBB:** Ligand A (79.411) has better BBB penetration than Ligand B (49.942). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.91) has a slightly better Caco-2 permeability than Ligand B (-5.096), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.851) has better aqueous solubility than Ligand B (-4.151). Solubility is important for bioavailability.

**hERG:** Ligand A (0.871) has a lower hERG risk than Ligand B (0.42), which is a significant advantage.

**Microsomal Clearance:** Ligand A (45.932) has lower microsomal clearance than Ligand B (61.544), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (23.473) has a longer half-life than Ligand B (9.163), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.014) has lower P-gp efflux than Ligand B (0.192), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-7.5) has a stronger binding affinity than Ligand A (-6.8). This is a 1.7 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.5 kcal/mol vs -6.8 kcal/mol). While Ligand A has better ADME properties across the board (solubility, metabolic stability, hERG, P-gp efflux, DILI), the potency advantage of Ligand B is substantial enough to make it the more promising candidate. The difference in binding affinity is greater than 1.5 kcal/mol, and the ADME properties of Ligand B are still within acceptable ranges.

Output:
1
2025-04-17 14:33:31,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.507 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.09) is significantly better than Ligand B (107.11). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have similar logP values (1.185 and 1.253), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (4). Lower HBDs generally improve permeability.

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

**QED:** Ligand A (0.676) is significantly better than Ligand B (0.339). A QED above 0.5 is desirable, and A meets this criterion, while B does not.

**DILI:** Ligand B (50.136) has a higher DILI risk than Ligand A (4.924). A lower DILI percentile is preferred, making A more favorable.

**BBB:** Ligand A (57.193) has a better BBB penetration potential than Ligand B (22.412), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.61) is better than Ligand B (-5.244), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.767) is better than Ligand B (-2.98), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.458) is better than Ligand B (0.247). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (38.316) has higher microsomal clearance than Ligand B (-8.229). Lower clearance is preferred for better metabolic stability, making Ligand B more favorable.

**In vitro Half-Life:** Ligand B (-9.525) has a longer in vitro half-life than Ligand A (15.338). Longer half-life is preferred.

**P-gp Efflux:** Ligand A (0.028) is better than Ligand B (0.084), indicating lower P-gp efflux.

**Binding Affinity:** Both ligands have strong binding affinities (-7.0 and -7.5 kcal/mol). Ligand B has a slightly better affinity, but the difference is not substantial enough to outweigh its other drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in most crucial ADME properties (TPSA, QED, DILI, Solubility, hERG, P-gp efflux) and has comparable potency. While Ligand B has better metabolic stability and half-life, the significantly better overall drug-like properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 14:33:31,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.423 and 355.312 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.09) is slightly higher than Ligand B (68.65). Both are under the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (1.773 and 2.875), 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.

**QED:** Both ligands have good QED scores (0.702 and 0.774), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (54.401 and 53.47), both being acceptable (<60).

**BBB:** Ligand B (64.482) shows better BBB penetration than Ligand A (17.914), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.082) has poor Caco-2 permeability, while Ligand B (-4.575) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands show poor aqueous solubility (-3.017 and -4.26), which is a concern.

**hERG:** Both ligands have low hERG inhibition liability (0.551 and 0.513), which is good.

**Microsomal Clearance:** Ligand A (32.228) has lower microsomal clearance than Ligand B (45.867), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-40.278) has a significantly longer in vitro half-life than Ligand B (-7.109), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.138 and 0.288).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.6 kcal/mol). Ligand A is slightly more potent.

**Conclusion:**

While Ligand A has a slightly better binding affinity and significantly better metabolic stability and half-life, its poor Caco-2 permeability is a major drawback. Ligand B has better TPSA and a slightly better Caco-2 permeability, but its metabolic stability and half-life are significantly worse. Given the importance of metabolic stability for kinase inhibitors, and the fact that the affinity difference is relatively small (0.9 kcal/mol), Ligand A is the more promising candidate, *provided* the poor permeability can be addressed through formulation or structural modification.

Output:
0
2025-04-17 14:33:31,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (378.529 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (95.41). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.41) is optimal, while Ligand B (1.927) is on the lower side. While not a deal-breaker, lower logP can sometimes indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.704) has a better QED score than Ligand B (0.581), indicating a more drug-like profile.

**DILI:** Ligand A (31.136) has a much lower DILI risk than Ligand B (56.96). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (72.858) is better than Ligand B (51.57).

**Caco-2 Permeability:** Ligand A (-4.813) is better than Ligand B (-4.953). Both are negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.876) is better than Ligand B (-3.247). Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.688) has a lower hERG risk than Ligand B (0.228), which is a major advantage.

**Microsomal Clearance:** Ligand A (63.779) has higher clearance than Ligand B (33.185), indicating lower metabolic stability. This is a negative for A.

**In vitro Half-Life:** Ligand B (-28.084) has a significantly longer half-life than Ligand A (8.078). This is a substantial advantage for B.

**P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux than Ligand B (0.131).

**Binding Affinity:** Ligand A (-6.9 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol). The difference is substantial (6.9 kcal/mol), and this is a key factor.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower DILI risk, better QED, better hERG profile, and better TPSA. These are all crucial factors for a kinase inhibitor. While Ligand A has higher microsomal clearance and lower half-life, the superior binding affinity and safety profile likely outweigh these drawbacks. Ligand B has a better half-life, but its significantly worse DILI risk, hERG liability, and lower binding affinity make it a less attractive candidate.

Output:
1
2025-04-17 14:33:31,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.382 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.68) is slightly higher than the ideal <140, but acceptable. Ligand B (67.23) is excellent, well below 140.

**logP:** Ligand A (0.574) is a bit low, potentially hindering permeability. Ligand B (2.152) 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 (A: 4, B: 4) are well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.666, B: 0.771), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (A: 30.244, B: 36.681), both below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.231) has a higher BBB score than Ligand A (59.364).

**Caco-2 Permeability:** Ligand A (-5.235) has poor Caco-2 permeability. Ligand B (-4.906) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.708, B: -2.918).

**hERG Inhibition:** Ligand A (0.102) shows very low hERG inhibition risk, which is excellent. Ligand B (0.408) is also low, but higher than A.

**Microsomal Clearance:** Ligand A (-17.009) has significantly *lower* (better) microsomal clearance than Ligand B (43.887), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (16.784) has a longer half-life than Ligand B (7.815).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.003, B: 0.208).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial.

**Conclusion:**

While Ligand B has better logP and TPSA, Ligand A is superior due to its significantly stronger binding affinity (-8.1 vs -7.6 kcal/mol), much better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. The lower logP and Caco-2 permeability of Ligand A are drawbacks, but the strong binding affinity and improved safety/PK profile outweigh these concerns for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:33:31,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.375 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.84) is better than Ligand B (100.35), both are acceptable but closer to the upper limit for good oral absorption.

**logP:** Ligand A (1.986) is optimal, while Ligand B (0.497) is a bit low, potentially hindering permeation.

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

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Ligand A (0.916) has a significantly better QED score than Ligand B (0.746), indicating a more drug-like profile.

**DILI:** Ligand B (36.758) has a much lower DILI risk than Ligand A (80.962), a significant advantage.

**BBB:** Ligand A (74.719) has a better BBB penetration score than Ligand B (35.285), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.638) is better than Ligand B (-5.484), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.727) is better than Ligand B (-1.143), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.323) has a slightly better hERG profile than Ligand B (0.073), but both are low risk.

**Microsomal Clearance:** Ligand B (-4.72) has significantly lower microsomal clearance than Ligand A (23.806), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (5.761) has a better in vitro half-life than Ligand A (18.058), reinforcing its better metabolic stability.

**P-gp Efflux:** Ligand A (0.055) has a slightly better P-gp efflux profile than Ligand B (0.004), but both are low risk.

**Binding Affinity:** Both ligands have very similar 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.

**Conclusion:**

While Ligand A has a slightly better QED, solubility, and Caco-2 permeability, Ligand B demonstrates a significantly better safety profile (lower DILI), and crucially, much better metabolic stability (lower Cl_mic and longer t1/2). Given that we are targeting an enzyme (SRC kinase), metabolic stability is a high priority. The similar binding affinities make the ADME/Tox advantages of Ligand B decisive.

Output:
1
2025-04-17 14:33:31,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.362 and 350.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.33) is better than Ligand B (67.67), both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.153) is optimal, while Ligand B (0.317) is a bit low, potentially hindering permeation.

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

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

**QED:** Ligand A (0.916) is excellent, indicating strong drug-likeness. Ligand B (0.734) is still good, but lower.

**DILI:** Ligand A (63.435) has a higher DILI risk than Ligand B (32.028). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 82.745, Ligand B: 84.684), but this is less critical for a non-CNS target like SRC.

**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:** Both ligands have very low hERG inhibition risk (Ligand A: 0.237, Ligand B: 0.263).

**Microsomal Clearance:** Ligand A (21.428) has a slightly higher microsomal clearance than Ligand B (18.993), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-28.795) has a significantly longer in vitro half-life than Ligand A (-19.811), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.062, Ligand B: 0.03).

**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 has a superior binding affinity, which is the most critical factor for an enzyme inhibitor. However, it has a significantly higher DILI risk and slightly lower metabolic stability. Ligand B has a better safety profile (lower DILI) and better metabolic stability (longer half-life) but weaker binding affinity. The difference in binding affinity (1.4 kcal/mol) is large enough to potentially overcome the DILI risk of Ligand A, especially if further optimization can mitigate the DILI signal. The poor Caco-2 and solubility values are concerning for both, and would need to be addressed.

Output:
1
2025-04-17 14:33:31,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.443 and 350.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.19) is better than Ligand B (67.43), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have similar logP values (2.786 and 2.805), falling within the optimal range of 1-3.

**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 threshold of 10.

**QED:** Ligand A (0.904) has a significantly better QED score than Ligand B (0.628), indicating a more drug-like profile.

**DILI:** Ligand A (39.899) has a much lower DILI risk than Ligand B (15.859), both are good (<40 is preferred).

**BBB:** Both ligands have good BBB penetration (79.333 and 70.686), but Ligand A is better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.977) is slightly worse than Ligand B (-4.61).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.982) is slightly worse than Ligand B (-3.89).

**hERG:** Ligand A (0.681) has a lower hERG risk than Ligand B (0.272), which is preferable.

**Microsomal Clearance:** Ligand A (4.164 mL/min/kg) has significantly lower microsomal clearance than Ligand B (85.725 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (43.772 hours) has a much longer half-life than Ligand B (-11.019 hours).

**P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.159), which is preferable.

**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 noteworthy.

**Conclusion:**

Ligand A is the superior candidate. It has a better QED score, significantly lower DILI risk, lower microsomal clearance (better metabolic stability), longer half-life, and slightly better binding affinity. While both ligands have issues with Caco-2 permeability and solubility, Ligand A's other advantages outweigh these drawbacks. The improved metabolic stability and longer half-life are particularly important for an enzyme inhibitor.

Output:
1
2025-04-17 14:33:31,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.555 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (62.55), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.18 and 3.081), 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, 3 HBA) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand B (0.835) has a higher QED score than Ligand A (0.537), indicating a more drug-like profile overall.

**DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (37.456), which is a crucial advantage.

**BBB:** Both ligands have reasonable BBB penetration (80.38 and 75.843), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.052) has a worse Caco-2 permeability than Ligand B (-4.891), but both are negative values, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-3.827) has slightly worse solubility than Ligand B (-3.434), but both are negative values, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.735) shows a lower hERG inhibition risk compared to Ligand B (0.304), which is a significant advantage.

**Microsomal Clearance:** Ligand A (83.052) has a higher microsomal clearance than Ligand B (39.283), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (14.548 hours) has a significantly longer in vitro half-life than Ligand A (-7.627 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.504) has a lower P-gp efflux liability than Ligand B (0.155), which is favorable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.4 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, hERG inhibition, and P-gp efflux. However, it suffers from significantly higher microsomal clearance, a shorter half-life, and lower Caco-2 permeability. Ligand B has a better QED score, longer half-life, and slightly better binding affinity. The metabolic stability and half-life are critical for kinase inhibitors, and Ligand B is significantly better in these aspects. While Ligand A has a better safety profile (DILI, hERG), the metabolic liabilities are too significant to ignore.

Output:
1
2025-04-17 14:33:31,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which could aid permeability, while Ligand B (353.463 Da) is also good.

**TPSA:** Ligand A (54.46) is significantly better than Ligand B (89.95). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (2.761) is optimal, while Ligand B (0.369) is quite low. A logP below 1 can hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2 respectively) and HBA (4 each) counts.

**QED:** Both ligands have reasonable QED scores (0.879 and 0.747), indicating good drug-like properties.

**DILI:** Both have low DILI risk (14.928 and 13.843), which is favorable.

**BBB:** Ligand A (77.705) has a better BBB percentile than Ligand B (53.781), but this isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**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.

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified, so it is hard to interpret.

**hERG:** Ligand A (0.774) has a lower hERG risk than Ligand B (0.101), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-5.845) has a *negative* microsomal clearance, which is impossible. This is likely an error in the data, and we must assume it has very high metabolic stability. Ligand A (32.652) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-11.178) has a negative half-life, which is impossible. This is likely an error in the data. Ligand A (0.698) has a very short half-life.

**P-gp Efflux:** Ligand A (0.13) has lower P-gp efflux than Ligand B (0.006), which is favorable.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the questionable Caco-2, solubility, half-life, and clearance data, Ligand A is the superior candidate. Its significantly better binding affinity (-9.2 vs -7.3 kcal/mol) is the most important factor for an enzyme inhibitor. Additionally, it has a better logP, TPSA, hERG risk, and P-gp efflux. The negative values for clearance and half-life for Ligand B are concerning and suggest data errors.

Output:
1
2025-04-17 14:33:31,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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 (356.491 Da) is also good.

**TPSA:** Ligand A (67.16) is higher than Ligand B (42.43). Both are below 140, indicating good oral absorption potential. Ligand B is significantly lower, which is favorable.

**logP:** Ligand A (4.657) is slightly higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (3.592) is within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable (<=10).

**QED:** Both ligands have good QED scores (A: 0.688, B: 0.731), indicating drug-like properties.

**DILI:** Ligand A (78.286) has a higher DILI risk than Ligand B (31.834). Ligand B is well below the 40% threshold, indicating low liver injury risk.

**BBB:** Both ligands have similar BBB penetration (A: 75.611, B: 77.007). This isn't a primary concern for a kinase inhibitor, but higher is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and indicates poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility.

**hERG:** Ligand A (0.811) has a slightly higher hERG risk than Ligand B (0.485). Lower is better here.

**Microsomal Clearance:** Ligand A (92.445) has a lower (better) microsomal clearance than Ligand B (117.506), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (28.466) has a better in vitro half-life than Ligand B (-40.312).

**P-gp Efflux:** Ligand A (0.657) has a lower P-gp efflux liability than Ligand B (0.276), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.9). This is a crucial advantage for an enzyme inhibitor, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, better metabolic stability (lower Cl_mic), and a better half-life. However, it has a higher DILI risk, slightly higher hERG risk, and a higher logP. Ligand B has better solubility and DILI, but significantly weaker binding affinity.

Given the priority for potency in enzyme inhibitors, the substantial difference in binding affinity (-8.0 vs -6.9 kcal/mol) is the most important factor. While Ligand A's ADME properties are not ideal, the strong binding could be optimized through further medicinal chemistry efforts. The poor solubility and permeability of both compounds are concerning and would need to be addressed.

Output:
1
2025-04-17 14:33:31,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.381 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is significantly better than Ligand B (110.01). A TPSA under 90 is preferred, and A is comfortably within that range, suggesting better permeability. B is above the ideal range for oral absorption.

**logP:** Both ligands have good logP values (1.754 and 1.581), 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=6). Lower counts are generally preferred for permeability, and A is closer to the ideal.

**QED:** Both ligands have similar and acceptable QED values (0.846 and 0.822), indicating good drug-likeness.

**DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (65.995). A value under 40 is good, and A is well within that, while B is considered high risk.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (78.829) is better than Ligand B (49.67), but neither is a major concern.

**Caco-2 Permeability:** Ligand A (-4.263) is better than Ligand B (-5.18), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.319 and -2.335). This is a potential issue for both, but needs to be balanced against other factors.

**hERG Inhibition:** Ligand A (0.407) has a significantly lower hERG risk than Ligand B (0.169). Lower is better, and A is much safer in this regard.

**Microsomal Clearance:** Ligand A (-5.546) has a much lower (better) microsomal clearance than Ligand B (42.55). This indicates greater metabolic stability for Ligand A, a key consideration for kinases.

**In vitro Half-Life:** Ligand A (-12.838) has a longer in vitro half-life than Ligand B (-11.821), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.059 and 0.023).

**Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-7.4). However, the difference is 1.7 kcal/mol, which is a significant advantage, but 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 critical ADME properties: lower DILI risk, lower hERG risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), better TPSA, and better Caco-2 permeability. These factors are particularly important for kinase inhibitors, where maintaining therapeutic concentrations and avoiding toxicity are crucial. The solubility is a concern for both, but the superior ADME profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 14:33:31,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.501 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.6) is better than Ligand B (84.42), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (3.376) is optimal, while Ligand B (1.606) is on the lower side, potentially impacting 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, while Ligand B has 5. Both are below the 10 limit.

**QED:** Ligand A (0.812) has a significantly better QED score than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand A (41.062) has a slightly higher DILI risk than Ligand B (25.436), but both are well below the concerning threshold of 60.

**BBB:** Ligand A (87.088) has a much higher BBB penetration percentile than Ligand B (59.054). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.44) and Ligand B (-4.896) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.641) is better than Ligand B (-0.571), both are poor, but Ligand A is less poor.

**hERG Inhibition:** Ligand A (0.384) has a much lower hERG inhibition risk than Ligand B (0.192), which is a significant advantage.

**Microsomal Clearance:** Ligand B (39.678) has a slightly lower microsomal clearance than Ligand A (30.725), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (18.961) has a significantly longer in vitro half-life than Ligand A (-1.527), which is a major advantage.

**P-gp Efflux:** Ligand A (0.048) has a slightly lower P-gp efflux liability than Ligand B (0.016), which is a slight advantage.

**Binding Affinity:** Ligand A (-7.7) has a significantly stronger binding affinity than Ligand B (0.0), a crucial factor for kinase inhibitors. The difference of 7.7 kcal/mol is substantial.

**Overall Assessment:**

Ligand A excels in binding affinity, QED, hERG risk, and BBB penetration. Ligand B has a better half-life and slightly better metabolic stability, but its lower affinity, poorer solubility, and higher hERG risk are significant drawbacks. The substantial difference in binding affinity (-7.7 vs 0.0 kcal/mol) outweighs the advantages of Ligand B. The improved solubility of Ligand A is also a plus.

Output:
1
2025-04-17 14:33:31,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.308 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is significantly better than Ligand B (59.08), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.891 and 1.842), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.629 and 0.685), indicating drug-likeness.

**DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (24.855). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (86.39 and 71.035), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.24 and -4.205). 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:** Ligand A (-4.566) has worse solubility than Ligand B (-2.039). Solubility is important for bioavailability, making Ligand B preferable.

**hERG:** Both ligands have low hERG risk (0.492 and 0.322).

**Microsomal Clearance:** Ligand A (90.416) has significantly higher microsomal clearance than Ligand B (60.236), indicating lower metabolic stability. This is a major disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (6.883) has a longer half-life than Ligand A (22.885). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.646 and 0.07).

**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 not huge, it is enough to be considered.

**Overall:**

Ligand B is the better candidate. It has a significantly lower DILI risk, better solubility, longer half-life, and slightly better binding affinity. Ligand A has a higher DILI risk and higher microsomal clearance, which are major concerns for an enzyme inhibitor. While Ligand A has a slightly better TPSA, the other ADME/Tox properties of Ligand B are superior.

Output:
1
2025-04-17 14:33:31,172 - INFO - Batch 306 complete. Total preferences: 4896
2025-04-17 14:33:31,172 - INFO - Processing batch 307/512...
2025-04-17 14:34:18,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (363.447 Da) is also good.

**TPSA:** Ligand A (59.75) is excellent, well below the 140 threshold for oral absorption. Ligand B (116.76) is still acceptable but higher, potentially impacting absorption.

**logP:** Ligand A (3.16) is optimal. Ligand B (0.581) is quite low, raising concerns about permeability and potentially requiring formulation strategies to enhance absorption.

**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 reasonable QED scores (A: 0.843, B: 0.691), indicating good drug-like properties.

**DILI:** Both have similar DILI risk (A: 60.682, B: 67.158), placing them in the moderate risk range. Further investigation would be needed, but it's not a decisive factor here.

**BBB:** Ligand A (78.364) has a better BBB percentile than Ligand B (25.126), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.207) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.992) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.73) and Ligand B (-1.604) both have negative solubility values, indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.551) has a very low hERG risk, which is excellent. Ligand B (0.046) also has very low hERG risk, which is also excellent.

**Microsomal Clearance:** Ligand A (82.191) has a higher microsomal clearance, suggesting faster metabolism and lower metabolic stability. Ligand B (25.764) has a significantly lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.536 hours) has a reasonable half-life. Ligand B (-4.642 hours) has a *negative* half-life, which is impossible. This is a major red flag and suggests a significant issue with the data or the molecule's stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.659, B: 0.02), which is favorable.

**Binding Affinity:** Both ligands have very strong binding affinity (A: -9.4 kcal/mol, B: -9.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite the similar binding affinities, Ligand A is significantly hampered by its poor Caco-2 permeability and higher microsomal clearance. The negative half-life for Ligand B is a critical issue, making it an unusable candidate. While both have solubility concerns, Ligand A's permeability issues are more problematic for an enzyme inhibitor. Therefore, considering all factors, Ligand A is marginally better, but both require significant optimization.

Output:
0
2025-04-17 14:34:18,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Ligand A (2.132) and Ligand B (3.64) are both within the optimal 1-3 range, but Ligand B is approaching the upper limit, potentially raising concerns about off-target effects.

**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 A (0.758) has a slightly better QED score than Ligand B (0.66), indicating a more drug-like profile.

**DILI:** Ligand B (16.053) has a significantly lower DILI risk than Ligand A (33.501), a major advantage.

**BBB:** Ligand A (71.501) and Ligand B (92.982) are both relatively high, but Ligand B is considerably better. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.276 and -4.536). This is unusual and suggests poor permeability. However, these values are on a log scale and the negative values could be due to experimental error or a specific assay characteristic. We'll need to consider this with caution.

**Aqueous Solubility:** Ligand A (-1.56) has slightly better solubility than Ligand B (-3.19), which is a positive.

**hERG Inhibition:** Both ligands have low hERG risk (0.304 and 0.389).

**Microsomal Clearance:** Ligand A (54.718) has lower microsomal clearance than Ligand B (71.405), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.623 hours) has a significantly longer half-life than Ligand B (-20.052 hours). The negative value for Ligand B is concerning and likely indicates very rapid metabolism or an experimental issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.334).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.9 kcal/mol), with Ligand B being slightly better. This difference is small and likely less important than the ADME differences.

**Overall Assessment:**

Ligand B has a significantly lower DILI risk, better BBB penetration, and slightly better binding affinity. However, it has a much worse in vitro half-life (negative value is a red flag) and slightly lower solubility. Ligand A has better metabolic stability and a longer half-life, better solubility, and a higher QED score. The negative Caco-2 values for both are concerning.

Given the enzyme-specific priorities, metabolic stability and solubility are crucial. The negative half-life for Ligand B is a significant drawback. While the affinity is slightly better, the DILI risk and half-life issues make Ligand B less attractive.

Output:
0
2025-04-17 14:34:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (393.531 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.85) is slightly above the preferred <140 for good absorption, while Ligand B (88.18) is well within the range.

**logP:** Both ligands (-0.584 and -0.456) are a bit low, potentially hindering permeation. However, this is less critical than other factors for an enzyme target.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.621 and 0.698), indicating drug-like properties.

**DILI:** Ligand A (31.718) has a slightly higher DILI risk than Ligand B (28.887), but both are below the concerning threshold of 60.

**BBB:** Both have low BBB penetration (58.511 and 52.346), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.501 and -4.995), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.894 and -0.601), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.125 and 0.05). This is excellent.

**Microsomal Clearance:** Ligand A (-1.033) has significantly *lower* (better) microsomal clearance than Ligand B (1.912). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-17.072) has a much longer in vitro half-life than Ligand B (2.329), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.02 and 0.008).

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

**Conclusion:**

While both ligands have significant solubility and permeability issues, Ligand B's substantially superior binding affinity (-8.5 vs -7.3 kcal/mol) is the deciding factor. The potency advantage is large enough to potentially overcome the solubility/permeability challenges through formulation strategies. Ligand A has better metabolic stability, but the difference in affinity is more critical for an enzyme target.

Output:
1
2025-04-17 14:34:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.511 and 354.801 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.64) is better than Ligand B (70.65), both are under the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.894 and 3.186), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (0 HBD, 7 HBA). Lower HBA is generally better for permeability.

**QED:** Ligand A (0.9) has a significantly better QED score than Ligand B (0.565), indicating a more drug-like profile.

**DILI:** Ligand A (30.128) has a much lower DILI risk than Ligand B (92.865). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (84.025) is better than Ligand B (54.827).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.951) is slightly better than Ligand B (-4.773).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.661) is slightly better than Ligand B (-3.853).

**hERG Inhibition:** Ligand A (0.731) has a lower hERG risk than Ligand B (0.33), which is preferable.

**Microsomal Clearance:** Ligand A (34.702) has lower microsomal clearance than Ligand B (48.127), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.284) has a longer in vitro half-life than Ligand B (-14.613), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.166) has lower P-gp efflux liability than Ligand B (0.601), indicating better bioavailability.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.3 and -8.6 kcal/mol). The difference is minimal.

**Conclusion:**

Ligand A is significantly better overall. It has a much lower DILI risk, better QED, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk. While both have poor Caco-2 and solubility, Ligand A is slightly better in these aspects. The binding affinity is comparable. Given the enzyme-specific priorities, the improved ADME properties of Ligand A outweigh any minor differences.

Output:
0
2025-04-17 14:34:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.805 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.4) is higher than Ligand B (60.85). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Both ligands have good logP values (2.668 and 2.567), 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 3. Both are acceptable, being under the 10 HBA threshold.

**QED:** Ligand B (0.801) has a significantly higher QED score than Ligand A (0.376), indicating a more drug-like profile.

**DILI:** Ligand A's DILI risk (59.131) is higher than Ligand B's (21.714). Ligand B is well below the 40 threshold, while Ligand A is approaching the concerning 60 level.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.898) has a higher BBB percentile than Ligand B (63.746), but this is not a major factor in this case.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.759 and -4.692). This is unusual and suggests poor permeability, but the scale isn't clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-3.299 and -2.474), again unusual and suggesting poor solubility.

**hERG:** Ligand A (0.353) has a slightly lower hERG risk than Ligand B (0.552), which is preferable.

**Microsomal Clearance:** Ligand B (52.564) has a significantly higher microsomal clearance than Ligand A (1.792). This means Ligand A is much more metabolically stable, a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (7.068) has a longer half-life than Ligand B (3.099), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.1) has much lower P-gp efflux than Ligand B (0.539), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A's better metabolic stability (lower Cl_mic, longer t1/2, lower Pgp efflux) and slightly lower hERG risk, Ligand B's substantially stronger binding affinity (-9.2 vs -8.3 kcal/mol) and superior QED and DILI scores make it the more promising candidate. The improved TPSA is also beneficial. While the negative Caco-2 and solubility values are concerning for both, the potency advantage of Ligand B is likely to be more impactful in driving forward development, and these properties could be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 14:34:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.389 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (96.53 and 95.33) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Both ligands have logP values (1.033 and 1.715) 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:** Ligand B (0.91) has a significantly better QED score than Ligand A (0.4), suggesting a more drug-like profile.

**DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (63.746), indicating better predicted liver safety.

**BBB:** Ligand A (80.458) has a higher BBB percentile than Ligand B (43.001), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.524) has a worse Caco-2 permeability than Ligand B (-4.987), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.367) has a worse aqueous solubility than Ligand B (-1.725), which could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.246 and 0.432).

**Microsomal Clearance:** Ligand A (-8.408) has significantly lower microsomal clearance than Ligand B (27.326), indicating much better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (1.279 hours) has a shorter half-life than Ligand B (-49.582 hours). This is a significant drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.088).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has a better QED, solubility and Caco-2 permeability, Ligand A is superior due to its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and comparable binding affinity.  For an enzyme target like SRC kinase, metabolic stability and safety are paramount. The better ADME properties of Ligand A outweigh the slight advantages of Ligand B in other areas.

Output:
0
2025-04-17 14:34:18,351 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [410.268, 99.5, 2.717, 1, 5, 0.551, 71.384, 62.97, -4.442, -4.396, 0.572, 109.574, 37.431, 0.13, -7.4]
**Ligand B:** [346.471, 67.43, 1.864, 2, 3, 0.546, 12.485, 53.703, -4.905, -2.733, 0.336, 10.277, 22.101, 0.061, -7.3]

**Step-by-step comparison:**

1. **MW:** A (410.268) is within the ideal range (200-500). B (346.471) is also good. No clear advantage.
2. **TPSA:** A (99.5) is acceptable, below 140. B (67.43) is also good, and slightly better.
3. **logP:** A (2.717) is optimal (1-3). B (1.864) is also within range, but slightly lower.
4. **HBD:** A (1) is good (<=5). B (2) is also good.
5. **HBA:** A (5) is good (<=10). B (3) is also good.
6. **QED:** Both A (0.551) and B (0.546) are above 0.5, indicating good drug-likeness.
7. **DILI:** A (71.384) is moderately high risk. B (12.485) is very low risk. This is a significant advantage for B.
8. **BBB:** A (62.97) is moderate. B (53.703) is also moderate. Not a major factor for a kinase inhibitor.
9. **Caco-2:** Both A (-4.442) and B (-4.905) are negative values, indicating poor permeability. This is a concern for both.
10. **Solubility:** Both A (-4.396) and B (-2.733) are negative values, indicating poor solubility. B is better here.
11. **hERG:** A (0.572) is better than B (0.336), indicating lower cardiotoxicity risk.
12. **Cl_mic:** A (109.574) is high, indicating faster metabolism. B (10.277) is much lower, indicating better metabolic stability. This is a major advantage for B.
13. **t1/2:** A (37.431) is moderate. B (22.101) is also moderate, but lower.
14. **Pgp:** A (0.13) is low, suggesting less efflux. B (0.061) is even lower, suggesting even less efflux.
15. **Affinity:** A (-7.4) is slightly better than B (-7.3), but the difference is small (0.1 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For enzyme inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

*   **Affinity:** A has a slightly better affinity, but the difference is minimal.
*   **Metabolic Stability:** B has *significantly* better metabolic stability (lower Cl_mic).
*   **Solubility:** B has better solubility.
*   **hERG:** A has a better hERG profile.
*   **DILI:** B has a much lower DILI risk.

**Conclusion:**

While Ligand A has a slightly better binding affinity and hERG profile, the significantly lower DILI risk and much improved metabolic stability (lower Cl_mic) of Ligand B outweigh these minor advantages. The poor Caco-2 and solubility for both compounds are concerning, but can be addressed with formulation strategies. Given the priorities for enzyme inhibitors, **Ligand B** is the more promising drug candidate.

Output:
1
2025-04-17 14:34:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (429.746 Da) is higher than Ligand B (344.499 Da), but both are acceptable.

**2. TPSA:** Ligand A (70.39) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is preferable as lower TPSA generally correlates with better cell permeability.

**3. logP:** Both ligands have similar logP values around 3 (A: 3.066, B: 2.986), 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 (4) is higher than Ligand B (2), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.677, B: 0.753), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand B (27.065) has a significantly lower DILI risk than Ligand A (50.33). This is a major advantage for Ligand B.

**8. BBB:** Both have moderate BBB penetration, but Ligand B (73.788) is better than Ligand A (55.642). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.911 and -4.929). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.558 and -4.454), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Ligand A (0.634) has a slightly higher hERG risk than Ligand B (0.219). Lower hERG risk is preferred.

**12. Microsomal Clearance:** Ligand B (57.313) has lower microsomal clearance than Ligand A (68.648), suggesting better metabolic stability. This is crucial for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-0.318) has a negative half-life, which is concerning and suggests rapid degradation. Ligand A (100.92) has a very long half-life. This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux than Ligand B (0.228), which is better for bioavailability.

**15. 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 of the ADME drawbacks.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and has better metabolic stability (lower Cl_mic) and lower hERG risk. Ligand A has a much better half-life, but the significantly stronger binding of Ligand B is a major factor. The poor solubility and permeability of both are concerns, but not insurmountable. The lower DILI risk of Ligand B is also a significant advantage.

Output:
1
2025-04-17 14:34:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.539 Da and 392.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is much better than Ligand B (123.85). TPSA < 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (2.673) is optimal (1-3), while Ligand B (-0.232) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=8) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED scores (0.836 and 0.595), indicating good drug-like properties.

**DILI:** Ligand B (79.139) has a significantly higher DILI risk than Ligand A (17.216). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.843) has a better BBB score than Ligand B (61.691).

**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 and suggests poor solubility. Again, the scale is undefined.

**hERG:** Both ligands have similar hERG risk (0.458 and 0.547), which is acceptable.

**Microsomal Clearance:** Ligand A (67.236) has higher clearance than Ligand B (22.799), meaning Ligand B is more metabolically stable. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (-7.093) has a much longer half-life than Ligand A (3.977). This is a major advantage for B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.083 and 0.03).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has better TPSA and logP, suggesting better absorption. However, Ligand B has significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and comparable binding affinity. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. While the solubility and permeability data are concerning for both, the lower DILI and improved metabolic profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 14:34:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.271 Da) is slightly higher than Ligand B (352.391 Da), but both are acceptable.

**TPSA:** Ligand A (55.4) is well below the 140 threshold for oral absorption, and good. Ligand B (115.45) is still below the threshold but higher, potentially indicating slightly reduced absorption compared to A.

**logP:** Ligand A (4.836) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.673) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, well within acceptable limits. Ligand B has 2 HBD and 6 HBA, also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (0.7 and 0.55), indicating reasonable drug-likeness.

**DILI:** Ligand A (69.523) has a higher DILI risk than Ligand B (33.695). This is a significant concern for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (72.896) has a better BBB score than Ligand B (20.783).

**Caco-2 Permeability:** Ligand A (-4.449) has better Caco-2 permeability than Ligand B (-5.127).

**Aqueous Solubility:** Ligand A (-5.865) has better aqueous solubility than Ligand B (-0.691). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.498) has a lower hERG risk than Ligand B (0.213), which is favorable.

**Microsomal Clearance:** Ligand A (72.282) has a higher, and thus worse, microsomal clearance than Ligand B (-18.931). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (116.165) has a longer half-life than Ligand B (3.521), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.611) has lower P-gp efflux than Ligand B (0.029), which is preferable.

**Binding Affinity:** Ligand A (-8.8 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 concerns.

**Conclusion:**

Despite Ligand A's higher DILI risk and logP, its significantly superior binding affinity (-8.8 vs -7.9 kcal/mol), better solubility, permeability, half-life, and lower P-gp efflux make it the more promising candidate. The improved potency is a critical factor for an enzyme inhibitor, and the other advantages help mitigate the risks. Ligand B's better metabolic stability is a plus, but the weaker binding is a major drawback.

Output:
1
2025-04-17 14:34:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.35 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.42) is higher than the preferred <140, but still reasonable. Ligand B (49.41) is excellent, well below 140.

**logP:** Ligand A (-0.894) is a bit low, potentially hindering permeability. Ligand B (3.575) is optimal.

**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 reasonable QED scores (0.32 and 0.612), with Ligand B being better.

**DILI:** Ligand A (44.126) has a moderate DILI risk, while Ligand B (31.601) has a lower, more favorable risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.87) is higher than Ligand B (54.75).

**Caco-2:** Ligand A (-5.473) is very poor, indicating poor absorption. Ligand B (-4.89) is also poor, but slightly better.

**Solubility:** Both ligands have very poor solubility (-2.058 and -2.727). This is a significant concern for both.

**hERG:** Both ligands have low hERG risk (0.198 and 0.432).

**Microsomal Clearance:** Ligand A (-1.077) shows good metabolic stability (negative value indicates slower clearance). Ligand B (23.566) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-8.999) has a very long half-life, which is excellent. Ligand B (-6.214) has a shorter, but still reasonable half-life.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is favorable. Ligand B (0.283) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.3) has significantly better binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a major advantage in binding affinity and metabolic stability (longer half-life, lower clearance) and P-gp efflux. However, its low logP and poor Caco-2 permeability are significant drawbacks. Ligand B has better physicochemical properties (logP, TPSA, QED, DILI) but suffers from poor metabolic stability and a much weaker binding affinity.

Given the enzyme-specific priorities, *binding affinity is paramount*. The substantial difference in affinity (-8.3 vs 0.0 kcal/mol) is likely to outweigh the drawbacks of Ligand A, especially if formulation strategies can be employed to address the solubility and permeability issues. The improved metabolic stability will also contribute to a more favorable pharmacokinetic profile.

Output:
1
2025-04-17 14:34:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.479 and 354.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.51) is well below the 140 threshold and favorable for oral absorption. Ligand B (113.76) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.02) is within the optimal 1-3 range. Ligand B (0.498) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.774 and 0.551), indicating good drug-likeness.

**DILI:** Ligand A (48.895) has a lower DILI risk than Ligand B (20.279), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (73.788) has a higher value than Ligand A (59.597).

**Caco-2 Permeability:** Ligand A (-4.758) shows poor permeability, while Ligand B (-5.484) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.864) has better solubility than Ligand B (-1.853).

**hERG:** Both ligands have low hERG inhibition risk (0.284 and 0.329).

**Microsomal Clearance:** Ligand A (50.757) has a more favorable (lower) microsomal clearance than Ligand B (-14.215), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.143) has a longer half-life than Ligand B (2.826), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.062 and 0.006).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability and BBB penetration, Ligand A excels in key areas for an enzyme inhibitor: significantly stronger binding affinity, lower DILI risk, better solubility, and improved metabolic stability (lower Cl_mic and longer half-life). The strong binding affinity of Ligand A is the most important factor, as it can compensate for the slightly lower Caco-2 permeability.

Output:
1
2025-04-17 14:34:18,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.369 and 359.543 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (79.04) is slightly above the preferred <140, but acceptable. Ligand B (44.29) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands (3.307 and 3.545) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, good. Ligand B has 6 HBA, still within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.791 and 0.854), indicating drug-like properties.

**DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (57.58), but both are below the concerning threshold of 60.

**BBB:** Both have high BBB penetration (81.698 and 83.637), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and could indicate issues with the measurement or a problem with the model. However, Ligand B (-5.085) is slightly better than Ligand A (-4.972).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-3.535) is slightly better than Ligand A (-4.547).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.58 and 0.955), which is excellent.

**Microsomal Clearance:** Ligand A (10.2) has significantly lower microsomal clearance than Ligand B (78.369), indicating better metabolic stability. This is a major advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (9.116) has a longer half-life than Ligand B (-5.647), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.18 and 0.515).

**Binding Affinity:** Ligand B (-8.2) 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 affinity difference is not as large as it appears, and the negative sign indicates the binding is favorable for both.

**Conclusion:**

While Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower DILI risk, Ligand B boasts a significantly stronger binding affinity (-8.2 vs -9.0 kcal/mol). For an enzyme target like SRC kinase, binding affinity is paramount. The difference in affinity is substantial enough to favor Ligand B, even considering the slightly higher DILI and lower metabolic stability. The negative solubility and Caco-2 values are concerning for both, but could be addressed with formulation strategies.

Output:
1
2025-04-17 14:34:18,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.419 Da and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.9) is better than Ligand B (117), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (-0.383) is slightly low, potentially hindering permeability. Ligand B (1.21) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, under the 5 limit.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.774 and 0.756), indicating good drug-likeness.

**DILI:** Ligand A (29.159) has a significantly lower DILI risk than Ligand B (65.529). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (46.375 and 48.391), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.911 and -5.545), indicating poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Ligand A (-0.806) is slightly better than Ligand B (-2.643), indicating better solubility.

**hERG Inhibition:** Ligand A (0.22) has a much lower hERG risk than Ligand B (0.575). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-0.418) has a much lower (better) microsomal clearance than Ligand B (-24.182). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-4.471) has a much longer in vitro half-life than Ligand B (-26.19). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux values (0.028 and 0.169).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -8.8 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

While Ligand B has a slightly better logP, Ligand A is significantly superior in terms of safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and solubility. The binding affinities are comparable. Given the enzyme-specific priorities, the improved ADME-Tox profile of Ligand A makes it the more promising drug candidate.

Output:
0
2025-04-17 14:34:18,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.422 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (40.62) as it is still within the acceptable range for oral absorption (<140), while ligand B is significantly lower, potentially indicating better permeability.

**logP:** Ligand B (3.869) is closer to the optimal range (1-3) than Ligand A (0.492), which is quite low and could hinder membrane permeability.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as it provides a better balance of solubility and permeability.

**H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (2) for the same reason as above.

**QED:** Ligand A (0.467) is slightly better than Ligand B (0.342), indicating a marginally more drug-like profile.

**DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (39.977), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (71.772) is slightly better than Ligand A (68.98). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.727) has a lower Caco-2 permeability than Ligand B (-4.257), but both are negative which is not ideal.

**Aqueous Solubility:** Ligand A (-1.573) has better aqueous solubility than Ligand B (-3.605). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.347) shows a lower hERG inhibition liability than Ligand B (0.835), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (-12.853) has a significantly *lower* (better) microsomal clearance than Ligand B (97.456), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (12.625) has a much longer in vitro half-life than Ligand A (3.503), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.617), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.5) has a significantly stronger binding affinity than Ligand A (-9.2). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a much better binding affinity, and a longer half-life. However, it has a higher DILI risk, higher hERG inhibition, and higher microsomal clearance. Ligand A has better solubility, lower DILI and hERG risk, and better metabolic stability. The difference in binding affinity (-7.5 vs -9.2) is significant. Given that we are targeting a kinase (enzyme), potency is paramount. While Ligand A has a better safety profile, the substantial binding affinity advantage of Ligand B is likely to be more important for achieving efficacy.

Output:
1
2025-04-17 14:34:18,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.503 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (86.88). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.711 and 2.308), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (3 HBD, 3 HBA). Lower HBDs are generally preferred.

**QED:** Both ligands have comparable QED scores (0.692 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A (13.959 percentile) has a much lower DILI risk than Ligand B (29.236 percentile). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.96) is better than Ligand B (60.876).

**Caco-2 Permeability:** Ligand A (-4.449) is slightly better than Ligand B (-5.278), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.03) is better than Ligand B (-2.656). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.52) has a lower hERG risk than Ligand B (0.398), which is a critical safety parameter.

**Microsomal Clearance:** Ligand A (70.401) has higher microsomal clearance than Ligand B (38.144). This indicates lower metabolic stability for Ligand A. This is a drawback.

**In vitro Half-Life:** Ligand B (-16.325) has a significantly longer in vitro half-life than Ligand A (3.15). This is a major advantage for Ligand B, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.074).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are excellent, the 0.8 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B has a superior half-life and slightly better binding affinity, which are critical for an enzyme target. While Ligand A has better solubility and a lower DILI risk, the significantly worse half-life and higher clearance are concerning. The difference in binding affinity, while not huge, combined with the metabolic stability advantage, tips the scales in favor of Ligand B.

Output:
1
2025-04-17 14:34:18,352 - INFO - Batch 307 complete. Total preferences: 4912
2025-04-17 14:34:18,352 - INFO - Processing batch 308/512...
2025-04-17 14:34:59,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.4 and 361.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.58) is excellent, well below the 140 threshold. Ligand B (38.77) is also very good.

**logP:** Ligand A (2.318) is optimal (1-3). Ligand B (3.594) is slightly higher but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is good. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Ligand A (0.898) is excellent, indicating high drug-likeness. Ligand B (0.597) is acceptable, but lower.

**DILI:** Ligand A (44.591) has a moderate DILI risk. Ligand B (14.385) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC kinase. Ligand B (98.216) is higher than Ligand A (69.95), but this is less important.

**Caco-2 Permeability:** Ligand A (-5.104) has poor Caco-2 permeability. Ligand B (-3.888) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.584) has poor solubility. Ligand B (-4.103) has even poorer solubility. This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.222) has a very low hERG risk. Ligand B (0.848) has a slightly higher hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (10.953) has lower clearance, indicating better metabolic stability. Ligand B (94.362) has very high clearance, a major drawback.

**In vitro Half-Life:** Ligand A (16.643) has a longer half-life. Ligand B (4.075) has a very short half-life.

**P-gp Efflux:** Ligand A (0.124) has low P-gp efflux. Ligand B (0.518) has slightly higher P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.6 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and significantly lower DILI risk. However, it suffers from very high microsomal clearance and a short half-life, and poor solubility. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI, but has poor Caco-2 permeability and solubility. Given the importance of metabolic stability for kinase inhibitors, and the acceptable DILI risk for Ligand A, I would choose Ligand A. The solubility and permeability issues might be addressable through formulation.

Output:
0
2025-04-17 14:34:59,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 368.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is slightly higher than Ligand B (59.08), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.397 and 1.718), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable, being less than 5.

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

**QED:** Both ligands have good QED scores (0.55 and 0.612), indicating good drug-like properties.

**DILI:** Ligand A (18.651) has a significantly lower DILI risk than Ligand B (37.069). This is a substantial advantage.

**BBB:** Ligand B (81.504) has a higher BBB penetration percentile than Ligand A (57.968). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.736 and -4.631), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.533 and -2.015), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.13) has a much lower hERG inhibition liability than Ligand B (0.432). This is a significant safety advantage.

**Microsomal Clearance:** Ligand B (34.298) has lower microsomal clearance than Ligand A (48.237), suggesting better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (22.706) has a longer in vitro half-life than Ligand A (14.743), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032 and 0.05), which is good.

**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 could outweigh some of the ADME drawbacks.

**Conclusion:**

While both ligands have significant ADME liabilities (poor solubility and permeability), Ligand B's superior binding affinity (-7.6 kcal/mol vs -6.9 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are compelling. The lower DILI and hERG risk of Ligand A are attractive, but the potency difference is more critical for an enzyme target like SRC. Therefore, Ligand B is the more promising candidate, despite its slightly higher DILI risk, as the potency advantage is likely to be more impactful in achieving efficacy. Further optimization would focus on improving solubility and permeability.

Output:
1
2025-04-17 14:34:59,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.363 and 360.797 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.42) is slightly above the preferred <140, while Ligand B (88.52) is well within. This favors B for absorption.

**logP:** Both ligands (2.78 and 2.764) are optimal, falling within the 1-3 range.

**H-Bond Donors:** Ligand A (4) is at the upper limit, while Ligand B (2) is better. Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, below the 10 threshold.

**QED:** Ligand B (0.855) has a significantly higher QED than Ligand A (0.574), indicating a more drug-like profile.

**DILI:** Ligand A (78.054) has a lower DILI risk than Ligand B (97.867), which is a significant advantage.

**BBB:** Ligand B (37.185) has a higher BBB penetration than Ligand A (19.93), but this is less critical for a kinase inhibitor unless CNS activity is desired.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.707) is slightly worse than Ligand B (-5.431).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.179) is slightly worse than Ligand B (-3.718).

**hERG Inhibition:** Ligand A (0.204) has a lower hERG risk than Ligand B (0.015), which is a substantial advantage.

**Microsomal Clearance:** Ligand B (-18.278) has a lower (better) microsomal clearance than Ligand A (11.292), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-10.809) has a longer half-life than Ligand A (-22.709), which is desirable.

**P-gp Efflux:** Both have very low values, suggesting minimal P-gp efflux. Ligand A (0.046) is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinities (-10.4 and -9.6 kcal/mol). Ligand A is slightly more potent, but the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG inhibition, and slightly better binding affinity and P-gp efflux. However, Ligand B excels in QED, metabolic stability (Cl_mic and t1/2), and has a better TPSA. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), Ligand B's superior metabolic stability and drug-likeness outweigh the slight potency advantage of Ligand A.

Output:
1
2025-04-17 14:34:59,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.307 and 382.448 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (75.27) is still acceptable, but less optimal.

**logP:** Both ligands have logP values (2.755 and 2.642) 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 H-bond characteristics, well within the guidelines.

**QED:** Ligand A (0.838) has a significantly better QED score than Ligand B (0.602), indicating a more drug-like profile.

**DILI:** Ligand A (64.444) has a higher DILI risk than Ligand B (44.591), which is a concern. However, it's not drastically high.

**BBB:** Both ligands show good BBB penetration (80.225 and 80.574), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.546 and -4.864). This is unusual and suggests a potential issue with the data or a very poor permeability. This is a significant flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.288 and -4.235). Similar to Caco-2, this is concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.786) has a slightly higher hERG risk than Ligand B (0.561), but both are relatively low.

**Microsomal Clearance:** Ligand A (13.799) has a significantly lower Cl_mic than Ligand B (50.2), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (20.066) has a much longer half-life than Ligand B (-31.667). The negative value for Ligand B is highly problematic and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.279 and 0.146).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is small, it's a positive for Ligand B.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, the significantly better metabolic stability (lower Cl_mic, longer half-life) and QED score of Ligand A, combined with a manageable DILI risk, make it the more promising candidate. The negative Caco-2 and solubility values for both are concerning and require further investigation (potential data errors or formulation challenges). However, the metabolic liabilities of Ligand B are far more severe, represented by the negative half-life. For a kinase inhibitor, metabolic stability is crucial for maintaining therapeutic concentrations.

Output:
0
2025-04-17 14:34:59,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (87.74) is better than Ligand B (49.41). Both are below 140, suggesting good oral absorption potential.

**logP:** Ligand B (3.01) is optimal, while Ligand A (0.047) is quite low. Low logP can hinder membrane permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=3) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.687, B: 0.704), indicating generally drug-like properties.

**DILI:** Ligand B (18.651) has a much lower DILI risk than Ligand A (33.501). This is a substantial advantage for Ligand B.

**BBB:** Ligand B (87.359) has a higher BBB percentile than Ligand A (34.975). While SRC is not a CNS target, higher BBB is generally a positive indicator of reduced off-target effects.

**Caco-2 Permeability:** Ligand A (-4.886) has worse Caco-2 permeability than Ligand B (-4.478). Both are negative, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-1.933) has slightly better solubility than Ligand B (-3.525), but both are very poor.

**hERG Inhibition:** Ligand A (0.064) has a slightly lower hERG risk than Ligand B (0.507), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (8.198) has significantly lower microsomal clearance than Ligand B (45.599). Lower clearance suggests better metabolic stability, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-10.065) has a longer half-life than Ligand B (26.648), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.022) has lower P-gp efflux than Ligand B (0.066), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, its extremely low logP and poor Caco-2 permeability are major concerns. The significantly higher DILI risk is also a negative. Ligand B, despite having higher Cl_mic and lower half-life, has a much better logP, lower DILI risk, and acceptable solubility. The binding affinity is the same for both. Given the enzyme-specific priorities, metabolic stability is important, but permeability and safety (DILI) are also crucial.

Output:
1
2025-04-17 14:34:59,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.341 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.26) is better than Ligand B (49.41) as it is still within the acceptable range for oral absorption (<140), but Ligand B is significantly lower.

**logP:** Both ligands have good logP values (2.741 and 3.49), 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar, good QED scores (0.841 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (68.011) has a higher DILI risk than Ligand B (40.054). Ligand B is well below the 60 threshold, indicating lower liver injury risk.

**BBB:** Ligand A (94.649) has a higher BBB penetration score than Ligand B (72.586). However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.555 and -4.547), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.478 and -4.276), which is also concerning, indicating very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.2) has a much lower hERG inhibition risk than Ligand B (0.653), which is a significant advantage.

**Microsomal Clearance:** Ligand A (32.069) has a lower microsomal clearance than Ligand B (70.085), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.249) has a shorter half-life than Ligand B (-5.398). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux than Ligand B (0.377), which is favorable.

**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.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is slightly favored. While it has a shorter half-life, it exhibits significantly lower hERG risk and better metabolic stability (lower Cl_mic). Ligand B has a better DILI score, but the higher hERG risk is a major concern. Both have poor solubility and permeability, which would need to be addressed during optimization, but the safety profile of Ligand A is more promising.

Output:
0
2025-04-17 14:34:59,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.899 Da) is slightly higher than Ligand B (341.455 Da), but both are acceptable.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (71.09). Lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (A: 3.72, B: 2.593), falling within the optimal 1-3 range.

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

**QED:** Both ligands have good QED scores (A: 0.695, B: 0.865), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (31.563) has a considerably lower DILI risk than Ligand B (44.397). This is a significant advantage for Ligand A.

**BBB:** Ligand A (84.064) has a better BBB penetration score than Ligand B (43.893), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.932 and -4.861), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.333 and -3.25), indicating very poor aqueous solubility. This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.531) has a slightly higher hERG risk than Ligand B (0.191), which is less desirable.

**Microsomal Clearance:** Ligand A (37.225 mL/min/kg) has a higher microsomal clearance than Ligand B (21.077 mL/min/kg), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Both ligands have similar negative half-lives (-3.5 and -3.074 hours), which is concerning and indicates rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.162 and 0.117), which is favorable.

**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 has a slightly better binding affinity and QED score, and lower hERG risk. However, Ligand A has a significantly lower DILI risk and better BBB penetration. Both ligands suffer from poor solubility and permeability, and rapid metabolism. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the lower DILI risk of Ligand A is a substantial advantage. While its metabolic stability is worse, the difference in binding affinity is small enough that optimization could potentially address this. The solubility issue is a major concern for both, but might be addressed through formulation strategies.

Output:
0
2025-04-17 14:34:59,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (366.615 Da) is also good.

**TPSA:** Ligand A (67.43) is higher than Ligand B (32.34). For an enzyme target, TPSA is less critical than for CNS targets, but lower is generally preferred for absorption. Ligand B has a significantly lower TPSA, suggesting better absorption.

**logP:** Ligand A (2.005) is within the optimal range (1-3). Ligand B (4.458) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1 respectively) and HBA (3 each) counts.

**QED:** Both ligands have good QED scores (0.638 and 0.78), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (23.885 and 32.842), which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (85.072) has a higher BBB score than Ligand A (67.584), but this is less important here.

**Caco-2 Permeability:** Ligand A (-4.648) has a lower Caco-2 permeability than Ligand B (-5.206), suggesting Ligand B might have better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.022) has better aqueous solubility than Ligand B (-4.773). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.338) has a lower hERG inhibition risk than Ligand B (0.683). This is a significant advantage for Ligand A, reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (66.721) has lower microsomal clearance than Ligand B (100.475), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-4.481) has a longer in vitro half-life than Ligand B (14.005), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux than Ligand B (0.532), potentially leading to better oral bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). 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 a slightly better binding affinity, Ligand A excels in critical ADME properties: better solubility, lower hERG risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. These factors are particularly important for an enzyme inhibitor like an SRC kinase inhibitor, where maintaining therapeutic concentrations over time is crucial. The small difference in binding affinity is outweighed by the superior ADME profile of Ligand A.

Output:
0
2025-04-17 14:34:59,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 78.43, which is acceptable for oral absorption (<=140).

**logP:** Ligand A (2.298) is slightly higher than Ligand B (1.83), both within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have 3 HBD and 3 HBA, which is good.

**QED:** Ligand A (0.589) has a better QED score than Ligand B (0.404), indicating a more drug-like profile.

**DILI:** Ligand A (4.731) has a slightly higher DILI risk than Ligand B (29.43), but both are below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.834 and -4.813), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.599 and -2.54), also indicating poor aqueous solubility. This is a substantial issue.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.232 and 0.224), which is excellent.

**Microsomal Clearance:** Ligand B (34.564 mL/min/kg) has a lower microsomal clearance than Ligand A (42.207 mL/min/kg), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (-19.607 hours) has a much longer in vitro half-life than Ligand A (-7.052 hours), further supporting its superior metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.269).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. The difference of 1.9 kcal/mol is substantial.

**Conclusion:**

Despite the shared issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -7.3 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher DILI risk and lower QED score. The potency difference is large enough to potentially overcome the solubility/permeability issues through formulation strategies.

Output:
1
2025-04-17 14:34:59,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.5 and 352.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is higher than Ligand B (57.95). Both are below 140, suggesting reasonable absorption, but B is better.

**logP:** Ligand A (1.288) is optimal, while Ligand B (4.166) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**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 (0.759) has a better QED score than Ligand B (0.542), indicating a more drug-like profile.

**DILI:** Ligand B (52.772) has a lower DILI risk than Ligand A (35.673), which is preferable.

**BBB:** Both have similar BBB penetration (69.4% and 68.9%), which isn't a primary concern for a non-CNS target like SRC.

**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 indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.235) has a much lower hERG risk than Ligand B (0.882), a crucial advantage.

**Microsomal Clearance:** Ligand A (59.749) has a higher microsomal clearance than Ligand B (49.639), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (23.851) has a significantly longer in vitro half-life than Ligand A (-26.088). This is a major advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.108) shows lower P-gp efflux than Ligand B (0.533), which is favorable.

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 2.2 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite Ligand B's higher logP and slightly higher DILI risk, its significantly superior binding affinity (-10.3 vs -8.1 kcal/mol) and longer half-life are decisive. The potency advantage is large enough to potentially overcome the solubility and permeability concerns, which can be addressed through formulation strategies. Ligand A's better hERG profile is a plus, but the weaker binding makes it less likely to be effective *in vivo*.

Output:
1
2025-04-17 14:34:59,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.443 and 344.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.74) is higher than Ligand B (49.41). Both are acceptable, but Ligand B is better, potentially indicating improved cell permeability.

**3. logP:** Both ligands have good logP values (2.51 and 3.3), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for off-target effects but isn't critical.

**4. H-Bond Donors:** Ligand A has 0 HBDs, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 2. Both are well below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.679 and 0.752), indicating drug-like properties.

**7. DILI:** Ligand A (43.777) has a slightly higher DILI risk than Ligand B (5.584). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (61.497) has a lower BBB penetration percentile than Ligand B (85.731). Since SRC is not a CNS target, this is less important, but still favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.367) has worse Caco-2 permeability than Ligand B (-4.719). Both are negative, indicating poor permeability, but Ligand B is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.929) has better aqueous solubility than Ligand B (-3.826). This is a positive for Ligand A.

**11. hERG Inhibition:** Ligand A (0.181) has a lower hERG inhibition risk than Ligand B (0.487). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (40.415) has lower microsomal clearance than Ligand B (57.76). Lower clearance indicates better metabolic stability, favoring Ligand A.

**13. In vitro Half-Life:** Ligand A (3.143) has a shorter in vitro half-life than Ligand B (-0.457). Negative half-life is not possible, so this is a data error for Ligand B. This is a major disadvantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux than Ligand B (0.027). Lower efflux is better, favoring Ligand A.

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

**Overall Assessment:**

Ligand A has advantages in metabolic stability (lower Cl_mic), hERG risk, and P-gp efflux. Ligand B has advantages in DILI risk, BBB penetration, and solubility. The half-life for Ligand B is likely a data error. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A appears to be the more promising candidate due to its better metabolic stability and lower hERG risk. The solubility difference is less critical, and the slightly higher DILI risk of Ligand A is acceptable given its other favorable properties.

Output:
0
2025-04-17 14:34:59,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.39 and 346.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.24) is slightly higher than Ligand B (69.64). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (-0.252) 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 has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.651) has a better QED score than Ligand B (0.495), indicating a more drug-like profile.

**DILI:** Ligand A (43.47) has a slightly higher DILI risk than Ligand B (6.32), but both are reasonably low.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (58.82) has a higher BBB percentile than Ligand A (31.91), but this is not a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.168 and -4.701), 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 (-0.871 and -1.972), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.177 and 0.211), which is excellent.

**Microsomal Clearance:** Ligand A (-4.787) has a much lower (better) microsomal clearance than Ligand B (21.541). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (33.864 hours) has a much longer half-life than Ligand B (-11.198 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.035 and 0.016).

**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 difference. A >1.5 kcal/mol advantage in binding affinity can often outweigh other ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a more favorable logP, which are critical for an enzyme inhibitor. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED, the substantial difference in binding affinity outweighs these advantages. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:34:59,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.463 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is better than Ligand B (88.33), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have good logP values (2.3 and 1.712), falling within the optimal 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:** Ligand A (0.827) has a significantly better QED score than Ligand B (0.723), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (27.608 and 29.042), both below the 40 threshold.

**8. BBB:** Both ligands have high BBB penetration (88.949 and 81), but SRC is not a CNS target, so this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.341) is better than Ligand B (-5.072), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.798) is better than Ligand B (-2.145), indicating better aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.288 and 0.376).

**12. Microsomal Clearance:** Ligand B (47.701) has lower microsomal clearance than Ligand A (59.435), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-5.082) has a significantly longer in vitro half-life than Ligand A (-1.903), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.08).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. The 8.7 kcal/mol difference is substantial and outweighs the slight advantages of Ligand A in other areas.

**Conclusion:**

While Ligand A has better QED, solubility, and Caco-2 permeability, Ligand B's significantly stronger binding affinity (-8.7 vs -0.0 kcal/mol) and improved metabolic stability (lower Cl_mic, longer t1/2) make it the more promising drug candidate for SRC kinase inhibition. The difference in binding affinity is so large that it overcomes the slight disadvantages in other properties.

Output:
1
2025-04-17 14:34:59,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (368.415 and 368.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (109.86) is better than Ligand B (119.19). Both are below the 140 A^2 threshold for good oral absorption, but closer to the ideal range.

**3. logP:** Ligand B (-1.047) is lower than Ligand A (0.369). Ligand B is slightly below the optimal 1-3 range, which could potentially hinder permeation. Ligand A is 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 8 respectively), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.751 and 0.695), indicating a drug-like profile.

**7. DILI:** Ligand B (71.345) has a lower DILI risk than Ligand A (84.606), which is favorable.

**8. BBB:** Ligand A (51.105) has a higher BBB penetration percentile than Ligand B (33.579). However, BBB is not a primary concern for an oncology target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.127 and -5.318), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.659 and -1.573), suggesting very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.095 and 0.048).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-14.831) has a much lower (better) microsomal clearance than Ligand B (7.233), indicating greater metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-15.246) has a much longer in vitro half-life than Ligand B (23.402), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.098).

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is relatively small (0.8 kcal/mol).

**Overall Assessment:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Both compounds have poor solubility and permeability, which are significant drawbacks that would need to be addressed through formulation or structural modification. However, the superior metabolic stability of Ligand A makes it a better starting point for optimization. The small affinity difference is likely outweighed by the ADME benefits of Ligand A.

Output:
0
2025-04-17 14:34:59,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.471 and 372.55 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.64 and 58.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.577 and 3.305) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**QED:** Both ligands have acceptable QED scores (0.543 and 0.653), indicating drug-like properties.

**DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (28.306). This is a major advantage.

**BBB:** Both ligands have good BBB penetration (78.79 and 83.443), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.924 and -4.821), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.247 and -4.564), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.26) has a lower hERG inhibition liability than Ligand B (0.592), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (58.778) has lower microsomal clearance than Ligand B (76.095), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.264) has a negative half-life, which is not physically possible. Ligand B (16.076) has a reasonable half-life. This is a major disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.094 and 0.33).

**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 not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is preferable despite the negative and unrealistic half-life value. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), lower hERG inhibition, and a lower number of H-bond donors. While both have poor solubility and permeability, the other advantages of Ligand A outweigh the slightly better binding affinity of Ligand B. The negative half-life is a serious issue, but could be a data error.

Output:
0
2025-04-17 14:34:59,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.43 and 352.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.48 and 86.71) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.636 and 1.529) 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 (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.645) has a better QED score than Ligand B (0.512), indicating a more drug-like profile.

**DILI:** Ligand A (24.54) has a significantly lower DILI risk than Ligand B (34.55), which is a major advantage.

**BBB:** Both ligands have low BBB penetration, which isn't critical for an oncology target like SRC. Ligand B is slightly higher (44.40) than Ligand A (26.02).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.158) is slightly worse than Ligand B (-4.681).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.467) is slightly worse than Ligand B (-2.078).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.298 and 0.174).

**Microsomal Clearance:** Ligand A (29.17) has higher microsomal clearance than Ligand B (21.75), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-46.34) has a much longer in vitro half-life than Ligand A (8.48), indicating better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.047 and 0.096).

**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 of the ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, a better QED score, and a much lower DILI risk. However, it suffers from higher microsomal clearance, shorter half-life, and worse Caco-2 permeability and solubility compared to Ligand B. The large difference in binding affinity (-8.9 vs -6.6 kcal/mol) is a >1.5 kcal/mol advantage and is a strong driver for selecting Ligand A. While the ADME properties of Ligand A are not ideal, the potency advantage is significant, and optimization efforts could potentially address the metabolic stability and solubility issues.

Output:
1
2025-04-17 14:34:59,372 - INFO - Batch 308 complete. Total preferences: 4928
2025-04-17 14:34:59,372 - INFO - Processing batch 309/512...
2025-04-17 14:35:38,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.471 and 362.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.22) is well below the 140 threshold, indicating good absorption potential. Ligand B (87.49) is also acceptable, but closer to the limit.

**logP:** Ligand A (3.701) is at the higher end of the optimal 1-3 range, potentially raising solubility concerns. Ligand B (1.852) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which is favorable. Ligand B has 0 HBD and 7 HBA, also acceptable.

**QED:** Ligand A (0.84) has a very good drug-likeness score. Ligand B (0.443) is below the 0.5 threshold, indicating a less drug-like profile.

**DILI:** Ligand A (33.812) has a low DILI risk, which is excellent. Ligand B (87.902) has a significantly higher DILI risk, a major concern.

**BBB:** Both ligands have acceptable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This needs further investigation, but could be a modeling artifact.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.932) has a low hERG risk. Ligand B (0.238) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (53.178) has a moderate clearance, suggesting reasonable metabolic stability. Ligand B (86.914) has a higher clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (24.076) has a good half-life. Ligand B (-0.752) has a very short half-life, a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol), a difference of 1.9 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a primary consideration for an enzyme inhibitor. However, it suffers from a significantly higher DILI risk, a very short half-life, and a lower QED score. Ligand A has a better safety profile (lower DILI), better predicted drug-likeness, and a longer half-life, but its binding affinity is weaker. The negative solubility and Caco-2 values for both are concerning and require further investigation.

Despite the superior affinity of Ligand B, the combination of high DILI risk and poor half-life make it a less attractive candidate. The improved ADME properties of Ligand A, coupled with acceptable affinity, make it the more viable starting point for further optimization.

Output:
0
2025-04-17 14:35:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (331.419 and 341.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (38.13) is significantly better than Ligand B (71.96). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.892 and 3.246), 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 numbers are generally preferred for permeability.

**QED:** Both ligands have good QED scores (0.73 and 0.84), indicating good drug-likeness.

**DILI:** Ligand A (64.211) has a higher DILI risk than Ligand B (46.297). Lower is better, so Ligand B is preferable here.

**BBB:** Ligand A (88.329) has better BBB penetration than Ligand B (72.005), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.82) has worse Caco-2 permeability than Ligand B (-5.103). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-4.089) has worse aqueous solubility than Ligand B (-3.136). Better solubility is preferred.

**hERG:** Both ligands have low hERG inhibition risk (0.835 and 0.716), which is excellent.

**Microsomal Clearance:** Ligand B (32.33) has significantly lower microsomal clearance than Ligand A (54.211), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (34.741) has a longer in vitro half-life than Ligand A (-19.374), which is also a positive for metabolic stability and dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.711 and 0.109).

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.0). While both are excellent, the difference is minimal.

**Overall Assessment:**

Ligand B is superior due to its better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility. While Ligand A has slightly better binding affinity and BBB penetration, these are less critical for a non-CNS kinase inhibitor. The improved ADME properties of Ligand B outweigh the minor difference in binding affinity.

Output:
1
2025-04-17 14:35:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (379.404 and 351.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.29) is slightly higher than Ligand B (77.93). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.271 and 2.307), 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.693 and 0.763), indicating drug-like properties.

**DILI:** Ligand A (41.877) has a slightly higher DILI risk than Ligand B (32.299), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (75.456) has a higher BBB percentile than Ligand A (61.38), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.433 and -5.133), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.882 and -2.384), suggesting very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.455 and 0.636), which is good.

**Microsomal Clearance:** Ligand A (3.783) has a significantly lower microsomal clearance than Ligand B (9.79), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-27.696) has a more negative in vitro half-life than Ligand B (-17.05), which is counterintuitive. A more negative value suggests a shorter half-life. This is a significant drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.08), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.8 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is slightly favored due to its lower microsomal clearance (better metabolic stability). However, the significantly worse in vitro half-life of Ligand A is a major concern. The binding affinities are nearly identical. Considering the enzyme-specific priorities, the better metabolic stability of Ligand A is more important than the slightly better BBB penetration of Ligand B.

Output:
0
2025-04-17 14:35:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 357.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (74.86), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.99) is optimal, while Ligand B (4.172) is approaching the upper limit, potentially causing solubility issues.

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

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

**QED:** Ligand A (0.743) is better than Ligand B (0.592), indicating a more drug-like profile.

**DILI:** Ligand A (41.877) has a significantly lower DILI risk than Ligand B (78.131). This is a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (71.074) and Ligand B (68.631) are comparable.

**Caco-2 Permeability:** Ligand A (-4.665) and Ligand B (-5.262) are both negative, indicating poor permeability. However, this is less critical if the compound demonstrates good potency and metabolic stability.

**Aqueous Solubility:** Ligand A (-3.557) is better than Ligand B (-4.194), both are poor, but A is slightly less poor.

**hERG Inhibition:** Ligand A (0.133) has a much lower hERG risk than Ligand B (0.812). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (68.328) has higher clearance than Ligand B (52.868), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (57.191) has a significantly longer half-life than Ligand A (-15.859). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands (0.123 and 0.151) have similar low P-gp efflux liability.

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG inhibition, solubility and QED. Ligand B has a significant advantage in metabolic stability (lower Cl_mic, longer t1/2). Given the importance of avoiding toxicity (low hERG, low DILI) and the excellent binding affinity being equal, Ligand A is the slightly better candidate. The metabolic stability of Ligand B is a concern that could be addressed through structural modifications, but the safety profile of Ligand A is more favorable as a starting point.

Output:
0
2025-04-17 14:35:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.443 and 382.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.19) is significantly better than Ligand B (78.35), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.786 and 2.463), 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. Ligand A is preferable here, staying further below the 10 threshold.

**QED:** Both ligands have acceptable QED scores (0.904 and 0.787), indicating good drug-likeness.

**DILI:** Ligand A (39.899) has a much lower DILI risk than Ligand B (67.003). This is a significant advantage.

**BBB:** Both have reasonable BBB penetration (79.333 and 73.517), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.977 and -5.46).

**Solubility:** Both have negative solubility values, which is also unusual and a concern. Ligand A (-2.982) is slightly better than Ligand B (-3.719).

**hERG:** Ligand A (0.681) has a lower hERG risk than Ligand B (0.495), which is preferable.

**Microsomal Clearance:** Ligand B (37.463) has a lower microsomal clearance than Ligand A (4.164), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (43.772) has a longer half-life than Ligand B (33.813), which is desirable.

**P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.094), suggesting better bioavailability.

**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 minor ADME drawbacks.

**Overall:**

Ligand A is superior due to its significantly better binding affinity, lower DILI risk, better TPSA and HBA values, longer half-life, and lower P-gp efflux. While Ligand B has better metabolic stability, the substantial affinity advantage of Ligand A, coupled with the safety profile (lower DILI, hERG), makes it the more promising candidate. The negative solubility and Caco-2 values are concerning for both, but the superior potency and safety of Ligand A make it a better starting point for optimization.

Output:
1
2025-04-17 14:35:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.403 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (363.868 Da) is also well within the range.

**TPSA:** Ligand A (95.08) is better than Ligand B (55.63) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (0.639) is a bit low, potentially hindering permeation. Ligand B (3.588) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Ligand B (0.901) has a significantly higher QED score than Ligand A (0.64), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A (52.617) being slightly higher than Ligand B (47.305), but both are below the 60 threshold.

**BBB:** Ligand B (88.445) has a higher BBB percentile than Ligand A (65.374), but BBB is less critical for a non-CNS target like SRC.

**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. Ligand A (-1.397) is slightly better than Ligand B (-4.104).

**hERG Inhibition:** Ligand A (0.043) has a very low hERG risk, which is excellent. Ligand B (0.337) is also reasonably low, but higher than Ligand A.

**Microsomal Clearance:** Ligand A (16.8 mL/min/kg) has a lower microsomal clearance than Ligand B (33.779 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.859 hours) has a significantly longer in vitro half-life than Ligand A (-17.774 hours). The negative value for Ligand A is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability, with Ligand A (0.068) being slightly lower than Ligand B (0.557).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This difference of 1.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better hERG profile and slightly better solubility, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.5 vs -7.9 kcal/mol) is the most important factor for an enzyme target like SRC. Furthermore, Ligand B has a much better QED score and a substantially longer in vitro half-life, indicating better overall drug-likeness and metabolic stability. While both have poor Caco-2 and solubility, the superior potency and stability of Ligand B make it the preferred choice for further optimization.

Output:
1
2025-04-17 14:35:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.475 and 346.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.96) is higher than Ligand B (50.16). While both are reasonably good, Ligand B is preferable as it's closer to the <140 threshold for good absorption.

**logP:** Both ligands have similar logP values (2.83 and 2.931), 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 (0.824 and 0.892), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 54.44, while Ligand B has a significantly lower risk of 10.585. This is a major advantage for Ligand B.

**BBB:** Ligand A (75.649) and Ligand B (89.957) both have good BBB penetration, but it's less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.133) and Ligand B (-4.874) both have negative values, which is unusual. Lower (more negative) values suggest poorer permeability. However, the difference is small.

**Aqueous Solubility:** Ligand A (-4.401) and Ligand B (-2.165) both have negative values, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.762) has a higher hERG risk than Ligand B (0.513). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (59.653) has a higher microsomal clearance than Ligand B (27.023). Lower clearance indicates better metabolic stability, favoring Ligand B.

**In vitro Half-Life:** Ligand A (-5.293) has a shorter half-life than Ligand B (14.376). Longer half-life is generally preferred, so Ligand B is better.

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux than Ligand B (0.206). Lower efflux is better, so Ligand A is slightly preferable.

**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 still a positive for Ligand B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in the most critical parameters for an enzyme inhibitor: DILI risk, microsomal clearance, and in vitro half-life. It also has a slightly better binding affinity and solubility. While Ligand A has slightly lower P-gp efflux, the other advantages of Ligand B outweigh this minor difference.

Output:
1
2025-04-17 14:35:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.881 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (72.78 and 75.71) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (3.922) is at the upper end of the optimal range (1-3), while Ligand B (1.564) is at the lower end. While Ligand B's logP might suggest better solubility, it could also indicate poor membrane permeability.

**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 (0.711 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 73.982, which is concerning (high risk). Ligand B has a much lower DILI risk of 29.042, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration (61.38 and 72.625), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.169) has poor Caco-2 permeability, while Ligand B (-4.763) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.148 and -1.507). This is a significant drawback for both, but may be mitigated by formulation strategies.

**hERG Inhibition:** Ligand A (0.899) has moderate hERG inhibition risk, while Ligand B (0.14) has very low risk. This is a major advantage for Ligand B.

**Microsomal Clearance:** Ligand A (41.964) and Ligand B (17.687) have reasonable microsomal clearance, but Ligand B is significantly better, indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (41.298) and Ligand B (6.18) have very different in vitro half-lives. Ligand A is significantly better.

**P-gp Efflux:** Ligand A (0.606) and Ligand B (0.047) have low P-gp efflux, which is favorable for both.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. Its significantly lower DILI risk, much lower hERG inhibition, better metabolic stability (lower Cl_mic), and *much* stronger binding affinity outweigh the slightly lower logP and shorter half-life. The higher affinity is particularly important for an enzyme target like SRC kinase. The poor solubility would need to be addressed through formulation, but the other advantages make Ligand B the preferred choice.

Output:
1
2025-04-17 14:35:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.341 and 360.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly above the preferred <140, while Ligand B (88.1) is well within. This favors B for absorption.

**logP:** Both ligands have good logP values (1.309 and 0.949), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which is acceptable.

**QED:** Both have reasonable QED scores (0.611 and 0.567), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 57.348, which is moderate but acceptable. Ligand B has a significantly lower DILI risk (35.983), which is a clear advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (74.758) has a higher BBB score than Ligand A (43.311), but this is not a major factor here.

**Caco-2:** Both have negative Caco-2 values which is unusual. Assuming these are percentile scores, both are poor.

**Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, both are poor.

**hERG:** Both ligands have low hERG risk (0.331 and 0.447), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand A has a higher Cl_mic (60.092) than Ligand B (17.403), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life (t1/2):** Ligand B has a negative half-life (-17.91), which is impossible. This is a major red flag. Ligand A has a half-life of 24.536, which is reasonable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.047 and 0.091).

**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 small.

**Overall Assessment:**

Ligand B initially appears better due to its lower DILI risk, better TPSA, and superior binding affinity. However, the negative in vitro half-life is a critical flaw. While Ligand A has a higher Cl_mic, its positive half-life makes it more viable. The solubility and Caco-2 values are poor for both, requiring further optimization. Considering the enzyme-specific priorities, metabolic stability (half-life) is crucial.

Output:
1
2025-04-17 14:35:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.433 Da) is slightly higher than Ligand B (343.387 Da), but both are acceptable.

**TPSA:** Ligand A (65.63) is significantly better than Ligand B (120). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (3.11) is optimal, while Ligand B (0.82) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (4 HBD, 5 HBA) are both within acceptable ranges.

**QED:** Both ligands have similar QED scores (0.562 and 0.555), indicating good drug-likeness.

**DILI:** Ligand A (41.411) has a lower DILI risk than Ligand B (55.176), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (70.415) shows better BBB penetration than Ligand B (19.814), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.76) is better than Ligand B (-5.773), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.048) is better than Ligand B (-2.672), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.874) has a lower hERG risk than Ligand B (0.069), which is a significant advantage.

**Microsomal Clearance:** Ligand A (34.72) has a significantly better microsomal clearance than Ligand B (5.996), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (58.742) has a much longer half-life than Ligand B (-24.995), which is highly desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux than Ligand B (0.006), indicating better bioavailability.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.7), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties (solubility, permeability, metabolic stability, hERG risk, P-gp efflux) and has a comparable binding affinity. While Ligand B has a slightly better binding affinity, the superior ADME profile of Ligand A, particularly its metabolic stability (Cl_mic and t1/2) and lower hERG risk, makes it a more promising drug candidate for SRC kinase inhibition. The difference in binding affinity is not substantial enough to outweigh the significant advantages in ADME properties.

Output:
1
2025-04-17 14:35:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.435 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.18) is slightly above the optimal <140 for oral absorption, while Ligand B (96.69) is well within.

**logP:** Ligand A (-1.057) is a bit low, potentially hindering permeability. Ligand B (0.992) is closer to the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.636 and 0.537), indicating good drug-like properties.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (47.964). This is a significant concern.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted cautiously.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.014) shows very low hERG inhibition risk, which is excellent. Ligand B (0.408) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-7.4) shows excellent metabolic stability (negative clearance). Ligand B (2.397) has a positive clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-1.184) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (14.657) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.028 and 0.03).

**Binding Affinity:** Ligand B (-7.5) has a significantly stronger binding affinity than Ligand A (-0.0). This is a crucial advantage for an enzyme inhibitor.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B has a significantly better binding affinity, lower DILI risk, and better metabolic stability. The negative half-life for Ligand A is a red flag, and its very weak binding affinity is a major disadvantage. Ligand A's low hERG risk is a positive, but it's outweighed by the other significant drawbacks. The poor solubility of both compounds would need to be addressed through formulation strategies, but the superior potency and safety profile of Ligand B make it the better starting point for optimization.

Output:
1
2025-04-17 14:35:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is slightly higher than Ligand B (78.51), both are below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (0.993) is a bit low, potentially hindering permeation, while Ligand B (1.756) 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 3. Both are below the 10 threshold.

**QED:** Both ligands have acceptable QED scores (0.478 and 0.518, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (23.497) has a significantly lower DILI risk than Ligand B (18.108), which is a major advantage.

**BBB:** Ligand B (66.46) has a higher BBB penetration percentile than Ligand A (45.638), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.044 and -5.041), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.898) has slightly better solubility than Ligand B (-2.632).

**hERG:** Both ligands have very low hERG inhibition risk (0.112 and 0.227), which is excellent.

**Microsomal Clearance:** Ligand A (33.057) has a lower microsomal clearance than Ligand B (38.093), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.822) has a positive half-life, while Ligand B (-2.276) has a negative half-life, suggesting faster metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.053).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better DILI, solubility, and metabolic stability, the significantly stronger binding affinity of Ligand B (-7.7 vs -6.4 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The improved potency is likely to be more impactful than the slightly less favorable ADME properties of Ligand B.

Output:
1
2025-04-17 14:35:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (361.393 and 360.424 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.14) is higher than the preferred <140, but still acceptable. Ligand B (50.16) is excellent, well below 90, suggesting good absorption.

**3. logP:** Ligand A (0.333) is quite low, potentially hindering permeability. Ligand B (3.276) 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 (4) is also good.

**6. QED:** Both ligands have good QED scores (0.557 and 0.735), indicating drug-like properties.

**7. DILI:** Ligand A (50.33) has a moderate DILI risk. Ligand B (23.226) has a very low DILI risk, which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (91.625) has a higher BBB score, but it's not a primary concern here. Ligand A (56.34) is lower.

**9. Caco-2 Permeability:** Ligand A (-5.337) has poor Caco-2 permeability, likely due to the low logP. Ligand B (-4.656) is better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-1.278) has poor aqueous solubility, consistent with its low logP. Ligand B (-3.417) also has poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.331 and 0.476), which is positive.

**12. Microsomal Clearance:** Ligand A (14.354) has lower microsomal clearance, indicating better metabolic stability. Ligand B (42.926) has higher clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (-1.902) has a shorter half-life, but this value is difficult to interpret without knowing the scale. Ligand B (16.81) has a longer half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.021 and 0.085), which is favorable.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While both have excellent binding affinity, Ligand B has a significantly lower DILI risk, a more favorable logP, and a longer in vitro half-life. Although its solubility is poor, the lower DILI and better logP outweigh the solubility concern. Ligand A's low logP and poor Caco-2 permeability are major drawbacks, despite its better metabolic stability. For an enzyme target like SRC kinase, metabolic stability is important, but a low DILI risk and good permeability are crucial for overall drug development success.

Output:
1
2025-04-17 14:35:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.381 and 347.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.09) is better than Ligand B (55.84). Both are below the 140 A^2 threshold for good oral absorption, but lower TPSA is generally preferred.

**logP:** Both ligands (3.294 and 3.728) are 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 ligands have 0 HBD and a reasonable number of HBA (5 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have acceptable QED scores (0.727 and 0.601), indicating good drug-likeness.

**DILI:** Ligand A (43.195) has a slightly higher DILI risk than Ligand B (28.577). This is a point in favor of Ligand B.

**BBB:** Ligand A (97.712) has significantly better BBB penetration than Ligand B (79.411). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.873) has slightly better Caco-2 permeability than Ligand B (-4.309), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-2.371) has better aqueous solubility than Ligand B (-4.32). This is a positive for Ligand A, as solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.945 and 0.776), which is excellent.

**Microsomal Clearance:** Ligand B (97.637) has significantly higher microsomal clearance than Ligand A (33.049). This means Ligand A is more metabolically stable, a crucial factor for an enzyme target.

**In vitro Half-Life:** Both ligands have negative in vitro half-life values (-17.005 and -17.644), which is unusual and potentially problematic. However, the values are similar.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.698 and 0.555), which is good.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the better candidate. Its significantly stronger binding affinity (-9.6 vs -8.1 kcal/mol) is a major advantage. While Ligand B has a lower DILI risk, the difference isn't large enough to offset the substantial affinity difference. Ligand A also has better solubility and significantly better metabolic stability (lower Cl_mic).

Output:
0
2025-04-17 14:35:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.845 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.25 and 72.96) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.236) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-0.33) is below 1, which could hinder permeation.

**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 acceptable QED scores (0.859 and 0.706), indicating good drug-likeness.

**DILI:** Ligand A (70.066) has a higher DILI risk than Ligand B (35.789). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (82.745) has a slightly better BBB score than Ligand B (64.637).

**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:** Both ligands have very low hERG inhibition liability (0.207 and 0.147), which is excellent.

**Microsomal Clearance:** Ligand A (70.377) has a higher microsomal clearance than Ligand B (20.352), suggesting lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-26.762) has a negative half-life, which is impossible. This is a major red flag. Ligand A (11.414) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.012).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), but the difference is relatively small (0.7 kcal/mol).

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its significantly higher DILI risk and higher microsomal clearance make it less desirable. The negative half-life for Ligand B is a showstopper. However, given the choice between the two, and acknowledging the unusual negative values for Caco-2 and Solubility, Ligand B is *marginally* better due to the lower DILI risk. The negative half-life is a data error that would need to be investigated.

Output:
1
2025-04-17 14:35:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.531 Da) and Ligand B (348.447 Da) are both acceptable.

**TPSA:** Ligand A (86.71) is better than Ligand B (67.67), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.23) is optimal, while Ligand B (0.938) is slightly low, potentially impacting 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 (5) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.648, B: 0.794), indicating drug-likeness.

**DILI:** Ligand A (31.989) has a significantly lower DILI risk than Ligand B (40.171). This is a substantial advantage.

**BBB:** Ligand A (36.487) has a lower BBB penetration than Ligand B (88.29). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.528) is significantly worse than Ligand B (-4.348), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.791) is slightly better than Ligand B (-1.288), but both are poor.

**hERG Inhibition:** Ligand A (0.055) has a much lower hERG risk than Ligand B (0.207). This is a significant advantage.

**Microsomal Clearance:** Ligand A (5.583) has a much lower microsomal clearance than Ligand B (43.79), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.134) has a much longer in vitro half-life than Ligand B (12.396), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.144), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.1) 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 due to its significantly better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has slightly better Caco-2 permeability and binding affinity, the improvements in ADME-Tox properties for Ligand A outweigh these minor differences. The slightly weaker binding affinity of Ligand A is acceptable given the substantial improvements in other critical parameters for an enzyme inhibitor.

Output:
0
2025-04-17 14:35:38,254 - INFO - Batch 309 complete. Total preferences: 4944
2025-04-17 14:35:38,254 - INFO - Processing batch 310/512...
2025-04-17 14:36:21,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.409 and 360.307 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.2 and 58.64) are below the 140 A^2 threshold for good absorption, which is positive.

**logP:** Both ligands have logP values within the optimal range (2.842 and 1.846). Ligand B is slightly lower, which might slightly improve solubility but could marginally reduce permeability.

**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 3 HBA, well below the limit of <=10.

**QED:** Ligand A (0.744) has a significantly better QED score than Ligand B (0.479), indicating a more drug-like profile.

**DILI:** Ligand A (34.742) has a lower DILI risk than Ligand B (47.693), which is a significant advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.617) has a higher BBB percentile than Ligand B (47.809).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.782 and -4.599), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.909 and -3.391), which is also unusual and indicates very low aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.404 and 0.426), which is excellent.

**Microsomal Clearance:** Ligand A (19.744 mL/min/kg) has a much lower microsomal clearance than Ligand B (42.244 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-7.979 hours) has a slightly longer in vitro half-life than Ligand A (-6.42 hours), but the difference is small.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.079 and 0.077).

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent and meets the criteria for a good starting point.

**Conclusion:**

Despite the shared strong binding affinity, Ligand A is the more promising candidate. It has a significantly better QED score, lower DILI risk, and, most importantly, much lower microsomal clearance, indicating improved metabolic stability. While both have poor predicted solubility and permeability, the metabolic advantage of Ligand A outweighs the slight differences in other parameters.

Output:
1
2025-04-17 14:36:21,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.421 Da) is slightly lower than Ligand B (383.857 Da), which is acceptable.

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand A (79.26) is better than Ligand B (84.67).

**logP:** Both ligands have acceptable logP values (Ligand A: 0.767, Ligand B: 2.489), falling within the 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 6 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.647, Ligand B: 0.828), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (35.983) has a significantly lower DILI risk than Ligand B (74.719). This is a major advantage for Ligand A.

**BBB:** Ligand A (65.413) has better BBB penetration than Ligand B (49.205), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.998) is slightly better than Ligand B (-4.81).

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Ligand A (-1.542) is slightly better than Ligand B (-3.678).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.253, Ligand B: 0.267), which is excellent.

**Microsomal Clearance:** Ligand B (25.644 mL/min/kg) has lower microsomal clearance than Ligand A (28.002 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (43.435 hours) has a significantly longer half-life than Ligand A (19.86 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.021, Ligand B: 0.316).

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8.3 kcal/mol, Ligand B: -8.7 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, QED, logP, and importantly, a significantly longer half-life. However, it has a considerably higher DILI risk and lower BBB penetration. Ligand A has a much lower DILI risk and slightly better solubility and Caco-2 permeability. Given the enzyme-specific priorities, metabolic stability (half-life) and potency (affinity) are key. While Ligand A's half-life is shorter, its significantly lower DILI risk makes it the more promising candidate. A higher DILI risk can be a deal-breaker in drug development.

Output:
0
2025-04-17 14:36:21,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (69.22) is significantly better than Ligand B (115.45). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Ligand A (3.067) is optimal, while Ligand B (0.673) is quite low. Low logP can lead to poor membrane permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (6 vs 3), which might slightly impact permeability.

**QED:** Ligand A (0.773) has a better QED score than Ligand B (0.55), indicating a more drug-like profile.

**DILI:** Ligand A (52.423) has a slightly higher DILI risk than Ligand B (33.695), but both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (38.813) has a lower BBB penetration than Ligand B (20.783).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it's hard to interpret the absolute values.

**Aqueous Solubility:** Both have negative solubility values, which is concerning. However, the scale is not specified, so it's hard to interpret the absolute values.

**hERG Inhibition:** Ligand A (0.872) has a lower hERG risk than Ligand B (0.213), which is a significant advantage.

**Microsomal Clearance:** This is crucial for enzymes. Ligand A (5.333) has a much *lower* (better) clearance than Ligand B (-18.931). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (4.207) has a slightly longer half-life than Ligand B (3.521).

**P-gp Efflux:** Ligand A (0.382) has lower P-gp efflux than Ligand B (0.029), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.9 kcal/mol).

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** While both have excellent binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of logP, TPSA, metabolic stability (Cl_mic), hERG risk, and P-gp efflux. The slightly higher DILI risk is less concerning than the significant drawbacks of Ligand B's low logP, high TPSA, and poor metabolic stability.

Output:
1
2025-04-17 14:36:21,632 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [349.391, 121.62 ,  -0.505,   2.   ,   5.   ,   0.717,  47.926,  43.311, -5.497,  -2.397,   0.127, -22.662,   7.395,   0.004,  -7.4  ]
**Ligand B:** [350.419, 103.79 ,  -1.145,   3.   ,   6.   ,   0.574,  24.506,  16.44 , -5.451,  -0.605,   0.032,   1.679,   8.365,   0.003,  -9.2  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da).
2. **TPSA:** Ligand A (121.62) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (103.79) is excellent, well below 140.
3. **logP:** Ligand A (-0.505) is a bit low, potentially hindering permeation. Ligand B (-1.145) is also on the low side, but slightly better than A.
4. **HBD:** Ligand A (2) is good. Ligand B (3) is also acceptable.
5. **HBA:** Ligand A (5) is good. Ligand B (6) is acceptable.
6. **QED:** Ligand A (0.717) is excellent, indicating strong drug-likeness. Ligand B (0.574) is still acceptable, but less optimal than A.
7. **DILI:** Ligand A (47.926) has a moderate DILI risk, but is still within a reasonable range. Ligand B (24.506) has a significantly lower DILI risk, which is a major advantage.
8. **BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.
9. **Caco-2:** Both have negative Caco-2 values which is unusual and indicates poor permeability.
10. **Solubility:** Both have negative solubility values which is unusual and indicates poor solubility.
11. **hERG:** Both ligands have very low hERG risk.
12. **Cl_mic:** Ligand A (-22.662) has a much lower (better) microsomal clearance than Ligand B (1.679), indicating greater metabolic stability.
13. **t1/2:** Ligand B (8.365) has a slightly longer in vitro half-life than Ligand A (7.395).
14. **Pgp:** Both have very low Pgp efflux liability.
15. **Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol) - a difference of 1.8 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in binding affinity, has a better DILI score, and a longer half-life. While Ligand A has better metabolic stability (lower Cl_mic), the substantial affinity advantage of Ligand B outweighs this. The solubility and Caco-2 values are poor for both, but can be addressed in later optimization stages.

**Conclusion:**

Ligand B is the more promising drug candidate due to its significantly stronger binding affinity and lower DILI risk, despite having slightly less favorable metabolic stability.

Output:
1
2025-04-17 14:36:21,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.383 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is better than Ligand B (63.57), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.905 and 1.725), 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:** Both ligands have 1 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have high QED scores (0.872 and 0.852), indicating good drug-like properties.

**DILI:** Ligand B (28.926) has a significantly lower DILI risk than Ligand A (72.043). This is a major advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (79.139 and 81.388), though this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. It is likely these are logP values, and both are poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. It is likely these are logS values and both are poor.

**hERG:** Ligand A (0.285) has a slightly lower hERG risk than Ligand B (0.6), which is preferable.

**Microsomal Clearance:** Ligand B (14.094) has a significantly lower microsomal clearance than Ligand A (33.138), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (18.25) has a much longer in vitro half-life than Ligand A (-0.706). This is another significant advantage for Ligand B.

**P-gp Efflux:** Ligand B (0.082) has lower P-gp efflux liability than Ligand A (0.139), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, as potency is a primary concern for enzyme inhibitors. The 1.9 kcal/mol difference is large enough to outweigh minor drawbacks.

**Conclusion:**

While Ligand A has a slightly better hERG profile and TPSA, Ligand B excels in almost every other critical parameter. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux liability make it a much more promising drug candidate. The solubility and Caco-2 values are concerning for both, but the potency and ADME advantages of Ligand B are compelling.

Output:
1
2025-04-17 14:36:21,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.419 and 350.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (105.76) is slightly above the preferred <140, but acceptable. Ligand B (85.25) is well within the range.

**3. logP:** Ligand A (0.169) is quite low, potentially hindering permeability. Ligand B (1.697) is much better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also good.

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

**6. QED:** Both ligands have good QED scores (0.605 and 0.818), indicating drug-like properties.

**7. DILI:** Ligand A (32.299) has a lower DILI risk than Ligand B (25.359), both are good.

**8. BBB:** Ligand A (66.848) has a moderate BBB penetration, while Ligand B (40.093) is lower. Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.075) has poor Caco-2 permeability, which is concerning. Ligand B (-4.77) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.929) has poor aqueous solubility, which is a significant drawback. Ligand B (-1.424) is also poor, but slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.117 and 0.124).

**12. Microsomal Clearance:** Ligand A (0.783) has much lower microsomal clearance than Ligand B (7.374), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.071) has a negative half-life, which is concerning. Ligand B (0.5) is better.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.014).

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has slightly better binding affinity than Ligand A (-7.0 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A suffers from poor logP, Caco-2 permeability, aqueous solubility, and a negative in vitro half-life. While its DILI risk is slightly lower and it has better metabolic stability, these advantages are outweighed by its significant ADME liabilities.

Ligand B has a better logP, slightly better Caco-2 permeability and solubility, and a positive in vitro half-life. Its binding affinity is marginally better. While its DILI risk is slightly higher, it is still within an acceptable range.

Considering the enzyme-specific priorities, Ligand B is the more promising candidate due to its improved ADME properties and comparable binding affinity.

Output:
1
2025-04-17 14:36:21,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.5) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (62.74) is slightly higher than Ligand B (58.87), but both are acceptable.

**logP:** Ligand A (1.751) is within the optimal range (1-3), while Ligand B (3.283) is towards the higher end. This suggests Ligand B might have potential solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.769, B: 0.853), indicating a generally drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (A: 36.022, B: 47.383), below the 60 threshold.

**BBB:** Both ligands show good BBB penetration (A: 80.07, B: 83.017), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.403) shows poor Caco-2 permeability, which is a significant concern. Ligand B (-5.073) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.91, B: -2.906). This could hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.241, B: 0.64), which is positive.

**Microsomal Clearance:** Ligand A (45.509) has higher microsomal clearance than Ligand B (27.401), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (37.767) has a longer in vitro half-life than Ligand A (11.558), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.108, B: 0.397).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

While both compounds have some shortcomings, **Ligand B** is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -7.5 kcal/mol) is a major advantage for an enzyme target. It also exhibits better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better DILI profile. Although both have poor solubility and Caco-2 permeability, the potency and metabolic stability advantages of Ligand B are more critical for initial optimization.

Output:
1
2025-04-17 14:36:21,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.5 and 349.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.1 and 88.1) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.02 and 1.32) are within the optimal 1-3 range.

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

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

**QED:** Both ligands have good QED scores (0.63 and 0.81), indicating drug-like properties.

**DILI:** Ligand A (23.8%) has a significantly lower DILI risk than Ligand B (74.8%). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (70.6%) has a higher BBB score than Ligand A (30.6%), but this is less important here.

**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 ligands 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 (0.265 and 0.282), which is good.

**Microsomal Clearance:** Ligand A (14.2 mL/min/kg) has a much lower microsomal clearance than Ligand B (51.6 mL/min/kg), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-1.48 hours) has a slightly worse in vitro half-life than Ligand B (-2.88 hours), but both are negative, which is unusual.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.033).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While a 0.2 kcal/mol difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A has significantly lower DILI risk and much better metabolic stability (lower Cl_mic). These factors are crucial for enzyme inhibitors. The negative solubility and Caco-2 values are concerning for both, but the superior safety and metabolic profile of Ligand A outweigh the small binding affinity difference.

Output:
0
2025-04-17 14:36:21,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.48) is slightly above the preferred <140, but acceptable. Ligand B (61.88) is excellent, well below 90.

**logP:** Both ligands (1.366 and 1.641) are within 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 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.744 and 0.684), indicating good drug-like properties.

**DILI:** Ligand A (52.734) has a moderate DILI risk, while Ligand B (7.949) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (76.541) is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.633 and -4.557), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.411 and -1.452), which is also concerning and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.068) has a very low hERG risk, which is excellent. Ligand B (0.55) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (11.583) and Ligand B (54.365) have reasonable microsomal clearance values. Lower is better, so Ligand A is slightly favored here.

**In vitro Half-Life:** Ligand A (-20.127) has a negative half-life, which is not possible and indicates an issue with the data or the molecule's stability. Ligand B (0.512) has a very short half-life, which is a concern.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.037).

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A's primary advantage is its significantly stronger binding affinity. However, its negative in vitro half-life is a major red flag, suggesting instability. Ligand B has a much better safety profile (lower DILI) and a better TPSA, but its affinity is weaker and its half-life is short. The solubility and permeability are poor for both.

Given the enzyme-specific priorities, potency is paramount. The 1 kcal/mol difference in binding affinity for Ligand A is substantial. While the negative half-life is concerning, it might be addressable through structural modifications. The poor solubility and permeability are also addressable. The DILI risk of Ligand A is moderate, but manageable.

Output:
1
2025-04-17 14:36:21,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.503 and 352.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is slightly higher than Ligand B (75.71), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.44) is optimal, while Ligand B (1.038) is a bit low, potentially hindering permeation.

**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 (0.74 and 0.767), indicating good drug-like properties.

**DILI:** Ligand A (21.714) has a significantly lower DILI risk than Ligand B (33.579), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (83.715) has a higher BBB percentile than Ligand A (63.784).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. However, the values are very close (-4.699 vs -4.701) and likely represent similar issues.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.296) is slightly better than Ligand A (-4.249), but both are problematic.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.442 and 0.318), which is positive.

**Microsomal Clearance:** Ligand A (67.575) has higher microsomal clearance than Ligand B (21.48), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-3.197) has a longer in vitro half-life than Ligand A (-11.187), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.139 and 0.064).

**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 (0.2 kcal/mol).

**Conclusion:**

While Ligand B has slightly better binding affinity and metabolic stability, Ligand A's significantly lower DILI risk and acceptable logP make it the more promising candidate. The solubility issues are a concern for both, but the lower DILI risk is a critical advantage for an oncology drug. The small difference in binding affinity is unlikely to outweigh the substantial difference in predicted toxicity.

Output:
0
2025-04-17 14:36:21,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.833 and 366.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.11) is slightly higher than Ligand B (81.67). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.928) is within the optimal 1-3 range. Ligand B (-0.249) is below 1, which might hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable, below the 5 threshold.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (7) are both below the 10 threshold.

**QED:** Both ligands have good QED scores (0.708 and 0.795), indicating good drug-like properties.

**DILI:** Ligand A (70.182) has a higher DILI risk than Ligand B (37.767). This favors Ligand B.

**BBB:** Both ligands have similar BBB penetration (64.676 and 67.623). Not a primary concern for a non-CNS target like SRC.

**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 (0.719) has a slightly higher hERG risk than Ligand B (0.273), favoring Ligand B.

**Microsomal Clearance:** Ligand A (-7.139) has a much lower (better) microsomal clearance than Ligand B (-4.01). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (1.628) has a shorter half-life than Ligand B (3.456), but both are relatively short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.067).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 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, lower DILI risk, and lower hERG risk. However, it suffers from a low logP, which could affect its permeability and bioavailability. Ligand A has a better logP and microsomal clearance, but a higher DILI and hERG risk, and a weaker binding affinity.

Given the importance of potency for kinase inhibitors, the stronger binding affinity of Ligand B is a decisive factor. While the low logP is a concern, it might be addressed through formulation strategies or further chemical modifications. The better metabolic stability of Ligand A is attractive, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 14:36:21,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.487 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.84) is well below the 140 threshold and excellent for oral absorption. Ligand B (89.87) is still acceptable, but less ideal.

**logP:** Ligand A (3.691) is within the optimal 1-3 range. Ligand B (1.442) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is favorable. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.837 and 0.713), indicating good drug-like properties.

**DILI:** Ligand A (46.297) has a moderate DILI risk, but acceptable. Ligand B (19.698) has a very low DILI risk, which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (87.553) has better BBB penetration than Ligand B (25.126).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.882 and -4.732), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.83 and -1.815), which is also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.86) has a slightly higher hERG risk than Ligand B (0.248), making B preferable.

**Microsomal Clearance:** Ligand A (65.449) has a higher Cl_mic, indicating faster metabolism and lower metabolic stability. Ligand B (12.095) has significantly lower clearance, suggesting better metabolic stability, a key factor for kinases.

**In vitro Half-Life:** Ligand B (-8.113) 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 (6.077) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.577 and 0.071), which is good.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-5.9 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and acceptable metabolic stability, but suffers from questionable solubility and permeability. Ligand B has superior metabolic stability (lower Cl_mic), lower DILI risk, and lower hERG risk, but its binding affinity is weaker and its half-life is reported as negative, which is impossible. Given the importance of metabolic stability for kinase inhibitors and the significant negative half-life for ligand B, I would prioritize ligand A despite its solubility/permeability concerns. These can potentially be addressed through formulation strategies. The negative half-life for ligand B is a showstopper.

Output:
0
2025-04-17 14:36:21,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (405.684 Da and 380.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.31) is well below the 140 threshold and favorable. Ligand B (76.88) is still within acceptable limits but higher.

**logP:** Ligand A (4.345) is slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects. Ligand B (2.939) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 7 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.549 and 0.747), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (62.001 and 61.497), placing them in a moderate risk category. This isn't a major differentiator.

**BBB:** Ligand A (92.71) shows good BBB penetration, while Ligand B (62.156) is lower. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.284) has poor Caco-2 permeability. Ligand B (-5.695) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.794) has poor aqueous solubility. Ligand B (-2.56) has better aqueous solubility.

**hERG Inhibition:** Ligand A (0.695) has a slightly higher hERG risk than Ligand B (0.367), but both are relatively low.

**Microsomal Clearance:** Ligand A (89.063) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (9.447) has significantly lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (62.13) has a moderate half-life. Ligand B (63.791) has a similar half-life.

**P-gp Efflux:** Ligand A (0.775) has moderate P-gp efflux. Ligand B (0.279) has lower P-gp efflux.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite Ligand A's slightly higher logP and poorer solubility/permeability, its significantly stronger binding affinity (-7.7 vs -6.2 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The difference in affinity is likely to outweigh the ADME drawbacks, especially considering the moderate DILI risk and acceptable hERG values for both compounds. Ligand B has better ADME properties, but the potency difference is too large to ignore.

Output:
1
2025-04-17 14:36:21,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.427 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.6) is better than Ligand B (77.57), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.716 and 1.042), falling within the 1-3 optimal range. Ligand A is slightly better.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

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

**QED:** Ligand A (0.924) has a significantly better QED score than Ligand B (0.735), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A (40.054) being slightly higher than Ligand B (38.193), but both are below the 60 threshold.

**BBB:** Ligand A (70.997) has a better BBB percentile than Ligand B (66.886), but BBB is not a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-4.82) shows better Caco-2 permeability than Ligand B (-5.119), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.081) is better than Ligand B (-0.671), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.511 and 0.48), which is excellent.

**Microsomal Clearance:** Ligand B (-11.85) has a significantly lower (better) microsomal clearance than Ligand A (27.722), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (14.588) has a longer half-life than Ligand A (38.899), which is also desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.11 and 0.007), which is good.

**Binding Affinity:** Ligand A (-8.4) has a significantly stronger binding affinity than Ligand B (-7.0). This is the most important factor. A difference of 1.4 kcal/mol is substantial.

**Overall Assessment:**

While Ligand B has superior metabolic stability (lower Cl_mic and longer t1/2) and slightly better DILI, Ligand A's significantly stronger binding affinity (-8.4 vs -7.0 kcal/mol) and better QED, solubility, and Caco-2 permeability outweigh these advantages. The binding affinity difference is large enough to overcome the slightly higher Cl_mic of Ligand A.

Output:
1
2025-04-17 14:36:21,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.766 Da) is higher, but still acceptable. Ligand B (352.45 Da) is slightly better.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (67.43) is lower than Ligand A (76.1), which is slightly favorable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.256) is slightly lower, while Ligand B (2.095) is closer to the middle of the range.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.669) and Ligand B (0.737) are comparable.

**DILI:** Ligand B (19.542) has a significantly lower DILI risk than Ligand A (33.773). This is a major advantage for Ligand B.

**BBB:** Ligand B (88.445) has a higher BBB penetration percentile than Ligand A (47.848). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.648) has a lower Caco-2 permeability than Ligand B (-4.916). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.693) has slightly better aqueous solubility than Ligand B (-2.429). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.586) has a lower hERG inhibition liability than Ligand B (0.323), which is a significant advantage. Lower hERG risk is crucial.

**Microsomal Clearance:** Ligand A (-9.508) has a much lower microsomal clearance than Ligand B (11.121). This indicates better metabolic stability for Ligand A, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-2.688) has a longer in vitro half-life than Ligand B (8.631). This further supports the better metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux liability than Ligand B (0.091). Lower efflux is generally favorable.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and superior metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. Ligand B has better solubility and lower DILI risk. However, the substantial difference in binding affinity (-9.2 vs -7.5 kcal/mol) and the importance of metabolic stability for kinase inhibitors make Ligand A the more promising candidate. The slightly higher DILI risk of Ligand A can be investigated further during optimization.

Output:
0
2025-04-17 14:36:21,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.25) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (73.64) is excellent, well below 140.

**logP:** Both ligands (1.522 and 2.192) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 4 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

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

**QED:** Both ligands (0.576 and 0.639) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (41.954) has a moderate DILI risk, but is acceptable. Ligand B (15.2) has a very low DILI risk, which is highly favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (18.961) and Ligand B (83.094) have percentile scores of 18.961 and 83.094 respectively.

**Caco-2 Permeability:** Ligand A (-5.391) has poor Caco-2 permeability. Ligand B (-4.338) has better Caco-2 permeability, but still not great.

**Aqueous Solubility:** Ligand A (-2.908) has poor aqueous solubility. Ligand B (-1.75) has better aqueous solubility.

**hERG:** Ligand A (0.138) has a very low hERG risk, which is excellent. Ligand B (0.507) has a slightly higher hERG risk, but still acceptable.

**Microsomal Clearance:** Ligand A (16.727) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (39.34) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-1.188) has a shorter half-life. Ligand B (-1.866) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better hERG profile and slightly better metabolic stability, Ligand B is superior overall. The significantly stronger binding affinity (-8.4 vs -7.4 kcal/mol) is the most important factor for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk, better solubility, and better Caco-2 permeability. The slightly higher metabolic clearance of Ligand B is a minor concern compared to the substantial gain in potency and reduced toxicity.

Output:
1
2025-04-17 14:36:21,634 - INFO - Batch 310 complete. Total preferences: 4960
2025-04-17 14:36:21,634 - INFO - Processing batch 311/512...
2025-04-17 14:37:00,965 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (346.435 and 341.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (84.22 and 80.12) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.725) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (2.238) is within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (0 and 1 respectively).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (6 and 5 respectively).

**6. QED:** Both ligands have good QED scores (0.75 and 0.904), indicating good drug-like properties.

**7. DILI:** Ligand A (38.969) has a lower DILI risk than Ligand B (64.793), which is a significant advantage.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (71.656) is slightly better than Ligand B (62.156). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**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 negative values could be artifacts or indicate very low permeability.

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

**11. hERG Inhibition:** Ligand A (0.075) has a much lower hERG inhibition liability than Ligand B (0.185), a crucial safety parameter.

**12. Microsomal Clearance (Cl_mic):** Both ligands have similar microsomal clearance rates (26.787 and 25.826 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (6.415 hours) has a longer half-life than Ligand A (-8.49 hours). The negative value for Ligand A is concerning and likely an artifact.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.087 and 0.03).

**15. 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, potentially outweighing some ADME concerns.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability, solubility, and hERG risk are paramount. Ligand B has superior binding affinity. While both have similar metabolic stability, Ligand A has a better DILI score and hERG inhibition profile. However, the negative solubility and half-life values for Ligand A are highly suspect and raise concerns. The superior affinity of Ligand B is likely to be more impactful than the slightly higher DILI risk, especially given the other acceptable parameters.

Output:
1
2025-04-17 14:37:00,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.53 and 349.35 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.69) is well below the 140 threshold, suggesting good absorption. Ligand B (126.13) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (2.817) is optimal (1-3). Ligand B (-1.173) is below 1, which may impede permeation.

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

**QED:** Both ligands have similar QED values (0.777 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (35.79) has a significantly lower DILI risk than Ligand B (60.92), placing it in the "good" category while B is borderline high risk.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (76.15) has better BBB penetration than Ligand B (45.91).

**Caco-2 Permeability:** Ligand A (-4.684) is very poor, while Ligand B (-5.502) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-2.191) is slightly better than Ligand B (-1.628), but both are poor.

**hERG:** Ligand A (0.615) has a lower hERG risk than Ligand B (0.045), which is a significant advantage.

**Microsomal Clearance:** Ligand A (0.809) has a lower Cl_mic, indicating better metabolic stability, while Ligand B (-12.06) suggests rapid clearance.

**In vitro Half-Life:** Ligand A (49.58 hours) has a much longer half-life than Ligand B (33.16 hours).

**P-gp Efflux:** Ligand A (0.399) has lower P-gp efflux than Ligand B (0.017), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.0) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have poor Caco-2 and solubility, Ligand A excels in crucial areas for an enzyme inhibitor: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, better P-gp efflux, and slightly better binding affinity. Ligand B's negative logP and high DILI risk are major drawbacks.

Output:
1
2025-04-17 14:37:00,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.387 Da and 350.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (102.96) is better than Ligand B (67.43), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.032 and 2.949, respectively) 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 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.508 and 0.595), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 67.739, which is moderate-high. Ligand B has a significantly lower DILI risk of 8.026, which is excellent. This is a major advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (76.309 and 61.807). This isn't a primary concern for a kinase inhibitor, but higher is slightly better.

**Caco-2 Permeability:** Ligand A (-5.029) has poor Caco-2 permeability, while Ligand B (-4.535) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.344 and -3.066). This is a potential issue, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.25 and 0.307), which is good.

**Microsomal Clearance:** Ligand A (48.789) has lower microsomal clearance than Ligand B (65.755), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-33.399) has a longer in vitro half-life than Ligand B (-8.59), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.152 and 0.083).

**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 has a superior binding affinity and better metabolic stability (lower Cl_mic and longer t1/2). However, Ligand B has a much lower DILI risk, which is a critical safety parameter. The difference in binding affinity (1.3 kcal/mol) is significant, and often outweighs minor ADME drawbacks. Given the enzyme class (kinase) and the importance of metabolic stability and safety, the lower DILI risk of Ligand B is a compelling factor. The slightly better metabolic stability of A is offset by the significantly higher DILI risk.

Output:
1
2025-04-17 14:37:00,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.498 and 382.913 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (58.64), but both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have a logP around 3 (3.121 and 3.082), 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:** Both ligands have good QED scores (0.622 and 0.851), indicating good drug-like properties.

**7. DILI:** Ligand A (10.469) has a significantly lower DILI risk than Ligand B (50.601). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (89.066 and 79.488), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**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 (-2.631 and -4.23), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.505 and 0.432).

**12. Microsomal Clearance:** Ligand A (27.566) has lower microsomal clearance than Ligand B (30.796), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.857) has a longer in vitro half-life than Ligand B (8.585), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.57).

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.6), but the difference is only 0.4 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and comparable ADME properties outweigh the small difference in binding affinity. Poor solubility is a concern for both, but can be addressed with formulation strategies. For an enzyme target like SRC kinase, metabolic stability and safety (DILI) are paramount.

Output:
0
2025-04-17 14:37:00,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.471 and 362.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is better than Ligand B (84.5), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (3.116 and 2.02), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 2 HBA) and Ligand B (2 HBD, 4 HBA) both satisfy the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED scores (0.635 and 0.647), indicating good drug-likeness.

**DILI:** Ligand A (35.983) has a slightly higher DILI risk than Ligand B (31.718), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.062) has a higher BBB penetration than Ligand A (63.901).

**Caco-2 Permeability:** Ligand A (-5.137) has a lower Caco-2 permeability than Ligand B (-4.619). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.726) has slightly worse solubility than Ligand B (-2.457). Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.536) has a slightly higher hERG risk than Ligand B (0.286). B is significantly better here.

**Microsomal Clearance:** Ligand B (58.641) has a lower microsomal clearance than Ligand A (63.364), suggesting better metabolic stability, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-27.39) has a significantly longer in vitro half-life than Ligand A (0.049), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.269 and 0.037).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This 0.8 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADMET properties, particularly in metabolic stability (lower Cl_mic) and half-life. The hERG risk is also lower for Ligand B. Given the enzyme-specific priorities, the improved metabolic stability and longer half-life of Ligand B are more crucial than the modest affinity difference. The slightly better solubility of Ligand B is also a plus.

Output:
1
2025-04-17 14:37:00,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.483 and 360.351 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (40.62 and 42.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.676 and 3.326) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3 HBA, both are below the 10 threshold.

**QED:** Ligand A (0.74) has a significantly better QED score than Ligand B (0.278), indicating a more drug-like profile.

**DILI:** Ligand A (14.618) has a much lower DILI risk than Ligand B (32.997). This is a significant advantage.

**BBB:** Both ligands have high BBB penetration (91.314 and 97.131), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.603 and -4.271). These values are unusual and suggest poor permeability. However, these values are on a log scale, and the negative values are not necessarily indicative of a complete lack of permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.098 and -3.39). These values are also unusual and suggest poor solubility.

**hERG Inhibition:** Ligand A (0.546) has a slightly lower hERG risk than Ligand B (0.723), which is preferable.

**Microsomal Clearance:** Ligand A (57.326) has a higher microsomal clearance than Ligand B (55.116). This suggests that Ligand B may have better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.444) has a significantly longer in vitro half-life than Ligand B (-5.791). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.253 and 0.207).

**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 substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. It has a significantly better QED score, a much lower DILI risk, a longer half-life, and slightly better binding affinity. While both ligands have concerningly low solubility and permeability values, the superior potency, safety profile, and metabolic stability of Ligand A make it more likely to succeed as a drug candidate.

Output:
1
2025-04-17 14:37:00,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (345.443 and 368.434 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.43) is better than Ligand B (97.12), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have acceptable logP values (1.677 and 2.584, respectively), falling within the 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 below the 10 limit.

**6. QED:** Both ligands have similar, good QED values (0.776 and 0.78).

**7. DILI:** Ligand A (33.773) has a significantly lower DILI risk than Ligand B (69.678). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (68.205) is slightly higher than Ligand A (47.111).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.004 and -5.031), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.333 and -4.404), indicating very poor aqueous solubility. This is a significant drawback for both, potentially impacting bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.312 and 0.257).

**12. Microsomal Clearance:** Ligand A (18.729) has significantly lower microsomal clearance than Ligand B (40.012), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-18.025) has a negative half-life, which is not physically possible and suggests a problem with the data. Ligand B (3.512) has a short half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.124).

**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 outweigh the ADME concerns.

**Overall Assessment:**

Ligand A is the more promising candidate despite the negative half-life value, which may be an error. It has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). While Ligand B has slightly better binding affinity, the substantial improvements in safety (DILI) and pharmacokinetics (Cl_mic) for Ligand A are more critical for overall drug development success, especially for an enzyme target. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies. The negative half-life for ligand A is a red flag and needs investigation.

Output:
0
2025-04-17 14:37:00,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.434 and 351.353 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.09 and 73.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.063) is optimal, while Ligand B (1.777) is slightly lower but still acceptable.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Ligand B (0.81) has a better QED score than Ligand A (0.561), indicating a more drug-like profile.

**DILI:** Ligand A (37.611) has a lower DILI risk than Ligand B (48.275), which is favorable. Both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (85.731) is significantly higher than Ligand A (68.36). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.806) is slightly better than Ligand B (-4.159).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.324) is slightly better than Ligand B (-2.409).

**hERG Inhibition:** Ligand A (0.306) has a lower hERG risk than Ligand B (0.536), which is a significant advantage.

**Microsomal Clearance:** Ligand B (15.972) has a much lower microsomal clearance than Ligand A (46.797), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-12.621) has a negative half-life, which is concerning. Ligand A (16.717) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.136).

**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:**

Ligand B has a better QED, BBB, and microsomal clearance. However, Ligand A has a better DILI score, hERG inhibition profile, and a more reasonable in vitro half-life. The improved metabolic stability of Ligand B is a significant advantage for a kinase inhibitor. While the affinity difference is small, the better metabolic stability and QED of Ligand B outweigh the slightly higher DILI and hERG risk. The negative half-life of Ligand B is a major concern, but could be addressed with structural modifications.

Output:
1
2025-04-17 14:37:00,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (359.354 and 360.376 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (106.2) is better than Ligand B (69.64). Both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (-0.492) is slightly low, potentially hindering permeation. Ligand B (1.724) is within the optimal 1-3 range. This favors Ligand B.

**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 3 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.62 and 0.593), indicating good drug-likeness.

**7. DILI:** Ligand A (59.829) has a higher DILI risk than Ligand B (32.028). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (59.364) and Ligand B (70.997). BBB is not a primary concern for a kinase inhibitor, but higher is generally better. Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-5.228) and Ligand B (-4.894). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.099) and Ligand B (-1.669). Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.104) has a slightly lower hERG risk than Ligand B (0.419), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-31.781) has significantly lower (better) microsomal clearance than Ligand B (-1.409), suggesting greater metabolic stability. This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (4.168) has a shorter half-life than Ligand B (-26.093), which is not ideal.

**14. P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux than Ligand B (0.097), which is preferable.

**15. Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.2). While A has a better affinity, the difference is not substantial enough to outweigh other factors.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer half-life), lower DILI risk, and a reasonable binding affinity. Ligand A has a slightly better affinity and hERG, but the metabolic stability and DILI risks are concerning.

Output:
1
2025-04-17 14:37:00,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.381 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is better than Ligand B (60.45), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.33) is optimal, while Ligand B (3.63) is approaching the upper limit.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.903 and 0.835), indicating drug-likeness.

**DILI:** Ligand A (49.166) has a lower DILI risk than Ligand B (58.705), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.633) has a higher BBB score than Ligand B (51.415).

**Caco-2 Permeability:** Ligand A (-4.849) is better than Ligand B (-4.584), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.271) is better than Ligand B (-4.733), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.81) has a slightly higher hERG risk than Ligand B (0.496), but both are reasonably low.

**Microsomal Clearance:** Ligand A (26.891) has significantly lower microsomal clearance than Ligand B (100.086), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.812) has a longer half-life than Ligand B (6.501), which is desirable.

**P-gp Efflux:** Ligand A (0.123) shows lower P-gp efflux than Ligand B (0.154).

**Binding Affinity:** This is the most critical factor. Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). The difference of 2.8 kcal/mol is substantial and likely outweighs the ADME advantages of Ligand A.

**Conclusion:**

Despite Ligand A having superior ADME properties (lower DILI, better solubility, lower clearance, longer half-life), the significantly stronger binding affinity of Ligand B (-7.6 kcal/mol vs -10.4 kcal/mol) makes it the more promising drug candidate for SRC kinase inhibition. A 2.8 kcal/mol difference in binding is a significant advantage that can often be optimized through further medicinal chemistry efforts.

Output:
1
2025-04-17 14:37:00,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.411 Da) is slightly lower, which could be beneficial for permeability. Ligand B (368.352 Da) is also good.

**TPSA:** Ligand A (81.7) is well below the 140 threshold for oral absorption. Ligand B (99.1) is still acceptable but less favorable.

**logP:** Ligand A (3.09) is optimal. Ligand B (-0.338) is significantly below the 1-3 range, raising concerns about permeability and potentially bioavailability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 3) and HBA (5 & 5) counts.

**QED:** Both ligands have reasonable QED scores (0.828 and 0.631), indicating good drug-like properties.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (16.789). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.986) has better BBB penetration than Ligand B (58.976).

**Caco-2 Permeability:** Ligand A (-4.036) has a worse Caco-2 permeability than Ligand B (-5.089), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.5) has better solubility than Ligand B (-1.115).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.305 and 0.276).

**Microsomal Clearance:** Ligand A (104.545) has higher microsomal clearance, indicating lower metabolic stability compared to Ligand B (-24.064). This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-16.782) has a longer in vitro half-life than Ligand A (-9.486), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.164 and 0.025).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so this doesn't significantly favor one over the other.

**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 solubility outweigh the slightly less optimal TPSA and logP values. Ligand A's higher DILI and lower metabolic stability are major concerns.

Output:
1
2025-04-17 14:37:00,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is higher than Ligand B (54.9). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands (2.95 and 2.247) are 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:** Ligand A has 4 HBA, and Ligand B has 6. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.734 and 0.772), indicating drug-like properties.

**DILI:** Ligand A (43.234) has a slightly higher DILI risk than Ligand B (28.693), but both are below the concerning 60 threshold.

**BBB:** Ligand A (71.733) and Ligand B (84.606) both have good BBB penetration, but it's less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.837 and -4.478), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.622 and -2.138), also unusual and concerning.

**hERG:** Both ligands have low hERG inhibition risk (0.386 and 0.551), which is excellent.

**Microsomal Clearance:** Ligand A (71.734) has a higher microsomal clearance than Ligand B (56.695), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-3.645) has a significantly longer in vitro half-life than Ligand A (-22.077), which is a major advantage.

**P-gp Efflux:** Ligand A (0.485) has slightly lower P-gp efflux than Ligand B (0.137), which is slightly favorable.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2), a difference of 0.2 kcal/mol. While a >1.5 kcal/mol advantage is considered significant, 0.2 kcal/mol is not.

**Conclusion:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. The key advantages of Ligand B are its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better Caco-2 permeability (less negative value). The solubility is also slightly better. While both have poor solubility and permeability, Ligand B is less problematic. The small difference in binding affinity is outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 14:37:00,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.491 and 381.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold and favorable for oral absorption. Ligand B (102.17) is still within acceptable limits but less optimal.

**logP:** Both ligands have logP values (1.829 and 2.58) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=8) in terms of these parameters, which are both within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.722 and 0.618), indicating good drug-likeness.

**DILI:** Ligand A (6.359) has a significantly lower DILI risk than Ligand B (89.802). This is a major advantage for Ligand A.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (81.388) has better BBB penetration than Ligand B (70.143).

**Caco-2 Permeability:** Ligand A (-4.617) shows poor Caco-2 permeability, while Ligand B (-5.164) is also poor.

**Aqueous Solubility:** Ligand A (-1.152) has better solubility than Ligand B (-3.351). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.425) has a lower hERG inhibition liability than Ligand B (0.599), which is a desirable characteristic.

**Microsomal Clearance:** Ligand A (38.27) has significantly lower microsomal clearance than Ligand B (73.718), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (56.086) has a longer in vitro half-life than Ligand A (1.01), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux liability, while Ligand B (0.186) is slightly higher.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is relatively small (0.7 kcal/mol) and may not outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, better solubility, lower hERG inhibition, and significantly lower microsomal clearance (better metabolic stability). The Caco-2 permeability is poor for both, but the other advantages of A make it a more promising candidate. The lower metabolic clearance and reduced toxicity risk are particularly important for kinase inhibitors, which are often developed for chronic use.

Output:
0
2025-04-17 14:37:00,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.383 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.14) is better than Ligand B (49.41) as it is still within the acceptable range for oral absorption (<140), while Ligand B is excellent.

**logP:** Both ligands have good logP values (2.78 and 3.131), 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.6 and 0.779), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 69.756, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (21.132), a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (91.043) compared to Ligand A (80.69), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-3.741) and Ligand B (-5.092) both have negative values, which is unusual and suggests poor permeability. Ligand B is slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.373 and -3.944). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.203) has a slightly lower hERG risk than Ligand B (0.387), which is preferable.

**Microsomal Clearance:** Ligand A (88.001) has higher microsomal clearance than Ligand B (54.09), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-31.856) has a much shorter in vitro half-life than Ligand B (1.669), again indicating lower metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.266), which is good.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-8.4 kcal/mol). This is a crucial advantage, as a 0.6 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility, Ligand B demonstrates a significantly better binding affinity, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. The improved binding affinity outweighs the slightly higher hERG risk.

Output:
1
2025-04-17 14:37:00,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.769 Da and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.55) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (71.53) is well within the acceptable range.

**logP:** Both ligands have good logP values (2.885 and 1.782), 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 (0.671 and 0.883), suggesting good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (89.88%), indicating potential liver toxicity. Ligand B has a much lower and acceptable DILI risk (44.048%). This is a major drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration (75.223 and 70.609), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.725 and -4.644). This is unusual and suggests poor permeability, but the scale is not clearly defined.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.474 and -1.497). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.539) has a slightly higher hERG risk than Ligand B (0.249), but both are relatively low.

**Microsomal Clearance:** Ligand A (56.653) has significantly higher microsomal clearance than Ligand B (21.832), indicating lower metabolic stability. This is a significant disadvantage.

**In vitro Half-Life:** Ligand B (-13.856) has a negative half-life, which is impossible and indicates a data error or unusual behavior. Ligand A (32.184) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.307 and 0.043).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its high DILI risk and higher microsomal clearance are major concerns. The negative half-life for Ligand B is a data quality issue, but the other parameters are more favorable. The difference in binding affinity (1.7 kcal/mol) is substantial, but the ADME/Tox profile of Ligand A is too risky. Ligand B, while having a weaker binding affinity, presents a much more favorable safety and metabolic stability profile.

Output:
1
2025-04-17 14:37:00,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 360.439 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (127.84) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (87.32) is well within the optimal range.

**logP:** Ligand A (-1.093) is a bit low, potentially hindering permeation. Ligand B (2.106) is within the optimal 1-3 range.

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

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

**QED:** Ligand A (0.181) is quite low, indicating a less drug-like profile. Ligand B (0.855) is excellent.

**DILI:** Ligand A (33.385) has a low DILI risk, which is favorable. Ligand B (59.946) is approaching a moderate risk, but still acceptable.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**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 unusual and suggests poor solubility. This is a significant concern for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.044 and 0.096), which is excellent.

**Microsomal Clearance:** Ligand A (-26.687) shows very low clearance, indicating high metabolic stability, which is a major advantage. Ligand B (10.978) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-4.543) shows a negative half-life, which is not possible and likely an error. Ligand B (-3.981) also shows a negative half-life, which is also likely an error.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.052), which is favorable.

**Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.3). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a better binding affinity and excellent metabolic stability (low Cl_mic). However, it suffers from a low QED, a low logP, and questionable solubility/permeability data. Ligand B has a better QED, a more favorable logP, and a lower TPSA. Both have issues with solubility and permeability. The negative half-life values are concerning and suggest data errors.

Despite the questionable solubility/permeability data, Ligand A's superior metabolic stability and slightly better binding affinity give it a slight edge, assuming the negative half-life can be resolved. However, the low QED of Ligand A is a significant drawback.

Output:
0
2025-04-17 14:37:00,968 - INFO - Batch 311 complete. Total preferences: 4976
2025-04-17 14:37:00,968 - INFO - Processing batch 312/512...
2025-04-17 14:37:41,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.381 and 343.387 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is significantly better than Ligand B (119.23).  A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Both ligands have acceptable logP values (2.33 and 1.523), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.903) has a much higher QED score than Ligand B (0.731), indicating better overall drug-likeness.

**DILI:** Ligand B (74.176) has a significantly higher DILI risk than Ligand A (49.166). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (92.633) is better than Ligand B (55.603).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are log values, they are similar and suggest poor permeability.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.271 and -3.265). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.81) has a slightly higher hERG risk than Ligand B (0.354), but both are relatively low.

**Microsomal Clearance:** Ligand A (26.891) has a higher microsomal clearance than Ligand B (24.021), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-40.386) has a *much* longer in vitro half-life than Ligand A (11.812). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.024), which is favorable.

**Binding Affinity:** Ligand A (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a crucial factor. The difference of 1.4 kcal/mol is substantial and can outweigh many ADME concerns.

**Overall Assessment:**

Ligand A is the stronger candidate. Its significantly superior binding affinity (-10.4 vs -9.0 kcal/mol) is the most important factor. While it has a higher microsomal clearance and slightly higher hERG risk, the much better QED, lower DILI risk, and better TPSA outweigh these drawbacks. The poor solubility is a concern for both, but can potentially be addressed with formulation strategies. Ligand B's primary advantage is its longer half-life, but the significantly higher DILI risk is a major red flag.

Output:
1
2025-04-17 14:37:41,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.371 and 352.563 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.44) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (32.78) is excellent, well below 140.

**logP:** Ligand A (2.377) is within the optimal 1-3 range. Ligand B (3.51) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both within acceptable limits. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Both ligands have acceptable QED scores (0.745 and 0.636, respectively), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 81.427, which is high and concerning. Ligand B has a very low DILI risk of 5.273, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 73.517, which isn't critical for a non-CNS target like SRC. Ligand B has 91.314, which is good but less relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.906 and -4.325), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.872 and -2.686), also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A has a very low hERG risk (0.07), which is excellent. Ligand B has a moderate hERG risk (0.867), which is less ideal but not immediately disqualifying.

**Microsomal Clearance:** Ligand A (46.008 mL/min/kg) has a moderate clearance, indicating moderate metabolic stability. Ligand B (71.727 mL/min/kg) has higher clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 4.118 hours, which is reasonable. Ligand B has a negative half-life (-2.528), which is impossible and indicates a data error or significant instability.

**P-gp Efflux:** Ligand A has low P-gp efflux (0.135), which is good. Ligand B has moderate P-gp efflux (0.347).

**Binding Affinity:** Ligand A has a stronger binding affinity (-7.5 kcal/mol) compared to Ligand B (-6.9 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the stronger binding affinity of Ligand A, its high DILI risk (81.427) and the impossible half-life value for Ligand B make Ligand B the more promising candidate. The DILI risk for Ligand A is a major red flag, and the negative half-life for Ligand B is a data quality issue, but the overall profile of Ligand B is superior. The solubility and permeability issues are shared by both, and would need to be addressed through formulation or further structural modifications. However, the lower DILI risk and better metabolic stability profile of Ligand B make it the preferred starting point for further optimization.

Output:
1
2025-04-17 14:37:41,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.378 Da and 356.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.67) is well below the 140 threshold, while Ligand B (116.17) is still acceptable but higher. This favors Ligand A for better absorption.

**logP:** Ligand A (3.591) is optimal, while Ligand B (-0.574) is significantly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD/HBA counts (A: 0/6, B: 3/6), within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.58, B: 0.526), indicating drug-like properties.

**DILI:** Ligand A (87.01) has a higher DILI risk than Ligand B (26.018). This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (87.01) has a higher value than Ligand B (33.85).

**Caco-2 Permeability:** Ligand A (-4.122) has a negative Caco-2 value which is concerning, while Ligand B (-5.021) is also negative. Both are poor.

**Aqueous Solubility:** Ligand A (-4.989) has a very poor solubility, while Ligand B (-1.149) is also poor, but slightly better.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.147, B: 0.128), which is good.

**Microsomal Clearance:** Ligand A (131.247) has a higher Cl_mic than Ligand B (9.008), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-16.019) has a negative half-life which is concerning, while Ligand A (36.816) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.379, B: 0.015), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). Although the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A has better TPSA and half-life, but suffers from poor solubility, higher DILI risk, and higher microsomal clearance. Ligand B has a slightly better binding affinity, significantly lower DILI risk, and lower microsomal clearance, despite having a lower logP and negative Caco-2 permeability. Considering the enzyme-specific priorities, metabolic stability (Cl_mic) and safety (DILI) are crucial. Ligand B's lower DILI and Cl_mic outweigh its lower logP.

Output:
1
2025-04-17 14:37:41,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.42 Da) is slightly higher than Ligand B (340.339 Da), but both are acceptable.

**TPSA:** Ligand A (50.69) is significantly better than Ligand B (109.73). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors. Ligand B is above the preferred threshold of 140.

**logP:** Ligand A (4.19) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.002) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds can sometimes improve permeability.

**QED:** Both ligands have similar QED values (0.838 and 0.735), indicating good drug-likeness.

**DILI:** Ligand A (75.301) has a lower DILI risk than Ligand B (95.502), which is a significant advantage.

**BBB:** Ligand A (81.621) has better BBB penetration than Ligand B (17.449), but this is less critical for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.924) has poor Caco-2 permeability, while Ligand B (-5.318) is also poor. Both are quite low, suggesting potential absorption issues.

**Aqueous Solubility:** Ligand A (-5.255) has very poor aqueous solubility, which is a major concern. Ligand B (-3.294) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.637) has a lower hERG risk than Ligand B (0.004). This is a significant advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (62.364) has higher microsomal clearance than Ligand B (-11.561). Ligand B's negative value suggests very high metabolic stability, which is highly desirable for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (1.893) has a shorter half-life than Ligand B (19.201). Ligand B's longer half-life is a significant advantage.

**P-gp Efflux:** Ligand A (0.718) has moderate P-gp efflux, while Ligand B (0.011) has very low P-gp efflux. Lower P-gp efflux is preferred for better bioavailability.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.8). However, the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B is the more promising candidate. While its TPSA is higher, its significantly better metabolic stability (Cl_mic and t1/2), lower DILI risk, lower hERG risk, and lower P-gp efflux outweigh the slightly weaker binding affinity and higher TPSA. The solubility of both compounds is a concern, but Ligand B is slightly better. The higher binding affinity of Ligand A is not enough to overcome its significant ADME liabilities.

Output:
1
2025-04-17 14:37:41,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.929 Da) is slightly higher than Ligand B (344.415 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (98.22). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.488) is optimal, while Ligand B (1.444) is on the lower side. Lower logP can sometimes hinder permeability.

**H-Bond Donors/Acceptors:** Both ligands 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 good QED scores (A: 0.868, B: 0.763), indicating drug-like properties.

**DILI:** Ligand A (53.044) has a slightly higher DILI risk than Ligand B (43.66), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (73.75) has better BBB penetration than Ligand B (56.029).

**Caco-2 Permeability:** Ligand A (-5.071) and Ligand B (-4.781) both have negative values, suggesting limited permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.193 and -3.907 respectively). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.405, B: 0.333), which is excellent.

**Microsomal Clearance:** Ligand B (-11.523) has significantly lower (better) microsomal clearance than Ligand A (37.175). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (12.912 hours) has a much longer half-life than Ligand A (-5.333 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.529, B: 0.102), which is favorable.

**Binding Affinity:** Ligand A (-9.8 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. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and slightly lower DILI risk, the significantly stronger binding affinity of Ligand A (-9.8 vs -8.4 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The difference in affinity is large enough to compensate for the slightly higher clearance and lower half-life. Solubility is a concern for both, but formulation strategies can be employed.

Output:
1
2025-04-17 14:37:41,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.415 and 363.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is excellent, well below the 140 threshold for oral absorption. Ligand B (122.19) is still acceptable but less favorable.

**logP:** Ligand A (0.489) is a bit low, potentially hindering permeation. Ligand B (0.259) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is well within the acceptable ranges. Ligand B (3 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.712 and 0.703), indicating good drug-likeness.

**DILI:** Ligand A (45.328) has a much lower DILI risk than Ligand B (87.398), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (54.711) has a slightly higher value than Ligand A (42.226).

**Caco-2 Permeability:** Ligand A (-4.889) shows better Caco-2 permeability than Ligand B (-5.537), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.978) has better aqueous solubility than Ligand B (-3.546), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.123 and 0.162).

**Microsomal Clearance:** Ligand A (-1.214) exhibits significantly lower microsomal clearance, indicating better metabolic stability, which is a key priority for kinase inhibitors. Ligand B (-4.092) has higher clearance.

**In vitro Half-Life:** Ligand A (9.373) has a longer in vitro half-life than Ligand B (138.84), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.087 and 0.072).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a considerably stronger binding affinity than Ligand A (-7.2 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 superior ADME properties (solubility, permeability, metabolic stability, DILI risk), Ligand B's significantly stronger binding affinity (-9.0 vs -7.2 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The potency advantage is large enough to compensate for the slightly less favorable ADME profile, particularly given that the ADME properties of Ligand B are still within reasonable bounds.

Output:
1
2025-04-17 14:37:41,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.431 and 343.383 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.01) is better than Ligand B (91.76) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand B (2.203) is better than Ligand A (0.026). A logP between 1-3 is optimal, and Ligand A's value is too low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBDs generally improve permeability.

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

**QED:** Both ligands have high QED scores (0.814 and 0.868), indicating good drug-like properties.

**DILI:** Ligand A (17.642) is significantly better than Ligand B (67.507). Lower DILI is critical, and Ligand B is approaching a concerning percentile.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (51.183) is better than Ligand B (36.177).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.615 and -4.681), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-0.718) is better than Ligand B (-3.209), though both are poor. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.16) is much better than Ligand B (0.209). Lower hERG inhibition is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (4.115) is significantly better than Ligand B (34.741). Lower clearance indicates better metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand A (14.578) is better than Ligand B (-11.471). A longer half-life is generally desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.05).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) is significantly better than Ligand B (-7.4 kcal/mol). The 1.2 kcal/mol difference in binding affinity is substantial and can outweigh some ADME drawbacks.

**Overall:**

Ligand A is the stronger candidate. While both have poor Caco-2 permeability and solubility, Ligand A excels in crucial areas: significantly better binding affinity, much lower DILI risk, lower microsomal clearance (better metabolic stability), and lower hERG inhibition. Its logP is suboptimal, but the strong binding affinity and improved safety profile are more important in this case.

Output:
0
2025-04-17 14:37:41,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.38 Da) is slightly lower, which could be advantageous for permeability. Ligand B (381.527 Da) is also good.

**TPSA:** Ligand A (29.1) is excellent, well below the 140 threshold for oral absorption. Ligand B (80.12) is higher but still acceptable, though it might slightly hinder absorption compared to A.

**logP:** Ligand A (4.403) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.533) is within the optimal range (1-3). This favors B.

**H-Bond Donors/Acceptors:** Both have a reasonable number of HBDs (1 each). Ligand B has more HBAs (7) than A (1), but both are within acceptable limits (<=10).

**QED:** Both ligands have reasonable QED scores (A: 0.816, B: 0.746), indicating good drug-like properties.

**DILI:** Ligand B (75.145) has a higher DILI risk than Ligand A (50.601). This is a significant concern.

**BBB:** Ligand A (91.663) has much better BBB penetration potential than Ligand B (32.416). While not a primary concern for a kinase inhibitor, it's a positive attribute for A.

**Caco-2 Permeability:** Ligand A (-4.503) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.174) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.897) has very poor aqueous solubility. Ligand B (-3.113) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.883) has a slightly higher hERG risk than Ligand B (0.264). This is a significant advantage for B.

**Microsomal Clearance:** Ligand B (56.106) has lower microsomal clearance than Ligand A (74.413), indicating better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand B (51.184) has a longer in vitro half-life than Ligand A (24.337), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.659) has slightly lower P-gp efflux than Ligand B (0.116), which could improve bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a crucial advantage, as a 1.6 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand A has a better BBB score and lower DILI risk, its extremely poor solubility and permeability (negative Caco-2 value) are major drawbacks. Ligand B, despite a higher DILI risk, possesses significantly better metabolic stability (lower Cl_mic, longer t1/2), a more favorable logP, and a substantially stronger binding affinity. The binding affinity difference is large enough to outweigh the higher DILI risk, especially given that DILI risk can be further mitigated through structural modifications. The solubility is also better than A.

Output:
1
2025-04-17 14:37:41,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.412 Da) is slightly higher than Ligand B (359.354 Da), but both are acceptable.

**TPSA:** Ligand A (74.91) is well below the 140 threshold for oral absorption. Ligand B (119.24) is also below the threshold, but closer.

**logP:** Ligand A (1.513) is within the optimal range (1-3). Ligand B (-1.551) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and are within acceptable limits. Ligand A has 7 HBA, and Ligand B has 6 HBA, both are acceptable.

**QED:** Ligand A (0.834) has a much better QED score than Ligand B (0.453), indicating a more drug-like profile.

**DILI:** Ligand B (44.552) has a significantly lower DILI risk than Ligand A (78.015). This is a substantial advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 74.641, Ligand B: 79.062). This isn't a primary concern for a kinase inhibitor, but it's not detrimental.

**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 ADME properties.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, these values can be unreliable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.251, Ligand B: 0.171). This is a positive attribute for both.

**Microsomal Clearance:** Ligand B (2.993) has significantly lower microsomal clearance than Ligand A (6.282), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-34.976) has a much longer in vitro half-life than Ligand A (-13.721). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux (Ligand A: 0.148, Ligand B: 0.026), which is favorable.

**Binding Affinity:** Both ligands have very similar, strong binding affinities (Ligand A: -8 kcal/mol, Ligand B: -7.7 kcal/mol). The difference of 0.3 kcal/mol is unlikely to outweigh the ADME advantages of Ligand B.

**Conclusion:**

While Ligand A has a better QED score and slightly better logP, Ligand B demonstrates superior ADME properties, particularly in terms of DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising drug candidate. The similar binding affinities further support this conclusion.

Output:
1
2025-04-17 14:37:41,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.851 Da) is slightly higher than Ligand B (356.457 Da), but both are acceptable.

**TPSA:** Ligand A (77.52) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is better positioned for good oral absorption.

**logP:** Both ligands have good logP values (A: 2.949, B: 3.031), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (A: 6, B: 2). Ligand B has a particularly favorable HBA count.

**QED:** Both ligands have good QED scores (A: 0.792, B: 0.744), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (94.959) compared to Ligand B (29.042). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B is better (96.084 vs 61.846). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.796) is slightly worse than Ligand B (-4.505).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-5.135) is slightly worse than Ligand B (-3.281).

**hERG:** Ligand A (0.29) has a slightly better hERG profile than Ligand B (0.729), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (18.571) has a lower microsomal clearance than Ligand A (37.34), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-13.016) has a negative half-life, which is concerning. Ligand A (19.572) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.333, B: 0.314).

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, its high DILI risk and poor solubility are significant drawbacks. Ligand B has a better safety profile (lower DILI), better metabolic stability, and slightly better solubility, but its binding affinity is weaker.

Given the strong affinity of Ligand A, it *could* be a viable candidate if the DILI risk can be mitigated through structural modifications. However, the high DILI risk is a major red flag. Ligand B, while less potent, presents a more favorable overall profile with a lower risk of liver toxicity and better metabolic stability.

Output:
1
2025-04-17 14:37:41,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.43) is better than Ligand B (101.56), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration if that were a consideration.

**logP:** Ligand A (1.544) is within the optimal 1-3 range. Ligand B (-0.682) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 3 respectively) and HBA (5 each) counts.

**QED:** Both ligands have good QED scores (0.577 and 0.613), indicating drug-like properties.

**DILI:** Ligand A (55.176) has a higher DILI risk than Ligand B (37.146). This is a significant negative for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (59.093) is slightly better than Ligand B (33.734).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.2) is slightly better than Ligand B (-5.709).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.017) is slightly better than Ligand B (-1.404).

**hERG:** Both ligands have very low hERG risk (0.204 and 0.173). This is excellent.

**Microsomal Clearance:** Ligand B (-10.674) has significantly lower (better) microsomal clearance than Ligand A (27.479). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (20.312) has a longer in vitro half-life than Ligand A (11.049), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.114 and 0.067).

**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's enough to be considered, especially given the other factors.

**Overall Assessment:**

Ligand B is the superior candidate. It has a lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better binding affinity. While both have poor Caco-2 and solubility, the metabolic and toxicity advantages of Ligand B outweigh the marginal differences in those properties. The slightly lower logP of Ligand B is a minor concern, but not a dealbreaker given its other strengths.

Output:
1
2025-04-17 14:37:41,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.748 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.92) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (67.23) is well within the optimal range.

**logP:** Ligand A (3.502) is at the upper end of the optimal 1-3 range, potentially raising concerns about solubility and off-target effects. Ligand B (1.909) is excellent, falling squarely 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 scores (0.547 and 0.803), indicating 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 (23.575 percentile), a major advantage.

**BBB:** Both ligands have moderate BBB penetration (59.519 and 61.535 percentile), which isn't crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-4.882), suggesting poor absorption. Ligand B also shows poor Caco-2 permeability (-5.04), but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A has poor aqueous solubility (-4.808). Ligand B has very poor aqueous solubility (-1.701).

**hERG Inhibition:** Ligand A has a moderate hERG risk (0.648). Ligand B has a very low hERG risk (0.374), a significant advantage.

**Microsomal Clearance:** Ligand A has moderate microsomal clearance (46.906 mL/min/kg). Ligand B has low microsomal clearance (18.444 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a reasonable half-life (55.493 hours). Ligand B has a very short half-life (-9.628 hours), a major drawback.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.534 and 0.028).

**Binding Affinity:** Ligand A has a significantly better binding affinity (-7.9 kcal/mol) than Ligand B (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for enzyme inhibitors. However, its high DILI risk, poor Caco-2 permeability, and poor aqueous solubility are major liabilities. Ligand B has better ADME properties (lower DILI, lower hERG, better metabolic stability), but its significantly weaker binding affinity is a substantial disadvantage.

Despite the strong affinity of Ligand A, the high DILI risk is a dealbreaker. While affinity can sometimes outweigh ADME concerns, a DILI risk of 95.502 is too high to proceed without significant medicinal chemistry efforts to mitigate it. The short half-life of Ligand B is also a concern, but potentially addressable.

Therefore, I would initially favor Ligand B, as the ADME properties are more amendable to optimization than a high DILI risk.

Output:
1
2025-04-17 14:37:41,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.53 and 347.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (116.42).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Ligand A (2.098) is optimal (1-3). Ligand B (-0.207) is below 1, which might impede permeation.

**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 similar QED values (0.724 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (37.15) has a much lower DILI risk than Ligand B (54.75). Both are below 60, but A is preferable.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (45.13) is slightly better than Ligand B (55.87).

**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 risk (0.283 and 0.257). This is excellent.

**Microsomal Clearance:** Ligand A (28.05 mL/min/kg) has significantly *lower* (better) microsomal clearance than Ligand B (-37.48 mL/min/kg). This suggests better metabolic stability for Ligand A. Note the negative value for B is concerning.

**In vitro Half-Life:** Ligand A (15.37 hours) has a much longer half-life than Ligand B (-36.20 hours). Again, the negative value for B is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.012).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: TPSA, logP, DILI, microsomal clearance, and in vitro half-life. The negative values for clearance and half-life of Ligand B are red flags. The better logP and TPSA of Ligand A suggest better absorption potential. The lower DILI risk is also a significant advantage. The small difference in binding affinity is outweighed by the substantial improvements in ADME properties.

Output:
0
2025-04-17 14:37:41,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 349.435 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.64 and 70.91) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.094) is within the optimal 1-3 range. Ligand B (-0.266) is below 1, which could potentially hinder permeation.

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

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6 HBAs, both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.715 and 0.732), indicating good drug-likeness.

**DILI:** Ligand A (22.722) has a lower DILI risk than Ligand B (25.165), both are below the 40 threshold.

**BBB:** Both ligands have similar BBB penetration (63.474 and 65.801). BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.322 and -4.604). 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.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.478 and 0.19). Again, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**hERG:** Both ligands have low hERG risk (0.437 and 0.321).

**Microsomal Clearance:** Ligand A (27.43 mL/min/kg) has higher clearance than Ligand B (-5.968 mL/min/kg). This indicates Ligand B is likely more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-9.94 hours) has a negative half-life, which is unusual. Ligand B (-2.297 hours) is also negative. These values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.02).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). The difference of 1.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While both ligands have some concerning ADME properties (negative Caco-2 and solubility values), Ligand B stands out due to its significantly stronger binding affinity (-8.6 kcal/mol vs -7.5 kcal/mol) and better metabolic stability (lower Cl_mic). The stronger binding is a critical advantage for an enzyme inhibitor, and the improved metabolic stability increases the likelihood of achieving therapeutic concentrations *in vivo*. The slightly lower logP of Ligand B is a minor concern compared to these benefits.

Output:
1
2025-04-17 14:37:41,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for oral absorption, but Ligand B is preferable due to the lower TPSA.

**logP:** Both ligands have logP values (2.461 and 2.65) 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.601 and 0.628), indicating good drug-likeness.

**DILI:** Ligand A (51.338) has a higher DILI risk than Ligand B (15.394). This is a significant advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration (76.774 and 51.066). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.793 and -4.743), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation (negative values often indicate issues with the assay or compound stability).

**Aqueous Solubility:** Ligand A (-4.059) has worse solubility than Ligand B (-2.218). Solubility is important for bioavailability, making Ligand B more favorable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.561 and 0.465).

**Microsomal Clearance:** Ligand A (31.011) has lower microsomal clearance than Ligand B (35.3), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (14.264) has a longer half-life than Ligand B (8.616), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.104 and 0.305).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly better binding affinity than Ligand A (-8.6 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significant advantage in binding affinity and a much lower DILI risk. It also has better solubility and a lower TPSA. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), the superior binding affinity of Ligand B is a crucial factor for an enzyme inhibitor. The Caco-2 permeability values are concerning for both, but the stronger binding of Ligand B makes it a more promising starting point for optimization.

Output:
1
2025-04-17 14:37:41,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.777 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.7) is slightly above the optimal <140 for good oral absorption, but acceptable. Ligand B (61.44) is well within the desired range.

**logP:** Both ligands (1.548 and 1.943) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, both acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.528 and 0.521), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 91.974, which is high and concerning. Ligand B has a much lower DILI risk of 10.896, which is very favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (51.105) than Ligand A (10.314), but it's not a major deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.683) shows poor permeability, while Ligand B (-4.814) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-3.837) has poor solubility, and Ligand B (-2.24) is also not great, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.169 and 0.196), which is excellent.

**Microsomal Clearance:** Ligand A (14.073) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (22.091).

**In vitro Half-Life:** Ligand A (69.659) has a significantly longer half-life than Ligand B (7.517), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.046 and 0.027).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). The difference is 0.4 kcal/mol, which is not a huge advantage, but still noticeable.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), its high DILI risk (91.974) and poor solubility and permeability are major drawbacks. Ligand B, while having slightly weaker binding and less favorable metabolic stability, exhibits a significantly lower DILI risk (10.896) and slightly better solubility and permeability. Given the enzyme-kinase specific priorities, minimizing toxicity (DILI) is crucial.

Output:
1
2025-04-17 14:37:41,127 - INFO - Batch 312 complete. Total preferences: 4992
2025-04-17 14:37:41,127 - INFO - Processing batch 313/512...
2025-04-17 14:38:19,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.495 Da and 341.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (101.22).  A TPSA under 140 is good for oral absorption, and both are under, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.706 and 1.152), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is better than Ligand B (HBD=1, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.791 and 0.875), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (33.695 and 62.66), but Ligand A is significantly lower. This is a crucial factor.

**BBB:** Both have moderate BBB penetration (60.76 and 68.282). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative (-5.027 and -4.958), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both are negative (-2.937 and -2.526), indicating poor aqueous solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.224 and 0.144), which is excellent.

**Microsomal Clearance:** Ligand A (12.938) has a lower Cl_mic than Ligand B (22.717), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.899) has a slightly longer half-life than Ligand B (-4.263).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.07 and 0.023).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a 1.6 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a considerably better binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A has a much better DILI score and better metabolic stability (lower Cl_mic). Both have poor solubility and permeability, which would require formulation strategies. The difference in binding affinity is significant enough to prioritize Ligand B, despite its higher DILI risk, assuming that the DILI risk can be mitigated through further structural modifications.

Output:
1
2025-04-17 14:38:19,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.454 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is significantly better than Ligand B (98.74). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (0.543) is slightly better than Ligand B (0.171), both are a little low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 3 H-bond donors and 4 acceptors, which are acceptable.

**QED:** Ligand A (0.772) has a higher QED score than Ligand B (0.58), indicating a more drug-like profile.

**DILI:** Ligand A (6.863) has a much lower DILI risk than Ligand B (12.796), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (60.915) is better than Ligand B (35.052).

**Caco-2 Permeability:** Both are negative (-5.131 and -5.157), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative (-1.203 and -1.8), indicating poor solubility. This is a concern for both.

**hERG:** Ligand A (0.305) has a much lower hERG risk than Ligand B (0.086), a major advantage.

**Microsomal Clearance:** Ligand A (-27.249) has a much lower (better) microsomal clearance than Ligand B (13.551), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.154) has a longer half-life than Ligand B (11.524), which is desirable.

**P-gp Efflux:** Both are very low (0.019 and 0.02), suggesting minimal P-gp efflux.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). While both are good, the 1.4 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has better QED, significantly lower DILI and hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have poor Caco-2 permeability and solubility, the improvements in safety and metabolic stability with Ligand A are crucial for a viable drug candidate. The slightly better affinity further strengthens its position.

Output:
1
2025-04-17 14:38:19,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.312 Da) is slightly higher than Ligand B (378.425 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, indicating good potential for oral absorption (Ligand A: 79.9, Ligand B: 75.71).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.346) is slightly higher than Ligand B (2.26), but both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both fall within the acceptable ranges.

**QED:** Ligand A (0.77) has a better QED score than Ligand B (0.467), indicating a more drug-like profile.

**DILI:** Ligand B (18.922) has a significantly lower DILI risk than Ligand A (53.432). This is a substantial advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 74.952, Ligand B: 72.237), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values, which is unusual and suggests potential issues with absorption prediction. However, the values are close enough to not be a major differentiator.

**Aqueous Solubility:** Ligand B (-1.514) has slightly better aqueous solubility than Ligand A (-5.187), although both are quite poor.

**hERG Inhibition:** Ligand A (0.541) has slightly better hERG inhibition profile than Ligand B (0.466), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (33.094 mL/min/kg) has significantly lower microsomal clearance than Ligand A (61.149 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (1.038 hours) has a very short half-life, while Ligand A (22.184 hours) has a much longer half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.559, Ligand B: 0.124).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a longer half-life. However, Ligand B has a significantly better DILI score and lower microsomal clearance, indicating better safety and metabolic stability. The solubility of both is poor. Considering the enzyme-specific priorities, the strong binding affinity of Ligand A is a critical factor. While the DILI risk is higher, the substantial potency advantage could allow for lower dosing, potentially mitigating the DILI concern. The longer half-life is also favorable.

Output:
1
2025-04-17 14:38:19,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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. Ligand B (360.885 Da) is also good.

**TPSA:** Ligand A (62.99) is moderately high, but still within acceptable limits for oral absorption. Ligand B (26.63) is excellent, suggesting better absorption potential.

**logP:** Ligand A (2.037) is optimal. Ligand B (3.909) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 4 HBA, which is favorable for drug-like properties.

**QED:** Ligand A (0.858) has a very strong drug-like profile. Ligand B (0.668) is still acceptable, but less optimal.

**DILI:** Ligand A (60.682) is at the higher end of acceptable risk, while Ligand B (22.838) has a much lower DILI risk, a significant advantage.

**BBB:** Both ligands have good BBB penetration, but Ligand B (92.943) is significantly better than Ligand A (81.737). This isn't a primary concern for a kinase inhibitor, but could be useful for off-target effects.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand B (-4.789) is slightly worse than Ligand A (-4.185).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-3.916) is slightly worse than Ligand A (-2.647).

**hERG:** Ligand A (0.167) has a slightly higher hERG risk than Ligand B (0.947), which is preferable.

**Microsomal Clearance:** Ligand A (39.454) has lower clearance, indicating better metabolic stability. Ligand B (57.598) has higher clearance, meaning it will be metabolized more quickly.

**In vitro Half-Life:** Ligand A (83.968) has a much longer half-life than Ligand B (32.794), a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux, which is good. Ligand A (0.089) is slightly better than Ligand B (0.749).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's higher logP and lower solubility, its significantly stronger binding affinity (-7.3 vs -9.6 kcal/mol) and lower DILI risk are compelling advantages. The longer half-life and lower clearance of Ligand A are attractive, but the affinity difference is substantial. For an enzyme target like SRC kinase, potency is paramount, and the 1.9 kcal/mol difference in binding is likely to have a major impact on efficacy.

Output:
1
2025-04-17 14:38:19,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.877 and 368.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is slightly higher than Ligand B (49.85). Both are below the 140 threshold for oral absorption, but B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (2.399 and 2.848), 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 (0.656 and 0.717), indicating good drug-like properties.

**DILI:** Ligand A (43.738) has a slightly higher DILI risk than Ligand B (20.279). B is preferable here.

**BBB:** Ligand A (60.644) has a lower BBB penetration than Ligand B (91.857). Since SRC is not a CNS target, this is less critical, but B is still better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.645 and -4.287). This is unusual and suggests poor permeability, but the scale is not specified so it is hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.899 and -2.926). Again, the scale is not specified, making interpretation difficult.

**hERG:** Ligand A (0.341) has a slightly lower hERG risk than Ligand B (0.55). This is a slight advantage for A.

**Microsomal Clearance:** Ligand B (27.852 mL/min/kg) has significantly lower microsomal clearance than Ligand A (45.957 mL/min/kg), indicating better metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (-14.669 hours) has a negative half-life, which is impossible. This is a major red flag. Ligand A (57.632 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.151) has lower P-gp efflux than Ligand B (0.087), suggesting better oral bioavailability.

**Binding Affinity:** Ligand B (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the most critical factor for an enzyme inhibitor is binding affinity. Ligand B's significantly stronger binding affinity (-10.4 kcal/mol vs -6.9 kcal/mol) is a major advantage. Furthermore, Ligand B has better metabolic stability (lower Cl_mic) and lower DILI risk. The negative half-life for Ligand B is a serious issue, but the binding affinity difference is so large it warrants further investigation into the half-life measurement.

Output:
1
2025-04-17 14:38:19,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.471 and 347.415 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.13) is significantly better than Ligand B (80.76). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.47 and 1.115), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 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 (0.712 and 0.807), indicating good drug-like properties.

**DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (30.593). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (65.258) is slightly better. This is less critical for a kinase inhibitor than for a CNS-targeting drug.

**Caco-2 Permeability:** Ligand A (-5.012) is slightly better than Ligand B (-4.604), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.607) is better than Ligand B (-1.952). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.395 and 0.307).

**Microsomal Clearance:** Ligand B (27.159) has lower microsomal clearance than Ligand A (34.303), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (6.066 hours) has a significantly longer half-life than Ligand A (-1.175 hours). 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 (0.301 and 0.014).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). A difference of 0.9 kcal/mol is meaningful, and can potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, DILI risk, solubility, Caco-2 permeability, and binding affinity. However, Ligand B has a significantly longer half-life and better metabolic stability (lower Cl_mic). The binding affinity difference is important, but the improved metabolic stability and half-life of Ligand B are crucial for an enzyme target like SRC kinase. A longer half-life translates to sustained target engagement and potentially better efficacy. The DILI risk is also a concern for Ligand A.

Output:
1
2025-04-17 14:38:19,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.283 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (52.49 and 57.58) well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.462) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.23) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.595 and 0.874), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 48.623, which is good (low risk). Ligand B has a very low DILI risk of 13.067, even better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (37.34) is lower than Ligand B (67.352).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.168 and -5.015), 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 (-4.205 and -0.976), indicating poor aqueous solubility. Ligand B is slightly better in this regard.

**hERG Inhibition:** Ligand A (0.92) has a moderate hERG risk, while Ligand B (0.32) has a very low risk. This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (12.141 mL/min/kg) has a higher clearance than Ligand B (-6.271 mL/min/kg). The negative value for Ligand B suggests excellent metabolic stability.

**In vitro Half-Life:** Ligand A (140.185 hours) has a very long half-life, which is excellent. Ligand B (11.729 hours) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.673) has moderate P-gp efflux liability, while Ligand B (0.021) has very low efflux liability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. The >1.5 kcal/mol advantage of Ligand B outweighs most of its minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having a longer half-life, Ligand B is the superior candidate. Its significantly stronger binding affinity, lower hERG risk, lower DILI risk, and better metabolic stability (negative Cl_mic) outweigh the slightly lower half-life and solubility concerns. The higher logP of Ligand A is also a concern.

Output:
1
2025-04-17 14:38:19,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.331 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.31) is slightly above the optimal <140 for oral absorption, while Ligand B (101.29) is well within the range.

**logP:** Ligand A (0.987) is a bit low, potentially hindering permeation. Ligand B (1.868) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 9 HBA, which is acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.591 and 0.61), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (94.223 percentile), a significant concern. Ligand B has a much lower DILI risk (19.542 percentile), a major advantage.

**BBB:** Both have similar BBB penetration (64.676 and 63.862 percentile), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.437) shows poor permeability, while Ligand B (-5.209) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.389) has poor solubility, while Ligand B (-3.147) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.684) has a moderate hERG risk, while Ligand B (0.093) has a very low risk, a significant advantage.

**Microsomal Clearance:** Ligand A (50.944 mL/min/kg) has moderate clearance, while Ligand B (37.479 mL/min/kg) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-34.013 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (-11.93 hours) also has a negative half-life, which is not possible. This is likely an error in the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.063 and 0.016), which is favorable.

**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:**

Despite the superior binding affinity of Ligand A, its extremely high DILI risk, poor solubility, and moderate hERG risk are major drawbacks. Ligand B, while having a slightly weaker affinity, exhibits a much more favorable safety profile (low DILI and hERG) and better metabolic stability. The difference in binding affinity (1.2 kcal/mol) is substantial, but the safety concerns with Ligand A are too significant to ignore. Given the enzyme-kinase target class, prioritizing metabolic stability, solubility, and minimizing toxicity is crucial.

Output:
1
2025-04-17 14:38:19,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.463 and 343.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is better than Ligand B (44.29) as it is still within the acceptable range for oral absorption (<140), while Ligand B is significantly lower and potentially better for CNS penetration (though not a priority here).

**logP:** Ligand B (3.096) is optimal (1-3), while Ligand A (0.463) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (1) as it is within the ideal range.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand B (0.86) has a higher QED score than Ligand A (0.603), indicating a more drug-like profile.

**DILI:** Ligand A (19.349) has a significantly lower DILI risk than Ligand B (52.036). This is a strong advantage for Ligand A.

**BBB:** Ligand B (96.743) has excellent BBB penetration, but this isn't a primary concern for a non-CNS target like SRC. Ligand A (33.734) is lower.

**Caco-2 Permeability:** Ligand A (-5.194) has a negative Caco-2 value, which is concerning. Ligand B (-4.81) is also negative, but less so. Both suggest poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.461) has better solubility than Ligand B (-3.196). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.204) has a much lower hERG risk than Ligand B (0.968). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand B (58.178) has a higher microsomal clearance than Ligand A (6.847), suggesting lower metabolic stability. Ligand A is significantly better here.

**In vitro Half-Life:** Ligand B (17.792) has a longer half-life than Ligand A (13.629), but the difference isn't substantial.

**P-gp Efflux:** Ligand A (0.015) has much lower P-gp efflux liability than Ligand B (0.248), improving bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -6.9 kcal/mol respectively). The difference of 0.1 kcal/mol is not significant enough to override other ADME issues.

**Overall Assessment:**

Ligand A has significant advantages in DILI risk, hERG inhibition, microsomal clearance, and P-gp efflux. While its logP is low and Caco-2 permeability is concerning, its superior safety profile and metabolic stability outweigh these drawbacks, especially given the comparable binding affinity. Ligand B has better QED and BBB penetration (irrelevant here), but suffers from higher DILI, hERG, and clearance.

Output:
0
2025-04-17 14:38:19,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (343.471 and 349.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (44.81) is significantly better than Ligand B (88.17).  For good oral absorption, we want TPSA <= 140, both meet this, but lower is better.

**3. logP:** Both ligands have good logP values (2.642 and 2.483), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 3, respectively), staying below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 and 6, respectively), staying below the 10 threshold.

**6. QED:** Ligand A (0.918) has a much better QED score than Ligand B (0.635), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.804) has a significantly lower DILI risk than Ligand B (48.119). This is a crucial advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.617) is higher than Ligand B (70.686).

**9. Caco-2 Permeability:** Ligand A (-4.325) is better than Ligand B (-5.104), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.251) is better than Ligand B (-2.98), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.81 and 0.629, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand A (0.659) has significantly lower microsomal clearance than Ligand B (70.359), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.962) has a shorter half-life than Ligand B (26.793), but this is less concerning given the significantly better metabolic stability (lower Cl_mic).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.16 and 0.068, respectively).

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5), a 0.5 kcal/mol difference.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, the substantial advantages of Ligand A in DILI risk, metabolic stability (Cl_mic), solubility, QED, and Caco-2 permeability outweigh this minor difference in potency. The lower DILI and improved metabolic stability are particularly important for long-term drug development.

Output:
0
2025-04-17 14:38:19,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.415 and 352.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.29) is better than Ligand B (70.08), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Ligand A (4.274) is higher than Ligand B (1.273). Ligand A is pushing the upper limit, potentially leading to solubility issues, while Ligand B is quite low, potentially hindering permeation.

**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 (0.696 and 0.635), indicating good drug-likeness.

**7. DILI:** Ligand A (98.759) has a very high DILI risk, which is a major concern. Ligand B (18.651) has a low DILI risk, a significant advantage.

**8. BBB:** Both ligands have similar BBB penetration (45.677 and 48.003), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Ligand A (-4.798) has worse Caco-2 permeability than Ligand B (-4.179), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-5.939) has significantly worse aqueous solubility than Ligand B (-1.836). This is a critical drawback for Ligand A.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.42 and 0.464), which is acceptable.

**12. Microsomal Clearance:** Ligand A (66.57) has higher microsomal clearance than Ligand B (28.327), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-3.201) has a shorter in vitro half-life than Ligand B (-1.486).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.74 and 0.164).

**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.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand A, its extremely high DILI risk, poor solubility, and lower metabolic stability are major red flags. Ligand B, while having a slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly the low DILI risk and better solubility. For an enzyme target like SRC kinase, metabolic stability and lack of toxicity are crucial. The 1.5 kcal/mol difference in binding affinity can often be overcome with further optimization of a compound with a better overall profile.

Output:
1
2025-04-17 14:38:19,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.431 and 360.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is better than Ligand B (61.8), both are acceptable but A is closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (4.196 and 3.629) within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3 HBA, well within the acceptable limits.

**QED:** Both ligands have good QED scores (0.661 and 0.843), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (11.128) has a significantly lower DILI risk than Ligand B (42.691). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (89.298 and 89.608), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.325 and -4.084). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.063 and -3.159), indicating poor solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.86) has a slightly higher hERG risk than Ligand B (0.574), but both are relatively low.

**Microsomal Clearance:** Ligand A (61.971) has a higher microsomal clearance than Ligand B (57.628), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-23.005) has a significantly longer in vitro half-life than Ligand A (0.685). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.127), which is favorable.

**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 ADME drawbacks.

**Conclusion:**

While Ligand A has a much better DILI profile and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-7.6 vs -9.0 kcal/mol) and longer half-life are more critical for an enzyme target like SRC kinase. The solubility and permeability issues are concerning for both, but can potentially be addressed through formulation strategies. The improved potency and stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 14:38:19,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.427 Da) is slightly better positioned.

**TPSA:** Ligand A (70.39) is significantly better than Ligand B (128.03). Lower TPSA generally improves absorption.

**logP:** Ligand A (3.01) is optimal. Ligand B (-0.583) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA is generally preferred for better permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.902, B: 0.633), indicating good drug-like properties.

**DILI:** Ligand A (63.203) has a higher DILI risk than Ligand B (49.399), but both are within an acceptable range.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (73.284) is slightly better than Ligand A (68.282).

**Caco-2:** Ligand A (-4.798) and Ligand B (-5.088) 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 (-3.517) is better than Ligand B (-1.935), both are quite poor. Solubility is a concern for both.

**hERG:** Ligand A (0.633) has a lower hERG risk than Ligand B (0.13), which is a significant advantage.

**Microsomal Clearance:** Ligand A (46.223) has higher clearance than Ligand B (20.632), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-17.534) has a negative half-life, which is impossible. This is a major red flag. Ligand A (36.462) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux than Ligand B (0.023), which is favorable.

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, its very low logP and impossible half-life are major drawbacks. Ligand A has more balanced properties, with better solubility, lower hERG risk, and a reasonable half-life, but its affinity is weaker. Given the critical importance of potency for kinase inhibitors, and the severe issue with Ligand B's half-life, I would cautiously lean towards Ligand A, but with a strong recommendation for further optimization to improve its binding affinity.

Output:
0
2025-04-17 14:38:19,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.451 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is significantly better than Ligand B (87.54). A TPSA below 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (4.418) is higher than the optimal 1-3 range, potentially leading to solubility issues, but still manageable. Ligand B (-0.391) is too 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 good QED scores (0.758 and 0.786, respectively), indicating drug-likeness.

**DILI:** Ligand A (62.427) has a higher DILI risk than Ligand B (37.069). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.993) and Ligand B (57.968) are similar.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.168). This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.524 and -1.135, respectively). This is a major drawback for both, but Ligand B is better.

**hERG:** Ligand A (0.823) has a slightly higher hERG risk than Ligand B (0.091). Ligand B is much better in this regard.

**Microsomal Clearance:** Ligand A (134.278) has a much higher microsomal clearance than Ligand B (12.323). This indicates lower metabolic stability for Ligand A, a significant disadvantage.

**In vitro Half-Life:** Ligand A (-5.168) has a very short in vitro half-life, while Ligand B (3.341) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.702) has slightly higher P-gp efflux than Ligand B (0.009).

**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 enough to consider, especially given the other ADME properties.

**Overall Assessment:**

Ligand B is the better candidate despite its low logP and Caco-2 permeability. Its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and better t1/2), and lower hERG risk are crucial advantages for an enzyme inhibitor. The slightly better binding affinity of Ligand B further supports this choice. While both have poor solubility and permeability, these can potentially be addressed through formulation strategies. The metabolic stability and safety profile of Ligand B are more difficult to improve post-synthesis.

Output:
1
2025-04-17 14:38:19,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.415 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.21) is slightly above the preferred <140, but acceptable. Ligand B (82.11) is excellent, well below 140.

**logP:** Ligand A (1.136) is within the optimal 1-3 range. Ligand B (-0.31) 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 HBA, which are within acceptable limits (<=5 and <=10, respectively).

**QED:** Both ligands have acceptable QED scores (0.8 and 0.709, both >0.5).

**DILI:** Ligand A (50.33) has a moderate DILI risk, while Ligand B (3.412) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.672) has a good BBB score, while Ligand B (35.052) is low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.125 and -5.133), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.37 and -0.527), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG:** Ligand A (0.399) has a low hERG risk, which is excellent. Ligand B (0.178) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (18.982) has a moderate microsomal clearance, indicating moderate metabolic stability. Ligand B (-23.261) has a *negative* clearance, which is not physically possible and likely indicates an issue with the prediction or data quality. This is a major red flag.

**In vitro Half-Life:** Ligand A (-14.025) has a negative half-life, which is impossible and suggests a data quality issue. Ligand B (-0.583) also has a negative half-life, indicating a significant data quality problem.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.016 and 0.003).

**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 for Ligand B, potentially outweighing some of its other drawbacks.

**Conclusion:**

Despite the concerning negative values for Caco-2 permeability and in vitro half-life for both compounds, the significantly better binding affinity and much lower DILI risk of Ligand B make it the more promising candidate. The negative clearance for Ligand B is a major concern and would require further investigation, but the large difference in binding affinity is a strong driver. The issues with solubility and permeability would need to be addressed through formulation or structural modifications. Ligand A's negative half-life is also a major issue.

Output:
1
2025-04-17 14:38:19,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.354 and 358.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.24) is better than Ligand B (67.87), being under the 140 threshold, but both are acceptable.

**logP:** Ligand A (-1.551) is a bit low, potentially hindering permeability. Ligand B (1.531) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both are acceptable.

**QED:** Both ligands have good QED scores (0.453 and 0.643, respectively), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (23.187), but both are below the concerning threshold of 60.

**BBB:** Ligand A (79.062) and Ligand B (93.912) both have acceptable BBB penetration, but Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.985 and -4.585), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.527 and -1.33), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.171) has a slightly higher hERG risk than Ligand B (0.564), but both are reasonably low.

**Microsomal Clearance:** Ligand A (2.993) has significantly lower microsomal clearance than Ligand B (21.099), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-34.976) has a much longer in vitro half-life than Ligand B (-2.628), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux than Ligand B (0.138), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has better logP and BBB penetration, Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly better DILI profile. Given that we are targeting an enzyme (SRC kinase), metabolic stability is a critical factor. The similar binding affinity means the ADME properties become the deciding factor. The poor Caco-2 and solubility for both are concerning, but the improved metabolic stability of Ligand A is more crucial for kinase inhibitors.

Output:
0
2025-04-17 14:38:19,982 - INFO - Batch 313 complete. Total preferences: 5008
2025-04-17 14:38:19,982 - INFO - Processing batch 314/512...
2025-04-17 14:38:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.471 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is well below the 140 threshold and favorable for oral absorption. Ligand B (83.56) is still below 140, but higher than A, potentially impacting absorption slightly.

**logP:** Ligand A (3.167) is optimal (1-3). Ligand B (1.341) is on the lower end, potentially causing permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Ligand A (0.929) is very strong, indicating high drug-likeness. Ligand B (0.777) is still good, but not as high as A.

**DILI:** Ligand A (36.099) has a low DILI risk. Ligand B (49.593) is slightly higher, but still within an acceptable range.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (89.298) is significantly better than Ligand B (73.827). While not a primary concern for a kinase inhibitor, higher BBB is never a detriment.

**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, comparing their values, Ligand A (-4.779) is slightly better than Ligand B (-4.936).

**Aqueous Solubility:** Both ligands have negative solubility values, again, likely an issue with the prediction. Ligand A (-2.978) is slightly better.

**hERG:** Ligand A (0.653) has a lower hERG risk than Ligand B (0.369), which is preferable.

**Microsomal Clearance:** Ligand A (33.148) has a higher clearance than Ligand B (27.543), meaning Ligand B is more metabolically stable. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (27.55) has a significantly longer half-life than Ligand A (5.71). This is a major advantage.

**P-gp Efflux:** Ligand A (0.423) has lower P-gp efflux than Ligand B (0.017), which is better for bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a better binding affinity than Ligand A (-8.3 kcal/mol). This is a significant advantage, and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has better QED, BBB, P-gp efflux, and slightly better solubility and hERG, the improved potency and metabolic stability of Ligand B are more critical for an enzyme inhibitor. The slightly lower logP of Ligand B is a minor concern, but the strong binding affinity should compensate.

Output:
1
2025-04-17 14:38:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.49 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.64) is higher than Ligand B (71.34). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have good logP values (1.554 and 3.265), 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 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are acceptable, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.662 and 0.832), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (33.695), but both are below the concerning threshold of 60.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (55.099) is slightly better than Ligand A (46.219).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both compounds.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.139) has a lower hERG risk than Ligand B (0.355), which is preferable.

**Microsomal Clearance:** Ligand A (41.674) has lower microsomal clearance than Ligand B (49.639), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-26.129) has a significantly *longer* in vitro half-life than Ligand B (44.461), which is a substantial benefit.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, a slightly better QED, and slightly better BBB penetration. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. Both compounds suffer from poor solubility and permeability. Given the importance of potency for kinase inhibitors, the stronger binding affinity of Ligand B is a major advantage. The better metabolic stability of Ligand A is valuable, but can potentially be addressed through structural modifications. The solubility and permeability issues are significant for both, and would require substantial optimization.

Output:
1
2025-04-17 14:38:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (384.267 Da and 367.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (110.0) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (71.53) is well within the acceptable range.

**3. logP:** Both ligands have logP values within the optimal range (1.949 and 2.658).

**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 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.492 and 0.728), indicating good drug-like properties. Ligand B is slightly better here.

**7. DILI:** Ligand A (64.599) has a higher DILI risk than Ligand B (52.346). Lower is better, so Ligand B is preferred.

**8. BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**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 (0.438 and 0.42).

**12. Microsomal Clearance:** Ligand A (17.368) has significantly lower microsomal clearance than Ligand B (63.931), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand B (19.734) has a longer in vitro half-life than Ligand A (5.878), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.214).

**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 crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand B has a better DILI score and in vitro half-life, the substantially stronger binding affinity of Ligand A (-8.7 vs -6.9 kcal/mol) is the most important factor for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic) of Ligand A is also a significant benefit. The slightly higher TPSA of Ligand A is a minor concern, but the strong binding affinity likely compensates for this. The unusual negative values for Caco-2 and solubility are concerning, but the difference in binding affinity is so large that it outweighs these concerns.

Output:
1
2025-04-17 14:38:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 344.375 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.43) is excellent, well below the 140 threshold for oral absorption. Ligand B (124.16) is still acceptable, but less optimal.

**logP:** Ligand A (1.383) is within the optimal range of 1-3. Ligand B (-0.228) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is good. Ligand B (HBD=3, HBA=7) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (0.728 and 0.665), indicating good drug-like properties.

**DILI:** Ligand A (59.442) has a lower DILI risk than Ligand B (68.476), which is preferable. Both are still within an acceptable range, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (45.444) and Ligand B (61.962) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.073 and -5.588). This is unusual and suggests poor permeability *in vitro*. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.002 and -2.776), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.121) has a much lower hERG risk than Ligand B (0.213), which is a significant advantage.

**Microsomal Clearance:** Ligand A (13.931) has a lower microsomal clearance than Ligand B (-22.682), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (12.325) has a longer in vitro half-life than Ligand B (-7.074), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.083 and 0.013).

**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 A is the superior candidate. While both have poor solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG inhibition. These are crucial factors for an enzyme inhibitor. The slightly better TPSA and logP also contribute to its favorability. The binding affinity difference is minimal.

Output:
0
2025-04-17 14:38:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.407 and 378.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.87) is better than Ligand B (58.2). Both are below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.721) is optimal, while Ligand B (4.261) is pushing the upper limit, potentially leading to solubility issues and off-target effects.

**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 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.703 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A (91.508) has a significantly higher DILI risk than Ligand B (49.864). This is a major concern for Ligand A.

**BBB:** Ligand A (24.506) has very low BBB penetration, while Ligand B (67.468) is better, but not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.575) has poor Caco-2 permeability, while Ligand B (-4.873) is slightly better, but both are negative values which is concerning.

**Aqueous Solubility:** Ligand A (-3.028) has poor aqueous solubility, while Ligand B (-4.125) is even worse.

**hERG Inhibition:** Ligand A (0.073) has a very low hERG risk, which is excellent. Ligand B (0.73) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (14.358) has lower microsomal clearance than Ligand B (55.533), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (17.313) has a shorter half-life than Ligand B (29.345), but both are reasonable.

**P-gp Efflux:** Ligand A (0.032) has very low P-gp efflux, while Ligand B (0.238) is higher.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.0 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. While its logP is higher and solubility is lower, its significantly lower DILI risk and better metabolic stability (lower Cl_mic) outweigh these drawbacks. Ligand A's high DILI risk is a major red flag, and its poor solubility and permeability are also concerning. The slightly better P-gp and hERG profiles of Ligand A are not enough to compensate for these significant liabilities.

Output:
1
2025-04-17 14:38:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.424 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have similar TPSA values (49.33 and 49.41), which are acceptable for oral absorption (<=140).

**logP:** Ligand A (4.22) is slightly higher than Ligand B (3.524). While both are within the optimal 1-3 range, Ligand A is approaching the upper limit, potentially raising concerns about off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 2 HBA) both have favorable numbers of hydrogen bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Ligand A (0.766) has a higher QED score than Ligand B (0.566), indicating a more drug-like profile.

**DILI:** Ligand B (8.569) has a significantly lower DILI risk than Ligand A (46.297), which is a major advantage.

**BBB:** Ligand B (83.637) has a much higher BBB penetration percentile than Ligand A (57.619). While SRC is not a CNS target, higher BBB values generally correlate with better overall permeability.

**Caco-2 Permeability:** Ligand A (-5.026) and Ligand B (-4.864) have similar, and poor, Caco-2 permeability values.

**Aqueous Solubility:** Ligand A (-4.173) and Ligand B (-3.239) have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.737 and 0.628, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (58.757) has a lower microsomal clearance than Ligand A (69.735), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.95) has a negative half-life, which is not possible. This is a red flag and suggests an issue with the data or the compound's stability. Ligand A (19.648) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.774) has slightly higher P-gp efflux liability than Ligand B (0.483), which is less desirable.

**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, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Overall Assessment:**

Despite the better QED, lower DILI, and better metabolic stability of Ligand B, the significantly superior binding affinity of Ligand A (-9.6 vs -7.2 kcal/mol) is the deciding factor. The strong binding is likely to overcome the slightly higher logP and P-gp efflux, and the acceptable DILI risk. The negative half-life for Ligand B is a showstopper.

Output:
1
2025-04-17 14:38:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 351.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.02) is better than Ligand B (52.65). While both are below 140, the lower TPSA of Ligand B is more favorable for cell permeability.

**logP:** Both ligands have good logP values (1.654 and 2.649), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.759 and 0.8), indicating good drug-like properties.

**DILI:** Ligand A (47.732) has a slightly higher DILI risk than Ligand B (11.09). Ligand B is significantly better here.

**BBB:** Ligand A (52.074) has a lower BBB penetration percentile than Ligand B (68.592). This is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.408) has worse Caco-2 permeability than Ligand B (-4.621). Both are negative, indicating low permeability, but B is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.375 and -2.202). This is a potential issue for both, requiring formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.333 and 0.364).

**Microsomal Clearance:** Ligand A (15.56) has significantly lower microsomal clearance than Ligand B (43.532). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-9.171) has a much longer in vitro half-life than Ligand B (4.964). This further supports the better metabolic stability of Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.09).

**Binding Affinity:** Ligand B (-8.7) has a significantly stronger binding affinity than Ligand A (-6.8). This is a 1.9 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk, the significantly stronger binding affinity of Ligand B (-8.7 vs -6.8 kcal/mol) is a critical advantage for an enzyme inhibitor. The difference in binding affinity is large enough to compensate for the slightly higher DILI risk and lower metabolic stability of Ligand B. Solubility is a concern for both, but can be addressed through formulation.

Output:
1
2025-04-17 14:38:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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:** Both ligands have TPSA values below 140, indicating good potential for oral absorption. Ligand A (59.08) is slightly better than Ligand B (63.25).

**logP:** Ligand A (1.207) is within the optimal range (1-3), while Ligand B (3.964) is approaching the upper limit. 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 (2 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (0.649 and 0.636), indicating good drug-likeness.

**DILI:** Ligand A (22.722) has a significantly lower DILI risk than Ligand B (88.329). This is a major advantage for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration (77.976 and 70.027), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests a potential issue with the data or the model. We'll proceed cautiously.

**Aqueous Solubility:** Ligand A (-1.658) has slightly better solubility than Ligand B (-4.136), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.336) has a much lower hERG inhibition liability than Ligand B (0.864), reducing the risk of cardiotoxicity. This is a significant advantage.

**Microsomal Clearance:** Ligand A (43.3 mL/min/kg) has lower microsomal clearance than Ligand B (98.502 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (54.026 hours) has a significantly longer half-life than Ligand A (1.92 hours). This is a potential advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux liability than Ligand B (0.849), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a 1.7 kcal/mol difference, which is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the primary driver for enzyme inhibitors. However, it suffers from higher DILI risk, higher hERG liability, higher microsomal clearance, and lower solubility. Ligand A has a much more favorable safety profile (DILI, hERG) and better metabolic stability, but its affinity is weaker.

Given the importance of potency for kinase inhibitors, the 1.7 kcal/mol advantage of Ligand B is substantial. While the ADME properties of Ligand B are concerning, they might be addressable through further optimization. The poor ADME profile of Ligand B is a significant concern, but the strong binding affinity is a compelling factor.

Output:
1
2025-04-17 14:38:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.406 and 368.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (80.32 and 80.49) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (1.518) is optimal, while Ligand B (2.641) is also within the acceptable range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 7 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.816 and 0.874), indicating drug-like properties.

**DILI:** Ligand A (44.397) has a significantly lower DILI risk than Ligand B (80.341). This is a major advantage.

**BBB:** Both have similar BBB penetration (87.553 and 82.474), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.779 and -4.839), which 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 (-2.113 and -3.856), which is concerning. Solubility is a critical factor for bioavailability. Ligand A is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.341 and 0.459), which is good.

**Microsomal Clearance:** Ligand A (16.96 mL/min/kg) has significantly lower microsomal clearance than Ligand B (47.669 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (18.66 hours) has a longer half-life than Ligand A (-1.93 hours). However, the negative value for Ligand A is problematic and likely indicates a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.195).

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic). While Ligand B has a slightly better binding affinity and half-life, the DILI and clearance concerns are more critical. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh the small affinity benefit of Ligand B. The negative half-life for Ligand A is a major red flag.

Output:
0
2025-04-17 14:38:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.359 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.06) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (63.13) is excellent, well below 140.

**logP:** Ligand A (0.294) is quite low, potentially hindering permeability. Ligand B (3.175) is 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 6 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.5 (0.756 and 0.674), indicating good drug-like properties.

**DILI:** Ligand A (77.976) has a higher DILI risk than Ligand B (25.204). Ligand B is well below the 40% threshold for low risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.919) shows better BBB penetration, but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-5.358) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.758) is also not great, but better than A.

**Aqueous Solubility:** Ligand A (-1.751) has poor solubility, which is concerning. Ligand B (-3.218) also has poor solubility, but is still slightly better.

**hERG Inhibition:** Ligand A (0.017) has very low hERG risk, which is excellent. Ligand B (0.696) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-28.473) exhibits very low microsomal clearance, indicating high metabolic stability. This is a significant advantage. Ligand B (48.947) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-12.909) has a very long in vitro half-life, consistent with low clearance. Ligand B (13.759) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.394).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This 0.8 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has excellent metabolic stability (low Cl_mic, long t1/2) and very low hERG risk, its poor logP, Caco-2 permeability, and solubility are major liabilities. Ligand B, despite slightly higher DILI and faster metabolism, has a better logP, TPSA, and crucially, a stronger binding affinity. The affinity difference is substantial enough to favor Ligand B, as potency is a primary driver for enzyme inhibitors.

Output:
1
2025-04-17 14:38:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.381 and 341.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is significantly better than Ligand B (107.18). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (2.021) is optimal (1-3), while Ligand B (0.967) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 8. Ligand A is preferable here, as keeping HBAs low improves permeability.

**QED:** Both ligands have good QED scores (0.772 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (27.414) has a much lower DILI risk than Ligand B (66.615). This is a significant advantage for Ligand A.

**BBB:** Ligand A (92.555) has a much higher BBB penetration score than Ligand B (57.929). While not a primary concern for a non-CNS target like SRC, it's a bonus.

**Caco-2 Permeability:** Ligand A (-4.952) and Ligand B (-5.067) are similar, indicating comparable intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.226) and Ligand B (-2.303) are similar, suggesting comparable solubility.

**hERG Inhibition:** Ligand A (0.615) has a slightly higher hERG risk than Ligand B (0.036). This is a point in favor of Ligand B, but the difference isn't dramatic.

**Microsomal Clearance:** Ligand A (2.927) has significantly lower microsomal clearance than Ligand B (12.599), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-10.68) has a longer in vitro half-life than Ligand B (-13.049), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux than Ligand B (0.028), which is preferable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 1.0 kcal/mol difference, which is significant, but not overwhelming given the 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: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a more favorable TPSA. These factors are particularly important for an enzyme target like SRC kinase, where maintaining adequate systemic exposure is crucial for efficacy. The slightly higher hERG risk for Ligand A is a minor concern compared to the substantial benefits in other areas.

Output:
1
2025-04-17 14:38:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (366.483 and 344.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (77.52 and 78.87) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands (2.57 and 2.157) are 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 (6) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands (0.829 and 0.821) have excellent drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (39.667). This is a significant negative for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.064) and Ligand B (33.385) are both relatively low.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand B (-5.006) is slightly better than Ligand A (-4.869), but both are concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-3.252) is slightly better than Ligand A (-3.389).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.143 and 0.276), which is good.

**12. Microsomal Clearance:** Ligand A (88.536) has significantly higher microsomal clearance than Ligand B (22.211). This suggests Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand B (-19.624) has a much longer in vitro half-life than Ligand A (-1.878). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.171 and 0.063).

**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 a positive for Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands have issues with Caco-2 permeability and solubility, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The slightly improved binding affinity is a bonus. The enzyme-specific priorities heavily favor Ligand B due to its superior pharmacokinetic properties.

Output:
1
2025-04-17 14:38:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (444.738 Da) is slightly higher than Ligand B (384.973 Da), but both are acceptable.

**TPSA:** Ligand A (71.53) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is preferable for potential absorption.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 3.406 and Ligand B at 4.585. Ligand A is better here, as Ligand B is approaching the upper limit where solubility issues can arise.

**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 HBA).

**QED:** Both ligands have good QED scores (A: 0.569, B: 0.747), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a higher DILI risk (85.227%) than Ligand B (36.216%). This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration, but Ligand B (71.733%) is slightly better than Ligand A (69.252%). This isn't a major factor for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close (-4.793 for A, -4.673 for B), so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are similar (-4.45 for A, -4.752 for B).

**hERG Inhibition:** Ligand A (0.21) has a slightly lower hERG risk than Ligand B (0.608), which is a positive.

**Microsomal Clearance:** Ligand A (43.997) has significantly lower microsomal clearance than Ligand B (86.679). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (16.302) has a shorter half-life than Ligand B (41.662), which is less desirable.

**P-gp Efflux:** Ligand A (0.231) has lower P-gp efflux than Ligand B (0.546), which is preferable.

**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 can outweigh some of the ADME drawbacks.

**Overall:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, lower P-gp efflux). Ligand B has a lower DILI risk and a slightly better QED and BBB. The significantly stronger binding affinity of Ligand A, coupled with its better metabolic stability, makes it the more promising candidate despite the slightly higher DILI risk and shorter half-life. The binding affinity difference is large enough to potentially overcome the other drawbacks through further optimization.

Output:
0
2025-04-17 14:38:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.475 and 372.481 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.65) is higher than the preferred <140, but still acceptable. Ligand B (41.57) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.223) is quite low, potentially hindering permeability. Ligand B (2.904) 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:** Ligand A (7) and Ligand B (4) are both acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.644 and 0.799), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (32.338 and 36.138), which is favorable.

**BBB:** Ligand A (29.973) has poor BBB penetration, while Ligand B (91.276) is excellent. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.394) has very poor Caco-2 permeability, which is a significant concern. Ligand B (-4.642) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.813) has poor aqueous solubility. Ligand B (-3.209) is even worse. This is a concern for both, but can be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.088) has very low hERG inhibition risk, which is excellent. Ligand B (0.796) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-15.803) has very low microsomal clearance, indicating high metabolic stability. Ligand B (61.841) has a much higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (31.3) has a reasonable half-life. Ligand B (35.177) is also acceptable.

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is favorable. Ligand B (0.169) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite solubility concerns for both, Ligand B is the more promising candidate. Its superior binding affinity, better logP, excellent BBB penetration (though not critical here), and acceptable ADME properties outweigh the slightly higher P-gp efflux and hERG risk compared to Ligand A. The biggest drawback for Ligand A is its very poor Caco-2 permeability and low logP, which would likely result in poor oral bioavailability. Ligand B's metabolic stability is a concern, but formulation strategies can be explored to address solubility, and metabolic hotspots can be investigated for potential modification.

Output:
1
2025-04-17 14:38:59,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.427 and 344.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.2) is better than Ligand B (59.07). Lower TPSA generally favors better absorption.

**logP:** Ligand A (1.915) is optimal (1-3), while Ligand B (4.147) is pushing the upper limit and could potentially lead to solubility issues or off-target effects.

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

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

**QED:** Both ligands have good QED scores (0.913 and 0.659, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (37.611 and 33.307 percentiles), which is favorable.

**BBB:** Ligand B (82.009) has a better BBB penetration score than Ligand A (50.95), but BBB is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.68) and Ligand B (-4.822) have similar Caco-2 permeability, both are negative values.

**Aqueous Solubility:** Ligand A (-4.139) and Ligand B (-4.432) have similar aqueous solubility, both are negative values.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.616 and 0.863), which is excellent.

**Microsomal Clearance:** Ligand A (38.877 mL/min/kg) has significantly *lower* microsomal clearance than Ligand B (93.748 mL/min/kg). This suggests better metabolic stability for Ligand A, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (38.142 hours) has a much longer in vitro half-life than Ligand A (-13.474 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.614).

**Binding Affinity:** Both ligands have the same binding affinity (-7 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has a longer half-life and better BBB penetration, Ligand A is superior due to its lower logP (reducing potential solubility/off-target issues), and significantly lower microsomal clearance, indicating better metabolic stability. The binding affinity is identical, so the ADME properties become the deciding factor. The lower clearance of Ligand A is a critical advantage for an enzyme inhibitor, as it suggests a longer duration of action and potentially lower dosing requirements.

Output:
0
2025-04-17 14:38:59,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.426 Da) is slightly lower, which is generally favorable for permeability. Ligand B (389.989 Da) is still acceptable.

**TPSA:** Ligand A (84.46) is better than Ligand B (60.77), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.203) is optimal, while Ligand B (4.387) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**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 (0.835) has a significantly better QED score than Ligand B (0.623), indicating a more drug-like profile.

**DILI:** Ligand A (45.638) has a lower DILI risk than Ligand B (13.61), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (88.057) is better than Ligand B (62.117).

**Caco-2 Permeability:** Ligand A (-4.949) is better than Ligand B (-4.655).

**Aqueous Solubility:** Ligand A (-2.58) is better than Ligand B (-3.84).

**hERG Inhibition:** Ligand A (0.549) has a lower hERG risk than Ligand B (0.777), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (20.568) has a significantly lower microsomal clearance than Ligand B (83.811), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.901) has a better in vitro half-life than Ligand B (66.075).

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux liability than Ligand B (0.71).

**Binding Affinity:** Ligand B (0.0) has a slightly better binding affinity than Ligand A (-7.1), but the difference is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall:** Ligand A demonstrates a superior ADMET profile across almost all parameters. While Ligand B has a slightly better binding affinity, Ligand A's better solubility, metabolic stability (lower Cl_mic and longer t1/2), lower toxicity (DILI, hERG), and better overall drug-likeness (QED) make it the more promising drug candidate.

Output:
1
2025-04-17 14:38:59,365 - INFO - Batch 314 complete. Total preferences: 5024
2025-04-17 14:38:59,365 - INFO - Processing batch 315/512...
2025-04-17 14:39:40,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.383 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.3) is slightly higher than Ligand B (78.09), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.714) is within the optimal 1-3 range. Ligand B (2.931) is also within range, but closer to the upper limit.

**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, <=10 HBA).

**QED:** Ligand A (0.871) has a significantly higher QED score than Ligand B (0.709), indicating better overall drug-likeness.

**DILI:** Ligand B (33.114) has a much lower DILI risk than Ligand A (56.223), indicating a safer profile regarding liver toxicity. This is a significant advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 46.336, Ligand B: 55.487). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.84 and -4.999), 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 (-1.607 and -2.5), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.025) has a much lower hERG inhibition risk than Ligand B (0.506), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (-8.769) has a significantly lower (better) microsomal clearance than Ligand B (43.296), indicating greater metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-1.745) has a negative half-life, which is unusual and likely indicates very rapid metabolism. Ligand B (-0.181) is also low, but less so.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.188).

**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 (0.4 kcal/mol).

**Overall Assessment:**

Ligand A has better binding affinity, QED, hERG risk, and metabolic stability. However, Ligand B demonstrates a significantly lower DILI risk. Both have poor solubility and permeability. The difference in binding affinity is not large enough to outweigh the substantial advantage of Ligand B's lower DILI risk and the concerningly rapid metabolism suggested by Ligand A's negative half-life. Given the enzyme-kinase specific priorities, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 14:39:40,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.366 and 359.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.46) is slightly higher than Ligand B (82.53), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.032 and 2.578, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 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 (0.86) has a significantly higher QED score than Ligand A (0.578), suggesting a more drug-like profile.

**DILI:** Ligand A has a DILI risk of 87.282, which is high. Ligand B has a much lower DILI risk of 42.536, which is good.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (51.105) and Ligand B (31.756) both have low BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.118) and Ligand B (-5.3) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-5.691) and Ligand B (-2.853) both have negative solubility values, indicating very poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.34 and 0.28, respectively).

**Microsomal Clearance:** Ligand A (57.527) has a moderate microsomal clearance, while Ligand B (-9.574) has a *negative* clearance, which is not physically possible and likely indicates an issue with the data or prediction method. However, it suggests significantly improved metabolic stability compared to Ligand A.

**In vitro Half-Life:** Ligand A (62.505) has a reasonable half-life, while Ligand B (-0.334) has a negative half-life, which is also not physically possible and reinforces the concern about the data quality for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.327 and 0.054, respectively).

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). However, the difference is relatively small.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, the significantly higher DILI risk and the questionable negative values for clearance and half-life of Ligand B make it a less attractive candidate. Ligand A, while having a moderate DILI risk, has more reasonable ADME properties. However, both compounds have poor solubility and permeability.

Output:
0
2025-04-17 14:39:40,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 353.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.25) is slightly higher than Ligand B (61.44), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.65 and 2.455), 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.907) has a significantly higher QED score than Ligand B (0.799), indicating a more drug-like profile.

**DILI:** Ligand A (56.689) has a higher DILI risk than Ligand B (17.604). This is a significant drawback for Ligand A.

**BBB:** Ligand A (65.413) has a lower BBB penetration percentile than Ligand B (90.772). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.491 and -4.588), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference isn't huge.

**Aqueous Solubility:** Ligand A (-3.819) has worse solubility than Ligand B (-2.462). Solubility is important for bioavailability, favoring Ligand B.

**hERG Inhibition:** Ligand A (0.26) has a lower hERG inhibition risk than Ligand B (0.784). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (49.389) has a higher microsomal clearance than Ligand B (8.098), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-7.992) has a much longer in vitro half-life than Ligand B (-1.919). This is a strong positive for Ligand A.

**P-gp Efflux:** Ligand A (0.392) has slightly higher P-gp efflux than Ligand B (0.146). Lower efflux is preferred, favoring Ligand B.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.992). 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 lower hERG risk, it suffers from higher DILI risk, lower solubility, and higher microsomal clearance. Ligand B has a better overall ADME profile, particularly regarding DILI and metabolic stability, and a slightly better binding affinity. The negative Caco-2 values for both are concerning and would require further investigation, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 14:39:40,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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 (386.489 Da) is also good.

**TPSA:** Ligand A (76.66) is better than Ligand B (42.43). Lower TPSA generally indicates better cell permeability.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.331, Ligand B: 3.672), falling within the 1-3 range. Ligand B is a bit higher, which *could* lead to some 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, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.827, Ligand B: 0.48). Ligand A is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (56.223) has a lower DILI risk than Ligand B (60.411), both are acceptable but A is preferred.

**BBB:** Ligand A (71.811) and Ligand B (94.261) both have good BBB penetration, but B is better. However, BBB isn't a primary concern for an oncology target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.674 and -4.965). This 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 (-3.215 and -4.072), indicating poor solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.46) has a lower hERG risk than Ligand B (0.848), which is a positive.

**Microsomal Clearance:** Ligand A (23.039 mL/min/kg) has a lower microsomal clearance than Ligand B (74.29 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (32.305 hours) has a much longer half-life than Ligand B (-20.14 hours). The negative value for B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux than Ligand B (0.612), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-9.6 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. A difference of 1.2 kcal/mol is quite significant.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme target like SRC kinase. While it has some ADME liabilities (higher logP, higher clearance, shorter half-life, higher P-gp efflux, and poor solubility), the potency advantage is likely to be decisive. Ligand A has better ADME properties overall, but the weaker binding affinity is a significant disadvantage. The negative solubility and Caco-2 values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:39:40,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.4 and 381.8 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.8 and 84.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.71) is optimal, while Ligand B (3.88) is at the higher end, potentially causing solubility issues.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6, both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.658 and 0.728), indicating drug-likeness.

**DILI:** Ligand A (26.5) has a significantly lower DILI risk than Ligand B (98.6), which is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (89.5) than Ligand A (38.2), but this is less important here.

**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:** Ligand A (-1.88) has better solubility than Ligand B (-5.21).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.57 and 0.48).

**Microsomal Clearance:** Ligand B (36.7) has lower microsomal clearance than Ligand A (56.2), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (22.0) has a longer half-life than Ligand A (-24.8), which is a positive attribute.

**P-gp Efflux:** Both have low P-gp efflux liability (0.30 and 0.38).

**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 of the ADME drawbacks.

**Conclusion:**

While Ligand B has a higher logP and a significantly higher DILI risk, its substantially stronger binding affinity (-7.9 vs -6.9 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are compelling advantages for an enzyme target like SRC kinase. The improved affinity is likely to be more impactful than the slightly elevated logP, and the DILI risk, while concerning, could be addressed through structural modifications in subsequent optimization rounds. The solubility of Ligand A is better, but the affinity difference is significant.

Output:
1
2025-04-17 14:39:40,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.416 Da) is slightly higher than Ligand B (349.435 Da), but both are acceptable.

**TPSA:** Ligand A (67.43) is well below the 140 threshold for oral absorption. Ligand B (89.35) is also acceptable, though approaching the upper limit.

**logP:** Ligand A (4.255) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.824) is quite low, which could hinder permeability.

**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 good QED scores (A: 0.55, B: 0.667), indicating generally drug-like properties.

**DILI:** Ligand A (61.225) has a higher DILI risk than Ligand B (45.715), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.531) has a better BBB score than Ligand B (56.534).

**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 (A: -5.211, B: -1.235). This is a significant concern.

**hERG Inhibition:** Ligand A (0.605) has a slightly higher hERG risk than Ligand B (0.076), which is a clear advantage for Ligand B.

**Microsomal Clearance:** Ligand B (24.93 mL/min/kg) has significantly lower microsomal clearance than Ligand A (81.203 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (3.214 hours) has a shorter half-life than Ligand A (21.513 hours), which is less desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.137, B: 0.012), which is good.

**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 is still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has lower logP and a shorter half-life, its significantly lower DILI risk, much better metabolic stability (lower Cl_mic), and lower hERG risk are crucial advantages for an enzyme inhibitor. The slightly better binding affinity of Ligand B further supports this choice. The poor solubility of both compounds is a concern that would need to be addressed through formulation strategies.



Output:
1
2025-04-17 14:39:40,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.406 Da and 384.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (105.39). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Both ligands have good logP values (2.153 and 1.419), falling within the 1-3 range.

**H-Bond Donors:** Both have 2 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 similar QED values (0.855 and 0.818), indicating good drug-likeness.

**DILI:** Ligand A (44.203) has a lower DILI risk than Ligand B (51.105), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (53.432 and 54.13), which is not a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.225) has a worse Caco-2 permeability than Ligand B (-5.282). Lower values indicate lower permeability.

**Solubility:** Ligand A (-2.073) has better solubility than Ligand B (-2.83). Higher values are better.

**hERG:** Ligand A (0.644) has a lower hERG risk than Ligand B (0.102), which is a significant advantage.

**Microsomal Clearance:** Ligand A (26.434) has higher microsomal clearance than Ligand B (-8.168), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-17.278) has a shorter in vitro half-life than Ligand B (-22.783). This is a negative for Ligand A.

**P-gp efflux:** Ligand A (0.279) has lower P-gp efflux than Ligand B (0.032), which is preferable.

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower DILI risk, better solubility, and lower hERG risk. While it has worse Caco-2 permeability, higher clearance, and shorter half-life than Ligand B, the substantial improvement in binding affinity and safety profile (hERG, DILI) outweighs these drawbacks, especially for an enzyme target where potency is crucial. The difference in affinity is >1.5 kcal/mol, making it a strong driver for selection.

Output:
0
2025-04-17 14:39:40,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.467 and 339.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is slightly higher than Ligand B (65.2). Both are acceptable, being under 140, but Ligand B is preferable.

**logP:** Ligand A (2.2) is within the optimal 1-3 range. Ligand B (3.079) 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 2 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA). Ligand B is slightly better due to fewer HBA.

**QED:** Both ligands have good QED scores (0.859 and 0.899), indicating good drug-like properties.

**DILI:** Ligand A (58.976) has a higher DILI risk than Ligand B (47.421). This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a kinase inhibitor, but Ligand B (78.945) has a higher percentile than Ligand A (54.362).

**Caco-2 Permeability:** Both have negative values (-5.358 and -5.016), indicating poor permeability. This is a concern for both, but similar.

**Aqueous Solubility:** Both have negative values (-2.617 and -4.421), indicating poor solubility. Ligand B is slightly better.

**hERG:** Ligand A (0.556) has a slightly lower hERG risk than Ligand B (0.737), which is preferable.

**Microsomal Clearance:** Ligand A (16.828 mL/min/kg) has significantly lower microsomal clearance than Ligand B (44.578 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-6.582 hours) has a longer half-life than Ligand B (-2.784 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.161 and 0.138).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having better DILI and solubility, Ligand A's significantly stronger binding affinity (-9.7 vs -8.1 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are critical for an enzyme inhibitor. The higher affinity is likely to translate to greater efficacy, and the improved metabolic stability will lead to a more favorable pharmacokinetic profile. While the permeability and solubility are concerns for both, the potency and stability advantages of Ligand A are more important for this target class.

Output:
1
2025-04-17 14:39:40,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.419 and 358.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.44) is higher than Ligand B (51.02). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.762) is lower than the optimal range (1-3), potentially hindering permeability. Ligand B (3.541) is within the optimal 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:** Both ligands have similar QED values (0.786 and 0.793), indicating good drug-likeness.

**DILI:** Ligand A (58.395) has a higher DILI risk than Ligand B (26.948). This is a significant advantage for Ligand B.

**BBB:** Ligand A (69.407) and Ligand B (84.839) both have acceptable BBB penetration, but Ligand B is better. This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.431) shows poor Caco-2 permeability, while Ligand B (-4.88) is slightly better.

**Aqueous Solubility:** Ligand A (-1.81) has better aqueous solubility than Ligand B (-3.924). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.36) has a lower hERG risk than Ligand B (0.508), which is desirable.

**Microsomal Clearance:** Ligand B (69.748) has significantly higher microsomal clearance than Ligand A (14.125). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand B (2.107) has a longer half-life than Ligand A (-0.33). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.013) has lower P-gp efflux than Ligand B (0.271), which is favorable.

**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. The difference of 8.4 kcal/mol is substantial and likely outweighs many of the ADME drawbacks.

**Conclusion:**

Despite Ligand B having better ADME properties in several areas (logP, DILI, BBB, t1/2), the dramatically superior binding affinity of Ligand A (-8.4 kcal/mol vs 0.0 kcal/mol) is the deciding factor. A difference of this magnitude suggests a much higher probability of achieving efficacy. While Ligand A's lower Caco-2 permeability and slightly higher DILI are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The strong binding affinity is a critical starting point for a kinase inhibitor.

Output:
0
2025-04-17 14:39:40,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.515 Da) and Ligand B (349.391 Da) are both acceptable.

**TPSA:** Ligand A (70.08) is well below the 140 threshold for good absorption. Ligand B (125.79) is still under 140, but closer to the limit. A favors absorption.

**logP:** Ligand A (0.978) is slightly below the optimal 1-3 range, but acceptable. Ligand B (0.043) is quite low, potentially hindering permeation. A is better.

**H-Bond Donors:** Both ligands are within the acceptable limit of 5. Ligand A (1) and Ligand B (2) are both fine.

**H-Bond Acceptors:** Both ligands are within the acceptable limit of 10. Ligand A (5) and Ligand B (7) are both fine.

**QED:** Both ligands have good QED scores (A: 0.781, B: 0.735), indicating good drug-like properties.

**DILI:** Ligand A (23.149) has a much lower DILI risk than Ligand B (65.762). This is a significant advantage for A.

**BBB:** Ligand A (40.558) and Ligand B (74.564). BBB is less critical for a kinase inhibitor, but B is better.

**Caco-2 Permeability:** Ligand A (-4.911) and Ligand B (-5). Both are very poor, but similar.

**Aqueous Solubility:** Ligand A (-1.733) and Ligand B (-2.403). Both are poor, but B is slightly worse. A is better.

**hERG Inhibition:** Ligand A (0.268) has a very low hERG risk, which is excellent. Ligand B (0.445) is also low, but higher than A. A is better.

**Microsomal Clearance:** Ligand A (16.764) has lower microsomal clearance than Ligand B (25.345), indicating better metabolic stability. This is a key advantage for A.

**In vitro Half-Life:** Ligand A (-5.372) has a much longer in vitro half-life than Ligand B (-21.097). This is a major advantage for A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.081, B: 0.087), which is good.

**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 difference is substantial.

**Overall:**

Ligand A is superior to Ligand B. While both have acceptable MW and QED, Ligand A excels in critical areas for an enzyme inhibitor: significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. Ligand B has a slightly better BBB score, but this is less important for a kinase inhibitor. The substantial difference in binding affinity and the favorable ADME properties of Ligand A make it the much more promising drug candidate.

Output:
1
2025-04-17 14:39:40,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (339.395 and 346.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (54.78) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (97.44) is still under 140, but less optimal than A.

**3. logP:** Ligand A (0.65) is slightly below the optimal range of 1-3, potentially impacting permeability. Ligand B (0.054) is quite low, raising concerns about membrane 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 good QED scores (A: 0.74, B: 0.78), indicating drug-like properties.

**7. DILI:** Ligand A (32.842) has a lower DILI risk than Ligand B (62.001), which is approaching a higher risk category.

**8. BBB:** BBB is not a primary concern for a kinase inhibitor, but Ligand A (62.97) is slightly better than Ligand B (59.325).

**9. Caco-2 Permeability:** Ligand A (-4.341) and Ligand B (-4.82) 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 very poor aqueous solubility (-2.404 and -2.218). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.102, B: 0.059).

**12. Microsomal Clearance (Cl_mic):** Ligand A (10.347) has a higher Cl_mic than Ligand B (-8.197).  Negative Cl_mic is unusual and likely indicates very high metabolic stability. This is a strong advantage for Ligand B.

**13. In vitro Half-Life (t1/2):** Ligand A (8.157) has a reasonable half-life. Ligand B (-18.847) has a very long half-life, which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.025, B: 0.031).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This difference of 2.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Enzyme-Specific Considerations:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and metabolic stability (very long half-life, negative Cl_mic). While both have poor solubility, the superior binding affinity of Ligand B is a major advantage. The slightly higher DILI risk for B is a concern, but the potency difference is likely to be more impactful.

Output:
1
2025-04-17 14:39:40,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.365 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.66) is well below the 140 threshold, while Ligand B (73.74) is still acceptable but higher. Lower TPSA generally favors better cell permeability.

**3. logP:** Ligand A (3.13) is optimal, while Ligand B (1.234) is slightly low, potentially hindering permeability.

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

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range.

**6. QED:** Both ligands have high QED scores (0.85 and 0.871), indicating good drug-like properties.

**7. DILI:** Ligand A (56.805) has a moderate DILI risk, while Ligand B (19.426) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Both have reasonable BBB penetration, but Ligand A is better (96.394 vs 55.487). However, BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, since both are similarly negative, this doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, similar for both.

**11. hERG Inhibition:** Ligand A (0.841) has a slightly higher hERG risk than Ligand B (0.225), which is a significant advantage for B.

**12. Microsomal Clearance:** Ligand A (43.346) has higher microsomal clearance than Ligand B (13.321), indicating lower metabolic stability. This is a crucial drawback for A.

**13. In vitro Half-Life:** Ligand B (-10.098) has a longer in vitro half-life than Ligand A (-12.597), which is a positive.

**14. P-gp Efflux:** Ligand A (0.426) has lower P-gp efflux than Ligand B (0.036), which is a slight advantage.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). While the difference is not huge, it's enough to be meaningful, especially considering the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better BBB penetration and P-gp efflux, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, longer t1/2), and slightly improved binding affinity. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization, but the advantages in safety and PK outweigh this.

Output:
1
2025-04-17 14:39:40,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 360.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have similar TPSA values (57 and 57.69 A^2), well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have logP values (2.381 and 2.457) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 4 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.758 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A (12.253) has a significantly lower DILI risk than Ligand B (27.336). This is a substantial advantage.

**BBB:** Both ligands have high BBB penetration (77.821 and 78.79), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.521 and -4.917), 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:** Ligand A (-0.433) has slightly better solubility than Ligand B (-2.088), although both are quite poor. Solubility is a concern for both, but less so than DILI or metabolic stability.

**hERG Inhibition:** Ligand A (0.528) has a slightly higher hERG risk than Ligand B (0.076). This favors Ligand B.

**Microsomal Clearance:** Ligand A (46.856) has a higher microsomal clearance than Ligand B (32.128), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-8.765) has a significantly longer in vitro half-life than Ligand A (38.252). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.112).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -8.7 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B is the better candidate. While both have good potency and drug-like properties, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The lower hERG risk is also a plus. The solubility is a concern for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 14:39:40,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.535 Da and 369.893 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.02) is well below the 140 threshold, while Ligand B (67.59) is still acceptable but higher.

**logP:** Ligand A (4.062) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.32) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the suggested limits.

**QED:** Both ligands have good QED scores (0.626 and 0.714), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 61.225, which is considered high risk. Ligand B has a much lower DILI risk of 21.908, which is good.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (82.319) has a higher BBB percentile than Ligand A (52.191).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.193 and -4.418), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.226 and -3.164), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.343) has a very low hERG risk, which is excellent. Ligand B (0.509) has a slightly higher but still acceptable hERG risk.

**Microsomal Clearance:** Ligand A (68.15) and Ligand B (60.436) have moderate microsomal clearance values. Lower is better, but these aren't extremely high.

**In vitro Half-Life:** Ligand B (24.494) has a slightly longer in vitro half-life than Ligand A (21.328), which is preferable.

**P-gp Efflux:** Ligand A (0.264) has lower P-gp efflux, which is better. Ligand B (0.524) has higher P-gp efflux.

**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 more promising candidate despite its slightly higher P-gp efflux. Its significantly stronger binding affinity (-8.0 kcal/mol vs 0.0 kcal/mol) is a major advantage. While both have poor Caco-2 and solubility, the lower DILI risk and longer half-life of Ligand B are also favorable. The higher logP of Ligand A is also a concern. The strong binding affinity of Ligand B suggests that solubility issues might be overcome with formulation strategies.

Output:
1
2025-04-17 14:39:40,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.435 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.12) is slightly higher than Ligand B (80.32), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.202) is quite low, potentially hindering permeability. Ligand B (1.922) 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, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.579 and 0.529), indicating drug-like properties.

**DILI:** Ligand A (32.842) has a lower DILI risk than Ligand B (39.511), which is favorable.

**BBB:** Both have similar BBB penetration (55.021 and 56.146), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.383 and -5.264). This is unusual and suggests poor permeability, but the scale is not specified.

**Aqueous Solubility:** Both have negative solubility values (-0.849 and -1.411). This is also unusual and suggests poor solubility, but the scale is not specified.

**hERG:** Ligand A (0.151) has a lower hERG risk than Ligand B (0.452), which is a significant advantage.

**Microsomal Clearance:** Ligand A (8.107) has significantly lower microsomal clearance than Ligand B (12.189), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.473) has a longer half-life than Ligand B (-0.923), which is highly desirable.

**P-gp Efflux:** Ligand A (0.014) has lower P-gp efflux than Ligand B (0.092), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), a difference of 0.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a better logP and slightly better affinity, Ligand A demonstrates superior ADME properties. Specifically, its lower hERG risk, significantly lower microsomal clearance, longer half-life, and lower P-gp efflux are crucial for a viable drug candidate, especially for an enzyme target where metabolic stability and minimizing off-target effects are paramount. The slightly lower affinity of Ligand A can potentially be optimized in subsequent iterations. The unusual negative values for Caco-2 and solubility are concerning, but the other ADME properties of Ligand A are more compelling.

Output:
0
2025-04-17 14:39:40,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.439 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.89) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (79.54) is excellent, well below 140.

**logP:** Both ligands (2.782 and 2.217) are 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:** Ligand A has 5 HBA, acceptable. Ligand B has 6 HBA, also acceptable.

**QED:** Ligand B (0.787) has a significantly better QED score than Ligand A (0.431), indicating a more drug-like profile.

**DILI:** Ligand A (42.885) has a slightly better DILI risk profile than Ligand B (52.191), but both are acceptable (<60).

**BBB:** Both ligands have good BBB penetration (69.407 and 76.464), but this is less critical for a non-CNS target like SRC.

**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 risk (0.196 and 0.282), which is excellent.

**Microsomal Clearance:** Ligand B (25.908 mL/min/kg) has significantly lower microsomal clearance than Ligand A (37.852 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.935 hours) has a much longer half-life than Ligand A (0.4 hours), a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.017 and 0.121), which is good.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), but the difference is relatively small (0.2 kcal/mol).

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is the superior candidate overall. Its significantly better QED score, lower microsomal clearance, and substantially longer half-life outweigh the minor difference in binding affinity. The solubility and permeability issues of both are concerning, but the ADME properties of Ligand B are more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 14:39:40,934 - INFO - Batch 315 complete. Total preferences: 5040
2025-04-17 14:39:40,934 - INFO - Processing batch 316/512...
2025-04-17 14:40:21,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (445.766 Da) is higher, but still acceptable. Ligand B (351.363 Da) is slightly better.

**TPSA:** Ligand A (53.01) is excellent, well below the 140 threshold. Ligand B (115.65) is higher, but still reasonable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.193) is at the upper end of the optimal range, potentially leading to solubility issues. Ligand B (-0.725) is too low, which could hinder membrane permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, within the acceptable range. Ligand B has 8 HBA, also acceptable, but approaching the upper limit.

**QED:** Both ligands have similar QED values (0.748 and 0.711), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (77.433 and 76.425), indicating a moderate risk. This isn't a major differentiator.

**BBB:** Both ligands have reasonably high BBB penetration (58.511 and 70.415). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.95 and -4.999), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.746 and -2.712), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.512) has a slightly higher hERG risk than Ligand B (0.042). Ligand B is much better in this regard.

**Microsomal Clearance:** Ligand A (37.64) has a higher microsomal clearance than Ligand B (25.226), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (-10.609) has a significantly longer in vitro half-life than Ligand A (-4.501), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.238 and 0.045).

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A's primary advantage is its much stronger binding affinity. However, it suffers from higher logP (potential solubility issues) and higher microsomal clearance (lower metabolic stability) compared to Ligand B. Both ligands have poor solubility and permeability. Ligand B has a better safety profile (lower hERG) and better metabolic stability.

Despite the solubility/permeability concerns for both, the significantly stronger binding affinity of Ligand A is a critical factor for an enzyme inhibitor. The potency advantage is likely to outweigh the ADME drawbacks, *provided* formulation strategies can be developed to address the solubility issue.

Output:
1
2025-04-17 14:40:21,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.32) is significantly better than Ligand B (95.5). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (1.156) is within the optimal 1-3 range. Ligand B (-0.293) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have similar HBD (0/1) and HBA (5/5) counts, which are acceptable.

**QED:** Both ligands have a QED of 0.74, indicating good drug-likeness.

**DILI:** Ligand A (16.44) has a much lower DILI risk than Ligand B (64.754). This is a significant advantage for A.

**BBB:** Ligand A (69.678) has better BBB penetration than Ligand B (53.276), although SRC is not a CNS target, so this is a minor consideration.

**Caco-2 Permeability:** Ligand A (-4.939) is worse than Ligand B (-4.503), but both are negative and suggest poor permeability.

**Aqueous Solubility:** Ligand A (-0.733) is better than Ligand B (-1.317), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.295) has a lower hERG risk than Ligand B (0.139), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (1.561) has significantly lower microsomal clearance than Ligand B (57.778), indicating better metabolic stability. This is a key advantage for A.

**In vitro Half-Life:** Ligand A (-0.396) has a better in vitro half-life than Ligand B (-39.491).

**P-gp Efflux:** Ligand A (0.013) has lower P-gp efflux than Ligand B (0.024).

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the superior candidate. While both have excellent binding affinity, Ligand A demonstrates significantly better ADME-Tox properties: lower DILI risk, better solubility, lower hERG inhibition, and significantly improved metabolic stability (lower Cl_mic and better half-life). The slightly lower Caco-2 permeability of A is a concern, but is outweighed by the other substantial advantages.

Output:
1
2025-04-17 14:40:21,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.379 and 343.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (79.9) is better than Ligand B (93.26). Both are below 140, indicating reasonable absorption potential.

**logP:** Ligand A (2.598) is optimal, while Ligand B (1.439) is slightly lower but still acceptable.

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

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), both are within the ideal range of <=10.

**QED:** Both ligands have good QED scores (0.536 and 0.848), suggesting good drug-like properties. Ligand B is better.

**DILI:** Ligand A (75.96) has a higher DILI risk than Ligand B (58.511). Ligand B is preferable.

**BBB:** Ligand A (42.148) is lower than Ligand B (68.941). Since SRC is not a CNS target, this is less critical, but a higher value is generally preferred.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.074 and -5.131), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.906 and -2.552), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.76) has a slightly higher hERG risk than Ligand B (0.159). Ligand B is preferable.

**Microsomal Clearance:** Ligand A (26.209) has lower microsomal clearance than Ligand B (30.541), indicating better metabolic stability. Ligand A is preferable.

**In vitro Half-Life:** Ligand A (-12.49) has a longer half-life than Ligand B (-21.478). Ligand A is preferable.

**P-gp Efflux:** Ligand A (0.236) has lower P-gp efflux than Ligand B (0.054), indicating better bioavailability. Ligand A is preferable.

**Binding Affinity:** Ligand B (-8.6 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 has a significantly better binding affinity (-8.6 vs -6.7 kcal/mol). While Ligand A has better metabolic stability and half-life, the strong binding of Ligand B is a critical advantage for an enzyme inhibitor. Ligand B also has a lower DILI and hERG risk. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:40:21,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (350.419 and 365.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.97) is better than Ligand B (82.68), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (-0.731) is slightly low, potentially hindering permeation. Ligand B (1.359) is within the optimal 1-3 range. This favors Ligand B.

**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 (9) is at the upper limit, but still acceptable.

**6. QED:** Both ligands have good QED scores (0.567 and 0.756, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (18.883) has a significantly lower DILI risk than Ligand B (59.829). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for an oncology target unless CNS penetration is specifically desired. Ligand B (54.711) is higher than Ligand A (43.001), but not a deciding factor here.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.287 and -5.819), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-1.076 and -1.783), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have very low hERG risk (0.138 and 0.084).

**12. Microsomal Clearance:** Ligand A (-47.926) has a much lower (better) microsomal clearance than Ligand B (20.555), indicating greater metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (2.979) has a shorter half-life than Ligand B (22.518). This favors Ligand B.

**14. P-gp:** Both ligands have very low P-gp efflux liability (0.003 and 0.106).

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.5), a 0.7 kcal/mol difference. This is a notable advantage for Ligand B, and could potentially outweigh some of the ADME concerns.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and half-life, Ligand A demonstrates superior safety (DILI) and metabolic stability (Cl_mic). The poor solubility and Caco-2 permeability are concerning for both, but the lower DILI risk and better metabolic stability of Ligand A are more critical for an oncology kinase inhibitor. The slight advantage in binding affinity of Ligand B is not enough to overcome these significant ADME drawbacks.

Output:
0
2025-04-17 14:40:21,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.403 and 369.466 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (92.18 and 95.04) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (target <90). This isn't a primary concern for a non-CNS target like SRC.

**logP:** Ligand A (3.151) is optimal, while Ligand B (1.555) is slightly lower, potentially impacting permeability.

**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 (0.71 and 0.699), indicating good drug-likeness.

**DILI:** Ligand A (94.804 percentile) has a significantly higher DILI risk than Ligand B (35.789 percentile). This is a major concern.

**BBB:** This is less important for SRC, but Ligand B (65.839) has a higher BBB penetration than Ligand A (22.993).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.485 and -5.137) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.171 and -2.003), indicating very poor aqueous solubility, a significant drawback.

**hERG Inhibition:** Ligand A (0.028) shows very low hERG inhibition risk, while Ligand B (0.392) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-3.565 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (8.022 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.605 hours) has a shorter half-life than Ligand B (-2.376 hours), but both are negative, indicating a very short half-life.

**P-gp Efflux:** Ligand A (0.023) shows very low P-gp efflux liability, while Ligand B (0.175) is slightly higher.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). The difference is 1.1 kcal/mol, which is not substantial enough to overcome other significant issues.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its significantly higher DILI risk and poor solubility are major drawbacks. Ligand B, while having a slightly lower affinity, presents a much better safety profile (lower DILI) and comparable metabolic stability. Both ligands have poor solubility and permeability. However, the DILI risk associated with Ligand A is a deal-breaker. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 14:40:21,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.352 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 88-89 A^2, which is acceptable for oral absorption, though not optimal for CNS penetration (not a priority here).

**logP:** Both ligands have logP values around 2.8, falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which is within the acceptable limits.

**QED:** Both ligands have QED scores > 0.7, indicating good drug-likeness.

**DILI:** Ligand A (76.968) has a significantly higher DILI risk than Ligand B (54.323). This is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (79.566) than Ligand A (52.889), but this is less important.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.419) is slightly worse than Ligand B (-4.668).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.956) is slightly worse than Ligand B (-2.938).

**hERG:** Both ligands have low hERG inhibition liability (0.611 and 0.247 respectively), which is good. Ligand B is better here.

**Microsomal Clearance:** Ligand A (27.121 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (49.669 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.642 hours) has a significantly longer half-life than Ligand B (6.587 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.207 and 0.057 respectively), which is good. Ligand B is better here.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 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, longer t1/2) but suffers from higher DILI risk and slightly poorer solubility and permeability. Ligand B has better DILI, permeability, solubility, and P-gp efflux, but weaker binding affinity and poorer metabolic stability.

Given the priorities for enzyme inhibitors, the binding affinity is crucial. The 0.5 kcal/mol difference in binding affinity for Ligand A is substantial. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The improved metabolic stability (longer half-life) is also a significant advantage. The solubility and permeability issues are also addressable during optimization.

Output:
1
2025-04-17 14:40:21,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.37 and 344.46 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have similar logP values (1.765 and 1.801), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 3. Lower HBA counts generally improve permeability, favoring Ligand B.

**QED:** Ligand A (0.812) has a significantly higher QED score than Ligand B (0.454), suggesting a more drug-like profile overall.

**DILI:** Ligand A (69.252) has a higher DILI risk than Ligand B (14.696). This is a substantial difference, and a lower DILI risk is highly desirable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (71.772) is slightly better than Ligand B (58.86). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.047) has a worse Caco-2 permeability than Ligand B (-5.091).

**Aqueous Solubility:** Ligand A (-3.766) has a worse aqueous solubility than Ligand B (-2.257). Solubility is important for formulation and bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.376 and 0.166), which is excellent.

**Microsomal Clearance:** Ligand A (8.434) has a lower microsomal clearance than Ligand B (39.77), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (38.03) has a better in vitro half-life than Ligand B (-31.12). This further supports the better metabolic stability of Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.091).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a 1.7 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better ADME properties (lower DILI, better solubility, lower TPSA, better Caco-2 permeability) despite a lower QED score. The significantly stronger binding affinity of Ligand B is a major advantage for an enzyme inhibitor, and the improvements in ADME properties are also beneficial. While Ligand A has better metabolic stability and half-life, the potency advantage of Ligand B is more critical in this case.

Output:
1
2025-04-17 14:40:21,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (432.265 Da) is slightly higher, but acceptable. Ligand B (361.389 Da) is also good.

**TPSA:** Ligand A (57.78) is excellent, well below the 140 threshold for oral absorption. Ligand B (89.95) is still reasonable, but less optimal.

**logP:** Ligand A (4.687) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-0.164) is quite low, which could hinder membrane permeability and bioavailability.

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

**QED:** Both ligands have similar, good QED values (0.629 and 0.659).

**DILI:** Ligand A (85.537) has a significantly higher DILI risk than Ligand B (27.918). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.2) is better than Ligand B (57.193).

**Caco-2 Permeability:** Ligand A (-5.106) has poor predicted Caco-2 permeability, while Ligand B (-4.943) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.395) has very poor predicted solubility, which is a significant drawback. Ligand B (-0.899) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.779) has a slightly higher hERG risk than Ligand B (0.19).

**Microsomal Clearance:** Ligand B (-16.738) has much lower (better) microsomal clearance than Ligand A (33.553), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.409) has a longer predicted half-life than Ligand A (50.13), which is desirable.

**P-gp Efflux:** Ligand A (0.633) has slightly higher P-gp efflux than Ligand B (0.011), which is less favorable.

**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:**

Ligand A has a much higher binding affinity, which is a key advantage for an enzyme inhibitor. However, it suffers from poor solubility, high DILI risk, and moderate metabolic clearance. Ligand B, while having a weaker binding affinity, exhibits a much better safety profile (lower DILI, lower hERG), better metabolic stability, and a longer half-life.

The difference in binding affinity (1.5 kcal/mol) is significant, but the poor ADME properties of Ligand A, particularly the high DILI risk and poor solubility, are major concerns. While optimization could potentially address these issues, starting with a molecule with a better initial ADME profile is often more efficient.

Output:
1
2025-04-17 14:40:21,191 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (341.37 & 350.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (99.69 & 92.59) are below the 140 A^2 threshold for good absorption, but not particularly optimized for CNS penetration (not a priority here).

**3. logP:** Ligand A (0.796) is within the optimal range (1-3), while Ligand B (-0.341) is slightly below, potentially hindering permeation.

**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 7 respectively), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.838 and 0.689), indicating drug-like properties.

**7. DILI:** Ligand A (53.01%) has a higher DILI risk than Ligand B (28.31%), which is preferable.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (65.45%) has a higher BBB score than Ligand A (26.72%), but this is less important.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.904) is slightly better than Ligand B (-5.783).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-0.871) is slightly better than Ligand A (-2.316).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.233 and 0.075), which is excellent.

**12. Microsomal Clearance:** Both ligands have similar, very low, microsomal clearance (-17.033 and -17.549 mL/min/kg), indicating good metabolic stability.

**13. In vitro Half-Life:** Ligand B (19.304 hours) has a significantly longer half-life than Ligand A (-14.33 hours), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.003).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). This 1.7 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better solubility and a significantly longer half-life, Ligand A boasts a superior binding affinity. The slightly higher DILI risk for Ligand A is a concern, but the difference isn't drastic. The negative Caco-2 and solubility values for both are concerning, but the strong binding affinity of Ligand A makes it more likely to be optimized to overcome these issues. The longer half-life of Ligand B is attractive, but the potency advantage of Ligand A is more critical for an enzyme target like SRC.

Output:
1
2025-04-17 14:40:21,191 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.815 and 365.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is slightly higher than Ligand B (58.48), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.336 and 2.275), 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.75 and 0.681), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 57.193, which is moderate. Ligand B has a significantly lower DILI risk of 14.696, which is excellent. This is a major advantage for Ligand B.

**BBB:** Both ligands have high BBB penetration (87.67 and 91.198), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.467 and -4.389), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.545 and -2.615), indicating poor aqueous solubility. This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.639 and 0.604), which is favorable.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (47.612) than Ligand B (10.232). This suggests Ligand B is more metabolically stable, a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (17.003 hours) than Ligand A (8.086 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.179 and 0.172).

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-8.7 kcal/mol) compared to Ligand A (-6.2 kcal/mol). This >1.5 kcal/mol difference in affinity is a substantial advantage, potentially outweighing some of the ADME concerns.

**Conclusion:**

While both ligands have some ADME liabilities (poor solubility and permeability), Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the shared solubility/permeability issues. The strong binding affinity is particularly important for an enzyme inhibitor.

Output:
1
2025-04-17 14:40:21,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (348.403 and 339.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (102.32 and 102.92) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (-0.155) is quite low, potentially hindering permeation. Ligand B (1.324) 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.

**H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (8) is also acceptable.

**QED:** Both ligands have good QED scores (0.636 and 0.757), indicating good drug-like properties.

**DILI:** Ligand A (59.907) has a moderate DILI risk, while Ligand B (68.786) has a slightly higher risk. Both are below the concerning >60 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.911) is slightly better than Ligand A (47.809).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.31 and -4.734), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.947 and -3.94). This is also concerning, indicating very poor solubility.

**hERG Inhibition:** Ligand A (0.084) has a very low hERG risk, which is excellent. Ligand B (0.308) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (3.687) has significantly lower microsomal clearance than Ligand B (50.427), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (8.184) has a reasonable half-life, while Ligand B (-8.322) has a negative half-life, which is not physically possible and suggests a problem with the data or the molecule's stability.

**P-gp Efflux:** Ligand A (0.024) has very low P-gp efflux, which is good. Ligand B (0.076) is also low.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage (1.7 kcal/mol difference) that can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most critical factor for an enzyme inhibitor. However, its significantly higher microsomal clearance and negative in vitro half-life are major concerns. The logP of Ligand A is suboptimal, but its much better metabolic stability (lower Cl_mic, positive t1/2) and very low hERG risk make it the more promising candidate. The solubility and permeability issues are shared by both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 14:40:21,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.326 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (125.87) is borderline, potentially impacting oral absorption. Ligand B (68.87) is well below the 140 threshold and is preferable.

**logP:** Ligand A (-1.22) is a bit low, potentially hindering permeation. Ligand B (3.018) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=3, HBA=6) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (0.697 and 0.672), indicating good drug-likeness.

**DILI:** Ligand A (78.713) has a higher DILI risk than Ligand B (66.15), though both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.9) has better BBB penetration, but it's not a deciding factor here.

**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 may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern for both compounds.

**hERG:** Ligand A (0.09) has a slightly lower hERG risk than Ligand B (0.909), which is preferable.

**Microsomal Clearance:** Ligand A (0.989) has significantly lower microsomal clearance than Ligand B (44.085), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-22.908) has a negative half-life, which is not possible. This is a red flag. Ligand B (39.601) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is good. Ligand B (0.186) is also acceptable.

**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, and could potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP, TPSA, and binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux. The negative half-life for Ligand A is a serious issue, indicating a problem with the data or the compound itself. While the binding affinity of Ligand A is slightly better, the metabolic stability and efflux profile of Ligand A are appealing. However, the negative half-life is a showstopper.

Output:
1
2025-04-17 14:40:21,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (368.503 and 362.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.46) is significantly better than Ligand B (102.32).  A TPSA under 90 is preferred, and A is closer to this threshold.

**3. logP:** Ligand A (1.29) is within the optimal range (1-3), while Ligand B (0.399) is slightly below, which *could* indicate permeability issues.

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

**5. H-Bond Acceptors:** Ligand A (6) is good, while Ligand B (7) is acceptable.

**6. QED:** Both ligands have similar and good QED values (0.734 and 0.774, respectively).

**7. DILI:** Ligand A (35.285) has a much lower DILI risk than Ligand B (79.604). This is a significant advantage for Ligand A.

**8. BBB:** Both have similar BBB penetration (56.65 and 52.617), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.107 and -4.957). This is unusual and suggests poor permeability. However, these values are on the same scale, so the difference is not decisive.

**10. Aqueous Solubility:** Both have negative solubility values (-1.392 and -3.031). Again, both are poor, and the difference isn't decisive.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.158 and 0.16).

**12. Microsomal Clearance:** Ligand A (55.223) has a higher microsomal clearance than Ligand B (17.89). This means Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (8.592) has a significantly longer half-life than Ligand A (-3.446). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.094 and 0.06).

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.5). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), the significantly lower DILI risk and better TPSA of Ligand A, coupled with its superior binding affinity, make it the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of A is substantial. The DILI risk of Ligand B is quite high, which is a major red flag.

Output:
0
2025-04-17 14:40:21,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.327 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (383.857 Da) is still well within the acceptable range.

**TPSA:** Ligand B (92.51) is significantly better than Ligand A (126.48). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have good logP values (A: 0.978, B: 1.995), falling within the optimal 1-3 range. Ligand B is slightly better.

**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, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.717, B: 0.852), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have relatively high DILI risk (A: 79.527, B: 84.335). This is a concern, but we'll consider it in the context of other properties.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (65.064) has a slightly better BBB score than Ligand B (53.625).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.957) is slightly better than Ligand B (-5.069).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.035) is slightly better than Ligand B (-4.098).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.303, B: 0.331), which is excellent.

**Microsomal Clearance:** Ligand A (31.915 mL/min/kg) has significantly lower microsomal clearance than Ligand B (69.124 mL/min/kg). This suggests better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (38.007 hours) has a much longer half-life than Ligand B (-20.129 hours). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.101, B: 0.245).

**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 of the ADME drawbacks. A difference of 1.6 kcal/mol is significant.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better permeability/solubility, the significantly stronger binding affinity of Ligand B (-8.9 vs -7.3 kcal/mol) is the deciding factor. For an enzyme target like a kinase, potency is paramount. The improved affinity of Ligand B is likely to outweigh the slightly higher metabolic clearance and lower half-life, especially if further optimization can address those issues. The DILI risk is a concern for both, but can be addressed in later stages of development.

Output:
1
2025-04-17 14:40:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.32 Da) is slightly higher than Ligand B (367.475 Da), but both are acceptable.

**TPSA:** Ligand A (130.88) is borderline for good oral absorption, while Ligand B (80.56) is well within the optimal range (<140). This favors Ligand B.

**logP:** Ligand A (2.051) is within the optimal range (1-3). Ligand B (0.258) is quite low, potentially hindering permeability. This favors Ligand A.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 7 HBA, which is within the acceptable range (<=10).

**QED:** Ligand B (0.759) has a better QED score than Ligand A (0.428), indicating a more drug-like profile. This favors Ligand B.

**DILI:** Ligand A (88.057) has a higher DILI risk than Ligand B (68.825), indicating a potential liver toxicity concern. This favors Ligand B.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (64.637) is slightly higher than Ligand A (39.977).

**Caco-2 Permeability:** Ligand A (-5.457) has poor Caco-2 permeability, while Ligand B (-4.966) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4 and -1.792 respectively). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.621) has a higher hERG inhibition liability than Ligand B (0.127). This favors Ligand B significantly, as cardiotoxicity is a major concern.

**Microsomal Clearance:** Ligand B (38.349) has a lower microsomal clearance than Ligand A (11.766), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (52.257) has a longer half-life than Ligand B (0.558). This favors Ligand A.

**P-gp Efflux:** Ligand A (0.166) has lower P-gp efflux than Ligand B (0.085), which is slightly favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a major advantage for Ligand B, and can outweigh some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**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 (-9.1 vs -7.5 kcal/mol), lower DILI risk, lower hERG inhibition, and better metabolic stability. The improved binding affinity is a critical advantage for an enzyme inhibitor, and the reduced toxicity risks are highly desirable. The lower logP is a concern, but might be mitigated with formulation strategies.

Output:
1
2025-04-17 14:40:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.463 and 356.442 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.1) is significantly better than Ligand B (96.25).  A TPSA under 140 is good for oral absorption, and A is closer to the ideal.

**3. logP:** Both ligands have acceptable logP values (0.962 and 1.335, respectively), 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 the same number of HBA (5), which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.666 and 0.655), indicating good drug-likeness.

**7. DILI:** Ligand A (15.859) has a much lower DILI risk than Ligand B (38.348). This is a significant advantage.

**8. BBB:** Ligand A (73.129) has a better BBB penetration score than Ligand B (64.831), though BBB isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.462) has better Caco-2 permeability than Ligand B (-4.976).

**10. Aqueous Solubility:** Ligand A (-0.634) has better solubility than Ligand B (-1.93). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.204) has a lower hERG inhibition risk than Ligand B (0.324). This is a crucial safety parameter.

**12. Microsomal Clearance:** Ligand A (27.836) has lower microsomal clearance than Ligand B (33.686), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.666) has a better in vitro half-life than Ligand B (-1.174).

**14. P-gp Efflux:** Ligand A (0.01) has lower P-gp efflux than Ligand B (0.046).

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-6.9). This is a 1.4 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better across almost all ADMET properties. The lower DILI, hERG, and Cl_mic, combined with better solubility, permeability, and half-life, make Ligand A a much more promising drug candidate. The 1.4 kcal/mol difference in binding affinity is unlikely to outweigh the substantial improvements in safety and pharmacokinetic properties offered by Ligand A. For an enzyme target like SRC kinase, metabolic stability, solubility, and safety are paramount.

Output:
0
2025-04-17 14:40:21,193 - INFO - Batch 316 complete. Total preferences: 5056
2025-04-17 14:40:21,193 - INFO - Processing batch 317/512...
2025-04-17 14:41:08,587 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [385.819, 55.4, 4.854, 1, 4, 0.748, 84.064, 77.472, -4.538, -6.128, 0.37, 85.406, 20.323, 0.18, -10.1]
**Ligand B:** [343.471, 75.43, 3.126, 2, 3, 0.59, 45.095, 80.962, -5.109, -3.624, 0.713, 55.183, 2.271, 0.188, -7.1]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (343.471) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** Ligand A (55.4) is better than Ligand B (75.43). Lower TPSA generally means better absorption.
3. **logP:** Ligand A (4.854) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (3.126) is within the optimal range.
4. **HBD:** Both are acceptable (Ligand A: 1, Ligand B: 2), well below the threshold of 5.
5. **HBA:** Both are acceptable (Ligand A: 4, Ligand B: 3), well below the threshold of 10.
6. **QED:** Ligand A (0.748) is better than Ligand B (0.59), indicating a more drug-like profile.
7. **DILI:** Ligand A (84.064) has a significantly higher DILI risk than Ligand B (45.095). This is a major concern.
8. **BBB:** Both have good BBB penetration (Ligand A: 77.472, Ligand B: 80.962). Not a primary concern for SRC kinase, but a bonus.
9. **Caco-2:** Ligand A (-4.538) is worse than Ligand B (-5.109), indicating lower intestinal absorption.
10. **Solubility:** Ligand A (-6.128) is worse than Ligand B (-3.624), which is a concern given its higher logP.
11. **hERG:** Ligand A (0.37) is better than Ligand B (0.713), indicating lower cardiotoxicity risk.
12. **Cl_mic:** Ligand A (85.406) has a higher microsomal clearance than Ligand B (55.183), suggesting lower metabolic stability.
13. **t1/2:** Ligand A (20.323) has a longer half-life than Ligand B (2.271), which is desirable.
14. **Pgp:** Both are similar (Ligand A: 0.18, Ligand B: 0.188), indicating similar P-gp efflux liability.
15. **Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has superior affinity and half-life, but suffers from poor solubility, high DILI risk, and high clearance. Ligand B has better solubility, lower DILI, and better clearance, but weaker affinity.

**Decision:**

The difference in binding affinity (-10.1 vs -7.1 kcal/mol) is very large. While Ligand A has concerning ADME properties (high DILI, poor solubility, high clearance), the substantial improvement in potency is likely to outweigh these drawbacks *initially*. Optimization efforts could then focus on improving the ADME profile of Ligand A.

Therefore, I would select **Ligand A** as the more promising starting point for drug development.

1
2025-04-17 14:41:08,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.39 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (89.27), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.376 and 1.512), 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 (4 and 3 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have high QED scores (0.855 and 0.868), indicating good drug-likeness.

**DILI:** Ligand A (36.603) has a significantly lower DILI risk than Ligand B (56.689). This is a major advantage.

**BBB:** Ligand A (74.796) has a better BBB penetration score than Ligand B (51.415), though BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.106) shows better Caco-2 permeability than Ligand B (-4.846).

**Aqueous Solubility:** Ligand A (-3.024) has slightly better aqueous solubility than Ligand B (-2.524).

**hERG:** Both ligands have very low hERG inhibition liability (0.545 and 0.415), which is excellent.

**Microsomal Clearance:** Ligand A (15.357) has significantly lower microsomal clearance than Ligand B (27.339), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.099) has a significantly longer in vitro half-life than Ligand B (-25.571). This is a critical advantage for kinase inhibitors.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.14).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all other crucial ADMET properties. The lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility of Ligand A are significant advantages for a kinase inhibitor. The 1.2 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand A, while mitigating the ADMET liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 14:41:08,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.861 and 357.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (29.54). While both are reasonably low, Ligand B is exceptionally low, which *could* indicate a lack of necessary interactions.

**logP:** Ligand A (2.008) is optimal, while Ligand B (4.978) is high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, which is also acceptable, but potentially less favorable for aqueous solubility.

**QED:** Ligand A (0.774) has a better QED score than Ligand B (0.516), indicating better overall drug-likeness.

**DILI:** Ligand A (34.703) has a lower DILI risk than Ligand B (19.969), which is a significant advantage.

**BBB:** Ligand A (66.615) has a lower BBB penetration than Ligand B (90.849). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.916) and Ligand B (-4.409) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.916) and Ligand B (-4.596) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.369) has a lower hERG risk than Ligand B (0.809), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (14.471) has a much lower microsomal clearance than Ligand B (54.911), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.478) has a negative half-life, which is concerning. Ligand B (24.166) has a positive half-life, which is much better.

**P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.567), which is favorable.

**Binding Affinity:** Both ligands have similar binding affinities (-8.8 and -8.3 kcal/mol), which are both excellent. The difference of 0.5 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A is superior despite the negative half-life. It has a better QED score, lower DILI risk, lower hERG risk, and significantly better metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the improved safety profile and metabolic stability of Ligand A outweigh the slightly better half-life of Ligand B. The negative half-life of Ligand A is a concern that would need to be addressed in further optimization, but it's not a deal-breaker at this stage.

Output:
0
2025-04-17 14:41:08,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 358.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.19) is higher than Ligand B (61.92). While both are reasonably low, Ligand B is significantly better, suggesting better permeability.

**logP:** Ligand A (0.526) is quite low, potentially hindering permeability. Ligand B (3.384) 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 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.651 and 0.749), indicating drug-like properties.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (17.914), but both are below the concerning threshold of 60.

**BBB:** Ligand A (40.093) has low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (75.611) has good BBB penetration, but this is less relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.33 and -5.166), which 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 (-2.517 and -3.157), indicating poor aqueous solubility, which is a concern.

**hERG Inhibition:** Ligand A (0.157) has a slightly better hERG profile than Ligand B (0.601).

**Microsomal Clearance:** Ligand A (-4.665) has significantly *lower* (better) microsomal clearance than Ligand B (59.122). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-15.438) has a longer half-life than Ligand B (-23.568), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, while Ligand B (0.19) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.7) has a *much* stronger binding affinity than Ligand B (0.0). This is a decisive factor. A difference of 8.7 kcal/mol is substantial.

**Conclusion:**

Despite the poor solubility and permeability indicated by the Caco-2 and solubility values, Ligand A is the superior candidate due to its significantly stronger binding affinity (-8.7 kcal/mol vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic and longer half-life). The affinity difference outweighs the drawbacks in solubility and permeability, especially for an enzyme target where potency is paramount.

Output:
0
2025-04-17 14:41:08,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.471 and 355.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (85.4), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.577 and 1.716), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (3 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have QED values above 0.5 (0.796 and 0.685), indicating good drug-likeness.

**DILI:** Ligand A (21.171) has a much lower DILI risk than Ligand B (35.983), which is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand B (92.71) shows higher BBB penetration than Ligand A (76.658). This is not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.695) shows better Caco-2 permeability than Ligand B (-4.489).

**Aqueous Solubility:** Ligand A (-2.548) has slightly better aqueous solubility than Ligand B (-2.835).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.258 and 0.192).

**Microsomal Clearance:** Ligand B (38.228) has a higher microsomal clearance than Ligand A (48.191), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (20.646) has a much longer in vitro half-life than Ligand B (-4.703), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.07 and 0.023).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly better binding affinity than Ligand B (-7.1 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It exhibits a significantly better binding affinity, lower DILI risk, better Caco-2 permeability, better solubility, and a longer in vitro half-life, all crucial for an enzyme inhibitor. While Ligand B has slightly better BBB penetration, this is not a priority for SRC kinase, which is not a CNS target. The superior potency and ADME properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 14:41:08,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.344 and 367.852 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (56.15 and 58.1) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.866 and 3.729) within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but not dramatically.

**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 (0.92 and 0.723), indicating drug-like properties.

**DILI:** Ligand A has a higher DILI risk (60.644) than Ligand B (47.732). This is a significant concern, as DILI is a major cause of drug attrition.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (89.608) has better BBB penetration than Ligand B (74.292).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.437 and -4.628), which is unusual and suggests poor permeability. This is a major red flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.721 and -4.646), also unusual and indicating very poor solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.638) has a slightly lower hERG risk than Ligand B (0.931), which is preferable.

**Microsomal Clearance:** Ligand A (39.924) has lower microsomal clearance than Ligand B (50.588), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (24.679 hours) has a significantly longer half-life than Ligand A (10.944 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.596 and 0.798).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.3 vs -9.6 kcal/mol) is a major driver. It also has a longer half-life and lower DILI risk compared to Ligand A. While the slightly higher logP of Ligand B is a minor concern, the substantial improvement in binding affinity and the better safety profile outweigh this. The poor permeability and solubility would need to be addressed through formulation strategies or further chemical modifications, but the core potency and metabolic stability are better with Ligand B.

Output:
1
2025-04-17 14:41:08,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.395 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.66) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (130.67) is still acceptable, but less optimal.

**logP:** Ligand A (1.663) is within the optimal 1-3 range. Ligand B (-0.68) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and acceptable HBA counts (4 and 7 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have QED values above 0.5 (0.678 and 0.556), indicating good drug-like properties.

**DILI:** Ligand A (63.397) has a slightly higher DILI risk than Ligand B (58.55), but both are still within an acceptable range (<60 is good).

**BBB:** Both ligands have moderate BBB penetration (60.566 and 65.335). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.045 and -5.486), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.354 and -1.564), indicating poor aqueous solubility. This is also a significant concern.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.404 and 0.278), which is excellent.

**Microsomal Clearance:** Ligand A (17.397) has a higher microsomal clearance than Ligand B (-3.835). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-6.945) has a significantly longer in vitro half-life than Ligand A (40.521). This further supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.109 and 0.005), which is favorable.

**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:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. It exhibits superior metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and a lower DILI risk. The negative Caco-2 and solubility values are concerning for both, but could potentially be addressed through formulation strategies. The improved metabolic stability of Ligand B is particularly important for kinase inhibitors, as they often require sustained exposure.

Output:
1
2025-04-17 14:41:08,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.893 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (70.08), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.133) is optimal, while Ligand B (1.127) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) both meet the <=10 criteria.

**QED:** Both ligands have good QED scores (0.618 and 0.827, respectively), indicating drug-likeness.

**DILI:** Ligand B (20.706) has a significantly lower DILI risk than Ligand A (42.885), which is a major advantage.

**BBB:** Ligand B (81.698) has a better BBB penetration score than Ligand A (52.268), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.04) is worse than Ligand B (-4.145), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.097) is worse than Ligand B (-1.929), which is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.298 and 0.383, respectively).

**Microsomal Clearance:** Ligand B (35.958) has a lower microsomal clearance than Ligand A (39.269), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.896) has a longer in vitro half-life than Ligand A (10.649), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.104 and 0.111, respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.8 kcal/mol, respectively). The difference of 0.4 kcal/mol is not substantial enough to outweigh the ADME advantages of Ligand B.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has a slightly better TPSA, Ligand B excels in crucial areas for an enzyme inhibitor: lower DILI risk, better solubility, better Caco-2 permeability, lower microsomal clearance, and a longer half-life. The binding affinity difference is minimal.

Output:
1
2025-04-17 14:41:08,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.431 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.21) is slightly higher than Ligand B (67.67). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**3. logP:** Both ligands (1.526 and 1.416) 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:** Both ligands have 5 HBA, which is within the acceptable range (<=10).

**6. QED:** Ligand A (0.807) has a significantly higher QED score than Ligand B (0.526), suggesting a more drug-like profile overall.

**7. DILI:** Ligand A (51.881) has a higher DILI risk than Ligand B (23.226). This is a significant concern, as lower DILI is preferred.

**8. BBB:** Both ligands have similar BBB penetration (78.868 and 78.519). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2:** Ligand A (-5.118) and Ligand B (-4.712) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so both are poor.

**10. Solubility:** Ligand A (-3.332) has worse solubility than Ligand B (-0.933). Solubility is important for bioavailability, so Ligand B is favored.

**11. hERG:** Ligand A (0.17) shows a slightly lower hERG risk than Ligand B (0.362), which is preferable.

**12. Cl_mic:** Ligand A (35.566) has a higher microsomal clearance than Ligand B (19.847), indicating lower metabolic stability. Ligand B is favored here.

**13. t1/2:** Ligand A (-22.391) has a negative in vitro half-life, which is not physically possible and likely an error or outlier. Ligand B (7.513) has a reasonable half-life. This is a major advantage for Ligand B.

**14. Pgp:** Ligand A (0.013) has lower P-gp efflux than Ligand B (0.096), which is favorable.

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -7.0 kcal/mol). While both are good, Ligand A has a slightly better affinity.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity and Pgp profile, Ligand B is the more promising candidate. The primary reasons are:

*   **DILI Risk:** Significantly lower for Ligand B.
*   **Metabolic Stability:** Ligand B has a much lower Cl_mic and a positive, reasonable t1/2.
*   **Solubility:** Ligand B has better aqueous solubility.
*   **t1/2:** Ligand A has a nonsensical negative half-life.

The lower DILI risk and improved metabolic stability of Ligand B outweigh the slight advantage in binding affinity of Ligand A.

Output:
1
2025-04-17 14:41:08,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 369.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good absorption, while Ligand B (124.03) is still acceptable, but less optimal.

**logP:** Both ligands (1.929 and 1.491) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (4) are well below the 10 threshold.

**QED:** Ligand A (0.688) has a significantly better QED score than Ligand B (0.382), indicating a more drug-like profile.

**DILI:** Ligand A (17.642) has a much lower DILI risk than Ligand B (33.307), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.986) has a better BBB score than Ligand B (46.026).

**Caco-2 Permeability:** Ligand A (-4.938) and Ligand B (-5.231) both have negative values, suggesting poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.786) has better solubility than Ligand B (-2.054), although both are relatively poor.

**hERG Inhibition:** Ligand A (0.367) has a lower hERG risk than Ligand B (0.12), which is a positive.

**Microsomal Clearance:** Ligand A (55.356) has higher microsomal clearance than Ligand B (30.094), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-1.22) has a longer half-life than Ligand A (11.224), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux than Ligand B (0.027), which is a positive.

**Binding Affinity:** Ligand B (-7.5 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 several advantages: better QED, significantly lower DILI risk, better BBB penetration, better solubility, and lower hERG risk. However, it suffers from higher microsomal clearance and shorter half-life. Ligand B has a better half-life and slightly better binding affinity, but has a higher DILI risk, lower QED, and poorer solubility.

Given the enzyme-specific priorities, metabolic stability (half-life) and safety (DILI, hERG) are crucial. While Ligand B has a better half-life and slightly better affinity, the significantly higher DILI risk and lower QED of Ligand B are major drawbacks. The slightly better affinity of Ligand B is unlikely to outweigh the safety concerns.

Output:
0
2025-04-17 14:41:08,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.256 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 A (74.43) is slightly higher than Ligand B (69.64), but both are good.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 3.205, Ligand B: 2.426), which is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (Ligand A: 0.564, Ligand B: 0.793), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A has a very high DILI risk (99.069%), which is a major red flag. Ligand B has a much lower, and acceptable, DILI risk (37.611%).

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (92.284%) has a higher value than Ligand B (61.225%).

**Caco-2 Permeability:** Ligand A (-4.196) shows poor Caco-2 permeability, while Ligand B (-5.255) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.326) has poor aqueous solubility, and Ligand B (-3.233) is also poor, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.546, Ligand B: 0.458), which is good.

**Microsomal Clearance:** Ligand A (69.362) has a higher microsomal clearance than Ligand B (40.947), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-24.336) has a negative half-life, indicating very poor stability. Ligand B (18.547) is much better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.384, Ligand B: 0.203), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.0 kcal/mol, Ligand B: -8.6 kcal/mol). Ligand B is slightly better.

**Conclusion:**

Despite similar binding affinities, Ligand B is significantly more promising due to its much lower DILI risk, better metabolic stability (lower Cl_mic, higher t1/2), and better solubility. Ligand A's extremely high DILI risk and poor metabolic stability are major drawbacks that outweigh its slightly better BBB penetration and Caco-2 permeability.

Output:
1
2025-04-17 14:41:08,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.459 and 357.479 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is better than Ligand B (62.3), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands (2.297 and 2.8) are within the optimal 1-3 range.

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

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

**QED:** Both ligands have similar QED values (0.842 and 0.829), indicating good drug-likeness.

**DILI:** Ligand A (37.65) has a significantly lower DILI risk than Ligand B (54.052). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (76.696 and 73.943), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.789 and -4.994), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.016 and -2.759), which is also a concern.

**hERG:** Ligand A (0.236) has a much lower hERG risk than Ligand B (0.57). This is a significant advantage.

**Microsomal Clearance:** Ligand A (59.996) has a lower microsomal clearance than Ligand B (74.522), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.326) has a slightly better (less negative) in vitro half-life than Ligand B (39.648).

**P-gp Efflux:** Ligand A (0.261) has lower P-gp efflux liability than Ligand B (0.392), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better half-life, while maintaining comparable binding affinity and drug-likeness properties. Although both have poor Caco-2 and solubility, the ADME/Tox profile of Ligand A is superior.

Output:
0
2025-04-17 14:41:08,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.375 and 376.563 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109) is higher than the preferred <140, but acceptable. Ligand B (75.71) is excellent, well below 90.

**logP:** Ligand A (0.461) is quite low, potentially hindering permeability. Ligand B (2.253) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also good.

**QED:** Both have reasonable QED scores (0.84 and 0.705), indicating good drug-like properties.

**DILI:** Ligand A (57.929) has a moderate DILI risk. Ligand B (23.769) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (80.613) has better BBB penetration than Ligand A (62.466).

**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, making interpretation difficult.

**hERG:** Ligand A (0.018) has a very low hERG risk, a major plus. Ligand B (0.619) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (3.514) has a low Cl_mic, indicating good metabolic stability. Ligand B (72.117) has a very high Cl_mic, suggesting rapid metabolism and a potential issue.

**In vitro Half-Life:** Ligand A (7.175) has a reasonable half-life. Ligand B (-32.559) has a very short half-life, a significant drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.031), which is favorable.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and good metabolic stability, but suffers from low logP and potentially poor solubility/permeability (due to negative Caco-2 and solubility values). Ligand B has better physicochemical properties (logP, TPSA, DILI) but a significantly weaker binding affinity and poor metabolic stability.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is the most important factor. While its ADME properties are not ideal, optimization could potentially address these issues. The large difference in binding affinity (-9.8 vs -6.6 kcal/mol) is a substantial advantage that likely outweighs the ADME concerns, especially considering the possibility of chemical modifications to improve those properties.

Output:
1
2025-04-17 14:41:08,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (352.475 and 352.414 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (76.66 and 78.07) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands have logP values within the optimal range (1.914 and 1.452).

**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 7. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.766 and 0.719), indicating drug-like properties.

**7. DILI:** Ligand A (15.161) has a significantly lower DILI risk than Ligand B (41.411). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (68.825 and 74.564). This isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.856 and -4.533), which is unusual and suggests poor permeability. However, these values are on a log scale and need to be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.98 and -0.91), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.18 and 0.228), which is excellent.

**12. Microsomal Clearance:** Ligand A (21.573 mL/min/kg) has significantly lower microsomal clearance than Ligand B (48.389 mL/min/kg). This suggests better metabolic stability for Ligand A, a crucial factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (9.371 hours) has a longer in vitro half-life than Ligand B (5.27 hours). This is another advantage for Ligand A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.026 and 0.133).

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most critical difference, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Ligand A is significantly better than Ligand B. The superior binding affinity (-9.7 vs -0.0 kcal/mol) is the most important factor. Additionally, Ligand A demonstrates a lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and is more potent. While both ligands have solubility and permeability concerns, the potency and safety profile of Ligand A make it the far more promising drug candidate.

Output:
1
2025-04-17 14:41:08,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 379.848 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.43) is better than Ligand B (81.91), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands (2.127 and 2.539) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**H-Bond Acceptors:** Ligand B (6) is higher than Ligand A (3), but both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.688 and 0.825), indicating drug-likeness.

**DILI:** Ligand A (30.05) has a significantly lower DILI risk than Ligand B (74.99). This is a major advantage for Ligand A.

**BBB:** Ligand B (71.268) has a higher BBB penetration than Ligand A (60.45), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.77) is worse than Ligand B (-5.098), both are quite poor.

**Aqueous Solubility:** Ligand A (-3.551) is better than Ligand B (-4.728), both are quite poor.

**hERG Inhibition:** Ligand A (0.256) has a lower hERG inhibition liability than Ligand B (0.711), which is a significant advantage.

**Microsomal Clearance:** Ligand B (20.098) has a considerably lower microsomal clearance than Ligand A (41.793), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-3.871) has a better in vitro half-life than Ligand A (17.189).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.165 and 0.167).

**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 for Ligand B, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic, better t1/2). However, Ligand A has a much lower DILI risk and lower hERG inhibition. Solubility and Caco-2 permeability are poor for both. The difference in binding affinity (-1.8 kcal/mol) is substantial enough to likely overcome the higher DILI and hERG risk of Ligand B, especially considering that these risks can be further mitigated during lead optimization. The improved metabolic stability of Ligand B is also a critical factor for kinase inhibitors.

Output:
1
2025-04-17 14:41:08,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.519 Da and 379.913 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.22) is better than Ligand B (71.09), both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.354) is optimal, while Ligand B (4.071) is approaching the higher end of the acceptable range. Higher logP can lead to off-target effects and solubility issues.

**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 similar QED values (0.76 and 0.711), indicating good drug-likeness.

**DILI:** Ligand A (13.649) has a significantly lower DILI risk than Ligand B (77.782). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (51.997 and 52.656), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.603) has worse Caco-2 permeability than Ligand B (-5.062), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.432) has better solubility than Ligand B (-5.149). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.078) has a much lower hERG inhibition risk than Ligand B (0.719). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-25.058) has significantly lower microsomal clearance, indicating better metabolic stability than Ligand B (74.676). This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (46.382) has a much longer in vitro half-life than Ligand A (6.585). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.01) has much lower P-gp efflux than Ligand B (0.492), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:**

Ligand A demonstrates a superior safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic). It also has better solubility and lower P-gp efflux. While Ligand B has a slightly better binding affinity and half-life, the ADME profile of Ligand A is far more favorable for development as a drug candidate. The improved metabolic stability and reduced toxicity risks of Ligand A are crucial for an enzyme target like SRC kinase.

Output:
0
2025-04-17 14:41:08,589 - INFO - Batch 317 complete. Total preferences: 5072
2025-04-17 14:41:08,589 - INFO - Processing batch 318/512...
2025-04-17 14:41:57,665 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.487 and 375.259 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is better than Ligand B (58.12), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.61 and 3.021), 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 within acceptable limits.

**QED:** Both ligands have good QED scores (0.718 and 0.835), indicating good drug-like properties.

**DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (76.154). This is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (90.112) shows better penetration than Ligand B (68.748).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.464 and -4.738). This is unusual and suggests poor permeability, but the scale isn't fully defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.727 and -4.467). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.484) has a lower hERG risk than Ligand B (0.706). This is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (52.203) has a higher microsomal clearance than Ligand B (25.793), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (9.9) has a better in vitro half-life than Ligand A (-16.678). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.176 and 0.278).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference isn't huge (less than 1.5 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG) and has a slightly better TPSA. However, it suffers from lower metabolic stability (higher Cl_mic, negative t1/2) and worse solubility. Ligand B has better metabolic stability and binding affinity, but significantly higher DILI and hERG risk.

Given the enzyme-specific priorities, metabolic stability and binding affinity are crucial. However, the very high DILI and hERG risk associated with Ligand B are major red flags. While Ligand A has some ADME drawbacks, they are less severe and potentially addressable through further optimization. The lower DILI and hERG risk make Ligand A the more promising candidate.

Output:
0
2025-04-17 14:41:57,666 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [368.79 ,  50.7  ,   3.811,   1.   ,   4.   ,   0.834,  56.495,  88.096, -4.807,  -4.174,   0.332,  25.114,   3.298,   0.204,   0.   ]
**Ligand B:** [353.419, 110.96 ,  -0.447,   2.   ,   5.   ,   0.696,  26.444,  51.221, -5.514,  -2.009,   0.064,  -8.159,  10.569,   0.007,  -9.1  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (368.79) is slightly higher than B (353.419), but both are acceptable.
2. **TPSA:** A (50.7) is excellent, well below the 140 threshold. B (110.96) is higher, but still potentially acceptable, though less ideal for oral absorption.
3. **logP:** A (3.811) is optimal. B (-0.447) is significantly low, which could hinder membrane permeability and bioavailability.
4. **HBD:** Both A (1) and B (2) are within the acceptable limit of 5.
5. **HBA:** Both A (4) and B (5) are within the acceptable limit of 10.
6. **QED:** A (0.834) is very good, indicating high drug-likeness. B (0.696) is still reasonable, but lower than A.
7. **DILI:** A (56.495) is acceptable, indicating moderate risk. B (26.444) is very good, indicating low risk.
8. **BBB:** A (88.096) is excellent. B (51.221) is lower, suggesting limited CNS penetration. (Not a primary concern for SRC, but a bonus).
9. **Caco-2:** A (-4.807) is concerningly low, suggesting poor intestinal absorption. B (-5.514) is also low, but slightly better than A.
10. **Solubility:** A (-4.174) is poor. B (-2.009) is also poor, but slightly better than A.
11. **hERG:** A (0.332) is very low risk. B (0.064) is also very low risk.
12. **Cl_mic:** A (25.114) is moderate. B (-8.159) is excellent, indicating high metabolic stability.
13. **t1/2:** A (3.298) is moderate. B (10.569) is very good, suggesting a longer duration of action.
14. **Pgp:** A (0.204) is low efflux. B (0.007) is very low efflux.
15. **Affinity:** A (0) is not great. B (-9.1) is *excellent*, significantly stronger binding.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand B has a *much* stronger binding affinity (-9.1 kcal/mol vs 0 kcal/mol). This is a huge advantage.
*   **Metabolic Stability:** Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2).
*   **Solubility:** Both have poor solubility, but B is slightly better.
*   **hERG:** Both have acceptable hERG risk.
*   **ADME Concerns:** Both have poor Caco-2 permeability. Ligand A has a better BBB score, but this is not a priority for a non-CNS target.

**Conclusion:**

Despite the poor Caco-2 and solubility for both compounds, the significantly superior binding affinity and metabolic stability of **Ligand B** outweigh the drawbacks. The strong binding affinity is a critical factor for kinase inhibitors, and the improved metabolic stability suggests a potentially longer duration of action.

Output:
1
2025-04-17 14:41:57,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.483 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (64.16), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.03 and 3.237), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is better than Ligand B (0 HBD, 6 HBA). While both are acceptable, fewer H-bonds generally improve permeability.

**QED:** Both ligands have acceptable QED scores (0.806 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (28.228) has a much lower DILI risk than Ligand B (43.66), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (75.107 and 78.558), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.797) has worse Caco-2 permeability than Ligand B (-5.096). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.756) has slightly worse aqueous solubility than Ligand B (-2.826). Both are negative, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.39 and 0.215), which is excellent.

**Microsomal Clearance:** Ligand A (56.859) has significantly lower microsomal clearance than Ligand B (89.818), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.362) has a much longer in vitro half-life than Ligand B (-1.159), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.27 and 0.273).

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8), but the difference is only 0.3 kcal/mol.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties. Specifically, its lower DILI risk, lower microsomal clearance, and longer half-life are crucial advantages for an enzyme target like SRC kinase. The TPSA is also better for Ligand A. The slight disadvantage in binding affinity is outweighed by the significantly improved pharmacokinetic profile.

Output:
1
2025-04-17 14:41:57,666 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [355.498, 61.44, 2.258, 2, 3, 0.667, 5.777, 75.107, -5.02, -1.733, 0.472, -4.863, -16.427, 0.019, -9.4]
**Ligand B:** [364.471, 85.25, 0.879, 2, 6, 0.783, 63.746, 52.036, -5.561, -2.097, 0.449, 28.671, 21.702, 0.07, -8.1]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (355.5) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (61.44) is better than B (85.25).  A is well below the 140 threshold for oral absorption, while B is approaching it.
3. **logP:** A (2.258) is optimal, while B (0.879) is a bit low, potentially hindering permeation.
4. **HBD:** Both have 2 HBD, which is good.
5. **HBA:** A (3) is better than B (6). Lower HBA generally improves permeability.
6. **QED:** Both are above 0.5 (A: 0.667, B: 0.783), indicating good drug-like properties. B is slightly better here.
7. **DILI:** A (5.777) is significantly better than B (63.746). This is a major advantage for A.
8. **BBB:** A (75.107) is better than B (52.036), although neither are exceptionally high. Not a primary concern for a non-CNS target like SRC.
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:** Both are low (A: 0.472, B: 0.449), indicating low cardiotoxicity risk.
12. **Cl_mic:** A (-4.863) is *much* better than B (28.671). A negative value suggests very low clearance and high metabolic stability, a crucial factor for kinase inhibitors.
13. **t1/2:** A (-16.427) is *much* better than B (21.702). A negative value suggests a very long half-life, which is highly desirable.
14. **Pgp:** Both are very low (A: 0.019, B: 0.07), indicating minimal P-gp efflux.
15. **Binding Affinity:** A (-9.4) is slightly better than B (-8.1). While both are strong binders, the 1.3 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in all these areas. Its significantly better metabolic stability (Cl_mic and t1/2) and lower DILI risk are particularly important. The slightly better binding affinity further solidifies its advantage. While both have poor Caco-2 and solubility, the superior ADME profile of A makes it a more promising candidate.

**Conclusion:**

Ligand A is the more viable drug candidate.

1
2025-04-17 14:41:57,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.348 Da) is slightly higher than Ligand B (377.413 Da), but both are acceptable.

**TPSA:** Ligand A (30.49) is significantly better than Ligand B (84.67). Lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (4.927) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.538) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands 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 good QED scores (A: 0.677, B: 0.776), indicating drug-likeness.

**DILI:** Ligand A (18.728) has a much lower DILI risk than Ligand B (66.77). This is a significant advantage for Ligand A.

**BBB:** Both ligands have relatively high BBB penetration (A: 78.596, B: 80.419), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.878 and -4.773), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.323 and -2.986), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.931) has a slightly higher hERG risk than Ligand B (0.172), but both are relatively low.

**Microsomal Clearance:** Ligand B (37.449) has significantly lower microsomal clearance than Ligand A (64.626), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (12.21) has a longer half-life than Ligand A (21.207), which is generally desirable.

**P-gp Efflux:** Ligand A (0.714) has slightly higher P-gp efflux than Ligand B (0.073), meaning B is less likely to be pumped out of cells.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it is a noticeable advantage.

**Overall Assessment:**

Ligand A has a significant advantage in terms of DILI risk and a slightly better BBB penetration. However, its higher logP and higher clearance are concerning. Ligand B excels in metabolic stability (lower Cl_mic), has a longer half-life, lower P-gp efflux, and a slightly better binding affinity. While its TPSA is higher and solubility is poor, the better ADME profile and comparable affinity make it a more promising candidate. The poor solubility and permeability of both compounds are major concerns that would need to be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 14:41:57,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (336.395 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.01) is slightly higher than Ligand B (78.51), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.044) is within the optimal 1-3 range, while Ligand B (1.733) is at the lower end, potentially impacting 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 (0.683 and 0.742, respectively), indicating drug-like properties.

**DILI:** Ligand A (44.087) has a slightly higher DILI risk than Ligand B (20.396), but both are below the concerning threshold of 60.

**BBB:** Ligand A (26.987) has a low BBB penetration, while Ligand B (66.111) has a moderate BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.595 and -5.179), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.337 and -2.752), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.289 and 0.203), which is excellent.

**Microsomal Clearance:** Ligand A (-4.358) shows significantly better metabolic stability (lower clearance) than Ligand B (3.456). This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-14.636) has a much longer in vitro half-life than Ligand B (0.84), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.03 and 0.04).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial difference (1.8 kcal/mol), which could potentially outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B's significantly stronger binding affinity (-7.5 kcal/mol vs -8.3 kcal/mol) and lower logP, combined with acceptable DILI and hERG, make it the more promising candidate. While Ligand A has better metabolic stability, the affinity difference is substantial enough to prioritize Ligand B, assuming solubility and permeability can be addressed through formulation or structural modifications.

Output:
1
2025-04-17 14:41:57,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (357.426 and 354.426 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.16) is better than Ligand B (87.46), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Ligand A (0.023) is quite low, potentially hindering permeability. Ligand B (2.364) 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 also acceptable.

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

**6. QED:** Both ligands have similar QED values (0.769 and 0.736), indicating good drug-like properties.

**7. DILI:** Ligand A (22.102) has a much lower DILI risk than Ligand B (47.732). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (46.568) has lower BBB penetration than Ligand B (82.474). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.48 and -4.847), 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.

**10. Aqueous Solubility:** Ligand A (-0.47) has slightly better solubility than Ligand B (-3.474). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.194) has a much lower hERG risk than Ligand B (0.452). This is a critical advantage for Ligand A.

**12. Microsomal Clearance:** Ligand B (21.96) has higher microsomal clearance than Ligand A (10.211), suggesting lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (-22.72) has a slightly longer half-life than Ligand A (-20.621), but both are negative values, which is unusual.

**14. P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.419), which is favorable for bioavailability.

**15. 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.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a better logP, Ligand A excels in critical areas for kinase inhibitors: lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), better binding affinity, and lower P-gp efflux. The low logP of Ligand A is a concern, but the superior binding affinity and safety profile likely outweigh this drawback. The negative Caco-2 values are concerning for both, but the other ADME properties of Ligand A are more favorable.

Output:
0
2025-04-17 14:41:57,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.45 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is better than Ligand B (49.41), both are below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.302 and 3.178, respectively), falling within the 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (0/1) and HBA (3/3) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.703 and 0.845), indicating good drug-likeness.

**DILI:** Ligand A (15.316) has a significantly lower DILI risk than Ligand B (35.479). This is a major advantage for Ligand A.

**BBB:** While not critical for a non-CNS target like SRC, Ligand A (94.067) has a higher BBB percentile than Ligand B (70.027).

**Caco-2 Permeability:** Ligand A (-4.358) and Ligand B (-5.007) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.194) is better than Ligand B (-3.742), indicating better solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.619 and 0.59, respectively).

**Microsomal Clearance:** Ligand A (38.034) has significantly lower microsomal clearance than Ligand B (84.904), suggesting better metabolic stability. This is a crucial advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-4.778) has a better in vitro half-life than Ligand B (-3.068).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.115 and 0.462, respectively).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.3 vs -6.5 kcal/mol) is a major positive. However, it is offset by higher DILI risk (35.479 vs 15.316), higher microsomal clearance (84.904 vs 38.034), and lower solubility (-3.742 vs -2.194). Given the enzyme-specific priorities, metabolic stability and lower toxicity are very important. While potency is key, the other factors are significant enough to favor Ligand A.

Output:
0
2025-04-17 14:41:57,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.53 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.51). Lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (2.055 and 1.013), 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 adhering to the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.635 and 0.798), indicating good drug-like properties.

**DILI:** Ligand A (23.5%) has a much lower DILI risk than Ligand B (40.8%). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (66.9%) has a higher BBB score than Ligand A (52.0%), but this is not a primary concern.

**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. Again, the scale is not specified, making interpretation difficult.

**hERG:** Both ligands have low hERG risk (0.362 and 0.318), which is good.

**Microsomal Clearance:** Ligand B (-24.3) has a *much* better (lower) microsomal clearance than Ligand A (31.5). This suggests significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (3.06) has a slightly longer half-life than Ligand A (8.92), but the difference isn't substantial.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.21 and 0.02), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). The difference of 1.2 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity and better metabolic stability (lower Cl_mic). However, Ligand A has a much lower DILI risk and better TPSA. The negative Caco-2 and solubility values are concerning for both compounds, but the affinity difference is substantial. Given the enzyme-kinase focus, potency and metabolic stability are paramount. The improved affinity and metabolic stability of Ligand B are more critical than the slightly higher DILI risk and worse TPSA of Ligand A.

Output:
1
2025-04-17 14:41:57,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (348.422 and 358.429 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (58.44 and 58.64) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.615) and Ligand B (2.344) both fall 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 (4) is preferable to Ligand B (3) as fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.834 and 0.821), indicating good drug-likeness.

**7. DILI:** Ligand B (25.242) has a significantly lower DILI risk than Ligand A (31.563), which is a substantial advantage.

**8. BBB:** Both ligands have very high BBB penetration (98.255 and 95.502), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.749 and -4.59), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.935 and -2.779), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.346) has a slightly lower hERG inhibition risk than Ligand B (0.459), which is preferable.

**12. Microsomal Clearance:** Ligand B (0.241) has a much lower microsomal clearance than Ligand A (39.062), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (4.375) has a significantly longer in vitro half-life than Ligand A (-20.104), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.067) has a lower P-gp efflux liability than Ligand B (0.046), which is preferable.

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.5), which is a significant advantage.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. While both have poor solubility and permeability, the significantly improved metabolic profile of Ligand B outweighs the slightly better hERG and P-gp properties of Ligand A. The lower DILI risk for Ligand B is also a positive factor.

Output:
1
2025-04-17 14:41:57,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.438 and 361.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is well within the acceptable range for oral absorption (<140). Ligand B (29.54) is excellent, suggesting good absorption.

**logP:** Ligand A (1.269) is optimal. Ligand B (4.296) is pushing the upper limit, potentially causing solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, both within acceptable limits. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.611 and 0.678, respectively), indicating drug-like properties.

**DILI:** Ligand A (14.463) has a significantly lower DILI risk than Ligand B (40.287). This is a major advantage for Ligand A.

**BBB:** Ligand A (58.511) has a moderate BBB penetration, while Ligand B (92.904) has high BBB penetration. Since SRC is not a CNS target, this is less important, but a slight advantage to B.

**Caco-2 Permeability:** Ligand A (-4.929) and Ligand B (-4.452) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.379) and Ligand B (-4.036) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.238) has a very low hERG risk, which is excellent. Ligand B (0.854) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (5.111) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (46.253) has a much higher clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-3.448) has a negative half-life, which is unusual and suggests very rapid degradation. Ligand B (16.488) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux, which is favorable. Ligand B (0.295) 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 is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The primary concerns for enzyme inhibitors are metabolic stability, solubility, and safety. Ligand A demonstrates significantly lower DILI risk and better metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the lower DILI risk and better metabolic stability of Ligand A are more critical for an enzyme target. The affinity difference, while notable, may be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 14:41:57,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.418 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.71) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (78.09) is still acceptable, but less favorable.

**3. logP:** Both ligands have a logP around 2.0, which is optimal for absorption and minimizing off-target effects.

**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 (3) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.87) has a significantly better QED score than Ligand B (0.635), indicating a more drug-like profile.

**7. DILI:** Ligand A (16.479) has a much lower DILI risk than Ligand B (20.279), which is a significant advantage.

**8. BBB:** Ligand A (78.868) has a better BBB penetration percentile than Ligand B (65.219), although this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.124) and Ligand B (-5.441) 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 (-1.227 and -1.877 respectively). This is a major concern and would require formulation strategies.

**11. hERG Inhibition:** Ligand A (0.95) has a lower hERG inhibition risk than Ligand B (0.158), which is a crucial safety parameter.

**12. Microsomal Clearance:** Ligand B (-6.472) has a *negative* microsomal clearance, which is not physically possible. This is likely an error in the data. Ligand A (9.886) has a reasonable clearance.

**13. In vitro Half-Life:** Ligand B (-41.741) has a negative half-life, which is impossible. This is also likely a data error. Ligand A (10.372) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.148) has a lower P-gp efflux liability than Ligand B (0.041), which is favorable.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 and -8.8 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Ligand A is significantly better than Ligand B. It has a superior QED score, lower DILI risk, better BBB penetration, lower hERG inhibition, and more plausible ADME properties (positive clearance and half-life). While both have poor solubility, Ligand A's overall profile is much more promising. The negative values for clearance and half-life in Ligand B are red flags indicating data errors or a fundamentally problematic molecule.

Output:
1
2025-04-17 14:41:57,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.411 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.04) is slightly higher than Ligand B (56.67), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (3.527) is at the upper end of the optimal range (1-3), while Ligand B (2.594) is comfortably within it.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have similar QED scores (0.793 and 0.785), indicating good drug-likeness.

**DILI:** Ligand A (74.409) has a significantly higher DILI risk than Ligand B (18.883). This is a major concern.

**BBB:** Ligand B (77.976) has a better BBB penetration percentile than Ligand A (52.385), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.564) shows poorer Caco-2 permeability than Ligand B (-4.804), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand B (-2.669) has better aqueous solubility than Ligand A (-4.494). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.848) has a slightly higher hERG inhibition risk than Ligand B (0.637), but both are reasonably low.

**Microsomal Clearance:** Ligand B (58.933 mL/min/kg) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand A (80.36 mL/min/kg).

**In vitro Half-Life:** Ligand B (38.389 hours) has a significantly longer in vitro half-life than Ligand A (22.613 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.61) has slightly lower P-gp efflux than Ligand B (0.34), but the difference is not substantial.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -9.2 kcal/mol), with Ligand B being marginally stronger. The difference is less than 1.5 kcal/mol, so it's not a deciding factor on its own.

**Conclusion:**

Despite similar binding affinities, Ligand B is significantly more promising due to its substantially lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and improved aqueous solubility. While Ligand A has slightly better Caco-2 permeability and P-gp efflux, the DILI risk is a major red flag. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 14:41:57,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.359 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.53) is slightly above the optimal <140 for oral absorption but still reasonable. Ligand B (58.44) is excellent, well below 140 and suggesting good absorption.

**logP:** Ligand A (0.546) is a bit low, potentially hindering permeation. Ligand B (2.719) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also good.

**QED:** Both ligands have similar QED values (0.67 and 0.645), indicating good drug-likeness.

**DILI:** Ligand A (50.136) has a moderate DILI risk, while Ligand B (29.624) has a lower, more favorable DILI risk.

**BBB:** Ligand A (19.542) has very low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (81.543) has good BBB penetration, but this is less relevant here.

**Caco-2 Permeability:** Ligand A (-5.503) shows poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.695) is better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.623 and -1.535). This is a concern for both, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.133) has a slightly higher hERG risk than Ligand B (0.772), but both are relatively low.

**Microsomal Clearance:** Ligand A (-0.505) has a negative clearance, indicating high metabolic stability, which is excellent. Ligand B (87.781) has a very high clearance, suggesting poor metabolic stability and a potential for rapid degradation.

**In vitro Half-Life:** Ligand A (-34.157) has a very long half-life, consistent with the low clearance. Ligand B (25.214) has a shorter half-life, reflecting the high clearance.

**P-gp Efflux:** Ligand A (0.032) has low P-gp efflux, which is good. Ligand B (0.588) has slightly higher P-gp efflux, but still reasonable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial advantage.

**Conclusion:**

While both ligands have issues with solubility, Ligand A has a much stronger binding affinity (-8.6 vs -6.2 kcal/mol) and significantly better metabolic stability (negative clearance, long half-life). The lower Caco-2 permeability and slightly lower logP of Ligand A are less concerning given the strong binding and metabolic stability. The lower DILI risk of Ligand B is a plus, but the poor metabolic stability is a major drawback for an enzyme inhibitor. The substantial affinity advantage of Ligand A outweighs its other shortcomings.

Output:
0
2025-04-17 14:41:57,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (334.47 & 344.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.16) is significantly better than Ligand B (104.7), being well below the 140 threshold for oral absorption. Ligand B's higher TPSA could hinder absorption.

**logP:** Ligand A (3.659) is within the optimal 1-3 range, while Ligand B (1.162) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) 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:** Both ligands have similar QED values (0.773 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (23.81) has a much lower DILI risk than Ligand B (51.14). This is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (84.37) is better than Ligand B (36.72).

**Caco-2 Permeability:** Ligand A (-5.223) is better than Ligand B (-5.607), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.314) is better than Ligand B (-1.917), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.988 and 0.454), which is good.

**Microsomal Clearance:** Ligand A (43.25 mL/min/kg) is higher than Ligand B (-7.93 mL/min/kg), indicating *lower* metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-17.66 hours) has a significantly longer half-life than Ligand A (-10.75 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.344 and 0.036).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.8 and -8.4 kcal/mol), which are both excellent. The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While Ligand A has better TPSA, logP, solubility, and DILI risk, Ligand B exhibits superior metabolic stability (lower Cl_mic, longer t1/2). Given the enzyme-specific priorities, metabolic stability is crucial. The slightly better affinity of Ligand A is not enough to overcome the significantly better metabolic profile of Ligand B. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 14:41:57,669 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (76.02) is slightly higher than Ligand B (64.43), but both are well within the acceptable range.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.029, Ligand B: 2.835), which is optimal.

**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 QED values above 0.5 (Ligand A: 0.756, Ligand B: 0.628), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 24.5%, while Ligand B has 14.2%. Both are good (below 40%), but Ligand B is preferable.

**BBB:** Ligand A has a BBB penetration of 65.7%, while Ligand B has 83.1%. BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired, but higher is generally better.

**Caco-2 Permeability:** Ligand A (-5.114) has poorer Caco-2 permeability than Ligand B (-4.451). Lower negative values indicate better permeability.

**Aqueous Solubility:** Both ligands have similar negative solubility values (-1.904 and -1.827), suggesting poor solubility. This is a potential issue for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.188) has a slightly lower hERG risk than Ligand B (0.445), which is favorable.

**Microsomal Clearance:** Ligand A (19.797 mL/min/kg) has significantly lower microsomal clearance than Ligand B (64.97 mL/min/kg). This indicates better metabolic stability for Ligand A, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (2.388 hours) has a shorter half-life than Ligand B (13.649 hours). This is a significant advantage for Ligand B, as a longer half-life can lead to less frequent dosing.

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.218), which is preferable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This difference of 1.1 kcal/mol is substantial and can outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic) and P-gp efflux. However, Ligand B has better Caco-2 permeability, a longer half-life, and a lower DILI risk. The difference in binding affinity is significant. Given the enzyme-specific priorities, the stronger binding affinity of Ligand A is the most important factor. While its solubility and half-life are less ideal, these can be addressed during lead optimization.

Output:
0
2025-04-17 14:41:57,669 - INFO - Batch 318 complete. Total preferences: 5088
2025-04-17 14:41:57,669 - INFO - Processing batch 319/512...
2025-04-17 14:42:48,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.35 and 352.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.84) is better than Ligand B (49.41) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (-0.558) is slightly low, potentially hindering permeation, while Ligand B (3.45) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 2 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.702 and 0.842), indicating drug-like properties.

**DILI:** Ligand A (63.01) has a higher DILI risk than Ligand B (17.22), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (89.38) shows better potential for BBB penetration than Ligand A (60.37).

**Caco-2 Permeability:** Ligand A (-5.608) has poor Caco-2 permeability, while Ligand B (-4.6) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.331) has poor solubility, while Ligand B (-4.079) is also poor.

**hERG:** Ligand A (0.01) has a very low hERG risk, a major advantage. Ligand B (0.707) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-42.23) exhibits significantly lower microsomal clearance, suggesting better metabolic stability than Ligand B (53.69).

**In vitro Half-Life:** Ligand A (-15.55) has a shorter half-life than Ligand B (-1.70), which is less desirable.

**P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux, while Ligand B (0.183) has a slightly higher efflux.

**Binding Affinity:** Both ligands have comparable binding affinities (-9.9 and -10.0 kcal/mol), which are excellent.

**Overall Assessment:**

While Ligand A has excellent binding affinity and low hERG risk and P-gp efflux, its poor solubility, Caco-2 permeability, and higher DILI risk are major drawbacks. Ligand B has better logP, lower DILI, and better metabolic stability, but has a slightly higher hERG risk. Given the enzyme-specific priorities, metabolic stability and low toxicity (DILI, hERG) are crucial. The similar binding affinities mean these are not deciding factors.

Output:
1
2025-04-17 14:42:48,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.413 and 370.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.2 and 67.87) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.325 and 1.852) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5 HBAs, both are within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.5 (0.843 and 0.744), indicating good drug-likeness.

**DILI:** Ligand A (28.577) has a significantly lower DILI risk than Ligand B (47.421). This is a major advantage.

**BBB:** Both ligands have good BBB penetration (83.133 and 91.043), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.7 and -4.715), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.273 and -2.757), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.548 and 0.61).

**Microsomal Clearance:** Ligand A (4.187) has a much lower microsomal clearance than Ligand B (20.675), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-10.083) has a more negative in vitro half-life than Ligand B (-8.811), suggesting a longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.122).

**Binding Affinity:** Ligand A (-7.4 kcal/mol) and Ligand B (-7.6 kcal/mol) have similar, strong binding affinities. The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have poor solubility and Caco-2 permeability, Ligand A exhibits significantly lower DILI risk and better metabolic stability (lower Cl_mic and more negative t1/2). These are key advantages for an enzyme target like SRC kinase. The slightly better binding affinity of Ligand B is not enough to compensate for the superior safety and pharmacokinetic properties of Ligand A.

Output:
0
2025-04-17 14:42:48,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 338.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is slightly higher than Ligand B (68.44), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.155 and 1.327), falling within the optimal 1-3 range. Ligand B is slightly lower, which could potentially affect permeability, but is still acceptable.

**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 high QED scores (0.848 and 0.868), indicating good drug-likeness.

**DILI:** Ligand A (57.39%) has a higher DILI risk than Ligand B (44.05%). This is a significant concern, as we want to minimize liver toxicity.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (83.09%) is better than Ligand B (73.83%). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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 very poor aqueous solubility (-2.637 and -3.141). This is a major drawback, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.335) shows a slightly lower hERG inhibition risk than Ligand B (0.757), which is preferable.

**Microsomal Clearance:** Ligand A (24.84 mL/min/kg) has a higher microsomal clearance than Ligand B (14.8 mL/min/kg), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand B (-24.866 hours) has a significantly longer in vitro half-life than Ligand A (24.124 hours), suggesting better metabolic stability. Note the negative value for Ligand B is unusual and may indicate an error or a different scale.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.051 and 0.074).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 1.7 kcal/mol is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -7.7 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, it exhibits lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG inhibition. While Ligand A has slightly better BBB penetration, this is less important for a kinase inhibitor. The negative Caco-2 values for both are concerning and require further investigation, but the overall profile of Ligand B is superior.

Output:
1
2025-04-17 14:42:48,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.467 and 351.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.57 and 80.12) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.724 and 1.113) are within the optimal 1-3 range.

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

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

**QED:** Both ligands have good QED scores (0.687 and 0.798), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 51.997, while Ligand B has 35.673. Both are below the 60 threshold, but Ligand B is preferable due to the lower risk.

**BBB:** Ligand A has a BBB penetration of 57.154, and Ligand B has 71.578. BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.82 and -4.978). This is unusual and suggests poor permeability. However, these values might be errors or represent a specific assay artifact.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.485 and -1.876). This is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.132 and 0.083). This is excellent.

**Microsomal Clearance:** Ligand A has a Cl_mic of 32.345, and Ligand B has -6.793. A negative value for Cl_mic is not physically possible and likely represents an error. Assuming the negative value is an error and represents a very low clearance, Ligand B is significantly better in terms of metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 24.438 hours, while Ligand B has -3.589 hours. Again, a negative half-life is impossible. Assuming this is an error, Ligand A is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.102 and 0.019). This is good.

**Binding Affinity:** Ligand A has a binding affinity of -7.6 kcal/mol, and Ligand B has -7.5 kcal/mol. Ligand A has a slightly better affinity, but the difference is small (0.1 kcal/mol).

**Overall Assessment:**

Despite the questionable Caco-2 and solubility values, and the impossible negative values for Cl_mic and t1/2, we can still make a reasonable assessment. Ligand A has a slightly better binding affinity and in vitro half-life (assuming the negative value is an error), but Ligand B has a lower DILI risk and potentially much better metabolic stability (again, assuming the negative Cl_mic is an error). Given the enzyme-specific priorities, metabolic stability is crucial.

Output:
1
2025-04-17 14:42:48,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.39 and 349.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.87) is slightly above the preferred <140, but acceptable. Ligand B (72.36) is well within the range.

**logP:** Ligand A (0.998) is a bit low, potentially hindering permeability. Ligand B (2.237) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Ligand A (0.864) has a very good QED score, indicating high drug-likeness. Ligand B (0.68) is still acceptable, but lower.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (28.306), which is a significant concern.

**BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (62.97) is slightly better.

**Caco-2 Permeability:** Ligand A (-5.284) has very poor Caco-2 permeability, a major red flag. Ligand B (-4.663) is better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.182 and -2.198 respectively).

**hERG:** Both ligands have very low hERG inhibition risk (0.135 and 0.172 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (15.217) has significantly lower microsomal clearance than Ligand B (45.961), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.197) has a negative half-life, which is not possible and indicates an issue with the data or prediction method. Ligand B (26.667) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.027 and 0.139 respectively).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the superior binding affinity of Ligand A, its extremely poor Caco-2 permeability, questionable half-life, and higher DILI risk make it a less viable candidate. The lower metabolic stability of Ligand B is a concern, but its better permeability, lower DILI risk, and reasonable half-life make it the more promising candidate overall. The substantial affinity difference *could* potentially be overcome with further optimization of Ligand B, whereas the permeability issues of Ligand A are harder to address without significantly altering its binding mode.

Output:
1
2025-04-17 14:42:48,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.42 Da) is slightly higher than Ligand B (347.375 Da), but both are acceptable.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (123.4). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.398) is within the optimal range (1-3). Ligand B (-0.253) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=4, HBA=4). Both are within acceptable limits, but fewer H-bonds are generally preferred for permeability.

**QED:** Ligand A (0.776) has a much better QED score than Ligand B (0.363), indicating a more drug-like profile.

**DILI:** Ligand B (66.77) has a higher DILI risk than Ligand A (49.166). Lower DILI is preferred.

**BBB:** Both have reasonable BBB penetration, but Ligand A (74.06) is slightly better than Ligand B (69.484). This isn't a primary concern for a kinase inhibitor, but a bonus.

**Caco-2 Permeability:** Ligand A (-4.865) is better than Ligand B (-5.492), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.809 and -2.807 respectively). This is a significant concern for both, but might be mitigated through formulation.

**hERG:** Both ligands have low hERG risk (0.28 and 0.057).

**Microsomal Clearance:** Ligand A (28.433) has a much better microsomal clearance than Ligand B (0.019). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-10.948) has a much longer in vitro half-life than Ligand B (-0.884).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.031 and 0.01).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly better binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Conclusion:**

Ligand A is clearly superior. It has a better QED score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better Caco-2 permeability, and, most importantly, a *much* stronger binding affinity. While both have poor solubility, the substantial advantage in potency and ADME properties of Ligand A outweighs this concern.

Output:
1
2025-04-17 14:42:48,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (349.387 and 368.478 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.37) is slightly higher than the preferred <140, but acceptable. Ligand B (67.35) is well within the optimal range.

**3. logP:** Ligand A (0.667) is a bit low, potentially hindering permeability. Ligand B (2.048) 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 6 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED scores (0.602 and 0.587), indicating reasonable drug-likeness.

**7. DILI:** Both ligands have similar and acceptable DILI risk (46.801 and 47.654).

**8. BBB:** Ligand A (65.297) and Ligand B (77.084) are both relatively low, which is not a major concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.817 and -4.986) which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.027 and -3.321) which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.226 and 0.479).

**12. Microsomal Clearance:** Ligand A (9.806) has significantly lower microsomal clearance than Ligand B (57.641), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.025) has a much longer half-life than Ligand B (3.245), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.051 and 0.077).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a substantial difference (1.3 kcal/mol), which can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better TPSA, Ligand B's significantly stronger binding affinity (-7.8 vs -6.5 kcal/mol) is a critical advantage for an enzyme inhibitor. The slightly lower logP of Ligand A is a concern. 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 initial optimization.

Output:
1
2025-04-17 14:42:48,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):**
*   Ligand A: 348.393 Da - Within the ideal range (200-500 Da).
*   Ligand B: 407.356 Da - Also within the ideal range.
*   *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 61.36 A<sup>2</sup> - Good for oral absorption (<=140 A<sup>2</sup>).
*   Ligand B: 51.02 A<sup>2</sup> - Also good for oral absorption.
*   *Slight advantage to B, lower TPSA generally favors permeability.*

**3. Lipophilicity (logP):**
*   Ligand A: 3.801 - Towards the higher end of optimal (1-3), but acceptable.
*   Ligand B: 4.066 - Slightly higher, potentially increasing off-target effects or solubility issues.
*   *Slight advantage to A.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 3 - Within the acceptable limit (<=5).
*   Ligand B: 0 - Also within the limit.
*   *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 2 - Within the acceptable limit (<=10).
*   Ligand B: 4 - Also within the limit.
*   *No clear advantage.*

**6. QED:**
*   Ligand A: 0.667 - Good drug-like profile (>=0.5).
*   Ligand B: 0.653 - Also good drug-like profile.
*   *No clear advantage.*

**7. DILI:**
*   Ligand A: 44.281 - Low risk of liver injury (<40 is good).
*   Ligand B: 38.736 - Even lower risk.
*   *Advantage to B.*

**8. BBB:**
*   Ligand A: 45.715 - Not a priority for a non-CNS target like SRC.
*   Ligand B: 87.088 - Not a priority.
*   *No clear advantage.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.972 - Indicates poor permeability.
*   Ligand B: -5.07 - Indicates poor permeability.
*   *No clear advantage.*

**10. Aqueous Solubility:**
*   Ligand A: -4.056 - Indicates poor solubility.
*   Ligand B: -3.857 - Indicates poor solubility.
*   *Slight advantage to B.*

**11. hERG Inhibition:**
*   Ligand A: 0.878 - Relatively low risk.
*   Ligand B: 0.341 - Very low risk.
*   *Advantage to B.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 70.399 mL/min/kg - Relatively high clearance, suggesting lower metabolic stability.
*   Ligand B: 81.261 mL/min/kg - Even higher clearance, suggesting even lower metabolic stability.
*   *Advantage to A.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: 0.384 hours - Very short half-life.
*   Ligand B: 5.061 hours - Longer half-life, more desirable.
*   *Advantage to B.*

**14. P-gp Efflux:**
*   Ligand A: 0.611 - Moderate efflux liability.
*   Ligand B: 0.623 - Moderate efflux liability.
*   *No clear advantage.*

**15. Binding Affinity:**
*   Ligand A: -8.9 kcal/mol - Excellent binding affinity.
*   Ligand B: -8.7 kcal/mol - Also excellent, but slightly weaker.
*   *Advantage to A.*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a significantly better binding affinity (-8.9 vs -8.7 kcal/mol), which is a major advantage. However, Ligand B shows better ADME properties regarding DILI, hERG, and in vitro half-life. While both have poor Caco-2 and solubility, the superior binding affinity of Ligand A is likely to outweigh these drawbacks, especially in early-stage optimization where potency is paramount. The higher clearance of Ligand A is a concern, but can be addressed through structural modifications.

Output:
1
2025-04-17 14:42:48,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.346 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.93) is slightly higher than Ligand B (75.88), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.927 and 1.178) 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 similar, good QED scores (0.74 and 0.748).

**DILI:** Ligand B (35.091) has a significantly lower DILI risk than Ligand A (74.254). This is a major advantage for Ligand B.

**BBB:** Ligand B (61.846) has a higher BBB penetration score than Ligand A (47.809), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.169) has a worse Caco-2 permeability than Ligand B (-4.478), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.851) has worse aqueous solubility than Ligand B (-1.304).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.075 and 0.089).

**Microsomal Clearance:** Ligand B (20.481) has significantly lower microsomal clearance than Ligand A (75.585), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-8.517) has a longer in vitro half-life than Ligand A (-35.05), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.187 and 0.029).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold that would strongly favor Ligand A despite other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates significantly better ADME properties, particularly regarding DILI risk and metabolic stability (lower Cl_mic and longer t1/2). The lower DILI and improved metabolic stability are crucial for a kinase inhibitor, outweighing the small difference in binding affinity. Solubility and permeability are also better for Ligand B.

Output:
1
2025-04-17 14:42:48,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 347.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.46) is slightly above the preferred <140, but acceptable. Ligand B (52.65) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands have good logP values (2.63 and 2.04), 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, <=10 HBA).

**QED:** Both ligands have similar QED scores (0.753 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (64.17) has a higher DILI risk than Ligand B (11.83). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (74.49) shows better potential for CNS penetration if needed.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially indicates issues with the experimental setup or prediction method. However, given the context, we'll assume this means very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.135) has a slightly higher hERG risk than Ligand B (0.369), but both are relatively low.

**Microsomal Clearance:** Ligand B (37.55) has significantly lower microsomal clearance than Ligand A (82.26), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (17.31) has a significantly longer half-life than Ligand A (-3.59), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.031).

**Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent and removes this as a differentiating factor.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher TPSA of Ligand A. While both have poor predicted solubility and permeability, metabolic stability is paramount for enzyme inhibitors, and Ligand B excels in this regard.

Output:
1
2025-04-17 14:42:48,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.415 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.4) is better than Ligand B (103.91). Both are acceptable, but lower TPSA generally favors better absorption.

**logP:** Ligand A (1.296) is better than Ligand B (0.488). Ligand B is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1), both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (7), both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.824 and 0.739), indicating good drug-likeness.

**DILI:** Ligand B (51.028) has a significantly lower DILI risk than Ligand A (61.846), making it preferable.

**BBB:** Ligand A (84.839) has a better BBB penetration percentile than Ligand B (49.787). However, BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.27 and -5.43), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.987 and -2.753), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.499) has a slightly better hERG profile than Ligand B (0.099), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (4.604 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (10.983 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (7.22 and 7.164 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.101 and 0.068).

**Binding Affinity:** Ligand B (-7.5 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 has a better binding affinity and a significantly lower DILI risk. However, it has a lower logP and higher microsomal clearance. Ligand A has better TPSA, logP, hERG, and microsomal clearance, but a higher DILI risk. The poor Caco-2 and solubility for both are major drawbacks. Given the importance of metabolic stability for kinase inhibitors, and the slightly better binding affinity of Ligand B, I would lean towards Ligand B, but with a strong caveat regarding the poor permeability and solubility. Further optimization would be needed to improve these properties.

Output:
1
2025-04-17 14:42:48,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.363 Da) is slightly better, being closer to the lower end which generally aids permeability.

**TPSA:** Ligand A (65.38) is significantly better than Ligand B (94.22). A TPSA under 140 is good for oral absorption, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (A: 3.204, B: 1.373), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=6) as it has fewer hydrogen bond donors and acceptors, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.798, B: 0.812), indicating good drug-like properties.

**DILI:** Ligand A (96.937) has a significantly higher DILI risk than Ligand B (42.613). This is a major concern for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (72.082) has better BBB penetration than Ligand B (17.642).

**Caco-2 Permeability:** Ligand A (-4.674) shows better Caco-2 permeability than Ligand B (-5.123).

**Aqueous Solubility:** Ligand A (-4.962) has slightly better solubility than Ligand B (-2.183).

**hERG Inhibition:** Ligand A (0.765) has a slightly higher hERG risk than Ligand B (0.208), but both are relatively low.

**Microsomal Clearance:** Ligand B (-11.285) has a *much* lower (better) microsomal clearance than Ligand A (64.237), indicating better metabolic stability. This is a critical advantage for Ligand B.

**In vitro Half-Life:** Ligand B (52.5) has a significantly longer half-life than Ligand A (23.549).

**P-gp Efflux:** Ligand A (0.534) has lower P-gp efflux than Ligand B (0.16), which is favorable.

**Binding Affinity:** Ligand B (-8.8 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 superior candidate. While Ligand A has slightly better permeability and a marginally better logP, the significantly higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter half-life) are major drawbacks. Ligand B's lower DILI risk, improved metabolic stability, and slightly better binding affinity outweigh the minor advantages of Ligand A. The enzyme-specific priorities strongly favor Ligand B.

Output:
1
2025-04-17 14:42:48,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 356.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (61.88) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (2.419) is optimal (1-3). Ligand B (4.065) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=3) both have reasonable values, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.776, B: 0.849), indicating drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (A: 41.915, B: 45.444), below the 60 threshold.

**BBB:** Ligand B (84.219) has a significantly higher BBB penetration score than Ligand A (53.742). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.948 and -4.694), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.471 and -4.199), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.284) has a lower hERG inhibition risk than Ligand B (0.796), which is preferable.

**Microsomal Clearance:** Ligand A (30.332) has a lower microsomal clearance than Ligand B (37.736), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.455) has a much longer in vitro half-life than Ligand B (17.871), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.135), which is favorable.

**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 a positive for Ligand B.

**Conclusion:**

Despite Ligand B's slightly better binding affinity, Ligand A is the more promising candidate. The key factors are Ligand A's superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. While both have poor solubility and permeability, the metabolic and safety profiles of Ligand A are more favorable for further development as an enzyme inhibitor. The small difference in binding affinity is unlikely to outweigh these significant ADME/Tox advantages.

Output:
0
2025-04-17 14:42:48,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.455 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.12) is better than Ligand B (104.46), both are acceptable but closer to the upper limit for good oral absorption.

**logP:** Both ligands have good logP values (2.358 and 1.682), falling within the optimal 1-3 range. Ligand B is slightly lower, potentially impacting permeability a bit more.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is slightly better than Ligand B (HBD=3, HBA=5) in terms of maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.748 and 0.679), indicating good drug-likeness.

**DILI:** Ligand A (58.976) has a higher DILI risk than Ligand B (45.948). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (57.774 and 58.085), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.235 and 0.068), which is excellent.

**Microsomal Clearance:** Ligand B (37.732) has significantly lower microsomal clearance than Ligand A (65.74), suggesting better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-30.976) has a negative half-life, which is not possible and indicates a significant issue with the data or the compound's stability. Ligand A (26.21) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.138 and 0.076), which is favorable.

**Binding Affinity:** Both ligands have identical binding affinities (-10.1 kcal/mol), which is excellent and strong.

**Overall Assessment:**

Despite the equal binding affinity, Ligand B is the more promising candidate. Its lower DILI risk and significantly lower microsomal clearance outweigh the slightly higher HBD count and lower logP. The negative Caco-2 and solubility values are concerning for both, but metabolic stability is a critical factor for kinase inhibitors. The negative half-life for Ligand B is a major red flag, however. Given the identical binding affinity, the lower DILI risk of Ligand B makes it slightly preferable, assuming the negative half-life is a data error.

Output:
1
2025-04-17 14:42:48,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.441 Da and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is better than Ligand B (103.35). Lower TPSA generally correlates with better cell permeability. Ligand A is well below the 140 A^2 threshold. Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.369 and 1.752), falling within the optimal 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 hydrogen bond donors, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.671 and 0.504), indicating drug-like properties. Ligand A is slightly better.

**DILI:** Both ligands have acceptable DILI risk (40.946 and 44.552), below the 60 threshold.

**BBB:** Ligand A (85.731) has a significantly better BBB percentile than Ligand B (54.634). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.197 and -5.142). This is unusual and suggests poor permeability *in vitro*. However, these values are very close and likely represent similar issues with the assay or molecule.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.121 and -2.803), indicating very poor aqueous solubility. This is a significant concern for *in vivo* bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.548 and 0.461), which is excellent.

**Microsomal Clearance:** Ligand A (30.857) has a significantly lower microsomal clearance than Ligand B (49.457), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (44.698) has a much longer in vitro half-life than Ligand A (-1.677). This is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.106 and 0.105).

**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 factor. A difference of >1.5 kcal/mol can often outweigh other ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, logP, HBD/HBA, QED, BBB, and Cl_mic, the significantly superior binding affinity of Ligand B (-7.9 vs 0.0 kcal/mol) is the dominant factor. The longer half-life of Ligand B is also a significant benefit. The poor solubility and permeability of both are concerning, but can potentially be addressed through formulation strategies. The strong binding affinity suggests that Ligand B is more likely to be effective *in vivo* despite its ADME liabilities.

Output:
1
2025-04-17 14:42:48,999 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [338.371, 93.96, 2.549, 2, 7, 0.687, 84.606, 72.237, -5.24, -3.815, 0.198, 35.897, 9.603, 0.368, 0]
**Ligand B:** [351.353, 82.53, 1.91, 2, 4, 0.866, 76.541, 46.026, -5.201, -4.053, 0.099, 5.023, 5.967, 0.01, -8.6]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (338.371) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** Both are reasonably good (A: 93.96, B: 82.53), below the 140 threshold for oral absorption. B is better, being closer to the 90 threshold.
3. **logP:** Both are within the optimal range (1-3). A (2.549) is slightly higher, which isn't a major concern.
4. **HBD:** Both have 2 HBD, which is acceptable.
5. **HBA:** A has 7 HBA, B has 4 HBA. B is better here, lower HBA generally improves permeability.
6. **QED:** Both have good QED scores (A: 0.687, B: 0.866). B is significantly better, indicating a more drug-like profile.
7. **DILI:** Both have high DILI risk (A: 84.606, B: 76.541), but B is lower, suggesting a slightly reduced risk of liver injury.
8. **BBB:** A has a good BBB percentile (72.237), but B is significantly lower (46.026). Since SRC is not a CNS target, this is less critical.
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 indicates very poor aqueous solubility. This is a major drawback for both.
11. **hERG:** Both have very low hERG risk (A: 0.198, B: 0.099). B is slightly better.
12. **Cl_mic:** A has a higher microsomal clearance (35.897) than B (5.023), indicating faster metabolism and lower metabolic stability. This is a significant advantage for B.
13. **t1/2:** A has a longer in vitro half-life (9.603) than B (5.967), which is generally desirable.
14. **Pgp:** Both have very low Pgp efflux liability (A: 0.368, B: 0.01). B is significantly better.
15. **Binding Affinity:** B has a much stronger binding affinity (-8.6 kcal/mol) compared to A (0 kcal/mol). This is a *major* advantage for B, easily outweighing most other concerns.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both compounds have issues with solubility and Caco-2 permeability, B excels in binding affinity and metabolic stability. The significantly stronger binding affinity of B (-8.6 kcal/mol) is a crucial advantage. The lower Cl_mic also indicates better metabolic stability.

**Conclusion:**

Despite the poor solubility and permeability indicated by the Caco-2 values, **Ligand B** is the more promising drug candidate due to its significantly superior binding affinity and metabolic stability. The strong binding affinity is likely to outweigh the solubility/permeability issues, and formulation strategies can be explored to address those challenges.

Output:
1
2025-04-17 14:42:48,999 - INFO - Batch 319 complete. Total preferences: 5104
2025-04-17 14:42:48,999 - INFO - Processing batch 320/512...
2025-04-17 14:43:36,790 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.5 and 370.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.9) is slightly higher than Ligand B (58.6). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (1.23) is within the optimal 1-3 range. Ligand B (2.69) is also good, but closer to the upper limit.

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

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

**QED:** Both ligands have similar QED values (0.654 and 0.678), indicating good drug-likeness.

**DILI:** Ligand A (4.65) has a significantly lower DILI risk than Ligand B (9.89). This is a major advantage for Ligand A.

**BBB:** Ligand B (83.6) has a much higher BBB penetration score than Ligand A (51.2). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.13 and -5.02), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.72 and -2.67), indicating poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.41) shows lower hERG inhibition risk than Ligand B (0.55), which is preferable.

**Microsomal Clearance:** Ligand A (1.49) has significantly lower microsomal clearance than Ligand B (50.06). This suggests better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (0.33) has a very short half-life, while Ligand B (-3.89) is also concerning. Both need improvement.

**P-gp Efflux:** Ligand A (0.04) has very low P-gp efflux, while Ligand B (0.10) is slightly higher. Lower is better.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (0.0). This is a significant advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

Ligand A is the better candidate. While both have solubility and permeability concerns, Ligand A demonstrates superior metabolic stability (lower Cl_mic), lower DILI risk, lower hERG risk, lower P-gp efflux, and slightly better binding affinity. The better binding affinity is a crucial advantage for an enzyme inhibitor. The slightly better BBB score for Ligand B is irrelevant given the target. The poor solubility and permeability of both compounds would need to be addressed through formulation or structural modifications, but Ligand A's other properties make it a more promising starting point.

Output:
0
2025-04-17 14:43:36,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.5 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.58) is well below the 140 threshold, while Ligand B (123.92) is still acceptable but higher.

**logP:** Ligand A (0.983) is at the lower end of optimal, but acceptable. Ligand B (-0.83) is below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (2) is acceptable.

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (8) is approaching the upper limit but still acceptable.

**QED:** Both ligands have similar QED values (0.752 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (28.5) has a much lower DILI risk than Ligand B (82.4), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.8) is lower than Ligand B (50.7).

**Caco-2:** Ligand A (-4.975) and Ligand B (-5.36) are both negative, indicating poor permeability.

**Solubility:** Ligand A (-0.919) is better than Ligand B (-1.94), both are poor.

**hERG:** Ligand A (0.61) has a lower hERG risk than Ligand B (0.174), which is a potential safety concern.

**Microsomal Clearance:** Ligand A (1.072) has significantly lower clearance than Ligand B (16.862), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.314) has a better half-life than Ligand B (23.75).

**P-gp Efflux:** Ligand A (0.057) has lower P-gp efflux than Ligand B (0.009).

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.8), a 0.6 kcal/mol difference.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, but Ligand A is superior in almost all other critical ADME-Tox properties. Specifically, Ligand A has a much lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and better solubility. The slightly weaker binding affinity of Ligand A can potentially be optimized through further medicinal chemistry efforts, while the poor ADME profile of Ligand B would be more challenging to address. Given the enzyme-specific priorities, Ligand A is the more promising candidate.

Output:
1
2025-04-17 14:43:36,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.328 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.83) is well below the 140 threshold for oral absorption, while Ligand B (89.35) is also acceptable, but closer to the limit.

**logP:** Ligand A (2.966) is optimal (1-3). Ligand B (0.761) is slightly low, potentially hindering permeation.

**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 are below the limit of 10.

**QED:** Both ligands have good QED scores (0.598 and 0.848, respectively), indicating drug-likeness.

**DILI:** Ligand A (52.966) has a slightly higher DILI risk than Ligand B (48.585), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.945) has better BBB penetration than Ligand B (51.221), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.514) has better Caco-2 permeability than Ligand B (-5.068), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.001) has better solubility than Ligand B (-1.711). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.686) has a lower hERG risk than Ligand B (0.096), which is a significant advantage.

**Microsomal Clearance:** Ligand A (73.146) has higher microsomal clearance than Ligand B (17.522), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (12.906) has a significantly longer half-life than Ligand A (-8.352), which is a major advantage.

**P-gp Efflux:** Ligand A (0.567) has lower P-gp efflux than Ligand B (0.019), which is favorable.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial factor for enzyme inhibitors, and the 1.9 kcal/mol difference is substantial.

**Conclusion:**

Despite Ligand A having slightly better solubility and P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-10.1 vs -8.1 kcal/mol) and longer half-life (12.906 vs -8.352) outweigh the slightly lower logP and higher P-gp efflux. The lower hERG risk of Ligand A is a plus, but the potency and metabolic stability advantages of Ligand B are more critical for an enzyme target.

Output:
1
2025-04-17 14:43:36,791 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [334.507, 24.06, 4.437, 2, 2, 0.845, 10.779, 87.631, -5.198, -3.15, 0.935, -9.301, 0.758, 0.238, 0]
**Ligand B:** [384.531, 96.17, 1.391, 2, 9, 0.752, 69.135, 71.888, -5.761, -2.7, 0.056, 23.011, 6.626, 0.091, -7.8]

**Step-by-step comparison:**

1. **MW:** Ligand A (334.5) is within the ideal range (200-500). Ligand B (384.5) is also acceptable.
2. **TPSA:** Ligand A (24.06) is excellent, well below the 140 threshold. Ligand B (96.17) is higher, but still potentially acceptable for a non-CNS target.
3. **logP:** Ligand A (4.437) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.391) is optimal.
4. **HBD:** Both ligands have 2 HBD, which is good.
5. **HBA:** Ligand A (2) is good. Ligand B (9) is at the upper limit, but still acceptable.
6. **QED:** Both ligands have similar QED values (0.845 and 0.752), indicating good drug-likeness.
7. **DILI:** Ligand A (10.779) has a very favorable DILI risk. Ligand B (69.135) is higher, indicating a moderate risk.
8. **BBB:** Ligand A (87.631) has good BBB penetration, while Ligand B (71.888) is moderate. This isn't a primary concern for SRC kinase, which isn't a CNS target.
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 ligands have negative solubility values, which is also concerning.
11. **hERG:** Ligand A (0.935) has a slightly elevated hERG risk, while Ligand B (0.056) is very low.
12. **Cl_mic:** Ligand A (-9.301) has a very low (and negative) microsomal clearance, suggesting excellent metabolic stability. Ligand B (23.011) has a moderate clearance.
13. **t1/2:** Ligand A (0.758) has a short half-life. Ligand B (6.626) has a much longer half-life, which is desirable.
14. **Pgp:** Ligand A (0.238) has low P-gp efflux. Ligand B (0.091) also has low P-gp efflux.
15. **Affinity:** Ligand B (-7.8) has significantly better binding affinity than Ligand A (0). This is a crucial factor.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. It has a substantially better binding affinity (-7.8 vs 0 kcal/mol), a longer half-life, and a much lower hERG risk. While its DILI risk is higher than Ligand A, the superior affinity and metabolic properties outweigh this concern, especially since the DILI risk is still within a moderate range. The slightly higher TPSA of Ligand B is not a major drawback for a non-CNS target.

Output:
1
2025-04-17 14:43:36,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly higher than Ligand B (339.363 Da), but both are acceptable.

**TPSA:** Ligand A (76.66) is well below the 140 threshold for good oral absorption. Ligand B (116.3) is still within range, but less optimal.

**logP:** Ligand A (2.614) is within the optimal 1-3 range. Ligand B (-0.413) is below 1, which may hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 9 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.691 and 0.671), indicating good drug-likeness.

**DILI:** Ligand A (36.603) has a significantly lower DILI risk than Ligand B (82.862). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (63.668) and Ligand B (46.336) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.604) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-6.024) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.979) has poor aqueous solubility, while Ligand B (-1.168) is also poor, but better than Ligand A.

**hERG:** Both ligands have very low hERG inhibition risk (0.294 and 0.034), which is excellent.

**Microsomal Clearance:** Ligand A (34.814) has a higher microsomal clearance than Ligand B (13.142), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (11.379 hours) has a significantly longer in vitro half-life than Ligand A (4.406 hours), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.02), which is favorable.

**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 is still a positive for Ligand B.

**Overall Assessment:**

Ligand B is preferable due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), better binding affinity, and lower DILI risk. While Ligand A has a better logP and slightly better TPSA, the issues with solubility, Caco-2 permeability, and metabolic stability are significant drawbacks. The affinity difference is not large enough to overcome these ADME issues for Ligand A.

Output:
1
2025-04-17 14:43:36,791 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 362.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (125.8). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Both ligands have good logP values (1.957 and 1.118), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 8 HBA). Lower counts generally improve permeability.

**QED:** Ligand A (0.856) has a much better QED score than Ligand B (0.595), indicating better overall drug-likeness.

**DILI:** Ligand A (14.696) has a significantly lower DILI risk than Ligand B (98.061). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (74.06) is better than Ligand B (49.011).

**Caco-2 Permeability:** Ligand A (-5.148) is better than Ligand B (-5.539), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.105) is better than Ligand B (-3.486), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.144) has a much lower hERG risk than Ligand B (0.527), a critical safety parameter.

**Microsomal Clearance:** Ligand B (39.565) has slightly better microsomal clearance than Ligand A (35.828), suggesting better metabolic stability. However, the difference is not substantial.

**In vitro Half-Life:** Ligand B (24.073) has a significantly longer half-life than Ligand A (-3.69). This is a positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.036) exhibits less P-gp efflux than Ligand B (0.026), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.1), but the difference is only 0.6 kcal/mol. Given the other significant advantages of Ligand A, this difference is unlikely to be decisive.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in drug-likeness (QED), safety (DILI, hERG), solubility, and permeability. While Ligand B has a slightly better half-life and binding affinity, the substantial advantages of Ligand A in ADME-Tox properties outweigh these minor benefits. The lower DILI and hERG risks for Ligand A are particularly important for a kinase inhibitor intended for oncology, where long-term treatment is often required.

Output:
0
2025-04-17 14:43:36,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.387 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (104.39) is better than Ligand B (62.66). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (2.957) is optimal (1-3), while Ligand A (-0.126) is quite low. This is a significant drawback for Ligand A, potentially hindering membrane permeability and bioavailability.

**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 (0.776) has a much better QED score than Ligand A (0.368), indicating a more drug-like profile.

**DILI:** Ligand B (55.176) has a slightly higher DILI risk than Ligand A (44.164), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (67.197) has a higher BBB percentile than Ligand A (23.071), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.338) and Ligand B (-4.482) both have negative Caco-2 values, which is unusual and indicates poor permeability.

**Aqueous Solubility:** Ligand A (-1.686) and Ligand B (-3.698) both have negative solubility values, which is also unusual and indicates poor solubility.

**hERG Inhibition:** Ligand A (0.14) has a lower hERG risk than Ligand B (0.711), which is a positive attribute.

**Microsomal Clearance:** Ligand A (-6.742) has a *much* lower (better) microsomal clearance than Ligand B (82.283). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-17.741) has a slightly lower in vitro half-life than Ligand B (-16.553), but both are negative, which is unusual and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.033) has a much lower P-gp efflux liability than Ligand B (0.241), indicating better absorption and bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has a significant advantage in metabolic stability (Cl_mic), P-gp efflux, and hERG risk. While its logP is low and Caco-2/Solubility are poor, the superior metabolic profile and lower toxicity risk are crucial for an enzyme target. Ligand B's better affinity is not enough to compensate for its poor metabolic stability and higher P-gp efflux. The poor solubility and permeability for both compounds are concerning, but can be addressed with formulation strategies.

Output:
0
2025-04-17 14:43:36,792 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [410.258, 38.33, 4.546, 1, 2, 0.759, 50.911, 79.217, -4.362, -5.557, 0.6, 79.952, 5.47, 0.395, -8.9]
**Ligand B:** [349.431, 86.88, 1.565, 1, 5, 0.872, 22.722, 73.827, -4.844, -1.015, 0.166, 27.207, -13.312, 0.087, -8.1]

**Step-by-step comparison:**

1. **MW:** Ligand A (410.258 Da) is within the ideal range. Ligand B (349.431 Da) is also acceptable, though on the lower side.
2. **TPSA:** Ligand A (38.33) is excellent, well below the 140 threshold. Ligand B (86.88) is still reasonable, but higher, potentially impacting absorption.
3. **logP:** Ligand A (4.546) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.565) is a bit low, which could hinder membrane permeability.
4. **HBD:** Both ligands have 1 HBD, which is good.
5. **HBA:** Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are acceptable, but Ligand A is preferable.
6. **QED:** Both ligands have good QED scores (A: 0.759, B: 0.872), indicating drug-like properties.
7. **DILI:** Ligand A (50.911) has a moderate DILI risk. Ligand B (22.722) has a very low DILI risk, a significant advantage.
8. **BBB:** Both have reasonable BBB penetration (A: 79.217, B: 73.827), but not critical for an oncology target.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, both are very poor.
10. **Solubility:** Ligand A (-5.557) has poor solubility. Ligand B (-1.015) has better, but still poor solubility.
11. **hERG:** Ligand A (0.6) has a low hERG risk. Ligand B (0.166) has a very low hERG risk.
12. **Cl_mic:** Ligand A (79.952) has a high microsomal clearance, suggesting poor metabolic stability. Ligand B (27.207) has a much lower clearance, indicating better metabolic stability.
13. **t1/2:** Ligand A (5.47) has a short in vitro half-life. Ligand B (-13.312) has a very long half-life.
14. **Pgp:** Ligand A (0.395) has low P-gp efflux. Ligand B (0.087) has very low P-gp efflux.
15. **Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This is a 0.8 kcal/mol difference, which is significant.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better in terms of metabolic stability (Cl_mic and t1/2), DILI risk, and Pgp efflux. The solubility is still a concern for both, but Ligand B is better. The higher logP of Ligand A is also a concern. The difference in affinity (0.8 kcal/mol) is not large enough to overcome the substantial advantages of Ligand B in ADME-Tox properties crucial for kinase inhibitors.

Therefore, I recommend prioritizing **Ligand B**.

1
2025-04-17 14:43:36,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.379 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.81) is higher than Ligand B (76.46). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.424) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (0.644) is also a bit low, but closer to the desired range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 8 HBA, 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 (0.765 and 0.82), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (69.794%) compared to Ligand B (17.371%). This is a major concern for Ligand A.

**BBB:** Both have similar BBB penetration (79.488% and 78.247%), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.609 and -4.871). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.689 and -1.504). This is also concerning and could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.058) has a slightly lower hERG risk than Ligand B (0.226), which is favorable.

**Microsomal Clearance:** Ligand A (48.057) has a higher microsomal clearance than Ligand B (2.874). This indicates Ligand B is more metabolically stable, a critical factor for enzymes.

**In vitro Half-Life:** Ligand B (6.843) has a significantly longer in vitro half-life than Ligand A (-2.918). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013).

**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 is still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The slightly better binding affinity further supports its selection. The lower TPSA and HBA count are also favorable.

Output:
1
2025-04-17 14:43:36,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.515 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is better than Ligand B (86.88). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (1.603 and 2.481), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=3, HBA=3). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have reasonable QED scores (0.833 and 0.722), indicating good drug-like properties.

**DILI:** Ligand A (28.228) has a significantly lower DILI risk than Ligand B (38.348), which is a major advantage.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.416) and Ligand B (-5.074) have similar, very low Caco-2 permeability values. This is a potential concern for oral bioavailability.

**Aqueous Solubility:** Ligand A (-2.087) is slightly better than Ligand B (-3.474), but both are quite poor. Solubility could be a formulation challenge.

**hERG:** Ligand A (0.112) has a much lower hERG risk than Ligand B (0.54), which is a critical advantage.

**Microsomal Clearance:** Ligand B (25.977) has a lower microsomal clearance than Ligand A (28.094), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.498) has a significantly longer in vitro half-life than Ligand A (1.48), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.057 and 0.046).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). The difference is 1.3 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG) and slightly better binding affinity. While Ligand B has better metabolic stability and half-life, the safety concerns with Ligand B are more critical, especially the hERG risk. The slightly lower solubility of Ligand A is a manageable issue compared to the potential cardiotoxicity of Ligand B.

Output:
0
2025-04-17 14:43:36,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 345.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.59) is better than Ligand B (79.7), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (3.06) is optimal (1-3), while Ligand B (-0.337) is significantly below 1, potentially hindering permeation. This is a major drawback for Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable (<=10).

**QED:** Both have similar QED values (0.883 and 0.808), indicating good drug-likeness.

**DILI:** Ligand A (46.995) has a slightly higher DILI risk than Ligand B (39.977), but both are below the 40 threshold, indicating low risk.

**BBB:** Ligand A (77.821) has a better BBB percentile than Ligand B (67.623). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.771) is worse than Ligand B (-5.08), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.571) is better than Ligand B (-2.451), both are negative indicating poor solubility.

**hERG:** Ligand A (0.545) has a slightly higher hERG risk than Ligand B (0.341), but both are relatively low.

**Microsomal Clearance:** Ligand A (56.644) has a higher microsomal clearance than Ligand B (26.605), meaning Ligand B is more metabolically stable. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (11.736) has a longer half-life than Ligand B (7.524). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.339) has lower P-gp efflux than Ligand B (0.014), which is beneficial for bioavailability.

**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 crucial factor for an enzyme inhibitor. The difference of 8.3 kcal/mol is substantial and likely outweighs many of the ADME drawbacks.

**Conclusion:**

Despite Ligand B having better metabolic stability and a slightly lower DILI risk, Ligand A's dramatically superior binding affinity (-8.3 vs. 0.0 kcal/mol) makes it the far more promising drug candidate. The potency advantage is so large that it likely compensates for the slightly worse ADME properties. The low logP of Ligand B is a significant concern, potentially leading to poor absorption.

Output:
1
2025-04-17 14:43:36,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (387.439 and 368.811 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.72) is better than Ligand B (45.48) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (-0.727) is slightly low, potentially hindering permeation, while Ligand B (4.978) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 2 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.703 and 0.812, respectively), indicating drug-like properties.

**DILI:** Ligand A (72.547) has a higher DILI risk than Ligand B (49.399), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (94.61) is higher, but this is less important.

**Caco-2 Permeability:** Ligand A (-5.502) is very poor, while Ligand B (-4.529) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.775) is very poor, while Ligand B (-5.44) is also poor. Both are problematic.

**hERG Inhibition:** Ligand A (0.045) has a very low hERG risk, which is excellent. Ligand B (0.76) has a moderate risk.

**Microsomal Clearance:** Ligand A (-17.764) has a significantly lower (better) microsomal clearance than Ligand B (8.144), indicating greater metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (68.248 and 72.045 hours).

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is good. Ligand B (0.204) has slightly higher efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.4 kcal/mol), with Ligand B being slightly stronger. However, the difference is small and may not outweigh other factors.

**Overall Assessment:**

Ligand A is preferable despite its lower logP and solubility due to its significantly better metabolic stability (lower Cl_mic), very low hERG risk, and very low P-gp efflux. The slightly stronger binding affinity of Ligand B is unlikely to compensate for its higher DILI risk, higher logP, and worse metabolic stability. The poor Caco-2 and solubility of both are concerning, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 14:43:36,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.382 Da) is slightly lower, which could be beneficial for permeability. Ligand B (351.403 Da) is also good.

**TPSA:** Ligand A (44.76) is significantly better than Ligand B (93.9). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much more likely to have good absorption.

**logP:** Ligand A (3.783) is optimal, while Ligand B (0.619) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (1 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improves permeability.

**QED:** Both ligands have good QED scores (A: 0.54, B: 0.836), indicating generally drug-like properties. Ligand B is slightly better here.

**DILI:** Both ligands have acceptable DILI risk (A: 61.031, B: 58.976), though ligand B is slightly better.

**BBB:** Ligand A (83.288) has a better BBB penetration score than Ligand B (57.968), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.471 and -4.652). This is unusual and suggests poor permeability, but the scale is not clearly defined.

**Aqueous Solubility:** Both have negative solubility values (-5.186 and -1.919). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.849) is better than Ligand B (0.196). Lower hERG inhibition is crucial to avoid cardiotoxicity. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (105.188) has higher clearance than Ligand B (11.186). This means Ligand B is more metabolically stable, which is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (23.378 hours) has a much longer half-life than Ligand A (-5.549 hours). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.656) has lower P-gp efflux than Ligand B (0.045), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand B's better metabolic stability and half-life, and significantly better binding affinity, the poor solubility and permeability (indicated by negative Caco-2 and solubility values) are concerning. Ligand A has much better predicted permeability (lower TPSA, better logP) and lower hERG risk. While its binding affinity is weaker, the better ADME profile, particularly the solubility and permeability, makes it a more promising starting point for optimization. The affinity difference, while significant, is not insurmountable with medicinal chemistry efforts.

Output:
0
2025-04-17 14:43:36,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (354.51 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is well below the 140 threshold and very favorable. Ligand B (87.66) is still under the 140 threshold, but less ideal than A.

**3. logP:** Ligand A (3.933) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (1.118) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher than ideal.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (4) is acceptable.

**6. QED:** Both ligands have similar QED values (0.65 and 0.642), indicating good drug-like properties.

**7. DILI:** Ligand A (29.081) has a very low DILI risk, which is excellent. Ligand B (14.889) also has a low DILI risk, but higher than A.

**8. BBB:** Ligand A (97.053) shows excellent BBB penetration, while Ligand B (53.587) is lower. While BBB isn't a primary concern for a kinase inhibitor, it's a bonus.

**9. Caco-2 Permeability:** Ligand A (-4.461) is poor, while Ligand B (-5.197) is even worse. Both are problematic.

**10. Aqueous Solubility:** Ligand A (-4.189) is poor, while Ligand B (-1.802) is better, but still not great.

**11. hERG Inhibition:** Ligand A (0.911) has a low hERG risk. Ligand B (0.156) is very low, excellent.

**12. Microsomal Clearance:** Ligand A (64.726) is relatively high, suggesting faster metabolism. Ligand B (10.266) is much lower, indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (2.603) has a short half-life. Ligand B (27.442) has a much longer half-life, a significant advantage.

**14. P-gp Efflux:** Ligand A (0.846) is moderate. Ligand B (0.014) is very low, suggesting minimal efflux.

**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 substantial difference (over 1.5 kcal/mol) and a major factor.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk, the significantly stronger binding affinity of Ligand A (-8.9 vs -7.2 kcal/mol) outweighs its drawbacks, particularly given that we are dealing with an enzyme target. The poor Caco-2 and solubility of both are concerns, but can be addressed with formulation strategies. The lower DILI risk of Ligand A is also a plus. The strong binding affinity suggests a higher probability of achieving efficacy.

Output:
1
2025-04-17 14:43:36,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.475 and 395.561 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.53) is slightly above the optimal <140, while Ligand B (91.83) is well within the range.

**logP:** Ligand A (0.053) is quite low, potentially hindering permeability. Ligand B (0.471) is also low, but better than A. Both are below 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:** Both ligands have similar, good QED values (0.66 and 0.675).

**DILI:** Both ligands have moderate DILI risk (44.087 and 47.615), not ideal but not alarming.

**BBB:** Ligand A (42.924) has poor BBB penetration, while Ligand B (78.209) is better, though not exceptional. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.719) has very poor Caco-2 permeability, a significant concern. Ligand B (-4.826) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.028) has poor solubility, while Ligand B (-3.35) is even worse. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.375 and 0.5), which is positive.

**Microsomal Clearance:** Ligand A (28.48) has lower microsomal clearance than Ligand B (39.271), suggesting better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (-8.745) has a significantly longer in vitro half-life than Ligand B (-11.551), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have negligible P-gp efflux (0.053 and 0.061).

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

**Overall Assessment:**

Ligand A's primary weaknesses are its low logP, poor Caco-2 permeability, and poor solubility. However, it has significantly better metabolic stability (lower Cl_mic and longer t1/2) and a slightly better DILI score. Ligand B has slightly better affinity, but suffers from even worse solubility and comparable permeability issues. Given the importance of metabolic stability for kinase inhibitors, and the fact that the affinity difference is small, Ligand A is the slightly more promising candidate. The poor solubility of both compounds would need to be addressed through formulation strategies.

Output:
0
2025-04-17 14:43:36,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.422 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is slightly higher than Ligand B (49.85), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.45) is within the optimal 1-3 range, while Ligand B (2.365) is also acceptable.

**H-Bond Donors:** Both ligands have 0 HBD, which is favorable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.64) has a better QED score than Ligand B (0.385), indicating a more drug-like profile.

**DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (31.059), which is a major advantage.

**BBB:** Ligand A (87.941) has a higher BBB penetration score than Ligand B (69.794). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.659) has a lower (worse) Caco-2 permeability than Ligand B (-4.519), but both are quite poor.

**Aqueous Solubility:** Ligand A (-0.469) has slightly better solubility than Ligand B (-2.195), which is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.479 and 0.415 respectively).

**Microsomal Clearance:** Ligand A (22.46) has a slightly lower microsomal clearance than Ligand B (26.288), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (8.515) has a longer in vitro half-life than Ligand A (6.336), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.286 respectively).

**Binding Affinity:** Ligand A (-7.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is the most critical factor for an enzyme inhibitor. The 7 kcal/mol difference is substantial.

**Conclusion:**

Despite Ligand B having a slightly better half-life and Caco-2 permeability, Ligand A is the superior candidate. The significantly stronger binding affinity (-7.0 vs -0.0 kcal/mol) outweighs the minor drawbacks in half-life and permeability. Furthermore, Ligand A exhibits a much lower DILI risk and a better QED score, making it a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 14:43:36,794 - INFO - Batch 320 complete. Total preferences: 5120
2025-04-17 14:43:36,794 - INFO - Processing batch 321/512...
2025-04-17 14:44:17,555 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.439 and 388.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.45 and 78.87) are below the 140 A^2 threshold for good absorption.

**logP:** Both ligands (2.387 and 2.004) 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 4 HBA, and Ligand B has 5 HBA, both are within the acceptable range (<=10).

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (29.779) has a significantly lower DILI risk than Ligand B (50.136). This is a major advantage for Ligand A.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC kinase, but Ligand B (65.917) has a slightly higher value than Ligand A (54.44).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.18) is slightly better than Ligand B (-4.983), but both are concerning.

**Aqueous Solubility:** Ligand A (-1.992) has better aqueous solubility than Ligand B (-3.718). This is beneficial for bioavailability.

**hERG:** Ligand A (0.411) has a lower hERG risk than Ligand B (0.777), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-11.233) has a much lower (better) microsomal clearance than Ligand B (14.276). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (14.677 hours) has a shorter half-life than Ligand B (20.675 hours), but both are reasonable.

**P-gp Efflux:** Ligand A (0.059) has lower P-gp efflux liability than Ligand B (0.181), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity, which is crucial for an enzyme inhibitor. However, Ligand A demonstrates a significantly better safety profile (lower DILI, lower hERG) and superior ADME properties (better solubility, lower clearance, lower P-gp efflux). While both have poor Caco-2 permeability, the other advantages of Ligand A are compelling. Given the enzyme-specific priorities, the improved metabolic stability and reduced toxicity risks of Ligand A make it a more promising candidate, despite the slightly weaker binding affinity. The 1.2 kcal/mol difference in binding could potentially be addressed through further optimization, while fixing the poor permeability and safety issues would be more challenging.

Output:
0
2025-04-17 14:44:17,555 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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, while Ligand B (370.45 Da) is still well within the range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (95.42). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.804) is optimal, while Ligand B (0.546) is a bit low, potentially hindering membrane permeation.

**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 reasonable QED scores (A: 0.864, B: 0.731), indicating good drug-like properties.

**DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (23.769). This is a significant concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (A: 76.58, B: 68.282), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.71) has poor Caco-2 permeability, while Ligand B (-5.096) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.95) has better aqueous solubility than Ligand B (-1.734). This is a positive attribute.

**hERG Inhibition:** Ligand A (0.263) has a lower hERG risk than Ligand B (0.123), which is favorable.

**Microsomal Clearance:** Ligand A (46.643) has a higher microsomal clearance than Ligand B (4.245), indicating faster metabolism and potentially lower *in vivo* exposure. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (6.432) has a shorter half-life than Ligand B (-25.554, which is excellent).

**P-gp Efflux:** Ligand A (0.179) has lower P-gp efflux than Ligand B (0.008), suggesting better bioavailability.

**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.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity, better solubility, lower hERG risk, and lower P-gp efflux. However, it suffers from poorer Caco-2 permeability, higher DILI risk, and significantly faster metabolic clearance (higher Cl_mic, shorter half-life). Ligand B has a lower binding affinity, but exhibits a much better safety profile (lower DILI) and superior metabolic stability (lower Cl_mic, longer half-life).

Given that we are targeting a kinase (enzyme), metabolic stability and safety are critical. The substantial difference in binding affinity (-8.9 vs -7.6 kcal/mol) is meaningful, but the poor metabolic stability and higher DILI risk of Ligand A are major concerns. While a difference of 1.3 kcal/mol is good, it is unlikely to overcome the ADME liabilities of Ligand A. Ligand B, despite its weaker binding, presents a more balanced profile with a significantly better chance of becoming a viable drug candidate.

Output:
1
2025-04-17 14:44:17,555 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.329 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (370.871 Da) is also good.

**TPSA:** Ligand A (93.37) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (32.34) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (1.242) is within the optimal range (1-3). Ligand B (4.261) is a bit high, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 7 HBAs, which is at the upper end of the preferred range but still acceptable. Ligand B has only 2 HBAs, which is favorable.

**QED:** Both ligands have reasonable QED scores (A: 0.84, B: 0.759), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 69.135, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (17.449), a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (93.098) is significantly higher than Ligand A (70.609). While SRC isn't a CNS target, higher BBB penetration can sometimes correlate with better overall distribution.

**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 aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.121, B: 0.942), which is excellent.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-0.718), which is excellent, indicating high metabolic stability. Ligand B has a high Cl_mic (39.717), suggesting rapid metabolism and potentially low bioavailability.

**In vitro Half-Life:** Ligand A has a very short half-life (-28.978), which is a significant concern. Ligand B has a better half-life (9.481), but it's still not ideal.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.024, B: 0.569), which is favorable.

**Binding Affinity:** Both have very similar and strong binding affinities (-9.7 kcal/mol and -9.5 kcal/mol). The difference of 0.2 kcal/mol is unlikely to be decisive.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While it has a higher logP and negative solubility, its significantly lower DILI risk and much better microsomal clearance outweigh these drawbacks. Ligand A's extremely short half-life is a major concern, and its higher DILI risk is also unfavorable. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 14:44:17,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.463 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.75) is slightly higher than Ligand B (75.8), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.04) is suboptimal, potentially leading to permeability issues. Ligand B (2.462) 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:** Ligand A (4) and Ligand B (5) are both acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.659 and 0.853, respectively), indicating drug-like properties.

**DILI:** Ligand A (8.802) has a significantly lower DILI risk than Ligand B (19.349), which is a major advantage.

**BBB:** Ligand A (50.058) has a lower BBB penetration than Ligand B (82.513), but BBB is not a primary concern for SRC kinase inhibitors unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.124) has poor Caco-2 permeability, while Ligand B (-4.557) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.106) has poor aqueous solubility, while Ligand B (-2.16) is even worse.

**hERG Inhibition:** Ligand A (0.107) shows very low hERG inhibition risk, a significant advantage. Ligand B (0.43) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-15.545) has much lower microsomal clearance (better metabolic stability) than Ligand B (59.54). This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-0.532) has a slightly negative half-life, which is unusual and suggests rapid metabolism or instability. Ligand B (19.18) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is favorable. Ligand B (0.237) has slightly higher P-gp efflux.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger 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:**

Ligand A has a much stronger binding affinity and significantly better metabolic stability (lower Cl_mic) and lower DILI risk, and lower hERG risk. While its solubility and Caco-2 permeability are poor, the strong binding affinity and improved safety profile are more critical for an enzyme inhibitor like an SRC kinase inhibitor. Ligand B has better solubility and permeability but is offset by higher DILI, higher hERG, and weaker binding.

Output:
0
2025-04-17 14:44:17,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.4 and 355.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than the ideal <140, but acceptable. Ligand B (66.07) is well within the acceptable range.

**logP:** Both ligands have logP values within the optimal 1-3 range (1.619 and 2.934 respectively).

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within the desirable limits.

**QED:** Ligand B (0.883) has a significantly better QED score than Ligand A (0.577), indicating a more drug-like profile.

**DILI:** Ligand A (62.35) has a moderate DILI risk, while Ligand B (85.227) has a high DILI risk. This is a significant concern for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (78.79) has a higher BBB score than Ligand A (48.391), but this is not a major factor in this decision.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value for Ligand A (-4.937) is slightly less negative than Ligand B (-4.913).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-4.65) is slightly worse than Ligand A (-2.682).

**hERG:** Ligand A (0.193) has a very low hERG risk, which is highly desirable. Ligand B (0.898) has a higher hERG risk, raising a safety concern.

**Microsomal Clearance:** Ligand A (-5.24) has a negative clearance, suggesting excellent metabolic stability. Ligand B (33.723) has a significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (7.735) has a better in vitro half-life than Ligand B (28.358).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.037 and 0.09 respectively).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >2 kcal/mol difference, which is a significant advantage.

**Conclusion:**

Despite Ligand B's superior binding affinity, the combination of high DILI risk, higher hERG risk, and significantly faster metabolic clearance makes it a less attractive candidate. Ligand A, while having a weaker binding affinity, exhibits a much better safety profile (low DILI and hERG) and excellent metabolic stability. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand A. Therefore, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 14:44:17,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.5 and 348.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.7) is slightly higher than Ligand B (67.7), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (4.08) is higher than the optimal range of 1-3, potentially causing solubility issues. Ligand B (0.938) is a bit low, potentially hindering permeation, but less concerning than A's high logP.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (0 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.817 and 0.794), indicating good drug-likeness.

**DILI:** Ligand A (64.5) has a higher DILI risk than Ligand B (40.2), which is a significant concern.

**BBB:** Both have reasonable BBB penetration, but Ligand B (88.3) is better than Ligand A (74.3). This isn't a primary concern for a kinase inhibitor, but is a bonus.

**Caco-2 Permeability:** Ligand A (-5.162) has poor Caco-2 permeability, which is a major drawback. Ligand B (-4.348) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.028) has very poor aqueous solubility, likely due to its high logP. Ligand B (-1.288) is better, but still not ideal.

**hERG:** Ligand A (0.602) has a slightly higher hERG risk than Ligand B (0.207), which is preferable.

**Microsomal Clearance:** Ligand A (62.185) has higher microsomal clearance than Ligand B (43.79), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand A (20.762) has a longer half-life than Ligand B (12.396), which is a positive.

**P-gp Efflux:** Ligand A (0.419) has less P-gp efflux than Ligand B (0.144), which is a positive.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a crucial advantage, as a 1.0 kcal/mol difference is substantial.

**Conclusion:**

Despite Ligand A's longer half-life and lower P-gp efflux, Ligand B is the more promising candidate. Ligand A suffers from poor solubility, poor permeability, higher DILI risk, and higher metabolic clearance. Ligand B has a significantly better binding affinity, lower DILI risk, and better solubility/permeability, outweighing its slightly shorter half-life and higher P-gp efflux. The stronger binding affinity is a critical advantage for an enzyme inhibitor.

Output:
1
2025-04-17 14:44:17,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.766 Da) is higher, but still acceptable. Ligand B (344.499 Da) is slightly better.

**TPSA:** Ligand A (76.1) is better than Ligand B (49.41). Both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (1.256) is optimal, while Ligand B (3.732) is approaching the upper limit. This favors Ligand A.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 2. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (A: 0.669, B: 0.79), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 33.773, B: 29.701), which is excellent.

**BBB:** Ligand A (47.848) has a lower BBB penetration than Ligand B (77.705). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.648) has poor Caco-2 permeability, while Ligand B (-4.78) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.693) has poor aqueous solubility, while Ligand B (-3.312) is even worse. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.586) has a slightly higher hERG risk than Ligand B (0.395), but both are relatively low.

**Microsomal Clearance:** Ligand A (-9.508) has excellent metabolic stability (low clearance), while Ligand B (62.064) has high clearance. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-2.688) has a long half-life, while Ligand B (-15.447) has a very short half-life. This further strengthens the case for Ligand A.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, while Ligand B (0.285) has slightly higher efflux.

**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 for an enzyme inhibitor.

**Conclusion:**

Despite the poor Caco-2 and solubility of both compounds, Ligand A is the far superior candidate. Its significantly higher binding affinity (-9.2 vs -0.0 kcal/mol) outweighs the drawbacks. Furthermore, Ligand A has much better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. While Ligand B has better BBB, this is not relevant for SRC.

Output:
0
2025-04-17 14:44:17,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.419 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.33) is well below the 140 threshold for good absorption, and preferable for kinases. Ligand B (133.21) is still acceptable but less optimal.

**logP:** Both ligands (-0.041 and -0.249) are slightly below the optimal 1-3 range, but not drastically so. This might slightly impact permeability, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is better than Ligand B (4 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.731) has a better QED score than Ligand B (0.541), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (45.25 and 39.667, respectively), below the 60 threshold. Ligand B is slightly better.

**BBB:** This is less critical for a non-CNS target like SRC. Both have reasonable values (59.364 and 62.117).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.167 and -5.571), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.232 and -2.644), which is also concerning and indicates poor solubility.

**hERG Inhibition:** Both ligands have very low hERG risk (0.067 and 0.111), which is excellent.

**Microsomal Clearance:** Ligand B (-3.278) has significantly *lower* (better) microsomal clearance than Ligand A (30.826), suggesting greater metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (0.753) has a slightly longer half-life than Ligand A (3.11), but both are quite short.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.005), which is favorable.

**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, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand B has superior ADME properties (lower Cl_mic, slightly better DILI, slightly longer half-life), Ligand A's significantly stronger binding affinity (-9.5 vs -8.1 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The potency advantage is large enough to potentially overcome the poorer solubility and permeability. The hERG risk is low for both, which is crucial.

Output:
0
2025-04-17 14:44:17,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 343.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (86.63) is better than Ligand B (104.12), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold if CNS penetration were a concern.

**logP:** Both ligands have good logP values (0.868 and 0.924), 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.

**QED:** Both ligands have excellent QED scores (0.855 and 0.859), indicating good drug-like properties.

**DILI:** Ligand A (30.399) has a significantly lower DILI risk than Ligand B (54.556). This is a major advantage for Ligand A.

**BBB:** Ligand A (58.511) has better BBB penetration potential than Ligand B (46.452), although this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.851) has a worse Caco-2 permeability than Ligand B (-5.592). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-0.653) has better aqueous solubility than Ligand B (-1.537). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.361 and 0.274).

**Microsomal Clearance:** Ligand A (8.284) has higher microsomal clearance than Ligand B (-2.548). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (4.697) has a shorter in vitro half-life than Ligand B (-25.979). This further supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.039).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -9.1 kcal/mol). Ligand B is slightly better, with a 1.1 kcal/mol advantage.

**Overall Assessment:**

Ligand B has a significant advantage in metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. However, Ligand A has a much lower DILI risk and better solubility. Given that SRC kinases are not typically CNS targets, the slightly lower BBB penetration of Ligand B is not a major concern. The improved metabolic stability and binding affinity of Ligand B outweigh the slightly higher DILI risk and lower solubility.

Output:
1
2025-04-17 14:44:17,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.383 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.14) is well below the 140 threshold for oral absorption, and good for kinase inhibitors. Ligand B (105.9) is still acceptable, but less optimal.

**logP:** Ligand A (2.78) is within the optimal 1-3 range. Ligand B (0.186) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.6 and 0.83 respectively), suggesting good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (69.756 and 80.07), which is a concern. However, this is often a trade-off and can be addressed in later optimization stages.

**BBB:** Ligand A shows good BBB penetration (80.69), while Ligand B is much lower (41.024). While not a primary concern for a non-CNS target like SRC, it's a slight advantage for A.

**Caco-2 Permeability:** Ligand A (-3.741) shows poor permeability, a significant drawback. Ligand B (-5.502) is even worse.

**Aqueous Solubility:** Ligand A (-3.373) has poor solubility, while Ligand B (-1.509) is slightly better, but still poor.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.203 and 0.101), which is excellent.

**Microsomal Clearance:** Ligand A (88.001) has higher clearance, indicating lower metabolic stability. Ligand B (3.343) has very low clearance, indicating excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-31.856) has a very short half-life, which is a major drawback. Ligand B (4.695) has a short half-life, but is better than A.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.075 and 0.009).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent and a primary driver of potency.

**Overall Assessment:**

While both ligands have excellent binding affinity and low hERG risk, Ligand B is significantly better due to its superior metabolic stability (low Cl_mic) and better (though still poor) solubility. Ligand A suffers from poor permeability, high clearance, and a short half-life, making it a less desirable candidate despite its slightly better BBB penetration. The poor Caco-2 and solubility of both are concerning, but metabolic stability is a more critical factor for kinase inhibitors.

Output:
1
2025-04-17 14:44:17,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.381 and 358.262 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.2) is higher than Ligand B (43.37). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Both ligands have similar logP values (4.359 and 4.39), slightly above the optimal range of 1-3, but not drastically so. This could potentially lead to some solubility issues, but is not a major concern.

**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 (0.838) has a significantly higher QED score than Ligand B (0.452), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (70.686 and 76.541), which is a concern. However, this is not a deciding factor between the two.

**BBB:** Both ligands have high BBB penetration (89.027 and 83.327), which isn't critical for a non-CNS target like SRC, but doesn't hurt.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.404 and -4.32), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.095 and -5.391). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.643 and 0.565), which is good.

**Microsomal Clearance:** Ligand A (57.746) has significantly lower microsomal clearance than Ligand B (81.108), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (59.281) has a longer in vitro half-life than Ligand B (31.598), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.61 and 0.693), which is favorable.

**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 notable, but may not be enough to overcome other deficiencies.

**Overall Assessment:**

Ligand A is preferable despite the slightly weaker binding affinity. Its superior QED score, significantly lower microsomal clearance, and longer half-life suggest it will have better overall pharmacokinetic properties. While both have poor solubility and permeability, the improved metabolic stability of Ligand A is crucial for an enzyme target. The DILI risk is a concern for both, but can be addressed in later optimization stages.

Output:
0
2025-04-17 14:44:17,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.487 and 354.491 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (67.87). Both are below 140, suggesting good absorption potential.

**3. logP:** Both ligands have good logP values (2.511 and 2.319), 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 4. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.751) has a significantly better QED score than Ligand B (0.611), indicating a more drug-like profile.

**7. DILI:** Ligand A (14.541) has a much lower DILI risk than Ligand B (12.253), which is a significant advantage.

**8. BBB:** Both have reasonable BBB penetration, but Ligand A (77.782) is better than Ligand B (69.756). While not a primary concern for a kinase inhibitor, higher BBB is never detrimental.

**9. Caco-2 Permeability:** Ligand A (-4.77) is slightly better than Ligand B (-4.488). Both are negative, indicating reasonable permeability.

**10. Aqueous Solubility:** Ligand A (-2.639) is better than Ligand B (-1.441). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.335 and 0.327).

**12. Microsomal Clearance:** Ligand A (56.839) has higher microsomal clearance than Ligand B (42.528), meaning it's less metabolically stable. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (8.585) has a significantly longer in vitro half-life than Ligand A (-2.373), indicating better metabolic stability. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.069).

**15. Binding Affinity:** Ligand B (-8.1) has slightly better binding affinity than Ligand A (-7.8), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A has advantages in QED, DILI risk, solubility, and BBB penetration. However, Ligand B has a substantially longer half-life and lower microsomal clearance, which are critical for an enzyme inhibitor. The slightly better binding affinity of Ligand B further strengthens its position. The difference in binding affinity is not large enough to overcome the significant metabolic stability advantage of Ligand B.

Output:
1
2025-04-17 14:44:17,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (354.451 and 347.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.98) is slightly higher than Ligand B (64.86). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**3. logP:** Ligand A (-0.804) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (3.058) is within the optimal range. This is a significant advantage for 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 (0.624 and 0.768, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (13.261) has a much lower DILI risk than Ligand B (28.306). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (24.738) has a low BBB penetration, while Ligand B (80.031) has high BBB penetration. Since SRC is not a CNS target, this is less critical, but still favors B.

**9. Caco-2 Permeability:** Both have negative values (-5.362 and -4.963), which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-0.822) has slightly better solubility than Ligand B (-3.735), which is a positive attribute.

**11. hERG Inhibition:** Ligand A (0.093) has a very low hERG risk, which is excellent. Ligand B (0.211) is also relatively low, but higher than A.

**12. Microsomal Clearance:** Ligand A (-11.953) has a much lower (better) microsomal clearance than Ligand B (28.874), indicating greater metabolic stability. This is a crucial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (3.056) has a shorter half-life than Ligand B (-3.893). The negative value for B is concerning and likely an error or an unusual scale.

**14. P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, while Ligand B (0.144) has slightly higher efflux.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better logP, which are key for enzyme inhibition. However, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, and a much lower hERG risk. The negative half-life for Ligand B is also concerning. While the affinity difference is significant, the improved safety and metabolic profile of Ligand A make it a more promising starting point for drug development.

Output:
0
2025-04-17 14:44:17,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.391 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.36) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (62.3) is excellent, well below 140.

**logP:** Ligand A (-0.243) is a bit low, potentially hindering permeability. Ligand B (3.315) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 9 HBA) is good. Ligand B (1 HBD, 4 HBA) is also good, potentially offering a slight advantage in permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.523 and 0.808), indicating drug-like properties.

**DILI:** Ligand A (87.204) has a higher DILI risk than Ligand B (44.63), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (72.237) is higher, but this is less important here.

**Caco-2 Permeability:** Both ligands have similar, poor Caco-2 permeability (-5.193 and -5.052). This is a potential issue for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.296 and -2.986). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.24) has a lower hERG risk than Ligand B (0.443), which is a significant advantage.

**Microsomal Clearance:** Ligand A (2.509 mL/min/kg) has significantly lower microsomal clearance than Ligand B (48.278 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.299 hours) has a much longer in vitro half-life than Ligand B (6.276 hours), a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.464).

**Binding Affinity:** Ligand B (-7.3 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 other significant ADME differences.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better affinity and TPSA, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG risk. The lower logP and solubility of Ligand A are concerns, but these can potentially be addressed through formulation. The superior metabolic stability and safety profile of Ligand A are crucial for an enzyme target like SRC kinase.

Output:
0
2025-04-17 14:44:17,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (360.435 and 350.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is well within the desirable range for oral absorption (<140), while Ligand B (33.95) is even better.

**logP:** Ligand A (1.835) is optimal (1-3). Ligand B (4.135) is slightly higher, potentially leading to solubility issues, but still within an acceptable range.

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

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

**QED:** Ligand A (0.85) is excellent, indicating high drug-likeness. Ligand B (0.601) is still acceptable, but lower.

**DILI:** Ligand A (73.013) has a higher DILI risk than Ligand B (55.448), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.217) has better BBB penetration than Ligand A (60.411), but it's not a major factor here.

**Caco-2 Permeability:** Ligand A (-4.981) and Ligand B (-5.017) both have negative values, which is unusual. Assuming these are logP-scaled Caco-2 values, lower (more negative) values indicate *lower* permeability. They are similar and both suggest moderate permeability.

**Aqueous Solubility:** Ligand A (-3.797) and Ligand B (-4.262) both have negative values, indicating poor solubility. Ligand B is slightly worse.

**hERG Inhibition:** Ligand A (0.355) has a lower hERG risk than Ligand B (0.783), which is a significant advantage.

**Microsomal Clearance:** Ligand A (9.423) has lower clearance than Ligand B (87.933), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (54.626) has a longer half-life than Ligand B (-40.856), which is a substantial benefit.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.601), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While this is a positive for Ligand B, the difference is not substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It exhibits a better safety profile (lower DILI, lower hERG), significantly improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity, the other ADME/Tox properties of Ligand A are far more favorable for development as a drug candidate. The solubility of both is poor, but this can be addressed with formulation strategies.



Output:
0
2025-04-17 14:44:17,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.823 Da) is slightly higher than Ligand B (347.39 Da), but both are acceptable.

**TPSA:** Ligand A (63.99) is better than Ligand B (73.74) as it is closer to the ideal threshold of <=140 for good oral absorption.

**logP:** Ligand A (3.026) is optimal, while Ligand B (0.768) is a bit 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 good QED scores (A: 0.734, B: 0.854), indicating drug-like properties.

**DILI:** Ligand A (82.59) has a significantly higher DILI risk than Ligand B (26.599). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (84.257) is slightly better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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. Ligand B (-1.732) is slightly better than Ligand A (-4.237), suggesting slightly better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.753, B: 0.445), which is good.

**Microsomal Clearance:** Ligand B (-22.476) has a much lower (better) microsomal clearance than Ligand A (48.896), indicating greater metabolic stability. This is a critical advantage for Ligand B.

**In vitro Half-Life:** Ligand B (8.328 hours) has a significantly longer half-life than Ligand A (43.783 percentile, which is unclear if it is hours or not, but likely shorter than B). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.605, B: 0.054), which is favorable. Ligand B is better.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 kcal/mol and -8.7 kcal/mol), with Ligand B being slightly better. The difference is small and likely not decisive on its own.

**Overall Assessment:**

Ligand B is the superior candidate. While both have good potency, Ligand B demonstrates significantly better ADMET properties: lower DILI risk, much lower microsomal clearance (better metabolic stability), and longer in vitro half-life. The slightly better solubility and P-gp efflux also contribute to its favorability. Although Ligand A has a slightly better TPSA, the DILI risk is a major red flag.

Output:
1
2025-04-17 14:44:17,559 - INFO - Batch 321 complete. Total preferences: 5136
2025-04-17 14:44:17,559 - INFO - Processing batch 322/512...
2025-04-17 14:44:59,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (80.57) is better than Ligand B (99.5), being comfortably below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (A: 2.775, B: 1.036) within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 2/4, B: 1/5), well within the guidelines.

**QED:** Both ligands have similar and good QED scores (A: 0.828, B: 0.812).

**DILI:** Ligand A (39.744) has a significantly lower DILI risk than Ligand B (68.166). This is a major advantage.

**BBB:** Ligand A (65.762) has a better BBB penetration score than Ligand B (48.895), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.784 and -4.745) which is unusual and suggests poor permeability, but the values are very similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.371 and -3.415). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.337) has a slightly lower hERG inhibition risk than Ligand B (0.578).

**Microsomal Clearance:** Ligand A (31.587) has lower microsomal clearance than Ligand B (36.938), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (44.941) has a significantly longer in vitro half-life than Ligand B (-7.991). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.147) has lower P-gp efflux liability than Ligand B (0.07).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While the difference is small, it's still a positive.

**Conclusion:**

Ligand A is the better candidate. It demonstrates a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better solubility, and a slightly better binding affinity. While both have poor aqueous solubility, the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 14:44:59,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.487 and 355.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.79) is better than Ligand B (58.81), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.128) is a bit low, potentially hindering permeation, while Ligand B (2.426) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (1) 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 reasonable QED values (0.751 and 0.603), indicating good drug-like properties.

**DILI:** Ligand A (16.402) has a significantly lower DILI risk than Ligand B (11.206), which is a major advantage.

**BBB:** Ligand A (58.55) has a lower BBB penetration than Ligand B (92.827). Since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we can compare the absolute values - Ligand A (-4.96) is slightly worse than Ligand B (-4.463).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and requires further investigation. Ligand A (-2.234) is slightly worse than Ligand B (-0.994).

**hERG:** Ligand A (0.076) has a much lower hERG inhibition liability than Ligand B (0.628), a significant safety advantage.

**Microsomal Clearance:** Ligand A (10.004) has a lower microsomal clearance than Ligand B (43.684), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-5.058) has a negative half-life, which is unusual and problematic. Ligand B (-2.301) is also negative, but less so.

**P-gp Efflux:** Ligand A (0.009) exhibits lower P-gp efflux than Ligand B (0.136), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and better logP, Caco-2 permeability, solubility, and BBB penetration. However, Ligand A demonstrates significantly better DILI, hERG, and microsomal clearance profiles, and lower P-gp efflux. The negative half-life values are concerning for both, but less so for Ligand B due to its stronger binding. Given the enzyme-specific priorities, the improved metabolic stability (lower Cl_mic) and reduced toxicity (lower DILI and hERG) of Ligand A are valuable. However, the substantial difference in binding affinity (-9.3 vs -7.6 kcal/mol) is a major factor. A 1.7 kcal/mol difference is significant and often drives lead selection.

Output:
1
2025-04-17 14:44:59,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.5 and 342.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (85.05). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is closer to the optimal range.

**logP:** Both ligands have good logP values (2.662 and 1.235), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better than Ligand B (1 HBD, 6 HBA) regarding the number of hydrogen bond donors and acceptors. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.628 and 0.782), indicating good drug-likeness.

**DILI:** Ligand A (9.461) has a much lower DILI risk than Ligand B (59.829). This is a significant advantage for Ligand A.

**BBB:** Ligand A (78.286) has a better BBB penetration percentile than Ligand B (68.554), but BBB is not a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-4.466) has a worse Caco-2 permeability than Ligand B (-4.864).

**Aqueous Solubility:** Ligand A (-3.311) has a better aqueous solubility than Ligand B (-2.889).

**hERG:** Ligand A (0.313) has a much lower hERG inhibition liability than Ligand B (0.145), a critical advantage.

**Microsomal Clearance:** Ligand B (43.584) has a significantly lower microsomal clearance than Ligand A (80.146), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (16.631) has a slightly longer in vitro half-life than Ligand A (13.646).

**P-gp Efflux:** Ligand A (0.036) has a lower P-gp efflux liability than Ligand B (0.124).

**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 A excels in safety parameters (DILI, hERG) and solubility, and has a slightly better logP. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly stronger binding affinity. The lower DILI and hERG risk of Ligand A are crucial for a drug candidate, outweighing the slightly better metabolic stability of Ligand B. The binding affinity difference is minimal.

Output:
1
2025-04-17 14:44:59,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.451 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.5) is slightly higher than Ligand B (67.23). Both are below the 140 threshold for good oral absorption, but B is better.

**logP:** Both ligands (2.267 and 2.373) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5. Ligand B is slightly better.

**H-Bond Acceptors:** Both ligands (4) are well below the threshold of 10.

**QED:** Both ligands have good QED scores (0.879 and 0.892), indicating good drug-like properties.

**DILI:** Ligand A (60.489) has a higher DILI risk than Ligand B (33.618). This is a significant advantage for Ligand B.

**BBB:** Ligand A (68.941) and Ligand B (85.498). Since SRC is not a CNS target, this is less important, but B is still better.

**Caco-2 Permeability:** Ligand A (-4.864) and Ligand B (-5.006). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands (-3.247 and -3.175) have very poor aqueous solubility. This is a concern for both, but similar.

**hERG Inhibition:** Ligand A (0.34) has a slightly lower hERG risk than Ligand B (0.487), which is preferable.

**Microsomal Clearance:** Ligand A (26.08) and Ligand B (25.138) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (12.682) has a longer half-life than Ligand B (0.148). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux liability than Ligand B (0.123), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has a better half-life and P-gp efflux, Ligand B's significantly stronger binding affinity (-9.5 vs -8.4 kcal/mol) and lower DILI risk are crucial advantages for an enzyme target like SRC kinase. The solubility is poor for both, and Caco-2 permeability is also low, but the potency advantage of B is substantial.

Output:
1
2025-04-17 14:44:59,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.393 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is significantly better than Ligand B (112.7). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Ligand A (3.714) is optimal, while Ligand B (1.387) is at the lower end of the optimal range. While still acceptable, it might have slightly reduced 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, while Ligand B has 6. Ligand A is preferable here, as higher HBA can sometimes reduce permeability.

**QED:** Both ligands have similar QED values (0.715 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (51.493) has a higher DILI risk than Ligand B (36.022). This is a concern for Ligand A, but not a dealbreaker at this stage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.831) has a higher BBB percentile than Ligand B (42.032), but this is not a major factor in this comparison.

**Caco-2:** Ligand A (-4.616) has a much better Caco-2 permeability than Ligand B (-5.375). This suggests better intestinal absorption for Ligand A.

**Solubility:** Ligand A (-4.432) has better solubility than Ligand B (-1.752). Solubility is important for bioavailability.

**hERG:** Ligand A (0.967) has a lower hERG inhibition liability than Ligand B (0.106), which is a significant advantage. Lower hERG risk is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand B (27.216) has significantly lower microsomal clearance than Ligand A (69.969). Lower clearance indicates better metabolic stability, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (15.446) has a much longer in vitro half-life than Ligand A (-1.784). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.566) shows lower P-gp efflux than Ligand B (0.012), which is preferable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a major advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B demonstrates a superior binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has advantages in TPSA, Caco-2 permeability, solubility, and hERG risk, the substantial improvement in binding affinity and metabolic stability of Ligand B outweigh these benefits. The DILI risk for Ligand A is also a concern.

Output:
1
2025-04-17 14:44:59,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.418 Da and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (107.11), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have similar logP values (0.453 and 0.48), which are within the optimal 1-3 range, suggesting reasonable permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly better than Ligand B (4 HBD, 5 HBA). While both are within acceptable limits, fewer HBDs are generally preferred.

**QED:** Ligand A (0.784) has a significantly better QED score than Ligand B (0.396), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (45.25 and 46.297), both falling below the concerning threshold of 60.

**BBB:** Ligand A (70.919) has a better BBB percentile than Ligand B (51.066), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.679) has a better Caco-2 permeability than Ligand B (-5.771), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.553) has better aqueous solubility than Ligand B (-2.515), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.225 and 0.372), which is excellent.

**Microsomal Clearance:** Ligand A (-8.052) has significantly lower (better) microsomal clearance than Ligand B (26.889), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.788 hours) has a much longer half-life than Ligand B (-15.954 hours), which is highly desirable for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.072 and 0.164).

**Binding Affinity:** Both ligands have the same binding affinity (0 kcal/mol).

**Overall Assessment:**

Ligand A is clearly superior. It exhibits better QED, Caco-2 permeability, solubility, metabolic stability (lower Cl_mic and longer t1/2), and a better BBB score. While both have acceptable DILI and hERG profiles, the ADME properties of Ligand A are significantly more favorable, making it a more promising drug candidate for SRC kinase inhibition. The similar binding affinity means the ADME advantages of A are the deciding factor.

Output:
1
2025-04-17 14:44:59,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 385.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (80.32), both are under the 140 threshold for good absorption.

**logP:** Both ligands (2.614 and 2.302) are 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 6. Ligand A is preferable here, as lower HBA generally improves permeability.

**QED:** Both ligands have similar QED values (0.691 and 0.682), indicating good drug-likeness.

**DILI:** Ligand A (36.603) has a significantly lower DILI risk than Ligand B (55.874). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (63.668) is slightly better than Ligand B (57.619).

**Caco-2 Permeability:** Ligand A (-4.604) is better than Ligand B (-5.078), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.979) is better than Ligand B (-3.393), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.294) has a lower hERG inhibition liability than Ligand B (0.392), reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (34.814) has a lower microsomal clearance than Ligand B (45.147), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (10.65) has a longer half-life than Ligand A (4.406). This is a positive for Ligand B, but might be offset by other factors.

**P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux liability than Ligand B (0.121), potentially improving bioavailability.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.2). While a 1.5 kcal/mol difference is significant, the other advantages of Ligand A are substantial.

**Overall:** Ligand A demonstrates a more favorable profile across several key ADME properties (DILI, solubility, hERG, metabolic stability, permeability, P-gp efflux) and has a very strong binding affinity. While Ligand B has a slightly better binding affinity and half-life, the superior safety and pharmacokinetic profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 14:44:59,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.361 and 349.347 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is well below the 140 threshold for good absorption, while Ligand B (136.65) is approaching the upper limit, potentially impacting absorption.

**logP:** Ligand A (3.447) is within the optimal 1-3 range. Ligand B (-1.21) is significantly below this, which could hinder membrane permeation and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is favorable. Ligand B (HBD=4, HBA=6) is slightly higher, but still within acceptable limits.

**QED:** Ligand A (0.871) has a very strong drug-like profile. Ligand B (0.381) is significantly lower, indicating a less desirable overall drug-likeness.

**DILI:** Ligand A (79.953) has a higher DILI risk than Ligand B (68.941), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (30.206) and Ligand B (18.961) both have low BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.669) has poor Caco-2 permeability, which is concerning. Ligand B (-5.765) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.9) has poor solubility, while Ligand B (-2.128) is slightly better, but still not ideal.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.175 and 0.107 respectively).

**Microsomal Clearance:** Ligand A (29.915) has a moderate clearance, while Ligand B (-12.191) has a *negative* clearance, which is highly unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (11.326 hours) has a reasonable half-life. Ligand B (21.836 hours) has a longer, and therefore more desirable, half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.061 and 0.011 respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol), with Ligand A being slightly better. However, the 0.2 kcal/mol difference is unlikely to outweigh other significant ADME differences.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B exhibits significantly better metabolic stability (negative Cl_mic, longer half-life), a better QED score, and slightly better solubility. The low logP of Ligand B is a concern, but the exceptional metabolic stability and improved QED outweigh this drawback. 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 at this stage.

Output:
1
2025-04-17 14:44:59,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.495 Da) is slightly lower, which could be advantageous for permeability. Ligand B (400.228 Da) is also good.

**TPSA:** Ligand A (67.33) is better than Ligand B (55.32) as it is closer to the 140 threshold.

**logP:** Ligand A (-0.159) is quite low, potentially hindering permeability. Ligand B (3.74) 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:** Ligand A (0.718) has a better QED score than Ligand B (0.493), indicating a more drug-like profile.

**DILI:** Ligand A (6.398) has a much lower DILI risk than Ligand B (47.77). This is a crucial advantage for Ligand A.

**BBB:** Ligand A (34.238) has a low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (92.71) has high BBB penetration, which is irrelevant here and doesn't add value.

**Caco-2:** Both ligands have negative Caco-2 values (-4.997 and -4.412), 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.

**Solubility:** Ligand A (0.087) has very poor solubility, while Ligand B (-4.119) is also poor, but slightly better. This is a concern for both.

**hERG:** Ligand A (0.161) has a very low hERG risk, significantly better than Ligand B (0.517). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (12.994) has a lower microsomal clearance than Ligand B (53.071), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-2.978) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (-21.769) also has a negative half-life. This is a major red flag for both.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.007 and 0.204).

**Binding Affinity:** Both ligands have similar binding affinities (-9.1 kcal/mol and -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Overall Assessment:**

Ligand A has significant advantages in DILI risk, hERG inhibition, and metabolic stability (Cl_mic). While its solubility and Caco-2 permeability are poor, these are somewhat offset by its better QED score. Ligand B has a better logP, but suffers from higher DILI risk, higher hERG risk, and poorer metabolic stability. The negative half-life values for both are concerning and suggest data quality issues, but we must proceed based on the available information. Given the enzyme-specific priorities, the lower DILI and hERG risks of Ligand A, combined with its better metabolic stability, make it the more promising candidate despite its solubility issues.

Output:
0
2025-04-17 14:44:59,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (384.542 and 373.837 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (93.9) is still under 140, but less optimal than A.

**logP:** Ligand A (3.672) is within the optimal 1-3 range. Ligand B (1.614) is also within range, but closer to the lower limit which *could* indicate permeability issues.

**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 (<=10).

**QED:** Both ligands have similar QED values (0.787 and 0.73), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (51.609 and 50.136), and are both below the 60 threshold, indicating low risk.

**BBB:** Both ligands have similar BBB penetration (82.784 and 81.039). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.835 and -4.678), which is unusual and suggests poor permeability. This is a significant red flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.468 and -2.63). This is also a significant red flag, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.694) has a slightly higher hERG risk than Ligand B (0.263), but both are relatively low.

**Microsomal Clearance:** Ligand A (44.765) has a higher microsomal clearance than Ligand B (25.418), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-5.144) has a negative half-life, which is not possible and indicates a data error or issue. Ligand A (10.916) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.427 and 0.168), which is favorable.

**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.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate due to its significantly stronger binding affinity (-8.3 vs -7.4 kcal/mol) and better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is concerning and needs investigation, but the binding affinity difference is significant enough to prioritize it *if* the half-life issue can be resolved. The slightly lower hERG risk for Ligand B is also a minor benefit. The TPSA is less favorable for Ligand B, but the potency difference is more important for an enzyme target.

Output:
1
2025-04-17 14:44:59,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 352.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.32) is higher than the preferred <140, but still reasonable. Ligand B (58.64) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.266) is quite low, potentially hindering permeability. Ligand B (3.147) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, within acceptable limits. Ligand B has 1 HBD and 3 HBA, also within limits.

**QED:** Both ligands have good QED scores (0.655 and 0.716), indicating drug-like properties.

**DILI:** Ligand A (38.503) has a slightly elevated DILI risk, but still acceptable. Ligand B (23.769) has a very low DILI risk, which is preferable.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand B (79.139) shows better potential for BBB penetration than Ligand A (50.795).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.792 and -4.098), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.003 and -3.107), which is also concerning and suggests very poor aqueous solubility.

**hERG:** Ligand A (0.036) has a very low hERG risk, which is excellent. Ligand B (0.269) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (57.194) has moderate clearance, while Ligand B (98.001) has high clearance, indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-7.967) has a very long half-life, which is highly desirable. Ligand B (16.945) has a moderate half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.123).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the better candidate. While Ligand B has a better logP and lower DILI risk, Ligand A has a significantly better *in vitro* half-life and a much lower microsomal clearance, indicating superior metabolic stability. The extremely low hERG risk for Ligand A is also a significant advantage. The similar binding affinities mean that the ADME properties become the deciding factor. The poor permeability and solubility are shared concerns that would need to be addressed in further optimization, but the metabolic stability profile of Ligand A makes it the more promising starting point.

Output:
0
2025-04-17 14:44:59,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.26 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (72.7) is significantly better than Ligand A (99.52). Lower TPSA generally improves oral absorption.

**logP:** Ligand B (3.309) is higher than Ligand A (1.133). While both are within the acceptable range, Ligand A is closer to the lower limit, which *could* hinder permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are acceptable.

**QED:** Ligand A (0.825) has a significantly better QED score than Ligand B (0.568), indicating a more drug-like profile.

**DILI:** Ligand B (44.552) has a much lower DILI risk than Ligand A (88.019). This is a major advantage for Ligand B.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (63.784) is higher, but this isn't decisive.

**Caco-2 Permeability:** Ligand A (-4.74) is significantly better than Ligand B (-5.208), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.539) is better than Ligand B (-4.294), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.191) has a lower hERG risk than Ligand B (0.23), which is preferable.

**Microsomal Clearance:** Ligand A (24.165) has lower microsomal clearance than Ligand B (41.284), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.327) has a longer in vitro half-life than Ligand B (-11.603), which is desirable.

**P-gp Efflux:** Ligand A (0.013) has lower P-gp efflux than Ligand B (0.079), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (0.0 kcal/mol) has a significantly better binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage that can outweigh some ADME concerns. A difference of 8.5 kcal/mol is very significant.

**Overall Assessment:**

Ligand B's primary advantage is its significantly stronger binding affinity. While Ligand A has better QED, solubility, metabolic stability, and lower hERG risk, the potency difference is substantial. For an enzyme target like SRC kinase, potency is paramount. The lower DILI risk of Ligand B is also a significant positive. The slightly higher logP of Ligand B is not a major concern, and its TPSA is favorable.

Output:
1
2025-04-17 14:44:59,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.364 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly higher than the preferred <140, but acceptable. Ligand B (59.08) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands (1.787 and 1.925) 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 good.

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

**QED:** Both ligands have similar QED values (0.72 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (7.794), but both are below the concerning threshold of 60.

**BBB:** Ligand A (54.285) and Ligand B (83.715) are both acceptable, but Ligand B's higher value is slightly better. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.028) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.256) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.949) has poor aqueous solubility, which is a major concern for bioavailability. Ligand B (-1.318) is also poor, but better than Ligand A.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.456 and 0.406), which is favorable.

**Microsomal Clearance:** Ligand A (6.56) has a lower microsomal clearance than Ligand B (38.729), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-5.181) has a longer in vitro half-life than Ligand B (-13.163), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.056 and 0.032), which is good.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 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 better metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from poor Caco-2 permeability and solubility. Ligand B has better permeability and solubility, but its binding affinity is considerably weaker. Given that SRC is a kinase (enzyme), potency is paramount. The substantial affinity advantage of Ligand A, coupled with acceptable (though not ideal) DILI and hERG profiles, makes it the more promising candidate, even with the solubility and permeability concerns. Formulation strategies could potentially mitigate the solubility issue.

Output:
1
2025-04-17 14:44:59,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (362.514 and 364.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (33.2) is excellent, well below the 140 threshold for oral absorption and very favorable. Ligand B (86.89) is still acceptable, but higher, potentially impacting absorption.

**3. logP:** Both ligands (4.066 and 3.71) are within the optimal 1-3 range, suggesting good permeability.

**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:** Ligand A (0.764) demonstrates excellent drug-likeness. Ligand B (0.274) is significantly lower, indicating a less favorable overall drug-like profile.

**7. DILI:** Ligand A (16.906) has a very low DILI risk. Ligand B (29.43) is higher, but still within an acceptable range.

**8. BBB:** Both ligands have high BBB penetration (94.921 and 70.376), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.723) shows poor Caco-2 permeability. Ligand B (-5.035) is similarly poor.

**10. Aqueous Solubility:** Ligand A (-4.761) has poor aqueous solubility. Ligand B (-2.697) is slightly better, but still low.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.793 and 0.519).

**12. Microsomal Clearance:** Ligand A (56.068) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (72.29) has higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (18.004 and 17.055 hours).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.672 and 0.239).

**15. Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-8.1), although the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior overall. The key advantages of Ligand A are its significantly better QED score and lower DILI risk. Although both have poor Caco-2 permeability and solubility, the better ADME properties of Ligand A, particularly its higher QED and lower DILI, make it the more promising candidate. The small difference in binding affinity is unlikely to outweigh these significant ADME benefits, especially for an enzyme target where metabolic stability and minimal toxicity are crucial.

Output:
0
2025-04-17 14:44:59,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.411 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (88.99 and 82.11) are below the 140 A^2 threshold for good oral absorption, and acceptable for kinase inhibitors.

**logP:** Ligand A (2.048) is optimal, while Ligand B (0.364) is slightly low, potentially hindering permeation.

**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:** Ligand A (0.824) has a better QED score than Ligand B (0.689), indicating a more drug-like profile.

**DILI:** Ligand B (5.196) has a significantly lower DILI risk than Ligand A (55.874), which is a major advantage.

**BBB:** Ligand A (54.207) has a slightly better BBB penetration than Ligand B (21.52), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-4.893) has a worse Caco-2 permeability than Ligand B (-5.067), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.332) has a slightly better aqueous solubility than Ligand B (-0.113).

**hERG Inhibition:** Both ligands (0.399 and 0.096) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand B (-0.692) has a significantly lower (better) microsomal clearance than Ligand A (11.897), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (4.61) has a much longer in vitro half-life than Ligand A (-13.006), which is a significant advantage.

**P-gp Efflux:** Both ligands (0.093 and 0.012) have low P-gp efflux liability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.5 and -9.7 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better solubility and BBB penetration, Ligand B is significantly better in terms of DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and Caco-2 permeability. Given the enzyme-kinase specific priorities, metabolic stability and lower toxicity are crucial. The similar binding affinities make these factors decisive. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 14:44:59,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (364.423 and 366.502 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.9) is better than Ligand B (49.41). Both are below 140, suggesting good oral absorption potential.

**3. logP:** Ligand B (3.388) is optimal (1-3), while Ligand A (0.253) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

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

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3), both are within the acceptable range.

**6. QED:** Both ligands have similar and good QED values (0.715 and 0.718).

**7. DILI:** Both ligands have acceptable DILI risk (50.756 and 48.507 percentile), below the 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (81.388 and 85.149 percentile), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.046 and -4.954). This is unusual and suggests potential issues with intestinal absorption, but the scale is not defined.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.805 and -3.622). This is also unusual and suggests potential formulation challenges.

**11. hERG Inhibition:** Ligand A (0.196) has a lower hERG risk than Ligand B (0.903), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (-2.326) has a much lower (better) microsomal clearance than Ligand B (70.154). This indicates greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (13.44) has a slightly longer half-life than Ligand A (12.936), but the difference is minimal.

**14. P-gp Efflux:** Ligand A (0.039) has a lower P-gp efflux liability than Ligand B (0.614), which is favorable.

**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).

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in metabolic stability (Cl_mic), hERG risk, and P-gp efflux, while Ligand B has a slightly better affinity. However, Ligand A's significantly better logP and metabolic stability outweigh the small affinity difference. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A make it a more promising candidate.

Output:
0
2025-04-17 14:44:59,065 - INFO - Batch 322 complete. Total preferences: 5152
2025-04-17 14:44:59,065 - INFO - Processing batch 323/512...
2025-04-17 14:45:41,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 345.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.23) is well below the 140 threshold for good absorption, while Ligand B (89.66) is also acceptable, though higher.

**logP:** Both ligands have good logP values (2.373 and 1.772), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 6 HBA) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have good QED scores (0.771 and 0.835), indicating drug-like properties.

**DILI:** Ligand A (21.946) has a significantly lower DILI risk than Ligand B (56.999), which is a major advantage.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (74.874) shows better BBB penetration than Ligand B (67.235).

**Caco-2 Permeability:** Ligand A (-4.919) has a more negative Caco-2 value, which is unusual and suggests *lower* permeability. Ligand B (-5.162) is also low.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.112 and -2.448). This is a significant drawback.

**hERG:** Both ligands have very low hERG inhibition risk (0.284 and 0.058). This is excellent.

**Microsomal Clearance:** Ligand A (34.988) has higher microsomal clearance than Ligand B (15.161), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (12.726 hours) has a much longer in vitro half-life than Ligand A (-1.568 hours), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.082).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a crucial difference, as a 1.7 kcal/mol advantage is substantial.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.1 vs -7.4 kcal/mol) outweighs the slightly higher TPSA and DILI risk. Furthermore, the improved metabolic stability (lower Cl_mic, longer t1/2) is critical for an enzyme target. While Ligand A has a lower DILI risk, the substantial improvement in binding affinity and metabolic stability with Ligand B makes it the better choice.

Output:
1
2025-04-17 14:45:41,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.447 Da) is slightly higher than Ligand B (339.399 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (88.39) is slightly better than Ligand A (99.1).

**logP:** Ligand B (1.463) is within the optimal range (1-3), while Ligand A (0.354) is slightly below, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 3/5, B: 2/5), falling within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.584, B: 0.78), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (16.014) has a significantly lower DILI risk than Ligand B (63.164). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (44.862) is slightly better than Ligand A (33.23).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are on a similar scale, so this doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the values are similar and don't provide a clear differentiator.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.175, B: 0.173), which is excellent.

**Microsomal Clearance:** Ligand B (2.961) has significantly lower microsomal clearance than Ligand A (17.331), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (1.584) has a slightly longer half-life than Ligand A (7.456), but both are relatively short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.058, B: 0.026), which is favorable.

**Binding Affinity:** Crucially, both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and meets the criteria.

**Overall Assessment:**

While Ligand B has better logP and microsomal clearance, the significantly lower DILI risk of Ligand A is a major advantage. DILI is a common reason for drug attrition, and minimizing this risk is crucial. The similar affinities mean that the ADME differences are the deciding factors. Given the importance of minimizing liver toxicity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 14:45:41,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.403 and 341.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.32) is slightly above the preferred <140 for good oral absorption, while Ligand B (79.51) is well within the range.

**logP:** Ligand A (0.199) is quite low, potentially hindering permeation. Ligand B (0.783) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (A: 5, B: 6) are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (A: 0.648, B: 0.61), indicating good drug-like properties.

**DILI:** Ligand A (32.183) has a significantly lower DILI risk than Ligand B (62.737), which is a substantial advantage.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.545) has very poor Caco-2 permeability, while Ligand B (-4.843) is slightly better but still low.

**Aqueous Solubility:** Ligand A (-2.476) and Ligand B (-1.574) both have poor solubility.

**hERG:** Ligand A (0.026) has a very low hERG risk, a major advantage. Ligand B (0.351) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (6.409) has a much lower microsomal clearance than Ligand B (26.659), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.575) has a longer half-life than Ligand B (-13.104).

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.007, B: 0.06).

**Binding Affinity:** Both ligands have comparable binding affinities (A: -7.0 kcal/mol, B: -6.9 kcal/mol), with Ligand A being slightly better.

**Conclusion:**

Despite Ligand B having a slightly better logP and Caco-2 permeability, Ligand A is the more promising candidate. The significantly lower DILI risk, substantially improved metabolic stability (lower Cl_mic and longer t1/2), and very low hERG risk outweigh the slightly lower logP and Caco-2 values. The binding affinity is comparable. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are critical, and Ligand A excels in these areas.

Output:
0
2025-04-17 14:45:41,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (386.206 and 369.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is higher than Ligand B (57.61). While both are acceptable, Ligand B's lower TPSA is slightly more favorable for permeability.

**logP:** Both ligands have logP values (4.465 and 3.657) that are above the optimal range of 1-3, but Ligand B is closer to the upper limit and therefore preferable. High logP can lead to solubility issues and off-target effects.

**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 (0.744 and 0.674), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (97.325%) compared to Ligand B (26.755%). This is a major red flag for Ligand A.

**BBB:** Ligand B has a higher BBB penetration percentile (76.309%) than Ligand A (34.936%), but BBB is less critical for a kinase inhibitor unless CNS involvement is specifically targeted.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.662) is slightly better than Ligand B (-4.879), but both are concerning.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-4.088) is slightly better than Ligand A (-4.806).

**hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition risk than Ligand B (0.415), which is favorable.

**Microsomal Clearance:** Ligand B has a much higher microsomal clearance (97.073) than Ligand A (7.434). This suggests that Ligand A is more metabolically stable, a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B has a negative half-life (-18.821), which is problematic and suggests rapid degradation. Ligand A has a half-life of 6.276 hours, which is better, though not ideal.

**P-gp Efflux:** Ligand B (0.774) has higher P-gp efflux than Ligand A (0.102), meaning it's more likely to be pumped out of cells, reducing bioavailability.

**Binding Affinity:** Ligand A (-10.8 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 drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Despite the better affinity of Ligand A, its extremely high DILI risk and poor metabolic stability are major concerns. Ligand B, while having a weaker affinity, exhibits a much better safety profile (lower DILI) and better metabolic stability (lower Cl_mic). The poor permeability and solubility of both compounds are drawbacks, but these can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The significantly stronger binding affinity of Ligand A is tempting, but the high DILI risk is a deal-breaker.

Output:
1
2025-04-17 14:45:41,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.519 Da and 357.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold for good absorption, and even favorable for potential CNS penetration (though not a priority here). Ligand B (98.74) is still under 140, but less optimal than A.

**logP:** Ligand A (2.861) is within the optimal 1-3 range. Ligand B (-0.022) is slightly below 1, which could potentially hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both well within acceptable limits. Ligand B has 3 HBD and 4 HBA, also acceptable, but slightly higher.

**QED:** Ligand A (0.772) has a better QED score than Ligand B (0.532), indicating a more drug-like profile.

**DILI:** Ligand A (12.253) has a significantly lower DILI risk than Ligand B (45.25), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (80.031) is higher than Ligand B (47.809).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.608 and -4.749), which is unusual and suggests poor permeability. This is a potential red flag for both, but we need to consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.034 and -1.751), suggesting very poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.438 and 0.493), which is positive.

**Microsomal Clearance:** Ligand A (47.198) has a higher microsomal clearance than Ligand B (40.732), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-31.209) has a significantly longer in vitro half-life than Ligand A (-15.648), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.304 and 0.216).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-7.0 and -7.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A has better QED, TPSA, and a much lower DILI risk. However, it has higher microsomal clearance and lower in vitro half-life. Ligand B has a longer half-life, but suffers from a higher DILI risk and lower QED, and a less optimal logP. The solubility is a major concern for both. Given the priority for metabolic stability and solubility (even though both are poor), the longer half-life of Ligand B is a significant advantage. The slightly better DILI profile of Ligand A is attractive, but the half-life difference is more impactful for an enzyme target. The similar binding affinities mean that ADME properties become the deciding factor.

Output:
1
2025-04-17 14:45:41,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (364.408 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (54.46), but both are well below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (2.689 and 3.229), 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 very good QED scores (0.788 and 0.806), indicating good drug-like properties.

**7. DILI:** Ligand A (29.236) has a lower DILI risk than Ligand B (19.426), suggesting a better safety profile regarding liver injury.

**8. BBB:** Both ligands have reasonably high BBB penetration (83.055 and 78.519), but this is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.81 and -4.811), which is unusual and likely indicates a problem with the data or the model's prediction. However, since both are similarly affected, it doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.746 and -3.42). This is a significant concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.34) has a significantly lower hERG inhibition liability than Ligand B (0.751), which is a major advantage in terms of cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (3.261) has much lower microsomal clearance than Ligand B (70.604), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (4.282) has a slightly longer in vitro half-life than Ligand B (4.046).

**14. P-gp Efflux:** Ligand A (0.042) shows very low P-gp efflux liability, while Ligand B (0.218) is somewhat higher.

**15. 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 some of the ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both have solubility issues, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower hERG risk, lower P-gp efflux, and, most importantly, a considerably stronger binding affinity. The improved safety profile (lower DILI) further strengthens its position. The slightly better half-life also contributes. The similar Caco-2 values are concerning for both, but the substantial advantage in potency and ADME properties makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 14:45:41,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 362.832 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (46.34). Both are below the 140 threshold for good absorption, but lower is generally better.

**logP:** Ligand A (2.925) is optimal (1-3), while Ligand B (4.742) is a bit high, 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 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.697) has a better QED score than Ligand A (0.487), suggesting a more drug-like profile.

**DILI:** Ligand A (12.02) has a significantly lower DILI risk than Ligand B (42.497), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (91.857) is higher than Ligand A (69.407). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.541) has slightly better solubility than Ligand B (-4.644), although both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.637 and 0.733, respectively).

**Microsomal Clearance:** Both have similar microsomal clearance (82.779 and 81.635 mL/min/kg), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand B (24.269 hours) has a significantly longer half-life than Ligand A (-4.759 hours). This is a substantial advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.205 and 0.727).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has a better safety profile (lower DILI) and slightly better solubility, Ligand B's significantly stronger binding affinity (-8.8 vs -7.5 kcal/mol) and longer half-life are critical advantages for an enzyme inhibitor. The higher logP of Ligand B is a concern, but the potency difference is likely to be more impactful. The longer half-life will also allow for less frequent dosing.

Output:
1
2025-04-17 14:45:41,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 388.892 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (74.35 and 75.27) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.225 and 2.445) 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 acceptable, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.688 and 0.704), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (40.287 and 41.838), falling within the acceptable range (<40 is good, >60 is high risk).

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a slightly higher BBB score (71.772) than Ligand A (64.87), but this is not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.629 and -5.024), which is unusual and suggests poor permeability. However, these values are on a scale where negative values can occur and don't necessarily preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.201 and -4.184), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.808 and 0.545), which is favorable.

**Microsomal Clearance:** Ligand A (31.704 mL/min/kg) has lower microsomal clearance than Ligand B (40.323 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (15.43 hours) has a significantly longer half-life than Ligand B (-17.67 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 (0.266 and 0.101), which is good.

**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 is within the range where it can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It exhibits better metabolic stability (lower Cl_mic), a longer half-life, and slightly higher binding affinity. While both ligands have poor solubility and permeability, the superior pharmacokinetic properties of Ligand A make it a more viable starting point for optimization.

Output:
1
2025-04-17 14:45:41,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (352.479 and 364.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (56.33 and 58.64) are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (-0.138) is slightly low, potentially hindering permeation. Ligand B (1.665) is within the optimal 1-3 range. This favors Ligand B.

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

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

**6. QED:** Both ligands have good QED scores (0.666 and 0.698), indicating drug-like properties.

**7. DILI:** Ligand A (4.343) has a very low DILI risk, significantly better than Ligand B (18.108). This is a substantial advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.464) has a higher BBB percentile than Ligand B (56.534), but this isn't a major deciding factor.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.764) appears to have lower permeability than Ligand B (-5.006).

**10. Aqueous Solubility:** Ligand A (-0.025) has slightly better solubility than Ligand B (-3.447).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.45 and 0.265, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand A (22.174) has a higher Cl_mic than Ligand B (19.705), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life (t1/2):** Ligand A (-27.972) has a significantly shorter half-life than Ligand B (-1.789). This is a major drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.102, respectively).

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-0). This is a significant advantage for Ligand A.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has superior binding affinity and lower DILI risk, but suffers from poor metabolic stability (high Cl_mic, short half-life) and a slightly lower logP. Ligand B has better metabolic stability, a more favorable logP, and slightly better solubility, but its binding affinity is significantly weaker and has a higher DILI risk.

The difference in binding affinity (-7.6 vs -0 kcal/mol) is substantial. While metabolic stability is important, a strong binding affinity can often be optimized through further medicinal chemistry efforts. The lower DILI risk of Ligand A is also a significant advantage. Therefore, despite its metabolic liabilities, Ligand A is the more promising starting point.

Output:
0
2025-04-17 14:45:41,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 352.454 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.25) is slightly higher than Ligand B (87.46), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.233 and 1.539, respectively), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 3 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.619) has a better QED score than Ligand A (0.462), suggesting a more drug-like profile.

**DILI:** Ligand B (24.506) has a significantly lower DILI risk than Ligand A (33.501), which is a major advantage.

**BBB:** Ligand B (67.701) has a higher BBB penetration percentile than Ligand A (31.02), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.312 and -5.297), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.568 and -1.97), indicating very low aqueous solubility, a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.052) has a slightly lower hERG inhibition liability than Ligand B (0.7), which is preferable.

**Microsomal Clearance:** Ligand B (11.295) has a significantly lower microsomal clearance than Ligand A (34.936), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-1.286) has a longer in vitro half-life than Ligand A (4.346), which is also a positive.

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.015), which is slightly better.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage (1.0 kcal/mol difference).

**Overall Assessment:**

While Ligand A boasts a better binding affinity, Ligand B demonstrates superior ADMET properties. Specifically, the significantly lower DILI risk and improved metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target like SRC kinase. The better QED score also contributes to its drug-likeness. The poor Caco-2 and solubility are concerning for both, but the improved safety and PK profile of Ligand B outweigh the affinity difference.

Output:
1
2025-04-17 14:45:41,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.503 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (61.44 and 60.85) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.084 and 2.262) are within the optimal 1-3 range.

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

**H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.693 and 0.719), indicating drug-like properties.

**DILI:** Ligand A (11.361) has a slightly higher DILI risk than Ligand B (10.896), but both are well below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (68.282 and 73.711), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.868 and -4.548). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values may indicate values less than 1, which is still possible.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.157 and -1.889). Similar to Caco-2, these values are on a log scale and indicate low solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.235 and 0.155). This is excellent.

**Microsomal Clearance:** Ligand B (26.256 mL/min/kg) has significantly lower microsomal clearance than Ligand A (42.922 mL/min/kg), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand B (-4.905 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (2.132 hours) has a reasonable half-life, but could be improved.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.054 and 0.064).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.5 kcal/mol difference is substantial and outweighs most minor ADME concerns.

**Conclusion:**

Ligand B is the superior candidate. While both have some issues with predicted solubility and permeability, Ligand B's significantly stronger binding affinity (-8.7 vs -7.2 kcal/mol) and better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme inhibitor. The DILI risk is slightly lower for Ligand B as well. The negative half-life for Ligand B is a data error, but even if it were a very short half-life, the binding affinity would likely still make it preferable.

Output:
1
2025-04-17 14:45:41,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.475 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.89 and 82.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.571 and 1.696) are within the optimal 1-3 range. Ligand B is slightly better here.

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

**H-Bond Acceptors:** Both ligands have 6 and 4 HBA, respectively, both within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.5 (0.58 and 0.721), indicating good drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 47.305, which is good (below 60). Ligand B has a very low DILI risk of 16.053, which is excellent.

**BBB:** Both ligands have reasonable BBB penetration (70.609 and 83.637). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.756 and -4.784), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.344 and -2.257), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A has a hERG risk of 0.913, which is acceptable. Ligand B has a very low hERG risk of 0.464, which is preferable.

**Microsomal Clearance:** Ligand A has a Cl_mic of 39.032 mL/min/kg, which is moderate. Ligand B has a *negative* Cl_mic (-3.464 mL/min/kg), which is impossible and likely indicates an error or artifact in the prediction. This is a major red flag.

**In vitro Half-Life:** Ligand A has a half-life of 39.106 hours, which is good. Ligand B has a half-life of 10.168 hours, which is acceptable, but less desirable than Ligand A.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.279, which is reasonable. Ligand B has a very low Pgp efflux liability of 0.038, which is excellent.

**Binding Affinity:** Ligand A has a binding affinity of -9.0 kcal/mol, which is excellent. Ligand B has a binding affinity of 0.0 kcal/mol, which is extremely poor.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and solubility, Ligand A is the far superior candidate. Its significantly stronger binding affinity (-9.0 vs 0.0 kcal/mol) outweighs its slightly higher DILI and Pgp efflux. The negative Cl_mic value for Ligand B is a fatal flaw, indicating a problem with the prediction or the molecule itself. While Ligand A's solubility and permeability need improvement, its potency and reasonable ADME properties make it the more viable starting point for optimization.

Output:
0
2025-04-17 14:45:41,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.426 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.06) is significantly better than Ligand B (89.35). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (3.276) is within the optimal 1-3 range. Ligand B (0.824) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBAs, while Ligand B has 6. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.76 and 0.667), indicating good drug-likeness.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (45.715). This is a significant drawback for Ligand A.

**BBB:** Ligand A (73.672) has better BBB penetration than Ligand B (56.534), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.826) has slightly better Caco-2 permeability than Ligand B (-5.075).

**Aqueous Solubility:** Ligand A (-3.73) has better aqueous solubility than Ligand B (-1.235). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.66) has a slightly higher hERG inhibition risk than Ligand B (0.076). Lower is better here, and Ligand B is much better.

**Microsomal Clearance:** Ligand B (24.93) has significantly lower microsomal clearance than Ligand A (46.27), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (3.214) has a longer in vitro half-life than Ligand A (27.988). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.278) has lower P-gp efflux than Ligand B (0.012), which is 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 small, it's enough to be considered, especially given the other factors.

**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 critical areas for kinase inhibitors: lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization.

Output:
1
2025-04-17 14:45:41,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.511 and 344.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is significantly better than Ligand B (84.85). Lower TPSA generally correlates with better cell permeability, important for kinase inhibitors to reach their intracellular target. Ligand B is approaching the upper limit for good oral absorption.

**logP:** Both ligands have good logP values (2.969 and 2.621), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 7. Both are acceptable, but lower is generally preferred.

**QED:** Both have acceptable QED scores (0.882 and 0.723), indicating good drug-like properties.

**DILI:** Ligand A (71.152) has a higher DILI risk than Ligand B (39.162). This is a significant drawback for Ligand A.

**BBB:** Both have reasonable BBB penetration (66.576 and 60.876). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.011 and -5.094), which is unusual and indicates very poor permeability. This is a major concern for both compounds.

**Aqueous Solubility:** Both have negative solubility values (-3.385 and -2.319), which is also a significant concern. Poor solubility will hinder formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.79) has a slightly higher hERG risk than Ligand B (0.582), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (20.541) has significantly lower microsomal clearance than Ligand A (30.221), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (59.03) has a much longer in vitro half-life than Ligand A (36.654), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.498) has lower P-gp efflux than Ligand B (0.022), which is favorable.

**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 is still a positive for Ligand B.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and slightly better binding affinity outweigh the slightly higher P-gp efflux and lower binding affinity. The poor permeability and solubility are serious issues that would need to be addressed through formulation or further chemical modification, but the ADME profile of Ligand B is more favorable overall.

Output:
1
2025-04-17 14:45:41,866 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both A (361.431 Da) and B (369.531 Da) fall within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (119.03) is slightly higher than Ligand B (90.27). Ligand B is better, being comfortably under the 140 threshold for oral absorption, and closer to the 90 threshold for CNS penetration (though that's not a primary concern for a general oncology target).

3. **logP:** Ligand A (0.233) is quite low, potentially hindering permeability. Ligand B (2.417) is within the optimal 1-3 range. This is a significant advantage for B.

4. **HBD:** Ligand A (2) is slightly higher than Ligand B (1). Both are acceptable, under the 5 threshold.

5. **HBA:** Ligand A (8) is higher than Ligand B (4). Ligand B is preferable, being well under the 10 threshold.

6. **QED:** Ligand A (0.787) has a better QED score than Ligand B (0.599), indicating a more drug-like profile.

7. **DILI:** Ligand A (62.001) has a considerably higher DILI risk than Ligand B (23.226). This is a major concern for Ligand A.

8. **BBB:** Both have reasonable BBB penetration (A: 70.88, B: 78.79), but this isn't a primary concern for an oncology target unless CNS penetration is specifically desired.

9. **Caco-2:** Ligand A (-5.389) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.978) is also poor, but slightly better.

10. **Solubility:** Ligand A (-3.216) and B (-2.86) both have poor aqueous solubility.

11. **hERG:** Ligand A (0.294) has a slightly higher hERG risk than Ligand B (0.771). Lower is better here, so B is preferable.

12. **Cl_mic:** Ligand A (-5.209) has a negative clearance, indicating very good metabolic stability. Ligand B (34.707) has a high clearance, suggesting rapid metabolism. This is a significant advantage for A.

13. **t1/2:** Ligand A (6.263) has a shorter half-life than Ligand B (-46.446). Negative half-life is not possible, so there is likely an error in the data for Ligand B. Assuming this is an error, we can disregard this parameter.

14. **Pgp:** Ligand A (0.043) has very low P-gp efflux, which is good. Ligand B (0.214) is slightly higher, but still relatively low.

15. **Binding Affinity:** Both ligands have very similar binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a better QED score and significantly better metabolic stability (Cl_mic). However, it suffers from very poor Caco-2 permeability, a low logP, and a higher DILI risk. Ligand B has a better logP, TPSA, lower DILI risk, and a slightly better hERG profile. While its metabolic stability is a concern, the other properties are more favorable. The similar binding affinities mean that ADME properties become the deciding factor. The poor permeability and DILI risk of Ligand A are significant drawbacks.

Output:
1
2025-04-17 14:45:41,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.336 Da) is slightly higher than Ligand B (374.482 Da), but both are acceptable.

**TPSA:** Ligand A (54.02) is significantly better than Ligand B (93.09). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (4.592) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.432) is within the optimal range.

**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).

**QED:** Both ligands have similar QED values (0.735 and 0.72), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (48.313 and 50.33, both <60).

**BBB:** Both have good BBB penetration (74.758 and 77.976), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.983) is slightly better than Ligand B (-5.074).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.024) is slightly better than Ligand B (-2.867).

**hERG Inhibition:** Ligand A (0.66) has a slightly higher hERG risk than Ligand B (0.2), which is undesirable.

**Microsomal Clearance:** Ligand B (20.213 mL/min/kg) has significantly lower microsomal clearance than Ligand A (58.285 mL/min/kg), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-15.634 hours) has a negative half-life, which is not possible and suggests an error in the data or a very rapidly metabolized compound. Ligand A (90.895 hours) has a good half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.43 and 0.109).

**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.

**Conclusion:**

Despite Ligand A's higher logP and slightly higher hERG risk, its significantly stronger binding affinity (-8.5 vs -7.2 kcal/mol) and better half-life are crucial for an enzyme target like SRC kinase. The difference in binding affinity is substantial enough to compensate for the slightly less favorable ADME properties. Ligand B has better metabolic stability and solubility, but its significantly weaker binding affinity makes it less likely to be a viable candidate. The negative half-life for Ligand B is also a major concern.

Output:
1
2025-04-17 14:45:41,866 - INFO - Batch 323 complete. Total preferences: 5168
2025-04-17 14:45:41,866 - INFO - Processing batch 324/512...
2025-04-17 14:46:21,767 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.539 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.24) is significantly better than Ligand B (113.93). TPSA < 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (3.811) is optimal (1-3), while Ligand B (-0.834) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=7) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have good QED scores (0.686 and 0.732), indicating drug-like properties.

**DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (40.364), both are acceptable, but A is slightly preferred.

**BBB:** Both ligands have similar BBB penetration (78.092 and 78.054), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.849) is slightly better than Ligand B (-5.142), but both are concerning.

**Aqueous Solubility:** Ligand A (-3.948) is better than Ligand B (-1.602), both are poor.

**hERG Inhibition:** Ligand A (0.607) has a lower hERG risk than Ligand B (0.201), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-12.609) has a *much* lower (better) microsomal clearance than Ligand A (62.147), indicating greater metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-13.663) has a longer half-life than Ligand A (18.627), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.526) has lower P-gp efflux than Ligand B (0.001), which is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.5 and -7.0 kcal/mol). The difference of 0.5 kcal/mol is not enough to overcome the significant ADME deficiencies of Ligand A.

**Conclusion:**

While Ligand A has slightly better solubility and P-gp efflux, Ligand B's significantly improved metabolic stability (lower Cl_mic and longer t1/2), better hERG profile, and acceptable logP outweigh these minor advantages. The poor Caco-2 permeability is a concern for both, but can be addressed with formulation strategies. The lower DILI risk for Ligand A is a minor benefit. Given the enzyme-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 14:46:21,767 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.43 & 369.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is higher than Ligand B (64.43). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Ligand A (-0.022) is slightly low, potentially hindering permeation. Ligand B (3.06) 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 0 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 (0.532 and 0.595), indicating drug-like properties.

**DILI:** Ligand A (45.25) has a moderate DILI risk, while Ligand B (19.70) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (47.81) and Ligand B (78.05) both have low BBB penetration. Since SRC is not a CNS target, this isn't a major factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.749 and -4.542), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.751 and -2.025), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.493 and 0.393).

**Microsomal Clearance:** Ligand A (40.73) has lower microsomal clearance than Ligand B (63.48), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-31.21) has a negative half-life, which is not possible. Ligand B (21.58) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.216 and 0.293).

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-6.8). 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 both have issues with permeability and solubility, Ligand B has a significantly lower DILI risk, a more optimal logP, and a reasonable in vitro half-life. Ligand A has a slightly better binding affinity and metabolic stability, but the DILI risk and suboptimal logP of Ligand A are concerning. The negative half-life for Ligand A is also a red flag.

Output:
1
2025-04-17 14:46:21,767 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 364.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is better than Ligand B (84.5), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (1.238) is slightly better than Ligand B (2.005), both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 4 HBA). Both are within acceptable limits.

**QED:** Ligand B (0.837) has a significantly higher QED score than Ligand A (0.539), indicating a more drug-like profile.

**DILI:** Ligand A (40.054) has a much lower DILI risk than Ligand B (67.003). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (60.14) is better than Ligand B (44.668).

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.897 and -4.869). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.701 and -2.926). This is a concern for formulation and bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.202 and 0.212). This is excellent.

**Microsomal Clearance:** Ligand A (23.8 mL/min/kg) has significantly lower microsomal clearance than Ligand B (59.144 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.579 hours) has a much longer half-life than Ligand B (-18.221 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.043 and 0.223).

**Binding Affinity:** Ligand B (-9.8 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 drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand B boasts a superior binding affinity and QED score, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and acceptable BBB. The strong binding affinity of Ligand B is compelling, but the poor metabolic stability and higher DILI risk are major concerns for an enzyme target. Given the priorities for kinase inhibitors, the improved ADME profile of Ligand A, coupled with a still very respectable binding affinity, makes it the more promising drug candidate.

Output:
0
2025-04-17 14:46:21,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (381.889 Da) is still well within the acceptable range.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (80.12) is better than Ligand B (88.91).

**logP:** Ligand A (1.069) is closer to the optimal range (1-3) than Ligand B (2.321). Ligand B is still acceptable, but higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both fall within the acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.764, Ligand B: 0.831), indicating drug-like properties.

**DILI:** Ligand A (33.23) has a significantly lower DILI risk than Ligand B (78.945). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (58.511) is better than Ligand B (50.446).

**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, again unusual and suggesting poor solubility. The scale is not specified, so it's hard to interpret.

**hERG Inhibition:** Ligand A (0.053) has a much lower hERG inhibition liability than Ligand B (0.25). This is a significant advantage for Ligand A, reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 6.333, Ligand B: 6.65), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (31.103 hours) has a significantly longer half-life than Ligand A (14.585 hours). This is a potential advantage for Ligand B, allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.035, Ligand B: 0.213).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a longer half-life, Ligand A excels in key areas: significantly lower DILI risk, lower hERG inhibition, and superior binding affinity. The slightly better TPSA and logP values of Ligand A also contribute to its favorability. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A outweigh this concern.

Output:
0
2025-04-17 14:46:21,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (366.893 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (78.09 and 80.12) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (not a priority here).

**3. logP:** Both ligands (2.856 and 1.62) are within the optimal 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for cell permeability, but Ligand B is still acceptable.

**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 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.86 and 0.828), indicating good drug-like properties.

**7. DILI:** Ligand A (39.201) has a slightly better DILI score than Ligand B (35.944), indicating a lower risk of liver injury. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (75.107) has a better BBB score than Ligand B (55.138), but this isn't a major concern for a non-CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.059 and -4.758) which is unusual. It suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-4.452 and -1.479), indicating poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.454 and 0.677).

**12. Microsomal Clearance:** Ligand A (27.835 mL/min/kg) has significantly lower microsomal clearance than Ligand B (58.942 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-26.41 hours) has a much longer in vitro half-life than Ligand B (-14.472 hours), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.09 and 0.065).

**15. 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, it's still a factor.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have issues with solubility and permeability, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a slightly better DILI score, and a marginally stronger binding affinity. The improved metabolic stability and half-life are particularly important for an enzyme target like SRC kinase, as they suggest a potentially more durable effect *in vivo*.

Output:
1
2025-04-17 14:46:21,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, well below the 140 threshold for oral absorption. Ligand B (132) is still reasonable, but less optimal.

**logP:** Ligand A (2.09) is optimal. Ligand B (0.336) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.843) is very good, indicating high drug-likeness. Ligand B (0.62) is acceptable, but lower.

**DILI:** Ligand B (77.123) has a higher DILI risk than Ligand A (67.003), but both are within a manageable range.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.466) and Ligand B (46.413) are both low.

**Caco-2 Permeability:** Ligand A (-4.399) is better than Ligand B (-5.422), indicating better intestinal absorption. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.203) is better than Ligand B (-2.012), indicating better solubility. Both are negative values, indicating low solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.26 and 0.215, respectively).

**Microsomal Clearance:** Ligand A (48.089) has significantly higher microsomal clearance than Ligand B (3.208). This suggests Ligand B is much more metabolically stable, a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand B (16.527 hours) has a much longer in vitro half-life than Ligand A (-15.982 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.047 and 0.058, respectively).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and better TPSA, the significant advantages of Ligand B in terms of metabolic stability (much lower Cl_mic, longer t1/2), solubility, and acceptable logP outweigh this difference. The lower logP of Ligand B is a concern, but the superior metabolic profile is critical for an enzyme target like SRC kinase. The slightly higher DILI risk for Ligand B is manageable.

Output:
1
2025-04-17 14:46:21,768 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (394.287 Da and 356.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.22) is slightly above the optimal <140, but acceptable. Ligand B (58.2) is well within the acceptable range.

**logP:** Both ligands (4.399 and 4.587) are slightly high, potentially leading to solubility issues or off-target effects. However, for kinases, this isn't as detrimental as for other targets.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, and Ligand B has 3 HBAs, both within the acceptable limit of <=10.

**QED:** Both ligands (0.688 and 0.646) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (89.841) has a significantly higher DILI risk than Ligand B (58.627). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (85.498) has a higher BBB value than Ligand A (45.909), but this is not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.716) is slightly better than Ligand B (-5.008).

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-5.453) is slightly better than Ligand B (-5.015).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.747 and 0.808).

**Microsomal Clearance:** Ligand A (49.643) has a lower microsomal clearance than Ligand B (77.807), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (71.794) has a much longer half-life than Ligand B (12.446), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.321 and 0.688).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the slightly higher logP and lower solubility, Ligand A is the more promising candidate due to its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and longer half-life. The affinity difference is substantial enough to overcome the slight solubility and logP concerns. The DILI risk associated with Ligand A is still a concern, but it is less severe than the overall profile of Ligand B.

Output:
0
2025-04-17 14:46:21,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (357.36 and 352.38 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.55) is higher than Ligand B (58.64). While both are below 140, the lower TPSA of Ligand B is generally more favorable for absorption.

**3. logP:** Ligand A (0.27) is quite low, potentially hindering membrane permeability. Ligand B (3.146) 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:** Ligand A (5) and Ligand B (3) are both within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.62 and 0.856), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (49.011) has a lower DILI risk than Ligand B (64.599), which is preferable.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (81.698) has a higher BBB score, but this isn't a major factor here.

**9. Caco-2:** Ligand A (-5.102) and Ligand B (-4.481) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so the difference might not be substantial.

**10. Solubility:** Ligand A (-1.583) and Ligand B (-3.856) both have negative solubility values, suggesting poor aqueous solubility. Ligand B is worse.

**11. hERG:** Ligand A (0.14) has a significantly lower hERG risk than Ligand B (0.784). This is a crucial advantage for Ligand A.

**12. Cl_mic:** Ligand A (-4.688) has a lower (better) microsomal clearance than Ligand B (68.315), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**13. t1/2:** Ligand A (45.103) has a longer in vitro half-life than Ligand B (-33.248), which is highly desirable.

**14. Pgp:** Ligand A (0.007) has a much lower Pgp efflux liability than Ligand B (0.294), suggesting better oral bioavailability and potentially better tissue distribution.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.6), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

While Ligand B has a better logP and QED, Ligand A demonstrates significantly better ADME properties, particularly regarding metabolic stability (Cl_mic, t1/2), hERG risk, and Pgp efflux. The slightly better affinity of Ligand B is unlikely to outweigh the substantial advantages of Ligand A in terms of drug-likeness and safety. The poor solubility of both is a concern, but can be addressed through formulation strategies.

Output:
0
2025-04-17 14:46:21,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.519 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is significantly better than Ligand B (82.11).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal for good absorption.

**logP:** Both ligands have good logP values (2.853 and 2.985), falling within the 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 similar and good QED scores (0.849 and 0.857), indicating good drug-like properties.

**DILI:** Ligand A (5.118) has a much lower DILI risk than Ligand B (28.306). This is a significant advantage for Ligand A.

**BBB:**  BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (82.047) is better than Ligand B (48.042).

**Caco-2 Permeability:** Ligand A (-4.646) is better than Ligand B (-5.164), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.756) is better than Ligand B (-3.209), which is crucial for formulation and bioavailability.

**hERG:** Ligand A (0.779) has a lower hERG inhibition liability than Ligand B (0.675), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-5.072) shows *much* better metabolic stability (lower clearance) than Ligand B (18.161). This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (12.184 hours) has a better in vitro half-life than Ligand B (-21.01 hours).

**P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux liability than Ligand B (0.302), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This difference of 2.9 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is clearly superior to Ligand B. It demonstrates better predicted ADME properties (solubility, permeability, metabolic stability, lower DILI, lower hERG, lower P-gp efflux), and, most importantly, a significantly stronger binding affinity for the SRC kinase. The substantial difference in binding affinity makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 14:46:21,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (376.503 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (80.12) is still under 140, but less optimal than A.

**logP:** Both ligands have good logP values (2.276 and 1.694), 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 similar QED scores (0.786 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 72.199, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 34.238, which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB score (79.682) than Ligand A (43.815), but this is less important.

**Caco-2 Permeability:** Ligand A (-5.156) and Ligand B (-4.832) both have negative values, which is unusual and requires careful interpretation. Lower (more negative) values typically indicate *lower* permeability. However, the scale isn't defined, so it's hard to interpret the absolute difference.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.187 and -2.314). Ligand B is slightly better, but both are suboptimal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.371 and 0.41), which is excellent.

**Microsomal Clearance:** Ligand A (70.473) has a higher microsomal clearance than Ligand B (52.722), indicating lower metabolic stability. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand A (-45.367) has a very negative half-life, indicating a very short half-life. Ligand B (-1.912) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.29 and 0.116), which is good.

**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 (1.9 kcal/mol difference).

**Conclusion:**

Despite the strong binding affinity of Ligand A, its high DILI risk and very poor in vitro half-life are major drawbacks. Ligand B, while having a slightly weaker binding affinity, presents a much better ADME-Tox profile, with a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a better (though still not great) half-life. The difference in binding affinity, while significant, can potentially be addressed through further optimization, whereas mitigating a high DILI risk is often much more challenging.

Output:
1
2025-04-17 14:46:21,769 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 342.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.62) is better than Ligand B (41.05), being closer to the <140 threshold for good absorption. Ligand B is exceptionally low, which *could* indicate good permeability but might also suggest a lack of necessary interactions.

**logP:** Ligand A (-0.226) is slightly low, potentially hindering permeation. Ligand B (4.792) is high, raising concerns about solubility and off-target effects.

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

**QED:** Both ligands have good QED scores (0.735 and 0.835), indicating drug-like properties.

**DILI:** Ligand A (50.291) has a slightly higher DILI risk than Ligand B (36.409), but both are below the concerning threshold of 60.

**BBB:** Ligand A (54.905) has a lower BBB penetration than Ligand B (93.912). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.46 and -5.069), which is unusual and suggests poor permeability. This needs further investigation, but is a significant concern for both.

**Aqueous Solubility:** Ligand A (-2.211) has very poor solubility. Ligand B (-4.846) is even worse. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.182) has a very low hERG risk, which is excellent. Ligand B (0.898) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-0.442) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (81.996) has a high clearance, suggesting rapid metabolism and potentially low bioavailability.

**In vitro Half-Life:** Ligand A (7.808) has a reasonable half-life. Ligand B (26.037) has a much longer half-life, which is a positive.

**P-gp Efflux:** Ligand A (0.061) has low P-gp efflux, which is favorable. Ligand B (0.579) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 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 of both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.1 vs -8.5 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand B has a longer half-life and lower DILI risk, and acceptable hERG. While the higher logP is a concern, the potency advantage is likely to be more impactful in initial optimization. The solubility issues would need to be addressed through formulation strategies or further chemical modifications.

Output:
1
2025-04-17 14:46:21,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 Da and 348.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (95.57). Both are below 140, but A is closer to the desirable threshold for good absorption.

**logP:** Both ligands have good logP values (2.182 and 1.504), 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=9) in terms of balancing solubility and permeability. Ligand B has a higher HBA count, which could potentially hinder permeability.

**QED:** Both ligands have acceptable QED values (0.492 and 0.695), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A (19.426) has a significantly lower DILI risk than Ligand B (41.877). This is a major advantage for Ligand A.

**BBB:** Ligand B (73.905) has a higher BBB penetration percentile than Ligand A (56.611). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.784) has a worse Caco-2 permeability than Ligand B (-5.351), but both are negative values which is not ideal.

**Aqueous Solubility:** Ligand A (-2.292) has a slightly better solubility than Ligand B (-1.856), but both are negative values which is not ideal.

**hERG:** Both ligands have very low hERG inhibition liability (0.258 and 0.131), indicating low cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (20.453) has a lower microsomal clearance than Ligand A (33.381), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (17.822 hours) has a much longer half-life than Ligand A (-5.454 hours). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.044 and 0.05).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are good, the 0.8 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is superior in terms of metabolic stability (lower Cl_mic, longer t1/2) and binding affinity, which are key priorities for kinase inhibitors. While Ligand A has a better DILI score, the difference isn't large enough to outweigh the advantages of Ligand B regarding potency and pharmacokinetics. The slightly worse solubility and permeability of Ligand B are less concerning than the poorer metabolic stability of Ligand A.

Output:
1
2025-04-17 14:46:21,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (338.426 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (23.55) is excellent, well below the 140 threshold for oral absorption. Ligand B (100.55) is still reasonable but higher, potentially impacting absorption.

**3. logP:** Ligand A (3.598) is optimal. Ligand B (0.561) is quite low, which could hinder membrane permeability and potentially reduce binding affinity.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (3) is acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is ideal. Ligand B (6) is acceptable, but approaching the upper limit.

**6. QED:** Both ligands have similar QED values (A: 0.752, B: 0.64), indicating good drug-likeness.

**7. DILI:** Ligand A (51.881) has a lower DILI risk than Ligand B (62.156), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand A (77.86) is higher than Ligand B (32.726), but this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.258) is better than Ligand B (-5.488), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.829) is better than Ligand B (-1.784), which is crucial for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.942) has a lower hERG risk than Ligand B (0.093), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (69.248) has higher clearance than Ligand B (5.937), suggesting lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (6.696) has a longer half-life than Ligand B (1.943), which is preferable.

**14. P-gp Efflux:** Ligand A (0.406) has lower P-gp efflux than Ligand B (0.046), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in binding affinity and has significantly better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has better solubility and lower hERG risk, the substantial affinity advantage of Ligand B, combined with the acceptable ADME profile, makes it the more promising candidate. The low logP of Ligand B is a concern, but can be addressed through prodrug strategies or formulation techniques.



Output:
1
2025-04-17 14:46:21,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.579) is slightly higher than Ligand B (347.415), but both are acceptable.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (111.55). Lower TPSA generally correlates with better cell permeability. Ligand B is above the preferred threshold of 140, which could hinder absorption.

**logP:** Ligand A (2.776) is optimal, while Ligand B (-0.013) is quite low. A logP below 1 can lead to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=4, HBA=5) are both within acceptable limits.

**QED:** Ligand A (0.72) has a better QED score than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Ligand A (37.456) has a slightly higher DILI risk than Ligand B (31.059), but both are well below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (49.36) is better than Ligand B (18.147).

**Caco-2 Permeability:** Ligand A (-5.242) is better than Ligand B (-5.035), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.613) is better than Ligand B (-1.848), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.176, Ligand B: 0.205), which is good.

**Microsomal Clearance:** Ligand A (13.785) has a significantly better (lower) microsomal clearance than Ligand B (4.134), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-1.421) has a better (longer) in vitro half-life than Ligand B (-14.3).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.095, Ligand B: 0.029).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial difference (1.9 kcal/mol), which can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has better logP, TPSA, QED, solubility, metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. While Ligand B has a slightly lower DILI risk, the other advantages of Ligand A, particularly its superior binding affinity and ADME properties relevant to an enzyme target, make it the more promising drug candidate.

Output:
1
2025-04-17 14:46:21,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.41 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.37) is higher than Ligand B (78.51). While both are reasonably good, Ligand B is better positioned for oral absorption given the <140 target.

**logP:** Ligand A (0.436) is quite low, potentially hindering permeability. Ligand B (1.294) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2-4 HBD/HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.576 and 0.788), indicating drug-likeness.

**DILI:** Both have acceptable DILI risk (30.865 and 37.999 percentile), below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.731) is better than Ligand B (41.838), but this isn't a primary concern.

**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 Inhibition:** Both have very low hERG inhibition risk (0.123 and 0.112), which is excellent.

**Microsomal Clearance:** Ligand A (-14.115) has *much* lower (better) microsomal clearance than Ligand B (33.041). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-7.502) has a much longer half-life than Ligand B (20.047). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.036).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a 2.0 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and significantly stronger binding affinity. However, Ligand A has superior metabolic stability (lower Cl_mic) and a longer half-life. The poor solubility and permeability are concerns for both. Given the importance of potency for kinase inhibitors, and the substantial 2.0 kcal/mol difference in binding affinity, Ligand B is the more promising candidate *despite* its higher clearance. Further optimization could address the solubility and permeability issues.

Output:
1
2025-04-17 14:46:21,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (341.455 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.5) is significantly better than Ligand B (104.12). A TPSA under 90 is preferred, and Ligand A is comfortably within this range, suggesting better absorption. Ligand B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.218 and 1.64), 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 are acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.847 and 0.708), indicating good drug-like properties.

**7. DILI:** Ligand A (24.622) has a much lower DILI risk than Ligand B (63.513). This is a significant advantage for Ligand A.

**8. BBB:** Both have similar BBB penetration (51.997 and 55.099). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.868) has better Caco-2 permeability than Ligand B (-5.501). Higher values are better, and while both are negative, A is less negative.

**10. Aqueous Solubility:** Ligand A (-2.124) has better aqueous solubility than Ligand B (-2.821). Better solubility is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.844) has a slightly better hERG profile than Ligand B (0.331), indicating lower cardiotoxicity risk. Lower is better.

**12. Microsomal Clearance:** Ligand A (31.062) has significantly lower microsomal clearance than Ligand B (57.245), suggesting better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (68.92) has a much longer in vitro half-life than Ligand B (2.428). This is a major advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.573 and 0.147).

**15. Binding Affinity:** Ligand B (-8.1) has slightly better binding affinity than Ligand A (-8.0). However, the difference is minimal (0.1 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all ADMET properties. Specifically, Ligand A demonstrates significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and better Caco-2 permeability. These factors are crucial for developing a viable drug candidate, especially for an enzyme target like SRC kinase. The small difference in binding affinity is outweighed by the substantial improvements in ADMET properties.

Output:
0
2025-04-17 14:46:21,771 - INFO - Batch 324 complete. Total preferences: 5184
2025-04-17 14:46:21,771 - INFO - Processing batch 325/512...
2025-04-17 14:47:04,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (330.431 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (361.433 Da) is also good.

**TPSA:** Ligand A (41.99) is significantly better than Ligand B (70.67). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (4.357) is higher than optimal (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (0.806) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=4) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar QED values (A: 0.73, B: 0.671), indicating reasonable drug-likeness.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (11.632). This is a significant drawback for Ligand A.

**BBB:** Ligand B (81.466) shows better BBB penetration than Ligand A (67.933), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.824) is worse than Ligand B (-5.022), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.09) is worse than Ligand B (-1.466), which is a significant concern given Ligand A's already high logP.

**hERG Inhibition:** Ligand A (0.754) has a slightly higher hERG risk than Ligand B (0.271).

**Microsomal Clearance:** Ligand A (49.786) has a higher microsomal clearance than Ligand B (1.883), meaning it's less metabolically stable. This is a critical disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-2.562) has a longer in vitro half-life than Ligand A (-4.414).

**P-gp Efflux:** Ligand A (0.362) has lower P-gp efflux than Ligand B (0.008), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.8 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the better candidate. While its logP is low, its significantly better DILI score, metabolic stability (lower Cl_mic, longer t1/2), solubility, and slightly better binding affinity outweigh the potential permeability concerns. Ligand A has several red flags: high DILI risk, poor solubility, and low metabolic stability. The slightly better P-gp efflux for Ligand A is not enough to compensate for these significant drawbacks.

Output:
1
2025-04-17 14:47:04,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.395 and 352.563 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.79) is higher than Ligand B (32.78). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have good logP values (2.363 and 3.51), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but isn't a major concern.

**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 (0.932) has a significantly higher QED score than Ligand B (0.636), indicating a more drug-like profile overall.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (5.273). This is a significant negative for Ligand A.

**BBB:** Both have high BBB penetration, but Ligand B (91.314) is better than Ligand A (84.917). This is less important for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand B (-4.325) is slightly better than Ligand A (-4.84).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-2.686) is slightly better than Ligand A (-3.03).

**hERG:** Both have low hERG inhibition risk (0.729 and 0.867), which is good.

**Microsomal Clearance:** Ligand A (44.937) has significantly lower microsomal clearance than Ligand B (71.727), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.779) has a longer half-life than Ligand B (-2.528). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux (0.425 and 0.347), which is good.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and longer half-life, both critical for an enzyme inhibitor. However, it has a higher DILI risk and lower solubility. Ligand B has better TPSA, solubility, and a much lower DILI risk, but significantly weaker binding affinity and a shorter half-life.

The difference in binding affinity (-8.8 vs -6.9 kcal/mol) is substantial (over 1.9 kcal/mol). Given that potency is a primary concern for kinase inhibitors, and the other differences are not overwhelmingly in favor of either compound, the stronger binding of Ligand A is the deciding factor. The DILI risk is a concern, but could be investigated further with structural modifications.

Output:
0
2025-04-17 14:47:04,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.941 Da) is slightly higher than Ligand B (347.375 Da), but both are acceptable.

**TPSA:** Ligand A (83.98) is well below the 140 threshold for oral absorption. Ligand B (133.14) is approaching the limit, but still acceptable.

**logP:** Ligand A (2.668) is optimal (1-3). Ligand B (0.32) is quite low, potentially hindering permeability.

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

**H-Bond Acceptors:** Both ligands (A: 6, B: 6) are below the 10 limit.

**QED:** Both ligands have similar QED values (A: 0.668, B: 0.615), indicating good drug-likeness.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 69.252, B: 69.019), both below the 60 threshold.

**BBB:** Ligand A (43.893) has a moderate BBB penetration, while Ligand B (21.714) is quite low. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.496 and -5.53), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values might represent very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.924 and -2.227), which is also unusual. This suggests very poor aqueous solubility, a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.217, B: 0.132), which is excellent.

**Microsomal Clearance:** Ligand A (64.776) has a moderate clearance, while Ligand B (-4.033) has a *negative* clearance, which is not physically possible and likely indicates a very stable compound. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (19.781) has a moderate half-life, while Ligand B (-26.525) has a negative half-life, which is also not physically possible and likely indicates a very long half-life. This further supports the high metabolic stability of Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.077, B: 0.046).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly better binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand B exhibits significantly better metabolic stability (negative clearance and half-life) and potentially better solubility (though both are poor). The negative values for clearance and half-life for Ligand B are concerning and likely represent limitations in the modeling or data. The low logP of Ligand B is also a drawback. Despite these issues, the substantial improvement in metabolic stability and the acceptable hERG risk make Ligand B a more promising starting point for optimization, *if* the negative clearance/half-life values can be explained and addressed. The superior binding affinity of Ligand A is very attractive, but the potential for rapid metabolism could limit its efficacy.

Output:
1
2025-04-17 14:47:04,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.33 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (65.12). A TPSA under 140 is good for oral absorption, and both are under, but A is much closer to the optimal range for permeability.

**logP:** Ligand A (3.664) is within the optimal 1-3 range, while Ligand B (1.241) is at the lower end, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5. Both are under the 10 threshold, but A is preferable.

**QED:** Both ligands have similar QED values (0.808 and 0.768), indicating good drug-likeness.

**DILI:** Ligand A (42.148) has a slightly higher DILI risk than Ligand B (28.306), but both are below the concerning threshold of 60.

**BBB:** Both have reasonable BBB penetration (A: 85.033, B: 78.945), but this is less critical for a non-CNS target like SRC.

**Caco-2:** 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 A (-4.512) is smaller than for B (-4.959), suggesting slightly better permeability.

**Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-1.31) is slightly better than A (-3.5).

**hERG:** Ligand A (0.749) has a higher hERG risk than Ligand B (0.548), which is undesirable.

**Microsomal Clearance:** Ligand A (37.568) has a lower microsomal clearance than Ligand B (43.452), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.273) has a significantly longer in vitro half-life than Ligand B (16.717). This is a major advantage.

**P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux liability than Ligand B (0.013), which is preferable.

**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 significant.

**Overall Assessment:**

Ligand A is the stronger candidate. It has better logP, TPSA, metabolic stability (lower Cl_mic and longer t1/2), P-gp efflux, and binding affinity. While it has a slightly higher DILI and hERG risk, the improvements in key pharmacokinetic parameters and potency outweigh these concerns. The negative solubility and Caco-2 values are concerning for both, but the values are slightly more favorable for A.

Output:
1
2025-04-17 14:47:04,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.908 and 350.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.61) is better than Ligand B (52.41), both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.921 and 2.732), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (0 HBD, 6 HBA) regarding the balance of solubility and permeability.

**QED:** Both ligands have similar QED values (0.763 and 0.685), indicating good drug-likeness.

**DILI:** Ligand A (35.556) has a significantly lower DILI risk than Ligand B (10.896), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration (75.107 and 82.047), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.965 and -4.892), 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 (-3.646 and -2.399), which also suggests poor solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG:** Ligand A (0.593) has a lower hERG risk than Ligand B (0.702), which is preferable.

**Microsomal Clearance:** Ligand A (-23.414) has *much* lower microsomal clearance than Ligand B (43.713). This indicates significantly better metabolic stability for Ligand A, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-0.537) has a negative half-life, which is unusual, but Ligand B (12.994) has a much more reasonable half-life.

**P-gp Efflux:** Ligand A (0.183) has lower P-gp efflux than Ligand B (0.447), which is favorable.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.3), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties, particularly DILI risk and microsomal clearance. The significantly lower DILI and clearance values of Ligand A suggest a safer and more metabolically stable drug candidate. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh this drawback. The slightly better half-life of Ligand B is not enough to overcome the other advantages of Ligand A.

Output:
0
2025-04-17 14:47:04,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (344.459 and 385.932 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.88) is better than Ligand B (29.54) as it is still within the acceptable range for oral absorption, while ligand B is significantly lower and might have issues with solubility.

**logP:** Ligand A (2.681) is optimal, while Ligand B (4.376) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**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 similar QED values (0.682 and 0.665), indicating good drug-likeness.

**DILI:** Ligand A (41.644) has a slightly higher DILI risk than Ligand B (10.896), but both are below the concerning threshold of 60.

**BBB:** Ligand A (50.872) has a lower BBB penetration than Ligand B (90.849). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.929) and Ligand B (-4.427) both have negative values which are not ideal, but are similar.

**Aqueous Solubility:** Ligand A (-3.267) has better solubility than Ligand B (-5.032). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.396) has a lower hERG inhibition risk than Ligand B (0.897), which is a significant advantage.

**Microsomal Clearance:** Ligand A (46.548) has lower microsomal clearance than Ligand B (94.799), suggesting better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand A (30.805) has a longer half-life than Ligand B (20.68), which is desirable.

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux liability than Ligand B (0.485), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is only 0.8 kcal/mol, and several other ADME properties of Ligand A are superior.

**Overall Assessment:**

Ligand A demonstrates a more balanced profile with better solubility, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity, the other advantages of Ligand A outweigh this difference, especially considering SRC is an enzyme target where metabolic stability and safety (hERG) are crucial.

Output:
1
2025-04-17 14:47:04,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.861 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is well below the 140 threshold and good for oral absorption. Ligand B (96.53) is still within acceptable limits, but higher.

**logP:** Ligand A (2.243) is optimal (1-3). Ligand B (0.729) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 threshold.

**QED:** Both ligands have reasonable QED scores (A: 0.751, B: 0.629), indicating drug-like properties.

**DILI:** Ligand A (47.693) has a lower DILI risk than Ligand B (20.822), which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (94.261) has better BBB penetration than Ligand B (45.754).

**Caco-2 Permeability:** Ligand A (-4.413) is poor, while Ligand B (-5.284) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.083) is poor, but Ligand B (-1.574) is slightly better.

**hERG:** Ligand A (0.535) has a lower hERG risk than Ligand B (0.116), which is a significant advantage.

**Microsomal Clearance:** Ligand A (7.086) has significantly lower clearance than Ligand B (21.32), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.95) has a shorter half-life than Ligand B (5.135), but both are acceptable.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.012), which is favorable.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is relatively small (0.7 kcal/mol).

**Overall Assessment:**

Ligand A is superior despite the slightly weaker binding affinity. Its significantly better DILI risk, lower hERG risk, lower microsomal clearance (better metabolic stability), and lower P-gp efflux outweigh the small difference in binding affinity. While both have poor Caco-2 permeability and solubility, the ADME profile of Ligand A is much more favorable for development as a drug candidate. The lower metabolic clearance and reduced toxicity risks are particularly important for an enzyme target.

Output:
1
2025-04-17 14:47:04,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Ligand A:**
*   **MW:** 407.308 Da - Within the ideal range (200-500).
*   **TPSA:** 64.35 - Good for oral absorption (<140).
*   **logP:** 3.831 - Slightly high, but acceptable. Could potentially lead to off-target effects.
*   **HBD:** 1 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.74 - Excellent drug-likeness.
*   **DILI:** 63.513 - Moderate risk of liver injury, above the preferred <40, but not extremely high.
*   **BBB:** 74.292 - Good, but not critical for a non-CNS target.
*   **Caco-2:** -4.576 - Poor permeability. A significant negative.
*   **Solubility:** -4.72 - Very poor solubility. A major drawback.
*   **hERG:** 0.535 - Low risk of hERG inhibition. Excellent.
*   **Cl_mic:** 91.347 - Relatively high microsomal clearance, indicating lower metabolic stability.
*   **t1/2:** 68.198 - Good in vitro half-life.
*   **Pgp:** 0.749 - Moderate P-gp efflux.
*   **Affinity:** -9.4 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 369.491 Da - Within the ideal range.
*   **TPSA:** 111.21 - Higher TPSA, potentially impacting absorption, but still within a reasonable range.
*   **logP:** 0.126 - Very low logP. This is a significant concern for permeability.
*   **HBD:** 3 - Good.
*   **HBA:** 6 - Good.
*   **QED:** 0.506 - Acceptable drug-likeness.
*   **DILI:** 26.095 - Very low risk of liver injury. Excellent.
*   **BBB:** 15.432 - Low BBB penetration, not a major concern here.
*   **Caco-2:** -6.079 - Very poor permeability. A significant negative.
*   **Solubility:** -0.996 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.155 - Very low risk of hERG inhibition. Excellent.
*   **Cl_mic:** -14.797 - Very low microsomal clearance, indicating high metabolic stability. Excellent.
*   **t1/2:** 4.979 - Short in vitro half-life. A drawback.
*   **Pgp:** 0.009 - Very low P-gp efflux. Excellent.
*   **Affinity:** -7.8 kcal/mol - Good binding affinity, but 1.6 kcal/mol weaker than Ligand A.

**Comparison and Decision:**

Both ligands have significant permeability issues (negative Caco-2 values). However, Ligand A has a much more severe solubility problem. Ligand A boasts a significantly stronger binding affinity (-9.4 vs -7.8 kcal/mol), which is a crucial factor for an enzyme inhibitor. Ligand B has superior metabolic stability (lower Cl_mic) and a lower DILI risk. However, the substantial difference in binding affinity favors Ligand A. While the poor solubility and permeability of Ligand A are concerning, these could potentially be addressed through formulation strategies. The higher affinity provides a larger window for optimization. Ligand B's weaker affinity makes it less likely to succeed even with improved ADME properties.

Output:
1
2025-04-17 14:47:04,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.427 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is well below the 140 threshold, and favorable for oral absorption. Ligand B (76.46) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.108) is within the optimal 1-3 range. Ligand B (0.965) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED scores (0.86 and 0.779), indicating good drug-like properties.

**DILI:** Ligand A (25.785) has a significantly lower DILI risk than Ligand B (45.173), which is a major advantage.

**BBB:** Ligand A (91.857) shows excellent BBB penetration, while Ligand B (65.374) is lower. While SRC is not a CNS target, better BBB penetration generally indicates better overall permeability.

**Caco-2 Permeability:** Ligand A (-4.48) has poor Caco-2 permeability, a significant concern. Ligand B (-5.082) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.744 and -1.186 respectively). This is a substantial drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.691) has a slightly higher hERG risk than Ligand B (0.166), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (31.55) has higher microsomal clearance than Ligand B (2.928), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-10.118) has a very short in vitro half-life, a major concern. Ligand B (6.32) has a better, though still not ideal, half-life.

**P-gp Efflux:** Ligand A (0.342) has lower P-gp efflux than Ligand B (0.03), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol), a difference of 0.8 kcal/mol. This is a substantial advantage that can outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While both have solubility and Caco-2 permeability issues, Ligand B has a significantly better binding affinity, lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. The stronger binding affinity is a key factor, especially for an enzyme target like SRC kinase. The solubility and permeability issues might be addressable through formulation strategies.



Output:
1
2025-04-17 14:47:04,043 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (380.861 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (105.31 and 104.65) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (1.546) is within the optimal 1-3 range. Ligand B (0.606) is a bit low, potentially impacting permeability.

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

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

**QED:** Both ligands (0.847 and 0.724) have good drug-likeness scores.

**DILI:** Ligand A (84.141) has a significantly higher DILI risk than Ligand B (30.593). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (65.374) is slightly higher.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.125) is slightly better than Ligand B (-4.901).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand B (-1.38) is slightly better than Ligand A (-2.682).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.194 and 0.23).

**Microsomal Clearance:** Ligand A (-0.058) has *much* lower (better) microsomal clearance than Ligand B (30.919), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.416) has a better (longer) in vitro half-life than Ligand B (-22.786).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.006).

**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.

**Conclusion:**

Despite the slightly better solubility of Ligand B, Ligand A is the superior candidate. The dramatically stronger binding affinity (-9.9 vs -7.5 kcal/mol) is a major advantage that can outweigh the slightly higher TPSA and poorer solubility. Critically, Ligand A has far superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk compared to Ligand B. While the DILI risk for Ligand A is still elevated, it is far less concerning than the high risk associated with Ligand B. The permeability is poor for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 14:47:04,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (382.5 and 353.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is higher than Ligand B (30.29). While both are reasonably low, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have good logP values (3.064 and 3.953), 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:** Both have low HBD (0) and reasonable HBA (5 and 4 respectively), satisfying the guidelines.

**QED:** Both ligands have good QED scores (0.738 and 0.815), indicating good drug-like properties.

**DILI:** Ligand A (77.55) has a higher DILI risk than Ligand B (35.48). This is a significant concern, as lower DILI is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (96.08) has a higher BBB score than Ligand A (65.61), but this isn't a major factor here.

**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 deciding factor.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the values are close enough that this isn't a deciding factor.

**hERG:** Ligand A (0.669) has a slightly lower hERG risk than Ligand B (0.936), which is favorable.

**Microsomal Clearance:** Ligand A (105.78) has a higher microsomal clearance than Ligand B (67.59), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (1.02) has a slightly longer half-life than Ligand A (8.36), which is desirable.

**P-gp Efflux:** Ligand A (0.213) has lower P-gp efflux than Ligand B (0.882), which is favorable.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.0). This 0.4 kcal/mol difference is potentially significant, but must be weighed against other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates significantly better ADME properties, particularly a much lower DILI risk and improved metabolic stability (lower Cl_mic, longer t1/2). The lower TPSA of Ligand B also suggests better permeability. The slightly higher hERG risk of Ligand B is a minor concern compared to the higher DILI and lower metabolic stability of Ligand A.

Output:
1
2025-04-17 14:47:04,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.503 and 389.493 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.15) is better than Ligand B (62.3). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is closer to the 90 A^2 threshold for CNS penetration (though that's not a priority here).

**logP:** Ligand A (1.133) is within the optimal range, while Ligand B (2.855) is approaching the upper limit.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have the same QED score of 0.729, indicating good drug-likeness.

**DILI:** Ligand A (14.036) has a significantly lower DILI risk than Ligand B (61.729). This is a major advantage for Ligand A.

**BBB:** Ligand A (74.564) and Ligand B (82.241) both have good BBB penetration, but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.635) and Ligand B (-5.062) both have negative values, which is unusual. Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.368) and Ligand B (-3.733) both have negative values, which is also unusual. Lower values indicate lower solubility.

**hERG Inhibition:** Ligand A (0.706) has a slightly higher hERG risk than Ligand B (0.537), but both are reasonably low.

**Microsomal Clearance:** Ligand A (46.194) has a higher microsomal clearance than Ligand B (18.491), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-16.663) has a much longer in vitro half-life than Ligand A (-3.138). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.173, respectively).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a much better DILI profile, which is a critical factor. However, Ligand B exhibits superior metabolic stability (lower Cl_mic, longer t1/2). Solubility and permeability are poor for both. Given the similar binding affinities, the lower DILI risk of Ligand A, and the importance of metabolic stability for kinase inhibitors, Ligand A is slightly favored.

Output:
0
2025-04-17 14:47:04,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.714 Da) is higher, but still acceptable. Ligand B (347.459 Da) is slightly preferred here.

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand B (63.57 A^2) is significantly lower than Ligand A (84.08 A^2), which is favorable for permeability.

**logP:** Both ligands have acceptable logP values (1-3). Ligand A (3.398) is at the higher end, potentially raising concerns about off-target effects, while Ligand B (1.725) is well within the optimal range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD/HBA counts. Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both have good QED scores (>0.5), indicating drug-likeness. Ligand B (0.852) is slightly better than Ligand A (0.6).

**DILI:** Ligand B (28.926) has a much lower DILI risk than Ligand A (70.105). This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (81.388) has a higher BBB score than Ligand A (41.411), but this is not a major deciding factor.

**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 B (-4.662) is slightly less negative than Ligand A (-5.502).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unspecified. Ligand B (-2.296) is slightly better than Ligand A (-3.41).

**hERG Inhibition:** Both have low hERG inhibition liability, which is good. Ligand B (0.6) is slightly better than Ligand A (0.741).

**Microsomal Clearance:** Ligand B (14.094 mL/min/kg) has significantly lower microsomal clearance than Ligand A (57.471 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (18.25 hours) has a longer in vitro half-life than Ligand A (27.676 hours). This is a positive attribute.

**P-gp Efflux:** Both have low P-gp efflux liability. Ligand B (0.082) is slightly lower than Ligand A (0.295).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a major advantage, as potency is a primary concern for enzyme inhibitors. The difference of 1.8 kcal/mol is substantial.

**Overall:**

Ligand B is superior to Ligand A across most key parameters. It has better potency (binding affinity), metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility and permeability (based on the negative values, though the scale is unknown). While both have some ADME liabilities, Ligand B's stronger binding affinity and improved ADME profile make it the more promising drug candidate.

Output:
1
2025-04-17 14:47:04,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.885 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (89.95). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases, and A is much closer to optimal.

**logP:** Ligand A (3.118) is optimal, while Ligand B (0.535) is quite low, potentially hindering membrane permeability.

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

**H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 5. Both are below the limit of 10, but A is preferable.

**QED:** Both ligands have good QED scores (0.579 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (35.905) has a lower DILI risk than Ligand B (42.924), both are acceptable, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.003) is better than Ligand B (30.089).

**Caco-2 Permeability:** Ligand A (-5.07) is better than Ligand B (-4.797), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.637) is better than Ligand B (-1.12), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.384) has a much lower hERG risk than Ligand B (0.117), a significant advantage.

**Microsomal Clearance:** Ligand A (32.485) has a higher (worse) microsomal clearance than Ligand B (9.638), suggesting lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand A (-2.415) is better than Ligand B (-2.351).

**P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux than Ligand B (0.077), which is favorable.

**Binding Affinity:** Ligand A (-8.7) has a slightly better binding affinity than Ligand B (-8.3). While both are excellent, the 0.4 kcal/mol difference is meaningful.

**Overall:**

Ligand A is superior in most key properties: TPSA, logP, solubility, hERG risk, and P-gp efflux. Although Ligand B has better metabolic stability (lower Cl_mic), the other advantages of A, particularly the significantly lower hERG risk and better solubility, outweigh this drawback for an enzyme target like SRC kinase. The slightly better binding affinity of A further strengthens its position.

Output:
1
2025-04-17 14:47:04,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.379 and 361.913 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (139.78) is at the upper limit of acceptable for good oral absorption, while Ligand B (29.54) is excellent.

**logP:** Ligand A (-1.903) is a bit low, potentially hindering permeability. Ligand B (4.531) is slightly high, potentially causing solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both within acceptable limits. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.498 and 0.744), indicating reasonable drug-likeness.

**DILI:** Ligand A (40.869) has a slightly higher DILI risk than Ligand B (23.885), but both are below the concerning threshold of 60.

**BBB:** Ligand A (27.142) has low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (92.672) has excellent BBB penetration, which is irrelevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.652 and -5.008), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.315 and -4.766), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.073) has a very low hERG risk, which is excellent. Ligand B (0.824) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-12.901) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (76.521) has high microsomal clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (10.878) has a moderate half-life. Ligand B (34.155) has a longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is good. Ligand B (0.734) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (0.0) has a significantly weaker binding affinity than Ligand B (-9.5). This is a crucial difference. A >1.5 kcal/mol advantage in binding affinity can often outweigh other drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the better candidate. The significantly stronger binding affinity (-9.5 kcal/mol vs 0.0 kcal/mol) is a major advantage for an enzyme inhibitor. While Ligand B has higher logP and clearance, the potency difference is substantial enough to prioritize it for further optimization. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the strong binding provides a solid starting point.

Output:
1
2025-04-17 14:47:04,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.37 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.59) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (49.41) is well within the optimal range.

**logP:** Ligand A (0.387) is a bit low, potentially hindering permeation. Ligand B (3.275) is near the upper end of 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 2 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.637 and 0.796, respectively), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 57.852, which is moderate. Ligand B has a lower DILI risk of 30.322, which is preferable.

**BBB:** Both ligands have relatively low BBB penetration (59.597 and 74.758 respectively), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.432) has poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.817) also has poor Caco-2 permeability, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.586) has poor aqueous solubility. Ligand B (-4.454) also has poor aqueous solubility, but slightly better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.113 and 0.348, respectively).

**Microsomal Clearance:** Ligand A (-1.132) has a negative clearance, which is unusual and likely indicates high metabolic stability. Ligand B (72.355) has a high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-26.275) has a very long in vitro half-life, consistent with the negative clearance. Ligand B (-3.473) has a short in vitro half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.367, respectively).

**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 is still a factor.

**Conclusion:**

Ligand B is the more promising candidate. While both have poor Caco-2 permeability and solubility, Ligand B has a significantly better binding affinity, a much lower DILI risk, and a more favorable logP. Most importantly, its metabolic stability is much worse than Ligand A, but this can be addressed with structural modifications. Ligand A's extremely long half-life and negative clearance are unusual and could indicate issues with the assay or compound behavior *in vivo*. The slightly better affinity of Ligand B, combined with its lower toxicity profile, makes it the preferred candidate for further optimization.

Output:
1
2025-04-17 14:47:04,044 - INFO - Batch 325 complete. Total preferences: 5200
2025-04-17 14:47:04,044 - INFO - Processing batch 326/512...
2025-04-17 14:47:50,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.42) is better than Ligand B (96.45), both are acceptable but closer to the upper limit for good oral absorption.

**logP:** Ligand A (0.981) is within the optimal range (1-3), while Ligand B (-0.248) is slightly below, which could potentially hinder permeability.

**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 acceptable limits.

**QED:** Ligand A (0.803) has a significantly higher QED score than Ligand B (0.597), indicating better overall drug-likeness.

**DILI:** Ligand B (35.673) has a much lower DILI risk than Ligand A (56.844), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 64.87, Ligand B: 62.156). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-5.398) is slightly better than Ligand B (-5.49).

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and suggests poor solubility. Ligand B (-0.217) is slightly better than Ligand A (-2.323).

**hERG Inhibition:** Ligand A (0.05) has a slightly lower hERG risk than Ligand B (0.102), which is preferable.

**Microsomal Clearance:** Ligand B (-5.72) has significantly lower (better) microsomal clearance than Ligand A (1.799), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.459) has a longer in vitro half-life than Ligand B (-1.299), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.027, Ligand B: 0.002), which is good.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.2 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and significantly better metabolic stability (lower Cl_mic) and lower DILI risk. The slightly lower logP and solubility are concerns, but the strong affinity and improved safety profile are more critical for an enzyme inhibitor. Ligand A has a better QED and half-life, but these are less important than the advantages offered by Ligand B.

Output:
1
2025-04-17 14:47:50,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.407 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.21) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (40.62) is excellent, well below 140, suggesting good absorption potential.

**logP:** Ligand A (-0.249) is a bit low, potentially hindering permeation. Ligand B (2.984) is within 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 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.541 and 0.74), indicating drug-like properties.

**DILI:** Ligand A (39.667) has a slightly higher DILI risk than Ligand B (17.72), but both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (71.656) is better than Ligand A (62.117). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.571) has poor Caco-2 permeability, which is a significant concern. Ligand B (-4.74) is better, but still indicates limited permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.644 and -3.289). This is a major drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.111) shows a slightly higher hERG risk than Ligand B (0.335), although both are relatively low.

**Microsomal Clearance:** Ligand A (-3.278) has much better metabolic stability (lower clearance) than Ligand B (63.316). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (0.753) has a shorter half-life than Ligand B (-9.169), which is unfavorable.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, a positive attribute. Ligand B (0.158) has slightly higher efflux.

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the better candidate. Its significantly improved metabolic stability (lower Cl_mic, though offset by a shorter half-life) and lower P-gp efflux outweigh its slightly lower logP and poorer Caco-2 permeability. The solubility is a concern for both, but can potentially be addressed with formulation strategies. Ligand B's poor metabolic stability is a major drawback for an enzyme inhibitor.

Output:
0
2025-04-17 14:47:50,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.439 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (129.72) is better than Ligand B (40.62) as it is closer to the threshold of 140.

**logP:** Ligand B (3.372) is optimal (1-3), while Ligand A (-0.727) is below 1, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 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 similar QED values (0.703 and 0.71), indicating good drug-likeness.

**DILI:** Ligand B (17.642) has a much lower DILI risk than Ligand A (72.547). This is a substantial advantage for Ligand B.

**BBB:** Ligand B (88.484) has a higher BBB penetration percentile than Ligand A (25.397), but BBB is less critical for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.502) has a very poor Caco-2 permeability, while Ligand B (-4.495) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-2.775) and Ligand B (-3.521) both have poor solubility.

**hERG:** Ligand A (0.045) has a slightly lower hERG risk than Ligand B (0.567), but both are relatively low.

**Microsomal Clearance:** Ligand A (-17.764) has a significantly lower (better) microsomal clearance than Ligand B (93.754), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (68.248) has a much longer half-life than Ligand B (11.052), which is a major advantage.

**P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux than Ligand B (0.511), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol). The difference of 1.4 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much lower DILI risk. While its solubility and Caco-2 permeability are poor, its metabolic stability is worse than Ligand A. However, the strong binding affinity and low DILI risk of Ligand B are more critical for an enzyme inhibitor. Ligand A has better metabolic stability and P-gp efflux, but suffers from poor logP and Caco-2 permeability, and a significantly higher DILI risk. The binding affinity difference is substantial.

Output:
1
2025-04-17 14:47:50,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.367 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.55) is slightly above the preferred <140, but acceptable. Ligand B (96.69) is excellent, well below 140.

**logP:** Ligand A (1.95) is within the optimal 1-3 range. Ligand B (0.992) is a bit low, potentially impacting permeability.

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

**H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (6) is also good.

**QED:** Both ligands have reasonable QED scores (0.664 and 0.537), indicating good drug-like properties.

**DILI:** Ligand A (54.634) has a slightly higher DILI risk than Ligand B (47.964), but both are below the concerning threshold of 60.

**BBB:** Both have low BBB penetration (37.96 and 36.293), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2:** Both have negative Caco-2 values (-5.282 and -5.255), which is unusual and suggests poor permeability. This is a significant issue.

**Solubility:** Both have negative solubility values (-4.242 and -1.262), indicating very poor aqueous solubility. This is a major drawback.

**hERG:** Ligand A (0.316) has a slightly better hERG profile than Ligand B (0.408), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (32.826) has a higher microsomal clearance than Ligand B (2.397), meaning it's less metabolically stable. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand A (-26.819) has a very short in vitro half-life, while Ligand B (14.657) is better, but still not ideal.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.011 and 0.03), which is favorable.

**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 could outweigh some ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability indicated by the Caco-2 and solubility values, Ligand A's substantially superior binding affinity (-8.4 vs -7.5 kcal/mol) is the deciding factor. The difference in potency is large enough to potentially overcome the ADME liabilities, especially given that these are *in vitro* values and could be improved through formulation or structural modifications. Ligand B's better metabolic stability is a plus, but the weaker binding makes it less likely to be a successful drug candidate.

Output:
0
2025-04-17 14:47:50,506 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [344.499, 49.41, 3.42, 1, 2, 0.853, 17.642, 83.482, -4.73, -4.02, 0.442, 47.202, -3.39, 0.187, -8.8]
**Ligand B:** [338.499, 49.84, 4.7, 2, 4, 0.617, 41.062, 77.162, -5.068, -5.742, 0.947, 98.043, 73.634, 0.717, -7.4]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (344.5) is slightly higher than B (338.5), but both are acceptable.
2. **TPSA:** Both are reasonably low (A: 49.41, B: 49.84), suggesting good potential for cell permeability. Both are well below the 140 A^2 threshold.
3. **logP:** A (3.42) is optimal, while B (4.7) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.
4. **HBD:** Both have acceptable HBD counts (A: 1, B: 2), well below the 5 threshold.
5. **HBA:** Both have acceptable HBA counts (A: 2, B: 4), well below the 10 threshold.
6. **QED:** A (0.853) is significantly better than B (0.617), indicating a more drug-like profile.
7. **DILI:** A (17.642) has a much lower DILI risk than B (41.062). This is a significant advantage for A.
8. **BBB:** A (83.482) has better BBB penetration potential than B (77.162), though this isn't a primary concern for a non-CNS target like SRC.
9. **Caco-2:** A (-4.73) is better than B (-5.068), indicating better intestinal absorption.
10. **Solubility:** A (-4.02) is better than B (-5.742), indicating better aqueous solubility.
11. **hERG:** A (0.442) has a lower hERG risk than B (0.947). This is a critical advantage for A, minimizing cardiotoxicity concerns.
12. **Cl_mic:** A (47.202) has lower microsomal clearance than B (98.043), suggesting better metabolic stability.
13. **t1/2:** B (73.634) has a significantly longer in vitro half-life than A (-3.39). This is a major advantage for B, potentially allowing for less frequent dosing.
14. **Pgp:** A (0.187) has lower P-gp efflux than B (0.717), which is favorable for bioavailability.
15. **Binding Affinity:** A (-8.8 kcal/mol) has a stronger binding affinity than B (-7.4 kcal/mol). This is a substantial difference, and a >1.5 kcal/mol advantage often outweighs minor ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Conclusion:**

While ligand B has a significantly longer half-life, ligand A excels in almost every other critical parameter. Its superior binding affinity (-8.8 vs -7.4 kcal/mol), lower DILI risk, lower hERG risk, better solubility, better Caco-2 permeability, and lower P-gp efflux outweigh the half-life disadvantage. The difference in binding affinity is particularly significant. The improved metabolic stability (lower Cl_mic) of A is also a positive.

Therefore, I predict **Ligand A** is the more viable drug candidate.

Output:
0

2025-04-17 14:47:50,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.423 and 352.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.84) is better than Ligand B (50.28). While both are below 140, lower TPSA generally favors permeability.

**logP:** Ligand A (1.33) is within the optimal 1-3 range. Ligand B (3.121) is at the higher end, potentially leading to solubility issues.

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

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

**QED:** Ligand B (0.857) has a significantly better QED score than Ligand A (0.354), indicating a more drug-like profile.

**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 B (84.839) shows better BBB penetration than Ligand A (64.095), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.803 and -4.379), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.425) has slightly better solubility than Ligand B (-4.38), although both are quite poor.

**hERG Inhibition:** Ligand A (0.215) has a lower hERG risk than Ligand B (0.76), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (3.368) has significantly lower microsomal clearance than Ligand B (43.955), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.549 hours) has a longer half-life than Ligand B (17.905 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.011) has much lower P-gp efflux than Ligand B (0.112), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.6 kcal/mol), with Ligand B being slightly better. However, the difference is small and can be outweighed by other factors.

**Overall Assessment:**

While Ligand B has a better QED and slightly better binding affinity, Ligand A is significantly better in terms of DILI risk, metabolic stability (Cl_mic and t1/2), hERG inhibition, and P-gp efflux. The poor Caco-2 permeability is a concern for both, but the other advantages of Ligand A, particularly the lower DILI and better metabolic profile, make it the more promising candidate for further development as an SRC kinase inhibitor.

Output:
0
2025-04-17 14:47:50,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.262 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.37) is significantly better than Ligand B (71.34). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is more favorable.

**logP:** Both ligands have good logP values (4.39 and 3.819) falling within the 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.

**QED:** Both ligands have acceptable QED scores (0.452 and 0.667), with B being slightly more drug-like.

**DILI:** Ligand B (29.779) has a much lower DILI risk than Ligand A (76.541), a significant advantage.

**BBB:** Ligand A (83.327) has better BBB penetration than Ligand B (69.446), but this is less critical for a non-CNS target like SRC.

**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:** Ligand B (-3.882) has better aqueous solubility than Ligand A (-5.391). This is a crucial factor for bioavailability.

**hERG Inhibition:** Ligand A (0.565) has a slightly lower hERG risk than Ligand B (0.725), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (81.108 and 78.366), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (25.808 hours) has a slightly longer half-life than Ligand A (31.598 hours).

**P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.693 and 0.768).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly stronger binding affinity than Ligand A (-9.2 kcal/mol). While A is better, the difference is not substantial.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity and BBB penetration, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, better aqueous solubility, and a slightly longer half-life. The TPSA is higher for B, but still within acceptable limits. The slightly better affinity of A is outweighed by the superior safety and pharmacokinetic properties of B.

Output:
1
2025-04-17 14:47:50,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.334 and 358.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.68) is significantly better than Ligand B (89.16).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (2.928 and 1.826, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 6 HBA) regarding the number of hydrogen bond donors and acceptors. Fewer are generally preferable for permeability.

**QED:** Both ligands have similar QED values (0.773 and 0.643), indicating good drug-likeness.

**DILI:** Ligand A (38.93) has a much lower DILI risk than Ligand B (70.841). This is a significant advantage for Ligand A.

**BBB:** Ligand A (88.445) has a better BBB penetration percentile than Ligand B (23.187). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.499) has a better Caco-2 permeability than Ligand B (-5.836), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.879) has better aqueous solubility than Ligand B (-2.43). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.485 and 0.206, respectively).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (29.915 and 29.76 mL/min/kg).

**In vitro Half-Life:** Ligand A (11.297 hours) has a better in vitro half-life than Ligand B (48.057 hours).

**P-gp Efflux:** Ligand A (0.064) has a lower P-gp efflux liability than Ligand B (0.036). Lower efflux is preferable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol). This is a crucial factor, and the 7.7 kcal/mol difference is substantial.

**Conclusion:**

Ligand A is significantly better than Ligand B. It has a lower DILI risk, better solubility, better permeability, a longer half-life, lower P-gp efflux, and, most importantly, a much stronger binding affinity. While Ligand B has acceptable properties, Ligand A's superior potency and safety profile make it the more promising drug candidate.

Output:
1
2025-04-17 14:47:50,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.407 Da) is slightly lower, which can be favorable for permeability. Ligand B (351.359 Da) is also good.

**2. TPSA:** Ligand A (65.36) is well below the 140 threshold for oral absorption and is quite favorable. Ligand B (121.71) is still under the threshold, but less optimal than A.

**3. logP:** Ligand A (3.942) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (-0.114) is significantly below 1, which raises concerns about permeability.

**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 slightly higher, but still within the acceptable limit of 10.

**6. QED:** Ligand A (0.924) is excellent, indicating high drug-likeness. Ligand B (0.73) is still reasonably good, but lower than A.

**7. DILI:** Ligand A (56.96) has a moderate DILI risk, but is acceptable. Ligand B (69.058) has a higher DILI risk, which is less desirable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.125) is higher than Ligand B (19.814).

**9. Caco-2 Permeability:** Ligand A (-4.499) is poor, suggesting limited intestinal absorption. Ligand B (-5.062) is also poor, but slightly worse than A.

**10. Aqueous Solubility:** Ligand A (-5.106) is poor, which could pose formulation challenges. Ligand B (-2.115) is also poor, but slightly better than A.

**11. hERG Inhibition:** Ligand A (0.856) has a low risk of hERG inhibition, which is excellent. Ligand B (0.046) has a very low risk, which is also excellent.

**12. Microsomal Clearance:** Ligand A (50.943) has moderate clearance, suggesting moderate metabolic stability. Ligand B (-15.551) has negative clearance, indicating very high metabolic stability, which is a significant advantage.

**13. In vitro Half-Life:** Ligand A (20.212) has a reasonable half-life. Ligand B (-34.443) 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 (0.329) has low P-gp efflux, which is good. Ligand B (0.021) has very low P-gp efflux, which is also good.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.9 kcal/mol and -8.3 kcal/mol respectively). Ligand A is slightly better (-8.9 kcal/mol).

**Overall Assessment:**

Ligand A has better drug-likeness (QED), better TPSA, and slightly better binding affinity. However, Ligand B exhibits significantly better metabolic stability (Cl_mic) and a lower P-gp efflux. Both have poor solubility and Caco-2 permeability. The negative half-life for Ligand B is a major red flag, suggesting a data error or a problematic prediction. Considering the enzyme-specific priorities, metabolic stability is crucial. While Ligand A has a slight edge in binding affinity, the superior metabolic stability of Ligand B is a significant advantage. Given the negative half-life for ligand B, I will choose ligand A.

Output:
0
2025-04-17 14:47:50,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 359.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.57 and 84.31) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.82 and 3.599) 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 4 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (45.173) has a slightly higher DILI risk than Ligand B (56.223), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (61.38 and 62.97), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.362) has worse Caco-2 permeability than Ligand B (-5.162). Lower values here indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-4.105) has slightly worse aqueous solubility than Ligand B (-3.998).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.508 and 0.471).

**Microsomal Clearance:** Ligand A (59.131) has a higher microsomal clearance than Ligand B (36.47). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.942) has a much longer in vitro half-life than Ligand A (55.302). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.11 and 0.215).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand B is more favorable. While both have excellent binding affinity and acceptable physicochemical properties, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic) and a longer in vitro half-life. These factors are crucial for *in vivo* efficacy and reduced dosing frequency. The slightly better Caco-2 permeability and solubility of Ligand B are also beneficial.

Output:
1
2025-04-17 14:47:50,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.422 and 348.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (79.3), both are below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (2.227 and 3.118), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially cause 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 6. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.562 and 0.595), indicating good drug-like properties.

**7. DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (27.104), which is preferable.

**8. BBB:** Ligand A (75.727) has a higher BBB penetration than Ligand B (60.644). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.774 and -4.951). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.965 and -2.639). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.731 and 0.812), which is excellent.

**12. Microsomal Clearance:** Ligand B (22.119 mL/min/kg) has significantly lower microsomal clearance than Ligand A (40.031 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (45.928 hours) has a much longer in vitro half-life than Ligand A (18.594 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.219 and 0.174).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

While both ligands have some drawbacks (poor Caco-2 and solubility), Ligand B is the more promising candidate. Its superior metabolic stability (lower Cl_mic and longer t1/2) and slightly better binding affinity outweigh the slightly higher logP and DILI risk. The differences in these parameters are significant enough to favor Ligand B, especially considering the enzyme-specific priorities.

Output:
1
2025-04-17 14:47:50,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.391 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.06) is higher than Ligand B (67.23). Both are below 140, suggesting reasonable absorption, but B is preferable.

**logP:** Ligand A (0.606) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (1.685) is closer to the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 4. Both are within the acceptable limit of 10, but B is better.

**QED:** Both ligands have QED values (0.877 and 0.606) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (32.726). B is significantly better here.

**BBB:** Both ligands have acceptable BBB penetration (74.021 and 70.415). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 issue for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.041 and 0.086). This is excellent.

**Microsomal Clearance:** Ligand A (12.302) has lower microsomal clearance than Ligand B (24.6), indicating better metabolic stability. This is a key advantage for A.

**In vitro Half-Life:** Ligand A (22.275) has a longer half-life than Ligand B (-10.695). This is a significant advantage for A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.051). This is good.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.8 vs -6.6 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, it has better metabolic stability (lower Cl_mic) and a longer half-life. While Ligand B has a lower DILI risk and slightly better TPSA and logP, the potency and PK advantages of Ligand A are more critical for a kinase inhibitor. The poor solubility and permeability would need to be addressed through formulation strategies, but the starting point of a potent, metabolically stable molecule is preferable.

Output:
1
2025-04-17 14:47:50,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (364.471 and 354.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.37) is well below the 140 threshold and acceptable for oral absorption. Ligand B (99.1) is still within range but higher, potentially impacting absorption slightly.

**3. logP:** Ligand A (2.617) is optimal (1-3). Ligand B (0.21) is quite low, which could hinder membrane permeability and bioavailability.

**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 (5) are both acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.752 and 0.568), suggesting good drug-like properties.

**7. DILI:** Ligand A (58.123) has a moderate DILI risk, but is preferable to Ligand B (11.206) which has a very low risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (49.205) and Ligand B (29.508) are both low.

**9. Caco-2:** Ligand A (-4.761) and Ligand B (-5.036) both have negative values, indicating poor permeability.

**10. Solubility:** Ligand A (-2.006) and Ligand B (-0.644) both have negative values, indicating poor solubility.

**11. hERG:** Ligand A (0.227) and Ligand B (0.08) both have low hERG risk, which is excellent.

**12. Cl_mic:** Ligand A (24.034) has a higher microsomal clearance than Ligand B (3.993), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. t1/2:** Ligand A (31.757) has a longer half-life than Ligand B (3.199), which is desirable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.026 and 0.03).

**15. Binding Affinity:** Ligand B (-9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7 kcal/mol). This 2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

While Ligand A has a longer half-life, Ligand B is superior due to its significantly stronger binding affinity (-9 vs -7 kcal/mol) and much better metabolic stability (lower Cl_mic). The lower logP of Ligand B is a concern, but the substantial binding affinity advantage is likely to compensate for this. Both have poor solubility and Caco-2 permeability, but these can be addressed through formulation strategies. The DILI risk is also low for both.

Output:
1
2025-04-17 14:47:50,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.479 and 364.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.57) is better than Ligand B (58.64), both are acceptable for an enzyme target.

**logP:** Ligand A (4.114) is slightly high, potentially leading to solubility issues, while Ligand B (2.496) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 3 HBA) both have reasonable counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.726 and 0.834), indicating good drug-like properties.

**DILI:** Ligand B (29.469) has a significantly lower DILI risk than Ligand A (46.452), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (89.608 and 81.892), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative values (-4.837 and -4.516) which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.166 and -2.487). This is a major drawback.

**hERG Inhibition:** Ligand A (0.569) has a slightly higher hERG risk than Ligand B (0.439), but both are relatively low.

**Microsomal Clearance:** Ligand B (12.01) has much lower microsomal clearance than Ligand A (101.079), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-13.196) has a much longer in vitro half-life than Ligand A (-2.832), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.533) has lower P-gp efflux than Ligand B (0.056), which could lead to better bioavailability.

**Binding Affinity:** Ligand A (-10.1 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 concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is the primary driver for kinase inhibitors. However, it suffers from high metabolic clearance, poor solubility, and a higher DILI risk. Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life), but a weaker binding affinity. Given the significant affinity difference, the better potency of Ligand A is likely to be more important, *provided* the solubility and metabolic stability issues can be addressed through further optimization.

Output:
1
2025-04-17 14:47:50,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 350.409 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.78) is higher than Ligand B (45.33). While both are reasonably low, Ligand B is better positioned for good oral absorption.

**logP:** Ligand A (2.291) is within the optimal 1-3 range. Ligand B (3.967) is slightly higher, potentially edging towards solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 2. Both are within acceptable limits (<=10).

**QED:** Both ligands have similar QED values (0.886 and 0.821), indicating good drug-likeness.

**DILI:** Ligand A (15.432) has a significantly lower DILI risk than Ligand B (59.131). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (84.374 and 89.957), but this is less critical for a kinase inhibitor unless CNS effects are specifically desired.

**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 have negative solubility values, which is also unusual. Ligand B (-4.044) is slightly worse than Ligand A (-2.542).

**hERG Inhibition:** Ligand A (0.591) has a lower hERG risk than Ligand B (0.898), which is preferable.

**Microsomal Clearance:** Ligand A (31.876) has lower microsomal clearance than Ligand B (40.803), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (21.064 hours) has a longer half-life than Ligand B (14.314 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.198) has lower P-gp efflux than Ligand B (0.462), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.0 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 of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand A has superior ADME properties (lower DILI, better metabolic stability, longer half-life, lower P-gp efflux, and lower hERG risk), Ligand B's binding affinity is considerably stronger. For an enzyme target like SRC kinase, potency is paramount. The 1.3 kcal/mol difference in binding affinity is significant enough to favor Ligand B despite its less favorable ADME profile. Optimization of Ligand B could potentially address the DILI and solubility concerns while retaining its high potency.

Output:
1
2025-04-17 14:47:50,509 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (351.466 and 351.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.2) is slightly higher than Ligand B (52.65). Both are below the 140 threshold for good absorption, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (3.127 and 2.672), 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 2 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.856) has a significantly higher QED score than Ligand B (0.684), suggesting better overall drug-likeness.

**7. DILI:** Ligand A (35.75) has a much lower DILI risk than Ligand B (16.324), indicating a safer profile.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (83.831) is better than Ligand B (78.209). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Solubility:** Ligand A (-3.705) has slightly better solubility than Ligand B (-2.962). Both are quite poor.

**11. hERG:** Ligand A (0.83) has a slightly higher hERG risk than Ligand B (0.508), but both are reasonably low.

**12. Cl_mic:** Ligand A (14.347) has significantly lower microsomal clearance than Ligand B (54.058), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**13. t1/2:** Ligand A (-12.74) has a negative half-life, which is not possible. Ligand B (3.063) has a short half-life.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.23).

**15. Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.7), but the difference is not substantial.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: significantly lower DILI risk, much better metabolic stability (lower Cl_mic), and a higher QED score. The solubility is poor for both, but can be addressed through formulation. The negative half-life for Ligand A is a major red flag and likely an error in the data.

Output:
1
2025-04-17 14:47:50,509 - INFO - Batch 326 complete. Total preferences: 5216
2025-04-17 14:47:50,509 - INFO - Processing batch 327/512...
2025-04-17 14:48:30,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.38 and 360.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.97) is better than Ligand B (78.35), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-1.144) is a bit low, potentially hindering permeation. Ligand B (2.472) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (2) is even better, both are below the 5 threshold.

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

**QED:** Ligand B (0.875) has a significantly better QED score than Ligand A (0.39), indicating a more drug-like profile.

**DILI:** Ligand A (25.824) has a much lower DILI risk than Ligand B (55.68). This is a significant advantage for Ligand A.

**BBB:** Ligand A (43.505) and Ligand B (35.13) are both low, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.49 and -5.282), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.434 and -3.873), indicating poor solubility. This is a significant drawback for both, but worse for Ligand B.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.267 and 0.412), which is good.

**Microsomal Clearance:** Ligand A (-28.497) has a much lower (better) microsomal clearance than Ligand B (63.564), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-5.934) has a slightly better (less negative) in vitro half-life than Ligand B (-7.602).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.055).

**Binding Affinity:** Both ligands have very similar and good binding affinities (-8.6 and -7.8 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

While Ligand B has a better QED and logP, Ligand A is superior due to its significantly lower DILI risk and much better metabolic stability (lower Cl_mic). The similar binding affinities make these factors decisive. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed with formulation strategies. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are paramount.

Output:
0
2025-04-17 14:48:30,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (345.443 Da) is comfortably within.

**TPSA:** Ligand A (42.96) is well below the 140 threshold for oral absorption. Ligand B (54.78) is also acceptable, though slightly higher.

**logP:** Both ligands have good logP values (A: 3.002, B: 1.529), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=0, HBA=4) both adhere to the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (A: 0.554, B: 0.761), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (A: 23.226, B: 34.354), well below the concerning threshold of 60.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (77.2) has a better BBB percentile than Ligand B (69.407).

**Caco-2 Permeability:** Ligand A (-5.127) has a lower Caco-2 permeability compared to Ligand B (-4.629), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.767, B: -1.298). This is a potential issue, but can be addressed through formulation strategies.

**hERG Inhibition:** Both ligands have low hERG risk (A: 0.848, B: 0.146). Ligand B is significantly better, posing a lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (38.037) has a higher microsomal clearance than Ligand B (31.252), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (20.596 hours) has a substantially longer in vitro half-life than Ligand A (5.465 hours). 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 (A: 0.459, B: 0.131). Ligand B is better.

**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 still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While both ligands have acceptable properties overall, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity. The solubility issues are present in both, but can be mitigated. The improved ADME profile of Ligand B outweighs the slightly lower Caco-2 permeability and BBB.

Output:
1
2025-04-17 14:48:30,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 364.486 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (40.62), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (1.709) is optimal, while Ligand B (3.697) is approaching the upper limit.

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

**H-Bond Acceptors:** Ligand A (4) is good, Ligand B (3) is also acceptable.

**QED:** Both ligands (0.586 and 0.547) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (3.218) has a significantly lower DILI risk than Ligand B (23.187). This is a major advantage.

**BBB:** Ligand A (80.807) is good, while Ligand B (95.347) is even better. However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.451) is poor, while Ligand B (-4.802) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-1.369) is poor, while Ligand B (-3.261) is even worse. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.517) is better than Ligand B (0.808), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (27.931) has a much lower microsomal clearance than Ligand B (62.852), suggesting better metabolic stability. This is crucial for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-26.14) has a negative half-life, which is concerning. Ligand B (3.261) has a short half-life, but it is positive.

**P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux than Ligand B (0.552), which is favorable for bioavailability.

**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:**

Ligand A is superior despite the negative in vitro half-life. It has a much lower DILI risk, better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. While its solubility and Caco-2 permeability are poor, these can potentially be addressed through formulation strategies. The slightly weaker binding affinity of Ligand A is less concerning given its superior ADME properties and safety profile. Ligand B's higher DILI risk and poorer metabolic stability are significant drawbacks.

Output:
0
2025-04-17 14:48:30,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.471 and 348.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.6) is significantly better than Ligand B (70.08). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.153) is optimal, while Ligand B (0.94) is a bit low, potentially hindering permeation.

**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 similar QED values (0.834 and 0.754), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (20.202 and 19.349 percentile), which is favorable.

**BBB:** Ligand A (92.672) shows better BBB penetration than Ligand B (63.358), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.668 and -4.656), which is unusual and requires further investigation. However, the values are very similar.

**Aqueous Solubility:** Ligand A (-3.46) is better than Ligand B (-1.442) in terms of solubility.

**hERG Inhibition:** Ligand A (0.793) has a lower hERG risk than Ligand B (0.134), which is a significant advantage.

**Microsomal Clearance:** Ligand A (60.187 mL/min/kg) has a higher clearance than Ligand B (11.455 mL/min/kg), indicating lower metabolic stability. This is a key drawback for Ligand A.

**In vitro Half-Life:** Ligand B (16.035 hours) has a significantly longer half-life than Ligand A (7.772 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.134 and 0.044).

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

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better TPSA and solubility, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a lower hERG risk. For an enzyme target like SRC kinase, metabolic stability and safety (hERG) are crucial. The slightly lower logP of Ligand B is a minor concern, potentially addressable through further optimization, but the significant improvement in metabolic stability outweighs this. The binding affinity is comparable between the two.

Output:
1
2025-04-17 14:48:30,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 360.523 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (58.2) is also below 140, but less optimal than A.

**logP:** Both ligands have logP values within the optimal range (A: 3.832, B: 2.353). Ligand A is slightly higher, which *could* present solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of hydrogen bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED values (A: 0.712, B: 0.74), indicating drug-like properties.

**DILI:** Ligand A (21.869) has a significantly lower DILI risk than Ligand B (31.33), which is a major advantage. Both are below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.319) has better BBB penetration than Ligand B (61.846), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.689) has a more negative Caco-2 value, suggesting *lower* permeability. Ligand B (-5.377) is even worse. Both are poor, but A is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.855 and -4.323 respectively). This is a significant concern.

**hERG Inhibition:** Ligand A (0.541) has a slightly higher hERG risk than Ligand B (0.156), which is a negative for A. B is very favorable here.

**Microsomal Clearance:** Ligand A (66.904) has higher microsomal clearance than Ligand B (39.158), indicating lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (6.529 hours) has a significantly longer half-life than Ligand A (-2.646 hours). This is a substantial advantage for B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.318, B: 0.074), which is good.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). While both are good, the 0.5 kcal/mol difference is meaningful, especially considering the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B exhibits superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and a stronger binding affinity. The lower DILI risk for Ligand A is attractive, but the significant advantages of Ligand B in metabolic stability and potency outweigh this benefit. The Caco-2 permeability is poor for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 14:48:30,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.9) is better than Ligand B (96.69), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration if that were a goal.

**logP:** Ligand A (-0.51) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (0.202) is also on the low side, but slightly better.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 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 (0.795 and 0.666, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (47.964 and 44.591, respectively), which is positive.

**BBB:** Ligand A (56.611) has a better BBB percentile than Ligand B (16.983), but this is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.537) has a worse Caco-2 permeability than Ligand B (-5.422), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.106 and -1.217, respectively). This is a significant concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.14 and 0.063, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-3.673) shows better metabolic stability (lower clearance) than Ligand B (-4.739).

**In vitro Half-Life:** Ligand B (17.815) has a significantly longer in vitro half-life than Ligand A (-3.103), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.08 and 0.008, respectively).

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the solubility issues with both compounds, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.2 kcal/mol vs -0.0 kcal/mol) is a critical advantage for an enzyme inhibitor. While Ligand B has a better half-life and slightly better Caco-2 permeability, the difference in binding affinity is substantial. The slightly better metabolic stability of Ligand A is also a plus. The solubility issue would need to be addressed through formulation strategies.

Output:
1
2025-04-17 14:48:30,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.391 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.55) is better than Ligand B (58.2). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly lower, which could be beneficial.

**logP:** Ligand B (2.728) is within the optimal 1-3 range, while Ligand A (-0.016) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 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 (0.446 and 0.698, respectively), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (68.554) has a higher DILI risk than Ligand B (15.859). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (55.099 and 54.246). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.795) has poor Caco-2 permeability, while Ligand B (-4.652) is better, but still low.

**Aqueous Solubility:** Ligand A (-1.435) has poor aqueous solubility, while Ligand B (-4.868) is also poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.109 and 0.123).

**Microsomal Clearance:** Ligand A (-1.097) has a negative clearance, indicating very high metabolic stability, which is excellent. Ligand B (12.629) has a moderate clearance.

**In vitro Half-Life:** Ligand A (20.136 hours) has a longer half-life than Ligand B (6.83 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.066).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). However, the difference is not substantial enough to outweigh other significant drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has excellent metabolic stability and half-life, but suffers from poor solubility, poor Caco-2 permeability, and a higher DILI risk. Its logP is also suboptimal. Ligand B, while having a slightly weaker binding affinity, has a much better safety profile (lower DILI), better logP, and a better QED score. The improved ADME properties of Ligand B outweigh the small difference in binding affinity.

Output:
1
2025-04-17 14:48:30,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.463 and 369.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (92.42), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.057 and 1.394), falling within the optimal 1-3 range. Ligand B is slightly lower, which could slightly improve solubility but might compromise permeability.

**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:** Both ligands have good QED scores (0.669 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (41.877) has a better DILI percentile than Ligand B (62.04), indicating lower liver injury risk. This is a significant advantage.

**BBB:** Both have reasonable BBB penetration (70.609 and 89.066), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.94 and -5.079), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-3.075 and -2.907), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.122 and 0.189), which is excellent.

**Microsomal Clearance:** Ligand B (26.463) has a lower microsomal clearance than Ligand A (30.543), suggesting better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (-23.335) has a significantly longer in vitro half-life than Ligand A (4.783), indicating better stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.076 and 0.134).

**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 a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While both compounds have issues with solubility and permeability, Ligand B stands out due to its significantly stronger binding affinity (-8.7 vs -7.1 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2). The lower DILI score of Ligand A is a positive, but the substantial binding affinity advantage of Ligand B is more critical for an enzyme inhibitor.

Output:
1
2025-04-17 14:48:30,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.389 Da) is slightly higher than Ligand B (353.507 Da), but both are acceptable.

**TPSA:** Ligand A (99.1) is higher than Ligand B (61.88). While both are under 140, the lower TPSA of Ligand B is preferable for better absorption.

**logP:** Ligand A (0.45) is lower than the optimal range (1-3), potentially hindering permeation. Ligand B (1.641) 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 and slightly more favorable due to lower counts.

**QED:** Both ligands have reasonable QED values (A: 0.45, B: 0.684), but Ligand B is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (28.228) has a slightly higher DILI risk than Ligand B (8.104), both are good, but B is better.

**BBB:** Both ligands have similar BBB penetration (A: 65.607, B: 64.482). This isn't a primary concern for a kinase inhibitor, but slightly higher is better.

**Caco-2:** Ligand A (-5.105) has a negative Caco-2 value, which is concerning for absorption. Ligand B (-4.805) is also negative, but less so.

**Solubility:** Ligand A (-2.147) has poor solubility, while Ligand B (-0.584) is better, but still not great. Solubility is a critical factor, and Ligand B is preferable.

**hERG:** Both ligands have low hERG risk (A: 0.565, B: 0.227), which is excellent. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (-17.434) has significantly lower (better) microsomal clearance than Ligand B (9.944), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-20.407) has a longer half-life than Ligand B (-7.356), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.051, B: 0.04), which is good.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), but suffers from poor solubility, low logP, and a negative Caco-2 value. Ligand B has better logP, QED, solubility, and a slightly better binding affinity. The difference in binding affinity (0.8 kcal/mol) is substantial enough to potentially overcome the slightly higher Cl_mic of Ligand B. Given the importance of potency and metabolic stability for kinase inhibitors, and the slightly better overall profile of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 14:48:30,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.503 Da) is slightly higher than Ligand B (344.383 Da), but both are acceptable.

**TPSA:** Ligand A (74.25) is significantly better than Ligand B (121.23). A TPSA under 140 is good for oral absorption, and Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (3.905) is optimal, while Ligand B (-0.512) is quite low. Low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is preferable to Ligand B (1 HBD, 10 HBA). While both are within acceptable ranges, fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.613 and 0.573), indicating good drug-likeness.

**DILI:** Ligand A (81.66) has a higher DILI risk than Ligand B (64.56), which is less desirable. However, both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (59.946 and 58.86), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.069 and -5.76), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.408 and -1.15), which is also unusual and suggests poor solubility. This is another significant drawback for both.

**hERG:** Ligand A (0.64) has a slightly higher hERG risk than Ligand B (0.052), which is less desirable. Ligand B is very low risk.

**Microsomal Clearance:** Ligand A (75.376) has a higher microsomal clearance than Ligand B (24.991), meaning it's less metabolically stable. Lower clearance is preferred.

**In vitro Half-Life:** Ligand A (59.899) has a longer half-life than Ligand B (4.779), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.654) has slightly higher P-gp efflux than Ligand B (0.094), which is less desirable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a crucial advantage, as a 0.8 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, a lower logP (though still low), and a much better metabolic stability profile (lower Cl_mic). While its TPSA is higher and solubility/permeability are poor, the strong binding affinity and improved metabolic stability outweigh these drawbacks. Ligand A has better TPSA and half-life, but suffers from a weaker binding affinity, higher DILI risk, and poorer metabolic stability. Given the enzyme-specific priorities, potency and metabolic stability are key.

Output:
1
2025-04-17 14:48:30,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.5 and 359.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (64.86). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.373 and 3.373), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor negative if it leads to solubility issues, but it's not a major concern.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED values (0.727 and 0.744), indicating good drug-like properties.

**DILI:** Ligand A (41.88%) has a slightly better DILI risk profile than Ligand B (49.01%), but both are acceptable (<60%).

**BBB:** Ligand A (53.97%) has a lower BBB penetration percentile than Ligand B (77.51%). Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Ligand A (-4.834) has a worse Caco-2 permeability than Ligand B (-5.369). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-2.187) has better aqueous solubility than Ligand B (-3.191). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.16 and 0.261), which is excellent.

**Microsomal Clearance:** Ligand A (22.716 mL/min/kg) has significantly lower microsomal clearance than Ligand B (47.806 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (16.055 hours) has a much longer in vitro half-life than Ligand B (-3.77 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.091 and 0.267).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a considerably stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount for an enzyme inhibitor. While Ligand A has better solubility and metabolic stability, the substantial difference in binding affinity makes Ligand B the more promising candidate. The slightly higher logP and DILI of Ligand B are acceptable given the potency advantage.

Output:
1
2025-04-17 14:48:30,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (352.391 and 360.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.71) is better than Ligand B (58.64), being below 140 and closer to the optimal for oral absorption.

**logP:** Ligand B (2.962) is optimal (1-3), while Ligand A (0.001) is significantly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is slightly higher in both counts, but still within acceptable limits. Ligand B (1 HBD, 5 HBA) is excellent.

**QED:** Both ligands have good QED scores (0.657 and 0.852), indicating drug-like properties.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (50.64), although both are moderately risky.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (78.945) has a higher percentile than Ligand A (54.634).

**Caco-2 Permeability:** Ligand A (-5.388) has very poor Caco-2 permeability, whereas Ligand B (-4.641) is better, but still low.

**Aqueous Solubility:** Ligand A (-1.713) has poor solubility, while Ligand B (-3.943) is also poor, but slightly better.

**hERG:** Ligand A (0.149) has a lower hERG risk than Ligand B (0.522), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-9.697) has much lower (better) microsomal clearance than Ligand B (73.764), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.2) has a shorter half-life than Ligand B (29.936), but both are reasonable.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.26), which is favorable.

**Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (-9.1). This is a crucial difference, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, better logP, and lower DILI risk. However, Ligand A has better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. The poor logP and Caco-2 permeability of Ligand A are major concerns. While the affinity difference is significant, the metabolic stability and safety profile of Ligand A are appealing. However, the significantly stronger binding affinity of Ligand B is a major advantage for an enzyme target. Given the importance of potency for kinase inhibitors, and the fact that the other issues with Ligand B are not catastrophic, it is the more promising candidate.

Output:
1
2025-04-17 14:48:30,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (383.275 and 360.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (76.15), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.436) is optimal (1-3), while Ligand B (0.591) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (0 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.843) is better than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand B (37.263) has a lower DILI risk than Ligand A (45.56), which is preferable.

**BBB:** Ligand B (89.608) has a higher BBB penetration percentile than Ligand A (67.274), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.061) and Ligand B (-4.267) both have negative values, which is unusual. Assuming these are log scale values, lower values indicate lower permeability. Ligand B is slightly better.

**Aqueous Solubility:** Ligand A (-3.781) has better solubility than Ligand B (-1.393).

**hERG Inhibition:** Ligand A (0.227) has a lower hERG risk than Ligand B (0.27), which is preferable.

**Microsomal Clearance:** Ligand B (27.117) and Ligand A (12.8) are both relatively low, suggesting good metabolic stability. Ligand A is better.

**In vitro Half-Life:** Ligand A (27.598) has a longer half-life than Ligand B (-8.719), which is desirable.

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux than Ligand B (0.051), indicating better bioavailability.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better QED, better solubility, better half-life, and lower P-gp efflux. While Ligand B has a slightly lower DILI risk and better BBB, these are less critical for a non-CNS kinase target. The substantial difference in binding affinity makes Ligand A the more promising candidate.

Output:
1
2025-04-17 14:48:30,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.523 Da) is slightly higher than Ligand B (339.399 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (80.32) is better than Ligand B (90.98).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.127) is slightly higher than Ligand B (1.502), but both are acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs and Ligand B has 4 HBAs, both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.699, B: 0.808), indicating drug-like properties.

**DILI:** Both ligands have DILI risk around the 60-70 percentile, suggesting moderate risk. Ligand A (67.274) is slightly higher than Ligand B (63.978), but the difference isn't substantial.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (38.736) is lower than Ligand B (56.107).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.291) is slightly better than Ligand B (-5.313).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.005) is slightly better than Ligand B (-3.319).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.475, B: 0.266). Ligand B is slightly better.

**Microsomal Clearance:** This is a key parameter for enzymes. Ligand A (61.729 mL/min/kg) has significantly higher clearance than Ligand B (28.724 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (5.293 hours) has a much shorter half-life than Ligand B (-31.106 hours - which is a very long half-life).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.336, B: 0.037). Ligand B is slightly better.

**Binding Affinity:** This is the most important parameter. Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). The 0.9 kcal/mol difference is substantial.

**Conclusion:**

Despite Ligand A having slightly better TPSA and logP, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.4 vs -8.5 kcal/mol) outweighs the slightly higher DILI risk and lower TPSA. Furthermore, Ligand B exhibits much better metabolic stability (lower Cl_mic, longer half-life) which is crucial for an enzyme target. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:48:30,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.229 Da) is slightly higher than Ligand B (344.375 Da), but both are acceptable.

**TPSA:** Ligand A (49.85) is well below the 140 threshold and suitable for oral absorption. Ligand B (114.91) is still under the threshold, but higher than A.

**logP:** Both ligands have optimal logP values (A: 2.838, B: 1.096) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD: 0, HBA: 3) is better than Ligand B (HBD: 2, HBA: 7) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.732, B: 0.853), indicating drug-like properties.

**DILI:** Ligand A (56.301) has a lower DILI risk than Ligand B (85.498), which is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (88.29) is higher than Ligand B (57.968).

**Caco-2 Permeability:** Ligand A (-4.552) has a worse Caco-2 permeability than Ligand B (-5.632).

**Aqueous Solubility:** Ligand A (-3.363) has a worse aqueous solubility than Ligand B (-2.152).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.598, B: 0.036), which is excellent.

**Microsomal Clearance:** Ligand A (38.082) has a higher microsomal clearance than Ligand B (-25.561), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (17.916) has a much longer in vitro half-life than Ligand A (-15.769), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.336, B: 0.027).

**Binding Affinity:** Both ligands have strong binding affinity (A: -9.0 kcal/mol, B: -8.8 kcal/mol). Ligand A is slightly better (-9.0 vs -8.8), but the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and TPSA, Ligand B excels in crucial ADME properties: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better aqueous solubility. The small difference in binding affinity is outweighed by these substantial ADME advantages, especially considering we are targeting a kinase.

Output:
1
2025-04-17 14:48:30,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.382 and 370.412 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.19) is better than Ligand B (78.87) as it is closer to the 140 threshold for oral absorption.

**logP:** Ligand B (1.429) is better than Ligand A (-0.439). A negative logP can indicate poor membrane permeability. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Both have 2-3 HBD, which is acceptable.

**H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.668 and 0.61), indicating good drug-likeness.

**DILI:** Ligand B (15.122) has a significantly lower DILI risk than Ligand A (59.131). This is a major advantage for Ligand B.

**BBB:** Ligand A (76.541) has a slightly better BBB penetration than Ligand B (67.468), but BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.185) has worse Caco-2 permeability than Ligand B (-4.539), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.307 and -2.477). This could pose formulation challenges, but is not a deal-breaker.

**hERG Inhibition:** Ligand A (0.227) has a lower hERG inhibition liability than Ligand B (0.685), which is a positive.

**Microsomal Clearance:** Ligand A (-7.141) has significantly lower microsomal clearance than Ligand B (52.436). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-12.04) has a longer in vitro half-life than Ligand B (-25.736), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.066).

**Binding Affinity:** Ligand B (-9.2) has a slightly better binding affinity than Ligand A (-8.2). A 1.0 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B has a significantly better safety profile (DILI) and better logP for permeability. The slightly better binding affinity of Ligand B is also a plus. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk, the DILI risk is a major concern. For an enzyme target like SRC kinase, metabolic stability is important, but a high DILI risk is often a non-starter. The affinity difference is not large enough to overcome the DILI issue.

Output:
1
2025-04-17 14:48:30,496 - INFO - Batch 327 complete. Total preferences: 5232
2025-04-17 14:48:30,496 - INFO - Processing batch 328/512...
2025-04-17 14:49:10,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 365.377 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.68) is well below the 140 threshold for good absorption, while Ligand B (116.76) is still acceptable but less optimal.

**logP:** Ligand A (0.911) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.15) is significantly low, raising concerns about membrane permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is within the preferred limits. Ligand B (4 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.792) has a good drug-likeness score. Ligand B (0.464) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (11.361) has a very low DILI risk. Ligand B (20.396) is also relatively low, but higher than Ligand A.

**BBB:** Both ligands have similar BBB penetration (61.846 and 62.466), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.22 and -5.055), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.786 and -1.63), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.226 and 0.21), which is positive.

**Microsomal Clearance:** Ligand A (-2.977) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand B (19.953) has a high clearance, suggesting rapid metabolism and potentially low bioavailability.

**In vitro Half-Life:** Ligand A (9.133 hours) has a reasonable half-life. Ligand B (-55.539 hours) is a negative value, which is not physically possible and indicates a problem with the data or the molecule.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.005).

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). The 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite both ligands having poor solubility and Caco-2 permeability, Ligand A is the more promising candidate. It has a significantly higher binding affinity, a much better QED score, lower DILI risk, and *especially* a much more favorable microsomal clearance/half-life profile. The negative clearance for Ligand A is highly unusual but suggests exceptional metabolic stability. Ligand B's negative half-life is a red flag. The stronger binding affinity of Ligand A is a critical advantage for an enzyme target like SRC kinase.

Output:
0
2025-04-17 14:49:10,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.873 and 350.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (75.93) is still under 140, but less favorable than A.

**logP:** Ligand A (3.693) is at the higher end of the optimal 1-3 range, while Ligand B (0.956) is slightly below. While both are acceptable, a logP too low can hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both within the acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.801 and 0.83), indicating good drug-like properties.

**DILI:** Ligand A (41.954) has a slightly higher DILI risk than Ligand B (37.185), but both are below the concerning threshold of 60.

**BBB:** Ligand A (81.388) shows better BBB penetration than Ligand B (70.648). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.05) has a worse Caco-2 permeability than Ligand B (-4.764). Lower values here suggest poorer absorption.

**Aqueous Solubility:** Ligand A (-4.498) has better aqueous solubility than Ligand B (-2.141). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.865) has a slightly higher hERG risk than Ligand B (0.344), which is a significant advantage for B.

**Microsomal Clearance:** Ligand B (7.172) has significantly lower microsomal clearance than Ligand A (53.337), indicating better metabolic stability. This is a major advantage for B.

**In vitro Half-Life:** Ligand A (40.935) has a longer half-life than Ligand B (-2.719). This is a positive for A.

**P-gp Efflux:** Ligand A (0.45) shows lower P-gp efflux than Ligand B (0.098), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -9.0 kcal/mol), with Ligand A being slightly better. However, the difference is less than the 1.5 kcal/mol threshold that would decisively favor A despite other drawbacks.

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic) and hERG risk, both critical for kinase inhibitors. While Ligand A has slightly better binding affinity and half-life, the benefits of B's improved ADME profile outweigh these minor differences. The solubility of A is also better, but the lower Cl_mic of B is more important for kinase inhibitors.

Output:
1
2025-04-17 14:49:10,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.373 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.87) is slightly higher than Ligand B (78.43), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.381) is quite low, potentially hindering permeability. Ligand B (2.38) 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 3 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.74 and 0.51, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (26.677 and 24.04, respectively), which is positive.

**BBB:** Both ligands have relatively low BBB penetration (57.929 and 49.011, respectively). This isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.698 and -4.839). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.904 and -2.437). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.501 and 0.063, respectively). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (-8.018) has significantly lower (better) microsomal clearance than Ligand B (25.207), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have similar and poor in vitro half-lives (-19.347 and -18.389 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux (0.031 and 0.075, respectively).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability, but suffers from very low logP and solubility. Ligand B has a better logP, slightly better hERG profile, but has worse metabolic stability and slightly weaker binding. The poor solubility of both is a major concern. However, the improved logP of Ligand B is likely to translate to better permeability *despite* the poor Caco-2 values, and the slightly better affinity of Ligand A may be overcome by its poor pharmacokinetic properties. Given the importance of metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, Ligand A is the slightly better candidate.

Output:
0
2025-04-17 14:49:10,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.74) is significantly better than Ligand B (106.14).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both have acceptable logP values (1.755 and 0.936), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 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 (0.797 and 0.823), indicating good drug-like properties.

**DILI:** Ligand A (17.72) has a much lower DILI risk than Ligand B (38.62). This is a significant advantage.

**BBB:** Both have similar BBB penetration (68.67 and 67.197).  BBB isn't a primary concern for SRC kinase inhibitors unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.498) is better than Ligand B (-5.461). Higher values are better.

**Aqueous Solubility:** Ligand A (-1.507) is better than Ligand B (-2.433). Higher values are better.

**hERG:** Both ligands have very low hERG inhibition risk (0.134 and 0.069), which is excellent.

**Microsomal Clearance:** Ligand A (8.372) has a lower microsomal clearance than Ligand B (8.875), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.642) has a positive half-life, while Ligand B (-16.436) has a negative half-life. This is a huge difference, and favors ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.016).

**Binding Affinity:** Both ligands have very strong binding affinities (-9.3 and -8.6 kcal/mol). Ligand A has a 0.7 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have good binding affinity and drug-like properties, Ligand A excels in critical ADME parameters: lower DILI risk, better solubility, better Caco-2 permeability, better half-life, and lower microsomal clearance. The 0.7 kcal/mol difference in binding affinity, combined with the ADME advantages, makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 14:49:10,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (396.265 and 362.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.46) is slightly higher than Ligand B (53.92), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.508 and 4.193) within the optimal 1-3 range, although Ligand B is pushing the upper limit.

**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 within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.8 and 0.803), indicating good drug-likeness.

**DILI:** Ligand A (43.389) has a slightly higher DILI risk than Ligand B (37.03), but both are below the concerning threshold of 60.

**BBB:** Ligand A (87.01) has a significantly higher BBB penetration percentile than Ligand B (51.377). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.518) has a worse Caco-2 permeability than Ligand B (-5.227). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.329) has a worse aqueous solubility than Ligand B (-4.027). Lower values indicate lower solubility.

**hERG Inhibition:** Ligand A (0.536) has a lower hERG inhibition risk than Ligand B (0.733), which is favorable.

**Microsomal Clearance:** Ligand A (34.068) has a much lower microsomal clearance than Ligand B (78.464), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (36.608) has a shorter in vitro half-life than Ligand B (45.138), but both are reasonable.

**P-gp Efflux:** Ligand A (0.185) has lower P-gp efflux liability than Ligand B (0.211), which is preferable.

**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, and a difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having better metabolic stability (lower Cl_mic) and lower hERG risk, the significantly stronger binding affinity of Ligand B (-7.6 kcal/mol vs -10.2 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. While Ligand B has slightly higher P-gp efflux and a higher logP, the substantial binding advantage outweighs these concerns.

Output:
1
2025-04-17 14:49:10,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 357.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.72) is slightly higher than Ligand B (69.12), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.125) and Ligand B (3.167) are both within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but not drastically.

**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 (0.804 and 0.815), indicating good drug-like properties.

**DILI:** Ligand A (53.432) has a slightly higher DILI risk than Ligand B (43.66), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (73.943 and 76.696), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.131) has worse Caco-2 permeability than Ligand B (-4.67). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.068) has better aqueous solubility than Ligand B (-3.982). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.201) has a much lower hERG inhibition risk than Ligand B (0.859). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (17.786) has significantly lower microsomal clearance than Ligand B (32.724). Lower clearance indicates better metabolic stability, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (51.069) has a longer in vitro half-life than Ligand B (-3.435). This is a significant advantage for Ligand A, suggesting less frequent dosing.

**P-gp Efflux:** Ligand A (0.019) has much lower P-gp efflux than Ligand B (0.15). Lower efflux is generally desirable.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.4). This is a 0.6 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a more favorable ADME profile, particularly regarding metabolic stability (lower Cl_mic, longer t1/2), hERG risk, and P-gp efflux. Given the enzyme-specific priorities, the improved metabolic stability and reduced toxicity risk of Ligand A are compelling. The 0.6 kcal/mol difference in binding affinity, while significant, is not insurmountable in a lead optimization campaign. Therefore, Ligand A is the more promising candidate.

Output:
0
2025-04-17 14:49:10,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.861 and 350.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.84) is slightly higher than Ligand B (58.2). Both are acceptable, but Ligand B is preferable.

**logP:** Ligand A (3.01) is within the optimal range (1-3). Ligand B (4.546) is slightly above, potentially leading to solubility issues or off-target interactions, but not drastically.

**H-Bond Donors:** Both ligands have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.806 and 0.85), indicating good drug-like properties.

**DILI:** Ligand A (51.377) has a better DILI score than Ligand B (77.2), indicating lower potential for liver injury. This is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (70.997 and 69.097), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.009) has worse Caco-2 permeability than Ligand B (-4.883).

**Aqueous Solubility:** Ligand A (-3.297) has better aqueous solubility than Ligand B (-5.552). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.15) has a significantly lower hERG inhibition liability than Ligand B (0.602). This is a crucial advantage, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (6.191) has higher microsomal clearance than Ligand B (50.999), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (34.073) has a much longer in vitro half-life than Ligand A (19.912), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux than Ligand B (0.541), which is favorable.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, lower hERG risk, better solubility, and lower P-gp efflux. However, it suffers from higher microsomal clearance and lower in vitro half-life, and worse Caco-2 permeability. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, but higher DILI risk and hERG liability, and a weaker binding affinity.

Given the importance of metabolic stability for kinase inhibitors (to ensure sufficient exposure) and the significant hERG risk associated with Ligand B, I prioritize Ligand A despite its slightly lower metabolic stability. The 1 kcal/mol difference in binding affinity is also a significant factor. The better solubility and lower P-gp efflux of Ligand A are also beneficial.

Output:
0
2025-04-17 14:49:10,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (388.339 and 365.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is better than Ligand B (67.07), both are acceptable, but lower is preferred for permeability.

**logP:** Both ligands have good logP values (2.376 and 3.321 respectively), 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 (HBD=2, HBA=3) is preferable to Ligand B (HBD=1, HBA=7) as it strikes a better balance between solubility and permeability. Ligand B has a higher number of HBA which might affect permeability.

**QED:** Both ligands have acceptable QED values (0.562 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (13.416) has a significantly lower DILI risk than Ligand B (19.349), which is a major advantage.

**BBB:** BBB is less important for a non-CNS target like SRC, but Ligand A (55.176) is slightly better than Ligand B (48.817).

**Caco-2 Permeability:** Both have negative values (-5.265 and -5.113), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.096 and -3.047), indicating poor aqueous solubility. This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.234) has a much lower hERG inhibition liability than Ligand B (0.593), which is a critical advantage for safety.

**Microsomal Clearance:** Ligand A (-3.51) has a much better (lower) microsomal clearance than Ligand B (40.882), indicating greater metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (21.733) has a better in vitro half-life than Ligand B (35.541), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.049) has a lower P-gp efflux liability than Ligand B (0.116), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-9.4 and -8.7 kcal/mol). The difference is less than 1.5 kcal/mol, so this doesn't significantly sway the decision.

**Overall:**

Ligand A is significantly better than Ligand B. It has a lower DILI risk, lower hERG inhibition, much better metabolic stability (lower Cl_mic and higher t1/2), lower P-gp efflux, and a slightly better TPSA. While both have poor solubility and permeability, the ADME-Tox profile of Ligand A is far superior, making it the more promising drug candidate.

Output:
0
2025-04-17 14:49:10,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.372 and 367.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (61.68), being well below the 140 threshold for good absorption.

**logP:** Ligand A (4.419) is a bit high, potentially causing solubility issues, but still within a manageable range. Ligand B (0.317) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (0 HBD, 6 HBA). Both are within acceptable limits.

**QED:** Ligand A (0.867) has a much better QED score than Ligand B (0.65), indicating a more drug-like profile.

**DILI:** Ligand B (21.753) has a significantly lower DILI risk than Ligand A (54.13), which is a major advantage.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 79.488, Ligand B: 59.946). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.542) has a negative Caco-2 value, which is concerning, while Ligand B (-5.216) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.349) has a negative solubility value, indicating poor solubility. Ligand B (-0.445) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.827) has a higher hERG risk than Ligand B (0.274), which is a significant concern.

**Microsomal Clearance:** Ligand B (19.427) has a much lower microsomal clearance than Ligand A (52.647), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.754) has a longer half-life than Ligand B (-11.401). The negative value for Ligand B is concerning and suggests very rapid metabolism.

**P-gp Efflux:** Ligand A (0.314) has lower P-gp efflux than Ligand B (0.028), which is favorable.

**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 doesn't significantly sway the decision.

**Conclusion:**

While Ligand A has a slightly longer half-life and lower P-gp efflux, Ligand B is superior overall. Ligand B has a much lower DILI risk and significantly better metabolic stability (lower Cl_mic). The lower logP and higher HBA count of Ligand B are less ideal, but the substantial improvements in safety (DILI, hERG) and metabolic stability outweigh these drawbacks, especially given the similar binding affinities. The solubility and Caco-2 permeability are poor for both, but Ligand B is slightly better.

Output:
1
2025-04-17 14:49:10,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.439 Da) and Ligand B (344.499 Da) are both acceptable.

**TPSA:** Ligand A (86.88) is better than Ligand B (40.62). Both are well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have good logP values (A: 2.414, B: 3.371), 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.848) has a significantly higher QED score than Ligand B (0.693), indicating better overall drug-likeness.

**DILI:** Ligand A (52.385) has a higher DILI risk than Ligand B (27.453), but both are below the concerning threshold of 60.

**BBB:** Ligand A (66.615) has a lower BBB penetration than Ligand B (84.839). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.253) and Ligand B (-4.841) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.788) has slightly better solubility than Ligand B (-3.436), but both are poor. Solubility is a key concern for enzymes.

**hERG Inhibition:** Ligand A (0.081) has a much lower hERG inhibition risk than Ligand B (0.382). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-14.177) has a much lower (better) microsomal clearance than Ligand B (67.803), indicating better metabolic stability. This is a crucial factor for enzymes.

**In vitro Half-Life:** Ligand A (-2.617) has a shorter half-life than Ligand B (-21.501), which is a disadvantage.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.529), which is favorable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This difference, while not huge, is still valuable.

**Overall Assessment:**

Ligand A is the better candidate. While its solubility and half-life are not ideal, it compensates with significantly better metabolic stability (lower Cl_mic), lower hERG risk, better QED, and slightly better binding affinity. Ligand B has better BBB penetration (irrelevant here) and half-life, but suffers from worse metabolic stability, higher hERG risk, and lower QED. Given the enzyme-specific priorities, metabolic stability and safety (hERG) are paramount, making Ligand A the preferred choice.

Output:
0
2025-04-17 14:49:10,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.46 and 352.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (103.01). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Both ligands have good logP values (2.14 and 1.16), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED scores (0.609 and 0.586), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (30.98 and 33.58), which is favorable.

**BBB:** Ligand A (74.76) has a much better BBB penetration percentile than Ligand B (35.32). While SRC isn't a CNS target, higher BBB is rarely detrimental, and can indicate better overall permeability.

**Caco-2 Permeability:** Ligand A (-5.11) is better than Ligand B (-5.78). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.03 and -1.19). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.45) has a lower hERG inhibition risk than Ligand B (0.16), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (26.31) has a slightly higher microsomal clearance than Ligand B (24.87), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (14.80) has a significantly longer in vitro half-life than Ligand A (-18.57). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.10 and 0.02).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a 1.3 kcal/mol difference, which is a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a clear advantage in binding affinity and a better safety profile (hERG). It also has better TPSA, BBB, and Caco-2 permeability. The major drawback for Ligand A is its lower in vitro half-life and slightly higher clearance. Ligand B has a better half-life, but suffers from a higher TPSA, lower binding affinity, and a slightly higher hERG risk. The solubility is poor for both, but this is a formulation challenge that can be addressed. Given the importance of potency for kinase inhibitors, and the significant difference in binding affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 14:49:10,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.5 & 348.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.78) is significantly better than Ligand B (67.43).  A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Ligand A (4.257) is slightly higher than the optimal 1-3 range, while Ligand B (2.416) is well within the range. This favors B slightly, but A isn't drastically outside the acceptable 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:** Ligand A (0.746) has a better QED score than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (24.86) has a much lower DILI risk than Ligand B (18.34), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 92.48, B: 75.38), though A is better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.515 and -4.518). This is unusual and suggests poor permeability. However, these values are on the same scale, so it doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.355 and -3.783). This is also unusual and suggests poor solubility. Again, they are similar.

**hERG Inhibition:** Ligand A (0.932) has a slightly higher hERG risk than Ligand B (0.289), which is a negative for A.

**Microsomal Clearance:** Ligand B (89.342) has a significantly higher microsomal clearance than Ligand A (62.819), meaning A is more metabolically stable.

**In vitro Half-Life:** Ligand A (21.945) has a much longer in vitro half-life than Ligand B (0.28), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.739) has a higher P-gp efflux liability than Ligand B (0.157), which is a negative for A.

**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, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a substantially better binding affinity, a better QED score, a lower DILI risk, and significantly better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has some drawbacks in logP, hERG, and P-gp, the strong binding affinity and favorable ADME properties (especially metabolic stability and DILI) outweigh these concerns. The poor Caco-2 and solubility values are concerning for both, but the potency of A is likely to compensate. Ligand B's very weak binding affinity makes it a poor candidate despite its slightly better logP and hERG.

Output:
1
2025-04-17 14:49:10,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.889 Da and 367.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (91.76). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is getting higher and could present absorption challenges.

**logP:** Both ligands have acceptable logP values (2.882 and 1.041, 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). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have reasonable QED scores (0.894 and 0.751), indicating good drug-like properties.

**DILI:** Ligand A (30.516) has a much lower DILI risk than Ligand B (42.187). This is a significant advantage for Ligand A.

**BBB:** Ligand A (70.841) has a better BBB penetration percentile than Ligand B (39.511). While not a primary concern for a non-CNS target like SRC, better BBB penetration can sometimes correlate with better overall drug distribution.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.844 and -4.88), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Ligand A (-3.357) is better than Ligand B (-1.153), indicating better solubility. Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.34 and 0.245), which is excellent.

**Microsomal Clearance:** Ligand A (32.656) has a higher microsomal clearance than Ligand B (-0.578). This means Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-13.477) has a negative half-life, which is not possible. This suggests a very rapid degradation. Ligand B (6.235) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.085 and 0.029).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Despite similar binding affinities, Ligand A has several concerning properties: a negative in vitro half-life and higher microsomal clearance, indicating poor metabolic stability. While it has advantages in TPSA, solubility, and DILI, the metabolic instability is a major drawback for an enzyme inhibitor. Ligand B, while having a higher TPSA, exhibits better metabolic stability (negative Cl_mic) and a positive half-life, making it the more promising candidate.

Output:
1
2025-04-17 14:49:10,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (369.531 Da and 347.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.3) is slightly above the preferred <90 for kinase inhibitors, while Ligand B (61.44) is well within the range.

**3. logP:** Both ligands have good logP values (1.588 and 1.918), 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 (4) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.663 and 0.799), indicating good drug-like properties.

**7. DILI:** Ligand A (30.438) has a lower DILI risk than Ligand B (21.908), which is preferable.

**8. BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (55.099) is slightly better than Ligand A (45.677).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.642 and -5.164), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.672 and -3.004), indicating very poor aqueous solubility. This is a major concern for *in vivo* bioavailability.

**11. hERG Inhibition:** Ligand A (0.129) has a slightly lower hERG risk than Ligand B (0.341), which is preferable.

**12. Microsomal Clearance:** Ligand A (20.77) and Ligand B (22.021) have similar microsomal clearance values. Both are relatively low, suggesting reasonable metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar *in vitro* half-lives (15.71 and 15.128 hours), which are acceptable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.136), which is good.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility. However, Ligand B has a substantially better binding affinity, which is the most critical factor for an enzyme inhibitor. The slightly better DILI and hERG scores for Ligand A are less important than the potency advantage of Ligand B. While the solubility and permeability issues need to be addressed through formulation or further chemical modifications, the stronger binding affinity of Ligand B makes it the more promising starting point.

Output:
1
2025-04-17 14:49:10,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (369.755 Da and 356.417 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.27) is slightly above the preferred <90 for kinases, while Ligand B (68.3) is well within the range.

**3. logP:** Both ligands have acceptable logP values (3.947 and 2.706), 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 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.617 and 0.746), indicating drug-like properties.

**7. DILI:** Ligand A (84.645) has a higher DILI risk than Ligand B (57.154). This is a significant concern.

**8. BBB:** BBB is less important for a non-CNS target like SRC. Ligand B (89.608) has a higher BBB percentile, but this is not a major factor here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, indicating 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:** Ligand A (0.587) has a slightly higher hERG risk than Ligand B (0.72).

**12. Microsomal Clearance:** Ligand A (55.421) has a higher microsomal clearance than Ligand B (47.49). This suggests lower metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (18.592) has a significantly longer in vitro half-life than Ligand A (66.388). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.171 and 0.111).

**15. 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.

**Overall Assessment:**

Ligand A has a superior binding affinity, which is the most critical factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a shorter half-life. Ligand B, while having a weaker affinity, exhibits a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable TPSA.

The difference in binding affinity (1.3 kcal/mol) is significant, but the ADME/Tox liabilities of Ligand A are substantial. Given the enzyme-specific priorities, the improved safety and metabolic stability of Ligand B outweigh the affinity difference, especially considering optimization can potentially improve the affinity of Ligand B.

Output:
1
2025-04-17 14:49:10,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.372 and 368.302 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.12) is slightly higher than Ligand B (72.8), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.909 and 2.69), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5/3 HBA, which are acceptable and balance solubility and permeability.

**QED:** Both ligands have good QED scores (0.677 and 0.716), indicating a drug-like profile.

**DILI:** Ligand A (86.157) has a significantly higher DILI risk than Ligand B (47.421). This is a major concern.

**BBB:** Both ligands have reasonable BBB penetration (73.75 and 64.211), but this is less critical for a non-CNS target like SRC.

**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 unknown.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.375 and 0.577), which is good.

**Microsomal Clearance:** Ligand B (-6.423) has a *much* lower (better) microsomal clearance than Ligand A (35.614). This suggests significantly better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (21.432) has a longer half-life than Ligand A (69.445).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.088 and 0.102).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a >1.5 kcal/mol advantage, which is very significant.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the clear advantages of Ligand B outweigh the slightly better TPSA of Ligand A. Ligand B has a significantly better binding affinity, much improved metabolic stability (lower Cl_mic, longer t1/2), and a lower DILI risk. The stronger binding affinity is the most important factor for an enzyme target like SRC, and the improved ADME properties further support its selection.

Output:
1
2025-04-17 14:49:10,698 - INFO - Batch 328 complete. Total preferences: 5248
2025-04-17 14:49:10,698 - INFO - Processing batch 329/512...
2025-04-17 14:50:00,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.502 and 358.551 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is slightly higher than Ligand B (33.2). Both are below the 140 threshold for oral absorption, but ligand B is preferable.

**logP:** Ligand A (3.777) and Ligand B (4.442) are both within the optimal 1-3 range, though ligand B is pushing the upper limit.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0).

**H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is acceptable.

**QED:** Both ligands have similar QED values (0.862 and 0.78), indicating good drug-likeness.

**DILI:** Ligand B (21.171) has a significantly lower DILI risk than Ligand A (41.411), making it more favorable.

**BBB:** Ligand A (95.347) has a higher BBB penetration percentile than Ligand B (87.515). However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-5.084) is slightly better than Ligand B (-5.281).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-4.028) is slightly better than Ligand B (-3.766).

**hERG Inhibition:** Both ligands exhibit low hERG inhibition risk (0.778 and 0.669).

**Microsomal Clearance:** Ligand B (93.514) has a significantly higher microsomal clearance than Ligand A (24.53), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (-5.862) has a shorter in vitro half-life than Ligand A (-1.102), further supporting the lower metabolic stability of Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.543 and 0.628).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and lower DILI risk, its significantly higher microsomal clearance and shorter half-life are major concerns for an enzyme target. Ligand A, despite its slightly lower affinity, exhibits much better metabolic stability. The difference in binding affinity (1.5 kcal/mol) is substantial, but the metabolic stability of Ligand A is more critical for a kinase inhibitor.

Output:
0
2025-04-17 14:50:00,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.439 Da) is slightly preferred as it's lower.

**TPSA:** Both ligands have TPSA values below 140, indicating good potential for oral absorption. Ligand B (81.06) is lower than Ligand A (100.55), which is slightly favorable.

**logP:** Both ligands have logP values between 1-3, which is optimal. Ligand B (3.923) is a bit higher than Ligand A (2.472), potentially leading to slight solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand B (0.772) is slightly higher.

**DILI:** Both ligands have high DILI risk (Ligand A: 84.102, Ligand B: 91.431). This is a significant concern for both, but Ligand A is slightly better.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

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

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. This is a significant issue for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.298, Ligand B: 0.111). Ligand B is preferred here.

**Microsomal Clearance:** Ligand A (77.238 mL/min/kg) has significantly lower clearance than Ligand B (12.823 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand B (99.828 hours) has a much longer half-life than Ligand A (24.208 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). This is a significant advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and longer half-life, which are crucial for an enzyme inhibitor. However, it has a higher DILI risk and a higher logP. Ligand A has better metabolic stability (lower Cl_mic) and a slightly lower DILI risk, but its half-life is considerably shorter. The poor Caco-2 and solubility for both are concerning.

Given the importance of potency and metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, the longer half-life of Ligand B is a more significant advantage than the better metabolic stability of Ligand A. The slightly higher DILI risk of Ligand B is a concern, but can be addressed with further optimization.

Output:
1
2025-04-17 14:50:00,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly better positioned.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (129.13). Lower TPSA generally favors better absorption.

**logP:** Ligand A (2.302) is optimal, while Ligand B (0.184) is quite low, potentially hindering membrane permeability.

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

**H-Bond Acceptors:** Ligand A (3) is good, and Ligand B (8) is acceptable but higher.

**QED:** Both ligands have acceptable QED values (A: 0.5, B: 0.453), indicating reasonable drug-likeness.

**DILI:** Ligand A (9.228) has a much lower DILI risk than Ligand B (61.574), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.162) is better than Ligand B (49.787).

**Caco-2 Permeability:** Ligand A (-4.463) is better than Ligand B (-5.527), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.618) is better than Ligand B (-2.908), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.455) has a lower hERG risk than Ligand B (0.666), a crucial safety factor.

**Microsomal Clearance:** Ligand A (41.007) is slightly better than Ligand B (37.753), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.733) has a significantly longer half-life than Ligand B (-21.538), which is highly desirable.

**P-gp Efflux:** Ligand A (0.279) has lower P-gp efflux liability than Ligand B (0.012), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.7), although both are good. The 1.3 kcal/mol difference is significant enough to outweigh some minor ADME drawbacks.

**Overall:** Ligand A consistently outperforms Ligand B across most critical parameters, especially DILI, solubility, hERG, metabolic stability (half-life), and permeability. While both have acceptable binding affinities, Ligand A's superior ADMET profile makes it a much more promising drug candidate.

Output:
1
2025-04-17 14:50:00,339 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [345.359, 122.71 ,   0.282,   3.   ,   7.   ,   0.54 ,  70.686,  46.995, -5.705,  -3.232,   0.222, -22.151, -29.446,   0.008,  -8.6  ]
**Ligand B:** [343.354,  60.7  ,   3.908,   1.   ,   5.   ,   0.688,  85.964,  70.609, -4.496,  -5.638,   0.873, 107.601,  73.001,   0.65 ,  -7.   ]

**Step-by-step comparison:**

1. **MW:** Both ligands (345.359 and 343.354 Da) are within the ideal range of 200-500 Da.
2. **TPSA:** Ligand A (122.71) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (60.7) is excellent, well below 140.
3. **logP:** Ligand A (0.282) is quite low, potentially hindering permeability. Ligand B (3.908) is near the upper end of the optimal range (1-3) but still acceptable.
4. **HBD:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (1) is also good.
5. **HBA:** Ligand A (7) is within the acceptable limit of <=10. Ligand B (5) is also good.
6. **QED:** Both ligands have good QED scores (0.54 and 0.688, respectively), indicating drug-like properties.
7. **DILI:** Ligand A (70.686) has a moderate DILI risk. Ligand B (85.964) has a higher DILI risk, which is concerning.
8. **BBB:** Both ligands have similar BBB penetration (46.995 and 70.609). Neither is particularly high, but it's less critical for a kinase inhibitor than for a CNS-targeting drug.
9. **Caco-2:** Ligand A (-5.705) has poor Caco-2 permeability. Ligand B (-4.496) also has poor Caco-2 permeability.
10. **Solubility:** Ligand A (-3.232) has poor solubility. Ligand B (-5.638) also has poor solubility.
11. **hERG:** Ligand A (0.222) has a very low hERG risk, which is excellent. Ligand B (0.873) has a slightly elevated hERG risk, but still relatively low.
12. **Cl_mic:** Ligand A (-22.151) has very low microsomal clearance, indicating good metabolic stability. Ligand B (107.601) has high microsomal clearance, indicating poor metabolic stability.
13. **t1/2:** Ligand A (-29.446) has a very long in vitro half-life, which is excellent. Ligand B (73.001) has a good in vitro half-life.
14. **Pgp:** Ligand A (0.008) has very low P-gp efflux, which is excellent. Ligand B (0.65) has moderate P-gp efflux.
15. **Affinity:** Ligand A (-8.6) has significantly better binding affinity than Ligand B (-7.0). This is a >1.5 kcal/mol advantage, which is substantial.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Conclusion:**

Despite the slightly elevated DILI risk, **Ligand A** is the more promising candidate. Its significantly superior binding affinity (-8.6 vs -7.0 kcal/mol) outweighs its slightly lower logP and TPSA. Furthermore, its excellent metabolic stability (very low Cl_mic, long t1/2), low hERG risk, and low P-gp efflux are highly desirable. While both have poor solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. Ligand B's high metabolic clearance is a significant drawback.

1
2025-04-17 14:50:00,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.495 and 365.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (90.9 and 88.91) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.517) is a bit low, potentially hindering permeation. Ligand B (1.382) is 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.

**QED:** Ligand B (0.727) has a better QED score than Ligand A (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (1.667) has a significantly lower DILI risk than Ligand B (44.126), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (56.611) is higher than Ligand B (39.55).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.106 and -5.504), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.612 and -1.778) which is also a concern.

**hERG:** Ligand A (0.365) has a much lower hERG risk than Ligand B (0.071), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-9.165) has a much lower (better) microsomal clearance than Ligand B (19.25), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.577) has a much longer in vitro half-life than Ligand B (-2.288), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.025).

**Binding Affinity:** Both ligands have comparable binding affinities (-7.2 and -7.0 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't the deciding factor.

**Overall Assessment:**

Ligand A is significantly better due to its superior safety profile (DILI and hERG), metabolic stability (Cl_mic and t1/2), and slightly better BBB penetration. While both have poor Caco-2 and solubility, the ADME properties of Ligand A are far more favorable. The similar binding affinities make the ADME advantages of Ligand A decisive.

Output:
0
2025-04-17 14:50:00,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 358.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.92) is better than Ligand B (99.1), both are below 140, suggesting good absorption potential.

**logP:** Ligand A (2.594) is optimal (1-3). Ligand B (0.821) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but slightly higher.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable range.

**QED:** Both ligands have reasonable QED scores (0.485 and 0.626), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (12.524). This is a significant concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (51.415 and 59.131). This isn't a primary concern for a non-CNS target like SRC.

**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:** Ligand A (0.811) has a slightly higher hERG risk than Ligand B (0.249).

**Microsomal Clearance:** Ligand B (-5.481) has a *much* lower (better) microsomal clearance than Ligand A (59.051). This indicates significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-13.504) has a much longer in vitro half-life than Ligand A (13.504).

**P-gp Efflux:** Ligand A (0.82) has higher P-gp efflux than Ligand B (0.008).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). The difference is 1.2 kcal/mol, which is a good margin.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better in terms of safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and P-gp efflux. The lower logP of Ligand B is a minor drawback, but the substantial advantages in ADME-Tox properties outweigh this. Given the priorities for enzyme inhibitors, Ligand B is the more promising candidate.

Output:
1
2025-04-17 14:50:00,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.423 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.59) is well below the 140 threshold, while Ligand B (133.21) is approaching the upper limit. This favors A for better absorption.

**logP:** Ligand A (3.773) is within the optimal 1-3 range. Ligand B (-0.249) is significantly below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=4, HBA=4) both have reasonable counts, below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have acceptable QED values (A: 0.891, B: 0.541), indicating good drug-like properties.

**DILI:** Ligand A (70.531) has a higher DILI risk than Ligand B (39.667). This is a concern for A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (85.072) shows better potential for CNS penetration than Ligand B (62.117).

**Caco-2 Permeability:** Ligand A (-4.596) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.571) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.948) has very poor aqueous solubility, while Ligand B (-2.644) is also poor but better than A.

**hERG:** Ligand A (0.808) has a slightly higher hERG risk than Ligand B (0.111).

**Microsomal Clearance:** Ligand A (83.85) has a significantly higher microsomal clearance than Ligand B (-3.278). This indicates that Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A (20.594) has a longer half-life than Ligand B (0.753).

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.504, B: 0.005), which is favorable.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-8.0). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly longer half-life and better BBB, its significantly lower logP, poor solubility, higher DILI risk, and higher metabolic clearance are major drawbacks. Ligand B has a better logP, lower DILI, and significantly better metabolic stability, and a slightly better binding affinity. The solubility of B is still a concern, but less so than A.

Output:
1
2025-04-17 14:50:00,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.523 and 371.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (97.83) is still below 140, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (3.914) is at the upper end of the optimal 1-3 range, while Ligand B (0.269) is significantly lower, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 3 HBAs, while Ligand B has 6. Both are within the acceptable range of <=10, but B is higher.

**QED:** Ligand A (0.885) has a much better QED score than Ligand B (0.593), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (50.95 and 59.131), both are acceptable but B is slightly higher.

**BBB:** Both ligands have good BBB penetration (74.176 and 70.376). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.872) and Ligand B (-5.21) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.409) and Ligand B (-1.459) both have negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.46) has a much lower hERG risk than Ligand B (0.247), which is preferable.

**Microsomal Clearance:** Ligand A (88.172) has a higher microsomal clearance than Ligand B (27.759), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-3.406) has a negative half-life, indicating very poor stability, while Ligand A (3.107) has a positive half-life.

**P-gp Efflux:** Ligand A (0.648) has a slightly higher P-gp efflux liability than Ligand B (0.015).

**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 difference.

**Conclusion:**

Ligand A is the superior candidate. While both have issues with solubility and permeability, Ligand A's significantly stronger binding affinity (-9.7 vs -7.5 kcal/mol) outweighs its slightly higher clearance and P-gp efflux. The better QED score and lower hERG risk further support this conclusion. Ligand B's extremely poor in vitro half-life is a major red flag.

Output:
1
2025-04-17 14:50:00,340 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.395, 111.47 ,  -1.168,   1.   ,   8.   ,   0.627,  57.154,  61.535, -5.394,  -1.251,   0.023,  -1.951,  22.964,   0.024,  -7.6  ]
**Ligand B:** [426.746,  72.7  ,   3.309,   1.   ,   5.   ,   0.568,  44.552,  63.784, -5.208,  -4.294,   0.23 ,  41.284, -11.603,   0.079,   0.   ]

**Step-by-step comparison:**

1. **MW:** Ligand A (352.395 Da) is within the ideal range (200-500 Da). Ligand B (426.746 Da) is also acceptable, though approaching the upper limit.
2. **TPSA:** Ligand A (111.47) is good for oral absorption, below 140. Ligand B (72.7) is excellent.
3. **logP:** Ligand A (-1.168) is a bit low, potentially hindering permeation. Ligand B (3.309) is optimal.
4. **HBD:** Both ligands have 1 HBD, which is good.
5. **HBA:** Ligand A has 8 HBA, acceptable. Ligand B has 5 HBA, also acceptable.
6. **QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.
7. **DILI:** Ligand A (57.154) has a moderate DILI risk. Ligand B (44.552) has a lower DILI risk, which is favorable.
8. **BBB:** Both ligands have similar BBB penetration, around 60-64%, not a primary concern for a non-CNS target like SRC.
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:** Ligand A (0.023) has very low hERG risk. Ligand B (0.23) is slightly higher, but still relatively low.
12. **Cl_mic:** Ligand A (-1.951) suggests good metabolic stability (negative value). Ligand B (41.284) indicates faster metabolism.
13. **t1/2:** Ligand A (22.964 hours) has a better in vitro half-life than Ligand B (-11.603 hours).
14. **Pgp:** Ligand A (0.024) has low P-gp efflux. Ligand B (0.079) also has low P-gp efflux.
15. **Affinity:** Ligand A (-7.6 kcal/mol) has a significantly better binding affinity than Ligand B (0.0 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite the poor Caco-2 and solubility values, Ligand A is the more promising candidate. The significantly stronger binding affinity (-7.6 kcal/mol vs 0.0 kcal/mol) is a major advantage that can outweigh the slightly higher DILI risk and lower logP. Furthermore, Ligand A has better metabolic stability (Cl_mic) and a longer half-life. The hERG risk is very low for both, but the affinity difference is substantial.

Output:
0
2025-04-17 14:50:00,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). A (368.302) is slightly higher than B (345.443), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. A (72.8) is better than B (78.51).

**logP:** Both have good logP values (1-3). A (2.69) is slightly better than B (0.987), which is closer to the lower limit and might have permeability issues.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (<=5) and HBA (<=10) counts. A has 3/3, while B has 2/3.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. A (0.716) is slightly better than B (0.746).

**DILI:** Ligand B (20.396) has a significantly lower DILI risk than Ligand A (47.421), which is a major advantage.

**BBB:** Both have moderate BBB penetration, but it's less critical for a non-CNS target like SRC. A (64.211) and B (67.352) are comparable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. A (-4.889) is slightly better than B (-5.132).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. A (-3.19) is slightly better than B (-2.293).

**hERG Inhibition:** Ligand A (0.577) has a slightly higher hERG risk than Ligand B (0.121), which is a significant advantage for B.

**Microsomal Clearance:** Ligand B (16.246) has a better metabolic stability profile (lower clearance) than Ligand A ( -6.423, which is negative and therefore problematic).

**In vitro Half-Life:** Ligand A (21.432) has a longer half-life than Ligand B (2.556), which is a positive attribute.

**P-gp Efflux:** Both have low P-gp efflux liability (0.102 and 0.016, respectively), which is good.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly better binding affinity than Ligand B (-8.2 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and longer half-life. However, Ligand B demonstrates a much better safety profile with significantly lower DILI and hERG risk, and better metabolic stability. The solubility and permeability are poor for both. Given the enzyme target class (kinase), potency and metabolic stability are key. The substantial affinity difference of Ligand A is compelling. While the negative clearance for A is concerning, it's likely an artifact of the modeling and doesn't necessarily preclude further investigation.

Output:
1
2025-04-17 14:50:00,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (341.411 and 350.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.37) is better than Ligand B (87.46), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have good logP values (1.601 and 1.021), falling 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 have good QED scores (0.652 and 0.83), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand B (39.356) has a lower DILI risk than Ligand A (44.668), making it slightly more favorable. Both are below the concerning 60 threshold.

**8. BBB:** Ligand A (67.08) has a better BBB penetration percentile than Ligand B (34.238). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.655 and -4.992). These values are unusual and suggest poor permeability. However, the absolute values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.456 and -2.429). These values are also unusual and suggest poor solubility. The values are very similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.096 and 0.115), which is excellent.

**12. Microsomal Clearance:** Ligand B (53.973) has a lower microsomal clearance than Ligand A (59.22), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (13.838 hours) has a significantly longer in vitro half-life than Ligand A (-25.841 hours). The negative value for Ligand A is concerning and suggests rapid degradation. This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.022).

**15. 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 the more promising candidate. While both ligands have acceptable MW, logP, QED, and hERG profiles, Ligand B demonstrates superior metabolic stability (lower Cl_mic), a longer half-life, and a slightly better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the significant improvement in metabolic stability and half-life for Ligand B outweighs these concerns.

Output:
1
2025-04-17 14:50:00,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (344.415 and 347.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (89.01 and 84.67) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (1.536 and 1.661) 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 good QED scores (0.805 and 0.899), indicating a strong drug-like profile.

**7. DILI:** Ligand A has a DILI risk of 57.348%, which is moderate. Ligand B has a significantly lower DILI risk of 34.82%, which is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (72.082%) than Ligand A (54.207%), but this is not a major deciding factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.076 and -4.863). 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 (-2.862 and -2.61). This is also unusual and suggests poor solubility, which is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.404 and 0.229), which is excellent.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (37.426 mL/min/kg) than Ligand B (10.427 mL/min/kg). Lower clearance is better for metabolic stability, favoring Ligand B.

**13. In vitro Half-Life:** Ligand B has a negative half-life (-0.1 hours), which is impossible. Ligand A has a half-life of 7.987 hours, which is reasonable. The negative value for Ligand B is a major red flag and suggests an issue with the data.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.165 and 0.04), which is favorable.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.2 kcal/mol) compared to Ligand A (-0.0 kcal/mol). This is a substantial advantage, and a difference of >1.5 kcal/mol can often outweigh minor ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the significantly superior binding affinity of Ligand B (-9.2 kcal/mol vs -0.0 kcal/mol) and its lower DILI risk (34.82% vs 57.348%) and better metabolic stability (lower Cl_mic) make it the more promising candidate. The negative half-life for Ligand B is a serious concern, suggesting a data error, but even ignoring that, the binding affinity difference is substantial.

Output:
1
2025-04-17 14:50:00,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.4 and 344.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (99.9 and 91.6) below 140, suggesting reasonable absorption potential.

**logP:** Both ligands have logP values (1.53 and 2.06) 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 hydrogen bond donors and acceptors, balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.6 and 0.72), indicating drug-like properties.

**DILI:** Ligand A (47.0) has a slightly higher DILI risk than Ligand B (41.9), but both are below the concerning threshold of 60.

**BBB:** BBB is not a high priority for a non-CNS target like SRC kinase. Ligand A (51.8) is slightly higher than Ligand B (38.3).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.95 and -4.80), which is unusual and requires further investigation. However, we'll proceed with the comparison assuming these are relative permeability values and lower numbers indicate lower permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.95 and -2.70), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.13) has a slightly lower hERG risk than Ligand B (0.42), which is preferable.

**Microsomal Clearance:** Ligand B (30.68) has significantly lower microsomal clearance than Ligand A (12.27), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (48.58) has a much longer in vitro half-life than Ligand A (-6.27), further supporting its superior metabolic stability.

**P-gp Efflux:** Ligand A (0.11) has slightly lower P-gp efflux than Ligand B (0.19), which could translate to better bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly stronger 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 more promising candidate. Its significantly improved metabolic stability (lower Cl_mic and longer t1/2) is a major advantage for an enzyme target like SRC kinase. The slightly better binding affinity and lower DILI risk also contribute to its favorability. While both ligands have questionable solubility and permeability values, the metabolic advantage of Ligand B outweighs the slightly better P-gp and hERG profiles of Ligand A.

Output:
1
2025-04-17 14:50:00,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (80.32) is significantly better than Ligand B (57.26). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (2.49) being slightly more favorable. Ligand B (4.606) is pushing the upper limit and could present solubility challenges.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (4/3) counts.

**QED:** Both ligands have good QED scores (0.794 and 0.682), indicating drug-likeness.

**DILI:** Ligand A (26.173) has a much lower DILI risk than Ligand B (63.94), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (74.292) is slightly better. However, BBB is less crucial for a kinase inhibitor unless CNS involvement is specifically targeted.

**Caco-2 Permeability:** Ligand A (-4.511) has a better Caco-2 permeability score than Ligand B (-4.824).

**Aqueous Solubility:** Ligand A (-2.923) has a better solubility score than Ligand B (-5.639). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.164) has a much lower hERG inhibition liability than Ligand B (0.828), a critical safety parameter.

**Microsomal Clearance:** Ligand A (70.279) has lower microsomal clearance than Ligand B (82.162), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (124.28) has a significantly longer in vitro half-life than Ligand A (-36.556). This is a strong point in favor of Ligand B.

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux liability than Ligand B (0.368).

**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 significant drawbacks.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. While Ligand B has a slightly better binding affinity and longer half-life, Ligand A excels in critical ADME properties like DILI risk, hERG inhibition, solubility, and permeability. The lower DILI and hERG scores are particularly important for kinase inhibitors, as these compounds can often have off-target effects. The improved solubility and permeability will likely translate to better bioavailability. The difference in binding affinity is not large enough to overcome these advantages.

Output:
0
2025-04-17 14:50:00,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.34 Da) is slightly higher than Ligand B (367.837 Da), but both are acceptable.

**TPSA:** Ligand A (58.95) is significantly better than Ligand B (115.98). Lower TPSA generally correlates with better cell permeability. Ligand B is above the preferred threshold of 140, which could hinder absorption.

**logP:** Ligand A (4.121) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.365) is quite low, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is preferable to Ligand B (HBD=4, HBA=4) as it's closer to the ideal ranges for both.

**QED:** Ligand A (0.76) has a better QED score than Ligand B (0.504), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 37.728, Ligand B: 39.822), both being below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.576) is better than Ligand B (54.44).

**Caco-2 Permeability:** Ligand A (-4.847) is better than Ligand B (-5.939), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.537) is better than Ligand B (-2.518), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.819) has a lower hERG risk than Ligand B (0.037), which is a significant advantage.

**Microsomal Clearance:** Ligand A (15.895) is higher than Ligand B (3.132), indicating faster metabolism and lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (36.647) has a longer half-life than Ligand B (-8.684), which is a positive.

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux than Ligand B (0.01), which is preferable.

**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 is still a positive factor.

**Overall Assessment:**

Ligand A is generally superior, despite its slightly higher logP and Cl_mic. It excels in TPSA, solubility, hERG risk, QED, and has a slightly better binding affinity. Ligand B's low logP and high Cl_mic are significant drawbacks. The better solubility and lower hERG risk of Ligand A are particularly important for an enzyme target, outweighing the slightly higher logP.

Output:
1
2025-04-17 14:50:00,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (368.459 Da) is also good.

**TPSA:** Ligand A (122.03) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (102.84) is well within the acceptable range.

**logP:** Ligand A (0.289) is quite low, potentially hindering permeability. Ligand B (-0.451) 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 is reasonable. Ligand B has 2 HBD and 6 HBA, also reasonable.

**QED:** Both ligands have good QED scores (A: 0.621, B: 0.701), indicating drug-like properties.

**DILI:** Ligand B (45.25) has a significantly lower DILI risk than Ligand A (74.68), which is a major advantage.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC kinase.

**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 indicates very poor solubility. This is a significant drawback for both.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.216, B: 0.041), which is excellent.

**Microsomal Clearance:** Ligand B (15.823) has lower microsomal clearance than Ligand A (17.878), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-27.459) has a *negative* half-life, which is biologically impossible and indicates a significant issue with the data or the molecule itself. Ligand A (29.307) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.006, B: 0.026).

**Binding Affinity:** Ligand B (-9.8 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.

**Conclusion:**

Despite both ligands having issues with solubility and permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.8 vs -8.3 kcal/mol) is a major advantage for an enzyme target. Furthermore, it has a lower DILI risk and better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is a red flag, but assuming this is a data error, the overall profile is superior. The low logP values for both are concerning, but the potency advantage of B is likely to be more impactful.

Output:
1
2025-04-17 14:50:00,342 - INFO - Batch 329 complete. Total preferences: 5264
2025-04-17 14:50:00,342 - INFO - Processing batch 330/512...
2025-04-17 14:50:41,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.378 and 345.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is slightly higher than Ligand B (69.21). Both are acceptable, but Ligand B's lower TPSA is preferable for potential absorption.

**logP:** Ligand A (0.449) is a bit low, potentially hindering permeability. Ligand B (2.188) is within the optimal 1-3 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 5 HBA, while Ligand B has 7. Both are within the acceptable limit of <=10.

**QED:** Both ligands have high QED scores (0.824 and 0.848), indicating good drug-like properties.

**DILI:** Ligand A (56.689) has a slightly higher DILI risk than Ligand B (52.423), but both are reasonably low and below the concerning threshold of 60.

**BBB:** Both have good BBB penetration (77.588 and 83.288), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.999 and -4.934), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.486 and -2.951). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.158) shows lower hERG inhibition risk than Ligand B (0.85). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-28.588) has significantly lower (better) microsomal clearance than Ligand B (36.803), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (6.328) has a slightly longer half-life than Ligand B (5.579).

**P-gp Efflux:** Ligand A (0.035) has lower P-gp efflux than Ligand B (0.022), suggesting better bioavailability.

**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 Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has slightly worse metabolic stability (higher Cl_mic) and a higher hERG risk, the significantly improved potency is likely to be decisive. Both compounds have poor solubility and permeability, which are major concerns that would need to be addressed through formulation or further chemical modifications. However, the potency advantage of Ligand B is substantial enough to make it the more promising candidate.

Output:
1
2025-04-17 14:50:41,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (353.438 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (75.44 and 70.16) below 140, suggesting reasonable absorption potential.

**3. logP:** Ligand A (2.346) is optimal (1-3), while Ligand B (0.339) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A has 1 HBD, within the acceptable limit. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, within the acceptable limit. Ligand B has 5, also acceptable.

**6. QED:** Both ligands have QED values (0.816 and 0.683) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (35.944) has a lower DILI risk than Ligand B (25.436), both are good.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.661) has a higher BBB percentile than Ligand B (55.099).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.363 and -4.516), which is unusual and requires further investigation. However, we'll proceed assuming these are errors or indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.642 and -1.164), which is also unusual and concerning. Poor solubility can significantly hinder bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.421 and 0.125).

**12. Microsomal Clearance:** Ligand A (65.055) has a higher microsomal clearance than Ligand B (18.222), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.377) has a longer in vitro half-life than Ligand A (-28.293), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.123 and 0.023).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the primary differentiating factors are logP and metabolic stability. Ligand A has a better logP, which is crucial for permeability. However, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2). Given that SRC is an enzyme, metabolic stability is a high priority. While the solubility and permeability concerns are significant for both, the superior metabolic stability of Ligand B, coupled with its equally strong binding affinity, makes it the more promising candidate. The negative solubility and permeability values would need to be addressed through formulation or structural modifications, but the metabolic advantage is harder to fix later in development.

Output:
1
2025-04-17 14:50:41,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (419.666 Da) is slightly higher than Ligand B (366.849 Da), but both are acceptable.

**TPSA:** Ligand A (77.0) is better than Ligand B (87.46). Both are below the 140 threshold for oral absorption, but lower TPSA is generally preferred.

**logP:** Ligand A (4.215) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (0.35) is quite low, which could hinder membrane permeability.

**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 (Ligand A: 0.685, Ligand B: 0.805), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.759%), which is a significant concern. Ligand B has a much lower DILI risk (41.76%), making it more favorable.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (61.846%) is slightly better than Ligand B (33.501%).

**Caco-2 Permeability:** Both have negative values, suggesting poor permeability. Ligand A (-4.697) is worse than Ligand B (-5.297).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (Ligand A: -5.676, Ligand B: -2.504). This is a major drawback for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.465) has a slightly higher hERG risk than Ligand B (0.101), but both are relatively low.

**Microsomal Clearance:** Ligand A (91.79) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (-1.314) has negative clearance, which is unusual and suggests very high stability.

**In vitro Half-Life:** Ligand A (0.956) has a very short half-life. Ligand B (-1.103) has a negative half-life, which is also unusual and suggests very high stability.

**P-gp Efflux:** Ligand A (0.319) has a low P-gp efflux liability, which is good. Ligand B (0.047) is even lower, indicating minimal efflux.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate despite its low logP and solubility. The significantly superior binding affinity (-9.9 kcal/mol vs 0.0 kcal/mol) outweighs the drawbacks. Furthermore, Ligand B has a much lower DILI risk and significantly better metabolic stability (negative clearance and half-life). The poor solubility is a concern, but formulation strategies could potentially address this. Ligand A's extremely high DILI risk and poor metabolic stability are deal-breakers.

Output:
1
2025-04-17 14:50:41,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.391 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.56) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (70.67) is excellent, well below 140.

**logP:** Ligand A (1.156) is within the optimal 1-3 range. Ligand B (0.689) is a bit low, potentially impacting permeability, but not drastically.

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

**QED:** Ligand A (0.776) has a better QED score than Ligand B (0.525), indicating better overall drug-likeness.

**DILI:** Ligand B (15.471) has a significantly lower DILI risk than Ligand A (94.106). This is a major advantage for Ligand B.

**BBB:** Ligand A (67.817) has a higher BBB penetration score than Ligand B (40.364). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.399 and -5.097), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.324 and -1.204), which is also concerning. This could lead to formulation challenges. Ligand B is slightly better.

**hERG:** Both ligands have low hERG risk (0.202 and 0.291), which is good.

**Microsomal Clearance:** Ligand B (10.007) has significantly lower microsomal clearance than Ligand A (27.111), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-0.904) has a negative half-life, which is concerning. Ligand A (10.435) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.242 and 0.012).

**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, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much better safety profile (DILI) and metabolic stability (Cl_mic). Both have concerning permeability and solubility issues. However, the significantly stronger binding affinity of Ligand A, coupled with acceptable hERG and P-gp efflux, makes it the more promising candidate, *assuming* the solubility and permeability issues can be addressed through formulation or structural modifications. The difference in binding affinity (-0.7 kcal/mol) is substantial enough to prioritize over the ADME concerns, especially for an enzyme target where potency is paramount.

Output:
1
2025-04-17 14:50:41,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.385 Da and 363.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (76.02 and 71.36) well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.333) is within the optimal range of 1-3, while Ligand B (3.521) is at the higher end, 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, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.693 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (33.734) has a lower DILI risk than Ligand B (41.76), which is preferable.

**BBB:** Both ligands have similar BBB penetration (70.648 and 69.756), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.715) shows poorer Caco-2 permeability than Ligand B (-5.238), which is less desirable.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.004 and -3.596), which is a significant concern.

**hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition liability than Ligand B (0.296), which is a major advantage.

**Microsomal Clearance:** Ligand A (-2.507) exhibits significantly lower microsomal clearance than Ligand B (72.184), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-11.16) has a shorter in vitro half-life than Ligand B (39.975), which is a disadvantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.006 and 0.18).

**Binding Affinity:** Ligand B (-7.4 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 concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has a slightly higher DILI risk and a higher logP, the substantial improvement in binding outweighs these concerns. Ligand A has better metabolic stability, lower hERG risk, and lower DILI, but its significantly weaker binding affinity makes it less likely to be a viable candidate. The solubility is poor for both, but this can be addressed with formulation strategies.

Output:
1
2025-04-17 14:50:41,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.909 Da) is slightly higher than Ligand B (350.463 Da), but both are acceptable.

**TPSA:** Ligand A (61.36) is significantly better than Ligand B (90.54). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (2.536) is optimal (1-3). Ligand B (0.008) is quite low, potentially hindering permeation. This is a significant drawback for B.

**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 is slightly more balanced.

**QED:** Both ligands have reasonable QED scores (A: 0.785, B: 0.575), suggesting drug-like properties. A is better.

**DILI:** Ligand A (22.838) has a much lower DILI risk than Ligand B (6.049), which is a critical advantage.

**BBB:** Ligand A (92.943) has a better BBB percentile than Ligand B (47.809), but BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**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 (0.577) has a lower hERG risk than Ligand B (0.112), which is a significant advantage.

**Microsomal Clearance:** Ligand A (11.407) has a higher (worse) microsomal clearance than Ligand B (-21.848). This means Ligand B is predicted to be *more* metabolically stable. This is a key advantage for B.

**In vitro Half-Life:** Ligand A (26.538) has a longer half-life than Ligand B (-3.215), which is a positive for A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.034, B: 0.004).

**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 B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, and significantly better metabolic stability. However, it suffers from a very low logP, which could severely impact its absorption. Ligand A has better overall ADME properties (logP, TPSA, DILI, hERG, half-life), but its binding affinity is extremely weak.

Given the enzyme-specific priorities, binding affinity is paramount. The >1.5 kcal/mol advantage of Ligand B is substantial. While the low logP is a concern, it might be addressable through formulation strategies. The poor solubility and permeability are also concerns, but the potency advantage is significant.

Output:
1
2025-04-17 14:50:41,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (335.363 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.16) is slightly above the preferred <90 for kinase inhibitors, while Ligand B (69.48) is well within the range.

**3. logP:** Ligand A (3.39) is at the upper end of the optimal range, while Ligand B (1.916) 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 (HBD):** Ligand A (1) and Ligand B (0) are both within the acceptable limit of <=5.

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

**6. QED:** Both ligands have good QED scores (0.604 and 0.785), indicating drug-like properties.

**7. DILI:** Ligand A (84.102) has a higher DILI risk than Ligand B (47.77). This is a significant concern, as a lower DILI risk is highly desirable.

**8. BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (75.572) has a slightly higher BBB score than Ligand A (67.352).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.488 and -4.584), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.432 and -2.353), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.514) has a slightly higher hERG risk than Ligand B (0.115). Lower hERG risk is preferred.

**12. Microsomal Clearance (Cl_mic):** Ligand A (92.505) has a higher microsomal clearance than Ligand B (49.247), indicating lower metabolic stability. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (63.821) has a longer half-life than Ligand B (18.623). Longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.51) has higher P-gp efflux liability than Ligand B (0.054). Lower efflux is preferred.

**15. Binding Affinity:** Ligand B (-7.6 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:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B appears to be the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a significantly lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. The slightly better binding affinity of Ligand B further supports this conclusion. The longer half-life of Ligand A is a positive, but is outweighed by the other drawbacks.

Output:
1
2025-04-17 14:50:41,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.51 and 75.88) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.532 and 1.544) are 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 B (0.779) has a better QED score than Ligand A (0.49), indicating a more drug-like profile.

**DILI:** Ligand A (16.557) has a significantly lower DILI risk than Ligand B (42.807). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (71.811 and 84.257), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.284) has poorer Caco-2 permeability than Ligand B (-4.463), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.685) has poorer aqueous solubility than Ligand B (-0.774). This is a drawback for Ligand A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.147 and 0.159).

**Microsomal Clearance:** Ligand A (21.264) has a significantly lower microsomal clearance than Ligand B (47.248), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Both ligands have similar and negative in vitro half-lives (-14.29 and -14.564). This suggests rapid metabolism, but the difference isn't significant.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.077).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.9 and -7.8 kcal/mol). The difference is minimal.

**Conclusion:**

While Ligand B has a better QED, Caco-2 permeability, and solubility, Ligand A exhibits significantly lower DILI risk and microsomal clearance, which are critical for enzyme inhibitors. The binding affinity is nearly identical. Given the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG), the improved metabolic stability and reduced liver toxicity of Ligand A outweigh the slightly better absorption and solubility profile of Ligand B.

Output:
0
2025-04-17 14:50:41,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (415.288 Da) is slightly higher than Ligand B (356.463 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 84-86, which is acceptable for oral absorption, though not optimal for CNS penetration (which isn't a priority here).

**logP:** Both ligands have logP values between 1 and 3 (1.737 and 2.197 respectively), falling within the optimal range.

**H-Bond Donors & Acceptors:** Both ligands have reasonable HBD (1 & 2) and HBA (5) counts, suggesting a good balance between solubility and permeability.

**QED:** Ligand A (0.81) has a significantly higher QED score than Ligand B (0.539), indicating a more drug-like profile.

**DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (30.748). This is a significant drawback for Ligand A.

**BBB:** BBB is not a high priority for a non-CNS target. Ligand B (83.87) has a higher BBB percentile than Ligand A (68.67), but this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-4.399 vs -4.587).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-1.965) is slightly better than Ligand A (-2.453).

**hERG:** Both ligands have very low hERG inhibition liability (0.295 and 0.262), which is excellent.

**Microsomal Clearance:** Ligand A (28.646 mL/min/kg) has significantly lower microsomal clearance than Ligand B (60.598 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-13.954 hours) has a negative half-life, which is unusual. Ligand B (9.918 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.091), which is favorable.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.6 and -8.6 kcal/mol). Ligand A has a 1 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, and metabolic stability (lower Cl_mic). However, it has a significantly higher DILI risk and a questionable half-life. Ligand B has a lower DILI risk and a reasonable half-life, but its QED is lower and its metabolic stability is worse.

Given the enzyme-specific priorities, metabolic stability and potency are key. The 1 kcal/mol difference in binding affinity, combined with the lower Cl_mic, gives Ligand A a significant edge. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The unusual half-life value for ligand A is also concerning and should be investigated.

Output:
1
2025-04-17 14:50:41,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (415.288 Da) is slightly higher than Ligand B (361.507 Da), but both are acceptable.

**TPSA:** Ligand A (96.74) is better than Ligand B (53.68) as it is still within the acceptable range for oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (2.837) being slightly more favorable than Ligand B (4.208). Higher logP can sometimes indicate 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 good QED scores (Ligand A: 0.527, Ligand B: 0.803), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (39.434) has a significantly lower DILI risk than Ligand B (54.789), which is a substantial advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (84.025) is better than Ligand B (61.613).

**Caco-2 Permeability:** Both have negative values, which is unusual and indicates very poor permeability. However, the absolute value for Ligand A (-5.031) is slightly less negative than Ligand B (-5.111), suggesting marginally better absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.023 and -4.468 respectively). This is a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.816 and 0.884 respectively), which is good.

**Microsomal Clearance:** Ligand A (-19.54) has a much lower (better) microsomal clearance than Ligand B (82.02). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (23.371 hours) has a significantly longer half-life than Ligand B (107.313 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.076 and 0.856 respectively).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it might 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 and QED, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better BBB penetration. The poor solubility and Caco-2 permeability are concerns for both, but the other advantages of Ligand A, particularly its metabolic stability and safety profile, outweigh the slightly weaker binding. SRC kinases are often targets where chronic dosing is anticipated, making metabolic stability and safety paramount.

Output:
0
2025-04-17 14:50:41,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.356 Da) is slightly better positioned than Ligand B (383.539 Da).

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (82.53). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**logP:** Ligand A (3.887) is at the higher end of the optimal range, while Ligand B (1.295) is at the lower end. While both are within acceptable limits, a logP that is too low can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.802 and 0.672), indicating good drug-likeness.

**DILI:** Ligand A (52.772) has a slightly higher DILI risk than Ligand B (37.456), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.672) has a better BBB score than Ligand B (46.762), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.68) has a worse Caco-2 permeability than Ligand B (-5.568), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.064) has worse aqueous solubility than Ligand B (-2.36). Solubility is important for bioavailability, and Ligand B is better here.

**hERG Inhibition:** Ligand A (0.689) has a slightly higher hERG risk than Ligand B (0.199). Lower hERG risk is preferred.

**Microsomal Clearance:** Ligand A (84.995) has significantly higher microsomal clearance than Ligand B (7.263). This suggests Ligand B is more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (10.939) has a longer half-life than Ligand B (4.995). A longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux than Ligand B (0.055), which is favorable.

**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 not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial areas for an enzyme inhibitor: metabolic stability (lower Cl_mic), solubility, and lower hERG risk. The lower TPSA of Ligand A is a positive, but the significantly better metabolic stability of Ligand B is more critical for a kinase inhibitor.

Output:
1
2025-04-17 14:50:41,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.435 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is slightly above the preferred <140, but acceptable. Ligand B (78.87) is well within the acceptable range.

**logP:** Ligand A (-0.593) is a bit low, potentially hindering permeability. Ligand B (1.336) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable (<=10).

**QED:** Both ligands have good QED scores (0.566 and 0.646, both >=0.5).

**DILI:** Ligand A (11.322) has a very low DILI risk, which is excellent. Ligand B (27.181) is also low, but higher than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (54.556) has a higher BBB percentile than A (36.06), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.256 and -4.71), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.574 and -2.837), indicating poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.053 and 0.194).

**Microsomal Clearance:** Ligand A (-18.662) has *much* lower (better) microsomal clearance than Ligand B (54.043), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (15.872) has a longer half-life than Ligand B (-2.537), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.11).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.5 and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor permeability and solubility for both, Ligand A is the better candidate. Its significantly lower microsomal clearance (higher metabolic stability) and longer half-life are crucial advantages for an enzyme target. The lower DILI risk is also a plus. While Ligand B has a slightly better logP, the ADME profile of Ligand A is substantially more favorable for *in vivo* efficacy. The similar binding affinities mean that the ADME advantages of Ligand A outweigh the minor logP difference.

Output:
0
2025-04-17 14:50:41,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.392 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is significantly better than Ligand B (100.55). A TPSA under 90 is preferred, and Ligand A is much closer to this threshold, suggesting better permeability.

**logP:** Both ligands have acceptable logP values (2.63 and 1.192), falling within the 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 donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.775 and 0.62), indicating good drug-likeness.

**DILI:** Ligand A (20.822) has a much lower DILI risk than Ligand B (33.812), which is a significant advantage.

**BBB:** Ligand A (82.513) has a higher BBB penetration percentile than Ligand B (52.036). While not a primary concern for a non-CNS target like SRC, it's a slight benefit.

**Caco-2 Permeability:** Ligand A (-4.505) and Ligand B (-4.958) 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 difference.

**Aqueous Solubility:** Ligand A (-2.669) and Ligand B (-1.331) both have negative solubility values, indicating poor aqueous solubility. This is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.613) has a lower hERG inhibition liability than Ligand B (0.344), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (25.775) has a lower microsomal clearance than Ligand B (34.578), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-19.234) has a much longer in vitro half-life than Ligand B (-7.923), indicating greater stability.

**P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux liability than Ligand B (0.027), which is a slight advantage.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are good, the 1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, lower DILI risk, lower hERG inhibition, lower microsomal clearance, longer half-life, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the other advantages of Ligand A outweigh these drawbacks. The improved metabolic stability and safety profile are particularly important for a kinase inhibitor.

Output:
1
2025-04-17 14:50:41,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (91.4 and 88.32) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.945) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (2.109) is well within the optimal range.

**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 good QED scores (0.719 and 0.832), indicating drug-like properties.

**DILI:** Ligand A (41.877) has a much lower DILI risk than Ligand B (73.09), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (51.997 and 55.138), which isn't a primary concern for a non-CNS target like SRC.

**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 interpret these values accurately.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. However, the scale is not specified, so we cannot interpret these values accurately.

**hERG Inhibition:** Ligand A (0.226) has a very low hERG risk, while Ligand B (0.004) is even lower, both are excellent.

**Microsomal Clearance:** Ligand A (15.801) has a slightly higher microsomal clearance than Ligand B (14.95), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-35.061) has a significantly longer in vitro half-life than Ligand A (9.423), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.018), which is favorable.

**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 minor ADME drawbacks.

**Conclusion:**

While Ligand A has a better DILI profile, Ligand B's significantly improved binding affinity (-9.0 vs -8.7 kcal/mol) and longer half-life are more critical for an enzyme target like SRC. The slightly higher DILI risk of Ligand B is a manageable concern, especially given its superior potency and stability. The permeability and solubility values are concerning for both, but the binding affinity difference is the deciding factor.

Output:
1
2025-04-17 14:50:41,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (386.539 Da) is still well within acceptable limits.

**TPSA:** Ligand A (124.44) is better than Ligand B (89.87), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 1.162, B: 1.321), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=8) is preferable to Ligand B (HBD=3, HBA=6) as it has fewer HBDs. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED values (A: 0.822, B: 0.71), indicating good drug-like properties.

**DILI:** Ligand A (81.466) has a higher DILI risk than Ligand B (55.642). This is a significant drawback for Ligand A.

**BBB:** Ligand A (90.772) has a much higher BBB penetration than Ligand B (25.591). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.734) has a more negative Caco-2 value than Ligand B (-5.307), suggesting slightly better permeability.

**Aqueous Solubility:** Ligand A (-2.731) has better solubility than Ligand B (-3.239).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.325, B: 0.271), which is excellent.

**Microsomal Clearance:** Ligand B (40.016) has lower microsomal clearance than Ligand A (48.557), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (13.023) has a significantly longer in vitro half-life than Ligand A (-34.614). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.02, B: 0.1).

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

**Conclusion:**

While Ligand A has slightly better TPSA and solubility, Ligand B is superior overall. The primary advantages of Ligand B are its significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. These factors are crucial for enzyme targets like SRC kinase. The comparable binding affinity makes the ADME improvements of Ligand B decisive.

Output:
1
2025-04-17 14:50:41,664 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.327 Da) is slightly lower, which could be beneficial for permeability. Ligand B (362.436 Da) is also good.

**TPSA:** Ligand A (100.09) is better than Ligand B (58.2). Lower TPSA generally favors better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (1.277) is within the optimal range (1-3). Ligand B (3.721) is at the higher end, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 9 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10). Ligand B's lower HBA/HBD count might slightly improve permeability.

**QED:** Both ligands have good QED scores (A: 0.518, B: 0.647), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (97.867), which is a significant concern. Ligand B has a much lower DILI risk (35.285), making it considerably safer from a liver toxicity perspective.

**BBB:** Both have reasonable BBB penetration (A: 76.27, B: 86.468), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-5.102) has poor Caco-2 permeability, while Ligand B (-4.524) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.571) has poor aqueous solubility, which could hinder bioavailability. Ligand B (-4.364) also has poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.165) has a slightly higher hERG risk than Ligand B (0.412), but both are relatively low.

**Microsomal Clearance:** Ligand A (80.8 mL/min/kg) has higher microsomal clearance, suggesting faster metabolism and potentially lower *in vivo* exposure. Ligand B (54.915 mL/min/kg) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.026) has a very short half-life, which is undesirable. Ligand B (4.347) has a better, but still short, half-life.

**P-gp Efflux:** Ligand A (0.467) has lower P-gp efflux, which is favorable. Ligand B (0.077) has very low P-gp efflux, which is even more favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.8 kcal/mol, B: -8.5 kcal/mol). Ligand A has a 1.3 kcal/mol advantage, which is substantial and could potentially outweigh some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk, poor solubility, and short half-life are major liabilities. Ligand B, while having a slightly weaker affinity, exhibits a much more favorable safety profile (low DILI), better metabolic stability (lower Cl_mic), and lower P-gp efflux. Considering the enzyme-specific priorities, the balance of properties favors Ligand B as the more viable drug candidate.

Output:
1
2025-04-17 14:50:41,664 - INFO - Batch 330 complete. Total preferences: 5280
2025-04-17 14:50:41,664 - INFO - Processing batch 331/512...
2025-04-17 14:51:22,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.441 and 366.799 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.99) is higher than Ligand B (50.16). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (2.633) is within the optimal 1-3 range. Ligand B (3.961) is slightly higher, approaching the upper limit, but still acceptable.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (3), both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.796 and 0.893), indicating good drug-like properties.

**DILI:** Ligand A (50.136) has a lower DILI risk than Ligand B (66.072), which is preferable.

**BBB:** Both have high BBB penetration (90.461 and 89.957), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2:** Both 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.

**Solubility:** Both have negative solubility values, which is also unusual. Again, we'll assume this indicates poor solubility.

**hERG:** Ligand A (0.715) has a lower hERG risk than Ligand B (0.562), which is a significant advantage.

**Microsomal Clearance:** Both have similar microsomal clearance values (27.478 and 27.864 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-30.205) has a significantly *longer* in vitro half-life than Ligand B (-19.279). This is a major advantage.

**P-gp:** Ligand A (0.264) has lower P-gp efflux liability than Ligand B (0.087), which is favorable for bioavailability.

**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 a reasonable advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADMET properties. Specifically, its lower DILI risk, lower hERG inhibition, longer half-life, and lower P-gp efflux are all critical advantages for a kinase inhibitor. The negative Caco-2 and solubility values are concerning for both, but the other benefits of Ligand A outweigh the slight potency difference. Given the enzyme-specific priorities, the improved safety and pharmacokinetic profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 14:51:22,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.433 Da) is slightly higher than Ligand B (350.547 Da), but both are acceptable.

**TPSA:** Ligand A (121.01) is borderline acceptable for oral absorption, while Ligand B (49.41) is well within the ideal range (<140).

**logP:** Ligand A (-0.479) is a bit low, potentially hindering permeation. Ligand B (4.302) is high, potentially causing solubility and off-target issues.

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

**QED:** Both ligands have similar QED values (0.64 and 0.63), indicating good drug-likeness.

**DILI:** Ligand A (39.628) has a slightly higher DILI risk than Ligand B (17.72), but both are below the concerning threshold of 60.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (77.007) is better than Ligand A (64.211). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.044) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.632) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.775) has poor solubility. Ligand B (-3.844) is also poor, but worse than Ligand A.

**hERG Inhibition:** Ligand A (0.25) has a lower hERG risk than Ligand B (0.666), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-21.848) has much lower microsomal clearance, indicating better metabolic stability, a crucial factor for kinase inhibitors. Ligand B (55.968) has high clearance.

**In vitro Half-Life:** Ligand A (-27.126) has a longer half-life than Ligand B (3.78), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux, which is favorable. Ligand B (0.333) has higher efflux.

**Binding Affinity:** Both ligands have similar binding affinities (-8.2 kcal/mol and -7.8 kcal/mol). Ligand A is slightly better, but the difference is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While its logP and solubility are not ideal, its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux outweigh the drawbacks. The slightly better affinity of Ligand A is a bonus. Ligand B's high logP and high clearance are major concerns.

Output:
0
2025-04-17 14:51:22,130 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.471 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.01) is slightly higher than Ligand B (72.28). Both are acceptable, but Ligand B's lower TPSA is favorable for permeability.

**logP:** Both ligands (1.188 and 1.406) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5. Ligand B is slightly better.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.635 and 0.744), indicating good drug-like properties.

**DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (40.403). Ligand B is preferred here.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (64.482) is higher than Ligand A (28.848).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.439) is worse than Ligand B (-4.896).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.538) is worse than Ligand B (-2.007).

**hERG:** Both ligands have low hERG inhibition risk (0.154 and 0.407), which is good.

**Microsomal Clearance:** Ligand A (21.526) has significantly lower microsomal clearance than Ligand B (46.962), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (31.879) has a longer half-life than Ligand B (0.34), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.165 and 0.206).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.4 kcal/mol difference is substantial and outweighs many of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower DILI risk, the significantly stronger binding affinity of Ligand B (-8.9 vs -7.5 kcal/mol) is the deciding factor for an enzyme target like SRC kinase. The improved potency is likely to outweigh the moderate ADME concerns, and these can be addressed through further optimization.

Output:
1
2025-04-17 14:51:22,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.322 Da) is slightly higher than Ligand B (348.422 Da), but both are acceptable.

**TPSA:** Ligand A (50.28) is better than Ligand B (76.02). Lower TPSA generally favors oral absorption.

**logP:** Ligand A (4.323) is higher than the optimal range (1-3), which could lead to solubility issues or off-target effects. Ligand B (1.49) is within the optimal range.

**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: 0.736, B: 0.866), indicating drug-like properties.

**DILI:** Ligand A (58.434) has a higher DILI risk than Ligand B (49.399), but both are reasonably low.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.676) is slightly better than Ligand B (78.907).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.83), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.901 and -2.917), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.866) has a slightly higher hERG risk than Ligand B (0.375). Lower is better here.

**Microsomal Clearance:** Ligand B (-11.729) has significantly lower (better) microsomal clearance than Ligand A (12.752), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (19.287 hours) has a much longer half-life than Ligand A (2.073 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.42) has lower P-gp efflux than Ligand B (0.061), which is slightly favorable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.8 vs -6.9 kcal/mol), much better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk outweigh the slightly higher P-gp efflux. While solubility and permeability are major concerns, these can potentially be addressed through formulation strategies. The potency and metabolic stability advantages of Ligand B are more difficult to improve post-hoc.

Output:
1
2025-04-17 14:51:22,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.5) is slightly higher than Ligand B (83.98). Both are below the 140 threshold for oral absorption, but neither is optimized for CNS penetration (below 90).

**logP:** Both ligands have good logP values (1.352 and 1.523) falling within the 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 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.71 and 0.769), indicating good drug-likeness.

**DILI:** Ligand A (20.822) has a significantly lower DILI risk than Ligand B (44.552). This is a major advantage for Ligand A.

**BBB:** Ligand A (65.839) has a better BBB percentile than Ligand B (48.662), but neither is particularly high, and this isn't a primary concern for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-5.246) has a worse Caco-2 permeability than Ligand B (-4.886).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.717 and -2.623). This is a concern for both, but might be addressable with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.121 and 0.155).

**Microsomal Clearance:** Ligand A (26.677) has a higher microsomal clearance than Ligand B (15.243), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-18.296) has a significantly longer in vitro half-life than Ligand A (8.835). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.024).

**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 significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk, but suffers from higher microsomal clearance and poorer Caco-2 permeability. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and permeability, but has a higher DILI risk and slightly weaker binding affinity.

Given the enzyme-kinase target class, metabolic stability and potency are key. The 1.1 kcal/mol difference in binding affinity for Ligand A is substantial. While the higher clearance is a concern, it might be mitigated through structural modifications. The lower DILI risk of Ligand A is also a significant benefit.

Output:
1
2025-04-17 14:51:22,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.868 Da) is slightly higher than Ligand B (351.397 Da), but both are acceptable.

**TPSA:** Ligand A (80.76) is better than Ligand B (54.34). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (Ligand A: 1.376, Ligand B: 2.092), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 3. Both are within acceptable limits (<=10).

**QED:** Both ligands have good QED scores (Ligand A: 0.685, Ligand B: 0.903), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (69.756) has a higher DILI risk than Ligand B (22.8). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.192) and Ligand B (95.967) are both acceptable.

**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:** Both ligands have low hERG inhibition liability (Ligand A: 0.395, Ligand B: 0.397), which is excellent.

**Microsomal Clearance:** Ligand A (18.096) has significantly higher microsomal clearance than Ligand B (4.128). This indicates lower metabolic stability for Ligand A, a major drawback.

**In vitro Half-Life:** Ligand B (-0.26) has a better in vitro half-life than Ligand A (36.702).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.113, Ligand B: 0.042), which is good.

**Binding Affinity:** Ligand B (-8.8 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 ADME concerns.

**Conclusion:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and solubility, Ligand B exhibits a significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a higher QED score. The strong binding affinity is the most important factor for an enzyme inhibitor, and Ligand B's advantage here is substantial.

Output:
1
2025-04-17 14:51:22,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.406 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is well below the 140 threshold for oral absorption and suitable for kinase inhibitors. Ligand B (113.44) is still within acceptable limits but less optimal.

**logP:** Ligand A (2.12) is within the optimal 1-3 range. Ligand B (0.115) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=3, HBA=6) is also acceptable but slightly higher, potentially impacting permeability.

**QED:** Both ligands have reasonable QED scores (0.798 and 0.671), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (43.971 and 49.011), both being acceptable (below 60).

**BBB:** Ligand A (87.941) shows better BBB penetration than Ligand B (43.66), though this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.618) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.249) is similarly poor.

**Solubility:** Ligand A (-3.294) has slightly better solubility than Ligand B (-1.391), although both are quite poor.

**hERG:** Ligand A (0.353) has a very low hERG risk, which is excellent. Ligand B (0.158) also has a low hERG risk, but higher than A.

**Microsomal Clearance:** Ligand A (48.753) has a higher clearance than Ligand B (-4.236). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (26.75) has a longer half-life than Ligand A (-4.999), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.255) shows lower P-gp efflux, which is favorable. Ligand B (0.016) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's lower logP and poor Caco-2 permeability, its significantly superior binding affinity (-9.8 vs -7.4 kcal/mol) and substantially better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The stronger binding is likely to be more impactful for an enzyme target like SRC kinase, and metabolic stability is crucial for maintaining therapeutic concentrations. While solubility is a concern for both, it can be addressed with formulation strategies.

Output:
1
2025-04-17 14:51:22,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (408.275 Da and 380.476 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.91) is slightly higher than Ligand B (49.41), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have a logP around 3 (3.079 and 3.01), which is optimal.

**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 QED scores (0.78 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 59.054, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 18.651, a significant advantage.

**BBB:** Both have high BBB penetration (88.639 and 87.359), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.864 and -4.478). This is unusual and suggests poor permeability, but the scale isn't clearly defined. It's difficult to interpret without knowing the units.

**Aqueous Solubility:** Both have negative solubility values (-2.999 and -3.525), also unusual and suggesting poor solubility. Again, the scale is unclear.

**hERG Inhibition:** Ligand A (0.372) has a slightly lower hERG risk than Ligand B (0.507), which is preferable.

**Microsomal Clearance:** Ligand A (51.309) has a higher microsomal clearance than Ligand B (45.599), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (26.648 hours) has a significantly longer in vitro half-life than Ligand A (-22.791 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.36) has lower P-gp efflux than Ligand B (0.066), which is preferable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the better candidate. While the binding affinity difference is minor, Ligand B has a significantly lower DILI risk, a much longer half-life, and lower P-gp efflux. The solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B outweigh these drawbacks. The improved metabolic stability (lower Cl_mic and higher t1/2) is particularly important for an enzyme inhibitor.

Output:
1
2025-04-17 14:51:22,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (89.15 and 89.87) below 140, suggesting good oral absorption potential.

**logP:** Both ligands exhibit optimal logP values (1.249 and 1.218), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is slightly better than Ligand B (3 HBD, 4 HBA) in terms of H-bonding potential, staying closer to the ideal thresholds.

**QED:** Ligand A (0.79) has a better QED score than Ligand B (0.666), indicating a more drug-like profile.

**DILI:** Ligand A (36.293) has a significantly lower DILI risk than Ligand B (19.504), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (42.148) has a higher BBB percentile than Ligand A (25.475).

**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, a significant drawback.

**hERG:** Both ligands have very low hERG inhibition liability (0.108 and 0.149), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (23.268 and 22.778 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-7.971 hours) has a significantly longer in vitro half-life than Ligand B (2.779 hours), a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.052 and 0.028).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). The difference is 0.6 kcal/mol, which is notable but not overwhelming.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly higher binding affinity, Ligand A demonstrates superior drug-like properties in several critical areas: significantly lower DILI risk, a better QED score, and a much longer in vitro half-life. The solubility issues are a concern for both, but the other advantages of Ligand A outweigh the minor affinity difference.

Output:
0
2025-04-17 14:51:22,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.431 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.89) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (71.11) is well within the optimal range.

**logP:** Ligand A (-0.12) is a bit low, potentially hindering permeation. Ligand B (0.238) is better, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.541 and 0.741), indicating good drug-like properties.

**DILI:** Ligand A (62.35) has a moderate DILI risk, while Ligand B (28.073) has a low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.67) is higher, but it's not a deciding factor here. Ligand A (15.432) is low.

**Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are percentile scores, Ligand B (-4.543) is slightly better than Ligand A (-5.945).

**Aqueous Solubility:** Both have negative values which is unusual. Assuming these are percentile scores, Ligand B (-1.241) is slightly better than Ligand A (-1.975).

**hERG:** Both ligands have very low hERG inhibition risk (0.109 and 0.121).

**Microsomal Clearance:** Ligand A (-25.983) has significantly lower (better) microsomal clearance than Ligand B (44.564), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.284) has a slightly better in vitro half-life than Ligand B (-2.394).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.024 and 0.019).

**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 ADME drawbacks.

**Conclusion:**

Despite Ligand B having better solubility, lower DILI risk, and a slightly better logP, the significantly improved metabolic stability (lower Cl_mic, longer t1/2) and the substantial binding affinity advantage of Ligand A make it the more promising candidate. The slightly lower logP of Ligand A is a concern, but the strong binding could compensate for that. The DILI risk of Ligand A is moderate, but manageable.

Output:
1
2025-04-17 14:51:22,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.171 Da) is slightly higher than Ligand B (355.434 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (45.23) is higher than Ligand B (37.38), but both are favorable.

**logP:** Both ligands have logP values between 4 and 5, which is slightly high. While not ideal, it's not a major concern if other properties are good. Ligand A (4.621) is slightly higher than Ligand B (4.256).

**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 QED values above 0.5 (Ligand A: 0.606, Ligand B: 0.701), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Both ligands have high DILI risk (Ligand A: 79.333, Ligand B: 77.627). This is a significant concern and needs to be addressed in further optimization.

**BBB:** Both ligands have good BBB penetration (Ligand A: 75.649, Ligand B: 83.133). However, since SRC is not a CNS target, this is less critical. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.613 and -4.988), which is unusual and suggests poor permeability. This is a major drawback.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.406 and -5.508). This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.575) has a slightly lower hERG inhibition risk than Ligand B (0.936), which is preferable.

**Microsomal Clearance:** Ligand A (60.522) has a lower microsomal clearance than Ligand B (63.527), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (77.539) has a significantly longer in vitro half-life than Ligand B (-30.692). This is a major advantage, as it suggests less frequent dosing.

**P-gp Efflux:** Ligand A (0.412) has lower P-gp efflux than Ligand B (0.436), which is slightly better.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor for an enzyme inhibitor, and the 7.8 kcal/mol difference is substantial.

**Conclusion:**

Despite the high DILI risk and poor solubility/permeability for both compounds, Ligand A is the more promising candidate due to its significantly stronger binding affinity (-7.8 kcal/mol vs -0.0 kcal/mol), better metabolic stability (lower Cl_mic), and longer half-life. The potency advantage outweighs the other drawbacks, and these ADME issues could potentially be addressed through further structural modifications. Ligand B's extremely poor affinity makes it unlikely to be a viable starting point.

Output:
0
2025-04-17 14:51:22,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.451 and 372.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.14) is slightly higher than Ligand B (75.71), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.035 and 2.068), falling within the 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 the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED scores (0.692 and 0.694), indicating good drug-likeness.

**DILI:** Ligand A (56.883) has a higher DILI risk than Ligand B (40.054). This is a significant negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (72.741 and 69.794), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.826 and -4.639). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference may not be substantial.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.168 and -3.1). This is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.142) has a slightly lower hERG inhibition risk than Ligand B (0.307), which is favorable.

**Microsomal Clearance:** Ligand A (48.052) has a significantly lower microsomal clearance than Ligand B (63.485), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.61 hours) has a much longer half-life than Ligand B (-37.666 hours). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.199) has lower P-gp efflux than Ligand B (0.046), suggesting better bioavailability.

**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 some ADME drawbacks.

**Conclusion:**

Despite the similar QED, logP, TPSA, and H-bond characteristics, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.6 vs -7.6 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme inhibitor. While Ligand A has a slightly higher DILI risk, the substantial improvements in potency and stability outweigh this concern. The poor solubility and Caco-2 permeability are shared concerns that would need to be addressed in further optimization, but the superior binding and metabolic profile of Ligand A make it the better starting point.

Output:
0
2025-04-17 14:51:22,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.511 and 363.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is better than Ligand B (89.35). Both are below 140, supporting reasonable absorption, but lower TPSA is generally preferred.

**3. logP:** Both ligands have good logP values (2.509 and 1.15), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

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

**6. QED:** Both ligands have good QED scores (0.696 and 0.832), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (70.221). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (55.448) is higher than Ligand A (41.14), but this isn't a deciding factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.151 and -5.087), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.477 and -2.021), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.25 and 0.181), which is excellent.

**12. Microsomal Clearance:** Ligand B (29.743) has lower microsomal clearance than Ligand A (42.978), suggesting better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (20.501 hours) has a longer half-life than Ligand A (13.695 hours), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.328 and 0.034), which is good.

**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 small.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED, Ligand A has a significantly lower DILI risk and a slightly better binding affinity. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. However, the substantial difference in DILI risk is a critical factor. DILI is a major cause of drug development failure, and minimizing this risk is paramount.

Output:
0
2025-04-17 14:51:22,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (367.427 and 382.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand B (98.32) is better than Ligand A (125.36) as it is closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (0.95 and 1.865, respectively), falling 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.735) has a better QED score than Ligand A (0.494), indicating a more drug-like profile.

**DILI:** Both ligands have similar, and concerningly high, DILI risk (65.491 and 67.507). This is a significant drawback for both.

**BBB:** Ligand A (38.736) has a slightly better BBB penetration percentile than Ligand B (19.504), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.231 and -5.228). This is a major concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.153 and -3.797). This could hinder formulation and bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.379 and 0.347), which is positive.

**Microsomal Clearance:** Ligand B (18.975) has significantly lower microsomal clearance than Ligand A (56.785), suggesting better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand B (-15.265) has a longer in vitro half-life than Ligand A (-28.864), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.071 and 0.174).

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

**Conclusion:**

While both compounds have concerning DILI scores and poor permeability/solubility, Ligand B is the better candidate. It has a superior QED score, significantly lower microsomal clearance, and a longer half-life, all of which are crucial for an enzyme target like SRC. The slight improvement in logP and TPSA also contribute to its favorability. The similar binding affinity means the ADME improvements of Ligand B outweigh any potential benefit from a slightly stronger binding interaction.

Output:
1
2025-04-17 14:51:22,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.36 and 343.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.94) is well below the 140 threshold, suggesting good absorption. Ligand B (80.12) is still acceptable, but less optimal.

**logP:** Ligand A (4.466) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.546) 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 4 HBA, and Ligand B has 5 HBA, both within acceptable limits.

**QED:** Ligand A (0.865) has a higher QED score, indicating better drug-likeness than Ligand B (0.69).

**DILI:** Ligand B (39.899) has a significantly lower DILI risk than Ligand A (52.966), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (61.54% and 69.41%), but this is less critical for a non-CNS target like SRC.

**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.

**Aqueous Solubility:** Both have very poor aqueous solubility (-6.039 and -3.305). This is a significant concern for both compounds.

**hERG Inhibition:** Ligand A (0.87) has a higher hERG risk than Ligand B (0.123), which is a substantial advantage for Ligand B.

**Microsomal Clearance:** Ligand B (45.417) has a lower microsomal clearance, indicating better metabolic stability than Ligand A (74.832).

**In vitro Half-Life:** Ligand B (-10.454) has a negative half-life, which is not possible. This is a major red flag. Ligand A (23.592) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.602 and 0.102).

**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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity, lower DILI risk, lower hERG risk, and better metabolic stability. However, the negative in vitro half-life is a critical flaw. Ligand A has a more reasonable half-life, but suffers from higher DILI and hERG risks, and a slightly weaker binding affinity. The solubility is poor for both. Given the importance of metabolic stability and safety (DILI, hERG) for kinase inhibitors, and the substantial affinity difference, Ligand B is still the more promising candidate *if* the half-life issue can be resolved. The negative half-life suggests a data error or a very rapid degradation, which needs investigation.

Output:
1
2025-04-17 14:51:22,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.435 Da and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.71) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (104.9) is still within acceptable limits for oral absorption (<140), but less optimal than A.

**logP:** Ligand A (3.006) is within the optimal 1-3 range. Ligand B (0.571) is quite low, potentially hindering permeability and absorption.

**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:** Both ligands have good QED scores (0.72 and 0.776), indicating drug-like properties.

**DILI:** Ligand A (72.276) has a higher DILI risk than Ligand B (38.62), which is a significant concern.

**BBB:** Both have reasonable BBB penetration, but Ligand A is slightly better (72.741 vs 62.699). This is less critical for a non-CNS target like SRC.

**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 the values. Ligand A (-5.06) is slightly worse than Ligand B (-5.018).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.615) is slightly worse than Ligand B (-1.979).

**hERG:** Ligand A (0.672) has a lower hERG risk than Ligand B (0.152), which is a positive.

**Microsomal Clearance:** Ligand A (48.883) has a higher microsomal clearance than Ligand B (-3.731), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (17.681) has a longer half-life than Ligand B (5.92), which is preferable.

**P-gp Efflux:** Ligand A (0.175) has lower P-gp efflux than Ligand B (0.095), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). The 0.7 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, TPSA, BBB, hERG, P-gp efflux, and in vitro half-life. However, it has a significantly higher DILI risk and lower metabolic stability (higher Cl_mic). Ligand B has a lower DILI risk and better metabolic stability, but suffers from a low logP, potentially impacting permeability, and a slightly weaker binding affinity.

Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. While Ligand A's affinity is better, the higher DILI risk and lower metabolic stability are major concerns. Ligand B, despite its weaker affinity, presents a more favorable safety and pharmacokinetic profile. The difference in affinity (0.7 kcal/mol) is not substantial enough to overcome the significant ADME liabilities of Ligand A.

Output:
1
2025-04-17 14:51:22,133 - INFO - Batch 331 complete. Total preferences: 5296
2025-04-17 14:51:22,133 - INFO - Processing batch 332/512...
2025-04-17 14:52:12,372 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.427 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is slightly higher than Ligand B (52.65). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.542) and Ligand B (2.57) 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 4 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.9) has a better QED score than Ligand B (0.685), indicating higher drug-likeness.

**DILI:** Ligand A (38.581) has a lower DILI risk than Ligand B (8.414), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 70.26, Ligand B: 79.566), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.791) is slightly worse than Ligand B (-4.653).

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual and indicating poor aqueous solubility. Ligand A (-2.163) is slightly worse than Ligand B (-1.764).

**hERG Inhibition:** Ligand A (0.156) has a lower hERG risk than Ligand B (0.431), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (11.963 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (34.887 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.699 hours) has a longer half-life than Ligand B (-0.452 hours), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.042, Ligand B: 0.053).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This 1.7 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have issues with Caco-2 permeability and solubility, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG inhibition, and a slightly better binding affinity. These advantages are particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 14:52:12,372 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.381 and 362.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is better than Ligand B (84.5), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have a logP of approximately 2.0, which is optimal.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as it has fewer hydrogen bond forming groups, which generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.772 and 0.647), indicating good drug-likeness.

**DILI:** Ligand A (27.414) has a significantly lower DILI risk than Ligand B (31.718), which is a crucial advantage.

**BBB:** Ligand A (92.555) has a much higher BBB penetration percentile than Ligand B (79.062). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.952) has better Caco-2 permeability than Ligand B (-4.619).

**Aqueous Solubility:** Ligand A (-3.226) has better aqueous solubility than Ligand B (-2.457). This is important for formulation and bioavailability.

**hERG:** Ligand A (0.615) has a lower hERG inhibition liability than Ligand B (0.286), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (2.927) has significantly lower microsomal clearance than Ligand B (58.641), suggesting better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-10.68) has a much longer in vitro half-life than Ligand B (-27.39), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.109) shows lower P-gp efflux liability than Ligand B (0.037).

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.5), with a difference of 0.8 kcal/mol. While affinity is paramount, the substantial advantages of Ligand A in ADME properties outweigh this minor difference.

**Conclusion:**

Ligand A is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly superior ADME properties, including lower DILI risk, better solubility, much better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG inhibition. These factors are critical for enzyme targets like SRC kinase and are more likely to translate into a viable drug.

Output:
0
2025-04-17 14:52:12,372 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.415 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than the preferred <140, but acceptable. Ligand B (60.85) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.547) is a bit low, potentially hindering permeability. Ligand B (1.424) 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 3 HBA, also good.

**QED:** Ligand B (0.606) has a better QED score than Ligand A (0.274), indicating a more drug-like profile.

**DILI:** Ligand B (8.414) has a significantly lower DILI risk than Ligand A (51.725), a major advantage.

**BBB:** Both have similar BBB penetration (Ligand A: 58.434, Ligand B: 61.109), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.699 and -4.638), which is unusual and suggests poor permeability *in vitro*. This is a concern for both, but doesn't necessarily disqualify them.

**Aqueous Solubility:** Both have negative solubility values (-2.436 and -2.341), also unusual and suggesting poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.141) has a slightly lower hERG risk than Ligand B (0.31), which is preferable.

**Microsomal Clearance:** Ligand B (16.939) has a significantly lower microsomal clearance than Ligand A (59.189), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-3.825) has a better (less negative) in vitro half-life than Ligand A (-41.497), further supporting its improved metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.111 and 0.091).

**Binding Affinity:** Both have excellent binding affinities (Ligand A: -8.1 kcal/mol, Ligand B: -7.8 kcal/mol). Ligand A is slightly better, but the difference (0.3 kcal/mol) is not substantial enough to outweigh other factors.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic, better t1/2), and a superior QED score. The slightly weaker binding affinity of Ligand B is less concerning given its improved ADME properties.

Output:
1
2025-04-17 14:52:12,372 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 405.336 Da - Within the ideal range (200-500 Da).
* Ligand B: 349.519 Da - Also within the ideal range.
* *No clear advantage here.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 44.73 - Good, below the 140 threshold for oral absorption.
* Ligand B: 52.65 - Still acceptable, below 140.
* *Slight advantage to Ligand A, but both are reasonable.*

**3. Lipophilicity (logP):**
* Ligand A: 4.403 - Slightly high, potentially leading to solubility issues or off-target effects.
* Ligand B: 2.119 - Optimal, within the 1-3 range.
* *Advantage to Ligand B.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Meets the <=5 criteria.
* Ligand B: 1 - Meets the <=5 criteria.
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 4 - Meets the <=10 criteria.
* Ligand B: 3 - Meets the <=10 criteria.
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.774 - Excellent, indicating good drug-like properties.
* Ligand B: 0.799 - Excellent, slightly better than A.
* *Slight advantage to Ligand B.*

**7. DILI:**
* Ligand A: 35.673 - Very good, low risk of liver injury.
* Ligand B: 4.963 - Excellent, even lower risk.
* *Advantage to Ligand B.*

**8. BBB:**
* Ligand A: 69.639 - Not a priority for a non-CNS target like SRC kinase.
* Ligand B: 90.19 - Not a priority.
* *No impact on decision.*

**9. Caco-2 Permeability:**
* Ligand A: -5.107 - Negative value is unusual and suggests very poor permeability.
* Ligand B: -4.689 - Negative value, also poor permeability, but slightly better than A.
* *Advantage to Ligand B.*

**10. Aqueous Solubility:**
* Ligand A: -4.19 - Poor solubility.
* Ligand B: -1.872 - Better solubility than A, but still not ideal.
* *Advantage to Ligand B.*

**11. hERG Inhibition:**
* Ligand A: 0.918 - Relatively low risk.
* Ligand B: 0.542 - Lower risk than A.
* *Advantage to Ligand B.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 36.964 mL/min/kg - Moderate clearance, suggesting moderate metabolic stability.
* Ligand B: 41.814 mL/min/kg - Higher clearance, lower metabolic stability.
* *Advantage to Ligand A.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 19.043 hours - Good half-life.
* Ligand B: 3.455 hours - Short half-life.
* *Advantage to Ligand A.*

**14. P-gp Efflux:**
* Ligand A: 0.432 - Low efflux, good.
* Ligand B: 0.064 - Very low efflux, excellent.
* *Advantage to Ligand B.*

**15. Binding Affinity:**
* Ligand A: -6.8 kcal/mol - Good binding affinity.
* Ligand B: -7.5 kcal/mol - Significantly better binding affinity (0.7 kcal/mol advantage).

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a significantly better binding affinity (-7.5 vs -6.8 kcal/mol), which is a substantial advantage. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), the difference in affinity is likely to outweigh this. Ligand B also demonstrates superior properties in terms of logP, DILI, solubility, hERG and P-gp efflux. The Caco-2 permeability is poor for both, but slightly better for Ligand B.

Output:
1
2025-04-17 14:52:12,372 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.299 Da and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is slightly higher than Ligand B (59.98). Both are acceptable, but Ligand B's lower TPSA is preferable for permeability.

**logP:** Ligand A (-0.93) is a bit low, potentially hindering permeation. Ligand B (3.611) 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 6 HBA. Both are within reasonable limits.

**QED:** Both ligands have similar QED values (0.627 and 0.645), indicating good drug-likeness.

**DILI:** Ligand A (35.944) has a much lower DILI risk than Ligand B (57.774). This is a substantial advantage for Ligand A.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have similar, very negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.336) has a much lower hERG risk than Ligand B (0.79). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-6.792) has a *much* lower (better) microsomal clearance than Ligand B (83.618). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-4.791) has a more negative (better) in vitro half-life than Ligand B (61.072), further supporting its improved metabolic stability.

**P-gp Efflux:** Ligand A (0.013) has a much lower P-gp efflux liability than Ligand B (0.807), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a 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:**

Ligand A is the better candidate. While both have poor solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, better t1/2), lower hERG risk, lower DILI risk, and a substantially stronger binding affinity. The stronger affinity is a key advantage for an enzyme inhibitor, and the improved ADME properties make it more likely to succeed. Ligand B's higher logP is its only real advantage, but it's outweighed by the other factors.

Output:
0
2025-04-17 14:52:12,372 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.355 and 365.909 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.65) is higher than Ligand B (59.11). While both are reasonably low, Ligand B is significantly better, suggesting improved cell permeability.

**logP:** Ligand A (0.232) is quite low, potentially hindering membrane permeability. Ligand B (2.813) 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.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable.

**QED:** Both ligands have high QED scores (0.806 and 0.855), indicating good drug-like properties.

**DILI:** Ligand A (77.394) has a higher DILI risk than Ligand B (20.396). This is a substantial concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (72.082) has a higher BBB percentile than Ligand A (21.985), but it's not a primary driver in this decision.

**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, values are similar.

**hERG:** Ligand A (0.141) has a lower hERG risk than Ligand B (0.562), which is favorable.

**Microsomal Clearance:** Ligand A (-10.905) has *much* lower microsomal clearance than Ligand B (32.489). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (21.921) has a longer half-life than Ligand A (9.522).

**P-gp Efflux:** Ligand A (0.059) shows lower P-gp efflux than Ligand B (0.37), which is beneficial for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.7 kcal/mol), with Ligand B being slightly better. The affinity difference is not large enough to overcome other issues.

**Overall Assessment:**

Ligand B has a better logP, TPSA, DILI score, and half-life. However, Ligand A has a significantly better microsomal clearance and P-gp efflux, and a lower hERG risk. The lower DILI risk and superior metabolic stability of Ligand A are crucial for an oncology target, where chronic dosing is often required. The low logP of Ligand A is a concern, but the strong binding affinity may compensate. The unusual Caco-2 and solubility values are a flag, but the other factors are more decisive.

Output:
0
2025-04-17 14:52:12,372 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.415 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly higher than Ligand B (61.88). Both are acceptable, but Ligand B's lower TPSA is preferable for permeability.

**logP:** Both ligands have good logP values (1.891 and 1.639), 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. Ligand B is slightly better.

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

**QED:** Both ligands have good QED scores (0.717 and 0.756), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 58.55, while Ligand B has a much lower risk of 11.09. This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (65.878 and 67.584). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.078) has significantly worse Caco-2 permeability than Ligand B (-4.697).

**Aqueous Solubility:** Ligand A (-3.582) has worse solubility than Ligand B (-1.519). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.417) has slightly higher hERG inhibition liability than Ligand B (0.296), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (32.6) has lower microsomal clearance than Ligand B (34.6), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.326) has a much longer in vitro half-life than Ligand B (6.334). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux than Ligand B (0.019), indicating better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.0 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a significant advantage in binding affinity and in vitro half-life and P-gp efflux. However, Ligand B has a much better DILI score, better Caco-2 permeability and solubility. Considering the enzyme-specific priorities, metabolic stability (half-life and clearance) and safety (DILI, hERG) are crucial. While Ligand A's affinity is better, the significantly lower DILI risk and better solubility of Ligand B are more important for overall drug development.

Output:
1
2025-04-17 14:52:12,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.487 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is better than Ligand B (87.66), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (3.172 and 1.531, respectively), 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=3, HBA=4) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.752 and 0.52), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (13.416) has a significantly lower DILI risk than Ligand B (6.592), which is a major advantage. Both are below the 40 threshold.

**BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (70.686) has a better BBB score than Ligand B (47.732).

**Caco-2 Permeability:** Ligand A (-4.714) has a better Caco-2 permeability score than Ligand B (-4.76).

**Aqueous Solubility:** Ligand A (-3.197) has a better solubility score than Ligand B (-1.346).

**hERG:** Both ligands have low hERG inhibition liability (0.518 and 0.138, respectively), which is good.

**Microsomal Clearance:** Ligand B (17.893) has a lower microsomal clearance than Ligand A (42.027), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (16.1) has a longer half-life than Ligand A (-18.894), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.013, respectively).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, H-bonds, QED, DILI, solubility, Caco-2, BBB) and has comparable binding affinity to Ligand B. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and a longer half-life. Given the enzyme-specific priority on metabolic stability, Ligand B is slightly more promising. The difference in binding affinity is minimal, and the better ADME profile of Ligand A is somewhat offset by the poorer metabolic stability.

Output:
1
2025-04-17 14:52:12,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.511 Da and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (87.46). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.067 and 1.021), 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 balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.704 and 0.83), indicating drug-likeness.

**DILI:** Ligand A (44.436) has a slightly better DILI score than Ligand B (39.356), both being reasonably low risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.837) is better than Ligand B (34.238), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.103) and Ligand B (-4.992) are similar and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-3.032) is slightly better than Ligand B (-2.429), both being poor.

**hERG:** Ligand A (0.362) has a much lower hERG risk than Ligand B (0.115), a significant advantage.

**Microsomal Clearance:** Ligand A (57.174) has a higher microsomal clearance than Ligand B (53.973), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.838 hours) has a significantly longer half-life than Ligand A (-5.527 hours), a major advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.314) has lower P-gp efflux than Ligand B (0.022), which is favorable.

**Binding Affinity:** Both ligands have identical binding affinities (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is preferable due to its significantly lower hERG risk and better TPSA. Ligand B's main advantage is its longer half-life, but the hERG risk associated with Ligand B is a major concern. The slightly better solubility of ligand A is also a plus. Given the enzyme-specific priorities, minimizing hERG risk is crucial.

Output:
0
2025-04-17 14:52:12,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.841 and 342.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.24) is well below the 140 threshold, while Ligand B (93.01) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (4.838) is slightly high, potentially causing solubility issues or off-target effects. Ligand B (1.247) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 3, B: 6) counts.

**QED:** Both ligands have good QED scores (A: 0.54, B: 0.853), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (58.627), which is preferable.

**BBB:** Both have similar BBB penetration (A: 63.125, B: 60.838), which is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 have negative solubility values, which is also unusual and indicates poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.706) has a slightly higher hERG risk than Ligand B (0.078). Ligand B is much better here.

**Microsomal Clearance:** Ligand B (33.401) has significantly lower microsomal clearance than Ligand A (82.416), suggesting better metabolic stability. This is a strong advantage for Ligand B.

**In vitro Half-Life:** Ligand A (41.212) has a longer half-life than Ligand B (1.624). This is a positive for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux (A: 0.389, B: 0.047), which is good. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a major advantage for Ligand B, and the 0.9 kcal/mol difference is substantial enough to outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While both ligands have issues with Caco-2 permeability and solubility, Ligand B's significantly higher binding affinity (-7.4 vs -8.3 kcal/mol) and lower microsomal clearance (33.4 vs 82.4) are critical advantages for an enzyme inhibitor. The lower hERG risk is also a plus. The slightly lower logP of Ligand B is less concerning than the high logP of Ligand A. The longer half-life of Ligand A is a benefit, but the affinity difference is more important.

Output:
1
2025-04-17 14:52:12,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.495 and 374.522 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (56.33 and 58.64) are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (-0.177) is slightly low, potentially hindering permeation. Ligand B (2.39) is within the optimal 1-3 range. This favors Ligand B.

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

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

**QED:** Both ligands (0.575 and 0.709) have good drug-likeness scores.

**DILI:** Ligand A (5.739) has a very low DILI risk, significantly better than Ligand B (26.095).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (93.68) has a higher BBB penetration, but it's not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.735 and -4.814), which is unusual and requires further investigation. However, we'll proceed with the comparison assuming these are errors or indicate poor permeability.

**Aqueous Solubility:** Ligand A (-0.01) is better than Ligand B (-2.969). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.499) has a lower hERG risk than Ligand B (0.642), which is preferable.

**Microsomal Clearance:** Ligand A (20.089 mL/min/kg) has significantly lower clearance than Ligand B (41.811 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.742 hours) has a negative half-life, which is impossible and suggests an issue with the data. Ligand B (-7.43 hours) also has a negative half-life, indicating data issues.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux liability, while Ligand B (0.291) is slightly higher.

**Binding Affinity:** Both ligands have similar binding affinities (-7.4 and -7.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the questionable half-life data, Ligand A appears more promising. It has a significantly lower DILI risk, better solubility, lower hERG risk, and better metabolic stability (lower Cl_mic). While Ligand B has a slightly better logP, Ligand A's advantages in safety and pharmacokinetic properties outweigh this. The negative Caco-2 values are concerning for both, but the other factors point towards Ligand A being the better candidate.

Output:
0
2025-04-17 14:52:12,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.89) is well below the 140 threshold, while Ligand B (92.94) is still acceptable but approaching the limit.

**logP:** Ligand A (2.158) is optimal (1-3), while Ligand B (0.476) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the 5 limit.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 for A, 4 for B), well below the 10 limit.

**QED:** Both ligands have good QED scores (0.706 and 0.72), indicating drug-like properties.

**DILI:** Ligand A (51.493) has a slightly higher DILI risk than Ligand B (25.436), but both are below the concerning threshold of 60.

**BBB:** Ligand A (83.831) has better BBB penetration than Ligand B (64.133), but this is less crucial for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.557) has poor Caco-2 permeability, while Ligand B (-4.928) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-2.416) has poor solubility, while Ligand B (-1.799) is also poor. Both are concerning.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.413 and 0.172).

**Microsomal Clearance:** Ligand A (55.253) has higher microsomal clearance than Ligand B (36.523), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.65) has a much longer in vitro half-life than Ligand A (1.236), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.146) has lower P-gp efflux than Ligand B (0.023), which is preferable.

**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 >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's poor Caco-2 permeability and solubility, and higher clearance, its *much* superior binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) makes it the more promising candidate. The strong binding is likely to outweigh the ADME liabilities, especially given that these can be addressed through further optimization. Ligand B's affinity is simply too weak to be a viable starting point.

Output:
1
2025-04-17 14:52:12,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.389 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is better than Ligand B (69.64), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.164) is slightly low, potentially hindering permeation, while Ligand B (1.55) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both 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:** Both ligands have good QED scores (0.659 and 0.742), indicating good drug-like properties.

**DILI:** Ligand A (27.918) has a significantly lower DILI risk than Ligand B (11.516). This is a major advantage for Ligand A.

**BBB:** Both have similar BBB penetration (57.193 and 57.619), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.943 and -4.714), 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 (-0.899 and -2.207), indicating poor aqueous solubility. Ligand B is worse.

**hERG:** Both ligands have very low hERG inhibition risk (0.19 and 0.223), which is excellent.

**Microsomal Clearance:** Ligand A (-16.738) has a lower (better) microsomal clearance than Ligand B (-17.706), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.409) has a worse in vitro half-life than Ligand B (4.576). This favors Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.052).

**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 less than the 1.5 kcal/mol threshold to override other issues, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in DILI risk and has better metabolic stability (lower Cl_mic). However, it has a lower logP and solubility. Ligand B has a better logP, half-life, and slightly better affinity, but has a higher DILI risk and worse solubility. Given the importance of metabolic stability and low toxicity (DILI) for enzyme inhibitors, and the relatively small affinity difference, Ligand A is the slightly better candidate.

Output:
0
2025-04-17 14:52:12,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 360.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (68.87), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.981) is within the optimal 1-3 range. Ligand B (3.018) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) both satisfy the <=5 rule.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) both satisfy the <=10 rule.

**QED:** Ligand A (0.815) has a significantly better QED score than Ligand B (0.672), indicating a more drug-like profile.

**DILI:** Ligand B (66.15) has a higher DILI risk than Ligand A (50.64), which is preferable.

**BBB:** Ligand B (82.9) has a better BBB penetration than Ligand A (70.686), but BBB is not a primary concern for a kinase inhibitor unless CNS activity is desired.

**Caco-2 Permeability:** Ligand A (-4.536) has a worse Caco-2 permeability than Ligand B (-5.622), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.456) has a worse aqueous solubility than Ligand B (-3.353).

**hERG Inhibition:** Ligand A (0.123) has a lower hERG inhibition risk than Ligand B (0.909), which is a significant advantage.

**Microsomal Clearance:** Ligand A (15.797) has a significantly lower microsomal clearance than Ligand B (44.085), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (39.601) has a much longer in vitro half-life than Ligand A (-5.989). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux than Ligand B (0.186), which is preferable.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.0), but the difference is relatively small (0.8 kcal/mol).

**Overall Assessment:**

Ligand A has better QED, lower DILI, lower hERG risk, lower microsomal clearance, and lower P-gp efflux. However, Ligand B has better Caco-2 permeability, solubility, and a longer half-life. The most important factors for an enzyme inhibitor are potency, metabolic stability, solubility, and safety (hERG, DILI). Ligand A's superior metabolic stability (lower Cl_mic) and lower hERG risk are compelling advantages, despite its slightly lower affinity and poorer solubility/permeability. The 0.8 kcal/mol difference in affinity is not substantial enough to outweigh these ADME/Tox benefits.

Output:
0
2025-04-17 14:52:12,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 and 359.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is better than Ligand B (42.16), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.83) is optimal (1-3), while Ligand B (4.706) is slightly high, potentially leading to solubility issues and off-target effects.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are below the threshold of 10.

**QED:** Both ligands have similar QED values (0.664 and 0.639), indicating good drug-likeness.

**DILI:** Ligand A (15.238) has a significantly lower DILI risk than Ligand B (49.399), which is a major advantage.

**BBB:** Ligand A (92.555) has better BBB penetration than Ligand B (79.217), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2:** Ligand A (-4.726) and Ligand B (-5.031) both have negative Caco-2 values, indicating poor permeability.

**Solubility:** Ligand A (-2.345) has better solubility than Ligand B (-4.247).

**hERG:** Ligand A (0.659) has a lower hERG risk than Ligand B (0.838), which is desirable.

**Microsomal Clearance:** Ligand A (65.255) has higher microsomal clearance than Ligand B (52.301), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (16.306) has a significantly longer half-life than Ligand A (2.697), which is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.317) has lower P-gp efflux than Ligand B (0.72), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a >1.5 kcal/mol advantage and is a critical factor.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.6 vs -6.2 kcal/mol) is the most important factor. While it has some drawbacks (higher logP, higher DILI, lower solubility, lower Caco-2), the potency advantage likely outweighs these concerns, especially for a kinase inhibitor where achieving sufficient target engagement is paramount. The longer half-life of Ligand B is also a significant benefit. Ligand A has better safety profiles (DILI, hERG) and solubility, but the binding affinity is considerably weaker.

Output:
1
2025-04-17 14:52:12,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.861 and 375.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.01) is slightly higher than the preferred <140, but acceptable. Ligand B (71.84) is well within the range.

**logP:** Ligand A (1.199) is optimal. Ligand B (3.163) is also within the optimal range, but closer to the upper limit.

**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 guidelines.

**QED:** Both ligands have similar QED values (0.812 and 0.78), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (80.729 and 77.045), which is moderately high, but not disqualifying at this stage.

**BBB:** Ligand A (51.066) and Ligand B (76.425) both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.555 and -5.14), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.38 and -3.978), indicating poor aqueous solubility. This is also a significant concern.

**hERG Inhibition:** Ligand A (0.138) has a very low hERG risk, which is excellent. Ligand B (0.617) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-3.071) has a negative clearance, which is not physically possible and likely indicates a very stable compound. Ligand B (56.972) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-0.981) has a negative half-life, which is not physically possible and likely indicates a very stable compound. Ligand B (32.043) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.059 and 0.213).

**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.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.1 vs -7.3 kcal/mol) outweighs the concerns about permeability and solubility, especially for a kinase inhibitor where potency is paramount. The negative values for clearance and half-life for Ligand A are suspect, but suggest potentially excellent metabolic stability. Ligand A also has a lower hERG risk. Ligand B's moderate clearance and half-life are less favorable.

Output:
0
2025-04-17 14:52:12,374 - INFO - Batch 332 complete. Total preferences: 5312
2025-04-17 14:52:12,374 - INFO - Processing batch 333/512...
2025-04-17 14:52:52,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.475 and 361.555 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is better than Ligand B (46.09), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (1.398) is optimal (1-3), while Ligand B (4.536) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**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 acceptable QED scores (0.763 and 0.638, both > 0.5).

**7. DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (41.877), placing it in a much more favorable category.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.015) has better BBB penetration than Ligand A (54.983), but it's not a primary concern here.

**9. Caco-2 Permeability:** Ligand A (-4.785) has a better Caco-2 permeability than Ligand B (-5.102).

**10. Aqueous Solubility:** Ligand A (-2.553) has better solubility than Ligand B (-4.082).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.272 and 0.474).

**12. Microsomal Clearance:** Ligand A (30.777) has significantly lower microsomal clearance than Ligand B (122.139), indicating better metabolic stability. This is a key factor for enzymes.

**13. In vitro Half-Life:** Ligand A (4.191) has a longer in vitro half-life than Ligand B (-1.291).

**14. P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux than Ligand B (0.539).

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

**Overall Assessment:**

Ligand A is superior due to its better ADME properties. It has lower DILI risk, better solubility, lower microsomal clearance (higher metabolic stability), longer half-life, and lower P-gp efflux. While Ligand B has slightly better BBB penetration, this is not a priority for SRC kinase, which is not a CNS target. The similar binding affinity makes the ADME advantages of Ligand A decisive.

Output:
0
2025-04-17 14:52:52,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.486 and 370.343 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (64.68) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.87) is still under 140, but less optimal than A.

**logP:** Ligand A (0.773) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.434) is even lower, raising more concern about permeability.

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

**QED:** Both ligands have QED values above 0.5 (0.674 and 0.608), indicating good drug-likeness.

**DILI:** Ligand A (5.7) has a very low DILI risk, which is excellent. Ligand B (22.838) has a moderate DILI risk, but still acceptable.

**BBB:** Both ligands have good BBB penetration (75.145 and 77.898), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.297) and Ligand B (-4.832) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is concerning, but we must consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.886 and -1.198), indicating poor solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.627) has a lower hERG risk than Ligand B (0.384), which is preferable.

**Microsomal Clearance:** Ligand A (-38.455) has a much lower (better) microsomal clearance than Ligand B (-3.302), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.352) has a longer in vitro half-life than Ligand B (-23.554), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.035).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.3 and -7.7 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't heavily favor one over the other.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. It has a significantly better DILI score, lower hERG risk, and *much* better metabolic stability (lower Cl_mic and longer t1/2). While both have poor solubility and permeability, the metabolic advantage of Ligand A is crucial for an enzyme target. Poor solubility can sometimes be addressed with formulation strategies, but poor metabolic stability is much harder to fix later in development.

Output:
0
2025-04-17 14:52:52,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (75.71).  A TPSA under 140 is good for oral absorption, and both are under, but lower is generally preferred.

**logP:** Both ligands have good logP values (1.969 and 1.729), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 4 HBA). Lower counts are generally preferable for permeability.

**QED:** Both ligands have acceptable QED scores (0.692 and 0.74), indicating good drug-like properties.

**DILI:** Ligand A (13.532) has a much lower DILI risk than Ligand B (36.332). This is a significant advantage.

**BBB:** Ligand A (85.459) has a higher BBB percentile than Ligand B (53.238), though this isn't a primary concern for a non-CNS target like SRC.

**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 interpret this as very low permeability.

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

**hERG:** Ligand A (0.467) has a lower hERG risk than Ligand B (0.161), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (49.182) has higher microsomal clearance than Ligand B (30.234). Lower clearance is better for metabolic stability, so Ligand B is favored here.

**In vitro Half-Life:** Ligand A (-1.428) has a longer in vitro half-life than Ligand B (-14.776). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.2) has lower P-gp efflux than Ligand B (0.172), which is slightly favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.5 kcal/mol). This difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better hERG profile, longer half-life, and lower TPSA. While both have issues with Caco-2 and solubility, the safety and PK advantages of Ligand A are more critical for an enzyme target like SRC. The slightly better metabolic stability of Ligand B is not enough to compensate for the other drawbacks.

Output:
1
2025-04-17 14:52:52,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.5 & 382.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (95.42). Both are below 140, supporting good oral absorption.

**logP:** Both ligands (2.168 & 2.404) are 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 6. Both are acceptable, being under 10.

**QED:** Both ligands have good QED scores (0.776 & 0.827), indicating drug-like properties.

**DILI:** Ligand A (43.622) has a significantly lower DILI risk than Ligand B (78.286). This is a major advantage.

**BBB:** Ligand A (53.974) has a better BBB penetration score than Ligand B (30.438), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.818) is slightly better than Ligand B (-4.939), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.682) is slightly better than Ligand B (-3.395).

**hERG:** Both ligands have very low hERG inhibition liability (0.159 & 0.138), which is excellent.

**Microsomal Clearance:** Ligand B (34.169) has a slightly higher microsomal clearance than Ligand A (30.491), implying slightly lower metabolic stability.

**In vitro Half-Life:** Ligand A (23.411) has a longer in vitro half-life than Ligand B (15.453), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.068 & 0.084).

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.1). This is a 0.9 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better DILI, solubility, half-life and BBB scores, the significantly superior binding affinity of Ligand B (-9.0 kcal/mol vs -8.1 kcal/mol) is the deciding factor for an enzyme target like SRC kinase. The 0.9 kcal/mol difference is large enough to potentially overcome the slightly higher DILI risk and lower half-life of Ligand B. The poor Caco-2 and solubility are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:52:52,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (438.631 Da) is slightly higher than Ligand B (350.511 Da), but both are acceptable.

**TPSA:** Ligand A (46.5) is well below the 140 threshold, and good for oral absorption. Ligand B (59.31) is also acceptable, though slightly higher.

**logP:** Ligand A (4.85) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.92) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (0 HBD, 7 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar and good QED values (0.729 and 0.749, respectively), indicating good drug-like properties.

**DILI:** Ligand A (78.945) has a significantly higher DILI risk than Ligand B (15.2). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (87.553) has a higher BBB value, but it's not crucial here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.653 and -4.761), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.723 and -1.58). This is a major issue that would need to be addressed.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.545 and 0.546), which is positive.

**Microsomal Clearance:** Ligand A (58.923) has a higher microsomal clearance than Ligand B (25.838), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (7.331 hours) has a significantly longer in vitro half-life than Ligand A (24.751). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.595 and 0.073), which is favorable.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). However, the difference (0.5 kcal/mol) is not substantial enough to outweigh the significant ADME liabilities of Ligand A.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising candidate. Ligand A has a significantly higher DILI risk, poorer metabolic stability (higher Cl_mic), and lower in vitro half-life. Both have poor solubility and permeability, but the ADME profile of Ligand B is considerably better overall. The small difference in binding affinity is not enough to overcome the substantial drawbacks of Ligand A.

Output:
1
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.435 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.33) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (67.67) is well within the ideal range.

**logP:** Ligand A (-0.72) is a bit low, potentially hindering permeability. Ligand B (1.484) is 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 (6) is acceptable. Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.528 and 0.758, respectively), indicating drug-like properties.

**DILI:** Ligand A (14.889) has a significantly lower DILI risk than Ligand B (38.116). This is a substantial advantage.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS effects are desired. Ligand B (66.615) has a higher BBB percentile than Ligand A (40.597).

**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 (0.126) has a very low hERG risk, a significant advantage. Ligand B (0.252) is also low, but higher than A.

**Microsomal Clearance:** Ligand A (4.32) has much lower microsomal clearance than Ligand B (17.859), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (27.741) has a longer half-life than Ligand B (9.751), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.005 and 0.041, respectively).

**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 and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity. However, Ligand A demonstrates superior ADMET properties: lower DILI risk, lower microsomal clearance, longer half-life, and a much lower hERG risk. While Ligand B's logP is better, Ligand A's other advantages, especially the lower DILI and improved metabolic stability, are crucial for kinase inhibitors. The negative solubility and Caco-2 values are concerning for both, but the difference in binding affinity is significant. Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity, I would favor Ligand B despite its slightly worse ADMET profile.

Output:
1
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (354.479 and 344.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.77) is well below the 140 threshold and is favorable. Ligand B (87.12) is still under the threshold, but closer, and slightly less favorable.

**3. logP:** Ligand A (3.806) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.068) is at the lower end, which might 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 high QED scores (0.887 and 0.899), indicating good drug-like properties.

**7. DILI:** Ligand A (69.252) has a slightly higher DILI risk than Ligand B (61.07), but both are within an acceptable range (<60 is good, >60 is high risk).

**8. BBB:** Ligand A (65.297) has a better BBB percentile than Ligand B (38.658). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability.

**10. Solubility:** Ligand A (-4.411) has very poor solubility. Ligand B (-1.686) has slightly better solubility, but still poor.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.13 and 0.18), which is excellent.

**12. Cl_mic:** Ligand B (21.826) has significantly lower microsomal clearance than Ligand A (37.418), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. t1/2:** Ligand B (-3.794) has a negative in vitro half-life, which is not possible and indicates an issue with the data. Ligand A (8.591) has a reasonable half-life.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.155 and 0.033).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's a noticeable advantage.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B appears more promising despite the questionable half-life data. Its significantly lower Cl_mic suggests better metabolic stability, and its slightly better binding affinity is a plus. The solubility is still poor for both, but Ligand B is slightly better. The negative half-life for Ligand B is a major red flag and needs to be investigated. However, assuming this is a data error, the other factors favor Ligand B.

Output:
1
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (390.483 and 387.263 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.01) is higher than Ligand B (71.78). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good oral absorption.

**logP:** Ligand A (-0.36) is quite low, potentially hindering permeability. Ligand B (2.637) 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 4 HBA. Both are within acceptable limits, but Ligand B has fewer, which generally favors permeability.

**QED:** Both ligands have similar QED values (0.586 and 0.577), indicating good drug-likeness.

**DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (49.283), though both are reasonably acceptable.

**BBB:** Ligand A (32.183) has a low BBB penetration, while Ligand B (75.107) is much higher. This isn't a primary concern for a non-CNS target like SRC, but it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-5.74) has poor Caco-2 permeability, while Ligand B (-4.729) is better, though still not great.

**Aqueous Solubility:** Ligand A (-1.167) has very poor solubility, a major concern. Ligand B (-3.88) is also poor, but less so than Ligand A.

**hERG Inhibition:** Ligand A (0.194) shows a slightly higher hERG risk than Ligand B (0.407), but both are relatively low.

**Microsomal Clearance:** Ligand A (-12.183) has a much lower (better) microsomal clearance than Ligand B (26.935), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.755) has a shorter half-life than Ligand B (50.443), which is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux than Ligand B (0.225), which is favorable.

**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.

**Conclusion:**

While Ligand A has better metabolic stability and lower P-gp efflux, its poor solubility, low Caco-2 permeability, and significantly weaker binding affinity are major drawbacks. Ligand B, despite having slightly worse metabolic stability and higher P-gp efflux, possesses a much better logP, TPSA, Caco-2 permeability, solubility, and, crucially, a significantly improved binding affinity. The stronger binding affinity of Ligand B is a critical advantage for an enzyme inhibitor.

Output:
1
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.491 and 362.901 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.87) is better than Ligand B (38.5). Lower TPSA generally improves cell permeability.

**logP:** Ligand A (2.137) is optimal, while Ligand B (4.358) is approaching the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as some H-bond donors can aid solubility.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range.

**QED:** Both ligands have similar QED values (0.61 and 0.629), indicating good drug-likeness.

**DILI:** Ligand A (20.279) has a significantly lower DILI risk than Ligand B (15.2), which is a major advantage.

**BBB:** Ligand B (85.033) has a higher BBB penetration percentile than Ligand A (66.344), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.425 and -4.786). This is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Ligand A (-1.968) has better aqueous solubility than Ligand B (-4.606).

**hERG Inhibition:** Ligand A (0.296) shows a much lower hERG inhibition liability than Ligand B (0.946), a critical safety parameter.

**Microsomal Clearance:** Ligand B (87.092) has a higher microsomal clearance than Ligand A (49.764), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (59.945) has a significantly longer in vitro half-life than Ligand A (1.779), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.023) exhibits lower P-gp efflux liability than Ligand B (0.683), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand B has a better binding affinity and longer half-life, Ligand A is superior in terms of safety (DILI, hERG) and ADME properties (logP, solubility, P-gp efflux). The significantly lower DILI and hERG risks for Ligand A are crucial for drug development. The slightly weaker binding affinity of Ligand A can potentially be optimized through further medicinal chemistry efforts. The poor Caco-2 permeability for both is concerning, but could be addressed with formulation strategies.

Output:
0
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.406 and 346.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.66) is slightly higher than Ligand B (49.41). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (1.183) is within the optimal range, while Ligand B (3.36) is approaching the upper limit.

**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:** Both ligands have similar QED values (0.752 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A (40.132) has a slightly higher DILI risk than Ligand B (10.508), but both are below the concerning threshold of 60.

**BBB:** Both have reasonable BBB penetration, with Ligand B (74.758) being slightly better than Ligand A (65.607). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.755 and -4.629), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.528 and -3.666), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.338 and 0.364).

**Microsomal Clearance:** Ligand A (20.527) has lower microsomal clearance than Ligand B (27.354), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.983) has a slightly longer in vitro half-life than Ligand B (-6.216).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.127).

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity, their poor solubility and permeability are major drawbacks. Considering the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) is crucial. Ligand A has a better metabolic profile (lower Cl_mic, longer t1/2) and a slightly lower DILI risk. However, the solubility and permeability issues are so significant that they would likely hinder *in vivo* efficacy for both.

Despite the shared issues, Ligand A's slightly improved metabolic stability and lower DILI risk make it marginally preferable.

Output:
0
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.426 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.7) is excellent, well below the 140 threshold for oral absorption. Ligand B (67.23) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.719) is at the upper end of the optimal range (1-3), while Ligand B (1.88) is towards the lower end. While Ligand B's logP is acceptable, a slightly higher value can sometimes improve membrane permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and Ligand A has 3 HBA and Ligand B has 5 HBA, both within the guidelines.

**QED:** Both ligands have good QED scores (0.924 and 0.812), indicating drug-like properties.

**DILI:** Ligand A (9.228) has a very low DILI risk, significantly better than Ligand B (52.423), which is moderate. This is a crucial advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (90.074) has a higher value than Ligand B (47.926).

**Caco-2 Permeability:** Ligand A (-4.707) has poor Caco-2 permeability, while Ligand B (-5.413) is also poor. This is a potential issue for both, but less critical if the compound shows good potency and metabolic stability.

**Aqueous Solubility:** Ligand A (-3.175) and Ligand B (-2.539) both have poor aqueous solubility. This could pose formulation challenges, but can be addressed with salt formation or other techniques.

**hERG Inhibition:** Ligand A (0.994) has a very low hERG risk, while Ligand B (0.136) has a low hERG risk. Both are good.

**Microsomal Clearance:** Ligand A (40.897) has a lower microsomal clearance than Ligand B (62.816), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (5.454) has a shorter half-life than Ligand B (13.981). This is a drawback for Ligand A, but could be mitigated by formulation or dosing strategies.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.975 and 0.181).

**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:**

Ligand B's significantly higher binding affinity (-8.5 kcal/mol vs 0.0 kcal/mol) is a decisive factor. While Ligand A has better DILI and metabolic stability, the potency advantage of Ligand B is substantial for an enzyme target like SRC kinase. The moderate DILI risk and lower metabolic stability of Ligand B can be addressed during lead optimization. The poor Caco-2 and solubility of both compounds are concerns, but can be tackled with formulation strategies.

Output:
1
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.443 and 348.422 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.87 and 75.19) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.849) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (2.329) is within the 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 (4) meet the HBA <= 10 criteria.

**6. QED:** Both ligands have good QED scores (0.551 and 0.829), indicating drug-like properties.

**7. DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (54.401). This is a major advantage for Ligand A.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (85.653) has better BBB penetration than Ligand A (28.848).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual, but we can assume they are percentile scores. Ligand A (-4.734) is worse than Ligand B (-4.421).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-1.705) is better than Ligand B (-2.687).

**11. hERG Inhibition:** Ligand A (0.098) has a very low hERG inhibition risk, while Ligand B (0.276) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (2.18 mL/min/kg) has significantly lower microsomal clearance than Ligand B (39.051 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (-1.53 hours) has a negative half-life, which is unusual, and worse than Ligand B (-10.98 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.033).

**15. Binding Affinity:** Ligand B (-7.0 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:**

While Ligand B boasts a much stronger binding affinity, Ligand A has a significantly better safety profile (lower DILI) and metabolic stability (lower Cl_mic). The higher affinity of Ligand B is attractive, but the higher DILI and clearance are concerning. Given that SRC kinases are intracellular targets, metabolic stability and minimizing off-target effects (reflected in DILI) are particularly important. The substantial difference in binding affinity (-7.0 vs 0.0) is a major factor.

Output:
1
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.64) is well below the 140 threshold, suggesting good absorption. Ligand B (118.89) is still within acceptable limits, but less optimal.

**logP:** Ligand A (1.538) is within the optimal 1-3 range. Ligand B (-0.152) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=5, HBA=5) is at the upper limit for HBD, potentially impacting permeability.

**QED:** Ligand A (0.79) has a strong drug-like profile. Ligand B (0.388) is significantly lower, indicating a less desirable overall drug-likeness.

**DILI:** Ligand A (7.135) has a very low DILI risk. Ligand B (15.083) has a moderate DILI risk, but still within acceptable bounds.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (68.67) and Ligand B (32.687) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.767) and Ligand B (-5.357) 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 (-1.303 and -1.088). This is also unusual and indicates very poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Ligand A (0.474) has a low hERG risk. Ligand B (0.066) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (-11.659) has a very *low* (highly desirable) microsomal clearance, indicating excellent metabolic stability. Ligand B (-6.394) also has a low clearance, but not as favorable as Ligand A.

**In vitro Half-Life:** Ligand A (2.889) has a short half-life. Ligand B (-0.95) 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 have very low P-gp efflux liability (0.02 and 0.015).

**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 concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from lower QED, a slightly higher DILI risk, and a problematic negative in vitro half-life. Ligand A has better overall ADME properties (QED, DILI, Cl_mic), but its binding affinity is extremely weak. The poor solubility and permeability for both are concerning, but the superior potency of Ligand B is likely to be more readily addressed through further optimization.

Output:
1
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.31) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (80.56) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (1.308) is within the optimal 1-3 range. Ligand B (0.258) is a bit low, potentially impacting membrane permeability.

**H-Bond Donors:** Ligand A has 3 HBDs, which is acceptable. Ligand B has 0, which is also acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBAs, within the acceptable limit of 10. Ligand B has 7 HBAs, also within the limit.

**QED:** Both ligands have good QED scores (0.706 and 0.759), indicating drug-like properties.

**DILI:** Ligand A (72.47) has a slightly higher DILI risk than Ligand B (68.825), but both are still reasonably low.

**BBB:** Both ligands have moderate BBB penetration (55.215 and 64.637). Since SRC is not a CNS target, this is not a major concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.597 and -4.966). This is unusual and suggests poor permeability *in vitro*. It's important to note that negative values can occur in these models and don't necessarily translate directly to *in vivo* poor absorption, but it's a flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.982 and -1.792). Similar to Caco-2, negative values are unusual and indicate very low solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.052 and 0.127), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (37.987 and 38.349 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A has a slightly negative half-life (-0.61), while Ligand B has a positive one (0.558). This suggests Ligand B might have slightly better *in vitro* stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.085).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly better binding affinity than Ligand A (-8.8 kcal/mol). This 0.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.1 vs -8.8 kcal/mol) is a key advantage for an enzyme target like SRC kinase. While its logP is a bit low, the other ADME properties are comparable or better than Ligand A, and the hERG risk is very low for both. The slightly better half-life of Ligand B is also a positive. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the potency advantage of Ligand B makes it the better starting point.

Output:
1
2025-04-17 14:52:52,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.296 and 353.329 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.23) is better than Ligand B (81.39), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.594 and 1.416), within the optimal 1-3 range. Ligand A is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=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.

**QED:** Both ligands have high QED scores (0.81 and 0.885), indicating good drug-like properties.

**DILI:** Ligand A (76.076) has a lower DILI risk than Ligand B (90.733). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.649) is slightly better than Ligand B (68.205).

**Caco-2 Permeability:** Both have negative values (-4.566 and -4.528), indicating poor permeability. This is a concern for both, but similar.

**Aqueous Solubility:** Both have negative values (-4.026 and -3.084), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.394) shows lower hERG inhibition risk than Ligand B (0.141). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (55.527) has higher microsomal clearance than Ligand B (-7.211). Ligand B exhibits negative clearance, which is highly favorable, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-29.913) has a negative half-life, which is not possible. Ligand B (-2.726) has a negative half-life, which is also not possible. Both are problematic.

**P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux than Ligand B (0.032), which is preferable.

**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 could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, and much better metabolic stability (lower Cl_mic). However, it has a higher DILI risk, worse hERG, and poorer P-gp efflux. Ligand A has better solubility, lower DILI, and lower hERG risk. The difference in binding affinity is large enough to potentially overcome the slightly worse ADME profile of Ligand B. Given the importance of potency for kinase inhibitors, and the relatively manageable ADME issues with Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 14:52:52,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.414 and 364.563 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.32) is slightly above the preferred <140, but acceptable. Ligand B (79.96) is well within the acceptable range.

**logP:** Both ligands have logP values (2.369 and 3.701) within the optimal 1-3 range. Ligand B is closer to the upper limit, which could potentially raise concerns about off-target effects, but not critically.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 7 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.628 and 0.796), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (62.505 and 62.66), placing them in a moderate risk category. This isn't ideal, but not a dealbreaker at this stage.

**BBB:** Ligand A (39.007) has a low BBB penetration percentile, while Ligand B (84.141) has a high one. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.344 and -5.157) which is unusual and suggests poor permeability. This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.321 and -5.067). This is a major drawback and could severely limit bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.445 and 0.633), which is positive.

**Microsomal Clearance:** Ligand A (50.11 mL/min/kg) has a moderate clearance, while Ligand B (84.923 mL/min/kg) has a higher clearance. Lower clearance is preferred for metabolic stability, so Ligand A is better here.

**In vitro Half-Life:** Ligand A (-18.002 hours) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (26.511 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.178 and 0.162), which is good.

**Binding Affinity:** Ligand A (-7.8 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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-7.8 vs -6.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. While Ligand B has a better half-life and BBB, these are less critical for this target. The negative half-life reported for Ligand A is a data quality issue that would need to be investigated. However, assuming the binding affinity is accurate, Ligand A is the better starting point for optimization, focusing on improving solubility and permeability.

Output:
0
2025-04-17 14:52:52,598 - INFO - Batch 333 complete. Total preferences: 5328
2025-04-17 14:52:52,598 - INFO - Processing batch 334/512...
2025-04-17 14:53:46,829 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.5 and 356.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold for good absorption. Ligand B (116.84) is still within acceptable limits, but higher.

**logP:** Ligand A (1.873) is optimal. Ligand B (-0.244) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is acceptable, but higher.

**QED:** Ligand A (0.773) is very good, indicating high drug-likeness. Ligand B (0.499) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (13.3) has a very low DILI risk. Ligand B (35.014) is higher, but still within a reasonable range.

**BBB:** Both ligands have similar BBB penetration (66.344 and 68.205), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.547) has poor Caco-2 permeability. Ligand B (-5.305) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.668) has poor solubility. Ligand B (-0.859) is slightly better, but still low.

**hERG:** Both ligands have very low hERG risk (0.176 and 0.102).

**Microsomal Clearance:** Ligand A (26.644) has moderate clearance. Ligand B (23.054) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.837) has a long half-life. Ligand B (-21.779) has an even longer half-life, which is very desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.026 and 0.006).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is not substantial.

**Overall Assessment:**

Ligand B is more promising. While both have poor Caco-2 and solubility, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and lower DILI risk outweigh the slightly less optimal logP and TPSA. Ligand A's poor Caco-2 permeability is a significant concern. The longer half-life of Ligand B is a substantial benefit for an enzyme inhibitor.

Output:
1
2025-04-17 14:53:46,829 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 358.473 Da - Within the ideal range (200-500 Da).
* Ligand B: 382.917 Da - Also within the ideal range.
* *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 58.2  - Excellent, well below the 140 threshold for oral absorption.
* Ligand B: 67.23 - Still good, below 140, but higher than A.
* *Ligand A has a slight advantage.*

**3. Lipophilicity (logP):**
* Ligand A: 3.302 - Optimal, within the 1-3 range.
* Ligand B: 1.96 - Acceptable, but closer to the lower limit, potentially impacting permeability.
* *Ligand A has a clear advantage.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Meets the <=5 criteria.
* Ligand B: 1 - Meets the <=5 criteria.
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 2 - Meets the <=10 criteria.
* Ligand B: 5 - Meets the <=10 criteria.
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.629 - Good drug-like profile (>=0.5).
* Ligand B: 0.808 - Excellent drug-like profile.
* *Ligand B has a slight advantage.*

**7. DILI:**
* Ligand A: 15.316 - Low risk of liver injury (<40 is good).
* Ligand B: 59.984 - Moderate risk, approaching the higher risk threshold.
* *Ligand A has a significant advantage.*

**8. BBB:**
* Ligand A: 85.847 - High, suggesting good potential for CNS penetration (though not a primary concern for SRC).
* Ligand B: 51.842 - Lower, less likely to cross the BBB.
* *Ligand A has a clear advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -4.627 - Negative values are unusual and suggest very poor permeability.
* Ligand B: -5.063 - Also poor permeability, but slightly worse than A.
* *Ligand A has a slight advantage.*

**10. Aqueous Solubility:**
* Ligand A: -3.591 - Poor aqueous solubility.
* Ligand B: -3.614 - Also poor aqueous solubility, similar to A.
* *No clear advantage.*

**11. hERG Inhibition:**
* Ligand A: 0.504 - Low risk of hERG inhibition.
* Ligand B: 0.367 - Very low risk of hERG inhibition.
* *Ligand B has a slight advantage.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 45.326 mL/min/kg - Moderate clearance, suggesting moderate metabolic stability.
* Ligand B: 37.172 mL/min/kg - Lower clearance, suggesting better metabolic stability.
* *Ligand B has a slight advantage.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 6.877 hours - Reasonable half-life.
* Ligand B: -26.36 hours - Negative half-life is not physically possible, indicating a data error or unusual behavior.
* *Ligand A has a significant advantage.*

**14. P-gp Efflux:**
* Ligand A: 0.122 - Low P-gp efflux, good.
* Ligand B: 0.207 - Higher P-gp efflux, less favorable.
* *Ligand A has a clear advantage.*

**15. Binding Affinity:**
* Ligand A: -6.4 kcal/mol - Good binding affinity.
* Ligand B: -8.4 kcal/mol - Excellent binding affinity, 2 kcal/mol stronger than A.
* *Ligand B has a significant advantage.*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability, solubility, and hERG risk are key. While Ligand B boasts a significantly stronger binding affinity (-8.4 vs -6.4 kcal/mol), which is a major plus, it has concerning issues with DILI risk and a nonsensical half-life value. Ligand A has a more balanced profile, with acceptable affinity, lower DILI risk, better BBB penetration, and a reasonable half-life. The poor Caco-2 and solubility for both are drawbacks, but can potentially be addressed through formulation strategies.

Given the questionable half-life of Ligand B and its higher DILI risk, I would prioritize **Ligand A** as the more viable drug candidate. The stronger affinity of Ligand B is tempting, but the safety and PK concerns are too significant to ignore at this stage.

Output:
0
2025-04-17 14:53:46,829 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.684 Da) is slightly higher than Ligand B (353.419 Da), but both are acceptable.

**TPSA:** Ligand A (42.31) is significantly better than Ligand B (104.9). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (4.345) is higher than Ligand B (0.515). While 4.345 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 (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Fewer hydrogen bonds can improve permeability.

**QED:** Both ligands have good QED scores (A: 0.549, B: 0.74), indicating good drug-like properties.

**DILI:** Ligand A (62.001) has a higher DILI risk than Ligand B (27.065). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.71) has better BBB penetration than Ligand B (49.011), but this isn't a primary driver in this case.

**Caco-2 Permeability:** Ligand A (-4.284) is better than Ligand B (-4.596), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.794) is better than Ligand B (-1.5). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.695) has a lower hERG risk than Ligand B (0.255), which is a significant advantage.

**Microsomal Clearance:** Ligand A (89.063) has a higher microsomal clearance than Ligand B (35.09). This suggests Ligand B is more metabolically stable, which is desirable.

**In vitro Half-Life:** Ligand A (62.13) has a longer half-life than Ligand B (-6.659), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.775) has higher P-gp efflux than Ligand B (0.012). Lower P-gp efflux is preferred, making Ligand B slightly better here.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). The 1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better TPSA, solubility, hERG risk, Caco-2 permeability, and half-life. However, it has a higher DILI risk and higher P-gp efflux. Ligand B has better metabolic stability (lower Cl_mic) and lower DILI risk, but its logP is very low, and its TPSA is high, potentially hindering permeability. The difference in binding affinity between A and B is substantial. Given the enzyme-specific priorities, the stronger binding affinity of Ligand A, coupled with acceptable (though not ideal) ADME properties, makes it the more promising candidate. The DILI risk of Ligand A could be addressed through structural modifications in subsequent optimization rounds.

Output:
1
2025-04-17 14:53:46,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.47 and 365.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is well below the 140 threshold for oral absorption, and is favorable. Ligand B (108.49) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.457) is within the optimal 1-3 range. Ligand B (0.469) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both within acceptable limits. Ligand B has 1 HBD and 7 HBA, also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.677 and 0.764), indicating drug-like properties.

**DILI:** Ligand A (42.071) has a lower DILI risk than Ligand B (73.245), which is a significant advantage.

**BBB:** Ligand A (69.523) has a moderate BBB penetration, while Ligand B (32.222) has low BBB penetration. This isn't a primary concern for a non-CNS target like SRC, but it's a data point.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.944 and -5.047). These values are unusual and suggest poor permeability. However, these values are on a log scale and negative values are not uncommon.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.739 and -1.912). These values are also unusual and suggest poor solubility.

**hERG Inhibition:** Ligand A (0.513) has a slightly higher hERG risk than Ligand B (0.279), but both are relatively low.

**Microsomal Clearance:** Ligand A (54.514) has a higher microsomal clearance than Ligand B (24.853), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-25.328) has a much longer in vitro half-life than Ligand A (-6.717), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.189 and 0.03).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), a difference of 1.0 kcal/mol. While a 1.5 kcal/mol advantage is considered substantial, 1.0 kcal/mol is less decisive.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a lower hERG risk. The slightly lower logP of Ligand B is a minor concern, but is outweighed by the other advantages. The unusual negative Caco-2 and solubility values for both compounds warrant further investigation, but do not immediately disqualify Ligand B.

Output:
1
2025-04-17 14:53:46,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.864 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (86.88). Lower TPSA generally favors better absorption.

**logP:** Ligand A (4.04) is at the upper end of the optimal range, while Ligand B (2.1) is closer to the lower end. While 4.04 isn't ideal, it's not drastically problematic.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=3). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have acceptable QED values (A: 0.797, B: 0.631), indicating good drug-like properties.

**DILI:** Ligand A (46.258) has a slightly higher DILI risk than Ligand B (34.161), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.172) has a higher BBB percentile than Ligand B (53.974).

**Caco-2:** Ligand A (-4.267) is better than Ligand B (-5.304). Higher values indicate better intestinal absorption.

**Solubility:** Ligand A (-4.935) is better than Ligand B (-2.557). Higher solubility is crucial for bioavailability.

**hERG:** Ligand A (0.46) has a significantly lower hERG risk than Ligand B (0.18). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (114.945) has a higher clearance than Ligand B (15.721), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-4.036) has a longer half-life than Ligand A (15.632), indicating better stability.

**P-gp Efflux:** Ligand A (0.467) has lower P-gp efflux than Ligand B (0.134), which is favorable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has better solubility and lower hERG risk, the stronger binding affinity of Ligand B is a critical advantage for an enzyme inhibitor. The difference in binding affinity is substantial enough to compensate for the slightly higher DILI and lower solubility of Ligand B.

Output:
1
2025-04-17 14:53:46,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (344.342 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is well below the 140 threshold for oral absorption, while Ligand B (95.74) is still acceptable but closer to the limit.

**logP:** Ligand A (2.869) is optimal (1-3). Ligand B (0.48) is slightly low, potentially hindering permeability.

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

**QED:** Both ligands have good QED scores (0.836 and 0.752), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (88.639 percentile), which is a significant concern. Ligand B has a very low DILI risk (12.33 percentile), a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (74.254) is better than Ligand B (43.311).

**Caco-2 Permeability:** Ligand A (-4.619) has poor Caco-2 permeability, while Ligand B (-5.378) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.862) has poor solubility, while Ligand B (-1.58) is better, though still not great.

**hERG:** Both ligands have very low hERG inhibition liability (0.58 and 0.101), which is excellent.

**Microsomal Clearance:** Ligand A (79.761) has moderate clearance, while Ligand B (-6.2) has *very* low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (29.024 hours) has a reasonable half-life, while Ligand B (-7.723 hours) has a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.247 and 0.005).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.7 and -7.6 kcal/mol). Ligand A is significantly more potent.

**Conclusion:**

Despite Ligand A's superior binding affinity, its high DILI risk and poor solubility/permeability are major drawbacks. Ligand B, while having slightly lower affinity, exhibits a much more favorable safety profile (low DILI), excellent metabolic stability (very low Cl_mic), and better solubility. The difference in binding affinity (2.1 kcal/mol) is substantial, but the ADME/Tox profile of Ligand A is concerning enough to outweigh this benefit. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 14:53:46,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.519 Da) is slightly higher than Ligand B (367.391 Da), but both are acceptable.

**TPSA:** Ligand A (72.47) is well below the 140 threshold for oral absorption. Ligand B (127.36) is still within acceptable limits but closer to the threshold.

**logP:** Ligand A (3.438) is optimal. Ligand B (-0.243) is significantly below the optimal range and could indicate poor permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is excellent. Ligand B (0 HBD, 9 HBA) is also acceptable, though slightly higher HBA could potentially affect permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.832, Ligand B: 0.523), indicating drug-like properties.

**DILI:** Ligand A (70.609) has a moderate DILI risk, while Ligand B (87.204) has a higher risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.482) and Ligand B (54.634) are both relatively low.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.96) is better than Ligand B (-5.193), indicating slightly better absorption.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-3.655) is better than Ligand B (-2.296), suggesting better solubility.

**hERG:** Ligand A (0.606) has a lower hERG risk than Ligand B (0.24), which is a significant advantage.

**Microsomal Clearance:** Ligand A (33.634) has a higher clearance than Ligand B (2.509), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (82.011) has a longer half-life than Ligand B (-23.299), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.423) has lower P-gp efflux liability than Ligand B (0.036), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This 1.5 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, it has significant drawbacks in logP (poor permeability), DILI risk, and metabolic stability (high clearance, short half-life). Ligand A has a more balanced profile with acceptable permeability, lower toxicity risk, better metabolic stability, and good solubility, despite slightly weaker binding.

Considering the enzyme-specific priorities, the improved metabolic stability and reduced toxicity of Ligand A are crucial. While the affinity difference is notable, it's not so large that it completely overrides the ADME concerns with Ligand B. Therefore, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 14:53:46,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.45) is slightly higher than Ligand B (75.27). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Ligand A (0.308) is quite low, potentially hindering permeation. Ligand B (2.502) 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, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.666) has a slightly better QED score than Ligand B (0.524), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 38.736, Ligand B: 41.605), below the 60 threshold.

**BBB:** Both have similar BBB penetration (Ligand A: 62.97, Ligand B: 60.566). BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.629 and -4.68), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.627 and -3.736), indicating extremely poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both have very low hERG inhibition risk (Ligand A: 0.075, Ligand B: 0.136). This is excellent.

**Microsomal Clearance:** Ligand A (19.696) has significantly lower microsomal clearance than Ligand B (47.116), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-28.555) has a negative half-life, which is not physically possible and suggests a data error or a very rapidly metabolized compound. Ligand B (-43.615) also has a negative half-life, indicating a similar issue.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.004, Ligand B: 0.18).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much better logP and significantly stronger binding affinity. The lower logP of Ligand A is a major concern. While Ligand A has better metabolic stability (lower Cl_mic), the binding affinity difference is substantial. Both compounds have poor solubility and permeability, and negative half-lives, which are significant liabilities. However, the potency advantage of Ligand B is likely to be more impactful for an enzyme inhibitor.

Output:
1
2025-04-17 14:53:46,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (84.64). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**logP:** Both ligands (2.169 and 2.232) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 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 (0.724 and 0.869), indicating drug-like properties.

**DILI:** Ligand A (15.394) has a significantly lower DILI risk than Ligand B (41.179). This is a major advantage.

**BBB:** Ligand A (69.019) has a better BBB score than Ligand B (53.121), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.042) has a worse Caco-2 permeability than Ligand B (-4.667).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.911 and -2.97). This could pose formulation challenges, but is not a dealbreaker.

**hERG Inhibition:** Ligand A (0.221) has a lower hERG inhibition liability than Ligand B (0.427), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (34.32) has a better (lower) microsomal clearance than Ligand B (16.365), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.471) has a better (longer) half-life than Ligand B (6.146).

**P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux liability than Ligand B (0.097), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.9), a difference of 0.4 kcal/mol. While affinity is a priority, the difference isn't large enough to outweigh the other significant advantages of Ligand A.

**Overall:** Ligand A is the better candidate. It demonstrates a significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity and Caco-2 permeability, the safety and pharmacokinetic advantages of Ligand A are more important for an enzyme inhibitor.

Output:
0
2025-04-17 14:53:46,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.82 and 348.443 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.66) is well below the 140 threshold, suggesting good absorption. Ligand B (87.66) is also below the threshold, but higher than A, potentially indicating slightly reduced absorption.

**logP:** Ligand A (4.099) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.485) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.645 and 0.631), indicating good drug-likeness.

**DILI:** Ligand A (75.766) has a significantly higher DILI risk than Ligand B (20.396). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (77.007) is higher than Ligand B (56.378), but this is less relevant.

**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 (0.678) has a slightly higher hERG risk than Ligand B (0.301), but both are relatively low.

**Microsomal Clearance:** Ligand A (75.358) has a higher microsomal clearance than Ligand B (28.41), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-11.733) has a negative half-life, which is not possible. Ligand A (53.764) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.88) has higher P-gp efflux than Ligand B (0.1), suggesting lower bioavailability.

**Binding Affinity:** Ligand A (-7.0) has a slightly better binding affinity than Ligand B (-6.8), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B is significantly better due to its much lower DILI risk (20.4 vs 75.8), lower microsomal clearance (28.4 vs 75.4), and lower P-gp efflux (0.1 vs 0.88). While Ligand A has slightly better binding affinity, the ADME/Tox profile of Ligand B is far superior, making it a more viable drug candidate. The negative values for Caco-2 and solubility are concerning for both, but the other factors weigh heavily in favor of Ligand B.

Output:
1
2025-04-17 14:53:46,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.439 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.41) is significantly better than Ligand B (99.77).  A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.328 and 1.742), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (3 HBD, 4 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.846) has a better QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand A (30.787) has a much lower DILI risk than Ligand B (22.8). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (73.827) is better than Ligand B (64.017). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.377) is significantly better than Ligand B (-5.417). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.885) is better than Ligand B (-2.38). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.489) has a lower hERG risk than Ligand B (0.046), a critical safety parameter.

**Microsomal Clearance:** Ligand A (47.062) has higher microsomal clearance than Ligand B (27.571), meaning it is less metabolically stable. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-19.949) has a much longer in vitro half-life than Ligand A (-9.694), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.093) has slightly lower P-gp efflux than Ligand B (0.008). Lower efflux is preferable.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has significant advantages in terms of DILI risk, solubility, Caco-2 permeability, hERG risk, QED, and TPSA. While Ligand A has higher microsomal clearance and shorter half-life, the other factors strongly favor it. The binding affinity is comparable. Given the enzyme-kinase focus, the lower hERG risk and better solubility of Ligand A are particularly important.

Output:
1
2025-04-17 14:53:46,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.423 and 346.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (112.38) is slightly above the optimal <140, but acceptable. Ligand B (96.25) is excellent, well below 140.

**logP:** Ligand A (-1.104) is a bit low, potentially hindering permeability. Ligand B (0.596) is also on the lower side but better than A. Both are below the optimal 1-3 range.

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

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.6 and 0.727, respectively), indicating drug-likeness.

**DILI:** Ligand A (30.942) has a lower DILI risk than Ligand B (38.62), both are good (<40 is preferred).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (33.501) has a higher BBB percentile than Ligand A (22.334), but this isn't a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.367 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 (-0.726 and -2.199), which is also concerning. Poor solubility can hinder bioavailability. Ligand B is worse than A.

**hERG Inhibition:** Ligand A (0.062) has a very low hERG risk, which is excellent. Ligand B (0.289) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (0.675) has a lower Cl_mic, indicating better metabolic stability than Ligand B (6.09). This is a significant advantage.

**In vitro Half-Life:** Ligand A (2.884) has a shorter half-life than Ligand B (9.4), but both are relatively low.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.025), which is favorable.

**Binding Affinity:** Ligand B (-8.1 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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most critical factor for an enzyme inhibitor. While its solubility is worse than A, and its Cl_mic is higher, the substantial improvement in binding affinity is likely to be decisive. Both ligands have concerning permeability and solubility issues. However, these can potentially be addressed through formulation strategies. The lower hERG risk of Ligand A is a plus, but the potency of Ligand B is a stronger driver.

Output:
1
2025-04-17 14:53:46,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 360.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (62.55), but both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.58) is optimal, while Ligand B (3.373) is at the higher end of the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the ideal limit of <=5.

**H-Bond Acceptors:** Both ligands have 4 HBA, also within the ideal limit of <=10.

**QED:** Both ligands have good QED scores (0.788 and 0.909, respectively), indicating good drug-like properties.

**DILI:** Ligand A (14.618) has a significantly lower DILI risk than Ligand B (43.932). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (63.048 and 63.746), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.55) shows poor permeability, while Ligand B (-5.102) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.751) has better aqueous solubility than Ligand B (-3.561). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.279) has a lower hERG risk than Ligand B (0.636). This is another advantage for Ligand A.

**Microsomal Clearance:** Ligand A (24.829) has significantly lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (45.296).

**In vitro Half-Life:** Ligand B (36.564) has a longer in vitro half-life than Ligand A (9.905).

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux liability than Ligand B (0.434).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). The difference is 0.8 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a superior binding affinity, and a longer half-life. However, Ligand A demonstrates significantly better safety profiles with lower DILI and hERG risk, better solubility, and lower P-gp efflux. It also has better metabolic stability. The affinity difference, while notable, is not so large as to completely negate the substantial ADME/Tox advantages of Ligand A. Given the enzyme-specific priorities, the improved safety and metabolic stability of Ligand A make it a more promising drug candidate.

Output:
0
2025-04-17 14:53:46,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 362.543 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is better than Ligand B (61.88), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.511) is optimal (1-3), while Ligand B (4.569) is pushing the upper limit and could present solubility issues.

**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 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.777 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (11.128) has a significantly lower DILI risk than Ligand B (56.689). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (79.527 and 70.609), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.553) and Ligand B (-5.283) both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but B is worse.

**Aqueous Solubility:** Ligand A (-2.448) is better than Ligand B (-3.973), both are poor.

**hERG Inhibition:** Ligand A (0.282) has a much lower hERG inhibition liability than Ligand B (0.774). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand A (33.953) has lower microsomal clearance than Ligand B (55.099), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.278) has a negative half-life, which is concerning. Ligand B (30.066) has a positive half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux than Ligand B (0.758), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.6), a 0.8 kcal/mol difference. While affinity is a priority, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly lower DILI risk, lower hERG inhibition, and lower microsomal clearance. The negative half-life for Ligand A is a concern, but can potentially be addressed through structural modifications. The poor Caco-2 and solubility for both ligands are drawbacks that would need to be addressed, but Ligand A's profile is more amenable to optimization.

Output:
0
2025-04-17 14:53:46,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.813 Da) is slightly higher than Ligand B (364.515 Da), but both are acceptable.

**TPSA:** Ligand A (119.27) is borderline acceptable for oral absorption, while Ligand B (66.49) is well within the optimal range (<140).

**logP:** Ligand A (3.079) is optimal. Ligand B (1.93) is a little low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, fitting the guidelines. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.604, B: 0.838), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.549%), which is a major concern. Ligand B has a very low DILI risk (21.753%), a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (60.954%) and B (77.2%) are both reasonable.

**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 (-4.726) is worse than Ligand B (-5.099).

**Aqueous Solubility:** Ligand A (-5.029) has poor solubility, while Ligand B (-1.229) is better, but still not ideal.

**hERG:** Ligand A (0.215) has a slightly elevated hERG risk, while Ligand B (0.569) is higher. Both are within a range that requires further investigation, but Ligand B is worse.

**Microsomal Clearance:** Ligand B (-14.647) exhibits significantly lower microsomal clearance, indicating better metabolic stability, which is crucial for an enzyme target. Ligand A (23.512) has higher clearance.

**In vitro Half-Life:** Ligand B (33.703) has a longer in vitro half-life than Ligand A (111.637), further supporting its better metabolic stability. Note the units are reversed here.

**P-gp Efflux:** Ligand A (0.272) has lower P-gp efflux, which is favorable. Ligand B (0.03) has very low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.3 kcal/mol, B: -7.9 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its extremely high DILI risk and poor solubility are major red flags. Ligand B, while having a slightly lower affinity, exhibits significantly better ADME properties, particularly a low DILI risk and improved metabolic stability (lower Cl_mic and longer t1/2). Given the enzyme-specific priorities, metabolic stability and safety (DILI) are paramount.

Output:
1
2025-04-17 14:53:46,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.487 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (84.64).  A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's higher TPSA could hinder cellular permeability.

**3. logP:** Both ligands have similar and optimal logP values (1.576 and 1.538), 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 preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.763 and 0.79), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (6.282 and 7.135), which is positive.

**8. BBB:** Both ligands have acceptable BBB penetration (72.741 and 68.67), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.692) is slightly better than Ligand B (-4.767), but both are quite poor.

**10. Aqueous Solubility:** Ligand A (-2.579) is significantly better than Ligand B (-1.303). Solubility is crucial for bioavailability, and Ligand A is much more soluble.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.477 and 0.474).

**12. Microsomal Clearance:** Ligand A (33.835) is significantly *higher* than Ligand B (-11.659). A negative value for Cl_mic indicates very high metabolic stability, making Ligand B much more favorable in this regard.

**13. In vitro Half-Life:** Ligand B (2.889) is better than Ligand A (14.901). A lower half-life is less desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.02).

**15. Binding Affinity:** Ligand A (-8.7) has a *much* stronger binding affinity than Ligand B (0). A difference of 8.7 kcal/mol is substantial and likely outweighs many other drawbacks.

**Overall Assessment:**

While Ligand B exhibits superior metabolic stability (lower Cl_mic) and a slightly better half-life, Ligand A's significantly stronger binding affinity (-8.7 vs 0 kcal/mol) is a decisive advantage for an enzyme inhibitor. The improved TPSA, HBD/HBA counts, and solubility of Ligand A further support its selection. The Caco-2 permeability is poor for both, but the potency advantage of A is likely to compensate.

Output:
1
2025-04-17 14:53:46,831 - INFO - Batch 334 complete. Total preferences: 5344
2025-04-17 14:53:46,831 - INFO - Processing batch 335/512...
2025-04-17 14:54:26,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.419 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.12) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (80.57) is excellent, well below 140.

**logP:** Ligand A (-0.899) is a bit low, potentially hindering permeation. Ligand B (2.408) is within the optimal 1-3 range.

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

**QED:** Both ligands have reasonable QED scores (0.419 and 0.673), with Ligand B being better.

**DILI:** Both ligands have low DILI risk (31.64 and 30.671 percentile), which is favorable.

**BBB:** Ligand A (44.94) and Ligand B (63.784) are both low, which is not a concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.445) is very poor, indicating very low intestinal absorption. Ligand B (-4.596) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-0.879) is poor, while Ligand B (-2.762) is even worse. Both pose formulation challenges.

**hERG Inhibition:** Ligand A (0.08) has a very low hERG risk, which is excellent. Ligand B (0.195) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-0.982) indicates good metabolic stability (negative value suggests lower clearance). Ligand B (54.535) has high microsomal clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (8.501 hours) is reasonable. Ligand B (28.452 hours) is excellent.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.02 and 0.082), which is favorable.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage.

**Conclusion:**

Despite solubility concerns for both, Ligand B is the superior candidate. Its significantly stronger binding affinity (-9.2 vs -7.6 kcal/mol) outweighs the slightly higher hERG risk and poorer Caco-2 permeability. Crucially, Ligand B also exhibits much better metabolic stability (lower Cl_mic, longer t1/2) which is a key consideration for kinase inhibitors. Ligand A's poor Caco-2 permeability is a significant drawback.

Output:
1
2025-04-17 14:54:26,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.295 and 391.295 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.39) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (71.78) is excellent, well below 140, suggesting good absorption.

**logP:** Both ligands (2.906 and 2.978) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands (0.56 and 0.519) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (99.147 percentile), which is a significant concern. Ligand B has a much lower DILI risk (29.391 percentile), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (82.629) has better BBB penetration than Ligand A (50.679), but this is not a primary factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.72 and -4.588), which is unusual and suggests poor permeability. This needs further investigation, but it's a shared weakness.

**Aqueous Solubility:** Both have negative solubility values (-4.879 and -3.717), which is also concerning and needs further investigation.

**hERG Inhibition:** Both ligands have similar, low hERG risk (0.514 and 0.591).

**Microsomal Clearance:** Ligand A (42.646) and Ligand B (48.122) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-8.887) has a worse in vitro half-life than Ligand B (42.959).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.184).

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

**Conclusion:**

Despite having identical binding affinities, Ligand B is the superior candidate due to its significantly lower DILI risk (29.391 vs 99.147). While both have concerningly low Caco-2 permeability and aqueous solubility, the DILI risk associated with Ligand A is a major red flag that would likely disqualify it early in development. The better BBB and in vitro half-life of Ligand B are additional benefits.

Output:
1
2025-04-17 14:54:26,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.371 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.32) is better than Ligand B (67.87), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (1.441) is optimal (1-3), while Ligand A (0.338) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, both are within the ideal range of <=5.

**H-Bond Acceptors:** Ligand A (6) is acceptable, while Ligand B (4) is even better, both are within the ideal range of <=10.

**QED:** Both ligands have reasonable QED scores (0.724 and 0.504), indicating good drug-like properties.

**DILI:** Ligand B (29.74) has a significantly lower DILI risk than Ligand A (71.694), which is a major advantage.

**BBB:** Ligand B (54.634) has a better BBB penetration than Ligand A (31.873), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.281) has a worse Caco-2 permeability than Ligand B (-4.402).

**Aqueous Solubility:** Ligand A (-2.89) has a worse aqueous solubility than Ligand B (-1.737).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.333 and 0.397).

**Microsomal Clearance:** Ligand B (13.282) has a lower microsomal clearance than Ligand A (16.561), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.623) has a longer in vitro half-life than Ligand A (24.121).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.089).

**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, and can outweigh some minor ADME concerns.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has a slightly better TPSA, Ligand B excels in almost every other critical parameter: better logP, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and *significantly* stronger binding affinity. The 1.2 kcal/mol difference in binding affinity is particularly important for an enzyme inhibitor.

Output:
1
2025-04-17 14:54:26,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.357 and 347.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.24) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (55.84) is still acceptable, but less favorable.

**logP:** Ligand A (4.991) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.684) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (0 HBD, 5 HBA) is also good, though slightly higher HBA count.

**QED:** Both ligands have acceptable QED scores (0.71 and 0.561), indicating reasonable drug-likeness.

**DILI:** Ligand A (79.333) has a significantly higher DILI risk than Ligand B (14.114). This is a major concern.

**BBB:** Both have reasonable BBB penetration, but Ligand B (81.466) is better than Ligand A (65.452). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

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

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a significant problem for *in vivo* efficacy.

**hERG:** Ligand A (0.843) has a slightly higher hERG risk than Ligand B (0.894), but both are within an acceptable range.

**Microsomal Clearance:** Ligand A (59.33) has lower microsomal clearance than Ligand B (68.215), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (48.311) has a significantly longer half-life than Ligand B (-13.144). This is a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.5 and 0.557).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.5 kcal/mol difference is significant, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has better metabolic stability and half-life, but suffers from a high DILI risk and poor solubility. Ligand B has a significantly better binding affinity and lower DILI risk, but has poorer metabolic stability and half-life. The solubility issues are problematic for both. However, the superior binding affinity of Ligand B, combined with the lower DILI risk, makes it the more promising candidate, *assuming* solubility can be addressed through formulation strategies. The potency advantage is substantial.

Output:
1
2025-04-17 14:54:26,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Ligand A:**

*   **MW:** 403.251 Da - Good (within 200-500 range)
*   **TPSA:** 44.12 - Good (<=140)
*   **logP:** 4.482 - Slightly high, potential solubility issues.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.59 - Good (>=0.5)
*   **DILI:** 80.807 - High risk.
*   **BBB:** 73.827 - Acceptable, but not a priority for a non-CNS target.
*   **Caco-2:** -4.629 - Very poor permeability.
*   **Solubility:** -6.26 - Very poor solubility.
*   **hERG:** 0.469 - Low risk.
*   **Cl_mic:** 125.866 - High clearance, poor metabolic stability.
*   **t1/2:** -2.034 - Very short half-life.
*   **Pgp:** 0.403 - Low efflux.
*   **Affinity:** -8.5 kcal/mol - Excellent.

**Ligand B:**

*   **MW:** 347.379 Da - Good (within 200-500 range)
*   **TPSA:** 109.24 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** -0.096 - Low, potential permeability issues.
*   **HBD:** 1 - Acceptable.
*   **HBA:** 7 - Acceptable.
*   **QED:** 0.782 - Very good (>=0.5)
*   **DILI:** 73.052 - Moderate risk.
*   **BBB:** 46.336 - Low, not a priority.
*   **Caco-2:** -5.196 - Very poor permeability.
*   **Solubility:** -1.838 - Poor solubility.
*   **hERG:** 0.157 - Low risk.
*   **Cl_mic:** 54.96 - Moderate clearance, better metabolic stability than A.
*   **t1/2:** -40.1 - Very short half-life.
*   **Pgp:** 0.044 - Low efflux.
*   **Affinity:** -8.7 kcal/mol - Excellent, slightly better than A.

**Comparison & Decision:**

Both ligands have excellent binding affinity. However, both have very poor Caco-2 permeability and solubility. Ligand A has a higher logP and significantly worse metabolic stability (higher Cl_mic, shorter t1/2) and a much higher DILI risk. Ligand B has a lower logP, better metabolic stability, and a lower DILI risk. While both have poor permeability and solubility, these can be addressed with formulation strategies. The lower DILI and better metabolic stability of Ligand B make it the more promising candidate, despite the lower logP. The slight improvement in binding affinity is a bonus.

Output:
1
2025-04-17 14:54:26,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (356.442 and 351.495 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (78.27 and 76.3) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (1.905 and 2.35) 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 7 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.538 and 0.725), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (28.306 and 23.187 percentile), which is favorable. Ligand B is slightly better.

**8. BBB:**  BBB is less critical for a non-CNS target like SRC kinase. Ligand A (72.896) is slightly better than Ligand B (67.662).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.674 and -5.188). This is unusual and suggests potential issues with intestinal absorption. However, negative values are often artifacts of the prediction method and don't necessarily preclude development.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.041 and -2.081). This is a significant concern for bioavailability and will require formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.49 and 0.548), which is good.

**12. Microsomal Clearance:** Ligand B (19.466 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (30.178 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (18.097 hours) has a much longer in vitro half-life than Ligand A (9.235 hours), further supporting its improved metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.102 and 0.509), which is favorable.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered significant, and here it's a massive 8.9 kcal/mol difference.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand B is clearly the superior candidate. Its significantly stronger binding affinity, lower microsomal clearance, and longer half-life outweigh the slightly lower BBB and similar solubility issues (which are problematic for both). The solubility issues would need to be addressed through formulation, but the potency and stability advantages of Ligand B are too significant to ignore.

Output:
1
2025-04-17 14:54:26,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.14) is slightly above the preferred <140, but acceptable. Ligand B (58.2) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.696) is a bit low, potentially hindering permeation. Ligand B (2.985) is optimal.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.684 and 0.835), indicating drug-like properties.

**DILI:** Ligand A (43.428) has a moderate DILI risk, but still acceptable. Ligand B (19.349) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (60.644) has a moderate BBB penetration. Ligand B (74.603) has good BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.697) has poor Caco-2 permeability. Ligand B (-4.621) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-0.77) has poor aqueous solubility. Ligand B (-3.568) has very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.048) has very low hERG inhibition risk, a major plus. Ligand B (0.393) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (7.55) has a relatively low microsomal clearance, indicating better metabolic stability. Ligand B (68.155) has a high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (44.546) has a moderate in vitro half-life. Ligand B (-3.051) has a very short in vitro half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.034) has low P-gp efflux. Ligand B (0.224) has slightly higher P-gp efflux.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.4 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much better safety profile (lower DILI, acceptable hERG). However, it suffers from poor solubility, poor permeability, and rapid metabolism (high Cl_mic, short t1/2). Ligand A has better solubility and metabolic stability, but weaker binding affinity and a slightly higher DILI risk.

Given the enzyme-specific priorities, the strong binding affinity of Ligand B is a critical factor. While its ADME properties are concerning, the potency advantage is significant. Optimization efforts could focus on improving solubility and metabolic stability of Ligand B.



Output:
1
2025-04-17 14:54:26,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.427 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is well below the 140 threshold, while Ligand B (77.1) is still acceptable but higher.

**logP:** Ligand A (1.796) is optimal (1-3). Ligand B (0.49) is slightly low, potentially impacting permeability.

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

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Ligand A (0.852) is excellent, indicating high drug-likeness. Ligand B (0.483) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (29.042) has a very low DILI risk. Ligand B (12.641) also has a low DILI risk.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (86.274) is better than Ligand B (77.2). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both 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 and suggests a potential issue with the data or the model.

**hERG Inhibition:** Ligand A (0.92) is preferable to Ligand B (0.237) as it indicates a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (61.433) has a higher clearance than Ligand B (12.77). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand A (-6.912) has a significantly longer half-life than Ligand B (1.953). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.508) has lower P-gp efflux liability than Ligand B (0.017), which is favorable.

**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 small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is superior due to its better QED score, lower hERG risk, significantly longer half-life, lower P-gp efflux, and slightly better binding affinity. While Ligand B has better metabolic stability (lower Cl_mic), the other advantages of Ligand A outweigh this benefit, especially considering the importance of potency and metabolic stability for kinase inhibitors. 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 14:54:26,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.459 Da and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.01) is higher than Ligand B (58.64). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good oral absorption.

**logP:** Ligand A (-0.463) is a bit low, potentially hindering permeation. Ligand B (2.019) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Both are acceptable (<=10), but Ligand B is preferable.

**QED:** Both ligands have good QED scores (0.671 and 0.794), indicating drug-like properties.

**DILI:** Ligand A (41.76) has a slightly higher DILI risk than Ligand B (14.618), but both are below the concerning threshold of 60.

**BBB:** Both have good BBB penetration (70.454 and 78.519). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.865 and -4.76), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.153 and -3.259), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.082) has a very low hERG risk, which is excellent. Ligand B (0.211) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-0.569) has a negative clearance, which is highly favorable, indicating excellent metabolic stability. Ligand B (21.058) has a moderate clearance, which is less desirable.

**In vitro Half-Life:** Ligand A (31.195) has a longer half-life than Ligand B (0.249), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.032).

**Binding Affinity:** Both ligands have very similar and strong 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 excels in metabolic stability (Cl_mic, t1/2) and hERG risk. Ligand B has better logP and TPSA, potentially improving absorption, but its metabolic stability is a concern. The negative Caco-2 and solubility values are concerning for both. However, the superior metabolic stability and longer half-life of Ligand A, combined with its excellent hERG profile, make it the more promising candidate, especially considering the enzyme-specific priorities.

Output:
0
2025-04-17 14:54:26,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.757 Da and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.63) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (84.94) is well within the ideal range.

**logP:** Both ligands (1.781 and 0.78) are within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 8 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.79) has a better QED score than Ligand B (0.542), indicating better overall drug-likeness.

**DILI:** Ligand A has a very high DILI risk (99.341), which is a significant concern. Ligand B has a much lower and acceptable DILI risk (35.518).

**BBB:** Both ligands have similar BBB penetration (50.756 and 50.679), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.754 and -4.704), which is unusual and suggests poor permeability. This needs further investigation, but is not a deciding factor at this stage.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.825 and -2.021), indicating poor solubility. This is a concern, but can potentially be addressed through formulation.

**hERG:** Ligand A (0.273) has a slightly higher hERG risk than Ligand B (0.053), but both are relatively low.

**Microsomal Clearance:** Ligand A (64.989) has a significantly higher microsomal clearance than Ligand B (5.316), suggesting lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-40.413) has a very short in vitro half-life, consistent with its high clearance. Ligand B (-0.078) has a slightly negative half-life, but far better than Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.202 and 0.027).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), although both are strong binders. The difference of 0.6 kcal/mol is not substantial enough to overcome other issues.

**Conclusion:**

Despite having a slightly better QED and comparable binding affinity, Ligand A is significantly hampered by its extremely high DILI risk and poor metabolic stability (high Cl_mic, short t1/2). Ligand B, while having a slightly lower QED, presents a much more favorable ADME profile with a low DILI risk, excellent metabolic stability, and acceptable hERG risk. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 14:54:26,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.427 and 348.378 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.6) is well below the 140 threshold for good absorption and is favorable. Ligand B (98.22) is still within acceptable limits, but less optimal than A.

**logP:** Ligand A (2.716) is within the optimal range of 1-3. Ligand B (0.9) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.924 and 0.845), indicating good drug-like properties.

**DILI:** Ligand A (40.054) has a lower DILI risk than Ligand B (62.893), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.997) has a better BBB score than Ligand B (53.083).

**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 negative solubility values, which is also unusual and suggests potential issues with the data or modeling. The values are similar.

**hERG:** Both ligands have very low hERG inhibition liability (0.511 and 0.516), which is excellent.

**Microsomal Clearance:** Ligand A (27.722) has a considerably *lower* (better) microsomal clearance than Ligand B (-28.704). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (38.899) has a much longer half-life than Ligand B (-1.504), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.11 and 0.031), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate**. While both ligands have excellent binding affinity and acceptable drug-like properties, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. These are crucial factors for an enzyme target like SRC kinase. The slightly better TPSA and BBB scores of Ligand A are additional benefits. The unusual negative values for Caco-2 and solubility are concerning, but similar for both compounds, so don't heavily influence the decision.

Output:
1
2025-04-17 14:54:26,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.447 and 355.777 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.6) is better than Ligand B (76.23), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.191) is lower than optimal (1-3), potentially hindering permeation. Ligand B (3.741) is within the optimal 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, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Ligand A (0.717) is slightly better than Ligand B (0.571), indicating a more drug-like profile.

**DILI:** Ligand A (40.946) has a much lower DILI risk than Ligand B (93.525). This is a major advantage for Ligand A.

**BBB:** Ligand A (64.482) has a better BBB penetration percentile than Ligand B (44.979), but BBB is not a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.827 and -4.88), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.156 and -5.149), also unusual and indicating very poor solubility. This is a significant drawback for both.

**hERG:** Both ligands have low hERG inhibition liability (0.151 and 0.189), which is good.

**Microsomal Clearance:** Ligand A (43.07 mL/min/kg) has significantly lower microsomal clearance than Ligand B (68.229 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-32.78 hours) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (30.934 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.028 and 0.385).

**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 factor.

**Overall Assessment:**

Ligand A has advantages in DILI risk and microsomal clearance, and a slightly better QED score. However, its negative in vitro half-life is a critical flaw. Ligand B has a better logP, which is important for permeability, and a slightly better binding affinity. Both have poor solubility and Caco-2 permeability. Given the importance of metabolic stability for kinase inhibitors and the questionable half-life of Ligand A, Ligand B appears to be the more promising candidate, despite the higher DILI risk. The binding affinity difference is small enough that it can be addressed in subsequent optimization.

Output:
1
2025-04-17 14:54:26,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.407 and 355.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.94) is better than Ligand B (113.53), being closer to the <140 threshold for good absorption.

**logP:** Ligand B (0.698) is slightly better than Ligand A (0.32), falling more comfortably within the 1-3 range. Ligand A is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 7 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.805) has a significantly better QED score than Ligand B (0.55), indicating a more drug-like profile.

**DILI:** Ligand B (59.984) has a slightly higher DILI risk than Ligand A (53.121), but both are reasonably acceptable (<60 is good).

**BBB:** Ligand B (72.276) has a better BBB penetration percentile than Ligand A (42.536), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.198 and -5.127), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-0.624) is better than Ligand B (-2.995) in terms of solubility, though both are poor.

**hERG Inhibition:** Ligand A (0.02) has a much lower hERG risk than Ligand B (0.327), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (2.098) has a significantly lower Cl_mic than Ligand B (11.297), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.605) has a much longer half-life than Ligand B (-12.705), which is a substantial benefit.

**P-gp Efflux:** Ligand A (0.046) has a much lower P-gp efflux liability than Ligand B (0.064).

**Binding Affinity:** Ligand A (-8.4) has a significantly stronger binding affinity than Ligand B (0.0). This is the most important factor.

**Overall:**

Ligand A is clearly superior. While both have poor Caco-2 permeability and solubility, Ligand A's significantly better binding affinity (-8.4 vs 0.0 kcal/mol), lower hERG risk, lower Cl_mic, longer half-life, better QED, and lower P-gp efflux outweigh the slightly lower logP and BBB. The strong binding affinity is a major advantage that can compensate for some ADME deficiencies.

Output:
0
2025-04-17 14:54:26,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.535 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.73) is well below the 140 threshold, while Ligand B (84.67) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (1.205 and 1.163), 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.604 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A (35.169) has a significantly lower DILI risk than Ligand B (54.634), which is a major advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (78.209) has a better BBB percentile than Ligand B (57.425).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.956 and -4.646). 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.

**Aqueous Solubility:** Both have negative solubility values (-1.502 and -2.124). Similar to Caco-2, this is unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.913) has a slightly higher hERG risk than Ligand B (0.052). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (14.96) has higher microsomal clearance than Ligand B (11.524), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-9.596) has a significantly longer in vitro half-life than Ligand A (29.019), which is a major advantage.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux than Ligand B (0.024), which is slightly favorable for A.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage for Ligand B, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the stronger candidate. Its significantly better binding affinity (-8.5 vs -6.8 kcal/mol) is a major driver. It also has a longer half-life, lower DILI risk (though both are acceptable), and lower microsomal clearance, all crucial for an enzyme inhibitor. While Ligand A has a slightly better P-gp efflux profile and BBB penetration, the advantages of Ligand B in potency and metabolic stability outweigh these factors. The negative Caco-2 and solubility values are concerning for both, but the superior binding affinity of B suggests it might overcome these issues with appropriate formulation strategies.

Output:
1
2025-04-17 14:54:26,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.39 and 355.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is slightly higher than Ligand B (61.88). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (1.99 and 1.098), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBDs, while Ligand B has 1. Both are within the acceptable limit of <=5.

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

**QED:** Both ligands have good QED scores (0.685 and 0.743), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 47.926, while Ligand B has 12.641. Ligand B is significantly better regarding potential liver toxicity.

**BBB:** Both ligands have similar BBB penetration (71.501 and 71.307). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.39) and Ligand B (-4.875) 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 (-3.343) and Ligand B (-1.025) both have negative values, indicating poor solubility. Ligand B is better here.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.419 and 0.478).

**Microsomal Clearance:** Ligand A (-6.053) and Ligand B (-8.773) both have negative values, which is unusual and suggests very slow clearance. This is a positive. Ligand B has a more negative value, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.997) and Ligand B (6.845). Ligand B has a significantly longer in vitro half-life, which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.081 and 0.022).

**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.

**Conclusion:**

Ligand B is clearly superior. While both ligands have acceptable MW, logP, HBD/HBA, QED, hERG, and P-gp efflux, Ligand B excels in key areas: significantly lower DILI risk, a much longer in vitro half-life, and, most importantly, a substantially stronger binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the strong affinity of Ligand B could potentially overcome these issues with appropriate formulation strategies.

Output:
1
2025-04-17 14:54:26,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.475 and 369.893 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is better than Ligand B (72.36), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.256 and 2.366) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), keeping in mind the preference for <=5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is good.

**QED:** Ligand A (0.823) is better than Ligand B (0.738), indicating a more drug-like profile.

**DILI:** Ligand A (16.014) has a significantly lower DILI risk than Ligand B (32.842). This is a major advantage.

**BBB:** Both have good BBB penetration (Ligand A: 71.113, Ligand B: 75.921). Not critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.932) is slightly better than Ligand B (-4.543), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.825) is significantly better than Ligand B (-3.838). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.32, Ligand B: 0.418).

**Microsomal Clearance:** Ligand A (57.194) has lower microsomal clearance than Ligand B (67.654), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.706) has a much longer half-life than Ligand B (41.861). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.172, Ligand B: 0.081).

**Binding Affinity:** Ligand A (-9.4) has a stronger binding affinity than Ligand B (-7.1). This is a substantial difference and a key driver in the decision.

**Overall:** Ligand A is superior to Ligand B across most critical parameters. It has a better QED score, significantly lower DILI risk, better solubility, lower clearance, longer half-life, and, most importantly, a much stronger binding affinity. While both have acceptable logP and hERG values, the combined advantages of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 14:54:26,169 - INFO - Batch 335 complete. Total preferences: 5360
2025-04-17 14:54:26,169 - INFO - Processing batch 336/512...
2025-04-17 14:55:09,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.5 and 364.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (81.7 and 78.9) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.42 and 1.49) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.555 and 0.725), indicating drug-like properties.

**DILI:** Ligand A (5.58) has a significantly lower DILI risk than Ligand B (12.14). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B (87.9) has a higher BBB score than Ligand A (32.0), but this is not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.54 and -4.73) and don't differentiate the compounds significantly.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.23 and -1.75), indicating poor solubility. Again, the values are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.47 and 0.28), which is excellent.

**Microsomal Clearance:** Ligand A (-4.52) has a much lower (better) microsomal clearance than Ligand B (3.40). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (26.48) has a significantly longer half-life than Ligand B (-33.79). This is a substantial advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.022).

**Binding Affinity:** Both ligands have identical binding affinities (-8.3 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand A is the superior candidate. It exhibits a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a longer in vitro half-life. These factors are crucial for enzyme inhibitors, outweighing the slightly lower BBB score.

Output:
1
2025-04-17 14:55:09,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 359.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is better than Ligand B (29.54) as it is still within the acceptable range for oral absorption, while Ligand B is significantly lower, which could potentially impact potency.

**logP:** Ligand A (2.397) is optimal, while Ligand B (4.137) is approaching the upper limit and could present solubility issues.

**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 B (0.803) has a higher QED score than Ligand A (0.55), indicating a more drug-like profile.

**DILI:** Ligand A (18.651) has a significantly lower DILI risk than Ligand B (37.611), which is a major advantage.

**BBB:** Ligand B (95.696) has excellent BBB penetration, while Ligand A (57.968) is moderate. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.736 and -4.557). This is unusual and suggests poor permeability. However, these values are on a log scale and could be misinterpreted; further investigation would be needed.

**Aqueous Solubility:** Ligand A (-1.533) has slightly better solubility than Ligand B (-4.885), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.13) has a much lower hERG risk than Ligand B (0.861), a critical safety parameter.

**Microsomal Clearance:** Ligand A (48.237) has lower microsomal clearance than Ligand B (86.453), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (17.471) has a slightly longer half-life than Ligand A (14.743), which is a minor advantage.

**P-gp Efflux:** Ligand A (0.032) has lower P-gp efflux than Ligand B (0.81), improving bioavailability.

**Binding Affinity:** Ligand B (-8.9 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:**

While Ligand B boasts a superior binding affinity and QED score, its higher DILI risk, poorer solubility, and higher hERG inhibition liability are significant drawbacks. Ligand A, despite its weaker affinity, presents a much more favorable safety and ADME profile, with lower DILI and hERG risk, better solubility, and lower P-gp efflux. The difference in binding affinity (2 kcal/mol) is substantial, but the safety concerns associated with Ligand B outweigh this benefit. Given the enzyme-kinase target class, metabolic stability (Cl_mic) and safety (hERG, DILI) are paramount.

Output:
0
2025-04-17 14:55:09,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (57.0) is well below the 140 threshold for oral absorption, and significantly better than Ligand B (67.4). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have logP values (1.959 and 2.133) 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 ligands have good QED scores (0.817 and 0.776), indicating drug-like properties.

**DILI:** Ligand A (5.545) has a significantly lower DILI risk than Ligand B (38.852), a major advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (70.609) shows better BBB penetration than Ligand B (60.644).

**Caco-2 Permeability:** Ligand A (-4.869) has a more favorable (less negative) Caco-2 value than Ligand B (-5.069), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.637) has better aqueous solubility than Ligand B (-1.281), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.435 and 0.37), which is good.

**Microsomal Clearance:** Ligand A (-2.955) has a lower (better) microsomal clearance than Ligand B (-5.423), indicating improved metabolic stability.

**In vitro Half-Life:** Ligand A (25.858 hours) has a significantly longer in vitro half-life than Ligand B (64.324 hours), which is desirable for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.315).

**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 not substantial enough to outweigh the numerous advantages of Ligand A in terms of ADME properties.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties across the board, including significantly lower DILI risk, better solubility, improved metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. These factors are critical for developing a viable drug candidate.

Output:
0
2025-04-17 14:55:09,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.471 Da) is slightly higher than Ligand B (347.455 Da), but both are acceptable.

**TPSA:** Ligand A (135.6) is borderline acceptable for oral absorption, while Ligand B (55.84) is well below the 140 threshold and is favorable.

**logP:** Ligand A (-0.455) is a bit low, potentially hindering permeation. Ligand B (3.728) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (0 HBD, 4 HBA) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (0.673 and 0.601), indicating good drug-likeness.

**DILI:** Ligand A (68.864) has a higher DILI risk than Ligand B (28.577), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.411) has a higher BBB score, but it's not a deciding factor here.

**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 ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is undefined.

**hERG:** Ligand A (0.062) has a very low hERG risk, which is excellent. Ligand B (0.776) has a slightly elevated hERG risk, but still within a reasonable range.

**Microsomal Clearance:** Ligand A (-12.003) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (97.637) has a high microsomal clearance, suggesting rapid metabolism and poor stability.

**In vitro Half-Life:** Ligand A (-23.306) has a negative half-life, which is not physically possible and indicates a data error. Ligand B (-17.644) also has a negative half-life, again indicating a data error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the questionable solubility and permeability data, the significant differences in metabolic stability and binding affinity are decisive. Ligand A has a problematic DILI risk and impossible clearance/half-life values. Ligand B, while having a higher clearance, exhibits a much stronger binding affinity (-8.1 vs -6.8 kcal/mol), which is a critical factor for enzyme inhibitors. The stronger binding is likely to outweigh the higher clearance, especially if further optimization can address the metabolic stability.

Output:
1
2025-04-17 14:55:09,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (386.298 Da) is still well within the acceptable range.

**TPSA:** Ligand A (68.5) is significantly better than Ligand B (37.61). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**logP:** Both ligands have logP values around 4 (A: 4.159, B: 4.529), which is slightly high. This could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker if other properties are favorable.

**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:** Both ligands have reasonable QED scores (A: 0.603, B: 0.559), indicating good drug-like properties.

**DILI:** Ligand A (80.69) has a higher DILI risk than Ligand B (32.493). This is a significant concern, as a lower DILI risk is highly desirable.

**BBB:** Both ligands have high BBB penetration (A: 76.309, B: 89.841), but this is less critical for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.698 and -4.781). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-6.305 and -5.212), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.697, B: 0.845), which is positive.

**Microsomal Clearance:** Ligand A (73.32) has a lower microsomal clearance than Ligand B (80.818), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.663) has a significantly longer in vitro half-life than Ligand B (38.11), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.4, B: 0.618).

**Binding Affinity:** Both ligands have strong binding affinities (A: -7.0 kcal/mol, B: -8.1 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.1 vs -7.0 kcal/mol) and a much lower DILI risk (32.493 vs 80.69). However, it has a higher microsomal clearance and shorter half-life. Both ligands suffer from poor solubility and permeability. Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, hERG), the stronger binding affinity and lower DILI risk of Ligand B outweigh the slightly worse metabolic stability. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the starting point is better with Ligand B.

Output:
1
2025-04-17 14:55:09,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.389 and 368.781 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.53) is better than Ligand B (133.21). TPSA < 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands (-0.352 and -0.98) are slightly below the optimal 1-3 range. Ligand B is slightly worse, potentially impacting permeability.

**H-Bond Donors & Acceptors:** Ligand A (4 HBD, 4 HBA) is better than Ligand B (3 HBD, 7 HBA). Both are within acceptable limits, but A is more balanced.

**QED:** Both ligands have reasonable QED scores (0.35 and 0.6), with Ligand B being better.

**DILI:** Ligand A (33.773) has a significantly lower DILI risk than Ligand B (67.468). This is a major advantage for Ligand A.

**BBB:** Ligand A (40.326) has a better BBB penetration than Ligand B (11.4), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.966 and -5.678), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.069 and -1.946), also unusual and suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.587) has a slightly higher hERG risk than Ligand B (0.045). This is a concern for Ligand A, but not a dealbreaker.

**Microsomal Clearance:** Ligand B (-14.93) has a much lower (better) microsomal clearance than Ligand A (13.18). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (36.307) has a significantly longer half-life than Ligand A (-16.12). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.044).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a better binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, which are crucial for an enzyme inhibitor. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. The superior affinity of Ligand A is a strong driver, and the DILI risk is acceptable.

Output:
1
2025-04-17 14:55:09,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (346.43 & 354.36 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (133.99) is still within acceptable limits for oral absorption but higher than A.

**3. logP:** Ligand A (1.115) is within the optimal 1-3 range. Ligand B (-1.231) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**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 (8) is higher, potentially impacting permeability.

**6. QED:** Both ligands (0.554 and 0.576) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (18.07) has a significantly lower DILI risk than Ligand B (43.66). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (71.97) has a better BBB percentile than Ligand B (13.38). While SRC isn't necessarily a CNS target, better BBB penetration can sometimes correlate with better overall bioavailability.

**9. Caco-2:** Both ligands show negative Caco-2 values, which 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, which is also unusual.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.211 and 0.046), which is excellent.

**12. Cl_mic:** Ligand B (11.54) has a lower microsomal clearance than Ligand A (30.64), indicating better metabolic stability. This is a key advantage for Ligand B, given our priority for enzymes.

**13. t1/2:** Ligand B (-12.57) has a longer in vitro half-life than Ligand A (-26.53), also favoring Ligand B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.025 and 0.044).

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.9), but the difference is small (0.3 kcal/mol).

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), Ligand B appears slightly more promising. Its superior metabolic stability (lower Cl_mic) and longer half-life are significant advantages. The slightly better binding affinity is a bonus. However, the lower logP and higher TPSA of Ligand B are slight concerns. Ligand A has a much better safety profile regarding DILI, but its metabolic stability is a concern. Given the small difference in binding affinity, the improved metabolic stability of Ligand B outweighs the DILI risk of Ligand A.

Output:
1
2025-04-17 14:55:09,340 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (347.463 and 349.479 Da) fall comfortably within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (70.47) is higher than Ligand B (53.96). Both are below the 140 threshold for oral absorption, but B is better positioned, especially considering kinase inhibitors don't necessarily *require* high CNS penetration.

3. **logP:** Both ligands (0.957 and 1.106) are within the optimal 1-3 range. Again, a minor difference.

4. **HBD:** Ligand A has 1 HBD, while Ligand B has 0. This is a slight advantage for Ligand B, as fewer HBDs generally correlate with better permeability.

5. **HBA:** Ligand A has 5 HBA, and Ligand B has 7. Ligand A is preferable here, staying closer to the ideal of <=10.

6. **QED:** Both ligands have similar QED values (0.778 and 0.762), indicating good drug-like properties.

7. **DILI:** Both ligands have low DILI risk (36.681 and 38.348 percentile), which is excellent. No significant difference.

8. **BBB:** Ligand B (88.833) has a significantly higher BBB penetration percentile than Ligand A (62.544). However, as SRC is not a CNS target, this is less critical.

9. **Caco-2:** Both have negative Caco-2 values (-4.807 and -4.716). This is unusual and suggests poor permeability. However, these are likely experimental artifacts or indicate a need for formulation strategies.

10. **Solubility:** Both ligands have very poor aqueous solubility (-1.044 and -1.49). This is a significant concern for both and would require addressing through formulation.

11. **hERG:** Both ligands have low hERG inhibition liability (0.345 and 0.847), which is good. Ligand A is slightly better.

12. **Cl_mic:** Ligand A (27.37 mL/min/kg) has a lower microsomal clearance than Ligand B (33.266 mL/min/kg), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

13. **t1/2:** Ligand A (3.935 hours) has a shorter in vitro half-life than Ligand B (19.131 hours). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

14. **Pgp:** Both ligands have very low Pgp efflux liability (0.027 and 0.035), which is favorable. No significant difference.

15. **Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A has superior affinity and lower Cl_mic, while Ligand B has a much better half-life. Both have poor solubility and acceptable hERG.

**Conclusion:**

While Ligand B has a significantly longer half-life, the substantial difference in binding affinity (-8.5 vs -7.5 kcal/mol) for Ligand A is a major advantage. The improved affinity is likely to translate to greater efficacy and potentially allow for a lower dose, mitigating some of the solubility concerns. The lower Cl_mic of Ligand A is also a positive. The solubility issue for both compounds would need to be addressed during formulation.

Therefore, I recommend **Ligand A** as the more viable drug candidate.

Output:
0
2025-04-17 14:55:09,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (336.355 and 349.351 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.83) is well below the 140 threshold for good absorption. Ligand B (139.27) is approaching the limit but still acceptable.

**logP:** Ligand A (1.382) is within the optimal 1-3 range. Ligand B (-1.926) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 9 HBA) is also acceptable, though higher HBA could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (0.762 and 0.636), indicating good drug-like properties.

**DILI:** Ligand A (92.168) has a higher DILI risk than Ligand B (65.568), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (52.268) and Ligand B (24.002) are both low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.058 and -5.701), which is unusual and suggests poor permeability. This needs further investigation, but is likely a modeling artifact.

**Aqueous Solubility:** Both have negative solubility values (-3.261 and -1.205), also unusual and potentially problematic. Again, this requires further investigation.

**hERG:** Ligand A (0.5) has a slightly higher hERG risk than Ligand B (0.031), but both are relatively low.

**Microsomal Clearance:** Ligand A (-5.598) has a much lower (better) microsomal clearance than Ligand B (6.117), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (0.224) has a very short half-life compared to Ligand B (15.073), a major drawback.

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.011), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is more promising. Its lower DILI risk, significantly better metabolic stability (lower Cl_mic and much longer t1/2), and lower P-gp efflux outweigh the slightly less optimal logP. The negative solubility and Caco-2 values are concerning for both, but the metabolic stability of Ligand B is a key advantage for an enzyme target. Ligand A's very short half-life is a major issue.

Output:
1
2025-04-17 14:55:09,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 341.415 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (88.91), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand B (1.135) is slightly better than Ligand A (0.564). Both are within the optimal 1-3 range, but A is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand B (5) is slightly better than Ligand A (4), both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.706 and 0.824), indicating drug-likeness.

**DILI:** Ligand A (7.91) has a significantly lower DILI risk than Ligand B (35.634). This is a major advantage for Ligand A.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (61.846) is slightly higher than Ligand A (58.821).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.4) is slightly better than Ligand B (-5.068).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-0.992) is slightly better than Ligand B (-1.794).

**hERG Inhibition:** Both have very low hERG inhibition risk (0.121 and 0.218), which is excellent.

**Microsomal Clearance:** Ligand A (-16.86) has a much lower (better) microsomal clearance than Ligand B (18.337). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (3.754) has a shorter half-life than Ligand B (-20.294). This is a negative for Ligand A, but the large negative value for B is suspect.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.018).

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better safety (DILI), metabolic stability (Cl_mic), and slightly better solubility and permeability. The difference in binding affinity is not large enough to outweigh these advantages, especially for an enzyme target where metabolic stability and safety are crucial.

Output:
0
2025-04-17 14:55:09,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (384.889 and 360.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.89 and 77.81) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.318) is optimal, while Ligand B (4.103) is approaching the upper limit and could potentially cause solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.866 and 0.779), indicating good drug-like properties.

**DILI:** Ligand A (63.552) has a slightly better DILI score than Ligand B (72.858), indicating a lower risk of liver injury. Both are acceptable, but lower is preferred.

**BBB:** This is less critical for a non-CNS target like SRC, but both are around the 50-55 percentile.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.838 and -4.762), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.581 and -5.705). This is a major drawback.

**hERG Inhibition:** Ligand A (0.332) has a much lower hERG inhibition liability than Ligand B (0.724), which is a significant advantage.

**Microsomal Clearance:** Ligand A (0.881) has significantly lower microsomal clearance than Ligand B (56.004), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (89.973) has a much longer in vitro half-life than Ligand A (12.535). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.571).

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol), although both are good. The 0.6 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the better candidate. While both have poor solubility and permeability, Ligand A has significantly better metabolic stability (lower Cl_mic), lower hERG risk, and slightly better binding affinity. The longer half-life of Ligand B is attractive, but the significantly higher metabolic clearance and hERG risk are major concerns. The slightly better affinity of Ligand A, combined with its superior safety and pharmacokinetic properties, make it the more promising drug candidate.

Output:
0
2025-04-17 14:55:09,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.446 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.29) is well below the 140 threshold and favorable for absorption. Ligand B (85.05) is still under 140, but less optimal than A.

**logP:** Ligand A (4.176) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.903) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6 HBA, both acceptable (<=10).

**QED:** Both ligands have similar QED values (0.886 and 0.873), indicating good drug-likeness.

**DILI:** Ligand A (18.961) has a much lower DILI risk than Ligand B (56.805). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.104) has a better BBB percentile than Ligand B (66.77).

**Caco-2:** Ligand A (-4.959) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.111) is also negative, but similar to A.

**Solubility:** Ligand A (-3.898) and Ligand B (-2.001) both have negative solubility values, suggesting poor aqueous solubility. Ligand B is slightly better.

**hERG:** Ligand A (0.847) has a slightly higher hERG risk than Ligand B (0.246). This favors Ligand B.

**Microsomal Clearance:** Ligand A (70.414) has higher microsomal clearance than Ligand B (38.62), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-19.793) has a negative half-life, which is concerning. Ligand B (19.706) has a positive half-life, suggesting better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.452 and 0.073 respectively), which is good.

**Binding Affinity:** Ligand A (-8.7 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 has a much better binding affinity and lower DILI risk. However, it has poorer Caco-2 permeability, higher microsomal clearance, and a negative in vitro half-life. Ligand B has better metabolic stability (lower Cl_mic, positive t1/2), lower hERG risk, and slightly better solubility, but its binding affinity is significantly weaker.

Given the enzyme-specific priorities, binding affinity is paramount. The 1.1 kcal/mol difference in binding affinity is substantial. While Ligand A's ADME properties are concerning, these can potentially be improved through further medicinal chemistry optimization. The weaker binding of Ligand B is harder to overcome.

Output:
0
2025-04-17 14:55:09,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.407 and 380.438 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (119.76 and 102.01) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.452) is within the optimal range of 1-3. Ligand B (-0.717) is slightly below 1, which *could* hinder permeation, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5 and 6) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.426 and 0.626), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (34.665) has a lower DILI risk than Ligand B (49.166), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (71.19 and 73.711), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, given they are both negative and similar in magnitude, it doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, similarity doesn't favor one over the other.

**hERG:** Both ligands have very low hERG inhibition risk (0.287 and 0.272), which is excellent.

**Microsomal Clearance:** Ligand B (-7.928) has a *negative* microsomal clearance, which is impossible. This suggests a significant error in the modeling or data. Ligand A (6.667) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (-6.862) has a negative half-life, which is impossible. This further reinforces the data quality issue with Ligand B. Ligand A (5.497) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.023).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a >2.6 kcal/mol difference, which is a substantial advantage that can outweigh minor ADME concerns.

**Conclusion:**

Due to the impossible values for microsomal clearance and half-life for Ligand B, and the significantly stronger binding affinity of Ligand A, **Ligand A is the more promising drug candidate.** The lower DILI risk for Ligand A further strengthens this conclusion. The negative solubility and Caco-2 values are concerning for both, but the binding affinity difference is the dominant factor in this comparison.

Output:
1
2025-04-17 14:55:09,342 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (400.327 Da) is within the ideal range. Ligand B (365.777 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (55.4) is well below the 140 threshold and suitable for oral absorption. Ligand B (103.35) is still under 140, but higher, potentially impacting absorption slightly. A is better.

3. **logP:** Ligand A (3.61) is within the optimal range. Ligand B (1.024) is at the lower end, potentially causing permeability issues. A is better.

4. **HBD:** Ligand A (1) is good. Ligand B (0) is also good. No clear advantage.

5. **HBA:** Ligand A (3) is good. Ligand B (8) is higher, potentially impacting permeability. A is better.

6. **QED:** Ligand A (0.737) is excellent. Ligand B (0.575) is acceptable but lower. A is better.

7. **DILI:** Ligand A (58.511) is good (low risk). Ligand B (83.87) is higher, indicating a greater potential for liver injury. A is significantly better.

8. **BBB:** Both are around 50-60, so BBB is not a major consideration for SRC kinase, which is not a CNS target.

9. **Caco-2:** Both are negative, indicating poor permeability. This is a concern for both, but the other factors will be more important.

10. **Solubility:** Ligand A (-4.708) is very poor. Ligand B (-2.799) is also poor, but better than A. B is better.

11. **hERG:** Ligand A (0.813) is a moderate risk. Ligand B (0.041) is very low risk. B is significantly better.

12. **Cl_mic:** Ligand A (61.914) is moderate. Ligand B (82.983) is higher, indicating faster metabolism and lower stability. A is better.

13. **t1/2:** Ligand A (16.191) is good. Ligand B (-21.784) is very short, a major drawback. A is significantly better.

14. **Pgp:** Ligand A (0.62) is moderate. Ligand B (0.217) is low, suggesting less efflux. B is better.

15. **Binding Affinity:** Ligand A (-9.1) is *much* stronger than Ligand B (0). This is a critical advantage, exceeding the 1.5 kcal/mol threshold.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and a lower DILI risk. While its solubility is poor, the strong affinity and favorable metabolic properties are likely to outweigh this. Ligand B has a better hERG profile and slightly better solubility, but its very short half-life and weaker binding affinity are major drawbacks. The substantial difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 14:55:09,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.307 and 366.615 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is slightly above the preferred <140, but acceptable. Ligand B (32.34) is well within the range.

**logP:** Ligand A (3.229) is optimal (1-3). Ligand B (4.458) is a bit high, potentially leading to solubility issues and off-target effects.

**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:** Both ligands have acceptable QED scores (0.885 and 0.78), indicating good drug-likeness.

**DILI:** Ligand A (38.348) has a lower DILI risk than Ligand B (32.842), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (85.072) has better penetration than Ligand A (61.109).

**Caco-2 Permeability:** Ligand A (-4.794) and Ligand B (-5.206) both have negative values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.257 and -4.773). This is a major drawback.

**hERG Inhibition:** Ligand A (0.364) has a lower hERG risk than Ligand B (0.683), which is a significant advantage.

**Microsomal Clearance:** Ligand A (53.852) has a lower Cl_mic, indicating better metabolic stability, than Ligand B (100.475). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (79.708) has a significantly longer half-life than Ligand B (14.005), which is highly desirable.

**P-gp Efflux:** Ligand A (0.164) shows lower P-gp efflux than Ligand B (0.532), which is beneficial for bioavailability.

**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's enough to tip the scales, especially when considering other factors.

**Overall Assessment:**

Ligand A is the better candidate. While both have poor solubility and permeability, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer half-life), lower DILI risk, lower hERG risk, and slightly better binding affinity. The higher logP of Ligand B is also a concern. The differences in metabolic stability and hERG risk are particularly important for an enzyme target like SRC kinase.

Output:
0
2025-04-17 14:55:09,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.375 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.45) is slightly above the preferred <140, but acceptable. Ligand B (84.3) is well within the range.

**logP:** Ligand A (-0.671) is a bit low, potentially hindering permeability. Ligand B (0.641) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is good. Ligand B (1 HBD, 6 HBA) is also good, both within acceptable limits.

**QED:** Both ligands have good QED scores (0.602 and 0.829), indicating drug-likeness.

**DILI:** Both ligands have similar DILI risk (57.425 and 59.984), which is acceptable (below 60).

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (58.434) and Ligand B (51.881) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.538 and -5.287), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.549 and -2.256), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.027 and 0.146), which is excellent.

**Microsomal Clearance:** Ligand A (10.635 mL/min/kg) has significantly lower microsomal clearance than Ligand B (24.216 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.143 hours) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (4.944 hours) is a reasonable half-life, but could be improved.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.046), which is favorable.

**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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -6.8 kcal/mol) outweighs the slightly worse logP and solubility. The lower microsomal clearance of Ligand A also suggests better metabolic stability. The negative half-life for Ligand A is a data quality issue that needs to be addressed, but the overall profile is still superior. Ligand B's half-life is reasonable, but its weaker binding and higher clearance make it less attractive. Addressing the solubility and permeability issues will be crucial for either compound.

Output:
0
2025-04-17 14:55:09,343 - INFO - Batch 336 complete. Total preferences: 5376
2025-04-17 14:55:09,343 - INFO - Processing batch 337/512...
2025-04-17 14:55:48,463 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.491 and 378.889 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (79.19 and 76.89) are below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have a logP around 3.1, which is optimal.

**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 similar QED scores (0.738 and 0.71), indicating good drug-likeness.

**7. DILI:** Ligand A (15.743) has a significantly lower DILI risk than Ligand B (88.251). This is a major advantage for Ligand A.

**8. BBB:**  BBB is less critical for a non-CNS target like SRC kinase. Ligand A (84.529) has a higher BBB percentile than Ligand B (69.407), but this is not a primary concern.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.242 and -5.19), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Ligand A (-1.766) has better (less negative) solubility than Ligand B (-3.783). Better solubility is desirable.

**11. hERG:** Ligand A (0.47) has a lower hERG risk than Ligand B (0.827), which is a positive attribute.

**12. Cl_mic:** Ligand A (-6.936) has much lower microsomal clearance than Ligand B (64.511). Lower clearance indicates better metabolic stability, a key factor for kinase inhibitors.

**13. t1/2:** Ligand A (24.109 hours) has a significantly longer in vitro half-life than Ligand B (5.61 hours). This is a substantial advantage.

**14. Pgp:** Ligand A (0.099) has lower P-gp efflux liability than Ligand B (0.533), which is favorable for oral bioavailability.

**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 good, the 0.5 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is clearly superior. While both have issues with Caco-2 permeability, Ligand A demonstrates significantly better ADME properties: lower DILI risk, better solubility, much lower microsomal clearance (better metabolic stability), longer half-life, lower P-gp efflux, and slightly better binding affinity. These factors are critical for an enzyme inhibitor like an SRC kinase inhibitor.

Output:
1
2025-04-17 14:55:48,463 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption (A: 81.75, B: 83.12).

**logP:** Ligand A (0.808) is a bit low, potentially hindering permeation. Ligand B (2.28) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=5) both fall within acceptable ranges.

**QED:** Ligand A (0.848) has a better QED score than Ligand B (0.659), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (A: 50.058, B: 46.375), below the 60 threshold.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (63.629) is slightly higher than A (54.246).

**Caco-2 Permeability:** Both show poor Caco-2 permeability (A: -4.764, B: -5.347). This is a concern for oral absorption.

**Aqueous Solubility:** Both have poor aqueous solubility (A: -2.18, B: -3.245). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.194, B: 0.449).

**Microsomal Clearance:** Ligand A (-8.961) has significantly lower (better) microsomal clearance than Ligand B (33.69). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (7.181 hours) has a better in vitro half-life than Ligand B (30.923 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.017, B: 0.047).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -7.9 kcal/mol, B: -8.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable safety profiles (DILI, hERG), Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better QED score. Although its logP and solubility are less ideal than Ligand B, the improved metabolic profile is more critical for an enzyme target like SRC kinase. The Caco-2 permeability is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 14:55:48,463 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.419 and 343.295 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.79) is better than Ligand B (135.55), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (-1.145) is slightly low, potentially hindering permeation, while Ligand B (1.173) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (2 HBD, 7 HBA) both have acceptable counts, well within the limits of 5 and 10 respectively.

**QED:** Both ligands have similar, good QED values (0.574 and 0.589).

**DILI:** Ligand A (24.506) has a significantly lower DILI risk than Ligand B (99.263), which is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (31.756) has a higher BBB percentile than Ligand A (16.44), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.451 and -5.257), 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 (-0.605 and -3.292), indicating poor aqueous solubility. Ligand A is slightly better.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.032 and 0.018), which is excellent.

**Microsomal Clearance:** Ligand A (1.679) has significantly lower microsomal clearance than Ligand B (26.508), indicating much better metabolic stability.

**In vitro Half-Life:** Ligand A (8.365) has a positive half-life, while Ligand B (-16.699) has a negative half-life, indicating a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.015).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.2 and -8.9 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

Ligand A is the superior candidate. While both have good binding affinity and low hERG risk, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), and slightly better TPSA and solubility. Ligand B's high DILI risk and poor metabolic stability are major drawbacks. The slightly lower logP of Ligand A is a minor concern compared to the advantages it offers.

Output:
0
2025-04-17 14:55:48,463 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly better positioned.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (90.54). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (A: 2.577, B: 1.001), falling within the 1-3 range. Ligand A is slightly preferred.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=4) as it has fewer hydrogen bond forming groups, which can improve permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.796, B: 0.615), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (21.171) has a significantly lower DILI risk than Ligand B (46.336). This is a crucial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.658) has a better BBB percentile than Ligand B (50.795).

**Caco-2 Permeability:** Ligand A (-4.695) is better than Ligand B (-5.353).

**Aqueous Solubility:** Both ligands show poor aqueous solubility (-2.548 and -2.717 respectively). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.258, B: 0.28).

**Microsomal Clearance:** Ligand B (-1.74) has a *negative* Cl_mic, which is highly unusual and suggests very high metabolic stability. Ligand A (48.191) has a moderate clearance. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-13.041) has a negative half-life, which is also unusual and suggests extreme stability. Ligand A (20.646) has a reasonable half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.07, B: 0.014).

**Binding Affinity:** Both ligands have very similar 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 factors.

**Conclusion:**

While Ligand B demonstrates exceptional metabolic stability (negative Cl_mic and half-life), which is a major advantage for an enzyme inhibitor, its higher TPSA and DILI risk are concerning. Ligand A has a better overall profile with lower TPSA, DILI risk, and better Caco-2 permeability, despite having a moderate microsomal clearance. Given the balance of properties, and the importance of minimizing off-target effects (DILI), I would choose **Ligand A** as the more viable drug candidate.

Output:
0
2025-04-17 14:55:48,463 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.419 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.6) is better than Ligand B (66.24), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.399) is slightly low, potentially hindering permeation, while Ligand B (2.968) is optimal.

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

**H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (6) is also good.

**QED:** Both ligands (0.464 and 0.419) are reasonably drug-like, but could be improved.

**DILI:** Ligand A (22.993) has a significantly lower DILI risk than Ligand B (64.637), which is a major advantage.

**BBB:** Ligand A (46.762) has a lower BBB penetration than Ligand B (70.648). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.788) has poor Caco-2 permeability, while Ligand B (-4.515) also has poor permeability.

**Aqueous Solubility:** Ligand A (-1.653) has slightly better solubility than Ligand B (-3.699).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.038 and 0.105, respectively).

**Microsomal Clearance:** Ligand A (-24.383) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (56.164).

**In vitro Half-Life:** Ligand A (-4.112) has a longer in vitro half-life than Ligand B (-14.602).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.005 and 0.482, respectively).

**Binding Affinity:** Both ligands have similar binding affinity (-8.2 and -8.8 kcal/mol).

**Conclusion:**

Ligand A is the better candidate. While Ligand B has a slightly better logP and BBB, Ligand A excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. The similar binding affinity makes these differences decisive. The lower Caco-2 permeability of Ligand A is a concern, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 14:55:48,463 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (363.527 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.34) is better than Ligand B (69.3), being closer to the <140 threshold for good absorption.

**3. logP:** Both ligands have a logP of 2.351, which 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:** Ligand A (0.844) has a slightly better QED score than Ligand B (0.772), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.442) has a significantly lower DILI risk than Ligand B (13.649). This is a major advantage.

**8. BBB:** Ligand B (82.164) has a higher BBB penetration percentile than Ligand A (58.085). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.302) has a worse Caco-2 permeability than Ligand B (-4.946), meaning it is less permeable.

**10. Aqueous Solubility:** Ligand A (-2.423) has a slightly worse aqueous solubility than Ligand B (-2.181).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.303 and 0.284, respectively).

**12. Microsomal Clearance:** Ligand B (26.797) has a lower microsomal clearance than Ligand A (30.05), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.912) has a significantly longer in vitro half-life than Ligand A (18.875). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.228 and 0.041, respectively).

**15. 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 significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and lower DILI, Ligand B's significantly stronger binding affinity (-8.7 vs -7.6 kcal/mol) and longer half-life are crucial for an enzyme target like SRC kinase. The lower microsomal clearance of Ligand B is also beneficial. The slightly lower solubility and Caco-2 permeability of Ligand B are less concerning than the weaker binding and shorter half-life of Ligand A.

Output:
1
2025-04-17 14:55:48,464 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.483 and 357.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is well below the 140 threshold, while Ligand B (108.62) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (1.93 and 1.187), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 7 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.858) has a significantly better QED score than Ligand B (0.65), indicating better overall drug-likeness.

**DILI:** Ligand B (90.927) has a higher DILI risk than Ligand A (44.552). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (82.202) has a higher BBB percentile than Ligand B (28.577).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is more important, and Ligand A (-5.189) is better than Ligand B (-5.544).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand A (-2.875) is slightly better than Ligand B (-3.876).

**hERG:** Both ligands have low hERG inhibition liability (0.52 and 0.288), which is good.

**Microsomal Clearance:** Ligand A (22.188) has a considerably lower microsomal clearance than Ligand B (9.894), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.877) has a longer in vitro half-life than Ligand B (23.597), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.078 and 0.055).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 1.1 kcal/mol, which is a notable advantage.

**Overall Assessment:**

Ligand B has a better binding affinity, but it is significantly hampered by its high DILI risk, lower QED, and poorer metabolic stability (higher Cl_mic, shorter t1/2). Ligand A, while having slightly weaker binding, presents a much more favorable ADME-Tox profile, with a lower DILI risk, better QED, better metabolic stability, and slightly better solubility and permeability. Given the enzyme-specific priorities, the improved ADME properties of Ligand A outweigh the slightly weaker binding affinity.

Output:
0
2025-04-17 14:55:48,464 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.351 Da) is slightly higher than Ligand B (345.451 Da), but both are acceptable.

**TPSA:** Ligand A (91.32) is better than Ligand B (110.75) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 2.542, B: 1.951), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 5 HBAs, while Ligand B has 7. Both are within the acceptable limit of <=10, but A is slightly preferable.

**QED:** Both ligands have similar QED values (A: 0.577, B: 0.568), indicating good drug-likeness.

**DILI:** Ligand A (49.632) has a lower DILI risk than Ligand B (55.758), making it more favorable. Both are below the 60 threshold, but lower is better.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (89.298) has a higher BBB value than Ligand A (48.468), but this is less important in this context.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.017 and -5.438), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-3.221 and -2.809), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.357) has a significantly lower hERG inhibition liability than Ligand B (0.745), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (19.287 mL/min/kg) has a much lower microsomal clearance than Ligand B (66.013 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Both have similar in vitro half-lives (A: 15.285, B: 15.099), which are acceptable.

**P-gp Efflux:** Ligand A (0.369) has lower P-gp efflux liability than Ligand B (0.259), which is favorable.

**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, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates superior ADMET properties. Specifically, Ligand A has lower DILI risk, significantly lower hERG inhibition, and much better metabolic stability (lower Cl_mic). The poor solubility and permeability are concerns for both, but the improved safety and metabolic profile of Ligand A are more critical for an enzyme target like SRC kinase. The 1.1 kcal/mol difference in binding affinity, while noticeable, is less critical than the substantial improvements in ADMET properties.

Output:
0
2025-04-17 14:55:48,464 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.435 and 336.355 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.56) is excellent, well below the 140 threshold for good absorption. Ligand B (114.41) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.527) is at the upper end of the optimal range (1-3), while Ligand B (1.515) is at the lower end. While both are within range, a logP that is too low can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but has more potential for off-target interactions.

**QED:** Both ligands have reasonable QED values (0.82 and 0.671), indicating good drug-like properties.

**DILI:** Ligand A (57.658) has a moderate DILI risk, but is still acceptable. Ligand B (97.402) has a *high* DILI risk, which is a significant concern.

**BBB:** Both ligands have similar BBB penetration (51.105 and 51.997), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.574) has poor Caco-2 permeability, while Ligand B (-5.865) is even worse. Both are quite low, suggesting absorption issues.

**Aqueous Solubility:** Ligand A (-4.411) has poor aqueous solubility. Ligand B (-3.773) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.615) has a low hERG risk, which is excellent. Ligand B (0.331) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (42.832) has moderate microsomal clearance, suggesting reasonable metabolic stability. Ligand B (0.697) has *very* low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (24.298 hours) has a good in vitro half-life. Ligand B (14.234 hours) is acceptable, but shorter.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.489 and 0.031), which is favorable.

**Binding Affinity:** Both ligands have very similar and 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.

**Conclusion:**

While Ligand B has superior metabolic stability and slightly better P-gp efflux, the *high* DILI risk is a major red flag. Ligand A, despite its lower Caco-2 permeability and solubility, has a much more acceptable safety profile (lower DILI) and a good in vitro half-life. Given the enzyme-specific priorities, minimizing toxicity is crucial. The slight absorption issues with Ligand A could potentially be addressed through formulation strategies.

Output:
0
2025-04-17 14:55:48,464 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.411 and 338.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.41) is better than Ligand B (58.2), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.897) is optimal, while Ligand B (3.498) is approaching the upper limit of the optimal range.

**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 2. Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.825 and 0.807), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (46.956 and 41.993 percentile), below the 60% threshold.

**BBB:** Ligand A (69.484) has a better BBB penetration score than Ligand B (55.874), but BBB is not a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.839 and -4.746), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.032 and -4.148), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.169 and 0.183).

**Microsomal Clearance:** Ligand A (23.661 mL/min/kg) has lower microsomal clearance than Ligand B (31.166 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (27.141 hours) has a significantly longer half-life than Ligand B (-5.403 hours). The negative value for ligand B is concerning and likely an artifact or error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.187 and 0.2).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially better binding affinity than Ligand A (-8.5 kcal/mol). This 0.7 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B stands out due to its significantly stronger binding affinity (-9.2 kcal/mol vs -8.5 kcal/mol). The longer half-life of Ligand A is attractive, but the substantial affinity advantage of Ligand B is more critical for an enzyme inhibitor. The negative half-life for ligand B is a red flag, but the binding affinity is so much better that it is still the better candidate.

Output:
1
2025-04-17 14:55:48,464 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (339.487 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.73) is well below the 140 threshold for good absorption, and even better for potential CNS penetration. Ligand B (104.89) is still within acceptable limits, but higher than A.

**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 (0.318) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 5 HBAs, and Ligand B has 7. Both are acceptable, but A is slightly better.

**QED:** Both ligands have reasonable QED scores (0.71 and 0.587), indicating drug-like properties.

**DILI:** Ligand A (19.542) has a significantly lower DILI risk than Ligand B (38.542), a major advantage.

**BBB:** Ligand A (83.986) shows better BBB penetration potential than Ligand B (25.242), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.08) has a negative value, which is unusual and suggests poor permeability. Ligand B (-4.869) is also negative, but slightly less so.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.543 and -1.147). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.886 and 0.096), which is excellent.

**Microsomal Clearance:** Ligand A (50.047) has moderate clearance, while Ligand B (-3.711) has negative clearance, which is very favorable, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (28.708 hours) has a better in vitro half-life than Ligand B (33.859 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.262 and 0.05), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -9.8 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.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the better candidate. While Ligand B has slightly better binding affinity and significantly better metabolic stability, Ligand A's lower DILI risk, better BBB penetration, and acceptable half-life outweigh these benefits. The poor solubility of both is a concern that would need to be addressed through formulation strategies, but the lower toxicity profile of Ligand A makes it the more promising starting point. The negative Caco-2 values are concerning for both, and would require further investigation.

Output:
0
2025-04-17 14:55:48,464 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.865 Da and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.09) is better than Ligand B (76.46), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.446) and Ligand B (0.835) are both within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly lower permeability, but it's not a major concern.

**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:** Ligand A (0.736) has a better QED score than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand A (47.421) has a slightly higher DILI risk than Ligand B (39.434), but both are below the concerning threshold of 60.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (65.452) is slightly better than Ligand A (55.991).

**Caco-2 Permeability:** Ligand A (-5.589) and Ligand B (-4.652) both have negative values, suggesting poor permeability. This is a potential drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.812 and -2.209 respectively). This is a significant concern for *both* compounds and will require formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.28 and 0.219 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (6.167) has a higher microsomal clearance than Ligand B (0.421), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-0.787) has a significantly longer predicted half-life than Ligand A (36.625). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.211 and 0.054 respectively).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered significant, and here it's a massive 7.8 kcal/mol difference.

**Conclusion:**

Despite both ligands having solubility issues, Ligand B is the far superior candidate. Its significantly stronger binding affinity (-7.8 vs -0.0 kcal/mol) outweighs the slightly lower QED and Caco-2 permeability. Furthermore, Ligand B demonstrates better metabolic stability (lower Cl_mic) and a longer half-life, both crucial for an enzyme inhibitor. The DILI risk is also slightly lower for Ligand B.

Output:
1
2025-04-17 14:55:48,465 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is slightly higher than Ligand B (69.72). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (1.43 and 1.787), 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 acceptable QED scores (0.813 and 0.76), indicating good drug-like properties.

**DILI:** Ligand A (54.634) has a higher DILI risk than Ligand B (20.047). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (64.948 and 65.452). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.144) has a lower Caco-2 permeability than Ligand B (-4.668). Both are negative, but B is better.

**Aqueous Solubility:** Ligand A (-1.982) has slightly better aqueous solubility than Ligand B (-2.154). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.135 and 0.122). This is excellent.

**Microsomal Clearance:** Ligand A (13.706) has lower microsomal clearance than Ligand B (54.122), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (15.408) has a positive half-life, while Ligand B (-9.486) has a negative half-life. This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.085).

**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 excels in metabolic stability (lower Cl_mic, positive t1/2) and has slightly better solubility. Ligand B has a significantly lower DILI risk and better Caco-2 permeability. Given the importance of metabolic stability for kinase inhibitors, and the acceptable DILI risk of Ligand A, Ligand A is the slightly better candidate. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 14:55:48,465 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.386 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.69) is significantly better than Ligand B (91.4). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is preferable.

**logP:** Ligand A (3.005) is optimal, while Ligand B (0.422) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) 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: 0.746, B: 0.773), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 35.595, B: 34.781), which is favorable.

**BBB:** Ligand A (85.692) has a better BBB percentile than Ligand B (64.211), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.132) is better than Ligand B (-5.019), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.94) is better than Ligand B (-1.693), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.564) has a much lower hERG risk than Ligand B (0.136), a significant advantage.

**Microsomal Clearance:** Ligand A (76.176) has higher clearance than Ligand B (-0.698). This means Ligand B is more metabolically stable, which is highly desirable for an enzyme target.

**In vitro Half-Life:** Ligand A (4.868) has a shorter half-life than Ligand B (-14.686), indicating faster metabolism. This is a significant drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.424) has lower P-gp efflux than Ligand B (0.016), which is favorable.

**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 concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and better solubility, permeability, and hERG risk. However, Ligand B has superior metabolic stability (lower Cl_mic, longer half-life). Given that SRC is an enzyme, metabolic stability is a high priority. The substantial difference in binding affinity (-8.9 vs -7.4) for Ligand A is a major advantage. While the lower half-life of Ligand A is a concern, it might be mitigated through formulation strategies. The lower logP of Ligand B is a significant drawback.

Output:
1
2025-04-17 14:55:48,465 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.36 and 350.39 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.55) is slightly higher than Ligand B (84.42). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have similar logP values (0.27 and 0.275), which are on the low side of optimal (1-3). This could potentially hinder permeation, but isn't a major concern at this stage.

**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. Ligand B is slightly better with fewer HBDs.

**QED:** Both have good QED scores (0.62 and 0.796), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both have acceptable DILI risk (49.01 and 46.22), well below the concerning threshold of 60.

**BBB:** Ligand A (55.60) has a lower BBB penetration percentile than Ligand B (81.12). Since SRC is not a CNS target, this is less critical, but higher BBB is generally favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.10 and -4.78), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.58 and -1.19), also concerning and indicating poor solubility.

**hERG:** Both have very low hERG inhibition liability (0.14 and 0.12), which is excellent.

**Microsomal Clearance:** Ligand A has a higher (worse) microsomal clearance (-4.69) than Ligand B (-3.29). Lower clearance indicates better metabolic stability, making Ligand B preferable.

**In vitro Half-Life:** Ligand A has a longer half-life (45.10 hours) than Ligand B (-4.91 hours). This is a significant advantage for Ligand A. However, the negative value for Ligand B is concerning and likely an error.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.019), which is good.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 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. Its superior binding affinity (-9.0 vs -7.6 kcal/mol) is the most important factor. It also has a better TPSA, QED, and microsomal clearance. While both have poor Caco-2 and solubility, the significantly better affinity of Ligand B makes it more likely to be a viable starting point for optimization. The negative half-life for Ligand B is a data quality issue that would need to be resolved.

Output:
1
2025-04-17 14:55:48,466 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (378.425 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.43) is better than Ligand B (49.41), both are under the 140 threshold for oral absorption.

**logP:** Both ligands have similar logP values (4.407 and 4.302), 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.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (1 HBD, 2 HBA) as it has fewer hydrogen bond donors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have identical QED scores (0.634 and 0.63), indicating good drug-likeness.

**DILI:** Ligand B (17.72) has a significantly lower DILI risk than Ligand A (94.533). This is a major advantage for Ligand B.

**BBB:** Ligand A (83.443) has a slightly better BBB penetration than Ligand B (77.007), but this is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.47 and -4.632). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand B (-3.844) is better than Ligand A (-5.853), indicating better solubility.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.6 and 0.666), which is acceptable.

**Microsomal Clearance:** Ligand B (55.968) has significantly lower microsomal clearance than Ligand A (105.342), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (3.78) has a shorter half-life than Ligand A (16.716). This is a drawback for Ligand B, but can be mitigated with formulation strategies.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.736 and 0.333), indicating moderate efflux.

**Binding Affinity:** Both ligands have identical binding affinities (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better BBB score and in vitro half-life, Ligand B excels in crucial areas for kinase inhibitors: significantly lower DILI risk, better solubility, and substantially improved metabolic stability (lower Cl_mic). The similar binding affinity makes these differences decisive. The negative Caco-2 values are concerning for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 14:55:48,466 - INFO - Batch 337 complete. Total preferences: 5392
2025-04-17 14:55:48,466 - INFO - Processing batch 338/512...
2025-04-17 14:56:29,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 367.921 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (49.41 and 47.36) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.36 and 3.573) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 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 scores (0.776 and 0.772), indicating good drug-likeness.

**DILI:** Ligand A (10.508) has a significantly lower DILI risk than Ligand B (29.973). This is a substantial advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (88.29) is better than Ligand A (74.758). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.629 and -4.873). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value simply means permeability is low, but not necessarily a complete barrier.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.666 and -3.389), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.364) has a lower hERG inhibition liability than Ligand B (0.523), which is preferable.

**Microsomal Clearance:** Ligand A (27.354 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (76.465 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (29.408 hours) has a longer in vitro half-life than Ligand A (-6.216 hours). This is a positive attribute, but the negative value for ligand A is concerning.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux liability than Ligand B (0.615), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). The difference is 1 kcal/mol, which is significant but may be outweighed by other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A demonstrates significantly lower DILI risk and microsomal clearance, and lower P-gp efflux. The lower DILI and clearance are critical for a viable drug candidate. The negative solubility and Caco-2 values are concerns for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 14:56:29,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.455 and 357.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold for oral absorption, while Ligand B (87.74) is still acceptable but higher.

**logP:** Ligand A (3.066) is optimal (1-3). Ligand B (0.527) is quite low, potentially hindering permeability.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4, both are within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED scores (0.747 and 0.63), indicating good drug-like properties.

**DILI:** Ligand A (45.444) has a slightly higher DILI risk than Ligand B (21.287), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (72.664) shows better BBB penetration than Ligand A (54.595).

**Caco-2 Permeability:** Ligand A (-4.393) and Ligand B (-4.99) 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:** Ligand A (-4.051) and Ligand B (-1.417) both have negative solubility values, indicating poor solubility. Ligand B is comparatively better.

**hERG Inhibition:** Ligand A (0.305) has a slightly higher hERG risk than Ligand B (0.161), but both are relatively low.

**Microsomal Clearance:** Ligand A (69.138) has a significantly higher microsomal clearance than Ligand B (13.896), suggesting lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-17.549) and Ligand B (-16.042) both have negative half-life values, which is unusual and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.207 and 0.017).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Ligand B is the more promising candidate. While both have solubility and permeability concerns (negative Caco-2 and solubility values), Ligand B exhibits a significantly stronger binding affinity, much better metabolic stability (lower Cl_mic), and a lower logP which, while not ideal, is less problematic than the high Cl_mic of Ligand A. The lower DILI and hERG risk are also favorable. The affinity difference is large enough to compensate for the slightly higher TPSA and lower logP.

Output:
1
2025-04-17 14:56:29,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.288 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**TPSA:** Ligand A (54.26) is significantly better than Ligand B (111.55). Lower TPSA generally improves cell permeability. Ligand B's TPSA is relatively high, potentially hindering absorption.

**logP:** Ligand A (4.093) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.963) is on the lower side, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better balanced than Ligand B (HBD=4, HBA=5). Both are within acceptable limits, but fewer H-bonds generally favor permeability.

**QED:** Both ligands have similar QED values (Ligand A: 0.656, Ligand B: 0.56), indicating reasonable drug-likeness.

**DILI:** Ligand A (68.244) has a higher DILI risk than Ligand B (36.293). This is a significant drawback for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand A (44.552) is slightly better than Ligand B (34.587).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.008) is slightly better than Ligand B (-5.151), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.32) is slightly better than Ligand B (-3.154), but both are problematic.

**hERG Inhibition:** Ligand A (0.702) has a slightly higher hERG risk than Ligand B (0.1), which is preferable.

**Microsomal Clearance:** Ligand A (25.89) has a higher microsomal clearance than Ligand B (12.379), meaning it's less metabolically stable. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand B (-23.976) has a significantly longer in vitro half-life than Ligand A (104.269). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.56) has a lower P-gp efflux liability than Ligand B (0.025), which is preferable.

**Binding Affinity:** Both ligands have very strong binding affinities (Ligand A: -9.2 kcal/mol, Ligand B: -8.1 kcal/mol). Ligand A has a 1.1 kcal/mol advantage, which is substantial and can potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significant advantage in binding affinity and slightly better permeability and solubility. However, it suffers from higher DILI risk and lower metabolic stability. Ligand B has a much better safety profile (lower DILI, lower hERG) and significantly better metabolic stability (longer half-life), but its TPSA is higher and affinity is slightly lower.

Given the enzyme-kinase target class, metabolic stability and safety (DILI, hERG) are crucial. The 1.1 kcal/mol difference in binding affinity, while substantial, is unlikely to overcome the significant safety and metabolic concerns associated with Ligand A. The longer half-life of Ligand B also suggests a potentially more favorable dosing regimen.

Output:
1
2025-04-17 14:56:29,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.447 Da) is slightly higher, but still acceptable.

**TPSA:** Ligand A (124.84) is borderline, but acceptable for an enzyme inhibitor. Ligand B (88.75) is well within the preferred range (<140).

**logP:** Ligand A (-1.663) is a bit low, potentially hindering permeability. Ligand B (3.407) is optimal.

**H-Bond Donors:** Both have 3 HBD, which is good.

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

**QED:** Both ligands have good QED scores (A: 0.549, B: 0.669), indicating drug-likeness.

**DILI:** Ligand A (25.514) has a much lower DILI risk than Ligand B (55.176), which is a significant advantage.

**BBB:** Not a major concern for a non-CNS target like SRC. Ligand B (78.402) has a higher BBB score than Ligand A (45.638), but this isn't critical here.

**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 concerning. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.041) has a very low hERG risk, a major advantage. Ligand B (0.727) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-17.333) has a negative clearance, which is impossible and likely an error in the data. This is a major red flag. Ligand B (67.155) has a high microsomal clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (-0.266) has a negative half-life, which is impossible and another data error. Ligand B (22.877) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux, which is good. Ligand B (0.262) has a low P-gp efflux, also good.

**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 concerns.

**Conclusion:**

Despite the stronger binding affinity of Ligand B, the data quality issues with Ligand A (negative clearance and half-life) are unacceptable. While Ligand B has a high clearance, the combination of its stronger binding affinity and moderate ADME properties makes it the more promising candidate. The negative solubility and permeability values for both compounds are concerning and would need to be addressed through further optimization.

Output:
1
2025-04-17 14:56:29,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.333 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.1) is excellent, well below the 140 threshold for oral absorption. Ligand B (91.3) is higher, potentially impacting absorption, though not drastically.

**logP:** Ligand A (4.666) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.377) is quite low, which could hinder membrane permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 1 HBA, while Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Ligand B (0.78) has a better QED score than Ligand A (0.468), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A at 48.895 and Ligand B at 41.76.

**BBB:** Ligand A (90.112) shows good BBB penetration, while Ligand B (55.176) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.374) and Ligand B (-5.053) both have negative Caco-2 values, indicating poor permeability. This is concerning for both.

**Aqueous Solubility:** Ligand A (-6.194) and Ligand B (-2.123) both have negative solubility values, indicating poor solubility. This is concerning for both.

**hERG Inhibition:** Ligand A (0.703) has a slightly higher hERG risk than Ligand B (0.095), which is preferable.

**Microsomal Clearance:** Ligand B (13.605) has significantly lower microsomal clearance than Ligand A (47.702), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-22.698) has a much longer in vitro half-life than Ligand A (37.464), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.231) has lower P-gp efflux than Ligand B (0.028), which is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.8 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux, but suffers from higher logP and higher metabolic clearance. Ligand B has a better QED, significantly better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and better solubility. While Ligand A's affinity is slightly better, the superior ADME properties of Ligand B, particularly its metabolic stability, make it a more promising drug candidate for an enzyme target like SRC kinase. The solubility and permeability issues are concerning for both, but metabolic stability is paramount for kinases.

Output:
1
2025-04-17 14:56:29,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.59 and 356.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold and excellent for oral absorption. Ligand B (96.69) is higher but still within an acceptable range, though potentially impacting absorption slightly more.

**logP:** Ligand A (3.70) is optimal. Ligand B (-0.065) is significantly low, potentially hindering membrane permeability and absorption.

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

**QED:** Both ligands have good QED scores (0.64 and 0.71), indicating drug-like properties.

**DILI:** Ligand A (19.35) has a much lower DILI risk than Ligand B (39.90), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.25) is better than Ligand B (65.41).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the experimental setup or the compounds themselves. 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 (0.72) has a lower hERG risk than Ligand B (0.24), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (92.35) has a higher (worse) microsomal clearance than Ligand B (-4.89). This indicates Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (10.65) has a significantly longer half-life than Ligand A (-13.04), which is a major advantage.

**P-gp Efflux:** Ligand A (0.33) has lower P-gp efflux than Ligand B (0.03), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.2), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B has a better binding affinity and significantly improved metabolic stability and half-life. However, its low logP, higher DILI risk, and higher hERG risk are major concerns. Ligand A has a more balanced profile with a good logP, lower DILI and hERG risk, and acceptable metabolic stability. The small difference in binding affinity is outweighed by the superior ADME/Tox profile of Ligand A.

Output:
0
2025-04-17 14:56:29,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.208 Da) is slightly higher than Ligand B (336.435 Da), but both are acceptable.

**TPSA:** Ligand A (94.18) is acceptable for oral absorption, while Ligand B (61.36) is even better.

**logP:** Ligand A (1.894) is optimal. Ligand B (4.065) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are within acceptable limits. Ligand B has 3 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.556, Ligand B: 0.774), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (98.527) has a very high DILI risk, which is a significant concern. Ligand B (50.291) has a much lower, and acceptable, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (61.846) has a higher BBB value than Ligand A (49.903), but this isn't a major factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This 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 (0.561) has a slightly higher hERG risk than Ligand B (0.715), but both are relatively low.

**Microsomal Clearance:** Ligand A (36.482) has a lower microsomal clearance, indicating better metabolic stability, which is a priority for kinase inhibitors. Ligand B (58.233) has higher clearance.

**In vitro Half-Life:** Ligand A (36.643) has a longer half-life than Ligand B (13.802), which is favorable.

**P-gp Efflux:** Ligand A (0.536) has lower P-gp efflux, which is good. Ligand B (0.33) is even lower.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. However, its major drawback is the very high DILI risk. Ligand B has a better safety profile (lower DILI) and slightly better QED, but its binding affinity is very weak.

Given the importance of potency for kinase inhibitors, and the possibility of mitigating DILI risk through structural modifications, Ligand A is the more promising candidate *despite* the high DILI. The substantial affinity difference (-7.9 vs 0.0 kcal/mol) is a significant advantage that could be worth pursuing with further optimization to address the DILI concern.

Output:
0
2025-04-17 14:56:29,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.431 and 344.411 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.67 and 80.57) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (1.592 and 2.031) 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 QED values (0.843 and 0.774) above 0.5, indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (32.338 and 35.401 percentile), which is favorable.

**BBB:** Both ligands have moderate BBB penetration (63.125 and 65.219 percentile). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.949 and -5.068). This is unusual and potentially problematic, indicating poor permeability. However, these values are on a log scale and negative values are possible, suggesting very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.151 and -2.566). Similar to Caco-2, this suggests very poor aqueous solubility, which is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.129 and 0.221 percentile), which is excellent.

**Microsomal Clearance:** Ligand B has a lower microsomal clearance (19.501 mL/min/kg) compared to Ligand A (27.723 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (47.844 hours) compared to Ligand A (11.861 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.036 percentile), which is favorable.

**Binding Affinity:** Both ligands have identical binding affinities (-7.5 kcal/mol), which is excellent and meets the criteria for a good starting point.

**Conclusion:**

While both ligands have excellent binding affinity and favorable safety profiles (low DILI, low hERG), Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic) and longer half-life. The poor Caco-2 and solubility values are concerning for both, but the improved pharmacokinetic properties of Ligand B outweigh this drawback.

Output:
1
2025-04-17 14:56:29,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is slightly higher than Ligand B (71.53), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have excellent logP values (2.512 and 2.448), 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 6 HBAs, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Ligand B (0.927) has a significantly higher QED score than Ligand A (0.626), indicating a more drug-like profile.

**DILI:** Ligand A (41.411) has a slightly better DILI score than Ligand B (56.727), both are acceptable, but lower is better.

**BBB:** Both ligands have good BBB penetration (71.229 and 83.404), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.772 and -4.682), which is unusual and requires further investigation. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.599 and -2.915), which is also unusual and problematic. Solubility is a key concern for kinase inhibitors.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.408 and 0.597), which is excellent.

**Microsomal Clearance:** Ligand B (18.064 mL/min/kg) has a much lower microsomal clearance than Ligand A (82.125 mL/min/kg). This suggests significantly better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (30.648 hours) has a much longer in vitro half-life than Ligand A (-6.876 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.27 and 0.149).

**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 not huge, it's still a positive factor.

**Overall Assessment:**

Ligand B is the superior candidate. It has a better QED score, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both have concerning negative solubility and Caco-2 values, the metabolic advantages of Ligand B are crucial for an enzyme target like SRC kinase. The slightly higher DILI risk for Ligand B is less concerning given the other benefits.

Output:
1
2025-04-17 14:56:29,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (370.515 Da) is also good.

**TPSA:** Ligand A (110.52) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (70.08) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (-0.641) is a bit low, potentially hindering membrane permeability. Ligand B (1.838) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also good, with a slight increase in donor count.

**QED:** Ligand B (0.8) has a significantly better QED score than Ligand A (0.474), indicating a more drug-like profile.

**DILI:** Ligand B (38.503) has a much lower DILI risk than Ligand A (55.797), which is a significant advantage.

**BBB:** Ligand A (76.696) has a better BBB penetration score than Ligand B (28.655), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on different scales and difficult to directly compare.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, difficult to directly compare.

**hERG:** Ligand A (0.016) has a very low hERG risk, a major advantage. Ligand B (0.155) is higher, but still relatively low.

**Microsomal Clearance:** Ligand B (43.521) has a lower microsomal clearance than Ligand A (54.387), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.6 hours) has a slightly better (less negative) half-life than Ligand A (-11.553 hours), suggesting better stability.

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux liability than Ligand B (0.167), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.8 kcal/mol and -7.0 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is significant.

**Conclusion:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B is the superior candidate overall. Its significantly better QED, lower DILI risk, and improved metabolic stability (lower Cl_mic, better half-life) outweigh the minor advantage in binding affinity and P-gp efflux of Ligand A. The logP of Ligand B is also more favorable. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial, and Ligand B excels in these areas.

Output:
1
2025-04-17 14:56:29,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (61.44) is significantly better than Ligand B (87.46). Lower TPSA generally improves oral absorption.

**logP:** Ligand A (3.975) is at the higher end of the optimal range, while Ligand B (0.953) is below the optimal range. A logP too low can hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (3 for A, 5 for B) counts.

**QED:** Both ligands have similar QED values (0.783 and 0.694), indicating good drug-likeness.

**DILI:** Ligand A (69.717) has a higher DILI risk than Ligand B (12.408). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.721) has a better BBB score than Ligand B (45.638).

**Caco-2 Permeability:** Ligand A (-4.691) has a worse Caco-2 permeability than Ligand B (-5.063). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-5.19) has a worse aqueous solubility than Ligand B (-0.623). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.736) has a slightly higher hERG inhibition risk than Ligand B (0.17). Lower is better.

**Microsomal Clearance:** Ligand A (73.957) has a higher microsomal clearance than Ligand B (18.935), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-13.058) has a negative half-life, which is concerning. Ligand A (35.137) has a much better half-life.

**P-gp Efflux:** Ligand A (0.582) has lower P-gp efflux than Ligand B (0.053), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-6.8 kcal/mol). The 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having better TPSA and P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.8 vs -6.8 kcal/mol) is a major advantage for an enzyme target. While Ligand A has a better half-life, Ligand B's lower DILI risk, better solubility, and lower hERG risk are also crucial. The negative half-life for Ligand B is a concern that would need further investigation, but the potency advantage is significant.

Output:
1
2025-04-17 14:56:29,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 354.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.32) is slightly higher than Ligand B (78.87), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.812 and 1.563), falling within the optimal range of 1-3.

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

**QED:** Both ligands have similar QED values (0.763 and 0.759), indicating good drug-likeness.

**DILI:** Ligand B (7.794) has a significantly lower DILI risk than Ligand A (40.403), which is a major advantage. Ligand B is well below the 40 threshold.

**BBB:** Both have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (65.801) is slightly higher than Ligand A (55.021).

**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 (0.581) has a slightly higher hERG risk than Ligand B (0.304), but both are relatively low.

**Microsomal Clearance:** Ligand B (38.932) has a lower microsomal clearance than Ligand A (24.236), indicating better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-11.382) has a negative half-life, which is impossible and suggests an issue with the data. Ligand A (27.57) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.037 and 0.021), which is good.

**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 relatively small.

**Conclusion:**

Considering all factors, **Ligand B is the more promising candidate.** Its significantly lower DILI risk and better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme target like SRC kinase. The slightly better binding affinity of Ligand B 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 for Ligand B is a data quality issue that would need to be investigated.

Output:
1
2025-04-17 14:56:29,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.56) is slightly higher than Ligand B (69.3). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets (though this isn't a CNS target).

**logP:** Ligand A (0.676) is a bit low, potentially hindering permeability. Ligand B (2.293) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 0 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 (0.723 and 0.913), indicating good drug-like properties.

**DILI:** Ligand A (42.575) has a slightly higher DILI risk than Ligand B (29.081), but both are below the concerning 60 threshold.

**BBB:** Both have good BBB penetration (78.364 and 74.06), but this is less critical for a non-CNS target like SRC.

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

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.08) shows very low hERG inhibition risk, which is excellent. Ligand B (0.622) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (41.12) has lower microsomal clearance than Ligand B (45.669), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (-4.548) has a significantly *longer* in vitro half-life than Ligand B (-36.665). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.075 and 0.069), which is favorable.

**Binding Affinity:** Ligand A (-7.6) has a slightly stronger binding affinity than Ligand B (-7.2), although the difference is relatively small.

**Overall Assessment:**

Ligand A is slightly favored due to its superior metabolic stability (lower Cl_mic, much longer t1/2), lower hERG risk, and slightly better binding affinity. While Ligand B has a better logP, the significant advantage of Ligand A in metabolic stability and half-life outweighs this. The poor Caco-2 and solubility for both are concerning and would require further investigation/optimization, but the better ADME profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 14:56:29,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 Da and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (69.72), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.775 and 0.944), falling within the optimal 1-3 range. Ligand B is slightly lower, which could potentially impact permeability, 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 (0.686) has a better QED score than Ligand B (0.384), indicating a more drug-like profile.

**DILI:** Both ligands have very similar, and acceptable, DILI risk (29.779% and 29.081%).

**BBB:** Both ligands have moderate BBB penetration (50.679% and 54.944%). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.82 and -4.596). 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 (-2.938 and -1.773). Again, these are on a log scale, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.234) has a slightly higher hERG risk than Ligand B (0.098), but both are relatively low.

**Microsomal Clearance:** Ligand A (67.198) has a higher microsomal clearance than Ligand B (27.597), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-29.763) has a significantly longer in vitro half-life than Ligand A (-16.071), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.178 and 0.014).

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor permeability and solubility predictions for both, the significantly stronger binding affinity of Ligand A (-8.7 kcal/mol vs -6.7 kcal/mol) and its better QED score outweigh its slightly higher DILI and hERG risk, and higher Cl_mic. The difference in binding affinity is substantial. The poor ADME properties would require optimization, but a strong starting point with high potency is crucial for kinase inhibitors. Ligand B's better metabolic stability is appealing, but the weaker affinity is a major disadvantage.

Output:
1
2025-04-17 14:56:29,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.495 and 355.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (65.12 and 66.65) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.156) is quite low, potentially hindering permeation. Ligand B (2.02) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 4, also acceptable.

**QED:** Both ligands have good QED scores (0.705 and 0.832), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 8.414, which is very low and excellent. Ligand B has a DILI risk of 37.999, still good, but higher than A.

**BBB:** Ligand A (43.583) has a low BBB penetration, which is not a major concern for a non-CNS target like SRC kinase. Ligand B (92.4) has high BBB penetration, which isn't particularly relevant here.

**Caco-2 Permeability:** Ligand A (-5.125) has poor Caco-2 permeability. Ligand B (-4.491) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (0.095) has very poor aqueous solubility. Ligand B (-1.709) is also poor, but better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.242 and 0.252).

**Microsomal Clearance:** Ligand A (-7.466) has very low (negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (26.279) has a higher clearance, suggesting faster metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (12.408 hours) has a reasonable half-life. Ligand B (-32.296 hours) has a negative half-life, which is not physically possible and likely an error or outlier. This is a major red flag for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.107).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-5.7 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME liabilities of Ligand B.

**Conclusion:**

While Ligand B has slightly better binding affinity, Ligand A is the superior candidate. Ligand A exhibits excellent metabolic stability (very low Cl_mic), low DILI risk, and a reasonable half-life. Ligand B has a negative half-life, which is a critical flaw, and higher microsomal clearance. Ligand A's lower logP and solubility are concerns, but the superior metabolic stability and safety profile outweigh these drawbacks.

Output:
0
2025-04-17 14:56:29,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.308 Da) is slightly higher than Ligand B (340.427 Da), but both are acceptable.

**TPSA:** Ligand A (70.23) is better than Ligand B (86.88). Lower TPSA generally favors oral absorption.

**logP:** Both ligands have good logP values (A: 3.429, B: 2.814), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 3 HBA, which is within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.62, B: 0.646), indicating good drug-likeness.

**DILI:** Ligand A (65.762) has a higher DILI risk than Ligand B (54.285). This is a negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.352) is slightly better than Ligand B (33.23).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. However, the magnitude of the negative value for Ligand A (-5.056) is worse than for Ligand B (-5.288).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.713 and -3.804 respectively).

**hERG Inhibition:** Ligand A (0.811) has a slightly higher hERG risk than Ligand B (0.463), which is unfavorable.

**Microsomal Clearance (Cl_mic):** Ligand B (23.437 mL/min/kg) has a lower Cl_mic than Ligand A (30.818 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life (t1/2):** Ligand A (86.427 hours) has a significantly longer half-life than Ligand B (22.511 hours). This is a strong positive for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.282, B: 0.131). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.6 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 factor.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. While Ligand A has a longer half-life, the risks associated with its higher DILI and hERG, coupled with the lower metabolic stability, outweigh this benefit. The solubility is poor for both, but this can be addressed with formulation strategies. The slightly better affinity of Ligand B is also a plus.

Output:
1
2025-04-17 14:56:29,989 - INFO - Batch 338 complete. Total preferences: 5408
2025-04-17 14:56:29,989 - INFO - Processing batch 339/512...
2025-04-17 14:57:16,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.5 and 349.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.92 and 74.58) are below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (0.73) is slightly low, potentially hindering permeation. Ligand B (3.318) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the 5 limit.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both below the 10 limit.

**QED:** Both ligands have good QED scores (0.768 and 0.707), indicating drug-likeness.

**DILI:** Ligand A (9.93) has a very low DILI risk, significantly better than Ligand B (31.56).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (85.46) has a higher BBB score than Ligand A (57.15), but this is not a primary concern.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual. Assuming these are logP-scale values, they indicate poor permeability.

**Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are logS values, they indicate poor solubility.

**hERG:** Ligand A (0.354) has a very low hERG risk, much better than Ligand B (0.785).

**Microsomal Clearance:** Ligand A (-17.24) has a *very* low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (65.50) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (13.67 hours) has a reasonable half-life. Ligand B (43.14 hours) has a significantly longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.048) has very low P-gp efflux, while Ligand B (0.451) has moderate efflux.

**Binding Affinity:** Ligand A (0.0 kcal/mol) has a significantly weaker binding affinity than Ligand B (-8.5 kcal/mol). This is the most critical factor. The 8.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.5 kcal/mol vs 0.0 kcal/mol). This outweighs the drawbacks of slightly higher logP, DILI, and P-gp efflux. While Ligand A has superior ADME properties (DILI, hERG, Cl_mic, P-gp), a drug needs to bind to its target to be effective. The large affinity difference makes Ligand B the more promising candidate, even if further optimization is needed to address its ADME profile.

Output:
1
2025-04-17 14:57:16,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.451 and 344.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.56) is better than Ligand B (59.07), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.087) is optimal (1-3), while Ligand B (4.147) is approaching the upper limit and could potentially cause solubility issues.

**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 (5), but both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.833) has a significantly better QED score than Ligand B (0.659), indicating a more drug-like profile.

**7. DILI:** Ligand B (33.307) has a much lower DILI risk than Ligand A (49.632), which is a significant advantage.

**8. BBB:** Ligand B (82.009) shows better BBB penetration than Ligand A (65.064), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.354) is better than Ligand B (-4.822), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.636) is better than Ligand B (-4.432), which is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.076) has a much lower hERG inhibition liability than Ligand B (0.863), a critical safety parameter.

**12. Microsomal Clearance:** Ligand B (93.748) has a higher microsomal clearance than Ligand A (50.229), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (38.142) has a longer half-life than Ligand A (-9.624), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.041) shows lower P-gp efflux than Ligand B (0.614), which is favorable for bioavailability.

**15. 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 some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better DILI score and half-life, Ligand A excels in crucial areas: significantly higher binding affinity, better QED, lower hERG risk, better solubility, and lower P-gp efflux. The stronger binding affinity of Ligand A is a major advantage for an enzyme target like SRC kinase. The better solubility and lower hERG risk also contribute to a more favorable safety profile.

Output:
1
2025-04-17 14:57:16,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.825 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.99) is better than Ligand B (93.46). Both are below 140, supporting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**3. logP:** Both ligands have good logP values (3.244 and 2.38), 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. This favors Ligand A, as fewer HBA generally improves permeability.

**6. QED:** Both ligands have reasonable QED scores (0.863 and 0.712), indicating good drug-like properties.

**7. DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (48.817). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (56.844) has a lower BBB penetration than Ligand B (73.672). Since SRC is not a CNS target, this is less critical, but still favors B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.573 and -4.731), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand B (-2.694) has better solubility than Ligand A (-5.36). Solubility is important for bioavailability, favoring B.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.584 and 0.222), which is good. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (51.763) has a higher microsomal clearance than Ligand B (32.385), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (18.76) has a longer half-life than Ligand A (30.747). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.113).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability, Ligand B demonstrates superior ADME properties: lower DILI risk, better solubility, lower microsomal clearance (better metabolic stability), and longer half-life. The binding affinity is comparable, so the ADME advantages of Ligand B outweigh the slight difference in potency.

Output:
1
2025-04-17 14:57:16,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.288 Da and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (90.93 and 84.3) below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have logP values (1.924 and 1.327) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5-6 HBA, which are acceptable.

**QED:** Both ligands have QED scores above 0.5 (0.561 and 0.84), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 75.456, which is concerning (high risk). Ligand B has a much lower DILI risk of 41.45, indicating a significantly better safety profile.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (89.104) has a slightly higher BBB score than Ligand B (67.158), but this is less important.

**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 the absolute values are similar (-4.942 vs -4.602).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-1.789) is slightly better than Ligand A (-3.96).

**hERG Inhibition:** Ligand A (0.67) has a higher hERG inhibition liability than Ligand B (0.181), which is undesirable.

**Microsomal Clearance:** Ligand B (38.504 mL/min/kg) has lower microsomal clearance than Ligand A (58.136 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.282 hours) has a slightly longer half-life than Ligand A (-2.173 hours), although both are quite short.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.26 and 0.1), which is good.

**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 can outweigh minor ADME drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the superior candidate. While both have some ADME concerns (poor solubility, permeability), Ligand B exhibits a significantly better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), and, most importantly, a substantially stronger binding affinity. The improved affinity is a key advantage for an enzyme inhibitor.

Output:
1
2025-04-17 14:57:16,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.43 & 352.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.57) is better than Ligand B (89.87). Both are below 140, supporting good oral absorption.

**logP:** Both ligands have acceptable logP values (1.027 & 1.196), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 4 HBA) regarding the number of hydrogen bond donors, though both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.573 & 0.693), indicating drug-like properties.

**DILI:** Ligand A (39.47) has a significantly lower DILI risk than Ligand B (10.93). This is a major advantage for Ligand A.

**BBB:** Ligand B (52.97) has a higher BBB penetration percentile than Ligand A (29.12). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.837 & -4.971), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.67 & -2.067), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.225) shows a much lower hERG inhibition liability than Ligand B (0.144), which is a crucial safety parameter. Lower is better.

**Microsomal Clearance:** Ligand A (-13.139) has a much lower (better) microsomal clearance than Ligand B (3.338), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-0.44) has a slightly better half-life than Ligand B (11.816).

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux liability than Ligand B (0.012), which is favorable.

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage for Ligand B. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While Ligand B boasts a much superior binding affinity, the significant drawbacks of poor solubility, higher DILI risk, and higher P-gp efflux are concerning. Ligand A, despite its weak binding affinity, has a much better safety profile (lower DILI, lower hERG, lower P-gp) and better metabolic stability. The poor solubility and permeability are shared concerns, but can potentially be addressed through formulation strategies. Given the enzyme-kinase focus, metabolic stability and safety are paramount. The large affinity difference is substantial, but the ADME/Tox profile of Ligand B is too risky.

Output:
0
2025-04-17 14:57:16,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.487 Da and 347.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.76) is slightly higher than Ligand B (64.86), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.297 and 2.839, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.746 and 0.588, respectively), indicating good drug-like properties.

**DILI:** Ligand B (39.589) has a significantly lower DILI risk than Ligand A (55.448), which is a major advantage. Ligand B is well below the 40 threshold, while Ligand A is moderately risky.

**BBB:** Ligand A (84.684) shows better BBB penetration than Ligand B (70.182), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand B (-5.003) has a slightly better Caco-2 permeability than Ligand A (-4.349), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-3.273) has better aqueous solubility than Ligand A (-3.553).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.517 and 0.496, respectively).

**Microsomal Clearance:** Ligand B (62.923) has a lower microsomal clearance than Ligand A (76.679), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (13.771 hours) has a longer in vitro half-life than Ligand A (31.112 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.261 and 0.339, 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 could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B presents a much more favorable ADME profile, particularly regarding DILI risk and metabolic stability (lower Cl_mic and longer half-life). The difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. The lower DILI and improved metabolic stability of Ligand B make it a safer and more likely candidate to progress further in development.

Output:
1
2025-04-17 14:57:16,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.354 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (60.45 and 58.64) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.781) is slightly higher than optimal (1-3), but still acceptable. Ligand B (2.464) is within the optimal 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 QED values above 0.5 (0.716 and 0.635), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (91.819 percentile) than Ligand B (17.759 percentile). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (75.107 and 71.035 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.226 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 (-5.575 and -2.848), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Ligand A (0.754) has a slightly higher hERG risk than Ligand B (0.357), but both are relatively low.

**Microsomal Clearance:** Ligand B has a considerably lower microsomal clearance (68.139 mL/min/kg) than Ligand A (131.387 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a negative in vitro half-life (-4.875 hours) which is problematic, while Ligand A has a positive value (20.944 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.259 and 0.104).

**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 for Ligand A.

**Overall Assessment:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.1 vs -7.0 kcal/mol) is a major advantage that could outweigh the other drawbacks. The longer in vitro half-life of Ligand A is also beneficial. However, the high DILI risk associated with Ligand A is a significant concern that would need to be addressed through structural modifications. Ligand B's lower DILI risk is attractive, but its weaker binding affinity and negative half-life are substantial drawbacks.

Output:
0
2025-04-17 14:57:16,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (378.416 and 360.439 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (88.44) is still under 140, but less optimal than A.

**logP:** Ligand A (4.255) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.954) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 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 (0.55 and 0.847), indicating drug-like properties.

**DILI:** Both ligands have DILI risk around 60-67, which is acceptable, but not ideal.

**BBB:** Ligand A (70.531) shows better BBB penetration than Ligand B (55.603), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.776) and Ligand B (-5.052) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Ligand A (-5.211) and Ligand B (-3.213) both have very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.605) has a slightly higher hERG risk than Ligand B (0.306), but both are reasonably low.

**Microsomal Clearance:** Ligand B (36.411) has significantly lower microsomal clearance than Ligand A (81.203), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-5.911) has a negative half-life, which is not possible. This is a red flag and suggests potential issues with the data or the compound itself. Ligand A (21.513) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.137 and 0.102).

**Binding Affinity:** Ligand B (-10.0 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.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-10.0 vs -8.5 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, its lower microsomal clearance suggests better metabolic stability. The negative in vitro half-life for Ligand B is a serious concern, but if this is a data error, it further strengthens the case for B. Ligand A's slightly higher logP and hERG risk are less concerning than B's superior potency and metabolic stability.

Output:
1
2025-04-17 14:57:16,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 347.371 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (65.78) is well below the 140 threshold, suggesting good absorption. Ligand B (110.53) is still within acceptable limits but less favorable than A.

**logP:** Ligand A (1.558) is optimal. Ligand B (0.927) is slightly low, potentially impacting permeability, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=6) regarding the balance between solubility and permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.883, B: 0.784), indicating good drug-like properties.

**DILI:** Ligand A (45.328) has a much lower DILI risk than Ligand B (67.507), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (55.215) is slightly better than Ligand B (43.001).

**Caco-2 Permeability:** Ligand A (-4.514) is better than Ligand B (-5.064), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.148) is better than Ligand B (-3.027), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.393) has a lower hERG risk than Ligand B (0.078), a critical safety parameter.

**Microsomal Clearance:** Ligand A (31.545) has a higher (worse) microsomal clearance than Ligand B (1.004), indicating lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (19.346) has a longer half-life than Ligand A (11.853), which is desirable.

**P-gp Efflux:** Ligand A (0.29) has lower P-gp efflux than Ligand B (0.023), which is a slight advantage.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.0), but the difference is relatively small (0.8 kcal/mol).

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, H-bonds, DILI, solubility, hERG, P-gp) and has a slightly better binding affinity. However, its significantly higher microsomal clearance is a major concern. Ligand B has a better metabolic profile (lower Cl_mic and longer t1/2) but suffers from a higher DILI risk, lower solubility, and a slightly weaker binding affinity.

Given the enzyme-specific priorities, metabolic stability is crucial. While Ligand A's affinity is slightly better, the substantial difference in Cl_mic makes Ligand B the more promising candidate. The difference in affinity (0.8 kcal/mol) is unlikely to overcome the significant metabolic disadvantage of Ligand A.

Output:
1
2025-04-17 14:57:16,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.423 and 361.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.7) is slightly above the preferred <90 for CNS, but acceptable. Ligand B (46.61) is excellent, well below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.109) is quite low, potentially hindering permeability. Ligand B (3.345) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both within acceptable limits. Ligand B has 0 HBD and 4 HBA, also good.

**QED:** Both ligands have good QED scores (0.772 and 0.808), indicating drug-like properties.

**DILI:** Ligand A (56.65) has a moderate DILI risk, while Ligand B (28.616) is very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (55.37) has a moderate BBB penetration, while Ligand B (85.847) is high. While SRC isn't a CNS target, higher BBB penetration *can* sometimes correlate with better overall distribution.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.088 and -4.822), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.908 and -3.244), indicating very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.288) has a slightly elevated hERG risk, while Ligand B (0.375) is also slightly elevated. Both are relatively low, but still warrant attention.

**Microsomal Clearance:** Ligand A (17.661) has lower clearance, suggesting better metabolic stability. Ligand B (67.734) has significantly higher clearance, indicating rapid metabolism. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.418) has a longer half-life than Ligand B (6.948). This is another point in favor of Ligand A.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.004 and 0.598).

**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, potentially outweighing some of the ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much lower DILI risk. However, it suffers from high microsomal clearance, which means it will be rapidly metabolized. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) but weaker binding affinity and a slightly higher DILI risk. Both have poor solubility and permeability.

Given the enzyme-specific priorities, potency (binding affinity) is paramount. The >1.5 kcal/mol difference in binding affinity is substantial. While the ADME profile of Ligand B is less ideal, the strong binding could potentially be optimized through further medicinal chemistry efforts. The poor solubility and permeability are shared issues that would need to be addressed regardless of which lead is chosen.

Output:
1
2025-04-17 14:57:16,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.473 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (75.27). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have good logP values (3.696 and 2.113), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (2 HBD, 3 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.769 and 0.802), indicating good drug-likeness.

**DILI:** Ligand A (16.208) has a much lower DILI risk than Ligand B (25.785), which is a significant advantage.

**BBB:** Ligand A (97.402) shows excellent BBB penetration, while Ligand B (55.176) is moderate. While not a primary concern for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.294) and Ligand B (-4.864) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.915) is slightly better than Ligand B (-2.718), but both are poor. Solubility is a concern for both, but slightly less so for A.

**hERG Inhibition:** Both ligands have very low hERG risk (0.679 and 0.076). This is excellent for both.

**Microsomal Clearance:** Ligand A (47.149) has higher microsomal clearance than Ligand B (23.512), meaning it's less metabolically stable. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-2.797) has a much better in vitro half-life than Ligand A (-21.973). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.058 and 0.06).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.6 kcal/mol). Ligand A is slightly better (-9.4 kcal/mol).

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, and better TPSA. However, it suffers from significantly higher microsomal clearance and a much shorter in vitro half-life, and poor Caco-2 permeability. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, but a higher DILI risk and slightly weaker binding affinity.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), Ligand B is the more promising candidate. While the binding affinity is slightly lower, the improved metabolic stability and half-life are crucial for *in vivo* efficacy. The DILI risk is manageable, and solubility can be addressed with formulation strategies. The permeability is a concern for both, but can be addressed with prodrug strategies.

Output:
1
2025-04-17 14:57:16,955 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [337.463, 38.33, 4.575, 1, 2, 0.803, 39.744, 69.911, -4.666, -5.402, 0.573, 111.14, -5.948, 0.507, -8.2]
**Ligand B:** [354.357, 87.47, 1.109, 2, 5, 0.748, 58.434, 84.025, -5.019, -1.826, 0.232, -19.07, -16.778, 0.025, -7.8]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (337.463) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (38.33) is excellent, well below the 140 threshold for oral absorption. B (87.47) is higher, but still acceptable, though less optimal.
3. **logP:** A (4.575) is a bit high, potentially leading to solubility issues and off-target interactions. B (1.109) is very good, within the optimal range.
4. **HBD:** Both have acceptable HBD counts (A: 1, B: 2), well below the limit of 5.
5. **HBA:** Both have acceptable HBA counts (A: 2, B: 5), below the limit of 10.
6. **QED:** Both are reasonably good (A: 0.803, B: 0.748), indicating drug-like properties.
7. **DILI:** A (39.744) has a lower DILI risk than B (58.434), which is a significant advantage.
8. **BBB:** A (69.911) has a moderate BBB penetration, while B (84.025) is better. However, SRC is not a CNS target, so this is less critical.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. A (-4.666) is slightly better than B (-5.019).
10. **Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. B (-1.826) is slightly better than A (-5.402).
11. **hERG:** A (0.573) has a lower hERG risk than B (0.232), which is a significant advantage.
12. **Cl_mic:** A (111.14) has a higher microsomal clearance than B (-19.07), indicating lower metabolic stability. This is a significant drawback for A.
13. **t1/2:** A (-5.948) has a shorter in vitro half-life than B (-16.778), indicating faster metabolism. This is another drawback for A.
14. **Pgp:** A (0.507) has a lower P-gp efflux liability than B (0.025), which is a slight advantage.
15. **Binding Affinity:** A (-8.2) has a significantly stronger binding affinity than B (-7.8). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Decision:**

While Ligand A boasts a much stronger binding affinity, its significantly higher microsomal clearance, shorter half-life, and lower solubility are major concerns. Ligand B, despite having a slightly weaker affinity, presents a much more favorable ADME-Tox profile with lower DILI risk, better metabolic stability, and better solubility. The difference in binding affinity (0.4 kcal/mol) is not large enough to overcome the substantial ADME deficiencies of Ligand A.

Therefore, I recommend **Ligand B** as the more viable drug candidate.

Output:
1
2025-04-17 14:57:16,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (375.47 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99) is higher than Ligand B (71.53). While both are reasonably good, Ligand B is better positioned for oral absorption.

**logP:** Ligand A (0.406) is quite low, potentially hindering permeability. Ligand B (2.916) 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 8 HBAs, while Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.795) has a better QED score than Ligand B (0.51), suggesting a more drug-like profile overall.

**DILI:** Ligand A (53.276) has a slightly higher DILI risk than Ligand B (43.505), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.392) is slightly better than Ligand B (42.769).

**Caco-2:** Ligand A (-4.918) and Ligand B (-5.176) have similar, very low Caco-2 permeability values, indicating poor intestinal absorption for both.

**Solubility:** Ligand A (-2.514) and Ligand B (-2.227) have similar, very low solubility values, which is a concern.

**hERG:** Ligand A (0.065) has a significantly lower hERG risk than Ligand B (0.236), which is a major advantage.

**Microsomal Clearance:** Ligand A (12.066) has a lower microsomal clearance than Ligand B (91.915), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.975) has a longer half-life than Ligand B (2.367), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.192), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and superior metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. It also has a lower hERG risk. While its logP is low and Caco-2/solubility are poor, the strong binding affinity and improved safety/stability profile are more critical for an enzyme target like SRC. Ligand B has a better logP and TPSA, but the weaker binding, poorer metabolic stability, and higher hERG risk are significant drawbacks.

Output:
0
2025-04-17 14:57:16,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (378.441 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (94.81), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.417) is optimal (1-3), while Ligand B (1.373) is on the lower end, potentially hindering permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.794 and 0.623), suggesting good drug-like properties.

**DILI:** Ligand A (71.539) has a higher DILI risk than Ligand B (11.361). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (64.831) is higher than Ligand B (26.561).

**Caco-2 Permeability:** Ligand A (-4.797) is worse than Ligand B (-5.347), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.874) is better than Ligand B (-1.042), which is a positive attribute for bioavailability.

**hERG Inhibition:** Ligand A (0.734) has a lower hERG risk than Ligand B (0.285), which is a significant advantage.

**Microsomal Clearance:** Ligand A (47.616) has a higher clearance than Ligand B (-2.442), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-15.891) has a shorter half-life than Ligand B (36.507), indicating faster metabolism.

**P-gp Efflux:** Ligand A (0.209) has lower P-gp efflux than Ligand B (0.023), which is a positive for bioavailability.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better solubility and hERG risk profile. However, it suffers from higher DILI risk, higher clearance, and shorter half-life. Ligand B has a much better safety profile (lower DILI, lower hERG) and better metabolic stability, but its lower logP and weaker binding affinity are concerning.

Given the importance of potency for kinase inhibitors, the 1 kcal/mol advantage of Ligand A is significant. While the DILI risk is a concern, it might be mitigated through structural modifications. The metabolic stability issues could also be addressed through prodrug strategies or structural changes. The lower logP of Ligand B is a more fundamental issue that may be harder to resolve without significantly impacting affinity.

Output:
1
2025-04-17 14:57:16,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.459 and 344.375 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (77.23) is well below the 140 threshold for good absorption and is favorable. Ligand B (124.16) is still under the threshold but less optimal than A.

**logP:** Ligand A (1.645) is within the optimal range of 1-3. Ligand B (-0.228) is slightly below 1, which *could* indicate permeability issues, though not drastically.

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

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 7. Ligand A is preferable here.

**QED:** Both ligands have similar QED values (0.76 and 0.665), indicating good drug-likeness.

**DILI:** Ligand A (15.355) has a significantly lower DILI risk than Ligand B (68.476). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (61.962) is slightly better than A (46.84) but not a deciding factor.

**Caco-2 Permeability:** Both have negative values (-5.316 and -5.588), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so these values are not useful.

**Aqueous Solubility:** Both have negative values (-2.392 and -2.776), again suggesting poor solubility. These values are on a scale where higher is better, so these values are not useful.

**hERG Inhibition:** Both ligands have low hERG risk (0.263 and 0.213).

**Microsomal Clearance:** Ligand A (-11.8) has a much lower (better) microsomal clearance than Ligand B (-22.682), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.536) has a better in vitro half-life than Ligand B (-7.074).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.013).

**Binding Affinity:** Ligand A (-9.1) has a slightly better binding affinity than Ligand B (-8.3). While both are good, the 0.8 kcal/mol difference is noticeable.

**Conclusion:**

Ligand A is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), better TPSA and HBA values, and slightly better binding affinity. While both have issues with predicted permeability and solubility, the ADME profile of Ligand A is superior, and the slightly improved binding affinity adds to its favorability.

Output:
1
2025-04-17 14:57:16,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (383.813 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.36) is slightly higher than the preferred <140, but still reasonable. Ligand B (76.02) is excellent, well below 140.

**logP:** Both ligands (1.194 and 1.907) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, meeting the <5 and <10 criteria. Ligand B has 2 HBD and 5 HBA, also meeting the criteria.

**QED:** Both ligands have good QED scores (0.795 and 0.727), indicating good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (96.976 percentile). Ligand B has a much lower and acceptable DILI risk (37.224 percentile). This is a significant negative for Ligand A.

**BBB:** Both have similar BBB penetration (51.377 and 53.897 percentile), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.758) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.486) also has poor Caco-2 permeability, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-3.512) and Ligand B (-2.681) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.263) shows a slightly higher hERG inhibition risk than Ligand B (0.13), though both are relatively low.

**Microsomal Clearance:** Ligand A (-1.637) has a negative value, indicating very low clearance and excellent metabolic stability. Ligand B (19.962) has a high clearance, suggesting poor metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-9.945) has a very long in vitro half-life, consistent with the low clearance. Ligand B (1.42) has a short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.057).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.7 kcal/mol). While a 0.6 kcal/mol difference isn't huge, it's noticeable.

**Overall Assessment:**

Ligand A has excellent metabolic stability and half-life, but suffers from poor Caco-2 permeability, poor solubility, and a very high DILI risk. Ligand B has better Caco-2 permeability, solubility, and a much lower DILI risk, but has poor metabolic stability and a shorter half-life.

Given the enzyme-specific priorities, metabolic stability is crucial. However, the extremely high DILI risk associated with Ligand A is a major red flag. While its metabolic stability is attractive, the potential for liver toxicity is too significant to ignore. Ligand B, despite its lower metabolic stability, presents a more balanced profile with a much more acceptable safety profile. The slightly better binding affinity of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 14:57:16,957 - INFO - Batch 339 complete. Total preferences: 5424
2025-04-17 14:57:16,957 - INFO - Processing batch 340/512...
2025-04-17 14:58:08,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (78.95), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.705) is slightly better than Ligand B (0.45), both are a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (1), as it provides a better balance of solubility and permeability.

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

**QED:** Ligand B (0.748) has a slightly better QED score than Ligand A (0.598), indicating a more drug-like profile.

**DILI:** Ligand A (18.651) has a significantly lower DILI risk than Ligand B (31.097). This is a major advantage for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 60.45, Ligand B: 66.615). Since SRC is not a CNS target, this isn't a primary concern.

**Caco-2 Permeability:** Ligand A (-5.013) is worse than Ligand B (-4.761), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.739) is better than Ligand B (-2.007), which is a significant advantage for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.197, Ligand B: 0.124).

**Microsomal Clearance:** Ligand B (3.491) has significantly lower microsomal clearance than Ligand A (31.228), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-13.744) has a much longer in vitro half-life than Ligand A (-0.635), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.018, Ligand B: 0.027).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5). While the difference is less than the 1.5 kcal/mol threshold, it is still a positive factor.

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity and QED score. However, Ligand A has a much lower DILI risk and better solubility. Considering the enzyme-specific priorities, metabolic stability is critical. The difference in binding affinity is not substantial enough to outweigh the significant advantage of Ligand B's metabolic profile. The lower DILI risk of Ligand A is good, but can be addressed during further optimization.

Output:
1
2025-04-17 14:58:08,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is slightly higher than the preferred <140, but acceptable. Ligand B (67.43) is well within the range.

**logP:** Both ligands have logP values (1.288 and 2.64) 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 5 HBA, and Ligand B has 3, both are within the acceptable limit of <=10.

**QED:** Ligand A (0.776) has a better QED score than Ligand B (0.672), indicating a more drug-like profile.

**DILI:** Ligand A (47.421) has a slightly higher DILI risk than Ligand B (12.214), but both are below the concerning threshold of 60.

**BBB:** Ligand A (58.201) has a lower BBB penetration percentile than Ligand B (74.06). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.622) has a very poor Caco-2 permeability, while Ligand B (-4.73) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.984) has poor aqueous solubility, while Ligand B (-3.25) is also poor.

**hERG:** Ligand A (0.052) has a very low hERG inhibition liability, which is excellent. Ligand B (0.379) is slightly higher, but still acceptable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (60.983 and 58.007 mL/min/kg), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand B (6.002 hours) has a significantly longer in vitro half-life than Ligand A (-30.786 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux liability, which is good. Ligand B (0.087) is slightly higher, but still low.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-8.0 kcal/mol). This is a crucial factor, as a 1.2 kcal/mol difference is substantial.

**Conclusion:**

While Ligand A has a slightly better QED and lower hERG risk, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better binding affinity and a much longer in vitro half-life. The slightly higher DILI and Pgp efflux of Ligand B are less concerning than the poor Caco-2 permeability and shorter half-life of Ligand A. The improved binding affinity of Ligand B is likely to outweigh the minor ADME drawbacks.

Output:
1
2025-04-17 14:58:08,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.41 and 356.388 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.31) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**logP:** Ligand A (0.311) is quite low, potentially hindering membrane permeability. Ligand B (2.438) 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 2 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.765) has a better QED score than Ligand B (0.561), indicating a more drug-like profile overall.

**DILI:** Ligand A (20.396) has a much lower DILI risk than Ligand B (12.641), which is a substantial advantage.

**BBB:** Both have high BBB penetration, but Ligand B (91.314) is slightly better than Ligand A (85.111). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.632) has poorer Caco-2 permeability than Ligand B (-4.464), though the difference is small.

**Aqueous Solubility:** Ligand A (-0.839) has slightly better solubility than Ligand B (-3.031). Solubility is important for kinases.

**hERG Inhibition:** Ligand A (0.293) has a lower hERG risk than Ligand B (0.481), which is favorable.

**Microsomal Clearance:** Ligand A (-9.134) has significantly *lower* (better) microsomal clearance than Ligand B (8.315), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (14.262) has a longer half-life than Ligand B (-3.163), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.081), which is a slight advantage.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.0 kcal/mol, respectively). Ligand A has a 1.9 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better DILI and metabolic stability, its low logP and poorer Caco-2 permeability are concerning. Ligand B has a more favorable logP and TPSA, suggesting better permeability, but its DILI risk and metabolic stability are worse. The binding affinity difference is significant, and for a kinase inhibitor, potency is paramount. The improved metabolic stability of Ligand A is also a major plus. Considering the enzyme-specific priorities, the binding affinity advantage and improved metabolic stability of Ligand A are more important than the slightly less optimal logP.

Output:
0
2025-04-17 14:58:08,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.434 and 340.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.27) is slightly higher than Ligand B (65.97), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands (3.363 and 3.549) 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, while Ligand B has 6.  Ligand A is preferable here, as lower HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.741 and 0.868), indicating drug-likeness.

**DILI:** Ligand A (55.176) has a slightly better DILI score than Ligand B (63.513), suggesting lower potential for liver injury. Both are acceptable, but lower is better.

**BBB:** Both have high BBB penetration (76.735 and 77.937), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.528 and -4.903), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.489 and -4.69), also indicating poor solubility. This is a major concern for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.548 and 0.81), which is excellent.

**Microsomal Clearance:** Ligand A (63.636) has a lower microsomal clearance than Ligand B (81.865), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (33.362) has a significantly longer in vitro half-life than Ligand A (11.366). This is a substantial benefit for dosing frequency.

**P-gp Efflux:** Both have low P-gp efflux (0.259 and 0.238), which is favorable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.3 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand A has a slight edge due to its better DILI score, lower HBA, and stronger binding affinity. However, both ligands suffer from poor predicted solubility and permeability. The longer half-life of Ligand B is a significant advantage. Given the importance of metabolic stability for enzyme inhibitors, and the substantial difference in half-life, Ligand B is slightly more promising *despite* the slightly worse DILI and HBA. The binding affinity difference is small enough to be outweighed by the improved PK profile.

Output:
1
2025-04-17 14:58:08,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (354.4 and 343.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is well below the 140 threshold for good absorption. Ligand B (112.82) is still acceptable, but higher.

**3. logP:** Ligand A (2.262) is optimal (1-3). Ligand B (0.776) 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 3 HBA, and Ligand B has 7 HBA, both within the acceptable limit of <=10, but Ligand B is approaching the upper limit.

**6. QED:** Both ligands have good QED scores (0.789 and 0.851), indicating drug-like properties.

**7. DILI:** Ligand A (40.054) is better than Ligand B (67.817), indicating a lower risk of drug-induced liver injury. Ligand B is approaching a higher risk category.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.823) is higher than Ligand B (51.532).

**9. Caco-2 Permeability:** Ligand A (-4.254) is better than Ligand B (-5.654), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.761) is better than Ligand B (-3.23), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.518) is better than Ligand B (0.061), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (31.297) is significantly better than Ligand B (0.254), suggesting much greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.185) is significantly better than Ligand B (10.68), indicating a longer half-life.

**14. P-gp Efflux:** Ligand A (0.084) is better than Ligand B (0.028), suggesting lower P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.2) is slightly better than Ligand B (0.0), indicating a stronger binding affinity.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, and has a slightly better binding affinity. Specifically, Ligand A has a much better metabolic stability profile (Cl_mic and t1/2), lower DILI risk, better solubility, and lower hERG risk. While Ligand B has a slightly higher QED, the significant advantages of Ligand A in key enzyme-specific parameters outweigh this. The lower logP of Ligand B is a concern.

Output:
1
2025-04-17 14:58:08,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Ligand A:**
*   **MW:** 367.431 Da - Good (within 200-500 range)
*   **TPSA:** 128.34 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 0.491 - Low, potentially hindering permeation.
*   **HBD:** 3 - Good.
*   **HBA:** 7 - Good.
*   **QED:** 0.611 - Good.
*   **DILI:** 83.288 - High risk of liver injury.
*   **BBB:** 50.446 - Low, not a concern for a non-CNS target.
*   **Caco-2:** -5.515 - Very poor permeability.
*   **Solubility:** -2.413 - Poor solubility.
*   **hERG:** 0.618 - Relatively low risk.
*   **Cl_mic:** -2.253 - Low clearance, good metabolic stability.
*   **t1/2:** -29.197 - Very long half-life, excellent.
*   **Pgp:** 0.048 - Low efflux, good.
*   **Affinity:** -6.9 kcal/mol - Good binding affinity.

**Ligand B:**
*   **MW:** 342.443 Da - Good (within 200-500 range)
*   **TPSA:** 59.39 - Excellent, promotes good absorption.
*   **logP:** 3.18 - Optimal.
*   **HBD:** 1 - Good.
*   **HBA:** 4 - Good.
*   **QED:** 0.877 - Excellent.
*   **DILI:** 36.293 - Low risk of liver injury.
*   **BBB:** 72.237 - Moderate, not a primary concern.
*   **Caco-2:** -4.735 - Poor permeability, but better than Ligand A.
*   **Solubility:** -3.821 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.881 - Relatively low risk.
*   **Cl_mic:** 76.184 - High clearance, poor metabolic stability.
*   **t1/2:** 8.195 - Short half-life.
*   **Pgp:** 0.526 - Moderate efflux.
*   **Affinity:** -10.0 kcal/mol - Excellent binding affinity.

**Comparison & Decision:**

Ligand B has a significantly stronger binding affinity (-10.0 kcal/mol vs -6.9 kcal/mol). This is a substantial advantage for an enzyme target like SRC kinase, and can potentially outweigh some of its drawbacks. While Ligand B has a higher Cl_mic and shorter t1/2 than Ligand A, the dramatic difference in binding affinity is the deciding factor. Ligand A's extremely poor Caco-2 and solubility, combined with the high DILI risk, make it a less attractive candidate despite its favorable metabolic stability and half-life. Ligand B's TPSA and logP are also more favorable for absorption.

Output:
1
2025-04-17 14:58:08,083 - INFO - Okay, let's analyze these two ligands (A and B) as potential drug candidates targeting SRC, a kinase. I'll follow the provided guidelines and prioritize potency, metabolic stability, solubility, and hERG risk.

**Ligand A: [421.259, 71.06, 3.502, 0, 6, 0.473, 55.68, 74.99, -4.138, -4.582, 0.664, 117.577, 14.163, 0.309, -7.5]**

*   **MW:** 421.259 Da - Within the ideal range (200-500).
*   **TPSA:** 71.06 - Good for oral absorption (<140).
*   **logP:** 3.502 - Optimal (1-3).
*   **HBD:** 0 - Low, good for permeability.
*   **HBA:** 6 - Acceptable (<10).
*   **QED:** 0.473 - Below the preferred threshold of 0.5, suggesting a less drug-like profile.
*   **DILI:** 55.68 - Moderate risk, but acceptable.
*   **BBB:** 74.99 - Good, indicating some potential for CNS penetration, though not crucial for SRC.
*   **Caco-2:** -4.138 - Poor permeability. This is a significant concern.
*   **Solubility:** -4.582 - Very poor solubility. A major drawback.
*   **hERG:** 0.664 - Low risk, good.
*   **Cl_mic:** 117.577 mL/min/kg - High metabolic clearance, suggesting poor metabolic stability.
*   **t1/2:** 14.163 hours - Moderate half-life.
*   **Pgp:** 0.309 - Low efflux, good.
*   **Affinity:** -7.5 kcal/mol - Excellent binding affinity.

**Ligand B: [366.845, 70.08, 2.035, 1, 4, 0.883, 55.68, 43.699, -4.918, -2.288, 0.048, 0.243, -2.155, 0.012, -7.3]**

*   **MW:** 366.845 Da - Within the ideal range (200-500).
*   **TPSA:** 70.08 - Good for oral absorption (<140).
*   **logP:** 2.035 - Optimal (1-3).
*   **HBD:** 1 - Low, good for permeability.
*   **HBA:** 4 - Acceptable (<10).
*   **QED:** 0.883 - Excellent drug-like profile.
*   **DILI:** 55.68 - Moderate risk, acceptable.
*   **BBB:** 43.699 - Lower, not a major concern for SRC.
*   **Caco-2:** -4.918 - Poor permeability.
*   **Solubility:** -2.288 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.048 - Very low risk, excellent.
*   **Cl_mic:** 0.243 mL/min/kg - Very low metabolic clearance, indicating excellent metabolic stability.
*   **t1/2:** -2.155 hours - Very short half-life, a significant drawback.
*   **Pgp:** 0.012 - Very low efflux, good.
*   **Affinity:** -7.3 kcal/mol - Very good binding affinity, slightly less than Ligand A.

**Comparison and Decision:**

Both ligands have similar binding affinities, with Ligand A being slightly better (-7.5 vs -7.3). However, Ligand A suffers from very poor solubility and high metabolic clearance, which are critical issues for an enzyme inhibitor. Ligand B has excellent metabolic stability (very low Cl_mic) and a better QED score, indicating a more drug-like profile. Although Ligand B has a very short half-life, this can potentially be addressed through structural modifications. The poor solubility and permeability of both compounds are concerning, but the metabolic stability of Ligand B is a significant advantage for a kinase inhibitor.

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, hERG), and the fact that the affinity difference is relatively small, **Ligand B is the more promising candidate**. The metabolic stability and better drug-like properties outweigh the slightly lower affinity and short half-life, which can be optimized in subsequent iterations.

1
2025-04-17 14:58:08,084 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.4 and 342.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is better than Ligand B (68.87) as it's closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.402 and 3.168), falling within the 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for off-target effects, but isn't critical.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=5) as it has fewer hydrogen bond donors and acceptors, generally improving permeability.

**QED:** Both have reasonable QED scores (0.886 and 0.752), indicating good drug-like properties.

**DILI:** Ligand A (39.67) has a significantly lower DILI risk than Ligand B (51.26), which is a major advantage.  Lower DILI is crucial.

**BBB:** Both have similar BBB penetration (89.92 and 89.07), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.578) has a more favorable Caco-2 permeability value than Ligand B (-5.44), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.798) has a slightly better solubility than Ligand B (-3.001), though both are quite poor. This could pose formulation challenges, but isn't a dealbreaker.

**hERG Inhibition:** Ligand A (0.478) has a lower hERG risk than Ligand B (0.933), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (24.675) has a lower microsomal clearance than Ligand B (31.617), indicating better metabolic stability. This is a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (-31.728) has a much longer in vitro half-life than Ligand B (15.323), which is a substantial benefit for dosing frequency.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.167), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-6.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While affinity is paramount, the difference of 0.5 kcal/mol is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall:** Ligand A is significantly better. It has a lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), better permeability, and comparable binding affinity. While Ligand B has slightly better affinity, the ADME/Tox profile of Ligand A is far superior, making it the more viable drug candidate.

Output:
0
2025-04-17 14:58:08,084 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.367 and 362.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.73) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (61.02) is well within the optimal range.

**3. logP:** Ligand A (1.765) is within the optimal 1-3 range. Ligand B (4.433) is a bit high, potentially leading to solubility issues 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 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.812 and 0.73), indicating good drug-like properties.

**7. DILI:** Ligand A (69.252) has a higher DILI risk than Ligand B (51.725), but both are still within a manageable range.

**8. BBB:** Both ligands have good BBB penetration (71.772 and 70.958). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.047 and -5.079). This is unusual and suggests poor permeability. However, these values might be experimental artifacts or indicate a specific transport mechanism.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.766 and -4.183). This is also concerning and could hinder bioavailability.

**11. hERG Inhibition:** Ligand A (0.376) has a lower hERG risk than Ligand B (0.9). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (8.434) has a lower microsomal clearance, indicating better metabolic stability, which is crucial for kinase inhibitors. Ligand B (80.682) has high clearance.

**13. In vitro Half-Life:** Ligand A (38.03) has a shorter half-life than Ligand B (69.005). While longer is generally better, the difference isn't drastic.

**14. P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux, which is favorable for bioavailability. Ligand B (0.366) has higher efflux.

**15. Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.6). Although the difference is less than 1.5 kcal/mol, it's still a positive factor.

**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 kinase inhibitors: lower hERG risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. Ligand B's higher logP and higher DILI risk are drawbacks. The solubility and permeability issues for both would need to be addressed through formulation or further structural modifications, but Ligand A provides a better starting point.

Output:
0
2025-04-17 14:58:08,084 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.419 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is slightly above the preferred <140, while Ligand B (70.08) is well within the range.

**logP:** Ligand A (0.529) is a bit low, potentially hindering permeation. Ligand B (1.334) is 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.

**QED:** Both ligands have good QED scores (0.59 and 0.78), indicating good drug-likeness.

**DILI:** Ligand A (37.146) has a moderate DILI risk, while Ligand B (17.875) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (54.44) and Ligand B (70.027) both have moderate BBB penetration. This is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.625) has poor Caco-2 permeability, while Ligand B (-4.311) is slightly better but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.72 and -1.559). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.152) and Ligand B (0.217) have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (-6.323) exhibits excellent metabolic stability (negative value indicates low clearance), while Ligand B (13.507) has moderate clearance. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-3.766) has a longer predicted half-life than Ligand B (-4.589), further supporting its favorable metabolic profile.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.042).

**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 of Ligand B.

**Conclusion:**

While Ligand A has better metabolic stability and a longer half-life, the significantly stronger binding affinity of Ligand B (-7.2 vs -6.4 kcal/mol) is a critical advantage for an enzyme inhibitor. The lower DILI risk of Ligand B is also a positive factor. Although Ligand B's Caco-2 permeability is not ideal, the potency advantage is likely to be more important for initial optimization.

Output:
1
2025-04-17 14:58:08,084 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.22 Da) is slightly higher than Ligand B (352.391 Da), but both are acceptable.

**TPSA:** Ligand A (104.05) is better than Ligand B (113.77) as it's closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (3.048) is optimal (1-3), while Ligand B (-0.422) is significantly below this, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=2, HBA=6) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.582, Ligand B: 0.657), indicating drug-like properties.

**DILI:** Ligand A (97.169) has a higher DILI risk than Ligand B (54.207). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (62.04) is slightly better than Ligand A (55.254), but neither is particularly high.

**Caco-2 Permeability:** Ligand A (-4.978) is significantly worse than Ligand B (-5.041). Both are very poor, but Ligand B is slightly better.

**Aqueous Solubility:** Ligand A (-5.454) is worse than Ligand B (-1.584). Solubility is important for bioavailability, and Ligand B has a better score.

**hERG Inhibition:** Ligand A (0.572) is better than Ligand B (0.166), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (55.406) has a higher clearance than Ligand B (4.106), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (74.88) has a longer half-life than Ligand B (9.039), which is desirable.

**P-gp Efflux:** Ligand A (0.259) is better than Ligand B (0.027), suggesting less efflux and potentially better bioavailability.

**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 substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.1 vs -7.4 kcal/mol), better metabolic stability (lower Cl_mic), better solubility, and a lower DILI risk. While Ligand A has a longer half-life and better P-gp efflux, the substantial affinity advantage of Ligand B, coupled with its better ADME properties (solubility, metabolic stability, DILI risk), makes it the more promising candidate. The low logP of Ligand B is a concern, but the strong binding affinity might compensate for this.

Output:
1
2025-04-17 14:58:08,084 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 358.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.69 and 86.33) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.577) is slightly low, potentially hindering permeation. Ligand B (1.918) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.789 and 0.808), indicating good drug-likeness.

**DILI:** Ligand A (51.183) has a higher DILI risk than Ligand B (29.701), although both are reasonably low.

**BBB:** Both have acceptable BBB penetration, but Ligand B (80.07) is better than Ligand A (72.237). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and problematic. Again, the magnitude is similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.21 and 0.274).

**Microsomal Clearance:** Ligand A (21.483 mL/min/kg) has significantly lower microsomal clearance than Ligand B (41.222 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (36.025 hours) has a much longer half-life than Ligand B (-0.618 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.011).

**Binding Affinity:** Ligand B (-7.5 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 ADME issues.

**Overall Assessment:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic) and longer half-life. While its logP is a bit low, the substantial improvement in pharmacokinetic properties outweighs this minor drawback. The negative Caco-2 and solubility values are concerning for both, but the better binding affinity of A and its improved metabolic profile make it the more promising candidate.

Output:
1
2025-04-17 14:58:08,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.451 and 357.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.0) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (78.51) is well within the ideal range.

**logP:** Ligand A (0.923) is a bit low, potentially hindering permeation. Ligand B (1.196) is also relatively 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, which are acceptable. Ligand B has 2 HBD and 3 HBA, which are also good.

**QED:** Both ligands have good QED scores (0.607 and 0.75), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 56.146, which is moderate. Ligand B has a significantly lower DILI risk of 27.608, which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB penetration (83.366) than Ligand A (36.371), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.396 and -4.863), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.667 and -2.23), which is also concerning and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.06 and 0.154), which is excellent.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (16.629 mL/min/kg) than Ligand B (1.054 mL/min/kg). This suggests that Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A has a negative half-life (-15.387 hours), which is not physically possible and likely an error. Ligand B has a negative half-life as well (-1.634 hours), also likely an error. Both are concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.01), which is favorable.

**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 of the ADME drawbacks.

**Conclusion:**

Despite both ligands having concerning permeability and solubility values, Ligand B is the more promising candidate. It has a significantly better binding affinity, lower DILI risk, and much better metabolic stability (lower Cl_mic). The negative half-life values are concerning for both, but the superior potency of Ligand B makes it the better choice, assuming the half-life values are errors. The lower logP values for both are a concern, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 14:58:08,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.422 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is better than Ligand B (51.66), being under the 140 threshold. Lower TPSA generally favors better cell permeability.

**3. logP:** Both ligands have good logP values (2.161 and 3.31), 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 (1) is preferable to Ligand B (0). While both are low, a single HBD can sometimes improve solubility.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA is generally favorable for permeability.

**6. QED:** Ligand A (0.882) has a significantly better QED score than Ligand B (0.671), indicating a more drug-like profile.

**7. DILI:** Ligand A (34.277) has a much lower DILI risk than Ligand B (21.287), which is a significant advantage.

**8. BBB:** Both ligands have high BBB penetration (82.745 and 81.194), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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, indicating poor solubility. This is a major concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.25 and 0.737), which is good.

**12. Microsomal Clearance:** Ligand A (19.875) has significantly lower microsomal clearance than Ligand B (100.453), suggesting better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (-30.147) has a negative half-life, which is impossible. Ligand B (25.89) is reasonable. The negative value for A is a red flag.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.192 and 0.601), which is favorable.

**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 poor solubility and Caco-2 permeability for both, Ligand A is the better candidate. It has a significantly better QED score, lower DILI risk, and dramatically better metabolic stability (lower Cl_mic). The negative in vitro half-life for Ligand A is a major concern and suggests a data error, but even disregarding that, the other advantages make it preferable. The similar binding affinities mean that the ADME properties become the deciding factor.

Output:
0
2025-04-17 14:58:08,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.825 and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Both ligands have good logP values (3.724 and 3.448), 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar, good QED values (0.821 and 0.842), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (80.729%) compared to Ligand B (35.983%). This is a major concern for Ligand A.

**BBB:** Both have high BBB penetration (77.162% and 86.623%), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.559 and -4.573), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.733 and -4.031). This is a substantial issue for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.552 and 0.714), which is positive.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (89.959) than Ligand B (34.162). Ligand B demonstrates better metabolic stability, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B has a negative in vitro half-life (-5.008), which is concerning. Ligand A has a more reasonable half-life of 56.704 hours.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.535).

**Binding Affinity:** Both ligands have identical and excellent binding affinities (-8.2 kcal/mol).

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand B is the more promising candidate. The primary driver is the significantly lower DILI risk (35.983% vs 80.729%). While both have poor solubility and permeability, the lower clearance of Ligand B suggests better metabolic stability, which is crucial for kinase inhibitors. The negative half-life for Ligand B is a concern, but the DILI risk for Ligand A is a more critical issue.

Output:
1
2025-04-17 14:58:08,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.451 and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.33) is slightly higher than Ligand B (84.5), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.338 and 1.561), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (5 and 4 respectively), satisfying the <5 HBD and <10 HBA criteria.

**QED:** Ligand A (0.808) has a significantly better QED score than Ligand B (0.616), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (39.977 and 44.668, both <40).

**BBB:** Both ligands have relatively low BBB penetration (59.131 and 52.966), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.988 and -4.873), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.755 and -2.992). This is a major concern for *in vivo* efficacy.

**hERG Inhibition:** Ligand A (0.103) has a much lower hERG inhibition risk than Ligand B (0.464), which is a significant advantage.

**Microsomal Clearance:** Ligand B (55.89) has a slightly higher microsomal clearance than Ligand A (47.476), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-50.957) has a very negative half-life, which is concerning. Ligand A (23.624) is more reasonable.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, while Ligand B (0.074) is slightly higher, but still low.

**Binding Affinity:** Ligand B (-7.0) has a substantially better binding affinity than Ligand A (0.0). This is a critical advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-7.0 kcal/mol vs 0.0 kcal/mol) is the most important factor. While both ligands have issues with solubility and Caco-2 permeability, the potency advantage of Ligand B is substantial. The slightly higher clearance and hERG risk of Ligand B are less concerning than the extremely weak binding of Ligand A. The negative half-life for Ligand B is a concern, but could be addressed with structural modifications.

Output:
1
2025-04-17 14:58:08,086 - INFO - Batch 340 complete. Total preferences: 5440
2025-04-17 14:58:08,086 - INFO - Processing batch 341/512...
2025-04-17 14:58:59,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (58.44). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands (2.517 and 2.727) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.66 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (27.414) has a significantly lower DILI risk than Ligand B (46.84). This is a major advantage for Ligand A.

**BBB:** Ligand B (85.964) has a higher BBB penetration percentile than Ligand A (39.162). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.896 and -4.646), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.653 and -2.325), indicating poor aqueous solubility. This is a significant drawback for both, but less severe for Ligand B.

**hERG Inhibition:** Ligand A (0.243) has a lower hERG inhibition liability than Ligand B (0.635), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (37.876) has a lower microsomal clearance than Ligand B (79.793), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand B (17.349 hours) has a significantly longer in vitro half-life than Ligand A (5.762 hours). This is a strong advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.316) has lower P-gp efflux liability than Ligand B (0.173). This is a slight advantage for Ligand A.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.2 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, and metabolic stability (Cl_mic). Ligand B has a longer half-life and better BBB penetration (less relevant here), and slightly better solubility. However, the lower DILI and hERG risk of Ligand A, combined with its acceptable metabolic stability, make it the more promising candidate, despite the shorter half-life. The poor Caco-2 and solubility are concerns for both and would require further optimization.

Output:
0
2025-04-17 14:58:59,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly better, being closer to the middle of the range.

**TPSA:** Ligand A (58.64) is excellent, well below 140 and suggesting good absorption. Ligand B (107.69) is higher, but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (2.798) is optimal (1-3). Ligand B (-0.537) is significantly lower, which could hinder membrane permeability and bioavailability.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, potentially impacting permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.751, B: 0.659), indicating drug-like properties.

**DILI:** Ligand A (16.751) has a very low DILI risk, which is excellent. Ligand B (47.77) is higher, indicating a moderate risk, but still within acceptable limits.

**BBB:** Ligand A (82.241) has good BBB penetration. Ligand B (10.392) has very poor BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.806) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.54) is similarly low.

**Solubility:** Ligand A (-3.045) is poor. Ligand B (-1.744) is also poor, but slightly better.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.319, B: 0.168), which is positive.

**Cl_mic:** Ligand A (39.728) has moderate metabolic clearance. Ligand B (-2.062) has *negative* clearance, which is unusual and likely an artifact of the prediction method, but suggests excellent metabolic stability.

**t1/2:** Ligand A (-1.782) has a negative half-life, which is also likely an artifact of the prediction method. Ligand B (3.814) has a reasonable in vitro half-life.

**Pgp:** Both ligands have low Pgp efflux (A: 0.24, B: 0.031), which is favorable.

**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 has a superior binding affinity and a much better DILI profile. However, it suffers from poor Caco-2 permeability and solubility, and questionable in vitro half-life. Ligand B has a lower affinity but better metabolic stability (indicated by the negative Cl_mic), a slightly better solubility, and a reasonable half-life. The biggest drawback for Ligand B is its low logP, which could severely limit its absorption.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is a major advantage. While its solubility and permeability are concerning, these can potentially be addressed through formulation strategies or further chemical modifications. The superior potency of Ligand A is likely to be more impactful than the slightly better ADME profile of Ligand B.

Output:
1
2025-04-17 14:58:59,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.463 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.89) is better than Ligand B (98.74), being closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (1.007) is optimal, while Ligand B (0.195) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) both meet the <=10 criteria.

**QED:** Ligand A (0.678) is significantly better than Ligand B (0.297), indicating a more drug-like profile.

**DILI:** Ligand A (34.626) has a much lower DILI risk than Ligand B (15.161), both are below the 40 threshold.

**BBB:** Ligand A (45.677) and Ligand B (62.078) are not particularly high, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative, which is unusual and problematic. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.141) has a much lower hERG risk than Ligand B (0.279), both are low.

**Microsomal Clearance:** Ligand A (18.65) is slightly higher than Ligand B (16.342), indicating slightly lower metabolic stability.

**In vitro Half-Life:** Ligand A (17.532) has a longer half-life than Ligand B (-2.419), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.032 respectively).

**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.

**Overall Assessment:**

Ligand A is significantly better overall. It has a superior QED score, lower DILI risk, lower hERG risk, and a longer half-life. While both have poor solubility and Caco-2 permeability, Ligand A's better ADME profile and comparable binding affinity make it the more promising candidate. The slightly higher clearance is a minor concern compared to the other advantages.

Output:
1
2025-04-17 14:58:59,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.34 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.77) is higher than Ligand B (59.08). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (-0.522) is quite low, potentially hindering membrane permeability. Ligand B (1.185) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (0) is even better, potentially improving permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**QED:** Both ligands have good QED scores (0.486 and 0.766 respectively), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (34.781) has a slightly higher DILI risk than Ligand B (18.069), though both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (82.047) is notably higher than Ligand A (70.88). While not a primary concern for a kinase inhibitor, it's a minor positive for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.61) is very poor, indicating poor intestinal absorption. Ligand B (-4.596) is also poor, but less so than Ligand A.

**Aqueous Solubility:** Both have negative solubility values (-1.058 and -1.599), indicating poor solubility. This is a concern for both, but the value for Ligand B is worse.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.125 and 0.319 respectively).

**Microsomal Clearance:** Ligand A (-8.783) has significantly lower (better) microsomal clearance than Ligand B (33.167), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-20.392) has a longer half-life than Ligand B (14.746), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.008 and 0.062 respectively).

**Binding Affinity:** Both ligands have similar and good binding affinities (-7.5 and -7.3 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has advantages in logP, TPSA, QED, and BBB. However, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better DILI risk. Given that we are targeting a kinase (enzyme), metabolic stability is paramount. The poor Caco-2 and solubility of both are concerning, but can potentially be addressed through formulation strategies. The slightly better potency of Ligand A is also a plus.

Output:
0
2025-04-17 14:58:59,358 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [414.221, 38.33, 4.754, 1, 2, 0.784, 64.909, 85.421, -4.67, -5.531, 0.812, 70.057, 38.075, 0.45, -10.1]
**Ligand B:** [354.491, 78.87, 1.563, 2, 4, 0.759, 7.794, 65.801, -4.542, -1.784, 0.304, 38.932, -11.382, 0.021, -7.4]

**Step-by-step comparison:**

1. **MW:** Ligand A (414.221 Da) is within the ideal range (200-500 Da). Ligand B (354.491 Da) is also within the ideal range. No clear advantage here.
2. **TPSA:** Ligand A (38.33) is excellent, well below the 140 threshold. Ligand B (78.87) is still acceptable, but higher. A favors absorption.
3. **logP:** Ligand A (4.754) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.563) is good, within the optimal range. B is better here.
4. **HBD:** Both ligands have acceptable HBD counts (A: 1, B: 2), well below the 5 limit.
5. **HBA:** Both ligands have acceptable HBA counts (A: 2, B: 4), below the 10 limit.
6. **QED:** Both ligands have similar QED scores (A: 0.784, B: 0.759), indicating good drug-likeness.
7. **DILI:** Ligand A (64.909) has a higher DILI risk than Ligand B (7.794). B is significantly better.
8. **BBB:** Ligand A (85.421) has better BBB penetration than Ligand B (65.801), but this isn't a primary concern for a kinase inhibitor.
9. **Caco-2:** Both have negative Caco-2 values which is unusual. Assuming these are percentile scores, both are poor.
10. **Solubility:** Ligand A (-5.531) has poor solubility. Ligand B (-1.784) has better, but still poor solubility.
11. **hERG:** Ligand A (0.812) has a slightly higher hERG risk than Ligand B (0.304). B is better.
12. **Cl_mic:** Ligand A (70.057) has higher microsomal clearance than Ligand B (38.932), meaning faster metabolism. B is better.
13. **t1/2:** Ligand A (38.075) has a longer in vitro half-life than Ligand B (-11.382). A is better.
14. **Pgp:** Ligand A (0.45) has lower P-gp efflux liability than Ligand B (0.021). A is better.
15. **Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme (kinase) target, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand A is *much* more potent. This is the most important factor.
*   **Metabolic Stability:** Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life.
*   **Solubility:** Ligand B has better solubility, but both are poor.
*   **hERG:** Ligand B has lower hERG risk.
*   **DILI:** Ligand B has significantly lower DILI risk.

**Conclusion:**

Despite Ligand B's advantages in metabolic stability, solubility, DILI, and hERG, the *much* stronger binding affinity of Ligand A (-10.1 vs -7.4 kcal/mol) is a decisive factor. A difference of 2.7 kcal/mol is substantial and can often outweigh minor ADME drawbacks, especially in the early stages of drug discovery. The potency advantage is likely to translate to efficacy. While solubility and DILI are concerns for A, these can be addressed through further optimization.

Output:
1
2025-04-17 14:58:59,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.526 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (16.13) is significantly better than Ligand B (75.44). A TPSA under 90 is generally favorable, and Ligand A is much closer to that threshold, suggesting better permeability.

**logP:** Ligand A (4.961) is slightly high, potentially leading to solubility issues and off-target effects. Ligand B (2.15) is 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) as it minimizes potential issues with both solubility and permeability.

**QED:** Both ligands have good QED scores (0.771 and 0.831), indicating generally drug-like properties.

**DILI:** Both ligands have low DILI risk (29.159 and 31.136), which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.012) has a higher BBB score than Ligand B (67.235), but this isn't a major factor in this decision.

**Caco-2 Permeability:** Ligand A (-4.887) and Ligand B (-4.664) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret these values.

**Aqueous Solubility:** Ligand A (-4.458) and Ligand B (-3.081) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.916) has a slightly higher hERG risk than Ligand B (0.093). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (42.556) has a higher microsomal clearance than Ligand B (5.664), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-2.317) has a longer in vitro half-life than Ligand A (6.622), which is preferable.

**P-gp Efflux:** Ligand A (0.849) has higher P-gp efflux than Ligand B (0.057), which is less desirable.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). The difference is 0.5 kcal/mol, which is significant, but must be weighed against the ADME properties.

**Overall Assessment:**

Ligand A has a better binding affinity, but suffers from higher logP, higher microsomal clearance, shorter half-life, and higher P-gp efflux. Ligand B has a better logP, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The solubility and Caco-2 permeability are poor for both, but the ADME profile of Ligand B is significantly more favorable overall, especially considering the enzyme-specific priorities. The 0.5 kcal/mol difference in binding affinity is not enough to overcome Ligand A's ADME liabilities.

Output:
1
2025-04-17 14:58:59,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.487 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (104.65). A TPSA below 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (2.703) is optimal (1-3), while Ligand B (0.606) is a bit 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 3 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10, but A is preferable.

**QED:** Ligand B (0.724) has a better QED score than Ligand A (0.382), indicating a more drug-like profile.

**DILI:** Ligand A (15.859) has a much lower DILI risk than Ligand B (30.593), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.78) is slightly better than Ligand B (65.374).

**Caco-2 Permeability:** Both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but we'll assume lower is worse.

**Aqueous Solubility:** Both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but we'll assume lower is worse.

**hERG Inhibition:** Ligand A (0.375) has a lower hERG risk than Ligand B (0.23), which is a significant advantage.

**Microsomal Clearance:** Ligand B (30.919) has a lower microsomal clearance than Ligand A (37.665), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.786) has a much longer half-life than Ligand A (-0.213), a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability.

**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.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower DILI and hERG risk. While Ligand B has a better QED score and metabolic stability (lower Cl_mic, longer t1/2), the significantly stronger binding of Ligand A is crucial for an enzyme inhibitor. The lower logP of Ligand B is also a concern. Considering the priorities for enzyme targets, the potency advantage of Ligand A is the most important factor.

Output:
1
2025-04-17 14:58:59,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands are below the 140 A^2 threshold (79.9 and 70.47 A^2), suggesting good potential for absorption.

**logP:** Ligand A (1.067) is optimal, while Ligand B (0.354) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both ligands are within the acceptable limit of 5 (Ligand A: 2, Ligand B: 1).

**H-Bond Acceptors:** Both ligands are within the acceptable limit of 10 (Ligand A: 5, Ligand B: 5).

**QED:** Both ligands have good QED scores (0.771 and 0.782), indicating drug-like properties.

**DILI:** Ligand A (41.45) has a better DILI percentile than Ligand B (14.773), indicating lower liver injury risk.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (72.431) has a higher BBB percentile than Ligand B (46.84).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are log values, they indicate very poor permeability. Ligand A (-5.034) is slightly better than Ligand B (-5.309).

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are log values, they indicate very poor solubility. Ligand A (-2.091) is slightly better than Ligand B (-1.142).

**hERG:** Both ligands show low hERG inhibition liability (0.282 and 0.146), which is excellent.

**Microsomal Clearance:** Ligand B (-23.031) has significantly lower (better) microsomal clearance than Ligand A (14.483), suggesting much greater metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (2.687) has a longer half-life than Ligand A (0.183), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.009).

**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 can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better logP and DILI, Ligand B's significantly stronger binding affinity (-8.3 vs -7.5 kcal/mol) and *much* improved metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor concern compared to the substantial potency and stability gains. The solubility and permeability are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 14:58:59,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is better than Ligand B (57.69), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands (1.442 and 1.615) are 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 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.708 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (23.614) has a significantly lower DILI risk than Ligand B (39.473), which is a major advantage.

**BBB:** Ligand A (54.013) has a lower BBB penetration than Ligand B (82.164). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.309) has worse Caco-2 permeability than Ligand B (-4.43).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.611 and -1.782). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.077) has a much lower hERG inhibition risk than Ligand B (0.3). This is a significant advantage.

**Microsomal Clearance:** Ligand A (10.191) has significantly lower microsomal clearance than Ligand B (53.92), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (24.138) has a longer in vitro half-life than Ligand A (12.638), which is a positive.

**P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux than Ligand B (0.267), which is favorable.

**Binding Affinity:** Ligand B (-7.8) has a stronger binding affinity than Ligand A (-10.2). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.8 kcal/mol vs -10.2 kcal/mol) and a longer half-life. However, Ligand A demonstrates a much better safety profile with significantly lower DILI and hERG risk, and better metabolic stability (lower Cl_mic). The affinity difference is substantial, and for an enzyme target, potency is paramount. While solubility is a concern for both, it is a formulation challenge that can be addressed. The improved safety profile of Ligand A is not enough to overcome the significant potency advantage of Ligand B.

Output:
1
2025-04-17 14:58:59,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 357.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is slightly higher than Ligand B (55.95). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands have good logP values (1.536 and 2.778), falling within the 1-3 optimal range.

**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 (0.693 and 0.653), indicating good drug-likeness.

**DILI:** Ligand A (14.967) has a significantly lower DILI risk than Ligand B (41.373). This is a major advantage for Ligand A.

**BBB:** Both have moderate BBB penetration (65.607 and 62.233). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.653) has worse Caco-2 permeability than Ligand B (-5.524).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.048 and -1.988). This is a potential issue, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.193) has a lower hERG inhibition risk than Ligand B (0.485). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (41.305) has lower microsomal clearance than Ligand B (58.546), indicating better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand B (9.024) has a much longer in vitro half-life than Ligand A (1.369). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux than Ligand B (0.268), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-7.7). The difference is 0.9 kcal/mol, which is a notable but not overwhelming advantage.

**Overall Assessment:**

Ligand A excels in safety parameters (DILI, hERG) and metabolic stability (Cl_mic), and P-gp efflux. Ligand B has a better half-life and slightly better binding affinity. The lower DILI and hERG risk of Ligand A are particularly important for kinase inhibitors, as these compounds often have off-target effects. The improved metabolic stability of Ligand A is also a significant advantage. While the affinity difference is notable, it doesn't fully compensate for the safety and stability benefits of Ligand A.

Output:
0
2025-04-17 14:58:59,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.387 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (387.948 Da) is still well within the range.

**TPSA:** Ligand A (114.62) is excellent, well below the 140 threshold for good oral absorption. Ligand B (29.54) is even better, suggesting potentially improved absorption.

**logP:** Ligand A (-0.01) is a bit low, potentially hindering membrane permeability. Ligand B (4.766) is high, potentially causing 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 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.674 and 0.675), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (38.969 and 36.099), which is positive.

**BBB:** Ligand A (60.915) has moderate BBB penetration, while Ligand B (89.919) has high BBB penetration. Since SRC is not a CNS target, this is less critical, but a slight advantage to B.

**Caco-2 Permeability:** Ligand A (-5.459) has poor Caco-2 permeability, a significant concern. Ligand B (-4.734) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.631) has poor aqueous solubility, which could limit bioavailability. Ligand B (-5.312) has even worse solubility.

**hERG Inhibition:** Ligand A (0.05) has very low hERG risk, a major advantage. Ligand B (0.914) has a higher, though still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-2.398) has negative clearance, indicating excellent metabolic stability. Ligand B (85.645) has high clearance, suggesting rapid metabolism and potentially low exposure.

**In vitro Half-Life:** Ligand A (7.175 hours) has a reasonable half-life. Ligand B (18.479 hours) has a significantly longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, meaning good bioavailability. Ligand B (0.76) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.8 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 ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a longer half-life, and better BBB penetration. However, it suffers from high logP, poor solubility, and higher P-gp efflux. Ligand A has better solubility, lower hERG risk, and better P-gp efflux, but its affinity is weaker and Caco-2 permeability is very poor.

Given the enzyme-specific priorities, binding affinity and metabolic stability (half-life) are paramount. The substantial difference in binding affinity (-9.8 vs -7.6 kcal/mol) is a major driver. While Ligand B's solubility and logP are concerning, these can potentially be addressed through formulation strategies or further chemical modifications. The poor permeability of Ligand A is a more difficult issue to overcome.

Output:
1
2025-04-17 14:58:59,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.447 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.63) is higher than Ligand B (58.64). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (1.807 and 2.292), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.899) has a much higher QED score than Ligand B (0.286), indicating a more drug-like profile.

**DILI:** Ligand A (30.399) has a significantly lower DILI risk than Ligand B (13.571), which is a major advantage.

**BBB:** Ligand B (70.764) has a higher BBB penetration score than Ligand A (57.929). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.19) has worse Caco-2 permeability than Ligand B (-4.711).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.032 and -2.071). This is a concern for both, but needs to be addressed in formulation.

**hERG Inhibition:** Ligand A (0.096) has a slightly lower hERG risk than Ligand B (0.313), which is preferable.

**Microsomal Clearance:** Ligand A (27.469) has a higher microsomal clearance than Ligand B (5), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-11.279) has a much shorter in vitro half-life than Ligand B (-1.414), further indicating lower metabolic stability.

**P-gp Efflux:** Ligand A (0.082) shows lower P-gp efflux than Ligand B (0.1), which is slightly favorable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.1 kcal/mol difference is not substantial enough to overcome the ADME liabilities of Ligand A.

**Conclusion:**

While Ligand A has slightly better binding affinity and a better QED score, the significantly worse metabolic stability (higher Cl_mic, shorter t1/2), higher DILI risk, and poorer Caco-2 permeability make it a less desirable candidate. Ligand B, despite its lower QED, presents a more favorable balance of properties, particularly regarding metabolic stability and safety (DILI, hERG). The slightly better BBB penetration of Ligand B is irrelevant for this target.

Output:
1
2025-04-17 14:58:59,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (378.441 and 346.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is excellent, well below the 140 threshold for oral absorption. Ligand B (79.1) is still acceptable, but less optimal.

**logP:** Both ligands have good logP values (1.196 and 2.481), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both have good QED scores (0.594 and 0.764), indicating drug-like properties.

**DILI:** Ligand A (35.479) has a significantly lower DILI risk than Ligand B (60.682). This is a major advantage.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.725) shows poor permeability, while Ligand B (-5.027) is also poor, but slightly better. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.24 and -2.84). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.689 and 0.891), which is good.

**Microsomal Clearance:** Ligand A (25.946) has a lower microsomal clearance than Ligand B (52.848), indicating better metabolic stability. This is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand B (71.738) has a significantly longer in vitro half-life than Ligand A (12.28). This is a substantial advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.1 and 0.414).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While a 0.5 kcal/mol difference isn't huge, it's noticeable.

**Overall Assessment:**

Ligand B has a better binding affinity and a significantly longer half-life. However, Ligand A has a much lower DILI risk and better metabolic stability (lower Cl_mic). The poor Caco-2 permeability and solubility are concerns for both, but the lower DILI risk of Ligand A is a significant advantage, especially considering the potential for chronic treatment in oncology. The slightly better affinity of Ligand B might be offset by its higher DILI risk and faster clearance.

Output:
0
2025-04-17 14:58:59,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.369 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.35) is well below the 140 threshold, indicating good absorption potential. Ligand B (89.35) is also below the threshold, but closer to it.

**logP:** Ligand A (1.825) is within the optimal 1-3 range. Ligand B (0.476) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5/6 HBA, which are acceptable values.

**QED:** Both ligands have similar QED values (0.787 and 0.773), indicating good drug-likeness.

**DILI:** Ligand A (56.844) has a higher DILI risk than Ligand B (42.536), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.733) shows better BBB penetration than Ligand B (46.724), but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.729) has *better* Caco-2 permeability than Ligand B (-5.008). A less negative number indicates better permeability.

**Aqueous Solubility:** Ligand A (-1.431) has slightly better aqueous solubility than Ligand B (-0.732).

**hERG Inhibition:** Ligand A (0.533) has a lower hERG risk than Ligand B (0.114), which is a significant advantage.

**Microsomal Clearance:** Ligand A (8.825) has *much* lower microsomal clearance than Ligand B (26.63). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.452) has a shorter half-life than Ligand B (14.408). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.028), which is favorable.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.6). This is a 1.4 kcal/mol advantage, which is substantial and can outweigh some ADME concerns.

**Conclusion:**

Ligand A is the better candidate. While it has a shorter half-life, its significantly superior binding affinity (-8.0 vs -6.6 kcal/mol), lower hERG risk, and lower microsomal clearance outweigh this drawback. The slightly better solubility and permeability also contribute to its favorability. Ligand B's longer half-life is offset by its weaker binding, higher hERG risk, and higher clearance.

Output:
1
2025-04-17 14:58:59,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.415 and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (102.76 and 105.64) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.835) is slightly better than Ligand B (0.456), being closer to the optimal 1-3 range. Ligand B is a bit low, potentially impacting permeability.

**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 H-bond acceptors, well within the limit of <=10.

**QED:** Both ligands have similar QED values (0.749 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (35.091) has a slightly better DILI score than Ligand B (22.451), indicating lower potential for liver injury. Both are well below the concerning threshold of 60.

**BBB:** Ligand B (54.478) has a significantly higher BBB penetration score than Ligand A (23.149). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.06 and -5.659), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.985 and -1.921), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.169 and 0.045), which is excellent.

**Microsomal Clearance:** Ligand B (0.937) has a much lower microsomal clearance than Ligand A (6.432), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-8.628) has a longer in vitro half-life than Ligand A (-24.813), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.014), which is good.

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

**Conclusion:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and a longer half-life. The binding affinity is identical, making these ADME properties the deciding factors. Given the enzyme-specific priorities, metabolic stability is crucial.

Output:
1
2025-04-17 14:58:59,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.435 Da and 360.361 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.76) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (94.48) is well within the range.

**logP:** Ligand A (-0.545) is a bit low, potentially hindering permeability. Ligand B (0.564) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which is acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.443 and 0.707), with Ligand B being significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (15.626) has a very low DILI risk, which is excellent. Ligand B (61.07) has a higher, but still moderate, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (74.292) has a better BBB score than Ligand A (39.162), but it's not a primary concern here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.623 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 (-0.313 and -2.491), which is also concerning and suggests poor solubility. Ligand B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.115 and 0.244), which is positive.

**Microsomal Clearance:** Ligand A (-11.834) has a much lower (better) microsomal clearance than Ligand B (5.243), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (17.818 hours) has a longer half-life than Ligand A (13.081 hours), which is preferable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.031).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), although the difference is relatively small.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity and a significantly lower DILI risk, its poor logP and solubility, coupled with the significantly better metabolic stability (lower Cl_mic) of Ligand A, make it a more promising candidate. The Caco-2 and solubility issues are concerning for both, but the metabolic advantage of Ligand A is crucial for an enzyme target like SRC kinase.

Output:
0
2025-04-17 14:58:59,360 - INFO - Batch 341 complete. Total preferences: 5456
2025-04-17 14:58:59,360 - INFO - Processing batch 342/512...
2025-04-17 14:59:46,466 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.395 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.33) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (92.78) is still within the acceptable range for oral absorption (<140), but less optimal than A.

**logP:** Ligand A (2.932) is within the optimal 1-3 range. Ligand B (0.582) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 for A, 5 for B), satisfying the <5 HBD and <10 HBA criteria.

**QED:** Ligand A (0.777) has a better QED score than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand A (74.254) has a higher DILI risk than Ligand B (41.722). This is a significant drawback for A.

**BBB:** Both ligands have reasonable BBB penetration (70.997 and 66.499 respectively), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a problem with the data or the prediction method. We'll proceed cautiously.

**Solubility:** Both have negative solubility values, again questionable. Assuming these represent low solubility, this is a concern, but can be addressed with formulation.

**hERG:** Ligand A (0.787) has a slightly higher hERG risk than Ligand B (0.055). B is significantly better here.

**Microsomal Clearance:** Ligand A (58.589) has a higher microsomal clearance than Ligand B (33.276), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-15.795) has a *much* longer in vitro half-life than Ligand A (-0.921). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.597) has slightly higher P-gp efflux than Ligand B (0.029), meaning B is less likely to be pumped out of cells.

**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 has a superior binding affinity, but suffers from higher DILI risk, higher microsomal clearance, shorter half-life, and higher P-gp efflux. Ligand B, while having a slightly lower affinity, exhibits much better ADME properties: lower DILI risk, significantly improved metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG risk. The 1.3 kcal/mol difference in binding affinity, while not negligible, can potentially be overcome with further optimization of Ligand B. Given the enzyme-kinase focus, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 14:59:46,466 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 368.331 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is well below the 140 threshold, and even better, under 90, suggesting good permeability. Ligand B (80.49) is still acceptable but less optimal than A.

**logP:** Both ligands have good logP values (3.229 and 2.086) 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 similar QED values (0.773 and 0.775), indicating good drug-likeness.

**DILI:** Ligand A (42.769) has a slightly higher DILI risk than Ligand B (58.705), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.755) has a higher BBB value than Ligand A (66.382), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.656 and -4.675), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.636 and -2.928), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.423 and 0.314), which is excellent.

**Microsomal Clearance:** Ligand A (76.416) has a higher microsomal clearance than Ligand B (19.595). This suggests Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-15.881) has a negative half-life, which is not possible. This is a major red flag and suggests a very short half-life or an issue with the assay. Ligand A (68.701) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.324 and 0.073), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A has better TPSA and a reasonable half-life, but suffers from higher DILI risk. Ligand B has better metabolic stability (lower Cl_mic) and lower DILI, but has a problematic negative in vitro half-life. The poor solubility and permeability are concerning for both. However, the negative half-life for Ligand B is a critical flaw. Therefore, despite the slightly higher DILI risk, Ligand A is the more promising candidate because of its plausible half-life. Further optimization would be needed to address the solubility and permeability issues for either compound.

Output:
0
2025-04-17 14:59:46,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.401 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold, suggesting good absorption. Ligand B (85.25) is also acceptable, but less optimal.

**logP:** Ligand A (1.358) is within the optimal 1-3 range. Ligand B (0.95) is slightly below 1, which *could* indicate potential permeability issues, though not critically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable H-bond characteristics, staying within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.696, B: 0.803), indicating drug-like properties.

**DILI:** Both ligands have very similar and acceptable DILI risk (A: 29.779, B: 29.236), well below the 40 threshold.

**BBB:** Ligand A (91.663) has significantly better BBB penetration potential than Ligand B (65.219). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.684) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.021) is also negative and similarly problematic. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -1.552, B: -2.415). This is a major drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.309, B: 0.114), which is excellent.

**Microsomal Clearance:** Ligand A (17.971) has lower microsomal clearance than Ligand B (24.437), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand B (31.21) has a much longer in vitro half-life than Ligand A (3.486). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.036, B: 0.024), which is favorable.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a >1.5 kcal/mol difference, and a major advantage for Ligand A, potentially outweighing some of its ADME deficiencies.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-9.5 vs -7.8 kcal/mol) and better metabolic stability (lower Cl_mic) are crucial for an enzyme target like SRC. The poor solubility could potentially be addressed with formulation strategies. The negative Caco-2 values are concerning, but the strong binding may allow for sufficient target engagement *in vivo* even with limited absorption. Ligand B's longer half-life is beneficial, but the weaker affinity is a more critical drawback.

Output:
1
2025-04-17 14:59:46,467 - INFO - Okay, let's analyze these two ligands for their potential as drug candidates targeting SRC, a kinase.

**Step-by-step comparison:**

1. **MW:** Ligand A (348.403 Da) is within the ideal range (200-500). Ligand B (373.913 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (85.69) is good for oral absorption (<140). Ligand B (53.94) is excellent. Advantage: B

3. **logP:** Ligand A (-0.012) is a bit low, potentially hindering permeation. Ligand B (4.186) is high, potentially causing solubility and off-target issues. Advantage: A (slightly, as very low logP isn't ideal either)

4. **HBD:** Both ligands have 1 HBD, which is within the acceptable limit of 5. No difference.

5. **HBA:** Both ligands have 6 HBA, which is within the acceptable limit of 10. No difference.

6. **QED:** Ligand A (0.76) is better than Ligand B (0.673), indicating a more drug-like profile. Advantage: A

7. **DILI:** Ligand A (63.086) has a slightly better DILI risk profile than Ligand B (70.88), but both are acceptable (<60 is good). Advantage: A (slightly)

8. **BBB:** Both ligands have reasonable BBB penetration (A: 71.578, B: 69.639). Not a major factor for a non-CNS target like SRC. No difference.

9. **Caco-2:** Ligand A (-4.779) is very poor, indicating poor intestinal absorption. Ligand B (-5.157) is also poor. No advantage.

10. **Solubility:** Ligand A (-1.83) is poor, while Ligand B (-5.041) is even worse. Both are problematic. No advantage.

11. **hERG:** Ligand A (0.043) has a very low hERG risk, which is excellent. Ligand B (0.773) has a higher, but still acceptable, hERG risk. Advantage: A

12. **Cl_mic:** Ligand A (30.019 mL/min/kg) has significantly lower microsomal clearance than Ligand B (116.798 mL/min/kg), suggesting better metabolic stability. Advantage: A

13. **t1/2:** Ligand A (23.747 hours) has a better in vitro half-life than Ligand B (35.77 hours). Advantage: A

14. **Pgp:** Ligand A (0.021) has very low P-gp efflux, which is good. Ligand B (0.414) has moderate P-gp efflux. Advantage: A

15. **Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -7.8 kcal/mol). Ligand B is slightly better, but the difference is small. Advantage: B (slightly)

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both ligands have good affinity, Ligand A significantly outperforms Ligand B in metabolic stability (lower Cl_mic, better t1/2), hERG risk, and P-gp efflux. Solubility is poor for both, but Ligand B's high logP is also concerning.

**Conclusion:**

Considering the enzyme-specific priorities and the overall profile, **Ligand A** is the more promising drug candidate. Its superior metabolic stability, lower hERG risk, and better P-gp efflux outweigh the slightly lower binding affinity and less ideal logP. The poor solubility of both is a concern that would need to be addressed in formulation, but is less critical than metabolic liabilities.

Output:
0
2025-04-17 14:59:46,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 351.437 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (117.67) is better than Ligand B (40.54), being closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (-0.146) is quite low, potentially hindering permeation. Ligand B (4.434) 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 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.604 and 0.852), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (15.781 and 16.402), both being relatively low and acceptable.

**BBB:** Ligand B (87.127) shows better BBB penetration than Ligand A (62.078), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-6.082) has very poor Caco-2 permeability, a significant drawback. Ligand B (-4.557) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-2.361) has poor aqueous solubility, while Ligand B (-5.178) is even worse. Both are problematic.

**hERG:** Ligand A (0.185) has a very low hERG risk, which is excellent. Ligand B (0.829) has a higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-14.61) has a significantly lower (better) microsomal clearance than Ligand B (100.126), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (23.508) has a better in vitro half-life than Ligand B (-12.094).

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is favorable. Ligand B (0.308) has slightly higher efflux.

**Binding Affinity:** Ligand B (-7.5) has a significantly better binding affinity than Ligand A (-9.2). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While its logP is high and solubility is poor, the superior affinity could potentially overcome these issues with appropriate formulation strategies. Ligand A has better metabolic stability and a lower hERG risk, but its very poor Caco-2 permeability and significantly weaker binding affinity are major drawbacks. The difference in binding affinity (-7.5 vs -9.2) is greater than 1.5 kcal/mol, making Ligand B the more promising candidate despite its other shortcomings.

Output:
1
2025-04-17 14:59:46,467 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.355, 114.84 ,   2.451,   2.   ,   6.   ,   0.612,  68.437,  36.526, -4.517,  -3.84 ,   0.534,  42.232,  25.642,   0.427,  -8.4  ]
**Ligand B:** [353.482,  61.44 ,   2.383,   2.   ,   3.   ,   0.691,  13.532,  86.041, -4.899,  -1.636,   0.607,  -8.323,  -5.671,   0.085,  -8.5  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (348.355) is slightly lower, which is generally favorable for permeability.
2. **TPSA:** A (114.84) is above the optimal <140 for oral absorption, but still reasonable. B (61.44) is excellent, well below 140.
3. **logP:** Both are within the optimal 1-3 range. A (2.451) and B (2.383) are very similar.
4. **HBD:** Both have 2 HBD, which is within the acceptable limit of <=5.
5. **HBA:** A has 6 HBA, and B has 3 HBA. Both are within the acceptable limit of <=10. B is preferable here, as fewer HBA generally leads to better permeability.
6. **QED:** Both have good QED scores (A: 0.612, B: 0.691), indicating drug-like properties. B is slightly better.
7. **DILI:** A (68.437) is moderately high risk, while B (13.532) is very low risk. This is a significant advantage for B.
8. **BBB:** A (36.526) is low, while B (86.041) is high. While SRC isn't a CNS target, higher BBB is rarely a detriment.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified. Assuming these are logP values, lower values indicate lower permeability. A (-4.517) is worse than B (-4.899).
10. **Solubility:** A (-3.84) is worse than B (-1.636). Solubility is crucial for enzyme inhibitors.
11. **hERG:** Both have low hERG risk (A: 0.534, B: 0.607).
12. **Cl_mic:** A (42.232) is higher than B (-8.323), meaning B has better metabolic stability. This is a key factor for kinase inhibitors.
13. **t1/2:** A (25.642) is better than B (-5.671), suggesting a longer half-life.
14. **Pgp:** A (0.427) is lower than B (0.085), indicating less P-gp efflux and potentially better bioavailability.
15. **Binding Affinity:** Both have excellent binding affinity (A: -8.4, B: -8.5). The difference is negligible.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Conclusion:**

While both ligands have excellent binding affinity, **Ligand B** is the more promising drug candidate. It has significantly lower DILI risk, superior metabolic stability (lower Cl_mic), better solubility, and fewer HBA. Although ligand A has a longer in vitro half-life and lower Pgp efflux, the advantages of B in DILI, metabolic stability, and solubility outweigh these factors. The Caco-2 values are concerning for both, but the other ADME properties of B are far more favorable.

Output:
1
2025-04-17 14:59:46,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (468.145 Da) is higher, but still acceptable. Ligand B (344.499 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (67.43) is higher than Ligand B (41.57). Both are below the 140 A^2 threshold for oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (A: 4.735, B: 4.096), falling within the 1-3 range, although A is slightly high.

**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 (A: 0.641, B: 0.897), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A has a significantly higher DILI risk (77.782%) compared to Ligand B (22.722%). This is a major concern for Ligand A.

**BBB:** Both have good BBB penetration (A: 78.984%, B: 89.492%). This isn't a primary concern for an enzyme target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. A (-4.788) and B (-4.308).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. A (-5.265) and B (-4.071).

**hERG:** Both ligands have low hERG risk (A: 0.749, B: 0.567), which is good.

**Microsomal Clearance:** Ligand A (61.127) has higher microsomal clearance than Ligand B (52.215), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (6.76 hours) compared to Ligand A (95.055 hours - this seems like an error in the data, likely should be 9.5055 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.503, B: 0.193), which is good.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite Ligand A's superior binding affinity, the significantly higher DILI risk and lower metabolic stability are major drawbacks. Ligand B, while having slightly weaker binding, presents a much more favorable ADMET profile, particularly the low DILI risk and better half-life. The difference in binding affinity (0.7 kcal/mol) is not large enough to outweigh the substantial safety and pharmacokinetic advantages of Ligand B.

Output:
1
2025-04-17 14:59:46,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is slightly above the preferred <140, but acceptable. Ligand B (71.53) is excellent, well below 140.

**logP:** Ligand A (-0.983) is a bit low, potentially hindering permeability. Ligand B (2.174) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which is reasonable. Ligand B has 1 HBD and 4 HBA, also good.

**QED:** Both ligands have acceptable QED scores (0.494 and 0.695, respectively), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (11.594) has a very low DILI risk, which is excellent. Ligand B (19.891) is also low, but higher than A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (80.419) is higher than A (40.675), but this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.292 and -4.367), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.833 and -1.839), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.05) has a very low hERG risk, which is excellent. Ligand B (0.534) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (11.231) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (46.076) has significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (18.675) has a longer half-life than Ligand B (-1.714), which is desirable.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is good. Ligand B (0.109) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Despite Ligand B having slightly better affinity and a more favorable logP, Ligand A is the more promising candidate. The primary reasons are its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While both ligands suffer from poor predicted solubility and permeability, the metabolic and safety advantages of Ligand A are more critical for an enzyme target like SRC. The slightly better affinity of Ligand B doesn't compensate for these drawbacks.

Output:
0
2025-04-17 14:59:46,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, potentially aiding permeability.

**TPSA:** Ligand A (84.95) is excellent, well below the 140 threshold for oral absorption. Ligand B (107.38) is still acceptable, but less favorable.

**logP:** Ligand A (2.812) is optimal (1-3). Ligand B (-1.01) is significantly lower, which could hinder permeability and absorption.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.614 and 0.592), indicating good drug-likeness.

**DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (25.165). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (45.909) is higher, but not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.296) is very poor, indicating very low intestinal absorption. Ligand B (-4.694) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-3.486) is very poor. Ligand B (-1.121) is also poor, but better than A.

**hERG:** Ligand A (0.864) has a slightly higher hERG risk than Ligand B (0.112), which is a positive for B.

**Microsomal Clearance:** Ligand A (36.245) has a higher clearance than Ligand B (25.769), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-0.916) has a longer half-life than Ligand A (-6.32), indicating better stability.

**P-gp Efflux:** Ligand A (0.267) has lower P-gp efflux than Ligand B (0.004), which is a positive for A.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.2). 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 issues with solubility and Caco-2 permeability, Ligand B has significantly better DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and a slightly better binding affinity. Ligand A's poor solubility, permeability, and higher DILI risk are major concerns. The slightly lower P-gp efflux for ligand A is not enough to offset these significant drawbacks.

Output:
1
2025-04-17 14:59:46,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.471 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, indicating good potential for oral absorption. Ligand B (45.59) is slightly better than Ligand A (50.16).

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.743, Ligand B: 4.287). 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 1 HBD and 4 HBA, which is within the desired range.

**QED:** Both have good QED scores (Ligand A: 0.91, Ligand B: 0.745), indicating drug-likeness. Ligand A is superior.

**DILI:** Ligand A (18.573) has a significantly lower DILI risk than Ligand B (8.414), which is a major advantage.

**BBB:** Both have good BBB penetration (Ligand A: 78.092, Ligand B: 82.435), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified.

**Aqueous Solubility:** Both have negative values, which is also unusual and suggests poor solubility. However, the scale is not specified.

**hERG Inhibition:** Both have low hERG inhibition risk (Ligand A: 0.544, Ligand B: 0.844), which is good. Ligand A is slightly better.

**Microsomal Clearance:** Ligand A (21.077 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (65.163 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (23.06 hours) has a longer half-life than Ligand A (13.685 hours), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (Ligand A: 0.282, Ligand B: 0.721). Ligand A is better.

**Binding Affinity:** Both have excellent binding affinities (Ligand A: -9 kcal/mol, Ligand B: -8.1 kcal/mol). Ligand A has a 0.9 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly longer half-life, Ligand A excels in almost every other critical parameter: significantly lower DILI risk, much better metabolic stability (lower Cl_mic), slightly better binding affinity, better QED, and better P-gp efflux. The slightly lower half-life of Ligand A is a manageable drawback compared to the substantial advantages it offers in safety and pharmacokinetics.

Output:
0
2025-04-17 14:59:46,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.331 and 356.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.51) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (66.48) is excellent, well below 140.

**logP:** Both ligands (1.396 and 2.873) are within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 8 HBA, both within acceptable limits. Ligand B has 1 HBD and 3 HBA, also well within limits.

**QED:** Both ligands have good QED scores (0.568 and 0.654, respectively), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 94.649, which is *very* high and a significant concern. Ligand B has a much lower DILI risk of 28.616, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.852) and Ligand B (73.788) are both moderate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.687 and -4.651). This is unusual and suggests poor permeability. However, these values can be unreliable and require experimental validation.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.667 and -2.838). Similar to Caco-2, negative values are concerning and require experimental confirmation.

**hERG Inhibition:** Ligand A (0.181) shows a slightly elevated hERG risk, while Ligand B (0.367) is slightly higher. Both are reasonably low, but Ligand B is preferable.

**Microsomal Clearance:** Ligand A (44.741) has a moderate clearance, while Ligand B (23.896) has a lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-31.758) has a very negative half-life, indicating rapid metabolism. Ligand B (-6.747) has a less negative half-life, suggesting better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.042 and 0.245).

**Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-8.4). This is a substantial advantage.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its extremely high DILI risk is a major red flag. The poor predicted solubility and permeability (negative Caco-2 and solubility values) are also concerning. Ligand B, while having a slightly weaker binding affinity, presents a much more favorable safety profile (low DILI), better metabolic stability (lower Cl_mic, better t1/2), and acceptable physicochemical properties. The difference in binding affinity (1.6 kcal/mol) is significant, but the safety concerns with Ligand A outweigh this benefit.

Output:
1
2025-04-17 14:59:46,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.5 & 391.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is better than Ligand B (58.2) as it's closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.014) is optimal (1-3), while Ligand B (4.044) is pushing the upper limit and could present solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=2) as it has a better balance for permeability and solubility.

**QED:** Ligand A (0.8) is significantly better than Ligand B (0.614), indicating a more drug-like profile.

**DILI:** Ligand A (5.545) has a much lower DILI risk than Ligand B (27.53), a crucial advantage.

**BBB:** Both have similar BBB penetration (68.864 vs 66.615), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative (-4.927 vs -4.859), indicating poor permeability. This is a concern for both, but less critical than other factors.

**Aqueous Solubility:** Ligand A (-1.68) is better than Ligand B (-5.158), indicating better solubility.

**hERG Inhibition:** Ligand A (0.36) has a much lower hERG risk than Ligand B (0.489), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-1.731) has lower clearance (better metabolic stability) than Ligand B (72.395). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-2.94) has a longer half-life than Ligand B (-6.293).

**P-gp Efflux:** Both are low (0.038 vs 0.259), indicating minimal P-gp efflux.

**Binding Affinity:** Both have similar, strong binding affinities (-9.4 vs -8.0 kcal/mol). Ligand A is slightly better.

**Overall:** Ligand A is clearly superior. It has a better QED score, significantly lower DILI and hERG risk, better solubility, and improved metabolic stability (lower Cl_mic and longer t1/2). While both have poor Caco-2 permeability, the other advantages of Ligand A outweigh this drawback, especially considering the strong binding affinity.

Output:
0
2025-04-17 14:59:46,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.478 and 386.298 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (37.61), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.512) is within the optimal 1-3 range, while Ligand B (4.529) is slightly above, potentially leading to solubility issues.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 3 HBA) as it strikes a better balance for permeability and solubility.

**QED:** Ligand A (0.797) has a significantly better QED score than Ligand B (0.559), indicating a more drug-like profile.

**DILI:** Ligand B (32.493) has a lower DILI risk than Ligand A (20.822), which is a positive attribute.

**BBB:** Both ligands have high BBB penetration (Ligand A: 96.161, Ligand B: 89.841), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.674) is slightly better than Ligand B (-4.781).

**Aqueous Solubility:** Ligand A (-3.903) has better solubility than Ligand B (-5.212).

**hERG Inhibition:** Ligand A (0.644) has a lower hERG inhibition liability than Ligand B (0.845), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand B (80.818) has a significantly higher microsomal clearance than Ligand A (31.187), suggesting poorer metabolic stability.

**In vitro Half-Life:** Ligand B (38.11) has a much longer in vitro half-life than Ligand A (-1.145), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.27) has lower P-gp efflux liability than Ligand B (0.618), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.1 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 other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and longer half-life, Ligand A excels in crucial ADME properties like QED, solubility, hERG risk, and metabolic stability (lower Cl_mic). The better QED and solubility of Ligand A, coupled with the lower hERG risk, make it a more favorable starting point for optimization. The negative Caco-2 values for both are concerning and would need to be addressed, but Ligand A's other properties are more easily optimized.

Output:
0
2025-04-17 14:59:46,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.375 and 346.406 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (116.42) is slightly above the preferred <140 for good oral absorption, while Ligand B (60.25) is well within this range.

**logP:** Ligand A (-0.234) is a bit low, potentially hindering permeation. Ligand B (2.42) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

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

**QED:** Both ligands have good QED scores (0.562 and 0.806), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (52.85 and 56.146), and are both acceptable (<60).

**BBB:** Ligand A (30.593) has low BBB penetration, while Ligand B (83.404) has good BBB penetration. This isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.234 and -4.361), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is significant.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.057 and -2.384), which is also unusual.

**hERG Inhibition:** Ligand A (0.047) has very low hERG inhibition risk, which is excellent. Ligand B (0.383) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-28.672) has significantly lower (better) microsomal clearance than Ligand B (51.43), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.719) has a negative half-life, which is not possible. Ligand B (-7.402) is also negative, which is not possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.305).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a 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.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.8 vs -7.5 kcal/mol) is a major advantage for an enzyme target. It also has a better logP, TPSA, and BBB penetration. While Ligand A has better hERG inhibition and slightly better microsomal clearance, the potency advantage of Ligand B is more critical. The negative half-life values for both compounds are concerning and would require further investigation.

Output:
1
2025-04-17 14:59:46,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 345.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is well below the 140 threshold for good absorption, while Ligand B (136.93) is approaching the limit but still acceptable.

**logP:** Ligand A (1.084) is within the optimal 1-3 range. Ligand B (-1.596) is slightly below 1, which *could* indicate potential permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, well within acceptable limits. Ligand B has 3 HBD and 8 HBA, also acceptable.

**QED:** Ligand A (0.775) has a better QED score than Ligand B (0.577), suggesting a more drug-like profile.

**DILI:** Ligand B (69.756) has a higher DILI risk than Ligand A (17.72), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.035) is better than Ligand B (39.55).

**Caco-2 Permeability:** Ligand A (-4.592) is worse than Ligand B (-6.126), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.327) is better than Ligand B (-2.134), which is good for formulation and bioavailability.

**hERG:** Ligand A (0.315) has a much lower hERG risk than Ligand B (0.072), a crucial advantage.

**Microsomal Clearance:** Ligand B (-5.151) shows *better* metabolic stability (lower clearance) than Ligand A (12.539).

**In vitro Half-Life:** Ligand B (-13.92) has a longer half-life than Ligand A (18.806), which is desirable.

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux than Ligand B (0.004), which is favorable.

**Binding Affinity:** Ligand B (-7.7) has slightly better binding affinity than Ligand A (-7.5), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is preferable. While Ligand B has slightly better affinity and metabolic stability, Ligand A demonstrates a significantly lower DILI risk and hERG inhibition liability. These are critical factors for drug development, especially for an oncology target where chronic administration is possible. The slightly lower Caco-2 permeability of Ligand A is a concern, but can potentially be addressed with formulation strategies. The better QED score and lower DILI/hERG risks outweigh the small difference in affinity and the Caco-2 value.

Output:
0
2025-04-17 14:59:46,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.503 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.32) is better than Ligand B (87.32), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.508) is slightly low, potentially hindering permeation. Ligand B (1.471) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the 5 threshold.

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

**QED:** Ligand A (0.678) is better than Ligand B (0.495), indicating a more drug-like profile.

**DILI:** Ligand A (26.871) has a significantly lower DILI risk than Ligand B (34.161), both are below the 40 threshold.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating 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 (0.349) has a much lower hERG risk than Ligand B (0.131), which is a significant advantage.

**Microsomal Clearance:** Ligand A (12.463) has a lower Cl_mic, suggesting better metabolic stability than Ligand B (25.109).

**In vitro Half-Life:** Ligand A (13.512) has a longer half-life than Ligand B (-11.595), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**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:**

Ligand A is the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand A demonstrates superior drug-like properties (higher QED), significantly lower DILI and hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The logP of Ligand A is a concern, but the other advantages outweigh this drawback.

Output:
0
2025-04-17 14:59:46,470 - INFO - Batch 342 complete. Total preferences: 5472
2025-04-17 14:59:46,470 - INFO - Processing batch 343/512...
2025-04-17 15:00:25,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.921 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.13) is well below the 140 threshold, and good for absorption. Ligand B (82.19) is still below 140, but higher than A.

**logP:** Ligand A (4.675) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.912) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 limit.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable, below the 10 limit.

**QED:** Both ligands have good QED scores (0.819 and 0.902), indicating good drug-like properties.

**DILI:** Ligand A (60.682) is approaching a concerning DILI risk, while Ligand B (50.136) is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.419) has better BBB penetration than Ligand B (45.405).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.083 and -5.382), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.798 and -2.039). This is a major drawback.

**hERG Inhibition:** Ligand A (0.809) has a slightly higher hERG risk than Ligand B (0.214), which is preferable.

**Microsomal Clearance:** Ligand A (6.687) has significantly better metabolic stability (lower clearance) than Ligand B (14.384).

**In vitro Half-Life:** Ligand A (41.686) has a much longer half-life than Ligand B (0.983). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.474) exhibits lower P-gp efflux than Ligand B (0.033), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.8 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-7.8 vs -9.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. While Ligand B has a slightly less favorable logP and higher DILI risk than Ligand A, the potency difference is substantial. Both ligands suffer from poor solubility and permeability, which would require formulation strategies to address. However, the improved metabolic stability and half-life of Ligand A are also beneficial. Considering the priorities for enzyme inhibitors, the binding affinity is paramount.

Output:
1
2025-04-17 15:00:25,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.395 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.43) is well below the 140 threshold for oral absorption, while Ligand B (95.74) is still acceptable but closer to the limit.

**logP:** Ligand A (3.607) is at the higher end of the optimal range (1-3), potentially raising concerns about off-target effects. Ligand B (0.708) is quite low, which might hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, both within acceptable limits. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.811 and 0.732), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 77.2, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk (20.279), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.459) has better BBB penetration than Ligand B (64.095).

**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, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.481 and -2.192 respectively). This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.261) has a very low hERG risk, which is excellent. Ligand B (0.115) also has a low hERG risk, but slightly lower than A.

**Microsomal Clearance:** Ligand A (94.958) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (19.134) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (-0.424) has a very short half-life, consistent with the high clearance. Ligand B (-16.351) has a very short half-life as well, which is a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.379 and 0.01 respectively).

**Binding Affinity:** Both ligands have strong binding affinities (-7.9 and -7.6 kcal/mol), which are both excellent. The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme target. While both have poor solubility and permeability, the metabolic stability issue with Ligand A is more concerning for *in vivo* efficacy. The lower logP of Ligand B is a drawback, but potentially addressable through structural modifications.

Output:
1
2025-04-17 15:00:25,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.391 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.08) is slightly above the optimal <140 for oral absorption, while Ligand B (72.88) is well within the range.

**logP:** Ligand A (-1.019) is a bit low, potentially hindering permeation. Ligand B (1.234) 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 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.57 and 0.62), indicating drug-like properties.

**DILI:** Ligand A (48.042) has a moderate DILI risk, while Ligand B (3.335) has a very low risk, which is a significant advantage.

**BBB:** Both have similar BBB penetration (51.958 and 47.15), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.88 and -4.84), 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 (-2.153 and -0.984), also unusual and suggesting poor solubility. Again, the scale is unknown.

**hERG:** Ligand A (0.07) has a very low hERG risk, while Ligand B (0.188) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (-24.009) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (16.14) has a moderate clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-4.61) has a negative half-life, which is not physically possible and likely an error. Ligand B (-6.721) also has a negative half-life, also likely an error.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable. Ligand B (0.023) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.8) has significantly stronger binding affinity than Ligand B (-0.0). This is a crucial factor for enzyme inhibitors.

**Overall Assessment:**

Despite the questionable solubility and permeability data, Ligand A stands out due to its significantly superior binding affinity (-8.8 kcal/mol vs -0.0 kcal/mol) and excellent metabolic stability (very low Cl_mic). The lower DILI risk of Ligand B is attractive, but the massive difference in binding affinity outweighs this benefit. The negative half-life values for both are concerning and suggest data quality issues, but the relative affinity difference is so large that it still drives the decision.

Output:
1
2025-04-17 15:00:25,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 Da and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.08 and 68.73) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.414) is optimal, while Ligand B (2.331) is also within the acceptable range of 1-3.

**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 (0.785 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (52.966). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (80.031 and 81.853), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.402 and -4.575). 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.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.372 and -2.549). Similar to Caco-2, these are on a scale where negative values are not directly interpretable.

**hERG Inhibition:** Ligand A (0.455) has a lower hERG inhibition liability than Ligand B (0.244), which is preferable.

**Microsomal Clearance:** Ligand A (16.474) has a significantly lower microsomal clearance than Ligand B (71.45), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (10.835) has a slightly longer in vitro half-life than Ligand B (9.709).

**P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux liability than Ligand B (0.416), which is favorable for oral bioavailability.

**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:**

Despite the better ADME profile of Ligand A, the significantly stronger binding affinity of Ligand B (-9.0 vs -7.2 kcal/mol) is a decisive factor. The potency advantage outweighs the higher DILI risk and slightly worse metabolic stability. While the negative Caco-2 and solubility values are concerning for both, the superior binding affinity of Ligand B suggests it may still be able to achieve sufficient target engagement *in vivo*. Further optimization could focus on improving the ADME properties of Ligand B while maintaining its potent binding.

Output:
1
2025-04-17 15:00:25,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.411 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.66) is better than Ligand B (52.61), being under the 140 threshold, but both are acceptable.

**logP:** Ligand A (2.756) is optimal (1-3), while Ligand B (4.299) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.408 and 0.735), with Ligand B being better.

**DILI:** Both ligands have low DILI risk (43.234 and 41.838), indicating a relatively safe profile.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand A (61.923) is slightly better than Ligand B (52.889).

**Caco-2 Permeability:** Ligand A (-5.413) and Ligand B (-4.779) have negative values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.844) is significantly better than Ligand B (-4.127). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.919 and 0.7), which is excellent.

**Microsomal Clearance:** Ligand A (14.446) has a much lower Cl_mic than Ligand B (79.922), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (12.879) has a longer half-life than Ligand B (0.466), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.874) has lower P-gp efflux than Ligand B (0.252), which is preferable.

**Binding Affinity:** Ligand B (-8.3 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. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand A has superior ADME properties (solubility, metabolic stability, lower clearance, lower P-gp efflux), Ligand B boasts a significantly stronger binding affinity (-8.3 vs -7.3 kcal/mol). Given that we are targeting an enzyme (SRC kinase), potency is paramount. The 1 kcal/mol difference is substantial enough to compensate for the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 15:00:25,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.535 and 361.477 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is slightly higher than Ligand B (43.86), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.653 and 2.459) 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 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.749) has a better QED score than Ligand B (0.634), indicating a more drug-like profile.

**DILI:** Ligand B (11.71) has a significantly lower DILI risk than Ligand A (8.298), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (70.531 and 87.941), but Ligand B is better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.926 and -4.49), 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 (-1.079 and -0.999), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.704 and 0.787), which is good.

**Microsomal Clearance (Cl_mic):** Ligand B (6 mL/min/kg) has significantly lower microsomal clearance than Ligand A (18.932 mL/min/kg), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life (t1/2):** Ligand B (-15.761 hours) has a much longer in vitro half-life than Ligand A (-3.661 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.103 and 0.088).

**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, potentially outweighing some of the ADME drawbacks. The difference is greater than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand B's superior ADME properties (lower DILI, lower Cl_mic, longer t1/2), Ligand A's significantly stronger binding affinity (-8.8 vs -7.5 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The potency advantage is large enough to potentially overcome the slightly higher DILI risk and poorer metabolic stability, especially in early-stage drug discovery.

Output:
1
2025-04-17 15:00:25,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.86 and 383.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.63) is better than Ligand B (80.32), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.78 and 2.24) 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) as it has fewer H-bond donors. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.86 and 0.738), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (56.727 and 54.323), which is acceptable (below 60).

**BBB:** Both ligands have similar BBB penetration (64.87 and 61.691), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.883) has slightly better Caco-2 permeability than Ligand B (-4.614). Higher values are better, so less negative is better.

**Aqueous Solubility:** Ligand A (-3.879) has slightly better aqueous solubility than Ligand B (-4.465). Higher values are better.

**hERG Inhibition:** Ligand A (0.746) has a significantly lower hERG inhibition risk than Ligand B (0.221). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (10.009) has significantly lower microsomal clearance than Ligand B (23.108). Lower clearance indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-10.037) has a significantly longer in vitro half-life than Ligand B (20.692). Longer half-life is desirable.

**P-gp Efflux:** Ligand A (0.37) has lower P-gp efflux than Ligand B (0.274), which is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -9.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh the ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more promising drug candidate. While both ligands exhibit excellent binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of lower hERG risk, lower microsomal clearance, and longer half-life. These factors are critical for an enzyme target like SRC kinase, where metabolic stability and minimizing off-target effects are paramount.

Output:
0
2025-04-17 15:00:25,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 345.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.85) is well below the 140 threshold and good for oral absorption. Ligand B (73.64) is also below 140, but higher than A.

**logP:** Both ligands have good logP values (2.711 and 1.722), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and acceptable HBA counts (3 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.692 and 0.781), indicating good drug-like properties.

**DILI:** Ligand A (13.959) has a significantly lower DILI risk than Ligand B (19.891), which is a major advantage. Both are below the 40 threshold.

**BBB:** Both ligands have similar BBB penetration (75.96 and 73.905), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.449 and -4.31), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.03 and -2.306), indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.52 and 0.581), which is good.

**Microsomal Clearance:** Ligand A (70.401) has higher microsomal clearance than Ligand B (18.871), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-1.644) has a negative half-life, which is not possible and suggests an issue with the data. Ligand A (3.15) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.053), which is favorable.

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.2 vs -7.5 kcal/mol) outweighs the higher DILI risk and the problematic negative half-life value. The lower microsomal clearance of Ligand B is also beneficial. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the potency advantage of B is substantial.

Output:
1
2025-04-17 15:00:25,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.41 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.37) is higher than Ligand B (57). While both are acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (0.436) is a bit low, potentially hindering permeation. Ligand B (2.381) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) 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 (0.576 and 0.758, respectively), indicating good drug-like properties.

**DILI:** Ligand A (30.865) has a lower DILI risk than Ligand B (12.253), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (85.731) is slightly higher than Ligand B (77.821). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2:** Ligand A (-5.414) has a very poor Caco-2 permeability, while Ligand B (-4.521) is better, but still not great.

**Solubility:** Ligand A (-2.491) has poor solubility, while Ligand B (-0.433) is better. Solubility is important for bioavailability.

**hERG:** Ligand A (0.123) has a lower hERG risk than Ligand B (0.528), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-14.115) has much lower microsomal clearance than Ligand B (46.856), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-7.502) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (38.252) has a much better in vitro half-life.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, while Ligand B (0.04) is slightly higher.

**Binding Affinity:** Both ligands have similar binding affinities (-6.6 and -7.5 kcal/mol). Ligand B has a slightly better affinity, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG, P-gp efflux, and especially microsomal clearance. However, it suffers from poor solubility, poor Caco-2 permeability, and a concerningly low in vitro half-life. Ligand B has better logP, TPSA, solubility, and a much better half-life. While its DILI and hERG risks are higher, the metabolic stability and solubility advantages of Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 15:00:25,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.471 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.91) is better than Ligand B (71.11), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (4.159) is higher than optimal (1-3), but still potentially manageable. Ligand B (0.095) is significantly low, which could hinder membrane permeability and potentially reduce potency due to poor binding.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.72 and 0.776), indicating generally drug-like properties.

**DILI:** Ligand A (52.385) has a moderate DILI risk, while Ligand B (29.236) has a low DILI risk. This favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.735) has better BBB penetration than Ligand B (55.293).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.737) is slightly worse than Ligand B (-4.598).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.826) is slightly worse than Ligand B (-1.164).

**hERG Inhibition:** Ligand A (0.722) has a slightly higher hERG risk than Ligand B (0.213), favoring Ligand B.

**Microsomal Clearance:** Ligand A (61.906) has a moderate clearance, while Ligand B (-21.594) has a *negative* clearance, which is highly unusual and suggests very high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (39.926 hours) has a reasonable half-life, but Ligand B (17.748 hours) is lower. However, the negative clearance of Ligand B suggests the in vitro half-life could be underestimated.

**P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux than Ligand B (0.046), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better BBB penetration and P-gp efflux, Ligand B demonstrates significantly better metabolic stability (negative Cl_mic) and lower DILI/hERG risk. The low logP of Ligand B is a concern, but the exceptional metabolic stability and safety profile outweigh this drawback, especially given the comparable binding affinities. For an enzyme target like SRC kinase, metabolic stability and safety are paramount.

Output:
1
2025-04-17 15:00:25,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.245 and 357.296 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.47) is well below the 140 threshold for oral absorption, and is preferable. Ligand B (97.54) is higher, potentially impacting absorption.

**logP:** Ligand A (4.435) is slightly above the optimal 1-3 range, potentially leading to solubility issues or off-target effects, but not dramatically so. Ligand B (0.277) is significantly low, which could hinder membrane permeability.

**H-Bond Donors:** Both ligands have 1 HBD, within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 3 HBA, well within the limit of 10. Ligand B has 8 HBA, which is still acceptable, but less ideal than A.

**QED:** Both ligands have similar QED values (0.813 and 0.785), indicating good drug-likeness.

**DILI:** Ligand A (68.825) has a slightly higher DILI risk than Ligand B (71.694), but both are reasonably acceptable.

**BBB:** Both ligands have good BBB penetration (77.084 and 88.174), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.565 and -4.809). This is unusual and suggests poor permeability, but the scale is not defined so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.113 and -2.625). This is also unusual and suggests poor solubility, which is a significant concern.

**hERG Inhibition:** Ligand A (0.767) has a slightly higher hERG risk than Ligand B (0.135). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (35.943) has lower microsomal clearance than Ligand B (41.72), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (38.439) has a longer in vitro half-life than Ligand B (-17.587), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.266) has lower P-gp efflux than Ligand B (0.07), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has *significantly* stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the overwhelmingly stronger binding affinity of Ligand A (-9.5 kcal/mol vs 0.0 kcal/mol) makes it the far more promising candidate. The better metabolic stability (lower Cl_mic and longer t1/2) and lower P-gp efflux also contribute to its favorability. While Ligand B has a lower hERG risk, the potency difference is too large to ignore. The solubility and permeability issues can be addressed with formulation strategies.

Output:
1
2025-04-17 15:00:25,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.413 and 360.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is better than Ligand B (81.17), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (2.325 and 1.444), 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 (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 7 HBA). Both are within acceptable limits, but ligand A is more favorable.

**QED:** Both ligands have similar, good QED values (0.843 and 0.835), indicating good drug-like properties.

**DILI:** Ligand A (28.577) has a significantly lower DILI risk than Ligand B (68.941). This is a major advantage for Ligand A.

**BBB:** Ligand A (83.133) has better BBB penetration than Ligand B (37.379), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.7) has better Caco-2 permeability than Ligand B (-5.579). Both are negative values, which is unusual and suggests poor permeability, but A is still better.

**Aqueous Solubility:** Ligand A (-3.273) has better aqueous solubility than Ligand B (-2.43). Both are negative, suggesting poor solubility, but A is less poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.548 and 0.64), which is good.

**Microsomal Clearance:** Ligand A (4.187) has significantly lower microsomal clearance than Ligand B (45.988). This indicates better metabolic stability for Ligand A, a crucial factor for kinases.

**In vitro Half-Life:** Ligand A (-10.083) has a much longer in vitro half-life than Ligand B (11.791). This is a significant advantage for Ligand A, reducing dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.017 and 0.043), which is good.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4). However, the difference is only 0.3 kcal/mol, and can be overcome by the superior ADME properties of Ligand A.

**Overall:**

Ligand A is clearly superior due to its significantly better DILI score, lower microsomal clearance, longer half-life, and better solubility and permeability. While Ligand B has slightly better binding affinity, the ADME advantages of Ligand A outweigh this minor difference, especially considering we are targeting a kinase.

Output:
1
2025-04-17 15:00:25,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.845 and 340.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.72 and 67.66) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.138) is optimal, while Ligand B (3.837) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Ligand A (1) is good, while Ligand B (2) is acceptable.

**H-Bond Acceptors:** Ligand A (3) is good, while Ligand B (6) is slightly higher but still within a reasonable range.

**QED:** Both ligands (0.894 and 0.75) have good drug-likeness scores.

**DILI:** Ligand A (42.458) has a lower DILI risk than Ligand B (61.264), which is preferable.

**BBB:** Both ligands have high BBB penetration (82.513 and 80.419), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.786 and -4.931), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.814 and -4.331). This is a major drawback.

**hERG Inhibition:** Ligand A (0.345) has a lower hERG risk than Ligand B (0.848), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-17.94) has a much lower (better) microsomal clearance than Ligand B (75.333), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (19.761) has a better in vitro half-life than Ligand B (37.234).

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux than Ligand B (0.657), which is favorable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 1.1 kcal/mol difference is meaningful.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. It has a better binding affinity, lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and lower P-gp efflux. While both ligands suffer from poor solubility and permeability, the superior ADME properties and binding affinity of Ligand A outweigh these drawbacks. The difference in binding affinity, combined with the improved ADME profile, makes Ligand A the stronger candidate for further optimization.

Output:
1
2025-04-17 15:00:25,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.491 and 360.439 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (55.4) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (75.63) is still under 140, but less optimal than A.

**logP:** Ligand A (3.99) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (0.653) is quite low, potentially hindering permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (0 HBD, 6 HBA) is also good, but the lower logP may mean it relies more on HBA for solubility, potentially impacting permeability.

**QED:** Both ligands (0.794 and 0.74) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Both ligands have acceptable DILI risk (54.556 and 50.136), below the 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.443) has a higher BBB score than Ligand B (64.715).

**Caco-2 Permeability:** Ligand A (-4.626) has a much better Caco-2 permeability than Ligand B (-5.004), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.801) has better aqueous solubility than Ligand B (-1.658).

**hERG Inhibition:** Ligand A (0.471) has a lower hERG risk than Ligand B (0.075), which is a significant advantage.

**Microsomal Clearance:** Ligand A (121.777) has a higher microsomal clearance than Ligand B (22.187), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (28.545) has a longer half-life than Ligand B (3.813), which is a positive.

**P-gp Efflux:** Ligand A (0.669) has lower P-gp efflux than Ligand B (0.092), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). The difference is 0.6 kcal/mol, which is not a huge advantage, but still notable.

**Overall Assessment:**

Ligand B has a better binding affinity and significantly better metabolic stability (lower Cl_mic). However, it suffers from a very low logP, which is a major concern for permeability and oral absorption. Ligand A has more favorable ADME properties overall (better TPSA, logP, solubility, Caco-2, hERG, and P-gp efflux), and a reasonable half-life, despite the higher Cl_mic. The slightly weaker binding affinity of Ligand A is likely outweighed by its superior ADME profile.

Output:
1
2025-04-17 15:00:25,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.291 Da) is slightly lower, which could be favorable for permeability, while Ligand B (351.403 Da) is also well within range.

**TPSA:** Ligand B (103.2) is better than Ligand A (118.4), both are under the 140 threshold for good oral absorption.

**logP:** Ligand A (3.474) is optimal (1-3). Ligand B (-0.396) is significantly below this range, potentially causing permeability issues.

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

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

**QED:** Both ligands have good QED scores (A: 0.575, B: 0.749), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.457%), which is a major red flag. Ligand B has a much lower and acceptable DILI risk (34.161%).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (55.099%) is higher than Ligand B (18.147%).

**Caco-2 Permeability:** Ligand A (-4.525) and Ligand B (-5.207) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-6.806) and Ligand B (-0.707) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.713) is better than Ligand B (0.105), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-5.034) has a negative clearance, which is not realistic. Ligand A (58.12) is a more reasonable value, but still indicates moderate metabolic clearance.

**In vitro Half-Life:** Ligand A (109.827) has a better half-life than Ligand B (2.291).

**P-gp Efflux:** Ligand A (0.532) is better than Ligand B (0.007), indicating lower efflux.

**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.

**Conclusion:**

Despite Ligand B's superior binding affinity, the extremely high DILI risk associated with Ligand A is a deal-breaker. While Ligand B has a lower logP and some questionable ADME properties (negative clearance and solubility), these can potentially be addressed through further optimization. The strong binding affinity of Ligand B makes it a more promising starting point, even with its drawbacks.

Output:
1
2025-04-17 15:00:25,196 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.5) is slightly higher than Ligand B (342.5), but both are acceptable.

**TPSA:** Ligand A (75.63) is higher than Ligand B (49.41). While both are below 140, Ligand B's lower TPSA is preferable for absorption.

**logP:** Both ligands have good logP values (A: 3.252, B: 2.89), 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, <=10 HBA). Ligand B is slightly better here.

**QED:** Ligand A (0.74) has a better QED score than Ligand B (0.571), indicating a more drug-like profile.

**DILI:** Ligand B (19.74) has a significantly lower DILI risk than Ligand A (45.68). This is a major advantage for Ligand B.

**BBB:** Ligand B (55.60) has a higher BBB penetration percentile than Ligand A (32.53). While not a primary concern for a non-CNS target like SRC, it's a slight positive for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.382) is worse than Ligand B (-4.59).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.018) is slightly worse than Ligand B (-4.48).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.121, B: 0.28), which is good.

**Microsomal Clearance:** Ligand B (56.39) has a higher microsomal clearance than Ligand A (42.13), meaning Ligand A is more metabolically stable. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand B (9.175) has a significantly longer in vitro half-life than Ligand A (-2.294). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.09, B: 0.337), which is good.

**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 has a significantly better binding affinity and better metabolic stability. However, Ligand B exhibits a much lower DILI risk and a longer half-life, and better Caco-2 and solubility. Given the enzyme-specific priorities, the stronger binding affinity of Ligand A is the most critical factor. While the ADME properties of Ligand A are not ideal, the potency advantage is significant enough to warrant further optimization.

Output:
1
2025-04-17 15:00:25,196 - INFO - Batch 343 complete. Total preferences: 5488
2025-04-17 15:00:25,196 - INFO - Processing batch 344/512...
2025-04-17 15:01:05,267 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.384 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Ligand A (56.15) is well below the 140 threshold for oral absorption. Ligand B (91.4) is still under 140, but getting closer to the limit.

**logP:** Ligand A (2.919) is optimal. Ligand B (0.422) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.821, B: 0.773), indicating good drug-like properties.

**DILI:** Ligand A (55.332) has a moderate DILI risk, while Ligand B (34.781) has a low DILI risk. This favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.878) has better BBB penetration than Ligand B (64.211), but it's not a major factor here.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. Ligand A (-4.964) is slightly worse than Ligand B (-5.019).

**Aqueous Solubility:** Both ligands have poor solubility (-3.82 and -1.693 respectively). Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.342) has a very low hERG risk, a significant advantage. Ligand B (0.136) also has a low hERG risk, but is still higher than A.

**Microsomal Clearance:** Ligand A (44.271) has moderate clearance, while Ligand B (-0.698) has *negative* clearance, which is highly favorable, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (11.701) has a reasonable half-life. Ligand B (-14.686) has a negative half-life, which is not possible and likely indicates a very long half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.497, B: 0.016), which is good.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol) - a difference of 1.4 kcal/mol. This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability (negative Cl_mic) and lower DILI risk, the significantly stronger binding affinity of Ligand A (-8.8 vs -7.4 kcal/mol) is the deciding factor. For an enzyme target, potency is paramount. While Ligand A has some ADME concerns (slightly higher DILI, poorer Caco-2 permeability, and solubility), these can potentially be addressed through further optimization. The strong binding affinity provides a solid foundation for a viable drug candidate.

Output:
1
2025-04-17 15:01:05,268 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (374.418 Da and 371.493 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.94) is better than Ligand B (40.54), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (1.711) is optimal, while Ligand B (4.453) is slightly high, potentially leading to solubility issues or off-target interactions.

**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 3 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.589 and 0.769, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (22.257) has a significantly lower DILI risk than Ligand B (13.959), which is preferable.

**8. BBB:** Ligand A (74.292) has a good BBB penetration, while Ligand B (89.841) is even better. However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.962) and Ligand B (-4.689) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.779) and Ligand B (-3.624) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.277) shows lower hERG inhibition risk than Ligand B (0.753), which is a significant advantage.

**12. Microsomal Clearance (Cl_mic):** Ligand A (44.595) has higher clearance than Ligand B (36.977), indicating lower metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (21.834 hours) has a significantly longer half-life than Ligand A (9.5 hours), which is highly desirable for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux than Ligand B (0.55), which is preferable.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol) by 1.5 kcal/mol. This is a substantial difference and a major advantage.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.8 vs -7.3 kcal/mol) and a much longer half-life (21.834 vs 9.5 hours). While its logP is slightly higher, the substantial improvement in affinity and metabolic stability outweighs this drawback. Ligand A has better DILI and hERG, but the potency and PK advantages of Ligand B are more important for an enzyme target.

Output:
1
2025-04-17 15:01:05,268 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.427 and 347.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (84.08 and 80.12) well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.115) is optimal, while Ligand B (1.458) is slightly below the optimal range, potentially hindering permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <= 5 criteria.

**H-Bond Acceptors:** Both ligands (5) meet the HBA <= 10 criteria.

**QED:** Both ligands have good QED scores (0.815 and 0.845), indicating good drug-likeness.

**DILI:** Ligand B (41.062) has a significantly lower DILI risk than Ligand A (56.572), making it more favorable from a toxicity perspective.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.67) has a higher BBB percentile than Ligand A (51.919), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.847) has a worse Caco-2 permeability than Ligand B (-5.334).

**Aqueous Solubility:** Ligand B (-1.984) has better aqueous solubility than Ligand A (-4.727).

**hERG:** Ligand A (0.559) has a higher hERG risk than Ligand B (0.171), a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (16.126) has significantly lower microsomal clearance than Ligand A (88.37), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.906) has a longer in vitro half-life than Ligand A (4.707).

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.032), which is slightly favorable.

**Binding Affinity:** Ligand A (-8.4 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, and can be outweighed by other factors.

**Overall:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties: lower DILI risk, better solubility, significantly lower microsomal clearance (better metabolic stability), and a longer half-life. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed with further optimization, but the advantages in safety and pharmacokinetic properties are substantial.

Output:
1
2025-04-17 15:01:05,268 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.483 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is significantly better than Ligand B (116.19).  A TPSA under 140 is good for oral absorption, but A is much closer to the ideal for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (3.879 and 2.293, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 4. Both are within the acceptable limit of 10, but A is preferable.

**QED:** Ligand A (0.853) has a much better QED score than Ligand B (0.272), indicating a more drug-like profile.

**DILI:** Ligand A (32.067) has a lower DILI risk than Ligand B (23.963), both are good.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (89.298) is better than Ligand B (59.519).

**Caco-2:** Ligand A (-4.691) is better than Ligand B (-5.127), indicating better intestinal absorption.

**Solubility:** Ligand A (-4.064) is better than Ligand B (-1.75), which is important for bioavailability.

**hERG:** Ligand A (0.533) has a slightly better hERG profile than Ligand B (0.333), but both are acceptable.

**Microsomal Clearance:** Ligand B (36.511) has lower microsomal clearance than Ligand A (50.648), suggesting better metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand A (27.642) has a positive half-life, while Ligand B (-22.321) has a negative half-life.

**P-gp Efflux:** Ligand A (0.391) has lower P-gp efflux than Ligand B (0.031), which is preferable.

**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 that 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 better drug-like profile (QED), solubility, and lower P-gp efflux. The difference in binding affinity is significant (1.7 kcal/mol), and for an enzyme target, potency is paramount. While Ligand A has more favorable ADME properties overall, the stronger binding of Ligand B is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 15:01:05,268 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 363.757 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is well below the 140 threshold for good absorption, while Ligand B (124.63) is still acceptable but closer to the limit.

**logP:** Both ligands have optimal logP values (1.862 and 1.781), falling within the 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 4 HBA, and Ligand B has 8 HBA. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**QED:** Both ligands have similar QED values (0.791 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (99.341). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (62.233) and Ligand B (50.756) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.135) and Ligand B (-4.754) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.383) and Ligand B (-4.825) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.111) has a lower hERG inhibition risk than Ligand B (0.273), which is preferable.

**Microsomal Clearance:** Ligand A (30.236) has a lower microsomal clearance than Ligand B (64.989), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.332 hours) has a positive half-life, while Ligand B (-40.413) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.113 and 0.202).

**Binding Affinity:** Ligand B (-7.6 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 all factors, especially the enzyme-specific priorities, Ligand A is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and acceptable physicochemical properties. The solubility and permeability issues are present in both, but the other advantages of Ligand A make it a better starting point for optimization.

Output:
0
2025-04-17 15:01:05,268 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.431 and 368.909 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.15) is better than Ligand B (60.25), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (2.948) is optimal (1-3), while Ligand A (0.55) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.73 and 0.724), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (37.03 and 34.587), which is good.

**BBB:** Ligand B (80.07) has better BBB penetration than Ligand A (57.193), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.413) has worse Caco-2 permeability than Ligand B (-4.933).

**Aqueous Solubility:** Ligand A (-1.603) has better aqueous solubility than Ligand B (-3.117).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.157 and 0.316).

**Microsomal Clearance:** Ligand A (40.565) has lower microsomal clearance than Ligand B (57.5), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (17.21) has a significantly longer half-life than Ligand A (-0.597).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.139).

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is minimal.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is slightly better. While Ligand A has better solubility and lower clearance, Ligand B has a significantly longer half-life, a more optimal logP, and comparable binding affinity. The longer half-life is a crucial advantage for kinase inhibitors, potentially allowing for less frequent dosing. The slightly lower logP of Ligand A is a concern, and the longer half-life of Ligand B outweighs the slight advantage of A's solubility.

Output:
1
2025-04-17 15:01:05,268 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.471 Da) is slightly higher than Ligand B (338.411 Da), but both are acceptable.

**TPSA:** Ligand A (97.39) is slightly higher than Ligand B (74.33). Both are below the 140 threshold for oral absorption, but Ligand B is preferable due to the lower TPSA.

**logP:** Both ligands have good logP values (Ligand A: 2.044, Ligand B: 1.725), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (Ligand A: 5, Ligand B: 4), satisfying the criteria.

**QED:** Both have high QED scores (Ligand A: 0.849, Ligand B: 0.871), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (Ligand A: 56.921, Ligand B: 58.938), both are acceptable but not ideal.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.035) has a slightly higher BBB penetration than Ligand B (54.052).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating *poor* permeability. Ligand B (-5.314) is slightly better than Ligand A (-4.817), but both are problematic.

**Aqueous Solubility:** Both have negative solubility values, indicating *poor* solubility. Ligand B (-2.501) is slightly better than Ligand A (-2.943).

**hERG Inhibition:** Ligand A (0.216) has a lower hERG risk than Ligand B (0.544), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-15.436) has a much lower (better) microsomal clearance than Ligand A (54.041), indicating greater metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (33.958) has a significantly longer in vitro half-life than Ligand A (-39.207), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.043, Ligand B: 0.028).

**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 a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better hERG profile and BBB penetration, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), slightly better solubility and permeability, and, most importantly, its much stronger binding affinity. The stronger binding affinity is a key factor for an enzyme target like SRC kinase. The ADME properties of Ligand B, while not perfect, are acceptable, and the potency advantage is likely to be decisive.

Output:
1
2025-04-17 15:01:05,268 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.5 & 366.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (55.2 & 53.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.24 & 4.66) within the optimal 1-3 range, although Ligand B is pushing the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Both ligands have QED values (0.727 & 0.647) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (47.7) has a slightly higher DILI risk than Ligand B (24.5), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (87.1 & 80.8), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.942 & -4.609), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.255 & -4.229), which is also unusual and suggests poor solubility. This is another significant concern.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.617 & 0.859), which is positive.

**Microsomal Clearance:** Ligand B (96.6) has a higher microsomal clearance than Ligand A (82.2), indicating lower metabolic stability. This is a negative for Ligand B.

**In vitro Half-Life:** Ligand A (17.2) has a slightly longer half-life than Ligand B (15.6), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.704 & 0.952), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 & -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is slightly more favorable. While both have concerningly low Caco-2 and solubility values, Ligand A has a better half-life, lower microsomal clearance (better metabolic stability), and a slightly lower DILI risk. The higher logP of Ligand B is also a minor concern. The poor permeability and solubility are major drawbacks for both, but Ligand A's slightly better ADME profile gives it a small edge. Further optimization would be needed to address these solubility and permeability issues for either compound.

Output:
0
2025-04-17 15:01:05,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.411 Da) is slightly lower, which could be beneficial for permeability. Ligand B (383.323 Da) is also good.

**TPSA:** Ligand A (65.07) is higher than Ligand B (51.97). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Ligand A (1.871) is within the optimal range (1-3). Ligand B (4.6) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (0/1) and HBA (5/5), falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.601 and 0.792), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have similar DILI risk (65.374 and 63.513), which is moderate.

**BBB:** Ligand A (67.313) has a slightly better BBB penetration percentile than Ligand B (55.099), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.277) has a worse Caco-2 permeability than Ligand B (-5.238). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-2.396) has better solubility than Ligand B (-4.071). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.243) has a much lower hERG inhibition risk than Ligand B (0.69). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (45.479) has a significantly lower microsomal clearance than Ligand A (80.909), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (69.774) has a much longer in vitro half-life than Ligand A (-13.658), which is a substantial benefit.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.125 and 0.754).

**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 a clear advantage in terms of metabolic stability (lower Cl_mic) and longer half-life. These are critical for an enzyme target. While Ligand A has better solubility and a significantly lower hERG risk, the metabolic liabilities of Ligand A are concerning. The similar binding affinities mean that the ADME properties become the deciding factor. The improved metabolic profile of Ligand B outweighs the slightly higher hERG risk and lower solubility.

Output:
1
2025-04-17 15:01:05,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.519 and 351.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is slightly higher than Ligand B (47.36). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands have good logP values (2.476 and 3.503), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**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 QED values (0.662 and 0.674), indicating good drug-likeness.

**DILI:** Ligand A (7.832) has a significantly lower DILI risk than Ligand B (14.541), which is a major advantage.

**BBB:** Ligand A (70.88) has a reasonable BBB penetration, while Ligand B (95.696) has excellent BBB penetration. However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-5.048) has worse Caco-2 permeability than Ligand B (-4.616), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.049) has slightly better aqueous solubility than Ligand B (-2.798).

**hERG:** Ligand A (0.457) has a lower hERG inhibition liability than Ligand B (0.715), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (27.006) has significantly lower microsomal clearance than Ligand B (64.883), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.717) has a much longer in vitro half-life than Ligand B (3.356), which is highly desirable.

**P-gp Efflux:** Ligand A (0.032) has lower P-gp efflux liability than Ligand B (0.458), potentially leading to better bioavailability.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity (-8.0 kcal/mol) than Ligand A (-7.7 kcal/mol). This is a 1.5 kcal/mol advantage, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A demonstrates superior ADMET properties. Specifically, its significantly lower DILI risk, hERG inhibition, microsomal clearance, and P-gp efflux, combined with a longer half-life and better solubility, make it a more promising drug candidate. The difference in binding affinity (0.3 kcal/mol) is outweighed by the substantial improvements in safety and pharmacokinetic properties.

Output:
0
2025-04-17 15:01:05,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 340.339 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (110.53 and 100.08) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.053) and Ligand B (0.674) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, satisfying the <5 and <10 rules, respectively.

**QED:** Both ligands have a QED score > 0.5 (0.711 and 0.727), indicating good drug-likeness.

**DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (70.182). This is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (59.636) is higher than Ligand B (12.912), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.712) and Ligand B (-5.22) both have negative Caco-2 values, which are not ideal. However, the absolute values are similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.647 and -2.537). This is a concern for both, but could potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.105 and 0.292).

**Microsomal Clearance:** Ligand A (56.539) has higher microsomal clearance than Ligand B (-2.857). This suggests Ligand B is more metabolically stable, a crucial factor for kinases.

**In vitro Half-Life:** Ligand B (21.595 hours) has a significantly longer half-life than Ligand A (-7.675 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.049).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While both have solubility issues, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity outweigh Ligand A's slightly better BBB penetration. For an enzyme target like SRC kinase, metabolic stability and potency are paramount.

Output:
1
2025-04-17 15:01:05,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.43 & 348.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.14 & 87.66) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.351) is optimal, while Ligand B (0.892) is slightly low, potentially impacting permeability.

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

**QED:** Both ligands (0.722 & 0.622) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (54.21%) has a moderate DILI risk, while Ligand B (31.21%) has a lower, more favorable DILI risk.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.824) has poor Caco-2 permeability, while Ligand B (-5.308) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.034 & -2.273). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.566) has a slightly higher hERG risk than Ligand B (0.121), which is preferable.

**Microsomal Clearance:** Ligand A (3.417 mL/min/kg) has significantly better metabolic stability (lower clearance) than Ligand B (10.733 mL/min/kg).

**In vitro Half-Life:** Ligand A (14.551 hours) has a longer half-life than Ligand B (8.691 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 & 0.067).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.5 kcal/mol). This difference of 1.6 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.9 vs -9.5 kcal/mol) is a major advantage for an enzyme target like SRC kinase. While Ligand A has better metabolic stability and a slightly lower hERG risk, the potency difference is more critical. The lower DILI risk for Ligand B is also a positive factor. Solubility would need to be addressed through formulation strategies, but the superior potency of Ligand B makes it the better starting point for optimization.

Output:
1
2025-04-17 15:01:05,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.471 and 375.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is well below the 140 threshold for good absorption, and preferable for kinases. Ligand B (128.03) is still within acceptable limits, but less optimal.

**logP:** Ligand A (1.799) is within the optimal 1-3 range. Ligand B (-0.583) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is excellent. Ligand B (2 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (0.829 and 0.633), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (47.499 and 49.399 percentile), both are low risk.

**BBB:** Ligand A (88.096) has better BBB penetration than Ligand B (73.284), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.718) has worse Caco-2 permeability than Ligand B (-5.088). Both are poor, but B is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.864 and -1.935). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.281 and 0.13). This is excellent.

**Microsomal Clearance:** Ligand A (-9.154) has significantly lower (better) microsomal clearance than Ligand B (20.632). This suggests much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (15.149 hours) has a significantly longer half-life than Ligand B (-17.534 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.023).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.8 kcal/mol). Ligand B is slightly more potent, but the difference (0.7 kcal/mol) isn't huge enough to overcome the ADME disadvantages.

**Conclusion:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2) and has a better TPSA. The solubility is a concern for both, but the superior metabolic profile of Ligand A is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:01:05,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.479 and 354.313 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (81.42) is well below the 140 threshold for good absorption. Ligand B (115.39) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.3) is within the optimal 1-3 range. Ligand B (-0.88) is below 1, which *could* impede permeation, a slight concern.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Ligand A (0.857) is very good, indicating high drug-likeness. Ligand B (0.574) is acceptable, but lower.

**DILI:** Ligand A (37.03) has a low DILI risk. Ligand B (58.24) is higher, indicating a moderate risk, but still below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.245) is better than Ligand B (40.093).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not provided, so it's hard to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not provided.

**hERG Inhibition:** Ligand A (0.692) has a lower hERG risk than Ligand B (0.198), which is a significant advantage.

**Microsomal Clearance:** Ligand A (18.851) has a much lower (better) microsomal clearance than Ligand B (-30.76). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (8.564) has a longer half-life than Ligand B (-40.557), further supporting its better metabolic stability.

**P-gp Efflux:** Both are very low, suggesting minimal P-gp efflux.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a >1.5 kcal/mol difference, which is a substantial advantage and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a better QED score, lower DILI risk, lower hERG risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a much stronger binding affinity. While both have issues with Caco-2 and solubility, the superior potency and ADME profile of Ligand A make it the more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 15:01:05,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (362.392 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is well below the 140 threshold and favorable for oral absorption. Ligand B (78.43) is still acceptable but less optimal.

**3. logP:** Both ligands have logP values within the optimal range (1.758 and 2.541).

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 1, Ligand B: 3).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (Ligand A: 3, Ligand B: 3).

**6. QED:** Both ligands have reasonable QED scores (Ligand A: 0.751, Ligand B: 0.589), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (16.402), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (90.074) has a higher BBB penetration than Ligand B (44.785), but this is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are very close (-4.57 vs -4.688) and don't strongly differentiate the two.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Again, the values are very close (-2.659 vs -2.856) and don't strongly differentiate the two.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.584, Ligand B: 0.183). Ligand B is slightly better here.

**12. Microsomal Clearance (Cl_mic):** Ligand A (32.164) has a lower Cl_mic, suggesting better metabolic stability, which is crucial for enzymes. Ligand B (44.914) has higher clearance.

**13. In vitro Half-Life (t1/2):** Ligand A (10.931) has a slightly longer half-life than Ligand B (9.728).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.04, Ligand B: 0.076).

**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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity. However, Ligand A has a much better safety profile (lower DILI) and better metabolic stability (lower Cl_mic). The poor solubility and permeability are a concern for both, but the large affinity difference of Ligand B is a strong driver. Given that we are targeting a kinase (enzyme), metabolic stability and potency are paramount. While the DILI risk of Ligand A is attractive, the substantial affinity advantage of Ligand B is more critical.

Output:
1
2025-04-17 15:01:05,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.518 Da and 350.423 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.53) is well below the 140 threshold, favorable for absorption. Ligand B (110.08) is still acceptable, but less optimal.

**logP:** Ligand A (1.706) is within the optimal range of 1-3. Ligand B (0.177) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.8 and 0.636), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (47.034 and 43.234), which is positive.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (63.862) has a higher BBB percentile than Ligand A (40.713), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-4.922) has a negative Caco-2 value which is concerning. Ligand B (-5.32) is also negative, but similar. Both suggest poor permeability.

**Aqueous Solubility:** Ligand A (-3.021) and Ligand B (-0.711) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG risk (0.168 and 0.022), which is excellent.

**Microsomal Clearance:** Ligand A (38.403) and Ligand B (35.373) have relatively low microsomal clearance, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (24.494 hours) has a much better in vitro half-life than Ligand B (-16.449 hours). The negative value for Ligand B is highly problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.05), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the superior candidate. Its significantly stronger binding affinity (-7.8 vs 0.0 kcal/mol) outweighs the concerns regarding solubility and permeability, particularly for an enzyme target where potency is paramount. Furthermore, Ligand A has a much more favorable in vitro half-life. Ligand B's negative half-life is a major red flag.

Output:
1
2025-04-17 15:01:05,270 - INFO - Batch 344 complete. Total preferences: 5504
2025-04-17 15:01:05,270 - INFO - Processing batch 345/512...
2025-04-17 15:01:45,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 354.426 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (72.8 and 69.48) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (0.799) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (1.694) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (0 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.79) has a better QED score than Ligand B (0.472), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (39.899 and 41.14), which is good.

**BBB:** Ligand A (76.464) has a moderate BBB penetration, while Ligand B (91.508) has a higher BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.856 and -4.517), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.353 and -1.277), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.265 and 0.273), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (32.061 and 31.716 mL/min/kg), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (7.134 hours) has a significantly longer half-life than Ligand B (-3.49 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.165).

**Binding Affinity:** Ligand A (-8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 0.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A is the more promising candidate. Its superior binding affinity (-8 vs -7.6 kcal/mol) and longer half-life (7.134 vs -3.49 hours) are critical advantages for an enzyme target like SRC kinase. The slightly better QED score also contributes to its favorability. While both have similar ADME liabilities, the potency and stability benefits of Ligand A are more important in this context. Further work would be needed to address the solubility and permeability issues, but the core pharmacodynamic properties of Ligand A are significantly better.

Output:
0
2025-04-17 15:01:45,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 349.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.83) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (73.91) is well within the desirable range.

**logP:** Ligand A (-0.397) is a bit low, potentially hindering permeability. Ligand B (2.78) is nearly ideal.

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

**QED:** Both ligands have good QED scores (0.533 and 0.681), indicating drug-like properties.

**DILI:** Ligand A (34.742) has a low DILI risk, which is excellent. Ligand B (14.308) also has a low DILI risk.

**BBB:** Both have acceptable BBB penetration (78.48 and 70.88), though not critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.881) shows poor permeability, a significant concern. Ligand B (-5.225) also shows poor permeability.

**Aqueous Solubility:** Ligand A (-0.616) has poor solubility, while Ligand B (-2.252) is even worse. Both are problematic.

**hERG:** Ligand A (0.289) 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 (29.238) has moderate clearance, while Ligand B (13.652) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.519 hours) has a short half-life. Ligand B (-0.062 hours) is even shorter, which is a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.077 and 0.124), which is good.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.6 vs -7.3 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, its lower microsomal clearance suggests better metabolic stability. While the half-life is very short, this can potentially be addressed through prodrug strategies or formulation approaches. Ligand A's lower affinity and poor permeability make it less attractive.

Output:
1
2025-04-17 15:01:45,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.311 Da) is slightly higher than Ligand B (346.515 Da), but both are acceptable.

**TPSA:** Ligand A (41.13) is better than Ligand B (49.41), both are acceptable for oral absorption.

**logP:** Ligand A (4.736) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (3.668) is closer to the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 1 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.742 and 0.746), indicating good drug-likeness.

**DILI:** Ligand A (38.852) has a slightly higher DILI risk than Ligand B (19.426), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 89.066, Ligand B: 77.084), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.696 and -4.796), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.511 and -3.764). This is a major drawback.

**hERG Inhibition:** Ligand A (0.875) has a slightly higher hERG risk than Ligand B (0.602), but both are relatively low.

**Microsomal Clearance:** Ligand A (79.622) has a lower microsomal clearance than Ligand B (80.058), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (71.101) has a significantly longer half-life than Ligand B (-15.979). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.493) has lower P-gp efflux than Ligand B (0.348), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor. The 7.8 kcal/mol advantage is significant enough to potentially overcome some of the ADME issues.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B's significantly stronger binding affinity (-7.8 kcal/mol vs 0.0 kcal/mol) is the deciding factor. The substantial potency advantage outweighs the ADME concerns, especially considering that formulation strategies could potentially address the solubility issue. The better metabolic stability and lower DILI risk of Ligand B are also favorable.

Output:
1
2025-04-17 15:01:45,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.431 and 361.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is well below the 140 threshold and is favorable. Ligand B (134.92) is still acceptable but less optimal.

**logP:** Ligand A (0.941) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.593) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is within the ideal ranges. Ligand B (4 HBD, 8 HBA) is also acceptable, but approaching the upper limits.

**QED:** Both ligands have reasonable QED scores (0.451 and 0.54), indicating acceptable drug-likeness.

**DILI:** Ligand A (31.291) has a significantly lower DILI risk than Ligand B (65.103), which is a substantial advantage.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.777) and Ligand B (-5.768) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.486 and -2.71), which could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.071 and 0.198).

**Microsomal Clearance:** Ligand A (63.389) has a higher microsomal clearance than Ligand B (-4.226), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (12.124 hours) has a much longer in vitro half-life than Ligand A (-23.149 hours), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.025).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-9.0 and -8.5 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other ADME concerns.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and slightly better QED outweigh the slightly less favorable TPSA and logP values. While both have poor solubility and permeability, the metabolic stability advantage of Ligand B is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:01:45,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.46 and 351.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is well below the 140 threshold for good absorption, while Ligand B (112.73) is still acceptable but closer to the limit.

**logP:** Ligand A (1.776) is optimal (1-3). Ligand B (0.014) is very low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3 respectively), below the threshold of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 each), below the threshold of 10.

**QED:** Both ligands have reasonable QED scores (0.79 and 0.626), indicating good drug-like properties.

**DILI:** Ligand A (21.71) has a significantly lower DILI risk than Ligand B (14.23), indicating a safer profile.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.283) has a more negative Caco-2 value, suggesting *lower* permeability, while Ligand B (-5.354) is similar. Both are very poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.337 and -1.944).

**hERG Inhibition:** Both ligands have very low hERG risk (0.092 and 0.091).

**Microsomal Clearance:** Ligand A (1.632) has a significantly lower Cl_mic, indicating better metabolic stability, than Ligand B (8.737).

**In vitro Half-Life:** Ligand A (14.39 hours) has a longer half-life than Ligand B (-2.934 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.012 and 0.006).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial difference.

**Conclusion:**

Ligand A is the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-9.2 vs -7.1 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic and longer half-life) outweigh its slightly lower TPSA and permeability. The difference in binding affinity is particularly important for an enzyme target like SRC kinase, and could compensate for the ADME deficiencies. Ligand B's very low logP is also a major concern.

Output:
1
2025-04-17 15:01:45,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.5 and 350.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (96.25). Both are below 140, but A is closer to the desirable threshold for good absorption.

**logP:** Ligand A (2.991) is optimal, while Ligand B (1.081) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) both meet the <=5 criteria.

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

**QED:** Both ligands have similar QED scores (0.623 and 0.621), indicating good drug-likeness.

**DILI:** Ligand A (73.83) has a significantly higher DILI risk than Ligand B (29.24). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.73) has a better BBB score than Ligand B (51.38).

**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 directly compare.

**Aqueous Solubility:** Both have negative solubility values, again unusual and suggesting poor solubility. The scale is not specified, so we cannot directly compare.

**hERG:** Ligand A (0.696) has a slightly higher hERG risk than Ligand B (0.052). Ligand B is much better here.

**Microsomal Clearance:** Ligand A (80.46) has a higher clearance than Ligand B (23.09). This means Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-0.463) has a better (longer) half-life than Ligand A (-5.944).

**P-gp Efflux:** Ligand A (0.279) has lower P-gp efflux than Ligand B (0.016), which is favorable.

**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 minor ADME drawbacks.

**Conclusion:**

Despite Ligand A's slightly better TPSA, BBB, and P-gp efflux, Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer half-life), and lower hERG risk outweigh the slight disadvantages in TPSA and P-gp. The poor solubility and permeability are concerns for both, but can be addressed through formulation strategies. The DILI risk for Ligand A is a serious red flag.

Output:
1
2025-04-17 15:01:45,216 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (384.351 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is better than Ligand B (90.9), both are under the 140 threshold for oral absorption.

**logP:** Ligand A (1.137) is optimal, while Ligand B (-0.121) is slightly low, potentially hindering permeation.

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

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

**QED:** Ligand A (0.72) is better than Ligand B (0.566), indicating a more drug-like profile.

**DILI:** Ligand B (6.747) has a significantly lower DILI risk than Ligand A (63.513), which is a major advantage.

**BBB:** Ligand A (55.797) has a better BBB penetration score than Ligand B (39.55), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.273 and -5.133), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.556 and -0.647), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.486 and 0.103).

**Microsomal Clearance:** Ligand B (7.417) has a much lower microsomal clearance than Ligand A (26.653), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (19.352) has a longer in vitro half-life than Ligand A (11.229), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.103 and 0.004).

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has superior ADME properties (lower DILI, better metabolic stability, longer half-life), Ligand A boasts a significantly stronger binding affinity. Given that we are targeting an enzyme (SRC kinase), potency is paramount. The 2.1 kcal/mol difference in binding affinity is substantial and likely to be more impactful than the ADME concerns, especially considering both ligands exhibit poor solubility and permeability. However, the high DILI risk for ligand A is concerning.

Output:
1
2025-04-17 15:01:45,216 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.81 and 359.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.37) is better than Ligand B (38.13) as it is closer to the threshold for good oral absorption.

**logP:** Both ligands have logP values (2.23 and 3.669) within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target effects, but not drastically.

**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 range of <=10.

**QED:** Both ligands have similar QED values (0.731 and 0.753), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (25.591 and 27.336), both well below the 40 threshold.

**BBB:** Ligand A (77.317) and Ligand B (91.508) both have good BBB penetration, but Ligand B is significantly better. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.162 and -5.288). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.026 and -3.755), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.659) has a lower hERG risk than Ligand B (0.849), which is preferable.

**Microsomal Clearance:** Ligand A (-8.242) exhibits significantly lower microsomal clearance than Ligand B (82.034). This suggests much better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (18.712 hours) has a longer half-life than Ligand B (12.11 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.118) has lower P-gp efflux than Ligand B (0.82), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better 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 slightly better binding affinity, Ligand A is significantly better in terms of metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and hERG risk. The poor solubility and permeability are concerns for both, but the metabolic advantages of Ligand A are crucial for an enzyme target like SRC kinase. The 1.2 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand A, while improving metabolic stability is often more challenging.

Output:
0
2025-04-17 15:01:45,216 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.5) is slightly higher than Ligand B (352.4).

**TPSA:** Ligand A (101.8) is better than Ligand B (124.4), falling comfortably under the 140 threshold for oral absorption.

**logP:** Ligand A (0.719) is within the optimal range (1-3), while Ligand B (-0.545) is slightly below 1, potentially impacting permeability.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 8 HBA) and Ligand B (3 HBD, 5 HBA) both satisfy the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED values (A: 0.654, B: 0.608), indicating good drug-like properties.

**DILI:** Ligand A (86.041) has a higher DILI risk than Ligand B (51.415). This is a significant drawback for Ligand A.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.727) and Ligand B (-4.988) both have negative Caco-2 permeability values, which is unusual and suggests poor absorption. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.664 and -2.338 respectively), which could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (0.147 and 0.067), which is excellent.

**Microsomal Clearance:** Ligand B (-7.031) has significantly lower (better) microsomal clearance than Ligand A (32.316), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.117) has a longer in vitro half-life than Ligand A (12.245), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.019).

**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.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is the more promising candidate overall. The primary reasons are its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and longer t1/2). The slightly lower logP of Ligand B is a minor concern, but the superior safety and pharmacokinetic properties outweigh this. The poor solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:01:45,216 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.706 Da) and Ligand B (350.547 Da) are both acceptable.

**TPSA:** Ligand A (97.16) is slightly higher than the preferred <140, but still reasonable. Ligand B (49.41) is excellent, well below 140.

**logP:** Both ligands have logP values (3.713 and 4.138) 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 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 (0.472 and 0.732), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A has a DILI risk of 92.051, which is high and concerning. Ligand B has a much lower DILI risk of 22.722, which is excellent.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (65.335) and Ligand B (82.474) are both reasonable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and are less critical than other factors.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.155 and -3.374). This is a significant drawback, but potentially addressable through formulation.

**hERG Inhibition:** Both ligands have low hERG risk (0.416 and 0.699), which is good.

**Microsomal Clearance:** Ligand A (54.257) has lower microsomal clearance than Ligand B (67.607), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (50.452) has a longer half-life than Ligand B (-12.669). The negative value for Ligand B is concerning and suggests very rapid metabolism.

**P-gp Efflux:** Both have low P-gp efflux (0.286 and 0.503), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -9.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. The significantly lower DILI risk and better QED score are major advantages. While solubility is poor for both, the longer half-life and lower clearance of Ligand A are appealing, but are outweighed by the high DILI risk. The negative in vitro half-life for Ligand B is a serious concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 15:01:45,216 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.5 and 356.8 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is better than Ligand B (96.5). Lower TPSA generally favors better absorption, although this is less critical for kinases than for CNS targets.

**logP:** Both ligands have acceptable logP values (2.76 and 3.06), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 5 HBA) as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.849 and 0.748), indicating good drug-like properties.

**DILI:** Ligand A (16.6) has a significantly lower DILI risk than Ligand B (88.6), a major advantage.

**BBB:** Both have similar BBB penetration (67.2 and 62.2), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.7) is better than Ligand B (-5.4), indicating better intestinal absorption.

**Solubility:** Ligand A (-3.06) is better than Ligand B (-3.85), which is important for bioavailability.

**hERG:** Ligand A (0.384) has a much lower hERG inhibition liability than Ligand B (0.155), a critical safety factor.

**Microsomal Clearance:** Ligand A (43.5) has a higher Cl_mic than Ligand B (10.4), meaning Ligand B is more metabolically stable. This is a key consideration for kinases.

**In vitro Half-Life:** Ligand B (9.83) has a significantly longer half-life than Ligand A (4.04), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux than Ligand B (0.215), potentially leading to better bioavailability.

**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 significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A excels in safety (DILI, hERG) and has better absorption/solubility properties. The substantial difference in DILI and hERG risk for Ligand A is a major advantage. While the affinity difference is notable, the improved ADME/Tox profile of Ligand A, particularly the lower DILI and hERG, makes it the more promising candidate. The slightly weaker binding could potentially be optimized in later stages of drug development.

Output:
0
2025-04-17 15:01:45,217 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.427 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.25) is well below the 140 threshold for good absorption, while Ligand B (96.87) is still acceptable but approaching the upper limit.

**logP:** Ligand A (2.575) is optimal (1-3). Ligand B (0.383) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.783 and 0.692, both > 0.5).

**DILI:** Ligand A (44.591) has a slightly higher DILI risk than Ligand B (31.02), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (59.636) is lower than Ligand B (22.412).

**Caco-2 Permeability:** Ligand A (-4.978) is significantly worse than Ligand B (-5.118), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.288) is better than Ligand B (-1.707).

**hERG:** Both ligands have low hERG risk (0.711 and 0.278).

**Microsomal Clearance:** Ligand A (26.499) has higher clearance than Ligand B (-12.906), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (10.664 hours) has a significantly longer half-life than Ligand A (2.392 hours).

**P-gp Efflux:** Ligand A (0.268) has lower P-gp efflux than Ligand B (0.055), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 2.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having slightly better solubility and lower P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.6 vs -7.4 kcal/mol), combined with its improved metabolic stability (lower Cl_mic, longer half-life) and acceptable ADME properties, make it a more promising drug candidate for SRC kinase inhibition. The lower logP of Ligand A is a concern for permeability.

Output:
1
2025-04-17 15:01:45,217 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.539 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (96.53). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.534) is optimal, while Ligand B (0.259) is quite low. Low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=4), as both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (A: 0.769, B: 0.641), indicating good drug-likeness.

**DILI:** Ligand A (17.371) has a much lower DILI risk than Ligand B (25.94). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.294) is better than Ligand B (43.699).

**Caco-2 Permeability:** Ligand A (-4.738) is better than Ligand B (-5.32). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.325) is better than Ligand B (-1.667). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.609) has a lower hERG risk than Ligand B (0.099). This is a critical safety parameter.

**Microsomal Clearance:** Ligand A (93.874) has a higher (worse) clearance than Ligand B (-5.441). Lower clearance is preferred for metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (13.809) has a longer half-life than Ligand B (10.074). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.404) has lower P-gp efflux than Ligand B (0.013), which is desirable.

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better solubility, lower DILI and hERG risk, and better permeability. However, its higher microsomal clearance is a concern. Ligand B has better metabolic stability, but suffers from poor logP, higher DILI and hERG risk, and weaker binding. Given the enzyme-specific priorities, the significantly improved binding affinity of Ligand A, coupled with acceptable (though not ideal) ADME properties, makes it the more promising candidate. The difference in binding affinity is substantial (>1.2 kcal/mol), and can compensate for the higher clearance.

Output:
1
2025-04-17 15:01:45,217 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.431 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (80.12 and 78.51) well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (0.989 and 1.2) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1 HBD) is preferable to Ligand B (2 HBDs) as lower HBD counts generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5 HBA) is preferable to Ligand B (3 HBA) as lower HBA counts generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.781 and 0.784), indicating good drug-like properties.

**7. DILI:** Ligand A (32.067) has a significantly lower DILI risk than Ligand B (11.283). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (70.027) is slightly better than Ligand B (64.599). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.114 and -5.065), which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.471 and -1.741), which is also unusual and suggests poor aqueous solubility. This is a potential issue for both.

**11. hERG Inhibition:** Ligand A (0.067) has a much lower hERG inhibition liability than Ligand B (0.116), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand B (-2.237) has a *negative* microsomal clearance, which is not physically possible. This suggests a data error or an extremely stable compound. Ligand A (18.521) has a reasonable clearance.

**13. In vitro Half-Life:** Ligand B (8.046) has a significantly longer in vitro half-life than Ligand A (-2.059). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.013).

**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 for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While both ligands have issues with Caco-2 permeability and solubility, Ligand A has a significantly better safety profile (lower DILI, lower hERG), a much stronger binding affinity, and a more reasonable microsomal clearance. The superior binding affinity (-9.8 vs -7.5 kcal/mol) is a critical advantage for an enzyme inhibitor, and the lower DILI and hERG risks are crucial for clinical development. The negative clearance for Ligand B is a red flag.

Output:
0
2025-04-17 15:01:45,217 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.483 and 358.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (69.64), being well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.324 and 2.807), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Ligand B (0.883) has a higher QED score than Ligand A (0.506), suggesting a more drug-like profile overall.

**DILI:** Ligand A (35.905) has a lower DILI risk than Ligand B (47.15), indicating a better safety profile regarding liver injury.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.005) has a better BBB percentile than Ligand B (41.683).

**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, indicating poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.651 and 0.518), which is positive.

**Microsomal Clearance:** Ligand B (21.106) has a lower microsomal clearance than Ligand A (33.831), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-25.252) has a longer in vitro half-life than Ligand B (-11.891). This is a positive.

**P-gp Efflux:** Both have low P-gp efflux liability (0.81 and 0.188).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.6 kcal/mol difference is substantial and likely outweighs many of the other differences.

**Conclusion:**

Despite Ligand A's better TPSA, DILI, and half-life, Ligand B's significantly stronger binding affinity (-9.9 vs -8.3 kcal/mol) and lower microsomal clearance are decisive advantages for an enzyme target like SRC kinase. The higher QED score of Ligand B also contributes to its favorability. While both have poor solubility, the potency advantage of Ligand B is likely to be more impactful in driving forward development, as solubility issues can sometimes be addressed through formulation strategies.

Output:
1
2025-04-17 15:01:45,218 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (378.46 and 358.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is higher than Ligand B (28.26). While both are acceptable, Ligand B is better positioned for good absorption.

**3. logP:** Ligand A (2.644) is within the optimal 1-3 range. Ligand B (4.859) is higher, potentially leading to solubility issues and off-target effects.

**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 (0.595 and 0.614), indicating drug-like properties.

**7. DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (15.2). This is a major advantage for Ligand A.

**8. BBB:** Both have high BBB penetration, but Ligand A (90.112) is slightly higher than Ligand B (79.411). While not a primary concern for a kinase inhibitor, it's a minor positive for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.809) has worse Caco-2 permeability than Ligand B (-5.651).

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-3.232 and -3.332). This is a concern for both, but might be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.431) has a lower hERG risk than Ligand B (0.956). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (37.196) has lower microsomal clearance than Ligand B (49.782), indicating better metabolic stability. This is crucial for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (-12.277) has a worse in vitro half-life than Ligand B (20.623).

**14. P-gp Efflux:** Ligand A (0.049) has much lower P-gp efflux than Ligand B (0.842), which is beneficial for bioavailability.

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

**Overall Assessment:**

Ligand A is the stronger candidate. While both have solubility issues, Ligand A excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and superior binding affinity. The better binding affinity is a significant advantage that can outweigh the slightly worse Caco-2 permeability and in vitro half-life. Ligand B's higher logP and associated potential for off-target effects and formulation challenges are also concerning.

Output:
1
2025-04-17 15:01:45,218 - INFO - Batch 345 complete. Total preferences: 5520
2025-04-17 15:01:45,218 - INFO - Processing batch 346/512...
2025-04-17 15:02:27,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.455 and 364.274 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.77) is better than Ligand B (61.2) as it is closer to the 90 A^2 threshold for CNS targets, though this is less critical for a non-CNS target like SRC.

**logP:** Both ligands have good logP values (3.215 and 2.29), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.755 and 0.797), indicating good drug-likeness.

**DILI:** Ligand A (94.765) has a significantly higher DILI risk than Ligand B (73.09). This is a major concern.

**BBB:** Both ligands have low BBB penetration, which is not a high priority for SRC.

**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 (0.579 and 0.403), which is good.

**Microsomal Clearance:** Ligand A (21.625 mL/min/kg) has a higher microsomal clearance than Ligand B (6.91 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.955 hours) has a negative half-life, which is impossible. This is a significant red flag. Ligand A (82.257 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.282 and 0.144), which is favorable.

**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, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better TPSA and half-life, the significantly higher DILI risk and lower binding affinity make it less attractive. Ligand B has a superior binding affinity, lower DILI risk, and lower P-gp efflux, but the negative in vitro half-life is a critical issue. However, the negative half-life is likely an error in the data. Assuming the half-life is a positive value, Ligand B is the better candidate due to its stronger binding affinity and lower DILI risk.

Output:
1
2025-04-17 15:02:27,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.247 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**2. TPSA:** Ligand A (109.98) is higher than Ligand B (58.64). While both are below 140 for oral absorption, Ligand B's lower TPSA is preferable for better absorption.

**3. logP:** Both ligands have good logP values (A: 2.237, B: 2.68), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Both are within the acceptable limit of 5, but B is better.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (3). Both are within the acceptable limit of 10, but B is better.

**6. QED:** Both ligands have acceptable QED values (A: 0.714, B: 0.593), indicating good drug-like properties.

**7. DILI:** Ligand A (79.333) has a significantly higher DILI risk than Ligand B (16.751). This is a major concern for Ligand A.

**8. BBB:** Both have moderate BBB penetration (A: 58.821, B: 76.309). Not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**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:** Ligand A (0.664) has a slightly higher hERG risk than Ligand B (0.288). Lower is better, so B is preferable.

**12. Cl_mic:** Ligand A (-3.464) has a *lower* (better) microsomal clearance than Ligand B (33.712). This suggests better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (44.943) has a longer in vitro half-life than Ligand B (-3.946). This is a significant advantage for Ligand A.

**14. Pgp:** Ligand A (0.207) has lower P-gp efflux liability than Ligand B (0.072). Lower is better, so A is preferable.

**15. Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (-9.3). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B has a superior profile regarding key ADME properties (lower DILI, lower hERG, lower TPSA, fewer H-bonds) and significantly better binding affinity. Despite the negative Caco-2 and solubility values, the strong binding affinity and favorable ADME profile make it a more promising candidate. Ligand A's higher DILI risk and weaker binding affinity are major drawbacks, even though it has better metabolic stability and half-life. The difference in binding affinity (-7.6 vs -9.3) is substantial and likely outweighs the benefits of Ligand A's slightly better metabolic properties.

Output:
1
2025-04-17 15:02:27,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.491 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.05) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (96.53) is still under 140, but less optimal.

**logP:** Ligand A (4.808) is slightly high, potentially leading to solubility issues and off-target effects. Ligand B (0.729) is low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is within acceptable limits. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.717 and 0.629), indicating drug-like properties.

**DILI:** Ligand A (65.995) has a higher DILI risk than Ligand B (20.822), which is a significant concern.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (77.239) has a better score than Ligand B (45.754).

**Caco-2 Permeability:** Ligand A (-4.975) is very poor, indicating very low intestinal absorption. Ligand B (-5.284) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.426) has poor solubility. Ligand B (-1.574) has better solubility.

**hERG Inhibition:** Ligand A (0.872) has a slightly higher hERG risk than Ligand B (0.116), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (72.234) has higher clearance, suggesting lower metabolic stability. Ligand B (21.32) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.919 hours) has a short half-life. Ligand B (5.135 hours) has a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.788 and 0.012).

**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.

**Conclusion:**

Despite Ligand A having a slightly better BBB score, Ligand B is the superior candidate. The substantially stronger binding affinity (-7.5 vs 0.0 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B exhibits significantly lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. While its logP is low, the strong binding affinity and improved ADME properties outweigh this concern. Ligand A's poor Caco-2 permeability and solubility are also significant drawbacks.

Output:
1
2025-04-17 15:02:27,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.463 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (72.28), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.554) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (0.744) is also a bit low, but marginally better.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 limit.

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

**QED:** Both ligands have good QED scores (0.597 and 0.797), indicating good drug-like properties.

**DILI:** Ligand A (12.33) has a significantly lower DILI risk than Ligand B (24.855), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.997) has a higher BBB penetration than Ligand A (55.797), but this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.714 and -4.964), which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.892 and -1.572), indicating poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.214) has a lower hERG risk than Ligand B (0.137), which is favorable.

**Microsomal Clearance:** Ligand A (10.96) has a higher microsomal clearance than Ligand B (1.537), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (10.16) has a longer half-life than Ligand B (4.126), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.027).

**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 relatively small (0.3 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and better metabolic stability, Ligand A has a significantly lower DILI risk and a longer half-life. Both ligands suffer from poor permeability and solubility. The lower DILI risk is a crucial factor in drug development, and the slightly better affinity of Ligand B doesn't outweigh this advantage, especially considering the similar binding energies.

Output:
1
2025-04-17 15:02:27,273 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both A (352.431 Da) and B (360.443 Da) are within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Both A (88.1) and B (84.22) are below the 140 A^2 threshold for good oral absorption, and are reasonably low. B is slightly better.

3. **logP:** A (0.085) is quite low, potentially hindering permeation. B (1.059) is better, falling within the optimal 1-3 range. This is a significant advantage for B.

4. **HBD:** A (2) and B (0) both meet the <=5 criteria. B is slightly better due to lower potential for off-target interactions.

5. **HBA:** A (5) and B (7) both meet the <=10 criteria.

6. **QED:** Both A (0.634) and B (0.817) are above 0.5, indicating good drug-like properties. B is better.

7. **DILI:** A (15.743) is excellent, indicating very low liver injury risk. B (64.909) is higher, suggesting moderate risk. This is a significant advantage for A.

8. **BBB:** A (68.282) and B (52.268) are both relatively low, which isn't a major concern for a non-CNS target like SRC.

9. **Caco-2:** Both A (-4.819) and B (-5.09) are negative, which is unusual and suggests very poor permeability. B is slightly worse.

10. **Solubility:** Both A (-1.275) and B (-1.298) are poor. Solubility is a concern for both.

11. **hERG:** A (0.213) is very low, indicating minimal hERG inhibition risk. B (0.355) is slightly higher, but still acceptable. A is better.

12. **Cl_mic:** A (26.154) is higher than B (19.987), suggesting faster metabolic clearance and lower metabolic stability. B is better.

13. **t1/2:** A (-1.37) is very short, indicating rapid elimination. B (-21.721) is much longer, suggesting better *in vitro* stability. This is a major advantage for B.

14. **Pgp:** A (0.021) is very low, suggesting minimal P-gp efflux. B (0.118) is slightly higher. A is better.

15. **Binding Affinity:** A (-8.3) is slightly better than B (-9.2). However, the difference is not substantial enough to overcome other issues.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a better DILI score, hERG, and Pgp efflux profile, and slightly better binding affinity. However, it suffers from very poor *in vitro* half-life and higher metabolic clearance. Its logP is also problematic.

Ligand B has better logP, QED, metabolic stability (Cl_mic and t1/2), and a slightly better TPSA. While its DILI score is higher, it's still within a moderate risk range. The poor Caco-2 values for both are concerning, but can potentially be addressed with formulation strategies.

Considering the enzyme-specific priorities, the improved metabolic stability and logP of Ligand B outweigh the slightly higher DILI risk and slightly weaker binding. The longer half-life is particularly valuable for a kinase inhibitor.

Output:
1
2025-04-17 15:02:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.311 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.9) is better than Ligand B (52.65) as it is closer to the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.44 and 1.843 respectively), 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.

**QED:** Both ligands have acceptable QED scores (0.43 and 0.657), with Ligand B being slightly better.

**DILI:** Ligand A has a DILI risk of 97.984, which is very high and concerning. Ligand B has a DILI risk of 56.883, which is still elevated but considerably better than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (58.007) and Ligand B (67.352) are both relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.005 and -4.911), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.437 and -1.902), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.447 and 0.394), which is positive.

**Microsomal Clearance:** Ligand A (89.456) has higher microsomal clearance than Ligand B (59.007), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.81) has a longer in vitro half-life than Ligand A (-4.329), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.306 and 0.218).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. The primary reason is the significantly better binding affinity (-7.2 vs -10.2 kcal/mol). This difference in potency is likely to outweigh the ADME drawbacks. Furthermore, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2) compared to Ligand A. Ligand A's extremely high DILI risk is a major red flag.

Output:
1
2025-04-17 15:02:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.383 and 352.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.3) is slightly higher than Ligand B (67.87). Both are below the 140 threshold for oral absorption, but B is preferable.

**3. logP:** Both ligands have good logP values (1.714 and 1.581), 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 (0.871) has a better QED score than Ligand B (0.788), indicating higher drug-likeness.

**7. DILI:** Ligand B (20.9) has a significantly lower DILI risk than Ligand A (56.223). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (72.121) has a better BBB penetration percentile than Ligand A (46.336), but this isn't a high priority for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.84) is slightly worse than Ligand B (-4.648).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.607) is slightly worse than Ligand B (-1.708).

**11. hERG Inhibition:** Ligand A (0.025) has a slightly better hERG profile than Ligand B (0.21), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-8.769) has a much lower (better) microsomal clearance than Ligand B (53.538). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (19.469) has a significantly longer in vitro half-life than Ligand A (-1.745). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.012) has a lower P-gp efflux liability than Ligand B (0.03).

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). This difference of 0.9 kcal/mol is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability, and slightly better hERG and P-gp profiles. However, Ligand B has a substantially lower DILI risk and a significantly longer half-life. The poor Caco-2 and solubility for both are concerning, but the DILI risk for Ligand A is high enough to be a major concern. The longer half-life of Ligand B is also very attractive for an enzyme inhibitor. Given the enzyme-specific priorities, the balance favors Ligand B due to its superior safety profile (DILI) and improved pharmacokinetic properties (half-life), despite the slightly weaker binding affinity.

Output:
1
2025-04-17 15:02:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.46 and 353.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (96.53).  A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have good logP values (2.515 and 1.878), 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) regarding the number of H-bond donors, staying closer to the ideal of <=5. Both are within the HBA limit of <=10.

**QED:** Ligand A (0.826) has a significantly higher QED score than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 39.94, Ligand B: 34.39), being below the 40 threshold.

**BBB:** Ligand A (82.47) has a higher BBB penetration percentile than Ligand B (75.11), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or calculation. However, we can still compare them relatively. Ligand A (-4.849) is slightly better than Ligand B (-4.755).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. Ligand B (-2.786) is slightly better than Ligand A (-3.877).

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.359, Ligand B: 0.103), which is excellent.

**Microsomal Clearance:** Ligand A (49.32 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (59.59 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.257 hours) has a positive half-life, while Ligand B (-12.665 hours) 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 (Ligand A: 0.133, Ligand B: 0.013).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is clearly superior. It has a better QED score, lower microsomal clearance (better metabolic stability), a positive and reasonable in vitro half-life, and slightly better binding affinity. While both have issues with Caco-2 and solubility (negative values are concerning), the half-life issue with Ligand B is a critical flaw. The slightly better TPSA and logP of Ligand A further support its selection.

Output:
0
2025-04-17 15:02:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.415 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.39) is slightly above the preferred <140, but acceptable. Ligand B (89.87) is excellent, well below 140.

**3. logP:** Ligand A (0.305) is quite low, potentially hindering permeability. Ligand B (1.44) is within 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:** Both ligands (A: 4, B: 4) are well below the limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.774, B: 0.697), indicating good drug-like properties.

**7. DILI:** Ligand A (30.593) has a very favorable DILI score, indicating low liver injury risk. Ligand B (16.092) is also excellent.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (70.26) is better than Ligand B (60.76). However, BBB is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Ligand A (-5.462) has poor Caco-2 permeability, which is concerning. Ligand B (-4.856) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.131 and -2.707). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.058, B: 0.18).

**12. Microsomal Clearance:** Ligand A (21.953) and Ligand B (19.154) have similar, relatively low, microsomal clearance, suggesting reasonable metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.49) has a very short half-life. Ligand B (-8.445) has a long half-life, which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.008, B: 0.05), which is good.

**15. Binding Affinity:** Ligand A (-8.5) has a slightly better binding affinity than Ligand B (-7.8), a difference of 0.7 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and DILI score, its extremely low logP and Caco-2 permeability are major concerns. The poor solubility of both compounds is also problematic. However, Ligand B's significantly longer half-life and better logP outweigh the slightly weaker binding affinity. The longer half-life is particularly important for an enzyme inhibitor, as it allows for less frequent dosing.

Output:
1
2025-04-17 15:02:27,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (437.384 Da) is slightly higher, but still acceptable. Ligand B (354.403 Da) is also good.

**TPSA:** Ligand A (51.22) is better than Ligand B (102.01) as it is closer to the ideal threshold of 140 for oral absorption.

**logP:** Ligand A (4.785) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.411) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.444 and 0.5), indicating acceptable drug-likeness.

**DILI:** Ligand A (79.333) has a higher DILI risk than Ligand B (40.403). Ligand B is preferable here.

**BBB:** Both have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 (0.57) has a slightly higher hERG risk than Ligand B (0.089). Ligand B is preferable.

**Microsomal Clearance:** Ligand A (123.32) has a higher microsomal clearance than Ligand B (30.209), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (-15.825) has a negative half-life, which is not possible. This is a major red flag. Ligand A (37.662) is acceptable.

**P-gp Efflux:** Ligand A (0.558) has a lower P-gp efflux liability than Ligand B (0.031), which is preferable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly better binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite Ligand B having a negative half-life (a critical issue), its significantly stronger binding affinity (-8.2 vs -7.4 kcal/mol) and lower DILI/hERG risk make it the more promising candidate. The negative half-life is a serious concern that would require further investigation (e.g., checking the data source, considering it an error), but the potency advantage is substantial. Ligand A has better metabolic stability, but the affinity difference is key for an enzyme target.

Output:
1
2025-04-17 15:02:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (365.503 Da) is also well within range.

**TPSA:** Both ligands have TPSA values (70.67 and 71.33 respectively) that are acceptable for oral absorption (<=140), but higher than optimal.

**logP:** Ligand A (0.455) is quite low, potentially hindering membrane permeability and absorption. Ligand B (2.045) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which is a good balance. Ligand B has 0 HBD and 6 HBA, also acceptable, although the lack of HBD might slightly impact aqueous solubility.

**QED:** Both ligands have reasonable QED scores (0.836 and 0.747), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 19.659, which is excellent (low risk). Ligand B has a higher DILI risk of 58.666, but still below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (70.337 and 80.419), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.152 and -4.859), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.616 and -2.535), indicating very poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.253 and 0.177), which is positive.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-1.993), which is excellent, suggesting very high metabolic stability. Ligand B has a higher Cl_mic (42.802), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A has a half-life of 31.055 hours, which is good. Ligand B has a negative half-life (-3.383), which is not physically meaningful and likely an artifact of the prediction.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.257), which is favorable.

**Binding Affinity:** Ligand A has a better binding affinity (-8.6 kcal/mol) than Ligand B (-7.1 kcal/mol). The 1.5 kcal/mol difference is substantial and could outweigh some of the ADME concerns.

**Overall Assessment:**

Despite the poor solubility and permeability predictions for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.6 vs -7.1 kcal/mol) is a major advantage for an enzyme target. Furthermore, its excellent metabolic stability (negative Cl_mic) and very low DILI risk are highly desirable. While the low logP and solubility are concerns, these might be addressed through formulation strategies or further chemical modifications. Ligand B's higher metabolic clearance and nonsensical half-life are significant drawbacks.

Output:
0
2025-04-17 15:02:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (385.921) is still well within the range.

**TPSA:** Ligand A (70.59) is better than Ligand B (84.14). Lower TPSA generally correlates with better cell permeability. Both are below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (A: 3.237, B: 2.992), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is more balanced and preferable to Ligand B (HBD=1, HBA=7). Excessive HBA can sometimes hinder permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.752, B: 0.717), indicating good drug-like properties.

**DILI:** Ligand A (44.087) has a significantly lower DILI risk than Ligand B (60.062). This is a major advantage for Ligand A.

**BBB:** Both have similar low BBB penetration (A: 43.815, B: 43.505). This isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.626 and -4.97). This is unusual and suggests poor permeability, but the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-3.135 and -2.672). Again, the scale isn't defined, but suggests poor solubility.

**hERG Inhibition:** Ligand A (0.712) has a slightly higher hERG risk than Ligand B (0.2), but both are relatively low.

**Microsomal Clearance:** Ligand B (36.565) has a lower microsomal clearance than Ligand A (55.556), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (34.408) has a much longer in vitro half-life than Ligand A (1.078). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.403, B: 0.467).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -8.2 kcal/mol, B: -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a clear advantage in terms of DILI risk and a slightly better TPSA. However, Ligand B shines with significantly better metabolic stability (lower Cl_mic) and a much longer in vitro half-life. Given that we are targeting a kinase (enzyme), metabolic stability and half-life are crucial. While both have poor predicted solubility and permeability, the improved PK profile of Ligand B outweighs the slightly better safety profile of Ligand A.

Output:
1
2025-04-17 15:02:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.429 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand A (52.65 A^2) is lower than Ligand B (43.18 A^2), suggesting potentially better absorption.

**3. logP:** Ligand A (2.272) is within the optimal range (1-3). Ligand B (4.484) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable, but Ligand B is closer to the upper limit of 10.

**6. QED:** Both ligands have QED values above 0.5 (Ligand A: 0.778, Ligand B: 0.619), indicating good drug-like properties.

**7. DILI:** Ligand A (22.489%) has a significantly lower DILI risk than Ligand B (33.307%). This is a major advantage for Ligand A.

**8. BBB:** Both have good BBB penetration, but Ligand B (85.459%) is slightly higher than Ligand A (75.223%). This is less crucial for a non-CNS target like SRC.

**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:** Ligand A (-1.028) has better solubility than Ligand B (-4.133). This is important for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.659, Ligand B: 0.718).

**12. Microsomal Clearance:** Ligand A (18.268 mL/min/kg) has lower microsomal clearance than Ligand B (52.052 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.758 hours) has a shorter half-life than Ligand B (10.606 hours), but both are reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.02, Ligand B: 0.628).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (Ligand A: -8.1 kcal/mol, Ligand B: -8.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While both have good binding affinity, Ligand A demonstrates superior ADME properties: lower DILI risk, better solubility, and lower microsomal clearance. The slightly lower logP and TPSA of Ligand A also suggest better absorption and permeability. The small difference in half-life is less critical than the other advantages.

Output:
0
2025-04-17 15:02:27,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.335 Da) is slightly lower, which could be beneficial for permeability. Ligand B (356.419 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (104.04) is slightly higher than Ligand B (97.33), but both are well within the acceptable range.

**logP:** Ligand A (3.484) is within the optimal range (1-3). Ligand B (-0.705) is significantly lower, which could lead to poor membrane permeability and bioavailability. This is a major drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both fall within the acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.532, B: 0.597), indicating a generally drug-like profile.

**DILI:** Ligand A has a high DILI risk (98.643%), which is a significant concern. Ligand B has a much lower DILI risk (16.014%), making it more favorable in this regard.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (33.967%) has a higher BBB value than Ligand A (23.42%), but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-5.335) is slightly worse than Ligand B (-5.032).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-0.468) is slightly better than Ligand A (-4.92).

**hERG Inhibition:** Ligand A (0.764) has a slightly higher hERG risk than Ligand B (0.127), but both are relatively low.

**Microsomal Clearance:** Ligand B (-4.586) has a *negative* microsomal clearance, which is impossible. This indicates a data error or an unusual compound behavior. Ligand A (69.614) is a more reasonable value, suggesting moderate metabolic clearance.

**In vitro Half-Life:** Ligand A (-21.463) has a negative half-life, which is impossible. Ligand B (22.44) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.213, B: 0.008).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.7 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's high DILI risk and impossible half-life, its significantly stronger binding affinity (-8.9 kcal/mol vs -5.7 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The difference in binding affinity is substantial (>1.5 kcal/mol). Ligand B has a better safety profile (lower DILI, lower hERG) but suffers from a poor logP, negative clearance, and a weaker binding affinity. The negative clearance and half-life values for Ligand B raise serious concerns about data quality.

Output:
0
2025-04-17 15:02:27,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.427 Da and 354.401 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (79.53) is well within the ideal range.

**logP:** Both ligands (2.321 and 2.018) are within the optimal 1-3 range.

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

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

**QED:** Ligand B (0.877) has a significantly higher QED score than Ligand A (0.632), indicating better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (39.201 and 34.781), both below the 40 threshold.

**BBB:** Ligand B (94.339) shows high BBB penetration, while Ligand A (60.682) is lower. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.023 and -4.806). This 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 (-2.776 and -2.002). This is also unusual and suggests poor solubility. Again, the scale is unknown.

**hERG Inhibition:** Ligand A (0.338) has a lower hERG risk than Ligand B (0.63), which is preferable.

**Microsomal Clearance:** Ligand B (-9.971) has a *negative* microsomal clearance, which is impossible and likely an error in the data. Ligand A (34.158) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (-8.824) has a negative half-life, which is also impossible and indicates a data error. Ligand A (25.943) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux than Ligand B (0.042), which is better.

**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.

**Conclusion:**

Despite the questionable solubility and permeability data, Ligand B is the stronger candidate due to its significantly improved binding affinity (-9.0 vs -7.3 kcal/mol). The higher QED score also favors Ligand B. The negative values for clearance and half-life for Ligand B are concerning and likely represent data errors, but the binding affinity difference is so large that it still makes Ligand B the better choice *if* those values can be corrected. Ligand A's hERG risk is slightly lower, but the affinity difference is more important for an enzyme target.

Output:
1
2025-04-17 15:02:27,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.379 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (76.89). Lower TPSA generally improves oral absorption. Ligand B's TPSA is quite high.

**logP:** Both ligands have good logP values (A: 3.667, B: 2.321), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=6). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.819) has a much better QED score than Ligand B (0.688), indicating a more drug-like profile.

**DILI:** Ligand A (39.977) has a lower DILI risk than Ligand B (56.727), which is a significant advantage. Both are under the 60 threshold, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.431) has a higher BBB score than Ligand B (52.811), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.621) has better Caco-2 permeability than Ligand B (-5.017), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.865) has better aqueous solubility than Ligand B (-3.153). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.867, B: 0.655), which is good.

**Microsomal Clearance:** Ligand A (9.691) has a lower microsomal clearance than Ligand B (36.02), suggesting better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-5.32) has a much longer in vitro half-life than Ligand B (34.824), which is highly desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.254) has lower P-gp efflux than Ligand B (0.062), which improves bioavailability.

**Binding Affinity:** Both ligands have similar and excellent binding affinities (A: -8.6 kcal/mol, B: -8.2 kcal/mol). The difference of 0.4 kcal/mol is not large enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties (TPSA, QED, DILI, Cl_mic, t1/2, solubility, permeability, P-gp efflux) while maintaining comparable binding affinity. These factors make it a significantly more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 15:02:27,276 - INFO - Batch 346 complete. Total preferences: 5536
2025-04-17 15:02:27,276 - INFO - Processing batch 347/512...
2025-04-17 15:03:07,413 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (399.559 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.47 and 75.19) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.566 and 2.641) 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.633 and 0.609), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 71.694, which is considered high risk (>60). Ligand B has a DILI risk of 41.877, which is acceptable (<40). This is a significant advantage for Ligand B.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (70.88) than Ligand A (46.219), but this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating 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 (0.465) has a slightly higher hERG risk than Ligand B (0.342), but both are relatively low.

**Microsomal Clearance:** Ligand A (28.382 mL/min/kg) has lower microsomal clearance than Ligand B (37.09 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.014 hours) has a significantly longer half-life than Ligand B (-13.804 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.465 and 0.154).

**Binding Affinity:** Ligand B (-8.3 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 ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much lower DILI risk. While Ligand A has a longer half-life, the DILI risk associated with Ligand A is a major concern. The stronger binding affinity of Ligand B is a critical factor for an enzyme inhibitor, and the lower DILI risk makes it a safer starting point for optimization. The poor Caco-2 and solubility for both compounds would need to be addressed through structural modifications.

Output:
1
2025-04-17 15:03:07,413 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.379 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (89.87 and 87.74) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.686) is optimal, while Ligand B (0.849) is a bit low, potentially hindering permeation.

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

**H-Bond Acceptors:** Both ligands (4) are below the 10 threshold.

**QED:** Ligand A (0.747) has a significantly better QED score than Ligand B (0.45), indicating better overall drug-likeness.

**DILI:** Ligand A (60.527) is borderline, but acceptable, while Ligand B (7.29) is very good, indicating a lower risk of liver injury.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (66.499) is slightly better than Ligand A (33.928).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.174) is slightly worse than Ligand B (-4.961).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.859) is slightly worse than Ligand B (-1.3).

**hERG:** Ligand A (0.461) has a slightly higher hERG risk than Ligand B (0.237), but both are relatively low.

**Microsomal Clearance:** Ligand A (-17.402) has a much lower (better) microsomal clearance than Ligand B (9.159), indicating greater metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-22.067) has a much longer in vitro half-life than Ligand B (-14.978), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.012).

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better QED, metabolic stability (Cl_mic and t1/2), and a slightly better hERG profile, Ligand B's significantly stronger binding affinity (-6.9 vs 0.0 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The difference in affinity is substantial. Although Ligand B has a lower logP and a slightly higher DILI risk, the potency advantage is likely to be more important in this case.

Output:
1
2025-04-17 15:03:07,413 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.383 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.84) is better than Ligand B (81.08), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.214 and 1.173), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as it has fewer H-bond donors, which can sometimes hinder permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.668 and 0.728), indicating drug-like properties.

**DILI:** Ligand A (61.574) has a higher DILI risk than Ligand B (17.449). This is a significant drawback for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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, indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.221), but both are relatively low.

**Microsomal Clearance:** Ligand B (0.564) has significantly better metabolic stability (lower clearance) than Ligand A (107.537). This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-0.472) has a better half-life than Ligand A (-3.489).

**P-gp Efflux:** Ligand A (0.346) has lower P-gp efflux liability than Ligand B (0.059), which is a slight advantage.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic and better half-life) outweigh the slight advantages of Ligand A in terms of P-gp efflux. The poor solubility and Caco-2 permeability are concerns for both, but metabolic stability and safety are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 15:03:07,414 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.454 and 351.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is well below the 140 threshold for good oral absorption, and even better for kinase inhibitors. Ligand B (121.71) is still acceptable, but less optimal.

**logP:** Ligand A (1.046) is within the optimal 1-3 range. Ligand B (-0.114) is slightly below 1, which *could* indicate permeability issues, although not drastically.

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

**QED:** Both ligands have similar QED values (0.74 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (18.147) has a much lower DILI risk than Ligand B (69.058). This is a significant advantage for Ligand A.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (78.247) has a better BBB score than Ligand B (19.814).

**Caco-2 Permeability:** Ligand A (-4.377) has a negative Caco-2 value, which is unusual and concerning. Ligand B (-5.062) is also negative, but similarly problematic. This suggests poor intestinal absorption for both, but is more concerning for Ligand A.

**Aqueous Solubility:** Ligand A (-1.058) has slightly better solubility than Ligand B (-2.115), though both are poor.

**hERG:** Both ligands have very low hERG risk (0.346 and 0.046), which is excellent.

**Microsomal Clearance:** Ligand A (18.767) has a higher microsomal clearance than Ligand B (-15.551). This suggests Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-34.443) has a significantly longer in vitro half-life than Ligand A (8.423), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.021).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). The difference of 1.4 kcal/mol is substantial and outweighs many of the ADME concerns with Ligand B.

**Conclusion:**

Despite some ADME drawbacks (low Caco-2 and solubility) in both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.3 vs -6.9 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme inhibitor. The lower DILI risk of Ligand A is attractive, but the potency and stability advantages of Ligand B are more important in this case.

Output:
1
2025-04-17 15:03:07,414 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (360.445 and 369.868 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (52.65), but both are well below the 140 threshold for good absorption.

**3. logP:** Both ligands have logP values (2.47 and 2.542) 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, which is well below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.685 and 0.803), indicating drug-like properties.

**7. DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (38.736). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (89.492 and 83.831), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.551 and -4.763), 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.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.441 and -2.633), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.816 and 0.803).

**12. Microsomal Clearance:** Ligand A (32.604) has a higher microsomal clearance than Ligand B (3.908). This suggests Ligand B is more metabolically stable, which is crucial for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (40.91) has a significantly longer in vitro half-life than Ligand A (0.003). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux than Ligand B (0.097).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a stronger binding affinity than Ligand B (-7.4 kcal/mol). The difference of 0.7 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic and longer t1/2). The poor Caco-2 and solubility for both are concerning, but the strong affinity of Ligand A is a significant advantage. Given the enzyme-specific priorities, the improved metabolic stability of Ligand B is very important, but the substantially stronger binding affinity of Ligand A is a more critical factor for a kinase inhibitor.

Output:
0
2025-04-17 15:03:07,414 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.491 and 347.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (104.11). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.49 and 1.638), 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) as lower HBD generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.745 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (19.155) has a much lower DILI risk than Ligand B (66.615). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.686) is slightly better than Ligand B (63.668).

**Caco-2 Permeability:** Ligand A (-4.791) is better than Ligand B (-5.297), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.749) is better than Ligand B (-2.744), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.275) has a much lower hERG inhibition liability than Ligand B (0.567), a crucial safety parameter.

**Microsomal Clearance:** Ligand A (57.886) has a higher (worse) microsomal clearance than Ligand B (13.997), indicating lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand A (-4.721) has a longer half-life than Ligand B (0.964), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux liability than Ligand B (0.061), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.3), a 0.7 kcal/mol difference. While affinity is paramount, the other ADME properties need to be considered.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile overall. It has significantly lower DILI and hERG risk, better solubility, and better Caco-2 permeability. While Ligand B has a slightly better binding affinity, the substantial improvements in safety and ADME properties for Ligand A outweigh this difference. The higher clearance of Ligand A is a concern, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 15:03:07,414 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.315 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is well below the 140 threshold, while Ligand B (84.3) is still acceptable but higher.

**logP:** Ligand A (3.139) is optimal. Ligand B (0.627) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**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 (0.505 and 0.512), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (96.704 percentile), which is a significant concern. Ligand B has a much lower DILI risk (29.042 percentile), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (54.556) and Ligand B (43.893) are both moderate.

**Caco-2 Permeability:** Ligand A (-4.43) is very poor, suggesting poor absorption. Ligand B (-5.506) is also poor but slightly worse.

**Aqueous Solubility:** Ligand A (-4.188) is poor. Ligand B (-0.821) is also poor, but comparatively better.

**hERG:** Ligand A (0.447) has a slightly elevated hERG risk, while Ligand B (0.333) is lower, which is preferable.

**Microsomal Clearance:** Ligand A (54.713 mL/min/kg) suggests moderate clearance. Ligand B (-6.358 mL/min/kg) indicates very low clearance and excellent metabolic stability, a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (42.944 hours) is good. Ligand B (0.892 hours) is very short, a major drawback.

**P-gp Efflux:** Ligand A (0.429) has moderate P-gp efflux. Ligand B (0.052) has very low P-gp efflux, which is beneficial.

**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 could outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, its high DILI risk, poor Caco-2 permeability, and poor solubility are major liabilities. Ligand B has a better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), and lower P-gp efflux, but its binding affinity is weaker and its in vitro half-life is very short.

Despite the affinity difference, the severe ADME liabilities of Ligand A, particularly the DILI risk, make it a less viable candidate. While the affinity difference is significant, the poor ADME profile of A is likely to lead to failure in later stages of development. Ligand B, while weaker in binding, offers a much more favorable starting point for optimization due to its better safety and pharmacokinetic properties.

Output:
1
2025-04-17 15:03:07,414 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.86) is better than Ligand B (49.85) as it is still within the acceptable range for oral absorption (<140), but Ligand B is better for potential CNS penetration. However, SRC is not a CNS target, so this is less important.

**logP:** Ligand B (1.808) is better than Ligand A (0.669). Ligand A is slightly below the optimal 1-3 range, which could hinder permeability. Ligand B is well within the optimal range.

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

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA. Both are below the threshold of 10.

**QED:** Both ligands have similar QED values (0.703 and 0.731), indicating good drug-like properties.

**DILI:** Ligand A (63.629) has a higher DILI risk than Ligand B (13.3). This is a significant negative for Ligand A.

**BBB:** Both have similar BBB penetration (72.354 and 70.027), which isn't critical for a non-CNS target.

**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 have negative solubility values, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.087 and 0.257).

**Microsomal Clearance:** Ligand B (20.022) has lower microsomal clearance than Ligand A (34.664), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-10.424) has a longer in vitro half-life than Ligand A (-26.475). This is another advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.116).

**Binding Affinity:** Both ligands have identical binding affinities (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Ligand B is the superior candidate. While both have excellent binding affinity, Ligand B demonstrates significantly better ADME properties, specifically lower DILI risk and improved metabolic stability (lower Cl_mic and longer t1/2). The slightly better logP of Ligand B also contributes to its favorability. The unusual negative values for Caco-2 and solubility are concerning for both, but the differences in DILI and metabolic stability are more decisive.

Output:
1
2025-04-17 15:03:07,414 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 340.318 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (86.03). A TPSA under 140 is good for oral absorption, and both are, but lower is preferred.

**logP:** Both ligands have acceptable logP values (1.17 and 1.238), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (0 HBD, 8 HBA). Both are within acceptable limits, but the higher number of HBA in B could potentially affect permeability.

**QED:** Both ligands have similar QED values (0.594 and 0.522), indicating good drug-likeness.

**DILI:** Ligand A (26.095) has a much lower DILI risk than Ligand B (98.255). This is a significant advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (67.08 and 73.517), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-4.88) has a slightly better (less negative) Caco-2 value than Ligand B (-4.486), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.706) has better aqueous solubility than Ligand B (-3.354). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.521) has a lower hERG inhibition liability than Ligand B (0.346), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (42.169) has a lower microsomal clearance than Ligand B (60.463), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.995) has a significantly longer in vitro half-life than Ligand B (-11.377). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.045).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.3 and -7.4 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A is the superior candidate**. While both ligands exhibit excellent binding affinity, Ligand A demonstrates significantly better ADMET properties, particularly regarding DILI risk, solubility, metabolic stability (lower Cl_mic and longer t1/2), and hERG inhibition. These factors are critical for developing a safe and effective kinase inhibitor.

Output:
1
2025-04-17 15:03:07,414 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.403 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (97.33 and 96.25) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.719) is slightly low, potentially hindering permeation, while Ligand B (1.32) is within the optimal 1-3 range. This gives a slight edge to Ligand B.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.676 and 0.75), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (38.852 and 36.952 percentile), which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (48.779) has a higher BBB percentile than Ligand A (28.81), but this is not a major factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.036 and -4.908), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.292 and -3.098), indicating very poor aqueous solubility. This is a major drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.171 and 0.238), which is excellent.

**Microsomal Clearance:** Ligand A (25.714 mL/min/kg) has a slightly higher clearance than Ligand B (23.926 mL/min/kg), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.258 hours) has a negative half-life, which is not possible, and indicates a potential data error or a very rapidly metabolized compound. Ligand A (17.522 hours) has a much more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.012 and 0.032), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.8 kcal/mol). The difference is negligible.

**Conclusion:**

Despite both having issues with solubility and Caco-2 permeability, Ligand B's negative in vitro half-life is a critical flaw. A negative half-life is impossible and suggests severe instability. Ligand A, while having slightly higher clearance, has a reasonable half-life and comparable binding affinity. The slightly better logP of Ligand B is outweighed by its instability. Therefore, Ligand A is the more viable candidate.

Output:
0
2025-04-17 15:03:07,415 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.503 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is significantly better than Ligand B (96.25). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.235) is slightly higher than Ligand B (1.752), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD is generally preferred for permeability.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA is generally preferred for permeability.

**QED:** Both ligands have similar QED values (0.661 and 0.624), indicating good drug-likeness.

**DILI:** Ligand A (15.394) has a much lower DILI risk than Ligand B (39.201). This is a significant advantage for A.

**BBB:** Both ligands have similar BBB penetration (76.347 and 73.905). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have similar, poor Caco-2 permeability (-4.836 and -4.835).

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-2.488 and -2.507).

**hERG Inhibition:** Ligand A (0.551) has a slightly better hERG profile than Ligand B (0.191), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (60.747) has a higher microsomal clearance than Ligand B (35.529), meaning it's less metabolically stable. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (19.942) has a significantly longer in vitro half-life than Ligand A (8.13). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.58) has better P-gp efflux profile than Ligand B (0.159).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, and better hERG profile, but suffers from higher microsomal clearance and shorter half-life. Ligand B has a better metabolic profile (lower Cl_mic, longer t1/2) but weaker binding affinity and higher DILI risk. Given the importance of potency for kinase inhibitors, the 1.3 kcal/mol advantage of Ligand A is substantial. While the metabolic stability of A is a concern, it could be addressed through structural modifications. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 15:03:07,415 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.447 Da) is slightly higher than Ligand B (350.459 Da), but both are acceptable.

**TPSA:** Ligand A (126.65) is borderline for good oral absorption (<=140), while Ligand B (81.08) is well within the acceptable range.

**logP:** Ligand A (-0.301) is a bit low, potentially hindering permeation. Ligand B (1.092) 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 4 HBA, also good.

**QED:** Both ligands have good QED scores (A: 0.634, B: 0.703), indicating drug-like properties.

**DILI:** Ligand A (44.862) has a moderate DILI risk, but is still acceptable. Ligand B (13.339) has a very low DILI risk, which is a significant advantage.

**BBB:** Both have similar BBB penetration (A: 62.544, B: 60.876), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.123 and -4.689), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.741 and -1.628), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.097) has a very low hERG risk, which is excellent. Ligand B (0.279) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-11.705) has a much lower (better) microsomal clearance than Ligand B (15.938), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.412) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (-11.504) also has a negative half-life, but is more negative, suggesting even faster degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.004, B: 0.135).

**Binding Affinity:** Ligand B (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This 2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is the better candidate. Its significantly stronger binding affinity (-10.6 vs -8.6 kcal/mol) is a major advantage for an enzyme target. Additionally, it has a much lower DILI risk and better metabolic stability (lower Cl_mic). The slightly better logP of Ligand B also contributes to its favorability. The negative half-lives are concerning for both, but the potency advantage of B is likely to be more impactful in initial optimization.

Output:
1
2025-04-17 15:03:07,415 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (345.443 and 364.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.43) is better than Ligand B (62.13). Both are below 140, suggesting good oral absorption potential.

**3. logP:** Ligand A (1.574) is within the optimal range (1-3). Ligand B (3.727) is approaching 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 (<=5).

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

**6. QED:** Both ligands have reasonable QED values (0.822 and 0.714), indicating good drug-like properties.

**7. DILI:** Ligand A (11.632) has a significantly lower DILI risk than Ligand B (23.032). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for an oncology target unless CNS penetration is specifically desired. Ligand A (71.966) is better than Ligand B (50.407), but neither are particularly high.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.827 and -4.908), which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.674 and -3.883), which is also concerning and suggests very poor solubility.

**11. hERG Inhibition:** Ligand A (0.529) has a lower hERG risk than Ligand B (0.84). This is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand A (13.683) has a lower microsomal clearance than Ligand B (99.354), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-19.932) has a negative half-life, which is not possible. Ligand B (9.942) is a reasonable value. This is a major drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.026) has a much lower P-gp efflux liability than Ligand B (0.522), which is beneficial.

**15. Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (0). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor for an enzyme target. However, it has a higher DILI risk, higher microsomal clearance, and higher P-gp efflux. Ligand A has better DILI, clearance, and P-gp properties, but its binding affinity is extremely weak, and its half-life is not possible. The negative Caco-2 and solubility values for both are concerning and would require significant optimization.

Despite the concerns with both compounds, the significantly stronger binding affinity of Ligand B outweighs its other drawbacks, *assuming* the negative solubility and permeability can be addressed through formulation or structural modifications. The negative half-life of Ligand A is a showstopper.

Output:
1
2025-04-17 15:03:07,415 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.471 and 375.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.39) is slightly higher than Ligand B (66.32). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (1.816) is within the optimal 1-3 range. Ligand B (3.248) is at the higher end, but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (6) are below the <=10 criteria.

**QED:** Ligand B (0.865) has a higher QED score than Ligand A (0.566), indicating a more drug-like profile.

**DILI:** Ligand A (74.952) has a higher DILI risk than Ligand B (65.568), though both are reasonably acceptable.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 51.997, Ligand B: 49.787). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.189 and -5.128), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.128 and -3.867), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.072) has a slightly lower hERG risk than Ligand B (0.396), which is preferable.

**Microsomal Clearance:** Ligand B (54.348) has a lower microsomal clearance than Ligand A (69.611), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (2.669) has a longer half-life than Ligand B (-0.785). This is a positive for Ligand A, but the negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux than Ligand B (0.207), which is better.

**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 substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, it has better metabolic stability (lower Cl_mic) and a higher QED score. While Ligand A has a slightly better hERG profile and half-life, the potency and metabolic stability of Ligand B are more critical for this target class. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the core potency and stability profile of Ligand B is superior.

Output:
1
2025-04-17 15:03:07,415 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 346.483 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.67) is better than Ligand B (86.34), both are under the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (1.299) is within the optimal 1-3 range. Ligand B (2.523) is also within range, but higher.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5, and Ligand B has 8. Ligand A is preferable here.

**QED:** Both ligands have similar QED values (0.84 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (25.359) has a significantly lower DILI risk than Ligand B (43.738). This is a major advantage for Ligand A.

**BBB:** Both have good BBB penetration (73.401 and 71.811), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2:** Ligand A (-4.64) has a better Caco-2 permeability than Ligand B (-5.38).

**Solubility:** Ligand A (-1.443) has better solubility than Ligand B (-2.748). Solubility is important for kinases.

**hERG:** Ligand A (0.355) has a lower hERG risk than Ligand B (0.095). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (3.611) has a lower microsomal clearance than Ligand B (28.216), indicating better metabolic stability, which is crucial for kinases.

**In vitro Half-Life:** Ligand A (3.981) has a longer half-life than Ligand B (-3.417). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.077).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is clearly superior. While both have comparable binding affinity, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, better solubility, lower hERG risk, lower microsomal clearance (better metabolic stability), and a longer half-life. These factors are all critical for kinase inhibitors.

Output:
1
2025-04-17 15:03:07,415 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.535 Da and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold and excellent for oral absorption. Ligand B (95.16) is still under 140, but less optimal than A.

**logP:** Ligand A (3.227) is within the optimal 1-3 range. Ligand B (1.321) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.728 and 0.76), indicating drug-likeness.

**DILI:** Ligand A (20.279) has a significantly lower DILI risk than Ligand B (52.385), which is a major advantage.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (71.307) has a better percentile than Ligand B (57.929).

**Caco-2 Permeability:** Ligand A (-4.328) and Ligand B (-4.934) 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 (-3.463) and Ligand B (-2.427) both have negative values, indicating poor solubility. This is a concern.

**hERG:** Both ligands have low hERG risk (0.564 and 0.264), which is good.

**Microsomal Clearance:** Ligand A (78.478) has a higher microsomal clearance than Ligand B (28.056). This means Ligand B is likely more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (6.342) has a slightly longer half-life than Ligand B (5.116).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.105 and 0.052), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having better metabolic stability (lower Cl_mic) and slightly better solubility, Ligand A is the more promising candidate. The significantly stronger binding affinity (-7.8 vs -7.2 kcal/mol) is a critical advantage for an enzyme inhibitor. The lower DILI risk is also a major positive. While both have poor solubility and permeability, the potency advantage of Ligand A is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 15:03:07,415 - INFO - Batch 347 complete. Total preferences: 5552
2025-04-17 15:03:07,415 - INFO - Processing batch 348/512...
2025-04-17 15:03:46,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.406 and 348.418 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.87) is better than Ligand B (75.27), both are acceptable, but lower is generally preferred for permeability.

**logP:** Ligand A (2.039) is optimal, while Ligand B (3.117) is approaching the upper limit.

**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.

**QED:** Both ligands have similar QED values (0.842 and 0.829), indicating good drug-likeness.

**DILI:** Ligand A (60.217) has a slightly higher DILI risk than Ligand B (40.442), but both are reasonably acceptable.

**BBB:** Ligand A (67.507) has a lower BBB penetration percentile than Ligand B (82.823). However, BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we can compare the absolute values; Ligand A (-4.349) is slightly better than Ligand B (-4.576).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. Ligand B (-3.013) is slightly better than Ligand A (-2.063).

**hERG:** Both ligands have very low hERG inhibition liability (0.217 and 0.164), which is excellent.

**Microsomal Clearance:** Ligand B (32.942) has significantly lower microsomal clearance than Ligand A (43.937), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (9.685) has a much longer in vitro half-life than Ligand A (1.464), further supporting its superior metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.063 and 0.13).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This 1.0 kcal/mol difference is substantial and outweighs the minor ADME drawbacks of Ligand B.

**Conclusion:**

Ligand B is the more promising drug candidate. Its superior binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower DILI risk outweigh the slightly higher logP and lower solubility. While both ligands have unusual Caco-2 and solubility values that would require further investigation, the potency and metabolic stability advantages of Ligand B are critical for an enzyme inhibitor.

Output:
1
2025-04-17 15:03:46,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.462 and 361.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.29) is higher than Ligand B (46.61). While both are reasonably low, Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (1.373 and 3.345), 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:** Ligand A has 3 HBD, while Ligand B has 0. Both are acceptable (<=5).

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

**QED:** Both ligands have good QED scores (0.73 and 0.808), indicating good drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (27.608 and 28.616 percentile), which is positive.

**BBB:** Ligand A (69.252) and Ligand B (85.847). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-5.781) and Ligand B (-4.822). Lower values suggest poorer permeability.

**Aqueous Solubility:** Ligand A (-2.629) and Ligand B (-3.244). Both are poor, but Ligand B is slightly worse.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.453 and 0.375), which is excellent.

**Microsomal Clearance:** Ligand A (-11.698) has a much *lower* (better) Cl_mic than Ligand B (67.734). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-0.598) has a negative half-life, which is unusual and likely indicates a very stable compound. Ligand B (6.948) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.044) has a much lower P-gp efflux liability than Ligand B (0.598), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has superior ADME properties (metabolic stability, P-gp efflux, and potentially permeability), Ligand B boasts a significantly better binding affinity. Given that we are targeting a kinase (enzyme), potency is paramount. The 1.3 kcal/mol difference in binding affinity is a substantial advantage. The slightly poorer ADME properties of Ligand B can potentially be addressed through further optimization, but improving a binding affinity of this magnitude is often more challenging.

Output:
1
2025-04-17 15:03:46,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.43 and 350.369 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (45.59) is better than Ligand B (58.44), both are below the 140 threshold for oral absorption, but A is closer to the ideal range.

**3. logP:** Ligand A (3.359) is optimal, while Ligand B (1.782) is a bit low, potentially impacting permeability.

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

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.862 and 0.765), indicating good drug-likeness.

**7. DILI:** Ligand A (30.942) has a significantly lower DILI risk than Ligand B (52.307), which is a major advantage.

**8. BBB:** Both ligands have high BBB penetration (88.135 and 88.523), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.652) is better than Ligand B (-4.29), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.013) is better than Ligand B (-1.565).

**11. hERG Inhibition:** Ligand A (0.964) has a lower hERG risk than Ligand B (0.442), which is a positive.

**12. Microsomal Clearance:** Ligand A (21.757) has significantly lower microsomal clearance than Ligand B (46.592), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (53.929) has a much longer in vitro half-life than Ligand B (5.583), which is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.776) has lower P-gp efflux liability than Ligand B (0.128), indicating better bioavailability.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This difference in affinity is substantial (>1.5 kcal/mol) and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A consistently outperforms Ligand B across most crucial parameters for an enzyme inhibitor. It has superior binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG risk, and better solubility and permeability. While both have good QED and BBB penetration, the other advantages of Ligand A make it a far more promising drug candidate.

Output:
1
2025-04-17 15:03:46,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.352 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.12) is slightly higher than Ligand B (73.2). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.411) and Ligand B (3.027) are both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). While both are acceptable, Ligand B is better.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit.

**QED:** Ligand A (0.746) has a better QED score than Ligand B (0.594), indicating a more drug-like profile.

**DILI:** Ligand A (47.732) has a significantly lower DILI risk than Ligand B (8.918), a crucial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (82.513) has a slightly better score than Ligand B (75.998).

**Caco-2 Permeability:** Ligand A (-5.197) shows better Caco-2 permeability than Ligand B (-4.809).

**Aqueous Solubility:** Ligand A (-2.41) has better aqueous solubility than Ligand B (-2.172).

**hERG Inhibition:** Ligand A (0.198) has a much lower hERG inhibition liability than Ligand B (0.473), a significant safety advantage.

**Microsomal Clearance:** Ligand A (-4.961) has a much lower (better) microsomal clearance than Ligand B (12.257), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.46) has a significantly longer in vitro half-life than Ligand B (-16.134), which is highly desirable.

**P-gp Efflux:** Ligand A (0.04) has a lower P-gp efflux liability than Ligand B (0.113).

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity (-9.0 kcal/mol) than Ligand A (-8.5 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. It has a lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, better permeability, and a better QED score. While Ligand B has a slightly better binding affinity, the substantial advantages of Ligand A in ADME-Tox properties outweigh this minor difference in potency.

Output:
1
2025-04-17 15:03:46,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.482 and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (82.61) is still acceptable, but less optimal than A.

**logP:** Ligand A (3.572) is at the higher end of the optimal range (1-3), while Ligand B (0.475) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both within acceptable limits. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.733 and 0.77), indicating drug-like properties.

**DILI:** Ligand A (19.698) has a very low DILI risk, which is excellent. Ligand B (30.942) is also low, but higher than A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (82.862) has a higher percentile than Ligand B (33.346).

**Caco-2 Permeability:** Ligand A (-4.302) is poor, while Ligand B (-5.122) is worse. Both are negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.63) and Ligand B (-2.399) are both poor.

**hERG Inhibition:** Ligand A (0.664) has a slightly higher hERG risk than Ligand B (0.081), but both are relatively low.

**Microsomal Clearance:** This is a crucial parameter for kinases. Ligand A (57.528) has moderate clearance, while Ligand B (-6.818) has *negative* clearance, indicating excellent metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (7.713 hours) has a much longer half-life than Ligand A (-3.609 hours). This is a major positive for B.

**P-gp Efflux:** Ligand A (0.187) has low P-gp efflux, which is good. Ligand B (0.004) has very low efflux, even better.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly 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 a better DILI score and slightly better Caco-2 permeability, Ligand B excels in the most critical areas for an enzyme inhibitor: binding affinity, metabolic stability (negative Cl_mic, long half-life), and P-gp efflux. The lower logP of Ligand B is a concern, but the exceptionally strong binding affinity likely compensates for this, and formulation strategies can be employed to address solubility issues. The significantly improved metabolic stability and half-life of Ligand B are also very important for *in vivo* efficacy.

Output:
1
2025-04-17 15:03:46,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (388.465 Da) is also good.

**TPSA:** Ligand A (78.53) is better than Ligand B (67.35). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.476) is within the optimal range (1-3). Ligand B (3.271) is at the higher end of optimal, potentially increasing off-target effects, but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**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.

**QED:** Ligand A (0.899) has a significantly better QED score than Ligand B (0.703), indicating a more drug-like profile.

**DILI:** Ligand A (35.285) has a much lower DILI risk than Ligand B (65.762). This is a significant advantage for Ligand A.

**BBB:** Ligand B (85.498) has a better BBB penetration score than Ligand A (55.874). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.84) is better than Ligand B (-5.19). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.66) is better than Ligand B (-3.578). Both are poor, but Ligand A is slightly better.

**hERG Inhibition:** Ligand A (0.176) has a much lower hERG inhibition risk than Ligand B (0.799). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (36.771) has lower microsomal clearance than Ligand B (43.24), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.434) has a better in vitro half-life than Ligand B (25.658).

**P-gp Efflux:** Both ligands have a P-gp efflux value of 0.021 and 0.254 respectively, indicating similar efflux liability.

**Binding Affinity:** Ligand B (-8.5 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:** Ligand A demonstrates a superior overall profile, particularly regarding safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and drug-likeness (QED). While Ligand B has slightly better binding affinity and BBB penetration, the ADME properties of Ligand A are more favorable for development as a drug candidate.

Output:
0
2025-04-17 15:03:46,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.277 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (104.31) is better than Ligand B (43.18). Both are below 140, but Ligand B is significantly lower, which *could* indicate better absorption, but also potentially reduced solubility.

**logP:** Ligand A (2.586) is optimal (1-3). Ligand B (4.019) is pushing the upper limit and could lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, well within the guidelines. Ligand B has 0 HBD and 6 HBA, also acceptable, but the lack of HBDs might negatively impact aqueous solubility.

**QED:** Both ligands have similar QED values (0.632 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (99.108), which is a major concern. Ligand B has a much lower DILI risk (35.75), making it significantly more favorable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (78.79) has a higher BBB percentile than Ligand A (31.64).

**Caco-2 Permeability:** Ligand A (-4.913) has poor Caco-2 permeability, while Ligand B (-5.173) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.975) has poor aqueous solubility, and Ligand B (-3.266) is slightly better.

**hERG:** Both ligands have similar hERG risk (0.714 and 0.796), indicating moderate risk.

**Microsomal Clearance:** Ligand A (61.199) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (50.503) has better metabolic stability.

**In vitro Half-Life:** Ligand B (13.803 hours) has a significantly longer half-life than Ligand A (-9.025 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.328 and 0.575).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's slightly better MW and TPSA, Ligand B is the superior candidate. The key factors driving this decision are:

*   **Significantly lower DILI risk:** Ligand B's DILI risk is much more acceptable.
*   **Stronger Binding Affinity:** The -7.9 kcal/mol affinity of Ligand B is substantially better than Ligand A's -9.1 kcal/mol.
*   **Better Metabolic Stability:** Lower Cl_mic and longer half-life for Ligand B.
*   **Slightly better solubility and Caco-2 permeability**

The higher logP of Ligand B is a minor concern, but the benefits in other critical areas outweigh this drawback.

Output:
1
2025-04-17 15:03:46,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.47 and 354.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (78.87) is still acceptable but less favorable.

**logP:** Ligand A (3.702) is at the higher end of the optimal 1-3 range, while Ligand B (1.709) is toward the lower end. While both are within range, higher logP can sometimes lead to off-target effects, but is less concerning than low solubility.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 4. Both are within the acceptable limits (<=10), but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (0.504 and 0.695), indicating drug-like properties.

**DILI:** Ligand A (36.681) has a slightly higher DILI risk than Ligand B (11.632), but both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (68.321 and 71.035), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.811 and -4.855), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.085 and -0.923), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.71) has a slightly higher hERG risk than Ligand B (0.323), but both are relatively low.

**Microsomal Clearance:** Ligand A (48.703) has a higher microsomal clearance than Ligand B (31.228), meaning it's less metabolically stable. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand B (3.381) has a longer in vitro half-life than Ligand A (-1.445), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.221 and 0.056), which is good.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite both compounds having significant solubility and permeability issues, Ligand B is the better candidate. Its substantially stronger binding affinity (-8.0 vs -7.2 kcal/mol) is a major advantage for an enzyme target. Additionally, Ligand B has better metabolic stability (lower Cl_mic, longer half-life) and lower DILI risk. While the solubility and permeability are concerning for both, the potency and metabolic advantages of Ligand B make it more likely to succeed with further optimization.

Output:
1
2025-04-17 15:03:46,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.491 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.1) is significantly better than Ligand B (75.5), being well below the 140 threshold for oral absorption.

**logP:** Ligand A (0.195) is a bit low, potentially hindering permeation, while Ligand B (2.397) is within the optimal 1-3 range.

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

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

**QED:** Both ligands have similar QED scores (0.712 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (5.157) has a much lower DILI risk than Ligand B (46.297), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (80.07 and 83.831), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.791) has a very poor Caco-2 permeability, while Ligand B (-5.042) is also poor, but slightly better.

**Solubility:** Ligand A (-0.316) has slightly better solubility than Ligand B (-3.169).

**hERG:** Ligand A (0.467) has a lower hERG risk than Ligand B (0.683), which is preferable.

**Microsomal Clearance:** Ligand A (-3.726) exhibits significantly lower microsomal clearance, indicating better metabolic stability, than Ligand B (58.318).

**In vitro Half-Life:** Ligand A (-3.211) has a longer in vitro half-life than Ligand B (-2.535).

**P-gp:** Both ligands have low P-gp efflux liability (0.008 and 0.161).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (0 kcal/mol). This is a crucial difference.

**Conclusion:**

Despite Ligand A's superior ADME properties (lower DILI, better metabolic stability, lower hERG, better solubility), the significantly stronger binding affinity of Ligand B (-8.3 vs 0 kcal/mol) is a decisive factor. A >1.5 kcal/mol advantage in binding can outweigh ADME drawbacks, and here the difference is much larger. While Ligand B's logP is good, its DILI and clearance are concerning, these can potentially be addressed through further optimization, but the potency advantage of Ligand B is hard to overcome.

Output:
1
2025-04-17 15:03:46,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.403 and 356.348 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.44) is better than Ligand B (58.44), being closer to the 140 A^2 threshold for good absorption.

**logP:** Ligand B (1.263) is optimal (1-3), while Ligand A (-0.102) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (6) is acceptable, while Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (0.565 and 0.747 respectively), indicating drug-likeness.

**DILI:** Ligand A (56.689) and Ligand B (48.623) both have acceptable DILI risk, below the 60 threshold. Ligand B is slightly better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.396) is higher, but it's not a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.457 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 (-1.638 and -1.835) which is also concerning.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.111 and 0.29), which is excellent.

**Microsomal Clearance:** Ligand A (2.569) has a lower Cl_mic than Ligand B (10.478), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (15.332) has a longer half-life than Ligand B (-6.187), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.022).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.8 kcal/mol), with Ligand B being slightly better. However, the difference is small.

**Overall Assessment:**

While Ligand B has slightly better affinity and DILI, Ligand A exhibits significantly better metabolic stability (lower Cl_mic and longer half-life) and a better TPSA. The negative Caco-2 and solubility values are a concern for both, but the improved metabolic profile of Ligand A is crucial for an enzyme target like SRC kinase. The slightly lower logP of Ligand A is a minor drawback compared to the metabolic advantages.

Output:
1
2025-04-17 15:03:46,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.491 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is well below the 140 threshold for good absorption, and even better for potential CNS penetration (though not a priority here). Ligand B (121.52) is still under 140, but less favorable than A.

**logP:** Ligand A (3.161) is optimal. Ligand B (0.459) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is well within the guidelines. Ligand B (4 HBD, 4 HBA) is also acceptable, but slightly less optimal.

**QED:** Both ligands have reasonable QED scores (0.607 and 0.546), indicating good drug-like properties.

**DILI:** Ligand A (37.185) has a slightly higher DILI risk than Ligand B (32.222), but both are below the concerning threshold of 60.

**BBB:** This is not a high priority for a non-CNS target. Ligand A (70.376) is better than Ligand B (41.218).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the assay or the compounds themselves. However, the magnitude of negativity is similar, so it doesn't strongly differentiate them.

**Aqueous Solubility:** Both have negative solubility values, again unusual. Ligand B (-2.898) is slightly worse than Ligand A (-4.3).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.37 and 0.16), which is excellent.

**Microsomal Clearance:** Ligand A (47.214 mL/min/kg) is significantly better than Ligand B (6.712 mL/min/kg). Lower clearance indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-9.607 hours) is significantly better than Ligand B (5.943 hours). A longer half-life is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.127 and 0.035).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.1 and -9.6 kcal/mol). Ligand B is 2.5 kcal/mol better, which is a substantial advantage and can outweigh some ADME concerns.

**Conclusion:**

While Ligand A has better TPSA, logP, and metabolic stability (Cl_mic and t1/2), the significantly superior binding affinity of Ligand B (-9.6 kcal/mol vs -7.1 kcal/mol) is a decisive factor. The 2.5 kcal/mol difference is substantial enough to compensate for the slightly lower logP and higher clearance. Both have acceptable safety profiles (DILI, hERG).

Output:
1
2025-04-17 15:03:46,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.479 and 355.341 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.09) is well below the 140 threshold for good oral absorption. Ligand B (112.73) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.13) is within the optimal range of 1-3. Ligand B (0.922) is slightly below 1, which *could* indicate potential permeability issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both within acceptable limits. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.588 and 0.631), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 66.731, which is moderately high. Ligand B has a much lower DILI risk (33.928), which is a significant advantage.

**BBB:** Both have moderate BBB penetration (46.801 and 65.801). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

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

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is another significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.335 and 0.369), which is excellent.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (74.562). Ligand B has a *very* low (and negative) clearance (-23.431), indicating excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A has a modest half-life (11.299 hours). Ligand B has a very long half-life (-28.027 hours), further supporting its superior metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.131 and 0.024).

**Binding Affinity:** Ligand B (-9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the stronger candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and superior binding affinity outweigh the slightly lower logP and the permeability/solubility concerns. The substantial improvement in binding affinity is a critical factor for an enzyme inhibitor.

Output:
1
2025-04-17 15:03:46,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.485 and 349.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (52.65) is better than Ligand B (61.44). Both are below 140, suggesting reasonable absorption.

**logP:** Both ligands have acceptable logP values (1.434 and 2.474), 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 maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.652 and 0.662), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (11.788 and 11.245 percentile), which is favorable.

**BBB:** Ligand A has a significantly higher BBB penetration (96.472%) than Ligand B (70.415%). While SRC is not a CNS target, higher BBB is generally not detrimental.

**Caco-2 Permeability:** Ligand A (-5.179) has a worse Caco-2 permeability than Ligand B (-4.835).

**Aqueous Solubility:** Ligand A (-2.32) has a worse aqueous solubility than Ligand B (-2.142).

**hERG Inhibition:** Ligand A (0.79) has a slightly higher hERG risk than Ligand B (0.237), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.134 mL/min/kg) has significantly lower microsomal clearance than Ligand B (43.976 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-11.826 hours) has a significantly longer in vitro half-life than Ligand B (2.693 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux than Ligand B (0.1), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-6.4 kcal/mol). This is a 2 kcal/mol difference, which is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A demonstrates superior ADME properties (metabolic stability, half-life, P-gp efflux, and TPSA), Ligand B has a significantly higher binding affinity. The 2 kcal/mol difference in binding affinity is a substantial advantage for an enzyme target like SRC kinase. Given the priorities for enzyme inhibitors, the stronger binding of Ligand B is likely to be more critical than the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 15:03:46,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (355.435 and 360.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.96) is better than Ligand B (134.19), being closer to the <140 threshold for good oral absorption.

**logP:** Both ligands (-0.321 and -0.596) are slightly low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) is slightly better than Ligand B (HBD=4, HBA=7) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.551) has a significantly better QED score than Ligand B (0.258), indicating a more drug-like profile.

**DILI:** Both ligands have high DILI risk (Ligand A: 16.053, Ligand B: 42.885). Ligand B is considerably worse.

**BBB:** Ligand A (42.226) has a better BBB percentile than Ligand B (20.744), but neither is particularly high, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative (-5.732 and -5.616), which is unusual and suggests very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.369 and -1.325), indicating very poor solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.104 and 0.1). This is positive.

**Microsomal Clearance:** Both ligands exhibit excellent metabolic stability with negative Cl_mic values (Ligand A: -13.702, Ligand B: -14.724). Lower (more negative) is better.

**In vitro Half-Life:** Ligand A (14.456 hours) has a better in vitro half-life than Ligand B (-10.088 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.019).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly better binding affinity than Ligand B (-8.3 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, QED, in vitro half-life, and slightly better TPSA and BBB. While both compounds suffer from poor Caco-2 permeability and solubility, the strong binding affinity of Ligand A could potentially compensate for these issues with formulation strategies. The DILI risk is high for both, but higher for Ligand B.

Output:
1
2025-04-17 15:03:46,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**
*   **MW:** 353.423 Da - Within the ideal range (200-500).
*   **TPSA:** 125.35 - Acceptable, but approaching the upper limit for good oral absorption.
*   **logP:** -0.902 - Low, potentially hindering permeation.
*   **HBD:** 4 - Acceptable.
*   **HBA:** 6 - Acceptable.
*   **QED:** 0.458 - Below the preferred threshold of 0.5, suggesting suboptimal drug-likeness.
*   **DILI:** 37.224 - Low risk.
*   **BBB:** 20.822 - Very low, not a concern as SRC is not a CNS target.
*   **Caco-2:** -5.552 - Very poor permeability.
*   **Solubility:** -1.219 - Poor solubility.
*   **hERG:** 0.107 - Low risk.
*   **Cl_mic:** 12.115 mL/min/kg - Moderate clearance, not ideal.
*   **t1/2:** 23.39 hours - Good in vitro half-life.
*   **Pgp:** 0.01 - Low efflux, favorable.
*   **Affinity:** -8.0 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 417.3 Da - Within the ideal range.
*   **TPSA:** 70.12 - Excellent, well below the 140 threshold.
*   **logP:** 2.797 - Optimal.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 6 - Acceptable.
*   **QED:** 0.546 - Good drug-likeness.
*   **DILI:** 45.677 - Moderate risk, but manageable.
*   **BBB:** 85.111 - High, not particularly relevant for SRC.
*   **Caco-2:** -4.681 - Poor permeability.
*   **Solubility:** -1.796 - Poor solubility.
*   **hERG:** 0.641 - Moderate risk.
*   **Cl_mic:** 26.111 mL/min/kg - Higher clearance than Ligand A, less favorable.
*   **t1/2:** 37.783 hours - Very good in vitro half-life.
*   **Pgp:** 0.131 - Low efflux, favorable.
*   **Affinity:** -8.9 kcal/mol - Exceptional binding affinity, 0.9 kcal/mol better than Ligand A.

**Comparison and Decision:**

Both ligands have poor Caco-2 permeability and solubility, which are significant drawbacks. However, Ligand B has a better logP, QED, and a significantly better binding affinity (-8.9 vs -8.0 kcal/mol). The difference in binding affinity is substantial and could outweigh the solubility/permeability concerns, especially given that SRC is an enzyme and potency is paramount. While Ligand B's DILI and hERG risks are slightly higher, they are not alarmingly so. Ligand A's lower logP is a major concern for oral bioavailability.

Output:
1
2025-04-17 15:03:46,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.491 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, and preferable to Ligand B (82.43). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (2.892 and 1.701, respectively) within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 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 (0.782 and 0.849), indicating good drug-like properties.

**DILI:** Ligand A (42.846) and Ligand B (38.581) both have low DILI risk, below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.249) is slightly better than Ligand B (71.268) but not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.742) and Ligand B (-4.351) have negative values, which is unusual. Lower values indicate poor permeability.

**Aqueous Solubility:** Ligand A (-3.994) and Ligand B (-2.781) both have negative solubility values, which is also unusual. Lower values indicate poor solubility.

**hERG:** Ligand A (0.373) and Ligand B (0.695) both have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (98.744) has a very high microsomal clearance, indicating poor metabolic stability. Ligand B (9.114) has a much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.867) has a negative half-life, which is not possible. This is a major red flag. Ligand B (12.854) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.367) and Ligand B (0.056) both have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), but both are strong binders.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While both ligands have acceptable MW, logP, QED, DILI, and hERG profiles, Ligand B excels in metabolic stability (much lower Cl_mic, positive half-life) and has a slightly better binding affinity. Ligand A's extremely high clearance and negative half-life are significant drawbacks, making it a less viable option despite its slightly lower TPSA.

Output:
1
2025-04-17 15:03:46,999 - INFO - Batch 348 complete. Total preferences: 5568
2025-04-17 15:03:46,999 - INFO - Processing batch 349/512...
2025-04-17 15:04:29,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (429.292 Da) is at the higher end, while Ligand B (349.391 Da) is more favorably positioned.

**TPSA:** Both ligands have similar TPSA values (around 98.5), which is slightly above the optimal <140 for oral absorption, but not a major concern for a kinase inhibitor.

**logP:** Ligand A (3.277) is within the optimal range (1-3). Ligand B (-0.786) is significantly below this, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (5/7) counts, falling within the recommended limits.

**QED:** Both ligands have good QED scores (0.395 and 0.693), suggesting reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A (85.653) has a higher DILI risk than Ligand B (48.662). This is a significant concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Both are moderate.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but potentially more problematic for Ligand B given its already low logP.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.819) has a slightly higher hERG risk than Ligand B (0.053). This favors Ligand B.

**Microsomal Clearance:** Ligand B (-5.498) has a *negative* microsomal clearance, which is impossible and likely an error in the data. Ligand A (79.89) has a high clearance, indicating poor metabolic stability. This is a major disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (19.699) has a better in vitro half-life than Ligand A (-22.005), which is a negative value and therefore unrealistic.

**P-gp Efflux:** Ligand A (0.737) has moderate P-gp efflux liability. Ligand B (0.006) has very low efflux, which is favorable.

**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 substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate despite the questionable Caco-2 and solubility data. Its significantly stronger binding affinity, lower DILI risk, lower hERG risk, lower P-gp efflux, and better half-life outweigh the concerns about its low logP and poor solubility. The negative microsomal clearance is a data error that needs to be investigated, but assuming it's a positive value, it would further strengthen the case for Ligand B. Ligand A suffers from high DILI risk and poor metabolic stability.

Output:
1
2025-04-17 15:04:29,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.386 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (75.44), being well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have good logP values (2.559 and 2.04), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (3/4) counts, well within the guidelines.

**QED:** Both ligands have high QED scores (0.93 and 0.835), indicating good drug-likeness.

**DILI:** Ligand A (52.772) has a slightly better DILI score than Ligand B (60.566), indicating a lower risk of liver injury, though both are acceptable.

**BBB:** Both ligands have good BBB penetration, but Ligand A (80.109) is better than Ligand B (74.254). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.764 and -4.746). 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 (-3.082 and -3.627). Again, the scale is unspecified, making interpretation difficult. However, similar negative values suggest comparable solubility.

**hERG:** Ligand A (0.43) has a significantly lower hERG risk than Ligand B (0.241), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (13.405) has a much lower microsomal clearance than Ligand B (19.499), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-1.417) has a slightly better in vitro half-life than Ligand B (-3.363).

**P-gp Efflux:** Ligand A (0.198) has lower P-gp efflux liability than Ligand B (0.37), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This 1 kcal/mol difference is significant, but needs to be weighed against the ADME properties.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, but Ligand A excels in almost all ADME properties: lower DILI, better BBB, lower hERG risk, significantly lower microsomal clearance (better metabolic stability), lower P-gp efflux, and a slightly better half-life. The improved metabolic stability and reduced toxicity risks of Ligand A are particularly important for kinase inhibitors, which often suffer from rapid metabolism and off-target effects. The Caco-2 and solubility values are concerning for both, but are similar. Given the enzyme-specific priorities, the superior ADME profile of Ligand A outweighs the slightly weaker binding affinity of Ligand A.

Output:
0
2025-04-17 15:04:29,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.367 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (383.861 Da) is still well within the range.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (101.7) is slightly higher than Ligand B (98.26), but both are acceptable.

**logP:** Both ligands have logP values between 1 and 3 (A: 3.789, B: 2.114), which is optimal for drug-likeness. Ligand A is a bit higher, potentially leading to some off-target interactions, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 8. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (A: 0.585, B: 0.755), indicating good overall drug-like properties, with Ligand B being slightly better.

**DILI:** Both ligands have high DILI risk (A: 89.841, B: 91.314), which is a concern. This will need to be addressed in further optimization.

**BBB:** Ligand A (16.363) has very low BBB penetration, while Ligand B (57.968) is better but still not ideal. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.058 and -4.866). This is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.473 and -3.849). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.317, B: 0.222), which is positive.

**Microsomal Clearance:** Ligand A (34.131 mL/min/kg) has lower clearance than Ligand B (45.377 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.582 hours) has a negative half-life, which is not physically possible. This is a data error and a major red flag. Ligand B (-0.798 hours) also has a very short half-life, indicating rapid metabolism.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.15, B: 0.039).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.5 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower microsomal clearance (better metabolic stability), and fewer HBA. However, it has a nonsensical half-life value and slightly higher logP. Ligand B has a better QED score and slightly better BBB penetration, but weaker binding affinity and higher clearance. Both have poor solubility and permeability, and high DILI risk.

Given the importance of potency for enzyme inhibitors, and the large difference in binding affinity, Ligand A is the more promising candidate *despite* the questionable half-life value. The negative half-life is likely a data error that needs to be investigated, but the strong binding affinity makes it worth pursuing. The solubility and permeability issues would need to be addressed through structural modifications.

Output:
0
2025-04-17 15:04:29,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.463 and 366.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is slightly higher than the ideal <140, but still acceptable. Ligand B (66.48) is well within the acceptable range.

**logP:** Ligand A (0.432) is quite low, potentially hindering permeability. Ligand B (2.546) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, both acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.575 and 0.601), indicating drug-like properties.

**DILI:** Ligand A (9.926) has a very low DILI risk, which is excellent. Ligand B (34.277) also has a low DILI risk, but higher than A.

**BBB:**  BBB isn't a primary concern for a non-CNS target like SRC. Ligand A (52.036) and Ligand B (66.266) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.896 and -4.632), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.953 and -2.721), indicating very poor aqueous solubility. This is a major drawback.

**hERG:** Both ligands have low hERG risk (0.251 and 0.28), which is favorable.

**Microsomal Clearance:** Ligand A (6.922) has a lower Cl_mic, suggesting better metabolic stability than Ligand B (35.225).

**In vitro Half-Life:** Ligand A (-9.693) has a significantly longer half-life than Ligand B (-20.763).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.109), which is good.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.3 vs -7.1 kcal/mol) is a major advantage for an enzyme inhibitor. While Ligand A has slightly better metabolic stability and lower DILI, the potency advantage of Ligand B is more critical. Addressing the solubility and permeability issues through formulation or structural modifications would be the next step for Ligand B.

Output:
1
2025-04-17 15:04:29,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.833 and 367.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.99) is better than Ligand B (71), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.259 and 2.18), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Both have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (64.172) has a higher DILI risk than Ligand B (33.618). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (75.107) is slightly better than Ligand B (61.38). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.788) is significantly worse than Ligand B (-5.057). Lower values suggest poorer permeability.

**Aqueous Solubility:** Ligand A (-4.249) is worse than Ligand B (-3.142). Lower values suggest poorer solubility.

**hERG Inhibition:** Ligand A (0.516) is higher than Ligand B (0.189), indicating a greater risk of hERG inhibition. This is a significant negative for Ligand A.

**Microsomal Clearance:** Ligand B (31.571) has a much lower microsomal clearance than Ligand A (60.081), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (2.124) has a slightly better half-life than Ligand A (16.626).

**P-gp Efflux:** Ligand A (0.344) has a higher P-gp efflux than Ligand B (0.062). This is a negative for Ligand A.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly better binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage for Ligand B, and the 1.7 kcal/mol difference is likely to outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has slightly better BBB penetration, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), better solubility, lower hERG inhibition, and lower P-gp efflux. The improved permeability also helps.

Output:
1
2025-04-17 15:04:29,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.405 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.45) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Ligand A (4.142) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.985) is within the optimal 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 similar QED values (0.83 and 0.795), indicating good drug-likeness.

**DILI:** Ligand A (93.37) has a significantly higher DILI risk than Ligand B (31.252). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.748) has a higher BBB value than Ligand A (50.64), but it's not a deciding factor here.

**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. However, the magnitude is similar.

**hERG:** Ligand A (0.112) has a slightly better hERG profile than Ligand B (0.133), but both are low risk.

**Microsomal Clearance:** Ligand A (6.079) has a lower microsomal clearance than Ligand B (21.381), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (28.108) has a longer half-life than Ligand B (-11.941). The negative value for Ligand B is concerning and suggests rapid degradation.

**P-gp Efflux:** Both have low P-gp efflux liability, which is good.

**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 advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite its higher logP and DILI risk, Ligand A is the more promising candidate due to its significantly superior binding affinity (-9.4 kcal/mol vs -6.9 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2). The large difference in binding affinity is a critical factor for an enzyme target like SRC kinase. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. The negative solubility and Caco-2 values for both compounds are concerning and would require further investigation.

Output:
1
2025-04-17 15:04:29,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is well below the 140 threshold for good absorption, and even below 90, which is good. Ligand B (82.61) is still under 140, but less optimal than A.

**logP:** Ligand A (0.835) is a bit low, potentially impacting permeability. Ligand B (1.137) is slightly better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly less favorable.

**QED:** Both ligands have good QED scores (0.667 and 0.849), indicating good drug-like properties.

**DILI:** Ligand A (5.7) has a very low DILI risk, which is excellent. Ligand B (49.244) is higher, but still within an acceptable range (below 60).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.078) is higher than Ligand B (47.111).

**Caco-2 Permeability:** Ligand A (-4.516) has poor Caco-2 permeability, which is a significant concern. Ligand B (-5.084) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-0.638) is poor, while Ligand B (-1.801) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.288) has very low hERG risk, which is excellent. Ligand B (0.079) is even lower, and even more favorable.

**Microsomal Clearance:** Ligand A (2.493) has low clearance, indicating good metabolic stability. Ligand B (11.612) has significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-2.892) has a relatively long half-life, which is desirable. Ligand B (10.128) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.021 and 0.018), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A has better solubility, lower DILI, better metabolic stability, and a longer half-life, and a slightly better binding affinity. However, its Caco-2 permeability is very poor and logP is low. Ligand B has a stronger binding affinity, but suffers from higher DILI, worse solubility, and faster metabolism.

The binding affinity difference is significant. A >1 kcal/mol difference can often outweigh other concerns, *especially* if the other properties aren't dramatically worse. In this case, while Ligand B's solubility and metabolic stability are less ideal, they aren't catastrophic. Solubility can be addressed with formulation strategies, and metabolic stability can sometimes be improved through structural modifications. The poor Caco-2 permeability of Ligand A is a more difficult issue to resolve.

Output:
1
2025-04-17 15:04:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.451 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is well below the 140 threshold, suggesting good absorption. Ligand B (92.55) is higher but still within an acceptable range, though potentially less optimal.

**logP:** Ligand A (4.411) is slightly high, potentially leading to solubility issues and off-target effects. Ligand B (1.197) is closer to 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, balancing solubility and permeability.

**QED:** Ligand A (0.769) has a better QED score than Ligand B (0.597), indicating a more drug-like profile.

**DILI:** Ligand A (47.538) has a moderate DILI risk, while Ligand B (14.734) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.88) has a higher BBB penetration than Ligand B (51.958).

**Caco-2 Permeability:** Ligand A (-4.908) shows poor permeability, while Ligand B (-5.149) also shows poor permeability.

**Aqueous Solubility:** Ligand A (-3.834) has slightly better solubility than Ligand B (-2.283), but both are quite poor.

**hERG Inhibition:** Ligand A (0.945) has a slightly higher hERG risk than Ligand B (0.13), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (-3.282) exhibits lower microsomal clearance, suggesting better metabolic stability than Ligand B (16.583).

**In vitro Half-Life:** Ligand A (14.661 hours) has a significantly longer half-life than Ligand B (0.752 hours), a major advantage.

**P-gp Efflux:** Ligand A (0.471) shows lower P-gp efflux than Ligand B (0.018), which is favorable.

**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 can outweigh 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 P-gp efflux. However, it has a higher logP, poorer Caco-2 permeability, and a moderate DILI risk. Ligand B has a much lower DILI risk and hERG inhibition, but weaker binding affinity and poorer metabolic stability.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is a major driver. While its solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The lower DILI and hERG risk of Ligand B are attractive, but the significantly weaker binding affinity makes it less likely to be a viable candidate.

Output:
1
2025-04-17 15:04:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (383.539 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (92.5 and 93.01) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (0.803) is a bit low, potentially hindering permeation. Ligand B (1.488) is better, falling within the 1-3 optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being <=5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both within the reasonable limit of <=10.

**QED:** Both ligands have good QED scores (0.733 and 0.87), indicating good drug-like properties.

**DILI:** Ligand A (20.861) has a significantly lower DILI risk than Ligand B (72.819). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (56.65) is better than Ligand B (43.932).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.498 and -5.147), which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.062 and -3.016), indicating very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.116 and 0.191), which is positive.

**Microsomal Clearance:** Ligand A (13.851) has significantly lower microsomal clearance than Ligand B (30.104), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-14.148) has a much longer in vitro half-life than Ligand B (-1.062), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.05).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol), although both are good. The 1.4 kcal/mol difference is significant.

**Overall Assessment:**

While both ligands have issues with solubility and permeability, Ligand A is the better candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The lower logP of Ligand A is a concern, but the substantial benefits in safety and PK outweigh this drawback. The poor solubility and permeability would need to be addressed through formulation strategies, but these are challenges that can be overcome.

Output:
0
2025-04-17 15:04:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.4 and 346.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is higher than Ligand B (41.57). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have good logP values (2.388 and 2.703), 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 excellent QED scores (0.898 and 0.915), indicating high drug-likeness.

**DILI:** Ligand A has a DILI risk of 77.28%, which is concerning (high risk). Ligand B has a much lower DILI risk of 33.35%, which is good.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (85.731) has a higher BBB percentile than Ligand A (79.294).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.926 and -4.598), 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 (-3.81 and -3.476), again suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**hERG:** Ligand A (0.375) has a slightly higher hERG risk than Ligand B (0.488), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (5.037) has a lower microsomal clearance than Ligand B (25.909), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (35.071) has a significantly longer in vitro half-life than Ligand B (-8.597). This is a major advantage.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.069), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.6 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.5 kcal/mol) is not substantial enough to outweigh other significant drawbacks.

**Conclusion:**

While Ligand A has slightly better binding affinity and metabolic stability, its significantly higher DILI risk and lower solubility are major concerns. Ligand B, despite slightly lower affinity and metabolic stability, presents a much more favorable safety profile (DILI) and potentially better permeability (lower TPSA). Considering the enzyme-specific priorities, the lower DILI risk of Ligand B is a crucial advantage, making it the more viable drug candidate.

Output:
1
2025-04-17 15:04:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.312 and 358.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (63.68 and 61.36) below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.225) is optimal, while Ligand B (3.114) is slightly higher but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 2 HBA) as it has fewer HBDs, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.763 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (63.358) has a significantly higher DILI risk than Ligand B (12.408). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (98.41) has better BBB penetration than Ligand B (80.574).

**Caco-2 Permeability:** Ligand A (-4.115) shows poor permeability, while Ligand B (-4.61) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.412 and -3.321), which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.586) has a slightly lower hERG risk than Ligand B (0.784), which is preferable.

**Microsomal Clearance:** Ligand A (35.543) has a higher microsomal clearance than Ligand B (20.227), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (25.881) has a much longer in vitro half-life than Ligand A (-1.7), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.339 and 0.311).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a crucial advantage, as a 0.5 kcal/mol difference can outweigh other concerns.

**Overall Assessment:**

While Ligand A has some favorable properties (better BBB, slightly lower hERG), its high DILI risk, poor Caco-2 permeability, and lower metabolic stability are significant liabilities. Ligand B, despite slightly higher logP and a slightly higher hERG risk, has a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and *significantly* stronger binding affinity. The superior affinity of Ligand B is a key factor for an enzyme inhibitor, and the improved safety and stability outweigh the minor drawbacks.

Output:
1
2025-04-17 15:04:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.364 Da) is slightly lower than Ligand B (388.53 Da), which is not a significant difference.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (66.48) is better than Ligand A (75.71).

**logP:** Ligand A (1.778) is within the optimal range (1-3), while Ligand B (3.131) is at the higher end. While still acceptable, the higher logP of B could potentially lead to off-target interactions or solubility issues.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.552, B: 0.814), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (29.081) has a significantly lower DILI risk than Ligand B (63.242). This is a major advantage for Ligand A.

**BBB:** Both have high BBB penetration, but Ligand A (92.672) is slightly better than Ligand B (87.01). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.707) has better Caco-2 permeability than Ligand B (-5.064).

**Aqueous Solubility:** Ligand A (-2.622) has better aqueous solubility than Ligand B (-4.339). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.44, B: 0.811). Ligand A is better.

**Microsomal Clearance:** Ligand A (17.343) has significantly lower microsomal clearance than Ligand B (36.303), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-19.331) has a much longer in vitro half-life than Ligand B (-6.625), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.038) shows lower P-gp efflux than Ligand B (0.372), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is relatively small (0.8 kcal/mol) and is outweighed by the significant ADME advantages of Ligand A.

**Overall:**

Ligand A demonstrates a superior ADME profile with lower DILI risk, better solubility, lower clearance, longer half-life, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the ADME advantages of Ligand A are more critical for developing a viable drug candidate, especially for an enzyme target where metabolic stability and bioavailability are paramount.

Output:
0
2025-04-17 15:04:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.423 and 351.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.63) is better than Ligand B (137.25), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.114) is within the optimal 1-3 range. Ligand B (-1.394) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand B (0.61) has a better QED score than Ligand A (0.385), suggesting a more drug-like profile overall.

**DILI:** Ligand A (24.04) has a significantly lower DILI risk than Ligand B (69.678). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (47.421) is better than Ligand B (23.73).

**Caco-2 Permeability:** Both are negative (-5.297 and -5.218), indicating poor permeability. This is a concern for both, but the scale is not clear, so it's hard to compare.

**Aqueous Solubility:** Both are negative (-0.353 and -2.614), indicating poor solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.13) has a much lower hERG risk than Ligand B (0.098). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-1.995) has a *better* (lower) microsomal clearance than Ligand B (-16.616), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (14.413) has a longer half-life than Ligand B (-7.442), which is desirable.

**P-gp Efflux:** Both are very low (0.011 and 0.005) indicating low P-gp efflux.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While a 0.4 kcal/mol difference is not huge, it's noticeable.

**Overall Assessment:**

Ligand A has several key advantages: lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and better TPSA. Ligand B has a slightly better binding affinity and QED. However, the significantly improved safety profile (DILI and hERG) and metabolic stability of Ligand A outweigh the small binding affinity advantage of Ligand B, especially for an enzyme target where potency can sometimes be optimized further while addressing ADME concerns. The solubility and permeability concerns are present in both, but are less critical than safety and metabolic stability.

Output:
0
2025-04-17 15:04:29,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.471 and 366.458 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.56) is slightly higher than Ligand B (66.48), but both are below the 140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (1.035 and 1.916), 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 (3), but both are below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.706 and 0.81), indicating good drug-like properties.

**7. DILI:** Ligand A (70.221) has a higher DILI risk than Ligand B (55.176). This is a concern for Ligand A.

**8. BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (79.217) is better than Ligand A (62.776).

**9. Caco-2:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have similar hERG risk (0.53 and 0.65), which is acceptable.

**12. Cl_mic:** Ligand A (42.823) has a lower microsomal clearance than Ligand B (65.379), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**13. t1/2:** Ligand A (26.628) has a shorter half-life than Ligand B (-37.622). This is a significant advantage for Ligand B.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.076 and 0.255).

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.1). While both are excellent, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability (lower Cl_mic), but a higher DILI risk and shorter half-life. Ligand B has a better DILI profile, BBB penetration and longer half-life, but slightly weaker binding affinity and worse metabolic stability.

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG), the slightly stronger binding affinity and better metabolic stability of Ligand A are more crucial than the slightly higher DILI risk. The poor solubility and Caco-2 values are a concern for both, but can be addressed with formulation strategies. The difference in binding affinity (0.8 kcal/mol) is substantial enough to potentially outweigh the DILI risk.

Output:
0
2025-04-17 15:04:29,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.394 and 374.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.94 and 76.15) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.279) is slightly low, potentially hindering permeation. Ligand B (0.987) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good. Both are well within the limit of 5.

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

**QED:** Ligand B (0.693) has a significantly 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 (53.47), which is a significant advantage.

**BBB:** Both have good BBB penetration, but Ligand A (92.4) is higher than Ligand B (76.425). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.717 and -4.707), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.309 and -2.324), which is also unusual and indicates very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.43 and 0.362), which is positive.

**Microsomal Clearance:** Ligand A (24.404) has a much lower microsomal clearance than Ligand B (64.375), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-18.489) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (-32.916) also has a negative half-life. Both are concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.124), which is favorable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). Although A is better, the difference is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand A has a better DILI score, better BBB penetration, and significantly better metabolic stability (lower Cl_mic). However, Ligand B has a better QED score and slightly better binding affinity. Both ligands have concerningly poor solubility and permeability, and negative half-lives. Given the importance of metabolic stability for kinase inhibitors, and the lower DILI risk, Ligand A is slightly more promising, *assuming the negative half-life can be resolved*. However, the poor solubility and permeability are major issues that would need to be addressed.

Output:
0
2025-04-17 15:04:29,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.379 Da) is slightly lower, which could be beneficial for permeability. Ligand B (392.262 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (75.19) is lower than Ligand B (81.33), which is slightly preferable.

**logP:** Both ligands have logP values between 1 and 3 (A: 1.183, B: 1.106), which is optimal.

**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 QED values above 0.5 (A: 0.833, B: 0.736), indicating good drug-like properties.

**DILI:** Ligand A (54.556) has a slightly higher DILI risk than Ligand B (47.693), but both are below the concerning threshold of 60.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase. Ligand B (63.125) is slightly higher.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.805) is slightly better than Ligand B (-5.308).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.494) is slightly better than Ligand B (-2.934).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.105, B: 0.341), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand A (-15.938) has significantly lower (better) microsomal clearance than Ligand B (-30.761), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life (t1/2):** Ligand A (-13.844) has a slightly longer half-life than Ligand B (-12.708), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.009, B: 0.052), which is favorable.

**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 is above the 1.5 kcal/mol threshold that can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has superior ADME properties (lower Cl_mic, longer t1/2, better solubility, and slightly better permeability) despite a slightly higher DILI risk. However, Ligand B has a slightly better binding affinity. Given the importance of metabolic stability for enzyme inhibitors, and the relatively small difference in binding affinity, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 15:04:29,743 - INFO - Batch 349 complete. Total preferences: 5584
2025-04-17 15:04:29,743 - INFO - Processing batch 350/512...
2025-04-17 15:05:12,549 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.443 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (76.66 and 75.44) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands (2.657 and 2.728) 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 below the 10 threshold.

**6. QED:** Ligand A (0.858) has a better QED score than Ligand B (0.662), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.116) has a lower DILI risk than Ligand B (41.218), both are good (<40 is preferred, but both are below 60).

**8. BBB:** Both ligands have similar BBB penetration (76.968 and 70.88), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.548) has a worse Caco-2 permeability than Ligand B (-4.95). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.434) has better aqueous solubility than Ligand B (-2.488). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.682) has a slightly higher hERG inhibition risk than Ligand B (0.354), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (63.714) has a higher microsomal clearance than Ligand B (60.801), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-29.373) has a significantly longer in vitro half-life than Ligand A (-2.081). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.191 and 0.395), which is relatively low.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and solubility, Ligand B's significantly improved in vitro half-life and stronger binding affinity are crucial for an enzyme target like SRC kinase. The slightly higher DILI and lower Caco-2 permeability of Ligand B are less concerning given the potency advantage and improved metabolic stability.

Output:
1
2025-04-17 15:05:12,549 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (346.427 and 350.384 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is higher than Ligand B (36.1). While both are reasonably low, Ligand B is significantly better, being well below the 140 threshold for oral absorption.

**3. logP:** Ligand A (2.393) is within the optimal range (1-3). Ligand B (4.285) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 1 HBA. Both are well within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.831 and 0.803), indicating good drug-likeness.

**7. DILI:** Ligand A (59.48) has a slightly higher DILI risk than Ligand B (53.276), but both are acceptable (<60).

**8. BBB:** Both ligands have high BBB penetration (90.617 and 87.864), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.341 and -4.255). This 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:** Ligand A (-2.774) has better solubility than Ligand B (-5.394). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.306) has a lower hERG inhibition risk than Ligand B (0.847). This is a significant advantage as it reduces the risk of cardiotoxicity.

**12. Microsomal Clearance (Cl_mic):** Ligand B (38.848) has lower microsomal clearance than Ligand A (43.265), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (29.538) has a longer half-life than Ligand B (14.743). This is generally desirable for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux than Ligand B (0.528), which could improve oral bioavailability.

**15. Binding Affinity:** Ligand B (-8.9 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.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity, and has better metabolic stability. Ligand A has better solubility, longer half-life, and lower hERG risk.

**Overall Assessment:**

While Ligand A has better solubility, hERG, and half-life, the significantly stronger binding affinity of Ligand B (-8.9 vs -7.8 kcal/mol) is the most critical factor for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic) of Ligand B also contributes to its favorability. The slightly higher logP of Ligand B is a minor concern, but the substantial affinity advantage outweighs it.

Output:
1
2025-04-17 15:05:12,549 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (104.65) is better than Ligand B (71.53) for oral absorption, being below the 140 A^2 threshold. Ligand B is excellent.

**logP:** Ligand A (0.716) is a bit low, potentially hindering permeation. Ligand B (2.766) is within the optimal range (1-3).

**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:** Both ligands have good QED scores (A: 0.717, B: 0.767), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (A: 43.66, B: 46.801), both well below the 60 threshold.

**BBB:** Both ligands have moderate BBB penetration (A: 50.64, B: 59.325). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.883) shows poor permeability, while Ligand B (-5.079) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.558) has poor solubility, while Ligand B (-2.593) is slightly better.

**hERG:** Both ligands have very low hERG risk (A: 0.068, B: 0.461), which is excellent.

**Microsomal Clearance:** Ligand A (29.611 mL/min/kg) has significantly lower clearance than Ligand B (66.195 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.183 hours) has a shorter half-life than Ligand B (10.986 hours), further supporting better metabolic stability for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.064, B: 0.127).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). However, the difference is small.

**Overall Assessment:**

Ligand A has a significant advantage in metabolic stability (lower Cl_mic and longer t1/2), which is crucial for kinase inhibitors. While its logP and solubility are less ideal, the strong binding affinity (-7.4 kcal/mol) and low hERG risk are positives. Ligand B has better logP and solubility, but its significantly higher clearance is a major drawback. The small difference in binding affinity doesn't outweigh the metabolic concerns with Ligand B.

Output:
0
2025-04-17 15:05:12,550 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.447 and 335.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.48) is better than Ligand B (78.86), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.916 and 2.557), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is slightly better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.785 and 0.687), indicating good drug-like properties.

**DILI:** Ligand A (47.77) has a significantly lower DILI risk than Ligand B (63.086). This is a crucial advantage.

**BBB:** This is less important for a non-CNS target like SRC kinase. Ligand A (75.572) is better than Ligand B (40.675).

**Caco-2 Permeability:** Ligand A (-4.584) is better than Ligand B (-5.358), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.353) is better than Ligand B (-3.062), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.115) has a much lower hERG inhibition liability than Ligand B (0.729). This is a significant safety advantage.

**Microsomal Clearance:** Ligand A (49.247) has lower microsomal clearance than Ligand B (67.547), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (45.932) has a longer in vitro half-life than Ligand A (18.623). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux liability than Ligand B (0.014), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.7 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand A demonstrates a superior ADMET profile with lower DILI risk, lower hERG inhibition, better solubility, and better permeability. While Ligand B has slightly better binding affinity and a longer half-life, the safety and pharmacokinetic advantages of Ligand A are more compelling for initial drug development. The difference in binding affinity is not large enough to offset the significant ADMET improvements of Ligand A.

Output:
0
2025-04-17 15:05:12,550 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (69.89) as it is closer to the 140 threshold.

**logP:** Ligand A (0.98) is slightly below the optimal 1-3 range, but acceptable. Ligand B (2.158) is well within the optimal range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0) as it is closer to the ideal range.

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

**QED:** Both ligands have similar QED values (0.771 and 0.706), indicating good drug-likeness.

**DILI:** Ligand A (30.399) has a significantly lower DILI risk than Ligand B (51.493), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (80.419 and 83.831), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.587 and -4.557). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.71 and -2.416) which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.242) has a much lower hERG inhibition risk than Ligand B (0.413), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (45.502) has lower microsomal clearance than Ligand B (55.253), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.7) has a longer in vitro half-life than Ligand B (1.236), indicating better stability.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.146), which is favorable.

**Binding Affinity:** Ligand A (-9.5) has a significantly stronger binding affinity than Ligand B (-8.0), a difference of 1.5 kcal/mol. This is a substantial advantage that can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both have issues with Caco-2 and solubility, Ligand A demonstrates a significantly better binding affinity, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The 1.5 kcal/mol advantage in binding affinity is a critical factor for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:05:12,550 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.407 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is significantly better than Ligand B (110.17). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.423 and 1.513, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 6 HBA), both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.791 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A (62.233) has a lower DILI risk than Ligand B (90.617). Both are above the 60 threshold, indicating high risk, but A is preferable.

**BBB:** This is less critical for a non-CNS target. Ligand B (59.325) is higher than Ligand A (36.526), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.586 and -4.892).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-4.141 and -3.894).

**hERG:** Ligand A (0.653) has a lower hERG risk than Ligand B (0.261), which is a significant advantage.

**Microsomal Clearance:** Ligand B (45.465) has significantly lower microsomal clearance than Ligand A (82.151), indicating better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand B (6.262 hours) has a longer half-life than Ligand A (-27.44 hours). The negative value for A is concerning and likely an error, but even if it were positive, B's half-life is more desirable.

**P-gp Efflux:** Ligand A (0.379) has lower P-gp efflux than Ligand B (0.09), which is preferable.

**Binding Affinity:** Ligand B (-7.7 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:**

While Ligand A has better TPSA, H-bonding, and P-gp efflux, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. The DILI risk for both is high, but the superior potency and safety profile of Ligand B make it the more promising candidate, despite the slightly higher TPSA.

Output:
1
2025-04-17 15:05:12,550 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.51 and 341.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.2) is better than Ligand B (73.2). Both are below 140, but lower TPSA generally favors absorption.

**3. logP:** Both ligands have good logP values (3.457 and 2.881), 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 (3), both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.623 and 0.829), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (27.453) has a significantly lower DILI risk than Ligand B (38.077). This is a substantial advantage.

**8. BBB:** Both have reasonable BBB penetration (67.701 and 72.935). Since SRC is not a CNS target, this is not a primary concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.451 and -4.223). This is unusual and requires further investigation, but it doesn't immediately disqualify either.

**10. Aqueous Solubility:** Both have negative solubility values (-4.692 and -3.604). This is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.683 and 0.542).

**12. Microsomal Clearance:** Ligand A (48.451) has lower microsomal clearance than Ligand B (65.354), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (26.541) has a significantly longer half-life than Ligand A (3.518). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.114 and 0.121).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.3 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has advantages in DILI risk and metabolic stability (lower Cl_mic). Ligand B has a better QED score and a much longer in vitro half-life. Both have poor solubility and Caco-2 permeability. The difference in binding affinity is minimal. Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the lower DILI risk and better metabolic stability of Ligand A are slightly more important than the longer half-life of Ligand B, especially considering the similar binding affinities. However, the solubility issues are a major concern for both.

Output:
0
2025-04-17 15:05:12,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (377.535 Da) is also well within the acceptable range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (59.23). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.437) is optimal, while Ligand B (3.94) is approaching the upper limit. Higher logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0 for A, 0 for B) and HBA (3 for A, 6 for B) counts.

**QED:** Both ligands have similar QED values (0.724 and 0.684), indicating good drug-likeness.

**DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (73.245). This is a significant advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (70.803 and 73.556), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.596) is better than Ligand B (-5.415), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.966) is better than Ligand B (-3.843), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.615) has a lower hERG risk than Ligand B (0.374), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (44.258) has a lower microsomal clearance than Ligand B (108.282), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.154) has a longer in vitro half-life than Ligand B (-11.632), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.668), suggesting better oral bioavailability.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.1), a difference of 0.6 kcal/mol. While affinity is a priority, the other ADME properties of Ligand A are significantly better.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile across multiple critical parameters (DILI, solubility, metabolic stability, hERG, permeability, P-gp efflux). While Ligand B has a slightly better binding affinity, the substantial improvements in safety and pharmacokinetic properties of Ligand A outweigh this difference. The 0.6 kcal/mol difference in binding affinity is unlikely to be decisive given the other advantages of Ligand A.

Output:
0
2025-04-17 15:05:12,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.362 Da) is slightly lower, which could be beneficial for permeability. Ligand B (368.463 Da) is also good.

**TPSA:** Ligand A (99.6) is better than Ligand B (112.12), being closer to the preferred threshold of <=140 for oral absorption.

**logP:** Ligand A (0.822) is within the optimal range (1-3), but on the lower side. Ligand B (-1.226) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is better than Ligand B (3 HBD, 7 HBA). Both are within acceptable limits, but lower counts generally favor permeability.

**QED:** Ligand A (0.82) is significantly better than Ligand B (0.556), indicating a more drug-like profile.

**DILI:** Ligand A (49.283) has a lower DILI risk than Ligand B (36.099), both are good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.801) is better than Ligand B (20.628).

**Caco-2 Permeability:** Ligand A (-4.987) is better than Ligand B (-6.116). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.239) is better than Ligand B (-2.017). Higher solubility is preferred.

**hERG:** Both ligands have very low hERG risk (0.051 and 0.049 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-6.088) has significantly better metabolic stability (lower clearance) than Ligand B (-14.61). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-0.814) has a better half-life than Ligand B (-7.069).

**P-gp Efflux:** Both are very low (0.009 and 0.002 respectively).

**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 minor ADME drawbacks. The difference of 1.7 kcal/mol is significant.

**Conclusion:**

Ligand A is clearly the superior candidate. It has better predicted permeability (Caco-2, TPSA, logP), solubility, metabolic stability (Cl_mic, t1/2), a higher QED score, and, most importantly, a significantly stronger binding affinity for the SRC kinase. While both have acceptable hERG and P-gp profiles, the overall profile of Ligand A makes it a much more promising drug candidate.

Output:
1
2025-04-17 15:05:12,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.973 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (82.53) is higher than Ligand B (71.09), but both are reasonable.

**3. logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.413, Ligand B: 2.793), which is optimal.

**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 QED values above 0.5 (Ligand A: 0.616, Ligand B: 0.747), indicating good drug-like properties. Ligand B has a slightly better QED.

**7. DILI:** Ligand A has a DILI risk of 63.629%, which is considered high risk (>60%). Ligand B has a DILI risk of 23.032%, which is good (<40%). This is a significant advantage for Ligand B.

**8. BBB:** This is less critical for an oncology target, but Ligand A (35.324%) has lower BBB penetration than Ligand B (58.821%).

**9. 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 (-5.289) is greater than that of Ligand B (-4.895), suggesting potentially lower permeability for Ligand A.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-3.431) is slightly worse than Ligand B (-2.468).

**11. hERG Inhibition:** Ligand A (0.611) has a higher hERG inhibition liability than Ligand B (0.221). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (39.421) has a lower microsomal clearance than Ligand B (52.349), indicating better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (25.457 hours) has a longer in vitro half-life than Ligand B (13.586 hours), which is desirable.

**14. P-gp Efflux:** Ligand A (0.512) has lower P-gp efflux liability than Ligand B (0.035), suggesting better bioavailability and potentially better tissue distribution.

**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 >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (Cl_mic), half-life, and P-gp efflux, the significantly higher DILI risk and hERG inhibition liability are major concerns. Ligand B, despite slightly less favorable metabolic stability, has a much better safety profile (lower DILI and hERG) and a substantially stronger binding affinity. The stronger binding affinity of Ligand B is a critical advantage for an enzyme inhibitor. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 15:05:12,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.248 Da) is slightly higher than Ligand B (353.853 Da), but both are acceptable.

**TPSA:** Ligand A (73.22) is higher than Ligand B (46.92). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have logP values (3.858 and 4.651) that are within the optimal range (1-3), but leaning towards the higher end. Ligand B is a bit higher, potentially increasing off-target interactions or solubility issues.

**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 (0.673 and 0.725), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.682%), while Ligand B has a much lower risk (74.99%). This is a significant advantage for Ligand B.

**BBB:** Both have reasonably high BBB penetration (80.962% and 64.444%), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.754 and -4.796), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.72 and -5.032). This is a major drawback for both compounds and could hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.606 and 0.731), which is positive.

**Microsomal Clearance:** Ligand A has higher microsomal clearance (130.734 mL/min/kg) than Ligand B (90.588 mL/min/kg). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (95.559 hours) than Ligand B (57.77 hours). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.735 and 0.603), which is good.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-7.7 kcal/mol) than Ligand B (-7.3 kcal/mol). This 0.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and longer half-life. However, its significantly higher DILI risk and higher microsomal clearance are major concerns. Ligand B has a lower DILI risk, lower clearance, and better TPSA, but its binding affinity is slightly weaker. Given the importance of minimizing toxicity (DILI) and maximizing metabolic stability for an enzyme inhibitor, and the relatively small difference in binding affinity, Ligand B is the more promising candidate. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:05:12,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.519 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (83.4). A TPSA under 140 is good for oral absorption, and A is much closer to the ideal for CNS penetration (under 90) than B.

**logP:** Ligand A (4.747) is a bit high, potentially causing solubility issues, while Ligand B (2.072) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 7 HBA), as both are within acceptable limits, but lower numbers generally improve permeability.

**QED:** Both ligands have similar QED values (0.76 and 0.758), indicating good drug-likeness.

**DILI:** Ligand A (44.63) has a lower DILI risk than Ligand B (59.713), which is a significant advantage. Both are below the concerning threshold of 60, but lower is better.

**BBB:** Ligand A (93.602) shows excellent BBB penetration, while Ligand B (71.772) is good, but not as high.  While SRC isn't necessarily a CNS target, better BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.999 and -5.049). This is unusual and suggests poor permeability, but the scale is not specified. We'll need to consider other factors.

**Aqueous Solubility:** Ligand A (-4.577) has slightly better solubility than Ligand B (-2.73), but both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.964 and 0.895).

**Microsomal Clearance:** Ligand A (103.529) has higher microsomal clearance than Ligand B (59.138), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (72.198) has a much longer in vitro half-life than Ligand A (50.768), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.77) has slightly higher P-gp efflux than Ligand B (0.118), which is less desirable.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has *significantly* better binding affinity than Ligand B (-0.0 kcal/mol). This is a massive difference and likely outweighs many of the ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand A's higher logP, poorer solubility, and higher clearance, its *exceptional* binding affinity (-9.1 kcal/mol vs -0.0 kcal/mol) is the dominating factor. A difference of over 9 kcal/mol is substantial and suggests Ligand A is far more potent. For an enzyme target like SRC kinase, potency is paramount. While the ADME properties of Ligand A are not ideal, they could potentially be improved through further optimization, whereas improving the affinity of Ligand B from -0.0 kcal/mol would be a much greater challenge.

Output:
1
2025-04-17 15:05:12,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.32 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (91.66) is better than Ligand B (41.29) as it is still within the acceptable range for oral absorption (<140), while ligand B is much lower and may indicate a lack of necessary interactions.

**logP:** Ligand A (0.764) is optimal (1-3), while Ligand B (4.16) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.73 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (41.877) has a slightly higher DILI risk than Ligand B (34.626), but both are below the concerning threshold of 60.

**BBB:** Both have good BBB penetration (85.459 and 82.784), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can still compare the relative values; Ligand A (-4.853) is slightly better than Ligand B (-4.721).

**Aqueous Solubility:** Ligand A (-2.508) is better than Ligand B (-4.441), indicating better solubility. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.406) has a lower hERG risk than Ligand B (0.882), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-14.943) has significantly lower (better) microsomal clearance than Ligand B (57.707), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-10.428) has a negative half-life, which is nonsensical. Ligand B (16.187) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.025) has significantly lower P-gp efflux than Ligand B (0.665), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While a 1.5 kcal/mol difference is generally significant, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (Cl_mic), solubility, hERG risk, and P-gp efflux. The negative half-life for Ligand A is a data issue, but the other properties are compelling. Ligand B's high logP and clearance are significant drawbacks.

Output:
0
2025-04-17 15:05:12,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.403 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.74) is better than Ligand B (61.44) as it is still within the acceptable range for oral absorption, while ligand B is significantly lower, potentially indicating a lack of necessary interactions.

**logP:** Ligand B (2.476) is optimal (1-3), while Ligand A (-0.323) is below 1, potentially hindering permeation. This is a significant negative for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) and Ligand B (2 HBD, 3 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.723 and 0.629), indicating good drug-like properties.

**DILI:** Ligand B (14.657) has a much lower DILI risk than Ligand A (87.864), a critical advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (71.578) is better than Ligand A (65.839). While not a primary concern for a kinase inhibitor, it's a slight positive for B.

**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 (0.203) has a slightly better hERG profile than Ligand B (0.46), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (40.611) has a slightly better microsomal clearance than Ligand A (35.26), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-11.008) has a better in vitro half-life than Ligand A (-18.978), suggesting greater metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.084).

**Binding Affinity:** Both ligands have similar binding affinities (-8.5 and -8.1 kcal/mol), which are both excellent.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have excellent binding affinity, Ligand B significantly outperforms Ligand A in key ADME properties: DILI risk, logP, and metabolic stability (Cl_mic and t1/2). Ligand A's low logP is a major concern, potentially leading to poor permeability and bioavailability. The much higher DILI risk for Ligand A is also a significant drawback.



Output:
1
2025-04-17 15:05:12,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.463 and 386.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is slightly higher than Ligand B (66.48), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (0.727) is a bit low, potentially hindering permeation. Ligand B (3.264) is 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.

**QED:** Both ligands have similar QED values (0.762 and 0.782), indicating good drug-likeness.

**DILI:** Ligand A (18.379) has a significantly lower DILI risk than Ligand B (35.983). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (67.352 and 70.182), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.243) has poor Caco-2 permeability, while Ligand B (-4.987) is slightly better but still not great.

**Aqueous Solubility:** Ligand A (-1.918) has slightly better solubility than Ligand B (-3.933).

**hERG:** Ligand A (0.493) exhibits a lower hERG inhibition liability than Ligand B (0.824), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (16.254) has a much lower microsomal clearance than Ligand B (48.594), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.05) has a shorter half-life than Ligand B (-21.345), but the negative value for Ligand B is concerning and likely indicates a very rapid degradation.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux liability, while Ligand B (0.421) has a moderate liability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is relatively small (0.9 kcal/mol) and can be potentially overcome with further optimization.

**Overall Assessment:**

Ligand A demonstrates a superior ADMET profile, with lower DILI risk, lower hERG inhibition, and significantly better metabolic stability (lower Cl_mic). While Ligand B has a marginally better binding affinity, the substantial advantages of Ligand A in terms of safety and pharmacokinetics outweigh this difference. The poor Caco-2 permeability of Ligand A is a concern, but could potentially be addressed through formulation strategies. The negative half-life for Ligand B is a red flag.

Output:
0
2025-04-17 15:05:12,553 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.371 and 345.443 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.75) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (84.23) is well within the range.

**logP:** Ligand A (0.936) is at the lower end of optimal, potentially impacting permeability. Ligand B (2.608) is well within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.716 and 0.674), indicating good drug-likeness.

**DILI:** Ligand A (51.144) has a slightly higher DILI risk than Ligand B (43.117), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (77.821) has a higher BBB percentile than Ligand A (29.585), but this is less critical.

**Caco-2 Permeability:** Ligand A (-5.74) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.822) is also not ideal, but better than A.

**Aqueous Solubility:** Ligand A (-1.775) has poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-3.967) is also poor, but still better than A.

**hERG Inhibition:** Ligand A (0.084) shows very low hERG inhibition risk, which is excellent. Ligand B (0.345) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-30.201) indicates very low microsomal clearance, suggesting excellent metabolic stability. Ligand B (69.899) has a much higher clearance, indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-6.797) suggests a long half-life, consistent with low clearance. Ligand B (0.433) suggests a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.388 respectively).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This difference of 1.8 kcal/mol is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk, its poor Caco-2 permeability and aqueous solubility are major concerns. Ligand B, despite its faster metabolism, has significantly better binding affinity, better logP, and slightly better solubility and permeability. The strong binding affinity of Ligand B is a critical advantage for an enzyme inhibitor, and the difference in affinity is large enough to compensate for the less favorable metabolic stability.

Output:
1
2025-04-17 15:05:12,553 - INFO - Batch 350 complete. Total preferences: 5600
2025-04-17 15:05:12,553 - INFO - Processing batch 351/512...
2025-04-17 15:05:58,307 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (376.909 and 356.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 58.2, which is acceptable for oral absorption (<=140).

**3. logP:** Both ligands have a logP around 4.6, which is slightly high, potentially leading to solubility issues or off-target effects.

**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, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.774) has a better QED score than Ligand B (0.646), indicating a more drug-like profile.

**7. DILI:** Ligand A (62.195) has a slightly higher DILI risk than Ligand B (58.627), but both are reasonably low.

**8. BBB:** Ligand B (85.498) has a significantly higher BBB penetration percentile than Ligand A (53.858). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.73) and Ligand B (-5.008) 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 poor aqueous solubility (-5.182 and -5.015 respectively). This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.653) has a slightly lower hERG inhibition liability than Ligand B (0.808), which is favorable.

**12. Microsomal Clearance:** Ligand B (77.807 mL/min/kg) has a much higher microsomal clearance than Ligand A (19.417 mL/min/kg). This suggests Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (49.459 hours) has a significantly longer in vitro half-life than Ligand B (12.446 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.275) has lower P-gp efflux liability than Ligand B (0.688), which is favorable for oral bioavailability.

**15. Binding Affinity:** Ligand B (-7.7 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 of the ADME drawbacks.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. While both have poor solubility and permeability, metabolic stability is a critical factor for kinase inhibitors, as they often require sustained exposure. The slightly lower hERG risk for Ligand A is also a benefit. The affinity difference, while notable, is not large enough to overcome the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 15:05:58,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.482 and 359.392 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is better than Ligand B (61.44), both are below the 140 threshold for oral absorption, and acceptable for kinase inhibitors.

**logP:** Both ligands have good logP values (2.539 and 1.231), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (1 & 2) and HBA (3 & 3) counts, well within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.763 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (8.414) has a significantly lower DILI risk than Ligand B (31.136). This is a major advantage.

**BBB:** Ligand A (92.71) has a much higher BBB penetration percentile than Ligand B (74.254). While not a primary concern for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.397) has better Caco-2 permeability than Ligand B (-4.753), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-2.582) has better aqueous solubility than Ligand B (-2.455), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.557) has a lower hERG inhibition liability than Ligand B (0.152), indicating a lower risk of cardiotoxicity. This is a significant advantage.

**Microsomal Clearance:** Ligand A (27.423) has a higher microsomal clearance than Ligand B (5.765), meaning it is less metabolically stable. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-15.834) has a longer in vitro half-life than Ligand A (-22.141), indicating better metabolic stability. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux liability than Ligand B (0.005), which is favorable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better 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.

**Overall Assessment:**

Ligand A excels in most ADME properties (DILI, BBB, Caco-2, Solubility, hERG, P-gp) and has a slightly better binding affinity. However, Ligand B has a significantly better in vitro half-life and lower microsomal clearance, indicating better metabolic stability. The lower DILI and hERG risks for Ligand A are crucial for drug development. The slightly better affinity of Ligand A, combined with its superior safety profile, outweighs the metabolic stability advantage of Ligand B.

Output:
1
2025-04-17 15:05:58,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (389.851 Da) is slightly higher than Ligand B (341.371 Da), but both are acceptable.

**TPSA:** Ligand A (55.4) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (101.53) is still within acceptable limits, but higher, potentially impacting absorption.

**logP:** Ligand A (4.225) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.19) is a bit low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better balanced. Ligand B (HBD=2, HBA=6) is also acceptable, but slightly higher HBA could affect permeability.

**QED:** Both ligands have good QED scores (A: 0.605, B: 0.701), indicating drug-like properties.

**DILI:** Both ligands show acceptable DILI risk (A: 69.678, B: 62.35), though A is slightly higher.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.698) has a higher BBB percentile than Ligand B (31.834).

**Caco-2 Permeability:** Ligand A (-4.541) has a negative Caco-2 value, which is concerning. Ligand B (-5.351) is also negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-5.674) and Ligand B (-2.14) both have negative solubility values, suggesting poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.391, B: 0.258).

**Microsomal Clearance:** Ligand A (94.518) has high microsomal clearance, indicating poor metabolic stability. Ligand B (18.4) has much lower clearance, suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (1.278 hours) has a short half-life. Ligand B (17.514 hours) has a much longer half-life, which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.214, B: 0.027).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.1 kcal/mol, B: -8.2 kcal/mol). The difference is minimal.

**Conclusion:**

While both ligands exhibit strong binding affinity, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower Caco-2 value, despite both being negative, is less concerning than the high Cl_mic of Ligand A. The slightly lower logP of Ligand B is also preferable. The solubility issues can be addressed through formulation strategies.

Output:
1
2025-04-17 15:05:58,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 364.433 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.8) is slightly above the preferred <140 for good absorption, while Ligand B (60.03) is well within the range.

**logP:** Ligand A (0.116) is quite low, potentially hindering permeation. Ligand B (1.981) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (A: 0.68, B: 0.678), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (A: 20.783, B: 19.542), which is positive.

**BBB:** Ligand A (42.109) has a low BBB penetration, while Ligand B (93.641) has high BBB penetration. Since SRC is not a CNS target, this is not a major factor, but it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-5.242) has poor Caco-2 permeability, which is concerning. Ligand B (-4.695) is also not great, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.707 and -1.717). This could present formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.095, B: 0.563), which is excellent.

**Microsomal Clearance:** Ligand A (-18.054) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (31.412). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (2.986) has a shorter half-life than Ligand B (-7.596). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.008, B: 0.033).

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.2). This 1.8 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the solubility concerns for both, Ligand A is the more promising candidate. The significantly better metabolic stability (lower Cl_mic) and slightly improved binding affinity outweigh the lower BBB penetration and shorter half-life. The low logP of Ligand A is a concern, but the strong binding affinity could compensate. Ligand B's better Caco-2 permeability is offset by its poorer metabolic stability.

Output:
0
2025-04-17 15:05:58,309 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [345.359, 108.33 ,   2.66 ,   1.   ,   9.   ,   0.659,  85.576,  61.962, -5.148,  -3.003,   0.251,  11.449,   5.343,   0.086,  -7.7  ]
**Ligand B:** [378.435, 114.19 ,   1.791,   2.   ,   7.   ,   0.648,  92.672,  38.775, -5.754,  -2.748,   0.265,   0.174,  42.258,   0.065,   0.   ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (345.359) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** Both are reasonably good (A: 108.33, B: 114.19), under the 140 threshold for oral absorption.
3. **logP:** Both are within the optimal range (1-3). A (2.66) is slightly better than B (1.791) as it's closer to the middle of the range.
4. **HBD:** Both are acceptable (A: 1, B: 2), well below the 5 limit.
5. **HBA:** Both are acceptable (A: 9, B: 7), below the 10 limit.
6. **QED:** Both are similar and good (A: 0.659, B: 0.648), indicating good drug-like properties.
7. **DILI:** Both have elevated DILI risk, but B (92.672) is significantly higher than A (85.576). This is a major concern.
8. **BBB:** A (61.962) is better than B (38.775), but BBB is not a high priority for a non-CNS target like SRC.
9. **Caco-2:** Both are negative, which is unusual and suggests very poor permeability. This is a significant drawback for both.
10. **Solubility:** Both are negative, suggesting very poor solubility. This is a significant drawback for both.
11. **hERG:** Both are very low (A: 0.251, B: 0.265), indicating a low risk of cardiotoxicity.
12. **Cl_mic:** A (11.449) is much better than B (0.174). Lower clearance indicates better metabolic stability, a key factor for kinase inhibitors.
13. **t1/2:** A (5.343) is better than B (42.258), but both are relatively short.
14. **Pgp:** Both are very low (A: 0.086, B: 0.065), suggesting minimal P-gp efflux.
15. **Binding Affinity:** A (-7.7) is significantly better than B (0.0). A difference of 7.7 kcal/mol is substantial and likely outweighs many ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. Ligand A excels in affinity and has a much better Cl_mic value than Ligand B. While both have poor solubility and Caco-2 permeability, the significantly stronger binding affinity of A is a major advantage. The higher DILI risk for B is also a serious concern.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, **Ligand A** is the more promising candidate due to its significantly higher binding affinity and better metabolic stability. The substantial difference in binding affinity is likely to outweigh the ADME drawbacks, especially considering that formulation strategies can sometimes mitigate solubility issues.

Output:
0
2025-04-17 15:05:58,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.503 and 347.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (61.44), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Ligand A (3.477) is slightly better than Ligand B (2.086). Both are within the optimal 1-3 range, but Ligand B is closer to the lower limit, potentially impacting 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 3 HBA, which is acceptable.

**6. QED:** Ligand B (0.693) has a better QED score than Ligand A (0.393), indicating a more drug-like profile.

**7. DILI:** Ligand B (4.343) has a significantly lower DILI risk than Ligand A (24.04), a major advantage.

**8. BBB:** Ligand B (70.531) has a better BBB penetration score than Ligand A (66.344), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.881) has better Caco-2 permeability than Ligand B (-5.307), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand B (-1.679) has better aqueous solubility than Ligand A (-3.046), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.547) has a slightly lower hERG inhibition risk than Ligand B (0.363), which is a positive.

**12. Microsomal Clearance:** Ligand B (-21.433) has significantly lower microsomal clearance than Ligand A (44.121), indicating much better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (-5.91) has a slightly longer in vitro half-life than Ligand A (-6.75), which is beneficial.

**14. P-gp Efflux:** Ligand A (0.136) has lower P-gp efflux than Ligand B (0.032), which could lead to better bioavailability.

**15. Binding Affinity:** Ligand B (-10.9 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 minor ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 permeability and P-gp efflux, Ligand B excels in critical areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic), stronger binding affinity, lower DILI risk, and better solubility. The QED score is also higher for Ligand B. The difference in binding affinity (-10.9 vs -8.7 kcal/mol) is substantial and likely to be decisive.

Output:
1
2025-04-17 15:05:58,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.443 and 370.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.17) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (84.94) is well within the range.

**logP:** Ligand A (-0.086) is a bit low, potentially hindering permeation. Ligand B (1.212) is 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 5 HBA, both are acceptable.

**QED:** Both ligands have good QED scores (0.752 and 0.861), indicating drug-like properties.

**DILI:** Ligand A (39.395) has a lower DILI risk than Ligand B (68.282), which is a significant advantage.

**BBB:** Both have moderate BBB penetration (65.801 and 68.67), not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-5.315 and -4.71), which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Both have negative solubility values (-2.952 and -2.932), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG:** Both ligands have low hERG risk (0.299 and 0.23), which is good.

**Microsomal Clearance:** Ligand A (31.705) has significantly lower microsomal clearance than Ligand B (52.239), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.44) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (2.033) has a short half-life, which is less ideal.

**P-gp Efflux:** Both have low P-gp efflux liability (0.029 and 0.16).

**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.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.7 vs -9.2 kcal/mol) outweighs the higher DILI risk and shorter half-life. The better logP value also favors Ligand B. The negative half-life for Ligand A is a major red flag. While both need improvement in solubility and permeability, the potency advantage of Ligand B is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:05:58,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (359.348 Da) is more favorably positioned.

**TPSA:** Ligand A (59.81) is better than Ligand B (68.46), both are acceptable.

**logP:** Ligand A (4.794) is high, potentially leading to solubility issues and off-target effects. Ligand B (2.439) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which is good. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.655, B: 0.826), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 64.599, which is concerning (high risk). Ligand B has a much lower DILI risk of 41.411, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.288) and Ligand B (99.186) are both reasonable.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both are very poor (-5.671 and -3.371 respectively).

**hERG Inhibition:** Ligand A (0.537) is slightly better than Ligand B (0.298), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (42.336) has higher clearance than Ligand B (6.165), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (71.344) has a much longer half-life than Ligand B (1.262), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.662) has a slightly higher P-gp efflux liability than Ligand B (0.115).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol).

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity and half-life, its high logP, high DILI risk, and higher microsomal clearance are major concerns. Ligand B has a more favorable balance of properties, particularly its lower DILI risk, better logP, and significantly improved metabolic stability. The slight difference in binding affinity is less important than these ADME-Tox properties for an enzyme target.

Output:
1
2025-04-17 15:05:58,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.362 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.42) is well below the 140 threshold for good absorption, while Ligand B (103.01) is still acceptable but less optimal.

**logP:** Ligand A (0.567) is a bit low, potentially hindering permeation. Ligand B (0.995) is also on the lower side, but better than A.

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

**QED:** Ligand A (0.809) has a better QED score than Ligand B (0.664), indicating a more drug-like profile.

**DILI:** Ligand A (77.007) has a higher DILI risk than Ligand B (31.097). This is a significant concern for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-4.374) has very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.219) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.091) has poor aqueous solubility, while Ligand B (-1.415) is somewhat better, but still not ideal.

**hERG Inhibition:** Ligand A (0.309) has a very low hERG risk, which is excellent. Ligand B (0.167) is even lower, which is also excellent.

**Microsomal Clearance:** Ligand A (10.208) has lower microsomal clearance, indicating better metabolic stability, which is favorable. Ligand B (-18.94) has a 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 (-31.727) has a negative half-life, which is not physically possible and suggests an error in the data. Ligand B (24.839) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-6.7). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better QED and lower hERG risk, its poor solubility, Caco-2 permeability, and the unrealistic negative values for half-life are major red flags. Ligand B, while having a slightly higher DILI risk and lower QED, possesses a much stronger binding affinity (-9.0 vs -6.7 kcal/mol) and a reasonable half-life. The significantly improved potency of Ligand B is a critical factor for an enzyme inhibitor, and can be addressed through further optimization. The negative clearance and half-life values for Ligand A are highly suspect and indicate a problematic profile.

Output:
1
2025-04-17 15:05:58,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.763 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.61) is significantly better than Ligand B (93.9).  A TPSA under 140 is desirable for oral absorption, and both meet this, but A is much closer to the ideal for permeability.

**logP:** Ligand A (3.631) is optimal, while Ligand B (1.1) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 6.  Ligand B is higher, but still within the acceptable range of <=10.

**QED:** Ligand A (0.9) is excellent, indicating high drug-likeness. Ligand B (0.707) is still acceptable, but lower.

**DILI:** Ligand A (78.054) has a higher DILI risk than Ligand B (62.35). This is a concern for A.

**BBB:**  BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (60.954) is higher than A (41.218), but neither is particularly high.

**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, making interpretation difficult.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.189 and 0.08), which is excellent.

**Microsomal Clearance:** Ligand A (3.179) has much lower microsomal clearance than Ligand B (21.864), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (1.167) has a shorter half-life than Ligand B (-21.539). The negative value for B is suspect and likely indicates a very rapid clearance or an issue with the assay.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.096 and 0.024).

**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, especially considering the other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. Despite a slightly higher DILI risk, its superior logP, TPSA, QED, metabolic stability (lower Cl_mic), and binding affinity outweigh the DILI concern. The negative solubility and Caco-2 values are concerning for both, but the other properties of A are more favorable. Ligand B's very high Cl_mic and negative half-life are major drawbacks.



Output:
0
2025-04-17 15:05:58,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.889 and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.36) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (107.97) is still under 140, but less optimal than A.

**logP:** Ligand A (4.725) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.323) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly less ideal.

**QED:** Ligand A (0.725) has a good drug-likeness score. Ligand B (0.365) is below the 0.5 threshold, indicating a less drug-like profile.

**DILI:** Ligand A (51.26) has a moderate DILI risk, but acceptable. Ligand B (13.61) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (76.774) has better BBB penetration than Ligand B (30.71).

**Caco-2:** Ligand A (-4.558) and Ligand B (-5.158) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Ligand A (-4.931) and Ligand B (-0.51) both have negative solubility values, which is also concerning.

**hERG:** Ligand A (0.512) has a low hERG risk, which is excellent. Ligand B (0.136) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (74.325) has higher clearance, indicating lower metabolic stability. Ligand B (50.879) has lower clearance, suggesting better metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand A (31.275) has a moderate half-life. Ligand B (-17.887) has a negative half-life, which is not possible and indicates a significant issue with the data or the molecule's stability.

**P-gp Efflux:** Ligand A (0.317) has lower P-gp efflux, which is favorable. Ligand B (0.005) has very low P-gp efflux, even more favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This 0.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic). It also has a much lower DILI risk and P-gp efflux. However, its logP is very low, and its QED is poor. The negative half-life is a major red flag. Ligand A has a better QED, TPSA, and BBB, but suffers from higher clearance and a slightly lower binding affinity. The negative solubility and Caco-2 values are concerning for both.

Despite the negative half-life, the superior binding affinity and metabolic stability of Ligand B, coupled with its low DILI and P-gp efflux, make it a more promising starting point for optimization, assuming the half-life issue can be resolved. The low logP can be addressed through structural modifications.

Output:
1
2025-04-17 15:05:58,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.69) is slightly higher than Ligand B (75.44). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands have good logP values (1.015 and 2.858), falling within the 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 (0.688 and 0.858), indicating drug-like properties.

**DILI:** Ligand A (50.601) has a slightly higher DILI risk than Ligand B (41.373), but both are below the concerning threshold of 60.

**BBB:** Ligand A (72.237) and Ligand B (84.606) both have acceptable BBB penetration, but B is higher. This isn't a major concern for a kinase inhibitor unless CNS effects are desired or problematic.

**Caco-2 Permeability:** Ligand A (-4.716) and Ligand B (-5.013) both have negative values, which is unusual. Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-1.794) and Ligand B (-2.58) both have negative solubility values, which is also unusual. Lower values indicate lower solubility.

**hERG Inhibition:** Ligand A (0.098) has a very low hERG risk, which is excellent. Ligand B (0.357) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (25.574) has a lower microsomal clearance than Ligand B (47.424), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-4.911) has a significantly longer in vitro half-life than Ligand B (-19.822). This is a major advantage.

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux than Ligand B (0.282), suggesting better bioavailability.

**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 relatively small (0.4 kcal/mol).

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and BBB penetration, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a much lower hERG risk. These factors are crucial for a successful drug candidate targeting a kinase. The slightly lower affinity of Ligand A can potentially be optimized in subsequent iterations.

Output:
0
2025-04-17 15:05:58,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 351.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.25) is better than Ligand B (102.57), both are acceptable for oral absorption (<140).

**logP:** Ligand A (1.392) is optimal (1-3). Ligand B (-0.447) is below 1, which might impede permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 4 respectively, both <=5).

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 4 respectively, both <=10).

**QED:** Ligand A (0.724) has a better QED score than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Ligand A (47.964) has a much lower DILI risk than Ligand B (11.322), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (around 40%), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.953) is better than Ligand B (-5.674), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.313) is better than Ligand B (-1.211), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.055 and 0.087 respectively).

**Microsomal Clearance:** Ligand A (27.957) has a significantly lower microsomal clearance than Ligand B (-53.786), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.876) has a shorter half-life than Ligand B (8.451), but the difference isn't dramatic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.001 respectively).

**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 has a much better binding affinity, which is the highest priority for an enzyme inhibitor. However, it has a significantly higher DILI risk, lower solubility, and a negative microsomal clearance. Ligand A has a better overall ADME profile (lower DILI, better solubility, better metabolic stability) and a good QED score, but its binding affinity is weaker.

The difference in binding affinity (1.8 kcal/mol) is substantial. While a good ADME profile is important, the potency advantage of Ligand B is likely to be decisive, especially in oncology where maximizing target engagement is critical. The DILI risk of Ligand B, while higher, might be manageable through careful formulation or patient selection.

Output:
1
2025-04-17 15:05:58,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 362.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is well below the 140 threshold, suggesting good absorption. Ligand B (102.74) is still within acceptable limits but less favorable than A.

**logP:** Ligand A (1.816) is optimal. Ligand B (0.597) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** 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 (0.565 and 0.848), indicating drug-like properties.

**DILI:** Ligand A (6.01) has a much lower DILI risk than Ligand B (68.941). This is a significant advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (65.374) has a better score than Ligand B (49.826).

**Caco-2 Permeability:** Ligand A (-4.398) and Ligand B (-4.905) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't interpret this definitively.

**Aqueous Solubility:** Ligand A (-1.747) and Ligand B (-2.81) both have negative values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG risk (0.205 and 0.219), which is excellent.

**Microsomal Clearance:** Ligand A (24.052) has a higher (worse) microsomal clearance than Ligand B (-14.978). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-4.71) has a shorter half-life than Ligand B (-7.634). This favors Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.048).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, it has a higher DILI risk and a lower logP. Ligand A has a lower DILI risk, better logP, and TPSA. The difference in binding affinity is significant, and for an enzyme target, potency is paramount. While Ligand B's DILI risk is elevated, it's not excessively high (68.941). The improved metabolic stability and binding affinity make Ligand B the more promising candidate, assuming the DILI risk can be mitigated through further optimization.

Output:
1
2025-04-17 15:05:58,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.371 and 366.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.81) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (40.62) is excellent, well below the 140 threshold for oral absorption.

**logP:** Ligand A (0.705) is a bit low, potentially hindering permeability. Ligand B (3.263) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, within acceptable limits. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Ligand A (0.855) has a better QED score than Ligand B (0.662), indicating a more drug-like profile.

**DILI:** Ligand B (6.437) has a significantly lower DILI risk than Ligand A (57.076), a major advantage.

**BBB:** Ligand B (92.4) shows excellent BBB penetration, while Ligand A (48.701) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.164 and -4.91), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.54 and -3.514), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.119) has a lower hERG risk than Ligand B (0.717), which is preferable.

**Microsomal Clearance:** Ligand B (92.979) has a much higher microsomal clearance than Ligand A (20.419), suggesting lower metabolic stability. This is a significant disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (22.581) has a longer in vitro half-life than Ligand B (-13.833), indicating better stability.

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.306), which is positive.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), although both are good.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, half-life, and lower P-gp efflux. However, Ligand B has a much lower DILI risk, better logP, and excellent BBB penetration. Both suffer from very poor predicted solubility and permeability. Given the enzyme-specific priorities, metabolic stability (half-life and Cl_mic) and safety (DILI, hERG) are crucial. While Ligand A has better metabolic stability, the significantly lower DILI risk of Ligand B is a major advantage. The binding affinity difference is not large enough to overcome the safety concerns with Ligand A.

Output:
1
2025-04-17 15:05:58,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.463 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is better than Ligand B (85.23) as it is closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.308) is optimal, while Ligand B (1.427) is slightly low, potentially impacting permeability.

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

**QED:** Ligand A (0.756) has a significantly better QED score than Ligand B (0.463), indicating a more drug-like profile.

**DILI:** Ligand B (18.418) has a much lower DILI risk than Ligand A (56.805), a significant advantage.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (53.16) is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.582) is slightly better than Ligand B (-4.847).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-5.14) is slightly better than Ligand B (-2.55).

**hERG Inhibition:** Ligand A (0.636) has a slightly higher hERG risk than Ligand B (0.405), but both are reasonably low.

**Microsomal Clearance:** Ligand B (24.84 mL/min/kg) has significantly lower microsomal clearance than Ligand A (74.787 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-45.312 hours) has a negative half-life, which is not possible. Ligand B (7.989 hours) is reasonable.

**P-gp Efflux:** Both have low P-gp efflux liability. Ligand B (0.029) is slightly lower.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), a 0.7 kcal/mol difference. This difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A has a better binding affinity and QED score, but suffers from higher DILI risk, higher microsomal clearance, and a nonsensical half-life. Ligand B has a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, reasonable t1/2), and slightly better permeability/solubility, despite a slightly weaker binding affinity. Given the enzyme-specific priorities, the improved safety and metabolic stability of Ligand B outweigh the modest difference in binding affinity.

Output:
1
2025-04-17 15:05:58,312 - INFO - Batch 351 complete. Total preferences: 5616
2025-04-17 15:05:58,312 - INFO - Processing batch 352/512...
2025-04-17 15:06:38,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 69.64, well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.855) is optimal, while Ligand B (2.949) is also within the acceptable 1-3 range.

**H-Bond Donors:** Both have 2 HBD, satisfying the <=5 rule.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4, both within the <=10 limit.

**QED:** Both ligands have good QED scores (0.747 and 0.839, respectively), indicating drug-like properties.

**DILI:** Ligand A (13.61 percentile) has a significantly lower DILI risk than Ligand B (40.636 percentile). This is a major advantage.

**BBB:** Ligand A (51.842 percentile) has a lower BBB penetration than Ligand B (76.347 percentile). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.026) and Ligand B (-4.856) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.042 and -3.464, respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.226 percentile) has a much lower hERG inhibition liability than Ligand B (0.597 percentile). This is a significant safety advantage.

**Microsomal Clearance:** Ligand A (12.192 mL/min/kg) has a lower microsomal clearance than Ligand B (43.101 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (19.394 hours) has a longer in vitro half-life than Ligand B (-3.067 hours). The negative value for Ligand B is concerning and suggests very rapid metabolism.

**P-gp Efflux:** Ligand A (0.078 percentile) has lower P-gp efflux than Ligand B (0.244 percentile), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the ADME and safety advantages of Ligand A are more compelling, especially considering the importance of these factors for enzyme inhibitors.

Output:
0
2025-04-17 15:06:38,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.47 & 346.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (78.09). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is much closer to the ideal for better absorption.

**logP:** Both ligands have a logP of around 3, which is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.917) has a much higher QED score than Ligand B (0.745), indicating a more drug-like profile.

**DILI:** Ligand A (13.84) has a significantly lower DILI risk than Ligand B (57.58). This is a major advantage for Ligand A.

**BBB:** Ligand A (95.81) has excellent BBB penetration, while Ligand B (57.85) is moderate. While not a primary concern for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.65) has better Caco-2 permeability than Ligand B (-5.21), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.016 and -3.904 respectively). This is a significant drawback for both, but potentially manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.819) has a lower hERG risk than Ligand B (0.601), which is preferable.

**Microsomal Clearance:** Ligand A (-4.606) has much better metabolic stability (lower clearance) than Ligand B (58.505). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (20.229 hours) has a significantly longer half-life than Ligand B (-10.838 hours). This is another major advantage.

**P-gp Efflux:** Ligand A (0.172) has lower P-gp efflux than Ligand B (0.396), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.0) has a substantially better binding affinity than Ligand A (0.0). This is a very significant advantage, potentially outweighing some of the ADME drawbacks of Ligand B. A difference of 9 kcal/mol is substantial.

**Overall Assessment:**

Ligand A has a superior ADME profile across almost all parameters (QED, DILI, BBB, Caco-2, hERG, Cl_mic, t1/2, Pgp). However, Ligand B's binding affinity is *much* stronger. Given that we are targeting an enzyme (SRC kinase), potency is paramount. The 9 kcal/mol difference in binding affinity is likely to be decisive, even considering the ADME liabilities of Ligand B. While the solubility and metabolic stability of Ligand B are concerning, these issues can potentially be addressed through formulation and structural modifications during lead optimization.

Output:
1
2025-04-17 15:06:38,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.467 and 353.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.59) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.22) is still acceptable, but less ideal.

**logP:** Ligand A (2.976) is optimal (1-3). Ligand B (1.05) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable range (<=10).

**QED:** Both ligands have reasonable QED scores (0.767 and 0.582), indicating good drug-like properties.

**DILI:** Ligand A (75.96) has a higher DILI risk than Ligand B (53.664). This is a concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (67.197 and 65.025). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.759) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.524) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.679) has poor aqueous solubility. Ligand B (-2.495) is also poor, but better than Ligand A.

**hERG:** Both ligands have low hERG inhibition risk (0.322 and 0.47), which is positive.

**Microsomal Clearance:** Ligand A (49.218) has moderate clearance, while Ligand B (9.069) has very low clearance, suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (20.031) has a moderate half-life. Ligand B (9.89) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.443 and 0.08), which is favorable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the slightly lower logP, Ligand B is the more promising candidate. Its significantly improved binding affinity, much lower microsomal clearance (better metabolic stability), and lower DILI risk outweigh the slightly poorer Caco-2 permeability and solubility compared to Ligand A. The poor Caco-2 and solubility of Ligand A are significant concerns, and the higher DILI risk is also undesirable. The strong binding affinity of Ligand B suggests it could be effective at lower doses, potentially mitigating some of the permeability/solubility issues.

Output:
1
2025-04-17 15:06:38,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.407 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (103.59 and 109.3) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (-1.306) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (-0.8) is closer to the ideal range.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (3 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED scores (0.662 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (33.85) has a lower DILI risk than Ligand B (39.511), which is a significant advantage. Both are below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (46.84) has a higher BBB value than Ligand A (28.383), but this isn't a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.284 and -5.535). These values are unusual and likely indicate poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.15 and -1.904), indicating poor solubility. Ligand B has worse solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.092 and 0.023), which is excellent.

**Microsomal Clearance:** Ligand A (-2.759) has a *better* (lower, more negative) microsomal clearance than Ligand B (-9.834), suggesting greater metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (20.379 hours) has a significantly longer half-life than Ligand B (-0.896 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.008).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -9.4 kcal/mol). Ligand B is slightly more potent, but the difference (1 kcal/mol) is likely outweighed by the other factors.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better solubility. These factors are more critical for an enzyme target like SRC kinase. The slightly lower logP of Ligand A is a minor concern compared to the substantial advantages in metabolic stability and safety.

Output:
0
2025-04-17 15:06:38,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.531 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is well below the 140 threshold for good oral absorption, while Ligand B (103.59) is still acceptable but closer to the limit.

**logP:** Ligand A (2.675) is optimal (1-3). Ligand B (-1.306) is significantly below 1, potentially hindering permeation.

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

**H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 7 HBAs, both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.664 and 0.662), indicating good drug-likeness.

**DILI:** Ligand A (49.011) has a slightly higher DILI risk than Ligand B (33.85), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (39.783) has a slightly better BBB score than Ligand B (28.383).

**Caco-2 Permeability:** Ligand A (-4.911) has a worse Caco-2 permeability than Ligand B (-5.284), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.86) has better aqueous solubility than Ligand B (-1.15). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.636) has a higher hERG risk than Ligand B (0.092). This is a significant concern for Ligand A.

**Microsomal Clearance:** Ligand A (57.782) has a higher microsomal clearance than Ligand B (-2.759), indicating lower metabolic stability. This is a substantial drawback for Ligand A.

**In vitro Half-Life:** Ligand A (29.229) has a longer half-life than Ligand B (20.379), which is desirable.

**P-gp Efflux:** Ligand A (0.437) has lower P-gp efflux than Ligand B (0.016), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.4 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has a slightly longer half-life and lower P-gp efflux, its significantly lower logP, higher hERG risk, and higher microsomal clearance are major drawbacks. Ligand B, despite slightly lower solubility and Caco-2 permeability, has a much better safety profile (lower hERG, lower DILI) and better metabolic stability, which are critical for an enzyme inhibitor. The binding affinity difference is minimal.

Output:
1
2025-04-17 15:06:38,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 351.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.17) is slightly higher than Ligand B (81.99). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Ligand A (-0.493) is a bit low, potentially hindering permeability. Ligand B (2.713) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being less than 10.

**QED:** Both ligands have good QED scores (0.593 and 0.705), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (22.993 and 24.544), below the 40 threshold.

**BBB:** Both ligands have good BBB penetration (84.335 and 81.892). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.097 and -4.683). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is significant. Ligand A is slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.603 and -3.844), indicating poor aqueous solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.192) has a lower hERG risk than Ligand B (0.738), which is a significant advantage.

**Microsomal Clearance:** Ligand A (22.596) has a significantly lower microsomal clearance than Ligand B (53.114), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (7.327) has a longer half-life than Ligand B (2.126), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.013 and 0.113).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a considerably 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 has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. While Ligand A has a slightly lower logP and Caco-2 permeability, the strong binding affinity and improved metabolic profile are more critical for an enzyme inhibitor. The solubility issues are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 15:06:38,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.514 and 364.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold and favorable. Ligand B (93.01) is still within range, but less optimal.

**logP:** Both ligands have good logP values (2.456 and 1.236), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 8 HBA. Ligand A is preferred here.

**QED:** Both ligands have similar QED values (0.761 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (8.492) has a significantly lower DILI risk than Ligand B (56.689), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.08) is higher than Ligand B (25.01).

**Caco-2 Permeability:** Ligand A (-4.524) is better than Ligand B (-5.371), indicating better absorption.

**Aqueous Solubility:** Ligand A (-1.793) is better than Ligand B (-0.983).

**hERG Inhibition:** Ligand A (0.721) has a much lower hERG risk than Ligand B (0.02). This is a critical advantage.

**Microsomal Clearance:** Ligand A (-8.146) has a much lower (better) microsomal clearance than Ligand B (36.138), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-4.699) has a longer half-life than Ligand B (3.205).

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux than Ligand B (0.043).

**Binding Affinity:** Ligand A (-7.3 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 to override other issues, it contributes to the overall preference.

**Conclusion:**

Ligand A is significantly better than Ligand B. It has a much lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, better permeability, and slightly better binding affinity. While Ligand B has a reasonable profile, the safety concerns (DILI, hERG) and poorer ADME properties of Ligand B make it a less desirable candidate.

Output:
0
2025-04-17 15:06:38,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.01) is slightly higher than Ligand B (76.66). Both are below the 140 threshold for good oral absorption, but B is better.

**logP:** Both ligands have acceptable logP values (1.278 and 2.119, respectively), falling within the 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:** Ligand A (0.789) has a better QED score than Ligand B (0.655), indicating a more drug-like profile.

**DILI:** Ligand B (28.655) has a significantly lower DILI risk than Ligand A (54.44), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration (65.374 and 73.401). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand B (-5.167) has a better Caco-2 permeability than Ligand A (-4.173), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.904) has better aqueous solubility than Ligand A (-1.334).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.187 and 0.361), which is excellent.

**Microsomal Clearance:** Ligand B (36.079) has a higher microsomal clearance than Ligand A (16.734), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-13.769) has a much longer in vitro half-life than Ligand B (25.506), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.025 and 0.079).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 and -7.5 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has better solubility and Caco-2 permeability, Ligand A is superior overall. Ligand A's significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk outweigh the slight advantages of Ligand B. The binding affinities are nearly identical, so potency isn't a differentiating factor. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial.

Output:
0
2025-04-17 15:06:38,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.434 and 374.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (77.1), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.871) is optimal, while Ligand B (0.523) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), both are below the threshold of 10.

**QED:** Both ligands have similar and acceptable QED values (0.744 and 0.625), indicating good drug-likeness.

**DILI:** Ligand A (16.092) has a significantly lower DILI risk than Ligand B (33.346), which is a major advantage.

**BBB:** Ligand A (81.698) has a better BBB penetration score than Ligand B (43.583), although BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.868) has a better Caco-2 permeability than Ligand B (-5.098).

**Aqueous Solubility:** Ligand A (-2.125) has better aqueous solubility than Ligand B (-1.668).

**hERG Inhibition:** Both ligands have similar and low hERG inhibition liability (0.31 and 0.317).

**Microsomal Clearance:** Ligand A (0.615) has significantly lower microsomal clearance than Ligand B (10.539), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.898) has a much longer in vitro half-life than Ligand B (14.402).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.08 and 0.029).

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.7), but the difference is less than 1.5 kcal/mol.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, **Ligand A is the more promising drug candidate**. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and better Caco-2 permeability. These factors are crucial for *in vivo* efficacy and safety. The small difference in binding affinity is outweighed by the substantial improvements in ADME properties.

Output:
0
2025-04-17 15:06:38,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.419 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.51 and 96.53) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (above 90 A^2). This is acceptable for an oncology target that doesn't necessarily require brain penetration.

**logP:** Ligand A (2.095) is optimal, while Ligand B (0.729) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable counts, well within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.752 and 0.539), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (75.339) has a higher DILI risk than Ligand B (23.885). This is a significant concern for Ligand A.

**BBB:** Both have similar BBB penetration (64.948 and 66.227), which is not a primary concern for an oncology target.

**Caco-2 Permeability:** Ligand A (-5.644) has poorer Caco-2 permeability than Ligand B (-4.884).

**Aqueous Solubility:** Ligand A (-2.723) has poorer aqueous solubility than Ligand B (-1.644). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.492 and 0.093), which is excellent.

**Microsomal Clearance:** Ligand A (34.642) has higher microsomal clearance than Ligand B (29.336), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (27.136) has a longer half-life than Ligand B (12.584). This is a positive attribute for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.007).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has significantly 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 much stronger binding affinity, a longer half-life, and similar P-gp efflux. However, it suffers from higher DILI risk, poorer solubility, and lower Caco-2 permeability. Ligand B has a better safety profile (lower DILI), better solubility and permeability, but significantly weaker binding affinity.

The difference in binding affinity (-8.7 vs -6.6 kcal/mol) is substantial. For an enzyme target like SRC kinase, potency is paramount. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications during lead optimization. The weaker binding of Ligand B would likely require a much larger structural overhaul to achieve comparable potency.

Output:
1
2025-04-17 15:06:38,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.36 and 345.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.52) is slightly above the preferred <140, while Ligand B (70.67) is well within the range.

**logP:** Both ligands have acceptable logP values (2.19 and 1.19), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (3 and 2) and HBA (4 and 4) counts, satisfying the <5 and <10 rules respectively.

**QED:** Both ligands have good QED scores (0.75 and 0.787), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (63.09%) than Ligand B (17.84%). This is a major concern.

**BBB:** Both have similar BBB penetration (68.40% and 63.47%). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.98 and -4.9), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values (-3.74 and -1.30), indicating poor aqueous solubility. Ligand B is better in this regard.

**hERG:** Both ligands exhibit low hERG inhibition risk (0.53 and 0.26).

**Microsomal Clearance:** Ligand B has a much lower (better) microsomal clearance (-13.23) compared to Ligand A (-49.30). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (16.79 hours) than Ligand A (-23.63 hours, which is negative and likely an error/outlier). This is a substantial advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.045 and 0.035).

**Binding Affinity:** Both ligands have comparable 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.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both have issues with solubility and Caco-2 permeability, Ligand B exhibits significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. The binding affinities are comparable. The lower DILI and improved metabolic profile are critical advantages for an enzyme inhibitor like an SRC kinase inhibitor.

Output:
1
2025-04-17 15:06:38,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (341.459 Da and 348.491 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (63.05 and 67.23) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.22 and 2.522) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, satisfying the <5 and <10 rules respectively.

**QED:** Both ligands have high QED scores (0.929 and 0.859), indicating good drug-likeness.

**DILI:** Ligand A (29.857) has a slightly higher DILI risk than Ligand B (24.351), but both are well below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (70.415 and 72.043), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.93 and -4.788), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable or reliable.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.306 and -2.346). This is a significant concern for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.284) has a lower hERG inhibition liability than Ligand B (0.637), which is favorable.

**Microsomal Clearance:** Ligand A (7.12 mL/min/kg) has significantly lower microsomal clearance than Ligand B (42.371 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.875 hours) has a much longer half-life than Ligand B (-0.545 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.046) shows lower P-gp efflux liability than Ligand B (0.218), suggesting better bioavailability.

**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 minor ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A is the superior candidate. Its significantly stronger binding affinity, lower hERG risk, dramatically improved metabolic stability (lower Cl_mic and much longer t1/2), and lower P-gp efflux outweigh the shared solubility issues. Addressing the solubility could be a formulation challenge, but the potency and pharmacokinetic advantages of Ligand A make it more likely to succeed as a drug candidate.

Output:
0
2025-04-17 15:06:38,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (346.402 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (97.11). TPSA < 140 is good for oral absorption, and both are within this limit, but A is much better.

**logP:** Both ligands have good logP values (A: 2.483, B: 2.16), falling within the 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, which generally improves permeability.

**QED:** Both ligands have acceptable QED values (A: 0.673, B: 0.746), indicating good drug-like properties.

**DILI:** Ligand A (40.287) has a much lower DILI risk than Ligand B (85.964). This is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (75.921) is better than Ligand B (52.966).

**Caco-2 Permeability:** Ligand A (-4.457) is better than Ligand B (-5.745), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.717) is better than Ligand B (-2.75), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.449) has a much lower hERG risk than Ligand B (0.019). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (53.748) has a higher microsomal clearance than Ligand B (4.146), meaning it is less metabolically stable. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-15.241) has a significantly longer in vitro half-life than Ligand A (8.364). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.034), which is favorable.

**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's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in most key ADME properties (TPSA, solubility, DILI, hERG, P-gp efflux) and has a slightly better binding affinity. However, Ligand B has a significantly better half-life and lower microsomal clearance, indicating better metabolic stability. The lower DILI and hERG risk for Ligand A are crucial advantages. Considering the enzyme-kinase target profile, the lower DILI and hERG risks of Ligand A outweigh the metabolic stability advantage of Ligand B.

Output:
1
2025-04-17 15:06:38,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.46 and 346.43 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (87.46) is still under 140, but less optimal than A.

**logP:** Ligand A (4.451) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.692) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.875 and 0.843), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (36.95 and 37.07 percentile), which is favorable.

**BBB:** Ligand A (91.86) shows good BBB penetration, while Ligand B (27.88) does not. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.347) and Ligand B (-4.972) both have negative values, indicating poor permeability. This is a concern.

**Aqueous Solubility:** Ligand A (-5.094) and Ligand B (-1.34) both have negative values, indicating poor solubility. This is a concern.

**hERG Inhibition:** Ligand A (0.763) has a slightly higher hERG risk than Ligand B (0.316), but both are relatively low.

**Microsomal Clearance:** Ligand A (55.201) has moderate clearance, while Ligand B (-0.249) has very low clearance, suggesting excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (36.411 hours) has a reasonable half-life. Ligand B (2.641 hours) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.538) has moderate P-gp efflux, while Ligand B (0.025) has very low efflux. This is favorable for Ligand B.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference isn't huge, it's enough to consider, especially given the other factors.

**Overall Assessment:**

Ligand B has a significantly better metabolic stability profile (lower Cl_mic, lower Pgp efflux) and a slightly better binding affinity. However, it suffers from poor permeability, poor solubility, and a very short half-life. Ligand A has better permeability and a reasonable half-life, but its logP is a bit high.

Considering the enzyme-specific priorities, metabolic stability is crucial. The improved metabolic stability of Ligand B, coupled with its slightly better affinity, outweighs its solubility and permeability issues *if* those can be addressed through formulation or prodrug strategies. The short half-life is a significant concern, but potentially addressable through structural modifications. Ligand A's higher logP and moderate metabolic stability are less desirable.

Output:
1
2025-04-17 15:06:38,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.77) is better than Ligand B (61.88), being under 140, but both are good.

**logP:** Both ligands have acceptable logP values (1.091 and 1.641), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.832) has a significantly better QED score than Ligand B (0.684), indicating a more drug-like profile.

**DILI:** Ligand A (12.33) has a much lower DILI risk than Ligand B (8.104), a crucial advantage.

**BBB:** Both have moderate BBB penetration, but Ligand B (64.482) is slightly better than Ligand A (56.805). This is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.916 and -4.805), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-0.836 and -0.584), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.123) has a lower hERG inhibition risk than Ligand B (0.227), which is a positive.

**Microsomal Clearance:** Ligand A (-31.099) has significantly lower microsomal clearance than Ligand B (9.944), indicating much better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (13.701) has a longer in vitro half-life than Ligand B (-7.356), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.003 and 0.04).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly better binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand B has a significantly better binding affinity, Ligand A demonstrates superior ADMET properties, particularly regarding DILI risk and metabolic stability (lower Cl_mic and longer t1/2). The poor Caco-2 and solubility for both are concerning, but the improved metabolic stability and safety profile of Ligand A, combined with acceptable potency, make it the more promising candidate. The binding affinity difference is significant, but not insurmountable, and could potentially be improved through further optimization of Ligand A.

Output:
0
2025-04-17 15:06:38,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.411 and 349.337 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.84) is better than Ligand B (84.22). Both are below the 140 A^2 threshold for oral absorption, but lower TPSA is generally preferred.

**logP:** Both ligands have good logP values (3.848 and 2.9), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.744 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A (77.356) has a lower DILI risk than Ligand B (91.431). This is a significant advantage.

**BBB:** Ligand A (64.599) has a lower BBB penetration than Ligand B (54.207). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.841 and -4.793), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-4.451 and -3.132), indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.448 and 0.119). This is excellent.

**Microsomal Clearance:** Ligand A (67.889) has a higher microsomal clearance than Ligand B (33.506). Ligand B is significantly better here, indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-31.271) has a much longer in vitro half-life than Ligand A (63.616). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.084 and 0.083).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). This 1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk. However, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), which is a critical factor for kinase inhibitors. Both have concerningly poor solubility and permeability. The difference in binding affinity, while present, is likely less impactful than the substantial improvement in metabolic stability offered by Ligand B. Given the enzyme-specific priorities, the improved metabolic stability of Ligand B outweighs the slightly better binding affinity of Ligand A, despite the shared solubility/permeability issues.

Output:
1
2025-04-17 15:06:38,708 - INFO - Batch 352 complete. Total preferences: 5632
2025-04-17 15:06:38,708 - INFO - Processing batch 353/512...
2025-04-17 15:07:29,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.477 and 366.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, suggesting good absorption. Ligand B (136.06) is approaching the upper limit, which *could* slightly hinder absorption, but is still acceptable.

**logP:** Ligand A (3.084) is optimal. Ligand B (-0.091) is significantly below the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 9 HBA) is acceptable, but the higher HBA count might slightly impact permeability.

**QED:** Both ligands (0.648 and 0.644) have good drug-likeness scores.

**DILI:** Ligand A (30.399) has a much lower DILI risk than Ligand B (86.002), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.537) is higher than Ligand B (56.534).

**Caco-2 Permeability:** Ligand A (-4.31) is poor, while Ligand B (-5.363) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.308) is poor, while Ligand B (-2.665) is slightly better, but still not ideal.

**hERG:** Ligand A (0.825) has a lower hERG risk than Ligand B (0.155), which is a major concern.

**Microsomal Clearance:** Ligand A (76.881) has higher clearance than Ligand B (4.993). This means Ligand B is much more metabolically stable, a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (17.688) has a longer half-life than Ligand B (-2.395), which is a positive.

**P-gp Efflux:** Ligand A (0.22) has lower P-gp efflux than Ligand B (0.016), which is a positive.

**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 ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, significantly lower microsomal clearance (better metabolic stability), and a lower hERG risk. However, it suffers from poor logP, Caco-2 permeability, and aqueous solubility, and a high DILI risk. Ligand A has better solubility, lower DILI, and better permeability, but weaker binding and higher clearance.

The stronger binding affinity of Ligand B is a major factor for an enzyme target. While the ADME properties are concerning, optimization efforts could potentially address these issues. The substantial potency advantage makes it the more promising candidate *despite* the ADME liabilities.

Output:
1
2025-04-17 15:07:29,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.837 and 374.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (93.9 and 90.03) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (1.614) is within the optimal range of 1-3. Ligand B (-0.534) is slightly below 1, which *could* indicate potential permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6 & 5) counts, well within the guidelines.

**QED:** Both ligands have QED scores (0.73 and 0.698) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (50.136) has a slightly higher DILI risk than Ligand B (25.553). This is a point in favor of Ligand B.

**BBB:** Ligand A (81.039) has better BBB penetration than Ligand B (49.826), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.678) has a more negative Caco-2 value than Ligand B (-5.158), suggesting slightly better permeability.

**Aqueous Solubility:** Ligand A (-2.63) has slightly better aqueous solubility than Ligand B (-1.382).

**hERG:** Both ligands have very low hERG inhibition liability (0.263 and 0.106), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand B (12.376 mL/min/kg) has significantly lower microsomal clearance than Ligand A (25.418 mL/min/kg). This suggests better metabolic stability for Ligand B, a key factor for enzymes.

**In vitro Half-Life (t1/2):** Ligand B (-41.382 hours) has a much longer in vitro half-life than Ligand A (-5.144 hours). This is a significant advantage for Ligand B, reducing dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.168 and 0.004).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a lower DILI risk. Given the enzyme target class, metabolic stability and minimizing potential toxicity (DILI) are paramount. The minimal difference in binding affinity doesn't outweigh the significant ADME advantages of Ligand B.

Output:
1
2025-04-17 15:07:29,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (349.366 and 348.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.88) is slightly above the preferred <140, but still acceptable. Ligand B (108.12) is better, being well below 140.

**3. logP:** Ligand A (0.625) is a bit low, potentially hindering permeability. Ligand B (1.453) is better, falling within 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 (6) is good. Ligand B (8) is also acceptable, but higher.

**6. QED:** Ligand A (0.781) is excellent, indicating good drug-likeness. Ligand B (0.38) is significantly lower, suggesting potential issues.

**7. DILI:** Both ligands have the same DILI risk (47.15%), which is good (below 40 is ideal, but <60 is acceptable).

**8. BBB:** Ligand A (68.282) is lower, while Ligand B (54.091) is even lower. BBB is not a high priority for a kinase inhibitor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.007 and -5.467), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.148 and -2.189), also unusual and concerning.

**11. hERG Inhibition:** Ligand A (0.132) has a very low hERG risk, which is excellent. Ligand B (0.763) is higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-11.356) has a negative clearance, which is impossible and likely an error in the data. Ligand B (48.852) has a moderate clearance, which is not ideal, but not alarming.

**13. In vitro Half-Life:** Ligand A (-30.635) has a negative half-life, which is impossible and likely an error in the data. Ligand B (55.45) is a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.12).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-8.4 kcal/mol). A difference of 1.2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better QED and hERG profile, but its permeability and solubility are questionable (negative values are problematic). Furthermore, the negative values for clearance and half-life are data errors and render it unusable. Ligand B, while having a lower QED and slightly higher hERG, has a significantly better binding affinity and more reasonable ADME properties (despite the negative Caco-2 and solubility values, they are not as extreme as Ligand A's impossible values). Given the enzyme-specific priority on potency, the superior binding affinity of Ligand B is a major advantage. The negative Caco-2 and solubility values for both compounds suggest a significant formulation challenge, but Ligand B is still the more promising candidate due to its superior affinity and more plausible ADME profile.

Output:
1
2025-04-17 15:07:29,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.467 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (52.65), both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.439 and 2.428), 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 (0.795 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A (46.724) has a slightly higher DILI risk than Ligand B (6.049). This is a significant advantage for Ligand B.

**BBB:** Ligand A (45.638) has a lower BBB penetration percentile than Ligand B (83.637). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Ligand A (-5.152) has worse Caco-2 permeability than Ligand B (-4.731). Both are negative, indicating poor permeability, but B is better.

**Aqueous Solubility:** Ligand A (-2.477) has slightly better aqueous solubility than Ligand B (-2.27).

**hERG Inhibition:** Ligand A (0.279) has a lower hERG inhibition liability than Ligand B (0.687), which is a significant advantage for A.

**Microsomal Clearance:** Ligand A (12.019 mL/min/kg) has significantly lower microsomal clearance than Ligand B (26.521 mL/min/kg), indicating better metabolic stability. This is a major advantage for A.

**In vitro Half-Life:** Ligand A (10.807 hours) has a longer half-life than Ligand B (-5.189 hours). This is a substantial advantage for A.

**P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux than Ligand B (0.065), which is slightly favorable.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). While both are excellent, the 1.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and hERG risk. Ligand B has a much lower DILI risk and better BBB penetration, but these are less critical for a non-CNS target like SRC. The better metabolic stability and binding affinity of Ligand A outweigh the slightly higher DILI risk and lower BBB. The Caco-2 permeability is a concern for both, but the superior potency and PK profile of A make it the more promising candidate.

Output:
1
2025-04-17 15:07:29,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (87.74) is better than Ligand B (66.48) as it is closer to the 90 A^2 threshold for CNS targets. However, since SRC is not a CNS target, this is less critical.

**logP:** Ligand A (0.577) is a bit low, potentially hindering permeation. Ligand B (3.211) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 2/4, B: 1/4), falling within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.685, B: 0.744), indicating drug-like properties.

**DILI:** Ligand A (14.541) has a much lower DILI risk than Ligand B (38.852). This is a substantial advantage for Ligand A.

**BBB:** Both have acceptable BBB penetration, but Ligand B (70.609) is slightly better. This is not a major concern for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-5.144) has poor Caco-2 permeability, a significant drawback. Ligand B (-4.775) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.154) has poor aqueous solubility, while Ligand B (-3.264) is even worse. Both are concerning.

**hERG Inhibition:** Ligand A (0.184) has a very low hERG risk, a major advantage. Ligand B (0.611) is higher, indicating a greater potential for cardiotoxicity.

**Microsomal Clearance:** Ligand A (-1.324) exhibits better metabolic stability (lower clearance) than Ligand B (35.611). This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-0.924) has a better in vitro half-life than Ligand B (45.088).

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, while Ligand B (0.248) is slightly higher.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and a good logP value. However, it suffers from higher DILI risk, poorer metabolic stability, worse solubility, and higher P-gp efflux. Ligand A has a significantly better safety profile (DILI, hERG), better metabolic stability, and better P-gp efflux. The lower binding affinity of Ligand A is a concern, but the substantial improvements in ADME/Tox properties, particularly the low hERG risk and DILI, make it a more promising starting point for optimization. The poor solubility and Caco-2 permeability of both compounds would need to be addressed, but these are more readily optimized than inherent toxicity risks.

Output:
0
2025-04-17 15:07:29,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.555 and 366.849 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (97.55).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.561) is optimal, while Ligand B (1.463) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.476 and 0.794), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A (36.758) has a much lower DILI risk than Ligand B (59.403). This is a significant advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (73.672 and 80.264), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both are negative (-5.03 and -5.083), which is unusual and suggests very poor permeability. This is a major red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.932 and -3.226). This is a significant drawback, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.463 and 0.408), which is positive.

**Microsomal Clearance:** Ligand A (86.613) has higher microsomal clearance than Ligand B (-0.657). This means Ligand B is more metabolically stable, a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (2.218 hours) has a slightly longer half-life than Ligand A (4.179 hours), but this difference isn't substantial.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.305 and 0.027), which is favorable.

**Binding Affinity:** Both ligands have identical, strong binding affinity (-7.4 kcal/mol). This removes affinity as a differentiating factor.

**Conclusion:**

Despite both compounds having excellent binding affinity, Ligand A is the more promising candidate. Its lower DILI risk, better TPSA, and more optimal logP outweigh the slightly higher microsomal clearance and shorter half-life. The poor Caco-2 and solubility are concerning for both, and would need to be addressed through formulation or further chemical modifications. However, given the choice between these two, A is preferable.

Output:
0
2025-04-17 15:07:29,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (377.897 and 360.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is significantly better than Ligand B (93.99). A TPSA under 140 is preferred for oral absorption, and both meet this, but A is closer to the optimal range for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (3.12 and 4.25), falling within the 1-3 range, though B is slightly higher.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.889) has a much higher QED score than Ligand B (0.483), indicating a more drug-like profile.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (50.291), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.107) has a slightly better BBB percentile than Ligand B (69.833).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.011 and -5.185), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.635 and -3.387), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Ligand A (0.531) has a slightly higher hERG risk than Ligand B (0.298), but both are relatively low.

**Microsomal Clearance:** Ligand A (73.388) has a higher microsomal clearance than Ligand B (35.748), meaning it's less metabolically stable. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand B (1.907) has a much longer in vitro half-life than Ligand A (47.512). This is a strong positive for Ligand B.

**P-gp Efflux:** Ligand A (0.594) has slightly higher P-gp efflux than Ligand B (0.185).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly better binding affinity than Ligand A (-10.2 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is the better candidate. The significantly stronger binding affinity (-8.3 vs -10.2 kcal/mol) is a major advantage for an enzyme target like SRC. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic, longer half-life) and lower P-gp efflux. While Ligand A has a better QED score, the superior potency and pharmacokinetic properties of Ligand B outweigh this benefit.

Output:
1
2025-04-17 15:07:29,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.861 Da and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is better than Ligand B (72.36). Both are below 140, suggesting reasonable absorption.

**logP:** Both ligands have good logP values (2.371 and 1.765), 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=4) as it has fewer H-bonds overall, potentially aiding permeability. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.894 and 0.753), indicating good drug-like properties.

**DILI:** Ligand A (33.152) has a significantly lower DILI risk than Ligand B (25.785), which is a crucial advantage.

**BBB:** Ligand A (77.162) has a better BBB percentile than Ligand B (54.789), but this isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.523) is better than Ligand B (-4.67), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.627) is better than Ligand B (-2.585), although both are quite poor. Solubility is a concern for both, but less so than other factors.

**hERG Inhibition:** Ligand A (0.581) has a lower hERG inhibition risk than Ligand B (0.13), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-12.153) exhibits *much* lower microsomal clearance than Ligand B (36.497). This suggests significantly better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (2.39) has a shorter half-life than Ligand B (10.876). This is a drawback for Ligand A, but the superior metabolic stability may compensate.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux liability than Ligand B (0.125), which is a slight advantage.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 kcal/mol and -7.0 kcal/mol). The 0.8 kcal/mol difference is not substantial enough to override other factors.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has a longer in vitro half-life, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, lower hERG inhibition, and slightly better solubility and permeability. These factors are more critical for an enzyme inhibitor than a slightly longer half-life, especially given the strong binding affinity of both compounds.

Output:
0
2025-04-17 15:07:29,076 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.487, 71.34, 3.819, 2, 3, 0.667, 29.779, 69.446, -4.718, -3.882, 0.725, 78.366, 25.808, 0.768, -8.5]
**Ligand B:** [361.833, 93.09, 1.677, 1, 4, 0.867, 38.736, 45.366, -5.129, -3.601, 0.328, 1.525, -13.508, 0.027, -8.4]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (348.487) is slightly preferred as it's a bit lower.
2. **TPSA:** A (71.34) is better than B (93.09).  TPSA < 140 is good for oral absorption, both are acceptable, but A is better.
3. **logP:** A (3.819) is optimal, while B (1.677) is on the lower side. Lower logP can impact permeability.
4. **HBD:** Both have acceptable HBD counts (A: 2, B: 1).
5. **HBA:** Both have acceptable HBA counts (A: 3, B: 4).
6. **QED:** Both have good QED scores (A: 0.667, B: 0.867). B is slightly better here.
7. **DILI:** A (29.779) has a significantly lower DILI risk than B (38.736). This is a major advantage for A.
8. **BBB:** A (69.446) is better than B (45.366), although neither is exceptionally high. Not a huge concern for a kinase inhibitor, but a slight edge to A.
9. **Caco-2:** A (-4.718) is better than B (-5.129), indicating better intestinal absorption.
10. **Solubility:** A (-3.882) is better than B (-3.601). Solubility is important for bioavailability.
11. **hERG:** A (0.725) is better than B (0.328), indicating lower cardiotoxicity risk.
12. **Cl_mic:** A (78.366) is worse than B (1.525). B has much better metabolic stability. This is a significant advantage for B.
13. **t1/2:** A (25.808) is better than B (-13.508). A has a much longer in vitro half-life.
14. **Pgp:** A (0.768) is better than B (0.027). Lower P-gp efflux is favorable.
15. **Binding Affinity:** Both have the same binding affinity (-8.4 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both ligands have excellent binding affinity, Ligand B has a dramatically better Cl_mic, suggesting much greater metabolic stability. Ligand A has a better half-life, but the difference in Cl_mic is more impactful. Ligand A has a significantly better DILI score and hERG risk profile. Solubility is slightly better for A.

**Conclusion:**

Although Ligand B has superior metabolic stability, the lower DILI risk, better solubility, and lower hERG risk of Ligand A are critical advantages. The slightly better absorption (Caco-2) and Pgp profile of A also contribute. Given these factors, especially the safety profile, **Ligand A is the more promising drug candidate.**

1
2025-04-17 15:07:29,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.427 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is higher than Ligand B (52.65). While both are reasonably good, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Both ligands have good logP values (1.814 and 2.572), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and acceptable QED values (0.656 and 0.685).

**DILI:** Ligand A has a DILI risk of 54.207, while Ligand B has 4.459. Ligand B is significantly better regarding liver injury risk.

**BBB:** Ligand A (47.111) and Ligand B (86.08) both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.756) has poor Caco-2 permeability, while Ligand B (-4.868) is also poor. Both are similarly unfavorable.

**Aqueous Solubility:** Ligand A (-3.275) has slightly better solubility than Ligand B (-1.255), though both are quite poor.

**hERG:** Ligand A (0.169) has a slightly better hERG profile than Ligand B (0.503), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (22.968) has a significantly better (lower) microsomal clearance than Ligand B (8.416), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.328) has a very short half-life, while Ligand B (-14.033) is even worse. Both are very unfavorable.

**P-gp Efflux:** Ligand A (0.104) has lower P-gp efflux than Ligand B (0.027), which is preferable.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (0.0). This is a significant advantage.

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux, and better metabolic stability. However, Ligand B has a much lower DILI risk and a lower TPSA. The difference in binding affinity (-7.6 vs 0.0) is substantial and likely outweighs the other drawbacks of Ligand A. The poor half-life of both is a concern, but can be addressed with prodrug strategies or formulation. The DILI risk of Ligand B is concerning, but could be mitigated with further structural modifications. Given the importance of potency for kinase inhibitors, and the significant difference in binding affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 15:07:29,076 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [359.495, 56.15, 3.122, 1, 5, 0.805, 52.346, 70.686, -5.121, -3.492, 0.686, 95.753, -24.728, 0.663, -9.5]
**Ligand B:** [348.491, 86.88, 2.632, 3, 3, 0.641, 12.369, 67.701, -5.221, -2.42, 0.302, 30.212, -32.846, 0.046, -8.9]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (359.5) is slightly higher, but acceptable.
2. **TPSA:** A (56.15) is good, well below the 140 threshold. B (86.88) is higher, but still reasonable for a non-CNS target.
3. **logP:** Both are within the optimal range (1-3). A (3.122) is slightly higher, but not concerning. B (2.632) is good.
4. **HBD:** A (1) is excellent. B (3) is acceptable, but slightly less favorable.
5. **HBA:** A (5) is good. B (3) is also good.
6. **QED:** A (0.805) is excellent, indicating high drug-likeness. B (0.641) is still acceptable, but lower.
7. **DILI:** A (52.346) is good, indicating low liver injury risk. B (12.369) is *very* good, significantly lower risk. This is a major advantage for B.
8. **BBB:** Both have reasonable BBB penetration, but A (70.686) is slightly better than B (67.701). Not a primary concern for SRC kinase, which isn't a CNS target.
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 have low hERG risk, which is good. A (0.686) is slightly higher than B (0.302), but both are acceptable.
12. **Cl_mic:** A (95.753) is high, indicating rapid metabolic clearance. B (30.212) is much lower, suggesting better metabolic stability. This is a key advantage for B, given our enzyme-specific priorities.
13. **t1/2:** A (-24.728) is very short, consistent with the high Cl_mic. B (-32.846) is also short, but less so than A.
14. **Pgp:** Both have low Pgp efflux, which is good. A (0.663) is slightly higher than B (0.046).
15. **Binding Affinity:** Both have strong binding affinities (-9.5 and -8.9 kcal/mol). A is slightly better (-9.5 kcal/mol), but the difference is less than 1.5 kcal/mol, so it doesn't outweigh other factors.

**Enzyme-specific priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

*   **Affinity:** A is slightly better, but not dramatically.
*   **Metabolic Stability:** B is *significantly* better (lower Cl_mic, less negative t1/2).
*   **Solubility:** Both are poor, but this is a formulation challenge that can potentially be overcome.
*   **hERG:** Both are good.
*   **DILI:** B is significantly better.

**Conclusion:**

Despite the slightly better affinity of Ligand A, **Ligand B** is the more promising drug candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic) are critical advantages for an enzyme target like SRC kinase. While both have issues with Caco-2 and solubility, these are formulation challenges that can be addressed. The improved metabolic stability of B is more likely to translate to *in vivo* efficacy.

Output:
1
2025-04-17 15:07:29,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.409 Da and 342.399 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.53) is well below the 140 threshold, suggesting good absorption. Ligand B (95.16) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.085) is optimal. Ligand B (0.847) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.729 and 0.796), indicating drug-like properties.

**DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (54.789), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.264) has a higher BBB percentile than Ligand B (40.946).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.817 and -4.995), which is unusual and problematic. These values likely indicate issues with the assay or the compounds themselves. However, we'll proceed assuming these are relative measurements and lower values are worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.615 and -3.53), which is also concerning. Poor solubility can significantly hinder bioavailability.

**hERG:** Ligand A (0.782) has a slightly higher hERG risk than Ligand B (0.279), but both are relatively low.

**Microsomal Clearance:** Ligand B (23.004) has a significantly lower microsomal clearance than Ligand A (14.907), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-22.366) has a negative half-life, which is impossible. This is a major red flag. Ligand A (58.716) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.558) has lower P-gp efflux liability than Ligand B (0.038), which is favorable.

**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, potentially outweighing some ADME concerns.

**Conclusion:**

Despite the problematic Caco-2 and solubility values for both compounds, Ligand B stands out due to its superior binding affinity (-9.4 kcal/mol vs -7.9 kcal/mol) and better metabolic stability (lower Cl_mic). The significantly stronger binding is a major factor for an enzyme inhibitor. While the negative half-life is a serious issue, it is likely an experimental error. The lower P-gp efflux and DILI are also positives. Ligand A has a better hERG profile, but the difference isn't substantial enough to overcome the affinity and stability advantages of Ligand B.

Output:
1
2025-04-17 15:07:29,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (383.901 and 357.47 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.44) is slightly above the preferred <140, but acceptable. Ligand B (61.88) is well within the acceptable range.

**3. logP:** Ligand A (3.367) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.058) is at the very low 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 HBAs, and Ligand B has 4, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.758 and 0.772), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 60.682, which is borderline high. Ligand B has a very low DILI risk of 5.894, which is excellent.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (31.136) and Ligand B (83.831) are not particularly relevant here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.993 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 disqualify the compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.249 and -1.12), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.287) has a slightly elevated hERG risk, while Ligand B (0.479) is also concerning. Both need further investigation.

**12. Microsomal Clearance:** Ligand A (76.395) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-10.467) 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 (58.569) has a moderate half-life. Ligand B (-5.844) has a negative half-life, which is impossible and indicates a data issue.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.175 and 0.004), which is favorable.

**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 crucial difference.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much stronger binding affinity. However, the negative values for Cl_mic and t1/2 are red flags, suggesting data errors. Ligand A has more reasonable (though not ideal) ADME properties, but very weak binding.

Given the significant difference in binding affinity and the questionable ADME data for Ligand B, and prioritizing potency for an enzyme target, I would cautiously favor Ligand A, *assuming* the negative values for Ligand B are data errors. The weak binding of Ligand A is a major drawback, but it's a more reliable starting point than a compound with impossible ADME properties. Further investigation and data validation are critical for both compounds.

Output:
0
2025-04-17 15:07:29,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (340.467 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (94.88). A TPSA below 140 is preferred for oral absorption, and both are within this range, but A is more favorable.

**3. logP:** Both ligands have acceptable logP values (3.325 and 2.681, respectively) falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands have a reasonable number of HBDs (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (4), both are below the threshold of 10.

**6. QED:** Ligand A (0.855) has a significantly higher QED score than Ligand B (0.682), indicating better overall drug-likeness.

**7. DILI:** Ligand A (25.126) has a much lower DILI risk than Ligand B (41.644), which is a crucial advantage. Both are below the 60 threshold, but A is significantly better.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (70.997) is better than Ligand B (50.872).

**9. Caco-2 Permeability:** Ligand A (-4.403) is better than Ligand B (-4.929). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-4.689) is better than Ligand B (-3.267). Higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.439 and 0.396, respectively).

**12. Microsomal Clearance:** Ligand B (46.548) has a lower microsomal clearance than Ligand A (70.202), suggesting better metabolic stability. This is a significant advantage for B.

**13. In vitro Half-Life:** Ligand B (30.805) has a much longer in vitro half-life than Ligand A (-3.259), which is a major advantage.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.314 and 0.124, respectively).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are critical for an enzyme inhibitor. While Ligand A has better QED, DILI, solubility, and TPSA, the potency and metabolic stability advantages of Ligand B are more important for this target class. The difference in binding affinity (-8.2 vs -9.0) is substantial.

Output:
1
2025-04-17 15:07:29,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.47 Da) is slightly higher than Ligand B (342.399 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is well below the 140 threshold for oral absorption. Ligand B (84.42) is also below, but closer to the limit.

**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 (1.064) is slightly below the optimal range, which could affect permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 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: 0.709, Ligand B: 0.885), indicating drug-like properties.

**DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (52.036), but both are still within an acceptable range (<60 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.488) has a higher BBB score than Ligand A (59.325).

**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 (-5.808 and -1.606 respectively). This is a significant concern.

**hERG Inhibition:** Ligand A (0.775) has a slightly higher hERG risk than Ligand B (0.12), but both are relatively low.

**Microsomal Clearance:** Ligand A (118.214) has significantly higher microsomal clearance than Ligand B (23.191), indicating lower metabolic stability. This is a major drawback.

**In vitro Half-Life:** Ligand A (3.684) has a shorter half-life than Ligand B (1.369), consistent with the higher clearance.

**P-gp Efflux:** Ligand A (0.524) has lower P-gp efflux than Ligand B (0.032), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 kcal/mol). This >1.5 kcal/mol difference is very significant and can outweigh many ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the better candidate. The significantly stronger binding affinity (-9.1 vs -7.6 kcal/mol) is a crucial advantage for an enzyme inhibitor. While Ligand A has slightly better P-gp efflux, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk are more important for an enzyme target. The solubility issue would need to be addressed through formulation strategies, but the potency and metabolic properties of Ligand B make it the more promising starting point.

Output:
1
2025-04-17 15:07:29,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.291 Da) and Ligand B (350.419 Da) are comparable.

**TPSA:** Ligand A (55.84) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (113.44) is still acceptable, but less optimal.

**logP:** Ligand A (2.303) is within the optimal range (1-3). Ligand B (0.059) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher HBD can sometimes impact permeability.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is also acceptable.

**QED:** Both ligands have reasonable QED scores, Ligand A (0.469) and Ligand B (0.641). Ligand B is slightly better here.

**DILI:** Ligand A (70.88) is moderately high, indicating a potential liver toxicity risk. Ligand B (46.219) is much better, suggesting a lower risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.672) is higher than Ligand B (43.156).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.377 and -4.96), which is unusual and suggests poor permeability *in vitro*. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.929 and -1.323). This is also a major concern, indicating very poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.418 and 0.079). This is positive.

**Microsomal Clearance:** Ligand A (48.594) has a higher clearance than Ligand B (7.427), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-7.953) has a longer half-life than Ligand A (-13.496), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.134 and 0.01).

**Binding Affinity:** Both ligands have identical binding affinity (-8.7 kcal/mol), which is excellent.

**Conclusion:**

Despite the equal binding affinity, Ligand B is the more promising candidate. Ligand B has a significantly better DILI score, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. While both have poor Caco-2 and solubility, the ADME profile of Ligand B is superior overall, making it more likely to succeed as a drug candidate. The low logP of Ligand B is a concern, but the strong binding affinity might compensate for this.

Output:
1
2025-04-17 15:07:29,077 - INFO - Batch 353 complete. Total preferences: 5648
2025-04-17 15:07:29,077 - INFO - Processing batch 354/512...
2025-04-17 15:08:09,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.382 and 357.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.19) is higher than Ligand B (78.51). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Ligand A (-0.439) is slightly low, potentially hindering permeability. Ligand B (1.22) 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 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.668 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (38.581). This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (76.541 and 78.209). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.185 and -4.867), 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 (-2.307 and -2.573), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.227 and 0.269).

**Microsomal Clearance:** Ligand A (-7.141) has a lower (better) microsomal clearance than Ligand B (-3.154), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.04) has a longer half-life than Ligand B (-13.391), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.017).

**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 is still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. It has a more favorable logP, a significantly lower DILI risk, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the improved metabolic stability and lower DILI risk of Ligand B outweigh the slightly better half-life of Ligand A. The binding affinity difference is also a plus.

Output:
1
2025-04-17 15:08:09,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.458 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.49) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (104.71) is still under 140, but less optimal.

**logP:** Ligand A (3.735) is at the higher end of the optimal 1-3 range, while Ligand B (2.142) is closer to the lower end. Both are acceptable, but Ligand A's higher logP *could* lead to off-target effects, something to consider.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, well within the guidelines. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.882) has a very strong drug-like profile. Ligand B (0.678) is still reasonable, but less optimal.

**DILI:** Ligand A (63.862) is moderately risky, while Ligand B (48.43) has a lower DILI risk, which is a significant advantage.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC kinase, but Ligand A (66.77) is better than Ligand B (32.454).

**Caco-2 Permeability:** Ligand A (-4.667) and Ligand B (-5.086) both have negative values, which is unusual and suggests very poor permeability. This is a major red flag for both.

**Aqueous Solubility:** Ligand A (-4.731) and Ligand B (-2.044) both have negative values, indicating poor solubility. This is another significant drawback for both.

**hERG:** Ligand A (0.939) has a slightly higher hERG risk than Ligand B (0.33), making B preferable.

**Microsomal Clearance:** Both ligands have similar and relatively low Cl_mic values (32.554 and 31.327 mL/min/kg), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (85.146) has a significantly longer half-life than Ligand B (38.678), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.505 and 0.153), which is good.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial difference (over 1.9 kcal/mol) and likely outweighs many of the ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a longer half-life, which are critical for an enzyme inhibitor. While it has a higher logP and DILI risk, and poor solubility/permeability, the strong binding affinity is a major driver. Ligand B has better DILI and hERG profiles, but its significantly weaker binding affinity is a major drawback. The poor solubility and permeability are concerning for both, but can potentially be addressed with formulation strategies. Given the potency advantage of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 15:08:09,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 350.415 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (79.31). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range for oral bioavailability.

**logP:** Ligand A (1.335) is within the optimal 1-3 range. Ligand B (-0.212) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Ligand A (0.812) has a better QED score than Ligand B (0.71), indicating a more drug-like profile.

**DILI:** Ligand A (20.9) has a significantly lower DILI risk than Ligand B (30.826), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.164) is better than Ligand B (50.679).

**Caco-2 Permeability:** Both have negative values (-4.846 and -4.757), 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 values (-1.469 and -1.171), again suggesting poor solubility. Similar to Caco-2, the difference isn't substantial.

**hERG Inhibition:** Ligand A (0.189) has a much lower hERG risk than Ligand B (0.127), which is a critical safety parameter.

**Microsomal Clearance:** Ligand A (9.74) has significantly lower microsomal clearance than Ligand B (21.122), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.589) has a better in vitro half-life than Ligand B (18.359).

**P-gp Efflux:** Both have low P-gp efflux liability (0.041 and 0.028).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme target.

**Overall:**

Ligand A is clearly superior. It has a significantly higher binding affinity, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), a better QED score, and a more favorable logP. While both have issues with Caco-2 and solubility, the strong affinity and improved safety/ADME profile of Ligand A outweigh these concerns. The substantial difference in binding affinity (-9.4 vs 0.0 kcal/mol) is a decisive advantage.

Output:
1
2025-04-17 15:08:09,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.49 and 391.877 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.81) is well below the 140 threshold, suggesting good absorption. Ligand B (110.53) is still within acceptable limits, but less favorable.

**3. logP:** Both ligands have good logP values (2.039 and 1.243), 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 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.836 and 0.754), indicating good drug-likeness.

**7. DILI:** Ligand A (20.822) has a significantly lower DILI risk than Ligand B (86.933). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (43.854) and Ligand B (55.913) are both relatively low.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.074 and -5.195), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.415 and -3.438), indicating very poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**11. hERG Inhibition:** Ligand A (0.784) has a lower hERG risk than Ligand B (0.224), which is preferable.

**12. Microsomal Clearance:** Ligand A (3.049) has a much lower microsomal clearance than Ligand B (41.477), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (30.937) has a much longer in vitro half-life than Ligand B (-16.471), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux liability than Ligand B (0.207), which is slightly favorable.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly in terms of DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and hERG risk. The poor solubility and permeability are concerns for both, but the other advantages of Ligand A outweigh the small binding affinity difference.

Output:
0
2025-04-17 15:08:09,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.304 Da) is slightly higher than Ligand B (335.451 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (47.56) is slightly higher than Ligand B (45.23), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.349) is a bit high, potentially leading to solubility issues or off-target interactions, while Ligand B (3.454) is better.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.871) is slightly better than Ligand A (0.779).

**DILI:** Ligand A has a significantly higher DILI risk (65.103) compared to Ligand B (21.791). This is a major concern for Ligand A.

**BBB:** BBB is less crucial for a non-CNS target like SRC kinase. Ligand B (87.864) has a higher BBB score than Ligand A (57.154), but this is not a primary concern.

**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.

**hERG:** Both ligands have low hERG inhibition liability, which is good. Ligand B (0.79) is slightly higher than Ligand A (0.713), but both are acceptable.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (72.9 mL/min/kg) than Ligand B (27.089 mL/min/kg). This suggests Ligand B is more metabolically stable, which is a key consideration for enzymes.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (18.758 hours) than Ligand A (82.203 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability, which is good. Ligand A (0.747) is slightly higher than Ligand B (0.221).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). However, the difference is only 0.2 kcal/mol, which is not substantial enough to outweigh the significant ADME drawbacks of Ligand A.

**Overall:**

Ligand B is the more promising candidate. While both have some issues with Caco-2 and solubility, Ligand B has significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slightly better binding affinity of Ligand A is not enough to compensate for its poorer ADME profile, especially the high DILI risk.

Output:
1
2025-04-17 15:08:09,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, but both are acceptable.

**TPSA:** Ligand A (91.22) is slightly higher than Ligand B (78.43). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 1.508, B: 1.957), 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (A: 0.79, B: 0.653), indicating good drug-like properties.

**DILI:** Ligand A (33.695) has a significantly lower DILI risk than Ligand B (42.807). This is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.97) is lower than Ligand B (52.501).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.046) is slightly better than Ligand B (-5.188), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.474) is slightly better than Ligand B (-2.324).

**hERG:** Both ligands have low hERG risk (A: 0.352, B: 0.24), which is excellent.

**Microsomal Clearance:** Ligand A (29.252 mL/min/kg) has significantly lower microsomal clearance than Ligand B (70.376 mL/min/kg). This suggests better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (14.453 hours) has a shorter half-life than Ligand B (31.689 hours), but still acceptable.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.062, B: 0.099).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference is not huge, it's a positive point for Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a lower DILI risk, significantly better metabolic stability (lower Cl_mic), and slightly better binding affinity. While both have poor Caco-2 and solubility, the metabolic stability and safety profile of Ligand A are more critical for an enzyme target like SRC. The slightly better affinity further supports this conclusion.

Output:
0
2025-04-17 15:08:09,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.511 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is better than Ligand B (73.64), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (3.227 and 2.048, respectively) within the 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 (0.791 and 0.778), indicating good drug-likeness.

**DILI:** Ligand A (46.375) has a higher DILI risk than Ligand B (22.024). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (70.105 and 79.566). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.904 and -4.166). These are unusual and suggest poor permeability. However, these values are on a log scale, and negative values are common. The values are relatively close.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.58 and -2.252). Again, these are on a log scale, and negative values indicate poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.519 and 0.47), which is good.

**Microsomal Clearance:** Ligand A (55.119) has lower microsomal clearance than Ligand B (60.099), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand B (-9.528) has a significantly longer in vitro half-life than Ligand A (5.365). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.565 and 0.127). Ligand B is better.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference is not huge, it is above the 1.5 kcal/mol threshold that can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a significantly lower DILI risk and a much longer half-life, which are crucial for drug development. It also has better P-gp efflux and solubility. Ligand A has better metabolic stability (lower Cl_mic) and slightly better binding affinity. However, the improvements in DILI and half-life for Ligand B are more impactful for overall drug viability. The binding affinity difference is relatively small.

Output:
1
2025-04-17 15:08:09,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.443 and 350.365 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.67) is slightly higher than Ligand B (71.34). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.693 and 2.482), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.876 and 0.768), indicating good drug-like properties.

**DILI:** Ligand A (80.225) has a higher DILI risk than Ligand B (52.113). This is a significant concern, as lower DILI is preferred.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (83.249) is slightly better than Ligand B (77.976). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.951 and -4.664). This is unusual and suggests poor permeability. The values are close enough that this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.976 and -3.309). This is also concerning and suggests poor solubility. Again, the values are close.

**hERG Inhibition:** Ligand A (0.203) has a slightly lower hERG inhibition liability than Ligand B (0.814), which is preferable.

**Microsomal Clearance:** Ligand A (-4.707) has a significantly lower (better) microsomal clearance than Ligand B (35.04). This indicates better metabolic stability, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (45.781) has a longer in vitro half-life than Ligand B (42.447). This is also a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.073 and 0.366), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have strong binding affinity, Ligand A is significantly better regarding metabolic stability (lower Cl_mic) and has a longer half-life. It also has a lower DILI risk and slightly lower hERG risk. Although Ligand A has a slightly higher TPSA, the benefits in ADME and toxicity outweigh this minor drawback. The solubility and Caco-2 permeability are poor for both, but this can be addressed through formulation strategies.

Output:
1
2025-04-17 15:08:09,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.507 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.04) is better than Ligand B (92.5), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (3.769) is optimal, while Ligand B (1.157) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands (4) are well within the acceptable limit of 10.

**QED:** Both ligands (0.654 and 0.679) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (17.72) has a significantly lower DILI risk than Ligand B (18.922), both are good.

**BBB:** Ligand A (76.851) has better BBB penetration than Ligand B (68.941), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-5.089) has slightly better Caco-2 permeability than Ligand B (-5.725).

**Aqueous Solubility:** Ligand A (-2.697) has better aqueous solubility than Ligand B (-1.507).

**hERG Inhibition:** Ligand A (0.835) has a lower hERG inhibition liability than Ligand B (0.269), which is a significant advantage.

**Microsomal Clearance:** Ligand A (29.2) has higher microsomal clearance than Ligand B (3.719), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-19.85) has a longer in vitro half-life than Ligand A (-17.9), which is a positive.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.08), which is a positive.

**Binding Affinity:** Ligand B (-8.7 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 of Ligand B.

**Overall Assessment:**

Ligand B has a substantially better binding affinity (-8.7 vs -6.9 kcal/mol). While Ligand A has better solubility, lower hERG risk, and better P-gp efflux, the potency advantage of Ligand B is significant for an enzyme target like SRC kinase. The improved metabolic stability (lower Cl_mic, longer t1/2) of Ligand B is also a positive. The slightly lower logP and Caco-2 permeability of Ligand B are concerns, but may be addressable through further optimization without sacrificing potency.

Output:
1
2025-04-17 15:08:09,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.375 and 377.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (97.11 and 91.22) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.213) is quite low, potentially hindering permeation. Ligand B (2.935) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (0) is ideal, while Ligand B (2) is acceptable.

**H-Bond Acceptors:** Ligand A (7) and Ligand B (6) are both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.664 and 0.81), indicating drug-likeness.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (79.682), but both are above the preferred threshold of <40.

**BBB:** Ligand A (71.772) has better BBB penetration than Ligand B (16.053), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.541) has poor Caco-2 permeability, while Ligand B (-5.008) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-0.996) has poor solubility, while Ligand B (-4.964) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.143) has a very low hERG risk, which is excellent. Ligand B (0.558) has a moderate hERG risk. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (85.834) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (47.387) has lower clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (11.359) has a shorter half-life than Ligand B (56.83), indicating faster metabolism. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.041) has very low P-gp efflux, which is good. Ligand B (0.443) has moderate P-gp efflux. This favors Ligand A.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 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 better metabolic stability (lower Cl_mic, longer t1/2) and a more optimal logP. While its solubility and Caco-2 permeability are poor, its binding affinity is strong enough to potentially overcome these issues through formulation strategies. Ligand A has better hERG and P-gp profiles, but its very low logP and poor Caco-2 permeability are major concerns. The difference in binding affinity (-7.8 vs -8.3) is substantial.

Output:
1
2025-04-17 15:08:09,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.379 Da and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (139.78) is close to the upper limit for good oral absorption (<=140), while Ligand B (58.64) is well below, suggesting potentially better absorption.

**logP:** Ligand A (-2.602) is a bit low, potentially hindering permeation. Ligand B (2.489) 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 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.491 and 0.769), indicating drug-like properties, with Ligand B being slightly better.

**DILI:** Ligand A (39.511) has a slightly higher DILI risk than Ligand B (6.747), though both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (77.898) has a higher BBB percentile, but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.882) shows poor permeability, while Ligand B (-4.767) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.553) shows poor solubility, while Ligand B (-2.211) is also poor. Solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.032) has very low hERG inhibition risk, which is excellent. Ligand B (0.368) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-12.241) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (20.041). This is a major advantage.

**In vitro Half-Life:** Ligand A (12.311) has a longer half-life than Ligand B (-2.248), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable. Ligand B (0.062) is slightly higher, but still low.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.4 kcal/mol and -6.8 kcal/mol). Ligand A has a substantial advantage in binding affinity (1.6 kcal/mol) which can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's lower logP and solubility, its significantly superior binding affinity (-8.4 vs -6.8 kcal/mol) and substantially better metabolic stability (lower Cl_mic and longer t1/2) make it the more promising candidate. The lower hERG risk and P-gp efflux are also beneficial. While solubility and logP are concerns, these can potentially be addressed through formulation strategies or further chemical modifications, but regaining 1.6 kcal/mol in binding affinity is much more challenging.

Output:
0
2025-04-17 15:08:09,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 360.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (78.35) is well within the ideal range.

**logP:** Both ligands (1.781 and 2.472) are 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.875) has a significantly better QED score than Ligand A (0.47), indicating a more drug-like profile.

**DILI:** Ligand A (46.452) has a lower DILI risk than Ligand B (55.68), both are acceptable but A is preferred.

**BBB:** Both ligands have low BBB penetration (27.181 and 35.13), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.997 and -5.282), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.422 and -3.873), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.379 and 0.412), which is good.

**Microsomal Clearance:** Ligand A (24.49) has a much lower microsomal clearance than Ligand B (63.564), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.577) has a negative half-life, which is not possible. Ligand B (-7.602) also has a negative half-life, which is not possible. This is a major issue for both compounds.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.055), which is favorable.

**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.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, the negative half-life values for both compounds are a critical flaw. However, Ligand A has better metabolic stability (lower Cl_mic) and a lower DILI risk. The QED score of Ligand B is much better, suggesting a more generally drug-like structure. The poor solubility and permeability are major concerns for both. Given the enzyme-specific priorities, metabolic stability is crucial.

Considering all factors, and acknowledging the problematic half-life values, Ligand A is marginally better due to its improved metabolic stability and lower DILI risk, despite its lower QED score. The slightly better affinity of B is not enough to overcome the other drawbacks.

Output:
0
2025-04-17 15:08:09,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.434 and 368.865 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (97.55). For good oral absorption, we want TPSA <= 140, both are under this threshold, but A is preferable.

**logP:** Both ligands (1.421 and 1.734) are within the optimal 1-3 range.

**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 under the acceptable limit of 10, but A is preferable.

**QED:** Ligand A (0.562) is slightly better than Ligand B (0.484), indicating a more drug-like profile. Both are above the 0.5 threshold.

**DILI:** Ligand A (15.936) has a much lower DILI risk than Ligand B (48.623). This is a significant advantage for Ligand A.

**BBB:** Ligand A (77.317) has better BBB penetration than Ligand B (68.088), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-4.907 and -5.064). This is unusual and suggests poor permeability. However, the values are similar.

**Solubility:** Both have negative solubility values (-2.235 and -2.492), which is also unusual and suggests poor aqueous solubility. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition risk (0.397 and 0.473).

**Microsomal Clearance:** Ligand A (-16.313) has *much* lower microsomal clearance than Ligand B (39.073). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-9.123) has a longer in vitro half-life than Ligand B (33.262), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.069 and 0.052).

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.5). However, the difference is only 0.2 kcal/mol, which is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior drug-like properties across multiple critical ADME parameters. Specifically, its lower DILI risk, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and better QED score make it a more viable option. The similar Caco-2 and solubility values are a concern for both, but the other advantages of A outweigh this.

Output:
0
2025-04-17 15:08:09,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (333.351 and 348.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.81) is well below the 140 threshold, while Ligand B (131.06) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (2.129) is within the optimal 1-3 range. Ligand B (-1.861) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, both acceptable. Ligand B has 2 HBD and 9 HBA, the latter being higher, but still within the reasonable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.491 and 0.6), indicating acceptable drug-likeness.

**DILI:** Ligand A has a DILI risk of 94.765, which is high. Ligand B has a DILI risk of 66.654, which is also elevated but lower than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (33.23) and Ligand B (21.946) both have low BBB penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.479 and -5.643), which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.675 and -1.064), indicating very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.476) has a slightly higher hERG risk than Ligand B (0.023), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (2.367) has a lower clearance than Ligand B (-2.864), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (71.94) has a much longer half-life than Ligand B (15.968), which is a major advantage.

**P-gp Efflux:** Ligand A (0.238) has lower P-gp efflux than Ligand B (0.013), which is beneficial.

**Binding Affinity:** Ligand A (-10.1 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:**

Ligand A has a much better binding affinity and longer half-life, and lower P-gp efflux, which are crucial for an enzyme inhibitor. However, it has a very high DILI risk and poor solubility. Ligand B has a better hERG profile and slightly better DILI, but weaker binding affinity, poor solubility, and a shorter half-life.

Given the importance of potency for kinase inhibitors, the significantly stronger binding affinity of Ligand A (-10.1 vs -7.0 kcal/mol) is the deciding factor. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The poor solubility is also a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:08:09,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.391 Da and 361.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.02) is slightly above the optimal <140 for good absorption, but still reasonable. Ligand B (70.16) is excellent, well below 140.

**logP:** Ligand A (1.654) is within the optimal 1-3 range. Ligand B (-0.009) is slightly below 1, which *could* indicate permeability issues, but is not drastically low.

**H-Bond Donors:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (6) is within the acceptable limit of <=10. Ligand B (4) is also good.

**QED:** Both ligands have acceptable QED values (0.759 and 0.667, both > 0.5).

**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:** This is less critical for a non-CNS target like SRC. Ligand B (76.347) has a higher BBB percentile than Ligand A (52.074).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.408 and -4.441), which is unusual and suggests potential issues with the assay or the compounds themselves. It is difficult to interpret these values without further information.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.375 and -0.655), which is also unusual and suggests potential issues with the assay or the compounds themselves. It is difficult to interpret these values without further information.

**hERG Inhibition:** Ligand A (0.333) has a slightly higher hERG risk than Ligand B (0.141), but both are relatively low.

**Microsomal Clearance:** Ligand A (15.56) has a lower microsomal clearance than Ligand B (17.426), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-9.171) has a much longer in vitro half-life than Ligand B (0.184). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.025).

**Binding Affinity:** Ligand A (-6.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the significantly stronger binding affinity (-6.8 vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) of Ligand A make it the more promising drug candidate. The slightly higher DILI and hERG risks are less concerning given the substantial potency advantage.

Output:
1
2025-04-17 15:08:09,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.337 Da and 361.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold for good absorption. Ligand B (88.09) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.576) is optimal. Ligand B (2.072) is slightly lower, but still within the acceptable 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 2 HBA) is ideal. Ligand B (2 HBD, 9 HBA) is acceptable, though the higher HBA count could slightly affect permeability.

**QED:** Both ligands have similar QED values (0.693 and 0.691), indicating good drug-likeness.

**DILI:** Ligand A (41.218) has a much lower DILI risk than Ligand B (78.907), which is a significant advantage.

**BBB:** Ligand A (98.139) shows excellent BBB penetration, while Ligand B (66.615) is lower. While SRC isn't necessarily a CNS target, good BBB penetration isn't detrimental.

**Caco-2 Permeability:** Ligand A (-4.499) is poor, while Ligand B (-5.247) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.655 and -3.122 respectively). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG risk (0.687 and 0.587).

**Microsomal Clearance:** Ligand A (30.079 mL/min/kg) has significantly lower microsomal clearance than Ligand B (59.948 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.055 hours) has a longer half-life than Ligand B (22.702 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.206 and 0.076).

**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.

**Conclusion:**

While Ligand A has better overall ADME properties (lower DILI, better metabolic stability, better BBB penetration), the significantly stronger binding affinity of Ligand B (-7.5 vs -9.3 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. A 1.8 kcal/mol difference in binding is substantial and can often compensate for moderate ADME liabilities, especially if formulation strategies can address the solubility issues.

Output:
1
2025-04-17 15:08:09,047 - INFO - Batch 354 complete. Total preferences: 5664
2025-04-17 15:08:09,047 - INFO - Processing batch 355/512...
2025-04-17 15:08:57,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.6) is slightly higher than Ligand B (344.4).

**TPSA:** Ligand A (72.5) is better than Ligand B (87.5) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (3.63) is optimal, while Ligand B (0.179) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands are within the acceptable limit of <=5. Ligand A has 1 HBD, and Ligand B has 2.

**H-Bond Acceptors:** Both ligands are within the acceptable limit of <=10. Ligand A has 6 HBA, and Ligand B has 5.

**QED:** Both ligands have good QED scores (A: 0.666, B: 0.798), indicating drug-like properties.

**DILI:** Ligand B (33.5) has a significantly lower DILI risk than Ligand A (85.1). This is a major advantage for Ligand B.

**BBB:** Ligand B (72.9) shows better BBB penetration than Ligand A (21.2), but this is less critical for a kinase inhibitor unless CNS involvement is specifically desired.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.094) is slightly worse than Ligand B (-4.994).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.684) is slightly worse than Ligand B (-2.032).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.147, B: 0.228), which is excellent.

**Microsomal Clearance:** Ligand B (6.681) has much lower microsomal clearance than Ligand A (59.627), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (12.984) has a longer half-life than Ligand A (36.968), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.255, B: 0.045), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.6 kcal/mol). Ligand B is slightly better (-8.6 kcal/mol).

**Conclusion:**

While both ligands exhibit strong binding affinity, Ligand B is the superior candidate. Its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity outweigh the slightly lower logP and solubility. The lower logP is a concern, but can potentially be addressed through further optimization without sacrificing the favorable metabolic properties.

Output:
1
2025-04-17 15:08:57,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.381 and 359.543 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (55.57) is slightly higher than Ligand B (46.84). Both are below the 140 threshold for good absorption, but lower is generally better.

**3. logP:** Both ligands have good logP values (4.005 and 3.308), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBDs, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are below the 10 threshold.

**6. QED:** Ligand A (0.72) has a better QED score than Ligand B (0.526), indicating a more drug-like profile.

**7. DILI:** Ligand B (22.761) has a significantly lower DILI risk than Ligand A (40.636). This is a major advantage for Ligand B.

**8. BBB:** Both have high BBB penetration, but Ligand B (96.937) is higher than Ligand A (84.374). While not a primary concern for a kinase inhibitor, higher BBB is never a disadvantage.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and could indicate issues with the prediction method. However, Ligand B (-5.668) is slightly better than Ligand A (-4.202).

**10. Aqueous Solubility:** Ligand B (-3.482) has slightly better aqueous solubility than Ligand A (-4.51).

**11. hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.639 and 0.743).

**12. Microsomal Clearance:** Ligand B (62.434) has a slightly higher microsomal clearance than Ligand A (59.429), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-8.505) has a significantly longer in vitro half-life than Ligand A (-4.742). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.22 and 0.679).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.1 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better QED and is more metabolically stable, Ligand B has a significantly lower DILI risk and a longer half-life. Given the enzyme-specific priorities, the lower DILI risk and longer half-life of Ligand B are more important than the slightly better metabolic stability of Ligand A. The binding affinity is identical, so that doesn't differentiate them.

Output:
1
2025-04-17 15:08:57,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.852 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (78.51). Lower TPSA generally correlates with better cell permeability, which is beneficial.

**logP:** Both ligands have acceptable logP values (2.728 and 1.689), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (1 & 2) and HBA (3 & 3) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.832 and 0.791), indicating good drug-like properties.

**DILI:** Ligand A (33.501) has a much lower DILI risk than Ligand B (20.822), which is a significant advantage. Lower DILI is crucial.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (86.041) has a higher BBB percentile than Ligand B (56.805).

**Caco-2 Permeability:** Ligand A (-5.135) has a slightly better (less negative) Caco-2 value than Ligand B (-4.924), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.297) has a slightly better (less negative) solubility value than Ligand B (-2.627).

**hERG:** Both ligands have very low hERG inhibition liability (0.316 and 0.11), which is excellent.

**Microsomal Clearance:** Ligand A (8.243) has a lower microsomal clearance than Ligand B (9.577), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-8.879) has a better (more negative) in vitro half-life than Ligand A (-4.321), indicating a longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.037).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are good, the 1.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a significantly lower DILI risk, better TPSA, better solubility, better metabolic stability (lower Cl_mic), and a substantially stronger binding affinity. While Ligand B has a slightly longer half-life, the other advantages of Ligand A are more critical for an enzyme inhibitor targeting oncology. The improved potency and safety profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 15:08:57,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.865 and 366.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.31) is better than Ligand B (88.93), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.068) is optimal, while Ligand B (1.678) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Both have 7 HBA, which is acceptable.

**QED:** Ligand A (0.842) has a significantly better QED score than Ligand B (0.688), indicating a more drug-like profile.

**DILI:** Ligand A (43.234) has a lower DILI risk than Ligand B (54.556), both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (85.459) is better than Ligand B (52.074).

**Caco-2:** Ligand A (-4.883) is better than Ligand B (-5.246), indicating better intestinal absorption.

**Solubility:** Ligand A (-3.421) is better than Ligand B (-3.031), indicating better aqueous solubility.

**hERG:** Ligand A (0.784) has a lower hERG risk than Ligand B (0.424), which is favorable.

**Microsomal Clearance:** Ligand A (44.075) has lower microsomal clearance than Ligand B (63.613), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.144) has a longer in vitro half-life than Ligand B (9.989), which is desirable.

**P-gp:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.143), which is favorable.

**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 (1.7 kcal/mol).

**Overall Assessment:**

Ligand B possesses a significantly stronger binding affinity, which is the most important factor for an enzyme target. While Ligand A has superior ADME properties (QED, solubility, metabolic stability, hERG, P-gp efflux), the difference in binding affinity is large enough to outweigh these benefits. The slightly lower logP of Ligand B is a minor concern, but can be addressed through further optimization.

Output:
1
2025-04-17 15:08:57,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (348.475 and 370.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (42.74) is well below the 140 threshold and favorable for oral absorption. Ligand B (74.76) is also below the threshold, but higher than A.

**3. logP:** Ligand A (4.217) is slightly above the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (1.761) is within the optimal range.

**4. H-Bond Donors (HBD):** Ligand A (1) and Ligand B (0) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.587) is good, exceeding the 0.5 threshold. Ligand B (0.482) is slightly below, indicating a less drug-like profile.

**7. DILI:** Ligand A (58.511) has a moderate DILI risk. Ligand B (35.13) has a lower, more favorable DILI risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.733) shows better BBB penetration than Ligand A (57.619).

**9. Caco-2 Permeability:** Ligand A (-5.425) and Ligand B (-4.825) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.359) and Ligand B (-1.744) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.871) has a slightly higher hERG risk than Ligand B (0.311), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand B (15.336) has significantly lower microsomal clearance than Ligand A (41.634), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand B (13.969) has a longer half-life than Ligand A (3.363), which is desirable.

**14. P-gp Efflux:** Ligand A (0.72) has higher P-gp efflux than Ligand B (0.221), meaning B will have better bioavailability.

**15. Binding Affinity:** Ligand B (-8.7 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:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the superior candidate. While Ligand A has a slightly better TPSA and QED, Ligand B's significantly stronger binding affinity, lower DILI risk, lower Cl_mic, longer half-life, lower P-gp efflux, and lower hERG risk are more important. The slightly higher logP of Ligand A is a concern, and the much better affinity of Ligand B outweighs the slightly lower QED.

Output:
1
2025-04-17 15:08:57,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403 Da) is slightly lower than Ligand B (369.487 Da), which is not a significant difference.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (92.51) is better than Ligand A (102.16).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (1.121) is slightly lower than Ligand A (1.673), which could slightly reduce permeability, but both are acceptable.

**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 QED values above 0.5, indicating good drug-like properties. Ligand A (0.826) is slightly better than Ligand B (0.704).

**DILI:** Ligand A has a DILI risk of 70.26%, which is considered high risk. Ligand B has a significantly lower DILI risk of 25.514%, which is good. This is a major advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Both are reasonably high, with Ligand A at 62.699% and Ligand B at 60.876%.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.726) is slightly better than Ligand B (-5.226), but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-0.952) is slightly better than Ligand A (-3.316).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.237 and 0.163 respectively), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (26.409 and 26.201 mL/min/kg), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand B (-13.803 hours) has a significantly longer half-life than Ligand A (-28.563 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.176 and 0.055 respectively).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be offset by other factors.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, Ligand B is the more promising candidate. Its significantly lower DILI risk, longer half-life, and slightly better solubility outweigh the small difference in binding affinity. The poor Caco-2 permeability is a concern for both, but can be addressed through formulation strategies. Given the enzyme-specific priorities, the lower DILI and better metabolic stability (longer half-life) of Ligand B make it the superior choice.

Output:
1
2025-04-17 15:08:57,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 350.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.2) is slightly above the preferred <90 for CNS targets, but acceptable for a non-CNS focused kinase inhibitor. Ligand B (85.77) is excellent, well below 90.

**logP:** Ligand A (-0.396) is a bit low, potentially hindering permeability. Ligand B (0.533) is better, falling within the 1-3 optimal range.

**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 (0.749 and 0.679), indicating drug-like properties.

**DILI:** Ligand A (34.161) has a significantly lower DILI risk than Ligand B (19.659), a major advantage.

**BBB:** Not a primary concern for a non-CNS target. Ligand B (33.501) has higher BBB penetration than Ligand A (18.147), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.207 and -4.906), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.707 and -1.09), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Both ligands have low hERG risk (0.105 and 0.264), which is positive.

**Microsomal Clearance:** Ligand A (-5.034) has much lower (better) microsomal clearance than Ligand B (40.879), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (2.291) has a shorter half-life than Ligand B (24.858), but the difference is less important given the poor solubility and permeability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.032).

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.5), but the difference is only 0.3 kcal/mol, which isn't substantial enough to overcome other issues.

**Conclusion:**

While Ligand B has slightly better affinity and a better logP, Ligand A is the superior candidate due to its significantly lower DILI risk and much better metabolic stability (lower Cl_mic). Both ligands suffer from poor solubility and permeability, which are major hurdles. However, metabolic stability is particularly important for kinase inhibitors, as rapid metabolism can limit efficacy. The lower DILI risk is also a significant safety advantage.

Output:
0
2025-04-17 15:08:57,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.531 and 367.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is significantly better than Ligand B (134.67). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Ligand A (2.361) is optimal, while Ligand B (0.921) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.869) has a higher QED score than Ligand B (0.646), indicating a more drug-like profile.

**DILI:** Ligand B (81.427) has a significantly higher DILI risk than Ligand A (56.534). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.309) has a better BBB percentile than Ligand B (37.418).

**Caco-2 Permeability:** Ligand A (-4.531) has a better Caco-2 permeability than Ligand B (-5.343).

**Aqueous Solubility:** Ligand A (-3.542) has better aqueous solubility than Ligand B (-3.142). Solubility is important for bioavailability.

**hERG:** Ligand A (0.898) has a lower hERG risk than Ligand B (0.083). This is a significant advantage.

**Microsomal Clearance:** Ligand A (13.857) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (18.17).

**In vitro Half-Life:** Ligand A (11.198 hours) has a longer half-life than Ligand B (6.51 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.289) has lower P-gp efflux than Ligand B (0.071), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While a 1.5 kcal/mol advantage is usually significant, the numerous ADME advantages of Ligand A outweigh this difference.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising drug candidate. It has superior ADME properties across the board, including lower DILI risk, better solubility, improved metabolic stability, and lower hERG risk. These factors are crucial for developing a safe and effective kinase inhibitor.

Output:
0
2025-04-17 15:08:57,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 369.893 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is better than Ligand B (75.43) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.792 and 2.424, respectively), 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. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.656 and 0.835), indicating good drug-like properties.

**DILI:** Ligand A (14.23 percentile) has a significantly lower DILI risk than Ligand B (39.201 percentile). This is a major advantage.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (70.415) is better than Ligand A (57.619). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.469) has a worse Caco-2 permeability than Ligand B (-4.629).

**Aqueous Solubility:** Ligand A (-1.694) has a slightly better aqueous solubility than Ligand B (-2.385).

**hERG Inhibition:** Ligand A (0.124) has a much lower hERG inhibition liability than Ligand B (0.071), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-8.264) has a much lower microsomal clearance than Ligand B (44.769), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (2.235 hours) has a shorter half-life than Ligand B (11.405 hours). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.013) has a much lower P-gp efflux liability than Ligand B (0.304), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-10.2 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:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme target. While Ligand B has a higher DILI risk and higher P-gp efflux, the substantial improvement in binding affinity (-10.2 vs -7.3 kcal/mol) is likely to outweigh these concerns, especially given that the DILI risk is still below 60. The improved half-life of Ligand B is also a positive. Ligand A has better metabolic stability, but the weaker binding affinity is a major disadvantage.

Output:
1
2025-04-17 15:08:57,029 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [411.246, 52.57, 3.809, 2, 3, 0.805, 69.794, 69.717, -4.884, -4.445, 0.887, 25.223, 4.563, 0.583, -9.4]
**Ligand B:** [343.471, 62.3, 3.078, 1, 3, 0.894, 33.695, 74.952, -4.556, -3.7, 0.225, 54.232, 0.406, 0.075, -9.1]

**Step-by-step comparison:**

1. **MW:** Ligand A (411.246 Da) is within the ideal range (200-500 Da). Ligand B (343.471 Da) is also within range, and slightly preferred due to being closer to the lower bound which can aid permeability.
2. **TPSA:** Ligand A (52.57) is good, well below 140. Ligand B (62.3) is also acceptable, but slightly higher.
3. **logP:** Both ligands have good logP values (A: 3.809, B: 3.078), falling within the 1-3 range. Ligand B is slightly preferred.
4. **HBD:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5. Ligand B is slightly preferred.
5. **HBA:** Both ligands have 3 HBA, which is good (<=10).
6. **QED:** Both ligands have high QED scores (A: 0.805, B: 0.894), indicating good drug-like properties. Ligand B is slightly preferred.
7. **DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (33.695). This is a significant negative for Ligand A.
8. **BBB:** Both ligands have acceptable BBB penetration (A: 69.717, B: 74.952), but not critical for SRC kinase as it's not a CNS target. Ligand B is slightly 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 have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.
11. **hERG:** Ligand A (0.887) has a higher hERG risk than Ligand B (0.225). This is a significant negative for Ligand A.
12. **Cl_mic:** Ligand A (25.223) has a lower (better) microsomal clearance than Ligand B (54.232), indicating better metabolic stability. This is a positive for Ligand A.
13. **t1/2:** Ligand A (4.563) has a longer half-life than Ligand B (0.406). This is a positive for Ligand A.
14. **Pgp:** Ligand A (0.583) has lower P-gp efflux than Ligand B (0.075). This is a positive for Ligand A.
15. **Affinity:** Both ligands have very similar and excellent binding affinities (A: -9.4 kcal/mol, B: -9.1 kcal/mol). The difference is minimal.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and Pgp efflux, its significantly higher DILI and hERG risk are major concerns. Ligand B has a better safety profile (lower DILI, hERG) and slightly better logP and QED. The Caco-2 and solubility values are concerning for both, but the safety profile outweighs the metabolic stability advantage of Ligand A.

Therefore, **Ligand B** is the more viable drug candidate.

Output:
1
2025-04-17 15:08:57,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.56) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (70.67) is excellent, well below 140.

**logP:** Ligand A (-1.515) is a bit low, potentially hindering permeation. Ligand B (0.908) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is good. Ligand B (2 HBD, 4 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.576 and 0.683), indicating drug-like properties.

**DILI:** Ligand A (46.297) has a moderate DILI risk, but is acceptable. Ligand B (6.863) has a very low DILI risk, which is highly favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (13.261) and Ligand B (76.192) are less relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.495 and -5.085), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.173 and -1.805), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.015) has very low hERG risk, excellent. Ligand B (0.391) also has low hERG risk, good.

**Microsomal Clearance:** Ligand A (-0.196) has very low microsomal clearance, suggesting high metabolic stability, which is excellent. Ligand B (7.394) has a higher clearance, indicating lower metabolic stability, which is less desirable.

**In vitro Half-Life:** Ligand A (22.725) has a reasonable in vitro half-life. Ligand B (6.637) has a shorter half-life, which is less favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.012).

**Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (-6.2), a difference of 1.9 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, excellent metabolic stability, and very low hERG risk. However, it suffers from low logP and poor solubility. Ligand B has better TPSA, logP, and DILI, but weaker binding affinity and lower metabolic stability. The superior binding affinity of Ligand A is a critical factor for an enzyme inhibitor, and the difference of 1.9 kcal/mol is substantial enough to potentially overcome the solubility and logP issues through formulation strategies.

Output:
1
2025-04-17 15:08:57,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (447.316 Da) is higher, but still acceptable. Ligand B (343.471 Da) is lower, which could be beneficial for permeability.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold for oral absorption. Ligand B (63.13) is still reasonable, but less optimal.

**logP:** Ligand A (4.693) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.47) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is very favorable. Ligand B (2 HBD, 3 HBA) is also acceptable.

**QED:** Both ligands have similar and good QED values (0.639 and 0.712 respectively).

**DILI:** Ligand A (44.63) has a moderate DILI risk, but is still acceptable. Ligand B (13.61) has a very low DILI risk, which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.887) has poor Caco-2 permeability, which is a concern. Ligand B (-5.012) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.617) has very poor aqueous solubility, a major drawback. Ligand B (-2.607) has better, but still poor, solubility.

**hERG Inhibition:** Ligand A (0.729) has a slightly elevated hERG risk, but still within a manageable range. Ligand B (0.395) has a very low hERG risk, a clear advantage.

**Microsomal Clearance:** Ligand A (81.406) has high microsomal clearance, indicating poor metabolic stability. Ligand B (34.303) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (30.332) has a reasonable half-life. Ligand B (-1.175) has a very short half-life, a significant disadvantage.

**P-gp Efflux:** Both ligands have low P-gp efflux, which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.8 and -8.8 kcal/mol). Ligand A has a 1 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a better binding affinity and acceptable DILI/hERG, but suffers from poor solubility, poor permeability, and high metabolic clearance. Ligand B has superior ADME properties (lower DILI, hERG, and clearance), but a slightly weaker binding affinity and a very short half-life.

Given the enzyme-specific priorities, metabolic stability (Cl_mic) and solubility are crucial. Ligand B's significantly better metabolic stability and lower toxicity profile outweigh the slightly weaker binding affinity. While the short half-life is a concern, it may be addressable through structural modifications. The poor solubility of Ligand A is a more difficult hurdle to overcome.

Output:
1
2025-04-17 15:08:57,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.56) is slightly higher than Ligand B (64.41). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have acceptable logP values (1.659 and 2.735), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.697) has a better QED score than Ligand B (0.55), suggesting a more drug-like profile.

**DILI:** Ligand B (32.183) has a significantly lower DILI risk than Ligand A (44.63), which is a major advantage.

**BBB:** Ligand B (55.719) has a higher BBB percentile than Ligand A (49.826), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.171) has a worse Caco-2 permeability than Ligand B (-4.446).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.664 and -2.86). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.164) has a slightly better hERG profile than Ligand B (0.576), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (46.352) has a significantly better microsomal clearance than Ligand A (12.438), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.631) has a much longer in vitro half-life than Ligand A (-4.837), a substantial advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux than Ligand B (0.223), which is a slight benefit.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This difference of 0.7 kcal/mol is significant, potentially outweighing some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has a better QED and slightly better hERG profile, Ligand B is superior overall. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity are crucial advantages for an enzyme target like SRC kinase. The solubility is a concern for both, but the other factors make Ligand B the more promising candidate.

Output:
1
2025-04-17 15:08:57,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.479 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is slightly higher than Ligand B (61.44), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.079 and 2.764), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of hydrogen bond donors and acceptors, well within the limits of 5 and 10 respectively.

**QED:** Ligand A (0.824) has a significantly higher QED score than Ligand B (0.471), indicating a more drug-like profile.

**DILI:** Ligand A (55.913) has a moderate DILI risk, while Ligand B (8.647) has a very low DILI risk, which is a significant advantage for B.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (82.164) is higher than Ligand A (72.237). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.762) is slightly better than Ligand B (-5.165).

**Aqueous Solubility:** Ligand A (-4.935) has slightly better solubility than Ligand B (-2.292), but both are poor.

**hERG Inhibition:** Both ligands have similar hERG inhibition liabilities (0.632 and 0.703), indicating moderate risk.

**Microsomal Clearance:** Ligand A (50.463) has a much better microsomal clearance than Ligand B (14.731). Lower clearance is preferred for improved metabolic stability.

**In vitro Half-Life:** Ligand A (5.204) has a positive half-life, while Ligand B (-15.231) has a negative half-life, indicating poor stability. This is a major drawback for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.171 and 0.151).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand B has a lower DILI risk, Ligand A is superior overall due to its significantly better QED score, much improved microsomal clearance and in vitro half-life. The slightly better solubility of A is also a plus. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 15:08:57,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase properties (potency, metabolic stability, solubility, and hERG risk).

**Ligand A:**

*   **MW:** 347.419 Da (Good)
*   **TPSA:** 87.54 (Good)
*   **logP:** 0.161 (Low - may impede permeation)
*   **HBD:** 1 (Good)
*   **HBA:** 5 (Good)
*   **QED:** 0.769 (Good)
*   **DILI:** 36.177 (Good)
*   **BBB:** 56.34 (Not a priority for a non-CNS target)
*   **Caco-2:** -4.806 (Very poor)
*   **Solubility:** -1.088 (Poor)
*   **hERG:** 0.031 (Excellent)
*   **Cl_mic:** -1.872 (Excellent - low clearance, high stability)
*   **t1/2:** -2.97 (Excellent - long half-life)
*   **Pgp:** 0.007 (Excellent - low efflux)
*   **Affinity:** -8.2 kcal/mol (Excellent)

**Ligand B:**

*   **MW:** 408.344 Da (Good)
*   **TPSA:** 56.07 (Good)
*   **logP:** 3.273 (Good)
*   **HBD:** 0 (Good)
*   **HBA:** 6 (Good)
*   **QED:** 0.671 (Good)
*   **DILI:** 13.3 (Excellent)
*   **BBB:** 76.851 (Not a priority for a non-CNS target)
*   **Caco-2:** -4.887 (Very poor)
*   **Solubility:** -3.074 (Very poor)
*   **hERG:** 0.54 (Acceptable)
*   **Cl_mic:** 47.141 (Poor - high clearance, low stability)
*   **t1/2:** 32.834 (Good)
*   **Pgp:** 0.17 (Good)
*   **Affinity:** -7.0 kcal/mol (Good)

**Comparison & Decision:**

Both ligands have excellent binding affinity and acceptable QED scores. Ligand A has a significantly better binding affinity (-8.2 vs -7.0 kcal/mol), which is a primary driver for enzyme inhibitors. Ligand A also exhibits superior metabolic stability (lower Cl_mic, longer t1/2) and lower Pgp efflux. While Ligand A's logP is low, its exceptional affinity and metabolic properties likely compensate for this. Both ligands have poor Caco-2 and solubility, which are concerns, but can be addressed with formulation strategies. Ligand B has a higher DILI score than Ligand A.

Considering the priorities for kinase inhibitors, Ligand A is the more promising candidate due to its superior affinity and metabolic stability.

Output:
1
2025-04-17 15:08:57,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (365.499 Da) is still well within the range.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (71.53) is lower than Ligand A (89.57), which is slightly better.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (0.897) is a bit lower, potentially impacting permeability, while Ligand B (1.998) is closer to the ideal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable values, balancing solubility and permeability.

**QED:** Both ligands have good QED scores, indicating drug-likeness (Ligand A: 0.613, Ligand B: 0.802). Ligand B is better here.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A at 44.087 and Ligand B at 37.999. Ligand B is slightly better.

**BBB:** This isn't a primary concern for a non-CNS target like SRC kinase, but Ligand B (63.629) has a higher BBB percentile than Ligand A (27.801).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.558) is slightly better than Ligand B (-5.195).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-1.933) is slightly better than Ligand B (-1.216).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.426, Ligand B: 0.158). Ligand B is significantly better, indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (12.451 mL/min/kg) has a lower microsomal clearance than Ligand A (17.598 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (5.404 hours) has a slightly longer half-life than Ligand A (6.815 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.238, Ligand B: 0.064). Ligand B is better.

**Binding Affinity:** This is the most critical factor. Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have some ADME liabilities (poor Caco-2 and solubility), Ligand B demonstrates significantly better potency (binding affinity), metabolic stability (lower Cl_mic), lower hERG risk, and better QED and DILI scores. The strong binding affinity of Ligand B makes it the more promising starting point for further optimization.

Output:
1
2025-04-17 15:08:57,030 - INFO - Batch 355 complete. Total preferences: 5680
2025-04-17 15:08:57,030 - INFO - Processing batch 356/512...
2025-04-17 15:09:37,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.123 Da) is slightly higher, but acceptable. Ligand B (349.391 Da) is also good.

**TPSA:** Ligand A (59.29) is excellent, well below the 140 threshold for oral absorption. Ligand B (115.3) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.369) is optimal. Ligand B (0.817) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (2 HBD, 8 HBA) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.401, Ligand B: 0.644), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A (94.765) has a very high DILI risk, which is a major concern. Ligand B (61.07) is elevated, but significantly lower than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.658) and Ligand B (52.423) are both moderate.

**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 (0.516) has a slightly elevated hERG risk, but is acceptable. Ligand B (0.152) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (52.588) has moderate clearance, suggesting reasonable metabolic stability. Ligand B (26.108) has lower clearance, indicating better metabolic stability, which is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (64.186) has a moderate half-life. Ligand B (19.901) has a shorter half-life, which is less desirable.

**P-gp Efflux:** Ligand A (0.574) has moderate P-gp efflux. Ligand B (0.07) has very low P-gp efflux, which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.7 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's primary drawback is its very high DILI risk. While its binding affinity is exceptional, the potential for liver toxicity is a major hurdle. Ligand B has a better safety profile (lower DILI, hERG, and P-gp efflux) and better metabolic stability, but its binding affinity is extremely weak.

Given the enzyme-kinase target class, potency and metabolic stability are key. The substantial difference in binding affinity (-8.7 vs 0.0 kcal/mol) is a critical factor. While Ligand A's DILI risk is concerning, it might be mitigated through structural modifications. Ligand B's lack of potency makes it unlikely to be a viable candidate, even with its better ADME properties.

Output:
1
2025-04-17 15:09:37,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.481 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (98.98) is still under 140, but less optimal than A.

**logP:** Ligand A (2.877) is within the optimal 1-3 range. Ligand B (-0.554) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond counts, well within the guidelines.

**QED:** Both ligands have similar QED values (0.73 and 0.712), indicating good drug-likeness.

**DILI:** Ligand A (20.396) has a much lower DILI risk than Ligand B (13.067), which is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (92.943) has a higher BBB percentile than Ligand B (53.974).

**Caco-2 Permeability:** Ligand A (-4.874) has a negative Caco-2 value, which is concerning. Ligand B (-5.34) is also negative, but slightly worse. This suggests poor intestinal absorption for both, but A is slightly better.

**Aqueous Solubility:** Ligand A (-3.976) has slightly better solubility than Ligand B (-1.178).

**hERG:** Ligand A (0.83) has a lower hERG risk than Ligand B (0.142), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (44.845) has higher microsomal clearance than Ligand B (-32.261). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-11.797) has a significantly longer in vitro half-life than Ligand A (-1.072), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.137 and 0.002).

**Binding Affinity:** Both ligands have strong binding affinities (-10.8 and -9.2 kcal/mol). Ligand A has a 1.6 kcal/mol advantage. This is a substantial difference and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a significant advantage in binding affinity and better scores for DILI, BBB, solubility, and hERG. However, it has a higher microsomal clearance and a shorter half-life, and a concerning negative Caco-2 value. Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2), but suffers from a lower logP, higher DILI, and a weaker binding affinity.

Given the importance of potency for kinase inhibitors, the 1.6 kcal/mol advantage of Ligand A is substantial. While the metabolic stability of Ligand B is attractive, the lower binding affinity is a major drawback. The negative Caco-2 values are a concern for both, but could potentially be addressed through formulation strategies. The lower DILI and hERG risk of Ligand A are also important safety considerations.

Output:
0
2025-04-17 15:09:37,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.503 and 351.426 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is well below the 140 threshold for good absorption, while Ligand B (80.12) is still acceptable but slightly higher.

**3. logP:** Both ligands have good logP values (2.183 and 1.291), 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 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 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.705 and 0.803), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (20.396 and 19.504 percentiles), which is excellent.

**8. BBB:** Both ligands have reasonable BBB penetration (77.162 and 88.135 percentiles), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.852) and Ligand B (-5.07) both 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 very poor aqueous solubility (-3.057 and -1.683). This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.541 and 0.081), which is excellent.

**12. Microsomal Clearance:** Ligand A (27.355 mL/min/kg) has higher clearance than Ligand B (-1.597 mL/min/kg). Ligand B's negative value suggests very high metabolic stability, a significant advantage.

**13. In vitro Half-Life:** Ligand A (-1.313 hours) has a short half-life, while Ligand B (-1.556 hours) is also short, but slightly better. Both are poor.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.344 and 0.024).

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.7 vs -8.4 kcal/mol) and dramatically improved metabolic stability (negative Cl_mic) are critical advantages for an enzyme inhibitor. The slightly better BBB and lower P-gp efflux also contribute. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 15:09:37,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.555 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (364.471 Da) is also good.

**TPSA:** Ligand A (32.26) is excellent, well below the 140 threshold for oral absorption. Ligand B (69.48) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (4.937) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.908) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is favorable. Ligand B (0 HBD, 7 HBA) is also acceptable, though the higher HBA count might slightly reduce permeability.

**QED:** Both ligands have similar and good QED values (0.701 and 0.783, respectively), indicating good drug-like properties.

**DILI:** Ligand A (8.414) has a very low DILI risk, which is excellent. Ligand B (49.864) is higher, indicating a moderate risk, but still within acceptable limits.

**BBB:** Both ligands have similar BBB penetration (67.468 and 68.399), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.758) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.049) also has poor Caco-2 permeability, but is slightly worse.

**Aqueous Solubility:** Ligand A (-4.708) and Ligand B (-1.232) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.893) has a low hERG risk, which is very favorable. Ligand B (0.264) has an even lower hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (44.665) has moderate clearance, while Ligand B (22.245) has low clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (32.697) has a moderate half-life, while Ligand B (15.747) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.809 and 0.073), which is good for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8 and -9 kcal/mol, respectively). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B has significantly better metabolic stability (lower Cl_mic) and a slightly better binding affinity. The lower DILI and hERG risk for Ligand B are also advantageous. Ligand A's high logP is a concern, and the slightly poorer metabolic stability is a disadvantage. The potency difference is not large enough to overcome the ADME advantages of Ligand B.

Output:
1
2025-04-17 15:09:37,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.471 Da) is slightly higher than Ligand B (338.407 Da), but both are acceptable.

**TPSA:** Ligand A (72.28) is slightly higher than Ligand B (59.59). Both are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (2.08) is within the optimal range (1-3). Ligand B (4.374) is a bit high, 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 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.883 and 0.87), indicating good drug-likeness.

**DILI:** Ligand A (66.072) has a lower DILI risk than Ligand B (80.923). This is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (75.145 and 73.866), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.848 and -4.777), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Ligand A (-2.809) has better solubility than Ligand B (-5.091), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.489) has a lower hERG risk than Ligand B (0.791). This is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (25.879) has significantly lower microsomal clearance than Ligand B (71.72). Lower clearance means better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (28.921) has a shorter half-life than Ligand B (46.845), but both are reasonably good.

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux than Ligand B (0.497), indicating better bioavailability.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). However, the difference is only 0.5 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, Ligand A excels in crucial ADME-Tox properties: lower DILI risk, lower hERG inhibition, significantly lower microsomal clearance (better metabolic stability), better solubility, and lower P-gp efflux. The negative Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh the small binding affinity difference. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 15:09:37,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.881 Da) is slightly higher than Ligand B (344.371 Da), but both are acceptable.

**TPSA:** Ligand A (59.81) is significantly better than Ligand B (87.76). Lower TPSA generally favors better absorption, and while not a CNS target, lower TPSA is still beneficial.

**logP:** Ligand A (4.386) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-0.378) is quite low, which could hinder membrane permeability.

**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: 0.675, B: 0.756), indicating generally drug-like properties.

**DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (62.97). Both are reasonably acceptable, but B is preferable.

**BBB:** Not a primary concern for a general oncology target. Ligand A (64.87) is slightly better than Ligand B (28.887).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.933) is slightly better than Ligand B (-4.805), but both are problematic.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.694) is slightly better than Ligand B (-2.636).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.301, B: 0.182), which is excellent.

**Microsomal Clearance:** Ligand B (-10.579) has significantly *lower* (better) microsomal clearance than Ligand A (52.293). This suggests better metabolic stability for Ligand B, a key consideration for enzymes.

**In vitro Half-Life:** Ligand B (6.503) has a slightly longer half-life than Ligand A (33.456).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.658, B: 0.016), which is favorable. Ligand B is significantly better.

**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 enough to potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is low, its superior metabolic stability (lower Cl_mic), longer half-life, lower P-gp efflux, and slightly better binding affinity outweigh the slightly lower BBB and solubility. The lower DILI risk is also a plus. Ligand A's higher logP and higher clearance are concerning. The small difference in binding affinity is less important than the ADME advantages of Ligand B.

Output:
1
2025-04-17 15:09:37,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.411 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (103.87). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**logP:** Both ligands (1.821 and 1.546) are 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 4 HBA, and Ligand B has 5. Both are below the 10 limit.

**QED:** Ligand A (0.856) has a better QED score than Ligand B (0.793), indicating a more drug-like profile.

**DILI:** Ligand A (38.813) has a significantly lower DILI risk than Ligand B (51.105). Both are below 60, which is good, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.044) is slightly better than Ligand B (41.334).

**Caco-2 Permeability:** Ligand A (-4.971) is better than Ligand B (-5.416). Higher values are better, and both are negative, indicating permeability issues. However, A is less negative.

**Aqueous Solubility:** Ligand A (-2.336) is better than Ligand B (-2.113). Higher values are better, and both are negative, indicating solubility issues. A is slightly better.

**hERG:** Both ligands have very low hERG risk (0.192 and 0.199), which is excellent.

**Microsomal Clearance:** Ligand A (29.194) has lower microsomal clearance than Ligand B (35.409), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.141) has a positive half-life, while Ligand B (-19.351) 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 (0.023 and 0.027).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). However, the difference is not substantial enough to outweigh the other advantages of Ligand A.

**Overall:** Ligand A is superior due to its better QED, lower DILI risk, better metabolic stability (lower Cl_mic, positive half-life), and slightly better solubility and permeability. While Ligand B has a marginally better binding affinity, the ADME properties of Ligand A make it a more promising drug candidate.

Output:
0
2025-04-17 15:09:37,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.431 and 361.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.1) is better than Ligand B (73.45) as it is closer to the threshold for good oral absorption.

**logP:** Ligand B (1.977) is optimal (1-3), while Ligand A (0.203) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both ligands are acceptable (2 and 1, respectively), being less than 5.

**H-Bond Acceptors:** Ligand B (8) is better than Ligand A (5) as it is closer to the threshold of 10.

**QED:** Both ligands have similar, good QED values (0.755 and 0.725).

**DILI:** Ligand A (28.306) has a significantly lower DILI risk than Ligand B (52.152), which is a major advantage.

**BBB:** Both have moderate BBB penetration, but Ligand A (61.38) is slightly better than Ligand B (59.131). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.75) is significantly worse than Ligand B (-5.809), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.68) is better than Ligand B (-2.665), which is a positive.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.191 and 0.102, respectively).

**Microsomal Clearance:** Ligand A (1.737) has significantly lower microsomal clearance than Ligand B (46.809), suggesting better metabolic stability. This is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand A (18.639 hours) has a much longer half-life than Ligand B (-5.245 hours), which is highly desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.074 and 0.177, respectively).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. While its logP is low and Caco-2 permeability is poor, the strong binding affinity and favorable safety/PK properties are likely to be more critical for an SRC kinase inhibitor. Ligand B has a better logP and Caco-2, but its higher DILI risk, poorer metabolic stability, and weaker binding affinity make it less attractive.

Output:
1
2025-04-17 15:09:37,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (374.409 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is slightly higher than Ligand B (76.02), both are well below the 140 threshold for oral absorption.

**3. logP:** Both ligands have similar logP values (2.113 and 2.12), 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 4. Both are below the acceptable limit of <=10.

**6. QED:** Ligand B (0.744) has a significantly better QED score than Ligand A (0.539), indicating a more drug-like profile.

**7. DILI:** Ligand A (61.574) has a higher DILI risk than Ligand B (25.553). Ligand B is well below the 40 threshold, while Ligand A is moderately risky.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.925) is slightly higher than Ligand B (56.029).

**9. Caco-2 Permeability:** Ligand A (-4.849) shows better Caco-2 permeability than Ligand B (-5.158), suggesting better absorption.

**10. Aqueous Solubility:** Ligand A (-3.526) has better aqueous solubility than Ligand B (-2.281).

**11. hERG Inhibition:** Ligand A (0.463) has a slightly lower hERG inhibition risk than Ligand B (0.122), which is preferable.

**12. Microsomal Clearance:** Ligand B (13.257) has significantly lower microsomal clearance than Ligand A (64.633), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (2.947) has a slightly longer half-life than Ligand A (23.741).

**14. P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux than Ligand B (0.039), which is preferable.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is the most crucial factor, and the 1.1 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability, solubility, and P-gp efflux, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better binding affinity, lower DILI risk, and much improved metabolic stability (lower Cl_mic and longer half-life). The higher QED score for Ligand B also supports its drug-like properties. The stronger binding affinity of Ligand B is likely to outweigh the minor drawbacks in permeability and solubility.

Output:
1
2025-04-17 15:09:37,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (335.371 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (112.28 and 105.55) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.839 and 1.277) 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 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.739 and 0.804), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 80.923, which is high. Ligand B has a much lower DILI risk of 42.846, which is good. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (58.666) than Ligand A (16.712).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.477 and -5.117). 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 (-3.94 and -1.932), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.453, which is relatively low. Ligand B has a slightly higher risk of 0.629, but still acceptable.

**Microsomal Clearance:** Ligand A has a Cl_mic of 11.889 mL/min/kg, while Ligand B has a significantly lower Cl_mic of -21.327 mL/min/kg. Lower clearance indicates better metabolic stability, making Ligand B more favorable.

**In vitro Half-Life:** Ligand A has a t1/2 of 6.458 hours, while Ligand B has a significantly longer t1/2 of -9.965 hours. This further supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.104, and Ligand B has a very low efflux liability of 0.007. Lower Pgp efflux is preferred.

**Binding Affinity:** Ligand A has a binding affinity of -8.9 kcal/mol, which is excellent. Ligand B has a binding affinity of -7.8 kcal/mol, which is also good, but 1.1 kcal/mol weaker.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better in terms of ADME properties, particularly DILI risk and metabolic stability (Cl_mic and t1/2). The high DILI risk associated with Ligand A is a major concern. The improved metabolic stability of Ligand B is crucial for an enzyme target, as it suggests a longer duration of action and potentially lower dosing requirements. The lower Pgp efflux is also a positive. The difference in binding affinity (1.1 kcal/mol) is not substantial enough to outweigh the significant ADME advantages of Ligand B.

Output:
1
2025-04-17 15:09:37,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.515 Da) is slightly higher than Ligand B (338.367 Da), but both are acceptable.

**TPSA:** Ligand A (63.24) is significantly better than Ligand B (86.23). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have good logP values (A: 3.836, B: 2.822), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and Ligand A has 4 HBA while Ligand B has 7. This is a slight advantage for Ligand A.

**QED:** Both ligands have reasonable QED scores (A: 0.833, B: 0.692), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (77.743) is better than Ligand B (91.78), indicating a lower risk of drug-induced liver injury.

**BBB:** This is less critical for a non-CNS target like SRC. Both are moderate (A: 50.834, B: 61.38).

**Caco-2 Permeability:** Ligand A (-5.217) is better than Ligand B (-4.624), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.078 and -4.277 respectively). This is a concern, but can sometimes be mitigated through formulation strategies.

**hERG Inhibition:** Ligand A (0.15) has a much lower hERG risk than Ligand B (0.64), which is a significant advantage.

**Microsomal Clearance:** Ligand A (17.955) has significantly lower microsomal clearance than Ligand B (109.338), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (52.58) has a much longer in vitro half-life than Ligand B (-1.65), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.31) has lower P-gp efflux than Ligand B (0.084), which is a slight advantage.

**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). Given the other significant advantages of Ligand A, this small difference in affinity is unlikely to be decisive.

**Overall:** Ligand A is significantly better than Ligand B. It has better TPSA, DILI, Caco-2 permeability, hERG risk, microsomal clearance, and in vitro half-life. While Ligand B has slightly better binding affinity, the other ADME/Tox properties of Ligand A make it a much more promising drug candidate.

Output:
0
2025-04-17 15:09:37,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.574 Da and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is significantly better than Ligand B (87.91). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (4.287) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.461) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is better balanced. Ligand B (1 HBD, 6 HBA) has a higher number of hydrogen bond acceptors, which could impact permeability.

**QED:** Both ligands have good QED scores (0.793 and 0.83), indicating generally drug-like properties.

**DILI:** Both ligands show low DILI risk (33.773 and 38.736 percentiles), which is favorable.

**BBB:** Ligand A (74.176) has better BBB penetration than Ligand B (55.138), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.843) and Ligand B (-4.776) both have very poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.876) and Ligand B (-1.322) both have poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.757 and 0.265), which is excellent.

**Microsomal Clearance:** Ligand A (39.694 mL/min/kg) has a higher clearance than Ligand B (0.43 mL/min/kg). This means Ligand B is significantly more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (30.23 hours) has a longer half-life than Ligand B (12.193 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.311 and 0.026).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.4 kcal/mol and -9.5 kcal/mol), essentially equivalent.

**Conclusion:**

While Ligand A has a slightly better TPSA and BBB, Ligand B is superior due to its significantly improved metabolic stability (much lower Cl_mic and a reasonable half-life) and acceptable solubility. The slightly lower logP of Ligand B is also preferable, even if it's on the low side. The binding affinity is comparable for both. Given the importance of metabolic stability for kinase inhibitors, Ligand B is the more promising candidate.

Output:
1
2025-04-17 15:09:37,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.46) is slightly above the preferred <140 for oral absorption, while Ligand B (101.74) is well within.

**logP:** Both ligands (0.92 and 1.015) 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 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.814) has a better QED score than Ligand B (0.666), indicating higher drug-likeness.

**DILI:** Ligand B (37.185) has a significantly lower DILI risk than Ligand A (56.068), which is a substantial advantage.

**BBB:** Both ligands have good BBB penetration (72.237 and 73.362), but this is less critical for a non-CNS target like SRC.

**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 hard to interpret without knowing the scale's range.

**Aqueous Solubility:** Both ligands have negative solubility values, again unusual and difficult to interpret.

**hERG:** Ligand A (0.058) has a lower hERG risk than Ligand B (0.126), which is favorable.

**Microsomal Clearance:** Ligand B (98.194) has a much higher microsomal clearance than Ligand A (39.245), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (-46.254) has a very negative half-life, which is concerning and indicates rapid degradation. Ligand A (-16.064) is better, but still negative.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.058).

**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 other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and lower DILI, its significantly higher microsomal clearance and very negative in vitro half-life are major concerns. Ligand A has better metabolic stability (lower Cl_mic, less negative t1/2) and a higher QED score, making it more likely to be a viable drug candidate. The unusual negative values for Caco-2 and solubility are concerning for both, but the metabolic stability advantage of A is more critical for an enzyme target.

Output:
0
2025-04-17 15:09:37,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.332 and 360.772 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (75.6 and 71.35) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.987 and 3.015) are within the optimal range of 1-3.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.742 and 0.909), indicating drug-like properties.

**DILI:** Both ligands have high DILI risk (84.645 and 89.221). This is a significant concern for both.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (62.97) has a slightly better value than Ligand B (58.821).

**Caco-2 Permeability:** Both have negative values (-5.353 and -4.571), which is unusual and suggests poor permeability. This is a major drawback for both.

**Aqueous Solubility:** Both have negative values (-3.867 and -5.005), indicating very poor aqueous solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.612 and 0.677), which is positive.

**Microsomal Clearance:** Ligand B (21.756 mL/min/kg) has lower microsomal clearance than Ligand A (3.713 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (43.279 hours) has a significantly longer half-life than Ligand A (24.969 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.262 and 0.337), which is favorable.

**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 difference is minor.

**Overall Assessment:**

Both ligands have significant drawbacks (poor solubility and permeability, high DILI risk). However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. Given the enzyme-specific priorities, metabolic stability is crucial. While the DILI risk is high for both, the improved pharmacokinetic profile of Ligand B makes it the more promising candidate, assuming further optimization can address the solubility and permeability issues.

Output:
1
2025-04-17 15:09:37,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.387 and 345.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.2) is slightly above the preferred <140 for good absorption, while Ligand B (93.68) is well within.

**logP:** Both ligands have logP values (1.617 and 1.927) within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 8. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.83) has a better QED score than Ligand B (0.675), indicating a more drug-like profile.

**DILI:** Ligand A (61.264) has a higher DILI risk than Ligand B (47.732), but both are still within a moderate risk range.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.719) shows poorer Caco-2 permeability than Ligand B (-5.603), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.616) has slightly poorer aqueous solubility than Ligand B (-1.861).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.354 and 0.233, respectively).

**Microsomal Clearance:** Ligand A (37.948) has significantly better microsomal clearance (lower) than Ligand B (14.121), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.435) has a longer in vitro half-life than Ligand B (8.578).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.347, respectively).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This difference of 2.7 kcal/mol is substantial and likely outweighs some of the ADME drawbacks of Ligand A.

**Conclusion:**

Despite Ligand A having slightly higher DILI risk and poorer Caco-2 permeability and solubility, its *significantly* superior binding affinity (-9.4 vs -6.7 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising drug candidate. The potency advantage is substantial enough to compensate for the minor ADME concerns.

Output:
1
2025-04-17 15:09:37,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (380.583 Da) is also well within range.

**TPSA:** Ligand A (78.87) is better than Ligand B (43.18) as it is closer to the ideal threshold of 140.

**logP:** Both ligands have good logP values (A: 3.145, B: 3.477), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is slightly better than Ligand B (HBD=0, HBA=7) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.82) has a significantly higher QED score than Ligand B (0.631), indicating a more drug-like profile.

**DILI:** Ligand A (65.219) has a higher DILI risk than Ligand B (10.237). This is a significant drawback for Ligand A.

**BBB:** Ligand B (77.976) has a better BBB percentile than Ligand A (63.94), but BBB is less important for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.954) has a lower Caco-2 permeability than Ligand B (-5.193), which is not ideal for either.

**Aqueous Solubility:** Ligand A (-4.566) has a lower solubility than Ligand B (-2.854).

**hERG Inhibition:** Ligand A (0.136) has a lower hERG inhibition risk than Ligand B (0.826), which is a positive attribute.

**Microsomal Clearance:** Ligand A (22.104 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (45.644 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.438 hours) has a negative half-life, which is a major concern. Ligand B (4.441 hours) is positive, but not ideal.

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.279).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity, its significantly higher DILI risk, lower solubility, and negative in vitro half-life are major red flags. Ligand B has a much more favorable safety profile (lower DILI, lower hERG), better solubility, and a positive, though not ideal, half-life. The slightly lower affinity of Ligand B can be addressed through further optimization.

Output:
1
2025-04-17 15:09:37,727 - INFO - Batch 356 complete. Total preferences: 5696
2025-04-17 15:09:37,727 - INFO - Processing batch 357/512...
2025-04-17 15:10:27,223 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.411 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.05) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (80.04) is well within the range.

**logP:** Ligand A (0.19) is quite low, potentially hindering permeation. Ligand B (2.982) is near optimal.

**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 are within the acceptable limit of <=10.

**QED:** Ligand A (0.81) has a better QED score than Ligand B (0.694), indicating better overall drug-likeness.

**DILI:** Ligand A (61.884) has a higher DILI risk than Ligand B (50.097), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (47.15) is slightly higher than Ligand A (39.667), but neither is particularly relevant.

**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 (0.172) has a much lower hERG risk than Ligand B (0.398), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-12.043) has a significantly *lower* (better) microsomal clearance than Ligand B (59.491), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-24.32) has a much longer in vitro half-life than Ligand B (5.857), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux liability, while Ligand B (0.558) has moderate efflux.

**Binding Affinity:** Ligand A (-9.1) has a significantly stronger binding affinity than Ligand B (-8.0). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A's lower logP and slightly higher TPSA, its significantly superior binding affinity (-9.1 vs -8.0 kcal/mol), much better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and lower P-gp efflux outweigh these drawbacks. The negative solubility and Caco-2 values are concerning for both, but the potency and metabolic advantages of Ligand A are compelling.

Output:
1
2025-04-17 15:10:27,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.836 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is significantly better than Ligand B (104.21). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B is approaching a level that could hinder absorption.

**logP:** Ligand A (3.839) is optimal, while Ligand B (1.29) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.849 and 0.657), indicating good drug-likeness.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (28.577). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.419) is higher than Ligand B (65.801).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.777 and -4.911), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference is small.

**Aqueous Solubility:** Ligand A (-5.126) is worse than Ligand B (-2.271). Solubility is important for bioavailability, and Ligand B has a better score.

**hERG:** Ligand A (0.644) has a slightly higher hERG risk than Ligand B (0.158). Lower is better here.

**Microsomal Clearance:** Ligand A (51.949) has a higher microsomal clearance than Ligand B (35.818), meaning it's less metabolically stable. Lower clearance is preferred.

**In vitro Half-Life:** Ligand B (-18.623) has a negative half-life, which is impossible and indicates a data error or a very rapidly metabolized compound. Ligand A (53.839) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.319) has lower P-gp efflux than Ligand B (0.004), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.7 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other significant ADME differences.

**Conclusion:**

Despite Ligand A's slightly better logP and P-gp efflux, Ligand B is the more promising candidate. Ligand B has significantly lower DILI risk, better solubility, and a more reasonable (though still problematic) half-life. The negative half-life for Ligand B is a major red flag, but the other properties are more favorable. Ligand A's higher DILI risk and worse solubility are concerning. The Caco-2 permeability is poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:10:27,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (348.443 and 370.563 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (67.87 and 64.68) well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.233) is within the optimal 1-3 range. Ligand B (0.919) is slightly below, which *could* indicate permeability issues, but isn't a major concern.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 2, respectively), staying below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (4 and 5, respectively), staying below the 10 threshold.

**6. QED:** Both ligands have similar, good QED scores (0.732 and 0.728), indicating good drug-like properties.

**7. DILI:** Ligand A (30.903) has a slightly higher DILI risk than Ligand B (20.279), but both are below the concerning 60 threshold.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.868) has a better BBB score than Ligand B (57.774), but this isn't a primary factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.535 and -5.533). This is unusual and suggests a potential issue with the data or the model. It's difficult to interpret without further information, but we'll proceed assuming it indicates poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-2.167 and -1.908). Similar to Caco-2, this is problematic and suggests potential formulation challenges.

**11. hERG Inhibition:** Both ligands exhibit low hERG inhibition risk (0.6 and 0.344), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (7.545) has significantly lower microsomal clearance than Ligand B (33.987), indicating better metabolic stability. This is a key priority for enzyme inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand A (-15.236) has a significantly longer in vitro half-life than Ligand B (2.563). This is a major advantage, suggesting less frequent dosing.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.142 and 0.017).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While both have excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic) and a longer half-life. The negative solubility and Caco-2 values are concerning for both, but the superior pharmacokinetic properties of Ligand A outweigh these drawbacks, especially given the strong binding affinity.

Output:
0
2025-04-17 15:10:27,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 359.503 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is well below the 140 threshold for oral absorption, while Ligand B (101.64) is still acceptable but approaching the limit.

**logP:** Ligand A (1.627) is within the optimal 1-3 range. Ligand B (3.751) 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 (1 HBD, 4 HBA) and Ligand B (3 HBD, 8 HBA) both fall within the recommended limits of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.606) has a better QED score than Ligand B (0.463), indicating a more drug-like profile.

**DILI:** Ligand A (21.753) has a significantly lower DILI risk than Ligand B (69.135), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.805) has a higher BBB percentile than Ligand B (60.45).

**Caco-2 Permeability:** Ligand A (-4.387) has a worse Caco-2 permeability than Ligand B (-5.314), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.953) has better aqueous solubility than Ligand B (-4.017). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.123) has a much lower hERG inhibition liability than Ligand B (0.556), which is a crucial safety consideration.

**Microsomal Clearance:** Ligand A (56.49) has a lower microsomal clearance than Ligand B (75.796), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.864) has a shorter in vitro half-life than Ligand B (18.059). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux than Ligand B (0.137), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 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 important factor for an enzyme inhibitor. However, it has concerningly high DILI and hERG risks, and a higher logP. Ligand A has a better safety profile (lower DILI and hERG), better solubility, and better metabolic stability, but its affinity is weaker and half-life is shorter.

Given the priorities for enzyme inhibitors, the stronger binding affinity of Ligand B is a significant advantage. While the ADME properties of Ligand B are less ideal, medicinal chemistry optimization could potentially address the DILI, hERG, and logP issues without sacrificing potency. The weaker affinity of Ligand A makes it less likely to succeed, even with its better ADME profile.

Output:
1
2025-04-17 15:10:27,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (340.47 and 346.43 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (70.83). A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (3.325 and 2.266), 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 2 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.855 and 0.842), indicating good drug-likeness.

**7. DILI:** Ligand A (25.13%) has a much lower DILI risk than Ligand B (34.43%). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (70.997% and 70.57%), which is acceptable but not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.403) has a slightly better (less negative) Caco-2 value than Ligand B (-4.461), suggesting slightly better absorption.

**10. Aqueous Solubility:** Ligand A (-4.689) has better aqueous solubility than Ligand B (-1.974). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.439) has a significantly lower hERG inhibition liability than Ligand B (0.086). This is a crucial advantage, reducing the risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (70.202) has higher microsomal clearance than Ligand B (40.314), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (20.65) has a much longer in vitro half-life than Ligand A (-3.259), suggesting better metabolic stability.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.314 and 0.157).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in safety parameters (DILI, hERG) and solubility, while Ligand B has better metabolic stability (lower Cl_mic, longer t1/2). However, the significantly lower DILI and hERG risk for Ligand A are critical advantages for a kinase inhibitor, outweighing the slightly higher clearance. The binding affinities are comparable. Therefore, Ligand A is the more promising candidate.

Output:
1
2025-04-17 15:10:27,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (380.539 and 340.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (65.54 and 67.66) are below the 140 A^2 threshold for good oral absorption, which is good.

**3. logP:** Ligand A (0.968) is closer to the optimal 1-3 range than Ligand B (3.837), which is approaching the upper limit and could potentially cause 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 6 HBA, which is acceptable (<=10).

**6. QED:** Ligand B (0.75) has a better QED score than Ligand A (0.453), indicating a more drug-like profile.

**7. DILI:** Ligand A (40.403) has a significantly lower DILI risk than Ligand B (61.264), which is a major advantage.

**8. BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (80.419) is higher than Ligand A (53.781), but this is less important.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-5.019) is slightly better than Ligand B (-4.931).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.936) is slightly better than Ligand B (-4.331).

**11. hERG Inhibition:** Ligand A (0.351) has a much lower hERG inhibition liability than Ligand B (0.848), which is a critical safety advantage.

**12. Microsomal Clearance:** Ligand A (30.728) has a lower microsomal clearance than Ligand B (75.333), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (37.234) has a much longer in vitro half-life than Ligand A (-16.058), which is a significant benefit.

**14. P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux liability than Ligand B (0.657), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a better binding affinity than Ligand A (-8.8 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 half-life, Ligand A demonstrates significantly better safety profiles (lower DILI and hERG) and better metabolic stability. The solubility and permeability are poor for both, but Ligand A is slightly better. Considering the enzyme-specific priorities, the lower hERG and DILI risks of Ligand A are crucial. The affinity difference of 1.5 kcal/mol is significant, but the safety concerns with Ligand B are substantial.

Output:
0
2025-04-17 15:10:27,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.503 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly above the preferred <60 for kinase inhibitors, while Ligand B (49.41) is well within the range.

**3. logP:** Both ligands have acceptable logP values (2.469 and 3.358), falling within the optimal 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:** Both ligands have a reasonable number of HBDs (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have a reasonable number of HBAs (3 and 2 respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.741 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A (12.369) has a significantly lower DILI risk than Ligand B (9.655), which is a substantial advantage.

**8. BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (88.29) has a higher BBB score than Ligand A (61.497).

**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 (0.231) has a lower hERG inhibition liability than Ligand B (0.656), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (36.77) has a lower microsomal clearance than Ligand B (60.302), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.553) has a shorter in vitro half-life than Ligand B (-5.829). This is a drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.116 and 0.113).

**15. Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-0.0). This is a major advantage.

**Overall Assessment:**

Ligand A is the better candidate. Despite the shorter half-life, its significantly better binding affinity, lower DILI risk, lower hERG inhibition, and better metabolic stability outweigh the slightly higher TPSA and shorter half-life. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A make it more promising.

Output:
1
2025-04-17 15:10:27,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (388.511 and 360.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (33.2). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand B (4.831) is high, potentially causing solubility issues and off-target effects. Ligand A (0.5) is quite low, which could hinder permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0).

**H-Bond Acceptors:** Ligand A (7) is preferable to Ligand B (3).

**QED:** Ligand B (0.728) is better than Ligand A (0.403), indicating a more drug-like profile.

**DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (31.214), which is a significant concern.

**BBB:** Ligand B (84.141) has better BBB penetration than Ligand A (54.246), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.064) is slightly better than Ligand B (-5.179).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.569) is slightly better than Ligand B (-4.127).

**hERG:** Ligand A (0.073) has a lower hERG risk than Ligand B (0.454), which is a positive attribute.

**Microsomal Clearance:** Ligand B (95.573) has a much higher microsomal clearance than Ligand A (39.237), indicating lower metabolic stability. This is a critical drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-36.549) has a longer in vitro half-life than Ligand B (-8.392), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux liability than Ligand B (0.608).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.6 and -7.4 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has a better QED and BBB, its significantly higher DILI risk and substantially worse metabolic stability (higher Cl_mic, shorter t1/2) are major drawbacks. Ligand A, despite a lower QED and slightly lower solubility, presents a much more favorable ADME-Tox profile, with lower DILI, better metabolic stability, and lower P-gp efflux. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 15:10:27,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.385 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.27) is better than Ligand B (104.39). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Both ligands have good logP values (1.317 and 1.171), falling within the 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Ligand A is preferred here, as lower HBA generally improves permeability.

**QED:** Both ligands have reasonable QED scores (0.807 and 0.75), indicating good drug-like properties.

**DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (65.064). This is a major advantage for Ligand A.

**BBB:** Ligand A (74.176) has better BBB penetration than Ligand B (51.803), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.866) shows better Caco-2 permeability than Ligand B (-4.651).

**Aqueous Solubility:** Ligand A (-2.365) has slightly better aqueous solubility than Ligand B (-2.827).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.378 and 0.09). This is excellent.

**Microsomal Clearance:** Ligand A (-29.744) exhibits significantly lower microsomal clearance than Ligand B (-72.377), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-27.676) has a better in vitro half-life than Ligand B (-24.659).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.023).

**Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-7.7). While the difference is not huge, it's still a positive factor.

**Overall:**

Ligand A consistently outperforms Ligand B across several key parameters, particularly DILI risk and metabolic stability (Cl_mic). While both ligands are reasonably drug-like, the lower DILI and better metabolic stability of Ligand A make it a more promising drug candidate for SRC kinase inhibition. The slightly better binding affinity further supports this conclusion.

Output:
1
2025-04-17 15:10:27,225 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision, considering the guidelines and enzyme-kinase specific priorities:

**1. Molecular Weight (MW):**
*   Ligand A: 344.463 Da - Within the ideal range (200-500).
*   Ligand B: 345.447 Da - Within the ideal range (200-500).
*   *Both are good.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 75.08 - Good for oral absorption (<140).
*   Ligand B: 90.98 - Still acceptable for oral absorption, but approaching the upper limit.
*   *Ligand A is slightly better.*

**3. Lipophilicity (logP):**
*   Ligand A: 2.009 - Optimal (1-3).
*   Ligand B: 1.855 - Optimal (1-3).
*   *Both are good.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 2 - Meets the criteria (<=5).
*   Ligand B: 2 - Meets the criteria (<=5).
*   *Both are good.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 5 - Meets the criteria (<=10).
*   Ligand B: 4 - Meets the criteria (<=10).
*   *Both are good.*

**6. QED:**
*   Ligand A: 0.768 - Excellent drug-like properties (>0.5).
*   Ligand B: 0.668 - Good drug-like properties (>0.5).
*   *Ligand A is slightly better.*

**7. DILI:**
*   Ligand A: 58.24 - Acceptable risk (<60).
*   Ligand B: 45.095 - Lower risk, better.
*   *Ligand B is better.*

**8. BBB:**
*   Ligand A: 63.086 - Not a priority for a non-CNS target.
*   Ligand B: 62.117 - Not a priority for a non-CNS target.
*   *Similar.*

**9. Caco-2 Permeability:**
*   Ligand A: -5.189 - Poor permeability.
*   Ligand B: -4.914 - Poor permeability.
*   *Similar, both are concerning.*

**10. Aqueous Solubility:**
*   Ligand A: -2.303 - Poor solubility.
*   Ligand B: -3.492 - Very poor solubility.
*   *Ligand A is better.*

**11. hERG Inhibition:**
*   Ligand A: 0.34 - Low risk.
*   Ligand B: 0.052 - Very low risk, better.
*   *Ligand B is better.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 20.082 - Moderate clearance.
*   Ligand B: 30.311 - Higher clearance, less desirable.
*   *Ligand A is better.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: 47.891 - Good half-life.
*   Ligand B: 2.271 - Very short half-life, concerning.
*   *Ligand A is significantly better.*

**14. P-gp Efflux:**
*   Ligand A: 0.092 - Low efflux, better.
*   Ligand B: 0.056 - Very low efflux, better.
*   *Ligand B is slightly better.*

**15. Binding Affinity:**
*   Ligand A: -9.1 kcal/mol - Excellent.
*   Ligand B: -9.2 kcal/mol - Excellent, slightly better.
*   *Ligand B is slightly better.*

**Summary & Decision:**

Given that we are targeting an enzyme (kinase), potency, metabolic stability, solubility, and hERG risk are key. While both ligands have excellent binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and better solubility. Ligand B has a slightly lower DILI risk and hERG inhibition, but its very short half-life and poor solubility are major drawbacks. The small advantage in binding affinity of ligand B is unlikely to overcome the significant ADME deficiencies.

Therefore, I recommend **Ligand A** as the more viable drug candidate.

1
2025-04-17 15:10:27,225 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [366.443, 102.32 ,   2.27 ,   2.   ,   6.   ,   0.845,  94.804,  48.662, -4.826,  -3.933,   0.352,  23.817, -14.91 ,   0.102,  -9.1  ]
**Ligand B:** [343.431,  83.02 ,   1.719,   2.   ,   4.   ,   0.867,  41.334,  39.046, -5.24 ,  -2.314,   0.349,  15.684, -29.455,   0.043, -10.2  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (366.443) is slightly higher than B (343.431), but both are acceptable.
2. **TPSA:** A (102.32) is slightly above the preferred <140, but still reasonable. B (83.02) is excellent, well below 140.
3. **logP:** Both are within the optimal 1-3 range. A (2.27) is slightly higher than B (1.719).
4. **HBD:** Both have 2 HBD, which is good.
5. **HBA:** A has 6 HBA, B has 4 HBA. Both are acceptable, below the 10 threshold.
6. **QED:** Both have high QED scores (A: 0.845, B: 0.867), indicating good drug-like properties.
7. **DILI:** A (94.804) has a very high DILI risk, significantly above the 60% threshold. B (41.334) is much better, below the 40% threshold. This is a major concern for Ligand A.
8. **BBB:** Not a primary concern for a kinase inhibitor, but A (48.662) and B (39.046) are both relatively low.
9. **Caco-2:** Both are negative, which is unusual and suggests poor permeability. A (-4.826) is slightly better than B (-5.24).
10. **Solubility:** Both are negative, suggesting poor solubility. A (-3.933) is slightly better than B (-2.314).
11. **hERG:** Both are very low (A: 0.352, B: 0.349), indicating a low risk of hERG inhibition.
12. **Cl_mic:** A (23.817) has a moderate clearance, while B (15.684) has a lower clearance, suggesting better metabolic stability.
13. **t1/2:** B (-29.455) has a much longer in vitro half-life than A (-14.91), indicating better persistence.
14. **Pgp:** Both have very low Pgp efflux liability (A: 0.102, B: 0.043).
15. **Binding Affinity:** Both have excellent binding affinities (A: -9.1 kcal/mol, B: -10.2 kcal/mol). B is slightly better, but the difference is not huge.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both ligands have good affinity, Ligand A has a significantly higher DILI risk and a shorter half-life, while Ligand B has better metabolic stability, a longer half-life, and a much lower DILI risk. The solubility and Caco-2 values are poor for both, but these can potentially be addressed through formulation strategies. The high DILI risk of Ligand A is a major red flag.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. Its lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and comparable binding affinity outweigh the slightly lower Caco-2 and solubility values.

1
2025-04-17 15:10:27,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.483 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.73) is better than Ligand B (76.15), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.67) is optimal, while Ligand B (0.98) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable.

**QED:** Both ligands have reasonable QED scores (0.724 and 0.639), indicating good drug-like properties.

**DILI:** Ligand A (48.623) has a slightly higher DILI risk than Ligand B (33.656), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (81.698 and 78.868), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** 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 (-4.738) is slightly worse than Ligand B (-4.161).

**Solubility:** Ligand A (-2.458) is worse than Ligand B (-0.95), indicating lower aqueous solubility.

**hERG:** Both ligands have very low hERG risk (0.301 and 0.176).

**Microsomal Clearance:** Ligand A (70.887) has higher clearance than Ligand B (64.634), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-16.629) has a longer half-life than Ligand A (-12.74).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.282 and 0.04).

**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 ADME drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.3 vs -7.0 kcal/mol) is a major advantage. While Ligand A has slightly better TPSA and DILI, Ligand B's superior affinity, longer half-life, and better solubility outweigh these minor differences. The slightly lower logP of Ligand B is a minor concern, but the strong affinity suggests it can still bind effectively.

Output:
1
2025-04-17 15:10:27,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (381.435 and 367.877 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (124.93) is better than Ligand B (73.83). Both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.383 and 2.851), 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:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.738 and 0.748), indicating good drug-likeness.

**7. DILI:** Ligand A (86.429) has a significantly higher DILI risk than Ligand B (41.179). This is a major concern for Ligand A.

**8. BBB:** Ligand A (14.153) has a very low BBB penetration, while Ligand B (61.923) has a moderate value. BBB is not a primary concern for SRC kinase inhibitors, as it's not a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.527) has poor Caco-2 permeability, while Ligand B (-4.802) is slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.365 and -3.306). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.111) has a slightly higher hERG inhibition risk than Ligand B (0.656).

**12. Microsomal Clearance:** Ligand A (4.685) has lower microsomal clearance than Ligand B (5.827), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (86.649) has a significantly longer in vitro half-life than Ligand A (32.581).

**14. P-gp Efflux:** Ligand A (0.1) has lower P-gp efflux than Ligand B (0.148), which is slightly favorable.

**15. Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Enzyme-Specific Priorities:** For SRC kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a much better binding affinity and lower Cl_mic, but suffers from a high DILI risk, poor Caco-2 permeability, and a short half-life. Ligand B has a better safety profile (lower DILI), better permeability, and a longer half-life, but its affinity is very weak.

**Conclusion:** Despite the significantly stronger binding affinity of Ligand A, the high DILI risk and poor pharmacokinetic properties (Caco-2, t1/2) are major drawbacks. Ligand B, while having a weak affinity, presents a much more favorable safety and pharmacokinetic profile. Given the importance of metabolic stability and safety for an enzyme inhibitor, and the potential to optimize the affinity of Ligand B through medicinal chemistry efforts, Ligand B is the more promising starting point.

Output:
1
2025-04-17 15:10:27,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.479 and 358.473 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.33) is better than Ligand B (40.62). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.405) is a bit low, potentially hindering permeation. Ligand B (3.552) 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 (5) is good. Ligand B (2) is also good.

**QED:** Both ligands (0.745 and 0.754) have excellent drug-likeness scores.

**DILI:** Ligand A (3.606) has a slightly better DILI score than Ligand B (26.444), indicating lower potential for liver injury.

**BBB:** Ligand A (27.84) has a low BBB penetration score, which isn't critical for a non-CNS target like SRC. Ligand B (87.088) has a high BBB score, which is irrelevant here and could even be a slight negative if off-target CNS effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.14) is very poor, suggesting poor intestinal absorption. Ligand B (-4.232) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (0.094) is very poor. Ligand B (-3.836) is also very poor. Solubility is a significant concern for both.

**hERG Inhibition:** Ligand A (0.331) is excellent, indicating very low cardiotoxicity risk. Ligand B (0.825) is higher, suggesting a moderate risk. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-3.989) indicates very low clearance and excellent metabolic stability. Ligand B (50.663) has high clearance, suggesting poor metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (17.458) has a reasonable half-life. Ligand B (-16.149) has a negative half-life, which is not possible and indicates a significant issue with the data or the compound's stability.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is good. Ligand B (0.254) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand A (-8.2) has significantly better binding affinity than Ligand B (-7.7). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having a better logP, Ligand A is the superior candidate. Its significantly stronger binding affinity (-8.2 vs -7.7 kcal/mol) and excellent metabolic stability (very low Cl_mic) are crucial for an enzyme inhibitor. The lower hERG risk is also a major benefit. While both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies. The negative half-life for Ligand B is a showstopper.

Output:
0
2025-04-17 15:10:27,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.447 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (111.66) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (71) is excellent, well below 140.

**logP:** Both ligands have good logP values (3.206 and 2.475), 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 9 HBAs, close to the upper limit of 10. Ligand B has 4, which is very good.

**QED:** Ligand B (0.829) has a significantly better QED score than Ligand A (0.329), indicating a more drug-like profile.

**DILI:** Ligand A has a high DILI risk (87.127), which is a major concern. Ligand B has a very low DILI risk (16.092), a significant advantage.

**BBB:** Both ligands have similar BBB penetration (70.415 and 70.26), which is acceptable but not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.249), suggesting poor permeability. Ligand B also has a negative value (-4.779), indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.419 and -3.333). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.172 and 0.129), which is positive.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (77.979) than Ligand B (44.549), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a negative in vitro half-life (-12.862), which is a major red flag, suggesting very rapid degradation. Ligand A has a half-life of 8.303 hours, which is reasonable.

**P-gp Efflux:** Ligand A has a low P-gp efflux liability (0.259), while Ligand B has very low efflux (0.086).

**Binding Affinity:** Ligand A has a better binding affinity (-7.9 kcal/mol) than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, but suffers from a high DILI risk, poor Caco-2 permeability, and moderate metabolic stability. Ligand B has a much better DILI profile, QED, and P-gp efflux, but its binding affinity is essentially non-existent, and it has a very poor in vitro half-life.

Given the enzyme-specific priorities, binding affinity is crucial. However, the extremely poor affinity of Ligand B and its very short half-life are dealbreakers. While Ligand A's DILI risk is concerning, it's potentially addressable through structural modifications. The strong binding affinity of Ligand A makes it a better starting point for optimization, even with the DILI concern.

Output:
0
2025-04-17 15:10:27,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.438 Da) is slightly higher than Ligand B (348.447 Da), but both are acceptable.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (89.27). Lower TPSA generally favors better absorption.

**logP:** Ligand A (4.927) is high, potentially causing solubility issues or off-target effects. Ligand B (1.512) is within the optimal 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.

**QED:** Both ligands have good QED scores (A: 0.769, B: 0.868), indicating good drug-like properties.

**DILI:** Ligand A (80.186) has a higher DILI risk than Ligand B (56.689). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.627) is slightly better than Ligand B (51.415).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.28 and -4.846), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Ligand A (-6.116) has very poor aqueous solubility, while Ligand B (-2.524) is also poor, but comparatively better.

**hERG Inhibition:** Ligand A (0.346) has a slightly higher hERG risk than Ligand B (0.415), but both are relatively low.

**Microsomal Clearance:** Ligand B (27.339) has significantly lower microsomal clearance than Ligand A (118.638), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (-25.571) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability. Ligand A (50.789) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.334, B: 0.14).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate despite some concerning properties. Its significantly stronger binding affinity (-9.7 vs -6.9 kcal/mol) is a major advantage for an enzyme target like SRC kinase. While its TPSA is higher, its lower logP, lower DILI risk, and significantly improved metabolic stability (lower Cl_mic) are all favorable. The negative half-life is a data issue that would need to be resolved, but the other properties suggest it's still the better starting point. Ligand A's poor solubility and high DILI risk are significant drawbacks.

Output:
1
2025-04-17 15:10:27,226 - INFO - Batch 357 complete. Total preferences: 5712
2025-04-17 15:10:27,226 - INFO - Processing batch 358/512...
2025-04-17 15:11:08,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.53 and 348.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.27) is well below the 140 threshold, while Ligand B (128.53) is closer but still acceptable.

**logP:** Ligand A (2.347) is optimal (1-3). Ligand B (-0.191) is below 1, which could hinder permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3 respectively), below the 5 threshold.

**H-Bond Acceptors:** Ligand A (3) is well below the 10 threshold. Ligand B (6) is also acceptable.

**QED:** Both ligands have similar, good QED values (0.679 and 0.664), indicating drug-likeness.

**DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (69.756), which is considered high risk. This is a significant advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (63.75) is better than Ligand B (8.18).

**Caco-2 Permeability:** Ligand A (-4.852) is very poor, while Ligand B (-5.633) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.63) is poor, while Ligand B (-1.954) is also poor. Both are problematic.

**hERG Inhibition:** Ligand A (0.176) has a very low hERG risk, while Ligand B (0.135) is also low.

**Microsomal Clearance:** Ligand A (67.868) has higher clearance than Ligand B (16.49). This suggests Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-23.948) has a very short half-life, while Ligand B (11.153) is better. This further supports Ligand B's better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.096 and 0.019).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 2.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

While Ligand A has a better safety profile (lower DILI, lower hERG), Ligand B's significantly superior binding affinity (-9.9 vs -7.4 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are more critical for an enzyme target like SRC kinase. The lower logP and solubility of Ligand B are drawbacks, but the potency advantage is likely to be decisive.

Output:
1
2025-04-17 15:11:08,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.378 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (69.64) is well within the range.

**logP:** Ligand A (0.844) is a little low, potentially impacting permeability. Ligand B (2.706) is optimal.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**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 good QED scores (0.767 and 0.791, respectively), indicating good drug-like properties.

**DILI:** Ligand A (50.64) has a slightly higher DILI risk than Ligand B (33.695), but both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (69.407 and 60.76), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.961) has poor Caco-2 permeability, while Ligand B (-5.027) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.164 and -2.937). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.327 and 0.224, respectively).

**Microsomal Clearance:** Ligand A (-3.573) has significantly better metabolic stability (lower clearance) than Ligand B (12.938). This is a major advantage.

**In vitro Half-Life:** Ligand A (-6.344) has a longer half-life than Ligand B (-4.899).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.148 and 0.07, respectively).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol) - a difference of 1.3 kcal/mol. This is a substantial advantage and can often outweigh other deficiencies.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate due to its significantly higher binding affinity (-8.1 vs -6.8 kcal/mol) and superior metabolic stability (lower Cl_mic and longer half-life). The 1.3 kcal/mol difference in binding affinity is substantial and outweighs the slightly higher DILI risk and lower logP. Improving solubility would be a key focus in further optimization.

Output:
0
2025-04-17 15:11:08,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.394 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 A (84.94) is slightly higher than Ligand B (75.27), but both are good.

**logP:** Ligand A (0.279) is quite low, potentially hindering membrane permeability. Ligand B (2.052) 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 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.663, B: 0.597), indicating drug-like properties.

**DILI:** Ligand A (29.43) has a much lower DILI risk than Ligand B (64.754). This is a substantial advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (87.67) has better BBB penetration than Ligand B (77.821).

**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 (0.226) has a much lower hERG risk than Ligand B (0.582). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (19.662) has a higher microsomal clearance than Ligand B (11.037), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-24.643) has a significantly longer in vitro half-life than Ligand A (-8.786). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Both ligands have excellent 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:**

Ligand B has advantages in logP, metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. However, Ligand A has significantly better DILI and hERG profiles, and better BBB penetration. Given the enzyme-specific priorities, metabolic stability and potency are important. The difference in binding affinity is small enough that the superior safety profile of Ligand A (lower DILI and hERG) and the slightly better permeability (due to lower MW and TPSA) makes it the more promising candidate. The negative solubility and Caco-2 values are concerning for both, and would require further investigation.

Output:
0
2025-04-17 15:11:08,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (367.515 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand A (71.84 A^2) is significantly lower than Ligand B (82.49 A^2), suggesting better potential for cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.074) is at the higher end, while Ligand B (2.32) is closer to the middle.

**H-Bond Donors & Acceptors:** Both have 2 HBD and reasonable HBA counts (4 and 5 respectively). This is acceptable for both.

**QED:** Both ligands have QED values > 0.5 (0.826 and 0.837), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 66.731, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 29.818, making it significantly safer in terms of liver toxicity. This is a major advantage for Ligand B.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (76.037) has a higher BBB percentile than Ligand B (43.815).

**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 unusual. This indicates poor aqueous solubility for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.205 and 0.365), which is good and minimizes cardiotoxicity risk.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (14.881 mL/min/kg) than Ligand B (34.096 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (55.008 hours) than Ligand B (28.851 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.38 and 0.058), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.3 kcal/mol) 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 superior binding affinity and better metabolic stability (lower Cl_mic and longer t1/2). However, it has a higher DILI risk and worse solubility. Ligand B has a much lower DILI risk, but weaker binding affinity and poorer metabolic stability.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), 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 solubility issue is also addressable. The significantly better affinity of Ligand A (-8.3 vs -7.0 kcal/mol) is a >1.5 kcal/mol advantage, and therefore outweighs the other concerns.

Output:
1
2025-04-17 15:11:08,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (342.374 and 341.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is better than Ligand B (82.27). Both are below the 140 threshold for oral absorption, but lower is generally preferred.

**3. logP:** Ligand A (3.3) is optimal, while Ligand B (1.375) 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:** Both ligands have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.899) has a much better QED score than Ligand B (0.466), indicating a more drug-like profile.

**7. DILI:** Ligand B (38.309) has a significantly lower DILI risk than Ligand A (70.686). This is a major advantage for Ligand B.

**8. BBB:** Ligand A (70.88) has a better BBB penetration score than Ligand B (35.673). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.776) has better Caco-2 permeability than Ligand B (-4.967).

**10. Aqueous Solubility:** Ligand B (-2.484) has better aqueous solubility than Ligand A (-4.496). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.627) has a higher hERG inhibition liability than Ligand B (0.362), which is undesirable.

**12. Microsomal Clearance:** Ligand A (-33.824) has significantly lower microsomal clearance than Ligand B (-2.243), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (41.623) has a longer in vitro half-life than Ligand B (-24.15).

**14. P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux than Ligand B (0.11).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). The difference is 0.9 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A has better binding affinity, metabolic stability (Cl_mic, t1/2), Caco-2 permeability, and P-gp efflux. However, Ligand B has a much lower DILI risk, better solubility, and lower hERG inhibition. The lower DILI and hERG risk of Ligand B are crucial for drug development. While the affinity difference is notable, the improved safety profile of Ligand B, coupled with acceptable solubility, makes it the more promising candidate.

Output:
1
2025-04-17 15:11:08,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.306 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.02) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (103.71) is excellent, well below 140.

**logP:** Ligand A (2.076) is within the optimal 1-3 range. Ligand B (0.82) is a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, both acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Ligand A (0.576) is good, indicating a drug-like profile. Ligand B (0.857) is even better, suggesting a higher probability of success.

**DILI:** Ligand A (97.829) has a very high DILI risk, a significant concern. Ligand B (15.82) has a very low DILI risk, a major advantage.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.861) shows poor permeability. Ligand B (-5.252) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-5.263) has poor solubility. Ligand B (-1.305) has slightly better solubility, but still poor.

**hERG Inhibition:** Ligand A (0.598) has a moderate hERG risk. Ligand B (0.171) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (22.217) has moderate clearance, indicating moderate metabolic stability. Ligand B (-9.016) has *negative* clearance, which is unusual and suggests very high metabolic stability - a major advantage.

**In vitro Half-Life:** Ligand A (69.79) has a good half-life. Ligand B (9.385) has a short half-life, a potential drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >2 kcal/mol difference is substantial and can outweigh many ADME concerns.

**Conclusion:**

Despite Ligand B's slightly lower logP and poor permeability/solubility, its overwhelmingly superior binding affinity, extremely low DILI and hERG risk, and exceptional metabolic stability make it the far more promising drug candidate. Ligand A's high DILI risk is a deal-breaker. The strong binding affinity of Ligand B suggests it might be possible to overcome the solubility/permeability issues through formulation strategies.

Output:
1
2025-04-17 15:11:08,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.328 Da and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.97 and 108.29) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.262 and 1.023), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is better than Ligand B (3 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.858 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A (85.459) has a significantly higher DILI risk than Ligand B (40.83). This is a major concern for Ligand A.

**BBB:** Both have similar BBB penetration (50.019 and 51.066), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.652) has significantly worse Caco-2 permeability than Ligand B (-5.436).

**Aqueous Solubility:** Ligand A (-4.582) is slightly better than Ligand B (-3.996).

**hERG Inhibition:** Ligand A (0.633) has a higher hERG inhibition liability than Ligand B (0.139), which is undesirable.

**Microsomal Clearance:** Ligand B (2.474 mL/min/kg) has much lower microsomal clearance than Ligand A (33.236 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.079 hours) has a significantly longer in vitro half-life than Ligand A (6.071 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.01).

**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 is still a factor.

**Overall Assessment:**

Ligand B is significantly better overall. While Ligand A has slightly better logP and solubility, Ligand B excels in critical areas for an enzyme inhibitor: metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG risk, and slightly better binding affinity. The Caco-2 permeability is also better for Ligand B. The higher DILI and hERG risk associated with Ligand A are major red flags.

Output:
1
2025-04-17 15:11:08,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.467 Da) is slightly lower, which could be beneficial for permeability. Ligand B (377.941 Da) is also good.

**TPSA:** Ligand A (71.84) is higher than Ligand B (26.79). While both are reasonably low, Ligand B's lower TPSA is more favorable for cell permeability.

**logP:** Both ligands have good logP values (A: 4.027, B: 3.52), 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 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.741, B: 0.815), indicating good drug-like properties.

**DILI:** Ligand B (35.285) has a significantly lower DILI risk than Ligand A (83.249). This is a major advantage for Ligand B.

**BBB:** Ligand A (61.613) has a lower BBB penetration than Ligand B (88.135). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close (-5.129 for A, -4.912 for B), so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are similar (-4.085 for A, -3.517 for B), so this isn't a major differentiator.

**hERG Inhibition:** Ligand A (0.626) has a slightly lower hERG risk than Ligand B (0.857), which is a small advantage.

**Microsomal Clearance:** Ligand A (39.772) has lower microsomal clearance than Ligand B (50.885), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (80.965) has a much longer half-life than Ligand B (-0.144). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.689) has lower P-gp efflux than Ligand B (0.617), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (-9.6). This is a substantial advantage for Ligand B, and likely outweighs many of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much lower DILI risk. While Ligand A has better metabolic stability and half-life, the strong binding of Ligand B is a critical factor for an enzyme inhibitor. The slight solubility and permeability concerns with Ligand B can potentially be addressed through formulation strategies. The lower DILI risk is also a major benefit.

Output:
1
2025-04-17 15:11:08,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.11) is better than Ligand B (99.77), being well below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (0.793 and 1.742, respectively), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.761 and 0.561), suggesting good drug-like properties. Ligand A is better.

**DILI:** Both ligands have similar low DILI risk (22.218 and 22.8 percentile).

**BBB:** Ligand B (64.017) has a higher BBB penetration score than Ligand A (44.397), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.85) has a worse Caco-2 permeability than Ligand B (-5.417), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.068) has a better aqueous solubility than Ligand B (-2.38).

**hERG:** Both ligands have very low hERG inhibition liability (0.52 and 0.046), which is excellent. Ligand B is better.

**Microsomal Clearance:** Ligand A (-18.462) has significantly lower (better) microsomal clearance than Ligand B (27.571), indicating greater metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-12.514) has a longer in vitro half-life than Ligand B (-19.949), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.008).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 1.3 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and acceptable solubility. While Ligand B has slightly better Caco-2 permeability and BBB, metabolic stability is a more critical factor for kinase inhibitors.

Output:
1
2025-04-17 15:11:08,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.3 and 86.09) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.105 and 2.772) are within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Both ligands have good QED scores (0.882 and 0.863), indicating good drug-likeness.

**DILI:** Ligand A (45.483) has a slightly higher DILI risk than Ligand B (39.046), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (81.233 and 81.039), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.812 and -4.888). This is unusual and suggests poor permeability, but the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.914 and -3.496). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.07) has a slightly lower hERG risk than Ligand B (0.539), which is preferable.

**Microsomal Clearance:** Ligand A (4.219 mL/min/kg) has significantly better metabolic stability (lower clearance) than Ligand B (21.375 mL/min/kg).

**In vitro Half-Life:** Ligand A (12.731 hours) has a much longer half-life than Ligand B (-1.363 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux than Ligand B (0.224).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). While the difference is small, it's still a positive.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. It has superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, slightly better binding affinity, and a lower hERG risk. While both have poor solubility and questionable permeability, the metabolic advantages of Ligand A are more critical for an enzyme target. The small difference in binding affinity further supports this choice.

Output:
0
2025-04-17 15:11:08,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.414 and 343.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (54.26). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (2.385 and 2.69), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while 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 good QED scores (0.608 and 0.809), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 81.117, which is high (>60). Ligand B has a DILI risk of 48.546, which is acceptable (<60). This is a significant advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration (64.056 and 79.139). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.777 and -4.723). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values aren't directly comparable without knowing the scale used.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.935 and -2.83). Similar to Caco-2, these values are on a scale where negative values indicate poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.263) has a slightly lower hERG risk than Ligand B (0.53).

**Microsomal Clearance:** Ligand A (52.827) has a lower microsomal clearance than Ligand B (87.403), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (44.486) has a longer half-life than Ligand B (19.68), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux than Ligand B (0.344), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This 1.5 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, but a significantly higher DILI risk. Ligand B has a better QED, lower DILI risk, slightly better solubility, and a superior binding affinity. The DILI risk associated with Ligand A is a major concern. While the slightly better metabolic stability of Ligand A is desirable, the improved binding affinity and significantly reduced toxicity risk of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 15:11:08,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.391 and 362.836 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.55) is better than Ligand B (50.28) as it is closer to the threshold of 140 for good oral absorption.

**logP:** Ligand A (-0.502) is slightly low, potentially hindering permeation. Ligand B (3.525) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (7) is acceptable, while Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.569 and 0.901), indicating drug-likeness.

**DILI:** Ligand A (54.517) has a better DILI score than Ligand B (68.515), indicating a lower risk of liver injury.

**BBB:** Ligand A (48.081) and Ligand B (81.039). BBB is not a major concern for SRC kinase, as it's not a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.28 and -4.82) which is not ideal.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.107 and -4.565) which is not ideal.

**hERG Inhibition:** Ligand A (0.037) has a significantly lower hERG risk than Ligand B (0.893). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (-0.244) has a lower (better) microsomal clearance than Ligand B (69.802), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.823) has a lower half-life than Ligand B (39.774).

**P-gp Efflux:** Ligand A (0.013) has a lower P-gp efflux liability than Ligand B (0.27), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This difference of 1.2 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall:**

Ligand A is the better candidate. While its logP and solubility are slightly concerning, its superior binding affinity, significantly lower hERG risk, lower DILI, lower microsomal clearance, and lower P-gp efflux outweigh these drawbacks. Ligand B has better logP, but suffers from a higher hERG risk and significantly worse metabolic stability. The potency advantage of Ligand A is also substantial.

Output:
0
2025-04-17 15:11:08,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.387 Da and 358.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.05) is slightly higher than Ligand B (76.66). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (-0.665) is a bit low, potentially hindering permeation. Ligand B (1.577) 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.717 and 0.656), indicating good drug-likeness.

**DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (18.147), though both are below the concerning 60 threshold.

**BBB:** Ligand A (32.144) has a low BBB penetration, while Ligand B (77.821) is quite good. Since SRC is not a CNS target, this is less critical, but still a positive for B.

**Caco-2 Permeability:** Both ligands have similar and very poor Caco-2 permeability (-4.594 and -4.684). This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.88 and -1.951). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.068) has a lower hERG risk than Ligand B (0.336), which is a positive.

**Microsomal Clearance:** Ligand A (-6.581) has a significantly lower (better) microsomal clearance than Ligand B (17.572), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (17.46) has a shorter half-life than Ligand B (21.123), but both are reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.016 and 0.025).

**Binding Affinity:** Both ligands have identical binding affinities (-7.5 kcal/mol), which is excellent.

**Conclusion:**

While Ligand A has a better metabolic stability profile (lower Cl_mic) and lower hERG risk, Ligand B has a more favorable logP and better BBB penetration. Both have poor solubility and Caco-2 permeability. However, given the enzyme-specific priorities, the superior metabolic stability of Ligand A is a crucial advantage. The similar binding affinity means potency is not a differentiating factor. The slightly higher DILI risk of A is not a major concern given the other benefits.

Output:
0
2025-04-17 15:11:08,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (371.825 Da) is also good.

**TPSA:** Ligand A (70.83) is better than Ligand B (96.77). Lower TPSA generally improves oral absorption.

**logP:** Ligand A (1.235) is within the optimal range, while Ligand B (0.236) is a bit low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 6 HBA, which are acceptable.

**QED:** Ligand A (0.883) has a significantly higher QED score than Ligand B (0.66), indicating better overall drug-likeness.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (56.572), but both are reasonably acceptable.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (81.388) is higher, but this is less important.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.535) is slightly better than Ligand B (-4.801).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.404) is slightly better than Ligand B (-2.261).

**hERG Inhibition:** Ligand A (0.581) has a higher hERG risk than Ligand B (0.06), which is a significant concern.

**Microsomal Clearance:** Ligand B (10.843) has a lower microsomal clearance than Ligand A (34.011), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (7.199) has a longer half-life than Ligand B (-2.825), which is desirable.

**P-gp Efflux:** Ligand A (0.177) has lower P-gp efflux than Ligand B (0.013), which is favorable.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better QED, half-life, and P-gp efflux, its significantly higher hERG risk is a major red flag. Ligand B, while having slightly poorer drug-likeness and permeability, exhibits much better metabolic stability (lower Cl_mic) and a much lower hERG risk. For an enzyme target like SRC kinase, metabolic stability and avoiding cardiotoxicity are paramount. The affinity difference, while notable, is less critical than these safety and PK parameters.

Output:
1
2025-04-17 15:11:08,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, suggesting good absorption. Ligand B (112.83) is still under the threshold, but higher, potentially impacting absorption less favorably than Ligand A.

**logP:** Ligand A (3.228) is within the optimal 1-3 range. Ligand B (0.891) is slightly below 1, which *could* hinder permeation, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is excellent. Ligand B (2 HBD, 7 HBA) is acceptable, but more polar.

**QED:** Both ligands have good QED scores (0.735 and 0.799, respectively), indicating drug-like properties.

**DILI:** Ligand A (20.124) has a much lower DILI risk than Ligand B (52.152). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (89.88) has a better BBB score than Ligand B (69.717).

**Caco-2 Permeability:** Ligand A (-4.68) is significantly better than Ligand B (-5.772), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.602) is better than Ligand B (-1.421), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.53) has a lower hERG risk than Ligand B (0.133), which is a significant advantage.

**Microsomal Clearance:** Ligand A (60.229) has a higher (worse) clearance than Ligand B (1.194), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-18.475) has a much longer half-life than Ligand A (1.871), which is a major advantage.

**P-gp Efflux:** Ligand A (0.467) has lower P-gp efflux than Ligand B (0.045), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a 1.2 kcal/mol difference, a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A excels in solubility, permeability, DILI risk, hERG, and P-gp efflux. However, its metabolic stability (high Cl_mic, short half-life) is a major concern.

Ligand B has a significantly better binding affinity and a much longer half-life, which are critical for an enzyme inhibitor. While its logP is slightly low and DILI risk is higher, the strong binding and improved metabolic stability are likely to be more important for SRC kinase inhibition. The difference in binding affinity is substantial enough to offset the slightly higher DILI risk and lower logP.

Output:
1
2025-04-17 15:11:08,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.377 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (56.59) as it is still within the acceptable range for oral absorption.

**logP:** Both ligands have good logP values (2.279 and 1.882), 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 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.817 and 0.747), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (93.835 percentile) compared to Ligand B (38.387 percentile). This is a major concern for Ligand A.

**BBB:** Ligand B has a higher BBB penetration (88.29%) than Ligand A (62.233%), but BBB is not a high priority for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B is slightly better (-2.79) than Ligand A (-4.534).

**hERG Inhibition:** Ligand A (0.519) has a slightly better hERG profile than Ligand B (0.875).

**Microsomal Clearance:** Ligand B has a much higher microsomal clearance (98.113) than Ligand A (74.079), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B has a very short in vitro half-life (8.202 hours) compared to the negative value for Ligand A (-24.517 hours). A negative half-life is not possible, so this is likely an error in the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.209 and 0.286).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.0 kcal/mol) than Ligand A (-7.6 kcal/mol), but the difference is not substantial.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While it has a higher DILI risk, the significantly better metabolic stability (lower Cl_mic, and more reasonable half-life) and comparable affinity outweigh the DILI concern. DILI risk can be further investigated and potentially mitigated through structural modifications. Ligand B's poor metabolic stability is a major hurdle that would be difficult to overcome. The solubility issues for both are concerning, but potentially addressable.

Output:
0
2025-04-17 15:11:08,254 - INFO - Batch 358 complete. Total preferences: 5728
2025-04-17 15:11:08,254 - INFO - Processing batch 359/512...
2025-04-17 15:11:47,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.359 Da and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.85) is close to the upper limit for good oral absorption (<=140), while Ligand B (78.95) is well below, suggesting potentially better absorption.

**logP:** Ligand A (-0.602) is slightly below the optimal range (1-3), potentially hindering permeation. Ligand B (0.531) is also on the lower side, but closer to the optimal range.

**H-Bond Donors & Acceptors:** Ligand A has 4 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Ligand B (0.801) has a significantly higher QED score than Ligand A (0.481), indicating a more drug-like profile.

**DILI:** Ligand A (54.323) has a higher DILI risk than Ligand B (18.728), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (80.031) has a higher BBB score, but it's not a primary factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.079 and -4.824), which is unusual and suggests poor permeability. This is a major red flag for both, but we need to consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.62 and -0.885), indicating very poor aqueous solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.046) has a slightly higher hERG risk than Ligand B (0.079), but both are relatively low.

**Microsomal Clearance:** Ligand B (1.913) has a much lower microsomal clearance than Ligand A (28.583), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand B (6.975) has a longer in vitro half-life than Ligand A (-31.49), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand B (0.009) shows very little P-gp efflux, while Ligand A (0.011) is slightly higher. Both are good.

**Binding Affinity:** Ligand A (-9.3) has a significantly stronger binding affinity than Ligand B (0.0). This is a crucial advantage. A difference of >1.5 kcal/mol can outweigh other issues.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both compounds, Ligand A's significantly superior binding affinity (-9.3 kcal/mol vs 0.0 kcal/mol) is a major advantage. The better metabolic stability and lower DILI risk of Ligand B are attractive, but the substantial difference in binding affinity is likely to be decisive. While the solubility and permeability issues need to be addressed through formulation or structural modifications, the potency advantage of Ligand A makes it the more promising starting point.

Output:
0
2025-04-17 15:11:47,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.3 and 362.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.15) is slightly higher than Ligand B (74.99), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (2.91 and 1.63), falling within the 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 5 HBA, which is within the acceptable range (<=10).

**QED:** Ligand A (0.863) has a higher QED score than Ligand B (0.778), indicating better overall drug-likeness.

**DILI:** Ligand B (59.364) has a lower DILI risk than Ligand A (78.558), which is a significant advantage. Lower DILI is highly desirable.

**BBB:** Ligand A (76.115) has a slightly higher BBB penetration potential than Ligand B (65.374), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.409) is slightly worse than Ligand B (-4.72).

**Aqueous Solubility:** Ligand A (-4.351) is slightly better than Ligand B (-1.696), indicating better solubility.

**hERG Inhibition:** Ligand A (0.686) has a slightly higher hERG inhibition risk than Ligand B (0.421), but both are relatively low.

**Microsomal Clearance:** Ligand B (29.098) has significantly lower microsomal clearance than Ligand A (40.403), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-6.947) has a longer in vitro half-life than Ligand A (-17.257), which is another strong advantage for metabolic stability and dosing frequency.

**P-gp Efflux:** Ligand B (0.201) has lower P-gp efflux than Ligand A (0.284), which is favorable for bioavailability.

**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 important factor for an enzyme inhibitor. A difference of 7.7 kcal/mol is substantial.

**Conclusion:**

Despite Ligand B's advantages in DILI, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and solubility, the dramatically superior binding affinity of Ligand A (-7.7 vs -0.0 kcal/mol) outweighs these concerns. A strong binding affinity is paramount for a kinase inhibitor, and the 7.7 kcal/mol difference is a significant advantage. The slightly higher DILI risk and lower metabolic stability of Ligand A can be addressed through further optimization, but the potency difference is harder to recover.

Output:
1
2025-04-17 15:11:47,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.319 Da) is slightly higher than Ligand B (361.511 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (A: 58.95, B: 62.3) below 140, suggesting good oral absorption potential.

**logP:** Both ligands have logP values within the optimal range (1-3), with A at 4.532 and B at 3.246. Ligand A is a bit high, potentially leading to off-target effects, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=4) both have reasonable H-bond properties, falling within the suggested limits.

**QED:** Both ligands have good QED scores (A: 0.734, B: 0.758), indicating a generally drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (A: 51.105, B: 42.148), below the 60 threshold. Ligand B is slightly better here.

**BBB:** Both ligands have moderate BBB penetration (A: 62.815, B: 68.282). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.989 and -4.785). These values are unusual and suggest poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.223 and -3.801), indicating very poor aqueous solubility. This is a major issue for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.473, B: 0.379), which is excellent.

**Microsomal Clearance:** Ligand A (39.748) has significantly lower microsomal clearance than Ligand B (75.421), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (89.563) has a much longer in vitro half-life than Ligand B (-5.444). This is a substantial benefit, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.347, B: 0.272).

**Binding Affinity:** Ligand B (-9.3 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 highly significant.

**Overall Assessment:**

While both compounds have significant drawbacks (poor solubility and permeability), Ligand B's substantially stronger binding affinity (-9.3 vs -7.4 kcal/mol) is a major advantage that outweighs its higher microsomal clearance and slightly higher DILI risk. The longer half-life and lower clearance of Ligand A are attractive, but the potency difference is too large to ignore. The poor solubility and permeability would need to be addressed through formulation strategies for either compound.

Output:
1
2025-04-17 15:11:47,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.446 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (110.01). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Both ligands have good logP values (2.352 and 1.59), 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) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.909 and 0.704), indicating good drug-like properties.

**DILI:** Ligand B (68.166) has a higher DILI risk than Ligand A (54.556), though both are reasonably acceptable.

**BBB:** Both ligands have similar BBB penetration (78.596 and 70.88), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.972) has a more negative Caco-2 value, suggesting *lower* permeability compared to Ligand B (-5.125). However, the scale is not clear and these values are very similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.958 and -2.81). This is a significant concern for both, but might be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.753) has a slightly higher hERG risk than Ligand B (0.241). This is a point in favor of Ligand B.

**Microsomal Clearance:** Ligand A (1.428) has significantly lower microsomal clearance than Ligand B (31.213), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-1.466) has a longer in vitro half-life than Ligand B (6.758), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.369) exhibits less P-gp efflux than Ligand B (0.058), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a 1.5 kcal/mol difference is often significant, the other ADME properties of Ligand A are more compelling.

**Overall:**

Ligand A demonstrates superior drug-like properties overall, particularly regarding metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux. While Ligand B has a slightly better binding affinity and lower hERG risk, the solubility issues and higher metabolic clearance are significant drawbacks. The better TPSA and lower DILI risk of Ligand A also contribute to its favorability. Given the enzyme-kinase target class, metabolic stability is paramount.

Output:
0
2025-04-17 15:11:47,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.375 and 365.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.19) is better than Ligand B (49.77) as it is closer to the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-1.925) is a bit low, potentially hindering permeability. Ligand B (3.751) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is excellent.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (7 and 4 respectively, both under 10).

**QED:** Ligand B (0.763) has a significantly better QED score than Ligand A (0.322), indicating a more drug-like profile.

**DILI:** Ligand B (17.72) has a much lower DILI risk than Ligand A (64.482), which is a significant advantage.

**BBB:** Ligand B (80.651) shows good BBB penetration, while Ligand A (23.187) does not. This isn't a primary concern for a non-CNS target like SRC, but is still a positive attribute.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.446 and -4.625), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.264 and -3.012), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.142) has a slightly lower hERG risk than Ligand B (0.751), but both are relatively low.

**Microsomal Clearance:** Ligand A (24.151) has a lower microsomal clearance than Ligand B (73.211), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (34.121) has a significantly longer in vitro half-life than Ligand A (-16.363).

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux than Ligand B (0.827), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.6 vs 0.0 kcal/mol) outweighs these drawbacks. The better QED score, lower DILI risk, and longer half-life also contribute to its favorability. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies. The strong binding affinity of Ligand B suggests it is more likely to be an effective SRC kinase inhibitor.

Output:
1
2025-04-17 15:11:47,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.393 and 363.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (105.9), being well below the 140 threshold for oral absorption. Ligand B is higher, potentially impacting absorption.

**logP:** Ligand A (2.555) is optimal (1-3). Ligand B (0.558) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A (2 HBA) is preferable to Ligand B (8 HBA) as fewer HBA generally improves permeability.

**QED:** Both ligands have similar, good QED scores (0.889 and 0.851), indicating good drug-like properties.

**DILI:** Ligand A (36.603) has a much lower DILI risk than Ligand B (66.344), which is considered high risk. This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.084) is higher than Ligand B (46.491).

**Caco-2 Permeability:** Ligand A (-4.663) is better than Ligand B (-5.581), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.707) is better than Ligand B (-2.037), which is crucial for bioavailability.

**hERG:** Ligand A (0.767) has a lower hERG risk than Ligand B (0.095), which is a major safety concern.

**Microsomal Clearance:** Ligand A (1.472) has significantly lower microsomal clearance than Ligand B (14.462), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.647) has a much longer in vitro half-life than Ligand B (0.543), which is desirable.

**P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux than Ligand B (0.042), which is preferable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While a 1.2 kcal/mol difference is notable, it is unlikely to outweigh the substantial advantages of Ligand A in other critical ADME/Tox properties.

**Conclusion:**

Ligand A is the superior candidate. It demonstrates significantly better predicted ADME/Tox properties (lower DILI, better solubility, lower hERG risk, better metabolic stability, longer half-life, lower P-gp efflux, and better Caco-2 permeability) despite a slightly weaker binding affinity. The differences in ADME/Tox are substantial enough to outweigh the modest affinity difference.

Output:
1
2025-04-17 15:11:47,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.455 and 344.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (96.11). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.043 and 1.16), 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 acceptable QED values (0.794 and 0.699), indicating good drug-like properties.

**7. DILI:** Ligand A (26.25) has a much lower DILI risk than Ligand B (56.185). This is a significant advantage.

**8. BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (84.025) has better BBB penetration than Ligand B (61.613).

**9. Caco-2 Permeability:** Ligand A (-4.841) is better than Ligand B (-5.385), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.98) is better than Ligand B (-3.519), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.353 and 0.256), which is excellent.

**12. Microsomal Clearance:** Ligand A (39.236) has a higher microsomal clearance than Ligand B (6.974), meaning it's less metabolically stable. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (15.789) has a slightly longer half-life than Ligand A (14.809).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.168 and 0.07).

**15. 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 the other ADME differences.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better TPSA, solubility, and a lower DILI risk, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer half-life). For an enzyme target like SRC kinase, metabolic stability is crucial. The slightly lower solubility and higher TPSA of Ligand B are less concerning than the higher clearance of Ligand A. The binding affinity difference is minimal.

Output:
1
2025-04-17 15:11:47,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.391 Da) is slightly lower, which could be beneficial for permeability. Ligand B (358.427 Da) is also good.

**TPSA:** Ligand A (59.59) is significantly better than Ligand B (92.49). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.516) is optimal, while Ligand B (1.354) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which is excellent. Ligand B has 1 HBD and 7 HBA, still acceptable but less ideal than Ligand A.

**QED:** Both ligands have reasonable QED scores (A: 0.822, B: 0.688), indicating good drug-like properties.

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (74.99), but both are above the 60 threshold, indicating a concern.

**BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (63.746) is slightly better than Ligand B (55.603).

**Caco-2 Permeability:** Ligand A (-4.645) shows better Caco-2 permeability than Ligand B (-5.754).

**Aqueous Solubility:** Ligand A (-4.569) has better solubility than Ligand B (-1.976). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.711) has a lower hERG risk than Ligand B (0.224), which is a significant advantage.

**Microsomal Clearance:** Ligand A (37.666) has lower microsomal clearance than Ligand B (55.048), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 22.954, B: 22.735).

**P-gp Efflux:** Ligand A (0.316) shows lower P-gp efflux than Ligand B (0.045), which is a positive.

**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 of the ADME drawbacks. A 1.3 kcal/mol difference is significant.

**Conclusion:**

Despite Ligand A having better ADME properties overall (TPSA, logP, solubility, hERG, clearance, P-gp), the significantly stronger binding affinity of Ligand B (-8.4 vs -7.1 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The potency advantage is likely to be more impactful than the slightly less favorable ADME profile, especially given that the ADME properties are not drastically poor. While the DILI risk is a concern for both, it can be addressed during further optimization.

Output:
1
2025-04-17 15:11:47,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.415 Da) and Ligand B (349.475 Da) are both acceptable.

**TPSA:** Ligand A (136.4) is borderline, but acceptable for oral absorption. Ligand B (65.79) is excellent, well below the 140 threshold.

**logP:** Ligand A (0.355) is quite low, potentially hindering permeability. Ligand B (1.826) is within the optimal range (1-3).

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (A: 0.645, B: 0.691), indicating drug-like properties.

**DILI:** Ligand A (82.435) has a concerningly high DILI risk. Ligand B (9.771) has a very low DILI risk, a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (59.093) is higher than Ligand A (24.195) but not crucial here.

**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 can be misleading.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.102) has a slightly elevated hERG risk. Ligand B (0.5) is better, but still warrants investigation.

**Microsomal Clearance:** Ligand A (-1.973) suggests good metabolic stability (negative value). Ligand B (17.796) indicates rapid clearance, a significant drawback.

**In vitro Half-Life:** Ligand A (-5.833) suggests a very long half-life. Ligand B (33.333) is moderate.

**P-gp Efflux:** Ligand A (0.073) has low P-gp efflux, which is good. Ligand B (0.029) also has low P-gp efflux.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -7.5 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 and better logP value outweigh the concerns about its higher microsomal clearance. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 15:11:47,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.5 and 363.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is slightly higher than the preferred <140, but acceptable. Ligand B (45.23) is excellent.

**logP:** Ligand A (2.474) is within the optimal 1-3 range. Ligand B (4.344) is a bit high, potentially causing solubility issues and off-target effects.

**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 scores (0.662 and 0.846), indicating good drug-like properties.

**DILI:** Ligand A (11.2) has a significantly lower DILI risk than Ligand B (36.45), a major advantage.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (64.83) is slightly better.

**Caco-2 Permeability:** Ligand A (-4.83) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.023) is similarly poor.

**Aqueous Solubility:** Ligand A (-1.848) has slightly better solubility than Ligand B (-3.312).

**hERG:** Ligand A (0.236) has a much lower hERG risk than Ligand B (0.562), a critical advantage.

**Microsomal Clearance:** Ligand A (30.32) has lower microsomal clearance than Ligand B (42.08), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.674) has a negative half-life, which is unusual and suggests very rapid clearance or instability. Ligand B (5.334) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.287).

**Binding Affinity:** Both ligands have comparable and good binding affinities (-6.5 and -6.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI and hERG risk, better metabolic stability) and slightly better solubility. However, its Caco-2 permeability is poor and its in vitro half-life is concerningly low. Ligand B has a higher logP and DILI/hERG risk, but better Caco-2 permeability and a reasonable half-life.

Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. The significantly lower DILI and hERG risk of Ligand A, coupled with its better metabolic stability, outweigh the concerns about its permeability and half-life, which could potentially be addressed through formulation or structural modifications. The poor permeability is a concern, but not insurmountable.

Output:
0
2025-04-17 15:11:47,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (367.519 and 347.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (78.43 and 79.38) are below the 140 A^2 threshold for good oral absorption, which is good.

**3. logP:** Ligand A (1.308) is optimal, while Ligand B (2.272) is still within the acceptable range (1-3).

**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 (6) are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.786 and 0.751) are above 0.5, indicating good drug-likeness.

**7. DILI:** Both ligands have the same DILI risk (29.973 and 40.403), which is good (<40 is preferred).

**8. BBB:** Ligand B (67.08) has a better BBB penetration percentile than Ligand A (40.403), but BBB is not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.369) has better Caco-2 permeability than Ligand B (-5.093).

**10. Aqueous Solubility:** Ligand A (-0.753) has better aqueous solubility than Ligand B (-2.415). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.101 and 0.435), which is excellent.

**12. Microsomal Clearance:** Ligand A (6.856) has lower microsomal clearance than Ligand B (27.525), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (27.046) has a slightly longer in vitro half-life than Ligand B (28.353).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.028).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent and the most important factor.

**Conclusion:**

While both ligands have excellent binding affinity and acceptable ADME properties, Ligand A is slightly favored due to its better Caco-2 permeability, aqueous solubility, and significantly lower microsomal clearance, indicating improved metabolic stability. These factors are crucial for kinase inhibitors to achieve adequate exposure and efficacy.

Output:
0
2025-04-17 15:11:47,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.443 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.57 and 78.51) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.504) is optimal (1-3), while Ligand B (0.981) is slightly below, potentially impacting 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 3, both are within the acceptable limit of <=10.

**QED:** Ligand A (0.707) has a better QED score than Ligand B (0.443), indicating a more drug-like profile.

**DILI:** Ligand A (44.048) has a slightly higher DILI risk than Ligand B (23.226), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.078) is slightly higher than Ligand B (52.268).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.796 and -4.612), 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 (-2.781 and -2.056), which is also unusual and suggests poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.471 and 0.044), which is excellent.

**Microsomal Clearance:** Ligand A (40.739) has a higher microsomal clearance than Ligand B (29.294), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-17.421) has a negative half-life, which is not possible. This is a data error and a major red flag. Ligand A (34.562) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.236 and 0.018).

**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:**

Despite the unusual negative values for Caco-2 and solubility, Ligand A is the better candidate. Ligand B has a nonsensical negative in vitro half-life, which immediately disqualifies it. Ligand A has a better QED score, slightly better BBB penetration, and a more reasonable (though still concerning) half-life. While Ligand A has slightly higher DILI risk and clearance, the critical issue with Ligand B's half-life makes Ligand A the preferable choice, pending further investigation into the solubility and permeability issues.

Output:
0
2025-04-17 15:11:47,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.32 Da) is slightly higher than Ligand B (368.543 Da), but both are acceptable.

**TPSA:** Ligand A (47.56) is well below the 140 threshold for oral absorption. Ligand B (78.43) is still within a reasonable range, but less optimal.

**logP:** Ligand A (4.103) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.08) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of hydrogen bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.753, B: 0.694), indicating good drug-like properties.

**DILI:** Both ligands show low DILI risk (A: 45.25, B: 39.434), which is positive.

**BBB:** Both ligands have moderate BBB penetration (A: 55.021, B: 49.748). Since SRC is not a CNS target, this is not a major concern.

**Caco-2 Permeability:** Ligand A (-4.667) shows poor Caco-2 permeability, while Ligand B (-5.381) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -4.724, B: -3.338). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.849) has a slightly higher hERG risk than Ligand B (0.254), which is preferable.

**Microsomal Clearance:** Ligand A (102.452) has higher microsomal clearance than Ligand B (26.479), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (23.287 hours) has a better in vitro half-life than Ligand B (12.74 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.418, B: 0.048), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.2 kcal/mol, B: -8.2 kcal/mol). Ligand A is 1 kcal/mol better, which is a substantial advantage.

**Conclusion:**

Despite Ligand A's superior binding affinity (-9.2 kcal/mol vs -8.2 kcal/mol), its significantly higher microsomal clearance (102.452 vs 26.479) and poor Caco-2 permeability (-4.667 vs -5.381) are major drawbacks. The lower metabolic stability and absorption will likely translate to poor *in vivo* exposure. Ligand B, while having slightly lower affinity, exhibits better metabolic stability and marginally better permeability, and a much lower hERG risk. Given the enzyme-specific priorities, metabolic stability and solubility are crucial. Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 15:11:47,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.404 and 361.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.08) is better than Ligand B (91.32), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (2.449 and 1.787), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.768 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (66.654) has a higher DILI risk than Ligand B (39.434). This is a significant negative for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (68.282) is slightly better than Ligand B (54.285).

**Caco-2 Permeability:** Ligand A (-4.949) has a worse Caco-2 permeability than Ligand B (-5.028), both are very poor.

**Aqueous Solubility:** Ligand A (-4.128) has worse solubility than Ligand B (-2.949). Solubility is important for kinases.

**hERG:** Both ligands have similar, low hERG risk (0.424 and 0.456).

**Microsomal Clearance:** Ligand A (70.693) has significantly higher microsomal clearance than Ligand B (6.56). This suggests Ligand B is more metabolically stable, a key factor for kinases.

**In vitro Half-Life:** Ligand B (-5.181) has a much better in vitro half-life than Ligand A (-11.277). This reinforces the metabolic stability advantage of Ligand B.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.085 and 0.056).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.7 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is the superior candidate. Its significantly lower DILI risk, better solubility, dramatically improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better Caco-2 permeability outweigh the minor advantages Ligand A has in TPSA and BBB. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity are paramount.

Output:
1
2025-04-17 15:11:47,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.415 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.29) is better than Ligand B (128.32), being closer to the <140 threshold for good absorption.

**logP:** Both ligands (0.902 and 0.789) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 3 HBDs, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBAs, while Ligand B has 5. Both are acceptable (<10).

**QED:** Both ligands have similar QED values (0.638 and 0.619), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (40.054 and 47.034, both <60).

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand B (67.08) has a higher percentile than Ligand A (48.546).

**Caco-2 Permeability:** Both are negative (-5.403 and -5.475), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both are negative (-2.423 and -2.532), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.286) has a much lower hERG inhibition liability than Ligand B (0.502), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (7.275) has a significantly *lower* (better) microsomal clearance than Ligand B (-19.719). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-0.23) has a slightly better (longer) half-life than Ligand B (9.044).

**P-gp Efflux:** Ligand A (0.128) has a lower P-gp efflux liability than Ligand B (0.028), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage that could potentially outweigh some of the ADME drawbacks.

**Conclusion:**

While both compounds have significant ADME liabilities (poor solubility and permeability), the dramatically superior binding affinity of Ligand B (-9.5 kcal/mol vs 0.0 kcal/mol) is a decisive factor. A binding affinity difference of this magnitude is likely to overcome the solubility and permeability issues, especially given that formulation strategies can sometimes mitigate these problems. Ligand A has better safety (hERG) and metabolic stability, but the potency difference is too large to ignore.

Output:
1
2025-04-17 15:11:47,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 140, and suggesting good absorption. Ligand B (96.89) is still acceptable, but less favorable.

**logP:** Ligand A (1.575) is optimal. Ligand B (0.364) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.726, B: 0.573), indicating drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (49.399) has a moderate risk, while Ligand B (23.304) has a very low risk of liver injury. This is a significant advantage for Ligand B.

**BBB:** Both have moderate BBB penetration (A: 57.154, B: 61.07). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-4.963) shows poor permeability, while Ligand B (-5.228) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.665) has poor solubility, while Ligand B (-1.544) has slightly better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.48, B: 0.35).

**Microsomal Clearance:** Ligand A (32.017) has a moderate clearance, while Ligand B (6.013) has a very low clearance, indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (11.21) has a moderate half-life, while Ligand B (4.253) has a short half-life. Ligand A is preferable here.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.066, B: 0.023).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This 0.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B stands out due to its superior binding affinity and significantly improved metabolic stability (lower Cl_mic) and lower DILI risk. While its logP is slightly low and solubility is not ideal, the strong binding affinity is a critical factor for an enzyme inhibitor. The better metabolic stability also suggests a potentially longer duration of action. Ligand A has better permeability and half-life, but the weaker binding and higher DILI risk are concerning.

Output:
1
2025-04-17 15:11:47,294 - INFO - Batch 359 complete. Total preferences: 5744
2025-04-17 15:11:47,294 - INFO - Processing batch 360/512...
2025-04-17 15:12:33,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.419 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.05 and 80.03) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.411) is a bit low, potentially hindering permeation. Ligand B (0.648) is slightly better but still on the lower side.

**H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also good.

**H-Bond Acceptors:** Both ligands have 6 HBAs, which is within the acceptable limit of <=10.

**QED:** Both ligands have high QED scores (0.851 and 0.805), indicating good drug-likeness.

**DILI:** Ligand A (56.689) has a slightly higher DILI risk than Ligand B (47.77). Both are acceptable (<60).

**BBB:** Ligand A (44.32) has lower BBB penetration than Ligand B (65.956). This is not a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-5.111) has worse Caco-2 permeability than Ligand B (-4.617). Both are negative, indicating poor permeability, but B is better.

**Aqueous Solubility:** Ligand A (-1.494) has slightly better solubility than Ligand B (-1.75). Both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.253 and 0.158).

**Microsomal Clearance:** Ligand A (30.756) has higher microsomal clearance than Ligand B (22.389), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (1.016) has a slightly longer half-life than Ligand A (8.193).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.039).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is small, it's still a factor.

**Conclusion:**

Ligand B is the more promising candidate. It has better metabolic stability (lower Cl_mic, longer half-life), better Caco-2 permeability, slightly better binding affinity, and a lower DILI risk. While both have suboptimal logP and solubility, the improved metabolic stability of Ligand B is crucial for an enzyme target like SRC kinase. The small advantage in binding affinity further supports this conclusion.

Output:
1
2025-04-17 15:12:33,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.374 and 337.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.7) is better than Ligand B (38.13), being closer to the 140 A^2 threshold. Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (2.184 and 3.47), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target effects, but is not a major concern.

**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:** Both ligands have good QED scores (0.773 and 0.838), 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 (30.012), a major advantage.

**BBB:** Ligand A (71.268) and Ligand B (96.045) both have good BBB penetration, but Ligand B is significantly better. However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.009 and -4.842). This is unusual and suggests poor permeability, but the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.81 and -2.797). This is a significant concern for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.16) has a slightly lower hERG risk than Ligand B (0.935), which is favorable.

**Microsomal Clearance:** Ligand A (36.586) has a higher microsomal clearance than Ligand B (12.588), indicating lower metabolic stability. This is a substantial drawback for Ligand A.

**In vitro Half-Life:** Ligand B (8.153) has a significantly longer in vitro half-life than Ligand A (-23.276), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.21) has lower P-gp efflux than Ligand B (0.473), which is slightly favorable.

**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 minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in the most critical areas for a kinase inhibitor: significantly better binding affinity, lower DILI risk, and much improved metabolic stability (lower Cl_mic and longer t1/2). The better BBB penetration is a bonus. The slightly higher logP and P-gp efflux are less concerning given the substantial advantages in other areas.

Output:
1
2025-04-17 15:12:33,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.434 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (76.66). Both are below 140, suggesting good absorption potential.

**3. logP:** Both ligands have good logP values (2.948 and 2.331), 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, while Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.794 and 0.827), indicating good drug-like properties.

**7. DILI:** Ligand A (44.048) has a slightly better DILI score than Ligand B (56.223), both are acceptable (<60 is good).

**8. BBB:** Ligand A (88.6) has a better BBB score than Ligand B (71.811). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**9. Caco-2 Permeability:** Ligand A (-4.237) has a slightly better Caco-2 permeability than Ligand B (-4.674).

**10. Aqueous Solubility:** Ligand A (-4.19) has slightly better aqueous solubility than Ligand B (-3.215). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.545 and 0.46), which is good.

**12. Microsomal Clearance:** Ligand A (69.049) has significantly higher microsomal clearance than Ligand B (23.039). This means Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (32.305) has a better in vitro half-life than Ligand A (41.282).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.119 and 0.171).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

While Ligand A has slightly better solubility and a marginally better DILI score, Ligand B's significantly stronger binding affinity (-8.4 vs -7.1 kcal/mol) and improved metabolic stability (lower Cl_mic and higher t1/2) outweigh these minor advantages. For an enzyme target like SRC kinase, potency and metabolic stability are paramount.

Output:
1
2025-04-17 15:12:33,072 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [354.491, 98.66, 1.488, 4, 4, 0.581, 15.045, 20.512, -5.032, -2.01, 0.099, 4.172, -3.77, 0.014, -7.9]
**Ligand B:** [373.551, 62.73, 4.854, 2, 7, 0.619, 74.176, 76.541, -5.205, -4.99, 0.662, 84.249, 51.352, 0.457, -8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (354.491) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (98.66) is better than B (62.73). While both are reasonably low, B is significantly lower, which could be beneficial for cell permeability.
3. **logP:** A (1.488) is optimal. B (4.854) is high, potentially leading to solubility issues and off-target interactions.
4. **HBD:** A (4) is acceptable. B (2) is also good.
5. **HBA:** A (4) is acceptable. B (7) is also acceptable.
6. **QED:** Both are good (A: 0.581, B: 0.619), indicating drug-like properties.
7. **DILI:** A (15.045) is *much* better than B (74.176). This is a major red flag for B.
8. **BBB:** A (20.512) is low, not a concern for a non-CNS target. B (76.541) is high, suggesting potential CNS penetration, which isn't a priority for SRC.
9. **Caco-2:** Both are negative, which is unusual and indicates poor permeability.
10. **Solubility:** Both are negative, indicating poor solubility.
11. **hERG:** A (0.099) is very low risk. B (0.662) is slightly higher, but still relatively low.
12. **Cl_mic:** A (4.172) is much better (lower) than B (84.249), indicating better metabolic stability.
13. **t1/2:** A (-3.77) is poor, while B (51.352) is excellent. This is a significant advantage for B.
14. **Pgp:** A (0.014) is very low, suggesting minimal efflux. B (0.457) is higher, indicating some efflux potential.
15. **Affinity:** B (-8) is slightly better than A (-7.9), but the difference is small.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B has a slightly better affinity, but the difference is small.
*   **Metabolic Stability:** A is significantly better (lower Cl_mic). B has a very long half-life, which is a major plus.
*   **Solubility:** Both are poor.
*   **hERG:** A is much better.
*   **DILI:** A is *vastly* superior.

**Conclusion:**

Despite B having a slightly better affinity and a very long half-life, the significantly higher DILI risk and poor metabolic stability make it a less desirable candidate. A's lower DILI risk, better metabolic stability, and acceptable hERG risk outweigh the slightly weaker binding affinity. The poor solubility and Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Therefore, I recommend **Ligand A** as the more viable drug candidate.

1
2025-04-17 15:12:33,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.45 and 348.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.73) is significantly better than Ligand B (95.42). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (2.565) is optimal (1-3), while Ligand B (0.664) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both have 2 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 reasonable QED values (0.881 and 0.78), indicating good drug-like properties.

**DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (65.491). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (77.821) has better BBB penetration than Ligand B (66.344).

**Caco-2 Permeability:** Ligand A (-5.294) has a worse Caco-2 permeability than Ligand B (-4.797), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.169) has slightly better solubility than Ligand B (-1.985), but both are poor.

**hERG Inhibition:** Ligand A (0.911) has a lower hERG risk than Ligand B (0.188), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (-13.827) has *much* lower microsomal clearance than Ligand B (-1.747), indicating significantly better metabolic stability. This is a major advantage for A.

**In vitro Half-Life:** Ligand A (6.285) has a longer half-life than Ligand B (-14.309).

**P-gp Efflux:** Ligand A (0.275) has lower P-gp efflux than Ligand B (0.018), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -10.4 kcal/mol). Ligand B is slightly better, but the difference is unlikely to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, including lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and better P-gp efflux. These factors are critical for developing a viable drug candidate, particularly for an enzyme target where metabolic stability and safety are paramount. The slight disadvantage in Caco-2 permeability is less concerning than the substantial benefits in other areas.

Output:
1
2025-04-17 15:12:33,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (361.558 Da and 367.852 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (46.61 and 45.55) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.564) is slightly higher than Ligand B (2.776), both are within the optimal 1-3 range.

**H-Bond Donors:** Both have 0 HBDs, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.403 and 0.806), with Ligand B being significantly better.

**DILI:** Ligand A (20.202) has a much lower DILI risk than Ligand B (41.062). This is a significant advantage for Ligand A.

**BBB:** Both have good BBB penetration (77.821 and 96.161), but Ligand B is better. This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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, suggesting poor solubility. Again, the scale is unknown.

**hERG:** Ligand A (0.831) has a slightly higher hERG risk than Ligand B (0.457), but both are reasonably low.

**Microsomal Clearance:** Ligand A (92.54) has higher microsomal clearance than Ligand B (18.361), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (10.547) has a significantly longer in vitro half-life than Ligand A (-6.233). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.846) has slightly higher P-gp efflux than Ligand B (0.237).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.7 kcal/mol difference is substantial and outweighs many other factors.

**Conclusion:**

While Ligand A has a lower DILI risk, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better binding affinity, much better metabolic stability (lower Cl_mic and higher t1/2), and a better QED score. The solubility and Caco-2 values are problematic for both, but the affinity and metabolic stability advantages of Ligand B are more impactful for initial drug candidate selection.

Output:
1
2025-04-17 15:12:33,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.436 and 358.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (41.73) is better than Ligand B (53.43), both are acceptable, but A is closer to the <140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (2.874 and 4.26), within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target effects, but not drastically.

**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 good QED scores (0.689 and 0.717), indicating drug-like properties.

**7. DILI:** Ligand A (8.104) has a significantly lower DILI risk than Ligand B (31.563). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.864) has better BBB penetration than Ligand B (56.65), but this isn't a primary concern.

**9. Caco-2 Permeability:** Ligand A (-4.508) has better Caco-2 permeability than Ligand B (-5.003).

**10. Aqueous Solubility:** Ligand A (-1.535) has better aqueous solubility than Ligand B (-3.541). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.992 and 0.598), which is positive.

**12. Microsomal Clearance:** Ligand A (-5.326) has significantly lower microsomal clearance than Ligand B (88.07). This indicates better metabolic stability, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-9.532) has a much longer in vitro half-life than Ligand B (25.674). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.313 and 0.667).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.7 kcal/mol). Ligand B is slightly better, but the difference is less than 1.5 kcal/mol and can be overcome by superior ADME properties.

**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, better metabolic stability (lower Cl_mic and longer t1/2), and improved solubility. These factors are crucial for developing a viable drug candidate, especially for a kinase inhibitor where sustained target engagement is important.

Output:
0
2025-04-17 15:12:33,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.98) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (54.71) is well within the ideal range.

**logP:** Ligand A (0.27) is quite low, potentially hindering permeation. Ligand B (3.517) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 threshold.

**QED:** Ligand B (0.781) has a significantly better QED score than Ligand A (0.485), indicating a more drug-like profile.

**DILI:** Ligand B (8.375) has a much lower DILI risk than Ligand A (16.596), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.79) has a higher BBB score than Ligand A (45.522).

**Caco-2 Permeability:** Ligand A (-5.683) has poor predicted permeability. Ligand B (-4.844) is better, but still not great.

**Aqueous Solubility:** Ligand A (-1.501) has poor predicted solubility. Ligand B (-2.516) is also poor.

**hERG Inhibition:** Ligand A (0.112) has a slightly lower hERG risk than Ligand B (0.505), but both are acceptable.

**Microsomal Clearance:** Ligand A (-1.052) has a negative clearance, indicating excellent metabolic stability. Ligand B (50.548) has a high clearance, suggesting rapid metabolism. This is a major drawback.

**In vitro Half-Life:** Ligand A (-30.512) has a very long predicted half-life, consistent with its low clearance. Ligand B (59.319) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.005, B: 0.098).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand B having slightly worse solubility and Caco-2 permeability, its significantly better binding affinity, QED, DILI, and metabolic stability (lower Cl_mic, longer half-life) make it the more promising drug candidate. The stronger binding affinity is particularly important for an enzyme target like SRC kinase. Ligand A's low logP and poor solubility are significant liabilities.

Output:
1
2025-04-17 15:12:33,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (360.841 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.4) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (87.74) is still under 140, but less optimal than A.

**3. logP:** Ligand A (3.355) is within the optimal 1-3 range. Ligand B (0.433) is quite 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:** Ligand A (3) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have reasonable QED scores (0.893 and 0.702), indicating good drug-like properties.

**7. DILI:** Ligand A (65.413) has a higher DILI risk than Ligand B (28.15), which is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.564) is higher than Ligand B (56.34).

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of negativity is similar (-4.742 vs -4.773).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and requires further investigation. Ligand B (-1.502) is slightly better than Ligand A (-5.283).

**11. hERG Inhibition:** Ligand A (0.617) has a lower hERG risk than Ligand B (0.11), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (19.057) has significantly lower microsomal clearance than Ligand B (42.4), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.694) has a longer half-life than Ligand B (-15.784), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.259) has lower P-gp efflux than Ligand B (0.015), suggesting better bioavailability.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -7.6 kcal/mol). Ligand A is slightly better (-8.0 vs -7.6), 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 lower DILI risk and slightly better solubility, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly better binding affinity. The lower hERG risk for Ligand A is also a critical advantage. The unusual negative values for Caco-2 and solubility are concerning for both, but the other ADME properties of Ligand A are more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 15:12:33,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.531 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is significantly better than Ligand B (104.46). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Ligand A (3.673) is within the optimal 1-3 range, while Ligand B (1.682) is at the lower end. While not terrible, lower logP can sometimes indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Both ligands have similar QED values (0.792 and 0.679), indicating good drug-likeness.

**DILI:** Ligand A (7.445) has a much lower DILI risk than Ligand B (45.948). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.492) is better than Ligand B (58.085).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so this is hard to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified, making comparison difficult.

**hERG Inhibition:** Ligand A (0.838) has a lower hERG risk than Ligand B (0.068). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (16.962) has significantly lower microsomal clearance than Ligand B (37.732), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (25.526) has a positive half-life, while Ligand B (-30.976) has a negative half-life. This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.076), indicating better bioavailability.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This is a substantial advantage for Ligand B. A >1.5 kcal/mol advantage can outweigh ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior ADMET properties (lower DILI, lower hERG, better metabolic stability, better half-life, lower P-gp efflux), Ligand B boasts a much stronger binding affinity (-10.1 vs -6.4 kcal/mol). The difference in binding affinity is substantial. Given that we are targeting an enzyme, potency is paramount. The improved ADMET profile of Ligand A is valuable, but the significantly better binding affinity of Ligand B is likely to outweigh these benefits, especially in early stages of drug development where optimization can address ADMET concerns.

Output:
1
2025-04-17 15:12:33,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 355.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is slightly higher than Ligand B (43.86). Both are well below the 140 threshold for oral absorption, and acceptable for a kinase inhibitor.

**logP:** Ligand A (3.152) is within the optimal 1-3 range, while Ligand B (1.577) is at the lower end. While lower logP can sometimes indicate solubility issues, it's not a major concern here given the other parameters.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.913) has a significantly better QED score than Ligand B (0.769), indicating a more drug-like profile.

**DILI:** Ligand B (12.524) has a much lower DILI risk than Ligand A (22.024), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (Ligand A: 89.531, Ligand B: 93.718). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.472 and -4.583). This 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:** Both have negative solubility values (-2.754 and -1.176). Similar to Caco-2, these values are difficult to interpret.

**hERG:** Both ligands have low hERG inhibition risk (Ligand A: 0.647, Ligand B: 0.539).

**Microsomal Clearance:** Ligand B (0.171) has *much* lower microsomal clearance than Ligand A (30.13), indicating significantly better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-9.259) has a much longer in vitro half-life than Ligand A (0.18). This reinforces the better metabolic stability of Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.13, Ligand B: 0.028).

**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.

**Conclusion:**

While Ligand A has a better QED score, Ligand B is superior overall. The significantly lower DILI risk, dramatically improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity outweigh the slightly lower QED and logP. The negative Caco-2 and solubility values are concerning for both, but the metabolic advantages of Ligand B are critical for kinase inhibitors.

Output:
1
2025-04-17 15:12:33,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.535 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (89.27). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have good logP values (2.841 and 1.921) within the 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Ligand A is better here (<=10).

**QED:** Both ligands have good QED scores (0.671 and 0.724), indicating good drug-like properties.

**DILI:** Ligand A (11.09) has a much lower DILI risk than Ligand B (45.638). This is a significant advantage for Ligand A.

**BBB:** This is less crucial for a non-CNS target like SRC, but Ligand A (72.78) is better than Ligand B (14.153).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.877) is slightly better than Ligand B (-4.918), but both are problematic.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.121) is slightly better than Ligand B (-2.465), but both are problematic.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.492 and 0.121).

**Microsomal Clearance:** Ligand A (20.161 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (37.248 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (17.623 hours) has a much longer half-life than Ligand B (-4.639 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.055).

**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:**

While Ligand B has a better binding affinity, Ligand A is superior in almost all ADMET properties. Specifically, the significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better TPSA, solubility, and permeability make Ligand A a more promising drug candidate. The difference in binding affinity, while notable, can potentially be overcome with further optimization of Ligand A, while the ADMET issues of Ligand B are more challenging to address. For an enzyme target, metabolic stability and safety (DILI) are crucial, making Ligand A the better choice.

Output:
0
2025-04-17 15:12:33,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.435 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (69.64) is significantly lower than Ligand A (89.35), which is favorable.

**logP:** Ligand A (0.476) is a bit low, potentially hindering permeation. Ligand B (1.727) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.773, B: 0.555), indicating drug-like properties.

**DILI:** Both ligands show low DILI risk (A: 42.536, B: 34.277), which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (70.027) has a higher BBB percentile than Ligand A (46.724), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can still compare them relatively. Ligand A (-5.008) is worse than Ligand B (-4.917).

**Aqueous Solubility:** Ligand A (-0.732) has slightly better solubility than Ligand B (-2.573). Solubility is important for enzymes.

**hERG:** Ligand A (0.114) has a much lower hERG risk than Ligand B (0.734), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-0.244) has a significantly *lower* (better) microsomal clearance than Ligand A (26.63), indicating greater metabolic stability. This is a key consideration for enzymes.

**In vitro Half-Life:** Ligand B (-3.997) has a much longer in vitro half-life than Ligand A (14.408). This is a major positive for Ligand B.

**P-gp Efflux:** Ligand A (0.028) has lower P-gp efflux than Ligand B (0.266), which is favorable.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is the most important factor for an enzyme inhibitor. The 2.8 kcal/mol difference is substantial and likely outweighs minor ADME drawbacks.

**Overall:**

Ligand B is the superior candidate. While Ligand A has slightly better solubility and lower P-gp efflux, Ligand B's significantly stronger binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), and acceptable ADME properties make it the more promising drug candidate for SRC kinase inhibition. The lower hERG risk of Ligand A is a consideration, but the potency advantage of Ligand B is likely to be more impactful.

Output:
1
2025-04-17 15:12:33,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**1. Molecular Weight:** Both ligands (361.431 and 372.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (119.03 and 113.01) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.233) is quite low, potentially hindering permeation. Ligand B (-0.767) 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:** Ligand A has 8 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.787) has a significantly better QED score than Ligand B (0.468), indicating a more drug-like profile.

**7. DILI:** Ligand A (62.001) has a higher DILI risk than Ligand B (27.608). This is a significant concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (70.88) is better than Ligand B (42.924).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.389 and -5.118), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.216 and -1.579), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.294) has a lower hERG risk than Ligand B (0.076), which is preferable.

**12. Microsomal Clearance:** Ligand A (-5.209) has a significantly lower (better) microsomal clearance than Ligand B (3.946), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.263 hours) has a better in vitro half-life than Ligand B (-55.97 hours - a negative value is problematic and likely an error or indicates very rapid degradation).

**14. P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor for an enzyme inhibitor. While its DILI risk is lower, its QED is lower, solubility is poor, and its in vitro half-life is concerningly low (potentially an artifact). Ligand A has a better QED, metabolic stability, and hERG risk, but its low logP and higher DILI risk are problematic. The poor solubility of both is a major concern. However, the significantly improved binding affinity of Ligand B makes it the more promising candidate, assuming the negative half-life can be addressed through structural modifications.

Output:
1
2025-04-17 15:12:33,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.353 and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is slightly higher than Ligand B (67.87), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.256) and Ligand B (2.138) are both within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 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:** Ligand A (0.886) has a significantly better QED score than Ligand B (0.714), indicating a more drug-like profile.

**DILI:** Ligand B (60.682) has a higher DILI risk than Ligand A (53.625), though both are reasonably acceptable.

**BBB:** Ligand A (87.67) has a much higher BBB percentile than Ligand B (63.358). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.457) has a worse Caco-2 permeability than Ligand B (-5.054). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.61 and -2.641). This is a potential concern for both.

**hERG Inhibition:** Ligand A (0.398) has a significantly lower hERG inhibition risk than Ligand B (0.237), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-7.833) has a much lower (better) microsomal clearance than Ligand B (28.369), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (8.159) has a better in vitro half-life than Ligand B (28.731).

**P-gp Efflux:** Ligand A (0.023) has a lower P-gp efflux liability than Ligand B (0.05).

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.1). While both are good, the 1.5 kcal/mol difference is noteworthy.

**Conclusion:**

Ligand A is the superior candidate. While both compounds have similar molecular weights, logP, and H-bond characteristics, Ligand A demonstrates significantly better predicted ADME properties: a higher QED score, lower DILI risk, better BBB penetration, substantially lower hERG inhibition, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The slightly better binding affinity further supports this conclusion. The poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:12:33,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.43 and 360.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.99) is excellent, well below the 140 threshold for oral absorption. Ligand B (84.94) is still acceptable, but less optimal.

**logP:** Ligand A (3.988) is at the higher end of the optimal range (1-3), while Ligand B (0.496) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**QED:** Ligand A (0.898) has a very strong drug-like profile, while Ligand B (0.387) is significantly lower, indicating potential issues.

**DILI:** Both ligands have acceptable DILI risk (33.77 and 37.38 respectively), below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.94) shows good BBB penetration, while Ligand B (75.11) is lower.

**Caco-2 Permeability:** Ligand A (-5.104) has poor Caco-2 permeability, while Ligand B (-4.842) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.418) has poor solubility, while Ligand B (-1.503) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.929) has a slightly higher hERG risk than Ligand B (0.336), but both are reasonably low.

**Microsomal Clearance:** Ligand A (30.402) has a moderate clearance, while Ligand B (-5.896) has negative clearance, which is highly favorable, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-23.55) has a very long half-life, while Ligand B (-4.887) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.661 and 0.015 respectively).

**Binding Affinity:** Ligand A (-8.8 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 superior binding affinity and a better QED score. However, it suffers from poor Caco-2 permeability and solubility. Ligand B has better solubility and metabolic stability (negative Cl_mic), but a significantly weaker binding affinity and a lower QED.

Given the priority for potency in enzyme inhibitors, the substantial binding affinity advantage of Ligand A (-8.8 vs -7.5 kcal/mol) outweighs its drawbacks in solubility and permeability. While permeability is a concern, it can potentially be addressed through formulation strategies. The strong binding affinity suggests a higher probability of achieving efficacy.

Output:
1
2025-04-17 15:12:33,076 - INFO - Batch 360 complete. Total preferences: 5760
2025-04-17 15:12:33,076 - INFO - Processing batch 361/512...
2025-04-17 15:13:13,759 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (335.386 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.67) is significantly better than Ligand B (86.88). A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (3.569 and 2.57), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=3) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.606) has a significantly better QED score than Ligand B (0.385), indicating a more drug-like profile.

**DILI:** Ligand B (35.673) has a much lower DILI risk than Ligand A (65.568). This is a significant advantage for Ligand B.

**BBB:** Both have moderate BBB penetration, but Ligand A (76.696) is better than Ligand B (53.432). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.282 and -5.315), 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 (-3.559 and -2.672), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.92) has a slightly higher hERG risk than Ligand B (0.336), meaning Ligand B is preferable.

**Microsomal Clearance:** Ligand B (16.058) has significantly lower microsomal clearance than Ligand A (49.906), indicating better metabolic stability. This is a crucial advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (31.559) has a positive half-life, while Ligand B (-12.646) has a negative half-life, which is impossible. This is a major red flag for Ligand B.

**P-gp Efflux:** Ligand A (0.821) has slightly lower P-gp efflux than Ligand B (0.105), which is preferable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly 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:**

Ligand A has a superior binding affinity, better QED, and better P-gp efflux. However, it has a higher DILI risk, higher hERG risk, and significantly higher microsomal clearance. Ligand B has a much lower DILI risk and better metabolic stability, but its binding affinity is weaker and its in vitro half-life is nonsensical.

Given the importance of potency and metabolic stability for enzyme inhibitors, and the significant affinity advantage of Ligand A, I would cautiously favor Ligand A. The poor solubility and DILI risk would need to be addressed through further optimization, but the strong binding is a critical starting point. The negative half-life for Ligand B is a showstopper.

Output:
0
2025-04-17 15:13:13,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (375.372 and 338.367 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.48) is well below the 140 threshold, while Ligand B (89.16) is still acceptable but closer to the limit.

**3. logP:** Both ligands have good logP values (3.503 and 3.135), 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 scores (0.785 and 0.765), indicating good drug-likeness.

**7. DILI:** Both ligands have high DILI risk (89.841 and 85.537), which is a concern. However, this is a predictive score and needs further investigation.

**8. BBB:** Ligand A has excellent BBB penetration (95.308), while Ligand B is moderate (51.803). This is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.827 and -4.979), which is unusual and suggests poor permeability. This is a significant drawback.

**10. Aqueous Solubility:** Both have negative solubility values (-4.94 and -3.94), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Ligand A has a low hERG risk (0.721), while Ligand B has a slightly higher risk (0.542).

**12. Microsomal Clearance:** Ligand A (46.893) has higher clearance than Ligand B (25.765), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a longer half-life (49.64 hours) compared to Ligand A (38.008 hours), which is desirable.

**14. P-gp Efflux:** Ligand A shows no P-gp efflux (0.4), while Ligand B has a higher efflux liability (0.172).

**15. Binding Affinity:** Ligand B has a significantly better binding affinity (-8.8 kcal/mol) compared to Ligand A (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor solubility and permeability for both compounds, Ligand B is the more promising candidate due to its significantly superior binding affinity (-8.8 kcal/mol vs 0.0 kcal/mol). The longer half-life also contributes to its favorability. While the DILI risk is high for both, the potency advantage of Ligand B is substantial enough to warrant further investigation and attempts to improve its solubility and permeability through structural modifications.



Output:
1
2025-04-17 15:13:13,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 352.381 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (67.43 and 69.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (2.359 and 1.847), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3 HBA, which are within the acceptable limits.

**QED:** Both ligands have good QED scores (0.746 and 0.85), indicating drug-like properties.

**DILI:** Ligand A (17.487) has a significantly lower DILI risk than Ligand B (40.054). This is a major advantage for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (76.696 and 63.862). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.722 and -4.783), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.398 and -2.693), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.505 and 0.665).

**Microsomal Clearance:** Ligand A (61.331) has a higher microsomal clearance than Ligand B (16.033), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (36.512 hours) has a significantly longer in vitro half-life than Ligand A (7.281 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.241 and 0.069).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a very significant advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference of 2 kcal/mol is substantial.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-9.3 vs -7.3 kcal/mol) and lower DILI risk are compelling advantages. The longer half-life of Ligand B and lower Cl_mic are favorable, but the potency difference is substantial. Given the enzyme-specific priorities, potency is paramount. The poor solubility could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 15:13:13,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (333.439 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.63) is significantly better than Ligand B (91.76). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is preferable.

**logP:** Ligand A (3.007) is optimal (1-3), while Ligand B (0.437) is quite low, potentially hindering permeability. This is a significant drawback for B.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED values (A: 0.78, B: 0.675), indicating good drug-like properties.

**DILI:** Ligand A (35.983) has a much lower DILI risk than Ligand B (12.408). Both are below 40, which is good, but A is significantly better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.833) is slightly better than Ligand B (53.16).

**Caco-2 Permeability:** Ligand A (-5.224) is better than Ligand B (-4.674). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-1.943) is better than Ligand B (-1.263). Higher values are preferred.

**hERG Inhibition:** Ligand A (0.773) has a lower hERG risk than Ligand B (0.06). This is a crucial advantage for A.

**Microsomal Clearance:** Ligand A (6.342) has lower clearance than Ligand B (34.79), suggesting better metabolic stability. This is a key advantage for A.

**In vitro Half-Life:** Ligand A (30.323) has a longer half-life than Ligand B (-7.429). This is a significant advantage for A.

**P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux than Ligand B (0.015), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.3) has slightly weaker binding affinity than Ligand B (-7.1). However, the difference is small (0.2 kcal/mol) and can be outweighed by the superior ADME properties of A.

**Conclusion:**

Ligand A is significantly more promising. It has better logP, DILI, hERG, metabolic stability (lower Cl_mic and longer t1/2), solubility, and P-gp efflux. While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A in ADME properties, particularly the lower hERG risk and improved metabolic stability, make it the more viable drug candidate.

Output:
0
2025-04-17 15:13:13,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.873 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (64.41), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.501) is slightly higher than Ligand B (2.589). Both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.832 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (37.069) has a higher DILI risk than Ligand B (17.449). This is a significant advantage for Ligand B.

**BBB:** Both have high BBB penetration (96.472 and 83.443), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the compounds themselves. It's hard to interpret this data without further investigation.

**Aqueous Solubility:** Ligand A (-4.755) has significantly worse solubility than Ligand B (-2.657). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.703) has a slightly higher hERG risk than Ligand B (0.462), but both are relatively low.

**Microsomal Clearance:** Ligand A (80.631) has a significantly higher microsomal clearance than Ligand B (41.617), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-16.833) has a much longer in vitro half-life than Ligand A (-2.146), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.333) has lower P-gp efflux than Ligand B (0.063), which is slightly favorable.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 1.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a slightly better binding affinity, but suffers from significantly worse solubility, higher DILI risk, and much poorer metabolic stability (higher Cl_mic, shorter t1/2) compared to Ligand B. The improved metabolic stability and lower toxicity profile of Ligand B are crucial for a kinase inhibitor, outweighing the modest difference in binding affinity.

Output:
1
2025-04-17 15:13:13,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 356.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.32) is excellent, well below the 140 threshold for oral absorption. Ligand B (106.12) is still acceptable but less optimal.

**logP:** Ligand A (2.341) is within the optimal 1-3 range. Ligand B (-0.654) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is favorable. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (A: 0.8, B: 0.507), indicating good drug-like properties.

**DILI:** Ligand A (27.259) has a very low DILI risk, significantly better than Ligand B (13.61).

**BBB:** Ligand A (77.821) shows moderate BBB penetration, while Ligand B (51.997) is lower. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.894) has poor Caco-2 permeability. Ligand B (-5.499) is also poor.

**Aqueous Solubility:** Ligand A (-2.046) has poor aqueous solubility. Ligand B (-0.689) is slightly better, but still poor.

**hERG:** Ligand A (0.409) has a very low hERG risk, while Ligand B (0.136) is also low. Both are good.

**Microsomal Clearance:** Ligand A (27.79) has a moderate clearance, while Ligand B (-2.227) has a negative clearance, which is unusual and likely indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (-7.774) has a very long half-life. Ligand B (32.654) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.057) has low P-gp efflux, while Ligand B (0.003) has very low P-gp efflux. Both are good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A's better TPSA, DILI, and longer half-life, Ligand B's significantly superior binding affinity (-8.7 vs -7.1 kcal/mol) and very high metabolic stability (negative Cl_mic) are decisive. The slightly lower logP of Ligand B is a concern, but the strong binding and stability are more critical for an enzyme target like SRC. The solubility of both compounds is poor, but this can be addressed with formulation strategies.

Output:
1
2025-04-17 15:13:13,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.475 and 355.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is slightly higher than Ligand B (54.46). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**3. logP:** Both ligands have acceptable logP values (1.891 and 2.723), 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 (0.61 and 0.779), indicating drug-likeness.

**7. DILI:** Both ligands have low DILI risk (20.744 and 22.451 percentile), which is good.

**8. BBB:** Ligand B (87.67) has a significantly higher BBB penetration percentile than Ligand A (66.576). While SRC is not a CNS target, higher BBB is generally not detrimental.

**9. Caco-2 Permeability:** Ligand A (-4.815) has poorer Caco-2 permeability than Ligand B (-4.043), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.838) has better aqueous solubility than Ligand B (-3.243). This is a positive for Ligand A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.319 and 0.435), which is favorable.

**12. Microsomal Clearance:** Ligand A (50.242) has lower microsomal clearance than Ligand B (61.053), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (3.808) has a shorter in vitro half-life than Ligand B (-9.571). The negative value for Ligand B suggests a very long half-life, which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.062).

**15. 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 substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and metabolic stability, the significantly stronger binding affinity of Ligand B (-9.7 vs -7.4 kcal/mol) and its superior in vitro half-life are decisive. The slightly lower solubility and higher clearance of Ligand B are less concerning given the potency advantage. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 15:13:13,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.342 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.4) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (71.09) is well within the ideal range.

**logP:** Ligand A (-1.308) is a bit low, potentially hindering permeation. Ligand B (2.09) is within the optimal 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 (0.56 and 0.864), indicating drug-likeness.

**DILI:** Both ligands have similar DILI risk (55.991 and 57.619), both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.117) and Ligand B (54.478) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.279 and -5.521), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.234 and -2.625), also unusual and concerning.

**hERG Inhibition:** Ligand A (0.053) has very low hERG risk, which is excellent. Ligand B (0.228) also has low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-8.764) has a negative clearance, which is impossible and likely an error, suggesting excellent metabolic stability. Ligand B (11.327) has a moderate clearance, which is less favorable.

**In vitro Half-Life:** Ligand A (-19.278) has a negative half-life, which is impossible and likely an error, suggesting a very long half-life. Ligand B (29.31) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.101), which is good.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-7.9 and -8.4 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Despite the similar binding affinities, Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, the negative values for Ligand A's clearance and half-life are clear errors and raise serious concerns about the data quality. Ligand B has a more reasonable profile for metabolic stability and half-life, and a slightly better logP. The slightly better affinity of Ligand B is a bonus. The low hERG risk for both is a positive. The negative Caco-2 and solubility values for both are problematic and would require further investigation (e.g., experimental validation).

Output:
1
2025-04-17 15:13:13,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (389.503 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.36) is slightly above the preferred <140 for good absorption, while Ligand B (88.1) is well within the range.

**logP:** Both ligands (-0.625 and -0.552) are a bit low, potentially hindering permeation. However, this is less critical than other factors for a kinase inhibitor.

**H-Bond Donors/Acceptors:** Both 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 similar QED values (0.543 and 0.526), indicating good drug-likeness.

**DILI:** Ligand A (52.074) has a slightly higher DILI risk than Ligand B (35.634), but both are below the concerning threshold of 60.

**BBB:** Both have similar, relatively low BBB penetration (41.334 and 40.713). This isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.841 and -4.739), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.32 and -1.679), indicating poor aqueous solubility, which is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.08) has a slightly lower hERG risk than Ligand B (0.215), which is preferable.

**Microsomal Clearance:** Ligand A (14.951) has a higher microsomal clearance than Ligand B (8.08), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-5.947) has a longer in vitro half-life than Ligand A (-18.341), which is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.034), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While both have poor Caco-2 and solubility, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly lower hERG risk. The binding affinity is essentially the same. The improved ADME properties of Ligand B outweigh the slightly higher TPSA.

Output:
1
2025-04-17 15:13:13,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, but both are acceptable.

**TPSA:** Ligand A (74.25) is higher than Ligand B (59.07). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.782) is within the optimal range (1-3), while Ligand B (4.64) is slightly above. This could potentially lead to solubility issues for Ligand B, but isn't a major concern.

**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.

**QED:** Both ligands have good QED scores (A: 0.683, B: 0.739), indicating good drug-like properties.

**DILI:** Ligand A (36.952) has a significantly lower DILI risk than Ligand B (69.833). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (A: 65.607, B: 63.125). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual. Assuming these are logP values, they are very poor.

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual.

**hERG:** Both ligands have low hERG risk (A: 0.634, B: 0.689).

**Microsomal Clearance:** Ligand A (32.834) has significantly lower microsomal clearance than Ligand B (56.329), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (106.612 hours) has a much longer half-life than Ligand B (22.627 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.261, B: 0.172).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity. However, Ligand A demonstrates a superior safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and acceptable permeability and solubility. The difference in binding affinity is significant, but the improved ADME properties of Ligand A, especially the lower DILI and better metabolic stability, make it the more promising candidate.

Output:
0
2025-04-17 15:13:13,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.491 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.7) is slightly higher than Ligand B (60.85). Both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have logP values around 2.1, which is optimal (1-3).

**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 higher QED score than Ligand B (0.75), indicating better overall drug-likeness.

**DILI:** Ligand A (4.692) has a significantly lower DILI risk than Ligand B (10.508). This is a major advantage for Ligand A.

**BBB:** Ligand B (84.529) has a higher BBB penetration score than Ligand A (63.784). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.758 and -4.686), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.026 and -2.404), indicating very poor aqueous solubility. This is a significant drawback for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.616) has a slightly lower hERG inhibition risk than Ligand B (0.421), which is preferable.

**Microsomal Clearance:** Ligand A (6.659) has a higher microsomal clearance than Ligand B (37.203), meaning it's less metabolically stable. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (5.799) has a longer in vitro half-life than Ligand A (36.067), indicating better metabolic stability. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.012) has much lower P-gp efflux liability than Ligand B (0.204), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). The 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. While its DILI risk is higher, the strong binding affinity could allow for a lower dose, potentially mitigating the DILI concern. Ligand A has a better QED, lower DILI, and lower P-gp efflux, but its weaker binding affinity and higher clearance are significant drawbacks. The poor solubility and permeability are concerning for both.

Given the priorities for kinase inhibitors, the stronger binding affinity of Ligand B is the most important factor.

Output:
1
2025-04-17 15:13:13,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.463 and 371.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is better than Ligand B (104.9), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.332) is optimal (1-3), while Ligand B (0.063) is quite low, potentially hindering permeation.

**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.

**QED:** Both ligands have similar QED values (0.678 and 0.666), indicating good drug-likeness.

**DILI:** Ligand A (42.148) has a lower DILI risk than Ligand B (54.285), both are acceptable (<60).

**BBB:** Ligand A (79.333) has a better BBB penetration score than Ligand B (22.606). While not a primary concern for a non-CNS target, it's a positive attribute.

**Caco-2:** Ligand A (-4.528) has a slightly better Caco-2 permeability than Ligand B (-5.43), suggesting better intestinal absorption.

**Solubility:** Ligand A (-3.75) has better aqueous solubility than Ligand B (-2.04). Solubility is important for bioavailability.

**hERG:** Ligand A (0.266) has a significantly lower hERG inhibition liability than Ligand B (0.085), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (58.916) has a higher (worse) microsomal clearance than Ligand B (16.268), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (12.295) has a longer half-life than Ligand B (-0.828), which is desirable.

**P-gp efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.02), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

Despite Ligand A having a longer half-life and better solubility, the significantly lower metabolic stability (higher Cl_mic) of Ligand A is a major concern. Ligand B, while having a lower logP and slightly higher DILI, exhibits much better metabolic stability, which is a critical factor for enzyme inhibitors. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 15:13:13,762 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.315 Da) is slightly lower, which could be beneficial for permeability. Ligand B (352.454 Da) is also good.

**TPSA:** Ligand A (134.36) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (78.09) is excellent, well below 140, suggesting good absorption.

**logP:** Both ligands have good logP values (A: 1.399, B: 2.685), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which is acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.512, B: 0.826), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A has a high DILI risk (98.449), which is a major concern. Ligand B has a much lower, and acceptable, DILI risk (39.318).

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (85.964) than Ligand A (29.12).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This suggests potential issues with the data or the model used to predict it.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests potential issues with the data or the model used to predict it.

**hERG:** Ligand A (0.498) has a slightly better hERG profile than Ligand B (0.765).

**Microsomal Clearance:** Ligand A has a lower Cl_mic (9.925) than Ligand B (23.385), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a positive half-life (10.995 hours) while Ligand B has a negative half-life (-23.078 hours). This is unusual and suggests potential issues with the data.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.143, B: 0.168).

**Binding Affinity:** Ligand A has a stronger binding affinity (-8.2 kcal/mol) than Ligand B (-7.8 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability. However, its extremely high DILI risk is a major red flag. Ligand B has a much better safety profile (DILI) and a better QED score, but its binding affinity is slightly weaker. Given the enzyme class, metabolic stability and safety are paramount. The substantial difference in DILI risk outweighs the slightly better affinity of Ligand A. The negative solubility and Caco-2 values for both are concerning and would need further investigation, but the DILI risk for A is a dealbreaker.

Output:
1
2025-04-17 15:13:13,762 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.795 Da) is slightly higher than Ligand B (335.451 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (80.52) is higher than Ligand B (68.01).

**logP:** Ligand A (4.05) is at the upper limit of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (2.81) is well 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.

**QED:** Both ligands have good QED scores, indicating drug-likeness (Ligand A: 0.569, Ligand B: 0.853). Ligand B is significantly better.

**DILI:** Ligand A (84.684) has a high DILI risk, which is a major concern. Ligand B (21.869) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have moderate BBB penetration. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.35) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.169) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-5.754) has very poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-2.273) has better solubility, though still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.696, Ligand B: 0.573).

**Microsomal Clearance:** Ligand A (48.584) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (0.853) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (76.06) has a good in vitro half-life. Ligand B (10.194) has a very short half-life, a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.498, Ligand B: 0.109). Ligand B is better.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 kcal/mol and -8.0 kcal/mol), with Ligand A being slightly better. However, the difference is small.

**Overall Assessment:**

Ligand B is the superior candidate despite the slightly lower binding affinity and poor Caco-2 permeability. The primary driver is the significantly lower DILI risk and excellent metabolic stability (low Cl_mic). The better QED and P-gp efflux also contribute. Ligand A's high DILI risk and poor solubility are major liabilities that outweigh its slightly better binding affinity and half-life. The poor Caco-2 permeability of both are concerning but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 15:13:13,762 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.5 and 340.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (89.35 and 75.19) well below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (0.857 and 1.718) 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 10.

**QED:** Both ligands have good QED scores (0.765 and 0.828), indicating drug-like properties.

**DILI:** Ligand A (47.15) has a slightly better DILI score than Ligand B (53.044), indicating lower potential for liver injury. Both are acceptable (<60).

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (76.735) has a higher BBB score than Ligand A (67.08), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.403 and -5.064), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.539 and -2.331), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.48) has a significantly lower hERG inhibition risk than Ligand B (0.286), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (-6.955) has a much lower (better) microsomal clearance than Ligand B (43.535), suggesting greater metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.257) has a longer half-life than Ligand B (-1.416), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.257 and 0.121).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is relatively small and is likely outweighed by the other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and a slightly better DILI profile. The small difference in binding affinity is less important than these ADME/Tox advantages, especially for a kinase inhibitor where metabolic stability is crucial for maintaining therapeutic concentrations. The poor solubility and permeability would need to be addressed through formulation strategies, but the underlying pharmacokinetic properties of Ligand A are more favorable.

Output:
0
2025-04-17 15:13:13,762 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 348.487 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.49) is better than Ligand B (49.85) as it is still within the acceptable range for oral absorption (<140), while Ligand B is significantly lower, which may be beneficial.

**logP:** Ligand A (0.633) is a bit low, potentially hindering permeability. Ligand B (2.302) 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 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.676 and 0.5), indicating good drug-like properties.

**DILI:** Ligand A (38.387) has a slightly higher DILI risk than Ligand B (13.532), but both are below the concerning threshold of 60.

**BBB:** Ligand A (42.264) has a low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (81.233) has better BBB penetration, but again, this is less critical here.

**Caco-2 Permeability:** Ligand A (-5.315) has poor Caco-2 permeability, a significant drawback. Ligand B (-4.436) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.214) has poor aqueous solubility, which could hinder bioavailability. Ligand B (-2.423) is also poor, but slightly worse.

**hERG Inhibition:** Ligand A (0.182) has a slightly higher hERG risk than Ligand B (0.479), but both are relatively low.

**Microsomal Clearance:** Ligand A (21.784) has a lower microsomal clearance, indicating better metabolic stability, which is a key priority for kinase inhibitors. Ligand B (51.249) has higher clearance.

**In vitro Half-Life:** Ligand A (-17.429) has a negative half-life, which is not realistic and indicates a potential issue with the data or the molecule's stability. Ligand B (10.365) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux, which is favorable. Ligand B (0.272) has higher efflux.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.4). However, the difference is small.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, but suffers from poor Caco-2 permeability, poor solubility, and an unrealistic half-life. Ligand B has better solubility, a reasonable half-life, and a slightly better binding affinity. The poor permeability and solubility of Ligand A, coupled with its unrealistic half-life, are major concerns. While Ligand B's logP is better, its metabolic stability is a concern.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), Ligand B is the more promising candidate despite its higher Cl_mic. The slightly better binding affinity and more reasonable ADME properties outweigh the metabolic stability concern, which could potentially be addressed through further optimization.

Output:
1
2025-04-17 15:13:13,762 - INFO - Batch 361 complete. Total preferences: 5776
2025-04-17 15:13:13,762 - INFO - Processing batch 362/512...
2025-04-17 15:14:02,452 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [364.471, 102.3  ,   1.359,   2.   ,   5.   ,   0.727,  52.772,  34.199, -4.999,  -2.677,   0.402,  29.767,  45.053,   0.125,  -7.5  ]
**Ligand B:** [350.503,  58.64 ,   2.737,   1.   ,   3.   ,   0.801,  21.714,  77.898, -4.782,  -2.942,   0.437,  79.874,  -8.733,   0.32 ,  -9.1  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (364.471) and B (350.503) are comparable.
2. **TPSA:** A (102.3) is slightly above the preferred <140 for good oral absorption, but still reasonable. B (58.64) is excellent, well below 140.
3. **logP:** Both are within the optimal 1-3 range. A (1.359) is slightly lower, B (2.737) is closer to the middle of the range.
4. **HBD:** A (2) and B (1) are both good, meeting the <=5 criteria.
5. **HBA:** A (5) and B (3) are both good, meeting the <=10 criteria.
6. **QED:** Both are good (A: 0.727, B: 0.801), indicating drug-like properties. B is slightly better.
7. **DILI:** A (52.772) is acceptable, below the 60 threshold. B (21.714) is *very* good, significantly lower risk.
8. **BBB:** A (34.199) is low, suggesting poor brain penetration. B (77.898) is good, indicating reasonable potential for CNS penetration, though SRC is not necessarily a CNS target.
9. **Caco-2:** Both are negative, indicating poor permeability. This is a significant concern for both.
10. **Solubility:** Both are negative, indicating poor solubility. This is a significant concern for both.
11. **hERG:** Both are low (A: 0.402, B: 0.437), suggesting low cardiotoxicity risk.
12. **Cl_mic:** A (29.767) is better (lower clearance) than B (79.874), indicating better metabolic stability.
13. **t1/2:** A (45.053) is better (longer half-life) than B (-8.733), suggesting less frequent dosing potential.
14. **Pgp:** A (0.125) is better (lower efflux) than B (0.32), indicating better bioavailability.
15. **Affinity:** B (-9.1) has a significantly stronger binding affinity than A (-7.5) - a difference of 1.6 kcal/mol.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both compounds have acceptable hERG risk, B has a *much* superior binding affinity. A has better metabolic stability and half-life, but the difference in binding affinity is substantial. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

**Conclusion:**

Despite the better metabolic stability of Ligand A, the significantly improved binding affinity of Ligand B (-9.1 vs -7.5 kcal/mol) is a major advantage that outweighs the drawbacks. The lower DILI risk is also a positive. While both have solubility and permeability issues, these can be addressed during lead optimization.

1
2025-04-17 15:14:02,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.388 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (89.31 and 88.99) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (3.718) is slightly higher than Ligand B (2.414), but both are 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:** Both ligands have good QED scores (0.602 and 0.862), indicating drug-like properties.

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (56.689), but both are acceptable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (77.2) is higher than Ligand B (53.044).

**Caco-2 Permeability:** Both ligands 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. Assuming these are logS values, both are poor.

**hERG Inhibition:** Ligand A (0.744) has a slightly higher hERG risk than Ligand B (0.331), but both are relatively low.

**Microsomal Clearance (Cl_mic):** Ligand B (23.235 mL/min/kg) has significantly lower microsomal clearance than Ligand A (43.779 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life (t1/2):** Ligand B (6.867 hours) has a longer half-life than Ligand A (14.34 hours). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.406) has lower P-gp efflux than Ligand B (0.063), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol) - a difference of 0.8 kcal/mol. This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better P-gp efflux and BBB, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity, lower microsomal clearance (better metabolic stability), and a longer half-life. The slightly lower DILI risk for Ligand B is also a bonus. The unusual negative values for Caco-2 and solubility are concerning for both, but the potency and metabolic stability advantages of Ligand B are more important for this target class.

Output:
1
2025-04-17 15:14:02,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.462 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.78) is significantly better than Ligand B (73.74). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.527 and 1.534), falling within the optimal 1-3 range.

**H-Bond Donors:** Both are acceptable (0 and 1, respectively), well below the limit of 5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.74 and 0.842), indicating good drug-like properties.

**DILI:** Ligand A (7.057) has a much lower DILI risk than Ligand B (38.813). This is a significant advantage.

**BBB:** Ligand A (96.937) has much better BBB penetration than Ligand B (52.268). While SRC isn't necessarily a CNS target, better BBB penetration can sometimes correlate with better overall distribution.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.549 and -4.653). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar.

**Aqueous Solubility:** Both have negative solubility values (-2.585 and -1.173). This is also concerning, suggesting poor solubility. Ligand B is slightly better in this regard.

**hERG Inhibition:** Ligand A (0.943) has a slightly higher hERG risk than Ligand B (0.266). This is a potential concern for Ligand A.

**Microsomal Clearance:** Ligand A (52.967) has significantly higher microsomal clearance than Ligand B (15.568), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-21.104) has a much shorter in vitro half-life than Ligand B (-2.935). This reinforces the concern about metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.172 and 0.083).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial difference and a key factor favoring Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. The stronger binding affinity of Ligand B likely outweighs the slightly lower solubility. The metabolic stability is a critical advantage for an enzyme target.

Output:
1
2025-04-17 15:14:02,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 353.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (57.61). Both are below 140, indicating good potential for oral absorption.

**logP:** Ligand A (1.221) is optimal, while Ligand B (3.91) is approaching the upper limit.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable, while Ligand B (3) is also good.

**QED:** Both ligands have similar QED values (0.643 and 0.648), indicating good drug-likeness.

**DILI:** Ligand A (11.283) has a significantly lower DILI risk than Ligand B (15.2), which is a crucial advantage.

**BBB:** Ligand B (83.521) has a higher BBB penetration, but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired. Ligand A (51.183) is lower.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.643 and -4.223), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.002 and -3.783), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.192) has a much lower hERG inhibition liability than Ligand B (0.531), a major advantage regarding safety.

**Microsomal Clearance:** Ligand A (29.065) has a significantly lower microsomal clearance than Ligand B (82.483), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.695) has a longer in vitro half-life than Ligand B (7.188), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.026) has a much lower P-gp efflux liability than Ligand B (0.626), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a significant advantage for Ligand B. The difference of 2.2 kcal/mol is large enough to potentially offset some of the ADME liabilities.

**Overall Assessment:**

While Ligand B boasts a significantly better binding affinity, Ligand A demonstrates superior ADMET properties, particularly regarding DILI risk, hERG inhibition, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. The poor Caco-2 and solubility for both are concerning, but the other advantages of Ligand A make it a more promising starting point for optimization. The stronger binding of Ligand B might be achievable with modifications to Ligand A, while addressing its ADMET issues is likely more challenging for Ligand B.

Output:
0
2025-04-17 15:14:02,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.475 Da) is slightly higher than Ligand B (354.495 Da), but both are acceptable.

**TPSA:** Ligand A (89.87) is better than Ligand B (104.53), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration, though that's not a primary concern here.

**logP:** Ligand A (-0.085) is slightly low, potentially hindering permeation, while Ligand B (1.757) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is better than Ligand B (3 HBD, 3 HBA). Both are within acceptable limits, but A has a more favorable balance.

**QED:** Both ligands have good QED scores (Ligand A: 0.8, Ligand B: 0.521), indicating good drug-like properties.

**DILI:** Ligand A (37.999) has a significantly lower DILI risk than Ligand B (22.489), which is a major advantage. Lower is better.

**BBB:** Ligand A (64.25) has a lower BBB penetration than Ligand B (78.674), but this isn't a high priority for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-4.896) has poor Caco-2 permeability, while Ligand B (-5.131) is also poor. Both are negative, suggesting poor absorption.

**Aqueous Solubility:** Ligand A (-1.724) has poor aqueous solubility, while Ligand B (-2.832) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.478) has a lower hERG inhibition liability than Ligand B (0.367), which is favorable. Lower is better.

**Microsomal Clearance:** Ligand A (26.971) has lower microsomal clearance than Ligand B (33.501), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-1.548) has a shorter half-life than Ligand B (-10.859). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux than Ligand B (0.056), which is favorable.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is the most important factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is paramount for an enzyme inhibitor. It also has a better logP and BBB. However, Ligand A has a much lower DILI risk, better H-bond characteristics, and better metabolic stability. The poor solubility and permeability of both are concerning, but can potentially be addressed with formulation strategies. The significantly stronger binding affinity of Ligand B outweighs the other drawbacks, especially given the importance of potency for enzyme inhibition.

Output:
1
2025-04-17 15:14:02,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.535 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, and excellent for oral absorption. Ligand B (93.45) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.227) is optimal. Ligand B (0.205) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, but still within the acceptable range of 10.

**QED:** Both ligands (0.728 and 0.787) have good drug-likeness scores.

**DILI:** Ligand A (20.279) has a much lower DILI risk than Ligand B (62.505), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (71.307) shows better potential for BBB penetration than Ligand B (60.566).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it's hard to interpret the absolute values.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.564) has a lower hERG risk than Ligand B (0.192), which is a significant advantage.

**Microsomal Clearance:** Ligand A (78.478) has higher clearance, suggesting lower metabolic stability, while Ligand B (-2.86) has negative clearance, which is not possible, and likely an error. Assuming this is a percentile, it suggests excellent metabolic stability.

**In vitro Half-Life:** Ligand A (6.342) has a reasonable half-life. Ligand B (-1.425) is problematic, suggesting a very short half-life.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux, which is favorable. Ligand B (0.023) has even lower efflux, which is also favorable.

**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 is still a factor.

**Overall Assessment:**

Ligand A has a better balance of properties. While its metabolic stability is a concern (higher Cl_mic), it excels in DILI risk, hERG inhibition, logP, and binding affinity. Ligand B has a problematic negative clearance value and a low logP, which raises concerns about permeability. The better binding affinity of Ligand A, combined with its superior safety profile (DILI, hERG), makes it the more promising candidate.

Output:
1
2025-04-17 15:14:02,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.419 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.12) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (84.42) is well within the range.

**logP:** Ligand A (-0.33) is a bit low, potentially hindering permeation. Ligand B (1.239) 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 (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.628, B: 0.834), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have moderate DILI risk (A: 47.615, B: 65.103). Ligand A is preferable here.

**BBB:** Both have similar BBB penetration (A: 65.374, B: 63.086). Not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-5.408 and -4.795). These values are unusual and suggest poor permeability.

**Solubility:** Both have negative solubility values (-1.918 and -1.683). These values are also unusual and suggest poor solubility.

**hERG:** Both ligands have very low hERG risk (0.135 and 0.134). This is excellent.

**Microsomal Clearance:** Ligand A (3.718 mL/min/kg) has significantly lower clearance than Ligand B (22.08 mL/min/kg), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (29.765 hours) has a much longer half-life than Ligand B (0.917 hours). This is a substantial benefit.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.016).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol) - a difference of 1.2 kcal/mol. This is a major advantage that can outweigh some ADME concerns.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better DILI score, Ligand B's significantly stronger binding affinity (-8.3 vs -7.1 kcal/mol) is a crucial factor for an enzyme inhibitor. The 1.2 kcal/mol difference is substantial and likely to translate to greater efficacy. The slightly higher clearance of Ligand B can be addressed through structural modifications in subsequent optimization rounds. The negative Caco-2 and solubility values are concerning for both, and would need to be addressed.

Output:
1
2025-04-17 15:14:02,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.447 and 350.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (80.12 and 85.23) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values within the optimal range (1.621 and 2.202).

**4. H-Bond Donors:** Ligand A (1 HBD) is preferable to Ligand B (2 HBDs), though both are acceptable.

**5. H-Bond Acceptors:** Ligand A (5 HBA) is preferable to Ligand B (4 HBA), though both are acceptable.

**6. QED:** Ligand A (0.795) has a better QED score than Ligand B (0.632), indicating a more drug-like profile.

**7. DILI:** Ligand A (36.565) has a significantly lower DILI risk than Ligand B (9.151), which is a major advantage.

**8. BBB:** Both ligands have similar BBB penetration (66.654 and 62.233). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.874 and -4.899). This is unusual and requires further investigation, but is likely a reporting artifact.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.665 and -1.911). This is also unusual and requires further investigation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.122 and 0.335).

**12. Microsomal Clearance:** Ligand B (29.937) has a lower microsomal clearance than Ligand A (36.573), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.095 hours) has a significantly longer in vitro half-life than Ligand A (-1.063 hours). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.005).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a 1.6 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has a better QED and lower DILI risk, the potency advantage of Ligand B is significant. The negative solubility and Caco-2 values are concerning for both, but could be experimental artifacts. Given the enzyme-specific priorities, the improved potency and metabolic stability of Ligand B are more critical.

Output:
1
2025-04-17 15:14:02,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.441 and 338.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (111.06).  A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's TPSA is relatively high.

**3. logP:** Both ligands have acceptable logP values (2.821 and 1.649), 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 2 HBAs, and Ligand B has 4. Both are below the limit of 10.

**6. QED:** Ligand A (0.797) has a much better QED score than Ligand B (0.29), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.641) has a significantly lower DILI risk than Ligand B (62.893). This is a major advantage for Ligand A.

**8. BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (90.074) is higher than Ligand B (32.416), but this isn't a primary concern.

**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:** Ligand A (0.596) has a lower hERG risk than Ligand B (0.114), which is favorable.

**12. Cl_mic:** Ligand A (26.812) has a higher (worse) microsomal clearance than Ligand B (3.149). This suggests Ligand B is more metabolically stable.

**13. t1/2:** Ligand A (-8.037) has a negative in vitro half-life, which is concerning. Ligand B (-20.631) is even worse. The negative values suggest something is off with the scale or data.

**14. Pgp:** Ligand A (0.096) has lower P-gp efflux liability than Ligand B (0.021).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.9 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Despite Ligand B having better metabolic stability (lower Cl_mic) and slightly better binding affinity, Ligand A is the more promising candidate. The significantly lower DILI risk, better QED score, lower hERG risk, and lower P-gp efflux liability outweigh the slightly higher Cl_mic. The TPSA is also much more favorable for Ligand A. The negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand A.

Output:
0
2025-04-17 15:14:02,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.459 Da and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (107.19 and 101.73) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (0.276) is quite low, potentially hindering permeability. Ligand B (0.59) is also low but slightly better. Both are below 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.628 and 0.562), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.707, which is considered high risk (>60). Ligand B has a significantly lower DILI risk of 10.585, which is excellent. This is a major advantage for Ligand B.

**BBB:** BBB is less crucial for a non-CNS target like SRC. Ligand B has a higher BBB percentile (75.107) than Ligand A (28.422), but this isn't a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.795 and -5.447), which is unusual and suggests poor permeability. However, these values are often predictions and can be unreliable.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.852 and -1.437), which is also unusual and suggests poor solubility. Again, these are predictions.

**hERG Inhibition:** Ligand A (0.05) and Ligand B (0.125) both have very low hERG inhibition liability, which is excellent.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (3.969 mL/min/kg) than Ligand B (0.457 mL/min/kg). Lower clearance is preferred for metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-12.101 hours) than Ligand A (-20.103 hours). A more negative value indicates a longer half-life, making Ligand B more favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.004).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall:**

Ligand B is the better candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly improved binding affinity outweigh the slightly lower logP and the questionable Caco-2/Solubility predictions. The high DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 15:14:02,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (341.43 and 348.49 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (58.64). Lower TPSA generally correlates with better cell permeability. Ligand A is well below the 140 A^2 threshold, while Ligand B is approaching it.

**logP:** Ligand A (3.973) is slightly higher than Ligand B (2.204), both are within the optimal range of 1-3, but A is closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 2 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 (0.842 and 0.793), indicating good drug-like properties.

**DILI:** Ligand A (50.99%) has a higher DILI risk than Ligand B (15.2%). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (82.05%) has better BBB penetration than Ligand B (63.01%).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.65 and -4.551), 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:** Ligand A (-4.445) has slightly worse solubility than Ligand B (-2.312). Both are poor, but B is better.

**hERG:** Ligand A (0.835) has a slightly higher hERG risk than Ligand B (0.215). This is a concern for Ligand A.

**Microsomal Clearance:** Ligand B (-7.92) has significantly *better* metabolic stability (lower clearance) than Ligand A (82.832). This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (3.789 hours) has a longer half-life than Ligand A (-11.503 hours). Again, a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.798) has slightly lower P-gp efflux than Ligand B (0.035).

**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 still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in metabolic stability (Cl_mic and t1/2), has a lower DILI risk, lower hERG risk, and slightly better binding affinity. Ligand A's higher DILI and hERG risk, coupled with its poor metabolic stability, make it a less attractive candidate despite its slightly better TPSA and BBB penetration. The difference in binding affinity, while not massive, tips the scale further in favor of Ligand B.

Output:
1
2025-04-17 15:14:02,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.365 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.45) is significantly better than Ligand B (96.69).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.502) is slightly higher than Ligand B (1.85). Both are within the optimal 1-3 range, but B is closer to the lower bound, potentially impacting 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 (4) is better than Ligand B (6). Lower HBA also contributes to better permeability.

**6. QED:** Both ligands have good QED scores (0.792 and 0.806), indicating good drug-like properties.

**7. DILI:** Ligand A (56.844) has a slightly higher DILI risk than Ligand B (47.77), but both are acceptable (<60).

**8. BBB:** Both ligands have similar BBB penetration (77.898 and 76.735). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.385 and -4.581), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Ligand A (-4.25) is slightly better than Ligand B (-3.2), but both are poor. Solubility is a critical factor for bioavailability.

**11. hERG:** Ligand A (0.461) is significantly better than Ligand B (0.279). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**12. Cl_mic:** Ligand B (45.668) has lower microsomal clearance than Ligand A (75.065), indicating better metabolic stability. This is a key advantage for B.

**13. t1/2:** Ligand B (7.891) has a significantly longer in vitro half-life than Ligand A (-27.288). A positive half-life is desirable, making B much better in this regard.

**14. Pgp:** Both ligands have very low Pgp efflux (0.151 and 0.139), which is good.

**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 stronger, the difference is not substantial enough to overcome the ADME deficiencies.

**Overall Assessment:**

Ligand B is the better candidate despite slightly weaker binding. It has superior metabolic stability (lower Cl_mic, longer t1/2), better hERG profile, and a more favorable TPSA. While both have poor solubility and Caco-2 permeability, B's other advantages are more critical for an enzyme inhibitor. The slightly better affinity of A is outweighed by its poorer ADME profile.

Output:
1
2025-04-17 15:14:02,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.455 and 371.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.84) is well below the 140 threshold, suggesting good absorption. Ligand B (96.53) is still acceptable, but approaching the upper limit.

**logP:** Ligand A (2.684) is optimal (1-3). Ligand B (0.974) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, within the suggested limits.

**QED:** Both ligands have good QED scores (0.561 and 0.733), indicating drug-like properties.

**DILI:** Ligand A (14.114) has a much lower DILI risk than Ligand B (68.205), a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (81.466) is higher than Ligand B (48.275).

**Caco-2 Permeability:** Ligand A (-4.468) has poor Caco-2 permeability, while Ligand B (-5.525) is also poor.

**Aqueous Solubility:** Ligand A (-3.252) has slightly better solubility than Ligand B (-2.34).

**hERG:** Ligand A (0.894) has a lower hERG risk than Ligand B (0.453), which is preferable.

**Microsomal Clearance:** Ligand A (68.215) has higher microsomal clearance than Ligand B (-20.862). This suggests Ligand B is more metabolically stable, a key factor for kinases.

**In vitro Half-Life:** Ligand A (-13.144) has a negative half-life, which is problematic. Ligand B (25.804) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.557 and 0.048), which is good.

**Binding Affinity:** Both ligands have similar binding affinities (-9.0 and -8.8 kcal/mol). The difference is minimal and doesn't strongly favor either.

**Conclusion:**

While Ligand A has a better DILI score and slightly better solubility, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, positive t1/2), which is crucial for kinase inhibitors. The slightly lower logP of Ligand B is a concern, but the superior metabolic profile and reasonable half-life outweigh this drawback. The poor Caco-2 permeability of both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:14:02,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (373.4 and 361.5) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly higher than Ligand B (51.39). Both are acceptable, but B is better for permeability.

**logP:** Both ligands have good logP values (2.809 and 3.857, respectively), 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.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.709 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 72.78, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 21.442, which is excellent. This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (80.264) has better BBB penetration than Ligand A (58.821), but this is not a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.091 and -5.078). This is unusual and suggests poor permeability. However, these values are on a logarithmic scale and close to zero, so the actual permeability might not be drastically low.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.942 and -3.654). Again, these are on a logarithmic scale, and the actual solubility might not be extremely poor, but it's not ideal.

**hERG Inhibition:** Ligand A has a hERG risk of 0.676, which is acceptable. Ligand B has a slightly higher hERG risk of 0.794, but still within a reasonable range.

**Microsomal Clearance:** Ligand A has a Cl_mic of 42.329, while Ligand B has a Cl_mic of 64.083. Lower is better, so Ligand A has better metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 21.33 hours, while Ligand B has a t1/2 of 12.912 hours. Ligand A has a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.208 and 0.438).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-7.9 kcal/mol) compared to Ligand A (-11.0 kcal/mol). This difference of 3.1 kcal/mol is substantial and outweighs many of the other drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A having better metabolic stability and half-life, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.9 vs -11.0 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk, which is critical for drug development. While both have poor Caco-2 and solubility values, the superior potency and safety profile of Ligand B make it the better choice.

Output:
1
2025-04-17 15:14:02,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.843) is slightly higher than Ligand B (347.459), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (74.43) is lower than Ligand A (89.87), which is slightly preferable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.357) and Ligand B (2.107) are both good.

**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 QED values above 0.5, indicating good drug-like properties. Ligand B (0.793) is slightly better than Ligand A (0.649).

**DILI:** Ligand B (25.669) has a significantly lower DILI risk than Ligand A (45.483). This is a major advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration. Ligand B (70.803) is slightly better than Ligand A (64.482), but BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 risk (0.31 and 0.393 respectively), which is good.

**Microsomal Clearance:** Ligand B (38.189) has a much lower microsomal clearance than Ligand A (6.467), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-11.978) has a negative half-life, which is not possible. This is a major red flag. Ligand A (3.945) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.065 and 0.037 respectively), which is good.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). However, the difference is not substantial enough to outweigh the other factors.

**Overall:**

Ligand B appears initially more promising due to its lower DILI risk and better metabolic stability (lower Cl_mic). However, the negative in vitro half-life is a critical flaw. A negative half-life is not physically possible and suggests an error in the data or a highly unstable compound. Ligand A has a reasonable half-life and slightly better binding affinity. While its DILI risk is higher, and its metabolic stability is lower, these are areas that could potentially be addressed through further optimization. Given the impossible value for Ligand B, Ligand A is the more viable candidate.

Output:
0
2025-04-17 15:14:02,455 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A: [340.427, 67.35, 2.667, 1, 4, 0.878, 39.667, 83.831, -4.213, -2.891, 0.306, 73.579, -20.249, 0.026, -8.8]**
**Ligand B: [370.475, 113.18, 0.932, 3, 5, 0.598, 45.25, 50.058, -5.28, -2.19, 0.263, 12.225, -41.522, 0.04, -6.8]**

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (340.427) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (67.35) is excellent, well below the 140 threshold. B (113.18) is higher, but still acceptable, though less ideal for oral absorption.
3. **logP:** A (2.667) is optimal. B (0.932) is a bit low, potentially hindering membrane permeability.
4. **HBD:** A (1) is good. B (3) is acceptable, but higher HBD can sometimes impact permeability.
5. **HBA:** A (4) is good. B (5) is acceptable.
6. **QED:** A (0.878) is very good, indicating high drug-likeness. B (0.598) is acceptable, but lower.
7. **DILI:** Both are reasonably low. A (39.667) is slightly better than B (45.25).
8. **BBB:** A (83.831) is good, suggesting reasonable potential for crossing the blood-brain barrier, though not crucial for SRC. B (50.058) is lower.
9. **Caco-2:** A (-4.213) is poor, indicating very low permeability. B (-5.28) is also poor, but slightly worse.
10. **Solubility:** A (-2.891) is poor. B (-2.19) is also poor, but slightly better.
11. **hERG:** Both are very low, indicating minimal hERG inhibition risk. A (0.306) is slightly better than B (0.263).
12. **Cl_mic:** A (73.579) is moderate. B (12.225) is excellent, indicating much better metabolic stability. This is a significant advantage for B.
13. **t1/2:** A (-20.249) is poor, indicating rapid clearance. B (-41.522) is even worse.
14. **Pgp:** Both are very low, indicating minimal P-gp efflux. A (0.026) is slightly better than B (0.04).
15. **Affinity:** A (-8.8) is significantly better than B (-6.8), representing a substantial advantage in binding potency (a difference of 2 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand A has a much stronger binding affinity.
*   **Metabolic Stability:** Ligand B has significantly better metabolic stability (lower Cl_mic).
*   **Solubility:** Both are poor, but B is slightly better.
*   **hERG:** Both are good.

**Overall Assessment:**

While Ligand B has a clear advantage in metabolic stability, the substantial difference in binding affinity (-8.8 kcal/mol vs -6.8 kcal/mol) for Ligand A is a major factor. A 2 kcal/mol difference is often enough to overcome minor ADME deficiencies, especially for an enzyme target where potency is paramount. The poor Caco-2 and solubility of both compounds are concerning, but could potentially be addressed through formulation strategies.

Therefore, despite the metabolic stability advantage of Ligand B, the superior binding affinity of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 15:14:02,455 - INFO - Batch 362 complete. Total preferences: 5792
2025-04-17 15:14:02,455 - INFO - Processing batch 363/512...
2025-04-17 15:14:48,227 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.1) is better than Ligand B (75.44), both are below the 140 threshold for good oral absorption.

**logP:** Ligand B (2.541) is optimal (1-3), while Ligand A (0.165) is quite 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 (0.576 and 0.784, respectively), indicating drug-like properties.

**DILI:** Ligand B (18.418) has a significantly lower DILI risk than Ligand A (11.361), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (74.176) is better than Ligand A (31.097).

**Caco-2 Permeability:** Ligand A (-4.7) is better than Ligand B (-5.244), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.885) is better than Ligand B (-1.585).

**hERG Inhibition:** Ligand A (0.168) has a lower hERG risk than Ligand B (0.321), which is preferable.

**Microsomal Clearance:** Ligand A (4.885) has a significantly lower Cl_mic than Ligand B (51.819), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-21.278) has a much longer half-life than Ligand A (-7.512), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux than Ligand B (0.092).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). The difference is >1.5 kcal/mol, making it a significant factor.

**Overall Assessment:**

Ligand B demonstrates a superior profile overall. While Ligand A has better solubility and a lower hERG risk, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, a longer half-life, and a more potent binding affinity. The slightly lower logP of Ligand B is a minor concern, potentially addressable through further optimization, but the benefits in other areas outweigh this drawback. The improved metabolic stability (lower Cl_mic) of Ligand A is also a positive, but the substantial difference in binding affinity favors Ligand B.

Output:
1
2025-04-17 15:14:48,227 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.487 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.07) is better than Ligand B (78.43), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.242) is within the optimal 1-3 range, while Ligand B (2.04) is also acceptable, but slightly higher.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3), as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Ligand A (0.781) has a better QED score than Ligand B (0.611), indicating a more drug-like profile.

**DILI:** Ligand A (34.82) has a significantly lower DILI risk than Ligand B (21.287), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.513) is better than Ligand B (42.497).

**Caco-2 Permeability:** Ligand A (-4.735) is better than Ligand B (-5.378).

**Aqueous Solubility:** Ligand A (-2.039) is better than Ligand B (-2.97).

**hERG Inhibition:** Ligand A (0.773) has a lower hERG risk than Ligand B (0.148), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (20.438) has a lower microsomal clearance than Ligand B (49.934), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.185) has a longer in vitro half-life than Ligand B (-13.206), which is desirable.

**P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux liability than Ligand B (0.036).

**Binding Affinity:** Ligand B (-8.2 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 advantages of Ligand A.

**Conclusion:**

Ligand A demonstrates superior overall drug-like properties, particularly in terms of safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), solubility, and permeability. While Ligand B has a marginally better binding affinity, the ADME profile of Ligand A is far more favorable for development as a drug candidate.

Output:
0
2025-04-17 15:14:48,227 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.491 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.09) is significantly better than Ligand B (78.67). Lower TPSA generally indicates better permeability.

**logP:** Both ligands have acceptable logP values (0.795 and 1.274), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.796 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A (6.786) has a much lower DILI risk than Ligand B (24.234). This is a significant advantage.

**BBB:** Both have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.795 and -4.926), which is unusual and suggests poor permeability. However, this is a *scale* value and the absolute value isn't as important as the comparison. The values are similar.

**Aqueous Solubility:** Both have negative solubility values (-0.633 and -0.749), indicating poor solubility. This is a concern, but can be addressed with formulation strategies. The values are similar.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.386 and 0.226), which is excellent.

**Microsomal Clearance:** Ligand A (-2.625) has significantly lower (better) microsomal clearance than Ligand B (25.754). This indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (11.17) has a longer half-life than Ligand B (8.619), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.015 and 0.073).

**Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.1), a difference of 0.7 kcal/mol. While a 1.5 kcal/mol advantage is significant, 0.7 kcal/mol is less impactful, especially considering other factors.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). While Ligand B has slightly better binding affinity, the improvements in safety and pharmacokinetic properties of Ligand A outweigh this difference. The solubility and permeability are similar and problematic for both, but these can be addressed during formulation.

Output:
1
2025-04-17 15:14:48,227 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.439 Da and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (81.81 and 85.43) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values within the optimal 1-3 range (2.081 and 1.517).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is slightly better than Ligand B (3 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.539 and 0.788), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 87.786, which is high. Ligand B has a much lower DILI risk of 45.522, which is good. This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (67.352) is better than Ligand B (43.001).

**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. Again, the scale is unclear.

**hERG:** Ligand A (0.539) has a slightly higher hERG inhibition risk than Ligand B (0.404), but both are relatively low.

**Microsomal Clearance:** Ligand A (65.865) has a higher microsomal clearance than Ligand B (10.532), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (38.797 hours) has a much longer half-life than Ligand B (-10.259 hours). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.648) has slightly higher P-gp efflux than Ligand B (0.061), which is less desirable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While both are good, the 0.7 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a longer half-life and slightly better BBB penetration, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic), and slightly higher binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh these issues. The very negative half-life for Ligand B is a red flag, but the other properties are so favorable that it's still preferred.

Output:
1
2025-04-17 15:14:48,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.46 and 370.52 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (84.3) is still acceptable but less favorable.

**3. logP:** Both ligands (1.83 and 2.01) 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 (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.77 and 0.72), indicating good drug-likeness.

**7. DILI:** Ligand A (11.63) has a significantly lower DILI risk than Ligand B (53.63). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (40.40) has a lower BBB penetration score than Ligand B (67.66). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.91 and -4.77), 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 (-2.07 and -2.94), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.34 and 0.29).

**12. Microsomal Clearance:** Ligand A (14.62) has a significantly lower microsomal clearance than Ligand B (81.86), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-15.17) has a more negative (longer) half-life than Ligand B (-23.70). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.14 and 0.08).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). While both have poor solubility and permeability, the improved safety and pharmacokinetic profile of Ligand A outweigh these drawbacks, especially given the equal binding affinity. The lower TPSA of Ligand A is also a slight advantage.

Output:
1
2025-04-17 15:14:48,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.81) is slightly higher than Ligand B (78.95). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (1.373 and 1.23), falling within the 1-3 range.

**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). Ligand B is slightly better due to fewer potential off-target interactions.

**QED:** Both ligands have good QED scores (0.623 and 0.7), indicating good drug-like properties.

**DILI:** Ligand A (11.361) has a significantly lower DILI risk than Ligand B (34.471). This is a major advantage for Ligand A.

**BBB:** Ligand A (26.561) has a lower BBB penetration than Ligand B (73.711). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.347) has worse Caco-2 permeability than Ligand B (-4.672), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.042) has slightly better aqueous solubility than Ligand B (-1.954).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.285 and 0.272).

**Microsomal Clearance:** Ligand A (-2.442) has a significantly *lower* (better) microsomal clearance than Ligand B (33.194). This indicates better metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (36.507) has a longer in vitro half-life than Ligand B (-12.943), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.023 and 0.111).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has slightly better Caco-2 permeability and BBB penetration (which are less important here), Ligand A demonstrates significantly lower DILI risk and *much* better metabolic stability (lower Cl_mic and longer t1/2). The similar binding affinities make the ADME advantages of Ligand A decisive.

Output:
0
2025-04-17 15:14:48,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.371 Da) is slightly lower, which can be beneficial for permeability, while Ligand B (354.407 Da) is also acceptable.

**TPSA:** Ligand A (87.45) is excellent, well below the 140 threshold for oral absorption. Ligand B (127.93) is still reasonable but less optimal.

**logP:** Ligand A (2.455) is within the optimal range (1-3). Ligand B (-1.357) is significantly lower, potentially hindering permeation and absorption.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is favorable. Ligand B (4 HBD, 7 HBA) is acceptable, but the higher number of HBDs could slightly impact permeability.

**QED:** Both ligands have acceptable QED values (A: 0.538, B: 0.431), indicating reasonable drug-likeness.

**DILI:** Ligand A (76.037) has a higher DILI risk than Ligand B (26.406), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (43.699) and B (23.071) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.42 and -5.859), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.085 and -0.23), indicating very poor aqueous solubility, a major issue for bioavailability.

**hERG Inhibition:** Ligand A (0.816) has a slightly higher hERG risk than Ligand B (0.022). B is very favorable.

**Microsomal Clearance:** Ligand A (19.155 mL/min/kg) has a higher clearance than Ligand B (-15.619 mL/min/kg - note the negative value suggests very high stability). This means Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand A (-30.753 hours) has a negative half-life, which is not possible. This is a data error. Ligand B (10.381 hours) is reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.109, B: 0.004), which is good.

**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.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, it has a significantly higher DILI risk and a questionable half-life value. Its solubility and permeability are also very poor. Ligand B has a lower affinity but exhibits much better metabolic stability, a significantly lower DILI risk, and a much lower hERG risk. While its logP is suboptimal, the substantial difference in binding affinity between A and B is a major consideration. Given the poor ADME profile of both, and the critical importance of potency for kinase inhibitors, I would lean towards Ligand A *if* the half-life data can be corrected or explained. However, the high DILI risk is a major concern.

Considering the totality of the data, and prioritizing safety and reasonable ADME properties, Ligand B is the more viable candidate, despite the lower binding affinity. The lower DILI and hERG risks, coupled with better metabolic stability, make it a more promising starting point for optimization.

Output:
1
2025-04-17 15:14:48,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 and 351.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.57) is better than Ligand B (38.13), being below 140 and suggesting good absorption.

**logP:** Both ligands have acceptable logP values (2.39 and 3.92, respectively), falling within the 1-3 range. Ligand B is slightly higher, which *could* pose a minor solubility risk, but is still within acceptable limits.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within the recommended limits (<=5 HBD, <=10 HBA).

**QED:** Both have reasonable QED scores (0.877 and 0.729), indicating good drug-like properties.

**DILI:** Ligand A (57.66%) has a higher DILI risk than Ligand B (35.29%). This is a significant drawback for Ligand A.

**BBB:** Ligand A (59.40%) has a lower BBB penetration than Ligand B (95.19%). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.215) has worse Caco-2 permeability than Ligand B (-4.38). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.865) has worse aqueous solubility than Ligand B (-4.072). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.276) has a slightly lower hERG risk than Ligand B (0.796), which is favorable.

**Microsomal Clearance:** Ligand A (-9.874) has *much* better microsomal clearance (lower clearance = better stability) than Ligand B (71.018). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (43.834 hours) has a significantly longer half-life than Ligand B (2.502 hours). This is a substantial benefit for Ligand A.

**P-gp Efflux:** Ligand A (0.108) has lower P-gp efflux than Ligand B (0.687), which is favorable.

**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 not huge.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), P-gp efflux, and binding affinity. However, it has a significantly higher DILI risk and lower solubility. Ligand B has better solubility, lower DILI, and better Caco-2 permeability, but suffers from poor metabolic stability and a shorter half-life.

Given that we are targeting a kinase (enzyme), metabolic stability and a reasonable half-life are paramount. The substantial advantage of Ligand A in these areas, coupled with its slightly better binding affinity, outweighs its higher DILI risk and lower solubility, especially since the DILI risk is still below 60%. The solubility issue can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 15:14:48,228 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [421.316, 72.2, 4.376, 1, 5, 0.679, 79.643, 58.899, -5.028, -4.62, 0.534, 55.273, 93.711, 0.777, -7.5]
**Ligand B:** [361.511, 62.3, 2.785, 1, 4, 0.792, 47.421, 74.292, -5.445, -3.216, 0.78, 55.302, 5.098, 0.192, -7.3]

**Step-by-step comparison:**

1. **MW:** Ligand A (421.316 Da) is within the ideal range, while Ligand B (361.511 Da) is a bit lower, but still acceptable.
2. **TPSA:** Ligand A (72.2) is slightly higher than ideal (<=140), but not concerning. Ligand B (62.3) is excellent.
3. **logP:** Ligand A (4.376) is a bit high, potentially causing solubility issues or off-target effects. Ligand B (2.785) is optimal.
4. **HBD:** Both ligands have 1 HBD, which is good.
5. **HBA:** Ligand A has 5 HBA, acceptable. Ligand B has 4 HBA, also good.
6. **QED:** Both ligands have good QED scores (A: 0.679, B: 0.792), indicating drug-like properties. Ligand B is slightly better.
7. **DILI:** Ligand A (79.643) has a significantly higher DILI risk than Ligand B (47.421). This is a major concern for Ligand A.
8. **BBB:** Ligand A (58.899) has a lower BBB penetration percentile than Ligand B (74.292). Not a primary concern for SRC kinase, but a slight advantage for B.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This needs further investigation, but we'll assume it means very low permeability for both.
10. **Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This needs further investigation, but we'll assume it means very low solubility for both.
11. **hERG:** Ligand A (0.534) has a slightly higher hERG risk than Ligand B (0.78).
12. **Cl_mic:** Both ligands have similar microsomal clearance (A: 55.273, B: 55.302).
13. **t1/2:** Ligand A (93.711) has a much longer in vitro half-life than Ligand B (5.098). This is a significant advantage for Ligand A.
14. **Pgp:** Ligand A (0.777) has lower P-gp efflux than Ligand B (0.192). This is a slight advantage for A.
15. **Affinity:** Ligand A (-7.5 kcal/mol) has slightly better binding affinity than Ligand B (-7.3 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Decision:**

Despite the slightly better affinity and longer half-life of Ligand A, the significantly higher DILI risk is a major red flag. The higher logP also raises concerns. Ligand B, while having a slightly lower affinity and shorter half-life, has a much more favorable safety profile (lower DILI) and better logP. The similar metabolic clearance is acceptable. While both have poor predicted permeability and solubility, the lower DILI risk of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 15:14:48,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.394 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is higher than Ligand B (76.58). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.348) is quite low, potentially hindering permeability. Ligand B (1.802) 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 1 HBD and 6 HBA. Both are acceptable, but Ligand B's lower HBD count is slightly preferable.

**QED:** Ligand B (0.808) has a much higher QED score than Ligand A (0.47), indicating a more drug-like profile.

**DILI:** Ligand A (22.218) has a significantly lower DILI risk than Ligand B (48.623), which is a major positive for Ligand A.

**BBB:** Ligand A (67.352) and Ligand B (83.831) both have acceptable BBB penetration, but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.028) shows poor permeability, while Ligand B (-4.65) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.968 and -1.814 respectively). This is a concern for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.29 and 0.323 respectively).

**Microsomal Clearance:** Ligand A (31.331) has a lower microsomal clearance than Ligand B (63.147), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (19.634) has a slightly longer half-life than Ligand B (17.319).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.041 respectively).

**Binding Affinity:** Ligand B (-10.0 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 of Ligand B. A difference of 3.2 kcal/mol is considerable.

**Overall Assessment:**

Ligand B has a superior binding affinity and better logP and TPSA values. However, it has a higher DILI risk and a worse metabolic stability profile (higher Cl_mic). Ligand A has a lower DILI risk, better metabolic stability, and a slightly longer half-life, but suffers from poor logP and Caco-2 permeability, and a significantly weaker binding affinity.

Given the enzyme-specific priorities, the strong binding affinity of Ligand B is the most important factor. While the DILI and metabolic stability are concerns, these can potentially be addressed through further optimization. The weaker affinity of Ligand A is a more difficult hurdle to overcome.

Output:
1
2025-04-17 15:14:48,229 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 354.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.64 and 57.69) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.267 and 1.357), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility but potentially lower permeability.

**H-Bond Donors & Acceptors:** Ligand A has 1 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 (0.686 and 0.752), indicating a drug-like profile.

**DILI:** Ligand A has a DILI risk of 15.898%, which is excellent (low risk). Ligand B has a DILI risk of 35.905%, still acceptable but higher than A.

**BBB:** Both ligands have reasonably good BBB penetration (72.896% and 87.67%), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.798 and -4.651), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.431 and -1.933), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.263 and 0.226), which is positive.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (51.9 mL/min/kg) compared to Ligand B (16.934 mL/min/kg).  This suggests Ligand B is more metabolically stable, a key priority for enzymes.

**In vitro Half-Life:** Ligand A has a very short in vitro half-life (-27.981 hours), which is problematic. Ligand B has a slightly better half-life (-22.695 hours), but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.114), which is good.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-10.7 kcal/mol) than Ligand B (-9.1 kcal/mol). This is a substantial advantage (1.6 kcal/mol difference) and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand A's significantly stronger binding affinity (-10.7 vs -9.1 kcal/mol) and lower DILI risk make it the more promising candidate. The improved potency is a critical factor for an enzyme target, and the lower DILI is a significant safety advantage. While metabolic stability is better for Ligand B, the difference isn't large enough to overcome the substantial potency difference. Addressing the solubility and permeability issues through formulation or structural modifications would be crucial for either compound.

Output:
0
2025-04-17 15:14:48,229 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (367.471 Da) is also good.

**TPSA:** Ligand A (67.35) is well below the 140 threshold for oral absorption and is favorable. Ligand B (97.39) is still acceptable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.166, B: 1.816), falling within the 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:** Ligand A (0.894) has a significantly higher QED score than Ligand B (0.566), indicating a more drug-like profile.

**DILI:** Ligand A (29.546) has a much lower DILI risk than Ligand B (74.952). This is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (90.229) has a higher BBB percentile than Ligand B (51.997), but this isn't a primary concern.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.73) is slightly better than Ligand B (-5.189).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-1.818) is slightly better than Ligand B (-3.128).

**hERG:** Both have very low hERG inhibition liability (A: 0.192, B: 0.072), which is excellent.

**Microsomal Clearance:** Ligand A (13.731 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (69.611 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.693 hours) has a much longer half-life than Ligand B (2.669 hours), which is highly desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.051, B: 0.131).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 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 a slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), higher QED, and better solubility. These factors are critical for developing a viable drug candidate, especially for an enzyme target where metabolic stability and bioavailability are key. The small difference in binding affinity is likely surmountable with further optimization of Ligand A.

Output:
0
2025-04-17 15:14:48,229 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (344.371 and 344.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.09) is higher than Ligand B (75.94). While both are reasonably good, Ligand B's lower TPSA is preferable for better absorption.

**3. logP:** Both ligands have good logP values (1.139 and 1.338), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Ligand B is preferable here, 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 and good QED values (0.752 and 0.784), indicating good drug-likeness.

**7. DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (45.483). Ligand B is significantly better in this regard.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (75.029) has a higher BBB percentile than Ligand A (27.608), but this isn't a major deciding factor.

**9. Caco-2 Permeability:** Ligand A (-5.395) shows poor Caco-2 permeability, while Ligand B (-4.501) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-2.988) has poor solubility while Ligand B (-1.84) is better, but still not great.

**11. hERG Inhibition:** Ligand A (0.065) has a slightly lower hERG risk than Ligand B (0.513), which is preferable.

**12. Microsomal Clearance:** Ligand A (-12.441) has significantly lower (better) microsomal clearance than Ligand B (36.089), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.027 hours) has a much longer half-life than Ligand A (2.824 hours), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.011) has a lower P-gp efflux liability than Ligand B (0.061), which is preferable.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This 0.8 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 hERG profile and P-gp efflux, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), a substantially stronger binding affinity, lower DILI risk, and better Caco-2 permeability and solubility. The lower TPSA of Ligand B is also a plus.

Output:
1
2025-04-17 15:14:48,229 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.467 and 391.295 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.02 and 75.71) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.637 and 2.019) 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.

**QED:** Ligand A (0.815) has a significantly better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Ligand A (68.437) has a higher DILI risk than Ligand B (31.563). This is a concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (65.801) has a higher BBB percentile than Ligand A (48.313), but this is not a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.337 and -5), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.393 and -3.076) which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.044) has a slightly lower hERG inhibition risk than Ligand B (0.261), which is preferable.

**Microsomal Clearance:** Ligand B (20.659 mL/min/kg) has lower microsomal clearance than Ligand A (28.855 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.779 hours) has a significantly longer in vitro half-life than Ligand B (-11.934 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056).

**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, potentially outweighing some of the ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a superior binding affinity and a much longer half-life, which are crucial for an enzyme inhibitor. While it has a higher DILI risk, the strong binding affinity and longer half-life are significant advantages. Both ligands have poor predicted permeability and solubility, which would need to be addressed through formulation or further chemical modifications. However, the potency and PK profile of ligand A are more promising.

Output:
1
2025-04-17 15:14:48,230 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.5 and 342.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.2 and 75.19) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have good logP values (3.03 and 2.04), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which is acceptable.

**QED:** Both ligands have high QED scores (0.90 and 0.93), indicating good drug-likeness.

**DILI:** Ligand A (50.14) has a slightly better DILI score than Ligand B (58.74), indicating lower potential for liver injury. Both are acceptable, being under 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.9) has a higher BBB score than Ligand A (60.68), but this is not a major factor in this case.

**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, suggesting poor solubility. This is a concern.

**hERG Inhibition:** Ligand A (0.604) has a slightly higher hERG risk than Ligand B (0.365), which is undesirable.

**Microsomal Clearance:** Ligand B (-1.264) has significantly *lower* (better) microsomal clearance than Ligand A (21.015). This indicates much better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-21.44) has a much longer in vitro half-life than Ligand A (1.511), further supporting its superior metabolic stability.

**P-gp Efflux:** Ligand B (0.051) has a lower P-gp efflux liability than Ligand A (0.297), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-10.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.9 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand B's superior ADME properties (lower Cl_mic, longer t1/2, lower Pgp efflux, lower hERG), the significantly stronger binding affinity of Ligand A (-10.0 vs -8.9 kcal/mol) is a decisive factor for an enzyme target. The potency advantage outweighs the ADME drawbacks, especially considering that both compounds have acceptable (though not ideal) ADME profiles. The slightly better DILI score for Ligand A is also a minor positive.

Output:
1
2025-04-17 15:14:48,230 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.431 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (81.93 and 76.02) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.795 and 1.49) are 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:** Both ligands have good QED scores (0.751 and 0.866), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (44.591 and 49.399 percentiles), which is favorable.

**BBB:** Both ligands have similar BBB penetration (76.309 and 78.907 percentiles). BBB isn't a primary concern for SRC kinase inhibitors unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.791 and -4.83), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.276 and -2.917), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.073) has a slightly lower hERG risk than Ligand B (0.375), which is preferable.

**Microsomal Clearance:** Ligand B (-11.729) has significantly lower microsomal clearance than Ligand A (54.923), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (19.287 hours) has a much longer in vitro half-life than Ligand A (-9.48 hours). This is a significant benefit, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.059 and 0.061).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the 1.2 kcal/mol difference is meaningful.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity outweigh the marginally higher hERG risk. The poor solubility and permeability would need to be addressed through formulation strategies, but the improved PK profile of Ligand B makes it a better starting point for optimization.

Output:
1
2025-04-17 15:14:48,230 - INFO - Batch 363 complete. Total preferences: 5808
2025-04-17 15:14:48,230 - INFO - Processing batch 364/512...
2025-04-17 15:15:31,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.861 and 371.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (71.84 and 73.14) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands (3.01 and 2.507) 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 7. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.806 and 0.713), indicating good drug-like properties.

**7. DILI:** Ligand A (51.377) has a slightly higher DILI risk than Ligand B (41.295), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (93.486) has a higher BBB penetration score than Ligand A (70.997), but this isn't a major deciding factor here.

**9. Caco-2 Permeability:** Ligand A (-5.009) has a more negative Caco-2 value than Ligand B (-4.36), suggesting potentially lower permeability. This is a slight negative for Ligand A.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.297 and -3.922), indicating poor aqueous solubility. This is a concern for both, but could be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.15) has a lower hERG inhibition liability than Ligand B (0.489), which is a significant advantage.

**12. Microsomal Clearance:** Ligand B (48.668) has a lower microsomal clearance than Ligand A (6.191), indicating better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-3.597) has a longer in vitro half-life than Ligand A (19.912). This is another advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux liability than Ligand B (0.218), which is a positive.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This 1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates superior ADME properties, particularly in metabolic stability (lower Cl_mic, longer t1/2) and hERG risk. While Ligand A has a slightly better binding affinity, the improved ADME profile of Ligand B is more critical for a kinase inhibitor, where maintaining adequate systemic exposure is essential. The solubility issue is a concern for both, but can be addressed during formulation.

Output:
1
2025-04-17 15:15:31,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.447 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (88.1) is better than Ligand B (96.25). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred <90 for CNS targets (though this isn't a CNS target).

**3. logP:** Both ligands have good logP values (1.286 and 1.0), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Both are within the acceptable limit of <=5.

**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 acceptable QED values (0.743 and 0.654), indicating good drug-like properties.

**7. DILI:** Ligand A (10.585) is significantly better than Ligand B (39.473). A lower DILI percentile is highly desirable. Ligand B is approaching a concerning level.

**8. BBB:** This isn't a primary concern for an oncology target. Ligand A (73.75) is better than Ligand B (39.511), but both are not particularly high.

**9. Caco-2 Permeability:** Both ligands are negative (-4.642 and -4.872), which is unusual. It suggests very poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands are negative (-1.827 and -2.943), which is also unusual. It suggests very poor solubility. However, the scale is not defined, so it's hard to interpret.

**11. hERG Inhibition:** Ligand A (0.482) is significantly better than Ligand B (0.098). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (5.952) is much better than Ligand B (36.458). Lower clearance indicates better metabolic stability, a key consideration for enzymes.

**13. In vitro Half-Life:** Ligand A (-6.519) is significantly better than Ligand B (-14.898). A longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.032) is much better than Ligand B (0.057). Lower P-gp efflux is desirable for better bioavailability.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) is significantly better than Ligand B (-8.3 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior to Ligand B. It demonstrates significantly better DILI risk, hERG inhibition, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and, most importantly, binding affinity. While both have poor Caco-2 and solubility values, the superior potency and safety profile of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 15:15:31,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (78.95) is better than Ligand B (62.3). Lower TPSA generally favors oral absorption, and both are reasonably low.

**logP:** Ligand A (0.761) is a bit low, potentially hindering permeation. Ligand B (2.79) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors:** Both ligands have 1 HBD, which is ideal.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.745 and 0.772, respectively), indicating good drug-like properties.

**DILI:** Ligand A (40.054) is slightly higher than Ligand B (29.585), but both are below the concerning threshold of 60. Ligand B is preferable here.

**BBB:** Both have moderate BBB penetration, but Ligand B (68.67) is better than Ligand A (61.923). This isn't a primary concern for a kinase inhibitor, but a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.429) is significantly worse than Ligand B (-5.151). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-1.938) is better than Ligand B (-3.575). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.233) is much better than Ligand B (0.428). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (24.14 mL/min/kg) is significantly better than Ligand B (59.211 mL/min/kg). Lower clearance indicates greater metabolic stability, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-38.901) is much better than Ligand B (5.238). A longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.025) is much better than Ligand B (0.184). Lower P-gp efflux improves bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) is significantly more potent than Ligand A (-7.8 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 optimal logP. However, Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, better hERG inhibition, and better Caco-2 permeability. The difference in binding affinity is significant, but the ADME profile of Ligand A is substantially better, particularly regarding metabolic stability and safety (hERG). Given the importance of metabolic stability for kinase inhibitors, and the acceptable binding affinity of Ligand A, I would lean towards Ligand A.

Output:
0
2025-04-17 15:15:31,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (363.424 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.36) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.51) is still under 140, but less optimal than A.

**logP:** Ligand A (3.734) is within the optimal 1-3 range. Ligand B (0.981) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which are both acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.723) has a good drug-likeness score, exceeding the 0.5 threshold. Ligand B (0.443) is below 0.5, indicating a less favorable drug-like profile.

**DILI:** Ligand A (29.934) has a lower DILI risk than Ligand B (23.226), both are good.

**BBB:** Ligand A (87.437) shows better BBB penetration than Ligand B (52.268), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.266) and Ligand B (-4.612) have negative values, which is unusual and requires careful interpretation. Lower (more negative) values generally indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-4.039) and Ligand B (-2.056) have negative values, indicating poor solubility. Ligand B is slightly better than A.

**hERG Inhibition:** Ligand A (0.616) has a lower hERG risk than Ligand B (0.044), which is a significant advantage.

**Microsomal Clearance:** Ligand A (90.971) has a higher microsomal clearance than Ligand B (29.294), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (9.784) has a shorter half-life than Ligand B (-17.421), indicating faster metabolism. This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.146) has lower P-gp efflux than Ligand B (0.018), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has better TPSA and P-gp efflux, Ligand B demonstrates a better QED score, lower microsomal clearance (better metabolic stability), a longer in vitro half-life, and a lower hERG risk. The slightly lower logP and solubility of Ligand B are less concerning than the poorer metabolic stability and shorter half-life of Ligand A, especially given the similar binding affinities.

Output:
1
2025-04-17 15:15:31,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.328 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 63, which is acceptable for oral absorption, though not optimal for CNS penetration (not a priority here).

**logP:** Both ligands have good logP values (A: 2.375, B: 1.312), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly better than Ligand B (0 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.801, B: 0.63), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (32.377) has a significantly lower DILI risk than Ligand B (23.846). This is a major advantage for Ligand A.

**BBB:** BBB isn't a high priority for a non-CNS target like SRC. Both are 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 hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unknown, making interpretation difficult.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.576, B: 0.224), which is excellent.

**Microsomal Clearance:** Ligand A (4.748) has significantly lower microsomal clearance than Ligand B (35.121), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (54.829 hours) has a much longer in vitro half-life than Ligand B (10.543 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.181, B: 0.06).

**Binding Affinity:** Both ligands have comparable and excellent 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:**

Ligand A is superior due to its significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and better QED score. While both have similar binding affinities, the improved ADME properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 15:15:31,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines. SRC is an enzyme, so potency, metabolic stability, solubility, and hERG risk are key.

**Molecular Weight:** Both ligands (347.503 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (61.44). Lower TPSA generally correlates with better cell permeability. Both are below the 140 threshold, but A is closer to the optimal range for oral absorption.

**logP:** Both ligands have acceptable logP values (2.112 and 2.476), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 3 HBA). Lower HBD counts can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.782 and 0.662), indicating good drug-like properties.

**DILI:** Ligand A (6.747) has a much lower DILI risk than Ligand B (7.832), which is a significant advantage. Lower DILI is crucial for drug development.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (86.002) has better BBB penetration than Ligand B (70.88).

**Caco-2 Permeability:** Ligand A (-4.787) shows better Caco-2 permeability than Ligand B (-5.048). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-0.924) has better aqueous solubility than Ligand B (-2.049). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.653 and 0.457), which is excellent.

**Microsomal Clearance:** Ligand A (13.206) has significantly lower microsomal clearance than Ligand B (27.006). This suggests better metabolic stability for Ligand A, a critical factor for enzymes.

**In vitro Half-Life:** Ligand A (-11.053) has a longer in vitro half-life than Ligand B (-6.717). This is also favorable, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.032).

**Binding Affinity:** Ligand A (-9.0) has a slightly better binding affinity than Ligand B (-7.7). While both are good, the 1.3 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially DILI risk, metabolic stability (Cl_mic and t1/2), solubility, and binding affinity. While both ligands are within acceptable ranges for many properties, the combined advantages of Ligand A make it a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 15:15:31,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (341.371 and 346.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.94) is better than Ligand B (113.24) as both are below the 140 A^2 threshold for good oral absorption, but closer to the 90 A^2 threshold is preferable.

**3. logP:** Ligand A (2.952) is optimal (1-3), while Ligand B (0.79) is slightly low, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD is generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (7) is better than Ligand B (5) as both are below the 10 threshold.

**6. QED:** Both ligands have similar good QED values (0.704 and 0.729, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (81.233) has a higher DILI risk than Ligand B (36.797). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (79.721 and 85.537), but this is less critical for a non-CNS target like SRC.

**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 not specified, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.267 and 0.299).

**12. Microsomal Clearance:** Ligand B (16.115) has significantly lower microsomal clearance than Ligand A (37.976), indicating better metabolic stability. This is a key priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand B (14.664) has a longer in vitro half-life than Ligand A (19.507).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.229 and 0.007).

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Conclusion:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly stronger binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP.

Output:
1
2025-04-17 15:15:31,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.487 and 360.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.2 and 75.94) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values within the optimal 1-3 range (3.004 and 2.69), suggesting good permeability and avoiding solubility issues.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1 each). Ligand B has a higher HBA count (7 vs 3), but still within the reasonable limit of 10.

**QED:** Both ligands have good QED scores (0.661 and 0.768), indicating a drug-like profile.

**DILI:** Ligand A has a DILI risk of 17.449, which is excellent (low risk). Ligand B has a higher DILI risk of 67.313, which is concerning (high risk).

**BBB:** Both ligands have similar BBB penetration (74.68 and 70.415), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.597 and -5.319). This is unusual and suggests a potential issue with intestinal absorption, but negative values aren't always directly interpretable and may indicate a limitation of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.03 and -3.095), which is also concerning. Similar to Caco-2, this might be a prediction artifact, but it warrants attention.

**hERG Inhibition:** Ligand A has a hERG risk of 0.626, which is relatively low. Ligand B has a slightly lower hERG risk (0.454), but both are acceptable.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (80.787 mL/min/kg) than Ligand B (40.046 mL/min/kg). This suggests that Ligand B is more metabolically stable, which is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (10.878 hours) compared to Ligand A (-7.882 hours). 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 (0.243 and 0.117), which is positive.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.2 kcal/mol) compared to Ligand A (-8.2 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While both ligands have some concerning solubility and permeability predictions, Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and comparable other properties make it more likely to be a viable drug candidate for SRC kinase inhibition. The higher DILI risk for Ligand A is a significant concern.

Output:
1
2025-04-17 15:15:31,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (341.386 and 343.387 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (101.22).  For kinases, TPSA isn't as critical as for BBB penetration, but lower TPSA generally correlates with better permeability. Ligand A is well below the 140 threshold. Ligand B is approaching it, which could be a minor concern.

**3. logP:** Both ligands have good logP values (2.62 and 1.718), 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 3 HBAs, while Ligand B has 6.  Ligand A is preferable here, as fewer HBAs generally improve permeability. Ligand B is approaching the upper limit of 10.

**6. QED:** Both ligands have high QED scores (0.93 and 0.907), indicating good drug-like properties.

**7. DILI:** Ligand A (53.354) has a lower DILI risk than Ligand B (71.229).  Both are acceptable (<60 is good), but A is better.

**8. BBB:** This is less critical for a kinase inhibitor, but Ligand A (81.698) has a better BBB score than Ligand B (68.205).

**9. Caco-2 Permeability:** Ligand A (-4.767) has a better Caco-2 permeability than Ligand B (-5.035). While both are negative, a less negative value indicates better permeability.

**10. Aqueous Solubility:** Ligand A (-3.263) has better aqueous solubility than Ligand B (-2.632). Both are negative, but A is better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.334 and 0.209).

**12. Microsomal Clearance:** Ligand A (20.587) has a slightly lower microsomal clearance than Ligand B (22.989), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.17) has a significantly longer in vitro half-life than Ligand B (-4.674). This is a major advantage for kinase inhibitors.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.137 and 0.031).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -7.1 kcal/mol). Ligand A is significantly more potent, with a 2.4 kcal/mol advantage. This is a substantial difference that can outweigh minor ADME concerns.

**Conclusion:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand A is the superior candidate. Its significantly stronger binding affinity, longer half-life, better solubility, lower DILI risk, and lower TPSA outweigh the slightly less favorable Caco-2 permeability and BBB scores compared to Ligand B. The potency difference is particularly compelling.

Output:
0
2025-04-17 15:15:31,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.485 and 393.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (115.81) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (1.434) is within the optimal 1-3 range. Ligand B (-1.238) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Ligand A (0.652) is good, indicating drug-likeness. Ligand B (0.446) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (11.788) has a very low DILI risk. Ligand B (44.552) is higher, indicating a moderate risk of liver injury.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.472) is high, while Ligand B (38.852) is low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.179 and -5.643), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.32 and -1.684), also unusual and concerning. This suggests very poor aqueous solubility, which will hinder bioavailability.

**hERG Inhibition:** Ligand A (0.79) has a low hERG risk. Ligand B (0.174) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (8.134) has a lower clearance than Ligand B (-16.347), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.826) has a negative half-life, which is not possible. Ligand B (-46.705) also has a negative half-life. These values are likely errors or indicate very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.006).

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.4 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. It has a better TPSA, logP, QED, and significantly lower DILI risk. The negative Caco-2 and solubility values are concerning for both, but the better metabolic stability (lower Cl_mic) of Ligand A is a significant advantage for an enzyme inhibitor. The negative half-life values are problematic for both and require further investigation, but the other factors favor Ligand A.

Output:
1
2025-04-17 15:15:31,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.885 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (50.36 and 49.41) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.655) is slightly higher than optimal (1-3), potentially leading to solubility issues. Ligand B (3.198) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.755 and 0.78), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 61.031, which is moderately high. Ligand B has a much lower DILI risk of 15.355, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration (61.458 and 71.811), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.688 and -4.84), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.646 and -3.384). This is a major drawback for both, but potentially more problematic for Ligand A due to its higher logP.

**hERG Inhibition:** Ligand A (0.833) has a slightly higher hERG risk than Ligand B (0.346), although both are relatively low.

**Microsomal Clearance:** Ligand A (80.004 mL/min/kg) has higher microsomal clearance than Ligand B (54.278 mL/min/kg), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-12.798 hours) has a negative half-life, which is not physically possible and suggests an issue with the data or the compound's stability. Ligand A (78.049 hours) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.636) shows moderate P-gp efflux, while Ligand B (0.117) shows very low efflux. This is a benefit for Ligand B.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). This 1.5 kcal/mol difference is significant and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, Ligand B appears to be the more promising candidate. The significantly lower DILI risk and P-gp efflux, combined with better metabolic stability (lower Cl_mic) and a more favorable logP, outweigh the modest difference in binding affinity. The negative half-life for Ligand B is a major red flag, but assuming this is a data error, the rest of its profile is superior. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 15:15:31,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.777 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values around 76, well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.741) is slightly higher than Ligand B (2.354). Both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 2. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBAs, well within the acceptable limit of <=10.

**QED:** Ligand B (0.796) has a better QED score than Ligand A (0.571), indicating a more drug-like profile.

**DILI:** Ligand A (93.525 percentile) has a significantly higher DILI risk than Ligand B (29.895 percentile). This is a major concern for Ligand A.

**BBB:** Ligand B (64.172) has a better BBB penetration score than Ligand A (44.979). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.88 and -4.873), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand B (-2.817) has better solubility than Ligand A (-5.149), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.189) has a slightly lower hERG inhibition risk than Ligand B (0.488), which is favorable.

**Microsomal Clearance:** Ligand B (41.066 mL/min/kg) has lower microsomal clearance than Ligand A (68.229 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.902 hours) has a negative half-life, which is problematic. Ligand A (30.934 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.385) has lower P-gp efflux than Ligand B (0.169), potentially leading to better bioavailability.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its half-life is concerningly negative, its significantly lower DILI risk, better QED, better solubility, and slightly better binding affinity outweigh the drawbacks of slightly higher P-gp efflux and a slightly worse hERG profile. Ligand A's high DILI risk is a major red flag. The negative Caco-2 values for both are concerning and would require further investigation, but the overall profile of Ligand B is superior.

Output:
1
2025-04-17 15:15:31,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Ligand A:**

*   **MW:** 349.406 Da - Good (within ideal range).
*   **TPSA:** 93.45 - Good (below 140, acceptable for oral absorption).
*   **logP:** 1.708 - Good (within optimal range).
*   **HBD:** 3 - Good (within acceptable limit).
*   **HBA:** 4 - Good (within acceptable limit).
*   **QED:** 0.467 - Marginal (slightly below the preferred 0.5, but not a major concern).
*   **DILI:** 54.052 - Good (low risk).
*   **BBB:** 81.466 - Good (relatively high, but not a primary concern for a non-CNS target).
*   **Caco-2:** -4.957 - Poor (negative value suggests very low permeability).
*   **Solubility:** -3.903 - Poor (negative value suggests very low solubility).
*   **hERG:** 0.584 - Good (low risk).
*   **Cl_mic:** 47.586 - Moderate (relatively low, suggesting reasonable metabolic stability).
*   **t1/2:** 6.677 - Moderate (acceptable, but could be better).
*   **Pgp:** 0.207 - Good (low efflux).
*   **Affinity:** -7.3 kcal/mol - Excellent (very strong binding).

**Ligand B:**

*   **MW:** 555.561 Da - Poor (above ideal range, potentially impacting permeability).
*   **TPSA:** 111.72 - Moderate (acceptable, but approaching the upper limit for oral absorption).
*   **logP:** 4.784 - Poor (high, potentially causing solubility/off-target issues).
*   **HBD:** 3 - Good (within acceptable limit).
*   **HBA:** 8 - Good (within acceptable limit).
*   **QED:** 0.341 - Poor (below preferred threshold).
*   **DILI:** 96.549 - Very Poor (high risk).
*   **BBB:** 26.871 - Poor (low, not a concern here).
*   **Caco-2:** -5.009 - Poor (negative value suggests very low permeability).
*   **Solubility:** -6.026 - Very Poor (negative value suggests very low solubility).
*   **hERG:** 0.89 - Moderate (slightly elevated risk).
*   **Cl_mic:** 71.585 - Moderate (higher than Ligand A, suggesting lower metabolic stability).
*   **t1/2:** 35.365 - Excellent (very long half-life).
*   **Pgp:** 0.822 - Moderate (higher efflux).
*   **Affinity:** 0.0 kcal/mol - Poor (very weak binding).

**Comparison & Conclusion:**

Ligand A has a significantly better binding affinity (-7.3 kcal/mol vs. 0.0 kcal/mol for Ligand B). While Ligand A's QED is slightly below the ideal, its DILI risk is low, and its hERG risk is minimal. The biggest drawbacks for Ligand A are the poor Caco-2 permeability and aqueous solubility. However, these can sometimes be addressed with formulation strategies. Ligand B has multiple serious issues: high MW, high logP, very poor solubility and permeability, high DILI risk, weak binding affinity, and higher Pgp efflux. The long half-life of Ligand B is not enough to compensate for its other deficiencies.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is the deciding factor. Even with the permeability and solubility concerns, it is a far more promising starting point for optimization than Ligand B.

Output:
1
2025-04-17 15:15:31,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.515 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.72) is better than Ligand B (78.87), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (1.246 and 1.034) are within the optimal range of 1-3.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2), both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is good.

**QED:** Ligand A (0.794) has a significantly better QED score than Ligand B (0.48), indicating a more drug-like profile.

**DILI:** Ligand A (26.173) has a much lower DILI risk than Ligand B (5.777), both are below the 40 threshold.

**BBB:** Ligand A (57.968) has a better BBB penetration than Ligand B (33.385), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.915) and Ligand B (-4.688) are both negative, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.99) and Ligand B (-1.784) are both negative, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.053) has a much lower hERG inhibition liability than Ligand B (0.415), which is a significant advantage.

**Microsomal Clearance:** Ligand A (19.166) has lower microsomal clearance than Ligand B (34.876), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-9.325) has a longer in vitro half-life than Ligand B (-1.894), which is a desirable property.

**P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux liability than Ligand B (0.075).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 1.8 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall:** Ligand A is superior to Ligand B. It has better QED, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a stronger binding affinity. While both have poor Caco-2 permeability and solubility, the advantages of Ligand A are more critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:15:31,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.543 and 365.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is better than Ligand B (75.44). Lower TPSA generally favors better absorption.

**logP:** Both ligands (2.669 and 2.348) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1) as it balances solubility and permeability.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the 10 threshold.

**QED:** Ligand B (0.883) has a significantly higher QED score than Ligand A (0.627), indicating better overall drug-likeness.

**DILI:** Ligand A (33.695) has a lower DILI risk than Ligand B (41.915), which is preferable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (80.419) is better than Ligand A (63.668). While not a primary concern for a kinase inhibitor, higher BBB is never a detriment.

**Caco-2 Permeability:** Ligand A (-5.175) is better than Ligand B (-4.926), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.37) is better than Ligand B (-2.777), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands (0.588 and 0.424) show low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand B (14.533) has significantly lower microsomal clearance than Ligand A (60.504), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (10.739) has a slightly better in vitro half-life than Ligand A (77.441).

**P-gp Efflux:** Both ligands (0.086 and 0.087) have low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has advantages in solubility and Caco-2 permeability, Ligand B's superior binding affinity (-8.4 vs -7.4 kcal/mol), significantly better metabolic stability (lower Cl_mic), and higher QED score make it the more promising drug candidate. The stronger binding is a critical factor for an enzyme inhibitor, and the improved metabolic stability will likely translate to better *in vivo* exposure.

Output:
1
2025-04-17 15:15:31,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (332.407 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.91) is higher than Ligand B (49.85). Both are acceptable, but Ligand B is preferable for permeability.

**logP:** Ligand A (3.816) is slightly higher than Ligand B (2.529). Both are within the optimal 1-3 range, but Ligand A is approaching the upper limit, potentially raising solubility concerns.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While both are acceptable, a small number of HBDs can sometimes improve binding.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is good.

**QED:** Both ligands have similar QED values (0.746 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (80.923) has a significantly higher DILI risk than Ligand B (37.728). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration (Ligand A: 68.282, Ligand B: 66.654), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.967 and -4.424). This is unusual and potentially problematic, suggesting poor permeability. However, these values are on a log scale and the absolute values are similar, so the difference is not a major discriminator.

**Aqueous Solubility:** Ligand A (-4.147) has worse solubility than Ligand B (-2.799).

**hERG Inhibition:** Ligand A (0.69) has a slightly higher hERG risk than Ligand B (0.431), but both are acceptable.

**Microsomal Clearance:** Ligand A (65.229) and Ligand B (68.113) have similar microsomal clearance, indicating similar metabolic stability.

**In vitro Half-Life:** Ligand B (-1.637) 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 (34.608) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.162 and 0.365).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the unusual Caco-2 permeability values, Ligand B is the better candidate. It has a significantly lower DILI risk, better solubility, and a substantially stronger binding affinity. The negative in vitro half-life for Ligand B is a concern, but the other advantages outweigh this issue, assuming it's a data error. Ligand A's high DILI risk is a major drawback.

Output:
1
2025-04-17 15:15:31,471 - INFO - Batch 364 complete. Total preferences: 5824
2025-04-17 15:15:31,471 - INFO - Processing batch 365/512...
2025-04-17 15:16:14,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 357.311 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.35) is well below the 140 threshold for good absorption, and even favorable. Ligand B (85) is still acceptable, but less optimal.

**logP:** Both ligands (2.898 and 2.387) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.799 and 0.769), indicating good drug-likeness.

**DILI:** Ligand A (57.348) has a moderate DILI risk, while Ligand B (74.215) has a higher risk. This favors Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (82.202) has a higher BBB percentile than Ligand A (61.613).

**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 unclear.

**hERG:** Both ligands have low hERG inhibition liability (0.655 and 0.729), which is good.

**Microsomal Clearance:** Ligand A (94.011) has significantly higher microsomal clearance than Ligand B (30.504). This indicates Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-11.517) has a much longer in vitro half-life than Ligand A (-0.367), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.104 and 0.128).

**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.

**Conclusion:**

While Ligand A has a better DILI score, Ligand B's significantly stronger binding affinity (-9.3 vs -7.8 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme target like SRC kinase. The higher binding affinity is likely to translate to greater efficacy, and the improved metabolic stability will lead to a longer duration of action and potentially lower dosing requirements. The slightly higher DILI risk of Ligand B is a concern, but could be mitigated through further structural optimization.

Output:
1
2025-04-17 15:16:14,277 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.403 and 365.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.12) is better than Ligand B (93.5), both are below the 140 threshold for oral absorption, but closer to the ideal range.

**logP:** Both ligands have good logP values (3.295 and 2.73), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (6 & 6) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Ligand A (0.73) has a better QED score than Ligand B (0.457), indicating a more drug-like profile.

**DILI:** Ligand B (63.086) has a lower DILI risk than Ligand A (95.386), which is a significant advantage.

**BBB:** Both have similar BBB penetration (63.746 and 61.923), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.869) is better than Ligand B (-5.311), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.503) is better than Ligand B (-3.003), indicating better solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.544 and 0.491).

**Microsomal Clearance:** Ligand B (-5.716) has significantly better metabolic stability (lower clearance) than Ligand A (90.33). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (3.778) has a slightly better half-life than Ligand A (58.693).

**P-gp Efflux:** Ligand A (0.545) is better than Ligand B (0.187), indicating lower P-gp efflux.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has better solubility and Caco-2 permeability, Ligand B shines in metabolic stability (Cl_mic) and DILI risk. Given the enzyme-specific priorities, metabolic stability and low toxicity are paramount. The slightly better half-life of Ligand B also contributes to its favorability. The binding affinity is almost identical, so the ADME properties become the deciding factors. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 15:16:14,277 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.296 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.79) is well below the 140 threshold, suggesting good absorption. Ligand B (117.62) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.854) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.752) is below 1, which could hinder permeation.

**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:** Ligand A (0.846) has a very good drug-likeness score. Ligand B (0.653) is still reasonable, but lower.

**DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (70.88), but both are still below the concerning threshold of 60.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (79.062) is higher than Ligand B (20.783).

**Caco-2 Permeability:** Ligand A (-4.259) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.256) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.766) has very poor solubility, a major concern. Ligand B (-2.604) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.809) has a slightly higher hERG risk than Ligand B (0.063), which is very favorable.

**Microsomal Clearance:** Ligand A (88.964) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-3.554) has negative clearance, which is excellent, suggesting very high metabolic stability.

**In vitro Half-Life:** Ligand A (2.015) has a short half-life. Ligand B (-18.327) has a very long half-life, a significant advantage.

**P-gp Efflux:** Ligand A (0.504) has moderate P-gp efflux. Ligand B (0.033) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, but suffers from poor solubility, poor permeability, and high metabolic clearance. These ADME properties are critical concerns for an enzyme inhibitor. Ligand B, while having a weaker binding affinity, exhibits much better ADME properties: excellent metabolic stability (negative clearance, long half-life), low P-gp efflux, and better solubility. The improved ADME profile of Ligand B, combined with a still-respectable binding affinity, makes it a more promising drug candidate. The difference in affinity, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 15:16:14,277 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk, as per the enzyme-class guidelines.

**1. Molecular Weight:** Both ligands (359.897 and 350.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.54) is better than Ligand B (49.41). Both are below the 140 A^2 threshold for good oral absorption, but lower TPSA is generally preferred.

**3. logP:** Both ligands have good logP values (4.227 and 3.062, respectively), 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 HBAs, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.681 and 0.775), indicating good drug-like properties.

**7. DILI:** Ligand A (15.122) has a significantly lower DILI risk than Ligand B (25.436). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (85.421) has a better BBB penetration percentile than Ligand A (58.899). However, BBB is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.784 and -4.301). These values are unusual and suggest poor permeability. However, since these are negative values, it's difficult to directly compare.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.801 and -3.343). These values are also unusual and suggest poor solubility. Again, difficult to directly compare.

**11. hERG Inhibition:** Ligand A (0.939) has a slightly higher hERG risk than Ligand B (0.766), but both are reasonably low.

**12. Microsomal Clearance:** Ligand A (37.678) has a lower microsomal clearance than Ligand B (41.337), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (103.601) has a significantly longer in vitro half-life than Ligand B (-19.734). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.878) has slightly lower P-gp efflux than Ligand B (0.26), indicating potentially better bioavailability.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While both are strong binders, the 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and lower P-gp efflux. While Ligand B has slightly better logP and BBB, these are less critical for a non-CNS enzyme target like SRC kinase. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand A is more favorable.

Output:
1
2025-04-17 15:16:14,278 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.435 Da) is slightly lower, which is generally favorable for permeability. Ligand B (389.543 Da) is also acceptable.

**TPSA:** Ligand A (122.11) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (97.39) is well within the acceptable range.

**logP:** Ligand A (1.119) is at the lower end of the optimal range (1-3), potentially impacting permeability. Ligand B (2.078) is better positioned within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which is good. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.546 and 0.63), indicating good drug-likeness.

**DILI:** Ligand A (39.822) has a significantly lower DILI risk than Ligand B (65.723). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (20.512) and Ligand B (59.558) are both low, which is expected.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-5.286) is slightly better than Ligand B (-4.763) but both are concerning.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.887) is slightly better than Ligand B (-3.071).

**hERG Inhibition:** Ligand A (0.662) has a lower hERG risk than Ligand B (0.381), which is a positive attribute.

**Microsomal Clearance:** Ligand A (13.962) has a significantly lower Cl_mic than Ligand B (61.645), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (8.962) has a positive half-life, while Ligand B (-45.79) has a negative half-life, indicating poor stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.119 and 0.441).

**Binding Affinity:** Ligand B (-7.9 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 the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, much lower microsomal clearance (better metabolic stability), and a positive in vitro half-life. The solubility and permeability are poor for both, but Ligand A is slightly better. The lower hERG risk for Ligand A is also a positive. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are critical, and Ligand A excels in these areas.

Output:
0
2025-04-17 15:16:14,278 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (393.286 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly above the optimal <60 for kinase inhibitors, but still reasonable. Ligand B (59.08) is better, falling comfortably under 60.

**3. logP:** Both ligands have good logP values (2.097 and 2.932), within the 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 3 HBAs, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have QED values (0.568 and 0.447) above 0.4, indicating reasonable drug-likeness. Ligand A is slightly better.

**7. DILI:** Ligand A (37.767) has a lower DILI risk than Ligand B (16.673), which is excellent. Both are below the 40 threshold.

**8. BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (89.027) has a higher BBB penetration than Ligand A (72.005).

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. This suggests poor permeability. Ligand A (-5.052) is worse than Ligand B (-4.054).

**10. Aqueous Solubility:** Both have negative solubility values which is also unusual. Ligand A (-2.985) is worse than Ligand B (-2.169).

**11. hERG Inhibition:** Ligand A (0.42) has a lower hERG risk than Ligand B (0.798), which is a significant advantage.

**12. Microsomal Clearance:** Ligand B (94.584) has significantly higher microsomal clearance than Ligand A (9.141), indicating poorer metabolic stability. This is a major drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (-10.897) has a longer in vitro half-life than Ligand B (-9.268), consistent with the lower clearance.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.274 and 0.227).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial difference (1.5 kcal/mol), and a key factor.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have acceptable MW, logP, HBD, HBA, and QED values, Ligand A excels in the critical areas for kinase inhibitors: significantly stronger binding affinity, lower DILI risk, lower hERG risk, and much better metabolic stability (lower Cl_mic and longer t1/2). The Caco-2 and solubility values are concerning for both, but the superior potency and safety profile of Ligand A outweigh these drawbacks.

Output:
1
2025-04-17 15:16:14,278 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.342 Da) is slightly lower than Ligand B (350.482 Da), but both are acceptable.

**TPSA:** Ligand A (91.22) is better than Ligand B (38.82) as it is still within the acceptable range for oral absorption (<140), while Ligand B is significantly lower.

**logP:** Both ligands have good logP values (A: 3.23, B: 2.446), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.817, B: 0.704), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 88.561, which is high. Ligand B has a much lower DILI risk of 13.106, which is very favorable. This is a significant advantage for Ligand B.

**BBB:** Ligand A (54.207) and Ligand B (90.035) both have moderate BBB penetration. This isn't a primary concern for an oncology target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.535 and -4.694). These values are unusual and suggest poor permeability. However, these values are on a log scale and can be interpreted as very low permeability.

**Aqueous Solubility:** Ligand A (-5.327) and Ligand B (-2.19) both have negative solubility values, suggesting poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.399) has a slightly higher hERG risk than Ligand B (0.957), but both are relatively low.

**Microsomal Clearance:** Ligand A (45.765) has a higher microsomal clearance than Ligand B (23.967), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (45.787) has a longer half-life than Ligand B (5.583), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux than Ligand B (0.089), which is slightly better.

**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 Ligand A. The difference of 1.2 kcal/mol is large enough to potentially overcome some ADME liabilities.

**Overall Assessment:**

Ligand A has a much better binding affinity, and a longer half-life, but suffers from a high DILI risk and higher microsomal clearance. Ligand B has a significantly lower DILI risk, better metabolic stability, and slightly better solubility, but its binding affinity is weaker.

Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. While the affinity difference is substantial, the high DILI risk associated with Ligand A is a major concern. The improved metabolic stability and significantly reduced DILI risk of Ligand B make it the more promising candidate, even with the weaker binding affinity. Further optimization of Ligand B to improve its potency might be more fruitful than attempting to mitigate the DILI risk of Ligand A.

Output:
1
2025-04-17 15:16:14,278 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.455 and 365.287 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.05 and 105.56) are reasonably low, suggesting good potential for cell permeability, though slightly above the optimal <140 for oral absorption.

**logP:** Ligand A (1.468) is better than Ligand B (0.617). A logP between 1-3 is optimal, and B is a bit low, potentially hindering membrane permeability.

**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 acceptable QED scores (0.839 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (83.288) has a higher DILI risk than Ligand B (60.682), which is a significant concern. While both are above the preferred <40, B is closer.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (85.459) has a higher BBB percentile than Ligand A (63.978), but this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.249 and -4.872). This is unusual and suggests poor permeability *in vitro*. This is a red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.346 and -3.264). This is a major issue for *in vivo* bioavailability and formulation.

**hERG Inhibition:** Ligand A (0.306) has a lower hERG risk than Ligand B (0.479), which is favorable.

**Microsomal Clearance:** Ligand B (4.874 mL/min/kg) has significantly lower microsomal clearance than Ligand A (32.588 mL/min/kg). This suggests better metabolic stability for Ligand B, a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-15.625 hours) has a much longer in vitro half-life than Ligand A (-0.646 hours). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.017), which is slightly better for bioavailability.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >7 kcal/mol is highly significant.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B is the better candidate. Its dramatically superior binding affinity (-8.0 vs 0.0 kcal/mol) outweighs the slightly higher DILI risk and lower logP. The improved metabolic stability (lower Cl_mic) and longer half-life are also critical advantages for an enzyme inhibitor. The lower hERG risk of Ligand A is a positive, but the lack of binding affinity is a deal-breaker. The solubility and permeability issues would need to be addressed through formulation or further structural modifications, but a strong starting point with high affinity is essential.

Output:
1
2025-04-17 15:16:14,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.392 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.73) is better than Ligand B (69.64), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.341 and 2.719) falling within the 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA. Both are below the 10 threshold.

**QED:** Ligand A (0.784) has a significantly better QED score than Ligand B (0.594), indicating better overall drug-likeness.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (12.408). This is a significant drawback for Ligand A.

**BBB:** Both have similar BBB penetration (56.611 and 70.143), and since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.203) has poor Caco-2 permeability, while Ligand B (-4.772) is slightly better. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-4.257) has poorer solubility than Ligand B (-2.466). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.076) has a very low hERG inhibition risk, while Ligand B (0.679) is slightly higher. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (20.879) has a lower microsomal clearance than Ligand B (53.598), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.345 hours) has a positive half-life, while Ligand B (-16.863 hours) has a negative half-life, indicating poor stability.

**P-gp Efflux:** Ligand A (0.04) has very low P-gp efflux, while Ligand B (0.6) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand B has a much stronger binding affinity (-7.1 kcal/mol vs 0.0 kcal/mol), which is paramount for an enzyme inhibitor. While it has a slightly higher hERG risk and lower QED than Ligand A, the substantial difference in binding affinity outweighs these concerns. Ligand A has better metabolic stability and lower DILI, but its extremely weak binding affinity makes it unlikely to be effective. The poor Caco-2 permeability and solubility of both compounds are concerns that would need to be addressed in further optimization, but are secondary to potency.

Output:
1
2025-04-17 15:16:14,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 and 339.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (92.42). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is much closer to the optimal range for permeability.

**logP:** Both ligands have acceptable logP values (0.568 and 0.701), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.521 and 0.646), indicating drug-like properties.

**DILI:** Ligand A (3.8) has a much lower DILI risk than Ligand B (68.825). This is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (69.407 and 64.87). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.696) has a worse Caco-2 permeability compared to Ligand B (-4.775). However, the difference is small.

**Aqueous Solubility:** Ligand A (-1.096) has better aqueous solubility than Ligand B (-2.601). This is important for bioavailability.

**hERG Inhibition:** Ligand A (0.335) has a lower hERG inhibition risk than Ligand B (0.126), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (5.608) has significantly lower microsomal clearance than Ligand B (12.6). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (6.975) has a better in vitro half-life than Ligand B (-37.05). This is a major advantage for dosing considerations.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.026 and 0.015).

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.3). While both are strong binders, the 0.4 kcal/mol difference is noticeable.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** It excels in key areas like DILI risk, metabolic stability (lower Cl_mic, longer t1/2), solubility, and hERG inhibition. While Ligand B has slightly better Caco-2 permeability, the advantages of Ligand A in safety and pharmacokinetic properties outweigh this minor difference. The slightly better binding affinity of Ligand A further supports this conclusion.

Output:
1
2025-04-17 15:16:14,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.49 & 350.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold for good absorption, and is favorable. Ligand B (96.55) is still within the acceptable range, but less optimal.

**logP:** Ligand A (2.247) is within the optimal 1-3 range. Ligand B (0.113) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA, both are within the acceptable range of <=10.

**QED:** Both ligands have a QED of ~0.72, indicating good drug-likeness.

**DILI:** Ligand A (15.01) has a significantly lower DILI risk than Ligand B (35.48), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (51.84) is slightly higher than Ligand A (45.13), but neither is particularly high.

**Caco-2 Permeability:** Ligand A (-4.859) is better than Ligand B (-5.397), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.004) is better than Ligand B (-1.148), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.266 and 0.235 respectively).

**Microsomal Clearance:** Ligand A (38.46) has a higher (worse) microsomal clearance than Ligand B (0.063), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-11.55) has a much longer in vitro half-life than Ligand A (4.96), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.127 and 0.024 respectively).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A having better solubility and lower DILI risk, Ligand B's substantially stronger binding affinity (-9.3 vs -8.4 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are more critical for an enzyme target like SRC kinase. While Ligand B's logP is low, the strong binding should compensate. The lower DILI of A is good, but the potency and stability advantages of B are more important.

Output:
1
2025-04-17 15:16:14,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (371.535 Da) is still well within the range.

**TPSA:** Ligand A (89.43) is excellent, well below the 140 threshold for oral absorption. Ligand B (53.94) is also very good, indicating good potential for absorption.

**logP:** Ligand A (0.827) is slightly below the optimal 1-3 range but still acceptable. Ligand B (4.03) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.763, B: 0.747), indicating good drug-likeness.

**DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (80.651), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (77.976) is higher than Ligand A (67.158). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.59) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.196) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.93) has poor solubility, while Ligand B (-4.235) is even worse. This is a concern for both, but more so for B.

**hERG Inhibition:** Ligand A (0.118) has a very low hERG risk, which is excellent. Ligand B (0.834) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (29.46 mL/min/kg) has a lower clearance than Ligand B (94.637 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.105 hours) has a very short half-life, which is a significant drawback. Ligand B (11.697 hours) has a much more reasonable half-life.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is favorable. Ligand B (0.381) has a moderate P-gp efflux.

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a better half-life, and acceptable BBB penetration. However, it suffers from higher DILI risk, worse solubility, and higher metabolic clearance. Ligand A has a much better safety profile (DILI, hERG) and lower efflux, but its poor solubility, permeability, and short half-life are major concerns.

Despite the superior binding affinity of Ligand B, the combination of poor solubility, high DILI risk, and high clearance makes it a less attractive candidate. The short half-life of Ligand A is a significant issue, but could potentially be addressed through prodrug strategies or structural modifications. The lower DILI and hERG risks of Ligand A are very valuable.

Output:
0
2025-04-17 15:16:14,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.371 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.8) is better than Ligand B (49.41), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.177) is optimal (1-3), while Ligand B (4.136) is pushing the upper limit and could present solubility issues.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 2. Both are within the acceptable range of <=10.

**QED:** Both ligands have similar QED scores (0.785 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (91.314) has a significantly higher DILI risk than Ligand B (18.418). This is a major concern for Ligand A.

**BBB:** Ligand A (46.413) has a lower BBB penetration percentile than Ligand B (79.217). While not a primary concern for a non-CNS target like SRC, it's a slight advantage for B.

**Caco-2 Permeability:** Ligand A (-5.274) has poor Caco-2 permeability, while Ligand B (-4.699) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-2.991) has poor solubility, while Ligand B (-4.01) is even worse.

**hERG Inhibition:** Ligand A (0.267) has a lower hERG inhibition liability than Ligand B (0.674), which is preferable.

**Microsomal Clearance:** Ligand A (60.32) has lower microsomal clearance than Ligand B (81.545), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-38.017) has a longer in vitro half-life than Ligand B (-12.103), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux than Ligand B (0.437), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-7.8), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a better binding affinity and lower DILI risk, but suffers from higher logP, worse solubility, and higher P-gp efflux. Ligand A has a better metabolic profile (lower Cl_mic, longer t1/2, lower P-gp efflux) and lower hERG risk, but has a significantly higher DILI risk and poor solubility. Given the importance of metabolic stability and minimizing off-target effects (hERG) for kinase inhibitors, and the relatively small difference in binding affinity, Ligand A is the more promising candidate *if* the DILI risk can be mitigated through structural modifications. However, the high DILI risk is a serious concern.

Output:
1
2025-04-17 15:16:14,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.29 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (72.48) is lower than Ligand A (84.22), which is slightly preferable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.456) and Ligand B (2.832) are both good.

**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, but Ligand A is slightly preferred.

**QED:** Both ligands have similar QED values (0.781 and 0.786), indicating good drug-likeness.

**DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (50.291). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (83.094) has a higher BBB percentile than Ligand A (67.623), but this isn't a deciding factor.

**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 a 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:** Ligand A (0.057) has a significantly lower hERG inhibition liability than Ligand B (0.893). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-5.151) has a much lower (better) microsomal clearance than Ligand B (36.894). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-22.346) has a much longer in vitro half-life than Ligand B (15.893). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.007) has a much lower P-gp efflux liability than Ligand B (0.154). This suggests better oral bioavailability for Ligand A.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is only 0.3 kcal/mol, which is less important than the ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A demonstrates superior ADME properties: lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG inhibition. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far more favorable for development as a drug candidate. The slightly better affinity of Ligand B does not outweigh the substantial benefits of Ligand A regarding safety and pharmacokinetic properties.

Output:
0
2025-04-17 15:16:14,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.407 and 367.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (118.01 and 113.48) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (-0.65) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (0.066) is closer to the optimal range.

**H-Bond Donors:** Both ligands have 3 HBDs, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 7. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.548 and 0.707), indicating drug-like properties.

**DILI:** Ligand A (40.403) has a lower DILI risk than Ligand B (68.941), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (55.642) than Ligand A (35.983).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.989 and -5.377), 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 (-1.298 and -2.431), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.034) has a much lower hERG inhibition liability than Ligand B (0.409), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-6.135) has a significantly lower (better) microsomal clearance than Ligand B (-16.766), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (30.08 hours) has a much longer half-life than Ligand B (12.125 hours), which is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.058).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a crucial factor, and the difference is substantial.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand A excels in critical areas: significantly better binding affinity, lower DILI risk, lower hERG inhibition, and superior metabolic stability (lower Cl_mic and longer half-life). The slightly lower logP of Ligand A is a minor concern compared to the substantial advantages it offers in potency and safety.

Output:
0
2025-04-17 15:16:14,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.511 and 358.551 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.91) is well below the 140 threshold, while Ligand B (32.34) is even better, suggesting good absorption potential for both.

**logP:** Ligand A (0.064) is quite low, potentially hindering permeation. Ligand B (4.73) is a bit high, potentially causing solubility/off-target issues, but closer to the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, within acceptable limits. Ligand B has 1 HBD and 3 HBA, also within limits.

**QED:** Both ligands have reasonable QED scores (0.482 and 0.789 respectively), with Ligand B being significantly better.

**DILI:** Both have low DILI risk (4.033 and 31.291 percentiles), which is excellent.

**BBB:** Ligand A (32.532) has poor BBB penetration, while Ligand B (92.361) is excellent. This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.462 and -5.412). This is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, since both are similarly poor, it doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-0.495 and -4.71). This is also concerning, but again, similar for both.

**hERG Inhibition:** Both ligands have very low hERG risk (0.213 and 0.752), which is highly desirable.

**Microsomal Clearance:** Ligand A (20.165 mL/min/kg) has a much lower clearance than Ligand B (66.539 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.804 hours) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (33.097 hours) has a good half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.002 and 0.642).

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity and low hERG risk, Ligand B is significantly better overall. Ligand B has a more favorable logP, a much better QED score, excellent BBB penetration, and a significantly longer in vitro half-life. Ligand A has a concerningly low logP and a nonsensical negative half-life. The better metabolic stability of Ligand A is overshadowed by its other deficiencies.

Output:
1
2025-04-17 15:16:14,281 - INFO - Batch 365 complete. Total preferences: 5840
2025-04-17 15:16:14,281 - INFO - Processing batch 366/512...
2025-04-17 15:16:52,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.34 Da) is slightly higher than Ligand B (341.411 Da), but both are acceptable.

**TPSA:** Ligand A (58.95) is significantly better than Ligand B (83.36). Lower TPSA generally improves cell permeability.

**logP:** Ligand A (4.121) is higher than Ligand B (1.321). While Ligand A is at the upper limit, it's still within the acceptable range. Ligand B is quite low, potentially hindering membrane permeability.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 3 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 (0.76 and 0.767), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (37.728 and 38.154), indicating low risk.

**BBB:** Both ligands have similar BBB penetration (66.576 and 65.374), which isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.847 and -4.823), which is unusual and suggests poor permeability. This could be a significant issue.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.537 and -2.353), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.819) is better than Ligand B (0.198). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (15.895) has a better (lower) microsomal clearance than Ligand B (-16.514). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (36.647) has a significantly longer half-life than Ligand B (16.922). This is a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux than Ligand B (0.07). Lower efflux is preferred for better bioavailability.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-10.6 kcal/mol). This is the most important factor for an enzyme inhibitor. The 3 kcal/mol difference is substantial.

**Conclusion:**

Despite both ligands having poor solubility and Caco-2 permeability, Ligand A is the superior candidate. Its significantly stronger binding affinity (-7.6 vs -10.6 kcal/mol) outweighs the slightly higher logP. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic, longer half-life), lower P-gp efflux, and a better hERG profile. Addressing the solubility issues through formulation strategies would be a priority for Ligand A.

Output:
1
2025-04-17 15:16:52,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.531 and 356.817 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (85.59), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.558 and 2.566), falling within the 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:** 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:** Both ligands have good QED scores (0.569 and 0.776), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (89.996). This is a major advantage for Ligand A.

**BBB:** Ligand A (53.47) has a better BBB penetration score than Ligand B (39.434), though this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both have negative values (-5.26 and -5.032). These values are unusual and likely represent logP-corrected Caco-2 values, where negative values indicate poor permeability. Ligand A is slightly better.

**Aqueous Solubility:** Both have negative values (-2.088 and -3.829), indicating poor aqueous solubility. Ligand B has worse solubility.

**hERG Inhibition:** Ligand A (0.384) has a lower hERG inhibition liability than Ligand B (0.174), which is preferable.

**Microsomal Clearance:** Ligand A (35.87) has lower microsomal clearance than Ligand B (55.111), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.771) has a longer in vitro half-life than Ligand B (1.589), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux liability than Ligand B (0.106).

**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 a reasonable advantage.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, and QED score. However, Ligand A is significantly better in terms of DILI risk, metabolic stability (lower Cl_mic and longer t1/2), hERG inhibition, and aqueous solubility. Given the enzyme-kinase specific priorities, the improved safety profile (DILI, hERG) and metabolic stability of Ligand A outweigh the slightly weaker binding affinity. The solubility issues of both are concerning but can be addressed with formulation strategies.

Output:
0
2025-04-17 15:16:52,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.5 and 356.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.6) is higher than Ligand B (50.8). Both are below 140, suggesting reasonable absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.75 and 3.25), falling within the 1-3 range.

**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 (0.747 and 0.9), indicating drug-like properties.

**DILI:** Ligand A (49.3) has a higher DILI risk than Ligand B (23.0). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (84.8) has a higher BBB score than Ligand A (61.4), but this is not a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates poor permeability. However, the values are similar (-4.72 and -4.25).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, values are similar (-3.26 and -3.13).

**hERG:** Ligand A (0.573) has a slightly lower hERG risk than Ligand B (0.837), which is favorable.

**Microsomal Clearance:** Ligand A (73.7) has a higher microsomal clearance than Ligand B (44.8). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand B (8.03) has a significantly longer half-life than Ligand A (-28.1). This is a major advantage for Ligand B, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.094), which is good.

**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 is still a positive for Ligand B.

**Overall:** Ligand B is the more promising candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and a lower TPSA. While both have unusual solubility and Caco-2 values, the other advantages of Ligand B outweigh these concerns.

Output:
1
2025-04-17 15:16:52,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 359.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.57) is significantly better than Ligand B (106.2). A TPSA below 140 is good for oral absorption, and both meet this, but A is preferable.

**logP:** Ligand A (1.658) is within the optimal 1-3 range. Ligand B (-1.236) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=6) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.575 and 0.506), indicating good drug-likeness.

**DILI:** Ligand A (11.322) has a much lower DILI risk than Ligand B (19.426), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (71.19) is better than Ligand B (49.826).

**Caco-2 Permeability:** Both have negative values (-5.004 and -5.261), which is unusual and requires further investigation. However, the values are very close.

**Aqueous Solubility:** Both have negative values (-1.334 and -1.235) which is also unusual and requires further investigation. The values are very close.

**hERG Inhibition:** Ligand A (0.33) has a much lower hERG risk than Ligand B (0.072), a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (7.041) has a lower clearance than Ligand B (10.286), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.627) has a longer half-life than Ligand B (-3.9), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.095 and 0.002).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.2 kcal/mol). The difference is negligible.

**Overall:**

Ligand A is significantly better across multiple critical ADME-Tox properties: DILI risk, hERG inhibition, microsomal clearance, and in vitro half-life. While both have similar potency and acceptable MW, TPSA, and QED, the superior safety and pharmacokinetic profile of Ligand A make it the more promising drug candidate. The slightly better logP and TPSA of Ligand A also contribute to its favorability.

Output:
0
2025-04-17 15:16:52,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.299 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.94) is slightly above the preferred <140 for good oral absorption, while Ligand B (59.08) is well below, suggesting potentially better absorption.

**logP:** Both ligands (0.877 and 0.963) 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 9 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.668 and 0.712), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (97.635), which is a significant concern. Ligand B has a very low DILI risk (24.234), a major advantage.

**BBB:** Ligand A has low BBB penetration (38.813), while Ligand B has good BBB penetration (71.733). While SRC isn't a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.577) and Ligand B (-4.138) have similar, and poor, Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.786) and Ligand B (-1.609) have poor aqueous solubility, but Ligand B is better.

**hERG:** Ligand A (0.227) has a slightly elevated hERG risk, while Ligand B (0.072) has very low hERG risk.

**Microsomal Clearance:** Ligand A (51.818) has higher microsomal clearance than Ligand B (16.518), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (8.827) has a longer in vitro half-life than Ligand A (-7.144), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.021).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.6 kcal/mol). While A is stronger, the difference is not substantial enough to overcome its other liabilities.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, Ligand B is the superior candidate due to its significantly lower DILI risk, better BBB penetration, lower microsomal clearance, longer half-life, and lower hERG risk. The improved ADME properties of Ligand B outweigh the small difference in binding affinity.

Output:
1
2025-04-17 15:16:52,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.483 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.34) is significantly better than Ligand B (74.33).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (3.582) is slightly higher than Ligand B (1.818), both within the optimal 1-3 range. Ligand B is closer to the lower bound, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 4 HBA). Lower counts are generally preferable for permeability.

**QED:** Both ligands have similar QED values (0.796 and 0.754), indicating good drug-likeness.

**DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (49.011). This is a significant advantage for Ligand A.

**BBB:** Ligand A (88.639) has a higher BBB penetration percentile than Ligand B (76.658). While not critical for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.508) has a slightly better Caco-2 permeability than Ligand B (-4.762).

**Aqueous Solubility:** Ligand A (-3.946) has a slightly better aqueous solubility than Ligand B (-3.149).

**hERG:** Ligand A (0.955) has a lower hERG inhibition liability than Ligand B (0.653), indicating a lower risk of cardiotoxicity. This is a crucial advantage.

**Microsomal Clearance:** Ligand A (70.644) has a higher microsomal clearance than Ligand B (47.564), meaning it's less metabolically stable. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (17.469) has a significantly longer in vitro half-life than Ligand A (-22.15). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.276) has lower P-gp efflux liability than Ligand B (0.074).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in properties related to safety (DILI, hERG) and permeability (TPSA, Caco-2, solubility). However, it suffers from higher metabolic clearance and a shorter half-life. Ligand B has a better metabolic profile (lower Cl_mic, longer t1/2), but has higher DILI and hERG risk. Given the importance of metabolic stability for kinases, and the relatively small difference in binding affinity, Ligand B is slightly favored. However, the DILI and hERG risks for Ligand B are concerning. The better safety profile of Ligand A is very attractive, and could be optimized with structural modifications.

Output:
1
2025-04-17 15:16:52,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.5 and 340.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (76.66). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is much closer to the ideal for better absorption.

**logP:** Both ligands have good logP values (2.99 and 1.89), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Lower counts generally improve permeability.

**QED:** Ligand B (0.842) has a better QED score than Ligand A (0.57), indicating a more drug-like profile.

**DILI:** Ligand A (11.52) has a much lower DILI risk than Ligand B (61.07). This is a significant advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (77.16 and 72.01), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.69 and -4.85), 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 (-3.69 and -4.32), which is also unusual and suggests poor solubility. Again, the absolute values are similar.

**hERG Inhibition:** Ligand A (0.279) has a much lower hERG risk than Ligand B (0.716), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (29.09) has lower microsomal clearance than Ligand B (40.18), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have negative half-life values (-20.85 and -22.09), which is not physically meaningful. This suggests the assay may have issues or the compounds are rapidly degraded.

**P-gp Efflux:** Ligand A (0.042) has lower P-gp efflux than Ligand B (0.28), indicating better bioavailability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). The difference is 1.1 kcal/mol, which is not substantial enough to outweigh the multiple ADME advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. It has a significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), lower P-gp efflux, and a more favorable TPSA. While Ligand B has a slightly better binding affinity and QED, the ADME properties of Ligand A are considerably better, making it a more viable drug candidate. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of A outweigh this.

Output:
0
2025-04-17 15:16:52,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.917 Da) is slightly higher than Ligand B (345.33 Da), but both are acceptable.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (97.39). Lower TPSA generally correlates with better cell permeability. Ligand B's TPSA is quite high, potentially hindering absorption.

**logP:** Ligand A (4.467) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.634) is within the optimal range (1-3).

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=5). Both are within acceptable limits, but Ligand A has a more favorable balance.

**QED:** Ligand A (0.809) is significantly better than Ligand B (0.634), indicating a more drug-like profile.

**DILI:** Ligand A (18.845) has a much lower DILI risk than Ligand B (87.01). This is a significant advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (Ligand A: 95.851, Ligand B: 67.623), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.613) is slightly better than Ligand B (-4.678).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.658) is slightly better than Ligand B (-3.89).

**hERG Inhibition:** Ligand A (0.897) has a slightly higher hERG risk than Ligand B (0.239), which is preferable.

**Microsomal Clearance:** Ligand A (62.036) has lower microsomal clearance than Ligand B (65.988), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (58.083) has a significantly longer half-life than Ligand B (24.101), which is a major advantage.

**P-gp Efflux:** Ligand A (0.306) has lower P-gp efflux than Ligand B (0.068), indicating better bioavailability.

**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 not substantial enough to override the other ADME differences.

**Overall:**

Ligand A is significantly better due to its superior QED, much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a more favorable H-bonding profile. While Ligand A has a slightly higher logP and hERG risk, these are outweighed by its advantages in other critical ADME properties. Ligand B's high TPSA and DILI risk are major drawbacks.

Output:
0
2025-04-17 15:16:52,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.817 and 360.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 81, well below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (2.995) is optimal, while Ligand B (1.444) is slightly lower, potentially impacting permeability.

**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.

**6. QED:** Both ligands have good QED scores (0.733 and 0.835), indicating drug-like properties.

**7. DILI:** Ligand A (87.631 percentile) has a higher DILI risk than Ligand B (68.941 percentile). This is a significant concern for Ligand A.

**8. BBB:** Ligand A (70.182 percentile) has better BBB penetration than Ligand B (37.379 percentile), but this is less crucial for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.882) has significantly better Caco-2 permeability than Ligand B (-5.579).

**10. Aqueous Solubility:** Ligand A (-4.485) has better aqueous solubility than Ligand B (-2.43).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.589 and 0.64).

**12. Microsomal Clearance:** Ligand A (76.012 mL/min/kg) has a higher microsomal clearance than Ligand B (45.988 mL/min/kg), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (11.791 hours) has a much longer in vitro half-life than Ligand A (61.918 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.342 and 0.043).

**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's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity and permeability, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The lower DILI risk is a critical advantage, and the improved metabolic stability suggests a potentially more favorable pharmacokinetic profile. The slightly lower logP of Ligand B is a minor drawback that could be addressed through further optimization.

Output:
1
2025-04-17 15:16:52,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (367.471 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (108.29 and 100.27) are acceptable, being below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.829) is optimal, while Ligand B (0.818) is slightly low, potentially impacting 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 (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.613 and 0.574), indicating good drug-like properties.

**7. DILI:** Ligand A (55.68) has a moderate DILI risk, while Ligand B (17.216) shows a very low DILI risk, which is a significant advantage.

**8. BBB:** This is less critical for an oncology target, but Ligand A (47.654) and Ligand B (40.52) are both relatively low, indicating limited brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.934) and Ligand B (-5.191) are both negative, suggesting poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-3.401) and Ligand B (-1.401) are both negative, indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.482 and 0.033), which is excellent.

**12. Microsomal Clearance:** Ligand A (30.508) has a higher microsomal clearance than Ligand B (15.978), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (10.435 hours) has a significantly longer half-life than Ligand A (-1.92 hours), indicating better in vitro stability. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.069 and 0.047).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). However, the difference is not substantial enough to outweigh the ADME advantages of Ligand B.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly in terms of DILI risk, microsomal clearance, and in vitro half-life. For an oncology kinase target, metabolic stability and minimizing toxicity (DILI) are crucial. The slightly weaker binding affinity of Ligand B can potentially be optimized in subsequent iterations of drug design.

Output:
1
2025-04-17 15:16:52,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (366.483 and 344.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.27) is better than Ligand B (101.8), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration if that were a target.

**3. logP:** Both ligands have good logP values (2.511 and 1.231), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as lower HBD counts generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (6).

**6. QED:** Both ligands have acceptable QED values (0.827 and 0.786), indicating good drug-like properties.

**7. DILI:** Ligand A (52.772) has a lower DILI risk than Ligand B (63.474), making it more favorable. Both are acceptable, but A is better.

**8. BBB:** Ligand A (70.919) has better BBB penetration than Ligand B (58.938). While not critical for a non-CNS target like SRC, it's a slight advantage.

**9. Caco-2 Permeability:** Ligand A (-4.841) has better Caco-2 permeability than Ligand B (-5.427).

**10. Aqueous Solubility:** Ligand A (-2.907) has better aqueous solubility than Ligand B (-2.024). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.107 and 0.082), which is excellent.

**12. Microsomal Clearance:** Ligand A (17.895) has higher microsomal clearance than Ligand B (16.423), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (30.444) has a significantly longer in vitro half-life than Ligand A (-1.52), indicating better metabolic stability. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.309) has higher P-gp efflux than Ligand B (0.004). Lower P-gp efflux is better, making Ligand B preferable.

**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 that can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has slightly worse metabolic stability (higher Cl_mic, shorter t1/2) and higher P-gp efflux, the substantial difference in binding affinity (-8.7 vs 0.0 kcal/mol) is likely to be decisive. The better solubility, permeability, and lower DILI risk of Ligand A further support its selection.

Output:
1
2025-04-17 15:16:52,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.347) is slightly lower, which can be beneficial for permeability.

**TPSA:** Ligand A (62.3) is better than Ligand B (71.53), being closer to the optimal threshold of <=140 for oral absorption.

**logP:** Both ligands have good logP values (A: 2.804, B: 3.448) within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), both are acceptable but lower is preferred.

**QED:** Both ligands have similar QED values (A: 0.802, B: 0.774), indicating good drug-likeness.

**DILI:** Ligand A (12.563) has a significantly lower DILI risk than Ligand B (83.094). This is a major advantage for Ligand A.

**BBB:** Ligand A (77.472) has a better BBB penetration score than Ligand B (58.123), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.016 and -5.088). 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 (-2.311 and -4.226). Again, the scale is unclear, but suggests poor solubility.

**hERG Inhibition:** Ligand A (0.633) has a lower hERG inhibition risk than Ligand B (0.252), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-10.024) has a much lower (better) microsomal clearance than Ligand B (51.366), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.62) has a negative half-life, which is unusual. Ligand B (13.589) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.317).

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -6.7 kcal/mol, B: -6.9 kcal/mol). The difference is minor.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both ligands have good binding affinity, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, lower hERG inhibition, and much better metabolic stability (lower Cl_mic). The slightly better TPSA and P-gp efflux also contribute to its advantage. The negative Caco-2 and solubility values are concerning for both, but the superior safety and metabolic profile of Ligand A outweigh these concerns.

Output:
1
2025-04-17 15:16:52,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.47 and 364.56 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (46.34 and 48.47) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.375) is slightly higher than optimal (1-3), while Ligand B (3.243) is within the optimal range. This favors Ligand B.

**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 (0.833 and 0.892), indicating good drug-likeness.

**DILI:** Ligand A (34.82) has a significantly lower DILI risk than Ligand B (16.91). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (88.87 and 91.55), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**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 aqueous solubility (-5.23 and -1.464). This is a significant concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.854) has a slightly higher hERG risk than Ligand B (0.76), but both are relatively low.

**Microsomal Clearance:** Ligand A (102.55) has a higher microsomal clearance than Ligand B (1.52), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-16.56) has a negative half-life, which is not possible. Ligand B (30.31) has a reasonable half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.796 and 0.271).

**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, and can outweigh some of the ADME concerns.

**Conclusion:**

While Ligand A has a lower DILI risk, Ligand B excels in several crucial areas for an enzyme inhibitor: significantly better binding affinity, a reasonable in vitro half-life, and better metabolic stability. The solubility is a concern for both, but the potency and stability advantages of Ligand B are more critical for initial development.

Output:
1
2025-04-17 15:16:52,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.426 and 356.373 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (26.19) is significantly better than Ligand B (93.21). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (4.113) is slightly high, potentially leading to solubility issues, but still within a manageable range. Ligand B (1.076) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 5 HBA) both have acceptable numbers.

**QED:** Both ligands (0.775 and 0.727) have good drug-likeness scores.

**DILI:** Ligand A (44.552) has a lower DILI risk than Ligand B (55.021), which is preferable. Both are below the concerning 60 threshold.

**BBB:** Both ligands have similar BBB penetration (88.29 and 80.729), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.073) is significantly worse than Ligand B (-4.661) suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.307) is worse than Ligand B (-2.1), indicating lower solubility.

**hERG Inhibition:** Ligand A (0.955) has a lower hERG risk than Ligand B (0.13), which is a significant advantage.

**Microsomal Clearance:** Ligand A (31.079) has a higher microsomal clearance than Ligand B (25.465), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (40.864) has a longer half-life than Ligand B (-42.727), which is a positive.

**P-gp Efflux:** Ligand A (0.879) has a lower P-gp efflux liability than Ligand B (0.024), which is preferable.

**Binding Affinity:** Ligand A (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.2 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having slightly worse Caco-2 permeability and solubility, and higher clearance, its *significantly* stronger binding affinity (-10.4 vs -9.2 kcal/mol) and lower hERG risk make it the more promising candidate. The potency advantage is substantial, and the other issues can potentially be addressed through formulation or further medicinal chemistry optimization.

Output:
1
2025-04-17 15:16:52,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 344.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.33) is well below the 140 threshold for good absorption and is quite favorable. Ligand B (84.22) is still under 140, but getting closer to the upper limit, potentially indicating slightly reduced absorption.

**logP:** Ligand A (3.769) is at the higher end of the optimal 1-3 range, but acceptable. Ligand B (0.479) is quite low, potentially leading to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is good. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.839 and 0.726), indicating good drug-likeness.

**DILI:** Ligand A (62.66) has a higher DILI risk than Ligand B (53.083), but both are reasonably acceptable.

**BBB:** Both ligands have good BBB penetration (67.197 and 76.658), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.556) has poor Caco-2 permeability, while Ligand B (-5.106) is even worse. This is concerning for oral bioavailability.

**Aqueous Solubility:** Ligand A (-4.828) has poor aqueous solubility, and Ligand B (-2.238) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.725) has a slightly higher hERG risk than Ligand B (0.034). Ligand B's hERG risk is very low, which is a significant advantage.

**Microsomal Clearance:** Ligand A (81.877) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (36.412) has significantly lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (76.35) has a reasonable half-life, while Ligand B (-7.131) has a very short half-life.

**P-gp Efflux:** Ligand A (0.306) has lower P-gp efflux, which is favorable. Ligand B (0.165) has even lower 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 B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in metabolic stability (lower Cl_mic, though the half-life is concerning), and has a significantly lower hERG risk. The slightly better binding affinity of Ligand B is a bonus. Ligand A's higher DILI risk and lower metabolic stability are drawbacks. The poor half-life of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 15:16:52,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (67.87) is higher than Ligand B (58.64), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (0.949) is slightly lower, potentially impacting permeability, while Ligand B (1.705) is better positioned.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4/5) counts, balancing solubility and permeability.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.774) is slightly better than Ligand A (0.549).

**DILI:** Ligand B (37.069) has a significantly lower DILI risk than Ligand A (9.965), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (81.349) has a higher BBB score than Ligand A (55.021), but this isn't a deciding factor.

**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:** Both ligands show low hERG inhibition liability (0.253 and 0.388), which is positive.

**Microsomal Clearance:** Ligand B (33.397) has slightly better microsomal clearance than Ligand A (28.339), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.687) has a slightly longer in vitro half-life than Ligand A (-5.451), which is favorable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.059 and 0.074), which is good.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a *significantly* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered substantial, and here it's a massive 8.5 kcal/mol difference.

**Overall:**

Ligand B is clearly superior. While both have issues with Caco-2 and solubility, the dramatically improved binding affinity of Ligand B (-8.5 kcal/mol vs -0.0 kcal/mol) outweighs these concerns. The lower DILI risk and better metabolic stability (Cl_mic, t1/2) further solidify its advantage. The slightly better logP and QED also contribute.

Output:
1
2025-04-17 15:16:52,635 - INFO - Batch 366 complete. Total preferences: 5856
2025-04-17 15:16:52,635 - INFO - Processing batch 367/512...
2025-04-17 15:17:32,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.479 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is better than Ligand B (49.41), both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.093 and 3.666), falling within the 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not drastically.

**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:** Ligand A (0.74) has a better QED score than Ligand B (0.538), indicating a more drug-like profile.

**DILI:** Ligand A (35.983) has a significantly higher DILI risk than Ligand B (10.198). This is a major concern for Ligand A.

**BBB:** Both have high BBB penetration, but Ligand B (93.757) is better than Ligand A (81.737). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-4.63 and -4.883).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are similar (-3.128 and -3.95).

**hERG Inhibition:** Ligand A (0.28) has a lower hERG inhibition risk than Ligand B (0.689), which is favorable.

**Microsomal Clearance:** Ligand A (78.968) has a higher microsomal clearance than Ligand B (54.556), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-3.649) has a longer in vitro half-life than Ligand A (-15.933), which is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.107 and 0.173).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a crucial advantage, as a 0.6 kcal/mol difference in binding is substantial.

**Conclusion:**

While Ligand A has a better QED and lower hERG risk, Ligand B is significantly better overall. The key advantages of Ligand B are its much lower DILI risk, longer half-life, and stronger binding affinity. The similar permeability and solubility issues are less concerning than the DILI and metabolic stability issues of Ligand A. The stronger binding affinity of Ligand B can potentially offset any minor ADME drawbacks.

Output:
1
2025-04-17 15:17:32,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.255 Da and 364.461 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.13) is higher than Ligand B (25.36). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Both ligands have similar logP values (4.771 and 4.529), both slightly above the optimal range of 1-3, potentially raising concerns about solubility and off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Both have 0 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4 HBA, both are within acceptable limits (<=10).

**QED:** Both ligands have good QED scores (0.65 and 0.753), indicating generally drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (76.464%) compared to Ligand B (23.73%). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (95.58) than Ligand A (75.107), but this is not a major deciding factor.

**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 can still compare them relatively. Ligand A (-4.394) is slightly better than Ligand B (-4.577).

**Aqueous Solubility:** Both have negative solubility values, again indicating a potential issue with the prediction. Ligand A (-5.248) is slightly better than Ligand B (-4.295).

**hERG:** Both ligands have low hERG inhibition liability (0.896 and 0.894), which is positive.

**Microsomal Clearance:** Ligand A (50.812) has lower microsomal clearance than Ligand B (55.065), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (2.71 hours) than Ligand A (43.663 hours). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.734 and 0.674).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better Caco-2 permeability and lower microsomal clearance, the significantly higher DILI risk and weaker binding affinity make it a less attractive candidate. Ligand B exhibits a much lower DILI risk, a substantially stronger binding affinity, and a longer half-life, making it the more promising drug candidate despite the slightly higher TPSA and similar logP.

Output:
1
2025-04-17 15:17:32,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (349.475 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.6) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for good oral absorption, but lower is generally preferred. Ligand B is better here.

**3. logP:** Both ligands have excellent logP values (2.553 and 2.489), 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 10 limit. Ligand B is better here.

**6. QED:** Both ligands have good QED scores (0.763 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A (9.151) has a significantly lower DILI risk than Ligand B (12.524). This is a major advantage for Ligand A.

**8. BBB:** Both have good BBB penetration (72.664 and 73.943), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.994 and -4.76), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.549 and -2.265), indicating very poor aqueous solubility. This is a major concern for both compounds.

**11. hERG Inhibition:** Ligand A (0.752) has a slightly higher hERG risk than Ligand B (0.351). This favors Ligand B.

**12. Microsomal Clearance:** Ligand A (49.16) has a higher microsomal clearance than Ligand B (29.637), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (1.362) has a slightly longer half-life than Ligand B (6.768). This favors Ligand A.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.112 and 0.107).

**15. Binding Affinity:** Ligand A (-8.8 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:**

Ligand A has a much stronger binding affinity, a lower DILI risk, and a slightly longer half-life. However, it has higher microsomal clearance, a slightly higher hERG risk, and poorer Caco-2 permeability and solubility. Ligand B has better ADME properties (lower clearance, lower hERG, better solubility and permeability), but its binding affinity is weaker.

Given the priority for potency in kinase inhibitors, the 0.9 kcal/mol difference in binding affinity is significant. While the solubility and permeability issues for both are concerning, these can potentially be addressed through formulation strategies. The lower DILI risk of Ligand A is also a significant advantage.

Output:
0
2025-04-17 15:17:32,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 and 349.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (70.08) is slightly higher than Ligand B (61.44), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.412) and Ligand B (2.167) are both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the limit of 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the limit of 10.

**QED:** Ligand A (0.785) has a higher QED score than Ligand B (0.66), indicating better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (Ligand A: 20.706, Ligand B: 19.465), well below the concerning threshold of 60.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 62.66, Ligand B: 68.166). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.508 and -4.656). This is unusual and suggests poor permeability, but the scale is not specified, so it's difficult to interpret precisely.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.991 and -1.8). Similar to Caco-2, the scale is unclear, but negative values likely indicate poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.389, Ligand B: 0.532).

**Microsomal Clearance:** Ligand A (35.72) has a higher microsomal clearance than Ligand B (16.977), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (5.497) has a longer half-life than Ligand B (-6.381). However, 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 (Ligand A: 0.24, Ligand B: 0.048).

**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 ADME concerns.

**Conclusion:**

Despite the questionable Caco-2 and solubility values, Ligand B is the more promising candidate. The significantly improved binding affinity (-8.2 vs -7.3 kcal/mol) is a major advantage for an enzyme target like SRC. While Ligand A has better QED and a slightly longer half-life, the lower metabolic stability (higher Cl_mic) is a significant concern. The negative half-life value for Ligand B is a red flag, but the superior binding affinity suggests it might be optimized to improve its metabolic stability.

Output:
1
2025-04-17 15:17:32,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.315 and 353.438 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (130.88) is borderline, but acceptable for oral absorption. Ligand B (64.09) is excellent, well below the 140 threshold.

**logP:** Ligand A (0.633) is a bit low, potentially hindering permeation. Ligand B (0.276) is even lower, raising concerns about absorption.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 6 HBA) is good. Ligand B (1 HBD, 4 HBA) is also very good. Both are within acceptable limits.

**QED:** Ligand B (0.697) has a better QED score than Ligand A (0.458), suggesting a more drug-like profile.

**DILI:** Ligand A (78.868) has a higher DILI risk than Ligand B (16.402), which is a significant concern.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (80.419) is better than Ligand A (54.517).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is concerning.

**hERG Inhibition:** Ligand A (0.121) has a slightly higher hERG risk than Ligand B (0.566), but both are relatively low.

**Microsomal Clearance:** Ligand A (17.456) has a higher microsomal clearance than Ligand B (14.118), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.344) has a longer half-life than Ligand A (-11.9), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly better binding affinity than Ligand B (-7.5 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A's primary advantage is its much stronger binding affinity. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and negative solubility/permeability. Ligand B has a better safety profile (lower DILI), better metabolic stability, and a better QED score, but its binding affinity is weaker.

Given the enzyme-specific priorities, binding affinity is paramount. The 0.6 kcal/mol difference in binding affinity is significant. While Ligand A has some ADME liabilities, these might be addressable through further optimization. The higher DILI risk is a concern, but not necessarily a dealbreaker at this stage, especially if the compound demonstrates strong efficacy *in vivo*. The poor solubility/permeability are also concerns, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:17:32,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (375.376 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.28) is better than Ligand B (104.81). Both are below 140, but A is closer to the preferred value for good absorption.

**logP:** Ligand A (2.327) is optimal (1-3). Ligand B (-0.429) 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 are within the acceptable limit of <=10.

**QED:** Ligand A (0.863) has a better QED score than Ligand B (0.606), indicating a more drug-like profile.

**DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (26.444). This is a negative for Ligand A, but the difference isn't massive.

**BBB:** Both ligands have similar BBB penetration (64.211 and 67.701). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.881) and Ligand B (-5.313) both have negative values, indicating poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.757 and -2.511). This is a significant issue for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.26) has a lower hERG risk than Ligand B (0.044), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-2.284) has a better (lower) microsomal clearance than Ligand B (-3.09), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.373 hours) has a longer half-life than Ligand B (-1.522 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.143) has lower P-gp efflux than Ligand B (0.006), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.9 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the higher DILI risk, Ligand A is the more promising candidate. Its superior logP, QED, metabolic stability (Cl_mic and t1/2), lower P-gp efflux, and slightly lower hERG risk outweigh the DILI concern. Ligand B's very low logP is a major drawback, likely leading to poor absorption. Both have poor solubility and Caco-2 permeability, but these issues might be addressed through formulation strategies. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 15:17:32,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.373 and 378.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (87.74 and 86.71) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (0.21) is a bit low, potentially hindering permeation. Ligand B (1.444) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both have good QED scores (0.503 and 0.669), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both have acceptable DILI risk (37.185 and 30.554), both below the 40 threshold. Ligand B is slightly better.

**BBB:** Both have high BBB penetration (77.898 and 74.796), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.056 and -5.102), which is unusual and indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-1.925 and -2.765). This is a major drawback for both compounds, potentially impacting bioavailability.

**hERG Inhibition:** Both have low hERG inhibition risk (0.22 and 0.633), which is positive.

**Microsomal Clearance:** Ligand A has a much lower (better) microsomal clearance (-19.293) compared to Ligand B (44.622), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (-9.587) compared to Ligand B (-35.124), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.016 and 0.093).

**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:**

While Ligand B has a slightly better logP, QED, and binding affinity, Ligand A significantly outperforms it in metabolic stability (lower Cl_mic and longer t1/2). The poor solubility and Caco-2 permeability are concerning for both, but metabolic stability is a crucial factor for kinase inhibitors. A compound with rapid metabolism will likely require high doses and may have limited efficacy. The slightly better binding affinity of Ligand B is unlikely to overcome the significant metabolic disadvantage.

Output:
0
2025-04-17 15:17:32,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (387.439 and 366.502 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.72) is slightly above the preferred <140, but acceptable. Ligand B (58.2) is excellent, well below 140.

**logP:** Ligand A (-0.727) is a bit low, potentially hindering permeability. Ligand B (3.463) is optimal.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.703 and 0.81), indicating drug-like properties.

**DILI:** Ligand A (72.547) has a higher DILI risk than Ligand B (37.379). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (82.241) has a better percentile.

**Caco-2:** Ligand A (-5.502) and Ligand B (-4.869) both have negative values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so this is difficult to interpret.

**Solubility:** Both ligands have negative solubility values (-2.775 and -3.909), which is concerning. Solubility is a key factor for oral bioavailability.

**hERG:** Ligand A (0.045) has a very low hERG risk, which is excellent. Ligand B (0.625) has a slightly elevated but still acceptable hERG risk.

**Microsomal Clearance:** Ligand A (-17.764) has a much lower (better) microsomal clearance than Ligand B (44.078), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (68.248) has a significantly longer half-life than Ligand B (14.565), which is desirable.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable. Ligand B (0.467) has a moderate P-gp efflux.

**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 factors.

**Overall Assessment:**

Ligand A has a superior metabolic profile (lower Cl_mic, longer t1/2) and lower P-gp efflux, and a very favorable hERG profile. However, its lower logP and higher DILI risk are significant drawbacks. Ligand B has better logP, TPSA, and DILI risk, but suffers from poorer metabolic stability and a shorter half-life.

Given the enzyme-specific priorities, metabolic stability and a low hERG risk are crucial. Ligand A's significantly better metabolic stability and extremely low hERG risk outweigh its slightly lower logP and higher DILI. The solubility issues for both are concerning and would need to be addressed in formulation, but the metabolic advantage of A is more critical at this stage.

Output:
0
2025-04-17 15:17:32,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.25 and 83.36) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.91 and 2.427) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have similar QED scores (0.712 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (30.012) has a slightly better DILI score than Ligand B (35.556), suggesting a lower risk of liver injury. Both are below the 40 threshold.

**BBB:** Both ligands have similar BBB penetration (66.925 and 64.831). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand B (-5.023) has slightly better Caco-2 permeability than Ligand A (-4.416), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.804) has better aqueous solubility than Ligand A (-2.69), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.1 and 0.187).

**Microsomal Clearance:** Ligand B (24.188) has significantly lower microsomal clearance than Ligand A (73.773), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (14.903 hours) has a much longer in vitro half-life than Ligand A (-10.083 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.036).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both ligands have good overall properties, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and a longer in vitro half-life. These are critical factors for enzyme inhibitors, as they directly impact drug exposure and dosing frequency. The slightly better solubility and Caco-2 permeability also contribute to its advantage. The difference in binding affinity is minimal and doesn't outweigh the ADME benefits of Ligand B.

Output:
1
2025-04-17 15:17:32,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.861 Da) is slightly higher than Ligand B (346.435 Da), but both are acceptable.

**TPSA:** Ligand A (118.41) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (78.07) is well within the acceptable range.

**logP:** Both ligands have good logP values (A: 2.138, B: 1.224), falling 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 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.604, B: 0.786), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.57, which is high and concerning. Ligand B has a much lower DILI risk of 37.301, which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (45.715) and Ligand B (59.364) are both relatively low, which is expected.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.12 and -5.032), which is unusual and suggests poor permeability. However, these values are on a log scale and might not be directly comparable without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.102 and -0.453), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.21, B: 0.191), which is excellent.

**Microsomal Clearance:** Ligand A (34.507) has a higher microsomal clearance than Ligand B (27.077), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (10.341 hours) compared to Ligand A (-2.445 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.217, B: 0.034), which is good.

**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 factor.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. The primary reason is its significantly lower DILI risk (37.301 vs 89.57) and longer in vitro half-life (10.341 vs -2.445). Although both have poor solubility and permeability, the lower DILI and better metabolic stability of Ligand B outweigh these drawbacks. The slightly better affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 15:17:32,227 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.49 and 363.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (75.44), both being below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.10 and 3.22), falling within the 1-3 range. Ligand B is slightly higher, which *could* present a minor solubility issue, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both satisfy the <5 HBD and <10 HBA criteria.

**QED:** Both ligands have good QED scores (0.748 and 0.855), indicating good drug-like properties.

**DILI:** Ligand A (23.61) has a significantly lower DILI risk than Ligand B (54.75), which is a major advantage. Both are below the concerning 60 threshold, but A is much safer.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.45) is slightly better than Ligand B (55.18).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.76 and -4.88), which is unusual and indicates very poor permeability. This is a significant drawback for both compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.41 and -3.58), also indicating poor solubility. This is a major issue for both compounds.

**hERG:** Both ligands have low hERG risk (0.21 and 0.39).

**Microsomal Clearance:** Ligand A (41.91) has significantly lower microsomal clearance than Ligand B (62.66), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-37.69) has a much longer in vitro half-life than Ligand B (51.20). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.17 and 0.14).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the better candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better BBB penetration. The equal binding affinity removes that as a differentiating factor. The poor permeability and solubility are concerning for both, but can potentially be addressed with formulation strategies. The lower toxicity and better metabolic profile of Ligand A make it the more promising starting point for optimization.

Output:
0
2025-04-17 15:17:32,227 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.391 and 387.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (107.37 and 96.44) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.321) is slightly low, potentially hindering permeation. Ligand B (0.161) is better, falling within the acceptable 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 similar QED values (0.754 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (43.35), indicating a potentially greater risk of liver injury.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.331 and -5.372), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.69 and -1.554), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.103 and 0.118), which is excellent.

**Microsomal Clearance:** Ligand A (21.077 mL/min/kg) has significantly higher microsomal clearance than Ligand B (1.449 mL/min/kg). This suggests Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A (10.781 hours) has a longer half-life than Ligand B (0.261 hours). However, the very short half-life of Ligand B is a major concern.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.033).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.1 vs -0.0 kcal/mol) outweighs the concerns regarding its very short half-life and lower metabolic stability compared to Ligand A. The lower DILI risk is also a positive factor. Addressing the solubility and permeability issues through formulation or structural modifications would be the next steps for Ligand B.

Output:
1
2025-04-17 15:17:32,227 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 353.438 Da, B: 346.515 Da) fall within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (80.32) is better than Ligand B (49.41) as it is closer to the ideal range for oral absorption.

3. **logP:** Both ligands have good logP values (A: 2.152, B: 3.215), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but not drastically.

4. **HBD:** Ligand A (2) and Ligand B (1) are both acceptable, well below the limit of 5. Ligand B is slightly better.

5. **HBA:** Ligand A (4) and Ligand B (2) are both acceptable, well below the limit of 10. Ligand B is better.

6. **QED:** Both ligands have good QED scores (A: 0.713, B: 0.795), indicating good drug-like properties. Ligand B is slightly better.

7. **DILI:** Ligand A (51.26) has a higher DILI risk than Ligand B (35.983). This is a significant advantage for Ligand B.

8. **BBB:** Both ligands have acceptable BBB penetration (A: 68.282, B: 71.772). Since SRC is not a CNS target, this is less critical, but B is slightly better.

9. **Caco-2:** Both ligands have negative Caco-2 values which is unusual. It suggests poor permeability.

10. **Solubility:** Both ligands have negative solubility values which is also unusual. It suggests poor solubility.

11. **hERG:** Both ligands have low hERG inhibition liability (A: 0.475, B: 0.449), which is good.

12. **Cl_mic:** Ligand B (41.896) has a slightly lower microsomal clearance than Ligand A (44.015), suggesting better metabolic stability.

13. **t1/2:** Ligand A (17.592) has a longer in vitro half-life than Ligand B (-12.423). This is a significant advantage for Ligand A.

14. **Pgp:** Both ligands have low P-gp efflux liability (A: 0.08, B: 0.088).

15. **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. A difference of 0.7 kcal/mol is meaningful.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a much stronger binding affinity and a longer half-life. Ligand B has better DILI and slightly better metabolic stability, but the affinity difference is significant.

**Conclusion:**

Despite the slightly better DILI profile of Ligand B, the significantly stronger binding affinity (-8.4 vs -7.7 kcal/mol) and longer half-life of Ligand A outweigh the minor advantages of Ligand B. The potency is the most important factor here.

Output:
1
2025-04-17 15:17:32,227 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 345.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is slightly higher than Ligand B (62.11), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.376) is within the optimal 1-3 range, while Ligand B (2.446) is also acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBAs, while Ligand B has 7. Both are below the 10 limit, but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (0.806 and 0.832), indicating good drug-like properties.

**DILI:** Ligand A (32.842) has a significantly lower DILI risk than Ligand B (65.529). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (75.107 and 86.894), but this is less critical for a kinase inhibitor unless CNS involvement is specifically targeted.

**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, again, the scale is not specified. This is concerning and needs further investigation.

**hERG Inhibition:** Ligand A (0.343) has a much lower hERG inhibition liability than Ligand B (0.97). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand A (37.385) has a higher (worse) microsomal clearance than Ligand B (50.206), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (31.64) has a longer in vitro half-life than Ligand A (9.197), which is desirable.

**P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux liability than Ligand B (0.367), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). The difference is 0.9 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B has a better binding affinity and longer half-life. However, Ligand A exhibits significantly better safety profiles with much lower DILI and hERG inhibition risks. The solubility and permeability are concerning for both, but the safety advantages of Ligand A are substantial, especially for an oncology target where chronic dosing may be required. The affinity difference, while significant, might be overcome with further optimization of Ligand A, while mitigating the safety concerns of Ligand B would likely be more challenging.

Output:
0
2025-04-17 15:17:32,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.43 and 346.35 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.58) is better than Ligand B (127.9), being closer to the <140 threshold for good absorption.

**logP:** Ligand B (-2.107) is significantly lower than the optimal 1-3 range, which could hinder permeability. Ligand A (0.42) is also a bit low, but closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 9 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.821 and 0.634, both >=0.5).

**DILI:** Both ligands have similar and acceptable DILI risk (70.84 and 72.04, both <80).

**BBB:** Ligand A (52.81) and Ligand B (43.82) are both low, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.9) is significantly worse than Ligand B (-5.61). Both are poor, but Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-3.657) is better than Ligand B (-1.721), indicating better solubility.

**hERG:** Ligand A (0.389) is much lower than Ligand B (0.013), suggesting a lower risk of cardiotoxicity. This is a critical advantage.

**Microsomal Clearance:** Ligand B (-0.737) has a negative value, which is excellent, indicating very low clearance and high metabolic stability. Ligand A (1.369) is higher, implying faster clearance.

**In vitro Half-Life:** Ligand B (7.551) has a much longer in vitro half-life than Ligand A (-7.155).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.025).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol). The difference is substantial (7.6 kcal/mol), which can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B shows excellent metabolic stability and half-life, Ligand A has a significantly better binding affinity (-7.6 vs 0.0 kcal/mol) and a much lower hERG risk. The superior binding affinity is a major advantage for an enzyme inhibitor, and the lower hERG risk is crucial for safety. The slightly lower solubility and permeability of Ligand A are less concerning than the very poor binding and higher hERG risk of Ligand B. Therefore, Ligand A is the more promising drug candidate.

Output:
1
2025-04-17 15:17:32,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.4 and 349.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.5) is higher than Ligand B (63.7). While both are acceptable, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (1.52) is within the optimal range, while Ligand B (3.075) is at the higher end. This could potentially lead to solubility issues for Ligand B, but isn't a major concern yet.

**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 (0.723 and 0.802), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (94.6%) compared to Ligand B (19.3%). This is a major red flag for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (85.5%) than Ligand A (57.2%), but this isn't a primary concern.

**Caco-2 Permeability:** Ligand A (-5.389) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.36) is better, but still not great.

**Aqueous Solubility:** Ligand A (-3.842) has poor aqueous solubility, while Ligand B (-2.434) is better.

**hERG:** Ligand A (0.121) has a slightly higher hERG risk than Ligand B (0.614), but both are relatively low.

**Microsomal Clearance:** Ligand A (10.08 mL/min/kg) has much lower microsomal clearance than Ligand B (33.57 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (99.95 hours) has a significantly longer half-life than Ligand B (3.09 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.103), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a significant advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's poor solubility and Caco-2 permeability, its significantly superior binding affinity (-9.4 vs -7.7 kcal/mol), much lower microsomal clearance, longer half-life, lower P-gp efflux, and, crucially, much lower DILI risk make it the more promising candidate. The strong binding affinity is a key factor for an enzyme inhibitor, and the improved metabolic stability and reduced toxicity are critical for drug development. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 15:17:32,228 - INFO - Batch 367 complete. Total preferences: 5872
2025-04-17 15:17:32,228 - INFO - Processing batch 368/512...
2025-04-17 15:18:16,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.342 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.86) is better than Ligand B (70.08), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.056) is optimal (1-3), while Ligand B (0.389) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.592 and 0.748 respectively), indicating good drug-like properties.

**DILI:** Ligand A (58.589) has a higher DILI risk than Ligand B (21.598). This is a significant drawback for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (57.852 and 51.493 respectively). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.841) and Ligand B (-4.367) both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-3.594) and Ligand B (-1.96) both have negative solubility values which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.694) has a slightly higher hERG risk than Ligand B (0.169), but both are relatively low.

**Microsomal Clearance:** Ligand B (-2.778) has significantly lower (better) microsomal clearance than Ligand A (89.331), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (0.829) has a slightly better half-life than Ligand A (-25.566).

**P-gp Efflux:** Ligand A (0.271) has a slightly lower P-gp efflux than Ligand B (0.019).

**Binding Affinity:** Ligand A (-6.9) has a significantly better binding affinity than Ligand B (0.0). This is a crucial advantage. The difference of 6.9 kcal/mol is substantial.

**Conclusion:**

Despite Ligand A's higher DILI risk and worse metabolic stability, its significantly superior binding affinity (-6.9 kcal/mol vs 0.0 kcal/mol) is a decisive factor. A strong binding affinity can often outweigh minor ADME drawbacks, especially for an enzyme target where potency is paramount. The difference in binding is so large that it is likely to overcome the other issues.

Output:
1
2025-04-17 15:18:16,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.5 & 357.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (78.6). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors. Ligand A is well below the 140 threshold, while Ligand B is approaching it.

**3. logP:** Both ligands have a logP of approximately 2.2, which is optimal.

**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 (5) for similar reasons as HBDs.

**6. QED:** Both ligands have good QED scores (0.762 and 0.864), indicating good drug-like properties.

**7. DILI:** Ligand A (14.541) has a much lower DILI risk than Ligand B (31.718). This is a significant advantage.

**8. BBB:** Both ligands have high BBB penetration (91.974 and 85.343), but Ligand A is better. While not a primary concern for a non-CNS target like SRC, it's not detrimental.

**9. Caco-2 Permeability:** Ligand A (-4.638) is better than Ligand B (-4.721), though both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.291) is better than Ligand B (-2.617), although both are poor. Solubility is a concern, but can be addressed through formulation.

**11. hERG Inhibition:** Ligand A (0.892) has a lower hERG risk than Ligand B (0.449). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (8.743) has lower microsomal clearance than Ligand B (14.43), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-16.144) has a significantly longer in vitro half-life than Ligand B (-2.06). This is a substantial advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux than Ligand B (0.089). Lower efflux is generally preferred.

**15. Binding Affinity:** Ligand B (-6.3) has a slightly better binding affinity than Ligand A (-0.0). This is a significant advantage. However, the other ADME properties of Ligand A are much better.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is significantly better across most ADME properties, including DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and solubility. The difference in binding affinity is not large enough to outweigh the substantial advantages of Ligand A in terms of safety and pharmacokinetic properties. For an enzyme target like SRC kinase, metabolic stability, solubility, and safety (hERG, DILI) are paramount.

Output:
0
2025-04-17 15:18:16,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.483 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is significantly better than Ligand B (81.08). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand B (1.107) is better than Ligand A (4.48). 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 2 HBD, which is good. Ligand B has 4 HBA, while Ligand A has 2. Both are acceptable, but Ligand B is slightly higher.

**QED:** Both ligands have similar QED values (0.845 and 0.792), indicating good drug-likeness.

**DILI:** Ligand B (27.414) has a much lower DILI risk than Ligand A (51.105). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (47.809) has a slightly better BBB score than Ligand B (20.512).

**Caco-2 Permeability:** Both are negative (-4.864 and -4.624), indicating poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Ligand B (-1.369) is better than Ligand A (-3.829). Solubility is crucial for bioavailability, and Ligand B has a better score.

**hERG Inhibition:** Ligand A (0.056) has a slightly lower hERG risk than Ligand B (0.401), which is preferable.

**Microsomal Clearance:** Ligand B (16.85) has a lower microsomal clearance than Ligand A (33.239), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-16.372) has a longer half-life than Ligand B (10.115). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.106).

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better half-life and lower hERG risk, Ligand B excels in critical areas for an enzyme inhibitor: lower DILI risk, better solubility, and significantly improved metabolic stability (lower Cl_mic). The slightly higher logP of Ligand B is acceptable, and its TPSA is better than Ligand A. The equal binding affinity makes these ADME properties the deciding factor.

Output:
1
2025-04-17 15:18:16,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (352.475 Da and 383.583 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is higher than Ligand B (52.65). Both are below the 140 A^2 threshold for good oral absorption, but lower is generally better.

**3. logP:** Both ligands have optimal logP values (1.868 and 1.45), 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 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.688 and 0.704), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (20.706 and 22.257), both well below the concerning threshold of 60.

**8. BBB:** Ligand A (79.217) has a better BBB penetration percentile than Ligand B (50.679). However, BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.65) has a worse Caco-2 permeability than Ligand B (-5.435). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.596) has better aqueous solubility than Ligand B (-2.262). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.401 and 0.37), which is excellent.

**12. Microsomal Clearance:** Ligand A (37.464) has a higher microsomal clearance than Ligand B (20.061). Lower clearance is preferred for better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.217 hours) has a longer in vitro half-life than Ligand B (7.254 hours), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.061).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand B having slightly better Caco-2 permeability, Ligand A is the superior candidate. The significantly stronger binding affinity (-7.8 vs -6 kcal/mol) is the most important factor for an enzyme target like SRC kinase. Ligand A also has a longer half-life and comparable, good ADME properties. The slightly higher TPSA and clearance of Ligand A are not major concerns given the substantial potency advantage.

Output:
1
2025-04-17 15:18:16,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.403 and 376.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.14) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (84.94) is excellent, well below 140 and suggesting good absorption.

**logP:** Ligand A (0.012) is very low, potentially hindering permeation. Ligand B (1.14) 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, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.528 and 0.578, respectively), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (94.765), a major concern. Ligand B has a very low DILI risk (25.204), a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (75.611) is higher than Ligand A (23.265), but this isn't a primary factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar and doesn't strongly differentiate them.

**Aqueous Solubility:** Both have negative solubility values, also unusual and requiring further investigation. Again, the values are similar.

**hERG:** Ligand A has a slightly higher hERG risk (0.13) than Ligand B (0.578), though both are relatively low.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-2.971), indicating very high metabolic stability (a good sign). Ligand B has a positive Cl_mic (23.321), suggesting faster metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a short half-life (6.677 hours), while Ligand B has a very long half-life (-26.63 hours). The negative value for Ligand B is suspect and likely an error, but even if it were a large positive value, the short half-life of Ligand A is a concern.

**P-gp Efflux:** Ligand A shows some P-gp efflux (0.069), while Ligand B has negligible efflux (0.096).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-9 kcal/mol) than Ligand A (-0 kcal/mol). This is a huge advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has excellent metabolic stability, its very low logP, high DILI risk, and significantly weaker binding affinity are major drawbacks. Ligand B's superior binding affinity, lower DILI risk, and more favorable logP make it a much more promising starting point, despite the potentially higher metabolic clearance. The negative values for Caco-2 and solubility are concerning for both, but the binding affinity difference is substantial.

Output:
1
2025-04-17 15:18:16,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.383 and 381.885 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.27) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (71.53) is well within the acceptable range.

**logP:** Both ligands have good logP values (2.943 and 2.253), falling within the 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 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.72 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (79.333) has a higher DILI risk than Ligand B (61.031). While both are not ideal, Ligand B is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.604) has a higher BBB value than Ligand A (49.205), but this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.712 and -4.964). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are common. The more negative value suggests slightly worse permeability for Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.52 and -3.473), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.66) has a higher hERG risk than Ligand B (0.335). Lower is better, making Ligand B preferable.

**Microsomal Clearance:** Ligand B (21.256) has significantly lower microsomal clearance than Ligand A (81.031), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (0.271) has a very short half-life, while Ligand A (28.45) has a much longer half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.274).

**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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity (-7.4 vs -9.4 kcal/mol) and better metabolic stability (lower Cl_mic, 21.256 vs 81.031). It also has a lower DILI risk and hERG inhibition liability. While Ligand A has a better in vitro half-life, the significantly stronger binding of Ligand B is a critical factor for an enzyme inhibitor. The solubility and permeability issues are concerning for both, but the potency and metabolic stability advantages of Ligand B are more important for initial optimization.

Output:
1
2025-04-17 15:18:16,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.326) is slightly higher than Ligand B (360.845), but both are acceptable.

**TPSA:** Ligand A (59.23) is significantly better than Ligand B (78.35). Lower TPSA generally indicates better permeability, which is desirable.

**logP:** Both ligands have good logP values (A: 3.805, B: 2.715) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (A: 0.759, B: 0.876), indicating good drug-like properties.

**DILI:** Both ligands show acceptable DILI risk (A: 74.952, B: 70.841), though ideally below 60.

**BBB:** Ligand A has a higher BBB penetration percentile (85.537) than Ligand B (56.107). While not a primary concern for a kinase inhibitor, higher BBB is never a detriment.

**Caco-2 Permeability:** Ligand A (-4.633) and Ligand B (-5.305) both have negative values, which is unusual and likely indicates very low permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.04 for A, -4.205 for B). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.372, B: 0.481), which is excellent.

**Microsomal Clearance:** Ligand A (38.456) has significantly lower microsomal clearance than Ligand B (71.252). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-32.554) has a much longer in vitro half-life than Ligand B (-9.329). This is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.169, B: 0.256).

**Binding Affinity:** Ligand B (-7.4 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 can outweigh other drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, the significantly stronger binding affinity of Ligand B (-7.4 kcal/mol vs -0.0 kcal/mol) is a decisive advantage. The improved metabolic stability (lower Cl_mic, longer t1/2) of Ligand A is appealing, but not enough to overcome the substantial difference in binding affinity. While solubility and permeability would need to be addressed through formulation or further chemical modifications, Ligand B is the more promising starting point due to its potency.

Output:
1
2025-04-17 15:18:16,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (350.459 Da) is also good.

**TPSA:** Ligand A (64.74) is significantly better than Ligand B (75.71). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have good logP values (A: 3.07, B: 1.524), 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:** Both ligands have acceptable HBD (1) and HBA (A: 5, B: 4) counts.

**QED:** Both ligands have good QED scores (A: 0.625, B: 0.788), indicating good drug-like properties.

**DILI:** Ligand A (88.251) has a significantly higher DILI risk than Ligand B (19.698). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 73.556, B: 74.06), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.134 for A and -4.753 for B).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the values are similar (-4.499 for A and -2.216 for B).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.736, B: 0.184), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (60.02) has a higher microsomal clearance than Ligand B (21.09), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-5.297) has a longer in vitro half-life than Ligand A (69.917), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.554, B: 0.053). Ligand B is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.3 kcal/mol, B: -9.0 kcal/mol). The difference is minimal (0.3 kcal/mol), and within the range where other factors become more important.

**Conclusion:**

While both ligands exhibit strong binding affinity, Ligand B is the more promising candidate. Its significantly lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly lower binding affinity and comparable permeability/solubility issues. The higher DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 15:18:16,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.543 and 360.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (106.85). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.037 and 1.02), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (4 HBD, 4 HBA). Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.457 and 0.618), indicating moderate drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have similar and acceptable DILI risk (7.057 and 55.332). Both are well below the concerning threshold of 60.

**BBB:** Ligand A (55.099) has a better BBB percentile than Ligand B (37.96), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.802) has a worse Caco-2 permeability than Ligand B (-5.801). Lower values indicate poorer permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.554 and -2.825). This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.298 and 0.202), which is excellent.

**Microsomal Clearance:** Ligand A (39.526) has a higher microsomal clearance than Ligand B (-16.007). This means Ligand B is more metabolically stable, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-3.618) has a shorter half-life than Ligand B (-2.711), further supporting the better metabolic stability of B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.076).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are good, the 0.6 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The TPSA is higher for B, but still acceptable. The difference in binding affinity, combined with the improved metabolic profile, outweighs the slightly poorer TPSA and Caco-2 permeability.

Output:
1
2025-04-17 15:18:16,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.463 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.32) is slightly above the preferred <140, but acceptable. Ligand B (71.25) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.167 and 2.536), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, fitting the criteria. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.552 and 0.822), indicating drug-like properties.

**DILI:** Ligand A (19.271) has a significantly lower DILI risk than Ligand B (39.201). This is a major advantage.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (67.352) is better than Ligand B (54.362).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability, but we'll consider other factors.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a significant drawback for both.

**hERG:** Both ligands have low hERG risk (0.101 and 0.233), which is good.

**Microsomal Clearance:** Ligand A (19.134) has much lower microsomal clearance than Ligand B (34.953), suggesting better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-8.601) has a more negative (longer) half-life than Ligand B (8.554).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.021 and 0.128).

**Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.4). However, the difference is only 0.4 kcal/mol, which is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A is the better candidate. While both have solubility issues, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better BBB score. The modest affinity difference is outweighed by these ADME/Tox advantages, particularly the lower DILI and improved metabolic stability, which are crucial for kinase inhibitors.

Output:
0
2025-04-17 15:18:16,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.409 and 374.566 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (40.62), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.842 and 3.599), 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 3 HBA, well within the acceptable range (<=10).

**QED:** Both ligands have QED values above 0.5 (0.744 and 0.684), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (34.742 and 36.448), both are below the 40 threshold.

**BBB:** Both ligands have high BBB penetration (90.617 and 93.137), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.782) is slightly worse than Ligand B (-4.551), but both are negative values which is not ideal.

**Aqueous Solubility:** Ligand A (-3.909) is slightly worse than Ligand B (-3.512), both are negative values which is not ideal.

**hERG Inhibition:** Ligand A (0.404) has a lower hERG risk than Ligand B (0.755), which is a significant advantage.

**Microsomal Clearance:** Ligand A (19.744) has significantly lower microsomal clearance than Ligand B (82.024), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-6.42) has a negative half-life, which is not ideal. Ligand B (6.992) has a positive half-life, which is better.

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux than Ligand B (0.483), which is a positive.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is small (0.3 kcal/mol) and can be outweighed by other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. It has a significantly lower microsomal clearance (better metabolic stability) and lower hERG risk, both crucial for drug development. While Ligand B has slightly better binding affinity and in vitro half-life, the advantages of Ligand A in metabolic stability and safety outweigh these minor differences.

Output:
0
2025-04-17 15:18:16,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**
*   **MW:** 379.591 Da - Within the ideal range (200-500).
*   **TPSA:** 29.54 - Excellent, well below the 140 threshold for absorption.
*   **logP:** 4.923 - Slightly high, potentially leading to solubility issues or off-target effects, but not drastically so.
*   **HBD:** 0 - Low, good for permeability.
*   **HBA:** 4 - Good, within the acceptable range.
*   **QED:** 0.619 - Good drug-likeness.
*   **DILI:** 33.23 - Very low risk of liver injury.
*   **BBB:** 76.309 - Moderate, not a primary concern for a non-CNS target like SRC.
*   **Caco-2:** -4.833 - Negative value is unusual, suggesting very poor permeability. This is a significant red flag.
*   **Solubility:** -4.465 - Very poor solubility, a major concern.
*   **hERG:** 0.762 - Low risk of hERG inhibition.
*   **Cl_mic:** 126.674 - High microsomal clearance, indicating poor metabolic stability.
*   **t1/2:** 45.422 - Moderate in vitro half-life.
*   **Pgp:** 0.857 - Moderate P-gp efflux.
*   **Affinity:** -7.3 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 351.437 Da - Within the ideal range.
*   **TPSA:** 40.54 - Good, below the 140 threshold.
*   **logP:** 4.434 - Acceptable, though approaching the higher end.
*   **HBD:** 1 - Low, good for permeability.
*   **HBA:** 2 - Good, within the acceptable range.
*   **QED:** 0.852 - Excellent drug-likeness.
*   **DILI:** 16.402 - Very low risk of liver injury.
*   **BBB:** 87.127 - Moderate, not a primary concern.
*   **Caco-2:** -4.557 - Negative value, suggesting very poor permeability. This is a significant red flag.
*   **Solubility:** -5.178 - Very poor solubility, a major concern.
*   **hERG:** 0.829 - Low risk of hERG inhibition.
*   **Cl_mic:** 100.126 - Moderate microsomal clearance, better than Ligand A.
*   **t1/2:** -12.094 - Negative half-life is not possible and indicates a problem with the data.
*   **Pgp:** 0.308 - Low P-gp efflux.
*   **Affinity:** -7.5 kcal/mol - Excellent, slightly better binding affinity than Ligand A.

**Comparison and Decision:**

Both ligands have excellent binding affinities, which is paramount for an enzyme inhibitor. However, both suffer from extremely poor Caco-2 permeability and aqueous solubility. Ligand A has a higher Cl_mic, indicating faster metabolism, while Ligand B has a nonsensical negative half-life. While Ligand B has a slightly better binding affinity and lower Pgp efflux, the negative half-life is a critical data quality issue.

Given the severe permeability and solubility issues of both, neither is a particularly promising candidate *as is*. However, the negative half-life for Ligand B is a clear indication of data problems, making it less reliable. Ligand A, despite its higher Cl_mic, has a plausible half-life and better overall ADME properties *excluding* the solubility and permeability. Therefore, Ligand A is marginally more likely to be a viable starting point for optimization, focusing on improving solubility and permeability.

Output:
0
2025-04-17 15:18:16,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.418 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (74.09), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.018 and 1.725), falling 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 B (7) is higher than Ligand A (3). Both are within the acceptable range (<=10).

**QED:** Both ligands have similar and good QED scores (0.855 and 0.805), indicating good drug-like properties.

**DILI:** Ligand A (29.973) has a significantly lower DILI risk than Ligand B (44.397). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (80.574 and 76.154), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.581) is better than Ligand B (-5.422), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.204) is better than Ligand B (-1.956), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.661 and 0.304), which is good.

**Microsomal Clearance:** Ligand A (-13.298) has significantly lower (better) microsomal clearance than Ligand B (39.06). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (7.71) has a better in vitro half-life than Ligand B (-9.142).

**P-gp Efflux:** Ligand A (0.121) has lower P-gp efflux than Ligand B (0.274), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is superior to Ligand B. It demonstrates better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, better solubility, better Caco-2 permeability, lower P-gp efflux, and a significantly stronger binding affinity. While both ligands are generally within acceptable ranges for most parameters, the combination of improved ADME properties and superior potency makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 15:18:16,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.463 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.11) is better than Ligand B (85.51). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal for oral bioavailability.

**logP:** Both ligands have good logP values (1.079 and 0.807), falling within the 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.724 and 0.807), indicating drug-like properties.

**DILI:** Ligand A (16.596) has a significantly lower DILI risk than Ligand B (20.047), which is a crucial advantage. Both are below 40, indicating low risk.

**BBB:** Ligand A (61.846) has a better BBB penetration score than Ligand B (46.879), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.268 and -5.246), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.876 and -1.853), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.217) has a much lower hERG inhibition liability than Ligand B (0.338), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (-31.948) has a *much* lower (better) microsomal clearance than Ligand A (-6.128). This indicates significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-11.058) has a more negative value, which translates to a longer in vitro half-life than Ligand A (24.851).

**P-gp Efflux:** Ligand A (0.005) exhibits very low P-gp efflux, which is better than Ligand B (0.012).

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-0.0). This is a substantial advantage and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have significant ADME issues (poor solubility and permeability), Ligand B stands out due to its dramatically superior binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer half-life). The stronger binding affinity is a critical factor for an enzyme inhibitor, and the improved metabolic stability is essential for achieving therapeutic concentrations *in vivo*. Ligand A has better DILI and hERG profiles, but the substantial difference in binding affinity and metabolic stability makes Ligand B the more promising candidate, even with the ADME challenges. Further optimization would focus on improving the solubility and permeability of Ligand B.

Output:
1
2025-04-17 15:18:16,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.901 and 334.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.34) is better than Ligand B (55.05), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have logP values (3.87 and 4.078) within the optimal 1-3 range, suggesting good permeability.

**H-Bond Donors & Acceptors:** Both ligands have a reasonable number of HBD (0) and HBA (3 and 5 respectively), balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.694 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (65.568), which is a major advantage. Ligand B's DILI is quite high.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (83.831) has slightly better BBB penetration than Ligand A (78.092).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-4.632 vs -4.929).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the values are similar (-3.684 vs -4.123).

**hERG Inhibition:** Both ligands have similar low hERG inhibition liability (0.834 and 0.835), which is good.

**Microsomal Clearance:** Ligand A (37.903) has significantly lower microsomal clearance than Ligand B (91.183), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (9.941) has a better in vitro half-life than Ligand B (-11.938). The negative value for Ligand B is concerning.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.335 and 0.665), which is reasonable.

**Binding Affinity:** Ligand B (-9.0 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. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand B's superior binding affinity, the significantly higher DILI risk and much worse metabolic stability (higher Cl_mic, negative half-life) make it a less desirable candidate. Ligand A has a much more favorable safety profile (DILI) and pharmacokinetic properties (Cl_mic, t1/2), even though its binding affinity is slightly lower. For an enzyme target like SRC kinase, metabolic stability and safety are critical, and the difference in binding affinity is not large enough to overcome the ADME liabilities of Ligand B.

Output:
0
2025-04-17 15:18:16,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.5 and 366.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.6) is significantly better than Ligand B (91.4). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (3.15 and 1.58), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA) in terms of maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.776 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A (7.1) has a much lower DILI risk than Ligand B (37.5). This is a significant advantage.

**BBB:** Both have similar BBB penetration (64.6 and 66.6), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.641) is better than Ligand B (-5.176), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.161 and -3.392). This is a potential issue that would need to be addressed during formulation.

**hERG Inhibition:** Ligand A (0.612) has a slightly better hERG profile than Ligand B (0.348), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (40.7) has a higher, less favorable, microsomal clearance than Ligand B (35.0). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-11.985) has a much longer in vitro half-life than Ligand A (16.304). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux than Ligand B (0.028), which is favorable for bioavailability.

**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 A excels in TPSA, DILI risk, Caco-2 permeability, hERG, and P-gp efflux. However, Ligand B has a significantly better in vitro half-life and lower microsomal clearance, which are crucial for an enzyme target. The similar binding affinities mean potency isn't a differentiating factor. While solubility is poor for both, the metabolic stability advantage of Ligand B is more important for an enzyme inhibitor.

Output:
1
2025-04-17 15:18:16,108 - INFO - Batch 368 complete. Total preferences: 5888
2025-04-17 15:18:16,108 - INFO - Processing batch 369/512...
2025-04-17 15:18:58,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (340.354 and 348.353 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.45) is significantly better than Ligand B (71.42). Lower TPSA generally favors better cell permeability.

**3. logP:** Both ligands have acceptable logP values (3.781 and 2.783, respectively), 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 the same number of HBA (5), which is within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.716 and 0.719), indicating good drug-likeness.

**7. DILI:** Ligand B (69.678) has a lower DILI risk than Ligand A (91.819), which is a significant advantage.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (75.107) is slightly better than Ligand B (67.468). However, BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.226) has better Caco-2 permeability than Ligand B (-5.016).

**10. Aqueous Solubility:** Ligand A (-5.575) has better aqueous solubility than Ligand B (-4.147). Solubility is crucial for bioavailability.

**11. hERG Inhibition:** Both ligands have similar and low hERG inhibition risk (0.754 and 0.795, respectively).

**12. Microsomal Clearance:** Ligand B (10.125) has significantly lower microsomal clearance than Ligand A (131.387). This indicates better metabolic stability for Ligand B, a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (20.944) has a longer in vitro half-life than Ligand B (1.254). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.259 and 0.205, respectively).

**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 Caco-2 permeability, solubility, BBB penetration, and half-life, Ligand B demonstrates a significantly better safety profile (lower DILI) and, critically, much better metabolic stability (lower Cl_mic). Given the enzyme-specific priorities, metabolic stability is paramount. The difference in Cl_mic is substantial. The similar binding affinity makes the ADME advantages of Ligand B decisive.

Output:
1
2025-04-17 15:18:58,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.84) is better than Ligand B (79.26) as it is still within the acceptable range for oral absorption (<140), but lower TPSA is generally preferred.

**logP:** Ligand A (-0.882) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.869) is closer to the ideal range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (3 and 2 respectively) and HBA (5 each) counts.

**QED:** Both ligands have good QED scores (0.537 and 0.695), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (47.77) has a better DILI score than Ligand B (7.716), indicating a lower risk of liver injury.

**BBB:**  BBB is less critical for a non-CNS target like SRC kinase. Ligand A (74.254) is better than Ligand B (55.874).

**Caco-2 Permeability:** Both have very poor Caco-2 permeability (-5.188 and -5.703). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.197 and -0.459). This is a significant concern for formulation and bioavailability.

**hERG:** Ligand A (0.074) has a much lower hERG inhibition liability than Ligand B (0.315), which is a major advantage.

**Microsomal Clearance:** Ligand B (-20.932) has a better (lower) microsomal clearance than Ligand A (-15.638), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.081) has a slightly better in vitro half-life than Ligand A (13.668), although both are relatively low.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.007).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly better binding affinity than Ligand A (-7.2 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic). However, Ligand A has a significantly better DILI score and lower hERG risk. Both have poor solubility and permeability. The difference in binding affinity is substantial. Given the enzyme-specific priorities, potency is paramount, and the improved metabolic stability of Ligand B is also a significant benefit. The lower hERG risk of Ligand A is attractive, but the binding affinity difference is more important.

Output:
1
2025-04-17 15:18:58,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.28) is slightly above the preferred <140 for good oral absorption, while Ligand B (109) is well within.

**logP:** Ligand A (0.71) is a bit low, potentially hindering permeation. Ligand B (0.952) is also on the lower side, but slightly better.

**H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.645 and 0.679), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (67.778 and 63.086), below the concerning threshold of 60.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (34.161) is slightly better than A (20.085).

**Caco-2:** Both have negative Caco-2 values, which is unusual and problematic. These values likely represent logP-corrected Caco-2 permeability, and negative values indicate very poor permeability. Ligand B (-6.089) is worse than Ligand A (-5.49).

**Solubility:** Both have negative solubility values, which is also unusual and problematic. These values likely represent logS, and negative values indicate very poor solubility. Ligand B (-2.021) is worse than Ligand A (-1.837).

**hERG:** Both ligands have very low hERG risk (0.064 and 0.025), which is excellent.

**Microsomal Clearance:** Ligand B (-5.492) has significantly *better* metabolic stability (lower clearance) than Ligand A (28.05). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (22.632) has a longer half-life than Ligand A (9.46), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.055 and 0.02), which is favorable.

**Binding Affinity:** Ligand B (-10.6 kcal/mol) has a *significantly* stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial difference and a major deciding factor. A 2.9 kcal/mol difference is very significant.

**Overall Assessment:**

While both ligands have acceptable DILI and hERG profiles, Ligand B is clearly superior. Its significantly stronger binding affinity and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower Caco-2 and solubility values. The negative Caco-2 and solubility values are concerning for both, but these issues might be addressed with formulation strategies. The large affinity difference is the most important factor.

Output:
1
2025-04-17 15:18:58,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.426 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.47) is significantly better than Ligand B (82.11), being well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.124) is optimal, while Ligand B (-0.413) is slightly below the preferred range, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.834) has a higher QED score than Ligand B (0.719), indicating better overall drug-likeness.

**DILI:** Ligand A (21.171) has a much lower DILI risk than Ligand B (13.532), which is a significant advantage.

**BBB:** Ligand A (91.198) exhibits better BBB penetration than Ligand B (45.444), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.919) has better Caco-2 permeability than Ligand B (-4.734).

**Aqueous Solubility:** Ligand A (-2.205) has better aqueous solubility than Ligand B (-0.618).

**hERG Inhibition:** Ligand A (0.328) has a lower hERG inhibition liability than Ligand B (0.12), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand A (-0.086) has a lower (better) microsomal clearance than Ligand B (-0.92).

**In vitro Half-Life:** Ligand A (-8.441) has a longer half-life than Ligand B (-8.806).

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.025).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has slightly better binding affinity than Ligand A (-7.1 kcal/mol), but the difference is less than the 1.5 kcal/mol threshold that would override other concerns.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties (DILI, solubility, hERG, permeability, metabolic stability). While Ligand B has slightly better binding affinity, the significant advantages of Ligand A in safety and pharmacokinetic properties make it the more promising drug candidate.

Output:
0
2025-04-17 15:18:58,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.332 Da) is slightly higher than Ligand B (351.416 Da), but both are acceptable.

**TPSA:** Ligand A (82.45) is acceptable for oral absorption, while Ligand B (21.06) is excellent.

**logP:** Ligand A (2.848) is within the optimal range. Ligand B (4.565) is slightly high, potentially leading to solubility issues or off-target effects.

**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 and good QED values (0.719 and 0.736, respectively).

**DILI:** Ligand A has a DILI risk of 55.797, which is moderate. Ligand B has a significantly lower DILI risk of 21.753, which is excellent.

**BBB:** Ligand A has a BBB penetration of 49.864, which is not a primary concern for a non-CNS target like SRC. Ligand B has a high BBB penetration (97.053), which is irrelevant here and could even be a negative if off-target CNS effects are a concern.

**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 has a low hERG risk (0.128), which is excellent. Ligand B has a slightly higher hERG risk (0.854), but still relatively low.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (90.473) than Ligand B (62.229), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (9.497 hours) than Ligand B (6.494 hours), which is preferable.

**P-gp Efflux:** Ligand A has a low P-gp efflux liability (0.082), which is good. Ligand B has a higher P-gp efflux liability (0.563).

**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 substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While its logP is slightly high, the significantly stronger binding affinity (-8.7 vs -7.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand B demonstrates a much lower DILI risk and better metabolic stability (lower Cl_mic). The negative Caco-2 and solubility values are concerning for both, but the superior potency and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 15:18:58,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.455 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.16) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (94.46) is excellent, well below 140.

**logP:** Ligand A (0.209) is quite low, potentially hindering permeability. Ligand B (0.125) is even lower, raising similar concerns. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, within acceptable limits. Ligand B has 2 HBD and 5 HBA, also within limits and slightly more favorable.

**QED:** Both ligands have good QED scores (0.5 and 0.682 respectively), indicating drug-like properties.

**DILI:** Ligand A (49.011) has a moderate DILI risk, but acceptable. Ligand B (19.426) has a very low DILI risk, which is a significant advantage.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.51 and -5.166), indicating potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.118 and -1.43). This is a major concern for *in vivo* efficacy.

**hERG Inhibition:** Ligand A (0.278) and Ligand B (0.38) have low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (18.236) has a moderate microsomal clearance. Ligand B (-7.352) has *negative* clearance, which is not physically possible and likely indicates an error or outlier data point. However, interpreting it as very high metabolic stability is reasonable.

**In vitro Half-Life:** Ligand A (1.17 hours) has a short half-life. Ligand B (14.699 hours) has a much longer half-life, a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.006), which is favorable.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol), a difference of 1.5 kcal/mol.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. The primary concerns for both are poor solubility and permeability. However, Ligand B has a significantly lower DILI risk, much better metabolic stability (indicated by the negative Cl_mic and long half-life), and a slightly more favorable HBD/HBA profile. The 1.5 kcal/mol difference in binding affinity is unlikely to overcome the substantial ADME advantages of Ligand B. The negative Cl_mic value for Ligand B is suspect, but even assuming it's an outlier, the long half-life suggests good metabolic stability.

Output:
1
2025-04-17 15:18:58,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.4 and 346.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.46) is slightly higher than Ligand B (78.87). Both are below the 140 threshold for good oral absorption, but B is better.

**3. logP:** Both ligands have good logP values (1.874 and 1.601, respectively), 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 similar, good QED values (0.762 and 0.786), indicating good drug-like properties.

**7. DILI:** Ligand A (56.34) has a higher DILI risk than Ligand B (36.76). This is a significant concern.

**8. BBB:** BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (40.52) is slightly better than Ligand A (56.534).

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.86) is slightly worse than Ligand B (-4.572).

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.307) is slightly worse than Ligand B (-2.007).

**11. hERG:** Both ligands have low hERG risk (0.329 and 0.532), which is good.

**12. Cl_mic:** Ligand A (34.532) has a lower microsomal clearance than Ligand B (37.604), suggesting better metabolic stability.

**13. t1/2:** Ligand B has a significantly longer in vitro half-life (-22.865 hours) compared to Ligand A (36.932 hours). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.045 and 0.227).

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.5 kcal/mol difference is substantial and outweighs many of the other minor differences.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly better binding affinity (-9.0 vs -8.5 kcal/mol) and longer half-life are crucial advantages for an enzyme inhibitor. The lower DILI risk is also a significant benefit. The slightly better TPSA and solubility are additional positives.

Output:
1
2025-04-17 15:18:58,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (398.359 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is well below the 140 threshold, while Ligand B (61.44) is still acceptable but higher.

**logP:** Ligand A (4.495) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.305) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (4 & 4) counts, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.828 and 0.79), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (64.172 and 60.062), placing them in a moderate risk category, but acceptable.

**BBB:** Both have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.647) shows poor permeability, while Ligand B (-5.089) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.356 and -4.121).

**hERG Inhibition:** Ligand A (0.775) has a slightly higher hERG risk than Ligand B (0.447), which is preferable.

**Microsomal Clearance:** Ligand A (9.303) has a lower microsomal clearance, indicating better metabolic stability than Ligand B (47.609). This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (42.959) has a longer half-life than Ligand B (32.531), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.693 and 0.209), which is good.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A's better metabolic stability, the significantly superior binding affinity of Ligand B (-8.8 vs -7.4 kcal/mol) is the deciding factor. The potency advantage is likely to be more impactful for an enzyme target like SRC kinase. While Ligand B has slightly worse solubility and higher clearance, these can potentially be addressed through formulation strategies or further chemical modifications.

Output:
1
2025-04-17 15:18:58,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is slightly higher than Ligand B (77.23), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.346 and 1.645), falling within the optimal 1-3 range. Ligand B is slightly more hydrophilic, which could be beneficial for solubility.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 3 HBA, meeting the criteria of <=5 and <=10 respectively.

**QED:** Ligand B (0.76) has a significantly better QED score than Ligand A (0.449), indicating a more drug-like profile.

**DILI:** Ligand B (15.355) has a much lower DILI risk than Ligand A (23.187), a significant advantage.

**BBB:** Both have similar BBB penetration (46.879 and 46.84), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.434 and -5.316), which is unusual and suggests poor permeability. This is a potential concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.177 and -2.392), indicating poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.346) has a slightly higher hERG inhibition liability than Ligand B (0.263), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (-11.8) exhibits significantly lower microsomal clearance than Ligand A (25.137), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-4.536) has a better (longer) in vitro half-life than Ligand A (-30.406).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.186 and 0.02).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both compounds have issues with solubility and Caco-2 permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, a higher QED score, and, most importantly, a much stronger binding affinity. The improved affinity is a critical factor for an enzyme inhibitor, and the other advantages make Ligand B a more promising starting point for optimization.

Output:
1
2025-04-17 15:18:58,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.738 Da) is higher, but still acceptable. Ligand B (365.413 Da) is slightly better.

**TPSA:** Ligand A (30.93) is excellent, well below the 140 threshold for absorption. Ligand B (71.76) is still reasonable, but less favorable.

**logP:** Ligand A (4.477) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.629) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is good. Ligand B (1 HBD, 8 HBA) is also acceptable, but slightly higher HBA count could affect permeability.

**QED:** Both ligands have similar and good QED values (A: 0.681, B: 0.749), indicating good drug-like properties.

**DILI:** Ligand A (37.611) has a lower DILI risk than Ligand B (91.47), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.48) is better than Ligand B (59.946).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.826) is slightly better than Ligand B (-4.995).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.452 and -3.892 respectively). This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.957 and 0.876 respectively), which is good.

**Microsomal Clearance:** Ligand B (33.222 mL/min/kg) has significantly lower clearance than Ligand A (49.977 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (12.334 hours) has a longer half-life than Ligand A (7.692 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.763 and 0.225 respectively). Ligand B is better.

**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:**

Ligand B is the stronger candidate despite its higher DILI risk. The significantly improved binding affinity (-8.4 vs -7.6 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target. While the solubility is poor for both, the affinity advantage of Ligand B is likely to be more impactful in driving efficacy. The DILI risk of Ligand B is a concern, but could potentially be mitigated through structural modifications.

Output:
1
2025-04-17 15:18:58,047 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (364.785 Da) and Ligand B (352.475 Da) both fall within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (81.91) is higher than Ligand B (59.08). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned, especially considering the enzyme class.

3. **logP:** Ligand A (4.022) is at the upper end of the optimal range (1-3), potentially raising solubility concerns. Ligand B (1.679) is well within the optimal range. This favors Ligand B.

4. **HBD:** Both ligands have 0 HBD, which is good.

5. **HBA:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

6. **QED:** Ligand B (0.775) has a better QED score than Ligand A (0.571), indicating a more drug-like profile.

7. **DILI:** Ligand A (84.994) has a significantly higher DILI risk than Ligand B (30.903). This is a major concern for Ligand A.

8. **BBB:** Both ligands have good BBB penetration (Ligand A: 64.482, Ligand B: 84.8). This isn't a primary concern for an enzyme target like SRC.

9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

10. **Solubility:** Ligand A (-4.148) has worse solubility than Ligand B (-1.532). This is consistent with its higher logP.

11. **hERG:** Ligand A (0.578) has a slightly higher hERG risk than Ligand B (0.343), but both are relatively low.

12. **Cl_mic:** Ligand A (66.62) has a higher microsomal clearance than Ligand B (30.592), indicating lower metabolic stability. This is a significant drawback for Ligand A.

13. **t1/2:** Ligand B (-11.713) has a much longer in vitro half-life than Ligand A (-5.46). This is a major advantage for Ligand B.

14. **Pgp:** Ligand A (0.276) has lower P-gp efflux than Ligand B (0.085), which is slightly favorable.

15. **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 contributes to the overall preference for Ligand B.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in these areas. It has better metabolic stability, a longer half-life, better solubility, and a lower DILI risk. The affinity difference is small, but still favors Ligand B.

**Conclusion:**

Ligand B is the more promising drug candidate. Its superior ADME properties, particularly the lower DILI risk, better metabolic stability, and longer half-life, outweigh the slight advantage of Ligand A in P-gp efflux.

Output:
1
2025-04-17 15:18:58,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.39 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.01) is higher than Ligand B (68.09). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.835) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (2.022) is within the optimal range.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.74 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (69.833) has a slightly higher DILI risk than Ligand B (55.758), but both are acceptable (<60 is good).

**BBB:** Both have reasonable BBB penetration, but Ligand A (70.415) is slightly better than Ligand B (63.358). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2:** Ligand A (-4.887) has a worse Caco-2 permeability than Ligand B (-5.307). Lower values are worse.

**Solubility:** Ligand A (-2.867) has worse solubility than Ligand B (-1.982). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.094 and 0.256), which is excellent.

**Microsomal Clearance:** Ligand B (41.918) has significantly lower microsomal clearance than Ligand A (11.461), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (47.095) has a better in vitro half-life than Ligand B (-10.359). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.047).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.9 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better half-life and BBB penetration, Ligand B excels in crucial areas for kinase inhibitors: better logP, lower TPSA, better solubility, and *significantly* lower microsomal clearance (better metabolic stability). The slightly better binding affinity of Ligand B further strengthens its position. The differences in half-life and BBB are less critical than the metabolic stability and solubility advantages of Ligand B.

Output:
1
2025-04-17 15:18:58,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.392 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.95 and 58.64) are below the 140 A^2 threshold for good absorption, which is positive.

**logP:** Ligand A (3.704) is at the upper end of the optimal 1-3 range, while Ligand B (2.122) is well within it. Ligand A's higher logP *could* potentially lead to off-target effects, but isn't a major concern at this level.

**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 (0.795 and 0.843), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 61.07%, which is considered high risk. Ligand B has a significantly lower DILI risk of 33.424%, which is much more favorable. This is a major advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 67.197%, while Ligand B has 89.531%. While BBB isn't a primary concern for a kinase inhibitor, higher BBB is generally a positive attribute.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.887 and -4.485). 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 (-4.241 and -2.479), again suggesting poor solubility. The scale isn't specified, making interpretation difficult.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.835, while Ligand B has 0.431. Lower is better, so Ligand B is preferable here.

**Microsomal Clearance:** Ligand A has a Cl_mic of 42.96 mL/min/kg, while Ligand B has 13.844 mL/min/kg. Lower clearance indicates better metabolic stability, making Ligand B significantly better.

**In vitro Half-Life:** Ligand A has a t1/2 of 37.508 hours, while Ligand B has -9.214 hours. The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.328, while Ligand B has 0.053. Lower is better, indicating less efflux and better bioavailability for Ligand B.

**Binding Affinity:** Ligand A has a binding affinity of -6.9 kcal/mol, while Ligand B has -7.0 kcal/mol. Ligand B has a slightly better affinity, but the difference is minimal.

**Overall Assessment:**

Ligand B is significantly more promising due to its much lower DILI risk, better metabolic stability (lower Cl_mic), lower hERG inhibition, and lower P-gp efflux. While Ligand A has a slightly longer in vitro half-life, the negative value for Ligand B's half-life is a concern, but the other advantages of Ligand B outweigh this. The slightly better affinity of Ligand B is a bonus. The poor Caco-2 and solubility values for both compounds are concerning and would require further investigation/optimization, but are less critical than the safety and metabolic stability profiles.

Output:
1
2025-04-17 15:18:58,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (373.551 Da) is also good.

**TPSA:** Ligand A (55.89) is excellent, well below the 140 threshold for oral absorption. Ligand B (62.73) is still acceptable, but slightly higher.

**logP:** Ligand A (0.851) is a bit low, potentially hindering permeation. Ligand B (4.854) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is optimal. Ligand B (HBD=2, HBA=7) is also acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.723, B: 0.619), indicating good drug-like properties.

**DILI:** Ligand A (8.375) has a very favorable DILI score, indicating low liver injury risk. Ligand B (74.176) has a significantly higher DILI score, raising a red flag.

**BBB:** Both have acceptable BBB penetration, but Ligand B (76.541) is better than Ligand A (61.729). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability. However, the scale is not specified, so the impact is uncertain.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.153 and -4.99). This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.202) has a very low hERG risk, which is excellent. Ligand B (0.662) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (3.023) has a low microsomal clearance, indicating good metabolic stability. Ligand B (84.249) has a very high clearance, suggesting rapid metabolism and potentially low exposure.

**In vitro Half-Life:** Ligand A (-14.1) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (51.352) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.005, B: 0.457), which is favorable.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME liabilities of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate despite the negative Caco-2 and solubility values. Its superior DILI score, lower hERG risk, and better metabolic stability (lower Cl_mic) are critical advantages for an enzyme inhibitor. The negative half-life is a data quality issue that needs to be addressed, but the other properties are more favorable. Ligand B's high DILI, high clearance, and poor solubility are significant drawbacks that outweigh its slightly better binding affinity.

Output:
0
2025-04-17 15:18:58,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.411 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.63) is better than Ligand B (76.46), both are below the 140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (2.524 and 1.133), 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 4 HBA, and Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Both ligands have acceptable QED scores (0.818 and 0.763), indicating good drug-likeness.

**7. DILI:** Ligand A (58.744) has a higher DILI risk than Ligand B (27.569). This is a significant drawback for Ligand A.

**8. BBB:** Both have reasonable BBB penetration, but Ligand A (70.182) is slightly better than Ligand B (64.793). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.63) has better Caco-2 permeability than Ligand B (-5.021).

**10. Aqueous Solubility:** Ligand A (-4.028) has better aqueous solubility than Ligand B (-0.84). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.677) has a lower hERG inhibition liability than Ligand B (0.143), which is favorable.

**12. Microsomal Clearance:** Ligand B (25.735) has significantly lower microsomal clearance than Ligand A (73.728), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (20.098) has a longer in vitro half-life than Ligand A (7.618), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.362) has lower P-gp efflux than Ligand B (0.019), which is favorable.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it may not be enough to overcome the significant ADME liabilities of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better affinity and P-gp efflux, Ligand B excels in critical areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and improved solubility. The difference in binding affinity is not substantial enough to outweigh these advantages.

Output:
1
2025-04-17 15:18:58,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.391 and 341.331 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.41) is better than Ligand B (129.89). Both are below the 140 A^2 threshold for good oral absorption, but Ligand A is closer to the desirable range.

**logP:** Ligand A (0.524) is slightly better than Ligand B (0.031), both are a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 8 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.702) has a significantly better QED score than Ligand B (0.478), indicating a more drug-like profile.

**DILI:** Ligand B (83.792) has a higher DILI risk than Ligand A (69.988), making Ligand A safer. Both are above the 60 threshold, so this is a concern for both.

**BBB:** Ligand A (36.487) has a better BBB penetration score than Ligand B (23.071), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.469) is better than Ligand B (-5.849), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.683) is better than Ligand B (-2.438), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.118 and 0.05, respectively).

**Microsomal Clearance:** Ligand A (16.729) has a significantly lower microsomal clearance than Ligand B (-16.173), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (14.026) has a slightly longer half-life than Ligand A (10.244).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.018, respectively).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.3 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better QED score, lower DILI risk, better TPSA, better solubility, and significantly better metabolic stability (lower Cl_mic). While both have similar binding affinities and low hERG risk, the ADME properties of Ligand A make it a more promising drug candidate. The slightly lower logP is a minor concern, but outweighed by the other advantages.

Output:
1
2025-04-17 15:18:58,049 - INFO - Batch 369 complete. Total preferences: 5904
2025-04-17 15:18:58,049 - INFO - Processing batch 370/512...
2025-04-17 15:19:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (67.23), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.22 and 2.14), falling within the 1-3 range. Ligand B is slightly more lipophilic.

**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 (0.75 and 0.91), indicating drug-like properties.

**DILI:** Ligand A (15.2%) has a significantly lower DILI risk than Ligand B (18.1%). This is a substantial advantage.

**BBB:** Ligand A (63.01%) has a higher BBB penetration score than Ligand B (52.81%), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.064) shows better Caco-2 permeability than Ligand B (-4.709), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.188) has better aqueous solubility than Ligand B (-1.447). This is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.15 and 0.244), which is good.

**Microsomal Clearance:** Ligand A (-3.626) has significantly lower microsomal clearance than Ligand B (39.303). This indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-3.962) has a longer in vitro half-life than Ligand B (-5.405), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.022 and 0.038).

**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 significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It exhibits a significantly better binding affinity, lower DILI risk, better solubility, and substantially improved metabolic stability (lower Cl_mic and longer t1/2) compared to Ligand B. While both ligands have acceptable overall profiles, the combination of potency and favorable ADME properties makes Ligand A the more promising drug candidate for targeting SRC kinase.

Output:
1
2025-04-17 15:19:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.487 and 383.279 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (97.39) is slightly higher than Ligand B (83.06), but both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.389) is within the optimal range (1-3). Ligand B (4.07) is at the upper end of the acceptable range and 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 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.649) has a better QED score than Ligand B (0.384), indicating a more drug-like profile.

**DILI:** Ligand A (38.077) has a slightly higher DILI risk than Ligand B (33.463), but both are below the concerning threshold of 60.

**BBB:** Ligand A (61.38) has a lower BBB penetration score than Ligand B (88.329). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.752) has a worse Caco-2 permeability than Ligand B (-4.922). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.421) has a better aqueous solubility than Ligand B (-4.808). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.197) has a much lower hERG inhibition liability than Ligand B (0.892), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (55.273) has a higher microsomal clearance than Ligand B (21.015), meaning it's less metabolically stable. This is a significant drawback.

**In vitro Half-Life:** Ligand A (-50.562) has a much shorter in vitro half-life than Ligand B (10.175), further reinforcing the metabolic instability concern.

**P-gp Efflux:** Ligand A (0.027) has a lower P-gp efflux liability than Ligand B (0.332), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME liabilities of Ligand B.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. Ligand B has a higher logP, significantly worse metabolic stability (higher Cl_mic, shorter t1/2), and a higher hERG risk. Ligand A, while not perfect, has a better QED score, lower hERG risk, better solubility, and lower P-gp efflux. The metabolic instability of Ligand A is a concern, but it might be addressable through structural modifications, whereas the combination of issues with Ligand B makes it a less attractive starting point.

Output:
0
2025-04-17 15:19:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.334 and 349.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.05) is slightly above the preferred <140, but acceptable. Ligand B (88.91) is excellent, well below 140.

**3. logP:** Ligand A (0.196) is quite low, potentially hindering permeability. Ligand B (1.585) 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, also within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values > 0.7, indicating good drug-like properties. Ligand A (0.823) is slightly better than Ligand B (0.708).

**7. DILI:** Ligand A (69.756) has a higher DILI risk than Ligand B (27.995). This is a significant concern.

**8. BBB:** Both ligands have moderate BBB penetration, with Ligand B (70.57) being slightly better than Ligand A (55.603). BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.913 and -4.971), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.983 and -2.012), also unusual and concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.29 and 0.048), which is excellent.

**12. Microsomal Clearance:** Ligand A (-15.203) has a much lower (better) microsomal clearance than Ligand B (34.637), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.238) has a longer (better) in vitro half-life than Ligand B (-8.41).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.025).

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.6 and -9.4 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B has a better logP, TPSA, and binding affinity. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The negative Caco-2 and solubility values are concerning for both, but the superior metabolic stability and lower DILI risk of Ligand A, combined with its strong binding affinity, make it the slightly more promising candidate. The poor permeability and solubility would need to be addressed through formulation or structural modifications, but these are potentially surmountable. The higher DILI risk of Ligand A is a concern, but it is less severe than the permeability issues with Ligand B.

Output:
0
2025-04-17 15:19:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (369.29 Da and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (84.22 and 89.87) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.456) is optimal, while Ligand B (0.829) is slightly 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:** Both ligands (4) are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.781 and 0.655) have good drug-like properties (>=0.5).

**7. DILI:** Ligand A (63.862) has a moderate DILI risk, while Ligand B (8.918) has a very low DILI risk, which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (67.623) is slightly better than Ligand B (52.617).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.095 and -5.04), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.817 and -1.387), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.057) has a very low hERG risk, while Ligand B (0.175) has a slightly higher, but still acceptable, risk.

**12. Microsomal Clearance:** Ligand A (-5.151) has a much lower (better) microsomal clearance than Ligand B (-0.986), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.346) has a significantly longer in vitro half-life than Ligand B (-3.966), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.03).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). The difference is 0.9 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is preferable due to its superior metabolic stability (lower Cl_mic, longer t1/2) and significantly lower DILI risk. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies. The slightly better affinity of Ligand B is not enough to overcome the higher DILI and lower metabolic stability.

Output:
0
2025-04-17 15:19:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (335.447 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.4) is significantly better than Ligand B (82.78). Lower TPSA generally favors better cell permeability, which is important for kinase inhibitors.

**logP:** Ligand A (4.641) is higher than Ligand B (2.123). While both are within the acceptable range (1-3 is optimal, up to 4 is tolerable), Ligand A is approaching the upper limit.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED values (0.69 and 0.82), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (34.626 and 36.06).

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (63.164) than Ligand A (35.052), but this is less important.

**Caco-2 Permeability:** Ligand A (-5.042) has a worse Caco-2 permeability than Ligand B (-4.624).

**Aqueous Solubility:** Ligand A (-4.127) has worse aqueous solubility than Ligand B (-2.908). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.959) has a slightly higher hERG risk than Ligand B (0.299). Lower hERG is preferred.

**Microsomal Clearance:** Ligand B (26.081) has a significantly lower microsomal clearance than Ligand A (33.345). Lower clearance indicates better metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (64.209) has a slightly longer in vitro half-life than Ligand A (68.278).

**P-gp Efflux:** Ligand A (0.865) has a slightly higher P-gp efflux than Ligand B (0.176). Lower efflux is preferred.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are strong binders, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the more promising candidate. It has better metabolic stability (lower Cl_mic), better solubility, lower hERG risk, and a slightly better binding affinity. While Ligand A has a lower TPSA, the benefits of Ligand B's improved ADME properties and potency outweigh this advantage. The solubility and permeability issues with Ligand A are also concerning.

Output:
1
2025-04-17 15:19:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.566 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (58.64) is still under 140, but less optimal than A.

**logP:** Ligand A (3.599) is within the optimal 1-3 range. Ligand B (2.37) is also acceptable, but slightly lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 HBA, both favorable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.684 and 0.768, respectively), indicating drug-like properties.

**DILI:** Ligand A (36.448) has a low DILI risk, well below the 40 threshold. Ligand B (14.23) is even lower, indicating very low liver injury risk.

**BBB:** Both ligands have high BBB penetration (93.137 and 82.202), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.551 and -4.732). This is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, given the other parameters, we'll proceed with caution and assume these values are not entirely reliable.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.512 and -2.467), which is also concerning. Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.755) shows slightly higher hERG inhibition risk than Ligand B (0.482), but both are relatively low.

**Microsomal Clearance:** Ligand A (82.024) has a higher microsomal clearance than Ligand B (40.087). This suggests Ligand B is more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (6.992) has a longer half-life than Ligand B (3.48), which is desirable.

**P-gp Efflux:** Ligand A (0.483) has slightly higher P-gp efflux than Ligand B (0.083), meaning B is less likely to be pumped out of cells.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity, a longer half-life, and acceptable DILI and hERG risks. However, it has higher microsomal clearance and slightly higher P-gp efflux. Ligand B has better metabolic stability, lower P-gp efflux, and lower DILI, but its binding affinity is extremely weak. The negative solubility and Caco-2 values are concerning for both.

Given the priority for potency in kinase inhibitors, the significantly stronger binding affinity of Ligand A (-7.3 kcal/mol vs -0.0 kcal/mol) is the deciding factor. While Ligand B has better ADME properties in some areas, a weak binding affinity makes it unlikely to be effective. The solubility and permeability issues could be addressed through formulation or further chemical modifications, but a weak binder is much harder to fix.

Output:
1
2025-04-17 15:19:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (476.384 Da) is higher, but still acceptable. Ligand B (371.373 Da) is preferable.

**TPSA:** Ligand A (66.49) is good, below the 140 threshold for oral absorption. Ligand B (115.16) is higher, but still within a reasonable range.

**logP:** Ligand A (3.538) is optimal. Ligand B (1.228) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is acceptable.

**QED:** Both ligands have acceptable QED values (A: 0.512, B: 0.44), indicating reasonable drug-likeness.

**DILI:** Ligand A (44.63) has a better DILI score than Ligand B (63.164), indicating a lower risk of liver injury.

**BBB:** Both ligands have good BBB penetration (A: 70.88, B: 67.972), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.031 and -5.028), 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 very poor aqueous solubility (-4.368 and -1.544). This is a significant concern.

**hERG Inhibition:** Ligand A (0.754) has a lower hERG risk than Ligand B (0.092), which is a major advantage.

**Microsomal Clearance:** Ligand A (51.456) has a higher clearance than Ligand B (5.81), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (44.906) has a longer half-life than Ligand B (-1.538), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.588) has a lower P-gp efflux liability than Ligand B (0.043), which is preferable.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive advantage, as potency is a primary concern for enzyme inhibitors. The 7.1 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both compounds, Ligand A is the more promising candidate. Its significantly higher binding affinity (-7.1 vs 0.0 kcal/mol) outweighs its drawbacks (higher Cl_mic). The lower hERG risk and better DILI score further support this conclusion. While solubility needs to be addressed, the potency advantage of Ligand A is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:19:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.362 and 364.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.46) is better than Ligand B (132.89). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (1.717) is within the optimal 1-3 range. Ligand B (-0.12) is below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (4) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both acceptable, being less than 10.

**QED:** Ligand A (0.706) is better than Ligand B (0.541), indicating a more drug-like profile.

**DILI:** Ligand B (62.35) has a higher DILI risk than Ligand A (52.617), though both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (44.242) is better than Ligand B (15.432).

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.231) has a significantly lower hERG risk than Ligand B (0.109), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (7.35) has a much lower Cl_mic than Ligand B (-25.983), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.727) has a better half-life than Ligand B (-13.284).

**P-gp Efflux:** Both are very low, indicating high efflux.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a slightly better binding affinity than Ligand B (-9.8 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has better TPSA, logP, QED, hERG risk, metabolic stability (Cl_mic and t1/2), and binding affinity. While both have poor Caco-2 and solubility, the improved ADME profile and slightly better potency of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 15:19:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (356.394 Da) is also good.

**TPSA:** Ligand A (38.77) is significantly better than Ligand B (104.73). A TPSA under 140 is good for oral absorption, but lower is generally preferred for enzymes. Ligand A is much more favorable here.

**logP:** Ligand A (4.071) is at the upper end of the optimal range (1-3), potentially leading to solubility issues, but still acceptable. Ligand B (0.348) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.787) has a much better QED score than Ligand B (0.47), indicating a more drug-like profile.

**DILI:** Ligand A (45.522) has a lower DILI risk than Ligand B (22.218), suggesting better liver safety.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (83.521) is higher than Ligand B (67.352).

**Caco-2 Permeability:** Ligand A (-4.403) is significantly worse than Ligand B (-5.028), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-6.192) is better than Ligand B (-1.968). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.946) has a slightly higher hERG risk than Ligand B (0.29), but both are relatively low.

**Microsomal Clearance:** Ligand A (127.444) has a higher clearance than Ligand B (31.331), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (19.634) has a much longer half-life than Ligand A (-15.466). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.616) is better than Ligand B (0.018), meaning less efflux and potentially better bioavailability.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly better 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 significantly better binding affinity and a better QED score, DILI, solubility, and P-gp efflux. However, it suffers from poor metabolic stability (high Cl_mic, short half-life) and lower Caco-2 permeability. Ligand B has better metabolic stability, permeability, and half-life, but its binding affinity is weaker, and its QED is lower.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, hERG), the strong binding affinity of Ligand A is a major advantage. While its metabolic stability is a concern, it might be addressable through structural modifications. The weaker binding affinity of Ligand B is a more difficult issue to overcome.

Output:
1
2025-04-17 15:19:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (474.172 Da) is within the ideal range, while Ligand B (363.483 Da) is towards the lower end, but still acceptable.

**TPSA:** Ligand A (59.81) is good for oral absorption. Ligand B (78.51) is higher, potentially impacting absorption, but not drastically.

**logP:** Ligand A (4.794) is slightly high, potentially leading to solubility issues and off-target effects. Ligand B (1.666) is optimal.

**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 (4) are both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.655, B: 0.755), indicating drug-like properties.

**DILI:** Ligand A (64.599) has a higher DILI risk than Ligand B (36.681), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.288) is higher than Ligand B (56.689).

**Caco-2 Permeability:** Ligand A (-4.817) has poor permeability, while Ligand B (-5.393) also has poor permeability.

**Aqueous Solubility:** Ligand A (-5.671) has very poor solubility, which is a major drawback. Ligand B (-1.85) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.537) has a slightly elevated hERG risk, while Ligand B (0.196) has a very low risk.

**Microsomal Clearance:** Ligand A (42.336) has lower clearance, suggesting better metabolic stability than Ligand B (52.858).

**In vitro Half-Life:** Ligand A (71.344) has a longer half-life than Ligand B (14.953), which is desirable.

**P-gp Efflux:** Ligand A (0.662) has moderate P-gp efflux, while Ligand B (0.066) has very low efflux, which is beneficial.

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Conclusion:**

Despite Ligand A having better metabolic stability and half-life, the significantly higher DILI risk, poor solubility, and weaker binding affinity make it a less attractive candidate. Ligand B's superior binding affinity, lower DILI risk, and lower P-gp efflux outweigh its slightly higher clearance and lower half-life. The solubility is still a concern, but potentially addressable through formulation strategies.

Output:
1
2025-04-17 15:19:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.913 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (86.88). Lower TPSA generally favors better absorption, which is important for oral bioavailability.

**logP:** Both ligands have acceptable logP values (Ligand A: 3.485, Ligand B: 2.137), falling within the optimal range of 1-3.

**H-Bond Donors & Acceptors:** Ligand A (HBD=0, HBA=3) is preferable to Ligand B (HBD=3, HBA=3). Fewer H-bond donors are generally better for permeability.

**QED:** Both ligands have similar QED values (Ligand A: 0.74, Ligand B: 0.641), indicating good drug-like properties.

**DILI:** Ligand A (44.009) has a slightly higher DILI risk than Ligand B (26.755), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.966) has better BBB penetration than Ligand B (56.96), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.604) shows better Caco-2 permeability than Ligand B (-5.341).

**Aqueous Solubility:** Ligand A (-4.389) has better aqueous solubility than Ligand B (-2.946). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.604) has a slightly higher hERG risk than Ligand B (0.365), but both are reasonably low.

**Microsomal Clearance:** Ligand B (30.213) has significantly lower microsomal clearance than Ligand A (60.279), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-19.273) has a longer in vitro half-life than Ligand A (19.605). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.107, Ligand B: 0.123).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While both are excellent, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better TPSA and solubility, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. The improved metabolic stability and binding are more critical for an enzyme target like SRC kinase. The differences in DILI and hERG are minor.

Output:
1
2025-04-17 15:19:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.355 and 357.405 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.6) is slightly higher than Ligand B (79.38). Both are below the 140 threshold for good oral absorption, but Ligand B is better.

**logP:** Ligand A (-0.907) is a bit low, potentially hindering permeation. Ligand B (1.363) 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 2 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.702 and 0.767), indicating good drug-like properties.

**DILI:** Ligand A (52.462) has a slightly higher DILI risk than Ligand B (38.62), though both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (86.274) has a higher BBB score than Ligand A (53.121), but this is not a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.581 and -4.828). This is unusual and suggests poor permeability. However, the values are very close.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.272 and -2.291). This is also concerning, indicating poor solubility. Again, the values are very similar.

**hERG Inhibition:** Ligand A (0.124) has a lower hERG inhibition liability than Ligand B (0.486), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-20.914) has *much* lower microsomal clearance than Ligand B (4.774). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-28.28) has a longer in vitro half-life than Ligand B (-11.805), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.018).

**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 substantial.

**Overall Assessment:**

While Ligand B has a better logP and slightly better binding affinity, Ligand A demonstrates superior ADMET properties, particularly regarding metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. The negative Caco-2 and solubility values are concerning for both, but the substantial difference in metabolic stability and hERG risk outweighs the small advantage in binding affinity for Ligand B. Given the enzyme-specific priorities, metabolic stability and safety (hERG) are crucial.

Output:
0
2025-04-17 15:19:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.397 and 364.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is well below the 140 threshold and excellent for oral absorption. Ligand B (89.07) is still acceptable, but less optimal.

**logP:** Ligand A (3.16) is within the optimal 1-3 range. Ligand B (1.134) is slightly low, potentially hindering permeation, but not drastically.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 8 HBA. Both are acceptable, but Ligand A is preferable.

**QED:** Both ligands have good QED scores (0.927 and 0.8), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (63.086 and 60.954), below the concerning threshold of 60.

**BBB:** Ligand A (93.563) shows excellent BBB penetration, while Ligand B (52.772) is lower. While SRC is not a CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.582) and Ligand B (-5.279) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-4.24) and Ligand B (-1.643) both have negative solubility values, which is also a concern. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.677) has a lower hERG risk than Ligand B (0.114), which is preferable.

**Microsomal Clearance:** Ligand A (35.407) has a significantly lower Cl_mic than Ligand B (11.001), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (19.274) has a longer half-life than Ligand B (10.377), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.234) has lower P-gp efflux than Ligand B (0.203), which is slightly better.

**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 could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B's significantly stronger binding affinity (-8.8 kcal/mol vs -7.7 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The better metabolic stability of Ligand A is appealing, but the potency difference is likely to be more impactful. The hERG risk is also lower for Ligand A. However, the binding affinity difference is large enough to favor Ligand B, assuming that solubility and permeability issues can be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 15:19:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is significantly better than Ligand B (98.92), being well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.533 and 2.378), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 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 QED values (0.782 and 0.713), indicating good drug-likeness.

**DILI:** Ligand A (20.008 percentile) has a much lower DILI risk than Ligand B (66.421 percentile). This is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (47.615) is better than Ligand B (36.409).

**Caco-2 Permeability:** Ligand A (-4.587) is better than Ligand B (-5.178), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.569) is significantly more soluble than Ligand B (-3.541). This is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.648 and 0.369), which is good.

**Microsomal Clearance:** Ligand A (36.25 mL/min/kg) has a higher clearance than Ligand B (21.441 mL/min/kg), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (40.513 hours) has a longer half-life than Ligand B (27.419 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.359 and 0.229).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). However, the difference is not substantial enough to outweigh the significant advantages of Ligand A in other key ADME properties.

**Overall:** Ligand A presents a more balanced profile with significantly lower DILI risk, better solubility, and a longer half-life. While Ligand B has slightly better binding affinity, the superior ADME properties of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 15:19:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 351.403 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.32) is better than Ligand B (111.99). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (1.641) is better than Ligand B (0.155). Ligand B is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (3).

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6).

**QED:** Ligand A (0.794) is significantly better than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Ligand A (40.287) is slightly higher than Ligand B (33.346), but both are acceptable.

**BBB:** Ligand A (52.966) is better than Ligand B (17.72), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.789) is better than Ligand B (-5.118), indicating better intestinal absorption.

**Solubility:** Ligand A (-3.089) is better than Ligand B (-1.127). Solubility is important for bioavailability.

**hERG:** Ligand A (0.254) is better than Ligand B (0.187). Both are low, which is good.

**Microsomal Clearance:** Ligand A (-10.973) is significantly better than Ligand B (-13.955), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.561) is better than Ligand B (-12.02), indicating a longer half-life.

**P-gp efflux:** Ligand A (0.034) is better than Ligand B (0.008).

**Binding Affinity:** Ligand B (-8.8) is significantly better than Ligand A (-5.9). This is a 1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has superior ADME properties across the board (better TPSA, logP, QED, solubility, metabolic stability, half-life, and P-gp efflux), Ligand B boasts a substantially stronger binding affinity (-8.8 kcal/mol vs -5.9 kcal/mol). Given that we are targeting a kinase (enzyme class), potency is paramount. The 2.9 kcal/mol difference in binding affinity is substantial enough to overcome the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 15:19:39,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (351.455 and 354.51 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (120.24) is better than Ligand B (40.62) as it is closer to the threshold of 140.

**3. logP:** Ligand A (-0.235) is slightly low, potentially hindering permeation. Ligand B (3.933) is within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 3, Ligand B: 0).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (Ligand A: 6, Ligand B: 2).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.595, Ligand B: 0.65), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (Ligand A: 26.444, Ligand B: 29.081), below the 40 threshold.

**8. BBB:** Ligand B (97.053) has significantly better BBB penetration than Ligand A (41.373). However, BBB penetration is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Ligand A (-5.82) is very poor, while Ligand B (-4.461) is also poor, but better than A.

**10. Aqueous Solubility:** Ligand A (-1.687) is poor, while Ligand B (-4.189) is also poor.

**11. hERG Inhibition:** Ligand A (0.07) has a very low hERG risk, while Ligand B (0.911) has a slightly higher, but still acceptable risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-15.012) has a much lower (better) clearance than Ligand B (64.726), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.892) has a longer half-life than Ligand B (2.603).

**14. P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, while Ligand B (0.846) has higher efflux.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This >1.5 kcal/mol difference is substantial.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has superior affinity, but suffers from higher clearance and lower half-life. Ligand A has better metabolic stability, lower hERG risk, and lower P-gp efflux, but its affinity is weaker and Caco-2 permeability and solubility are poor. The difference in binding affinity is significant enough to outweigh the ADME drawbacks of Ligand B, especially considering that formulation strategies can sometimes mitigate solubility issues.

Output:
1
2025-04-17 15:19:39,356 - INFO - Batch 370 complete. Total preferences: 5920
2025-04-17 15:19:39,356 - INFO - Processing batch 371/512...
2025-04-17 15:20:19,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.38 and 358.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.15) is better than Ligand B (58.64) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (-0.421) is slightly low, potentially hindering permeation, while Ligand B (3.073) is optimal.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit.

**QED:** Both ligands have good QED scores (0.547 and 0.761), indicating drug-like properties.

**DILI:** Ligand A (15.36) has a significantly lower DILI risk than Ligand B (30.32). This is a major advantage.

**BBB:** Ligand B (91.39) shows much better BBB penetration than Ligand A (54.44), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.542) has a negative Caco-2 value, which is concerning, while Ligand B (-4.257) is also low, but less so.

**Aqueous Solubility:** Ligand A (-1.407) has better aqueous solubility than Ligand B (-3.496). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.287) has a lower hERG risk than Ligand B (0.681), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (7.289) has a much lower microsomal clearance than Ligand B (46.709), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.806) has a much longer in vitro half-life than Ligand B (3.53). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux than Ligand B (0.16).

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is small (0.2 kcal/mol), and other factors are more important.

**Overall Assessment:**

Ligand A is superior despite slightly lower affinity. It exhibits significantly better DILI risk, hERG inhibition, metabolic stability (lower Cl_mic, longer t1/2), solubility, and P-gp efflux. While Ligand B has a slightly better logP and BBB penetration, these are less critical for a non-CNS kinase target. The negative Caco-2 value for Ligand A is a concern, but the other advantages outweigh this drawback.

Output:
0
2025-04-17 15:20:19,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.411 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.72 and 76.02) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.104 and 2.744) are 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:** Both ligands have good QED scores (0.749 and 0.682), indicating drug-like properties.

**DILI:** Ligand A (54.052) has a higher DILI risk than Ligand B (30.787). This is a significant concern.

**BBB:** Ligand A (38.193) has a lower BBB penetration percentile than Ligand B (75.107). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.1 and -4.851). 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 ligands have negative solubility values (-2.799 and -2.85). This is also concerning, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.233 and 0.606).

**Microsomal Clearance:** Ligand A (8.355 mL/min/kg) has significantly lower microsomal clearance than Ligand B (67.24 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-22.107 hours) has a longer in vitro half-life than Ligand B (-19.029 hours).

**P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux than Ligand B (0.423), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is not substantial (0.4 kcal/mol).

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The primary driver is the significantly lower DILI risk (54.052 vs 30.787) and better metabolic stability (lower Cl_mic and longer t1/2). The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The slightly better P-gp efflux of Ligand A is also a plus. The small difference in binding affinity is outweighed by the ADME/Tox advantages of Ligand A.

Output:
1
2025-04-17 15:20:19,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.535 and 364.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is well below the 140 threshold and favorable for oral absorption. Ligand B (78.87) is still below 140, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (2.77) is optimal (1-3). Ligand B (1.493) is at the lower end of optimal, potentially causing permeability issues, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 4 HBA) is also good, within the acceptable limits.

**QED:** Both ligands have good QED scores (0.569 and 0.725), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (11.632 and 12.136), which is favorable.

**BBB:** Both ligands have reasonable BBB penetration (75.727 and 87.864), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.607 and -4.727). This is unusual and suggests a potential issue with in vitro permeability assessment or a calculation error. However, given the other favorable properties, this is not a dealbreaker at this stage.

**Aqueous Solubility:** Both have negative solubility values (-1.397 and -1.751). This is also unusual and warrants further investigation. Poor solubility can hinder bioavailability.

**hERG:** Both ligands have very low hERG risk (0.765 and 0.275), which is excellent.

**Microsomal Clearance:** Ligand A (48.438) has a moderate clearance, while Ligand B (3.403) has very low clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (20.593 hours) has a good half-life. Ligand B (-33.786 hours) has a negative half-life, which is impossible and indicates a problem with the data.

**P-gp Efflux:** Both have low P-gp efflux (0.274 and 0.022), which is favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh minor ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -7.6 kcal/mol) and substantially improved metabolic stability (lower Cl_mic) are critical advantages for an enzyme inhibitor. The lower P-gp efflux is also beneficial. The negative half-life for Ligand B is a major concern and needs to be investigated, but the other factors point towards it being a better starting point for optimization.

Output:
1
2025-04-17 15:20:19,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.356 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.26) is well below the 140 threshold and excellent for absorption. Ligand B (79.38) is still acceptable, but less optimal.

**logP:** Ligand A (3.726) is at the upper end of the optimal range (1-3), while Ligand B (2.013) is closer to the lower end. Both are acceptable, but Ligand A's higher logP *could* lead to off-target effects, which needs consideration.

**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 (0.756 and 0.871), indicating good drug-like properties.

**DILI:** Ligand A (23.653) has a significantly lower DILI risk than Ligand B (51.028), a major advantage.

**BBB:** Both have high BBB penetration, but Ligand A (95.618) is better than Ligand B (88.445). While not a primary concern for a kinase inhibitor, it's a positive attribute.

**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 negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.369) has a very low hERG risk, while Ligand B (0.61) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (53.551) has lower microsomal clearance than Ligand B (63.28), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.33) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (11.466) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.523) has lower P-gp efflux than Ligand B (0.039), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-0.0) has significantly weaker binding affinity compared to Ligand B (-9.5). This is the most critical difference. A 9.5 kcal/mol advantage is substantial and likely outweighs many of the other drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand B's substantially superior binding affinity (-9.5 kcal/mol vs -0.0 kcal/mol) is the deciding factor. The improved half-life and lower P-gp efflux are also beneficial. While Ligand A has a better DILI score and hERG profile, potency is paramount for kinase inhibitors. The poor solubility and permeability would need to be addressed through formulation strategies, but the strong binding affinity of Ligand B provides a much better starting point for optimization. The negative half-life for Ligand A is also a data quality issue.

Output:
1
2025-04-17 15:20:19,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.328 Da) is slightly higher than Ligand B (342.483 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (71.53) is higher than Ligand B (58.2), but both are reasonable.

**logP:** Both ligands have logP values within the optimal range (1-3), at 3.247 and 3.463 respectively.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness (0.806 for A and 0.711 for B).

**DILI:** Both ligands have low DILI risk, with percentiles of 33.695 and 35.789, respectively. Both are well below the concerning threshold of 60.

**BBB:** Ligand A has a higher BBB penetration percentile (83.211) than Ligand B (71.733). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.339) is slightly better than Ligand B (-4.798).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-3.207) is slightly better than Ligand B (-4.001).

**hERG:** Both ligands have very low hERG inhibition liability (0.164 and 0.469), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (73.477 and 74.091), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A has a positive half-life (20.941 hours) while Ligand B has a negative half-life (-2.439 hours). This is a significant difference, suggesting Ligand A is much more metabolically stable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.478), which is favorable.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.8 kcal/mol) compared to Ligand A (-7.6 kcal/mol). This is a difference of 2.2 kcal/mol, which is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has a better in vitro half-life and slightly better solubility and Caco-2 permeability, the significantly stronger binding affinity of Ligand B (-9.8 kcal/mol vs -7.6 kcal/mol) is the most critical factor for an enzyme inhibitor. The difference in binding affinity is large enough to compensate for the slightly less favorable ADME properties of Ligand B. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 15:20:19,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.442 and 360.885 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.87) is better than Ligand B (42.43), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.45) is suboptimal, potentially hindering permeation. Ligand B (4.011) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is better than Ligand B (0 HBD, 3 HBA) as it is closer to the ideal range.

**QED:** Both ligands have good QED scores (0.667 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (63.513) has a higher DILI risk than Ligand B (31.989). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (77.007 and 77.743). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.548 and -4.896), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.981 and -3.946), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.036) has a very low hERG risk, which is excellent. Ligand B (0.71) is higher, posing a potential cardiotoxicity concern.

**Microsomal Clearance:** Ligand A (7.841) has significantly lower microsomal clearance than Ligand B (69.287), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.846) has a negative half-life, which is not realistic. Ligand B (2.517) has a very short half-life, which is undesirable.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.422), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (0.0). This is a crucial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better metabolic stability (lower Cl_mic), lower P-gp efflux, and a very low hERG risk. However, it suffers from poor logP, poor solubility, and a higher DILI risk. Ligand B has a better logP and lower DILI, but its binding affinity is very weak, and it has poor metabolic stability.

Given that potency (affinity) and metabolic stability are the highest priorities for enzyme inhibitors, and the substantial difference in binding affinity (-8.1 vs 0.0 kcal/mol), Ligand A is the more promising candidate *despite* its drawbacks. The poor solubility and logP could potentially be addressed through formulation or further chemical modifications. The DILI risk is concerning, but might be mitigated with further optimization. The negative half-life for ligand A is a data error and should be investigated.

Output:
1
2025-04-17 15:20:19,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (371.405 and 354.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.63) is well below the 140 threshold, and even better, below 90, suggesting good absorption. Ligand B (85.89) is still under 140, but less optimal than A.

**3. logP:** Ligand A (2.99) is within the optimal 1-3 range. Ligand B (0.618) 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 (A: 5, B: 5) are below the 10 threshold.

**6. QED:** Both ligands (A: 0.773, B: 0.73) have good drug-like scores, exceeding 0.5.

**7. DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (37.185). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (A: 75.843, B: 71.733), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and likely indicates a problem with the data or the model. However, we can still compare them relative to each other. A value closer to 0 is better. Ligand A (-4.968) is slightly better than Ligand B (-4.89).

**10. Solubility:** Both ligands have negative solubility values, again suggesting a data issue. Ligand B (-1.359) is slightly better than Ligand A (-2.997).

**11. hERG:** Ligand A (0.811) has a slightly higher hERG risk than Ligand B (0.176). This is a positive for Ligand B.

**12. Cl_mic:** Ligand A (18.741) has a higher microsomal clearance than Ligand B (2.306), indicating lower metabolic stability. This is a significant negative for Ligand A.

**13. t1/2:** Ligand B (15.665) has a longer in vitro half-life than Ligand A (12.198), which is desirable.

**14. Pgp:** Ligand A (0.346) has lower P-gp efflux than Ligand B (0.027), which is favorable.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with solubility and Caco-2 permeability (likely data related), Ligand B demonstrates superior potency (binding affinity), metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG risk. The slightly lower logP of Ligand B is a minor concern, but the strong affinity and improved safety profile outweigh this.

Output:
1
2025-04-17 15:20:19,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.435 and 388.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.7 and 103.95) are slightly above the optimal <140 for oral absorption, but acceptable.

**logP:** Ligand A (1.156) is slightly lower than optimal (1-3), while Ligand B (2.222) is within the ideal range. This gives a slight edge to Ligand B regarding permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.667) has a better QED score than Ligand B (0.573), indicating a more drug-like profile.

**DILI:** Ligand A (48.662) has a significantly lower DILI risk than Ligand B (83.792). This is a major advantage for Ligand A.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility. This is a significant concern for both, but the values are similar.

**hERG Inhibition:** Ligand A (0.065) has a much lower hERG inhibition liability than Ligand B (0.632). This is a critical advantage for Ligand A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (6.437 mL/min/kg) has a lower microsomal clearance than Ligand B (46.708 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.668 hours) has a significantly longer half-life than Ligand B (1.776 hours), which is highly desirable for dosing convenience.

**P-gp Efflux:** Ligand A (0.015) has much lower P-gp efflux liability than Ligand B (0.302), suggesting better oral bioavailability.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While a difference of 1.1 kcal/mol is good, the other ADME properties of Ligand A are much more favorable.

**Overall Assessment:**

Ligand A demonstrates a significantly better ADME profile than Ligand B. It has lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a better QED score. While Ligand B has a slightly better binding affinity, the substantial improvements in ADME properties for Ligand A outweigh this difference, especially considering the acceptable affinity 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 15:20:19,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (346.402 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.33) is higher than Ligand B (47.1). Both are below the 140 threshold for oral absorption, but lower is generally better. Ligand B is preferable here.

**logP:** Ligand A (3.179) is optimal, while Ligand B (0.482) is quite low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as a single donor can aid solubility without significantly impacting permeability.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range.

**QED:** Ligand A (0.838) has a higher QED score than Ligand B (0.64), indicating better overall drug-likeness.

**DILI:** Ligand B (3.296) has a much lower DILI risk than Ligand A (55.021). This is a substantial advantage for Ligand B.

**BBB:** Ligand A (75.107) has a good BBB percentile, while Ligand B (90.074) is even better. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.912) is slightly worse than Ligand A (-4.542).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.91) is slightly better than Ligand B (-0.576).

**hERG Inhibition:** Ligand A (0.66) has a slightly higher hERG risk than Ligand B (0.621), but both are relatively low.

**Microsomal Clearance:** Ligand B (21.551) has significantly lower microsomal clearance than Ligand A (43.848), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-11.213) has a negative half-life, which is not physically possible and indicates a very rapid degradation. Ligand A (29.443) has a reasonable half-life. This is a major drawback for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.246 and 0.01 respectively).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity and lower DILI risk, and better metabolic stability. However, it has a very poor in vitro half-life and low logP. Ligand A has a better QED, half-life, and logP, but a higher DILI risk.

Given that SRC is a kinase, potency (binding affinity) and metabolic stability are paramount. The 1.1 kcal/mol difference in binding affinity is significant. While the negative half-life of Ligand B is concerning, it might be addressable through structural modifications. The low logP is also a concern, but potentially manageable. The lower DILI risk is also a strong positive.

Output:
1
2025-04-17 15:20:19,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.463 and 353.507 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.02) is slightly higher than Ligand B (72.88), but both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have optimal logP values (1.615 and 1.399), 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 5 HBA, and Ligand B has 4. Both are below the 10 limit.

**6. QED:** Both ligands have similar QED scores (0.659 and 0.615), indicating good drug-likeness.

**7. DILI:** Ligand B (4.382) has a significantly lower DILI risk than Ligand A (19.581). This is a major advantage for Ligand B.

**8. BBB:** Ligand A (67.39) has a slightly better BBB penetration than Ligand B (54.013), but BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Ligand A (-4.809) and Ligand B (-4.939) have similar Caco-2 permeability values, suggesting comparable intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.596) and Ligand B (-1.23) have similar aqueous solubility values, suggesting comparable solubility.

**11. hERG Inhibition:** Ligand A (0.159) has a slightly lower hERG inhibition liability than Ligand B (0.298), which is preferable.

**12. Microsomal Clearance:** Ligand B (11.272) has a significantly lower microsomal clearance than Ligand A (33.238). This indicates better metabolic stability for Ligand B, a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (11.969) has a much longer in vitro half-life than Ligand A (-1.615). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.024 and 0.037).

**15. Binding Affinity:** Ligand A (-8.3 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, and can be outweighed by other factors.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and hERG profile, Ligand B demonstrates superior ADME properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life. For an enzyme like SRC kinase, metabolic stability and minimizing toxicity (DILI) are crucial. The modest difference in binding affinity is less important than these factors.

Output:
1
2025-04-17 15:20:19,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.75 and 355.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.25) is well below the 140 threshold, while Ligand B (116.48) is still acceptable but closer to the limit.

**logP:** Ligand A (3.481) is optimal (1-3), while Ligand B (-2.205) is significantly lower, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (8) are both within the acceptable limit of 10.

**QED:** Ligand A (0.863) has a much better QED score than Ligand B (0.594), indicating a more drug-like profile.

**DILI:** Ligand A (84.529) has a higher DILI risk than Ligand B (38.813), which is a concern. However, the difference isn't drastic.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.627) is higher than Ligand B (34.005).

**Caco-2 Permeability:** Ligand A (-4.525) and Ligand B (-5.631) both have negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-4.262) and Ligand B (-0.381) both have negative values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.132) has a very low hERG risk, while Ligand B (0.033) is even lower, both are excellent.

**Microsomal Clearance:** Ligand A (73.106) has a higher Cl_mic, indicating faster metabolism, while Ligand B (-20.253) has a negative value, suggesting very high metabolic stability.

**In vitro Half-Life:** Ligand A (-15.964) has a negative half-life, which is not possible. Ligand B (-0.918) is also negative, which is also not possible.

**P-gp Efflux:** Ligand A (0.19) and Ligand B (0.005) both have low P-gp efflux liability.

**Binding Affinity:** Ligand A (-10.2 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.

**Conclusion:**

Despite Ligand A's higher DILI risk and questionable solubility, its significantly superior binding affinity (-10.2 vs -7.9 kcal/mol) and better QED score make it the more promising candidate. The large affinity difference is a major advantage for an enzyme target like SRC kinase. The negative values for Caco-2 permeability and solubility are concerning and would need further investigation, but the strong binding is a compelling factor.

Output:
1
2025-04-17 15:20:19,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 347.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.83) is well below the 140 threshold for oral absorption, while Ligand B (99.77) is still acceptable but less optimal.

**logP:** Both ligands (1.197 and 1.715) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, fitting the <5 and <10 guidelines respectively.

**QED:** Both ligands have similar QED values (0.77 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (53.432). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (67.39) is better than Ligand B (51.183).

**Caco-2 Permeability:** Both have negative values (-5.088 and -5.217), 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 (-1.549 and -2.954) which, similar to Caco-2, is difficult to interpret without knowing the scale. Ligand B appears slightly worse.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.511 and 0.454), which is positive.

**Microsomal Clearance:** Ligand A (-17.78) exhibits *much* lower microsomal clearance than Ligand B (23.913). This suggests significantly better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (13.973) has a considerably longer in vitro half-life than Ligand B (4.321). This further supports its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.041 and 0.016).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This difference of 1.6 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both ligands meet many of the basic drug-likeness criteria, Ligand A excels in the most critical areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a substantially stronger binding affinity. The Caco-2 and solubility values are concerning for both, but the superior potency and metabolic profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 15:20:19,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.418 and 345.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.63) is better than Ligand B (66.4) and both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (2.323) is optimal (1-3), while Ligand B (4.48) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), below the threshold of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 2, respectively), below the threshold of 10.

**QED:** Both ligands have good QED scores (0.908 and 0.845), indicating good drug-like properties.

**DILI:** Ligand A (21.481) has a significantly lower DILI risk than Ligand B (51.105), which is a major advantage.

**BBB:** Ligand A (94.223) has a much higher BBB penetration potential than Ligand B (47.809). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.523 and -4.864). These values are unusual and suggest poor permeability. However, the absolute values are similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.93 and -3.829). Again, these are unusual and suggest poor solubility. Ligand B is slightly worse.

**hERG:** Ligand A (0.578) has a slightly higher hERG risk than Ligand B (0.056), but both are relatively low.

**Microsomal Clearance:** Ligand A (26.646) has a lower microsomal clearance than Ligand B (33.239), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.886) has a longer in vitro half-life than Ligand B (-16.372), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.045).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol) - a difference of 1.1 kcal/mol. This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's better ADME profile (lower DILI, better BBB, better metabolic stability, longer half-life), Ligand B's significantly stronger binding affinity (-9.0 vs -7.9 kcal/mol) is a critical factor for an enzyme target like SRC kinase. A 1.1 kcal/mol difference is substantial and likely to translate to greater efficacy. The slightly higher logP and DILI of Ligand B are acceptable trade-offs given the potency advantage.

Output:
1
2025-04-17 15:20:19,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.39 and 357.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.01) is slightly above the preferred <140, while Ligand B (91.34) is well within.

**logP:** Ligand A (1.59) is optimal, while Ligand B (-0.931) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Ligand A (0.704) has a better QED score than Ligand B (0.583), indicating better overall drug-likeness.

**DILI:** Ligand A (68.17) has a higher DILI risk than Ligand B (14.39), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (70.88) shows better penetration than Ligand B (28.34).

**Caco-2:** Ligand A (-5.125) and Ligand B (-4.913) have similar, and poor, Caco-2 permeability.

**Solubility:** Ligand A (-2.81) shows poor solubility, while Ligand B (-0.311) is slightly better, but still not ideal.

**hERG:** Ligand A (0.241) has a much lower hERG risk than Ligand B (0.191), a crucial advantage.

**Microsomal Clearance:** Ligand B (-11.472) has significantly lower (better) microsomal clearance than Ligand A (31.213), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.942) has a longer half-life than Ligand A (6.758), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.058 and 0.006 respectively).

**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 huge, but still noticeable.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity. While Ligand A has better QED and lower hERG risk, the DILI risk is a major red flag. The slightly lower logP of Ligand B is a minor drawback that might be addressable through further optimization, but the metabolic stability and safety profile are more critical at this stage.

Output:
1
2025-04-17 15:20:19,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.487 and 357.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (95.66). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.501 and 1.675), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=4) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.825) has a significantly higher QED score than Ligand B (0.617), indicating a more drug-like profile.

**DILI:** Ligand B (45.56) has a lower DILI risk than Ligand A (12.524), which is a significant advantage.

**BBB:** Ligand A (82.745) has a higher BBB penetration percentile than Ligand B (56.65). While not a primary concern for a non-CNS target like SRC, it's a neutral factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.897 and -4.997), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.293 and -1.974), which is also unusual and suggests poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.452) shows a lower hERG inhibition liability than Ligand B (0.645), which is a favorable characteristic.

**Microsomal Clearance:** Ligand A (47.631) has a higher microsomal clearance than Ligand B (26.619). This indicates Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (24.871) has a significantly longer in vitro half-life than Ligand A (-4.82), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.378) has lower P-gp efflux liability than Ligand B (0.181), which is slightly favorable.

**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 drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better QED, TPSA, hERG, and P-gp efflux. However, Ligand B demonstrates 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 the strong binding affinity of Ligand A is a major advantage for an enzyme target. Given the importance of potency for kinase inhibitors, and the fact that solubility/permeability issues can sometimes be addressed through formulation, Ligand A is the more promising candidate.

Output:
0
2025-04-17 15:20:19,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 344.342 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (50.8) is well below the 140 threshold and good for oral absorption. Ligand B (73.44) is still acceptable, but less optimal.

**logP:** Both ligands (3.099 and 3.084) are 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 has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.771) has a better QED score than Ligand B (0.527), indicating a more drug-like profile.

**DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (91.004). This is a major advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (73.827) has a slightly better BBB percentile than Ligand B (62.776).

**Caco-2 Permeability:** Ligand A (-4.754) has slightly better Caco-2 permeability than Ligand B (-4.496).

**Aqueous Solubility:** Ligand A (-1.852) has better aqueous solubility than Ligand B (-4.933). This is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands (0.8 and 0.85) have similar, and acceptable, hERG inhibition liabilities.

**Microsomal Clearance:** Ligand B (97.215) has a much higher microsomal clearance than Ligand A (30.212), suggesting lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-6.525) has a longer in vitro half-life than Ligand B (-4.428), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands (0.236 and 0.48) have similar P-gp efflux liabilities.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a better binding affinity than Ligand A (-6.9 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.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising drug candidate. The significantly lower DILI risk, better solubility, and substantially improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand A are critical advantages for an enzyme target. While the affinity difference is notable, it doesn't fully compensate for the potential safety and pharmacokinetic liabilities of Ligand B.



Output:
0
2025-04-17 15:20:19,853 - INFO - Batch 371 complete. Total preferences: 5936
2025-04-17 15:20:19,853 - INFO - Processing batch 372/512...
2025-04-17 15:21:03,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.782 and 374.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.84) is better than Ligand B (93.73), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (3.902) is optimal, while Ligand B (0.795) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (4) is acceptable, and Ligand B (2) is also good.

**H-Bond Acceptors:** Ligand A (3) is good, and Ligand B (5) is also acceptable.

**QED:** Both ligands have good QED scores (0.578 and 0.655, respectively), indicating drug-likeness.

**DILI:** Ligand B (42.148) has a significantly lower DILI risk than Ligand A (75.649), which is a major advantage.

**BBB:** Ligand A (64.25) has a slightly better BBB penetration than Ligand B (57.464), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.108) is slightly better than Ligand B (-5.403) but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.899) is slightly better than Ligand B (-1.943) but both are concerning.

**hERG Inhibition:** Ligand A (0.569) has a lower hERG risk than Ligand B (0.29), which is favorable.

**Microsomal Clearance:** Ligand B (17.674) has a lower microsomal clearance than Ligand A (22.813), suggesting better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand A (22.752) has a longer half-life than Ligand B (-7.411), which is desirable.

**P-gp Efflux:** Ligand A (0.315) has lower P-gp efflux than Ligand B (0.032), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -9.2 kcal/mol), with Ligand B being slightly better. The affinity difference is small, but significant.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better BBB and half-life, Ligand B demonstrates significantly lower DILI risk and better metabolic stability (lower Cl_mic). The slightly better binding affinity of Ligand B is a bonus. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies. The lower DILI and improved metabolic stability of Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 15:21:03,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 and 334.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is well below the 140 threshold and excellent for oral absorption. Ligand B (105.2) is still acceptable but less optimal.

**logP:** Both ligands (1.034 and 1.102) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which is good. Ligand B has 1 HBD and 8 HBA, which is also acceptable, but the higher HBA count might slightly impact permeability.

**QED:** Ligand A (0.48) is slightly below the desirable 0.5 threshold, while Ligand B (0.719) is above it, indicating better overall drug-likeness.

**DILI:** Ligand A (5.777) has a very low DILI risk, significantly better than Ligand B (69.833), which indicates a high risk of liver injury.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (33.385) is lower than Ligand B (46.491).

**Caco-2 Permeability:** Ligand A (-4.688) has a negative Caco-2 value which is concerning, indicating poor permeability. Ligand B (-5.731) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.784) has poor solubility, while Ligand B (-2.469) is even worse. Both are problematic.

**hERG:** Ligand A (0.415) has a low hERG risk, which is excellent. Ligand B (0.078) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (34.876) has moderate clearance, while Ligand B (-5.736) has negative clearance, which is highly unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-1.894) has a negative half-life, which is also highly unusual and suggests very high stability. Ligand B (26.73) has a reasonable half-life.

**P-gp Efflux:** Both ligands (0.075 and 0.046) have low P-gp efflux, which is favorable.

**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 could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the better candidate despite its higher DILI risk and lower solubility. The significantly stronger binding affinity (-8.5 vs -7.3 kcal/mol) is a major advantage for an enzyme target like SRC. The negative microsomal clearance and half-life values are unusual, but suggest exceptional metabolic stability. While the DILI risk is a concern, it may be mitigated through structural modifications during lead optimization. Ligand A's poor Caco-2 permeability and solubility are significant drawbacks that are harder to overcome.

Output:
1
2025-04-17 15:21:03,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (347.463 and 350.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.12) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (58.64) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (1.595) is within the optimal range of 1-3. Ligand B (3.189) is also within the optimal range, leaning towards the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, both within acceptable limits. Ligand B has 1 HBD and 3 HBA, also within acceptable limits.

**QED:** Ligand A (0.443) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.718) is above 0.5, indicating a more drug-like profile.

**DILI:** Ligand A (32.183) has a lower DILI risk than Ligand B (27.918), both are good.

**BBB:** Ligand A (43.815) has a lower BBB penetration than Ligand B (71.229). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.366) has poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.441) is also poor, but better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.021 and -2.529 respectively). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.369) has a lower hERG inhibition risk than Ligand B (0.199), which is preferable.

**Microsomal Clearance:** Ligand A (1.859) has a much lower microsomal clearance than Ligand B (89.461), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-0.271) has a slightly negative half-life, which is unusual and potentially problematic. Ligand B (0.972) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux than Ligand B (0.249), which is favorable.

**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.

**Overall Assessment:**

Ligand B possesses a significantly stronger binding affinity (-7.2 vs -8.1 kcal/mol) and a better QED score (0.718 vs 0.443). While both have poor solubility, the superior affinity and metabolic stability (lower Cl_mic) of Ligand B are more critical for an enzyme target like SRC. Ligand A has better hERG and P-gp profiles, but the potency difference is substantial.

Output:
1
2025-04-17 15:21:03,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.4 and 367.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.45) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (61.88) is well within the ideal range.

**logP:** Both ligands (2.105 and 1.954) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**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 (0.683 and 0.864), indicating drug-like properties.

**DILI:** Ligand A (68.941) has a higher DILI risk than Ligand B (30.826). This is a significant negative for Ligand A.

**BBB:** Both ligands have similar BBB penetration (53.936 and 55.642). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.997 and -4.799). This is unusual and suggests poor permeability. However, these values are on a log scale, so even negative numbers can represent some permeability.

**Aqueous Solubility:** Ligand A (-3.841) has worse solubility than Ligand B (-1.044). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.635) has a slightly higher hERG risk than Ligand B (0.194). Lower is better here.

**Microsomal Clearance:** Ligand B (12.524) has significantly lower microsomal clearance than Ligand A (31.817), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (18.398) has a longer in vitro half-life than Ligand A (-25.906). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.14) shows slightly more P-gp efflux than Ligand B (0.02), but both are low.

**Binding Affinity:** Ligand A (-7.9) has a significantly better binding affinity than Ligand B (0.0). A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk, poorer solubility, higher hERG risk, and much worse metabolic stability (higher Cl_mic and shorter t1/2) are major drawbacks. Ligand B, despite the weaker binding affinity, presents a much more favorable ADMET profile. The improved metabolic stability and lower toxicity risk are particularly important for kinase inhibitors, where chronic dosing is often required. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand B, whereas mitigating the ADMET liabilities of Ligand A would be far more challenging.

Output:
1
2025-04-17 15:21:03,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.547 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**2. TPSA:** Ligand A (50.36) is better than Ligand B (63.4), both are acceptable but lower is better for permeability.

**3. logP:** Both ligands have similar logP values around 4.2-4.3, which is slightly high but not alarming.

**4. H-Bond Donors:** Ligand A (2) is slightly worse than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand B (6) is slightly worse than Ligand A (2), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.748 and 0.671), indicating good drug-like properties.

**7. DILI:** Both ligands have high DILI risk (23.846 and 62.621). Ligand A is significantly better in this regard.

**8. BBB:** Ligand A (85.459) has a better BBB penetration percentile than Ligand B (72.78). While not a primary concern for a non-CNS target like SRC, better BBB penetration can sometimes correlate with better overall bioavailability.

**9. Caco-2 Permeability:** Ligand A (-4.667) has better Caco-2 permeability than Ligand B (-5.372).

**10. Aqueous Solubility:** Ligand A (-4.363) has better aqueous solubility than Ligand B (-4.006). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.67) has a slightly higher hERG inhibition risk than Ligand B (0.591), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (54.798) has lower microsomal clearance than Ligand A (62.285), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (24.77) has a much better in vitro half-life than Ligand B (-14.373). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.195) has lower P-gp efflux than Ligand B (0.381), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly better binding affinity than Ligand B (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of 8.6 kcal/mol is substantial and likely outweighs minor drawbacks in other properties.

**Overall:**

Ligand A is the superior candidate. While Ligand B has better metabolic stability, Ligand A's significantly stronger binding affinity (-8.6 vs 0.0 kcal/mol), better solubility, permeability, half-life, and lower DILI risk make it a much more promising drug candidate. The substantial difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 15:21:03,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (370.559 Da and 352.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (49.85). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable due to its lower TPSA.

**3. logP:** Both ligands have good logP values (2.878 and 3.076), 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:** Both ligands have similar QED values (0.62 and 0.641), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 21.908, while Ligand B has 13.532. Ligand B is significantly better in terms of DILI risk.

**8. BBB:** Ligand A (68.36) and Ligand B (86.623) both have reasonable BBB penetration, but Ligand B is better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.958 and -4.084). 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 negative solubility values (-3.28 and -2.795). Similar to Caco-2, these values are on a log scale and indicate poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.434 and 0.483).

**12. Microsomal Clearance:** Ligand A (68.256) has a slightly lower microsomal clearance than Ligand B (73.163), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.433 hours) has a longer half-life than Ligand B (5.65 hours), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.141).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 kcal/mol and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is slightly more favorable. While Ligand A has a longer half-life and slightly better metabolic stability, Ligand B demonstrates a significantly lower DILI risk, better BBB penetration, and a lower TPSA. The binding affinities are essentially identical, so the ADME properties become the deciding factors. For an enzyme inhibitor, minimizing toxicity (DILI) and maximizing favorable ADME properties are crucial.

Output:
1
2025-04-17 15:21:03,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.845 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.02) is slightly higher than Ligand B (52.65). Both are acceptable, but B is better for permeability.

**logP:** Both ligands (2.781 and 3.214) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**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 good QED scores (0.749 and 0.835), indicating good drug-like properties.

**DILI:** Ligand A (58.627) has a slightly better DILI score than Ligand B (66.615), indicating lower potential for liver injury. Both are acceptable, but A is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.482) is higher than Ligand B (67.623).

**Caco-2 Permeability:** Both have negative values (-4.686 and -4.828), which is unusual and suggests poor permeability. However, the values are very close.

**Aqueous Solubility:** Both have negative values (-3.548 and -3.905), which also suggests poor solubility. Again, values are very close.

**hERG:** Both ligands have low hERG risk (0.573 and 0.537).

**Microsomal Clearance:** Ligand A (30.717) has significantly lower microsomal clearance than Ligand B (58.682), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (61.197) has a slightly longer half-life than Ligand B (54.759).

**P-gp Efflux:** Both have low P-gp efflux (0.241 and 0.188).

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This 1.0 kcal/mol difference is substantial and outweighs minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have some ADME liabilities (poor Caco-2 and solubility), Ligand A's significantly stronger binding affinity (-7.4 vs -6.4 kcal/mol) and lower microsomal clearance (30.7 vs 58.7) are critical advantages for an enzyme target like SRC kinase. The slightly better DILI score also contributes to its favorability.

Output:
1
2025-04-17 15:21:03,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**
*   **MW:** 344.39 Da - Good, within the ideal range.
*   **TPSA:** 83.98 - Good, below the 140 threshold for oral absorption.
*   **logP:** 2.148 - Excellent, within the optimal 1-3 range.
*   **HBD:** 2 - Good, within the acceptable limit.
*   **HBA:** 4 - Good, within the acceptable limit.
*   **QED:** 0.719 - Excellent, indicating strong drug-likeness.
*   **DILI:** 51.454 - Good, low risk of liver injury.
*   **BBB:** 81.543 - Good, suggesting reasonable potential for some CNS penetration, though not a primary concern for SRC.
*   **Caco-2:** -4.893 - Poor, indicating low intestinal absorption. This is a significant drawback.
*   **Solubility:** -3.188 - Poor, indicating low aqueous solubility. This is a significant drawback.
*   **hERG:** 0.447 - Good, low risk of hERG inhibition.
*   **Cl_mic:** 13.848 mL/min/kg - Moderate, not ideal, but not terrible.
*   **t1/2:** 12.486 hours - Good, reasonable in vitro half-life.
*   **Pgp:** 0.044 - Good, low P-gp efflux.
*   **Affinity:** -8.2 kcal/mol - Excellent, very strong binding affinity.

**Ligand B:**
*   **MW:** 375.447 Da - Good, within the ideal range.
*   **TPSA:** 121.97 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** -0.097 - Poor, below 1, potentially hindering permeation.
*   **HBD:** 2 - Good, within the acceptable limit.
*   **HBA:** 7 - Good, within the acceptable limit.
*   **QED:** 0.682 - Good, indicating reasonable drug-likeness.
*   **DILI:** 54.323 - Good, low risk of liver injury.
*   **BBB:** 42.962 - Low, suggesting poor CNS penetration. Not a major concern for SRC.
*   **Caco-2:** -5.018 - Poor, indicating low intestinal absorption. This is a significant drawback.
*   **Solubility:** -2.034 - Poor, indicating low aqueous solubility. This is a significant drawback.
*   **hERG:** 0.229 - Good, low risk of hERG inhibition.
*   **Cl_mic:** 13.83 mL/min/kg - Moderate, similar to Ligand A.
*   **t1/2:** -31.961 hours - Excellent, very long in vitro half-life.
*   **Pgp:** 0.036 - Good, low P-gp efflux.
*   **Affinity:** -8.0 kcal/mol - Excellent, strong binding affinity, slightly less than Ligand A.

**Comparison and Decision:**

Both ligands have excellent binding affinities and acceptable safety profiles (DILI, hERG). Both have poor Caco-2 permeability and solubility. However, Ligand A has a better logP, QED, and a slightly better binding affinity. The longer half-life of Ligand B is attractive, but the significantly lower logP is a major concern for oral bioavailability. The poor Caco-2 and solubility for both compounds are significant hurdles, but the better overall profile of Ligand A, particularly its logP and QED, makes it the more promising candidate. Formulation strategies could potentially address the solubility and permeability issues, but starting with a molecule possessing better inherent properties is preferable.

Output:
1
2025-04-17 15:21:03,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.439 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is slightly higher than Ligand B (49.85), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.957 and 2.894, respectively) 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 3 HBAs, which is well within the acceptable range (<=10).

**QED:** Ligand A (0.636) has a better QED score than Ligand B (0.475), indicating a more drug-like profile.

**DILI:** Ligand B (17.798) has a significantly lower DILI risk than Ligand A (26.095), which is a major advantage.

**BBB:** Ligand B (90.655) has a much higher BBB penetration percentile than Ligand A (58.938). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.783) has slightly better Caco-2 permeability than Ligand B (-4.579), though both are negative values, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-2.432) has slightly better aqueous solubility than Ligand B (-2.044), but both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.261) has a lower hERG inhibition liability than Ligand B (0.602), which is a significant advantage.

**Microsomal Clearance:** Ligand B (67.201) has a significantly higher microsomal clearance than Ligand A (22.62), suggesting lower metabolic stability. This is a critical drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-11.085) has a longer in vitro half-life than Ligand B (-8.732), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux than Ligand B (0.304), which is favorable.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG inhibition, and a better QED score. The solubility and Caco-2 permeability are poor for both, but can be addressed through formulation strategies. The slightly better affinity of Ligand B is not enough to overcome the significant metabolic liabilities.

Output:
0
2025-04-17 15:21:03,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.507 and 366.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (50.6 and 53.43) well below the 140 threshold for oral absorption.

**logP:** Ligand A (2.449) is within the optimal 1-3 range. Ligand B (4.661) is slightly above, potentially hinting at solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable H-bond characteristics, well within the guidelines.

**QED:** Both ligands have similar QED scores (0.65 and 0.647), indicating good drug-likeness.

**DILI:** Ligand A (7.755 percentile) has a significantly lower DILI risk than Ligand B (24.467 percentile). This is a major advantage for Ligand A.

**BBB:** Both have high BBB penetration (90.772 and 80.807 percentile), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.296 and -4.609). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without knowing the base of the log.

**Aqueous Solubility:** Ligand A (-1.298) has better (less negative) solubility than Ligand B (-4.229). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.45) shows lower hERG inhibition liability than Ligand B (0.859), a significant safety advantage.

**Microsomal Clearance:** Ligand A (76.548) has lower microsomal clearance than Ligand B (96.632), indicating better metabolic stability. This is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand B (15.571 hours) has a considerably longer half-life than Ligand A (3.796 hours). This is a positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.048) has much lower P-gp efflux liability than Ligand B (0.952), improving oral bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol), a difference of 0.8 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. However, Ligand A demonstrates a much more favorable safety profile with lower DILI and hERG risk, and lower P-gp efflux. It also has better solubility and metabolic stability. The difference in binding affinity (0.8 kcal/mol) is substantial, but the combined advantages of Ligand A in terms of safety and ADME properties are compelling. Given the enzyme class (kinase), metabolic stability and safety are very important.

Output:
0
2025-04-17 15:21:03,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.422 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (66.4) is significantly better than Ligand B (112.81). Lower TPSA generally favors better absorption.

**logP:** Ligand A (2.257) is optimal, while Ligand B (0.264) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0/2) and HBA (4/4) counts.

**QED:** Both ligands have reasonable QED scores (0.791 and 0.595), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (32.299 and 33.501), which is good.

**BBB:** Ligand A (95.89) shows excellent BBB penetration, while Ligand B (62.233) is lower. While SRC is not a CNS target, good BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2:** Ligand A (-4.103) and Ligand B (-5.269) both have negative Caco-2 values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-2.809) and Ligand B (-2.369) both have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Both ligands have very low hERG risk (0.345 and 0.087), which is excellent.

**Microsomal Clearance:** Ligand A (54.74) has higher clearance than Ligand B (24.425). Lower clearance is preferred for better metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (-16.889) has a longer half-life than Ligand A (-13.079), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.02 and 0.006), which is favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly better binding affinity than Ligand B (-7.7 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some of the ADME concerns.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the better candidate. Its superior binding affinity (-8.7 vs -7.7 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has a better logP and TPSA. While Ligand B has better metabolic stability (lower Cl_mic and longer half-life), the potency difference is more critical. The poor solubility and permeability of both compounds would need to be addressed through formulation or structural modifications, but starting with the more potent ligand is a better strategy.

Output:
0
2025-04-17 15:21:03,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.403 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.58) is slightly above the optimal <140, but acceptable. Ligand B (76.66) is excellent, well below 140.

**logP:** Ligand A (-0.012) is slightly low, potentially hindering permeation. Ligand B (1.772) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (2) is also good.

**H-Bond Acceptors:** Both ligands (A: 5, B: 4) are well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.572, B: 0.764), indicating good drug-like properties.

**DILI:** Ligand A (60.062) is borderline, indicating moderate risk. Ligand B (31.214) is much better, with low DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (62.621) is higher than Ligand A (51.57), but neither are particularly high.

**Caco-2 Permeability:** Both are negative, which is unusual. Assuming these are percentile scores, both have poor permeability.

**Aqueous Solubility:** Both are negative, which is unusual. Assuming these are percentile scores, both have poor solubility.

**hERG:** Ligand A (0.08) has a very low hERG risk. Ligand B (0.213) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (-14.271) is excellent, indicating high metabolic stability. Ligand B (36.589) is significantly higher, suggesting faster metabolism.

**In vitro Half-Life:** Both ligands have similar half-lives (A: 26.269, B: 26.68).

**P-gp Efflux:** Both ligands show minimal P-gp efflux (A: 0.003, B: 0.029).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has excellent metabolic stability, Ligand B's significantly stronger binding affinity (-8.7 vs -0.0 kcal/mol) outweighs the moderate increase in microsomal clearance. The lower DILI risk and better logP of Ligand B are also favorable. The poor Caco-2 and solubility scores for both compounds are concerning and would need to be addressed in further optimization, but the potency advantage of B is substantial.

Output:
1
2025-04-17 15:21:03,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.05) is slightly above the preferred <140, but acceptable. Ligand B (89.35) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.028 and 0.741), 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 6 H-bond acceptors, which is within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.661 and 0.748), indicating drug-like properties.

**DILI:** Ligand A (57.619) has a higher DILI risk than Ligand B (42.613), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.513) has a higher BBB percentile than Ligand A (51.725).

**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. This is a significant concern for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.088 and 0.2), which is excellent.

**Microsomal Clearance:** Ligand A (38.739) has a higher microsomal clearance than Ligand B (20.918), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (8.225) has a significantly longer in vitro half-life than Ligand A (-5.845), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.06), which is favorable.

**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 substantial and could outweigh some ADME concerns.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is superior overall due to its better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better TPSA. The solubility issues are a concern for both, but the metabolic stability difference is crucial for an enzyme target like SRC. The improved ADME properties of Ligand B make it a more promising drug candidate.

Output:
1
2025-04-17 15:21:03,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.356 and 366.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.77) is higher than Ligand B (49.41). While both are acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (0.544) is slightly low, potentially hindering permeability. Ligand B (3.309) is within the optimal 1-3 range. This favors Ligand B.

**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.

**QED:** Both ligands have good QED scores (0.57 and 0.83, respectively), indicating good drug-like properties.

**DILI:** Ligand A (28.112) has a slightly higher DILI risk than Ligand B (16.208), but both are below the concerning threshold of 60.

**BBB:** Both have high BBB penetration (85.537 and 81.698), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is concerning for both, but Ligand A (-5.486) is slightly better than Ligand B (-5.03).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.282) is slightly better than Ligand B (-4.149).

**hERG Inhibition:** Ligand A (0.221) has a slightly lower hERG risk than Ligand B (0.538), which is favorable.

**Microsomal Clearance:** Ligand A (-43.217) has significantly *lower* (better) microsomal clearance than Ligand B (64.281). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-15.542) has a slightly better in vitro half-life than Ligand B (-11.87), suggesting slower metabolism.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.207, respectively), which is good.

**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.

**Overall Assessment:**

Ligand A excels in binding affinity and metabolic stability (lower Cl_mic, better t1/2), which are crucial for kinase inhibitors. While its logP is a bit low and Caco-2/Solubility are poor, the strong binding affinity (-8.2 kcal/mol) can often compensate for minor ADME deficiencies. Ligand B has a better logP and TPSA, but its weaker binding affinity and poorer metabolic stability are significant drawbacks. The slightly better hERG risk for A is also a plus.

Output:
1
2025-04-17 15:21:03,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.459 and 371.497 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.32) is higher than the preferred <140, but acceptable. Ligand B (45.23) is excellent, well below 90, suggesting good absorption.

**logP:** Ligand A (0.471) is quite low, potentially hindering permeability. Ligand B (3.486) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.647 and 0.798), indicating drug-like properties.

**DILI:** Ligand A (67.468) has a higher DILI risk than Ligand B (26.91), which is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (90.229) has a higher BBB score than Ligand A (52.501), but this is not a primary factor here.

**Caco-2 Permeability:** Ligand A (-5.335) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.885) is also not great, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.833 and -3.36). This is a potential issue, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.1) has a very low hERG risk, which is excellent. Ligand B (0.764) has a moderate hERG risk, requiring further investigation.

**Microsomal Clearance:** Ligand A (61.345) has a moderate clearance, while Ligand B (8.131) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.418) has a moderate half-life. Ligand B (-0.08) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.024) has low P-gp efflux, which is good. Ligand B (0.234) has slightly higher P-gp efflux.

**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 concerns.

**Conclusion:**

Despite the slightly shorter half-life and moderate hERG risk, Ligand B is the more promising candidate. The significantly higher binding affinity (-8.9 vs -7.8 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk, better logP, and superior metabolic stability (lower Cl_mic). While solubility and Caco-2 permeability are concerns for both, they are secondary to the potency and safety profile.

Output:
1
2025-04-17 15:21:03,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.375 and 358.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.25) is slightly above the optimal <140, but acceptable. Ligand B (91.23) is well within the acceptable range.

**logP:** Ligand A (-0.338) is a bit low, potentially hindering permeability. Ligand B (1.492) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.517 and 0.764 respectively), indicating good drug-like properties.

**DILI:** Ligand A (54.634) has a moderate DILI risk, while Ligand B (71.19) has a higher DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (47.15) and Ligand B (28.461) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.775 and -5.218), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.065 and -4.483), which is also unusual and suggests poor solubility. This is a significant concern.

**hERG:** Ligand A (0.026) has a very low hERG risk, which is excellent. Ligand B (0.303) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (9.89) has a lower clearance, indicating better metabolic stability. Ligand B (-0.565) has a negative clearance, which is not physically possible and likely indicates an issue with the data.

**In vitro Half-Life:** Ligand A (-5.132) has a negative half-life, which is not physically possible and likely indicates an issue with the data. Ligand B (13.129) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.017) has low P-gp efflux, which is good. Ligand B (0.128) also has low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.1 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, the negative values for Caco-2 permeability, aqueous solubility and in vitro half-life are major red flags. These values are likely errors in the data, but assuming they are accurate, they indicate severe issues with absorption and metabolic stability. Ligand B, while having a slightly weaker binding affinity, has more plausible ADME properties. The higher DILI risk is a concern, but potentially manageable. The negative clearance value for Ligand B is also a concern, but less so than the issues with Ligand A.

Given the enzyme-specific priorities, metabolic stability and solubility are critical. While Ligand A has a better binding affinity, the questionable ADME properties make it a less viable candidate than Ligand B.

Output:
1
2025-04-17 15:21:03,051 - INFO - Batch 372 complete. Total preferences: 5952
2025-04-17 15:21:03,051 - INFO - Processing batch 373/512...
2025-04-17 15:21:57,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (362.459 Da and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (103.91) is slightly above the preferred <140, but acceptable. Ligand B (81.08) is well within the acceptable range.

**3. logP:** Ligand A (0.488) is a bit low, potentially hindering permeation. Ligand B (1.092) is better, falling within the optimal 1-3 range.

**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: 7, Ligand B: 4).

**6. QED:** Both ligands have good QED scores (A: 0.739, B: 0.703), indicating drug-like properties.

**7. DILI:** Ligand A (51.028) has a moderately elevated DILI risk, but still acceptable. Ligand B (13.339) has a much lower, and preferable, DILI risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (49.787) and Ligand B (60.876) are both relatively low.

**9. Caco-2 Permeability:** Both have negative 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 have negative values, which is also unusual. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.099, B: 0.279).

**12. Microsomal Clearance (Cl_mic):** Ligand A (10.983) has lower clearance, suggesting better metabolic stability. Ligand B (15.938) has higher clearance.

**13. In vitro Half-Life:** Ligand A (7.164) has a longer half-life, which is desirable. Ligand B (-11.504) has a negative half-life, which is not physically possible and suggests a problem with the data.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.068, B: 0.135).

**15. Binding Affinity:** Ligand B (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a >1.5 kcal/mol advantage, which is highly significant.

**Enzyme-Specific Considerations:** For an enzyme like SRC kinase, potency (binding affinity), metabolic stability, solubility, and hERG risk are paramount. Ligand B demonstrates a substantially stronger binding affinity. While Ligand A has better metabolic stability and half-life, the negative half-life for Ligand B is a major red flag, suggesting a data error. However, even with the questionable half-life, the significantly improved binding affinity of Ligand B outweighs the other factors.

Output:
1
2025-04-17 15:21:57,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 359.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.35) is higher than Ligand B (29.54). While both are reasonably low, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Ligand A (0.145) is quite low, potentially hindering membrane permeability. Ligand B (4.808) is high, bordering on problematic, potentially leading to off-target effects or solubility issues.

**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:** Ligand A (0.702) has a better QED score than Ligand B (0.593), suggesting a more drug-like profile overall.

**DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (33.695), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.037) has a higher BBB score than Ligand A (48.003).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.179 and -5.159). This is unusual and requires further investigation, but doesn't immediately disqualify either.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.949 and -5.158). This is also concerning. Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.212) has a very low hERG risk, a significant advantage. Ligand B (0.552) is higher, indicating a greater potential for cardiotoxicity.

**Microsomal Clearance:** Ligand A (-9.706) has a *much* lower (better) microsomal clearance than Ligand B (129.433). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-9.3) has a longer in vitro half-life than Ligand B (6.619), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is good. Ligand B (0.609) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (0.0). This is a major advantage, potentially outweighing some of its ADME drawbacks. A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

Ligand B's primary strength is its significantly higher binding affinity. However, it suffers from a high logP, moderate P-gp efflux, and very high microsomal clearance. Ligand A has a better overall ADME profile (lower clearance, better solubility, lower hERG, lower P-gp efflux, better QED), but its binding affinity is very weak.

Given that we're targeting a kinase (enzyme), potency (binding affinity) is paramount. The 1.7 kcal/mol advantage of Ligand B is substantial enough to potentially overcome its ADME liabilities, *provided* those liabilities can be addressed through further optimization. The poor metabolic stability of Ligand B is a major concern, but could be tackled with structural modifications. The solubility issues of both compounds would also need to be addressed.

Output:
1
2025-04-17 15:21:57,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.39 Da) is slightly lower, which could be advantageous for permeability. Ligand B (370.837 Da) is also acceptable.

**TPSA:** Ligand A (56.59) is significantly better than Ligand B (113.44). Lower TPSA generally correlates with better cell permeability. Ligand B is above the preferred threshold of 140, which could hinder absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.882, Ligand B: 1.354), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Lower HBD counts generally improve permeability. Both have acceptable HBA counts.

**QED:** Ligand A (0.747) has a better QED score than Ligand B (0.536), indicating a more drug-like profile.

**DILI:** Ligand A (38.387) has a lower DILI risk than Ligand B (50.485), which is a significant advantage. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.29) has better BBB penetration than Ligand B (52.074), but this isn't a primary concern.

**Caco-2 Permeability:** Ligand A (-4.411) has a higher Caco-2 permeability than Ligand B (-5.431).

**Aqueous Solubility:** Ligand A (-2.79) has better aqueous solubility than Ligand B (-2.449). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.875, Ligand B: 0.182), which is excellent.

**Microsomal Clearance:** Ligand A (98.113) has a higher microsomal clearance than Ligand B (33.295), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-14.556) has a longer in vitro half-life than Ligand A (8.202), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.286, Ligand B: 0.035).

**Binding Affinity:** Both ligands have similar, strong binding affinities (Ligand A: -8.0 kcal/mol, Ligand B: -8.8 kcal/mol). Ligand B is slightly better, but the difference is small.

**Conclusion:**

Despite Ligand A having a slightly better QED, solubility, and Caco-2 permeability, Ligand B is the superior candidate. The primary reason is Ligand B's significantly better metabolic stability (lower Cl_mic and longer half-life). This is crucial for an enzyme target like SRC kinase, as a longer half-life translates to less frequent dosing. While Ligand A has a slightly better TPSA, the metabolic stability advantage of Ligand B outweighs this. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 15:21:57,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.387 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.34 and 98.32) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.111) is optimal, while Ligand B (0.459) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) is better than Ligand B (3 HBD, 4 HBA), as it's closer to the ideal ranges for both.

**QED:** Both ligands have good QED scores (0.565 and 0.694), indicating drug-like properties.

**DILI:** Ligand A (51.377) has a better DILI score than Ligand B (35.324), indicating lower potential for liver injury.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (69.407) is higher than Ligand B (39.473).

**Caco-2 Permeability:** Both are negative (-5.033 and -5.048), which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both are also negative (-1.673 and -2.496), indicating very poor solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.22 and 0.168), which is excellent.

**Microsomal Clearance:** Ligand A (70.118) has a higher microsomal clearance than Ligand B (-19.727), meaning Ligand B is more metabolically stable. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-37.562) has a much longer in vitro half-life than Ligand A (1.269), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.158 and 0.024).

**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 substantial.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and a better DILI score. However, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED. Both have poor solubility and permeability. Given the enzyme-specific priorities, metabolic stability is crucial. The 0.8 kcal/mol difference in binding affinity can potentially be overcome with further optimization, while poor metabolic stability is much harder to fix later in development.

Output:
1
2025-04-17 15:21:57,386 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision, considering the guidelines and enzyme-kinase specific priorities:

**1. Molecular Weight (MW):**
*   Ligand A: 358.463 Da - Within the ideal range (200-500 Da).
*   Ligand B: 350.375 Da - Within the ideal range (200-500 Da).
*   *Both are good.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 68.29  - Excellent, well below the 140 A^2 threshold for oral absorption.
*   Ligand B: 127.8 - Still acceptable for oral absorption, but higher than Ligand A.
*   *Ligand A is better.*

**3. Lipophilicity (logP):**
*   Ligand A: 3.577 - Slightly high, approaching the upper limit where solubility issues can arise.
*   Ligand B: 0.812 - Low, potentially hindering permeability.
*   *Ligand A is better.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 1 - Excellent, within the recommended limit.
*   Ligand B: 2 - Acceptable, within the recommended limit.
*   *Ligand A is slightly better.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 5 - Excellent, within the recommended limit.
*   Ligand B: 5 - Excellent, within the recommended limit.
*   *Both are good.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.83 - Excellent, indicating a strong drug-like profile.
*   Ligand B: 0.555 - Acceptable, but lower than Ligand A.
*   *Ligand A is better.*

**7. DILI Risk (DILI):**
*   Ligand A: 74.603 - Moderate risk.
*   Ligand B: 57.58 - Lower risk, more desirable.
*   *Ligand B is better.*

**8. Blood-Brain Barrier Penetration (BBB):**
*   Ligand A: 63.086 - Not a priority for a non-CNS target like SRC.
*   Ligand B: 76.735 - Not a priority for a non-CNS target like SRC.
*   *Both are similar.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.489 - Poor permeability.
*   Ligand B: -5.214 - Poor permeability.
*   *Both are similar and poor.*

**10. Aqueous Solubility:**
*   Ligand A: -3.945 - Poor solubility.
*   Ligand B: -2.378 - Better solubility than Ligand A.
*   *Ligand B is better.*

**11. hERG Inhibition:**
*   Ligand A: 0.181 - Very low risk of hERG inhibition.
*   Ligand B: 0.163 - Very low risk of hERG inhibition.
*   *Both are good.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 86.254 - High clearance, indicating poor metabolic stability.
*   Ligand B: 13.311 - Low clearance, indicating good metabolic stability.
*   *Ligand B is significantly better.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: -18.455 - Very short half-life.
*   Ligand B: 15.401 - Good half-life.
*   *Ligand B is significantly better.*

**14. P-gp Efflux:**
*   Ligand A: 0.266 - Low efflux, desirable.
*   Ligand B: 0.033 - Very low efflux, even more desirable.
*   *Ligand B is better.*

**15. Binding Affinity:**
*   Ligand A: -8.3 kcal/mol - Excellent binding affinity.
*   Ligand B: 0.0 kcal/mol - Very weak binding affinity.
*   *Ligand A is vastly superior.*

**Overall Assessment:**

For an enzyme target like SRC, potency (binding affinity), metabolic stability (Cl_mic, t1/2), and solubility are key. Ligand A has a *much* stronger binding affinity (-8.3 vs 0.0 kcal/mol), which is a huge advantage. However, it suffers from poor metabolic stability (high Cl_mic, short t1/2) and poor solubility. Ligand B has better metabolic stability, solubility, and lower DILI risk, but its binding affinity is essentially non-existent.

Despite the ADME drawbacks of Ligand A, the substantial difference in binding affinity is likely to outweigh these concerns *as a starting point for optimization*. It's easier to improve ADME properties than to dramatically increase binding affinity. Ligand B, with its very weak binding, is unlikely to be a viable starting point even with extensive optimization.

1
2025-04-17 15:21:57,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.279 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Ligand A (78.87) is better than Ligand B (52.65) as it is still within the acceptable range for oral absorption (<140).

**logP:** Both ligands have good logP values (A: 2.982, B: 1.483), falling within the optimal 1-3 range.

**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, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have similar QED values (A: 0.83, B: 0.768), indicating good drug-likeness.

**DILI:** Ligand A (36.603) has a lower DILI risk than Ligand B (6.941), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.794) has a higher BBB value than Ligand A (51.842), but this is not a major deciding 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 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, so it's hard to interpret.

**hERG Inhibition:** Ligand A (0.587) has a slightly higher hERG risk than Ligand B (0.244), which is less desirable.

**Microsomal Clearance:** Ligand A (34.954) has a higher microsomal clearance than Ligand B (0.568). This means Ligand B is more metabolically stable, which is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-0.463) has a longer in vitro half-life than Ligand A (-8.856). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.2 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 of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a clear advantage in terms of metabolic stability (lower Cl_mic, longer t1/2) and DILI risk. While Ligand A has slightly better binding affinity, the improved ADME profile of Ligand B, particularly the lower DILI and better metabolic stability, makes it a more promising drug candidate. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B are more impactful for an enzyme target.

Output:
1
2025-04-17 15:21:57,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.415 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.46) is slightly higher than Ligand B (76.15). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.804 and 0.98), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5). Ligand B is slightly better here.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.734 and 0.639), indicating good drug-likeness.

**DILI:** Ligand A (54.052) has a higher DILI risk than Ligand B (33.656). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (75.223 and 78.868). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.931 and -4.161). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are common, indicating low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.19 and -0.95). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.175 and 0.176). This is excellent.

**Microsomal Clearance:** Ligand A (39.966) has significantly lower microsomal clearance than Ligand B (64.634), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-1.475) has a negative half-life, which is problematic. Ligand B (-16.629) is even worse. Both are very poor.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.089 and 0.04).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This 0.8 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and lower microsomal clearance (better metabolic stability). However, Ligand B has a significantly lower DILI risk and slightly better TPSA. Both have poor solubility and permeability, and very poor half-lives. The difference in binding affinity (0.8 kcal/mol) is substantial, and given the enzyme target class, this is the most important factor. The lower DILI risk of Ligand B is also a significant benefit. The poor half-lives of both compounds would need to be addressed through structural modifications.

Output:
1
2025-04-17 15:21:57,387 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.356, 46.34, 4.621, 0, 3, 0.806, 61.342, 98.178, -4.422, -5.328, 0.824, 32.632, -12.125, 0.839, -8.4]
**Ligand B:** [346.45, 70.07, 3.671, 3, 5, 0.68, 71.152, 77.588, -4.794, -4.1, 0.879, 51.302, 97.71, 0.478, -7.8]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (352.356) and B (346.45) are comparable.
2. **TPSA:** Ligand A (46.34) is significantly better than Ligand B (70.07).  TPSA < 140 is good for oral absorption, and A is much closer to the ideal for kinase inhibitors.
3. **logP:** Both are within the optimal range (1-3), but Ligand B (3.671) is slightly lower than Ligand A (4.621). A is getting a bit high, but still acceptable.
4. **HBD:** Ligand A (0) is better than Ligand B (3). Fewer HBDs generally improve permeability.
5. **HBA:** Ligand A (3) is better than Ligand B (5). Fewer HBAs generally improve permeability.
6. **QED:** Ligand A (0.806) is significantly better than Ligand B (0.68), indicating a more drug-like profile.
7. **DILI:** Both have concerning DILI risk. Ligand A (61.342) is slightly better than Ligand B (71.152), but both are above the preferred threshold of <40. This will need to be addressed in optimization.
8. **BBB:** Ligand A (98.178) is much better than Ligand B (77.588). While SRC isn't a CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.422) is slightly better than Ligand B (-4.794), but both are problematic.
10. **Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-5.328) is slightly better than Ligand B (-4.1).
11. **hERG:** Both are low risk (0.824 and 0.879).
12. **Cl_mic:** Ligand A (32.632) has significantly better metabolic stability than Ligand B (51.302). Lower Cl_mic is preferred.
13. **t1/2:** Ligand B (97.71) has a much longer in vitro half-life than Ligand A (-12.125). This is a major advantage for B.
14. **Pgp:** Ligand A (0.839) is slightly better than Ligand B (0.478), indicating lower efflux.
15. **Binding Affinity:** Ligand A (-8.4) has a significantly stronger binding affinity than Ligand B (-7.8). A difference of 0.6 kcal/mol is substantial.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a much better affinity and Cl_mic. Ligand B has a better half-life. Both have poor solubility and concerning DILI risk.

**Conclusion:**

Despite the longer half-life of Ligand B, the significantly superior binding affinity and metabolic stability of Ligand A, coupled with its better TPSA, QED, BBB and Pgp properties, make it the more promising candidate. The poor solubility and DILI risk are concerns that would need to be addressed through structural modifications, but the strong affinity provides a solid starting point.

Output:
1
2025-04-17 15:21:57,387 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both A (346.471 Da) and B (344.415 Da) are within the ideal range of 200-500 Da. No clear advantage here.

2. **TPSA:** Ligand A (69.64) is significantly better than Ligand B (86.37).  A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

3. **logP:** Both ligands have good logP values (A: 1.694, B: 1.108) falling within the optimal 1-3 range. B is slightly lower, which *could* indicate slightly poorer membrane permeability, but the difference isn't huge.

4. **HBD:** Ligand A (2) is slightly higher than Ligand B (1), but both are well below the limit of 5.

5. **HBA:** Ligand A (3) is slightly higher than Ligand B (4), but both are well below the limit of 10.

6. **QED:** Ligand B (0.832) has a better QED score than Ligand A (0.601), suggesting a more inherently drug-like profile.

7. **DILI:** Ligand A (31.291) has a much lower DILI risk than Ligand B (51.881). This is a significant advantage for A.  A DILI <40 is preferred, and A is closer to that threshold.

8. **BBB:** Both have low BBB penetration (A: 46.219, B: 49.399). Since SRC is not a CNS target, this is not a major concern.

9. **Caco-2:** Both ligands have negative Caco-2 values (-4.818 and -4.862). This is unusual and suggests poor permeability.

10. **Solubility:** Both have negative solubility values (-2.918 and -2.242). This is also concerning, suggesting poor aqueous solubility.

11. **hERG:** Both ligands have very low hERG risk (A: 0.385, B: 0.264). This is good.

12. **Cl_mic:** Ligand B (30.162) has significantly lower microsomal clearance than Ligand A (51.452). This indicates better metabolic stability for B, which is a key consideration for kinase inhibitors.

13. **t1/2:** Ligand B (-19.979) has a much longer in vitro half-life than Ligand A (-10.498). This is a significant advantage for B, potentially allowing for less frequent dosing.

14. **Pgp:** Both have very low Pgp efflux (A: 0.394, B: 0.088). This is good.

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 *major* advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Conclusion:**

While Ligand A has a lower DILI risk and better TPSA, Ligand B's significantly stronger binding affinity (-7.1 vs 0.0 kcal/mol), lower Cl_mic, and longer t1/2 outweigh the advantages of Ligand A. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies. The substantial binding affinity difference makes Ligand B the more promising candidate.

Output:
1

2025-04-17 15:21:57,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.431 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.94) is slightly above the preferred <140, but acceptable. Ligand B (93.01) is well within the range.

**logP:** Ligand A (-0.283) is a bit low, potentially hindering permeation. Ligand B (1.247) is within the optimal 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, below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.712 and 0.853), indicating drug-like properties.

**DILI:** Ligand A (10.857) has a very low DILI risk, significantly better than Ligand B (58.627).

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (60.838) has a higher BBB value than Ligand A (45.366), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.261 and -5.033), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.104 and -2.689), indicating poor aqueous solubility. This is a major drawback for both.

**hERG:** Both ligands have very low hERG risk (0.061 and 0.078), which is excellent.

**Microsomal Clearance:** Ligand A (-11.917) has a much lower (better) microsomal clearance than Ligand B (33.401), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar, short in vitro half-lives (1.527 and 1.624 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.047).

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.2), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is preferable due to its significantly lower DILI risk and much better metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the lower DILI and better metabolic stability are more critical for an enzyme target like SRC. The slight advantage in binding affinity of Ligand B is unlikely to outweigh these ADME concerns.

Output:
0
2025-04-17 15:21:57,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.829 Da and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.48) is well below the 140 threshold for oral absorption, and suitable. Ligand B (82.11) is also acceptable, but slightly higher.

**logP:** Ligand A (3.723) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (-0.247) is significantly below 1, which could hinder 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 (0.822) has a very good drug-likeness score, while Ligand B (0.59) is acceptable but less optimal.

**DILI:** Ligand A (69.135) has a higher DILI risk than Ligand B (6.592). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.898) is higher than Ligand B (19.969).

**Caco-2 Permeability:** Ligand A (-4.408) shows poor permeability, while Ligand B (-5.179) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.111) has very poor solubility, a major concern. Ligand B (-1.281) is also poor, but better than Ligand A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.253 and 0.201 respectively).

**Microsomal Clearance:** Ligand A (74.403) has higher clearance, indicating lower metabolic stability. Ligand B (-0.126) has very low clearance, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (6.44) has a moderate half-life. Ligand B (10.824) has a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.009 respectively).

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is not substantial enough to outweigh other factors.

**Conclusion:**

Ligand B is the more promising candidate. While both have poor Caco-2 and solubility, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a slightly better binding affinity. Ligand A's poor solubility and higher DILI risk are major drawbacks. The slightly lower logP of Ligand B is a concern, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 15:21:57,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.419 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.7) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (71.54) is well within the acceptable range.

**logP:** Both ligands (1.162 and 1.839) 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 7 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have acceptable QED values (0.701 and 0.659, both >0.5).

**DILI:** Ligand A (51.144) has a higher DILI risk than Ligand B (26.095). Lower is better, so Ligand B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.399) has a higher BBB score than Ligand A (36.72), but this isn't a major factor here.

**Caco-2 Permeability:** Both have negative values (-5.607 and -5.104), 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 (-1.917 and -1.905), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Ligand A (0.454) has a slightly lower hERG risk than Ligand B (0.905), which is preferable.

**Microsomal Clearance:** Ligand A (-7.928) exhibits significantly lower microsomal clearance than Ligand B (34.4). Lower clearance indicates better metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand A (-17.662) has a much longer in vitro half-life than Ligand B (24.734). Longer half-life is desirable.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux than Ligand B (0.017), which is preferable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This difference of 0.8 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and lower P-gp efflux. While Ligand B has a lower DILI risk, the improvements in metabolic stability and binding affinity of Ligand A are more crucial for an enzyme target like SRC kinase. The solubility and permeability concerns are present in both, but the potency and metabolic advantages of A are more impactful.

Output:
0
2025-04-17 15:21:57,387 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (334.419 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.19) is significantly better than Ligand B (104.46). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.407) is optimal, while Ligand B (1.682) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better than Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Ligand A (0.884) has a significantly higher QED score than Ligand B (0.679), indicating a more drug-like profile.

**DILI:** Ligand B (45.948) has a lower DILI risk than Ligand A (62.195), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (80.264) has a higher BBB percentile than Ligand B (58.085).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.176) is slightly better than Ligand B (-4.96).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-4.014) is slightly better than Ligand B (-2.444).

**hERG:** Ligand A (0.62) has a much lower hERG risk than Ligand B (0.068), which is a critical advantage.

**Microsomal Clearance:** Ligand A (17.135 mL/min/kg) has significantly lower microsomal clearance than Ligand B (37.732 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-30.976 hours) has a negative half-life, which is not possible. This is a major red flag. Ligand A (28.12 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.671) has lower P-gp efflux than Ligand B (0.076), which is preferable.

**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 ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, its negative in vitro half-life is a critical flaw, indicating rapid degradation and making it unlikely to be a viable drug candidate. Ligand A has a more balanced profile with better metabolic stability, lower hERG risk, and a reasonable half-life, despite its weaker binding affinity. Given the enzyme-specific priorities and the severe issue with Ligand B's half-life, Ligand A is the more promising candidate.

Output:
0
2025-04-17 15:21:57,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (382.507 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.92) is slightly above the optimal <140, but acceptable. Ligand B (58.64) is well within the acceptable range.

**3. logP:** Both ligands have good logP values (3.064 and 2.204), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (0) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors (HBA):** Ligand A (5) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.738 and 0.793), indicating good drug-like properties.

**7. DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (15.2), which is a significant concern. Ligand A is above the 60 threshold for high risk.

**8. BBB:** Both ligands have acceptable BBB penetration (65.607 and 63.009), but this is less critical for a kinase inhibitor than other factors.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.621 and -4.551), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.137 and -2.312), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.669 and 0.215), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (105.779) has a higher microsomal clearance than Ligand B (-7.92). Lower clearance is preferred for metabolic stability, making Ligand B more favorable.

**13. In vitro Half-Life:** Ligand A (8.357) has a longer half-life than Ligand B (3.789), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.213) has lower P-gp efflux than Ligand B (0.035), which is favorable.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). The difference of 1.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. Ligand B excels in affinity and metabolic stability, while Ligand A has a longer half-life but a significantly higher DILI risk and worse metabolic stability. The poor solubility and Caco-2 permeability are concerns for both, but the superior affinity of Ligand B is a major advantage.

Output:
1
2025-04-17 15:21:57,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.523 and 375.965 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly higher than Ligand B (12.47). While both are below 140, the lower TPSA of Ligand B is favorable for permeability.

**logP:** Ligand A (3.525) is within the optimal 1-3 range. Ligand B (4.971) is slightly higher, potentially leading to solubility issues and off-target effects, but not dramatically so.

**H-Bond Donors/Acceptors:** Ligand A has 1 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 (0.623 and 0.677), indicating good drug-likeness.

**DILI:** Both ligands have very similar, low DILI risk (25.785 and 25.436 percentile).

**BBB:** Ligand A (65.025) has a lower BBB penetration percentile than Ligand B (95.851). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.653) shows poor Caco-2 permeability, while Ligand B (-5.227) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.404 and -4.57). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.552) has a slightly lower hERG risk than Ligand B (0.956), which is preferable.

**Microsomal Clearance:** Ligand A (44.328) has lower microsomal clearance than Ligand B (53.375), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.118 hours) has a longer half-life than Ligand B (9.973 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.398) has lower P-gp efflux than Ligand B (0.884), indicating better bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability, half-life, and P-gp efflux, the significantly stronger binding affinity of Ligand B (-7.6 vs -8.2 kcal/mol) is the most critical factor for an enzyme inhibitor. The slightly higher logP and hERG risk of Ligand B are manageable, especially given the potency advantage. The solubility of both is poor and would need to be addressed during lead optimization. The lower TPSA of Ligand B is also favorable.

Output:
1
2025-04-17 15:21:57,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (473.14 Da) is within the ideal range, while Ligand B (368.459 Da) is also acceptable, though closer to the lower limit.

**TPSA:** Ligand A (56.15) is good for oral absorption. Ligand B (87.76) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.948) is optimal. Ligand B (0.361) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.735 and 0.667), indicating good drug-likeness.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (51.26). This is a concern for Ligand A.

**BBB:** Not a primary concern for a general oncology target like SRC, but Ligand A (89.725) has better BBB penetration than Ligand B (64.87).

**Caco-2:** Ligand A (-4.554) is very poor, indicating extremely low intestinal absorption. Ligand B (-5.176) is also poor, but slightly better than A.

**Solubility:** Ligand A (-6.334) has very poor aqueous solubility. Ligand B (-2.862) is also poor, but better than A.

**hERG:** Ligand A (0.583) has a slightly higher hERG risk than Ligand B (0.375), but both are reasonably low.

**Microsomal Clearance:** Ligand A (76.617) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (18.888) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (24.562) has a moderate half-life. Ligand B (-21.852) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.715 and 0.022), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -6.6 kcal/mol). Ligand A is significantly more potent, with a 2.4 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from very poor solubility, poor Caco-2 permeability, higher DILI risk, and faster metabolic clearance. Ligand B has better solubility, permeability, metabolic stability, and lower DILI risk, but its binding affinity is considerably weaker.

Despite the superior potency of Ligand A, the poor ADME properties are major liabilities. The significantly better metabolic stability of Ligand B, coupled with acceptable (though not ideal) solubility and permeability, makes it a more promising starting point for optimization. The potency gap could potentially be closed through medicinal chemistry efforts, while addressing the poor ADME properties of Ligand A would be a much more substantial undertaking.

Output:
1
2025-04-17 15:21:57,388 - INFO - Batch 373 complete. Total preferences: 5968
2025-04-17 15:21:57,388 - INFO - Processing batch 374/512...
2025-04-17 15:22:43,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.412 Da) is slightly higher than Ligand B (350.375 Da), but both are acceptable.

**TPSA:** Ligand A (54.45) is significantly better than Ligand B (104.45). Lower TPSA generally improves cell permeability.

**logP:** Ligand A (2.919) is optimal, while Ligand B (0.351) is quite low. A logP below 1 can hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 6 HBA). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have similar QED values (A: 0.799, B: 0.609), indicating good drug-likeness.

**DILI:** Both have acceptable DILI risk, with Ligand A (42.846) being slightly better than Ligand B (48.74).

**BBB:** Ligand A (90.151) has a much higher BBB percentile than Ligand B (37.456). While SRC isn't a CNS target, higher BBB often correlates with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.559) is better than Ligand B (-4.883), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.369) is better than Ligand B (-1.403) which is important for formulation and bioavailability.

**hERG:** Ligand A (0.697) is significantly better than Ligand B (0.081), indicating a lower risk of cardiotoxicity. This is a crucial factor.

**Microsomal Clearance:** Ligand A (5.45 mL/min/kg) is *much* better than Ligand B (31.142 mL/min/kg). Lower clearance suggests better metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand A (18.995 hours) is significantly better than Ligand B (57.575 hours). Longer half-life is desirable.

**P-gp Efflux:** Ligand A (0.539) is better than Ligand B (0.039), indicating lower efflux and potentially better bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 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 consistently outperforms Ligand B across most critical ADME properties (TPSA, logP, solubility, hERG, clearance, half-life, P-gp efflux). While Ligand B has a marginally better binding affinity, the superior ADME profile of Ligand A, particularly its metabolic stability (lower Cl_mic) and reduced hERG risk, makes it the more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 15:22:43,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.816 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.02) is better than Ligand B (58.44), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (4.144) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.283) is closer to the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better than Ligand B (0 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.721 and 0.824), indicating drug-like properties.

**DILI:** Ligand A (80.147) has a significantly higher DILI risk than Ligand B (23.187). This is a major concern for Ligand A.

**BBB:** Both have good BBB penetration, but Ligand B (85.459) is slightly better than Ligand A (70.997). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.954 and -4.719), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand B (-1.764) is much better than Ligand A (-4.556). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.695) has a higher hERG risk than Ligand B (0.283). Lower hERG risk is preferred.

**Microsomal Clearance:** Ligand B (12.318 mL/min/kg) has much lower microsomal clearance than Ligand A (78.175 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.797 hours) has a negative half-life, which is not possible. This is a significant data quality issue. Ligand A has a reasonable half-life (108.88 hours).

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux than Ligand B (0.033). Lower efflux is generally preferred.

**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 not huge.

**Overall Assessment:**

Ligand B appears to be the better candidate despite the negative half-life value. It has a lower DILI risk, better solubility, better metabolic stability (lower Cl_mic), and a slightly better binding affinity. Ligand A has a high DILI risk and higher hERG risk, and significantly worse metabolic stability. The negative half-life for Ligand B is a red flag and needs investigation, but the other properties are more favorable. The Caco-2 permeability is concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 15:22:43,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.495 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.9 and 98.66) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.109) is quite low, potentially hindering permeation. 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 4 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Ligand A (0.444) is below the desirable 0.5 threshold, suggesting a less drug-like profile. Ligand B (0.632) is above 0.5, indicating better drug-likeness.

**DILI:** Ligand A (2.792) has a very low DILI risk, which is excellent. Ligand B (37.65) is higher, but still below the concerning 60 threshold.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both 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 very poor solubility.

**hERG:** Ligand A (0.252) has a very low hERG risk, a major advantage. Ligand B (0.165) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-21.6) has a very low (negative) clearance, indicating excellent metabolic stability. Ligand B (60.791) has a much higher clearance, suggesting faster metabolism. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-4.72) has a negative half-life, which is not physically meaningful. Ligand B (0.867) has a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.5 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior safety profile (DILI, hERG) and metabolic stability (Cl_mic). However, its low logP and QED are concerning, and its solubility is very poor. Ligand B has a much better binding affinity, a good logP, and acceptable DILI and hERG risks. However, its metabolic clearance is high, and its half-life is short. The solubility is also very poor.

Given the priority for potency in enzyme inhibition, the significantly stronger binding affinity of Ligand B (-7.9 kcal/mol vs -7.3 kcal/mol) is a decisive factor. While the higher clearance of Ligand B is a concern, it could potentially be addressed through structural modifications during lead optimization. The poor solubility of both compounds would need to be addressed regardless of which is chosen.

Output:
1
2025-04-17 15:22:43,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.361 and 361.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.9) is slightly higher than Ligand B (80.32). Both are below the 140 threshold for good absorption, but closer to the 90 threshold for CNS targets (not relevant here). Ligand B is preferable.

**logP:** Ligand A (0.925) is a bit low, potentially impacting permeability. Ligand B (2.086) is better, falling within the optimal 1-3 range. Ligand B is preferable.

**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 similar QED values (0.665 and 0.679), indicating good drug-likeness.

**DILI:** Ligand A (44.862) has a lower DILI risk than Ligand B (50.485), which is preferable.

**BBB:** This is less important for a non-CNS target. Ligand A (77.821) has a slightly higher BBB percentile than Ligand B (52.811).

**Caco-2 Permeability:** Ligand A (-4.576) has a better (less negative) Caco-2 permeability than Ligand B (-5.355), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.294) has better aqueous solubility than Ligand B (-1.97). This is a significant advantage for bioavailability.

**hERG Inhibition:** Both ligands have very similar, and low, hERG inhibition liability (0.255 and 0.263). This is good.

**Microsomal Clearance:** Ligand B (30.322) has a lower microsomal clearance than Ligand A (48.755), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (29.815) has a longer in vitro half-life than Ligand A (-30.409). This is also a key advantage for an enzyme target.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.046 and 0.094).

**Binding Affinity:** Both ligands have the same binding affinity (-6.9 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, Caco-2 permeability, and solubility, Ligand B excels in metabolic stability (lower Cl_mic) and half-life, which are critical for kinase inhibitors. The slightly better logP of Ligand B also contributes to its overall profile. The binding affinity is the same for both. Considering the enzyme-specific priorities, the improved metabolic stability and half-life of Ligand B outweigh the slight advantages of Ligand A.

Output:
1
2025-04-17 15:22:43,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.439 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (92.34). A TPSA under 140 is good for oral absorption, but lower is generally preferred for enzymes. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.208, Ligand B: 1.176), falling within the optimal 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). Lower counts are generally better for permeability.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.854, Ligand B: 0.703), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (35.401) has a lower DILI risk than Ligand B (45.25), which is a significant advantage. Both are below the 60 threshold, but lower is always better.

**BBB:** Both have good BBB penetration (Ligand A: 78.596, Ligand B: 82.9). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.468) has better Caco-2 permeability than Ligand B (-5.118), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.292) has better aqueous solubility than Ligand B (-2.25). Solubility is crucial for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.183, Ligand B: 0.151), which is excellent.

**Microsomal Clearance:** Ligand B (-12.342) has significantly lower microsomal clearance than Ligand A (38.342), suggesting better metabolic stability. This is a key advantage for enzymes.

**In vitro Half-Life:** Ligand B (14.559) has a longer in vitro half-life than Ligand A (-13.205), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.156, Ligand B: 0.085).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (Ligand A: -8.1 kcal/mol, Ligand B: -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, H-bonds, QED, DILI, solubility, Caco-2), but suffers from higher microsomal clearance and shorter half-life. Ligand B has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). Given the enzyme-specific priorities, the improved metabolic stability of Ligand B outweighs the slightly better ADME profile of Ligand A. The binding affinity is comparable, and metabolic stability is critical for maintaining therapeutic concentrations.

Output:
1
2025-04-17 15:22:43,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (382.873 and 379.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.54 and 71.53) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (2.746 and 2.605) are within the optimal 1-3 range, suggesting good permeability and avoiding solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Both ligands have high QED scores (0.812 and 0.825), indicating good drug-like properties.

**DILI:** Ligand A (70.803) has a slightly higher DILI risk than Ligand B (62.389), but both are acceptable.

**BBB:** Ligand A (68.864) has lower BBB penetration than Ligand B (82.125). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.843 and -4.655), which is unusual and suggests poor permeability. However, these values are on a log scale, and a negative value doesn't necessarily preclude absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.037 and -3.503), which is also unusual. This could be a significant issue for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.149) has a lower hERG inhibition liability than Ligand B (0.485), which is preferable.

**Microsomal Clearance:** Ligand B (23.722 mL/min/kg) has significantly lower microsomal clearance than Ligand A (34.636 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-23.455 hours) has a much longer in vitro half-life than Ligand A (-6.096 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.2 and 0.124).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -7.9 kcal/mol). The difference is minimal.

**Conclusion:**

While both ligands have good potency, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. The slightly better BBB penetration of Ligand B is a minor benefit, but not critical for a non-CNS target like SRC. The solubility and Caco-2 values are concerning for both, but the ADME advantages of Ligand B outweigh these concerns.

Output:
1
2025-04-17 15:22:43,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.853 and 353.369 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (80.66 and 73.22) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (3.561) is slightly higher than Ligand B (2.553), both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5-6 HBA, satisfying the criteria for good balance.

**QED:** Both ligands have good QED scores (0.69 and 0.74), indicating drug-like properties.

**DILI:** Ligand A (88.6) has a higher DILI risk than Ligand B (59.984). This is a significant concern, as a value >60 is considered high risk.

**BBB:** BBB is less crucial for a non-CNS target like SRC. Ligand B (82.435) has a slightly higher BBB value than Ligand A (62.97), but this is not a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-5.285) is worse than Ligand B (-4.292).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-3.661) is worse than Ligand B (-2.557).

**hERG:** Ligand A (0.145) has a slightly lower hERG risk than Ligand B (0.568), which is preferable.

**Microsomal Clearance:** Ligand B (89.099) has a significantly higher microsomal clearance than Ligand A (52.878), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (27.166 hours) has a much longer half-life than Ligand B (6.289 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.12 and 0.391).

**Binding Affinity:** Ligand A (-9.4 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 threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -8.0 kcal/mol) and longer half-life (27.166 vs 6.289 hours) outweigh the higher DILI risk and slightly worse hERG. The lower microsomal clearance of Ligand A also suggests better metabolic stability. The poor permeability and solubility would need to be addressed through formulation or further chemical modifications, but the strong binding and metabolic stability of Ligand A provide a better starting point for optimization.

Output:
1
2025-04-17 15:22:43,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.388 Da and 367.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.13) is excellent, well below the 140 threshold for oral absorption. Ligand B (116.67) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.398) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (-0.2) is significantly lower than ideal, which could hinder permeability.

**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:** Both ligands have similar QED values (0.799 and 0.761), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (52.772 and 43.66), which is good.

**BBB:** Ligand A has a high BBB percentile (91.121), while Ligand B is much lower (38.232). This isn't a primary concern for a non-CNS target like SRC, but it could be a factor if off-target CNS effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.309) has poor Caco-2 permeability, which is concerning. Ligand B (-5.263) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.521) has poor aqueous solubility, consistent with its high logP. Ligand B (-2.899) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.833) has a low hERG risk, which is excellent. Ligand B (0.061) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (43.154) has moderate clearance, while Ligand B (-19.501) has negative clearance (indicating high stability). This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-18.538) has a negative half-life (indicating high stability), while Ligand B (3.147) has a short half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.461 and 0.009).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite Ligand A's better BBB and similar QED, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.3 vs -7.5 kcal/mol) is a major advantage for an enzyme target like SRC. Furthermore, Ligand B exhibits superior metabolic stability (negative Cl_mic), which is crucial for *in vivo* efficacy. While Ligand B has lower solubility and permeability, these can potentially be addressed through formulation strategies. Ligand A's poor Caco-2 permeability is a more difficult hurdle to overcome.

Output:
1
2025-04-17 15:22:43,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (354.51 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is well below the 140 threshold, and even comfortably below 90, suggesting good permeability. Ligand B (71.53) is still within acceptable limits for oral absorption (<140), but higher than A.

**3. logP:** Ligand A (3.457) is optimal (1-3). Ligand B (1.782) is on the lower side, potentially impacting 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 (2 and 4, respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.623 and 0.903), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (27.453) has a lower DILI risk than Ligand B (37.999), both are good (<40).

**8. BBB:** This is less critical for a systemic oncology target. Ligand A (67.701) is higher than Ligand B (58.627).

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.451) is worse than Ligand B (-4.551).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.692) is worse than Ligand B (-2.373).

**11. hERG Inhibition:** Ligand A (0.683) has a lower hERG risk than Ligand B (0.267), which is preferable.

**12. Microsomal Clearance:** Ligand B (31.396) has lower clearance than Ligand A (48.451), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.948) has a longer half-life than Ligand A (3.518), which is desirable.

**14. P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.053), which is preferable.

**15. Binding Affinity:** Ligand B (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand B demonstrates a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and a better QED score. While Ligand A has a slightly better logP and lower DILI/hERG risk, the substantial affinity advantage of Ligand B outweighs these minor drawbacks, especially for an enzyme target where potency is paramount. The slightly lower logP of Ligand B is a concern, but can be addressed through further optimization.

Output:
1
2025-04-17 15:22:43,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 58.64, well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.384) is slightly higher than Ligand B (2.798), both 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 also good.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (31.02) has a significantly lower DILI risk than Ligand B (16.751), indicating a better safety profile. This is a crucial advantage.

**8. BBB:** Both ligands have high BBB penetration (87.67 and 82.241), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.613 and -4.806), which 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 (-3.455 and -3.045), which is also concerning. Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.769 and 0.319), which is excellent.

**12. Microsomal Clearance:** Ligand A (49.023) has a higher microsomal clearance than Ligand B (39.728), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-1.782) has a negative half-life, which is not possible. This is a data error. Ligand A (19.969) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.482 and 0.24), which is favorable.

**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 slightly better metabolic stability profile (lower Cl_mic) and a more favorable P-gp efflux, the significantly lower DILI risk for Ligand A and the erroneous half-life for Ligand B make Ligand A the more promising candidate. The binding affinities are essentially identical, so the ADME/Tox profile becomes the deciding factor. The negative half-life for Ligand B is a major red flag, suggesting a data quality issue.

Output:
0
2025-04-17 15:22:43,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.422 and 350.423 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.16) is better than Ligand B (93.45).  A TPSA under 140 is good for oral absorption, both are, but lower is generally preferred.

**logP:** Ligand A (2.072) is optimal (1-3), while Ligand B (0.035) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (3) is within the acceptable limit of 5. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (3) is within the acceptable limit of 10. Ligand B (7) is also good.

**QED:** Both ligands have good QED scores (0.748 and 0.761), indicating good drug-like properties.

**DILI:** Ligand A (47.732) and Ligand B (52.617) both have acceptable DILI risk, below the 60 threshold.

**BBB:** Ligand A (73.866) has a better BBB percentile than Ligand B (59.946), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.743 and -4.781), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.486 and -1.202), also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG:** Ligand A (0.402) has a lower hERG risk than Ligand B (0.04), which is preferable.

**Microsomal Clearance:** Ligand A (26.736) has significantly lower microsomal clearance than Ligand B (8.408), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (86.693) has a much longer in vitro half-life than Ligand B (7.422), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.023), which is favorable.

**Binding Affinity:** Ligand B (-7.8 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 concerns.

**Overall Assessment:**

While Ligand A has better ADME properties (solubility, permeability, metabolic stability, hERG), Ligand B boasts a significantly higher binding affinity (-7.8 vs -6.4 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. The 1.4 kcal/mol difference is substantial and could translate to a much more effective drug. The poor solubility and permeability of Ligand B are concerning, but formulation strategies might mitigate these issues. The metabolic stability of Ligand A is appealing, but the potency difference is likely more critical.

Output:
1
2025-04-17 15:22:43,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (416.228 Da and 410.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.2) is higher than Ligand B (52.65). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good oral absorption.

**logP:** Ligand A (0.972) is slightly lower than the optimal range (1-3), potentially hindering permeation. Ligand B (2.362) is well within the optimal 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:** Ligand A (0.709) has a better QED score than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Ligand A (82.319) has a significantly higher DILI risk than Ligand B (21.946). This is a major concern for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (66.537) is slightly better than Ligand A (55.874).

**Caco-2 Permeability:** Ligand A (-4.81) has poorer Caco-2 permeability than Ligand B (-5.094), though both are negative values indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.923) has poorer aqueous solubility than Ligand B (-2.366). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.411) has a slightly lower hERG inhibition risk than Ligand B (0.649), which is favorable.

**Microsomal Clearance:** Ligand A (20.719) has a lower microsomal clearance than Ligand B (43.178), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-8.557) has a longer in vitro half-life than Ligand B (-8.16), which is also favorable for Ligand A.

**P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux than Ligand B (0.27), suggesting better bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a better QED score, its significantly higher DILI risk and poorer solubility are major drawbacks. Ligand B, despite having a lower QED and higher clearance, presents a much more favorable safety profile (lower DILI) and better solubility. Given the enzyme-specific priorities, a lower DILI risk is critical. The binding affinity is the same for both, so the ADME/Tox profile becomes the deciding factor.

Output:
1
2025-04-17 15:22:43,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (97.11). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is much closer to the ideal for good permeability.

**logP:** Both ligands have similar logP values (2.574 and 2.505), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=5) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar, good QED scores (0.721 and 0.732), indicating good drug-like properties.

**DILI:** Ligand A (18.302) has a much lower DILI risk than Ligand B (76.89), which is a significant advantage. Ligand B is in the high-risk category (>60).

**BBB:** Ligand A (74.098) has a better BBB percentile than Ligand B (56.805), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.575) has a better (more negative) Caco-2 permeability value than Ligand B (-5.533), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.86) has better aqueous solubility than Ligand B (-4.309). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.152) has a much lower hERG inhibition liability than Ligand B (0.58), a crucial advantage regarding cardiotoxicity.

**Microsomal Clearance:** Ligand A (48.184) has a higher (worse) microsomal clearance than Ligand B (5.615), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (0.118) has a much shorter in vitro half-life than Ligand B (24.399). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux liability than Ligand B (0.168), which is favorable.

**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 ADME drawbacks.

**Overall:** Despite the metabolic stability and half-life concerns with Ligand A, its significantly superior binding affinity and much better safety profile (DILI, hERG) make it the more promising candidate. The strong binding is likely to compensate for potential formulation challenges related to clearance and half-life. Ligand B's high DILI and hERG risk are major red flags.

Output:
1
2025-04-17 15:22:43,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.767 Da and 382.957 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.29) is better than Ligand B (34.59). Lower TPSA generally favors better cell permeability, which is beneficial.

**logP:** Both ligands have logP values around 4 (4.221 and 4.931). Ligand B is slightly higher, which could potentially lead to solubility issues or off-target interactions, but is still within an acceptable 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:** Ligand A (0.823) has a significantly higher QED score than Ligand B (0.583), indicating a more drug-like profile.

**DILI:** Ligand A (84.413) has a higher DILI risk than Ligand B (35.44). This is a significant concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (77.705) is better than Ligand A (59.248). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.107 and -4.813), suggesting poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.509 and -5.098), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.384) has a slightly better hERG profile than Ligand B (0.853). Lower hERG inhibition is preferred.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (101.446 and 102.322), indicating relatively rapid metabolism.

**In vitro Half-Life:** Ligand A (67.32) has a longer half-life than Ligand B (46.66), which is preferable.

**P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux than Ligand B (0.608), which is a positive attribute.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of 8.6 kcal/mol is substantial and likely outweighs many of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having better QED, half-life, and P-gp efflux, Ligand B's dramatically superior binding affinity (-8.6 vs 0.0 kcal/mol) is the deciding factor. While both compounds have significant ADME liabilities (poor solubility and permeability, moderate DILI), the potency advantage of Ligand B is substantial enough to warrant further optimization efforts. The poor ADME properties can be addressed through medicinal chemistry strategies, but a weak binder is much harder to improve.

Output:
1
2025-04-17 15:22:43,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.507 and 385.814 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is significantly better than Ligand B (78.59). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have good logP values (2.249 and 2.041), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have similar and good QED values (0.757 and 0.785), indicating good drug-likeness.

**DILI:** Ligand A (12.796) has a much lower DILI risk than Ligand B (34.665). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.884) is better than Ligand B (68.36), but the difference isn't decisive.

**Caco-2 Permeability:** Both have negative values (-4.664 and -4.68), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.637) is better than Ligand B (-2.824). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.57) has a slightly better hERG profile than Ligand B (0.409), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (42.095) has higher microsomal clearance than Ligand B (22.217), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (6.481) has a slightly longer half-life than Ligand A (11.737). Longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.067 and 0.332).

**Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-9.5). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand A has significant advantages in DILI risk, solubility, and hERG inhibition. Ligand B has a slight edge in binding affinity and half-life, but a much higher DILI risk and lower solubility. Given the enzyme-specific priorities, the lower DILI risk and better solubility of Ligand A are more important than the slightly better affinity of Ligand B. The higher clearance of Ligand A is a concern, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 15:22:43,273 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.403, 95.22, 0.085, 1, 7, 0.778, 56.805, 63.086, -4.909, -1.892, 0.095, 45.237, 0.878, 0.113, -7.6]
**Ligand B:** [361.463, 56.79, 3.635, 1, 5, 0.693, 53.742, 79.721, -4.586, -4.358, 0.75, 75.004, 8.564, 0.671, -7]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (348.4) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (95.22) is higher than ideal (<140), but still acceptable. B (56.79) is excellent, well below the threshold. This favors B.
3. **logP:** A (0.085) is quite low, potentially hindering membrane permeability. B (3.635) is optimal. This is a significant advantage for B.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A has 7 HBA, acceptable. B has 5 HBA, also good.
6. **QED:** A (0.778) is better than B (0.693), indicating a more drug-like profile.
7. **DILI:** Both are acceptable, with A (56.8) and B (53.7) both under the 60% threshold.
8. **BBB:** A (63.1) is lower than B (79.7). Since SRC is not a CNS target, this is less critical, but B is still better.
9. **Caco-2:** Both are negative values, indicating poor permeability. A (-4.9) is worse than B (-4.6).
10. **Solubility:** Both have negative values, indicating poor solubility. A (-1.9) is worse than B (-4.4).
11. **hERG:** Both are very low, indicating minimal hERG inhibition risk.
12. **Cl_mic:** A (45.2) is better (lower) than B (75.0), suggesting better metabolic stability. This is a key advantage for A.
13. **t1/2:** A (0.88) is much lower than B (8.56), indicating faster clearance and potentially requiring more frequent dosing. This is a significant advantage for B.
14. **Pgp:** A (0.113) is better (lower) than B (0.671), indicating less P-gp efflux.
15. **Binding Affinity:** A (-7.6) is slightly better than B (-7.0), a 0.6 kcal/mol difference. This is a meaningful difference, and can outweigh some ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

*   **Affinity:** A has a slightly better affinity.
*   **Metabolic Stability:** A has a better Cl_mic, but a significantly worse t1/2.
*   **Solubility:** B is better.
*   **hERG:** Both are good.
*   **Permeability:** Both are poor, but A is worse.

**Conclusion:**

While Ligand A has a slightly better binding affinity and better metabolic clearance, the significantly longer half-life of Ligand B, coupled with its better logP, TPSA, and solubility, makes it the more promising candidate. The difference in affinity is not large enough to overcome the substantial ADME advantages of Ligand B. The poor permeability of both is a concern, but can be addressed with formulation strategies.

1
2025-04-17 15:22:43,274 - INFO - Batch 374 complete. Total preferences: 5984
2025-04-17 15:22:43,274 - INFO - Processing batch 375/512...
2025-04-17 15:23:20,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (65.79). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.366 and 1.58), within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but is still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria. Ligand B is slightly better.

**H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.672 and 0.88), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (37.65) and Ligand B (24.157) both have low DILI risk, well below the concerning threshold of 60. Ligand B is preferable.

**BBB:** Both ligands have similar BBB penetration (59.131 and 58.201). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.077 and -5.059). This is unusual and suggests poor permeability. However, these values are very close, so it's not a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.126 and -0.581). This is also concerning, indicating poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.46 and 0.337), which is excellent.

**Microsomal Clearance:** Ligand A (30.135) has a higher microsomal clearance than Ligand B (9.363). This means Ligand B is more metabolically stable, a key consideration for enzymes.

**In vitro Half-Life:** Ligand B (34.059) has a significantly longer in vitro half-life than Ligand A (9.747). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.153 and 0.067), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent and the most important factor.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is the superior candidate. It has better QED, lower DILI risk, better solubility, significantly lower microsomal clearance (higher metabolic stability), and a longer in vitro half-life. The slightly lower TPSA and HBD count are also favorable. The Caco-2 and aqueous solubility values are concerning for both, but are similar. Since SRC is an enzyme, metabolic stability and half-life are crucial, making Ligand B the stronger choice.

Output:
1
2025-04-17 15:23:20,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.757 Da and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.63) is better than Ligand B (32.78) as it is below the 140 A^2 threshold.

**logP:** Ligand A (1.781) is within the optimal 1-3 range, while Ligand B (3.552) is slightly higher but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also reasonable.

**QED:** Both ligands have acceptable QED scores (0.79 and 0.604, respectively), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (99.341 percentile), which is a significant concern. Ligand B has a very low DILI risk (4.42 percentile), a major advantage.

**BBB:** Both ligands have relatively high BBB penetration (50.756 and 92.827, respectively), but this is less critical for a non-CNS target like SRC.

**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 (0.273) has a slightly better hERG profile than Ligand B (0.856).

**Microsomal Clearance:** Ligand A (64.989 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (103.497 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-40.413 hours) has a negative half-life, which is not possible and indicates a problem with the data. Ligand B (25.307 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.202 and 0.252, respectively).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly better binding affinity than Ligand B (-6.8 kcal/mol). The 0.8 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk and impossible half-life are major red flags. Ligand B, while having slightly weaker binding, presents a much more favorable safety profile (low DILI) and a reasonable half-life. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies. Given the enzyme-kinase focus, metabolic stability and safety are paramount.

Output:
1
2025-04-17 15:23:20,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.836 and 362.792 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.25) is better than Ligand B (90.04). Both are acceptable, but A is closer to the preferred <140 for oral absorption.

**3. logP:** Both ligands have a logP around 3.6, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A (3) is preferable to Ligand B (4). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable range.

**6. QED:** Ligand A (0.684) has a better QED score than Ligand B (0.571), indicating a more drug-like profile.

**7. DILI:** Ligand B (72.082) has a higher DILI risk than Ligand A (51.609). A is preferred.

**8. BBB:** Ligand A (45.599) has a slightly better BBB score than Ligand B (26.483), but this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.844) is better than Ligand B (-5.325), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.357) is better than Ligand B (-3.846). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.179) has a lower hERG risk than Ligand B (0.577). This is a significant advantage.

**12. Microsomal Clearance:** Ligand B (22.92) has a lower microsomal clearance than Ligand A (27.951), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (88.832) has a much longer in vitro half-life than Ligand B (-5.731). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.247) has lower P-gp efflux than Ligand B (0.155), which is preferable.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is the most important factor for an enzyme inhibitor. The difference of 2.2 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A is superior to Ligand B. While Ligand B has slightly better metabolic stability, Ligand A excels in almost every other crucial parameter: significantly better binding affinity, lower DILI risk, lower hERG risk, better solubility, better Caco-2 permeability, longer half-life, and a higher QED score. The strong binding affinity of Ligand A is particularly important for a kinase inhibitor.

Output:
1
2025-04-17 15:23:20,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.401 and 386.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.39) is better than Ligand B (83.63), being closer to the <140 cutoff for good absorption.

**logP:** Both ligands have acceptable logP values (1.948 and 2.961, respectively) 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 5. Both are acceptable (<10).

**QED:** Both ligands have good QED scores (0.853 and 0.706), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (38.813 and 36.681), both well below the 40 threshold.

**BBB:** Ligand A (85.847) has better BBB penetration than Ligand B (61.923), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.613) has a slightly better Caco-2 permeability than Ligand B (-5.289), suggesting better absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.529 and -2.586). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.291 and 0.57), which is excellent.

**Microsomal Clearance:** Ligand A (15.735) has significantly lower microsomal clearance than Ligand B (50.614), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (10.578) has a longer in vitro half-life than Ligand B (-8.222), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux than Ligand B (0.393), potentially leading to better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.9 and -9.4 kcal/mol). Ligand A is slightly better (-9.9 vs -9.4), but the difference is relatively small.

**Conclusion:**

Ligand A is the better candidate. While both ligands have good potency and acceptable ADME properties, Ligand A demonstrates superior metabolic stability (lower Cl_mic and longer t1/2), better Caco-2 permeability, and lower P-gp efflux. These factors are particularly important for an enzyme target like SRC kinase, as they contribute to improved bioavailability and duration of action. The slightly better binding affinity of Ligand A further strengthens its position.

Output:
0
2025-04-17 15:23:20,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.351 and 370.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is better than Ligand B (75.21), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.137) is within the optimal 1-3 range, while Ligand B (0.401) is slightly below 1, which *could* indicate potential permeability issues.

**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 (7) is also within the acceptable limit of 10.

**QED:** Both ligands have a QED of 0.72, indicating good drug-likeness.

**DILI:** Ligand A (63.513) is slightly higher than Ligand B (55.138), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (55.797 and 57.968), and this isn't a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.273) is worse than Ligand B (-4.586), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.556) is worse than Ligand B (-1.611), indicating lower solubility.

**hERG Inhibition:** Ligand A (0.486) is better than Ligand B (0.281), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (26.653) is significantly better than Ligand B (39.332), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.229) is better than Ligand B (-16.219), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.103) is better than Ligand B (0.061), indicating lower P-gp efflux.

**Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.8), but the difference is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), better hERG risk profile, and better P-gp efflux. Solubility is a concern for Ligand A, but can be addressed through formulation strategies. The slightly lower affinity of Ligand A is acceptable given its superior ADME properties.

Output:
1
2025-04-17 15:23:20,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (79.54) is significantly better than Ligand B (109). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (A: 1.58, B: 1.151), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) is better than Ligand B (HBD=3, HBA=5). Lower HBD is generally preferred.

**QED:** Ligand A (0.844) has a significantly higher QED score than Ligand B (0.605), indicating a more drug-like profile.

**DILI:** Ligand B (56.301) has a slightly higher DILI risk than Ligand A (49.632), but both are reasonably low.

**BBB:** Ligand A (83.986) has a much higher BBB penetration percentile than Ligand B (52.579). While SRC is not a CNS target, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Ligand A (-4.937) has a higher (less negative) Caco-2 value than Ligand B (-5.505), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.668) has better aqueous solubility than Ligand B (-2.587). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.348, B: 0.191), which is excellent.

**Microsomal Clearance:** Ligand A (44.115) has a higher microsomal clearance than Ligand B (24.871). This means Ligand B is more metabolically stable, a key consideration for enzymes.

**In vitro Half-Life:** Ligand B (25.213) has a significantly longer in vitro half-life than Ligand A (3.718). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.014, B: 0.058).

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-0.0). This is a crucial factor.

**Overall Assessment:**

Ligand A has a superior profile in most ADME properties (QED, TPSA, solubility, Caco-2, BBB) and a slightly better binding affinity. However, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2). Given that we are targeting a kinase (an enzyme), metabolic stability is paramount. While the affinity difference is notable, a 7.2 kcal/mol binding affinity is already excellent, and the improved metabolic profile of Ligand B is likely to translate to better *in vivo* efficacy.

Output:
1
2025-04-17 15:23:20,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.341 and 360.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is better than Ligand B (33.95) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (1.337) is optimal, while Ligand B (4.968) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is acceptable.

**H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is within the acceptable range.

**QED:** Ligand A (0.854) has a significantly better QED score than Ligand B (0.666), indicating a more drug-like profile.

**DILI:** Ligand A (84.374) has a higher DILI risk than Ligand B (15.626). This is a significant drawback for Ligand A.

**BBB:** Both ligands have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 concerning.

**hERG Inhibition:** Ligand A (0.469) has a lower hERG inhibition liability than Ligand B (0.854), which is preferable.

**Microsomal Clearance:** Ligand A (3.827) has a much lower microsomal clearance than Ligand B (46.406), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-9.079) has a significantly longer in vitro half-life than Ligand B (3.785), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux liability than Ligand B (0.621).

**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 factors are more critical.

**Overall Assessment:**

Ligand A is superior despite the higher DILI risk. Its significantly better QED, metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG risk outweigh the slightly weaker binding affinity and higher DILI. The high logP of Ligand B is a major concern, potentially leading to poor solubility and bioavailability. While the DILI risk for Ligand A is elevated, it might be mitigated through structural modifications during lead optimization.

Output:
0
2025-04-17 15:23:20,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.459 Da and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.12) is slightly above the preferred <140, while Ligand B (86.88) is well within.

**logP:** Ligand A (0.45) is a bit low, potentially hindering permeability. Ligand B (2.045) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher than ideal.

**H-Bond Acceptors:** Ligand A (7) is good. Ligand B (3) is also good.

**QED:** Both ligands have acceptable QED scores (0.772 and 0.663, both > 0.5).

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (57.619), but both are reasonably acceptable.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (64.25) is slightly better.

**Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.979) is slightly better than Ligand B (-5.241).

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.524) is slightly better than Ligand B (-3.663).

**hERG:** Ligand A (0.128) has a very low hERG risk, which is excellent. Ligand B (0.359) is also low, but higher than A.

**Microsomal Clearance:** Ligand A (39.186) has a higher microsomal clearance than Ligand B (30.026), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (17.337) has a significantly longer half-life than Ligand A (-8.552), which is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.121 and 0.323).

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2), but the difference is relatively small (0.2 kcal/mol).

**Conclusion:**

While Ligand A has a slightly better binding affinity and hERG profile, Ligand B is superior overall. The significantly longer *in vitro* half-life of Ligand B is a crucial advantage for an enzyme target, suggesting better metabolic stability and potential for less frequent dosing. Ligand B also has a more favorable logP and a slightly lower DILI risk. The solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B outweigh the small affinity difference.

Output:
1
2025-04-17 15:23:20,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.352 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.12 and 75.27) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.769) is slightly lower than optimal (1-3), potentially impacting permeation. Ligand B (2.113) is within the optimal 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:** Both ligands have good QED scores (0.842 and 0.802), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.644, which is bordering on high risk. Ligand B has a significantly lower DILI risk (25.785), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (70.105) is better than Ligand B (55.176).

**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 (-2.603 and -2.718). This is a significant concern.

**hERG:** Both ligands show very low hERG inhibition liability (0.183 and 0.076), which is excellent.

**Microsomal Clearance:** Ligand A (1.76 mL/min/kg) has a much lower microsomal clearance than Ligand B (23.512 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-9.619 hours) than Ligand B (-2.797 hours).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.018 and 0.06).

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol), but the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand B is preferable. While Ligand A has slightly better binding affinity and metabolic stability, Ligand B has a much lower DILI risk, which is a critical factor. Both have poor solubility, but the lower DILI risk of Ligand B is a more manageable issue to address through formulation strategies. The difference in binding affinity is not large enough to outweigh the safety concerns associated with Ligand A.

Output:
1
2025-04-17 15:23:20,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.431 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (79.6 and 80.12) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands (1.569 and 1.069) are within the optimal 1-3 range, suggesting good permeability and avoiding solubility issues.

**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 have good QED scores (0.638 and 0.764), indicating drug-like properties.

**7. DILI:** Ligand A (47.926) has a slightly higher DILI risk than Ligand B (33.23), but both are below the concerning threshold of 60.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (74.176) has a higher BBB percentile than Ligand B (58.511), but this is less important here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.147 and -5.111). This is unusual and potentially problematic, indicating poor permeability. However, these values might be errors or represent a specific assay artifact.

**10. Aqueous Solubility:** Both have negative solubility values (-2.287 and -1.188). This is also concerning, and suggests formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.129 and 0.053), which is excellent.

**12. Microsomal Clearance:** Ligand B (6.333 mL/min/kg) has significantly lower microsomal clearance than Ligand A (35.936 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (14.585 hours) has a longer in vitro half-life than Ligand A (11.814 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.187 and 0.035), which is favorable.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), though the difference is small.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both ligands have issues with Caco-2 permeability and solubility, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic and longer t1/2) and a slightly better binding affinity. These factors are particularly important for an enzyme target like SRC kinase. The lower DILI risk is also a positive attribute.

Output:
1
2025-04-17 15:23:20,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.453 and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.43) is slightly higher than Ligand B (67.87), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.411 and 2.138), 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:** Both ligands have good QED scores (0.57 and 0.714), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (61.691 and 60.682), placing them in a moderate risk category, but not excessively high.

**BBB:** Both ligands have moderate BBB penetration (76.774 and 63.358). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.099 and -5.054). This is a potential issue for oral absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.682 and -2.641). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.817) has a slightly higher hERG risk than Ligand B (0.237). Lower hERG is preferred.

**Microsomal Clearance:** Ligand B (28.369) has a lower microsomal clearance than Ligand A (32.916), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (28.731) has a significantly longer in vitro half-life than Ligand A (8.141), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.078 and 0.05).

**Binding Affinity:** Ligand B (-7.1 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.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have solubility and permeability issues, Ligand B exhibits significantly better metabolic stability (lower Cl_mic and longer t1/2) and a slightly better binding affinity. The lower hERG risk is also a plus. The small difference in binding affinity is outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 15:23:20,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.403 and 366.502 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.18) is better than Ligand B (49.41), being under the 140 threshold.

**logP:** Ligand A (0.82) is a bit low, potentially impacting permeability. Ligand B (2.863) is optimal.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better.

**H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.602 and 0.807), indicating drug-likeness.

**DILI:** Ligand A (53.858) has a moderate DILI risk, while Ligand B (18.069) has a very low DILI risk, which is a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (59.946) is higher than Ligand A (48.313), but it's not a deciding factor.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.308) is larger than for Ligand B (-4.813), suggesting potentially worse absorption for Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-3.204) is slightly better than Ligand A (-2.04).

**hERG Inhibition:** Ligand A (0.095) has a very low hERG risk, which is excellent. Ligand B (0.596) is still relatively low, but higher than Ligand A.

**Microsomal Clearance:** Ligand A (33.102) and Ligand B (36.94) are similar, and both are acceptable.

**In vitro Half-Life:** Ligand B (-1.822) has a slightly better half-life than Ligand A (-22.019).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.111).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). Although the difference is small, it is still a factor.

**Overall:**

Ligand B is preferable. While Ligand A has a slightly better binding affinity and hERG risk, Ligand B excels in several critical areas: significantly lower DILI risk, better logP, fewer H-bond donors/acceptors, and a slightly better half-life. The solubility and Caco-2 permeability values are concerning for both, but Ligand B is marginally better. The lower DILI risk is a major advantage for drug development.

Output:
1
2025-04-17 15:23:20,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.447 and 340.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.89) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (66.29) is well within the ideal range.

**logP:** Both ligands (0.786 and 0.751) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**H-Bond Acceptors:** Ligand A (7) is acceptable, and Ligand B (6) is also good.

**QED:** Ligand B (0.89) is significantly better than Ligand A (0.467), indicating a more drug-like profile.

**DILI:** Ligand B (37.922) has a much lower DILI risk than Ligand A (61.419), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (59.248 and 67.041), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-6.154) shows poor permeability, while Ligand B (-5.113) is better, though still not ideal.

**Aqueous Solubility:** Ligand A (-2.985) has poor solubility, while Ligand B (-0.673) is better. Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.691 and 0.564).

**Microsomal Clearance:** Ligand B (19.004) has significantly lower microsomal clearance than Ligand A (33.935), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.072) has a slightly longer half-life than Ligand A (-13.892), which is a positive attribute.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.075 and 0.01).

**Binding Affinity:** Ligand B (-7.6) has a stronger binding affinity than Ligand A (-8.0). While A is slightly better, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B is the superior candidate. It has a better QED score, significantly lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), better solubility, and comparable binding affinity. While Ligand A has slightly better binding affinity, the ADME properties of Ligand B are far more favorable, making it a more promising drug candidate.

Output:
1
2025-04-17 15:23:20,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.455 Da) is slightly lower, which can be favorable for permeability. Ligand B (376.551 Da) is also good.

**TPSA:** Ligand A (42.01) is excellent, well below the 140 threshold for oral absorption. Ligand B (58.12) is still acceptable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.796, B: 3.648), falling within the 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability. Fewer H-bonds generally improve membrane permeability.

**QED:** Both ligands have similar and good QED values (A: 0.786, B: 0.807), indicating good drug-like properties.

**DILI:** Ligand A (25.94) has a significantly lower DILI risk than Ligand B (71.384), which is a major advantage. A DILI percentile above 60 is concerning.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (83.831) has better BBB penetration than Ligand B (75.107), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.515) has a more negative Caco-2 value than Ligand B (-5.186), suggesting slightly better permeability.

**Aqueous Solubility:** Ligand A (-1.545) has better aqueous solubility than Ligand B (-4.059). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.829, B: 0.747), which is good.

**Microsomal Clearance:** Ligand A (2.678) has a significantly lower microsomal clearance than Ligand B (67.769). This indicates better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (9.486) has a longer in vitro half-life than Ligand B (15.958). This is a positive attribute, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.403, B: 0.254), which is favorable.

**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 noticeable advantage.

**Overall:** Ligand A is superior due to its significantly lower DILI risk, better solubility, lower microsomal clearance (better metabolic stability), longer half-life, and slightly better binding affinity. While Ligand B has a slightly higher logP, the advantages of Ligand A outweigh this minor drawback.

Output:
0
2025-04-17 15:23:20,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.454 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good absorption, while Ligand B (85.94) is also acceptable, though slightly higher.

**logP:** Both ligands have good logP values (1.531 and 1.205), falling within the optimal 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 maintaining a balance between solubility and permeability.

**QED:** Both ligands have good QED scores (0.643 and 0.759), indicating drug-like properties.

**DILI:** Ligand A (23.187) has a significantly lower DILI risk than Ligand B (14.618), which is a major advantage.

**BBB:**  BBB isn't a primary concern for SRC kinase inhibitors (unless CNS penetration is specifically desired), but Ligand A (93.912) has a much higher percentile than Ligand B (67.197).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, and suggests poor permeability. Ligand A (-4.585) is slightly better than Ligand B (-4.934).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-1.33) is slightly better than Ligand B (-2.289).

**hERG:** Both ligands show low hERG inhibition liability (0.564 and 0.65), which is good.

**Microsomal Clearance:** Ligand A (21.099) has a higher microsomal clearance than Ligand B (6.336), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (65.414) has a much longer in vitro half-life than Ligand A (-2.628), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.138 and 0.051).

**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 ADME drawbacks.

**Conclusion:**

While Ligand A has a better DILI score and slightly better permeability and solubility, Ligand B's substantially stronger binding affinity (-8.8 vs -7.7 kcal/mol) and significantly improved metabolic stability (longer half-life, lower clearance) are more critical for an enzyme inhibitor. The higher binding affinity is likely to translate to greater efficacy. The DILI risk for Ligand B is still acceptable.

Output:
1
2025-04-17 15:23:20,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.841 and 371.439 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.4) is better than Ligand B (65.49), both are acceptable, but lower TPSA generally favors better absorption.

**logP:** Both ligands have logP values (3.355 and 4.277) within the optimal range of 1-3, although Ligand B is pushing the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.893) has a significantly better QED score than Ligand B (0.38), indicating a more drug-like profile.

**DILI:** Ligand B (97.635) has a very high DILI risk, significantly higher than Ligand A (65.413). This is a major concern.

**BBB:** Ligand A (74.564) has better BBB penetration than Ligand B (54.827), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.742 and -4.764), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.283 and -5.812), indicating very poor aqueous solubility, a major issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.617 and 0.276), which is positive.

**Microsomal Clearance:** Ligand A (19.057 mL/min/kg) has a much lower microsomal clearance than Ligand B (112.79 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (34.694 hours) has a significantly longer half-life than Ligand B (-20.915 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.259 and 0.676).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -8.3 kcal/mol), which are excellent.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. It has a significantly better QED score, lower DILI risk, lower microsomal clearance (better metabolic stability), and a longer half-life. The binding affinity is comparable between the two. The high DILI risk of Ligand B is a major red flag. While both have solubility and permeability issues, these can potentially be addressed with formulation strategies. The metabolic stability and safety profile of Ligand A make it the preferred choice.

Output:
0
2025-04-17 15:23:20,726 - INFO - Batch 375 complete. Total preferences: 6000
2025-04-17 15:23:20,726 - INFO - Processing batch 376/512...
2025-04-17 15:24:02,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (385.917 and 379.522 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (29.54), being below 140, but Ligand B is significantly better.

**logP:** Ligand A (2.65) is within the optimal 1-3 range. Ligand B (4.247) is slightly above, potentially raising solubility concerns, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, fitting the <5 and <10 rules. Ligand B has 0 HBD and 4 HBA, also within acceptable limits.

**QED:** Both ligands have good QED scores (0.674 and 0.752), indicating drug-like properties.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (41.644). This is a significant negative for Ligand A.

**BBB:** Ligand A (50.679) has a lower BBB penetration percentile than Ligand B (95.463). While not crucial for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.203) shows poor permeability, while Ligand B (-4.881) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.702 and -4.933). This is a major concern for both, requiring formulation strategies.

**hERG Inhibition:** Ligand A (0.316) has a slightly higher hERG risk than Ligand B (0.917).

**Microsomal Clearance:** Ligand A (37.898) has significantly lower microsomal clearance than Ligand B (111.295), indicating better metabolic stability. This is a strong positive for Ligand A.

**In vitro Half-Life:** Ligand A (39.647) has a longer half-life than Ligand B (22.365), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.232) has lower P-gp efflux than Ligand B (0.822), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.4 vs -8.9 kcal/mol) is a critical advantage for an enzyme inhibitor. While both have poor solubility, the lower DILI risk and better Caco-2 permeability of Ligand B make it preferable. The slightly higher logP of Ligand B is manageable.

Output:
1
2025-04-17 15:24:02,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.853 and 370.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.76) is slightly higher than Ligand B (51.66). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have good logP values (1.679 and 2.888), falling within the optimal 1-3 range.

**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:** Ligand A (0.822) has a higher QED score than Ligand B (0.593), suggesting a more drug-like profile.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (34.742). Ligand B is well below the 40% threshold, indicating a significantly lower risk of liver injury.

**BBB:** Ligand A (19.698) has a very low BBB penetration, while Ligand B (88.29) has a high BBB penetration. Since SRC is not a CNS target, this is less critical, but a lower BBB value is preferable to avoid off-target effects.

**Caco-2 Permeability:** Ligand A (-4.786) has poor Caco-2 permeability, while Ligand B (-4.574) also has poor Caco-2 permeability. This suggests potential absorption issues for both, but is less concerning for kinases.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.565 and -2.697). This could pose formulation challenges, but is not a deal-breaker.

**hERG Inhibition:** Ligand A (0.287) has a slightly lower hERG inhibition risk than Ligand B (0.877). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (34.001) has significantly lower microsomal clearance than Ligand B (84.158), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-17.353) has a negative half-life, which is concerning. Ligand B (20.948) has a reasonable in vitro half-life.

**P-gp Efflux:** Ligand A (0.156) has lower P-gp efflux than Ligand B (0.289), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.1) has a slightly stronger binding affinity than Ligand A (-7.6). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B has a significantly better safety profile (lower DILI) and metabolic stability (lower Cl_mic), and a slightly better binding affinity. While Ligand A has a better QED and lower hERG risk, the poor half-life and higher DILI are major concerns. The slightly better affinity of Ligand B outweighs the minor advantages of Ligand A, especially considering the importance of metabolic stability for kinase inhibitors.

Output:
1
2025-04-17 15:24:02,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.443 and 358.408 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (61.28), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.363) is optimal, while Ligand B (3.137) is towards the higher end of 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 4 HBA, and Ligand B has 5 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.681 and 0.847, respectively), indicating drug-like properties.

**7. DILI:** Ligand B (48.313) has a higher DILI risk than Ligand A (17.798). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (77.821) has better BBB penetration than Ligand A (47.15). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.755) is slightly better than Ligand B (-4.963).

**10. Aqueous Solubility:** Ligand A (-1.621) has better aqueous solubility than Ligand B (-3.95). This is a positive for Ligand A.

**11. hERG Inhibition:** Ligand A (0.191) has a much lower hERG inhibition liability than Ligand B (0.864). This is a crucial advantage for Ligand A, minimizing cardiotoxicity risk.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (27.779 and 27.389 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (11.689 hours) has a significantly longer in vitro half-life than Ligand A (-1.946 hours). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux liability than Ligand B (0.164). This is a slight advantage for Ligand A.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a 0.9 kcal/mol difference, which is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a better binding affinity and a longer half-life, which are important for an enzyme target. However, Ligand A exhibits significantly better safety profiles with lower DILI and hERG risk, and better solubility. The affinity difference, while notable, isn't large enough to overcome the substantial safety concerns associated with Ligand B. Considering the enzyme-specific priorities, the improved safety profile of Ligand A makes it the more viable drug candidate.

Output:
0
2025-04-17 15:24:02,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.491 Da) is slightly higher than Ligand B (342.403 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (101.8) is slightly better than Ligand A (111.21).

**logP:** Ligand A (0.126) is quite low, potentially hindering permeability. Ligand B (0.847) is better, falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 3/6, B: 2/6), within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.506, B: 0.81), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (26.095) has a much lower DILI risk than Ligand B (56.805), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (48.74) has a higher BBB value than Ligand A (15.432), but this is less important.

**Caco-2 Permeability:** Ligand A (-6.079) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.189) is better, but still not great.

**Aqueous Solubility:** Ligand A (-0.996) has poor aqueous solubility. Ligand B (-2.12) is even worse. This is a significant drawback for both.

**hERG:** Ligand A (0.155) has a very low hERG risk, a major advantage. Ligand B (0.408) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-14.797) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (0.2) has a very high clearance, suggesting rapid metabolism. This is a critical difference.

**In vitro Half-Life:** Ligand A (4.979) has a longer half-life than Ligand B (2.509), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.009, B: 0.029).

**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 ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a better logP value. However, it suffers from higher DILI risk, significantly higher microsomal clearance (lower metabolic stability), and worse solubility. Ligand A has a much better safety profile (DILI, hERG) and metabolic stability, but its low logP and poor Caco-2 permeability are major concerns.

Despite the affinity advantage of Ligand B, the combination of poor metabolic stability and solubility, coupled with the higher DILI risk, makes it a less attractive candidate. Ligand A's superior metabolic stability and safety profile, while hampered by permeability issues, provides a better starting point for optimization. Solubility and permeability can be addressed through structural modifications, while improving metabolic stability is often more challenging.

Output:
0
2025-04-17 15:24:02,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.407 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.15) is slightly higher than Ligand B (61.88). Both are within acceptable limits for oral absorption (<140), but Ligand B is significantly better.

**logP:** Both ligands have good logP values (1.608 and 1.17), 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.

**QED:** Ligand B (0.594) has a better QED score than Ligand A (0.352), indicating a more drug-like profile.

**DILI:** Ligand A (87.786) has a significantly higher DILI risk than Ligand B (26.095). This is a major concern for Ligand A.

**BBB:**  BBB is not a primary concern for a general oncology target like SRC, but Ligand B (67.08) has a higher percentile than Ligand A (48.662).

**Caco-2 Permeability:** Ligand A (-5.84) has a negative Caco-2 value, which is concerning and suggests poor permeability. Ligand B (-4.88) is also negative, but less so.

**Aqueous Solubility:** Ligand A (-3.483) has very poor aqueous solubility, while Ligand B (-0.706) is better, though still not ideal.

**hERG:** Ligand A (0.166) has a slightly higher hERG risk than Ligand B (0.521), but both are relatively low.

**Microsomal Clearance:** Ligand A (46.544) and Ligand B (42.169) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-25.995) has a significantly longer in vitro half-life than Ligand A (15.49). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.195) has lower P-gp efflux liability than Ligand B (0.02), which is favorable.

**Binding Affinity:** Ligand A (-9.5 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 Ligand A's superior binding affinity, its poor solubility, negative Caco-2 permeability, high DILI risk, and lower half-life are significant drawbacks. Ligand B, while having a weaker binding affinity, presents a much more favorable ADME-Tox profile, with better solubility, permeability, lower DILI risk, and a longer half-life. The 2.2 kcal/mol difference in binding affinity could potentially be overcome with further optimization of Ligand B, whereas addressing the severe ADME issues of Ligand A would likely require substantial structural changes that could diminish its potency.

Output:
1
2025-04-17 15:24:02,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.6) is significantly better than Ligand B (89.87). TPSA < 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have good logP values (2.553 and 1.299), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4). Both are within the acceptable range of <=10.

**QED:** Ligand A (0.763) is better than Ligand B (0.643), indicating a more drug-like profile.

**DILI:** Ligand A (9.151) has a much lower DILI risk than Ligand B (13.183). This is a significant advantage.

**BBB:** Ligand A (72.664) has a better BBB penetration percentile than Ligand B (32.959). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.994) is better than Ligand B (-4.673), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-1.549 and -1.715). This is a potential concern for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.752) has a lower hERG risk than Ligand B (0.233). This is a crucial advantage, minimizing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (49.16) has a slightly better (lower) microsomal clearance than Ligand B (41.736), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.362) has a slightly better in vitro half-life than Ligand B (-0.793).

**P-gp Efflux:** Ligand A (0.112) has a lower P-gp efflux liability than Ligand B (0.047), which is favorable for bioavailability.

**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 A consistently outperforms Ligand B across most ADME-Tox properties, including DILI, hERG, BBB, and P-gp efflux. While both have similar binding affinities and solubility concerns, the superior safety profile and predicted absorption/distribution characteristics of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 15:24:02,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.466 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.95) is still under 140, but less favorable than A.

**3. logP:** Ligand A (2.173) is optimal (1-3). Ligand B (0.45) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well within the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 4 respectively), within the limit of 10.

**6. QED:** Both ligands have good QED scores (0.816 and 0.748), indicating drug-like properties.

**7. DILI:** Ligand A (18.379) has a much lower DILI risk than Ligand B (31.097). This is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.327) is higher than Ligand B (66.615).

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it is hard to interpret.

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified, so it is hard to interpret.

**11. hERG Inhibition:** Ligand A (0.316) has a much lower hERG risk than Ligand B (0.124). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (2.126) has lower clearance, suggesting better metabolic stability, than Ligand B (3.491).

**13. In vitro Half-Life:** Ligand A (-10.931) has a longer half-life than Ligand B (-13.744).

**14. P-gp Efflux:** Both are very low, indicating high efflux.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While both are good, the 1.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better logP, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer half-life), and slightly better binding affinity. While both have issues with Caco-2 and solubility, the ADME properties of Ligand A are significantly more favorable, making it a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 15:24:02,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.435 and 364.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (90.98 and 97.11) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.209) is slightly low, potentially hindering permeation. Ligand B (2.819) 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 reasonable numbers of H-bond donors and acceptors, likely not causing major issues.

**QED:** Both ligands have good QED scores (0.69 and 0.735), indicating drug-like properties.

**DILI:** Ligand A (14.23) has a significantly lower DILI risk than Ligand B (68.321), which is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (64.482) has a higher BBB value than Ligand A (46.879), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.208 and -4.747). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon.

**Aqueous Solubility:** Ligand A (-0.796) has slightly better solubility than Ligand B (-3.702). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.185 and 0.18), which is excellent.

**Microsomal Clearance:** Ligand A (-38.777) has a much lower (better) microsomal clearance than Ligand B (23.077), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-7.719) has a longer in vitro half-life than Ligand B (6.884), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.001 and 0.064).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). The difference is 1.4 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a better binding affinity and a logP within the optimal range. However, its significantly higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2) are major drawbacks. Ligand A, while having a slightly lower affinity and a less optimal logP, exhibits a much more favorable safety profile (lower DILI) and better metabolic stability. Given the enzyme-kinase specific priorities, metabolic stability and safety are crucial. The 1.4 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand A, while mitigating the high DILI risk of Ligand B would be more challenging.

Output:
0
2025-04-17 15:24:02,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.53 Da and 355.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (133.7) is still under 140, but less favorable than A.

**logP:** Ligand A (3.102) is optimal (1-3). Ligand B (0.618) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 6 HBA) is acceptable but less optimal.

**QED:** Ligand A (0.713) is strong, indicating good drug-likeness. Ligand B (0.224) is poor, raising concerns.

**DILI:** Both ligands have acceptable DILI risk (28.34 and 33.35 respectively, both <40).

**BBB:** Ligand A (86.43) has better BBB penetration potential than Ligand B (42.0). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.901 and -4.944). This is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, we must consider this in conjunction with other properties.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.024 and -0.914). Again, this is concerning and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.398 and 0.107).

**Microsomal Clearance:** Ligand A (60.124) has higher clearance than Ligand B (39.263). This means Ligand B is more metabolically stable, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-18.39) has a significantly longer half-life than Ligand A (-8.44). This is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.293 and 0.009).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.6 and -8.2 kcal/mol). Ligand B is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand B has a significant advantage in metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. However, Ligand A has superior TPSA, logP, QED, and BBB penetration. Both have concerningly low solubility and Caco-2 permeability values. The better metabolic stability and half-life of Ligand B are crucial for an enzyme target like SRC kinase, outweighing the slightly better physicochemical properties of Ligand A. The negative solubility and permeability values are red flags for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 15:24:02,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (330.475 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (27.82) is significantly better than Ligand B (58.64). A TPSA under 140 is good for oral absorption, and both are well within this limit, but A is preferable.

**logP:** Ligand A (4.882) is a bit high, potentially leading to solubility issues, while Ligand B (2.511) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 1 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 (0.662 and 0.751), indicating good drug-like properties.

**DILI:** Ligand A (32.571) has a slightly higher DILI risk than Ligand B (24.738), but both are below the concerning threshold of 60.

**BBB:** Both have reasonable BBB penetration, but Ligand A (83.56) is better than Ligand B (76.076). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.236) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.667) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.546) has very poor solubility, while Ligand B (-3.159) is better, though still not ideal.

**hERG Inhibition:** Ligand A (0.948) has a lower hERG risk than Ligand B (0.216), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-9.21) has a *much* lower (better) microsomal clearance than Ligand B (53.368), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (16.351) has a longer half-life than Ligand B (4.565), which is desirable.

**P-gp Efflux:** Ligand A (0.648) has a lower P-gp efflux liability than Ligand B (0.078), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.3) has a significantly stronger binding affinity than Ligand A (0.0). This is the most important factor for an enzyme inhibitor. The difference of >9 kcal/mol is substantial.

**Overall Assessment:**

While Ligand A has some advantages in terms of hERG, metabolic stability, half-life, and P-gp efflux, its extremely poor solubility and Caco-2 permeability are major drawbacks. Ligand B's significantly superior binding affinity (-9.3 vs 0.0 kcal/mol) outweighs its slightly higher logP, DILI, and P-gp efflux. The binding affinity difference is so large that it's likely to overcome the other ADME liabilities, especially if formulation strategies can be employed to improve solubility.

Output:
1
2025-04-17 15:24:02,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 Da and 364.433 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.79) is better than Ligand B (78.87). Both are below the 140 A^2 threshold for good absorption, but lower TPSA is generally preferred.

**logP:** Both ligands have good logP values (2.183 and 1.418), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 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:** Ligand A (0.907) has a significantly higher QED score than Ligand B (0.649), indicating a more drug-like profile.

**DILI:** Ligand A (15.626) has a much lower DILI risk than Ligand B (11.361), which is a significant advantage. Both are below the 40 threshold.

**BBB:** Both ligands have reasonable BBB penetration (69.407 and 65.878), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.977 and -4.823). 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 (-1.6 and -1.356). Again, the scale is not specified, but negative values suggest poor solubility.

**hERG Inhibition:** Ligand A (0.615) has a lower hERG inhibition liability than Ligand B (0.489), which is preferable. Both are relatively low risk.

**Microsomal Clearance:** Ligand A (0.977) has significantly lower microsomal clearance than Ligand B (24.631), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (20.731) has a much longer in vitro half-life than Ligand B (-6.011), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.08).

**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 difference that can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better QED score, lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a much stronger binding affinity. While both have questionable solubility and permeability based on the negative values, the superior potency and ADME properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 15:24:02,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (331.379 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (83.56 and 79.9) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.684 and 2.394) within the optimal 1-3 range. Ligand B is slightly better here, being closer to 1.

**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 within the acceptable limit of 10.

**QED:** Both ligands have QED values (0.587 and 0.557) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 88.872, which is high. Ligand B has a DILI risk of 54.285, which is considerably better, falling within the acceptable range (<60). This is a significant advantage for Ligand B.

**BBB:** Both ligands have relatively low BBB penetration (56.107 and 89.453). Since SRC is not a CNS target, this is not a major concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.436 and -5.146), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.609 and -2.942), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.882 and 0.703), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (21.408) than Ligand B (26.987), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (65.674) than Ligand B (22.463), which is desirable. This is another positive for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.681 and 0.131), which is good.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-8.3 kcal/mol) 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 has a much stronger binding affinity and better metabolic stability and half-life. However, it has a significantly higher DILI risk and poor solubility. Ligand B has a much lower DILI risk, but weaker binding affinity and poorer metabolic stability.

Given the priorities for enzyme inhibitors, binding affinity is paramount. The 1.3 kcal/mol difference in binding affinity is substantial. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications during lead optimization. The poor solubility of both is a significant issue, but can also be addressed through formulation strategies or chemical modifications.

Output:
0
2025-04-17 15:24:02,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (85.25) is higher than Ligand B (67.43), but both are within acceptable limits.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 1.442, Ligand B: 2.49), which is optimal.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2) and HBA (Ligand A: 5, Ligand B: 4) counts, suggesting a good balance between solubility and permeability.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.708, Ligand B: 0.646), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (Ligand A: 23.614, Ligand B: 26.25), which is favorable.

**BBB:** Ligand B (74.758) has a better BBB penetration percentile than Ligand A (54.013), but BBB is not a primary concern for a non-CNS target like SRC.

**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 not uncommon. We'll need to consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests very poor aqueous solubility, a significant concern for bioavailability. Ligand A (-1.611) is slightly better than Ligand B (-3.171).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.077, Ligand B: 0.463), which is excellent.

**Microsomal Clearance:** Ligand A (10.191 mL/min/kg) has significantly lower microsomal clearance than Ligand B (67.284 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (12.638 hours) has a longer in vitro half-life than Ligand B (19.55 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.023, Ligand B: 0.145), which is good.

**Binding Affinity:** Ligand A (-10.2 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 better candidate. While both have issues with solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-10.2 vs -8.4 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme target like SRC kinase. The slightly better solubility of Ligand A is also a minor benefit. The solubility issues would need to be addressed through formulation strategies, but the potency and metabolic stability of Ligand A make it a more promising starting point.

Output:
0
2025-04-17 15:24:02,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (346.515 and 349.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (114.87) is still within acceptable limits, but higher than A.

**3. logP:** Ligand A (3.809) is optimal (1-3). Ligand B (-0.467) is significantly below 1, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 1-2 HBD, within the acceptable limit of 5.

**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 similar QED values (0.795 and 0.721), indicating good drug-likeness.

**7. DILI:** Both ligands have the same DILI risk (29.042), which is low and favorable.

**8. BBB:** Ligand A (73.362) has better BBB penetration than Ligand B (35.324), but BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.624) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.624) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.668) has poor aqueous solubility. Ligand B (-2.077) is also poor, but slightly better than A.

**11. hERG Inhibition:** Ligand A (0.405) has a low hERG risk. Ligand B (0.071) has an even lower, more favorable hERG risk.

**12. Microsomal Clearance:** Ligand A (70.678) has higher clearance, indicating lower metabolic stability. Ligand B (-10.511) has negative clearance, which is highly unusual and suggests excellent metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.86) has a negative half-life, which is not possible. Ligand B (11.865) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.404) has moderate P-gp efflux. Ligand B (0.006) has very low P-gp efflux, which is favorable.

**15. Binding Affinity:** Ligand A (-9.2) has significantly better binding affinity than Ligand B (-6.9). The difference of 2.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its poor Caco-2 permeability, poor solubility, and questionable half-life are major concerns. Ligand B, while having a weaker binding affinity, exhibits significantly better ADME properties, including excellent metabolic stability (negative Cl_mic), low P-gp efflux, and a reasonable half-life. Given the enzyme-specific priorities, metabolic stability and reasonable solubility are crucial. The 2.3 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, while fixing the ADME issues of Ligand A would be more challenging.

Output:
1
2025-04-17 15:24:02,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Ligand A (491.585 Da) is within the ideal range (200-500 Da). Ligand B (345.359 Da) is also within range, and on the lower side, which *could* be beneficial for permeability, but isn't a major concern.

**TPSA:** Ligand A (54.02) is good for oral absorption. Ligand B (120.32) is approaching the upper limit for good absorption, but is still acceptable.

**logP:** Ligand A (4.751) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.294) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is well within acceptable limits. Ligand B (HBD=3, HBA=6) is also acceptable, but has more HBA.

**QED:** Ligand A (0.369) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.703) is above 0.5, suggesting better drug-likeness.

**DILI:** Ligand A (82.241) has a higher DILI risk than Ligand B (56.146), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (61.535) is better than Ligand B (19.349).

**Caco-2 Permeability:** Ligand A (-4.944) has poor predicted permeability. Ligand B (-5.408) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-6.293) has very poor predicted solubility. Ligand B (-2.832) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.621) has a slightly higher hERG risk than Ligand B (0.202), which is preferable.

**Microsomal Clearance:** Ligand A (28.527) has moderate clearance. Ligand B (-18.016) has negative clearance, indicating high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (50.772) has a reasonable half-life. Ligand B (-35.024) has a negative half-life, which is not realistic but indicates extremely high stability.

**P-gp Efflux:** Ligand A (0.217) has low P-gp efflux, which is good. Ligand B (0.013) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-9.3 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor solubility, moderate clearance, and a lower QED score. Ligand B has better ADME properties (solubility, metabolic stability, QED, P-gp efflux) but significantly weaker binding affinity.

Despite the ADME concerns with Ligand A, the substantial difference in binding affinity (-10.1 vs -9.3 kcal/mol) is likely to be the dominant factor in *in vivo* efficacy. The lower solubility and moderate clearance can potentially be addressed through formulation strategies or further chemical modifications. The higher DILI risk is a concern, but not insurmountable.

Output:
1
2025-04-17 15:24:02,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.35 and 352.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (126.13 and 123.22) are slightly above the optimal <140 for good oral absorption, but acceptable.

**logP:** Ligand A (-1.173) is a bit low, potentially hindering permeation. Ligand B (-0.973) is also on the lower side, but slightly better than A.

**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 10 HBA. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**QED:** Both ligands have QED values (0.69 and 0.523) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (60.92) has a higher DILI risk than Ligand B (57.00), but both are acceptable.

**BBB:** Ligand A (45.91) has a lower BBB penetration than Ligand B (73.79). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.502 and -5.316), indicating poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.628 and -0.33), indicating poor solubility. This is also a significant concern.

**hERG Inhibition:** Ligand A (0.045) has a very low hERG risk, which is excellent. Ligand B (0.264) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-12.06) has a much lower (better) microsomal clearance than Ligand B (36.667), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (33.161) has a longer half-life than Ligand B (20.914), which is desirable.

**P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, while Ligand B (0.11) has slightly higher efflux.

**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 of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both compounds, Ligand B's substantially stronger binding affinity (-8.5 kcal/mol vs 0.0 kcal/mol) is a decisive factor. The difference in affinity is large enough to compensate for the slightly higher P-gp efflux and DILI risk. The better metabolic stability of Ligand A is a plus, but the potency of Ligand B is paramount for an enzyme target like SRC.

Output:
1
2025-04-17 15:24:02,611 - INFO - Batch 376 complete. Total preferences: 6016
2025-04-17 15:24:02,611 - INFO - Processing batch 377/512...
2025-04-17 15:24:42,443 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.475 and 336.351 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (102.57 and 95.42) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (1.311) is optimal, while Ligand B (0.205) is slightly low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A (4 HBD, 4 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable values within the guidelines.

**QED:** Both ligands have good QED scores (0.63 and 0.778), indicating drug-like properties.

**DILI:** Ligand A (45.56) has a lower DILI risk than Ligand B (64.56), which is preferable.

**BBB:** Ligand A (61.38) has a moderate BBB score, while Ligand B (13.067) is very low. Since SRC is not a CNS target, this is less critical, but still a slight advantage for A.

**Caco-2 Permeability:** Ligand A (-5.607) has a lower Caco-2 permeability than Ligand B (-4.864), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.645 and -2.562 respectively). This is a significant concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.566 and 0.128), which is excellent.

**Microsomal Clearance:** Ligand A (-39.173) has significantly lower microsomal clearance than Ligand B (-34.329), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (90.869) has a much longer in vitro half-life than Ligand B (10.498), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.016 and 0.021), which is good.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This is a 1.4 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADMET properties, particularly in metabolic stability (lower Cl_mic and longer t1/2) and lower DILI risk. The solubility is poor for both, but the metabolic advantages of Ligand A are more critical for an enzyme target like SRC kinase. The slightly lower Caco-2 permeability of A is a concern, but can potentially be addressed through formulation strategies. The better binding affinity of B is not enough to overcome the metabolic liabilities.

Output:
1
2025-04-17 15:24:42,443 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.555 Da and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (104.73) is still within acceptable limits, but less favorable.

**logP:** Ligand A (3.372) is optimal. Ligand B (0.994) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.778) is very good, indicating strong drug-likeness. Ligand B (0.563) is acceptable, but less optimal.

**DILI:** Ligand A (31.601) has a very low DILI risk. Ligand B (19.155) also has a low DILI risk, but slightly higher than A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (74.176) is better than Ligand B (50.679).

**Caco-2 Permeability:** Ligand A (-5.17) is poor, indicating low intestinal absorption. Ligand B (-4.786) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.438 and -2.285 respectively). This is a significant concern for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.259 and 0.14 respectively).

**Microsomal Clearance:** Ligand A (46.611) has a lower clearance, suggesting better metabolic stability. Ligand B (63.617) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-13.298) has a longer half-life. Ligand B (-38.056) has a much shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.197 and 0.038 respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.6 kcal/mol). Ligand B is slightly better.

**Conclusion:**

While both ligands have strong binding affinity, Ligand A is superior overall. Its better TPSA, logP, QED, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly poorer Caco-2 permeability. The solubility is a concern for both, but can be addressed with formulation strategies. The slightly better affinity of Ligand B is not enough to overcome the significant metabolic liability.

Output:
0
2025-04-17 15:24:42,443 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 360.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.45) is slightly above the optimal <140, but acceptable. Ligand B (58.64) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands (1.475 and 2.287) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is good. Ligand B has 1 HBD, also good.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.557 and 0.82), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (47.421 and 38.503), both below the 40 threshold. Ligand B is slightly better.

**BBB:** Ligand A (53.121) and Ligand B (71.617). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.159) and Ligand B (-4.808) are both negative, 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. Without knowing the scale, it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.445 and -3.379). This is a concern and would need to be addressed through formulation or structural modification.

**hERG Inhibition:** Both ligands have low hERG risk (0.48 and 0.406).

**Microsomal Clearance:** Ligand A (43.93) has moderate clearance, while Ligand B (-2.835) has *negative* clearance, which is highly unusual and suggests excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-3.348) has a negative half-life, which is not possible. This is a data error. Ligand B (13.942) has a good half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.048 and 0.407).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. It has a better binding affinity, excellent metabolic stability (negative Cl_mic), a good half-life, and a slightly better DILI score. While both have poor solubility, the strong binding affinity and metabolic stability of Ligand B make it more likely to succeed, even with formulation challenges. The negative half-life for Ligand A is a clear red flag, likely a data error, and further disqualifies it.

Output:
1
2025-04-17 15:24:42,443 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.66) is better than Ligand B (89.35), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.818) is optimal, while Ligand B (0.615) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 threshold.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 6, respectively), well below the 10 threshold.

**QED:** Both ligands have good QED scores (0.802 and 0.843), indicating drug-like properties.

**DILI:** Ligand A (37.495) has a significantly lower DILI risk than Ligand B (59.752). This is a major advantage.

**BBB:** Ligand A (84.684) has better BBB penetration than Ligand B (70.803), but BBB isn't a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.837 and -4.864), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.5 and -2.181), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.78) has a lower hERG risk than Ligand B (0.113). This is a significant advantage.

**Microsomal Clearance:** Ligand A (11.788 mL/min/kg) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (14.227 mL/min/kg).

**In vitro Half-Life:** Ligand A (-14.617 hours) has a much longer half-life than Ligand B (-3.095 hours). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux liability than Ligand B (0.04).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). However, the difference is small (0.2 kcal/mol) and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADMET properties: lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand A is more favorable for development as an enzyme inhibitor.

Output:
1
2025-04-17 15:24:42,444 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.482 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (71.78), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands (2.514 and 2.402) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.762 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A (19.232) has a significantly lower DILI risk than Ligand B (21.404), which is a crucial advantage.

**BBB:** Ligand A (92.904) has a much higher BBB penetration potential than Ligand B (74.486). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.286) shows better Caco-2 permeability than Ligand B (-4.888).

**Aqueous Solubility:** Ligand A (-2.369) has better aqueous solubility than Ligand B (-1.837). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.552) has a slightly higher hERG risk than Ligand B (0.299). This is a concern, but not a deal-breaker.

**Microsomal Clearance:** Ligand A (29.505) has significantly lower microsomal clearance than Ligand B (44.516), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-12.435) has a much longer in vitro half-life than Ligand B (41.295). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.164) shows lower P-gp efflux than Ligand B (0.061). Lower efflux is preferable for better bioavailability.

**Binding Affinity:** Ligand B (-9.4) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is only 0.9 kcal/mol, and the other advantages of Ligand A likely outweigh this.

**Conclusion:**

Ligand A is the more promising drug candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME properties, including lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and better Caco-2 permeability. These factors are particularly important for an enzyme target like SRC kinase. The hERG risk for Ligand A is slightly higher, but manageable.

Output:
1
2025-04-17 15:24:42,444 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (344.419 and 346.475 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.05) is slightly higher than Ligand B (76.02), but both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.903) is slightly lower than the optimal range (1-3), potentially impacting permeability. Ligand B (2.811) is within the optimal range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) 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 (0.873 and 0.76), indicating good drug-like properties.

**7. DILI:** Ligand A (56.805) and Ligand B (47.926) both have low DILI risk, below the 60 threshold. Ligand B is slightly better.

**8. BBB:** Both ligands have similar BBB penetration (66.77 and 61.923), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.111 and -4.948), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.001 and -3.903), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.246 and 0.337).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance rates (38.62 and 37.849), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.706) has a significantly longer half-life than Ligand B (8.873). This is a major advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.073 and 0.187).

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 0.4 kcal/mol difference is notable.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison:**

Ligand A has a better binding affinity and a significantly longer half-life. However, both ligands suffer from poor predicted permeability and solubility. Ligand B has a slightly better logP and DILI score. The difference in binding affinity (0.4 kcal/mol) is significant enough to potentially outweigh the slightly better logP and DILI of Ligand B, *if* the solubility and permeability issues can be addressed through formulation or further chemical modification. The longer half-life of Ligand A is also a substantial benefit.

Output:
0
2025-04-17 15:24:42,444 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.535 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.79) is better than Ligand B (58.64), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (2.406) is optimal (1-3), while Ligand A (0.506) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**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 (0.668 and 0.795, respectively), indicating drug-like properties.

**DILI:** Ligand A (29.003) has a significantly lower DILI risk than Ligand B (18.418), indicating a safer profile.

**BBB:** Ligand B (76.735) has a better BBB penetration score than Ligand A (46.026), but BBB is not a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.314) has a worse Caco-2 permeability than Ligand B (-4.844).

**Aqueous Solubility:** Ligand A (-1.256) has a slightly better aqueous solubility than Ligand B (-3.35).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.234 and 0.26, respectively).

**Microsomal Clearance:** Ligand A (-0.961) has a better (lower) microsomal clearance than Ligand B (15.904), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.588 hours) has a slightly better in vitro half-life than Ligand B (18.799 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.095, respectively).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is slightly more favorable. While Ligand B has a better logP and Caco-2 permeability, Ligand A demonstrates a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The binding affinities are essentially the same. The slightly better solubility of Ligand A is also a plus. Therefore, Ligand A is the more promising candidate.

Output:
0
2025-04-17 15:24:42,445 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.37 and 342.41 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (94.05) is slightly above the preferred <140, but acceptable. Ligand B (48.15) is excellent, well below 140.

**logP:** Ligand A (3.232) is within the optimal range of 1-3. Ligand B (4.975) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, well within acceptable limits. Ligand B has 0 HBD and 4 HBA, also good.

**QED:** Both ligands have similar QED values (0.785 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (82.784) has a higher DILI risk than Ligand B (60.682), indicating a potential liver toxicity concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.978) has a higher BBB penetration than Ligand A (58.782), but this isn't a major factor here.

**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:** Ligand A (-3.926) has better solubility than Ligand B (-6.032). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.164 and 0.639).

**Microsomal Clearance:** Ligand A (47.738) has significantly lower microsomal clearance than Ligand B (80.728), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-33.726) has a longer in vitro half-life than Ligand B (-17.32), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.781).

**Binding Affinity:** Ligand A (-9.4 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.

**Conclusion:**

Despite Ligand A's higher DILI risk, its substantially stronger binding affinity (-9.4 vs -7.9 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) make it the more promising candidate. The difference in affinity is significant enough to prioritize over the slightly elevated DILI risk, especially since the hERG risk is low for both. Solubility is better for A as well.

Output:
0
2025-04-17 15:24:42,445 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (87.74) is better than Ligand B (99.67), falling well below the 140 threshold for oral absorption.

**logP:** Ligand A (-0.551) is a bit low, potentially hindering permeation. Ligand B (1.49) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.721 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (44.591) has a slightly higher DILI risk than Ligand B (35.867), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.97) is better than Ligand B (33.54).

**Caco-2 Permeability:** Ligand A (-4.925) has a very poor Caco-2 value, indicating poor intestinal absorption. Ligand B (-5.562) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.41 and -3.115). This is a significant concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.109 and 0.222).

**Microsomal Clearance:** Ligand A (23.316 mL/min/kg) has a significantly lower (better) microsomal clearance than Ligand B (8.934 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.207 hours) has a very short half-life, while Ligand B (0.7 hours) is slightly better. Both are poor.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.015 and 0.062).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks. The difference of 1.5 kcal/mol is significant.

**Conclusion:**

Despite the solubility and permeability concerns for both, Ligand A's significantly superior binding affinity (-9.4 kcal/mol vs -7.9 kcal/mol) and better metabolic stability (lower Cl_mic) make it the more promising candidate. While Ligand B has a better logP, the potency difference is substantial. Addressing the solubility issues through formulation strategies might be feasible, but improving potency is much more challenging.

Output:
0
2025-04-17 15:24:42,445 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.312 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is better than Ligand B (71.34) as both are below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.767 and 3.322), falling within the 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 (HBD=1, HBA=4) is slightly better than Ligand B (HBD=2, HBA=3) in terms of H-bonding potential, being closer to the ideal thresholds.

**QED:** Both ligands have similar QED scores (0.863 and 0.831), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (81.427%) compared to Ligand B (25.979%). This is a major red flag for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (94.455%) has a higher BBB penetration than Ligand B (49.787%).

**Caco-2 Permeability:** Ligand A (-4.231) shows better Caco-2 permeability than Ligand B (-4.82).

**Aqueous Solubility:** Ligand A (-4.156) has slightly better aqueous solubility than Ligand B (-3.793).

**hERG Inhibition:** Ligand A (0.582) has a slightly higher hERG inhibition risk than Ligand B (0.149). Ligand B is much preferred here.

**Microsomal Clearance:** Ligand A (82.314) has a higher microsomal clearance than Ligand B (49.815), suggesting lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand B (28.896 hours) has a much longer in vitro half-life than Ligand A (0.072 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux than Ligand B (0.136).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 0.7 kcal/mol is substantial and favors Ligand B.

**Conclusion:**

Despite Ligand A having slightly better Caco-2 permeability and BBB penetration, Ligand B is the far superior candidate. The critical factors driving this decision are: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and a stronger binding affinity. These properties are crucial for an enzyme inhibitor to be a viable drug candidate.

Output:
1
2025-04-17 15:24:42,446 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.49) is slightly higher than Ligand B (350.43).

**TPSA:** Both are below the 140 A^2 threshold for good absorption. Ligand B (67.43) is preferable to Ligand A (83.56) as lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.261) is slightly lower than Ligand B (2.948).

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA. Ligand B is preferable here, as fewer HBA generally improve permeability.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-likeness. Ligand B (0.794) is slightly better than Ligand A (0.759).

**DILI:** Ligand A (31.291) has a significantly lower DILI risk than Ligand B (44.048), which is a major advantage.

**BBB:** Ligand B (88.6) shows significantly better BBB penetration than Ligand A (60.023). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.113) has better Caco-2 permeability than Ligand B (-4.237).

**Aqueous Solubility:** Ligand A (-1.843) has better aqueous solubility than Ligand B (-4.19). This is a positive attribute for bioavailability.

**hERG Inhibition:** Ligand A (0.212) has a lower hERG inhibition risk than Ligand B (0.545), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (-13.349) has a much lower (better) microsomal clearance than Ligand B (69.049), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (41.282) has a longer in vitro half-life than Ligand A (11.153). This is a positive attribute, but can be offset by higher clearance.

**P-gp Efflux:** Ligand A (0.034) has lower P-gp efflux liability than Ligand B (0.119), which is preferable.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.7). However, the difference is less than 1.5 kcal/mol, and can be outweighed by 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 critical areas for an enzyme inhibitor: lower DILI risk, lower hERG risk, significantly better metabolic stability (lower Cl_mic), better solubility, and lower P-gp efflux. These factors are more important than the marginal difference in binding affinity. The better Caco-2 permeability also supports better absorption.

Output:
0
2025-04-17 15:24:42,446 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.37 and 346.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.73 and 95.32) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands (1.765 and 1.771) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have a QED of 0.812, indicating a strong drug-like profile.

**DILI:** Ligand A has a DILI risk of 69.252, while Ligand B is 43.66. Ligand B is significantly better here, falling well below the 60 threshold for high risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.772) is slightly better than Ligand B (36.448).

**Caco-2 Permeability:** Ligand A (-5.047) is slightly better than Ligand B (-4.542), indicating potentially better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.766) is better than Ligand B (-2.172), which is a significant advantage for formulation and bioavailability.

**hERG:** Ligand A (0.376) has a lower hERG risk than Ligand B (0.402), which is preferable.

**Microsomal Clearance:** Ligand A (8.434 mL/min/kg) has much lower clearance than Ligand B (49.368 mL/min/kg), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (38.03 hours) has a significantly longer half-life than Ligand B (-3.048 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.034), which is favorable.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial difference (2.1 kcal/mol) and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding metabolic stability (Cl_mic and t1/2), DILI risk, and solubility. The difference in binding affinity is substantial, but the poor metabolic stability of Ligand B is a major concern for an enzyme inhibitor. A rapidly cleared compound will likely require high doses and may have limited efficacy *in vivo*. The lower DILI risk and better solubility of Ligand A also contribute to its potential for clinical success.

Output:
0
2025-04-17 15:24:42,446 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.79) is better than Ligand B (79.26), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.037) is slightly low, potentially hindering permeation, while Ligand B (0.315) 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 (1 HBD, 7 HBA) is preferable to Ligand B (2 HBD, 5 HBA) as it has fewer hydrogen bond donors and acceptors, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.738 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (6.049). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (79.566 and 64.017), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.1 and -5.446). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.516 and -0.71). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.065) has a lower hERG inhibition risk than Ligand B (0.131), which is favorable.

**Microsomal Clearance:** Ligand B (-24.681) has significantly better metabolic stability (lower clearance) than Ligand A (11.32). This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (10.276) has a longer half-life than Ligand B (0.864).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.004).

**Binding Affinity:** Ligand B (-9.7 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 drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.7 vs -8.2 kcal/mol) and substantially improved metabolic stability (Cl_mic = -24.681 vs 11.32) are critical advantages for an enzyme inhibitor. The lower DILI risk is also a significant benefit. While Ligand A has a slightly better hERG profile and half-life, these are less important than affinity and metabolic stability in this context.

Output:
1
2025-04-17 15:24:42,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.832 Da) is slightly higher than Ligand B (360.451 Da), but both are acceptable.

**TPSA:** Ligand A (80.32) is well below the 140 threshold for oral absorption. Ligand B (119.33) is also below, but closer to the limit.

**logP:** Ligand A (3.718) is within the optimal range (1-3). Ligand B (-0.884) is significantly below, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is good. Ligand B (HBD=4, HBA=6) is also acceptable, but slightly higher.

**QED:** Both ligands have QED values (0.625 and 0.468) indicating reasonable drug-likeness, but Ligand A is better.

**DILI:** Ligand A (93.757) has a high DILI risk, which is a major concern. Ligand B (11.128) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.123) is moderate, while Ligand B (38.581) is low.

**Caco-2 Permeability:** Ligand A (-4.379) is poor, while Ligand B (-5.087) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-5.178) is poor, while Ligand B (-0.68) is also poor, but better than Ligand A.

**hERG:** Ligand A (0.44) is low risk, which is good. Ligand B (0.17) is even lower, and therefore better.

**Microsomal Clearance:** Ligand A (81.837) is relatively high, suggesting faster metabolism. Ligand B (-1.56) is very low, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (74.999) is good, while Ligand B (-18.784) is very poor.

**P-gp Efflux:** Ligand A (0.583) is moderate. Ligand B (0.014) is very low, suggesting minimal efflux.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has 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, but suffers from high DILI risk, poor solubility, and moderate metabolic clearance. Ligand B has excellent metabolic stability (very low Cl_mic), low DILI risk, and low P-gp efflux, but its binding affinity is weaker and logP is concerningly low.

Given the priorities for enzyme inhibitors, metabolic stability and safety (DILI, hERG) are crucial. While the affinity of Ligand A is very attractive, the high DILI risk is a major red flag. The significantly better ADMET profile of Ligand B, particularly the low DILI and excellent metabolic stability, makes it the more promising candidate, despite the weaker binding. Further optimization of Ligand B to improve its affinity and logP would be a reasonable next step.

Output:
1
2025-04-17 15:24:42,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.375 and 354.361 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.14) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (84.65) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (0.457) is quite low, potentially hindering permeability. Ligand B (1.056) is better, falling within 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 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.722 and 0.763), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (58.434 and 61.225), both are acceptable, below the 60 threshold.

**BBB:** Ligand A (61.535) has a moderate BBB penetration, while Ligand B (93.137) has high BBB penetration. This isn't a primary concern for a non-CNS target like SRC kinase, but could be relevant if off-target effects in the CNS are a concern.

**Caco-2 Permeability:** Ligand A (-5.532) has poor Caco-2 permeability, which is a significant concern. Ligand B (-4.647) is better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.99 and -3.295). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.186) has a very low hERG risk, which is excellent. Ligand B (0.31) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (4.713) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (48.168) has significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-46.246) has a very long in vitro half-life, which is highly desirable. Ligand B (14.032) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.004 and 0.031), which is favorable.

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a better binding affinity than Ligand A (-8.8 kcal/mol). The difference is 2 kcal/mol, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a lower hERG risk, its poor Caco-2 permeability and low logP are major drawbacks. Ligand B, despite having higher clearance and a slightly higher hERG risk, has a significantly better binding affinity and a more favorable logP. The stronger binding affinity of Ligand B is likely to be more important for an enzyme inhibitor, and the difference in affinity is large enough to compensate for the slightly less favorable ADME properties.

Output:
1
2025-04-17 15:24:42,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.362 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.82) is slightly above the preferred <140, but acceptable. Ligand B (88.16) is excellent, well below 140.

**logP:** Ligand A (0.494) is a bit low, potentially hindering permeability. Ligand B (2.067) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also good.

**QED:** Both ligands have good QED scores (0.721 and 0.776), indicating drug-likeness.

**DILI:** Ligand A (36.138) has a lower DILI risk than Ligand B (59.519), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (59.364) is slightly better than A (48.197).

**Caco-2:** 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.

**Solubility:** Both have negative solubility values, also unusual. Again, difficult to interpret.

**hERG:** Both ligands have low hERG risk (0.468 and 0.154), which is excellent.

**Microsomal Clearance:** Ligand A (-33.166) has *much* lower (better) microsomal clearance than Ligand B (45.235), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (37.781) has a longer half-life than Ligand B (-48.83), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.022 and 0.071).

**Binding Affinity:** Both have strong binding affinities (-9.5 and -8.1 kcal/mol). Ligand A is slightly better (-9.5 kcal/mol).

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better logP and TPSA, Ligand A has a significantly better DILI score, dramatically better metabolic stability (lower Cl_mic, longer half-life), and slightly better binding affinity. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (DILI) are crucial. The slightly lower logP of Ligand A is a manageable concern, especially given its superior metabolic profile and binding. The unusual Caco-2 and solubility values are concerning for both, but the other factors outweigh this.

Output:
0
2025-04-17 15:24:42,447 - INFO - Batch 377 complete. Total preferences: 6032
2025-04-17 15:24:42,447 - INFO - Processing batch 378/512...
2025-04-17 15:25:24,486 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (361.383 and 365.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.81) is slightly above the preferred <140, while Ligand B (126.13) is well within. This favors Ligand B for better absorption.

**logP:** Ligand A (-0.021) is a bit low, potentially hindering permeation. Ligand B (-0.698) is also on the lower side, but slightly better than A. Both are acceptable, but not optimal.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, while Ligand B has 2 HBD and 9 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.555 and 0.693), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 90.074, which is high. Ligand B has a DILI risk of 76.425, which is still concerning but lower than A. This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (32.067) and Ligand B (23.071) both have low BBB penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.502 and -5.755), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.741 and -1.461), indicating very poor aqueous solubility, a major issue for bioavailability. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.286 and 0.049), which is good.

**Microsomal Clearance:** Ligand A (19.805) has a higher microsomal clearance than Ligand B (3.67), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-9.33) has a negative half-life, which is unrealistic and indicates a very short half-life. Ligand B (1.046) has a short half-life, but is far more reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.034).

**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 small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is significantly better than Ligand A. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A has a very high DILI risk and an unrealistic half-life. Ligand B has a lower DILI risk, better metabolic stability (lower Cl_mic), a more reasonable half-life, and slightly better binding affinity. The slightly better TPSA and QED also contribute to its favorability.



Output:
1
2025-04-17 15:25:24,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.43 and 345.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is better than Ligand B (80.12), both are acceptable but closer to the upper limit for good oral absorption.

**logP:** Both ligands have good logP values (2.233 and 1.483), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.753 and 0.847), indicating good drug-likeness.

**DILI:** Ligand A (23.23) has a significantly lower DILI risk than Ligand B (41.41), which is a major advantage.

**BBB:** Ligand A (56.03) has a lower BBB penetration than Ligand B (69.76). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-4.967) has better Caco-2 permeability than Ligand B (-5.026), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.113) has better aqueous solubility than Ligand B (-2.828), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.124 and 0.179).

**Microsomal Clearance:** Ligand A (7.208) has significantly lower microsomal clearance than Ligand B (46.16), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.155) has a shorter half-life than Ligand B (-19.498), which is a negative. However, the negative value for Ligand B is suspect and likely an error or outlier.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.1).

**Binding Affinity:** Ligand B (-9.5 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.

**Conclusion:**

While Ligand B has a substantially better binding affinity, Ligand A demonstrates superior ADME properties, particularly regarding DILI risk and metabolic stability (lower Cl_mic). The difference in binding affinity is significant, but the improved safety and pharmacokinetic profile of Ligand A are compelling. Given the enzyme-kinase focus, metabolic stability and safety are crucial. The questionable half-life value for Ligand B further reduces its appeal.

Output:
0
2025-04-17 15:25:24,487 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 348.487 Da, B: 346.391 Da) fall comfortably within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (69.64) is significantly better than Ligand B (114.94).  A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

3. **logP:** Both ligands have acceptable logP values (A: 2.249, B: 1.102), falling within the optimal 1-3 range. A is slightly better, being closer to the middle of the range.

4. **HBD:** Both have 2 H-bond donors, which is good.

5. **HBA:** Ligand A has 3 H-bond acceptors, while Ligand B has 7.  Ligand A is preferable here, as keeping HBA below 10 is generally desired.

6. **QED:** Both ligands have good QED scores (A: 0.693, B: 0.74), indicating a generally drug-like profile.  B is slightly better.

7. **DILI:** Both have relatively low DILI risk (A: 6.941, B: 69.911). Ligand A is *much* better here, being well below the 40% threshold for low risk. Ligand B is approaching a concerning level.

8. **BBB:** Not a primary concern for a kinase inhibitor, but A (66.111) is better than B (57.193).

9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.646) is slightly better than B (-5.148), but both are very poor.

10. **Solubility:** Both are negative, indicating poor solubility. A (-2.264) is slightly better than B (-2.694).

11. **hERG:** Both have very low hERG inhibition risk (A: 0.217, B: 0.078). B is slightly better.

12. **Cl_mic:** Ligand A (32.98) has a significantly lower microsomal clearance than Ligand B (43.476). This suggests better metabolic stability for A, a key consideration for kinase inhibitors.

13. **t1/2:** Ligand A (-4.308) has a much longer in vitro half-life than Ligand B (-20.067). This is a significant advantage for A.

14. **Pgp:** Both have very low Pgp efflux liability (A: 0.014, B: 0.048). A is slightly better.

15. **Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent. This removes affinity as a differentiating factor.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While both ligands have excellent affinity, Ligand A clearly wins on metabolic stability (lower Cl_mic, longer t1/2) and DILI risk. Solubility is poor for both, but slightly better for A.



**Conclusion:**

Ligand A is the more promising drug candidate due to its superior metabolic stability, lower DILI risk, and slightly better TPSA, solubility, and Pgp efflux. While both have poor Caco-2 permeability, the other advantages of A outweigh this drawback.

Output:
1
2025-04-17 15:25:24,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.395 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.26) is well below the 140 threshold for good absorption, while Ligand B (110.44) is still acceptable but higher.

**logP:** Ligand A (2.796) is optimal (1-3). Ligand B (0.762) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar, good QED values (0.776 and 0.786, both >= 0.5).

**DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (58.395), but both are acceptable, being below 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.864) has a higher BBB percentile than Ligand B (69.407).

**Caco-2 Permeability:** Ligand A (-4.999) has a worse Caco-2 permeability than Ligand B (-5.431), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.977) has a slightly better solubility than Ligand B (-1.81), but both are negative values, indicating poor solubility.

**hERG:** Ligand A (0.763) has a lower hERG risk than Ligand B (0.36), which is preferable.

**Microsomal Clearance:** Ligand A (60.251) has a higher microsomal clearance than Ligand B (14.125), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (47.793) has a longer half-life than Ligand B (-0.33), which is preferable.

**P-gp Efflux:** Ligand A (0.584) has lower P-gp efflux than Ligand B (0.013), which is preferable.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Conclusion:**

Despite Ligand A's higher DILI risk and worse Caco-2 permeability and solubility, its significantly superior binding affinity (-9.7 vs -8.4 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) outweigh these drawbacks. The strong binding affinity is crucial for an enzyme inhibitor, and the improved metabolic stability suggests a potentially longer duration of action. The hERG risk is also lower for Ligand A.

Output:
1
2025-04-17 15:25:24,487 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (376.791 and 362.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is slightly higher than the ideal <140, but still acceptable. Ligand B (67.35) is excellent, well below 90, suggesting good absorption.

**logP:** Both ligands have good logP values (1.028 and 2.34), 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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.723 and 0.833), indicating drug-like properties.

**DILI:** Ligand A (40.054) has a better DILI score than Ligand B (71.694), indicating lower liver injury risk. This is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (65.801 and 74.952). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a major concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.893 and -5.039). These values are unusual and likely represent logPapp values, where negative values indicate poor permeability. Ligand B is slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.664 and -3.164). These values are also unusual and likely represent logS values, where negative values indicate poor solubility. Ligand B is slightly worse.

**hERG Inhibition:** Ligand A (0.217) shows a lower hERG inhibition liability than Ligand B (0.534), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (1.47 mL/min/kg) has significantly lower microsomal clearance than Ligand B (44.904 mL/min/kg), indicating much better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (-12.733 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (24.748 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux liability, while Ligand B (0.219) is slightly higher.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.7 vs -6.8 kcal/mol). However, Ligand A demonstrates superior ADMET properties: lower DILI risk, lower hERG inhibition, and *much* lower microsomal clearance. The negative half-life for Ligand A is a data error and cannot be considered. The poor Caco-2 and solubility for both ligands are concerning, but the difference in metabolic stability is substantial. Given the enzyme target class, metabolic stability is crucial. The stronger binding of Ligand B is attractive, but the significantly higher clearance could lead to rapid elimination and require higher doses, potentially exacerbating other toxicity concerns.

Output:
0
2025-04-17 15:25:24,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.5 and 352.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold for absorption. Ligand B (58.2) is still reasonable, but higher.

**logP:** Ligand A (4.73) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (3.64) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is good. Ligand B (2 HBD, 2 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.567 and 0.623), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.55%), which is a significant concern. Ligand B has a much lower DILI risk (27.61%), a major advantage.

**BBB:** Both have reasonable BBB penetration (73.71% and 83.64%), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.748 and -4.814). This is unusual and suggests potential issues with intestinal absorption, but negative values aren't always reliable predictors.

**Aqueous Solubility:** Both have very poor aqueous solubility (-6.489 and -4.739). This is a significant drawback, but could potentially be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.527) has a slightly elevated hERG risk, while Ligand B (0.671) is also concerning, but slightly better. Both are areas for concern.

**Microsomal Clearance:** Ligand A (90.19 mL/min/kg) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (59.61 mL/min/kg) is better, but still not ideal.

**In vitro Half-Life:** Ligand A (49.33 hours) has a good in vitro half-life. Ligand B (13.13 hours) is shorter, which could necessitate more frequent dosing.

**P-gp Efflux:** Both have low P-gp efflux liability (0.877 and 0.554), which is favorable.

**Binding Affinity:** Ligand A (-10.0 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, its extremely high DILI risk is a major red flag. Ligand B has a better safety profile (lower DILI) and better logP, but its affinity is considerably weaker. Given the importance of potency for kinase inhibitors, the superior binding affinity of Ligand A is compelling. However, the DILI risk is so high that it makes Ligand A a very risky candidate. The difference in affinity (1.7 kcal/mol) is significant, but not insurmountable. Further optimization of Ligand B to improve its affinity, while maintaining its better safety profile, is a more promising path forward.

Output:
1
2025-04-17 15:25:24,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.363 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (358.404 Da) is also good.

**TPSA:** Ligand A (119.04) is better than Ligand B (42.43). Lower TPSA generally improves oral absorption. Ligand A is well below the 140 threshold, while Ligand B is significantly lower and thus preferable.

**logP:** Ligand A (-0.189) is quite low, potentially hindering membrane permeability. Ligand B (3.656) 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 8 HBA, which is acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.721 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 79.333, which is concerning (high risk). Ligand B has a much lower DILI risk of 20.163, which is excellent.

**BBB:** Ligand A (53.587) and Ligand B (96.161). BBB isn't a primary concern for a kinase inhibitor, but higher is generally better.

**Caco-2 Permeability:** Ligand A (-5.54) is very poor, indicating poor intestinal absorption. Ligand B (-4.106) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.139) is poor. Ligand B (-3.775) is also poor. Solubility is a concern for both, but Ligand B is worse.

**hERG Inhibition:** Ligand A (0.029) has very low hERG risk, which is excellent. Ligand B (0.636) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (42.385) has a moderate clearance, while Ligand B (67.514) has a higher clearance. Lower clearance is preferred for better metabolic stability, favoring Ligand A.

**In vitro Half-Life:** Ligand A (-12.782) has a very short half-life, which is a major drawback. Ligand B (-6.615) has a better, but still short, half-life.

**P-gp Efflux:** Ligand A (0.134) has low P-gp efflux, which is good. Ligand B (0.215) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.2 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:**

Ligand A has a superior binding affinity and lower clearance, but suffers from poor solubility, permeability, and a high DILI risk, and a very short half-life. Ligand B has better logP, TPSA, and a significantly lower DILI risk, but weaker binding affinity and a higher clearance.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the stronger binding affinity of Ligand A is a major advantage that could potentially outweigh its drawbacks with further optimization. However, the high DILI risk and poor half-life are significant concerns. The better ADME profile of Ligand B makes it a more immediately viable starting point for optimization, despite its weaker binding.

Output:
1
2025-04-17 15:25:24,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.397 and 348.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold for oral absorption. Ligand B (109.83) is still acceptable but higher, potentially impacting absorption.

**logP:** Ligand A (2.042) is optimal (1-3). Ligand B (0.601) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also acceptable, though slightly higher in HBA count.

**QED:** Both ligands have good QED scores (0.621 and 0.786, respectively), indicating drug-like properties.

**DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (72.703), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.47) has better BBB penetration than Ligand B (34.626), but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.598) and Ligand B (-5.088) 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 (-2.462 and -2.263 respectively). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.367 and 0.221), which is excellent.

**Microsomal Clearance:** Ligand A (22.188 mL/min/kg) has a higher clearance than Ligand B (5.878 mL/min/kg), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (23.017 hours) has a significantly longer half-life than Ligand A (-17.787 hours), a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.051), which is good.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). This difference, while not huge, is enough to potentially overcome some of the ADME deficiencies.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a significantly longer half-life, lower microsomal clearance, and a slightly better binding affinity. The lower DILI risk of Ligand A is attractive, but the substantial improvement in metabolic stability and half-life with Ligand B outweighs this benefit. The binding affinity difference is also a positive for Ligand B.

Output:
1
2025-04-17 15:25:24,488 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 357.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.83) is well below the 140 threshold, suggesting good absorption. Ligand B (92.18) is still acceptable but closer to the limit.

**logP:** Ligand A (1.197) is within the optimal range. Ligand B (2.972) is also good, but higher, potentially leading to some off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, both within acceptable limits. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.77 and 0.732), indicating good drug-likeness.

**DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (98.371). This is a major advantage for Ligand A.

**BBB:** Ligand A (67.39) has moderate BBB penetration, while Ligand B (23.304) has very low penetration. Since SRC is not a CNS target, this is less critical, but still favors A slightly.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.088 and -5.148), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation (negative values are often artifacts of the prediction method).

**Aqueous Solubility:** Both ligands have negative solubility values (-1.549 and -3.75), which is also concerning and requires experimental validation. Ligand B appears slightly worse here.

**hERG Inhibition:** Ligand A (0.511) has a lower hERG risk than Ligand B (0.115), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-17.78) has a much lower (better) microsomal clearance than Ligand B (1.568), indicating greater metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (13.973) has a longer half-life than Ligand B (-3.247), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.022).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This 1.2 kcal/mol difference is significant, but needs to be weighed against the ADME properties.

**Overall Assessment:**

Despite Ligand B having a slightly better binding affinity, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. While both have concerningly low predicted solubility and permeability, the ADME profile of Ligand A is substantially more favorable for development as an SRC kinase inhibitor. The binding affinity difference, while notable, is likely surmountable with further optimization, whereas fixing severe ADME liabilities is often much more challenging.

Output:
0
2025-04-17 15:25:24,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.475 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is slightly higher than Ligand B (59.08). Both are below the 140 threshold for good oral absorption, but B is better.

**3. logP:** Ligand A (3.192) is within the optimal 1-3 range. Ligand B (1.623) is also acceptable, but closer to the lower bound, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (A: 0.532, B: 0.493), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (48.313) has a higher DILI risk than Ligand B (20.396). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (A: 78.596, B: 73.866), but this is less critical for a non-CNS target like SRC.

**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 (-4.949 vs -4.423).

**10. Aqueous Solubility:** Ligand A (-3.635) has slightly better solubility than Ligand B (-0.944), which is beneficial for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.406, B: 0.506), which is excellent.

**12. Microsomal Clearance:** Ligand A (68.305) has significantly higher microsomal clearance than Ligand B (23.717). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (20.338) has a longer half-life than Ligand B (4.29). This is a positive for Ligand A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.465, B: 0.112), with B being slightly better.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and dominates other considerations.

**Overall Assessment:**

While Ligand A has a slightly longer half-life and better solubility, Ligand B demonstrates a significantly better safety profile (lower DILI) and improved metabolic stability (lower Cl_mic). Given that both compounds have identical binding affinity, the ADME properties become the deciding factor. The lower DILI and clearance of Ligand B make it the more promising candidate for further development as an SRC kinase inhibitor.

Output:
1
2025-04-17 15:25:24,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140 (A: 84.67, B: 80.32), indicating good potential for oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3), with A at 2.248 and B at 2.731.

**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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (A: 0.629, B: 0.69), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 49.399, and Ligand B has 34.471. Both are below the 60 threshold, indicating acceptable liver injury risk, with Ligand B being slightly better.

**BBB:** Both ligands have similar BBB penetration (A: 67.701, B: 65.103). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.105 and -5.04), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.761 and -3.012), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A has a very low hERG risk (0.18), while Ligand B has a slightly higher but still acceptable risk (0.502). This favors Ligand A.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (25.03 mL/min/kg) than Ligand B (53.571 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a negative half-life (-5.177 hours), which is not possible, and indicates a problem with the data. Ligand B has a half-life of 42.976 hours, which is good.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.072, B: 0.179), which is favorable.

**Binding Affinity:** Ligand B has a significantly better binding affinity (-7.2 kcal/mol) than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor for an enzyme inhibitor. While it has a higher microsomal clearance and slightly higher hERG risk than Ligand A, the substantial improvement in binding affinity is likely to be more impactful. Both compounds suffer from poor solubility and permeability, which would need to be addressed through formulation or structural modifications. The negative half-life for Ligand A is a data quality issue and makes it less reliable.

Output:
1
2025-04-17 15:25:24,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.5 and 347.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (92.5). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.969 and 1.662, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 3 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.722) has a better QED score than Ligand B (0.565), indicating a more drug-like profile.

**DILI:** Ligand A (15.277) has a significantly lower DILI risk than Ligand B (22.102), which is a crucial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (78.945) has a higher BBB penetration than Ligand A (61.07).

**Caco-2 Permeability:** Ligand A (-4.562) has a more negative Caco-2 value, suggesting *lower* permeability than Ligand B (-5.24). This is a negative for A.

**Aqueous Solubility:** Ligand A (-4.001) has a more negative solubility value, indicating *lower* solubility than Ligand B (-2.629). This is a negative for A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.32 and 0.159, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (26.417) has lower microsomal clearance than Ligand A (38.206), suggesting better metabolic stability, which is a key consideration for kinases.

**In vitro Half-Life:** Ligand B (-14.553) has a negative half-life, which is very concerning. Ligand A (10.77) has a positive half-life, indicating a better in vitro stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.193 and 0.061, respectively).

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.0), a difference of 0.9 kcal/mol. This is a significant advantage that can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better QED score, and slightly higher binding affinity. While Ligand A has lower Caco-2 permeability and solubility, the strong binding affinity and lower toxicity profile are more important for an enzyme target like SRC kinase. Ligand B's negative in vitro half-life is a major red flag.

Output:
1
2025-04-17 15:25:24,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.917 Da) is slightly higher than Ligand B (344.375 Da), but both are acceptable.

**TPSA:** Ligand A (77.92) is significantly better than Ligand B (123.05). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.662) is within the optimal range (1-3). Ligand B (-0.158) is slightly below 1, which *could* indicate permeability issues, though not severely.

**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 similar QED values (0.83 and 0.792), indicating good drug-likeness.

**DILI:** Ligand A (16.789) has a much lower DILI risk than Ligand B (49.942). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (63.784) is better than Ligand B (46.219).

**Caco-2 Permeability:** Ligand A (-4.776) is better than Ligand B (-5.357), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.711) is better than Ligand B (-2.085), suggesting better formulation potential.

**hERG Inhibition:** Both ligands have very low hERG risk (0.423 and 0.043). This is excellent.

**Microsomal Clearance:** Ligand A (-31.496) exhibits significantly lower microsomal clearance than Ligand B (-13.407). This suggests much better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (15.799 hours) has a considerably longer half-life than Ligand B (-24.332 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.128 and 0.013).

**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). Given the other significant advantages of Ligand A, this small difference in affinity is unlikely to be decisive.

**Overall:** Ligand A is superior due to its significantly better DILI score, metabolic stability (lower Cl_mic, longer t1/2), solubility, and Caco-2 permeability. While Ligand B has marginally better binding affinity, the improvements in ADME properties for Ligand A outweigh this small difference in potency.

Output:
1
2025-04-17 15:25:24,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.782 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.84) is better than Ligand B (91.42), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.902) is optimal (1-3), while Ligand B (0.284) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (3) is good, and Ligand B (5) is acceptable.

**QED:** Both ligands have good QED scores (0.578 and 0.848), indicating drug-like properties.

**DILI:** Ligand A (75.649) has a higher DILI risk than Ligand B (51.338), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.25) and Ligand B (52.579) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.108 and -5.214), 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 -0.917), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.569) has a lower hERG risk than Ligand B (0.126), which is preferable.

**Microsomal Clearance:** Ligand A (22.813 mL/min/kg) is higher than Ligand B (15.245 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (22.752 hours) has a longer half-life than Ligand B (-3.571 hours). The negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.315) has lower P-gp efflux than Ligand B (0.013), which is better for bioavailability.

**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.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.9 vs -7.9 kcal/mol) outweighs its slightly higher DILI and clearance. The better hERG profile and P-gp efflux also contribute to its favorability. Ligand B's extremely low logP and negative half-life are major red flags. While both have issues, the potency advantage of Ligand A is crucial for an enzyme inhibitor. Further work would be needed to improve solubility and permeability for either compound.

Output:
0
2025-04-17 15:25:24,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.407 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.28) is higher than Ligand B (71.53). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (0.122) is quite low, potentially hindering permeability. Ligand B (2.305) 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.67 and 0.77), indicating drug-like properties.

**DILI:** Ligand A (42.769) and Ligand B (32.377) both have low DILI risk, below the 40 threshold, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.282) has a higher BBB percentile than Ligand A (35.091), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.395) has poor Caco-2 permeability, while Ligand B (-4.505) is slightly better. Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.178) and Ligand B (-2.114) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.076) has a very low hERG risk, which is excellent. Ligand B (0.254) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (27.142) has lower microsomal clearance than Ligand B (33.834), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (50.72) has a significantly longer half-life than Ligand B (14.416), which is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.026 and 0.042).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This difference of 1.9 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability and a longer half-life, Ligand B's significantly stronger binding affinity (-8.8 vs -6.9 kcal/mol) and better logP value are crucial advantages for an enzyme inhibitor. The lower TPSA of Ligand B is also favorable. The slight difference in solubility and permeability is less concerning given the potency advantage. The hERG risk is acceptable for both. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 15:25:24,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.284 Da and 372.42 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (82.63 and 78.52) below 140, suggesting good oral absorption potential.

**logP:** Both ligands have logP values (2.871 and 3.689) within the optimal range of 1-3. Ligand B is slightly higher, potentially increasing off-target interactions, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 6 HBA) both have reasonable numbers of hydrogen bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have QED values (0.888 and 0.718) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (86.39) has a higher DILI risk than Ligand B (78.209). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.699) and Ligand B (54.13) are both relatively low, which is acceptable.

**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 possible.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.142) has a much lower hERG inhibition risk than Ligand B (0.649), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-2.276) has a significantly *lower* (better) microsomal clearance than Ligand B (47.962). This suggests much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-26.248) has a much longer in vitro half-life than Ligand B (20.108), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux liability than Ligand B (0.304), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This 1.5 kcal/mol difference is potentially significant, but needs to be weighed against the ADME properties.

**Overall Assessment:**

Ligand A has a significant advantage in terms of metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk. The slightly weaker binding affinity of Ligand A is likely outweighed by its superior ADME profile, particularly the lower DILI risk and improved metabolic stability. The poor solubility is a concern for both, but the other advantages of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 15:25:24,490 - INFO - Batch 378 complete. Total preferences: 6048
2025-04-17 15:25:24,490 - INFO - Processing batch 379/512...
2025-04-17 15:26:11,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.486 and 344.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold and favorable for oral absorption. Ligand B (68.84) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.697) is within the optimal 1-3 range. Ligand B (1.934) is slightly lower, potentially impacting permeability, but still acceptable.

**H-Bond Donors/Acceptors:** Both have a reasonable number of HBDs (0) and HBAs (3 for A, 6 for B), staying within the guidelines.

**QED:** Both ligands have good QED scores (0.547 and 0.77), indicating good drug-likeness.

**DILI:** Ligand A (23.187) has a significantly lower DILI risk than Ligand B (34.238), which is a major advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (95.347) shows better BBB penetration than Ligand B (70.686).

**Caco-2 Permeability:** Ligand A (-4.802) shows better Caco-2 permeability than Ligand B (-4.932).

**Aqueous Solubility:** Ligand A (-3.261) has better aqueous solubility than Ligand B (-0.892). This is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.808) has a lower hERG inhibition risk than Ligand B (0.212), which is highly desirable.

**Microsomal Clearance:** Ligand A (62.852) has a higher microsomal clearance than Ligand B (41.063), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-5.985) has a longer in vitro half-life than Ligand A (3.261), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.552) has lower P-gp efflux than Ligand B (0.173), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) exhibits a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.5 kcal/mol difference, a significant advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A demonstrates a much better safety profile (lower DILI, lower hERG) and improved solubility and permeability. The difference in binding affinity is significant, but the ADME/Tox profile of Ligand A is substantially more favorable. For an enzyme target like SRC kinase, a slightly lower affinity can be tolerated if it translates to a safer and more bioavailable drug.

Output:
0
2025-04-17 15:26:11,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.482 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.87) is still under 140, but less optimal than A.

**logP:** Ligand A (1.964) is within the optimal 1-3 range. Ligand B (0.849) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**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.

**QED:** Ligand A (0.794) has a better QED score than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Ligand A (8.802) has a significantly lower DILI risk than Ligand B (18.728), which is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (86.739) is higher than Ligand B (28.848), but this is not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.802) has a more negative Caco-2 value, which is unusual and suggests *poor* permeability. Ligand B (-4.734) is similarly poor. This is concerning for both, but the difference is minimal.

**Aqueous Solubility:** Both ligands have very negative solubility values (-2.523 and -1.705 respectively), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.686) has a lower hERG risk than Ligand B (0.098), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (23.923) has a higher (worse) microsomal clearance than Ligand B (2.18). This means Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-14.403) has a very negative half-life, indicating very rapid metabolism. Ligand B (-1.53) is better, but still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.037), which is good.

**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 advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI/hERG risk. However, it suffers from poor Caco-2 permeability and a very high microsomal clearance/short half-life. Ligand B has better metabolic stability, but its binding affinity is extremely weak, and its DILI/hERG risk is higher.

Despite the ADME concerns with Ligand A, the substantially superior binding affinity is paramount for an enzyme inhibitor. The poor ADME properties could potentially be addressed through further optimization, but a weak binder is unlikely to become a viable drug.

Output:
1
2025-04-17 15:26:11,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 and 361.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.87 and 68.54) are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (2.304) is optimal (1-3). Ligand B (4.967) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both ligands have 1 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 (0.908) has a very strong drug-like profile. Ligand B (0.506) is acceptable, but less ideal.

**DILI:** Ligand A (43.622) has a low DILI risk. Ligand B (68.941) has a moderately elevated DILI risk, though still not critically high.

**BBB:** Both ligands have high BBB penetration (87.71 and 83.33), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.471 and -4.686), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.848 and -5.938), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.581 and 0.648).

**Microsomal Clearance:** Ligand A (-6.391) has excellent metabolic stability (negative clearance). Ligand B (120.349) has high microsomal clearance, indicating rapid metabolism and potentially a short half-life.

**In vitro Half-Life:** Ligand A (11.823 hours) has a good in vitro half-life. Ligand B (64.1 hours) also has a good in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.081 and 0.799).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most crucial factor for an enzyme inhibitor. However, it suffers from higher logP, a higher DILI risk, and significantly higher microsomal clearance. Ligand A has better ADME properties overall (lower logP, lower DILI, better metabolic stability), but its binding affinity is weaker.

Despite the better ADME profile of Ligand A, the substantial binding affinity advantage of Ligand B (-7.9 vs -8.6 kcal/mol) is likely to outweigh the ADME drawbacks, especially considering optimization can address the logP and metabolic stability issues. The difference in binding affinity is >1.5 kcal/mol, making it a strong driver for selection.

Output:
1
2025-04-17 15:26:11,886 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [356.369, 79.62, 1.837, 1, 4, 0.873, 39.24, 84.413, -4.643, -2.761, 0.431, 0.956, -25.356, 0.143, -9.2]
**Ligand B:** [354.447, 99.1, -0.097, 3, 5, 0.502, 27.336, 29.779, -4.852, -1.241, 0.209, 21.483, -14.512, 0.017, -7.9]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A: 356.369, B: 354.447. No significant difference.
2. **TPSA:** Ligand A (79.62) is better than Ligand B (99.1).  We want TPSA <= 140 for good absorption, both are within this range, but A is preferable.
3. **logP:** Ligand A (1.837) is optimal (1-3). Ligand B (-0.097) is slightly below 1, which *could* indicate permeability issues. A is better.
4. **HBD:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes lead to poorer permeability. A is better.
5. **HBA:** Ligand A (4) is good. Ligand B (5) is acceptable, but slightly higher. A is better.
6. **QED:** Ligand A (0.873) is excellent. Ligand B (0.502) is acceptable, but lower. A is better.
7. **DILI:** Ligand A (39.24) is very good (low risk). Ligand B (27.336) is also good, but slightly lower. B is better.
8. **BBB:** Ligand A (84.413) is good, indicating some potential for CNS penetration. Ligand B (29.779) is low. Since SRC is not a CNS target, this is less critical, but A is still better.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.643) is slightly better than B (-4.852).
10. **Solubility:** Both are negative, indicating poor solubility. A (-2.761) is slightly better than B (-1.241).
11. **hERG:** Both are very low (0.431 and 0.209), indicating a low risk of cardiotoxicity. B is slightly better.
12. **Cl_mic:** Ligand A (0.956) is *much* lower than Ligand B (21.483). This indicates significantly better metabolic stability for ligand A, a critical factor for an enzyme inhibitor. A is *much* better.
13. **t1/2:** Ligand A (-25.356) is better than Ligand B (-14.512). Longer half-life is generally preferred. A is better.
14. **Pgp:** Both are very low (0.143 and 0.017), suggesting minimal P-gp efflux. B is slightly better.
15. **Binding Affinity:** Ligand A (-9.2) is significantly stronger than Ligand B (-7.9). A 1.3 kcal/mol difference is substantial and can outweigh minor ADME drawbacks. A is *much* better.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in affinity and metabolic stability, and has acceptable solubility and hERG risk. While Ligand B has a slightly better DILI score, the significant advantages of Ligand A in potency, metabolic stability, and overall drug-likeness outweigh this minor difference.

**Conclusion:**

Ligand A is the more viable drug candidate.

1
2025-04-17 15:26:11,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.52) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (75.88) is well within the optimal range.

**logP:** Ligand A (0.49) is quite low, potentially hindering permeability. Ligand B (1.582) is 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 (5) is also good.

**QED:** Both ligands have good QED scores (0.525 and 0.828), indicating drug-like properties.

**DILI:** Ligand A (25.63) has a very favorable DILI score. Ligand B (42.885) is still acceptable, but less favorable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (75.688) is better than Ligand A (62.97). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2:** Ligand A (-5.305) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.416) is also poor, but better than ligand A.

**Solubility:** Ligand A (-2.612) has poor aqueous solubility. Ligand B (-1.06) is better, but still not ideal.

**hERG:** Ligand A (0.049) has a very low hERG risk. Ligand B (0.316) is also low risk.

**Microsomal Clearance:** Ligand A (46.727) has moderate clearance, suggesting moderate metabolic stability. Ligand B (31.845) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.276) has a short half-life. Ligand B (-25.059) has a significantly longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.008 and 0.141).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). The 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better DILI score and hERG risk, Ligand B is superior overall. The significantly stronger binding affinity (-9.4 vs -7.7 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme inhibitor. Although both have suboptimal Caco-2 and solubility, the potency and metabolic advantages of Ligand B are more important for this target class.

Output:
1
2025-04-17 15:26:11,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (362.323 Da and 350.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is well below the 140 A^2 threshold, while Ligand B (87.47) is still acceptable but closer to the limit.

**3. logP:** Ligand A (3.132) is optimal, while Ligand B (1.592) 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 3 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.791 and 0.743), indicating good drug-likeness.

**7. DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (17.604). This is a significant drawback for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.107) is slightly better than Ligand B (67.662).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.837) is slightly better than Ligand B (-4.98).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.453) is slightly better than Ligand B (-1.117).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.385 and 0.204).

**12. Microsomal Clearance:** Ligand A (20.424) has higher clearance than Ligand B (-0.217), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (14.041) has a significantly longer half-life than Ligand A (-8.381). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.146 and 0.012).

**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 outweighs many of the other drawbacks of Ligand B.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B excels in binding affinity and half-life, and has a much lower DILI risk. While its logP and solubility are slightly lower, the superior affinity and metabolic stability are more critical.

Output:
1
2025-04-17 15:26:11,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.383 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.11) is slightly above the preferred <90 for CNS penetration, but acceptable for a non-CNS target like SRC. Ligand B (75.71) is well within the ideal range.

**logP:** Both ligands (1.247 and 1.573) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range of <=10.

**QED:** Ligand A (0.763) has a better QED score than Ligand B (0.601), indicating a more drug-like profile.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (28.228). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for SRC, but Ligand B (84.451) has a higher percentile than Ligand A (52.811).

**Caco-2 Permeability:** Ligand A (-5.342) has a negative Caco-2 value, which is concerning. Ligand B (-4.638) is also negative, but less so. Both suggest poor intestinal absorption, but A is worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.952 and -2.686 respectively). This is a significant drawback for both, requiring formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.194 and 0.306).

**Microsomal Clearance:** Ligand A (-20.668) has a significantly *lower* (better) microsomal clearance than Ligand B (45.813), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.843) has a shorter half-life than Ligand B (-4.182), which is negative.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.074).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.0 kcal/mol). The difference is relatively small.

**Overall Assessment:**

Ligand A has a better QED and significantly better metabolic stability (lower Cl_mic). However, it has a higher DILI risk, a worse Caco-2 permeability, and a shorter half-life. Ligand B has a lower DILI risk, better Caco-2 permeability, and a longer half-life. While Ligand A's metabolic stability is a significant advantage, the higher DILI risk and poor permeability are major concerns. Given the enzyme-specific priorities, metabolic stability is important, but not at the expense of safety and absorption. The binding affinity difference is not substantial enough to overcome the ADME liabilities of Ligand A.

Output:
1
2025-04-17 15:26:11,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.873 Da) is slightly higher than Ligand B (344.367 Da), but both are acceptable.

**TPSA:** Ligand A (83.31) is well below the 140 threshold for oral absorption. Ligand B (113.86) is also acceptable, but closer to the limit.

**logP:** Ligand A (3.573) is optimal. Ligand B (0.609) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) and Ligand B (4 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED scores (A: 0.707, B: 0.651), indicating good drug-likeness.

**DILI:** Ligand A (77.356) has a higher DILI risk than Ligand B (56.456), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.639) is higher than Ligand B (21.326).

**Caco-2 Permeability:** Ligand A (-4.628) is poor, while Ligand B (-5.521) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-5.262) is poor, while Ligand B (-2.441) is also poor. Both are negative values, indicating low solubility.

**hERG Inhibition:** Ligand A (0.222) has a very low hERG risk, which is excellent. Ligand B (0.065) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (121.378) has a higher clearance, suggesting lower metabolic stability. Ligand B (-37.743) has a *negative* clearance, which is highly unusual and suggests very high metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (39.013) has a moderate half-life. Ligand B (-10.838) 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 have very low P-gp efflux liability (A: 0.727, B: 0.002).

**Binding Affinity:** Both ligands have equivalent binding affinity (-8.4 and -8.5 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand A's slightly better logP and lower DILI risk, Ligand B is the more promising candidate due to its exceptionally low P-gp efflux and *extremely* high metabolic stability (indicated by the negative microsomal clearance and half-life, though the latter is suspect). The low logP of Ligand B is a concern, but the strong binding affinity might compensate for this. The negative values for clearance and half-life are concerning and require further investigation, but the overall profile of Ligand B is more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 15:26:11,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (364.917 and 369.795 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (41.57) is better than Ligand B (49.77), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have good logP values (4.526 and 4.238), 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 similar QED scores (0.856 and 0.828), indicating good drug-likeness.

**7. DILI:** Ligand A (11.283) has a significantly lower DILI risk than Ligand B (37.611). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (89.608) has a better BBB penetration percentile than Ligand B (46.879), but this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.66 and -4.613), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-4.335 and -4.544), indicating very poor aqueous solubility. This is a major concern for both compounds.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.852 and 0.885).

**12. Microsomal Clearance:** Ligand A (35.436 mL/min/kg) has a lower microsomal clearance than Ligand B (79.66 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (17.907 hours) has a longer half-life than Ligand B (22.893 hours).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.512 and 0.339).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic). The poor solubility and permeability are concerning for both, but can potentially be addressed through formulation strategies. The lower DILI and better metabolic stability are more difficult to improve post-hoc. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial.

Output:
0
2025-04-17 15:26:11,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.813 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (408.275 Da) is still well within the acceptable range.

**TPSA:** Ligand A (68.92) is significantly better than Ligand B (85.83). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have good logP values (A: 3.284, B: 2.393), 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 (HBD <=5, HBA <=10).

**QED:** Both ligands have good QED scores (A: 0.783, B: 0.814), indicating good drug-like properties.

**DILI:** Ligand A has a higher DILI risk (83.637) compared to Ligand B (55.138). This is a significant concern.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (79.217) is slightly higher than Ligand B (69.407). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.438) has worse Caco-2 permeability than Ligand B (-5.296). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.735) has worse solubility than Ligand B (-2.595). Solubility is important for formulation and bioavailability.

**hERG:** Ligand A (0.642) has a slightly higher hERG risk than Ligand B (0.291), but both are relatively low.

**Microsomal Clearance:** Ligand B (3.729) has significantly better metabolic stability (lower clearance) than Ligand A (41.083). This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (13.55) has a longer half-life than Ligand A (25.217). This is also a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.222, B: 0.191).

**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 difference and a major factor in favor of Ligand B.

**Conclusion:**

Despite Ligand A's slightly better TPSA and BBB, Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility outweigh the minor drawbacks in TPSA and BBB. The substantial difference in binding affinity (-7.6 vs -9.6 kcal/mol) is particularly compelling.

Output:
1
2025-04-17 15:26:11,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.356 and 346.471 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (44.76) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.43) is still under 140, but less favorable than A.

**logP:** Ligand A (3.807) is at the higher end of the optimal range (1-3), while Ligand B (2.169) is closer to the lower end. Both are acceptable, but A's higher logP could potentially lead to off-target effects, though it might also aid in membrane permeability.

**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 within the guidelines.

**QED:** Both ligands have similar QED values (0.768 and 0.724), indicating good drug-likeness.

**DILI:** Ligand A (48.817) has a higher DILI risk than Ligand B (15.394). This is a significant negative for Ligand A.

**BBB:** Both have good BBB penetration, but Ligand A (91.702) is significantly better than Ligand B (69.019). However, BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.752) has poor Caco-2 permeability, while Ligand B (-5.042) is also poor, but slightly less so.

**Aqueous Solubility:** Ligand A (-4.553) has poor aqueous solubility, and Ligand B (-2.911) is also poor. This is a concern for both, but A is worse.

**hERG:** Ligand A (0.725) has a slightly higher hERG risk than Ligand B (0.221). This is a negative for Ligand A.

**Microsomal Clearance:** Ligand A (50.133) has higher microsomal clearance than Ligand B (34.32), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (-0.053) has a slightly longer half-life than Ligand B (-0.471).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.237 and 0.053).

**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 and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from significant drawbacks in DILI risk, solubility, Caco-2 permeability, and metabolic stability (higher Cl_mic). Ligand B is less potent but has a much better safety profile (lower DILI, lower hERG) and slightly better metabolic stability.

Given the priorities for kinase inhibitors, the improved potency of Ligand A is a major advantage. While the ADME properties are suboptimal, they might be addressable through further optimization. The lower DILI and better metabolic stability of Ligand B are attractive, but the lower binding affinity is a substantial hurdle.

Output:
1
2025-04-17 15:26:11,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.439 and 383.319 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (62.55 and 58.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.679 and 3.139) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 2 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Ligand A (0.915) has a significantly better QED score than Ligand B (0.768), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (30.826 and 36.448 percentiles), which is good.

**BBB:** Both ligands have similar BBB penetration (62.97 and 61.962 percentiles), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.078 and -5.075), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.994 and -3.859), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.204 and 0.434), which is excellent.

**Microsomal Clearance:** Ligand A (19.815 mL/min/kg) has a slightly higher, but still acceptable, microsomal clearance than Ligand B (17.183 mL/min/kg). Lower is better, but both are reasonable.

**In vitro Half-Life:** Ligand A (38.197 hours) has a significantly longer in vitro half-life than Ligand B (20.936 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.2 and 0.262), which is favorable.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a 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.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. It has a significantly better QED score, a longer half-life, and a substantially stronger binding affinity. The binding affinity advantage is particularly important for an enzyme target like SRC. While the solubility and permeability issues need to be addressed through formulation or further chemical modification, the superior potency and pharmacokinetic properties of Ligand A make it the better starting point for drug development.

Output:
0
2025-04-17 15:26:11,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.441 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for good absorption, and even favorable. Ligand B (78.09) is still under 140, but less optimal than A.

**logP:** Both ligands (2.967 and 2.243) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=4) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar QED values (0.825 and 0.795), indicating good drug-likeness.

**DILI:** Ligand A (14.036) has a significantly lower DILI risk than Ligand B (51.493). This is a major advantage.

**BBB:** Ligand A (89.608) has a better BBB percentile than Ligand B (29.818), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.759) has a better Caco-2 permeability than Ligand B (-5.443), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-3.151) has better aqueous solubility than Ligand B (-2.451).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.652 and 0.384).

**Microsomal Clearance:** Ligand A (24.723) has higher microsomal clearance than Ligand B (2.806), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-8.705) has a better in vitro half-life than Ligand A (-17.461). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.115 and 0.168).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.5 and -8.9 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has advantages in TPSA, solubility, Caco-2 permeability, and DILI risk. However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2). Given that we are targeting a kinase, metabolic stability is crucial. While the binding affinity is slightly better for A, the difference is not substantial enough to outweigh the better metabolic profile of B. The significantly lower DILI risk of A is also a strong point, but the improved stability of B is more critical for an enzyme target.

Output:
1
2025-04-17 15:26:11,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443 Da) is slightly better positioned.

**TPSA:** Ligand A (66.4) is significantly better than Ligand B (127.94). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**logP:** Ligand A (2.06) is optimal, while Ligand B (-0.165) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (2) is acceptable, but more donors can sometimes reduce permeability.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is also acceptable, but higher values can sometimes be problematic.

**QED:** Both ligands have similar, good QED values (0.768 and 0.774).

**DILI:** Ligand A (24.583) has a much lower DILI risk than Ligand B (87.476), which is a significant advantage.

**BBB:** This is less crucial for a non-CNS target like SRC, but Ligand A (84.684) has a better BBB percentile than Ligand B (25.126).

**Caco-2 Permeability:** Ligand A (-4.715) is better than Ligand B (-5.312), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.393) is better than Ligand B (-2.574), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.221) has a lower hERG risk than Ligand B (0.148), which is a critical safety parameter.

**Microsomal Clearance:** Ligand A (16.405) has a higher (worse) microsomal clearance than Ligand B (-4.2). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-4.168) has a shorter half-life than Ligand B (-24.865), indicating faster metabolism.

**P-gp Efflux:** Ligand A (0.034) has lower P-gp efflux than Ligand B (0.017), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 1.3 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A is superior due to its significantly better ADME profile (lower DILI, better solubility, better permeability, lower hERG risk) and acceptable potency. While Ligand B has slightly better binding affinity and metabolic stability, the ADME liabilities of Ligand B are concerning. The improved ADME properties of Ligand A are more likely to translate to a viable drug candidate, even with a slightly weaker binding affinity.

Output:
0
2025-04-17 15:26:11,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.401 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.72 and 69.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.009) is optimal, while Ligand B (2.391) is still within the acceptable range (1-3) but trending higher.

**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, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.546 and 0.694), indicating drug-like properties.

**DILI:** Ligand A (31.989) has a significantly lower DILI risk than Ligand B (6.32), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (69.523) is slightly better than Ligand B (59.636).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.671 and -4.892), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.751 and -1.938), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.206 and 0.225), which is excellent.

**Microsomal Clearance:** Ligand A (-1.564) has a lower (better) microsomal clearance than Ligand B (-1.948), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.362) has a significantly longer in vitro half-life than Ligand B (2.259), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.055), which is favorable.

**Binding Affinity:** Ligand B (-8.0 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 can be overcome by other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better BBB penetration. Both have poor solubility and permeability, but the superior safety and metabolic profile of Ligand A outweigh the small affinity difference. Addressing the solubility and permeability issues would be a priority in further optimization, but starting with a safer and more stable molecule is preferable.

Output:
0
2025-04-17 15:26:11,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.409 Da and 369.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.22) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (46.32) is excellent, well below 140.

**logP:** Ligand A (2.609) is within the optimal 1-3 range. Ligand B (4.067) is at the upper end of the optimal range, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are within acceptable limits. Ligand B has 0 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.487 and 0.514, respectively), indicating reasonable drug-likeness.

**DILI:** Both ligands have DILI risk around 63-69%, which is moderately concerning. It's not a deal-breaker at this stage, but needs monitoring.

**BBB:** Both have relatively low BBB penetration (54.246 and 68.864). This is not a high priority for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.794 and 0.879), which is positive.

**Microsomal Clearance:** Ligand A (46.579) has lower microsomal clearance than Ligand B (50.288), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.609) has a significantly longer in vitro half-life than Ligand B (6.813). This is a substantial advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.222 and 0.709), which is favorable.

**Binding Affinity:** Ligand B (-9.2 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:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility. However, Ligand A has a better metabolic profile (lower Cl_mic, longer t1/2) and a slightly better overall balance of properties, despite the slightly weaker binding affinity. The longer half-life is a significant advantage for a kinase inhibitor, potentially allowing for less frequent dosing. The slight affinity difference can be overcome with further optimization.

Output:
0
2025-04-17 15:26:11,888 - INFO - Batch 379 complete. Total preferences: 6064
2025-04-17 15:26:11,888 - INFO - Processing batch 380/512...
2025-04-17 15:26:57,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.427 and 358.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.35) is well below the 140 threshold, while Ligand B (95.94) is still acceptable but closer to the limit.

**logP:** Ligand A (3.945) is at the upper end of the optimal range (1-3), while Ligand B (1.193) is slightly below, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (5) counts.

**QED:** Ligand A (0.916) has a very strong drug-like profile, significantly better than Ligand B (0.572).

**DILI:** Ligand A (61.031) has a moderate DILI risk, while Ligand B (12.718) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (70.803) has better BBB penetration than Ligand B (25.94).

**Caco-2 Permeability:** Ligand A (-4.665) has poor Caco-2 permeability, while Ligand B (-4.716) is similar. Both are very low and potentially problematic.

**Aqueous Solubility:** Ligand A (-4.599) has poor solubility, while Ligand B (-0.81) is better, though still not ideal.

**hERG:** Ligand A (0.63) has a slightly higher hERG risk than Ligand B (0.176), which is a considerable advantage for B.

**Microsomal Clearance:** Ligand A (51.786) has a lower (better) microsomal clearance than Ligand B (78.887), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.815) has a short half-life, while Ligand B (-29.451) has a very long half-life, a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.201 and 0.023).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 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 affinity and a better QED score, Ligand B excels in critical ADME properties. Specifically, its significantly lower DILI risk, much longer half-life, and lower hERG risk are major advantages for an enzyme target like SRC kinase. The solubility is still a concern for B, but is better than A. The slightly lower affinity of B is outweighed by its superior ADME profile.

Output:
1
2025-04-17 15:26:57,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.443 and 339.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (54.34), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands (1.196 and 1.957) are within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor advantage for membrane permeability.

**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 (0.748 and 0.636), indicating good drug-like properties.

**DILI:** Ligand A (19.93) has a significantly lower DILI risk than Ligand B (26.095), which is a major advantage. Lower DILI is crucial.

**BBB:** Both ligands have similar BBB penetration (60.411 and 58.938), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.802 and -4.783). These values are difficult to interpret without knowing the scale, but the similarity suggests comparable absorption potential.

**Aqueous Solubility:** Both have negative solubility values (-1.917 and -2.432). Similar to Caco-2, the scale is unknown, but the similarity suggests comparable solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.296 and 0.261), which is excellent.

**Microsomal Clearance:** Ligand A (11.434) has a lower microsomal clearance than Ligand B (22.62), suggesting better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-11.441) has a longer in vitro half-life than Ligand B (-11.085). Again, the scale is unknown, but a longer half-life is generally desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.048 and 0.206).

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is relatively small (0.8 kcal/mol).

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk (19.93 vs 26.095) and better metabolic stability (lower Cl_mic and longer t1/2). While Ligand B has a slightly better binding affinity, the ADME improvements of Ligand A outweigh this small difference in potency, especially considering the importance of minimizing toxicity and maximizing exposure for an enzyme inhibitor.

Output:
1
2025-04-17 15:26:57,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.369 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (73.74) is significantly better than Ligand B (47.36). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.98, Ligand B: 3.456), falling within the optimal 1-3 range. Ligand B is a bit higher, potentially leading to slight solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=0, HBA=5). While both are within acceptable limits, a balance is good.

**QED:** Ligand A (0.84) has a much better QED score than Ligand B (0.477), indicating a more drug-like profile.

**DILI:** Ligand A (48.468) has a slightly higher DILI risk than Ligand B (35.75), but both are below the concerning threshold of 60.

**BBB:** Both have good BBB penetration, but Ligand B (92.555) is slightly better than Ligand A (88.135). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 (-4.407 for A, -4.365 for B).

**Aqueous Solubility:** Ligand A (-2.212) has better aqueous solubility than Ligand B (-4.768). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (Ligand A: 0.267, Ligand B: 0.472).

**Microsomal Clearance:** Ligand A (25.839) has significantly lower microsomal clearance than Ligand B (97.103). This indicates better metabolic stability for Ligand A, a crucial factor for enzymes.

**In vitro Half-Life:** Ligand A (-43.475) has a much longer in vitro half-life than Ligand B (10.239). This further supports its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.05, Ligand B: 0.489).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.7 kcal/mol, Ligand B: -8.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Overall:**

Ligand A is significantly better due to its superior QED, solubility, metabolic stability (lower Cl_mic and longer t1/2), and lower TPSA. While Ligand B has slightly better BBB penetration, this is less important for a kinase inhibitor. The binding affinity difference is minimal.

Output:
1
2025-04-17 15:26:57,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (344.455 Da) is more favorably positioned.

**TPSA:** Ligand A (104.31) is slightly above the preferred <140 for good absorption, but not critically so. Ligand B (75.27) is well within the acceptable range.

**logP:** Both ligands have good logP values (A: 3.148, B: 2.113), 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 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.533, B: 0.802), indicating good drug-like properties. Ligand B is significantly better here.

**DILI:** Ligand A has a high DILI risk (97.712), which is a major concern. Ligand B has a very low DILI risk (25.785), a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (55.176) than Ligand A (22.218), but this isn't a deciding factor.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.864 and -5.6), indicating potential absorption issues.

**Aqueous Solubility:** Both have poor aqueous solubility (-4.834 and -2.718).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.163, B: 0.076).

**Microsomal Clearance:** Ligand A has significantly better microsomal clearance (-16.288) than Ligand B (23.512), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (50.953 hours) than Ligand B (-2.797 hours), a substantial advantage.

**P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (A: 0.052, B: 0.06).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.8 kcal/mol, B: -8.6 kcal/mol). Ligand A is slightly better, with a 1.2 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, its extremely high DILI risk is a major red flag. Ligand B has a much better safety profile (low DILI), a better QED score, and acceptable ADME properties, despite slightly lower affinity and poorer metabolic stability.

Considering the enzyme-kinase specific priorities, metabolic stability and safety are crucial. While Ligand A's affinity is better, the high DILI risk makes it a less viable candidate. Ligand B, with its favorable safety profile and good overall properties, is the more promising drug candidate.

Output:
1
2025-04-17 15:26:57,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.2 and 59.08) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.144) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.375) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, which is good. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.695 and 0.72), indicating good drug-likeness.

**DILI:** Both ligands have very similar and acceptable DILI risk (33.928 and 33.812 percentile).

**BBB:** Both ligands have reasonable BBB penetration (68.282 and 60.644 percentile), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.663 and -4.397), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.462 and -1.522), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.806 and 0.173 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (62.961 mL/min/kg) has higher clearance than Ligand B (31.681 mL/min/kg). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand B (-11.729 hours) has a negative half-life, which is impossible. Ligand A (35.28 hours) 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 (0.433 and 0.028 percentile), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.8 and -9.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand A is slightly more favorable. It has a reasonable in vitro half-life, while Ligand B has an impossible negative value. Ligand B has better metabolic stability (lower Cl_mic), but the half-life issue is a critical concern. The binding affinity difference is not substantial enough to favor Ligand B given the other factors. Both compounds would require significant medicinal chemistry work to improve solubility and permeability.

Output:
0
2025-04-17 15:26:57,604 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.284 Da) is slightly higher than Ligand B (350.482 Da), but both are acceptable.

**TPSA:** Ligand A (77.63) is higher than Ligand B (38.82). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have good logP values (A: 2.796, B: 2.446), 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 3. Ligand B is preferable here, as fewer HBA generally correlate with better membrane permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.687, B: 0.704), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (83.211) compared to Ligand B (13.106). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (90.035) than Ligand A (43.273), but this is less critical.

**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 relative, and Ligand B (-4.694) is slightly better than Ligand A (-5.435).

**Aqueous Solubility:** Both have negative solubility values, again suggesting a data/model issue. Ligand A (-3.653) is slightly worse than Ligand B (-2.19).

**hERG:** Ligand A (0.187) has a slightly higher hERG risk than Ligand B (0.957), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand B (23.967 mL/min/kg) has significantly lower microsomal clearance than Ligand A (52.654 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (5.583 hours) has a longer half-life than Ligand A (33.666 hours). This is a positive feature for Ligand B.

**P-gp Efflux:** Ligand A (0.167) has lower P-gp efflux than Ligand B (0.089), which is slightly favorable.

**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 enough to be considered, especially given the other advantages of Ligand B.

**Overall:**

Ligand B is the superior candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better TPSA and HBA, and slightly better binding affinity. While both have issues with Caco-2 and solubility (likely data related), Ligand B is better in both respects. The higher DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 15:26:57,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.387 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.2 and 98.98) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.617) is within the optimal 1-3 range. Ligand B (-0.554) is slightly below 1, which *could* indicate potential permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and reasonable HBA counts (6 and 4 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 (61.264) has a higher DILI risk than Ligand B (13.067). This is a significant negative for Ligand A.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (58.938) is slightly better than Ligand B (53.974).

**Caco-2 Permeability:** Ligand A (-4.719) has worse Caco-2 permeability than Ligand B (-5.34). Both are quite poor, suggesting potential absorption issues.

**Aqueous Solubility:** Ligand A (-2.616) has slightly better solubility than Ligand B (-1.178), but both are poor.

**hERG:** Both ligands have very low hERG risk (0.354 and 0.142), which is excellent.

**Microsomal Clearance:** Ligand B (-32.261) has significantly lower (better) microsomal clearance than Ligand A (37.948), indicating greater metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-11.797) has a longer in vitro half-life than Ligand A (12.435), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.038 and 0.002).

**Binding Affinity:** Both ligands have very similar, excellent binding affinities (-9.4 and -9.2 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

While both ligands have good potency, Ligand B is significantly better overall. Its substantially lower DILI risk and markedly improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP and solubility. The Caco-2 permeability is poor for both, but the other advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 15:26:57,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.378 and 349.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.91) is better than Ligand B (72.88), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.801) is within the optimal 1-3 range. Ligand B (0.469) 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 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have reasonable QED values (0.835 and 0.783), indicating good drug-like properties.

**7. DILI:** Ligand A (63.358) has a higher DILI risk than Ligand B (21.869). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have acceptable BBB penetration (79.566 and 67.701), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.62 and -4.848). This is unusual and suggests poor permeability. However, these values are on a log scale, so the actual permeability might not be as low as it appears.

**10. Aqueous Solubility:** Ligand A (-3.78) is better than Ligand B (-1.42), indicating better solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.202 and 0.422).

**12. Microsomal Clearance:** Ligand B (-47.001) has significantly lower (better) microsomal clearance than Ligand A (39.674), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.477) has a longer half-life than Ligand A (9.481), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.071 and 0.025).

**15. Binding Affinity:** Ligand A (-9.5) has a slightly better binding affinity than Ligand B (-8.6). However, the difference is less than 1.5 kcal/mol, so it doesn't completely outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and comparable solubility and permeability. The lower logP of Ligand B is a minor concern, but the substantial advantages in safety and PK outweigh this. Given the enzyme-specific priorities, metabolic stability and safety are crucial, making Ligand B the preferred choice.

Output:
1
2025-04-17 15:26:57,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.12) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (81.77) is well within the range.

**3. logP:** Both ligands (-0.192 and -0.413) are a bit low. While not immediately disqualifying, lower logP can sometimes hinder cell 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:** Ligand B (0.801) has a significantly better QED score than Ligand A (0.567), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (Ligand A: 40.287, Ligand B: 36.448), both below the 40 threshold. Ligand B is slightly better.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Both are low (A: 41.218, B: 36.448).

**9. Caco-2 Permeability:** Both are negative, suggesting poor permeability. Ligand A (-5.861) is worse than Ligand B (-4.895).

**10. Aqueous Solubility:** Both are negative, suggesting poor solubility. Ligand A (-1.673) is worse than Ligand B (-0.988).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.029, B: 0.494).

**12. Microsomal Clearance:** Ligand A (-14.506) has a much lower (better) microsomal clearance than Ligand B (9.657), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (22.811) has a longer half-life than Ligand B (-10.83), which is a significant advantage.

**14. P-gp Efflux:** Both are low (A: 0.008, B: 0.022), suggesting minimal P-gp efflux.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.0 and -7.2 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 t1/2). However, Ligand B has a much better QED score, slightly better DILI, and better solubility. The poor Caco-2 and solubility for both are concerning, but the superior metabolic stability of Ligand A is crucial for an enzyme target. Given the importance of metabolic stability for kinases, and the only slight advantage in binding affinity for A, I would choose Ligand A.

Output:
0
2025-04-17 15:26:57,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**
*   **MW:** 379.335 Da - Good. Within the ideal range.
*   **TPSA:** 22.61 - Excellent. Well below the 140 threshold for absorption.
*   **logP:** 4.165 - Slightly high, potentially leading to solubility issues or off-target effects.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.796 - Excellent. Highly drug-like.
*   **DILI:** 52.966 - Good. Low risk of liver injury.
*   **BBB:** 89.841 - Very good, but less critical for a non-CNS target like SRC.
*   **Caco-2:** -4.72 - Very poor permeability. A significant concern.
*   **Solubility:** -3.916 - Very poor solubility. A major issue.
*   **hERG:** 0.971 - Low risk of hERG inhibition.
*   **Cl_mic:** 56.472 - Moderate clearance, not ideal for metabolic stability.
*   **t1/2:** 19.378 - Moderate half-life.
*   **Pgp:** 0.668 - Moderate P-gp efflux.
*   **Affinity:** -6.7 kcal/mol - Good binding affinity.

**Ligand B:**
*   **MW:** 362.411 Da - Good. Within the ideal range.
*   **TPSA:** 102.74 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 0.597 - Low. May hinder permeation.
*   **HBD:** 1 - Acceptable.
*   **HBA:** 6 - Acceptable.
*   **QED:** 0.848 - Excellent. Highly drug-like.
*   **DILI:** 68.941 - Moderate risk of liver injury.
*   **BBB:** 49.826 - Low. Not a concern for a non-CNS target.
*   **Caco-2:** -4.905 - Very poor permeability. A significant concern.
*   **Solubility:** -2.81 - Poor solubility.
*   **hERG:** 0.219 - Very low risk of hERG inhibition.
*   **Cl_mic:** -14.978 - Excellent. Very high metabolic stability.
*   **t1/2:** -7.634 - Excellent. Very long half-life.
*   **Pgp:** 0.048 - Very low P-gp efflux.
*   **Affinity:** -8.7 kcal/mol - Excellent binding affinity. Significantly better than Ligand A.

**Comparison & Decision:**

Both ligands have significant permeability and solubility issues. However, Ligand B has a *much* stronger binding affinity (-8.7 vs -6.7 kcal/mol), significantly better metabolic stability (Cl_mic = -14.978 vs 56.472), and a longer half-life. The 1.5 kcal/mol advantage in binding affinity can outweigh the ADME drawbacks, especially given the target is an enzyme. While the solubility and permeability are concerning for both, these can be addressed with formulation strategies. Ligand A's higher logP is also a concern. Ligand B's DILI risk is higher, but not critically so.

Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 15:26:57,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (382.913 and 357.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (63.91), both are below the 140 threshold for oral absorption, and acceptable for a kinase inhibitor.

**logP:** Both ligands (2.652 and 2.285) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are acceptable, fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand B (6) is better than Ligand A (4). Both are below the 10 threshold.

**QED:** Ligand A (0.851) is significantly better than Ligand B (0.536), indicating a more drug-like profile.

**DILI:** Ligand A (33.695) has a much lower DILI risk than Ligand B (48.895), which is a significant advantage. Both are below the 60 threshold.

**BBB:** Ligand A (71.229) has better BBB penetration than Ligand B (61.613), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.999) is better than Ligand B (-5.135). Both are poor.

**Aqueous Solubility:** Ligand A (-3.784) is better than Ligand B (-2.821). Both are poor.

**hERG:** Both ligands (0.447 and 0.488) have low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (30.615) has lower microsomal clearance than Ligand B (36.918), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (10.884) has a longer half-life than Ligand A (5.86), which is a positive attribute.

**P-gp Efflux:** Both ligands (0.19 and 0.218) have low P-gp efflux liability.

**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.

**Overall Assessment:**

Ligand A has a superior overall profile. It excels in QED, DILI risk, and metabolic stability. While Ligand B has a slightly better binding affinity and half-life, the advantages of Ligand A in safety (DILI) and drug-likeness (QED) are more important for overall developability. The solubility and Caco-2 permeability are poor for both, but can be addressed through formulation.

Output:
1
2025-04-17 15:26:57,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.405 and 387.267 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is better than Ligand B (76.46), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.317) is optimal (1-3), while Ligand B (1.859) is at the lower end, potentially impacting permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.809 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A (37.185) has a lower DILI risk than Ligand B (48.468), which is a significant advantage.

**BBB:** Both have the same BBB penetration (65.801), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.501 and -4.749), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.907 and -3.274), which is also concerning and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.589) has a slightly higher hERG risk than Ligand B (0.259), but both are relatively low.

**Microsomal Clearance:** Ligand B (37.068) has a lower microsomal clearance than Ligand A (65.375), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.341) has a negative half-life, which is concerning. Ligand A (36.541) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.19) has lower P-gp efflux than Ligand B (0.096), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand B has some ADME liabilities (lower logP, negative half-life), its significantly stronger binding affinity (-7.8 vs -9.1 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The improved metabolic stability (lower Cl_mic) also favors Ligand B. Ligand A has a better DILI score, but the affinity difference is more critical.

Output:
1
2025-04-17 15:26:57,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.5) is slightly better positioned.

**TPSA:** Ligand B (32.34) is significantly better than Ligand A (58.64). Lower TPSA generally improves cell permeability, which is beneficial.

**logP:** Ligand B (4.882) is a bit high, potentially leading to solubility issues and off-target effects. Ligand A (3.477) is closer to the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are acceptable.

**QED:** Ligand B (0.686) has a better QED score than Ligand A (0.393), suggesting a more drug-like profile.

**DILI:** Ligand A (24.04) has a much lower DILI risk than Ligand B (41.411), which is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (90.112) has higher BBB penetration than Ligand A (66.344).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.881) is slightly better than Ligand B (-4.773).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-4.769) is slightly better than Ligand A (-3.046).

**hERG Inhibition:** Ligand A (0.547) has a lower hERG risk than Ligand B (0.748), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand B (82.522) has a higher microsomal clearance than Ligand A (44.121), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (76.509) has a significantly longer half-life than Ligand A (-6.75), which is a substantial advantage.

**P-gp Efflux:** Both have low P-gp efflux liability. Ligand A (0.136) is slightly better.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a better binding affinity than Ligand A (-8.7 kcal/mol). The 1.5 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and half-life, but suffers from higher logP, higher DILI risk, and higher microsomal clearance. Ligand A has better solubility, lower DILI, lower hERG risk, and lower clearance, but a weaker binding affinity.

Given the enzyme-specific priorities, metabolic stability (Cl_mic) and hERG risk are critical. While the affinity difference is notable, Ligand A's superior metabolic stability and lower toxicity profile make it the more promising candidate. The slightly weaker binding can potentially be optimized in subsequent iterations.

Output:
0
2025-04-17 15:26:57,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.427 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.32 and 76.02) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.75 and 1.861) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.771 and 0.854), indicating drug-like properties.

**DILI:** Ligand B (30.593) has a significantly lower DILI risk than Ligand A (47.344). This is a major advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (61.535 and 61.962). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.042 and -4.985), which is unusual and suggests poor permeability. This is a significant drawback for both. However, the values are very similar.

**Aqueous Solubility:** Both have negative solubility values (-2.467 and -2.31). This is also a concern, indicating poor aqueous solubility. Again, the values are very similar.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.101 and 0.088). This is excellent.

**Microsomal Clearance:** Ligand B (15.242) has a significantly lower microsomal clearance than Ligand A (7.353), suggesting better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** The in vitro half-lives are very similar (10.981 and 10.825 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.036).

**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 (1.6 kcal/mol), it's enough to be considered, especially in the context of other favorable properties.

**Conclusion:**

Ligand B is the more promising candidate. It has a significantly lower DILI risk and better metabolic stability (lower Cl_mic) than Ligand A. The binding affinity is also slightly better. While both have poor Caco-2 permeability and solubility, the improvements in safety and metabolic stability outweigh these drawbacks, making Ligand B the preferred choice.

Output:
1
2025-04-17 15:26:57,605 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [380.363, 69.64, 1.573, 2, 4, 0.78, 50.446, 67.623, -5.001, -2.627, 0.355, -0.775, -13.975, 0.055, -8.8]
**Ligand B:** [371.439, 65.49, 4.277, 0, 7, 0.38, 97.635, 54.827, -4.764, -5.812, 0.276, 112.79, -20.915, 0.676, -8.3]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (380.363) is slightly higher than B (371.439), but both are acceptable.
2. **TPSA:** Both are below the 140 A^2 threshold for oral absorption. A (69.64) is slightly higher than B (65.49), but both are good.
3. **logP:** A (1.573) is optimal, while B (4.277) is pushing the upper limit and could present solubility issues.
4. **HBD:** A (2) is good, B (0) is acceptable.
5. **HBA:** A (4) is good, B (7) is acceptable, but getting towards the higher end.
6. **QED:** A (0.78) is excellent, indicating strong drug-like properties. B (0.38) is significantly lower, raising concerns about developability.
7. **DILI:** A (50.446) is good (low risk). B (97.635) is very high risk. This is a major red flag.
8. **BBB:** Both are acceptable, but A (67.623) is better than B (54.827). Not a primary concern for a kinase inhibitor, but a slight advantage for A.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-5.001) is slightly better than B (-4.764), but both are concerning.
10. **Solubility:** Both are negative, indicating poor solubility. A (-2.627) is better than B (-5.812).
11. **hERG:** Both are low risk. A (0.355) is slightly better than B (0.276).
12. **Cl_mic:** A (-0.775) indicates *lower* clearance and therefore better metabolic stability, which is highly desirable for a kinase inhibitor. B (112.79) indicates very *high* clearance, a significant drawback.
13. **t1/2:** A (-13.975) indicates a longer half-life, which is beneficial. B (-20.915) indicates an even longer half-life, but this is overshadowed by the high clearance.
14. **Pgp:** A (0.055) indicates low P-gp efflux, which is good. B (0.676) indicates higher efflux, potentially reducing bioavailability.
15. **Binding Affinity:** Both are excellent (-8.8 and -8.3 kcal/mol). The difference of 0.5 kcal/mol is not large enough to overcome the significant ADME deficiencies of Ligand B.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in metabolic stability (Cl_mic, t1/2) and has a better solubility profile. Ligand B has a very high DILI risk and poor metabolic stability, which are major concerns.

**Conclusion:**

Considering all factors, especially the critical ADME properties and the enzyme-specific priorities, **Ligand A** is significantly more likely to be a viable drug candidate.

Output:
0

2025-04-17 15:26:57,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.471 and 360.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.43) is significantly better than Ligand B (99.1), being well below the 140 threshold for good absorption.

**logP:** Ligand A (2.37) is optimal (1-3), while Ligand B (0.156) 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 reasonable QED scores (0.885 and 0.509, respectively), indicating drug-likeness.

**DILI:** Ligand A (38.93) has a much lower DILI risk than Ligand B (16.712), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (85.343) is better than Ligand B (49.826).

**Caco-2 Permeability:** Ligand A (-4.987) is better than Ligand B (-5.058), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.1) is better than Ligand B (-1.224), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.471) has a lower hERG risk than Ligand B (0.22), which is a significant advantage.

**Microsomal Clearance:** Ligand A (42.756) has higher clearance than Ligand B (13.272), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (1.45) has a shorter half-life than Ligand B (0.392).

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux than Ligand B (0.025).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). The 1.9 kcal/mol difference in binding is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, Ligand A excels in almost every other critical parameter. Its significantly stronger binding affinity, better logP, lower DILI risk, better solubility, and lower hERG risk outweigh the slightly higher clearance. The better TPSA and Caco-2 permeability also suggest better absorption.

Output:
1
2025-04-17 15:26:57,606 - INFO - Batch 380 complete. Total preferences: 6080
2025-04-17 15:26:57,606 - INFO - Processing batch 381/512...
2025-04-17 15:27:38,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.435 and 352.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.05) is better than Ligand B (110.26). Lower TPSA generally correlates with better cell permeability, which is beneficial.

**logP:** Ligand B (1.35) is better than Ligand A (0.521). A logP between 1-3 is optimal. Ligand A is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Fewer HBDs are generally preferred for better permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**QED:** Both ligands have similar QED values (0.755 and 0.742), indicating good drug-likeness.

**DILI:** Ligand A (33.812) has a significantly lower DILI risk than Ligand B (57.154). This is a major advantage for Ligand A.

**BBB:** Ligand B (70.764) has better BBB penetration than Ligand A (37.418). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and problematic. However, the magnitude of the negative value is smaller for Ligand B (-4.966) compared to Ligand A (-5.315), suggesting slightly better permeability.

**Aqueous Solubility:** Ligand A (-0.715) has better aqueous solubility than Ligand B (-3.047). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.079) has a much lower hERG inhibition risk than Ligand B (0.248). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (20.352) has significantly lower microsomal clearance than Ligand B (58.044). Lower clearance indicates better metabolic stability, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (27.748) has a much longer in vitro half-life than Ligand B (8.657). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.011) has lower P-gp efflux than Ligand B (0.074), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While a difference of 0.8 kcal/mol is noticeable, the other ADME properties of Ligand A are far more favorable.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A excels in critical ADME properties: lower DILI risk, lower hERG inhibition, significantly better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and lower P-gp efflux. These factors are particularly important for an enzyme inhibitor like an SRC kinase inhibitor. The slightly lower logP of Ligand A is a minor drawback that can potentially be addressed through further optimization.



Output:
0
2025-04-17 15:27:38,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.41 and 357.841 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is higher than Ligand B (55.32). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (2.254) is within the optimal 1-3 range. Ligand B (3.507) is slightly higher, potentially edging towards solubility issues, but 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 similar QED values (0.847 and 0.821), indicating good drug-likeness.

**DILI:** Ligand A (65.064) has a higher DILI risk than Ligand B (38.581). This is a significant advantage for Ligand B.

**BBB:** Both have high BBB penetration (91.392 and 83.288), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially concerning. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and concerning. Again, the scale is unknown.

**hERG Inhibition:** Ligand A (0.15) has a lower hERG risk than Ligand B (0.553). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (73.688) has lower microsomal clearance than Ligand B (92.968), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (1.359) has a shorter half-life than Ligand B (-23.733). The negative value for Ligand B is suspect and likely an error. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.102 and 0.103).

**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, potentially outweighing minor ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand B having a better DILI score, Ligand A is the superior candidate. The significantly stronger binding affinity (-8.8 vs -6.7 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand A has better metabolic stability (lower Cl_mic) and a more reasonable in vitro half-life. The solubility and Caco-2 values are concerning for both, but the potency and metabolic stability of Ligand A are more critical for initial optimization.

Output:
1
2025-04-17 15:27:38,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.309 Da and 354.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.29) is slightly higher than Ligand B (88.1). Both are below the 140 threshold for good oral absorption, but neither is optimized for CNS penetration (below 90).

**logP:** Ligand A (3.095) is within the optimal 1-3 range. Ligand B (0.515) is quite low, potentially hindering permeability. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 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 (0.564 and 0.62), indicating good drug-like properties.

**DILI:** Ligand A (63.901) has a higher DILI risk than Ligand B (32.144). This is a concern for Ligand A.

**BBB:** Ligand A (82.551) has better BBB penetration than Ligand B (50.058), but neither is particularly high, and BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.474 and -4.721), suggesting potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.592 and -0.89). This is a significant issue for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.831 and 0.2), which is excellent.

**Microsomal Clearance:** Ligand A (57.502) has higher microsomal clearance than Ligand B (21.002), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-8.179) has a longer in vitro half-life than Ligand A (-28.865), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.205 and 0.05).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 kcal/mol and -8.4 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While Ligand A has a better BBB score and similar binding affinity, its higher DILI risk and significantly higher microsomal clearance are major drawbacks. Ligand B, despite its lower logP and solubility, demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Given the enzyme-kinase focus, metabolic stability and minimizing toxicity (DILI) are crucial. The poor solubility of both is a concern, but can potentially be addressed through formulation strategies. The low logP of Ligand B is more readily addressed through structural modifications than the metabolic instability of Ligand A.

Output:
1
2025-04-17 15:27:38,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 372.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (78.51 and 76.15) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.853) is slightly better than Ligand B (0.359), falling comfortably within the 1-3 range. Ligand B is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, which is also 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 reasonable QED scores (0.747 and 0.696), indicating good drug-like properties.

**DILI:** Ligand A (8.453) has a significantly lower DILI risk than Ligand B (20.357). This is a major advantage for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration (64.87 and 74.292), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.394) has poor Caco-2 permeability. Ligand B (-4.701) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.235 and -1.496). This is a concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.176 and 0.214), which is excellent.

**Microsomal Clearance:** Ligand A (-15.698) has *much* lower microsomal clearance than Ligand B (14.256). This suggests significantly better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-3.734) has a negative half-life, indicating a very long half-life. Ligand B (6.097) has a reasonable half-life, but not as good as Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.007 and 0.019).

**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 of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the superior candidate. Its significantly stronger binding affinity, much lower DILI risk, and dramatically improved metabolic stability (lower Cl_mic and longer half-life) outweigh the permeability concerns. The potency advantage is particularly important for a kinase inhibitor.

Output:
1
2025-04-17 15:27:38,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.43 and 353.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.84) is better than Ligand B (48.99), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.468) is optimal, while Ligand B (4.187) is approaching the upper limit of the preferred range. This could potentially lead to solubility issues.

**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.

**QED:** Ligand A (0.804) has a significantly better QED score than Ligand B (0.625), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (54.29 and 50.21), both are acceptable.

**BBB:** Ligand A (89.10) has a better BBB penetration score than Ligand B (59.83), but BBB is not a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Both ligands 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:** Ligand A (-3.278) has better aqueous solubility than Ligand B (-5.58). Solubility is important for kinases.

**hERG Inhibition:** Ligand A (0.502) has a lower hERG risk than Ligand B (0.755), which is a significant advantage.

**Microsomal Clearance:** Ligand A (35.122) has a lower microsomal clearance than Ligand B (57.586), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-10.025) has a longer in vitro half-life than Ligand B (8.217), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.332) has lower P-gp efflux than Ligand B (0.558), which is favorable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a better QED score, better solubility, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and, most importantly, a significantly stronger binding affinity for the SRC kinase. While both ligands have acceptable molecular weights and DILI risk, Ligand A's overall profile is more favorable for development as a drug candidate.

Output:
1
2025-04-17 15:27:38,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (336.395 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.25) is slightly higher than Ligand B (66.48), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.952 and 1.544), falling within the optimal 1-3 range. Ligand B is slightly lower, potentially impacting permeability a bit more.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED scores (0.846 and 0.821), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (75.184 percentile) than Ligand B (23.575 percentile). This is a major concern for Ligand A.

**BBB:** Both have similar BBB penetration (64.637 and 64.87), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.57 and -4.877), 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:** Ligand B (-2.731) has better solubility than Ligand A (-5.378). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.756) shows slightly higher hERG inhibition risk than Ligand B (0.214). Lower is better here.

**Microsomal Clearance:** Ligand B (29.82 mL/min/kg) has significantly lower microsomal clearance than Ligand A (103.016 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-4.206 hours) has a longer half-life than Ligand A (26.246 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.328 and 0.138).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are excellent, the 0.5 kcal/mol difference is noteworthy.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have good potency and drug-like properties, Ligand B exhibits a much lower DILI risk, better solubility, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The lower DILI and improved metabolic stability are critical advantages for an enzyme inhibitor intended for systemic administration.

Output:
1
2025-04-17 15:27:38,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.487 and 356.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (62.3 and 61.88) below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have logP values (3.191 and 3.549) 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 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 QED values (0.787 and 0.735) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (30.593) has a lower DILI risk than Ligand B (44.087), which is a significant advantage.

**8. BBB:** Both ligands have similar BBB penetration (70.919 and 70.027), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.698 and -5.336). 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 (-2.871 and -3.803), suggesting poor aqueous solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.513 and 0.633).

**12. Microsomal Clearance:** Ligand A (56.327) has lower microsomal clearance than Ligand B (62.91), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.54) has a longer in vitro half-life than Ligand B (2.135).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.235 and 0.347).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.5 kcal/mol). The difference is less than 0.5 kcal/mol, so it's unlikely to be a deciding factor.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both ligands have comparable potency and acceptable physicochemical properties, Ligand A demonstrates a significantly lower DILI risk and better metabolic stability (lower Cl_mic and longer t1/2). These factors are crucial for enzyme inhibitors, as metabolic stability and minimizing toxicity are paramount. The slightly better DILI and metabolic stability profile of Ligand A outweigh the minor differences in other parameters.

Output:
0
2025-04-17 15:27:38,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.438 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (1.187) is within the optimal 1-3 range. Ligand B (3.189) is at the higher end of optimal, but 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 QED values (0.701 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A (20.202) has a significantly lower DILI risk than Ligand B (27.918), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand B (71.229) has a slightly higher BBB penetration than Ligand A (66.499), but BBB is not a high priority for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.739 and -4.441), which is unusual and suggests poor permeability. However, these values are on a log scale and the absolute value is more important. Ligand B is slightly less negative.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.548 and -2.529), indicating poor aqueous solubility. Ligand A is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.258 and 0.199), which is excellent.

**Microsomal Clearance:** Ligand A (1.432) has significantly lower microsomal clearance than Ligand B (89.461), indicating much better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (0.775) has a slightly longer half-life than Ligand B (0.972), although both are relatively short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.037 and 0.249).

**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 less than the 1.5 kcal/mol threshold, it contributes to the overall preference for Ligand A.

**Conclusion:**

Ligand A is the more promising candidate. While both ligands have acceptable MW, QED, hERG, and P-gp properties, Ligand A significantly outperforms Ligand B in DILI risk and microsomal clearance (metabolic stability). The slightly better binding affinity of Ligand A further supports this conclusion. The solubility and Caco-2 values are concerning for both, but the metabolic stability advantage of Ligand A is crucial for an enzyme inhibitor.

Output:
0
2025-04-17 15:27:38,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.372 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is significantly better than Ligand B (98.06). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (3.222) is optimal, while Ligand B (1.335) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3), as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.76 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (31.64) has a much lower DILI risk than Ligand B (44.513), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (88.29) is better than Ligand B (46.181).

**Caco-2:** Ligand A (-4.224) is better than Ligand B (-5.069), indicating better intestinal absorption.

**Solubility:** Ligand A (-3.323) is better than Ligand B (-2.898), which is crucial for bioavailability.

**hERG:** Ligand A (0.784) has a lower hERG risk than Ligand B (0.21), which is a major safety concern.

**Microsomal Clearance:** Ligand A (72.988) has a higher (worse) Cl_mic than Ligand B (-5.066). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-15.062) has a shorter half-life than Ligand B (-12.013). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.245) has lower P-gp efflux than Ligand B (0.03), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-9.3 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in key ADME properties like TPSA, logP, DILI, solubility, and hERG risk. While Ligand B has better metabolic stability and half-life, the superior safety profile and absorption/distribution characteristics of Ligand A outweigh these drawbacks, especially given the similar binding affinities. The lower DILI and hERG risks are particularly important for an oncology drug.

Output:
1
2025-04-17 15:27:38,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.55) is better than Ligand B (67.6), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.588 and 2.9), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable range (<=10).

**QED:** Ligand B (0.781) has a slightly better QED score than Ligand A (0.557), indicating a more drug-like profile.

**DILI:** Ligand B (8.841) has a significantly lower DILI risk than Ligand A (54.789). This is a major advantage for Ligand B.

**BBB:** Ligand B (91.508) has a much higher BBB penetration percentile than Ligand A (65.413). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.496 and -4.698). These values are unusual and suggest poor permeability. However, these are likely experimental errors or indicate the compounds are not well-suited for Caco-2 assays.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.24 and -3.033). Similar to Caco-2, these are likely experimental errors or indicate poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.541 and 0.583).

**Microsomal Clearance:** Ligand A (32.628) has lower microsomal clearance than Ligand B (51.625), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.585) has a negative half-life, which is not possible. Ligand B (4.767) has a positive half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.091 and 0.111).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 0.4 kcal/mol difference is substantial and outweighs many other concerns.

**Conclusion:**

Despite the questionable Caco-2 and solubility values, Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, better QED, and more reasonable half-life outweigh the slightly higher microsomal clearance. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 15:27:38,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (345.443 and 356.457 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is slightly higher than the preferred <140, but acceptable. Ligand B (49.41) is well within the ideal range.

**3. logP:** Both ligands have good logP values (2.069 and 3.066), 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 4 HBAs, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.821 and 0.762), indicating good drug-like properties.

**7. DILI:** Ligand A (27.801) has a significantly lower DILI risk than Ligand B (14.889). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (67.429) has a lower BBB penetration percentile than Ligand B (94.843). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.23) has a worse Caco-2 permeability than Ligand B (-4.5).

**10. Aqueous Solubility:** Ligand A (-2.103) has better aqueous solubility than Ligand B (-3.504).

**11. hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition risk than Ligand B (0.603). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (46.487) has higher microsomal clearance than Ligand B (34.8). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-23.974) has a shorter in vitro half-life than Ligand B (-17.793). This is a disadvantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux liability than Ligand B (0.156).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.4). While the difference is relatively small, it's still a positive for Ligand A.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI and hERG risk) and slightly better binding affinity. While Ligand B has better metabolic stability and Caco-2 permeability, the lower DILI and hERG risks of Ligand A are more critical for an oncology target where chronic dosing is possible. The slightly better solubility of Ligand A is also beneficial. The difference in half-life is not substantial enough to outweigh the safety advantages.

Output:
0
2025-04-17 15:27:38,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.73 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.58) is slightly higher than Ligand B (61.88). Both are below the 140 A^2 threshold for good absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (3.684 and 3.143), 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:** Both ligands have excellent QED scores (0.806 and 0.833), indicating good drug-like properties.

**DILI:** Ligand A (82.241) has a significantly higher DILI risk than Ligand B (46.258). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration, but Ligand B (91.935) is better than Ligand A (74.447). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**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. Ligand A (-4.805) is slightly worse than Ligand B (-4.53).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-5.332) is slightly worse than Ligand B (-3.661).

**hERG:** Both ligands have low hERG inhibition risk (0.726 and 0.658), which is good.

**Microsomal Clearance:** Ligand B (85.861) has a much higher microsomal clearance than Ligand A (20.441). This indicates Ligand A is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (39.116) has a significantly longer half-life than Ligand A (8.245). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.264 and 0.177).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). This difference, while not huge, is still significant.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better metabolic stability (lower Cl_mic), the significantly higher DILI risk is a major red flag. Ligand B has a lower DILI risk, better solubility, longer half-life, and slightly better binding affinity. The slightly worse metabolic stability of Ligand B is a manageable concern compared to the potential liver toxicity of Ligand A.

Output:
1
2025-04-17 15:27:38,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.394 and 347.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (68.54 and 64.86) well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.998) is at the upper end of the optimal range (1-3), while Ligand B (2.895) is comfortably within it.

**H-Bond Donors:** Both 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 good QED scores (0.721 and 0.783), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 85.149, which is high. Ligand B has a much lower DILI risk of 21.753, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration (64.637 and 79.256). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.63 and -5.09), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-5.071 and -2.386), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.865) has a slightly higher hERG risk than Ligand B (0.452), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (49.192) has a higher microsomal clearance than Ligand B (34.02), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (13.987) has a longer in vitro half-life than Ligand A (21.451), which is desirable.

**P-gp Efflux:** Ligand A (0.454) has slightly lower P-gp efflux than Ligand B (0.267), which is slightly favorable.

**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 for Ligand B.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity outweigh the minor disadvantages in P-gp efflux. The high DILI risk of Ligand A is a major concern that would likely preclude further development.

Output:
1
2025-04-17 15:27:38,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 340.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is well below the 140 threshold and excellent for oral absorption. Ligand B (112.66) is still acceptable but less optimal, being higher.

**logP:** Ligand A (1.718) is within the optimal 1-3 range. Ligand B (0.742) is slightly below 1, which *could* indicate potential permeability issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Ligand A (0.731) is strong, indicating good drug-like properties. Ligand B (0.508) is acceptable, but lower.

**DILI:** Ligand A (12.214) has a very low DILI risk, which is excellent. Ligand B (61.691) is higher, indicating a moderate risk of liver injury.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (74.254) has better BBB penetration than Ligand B (20.744).

**Caco-2 Permeability:** Ligand A (-4.507) is poor, while Ligand B (-5.366) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-0.722) is poor, but Ligand B (-2.464) is significantly worse.

**hERG Inhibition:** Ligand A (0.434) has a very low hERG risk, which is excellent. Ligand B (0.091) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (17.86) is moderate, indicating reasonable metabolic stability. Ligand B (-9.712) is *very* negative, suggesting very slow clearance and high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (-2.409) is poor. Ligand B (-15.843) is excellent, indicating a long half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.024 and 0.016), which is good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.8 kcal/mol). This 1.9 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and DILI profile, Ligand B stands out due to its significantly stronger binding affinity (-8.7 vs -6.8 kcal/mol) and excellent metabolic stability (very negative Cl_mic and long half-life). The lower Caco-2 permeability and solubility of Ligand B are concerns, but these can potentially be addressed through formulation strategies. The stronger binding affinity is crucial for an enzyme inhibitor, and the improved metabolic stability will likely translate to a better *in vivo* profile.

Output:
1
2025-04-17 15:27:38,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.395 and 337.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.56) is well below the 140 threshold for oral absorption, and good for kinase inhibitors. Ligand B (101.38) is still within acceptable limits, but less favorable.

**logP:** Both ligands have good logP values (2.07 and 1.432), 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 2 HBD and 6 HBA, also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (0.872 and 0.708), suggesting good drug-like properties.

**DILI:** Ligand A (55.021) has a lower DILI risk than Ligand B (75.766), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (63.28) has a slightly better score than Ligand B (57.193).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value for Ligand A (-4.943) is less negative than Ligand B (-5.637), indicating slightly better potential absorption.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.288) is slightly better than Ligand B (-2.765).

**hERG Inhibition:** Ligand A (0.271) has a much lower hERG inhibition liability than Ligand B (0.081), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (24.187) has a lower microsomal clearance than Ligand B (27.188), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.028) has a significantly longer in vitro half-life than Ligand B (-27.131), which is a major advantage.

**P-gp Efflux:** Ligand A (0.215) has lower P-gp efflux liability than Ligand B (0.095), indicating better bioavailability.

**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 of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The solubility and permeability are poor for both, but slightly better for A. The difference in binding affinity (-1.7 kcal/mol) is substantial, and in this case, likely outweighs the ADME concerns, assuming formulation strategies can address the solubility/permeability issues.

Output:
1
2025-04-17 15:27:38,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (448.308 Da) is closer to the upper limit, while Ligand B (351.447 Da) is comfortably within the range.

**TPSA:** Ligand A (51.02) is well below the 140 threshold for oral absorption. Ligand B (84.67) is also below the threshold, but higher than A.

**logP:** Ligand A (4.115) is slightly above the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.186) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable counts, falling within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.565, B: 0.776), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (59.17) has a moderate DILI risk. Ligand B (40.675) has a lower, more favorable DILI risk.

**BBB:** Both ligands have reasonable BBB penetration (A: 79.217, B: 76.541), but this is less critical for a non-CNS target like SRC.

**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 negative solubility values, which is also unusual and indicates poor solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.847, B: 0.247), which is positive. Ligand B is better.

**Microsomal Clearance:** Ligand A (98.355) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (41.769) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (103.49) has a longer half-life than Ligand B (-15.714). However, the negative value for B is concerning and potentially indicates an issue with the assay or molecule.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.571, B: 0.045). Ligand B is better.

**Binding Affinity:** Both ligands have strong binding affinities (A: -9.4 kcal/mol, B: -8.3 kcal/mol). Ligand A has a 1.1 kcal/mol advantage, which is significant and could outweigh some of its other drawbacks.

**Overall Assessment:**

Ligand A has a stronger binding affinity, a longer half-life, and a slightly better TPSA. However, it has a higher logP, higher DILI risk, and higher microsomal clearance. Ligand B has better solubility, lower DILI, lower clearance, and lower P-gp efflux. The negative Caco-2 and solubility values for both are concerning and need further investigation.

Given the enzyme-kinase specific priorities, metabolic stability (lower Cl_mic) and lower toxicity (lower DILI) are crucial. While the affinity difference is notable, the better ADME profile of Ligand B, particularly its lower DILI and clearance, makes it the more promising candidate. The negative solubility and permeability values for both are red flags that would require addressing through formulation or structural modification, but B starts from a better position.

Output:
1
2025-04-17 15:27:38,479 - INFO - Batch 381 complete. Total preferences: 6096
2025-04-17 15:27:38,479 - INFO - Processing batch 382/512...
2025-04-17 15:28:19,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.387 and 356.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (90.54), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.521) is slightly higher than optimal (1-3), but still acceptable. Ligand B (1.589) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=3, HBA=3) as it strikes a better balance between solubility and permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.449, B: 0.519), indicating reasonable drug-likeness.

**DILI:** Ligand A (94.843) has a significantly higher DILI risk than Ligand B (18.108). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (73.827) has a higher BBB value than Ligand A (52.617), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.341) has a worse Caco-2 permeability than Ligand B (-4.892), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.062) has a worse aqueous solubility than Ligand B (-2.103), which could pose formulation challenges.

**hERG:** Both ligands have relatively low hERG inhibition risk (A: 0.406, B: 0.634), which is good.

**Microsomal Clearance:** Ligand A (92.16) has a much higher microsomal clearance than Ligand B (35.123), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-2.315) has a negative half-life, which is very concerning. Ligand B (0.024) has a very short half-life, but is still better than a negative value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.654, B: 0.013), which is favorable.

**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 for Ligand B.

**Conclusion:**

While Ligand A has a slightly better TPSA and logP, it is significantly hampered by its high DILI risk, poor metabolic stability (high Cl_mic), extremely short in vitro half-life, and weaker binding affinity. Ligand B, despite a slightly less optimal logP and TPSA, exhibits a much more favorable safety profile (low DILI), better metabolic stability, a longer half-life, and, crucially, a significantly stronger binding affinity. The difference in binding affinity is substantial enough to outweigh the minor ADME drawbacks of Ligand B.

Output:
1
2025-04-17 15:28:19,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.391 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.64) is slightly higher than Ligand B (90.9). Both are below the 140 threshold for oral absorption, but neither are optimized for CNS penetration (below 90).

**logP:** Ligand A (2.602) is within the optimal 1-3 range. Ligand B (0.764) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, well within acceptable limits. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.679) has a better QED score than Ligand B (0.306), indicating a more drug-like profile.

**DILI:** Ligand A (99.031) has a very high DILI risk, which is a significant concern. Ligand B (12.524) has a very low DILI risk, a major advantage.

**BBB:** Both ligands have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.9) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.657) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.305) has poor aqueous solubility. Ligand B (-0.413) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.674) has a moderate hERG risk. Ligand B (0.174) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (21.214) has moderate microsomal clearance. Ligand B (-5.505) has *negative* clearance, which is highly unusual and suggests exceptional metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (84.703) has a good in vitro half-life. Ligand B (23.026) has a moderate in vitro half-life.

**P-gp Efflux:** Ligand A (0.244) has low P-gp efflux. Ligand B (0.009) has very low P-gp efflux, a slight advantage.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 kcal/mol and -7.0 kcal/mol, respectively). The difference of 0.4 kcal/mol is not substantial enough to override other significant ADME differences.

**Conclusion:**

Despite similar binding affinities, Ligand B is the superior candidate. Its significantly lower DILI risk, exceptionally low microsomal clearance (indicating high metabolic stability), and very low hERG risk outweigh the slightly lower QED, solubility, and Caco-2 permeability. While both have poor solubility and permeability, the metabolic stability and safety profile of Ligand B are far more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 15:28:19,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.415 and 356.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.55) is slightly higher than Ligand B (83.98), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.889) is a bit low, potentially hindering permeation. Ligand B (2.415) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) 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 (0.68 and 0.862, respectively), indicating drug-like properties.

**DILI:** Ligand A (23.924) has a significantly lower DILI risk than Ligand B (70.182). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar, moderate BBB penetration (49.67 and 49.011). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.014 and -5.367). 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 (-1.708 and -3.192). This indicates poor aqueous solubility, which is a concern. Ligand B is slightly worse.

**hERG Inhibition:** Ligand A (0.065) shows very low hERG inhibition risk, while Ligand B (0.136) is slightly higher but still low.

**Microsomal Clearance:** Ligand A (11.662) has a higher microsomal clearance than Ligand B (-0.307). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (25.411) has a significantly longer in vitro half-life than Ligand A (1.556). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.012 and 0.063).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a much better safety profile (lower DILI, lower hERG), Ligand B demonstrates superior potency (binding affinity) and metabolic stability (lower Cl_mic, longer t1/2). Given the enzyme-kinase specific priorities, the stronger binding affinity and improved metabolic stability of Ligand B are more critical. The solubility issues are a concern for both, but could be addressed with formulation strategies.

Output:
1
2025-04-17 15:28:19,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (372.446 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is significantly better than Ligand B (93.9), being well below the 140 threshold for oral absorption. Ligand B is approaching the upper limit and could present absorption challenges.

**logP:** Both ligands have acceptable logP values (2.469 and 0.759), falling within the 1-3 range. Ligand B is on the lower side, which *could* impact permeability, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 6 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 (0.614 and 0.862), indicating good drug-like properties.

**DILI:** Ligand A (16.402 percentile) has a much lower DILI risk than Ligand B (67.429 percentile). This is a significant advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (79.682) is better than Ligand B (63.086), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.506 and -4.919). This is unusual and suggests poor permeability *in vitro*. However, this is a relative measure and needs to be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.698 and -1.341), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.313 percentile) has a much lower hERG inhibition risk than Ligand B (0.204 percentile). This is a significant advantage for Ligand A.

**Microsomal Clearance (Cl_mic):** Ligand A (51.896 mL/min/kg) has a higher Cl_mic than Ligand B (37.963 mL/min/kg), indicating *lower* metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life (t1/2):** Ligand B (-4.535 hours) has a longer half-life than Ligand A (2.657 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.084 and 0.045).

**Binding Affinity:** Ligand A (-7.0 kcal/mol) has slightly better binding affinity than Ligand B (-6.7 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is the better candidate. While it has a higher Cl_mic and shorter half-life, its significantly lower DILI and hERG risk, better TPSA, and slightly better binding affinity outweigh this drawback. The poor solubility and permeability (indicated by negative Caco-2 and solubility values) are concerns for both, but can potentially be addressed through formulation strategies. The lower toxicity profile of Ligand A is crucial for a kinase inhibitor intended for oncology.

Output:
1
2025-04-17 15:28:19,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.351 Da) is slightly lower, which could be beneficial for permeability. Ligand B (353.849 Da) is also good.

**TPSA:** Ligand A (91.73) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (42.24) is excellent, well below the threshold, suggesting good absorption.

**logP:** Ligand A (2.649) is within the optimal 1-3 range. Ligand B (4.995) 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 (Ligand A: 5, Ligand B: 2) counts.

**QED:** Ligand A (0.869) has a very good QED score, indicating high drug-likeness. Ligand B (0.717) is still acceptable, but lower.

**DILI:** Ligand A (90.733) has a high DILI risk, which is a significant concern. Ligand B (59.907) has a moderate DILI risk, which is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (59.325) and Ligand B (62.854) are both moderate.

**Caco-2 Permeability:** Both have negative Caco-2 values which is concerning.

**Aqueous Solubility:** Both have negative solubility values, which is concerning.

**hERG:** Ligand A (0.259) has a very low hERG risk, which is excellent. Ligand B (0.691) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-11.955) has a very low (negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (62.41) has a high clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (41.209 hours) has a good half-life. Ligand B (185.663 hours) has a very long half-life, which is positive.

**P-gp Efflux:** Ligand A (0.162) has low P-gp efflux, which is good. Ligand B (0.757) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor for an enzyme inhibitor. While it has a higher logP and moderate DILI/Pgp, the significantly improved potency and long half-life are compelling. Ligand A's main drawback is the high DILI risk, which is a major red flag. The superior metabolic stability of Ligand A is good, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 15:28:19,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 Da and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.87 and 80.32) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values (3.093 and 2.372) 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 5. Both are acceptable, being under the 10 limit.

**QED:** Both ligands have QED values (0.669 and 0.52) above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (37.301) has a lower DILI risk than Ligand B (51.493), which is a significant advantage. Both are below the concerning 60 threshold, but lower is better.

**BBB:** Both are relatively low, which is not a major concern for a non-CNS target like SRC. Ligand B (66.421) is slightly higher than Ligand A (50.989).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.237 and -4.927), which is unusual and indicates poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.923 and -2.556), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.374 and 0.264), which is excellent.

**Microsomal Clearance:** Ligand A (16.941) has considerably lower microsomal clearance than Ligand B (39.639). Lower clearance indicates better metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand A (-9.607) has a more negative (longer) in vitro half-life than Ligand B (12.343). This is a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.014 and 0.269).

**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 small (0.3 kcal/mol), it's still a positive factor.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. It has a lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both ligands suffer from poor Caco-2 permeability and solubility, the improvements in safety and pharmacokinetics for Ligand A outweigh the small difference in binding affinity.

Output:
0
2025-04-17 15:28:19,060 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.391 and 359.348 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.56) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (78.51) is well within the optimal range.

**logP:** Ligand A (-0.576) is a bit low, potentially hindering permeability. Ligand B (1.025) is 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 acceptable, but Ligand B is slightly better.

**QED:** Both ligands have similar QED values (0.715 and 0.736), indicating good drug-likeness.

**DILI:** Ligand A (49.864) has a slightly higher DILI risk than Ligand B (37.611), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.721) has a higher BBB percentile than Ligand A (65.529).

**Caco-2 Permeability:** Both have negative values (-5.158 and -4.951), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative values (-1.472 and -2.522), indicating poor solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.052 and 0.069). This is excellent.

**Microsomal Clearance:** Ligand A (-7.841) has significantly lower (better) microsomal clearance than Ligand B (-1.499). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-5.676) has a longer half-life than Ligand B (-29.36). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.004 and 0.012).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite the poor Caco-2 permeability and solubility for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.9 vs -7.0 kcal/mol) outweighs the slightly lower logP and higher DILI risk. Furthermore, Ligand A exhibits superior metabolic stability (lower Cl_mic) and a longer half-life, which are critical for an enzyme inhibitor. The slightly better solubility and lower DILI risk of Ligand B are not enough to compensate for the much weaker binding.

Output:
0
2025-04-17 15:28:19,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.43 & 348.49 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (75.27). Both are below 140, supporting reasonable absorption.

**logP:** Both ligands have acceptable logP values (2.296 & 2.749), 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 maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.831) has a significantly higher QED score than Ligand B (0.725), indicating better overall drug-likeness.

**DILI:** Ligand A (28.62) has a lower DILI risk than Ligand B (24.16), both are good.

**BBB:** Ligand A (95.43) has a much higher BBB penetration percentile than Ligand B (67.62). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.632) has a better Caco-2 permeability than Ligand B (-4.776).

**Aqueous Solubility:** Ligand A (-2.194) has better aqueous solubility than Ligand B (-3.378). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.489) has a lower hERG inhibition risk than Ligand B (0.071). This is a significant advantage as it reduces the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (19.88 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (54.97 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.095 hours) has a better in vitro half-life than Ligand B (-27.96 hours).

**P-gp Efflux:** Ligand A (0.09) has a lower P-gp efflux liability than Ligand B (0.071).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). However, the difference is small and can be outweighed by other factors.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME-Tox properties. It has a better QED score, lower DILI, better solubility, significantly lower microsomal clearance (better metabolic stability), better hERG profile, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the improvements in ADME-Tox properties for Ligand A are substantial and outweigh this minor difference in potency.

Output:
1
2025-04-17 15:28:19,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.326 Da and 354.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (83.58 and 79.9) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Both ligands have logP values (3.043 and 3.22) 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values (0.68 and 0.754) above 0.5, indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (83.521 and 82.319 percentile), which is relatively high, but not drastically concerning.

**BBB:** Both ligands have low BBB penetration (55.138 and 54.13 percentile). This isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.259 and -5.289). This 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 (-4.808 and -3.889). This is also concerning, as poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A has a low hERG risk (0.841 percentile), which is excellent. Ligand B has a slightly higher, but still acceptable, hERG risk (0.596 percentile).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (32.655 mL/min/kg) than Ligand B (19.242 mL/min/kg). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (17.945 hours) compared to Ligand A (-22.205 hours). A negative value suggests a very short half-life.

**P-gp Efflux:** Ligand A has no P-gp efflux liability (0.092), while Ligand B has a moderate efflux liability (0.563). Lower efflux is preferred.

**Binding Affinity:** Ligand B has a much stronger binding affinity (-9.8 kcal/mol) than Ligand A (0 kcal/mol). This is a substantial difference and a major advantage.

**Conclusion:**

Despite similar DILI and somewhat concerning solubility/permeability profiles for both, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.8 kcal/mol vs 0 kcal/mol) outweighs the slightly higher P-gp efflux and similar DILI risk. Furthermore, Ligand B exhibits a much longer in vitro half-life and lower microsomal clearance, indicating better metabolic stability. The hERG risk is also acceptable. While both compounds have solubility issues, the potency and metabolic stability advantages of Ligand B make it more likely to be a viable drug candidate.

Output:
1
2025-04-17 15:28:19,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.4 and 346.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (40.62), being under the 140 threshold, but still relatively high. Ligand B is excellent.

**logP:** Ligand A (1.516) is optimal, while Ligand B (3.916) is approaching the upper limit.

**H-Bond Donors:** Ligand A (3) is within the acceptable limit, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) is within the acceptable limit, while Ligand B (2) is also good.

**QED:** Ligand A (0.576) is better than Ligand B (0.444), indicating a more drug-like profile.

**DILI:** Ligand A (20.9) has a significantly lower DILI risk than Ligand B (16.983), which is a major advantage.

**BBB:** Ligand A (77.937) is good, while Ligand B (90.074) is excellent. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values (-4.835 and -4.721), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-1.287) is better than Ligand B (-3.76), indicating slightly better aqueous solubility.

**hERG:** Ligand A (0.465) has a lower hERG risk than Ligand B (0.674), which is a crucial safety parameter.

**Cl_mic:** Ligand A (3.75) has much lower microsomal clearance than Ligand B (69.854), indicating better metabolic stability. This is a significant advantage for Ligand B.

**t1/2:** Ligand A (-12.952) has a negative in vitro half-life, which is concerning. Ligand B (4.666) has a reasonable half-life.

**Pgp:** Ligand A (0.058) has lower P-gp efflux liability than Ligand B (0.778), which is a positive.

**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, which is the most important factor for an enzyme inhibitor. While it has some ADME liabilities (higher logP, higher Cl_mic, and Pgp efflux), the strong binding affinity and reasonable half-life make it a more promising candidate. Ligand A has better DILI and hERG profiles, but its weaker binding affinity and negative half-life are major drawbacks. The Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:28:19,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.39) is better than Ligand B (41.57) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (0.305) is a bit low, potentially hindering permeation. Ligand B (3.777) is within the optimal range (1-3).

**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 (0.774 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (30.593) has a slightly higher DILI risk than Ligand B (27.608), but both are below the 40 threshold and considered good.

**BBB:** Both ligands have good BBB penetration (70.26 and 77.433), but this is less crucial for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.462) has very poor Caco-2 permeability, while Ligand B (-4.537) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.131) has poor aqueous solubility, while Ligand B (-4.389) is even worse. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.058) has a very low hERG risk, which is excellent. Ligand B (0.831) has a higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (21.953) has much lower microsomal clearance than Ligand B (85.567), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (1.49) has a very short half-life, while Ligand B (42.004) has a long half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.008 and 0.497).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.6 kcal/mol).

**Conclusion:**

Despite Ligand A's excellent hERG profile, Ligand B is the more promising candidate. The significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability of Ligand B outweigh the slightly lower logP and higher DILI risk. The binding affinity is comparable, making the ADME properties the deciding factors. The poor solubility of both compounds is a concern that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 15:28:19,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.479 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (354.491 Da) is also good.

**TPSA:** Ligand A (38.33) is excellent, well below the 140 threshold for oral absorption. Ligand B (78.87) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (4.772) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.704) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but has more HBA.

**QED:** Both ligands have good QED scores (A: 0.668, B: 0.735), indicating drug-like properties.

**DILI:** Ligand A (37.03) has a low DILI risk, which is excellent. Ligand B (15.006) also has a very low DILI risk.

**BBB:** Both have moderate BBB penetration (A: 54.983, B: 51.842), which isn't critical for a non-CNS target like SRC.

**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 major concern. This suggests poor solubility and potential formulation challenges.

**hERG:** Both ligands show low hERG inhibition risk (A: 0.871, B: 0.425). This is a positive attribute.

**Microsomal Clearance:** Ligand A (107.02) has higher clearance than Ligand B (77.165), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-14.461) has a significantly longer half-life than Ligand A (-3.491). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.799, B: 0.276).

**Binding Affinity:** Both have strong binding affinities (A: -9.1 kcal/mol, B: -8.2 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.9 kcal/mol) isn't huge enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is the better candidate. While both have concerning permeability and solubility issues, Ligand B has superior metabolic stability (lower Cl_mic, longer half-life), a more favorable logP, and a lower P-gp efflux liability. The slightly weaker binding affinity of Ligand B is outweighed by these ADME advantages, particularly the improved metabolic stability and half-life, which are critical for an enzyme target. The solubility and permeability issues would need to be addressed through formulation strategies, but the core pharmacokinetic profile of Ligand B is more promising.

Output:
1
2025-04-17 15:28:19,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (355.36 and 352.454 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (78.09). TPSA < 140 is good for oral absorption, and both are well below this, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (2.022 and 2.55), 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, well below the threshold of 10.

**6. QED:** Both have reasonable QED scores (0.794 and 0.635), indicating good drug-like properties.

**7. DILI:** Ligand A (42.458) has a slightly better DILI score than Ligand B (54.944), both being under the 60 threshold, but A is preferable.

**8. BBB:** Both have similar BBB penetration (75.921 and 77.627). This isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.626 and -4.881). This is unusual and suggests poor permeability. However, the values are close enough that it doesn't strongly differentiate the two.

**10. Aqueous Solubility:** Both have negative solubility values (-2.306 and -2.846), again indicating poor solubility. Similar to Caco-2, the difference isn't substantial.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.309 and 0.604), which is excellent.

**12. Microsomal Clearance:** Ligand A (30.379) has a lower microsomal clearance than Ligand B (42.359), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-25.935) has a *much* longer in vitro half-life than Ligand B (21.282). This is a major advantage, as it suggests less frequent dosing potential.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.029 and 0.169).

**15. Binding Affinity:** Both have excellent binding affinities (-6.1 and -5.8 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:**

Ligand A is superior. While both ligands have similar binding affinities and acceptable ADME properties, Ligand A demonstrates better metabolic stability (lower Cl_mic), a significantly longer half-life, and a slightly better DILI score. The lower TPSA is also a minor advantage. The negative Caco-2 and solubility values are concerning for both, but the improved PK profile of A outweighs this concern.

Output:
1
2025-04-17 15:28:19,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.495 and 343.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold and favorable for absorption. Ligand B (87.97) is also below 140, but closer to the limit.

**logP:** Ligand A (3.126) is optimal. Ligand B (1.351) is a bit low, potentially impacting 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 7. Both are within the acceptable limit of 10, but Ligand B is higher.

**QED:** Both ligands have good QED scores (0.663 and 0.875), indicating drug-like properties.

**DILI:** Ligand A (42.613) has a lower DILI risk than Ligand B (77.627), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (72.896) is slightly better than Ligand A (68.67). However, BBB is less crucial for a non-CNS target like SRC.

**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:** Ligand A (0.349) has a much lower hERG risk than Ligand B (0.481), which is a critical advantage.

**Microsomal Clearance:** Ligand A (68.335) has higher microsomal clearance than Ligand B (43.276), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (5.921) has a longer half-life than Ligand A (-11.658), which is a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability.

**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 less than the 1.5 kcal/mol threshold, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG) and slightly better binding affinity. Ligand B has better metabolic stability (lower Cl_mic, longer half-life) but higher DILI and hERG risk. Given the enzyme-specific priorities, the safety profile and binding affinity of Ligand A are more important than the slightly better metabolic stability of Ligand B. The poor Caco-2 and solubility for both are concerning and would need to be addressed in further optimization, but the starting point of Ligand A is more promising due to its safety and potency.

Output:
1
2025-04-17 15:28:19,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**
*   **MW:** 385.247 Da - Within the ideal range (200-500).
*   **TPSA:** 84.63 - Good for oral absorption (<140).
*   **logP:** 3.474 - Optimal (1-3).
*   **HBD:** 2 - Acceptable (<=5).
*   **HBA:** 5 - Acceptable (<=10).
*   **QED:** 0.392 - Below ideal (>=0.5), a slight concern.
*   **DILI:** 54.75 - Acceptable risk (<60).
*   **BBB:** 47.15 - Not a priority for a non-CNS target.
*   **Caco-2:** -4.924 - Very poor permeability. A significant drawback.
*   **Solubility:** -4.344 - Very poor solubility. A significant drawback.
*   **hERG:** 0.943 - Low risk.
*   **Cl_mic:** 25.597 mL/min/kg - Moderate clearance, could be better.
*   **t1/2:** 25.476 hours - Good in vitro half-life.
*   **Pgp:** 0.8 - Moderate efflux.
*   **Affinity:** -7.9 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 345.443 Da - Within the ideal range (200-500).
*   **TPSA:** 60.93 - Good for oral absorption (<140).
*   **logP:** 1.19 - Acceptable, but on the lower side.
*   **HBD:** 0 - Acceptable (<=5).
*   **HBA:** 3 - Acceptable (<=10).
*   **QED:** 0.722 - Good drug-like profile (>=0.5).
*   **DILI:** 47.693 - Acceptable risk (<60).
*   **BBB:** 71.462 - Not a priority for a non-CNS target.
*   **Caco-2:** -4.567 - Poor permeability, but better than Ligand A.
*   **Solubility:** -1.666 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.39 - Low risk.
*   **Cl_mic:** 43.402 mL/min/kg - Higher clearance, a concern.
*   **t1/2:** -8.919 hours - Very short half-life. A significant drawback.
*   **Pgp:** 0.128 - Low efflux.
*   **Affinity:** -7.8 kcal/mol - Very good binding affinity, close to Ligand A.

**Comparison and Decision:**

Both compounds have excellent binding affinity. Ligand A has a slightly better affinity (-7.9 vs -7.8 kcal/mol), but its extremely poor Caco-2 permeability and solubility are major liabilities. Ligand B has a shorter half-life and higher clearance, but its permeability and solubility, while still not ideal, are significantly better than Ligand A's. Given the enzyme-kinase focus, metabolic stability (half-life and clearance) and solubility are critical. While Ligand B's half-life is concerning, the better permeability and solubility offer more opportunities for optimization. The poor ADME properties of Ligand A are harder to overcome.

Output:
1
2025-04-17 15:28:19,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.807 Da) is slightly higher than Ligand B (351.403 Da), but both are acceptable.

**TPSA:** Ligand A (72.47) is well below the 140 threshold for oral absorption. Ligand B (117.52) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.42) is within the optimal range (1-3). Ligand B (0.067) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, both within acceptable limits. Ligand B has 2 HBD and 6 HBA, also within limits.

**QED:** Both ligands have reasonable QED values (A: 0.793, B: 0.568), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (93.292), which is a significant concern. Ligand B has a much lower DILI risk (32.028), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.282) and Ligand B (55.603) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.303) shows poor permeability, likely due to its higher TPSA and lower logP. Ligand B (-5.212) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-5.377) has poor solubility. Ligand B (-1.538) is slightly better, but still suboptimal.

**hERG Inhibition:** Ligand A (0.503) shows some hERG inhibition risk, but it's not extremely high. Ligand B (0.132) has very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (64.521) has moderate clearance, suggesting moderate metabolic stability. Ligand B (4.906) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (110.724) has a good half-life. Ligand B (-10.565) has a very short half-life, a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.513, B: 0.011), which is favorable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate despite its poor half-life and solubility. The significantly improved binding affinity (-7.4 vs 0.0 kcal/mol) is a major driver. Furthermore, Ligand B has a much lower DILI risk and hERG inhibition liability, and better metabolic stability. While the half-life is a concern, this can potentially be addressed through structural modifications. Ligand A's high DILI risk is a dealbreaker.

Output:
1
2025-04-17 15:28:19,062 - INFO - Batch 382 complete. Total preferences: 6112
2025-04-17 15:28:19,062 - INFO - Processing batch 383/512...
2025-04-17 15:28:58,764 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.483 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.66) is slightly higher than Ligand B (64.09), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.443) is optimal, while Ligand B (0.693) is a bit low, 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 (0.787 and 0.814), indicating drug-like properties.

**DILI:** Ligand A (46.297) has a slightly higher DILI risk than Ligand B (9.655), but both are below the concerning threshold of 60.

**BBB:** Both have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (60.14) is a bit higher than Ligand A (57.619).

**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. This is a significant concern for both.

**hERG:** Both ligands have low hERG inhibition liability (0.443 and 0.432), which is good.

**Microsomal Clearance:** Ligand A (-10.522) has significantly lower (better) microsomal clearance than Ligand B (21.545), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (37.163) has a longer half-life than Ligand B (-8.909), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.235 and 0.106).

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity and acceptable QED scores, Ligand A is the more promising candidate due to its significantly better metabolic stability (lower Cl_mic, longer half-life) and slightly better DILI profile. The negative solubility and Caco-2 values are concerning for both, but the metabolic advantages of Ligand A outweigh these concerns, especially for a kinase inhibitor where maintaining therapeutic concentrations is crucial.

Output:
1
2025-04-17 15:28:58,764 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.391 Da) is slightly lower than Ligand B (365.503 Da), which is not a major concern.

**TPSA:** Ligand B (88.91) is significantly better than Ligand A (128.45). Lower TPSA generally improves cell permeability.

**logP:** Ligand B (1.382) is within the optimal range (1-3), while Ligand A (0.075) is quite low, potentially hindering permeability.

**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, but Ligand B has a slightly more favorable balance.

**QED:** Both ligands have good QED scores (Ligand A: 0.504, Ligand B: 0.727), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (65.529) has a higher DILI risk than Ligand B (44.126). Lower DILI is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (39.55) is higher than Ligand A (21.753), but this isn't a deciding factor.

**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. Again, the scale is not defined, making interpretation difficult.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.101, Ligand B: 0.071).

**Microsomal Clearance:** Ligand A (-17.126) has significantly *lower* (better) microsomal clearance than Ligand B (19.25). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (2.719) has a slightly lower half-life than Ligand B (-2.288), but both are quite low and potentially problematic.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.028, Ligand B: 0.025).

**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 (2.1 kcal/mol difference).

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the key factors point towards Ligand A being the better candidate. The significantly stronger binding affinity (-9.1 vs -7.0 kcal/mol) is a major advantage for an enzyme inhibitor and likely outweighs the slightly lower TPSA and logP. Additionally, Ligand A has better metabolic stability (lower Cl_mic) and a lower DILI risk. While both have poor predicted half-lives, this can be addressed through structural modifications.

Output:
1
2025-04-17 15:28:58,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.445 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (58.95 and 54.78) well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (4.202) is slightly above the optimal 1-3 range, potentially leading to solubility issues. Ligand B (1.773) is within the ideal 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 similar, good QED values (0.854 and 0.856).

**DILI:** Ligand A (38.581) has a significantly lower DILI risk than Ligand B (60.682), which is a substantial advantage. Ligand B is bordering on high risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.772) has better BBB penetration than Ligand B (49.244).

**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 (0.583) has a slightly higher hERG risk than Ligand B (0.352), but both are relatively low.

**Microsomal Clearance:** Ligand A (40.334) has a higher microsomal clearance than Ligand B (23.041), suggesting lower metabolic stability. This is a key disadvantage.

**In vitro Half-Life:** Ligand B (-8.983) has a significantly longer in vitro half-life than Ligand A (39.834), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.108) has lower P-gp efflux liability than Ligand B (0.209), which is favorable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), although both are very good. The 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk and lower P-gp efflux, Ligand B's significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly improved binding affinity are more critical for an enzyme target like SRC kinase. The higher DILI risk of Ligand B is a concern, but potentially mitigable with further structural modifications. The solubility and permeability issues with both compounds would need to be addressed.

Output:
1
2025-04-17 15:28:58,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.53 and 351.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (87.74) is still under 140, but less favorable than A.

**logP:** Ligand A (2.894) is optimal (1-3). Ligand B (0.599) is a bit low, potentially hindering permeation.

**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 scores (0.804 and 0.658), indicating good drug-like properties.

**DILI:** Ligand A (26.483) has a lower DILI risk than Ligand B (22.838), both are good.

**BBB:** Ligand A (78.945) has a better BBB penetration score than Ligand B (53.083), but BBB isn't a high priority for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.729) has a more favorable Caco-2 permeability than Ligand B (-4.919).

**Aqueous Solubility:** Ligand A (-3.216) has better aqueous solubility than Ligand B (-1.156). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.922) has a lower hERG risk than Ligand B (0.061), which is a significant advantage.

**Microsomal Clearance:** Ligand A (58.574) has a higher microsomal clearance than Ligand B (22.6). This means Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-58.736) has a much longer in vitro half-life than Ligand B (3.223), a significant advantage.

**P-gp Efflux:** Ligand A (0.367) has lower P-gp efflux than Ligand B (0.016), indicating better bioavailability.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.8 and -8.4 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other ADME considerations.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has better metabolic stability, Ligand A excels in solubility, hERG risk, permeability, and has a longer half-life and lower P-gp efflux. The binding affinity difference is minimal. The combination of favorable ADME properties, coupled with strong binding, makes Ligand A the superior choice for further development as an SRC kinase inhibitor.

Output:
1
2025-04-17 15:28:58,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.797 Da and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.88) is slightly higher than Ligand B (49.41). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Both ligands have similar logP values (3.504 and 3.614), 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 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.732 and 0.611), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (82.319 percentile) than Ligand B (12.214 percentile). This is a major concern for Ligand A.

**BBB:** Both have good BBB penetration, but Ligand B is better (85.964 vs 62.233). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 a concern for both, but potentially more manageable than the DILI risk.

**hERG Inhibition:** Ligand A (0.243) has a slightly better hERG profile than Ligand B (0.593), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A has a very high microsomal clearance (95.702), indicating poor metabolic stability. Ligand B has a much lower clearance (36.792), which is a significant advantage.

**In vitro Half-Life:** Ligand A has a negative half-life (-15.449), which is not physically possible and indicates a serious issue. Ligand B has a short but positive half-life (3.242 hours).

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.181), which is favorable.

**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 substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is the far superior candidate. The critical factors are the significantly lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), and substantially stronger binding affinity. Ligand A's high DILI risk and negative half-life are deal-breakers.

Output:
1
2025-04-17 15:28:58,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (362.407 and 346.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.8) is better than Ligand B (121.69). Both are under 140, but A is closer to the optimal threshold for good absorption.

**logP:** Ligand A (1.471) is within the optimal 1-3 range, while Ligand B (-0.238) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (7). Lower HBA is generally preferred.

**QED:** Both ligands have similar QED values (0.865 and 0.771), indicating good drug-likeness.

**DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (72.47), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (54.634) is higher than Ligand A (25.979), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both are negative (-5.28 and -5.632), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative (-2.812 and -2.43), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.016 and 0.038), which is excellent.

**Microsomal Clearance:** Ligand A (-4.344) has a lower (better) microsomal clearance than Ligand B (-5.385), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-21.713) has a longer half-life than Ligand B (-4.909), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.056).

**Binding Affinity:** Ligand B (-9.2 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 threshold.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B's substantially stronger binding affinity (-9.2 kcal/mol vs 0.0 kcal/mol) outweighs the minor ADME drawbacks of slightly higher HBD/HBA and lower logP. The improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand A is a plus, but the potency difference is too significant to ignore.

Output:
1
2025-04-17 15:28:58,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.447 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.33) is slightly higher than Ligand B (58.2). Both are below the 140 threshold for good absorption, but Ligand B is preferable due to its lower TPSA.

**logP:** Ligand A (1.005) is within the optimal range, while Ligand B (3.402) is approaching the upper limit. This favors Ligand A slightly.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable range of <=10.

**QED:** Both ligands have similar QED values (0.856 and 0.819), indicating good drug-likeness.

**DILI:** Ligand A (24.118) has a significantly lower DILI risk than Ligand B (33.23). This is a major advantage for Ligand A.

**BBB:** Ligand B (73.866) has a higher BBB percentile than Ligand A (67.003). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.254) has worse Caco-2 permeability compared to Ligand B (-4.68).

**Aqueous Solubility:** Ligand A (-2.389) has worse aqueous solubility than Ligand B (-4.326).

**hERG:** Both ligands have low hERG inhibition risk (0.395 and 0.415).

**Microsomal Clearance:** Ligand A (-5.144) has significantly lower (better) microsomal clearance than Ligand B (24.097). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-13.554) has a much longer in vitro half-life than Ligand B (38.02). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.142).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5). This is a 0.5 kcal/mol advantage.

**Overall Assessment:**

Ligand A demonstrates superior ADMET properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and solubility. While Ligand B has a slightly better binding affinity (0.5 kcal/mol), the substantial improvements in ADMET for Ligand A, especially the lower DILI and improved metabolic stability, outweigh this small difference in potency. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity are crucial.

Output:
0
2025-04-17 15:28:58,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.39 and 344.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is better than Ligand B (91.23). TPSA < 140 is good for oral absorption, both are within this limit, but A is preferable.

**3. logP:** Both ligands have good logP values (1.677 and 2.215), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands are acceptable (1 and 2 respectively), staying below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands are acceptable (4 each), staying below the 10 threshold.

**6. QED:** Both ligands have high QED scores (0.845 and 0.87), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (60.489 and 60.644), placing them in a moderate risk category. This isn't ideal, but not immediately disqualifying.

**8. BBB:** Both ligands have similar BBB penetration (71.656 and 61.962). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.609) has a slightly better (less negative) Caco-2 permeability score than Ligand B (-4.954), suggesting better absorption.

**10. Aqueous Solubility:** Ligand A (-2.006) is better than Ligand B (-3.063), indicating better solubility. Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.243 and 0.186), which is excellent.

**12. Microsomal Clearance:** Ligand A (-9.735) has significantly *lower* (better) microsomal clearance than Ligand B (19.764). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (18.095) has a shorter half-life than Ligand B (23.79), but both are reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.096).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is slightly better overall. While both ligands have similar binding affinity and acceptable ADME properties, Ligand A stands out due to its better TPSA, Caco-2 permeability, aqueous solubility, and *significantly* improved metabolic stability (lower Cl_mic). For an enzyme target like SRC kinase, metabolic stability is a key factor for achieving adequate drug exposure.

Output:
0
2025-04-17 15:28:58,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (67.23) is higher than Ligand B (58.64), but both are reasonable.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 1.897, Ligand B: 2.654), which is optimal.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are well within the acceptable limits.

**QED:** Ligand A (0.924) has a significantly higher QED score than Ligand B (0.733), indicating a more drug-like profile.

**DILI:** Ligand A (34.587) has a slightly higher DILI risk than Ligand B (22.024), but both are below the 40 threshold and considered good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (86.623) has a higher BBB score than Ligand A (67.352), but this is not a major factor in this decision.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.084) is worse than Ligand B (-4.415).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.996) is worse than Ligand B (-3.812).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.503, Ligand B: 0.398), which is positive.

**Microsomal Clearance:** Ligand A (7.763) has significantly lower microsomal clearance than Ligand B (73.148), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-14.637) has a much longer in vitro half-life than Ligand B (-29.089), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.107, Ligand B: 0.033).

**Binding Affinity:** Ligand A (-9.3 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, it still contributes to its favorability.

**Overall Assessment:**

Ligand A is the better candidate. Its superior QED score, significantly lower microsomal clearance, longer half-life, and slightly better binding affinity outweigh its slightly higher DILI risk and poorer Caco-2/solubility values. The metabolic stability profile of Ligand A is particularly important for an enzyme inhibitor, as it suggests a longer duration of action and potentially lower dosing requirements. The solubility and permeability issues of both compounds would need to be addressed during lead optimization, but the stronger starting point of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 15:28:58,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (386.42 and 340.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.69) is better than Ligand B (67.35), both are acceptable but A is closer to the <140 threshold for good absorption.

**3. logP:** Both ligands have similar logP values (4.19 and 3.945), slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects, but not drastically.

**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 (0.838 and 0.916), indicating a generally drug-like profile.

**7. DILI:** Ligand A (75.301) has a higher DILI risk than Ligand B (61.031). This is a negative for Ligand A.

**8. BBB:** Both have reasonable BBB penetration, but Ligand A (81.621) is better than Ligand B (70.803). This is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.924 and -4.665), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-5.255 and -4.599), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.637 and 0.63). This is good.

**12. Microsomal Clearance:** Ligand B (51.786) has lower microsomal clearance than Ligand A (62.364), indicating better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (2.815) has a slightly longer half-life than Ligand A (1.893), which is preferable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.718 and 0.201). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.2 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:**

While both compounds have significant issues with solubility and permeability, Ligand B appears slightly more favorable. It has better metabolic stability (lower Cl_mic), a slightly longer half-life, and a marginally better binding affinity. The DILI risk is also lower for Ligand B. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the ADME profile of Ligand B is slightly more promising.

Output:
1
2025-04-17 15:28:58,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.451 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is better than Ligand B (52.65), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.767) is slightly higher than Ligand B (2.262), both are within the optimal 1-3 range, but Ligand A is closer to the upper limit.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is acceptable.

**QED:** Both ligands have good QED scores (0.605 and 0.767, respectively), indicating drug-likeness.

**DILI:** Ligand B (4.808) has a significantly lower DILI risk than Ligand A (46.452), making it safer from a liver toxicity perspective. This is a major advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration, but Ligand A (83.249) is slightly better than Ligand B (79.488). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.611) is slightly better than Ligand B (-4.942), but both are problematic.

**Aqueous Solubility:** Ligand A (-4.13) is better than Ligand B (-1.57), indicating better solubility. Solubility is important for bioavailability.

**hERG:** Ligand A (0.371) has a lower hERG risk than Ligand B (0.58), which is preferable.

**Microsomal Clearance:** Ligand A (71.281) has a higher microsomal clearance than Ligand B (5.937), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (3.843) has a longer in vitro half-life than Ligand A (-20.401), suggesting better metabolic stability.

**P-gp Efflux:** Ligand A (0.287) has lower P-gp efflux than Ligand B (0.028), which is preferable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is small, it's enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better solubility and P-gp efflux, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The Caco-2 permeability is poor for both, but the other advantages of Ligand B outweigh this concern.

Output:
1
2025-04-17 15:28:58,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.503 and 350.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (62.3 and 64.33) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.652) is optimal, while Ligand B (3.252) is slightly higher 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 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.647 and 0.743), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 66.576, which is concerning (high risk). Ligand B has a much lower DILI risk of 13.959, which is excellent. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B has a higher BBB penetration (88.29) than Ligand A (57.852), but this is not a major factor in this decision.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.429) is worse than Ligand B (-4.187).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.171) is slightly better than Ligand B (-3.501).

**hERG Inhibition:** Ligand A (0.32) has a lower hERG inhibition liability than Ligand B (0.907), which is preferable.

**Microsomal Clearance:** Ligand B (44.152 mL/min/kg) has significantly lower microsomal clearance than Ligand A (60.94 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (18.859 hours) has a much longer in vitro half-life than Ligand A (-0.053 hours), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.343 and 0.409).

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand B is the superior candidate due to its significantly lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. The slightly higher hERG risk for Ligand B is a minor concern compared to the substantial DILI risk associated with Ligand A.

Output:
1
2025-04-17 15:28:58,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.93 and 358.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (67.43), both being below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.33 and 2.42), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 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 A (0.847) has a significantly higher QED score than Ligand B (0.622), indicating a more drug-like profile.

**DILI:** Ligand B (29.04) has a much lower DILI risk than Ligand A (40.87), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (78.83 and 89.07), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.83 and -4.86), which is unusual and suggests poor permeability. This is a potential concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.02 and -2.69), indicating poor aqueous solubility. This is a significant drawback for both, potentially impacting bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.45 and 0.42).

**Microsomal Clearance:** Ligand B (24.16) has a lower microsomal clearance than Ligand A (32.66), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.17) has a slightly longer half-life than Ligand A (10.22), although both are relatively short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.30 and 0.03).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). The difference is 0.5 kcal/mol, which is a good advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity and QED score, Ligand B demonstrates a significantly lower DILI risk and better metabolic stability (lower Cl_mic). Both ligands suffer from poor predicted solubility and permeability. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the lower DILI and better metabolic stability of Ligand B are more valuable than the slightly improved affinity of Ligand A, especially given the similar binding energies. The solubility issues would need to be addressed through formulation strategies for either compound.

Output:
1
2025-04-17 15:28:58,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.296 Da) is towards the higher end, while Ligand B (364.511 Da) is more optimal.

**TPSA:** Ligand A (123.29) is acceptable, being under the 140 threshold for oral absorption. Ligand B (53.76) is excellent, suggesting good absorption.

**logP:** Ligand A (0.747) is a bit low, potentially hindering permeation. Ligand B (3.501) 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 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.621, B: 0.751), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.88, which is high and concerning. Ligand B has a much lower DILI risk of 48.623, which is good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (77.045) than Ligand A (39.318), but it's not a major factor here.

**Caco-2 Permeability:** Ligand A (-5.665) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.827) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.472 and -3.8 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.047) has very low hERG inhibition risk, which is excellent. Ligand B (0.578) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (10.905) has lower microsomal clearance, indicating better metabolic stability, which is a key priority for enzymes. Ligand B (75.97) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (16.614 hours) has a better in vitro half-life than Ligand B (12.783 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.644 respectively).

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability, and a very low hERG risk. However, its high DILI risk and poor Caco-2 permeability are major concerns. Ligand B has a better safety profile (lower DILI) and slightly better permeability, but weaker binding affinity and poorer metabolic stability.

Given the enzyme-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 during lead optimization. The poor permeability is also a concern, but could potentially be addressed through formulation strategies. The metabolic instability of Ligand B is a more difficult issue to resolve.

Output:
1
2025-04-17 15:28:58,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.459 and 362.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.54) is better than Ligand B (23.55). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand B (4.061) is slightly higher than Ligand A (2.225). While both are within the acceptable range (1-3 is optimal, and up to 4 is tolerable), Ligand B is approaching a value that could cause solubility issues.

**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 (0.77 and 0.619), indicating good drug-like properties.

**DILI:** Ligand A (41.877) has a slightly higher DILI risk than Ligand B (9.383), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (77.433 and 80.031), but since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.973). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are common. The absolute values are similar, so this doesn't differentiate the two significantly.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.416 and -3.228), indicating poor aqueous solubility. Ligand B is slightly worse.

**hERG Inhibition:** Ligand A (0.598) has a slightly lower hERG inhibition risk than Ligand B (0.97), which is preferable.

**Microsomal Clearance:** Ligand B (78.953) has a significantly higher microsomal clearance than Ligand A (40.235). This indicates that Ligand A is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** The in vitro half-lives are similar (13.886 and 13.543 hours).

**P-gp Efflux:** Ligand A (0.053) has a much lower P-gp efflux liability than Ligand B (0.82), which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are excellent, the 0.5 kcal/mol difference is meaningful and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a better TPSA, lower logP, lower DILI risk, lower hERG inhibition, significantly lower microsomal clearance (better metabolic stability), lower P-gp efflux, and slightly better binding affinity. While both have poor solubility and permeability, the superior ADME properties and potency of Ligand A make it the preferred choice.

Output:
0
2025-04-17 15:28:58,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.487 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is well below the 140 threshold, suggesting good absorption. Ligand B (111.53) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.956) is optimal (1-3). Ligand B (-0.961) is below 1, which might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 6 HBA) is acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (0.912 and 0.686), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (36.332 and 35.75), which is positive.

**BBB:** Ligand A (61.38) has moderate BBB penetration, while Ligand B (23.342) has very low BBB penetration. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.664) and Ligand B (-5.171) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.869) and Ligand B (-1.009) both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.513) has a very low hERG risk, which is excellent. Ligand B (0.037) has an extremely low hERG risk, also excellent.

**Microsomal Clearance:** Ligand A (30.307) has moderate clearance, while Ligand B (-9.268) has *negative* clearance, which is impossible and likely an artifact of the prediction method. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (5.672) has a reasonable half-life. Ligand B (-31.006) has a negative half-life, which is impossible and further reinforces the concerns about its predicted properties.

**P-gp Efflux:** Ligand A (0.163) has low P-gp efflux, which is good. Ligand B (0.007) has very low P-gp efflux, also good.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 kcal/mol and -9.0 kcal/mol). Ligand B is slightly better.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more viable candidate. Ligand B exhibits impossible predicted values for microsomal clearance and in vitro half-life, indicating significant issues with the prediction model or inherent instability. While both have permeability and solubility concerns, the unrealistic ADME predictions for Ligand B make it a non-starter. Ligand A, while not perfect, has a more plausible ADME profile and a very favorable hERG risk.

Output:
0
2025-04-17 15:28:58,766 - INFO - Batch 383 complete. Total preferences: 6128
2025-04-17 15:28:58,766 - INFO - Processing batch 384/512...
2025-04-17 15:29:47,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (337.47 & 362.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.78) is significantly better than Ligand B (73.99). Lower TPSA generally favors better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**3. logP:** Ligand A (3.97) is slightly higher than Ligand B (1.62). Both are within the optimal 1-3 range, but Ligand A is closer to the upper limit.

**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 (2) is better than Ligand B (5), keeping within the preferred range of 10 or less.

**6. QED:** Both ligands have similar QED values (0.887 and 0.865), indicating good drug-likeness.

**7. DILI:** Ligand A (25.09%) has a significantly lower DILI risk than Ligand B (38.50%). This is a crucial advantage.

**8. BBB:** Both ligands have similar BBB penetration (68.63% and 67.12%). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.983 and -4.931), which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Aqueous Solubility:** Ligand A (-4.307) is slightly better than Ligand B (-2.973), suggesting better solubility.

**11. hERG Inhibition:** Ligand A (0.697) shows a lower hERG inhibition risk than Ligand B (0.35). This is a significant advantage.

**12. Microsomal Clearance:** Ligand B (23.96) has a lower microsomal clearance than Ligand A (47.29). Lower clearance indicates better metabolic stability, which is a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (51.11) has a significantly longer in vitro half-life than Ligand A (-31.90). This is a major advantage, suggesting less frequent dosing could be possible.

**14. P-gp Efflux:** Ligand A (0.233) has a lower P-gp efflux liability than Ligand B (0.129), which is favorable for oral bioavailability.

**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 and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a longer half-life, and better metabolic stability. However, Ligand A has a lower DILI risk and lower hERG inhibition. The significantly stronger binding affinity of Ligand B is the most important factor for an enzyme inhibitor, and the longer half-life is also highly desirable. While the Caco-2 values are concerning for both, the superior potency and stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 15:29:47,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.829 and 352.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.05) is slightly higher than Ligand B (67.43). Both are below the 140 A^2 threshold for good oral absorption, but B is preferable.

**3. logP:** Both ligands have good logP values (3.481 and 3.193), 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 below the 10 threshold.

**6. QED:** Both ligands have reasonable QED scores (0.707 and 0.659), indicating good drug-like properties.

**7. DILI:** This is a significant differentiator. Ligand A has a DILI risk of 79.449%, which is high. Ligand B has a much lower DILI risk of 19.426%, which is excellent.

**8. BBB:** Both have reasonable BBB penetration (69.639% and 75.378%). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.035 and -4.486). 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.

**10. Aqueous Solubility:** Both have negative solubility values (-3.887 and -3.709), also on a log scale. This suggests poor aqueous solubility.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.392 and 0.192).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (67.538 and 68.48 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A has a much longer half-life (102.241 hours) than Ligand B (4.851 hours). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.262 and 0.056).

**15. Binding Affinity:** Both have excellent binding affinities (-8.6 and -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and a significantly longer half-life, the extremely high DILI risk (79.449%) is a major red flag. DILI is a common reason for drug development failure. Ligand B, despite the shorter half-life, has a much more favorable safety profile with a low DILI risk. The similar affinities suggest that optimizing Ligand B's half-life might be more fruitful than attempting to mitigate the DILI risk 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 15:29:47,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.754 Da) is slightly higher than Ligand B (349.347 Da), but both are acceptable.

**TPSA:** Ligand A (54.02) is well below the 140 threshold for good oral absorption. Ligand B (126.13) is still within acceptable limits, but higher.

**logP:** Ligand A (4.558) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-1.173) is quite low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 7 HBAs. Both are within the acceptable range, but Ligand A is preferable.

**QED:** Both ligands have similar QED values (0.688 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (48.081) has a lower DILI risk than Ligand B (60.915), making it safer from a liver toxicity perspective.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (65.219) is higher than Ligand B (45.909).

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.504) has a much better hERG profile than Ligand B (0.045), significantly reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (39.518) has a better (lower) microsomal clearance than Ligand B (-12.06), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (84.471) has a longer half-life than Ligand B (33.161), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux than Ligand B (0.017), which is preferable.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. The 8.1 kcal/mol difference is substantial.

**Conclusion:**

Ligand A is the superior candidate. While its logP is slightly elevated, its significantly stronger binding affinity, lower DILI risk, better hERG profile, improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux outweigh the potential drawbacks. Ligand B's very low logP and weak binding affinity are major liabilities.

Output:
1
2025-04-17 15:29:47,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.439 Da) is slightly lower, which could be beneficial for permeability. Ligand B (371.413 Da) is also acceptable.

**TPSA:** Ligand A (55.63) is well below the 140 threshold for oral absorption. Ligand B (73.14) is still acceptable, but higher.

**logP:** Both ligands have good logP values (A: 3.007, B: 2.507), 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 0 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.78, B: 0.713), indicating good drug-likeness.

**DILI:** Ligand A (35.983) has a lower DILI risk than Ligand B (41.295), which is preferable. Both are below the concerning 60 threshold.

**BBB:** Ligand A (69.833) has a lower BBB penetration than Ligand B (93.486). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.224) has a negative Caco-2 value, which is concerning. Ligand B (-4.36) is also negative, but less so. Both suggest poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.943) has slightly better solubility than Ligand B (-3.922), although both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.773) has a lower hERG risk than Ligand B (0.489), which is a significant advantage.

**Microsomal Clearance:** Ligand A (6.342) has significantly lower microsomal clearance than Ligand B (48.668), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (30.323) has a longer half-life than Ligand B (-3.597), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.206, B: 0.218).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.0 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand B's superior binding affinity, Ligand A has a much better ADME profile, specifically regarding metabolic stability (lower Cl_mic), longer half-life, and lower hERG risk. The negative Caco-2 and solubility values are concerning for both, but the metabolic advantages of Ligand A are crucial for an enzyme target like SRC kinase. While the affinity difference is notable, the improved pharmacokinetic properties of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 15:29:47,863 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.503 and 368.861 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is better than Ligand B (59.08), both are below the 140 threshold for oral absorption, but lower TPSA is generally preferred.

**3. logP:** Ligand A (3.55) is optimal, while Ligand B (1.718) is on the lower side, potentially impacting permeability.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4), both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.688 and 0.612), indicating good drug-likeness.

**7. DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (37.069), but both are below the concerning 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (84.917 and 81.504), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.848) has slightly better Caco-2 permeability than Ligand B (-4.631).

**10. Aqueous Solubility:** Ligand A (-3.287) has better aqueous solubility than Ligand B (-2.015).

**11. hERG Inhibition:** Ligand A (0.684) has a slightly better hERG profile than Ligand B (0.432), both are acceptable.

**12. Microsomal Clearance:** Ligand A (54.121) has higher microsomal clearance than Ligand B (34.298), indicating lower metabolic stability. This is a significant drawback.

**13. In vitro Half-Life:** Ligand B (22.706) has a significantly longer in vitro half-life than Ligand A (-15.815), a major advantage.

**14. P-gp Efflux:** Ligand A (0.383) has lower P-gp efflux than Ligand B (0.05), which is preferable.

**15. Binding Affinity:** Ligand B (-7.6) has a substantially stronger binding affinity than Ligand A (-8.5). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has slightly better solubility and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.6 vs -8.5 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) outweigh these minor advantages. The slightly lower logP of Ligand B is a minor concern, but the potency and stability benefits are more important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:29:47,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.46 and 346.52 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is significantly better, being closer to the <90 target, which is beneficial for permeability.

**3. logP:** Both ligands have good logP values (2.05 and 3.22), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* present a minor solubility concern, but is generally acceptable.

**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 within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.78 and 0.69), indicating good drug-like properties.

**7. DILI:** Ligand A (31.37%) has a slightly higher DILI risk than Ligand B (18.92%), but both are well below the concerning threshold of 60%.

**8. BBB:** Ligand A (76.15%) has better BBB penetration than Ligand B (64.95%). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.67) has worse Caco-2 permeability than Ligand B (-4.39). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.71) has better aqueous solubility than Ligand B (-4.09). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.49) has a slightly higher hERG risk than Ligand B (0.27), but both are low and acceptable.

**12. Microsomal Clearance:** Ligand A (70.83) has higher microsomal clearance than Ligand B (65.34). Lower clearance is preferred for metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.79) has a significantly longer in vitro half-life than Ligand B (10.28). This is a major advantage for dosing frequency.

**14. P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.172). Lower efflux is generally preferred.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.0 kcal/mol difference is substantial and outweighs many of the minor ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most crucial factor for an enzyme inhibitor. It also has better TPSA, Caco-2 permeability, and lower P-gp efflux. While Ligand A has better solubility and half-life, the binding affinity difference is significant enough to favor Ligand B. The slightly higher logP of Ligand B is not a major concern.

Output:
1
2025-04-17 15:29:47,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.815 Da) and Ligand B (349.519 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (67.43) is slightly higher than Ligand B (52.65).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.399) is slightly higher than Ligand B (2.26), but both are 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.775, Ligand B: 0.828), indicating drug-like properties.

**DILI:** Ligand B (8.414) has a significantly lower DILI risk than Ligand A (52.54), which is a major advantage.

**BBB:** Both ligands show good BBB penetration (Ligand A: 82.823, Ligand B: 88.174), but this is less critical for a non-CNS target like SRC.

**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. Again, the scale is not defined, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.677) has a slightly higher hERG inhibition liability than Ligand B (0.355), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (26.589) and Ligand B (24.163) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Both ligands have similar and negative in vitro half-life values (-4.875 and -4.447 respectively), which is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.091, Ligand B: 0.069).

**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 could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's superior DILI profile and slightly better solubility/hERG, the significantly stronger binding affinity of Ligand A (-8.6 vs -7.5 kcal/mol) makes it the more promising candidate. For an enzyme target like SRC kinase, potency is paramount. While the negative solubility and half-life values are concerning, these can potentially be addressed through formulation or structural modifications without sacrificing the strong binding affinity.

Output:
1
2025-04-17 15:29:47,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.399 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is better than Ligand B (62.55), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.759 and 3.395), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for off-target effects, but isn't a major issue.

**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 (0.818) has a significantly better QED score than Ligand B (0.609), indicating a more drug-like profile.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (45.328). This is a significant negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (79.682) is slightly better than Ligand B (64.482). However, BBB isn't a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.107) is worse than Ligand B (-4.711).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.631) is slightly worse than Ligand B (-3.486).

**hERG:** Ligand A (0.113) has a slightly better hERG profile than Ligand B (0.681), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (79.926) has a significantly higher microsomal clearance than Ligand A (24.433), suggesting lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (40.012) has a longer half-life than Ligand A (29.15), which is generally desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.119 and 0.764).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.4 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is the better candidate. While it has a higher DILI risk and slightly worse solubility/permeability, its significantly lower microsomal clearance (better metabolic stability) and higher QED score are more important. The binding affinity is comparable between the two. The lower clearance of Ligand A suggests it will have a longer duration of action *in vivo*.

Output:
0
2025-04-17 15:29:47,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.375 and 344.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.77) is slightly above the preferred <140, but acceptable. Ligand B (89.53) is excellent, well below 140.

**logP:** Ligand A (-0.453) is a bit low, potentially hindering permeability. Ligand B (0.173) is better, within the optimal 1-3 range, but still on the lower side.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.64 and 0.815), indicating good drug-like properties.

**DILI:** Ligand A (53.858) has a moderate DILI risk, but is still acceptable. Ligand B (29.236) has a significantly lower DILI risk, which is a major advantage.

**BBB:** Both have relatively low BBB penetration (37.301 and 38.193), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.237 and -5.277), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.678 and -1.967), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.048) has very low hERG inhibition risk, a significant advantage. Ligand B (0.156) has a slightly higher, but still low, hERG risk.

**Microsomal Clearance:** Ligand A (-10.846) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (3.389) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-7.974) has a very long in vitro half-life, consistent with the low clearance. Ligand B (-11.311) also has a long half-life, but not as impressive as A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.011).

**Binding Affinity:** Ligand B (-9.6 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.

**Conclusion:**

While both ligands have significant ADME liabilities (poor solubility and permeability), Ligand B is the more promising candidate. Its substantially stronger binding affinity (-9.6 vs -7.0 kcal/mol) is a critical advantage for an enzyme inhibitor. The lower DILI risk and better metabolic stability (though still not ideal) also favor Ligand B. Ligand A's primary advantage is its very low hERG risk, but the difference isn't large enough to overcome the weaker binding. The poor solubility and permeability would need to be addressed through formulation or further chemical modifications for either compound.

Output:
1
2025-04-17 15:29:47,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.917 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (76.66 and 77.57) below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.469) is slightly higher than Ligand B (1.042), but both are good.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.645 and 0.735), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (36.487 and 38.193), which is favorable.

**BBB:** Both ligands have reasonable BBB penetration (69.329 and 66.886), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.765) has a worse Caco-2 permeability compared to Ligand B (-5.119), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand B (-0.671) has better aqueous solubility than Ligand A (-3.607), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.367 and 0.48), which is excellent.

**Microsomal Clearance:** Ligand B (-11.85) has significantly lower microsomal clearance than Ligand A (56.88), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (14.588 hours) has a much longer in vitro half-life than Ligand A (46.635 hours). This is also a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.102 and 0.007).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). While a 0.6 kcal/mol difference is noticeable, the ADME advantages of Ligand B are substantial.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, Ligand B is the more promising drug candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2) and better aqueous solubility outweigh the minor difference in binding affinity. These factors are critical for an enzyme inhibitor, as they impact bioavailability and duration of action.

Output:
1
2025-04-17 15:29:47,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.411 and 355.498 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.78) is better than Ligand B (61.44), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.123 and 2.4), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (4 and 3 respectively), satisfying the criteria of <=5 and <=10.

**QED:** Ligand A (0.82) has a significantly better QED score than Ligand B (0.668), indicating a more drug-like profile.

**DILI:** Ligand B (23.846) has a much lower DILI risk than Ligand A (36.06), which is a significant advantage.

**BBB:** Ligand B (89.492) shows better BBB penetration than Ligand A (63.164), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.624 and -4.687), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.908 and -2.348), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.299) has a slightly lower hERG risk than Ligand B (0.492), which is preferable.

**Microsomal Clearance:** Ligand A (26.081) has a lower microsomal clearance than Ligand B (51.198), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (64.209) has a significantly longer in vitro half-life than Ligand B (5.532), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.176 and 0.162).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a crucial factor for enzyme inhibitors. The 1.4 kcal/mol difference is significant.

**Overall Assessment:**

Despite the poor solubility and permeability for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.8 vs -7.4 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher DILI risk and lower BBB. The better QED score also contributes to its favorability. Addressing the solubility and permeability issues through formulation or structural modifications would be critical for further development, but the potency and stability profile of Ligand A make it a better starting point.

Output:
1
2025-04-17 15:29:47,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.408 and 362.436 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (58.2), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.588 and 3.721), falling within the 1-3 range. Ligand B is slightly higher, which *could* pose a minor solubility issue, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 2 HBA) as lower HBD/HBA generally improves permeability. Both are within acceptable limits.

**QED:** Both have similar QED scores (0.747 and 0.647), indicating good drug-like properties.

**DILI:** Ligand A (21.404) has a much lower DILI risk than Ligand B (35.285), a significant advantage.

**BBB:** Ligand A (95.076) shows excellent BBB penetration, while Ligand B (86.468) is still good, but less favorable. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.393) is slightly better than Ligand B (-4.524), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.093) is significantly better than Ligand B (-4.364), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.653 and 0.412), which is excellent.

**Microsomal Clearance:** Ligand A (33.853) has a lower microsomal clearance than Ligand B (54.915), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.527) has a much longer in vitro half-life than Ligand B (4.347), a major advantage for dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.077).

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-9.0). While a 0.5 kcal/mol difference is noticeable, the other ADME properties of Ligand A are far more compelling.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in almost all other critical parameters, particularly DILI risk, solubility, metabolic stability (lower Cl_mic and longer t1/2), and Caco-2 permeability. These factors are more important for an enzyme inhibitor than a small difference in binding affinity. The lower DILI risk and improved metabolic stability of Ligand A significantly increase its chances of success in development.

Output:
0
2025-04-17 15:29:47,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.527 Da) is slightly lower, which could be beneficial for permeability. Ligand B (365.499 Da) is also good.

**TPSA:** Ligand A (23.55) is excellent, well below the 140 threshold for oral absorption. Ligand B (87.3) is higher, but still acceptable, though it might slightly hinder absorption compared to A.

**logP:** Ligand A (4.183) is at the upper end of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (1.925) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable, minimizing potential permeability issues. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.742, B: 0.658), indicating good drug-like properties.

**DILI:** Ligand A (5.118) has a very low DILI risk, which is excellent. Ligand B (39.511) is also acceptable, but higher than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.555) shows good BBB penetration, while Ligand B (59.791) is lower.

**Caco-2 Permeability:** Ligand A (-4.7) has poor Caco-2 permeability. Ligand B (-5.289) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.622) has poor solubility. Ligand B (-2.673) has slightly better solubility than A, but still poor.

**hERG Inhibition:** Ligand A (0.938) has a low hERG risk, which is excellent. Ligand B (0.274) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (79.487) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (29.711) has a significantly lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.321) has a long in vitro half-life. Ligand B (13.626) has a shorter in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.448, B: 0.076), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.2 kcal/mol), which is excellent.

**Conclusion:**

Despite the equal binding affinity, Ligand B is the more promising candidate. While Ligand A has a slightly lower MW and better DILI score, Ligand B has significantly better metabolic stability (lower Cl_mic) and a slightly better solubility profile. The poor Caco-2 permeability of both is a concern, but the metabolic stability is a more critical factor for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:29:47,864 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [338.363, 102.42 ,   2.78 ,   4.   ,   3.   ,   0.574,  78.054,  19.93 , -5.707,  -4.179,   0.204,  11.292, -22.709,   0.046, -10.4  ]
**Ligand B:** [343.471,  73.99 ,   2.972,   3.   ,   2.   ,   0.571,  27.026,  69.484, -4.824,  -3.844,   0.415,  54.021, -13.24 ,   0.096,  -7.7  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (338.363) is slightly lower, which is generally favorable for permeability.
2. **TPSA:** A (102.42) is higher than B (73.99). Both are below 140, but B is better for oral absorption.
3. **logP:** Both are within the optimal range (1-3). A (2.78) and B (2.972) are comparable.
4. **HBD:** Both have acceptable HBD counts (A: 4, B: 3).
5. **HBA:** Both have acceptable HBA counts (A: 3, B: 2).
6. **QED:** Both have similar and good QED values (A: 0.574, B: 0.571).
7. **DILI:** A (78.054) has a significantly higher DILI risk than B (27.026). This is a major concern.
8. **BBB:** A (19.93) has very poor BBB penetration, while B (69.484) is better, although not exceptionally high.  Not a primary concern for a non-CNS target like SRC.
9. **Caco-2:** A (-5.707) has a very poor Caco-2 permeability, while B (-4.824) is better, but still low.
10. **Solubility:** A (-4.179) has poor aqueous solubility, while B (-3.844) is slightly better.
11. **hERG:** A (0.204) has a slightly higher hERG risk than B (0.415).
12. **Cl_mic:** A (11.292) has a lower microsomal clearance, indicating better metabolic stability than B (54.021). This is a positive for A.
13. **t1/2:** A (-22.709) has a much longer in vitro half-life than B (-13.24). This is a significant advantage for A.
14. **Pgp:** A (0.046) has lower P-gp efflux liability than B (0.096), which is favorable.
15. **Binding Affinity:** A (-10.4) has a substantially stronger binding affinity than B (-7.7). This is a very significant advantage for A, potentially outweighing some ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A is significantly better.
*   **Metabolic Stability:** A is better (lower Cl_mic, longer t1/2).
*   **Solubility:** B is slightly better, but both are poor.
*   **hERG:** B is slightly better.
*   **DILI:** B is *much* better.
*   **Caco-2 & Solubility:** Both are poor, but could be improved with formulation strategies.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, **Ligand A** is the more promising candidate due to its significantly higher binding affinity and improved metabolic stability. The lower DILI risk of Ligand B is attractive, but the substantial difference in binding affinity (-10.4 vs -7.7 kcal/mol) is a major advantage that can be addressed through further optimization. The DILI risk of Ligand A is concerning, but could potentially be mitigated with structural modifications during lead optimization.

1
2025-04-17 15:29:47,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.483 and 368.594 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.46) is higher than Ligand B (49.85). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Both ligands have good logP values (3.54 and 2.91), 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 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.683 and 0.701), indicating good drug-like properties.

**DILI:** Ligand A (43.971) has a slightly higher DILI risk than Ligand B (15.936). This is a point in favor of Ligand B.

**BBB:** Ligand A (38.813) has a lower BBB penetration percentile than Ligand B (81.892). Since SRC is not a CNS target, this is less important, but still favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.497) has a lower Caco-2 permeability than Ligand B (-4.284). Both are negative, indicating poor permeability, but Ligand B is better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.505 and -3.052). This is a concern for both, but not a deciding factor.

**hERG:** Ligand A (0.275) has a slightly higher hERG inhibition liability than Ligand B (0.608). Lower is better, favoring Ligand B.

**Microsomal Clearance:** Ligand A (86.496) has a higher microsomal clearance than Ligand B (69.843), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-11.098) has a significantly longer in vitro half-life than Ligand A (-7.706), which is a major advantage.

**P-gp Efflux:** Ligand A (0.345) has a lower P-gp efflux liability than Ligand B (0.447). Lower is better, favoring Ligand A.

**Binding Affinity:** Both ligands have very similar binding affinities (-9.1 and -7.7 kcal/mol). Ligand A has a 1.4 kcal/mol advantage, which is substantial and could outweigh some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B demonstrates a superior ADME profile, particularly regarding metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better Caco-2 permeability. The difference in binding affinity, while significant, may be overcome with further optimization of Ligand B, while addressing the solubility issues. The better ADME profile of Ligand B makes it a more promising starting point for drug development.

Output:
1
2025-04-17 15:29:47,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.422 and 345.359 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.71) is better than Ligand B (109.85). TPSA < 140 is good for oral absorption, and both are within this range, but A is preferable.

**3. logP:** Both ligands have good logP values (1.946 and 1.175), 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 within the acceptable limit of <=10, but A is slightly better.

**6. QED:** Both ligands have similar QED values (0.605 and 0.624), indicating good drug-likeness.

**7. DILI:** Ligand A (37.96) has a significantly lower DILI risk than Ligand B (64.327). This is a major advantage for Ligand A.

**8. BBB:** Both have reasonable BBB penetration, but Ligand A (88.445) is better than Ligand B (77.821). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Ligand A (-4.158) has better Caco-2 permeability than Ligand B (-5.025). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.665) has better aqueous solubility than Ligand B (-3.552). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.285 and 0.195), which is excellent.

**12. Microsomal Clearance:** Ligand A (72.213) has higher microsomal clearance than Ligand B (34.078). Lower clearance is better for metabolic stability, so Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand B (3.222) has a longer in vitro half-life than Ligand A (-29.277). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.055).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in properties related to absorption (TPSA, Caco-2, Solubility), has a much lower DILI risk, and slightly better BBB penetration. Ligand B has better metabolic stability (lower Cl_mic and longer t1/2). However, the significantly lower DILI risk of Ligand A is a critical advantage, and the differences in metabolic stability are not substantial enough to outweigh this benefit. The binding affinity is identical. Considering these factors, Ligand A is the more promising candidate.

Output:
1
2025-04-17 15:29:47,865 - INFO - Batch 384 complete. Total preferences: 6144
2025-04-17 15:29:47,865 - INFO - Processing batch 385/512...
2025-04-17 15:30:26,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.559 Da and 366.824 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is better than Ligand B (66.71), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.728 and 2.504, respectively), falling within the 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**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 within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.686 and 0.854), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (15.083) has a significantly lower DILI risk than Ligand B (67.003). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (78.558 and 81.815). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.496) has worse Caco-2 permeability than Ligand B (-4.347), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.105) has slightly better aqueous solubility than Ligand B (-3.747).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.466 and 0.376), which is good.

**Microsomal Clearance:** Ligand A (45.397) has lower microsomal clearance than Ligand B (52.534), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (53.133) has a significantly longer in vitro half-life than Ligand A (3.14). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux than Ligand B (0.171), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a stronger binding affinity than Ligand B (-7.4 kcal/mol). This 0.7 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a substantially better binding affinity and a much lower DILI risk, and better metabolic stability. Ligand B has a longer half-life and slightly better Caco-2 permeability and QED. However, the superior affinity and lower toxicity of Ligand A are more critical for an oncology target. The longer half-life of B is good, but can potentially be improved with structural modifications. The slightly lower Caco-2 of A is less concerning than the high DILI risk of B.

Output:
0
2025-04-17 15:30:26,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (361.349 Da and 354.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (124.47 and 122.55) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.094) is optimal, while Ligand B (0.259) is slightly 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:** Both ligands (A: 5, B: 4) are within the acceptable limit of 10.

**6. QED:** Ligand B (0.444) is better than Ligand A (0.217), indicating a more drug-like profile.

**7. DILI:** Ligand B (20.977) has a significantly lower DILI risk than Ligand A (35.091), which is a major advantage.

**8. BBB:** Both ligands have similar BBB penetration (A: 78.054, B: 71.578), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.714) has better Caco-2 permeability than Ligand B (-5.456).

**10. Aqueous Solubility:** Ligand A (-1.052) has better aqueous solubility than Ligand B (-2.47).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.237, B: 0.123).

**12. Microsomal Clearance:** Ligand B (29.793) has significantly lower microsomal clearance than Ligand A (46.917), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.616) has a better in vitro half-life than Ligand A (-28.417).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.023, B: 0.017).

**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 the 1.5 kcal/mol threshold where affinity overwhelmingly dominates.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and Caco-2 permeability, Ligand B demonstrates superior ADMET properties. Specifically, its significantly lower DILI risk and improved metabolic stability (lower Cl_mic, longer t1/2) are crucial for a kinase inhibitor. The slightly lower logP of Ligand B is a minor concern, but the benefits of reduced toxicity and increased metabolic stability outweigh this drawback.

Output:
1
2025-04-17 15:30:26,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (372.515 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is well below the 140 threshold, and good for oral absorption. Ligand B (78.87) is also below 140, but higher than A.

**logP:** Ligand A (4.352) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.492) is quite low, which might hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.676) has a good drug-likeness score, while Ligand B (0.467) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (12.524). This is a significant concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (61.109 and 68.98), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.927 and -4.727), which is unusual and suggests poor permeability. This could be due to experimental error or a specific property of the molecules.

**Aqueous Solubility:** Both have negative solubility values (-3.553 and -1.573), which is also unusual and concerning.

**hERG Inhibition:** Ligand A (0.771) has a slightly higher hERG risk than Ligand B (0.347), but both are relatively low.

**Microsomal Clearance:** Ligand B (-12.853) has a *much* lower (better) microsomal clearance than Ligand A (68.537), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand B (3.503) has a very short half-life, while Ligand A (61.875) has a much longer one.

**P-gp Efflux:** Ligand A (0.737) has a slightly higher P-gp efflux liability than Ligand B (0.039), but both are relatively low.

**Binding Affinity:** Ligand B (-9.2) has a significantly stronger binding affinity than Ligand A (-8.7). This difference of 0.5 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -8.7 kcal/mol) and much better metabolic stability (lower Cl_mic, longer half-life) are crucial for an enzyme target. While Ligand A has a better QED score, Ligand B's lower DILI risk is also a significant advantage. The lower logP of Ligand B is a concern, but the superior binding affinity and metabolic stability are more important for an SRC kinase inhibitor.

Output:
1
2025-04-17 15:30:26,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.34 Da) is slightly higher than Ligand B (361.364 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (58.22 and 63.52) well below the 140 threshold for oral absorption.

**logP:** Both ligands have logP values (4.125 and 3.023) within the optimal range of 1-3, though Ligand A is a bit high.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 and 5) counts.

**QED:** Both ligands have good QED scores (0.777 and 0.705), indicating drug-like properties.

**DILI:** Ligand A (26.018) has a significantly lower DILI risk than Ligand B (35.789), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (74.292 and 74.564), which isn't a primary concern for a non-CNS target like SRC.

**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 represent a different type of measurement.

**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 (0.894 and 0.862).

**Microsomal Clearance:** Ligand B (44.643) has a lower microsomal clearance than Ligand A (67.49), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (18.758) has a significantly longer in vitro half-life than Ligand A (-5.127), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.373 and 0.472).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a significant advantage, as potency is a key priority for enzyme inhibitors.

**Overall Assessment:**

While Ligand A has a slightly better logP and a much lower DILI risk, Ligand B excels in the most critical areas for an enzyme inhibitor: binding affinity and metabolic stability (half-life and clearance). The 1.5 kcal/mol advantage in binding affinity is substantial enough to outweigh the slightly higher DILI risk and lower metabolic stability of Ligand A. The negative solubility and Caco-2 values are concerning for both, but these could be addressed with formulation strategies.

Output:
1
2025-04-17 15:30:26,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.535 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (99.77). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 3.227, B: 2.466), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=4) as it has fewer hydrogen bond forming groups, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.613, B: 0.617), indicating good drug-likeness.

**DILI:** Ligand A (7.794) has a much lower DILI risk than Ligand B (71.656). This is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (81.039) is slightly better than Ligand B (78.79).

**Caco-2 Permeability:** Ligand A (-4.126) shows better Caco-2 permeability than Ligand B (-5.299), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.756) has better aqueous solubility than Ligand B (-3.597). Solubility is important for formulation and bioavailability.

**hERG:** Ligand A (0.638) has a lower hERG inhibition liability than Ligand B (0.401), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (65.438) has a higher microsomal clearance than Ligand B (19.992), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (0.666) has a longer in vitro half-life than Ligand A (5.347). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux liability than Ligand B (0.15), which is slightly favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the 0.4 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in several key areas: TPSA, solubility, DILI risk, and hERG. However, its significantly higher microsomal clearance and shorter half-life are major concerns. Ligand B, while slightly worse in some ADME properties, demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. Given the enzyme-specific priorities, metabolic stability is crucial. The small advantage in binding affinity of Ligand B, combined with its improved metabolic profile, outweighs the slightly less favorable TPSA and solubility.

Output:
1
2025-04-17 15:30:26,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.276 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.72) is excellent, well below the 140 threshold for oral absorption. Ligand B (104.29) is still acceptable, but less optimal.

**logP:** Ligand A (1.735) is within the optimal 1-3 range. Ligand B (0.246) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.

**H-Bond Acceptors:** Ligand A (8) is good. Ligand B (5) is good.

**QED:** Both ligands have good QED scores (0.65 and 0.701), indicating generally drug-like properties.

**DILI:** Ligand A (97.402) has a high DILI risk, which is a significant concern. Ligand B (35.789) has a very low DILI risk, a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.972) is reasonable, while Ligand B (61.264) is lower.

**Caco-2 Permeability:** Ligand A (-4.419) is poor. Ligand B (-5.313) is also poor.

**Aqueous Solubility:** Ligand A (-3.382) is poor. Ligand B (-1.76) is also poor, but slightly better.

**hERG:** Ligand A (0.131) has very low hERG risk, a strong positive. Ligand B (0.022) has extremely low hERG risk, even better.

**Microsomal Clearance:** Ligand A (100.207) has high clearance, indicating poor metabolic stability. Ligand B (16.534) has low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (-22.317) has a very short half-life. Ligand B (2.701) has a short half-life, but is better than Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.4 and 0.005), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a 0.9 kcal/mol advantage in binding affinity over Ligand A (-7.0 kcal/mol). This is a substantial difference and can often outweigh other minor drawbacks.

**Conclusion:**

Despite Ligand A's good TPSA and hERG profile, its high DILI risk, poor metabolic stability (high Cl_mic, short t1/2), and poor Caco-2 permeability are significant liabilities. Ligand B, while having a slightly lower TPSA and solubility, exhibits a much lower DILI risk, superior metabolic stability, and a significantly stronger binding affinity. The binding affinity difference is large enough to compensate for the slightly less optimal TPSA and solubility. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 15:30:26,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.407 and 355.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.35) is slightly above the preferred <140, but acceptable. Ligand B (87.74) is excellent, well below 140.

**logP:** Ligand A (0.782) is a bit low, potentially impacting permeability. Ligand B (1.073) is also on the lower side, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (6 and 4 respectively). This is within acceptable limits.

**QED:** Ligand A (0.769) has a better QED score than Ligand B (0.648), indicating better overall drug-likeness.

**DILI:** Ligand A (48.662) has a significantly lower DILI risk than Ligand B (11.128), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (62.466) has a higher BBB value than Ligand A (20.085), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.039 and -5.132), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.491 and -1.297), indicating poor aqueous solubility. This is a drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.228 and 0.289), which is excellent.

**Microsomal Clearance:** Ligand A (14.616) has a higher microsomal clearance than Ligand B (-2.055). This means Ligand B is likely more metabolically stable, a key consideration for enzymes.

**In vitro Half-Life:** Ligand B (-1.33) has a slightly better in vitro half-life than Ligand A (-16.365), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.008).

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-6.5). This is a crucial advantage, as a 1.5 kcal/mol difference can often outweigh other drawbacks.

**Conclusion:**

Despite the poor permeability and solubility of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.0 vs -6.5 kcal/mol) is a major advantage for an enzyme target. Furthermore, it exhibits better metabolic stability (lower Cl_mic, better t1/2) and a much lower DILI risk. While both have poor Caco-2 and solubility, these can potentially be addressed through formulation strategies. The potency and metabolic stability advantages of Ligand B outweigh the drawbacks.

Output:
1
2025-04-17 15:30:26,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.452 and 345.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.74) is well below the 140 threshold and good for oral absorption. Ligand B (72.91) is still acceptable, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (3.968) is at the upper end of the optimal range (1-3), while Ligand B (1.96) is towards the lower end. Higher logP can sometimes cause issues, but isn't a major concern here.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, both within acceptable limits. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.679 and 0.763), indicating generally drug-like properties.

**DILI:** Ligand A (14.036) has a very low DILI risk, significantly better than Ligand B (39.783), which is still acceptable but higher.

**BBB:** Both ligands have high BBB penetration (92.323 and 88.91), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.727 and -4.182). These values are unusual and suggest 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 (-3.637 and -3.325), suggesting very poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.829) has a slightly higher hERG risk than Ligand B (0.576), but both are reasonably low.

**Microsomal Clearance:** Ligand A (8.323) has a significantly lower microsomal clearance than Ligand B (75.949), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (13.751) has a longer half-life than Ligand B (6.406), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.606) shows lower P-gp efflux than Ligand B (0.298), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.0) has a stronger binding affinity than Ligand B (-6.9). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While both have poor solubility and permeability, Ligand A's significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower P-gp efflux, and *much* stronger binding affinity outweigh the slightly higher logP and hERG risk. The strong binding affinity is particularly important for an enzyme target like SRC kinase. Addressing the solubility and permeability issues through formulation strategies would be a priority in further development.

Output:
1
2025-04-17 15:30:26,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.446 and 340.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.48) is higher than Ligand B (40.62). Both are acceptable, but Ligand B is better, potentially indicating improved cell permeability.

**logP:** Both ligands have good logP values (3.729 and 2.758) within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits. Lower HBD/HBA generally favors permeability, so Ligand B has a slight edge.

**QED:** Both ligands have reasonable QED scores (0.816 and 0.725), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 68.166, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 17.836, a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B (87.476) has higher BBB penetration than Ligand A (49.864), but this is not a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.528 and -4.793) which is unusual and suggests poor permeability. This is a concern for both, but similar for both.

**Aqueous Solubility:** Both have negative solubility values (-3.252 and -3.276). This is also a concern for both, suggesting poor solubility.

**hERG:** Ligand A has a hERG risk of 0.137, which is very low. Ligand B has a slightly higher hERG risk of 0.368, but still acceptable.

**Microsomal Clearance:** Ligand A (49.026) has lower microsomal clearance than Ligand B (53.724), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.538) has a positive half-life, while Ligand B (-6.997) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.183 and 0.328).

**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, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.9 vs -9.0 kcal/mol) and a much lower DILI risk (17.8 vs 68.2). While Ligand A has a better in vitro half-life, the superior potency and safety profile of Ligand B are more critical for an enzyme target like SRC kinase. The similar poor Caco-2 and solubility values are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 15:30:26,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.921 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.17) is well below the 140 threshold, while Ligand B (78.87) is still acceptable but higher. Lower TPSA generally favors better cell permeability.

**logP:** Ligand A (4.37) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.931) is a bit low, potentially hindering permeation.

**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, falling within the acceptable limits.

**QED:** Ligand A (0.862) has a better QED score than Ligand B (0.67), indicating a more drug-like profile.

**DILI:** Ligand B (9.306) has a significantly lower DILI risk than Ligand A (54.983), which is a major advantage.

**BBB:** Ligand A (86.817) has a higher BBB penetration percentile than Ligand B (34.548), but BBB is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.502 and -4.508), which is unusual and problematic. This suggests poor intestinal absorption for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.432 and -0.851), indicating very poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.859) has a slightly higher hERG risk than Ligand B (0.214). Lower hERG risk is preferred.

**Microsomal Clearance:** Ligand B (12.421 mL/min/kg) has a much lower microsomal clearance than Ligand A (60.179 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (80.3 hours) has a significantly longer half-life than Ligand B (2.532 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.692) has a lower P-gp efflux liability than Ligand B (0.047), which is favorable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and half-life, its significantly higher DILI risk, higher hERG risk, and much higher microsomal clearance are major concerns. Ligand B, while having a slightly weaker binding affinity, presents a much more favorable ADME profile with a low DILI risk and better metabolic stability. The poor solubility and Caco-2 permeability are shared concerns that would need to be addressed through formulation or further chemical modification. However, the ADME profile of Ligand B is more readily optimizable than the safety concerns associated with Ligand A.

Output:
1
2025-04-17 15:30:26,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.388 and 368.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is significantly better than Ligand B (116.88). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit and may have absorption issues.

**logP:** Ligand A (3.796) is optimal, while Ligand B (1.029) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 7. Ligand B is higher, potentially impacting permeability.

**QED:** Ligand A (0.841) is excellent, indicating high drug-likeness. Ligand B (0.627) is still acceptable but less favorable.

**DILI:** Ligand A (35.789) has a much lower DILI risk than Ligand B (55.293). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (84.064) is better than Ligand B (65.025).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not provided, so it's hard to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not provided.

**hERG:** Ligand A (0.694) has a lower hERG risk than Ligand B (0.076), which is a critical advantage.

**Microsomal Clearance:** Ligand A (40.857) has a higher (worse) clearance than Ligand B (7.569). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (1.395) has a shorter half-life than Ligand B (2.578). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.396) has lower P-gp efflux than Ligand B (0.022), which is better for bioavailability.

**Binding Affinity:** Ligand B (-10.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol, making it a key factor.

**Overall:**

Ligand A has better drug-likeness (QED, DILI, hERG, P-gp), and acceptable TPSA and logP. However, its metabolic stability (Cl_mic, t1/2) is worse, and its binding affinity is significantly weaker.

Ligand B has a much stronger binding affinity, better metabolic stability, but suffers from higher TPSA, lower logP, higher DILI risk, and a higher risk of hERG inhibition.

Given the importance of potency for kinase inhibitors, the significantly stronger binding affinity of Ligand B (-10.0 kcal/mol vs -7.1 kcal/mol) is the deciding factor, despite its ADME liabilities. Optimization efforts could then focus on improving the ADME profile of Ligand B.

Output:
1
2025-04-17 15:30:26,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.371 and 349.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (99.51) is slightly above the preferred <90 for CNS penetration but acceptable for a non-CNS target. Ligand B (84.67) is well within the acceptable range.

**logP:** Ligand A (0.507) is a bit low, potentially hindering permeability. Ligand B (1.978) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.874 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.164, placing it in the higher risk category (>60). Ligand B has a significantly lower DILI risk (28.306), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (76.58) than Ligand A (51.415).

**Caco-2 Permeability:** Ligand A (-5.043) has very poor predicted Caco-2 permeability. Ligand B (-4.223) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor predicted solubility (-1.552 and -2.747). This is a concern, but can sometimes be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.152 and 0.17), which is positive.

**Microsomal Clearance:** Ligand A (5.585) has lower microsomal clearance than Ligand B (53.474), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.813) has a negative half-life, which is concerning. Ligand B (11.56) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.066).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.0 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite Ligand A having slightly better metabolic stability, its significantly higher DILI risk, very poor Caco-2 permeability, and negative in vitro half-life are major drawbacks. Ligand B, while having a higher Cl_mic, presents a much more favorable overall profile with a lower DILI risk, better Caco-2 permeability, and a positive half-life. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 15:30:26,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.407 and 366.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.25) is slightly higher than Ligand B (93.21). Both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets, which isn't a priority here.

**logP:** Both ligands have good logP values (1.684 and 1.471), falling 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.659 and 0.724), indicating drug-like properties.

**DILI:** Ligand A (88.29) has a higher DILI risk than Ligand B (66.615). This is a significant concern, as we want to minimize liver toxicity.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC. Ligand A (63.629) and Ligand B (50.523) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.581) has worse Caco-2 permeability than Ligand B (-4.888), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.441) has worse solubility than Ligand B (-2.938). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.57) has a higher hERG risk than Ligand B (0.212). Lower hERG risk is crucial to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (25.601) has significantly lower microsomal clearance than Ligand B (47.124), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (77.738) has a much longer half-life than Ligand B (-18.892). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux than Ligand B (0.047), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While A is stronger, the difference is not substantial enough to outweigh its other liabilities.

**Overall Assessment:**

Ligand A has a better half-life, lower P-gp efflux, and slightly better binding affinity, but suffers from significantly higher DILI risk, hERG risk, and lower solubility/permeability. Ligand B, while having a slightly weaker affinity, presents a much more favorable safety profile (lower DILI and hERG) and better solubility/permeability. Given the enzyme-specific priorities, the improved safety and ADME properties of Ligand B outweigh the modest difference in binding affinity.

Output:
1
2025-04-17 15:30:26,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.769 Da and 344.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.54) is slightly higher than Ligand B (76.69), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.938) is at the upper end of the optimal range (1-3), while Ligand B (0.773) is below it. A logP too low can hinder permeation.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 8. Both are within the acceptable limit of 10.

**QED:** Ligand B (0.834) has a significantly higher QED score than Ligand A (0.435), indicating better overall drug-likeness.

**DILI:** Ligand A has a very high DILI risk (96.51%), which is a major concern. Ligand B has a low DILI risk (13.61%).

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (75.107) is slightly better than Ligand A (63.086). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 unclear.

**hERG Inhibition:** Ligand A (0.532) has a slightly higher hERG risk than Ligand B (0.311), but both are relatively low.

**Microsomal Clearance:** Ligand B (-11.45) has a *negative* microsomal clearance, which is impossible. This is a red flag and suggests a data error. Ligand A (89.016) has a high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand B (-9.822) has a negative half-life, which is also impossible and indicates a data error. Ligand A (42.212) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.55) has a lower P-gp efflux liability than Ligand B (0.045), which is favorable.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.6). This is a substantial advantage.

**Conclusion:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk and poor metabolic stability are major drawbacks. The negative values for Caco-2, solubility, clearance, and half-life for Ligand B are concerning and likely indicate data errors. However, even assuming those values are errors, the DILI risk for Ligand A is almost disqualifying. The better QED, lower DILI, and potentially better permeability/solubility (if the negative values are errors) make Ligand B the more promising candidate, *assuming the negative values are corrected*. The affinity difference, while significant, can potentially be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 15:30:26,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.401 and 372.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (74.58) is well below the 140 threshold, suggesting good absorption. Ligand B (90.98) is still acceptable, but closer to the limit.

**logP:** Ligand A (2.753) is optimal (1-3). Ligand B (-0.113) is significantly below 1, which could hinder permeation.

**H-Bond Donors:** Both 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 within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.5 (0.769 and 0.679), indicating good drug-like properties.

**DILI:** Ligand A (29.43) has a lower DILI risk than Ligand B (40.287), both are acceptable (<40 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.064) has a higher BBB percentile than Ligand B (63.203).

**Caco-2 Permeability:** Ligand A (-4.521) and Ligand B (-5.276) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.883) and Ligand B (-1.377) both have negative values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.271) has a lower hERG risk than Ligand B (0.14), both are acceptable.

**Microsomal Clearance:** Ligand A (35.651) has a higher microsomal clearance than Ligand B (-6.987), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (38.876) has a shorter half-life than Ligand B (-21.135), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.004).

**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 a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher clearance and shorter half-life, its substantially stronger binding affinity (-8.6 vs -7.5 kcal/mol) is a decisive factor. The potency advantage is likely to be more impactful for an enzyme target like SRC kinase than the slightly worse metabolic stability. Both compounds have solubility and permeability concerns, but these can be addressed through formulation strategies. Ligand B's low logP is a more fundamental issue.

Output:
1
2025-04-17 15:30:26,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 and 351.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.62) is well below the 140 threshold for good absorption, while Ligand B (111.13) is still acceptable but less optimal.

**logP:** Ligand A (1.318) is within the optimal 1-3 range. Ligand B (-1.358) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (4 HBD, 6 HBA) is still within acceptable limits, but higher HBDs can sometimes affect permeability.

**QED:** Both ligands have similar and acceptable QED values (0.445 and 0.483, respectively).

**DILI:** Both ligands have low DILI risk (37.03 and 31.06), which is favorable.

**BBB:** Ligand A (65.41) has moderate BBB penetration, while Ligand B (19.70) is low. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.407) has poor Caco-2 permeability, a significant concern. Ligand B (-5.776) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.453) has poor solubility. Ligand B (-0.779) is also poor, but slightly better.

**hERG:** Both ligands have very low hERG risk (0.225 and 0.082), which is excellent.

**Microsomal Clearance:** Ligand A (41.376) has a moderate clearance, while Ligand B (-10.594) has a negative clearance, indicating excellent metabolic stability. This is a *major* advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-24.348) has a negative half-life, which is unusual and likely indicates a very long half-life. Ligand B (14.026) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.173 and 0.007), which is favorable.

**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 meaningful.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 permeability and solubility, Ligand B's significantly improved metabolic stability (negative Cl_mic, better half-life) and slightly better binding affinity outweigh the slightly less favorable TPSA and logP. The poor Caco-2 and solubility can be addressed with formulation strategies. Ligand A's poor Caco-2 permeability is a more difficult hurdle to overcome.

Output:
1
2025-04-17 15:30:26,868 - INFO - Batch 385 complete. Total preferences: 6160
2025-04-17 15:30:26,868 - INFO - Processing batch 386/512...
2025-04-17 15:31:12,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.845 and 357.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is well below the 140 threshold, while Ligand B (101.9) is still acceptable but closer to the limit.

**logP:** Ligand A (3.222) is optimal (1-3), while Ligand B (0.109) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (4 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.855) has a strong drug-like profile, significantly better than Ligand B (0.444).

**DILI:** Ligand A (54.75) has a moderate DILI risk, while Ligand B (2.792) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (55.176) and Ligand B (23.42) are both low, which is not a major concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.879) and Ligand B (-5.609) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.584) and Ligand B (-0.652) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.388) has a low hERG risk, while Ligand B (0.252) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (62.661) has moderate clearance, while Ligand B (-21.6) has negative clearance, which is highly desirable, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (51.204) has a reasonable half-life, while Ligand B (-4.72) has a negative half-life, which is extremely good.

**P-gp Efflux:** Ligand A (0.136) has low P-gp efflux, while Ligand B (0.005) has very low P-gp efflux.

**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 drawbacks.

**Conclusion:**

Despite Ligand B's superior metabolic stability (Cl_mic and t1/2) and lower DILI risk, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.6 vs -7.3 kcal/mol) is a critical advantage for an enzyme inhibitor. While Ligand A has a slightly higher DILI risk and lower QED, the potency difference is likely to be more impactful in driving efficacy. The permeability and solubility are poor for both, but these can be addressed with formulation strategies.

Output:
1
2025-04-17 15:31:12,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.467 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.85 and 70.44) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.546) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (3.35) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable.

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also acceptable.

**QED:** Both ligands have good QED scores (0.43 and 0.623), indicating reasonable drug-likeness.

**DILI:** Both ligands have elevated DILI risk (60.527 and 69.135), which is a concern. This will need to be addressed in further optimization.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.466) is higher than Ligand B (70.997).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant issue.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.868 and -3.561). This is a major drawback.

**hERG Inhibition:** Ligand A (0.611) has a slightly better hERG profile than Ligand B (0.904), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (5.015) has significantly lower microsomal clearance than Ligand A (53.078), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (18.044 hours) has a much longer half-life than Ligand A (3.176 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.633) shows lower P-gp efflux than Ligand B (0.358), potentially leading to better bioavailability.

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, lower P-gp efflux, and a slightly better hERG profile. However, it suffers from higher microsomal clearance, a shorter half-life, and a higher logP. Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2) and a more favorable logP, but its binding affinity is weaker.

Given the enzyme-specific priorities, metabolic stability and half-life are critical. The substantial difference in these parameters favors Ligand B. While the binding affinity of Ligand A is attractive, the poor metabolic properties are a significant concern for *in vivo* efficacy. The solubility issues for both ligands are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 15:31:12,934 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [384.173, 82.7, 4.701, 3, 3, 0.573, 99.341, 53.974, -4.751, -6.525, 0.401, 25.237, 102.667, 0.168, -8.4]
**Ligand B:** [408.252, 78.86, 3.757, 0, 7, 0.599, 79.449, 77.898, -4.933, -3.885, 0.325, 81.085, 62.897, 0.401, -8.5]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (384.173) is slightly preferred.
2. **TPSA:** Both are below 140, good for oral absorption. B (78.86) is slightly better than A (82.7).
3. **logP:** Both are within the optimal range (1-3). B (3.757) is slightly better than A (4.701), but A is still acceptable.
4. **HBD:** A (3) is acceptable, B (0) is also acceptable.
5. **HBA:** A (3) is acceptable, B (7) is acceptable.
6. **QED:** Both are above 0.5, indicating good drug-like properties. B (0.599) is slightly better than A (0.573).
7. **DILI:** A (99.341) is *very* high risk, a significant concern. B (79.449) is still elevated, but considerably better.
8. **BBB:** A (53.974) is not particularly high, but not a major concern for a non-CNS target. B (77.898) is better, but also not critical here.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.751) is slightly worse than B (-4.933).
10. **Solubility:** Both are negative, indicating poor solubility. A (-6.525) is slightly better than B (-3.885).
11. **hERG:** Both are low, indicating low risk of cardiotoxicity. A (0.401) is slightly better than B (0.325).
12. **Cl_mic:** A (25.237) is much better than B (81.085), indicating better metabolic stability. This is a key factor for kinase inhibitors.
13. **t1/2:** A (102.667) is much better than B (62.897), indicating a longer half-life. This is also a key factor for kinase inhibitors.
14. **Pgp:** Both are low, indicating low efflux. A (0.168) is slightly better than B (0.401).
15. **Binding Affinity:** B (-8.5) is slightly better than A (-8.4), but the difference is small.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While B has a slightly better affinity and TPSA, A significantly outperforms B in metabolic stability (Cl_mic and t1/2) and has a lower DILI risk. The poor solubility and Caco-2 permeability of both are concerns, but can be addressed with formulation strategies. The extremely high DILI risk for ligand A is a major red flag.

**Conclusion:**

Despite the slightly better affinity of Ligand B, the significantly better metabolic stability (Cl_mic and t1/2) and lower DILI risk of Ligand A make it the more promising candidate. The solubility and permeability issues are addressable, but high DILI is a difficult property to fix later in development.

Output:
1
2025-04-17 15:31:12,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.382 Da) is slightly lower, which could be beneficial for permeability. Ligand B (376.953 Da) is also good.

**TPSA:** Ligand A (126.21) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (25.36) is excellent, suggesting good absorption.

**logP:** Ligand A (0.098) is quite low, potentially hindering membrane permeability and bioavailability. Ligand B (4.842) is high, which could lead to solubility issues and off-target interactions, but is still within a reasonable range.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also acceptable, potentially improving membrane permeability.

**H-Bond Acceptors:** Both ligands have 4-5 HBA, which is within the acceptable range.

**QED:** Both ligands have good QED scores (A: 0.518, B: 0.721), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (56.999) has a moderate DILI risk. Ligand B (14.618) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (78.674) has moderate BBB penetration. Ligand B (93.292) has high BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.666 and -5.241). This 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 (-2.518 and -3.946). This is also unusual and suggests poor solubility. Again, the scale is unclear.

**hERG Inhibition:** Ligand A (0.303) has a low hERG risk, which is excellent. Ligand B (0.824) has a slightly elevated hERG risk, but still within a manageable range.

**Microsomal Clearance:** Ligand A (-11.576) has very low microsomal clearance, indicating high metabolic stability. Ligand B (52.504) has moderate clearance, suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (6.735) has a moderate half-life. Ligand B (-4.789) has a negative half-life, which is not physically possible and likely indicates an issue with the data.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is favorable. Ligand B (0.582) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9.1) has a significantly stronger binding affinity than Ligand B (-8.0). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, excellent metabolic stability, and low hERG risk. However, it suffers from low logP and potentially poor solubility/permeability. Ligand B has better TPSA, lower DILI risk, and better QED, but its binding affinity is weaker, and its in vitro half-life is problematic.

Given the enzyme-specific priorities, **binding affinity is paramount**. The 1.1 kcal/mol difference in binding affinity is substantial. The poor solubility/permeability of Ligand A could potentially be addressed through formulation strategies. The negative half-life for Ligand B is a major red flag.

Output:
0
2025-04-17 15:31:12,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.284 and 360.797 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.02) is slightly higher than Ligand B (79.73), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have excellent logP values (2.462 and 2.189), 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:** Ligand A (0.765) has a better QED score than Ligand B (0.5), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (70.686 and 78.054), which is a concern. However, this is a percentile, and we need to consider other factors.

**BBB:** Ligand A (35.091) has a lower BBB penetration than Ligand B (57.736). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.853 and -4.709), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.173 and -3.519), indicating very poor aqueous solubility. This is a major concern for oral bioavailability.

**hERG Inhibition:** Ligand A (0.603) has a slightly higher hERG risk than Ligand B (0.28), but both are reasonably low.

**Microsomal Clearance:** Ligand B (69.728) has a higher microsomal clearance than Ligand A (31.454), meaning Ligand A is more metabolically stable. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-12.738) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the compound. Ligand B (0.865) has a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.117 and 0.348).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly 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 drawbacks.

**Overall Assessment:**

Despite the slightly better QED of Ligand A, the negative and unrealistic in vitro half-life is a deal-breaker. The poor solubility and permeability of both compounds are also major concerns. However, Ligand B has a significantly better binding affinity and better metabolic stability (lower Cl_mic). While the DILI risk is high for both, the binding affinity advantage of Ligand B is substantial enough to make it the more promising candidate, *assuming the half-life data is accurate*. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications.

Output:
1
2025-04-17 15:31:12,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.471 and 385.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.5) is slightly above the preferred <140, but acceptable. Ligand B (80.32) is well within the range.

**logP:** Both ligands have logP values (0.962 and 2.272) within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.751 and 0.752), indicating good drug-likeness.

**DILI:** Ligand A (32.338) has a significantly lower DILI risk than Ligand B (67.507). This is a major advantage for Ligand A.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.222 and 0.241).

**Microsomal Clearance:** Ligand A (-8.56 mL/min/kg) exhibits *much* lower microsomal clearance than Ligand B (27.126 mL/min/kg). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-10.979 hours) has a negative half-life, which is unusual and suggests a very rapid clearance or instability. Ligand B (41.049 hours) is a more reasonable value. However, the negative value for A is likely an artifact of the modeling and should be interpreted cautiously.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.056).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a stronger binding affinity than Ligand B (-6.7 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand A's significantly better DILI score, much lower microsomal clearance (indicating better metabolic stability), and superior binding affinity are decisive advantages. The negative in vitro half-life for A is concerning, but the strong binding affinity suggests it may be a modeling artifact. Ligand B's higher DILI risk and faster clearance are significant drawbacks.

Output:
0
2025-04-17 15:31:12,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.458 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (102.49) is still within acceptable limits but less optimal than A.

**logP:** Ligand A (3.879) is at the upper end of the optimal range (1-3), while Ligand B (0.242) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 7 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.866 and 0.803), indicating good drug-likeness.

**DILI:** Ligand A (71.888) has a higher DILI risk than Ligand B (47.964). This is a negative for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand A (67.197) is slightly higher than Ligand B (55.176). This isn't a major factor for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.744 and -4.963). This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.01 and -2.297). This is a significant drawback for both.

**hERG Inhibition:** Both ligands exhibit low hERG inhibition risk (0.302 and 0.139). This is positive for both.

**Microsomal Clearance:** Ligand A (17.238) has significantly higher microsomal clearance than Ligand B (4.158), indicating lower metabolic stability. This is a major negative for Ligand A.

**In vitro Half-Life:** Both have similar in vitro half-lives (27.937 and 27.955 hours), which are acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.156 and 0.036), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.1 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B exhibits significantly better metabolic stability (lower Cl_mic) and a lower DILI risk. Ligand A's higher logP and clearance are concerning. The slightly better TPSA of Ligand A is not enough to offset these drawbacks.

Output:
1
2025-04-17 15:31:12,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.356 and 369.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.62) is well below the 140 threshold, while Ligand B (95.5) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.233) is optimal (1-3), while Ligand B (0.218) is quite low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.72 and 0.801), indicating drug-likeness.

**DILI:** Ligand A (82.435) has a higher DILI risk than Ligand B (63.358), which is less desirable.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. This is a concern for both, but the lower value for Ligand B (-5.058) is worse than Ligand A (-5.014).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.497) is slightly better than Ligand B (-2.611).

**hERG:** Ligand A (0.723) has a slightly higher hERG risk than Ligand B (0.139), which is preferable.

**Microsomal Clearance:** Ligand A (34.855) has higher clearance than Ligand B (15.093), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (20.494 hours) has a much longer half-life than Ligand B (-6.284 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.568) has lower P-gp efflux than Ligand B (0.034), which is preferable.

**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 a positive for Ligand B.

**Overall Assessment:**

Ligand A has advantages in logP, TPSA, in vitro half-life, and P-gp efflux. However, Ligand B has a better binding affinity, lower DILI risk, and better metabolic stability. The poor Caco-2 and solubility for both are concerning, but the slightly better affinity of Ligand B and its lower DILI risk, combined with better metabolic stability, make it a more promising starting point, assuming solubility and permeability can be improved through structural modifications. The affinity difference is small enough that optimizing the ADME properties of Ligand B is likely to yield a better candidate than trying to address the permeability issues of Ligand A.

Output:
1
2025-04-17 15:31:12,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (366.433 and 368.949 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (50.36 and 49.41) well below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (3.955) is closer to the optimal range of 1-3 than Ligand B (4.233), but both are acceptable.

**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 (0.549 and 0.762), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 59.984, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (15.626), which is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (74.758 and 72.78). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.726 and -4.389). This is unusual and suggests poor permeability. However, these values are on a scale where negative numbers are possible and don't necessarily indicate a complete lack of permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.526 and -4.469). Similar to Caco-2, these are on a scale where negative values are possible. This suggests poor aqueous solubility, which could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.873 and 0.587).

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (87.631) than Ligand B (89.884), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (39.349 hours) than Ligand A (2.953 hours). This is a major advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.546 and 0.261).

**15. Binding Affinity:** Ligand B has a slightly better binding affinity (-7.7 kcal/mol) than Ligand A (-7.4 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand B excels in metabolic stability (t1/2) and has a significantly lower DILI risk. The slightly better affinity of Ligand B is a bonus. While both have poor solubility and permeability, the superior metabolic profile and safety of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 15:31:12,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (343.515 and 351.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.36) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.95) is still under 140, but less optimal than A.

**3. logP:** Ligand A (2.674) is within the optimal 1-3 range. Ligand B (1.538) is slightly lower, potentially impacting permeability, 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 (3 and 4 respectively), well below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.864 and 0.736), indicating drug-like properties.

**7. DILI:** Ligand A (2.21) has a very low DILI risk, significantly better than Ligand B (28.306), which is approaching a moderate risk.

**8. BBB:** Ligand A (82.202) shows better BBB penetration potential than Ligand B (71.811), although BBB isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.248) has a negative Caco-2 value, indicating poor permeability. Ligand B (-4.552) also has a negative Caco-2 value, but is slightly better than A.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.271 and -1.678), suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.804) has a lower hERG risk than Ligand B (0.198), which is a significant advantage.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-32.655) has a much lower (better) microsomal clearance than Ligand B (1.405), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.56) has a longer in vitro half-life than Ligand B (-18.62), which is a positive attribute.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.031).

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.5 kcal/mol advantage, which is significant.

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a better binding affinity, which is a major plus. However, Ligand A demonstrates significantly better ADME properties: lower DILI risk, better BBB penetration, lower hERG risk, and substantially improved metabolic stability (lower Cl_mic and longer t1/2). Both have poor solubility and permeability. Considering the importance of metabolic stability and safety (DILI, hERG) for an enzyme target, and the substantial advantage Ligand A has in these areas, it is the more promising candidate despite the slightly lower affinity. The affinity difference is not large enough to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 15:31:12,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.451 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.08) is significantly better than Ligand B (105.98). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Ligand A (3.779) is within the optimal 1-3 range, while Ligand B (0.85) is slightly below, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.503 and 0.678), indicating drug-like properties.

**DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (53.432), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (63.474) shows slightly better potential for BBB penetration than Ligand B (56.883).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.118 and -5.056), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.987 and -2.564), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.976) has a lower hERG risk than Ligand B (0.027), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (41.894) has a higher microsomal clearance than Ligand B (29.171), meaning Ligand B is more metabolically stable. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-7.145) has a longer in vitro half-life than Ligand A (-8.931), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.935 and 0.053).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 0.4 kcal/mol difference is significant, and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and lower hERG risk and DILI, but suffers from higher clearance and poor solubility. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, but has a weaker binding affinity and higher hERG risk. Given the importance of potency for kinase inhibitors, and the relatively small difference in binding affinity, Ligand A is the more promising candidate. The poor solubility and permeability of both are significant concerns that would need to be addressed through formulation or further chemical modification. However, the better potency and safety profile of Ligand A make it the preferred starting point.

Output:
0
2025-04-17 15:31:12,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (341.367 and 347.375 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.62) is well below the 140 threshold for good absorption and is also favorable. Ligand B (122.28) is still under the 140 threshold, but higher than A.

**3. logP:** Ligand A (2.004) is optimal. Ligand B (0.849) is slightly below the optimal range, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher than ideal.

**5. H-Bond Acceptors:** Both ligands (A: 7, B: 7) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.787) has a better QED score than Ligand B (0.638), indicating a more drug-like profile.

**7. DILI:** Ligand A (83.715) has a higher DILI risk than Ligand B (64.909). This is a significant drawback for Ligand A.

**8. BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand A (78.868) is higher than Ligand B (54.634).

**9. Caco-2 Permeability:** Ligand A (-4.321) shows better Caco-2 permeability than Ligand B (-5.162).

**10. Aqueous Solubility:** Ligand A (-3.963) has better aqueous solubility than Ligand B (-3.054).

**11. hERG Inhibition:** Both ligands (A: 0.334, B: 0.332) have very similar, and low, hERG inhibition liability.

**12. Microsomal Clearance:** Ligand B (41.053) has significantly lower microsomal clearance than Ligand A (88.714), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (-23.069) has a much longer in vitro half-life than Ligand A (-6.201), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands (A: 0.068, B: 0.082) have similar P-gp efflux liability.

**15. Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and metabolic stability, while Ligand A has a higher DILI risk.

**Conclusion:** Despite the higher DILI risk, Ligand B's superior binding affinity and significantly better metabolic stability make it the more promising drug candidate. The strong binding affinity is a critical advantage for an enzyme inhibitor, and the improved half-life will likely translate to better *in vivo* exposure.

Output:
1
2025-04-17 15:31:12,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (383.901 and 389.945 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (59). Both are below 140, suggesting good absorption potential.

**logP:** Ligand A (1.427) is optimal, while Ligand B (3.331) is approaching the upper limit.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**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 (0.803 and 0.777), indicating good drug-likeness.

**DILI:** Ligand A (54.207) has a slightly higher DILI risk than Ligand B (44.591), but both are below the concerning threshold of 60.

**BBB:** Ligand B (57.425) has a higher BBB penetration percentile than Ligand A (27.414). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.259) has a worse Caco-2 permeability than Ligand B (-4.734).

**Aqueous Solubility:** Ligand A (-2.988) has a worse aqueous solubility than Ligand B (-3.471).

**hERG Inhibition:** Ligand A (0.335) has a lower hERG inhibition liability than Ligand B (0.537), which is preferable.

**Microsomal Clearance:** Ligand A (-2.723) has a significantly lower (better) microsomal clearance than Ligand B (43.49). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (7.776) has a lower in vitro half-life than Ligand B (55.021).

**P-gp Efflux:** Ligand A (0.112) has a lower P-gp efflux liability than Ligand B (0.636), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.3 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. It has superior metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. While Ligand B has slightly better solubility and Caco-2 permeability, the metabolic stability and safety profiles of Ligand A are more critical for a successful drug candidate.

Output:
0
2025-04-17 15:31:12,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 349.391 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.11) is better than Ligand B (131.54). Lower TPSA generally improves oral absorption, and while not a strict requirement for kinases, it's a plus.

**logP:** Both ligands have good logP values (1.728 and 1.829), 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.654) has a significantly better QED score than Ligand B (0.288), indicating a more drug-like profile.

**DILI:** Ligand B (34.277) has a much lower DILI risk than Ligand A (58.162), which is a significant advantage.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B is slightly better (38.426 vs 35.44).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates very poor permeability. Ligand A (-4.704) is slightly better than Ligand B (-4.976), but both are problematic.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand B (-1.009) is slightly better than Ligand A (-3.317).

**hERG:** Both ligands have low hERG inhibition liability (0.318 and 0.172), which is excellent.

**Microsomal Clearance:** Ligand B (2.406) has significantly lower microsomal clearance than Ligand A (37.124), indicating much better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (23.524 hours) has a much longer in vitro half-life than Ligand A (-28.386 hours - a negative value is concerning). This is another significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.124 and 0.031), which is good.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a major advantage, and the 1.5 kcal/mol difference can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a better QED and slightly better TPSA and Caco-2, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and substantially stronger binding affinity. The poor solubility and permeability are concerns for both, but the potency and metabolic stability advantages of Ligand B are more impactful for kinase inhibition.

Output:
1
2025-04-17 15:31:12,936 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [335.451, 54.02, 4.35, 2, 2, 0.873, 55.176, 87.747, -4.713, -4.726, 0.795, 53.981, 79.279, 0.41, 0]
**Ligand B:** [344.459, 76.44, 0.841, 1, 4, 0.802, 5.894, 71.229, -4.937, -2.072, 0.511, -16.258, 9.108, 0.004, -7.5]

**Step-by-step Comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (335.451) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** A (54.02) is well below the 140 threshold and good for oral absorption. B (76.44) is still acceptable but less optimal.
3. **logP:** A (4.35) is a bit high, potentially leading to solubility issues and off-target effects. B (0.841) is low, which could hinder membrane permeation.
4. **HBD:** Both A (2) and B (1) are within the acceptable limit of 5.
5. **HBA:** A (2) and B (4) are both under the 10 limit.
6. **QED:** Both A (0.873) and B (0.802) have excellent drug-likeness scores.
7. **DILI:** A (55.176) has a moderate DILI risk. B (5.894) has a very low DILI risk, which is a significant advantage.
8. **BBB:** A (87.747) has good BBB penetration. B (71.229) is acceptable, but lower. This is less critical for a non-CNS target like SRC.
9. **Caco-2:** Both A (-4.713) and B (-4.937) have very poor Caco-2 permeability. This is a major concern for oral bioavailability.
10. **Solubility:** A (-4.726) and B (-2.072) both have poor aqueous solubility. B is slightly better.
11. **hERG:** A (0.795) has a slightly elevated hERG risk. B (0.511) is better.
12. **Cl_mic:** A (53.981) has a moderate microsomal clearance. B (-16.258) has *very* low clearance, indicating excellent metabolic stability. This is a major advantage for an enzyme target.
13. **t1/2:** A (79.279) has a good in vitro half-life. B (9.108) has a short half-life, which is a drawback.
14. **Pgp:** A (0.41) has moderate P-gp efflux. B (0.004) has very low P-gp efflux, which is favorable.
15. **Affinity:** A (0) has no binding affinity. B (-7.5) has strong binding affinity.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Conclusion:**

Despite Ligand A's better BBB penetration, **Ligand B** is the far more promising candidate. Its significantly stronger binding affinity (-7.5 kcal/mol vs 0 kcal/mol) is a decisive advantage. Furthermore, its excellent metabolic stability (very low Cl_mic), low DILI risk, and low P-gp efflux outweigh its lower Caco-2 permeability and shorter half-life. While solubility is a concern for both, the binding affinity and metabolic stability of B are critical for an enzyme inhibitor.

Output:
1
2025-04-17 15:31:12,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (355.345 and 355.435 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.33) is better than Ligand B (110.01). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred threshold for oral absorption.

**3. logP:** Both ligands have acceptable logP values (-0.493 and -0.055), falling within the 1-3 range. Ligand B is slightly better, being closer to 1.

**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 acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.765 and 0.623), indicating good drug-like properties.

**7. DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (34.277). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (73.478 and 60.838), but this is less critical for a kinase inhibitor than for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.168 and -5.347), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.473 and -1.037), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.197 and 0.104). This is positive for both.

**12. Microsomal Clearance:** Ligand A (-17.191) has significantly lower (better) microsomal clearance than Ligand B (25.767). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-5.753) has a slightly lower half-life than Ligand B (-3.472), but both are negative values which is concerning.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.012). This is positive for both.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage for Ligand A. The difference of 2.3 kcal/mol is large enough to potentially overcome some of the ADME liabilities.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, significantly better metabolic stability (lower Cl_mic), and acceptable TPSA and logP. However, it has a higher DILI risk and poor solubility. Ligand B has a lower DILI risk, but weaker binding affinity and poorer metabolic stability. Given the enzyme-specific priorities, the potency (binding affinity) and metabolic stability are paramount. The substantial advantage in binding affinity of Ligand A, coupled with better metabolic stability, outweighs its higher DILI risk and solubility concerns, especially considering that solubility issues can often be addressed through formulation strategies.

Output:
1
2025-04-17 15:31:12,937 - INFO - Batch 386 complete. Total preferences: 6176
2025-04-17 15:31:12,937 - INFO - Processing batch 387/512...
2025-04-17 15:31:51,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.515 Da and 369.893 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values below 140 (87.3 and 80.32), suggesting good potential for oral absorption.

**3. logP:** Ligand A (1.366) is closer to the optimal range (1-3) than Ligand B (2.731), but both are acceptable.

**4. H-Bond Donors:** Ligand A has 3 HBD, and 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 QED values above 0.5 (0.593 and 0.69), indicating good drug-likeness.

**7. DILI:** Ligand A (18.845) has a significantly lower DILI risk than Ligand B (34.471). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (65.103) has a higher BBB percentile than Ligand A (52.423), but BBB is not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.462 and -5.04), which 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 (-2.456 and -3.012), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Ligand A (0.075) has a much lower hERG inhibition liability than Ligand B (0.502). This is a significant advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (53.571) has a higher microsomal clearance than Ligand A (38.756), indicating lower metabolic stability. Lower clearance is preferred for enzymes.

**13. In vitro Half-Life:** Ligand B (42.976) has a longer in vitro half-life than Ligand A (-6.815). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.179), which is favorable for bioavailability.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.2 kcal/mol), which is excellent.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While both have good potency, Ligand A exhibits significantly lower DILI and hERG risk, and lower P-gp efflux. Although Ligand B has a longer half-life, the safety advantages of Ligand A outweigh this benefit. The poor solubility and permeability are concerns for both, but formulation strategies can be explored to address these issues.

Output:
0
2025-04-17 15:31:51,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.5 and 359.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (97.64) is still under 140, but less optimal.

**logP:** Both ligands have acceptable logP values (3.36 and 2.53), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=3, HBA=3) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.848 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A (15.94) has a significantly lower DILI risk than Ligand B (48.47). This is a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (81.70) is better than Ligand B (53.39).

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of negativity is similar.

**Solubility:** Ligand A (-3.88) has better predicted solubility than Ligand B (-2.94).

**hERG:** Both ligands have low hERG risk (0.473 and 0.579).

**Microsomal Clearance:** Ligand A (51.98) has a higher (worse) microsomal clearance than Ligand B (-3.59). This indicates Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-20.12) has a much longer predicted half-life than Ligand A (-7.16). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.178 and 0.128).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and significantly improved metabolic stability (lower Cl_mic, longer half-life). However, Ligand A has a much lower DILI risk and better solubility. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the improved potency and metabolic stability of Ligand B, coupled with acceptable solubility and hERG, make it the more promising candidate. The lower DILI risk of Ligand A is appealing, but the affinity difference is substantial enough to prioritize Ligand B.

Output:
1
2025-04-17 15:31:51,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.387 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.28) is slightly above the preferred <100 for optimal absorption, while Ligand B (96.25) is well within the range.

**logP:** Ligand A (0.718) is a bit low, potentially hindering permeation. Ligand B (-0.571) is even lower, raising more concerns about permeability.

**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 good QED scores (0.704 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A (64.366) has a higher DILI risk than Ligand B (30.942), which is a significant concern.

**BBB:** Both have relatively low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Solubility:** Ligand A (-2.232) has very poor aqueous solubility, a major drawback. Ligand B (-0.016) is slightly better but still indicates poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.031 and 0.05), which is excellent.

**Microsomal Clearance:** Ligand A (27.02) has a higher microsomal clearance than Ligand B (-3.857). The negative value for Ligand B is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (8.232) has a shorter half-life than Ligand B (13.329).

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.005 and 0.011).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of its drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, its poor solubility and higher DILI risk are significant concerns. Ligand B has better solubility and a lower DILI risk, but its binding affinity is considerably weaker, and its logP is very low. Given the substantial difference in binding affinity, and the fact that SRC is not a CNS target, I would cautiously favor Ligand A, *but* with a strong recommendation for medicinal chemistry efforts to improve its solubility and reduce its DILI risk. The potency advantage is large enough to warrant further investigation, assuming solubility can be addressed.

Output:
1
2025-04-17 15:31:51,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 346.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.32) is slightly above the optimal <140 for good oral absorption, but acceptable. Ligand B (67.23) is well within the range, and preferable.

**logP:** Ligand A (0.796) is a bit low, potentially hindering permeation. Ligand B (2.317) 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, which is even better for permeability.

**QED:** Both ligands have similar QED values (0.671 and 0.657), indicating good drug-likeness.

**DILI:** Ligand A (36.952) has a lower DILI risk than Ligand B (58.55), which is a significant advantage.

**BBB:** Ligand A (58.434) has a lower BBB penetration than Ligand B (76.231). Since SRC is not a CNS target, this is less crucial, but still a slight edge to B.

**Caco-2 Permeability:** Ligand A (-5.587) has poor Caco-2 permeability, while Ligand B (-4.619) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.676 and -2.285). This is a major concern for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.091) has a very low hERG risk, significantly better than Ligand B (0.604). This is a crucial advantage for A.

**Microsomal Clearance:** Ligand A (-6.848) has a much lower (better) microsomal clearance than Ligand B (35.187), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.027 hours) has a substantially longer half-life than Ligand B (2.115 hours). This is a significant advantage for A.

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, while Ligand B (0.278) is slightly higher.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it's not overwhelming.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), hERG risk, and P-gp efflux. Its DILI risk is also lower. While its logP and Caco-2 permeability are less ideal, these can potentially be mitigated. Ligand B has a slightly better binding affinity and BBB penetration, but suffers from higher DILI risk, poorer metabolic stability, and a shorter half-life. Given the enzyme-specific priorities, metabolic stability and safety (hERG, DILI) are paramount. The slightly stronger binding of Ligand B is unlikely to outweigh the significant advantages of Ligand A in these critical ADME/Tox properties.

Output:
0
2025-04-17 15:31:51,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.808 and 343.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.74) is better than Ligand B (55.21), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (4.615) is slightly high, potentially causing solubility issues, while Ligand B (3.334) is optimal.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar, good QED values (0.837 and 0.836).

**DILI:** Ligand A (85.964) has a significantly higher DILI risk than Ligand B (38.813). This is a major concern.

**BBB:** Both have reasonable BBB penetration, but Ligand B (78.868) is slightly better than Ligand A (64.211). This isn't a primary concern for a kinase inhibitor, but a slight advantage.

**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 and suggests poor solubility. Again, the scale is not defined.

**hERG:** Ligand A (0.402) has a slightly better hERG profile than Ligand B (0.934), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (90.39) has a higher microsomal clearance than Ligand A (54.083), meaning Ligand A is more metabolically stable. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (76.45) has a better in vitro half-life than Ligand B (43.289), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.168 and 0.315).

**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 has a better logP, slightly better affinity, and significantly lower DILI risk. However, Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better hERG profile. The DILI risk associated with Ligand A is a significant concern, but its metabolic stability is a strong positive. Given the importance of metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, Ligand A is the more promising candidate, *provided* the DILI risk can be mitigated through structural modifications.

Output:
0
2025-04-17 15:31:51,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 382.913 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is better than Ligand B (69.64) as it is closer to the optimal threshold of <=140 for oral absorption.

**logP:** Both ligands (1.958 and 2.673) are 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=4) as it has fewer H-bond donors/acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.748 and 0.841), indicating good drug-like properties.

**DILI:** Ligand A (16.402) has a significantly lower DILI risk than Ligand B (32.726). This is a major advantage.

**BBB:** Both ligands have similar BBB penetration (60.45 and 64.87), which isn't a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-4.716) has a worse Caco-2 permeability than Ligand B (-5.156).

**Aqueous Solubility:** Ligand A (-2.999) has a better aqueous solubility than Ligand B (-3.577).

**hERG Inhibition:** Ligand A (0.284) has a lower hERG inhibition liability than Ligand B (0.512), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (33.833) has a better microsomal clearance than Ligand B (8.915), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (17.189) has a better in vitro half-life than Ligand B (-11.896).

**P-gp Efflux:** Ligand A (0.075) has a lower P-gp efflux liability than Ligand B (0.32).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.8 kcal/mol). The difference is negligible.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG inhibition, lower P-gp efflux, and better aqueous solubility. While Ligand B has slightly better Caco-2 permeability, the other advantages of Ligand A outweigh this minor difference. The binding affinities are essentially the same.

Output:
0
2025-04-17 15:31:51,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.358 and 342.374 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (88) is slightly higher than Ligand B (75.19). Both are below the 140 threshold for good absorption, and acceptable for a non-CNS target like SRC.

**logP:** Both ligands (2.427 and 2.039) fall 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 (0.745 and 0.926), indicating good drug-like properties.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (58.744). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.9) has a higher BBB percentile than Ligand A (66.576), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.161) has worse Caco-2 permeability than Ligand B (-4.622). While both are negative, a less negative value is preferable.

**Aqueous Solubility:** Ligand A (-3.591) has worse solubility than Ligand B (-2.693). Solubility is important for bioavailability, making Ligand B preferable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.519 and 0.365), which is good.

**Microsomal Clearance:** Ligand B (-1.264) has significantly *lower* (better) microsomal clearance than Ligand A (62.158). This indicates better metabolic stability for Ligand B, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-21.44) has a much longer in vitro half-life than Ligand A (-15.735). This is another strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.214 and 0.051).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.9 kcal/mol). Ligand B is slightly better (-8.9 kcal/mol), but the difference is relatively small.

**Overall:**

Ligand B is clearly superior. While both have good potency and drug-like properties, Ligand B demonstrates significantly better ADME characteristics: lower DILI risk, better solubility, much lower microsomal clearance (better metabolic stability), and a longer half-life. These factors are crucial for enzyme inhibitors. The slight advantage in binding affinity for Ligand B further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 15:31:51,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 336.435 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.46) is better than Ligand B (40.62), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.115) is within the optimal range (1-3), while Ligand B (3.185) is at the higher end but still acceptable.

**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.

**QED:** Both ligands have good QED scores (0.643 and 0.76), indicating good drug-likeness.

**DILI:** Ligand A (16.906) has a much lower DILI risk than Ligand B (48.623). This is a significant advantage.

**BBB:** Ligand A (73.517) and Ligand B (91.353) both have high BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.018) has a negative Caco-2 value, which is concerning. Ligand B (-4.587) is also negative, but slightly less so. Both suggest poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.65) has slightly better solubility than Ligand B (-4.13).

**hERG Inhibition:** Ligand A (0.172) has a much lower hERG risk than Ligand B (0.894). This is a critical advantage.

**Microsomal Clearance:** Ligand A (26.689) has significantly lower microsomal clearance than Ligand B (105.441), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.375) has a shorter half-life than Ligand B (21.706), but both are reasonable.

**P-gp Efflux:** Ligand A (0.052) has much lower P-gp efflux than Ligand B (0.808), suggesting better bioavailability.

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a substantially better binding affinity. However, it has significantly higher DILI risk, hERG inhibition, microsomal clearance, and P-gp efflux. Ligand A has better ADME properties across the board (DILI, hERG, clearance, efflux, solubility), but weaker binding. Given the importance of potency for kinase inhibitors, the 1.7 kcal/mol difference in binding affinity is substantial. While the ADME profile of Ligand B is concerning, it is not prohibitive, and optimization could potentially address these issues. The stronger binding of Ligand B makes it a more promising starting point for further development.

Output:
1
2025-04-17 15:31:51,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.411 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.94) is better than Ligand B (64.09), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (3.325) is good, while Ligand B (1.023) is on the lower side, potentially impacting permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5, and Ligand B has 4, both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.748 and 0.753), indicating good drug-likeness.

**DILI:** Ligand A (84.374) has a significantly higher DILI risk than Ligand B (8.802). This is a major concern for Ligand A.

**BBB:** Ligand B (54.246) shows better BBB penetration than Ligand A (32.571), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.173) has poor Caco-2 permeability, while Ligand B (-4.697) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand B (-0.563) has better aqueous solubility than Ligand A (-3.827).

**hERG:** Ligand A (0.052) has a very low hERG risk, which is excellent. Ligand B (0.147) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand B (4.797) has significantly lower microsomal clearance than Ligand A (23.049), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.932) has a much longer in vitro half-life than Ligand A (-27.521), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.113 and 0.04 respectively).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial difference, as a >1.5 kcal/mol advantage often outweighs other drawbacks.

**Conclusion:**

Despite Ligand A's excellent hERG profile, Ligand B is the superior candidate. The significantly stronger binding affinity (-8.6 vs 0.0 kcal/mol) of Ligand B is paramount for an enzyme inhibitor. Furthermore, Ligand B exhibits much better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and improved solubility. While Ligand A has a better TPSA and hERG, the other factors heavily favor Ligand B. The poor permeability of both is a concern, but can be addressed in later optimization stages.

Output:
1
2025-04-17 15:31:51,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.378 and 353.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.69) is better than Ligand B (90.98), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have acceptable logP values (1.063 and 1.998), falling within the 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.86) has a slightly better QED score than Ligand B (0.784), indicating better overall drug-likeness.

**DILI:** Ligand B (43.234) has a significantly lower DILI risk than Ligand A (60.217). This is a major advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (85.964) is higher than Ligand A (67.623).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.17) is slightly better than Ligand B (-4.925), but both are problematic.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-3.214) is slightly better than Ligand A (-2.618), but both are problematic.

**hERG Inhibition:** Ligand A (0.445) has a lower hERG inhibition liability than Ligand B (0.714), which is preferable.

**Microsomal Clearance:** Ligand A (14.046) has a higher microsomal clearance than Ligand B (9.376), suggesting lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand B (-13.253) has a longer in vitro half-life than Ligand A (-17.387), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.009) has lower P-gp efflux than Ligand B (0.192), which is preferable.

**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 for Ligand A. The 2 kcal/mol difference is significant enough to potentially offset some ADME liabilities.

**Overall Assessment:**

While Ligand B has better ADME properties (lower DILI, better metabolic stability, slightly better solubility), Ligand A's significantly stronger binding affinity (-8.2 vs -6.2 kcal/mol) is a critical factor for an enzyme target like SRC kinase. The potency advantage is likely to outweigh the ADME concerns, especially considering optimization can address those issues. The hERG risk for Ligand A is also lower.

Output:
0
2025-04-17 15:31:51,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.5 and 369.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (115.98).  A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit and may have absorption issues.

**logP:** Both ligands have good logP values (1.73 and 1.14), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=4, HBA=5) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.843) has a much higher QED score than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Ligand A (3.99) has a significantly lower DILI risk than Ligand B (65.57), a major advantage.

**BBB:**  BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (82.16) is better than Ligand B (65.84).

**Caco-2 Permeability:** Ligand A (-4.898) is better than Ligand B (-5.469), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.565) is better than Ligand B (-3.655), which is crucial for formulation and bioavailability.

**hERG:** Both ligands have similar hERG values (0.526 and 0.573), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (7.562) has a lower microsomal clearance than Ligand B (34.89), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.806) has a better in vitro half-life than Ligand B (-17.078).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.025 and 0.061), which is good.

**Binding Affinity:** Ligand B (-9.5 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 boasts a much stronger binding affinity, the ADME properties of Ligand A are vastly superior. Ligand B has a high DILI risk, poor solubility, and higher clearance. The significantly better ADME profile of Ligand A, coupled with acceptable (though not stellar) binding affinity, makes it the more promising drug candidate. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand A, whereas fixing the ADME issues of Ligand B would likely require more extensive structural changes.

Output:
0
2025-04-17 15:31:51,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.427 and 356.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.49) is better than Ligand B (70.08), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.496 and 2.045), 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.

**QED:** Both ligands have acceptable QED scores (0.846 and 0.758), indicating good drug-likeness.

**DILI:** Ligand A (34.703) has a significantly lower DILI risk than Ligand B (24.351), which is a major advantage.

**BBB:** Ligand A (68.088) has a better BBB penetration score than Ligand B (44.552), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.336) has a worse Caco-2 permeability than Ligand B (-4.311), but both are negative values, suggesting limited permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.449 and -1.592). This could be a formulation challenge, but is not a dealbreaker if other properties are favorable.

**hERG Inhibition:** Ligand A (0.673) has a slightly better hERG profile than Ligand B (0.203), suggesting lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-42.889) has a significantly *lower* (better) microsomal clearance than Ligand B (38.772), indicating greater metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (38.069) has a much longer in vitro half-life than Ligand B (5.504), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.04) has a lower P-gp efflux liability than Ligand B (0.098), which is favorable for oral bioavailability.

**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 noticeable, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better P-gp efflux. These factors are critical for an enzyme inhibitor, outweighing the small difference in binding affinity. Solubility is a concern for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 15:31:51,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (370.519 Da) is also good.

**TPSA:** Ligand A (74.57) is better than Ligand B (93.09), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have good logP values (A: 1.944, B: 1.837), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand A has 4 HBA, while Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (A: 0.753, B: 0.649), indicating drug-like properties.

**DILI:** Ligand A (24.467) has a significantly lower DILI risk than Ligand B (34.161), which is a major advantage. Both are below the 40 threshold, but A is much safer.

**BBB:** Both have low BBB penetration (A: 47.732, B: 42.924). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.737) has a better (less negative) Caco-2 value than Ligand B (-5.291), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.715) has better solubility than Ligand B (-1.978).

**hERG:** Ligand A (0.343) has a lower hERG risk than Ligand B (0.522), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (23.067) has a lower Cl_mic than Ligand B (22.317), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.414) has a better half-life than Ligand B (-39.138). This is a significant advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.164) has lower P-gp efflux than Ligand B (0.048), which is desirable.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.4), a difference of 0.5 kcal/mol. While affinity is paramount, the other ADME properties of Ligand A are significantly better.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates a superior overall profile, particularly regarding safety (DILI, hERG) and pharmacokinetic properties (Cl_mic, t1/2, solubility, Caco-2). The 0.5 kcal/mol difference in binding affinity is unlikely to outweigh the substantial advantages of Ligand A in terms of ADME-Tox properties for an enzyme target like SRC kinase.

Output:
0
2025-04-17 15:31:51,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (65.9) is better than Ligand B (100.78). Lower TPSA generally favors oral absorption.

**logP:** Ligand A (2.219) is optimal, while Ligand B (0.91) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.903) has a significantly better QED score than Ligand B (0.697), indicating a more drug-like profile.

**DILI:** Ligand B (45.056) has a lower DILI risk than Ligand A (64.986), which is a positive attribute.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.217) has a higher BBB percentile than Ligand A (49.748), but this is not a major factor in this case.

**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 for both.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, we'll assume this indicates poor solubility for both.

**hERG:** Both ligands have low hERG risk (0.222 and 0.258 respectively), which is excellent.

**Microsomal Clearance:** Ligand B (-2.024) has a *negative* microsomal clearance, which is not physically possible and indicates a data issue. Ligand A (1.049) has a reasonable clearance. This is a significant advantage for Ligand A, as lower clearance indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (20.224 hours) has a much longer half-life than Ligand B (-19.53 hours), which is another significant advantage. A negative half-life is not possible, further highlighting a data issue with Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.096), which is good.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference of 2.8 kcal/mol is considerable.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the most critical factor for an enzyme inhibitor is binding affinity. Ligand B's significantly stronger binding affinity (-9.4 kcal/mol vs -6.6 kcal/mol) is a major advantage. However, the negative values for clearance and half-life are concerning and likely indicate data errors. Assuming these are errors, and focusing on the remaining data, the superior affinity of Ligand B is likely to be the deciding factor.

Output:
1
2025-04-17 15:31:51,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (478.181 Da) is at the higher end, while Ligand B (349.475 Da) is comfortably within the range.

**TPSA:** Both ligands have TPSA values (76.66 and 78.51) below the 140 threshold for good oral absorption, which is positive.

**logP:** Ligand A (3.022) is optimal. Ligand B (1.302) is slightly below the optimal range, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2) and HBA (4 and 3) counts, satisfying the criteria of <=5 and <=10, respectively.

**QED:** Both ligands have good QED scores (0.592 and 0.759), indicating drug-likeness.

**DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (10.392), but both are below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (86.894) has a higher percentile than Ligand B (70.997).

**Caco-2 Permeability:** Ligand A (-4.696) shows poor permeability, while Ligand B (-5.062) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.875) has better solubility than Ligand B (-1.961). Solubility is important for bioavailability.

**hERG:** Ligand A (0.606) has a lower hERG risk than Ligand B (0.138), which is a significant advantage.

**Microsomal Clearance:** Ligand A (78.59) has higher clearance than Ligand B (-6.955), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (16.663) has a shorter half-life than Ligand B (-14.742), which is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.177) has lower P-gp efflux than Ligand B (0.013), which is positive.

**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, and can outweigh some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's slightly higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2), its *significantly* stronger binding affinity (-8.4 vs 0.0 kcal/mol) is the most important factor for an enzyme inhibitor. The potency advantage is substantial and likely to overcome the ADME liabilities, especially considering the ADME properties are not severely problematic. Ligand B's poor affinity makes it a less attractive candidate.

Output:
1
2025-04-17 15:31:51,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (110.16), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.793) is optimal (1-3), while Ligand B (0.41) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the 5 threshold.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both within the acceptable range of <=10.

**QED:** Ligand A (0.706) has a better QED score than Ligand B (0.484), indicating a more drug-like profile.

**DILI:** Ligand B (72.819) has a higher DILI risk than Ligand A (49.477), which is undesirable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (55.293) is higher than Ligand A (38.813).

**Caco-2 Permeability:** Ligand A (-4.904) and Ligand B (-5.288) both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute difference.

**Aqueous Solubility:** Ligand A (-4.116) and Ligand B (-2.816) both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.326) has a lower hERG risk than Ligand B (0.235), which is preferable.

**Microsomal Clearance:** Ligand B (40.962) has a significantly lower Cl_mic than Ligand A (80.35), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-31.51) has a longer in vitro half-life than Ligand A (-23.595), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux liability than Ligand B (0.128), which is slightly favorable.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-6.1), a difference of 1.2 kcal/mol. This is a substantial advantage and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better QED, lower DILI risk, and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-7.3 vs -6.1 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme inhibitor. The slightly lower logP and higher DILI risk of Ligand B are less concerning given the potency advantage.

Output:
1
2025-04-17 15:31:51,697 - INFO - Batch 387 complete. Total preferences: 6192
2025-04-17 15:31:51,697 - INFO - Processing batch 388/512...
2025-04-17 15:32:29,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.431 and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is slightly higher than Ligand B (67.87), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.187 and 1.358), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the criteria.

**QED:** Ligand B (0.696) has a better QED score than Ligand A (0.457), indicating a more drug-like profile.

**DILI:** Ligand B (29.779) has a significantly lower DILI risk than Ligand A (45.483), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (91.663) has a higher BBB percentile than Ligand A (68.36), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.861 and -4.684), 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 (-1.704 and -1.552), indicating poor aqueous solubility. This is a concern and would require formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.211 and 0.309), which is excellent.

**Microsomal Clearance:** Ligand A (11.247 mL/min/kg) has a lower microsomal clearance than Ligand B (17.971 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (3.486 hours) has a longer in vitro half-life than Ligand A (-3.876 hours). The negative value for Ligand A is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032 and 0.036).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While both are good, the 0.7 kcal/mol difference is significant.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have solubility concerns, Ligand B demonstrates a significantly lower DILI risk, a longer half-life, and a slightly better binding affinity. The improved QED score also supports its drug-like properties. The better metabolic stability of Ligand A is offset by its very short predicted half-life.

Output:
1
2025-04-17 15:32:29,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.9) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (76.66) is well within the acceptable range.

**logP:** Ligand A (0.764) is a bit low, potentially hindering permeation. Ligand B (1.192) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also good.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**QED:** Ligand B (0.671) has a significantly better QED score than Ligand A (0.306), indicating a more drug-like profile.

**DILI:** Both ligands have the same DILI risk (39.55), which is good (low risk).

**BBB:** Ligand B (69.446) has a better BBB penetration percentile than Ligand A (39.55), although BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.657) has poor Caco-2 permeability. Ligand B (-5.302) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.413) has slightly better solubility than Ligand B (-2.667).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.174 and 0.281, respectively).

**Microsomal Clearance:** Ligand A (-5.505) has significantly lower (better) microsomal clearance than Ligand B (31.015), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.026 hours) has a much longer half-life than Ligand B (11.124 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.009 and 0.112, respectively).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), a 0.9 kcal/mol advantage.

**Overall Assessment:**

Ligand B has a better QED, logP, BBB, and binding affinity. However, Ligand A has a significantly better microsomal clearance and in vitro half-life, and slightly better solubility. The difference in binding affinity (0.9 kcal/mol) is notable, but the improved metabolic stability and half-life of Ligand A are crucial for an enzyme target like SRC kinase. The poor Caco-2 permeability of both is a concern, but can potentially be addressed with formulation strategies. Given the enzyme-specific priorities, the metabolic stability and longer half-life of Ligand A are more valuable than the slightly improved binding affinity of Ligand B.

Output:
0
2025-04-17 15:32:29,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.861 and 383.857 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.04) is significantly better than Ligand B (93.46).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (2.106 and 2.474), falling within the 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 reasonable QED scores (0.885 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A (14.618) has a much lower DILI risk than Ligand B (70.919). This is a significant advantage for Ligand A.

**BBB:** Ligand A (87.941) has a better BBB penetration percentile than Ligand B (60.411), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-4.911) is slightly better than Ligand B (-5.059), indicating potentially better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.262) is better than Ligand B (-3.91), indicating better solubility. This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.836) has a lower hERG inhibition risk than Ligand B (0.318). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (-4.633) has a *much* lower microsomal clearance than Ligand B (15.334). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (77.105) has a significantly longer in vitro half-life than Ligand A (16.309). This is a positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.056) has a lower P-gp efflux liability than Ligand B (0.336), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in key ADME properties (DILI, hERG, Cl_mic, Solubility, P-gp efflux) while maintaining comparable potency to Ligand B. The longer half-life of Ligand B is a benefit, but the substantial improvements in safety and metabolic stability with Ligand A outweigh this advantage.

Output:
0
2025-04-17 15:32:29,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.865 and 363.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.31 and 79.82) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.068) is optimal, while Ligand B (1.587) is slightly lower, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 7 HBA, which are within acceptable limits.

**QED:** Both ligands have high QED scores (0.842 and 0.869), indicating good drug-likeness.

**DILI:** Ligand A (43.234) has a lower DILI risk than Ligand B (84.529). This is a significant advantage.

**BBB:** Ligand A (85.459) has better BBB penetration than Ligand B (64.211), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.883 and -4.724). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are very close, so the difference is likely not significant.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.421 and -2.984), indicating poor solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.784) has a slightly higher hERG risk than Ligand B (0.473), but both are relatively low.

**Microsomal Clearance:** Ligand A (44.075) has lower microsomal clearance than Ligand B (46.188), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.144) has a significantly longer in vitro half-life than Ligand B (-18.888). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.081 and 0.031).

**Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have similar potency and permeability issues (negative Caco-2 and solubility), Ligand A exhibits a significantly better safety profile (lower DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better BBB penetration. These advantages outweigh the slightly higher hERG risk.

Output:
1
2025-04-17 15:32:29,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 367.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.7) is significantly better than Ligand B (132.37), being well below the 140 threshold for good absorption. Ligand B is approaching the upper limit.

**logP:** Ligand A (-0.337) is slightly low, potentially hindering permeation, while Ligand B (1.053) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 8 HBA) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Ligand A (0.808) has a significantly better drug-likeness score than Ligand B (0.666).

**DILI:** Both ligands have relatively high DILI risk (Ligand A: 39.977, Ligand B: 65.917), but Ligand A is considerably lower.

**BBB:** Both have moderate BBB penetration (Ligand A: 67.623, Ligand B: 60.876), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.08 and -5.465). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.451 and -3.195). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.341 and 0.339). This is excellent.

**Microsomal Clearance:** Ligand A (26.605) has a higher microsomal clearance than Ligand B (16.366), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-7.836) has a significantly longer predicted half-life than Ligand A (7.524). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.064).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most critical factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having a better QED, lower DILI risk, and better TPSA, the significantly stronger binding affinity of Ligand B (-8.4 vs -0.0 kcal/mol) and its longer half-life are decisive. While both have poor solubility and Caco-2 permeability, the potency advantage of Ligand B is substantial enough to warrant further optimization efforts to address these ADME issues. The lower metabolic clearance of Ligand B is also a positive.

Output:
1
2025-04-17 15:32:29,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.362 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (91.64) is higher but still within a reasonable range.

**logP:** Ligand A (3.26) is optimal. Ligand B (0.89) is a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 5 HBA) both satisfy the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED scores (0.7 and 0.775), indicating good drug-likeness.

**DILI:** Ligand A (33.812) has a much lower DILI risk than Ligand B (55.758), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (86.584) has a higher BBB percentile than Ligand B (32.92).

**Caco-2 Permeability:** Ligand A (-4.603) has a lower Caco-2 permeability than Ligand B (-4.858), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.293) has slightly better solubility than Ligand B (-2.046).

**hERG:** Ligand A (0.649) has a lower hERG risk than Ligand B (0.118), which is a critical advantage.

**Microsomal Clearance:** Ligand A (24.523) has a higher microsomal clearance than Ligand B (-5.767), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-15.846) has a shorter half-life than Ligand B (-2.277), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux than Ligand B (0.037), which is a slight advantage.

**Binding Affinity:** Ligand B (-6.9 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 the ADME concerns.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a lower hERG risk. These factors are crucial for developing a viable drug candidate. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization.

Output:
1
2025-04-17 15:32:29,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.877 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.83) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Both ligands have good logP values (2.851 and 3.423), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits. Ligand B is slightly preferable due to fewer potential off-target interactions.

**QED:** Both ligands have similar QED values (0.748 and 0.725), indicating good drug-likeness.

**DILI:** Ligand A (41.179) has a higher DILI risk than Ligand B (14.036). This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration, but Ligand B (88.717) is considerably better than Ligand A (61.923). While SRC isn't a CNS target, better BBB penetration generally suggests better overall permeability.

**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, also unusual. Again, values are similar.

**hERG:** Both ligands have low hERG inhibition risk (0.656 and 0.558), which is good.

**Microsomal Clearance:** Ligand A (5.827) has a lower microsomal clearance than Ligand B (84.974), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (86.649) has a much longer in vitro half-life than Ligand B (-7.445). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.148) has lower P-gp efflux liability than Ligand B (0.4), which is favorable.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a critical advantage for Ligand B, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better ADME properties (lower DILI, better BBB, lower P-gp efflux). While Ligand A has better metabolic stability (lower Cl_mic) and half-life, the substantial difference in binding affinity makes Ligand B the more promising candidate. The negative solubility and Caco-2 values are concerning for both, but the potency advantage of Ligand B is likely to be more impactful in early optimization.

Output:
1
2025-04-17 15:32:29,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.447 Da) is slightly better being closer to the middle of the range.

**TPSA:** Ligand A (79.31) is better than Ligand B (96.89). Both are below 140, suggesting reasonable absorption, but lower TPSA is generally preferred.

**logP:** Ligand A (1.097) is within the optimal range (1-3), while Ligand B (-0.227) is slightly below 1. This could potentially hinder permeation for Ligand B.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBDs are generally preferred for better permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (6). Both are within the acceptable limit of 10.

**QED:** Ligand A (0.8) is significantly better than Ligand B (0.571), indicating a more drug-like profile.

**DILI:** Ligand A (22.218) has a much lower DILI risk than Ligand B (32.338). This is a significant advantage for Ligand A.

**BBB:** Ligand A (59.364) is better than Ligand B (41.218), although BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.88) is better than Ligand B (-5.621), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.317) is better than Ligand B (-2.366). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.299) has a much lower hERG inhibition liability than Ligand B (0.141). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (-0.149) has a significantly lower (better) microsomal clearance than Ligand B (18.841). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-3.847) has a better in vitro half-life than Ligand B (28.475).

**P-gp Efflux:** Ligand A (0.084) has a lower P-gp efflux liability than Ligand B (0.01).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). The difference is 1.7 kcal/mol, which is significant enough to outweigh some minor ADME drawbacks.

**Overall:**

Ligand A consistently outperforms Ligand B across most crucial parameters, especially DILI, hERG, metabolic stability (Cl_mic and t1/2), solubility, and QED. While Ligand B has a reasonable binding affinity, the superior ADME profile of Ligand A makes it a much more promising drug candidate. The affinity difference is substantial enough to favor A.

Output:
1
2025-04-17 15:32:29,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 348.495 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.23) is slightly higher than Ligand B (73.39), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.577 and 1.644), 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 6. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED scores (0.667 and 0.661), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (23.032 and 22.8), which is favorable.

**BBB:** Ligand B (79.217) has a significantly higher BBB penetration percentile than Ligand A (41.218). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.143) has a lower Caco-2 permeability than Ligand B (-5.286), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.287) has slightly lower aqueous solubility than Ligand B (-1.376). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.275) shows a lower hERG inhibition liability than Ligand B (0.775), which is a significant advantage.

**Microsomal Clearance:** Ligand B (18.288) has a lower microsomal clearance than Ligand A (28.232), indicating better metabolic stability. This is a key consideration for kinases.

**In vitro Half-Life:** Ligand B (3.047) has a significantly shorter in vitro half-life than Ligand A (10.787). A longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.009) has a much lower P-gp efflux liability than Ligand B (0.029), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.0 kcal/mol). This difference of 2.6 kcal/mol is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand B has better metabolic stability and a significantly stronger binding affinity, Ligand A has a better safety profile (lower hERG) and better half-life. The affinity difference is substantial. Given that SRC is an enzyme, potency and metabolic stability are prioritized. The stronger binding of Ligand B is likely to be the dominant factor, despite its slightly higher hERG and shorter half-life.

Output:
1
2025-04-17 15:32:29,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (71.53), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (1.868 and 2.766), falling within the 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 4 HBA, while Ligand B has 5. Both are acceptable, below the 10 threshold.

**QED:** Both ligands have good QED scores (0.688 and 0.767), indicating drug-like properties.

**DILI:** Ligand A (20.706) has a significantly lower DILI risk than Ligand B (46.801). This is a major advantage for Ligand A.

**BBB:** Ligand A (79.217) has a better BBB penetration score than Ligand B (59.325). While not a primary concern for a kinase inhibitor, it's a slight benefit.

**Caco-2 Permeability:** Ligand A (-4.65) has a worse Caco-2 permeability than Ligand B (-5.079). Both are poor, indicating potential absorption issues.

**Aqueous Solubility:** Ligand A (-1.596) has better aqueous solubility than Ligand B (-2.593). This is a positive attribute for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.401 and 0.461).

**Microsomal Clearance:** Ligand A (37.464) has a lower microsomal clearance than Ligand B (66.195), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (13.217) has a slightly longer half-life than Ligand B (10.986).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.127).

**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, which is not substantial enough to outweigh the ADME advantages of Ligand A.

**Overall:**

Ligand A demonstrates a superior ADME profile, particularly regarding DILI risk and metabolic stability. While Ligand B has slightly better binding affinity, the difference is not large enough to compensate for the significant advantages of Ligand A in terms of safety and pharmacokinetic properties. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (DILI) are crucial.

Output:
0
2025-04-17 15:32:29,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.398 and 361.348 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the preferred <140, while Ligand B (77.54) is well within. This favors Ligand B for potential absorption.

**logP:** Ligand A (2.609) is optimal, while Ligand B (4.185) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues, making Ligand A slightly better here.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable. No clear advantage.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable range of <=10.

**QED:** Ligand B (0.821) has a significantly higher QED score than Ligand A (0.577), indicating a more drug-like profile.

**DILI:** Ligand A (75.456) has a higher DILI risk than Ligand B (55.332). Lower DILI is preferred, giving an advantage to Ligand B.

**BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (88.135) has a higher BBB percentile than Ligand A (43.583), but this is less crucial.

**Caco-2 Permeability:** Ligand A (-5.399) and Ligand B (-4.346) both have negative values, which is unusual. Lower (more negative) values indicate poorer permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.116 and -5.117 respectively). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.435 and 0.465 respectively), which is good.

**Microsomal Clearance:** Ligand B (1.981) has significantly lower microsomal clearance than Ligand A (34.802), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-3.099) has a longer in vitro half-life than Ligand A (-7.14), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.149 and 0.337 respectively).

**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 concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility, Ligand B excels in key areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), a higher QED score, lower DILI risk, and a substantially stronger binding affinity. The slightly higher logP is a minor concern compared to these advantages.

Output:
1
2025-04-17 15:32:29,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (345.443 and 372.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.83) is better than Ligand B (87.66), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Both ligands (1.197 and 1.483) are within the optimal 1-3 range.

**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 5. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.77) has a better QED score than Ligand B (0.506), indicating better overall drug-likeness.

**7. DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (19.038), which is a major advantage.

**8. BBB:** This is less critical for an oncology target unless CNS penetration is specifically desired. Ligand A (67.39) is better than Ligand B (51.26).

**9. Caco-2:** Both have negative values, indicating poor permeability. Ligand A (-5.088) is slightly better than Ligand B (-5.045).

**10. Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.549) is slightly better than Ligand B (-2.858).

**11. hERG:** Ligand A (0.511) has a lower hERG risk than Ligand B (0.145), which is favorable.

**12. Cl_mic:** Ligand A (-17.78) has *much* lower (better) microsomal clearance than Ligand B (46.961), indicating significantly improved metabolic stability. This is a critical factor for kinase inhibitors.

**13. t1/2:** Ligand A (13.973) has a longer in vitro half-life than Ligand B (-1.2), which is desirable.

**14. Pgp:** Ligand A (0.041) has a lower Pgp efflux liability than Ligand B (0.098), which is favorable.

**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 difference is notable.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It demonstrates better drug-likeness (QED), significantly lower DILI risk, much improved metabolic stability (Cl_mic and t1/2), lower hERG risk, lower Pgp efflux, and slightly better binding affinity. While both have issues with Caco-2 and solubility, the ADME/Tox profile of Ligand A is substantially more promising, especially the metabolic stability, which is crucial for kinase inhibitors.

Output:
0
2025-04-17 15:32:29,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.415 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (96.89 and 91.76) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.7) is optimal, while Ligand B (0.352) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the limit of 5.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.679 and 0.726), indicating drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (47.926 and 40.132), below the 60 threshold.

**BBB:** Ligand A (66.576) has a better BBB score than Ligand B (32.881), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.459) has a worse Caco-2 permeability than Ligand B (-5.063), but both are quite poor.

**Aqueous Solubility:** Ligand A (-2.915) has a worse aqueous solubility than Ligand B (-1.296), which is a concern.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.212 and 0.138), which is good.

**Microsomal Clearance:** Ligand B (-11.23) has significantly lower microsomal clearance than Ligand A (50.318), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (16.061) has a longer in vitro half-life than Ligand A (-19.346), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.089 and 0.009).

**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.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly its much better metabolic stability (lower Cl_mic and longer t1/2) and better solubility. Given that SRC is an enzyme, metabolic stability is a crucial factor. The 1.4 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, while improving metabolic stability is often more challenging. The lower logP of Ligand B is a slight concern, but not a dealbreaker given the other advantages.

Output:
1
2025-04-17 15:32:29,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.367 Da) is slightly lower, which can be favorable for permeability. Ligand B (386.543 Da) is also good.

**TPSA:** Ligand A (75.99) is better than Ligand B (101.05). TPSA < 140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (A: 1.66, B: 1.482), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=7) and Ligand B (HBD=2, HBA=7) both have acceptable H-bond donor and acceptor counts.

**QED:** Both ligands have good QED scores (A: 0.676, B: 0.795), indicating good drug-like properties.

**DILI:** Ligand A (72.276) has a slightly higher DILI risk than Ligand B (66.382), but both are still reasonably low.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (70.803) is slightly better.

**Caco-2 Permeability:** Ligand A (-4.145) has a worse Caco-2 permeability than Ligand B (-5.635). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.841 and -2.769 respectively). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.24, B: 0.256). This is excellent.

**Microsomal Clearance:** Ligand B (3.16 mL/min/kg) has significantly lower microsomal clearance than Ligand A (73.241 mL/min/kg). This suggests much better metabolic stability for Ligand B, a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand B (25.948 hours) has a much longer in vitro half-life than Ligand A (-27.5 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.275, B: 0.118). Ligand B is slightly better.

**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.

**Conclusion:**

While Ligand A boasts a better binding affinity, Ligand B demonstrates superior ADME properties, particularly regarding metabolic stability (lower Cl_mic) and half-life. The significantly better metabolic stability and half-life of Ligand B outweigh the affinity difference, especially for an enzyme target where maintaining therapeutic concentrations is critical. The solubility is a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 15:32:29,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.901 Da) is slightly higher than Ligand B (347.503 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (80.75) is slightly higher than Ligand B (73.2), but both are good.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.936, Ligand B: 3.273), indicating good lipophilicity for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 3 HBA) both fall within acceptable ranges.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.723, Ligand B: 0.685), indicating good drug-like properties.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (19.349). This is a significant concern.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 56.34, Ligand B: 58.24). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.376 and -4.651), which is unusual and suggests poor permeability. This is a red flag for both compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.964 and -3.073), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Ligand A (0.123) has a lower hERG risk than Ligand B (0.619), which is favorable.

**Microsomal Clearance:** Ligand B (42.313 mL/min/kg) has a lower microsomal clearance than Ligand A (67.392 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (76.498 hours) has a significantly longer in vitro half-life than Ligand B (-0.567 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.232, Ligand B: 0.136).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -7.1 kcal/mol, Ligand B: -7.0 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. The significantly longer half-life (76.498 hours vs -0.567 hours) is a huge advantage, outweighing the higher DILI risk. The lower hERG risk is also favorable. The poor solubility and permeability are concerning for both, but can potentially be addressed with formulation strategies. Ligand B's extremely short half-life is a major drawback that is unlikely to be overcome.

Output:
1
2025-04-17 15:32:29,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.41 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is slightly higher than Ligand B (43.86). Both are acceptable, but Ligand B is better, potentially indicating improved permeability.

**logP:** Ligand A (4.626) is higher than Ligand B (2.275). Ligand A is pushing the upper limit, potentially leading to solubility issues and off-target effects. Ligand B is within the optimal range.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both good, well below the threshold of 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both good, well below the threshold of 10.

**QED:** Both ligands have similar QED values (0.741 and 0.717), indicating good drug-likeness.

**DILI:** Ligand A (98.682) has a very high DILI risk, a significant concern. Ligand B (5.777) has a very low DILI risk, a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (81) is better than Ligand A (71.384). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the measurement or the compounds themselves. However, the values are similar (-4.38 and -4.59) and don't significantly differentiate the two.

**Aqueous Solubility:** Ligand A (-5.575) has very poor aqueous solubility, consistent with its higher logP. Ligand B (-1.752) is better, but still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.5 and 0.582), which is good.

**Microsomal Clearance:** Ligand A (96.234) has very high microsomal clearance, indicating poor metabolic stability. Ligand B (23.524) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.791 hours) has a significantly longer half-life than Ligand A (12.08 hours), a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.473 and 0.052), which is good.

**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 not substantial enough to overcome its ADME liabilities.

**Conclusion:**

Ligand B is the far superior candidate. While Ligand A has slightly better binding affinity, its extremely high DILI risk, poor solubility, and high metabolic clearance are major drawbacks. Ligand B exhibits a much more favorable ADME profile, with low DILI risk, better solubility, improved metabolic stability (lower Cl_mic and longer t1/2), and acceptable permeability. These factors are critical for kinase inhibitors.

Output:
1
2025-04-17 15:32:29,476 - INFO - Batch 388 complete. Total preferences: 6208
2025-04-17 15:32:29,476 - INFO - Processing batch 389/512...
2025-04-17 15:33:18,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 361.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.83) is significantly better than Ligand B (93.09), being well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.197 and 1.677), 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.77 and 0.867), indicating good drug-likeness.

**DILI:** Ligand A (13.843 percentile) has a much lower DILI risk than Ligand B (38.736 percentile). This is a significant advantage.

**BBB:** Ligand A (67.39 percentile) has better BBB penetration than Ligand B (45.366 percentile), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.088 and -5.129), which is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.549 and -3.601), indicating poor aqueous solubility. Ligand B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.511 and 0.328), which is good.

**Microsomal Clearance:** Ligand A (-17.78 mL/min/kg) has significantly lower microsomal clearance than Ligand B (1.525 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (13.973 hours) has a longer half-life than Ligand B (-13.508 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.027).

**Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent.

**Conclusion:**

Ligand A is superior to Ligand B. While both have excellent binding affinity, Ligand A demonstrates significantly better DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and slightly better TPSA and BBB. The solubility is poor for both, but Ligand A is less poor. The similar Caco-2 permeability is a concern for both, but the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 15:33:18,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.455 and 347.342 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.5) is slightly above the preferred <140, but acceptable. Ligand B (73.86) is well within the acceptable range.

**logP:** Ligand A (1.777) is optimal. Ligand B (3.178) is also within the optimal range, but closer to the upper limit.

**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 (6) are both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.764 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A (64.288) has a lower DILI risk than Ligand B (89.686). This is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (77.317 and 64.521), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.972) has slightly better Caco-2 permeability than Ligand B (-4.361), although both are negative values suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-3.959) has better aqueous solubility than Ligand B (-5.64). This is a positive attribute for bioavailability.

**hERG Inhibition:** Ligand A (0.793) has a slightly higher hERG risk than Ligand B (0.651), but both are relatively low.

**Microsomal Clearance:** Ligand A (43.634) has significantly lower microsomal clearance than Ligand B (99.72). This indicates better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (6.639) has a shorter half-life than Ligand B (-18.235). However, the negative value for ligand B is concerning and likely an error or outlier.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.127 and 0.171).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -7.8 kcal/mol), both of which are excellent. The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have good potency, Ligand A demonstrates superior metabolic stability (lower Cl_mic), better solubility, and a lower DILI risk. These factors are particularly important for kinase inhibitors. The slightly better Caco-2 permeability and solubility further support this conclusion.

Output:
0
2025-04-17 15:33:18,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.383 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.27) is better than Ligand B (64.09) as it is closer to the 140 threshold.

**logP:** Ligand A (-0.938) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (0.276) is also on the lower side but better than A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 8 HBA) is slightly higher in HBA than Ligand B (1 HBD, 4 HBA), but both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.637 and 0.697, respectively), indicating good drug-like properties.

**DILI:** Ligand A (63.397) has a significantly higher DILI risk than Ligand B (16.402). This is a major concern for Ligand A.

**BBB:** Ligand A (54.246) and Ligand B (80.419). BBB is not a primary concern for an oncology target, but higher is generally preferable.

**Caco-2 Permeability:** Ligand A (-5.534) and Ligand B (-4.69). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.663) and Ligand B (-0.963). Both are poor, but B is slightly worse.

**hERG:** Ligand A (0.037) has a very low hERG risk, which is excellent. Ligand B (0.566) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-11.02) has a significantly *lower* (better) microsomal clearance than Ligand B (14.118), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.796) has a much longer half-life than Ligand B (6.344), which is a significant advantage.

**P-gp Efflux:** Ligand A (0) has no P-gp efflux, while Ligand B (0.035) has minimal efflux. Both are good.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.5). While both are good, the 1.5 kcal/mol difference is not huge.

**Overall Assessment:**

Ligand A has a better binding affinity, superior metabolic stability (lower Cl_mic, longer t1/2), and negligible P-gp efflux. However, its significantly higher DILI risk and lower Caco-2 permeability are major drawbacks. Ligand B has a lower DILI risk and slightly better logP, but its metabolic stability is much poorer.

Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. While Ligand A's affinity is slightly better, the high DILI risk is a significant concern that would likely halt its development. Ligand B, despite its lower affinity and poorer metabolic stability, presents a much safer starting point for optimization.

Output:
1
2025-04-17 15:33:18,358 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [385.339, 88.6, 1.173, 1, 5, 0.712, 66.615, 75.107, -4.825, -3.115, 0.444, 7.85, -46.929, 0.024, -8.4]
**Ligand B:** [343.515, 44.37, 2.687, 2, 3, 0.8, 11.128, 86.274, -4.939, -2.06, 0.846, 29.45, 20.558, 0.073, -7.5]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (343.515) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.
2. **TPSA:** Ligand A (88.6) is higher than Ligand B (44.37).  Both are below 140, but Ligand B is significantly better for oral absorption.
3. **logP:** Ligand A (1.173) is within the optimal range. Ligand B (2.687) is also good, leaning towards the higher end of optimal.
4. **HBD:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).
5. **HBA:** Ligand A (5) and Ligand B (3) are both acceptable (<=10).
6. **QED:** Both ligands have good QED scores (A: 0.712, B: 0.8), indicating good drug-like properties.
7. **DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (11.128). This is a significant concern for Ligand A.
8. **BBB:** Both have good BBB penetration, but Ligand B (86.274) is better than Ligand A (75.107). While not a primary concern for an oncology target, better BBB penetration can sometimes reduce off-target effects.
9. **Caco-2:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.825) is slightly worse than Ligand B (-4.939).
10. **Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-2.06) is slightly better than Ligand A (-3.115).
11. **hERG:** Ligand A (0.444) has a lower hERG risk than Ligand B (0.846), which is favorable.
12. **Cl_mic:** Ligand A (7.85) has significantly lower microsomal clearance than Ligand B (29.45), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.
13. **t1/2:** Ligand A (-46.929) has a much longer in vitro half-life than Ligand B (20.558), further supporting its better metabolic stability.
14. **Pgp:** Ligand A (0.024) has much lower P-gp efflux liability than Ligand B (0.073), which is favorable for bioavailability.
15. **Binding Affinity:** Ligand A (-8.4) has a significantly stronger binding affinity than Ligand B (-7.5). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme (kinase) target like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in affinity and metabolic stability, while Ligand B has a lower DILI risk and slightly better solubility. The poor Caco-2 and solubility values for both are concerning, but can potentially be addressed through formulation strategies.

**Conclusion:**

Despite the higher DILI risk, Ligand A's significantly superior binding affinity (-8.4 vs -7.5 kcal/mol) and substantially better metabolic stability (lower Cl_mic, longer t1/2) and lower Pgp efflux make it the more promising candidate. The strong binding is likely to be more impactful than the moderate DILI risk, which can be further investigated and potentially mitigated.

Output:
1
2025-04-17 15:33:18,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.471 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (67.43), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.929 and 2.265), 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 H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.849 and 0.862), indicating strong drug-like properties.

**DILI:** Ligand A (6.359) has a significantly lower DILI risk than Ligand B (31.214). This is a major advantage.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (77.549) has a better BBB score than Ligand B (61.846).

**Caco-2 Permeability:** Ligand A (-4.614) has a better Caco-2 permeability than Ligand B (-5.148).

**Aqueous Solubility:** Ligand A (-2.246) has better aqueous solubility than Ligand B (-2.645).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.251 and 0.181).

**Microsomal Clearance:** Ligand B (10.002) has a lower microsomal clearance than Ligand A (13.281), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (38.082) has a significantly longer in vitro half-life than Ligand A (0.236). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.041).

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This difference of 1.5 kcal/mol is significant.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, solubility, and Caco-2 permeability. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2). The 1.5 kcal/mol difference in binding affinity for ligand A is a significant advantage that can often outweigh minor ADME drawbacks, especially considering the substantially lower DILI risk. The longer half-life of Ligand B is attractive, but the higher DILI risk is a major concern. Given the enzyme-specific priorities, the potency and safety profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 15:33:18,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.46 and 362.514 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (21.26) is significantly better than Ligand B (33.2).  A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (4.683 and 4.066), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 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 (0.792 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A (13.339) has a significantly lower DILI risk than Ligand B (16.906). This is a crucial advantage.

**BBB:** Both ligands have high BBB penetration (89.957 and 94.921). While not a primary concern for a non-CNS target like SRC, it doesn't detract from their potential.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.688 and -4.723). This 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 (-4.887 and -4.761). This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.792 and 0.793), which is excellent.

**Microsomal Clearance:** Ligand A (13.068) has a much lower microsomal clearance than Ligand B (56.068). This indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (24.593) has a longer in vitro half-life than Ligand B (18.004), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.265 and 0.672).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -8.1 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Conclusion:**

Ligand A is the more promising candidate. While both have excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The TPSA is also more favorable for Ligand A. The poor solubility and Caco-2 permeability are concerns for both, but the superior ADME profile of Ligand A outweighs these drawbacks.

Output:
0
2025-04-17 15:33:18,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.4 and 340.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.61) is higher than Ligand B (71.34). While both are acceptable, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (-0.904) is quite low, potentially hindering permeability. Ligand B (3.253) 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, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.515) has a better QED score than Ligand A (0.387), indicating a more drug-like profile.

**DILI:** Ligand A (23.614) has a much lower DILI risk than Ligand B (54.517). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (63.862 and 61.729 percentile). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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. Ligand A (-1.809) is slightly better than Ligand B (-3.517).

**hERG Inhibition:** Ligand A (0.163) has a lower hERG risk than Ligand B (0.828). This is a critical advantage for Ligand A, as kinase inhibitors can sometimes have cardiotoxicity issues.

**Microsomal Clearance:** Ligand A (-18.083) has significantly lower (better) microsomal clearance than Ligand B (17.02). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (71.668) has a much longer in vitro half-life than Ligand A (-4.641). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux liability, while Ligand B (0.412) has moderate efflux. This is an advantage for Ligand A.

**Binding Affinity:** Ligand A (-8.2) has a significantly stronger binding affinity than Ligand B (0.0). This is the most important factor. A difference of >7 kcal/mol is highly significant.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, lower DILI risk, lower hERG risk, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. These are all highly desirable properties for a kinase inhibitor. While Ligand A has lower solubility and permeability, the significantly improved binding affinity and safety profile outweigh these drawbacks. Ligand B has better logP, QED, and half-life, but the weak binding affinity is a deal-breaker.

Output:
0
2025-04-17 15:33:18,359 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [347.463, 106.96 ,   3.224,   2.   ,   3.   ,   0.22 ,  19.659,  54.634, -5.04 ,  -2.05 ,   0.313,  15.219,   4.533,   0.066,   0.   ]
**Ligand B:** [350.409,  53.43 ,   3.248,   1.   ,   3.   ,   0.821,  22.683,  91.276, -4.451,  -3.367,   0.56 ,  31.777,  -7.547,   0.394,  -9.3  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (347.463) and B (350.409) are very similar.
2. **TPSA:** A (106.96) is higher than B (53.43). While both are reasonably good, B is significantly better for permeability.
3. **logP:** Both are optimal (around 3.2). A (3.224) and B (3.248) are very similar.
4. **HBD:** A (2) and B (1) are both acceptable. B is slightly better.
5. **HBA:** Both A (3) and B (3) are within the ideal range.
6. **QED:** A (0.22) is quite low, indicating poor drug-likeness. B (0.821) is excellent.
7. **DILI:** A (19.659) is good, while B (22.683) is also good, but slightly higher.
8. **BBB:** A (54.634) is low, B (91.276) is very good. Not a primary concern for a kinase inhibitor, but a bonus for B.
9. **Caco-2:** A (-5.04) is very poor, suggesting poor absorption. B (-4.451) is also poor, but better than A.
10. **Solubility:** A (-2.05) is poor. B (-3.367) is also poor. Both are potential formulation challenges.
11. **hERG:** A (0.313) is low risk. B (0.56) is slightly higher risk but still acceptable.
12. **Cl_mic:** A (15.219) is moderate. B (31.777) is higher, indicating faster metabolism and potentially lower *in vivo* exposure.
13. **t1/2:** A (4.533) is relatively short. B (-7.547) is excellent, suggesting a long half-life.
14. **Pgp:** A (0.066) is low efflux, which is good. B (0.394) is slightly higher, but still reasonable.
15. **Binding Affinity:** A (0) is weak. B (-9.3) is *very* strong. This is a huge difference.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand B has a vastly superior binding affinity (-9.3 kcal/mol vs 0 kcal/mol). This difference is substantial and likely to outweigh many other drawbacks.
*   **Metabolic Stability:** Ligand B has a significantly longer half-life and lower clearance, indicating better metabolic stability.
*   **Solubility:** Both are poor, presenting formulation challenges.
*   **hERG:** Both are acceptable, but A is slightly better.
*   **ADME:** Ligand B has better Caco-2 and BBB penetration, and lower Pgp efflux.

**Conclusion:**

Despite the poor solubility of both compounds, the overwhelmingly stronger binding affinity and improved metabolic stability of **Ligand B** make it the far more promising drug candidate. The difference in affinity is so large that it is likely to compensate for the solubility issues.

Output:
1
2025-04-17 15:33:18,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.419 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.27) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (80.56) is well within the range.

**logP:** Both ligands have good logP values (1.814 and 1.192), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.906) has a significantly higher QED score than Ligand B (0.798), indicating better overall drug-likeness.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (42.924). This is a significant concern.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (70.88) is better than Ligand A (59.636). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.774 and -4.737). This is unusual and suggests poor permeability. Further investigation would be needed to understand the reason for these negative values.

**Aqueous Solubility:** Ligand A (-4.861) has worse solubility than Ligand B (-1.585). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.59) has a higher hERG risk than Ligand B (0.089). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (62.646) has a higher microsomal clearance than Ligand B (20.37). This indicates lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-4.899) has a shorter in vitro half-life than Ligand B (1.019). This further supports the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.184) has lower P-gp efflux than Ligand B (0.045). Lower P-gp efflux is generally favorable.

**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 a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand A having a better QED and lower P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.5 vs -6.9 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, Ligand B demonstrates a substantially lower DILI risk, a lower hERG risk, better solubility, and improved metabolic stability (lower Cl_mic and longer t1/2). While Caco-2 permeability is concerning for both, the overall profile of Ligand B is superior for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 15:33:18,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.343 and 358.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.02) is slightly higher than Ligand B (87.66). Both are below the 140 threshold for good oral absorption, but Ligand B is closer to the desirable <90 for potential CNS penetration (though that's not a primary concern here).

**logP:** Both ligands have good logP values (1.848 and 1.644), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 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 (0.646 and 0.659), indicating good drug-likeness.

**DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (47.15). This is a significant negative for Ligand A.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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 don't necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, these values are on a scale where negative values are possible.

**hERG:** Ligand A (0.22) has a slightly lower hERG risk than Ligand B (0.543), which is preferable.

**Microsomal Clearance:** Ligand B (40.355) has lower microsomal clearance than Ligand A (53.224), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Both have negative half-life values, which is unusual.

**P-gp Efflux:** Both have low P-gp efflux liability (0.184 and 0.195).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.0 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have similar binding affinities and acceptable physicochemical properties, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The slightly lower TPSA and HBD/HBA counts of Ligand B are also favorable. The unusual negative values for Caco-2 and solubility are a concern for both, but the more favorable ADME-Tox profile of Ligand B outweighs this.

Output:
1
2025-04-17 15:33:18,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is well below the 140 threshold for good absorption, and a good value for an enzyme target. Ligand B (93.7) is higher, but still within acceptable limits, though less optimal.

**logP:** Both ligands have logP values (1.343 and 1.663) within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent, minimizing potential off-target interactions. Ligand B (4) is acceptable, but higher.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both good, below the 10 threshold.

**QED:** Ligand A (0.82) has a superior QED score compared to Ligand B (0.624), indicating better overall drug-likeness.

**DILI:** Ligand A (47.77) has a lower DILI risk than Ligand B (32.61), which is preferable.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (85.072) has a higher BBB percentile than Ligand B (68.748).

**Caco-2 Permeability:** Ligand A (-4.423) has a more negative Caco-2 value than Ligand B (-5.244) which is better.

**Aqueous Solubility:** Ligand A (-1.088) has a better solubility than Ligand B (-2.545).

**hERG Inhibition:** Ligand A (0.562) shows a lower hERG risk than Ligand B (0.421), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (3.721) has a significantly lower microsomal clearance than Ligand B (-12.785), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.039) has a shorter half-life than Ligand B (-5.276), which is less desirable.

**P-gp Efflux:** Ligand A (0.055) exhibits lower P-gp efflux than Ligand B (0.007), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). The difference is 1.7 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile across most parameters (QED, DILI, solubility, hERG, metabolic stability, P-gp efflux). While Ligand B has a slightly better binding affinity, the substantial improvements in ADME properties for Ligand A, particularly the lower DILI and significantly better metabolic stability, make it a more promising drug candidate. The better solubility and lower hERG risk further solidify this conclusion.

Output:
0
2025-04-17 15:33:18,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.47 & 358.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (87.66).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Both ligands have acceptable logP values (1.53 & 2.39), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (3 HBD, 4 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both have reasonable QED scores (0.729 & 0.523), indicating drug-like properties, but Ligand A is better.

**DILI:** Both ligands have low DILI risk (13.57 & 12.80), which is good.

**BBB:** Ligand A (87.48) has a significantly higher BBB percentile than Ligand B (64.10). While SRC isn't a CNS target, higher BBB can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.631 & -4.614), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.574 & -2.518), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Both ligands have low hERG risk (0.538 & 0.507).

**Microsomal Clearance:** Ligand A (15.46 mL/min/kg) has much lower microsomal clearance than Ligand B (58.53 mL/min/kg). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-0.55 hours) has a slightly better in vitro half-life than Ligand B (0.508 hours), but both are very short and concerning.

**P-gp Efflux:** Both have low P-gp efflux liability (0.107 & 0.056).

**Binding Affinity:** Ligand A (-9.2 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 some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -6.5 kcal/mol), lower microsomal clearance (better metabolic stability), and better TPSA and BBB values outweigh the shared issues of poor solubility and permeability. The improved ADME properties of Ligand A suggest it's more likely to achieve sufficient *in vivo* exposure to exert its potent inhibitory effect. Further work would be needed to address the solubility and permeability issues, but the potency advantage of Ligand A is a strong starting point.

Output:
1
2025-04-17 15:33:18,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.411 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.09) is higher than Ligand B (78.51). While both are reasonably good, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Ligand A (0.746) is slightly higher than Ligand B (0.564). Both are within the optimal 1-3 range, but closer to the lower end.

**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 (0.847 and 0.706, respectively), indicating good drug-like properties.

**DILI:** Ligand A (79.915) has a significantly higher DILI risk than Ligand B (7.91). This is a major concern for Ligand A.

**BBB:** Ligand A (46.646) and Ligand B (58.821) both have low BBB penetration, which isn't critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.105 and -5.4), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-4.02) and Ligand B (-0.992) both have negative solubility values, indicating poor aqueous solubility. Ligand B is better in this regard.

**hERG Inhibition:** Ligand A (0.367) has a lower hERG inhibition risk than Ligand B (0.121), which is favorable.

**Microsomal Clearance:** Ligand A (46.211) has a higher microsomal clearance than Ligand B (-16.86). The negative value for Ligand B suggests excellent metabolic stability, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (13.221 hours) has a longer half-life than Ligand B (3.754 hours). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.194) has lower P-gp efflux than Ligand B (0.006), which is better for bioavailability.

**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 the more promising candidate. While both have poor Caco-2 and solubility, Ligand B has a much lower DILI risk and significantly better metabolic stability (negative Cl_mic), which are crucial for kinase inhibitors. The slightly better binding affinity of Ligand B further supports this conclusion. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 15:33:18,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.431 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values around 93-94, which is acceptable for general oral absorption but not ideal for CNS penetration (though not a priority for SRC).

**logP:** Ligand A (1.078) is closer to the optimal range (1-3) than Ligand B (2.46). While 2.46 is still within range, the lower logP of A might indicate better solubility and potentially fewer 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (A: 0.478, B: 0.689). Ligand B's score is better, indicating a more drug-like profile.

**DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (44.591). This is a major advantage for Ligand A.

**BBB:** Ligand B (82.047) has better BBB penetration than Ligand A (68.748), but this isn't a critical factor for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.864 and -4.741), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.145 and -3.617), indicating very poor aqueous solubility. This is a major drawback for both compounds and could hinder bioavailability.

**hERG Inhibition:** Ligand A (0.082) has a much lower hERG inhibition liability than Ligand B (0.383). This is a critical advantage for Ligand A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (66.165) has higher microsomal clearance than Ligand B (35.288), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-1.102) has a slightly better (less negative) in vitro half-life than Ligand A (-8.064), indicating better stability.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux liability, while Ligand B (0.143) has slightly higher efflux. This is a minor advantage for Ligand A.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.1 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a slightly better QED and in vitro half-life, Ligand A is significantly better in terms of safety (DILI and hERG) and has lower P-gp efflux. The poor solubility and permeability are concerning for both, but the safety profile is paramount. Given the enzyme-specific priorities, the lower hERG risk and DILI risk of Ligand A outweigh its slightly higher clearance.

Output:
0
2025-04-17 15:33:18,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (419.666 Da) is higher, but still acceptable. Ligand B (352.381 Da) is slightly preferred.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (59.5) is better than Ligand A (77).

**logP:** Ligand A (4.215) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.621) is within the optimal range (1-3).

**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 values (A: 0.685, B: 0.785), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a high DILI risk (98.759%), a significant concern. Ligand B has a much lower DILI risk (38.503%), making it far more favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (97.945%) is higher than Ligand A (61.846%), but it's not a deciding factor.

**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 solubility values, indicating poor solubility. Ligand B (-3.431) is slightly better than Ligand A (-5.676).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.465, B: 0.454), which is good.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (91.79), indicating poor metabolic stability. Ligand B has a lower clearance (77.29), suggesting better stability.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (-17.611 hours) compared to Ligand A (0.956 hours). This is a major advantage.

**P-gp Efflux:** Ligand A shows no P-gp efflux (0.319), while Ligand B has a low P-gp efflux (0.191). Both are good.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-7.8 kcal/mol) compared to Ligand A (0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor.

**Conclusion:**

Considering all factors, **Ligand B is significantly more promising**. While both have issues with solubility and Caco-2 permeability, Ligand B's superior binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and acceptable logP outweigh the drawbacks. Ligand A's extremely high DILI risk and very weak binding affinity make it a poor candidate.

Output:
1
2025-04-17 15:33:18,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 373.465 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.07) is better than Ligand B (49.77) as it is closer to the 140 threshold for oral absorption.

**logP:** Ligand A (0.894) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (3.429) is within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (7) and Ligand B (4) are both acceptable, being less than 10.

**QED:** Both ligands have similar QED values (0.805 and 0.797), indicating good drug-likeness.

**DILI:** Ligand A (44.94) has a slightly higher DILI risk than Ligand B (20.9), but both are below the concerning threshold of 60.

**BBB:** Ligand A (24.389) has a low BBB penetration, while Ligand B (86.545) has a high BBB penetration. Since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-5.273) has poor Caco-2 permeability, while Ligand B (-4.492) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.66) has slightly better solubility than Ligand B (-3.433).

**hERG Inhibition:** Ligand A (0.028) has a very low hERG risk, which is excellent. Ligand B (0.711) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-16.928) has significantly lower (better) microsomal clearance than Ligand B (47.509), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.951) has a slightly longer half-life than Ligand B (22.871).

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, while Ligand B (0.544) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's slightly lower logP and Caco-2 permeability, its significantly stronger binding affinity (-9.8 vs -8.3 kcal/mol), much better metabolic stability (lower Cl_mic), lower P-gp efflux, and very low hERG risk make it the more promising drug candidate. The better solubility also contributes positively. The slightly higher DILI risk is less concerning than the other advantages.

Output:
1
2025-04-17 15:33:18,360 - INFO - Batch 389 complete. Total preferences: 6224
2025-04-17 15:33:18,360 - INFO - Processing batch 390/512...
2025-04-17 15:33:58,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.443 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is slightly higher than Ligand B (67.23), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.535 and 2.045), 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 (0.91 and 0.803), indicating good drug-like properties.

**7. DILI:** Ligand A (49.632) has a higher DILI risk than Ligand B (19.504). This is a significant drawback for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (77.278) has a higher BBB score than Ligand A (60.45), but this isn't a major deciding factor here.

**9. Caco-2 Permeability:** Ligand A (-4.467) has a worse Caco-2 permeability than Ligand B (-5.17), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.871) has worse solubility than Ligand B (-2.099). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.256 and 0.116), which is excellent.

**12. Microsomal Clearance:** Ligand A (33.223) has a higher microsomal clearance than Ligand B (21.823), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Both have negative half-lives (-6.46 and -6.807), which is unusual. However, the absolute value is more important, and Ligand B has a slightly longer *predicted* half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.161 and 0.073).

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands have good overall drug-like properties, Ligand B demonstrates a significantly lower DILI risk, better solubility, better Caco-2 permeability, better metabolic stability (lower Cl_mic), and a substantially stronger binding affinity. The difference in binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:33:58,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.38 Da) is slightly higher than Ligand B (347.39 Da), but both are acceptable.

**TPSA:** Ligand A (93.53) is slightly higher than Ligand B (73.74). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (0.515) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (0.951) is closer to the optimal range. This favors Ligand B.

**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, but Ligand B is slightly better.

**QED:** Both ligands have good QED scores (A: 0.772, B: 0.823), indicating good drug-like properties.

**DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (35.285). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration, but Ligand A (81.815) is slightly better than Ligand B (72.78). However, BBB is less critical for a kinase inhibitor compared to other properties.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and concerning. It suggests poor permeability. However, the value for Ligand A (-4.798) is less negative than Ligand B (-4.614), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also concerning. Ligand B (-1.465) is slightly better than Ligand A (-2.655).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.337, B: 0.409), which is good.

**Microsomal Clearance:** Ligand A (20.353) has a higher microsomal clearance than Ligand B (11.901), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-40.502) has a significantly shorter in vitro half-life than Ligand B (-23.586), further supporting the better metabolic stability of Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.113, B: 0.05), which is good.

**Binding Affinity:** Both ligands have similar strong binding affinities (A: -9.1 kcal/mol, B: -8.8 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other ADME concerns.

**Overall:** Considering all factors, Ligand B is the more promising candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), a more favorable logP, and fewer HBA. While Ligand A has slightly better BBB penetration and Caco-2 permeability, the ADME advantages of Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 15:33:58,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (354.491 and 354.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.87) is better than Ligand B (96.35), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (though that's not a priority here).

**3. logP:** Ligand A (1.44) is within the optimal 1-3 range. Ligand B (-1.92) is below 1, which could hinder permeation.

**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 6. Both are below the 10 threshold, but A is preferable.

**6. QED:** Ligand A (0.697) has a better QED score than Ligand B (0.515), indicating better overall drug-likeness.

**7. DILI:** Ligand A (16.092) has a significantly lower DILI risk than Ligand B (6.863), which is a major advantage.

**8. BBB:** This is not a primary concern for a kinase inhibitor, but Ligand A (60.76) is better than Ligand B (9.965).

**9. Caco-2 Permeability:** Ligand A (-4.856) is better than Ligand B (-5.477), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.707) is better than Ligand B (-0.32), which is crucial for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.18 and 0.12, respectively).

**12. Microsomal Clearance:** Ligand B (-8.994) has a *negative* clearance, which is not physically possible and suggests an error or outlier in the data. Ligand A (19.154) is higher, but still reasonable. This is a major red flag for Ligand B.

**13. In vitro Half-Life:** Ligand B (2.125) has a very short half-life, while Ligand A (-8.445) has a negative half-life, which is also not physically possible.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.002, respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -8.5 kcal/mol). The difference of 0.7 kcal/mol is not large enough to overcome the significant ADME deficiencies of Ligand B.

**Conclusion:**

Ligand A is significantly more promising. While both have good binding affinity, Ligand A has superior drug-like properties (QED, solubility, permeability, DILI risk) and more plausible ADME characteristics (clearance and half-life). Ligand B's negative clearance and half-life are major concerns, and its lower logP and solubility are also unfavorable.

Output:
1
2025-04-17 15:33:58,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (339.4 Da) are within the ideal range (200-500 Da).

**2. TPSA:** Ligand A (81.07) is slightly higher than Ligand B (63.05). Both are below the 140 threshold for oral absorption, but B is better.

**3. logP:** Both ligands have good logP values (A: 1.957, B: 2.463), 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 (6) and Ligand B (5) are both within the acceptable limit of 10. B is slightly better.

**6. QED:** Both ligands have good QED scores (A: 0.643, B: 0.909), indicating good drug-like properties. B is significantly better.

**7. DILI:** Ligand A (70.919) has a higher DILI risk than Ligand B (24.816). This is a significant concern for A.

**8. BBB:** Ligand A (68.941) and Ligand B (90.151). BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-5.355) and Ligand B (-4.933). Both are negative, which is unusual, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-2.339) and Ligand B (-2.843). Both are negative, indicating poor solubility. B is slightly better.

**11. hERG Inhibition:** Ligand A (0.763) and Ligand B (0.47). Both are relatively low, suggesting a low risk of cardiotoxicity, but B is better.

**12. Microsomal Clearance:** Ligand A (46.216) has higher clearance than Ligand B (32.139), indicating lower metabolic stability. This is a significant drawback for A.

**13. In vitro Half-Life:** Ligand A (54.066) has a longer half-life than Ligand B (11.524). This is a positive for A, but the other ADME properties of A are worse.

**14. P-gp Efflux:** Ligand A (0.197) and Ligand B (0.08). Both are low, indicating low P-gp efflux. B is better.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly superior. While both compounds have some solubility issues, Ligand B has a much better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), and significantly higher binding affinity. The longer half-life of A is a positive, but it's overshadowed by the other deficiencies. The difference in binding affinity is also significant.

Output:
1
2025-04-17 15:33:58,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 359.461 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.37) is higher than the preferred <140, but still reasonable. Ligand B (52.65) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.798) is a bit low, potentially hindering permeation. Ligand B (2.137) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (3) is also good.

**QED:** Both ligands have reasonable QED scores (0.325 and 0.608), with Ligand B being better.

**DILI:** Ligand A (34.781) has a moderate DILI risk, but is still good (<40). Ligand B (12.33) has a very low DILI risk, which is a significant advantage.

**BBB:** Both have reasonable BBB penetration (77.084 and 73.943). This isn't a major concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-5.319) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.912) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.656) has poor solubility. Ligand B (-1.129) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.068) has very low hERG risk, a major advantage. Ligand B (0.468) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (26.254) has moderate clearance. Ligand B (2.091) has very low clearance, indicating excellent metabolic stability. This is a critical factor for kinases.

**In vitro Half-Life:** Both ligands have negative half-lives (-3.872 and -9.014), which is unusual and likely indicates a problem with the assay or data. However, the more negative value for Ligand B suggests it might be even less stable *in vitro*.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.021 and 0.02), which is good.

**Binding Affinity:** Ligand A (-9.3) has significantly better binding affinity than Ligand B (-6.6), with a difference of 2.7 kcal/mol. This is a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability and solubility. Ligand B has better ADME properties (lower DILI, better solubility, excellent metabolic stability), but its binding affinity is considerably weaker.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, hERG), the strong binding affinity of Ligand A is the deciding factor. While its ADME properties are not ideal, they can potentially be improved through further optimization. The 2.7 kcal/mol difference in binding is substantial and likely to translate to a significant difference in *in vivo* efficacy.

Output:
0
2025-04-17 15:33:58,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.395 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.82) is better than Ligand B (106.6), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (1.026 and 1.102), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 4. Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.749 and 0.846), indicating drug-like properties.

**DILI:** Ligand A (60.333) has a higher DILI risk than Ligand B (38.154). This is a significant negative for Ligand A.

**BBB:** Ligand A (91.508) has a much higher BBB penetration percentile than Ligand B (32.92). However, since SRC is not a CNS target, this is less important.

**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:** Both ligands have very low hERG inhibition liability (0.091 and 0.02), which is excellent.

**Microsomal Clearance:** Ligand A (-11.44) has a lower (better) microsomal clearance than Ligand B (-14.098). Lower clearance suggests better metabolic stability.

**In vitro Half-Life:** Ligand A (4.61) has a shorter half-life than Ligand B (-32.263). This is a negative for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.004), which is favorable.

**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 a major advantage for Ligand B.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly stronger binding affinity (-9.3 vs -7.9 kcal/mol) and lower DILI risk (38.154 vs 60.333) outweigh the slightly worse metabolic stability (higher clearance) and lower BBB penetration (which is irrelevant for this target). The improved affinity is likely to translate to better efficacy, and the lower DILI risk is crucial for safety.

Output:
1
2025-04-17 15:33:58,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.46 and 347.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (82.68).  A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Ligand A (3.309) is optimal, while Ligand B (1.655) is on the lower side. While not a dealbreaker, lower logP can sometimes hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 8 HBA). Lower counts are generally better for permeability.

**QED:** Both ligands have similar QED values (0.762 and 0.658), indicating good drug-likeness.

**DILI:** Ligand A (23.19) has a much lower DILI risk than Ligand B (42.54), a significant advantage.

**BBB:** Ligand A (97.21) shows excellent BBB penetration, while Ligand B (73.40) is moderate.  BBB isn't a primary concern for SRC kinase inhibitors unless CNS effects are desired, but it's a bonus.

**Caco-2 Permeability:** Ligand A (-4.416) is better than Ligand B (-5.519), indicating improved intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.066) is better than Ligand B (-1.519), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.637) has a lower hERG risk than Ligand B (0.15), a critical safety parameter.

**Microsomal Clearance:** Ligand A (30.418) has a higher (worse) microsomal clearance than Ligand B (25.355), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-17.986) has a significantly longer in vitro half-life than Ligand B (3.361), a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.251) has lower P-gp efflux than Ligand B (0.181), which is good for bioavailability.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial difference (1.5 kcal/mol), and is a significant factor.

**Overall Assessment:**

Ligand B has a better binding affinity. However, Ligand A excels in almost all ADME-Tox properties. Specifically, the lower DILI, better solubility, lower hERG risk, and significantly longer half-life of Ligand A are very compelling. While the affinity difference is notable, the improved safety and pharmacokinetic profile of Ligand A outweigh this concern, especially considering the already good affinity of -7.4 kcal/mol. The longer half-life alone is a major advantage for a kinase inhibitor.

Output:
1
2025-04-17 15:33:58,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.284 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 140 threshold for oral absorption. Ligand B (87.46) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.601) is optimal (1-3). Ligand B (0.179) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of hydrogen bond donors and acceptors, within acceptable limits.

**QED:** Both ligands have similar QED values (0.823 and 0.798), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (30.167 and 33.463), which is positive.

**BBB:** Ligand A (92.827) shows good BBB penetration, while Ligand B (72.858) is lower. While not a primary concern for a non-CNS target like SRC, it doesn't detract significantly.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.784 and -4.994), which is unusual and suggests poor permeability. This is a significant concern for both, but potentially more so for Ligand B given its already low logP.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.452 and -2.032), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.932 and 0.228), which is excellent.

**Microsomal Clearance:** Ligand A (-15.687) has significantly lower (better) microsomal clearance than Ligand B (6.681), indicating greater metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (4.125 hours) has a better in vitro half-life than Ligand B (12.984 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.2 and 0.045), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.6 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite both compounds having good binding affinity and low hERG risk, Ligand A is the more promising candidate. Its superior logP, lower microsomal clearance (better metabolic stability), and better in vitro half-life outweigh the slightly lower BBB penetration. The poor solubility and Caco-2 permeability are concerns for both, but Ligand A's better overall profile makes it the preferred choice for further optimization.

Output:
1
2025-04-17 15:33:58,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (393.77 and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is slightly higher than Ligand B (67.87), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (4.867) is high, potentially leading to solubility issues and off-target effects. Ligand B (1.153) is closer to 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 10 threshold.

**QED:** Both ligands have good QED scores (A: 0.777, B: 0.799), indicating good drug-like properties.

**DILI:** Ligand A (93.525) has a significantly higher DILI risk than Ligand B (44.707). This is a major concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (87.01) has a higher BBB value than Ligand A (30.128), but this is not a primary concern.

**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, suggesting poor aqueous solubility. Ligand B (-1.994) is slightly better than Ligand A (-4.012).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.19, B: 0.384), which is good.

**Microsomal Clearance:** Ligand A (17.697) has a higher microsomal clearance than Ligand B (15.651), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-9.489) has a negative half-life, which is concerning. Ligand A (22.048) has a more reasonable value. However, negative values are suspect and require further investigation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.074, B: 0.035).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.7 kcal/mol, B: -8.1 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its lower logP, significantly lower DILI risk, and slightly better solubility are crucial advantages. While the negative half-life is concerning, the higher DILI risk associated with Ligand A is a more significant issue for drug development. The slightly higher metabolic clearance of Ligand A is also a negative.

Output:
1
2025-04-17 15:33:58,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (451.26 Da) is slightly higher, but acceptable. Ligand B (358.345 Da) is also good.

**TPSA:** Ligand A (68.55) is good, below the 140 threshold for oral absorption. Ligand B (93.65) is also acceptable, but closer to the threshold.

**logP:** Ligand A (4.063) is at the upper end of the optimal range, potentially leading to solubility issues. Ligand B (0.163) is quite low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.39, Ligand B: 0.548), with Ligand B being slightly more drug-like.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 68.864, Ligand B: 64.521), though Ligand B is slightly better.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (18.651) and Ligand B (73.866) are not particularly relevant here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.446 and -4.796), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.446 and -1.567). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.537) has a slightly higher hERG risk than Ligand B (0.206), but both are relatively low.

**Microsomal Clearance:** Ligand A (91.713) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (33.384) has much better metabolic stability.

**In vitro Half-Life:** Ligand A (34.391) has a moderate half-life. Ligand B (-15.299) has a *very* short half-life, which is a major concern.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.296, Ligand B: 0.012), which is good.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly better binding affinity than Ligand B (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A's primary advantage is its much stronger binding affinity. However, it suffers from higher logP, higher clearance, and lower solubility. Ligand B has better metabolic stability and lower DILI, but its binding affinity is weaker, and it has very poor solubility and a very short half-life.

Given the enzyme-specific priorities, binding affinity is paramount. The difference in affinity (-8.1 vs -9.0) is significant. While Ligand A has some ADME drawbacks, these might be addressable through further optimization. The extremely short half-life of Ligand B is a more difficult problem to solve. The poor solubility of both is a concern, but potentially manageable with formulation strategies.

Output:
0
2025-04-17 15:33:58,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.45 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is slightly higher than Ligand B (58.64), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have excellent logP values (2.405 and 2.37), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, satisfying the <5 and <10 rules respectively.

**QED:** Both ligands have good QED scores (0.682 and 0.768), indicating drug-like properties.

**DILI:** Ligand A (17.72) has a slightly higher DILI risk than Ligand B (14.23), but both are comfortably below the concerning threshold of 60.

**BBB:** Both have high BBB penetration (89.531 and 82.202), which isn't a primary concern for a non-CNS target like SRC kinase, but isn't detrimental.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.572 and -4.732). This is unusual and requires further investigation, but it doesn't immediately disqualify either.

**Aqueous Solubility:** Both have negative solubility values (-2.615 and -2.467). This is also unusual and a potential concern, but similar for both.

**hERG Inhibition:** Ligand A (0.157) has a slightly lower hERG inhibition liability than Ligand B (0.482), which is favorable.

**Microsomal Clearance:** Ligand A (23.317) has significantly lower microsomal clearance than Ligand B (40.087). This suggests better metabolic stability for Ligand A, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-20.759) has a much longer in vitro half-life than Ligand B (3.48). This further supports the better metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.048) exhibits lower P-gp efflux than Ligand B (0.083), which is a slight advantage.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a much weaker binding affinity than Ligand A (-7.0 kcal/mol). This is the most significant difference. A difference of 7 kcal/mol is substantial and outweighs any minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have acceptable physicochemical properties, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and, crucially, a much stronger binding affinity (-7.0 kcal/mol vs -0.0 kcal/mol). The stronger binding affinity is the most important factor for an enzyme inhibitor, and the improved metabolic stability increases the likelihood of achieving therapeutic concentrations *in vivo*. The slightly better hERG profile of Ligand A is an additional benefit.

Output:
1
2025-04-17 15:33:58,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (375.803 and 359.352 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.32 and 87.22) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.172) is optimal, while Ligand B (0.916) 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 4 HBA, and Ligand B has 5 HBA, both acceptable (<=10).

**QED:** Both ligands have similar QED values (0.798 and 0.756), indicating good drug-likeness.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (58.744), but both are acceptable (<60 is good).

**BBB:** Both ligands have good BBB penetration (65.723 and 79.488), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.038 and -4.778). These values are unusual and suggest poor permeability. However, Caco-2 values can be unreliable and are often used as a relative comparison.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.761 and -2.552), which is concerning. Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.201 and 0.228), which is excellent.

**Microsomal Clearance:** Ligand A (8.707 mL/min/kg) has significantly lower microsomal clearance than Ligand B (32.085 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.286 hours) has a much longer half-life than Ligand B (-15.911 hours), which is a significant advantage. The negative value for Ligand B is problematic and likely indicates very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.006).

**Binding Affinity:** Ligand A (-9.2 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 minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much stronger binding affinity. The lower DILI risk of Ligand B is offset by its poor metabolic profile and weaker binding. The strong binding affinity of Ligand A is a key advantage for an enzyme inhibitor.

Output:
1
2025-04-17 15:33:58,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.853 Da and 343.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.9) is higher than Ligand B (35.5). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Both ligands have good logP values (4.011 and 2.943, respectively) within the optimal 1-3 range. Ligand B is slightly preferred.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.637 and 0.84), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 92.284, which is high. Ligand B has a much lower DILI risk of 34.703, making it significantly safer.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (87.515) has a higher BBB percentile than Ligand A (31.02), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-5.305) and Ligand B (-4.995) are both negative, which is unusual. However, the values are close and don't strongly differentiate the two.

**Aqueous Solubility:** Ligand A (-5.149) and Ligand B (-2.266) both have negative solubility values, indicating poor solubility. Ligand B is better, but both need improvement.

**hERG Inhibition:** Ligand A (0.406) has a slightly lower hERG risk than Ligand B (0.944), which is preferable.

**Microsomal Clearance:** Ligand A (46.37) has higher microsomal clearance than Ligand B (29.536), indicating lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand A (21.855) has a longer half-life than Ligand B (17.617), which is desirable.

**P-gp Efflux:** Ligand A (0.508) has lower P-gp efflux than Ligand B (0.355), suggesting better bioavailability.

**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 the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better P-gp efflux and half-life, Ligand B excels in critical areas: significantly lower DILI risk, better solubility, better metabolic stability, and, most importantly, a much stronger binding affinity. The superior affinity of Ligand B (-7.7 kcal/mol vs. -9.4 kcal/mol) is a decisive factor for an enzyme target like SRC kinase.



Output:
1
2025-04-17 15:33:58,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (347.419 and 361.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.28) is better than Ligand B (62.39) as it is closer to the 140 threshold, indicating better potential for oral absorption.

**logP:** Both ligands have good logP values (2.889 and 3.357), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Ligand A (0.845) has a significantly higher QED score than Ligand B (0.667), indicating a more drug-like profile.

**DILI:** Ligand B (47.15) has a much lower DILI risk than Ligand A (60.682), which is a significant advantage.

**BBB:** Ligand A (92.4) has a much higher BBB penetration score than Ligand B (51.415). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.151) has a lower Caco-2 permeability than Ligand B (-5.216), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.98) has slightly better solubility than Ligand B (-2.881).

**hERG Inhibition:** Ligand A (0.174) has a lower hERG inhibition liability than Ligand B (0.833), which is a critical advantage for safety.

**Microsomal Clearance:** Ligand B (45.105) has a lower microsomal clearance than Ligand A (57.951), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (32.751) has a longer in vitro half-life than Ligand A (-21.214), which is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.179) has a lower P-gp efflux liability than Ligand B (0.625), potentially leading to better bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This difference of 1.6 kcal/mol is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better QED and P-gp efflux, Ligand B excels in the most critical areas for an enzyme target: significantly higher binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2). The lower hERG risk of Ligand A is a plus, but the strong affinity of Ligand B is likely to drive efficacy and could allow for lower doses, potentially mitigating other risks.

Output:
1
2025-04-17 15:33:58,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (336.4 and 361.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (101.6 and 97.6) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.32 and 1.42) falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 8. Both are acceptable, but Ligand A is slightly better.

**6. QED:** Both ligands have good QED scores (0.68 and 0.80), indicating drug-likeness.

**7. DILI:** Ligand A (68.4) has a slightly higher DILI risk than Ligand B (62.6), but both are within a manageable range.

**8. BBB:** Both ligands have relatively low BBB penetration (45.7 and 57.7), which is not a major concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.62 and -5.66), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.14 and -2.56), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.74) has a slightly higher hERG risk than Ligand B (0.13). This is a concern for Ligand A.

**12. Microsomal Clearance:** Ligand A (-16.9) has significantly lower (better) microsomal clearance than Ligand B (2.82). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (28.9) has a longer in vitro half-life than Ligand B (15.6), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.13) has lower P-gp efflux than Ligand B (0.01), which is favorable.

**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 crucial advantage.

**Overall Assessment:**

Despite the poor solubility and permeability of both compounds, Ligand B stands out due to its significantly superior binding affinity (-8.8 kcal/mol vs 0.0 kcal/mol). The strong binding is likely to outweigh the ADME concerns, especially given that formulation strategies can sometimes mitigate solubility issues. The better metabolic stability of Ligand A is attractive, but the difference in binding affinity is substantial.

Output:
1
2025-04-17 15:33:58,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.861 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.73) is well below the 140 threshold for good absorption, while Ligand B (93.21) is still acceptable but closer to the limit.

**logP:** Ligand A (3.331) is optimal, while Ligand B (1.318) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED scores (0.762 and 0.649, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (46.297 and 42.303 percentiles), which is favorable.

**BBB:** Ligand A (73.672) has better BBB penetration potential than Ligand B (61.613), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.438) has poor Caco-2 permeability, while Ligand B (-5.342) is also poor. Both are quite low.

**Aqueous Solubility:** Ligand A (-3.553) has slightly better aqueous solubility than Ligand B (-2.224), though both are quite poor.

**hERG Inhibition:** Ligand A (0.418) has a lower hERG inhibition liability than Ligand B (0.075), which is a significant advantage.

**Microsomal Clearance:** Ligand A (66.133 mL/min/kg) has higher microsomal clearance than Ligand B (28.098 mL/min/kg), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (6.431 hours) has a slightly longer half-life than Ligand B (0.168 hours), but both are relatively short.

**P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.008), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Conclusion:**

While Ligand A has better solubility and lower hERG risk, Ligand B's significantly stronger binding affinity (-7.2 vs -8.0 kcal/mol) and better metabolic stability (lower Cl_mic) are more crucial for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed with further optimization. The poor Caco-2 and solubility of both are concerning, but the potency advantage of B is significant.

Output:
1
2025-04-17 15:33:58,611 - INFO - Batch 390 complete. Total preferences: 6240
2025-04-17 15:33:58,611 - INFO - Processing batch 391/512...
2025-04-17 15:34:38,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 345.487 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.18) is slightly above the optimal <60 for good absorption, but still reasonable. Ligand B (52.65) is excellent.

**logP:** Ligand A (4.19) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.765) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 3 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.823 and 0.826), indicating good drug-like properties.

**DILI:** Ligand A (42.846) has a moderate DILI risk, but is acceptable. Ligand B (15.936) has a very low DILI risk, which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, these values can be unreliable and should be confirmed experimentally.

**Aqueous Solubility:** Both have negative solubility values, which also is unusual and suggests potential issues with aqueous solubility. However, these values can be unreliable and should be confirmed experimentally.

**hERG:** Ligand A (0.922) has a slightly higher hERG risk than Ligand B (0.381), which is preferable.

**Microsomal Clearance:** Ligand A (93.74) has high microsomal clearance, suggesting poor metabolic stability. Ligand B (4.303) has very low clearance, indicating excellent metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (46.237) has a moderate half-life. Ligand B (23.125) has a shorter half-life, but the low clearance suggests it could be improved with structural modifications.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.094), which is preferable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a higher logP, higher DILI risk, and significantly higher microsomal clearance, indicating poorer metabolic stability. Ligand B has better ADME properties across the board (lower logP, lower DILI, much lower clearance, lower hERG), but a weaker binding affinity.

Given the substantial difference in binding affinity (-8.6 vs -7.1 kcal/mol), the improved potency of Ligand A is likely to outweigh its ADME liabilities, *provided* those liabilities can be addressed through further optimization. The lower clearance of Ligand B is very attractive, but the potency difference is significant.

Output:
0
2025-04-17 15:34:38,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.5 and 389.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (74.77). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (3.539) is optimal, while Ligand B (1.299) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.716 and 0.712), indicating good drug-likeness.

**DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (49.593), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.464) is slightly better than Ligand B (66.072).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.774 and -4.723), which is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.504 and -2.543), indicating poor aqueous solubility. This is a concern, but similar for both.

**hERG:** Ligand A (0.315) has a lower hERG risk than Ligand B (0.447), which is a positive.

**Microsomal Clearance:** Ligand A (52.904) has higher microsomal clearance than Ligand B (14.596), meaning it is less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (7.957) has a longer in vitro half-life than Ligand A (-8.986), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.264) has lower P-gp efflux than Ligand B (0.013), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This 1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has advantages in TPSA, logP, DILI, hERG, and P-gp efflux, Ligand B's significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly improved binding affinity are more crucial for an enzyme target like SRC kinase. The similar poor permeability and solubility are concerns for both, but can be addressed with formulation strategies. The DILI risk for Ligand B is higher, but not critically so.

Output:
1
2025-04-17 15:34:38,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (341.342 and 341.411 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.08) is slightly higher than Ligand B (63.69). Both are below the 140 A^2 threshold for oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Ligand A (1.396) is within the optimal range (1-3), while Ligand B (3.257) is at the higher end but still acceptable.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is well within the limit of 10.

**QED:** Ligand B (0.907) has a significantly higher QED score than Ligand A (0.654), suggesting a more drug-like profile overall.

**DILI:** Ligand A (85.847) has a higher DILI risk than Ligand B (56.727). Ligand B is well below the concerning threshold of 60, while Ligand A is higher.

**BBB:** Ligand B (73.594) has a higher BBB penetration percentile than Ligand A (44.707), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.224) has a very poor Caco-2 permeability score, suggesting poor absorption. Ligand B (-4.423) is also poor, but better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.014 and -3.532 respectively). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.708 and 0.62 respectively).

**Microsomal Clearance:** Ligand A (2.731) has a lower microsomal clearance than Ligand B (28.96), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (22.615) has a longer in vitro half-life than Ligand B (8.772), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.156 and 0.05 respectively).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), the significantly stronger binding affinity of Ligand B (-8.2 vs -9.0 kcal/mol) is a critical advantage for an enzyme target. Ligand B also has a better QED score and lower DILI risk. The lower Caco-2 permeability and solubility are concerns, but potentially manageable with formulation. The slightly higher logP of Ligand B is acceptable.

Output:
1
2025-04-17 15:34:38,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 355.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.87) is better than Ligand B (59.22), being under the 140 threshold, but both are acceptable.

**logP:** Ligand A (0.928) is within the optimal 1-3 range, while Ligand B (3.765) is approaching the upper limit. This favors Ligand A slightly.

**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 within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.828, B: 0.858), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 40.83, B: 38.348), below the 40 threshold.

**BBB:** Ligand A (29.74) has a low BBB penetration, while Ligand B (92.555) has high BBB penetration. Since SRC is not a CNS target, this is not a major factor, and favors Ligand B.

**Caco-2 Permeability:** Ligand A (-4.847) has poor Caco-2 permeability, while Ligand B (-5.009) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.562) has poor solubility, while Ligand B (-3.884) has even poorer solubility. This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.269) has a very low hERG risk, while Ligand B (0.871) has a higher, but still acceptable, hERG risk. This favors Ligand A.

**Microsomal Clearance:** Ligand A (-2.941) has a negative clearance, indicating very high metabolic stability, while Ligand B (76.594) has high clearance. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.941) has a very long half-life, while Ligand B (0.524) has a very short half-life. This strongly favors Ligand A.

**P-gp Efflux:** Ligand A (0.036) has very low P-gp efflux, while Ligand B (0.706) has moderate P-gp efflux. This favors Ligand A.

**Binding Affinity:** Ligand B (-9.7 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:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), hERG risk, and P-gp efflux. Ligand B has a stronger binding affinity, and better BBB penetration. However, the poor solubility and high clearance of Ligand B are significant drawbacks for an enzyme target. Ligand A, despite the poor Caco-2 permeability, is more likely to be a viable drug candidate due to its superior ADME properties and acceptable affinity. The difference in binding affinity is not large enough to overcome the ADME deficiencies of Ligand B.

Output:
0
2025-04-17 15:34:38,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (399.263 and 381.929 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (34.89) is significantly better than Ligand B (52.65). Lower TPSA generally favors better absorption.

**logP:** Ligand A (4.823) is higher than Ligand B (2.601). While Ligand A is approaching the upper limit, it's still within a reasonable range. Ligand B is well within the optimal range.

**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 (0.59 and 0.824), indicating good drug-like properties.

**DILI:** Ligand A (60.915) has a higher DILI risk than Ligand B (23.032). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (82.047) is slightly better than Ligand B (77.743). This is less critical for a kinase inhibitor than for a CNS-targeted drug.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating 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:** Ligand A (0.814) has a slightly higher hERG risk than Ligand B (0.416), but both are relatively low.

**Microsomal Clearance:** Ligand B (7.064) has significantly lower microsomal clearance than Ligand A (49.193), suggesting better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (34.392) has a longer in vitro half-life than Ligand A (27.319), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.967) has slightly higher P-gp efflux than Ligand B (0.137), which is unfavorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.3 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to overcome the ADME deficiencies of Ligand A.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand B is the better candidate. While both have poor Caco-2 and solubility, Ligand B's significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux outweigh the slightly lower binding affinity and slightly lower BBB penetration. Ligand A's higher DILI risk and poor metabolic stability are major concerns.

Output:
1
2025-04-17 15:34:38,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.389 Da and 365.382 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.33) is significantly better than Ligand B (81.7).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (3.823 and 3.036), 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 6. Ligand A is preferable here, as fewer HBA generally improves permeability.

**6. QED:** Ligand A (0.915) has a much higher QED score than Ligand B (0.796), indicating a more drug-like profile.

**7. DILI:** Ligand B (92.982) has a considerably higher DILI risk than Ligand A (61.691). This is a significant concern.

**8. BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (94.106) has better BBB penetration than Ligand B (79.139).

**9. Caco-2 Permeability:** Both have negative values, indicating low permeability. Ligand A (-4.545) is slightly better than Ligand B (-4.736), but both are poor.

**10. Aqueous Solubility:** Both have negative values, indicating low solubility. Ligand A (-4.508) is slightly better than Ligand B (-4.679).

**11. hERG Inhibition:** Ligand A (0.885) has a lower hERG risk than Ligand B (0.524), which is a major advantage.

**12. Microsomal Clearance:** Ligand B (110.712) has a much higher microsomal clearance than Ligand A (41.802), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.263 hours) has a longer half-life than Ligand B (8.989 hours).

**14. P-gp Efflux:** Ligand A (0.716) has lower P-gp efflux than Ligand B (0.404), which is favorable.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, the substantial drawbacks in DILI risk, metabolic stability (high Cl_mic, low t1/2), and P-gp efflux, coupled with a lower QED and higher hERG risk, make it a less attractive candidate. Ligand A, despite its weaker binding, presents a much more balanced profile with better ADME properties and a significantly lower safety liability. The difference in binding affinity, while important, may be surmountable with further optimization, whereas the ADME/Tox issues with Ligand B are more challenging to address.

Output:
0
2025-04-17 15:34:38,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.11) is slightly higher than Ligand B (88.58), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.728 and 2.563), falling within the 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 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 (0.654 and 0.9), indicating drug-like properties. Ligand B is better.

**DILI:** Both ligands have similar DILI risk (58.162 and 54.866), both are acceptable.

**BBB:** Ligand B (71.229) has a significantly higher BBB penetration percentile than Ligand A (35.44). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.704 and -4.734). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.317 and -2.798), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.318 and 0.199), which is excellent.

**Microsomal Clearance:** Ligand A (37.124) has a higher microsomal clearance than Ligand B (41.3), suggesting potentially better metabolic stability. Lower is better.

**In vitro Half-Life:** Ligand B (-20.329) has a longer in vitro half-life than Ligand A (-28.386), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.124 and 0.118), which is favorable.

**Binding Affinity:** Ligand B (-10.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite similar molecular weights and acceptable logP/H-bond properties, Ligand B is the superior candidate. The significantly stronger binding affinity (-10.0 vs -7.4 kcal/mol) outweighs the slightly higher TPSA and lower solubility. The better half-life and BBB penetration are also beneficial. While both have poor solubility and permeability, the potency advantage of Ligand B is critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:34:38,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.67) is higher than Ligand B (62.62). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.647) is slightly low, potentially hindering permeation. Ligand B (1.318) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is even better, potentially improving permeability.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Ligand A (0.566) is better than Ligand B (0.445), indicating a more drug-like profile.

**DILI:** Both ligands have similar, acceptable DILI risk (36.758 and 37.03, respectively), both well below the 60 threshold.

**BBB:** Ligand A (39.007) and Ligand B (65.413). BBB isn't a critical factor for SRC kinase inhibitors unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.618) is very poor, while Ligand B (-4.407) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.41) and Ligand B (-2.453) both indicate poor aqueous solubility, which is a concern.

**hERG:** Ligand A (0.044) is very low risk, while Ligand B (0.225) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (1.319) has much lower clearance than Ligand B (41.376), indicating better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (23.446) has a longer half-life than Ligand B (-24.348), which is desirable.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, while Ligand B (0.173) is slightly higher.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. The difference of 7.5 kcal/mol is substantial and likely outweighs the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A having better QED and lower clearance, the overwhelmingly stronger binding affinity of Ligand B (-7.5 kcal/mol vs 0.0 kcal/mol) makes it the more promising candidate. The improved TPSA and logP of Ligand B also contribute to its potential. While solubility and Caco-2 permeability are concerns for both, the potency advantage of Ligand B is likely to be decisive.

Output:
1
2025-04-17 15:34:38,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (356.438 and 355.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (84.5 and 82.11) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.664) is optimal, while Ligand B (0.386) is slightly low, potentially hindering permeation.

**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 5, both are below the 10 limit.

**6. QED:** Both ligands have QED values (0.68 and 0.585) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (56.844) has a higher DILI risk than Ligand B (21.791). This is a significant drawback for Ligand A.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (80.574) is higher than Ligand B (24.002), but this is less important.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.995 and -4.951). 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 (-2.332 and -0.405). Again, the scale is unclear, but suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.194 and 0.07). This is excellent.

**12. Microsomal Clearance:** Ligand A (20.907) has higher microsomal clearance than Ligand B (17.003), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.177) has a significantly longer in vitro half-life than Ligand A (2.448). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.012).

**15. Binding Affinity:** Ligand B (-7.6 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 both have some solubility/permeability concerns (indicated by the negative Caco-2 and solubility values), Ligand B has a significantly better safety profile (lower DILI risk), superior metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The slightly lower logP of Ligand B is a minor concern compared to the advantages it offers in terms of safety and pharmacokinetics.

Output:
1
2025-04-17 15:34:38,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 352.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.44) is better than Ligand B (41.99) as it is still within the acceptable range for oral absorption, while ligand B is very low, which could indicate poor potency.

**logP:** Ligand A (1.518) is optimal, while Ligand B (4.705) is high, potentially leading to solubility issues and off-target effects.

**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 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.723 and 0.792, respectively), indicating drug-likeness.

**DILI:** Ligand A (9.926) has a significantly lower DILI risk than Ligand B (48.701). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (73.478 and 70.182), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.043) and Ligand B (-4.839) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.91) is better than Ligand B (-5.308), indicating better solubility.

**hERG Inhibition:** Ligand A (0.478) has a lower hERG risk than Ligand B (0.288), which is preferable.

**Microsomal Clearance:** Ligand A (-5.212) has a *much* better microsomal clearance (more negative = slower clearance = better metabolic stability) than Ligand B (92.593). This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (11.118 hours) has a better in vitro half-life than Ligand B (-26.008 hours).

**P-gp Efflux:** Ligand A (0.006) has lower P-gp efflux than Ligand B (0.433), which is preferable.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a lower DILI risk, better metabolic stability (much lower Cl_mic and better half-life), better solubility, lower hERG risk, lower P-gp efflux, and comparable binding affinity. While both have poor Caco-2 permeability, the other advantages of Ligand A outweigh this drawback, especially considering SRC is not a CNS target. Ligand B's high logP and poor metabolic stability are major concerns.

Output:
1
2025-04-17 15:34:38,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.43) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (73.2) is excellent, well below 140.

**logP:** Ligand A (-0.219) is a bit low, potentially hindering permeation. Ligand B (2.653) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both within acceptable limits. Ligand B has 1 HBD and 4 HBA, also good.

**QED:** Both ligands have good QED scores (0.627 and 0.738, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (37.999 and 30.593 percentiles), which is favorable.

**BBB:** Both have moderate BBB penetration (53.974 and 62.117), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.419 and -5.013). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon, particularly if the assay is reported as a ratio.

**Aqueous Solubility:** Both have negative solubility values (-1.132 and -3.328). Similar to Caco-2, these are likely log scale values and indicate poor solubility.

**hERG Inhibition:** Ligand A (0.015) has a very low hERG risk, which is excellent. Ligand B (0.478) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (8.968 mL/min/kg) has lower clearance than Ligand B (55.838 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.283 hours) has a longer half-life than Ligand B (2.327 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.063).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol) - a difference of 1.3 kcal/mol. This is a substantial advantage.

**Conclusion:**

Despite both ligands having some solubility/permeability concerns (indicated by the negative Caco-2 and solubility values), Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.4 kcal/mol) outweighs the slightly lower logP and TPSA. Furthermore, Ligand A demonstrates better metabolic stability (lower Cl_mic and longer t1/2) and a superior hERG profile. The difference in binding affinity is substantial enough to overcome the minor ADME drawbacks.

Output:
0
2025-04-17 15:34:38,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.451 and 350.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (53.43), both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.956) is within the optimal 1-3 range, while Ligand B (3.574) is at the higher end, potentially causing solubility issues.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.634 and 0.741, respectively), indicating good drug-like properties.

**DILI:** Ligand A (35.983) has a significantly lower DILI risk than Ligand B (6.592), which is a major advantage.

**BBB:** Ligand A (53.083) has a lower BBB penetration than Ligand B (93.68). This is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.957) has worse Caco-2 permeability than Ligand B (-4.388).

**Aqueous Solubility:** Ligand A (-0.937) has better aqueous solubility than Ligand B (-2.84).

**hERG:** Ligand A (0.022) has a much lower hERG risk than Ligand B (0.832). This is a critical advantage.

**Microsomal Clearance:** Ligand B (56.843) has higher microsomal clearance than Ligand A (29.63), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.612) has a significantly shorter in vitro half-life than Ligand A (-0.846).

**P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux than Ligand B (0.603).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-6.4 kcal/mol). This is a 1.1 kcal/mol difference, which is a good advantage.

**Overall Assessment:**

Ligand B has a better binding affinity and BBB penetration. However, Ligand A demonstrates a significantly better safety profile with lower DILI and hERG risk, better solubility, and improved metabolic stability (lower Cl_mic and longer t1/2). The slightly weaker binding affinity of Ligand A is likely outweighed by its superior ADME-Tox properties, especially the lower hERG risk and DILI. For an enzyme target like SRC kinase, metabolic stability and safety are crucial.

Output:
0
2025-04-17 15:34:38,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.43 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is slightly higher than Ligand B (75.71), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.058 and 2.039), falling within the 1-3 range. Ligand B is slightly more lipophilic.

**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:** Ligand A (0.837) has a significantly higher QED score than Ligand B (0.563), indicating better overall drug-likeness.

**DILI:** Ligand A (32.45) has a lower DILI risk than Ligand B (23.58), suggesting a safer profile.

**BBB:** Ligand A (46.88) has a lower BBB penetration percentile than Ligand B (71.73). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-5.035) has a lower Caco-2 permeability than Ligand B (-4.5). Both are negative, which is unusual, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.284) has worse aqueous solubility than Ligand B (-1.908). Solubility is important for bioavailability, so B is preferable here.

**hERG Inhibition:** Ligand A (0.225) has a lower hERG inhibition liability than Ligand B (0.146), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-10.525) has significantly lower microsomal clearance than Ligand B (63.644), suggesting much better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (4.246) has a shorter in vitro half-life than Ligand B (-19.168). The negative value for B is unusual and likely indicates a very long half-life.

**P-gp Efflux:** Ligand A (0.033) has lower P-gp efflux liability than Ligand B (0.074), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.2), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B has a slightly better binding affinity and Caco-2 permeability, and better BBB penetration. However, Ligand A excels in crucial areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG inhibition, and a higher QED score. The small affinity difference is outweighed by these substantial ADME/Tox advantages.

Output:
0
2025-04-17 15:34:38,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.471 and 342.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the optimal <140, while Ligand B (78.09) is well within the range.

**logP:** Both ligands have acceptable logP values (1.041 and 2.157), 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 3. Both are acceptable, being under the 10 HBA limit.

**QED:** Both ligands have good QED scores (0.751 and 0.836), indicating good drug-like properties.

**DILI:** Ligand A (42.187) has a lower DILI risk than Ligand B (64.521), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B (77.084) has a higher BBB percentile than Ligand A (39.511), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.88 and -4.828), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.153 and -3.199), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.245) has a lower hERG risk than Ligand B (0.526), which is a positive.

**Microsomal Clearance:** Ligand B (-3.975) has a significantly lower (better) microsomal clearance than Ligand A (-0.578). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-27.719) has a much longer in vitro half-life than Ligand A (6.235). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.029 and 0.041).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a better solubility profile (though still poor). The affinity difference, while notable, might be overcome with further optimization. The poor solubility and permeability of both compounds are concerning, but the metabolic stability and safety profile of Ligand B are more favorable. Given the enzyme-specific priorities, the improved metabolic stability and reduced toxicity of Ligand B are more important than the slightly better binding affinity of Ligand A.

Output:
1
2025-04-17 15:34:38,866 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.414 Da) is slightly lower, which *could* be beneficial for permeability, while Ligand B (375.491 Da) is also well within range.

**TPSA:** Ligand A (47.56) is significantly better than Ligand B (96.97). A TPSA under 140 is good for oral absorption, but Ligand B is approaching a level that could hinder it.

**logP:** Ligand A (4.007) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-0.549) is *below* the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=6). Both are within acceptable limits, but lower counts generally favor permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.804, B: 0.647), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 49.981, B: 48.895), both below the 60 threshold.

**BBB:** Ligand A (60.644) has a moderate BBB penetration, while Ligand B (44.552) is lower. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.295) and Ligand B (-5.527) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-5.495) and Ligand B (-1.06) both have negative solubility values, which is also concerning. Poor solubility can limit bioavailability.

**hERG Inhibition:** Ligand A (0.777) has a lower hERG risk than Ligand B (0.133), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-4.259) has a *negative* microsomal clearance, which is impossible. This is a data error and a major red flag. Ligand A (115.451) has a high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand B (-8.128) has a negative half-life, another data error. Ligand A (5.353) has a relatively short half-life, which isn't ideal.

**P-gp Efflux:** Ligand A (0.213) has lower P-gp efflux than Ligand B (0.01), which is preferable.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.5 kcal/mol, B: -8.8 kcal/mol). Ligand B is slightly better, but the difference is small.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more viable candidate. The primary reason is the data quality issues with Ligand B (negative clearance and half-life). Beyond that, Ligand A has a better TPSA, lower hERG risk, and lower P-gp efflux. While both have poor solubility and permeability, the issues with Ligand B's data make it a non-starter. The high clearance of Ligand A is a concern but could be addressed through structural modifications.

Output:
0
2025-04-17 15:34:38,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 and 344.32 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (106.87).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.37 and 1.27), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within the acceptable limits of 5 HBD and 10 HBA.

**QED:** Both ligands have good QED scores (0.514 and 0.604), indicating drug-like properties.

**DILI:** Ligand A (23.89) has a much lower DILI risk than Ligand B (90.07). This is a significant advantage for Ligand A.

**BBB:**  BBB is less critical for a non-CNS target like SRC, but Ligand A (52.93) is slightly lower than Ligand B (61.85).

**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 again is unusual and suggests poor solubility. The scale is not specified, so it's difficult to interpret.

**hERG:** Both ligands have very low hERG risk (0.271 and 0.223).

**Microsomal Clearance:** Ligand A (41.65) has a higher microsomal clearance than Ligand B (-20.46). A negative value for Ligand B suggests very high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (-7.49) and Ligand B (-4.61) both have negative half-life values, which is unusual.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.081 and 0.085).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.7 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have good binding affinity, Ligand A is superior due to its significantly lower DILI risk (23.9 vs 90.1) and better TPSA (58.6 vs 106.9). Ligand B has better metabolic stability (lower Cl_mic), but the lower DILI risk of Ligand A is a more critical factor for an enzyme inhibitor, as liver toxicity is a common issue in drug development. The unusual negative values for Caco-2 and solubility are concerning for both, but the DILI risk is the deciding factor here.

Output:
1
2025-04-17 15:34:38,867 - INFO - Batch 391 complete. Total preferences: 6256
2025-04-17 15:34:38,867 - INFO - Processing batch 392/512...
2025-04-17 15:35:21,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.304 and 349.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.27) is better than Ligand B (113.34), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (0.815 and 1.03), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 6 HBAs and Ligand B has 5, both acceptable.

**QED:** Both ligands have reasonable QED scores (0.753 and 0.674), indicating good drug-likeness.

**DILI:** Ligand B (78.247) has a significantly higher DILI risk than Ligand A (67.468). This is a major concern.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.792) is slightly better than Ligand B (-5.083).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-3.282) is worse than Ligand A (-2.5).

**hERG:** Both have low hERG inhibition risk (0.234 and 0.565), which is good.

**Microsomal Clearance:** Ligand A (-4.335) has a much lower (better) microsomal clearance than Ligand B (21.045), suggesting better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Both have negative half-life values, which is unusual. Ligand A (-21.038) is slightly better than Ligand B (-21.547).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.03 and 0.031).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 2.1 kcal/mol difference, which is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its significantly higher DILI risk and worse metabolic stability (higher Cl_mic) are major drawbacks. The poor solubility and permeability of both compounds are also concerning, but could potentially be addressed through formulation strategies. However, the DILI risk is harder to mitigate. Ligand A, despite its weaker affinity, has a much more favorable safety profile (lower DILI) and better metabolic stability. Given the enzyme-specific priorities, metabolic stability and safety are crucial.

Output:
0
2025-04-17 15:35:21,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.863 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**TPSA:** Ligand A (46.17) is well below the 140 threshold for oral absorption. Ligand B (71.09) is also below, but closer to the limit.

**logP:** Ligand A (4.308) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.795) 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 reasonable numbers of hydrogen bond donors and acceptors, well within the recommended limits.

**QED:** Ligand A (0.779) has a better QED score than Ligand B (0.507), indicating a more drug-like profile.

**DILI:** Ligand B (34.393) has a significantly lower DILI risk than Ligand A (63.086), which is a major advantage.

**BBB:** Ligand A (70.105) shows better BBB penetration than Ligand B (55.293), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 investigated further.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern, but potentially addressable through formulation.

**hERG Inhibition:** Ligand A (0.637) has a slightly higher hERG risk than Ligand B (0.489), but both are relatively low.

**Microsomal Clearance:** Ligand A (38.164) has a significantly lower microsomal clearance than Ligand B (53.208), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (39.474) has a longer in vitro half-life than Ligand B (14.072), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.225) has lower P-gp efflux than Ligand B (0.104), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -8.0 kcal/mol respectively). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B has a significantly better safety profile (lower DILI) and slightly better potency. However, Ligand A has better QED, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. The poor solubility and permeability of both compounds are concerning, but potentially addressable. Given the enzyme-specific priorities, the improved metabolic stability of Ligand A is a significant advantage for a kinase inhibitor, as it suggests a longer duration of action. The slightly higher potency of Ligand B is attractive, but the DILI risk is a major concern.

Output:
1
2025-04-17 15:35:21,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.18) is better than Ligand B (58.2). Both are below 140, suggesting good absorption potential.

**logP:** Ligand A (-0.071) is slightly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.353) is within the optimal range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) both meet the <=10 criteria.

**QED:** Both ligands have similar QED values (0.747 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (26.871) has a significantly lower DILI risk than Ligand B (31.33), which is preferable. Both are below the 40 threshold.

**BBB:** Both ligands have moderate BBB penetration (54.091 and 61.846). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.968) has worse Caco-2 permeability than Ligand B (-5.377). Both are quite poor.

**Aqueous Solubility:** Ligand A (-1.033) has better aqueous solubility than Ligand B (-4.323). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.12 and 0.156).

**Microsomal Clearance:** Ligand A (-0.844) has significantly lower microsomal clearance than Ligand B (39.158), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (0.032) has a very short half-life, while Ligand B (6.529) has a much longer half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.009 and 0.074).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.4 kcal/mol). The difference is small and unlikely to be decisive.

**Conclusion:**

While Ligand A has better solubility and lower DILI risk, Ligand B has a significantly longer half-life and better metabolic stability (lower Cl_mic). Given the enzyme-specific priorities, metabolic stability and longer half-life are more important than slightly better solubility. The binding affinity is similar between the two. The Caco-2 permeability is poor for both, but the longer half-life of Ligand B may compensate for this.

Output:
1
2025-04-17 15:35:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.439 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (95.8) is still under 140, but less optimal than A.

**logP:** Ligand A (3.567) is at the upper end of the optimal range (1-3), while Ligand B (0.962) is slightly below, potentially impacting 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, but A is slightly better.

**QED:** Both ligands have reasonable QED scores (0.84 and 0.593), indicating drug-likeness. Ligand A is superior.

**DILI:** Ligand A (59.984) is borderline, but acceptable. Ligand B (64.405) is also acceptable, but slightly higher risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.776) is higher than Ligand B (45.909).

**Caco-2 Permeability:** Ligand A (-4.462) is better than Ligand B (-5.305), indicating better absorption.

**Aqueous Solubility:** Ligand A (-4.984) is better than Ligand B (-2.178), which is a significant advantage for *in vivo* performance.

**hERG:** Both ligands have low hERG risk (0.481 and 0.206), which is excellent.

**Microsomal Clearance:** Ligand A (50.994) has higher clearance than Ligand B (15.877), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-2.301) has a longer half-life than Ligand A (55.331), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.217 and 0.051).

**Binding Affinity:** Ligand A (-9.6 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 concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better TPSA, solubility, and Caco-2 permeability. However, it has higher microsomal clearance and a shorter half-life. Ligand B has better metabolic stability and half-life, but weaker binding affinity, lower solubility and permeability.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is crucial. While its metabolic stability is a concern, it can potentially be addressed through structural modifications during lead optimization. The improved solubility and permeability also contribute to better potential *in vivo* performance.

Output:
1
2025-04-17 15:35:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.442 and 371.522 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is higher than Ligand B (54.46). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (3.863 and 3.427), 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.

**QED:** Both ligands have acceptable QED scores (0.728 and 0.676), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 67.313, which is moderately high. Ligand B has a significantly lower DILI risk of 26.444, which is excellent. This is a major advantage for Ligand B.

**BBB:** Ligand A (41.799) and Ligand B (91.431). BBB is not a primary concern for a non-CNS target like SRC kinase, but higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.151) and Ligand B (-4.743) are both negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.766 and -3.875).

**hERG Inhibition:** Ligand A (0.551) and Ligand B (0.873). Lower is better. Ligand A is better in this regard.

**Microsomal Clearance:** Ligand A (69.162) and Ligand B (61.148). Lower is better, indicating greater metabolic stability. Ligand B is slightly better.

**In vitro Half-Life:** Ligand A (-9.869) and Ligand B (-8.516). Higher is better. Ligand B is better.

**P-gp Efflux:** Ligand A (0.242) and Ligand B (0.678). Lower is better. Ligand A is better.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 and -8.8 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good potency, Ligand B is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic and higher t1/2), and better BBB penetration. The slightly better Caco-2 permeability and TPSA of Ligand B also contribute to its advantage. The small differences in hERG and P-gp efflux are less critical given the other benefits of Ligand B.

Output:
1
2025-04-17 15:35:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 361.921 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.27) is better than Ligand B (55.63) as it is closer to the 90 A^2 threshold for CNS targets, although SRC is not a CNS target, lower TPSA generally aids absorption.

**logP:** Ligand A (2.56) is optimal, while Ligand B (4.303) is pushing the upper limit and could present solubility issues.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.61 and 0.761, respectively), indicating drug-like properties.

**DILI:** Ligand A (42.846) has a slightly higher DILI risk than Ligand B (37.611), but both are below the concerning threshold of 60.

**BBB:** Ligand A (50.679) has lower BBB penetration than Ligand B (76.386), but BBB is not a major concern for SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which indicates poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values which indicates poor solubility.

**hERG:** Ligand A (0.791) has a slightly higher hERG risk than Ligand B (0.363), but both are relatively low.

**Microsomal Clearance:** Ligand A (12.156) has significantly lower microsomal clearance than Ligand B (33.016), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (13.621) has a slightly longer half-life than Ligand B (32.084).

**P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.449), which is favorable for bioavailability.

**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 minor ADME drawbacks.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.6 kcal/mol vs -7.5 kcal/mol) is a major advantage. Furthermore, it exhibits better metabolic stability (lower Cl_mic) and lower P-gp efflux. While Ligand B has a slightly better DILI score and BBB penetration, these are less critical for a non-CNS enzyme target like SRC. The slightly higher hERG risk of Ligand A is not a major concern given its overall profile.

Output:
1
2025-04-17 15:35:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.481 and 374.453 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold for good absorption, while Ligand B (78.43) is still acceptable but higher.

**logP:** Both ligands have logP values within the optimal 1-3 range (3.245 and 2.598).

**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 acceptable QED scores (0.762 and 0.621), indicating good drug-likeness.

**DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (36.06), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (85.033) has a higher BBB percentile than Ligand B (48.003).

**Caco-2 Permeability:** Ligand A (-4.626) has a more negative Caco-2 value, indicating potentially *lower* permeability compared to Ligand B (-5.681). However, both are quite poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.215 and -3.35). This is a concern, but formulation strategies might mitigate it.

**hERG Inhibition:** Ligand A (0.669) has a lower hERG risk than Ligand B (0.464), which is favorable.

**Microsomal Clearance:** Ligand A (62.999) has lower microsomal clearance than Ligand B (89.06), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.264 hours) has a shorter half-life than Ligand B (-13.638 hours). This is a significant drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.243) has lower P-gp efflux liability than Ligand B (0.083), which is beneficial for bioavailability.

**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 factor.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG inhibition, metabolic stability, and P-gp efflux. However, its significantly shorter half-life and lower Caco-2 permeability are major concerns. Ligand B has a slightly better binding affinity and a much longer half-life, but its higher DILI risk and lower hERG safety are drawbacks.

Considering the enzyme-specific priorities, metabolic stability (longer half-life) is crucial. While Ligand A has better scores in several other areas, the substantial difference in half-life makes Ligand B the more promising candidate. The solubility issues are present in both, and could be addressed with formulation. The slightly better binding affinity of Ligand B further supports this decision.

Output:
1
2025-04-17 15:35:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.375 and 352.523 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (56.07 and 50.6) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.698 and 2.758) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5 HBA, both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.751 and 0.686), indicating drug-like properties.

**DILI:** Ligand A (35.867) has a significantly lower DILI risk than Ligand B (12.253), placing it in a much more favorable category.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (95.308) shows better BBB penetration than Ligand B (81.194).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.646 and -4.451), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-3.505) has slightly better solubility than Ligand B (-1.99), but both are poor.

**hERG Inhibition:** Ligand A (0.595) has a lower hERG inhibition risk than Ligand B (0.748), which is preferable.

**Microsomal Clearance:** Ligand A (24.522) has a significantly lower microsomal clearance than Ligand B (87.721), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (26.791) has a longer in vitro half-life than Ligand A (-4.014), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.215) shows lower P-gp efflux liability than Ligand B (0.097), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.6 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 is the more promising candidate. While both compounds have poor Caco-2 permeability and solubility, Ligand A demonstrates superior metabolic stability (lower Cl_mic), lower DILI risk, lower hERG inhibition, and slightly better binding affinity. The longer half-life of Ligand B is a benefit, but is outweighed by the other factors.

Output:
0
2025-04-17 15:35:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (374.507 and 370.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.32) is better than Ligand B (129.13), being closer to the <140 threshold for good absorption.

**3. logP:** Ligand A (0.994) is within the optimal 1-3 range, while Ligand B (0.184) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (3) is good, while Ligand B (4) is acceptable but slightly less favorable.

**5. H-Bond Acceptors:** Ligand A (6) is good, while Ligand B (8) is acceptable but slightly less favorable.

**6. QED:** Both ligands have reasonable QED scores (0.529 and 0.453), indicating acceptable drug-likeness.

**7. DILI:** Ligand A (26.948) has a significantly lower DILI risk than Ligand B (61.574), which is a major advantage. Ligand B is approaching the concerning >60 percentile.

**8. BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (38.542) is lower than Ligand B (49.787).

**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 direct comparison is difficult without knowing the scale's boundaries.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Similar to Caco-2, direct comparison is difficult.

**11. hERG:** Ligand A (0.334) has a much lower hERG risk than Ligand B (0.666). This is a critical advantage.

**12. Cl_mic:** Ligand A (0.324) has significantly lower microsomal clearance than Ligand B (37.753), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. t1/2:** Ligand A (26.426) has a longer in vitro half-life than Ligand B (-21.538). The negative value for Ligand B is concerning and suggests very rapid degradation.

**14. Pgp:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.012).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol), although both are good. The 1.2 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It demonstrates better metabolic stability (lower Cl_mic, longer t1/2), lower toxicity risk (lower DILI, hERG), and slightly better binding affinity. While both have issues with Caco-2 and solubility, the ADME/Tox profile of Ligand A is far more favorable, making it a much more promising starting point for drug development targeting SRC kinase.

Output:
0
2025-04-17 15:35:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.893 and 360.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.04) is higher than Ligand B (33.95). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cell permeability.

**logP:** Ligand A (3.225) is within the optimal range (1-3), while Ligand B (4.968) is slightly above, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Ligand A (0.854) has a better QED score than Ligand B (0.666), indicating a more drug-like profile.

**DILI:** Ligand B (15.626) has a much lower DILI risk than Ligand A (29.236), a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 77.2, B: 79.062), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.981) and Ligand B (-5.148) are both negative, indicating poor permeability. However, the values are very similar.

**Aqueous Solubility:** Ligand A (-2.88) and Ligand B (-3.656) both have poor aqueous solubility. Ligand B is slightly worse.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.784, B: 0.854).

**Microsomal Clearance:** Ligand A (49.364) and Ligand B (46.406) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (22.789) has a significantly longer half-life than Ligand B (3.785), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.09, B: 0.621), indicating good bioavailability. Ligand A is better.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a crucial factor, as a 1.6 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much lower DILI risk. While Ligand A has a better QED score and in vitro half-life, the stronger binding affinity of Ligand B is a decisive factor for an enzyme target like SRC kinase. The slightly higher logP of Ligand B is a concern, but the substantial affinity advantage likely outweighs this drawback. The similar permeability and solubility values are not enough to favor Ligand A.

Output:
1
2025-04-17 15:35:21,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight:** Both ligands (344.455 and 360.445 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.58) is slightly above the preferred <140, but acceptable. Ligand B (58.64) is well within the acceptable range.

**3. logP:** Both ligands (2.36 and 2.448) 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 (4) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.533 and 0.643), indicating drug-like properties.

**7. DILI:** Ligand A (12.136) has a much lower DILI risk than Ligand B (20.861). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (94.106) is significantly higher than Ligand A (70.997). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.834 and -4.696), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.79 and -2.8). This is also a concern, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.678 and 0.69).

**12. Microsomal Clearance:** Ligand A (33.968) has a lower microsomal clearance than Ligand B (62.083), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-17.181) has a significantly longer in vitro half-life than Ligand B (-1.116). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.121 and 0.091).

**15. Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-7.8). The difference is 0.7 kcal/mol, which is not a huge advantage, but noticeable.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and acceptable TPSA and logP values. The poor Caco-2 and solubility for both are concerning and would require further optimization, but the superior ADME profile of Ligand A outweighs the small difference in binding affinity.

Output:
0
2025-04-17 15:35:21,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (356.769 Da and 386.298 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.92) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (41.29) is well within the ideal range.

**3. logP:** Ligand A (3.605) is within the optimal 1-3 range. Ligand B (4.491) is slightly higher, potentially leading to solubility issues, but still within a tolerable range.

**4. H-Bond Donors (HBD):** Both ligands (A: 2, B: 1) are well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands (A: 5, B: 4) are below the limit of 10.

**6. QED:** Both ligands (A: 0.584, B: 0.762) have good drug-like profiles, exceeding the 0.5 threshold. Ligand B is better.

**7. DILI:** Ligand A (98.371) has a very high DILI risk, which is a significant concern. Ligand B (18.379) has a low DILI risk, a major advantage.

**8. BBB:** Ligand A (36.371) has poor BBB penetration. Ligand B (73.827) has good BBB penetration, but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.297 and -4.871), which is unusual and suggests poor permeability. This needs further investigation, but is a negative for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.361 and -4.692), which is also unusual and suggests poor solubility. This is a negative for both.

**11. hERG Inhibition:** Ligand A (0.47) has a slightly higher hERG risk than Ligand B (0.902), but both are reasonably low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (36.595) has lower clearance, indicating better metabolic stability, which is good. Ligand B (69.744) has higher clearance, which is less desirable.

**13. In vitro Half-Life:** Ligand A (139.823) has a longer half-life, which is favorable. Ligand B (-2.827) has a negative half-life, which is not possible and indicates a problem with the data or the compound.

**14. P-gp Efflux:** Ligand A (0.476) has lower P-gp efflux, which is good. Ligand B (0.687) has slightly higher efflux.

**15. 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.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite similar binding affinities, Ligand B is significantly better due to its dramatically lower DILI risk and better QED score. While both compounds have issues with Caco-2 permeability and solubility, the high DILI risk of Ligand A is a major red flag. The negative half-life of Ligand B is concerning and suggests a data error, but even without that, the DILI risk of Ligand A is a dealbreaker.

Output:
1
2025-04-17 15:35:21,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.3) is slightly higher than the preferred <140, but acceptable. Ligand B (58.44) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.542 and 2.394), falling 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 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.574 and 0.79), indicating drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (43.66 and 43.234 percentile).

**BBB:** Ligand A (63.048) and Ligand B (72.082) both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.755 and -4.61), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.715 and -1.68), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.084) and Ligand B (0.527) have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (47.912) has lower microsomal clearance than Ligand B (56.925), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.537) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound itself. Ligand B (-10.029) also has a negative half-life, also concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.048 and 0.291), which is favorable.

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite both compounds having issues with solubility and permeability, Ligand A's significantly stronger binding affinity (-9.1 vs -7.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The lower microsomal clearance of Ligand A is also favorable. However, the negative half-life values for both compounds raise serious concerns about data quality or inherent instability. Given the choice, and assuming the binding affinity data is reliable, I would prioritize Ligand A for further investigation, but with a strong emphasis on resolving the half-life issue and improving solubility/permeability.

Output:
1
2025-04-17 15:35:21,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.439 and 354.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.19) is slightly higher than Ligand B (60.25), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.656 and 2.674), 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, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.833 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (62.233) has a lower DILI risk than Ligand B (77.394), which is preferable.

**BBB:** Both ligands have good BBB penetration (77.821 and 80.07), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.466 and -4.704). This 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 (-5.096 and -3.518), indicating poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.507) shows slightly higher hERG inhibition risk than Ligand B (0.367), but both are relatively low.

**Microsomal Clearance:** Ligand B (89.245) has a higher microsomal clearance than Ligand A (73.669), indicating lower metabolic stability. This is a disadvantage for Ligand B.

**In vitro Half-Life:** Ligand B (7.365 hours) has a significantly longer half-life than Ligand A (-0.229 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.241) has lower P-gp efflux than Ligand B (0.539), which is favorable.

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative values, Ligand A's significantly stronger binding affinity (-8.5 kcal/mol vs -6.9 kcal/mol) and lower DILI risk make it the more promising candidate. The difference in binding affinity is substantial (>1.5 kcal/mol), and for an enzyme target, potency is paramount. While Ligand B has a better half-life, the potency difference is more critical. Improving solubility and permeability through structural modifications would be the next step in optimizing Ligand A.

Output:
0
2025-04-17 15:35:21,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (359.411 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (110.32) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (78.51) is well within the acceptable range.

**3. logP:** Ligand A (0.831) is a bit low, potentially hindering permeation. Ligand B (1.235) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, and Ligand B has 3 HBA, both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.84) has a higher QED than Ligand B (0.71), indicating a more drug-like profile.

**7. DILI:** Ligand A (83.986) has a significantly higher DILI risk than Ligand B (16.053). This is a major concern for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (57.697 and 59.597), which isn't a primary concern for a non-CNS target like SRC.

**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 (0.274 and 0.13).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-5.646) has a negative clearance, which is not physically possible and indicates an issue with the data. Ligand B (-9.146) also has a negative clearance, indicating an issue with the data.

**13. In vitro Half-Life (t1/2):** Ligand A (0.083) has a very short half-life. Ligand B (-6.736) also has a negative half-life, indicating an issue with the data.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.021).

**15. Binding Affinity:** Ligand A (-9.1) has a slightly better binding affinity than Ligand B (-0.0).

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Overall Assessment:**

Ligand A has a better binding affinity and QED, but its extremely high DILI risk and questionable Cl_mic/t1/2 values are major red flags. The negative values for Cl_mic and t1/2 are concerning and likely indicate data errors. Ligand B has a lower affinity but significantly lower DILI risk and a more reasonable logP. While the negative values for Caco-2, solubility, Cl_mic and t1/2 are concerning, the lower DILI risk makes Ligand B a more promising starting point for optimization, assuming the negative values are data errors.

Output:
1
2025-04-17 15:35:21,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.395 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (131.27) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (66.4) is excellent, well below 140.

**logP:** Ligand A (-0.621) is a bit low, potentially hindering permeability. Ligand B (1.783) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) both meet the <=10 criteria.

**QED:** Both ligands have acceptable QED values (0.417 and 0.66), with Ligand B being slightly more drug-like.

**DILI:** Both ligands have similar, low DILI risk (34.393 and 38.891 percentile), indicating minimal liver injury potential.

**BBB:** Both ligands have similar BBB penetration (76.58 and 76.813 percentile), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.467 and -5.249), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.111 and -1.625), which is also concerning and indicates poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.069 and 0.239 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (3.871) has significantly lower microsomal clearance than Ligand B (36.826), suggesting better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (-10.462) has a negative half-life, which is not physically possible and indicates a potential data error or a very rapidly metabolized compound. Ligand B (-1.914) is also negative, but less extreme.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.032 percentile), which is favorable.

**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 relatively small.

**Overall Assessment:**

Despite the similar affinities, Ligand A is problematic due to the negative and very low in vitro half-life. The negative solubility and Caco-2 values for both are also concerning. However, Ligand A's significantly lower microsomal clearance is a major advantage. Ligand B has better TPSA and logP values, but the much higher clearance is a significant drawback. Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) is crucial. While Ligand A's half-life is a major red flag, the substantial difference in clearance makes it potentially more viable *if* the half-life data is an error. However, assuming the data is correct, Ligand B is the better candidate.

Output:
1
2025-04-17 15:35:21,195 - INFO - Batch 392 complete. Total preferences: 6272
2025-04-17 15:35:21,195 - INFO - Processing batch 393/512...
2025-04-17 15:36:03,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.463 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than Ligand B (58.44). While both are under the 140 threshold for oral absorption, Ligand B's lower TPSA is generally more favorable for permeability.

**logP:** Ligand A (0.432) is quite low, potentially hindering permeability. Ligand B (2.719) 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 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.614 and 0.645), indicating good drug-likeness.

**DILI:** Ligand A (9.267) has a very low DILI risk, significantly better than Ligand B (29.624). This is a major positive for Ligand A.

**BBB:** Ligand A (51.415) has a lower BBB penetration percentile than Ligand B (81.543). However, BBB penetration is less crucial for a kinase inhibitor unless CNS targets are specifically desired.

**Caco-2 Permeability:** Ligand A (-4.922) has a lower Caco-2 permeability than Ligand B (-4.695), but both are negative values and therefore difficult to interpret without knowing the scale.

**Aqueous Solubility:** Ligand A (-0.614) has slightly better solubility than Ligand B (-1.535).

**hERG Inhibition:** Ligand A (0.102) has a much lower hERG inhibition risk than Ligand B (0.772). This is a critical advantage for Ligand A, as kinase inhibitors can sometimes exhibit cardiotoxicity.

**Microsomal Clearance:** Ligand A (-10.992) has significantly lower microsomal clearance, indicating better metabolic stability, than Ligand B (87.781). This is a substantial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (1.343) has a shorter half-life than Ligand B (25.214). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux liability, while Ligand B (0.588) has moderate liability.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.2 kcal/mol). The 2 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for an enzyme inhibitor: strong binding affinity, very low DILI risk, low hERG inhibition, and excellent metabolic stability (low Cl_mic). Its lower logP and shorter half-life are concerns, but the superior binding affinity and safety profile are compelling. Ligand B has better logP and half-life, but suffers from higher DILI, hERG, and P-gp efflux risks, and a weaker binding affinity.

Considering the priorities for kinase inhibitors, the benefits of Ligand A's superior potency and safety profile outweigh its drawbacks.

Output:
1
2025-04-17 15:36:03,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.407 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.06) is well below the 140 threshold, and quite favorable. Ligand B (113.18) is still within acceptable limits, but less optimal.

**logP:** Both ligands (1.361 and 1.493) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent, minimizing potential issues with permeability. Ligand B (3) is acceptable, but slightly higher.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Ligand A (0.824) has a significantly better QED score than Ligand B (0.543), indicating a more drug-like profile.

**DILI:** Ligand A (82.784) has a higher DILI risk than Ligand B (67.39), which is concerning. However, the difference isn't massive.

**BBB:** Both ligands have similar BBB penetration (64.444 and 65.258), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.343) has a worse Caco-2 permeability than Ligand B (-5.101). Lower values indicate reduced permeability.

**Aqueous Solubility:** Ligand A (-4.117) has worse aqueous solubility than Ligand B (-3.36). Lower values indicate reduced solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.389 and 0.295).

**Microsomal Clearance:** Ligand A (59.785) has a higher microsomal clearance than Ligand B (18.725), suggesting lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (-12.785) has a shorter in vitro half-life than Ligand B (-11.046), further supporting the lower metabolic stability concern.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.246 and 0.041).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is better, the difference is not huge.

**Overall Assessment:**

Ligand A has a better QED score and slightly better binding affinity. However, it suffers from significantly higher microsomal clearance, shorter half-life, and reduced solubility and permeability. Ligand B, while having a slightly lower binding affinity, demonstrates better ADME properties, particularly in terms of metabolic stability and solubility. Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and solubility are crucial. The improved ADME profile of Ligand B outweighs the small difference in binding affinity.

Output:
1
2025-04-17 15:36:03,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.479 and 370.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.54) is slightly higher than the preferred <140, but acceptable. Ligand B (66.92) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.398) is quite low, potentially hindering permeability. Ligand B (1.634) 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 5 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.56 and 0.665), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (9.849 and 44.824), below the concerning threshold of 60.

**BBB:** Ligand A (43.117) and Ligand B (53.703) both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.724) shows very poor permeability, a significant concern. Ligand B (-4.625) is better, but still indicates limited permeability.

**Aqueous Solubility:** Ligand A (-0.611) and Ligand B (-2.586) both have poor aqueous solubility, which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.148) shows very low hERG inhibition risk, which is excellent. Ligand B (0.368) is also low risk.

**Microsomal Clearance:** Ligand A (-15.463) has very low microsomal clearance, indicating high metabolic stability. This is a major advantage. Ligand B (86.609) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (5.483) has a relatively short half-life. Ligand B (-20.099) has a very long half-life, which is highly desirable.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.005 and 0.152).

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.4), but the difference is less than 1.5 kcal/mol.

**Conclusion:**

While Ligand A has a slightly better binding affinity and excellent hERG and metabolic stability, its extremely poor Caco-2 permeability and low logP are major drawbacks. Ligand B, despite having slightly weaker affinity and higher clearance, has better permeability characteristics (though still not great) and a significantly longer half-life. Given the enzyme-specific priorities, metabolic stability and half-life are crucial. The better half-life of Ligand B, combined with acceptable (though not ideal) permeability, makes it a more promising starting point for optimization.

Output:
1
2025-04-17 15:36:03,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.407 and 392.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (124.78 and 123.85) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.984) is within the optimal 1-3 range, while Ligand B (-0.232) is slightly below 1, potentially impacting permeability.

**H-Bond Donors:** Both have 2 HBD, well within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 8. Both are below the 10 limit, but Ligand A is preferable.

**QED:** Ligand B (0.595) has a better QED score than Ligand A (0.316), indicating better overall drug-likeness.

**DILI:** Ligand A (41.14) has a significantly lower DILI risk than Ligand B (79.139). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (61.691) has a higher BBB score than Ligand A (31.718), but it's not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.311 and -5.467), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.509 and -2.498), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.062) has a much lower hERG risk than Ligand B (0.547). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (18.601) has a lower microsomal clearance than Ligand B (22.799), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.093) has a negative half-life, which is not possible. This is a major red flag. Ligand A (1.295) has a short half-life, but it's a realistic value.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.03).

**Binding Affinity:** Both ligands have strong binding affinities (-9.1 and -8.3 kcal/mol). Ligand A is slightly more potent, with a 0.8 kcal/mol advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and permeability, Ligand A has a significantly better safety profile (lower DILI and hERG risk), better metabolic stability (lower Cl_mic), and a slightly better binding affinity. Ligand B has a problematic negative in vitro half-life and higher DILI/hERG risk, making it less desirable. The 0.8 kcal/mol affinity difference is not enough to overcome the ADME/Tox concerns with Ligand B.

Output:
0
2025-04-17 15:36:03,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.391 and 350.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (124.2 and 125.03) are slightly above the optimal <140 for good oral absorption, but not drastically so.

**logP:** Ligand A (2.384) is within the optimal 1-3 range. Ligand B (-1.147) is significantly below this, which could hinder permeability.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (2 HBD, 8 HBA), as it's closer to the ideal ranges for both.

**QED:** Ligand B (0.698) has a better QED score than Ligand A (0.352), suggesting a more drug-like profile overall.

**DILI:** Both ligands have relatively high DILI risk (60.217 and 63.668), which is a concern.

**BBB:** Ligand A (61.807) has a slightly better BBB penetration score than Ligand B (22.179), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.86) has a worse Caco-2 permeability than Ligand B (-5.317), indicating poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.527) has better aqueous solubility than Ligand B (-1.232). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.068 and 0.081), which is excellent.

**Microsomal Clearance:** Ligand B (-13.594) has significantly lower (better) microsomal clearance than Ligand A (54.53), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-27.053) has a much longer in vitro half-life than Ligand A (-3.65), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.002).

**Binding Affinity:** Both ligands have the same binding affinity (-7.0 kcal/mol), which is excellent and meets the criteria.

**Conclusion:**

While Ligand B has a better QED score and significantly improved metabolic stability (lower Cl_mic and longer t1/2), its low logP is a significant drawback. Ligand A has a more favorable logP, better solubility, and a slightly better BBB score. However, the improved metabolic stability of Ligand B is a crucial factor for an enzyme target like SRC kinase. The strong binding affinity is the same for both, so the ADME properties become the deciding factor. Given the importance of metabolic stability for kinases, I would choose Ligand B, but with a caveat that the low logP needs to be addressed in further optimization.

Output:
1
2025-04-17 15:36:03,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.933 and 366.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (74.33) is well below the 140 threshold for oral absorption, while Ligand B (95.74) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (2.296 and 1.453), 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 similar QED scores (0.789 and 0.729), indicating good drug-likeness.

**DILI:** Ligand A (46.336) has a slightly higher DILI risk than Ligand B (22.722), but both are below the concerning threshold of 60.

**BBB:** Both ligands have acceptable BBB penetration, with Ligand B (77.937) being slightly better than Ligand A (65.568). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired or problematic.

**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 significant concern. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.622) has a slightly higher hERG risk than Ligand B (0.117). Lower hERG is preferred.

**Microsomal Clearance:** Ligand B (31.708) has a significantly higher microsomal clearance than Ligand A (4.564). This indicates that Ligand A is more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (49.452) has a much longer in vitro half-life than Ligand B (-2.033). This is a major advantage for Ligand A, as it suggests less frequent dosing could be possible.

**P-gp Efflux:** Ligand A (0.209) has lower P-gp efflux than Ligand B (0.016), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial difference (1.4 kcal/mol), and is a major factor.

**Overall Assessment:**

While Ligand A has better ADME properties (lower clearance, longer half-life, lower P-gp efflux, and slightly lower DILI), Ligand B has a significantly stronger binding affinity. For an enzyme target like SRC kinase, potency is paramount. The 1.4 kcal/mol difference in binding affinity is substantial enough to potentially overcome the ADME liabilities of Ligand B, especially if formulation strategies can address the solubility and permeability issues. The better metabolic stability and half-life of Ligand A are attractive, but a potent compound is more likely to show efficacy, and optimization can often improve ADME properties.

Output:
1
2025-04-17 15:36:03,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.231 Da) is slightly higher than Ligand B (352.435 Da), but both are acceptable.

**2. TPSA:** Ligand A (85.25) is well below the 140 threshold for oral absorption. Ligand B (96.69) is also acceptable, though slightly higher.

**3. logP:** Ligand A (1.725) is within the optimal range (1-3). Ligand B (0.094) 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 5 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.734 and 0.725), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 89.259, which is high. Ligand B has a much lower DILI risk of 20.202, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 70.803, which is reasonable. Ligand B has a BBB penetration of 36.06, which is low. However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.855) has better Caco-2 permeability than Ligand B (-4.609), suggesting better absorption.

**10. Aqueous Solubility:** Ligand A (-4.116) has better aqueous solubility than Ligand B (-0.825). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.61) has a slightly higher hERG risk than Ligand B (0.35), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (52.818) has higher microsomal clearance than Ligand B (12.086), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (10.143) has a longer half-life than Ligand B (-6.225). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.47) has lower P-gp efflux than Ligand B (0.014), suggesting better bioavailability.

**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 major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's better Caco-2 permeability, solubility, half-life, and P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-6.5 vs 0 kcal/mol) is crucial for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk, which is a critical safety concern. While Ligand B's logP is low, its superior potency and safety profile make it the preferred choice.

Output:
1
2025-04-17 15:36:03,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.451 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (98.82 and 100.35) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (-0.269) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.2) is closer to the lower end of 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 4 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.615 and 0.764), indicating drug-like properties.

**7. DILI:** Ligand A (26.638) has a significantly lower DILI risk than Ligand B (42.807), which is a major advantage.

**8. BBB:** Both have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (60.527) is slightly higher than Ligand A (45.328).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.873 and -5.169), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.459 and -1.744), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.034 and 0.233), which is excellent.

**12. Microsomal Clearance:** Ligand A (29.434) has a higher microsomal clearance than Ligand B (2.273), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-9.169) has a significantly longer in vitro half-life than Ligand A (-18.77), indicating better stability.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.038).

**15. Binding Affinity:** Both have the same binding affinity (-8.1 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While both compounds have excellent binding affinity and low hERG risk, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better Caco-2 permeability. Ligand A's higher clearance is a major concern. The poor solubility and permeability are shared issues that would need to be addressed through formulation or further structural modifications, but the ADME profile of Ligand B is more favorable overall.

Output:
1
2025-04-17 15:36:03,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 Da and 344.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.5 and 83.98) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.165 and 2.148) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, satisfying the <5 and <10 rules respectively.

**QED:** Both ligands have good QED scores (0.623 and 0.719), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (52.346 and 51.454 percentiles), below the concerning 60 threshold.

**BBB:** Ligand B (81.543) has a slightly higher BBB penetration percentile than Ligand A (64.637), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.874 and -4.893), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.631 and -3.188), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.101 and 0.447), which is positive.

**Microsomal Clearance:** Ligand B (13.848 mL/min/kg) has significantly lower microsomal clearance than Ligand A (44.237 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (12.486 hours) has a much longer in vitro half-life than Ligand A (-10.94 hours). The negative value for Ligand A is concerning. This is another significant advantage for Ligand B.

**P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.222 and 0.044).

**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 substantial and outweighs some of the ADME concerns.

**Conclusion:**

While both ligands have significant ADME liabilities (poor solubility and permeability), Ligand B is the more promising candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2) and stronger binding affinity are critical advantages for an enzyme target like SRC kinase. The slightly better BBB value is a minor benefit. Addressing the solubility and permeability issues will be essential for further development, but the improved potency and pharmacokinetics of Ligand B make it the better starting point.

Output:
1
2025-04-17 15:36:03,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.4 and 342.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.35) is better than Ligand B (99.24). Both are below 140, suggesting reasonable absorption, but A is preferable.

**logP:** Ligand A (0.895) is slightly lower than optimal (1-3), but still acceptable. Ligand B (1.839) is better positioned within the optimal range.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 6. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.791 and 0.78), indicating good drug-likeness.

**DILI:** Ligand A (75.38) has a higher DILI risk than Ligand B (59.83). This is a significant negative for Ligand A.

**BBB:** Ligand A (20.86) has very low BBB penetration, while Ligand B (71.66) has good BBB penetration. Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2:** Both have negative Caco-2 values (-4.979 and -4.98), which is unusual and problematic. It suggests poor permeability. However, these values are very similar.

**Solubility:** Ligand A (-2.39) is slightly better than Ligand B (-3.077), indicating better aqueous solubility.

**hERG:** Ligand A (0.551) has a slightly higher hERG risk than Ligand B (0.422), but both are relatively low.

**Microsomal Clearance:** Ligand A (-21.03) has significantly lower (better) microsomal clearance than Ligand B (14.93). This suggests much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-2.335) has a shorter half-life than Ligand B (38.074). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.065).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.7 kcal/mol), which are excellent. The difference is negligible.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic) and solubility, but suffers from higher DILI risk and a shorter half-life. Ligand B has better BBB penetration (though less relevant here), a longer half-life, and lower DILI risk. The binding affinity is essentially the same. Given the enzyme-specific priorities, metabolic stability and DILI are crucial. While A has better stability, the higher DILI risk is a major concern. The longer half-life of B is also a significant advantage.

Output:
1
2025-04-17 15:36:03,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.451 and 337.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (63.69 and 62.73) are below the 140 A^2 threshold for good oral absorption and well within range.

**3. logP:** Ligand A (1.942) is optimal, while Ligand B (4.32) is slightly high, potentially leading to solubility issues or off-target interactions.

**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 (6 and 5, respectively), below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.884 and 0.796), indicating drug-likeness.

**7. DILI:** Ligand A (68.476) has a higher DILI risk than Ligand B (45.173). This is a concern for Ligand A.

**8. BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**9. 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 the absolute impact is unclear.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified, so the absolute impact is unclear.

**11. hERG Inhibition:** Ligand A (0.403) has a lower hERG inhibition liability than Ligand B (0.718), which is favorable.

**12. Microsomal Clearance:** Ligand B (43.981) has significantly higher microsomal clearance than Ligand A (11.973), indicating lower metabolic stability. This is a major drawback for Ligand B.

**13. In vitro Half-Life:** Ligand B (41.842) has a much longer in vitro half-life than Ligand A (1.934), which is generally desirable. However, this benefit is offset by the high clearance.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.154, respectively).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.5 and -9.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other ADME considerations.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While it has a higher DILI risk, its significantly lower microsomal clearance (better metabolic stability) and lower hERG inhibition are crucial advantages. Ligand B's high clearance is a major concern, potentially leading to rapid drug metabolism and reduced efficacy. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 15:36:03,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.276 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**2. TPSA:** Ligand A (66.84) is better than Ligand B (80.12). Both are below 140, indicating reasonable oral absorption potential.

**3. logP:** Both ligands have good logP values (A: 2.911, B: 1.603), 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 limit of <=10.

**6. QED:** Both ligands have similar QED values (A: 0.75, B: 0.76), indicating good drug-likeness.

**7. DILI:** Ligand A (59.984) has a higher DILI risk than Ligand B (31.989). This is a significant concern, as we want to minimize liver injury risk.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (73.827) is better than Ligand A (54.207). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Ligand A (-4.683) has a worse Caco-2 permeability than Ligand B (-5.107). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.046) has a worse aqueous solubility than Ligand B (-2.358). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.8) has a higher hERG inhibition risk than Ligand B (0.206). Lower hERG risk is crucial to avoid cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (72.396) has a higher microsomal clearance than Ligand B (60.618). Lower clearance is preferred for better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.274) has a longer in vitro half-life than Ligand A (5.213). This is a significant advantage for dosing frequency.

**14. P-gp Efflux:** Ligand A (0.539) has a higher P-gp efflux liability than Ligand B (0.091). Lower efflux is desirable for better bioavailability.

**15. Binding Affinity:** Ligand A (-7.7) has a significantly better binding affinity than Ligand B (-6.7). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, hERG inhibition, and P-gp efflux, and lower solubility and half-life. Ligand B has a better safety profile (lower DILI, hERG) and better ADME properties (solubility, half-life, P-gp efflux), but its binding affinity is considerably weaker.

Given the significant affinity advantage of Ligand A (-7.7 vs -6.7 kcal/mol), and the fact that ADME issues can often be addressed through further optimization, I would initially favor Ligand A. The improved potency is likely to be more impactful than the ADME liabilities, which can be mitigated in subsequent rounds of optimization.

Output:
1
2025-04-17 15:36:03,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.479 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (104.53 and 109.42) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands have acceptable logP values (1.246 and 0.767), falling within the 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 3 HBA, while Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.627 and 0.703), indicating good drug-like properties.

**7. DILI:** Ligand A (26.173) has a significantly lower DILI risk than Ligand B (44.591). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (67.817 and 67.701). Since SRC is not a CNS target, this is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.112 and -4.91). This is unusual and suggests poor permeability. However, these values are on a log scale, so a small difference can be significant.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.226 and -1.953), indicating 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 (0.191 and 0.064), which is excellent.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (17.956 and 18.909), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand A has a very short half-life (0.127 hours) compared to the negative value for Ligand B (-11.96). This is a significant disadvantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.013).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 1.6 kcal/mol difference is substantial and outweighs many other concerns.

**Overall Assessment:**

While Ligand A has a better DILI profile, Ligand B's significantly stronger binding affinity (-8.3 vs -6.7 kcal/mol) is the most critical factor for an enzyme inhibitor. The improved potency is likely to outweigh the slightly higher DILI risk and the poorer half-life, which can be addressed through structural modifications. The permeability and solubility issues are shared by both compounds and can be tackled during formulation.

Output:
1
2025-04-17 15:36:03,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (352.435 and 343.333 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.69) is better than Ligand B (49.17), both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (-0.119) is quite low, potentially hindering permeation. Ligand B (3.408) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.572 and 0.731), indicating drug-likeness.

**DILI:** Ligand A (16.673) has a much lower DILI risk than Ligand B (81.039). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (32.842) and Ligand B (78.868). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.121) and Ligand B (-4.375). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (0.16) is very poor, while Ligand B (-4.923) is also poor. Solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.211) has a lower hERG risk than Ligand B (0.673). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (15.281) has a lower Cl_mic, suggesting better metabolic stability than Ligand B (53.361). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-11.323) has a negative half-life, which is concerning. Ligand B (-31.032) is also negative, and worse.

**P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux liability than Ligand B (0.754), which is favorable.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage for Ligand B, and likely outweighs some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most critical factor for an enzyme inhibitor. While it has a higher DILI risk and worse metabolic stability than Ligand A, the difference in binding affinity (-9.6 vs -6.9 kcal/mol) is substantial (a 2.7 kcal/mol difference). This difference in potency is likely to outweigh the ADME concerns, especially if further optimization can address the DILI and metabolic stability issues. Ligand A's very poor solubility is also a significant drawback.

Output:
1
2025-04-17 15:36:03,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.405 Da) is slightly preferred due to being lower in MW.

**TPSA:** Ligand A (61.19) is significantly better than Ligand B (88.6). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (A: 3.097, B: 2.53), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is better than Ligand B (1 HBD, 6 HBA). Lower HBD counts can improve permeability. Both have acceptable HBA counts.

**QED:** Both ligands have good QED scores (A: 0.427, B: 0.704), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Both ligands have similar, acceptable DILI risk (A: 70.143, B: 79.721).

**BBB:** Ligand A (98.333) has significantly higher BBB penetration than Ligand B (77.2). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.211) is slightly better than Ligand B (-4.823), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.167) is better than Ligand B (-3.455), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.533) has a lower hERG inhibition risk than Ligand B (0.342), which is a significant advantage.

**Microsomal Clearance:** Ligand A (95.374) has a higher microsomal clearance than Ligand B (71.612), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (18.564) has a significantly longer in vitro half-life than Ligand A (-2.163), which is a major advantage.

**P-gp Efflux:** Ligand A (0.457) has a lower P-gp efflux liability than Ligand B (0.279), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.3 kcal/mol, B: -8.6 kcal/mol), with Ligand B being slightly better. However, the difference is small.

**Overall Assessment:**

Ligand A has advantages in TPSA, solubility, hERG, and P-gp efflux. However, Ligand B excels in QED, in vitro half-life, and has slightly better binding affinity. The biggest concern with Ligand A is its higher microsomal clearance (lower metabolic stability) and negative in vitro half-life. Considering the importance of metabolic stability for kinase inhibitors, Ligand B appears to be the more promising candidate despite a slightly lower solubility and higher P-gp efflux.

Output:
1
2025-04-17 15:36:03,151 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447 Da) is slightly better positioned.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (88.61) is slightly better than Ligand A (100.29).

**logP:** Ligand A (2.074) is within the optimal range (1-3). Ligand B (4.392) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (2 HBD, 7 HBA) both fall within acceptable limits.

**QED:** Ligand A (0.624) has a better QED score than Ligand B (0.343), indicating a more drug-like profile.

**DILI:** Ligand A (36.758) has a significantly lower DILI risk than Ligand B (87.515). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (59.364) is better than Ligand B (49.515).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.843) is slightly better than Ligand A (-5.037), but both are problematic.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.343) is slightly better than Ligand B (-4.175).

**hERG Inhibition:** Ligand A (0.213) has a much lower hERG inhibition liability than Ligand B (0.915). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 50.793, Ligand B: 52.576), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (66.864) has a significantly longer in vitro half-life than Ligand A (7.59). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux liability than Ligand B (0.82), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand A is the superior candidate. While both have poor Caco-2 and solubility, Ligand A's significantly stronger binding affinity (-8.3 vs -0.0 kcal/mol) and much lower DILI and hERG risks outweigh the longer half-life of Ligand B. The better QED score and lower P-gp efflux also contribute to its favorability. The high potency of Ligand A suggests it can overcome some of the ADME liabilities with appropriate formulation strategies.

Output:
1
2025-04-17 15:36:03,151 - INFO - Batch 393 complete. Total preferences: 6288
2025-04-17 15:36:03,151 - INFO - Processing batch 394/512...
2025-04-17 15:36:45,307 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.423 and 346.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.31 and 101.8) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (0.75) is slightly better than Ligand B (0.469). Both are a bit low, potentially hindering permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is preferable to Ligand B (2 HBD, 6 HBA) as it has fewer HBDs. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.781 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (52.656) has a lower DILI risk than Ligand B (57.697), which is a positive. Both are below the concerning 60 threshold.

**BBB:** Both ligands have reasonably high BBB penetration (78.907 and 71.501), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.95) has a better (more negative) Caco-2 value than Ligand B (-5.285), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.947) has better aqueous solubility than Ligand B (-2.732), which is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.211 and 0.235), which is excellent.

**Microsomal Clearance:** Ligand A (49.59) has a significantly better (lower) microsomal clearance than Ligand B (4.305). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-18.423) has a much longer in vitro half-life than Ligand B (5.857), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.051 and 0.007), which is positive.

**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 (1.2 kcal/mol difference), and can often outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A demonstrates superior ADME properties, particularly in metabolic stability (lower Cl_mic, longer t1/2) and solubility, Ligand B's substantially stronger binding affinity (-8.5 vs -7.3 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. The difference in affinity is large enough to compensate for the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 15:36:45,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (430.368 Da) is slightly higher than Ligand B (360.483 Da), but both are acceptable.

**TPSA:** Ligand A (91.22) is slightly above the preferred <140, while Ligand B (78.25) is well within the range. This favors Ligand B for absorption.

**logP:** Ligand A (3.257) is optimal, while Ligand B (1.889) is a bit low, potentially impacting permeability.

**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: 0.628, B: 0.784), indicating drug-like properties.

**DILI:** Ligand A (57.697) has a moderate DILI risk, while Ligand B (21.946) has a very low risk, a significant advantage for B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.811) is better than Ligand B (61.923).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the absolute value is more important. Ligand A (-4.951) is slightly better than Ligand B (-5.091).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.447) is slightly better than Ligand A (-4.112).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.751, B: 0.589), which is good.

**Microsomal Clearance:** Ligand A (45.377) has a higher clearance than Ligand B (41.171), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (35.929 hours) has a significantly longer half-life than Ligand B (3.572 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.197, B: 0.054), which is favorable.

**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 ADME concerns.

**Overall Assessment:**

Ligand B has a much better safety profile (lower DILI) and superior binding affinity. While its logP is slightly lower and half-life shorter, the strong binding and low toxicity are critical for an enzyme target like SRC. Ligand A's longer half-life is attractive, but the higher DILI risk and weaker binding are concerning. The negative solubility and Caco-2 values are problematic for both, but the stronger binding of B makes it more likely to overcome these issues with formulation strategies.

Output:
1
2025-04-17 15:36:45,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-specific properties (affinity, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (120.29). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have acceptable logP values (A: 1.108, B: 1.528), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), keeping within the desirable range.

**QED:** Ligand A (0.73) has a better QED score than Ligand B (0.467), indicating a more drug-like profile.

**DILI:** Ligand A (21.481) has a much lower DILI risk than Ligand B (62.233). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.613) is better than Ligand B (55.099).

**Caco-2 Permeability:** Ligand A (-4.684) is better than Ligand B (-5.119). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.96) is better than Ligand B (-1.693). Higher solubility is preferred.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.213, B: 0.102), which is excellent.

**Microsomal Clearance:** Ligand A (8.139) has a significantly lower Cl_mic than Ligand B (20.754), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.08) has a lower half-life than Ligand B (19.591). This is a drawback for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.055, B: 0.039).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.6 kcal/mol and -9.2 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:**

Ligand A is clearly superior. It has better TPSA, QED, DILI risk, solubility, Caco-2 permeability, and microsomal clearance. While its half-life is shorter, the other advantages, particularly the significantly lower DILI risk and better ADME profile, make it a more promising candidate. The slightly better binding affinity of Ligand A is a bonus.

Output:
1
2025-04-17 15:36:45,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.419 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.17) is better than Ligand B (96.25), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (0.735 and 1.418), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is preferable to Ligand B (3 HBD, 5 HBA) as it has fewer HBDs, which can sometimes hinder permeability. Both are within acceptable ranges.

**QED:** Ligand A (0.88) has a significantly better QED score than Ligand B (0.626), indicating a more drug-like profile.

**DILI:** Ligand A (61.419) has a higher DILI risk than Ligand B (15.238). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.786) is slightly better than Ligand B (23.071).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.139 and -5.307), 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 (-1.458 and -1.197), indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**hERG Inhibition:** Ligand A (0.547) has a lower hERG inhibition risk than Ligand B (0.164), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-12.174) has a much lower (better) microsomal clearance than Ligand B (21.522), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (33.177) has a longer half-life than Ligand B (-9.858), which is desirable.

**P-gp Efflux:** Ligand A (0.058) shows lower P-gp efflux than Ligand B (0.025), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has slightly better binding affinity than Ligand A (-7.5 kcal/mol). While a 1.1 kcal/mol difference is notable, it may not be enough to overcome the ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A has a better overall profile. It exhibits superior QED, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk. While its DILI risk is higher, the significant improvements in metabolic stability and drug-likeness outweigh this concern, especially considering the slightly better binding affinity of Ligand B isn't substantial enough to compensate for its poor ADME properties. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 15:36:45,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.515 and 369.305 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (29.54). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**3. logP:** Ligand A (0.804) is within the optimal range (1-3). Ligand B (4.234) is slightly high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also acceptable, but may impact aqueous solubility.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (2) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.664 and 0.703), indicating drug-like properties.

**7. DILI:** Ligand A (13.649) has a significantly lower DILI risk than Ligand B (26.134), a crucial advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (96.123) has a high BBB score, but this is not a primary concern here. Ligand A (46.064) is lower, as expected.

**9. Caco-2 Permeability:** Ligand A (-5.749) is better than Ligand B (-4.136), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.271) is better than Ligand B (-5.232), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.104) has a much lower hERG risk than Ligand B (0.834), a critical safety factor.

**12. Microsomal Clearance:** Ligand A (-3.098) has a lower (better) microsomal clearance than Ligand B (58.674), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.101) has a longer (better) in vitro half-life than Ligand B (-9.777).

**14. P-gp Efflux:** Ligand A (0.014) has lower P-gp efflux liability than Ligand B (0.253), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-10.3) has a significantly stronger binding affinity than Ligand A (-7.5). This is a 2.8 kcal/mol difference, which is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding DILI, hERG, metabolic stability, and solubility. The difference in binding affinity is significant, but the safety and pharmacokinetic advantages of Ligand A are compelling. For a kinase inhibitor, metabolic stability and lack of off-target effects (like hERG inhibition) are paramount.

Output:
0
2025-04-17 15:36:45,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight (MW):** Both ligands (348.447 and 356.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.25) is well below the 140 threshold for good oral absorption, and even below the 90 for CNS targets. Ligand B (107.89) is still within acceptable limits for oral absorption, but higher than A.

**3. logP:** Ligand A (1.424) is within the optimal range of 1-3. Ligand B (0.479) is slightly below 1, which *could* indicate permeability issues, but not drastically.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 4 respectively), 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:** Ligand A (0.78) has a significantly better QED score than Ligand B (0.45), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (28.228 and 22.8), well below the concerning threshold of 60.

**8. BBB:** Ligand A (57.464) has a moderate BBB penetration, while Ligand B (40.52) is lower. Since SRC is not a CNS target, this is less critical, but still a slight advantage for A.

**9. Caco-2 Permeability:** Ligand A (-4.931) has better Caco-2 permeability than Ligand B (-5.315), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.375 and -1.269 respectively). This is a potential issue for both, but needs to be considered alongside other properties.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.107 and 0.262), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand A (17.329) has a higher microsomal clearance than Ligand B (6.047), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (24.887) has a longer half-life than Ligand B (6.859), which is a positive. However, this benefit is somewhat offset by the higher Cl_mic.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.057), which is favorable.

**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 >1.5 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has superior affinity, but worse metabolic stability (higher Cl_mic). Ligand B has better metabolic stability, but lower affinity. The difference in affinity is substantial.

**Conclusion:**

Despite Ligand A's higher Cl_mic, the significantly stronger binding affinity (-8.3 vs -6.9 kcal/mol) is a major advantage for an enzyme target. The improved QED and Caco-2 permeability also contribute to its favorability. While solubility is a concern for both, the potency advantage of Ligand A is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 15:36:45,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.459 Da and 375.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.44) is better than Ligand B (121.97), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.632) is slightly better than Ligand B (-0.097). Both are a bit low, potentially impacting permeability, but Ligand A is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 7 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.616 and 0.682), indicating drug-likeness.

**DILI:** Ligand B (54.323) has a significantly lower DILI risk than Ligand A (80.186). This is a substantial advantage.

**BBB:** Both have low BBB penetration (46.879 and 42.962), which isn't a major concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-5.445 and -5.018) which is unusual and suggests poor permeability.

**Solubility:** Both have negative solubility values (-3.018 and -2.034), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG:** Both have low hERG inhibition liability (0.32 and 0.229), which is excellent.

**Microsomal Clearance:** Ligand B (13.83 mL/min/kg) has much lower microsomal clearance than Ligand A (41.575 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Both have negative in vitro half-life values (-31.068 and -31.961), which is unusual and suggests rapid degradation.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.033 and 0.036).

**Binding Affinity:** Ligand B (-8.0 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 positive factor.

**Overall Assessment:**

Ligand B is the better candidate. While both compounds have poor solubility and Caco-2 permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic) and a lower DILI risk. The slightly improved binding affinity is a bonus. The solubility issue is a major concern for both, but could potentially be addressed through formulation strategies. The metabolic stability advantage of Ligand B is particularly important for an enzyme target.

Output:
1
2025-04-17 15:36:45,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 366.575 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.87) is better than Ligand B (52.23), being closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (-0.399) is slightly low, potentially hindering permeation. Ligand B (3.176) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (6) is acceptable, while Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (0.642 and 0.691, respectively), indicating drug-likeness.

**DILI:** Ligand A (45.87) has a lower DILI risk than Ligand B (15.355), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (56.921) has a higher BBB score than Ligand A (40.403), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-4.786) has poor Caco-2 permeability, while Ligand B (-5.66) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-1.764) has slightly better solubility than Ligand B (-2.308), though both are quite low.

**hERG:** Ligand A (0.177) has a much lower hERG risk than Ligand B (0.836), a significant advantage.

**Microsomal Clearance:** Ligand A (-18.152) exhibits much lower microsomal clearance, indicating better metabolic stability, which is crucial for an enzyme target. Ligand B (72.755) has high clearance.

**In vitro Half-Life:** Ligand A (14.315 hours) has a longer half-life than Ligand B (12.465 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux liability than Ligand B (0.223), which is beneficial.

**Binding Affinity:** Ligand B (-8.0 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 ADME liabilities of Ligand B.

**Overall:**

Ligand A, despite its slightly lower logP and Caco-2 permeability, is the more promising candidate. It has significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG risk, and lower P-gp efflux. The slightly better binding affinity of Ligand B is outweighed by its poorer ADME profile.

Output:
0
2025-04-17 15:36:45,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.491 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (83.12), both are under the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.835 and 2.43), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is slightly better than Ligand B (HBD=3, HBA=4) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED values (0.63 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (51.493). This is a major advantage for Ligand A.

**BBB:** Ligand B (77.511) has a higher BBB penetration percentile than Ligand A (67.158). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.733 and -4.806). This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.335 and -3.542). This could present formulation challenges.

**hERG:** Ligand A (0.191) has a much lower hERG inhibition liability than Ligand B (0.575). This is a significant advantage for Ligand A, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (43.554) has lower microsomal clearance than Ligand B (54.241), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.432) has a slightly better (less negative) in vitro half-life than Ligand B (16.453).

**P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.064), which is favorable for absorption and bioavailability.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.4), 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:**

Ligand A is the more promising drug candidate. It demonstrates significantly better safety profiles (lower DILI and hERG) and better metabolic stability (lower Cl_mic). While both have poor solubility and Caco-2 permeability, the superior ADME-Tox profile of Ligand A outweighs the slightly better binding affinity of Ligand B.

Output:
0
2025-04-17 15:36:45,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.36 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is better than Ligand B (67.67), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.456) is optimal, while Ligand B (1.104) 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 (3) is good, while Ligand B (5) is acceptable but higher.

**QED:** Both ligands have similar QED values (0.87 and 0.799), indicating good drug-likeness.

**DILI:** Ligand A (48.313) has a slightly higher DILI risk than Ligand B (28.306), but both are below the concerning threshold of 60.

**BBB:** Ligand A (86.739) has better BBB penetration than Ligand B (59.364), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.89) and Ligand B (-4.621) are both negative, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.297) has slightly better solubility than Ligand B (-1.128), but both are poor.

**hERG Inhibition:** Ligand A (0.816) has a slightly higher hERG risk than Ligand B (0.161). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (10.583) has lower microsomal clearance than Ligand B (20.619), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.614) has a longer half-life than Ligand B (14.792), which is desirable.

**P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux than Ligand B (0.026), indicating better bioavailability.

**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.

**Conclusion:**

Despite Ligand B having a better hERG profile and lower DILI risk, Ligand A's substantially stronger binding affinity (-9.2 vs -8.2 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are more critical for an enzyme target like SRC kinase. While solubility and permeability are concerns for both, the potency advantage of Ligand A is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 15:36:45,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.472 and 373.469 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (56.67).  A TPSA under 140 is good for oral absorption, and both are well below this, but lower is generally preferred.

**logP:** Ligand A (4.626) is slightly higher than the optimal range (1-3), while Ligand B (2.218) is within the optimal range. High logP can cause issues, but the binding affinity difference will be a key factor.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are acceptable, but fewer is generally better.

**QED:** Both ligands have good QED scores (0.72 and 0.86), indicating drug-likeness.

**DILI:** Ligand A (14.696) has a much lower DILI risk than Ligand B (20.706), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (92.943 and 91.896), but SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.52 and -4.673). This is unusual and suggests poor permeability, but could be an artifact of the prediction method.

**Aqueous Solubility:** Ligand A (-4.837) has worse solubility than Ligand B (-1.94). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.917) has a slightly higher hERG risk than Ligand B (0.525), but both are relatively low.

**Microsomal Clearance:** Ligand A (77.06) has significantly higher microsomal clearance than Ligand B (8.744). This means Ligand B is much more metabolically stable, which is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (4.824) has a longer half-life than Ligand B (-12.175). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.387) has lower P-gp efflux than Ligand B (0.094), which is favorable.

**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 not huge (1.5 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better half-life and lower P-gp efflux, Ligand B's significantly improved metabolic stability (lower Cl_mic) and slightly better binding affinity outweigh the drawbacks of its higher TPSA and slightly lower solubility. The lower DILI risk for Ligand A is a plus, but the metabolic stability of Ligand B is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:36:45,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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, while Ligand B (365.503 Da) is still well within the acceptable range.

**TPSA:** Ligand A (61.36) is significantly better than Ligand B (80.12). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (4.065) is at the higher end of the optimal range, while Ligand B (1.307) is at the lower end. While Ligand B's logP might lead to solubility issues, Ligand A's could cause off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 2 HBA, which is a good balance. Ligand B has 1 HBD and 6 HBA. Both are acceptable, but Ligand A's profile is slightly more favorable.

**QED:** Both ligands have similar and good QED values (0.774 and 0.788, respectively).

**DILI:** Ligand A (50.291) has a slightly higher DILI risk than Ligand B (44.203), but both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (61.846) is lower than Ligand B (54.983).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.126 and -5.641), indicating poor permeability. This is a significant drawback for both, but the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.447 and -2.216), indicating poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.715) has a higher hERG risk than Ligand B (0.155). This is a critical factor, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (27.013 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (58.233 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.17 hours) has a negative half-life, which is unusual and likely indicates rapid degradation. Ligand A (13.802 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.33 and 0.023).

**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 the ADME drawbacks.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.6 kcal/mol vs 0.0 kcal/mol) is the most compelling factor. While it has some ADME liabilities (lower solubility, negative half-life), the potency advantage is substantial. The lower hERG risk is also a significant benefit. Ligand A has better TPSA and half-life, but the binding affinity is very weak. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 15:36:45,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.491 and 352.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (78.43). A TPSA under 90 is generally good, and A is closer to the optimal range for oral absorption (<140).

**logP:** Both ligands have acceptable logP values (1.415 and 2.622, respectively), 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). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.705) has a better QED score than Ligand B (0.529), indicating a more drug-like profile.

**DILI:** Ligand A (7.135) has a much lower DILI risk than Ligand B (13.92), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.474) is lower than Ligand B (48.003).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.822 and -4.803), 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 (-0.345 and -4.129). This is also a concern for both, but B is worse.

**hERG Inhibition:** Ligand A (0.271) has a significantly lower hERG risk than Ligand B (0.515), a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-1.01) has a lower (better) microsomal clearance than Ligand B (58.264), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17) has a worse half-life than Ligand B (-8.173), but both are negative and concerning.

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.403), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.4) has a slightly better binding affinity than Ligand B (-7.8), although the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is clearly superior. It demonstrates better drug-likeness (QED), significantly lower DILI and hERG risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. While both have concerning solubility and permeability values, the ADME/Tox profile of Ligand A is far more favorable. The difference in binding affinity is not large enough to overcome the substantial advantages of Ligand A in other critical parameters.

Output:
1
2025-04-17 15:36:45,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.407 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.84) is well below the 140 threshold, suggesting good absorption. Ligand B (92.01) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (3.294) is optimal (1-3). Ligand B (0.564) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly less optimal.

**QED:** Both ligands have similar QED values (0.783 and 0.733), indicating good drug-likeness.

**DILI:** Ligand A (67.003) has a moderate DILI risk. Ligand B (35.169) has a significantly lower and more favorable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.157) is higher than Ligand B (24.661).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the scale is not specified, so we cannot interpret this value.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. The scale is not specified, so we cannot interpret this value.

**hERG:** Ligand A (0.676) has a low hERG risk, which is excellent. Ligand B (0.24) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (93.23) has high microsomal clearance, suggesting rapid metabolism and lower metabolic stability. Ligand B (-14.666) has negative clearance, which is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (4.385) has a relatively short half-life. Ligand B (2.044) has an even shorter half-life.

**P-gp Efflux:** Ligand A (0.468) has low P-gp efflux, which is good. Ligand B (0.16) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial difference.

**Conclusion:**

Despite Ligand B's superior DILI, P-gp efflux, and potentially metabolic stability, the significantly stronger binding affinity of Ligand A (-8.3 vs -6.8 kcal/mol) is a decisive advantage for an enzyme target like SRC kinase. The 1.5 kcal/mol difference is substantial and can outweigh the drawbacks of its slightly higher DILI risk and faster clearance. The poor Caco-2 and solubility values are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:36:45,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (362.861 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is slightly higher than Ligand B (67.87). Both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets (though this isn't a CNS target).

**3. logP:** Both ligands have good logP values (2.323 and 1.865), 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, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.872) has a higher QED than Ligand B (0.759), indicating a more drug-like profile.

**7. DILI:** Ligand B (32.377) has a significantly lower DILI risk than Ligand A (55.719), making it more favorable from a toxicity standpoint.

**8. BBB:** Both have reasonable BBB penetration, but Ligand A is higher (75.805) than Ligand B (65.801). This isn't a primary concern for a non-CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.978 and -4.57), which is unusual and suggests poor permeability. This is a significant drawback for both, but the values are similar.

**10. Aqueous Solubility:** Ligand B (-1.936) has better (less negative) aqueous solubility than Ligand A (-3.077). Better solubility is preferred.

**11. hERG Inhibition:** Ligand A (0.147) has a slightly lower hERG inhibition risk than Ligand B (0.34), which is favorable.

**12. Microsomal Clearance:** Ligand A (29.675) has lower microsomal clearance than Ligand B (33.065), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (34.217) has a significantly longer in vitro half-life than Ligand A (13.674), which is a major advantage.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.056 and 0.066), which is good.

**15. Binding Affinity:** Ligand B (-9.5 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 other drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better QED and hERG profile, Ligand B is significantly better in several critical areas for an enzyme inhibitor: lower DILI risk, better aqueous solubility, *much* longer half-life, and, most importantly, a substantially stronger binding affinity. The Caco-2 permeability is poor for both, but the superior binding affinity of Ligand B makes it more likely to be effective *in vivo* even with limited absorption. The longer half-life also mitigates the permeability issue to some extent.

Output:
1
2025-04-17 15:36:45,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.5 & 339.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is slightly higher than Ligand B (64.86), but both are below the 140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (2.54 & 3.24), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting 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 6. Both are below the 10 threshold.

**6. QED:** Ligand B (0.926) has a significantly better QED score than Ligand A (0.538), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.97) has a much lower DILI risk than Ligand B (48.31), which is a significant advantage.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (82.51) is higher than Ligand A (65.41). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.44) is slightly better than Ligand B (-4.85).

**10. Aqueous Solubility:** Ligand A (-1.99) has better solubility than Ligand B (-4.23). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.27 & 0.36), which is good.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (51.29 & 52.26), indicating comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.68) has a slightly better in vitro half-life than Ligand A (-20.25), suggesting better stability.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.09 & 0.397).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly better binding affinity than Ligand A (-7.5 kcal/mol). This 1.3 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 in vitro half-life. However, Ligand A has a much lower DILI risk and better solubility, and slightly better Caco-2 permeability. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the significantly stronger binding affinity of Ligand B is the most crucial factor. While the DILI risk is higher for Ligand B, it's still below 60, and the improved potency could allow for a lower dose, potentially mitigating the DILI risk.

Output:
1
2025-04-17 15:36:45,311 - INFO - Batch 394 complete. Total preferences: 6304
2025-04-17 15:36:45,311 - INFO - Processing batch 395/512...
2025-04-17 15:37:29,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.471 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold and is favorable. Ligand B (89.15) is still below 140, but less optimal than A.

**logP:** Ligand A (2.568) is within the optimal 1-3 range. Ligand B (-0.206) is below 1, which could indicate poor membrane permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (3) and Ligand B (7) are both acceptable (<=10), but B is higher.

**QED:** Both ligands (0.883 and 0.77) have good drug-likeness scores (>0.5).

**DILI:** Ligand A (13.649) has a significantly lower DILI risk than Ligand B (60.915). This is a major advantage for Ligand A.

**BBB:** Ligand A (73.905) has a better BBB penetration percentile than Ligand B (46.375), but BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both are negative (-4.921 and -4.928), which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.862 and -1.138), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.713) has a lower hERG inhibition risk than Ligand B (0.195), which is favorable.

**Microsomal Clearance:** Ligand A (-1.938) has a significantly *lower* (better) microsomal clearance than Ligand B (42.469), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (35.818) has a longer half-life than Ligand B (-4.614), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.064).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.3 kcal/mol), with Ligand B being slightly better. However, the difference is small and may not be significant.

**Conclusion:**

Ligand A is the better candidate. While both ligands have good binding affinity, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better BBB penetration. Ligand B's low logP and high DILI risk are significant drawbacks. The slight advantage in binding affinity for Ligand B is outweighed by these ADMET concerns.

Output:
0
2025-04-17 15:37:29,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 significantly better than Ligand B (37.61). Lower TPSA generally favors better absorption.

**logP:** Ligand A (2.087) is optimal, while Ligand B (4.773) is pushing the upper limit and could lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is well within the acceptable ranges. Ligand B (HBD=0, HBA=5) is also acceptable, but the lower number of H-bond donors might slightly reduce aqueous solubility.

**QED:** Ligand A (0.664) has a better QED score than Ligand B (0.445), indicating a more drug-like profile.

**DILI:** Ligand A (23.769) has a much lower DILI risk than Ligand B (67.701), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (66.266) has a higher BBB value than Ligand A (45.095), but this is not a major factor in this case.

**Caco-2 Permeability:** Ligand A (-4.868) and Ligand B (-5.278) both have negative values, which indicates poor permeability.

**Aqueous Solubility:** Ligand A (-2.727) is better than Ligand B (-3.867), indicating better solubility.

**hERG:** Ligand A (0.104) has a much lower hERG risk than Ligand B (0.713), which is a critical advantage.

**Microsomal Clearance:** Ligand A (29.891) has a significantly lower microsomal clearance than Ligand B (89.814), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.556) has a lower half-life than Ligand B (16.994), but both are acceptable.

**P-gp Efflux:** Ligand A (0.094) has a lower P-gp efflux liability than Ligand B (0.803), which is favorable.

**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 notable, but not overwhelming given the other factors.

**Overall Assessment:**

Ligand A is significantly better overall. It has a better QED score, lower DILI and hERG risk, better solubility, and significantly better metabolic stability (lower Cl_mic). While Ligand B has slightly better binding affinity, the superior ADME properties of Ligand A outweigh this difference. The lower logP and TPSA of Ligand A are also beneficial for absorption.

Output:
0
2025-04-17 15:37:29,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.45) is significantly better than Ligand B (78.43), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (3.861 and 2.763, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=3, HBA=3) as it has fewer HBDs, potentially improving permeability.

**QED:** Both ligands have reasonable QED scores (0.758 and 0.597), indicating good drug-like properties.

**DILI:** Ligand A (10.896) has a much lower DILI risk than Ligand B (15.2). This is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (78.519) shows better BBB penetration than Ligand B (49.787).

**Caco-2 Permeability:** Ligand A (-4.288) has slightly better Caco-2 permeability than Ligand B (-4.728).

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-3.617 and -3.872). This could be a formulation challenge for both.

**hERG Inhibition:** Ligand A (0.532) exhibits a lower hERG inhibition liability than Ligand B (0.352), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (77.719) has higher microsomal clearance than Ligand B (62.581), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-12.213) has a significantly longer in vitro half-life than Ligand A (-7.847), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.115 and 0.248).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in DILI risk, TPSA, and hERG inhibition. However, its higher microsomal clearance and shorter half-life are concerning. Ligand B has a better half-life and slightly better binding affinity, but its DILI risk is higher and TPSA is less favorable. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is slightly more promising due to its superior metabolic stability and binding affinity, despite the higher DILI risk. The difference in binding affinity isn't substantial enough to outweigh the metabolic concerns with Ligand A.

Output:
1
2025-04-17 15:37:29,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.43 & 358.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.22) is better than Ligand B (47.09). While both are reasonably low, Ligand B is exceptionally low, which *could* indicate poor binding due to lack of polar interactions with the target.

**logP:** Ligand A (1.878) is optimal (1-3). Ligand B (4.484) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, fitting well within the guidelines. Ligand B has 0 HBD and 5 HBA, also acceptable, but the lack of HBDs could be a slight disadvantage for binding.

**QED:** Both ligands have similar QED values (0.637 and 0.663), indicating good drug-likeness.

**DILI:** Ligand A (38.852) has a slightly higher DILI risk than Ligand B (24.738), but both are below the concerning threshold of 60.

**BBB:** Ligand A (54.44) has a lower BBB penetration than Ligand B (89.066). However, SRC is not a CNS target, so this is not a major factor.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.757 and -4.755). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.205 and -4.424). This is a concern, but potentially manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.432) shows slightly better hERG inhibition profile than Ligand B (0.94), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (25.146) has a lower microsomal clearance than Ligand B (39.07), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-8.341) has a significantly longer in vitro half-life than Ligand B (19.085), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux than Ligand B (0.681), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both ligands have similar potency, Ligand A demonstrates superior ADME properties: lower microsomal clearance, longer half-life, lower P-gp efflux, and better hERG profile. The slightly higher DILI risk is less concerning than the poorer ADME profile of Ligand B. The poor Caco-2 and solubility are shared drawbacks that would need to be addressed during formulation.

Output:
0
2025-04-17 15:37:29,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (379.222 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is significantly better than Ligand B (96.11). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (4.333) is higher than the optimal range (1-3), potentially causing solubility issues, but not drastically so. Ligand B (1.139) is at the lower end, which could hinder permeability.

**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, being under 10.

**QED:** Both ligands have good QED scores (0.734 and 0.877), indicating good drug-like properties.

**DILI:** Ligand A (88.019) has a higher DILI risk than Ligand B (51.725). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (73.827) is better than Ligand B (63.862). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. This is difficult to interpret without further information.

**Aqueous Solubility:** Both have negative solubility values, again unusual. Ligand B (-1.804) is slightly better than Ligand A (-5.99).

**hERG Inhibition:** Ligand A (0.523) has a slightly higher hERG risk than Ligand B (0.233), but both are relatively low.

**Microsomal Clearance:** Ligand A (72.129) has higher clearance than Ligand B (29.474). This means Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-20.877) has a negative half-life, which is impossible and indicates a data issue. Ligand A (31.671) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.495) has lower P-gp efflux than Ligand B (0.143), which is favorable.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand B appears to be the better candidate despite the questionable Caco-2 and solubility values, and the impossible half-life. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme inhibitor. The slightly lower affinity is less concerning given the other benefits. The negative values for Caco-2 and solubility are red flags that would require further investigation, but the other factors strongly favor Ligand B. Ligand A's higher DILI risk is a significant concern.

Output:
1
2025-04-17 15:37:29,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.466 Da) is slightly better, being closer to the middle of the range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (118.36). A TPSA below 140 is good for oral absorption, but lower is generally preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.293, Ligand B: 0.889), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=4). Lower counts are generally better for permeability.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.763, Ligand B: 0.556), indicating drug-like properties. Ligand A is better.

**DILI:** Ligand A (14.541) has a much lower DILI risk than Ligand B (33.928). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (91.276) has a better BBB score than Ligand B (55.176).

**Caco-2 Permeability:** Ligand A (-4.406) has a better Caco-2 permeability than Ligand B (-5.346).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.801 and -2.933 respectively). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.49, Ligand B: 0.093). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (29.219) has a significantly lower microsomal clearance than Ligand B (37.789), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-0.037) has a better in vitro half-life than Ligand B (-52.772). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (Ligand A: 0.035, Ligand B: 0.038).

**Binding Affinity:** Both ligands have comparable binding affinity (Ligand A: -8.0 kcal/mol, Ligand B: -8.5 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand B has slightly better binding affinity and hERG inhibition, Ligand A excels in crucial ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), better TPSA, and better Caco-2 permeability. These factors are particularly important for an enzyme inhibitor, where maintaining adequate systemic exposure is critical. The slightly better affinity of Ligand B is unlikely to outweigh the substantial ADME advantages of Ligand A.

Output:
1
2025-04-17 15:37:29,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.4 and 350.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (138.6) is borderline acceptable for oral absorption, while Ligand B (51.02) is excellent, well below the 140 threshold.

**logP:** Ligand A (-1.07) is a bit low, potentially hindering permeation. Ligand B (3.613) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (A: 8, B: 4) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.504, B: 0.639), indicating drug-like properties.

**DILI:** Ligand A (68.05) has a moderate DILI risk, while Ligand B (16.208) has a very low risk, which is a significant advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand B (89.066) has a higher BBB value, but this is less critical here.

**Caco-2 Permeability:** Ligand A (-5.116) has poor permeability, while Ligand B (-4.385) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.241) has poor solubility, while Ligand B (-4.404) also has poor solubility. This is a concern for both.

**hERG:** Ligand A (0.032) has very low hERG risk, which is excellent. Ligand B (0.356) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-8.118) has very low microsomal clearance, indicating high metabolic stability, a key advantage for an enzyme target. Ligand B (62.102) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (34.762) has a reasonable half-life, while Ligand B (-16.22) has a negative half-life, which is not possible and likely an error in the data.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, while Ligand B (0.09) is also low.

**Binding Affinity:** Ligand A (-8.7) has significantly stronger binding affinity than Ligand B (-7.2), a difference of 1.5 kcal/mol, which is a substantial advantage.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.2 kcal/mol) and excellent metabolic stability (low Cl_mic) outweigh the slightly lower logP and moderate DILI risk. The negative half-life for Ligand B is a critical flaw. The lower hERG risk for Ligand A is also a positive. For an enzyme target, potency and metabolic stability are paramount.

Output:
0
2025-04-17 15:37:29,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.889 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (62.3 and 61.68) are below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (3.026) is optimal, while Ligand B (1.133) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A has 1 HBD, within the acceptable limit. Ligand B has 0, also good.

**H-Bond Acceptors:** Ligand A has 3 HBA, within the acceptable limit. Ligand B has 5, still acceptable.

**QED:** Both ligands have similar QED values (0.874 and 0.8), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (23.187 and 21.869 percentile), which is favorable.

**BBB:** Both ligands have good BBB penetration (74.796 and 70.997 percentile), though not crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.867 and -4.79), which is unusual and suggests a potential issue with intestinal absorption. This needs further investigation, but it's a flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.306 and 0.17). This is a significant concern for bioavailability and formulation.

**hERG Inhibition:** Ligand A (0.404) has a slightly higher hERG risk than Ligand B (0.647), but both are relatively low.

**Microsomal Clearance:** Ligand A (46.031 mL/min/kg) has higher clearance than Ligand B (20.056 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.958 hours) has a significantly longer half-life than Ligand A (-8.097 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.057 and 0.059), which is good.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial difference (0.8 kcal/mol), and a key factor.

**Overall Assessment:**

Ligand A has a better binding affinity, which is the highest priority for an enzyme inhibitor. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better hERG profile. Both have poor solubility and questionable Caco-2 permeability. The difference in binding affinity (0.8 kcal/mol) is significant enough to outweigh the metabolic stability advantage of Ligand B, *assuming* the solubility issues can be addressed through formulation.

Output:
1
2025-04-17 15:37:29,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.471 and 365.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (92.63). A TPSA under 140 is good for oral absorption, and both meet this, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.317 and 1.627), 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 9 HBA. Lower HBA is generally preferred for better permeability, making Ligand A better.

**QED:** Both ligands have similar QED scores (0.799 and 0.765), indicating good drug-likeness.

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (75.184). This is a significant advantage for Ligand A.

**BBB:** Ligand A (70.919) has better BBB penetration than Ligand B (44.552), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.718) is slightly better than Ligand B (-4.911), but both are problematic.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.364) is slightly better than Ligand B (-3.377).

**hERG Inhibition:** Ligand A (0.434) has a lower hERG inhibition liability than Ligand B (0.754), which is a significant advantage.

**Microsomal Clearance:** Ligand A (38.373) has lower microsomal clearance than Ligand B (59.248), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.728) has a negative half-life, which is unusual. Ligand B (6.347) has a positive half-life, indicating better stability. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.059).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.5 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, lower hERG inhibition, better TPSA, lower HBA, and slightly better binding affinity and solubility. While both have poor Caco-2 permeability, the other advantages of Ligand A outweigh this drawback. Ligand B's only advantage is a positive in vitro half-life, but this is overshadowed by its higher DILI and hERG risks.

Output:
0
2025-04-17 15:37:29,517 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [345.487, 73.2, 3.004, 1, 3, 0.661, 17.449, 74.68, -4.597, -4.03, 0.626, 80.787, -7.882, 0.243, -8.2]
**Ligand B:** [383.279, 83.06, 4.07, 0, 5, 0.384, 33.463, 88.329, -4.922, -4.808, 0.892, 21.015, 10.175, 0.332, -9.7]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (345.487) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (73.2) is better than B (83.06) as it's closer to the <140 threshold for good absorption.
3. **logP:** A (3.004) is optimal. B (4.07) is pushing the upper limit and could present solubility issues.
4. **HBD:** A (1) is good. B (0) is acceptable, but some HBD can aid solubility.
5. **HBA:** A (3) is good. B (5) is acceptable, but higher HBA can sometimes hinder permeability.
6. **QED:** A (0.661) is significantly better than B (0.384), indicating a more drug-like profile.
7. **DILI:** A (17.449) is much better than B (33.463), indicating a lower risk of liver injury.
8. **BBB:** Both are reasonably good, but B (88.329) is better than A (74.68). However, SRC is not a CNS target, so this is less critical.
9. **Caco-2:** Both are negative, indicating poor permeability.
10. **Solubility:** Both are negative, indicating poor solubility.
11. **hERG:** A (0.626) is better than B (0.892), suggesting lower cardiotoxicity risk.
12. **Cl_mic:** A (80.787) is higher than B (21.015), meaning A has faster metabolic clearance and lower metabolic stability. This is a significant drawback.
13. **t1/2:** B (10.175) is much better than A (-7.882), indicating a longer half-life and potentially less frequent dosing. This is a major advantage for B.
14. **Pgp:** A (0.243) is better than B (0.332), suggesting less P-gp efflux.
15. **Binding Affinity:** B (-9.7) is significantly better than A (-8.2), representing a substantial potency advantage (1.5 kcal/mol difference). This is the most important factor for an enzyme inhibitor.

**Enzyme-specific priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

While Ligand A has better QED, DILI, hERG, and Pgp properties, Ligand B's significantly superior binding affinity (-9.7 vs -8.2 kcal/mol) and much improved *in vitro* half-life outweigh the drawbacks of its slightly higher logP and worse DILI. The improved half-life is particularly important for an enzyme target, as it suggests a longer duration of action. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Therefore, I recommend **Ligand B** as the more viable drug candidate.

1
2025-04-17 15:37:29,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (353.813 and 357.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.6) is better than Ligand B (90.9). Both are below 140, but A is closer to the optimal range for good absorption.

**3. logP:** Ligand A (3.341) is optimal, while Ligand B (0.515) is quite low, potentially hindering 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 (4) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.593 and 0.53), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (85.459) has a higher DILI risk than Ligand B (4.731). This is a significant drawback for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.076) and Ligand B (25.475) are both relatively low.

**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.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.809 and 0.082). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (42.871) has a moderate clearance, while Ligand B (-18.221) has a negative clearance, which is unusual and suggests *very* high metabolic stability. This is a major advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (24.531) has a reasonable half-life, while Ligand B (5.37) has a very short half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.555 and 0.006).

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This 0.4 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate despite its low logP and solubility. Its exceptionally high metabolic stability (negative Cl_mic), significantly stronger binding affinity, and very low DILI risk are major advantages. While the low logP and solubility are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. Ligand A's higher DILI risk is a significant concern, and its lower binding affinity makes it less attractive.

Output:
1
2025-04-17 15:37:29,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.194 Da) is slightly higher than Ligand B (366.527 Da), but both are acceptable.

**TPSA:** Ligand A (81.47) is higher than Ligand B (49.85). While both are reasonably low, Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (4.124) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.494) is within the optimal range (1-3).

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (Ligand A: 0.597, Ligand B: 0.77), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (38.658). Ligand B is well below the 40% threshold, indicating low liver injury risk.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (71.229) has a better BBB score than Ligand A (60.45).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.678 and -4.65), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.045 and -3.895). This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.642) has a slightly higher hERG risk than Ligand B (0.364), although both are relatively low.

**Microsomal Clearance:** Ligand A (57.143) has lower microsomal clearance than Ligand B (72.772), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (47.381) has a longer half-life than Ligand B (1.709), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.493) has lower P-gp efflux than Ligand B (0.215), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.1 and -9.3 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has better physicochemical properties (logP, TPSA, DILI, BBB) and slightly better QED. However, Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. Both have poor solubility and permeability. Given the enzyme-specific priorities, metabolic stability is crucial for kinase inhibitors. The slightly better ADME profile of ligand B is offset by the superior metabolic stability of ligand A.

Output:
1
2025-04-17 15:37:29,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (352.435 Da and 384.567 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.39) is better than Ligand B (66.48), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.557) is within the optimal 1-3 range. Ligand B (3.464) is at the higher end of the optimal range, potentially raising solubility concerns.

**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:** Ligand B (0.663) has a better QED score than Ligand A (0.491), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (49.128), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.67) is higher than Ligand A (36.526), but this isn't a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-5.467) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.963) is also poor, but slightly better than Ligand A.

**10. Aqueous Solubility:** Ligand A (-0.505) has slightly better solubility than Ligand B (-3.706).

**11. hERG Inhibition:** Both ligands (0.333 and 0.495) show low hERG inhibition risk, which is good.

**12. Microsomal Clearance:** Ligand A (37.186) has significantly lower microsomal clearance than Ligand B (111.342), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-36.45) has a negative half-life, which is concerning, and indicates very rapid metabolism. Ligand B (17.924) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands (0.028 and 0.419) have low P-gp efflux, which is favorable.

**15. Binding Affinity:** Both ligands have strong binding affinities (-7.9 and -7.5 kcal/mol). Ligand A is slightly better (-7.9 kcal/mol).

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While Ligand A has a slightly better affinity, it suffers from very poor Caco-2 permeability, a negative in vitro half-life, and a significantly better DILI profile. Ligand B has a better QED, better half-life, and slightly better Caco-2 permeability, but a higher DILI risk and higher clearance.

Considering the balance, the improved metabolic stability and lower DILI risk of Ligand A, coupled with its slightly better binding affinity, outweigh its permeability issues. The poor permeability could potentially be addressed with formulation strategies. The negative half-life is a major concern, but could be improved with structural modifications.

Output:
0
2025-04-17 15:37:29,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.423 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.64) is better than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly lower and potentially better for cell permeability.

**logP:** Both ligands (2.276 and 2.924) 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 (4 and 3) are well within the acceptable limit of <=10.

**QED:** Ligand B (0.721) has a significantly better QED score than Ligand A (0.259), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 37.611, Ligand B: 41.411), below the 60 threshold.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (65.103) is slightly better than Ligand A (53.121).

**Caco-2 Permeability:** Ligand A (-5.37) is worse than Ligand B (-4.704). Higher values are better, indicating better absorption.

**Aqueous Solubility:** Ligand A (-1.729) is better than Ligand B (-3.21), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG risk (0.562 and 0.271), which is excellent.

**Microsomal Clearance:** Ligand A (-0.549) exhibits *much* better metabolic stability than Ligand B (93.491). Lower is better. This is a critical advantage.

**In vitro Half-Life:** Ligand A (-19.861) has a better in vitro half-life than Ligand B (-17.625).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.038 and 0.412), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.6 and -8.2 kcal/mol). Ligand A is slightly better (-9.6 vs -8.2). The difference is 1.4 kcal/mol, which is significant.

**Conclusion:**

While Ligand B has a better QED and Caco-2 permeability, Ligand A's significantly better metabolic stability (Cl_mic) and slightly better binding affinity are more crucial for an enzyme target like SRC kinase. The improved solubility of Ligand A is also a benefit. The 1.4 kcal/mol difference in binding affinity is substantial enough to outweigh the slightly lower QED and Caco-2 values of Ligand A.

Output:
0
2025-04-17 15:37:29,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.431 and 351.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is well below the 140 threshold for good absorption, and even favorable for potential CNS penetration (though not a priority here). Ligand B (137.25) is still under the 140 threshold, but higher than A.

**logP:** Ligand A (1.187) is within the optimal 1-3 range. Ligand B (-1.394) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, well within acceptable limits. Ligand B has 3 HBD and 6 HBA, also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (0.457 and 0.61), indicating acceptable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (45.483) has a lower DILI risk than Ligand B (69.678), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (68.36) has a better percentile than Ligand B (23.73).

**Caco-2:** Ligand A (-4.861) and Ligand B (-5.218) have similar negative values, indicating poor Caco-2 permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.704) has slightly better solubility than Ligand B (-2.614).

**hERG:** Both ligands have very low hERG risk (0.211 and 0.098), which is excellent.

**Microsomal Clearance:** Ligand A (11.247) has a better (lower) microsomal clearance than Ligand B (-16.616), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-3.876) has a better (longer) in vitro half-life than Ligand B (-7.442). This further supports its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.005).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.8 and -8.1 kcal/mol). The difference of 0.7 kcal/mol is not large enough to outweigh other factors.

**Conclusion:**

Ligand A is the more promising candidate. While both have good binding affinity and low hERG risk, Ligand A demonstrates superior ADME properties, specifically lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. The slightly lower logP of Ligand B is a minor concern, but the significant differences in DILI and metabolic stability make Ligand A the preferred choice for further development.

Output:
0
2025-04-17 15:37:29,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.507 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is better than Ligand B (52.65), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.05) is optimal, while Ligand B (1.937) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable range.

**QED:** Both ligands have acceptable QED scores (0.812 and 0.749, both > 0.5).

**DILI:** Ligand A (21.946) has a significantly lower DILI risk than Ligand B (4.924), a major advantage.

**BBB:** Both ligands have high BBB penetration (85.111 and 83.288), but this is less critical for a non-CNS target like SRC.

**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.

**Aqueous Solubility:** Ligand A (-3.344) has better solubility than Ligand B (-1.427), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.344) has a much lower hERG risk than Ligand B (0.7), a critical safety factor.

**Microsomal Clearance:** Ligand A (39.234) has a higher (worse) microsomal clearance than Ligand B (9.367), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-3.548) has a longer half-life than Ligand A (8.76), which is desirable.

**P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux than Ligand B (0.056), which is beneficial for bioavailability.

**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 ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-9.2 vs -7.5 kcal/mol). While Ligand A has advantages in DILI risk, solubility, and P-gp efflux, the superior affinity of Ligand B, coupled with a better half-life, makes it the more promising candidate. The slightly lower logP of Ligand B is a minor concern, but the strong binding is likely to compensate. The higher clearance of Ligand A is also a concern.

Output:
1
2025-04-17 15:37:29,518 - INFO - Batch 395 complete. Total preferences: 6320
2025-04-17 15:37:29,518 - INFO - Processing batch 396/512...
2025-04-17 15:38:19,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.381 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is well below the 140 threshold for good absorption, while Ligand B (93.01) is approaching it but still acceptable.

**logP:** Both ligands (2.021 and 1.799) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**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.

**QED:** Both ligands have good QED scores (0.772 and 0.862), indicating good drug-like properties.

**DILI:** Ligand A (27.414) has a significantly lower DILI risk than Ligand B (60.295). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (92.555) has a higher BBB percentile than Ligand B (57.154).

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values (-4.952 and -4.872), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.226 and -2.652), which is also unusual and indicates very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.615) has a lower hERG inhibition liability than Ligand B (0.225), which is preferable.

**Microsomal Clearance:** Ligand A (2.927) has a much lower microsomal clearance than Ligand B (45.721), suggesting better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-10.68) has a negative half-life, which is not possible. Ligand B (11.162) has a reasonable half-life. However, the negative value for Ligand A is a clear red flag.

**P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux liability than Ligand B (0.03), which is preferable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While a 1.3 kcal/mol difference is notable, it might be outweighed by other factors.

**Overall Assessment:**

Ligand A is significantly better due to its much lower DILI risk, better metabolic stability (lower Cl_mic), lower hERG inhibition, and lower P-gp efflux. While Ligand B has a slightly better binding affinity, the ADME properties of Ligand A are far more favorable, particularly the DILI and metabolic stability. The negative half-life for Ligand A is a serious issue, but the other advantages are substantial enough to still favor it over Ligand B. The poor solubility and permeability are concerns for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 15:38:19,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (369.487 Da) is still well within the range.

**TPSA:** Both ligands have TPSA values below 140 (A: 97.39, B: 91.76), suggesting reasonable oral absorption potential.

**logP:** Both ligands have optimal logP values (A: 1.47, B: 0.826), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (A: 5, B: 6) counts, balancing solubility and permeability.

**QED:** Both ligands have QED values above 0.5 (A: 0.825, B: 0.708), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (92.904) compared to Ligand B (37.03). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a general oncology target like SRC. Ligand A (55.099) and Ligand B (31.912) both have low BBB penetration.

**Caco-2 Permeability:** Both ligands show negative Caco-2 values, indicating poor permeability. Ligand A (-4.788) is slightly better than Ligand B (-5.007).

**Aqueous Solubility:** Ligand A (-4.143) has slightly better solubility than Ligand B (-1.297), although both are quite poor.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.292, B: 0.096), which is excellent.

**Microsomal Clearance:** Ligand A (54.712) has a higher microsomal clearance than Ligand B (3.031), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (8.158 hours) has a longer in vitro half-life than Ligand A (11.923 hours).

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (A: 0.037, B: 0.043).

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the superior binding affinity of Ligand A, its high DILI risk and higher microsomal clearance are major concerns. Ligand B, while having a weaker binding affinity, exhibits a much better safety profile (lower DILI) and improved metabolic stability (lower Cl_mic). For an enzyme target like SRC kinase, metabolic stability and safety are crucial. The substantial difference in binding affinity (-8.0 vs -0.0) is significant, but can potentially be overcome with further optimization of Ligand B. The poor Caco-2 and solubility of both compounds would need to be addressed, but the starting point of Ligand B is more favorable.

Output:
1
2025-04-17 15:38:19,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.808 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is slightly higher than Ligand B (58.44), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.975 and 2.576), 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 well within the acceptable limit of <=10.

**QED:** Both ligands have similar, good QED scores (0.828 and 0.84), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 70.182, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 19.193, a significant advantage.

**BBB:** Both ligands have high BBB penetration (76.192 and 76.347), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values (-4.616 and -4.544). This is unusual and suggests a potential issue with intestinal absorption, but the scale isn't fully defined and negative values might indicate a different measurement.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.56 and -2.376). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.27 and 0.294), which is excellent.

**Microsomal Clearance:** Ligand A (42.387) has a higher microsomal clearance than Ligand B (36.326), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (8.926 hours) compared to Ligand A (31.752 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.235 and 0.073).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.5 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good potency and drug-like properties, Ligand B is the more promising candidate. Its significantly lower DILI risk and longer in vitro half-life outweigh the slightly higher TPSA and lower solubility. The similar binding affinity makes these secondary properties the deciding factors.

Output:
1
2025-04-17 15:38:19,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (354.51 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is well below the 140 threshold and suitable for oral absorption. Ligand B (95.42) is still within the acceptable range, but higher than A.

**3. logP:** Ligand A (4.006) is slightly above the optimal 1-3 range, potentially causing solubility issues. Ligand B (0.994) is below the optimal range and may have permeability issues.

**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 (2 and 5, respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.476 and 0.829), indicating drug-like properties. Ligand B is significantly better.

**7. DILI:** Ligand A (17.255) has a lower DILI risk than Ligand B (39.667), which is preferable.

**8. BBB:** Ligand A (83.288) has better BBB penetration potential than Ligand B (61.846), although this isn't a primary concern for a kinase inhibitor.

**9. Caco-2 Permeability:** Ligand A (-4.6) has a more negative Caco-2 value, indicating *lower* permeability than Ligand B (-5.039). This is a negative for Ligand A.

**10. Aqueous Solubility:** Ligand A (-3.905) has better aqueous solubility than Ligand B (-2.014).

**11. hERG Inhibition:** Ligand A (0.83) has a lower hERG risk than Ligand B (0.383), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (83.843) has a higher Cl_mic, indicating faster metabolism and lower metabolic stability compared to Ligand B (9.158). This is a significant negative for Ligand A.

**13. In vitro Half-Life:** Ligand A (7.708) has a shorter half-life than Ligand B (-10.934), indicating faster degradation. This is a negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.556) has lower P-gp efflux liability than Ligand B (0.093), which is preferable.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has better solubility and lower hERG risk, the substantial difference in binding affinity and metabolic stability of Ligand B outweighs these advantages. The slightly lower logP of Ligand B is a minor concern, but can be addressed through further optimization.

Output:
1
2025-04-17 15:38:19,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.12) is slightly higher than Ligand B (49.41). While both are reasonably low, Ligand B's lower TPSA is more favorable for cell permeability.

**logP:** Ligand A (2.204) and Ligand B (3.757) are both within the optimal 1-3 range, but Ligand B is approaching the upper limit.

**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 similar QED values (0.738 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (45.173) has a slightly higher DILI risk than Ligand B (33.501), but both are below the concerning threshold of 60.

**BBB:** Ligand A (68.205) has a lower BBB penetration percentile than Ligand B (93.68).  BBB is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.862) shows poor Caco-2 permeability, while Ligand B (-4.675) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.254 and -4.33). This is a significant concern.

**hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, significantly lower than Ligand B (0.551). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (22.841) has a lower microsomal clearance than Ligand B (49.627), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (1.716) has a shorter half-life than Ligand B (-2.726, which is unusual and likely indicates a very long half-life).

**P-gp Efflux:** Ligand A (0.026) has very low P-gp efflux liability, while Ligand B (0.315) is higher.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.5 and -7.4 kcal/mol), which are both excellent. The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its significantly lower hERG risk and lower microsomal clearance (better metabolic stability) outweigh the slightly lower BBB penetration and poorer Caco-2 permeability. The solubility is a concern for both, but can potentially be addressed through formulation strategies. Ligand B's higher logP and P-gp efflux could also lead to issues.

Output:
0
2025-04-17 15:38:19,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.438 and 374.547 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (84.5), both are below the 140 threshold for good absorption.

**3. logP:** Both ligands have acceptable logP values (1.018 and 2.196), 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 have 2 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both have 4 HBA, also within the acceptable limit of 10.

**6. QED:** Ligand A (0.771) has a slightly better QED score than Ligand B (0.682), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.598) has a significantly lower DILI risk than Ligand B (29.857). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (62.97 and 61.923), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. However, the value for Ligand A (-4.817) is less negative than Ligand B (-5.174), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also problematic. Ligand A (-1.239) is slightly better than Ligand B (-2.542).

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.28 and 0.389), which is good.

**12. Microsomal Clearance:** Ligand A (-15.197) has a much lower (better) microsomal clearance than Ligand B (37.192). This suggests significantly improved metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (14.875) has a much longer in vitro half-life than Ligand B (-29.577). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.046), which is favorable.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a 0.4 kcal/mol difference is noticeable, the other ADME properties of Ligand A are significantly better.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a slightly better QED score. The solubility and permeability issues are concerning for both, but Ligand A is marginally better in these respects. Given the enzyme-specific priorities, the improved metabolic stability and safety profile of Ligand A outweigh the minor affinity difference.

Output:
0
2025-04-17 15:38:19,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.434 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.09 and 66.48) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have similar logP values (3.063 and 3.079), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**QED:** Ligand B (0.731) has a slightly better QED score than Ligand A (0.561), indicating better overall drug-likeness.

**DILI:** Ligand B (22.993) has a significantly lower DILI risk than Ligand A (37.611), which is a major advantage.

**BBB:** Ligand B (79.798) has a higher BBB penetration percentile than Ligand A (68.36), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.806 and -4.848), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.324 and -3.635), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.306) has a lower hERG inhibition liability than Ligand B (0.607), which is favorable.

**Microsomal Clearance:** Ligand A (46.797) has a lower microsomal clearance than Ligand B (66.159), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (16.717 hours) has a significantly longer half-life than Ligand B (-50.125 hours - a negative value is suspect and likely indicates very rapid degradation). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.105).

**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 significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, longer half-life, and lower hERG risk and clearance. However, Ligand B has a better QED score and a significantly lower DILI risk. Both compounds have poor solubility and permeability. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), the stronger binding affinity and better metabolic stability of Ligand A are more critical. While the solubility is a concern, it can be addressed with formulation strategies. The DILI risk of Ligand B is low, but the poor half-life is a major issue.

Output:
1
2025-04-17 15:38:19,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 357.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is better than Ligand B (55.95), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.86) is slightly lower than optimal (1-3), potentially impacting permeability, while Ligand B (2.778) is within the ideal range.

**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 reasonable QED scores (0.743 and 0.653), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (23.226 and 41.373), both are good (low risk).

**BBB:** Ligand A (41.373) has a lower BBB penetration than Ligand B (62.233). Since SRC is not a CNS target, this is less critical.

**Caco-2:** Ligand A (-4.655) has a very poor Caco-2 permeability, while Ligand B (-5.524) is also poor.

**Solubility:** Ligand A (-1.411) has slightly better solubility than Ligand B (-1.988).

**hERG:** Both ligands have low hERG inhibition liability (0.338 and 0.485), which is excellent.

**Microsomal Clearance:** Ligand A (3.864) has significantly lower microsomal clearance than Ligand B (58.546), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (7.143) has a shorter half-life than Ligand B (9.024), but both are acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.268).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). The difference is 0.9 kcal/mol, which is substantial.

**Conclusion:**

While Ligand A has better solubility and lower clearance, the significantly improved binding affinity of Ligand B (-8.6 vs -7.7 kcal/mol) outweighs the slightly lower metabolic stability and solubility. The difference in binding affinity is substantial enough to be a key driver in selecting a candidate. Both ligands have acceptable ADME properties and low toxicity risk.

Output:
1
2025-04-17 15:38:19,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.463 and 373.421 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.53) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (55.84) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.144 and 3.313), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is reasonable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.6) is better than Ligand B (0.379), indicating a more drug-like profile.

**DILI:** Ligand A (22.567) has a significantly lower DILI risk than Ligand B (45.173), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (80.031 and 89.259), but this is less critical for a non-CNS target like SRC.

**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. This is a concern.

**hERG:** Ligand A (0.146) has a much lower hERG risk than Ligand B (0.55), a critical advantage for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (25.535) has a lower microsomal clearance than Ligand B (47.869), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.974) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (18.351) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, while Ligand B (0.423) has moderate efflux.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Ligand A is the more promising candidate. While its solubility and Caco-2 permeability values are concerning (and potentially erroneous given the negative values), it excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly lower hERG risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and a better QED score. The slightly weaker binding affinity is outweighed by these favorable ADME-Tox properties. The negative half-life for Ligand A is a red flag and needs investigation, but the other properties are more compelling.

Output:
0
2025-04-17 15:38:19,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.5) is slightly higher than Ligand B (342.5), but both are acceptable.

**TPSA:** Ligand A (75.63) is higher than Ligand B (58.2). While both are below 140, lower TPSA generally favors absorption. Ligand B is preferable here.

**logP:** Both ligands have good logP values (A: 3.252, B: 2.985), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 2. Lower HBA is generally preferred for better permeability, making Ligand B slightly better.

**QED:** Both ligands have good QED scores (A: 0.74, B: 0.835), indicating good drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (45.68) has a moderate DILI risk, while Ligand B (19.35) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (32.53) has low BBB penetration, while Ligand B (74.60) has good BBB penetration. Since SRC is not a CNS target, this is less critical, but still a slight 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. Ligand B (-4.621) is slightly better than Ligand A (-5.382).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-3.568) is slightly better than Ligand A (-3.018).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.121, B: 0.393), which is excellent.

**Microsomal Clearance:** Ligand A (42.125) has lower microsomal clearance than Ligand B (68.155), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-2.294) has a slightly longer in vitro half-life than Ligand B (-3.051).

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.09, B: 0.224).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This is a significant advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a clear advantage in terms of safety (DILI), solubility, and binding affinity. While Ligand A has better metabolic stability, the difference isn't substantial enough to overcome the other advantages of Ligand B. The slightly better binding affinity of Ligand B is also a key factor.

Output:
1
2025-04-17 15:38:19,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (359.447 and 354.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.47) is slightly higher than Ligand B (67.43), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.38) is slightly higher than Ligand B (2.483), both 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:** Ligand A (4) is better than Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.85) is better than Ligand B (0.77), indicating a more drug-like profile.

**7. DILI:** Ligand A (89.957) has a significantly higher DILI risk than Ligand B (34.471). This is a major concern for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 71.035, Ligand B: 70.803). BBB is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with the experimental setup or prediction method. However, the values are similar (-4.492 and -4.753).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-3.005) is slightly better than Ligand A (-4.833).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.528, Ligand B: 0.512).

**12. Microsomal Clearance:** Ligand A (69.704) has a significantly higher microsomal clearance than Ligand B (14.724), indicating lower metabolic stability. This is a major drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (35.964) has a longer half-life than Ligand B (22.399), which is a positive attribute.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.328, Ligand B: 0.202).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. Despite similar MW, TPSA, logP, Caco-2, and P-gp efflux, Ligand B demonstrates significantly better safety (lower DILI risk) and metabolic stability (lower Cl_mic). The slightly better binding affinity of Ligand B further supports this conclusion. Ligand A's high DILI risk and poor metabolic stability are major red flags. The unusual negative solubility and Caco-2 values for both compounds warrant further investigation, but do not outweigh the other factors.

Output:
1
2025-04-17 15:38:19,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.515 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.87 and 80.32) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.189 and 0.814) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**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 QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (22.489) has a significantly lower DILI risk than Ligand B (54.478). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (79.411) has a higher BBB percentile than Ligand A (25.824).

**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 definitively say how problematic this is.

**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 (0.133 and 0.206).

**Microsomal Clearance:** Ligand A (28.613) has a lower microsomal clearance than Ligand B (30.678), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.234) has a significantly longer in vitro half-life than Ligand A (-3.959). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.037).

**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 relatively small (0.4 kcal/mol), it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in DILI risk and has slightly better metabolic stability. However, Ligand B has a significantly longer half-life and slightly better binding affinity. The poor Caco-2 and solubility values for both are concerning, but the difference in DILI risk is substantial. Given the enzyme-specific priorities, metabolic stability and potency are key. The slightly better potency and half-life of Ligand B outweigh the lower DILI score of Ligand A.

Output:
1
2025-04-17 15:38:19,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.368 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.19) is better than Ligand B (78.51), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.776) is within the optimal 1-3 range. Ligand B (1.013) is slightly below, which *could* indicate permeability issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within acceptable ranges (<=5 for HBD, <=10 for HBA). Ligand B has 3 HBA, slightly better.

**QED:** Both ligands have good QED scores (0.848 and 0.798), indicating drug-likeness.

**DILI:** Ligand A (65.413) has a higher DILI risk than Ligand B (40.83). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration (76.347 and 66.886), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.068 and -4.971). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values (-4.07 and -2.87). This is concerning, as solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.527) has a slightly higher hERG risk than Ligand B (0.318).

**Microsomal Clearance:** Ligand B (-24.298) has *much* better metabolic stability (lower clearance) than Ligand A (4.538). This is a major advantage.

**In vitro Half-Life:** Ligand B (3.059) has a slightly better half-life than Ligand A (13.217).

**P-gp Efflux:** Ligand A (0.498) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 0.7 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's significantly improved metabolic stability (lower Cl_mic, better half-life) and superior binding affinity are crucial advantages for an enzyme inhibitor. The lower DILI risk is also a major positive. Ligand A's higher DILI risk and weaker binding make it less attractive.

Output:
1
2025-04-17 15:38:19,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (106) is better than Ligand B (65.04). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (-0.535) is significantly lower than the optimal range (1-3), potentially hindering permeability. Ligand B (3.793) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors & Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (2 HBD, 4 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.522, Ligand B: 0.784), indicating drug-like properties. Ligand B is better.

**DILI:** Both ligands have low DILI risk (Ligand A: 14.7, Ligand B: 13.9), which is excellent.

**BBB:** Ligand A (19.1) has a very low BBB penetration, while Ligand B (45.6) is moderate. Since SRC is not a CNS target, this is less critical, but a higher BBB value isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.441 and -5.363), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (0.006) has extremely poor solubility, a major drawback. Ligand B (-3.456) also has poor solubility, but is better than Ligand A.

**hERG Inhibition:** Ligand A (0.21) has a very low hERG risk, which is excellent. Ligand B (0.718) has a slightly higher risk, but still acceptable.

**Microsomal Clearance:** Ligand A (-14.241) has very low microsomal clearance, indicating high metabolic stability, which is a significant advantage. Ligand B (16.791) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (22.514 hours) has a good half-life. Ligand B (59.505 hours) has a very good half-life.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is favorable. Ligand B (0.26) has slightly higher efflux, but still acceptable.

**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 A has advantages in metabolic stability (Cl_mic) and P-gp efflux, and hERG. However, its extremely poor solubility and low logP are major concerns. Ligand B, while having slightly higher clearance and P-gp efflux, has a much better logP, and a better QED score. Both have poor Caco-2 permeability, but the solubility issue with Ligand A is more critical. Given the enzyme-specific priorities, metabolic stability and solubility are key. While Ligand A's stability is excellent, its solubility is a showstopper.

Output:
1
2025-04-17 15:38:19,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.479 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (75.71). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is much closer to the ideal for good permeability.

**logP:** Ligand A (4.772) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (1.455) is within the optimal range.

**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 acceptable.

**QED:** Ligand A (0.668) has a better QED score than Ligand B (0.529), indicating better overall drug-likeness.

**DILI:** Ligand A (37.03) has a slightly higher DILI risk than Ligand B (15.394), but both are below the concerning threshold of 60.

**BBB:** Ligand A (54.983) has a lower BBB penetration than Ligand B (85.459). However, since SRC is not a CNS target, this is less crucial.

**Caco-2 Permeability:** Ligand A (-4.869) and Ligand B (-4.524) both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-4.994) has worse solubility than Ligand B (-1.777).

**hERG:** Ligand A (0.871) has a slightly higher hERG risk than Ligand B (0.244), but both are relatively low.

**Microsomal Clearance:** Ligand A (107.02) has significantly higher microsomal clearance than Ligand B (37.945), indicating poorer metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-3.491) has a negative half-life, which is not possible and indicates a significant issue with the data or the compound. Ligand B (-20.014) also has a negative half-life, which is also concerning.

**P-gp Efflux:** Ligand A (0.799) has lower P-gp efflux than Ligand B (0.018), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage, and a difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having a better QED and P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.8 vs -9.1 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic), better solubility, and a lower hERG risk. The negative half-life values for both compounds are concerning and require further investigation, but the superior affinity of Ligand B makes it the better choice.

Output:
1
2025-04-17 15:38:19,692 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [360.439, 115.16 ,   3.611,   2.   ,   4.   ,   0.446,  67.003,  70.997, -4.736,  -5.009,   0.628,  42.303, -16.51 ,   0.229,  -7.9  ]
**Ligand B:** [344.323, 108.63 ,   2.696,   0.   ,   7.   ,   0.45 ,  86.157,  66.344, -4.429,  -5.385,   0.397, 121.766,  15.377,   0.405,  -8.7  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (360.439) is slightly higher than B (344.323), but both are acceptable.
2. **TPSA:** Both are below the 140 A<sup>2</sup> threshold for good oral absorption. A (115.16) is slightly higher than B (108.63), but both are reasonable.
3. **logP:** Both are within the optimal range (1-3). A (3.611) is slightly higher than B (2.696). This could be a minor concern for A, potentially increasing off-target interactions, but not a dealbreaker.
4. **HBD:** A (2) is preferable to B (0). Having some HBD can improve solubility.
5. **HBA:** A (4) is preferable to B (7). Lower HBA is generally better for permeability.
6. **QED:** Both are similar and acceptable (A: 0.446, B: 0.45).
7. **DILI:** A (67.003) is significantly better than B (86.157). Lower DILI is crucial.
8. **BBB:** A (70.997) is slightly better than B (66.344), but BBB isn't a primary concern for a non-CNS target like SRC.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.736) is slightly worse than B (-4.429). This is a concern for both.
10. **Solubility:** Both are negative, indicating poor solubility. A (-5.009) is slightly worse than B (-5.385). This is a concern for both.
11. **hERG:** Both are low, indicating low risk of cardiotoxicity. A (0.628) is slightly higher than B (0.397), but both are acceptable.
12. **Cl_mic:** A (42.303) is significantly better than B (121.766). Lower clearance is preferred for metabolic stability.
13. **t1/2:** A (-16.51) is significantly better than B (15.377). Longer half-life is preferred.
14. **Pgp:** Both are low, indicating low efflux. A (0.229) is slightly better than B (0.405).
15. **Binding Affinity:** B (-8.7) is significantly better than A (-7.9). A 0.8 kcal/mol difference in binding affinity is substantial.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

*   **Affinity:** B has a significantly better binding affinity.
*   **Metabolic Stability:** A has much better microsomal clearance and in vitro half-life.
*   **Solubility:** Both are poor, but B is slightly worse.
*   **hERG:** Both are acceptable.
*   **DILI:** A has a much lower DILI risk.

**Conclusion:**

While ligand A has better metabolic stability and lower DILI risk, the significantly stronger binding affinity of ligand B (-8.7 kcal/mol vs -7.9 kcal/mol) outweighs the drawbacks of slightly higher DILI, slightly worse solubility, and lower metabolic stability. A 0.8 kcal/mol difference is a substantial advantage in potency for an enzyme target. The poor Caco-2 and solubility for both compounds are concerning and would need to be addressed in further optimization, but the initial potency advantage of B makes it the more promising candidate.

1
2025-04-17 15:38:19,692 - INFO - Batch 396 complete. Total preferences: 6336
2025-04-17 15:38:19,692 - INFO - Processing batch 397/512...
2025-04-17 15:39:00,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.479 Da) is slightly lower, which can be favorable for permeability. Ligand B (367.475 Da) is also good.

**TPSA:** Ligand A (32.7) is excellent, well below the 140 threshold for oral absorption. Ligand B (103.43) is higher, potentially impacting absorption, but still within a reasonable range.

**logP:** Ligand A (4.225) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.102) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=6) is acceptable, but higher HBA could slightly reduce permeability.

**QED:** Ligand A (0.885) has a very good drug-likeness score. Ligand B (0.595) is acceptable, but lower.

**DILI:** Ligand A (9.849) has a very low DILI risk. Ligand B (33.695) is also low, but higher than Ligand A.

**BBB:** Ligand A (69.407) has moderate BBB penetration. Ligand B (20.396) has very low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.741) has poor Caco-2 permeability. Ligand B (-5.734) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.278) has poor aqueous solubility. Ligand B (-1.925) has slightly better, but still poor, aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.979, Ligand B: 0.159).

**Microsomal Clearance:** Ligand A (40.837) has moderate clearance, suggesting moderate metabolic stability. Ligand B (-6.816) has negative clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-18.663) has a long in vitro half-life, which is excellent. Ligand B (4.223) has a short in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.933, Ligand B: 0.006).

**Binding Affinity:** Both ligands have strong binding affinities (Ligand A: -8.5 kcal/mol, Ligand B: -8.1 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Ligand A has a better QED score, lower DILI risk, and a slightly better binding affinity. However, its logP is higher, and Caco-2 permeability and aqueous solubility are poor. Ligand B has a significantly better metabolic stability (lower Cl_mic, longer half-life) and slightly better solubility, but its logP is very low, and QED is lower.

Considering the enzyme-specific priorities, metabolic stability is crucial. While Ligand A has slightly better potency, Ligand B's superior metabolic stability and acceptable safety profile make it more likely to succeed as a drug candidate. The poor solubility of both compounds is a concern that would need to be addressed during formulation.

Output:
1
2025-04-17 15:39:00,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.415 and 347.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.56) is slightly higher than Ligand B (87.74), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (0.474) is a bit low, potentially hindering permeation. Ligand B (0.804) is better, but still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 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 4. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.698 and 0.737, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (25.281) has a significantly lower DILI risk than Ligand B (32.338), which is a major advantage.

**8. BBB:** Both ligands have similar BBB penetration (68.941 and 68.748), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.066) has worse Caco-2 permeability than Ligand B (-4.879), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.213) has worse aqueous solubility than Ligand B (-1.663).

**11. hERG Inhibition:** Ligand A (0.497) has a slightly higher hERG risk than Ligand B (0.105), which is undesirable.

**12. Microsomal Clearance:** Ligand A (-11.619) has *much* lower (better) microsomal clearance than Ligand B (-4.62), indicating significantly improved metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.97) has a better in vitro half-life than Ligand B (-5.507).

**14. P-gp Efflux:** Ligand A (0.002) has significantly lower P-gp efflux than Ligand B (0.016), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-9.3) has a stronger binding affinity than Ligand A (-8.2), a difference of 1.1 kcal/mol. This is a substantial difference and a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B has a clear advantage in binding affinity (-9.3 vs -8.2 kcal/mol). However, Ligand A demonstrates superior ADMET properties, particularly in DILI risk, microsomal clearance, P-gp efflux, and in vitro half-life. The lower binding affinity of Ligand A is somewhat offset by its improved safety and pharmacokinetic profile. Given the importance of metabolic stability and reduced toxicity for kinase inhibitors, and the substantial difference in Cl_mic and DILI, Ligand A is the more promising candidate. The slightly lower logP and Caco-2 permeability of Ligand A could be addressed through further optimization.

Output:
0
2025-04-17 15:39:00,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (348.443 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.92) is well below the 140 threshold for oral absorption, and a good value for an enzyme inhibitor. Ligand B (81.67) is still acceptable, but slightly higher.

**3. logP:** Both ligands have good logP values (1.769 and 1.316), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, which is excellent. Ligand B has 3 HBD, still acceptable but less ideal.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of 10.

**6. QED:** Both ligands have acceptable QED values (0.417 and 0.651), with Ligand B being slightly more drug-like.

**7. DILI:** Ligand A (34.703) has a lower DILI risk than Ligand B (46.219), both are below the 60 threshold, but A is preferable.

**8. BBB:** This is less critical for a kinase inhibitor, but Ligand A (76.735) has a higher BBB percentile than Ligand B (54.75).

**9. Caco-2 Permeability:** Ligand A (-4.523) has a more negative Caco-2 value, indicating poorer permeability than Ligand B (-4.922). This is a negative for Ligand A.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.85 and -2.061), indicating poor solubility. This is a concern for both, but is a more significant issue for Ligand B.

**11. hERG Inhibition:** Ligand A (0.227) has a much lower hERG inhibition liability than Ligand B (0.5), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (54.575) has a higher microsomal clearance than Ligand B (2.456), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (18.538) has a significantly longer in vitro half-life than Ligand A (-26.001), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux liability than Ligand B (0.064), which is a slight advantage.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This difference of 1.3 kcal/mol is substantial and outweighs many of the ADME drawbacks of Ligand B.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has better DILI and hERG profiles, Ligand B's significantly stronger binding affinity (-8.9 vs -7.6 kcal/mol) and longer half-life are critical advantages. The slightly higher TPSA and DILI risk of Ligand B are less concerning given the substantial potency difference. The solubility issues are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 15:39:00,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.47 and 357.384 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.14 and 84.31) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.303 and 2.153), falling within the optimal 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, being under 10.

**QED:** Both ligands have good QED scores (0.738 and 0.793), indicating good drug-likeness.

**DILI:** Ligand A (39.318) has a lower DILI risk than Ligand B (51.842), both are acceptable, but A is better.

**BBB:** Ligand A (97.014) has a significantly higher BBB penetration score than Ligand B (72.741). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.732) has better Caco-2 permeability than Ligand B (-5.226), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.179 and -3.033). This is a potential issue that might require formulation strategies.

**hERG Inhibition:** Ligand A (0.705) has a lower hERG inhibition liability than Ligand B (0.185), which is a significant advantage, reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (45.468) has a higher microsomal clearance than Ligand B (-10.638). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-16.209) has a much longer in vitro half-life than Ligand A (-7.516), which is a major advantage.

**P-gp Efflux:** Ligand A (0.293) has lower P-gp efflux liability than Ligand B (0.106), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial difference (1.4 kcal/mol) and is a critical factor.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much longer half-life, which are crucial for an enzyme inhibitor. While Ligand A has better solubility and lower hERG risk, the potency and metabolic stability advantages of Ligand B outweigh these concerns. The solubility and hERG issues can potentially be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 15:39:00,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.527 and 358.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is slightly higher than Ligand B (51.02), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (2.491) is within the optimal 1-3 range. Ligand B (3.541) is a bit higher, potentially raising concerns about off-target effects, but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) both satisfy the <=5 rule.

**H-Bond Acceptors:** Both ligands (4) are well below the 10 threshold.

**QED:** Both ligands have similar QED values (0.816 and 0.793), indicating good drug-likeness.

**DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (26.948). This is a significant advantage for Ligand A.

**BBB:** Ligand B (84.839) has a higher BBB penetration percentile than Ligand A (62.737). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.647) has a worse Caco-2 permeability than Ligand B (-4.88).

**Aqueous Solubility:** Ligand A (-1.62) has better aqueous solubility than Ligand B (-3.924). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.513 and 0.508).

**Microsomal Clearance:** Ligand B (69.748) has a significantly higher microsomal clearance than Ligand A (1.861). This suggests Ligand A is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (46.621) has a longer in vitro half-life than Ligand B (2.107). This is another positive for Ligand A, supporting better duration of action.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.031 and 0.271).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of almost 9 kcal/mol is extremely significant and likely outweighs any minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better solubility outweigh the slightly lower Caco-2 permeability and BBB penetration (which isn't critical for this target).

Output:
1
2025-04-17 15:39:00,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 372.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 49.41, which is well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values around 2.9, which is 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 3 HBA, both are acceptable (<=10).

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 27.1%, while Ligand B has 20.4%. Both are good (below 40%), but Ligand B is slightly better.

**BBB:** Ligand A has a BBB penetration of 73.8%, while Ligand B has 92.9%. While not a primary concern for a non-CNS target like SRC, higher BBB is generally not detrimental.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.929 and -4.874). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are common. The absolute values are similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values (-4.454 and -3.976). Similar to Caco-2, these are log scale values, and negative values are common. The absolute values are similar, so this isn't a major differentiator.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.219, while Ligand B has 0.83. Ligand A is significantly better here, indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A has a Cl_mic of 57.3 mL/min/kg, while Ligand B has 44.8 mL/min/kg. Lower is better for metabolic stability, so Ligand B is preferable.

**In vitro Half-Life:** Ligand A has a half-life of -0.318 hours, while Ligand B has -1.072 hours. Both are very short, which is concerning. However, negative values can occur in these predictions. The difference isn't huge.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.228, while Ligand B has 0.137. Lower is better, so Ligand B is preferable.

**Binding Affinity:** Ligand A has a binding affinity of -9.3 kcal/mol, while Ligand B has -10.8 kcal/mol. Ligand B has a significantly stronger binding affinity. This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Ligand B has a significantly better binding affinity (-10.8 vs -9.3 kcal/mol) and better metabolic stability (lower Cl_mic) and P-gp efflux. While Ligand A has a better hERG profile, the stronger binding of Ligand B is a critical advantage for an enzyme target like SRC kinase. The slight improvements in DILI and BBB for Ligand B are also favorable. The similar, and problematic, Caco-2 and Solubility values don't strongly favor either compound.

Output:
1
2025-04-17 15:39:00,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.378 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (396.192 Da) is still well within the acceptable range.

**TPSA:** Ligand A (95.67) is better than Ligand B (53.68) as it is closer to the threshold for good oral absorption (<140).

**logP:** Ligand A (0.844) is within the optimal range (1-3), but on the lower side. Ligand B (3.871) is also within the optimal range, but closer to 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 (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.767) has a better QED score than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 50.64, Ligand B: 48.74), and are both below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 69.407, Ligand B: 70.376). This isn't a primary concern for a kinase inhibitor, but it's not detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.961) is slightly worse than Ligand B (-4.661).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.164) is slightly better than Ligand B (-3.975).

**hERG Inhibition:** Ligand A (0.327) has a significantly lower hERG inhibition liability than Ligand B (0.891), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (-3.573) has a much lower (better) microsomal clearance than Ligand B (59.473), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.344) has a much longer in vitro half-life than Ligand B (69.217), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.148) has lower P-gp efflux liability than Ligand B (0.802), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 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 significantly better ADMET properties, particularly in terms of metabolic stability (Cl_mic, t1/2), hERG risk, and P-gp efflux. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh the affinity difference, especially given that the affinity of Ligand A is still quite good. The improved ADMET profile of Ligand A suggests a higher probability of success as a drug candidate.

Output:
0
2025-04-17 15:39:00,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.5 & 362.8 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.3) is better than Ligand B (50.3) as it is closer to the <140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.99 & 3.35), 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.

**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) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.69 & 0.90), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (37.9%) has a significantly lower DILI risk than Ligand B (50.9%). This is a crucial advantage.

**8. BBB:** Ligand B (90.1%) has a much higher BBB penetration potential than Ligand A (52.0%). However, SRC is not a CNS target, so this is less important.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.17 & -4.81), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.48 & -4.19), indicating poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.19 & 0.87). This is good.

**12. Microsomal Clearance:** Ligand A (34.2 mL/min/kg) has a lower microsomal clearance than Ligand B (61.9 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (18.8 hr) has a lower in vitro half-life than Ligand B (27.9 hr). This is a slight advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.06 & 0.39).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), Ligand A is the better candidate. While both have poor solubility and permeability, Ligand A has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The slightly longer half-life of Ligand B is not enough to offset these advantages. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
0
2025-04-17 15:39:00,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 376.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.55) is better than Ligand B (121.6), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.424) is optimal, while Ligand B (0.371) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.462 and 0.477), indicating moderate drug-likeness.

**DILI:** Ligand B (33.695) has a significantly lower DILI risk than Ligand A (41.45), making it more favorable from a toxicity perspective.

**BBB:** Both ligands have low BBB penetration (47.77 and 43.815), which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.145 and -5.38), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.091 and -1.785), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.261 and 0.219), which is excellent.

**Microsomal Clearance:** Ligand A (7.376) has a significantly lower Cl_mic than Ligand B (40.419), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.726) has a slightly better in vitro half-life than Ligand B (-7.543), although both are quite low.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.006).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 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 and a lower DILI risk. However, it suffers from a lower logP and significantly higher microsomal clearance. Both ligands have very poor solubility and permeability. Given the enzyme-specific priorities, the stronger binding affinity of Ligand B is the most critical factor. While the poor solubility and permeability are concerning, they might be addressed through formulation strategies. The improved metabolic stability of Ligand A is attractive, but the affinity difference is more important for an enzyme target.

Output:
1
2025-04-17 15:39:00,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.361 and 348.462 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.77) is significantly better than Ligand B (49.41). Both are under 140, but lower TPSA generally favors better absorption.

**3. logP:** Both ligands have good logP values (3.318 and 2.978), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.796 and 0.794), indicating good drug-like properties.

**7. DILI:** Ligand A (49.593) has a higher DILI risk than Ligand B (30.71). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands show good BBB penetration (92.827 and 88.019). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.184 and -4.777). 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 used.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.174 and -4.035). Similar to Caco-2, the scale is unknown, but these suggest poor solubility.

**11. hERG Inhibition:** Ligand A (0.926) has a slightly higher hERG risk than Ligand B (0.506). Lower is better here, favoring Ligand B.

**12. Microsomal Clearance:** Ligand A (94.32) has significantly higher microsomal clearance than Ligand B (56.58). This indicates lower metabolic stability for Ligand A, a major drawback for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (-6.96) has a longer in vitro half-life than Ligand A (-5.862). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.482) has lower P-gp efflux than Ligand B (0.307). Lower efflux is generally preferred, giving a slight edge to Ligand A.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-9.0). This is a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in the most important areas for an enzyme inhibitor: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly stronger binding affinity. The TPSA is also more favorable for Ligand B. The poor Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 15:39:00,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.268 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (86.36) is slightly higher than Ligand B (71.09).

**logP:** Both ligands have logP values between 1-3 (Ligand A: 2.584, Ligand B: 3.067), which is optimal.

**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, <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.684, Ligand B: 0.807), indicating a drug-like profile.

**DILI:** Ligand A has a DILI risk of 88.639, which is high. Ligand B has a DILI risk of 39.667, which is good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 61.613, Ligand B: 68.399). BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.111 and -4.905), 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 (-4.114 and -3.783), suggesting poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.248, Ligand B: 0.403).

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (18.264 mL/min/kg) than Ligand B (45.039 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (37.039 hours) than Ligand B (-6.5 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 (Ligand A: 0.051, Ligand B: 0.22).

**Binding Affinity:** Both ligands have strong binding affinities (Ligand A: -9.6 kcal/mol, Ligand B: -8.1 kcal/mol). Ligand A is slightly more potent.

**Conclusion:**

While Ligand A has a slightly better binding affinity and metabolic stability, the significantly higher DILI risk and the extremely short half-life of Ligand B are major drawbacks. Ligand B, despite its weaker affinity and faster clearance, presents a much more favorable safety profile (lower DILI, low hERG) and a reasonable P-gp efflux. Given the enzyme-specific priorities, the lower DILI risk of Ligand B outweighs the slightly better affinity and metabolic stability of Ligand A.

Output:
1
2025-04-17 15:39:00,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.423 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.96) is slightly higher than the preferred <140, but acceptable. Ligand B (49.85) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.927) is a bit low, potentially hindering permeation. Ligand B (2.394) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 8 HBA, acceptable. Ligand B has 4 HBA, also good.

**QED:** Both ligands have similar QED values (0.74 and 0.692), indicating good drug-likeness.

**DILI:** Ligand A (59.131) has a moderate DILI risk. Ligand B (20.744) has a significantly lower and preferable DILI risk.

**BBB:** Both have acceptable BBB penetration, but Ligand B (80.419) is better than Ligand A (70.88). This is less crucial for a kinase inhibitor than for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.635) and Ligand B (-4.898) have negative values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.514 and -2.424). This is a major drawback.

**hERG Inhibition:** Ligand A (0.046) has a very low hERG risk, which is excellent. Ligand B (0.365) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (54.594) has a moderate clearance, suggesting moderate metabolic stability. Ligand B (74.032) has higher clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (21.313 hours) has a good half-life. Ligand B (1.947 hours) has a very short half-life, which is a significant concern.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.19 and 0.149), which is good.

**Binding Affinity:** Ligand B (-9.4 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 many other drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -7.2 kcal/mol) is a major advantage for an enzyme inhibitor. It also has a much lower DILI risk and better BBB penetration, and a slightly lower hERG risk. While its metabolic stability (higher clearance, shorter half-life) is worse than Ligand A, the potency advantage is likely to be more impactful, and metabolic stability can be improved through further optimization. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the superior binding affinity makes Ligand B the better starting point.

Output:
1
2025-04-17 15:39:00,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.845 and 369.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.59) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (117.36) is still under 140, but less favorable than A.

**logP:** Ligand A (2.267) is optimal (1-3). Ligand B (0.793) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is acceptable, but the 3 donors are less ideal.

**QED:** Ligand A (0.763) is good, indicating drug-likeness. Ligand B (0.524) is acceptable, but lower.

**DILI:** Ligand B (77.472) has a higher DILI risk than Ligand A (58.55). Both are acceptable, but A is preferable.

**BBB:** Ligand A (71.811) has a good BBB penetration percentile, while Ligand B (35.246) is low. While not a primary concern for a non-CNS target like SRC, it's a slight advantage for A.

**Caco-2 Permeability:** Ligand A (-4.609) is better than Ligand B (-5.206), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.483) is better than Ligand B (-3.113), indicating better solubility.

**hERG Inhibition:** Ligand A (0.379) has a much lower hERG risk than Ligand B (0.089). This is a significant advantage for A.

**Microsomal Clearance:** Ligand A (81.535) has a higher clearance than Ligand B (21.935), meaning it is less metabolically stable. This is a significant drawback for A.

**In vitro Half-Life:** Ligand A (-8.245) has a shorter half-life than Ligand B (-6.497). This is a drawback for A.

**P-gp Efflux:** Ligand A (0.371) has lower P-gp efflux than Ligand B (0.09). This is a slight advantage for A.

**Binding Affinity:** Both ligands have excellent binding affinity (-6.8 and -8.1 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability, but suffers from a lower logP, higher DILI risk, and a significantly higher hERG risk. Ligand A has better solubility, lower hERG risk, and better permeability. Given the enzyme-specific priorities, the lower hERG risk and better solubility of Ligand A are crucial. While the metabolic stability is a concern, it could potentially be addressed with structural modifications. The slightly better binding affinity of Ligand B is not enough to outweigh the safety concerns.

Output:
1
2025-04-17 15:39:00,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands fall within the ideal 200-500 Da range (A: 350.447, B: 448.77).

**TPSA:** Ligand A (58.12) is well below the 140 threshold, suggesting good absorption. Ligand B (84.22) is also acceptable, but higher.

**logP:** Both ligands have good logP values (A: 3.84, B: 3.426), falling within the 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, well within the limit of <=10.

**QED:** Both ligands have acceptable QED values (A: 0.78, B: 0.709), indicating good drug-like properties.

**DILI:** Ligand A (90.733) has a significantly higher DILI risk than Ligand B (81.039). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.827) is higher than Ligand B (44.785).

**Caco-2 Permeability:** Ligand A (-4.895) is better than Ligand B (-5.231), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.901) is slightly better than Ligand B (-5.032), but both are quite poor.

**hERG Inhibition:** Ligand A (0.758) has a lower hERG risk than Ligand B (0.407), which is preferable.

**Microsomal Clearance:** Ligand A (93.79) has a higher microsomal clearance than Ligand B (41.787), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (75.587) has a longer half-life than Ligand B (29.679), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.9) has lower P-gp efflux than Ligand B (0.487), which is favorable.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a substantially 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 ADME concerns.

**Conclusion:**

Despite Ligand A having better Caco-2 permeability, P-gp efflux, and in vitro half-life, the significantly higher DILI risk and lower metabolic stability (higher Cl_mic) are major concerns. More importantly, Ligand B's *much* stronger binding affinity (-9.6 vs -7.3 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The improved potency is likely to compensate for the slightly less favorable ADME properties.

Output:
1
2025-04-17 15:39:00,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.387 and 346.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (105.12 and 104.39) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.162) is within the optimal range (1-3). Ligand B (-0.305) is slightly below 1, which *could* indicate potential permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3 and 2 respectively) and HBA (5 each) counts.

**QED:** Both ligands have similar and good QED scores (0.685 and 0.688), indicating good drug-likeness.

**DILI:** Ligand A (77.007) has a higher DILI risk than Ligand B (50.33). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (56.146) and Ligand B (33.85) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.178 and -4.82), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.728 and -2.582), which is also concerning and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.18 and 0.164), which is excellent.

**Microsomal Clearance:** Ligand A (-5.461) has lower (better) microsomal clearance than Ligand B (-4.862), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (57.486) has a significantly longer in vitro half-life than Ligand B (-26.21). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.015).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

While both ligands have good potency and acceptable physicochemical properties (except for permeability and solubility), Ligand A is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly lower DILI risk outweigh the minor differences in other parameters. The poor permeability and solubility are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 15:39:00,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.336 Da) is slightly higher than Ligand B (352.435 Da), but both are acceptable.

**TPSA:** Ligand A (44.73) is significantly better than Ligand B (94.48). Lower TPSA generally favors better cell permeability.

**logP:** Ligand A (4.403) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (0.406) is quite low, which might hinder 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, and Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.774 and 0.628), indicating reasonable drug-likeness.

**DILI:** Both ligands have low DILI risk (35.673 and 34.161), which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (69.639) has a better BBB percentile than Ligand B (59.093).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.107 and -5.181), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.19 and -0.724). This is a major drawback.

**hERG Inhibition:** Ligand A (0.918) has a slightly higher hERG risk than Ligand B (0.538), but both are relatively low.

**Microsomal Clearance:** Ligand B (8.339 mL/min/kg) has significantly lower microsomal clearance than Ligand A (36.964 mL/min/kg), indicating better metabolic stability. This is a crucial advantage.

**In vitro Half-Life:** Ligand B (5.059 hours) has a much shorter half-life than Ligand A (19.043 hours). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.432) has lower P-gp efflux than Ligand B (0.026), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.5 vs -6.8 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are critical advantages for an enzyme inhibitor. While Ligand A has better P-gp efflux, the affinity difference and metabolic stability of Ligand B are more important. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the core potency and stability profile of Ligand B is superior.

Output:
1
2025-04-17 15:39:00,325 - INFO - Batch 397 complete. Total preferences: 6352
2025-04-17 15:39:00,325 - INFO - Processing batch 398/512...
2025-04-17 15:39:42,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (410.331 Da) is still acceptable.

**TPSA:** Ligand A (123.84) is better than Ligand B (38.13) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (-0.419) is a bit low, potentially hindering permeation. Ligand B (3.866) is optimal.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (3) is also good.

**QED:** Both ligands have similar QED values (0.64 and 0.65), indicating good drug-likeness.

**DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (29.236), which is a significant concern.

**BBB:** Ligand A (45.715) has a lower BBB penetration than Ligand B (82.319). This is not a primary concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-5.549) has a very poor Caco-2 permeability. Ligand B (-4.907) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-3.037) has poor solubility. Ligand B (-4.457) has even worse solubility.

**hERG:** Ligand A (0.225) has a lower hERG risk than Ligand B (0.868), which is preferable.

**Microsomal Clearance:** Ligand A (6.839) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (90.176).

**In vitro Half-Life:** Ligand A (10.439) has a shorter half-life than Ligand B (36.195).

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux, which is favorable. Ligand B (0.718) has higher P-gp efflux.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.3 and -8.4 kcal/mol), which are excellent.

**Overall Assessment:**

Ligand B has a better logP, lower DILI risk, and a longer half-life. However, Ligand A has better metabolic stability (lower Cl_mic), lower P-gp efflux, and lower hERG risk. The poor solubility and Caco-2 permeability of both are concerning, but the significantly higher DILI risk associated with Ligand A is a major drawback. Given the enzyme-kinase target class, metabolic stability and minimizing toxicity are critical. Although the binding affinity is similar, the lower DILI risk and better logP of Ligand B make it the more promising candidate, despite its poorer metabolic stability.

Output:
1
2025-04-17 15:39:42,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.459 and 349.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (77.77) is well below the 140 threshold for oral absorption. Ligand B (121.23) is also below, but closer to the limit.

**logP:** Ligand A (3.362) is within the optimal range of 1-3. Ligand B (1.329) is at the lower end, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the HBD <=5 criteria.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are below the HBA <=10 threshold.

**QED:** Ligand A (0.794) has a better QED score than Ligand B (0.593), indicating a more drug-like profile.

**DILI:** Ligand A (44.824) has a significantly lower DILI risk than Ligand B (63.746), which is approaching the higher risk threshold.

**BBB:** Both ligands have moderate BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.246) has a worse Caco-2 permeability than Ligand B (-4.868).

**Aqueous Solubility:** Ligand A (-4.014) has a worse aqueous solubility than Ligand B (-3.559).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.413, B: 0.208).

**Microsomal Clearance:** Ligand A (100.99) has significantly higher microsomal clearance than Ligand B (11.571), suggesting lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (63.154) has a longer half-life than Ligand B (-5.106).

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.112, B: 0.099).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.7), although both are excellent.

**Conclusion:**

Despite Ligand A's better QED score and slightly longer half-life, Ligand B is the more promising candidate. The primary reason is Ligand B's significantly better metabolic stability (lower Cl_mic, and therefore likely a longer *in vivo* half-life) and lower DILI risk. While Ligand A has a slightly better Caco-2 permeability and solubility, these are less critical than metabolic stability for an enzyme target. The difference in binding affinity is minor and doesn't outweigh the ADME advantages of Ligand B.

Output:
1
2025-04-17 15:39:42,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.773 and 384.885 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.0) is slightly above the preferred <140 for good oral absorption, while Ligand B (82.78) is well within this range.

**logP:** Both ligands have logP values (1.962 and 2.937) within the optimal 1-3 range.

**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 within the limit of 10.

**QED:** Both ligands have good QED scores (0.72 and 0.8), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 96.782, which is very high and concerning. Ligand B has a DILI risk of 73.866, still elevated but significantly better than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (33.579) and Ligand B (24.738) both have low BBB penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.686 and -5.085), which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.032 and -4.683). This is a significant drawback.

**hERG:** Ligand A (0.033) has a very low hERG risk, which is excellent. Ligand B (0.654) has a moderate hERG risk, which is acceptable but requires attention.

**Microsomal Clearance:** Ligand A (-4.19) has a negative clearance, which is not physically possible and likely indicates a very stable compound. Ligand B (42.442) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (9.077) has a moderate half-life, while Ligand B (41.558) has a long half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.043 and 0.283).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.7 kcal/mol), with Ligand B being slightly better.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. The primary reason is the significantly lower DILI risk compared to Ligand A. While both have poor solubility and permeability, the higher metabolic stability (longer half-life and lower clearance) of Ligand B is also a major advantage. Ligand A's extremely high DILI risk is a deal-breaker, even with its slightly better hERG profile. The negative clearance for Ligand A is also a red flag, suggesting an issue with the data or the model.

Output:
1
2025-04-17 15:39:42,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 343.45 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (71) is slightly above the optimal <140, but acceptable. Ligand B (55.63) is well within the acceptable range.

**logP:** Ligand A (2.475) is optimal (1-3). Ligand B (3.594) is a bit higher, potentially raising concerns about solubility and off-target effects, but still within a reasonable range.

**H-Bond Donors:** Both ligands have 1 HBD, which is excellent.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both are acceptable (<=10).

**QED:** Ligand A (0.829) has a significantly better QED score than Ligand B (0.67), indicating a more drug-like profile.

**DILI:** Ligand A (16.092) has a much lower DILI risk than Ligand B (36.448), a significant advantage.

**BBB:** Ligand A (70.26) shows good BBB penetration, while Ligand B (90.617) is even better. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.779) and Ligand B (-5.077) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.333 and -3.62 respectively). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.129) has a very low hERG risk, while Ligand B (0.599) is moderately risky. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (44.549) has lower microsomal clearance than Ligand B (56.253), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.862) has a negative half-life, which is problematic. Ligand B (3.887) has a positive half-life, indicating better stability.

**P-gp Efflux:** Ligand A (0.086) has very low P-gp efflux, while Ligand B (0.519) has moderate efflux.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage that could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A has better DILI, hERG, P-gp efflux, and QED scores. The solubility and Caco-2 permeability are poor for both. The half-life is also concerning for Ligand A. While the affinity difference is large, the poor solubility and permeability of both compounds are significant hurdles. Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity, I would choose Ligand B, but with a strong caveat that solubility and permeability *must* be addressed through further optimization.

Output:
1
2025-04-17 15:39:42,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 355.563 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.45) is slightly above the preferred <140, but acceptable. Ligand B (60.77) is well within the desirable range.

**logP:** Ligand A (0.308) is quite low, potentially hindering permeability. Ligand B (4.134) is at the upper end of the optimal range, potentially causing solubility issues but acceptable.

**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 3 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.666 and 0.619), indicating good drug-likeness.

**DILI:** Ligand A (38.736) has a slightly higher DILI risk than Ligand B (12.02), but both are below the concerning threshold of 60.

**BBB:** Ligand A (62.97) and Ligand B (80.69) both have acceptable BBB penetration, but SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-4.629) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.25) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.627) and Ligand B (-3.748) both have poor aqueous solubility, which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.075) has a very low hERG risk, which is excellent. Ligand B (0.855) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (19.696) has lower microsomal clearance than Ligand B (71.809), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-28.555) has a negative half-life, indicating very rapid metabolism. Ligand B (20.425) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable. Ligand B (0.668) has a moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.5 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 has a much stronger binding affinity, a lower DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic). However, it suffers from poor Caco-2 permeability, low logP, and a very short in vitro half-life. Ligand B has better Caco-2 permeability, better solubility, and a more reasonable half-life, but its binding affinity is very weak.

Given that SRC is a kinase, potency (binding affinity) and metabolic stability are paramount. The substantial difference in binding affinity (-8.5 vs -0.0 kcal/mol) is a major factor. While Ligand A's ADME properties are concerning, optimization efforts could potentially address these issues. The weak binding of Ligand B makes it a less attractive starting point, as significant structural modifications would be needed to achieve sufficient potency.

Output:
0
2025-04-17 15:39:42,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.86 & 371.84 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.91) is better than Ligand B (73.74), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.88) is slightly higher than Ligand B (1.91). Ligand B is a bit low, potentially hindering permeation. Ligand A is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.854 and 0.794), indicating good drug-likeness.

**DILI:** Ligand B (30.48) has a significantly lower DILI risk than Ligand A (49.98). This is a major advantage for Ligand B.

**BBB:** Ligand A (80.88) has better BBB penetration than Ligand B (66.19), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.945) has a more negative Caco-2 value, suggesting *better* permeability than Ligand B (-4.451). Note that lower (more negative) values indicate better permeability in this scale.

**Aqueous Solubility:** Ligand A (-3.988) has slightly better solubility than Ligand B (-1.652).

**hERG:** Ligand A (0.162) has a lower hERG risk than Ligand B (0.443), which is favorable.

**Microsomal Clearance:** Ligand A (9.131) has a lower microsomal clearance than Ligand B (11.132), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (32.51 and 32.46 hours).

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux than Ligand B (0.3), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better permeability, solubility, metabolic stability, and P-gp efflux, Ligand B has a significantly lower DILI risk. Given the enzyme-kinase target class priority on minimizing toxicity, the lower DILI risk of Ligand B is a decisive factor. The binding affinities are comparable, so the improved safety profile of Ligand B makes it the more promising drug candidate.

Output:
1
2025-04-17 15:39:42,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.353 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.46) is well below the 140 threshold for good absorption, while Ligand B (93.19) is still acceptable but closer to the limit.

**logP:** Ligand A (0.768) is a bit low, potentially hindering permeation, while Ligand B (-1.194) is even lower and more concerning for permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, both within acceptable limits. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.735) has a better QED score than Ligand B (0.562), indicating a more drug-like profile.

**DILI:** Ligand A (61.225) has a higher DILI risk than Ligand B (6.475). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.843) is better than Ligand B (20.512).

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests very poor permeability. Ligand A (-5.314) is slightly better than Ligand B (-5.491).

**Aqueous Solubility:** Ligand A (-3.38) is better than Ligand B (0.062), indicating better solubility.

**hERG:** Ligand A (0.455) has a much lower hERG risk than Ligand B (0.059), which is a major advantage.

**Microsomal Clearance:** Ligand A (0.095) has a much lower Cl_mic than Ligand B (-11.77), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (46.375) has a significantly longer half-life than Ligand B (-28.676), a crucial advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.02) has lower P-gp efflux than Ligand B (0.001), suggesting better bioavailability.

**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.

**Overall:**

Ligand A is superior despite the higher DILI risk. Its advantages in solubility, metabolic stability (lower Cl_mic and longer half-life), lower hERG risk, better P-gp efflux, and slightly better affinity outweigh the DILI concern. Ligand B's very low logP and extremely high Cl_mic are major red flags. The DILI risk for Ligand A is elevated but manageable with further optimization, whereas Ligand B has several properties that are difficult to improve significantly.

Output:
0
2025-04-17 15:39:42,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.416 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold, suggesting good absorption. Ligand B (88.39) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.42) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.853) is optimal.

**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 (0.677 and 0.831), indicating drug-like properties.

**DILI:** Ligand A (8.298) has a very low DILI risk, which is excellent. Ligand B (74.603) has a significantly higher DILI risk, which is concerning.

**BBB:** Ligand A (95.541) has excellent BBB penetration, though this isn't a primary concern for a non-CNS target like SRC. Ligand B (53.819) is lower.

**Caco-2 Permeability:** Ligand A (-4.546) has poor Caco-2 permeability. Ligand B (-5.055) is also poor.

**Aqueous Solubility:** Ligand A (-4.433) has poor aqueous solubility. Ligand B (-3.077) is better, but still poor.

**hERG Inhibition:** Ligand A (0.979) has a low hERG risk, which is excellent. Ligand B (0.238) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (48.934) has moderate clearance. Ligand B (36.393) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.876) has a moderate half-life. Ligand B (17.266) has a significantly longer half-life, which is highly desirable.

**P-gp Efflux:** Ligand A (0.562) has moderate P-gp efflux. Ligand B (0.069) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand B is significantly better. While both have issues with Caco-2 and solubility, Ligand B's substantially superior binding affinity (-8.7 vs -0.0 kcal/mol) outweighs these drawbacks. Its lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux further solidify its advantage. Ligand A's high logP and poor binding affinity are major concerns.

Output:
1
2025-04-17 15:39:42,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.352 and 360.841 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.33) is slightly higher than Ligand B (51.66). Both are below 140, suggesting reasonable absorption potential.

**logP:** Ligand A (1.108) is slightly lower than the optimal range (1-3), while Ligand B (2.983) is closer to the ideal.

**H-Bond Donors:** Both have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5, and Ligand B has 4, both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED scores (0.811 and 0.794), indicating good drug-likeness.

**DILI:** Ligand A (50.911) has a slightly higher DILI risk than Ligand B (36.409), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (85.925 and 80.535), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.568 and -4.765), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.064 and -3.059), indicating very poor aqueous solubility. This is a major issue for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.232) has a lower hERG inhibition risk than Ligand B (0.5), which is favorable.

**Microsomal Clearance:** Ligand A (16.648 mL/min/kg) has significantly lower microsomal clearance than Ligand B (63.953 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.351 hours) has a negative half-life, which is not possible. Ligand B (51.549 hours) has a reasonable half-life. This is a serious issue for Ligand A.

**P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux than Ligand B (0.255), which is beneficial.

**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 must be weighed against the ADME properties.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its extremely poor *in vitro* half-life (negative value) and poor solubility are major red flags. Ligand B, while having a slightly lower affinity, has a reasonable half-life, better metabolic stability (lower Cl_mic), and a lower hERG risk. Both have poor Caco-2 permeability and solubility, but the metabolic stability and half-life issues with Ligand A are more critical for an enzyme target. Therefore, Ligand B is the more viable candidate.

Output:
1
2025-04-17 15:39:42,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.515 and 359.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (62.91), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.671) is optimal, while Ligand B (4.072) is approaching the upper limit and could potentially cause solubility issues.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands (A: 0.74, B: 0.72) have good drug-likeness scores.

**DILI:** Ligand A (40.287) has a lower DILI risk than Ligand B (53.509), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (65.529) is better than Ligand B (48.662).

**Caco-2 Permeability:** Ligand A (-4.668) is better than Ligand B (-5.095), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.426) is better than Ligand B (-4.87), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.267) has a significantly lower hERG risk than Ligand B (0.845), a major advantage.

**Microsomal Clearance:** Ligand A (54.199) has lower clearance than Ligand B (96.839), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (31.143) has a shorter half-life than Ligand B (78.548), but still acceptable.

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux than Ligand B (0.638), which is beneficial.

**Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-0.0). This is a significant advantage.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties (solubility, metabolic stability, hERG risk, DILI, permeability) and has a significantly better binding affinity. While Ligand B has a longer half-life, the other advantages of Ligand A outweigh this single benefit.

Output:
1
2025-04-17 15:39:42,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.443 Da) is slightly lower, which could be beneficial for permeability. Ligand B (363.805 Da) is also acceptable.

**TPSA:** Ligand A (69.73) is excellent, well below the 140 threshold for oral absorption. Ligand B (105.21) is still reasonable, but less optimal.

**logP:** Ligand A (3.023) is ideal. Ligand B (1.346) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is good. Ligand B (HBD=3, HBA=7) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.749) is very good, indicating high drug-likeness. Ligand B (0.585) is still above the 0.5 threshold, but less favorable.

**DILI:** Ligand B (77.782) has a significantly higher DILI risk than Ligand A (64.754). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.97) and Ligand B (43.893) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.478 and -5.483). This is unusual and suggests poor permeability *in vitro*. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.244 and -2.752). This is also unusual and suggests poor solubility *in vitro*.

**hERG:** Ligand A (0.897) has a lower hERG risk than Ligand B (0.331), which is a positive.

**Microsomal Clearance:** Ligand A (52.209) has a higher microsomal clearance than Ligand B (28.641). This means Ligand B is more metabolically stable, which is highly desirable for an enzyme target.

**In vitro Half-Life:** Ligand B (104.27) has a significantly longer half-life than Ligand A (24.316), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.251) has slightly higher P-gp efflux liability than Ligand B (0.06).

**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 advantage that can outweigh many other drawbacks.

**Overall Assessment:**

Despite the poor *in vitro* permeability and solubility predictions for both, Ligand B is the stronger candidate. The significantly improved binding affinity (-8.4 vs 0 kcal/mol) is the most important factor. The lower DILI risk and superior metabolic stability (lower Cl_mic, longer t1/2) of Ligand B are also crucial advantages for an enzyme target. While the logP is a bit low, the strong binding may compensate. The permeability and solubility issues would need to be addressed through formulation or further structural modifications, but the starting point is much better with Ligand B.

Output:
1
2025-04-17 15:39:42,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (374.438 Da) is also good.

**TPSA:** Ligand A (58.44) is excellent, well below the 140 threshold for oral absorption. Ligand B (112.23) is higher, but still acceptable, though it might slightly reduce absorption compared to A.

**logP:** Ligand A (2.297) is optimal. Ligand B (0.21) is quite low, potentially hindering membrane permeability and absorption.

**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 (A: 0.842, B: 0.739), indicating drug-like properties.

**DILI:** Ligand A (37.65) has a lower DILI risk than Ligand B (63.552), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.696) is higher than Ligand B (55.874).

**Caco-2 Permeability:** Ligand A (-4.789) has a better (less negative) Caco-2 value than Ligand B (-5.238), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.016) has better solubility than Ligand B (-2.569). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG risk (A: 0.236, B: 0.331).

**Microsomal Clearance:** Ligand A (59.996) has a higher (worse) microsomal clearance than Ligand B (-6.424). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-29.103) has a significantly longer in vitro half-life than Ligand A (-0.326), indicating greater stability.

**P-gp Efflux:** Both ligands have similar low P-gp efflux liability (A: 0.261, B: 0.048).

**Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2), Ligand A has a significantly better overall profile. Its higher logP, lower TPSA, better solubility, and lower DILI risk outweigh the slightly higher microsomal clearance. The binding affinity is identical, so the ADME properties become the deciding factor. Ligand A is more likely to be a viable drug candidate.

Output:
0
2025-04-17 15:39:42,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (374.897 Da) is still well within the range.

**TPSA:** Ligand A (126.88) is closer to the upper limit for good oral absorption (<=140), while Ligand B (61.92) is excellent.

**logP:** Ligand A (-0.185) is quite low, potentially hindering permeability. Ligand B (3.545) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA. Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.405, B: 0.776), indicating drug-likeness, with B being significantly better.

**DILI:** Ligand A (61.846) has a higher DILI risk than Ligand B (47.421), though both are reasonably acceptable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (80.884) has a higher BBB score, but this is less important here.

**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 unspecified.

**hERG:** Ligand A (0.148) has a slightly lower hERG risk than Ligand B (0.537), which is preferable.

**Microsomal Clearance:** Ligand A (-13.314) has a *much* lower (better) microsomal clearance than Ligand B (71.877), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (13.065) has a longer half-life than Ligand B (10.896).

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux liability than Ligand B (0.545), which is beneficial.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >1.1 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better metabolic stability and lower P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.3 vs -7.2 kcal/mol) is the deciding factor. The improved QED and lower DILI risk of Ligand B also contribute to its favorability. While the logP of A is concerning, the substantial binding affinity advantage of B makes it the more promising candidate.

Output:
1
2025-04-17 15:39:42,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.419 and 354.372 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.23) is higher than Ligand B (58.2). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cellular permeability.

**logP:** Ligand A (0.391) is quite low, potentially hindering membrane permeability. Ligand B (2.366) 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 5 HBAs, while Ligand B has only 2. Lower HBA counts generally improve permeability, favoring Ligand B.

**QED:** Both ligands have good QED scores (0.63 and 0.704), indicating generally drug-like properties.

**DILI:** Ligand A (42.613) and Ligand B (35.789) both have acceptable DILI risk, with Ligand B being slightly better.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand B has a higher BBB percentile (89.492) than Ligand A (41.373), but this is not a primary concern here.

**Caco-2 Permeability:** Ligand A (-5.109) has poor Caco-2 permeability, while Ligand B (-4.584) is better, though still not great.

**Aqueous Solubility:** Ligand A (-1.821) has poor solubility, while Ligand B (-3.424) is even worse. Both are problematic, but the difference isn't huge.

**hERG Inhibition:** Both ligands have low hERG risk (0.504 and 0.522).

**Microsomal Clearance:** Ligand A (19.006 mL/min/kg) has lower clearance than Ligand B (38.436 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (27.636 hours) has a significantly longer half-life than Ligand B (-10.099 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.12).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive factor. A difference of >1.5 kcal/mol can often outweigh other ADME concerns.

**Overall Assessment:**

Ligand B excels in binding affinity and has better logP and TPSA values, making it more likely to permeate cells. However, it has worse solubility and metabolic stability. Ligand A has better metabolic stability and a longer half-life, but suffers from poor logP, solubility, and Caco-2 permeability, and very weak binding. The significantly stronger binding affinity of Ligand B (-7.7 kcal/mol vs 0.0 kcal/mol) is a critical advantage that likely outweighs its ADME drawbacks, especially given that SRC is an intracellular kinase. The improved logP and TPSA also contribute to better potential for cellular entry.

Output:
1
2025-04-17 15:39:42,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.475 Da) is slightly higher than Ligand B (342.399 Da), but both are acceptable.

**TPSA:** Ligand A (93.01) is better than Ligand B (107.11), as lower TPSA generally favors oral absorption. Both are still reasonably within an acceptable range.

**logP:** Ligand A (1.311) is slightly better than Ligand B (0.816), falling comfortably within the optimal 1-3 range. Ligand B is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) is preferable to Ligand B (HBD=4, HBA=4). Ligand A has a better balance, while Ligand B has a higher number of HBDs which could affect permeability.

**QED:** Ligand A (0.762) has a higher QED score than Ligand B (0.597), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 54.207, Ligand B: 51.725), and both are reasonably low, below the 60 threshold.

**BBB:** Ligand A (55.176) has a better BBB percentile than Ligand B (41.218), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.336) is slightly better than Ligand B (-5.461).

**Aqueous Solubility:** Ligand A (-1.486) is better than Ligand B (-3.165), indicating better solubility. Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (Ligand A: 0.177, Ligand B: 0.268), which is excellent.

**Microsomal Clearance:** Ligand B (-10.452) has significantly lower (better) microsomal clearance than Ligand A (48.854), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-2.386) has a better (longer) in vitro half-life than Ligand A (28.734), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.066, Ligand B: 0.028).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This >1.5 kcal/mol difference in affinity is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and a slightly better QED, Ligand B's significantly stronger binding affinity (-9.0 vs -6.5 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed with further optimization.

Output:
1
2025-04-17 15:39:42,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.555 Da and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, and even below the 90 for CNS targets. Ligand B (89.95) is still under 140, but higher, potentially impacting absorption.

**logP:** Ligand A (2.729) is optimal (1-3). Ligand B (0.369) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (2) is acceptable.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is acceptable.

**QED:** Both ligands (0.728 and 0.747) have good drug-likeness scores (>0.5).

**DILI:** Ligand A (19.542) has a very low DILI risk. Ligand B (13.843) also has a low DILI risk, but higher than A.

**BBB:** Ligand A (88.406) shows good BBB penetration, while Ligand B (53.781) is lower. This is less critical for a non-CNS target like SRC, but still a positive for A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.965 and -4.934). This is unusual and suggests a potential issue with the calculation or data quality. However, given the other parameters, it's less impactful than other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.587 and -1.227). This is also concerning and suggests poor solubility. Ligand B is slightly better than A in this regard.

**hERG Inhibition:** Ligand A (0.735) has a lower hERG risk than Ligand B (0.101). This is a significant advantage for A.

**Microsomal Clearance:** Ligand A (80.332) has higher clearance than Ligand B (-5.845). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-11.178) has a longer half-life than Ligand A (-6.116), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.299) has lower P-gp efflux than Ligand B (0.006), which is favorable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has better solubility, lower hERG risk, and better BBB penetration. The low logP of Ligand B is a significant concern. The negative solubility and Caco-2 values for both are problematic, but the strong affinity of Ligand B makes it more likely to be optimized to overcome these issues. Given the importance of potency for kinase inhibitors, and the significant difference in binding affinity, I would prioritize Ligand B.

Output:
1
2025-04-17 15:39:42,312 - INFO - Batch 398 complete. Total preferences: 6368
2025-04-17 15:39:42,312 - INFO - Processing batch 399/512...
2025-04-17 15:40:22,210 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (329.407 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.6) is better than Ligand B (82.5). Both are below the 140 threshold for oral absorption, but lower TPSA generally favors better cell permeability.

**logP:** Both ligands have good logP values (3.133 and 2.267), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as lower HBD counts generally improve permeability. Both are within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have the same HBA count (4), which is well within the acceptable limit of 10.

**QED:** Both ligands have similar and good QED values (0.801 and 0.879), indicating good drug-like properties.

**DILI:** Ligand A (35.595) has a significantly lower DILI risk than Ligand B (60.489). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.941) is slightly higher than Ligand A (48.74), but this is not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.304 and -4.864), 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 exact scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.452 and -3.247), which is also unusual and indicates poor aqueous solubility. This is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.873) has a slightly lower hERG inhibition risk than Ligand B (0.34), which is preferable.

**Microsomal Clearance:** Ligand A (16.565) has a lower microsomal clearance than Ligand B (26.08), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-35.967) has a much longer in vitro half-life than Ligand B (12.682), suggesting slower metabolism and potentially less frequent dosing. This is a major advantage.

**P-gp Efflux:** Ligand A (0.233) has lower P-gp efflux liability than Ligand B (0.04), which is preferable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.8 and -8.4 kcal/mol). The difference of 1.4 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It exhibits lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better hERG risk. While both have poor solubility and permeability based on the provided values, the superior ADME profile of Ligand A, combined with comparable binding affinity, makes it the preferred choice.

Output:
0
2025-04-17 15:40:22,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 370.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.58) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (94.48) is well within the acceptable range.

**logP:** Ligand A (-0.819) is a bit low, potentially hindering permeation. Ligand B (0.193) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (3 and 2 respectively) and HBA (7 each) counts.

**QED:** Both ligands have good QED scores (0.637 and 0.571), indicating drug-likeness.

**DILI:** Ligand A (45.25) has a better DILI score than Ligand B (60.915), indicating lower potential for liver injury.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (60.023) compared to Ligand A (18.961), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.484 and -5.622), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.707 and -2.149), which is also concerning and suggests poor solubility.

**hERG:** Both ligands show very low hERG inhibition risk (0.01 and 0.185). This is excellent.

**Microsomal Clearance:** Ligand A (-16.135) has a much lower (better) microsomal clearance than Ligand B (18.958), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (20.968) has a better in vitro half-life than Ligand A (10.384).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.021).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.7 and -8.1 kcal/mol), both being strong binders. The difference of 0.6 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is slightly favored despite the similar binding affinity. Its significantly lower microsomal clearance (better metabolic stability) and lower DILI risk are key advantages. While both have poor predicted permeability and solubility, the metabolic stability is more crucial for an enzyme target. The slightly better logP of Ligand B is not enough to offset the metabolic concerns.

Output:
0
2025-04-17 15:40:22,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.452 and 364.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.74) is significantly better than Ligand B (66.91).  A TPSA under 140 is desirable for oral absorption, and both meet this, but lower is generally better.

**logP:** Both ligands have a logP around 4 (3.968 and 4.014), which is at the higher end of the optimal range. This could potentially lead to solubility issues, but isn't a dealbreaker.

**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 forming groups, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.679 and 0.616), indicating good drug-likeness.

**DILI:** Ligand A (14.036) has a much lower DILI risk than Ligand B (35.673). This is a significant advantage for Ligand A.

**BBB:** Ligand A (92.323) shows better BBB penetration than Ligand B (77.162), although this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.727) has a worse Caco-2 permeability than Ligand B (-5.202). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.637) has slightly better aqueous solubility than Ligand B (-3.85).

**hERG:** Both ligands have very low hERG risk (0.829 and 0.725), which is excellent.

**Microsomal Clearance:** Ligand A (8.323) has significantly lower microsomal clearance than Ligand B (74.946). This suggests better metabolic stability for Ligand A, a crucial factor for kinases.

**In vitro Half-Life:** Ligand A (13.751 hours) has a much longer half-life than Ligand B (35.404 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.606 and 0.556).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.0 and -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** While both have good potency, Ligand A demonstrates superior ADMET properties, specifically a much lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and better BBB penetration. These factors are particularly important for kinase inhibitors, where maintaining adequate exposure and minimizing toxicity are critical. The slightly worse Caco-2 permeability of Ligand A is a minor drawback compared to the substantial benefits in other areas.

Output:
1
2025-04-17 15:40:22,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.328 Da and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (65.46 and 62.55) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values (3.827 and 3.229) within the optimal 1-3 range. Ligand B is slightly preferred here.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 guideline. Ligand B is slightly better.

**H-Bond Acceptors:** Both ligands (3) are well below the 10 limit.

**QED:** Both ligands (0.864 and 0.773) are above 0.5, indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (52.966) and Ligand B (42.769) both have acceptable DILI risk, below the 60 threshold. Ligand B is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.625) is slightly better than Ligand B (66.382).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.078 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 (-4.414 and -2.636), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.627 and 0.423), which is excellent. Ligand B is preferred.

**Microsomal Clearance:** Ligand A (32.94) has a lower (better) microsomal clearance than Ligand B (76.416), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-14.097) has a negative half-life, which is concerning. Ligand B (68.701) has a much better, longer half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.146 and 0.324), which is good. Ligand A is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -8.7 kcal/mol). Ligand A has a 0.7 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a better binding affinity and lower microsomal clearance, but suffers from a negative in vitro half-life and poor solubility. Ligand B has a better half-life, lower DILI, and slightly better solubility, but a weaker binding affinity and higher clearance. Given the importance of metabolic stability and reasonable half-life for an enzyme inhibitor, and the substantial binding affinity advantage of Ligand A, I would lean towards Ligand A. However, the negative half-life and poor solubility of Ligand A are major concerns that would need to be addressed through further optimization. The poor Caco-2 and solubility for both are concerning.

Output:
0
2025-04-17 15:40:22,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (350.503 and 375.485 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (60.85) is better than Ligand B (71.09). Both are below the 140 A^2 threshold for good oral absorption, but lower TPSA is generally preferred.

**3. logP:** Both ligands have good logP values (2.732 and 3.013), falling within the optimal range of 1-3.

**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: 3, Ligand B: 4).

**6. QED:** Both ligands have similar and acceptable QED values (0.776 and 0.734), indicating good drug-like properties.

**7. DILI:** Ligand A (30.322) has a significantly lower DILI risk than Ligand B (44.591). This is a crucial advantage.

**8. BBB:** Both ligands have similar BBB penetration (58.782 and 58.317). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.489 and -4.907), which is unusual and indicates poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.686 and -3.316), also indicating poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.299 and 0.363).

**12. Microsomal Clearance (Cl_mic):** Ligand A (39.238) has lower microsomal clearance than Ligand B (45.238), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.266) has a slightly longer half-life than Ligand B (4.856).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.366 and 0.089).

**15. Binding Affinity:** Ligand B (-7.6 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 other disadvantages.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a slightly better affinity, but Ligand A has significantly better DILI risk, better metabolic stability (lower Cl_mic), and a slightly longer half-life. The poor solubility and permeability are concerning for both. However, the lower DILI risk of Ligand A is a substantial advantage, as liver toxicity is a common issue with kinase inhibitors.

Output:
0
2025-04-17 15:40:22,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.5 and 370.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (59.08). Both are below the 140 threshold for oral absorption, but neither is optimized for CNS penetration (below 90).

**logP:** Both ligands have good logP values (1.249 and 1.729), 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 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.685 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A (29.159) has a significantly lower DILI risk than Ligand B (44.63). This is a major advantage for Ligand A.

**BBB:** Ligand B (79.217) has a better BBB penetration percentile than Ligand A (56.146), but BBB is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.915 and -4.705), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.152 and -2.373), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.193 and 0.201), which is excellent.

**Microsomal Clearance:** Ligand A (16.982) has significantly lower microsomal clearance than Ligand B (52.066), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (15.179) has a positive half-life, while Ligand B (-6.354) has a negative half-life. This indicates that Ligand A is more stable *in vitro*.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.071).

**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 relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, positive t1/2) and a much lower DILI risk. The slightly better binding affinity of Ligand B is unlikely to outweigh these substantial ADME advantages of Ligand A, especially considering we are targeting an enzyme. Addressing the solubility and permeability issues through formulation or structural modifications would be the next step for Ligand A.

Output:
0
2025-04-17 15:40:22,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (69.64) is excellent, well below the 140 threshold for good absorption. Ligand B (104.23) is still acceptable but less favorable.

**logP:** Both ligands have good logP values (A: 2.391, B: 1.785), 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 6.  Ligand A is preferable here, as higher HBA can sometimes hinder permeability.

**QED:** Both ligands have good QED scores (A: 0.724, B: 0.834), indicating drug-like properties.

**DILI:** Ligand A (19.426) has a very low DILI risk, which is excellent. Ligand B (86.002) has a significantly higher DILI risk, a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.203) is moderate, while Ligand B (13.377) is very low.

**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. This is a concern, but can be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.324) has a very low hERG risk, which is excellent. Ligand B (0.104) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (36.907) has a moderate clearance, while Ligand B (-2.082) has a *negative* clearance, which is not physically possible and suggests an issue with the data or model. This is a significant red flag.

**In vitro Half-Life:** Ligand A (-8.039) has a negative half-life, which is not physically possible. Ligand B (-25.654) also has a negative half-life. This suggests issues with the data.

**P-gp Efflux:** Ligand A (0.25) has low P-gp efflux, which is good. Ligand B (0.051) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has significantly better binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A is clearly the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand A has a much better safety profile (DILI, hERG), significantly stronger binding affinity, and more reasonable ADME properties (despite the negative half-life, which is likely a data error). The negative clearance and half-life for Ligand B are major red flags, and the significantly higher DILI risk is also a serious concern. The superior binding affinity of Ligand A can potentially outweigh the solubility/permeability issues.

Output:
1
2025-04-17 15:40:22,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (365.499 Da) is also good.

**TPSA:** Ligand A (105.66) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (71.41) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (-0.202) is quite low, potentially hindering membrane permeability. Ligand B (1.494) 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 4 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.592, B: 0.829), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (11.981) has a very low DILI risk, which is excellent. Ligand B (44.436) is higher, but still below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (18.534) and Ligand B (59.364) are both relatively low, which is fine.

**Caco-2 Permeability:** Both have negative values (-5.481 and -4.978), which is unusual. It suggests very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.799 and -2.583), indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG risk (A: 0.136, B: 0.269), which is excellent.

**Microsomal Clearance:** Ligand A (-10.259) has a negative clearance, suggesting very high metabolic stability. Ligand B (41.644) has a higher clearance, indicating faster metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.7) has a negative half-life, which is unrealistic. Ligand B (5.745) has a short half-life, which is a concern.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.004, B: 0.11), which is favorable.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-7.6). This 0.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and excellent metabolic stability (negative clearance). However, it has very low solubility and permeability, and a negative half-life. Ligand B has better logP and TPSA, but weaker binding affinity and poorer metabolic stability. The solubility and permeability issues are critical for *both* compounds, but the significantly stronger binding of Ligand A, coupled with its excellent metabolic stability, makes it the more promising starting point for optimization. The solubility and permeability can be addressed through structural modifications, but a weaker binder is much harder to improve.

Output:
0
2025-04-17 15:40:22,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (378.881 and 346.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.64 and 70.07) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.965 and 3.671) are within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but not drastically.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being less than 10.

**QED:** Both ligands (0.807 and 0.68) have good drug-likeness scores, well above the 0.5 threshold.

**DILI:** Ligand A (47.344) has a lower DILI risk than Ligand B (71.152), which is preferable. Both are below the concerning 60 threshold, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.588) has a slightly higher BBB penetration than Ligand A (69.213), but it's not a major factor here.

**Caco-2 Permeability:** Both ligands (-4.768 and -4.794) have similar, and poor, Caco-2 permeability. This could be a formulation challenge.

**Aqueous Solubility:** Both ligands (-4.484 and -4.1) have similar, and poor, aqueous solubility. This could also be a formulation challenge.

**hERG Inhibition:** Ligand A (0.592) has a lower hERG risk than Ligand B (0.879), which is a significant advantage.

**Microsomal Clearance:** Ligand A (14.361) has a significantly lower microsomal clearance than Ligand B (51.302), indicating better metabolic stability. This is a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand B (97.71) has a much longer in vitro half-life than Ligand A (5.717), which is desirable.

**P-gp Efflux:** Both ligands (0.453 and 0.478) have similar P-gp efflux liability, which is relatively low.

**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 superior binding affinity and a longer half-life. However, Ligand A exhibits better metabolic stability (lower Cl_mic), lower DILI risk, and lower hERG inhibition. The difference in binding affinity (-7.8 vs -9.5) is substantial (1.7 kcal/mol), and this is a key driver for kinase inhibitors. While the solubility and permeability are poor for both, the metabolic stability and safety profile of Ligand A are concerning. The improved potency of Ligand B is likely to be more impactful than the slightly worse ADME properties.

Output:
1
2025-04-17 15:40:22,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.419 and 352.454 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (116.17) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (87.46) is well within the ideal range.

**3. logP:** Ligand A (-0.574) is a bit low, potentially hindering permeation. Ligand B (1.539) is 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, acceptable. Ligand B has 4 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.526 and 0.619), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (26.018 and 24.506), which is excellent.

**8. BBB:** Ligand A (33.85) has poor BBB penetration, while Ligand B (67.701) is better, though not exceptional. BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.021 and -5.297). 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 very poor aqueous solubility (-1.149 and -1.97). This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG risk (0.128 and 0.7), which is highly desirable.

**12. Microsomal Clearance:** Ligand A (9.008) has lower microsomal clearance than Ligand B (11.295), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.019) has a very negative half-life, which is concerning and likely indicates rapid degradation. Ligand B (-1.286) is also negative, but less so. Again, the scale is unclear.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.015), which is favorable.

**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 huge.

**Overall Assessment:**

Ligand A has a better binding affinity and lower clearance, but suffers from very poor solubility and a concerning half-life. Its low logP is also a drawback. Ligand B has better solubility, a more favorable logP, and a better BBB score (though not crucial here). While its affinity is slightly lower, it's still in a good range. The solubility and metabolic stability issues with Ligand A are more problematic than the slight affinity difference.

Output:
1
2025-04-17 15:40:22,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 and 355.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.9) is better than Ligand B (38.25) as it is closer to the threshold for good oral absorption.

**logP:** Ligand B (4.061) is higher than the optimal range (1-3), potentially causing solubility issues and off-target effects. Ligand A (0.025) is very low, which may impede permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it strikes a better balance between solubility and permeability.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.809 and 0.751 respectively), indicating good drug-like properties.

**DILI:** Ligand A (38.736) has a slightly higher DILI risk than Ligand B (24.544), but both are below the concerning threshold of 60.

**BBB:** Ligand B (88.833) has a significantly higher BBB penetration percentile than Ligand A (39.24). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.755) has a very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.194) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (0.06) has very poor aqueous solubility, while Ligand B (-3.152) is also poor.

**hERG Inhibition:** Ligand A (0.256) has a much lower hERG inhibition liability than Ligand B (0.869), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-14.53) has a much lower (better) microsomal clearance than Ligand B (57.936), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (16.816) has a longer in vitro half-life than Ligand A (7.092), which is desirable.

**P-gp Efflux:** Ligand A (0.023) has a much lower P-gp efflux liability than Ligand B (0.654), indicating better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -7.9 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to overcome its other drawbacks.

**Overall Assessment:**

Despite Ligand B's slightly better binding affinity and half-life, Ligand A is the more promising candidate. Ligand B's high logP, poor solubility, and higher hERG risk are significant concerns. Ligand A has a much better safety profile (lower hERG, lower P-gp efflux), and superior metabolic stability (lower Cl_mic). While its solubility and Caco-2 permeability are poor, these can potentially be addressed through formulation strategies. The difference in binding affinity is not large enough to outweigh the ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 15:40:22,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.353 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) and Ligand B (80.12) are both below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (2.538) is within the optimal 1-3 range. Ligand B (1.354) is slightly below, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, well within acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.872 and 0.72), indicating good drug-like properties.

**DILI:** Ligand A (69.097) has a higher DILI risk than Ligand B (30.826). This is a significant negative for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand A (80.031) is better than Ligand B (51.803). This is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 unusual and indicates very poor solubility. This is a significant concern for both.

**hERG:** Ligand A (0.652) has a slightly higher hERG risk than Ligand B (0.069). Lower is better here, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (9.89 mL/min/kg) has significantly lower microsomal clearance than Ligand B (21.44 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (13.79 hours) has a longer half-life than Ligand B (-0.682 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux than Ligand B (0.018), which is preferable.

**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 (0.3 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand B has a significantly lower DILI risk and a better hERG profile. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. Both have poor solubility and permeability. The slightly better binding affinity of Ligand B is a plus, but the metabolic advantages of Ligand A are more critical for an enzyme inhibitor, especially considering the potential for optimization of solubility/permeability. The lower DILI risk of Ligand B is also a significant factor.

Output:
1
2025-04-17 15:40:22,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.46 Da) is slightly lower, which could be beneficial for permeability. Ligand B (380.501 Da) is also good.

**TPSA:** Ligand A (21.26) is excellent, well below the 140 threshold for oral absorption. Ligand B (58.64) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (4.683) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.402) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (2 for A, 4 for B) counts, falling within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.792 and 0.624), indicating good drug-like properties.

**DILI:** Ligand A (13.339) has a very low DILI risk, which is a significant advantage. Ligand B (31.291) is higher, but still within an acceptable range.

**BBB:** Both have good BBB penetration, but Ligand A (89.957) is better than Ligand B (79.217). While not a primary concern for a kinase inhibitor, it's a slight positive for A.

**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 aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.792 and 0.742), which is excellent.

**Microsomal Clearance:** Ligand A (13.068) has significantly lower microsomal clearance than Ligand B (56.203), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (24.593) has a longer half-life than Ligand B (8.03), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.265 and 0.087).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.9 vs -7.7 kcal/mol), much lower DILI risk, and superior metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher logP. The better TPSA and BBB values are additional benefits. Addressing the solubility and permeability issues would be critical in further development, but the potency and safety profile of Ligand A make it the better starting point.

Output:
0
2025-04-17 15:40:22,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.475 and 342.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.65 and 89.19) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (1.531 and 2.237) 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.79 and 0.861), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.086, which is moderately high. Ligand B has a lower DILI risk of 47.499, which is preferable.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (66.344) has slightly better BBB penetration than Ligand B (57.619).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.838 and -5.206). 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 negative solubility values (-2.1 and -2.43). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.05 and 0.68), which is excellent.

**Microsomal Clearance:** Ligand B (26.175 mL/min/kg) has significantly lower microsomal clearance than Ligand A (50.793 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.548 hours) has a much longer in vitro half-life than Ligand A (-28.841 hours). The negative value for Ligand A is concerning and likely an artifact of the prediction method.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.015).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.7 and -8.4 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Conclusion:**

Ligand B is the more promising candidate. While both have similar potency, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Although both have poor predicted solubility and permeability, the metabolic advantages of Ligand B outweigh these concerns, especially for a kinase inhibitor where metabolic stability is crucial. The negative half-life value for Ligand A is a red flag.

Output:
1
2025-04-17 15:40:22,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is slightly higher than Ligand B (75.71). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (0.913 and 0.959) within the 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 5 HBA, within the acceptable limit of <=10.

**QED:** Ligand A (0.826) has a slightly better QED score than Ligand B (0.754), indicating a more drug-like profile.

**DILI:** Ligand B (35.479) has a significantly lower DILI risk than Ligand A (46.258), making it more favorable.

**BBB:** Ligand B (76.309) has a higher BBB penetration percentile than Ligand A (51.842). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.034 and -5.098), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.717 and -2.399), also indicating poor solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.101) has a lower hERG inhibition liability than Ligand B (0.311), which is a positive.

**Microsomal Clearance:** Ligand B (37.623) has a higher microsomal clearance than Ligand A (18.374), indicating faster metabolism and lower metabolic stability. Ligand A is preferable here.

**In vitro Half-Life:** Ligand A (-19.986) has a more negative half-life, indicating a shorter half-life, while Ligand B (16.787) has a longer half-life. Ligand B is preferable.

**P-gp Efflux:** Ligand A (0.022) has lower P-gp efflux liability than Ligand B (0.154), which is a slight advantage.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B appears to be the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B's superior binding affinity (-9.4 vs -8.6 kcal/mol) and lower DILI risk are significant advantages. The longer in vitro half-life also contributes to its favorability. Although Ligand A has better metabolic stability and lower hERG risk, the potency advantage of Ligand B is more critical for an enzyme target like SRC kinase. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the core potency and safety profile of Ligand B is better.

Output:
1
2025-04-17 15:40:22,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.35 & 342.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.45) is better than Ligand B (106.35), both are acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.943) is slightly better than Ligand B (0.308). Both are a bit low, potentially impacting permeability, but A is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 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 (0.721 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (81.97) has a significantly higher DILI risk than Ligand B (66.382). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.464) is better than Ligand B (50.097).

**Caco-2 Permeability:** Ligand A (-5.102) is better than Ligand B (-4.904), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.495) is better than Ligand B (-2.694), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.326) has a lower hERG inhibition risk than Ligand B (0.169), which is a significant advantage.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (Ligand A: -5.105, Ligand B: 29.309). However, negative values are unusual and likely indicate very low clearance, which is positive.

**In vitro Half-Life:** Ligand A (29.964 hours) has a substantially longer half-life than Ligand B (-14.931 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux than Ligand B (0.033), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). While A is stronger, the difference is not substantial enough to overcome its other liabilities.

**Overall Assessment:**

Ligand A has better solubility, permeability, and a longer half-life, and lower P-gp efflux. However, Ligand B has a significantly lower DILI risk and a slightly better binding affinity. Considering the enzyme-specific priorities, metabolic stability (indicated by half-life and clearance) and safety (DILI, hERG) are crucial. While Ligand A's affinity is better, the higher DILI risk is a significant concern. The slightly better affinity of Ligand B, combined with its much lower DILI risk and acceptable other properties, makes it the more promising candidate.

Output:
1
2025-04-17 15:40:22,213 - INFO - Batch 399 complete. Total preferences: 6384
2025-04-17 15:40:22,213 - INFO - Processing batch 400/512...
2025-04-17 15:41:07,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (441.332 Da) is higher, but still acceptable. Ligand B (363.384 Da) is slightly better.

**TPSA:** Both ligands have TPSA values (101.05 and 98.17) below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values around 3 (3.179 and 3.019), 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:** Ligand A (0.648) has a better QED score than Ligand B (0.279), indicating a more drug-like profile.

**DILI:** Ligand A has a significantly higher DILI risk (95.192 percentile) compared to Ligand B (27.181 percentile). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (88.91) is better than Ligand A (70.803). While not a primary concern for a kinase inhibitor, it's a slight advantage for B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.15) is slightly better than Ligand B (-4.651), but both are problematic.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand B (-2.519) is slightly better than Ligand A (-4.085).

**hERG:** Both have low hERG inhibition liability (0.338 and 0.602), which is good.

**Microsomal Clearance:** Ligand A (29.97 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (30.165 mL/min/kg).

**In vitro Half-Life:** Ligand B (-12.412 hours) has a much longer half-life than Ligand A (141.393 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.353 and 0.059).

**Binding Affinity:** Both ligands have similar binding affinities (-6.6 and -6.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a significantly lower DILI risk, a longer half-life, and slightly better BBB penetration. The binding affinity is comparable. The high DILI risk associated with Ligand A is a major red flag, outweighing its slightly better QED and clearance.

Output:
1
2025-04-17 15:41:07,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (378.969 Da) is still well within range.

**TPSA:** Ligand A (105.5) is better than Ligand B (33.2). Lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (0.236) is quite low, potentially hindering membrane permeability and bioavailability. Ligand B (4.93) is higher, approaching the upper limit but still acceptable.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (3) is also good.

**QED:** Both ligands have similar and good QED values (A: 0.706, B: 0.728), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 25.281, B: 22.722), which is positive.

**BBB:** Ligand A (67.197) has a moderate BBB penetration, while Ligand B (87.127) has a higher BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests potential issues with the data or the model. However, we proceed with caution.

**Aqueous Solubility:** Both ligands have negative aqueous solubility values, which is also unusual and suggests potential issues with the data or the model. However, we proceed with caution.

**hERG Inhibition:** Both ligands have low hERG risk (A: 0.261, B: 0.765), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (-31.101) has a negative clearance, which is not physically possible and indicates a data issue. Ligand B (88.877) has a high clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (-23.665) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (3.088) has a short half-life, which is not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.004, B: 0.497), which is favorable.

**Binding Affinity:** Both ligands have similar binding affinities (A: -8.7 kcal/mol, B: -8.2 kcal/mol). Ligand A has a slightly better affinity.

**Conclusion:**

Despite the unusual negative values for Caco-2 permeability, solubility, clearance and half-life, Ligand A appears to be the better candidate. It has a slightly better binding affinity, a lower TPSA, and lower DILI risk. The biggest concern with Ligand B is its high microsomal clearance, indicating rapid metabolism. The negative values for A are concerning and would require further investigation, but the slightly better affinity and other favorable properties make it the more promising candidate *given the available data*.

Output:
0
2025-04-17 15:41:07,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is slightly higher than Ligand B (43.86), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (2.751) is optimal, while Ligand B (1.97) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Both have 0 HBD, which is good.

**H-Bond Acceptors:** Both have 3 HBA, which is also good.

**QED:** Ligand A (0.737) has a better QED score than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand B (5.235) has a significantly lower DILI risk than Ligand A (35.905), a major advantage.

**BBB:** Ligand A (70.105) has better BBB penetration than Ligand B (59.403), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.631) has slightly better Caco-2 permeability than Ligand B (-4.332).

**Aqueous Solubility:** Ligand B (-1.019) has better aqueous solubility than Ligand A (-2.671).

**hERG Inhibition:** Ligand A (0.508) has a slightly better hERG profile than Ligand B (0.627), but both are acceptable.

**Microsomal Clearance:** Ligand B (-4.681) has significantly lower microsomal clearance than Ligand A (51.504), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-14.531) has a much longer in vitro half-life than Ligand A (21.827), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand B (0.079) has lower P-gp efflux than Ligand A (0.256), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (0.0 kcal/mol). This is a very significant difference.

**Overall Assessment:**

While Ligand B excels in ADME properties (DILI, metabolic stability, solubility, P-gp efflux), Ligand A's binding affinity is dramatically superior. The difference in affinity (-8.9 vs 0.0 kcal/mol) is so large that it likely outweighs the ADME advantages of Ligand B. A strong binding affinity is paramount for an enzyme inhibitor, and a 1.5 kcal/mol advantage is often considered significant, but here the advantage is >8 kcal/mol. The ADME properties of Ligand A are still within acceptable ranges, and optimization could further improve them.

Output:
1
2025-04-17 15:41:07,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.391 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (124.26) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (74.43) is well within the optimal range.

**logP:** Ligand A (-0.593) is a bit low, potentially hindering permeation. Ligand B (2.107) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is good. Ligand B (2 HBD, 3 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.567 and 0.793), indicating drug-like properties.

**DILI:** Ligand A (70.26) has a higher DILI risk than Ligand B (25.669). This is a significant concern.

**BBB:** Both have similar BBB penetration (38.232 and 70.803). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.412 and -4.758), which is unusual and suggests poor permeability. These values are likely errors or indicate very poor absorption.

**Aqueous Solubility:** Both have negative solubility values (-2.774 and -2.951), which is also unusual and suggests very poor solubility. These values are likely errors or indicate very poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.258 and 0.393). This is favorable.

**Microsomal Clearance:** Ligand A (13.804) has significantly lower microsomal clearance than Ligand B (38.189), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.434) has a negative half-life, which is impossible and suggests an error in the data. Ligand B (-11.978) also has a negative half-life, indicating an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.037).

**Binding Affinity:** Both ligands have similar binding affinities (-8.6 and -7.7 kcal/mol), both of which are good. Ligand A is slightly better.

**Overall Assessment:**

Despite Ligand A having slightly better binding affinity and lower clearance, the significantly higher DILI risk and the impossible half-life are major red flags. The negative solubility and Caco-2 values for both are concerning and suggest data errors. However, assuming these are errors and focusing on the remaining data, Ligand B is preferable due to its lower DILI risk, better logP, and more reasonable (though still problematic) ADME properties. The better logP of Ligand B suggests it may have better permeability than Ligand A, even with the questionable Caco-2 values.

Output:
1
2025-04-17 15:41:07,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.5 and 346.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (83.12). A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Ligand A (4.637) is slightly higher than the optimal 1-3 range, while Ligand B (2.43) is within the ideal range. This favors Ligand B initially, but the difference isn't drastic.

**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 similar QED values (0.676 and 0.675), indicating comparable drug-likeness.

**DILI:** Ligand A (55.758) has a slightly higher DILI risk than Ligand B (51.493), but both are acceptable (<60).

**BBB:** Ligand A (92.672) shows better BBB penetration than Ligand B (77.511), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.693) has a worse Caco-2 permeability than Ligand B (-4.806). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.075) has slightly better aqueous solubility than Ligand B (-3.542).

**hERG Inhibition:** Ligand A (0.978) has a slightly higher hERG risk than Ligand B (0.575). Lower is better, so B is favored here.

**Microsomal Clearance:** Ligand A (108.861) has a higher microsomal clearance than Ligand B (54.241). Lower clearance is preferred for metabolic stability, so B is favored.

**In vitro Half-Life:** Ligand A (105.773) has a longer half-life than Ligand B (16.453). A longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.91) has a lower P-gp efflux liability than Ligand B (0.064). Lower efflux is preferred.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). The difference is 0.3 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a more favorable profile overall. While Ligand A has better BBB penetration and half-life, Ligand B excels in crucial areas for an enzyme inhibitor: better logP, lower hERG risk, significantly lower microsomal clearance (better metabolic stability), and slightly better binding affinity. The solubility and DILI are comparable. The Caco-2 permeability is slightly worse for B, but not critically so. The 0.3 kcal/mol difference in binding affinity is also a key factor, as potency is paramount for kinase inhibitors.

Output:
1
2025-04-17 15:41:07,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 368.825 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (96.09) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.69 and 0.747), 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) in terms of balancing solubility and permeability. Ligand B has a higher number of HBA which could potentially impact permeability.

**QED:** Both ligands have similar and good QED scores (0.764 and 0.774), indicating good drug-likeness.

**DILI:** Ligand A (25.824) has a significantly lower DILI risk than Ligand B (79.604). This is a major advantage.

**BBB:** Ligand A (70.803) has a better BBB penetration score than Ligand B (59.054), although BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.02 and -5.051), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.467 and -2.471), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.13 and 0.145), which is excellent.

**Microsomal Clearance:** Ligand A (38.539) has a higher microsomal clearance than Ligand B (13.654), meaning Ligand B is more metabolically stable. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (26.786) has a much longer in vitro half-life than Ligand A (-1.671). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.164).

**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, it is still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk. However, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a better BBB score. The poor solubility and permeability are concerning for both, but the metabolic stability is crucial for an enzyme inhibitor. The slightly better affinity of Ligand A is unlikely to outweigh the substantial advantages of Ligand B in terms of metabolic stability and half-life.

Output:
1
2025-04-17 15:41:07,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.46 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.23) is better than Ligand B (65.12) as it's still within the acceptable range for oral absorption (<140), but lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (1.8) is optimal, while Ligand B (-0.314) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.715 and 0.666, respectively), indicating good drug-likeness.

**DILI:** Ligand A (14.812) has a significantly lower DILI risk than Ligand B (15.2), which is a crucial advantage.

**BBB:** Ligand A (39.705) has a lower BBB penetration than Ligand B (52.85). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.281) has worse Caco-2 permeability than Ligand B (-5.004). Both are poor, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.303) has slightly better solubility than Ligand B (-1.074).

**hERG:** Both ligands have very low hERG risk (0.455 and 0.316, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (9.21) has significantly lower microsomal clearance than Ligand B (21.317), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (14.038 hours) has a much longer half-life than Ligand B (2.371 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.007, respectively).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While a 1.0 kcal/mol difference is noticeable, the other ADME properties of Ligand A are more favorable.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile, particularly regarding metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. While Ligand B has slightly better binding affinity and Caco-2 permeability, the advantages of Ligand A in terms of metabolic stability and safety are more critical for an enzyme target like SRC kinase. The slightly lower affinity of Ligand A can potentially be optimized in subsequent iterations.

Output:
0
2025-04-17 15:41:07,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.479 Da) is slightly preferred due to being lower in MW.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (97.11). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 3.945, B: 2.658), falling within the 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=5). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.897) has a much higher QED score than Ligand B (0.685), indicating a more drug-like profile.

**DILI:** Ligand B (97.169) has a very high DILI risk, significantly higher than Ligand A (19.504). This is a major red flag.

**BBB:** Ligand A (87.67) has a better BBB percentile than Ligand B (16.983), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.915) has a better Caco-2 permeability than Ligand B (-5.411).

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-3.37 and -3.429 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.977) has a lower hERG inhibition risk than Ligand B (0.064), which is a significant advantage.

**Microsomal Clearance:** Ligand B (0.982) has a much lower microsomal clearance than Ligand A (3.5). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A (15.957) has a longer in vitro half-life than Ligand B (14.469).

**P-gp Efflux:** Ligand A (0.649) has lower P-gp efflux than Ligand B (0.015), indicating better bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-10.2 kcal/mol and -9.2 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Conclusion:**

Considering all factors, Ligand A is significantly more promising. While Ligand B has slightly better metabolic stability, the extremely high DILI risk, poor P-gp profile, and lower QED score are major drawbacks. Ligand A excels in most ADME properties (TPSA, QED, DILI, hERG, P-gp, Caco-2, BBB) and has comparable binding affinity. The slightly lower metabolic stability of Ligand A can be addressed through structural modifications during lead optimization.

Output:
1
2025-04-17 15:41:07,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.454 Da and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is well below the 140 threshold for good absorption and is even favorable for potential CNS penetration (though not a primary goal here). Ligand B (129.23) is still within acceptable limits, but higher than A.

**logP:** Ligand A (1.583) is optimal. Ligand B (-0.164) is slightly below the 1-3 range, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is well within the recommended limits. Ligand B (4 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (0.587 and 0.524), indicating good drug-likeness.

**DILI:** Ligand A (38.116) has a significantly lower DILI risk than Ligand B (63.978), which is approaching a higher risk category.

**BBB:** Ligand A (70.027) shows reasonable BBB penetration, while Ligand B (20.977) is low. This isn't a primary concern for a non-CNS target, but it's a positive for A.

**Caco-2 Permeability:** Ligand A (-5.099) and Ligand B (-5.634) both have negative Caco-2 values, indicating poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.681 and -2.568). This is a major drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.264 and 0.3), which is positive.

**Microsomal Clearance:** Ligand A (6.954) has a lower microsomal clearance than Ligand B (9.996), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.652) has a more negative (longer) in vitro half-life than Ligand B (7.31).

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.022), indicating better bioavailability.

**Binding Affinity:** Ligand A (-6.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have poor solubility and permeability, Ligand A's substantially stronger binding affinity (-6.9 vs 0.0 kcal/mol) outweighs these drawbacks. It also exhibits lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. Ligand B's low logP and weak binding affinity make it a less promising candidate.

Output:
1
2025-04-17 15:41:07,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.441 Da) is slightly higher than Ligand B (342.403 Da), but both are acceptable.

**TPSA:** Ligand A (87.3) is better than Ligand B (111.06). Lower TPSA generally indicates better permeability.

**logP:** Both ligands have good logP values (Ligand A: 1.203, Ligand B: 1.915), falling within the optimal range of 1-3.

**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:** Ligand A (0.605) has a significantly better QED score than Ligand B (0.353), indicating a more drug-like profile.

**DILI:** Ligand A (43.389) has a slightly higher DILI risk than Ligand B (36.06), but both are below the concerning threshold of 60.

**BBB:** Ligand A (72.16) has a better BBB percentile than Ligand B (64.444), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.063) and Ligand B (-5.131) have similar Caco-2 permeability, suggesting comparable intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.291) has slightly better solubility than Ligand B (-1.086).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.278, Ligand B: 0.339).

**Microsomal Clearance:** Ligand A (24.906) has significantly better metabolic stability (lower clearance) than Ligand B (1.11). This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-1.625) has a much longer in vitro half-life than Ligand B (-21.193). This is another key advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.027, Ligand B: 0.026).

**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's still a positive factor.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a better QED score, significantly better metabolic stability (lower Cl_mic and longer t1/2), slightly better solubility, and a slightly stronger binding affinity. While Ligand B has a slightly lower DILI risk, the improvements in metabolic stability and drug-likeness for Ligand A outweigh this minor difference, especially for an enzyme target where maintaining therapeutic concentrations is critical.

Output:
1
2025-04-17 15:41:07,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.356 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is well below the 140 threshold and excellent for oral absorption. Ligand B (93.65) is still within acceptable limits, but less favorable.

**logP:** Ligand A (3.485) is optimal. Ligand B (1.037) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 7 HBA. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have similar QED values (0.628 and 0.541), indicating reasonable drug-likeness.

**DILI:** Ligand A (49.864) has a slightly better DILI score than Ligand B (56.572), indicating lower liver injury risk. Both are below the concerning threshold of 60.

**BBB:** Ligand A (94.416) shows excellent BBB penetration, while Ligand B (69.717) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a positive attribute for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.331) shows better Caco-2 permeability than Ligand B (-5.133).

**Aqueous Solubility:** Ligand A (-4.668) has better aqueous solubility than Ligand B (-2.238). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.534) has a much lower hERG risk than Ligand B (0.167). This is a significant advantage.

**Microsomal Clearance:** Ligand A (72.896) has higher microsomal clearance than Ligand B (28.685), meaning it's less metabolically stable. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (10.282) has a significantly longer in vitro half-life than Ligand A (-7.703). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux than Ligand B (0.022), which is favorable.

**Binding Affinity:** Ligand A (-6.4) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand A excels in several key areas: TPSA, logP, solubility, hERG risk, and P-gp efflux. It also has slightly better binding affinity. However, its major weakness is its higher microsomal clearance and shorter half-life.

Ligand B has a longer half-life and lower clearance, which are significant advantages for *in vivo* efficacy. However, it suffers from lower logP, lower solubility, and a higher hERG risk.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the longer half-life and lower clearance of Ligand B are more critical than the slightly better affinity of Ligand A. The solubility and hERG risk are also concerning for Ligand B.

Output:
1
2025-04-17 15:41:07,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.439 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.0) is significantly better than Ligand B (104.21). A TPSA under 140 is good for oral absorption, but lower is generally preferred, especially for kinases where permeability isn't the primary concern.

**logP:** Both ligands have acceptable logP values (2.413 and 1.74), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (3 HBD, 6 HBA). Lower HBD/HBA generally improves permeability, but isn't a major concern for kinases.

**QED:** Both ligands have reasonable QED values (0.788 and 0.616), indicating good drug-like properties.

**DILI:** Ligand A (9.926) has a much lower DILI risk than Ligand B (44.552). This is a significant advantage.

**BBB:** This is less important for a non-CNS target like SRC. Ligand A (94.649) is higher, but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.486) is better than Ligand B (-5.275), indicating better absorption.

**Aqueous Solubility:** Ligand A (-2.762) is better than Ligand B (-2.487), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.884) has a lower hERG risk than Ligand B (0.169), which is a critical safety parameter.

**Microsomal Clearance:** Ligand A (55.438) has higher clearance than Ligand B (5.844), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (18.346) has a significantly longer half-life than Ligand A (-1.464), which is a major advantage.

**P-gp Efflux:** Ligand A (0.327) has lower P-gp efflux than Ligand B (0.195), which is favorable.

**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 small (0.3 kcal/mol), it's still a positive point for Ligand A.

**Overall Assessment:**

Ligand A has several advantages: lower DILI risk, better solubility, lower hERG risk, better Caco-2 permeability, and slightly better binding affinity. However, its major weakness is its higher microsomal clearance and shorter half-life. Ligand B has a significantly better half-life and lower clearance, but suffers from higher DILI risk, lower solubility, and a higher hERG risk.

Considering the priorities for enzyme inhibitors, the lower DILI and hERG risks of Ligand A are crucial. While the metabolic stability is a concern, it might be addressable through structural modifications. The slightly better binding affinity also tips the balance.

Output:
1
2025-04-17 15:41:07,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.45 and 364.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is significantly better than Ligand B (67.43), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.04 and 3.159, respectively), falling within the 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=1, HBA=4) and Ligand B (HBD=2, HBA=3) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Ligand A (0.884) has a much higher QED score than Ligand B (0.522), indicating a more drug-like profile.

**DILI:** Ligand A (16.479) has a significantly lower DILI risk than Ligand B (24.893). Both are below the 40 threshold, but A is much preferred.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (93.408) has a higher BBB percentile than Ligand B (69.523).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.555 and -4.704), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.405) is better than Ligand B (-3.718), indicating slightly better solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.851 and 0.728), which is good.

**Microsomal Clearance:** Ligand A (6.272) has a much lower microsomal clearance than Ligand B (33.535), suggesting better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (41.275) has a shorter half-life than Ligand B (54.722), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.138 and 0.243).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is the superior candidate. While both have similar binding affinities, Ligand A demonstrates significantly better predicted ADME properties: a higher QED score, lower DILI risk, lower microsomal clearance (better metabolic stability), and slightly better solubility. The lower TPSA is also beneficial. The negative Caco-2 values are a concern for both, but the other advantages of Ligand A outweigh this shared drawback.

Output:
0
2025-04-17 15:41:07,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.4 and 379.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.2) is better than Ligand B (29.5). While both are reasonably low, Ligand B is exceptionally low, which *could* indicate poor binding due to lack of necessary polar interactions.

**logP:** Ligand A (3.49) is within the optimal 1-3 range. Ligand B (4.463) is slightly higher, potentially increasing off-target effects and decreasing solubility.

**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, but potentially less capable of forming key interactions with the kinase active site.

**QED:** Both ligands have similar QED values (0.731 and 0.623), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (97.8%), which is a major concern. Ligand B has a very low DILI risk (11.9%), a significant advantage.

**BBB:** Both ligands have high BBB penetration (52.4% and 97.1%), but this is less critical for a kinase inhibitor unless CNS involvement is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.623 and -4.443), which is unusual and suggests poor permeability. This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have negative solubility values (-6.319 and -5.285), indicating very poor aqueous solubility, which is a significant hurdle for drug development.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.658 and 0.771), which is positive.

**Microsomal Clearance:** Ligand A (116.7 mL/min/kg) has higher clearance than Ligand B (75.5 mL/min/kg), indicating lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (2.78 hours) has a slightly longer half-life than Ligand A (35.85 hours), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.399 and 0.386), which is good.

**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 can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity (-9.1 vs -8.3 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, its much lower DILI risk (11.9% vs 97.8%) is a critical factor, as liver toxicity is a common reason for drug failure. While Ligand A has better TPSA and slightly better metabolic stability, the superior affinity and safety profile of Ligand B make it the better choice. The solubility and permeability issues would need to be addressed through formulation or further structural modifications, but the starting point is more favorable with Ligand B.

Output:
1
2025-04-17 15:41:07,844 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [359.809, 71.55, 3.649, 2, 4, 0.659, 73.362, 37.96, -4.991, -5.14, 0.63, 41.837, 25.341, 0.575, -8.2]
**Ligand B:** [342.443, 66.71, 2.347, 1, 4, 0.907, 38.891, 61.962, -4.7, -2.206, 0.664, 39.874, -8.356, 0.065, -7.5]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (359.8) is slightly higher than B (342.4).
2. **TPSA:** Both are below the 140 A^2 threshold for good oral absorption. A (71.55) is higher than B (66.71).
3. **logP:** Both are within the optimal range (1-3). A (3.649) is a bit higher than B (2.347).
4. **HBD:** A (2) and B (1) are both acceptable (<=5). B is slightly better.
5. **HBA:** Both are at 4, which is acceptable (<=10).
6. **QED:** Both are above 0.5, indicating good drug-likeness. B (0.907) is significantly better than A (0.659).
7. **DILI:** A (73.362) has a higher DILI risk than B (38.891). B is much preferred here.
8. **BBB:** A (37.96) has lower BBB penetration than B (61.962). Not a primary concern for a non-CNS target like SRC, but B is better.
9. **Caco-2:** Both have negative values, which is unusual. Assuming these are log values, higher is better. A (-4.991) is slightly worse than B (-4.7).
10. **Solubility:** Both have negative values, indicating poor solubility. A (-5.14) is worse than B (-2.206). Solubility is a key concern for kinase inhibitors.
11. **hERG:** Both are low, indicating low cardiotoxicity risk. A (0.63) is slightly higher than B (0.664).
12. **Cl_mic:** A (41.837) has slightly higher microsomal clearance than B (39.874). Lower is better for metabolic stability.
13. **t1/2:** A (25.341) has a shorter in vitro half-life than B (-8.356). B is much preferred here.
14. **Pgp:** A (0.575) has higher P-gp efflux than B (0.065). Lower is better. B is much preferred.
15. **Binding Affinity:** A (-8.2 kcal/mol) has a slightly better binding affinity than B (-7.5 kcal/mol). This is a 1.7 kcal/mol difference, which is significant.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better across several critical ADME properties. Specifically, B has a much lower DILI risk, better solubility, a longer half-life, and lower P-gp efflux. The 1.7 kcal/mol difference in binding affinity is likely outweighed by the substantial improvements in ADME. Poor solubility and high DILI risk are major red flags in drug development.

Therefore, I recommend **Ligand B** as the more viable drug candidate.

Output:
1
2025-04-17 15:41:07,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is slightly higher than Ligand B (69.64). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (1.582 and 1.38), 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 3. Both are below the 10 limit.

**QED:** Both ligands have good QED scores (0.631 and 0.868), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (48.197) has a slightly higher DILI risk than Ligand B (29.159). Both are below the 60 threshold, so the risk is acceptable, but Ligand B is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (64.831) has a higher BBB percentile than Ligand A (28.848).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.539 and -4.773), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.468 and -2.611). This is also a major concern, indicating very poor aqueous solubility. Ligand B is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.461 and 0.45), which is good.

**Microsomal Clearance:** Ligand A (55.066) has a higher microsomal clearance than Ligand B (29.134), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (5.489 hours) has a longer half-life than Ligand A (3.51 hours), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.191 and 0.169), which is good.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the superior candidate. Its significantly stronger binding affinity (-9.4 vs -8.0 kcal/mol), lower DILI risk, better metabolic stability (lower Cl_mic), longer half-life, and slightly better TPSA and solubility outweigh the shared concerns regarding permeability and solubility. The binding affinity difference is substantial enough to potentially overcome the ADME liabilities with appropriate formulation strategies.

Output:
1
2025-04-17 15:41:07,845 - INFO - Batch 400 complete. Total preferences: 6400
2025-04-17 15:41:07,845 - INFO - Processing batch 401/512...
2025-04-17 15:41:49,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.849 and 338.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.29) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.18) is still under 140, but less optimal than A.

**logP:** Ligand A (4.287) is slightly high, potentially leading to solubility issues or off-target effects, but still within a manageable range. Ligand B (2.483) is excellent, falling squarely within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (0 HBD, 7 HBA) is also acceptable, though slightly higher HBA could potentially affect permeability.

**QED:** Both ligands have similar QED values (0.584 and 0.655), indicating good drug-likeness.

**DILI:** Ligand A (90.229) has a concerningly high DILI risk (above 60). Ligand B (59.907) is better, but still warrants attention.

**BBB:** This isn't a primary concern for a non-CNS target like SRC kinase, but Ligand A (65.374) is slightly better than Ligand B (57.968).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.058 and -5.11), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.735 and -2.125). This is a major concern for *in vivo* bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.686 and 0.581), which is positive.

**Microsomal Clearance:** Ligand A (72.304) has higher clearance than Ligand B (41.145), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (54.014) has a slightly longer half-life than Ligand A (51.612), which is beneficial.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.676 and 0.024), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.4 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Despite the similar binding affinities, Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B has a significantly better DILI score, lower microsomal clearance (better metabolic stability), and a slightly longer half-life. The logP value for Ligand B is also more optimal. The high DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 15:41:49,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.439 and 345.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (52.65), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.465) is within the optimal range (1-3), while Ligand B (2.758) is approaching the upper limit.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD and 3 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.773 and 0.893), indicating drug-like properties.

**DILI:** Ligand A (29.624) has a significantly lower DILI risk than Ligand B (11.594), which is a major advantage.

**BBB:** Ligand B (86.623) has a higher BBB penetration score than Ligand A (60.644). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have similar, very negative Caco-2 values (-4.642 and -4.643), suggesting poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.672) has slightly worse solubility than Ligand B (-2.035), but both are poor.

**hERG:** Ligand A (0.344) has a much lower hERG risk than Ligand B (0.804), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-3.549) has a negative Cl_mic, indicating very good metabolic stability, while Ligand A (17.499) has a higher clearance. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (7.423) has a slightly longer half-life than Ligand A (10.474).

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux liability than Ligand B (0.127), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 and -8.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has better metabolic stability and slightly longer half-life, Ligand A has a significantly lower DILI risk and hERG inhibition liability, both of which are crucial for drug safety. The similar binding affinities make these ADME/Tox differences the deciding factors. The poor Caco-2 values are a concern for both, but can be addressed during lead optimization.

Output:
0
2025-04-17 15:41:49,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (351.393 and 346.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (55.4) is well below the 140 threshold and excellent for oral absorption. Ligand B (113.24) is still within acceptable limits, but less favorable than A.

**3. logP:** Ligand A (3.606) is optimal. Ligand B (0.191) is quite low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands (A: 1, B: 3) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (A: 3, B: 6) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.512, B: 0.634), indicating drug-like properties.

**7. DILI:** Ligand A (60.954) is approaching a concerning DILI risk, while Ligand B (36.758) is quite good.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.617) has better BBB penetration than Ligand B (68.67).

**9. Caco-2 Permeability:** Ligand A (-4.081) is poor, while Ligand B (-5.709) is even worse. Both are problematic.

**10. Aqueous Solubility:** Ligand A (-4.54) is poor, and Ligand B (-1.655) is also poor. Both are concerning.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.445, B: 0.431).

**12. Microsomal Clearance (Cl_mic):** Ligand A (95.92) shows high metabolic clearance, indicating poor metabolic stability. Ligand B (-38.393) is excellent, indicating very good metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.888) has a very short half-life. Ligand B (-10.409) is similarly short.

**14. P-gp Efflux:** Ligand A (0.329) has moderate P-gp efflux, while Ligand B (0.005) has very low P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.3) has a significantly stronger binding affinity than Ligand B (0.0). This is a crucial advantage.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability, poor solubility, high metabolic clearance, and a short half-life, and approaching concerning DILI risk. Ligand B has excellent metabolic stability and low P-gp efflux, but its binding affinity is essentially non-existent and its logP is very low.

Despite the ADME concerns with Ligand A, the substantial difference in binding affinity (-7.3 vs 0.0 kcal/mol) is a major advantage that could potentially be overcome with further optimization. The poor ADME properties of Ligand A are more readily addressed through medicinal chemistry efforts than improving the affinity of Ligand B from 0.0 kcal/mol.

Output:
1
2025-04-17 15:41:49,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (A: 423.292, B: 386.945) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.75) is slightly higher than Ligand B (66.48), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 3.483, B: 3.211), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.634, B: 0.744), indicating good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (98.139), while Ligand B has a much lower and acceptable risk (38.852). This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (70.609) than Ligand A (55.021).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.767 and -4.775), 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 (-4.874 and -3.264), indicating poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.571, B: 0.611).

**Microsomal Clearance:** Ligand B has significantly lower microsomal clearance (35.611 mL/min/kg) than Ligand A (75.158 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (A: 45.413, B: 45.088).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.639, B: 0.248). Ligand B is slightly better.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-8.4 kcal/mol) than Ligand A (-7.2 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite similar MW, logP, HBD/HBA, QED, and in vitro half-life, Ligand B is clearly the superior candidate. The most critical factors are the drastically lower DILI risk and the significantly improved binding affinity. While both have poor solubility and Caco-2 permeability, these issues can be addressed during formulation. The better metabolic stability (lower Cl_mic) of Ligand B further strengthens its case.

Output:
1
2025-04-17 15:41:49,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (383.857 Da) is still well within range.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand B (92.51 A^2) is better than Ligand A (109.62 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.26) and Ligand B (1.995) are very similar.

**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:** Both ligands have good QED scores, indicating drug-likeness. Ligand B (0.852) is better than Ligand A (0.594).

**DILI:** Ligand A (69.756) has a higher DILI risk than Ligand B (84.335). Lower is better, so Ligand B is preferable.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (53.625) has slightly better BBB penetration than Ligand A (47.15).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.277) is slightly better than Ligand B (-5.069), but both are a concern.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.603) is slightly better than Ligand B (-4.098), but both are a concern.

**hERG Inhibition:** Both ligands have low hERG inhibition liability. Ligand A (0.439) is slightly higher than Ligand B (0.331), but both are acceptable.

**Microsomal Clearance:** Ligand A (38.24 mL/min/kg) has significantly lower microsomal clearance than Ligand B (69.124 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.194 hours) has a much longer half-life than Ligand B (-20.129 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability. Ligand A (0.092) is slightly lower than Ligand B (0.245), which is preferable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.9 vs -7.5 kcal/mol) is the most important factor for an enzyme inhibitor. The difference in affinity is substantial enough to compensate for the slightly higher DILI risk and poorer metabolic stability. The solubility and permeability are concerns for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 15:41:49,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 366.824 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is well below the 140 threshold, while Ligand B (88.32) is still acceptable but higher.

**logP:** Both ligands have good logP values (2.18 and 1.684), 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 reasonable numbers of hydrogen bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar and acceptable QED values (0.616 and 0.629), indicating good drug-like properties.

**DILI:** Ligand A (8.453) has a significantly lower DILI risk than Ligand B (58.86). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand B (80.031) shows higher penetration than Ligand A (54.634).

**Caco-2 Permeability:** Ligand A (-4.27) has a worse Caco-2 permeability than Ligand B (-5.454), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.233) has a slightly better solubility than Ligand B (-3.698).

**hERG Inhibition:** Ligand A (0.345) has a lower hERG inhibition risk than Ligand B (0.551). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (41.497) has a higher microsomal clearance than Ligand B (0.512), suggesting lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-17.208) has a much longer in vitro half-life than Ligand A (3.316). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.136) has lower P-gp efflux than Ligand B (0.034), which is favorable.

**Binding Affinity:** Ligand B (-9.3 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 ADME drawbacks.

**Overall Assessment:**

Ligand B possesses a much stronger binding affinity and a significantly longer half-life, which are crucial for an enzyme inhibitor. While it has a higher DILI risk and slightly worse solubility, the potency advantage is substantial. Ligand A has better DILI and hERG profiles, but its weaker binding and lower half-life are significant drawbacks. Considering the priorities for kinase inhibitors, the stronger binding affinity and improved metabolic stability of Ligand B are more important.

Output:
1
2025-04-17 15:41:49,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (347.415 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (58.64), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have acceptable logP values (1.343 and 1.96), falling within the 1-3 range. Ligand B is slightly higher, which could be a minor concern for off-target effects, but not a major issue.

**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 HBA, both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.869) has a better QED score than Ligand B (0.795), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (35.634 and 32.377 percentile), which is favorable.

**8. BBB:** Both ligands have good BBB penetration (77.821 and 71.694 percentile), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-5.12) has a worse Caco-2 permeability than Ligand B (-4.602), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.056) has a worse aqueous solubility than Ligand B (-2.652), which is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.068) has a lower hERG inhibition risk than Ligand B (0.397), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (22.839 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (48.697 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.756 hours) has a much longer in vitro half-life than Ligand A (-7.617 hours), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.115), which is favorable.

**15. Binding Affinity:** Ligand B (-6.1 kcal/mol) has a better binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial difference in potency, exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. While Ligand A has better hERG and P-gp profiles, the substantial potency advantage of Ligand B outweighs these benefits. The solubility of Ligand B is a concern, but formulation strategies can often mitigate this. The lower metabolic stability of Ligand B is also a concern, but not as significant as the potency difference.

Output:
1
2025-04-17 15:41:49,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.402) is slightly lower, which could be beneficial for permeability. Ligand B (368.371) is also acceptable.

**TPSA:** Ligand A (54.46) is well below the 140 threshold for oral absorption. Ligand B (69.64) is also good, though slightly higher.

**logP:** Ligand A (3.61) is within the optimal range (1-3). Ligand B (1.793) is also within range, but towards the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, both acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.841) has a very good drug-likeness score. Ligand B (0.673) is still acceptable, but lower.

**DILI:** Ligand A (62.35) has a moderate DILI risk, but is still acceptable. Ligand B (14.889) has a very low DILI risk, which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (around 82%), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.582 and -4.715), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.677 and -1.962), which is also a significant concern. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.774 and 0.647), which is positive.

**Microsomal Clearance:** Ligand A (86.929) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-4.131) has *negative* clearance, which is not physically possible and likely an error or outlier. However, even if we interpret this as very low clearance, it's a substantial advantage.

**In vitro Half-Life:** Ligand A (28.651) has a moderate half-life. Ligand B (-43.183) has a negative half-life, which is impossible and indicates a data issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.425 and 0.037), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.7 kcal/mol), with Ligand B being slightly better. This is the most important factor.

**Overall Assessment:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk and potentially much better metabolic stability (indicated by the negative, though likely erroneous, clearance value) outweigh the slightly lower logP and QED scores. The negative solubility and Caco-2 values are concerning for both, but could be addressed through formulation strategies. The data issues with Ligand B's clearance and half-life need to be investigated, but even with those concerns, its other properties are more favorable.

Output:
1
2025-04-17 15:41:49,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.379 and 351.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.45) is better than Ligand B (136.23), being closer to the <140 threshold for good absorption.

**logP:** Ligand B (0.988) is slightly better than Ligand A (-0.31), falling within the optimal 1-3 range, while Ligand A is a bit low, potentially hindering permeation.

**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 acceptable (<=10).

**QED:** Ligand A (0.703) has a significantly better QED score than Ligand B (0.368), indicating a more drug-like profile.

**DILI:** Ligand B (20.783) has a much lower DILI risk than Ligand A (54.711), which is a significant advantage.

**BBB:** Ligand A (70.182) has a better BBB penetration percentile than Ligand B (35.207). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.964) and Ligand B (-5.796) both have negative values, indicating poor permeability. However, the values are similar.

**Aqueous Solubility:** Ligand A (-1.437) has slightly better solubility than Ligand B (-0.508).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.032 and 0.073, respectively).

**Microsomal Clearance:** Ligand B (16.261) has a lower microsomal clearance than Ligand A (28.788), suggesting better metabolic stability, which is crucial for kinases.

**In vitro Half-Life:** Ligand B (25.155) has a significantly longer in vitro half-life than Ligand A (-1.835), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.004, respectively).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While Ligand A's affinity is better, the difference is not substantial enough to outweigh the other ADME properties.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has a slightly better binding affinity and BBB penetration, Ligand B excels in critical ADME properties for an enzyme target: significantly lower DILI risk, lower microsomal clearance, and a longer in vitro half-life. Its QED score is lower, but the improved metabolic stability and safety profile outweigh this drawback.

Output:
1
2025-04-17 15:41:49,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.475 and 360.489 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.21) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Ligand A (0.401) is quite low, potentially hindering permeation. Ligand B (3.945) is closer to the optimal 1-3 range.

**H-Bond Donors:** Both have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBAs, while Ligand B has 2. Both are within the acceptable limit of 10, but Ligand B is preferable.

**QED:** Ligand A (0.722) has a better QED score than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand A (55.138) has a higher DILI risk than Ligand B (21.869). Ligand B is significantly better here.

**BBB:** Ligand A (57.968) and Ligand B (97.674). BBB is less critical for a non-CNS target like SRC, but higher is generally better. Ligand B is significantly better.

**Caco-2:** Both have negative Caco-2 values (-4.586 and -4.224). This is unusual and suggests poor permeability. However, the values are very close.

**Solubility:** Ligand A (-1.611) and Ligand B (-3.887) both have negative solubility values, indicating poor aqueous solubility. Ligand B is worse.

**hERG:** Ligand A (0.281) has a lower hERG risk than Ligand B (0.91). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (39.332) has a lower Cl_mic than Ligand B (74.9), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-16.219) has a negative half-life, which is not possible and indicates a problem with the data. Ligand B (3.676) has a reasonable half-life.

**P-gp:** Ligand A (0.061) has lower P-gp efflux than Ligand B (0.445).

**Binding Affinity:** Ligand A (-9.1) has a significantly stronger binding affinity than Ligand B (-7.9). 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, though the half-life data is suspect). It also has lower hERG and P-gp efflux. However, it suffers from poor logP and solubility, and a higher DILI risk. Ligand B has better TPSA, BBB, and DILI, but weaker binding affinity and poorer metabolic stability.

Given the priority for potency in enzyme inhibitors, and the substantial difference in binding affinity (-9.1 vs -7.9 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 solubility and reduce DILI. The negative half-life for Ligand A is a red flag, but the overall profile is still better due to the affinity.

Output:
0
2025-04-17 15:41:49,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.387 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.41) is slightly above the preferred <140, but acceptable. Ligand B (87.74) is well within the ideal range.

**logP:** Both ligands have good logP values (1.126 and 1.522), falling within the optimal 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:** Ligand A (0.714) has a better QED score than Ligand B (0.583), indicating a more drug-like profile.

**DILI:** Ligand A (41.877) has a slightly higher DILI risk than Ligand B (22.8), but both are considered good (<40 is preferred, both are below 60).

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (82.435) has a higher BBB percentile than Ligand A (47.926), but this is less critical.

**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.

**hERG:** Both ligands have very low hERG inhibition liability (0.369 and 0.311), which is excellent.

**Microsomal Clearance:** Ligand A (9.807) has significantly lower microsomal clearance than Ligand B (59.715), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (15.107 hours) has a much longer half-life than Ligand B (-25.535 hours). The negative value for Ligand B is concerning and indicates very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.022 and 0.047), which is favorable.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold where affinity overwhelmingly dictates choice.

**Overall Assessment:**

While Ligand B has slightly better binding affinity, Ligand A is the superior candidate. The key factors driving this decision are:

*   **Metabolic Stability:** Ligand A's significantly lower microsomal clearance and longer half-life are critical for an enzyme inhibitor, as it suggests the drug will remain active in the body for a longer duration.
*   **QED:** Ligand A's higher QED score indicates a better overall drug-like profile.
*   **DILI:** Ligand A has a slightly better DILI profile.

Both compounds suffer from poor solubility and permeability, which would require formulation strategies to address. However, the metabolic advantages of Ligand A outweigh the slightly better affinity of Ligand B.

Output:
0
2025-04-17 15:41:49,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.43 and 350.46 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.66 and 72.96) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.899) is optimal (1-3). Ligand B (-0.086) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 1 respectively) and HBA (4 each) counts.

**QED:** Both ligands have good QED scores (0.744 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A (48.662) has a moderate DILI risk, while Ligand B (21.714) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.723) has better BBB penetration than Ligand B (65.413), but this is not a major factor in this case.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.354 and -4.92), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.851 and -0.956), indicating very poor solubility. This is a major issue that would require significant formulation work.

**hERG Inhibition:** Ligand A (0.522) has a slightly higher hERG risk than Ligand B (0.177), which is preferable.

**Microsomal Clearance:** Ligand B (20.911) has significantly lower microsomal clearance than Ligand A (83.103), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-7.389) has a negative half-life, which is concerning. Ligand A (32.622) has a more reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.192 and 0.007).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.3 kcal/mol). The difference of 0.5 kcal/mol is not enough to overcome other significant drawbacks.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme target like SRC kinase. The negative solubility and Caco-2 values are concerning for both, but formulation strategies might mitigate these issues. Ligand A's better half-life is a plus, but doesn't outweigh the benefits of Ligand B's improved safety and metabolic profile.

Output:
1
2025-04-17 15:41:49,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.921 and 363.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is higher than Ligand B (38.77). Both are below the 140 threshold for oral absorption, but B is better.

**3. logP:** Ligand A (1.985) is within the optimal 1-3 range. Ligand B (3.791) is 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 (3) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have acceptable QED values (0.773 and 0.627, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (26.018), both are good.

**8. BBB:** Ligand A (58.085) has a lower BBB penetration than Ligand B (84.141). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.933) has worse Caco-2 permeability than Ligand B (-4.883). Both are poor, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-2.443) has better aqueous solubility than Ligand B (-3.786). This is a positive attribute for an enzyme inhibitor.

**11. hERG Inhibition:** Ligand A (0.364) shows a lower hERG inhibition risk than Ligand B (0.677). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (9.136) has a much lower microsomal clearance than Ligand B (74.412), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (10.665) has a shorter half-life than Ligand B (24.655). However, the difference isn't massive, and the lower clearance of A suggests a potentially longer *in vivo* half-life.

**14. P-gp Efflux:** Ligand A (0.167) has lower P-gp efflux than Ligand B (0.736), which is favorable for bioavailability.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.0 kcal/mol, respectively). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better BBB penetration and Caco-2 permeability, Ligand A excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly lower microsomal clearance (better metabolic stability), lower hERG inhibition, and lower P-gp efflux. The slightly better solubility of A is also beneficial. The small advantage in binding affinity further supports choosing A.



Output:
0
2025-04-17 15:41:49,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.333 and 369.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.93) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (92.42) is well within the range.

**logP:** Both ligands have good logP values (1.079 and 1.394), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.722 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (49.321) has a better DILI score than Ligand B (62.04), indicating a lower risk of liver injury. This is a significant advantage.

**BBB:** Both ligands have high BBB penetration (82.435 and 89.066), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.786 and -5.079). This 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 (-2.223 and -2.907), which is also unusual and suggests poor solubility. Again, these are log scale values and can be misleading.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.374 and 0.189), which is excellent.

**Microsomal Clearance:** Ligand A (-11.399) has significantly better microsomal clearance (lower value = more stable) than Ligand B (26.463). This is a major advantage for metabolic stability.

**In vitro Half-Life:** Ligand A (-35.643) has a better in vitro half-life than Ligand B (-23.335).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.134).

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-8.8 and -8.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The slightly better DILI score and significantly improved metabolic stability outweigh the slightly higher TPSA and similar binding affinity. The negative Caco-2 and solubility values are concerning for both, but could be addressed through formulation strategies.

Output:
0
2025-04-17 15:41:49,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.809 and 345.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is slightly above the optimal <140, but acceptable. Ligand B (52.65) is well within the acceptable range.

**logP:** Both ligands have good logP values (2.893 and 1.488), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2 and 1) and HBA (3 and 3) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.782 and 0.678), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (74.641 percentile) than Ligand B (6.282 percentile). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (65.413) is slightly better than Ligand B (53.005).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.577 and -4.837), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-5.095) and Ligand B (-1.512) both have negative solubility values, indicating poor aqueous solubility. Ligand B is slightly better.

**hERG:** Ligand A (0.664) has a slightly higher hERG risk than Ligand B (0.491), but both are reasonably low.

**Microsomal Clearance:** Ligand B (-16.921) has a much lower (better) microsomal clearance than Ligand A (38.65). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Both ligands have similar negative in vitro half-lives (-5.582 and -5.665), indicating poor stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.221 and 0.011).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is significantly more promising. Its substantially better binding affinity, much lower DILI risk, and improved metabolic stability (lower Cl_mic) outweigh the slightly better BBB penetration of Ligand A. The large difference in binding affinity (-7.2 vs -0.0 kcal/mol) is a decisive factor.

Output:
1
2025-04-17 15:41:49,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.355 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.65 and 103.79) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.232) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (-0.015) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 7 HBA) both have acceptable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.806 and 0.652), indicating good drug-like properties.

**DILI:** Ligand A (77.394) has a higher DILI risk than Ligand B (35.556). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (41.179) has a higher BBB value than Ligand A (21.985), but this is not a major factor in this case.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.985 and -5.364), which is unusual and suggests very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.736 and -1.647), suggesting very poor solubility. This is a significant issue for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.141 and 0.188), which is excellent.

**Microsomal Clearance:** Ligand A (-10.905) has a lower (better) microsomal clearance than Ligand B (-17.237), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.522) has a longer half-life than Ligand B (-6.188), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.059 and 0.019).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is not huge (1.8 kcal/mol), it is enough to consider.

**Overall Assessment:**

Both ligands have significant issues with permeability and solubility. However, Ligand B has a substantially better binding affinity and a much lower DILI risk. While its metabolic stability and half-life are worse than Ligand A, the improved binding and reduced toxicity are more important for an enzyme target like SRC. The slightly better binding affinity of Ligand B could potentially outweigh the minor ADME drawbacks.

Output:
1
2025-04-17 15:41:49,116 - INFO - Batch 401 complete. Total preferences: 6416
2025-04-17 15:41:49,116 - INFO - Processing batch 402/512...
2025-04-17 15:42:37,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.495 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (100.35). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.62, B: 1.285), 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=4) as lower HBD counts can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.838, B: 0.764), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 21.908, B: 21.946), well below the concerning threshold of 60.

**BBB:** Ligand A (86.351) has a higher BBB penetration percentile than Ligand B (64.831). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.638) is better than Ligand B (-5.14), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.892) is better than Ligand B (-1.882), which is crucial for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.489, B: 0.395), minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (20.532) has a significantly *lower* (better) microsomal clearance than Ligand B (-45.048). This suggests better metabolic stability for Ligand A, a key consideration for enzymes.

**In vitro Half-Life:** Ligand B (21.628) has a longer half-life than Ligand A (8.955). This is generally desirable, but the difference is somewhat offset by the metabolic stability advantage of Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.094, B: 0.007), which is good.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This 0.9 kcal/mol difference is significant, but must be weighed against the ADME properties.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, which is a high priority. However, Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic) and solubility. The difference in binding affinity (0.9 kcal/mol) is not substantial enough to outweigh the significant advantage in metabolic stability and solubility offered by Ligand A. SRC kinases are often targets where chronic dosing is anticipated, making metabolic stability paramount.

Output:
0
2025-04-17 15:42:37,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.415 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.39) is better than Ligand B (49.85) as it is closer to the 140 threshold.

**logP:** Both ligands (1.853 and 2.394) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (0) as it is closer to the ideal range of 5.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4) as it is closer to the ideal range of 10.

**QED:** Ligand A (0.831) is significantly better than Ligand B (0.692), indicating a more drug-like profile.

**DILI:** Ligand B (20.744) has a much lower DILI risk than Ligand A (74.603), which is a significant advantage.

**BBB:** Ligand B (80.419) has better BBB penetration than Ligand A (53.819), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.055 and -4.898), which is unusual and suggests poor permeability. However, these values are on a log scale and the absolute value is important. Both are similar and suggest a permeability issue.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.077 and -2.424), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.238 and 0.365), which is excellent.

**Microsomal Clearance:** Ligand A (36.393) has a lower microsomal clearance than Ligand B (74.032), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (17.266) has a longer half-life than Ligand B (1.947), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.069 and 0.149).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and a significantly lower DILI risk. While Ligand A has better QED, TPSA, and metabolic stability, the strong binding affinity of Ligand B is paramount for an enzyme inhibitor. The poor solubility and permeability are concerns for both, but formulation strategies can be explored. The lower DILI risk of Ligand B is a major advantage.

Output:
1
2025-04-17 15:42:37,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.71 Da) is slightly higher than Ligand B (362.459 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is better than Ligand B (103.01). Lower TPSA generally improves absorption, though it's not a critical factor for kinases.

**logP:** Ligand A (3.912) is within the optimal range, while Ligand B (1.01) is on the lower side. A logP too low can hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=6) as it has fewer hydrogen bond forming groups, which can improve permeability.

**QED:** Both ligands have similar QED values (A: 0.6, B: 0.578), indicating reasonable drug-likeness.

**DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (39.473). This is a significant concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (80.109) has a better BBB score than Ligand B (46.336).

**Caco-2 Permeability:** Ligand A (-4.934) has a worse Caco-2 permeability than Ligand B (-6.001). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.431) has worse solubility than Ligand B (-2.396). Solubility is important for bioavailability.

**hERG:** Ligand A (0.311) has a better hERG profile than Ligand B (0.437), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (40.255) has a higher microsomal clearance than Ligand B (-4.202). This suggests Ligand B is more metabolically stable. Lower clearance is preferred.

**In vitro Half-Life:** Ligand A (14.025) has a slightly longer half-life than Ligand B (12.181).

**P-gp Efflux:** Ligand A (0.427) has lower P-gp efflux than Ligand B (0.017). Lower efflux is generally preferred.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a crucial 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 for an enzyme inhibitor. It also has better hERG and P-gp efflux profiles. However, it suffers from higher DILI risk, lower solubility, and higher microsomal clearance. Ligand B has a better safety profile (lower DILI) and metabolic stability, but its binding affinity is considerably weaker.

Given the strong binding affinity of Ligand A, and the fact that issues like DILI and metabolic stability can be addressed through further optimization, I would prioritize Ligand A. The potency advantage is substantial and outweighs the ADME concerns at this stage.

Output:
1
2025-04-17 15:42:37,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.383 and 350.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.19) is slightly higher than Ligand B (58.44). Both are below the 140 threshold for good oral absorption, but B is better.

**logP:** Both ligands have good logP values (2.735 and 1.819), 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.75 and 0.786), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 75.339, which is relatively high. Ligand B has a much lower DILI risk of 23.11, which is a significant advantage.

**BBB:** Ligand A (64.948) and Ligand B (96.782). BBB is not a major concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.953 and -4.581). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.287 and -2.35). Again, this is unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.356) has a slightly lower hERG risk than Ligand B (0.741), which is preferable.

**Microsomal Clearance:** Ligand A (29.688) has lower microsomal clearance than Ligand B (40.243), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (32.979) has a positive half-life, while Ligand B has a negative half-life (-30.829). This is a major red flag for Ligand B, suggesting very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.195).

**Binding Affinity:** Both ligands have identical binding affinities (-9.0 and -9.1 kcal/mol), which are excellent and comparable.

**Conclusion:**

Despite similar binding affinities, Ligand B is significantly better due to its much lower DILI risk and substantially improved *in vitro* half-life. While both have issues with Caco-2 and solubility, the metabolic stability is crucial for an enzyme inhibitor. The lower DILI risk is also a major advantage.

Output:
1
2025-04-17 15:42:37,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.694 Da) is slightly higher than Ligand B (355.364 Da), but both are acceptable.

**TPSA:** Ligand A (59.5) is well below the 140 threshold for good oral absorption. Ligand B (71.84) is also acceptable.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (4.186) being slightly higher than Ligand B (3.501). While 4.186 is approaching the upper limit, it's not a major concern.

**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 (HBD <=5, HBA <=10).

**QED:** Both ligands have good QED scores (Ligand A: 0.68, Ligand B: 0.862), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 77.2, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 52.036, which is preferable.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (83.288) has a slightly higher BBB penetration than Ligand B (75.805).

**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, indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.582) has a slightly higher hERG inhibition risk than Ligand B (0.31), but both are relatively low.

**Microsomal Clearance:** Ligand A (130.754 mL/min/kg) has significantly higher microsomal clearance than Ligand B (17.285 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (27.044 hours) has a much longer in vitro half-life than Ligand A (51.713 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.6) has a slightly higher P-gp efflux liability than Ligand B (0.05).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 1.4 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having poor solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -6.8 kcal/mol), lower DILI risk (52.036 vs 77.2), lower microsomal clearance (17.285 vs 130.754), and longer half-life (27.044 vs 51.713) outweigh the slightly better BBB penetration of Ligand A. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the superior potency and metabolic stability of Ligand B make it the better starting point.

Output:
1
2025-04-17 15:42:37,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.4 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.04 and 73.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.116) is slightly high, potentially leading to solubility issues. Ligand B (1.273) is a bit low, potentially impacting permeability, but is preferable to A.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also good.

**H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable range.

**QED:** Both ligands have acceptable QED scores (0.692 and 0.578, both >0.5).

**DILI:** Ligand A (68.05 percentile) has a higher DILI risk than Ligand B (51.221 percentile).

**BBB:** BBB is not a primary concern for an oncology target, so these values (76.425 and 56.883) are less critical.

**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. However, 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 (0.679). Lower is better here.

**Microsomal Clearance:** Ligand B (8.816 mL/min/kg) has significantly lower microsomal clearance than Ligand A (53.211 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-2.095 hours) has a negative half-life, which is not possible. Ligand A (18.365 hours) has a good half-life. This is a major issue for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.24 and 0.118), which is favorable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). The difference is 0.7 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B is the better candidate. While its logP is a little low, its significantly improved metabolic stability (lower Cl_mic), better binding affinity, and lower DILI risk outweigh the potential permeability concerns. The negative values for Caco-2 and solubility are concerning, but the difference in binding affinity and metabolic stability are more important for an enzyme inhibitor. The half-life for Ligand B is not possible, which is a major issue.

Output:
1
2025-04-17 15:42:37,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly better positioned.

**TPSA:** Ligand A (76.83) is significantly better than Ligand B (135.7). Lower TPSA generally improves absorption.

**logP:** Ligand A (2.693) is optimal, while Ligand B (-0.917) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3).

**H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (6).

**QED:** Both ligands have reasonable QED scores (A: 0.833, B: 0.564), indicating good drug-like properties.

**DILI:** Ligand B (65.568) has a higher DILI risk than Ligand A (56.301), though both are acceptable.

**BBB:** Ligand A (75.262) has a much higher BBB penetration potential than Ligand B (12.602). While SRC isn't a CNS target, better BBB penetration can sometimes correlate with better overall permeability.

**Caco-2 Permeability:** Ligand A (-4.535) is better than Ligand B (-5.941), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.559) is better than Ligand B (-2.693).

**hERG Inhibition:** Ligand A (0.375) has a lower hERG risk than Ligand B (0.023), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-8.763) has a *negative* clearance, which is not physically possible and suggests a data error or unusual metabolic behavior. Ligand A (77.877) has a reasonable clearance. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (3.491) has a better half-life than Ligand B (-18.61), which is also likely an error.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.004).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.4 kcal/mol). The difference is minimal.

**Conclusion:**

Ligand A is significantly better overall. It has more favorable physicochemical properties (logP, TPSA, HBD/HBA), better predicted permeability (Caco-2), lower hERG risk, and more realistic ADME properties (Cl_mic, t1/2). While both have excellent binding affinity, the ADME profile of Ligand B is highly suspect due to the negative clearance and half-life values. Therefore, Ligand A is the more viable drug candidate.

Output:
1
2025-04-17 15:42:37,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.419 Da and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.56 and 81.08) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.146) is optimal, while Ligand B (1.294) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, well within the limits. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.581 and 0.755), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 69.639, which is moderately high. Ligand B has a very low DILI risk of 13.067, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.466) and Ligand B (66.499) are both reasonable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.546 and -4.69), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.146 and -2.067), indicating poor aqueous solubility, which could hinder bioavailability.

**hERG:** Ligand A (0.149) has a slightly higher hERG risk than Ligand B (0.3), but both are relatively low.

**Microsomal Clearance:** Ligand A (90.724) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (34.733) has significantly lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.658) has a longer in vitro half-life than Ligand A (-2.322), which is beneficial.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux than Ligand B (0.052), which is slightly favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 kcal/mol and -7.8 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have good potency, Ligand B is the more promising candidate. Its significantly lower DILI risk and improved metabolic stability (lower Cl_mic and longer t1/2) are crucial advantages for an enzyme target. Although both have poor predicted permeability and solubility, the metabolic and safety profiles of Ligand B are superior.

Output:
1
2025-04-17 15:42:37,172 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [345.403, 117.42 ,   0.075,   3.   ,   5.   ,   0.668,  68.941,  55.37 ,
  -5.288,  -2.814,   0.153,   8.62 , -32.706,   0.015,  -7.8  ]
**Ligand B:** [350.503,  43.82 ,   3.38 ,   0.   ,   5.   ,   0.647,   9.112,  81.039,
  -4.537,  -2.72 ,   0.859,  76.229,  -6.066,   0.181,  -7.1  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (345.4) is slightly lower, which is generally favorable for permeability.
2. **TPSA:** Ligand A (117.42) is better than Ligand B (43.82) as it is closer to the threshold of 140.
3. **logP:** Ligand B (3.38) is optimal, while Ligand A (0.075) is quite low. This is a significant drawback for A, potentially hindering membrane permeability and bioavailability.
4. **HBD:** Ligand A (3) is acceptable, while Ligand B (0) is also good.
5. **HBA:** Both ligands have 5 HBA, which is within the acceptable range.
6. **QED:** Both ligands have similar QED scores (A: 0.668, B: 0.647), indicating good drug-like properties.
7. **DILI:** Ligand B (9.112) has a much lower DILI risk than Ligand A (68.941). This is a major advantage for B.
8. **BBB:** Ligand B (81.039) has better BBB penetration than Ligand A (55.37), but this is less critical for a non-CNS target like SRC.
9. **Caco-2:** Ligand A (-5.288) has a very poor Caco-2 permeability, while Ligand B (-4.537) is also poor.
10. **Solubility:** Both ligands have poor solubility (-2.814 and -2.72).
11. **hERG:** Ligand A (0.153) has a lower hERG risk than Ligand B (0.859), which is preferable.
12. **Cl_mic:** Ligand A (8.62) has a lower microsomal clearance than Ligand B (76.229), indicating better metabolic stability. This is a key advantage for A.
13. **t1/2:** Ligand A (-32.706) has a much longer in vitro half-life than Ligand B (-6.066). This is a significant advantage for A.
14. **Pgp:** Ligand A (0.015) has lower P-gp efflux than Ligand B (0.181), which is favorable.
15. **Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.1). While both are good, the 1.5kcal/mol difference is notable.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Overall Assessment:**

Ligand A has a better affinity, metabolic stability, half-life, and Pgp efflux. However, its very low logP and poor Caco-2 permeability are major concerns. Ligand B has a much better logP, lower DILI risk, and better BBB penetration, but suffers from higher metabolic clearance and a shorter half-life.

The difference in affinity is not substantial enough to overcome the significant permeability issues of Ligand A. The lower DILI risk and better logP of Ligand B make it a more promising starting point, despite its metabolic liabilities. Metabolic stability can be improved through structural modifications, but fixing a very low logP is often more challenging.

Output:
1
2025-04-17 15:42:37,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (353.34 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (57.61) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (100.45) is still acceptable but less favorable.

**3. logP:** Both ligands have acceptable logP values (2.919 and 1.051), falling within the 1-3 range. Ligand A is slightly more optimal.

**4. H-Bond Donors (HBD):** Both ligands are at or below the 5 HBD threshold (1 and 2 respectively).

**5. H-Bond Acceptors (HBA):** Both ligands are at or below the 10 HBA threshold (2 and 5 respectively).

**6. QED:** Both ligands have reasonable QED scores (0.85 and 0.723), indicating good drug-like properties.

**7. DILI:** Ligand A (53.276) has a slightly higher DILI risk than Ligand B (47.693), but both are still considered relatively low risk (<60).

**8. BBB:** Ligand A (78.79) has better BBB penetration potential than Ligand B (50.679). While not critical for a non-CNS target like SRC, it doesn't hurt.

**9. Caco-2 Permeability:** Ligand A (-4.701) has significantly better Caco-2 permeability than Ligand B (-5.154).

**10. Aqueous Solubility:** Ligand A (-3.287) has better aqueous solubility than Ligand B (-2.129).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.144 and 0.189).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-6.919) has *much* lower microsomal clearance than Ligand B (3.063), indicating significantly better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (0.445) has a shorter half-life than Ligand B (16.205). This is a disadvantage for Ligand A, but can be mitigated with formulation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.073 and 0.024).

**15. 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 crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered very substantial.

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in affinity and metabolic stability, and has acceptable solubility and hERG risk. While its half-life is shorter, the superior binding affinity and metabolic stability outweigh this drawback. Ligand B's affinity is extremely weak.

Output:
1
2025-04-17 15:42:37,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (376.36 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.4 and 88.58) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (1.394 and 2.318) within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.614 and 0.898), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 72.043, which is moderately high. Ligand B has a lower DILI risk of 44.591, which is preferable.

**BBB:** Both ligands have similar BBB penetration (66.925 and 69.95), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.999 and -5.104). This is unusual and suggests poor permeability. However, these values might be errors or indicate a specific experimental artifact.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.241 and -2.584), which is highly problematic. Poor solubility will severely hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.179 and 0.222), which is excellent.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (17.588 mL/min/kg) than Ligand B (10.953 mL/min/kg). Lower clearance is preferred for better metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (16.643 hours) compared to Ligand A (-11.669 hours). This is a major advantage for Ligand B, suggesting less frequent dosing could be possible.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.066 and 0.124), which is good.

**Binding Affinity:** Ligand B has a stronger binding affinity (-8.3 kcal/mol) than Ligand A (-7.1 kcal/mol). This 1.2 kcal/mol difference is substantial and a key factor.

**Overall Assessment:**

Despite the concerning negative solubility and Caco-2 values for both, Ligand B is the more promising candidate. It has a better DILI score, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and, most importantly, a substantially stronger binding affinity. The negative solubility and permeability values are red flags that would require further investigation (e.g., salt formation, formulation studies), but the superior potency and pharmacokinetic properties of Ligand B make it the better choice for further development.

Output:
1
2025-04-17 15:42:37,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (368.88 and 364.555 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.56) is slightly higher than Ligand B (42.43). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**3. logP:** Ligand A (3.157) is within the optimal 1-3 range. Ligand B (4.617) is a bit high, potentially leading to solubility issues and off-target effects.

**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 (4) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.888) has a significantly better QED score than Ligand B (0.676), indicating a more drug-like profile.

**7. DILI:** Ligand A (15.665) has a much lower DILI risk than Ligand B (31.291), which is a significant advantage.

**8. BBB:** Both ligands have high BBB penetration (Ligand A: 92.982, Ligand B: 81.698). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.914) is slightly better than Ligand B (-4.565).

**10. Aqueous Solubility:** Ligand A (-2.546) is better than Ligand B (-5.006) in terms of solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.784, Ligand B: 0.773).

**12. Microsomal Clearance:** Ligand A (8.314) has significantly lower microsomal clearance than Ligand B (94.832), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.712) has a shorter half-life than Ligand B (18.278), but both are reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.194, Ligand B: 0.86).

**15. Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.2 kcal/mol, Ligand B: -8.4 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties. Specifically, its lower DILI risk, significantly better metabolic stability (lower Cl_mic), higher QED, and better solubility make it a more viable drug candidate. The slightly lower TPSA and better solubility are also beneficial. The Caco-2 permeability is concerning for both, but the other advantages of Ligand A outweigh this drawback.

Output:
0
2025-04-17 15:42:37,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.423 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.64) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (88.1) is well within the range, and potentially better for absorption.

**logP:** Ligand A (-1.063) is a bit low, potentially hindering permeation. Ligand B (-0.082) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is reasonable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.466 and 0.698), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (22.761) has a lower DILI risk than Ligand B (14.424), which is a significant advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (65.839) has a higher BBB percentile than Ligand B (48.468).

**Caco-2 Permeability:** Ligand A (-5.442) and Ligand B (-4.886) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.981) and Ligand B (-1.406) both have negative solubility values, indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.03) has a very low hERG risk, which is excellent. Ligand B (0.195) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-23.696) has a much lower (better) microsomal clearance than Ligand B (2.343), indicating greater metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (2.928) has a shorter half-life than Ligand B (29.095). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.001 and 0.012).

**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 for Ligand B, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount for an enzyme inhibitor. While its solubility is poor, its metabolic stability is better than Ligand A. Ligand A has a better DILI score and hERG profile, and better metabolic stability, but its lower binding affinity is a major drawback. Given the importance of potency for enzyme inhibition, and the relatively acceptable (though not ideal) ADME profile of Ligand B, I would favor Ligand B. Further optimization could focus on improving solubility.

Output:
1
2025-04-17 15:42:37,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.451 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (58.64) is still acceptable but less optimal.

**logP:** Ligand A (4.952) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.488) is quite low, which might hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (2 for A, 3 for B) counts.

**QED:** Ligand A (0.801) has a very good QED score, indicating excellent drug-likeness. Ligand B (0.588) is still acceptable, but lower.

**DILI:** Ligand A (49.709) has a moderate DILI risk, while Ligand B (14.036) has a very low DILI risk, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (95.192) has high BBB penetration, while Ligand B (67.468) has moderate penetration.

**Caco-2 Permeability:** Ligand A (-4.553) has poor Caco-2 permeability, likely due to its high logP. Ligand B (-4.848) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.067 and -3.188 respectively).

**hERG:** Ligand A (0.853) has a slightly elevated hERG risk, while Ligand B (0.183) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (78.76) has moderate clearance, while Ligand B (13.759) has low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (45.372) has a moderate half-life, while Ligand B (-2.028) has a very short half-life, a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.608 and 0.072), which is favorable.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity and a good QED score. However, its high logP, poor Caco-2 permeability, moderate DILI and hERG risk, and moderate clearance are concerning. Ligand B has a better safety profile (lower DILI and hERG) and better metabolic stability, but its lower binding affinity and poor solubility are significant drawbacks.

Despite the drawbacks, the significantly stronger binding affinity of Ligand A is a crucial factor for an enzyme inhibitor. While the ADME properties of Ligand A are suboptimal, medicinal chemistry efforts could focus on addressing the logP and solubility issues without sacrificing potency. The difference in binding affinity is likely to be more impactful than the other differences.

Output:
1
2025-04-17 15:42:37,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.503 and 390.477 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (103.35) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (76.13) is well within the acceptable range.

**logP:** Both ligands have good logP values (1.752 and 2.338), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.504 and 0.739), indicating good drug-like properties.

**DILI:** Ligand A (44.552) has a lower DILI risk than Ligand B (62.233), which is preferable.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (82.978) has a higher percentile than Ligand A (54.634).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-5.142) is slightly better than Ligand B (-4.94).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.803) is slightly better than Ligand B (-3.015).

**hERG:** Both ligands have low hERG risk (0.461 and 0.203), which is excellent.

**Microsomal Clearance:** Ligand A (49.457) has significantly better microsomal clearance (lower value) than Ligand B (0.574), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (44.698) has a longer in vitro half-life than Ligand B (13.559), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.411), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). The difference is 0.3 kcal/mol, which is not a huge difference.

**Overall Assessment:**

Ligand A demonstrates a more favorable ADME profile overall, particularly regarding metabolic stability (Cl_mic and t1/2), DILI risk, and P-gp efflux. While Ligand B has a slightly better binding affinity, the difference is not substantial enough to outweigh the ADME advantages of Ligand A. The poor Caco-2 and solubility values for both are concerning and would require further investigation, but the better metabolic stability of Ligand A makes it a more promising starting point for optimization.

Output:
0
2025-04-17 15:42:37,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.717 Da) is slightly higher than Ligand B (384.527 Da), but both are acceptable.

**TPSA:** Ligand A (50.36) is significantly better than Ligand B (96.11). A TPSA under 140 is good for oral absorption, but Ligand B's value is approaching a concerning level.

**logP:** Ligand A (4.985) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.901) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is optimal. Ligand B (HBD=3, HBA=6) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED values (A: 0.704, B: 0.674), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (A: 54.634, B: 59.907), and are within an acceptable range (<60 is good).

**BBB:** Ligand A (58.085) has a better BBB percentile than Ligand B (41.218), but BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.66) is significantly better than Ligand B (-5.733), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.717) is better than Ligand B (-3.279), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.787) has a lower hERG inhibition liability than Ligand B (0.254), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (78.728) has a higher microsomal clearance than Ligand B (20.49). This means Ligand B is more metabolically stable, a significant advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (37.027) has a longer half-life than Ligand B (8.978), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.374) has lower P-gp efflux than Ligand B (0.016), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 kcal/mol and -8.5 kcal/mol respectively). Ligand B has a slightly better affinity, but the difference is small.

**Overall Assessment:**

Ligand B has a slight edge in binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A excels in TPSA, Caco-2 permeability, solubility, hERG risk, and P-gp efflux. The high logP of Ligand A is a concern, but its superior solubility and permeability might mitigate this. Given the importance of metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 15:42:37,173 - INFO - Batch 402 complete. Total preferences: 6432
2025-04-17 15:42:37,173 - INFO - Processing batch 403/512...
2025-04-17 15:43:17,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.806 and 361.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is higher than Ligand B (43.86). Both are acceptable, but Ligand B is better, being closer to the <90 for CNS targets, although CNS penetration isn't a primary concern for an oncology target.

**logP:** Ligand A (4.414) is high, potentially leading to solubility issues and off-target effects. Ligand B (1.732) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 1 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 (0.745 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 55.68, which is moderate. Ligand B has a significantly lower DILI risk of 13.843, which is excellent.

**BBB:**  BBB is less important for an oncology target. Ligand B (85.964) is higher than Ligand A (60.295).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.469 and -4.634). 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 (-4.805 and -1.843), indicating poor solubility. Ligand B is better here.

**hERG:** Ligand A (0.493) has a slightly higher hERG risk than Ligand B (0.841), but both are reasonably low.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (100.604), indicating poor metabolic stability. Ligand B has a negative clearance (-13.34), which is *very* good, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (35.907) has a moderate half-life. Ligand B (-2.201) has a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.146).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the superior binding affinity of Ligand A, its high logP, moderate DILI risk, and poor metabolic stability (high Cl_mic, short half-life) are significant drawbacks. Ligand B, while having a weaker binding affinity, exhibits a much more favorable ADME profile: lower logP, significantly lower DILI risk, and excellent metabolic stability (negative Cl_mic, long half-life). For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity are crucial. 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 be more challenging.

Output:
1
2025-04-17 15:43:17,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.678 Da) is slightly higher than Ligand B (350.423 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (114.27 and 118.01) slightly above the optimal <140 for good oral absorption, but not drastically so.

**logP:** Ligand A (1.971) is within the optimal range (1-3). Ligand B (-0.396) is below 1, which *could* indicate permeability issues, though not a definitive dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=3, HBA=6) both fall within the acceptable ranges (HBD <= 5, HBA <= 10).

**QED:** Both ligands have similar QED values (0.598 and 0.56), indicating good drug-like properties.

**DILI:** Ligand A (87.049) has a significantly higher DILI risk than Ligand B (42.962). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (49.942) has a higher BBB value than Ligand A (32.765), but this is not a primary factor in this decision.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.891 and -5.263). These values are unusual and suggest poor permeability. However, *in vitro* permeability can be difficult to predict accurately.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.67 and -1.665), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.073) has a very low hERG risk, which is excellent. Ligand B (0.164) is slightly higher, but still relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (14.059 and 14.928 mL/min/kg), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand A (8.722 hours) has a slightly longer half-life than Ligand B (6.288 hours), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.08 and 0.01), which is favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a *significantly* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial difference. A >1.5 kcal/mol advantage in binding affinity can outweigh other drawbacks.

**Conclusion:**

Despite the permeability and solubility concerns for both, Ligand B is the far superior candidate. The dramatically stronger binding affinity (-7.7 vs 0.0 kcal/mol) is the deciding factor. While Ligand A has a better hERG profile, Ligand B's much lower DILI risk and significantly improved potency make it the more promising starting point for further optimization. The permeability and solubility issues can be addressed through medicinal chemistry efforts, but a weak binder is much harder to improve.

Output:
1
2025-04-17 15:43:17,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (378.523 and 366.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (68.09 and 66.48) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.268 and 1.916) 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 good QED scores (0.747 and 0.81), indicating a drug-like profile.

**DILI:** Ligand A has a DILI risk of 75.766, which is concerningly high (>60). Ligand B has a much lower DILI risk of 55.176, which is still above the ideal <40, but significantly better than Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (64.017 and 79.217), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.125 and -4.895). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values aren't directly interpretable without knowing the assay details. We'll consider this a potential drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.035 and -3.645). This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.324) has a lower hERG inhibition risk than Ligand B (0.65), which is preferable.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (81.592) than Ligand B (65.379), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-37.622 hours) compared to Ligand A (2.365 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.425) has lower P-gp efflux than Ligand B (0.255), which is slightly favorable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-6.7 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to outweigh major ADME issues, it's still a positive.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B has a significantly better DILI score, a much longer half-life, and slightly better binding affinity. The lower DILI and improved metabolic stability are crucial for kinase inhibitors. Ligand A's high DILI risk is a major red flag.



Output:
1
2025-04-17 15:43:17,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.53) is better than Ligand B (70.81), both are below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.156 and 1.942), falling within the 1-3 range. Ligand B is slightly better.

**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, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.835 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (33.307) has a significantly lower DILI risk than Ligand B (39.356), both are below the 40 threshold.

**BBB:** Ligand B (72.237) has a higher BBB penetration percentile than Ligand A (32.803). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.134) has worse Caco-2 permeability than Ligand B (-4.686).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.517 and -1.488). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.124) has a much lower hERG inhibition liability than Ligand B (0.534). This is a significant advantage.

**Microsomal Clearance:** Ligand A (11.715 mL/min/kg) has a much lower microsomal clearance than Ligand B (56.097 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-18.304 hours) has a negative half-life, which is not physically possible. This is a major red flag. Ligand B (21.147 hours) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux liability than Ligand B (0.183).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand A's better DILI and P-gp efflux, the negative in vitro half-life is a critical flaw. Ligand B demonstrates superior binding affinity, metabolic stability (lower Cl_mic, better t1/2), and acceptable safety profiles. While solubility is a concern for both, the strong binding affinity of Ligand B makes it the more promising candidate, as potency can often outweigh minor ADME drawbacks.

Output:
1
2025-04-17 15:43:17,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.47 and 381.973 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.51) is better than Ligand B (30.29) as it is still within the acceptable range for oral absorption. Ligand B is quite low, which might suggest poor aqueous solubility.

**logP:** Ligand A (2.33) is optimal, while Ligand B (4.616) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is better balanced than Ligand B (0 HBD, 5 HBA).

**QED:** Both ligands have similar QED values (0.697 and 0.6), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (37.456 and 33.501 percentile), which is favorable.

**BBB:** Ligand A (65.025) has a moderate BBB penetration, while Ligand B (48.895) is lower. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.918) is significantly worse than Ligand B (-5.061). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.156) is better than Ligand B (-4.536), suggesting better formulation potential.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.826 and 0.919), which is excellent.

**Microsomal Clearance:** Ligand A (24.725 mL/min/kg) has significantly lower clearance than Ligand B (88.65 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (34.516 hours) has a better half-life than Ligand B (49.809 hours).

**P-gp Efflux:** Ligand A (0.266) has lower P-gp efflux than Ligand B (0.792), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.7 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 critical.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties: lower logP, better TPSA, better solubility, significantly lower microsomal clearance, longer half-life, and lower P-gp efflux. These factors collectively contribute to a more favorable pharmacokinetic profile and a higher probability of success as a drug. The slight difference in binding affinity is outweighed by the substantial improvements in ADME properties.

Output:
0
2025-04-17 15:43:17,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.486 Da) is slightly higher than Ligand B (363.483 Da), but both are acceptable.

**TPSA:** Ligand A (66.92) is better than Ligand B (78.51). Lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (A: 1.424, B: 1.93), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is better than Ligand B (2 HBD, 3 HBA). Lower numbers are generally preferred for permeability.

**QED:** Both ligands have good QED scores (A: 0.711, B: 0.858), indicating good drug-like properties.

**DILI:** Ligand A (64.172) has a higher DILI risk than Ligand B (44.552). This is a significant negative for Ligand A.

**BBB:** Both have acceptable BBB penetration (A: 77.162, B: 82.202). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.472) has a very poor Caco-2 permeability, while Ligand B (-5.189) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.348) has poor solubility, while Ligand B (-2.875) is slightly better. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.723) has a slightly higher hERG risk than Ligand B (0.52).

**Microsomal Clearance:** Ligand A (98.323) has significantly higher microsomal clearance than Ligand B (22.188). This suggests Ligand A will be rapidly metabolized, leading to lower exposure.

**In vitro Half-Life:** Ligand A (-43.793) has a very short half-life, while Ligand B (-9.877) is better.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.137, B: 0.078).

**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.

**Conclusion:**

Ligand B is significantly better. While both have issues with Caco-2 permeability and solubility, Ligand B has a much stronger binding affinity, lower DILI risk, lower microsomal clearance, and a longer half-life. The significantly better affinity of Ligand B outweighs the minor ADME drawbacks. Ligand A's very poor affinity and high clearance make it a less viable candidate.

Output:
1
2025-04-17 15:43:17,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (386.901 and 356.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.86) is slightly higher than Ligand B (64.36). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.903) is within the optimal 1-3 range. Ligand B (4.215) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.739 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A (37.03) has a significantly lower DILI risk than Ligand B (77.433), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (82.745) has a higher BBB penetration than Ligand B (35.401).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close.

**Aqueous Solubility:** Ligand A (-2.98) has better solubility than Ligand B (-4.651).

**hERG:** Ligand A (0.264) shows a lower hERG inhibition liability than Ligand B (0.463), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (32.998) has lower microsomal clearance than Ligand B (67.171), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (59.337) has a significantly longer in vitro half-life than Ligand A (10.228). This is a strong advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.14) has lower P-gp efflux liability than Ligand B (0.459), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. However, it has higher logP, higher DILI risk, lower solubility, and higher P-gp efflux. Ligand A has better ADME properties (lower DILI, better solubility, lower hERG, lower P-gp efflux, better metabolic stability), but its affinity is weaker.

Considering the enzyme-specific priorities, the binding affinity advantage of Ligand B is significant. While the ADME properties of Ligand B are less ideal, the potency difference is large enough to warrant further optimization of Ligand B. The DILI and solubility issues could potentially be addressed through structural modifications.

Output:
1
2025-04-17 15:43:17,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.451 and 350.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is well below the 140 threshold for good absorption, and favorable for kinase inhibitors. Ligand B (133.39) is higher, but still within acceptable limits, though potentially impacting permeability slightly.

**logP:** Ligand A (2.218) is optimal (1-3). Ligand B (-0.444) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is excellent. Ligand B (3 HBD, 7 HBA) is acceptable, but higher donor count could affect permeability.

**QED:** Both ligands have reasonable QED scores (0.783 and 0.637), indicating good drug-like properties.

**DILI:** Ligand A (72.043) has a slightly higher DILI risk than Ligand B (62.893), but both are still within acceptable ranges (<60 is good).

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (76.154) is slightly better than Ligand B (58.278).

**Caco-2:** Ligand A (-4.82) is significantly better than Ligand B (-5.516), indicating better intestinal absorption.

**Solubility:** Ligand A (-2.203) is better than Ligand B (-1.946), though both are negative, suggesting limited solubility.

**hERG:** Ligand A (0.441) has a much lower hERG risk than Ligand B (0.042), which is a significant advantage.

**Microsomal Clearance:** Ligand A (31.517) has higher microsomal clearance than Ligand B (-3.288), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-3.326) has a shorter half-life than Ligand B (10.045), further supporting Ligand B's better metabolic stability.

**P-gp Efflux:** Ligand A (0.505) has slightly better P-gp efflux properties than Ligand B (0.018).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol) - a difference of 1.2 kcal/mol. This is a substantial advantage that can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having better Caco-2 permeability and a lower hERG risk, Ligand B's significantly stronger binding affinity (-8.3 vs -7.1 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) make it the more promising drug candidate for SRC kinase inhibition. The lower logP of Ligand B is a concern, but the potency advantage is substantial.

Output:
1
2025-04-17 15:43:17,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 345.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is well below the 140 threshold for good absorption and is favorable. Ligand B (132.13) is still within acceptable range, but less optimal.

**logP:** Ligand A (0.835) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (-0.18) is even lower, raising concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is within acceptable limits. Ligand B (5 HBD, 5 HBA) is also acceptable, though at the higher end for donors.

**QED:** Both ligands have similar QED values (0.56 and 0.524), indicating reasonable drug-likeness.

**DILI:** Ligand A (39.434) has a much lower DILI risk than Ligand B (79.915), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (65.452) is better than Ligand B (25.979).

**Caco-2 Permeability:** Ligand A (-4.652) is poor, while Ligand B (-5.651) is even worse, both indicating poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.209) is better than Ligand B (-3.166), although both are quite poor.

**hERG Inhibition:** Ligand A (0.219) has a very low hERG risk, a major advantage. Ligand B (0.124) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (0.421) has a much lower Cl_mic, indicating better metabolic stability, which is crucial for an enzyme target. Ligand B (-19.769) has a very high Cl_mic, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-0.787) has a slightly better half-life than Ligand B (35.907).

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux, which is favorable. Ligand B (0.014) is even lower.

**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.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, its significantly higher DILI risk and very high microsomal clearance are major drawbacks. The poor solubility and permeability of both compounds are concerning, but can potentially be addressed through formulation strategies. However, the metabolic instability of Ligand B is a more difficult hurdle to overcome. Ligand A, despite the weaker binding, presents a much more favorable ADME-Tox profile, particularly regarding liver toxicity and metabolic stability, which are critical for kinase inhibitors. The difference in binding affinity (2 kcal/mol) might be overcome with further optimization of Ligand A, while mitigating the issues with Ligand B would be far more challenging.

Output:
0
2025-04-17 15:43:17,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (389.901 and 374.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.75) is better than Ligand B (92.34) as it's closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.936 and 1.786, respectively), falling within the 1-3 range. Ligand A is slightly better.

**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 (0.723) has a better QED score than Ligand B (0.5), indicating a more drug-like profile.

**DILI:** Ligand B (57.348) has a lower DILI risk than Ligand A (66.615), which is preferable.

**BBB:** Both ligands have reasonable BBB penetration (56.34 and 75.805, respectively). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.376 and -4.703).

**Aqueous Solubility:** Both ligands have negative solubility values (-2.964 and -2.54), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.123 and 0.215, respectively).

**Microsomal Clearance:** Ligand B (30.955) has significantly lower microsomal clearance than Ligand A (67.392), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (25.44 hours) has a longer in vitro half-life than Ligand A (76.498 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.232 and 0.151, respectively).

**Binding Affinity:** Ligand B (-8.3 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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.3 vs -7.1 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher DILI risk. The better QED score also supports Ligand B. Addressing the solubility issue through formulation strategies would be a priority in further development.

Output:
1
2025-04-17 15:43:17,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.348 and 390.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.64) is higher than Ligand B (52.65). Both are below the 140 threshold for good absorption, but Ligand B is preferable.

**logP:** Ligand A (1.135) is slightly lower than the optimal 1-3 range, while Ligand B (2.408) is well within the range. Ligand B is better here.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (3), but both are acceptable.

**QED:** Both ligands have good QED scores (0.667 and 0.734), indicating drug-like properties.

**DILI:** Ligand A (39.55) has a much lower DILI risk than Ligand B (12.834), making it safer. This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.721) has a higher BBB score than Ligand B (66.111), but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.441) has a worse Caco-2 permeability than Ligand B (-5.122).

**Aqueous Solubility:** Ligand A (-1.377) has better solubility than Ligand B (-2.404). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.46 and 0.531), which is good.

**Microsomal Clearance:** Ligand A (2.875) has significantly lower microsomal clearance than Ligand B (6.437), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-13.641) has a much longer in vitro half-life than Ligand B (9.5), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.059).

**Binding Affinity:** Ligand A (-9.0) has a slightly better binding affinity than Ligand B (-8.5). While both are good, the 0.5 kcal/mol difference is noticeable.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While Ligand B has a slightly better logP and TPSA, the safety and pharmacokinetic advantages of Ligand A outweigh these minor differences, especially for an enzyme target where metabolic stability is crucial.

Output:
1
2025-04-17 15:43:17,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (359.348 and 353.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.69) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (92.37) is still within the acceptable range for oral absorption (<140), but less optimal than A.

**3. logP:** Both ligands have good logP values (3.026 and 2.216), falling within the 1-3 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 (4 and 5, respectively), below the limit of 10.

**6. QED:** Both ligands have reasonable QED scores (0.882 and 0.747), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (43.66 and 39.356), both below the 40 threshold.

**8. BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A has a significantly higher BBB penetration percentile (96.937) compared to Ligand B (80.962).

**9. Caco-2 Permeability:** Ligand A (-4.643) has a more favorable Caco-2 permeability value than Ligand B (-5.04), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.733) shows better aqueous solubility than Ligand B (-1.809). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.583 and 0.274), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand B (-7.699) has a *much* lower (better) microsomal clearance than Ligand A (13.469). This suggests greater metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (14.234 hours) has a significantly longer in vitro half-life than Ligand A (-2.011 hours). This is a major advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.248 and 0.028).

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). The difference is 2.5 kcal/mol, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts 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 an enzyme target like SRC kinase, metabolic stability and duration of action are critical. The 2.5 kcal/mol difference in binding affinity, while notable, is likely surmountable with further optimization of Ligand B. The better solubility and permeability of Ligand A are also beneficial, but the improved metabolic profile of Ligand B is more impactful for an enzyme inhibitor.

Output:
1
2025-04-17 15:43:17,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (406.328 Da and 372.868 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.19) is slightly higher than Ligand B (55.57), both are acceptable for oral absorption (<140).

**logP:** Ligand A (2.375) is within the optimal 1-3 range. Ligand B (3.697) is a bit higher, potentially leading to solubility issues, but still within a reasonable range.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good, potentially aiding membrane permeability.

**H-Bond Acceptors:** Both ligands (A: 5, B: 4) are well within the acceptable limit of 10.

**QED:** Ligand A (0.801) has a significantly better QED score than Ligand B (0.49), indicating a more drug-like profile.

**DILI:** Ligand A (32.377) has a lower DILI risk than Ligand B (21.287), both are good.

**BBB:** Ligand A (74.758) and Ligand B (95.89) are both reasonably high, but not critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.255) is worse than Ligand B (-4.55), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.948) is worse than Ligand B (-3.626), indicating lower solubility.

**hERG Inhibition:** Both ligands (A: 0.576, B: 0.593) have similar, and acceptable, hERG inhibition liabilities.

**Microsomal Clearance:** Ligand A (4.748) has a much lower microsomal clearance than Ligand B (104.579), suggesting better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (54.829) has a longer half-life than Ligand B (-6.712), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.181) has lower P-gp efflux than Ligand B (0.777), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 kcal/mol and -8.7 kcal/mol), with Ligand B being slightly better. However, the difference is small and can be potentially overcome with further optimization.

**Conclusion:**

Despite Ligand B having slightly better binding affinity and Caco-2 permeability, Ligand A is the more promising candidate. Its superior QED score, significantly lower microsomal clearance, longer half-life, and lower P-gp efflux outweigh the minor differences in binding affinity and permeability. The better metabolic stability of Ligand A is crucial for an enzyme target like SRC kinase, as it suggests a longer duration of action and potentially lower dosing requirements.

Output:
0
2025-04-17 15:43:17,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.39 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.49) is better than Ligand B (79.7). Both are below the 140 threshold for oral absorption, but Ligand B is closer to the 90 threshold for CNS penetration, though that's not a primary concern here.

**logP:** Ligand A (1.361) is optimal (1-3). Ligand B (-0.337) is slightly low, potentially hindering permeation.

**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 the same HBA count (6), which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.763 and 0.808), indicating good drug-like properties.

**DILI:** Ligand A (71.384) has a higher DILI risk than Ligand B (39.977). This is a significant drawback for Ligand A.

**BBB:** Ligand A (38.891) and Ligand B (67.623) both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.918) has poor Caco-2 permeability, while Ligand B (-5.08) is also poor. Both are quite low, indicating potential absorption issues.

**Aqueous Solubility:** Ligand A (-3.505) has poor aqueous solubility, while Ligand B (-2.451) is slightly better. Solubility is a concern for both, but less so for Ligand B.

**hERG Inhibition:** Ligand A (0.143) has a slightly higher hERG risk than Ligand B (0.341), but both are relatively low.

**Microsomal Clearance:** Ligand A (30.584) has a higher microsomal clearance than Ligand B (26.605), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.524) has a significantly longer in vitro half-life than Ligand A (-31.056), which is a major advantage.

**P-gp Efflux:** Ligand A (0.1) has lower P-gp efflux than Ligand B (0.014), which is better.

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux, but suffers from poor solubility, permeability, higher DILI risk, and lower metabolic stability (higher clearance, shorter half-life). Ligand B, while having a significantly weaker binding affinity, exhibits better ADME properties: lower DILI risk, better solubility, longer half-life, and acceptable hERG risk.

Given the importance of metabolic stability and safety (DILI) for an enzyme target like SRC kinase, and the substantial difference in half-life, Ligand B is the more promising candidate, despite its weaker binding affinity. The affinity difference is large enough that optimization of Ligand B could potentially achieve a comparable binding affinity while retaining its superior ADME profile.

Output:
1
2025-04-17 15:43:17,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.542 Da) is slightly higher than Ligand B (352.475 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (86.71). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (3.672) is within the optimal range (1-3), while Ligand B (1.365) is at the lower end. A lower logP can sometimes hinder permeability.

**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, falling within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.787, B: 0.656), indicating good drug-like properties.

**DILI:** Ligand A (51.609) has a higher DILI risk than Ligand B (9.655). This is a significant concern.

**BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (82.784) has a higher BBB percentile than Ligand B (53.16), but it's not a primary driver in this case.

**Caco-2 Permeability:** Ligand A (-4.835) and Ligand B (-4.942) both have negative Caco-2 values, which is unusual and requires further investigation. It suggests poor permeability.

**Aqueous Solubility:** Ligand A (-4.468) and Ligand B (-0.991) both have negative solubility values. This is a significant concern for both compounds.

**hERG Inhibition:** Ligand A (0.694) has a slightly higher hERG risk than Ligand B (0.181). Lower hERG is preferred.

**Microsomal Clearance:** Ligand B (10.231) has a significantly lower microsomal clearance than Ligand A (44.765). This suggests better metabolic stability for Ligand B, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-10.89) has a negative half-life, which is not physically possible and indicates an issue with the data or the compound's stability. Ligand A (10.916) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.427) has lower P-gp efflux than Ligand B (0.025), which is favorable.

**Binding Affinity:** Ligand B (-9.6 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.

**Conclusion:**

Despite the concerns around solubility and Caco-2 permeability for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.6 vs -7.4 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, its lower microsomal clearance suggests better metabolic stability, and its lower DILI risk is also favorable. The negative half-life for Ligand B is a red flag, but the superior binding affinity makes it worth further investigation to determine the source of this anomaly. Ligand A's higher DILI risk is a significant drawback.

Output:
1
2025-04-17 15:43:17,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.45 & 354.49 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is better than Ligand B (87.66) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.86 & 1.32), 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=4) as it has fewer HBDs, which generally improves permeability. Both are within acceptable limits.

**QED:** Ligand A (0.763) has a higher QED score than Ligand B (0.552), indicating a more drug-like profile.

**DILI:** Ligand A (32.07%) has a significantly lower DILI risk than Ligand B (10.20%). Both are good, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.51%) has a higher BBB penetration than Ligand B (57.62%).

**Caco-2 Permeability:** Ligand A (-4.875) has a slightly better Caco-2 permeability than Ligand B (-4.68), suggesting better absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.448 and -2.949 respectively). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.324 and 0.285 respectively).

**Microsomal Clearance:** Ligand A (40.83 mL/min/kg) has a lower microsomal clearance than Ligand B (59.63 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.627 hours) has a longer in vitro half-life than Ligand B (7.763 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.281 and 0.085 respectively).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly better binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A demonstrates superior ADME properties (lower DILI, better metabolic stability, better QED, better permeability), the significantly stronger binding affinity of Ligand B (-7.7 vs -9.3 kcal/mol) is a critical advantage for an enzyme target. The difference in affinity is large enough to outweigh the ADME concerns, especially since both ligands are within acceptable ranges for most parameters. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:43:17,460 - INFO - Batch 403 complete. Total preferences: 6448
2025-04-17 15:43:17,461 - INFO - Processing batch 404/512...
2025-04-17 15:43:58,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.403 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.16) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (87.66) is well within the acceptable range.

**logP:** Both ligands have good logP values (1.673 and 1.26), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 7 HBA) is better than Ligand B (3 HBD, 4 HBA) as it has fewer HBDs. Both are within acceptable limits.

**QED:** Ligand A (0.826) has a significantly better QED score than Ligand B (0.615), indicating a more drug-like profile.

**DILI:** Ligand B (21.946) has a much lower DILI risk than Ligand A (70.26), which is a significant advantage.

**BBB:** Ligand A (62.699) has a slightly better BBB penetration than Ligand B (44.203), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.726) has a lower Caco-2 permeability than Ligand B (-5.375), suggesting potentially poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.316) has a slightly better aqueous solubility than Ligand B (-2.426).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.237 and 0.222), which is excellent.

**Microsomal Clearance:** Ligand B (4.911) has significantly lower microsomal clearance than Ligand A (26.409), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (31.323) has a longer in vitro half-life than Ligand A (-28.563), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.176 and 0.058).

**Binding Affinity:** Ligand B (-10.0) has a significantly stronger binding affinity than Ligand A (-8.4), a difference of 1.6 kcal/mol. This is a major advantage, potentially outweighing minor ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better QED and solubility, Ligand B overwhelmingly wins due to its significantly stronger binding affinity (-10.0 vs -8.4 kcal/mol), much lower DILI risk (21.946 vs 70.26), and superior metabolic stability (lower Cl_mic and longer t1/2). The stronger binding affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:43:58,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.738 Da) is slightly higher, but acceptable. Ligand B (348.539 Da) is also good.

**TPSA:** Ligand A (41.57) is well below the 140 threshold and suitable for oral absorption. Ligand B (49.22) is also good, below the threshold.

**logP:** Ligand A (4.496) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.146) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 3, Ligand B: 6) counts.

**QED:** Both ligands have similar and good QED scores (Ligand A: 0.787, Ligand B: 0.78), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 57.038, which is approaching the higher risk zone (>60). Ligand B has a very low DILI risk (4.265), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.621) and Ligand B (75.921) are both reasonable.

**Caco-2 Permeability:** Ligand A (-4.753) and Ligand B (-5.426) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -5.209, Ligand B: -0.664). Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.92, Ligand B: 0.872).

**Microsomal Clearance:** Ligand A has a high microsomal clearance (81.452), indicating poor metabolic stability. Ligand B has a significantly lower clearance (-40.031), a major advantage.

**In vitro Half-Life:** Ligand A has a moderate half-life (51.433 hours). Ligand B has a very short half-life (10.099 hours), a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.758, Ligand B: 0.02).

**Binding Affinity:** Ligand A has a better binding affinity (-7.7 kcal/mol) than Ligand B (-6.9 kcal/mol). This is a 0.8 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand A has a stronger binding affinity, which is a key factor for enzyme inhibitors. However, it suffers from a higher DILI risk, higher metabolic clearance, and poor aqueous solubility. Ligand B has a much better safety profile (DILI), significantly improved metabolic stability (lower Cl_mic), and slightly better solubility, but its binding affinity is weaker and its half-life is short.

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the improved metabolic stability and safety profile of Ligand B outweigh the slightly weaker binding affinity. While the affinity difference is notable, it might be addressable through further optimization, whereas fixing the poor metabolic stability of Ligand A would likely require more substantial structural changes. The short half-life of Ligand B is a concern, but could potentially be addressed through prodrug strategies or formulation approaches.

Output:
1
2025-04-17 15:43:58,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (377.388 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.36) is slightly above the optimal <140 for oral absorption, while Ligand B (78.51) is well within the range.

**logP:** Both ligands have good logP values (1.2 and 1.078), falling within the 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:** Both ligands have reasonable QED scores (0.836 and 0.706), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 62.737, which is moderately high, while Ligand B has a much lower DILI risk of 16.053, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (93.37 and 63.358), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.928) has poor Caco-2 permeability, while Ligand B (-5.16) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-2.957) has poor aqueous solubility, while Ligand B (-1.858) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.69) has a moderate hERG risk, while Ligand B (0.104) has a very low hERG risk. This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (-10.748) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (5.584) has moderate clearance, suggesting faster metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (5.114) has a moderate half-life, while Ligand B (-1.555) has a very short half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.032).

**Binding Affinity:** Ligand B (-8.7 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 excels in metabolic stability (low Cl_mic, moderate t1/2) and has a reasonable binding affinity. However, it suffers from poor solubility, poor permeability, and a moderately high DILI risk and moderate hERG risk.

Ligand B has a significantly lower DILI risk and a very low hERG risk, and slightly better binding affinity. However, it has a shorter half-life and moderate clearance.

Considering the enzyme-specific priorities, metabolic stability and minimizing toxicity (DILI, hERG) are crucial. While Ligand A has better metabolic stability, the lower DILI and hERG risk of Ligand B are more important. The slight difference in binding affinity is less critical than the improved safety profile of Ligand B.

Output:
1
2025-04-17 15:43:58,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.434 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (49.41), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.076) is optimal, while Ligand B (3.783) is approaching the upper limit.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, well below the 5 threshold.

**H-Bond Acceptors:** Both ligands (3) are well below the 10 threshold.

**QED:** Both ligands have good QED scores (0.721 and 0.839), indicating drug-likeness.

**DILI:** Ligand A (26.134) has a significantly lower DILI risk than Ligand B (37.999), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand A (89.608) has better BBB penetration than Ligand B (77.084), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.595) has better Caco-2 permeability than Ligand B (-5.072).

**Aqueous Solubility:** Ligand A (-2.315) has better aqueous solubility than Ligand B (-4.318).

**hERG:** Both ligands have very low hERG inhibition risk (0.563 and 0.504).

**Microsomal Clearance:** Ligand A (18.505) has significantly lower microsomal clearance than Ligand B (51.527), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.096) has a better in vitro half-life than Ligand B (-9.378).

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.38).

**Binding Affinity:** Ligand B (0.0) has a significantly better binding affinity than Ligand A (-8.2). This is a substantial advantage.

**Conclusion:**

While Ligand A excels in ADME properties (lower DILI, better metabolic stability, solubility, permeability, and lower efflux), Ligand B has a much stronger binding affinity (-8.2 kcal/mol vs 0.0 kcal/mol). Given that we are targeting an enzyme (SRC kinase), potency is the most critical factor. The significant binding affinity advantage of Ligand B outweighs the ADME drawbacks, which are still within reasonable ranges.

Output:
1
2025-04-17 15:43:58,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 357.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is better than Ligand B (38.13) as it is still within the acceptable range for oral absorption (<140), while ligand B is significantly lower.

**logP:** Ligand A (1.428) is optimal, while Ligand B (3.89) is approaching the upper limit.

**H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Ligand A (5) is good, while Ligand B (3) is also acceptable.

**QED:** Ligand A (0.779) is better than Ligand B (0.695), indicating a more drug-like profile.

**DILI:** Ligand A (35.169) has a slightly higher DILI risk than Ligand B (30.748), but both are below the concerning threshold of 60.

**BBB:** Ligand A (65.413) is lower than Ligand B (94.61), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.78) is worse than Ligand B (-4.202), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.786) is significantly better than Ligand B (-3.763). Solubility is a key factor for enzyme inhibitors.

**hERG Inhibition:** Ligand A (0.071) has a much lower hERG risk than Ligand B (0.626). This is a critical advantage.

**Microsomal Clearance:** Ligand A (15.497) has a significantly lower Cl_mic than Ligand B (60.136), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.041) has a better half-life than Ligand B (-10.97).

**P-gp Efflux:** Ligand A (0.004) has a much lower P-gp efflux liability than Ligand B (0.34).

**Binding Affinity:** Ligand B (-8.9) has a significantly stronger binding affinity than Ligand A (-5.7). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.9 kcal/mol vs -5.7 kcal/mol). This is a major advantage for an enzyme inhibitor. However, it has some drawbacks in terms of metabolic stability (higher Cl_mic), solubility, and hERG risk. Ligand A has better ADME properties (solubility, hERG, Cl_mic, Pgp) and a good QED score, but its binding affinity is considerably weaker.

The difference in binding affinity (3.2 kcal/mol) is substantial enough to potentially overcome the ADME liabilities of Ligand B, especially given that the DILI and hERG risks are not excessively high. Improved metabolic stability and solubility could be addressed through further optimization.

Output:
1
2025-04-17 15:43:58,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 360.336 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (88.33 and 87.32) below 140, suggesting good oral absorption potential.

**logP:** Both ligands have logP values (1.812 and 1.152) 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 good QED scores (0.898 and 0.843), indicating drug-like properties.

**DILI:** Ligand A (44.397) has a lower DILI risk than Ligand B (65.917), which is a significant advantage. Both are below the concerning threshold of 60, but A is preferable.

**BBB:** Both have reasonable BBB penetration, but Ligand A (74.719) is slightly better than Ligand B (67.158). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.187 and -4.933). These values are unusual and suggest poor permeability, but are likely reported as logP values and are therefore negative.

**Aqueous Solubility:** Both have negative solubility values (-2.984 and -3.015), again likely logS values and suggesting poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.137) shows a lower hERG inhibition liability than Ligand B (0.387), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (58.323) has a higher microsomal clearance than Ligand B (5.221), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-5.054) has a longer in vitro half-life than Ligand A (-6.787), indicating better stability.

**P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux liability than Ligand B (0.018), which is a slight advantage.

**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 not substantial enough to outweigh other factors.

**Overall:**

Ligand A has advantages in DILI risk, hERG inhibition, and P-gp efflux. However, Ligand B has a significantly better in vitro half-life and slightly better binding affinity. The solubility and Caco-2 permeability are poor for both, but the DILI and hERG profiles are critical for kinase inhibitors. Given the importance of minimizing toxicity and the relatively small difference in binding affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 15:43:58,094 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 346.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.61) is better than Ligand B (49.41) as it is still within the acceptable range for oral absorption, while ligand B is excellent.

**logP:** Ligand A (1.274) is optimal, while Ligand B (3.953) is approaching the upper limit. This could potentially lead to solubility issues or off-target effects.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit.

**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 similar QED values (0.816 and 0.784), indicating good drug-likeness.

**DILI:** Both ligands have similar, low DILI risk (30.012 and 30.593 percentile).

**BBB:** Ligand A (59.519) has a lower BBB penetration than Ligand B (78.558). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.779) has a worse Caco-2 permeability than Ligand B (-4.863).

**Aqueous Solubility:** Ligand A (-1.053) has a better aqueous solubility than Ligand B (-4.056). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.213 and 0.319).

**Microsomal Clearance:** Ligand A (40.41) has a better microsomal clearance than Ligand B (59.863), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.279) has a longer in vitro half-life than Ligand B (-1.734). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.055 and 0.409).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial factor for enzyme inhibitors. The 7.3 kcal/mol difference is substantial and likely outweighs the minor ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A having better solubility and metabolic stability, the significantly superior binding affinity of Ligand B (-7.3 kcal/mol vs -0.0 kcal/mol) makes it the more promising drug candidate. The difference in binding affinity is large enough to compensate for the slightly higher logP and lower solubility of Ligand B.

Output:
1
2025-04-17 15:43:58,094 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (349.475 and 348.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.32) is better than Ligand B (95.57), both are acceptable but closer to the upper limit for good oral absorption (<=140).

**3. logP:** Ligand A (2.793) is optimal, while Ligand B (1.504) is slightly lower, potentially impacting permeability.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (Ligand A: 3, Ligand B: 1), falling under the threshold of 5.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is better than Ligand B (9), being closer to the ideal threshold of <=10.

**6. QED:** Both ligands have similar QED values (Ligand A: 0.706, Ligand B: 0.695), indicating good drug-like properties.

**7. DILI:** Ligand B (41.877) has a lower DILI risk than Ligand A (49.477), which is preferable.

**8. BBB:** Ligand B (73.905) has significantly better BBB penetration than Ligand A (38.813). However, since SRC is not a CNS target, this is less crucial.

**9. Caco-2 Permeability:** Ligand A (-4.904) has better Caco-2 permeability than Ligand B (-5.351).

**10. Aqueous Solubility:** Ligand B (-1.856) has better aqueous solubility than Ligand A (-4.116), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.326) exhibits lower hERG inhibition risk compared to Ligand B (0.131), which is a significant advantage.

**12. Microsomal Clearance (Cl_mic):** Ligand B (20.453) has a much lower microsomal clearance than Ligand A (80.35), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand B (17.822) has a longer in vitro half-life than Ligand A (-23.595), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux than Ligand B (0.05), which is slightly preferable.

**15. 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 substantial and can outweigh some ADME drawbacks.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are critical. Ligand B excels in affinity and metabolic stability, and has better solubility. While Ligand A has a slightly better hERG profile, the substantial difference in binding affinity and metabolic stability of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 15:43:58,094 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.39 and 371.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (85.09 and 81.67) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.285) is optimal, while Ligand B (0.602) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, well within acceptable limits. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.692) has a better QED score than Ligand B (0.492), indicating a more drug-like profile.

**DILI:** Ligand A (80.225) has a higher DILI risk than Ligand B (18.457). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.074) has a higher BBB penetration than Ligand A (32.183), but this is not a primary concern here.

**Caco-2 Permeability:** Ligand A (-5.266) has worse Caco-2 permeability than Ligand B (-4.963). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.07) has worse solubility than Ligand B (-0.658). Solubility is important for bioavailability, making Ligand B preferable.

**hERG Inhibition:** Ligand A (0.111) has a slightly higher hERG risk than Ligand B (0.437), but both are relatively low.

**Microsomal Clearance:** Ligand A (19.11 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (-6.504 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (46.427 hours) has a significantly longer half-life than Ligand B (-10.242 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.372) has lower P-gp efflux than Ligand B (0.005), which is preferable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). The difference is 0.4 kcal/mol, which is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has better solubility, a lower DILI risk, and slightly better binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic, longer half-life), better P-gp efflux, and a higher QED score. The DILI risk of Ligand A is a significant concern, but the improved metabolic stability and half-life are crucial for an enzyme target. The slightly better binding affinity of Ligand B isn't enough to overcome the metabolic liabilities.

Output:
1
2025-04-17 15:43:58,094 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.816 and 351.372 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.33) is better than Ligand B (48.13), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (4.388) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (3.334) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (2 & 2) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.708 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (53.044), which is preferable. Both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (88.29) has a higher BBB score than Ligand A (70.764), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.714 and -4.748), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.702 and -3.487), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.842) has a slightly higher hERG risk than Ligand B (0.913), meaning Ligand B is preferable.

**Microsomal Clearance:** Ligand B (-15.836) has significantly lower (better) microsomal clearance than Ligand A (79.541). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (13.285 hours) has a much longer half-life than Ligand A (40.671 hours).

**P-gp Efflux:** Ligand A (0.694) has lower P-gp efflux than Ligand B (0.252), which is preferable.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.7 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, the significantly stronger binding affinity of Ligand A (-7.7 kcal/mol vs -9.7 kcal/mol) and its lower P-gp efflux outweighs its slightly higher DILI and hERG risk. The better metabolic stability of ligand B is a plus, but the potency difference is substantial. Given that we are targeting an enzyme, potency is paramount.

Output:
0
2025-04-17 15:43:58,094 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (375.837 and 365.905 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.27) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (52.65) is well within the ideal range.

**3. logP:** Both ligands have logP values (2.921 and 3.866) within the optimal 1-3 range. Ligand B is slightly higher, potentially raising concerns about 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 4 HBAs, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.892 and 0.884), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 94.882, which is high. Ligand B has a much lower DILI risk of 43.273, which is good. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (38.426) has poor BBB penetration, while Ligand B (87.941) has good BBB penetration. While not a primary concern for a kinase inhibitor, it's a slight advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.873 and -4.52), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.08 and -4.588), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.594) has a slightly higher hERG risk than Ligand B (0.751), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (11.021) has lower microsomal clearance than Ligand B (46.02), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (76.967) has a longer in vitro half-life than Ligand B (60.57), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.277) has lower P-gp efflux than Ligand B (0.097), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-8.2 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 better safety profile (lower DILI) and significantly higher binding affinity. While both have poor solubility and permeability, the strong binding affinity of Ligand B is a critical advantage for an enzyme inhibitor. The better metabolic stability of Ligand A is appealing, but the significantly higher DILI risk and weaker binding make it less attractive. The difference in binding affinity (>1.5 kcal/mol) is substantial enough to favor Ligand B despite the other issues.

Output:
1
2025-04-17 15:43:58,094 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (352.435 and 351.451 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (112.81) is slightly higher than Ligand B (109.61), but both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.12) is within the optimal range, while Ligand B (2.076) is approaching the higher end.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), both are acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (4), but both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.347 and 0.43), indicating moderate drug-likeness.

**7. DILI:** Ligand A (25.436) has a significantly lower DILI risk than Ligand B (20.589), which is a major advantage.

**8. BBB:** Ligand A (62.699) has a higher BBB percentile than Ligand B (22.257), but BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.704) has worse Caco-2 permeability than Ligand B (-4.858). Both are very poor.

**10. Aqueous Solubility:** Ligand A (-2.107) has worse aqueous solubility than Ligand B (-1.184). Both are very poor.

**11. hERG Inhibition:** Ligand A (0.496) has a slightly higher hERG risk than Ligand B (0.178), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (46.338) has a higher microsomal clearance than Ligand B (18.578), suggesting lower metabolic stability. This is a significant disadvantage.

**13. In vitro Half-Life:** Ligand B (15.725) has a much longer in vitro half-life than Ligand A (-3.001), indicating better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.039), which is favorable.

**15. 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 outweigh other factors.

**Enzyme-Specific Priorities:** For a kinase inhibitor (SRC), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk, which are crucial for a viable drug candidate. Although Ligand A has a slightly better binding affinity, the differences in metabolic stability and DILI risk are more important.

Output:
1
2025-04-17 15:43:58,095 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.487 and 379.295 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (62.63), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.509 and 3.278) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5), both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.686 and 0.668), indicating good drug-likeness.

**DILI:** Ligand A (17.255) has a significantly lower DILI risk than Ligand B (36.758). This is a substantial advantage.

**BBB:** Both ligands have good BBB penetration (75.805 and 70.997), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.899) is better than Ligand B (-5.428), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.035) is better than Ligand B (-2.678), indicating better solubility.

**hERG Inhibition:** Ligand A (0.261) has a lower hERG inhibition liability than Ligand B (0.714). This is a significant safety advantage.

**Microsomal Clearance:** Ligand A (58.096) has higher microsomal clearance than Ligand B (11.37), meaning it is less metabolically stable. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-11.814) has a shorter half-life than Ligand B (7.819). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux than Ligand B (0.231), which is favorable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand A has better ADME properties (lower DILI, hERG, better solubility, permeability, and P-gp efflux), Ligand B's substantially stronger binding affinity (-9.5 vs -7.3 kcal/mol) is a critical advantage for an enzyme inhibitor. The improved potency is likely to outweigh the slightly higher DILI and hERG risks, and the lower metabolic stability can be addressed through structural modifications in later optimization stages.

Output:
1
2025-04-17 15:43:58,095 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (382.53 & 359.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is slightly higher than Ligand B (28.6). Both are below the 140 threshold for good absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (2.66 & 3.95), 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 0 HBD and acceptable HBA counts (4 & 5 respectively), satisfying the criteria.

**QED:** Both ligands have acceptable QED values (0.75 & 0.68), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (60.22%) compared to Ligand B (23.81%). This is a substantial negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B is significantly better (93.33% vs 71.00%). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**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 have negative solubility values, indicating poor solubility. Ligand A (-5.48) is slightly worse than Ligand B (-4.34).

**hERG:** Both ligands have similar hERG risk (0.86 & 0.93), which is acceptable.

**Microsomal Clearance:** Ligand A (103.90) has higher microsomal clearance than Ligand B (84.58), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (19.62 hours) than Ligand A (-24.48 hours - a negative value). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.47 & 0.84).

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Conclusion:**

Despite having equal binding affinity, Ligand B is the superior candidate. It exhibits significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better BBB penetration. While both have poor predicted solubility and permeability, Ligand B's overall profile is more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 15:43:58,095 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the optimal <140, but acceptable. Ligand B (70.67) is well within the ideal range.

**logP:** Ligand A (2.124) is within the optimal 1-3 range. Ligand B (0.666) is slightly below, potentially impacting permeability.

**H-Bond Donors:** Both ligands have 2-3 HBD, which is acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.706 and 0.717), indicating good drug-likeness.

**DILI:** Ligand A (26.599) has a lower DILI risk than Ligand B (32.261), which is favorable.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2:** Both 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.

**Solubility:** Ligand A (-3.392) has worse solubility than Ligand B (-1.732). Solubility is a key factor for kinase inhibitors.

**hERG:** Both ligands have very low hERG inhibition risk (0.106 and 0.318), which is excellent.

**Microsomal Clearance:** Ligand B (-8.381) has significantly *lower* (better) microsomal clearance than Ligand A (47.128), indicating greater metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (2.242) has a slightly better in vitro half-life than Ligand A (-39.714).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.045), which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.9 and -8.8 kcal/mol). This difference is negligible.

**Conclusion:**

While both ligands have good overall profiles, Ligand B is more promising due to its significantly improved metabolic stability (lower Cl_mic) and slightly better solubility and half-life. The slightly lower logP is a minor concern, but the substantial improvement in metabolic stability outweighs this. The similar binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 15:43:58,095 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (420.782 Da) is slightly higher than Ligand B (353.417 Da), but both are acceptable.

**TPSA:** Ligand A (19.37) is excellent, well below the 140 threshold for good absorption. Ligand B (61.36) is still reasonable but higher, potentially impacting absorption slightly.

**logP:** Ligand A (4.913) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.094) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (1 HBD, 5 HBA) is also good, within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.703, B: 0.878), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 33.695, B: 42.264), below the 60 threshold.

**BBB:** Both ligands have high BBB penetration (A: 98.333, B: 91.392), which isn't critical for a non-CNS target like SRC, but isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.784 and -4.768). This is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, given the other properties, we'll consider this a data quality issue for now, but it's a flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.568 and -3.071). Similar to Caco-2, this is concerning and suggests potential formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.963, B: 0.757), which is excellent.

**Microsomal Clearance:** Ligand A (39.123 mL/min/kg) has a better (lower) clearance than Ligand B (47.344 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.418 hours) has a significantly longer half-life than Ligand B (-20.186 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.76, B: 0.207).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better metabolic stability and half-life, the substantial affinity advantage of Ligand B is likely to be more impactful. The negative solubility and Caco-2 values are concerning for both, but the superior potency of Ligand B makes it the more promising candidate, assuming these solubility issues can be addressed through formulation strategies.

Output:
1
2025-04-17 15:43:58,095 - INFO - Batch 404 complete. Total preferences: 6464
2025-04-17 15:43:58,095 - INFO - Processing batch 405/512...
2025-04-17 15:44:38,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.386 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (69.64).  A TPSA under 90 is generally favorable, and A is closer to the ideal for oral absorption (<140).

**3. logP:** Both ligands have good logP values (2.999 and 2.003), 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 (3). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.87) has a better QED score than Ligand B (0.723), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (6.979). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (96.743) has much better BBB penetration than Ligand B (63.629). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.51) is slightly better than Ligand B (-4.895), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.501) is slightly better than Ligand B (-2.366).

**11. hERG Inhibition:** Ligand A (0.882) has a slightly higher hERG risk than Ligand B (0.278). Lower is better here.

**12. Microsomal Clearance:** Ligand B (22.334) has significantly lower microsomal clearance than Ligand A (40.625), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand B (8.794) has a longer in vitro half-life than Ligand A (-11.526). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux than Ligand B (0.056), which is slightly better.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), so this doesn't differentiate them.

**Overall Assessment:**

While Ligand A has some advantages in terms of TPSA, Caco-2 permeability, solubility, and BBB penetration (which isn't crucial here), Ligand B is significantly better regarding metabolic stability (lower Cl_mic, longer t1/2) and DILI risk. The lower DILI risk and improved metabolic stability of Ligand B are critical for an enzyme inhibitor. The slightly better hERG profile of Ligand B is also a plus.

Output:
1
2025-04-17 15:44:38,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.471 Da) is slightly better positioned.

**TPSA:** Ligand A (135.6) is excellent, well below the 140 threshold for good absorption. Ligand B (46.84) is also good.

**logP:** Ligand A (-0.455) is a bit low, potentially hindering permeation. Ligand B (4.529) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is good. Ligand B (0 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.673 and 0.613), indicating good drug-likeness.

**DILI:** Ligand A (68.864) has a higher DILI risk than Ligand B (36.138), which is preferable.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase. Ligand B (90.074) has higher BBB penetration, but this is less important 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 ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.062) has a much lower hERG risk than Ligand B (0.454), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-12.003) has a much lower (better) microsomal clearance than Ligand B (50.203), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.306) has a longer half-life than Ligand B (24.959), which is desirable.

**P-gp Efflux:** Ligand A (0.011) has lower P-gp efflux than Ligand B (0.375), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from high logP, moderate DILI risk, and poor solubility. Ligand A has better ADME properties (lower hERG, better metabolic stability, lower P-gp efflux, better solubility, and lower DILI), but its binding affinity is weaker and logP is low.

Despite the affinity advantage of Ligand B, the poor ADME profile, particularly the high logP and poor solubility, raise significant concerns about its developability. The solubility issues alone could be insurmountable. Ligand A, while weaker in binding, presents a more balanced profile with better potential for optimization. The affinity difference (2 kcal/mol) *could* be overcome with medicinal chemistry efforts, while fixing the ADME issues of Ligand B would be more challenging.

Output:
0
2025-04-17 15:44:38,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.423 and 360.805 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (127.63) is slightly above the preferred <140 for good oral absorption, while Ligand B (103.87) is well within the range.

**logP:** Ligand A (0.828) is a bit low, potentially hindering permeation. Ligand B (1.196) is better, falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable.

**QED:** Ligand B (0.855) has a significantly better QED score than Ligand A (0.38), indicating a more drug-like profile.

**DILI:** Ligand A (12.059) has a much lower DILI risk than Ligand B (69.097). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.974) is lower than Ligand B (40.093).

**Caco-2 Permeability:** Ligand A (-4.952) has a significantly worse Caco-2 permeability than Ligand B (-5.369).

**Aqueous Solubility:** Ligand A (-1.035) has better aqueous solubility than Ligand B (-3.37).

**hERG:** Both ligands have very low hERG inhibition risk (0.097 and 0.172 respectively).

**Microsomal Clearance:** Ligand A (-14.561) has a much lower (better) microsomal clearance than Ligand B (-11.298), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.835) has a significantly longer in vitro half-life than Ligand A (1.998).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.058 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has better QED, Caco-2 permeability, and in vitro half-life, Ligand A excels in DILI risk and microsomal clearance, both crucial for enzyme inhibitors. The binding affinity is identical, so that doesn't differentiate them. The lower DILI and better metabolic stability of Ligand A are more important considerations for an oncology target where chronic dosing is likely. The slightly lower logP and TPSA of Ligand A are less concerning given the strong binding affinity.

Output:
0
2025-04-17 15:44:38,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.853 and 344.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.9) is slightly higher than Ligand B (68.1), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (4.011) is slightly higher than the optimal range of 1-3, potentially leading to solubility issues. Ligand B (2.433) is within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.637 and 0.793, respectively), indicating drug-like properties.

**DILI:** Ligand A (92.284) has a significantly higher DILI risk than Ligand B (36.332). This is a major concern for Ligand A.

**BBB:** This is less crucial for a non-CNS target like SRC kinase. Ligand B (74.176) has a higher BBB penetration than Ligand A (31.02).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.305 and -5.165), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.149 and -2.532), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Ligand A (0.406) has a slightly higher hERG inhibition risk than Ligand B (0.467), but both are relatively low.

**Microsomal Clearance:** Ligand B (30.159 mL/min/kg) has a lower microsomal clearance than Ligand A (46.37 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (25.399 hours) has a longer in vitro half-life than Ligand A (21.855 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.508 and 0.129, respectively).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a much stronger binding affinity. The slightly better logP also contributes to its favorability. While the solubility and permeability are concerning for both, the superior potency and safety profile of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 15:44:38,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.797 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.25 and 78.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.097) is at the higher end of the optimal range, while Ligand B (0.785) is slightly below, potentially impacting permeability.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**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 (0.547 and 0.79), indicating drug-likeness.

**DILI:** Ligand A has a high DILI risk (95.812%), which is a significant concern. Ligand B has a much lower DILI risk (19.698%), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B shows higher BBB penetration (75.301%) compared to Ligand A (57.852%).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.69 and -1.164). While not ideal, this can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.372) has a slightly higher hERG risk than Ligand B (0.24), but both are relatively low.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (115.914 mL/min/kg), indicating poor metabolic stability. Ligand B has a very low clearance (3.133 mL/min/kg), a significant advantage.

**In vitro Half-Life:** Ligand A has a moderate half-life (51.77 hours), while Ligand B has a very short half-life (3.23 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.234 and 0.006).

**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.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the superior candidate. The major deciding factors are the significantly lower DILI risk and much better metabolic stability (lower Cl_mic, though at the cost of a shorter half-life). The slightly lower logP of Ligand B is a minor concern compared to the high DILI risk of Ligand A. The poor solubility and Caco-2 values are drawbacks for both, but can be addressed during formulation.

Output:
1
2025-04-17 15:44:38,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.433 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (71.09), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.924 and 3.293), falling 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 the same number of H-bond acceptors (3), which is well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.634 and 0.721), indicating good drug-like properties.

**DILI:** Ligand B (32.183) has a significantly lower DILI risk than Ligand A (40.869), making it more favorable.

**BBB:** Ligand B (77.937) has a higher BBB penetration percentile than Ligand A (59.131), but BBB is not a primary concern for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.232) has worse Caco-2 permeability than Ligand B (-4.718), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.827) has worse aqueous solubility than Ligand B (-3.703). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.48) has a slightly lower hERG inhibition risk than Ligand B (0.664), which is favorable.

**Microsomal Clearance:** Ligand B (63.22) has a significantly higher microsomal clearance than Ligand A (16.109), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-22.205) has a much longer in vitro half-life than Ligand B (1.497), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux liability than Ligand B (0.139), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-6.4) has a significantly stronger binding affinity than Ligand A (0.0), which is a crucial advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite Ligand B's better solubility, lower DILI risk, and superior binding affinity, its significantly higher microsomal clearance and shorter half-life are major concerns for an enzyme inhibitor. Ligand A, while having a weaker binding affinity, exhibits much better metabolic stability (lower Cl_mic and longer t1/2), which is critical for maintaining therapeutic concentrations *in vivo*. The difference in binding affinity (-6.4 vs 0.0 kcal/mol) is substantial, but the metabolic liabilities of Ligand B are too significant to ignore.

Output:
0
2025-04-17 15:44:38,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.523 Da and 356.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is better than Ligand B (58.64), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.166) is within the optimal 1-3 range, while Ligand B (2.544) is also acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is well within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the 10 limit.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness. Ligand A (0.712) is slightly better than Ligand B (0.646).

**DILI:** Ligand A (6.747%) has a significantly lower DILI risk than Ligand B (10.469%). This is a major advantage for Ligand A.

**BBB:** Ligand A (54.556%) has a lower BBB penetration than Ligand B (89.88%). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.885) has worse Caco-2 permeability than Ligand B (-4.54).

**Aqueous Solubility:** Ligand A (-0.897) has better aqueous solubility than Ligand B (-2.733). This is important for bioavailability.

**hERG Inhibition:** Ligand A (0.619) has a lower hERG risk than Ligand B (0.772). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (12.918 mL/min/kg) has significantly lower microsomal clearance than Ligand B (45.339 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.078 hours) has a longer in vitro half-life than Ligand B (-2.259 hours). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.009) has lower P-gp efflux than Ligand B (0.185).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 1.1 kcal/mol, which is a notable advantage, but not overwhelming.

**Overall Assessment:**

Ligand A demonstrates a superior ADMET profile. It has lower DILI risk, lower hERG inhibition, better solubility, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has a slightly better binding affinity, the improvements in ADMET properties for Ligand A are more critical for developing a viable drug candidate, particularly for an enzyme target like SRC kinase. The improved metabolic stability and reduced toxicity risks of Ligand A outweigh the modest difference in binding affinity.

Output:
0
2025-04-17 15:44:38,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.471 and 384.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.96) is better than Ligand B (88.85) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.439 and 1.44), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.821 and 0.685), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (56.146) has a slightly higher DILI risk than Ligand B (46.181), but both are below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (69.639 and 64.948), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.764 and -4.924). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is not huge.

**Aqueous Solubility:** Both have negative solubility values (-2.833 and -2.865), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.586 and 0.516), which is good.

**Microsomal Clearance:** Ligand B (35.109) has significantly lower microsomal clearance than Ligand A (54.479), indicating better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-10.369) has a longer in vitro half-life than Ligand A (-24.638). This also supports better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.331 and 0.037), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.6 vs -6.5 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher DILI risk. The similar BBB and P-gp values are neutral. Addressing the solubility issues through formulation strategies would be a priority for further development of Ligand B.

Output:
1
2025-04-17 15:44:38,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.463 and 362.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.28) is better than Ligand B (51.22) as it is still within the acceptable range for oral absorption.

**logP:** Ligand A (1.294) is optimal, while Ligand B (4.06) is at the higher end, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.84 and 0.843), indicating good drug-likeness.

**DILI:** Ligand A (18.224) has a significantly lower DILI risk than Ligand B (63.513). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (82.396) is slightly better than Ligand A (71.229). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.058) has poor Caco-2 permeability. Ligand B (-4.765) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.679) has better solubility than Ligand B (-4.278).

**hERG Inhibition:** Ligand A (0.19) has a much lower hERG inhibition liability than Ligand B (0.686), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (13.475) has a lower microsomal clearance, suggesting better metabolic stability compared to Ligand B (36.52).

**In vitro Half-Life:** Ligand B (20.39) has a longer in vitro half-life than Ligand A (10.894).

**P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux liability than Ligand B (0.813).

**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 of the ADME drawbacks. The difference of 1.8 kcal/mol is significant.

**Overall Assessment:**

Ligand B boasts a substantially better binding affinity (-9.5 vs -7.7 kcal/mol). However, it suffers from higher logP, higher DILI risk, higher hERG inhibition, and higher P-gp efflux. Ligand A has better solubility, lower toxicity (DILI and hERG), and better metabolic stability (lower Cl_mic). The improved binding affinity of Ligand B is a strong point, but the safety concerns associated with its ADME profile are substantial. Given the enzyme class and the importance of minimizing off-target effects and toxicity, the more balanced profile of Ligand A, despite the lower affinity, makes it a more promising starting point for optimization. The affinity gap could potentially be addressed through medicinal chemistry efforts, while mitigating the ADME liabilities of Ligand B might be more challenging.

Output:
0
2025-04-17 15:44:38,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.451 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.34) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (76.27) is well within the range.

**logP:** Ligand A (-1.055) is a bit low, potentially hindering permeation. Ligand B (2.061) is within 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 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.512 and 0.809), indicating drug-like properties.

**DILI:** Ligand A (10.896) has a very low DILI risk, which is excellent. Ligand B (35.13) is moderate, but still acceptable.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.108 and -4.978), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.298 and -2.473), which is also a major concern. Poor solubility can severely limit bioavailability.

**hERG Inhibition:** Ligand A (0.066) shows very low hERG inhibition risk, which is excellent. Ligand B (0.301) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (9.853) has lower clearance, suggesting better metabolic stability. Ligand B (20.239) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-8.588) has a negative half-life, which is not possible and likely indicates an issue with the data or assay. Ligand B (34.286) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.084).

**Binding Affinity:** Ligand B (-9.2 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 B is the better candidate despite its moderate DILI and slightly higher hERG risk. Its significantly superior binding affinity (-9.2 vs -7.7 kcal/mol) is a major advantage for an enzyme target like SRC kinase. While both ligands have concerningly low/negative Caco-2 and solubility values, the stronger binding of Ligand B gives it a higher chance of success with formulation optimization. The negative half-life for Ligand A is a showstopper. Ligand A's low DILI and hERG are positives, but are overshadowed by the poor half-life and weaker affinity.

Output:
1
2025-04-17 15:44:38,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.423 and 348.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (61.44 and 58.64) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.978 and 2.514) within the optimal range of 1-3.

**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 A (0.847) has a significantly better QED score than Ligand B (0.375), indicating a more drug-like profile.

**DILI:** Ligand A (85.653) has a high DILI risk, while Ligand B (19.504) has a low DILI risk. This is a major concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (62.699 and 68.05). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.847 and -4.264), 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.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.542 and -2.343), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.622) has a slightly higher hERG inhibition risk than Ligand B (0.27), but both are relatively low.

**Microsomal Clearance:** Ligand B (61.98) has a significantly higher microsomal clearance than Ligand A (15.686), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (30.666) has a longer in vitro half-life than Ligand B (-2.602). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.27 and 0.152).

**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 for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and a significantly lower DILI risk, which are the most important factors for an enzyme inhibitor. While Ligand A has a better QED and longer half-life, its high DILI risk is a major red flag. The solubility issues are concerning for both, but can potentially be addressed through formulation. The Caco-2 permeability values are problematic for both, but the binding affinity advantage of B is significant.

Output:
1
2025-04-17 15:44:38,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.372 Da) is slightly higher than Ligand B (342.443 Da), but both are acceptable.

**TPSA:** Ligand A (63.91) is better than Ligand B (75.19). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.268) is optimal, while Ligand B (1.71) is on the lower side. A logP below 1 can sometimes hinder permeation, so Ligand A has an advantage here.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (1 HBD, 4 HBA) as it has fewer hydrogen bond donors which can improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.708) is better than Ligand B (0.548), indicating a more drug-like profile.

**DILI:** Ligand B (35.169) has a significantly lower DILI risk than Ligand A (92.633). This is a major advantage for Ligand B.

**BBB:** Ligand A (89.104) has better BBB penetration than Ligand B (58.821), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.545) is better than Ligand B (-5.205), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.13) is better than Ligand B (-0.936), which is a significant advantage for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.383) has a lower hERG inhibition risk than Ligand B (0.293), which is preferable.

**Microsomal Clearance:** Ligand B (5.654) has significantly lower microsomal clearance than Ligand A (68.719), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-11.247) has a longer in vitro half-life than Ligand A (21.961), which is also a positive for dosing considerations.

**P-gp Efflux:** Ligand A (0.607) has higher P-gp efflux than Ligand B (0.036), meaning Ligand B will likely have better oral bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). The difference of 1.3 kcal/mol is substantial enough to be a deciding factor.

**Overall Assessment:**

Ligand B demonstrates a superior ADME profile, particularly regarding metabolic stability (lower Cl_mic, longer t1/2), DILI risk, and P-gp efflux. While Ligand A has slightly better solubility and Caco-2 permeability, the advantages of Ligand B in key areas like metabolic stability and safety (DILI) outweigh these. The slightly better binding affinity of Ligand B further solidifies its potential.

Output:
1
2025-04-17 15:44:38,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (376.551 Da) is still well within the acceptable range.

**TPSA:** Ligand A (120.24) is better than Ligand B (51.02) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (-0.463) is a bit low, potentially hindering permeation. Ligand B (3.536) is excellent, falling squarely within the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**H-Bond Acceptors:** Both Ligand A (6) and Ligand B (6) are within the acceptable limit of 10.

**QED:** Ligand A (0.621) is better than Ligand B (0.362), indicating a more drug-like profile.

**DILI:** Ligand A (49.826) has a lower DILI risk than Ligand B (57.852), which is preferable.

**BBB:** Ligand A (52.889) and Ligand B (67.158) are both relatively low, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.861 and -5.503), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.469 and -2.191), which is also unusual and indicates poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.469) has a slightly lower hERG risk than Ligand B (0.662), which is preferable.

**Microsomal Clearance:** Ligand A (3.997) has a significantly lower microsomal clearance than Ligand B (95.509), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.311) has a negative half-life, which is not possible. Ligand B (6.795) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.006 and 0.658), which is good.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While both ligands have issues with Caco-2 permeability and solubility, Ligand A's significantly stronger binding affinity (-8.4 vs -6.9 kcal/mol) and lower microsomal clearance (3.997 vs 95.509) are critical advantages for an enzyme inhibitor. The lower DILI risk and slightly lower hERG risk also contribute to its favorability. The negative half-life for ligand A is a data error and should be investigated.

Output:
1
2025-04-17 15:44:38,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.788 Da) is slightly higher than Ligand B (338.411 Da), but both are acceptable.

**TPSA:** Ligand A (103.29) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (66.71) is well within the acceptable range.

**logP:** Both ligands have good logP values (A: 1.989, B: 2.165), 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 (HBD <=5, HBA <=10).

**QED:** Both ligands have good QED scores (A: 0.552, B: 0.869), indicating good drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A has a DILI risk of 98.488, which is very high. Ligand B has a DILI risk of 64.831, which is still elevated but considerably lower than Ligand A. This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (A: 71.229, B: 60.838), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 (0.024) has a very low hERG risk, which is excellent. Ligand B (0.323) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance (Cl_mic):** Ligand A (45.948) has a moderate Cl_mic, while Ligand B (55.044) is slightly higher. Lower is better for metabolic stability.

**In vitro Half-Life (t1/2):** Ligand A (29.417) has a longer half-life than Ligand B (-5.922). This is a significant advantage for Ligand A, *if* the negative value for B is not an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.262, B: 0.084), which is favorable.

**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 is substantial.

**Overall Assessment:**

Ligand B is the stronger candidate despite the slightly higher DILI risk. The significantly improved binding affinity (-8.6 vs -7.1 kcal/mol) outweighs the moderate differences in other ADME properties. The high DILI risk for Ligand A is a major red flag. The negative values for Caco-2 and solubility are concerning for both, but the superior potency of Ligand B makes it more likely to be optimized to overcome these issues.

Output:
1
2025-04-17 15:44:38,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.36 Da) is slightly higher than Ligand B (352.519 Da), but both are acceptable.

**TPSA:** Both are around 78, which is slightly above the ideal <140 for good oral absorption, but not a major concern for a kinase inhibitor.

**logP:** Both ligands have similar logP values (A: 2.748, B: 2.763), falling within the optimal range of 1-3.

**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, <=10 HBA).

**QED:** Ligand A (0.814) has a better QED score than Ligand B (0.688), suggesting a more drug-like profile.

**DILI:** Ligand A (42.264) has a higher DILI risk than Ligand B (18.767). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 53.121, B: 51.803), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern, but can be mitigated with formulation strategies.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a significant issue for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.316, B: 0.155), which is excellent.

**Microsomal Clearance:** Ligand A (3.464 mL/min/kg) has significantly lower microsomal clearance than Ligand B (15.296 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (A: 1.213, B: 1.37 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.145, B: 0.066).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability (lower Cl_mic), and a better QED score. However, it has a significantly higher DILI risk and poor solubility. Ligand B has a lower DILI risk, but weaker binding affinity and poorer metabolic stability.

Given the priorities for kinase inhibitors, the binding affinity is paramount. The 0.8 kcal/mol difference in affinity for Ligand A is substantial. While the DILI risk is concerning, it might be manageable with careful preclinical and clinical monitoring. The poor solubility is a bigger issue, but formulation strategies could potentially address this. The improved metabolic stability of Ligand A is also a significant advantage.

Output:
1
2025-04-17 15:44:38,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.431 and 390.893 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.15) is excellent, well below the 140 threshold for good absorption. Ligand B (106) is still acceptable, but less optimal.

**logP:** Ligand A (0.673) is a bit low, potentially hindering permeation. Ligand B (-0.199) is even lower, raising concerns about absorption.

**H-Bond Donors/Acceptors:** Ligand A (0 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 reasonable QED scores (0.68 and 0.595), indicating good drug-like properties.

**DILI:** Ligand A (25.475) has a significantly lower DILI risk than Ligand B (41.218), which is a major advantage.

**BBB:** Ligand A (69.562) has moderate BBB penetration, while Ligand B (9.732) is very low. This isn't a primary concern for a non-CNS target like SRC, but it's a point in favor of A.

**Caco-2 Permeability:** Ligand A (-4.479) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.393) is similarly poor.

**Aqueous Solubility:** Ligand A (-1.859) has poor aqueous solubility. Ligand B (-0.805) is slightly better, but still not ideal.

**hERG:** Ligand A (0.345) has a very low hERG risk, which is excellent. Ligand B (0.118) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (67.792) has moderate microsomal clearance. Ligand B (-28.36) has *negative* clearance, which is not physically possible and likely an error in the data. This is a huge red flag.

**In vitro Half-Life:** Ligand A (-1.592) has a negative half-life, which is also not physically possible and suggests data error. Ligand B (16.02) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.039 and 0.05), which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-7.7 and -7.2 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A has a better safety profile (DILI, hERG) and slightly better binding affinity. However, its Caco-2 permeability and aqueous solubility are poor, and its reported half-life is impossible. Ligand B has a higher DILI risk, lower BBB penetration, and slightly weaker affinity, but has a reasonable half-life. The negative clearance for Ligand B is a critical flaw. Given the data errors for both compounds, and prioritizing safety and potency, Ligand A is still the better candidate *if* the half-life and permeability issues can be addressed through structural modifications. The negative clearance for Ligand B is a showstopper.

Output:
0
2025-04-17 15:44:38,535 - INFO - Batch 405 complete. Total preferences: 6480
2025-04-17 15:44:38,535 - INFO - Processing batch 406/512...
2025-04-17 15:45:19,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.798 Da) is slightly higher than Ligand B (340.423 Da), but both are acceptable.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (62.55), falling well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (A: 1.063, B: 2.221), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=4) is more favorable than Ligand B (HBD=1, HBA=3). Lower HBD is generally preferred for better permeability.

**QED:** Both ligands have good QED scores (A: 0.681, B: 0.836), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 45.173, B: 39.705), below the 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.566) has a higher BBB percentile than Ligand B (59.364).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or the model. However, the values are similar (-4.553 for A, -4.87 for B), so this doesn't strongly favor one over the other.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.217, B: -3.388). Ligand B is worse.

**hERG Inhibition:** Ligand A (0.447) shows a much lower hERG risk than Ligand B (0.239), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-7.737) has a significantly lower (better) microsomal clearance than Ligand B (14.797), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-11.984) has a much longer in vitro half-life than Ligand B (27.523), which is highly desirable.

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux liability than Ligand B (0.232), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, lower P-gp efflux, and a slightly better binding affinity. While both have poor solubility, Ligand A's other advantages, particularly the metabolic stability and safety profile, make it a much more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 15:45:19,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.427 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.91) is slightly above the optimal <140, while Ligand B (53.09) is well within the range. This favors Ligand B for better absorption.

**logP:** Ligand A (-0.262) is a bit low, potentially hindering permeation. Ligand B (1.244) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 8 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.52 and 0.63), indicating drug-likeness.

**DILI:** Ligand A (64.599) has a higher DILI risk than Ligand B (17.371). This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration (76.541 and 73.129), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.722 and -4.313). This is unusual and suggests poor permeability, but the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values (-1.983 and -0.304). This is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.157) has a slightly higher hERG risk than Ligand B (0.512). Lower is better, so Ligand B is preferred.

**Microsomal Clearance:** Both have similar microsomal clearance (55.918 and 53.723 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-17.04) has a significantly longer half-life than Ligand A (-10.722), which is a major advantage.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux than Ligand B (0.094), which is slightly favorable.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.7). While the difference is less than the 1.5 kcal/mol threshold, it still contributes to its favorability.

**Overall:** Ligand B is superior due to its better logP, significantly lower DILI risk, longer half-life, and slightly better binding affinity. While both have issues with Caco-2 and solubility, Ligand B's profile is more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 15:45:19,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.47 and 375.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.9) is better than Ligand B (61.44) as it is closer to the 90 threshold for CNS targets, although SRC is not a CNS target, lower TPSA generally correlates with better permeability.

**logP:** Both ligands have good logP values (2.47 and 3.74), 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:** 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 (0.742) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (45.52 and 49.79 percentile), below the 60% threshold.

**BBB:** Ligand B (87.94) has a higher BBB penetration than Ligand A (71.58). However, as SRC is not a CNS target, this is less critical.

**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 further information.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.18 and -4.31). This is a significant concern for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.261) has a much lower hERG risk than Ligand B (0.762). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (32.59) has significantly lower microsomal clearance than Ligand A (45.66), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-7.97) has a much longer in vitro half-life than Ligand A (5.11). This is another significant advantage, suggesting less frequent dosing could be possible.

**P-gp Efflux:** Ligand A (0.561) has lower P-gp efflux than Ligand B (0.216), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-9.0). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), Ligand A has a significantly better hERG profile and a better QED score. The poor solubility of both is a major concern. However, the stronger binding affinity of Ligand B is a critical factor for an enzyme inhibitor. Given the importance of potency for enzyme targets, and the relatively minor differences in other ADME properties, the superior binding affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 15:45:19,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is well below the 140 threshold for oral absorption, while Ligand B (104.39) is still acceptable but less optimal.

**logP:** Ligand A (2.029) is within the optimal 1-3 range. Ligand B (-0.126) is below 1, 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, and Ligand B has 5, both within the acceptable limit of <=10.

**QED:** Ligand A (0.756) has a significantly better QED score than Ligand B (0.368), indicating better drug-likeness.

**DILI:** Ligand A (24.506) has a much lower DILI risk than Ligand B (44.164), which is a significant advantage. Both are below the concerning threshold of 60.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (65.684) is better than Ligand B (23.071).

**Caco-2 Permeability:** Ligand A (-5.114) and Ligand B (-5.338) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.904) and Ligand B (-1.686) both have negative values, indicating poor solubility. This is a concern for both.

**hERG:** Both ligands have low hERG risk (0.188 and 0.14, respectively).

**Microsomal Clearance:** Ligand A (19.797) has a higher (worse) microsomal clearance than Ligand B (-6.742). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-17.741) has a much longer in vitro half-life than Ligand A (2.388), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.033, respectively).

**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:**

Ligand A has a significantly better QED, lower DILI risk, and better binding affinity. However, Ligand B exhibits superior metabolic stability (lower Cl_mic, longer t1/2). Both have poor Caco-2 permeability and solubility. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, hERG), the stronger binding affinity of Ligand A, combined with its better overall drug-likeness and safety profile (DILI), makes it the more promising candidate despite the slightly higher clearance. The difference in binding affinity is significant enough to potentially overcome the solubility/permeability issues through formulation strategies.

Output:
1
2025-04-17 15:45:19,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 350.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is slightly higher than Ligand B (51.66). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands (2.657 and 2.934) 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:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**QED:** Ligand A (0.858) has a better QED score than Ligand B (0.759), indicating a more drug-like profile.

**DILI:** Ligand A (38.116) has a slightly higher DILI risk than Ligand B (26.948), but both are below the concerning threshold of 60.

**BBB:** Ligand A (76.968) and Ligand B (85.149) both have good BBB penetration, but Ligand B is slightly better. This isn't a major concern for a kinase inhibitor unless CNS effects are desired or problematic.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.682 and 0.607, respectively). This is positive.

**Microsomal Clearance:** Ligand B (41.249) has a lower microsomal clearance than Ligand A (63.714), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (19.95 hours) has a significantly longer half-life than Ligand A (-2.081 hours). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.191 and 0.157, respectively).

**Binding Affinity:** Ligand B (-11.0 kcal/mol) has a *much* stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a decisive factor, as a >1.5 kcal/mol advantage is considered significant.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the superior candidate. The significantly improved metabolic stability (lower Cl_mic, longer t1/2) and, crucially, the much stronger binding affinity (-11.0 vs -7.9 kcal/mol) outweigh the slightly higher DILI risk and lower QED score. The binding affinity difference is large enough to potentially overcome formulation challenges related to solubility and permeability.

Output:
1
2025-04-17 15:45:19,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 350.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is well below the 140 threshold for oral absorption, and even better for kinase inhibitors. Ligand B (120.33) is still acceptable but less favorable.

**logP:** Ligand A (2.061) is optimal (1-3). Ligand B (-1.63) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is still within acceptable ranges, but slightly less optimal.

**QED:** Ligand A (0.769) is very good, indicating high drug-likeness. Ligand B (0.476) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (12.098) has a very low DILI risk. Ligand B (61.574) is higher, indicating a moderate risk of liver injury.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (57.736) is better than Ligand B (19.038).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it's hard to interpret the absolute values.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.231) has a very low hERG risk. Ligand B (0.16) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-4.842) indicates very good metabolic stability (negative values are better). Ligand B (-13.716) is even better.

**In vitro Half-Life:** Ligand A (-6.14) suggests a long half-life. Ligand B (1.922) suggests a short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.007).

**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 the other significant differences.

**Conclusion:**

Ligand A is significantly better overall. It has a better QED score, lower DILI risk, better logP, and superior metabolic stability (lower Cl_mic, longer t1/2). While both have good binding affinity, Ligand A's superior ADME properties make it the more promising drug candidate.

Output:
1
2025-04-17 15:45:19,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.873 and 352.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (117.87). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Ligand A (3.428) is optimal (1-3), while Ligand B (0.166) is quite low, potentially causing permeability issues.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=6) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.814) has a much better drug-likeness score than Ligand B (0.574).

**DILI:** Ligand B (49.477) has a lower DILI risk than Ligand A (33.075), which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.151) is better than Ligand B (52.268).

**Caco-2 Permeability:** Ligand A (-4.396) is better than Ligand B (-4.886). Higher values indicate better permeability.

**Aqueous Solubility:** Ligand A (-4.569) is better than Ligand B (-1.655), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.622) has a lower hERG risk than Ligand B (0.209), which is a significant advantage.

**Microsomal Clearance:** Ligand B (41.744) has a lower microsomal clearance than Ligand A (68.607), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (4.047) has a longer in vitro half-life than Ligand A (-4.342), which is also favorable.

**P-gp Efflux:** Ligand A (0.21) has a lower P-gp efflux than Ligand B (0.093), which is a slight advantage.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.9 kcal/mol), with Ligand B being slightly better. However, the difference is minimal and can be overcome by other factors.

**Overall Assessment:**

Ligand A excels in most key ADME properties (TPSA, logP, solubility, hERG) and has a very good QED score. While Ligand B has slightly better metabolic stability and binding affinity, its poor logP, higher TPSA, and lower solubility are significant drawbacks. The better ADME profile of Ligand A, coupled with its acceptable binding affinity, makes it the more promising candidate.

Output:
1
2025-04-17 15:45:19,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.479 and 358.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.5) is slightly higher than Ligand B (49.85), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (0.635) is a bit low, potentially hindering permeation. Ligand B (1.702) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.678 and 0.608), indicating good drug-likeness.

**DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (39.434), which is a major advantage.

**BBB:** Ligand A (64.87) has a lower BBB penetration than Ligand B (74.564). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.856) has poorer Caco-2 permeability than Ligand B (-4.683), but both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (0.017) has very poor aqueous solubility, while Ligand B (-2.875) is also poor, but less so.

**hERG Inhibition:** Ligand A (0.195) has a lower hERG inhibition risk than Ligand B (0.58), which is a significant advantage.

**Microsomal Clearance:** Ligand A (8.225) has a much lower microsomal clearance than Ligand B (45.493), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.093) has a longer in vitro half-life than Ligand B (0.729), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux than Ligand B (0.486), indicating better bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.2 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand B having a slightly better logP and Caco-2 permeability, Ligand A is the superior candidate. Its significantly lower DILI risk, hERG inhibition, microsomal clearance, and P-gp efflux, coupled with a longer half-life and better solubility (although still poor) outweigh the slightly lower BBB penetration and Caco-2 value. The equal binding affinity ensures potency is not compromised. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 15:45:19,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.5 and 348.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.2) is significantly better than Ligand B (122.3), being well below the 140 threshold for good absorption.

**logP:** Ligand A (2.903) is optimal (1-3), while Ligand B (-1.376) is below 1, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 threshold.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (9), closer to the ideal of 10 or less.

**QED:** Both ligands have reasonable QED values (0.862 and 0.678), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (54.6 and 58.4 percentile), both being acceptable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (57.7) is better than Ligand B (40.8).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are log values, the closer to zero the better. Ligand A (-5.388) is better than Ligand B (-5.517).

**Aqueous Solubility:** Ligand A (-3.575) is better than Ligand B (-0.828). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.6 and 0.096), which is excellent.

**Microsomal Clearance:** Ligand A (40.653) has higher clearance than Ligand B (20.458), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-3.664) has a better half-life than Ligand A (-9.693).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.354 and 0.011).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.7 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Ligand B is the more promising candidate. While both have good potency and low hERG risk, Ligand B demonstrates superior predicted permeability (better logP, Caco-2), solubility, and, crucially, significantly better metabolic stability (lower Cl_mic, longer half-life). Ligand A's higher clearance is a major concern for *in vivo* efficacy.

Output:
1
2025-04-17 15:45:19,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.259 Da) is slightly higher than Ligand B (369.893 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (83.48) is higher than Ligand B (72.36), but both are well within the acceptable range.

**3. logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.783, Ligand B: 2.366), indicating good lipophilicity for membrane permeability.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. 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 QED values above 0.5 (Ligand A: 0.653, Ligand B: 0.738), indicating a generally drug-like profile.

**7. DILI:** Ligand A has a DILI risk of 62.893%, which is considered high risk. Ligand B has a much lower DILI risk of 32.842%, which is good. This is a significant advantage for Ligand B.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (46.375%) is lower than Ligand B (75.921%), but this isn't a major deciding factor.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of negativity is similar, so it doesn't differentiate them significantly.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are comparable.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.492, Ligand B: 0.418), which is favorable.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (31.93 mL/min/kg) than Ligand B (67.654 mL/min/kg), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (41.861 hours) than Ligand A (25.759 hours), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.194, Ligand B: 0.081), which is good.

**15. Binding Affinity:** Ligand B has a significantly better binding affinity (-7.1 kcal/mol) than Ligand A (0.0 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference is often enough to outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability (lower Cl_mic), the significantly superior binding affinity of Ligand B (-7.1 kcal/mol vs 0.0 kcal/mol) and its much lower DILI risk (32.842% vs 62.893%) are decisive advantages. The longer half-life of Ligand B is also beneficial. The similar, and somewhat unusual, negative values for Caco-2 and solubility don't strongly favor either compound.

Output:
1
2025-04-17 15:45:19,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.422 and 387.307 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is slightly higher than Ligand B (67.43), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.139 and 2.694), 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:** Ligand A (0.852) has a significantly higher QED score than Ligand B (0.262), indicating a much more drug-like profile.

**DILI:** Ligand A (25.785) has a considerably lower DILI risk than Ligand B (31.718), which is a significant advantage. Both are below the 40 threshold.

**BBB:** Ligand A (89.531) shows better BBB penetration potential than Ligand B (68.127), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands exhibit poor Caco-2 permeability (-4.591 and -4.787), suggesting potential absorption issues.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.449 and -3.297).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.4 and 0.334), which is positive.

**Microsomal Clearance:** Ligand A (23.55) has a lower microsomal clearance than Ligand B (44.594), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.399) has a shorter half-life than Ligand B (13.436), but both are relatively low.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.097 and 0.196).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a significantly better QED score, lower DILI risk, better metabolic stability (lower Cl_mic), and better BBB penetration. While both have poor solubility and Caco-2 permeability, the superior ADME profile of Ligand A outweighs these concerns. The binding affinity difference is minimal.

Output:
1
2025-04-17 15:45:19,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.483 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (72.88 and 71.53) below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.648) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (2.916) is within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**QED:** Ligand A (0.698) has a better QED score than Ligand B (0.51), indicating a more drug-like profile.

**DILI:** Ligand A (22.451) has a significantly lower DILI risk than Ligand B (43.505), which is a major advantage.

**BBB:** Ligand A (67.584) has a higher BBB penetration score than Ligand B (42.769), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.394 and -5.176), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.037 and -2.227), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.276 and 0.236), which is good.

**Microsomal Clearance:** Ligand A (-5.151) has a significantly lower (better) microsomal clearance than Ligand B (91.915), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.509) has a longer half-life than Ligand B (2.367), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.192).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), though both are excellent. The 0.8 kcal/mol difference is significant.

**Conclusion:**

Ligand A is the more promising candidate. While both have poor solubility and permeability, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a significantly lower DILI risk, and a slightly better binding affinity. The better QED score also supports its drug-like properties. The slightly lower logP of Ligand A is a minor concern compared to the substantial benefits in other key ADME/Tox properties.

Output:
0
2025-04-17 15:45:19,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 Da and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is better than Ligand B (75.43), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.271) is optimal, while Ligand B (3.126) is approaching the upper limit of the optimal 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 (0.809) has a significantly higher QED score than Ligand B (0.59), indicating a more drug-like profile.

**DILI:** Ligand A (7.871) has a much lower DILI risk than Ligand B (45.095). This is a significant advantage.

**BBB:** Ligand B (80.962) has better BBB penetration than Ligand A (67.158), but BBB is not a high priority for a kinase inhibitor unless CNS targets are desired.

**Caco-2 Permeability:** Ligand A (-4.452) has a worse Caco-2 permeability than Ligand B (-5.109).

**Aqueous Solubility:** Ligand A (-1.114) has better solubility than Ligand B (-3.624).

**hERG Inhibition:** Ligand A (0.358) has a much lower hERG inhibition liability than Ligand B (0.713). This is a crucial advantage, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (15.905) has significantly lower microsomal clearance than Ligand B (55.183), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.533) has a lower in vitro half-life than Ligand B (2.271).

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.188).

**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 A is clearly the better candidate. It has a superior QED score, significantly lower DILI and hERG risk, and better metabolic stability (lower Cl_mic). While Ligand B has slightly better binding affinity and BBB penetration, the ADME-Tox profile of Ligand A is far more favorable for a kinase inhibitor. The improved solubility is also a plus. The slightly lower half-life of Ligand A is less concerning than the potential toxicity issues with Ligand B.

Output:
0
2025-04-17 15:45:19,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.403 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.38) is higher than Ligand B (58.44). While both are reasonably low, Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (-1.01) is slightly low, potentially hindering permeability. Ligand B (1.902) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.592 and 0.843), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have very similar, low DILI risk (25.165 and 25.591 percentile).

**BBB:** Ligand A (45.909) has a lower BBB penetration than Ligand B (77.2). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.694 and -4.584), which is unusual and suggests poor permeability *in vitro*. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.121 and -1.313), also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG risk (0.112 and 0.295).

**Microsomal Clearance:** Ligand A (25.769 mL/min/kg) has lower clearance than Ligand B (35.249 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.916 hours) has a shorter half-life than Ligand B (-6.003 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.129).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This 0.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have concerning Caco-2 and solubility values, Ligand B has a significantly better logP, better in vitro half-life, and, most importantly, a stronger binding affinity. The lower metabolic clearance of Ligand A is a plus, but the stronger binding of Ligand B is a more critical factor for an enzyme target like SRC kinase. The slightly better QED and BBB values of Ligand B are also beneficial. The negative solubility and permeability values are red flags for both, and would require further investigation (e.g., salt formation, formulation strategies) but are not disqualifying at this stage given the potency advantage of Ligand B.

Output:
1
2025-04-17 15:45:19,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.462 and 340.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (79.54). A TPSA under 140 is good for oral absorption, and both are within that range, but A is preferable.

**logP:** Both ligands have good logP values (2.524 and 1.753), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is better than Ligand B (0 HBD, 5 HBA). Both are within acceptable limits, but A's profile is slightly more balanced.

**QED:** Both ligands have similar, good QED values (0.852 and 0.832), indicating good drug-likeness.

**DILI:** Ligand A (30.826) has a much lower DILI risk than Ligand B (63.668). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (74.564) is better than Ligand B (44.591).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.812 and -4.879), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.658 and -2.306), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.504) has a lower hERG inhibition liability than Ligand B (0.242), which is a positive.

**Microsomal Clearance:** Ligand A (-3.858) has a much lower (better) microsomal clearance than Ligand B (25.622), indicating better metabolic stability. This is a crucial advantage for A.

**In vitro Half-Life:** Ligand B (29.064) has a significantly longer in vitro half-life than Ligand A (1.963). This is a positive for B, but can be mitigated with formulation strategies.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.131 and 0.146).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). This 0.7 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and a longer half-life, Ligand A excels in critical areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic), and a lower hERG risk. The poor solubility and permeability are concerns for both, but can be addressed through formulation. The improved safety profile and metabolic stability of Ligand A outweigh the modest affinity difference.

Output:
0
2025-04-17 15:45:19,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (369.849 Da) is still well within the range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (76.82). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.975) is at the higher end of the optimal range, while Ligand B (0.98) is quite low. A logP below 1 can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are both acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (A: 0.783, B: 0.809), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 69.717, which is approaching the higher risk threshold. Ligand B has a much lower DILI risk of 35.983, a significant advantage.

**BBB:** Both have similar BBB penetration (A: 79.721, B: 70.997). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.691 and -4.778), which is unusual and suggests poor permeability *in vitro*. This is a concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.19 and -2.918). This is a major drawback for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.736) shows a slightly higher risk of hERG inhibition than Ligand B (0.362), though both are relatively low.

**Microsomal Clearance:** Ligand A (73.957) has a higher microsomal clearance than Ligand B (49.325), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Both have similar in vitro half-lives (A: 35.137, B: 36.566).

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.582, B: 0.122), which is favorable.

**Binding Affinity:** Ligand B (-8.8 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.

**Conclusion:**

Despite both ligands having poor solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.8 vs -6.8 kcal/mol) is a crucial advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic). While Ligand A has a slightly better logP, the other factors heavily favor Ligand B.

Output:
1
2025-04-17 15:45:19,743 - INFO - Batch 406 complete. Total preferences: 6496
2025-04-17 15:45:19,743 - INFO - Processing batch 407/512...
2025-04-17 15:46:10,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.459 Da and 386.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.69) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (67.87) is excellent, well below 140.

**logP:** Both ligands (1.52 and 2.34) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.501 and 0.762), indicating drug-like properties.

**DILI:** Ligand A (78.17) has a higher DILI risk than Ligand B (68.205), but both are still reasonably low.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (72.78) shows slightly better BBB penetration than Ligand B (59.984).

**Caco-2 Permeability:** Ligand A (-5.473) has significantly worse Caco-2 permeability than Ligand B (-4.784). This suggests lower intestinal absorption for Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.279 and -2.973). This is a significant concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.364 and 0.31).

**Microsomal Clearance:** Ligand B (20.432) has significantly lower microsomal clearance than Ligand A (41.525), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (16.516 and 16.874 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.125 and 0.137).

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a significantly better binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite similar molecular weights, QED, and hERG risk, Ligand B is the superior candidate. Its significantly better binding affinity, lower microsomal clearance (better metabolic stability), and better Caco-2 permeability outweigh the slightly lower BBB penetration and solubility. The solubility issue is a concern for both, but can be addressed through formulation strategies. The improved potency and metabolic stability of Ligand B make it more likely to translate into a viable drug candidate for SRC kinase.

Output:
1
2025-04-17 15:46:10,867 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (376.523 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.82) is slightly higher than Ligand B (83.98), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.382) is a bit low, potentially hindering permeation. Ligand B (2.101) is within the optimal 1-3 range. This favors Ligand B.

**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 below the 10 threshold.

**QED:** Both ligands have good QED scores (0.602 and 0.793, respectively), indicating drug-likeness.

**DILI:** Both have low DILI risk (33.695 and 35.944), which is good.

**BBB:** Ligand A (36.952) and Ligand B (63.125). BBB isn't a primary concern for a non-CNS target like SRC, but higher is generally better. Ligand B is better here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.541 and -5.013). 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.

**Aqueous Solubility:** Both have negative solubility values (-1.35 and -2.589). Again, these are on a log scale, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.081 and 0.258). This is excellent.

**Microsomal Clearance:** Ligand A (31.119 mL/min/kg) has lower clearance than Ligand B (44.063 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-17.572 hours) has a negative half-life, which is not physically possible. This is likely an error in the data. Ligand B (-6.395 hours) also has a negative half-life, also likely an error.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.044).

**Binding Affinity:** Both have strong binding affinities (-8 kcal/mol and -7.9 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B has a better logP and BBB, suggesting better absorption and distribution. However, Ligand A has significantly better metabolic stability (lower Cl_mic) and a comparable binding affinity. The negative half-life values for both are concerning and suggest data errors. Given the priority for metabolic stability in enzyme inhibitors, and the comparable binding affinity, Ligand A is slightly more promising, *assuming the half-life value is corrected*. The poor solubility and permeability are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 15:46:10,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.344 Da) is slightly higher than Ligand B (344.375 Da), but both are acceptable.

**TPSA:** Ligand A (66.49) is significantly better than Ligand B (111.03). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.087) is optimal, while Ligand B (-0.168) is quite low, potentially hindering membrane permeability and bioavailability.

**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 preferable.

**QED:** Both ligands have good QED scores (0.748 and 0.779, respectively), indicating good drug-like properties.

**DILI:** Ligand B (81.078) has a considerably higher DILI risk than Ligand A (18.728). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.217) has a better BBB score than Ligand B (43.583).

**Caco-2 Permeability:** Ligand A (-4.977) is better than Ligand B (-5.419), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.718 and -1.775). This could pose formulation challenges, but isn't a dealbreaker.

**hERG:** Ligand A (0.679) has a lower hERG risk than Ligand B (0.048), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-17.909) has much lower (better) microsomal clearance than Ligand B (4.956), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.926 hours) has a longer half-life than Ligand B (19.895 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.003), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.1 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:**

Ligand A is significantly better than Ligand B across several critical ADME properties, including DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and P-gp efflux. It also has a slightly better binding affinity and TPSA. While both have poor solubility, the other advantages of Ligand A outweigh this concern. Ligand B's low logP and high DILI risk are major drawbacks.

Output:
1
2025-04-17 15:46:10,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.28 Da) is slightly higher than Ligand B (352.475 Da), but both are acceptable.

**TPSA:** Ligand A (64.16) is better than Ligand B (70.08). Both are below 140, indicating reasonable absorption potential.

**logP:** Ligand A (3.571) is within the optimal range (1-3), while Ligand B (1.412) is on the lower end. Lower logP can sometimes indicate poor membrane permeability.

**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.

**QED:** Both ligands have good QED scores (Ligand A: 0.654, Ligand B: 0.785), suggesting good drug-like properties.

**DILI:** Ligand A (56.689) has a higher DILI risk than Ligand B (20.706). This is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (71.384) is slightly better than Ligand B (62.66).

**Caco-2 Permeability:** Ligand A (-5.137) has poor Caco-2 permeability, while Ligand B (-4.508) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.035) has poor aqueous solubility, while Ligand B (-1.991) is also poor, but slightly better.

**hERG:** Ligand A (0.724) has a slightly higher hERG risk than Ligand B (0.389).

**Microsomal Clearance:** Ligand A (86.659) has higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (35.72). This is a significant drawback.

**In vitro Half-Life:** Ligand A (-10.32) has a very short half-life, while Ligand B (5.497) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.532) has lower P-gp efflux than Ligand B (0.24), which is favorable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly better binding affinity than Ligand A (-8.4 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the better candidate. While both have some ADME liabilities (poor solubility and permeability), Ligand B possesses a significantly stronger binding affinity (-7.3 vs -8.4 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2). The superior binding affinity outweighs the minor ADME concerns. Ligand A's high DILI risk and poor metabolic stability are major red flags.

Output:
1
2025-04-17 15:46:10,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.438 and 386.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.68) is well below the 140 threshold, and even below 90, suggesting good absorption. Ligand B (84.5) is still acceptable but less optimal.

**3. logP:** Both ligands have logP values (1.488 and 2.07) 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:** Ligand A (0.816) has a significantly better QED score than Ligand B (0.603), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (37.146 and 41.915, both <40).

**8. BBB:** Ligand A (89.686) has better BBB penetration than Ligand B (63.164), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.858) has a better Caco-2 permeability than Ligand B (-5.273), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.254) has slightly better aqueous solubility than Ligand B (-2.793).

**11. hERG Inhibition:** Ligand A (0.803) has a lower hERG inhibition risk than Ligand B (0.297), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (23.78) has a much lower microsomal clearance than Ligand B (69.827), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.024) has a better in vitro half-life than Ligand B (-6.244).

**14. P-gp Efflux:** Ligand A (0.023) has significantly lower P-gp efflux than Ligand B (0.23), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-6.2). While both are good, the 1.3 kcal/mol difference is noticeable and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties (solubility, metabolic stability, P-gp efflux, hERG) and has a slightly better binding affinity and QED score. While Ligand B is acceptable, Ligand A presents a much more promising drug candidate profile for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:46:10,868 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as drug candidates targeting SRC, a kinase. I will follow the provided guidelines and protein-class-specific priorities (enzymes: potency, metabolic stability, solubility, and hERG risk).

**Ligand A: [386.876, 75.27, 2.227, 2, 3, 0.557, 52.734, 81.737, -4.996, -3.668, 0.65, 48.328, 9.387, 0.359, -9.3]**
**Ligand B: [356.482, 66.48, 2.873, 1, 3, 0.654, 28.616, 73.788, -4.651, -2.838, 0.367, 23.896, -6.747, 0.245, -8.4]**

**1. Molecular Weight:** Both are within the ideal range (200-500 Da). A (386.876) is slightly higher than B (356.482), but both are acceptable.

**2. TPSA:** Both are below the 140 A<sup>2</sup> threshold for good oral absorption. A (75.27) is higher than B (66.48), but both are reasonably good.

**3. logP:** Both are within the optimal range (1-3). A (2.227) and B (2.873) are both good, with B being slightly higher.

**4. H-Bond Donors:** A (2) and B (1) are both within the acceptable limit of <=5. B is slightly better.

**5. H-Bond Acceptors:** Both are at 3, well within the acceptable limit of <=10.

**6. QED:** Both have good QED scores (A: 0.557, B: 0.654), indicating a drug-like profile. B is slightly better.

**7. DILI:** A (52.734) is higher than B (28.616). B has a significantly lower DILI risk, which is a major advantage.

**8. BBB:** A (81.737) is higher than B (73.788). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2:** Both have negative values, indicating poor permeability. A (-4.996) is worse than B (-4.651). This is a concern for both.

**10. Solubility:** Both have negative values, indicating poor solubility. A (-3.668) is worse than B (-2.838). This is a concern for both.

**11. hERG:** Both have very low hERG inhibition risk (A: 0.65, B: 0.367). B is slightly better.

**12. Cl_mic:** A (48.328) has higher microsomal clearance than B (23.896). B has better metabolic stability, which is crucial for an enzyme inhibitor.

**13. t1/2:** A (9.387) has a longer half-life than B (-6.747). This is a positive for A.

**14. Pgp:** A (0.359) has lower P-gp efflux than B (0.245). This is a positive for A.

**15. Binding Affinity:** A (-9.3) has a slightly better binding affinity than B (-8.4). This is a 0.9 kcal/mol difference, which is significant.

**Summary & Decision:**

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), **Ligand B is the more promising candidate.**

Here's why:

*   **DILI Risk:** B has a significantly lower DILI risk (28.616 vs 52.734).
*   **Metabolic Stability:** B has significantly lower microsomal clearance (23.896 vs 48.328) and therefore better metabolic stability.
*   **hERG Risk:** B has a slightly lower hERG risk.
*   **Solubility & Caco-2:** While both are poor, B is slightly better in both categories.

Although A has a slightly better binding affinity (-9.3 vs -8.4) and a longer half-life, the superior safety profile (lower DILI) and metabolic stability of B outweigh these advantages. The 0.9 kcal/mol difference in binding affinity can potentially be optimized during lead optimization, whereas addressing significant DILI or poor metabolic stability is often much more challenging.

Output:
1
2025-04-17 15:46:10,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.415 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.47) is better than Ligand B (105.14), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration (though that's not a primary concern here).

**logP:** Ligand A (0.311) is a bit low, potentially hindering permeability. Ligand B (0.645) is better, falling within the optimal 1-3 range.

**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 limit.

**QED:** Ligand A (0.756) has a significantly better QED score than Ligand B (0.512), indicating a more drug-like profile.

**DILI:** Ligand A (37.999) has a much lower DILI risk than Ligand B (60.14), placing it well below the 40% threshold for good safety. Ligand B is approaching the high-risk zone.

**BBB:** This is less critical for a non-CNS target. Ligand A (54.13) is slightly better than Ligand B (44.126).

**Caco-2 Permeability:** Both are negative (-5.006 and -5.587), indicating poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both are negative (-2.278 and -1.272), indicating poor solubility. This is also a significant concern for both.

**hERG Inhibition:** Ligand A (0.678) has a lower hERG risk than Ligand B (0.361), which is preferable.

**Microsomal Clearance:** Ligand A (-47.418) has a much lower (better) microsomal clearance than Ligand B (32.77), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.349) has a longer half-life than Ligand B (-6.04), which is desirable.

**P-gp Efflux:** Both are very low (0.003 and 0.026), indicating minimal P-gp efflux.

**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 noticeable.

**Overall Assessment:**

Ligand A is significantly better overall. It has a superior QED score, much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity. While both have issues with Caco-2 permeability and solubility, the ADME profile of Ligand A is far more favorable, particularly its safety profile and metabolic stability. The slightly better affinity of A further strengthens its position.

Output:
0
2025-04-17 15:46:10,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (371.547 and 350.369 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is better than Ligand B (80.04), being closer to the <140 threshold for good absorption.

**3. logP:** Both ligands (1.205 and 1.657) are 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:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.65 and 0.83), indicating drug-like properties.

**7. DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (50.136). This is a major advantage.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (73.284) has a higher value than Ligand A (60.333).

**9. Caco-2 Permeability:** Ligand A (-5.175) and Ligand B (-4.932) are both negative, indicating poor permeability. However, this is a relative scale and the difference isn't huge.

**10. Aqueous Solubility:** Ligand A (-1.619) is better than Ligand B (-2.81), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.403) has a lower hERG risk than Ligand B (0.133), which is crucial for avoiding cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (24.408) has a lower microsomal clearance than Ligand A (33.011), suggesting better metabolic stability. This is a positive for Ligand B.

**13. In vitro Half-Life:** Ligand B (-23.773) has a significantly longer in vitro half-life than Ligand A (3.301). This is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.12), which is preferable.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This difference of 1.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates a significantly stronger binding affinity and a longer half-life, which are critical for an enzyme inhibitor. While Ligand A has a better DILI score and hERG risk, the potency and metabolic stability advantages of Ligand B are more important for SRC kinase inhibition. The slightly higher P-gp efflux and DILI risk of Ligand B are acceptable given its superior binding affinity and half-life.

Output:
1
2025-04-17 15:46:10,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (337.375 and 345.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (64.63 and 66.65) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.831 and 2.791) are 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:** Both ligands have 4 HBAs, which is within the acceptable range (<=10).

**6. QED:** Ligand A (0.852) has a slightly better QED score than Ligand B (0.773), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Both ligands have DILI risk around the 55-58 percentile, which is good (below 60).

**8. BBB:** Ligand B (83.172) has a higher BBB penetration percentile than Ligand A (66.615). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.48 and -4.517). This is unusual and suggests poor permeability. However, these are reported as negative values, which is not standard. We'll proceed with caution.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.116 and -2.884). This is also unusual and suggests poor solubility. Again, proceed with caution.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.415 and 0.437).

**12. Microsomal Clearance:** Ligand B (78.155) has a higher microsomal clearance than Ligand A (44.343). This suggests Ligand A is more metabolically stable, which is a high priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand B (-38.506) has a significantly longer in vitro half-life than Ligand A (-15.39). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.178 and 0.53).

**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 some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower microsomal clearance (better metabolic stability), and a slightly better QED score. Ligand B has a longer half-life and better BBB penetration, but the latter is not crucial for a non-CNS target like SRC. The negative Caco-2 and solubility values for both are concerning and need further investigation, but the substantial difference in binding affinity favors Ligand A. Given the enzyme-specific priorities, the stronger binding affinity and improved metabolic stability of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 15:46:10,868 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.439 and 363.853 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.59) is better than Ligand B (110.75). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Both ligands have similar logP values (1.581 and 1.575), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3), as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (7), as fewer HBAs generally improve permeability.

**QED:** Ligand A (0.801) has a significantly better QED score than Ligand B (0.695), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (67.623 and 69.678), both are acceptable but not ideal.

**BBB:** Ligand A (73.284) has a slightly better BBB penetration percentile than Ligand B (64.482), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.68) is significantly better than Ligand B (-5.709), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.36) is slightly better than Ligand B (-2.625), though both are poor.

**hERG Inhibition:** Ligand A (0.089) has a much lower hERG inhibition liability than Ligand B (0.216), which is a significant advantage.

**Microsomal Clearance:** Ligand B (44.288) has a lower microsomal clearance than Ligand A (53.759), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (26.35) has a longer half-life than Ligand A (19.653), which is desirable.

**P-gp Efflux:** Ligand A (0.189) has lower P-gp efflux liability than Ligand B (0.05), which is preferable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.0 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other ADME considerations.

**Overall Assessment:**

Ligand A is superior due to its better QED, TPSA, Caco-2 permeability, hERG inhibition profile, and lower P-gp efflux. While Ligand B has slightly better metabolic stability (lower Cl_mic and longer t1/2), the advantages of Ligand A in other critical ADME properties, coupled with comparable binding affinity, make it the more promising drug candidate. The solubility of both is a concern, but can be addressed with formulation strategies.

Output:
0
2025-04-17 15:46:10,869 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.355 and 349.381 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.43) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (62.3) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands have good logP values (1.653 and 2.294), falling 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. Ligand B has 3 HBA, which is also good.

**QED:** Both ligands have good QED scores (0.753 and 0.83), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 80.186, which is concerningly high. Ligand B has a much lower DILI risk of 32.028, which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB penetration (96.123) than Ligand A (43.699), but this is less important here.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-4.909) which is unusual and suggests poor permeability. Ligand B has a negative Caco-2 value as well (-4.4), also suggesting poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.878 and -2.933), which is concerning. Solubility issues can hinder bioavailability.

**hERG:** Both ligands have low hERG risk (0.504 and 0.552), which is good.

**Microsomal Clearance:** Ligand A has a moderate Cl_mic of 35.347 mL/min/kg. Ligand B has a lower Cl_mic of 25.332 mL/min/kg, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a reasonable t1/2 of 7.605 hours. Ligand B has a significantly *negative* t1/2 (-15.648 hours), which is not physically possible and indicates a serious issue with the data or the molecule's stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.203 and 0.025), which is favorable.

**Binding Affinity:** Ligand B (-8.6 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 be considered.

**Conclusion:**

Despite both ligands having some issues with solubility and Caco-2 permeability, Ligand B is the better candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly better binding affinity. 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. Ligand A's high DILI risk is a significant concern.

Output:
1
2025-04-17 15:46:10,869 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (378.441 and 367.921 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.34) is slightly higher than the preferred <140, but acceptable. Ligand B (52.65) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands (1.176 and 1.699) 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:** Both ligands have good QED scores (0.703 and 0.772), indicating drug-like properties.

**DILI:** Ligand A (45.25) has a moderate DILI risk, but acceptable. Ligand B (10.702) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.9) is higher than Ligand B (61.884).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.118 and -5.0). This is unusual and suggests poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.25 and -1.739). This is also unusual and suggests poor solubility. Again, the absolute values are similar.

**hERG:** Ligand A (0.151) has a slightly higher hERG risk than Ligand B (0.5), which is preferable.

**Microsomal Clearance:** Ligand A (-12.342) has a much lower (better) microsomal clearance than Ligand B (2.469), indicating significantly better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (14.559 and 14.294 hours), which are good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.063).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol) - a difference of 1.8 kcal/mol, which is substantial.

**Conclusion:**

While both ligands have some concerning solubility and permeability issues (negative Caco-2 and solubility values), Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.3 vs -6.5 kcal/mol) outweighs the slightly higher DILI and hERG risks. Furthermore, Ligand A's much lower microsomal clearance suggests better metabolic stability, a crucial factor for kinase inhibitors. The lower DILI risk of Ligand B is attractive, but the substantial difference in binding affinity makes Ligand A the better choice for further optimization.

Output:
1
2025-04-17 15:46:10,869 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (342.439 Da and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (83.22). TPSA <140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**3. logP:** Both ligands have acceptable logP values (1.087 and 2.348, respectively), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially hinting at slightly reduced solubility.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 3, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 each), well below the 10 threshold.

**6. QED:** Ligand A (0.752) has a better QED score than Ligand B (0.567), indicating a more drug-like profile.

**7. DILI:** Ligand A (40.752) has a slightly higher DILI risk than Ligand B (25.436), but both are below the concerning threshold of 60.

**8. BBB:** Both have similar BBB penetration (54.75 and 59.519), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.766) has a worse Caco-2 permeability than Ligand B (-5.051). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.164) has better aqueous solubility than Ligand B (-2.4). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.22 and 0.321, respectively).

**12. Microsomal Clearance:** Ligand A (7.636) has significantly lower microsomal clearance than Ligand B (32.544). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (7.449) has a longer in vitro half-life than Ligand B (0.634), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.049 and 0.097, respectively).

**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 (1.2 kcal/mol difference), and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better ADME properties (QED, solubility, metabolic stability, half-life), Ligand B boasts a considerably stronger binding affinity. For an enzyme target like SRC kinase, potency is paramount. The 1.2 kcal/mol difference in binding affinity is significant and likely to translate into greater efficacy *in vivo*. The slightly worse ADME profile of Ligand B can potentially be addressed through further optimization, but improving a weaker binding affinity is often more challenging.

Output:
1
2025-04-17 15:46:10,869 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (357.439 and 360.336 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84) is slightly above the preferred <140, but acceptable. Ligand B (78.79) is well within the acceptable range.

**3. logP:** Both ligands have good logP values (2.297 and 1.579), 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 7 HBAs, and Ligand B has 6, both within the acceptable limit of <=10.

**6. QED:** Ligand B (0.863) has a significantly better QED score than Ligand A (0.394), indicating a more drug-like profile.

**7. DILI:** Ligand B (55.176) has a much lower DILI risk than Ligand A (83.288). This is a significant advantage for Ligand B.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (89.066) is higher than Ligand A (70.027). While not a primary concern for a kinase inhibitor, it's a slight benefit.

**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 magnitude is unclear. Ligand B (-4.438) is slightly better than Ligand A (-5.196).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-2.877) is slightly better than Ligand A (-4.264).

**11. hERG Inhibition:** Ligand B (0.265) has a much lower hERG risk than Ligand A (0.755). This is a critical advantage.

**12. Microsomal Clearance:** Ligand B (40.177) has significantly lower microsomal clearance than Ligand A (116.822), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.613) has a longer in vitro half-life than Ligand A (-12.739).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.17 and 0.63 respectively).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Overall Assessment:**

Ligand B is clearly superior. It demonstrates a significantly better safety profile (lower DILI and hERG), improved drug-likeness (higher QED), and better pharmacokinetic properties (lower Cl_mic, longer t1/2). While both have issues with Caco-2 and solubility, Ligand B is better in both regards. The binding affinity is comparable, so the improved ADME properties of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 15:46:10,869 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Ligand A (67.08) is better than Ligand B (80.04). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.256) is within the optimal range (1-3), while Ligand B (4.585) is slightly higher. While not a dealbreaker, higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=3, HBA=3). Lower HBD and HBA generally improve permeability.

**QED:** Ligand A (0.789) has a significantly better QED score than Ligand B (0.583), indicating a more drug-like profile.

**DILI:** Ligand B (92.168) has a substantially higher DILI risk than Ligand A (65.646). This is a significant concern.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 73.672, Ligand B: 72.78). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-5.343) has a more favorable Caco-2 permeability than Ligand B (-4.875), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.983) has better aqueous solubility than Ligand B (-5.835). Solubility is important for formulation and bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.674, Ligand B: 0.661). This is excellent.

**Microsomal Clearance:** Ligand B (40.808) has lower microsomal clearance than Ligand A (55.599), indicating better metabolic stability. This is a positive attribute.

**In vitro Half-Life:** Ligand B (109.409) has a significantly longer in vitro half-life than Ligand A (23.358). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.724, Ligand B: 0.215), which is good.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This difference of 1.2 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better overall drug-like profile (higher QED, better solubility, permeability, and lower DILI risk) and a slightly better binding affinity. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2). The DILI risk associated with Ligand B is concerning, but the substantial improvement in half-life is a significant advantage for an enzyme inhibitor. Given the importance of potency and metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 15:46:10,870 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.384 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.29) is significantly better than Ligand B (81.67). TPSA < 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have acceptable logP values (0.74 and 1.033), 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). Both are within acceptable limits (<=5 HBD, <=10 HBA), but fewer H-bonds generally improves permeability.

**QED:** Ligand A (0.858) has a substantially better QED score than Ligand B (0.61), indicating a more drug-like profile.

**DILI:** Ligand A (36.448) has a much lower DILI risk than Ligand B (12.641). Both are below 40, which is good, but A is significantly safer.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.425) is better than Ligand B (40.558).

**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 (-5.067 vs -5.119), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.829) is slightly better than Ligand B (-2.305).

**hERG:** Both ligands have low hERG risk (0.501 and 0.152), which is excellent.

**Microsomal Clearance:** Ligand A (-22.793) has a much lower (better) microsomal clearance than Ligand B (33.452), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.463) has a better in vitro half-life than Ligand B (-1.626).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.047 and 0.044).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is only 0.5 kcal/mol, which is less significant than the substantial ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: QED, DILI, metabolic stability (Cl_mic and t1/2), solubility, and permeability (Caco-2). These factors are particularly important for an enzyme target like SRC kinase, where maintaining adequate exposure and minimizing toxicity are critical. The 0.5 kcal/mol difference in binding affinity is unlikely to outweigh the substantial improvements in drug-like properties offered by Ligand A.

Output:
0
2025-04-17 15:46:10,870 - INFO - Batch 407 complete. Total preferences: 6512
2025-04-17 15:46:10,870 - INFO - Processing batch 408/512...
2025-04-17 15:46:50,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.443 Da) is slightly lower than Ligand B (348.403 Da), which is acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (91.84) is slightly better than Ligand A (96.69).

**logP:** Ligand A (2.15) is within the optimal range (1-3). Ligand B (-0.174) is below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (A: 0.798, B: 0.545), indicating drug-like properties. Ligand A is better.

**DILI:** Both ligands have acceptable DILI risk (A: 44.009, B: 39.162), below the 60 threshold. Ligand B is slightly better.

**BBB:** Both ligands have similar, moderate BBB penetration (A: 59.364, B: 59.093). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both, but the magnitude is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the magnitude is similar.

**hERG:** Both ligands have low hERG risk (A: 0.501, B: 0.27). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (-1.919 mL/min/kg) has significantly *lower* (better) microsomal clearance than Ligand B (10.179 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (12.097 hours) has a much longer half-life than Ligand B (-15.869 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.118, B: 0.015). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This is a 0.6 kcal/mol difference, which is notable but not overwhelming.

**Overall Assessment:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and better QED score. While Ligand B has a slightly better binding affinity and lower P-gp efflux, the ADME properties of Ligand A are more favorable for development as an enzyme inhibitor. The negative Caco-2 and solubility values are concerning for both, but the metabolic stability advantage of A is more critical for an enzyme target.

Output:
0
2025-04-17 15:46:50,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.809 and 347.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is better than Ligand B (71.09), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (3.729 and 3.063), 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:** Both ligands have acceptable QED scores (0.652 and 0.561), indicating reasonable drug-likeness.

**DILI:** Ligand B (37.611) has a significantly lower DILI risk than Ligand A (93.525). This is a major advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (68.36) is slightly higher, but neither is particularly high.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.692) is slightly better than Ligand B (-4.806), but both are concerning.

**Aqueous Solubility:** Ligand B (-2.324) has better aqueous solubility than Ligand A (-5.358). This is a positive for Ligand B.

**hERG:** Both ligands have low hERG inhibition liability (0.161 and 0.306), which is good.

**Microsomal Clearance:** Ligand A (40.397) has lower microsomal clearance than Ligand B (46.797), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.712) has a slightly longer in vitro half-life than Ligand B (16.717).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.222 and 0.084).

**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 still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate despite the slightly weaker binding affinity. The significantly lower DILI risk and better solubility are crucial advantages. The slightly better half-life of Ligand A is outweighed by the higher DILI risk. Both ligands have poor Caco-2 permeability, which is a concern that would need to be addressed in further optimization.

Output:
1
2025-04-17 15:46:50,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.451 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.7) is slightly above the preferred <140, while Ligand B (97.12) is well within. This favors Ligand B for absorption.

**logP:** Both ligands have logP values (1.387 and 2.501) within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, satisfying the <5 and <10 rules respectively.

**QED:** Both ligands have good QED scores (0.7 and 0.823), indicating drug-like properties.

**DILI:** Ligand A (36.022) has a significantly lower DILI risk than Ligand B (65.103). This is a major advantage for Ligand A.

**BBB:** Both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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, which is also unusual. Ligand B is worse (-3.905) than Ligand A (-1.752).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.106 and 0.22), which is good.

**Microsomal Clearance:** Ligand A (27.216) has lower microsomal clearance than Ligand B (30.98), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.233) has a longer in vitro half-life than Ligand A (15.446), which is generally desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.012 and 0.23).

**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 ADME concerns.

**Conclusion:**

While Ligand A has a much better safety profile (lower DILI) and slightly better metabolic stability, the significantly improved binding affinity of Ligand B (-8.8 vs -7.7 kcal/mol) is the most critical factor for an enzyme inhibitor. The difference in binding affinity is large enough to compensate for the higher DILI risk and slightly shorter half-life. The solubility issues are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:46:50,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.5 and 355.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (56.15 and 52.65) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have good logP values (3.235 and 2.211) falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 and 3 respectively), satisfying the <5 and <10 rules.

**QED:** Both ligands have QED values above 0.5 (0.661 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (15.394) has a slightly higher DILI risk than Ligand B (14.541), but both are well below the concerning threshold of 60.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand B (91.974) has a higher percentile than Ligand A (76.347).

**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 more context.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, these values are on a different scale and hard to interpret without more context.

**hERG Inhibition:** Ligand A (0.551) has a slightly lower hERG inhibition liability than Ligand B (0.892), which is preferable.

**Microsomal Clearance:** Ligand B (8.743 mL/min/kg) has significantly lower microsomal clearance than Ligand A (60.747 mL/min/kg), indicating better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-16.144 hours) has a significantly longer in vitro half-life than Ligand A (8.13 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.58) has lower P-gp efflux liability than Ligand B (0.229), which could improve bioavailability.

**Binding Affinity:** Ligand A (-9.3 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. The difference is greater than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite Ligand B having better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility and DILI profiles, the significantly stronger binding affinity of Ligand A (-9.3 vs -6.3 kcal/mol) is the most crucial factor for an enzyme target like SRC kinase. The difference in binding affinity is substantial enough to compensate for the slightly higher Cl_mic and lower half-life of Ligand A.

Output:
1
2025-04-17 15:46:50,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.392 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.6) is well below the 140 threshold for oral absorption, and is favorable. Ligand B (78.87) is still within acceptable range, but less optimal.

**logP:** Both ligands have logP values (2.786 and 1.704) within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**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 (0.821 and 0.735), indicating good drug-likeness.

**DILI:** Both ligands have the same DILI risk (15%), which is low and favorable.

**BBB:** Ligand A (85.033) has a significantly higher BBB penetration percentile than Ligand B (51.842). While not a primary concern for a non-CNS target like SRC, it isn't a detriment.

**Caco-2 Permeability:** Ligand A (-4.909) shows better Caco-2 permeability than Ligand B (-4.544), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.061) has slightly better aqueous solubility than Ligand B (-2.416). Both are poor, but A is better.

**hERG Inhibition:** Both ligands have very similar, low hERG inhibition risk (0.733 and 0.425).

**Microsomal Clearance:** This is a crucial parameter for enzymes. Ligand A (-2.47) has a *much* lower (better) microsomal clearance than Ligand B (77.165). This indicates significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (12.061 hours) has a significantly longer half-life than Ligand B (-14.461 hours). This is a major advantage for Ligand A, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.276).

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Conclusion:**

While both ligands exhibit good binding affinity and acceptable drug-likeness, Ligand A is significantly superior due to its much better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility and Caco-2 permeability. These factors are critical for an enzyme inhibitor to achieve adequate exposure and efficacy *in vivo*. The higher BBB value is a neutral benefit.

Output:
1
2025-04-17 15:46:50,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.426 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold for good absorption. Ligand B (58.64) is still reasonable, but higher.

**logP:** Ligand A (4.151) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.489) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 3 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.757 and 0.769), indicating good drug-likeness.

**DILI:** Ligand A (31.873) has a much lower DILI risk than Ligand B (6.747), which is a significant advantage.

**BBB:** Ligand A (91.392) shows better BBB penetration than Ligand B (77.898), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.332) has a worse Caco-2 permeability than Ligand B (-4.767).

**Aqueous Solubility:** Ligand A (-4.394) has worse aqueous solubility than Ligand B (-2.211).

**hERG:** Ligand A (0.809) has a slightly higher hERG risk than Ligand B (0.368), which is preferable.

**Microsomal Clearance:** Ligand A (58.703) has a higher microsomal clearance than Ligand B (20.041), indicating lower metabolic stability. This is a key disadvantage.

**In vitro Half-Life:** Ligand B (-2.248) has a longer in vitro half-life than Ligand A (13.619), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.302) has lower P-gp efflux than Ligand B (0.062), which is favorable.

**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.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, and better P-gp efflux. However, it suffers from higher logP, lower solubility, higher microsomal clearance, and shorter half-life. Ligand B has better ADME properties (solubility, metabolic stability, half-life, lower hERG), but weaker binding affinity.

Given that SRC is a kinase, potency (binding affinity) is paramount. The 1.3 kcal/mol difference in binding affinity is substantial. While Ligand A's ADME properties are not ideal, they are not catastrophic, and optimization could potentially address these issues. The stronger binding is likely to translate to greater efficacy *in vivo*, and the lower DILI risk is a major plus.

Output:
0
2025-04-17 15:46:50,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (334.335 and 347.379 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (104.04) is better than Ligand B (129.03), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.528) is optimal, while Ligand B (0.129) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 7. Both are acceptable, being <=10.

**QED:** Both ligands have good QED scores (0.516 and 0.681, respectively), indicating drug-like properties.

**DILI:** Ligand A (97.286) has a significantly higher DILI risk than Ligand B (71.268). This is a major concern for Ligand A.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the low logP of Ligand B exacerbates this issue.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG:** Ligand A (0.206) has a slightly higher hERG risk than Ligand B (0.064), but both are relatively low.

**Microsomal Clearance:** Ligand B (-5.27) has a significantly lower (better) microsomal clearance than Ligand A (2.398), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-27.52) has a much longer in vitro half-life than Ligand A (2.798), indicating better stability.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**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.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is paramount for an enzyme inhibitor. However, its high DILI risk is a significant drawback. Ligand B, while having weaker affinity, exhibits much better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The poor permeability and solubility are concerns for both, but the affinity difference is substantial. Given the importance of potency for enzyme inhibition, and the potential to address solubility/permeability with formulation strategies, the stronger affinity of Ligand A is likely to outweigh its higher DILI risk, *provided* further investigation confirms the DILI prediction and mitigation strategies are feasible.

Output:
1
2025-04-17 15:46:50,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.441 Da) is slightly lower, which could be beneficial for permeability. Ligand B (425.396 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (58.12) is lower than Ligand A (69.72), which is slightly preferable.

**logP:** Ligand A (1.1) is within the optimal range, while Ligand B (3.774) is approaching the upper limit. Higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a slightly higher HBA count (5) compared to Ligand A (3), but both are within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.751) is slightly better than Ligand B (0.665).

**DILI:** Ligand A (23.071) has a significantly lower DILI risk than Ligand B (33.23), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (83.482) is better than Ligand B (71.384). While not a primary concern for a kinase inhibitor, higher BBB is never detrimental.

**Caco-2 Permeability:** Ligand A (-4.788) has a better Caco-2 permeability than Ligand B (-5.38).

**Aqueous Solubility:** Ligand A (-2.997) has better aqueous solubility than Ligand B (-3.274). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.363) has a lower hERG inhibition risk than Ligand B (0.799), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-14.043) exhibits significantly lower microsomal clearance, indicating better metabolic stability, than Ligand B (77.419). This is a critical advantage for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-42.11) has a longer in vitro half-life than Ligand B (63.75).

**P-gp Efflux:** Ligand A (0.011) has lower P-gp efflux liability than Ligand B (0.348), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). The difference is 0.8 kcal/mol, which is a substantial advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME-Tox properties across the board. Specifically, its lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG inhibition, and better solubility are crucial advantages for a kinase inhibitor. The 0.8 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand A, while mitigating the ADME liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 15:46:50,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.877 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (70.67 and 74.43) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (not a priority here).

**3. logP:** Both ligands (2.451 and 2.353) are 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 10 limit.

**6. QED:** Both ligands have high QED scores (0.784 and 0.793), indicating good drug-like properties.

**7. DILI:** Ligand A (34.277) has a slightly higher DILI risk than Ligand B (25.359), but both are below the 40 threshold and considered good.

**8. BBB:** This is not a major concern for a non-CNS target. Ligand A (76.696) has a higher BBB percentile than Ligand B (64.637).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.766 and -4.769). 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, but rather lower than ideal.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.906 and -2.551). Again, these are on a log scale and indicate poor aqueous solubility. This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.468 and 0.579).

**12. Microsomal Clearance:** Ligand B (12.067) has a lower microsomal clearance than Ligand A (17.372), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (-9.45) has a significantly longer in vitro half-life than Ligand A (24.098). This is a substantial advantage, potentially allowing for less frequent dosing. Note the negative value for ligand B is likely an error.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.138).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have similar potency and acceptable safety profiles, Ligand B exhibits significantly better metabolic stability (lower Cl_mic) and a longer in vitro half-life. These factors are crucial for enzyme inhibitors, as they contribute to sustained target engagement and potentially lower dosing frequency. The slightly lower DILI risk of Ligand B is also a minor benefit. The solubility and permeability issues are shared by both, and would need to be addressed through formulation strategies.

Output:
1
2025-04-17 15:46:50,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.415 and 362.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.97 and 78.43) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (2.94) is optimal, while Ligand B (1.915) is slightly lower but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 3 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.709) has a better QED score than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand A (63.164) has a higher DILI risk than Ligand B (18.651). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (73.672 and 79.488), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is important. -4.916 (Ligand B) is better than -5.217 (Ligand A).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. -2.401 (Ligand A) is slightly better than -2.527 (Ligand B).

**hERG Inhibition:** Ligand A (0.805) has a slightly higher hERG risk than Ligand B (0.336), but both are relatively low.

**Microsomal Clearance:** Ligand A (19.212 mL/min/kg) has lower microsomal clearance than Ligand B (24.424 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (55.741 hours) has a significantly longer half-life than Ligand B (-8.933 hours). The negative value for Ligand B is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.076).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This 0.7 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and longer half-life, its significantly higher DILI risk is a major concern. Ligand B has a lower DILI risk, better binding affinity, and better Caco-2 permeability, despite its slightly lower QED and shorter half-life. The binding affinity difference is also significant enough to outweigh the other minor drawbacks.

Output:
1
2025-04-17 15:46:50,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.487 Da and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.51) is slightly higher than Ligand B (82.53), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.121) is optimal, while Ligand B (2.609) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.704 and 0.836), indicating good drug-like properties.

**DILI:** Ligand A (25.514) has a significantly lower DILI risk than Ligand B (63.513). This is a major advantage for Ligand A.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (66.033) is slightly higher than Ligand A (60.876). However, BBB is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.226 and -5.018), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.952) has slightly better solubility than Ligand B (-3.841), although both are quite poor.

**hERG Inhibition:** Ligand A (0.163) has a much lower hERG inhibition liability than Ligand B (0.724). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (24.072) has lower microsomal clearance than Ligand A (26.201), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (3.194) has a longer in vitro half-life than Ligand A (-13.803). This is a clear advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux than Ligand B (0.281), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 0.6 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better affinity and half-life, Ligand A demonstrates significantly better safety profiles with much lower DILI and hERG risk. The slightly better solubility and P-gp efflux of Ligand A are also beneficial. The poor Caco-2 permeability is a concern for both, but the safety advantages of Ligand A outweigh the minor affinity difference. For an oncology target, minimizing off-target effects and toxicity is crucial.

Output:
0
2025-04-17 15:46:50,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (400.825 Da) is slightly higher than Ligand B (355.383 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, indicating good potential for oral absorption. Ligand B (116.76) is slightly lower, which is marginally better.

**logP:** Ligand A (2.315) is within the optimal range (1-3). Ligand B (0.664) is below 1, which could hinder permeation. This is a significant negative for Ligand B.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (1 & 2 respectively) and HBA (8) counts, falling within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand B (0.66) is slightly better.

**DILI:** Ligand A has a very high DILI risk (99.457%), which is a major concern. Ligand B has a DILI risk of 92.982%, still high, but better than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Both have moderate BBB penetration.

**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, also unusual and concerning for bioavailability.

**hERG:** Ligand A (0.183) has a very low hERG risk, which is excellent. Ligand B (0.464) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (10.259 mL/min/kg) has a much lower microsomal clearance than Ligand B (19.069 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (83.336 hours) has a significantly longer half-life than Ligand B (7.617 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.49) has lower P-gp efflux than Ligand B (0.09), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. The difference of 7.6 kcal/mol is substantial and likely outweighs many of the ADME drawbacks.

**Conclusion:**

Despite the concerning DILI score and poor permeability/solubility for both, Ligand A is the far superior candidate. Its significantly stronger binding affinity (-7.6 vs 0.0 kcal/mol), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux outweigh the drawbacks. The high DILI risk is a serious concern that would need to be addressed in further optimization, but the potency advantage is too significant to ignore. Ligand B's low logP and extremely weak binding affinity make it unlikely to be a viable drug candidate.

Output:
1
2025-04-17 15:46:50,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.431 and 360.445 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.53) is better than Ligand B (58.64), being closer to the upper limit for good oral absorption (<=140).

**3. logP:** Both ligands have acceptable logP values (1.053 and 2.305, respectively), 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 (4) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.834 and 0.791), indicating good drug-like properties.

**7. DILI:** Ligand A (24.661) has a significantly lower DILI risk than Ligand B (16.789), which is a crucial advantage.

**8. BBB:** Ligand B (93.641) has a higher BBB penetration percentile than Ligand A (54.983). However, since SRC is not a CNS target, this is less important.

**9. Caco-2 Permeability:** Ligand A (-5.02) has worse Caco-2 permeability than Ligand B (-4.523).

**10. Aqueous Solubility:** Ligand A (-1.785) has slightly better aqueous solubility than Ligand B (-2.548).

**11. hERG Inhibition:** Ligand A (0.176) shows a lower hERG inhibition liability than Ligand B (0.561), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (-10.068) has significantly lower microsomal clearance than Ligand B (46.029), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.808) has a longer in vitro half-life than Ligand B (-17.51), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.01) has lower P-gp efflux liability than Ligand B (0.021).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are good, the 1.5kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the superior candidate. It has a lower DILI risk, lower hERG inhibition, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While Ligand B has better Caco-2 permeability and BBB penetration, these are less critical for a non-CNS enzyme target like SRC. The improved safety profile and metabolic stability of Ligand A outweigh the minor advantage of Ligand B in permeability.

Output:
1
2025-04-17 15:46:50,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.531 and 359.392 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.32) is slightly above the preferred <140, but acceptable. Ligand B (54.46) is well within the acceptable range.

**logP:** Both ligands (2.447 and 2.583) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (0.623 and 0.848), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (41.877 and 32.997), which is favorable.

**BBB:** Ligand A (12.447) has very low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (91.392) has high BBB penetration, which isn't particularly useful here.

**Caco-2 Permeability:** Ligand A (-5.088) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.416) also has poor Caco-2 permeability, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.928 and -2.846). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.299 and 0.631), which is excellent.

**Microsomal Clearance:** Ligand A (33.129) has higher microsomal clearance than Ligand B (25.422). Lower clearance is preferred for better metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (-24.679) has a negative half-life, which is not possible. This is a data error and a major red flag. Ligand A (32.506) has a reasonable in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.138 and 0.125), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Despite both ligands having excellent binding affinity and acceptable safety profiles, Ligand A is significantly hampered by its poor Caco-2 permeability. Ligand B has a data error with a negative in vitro half-life, which is a critical issue. Given the importance of metabolic stability for kinase inhibitors, and the fact that the binding affinity is nearly identical, Ligand A is the more viable candidate *despite* the permeability issue, as permeability can sometimes be improved with formulation strategies. The negative half-life for Ligand B is a showstopper.

Output:
0
2025-04-17 15:46:50,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 351.506 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.92) is better than Ligand B (29.54) as it is still within a reasonable range for oral absorption, while ligand B is very low and may indicate poor potency.

**logP:** Ligand A (1.011) is within the optimal range (1-3). Ligand B (4.659) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both acceptable.

**QED:** Ligand A (0.853) has a significantly better QED score than Ligand B (0.47), indicating a more drug-like profile.

**DILI:** Ligand A (38.426) has a much lower DILI risk than Ligand B (10.275), which is a significant advantage.

**BBB:** Ligand A (60.876) and Ligand B (95.967). BBB is not a high priority for this target.

**Caco-2:** Ligand A (-4.719) and Ligand B (-4.412) are similar.

**Solubility:** Ligand A (-1.641) is better than Ligand B (-4.143).

**hERG:** Ligand A (0.166) is much better than Ligand B (0.842), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-18.868) has a much lower (and therefore better) microsomal clearance than Ligand B (88.415), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (25.872) has a longer half-life than Ligand B (14.77), which is desirable.

**P-gp:** Both ligands (0.014 and 0.742) are similar.

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better across most crucial ADME-Tox properties. It has a better QED score, lower DILI risk, lower hERG risk, better solubility, and significantly improved metabolic stability (lower Cl_mic and longer half-life). While Ligand B has a slightly higher BBB penetration, this is less important for a kinase inhibitor. The similar binding affinity means that the superior ADME profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 15:46:50,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.391 and 349.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.0) is higher than the preferred <140 for oral absorption, but still reasonable. Ligand B (53.52) is excellent, well below 140.

**logP:** Ligand A (-0.164) is quite low, potentially hindering permeability. Ligand B (2.792) 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 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.695 and 0.692), indicating good drug-likeness.

**DILI:** Ligand A (62.233) has a higher DILI risk than Ligand B (32.261), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (87.476) has a higher BBB value than Ligand A (32.377), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.537 and -4.982), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.349 and -2.161), indicating poor solubility. This is also a significant concern for both.

**hERG:** Ligand A (0.114) has a slightly lower hERG risk than Ligand B (0.965), which is favorable.

**Microsomal Clearance:** Ligand A (-19.179) has a much lower (better) microsomal clearance than Ligand B (55.327), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.826) has a longer in vitro half-life than Ligand B (32.652), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.006 and 0.446).

**Binding Affinity:** Ligand A (-8.8) has a significantly stronger binding affinity than Ligand B (-7.7), a difference of 1.1 kcal/mol. This is a substantial advantage.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand A is the better candidate. Its significantly stronger binding affinity (-8.8 vs -7.7 kcal/mol) outweighs the slightly higher DILI risk and lower logP. Furthermore, Ligand A exhibits superior metabolic stability (lower Cl_mic) and a longer half-life, crucial for an enzyme inhibitor. The lower hERG risk is also a plus. While both need improvement in solubility and permeability, the potency and pharmacokinetic advantages of Ligand A make it the more promising starting point for optimization.

Output:
0
2025-04-17 15:46:50,106 - INFO - Batch 408 complete. Total preferences: 6528
2025-04-17 15:46:50,106 - INFO - Processing batch 409/512...
2025-04-17 15:47:33,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (84.74). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (1.855) is optimal, while Ligand B (0.397) is a bit low. A logP below 1 can sometimes hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=0, HBA=7). Both are within acceptable limits, but Ligand A's profile is more balanced.

**QED:** Both ligands have similar and good QED values (A: 0.747, B: 0.767), indicating good drug-like properties.

**DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (68.786). This is a significant advantage for Ligand A.

**BBB:** Both have relatively low BBB penetration, which isn't a primary concern for an oncology target like SRC.

**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 Inhibition:** Ligand A (0.226) has a much lower hERG risk than Ligand B (0.452). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (12.192) has lower microsomal clearance than Ligand B (20.604), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (19.394) has a significantly longer half-life than Ligand B (3.239). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While a 0.9 kcal/mol difference is noticeable, the other ADME properties of Ligand A are significantly more favorable.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, including lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and more favorable TPSA and logP values. These factors are critical for developing a viable drug candidate, especially for an enzyme target where metabolic stability and safety are paramount.

Output:
0
2025-04-17 15:47:33,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 349.435 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.46) is slightly above the preferred <140 for good absorption, while Ligand B (91.57) is well within the range.

**logP:** Ligand A (1.169) is within the optimal 1-3 range. Ligand B (0.45) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, both acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.581 and 0.733), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (31.989 and 28.189 percentile), which is favorable.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand B (81.466) has a higher BBB value than Ligand A (47.15), but this is less critical.

**Caco-2:** Both have negative Caco-2 values (-5.402 and -5.338), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both have negative solubility values (-0.962 and -1.628), indicating poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Both ligands have very low hERG risk (0.17 and 0.091), which is excellent.

**Microsomal Clearance:** Ligand A (10.487 mL/min/kg) has lower clearance than Ligand B (13.315 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.805 hours) has a positive half-life, while Ligand B (-2.862 hours) has a negative half-life, which is impossible. This is a major red flag for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.081 and 0.026).

**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 outweigh some ADME drawbacks.

**Conclusion:**

Despite both ligands having solubility and permeability issues, Ligand A is the more promising candidate. Its significantly higher binding affinity (-9.4 vs -8.1 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic) and a plausible half-life, while Ligand B has a negative half-life which is not possible. While both have poor solubility and permeability, these can potentially be addressed through formulation strategies. The superior potency and stability profile of Ligand A make it the better choice.

Output:
1
2025-04-17 15:47:33,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.422 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is slightly higher than Ligand B (67.23), but both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have logP values (2.139 and 2.391) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, satisfying the <5 and <10 rules, respectively.

**QED:** Ligand A (0.852) has a significantly higher QED score than Ligand B (0.551), indicating better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (25.785 and 24.506 percentile), which is favorable.

**BBB:** Ligand A (89.531) shows better BBB penetration than Ligand B (76.58), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.591) exhibits slightly better Caco-2 permeability than Ligand B (-4.648), though both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-2.449) has slightly better aqueous solubility than Ligand B (-2.156), which is a positive attribute.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.4 and 0.125), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand A (23.55 mL/min/kg) has significantly lower microsomal clearance than Ligand B (44.741 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life (t1/2):** Ligand A (8.399 hours) has a shorter half-life than Ligand B (13.122 hours). However, the lower Cl_mic of Ligand A suggests it *could* be improved with structural modifications, while B's higher clearance is harder to address.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.097 and 0.073).

**Binding Affinity:** Both ligands have strong binding affinities (-8.5 and -8.2 kcal/mol), both being below the -7.0 kcal/mol threshold. Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly longer half-life, Ligand A demonstrates superior drug-likeness (QED), metabolic stability (lower Cl_mic), and slightly better solubility and permeability. The difference in binding affinity is small enough that the ADME advantages of Ligand A outweigh it. The lower Cl_mic is particularly important for a kinase inhibitor, as it suggests a potentially longer duration of action *in vivo*.

Output:
0
2025-04-17 15:47:33,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (332.411 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.63 and 75.44) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.219 and 2.407), 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 similar QED scores (0.77 and 0.779), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 77.627, which is considered high risk (>60). Ligand B has a much lower DILI risk of 23.769, which is good (<40). This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (64.87) and Ligand B (86.817) are both reasonable, but Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.167 and -4.551), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.84 and -2.323), also unusual. Again, the absolute values are close, suggesting similar solubility issues.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.94, which is relatively low. Ligand B has a very low hERG risk of 0.238, making it preferable.

**Microsomal Clearance:** Ligand A has a Cl_mic of 41.369 mL/min/kg, while Ligand B has 33.993 mL/min/kg. Lower is better, so Ligand B has a slight advantage in metabolic stability.

**In vitro Half-Life:** Ligand A has a t1/2 of 34.752 hours, while Ligand B has 15.072 hours. Ligand A is significantly better here, suggesting a longer duration of action.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.513, and Ligand B has 0.088. Lower is better, so Ligand B is significantly better here.

**Binding Affinity:** Ligand A has a binding affinity of -9.9 kcal/mol, while Ligand B has -7.6 kcal/mol. Ligand A has a significantly stronger binding affinity, which is a major advantage. The 2.3 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity (-9.9 kcal/mol vs -7.6 kcal/mol) and a longer half-life (34.752 vs 15.072). However, it has a significantly higher DILI risk (77.627 vs 23.769). Ligand B excels in ADME properties, with lower DILI, hERG, and P-gp efflux, and slightly better metabolic stability.

Given the enzyme-specific priorities, potency (binding affinity) is paramount. The large difference in binding affinity favors Ligand A. While the DILI risk is concerning, it can be investigated further through structural modifications. The other ADME properties of Ligand A are not drastically worse than Ligand B, and the superior potency is likely to be more impactful.

Output:
0
2025-04-17 15:47:33,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.47 & 380.58 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.54) is higher than Ligand B (58.2). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have good logP values (1.58 & 2.78), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (4 & 4) counts, unlikely to cause major issues.

**QED:** Both ligands have good QED scores (0.88 & 0.72), indicating good drug-like properties.

**DILI:** Ligand A (49.86) has a slightly higher DILI risk than Ligand B (37.46), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.64) has a higher BBB score than Ligand B (49.36), but this isn't a major factor in this decision.

**Caco-2 Permeability:** Ligand A (-4.982) and Ligand B (-5.242) both have negative Caco-2 permeability values, indicating poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.177 & -3.613). This is a major concern for *in vivo* bioavailability and could necessitate formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.195 & 0.176), which is excellent.

**Microsomal Clearance:** Ligand A (14.84) has slightly higher microsomal clearance than Ligand B (13.79), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.421) has a *negative* half-life, which is not physically possible and suggests an issue with the data or the assay. Ligand A (28.2) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.139 & 0.095), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.6 & -8.6 kcal/mol). Ligand A has a 1 kcal/mol advantage, which is significant.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand A is the better candidate. It has a significantly better binding affinity (-9.6 vs -8.6 kcal/mol), a reasonable in vitro half-life (28.2 hours), and a slightly lower DILI risk. The negative half-life reported for Ligand B is a major red flag, indicating a data quality issue or a severe instability problem. While solubility and permeability need to be addressed for either compound, the stronger binding affinity of Ligand A makes it the more promising starting point for optimization.

Output:
0
2025-04-17 15:47:33,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (463.012 Da) is within the ideal range, while Ligand B (342.399 Da) is also acceptable, though on the lower side.

**TPSA:** Ligand A (64.11) is good, suggesting reasonable permeability. Ligand B (84.42) is also acceptable, but higher than A.

**logP:** Ligand A (4.878) is high, potentially leading to solubility issues and off-target effects. Ligand B (1.064) is low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4/5) counts.

**QED:** Both ligands have good QED scores (0.658 and 0.885), indicating drug-likeness.

**DILI:** Ligand A (98.449) has a very high DILI risk, a significant concern. Ligand B (52.036) has a much lower, and acceptable, DILI risk.

**BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand B (79.488) has a higher BBB score than Ligand A (67.623), but this is not a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a red flag for both.

**hERG:** Ligand A (0.424) has a slightly higher hERG risk than Ligand B (0.12), but both are relatively low.

**Microsomal Clearance:** Ligand A (73.34) has higher clearance, indicating lower metabolic stability. Ligand B (23.191) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (33.759) has a shorter half-life than Ligand B (1.369), indicating faster metabolism.

**P-gp Efflux:** Ligand A (0.311) has lower P-gp efflux, which is favorable. Ligand B (0.032) has very low P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite both ligands having issues with Caco-2 and solubility, Ligand B is the more promising candidate. Its significantly higher binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly lower logP. The high DILI risk associated with Ligand A is a major concern that makes it less viable.

Output:
1
2025-04-17 15:47:33,572 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.34 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.77) is higher than Ligand B (54.34). While both are reasonably low, Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Ligand A (-0.522) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.917) is within the optimal range.

**H-Bond Donors:** Ligand A (4) is at the upper limit, while Ligand B (1) is excellent.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.486 and 0.649, respectively), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (34.781 and 32.183, respectively), which is favorable.

**BBB:** Ligand A (70.88) has a better BBB score than Ligand B (65.413), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.61 and -5.426), which 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 negative solubility values (-1.058 and -2.575), also on a log scale, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.125) has a lower hERG risk than Ligand B (0.801), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-8.783) has much lower (better) microsomal clearance than Ligand B (74.353), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.392) has a longer half-life than Ligand B (11.008), which is desirable.

**P-gp Efflux:** Ligand A (0.008) has lower P-gp efflux than Ligand B (0.638), suggesting better bioavailability.

**Binding Affinity:** Both ligands have similar and good binding affinities (-7.5 and -8.1 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand A demonstrates superior ADME properties, particularly regarding metabolic stability (Cl_mic, t1/2), P-gp efflux, and hERG risk. While Ligand B has a slightly better binding affinity and logP, the significant advantages of Ligand A in ADME, especially metabolic stability and safety (hERG), outweigh these minor differences. The poor solubility and permeability indicated by the Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. Given the enzyme-kinase focus, metabolic stability and safety are paramount.

Output:
0
2025-04-17 15:47:33,572 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.474 and 360.439 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is significantly better than Ligand B (88.44). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands have a logP around 1.9-2.0, which is optimal.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 7. Lower HBA is generally preferred for better permeability, making Ligand A better.

**QED:** Both ligands have good QED scores (0.763 and 0.847), indicating drug-likeness.

**DILI:** Ligand A (26.948) has a much lower DILI risk than Ligand B (66.886). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.492) is better than Ligand B (55.603), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.823) is better than Ligand B (-5.052), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have the same solubility (-3.213).

**hERG Inhibition:** Ligand A (0.682) is better than Ligand B (0.306), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (30.286) has a lower clearance than Ligand B (36.411), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-32.263) has a significantly longer half-life than Ligand B (-5.911). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.149) is better than Ligand B (0.102), indicating lower P-gp efflux.

**Binding Affinity:** Ligand B (-10.0) has a significantly stronger binding affinity than Ligand A (-7.8). This is a substantial advantage for Ligand B. However, the difference in affinity (2.2 kcal/mol) must be weighed against the multiple ADME advantages of Ligand A.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is a key factor for enzyme inhibitors. However, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and better Caco-2 permeability. The improved ADMET profile of Ligand A could translate to a more viable drug candidate despite the slightly weaker binding affinity. Given the substantial difference in DILI and half-life, I lean towards Ligand A.

Output:
0
2025-04-17 15:47:33,572 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.435 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.33) is better than Ligand B (137.39). Lower TPSA generally correlates with better cell permeability. Ligand A is comfortably under the 140 A^2 threshold, while Ligand B is approaching it.

**logP:** Both ligands (-0.554 and -0.428) are a bit low, potentially hindering membrane permeability. However, they are not excessively low.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 4 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.483 and 0.505), indicating reasonable drug-likeness.

**DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (36.099). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (56.65) has a higher BBB value than Ligand A (40.791), but this isn't a deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.233 and -5.787), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.715 and -1.891), again suggesting poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.102 and 0.109), which is excellent.

**Microsomal Clearance:** Ligand B (-6.908) has a significantly *lower* (better) microsomal clearance than Ligand A (28.934). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (5.811) has a longer half-life than Ligand A (-16.28). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.013).

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.4). While the difference is small (0.3 kcal/mol), it is still a positive for Ligand B.

**Overall Assessment:**

Ligand A has a significant advantage in terms of DILI risk and TPSA. However, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. The poor Caco-2 and solubility for both are concerning, but could potentially be addressed with formulation strategies. Given the enzyme-specific priorities, metabolic stability is crucial. The lower DILI risk of Ligand A is attractive, but the substantial difference in metabolic stability in favor of Ligand B outweighs this benefit.

Output:
1
2025-04-17 15:47:33,572 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 350.419 Da, B: 349.387 Da) fall comfortably within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Both ligands (A: 105.34, B: 106.85) are below the 140 A^2 threshold for good oral absorption, but not optimized for CNS penetration (above 90 A^2). Again, no major difference.

3. **logP:** Ligand A (0.811) is better than Ligand B (0.192). Ligand B is quite low, potentially hindering permeability. A logP between 1-3 is optimal, and A is closer to this.

4. **HBD:** Ligand A (3) is slightly higher than Ligand B (2), but both are within the acceptable limit of <=5.

5. **HBA:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

6. **QED:** Ligand B (0.807) has a significantly better QED score than Ligand A (0.451), indicating a more drug-like profile overall.

7. **DILI:** Ligand B (34.548) has a lower DILI risk than Ligand A (38.891), which is preferable. Both are below the 40 threshold, so the risk is low for both.

8. **BBB:** Ligand A (55.021) has a higher BBB percentile than Ligand B (34.083). However, since SRC is not a CNS target, this is not a primary concern.

9. **Caco-2:** Ligand A (-5.387) has a worse Caco-2 permeability than Ligand B (-4.939). Higher values are better, so B is slightly favored.

10. **Solubility:** Ligand A (-2.164) has a worse solubility than Ligand B (-1.707). Higher values are better, so B is slightly favored.

11. **hERG:** Both ligands have very low hERG inhibition liability (A: 0.21, B: 0.261), which is excellent.

12. **Cl_mic:** Ligand B (-4.381) has a significantly lower (better) microsomal clearance than Ligand A (-12.677), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

13. **t1/2:** Ligand B (-46.996) has a much longer in vitro half-life than Ligand A (-6.758), further supporting its better metabolic stability.

14. **Pgp:** Both ligands have very low Pgp efflux liability (A: 0.016, B: 0.015).

15. **Binding Affinity:** Ligand A (-6.9 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 factors.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important. Ligand B excels in metabolic stability (Cl_mic and t1/2) and solubility, while Ligand A has a better binding affinity. The difference in affinity is substantial (-6.9 vs 0.0 kcal/mol).

**Conclusion:**

Despite Ligand B's better QED, DILI, and metabolic stability, the significantly stronger binding affinity of Ligand A (-6.9 kcal/mol) is a decisive factor. A strong binding affinity is crucial for kinase inhibitors, and the difference here is large enough to outweigh the other advantages of Ligand B.

Output:
1
2025-04-17 15:47:33,573 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.503 Da) is slightly higher than Ligand B (356.442 Da), but both are acceptable.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption. Ligand A (121.36) is slightly higher than Ligand B (116.29), but both are good.

**logP:** Ligand A (-0.625) is a bit low, potentially hindering permeation. Ligand B (1.129) is within the optimal 1-3 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, while Ligand B has 4. Both are below the 10 limit.

**QED:** Both ligands have good QED scores (A: 0.543, B: 0.644), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (52.074) has a higher DILI risk than Ligand B (28.693). This favors Ligand B.

**BBB:** Ligand A (41.334) has a lower BBB penetration percentile than Ligand B (68.67). Since SRC is not a CNS target, this is less critical but still favors Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.841) is slightly better than Ligand B (-5.175).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.32) is slightly better than Ligand B (-2.008).

**hERG Inhibition:** Ligand A (0.08) has a slightly lower hERG inhibition risk than Ligand B (0.504). This favors Ligand A.

**Microsomal Clearance:** Ligand A (14.951 mL/min/kg) has significantly lower microsomal clearance than Ligand B (32.092 mL/min/kg), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.341 hours) has a negative half-life, which is not possible. Ligand B (-8.655 hours) also has a negative half-life, which is also not possible. This suggests an issue with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.017, B: 0.057).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.4 kcal/mol for A and -8.6 kcal/mol for B). Ligand B is slightly stronger.

**Overall Assessment:**

Ligand B has advantages in logP, DILI, BBB, and binding affinity. However, Ligand A has a significant advantage in microsomal clearance, suggesting better metabolic stability, which is crucial for an enzyme inhibitor. The hERG risk is also slightly lower for Ligand A. The solubility and Caco-2 values are problematic for both, but slightly better for Ligand A. Considering the importance of metabolic stability for kinase inhibitors, and the slightly better hERG profile, Ligand A is the more promising candidate despite the slightly lower logP.

Output:
0
2025-04-17 15:47:33,573 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (337.463 and 357.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (93.11). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is relatively high, potentially hindering absorption.

**logP:** Ligand A (4.364) is higher than the optimal range (1-3), potentially causing solubility issues or off-target effects. Ligand B (0.061) is very low, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=3, HBA=5) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.777) has a better QED score than Ligand B (0.571), indicating a more drug-like profile.

**DILI:** Ligand A (27.724) has a much lower DILI risk than Ligand B (9.771), which is a significant advantage.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand A (71.811) is better than Ligand B (12.99).

**Caco-2 Permeability:** Ligand A (-4.54) is better than Ligand B (-5.289), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.387) is better than Ligand B (-0.465). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.809) has a lower hERG risk than Ligand B (0.353), which is a critical safety consideration.

**Microsomal Clearance:** Ligand A (62.531) has a higher Cl_mic than Ligand B (19.599), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (20.345) has a longer half-life than Ligand B (14.65), which is desirable.

**P-gp Efflux:** Ligand A (0.318) has lower P-gp efflux than Ligand B (0.016), which is better for bioavailability.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a crucial factor, and the 1.4 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is the superior candidate. While its logP is slightly high, its significantly better binding affinity, lower DILI risk, better solubility, lower hERG risk, and more favorable QED and permeability profiles outweigh this drawback. Ligand B's very low logP and higher DILI risk are major concerns. The stronger binding affinity of Ligand A is a decisive advantage for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:47:33,573 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 360.885 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is higher than Ligand B (26.63). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (1.385) is within the optimal range. Ligand B (3.909) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**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 within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (A: 0.617, B: 0.668), indicating good drug-like properties.

**DILI:** Ligand A (17.642) has a much lower DILI risk than Ligand B (22.838), which is a significant advantage.

**BBB:** Ligand A (52.036) has a lower BBB penetration percentile than Ligand B (92.943). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.248) has a negative Caco-2 value, indicating poor permeability, while Ligand B (-4.789) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.561) has slightly better aqueous solubility than Ligand B (-3.916), which is a positive.

**hERG Inhibition:** Ligand A (0.173) shows very low hERG inhibition risk, significantly better than Ligand B (0.947). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (30.726) has a lower microsomal clearance than Ligand B (57.598), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (32.794) has a significantly longer in vitro half-life than Ligand A (8.686), which is a positive.

**P-gp Efflux:** Ligand A (0.021) has a much lower P-gp efflux liability than Ligand B (0.749), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). The 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior. While Ligand B has a better half-life and BBB penetration (irrelevant here), Ligand A excels in critical areas: significantly better binding affinity, lower DILI risk, lower hERG inhibition, lower microsomal clearance, and lower P-gp efflux. The poor Caco-2 permeability of Ligand A is a concern, but the strong binding affinity and favorable safety profile make it a more promising candidate.

Output:
0
2025-04-17 15:47:33,573 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (108.02). Both are below 140, supporting oral absorption, but A is closer to the preferred <90 for potential CNS penetration (though not a priority here).

**logP:** Both ligands have good logP values (2.045 and 1.642), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is slightly better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.663 and 0.744), indicating good drug-like properties.

**DILI:** Ligand A (57.619) has a higher DILI risk than Ligand B (29.352). This is a significant drawback for Ligand A.

**BBB:** Both have similar BBB penetration (64.25 and 65.568). Not a major factor for a non-CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.241 and -4.915). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is not huge.

**Aqueous Solubility:** Both have negative solubility values (-3.663 and -2.36). Again, this is unusual and suggests poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.359) has a slightly higher hERG risk than Ligand B (0.142). Lower is better, so B is preferable.

**Microsomal Clearance:** Ligand A (30.026) has lower microsomal clearance than Ligand B (34.237), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (17.337 hours) has a significantly longer half-life than Ligand B (-10.907 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.323) has slightly lower P-gp efflux liability than Ligand B (0.025), which is favorable.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor, and a difference of 7.2 kcal/mol is substantial.

**Overall Assessment:**

Despite the DILI risk and solubility issues of Ligand A, its *significantly* stronger binding affinity (-7.2 vs -0.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the drawbacks. The affinity difference is so large that it's likely to overcome permeability and solubility issues with appropriate formulation. Ligand B's very weak binding affinity makes it a poor candidate.

Output:
1
2025-04-17 15:47:33,574 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.519 Da and 356.432 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.09) is acceptable, being under 140, but higher than ideal. Ligand B (25.36) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (1.837) is optimal. Ligand B (4.519) 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 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.649 and 0.577), indicating reasonable drug-likeness.

**DILI:** Ligand A (34.161) has a low DILI risk. Ligand B (6.398) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (42.924) has low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (98.139) has very high BBB penetration, irrelevant in this case.

**Caco-2 Permeability:** Ligand A (-5.291) has poor Caco-2 permeability. Ligand B (-4.422) has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.978) has poor aqueous solubility. Ligand B (-3.903) has very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.522) has a low hERG risk. Ligand B (0.967) has a slightly higher hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (22.317 mL/min/kg) has moderate clearance, suggesting moderate metabolic stability. Ligand B (43.762 mL/min/kg) has high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (-39.138 hours) has a long half-life, which is very desirable. Ligand B (27.127 hours) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.048) has low P-gp efflux, which is good. Ligand B (0.745) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.0 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.

**Conclusion:**

Despite Ligand B's higher logP and poor solubility, its significantly superior binding affinity (-9.0 vs -7.9 kcal/mol) and very low DILI risk make it the more promising candidate. The improved potency is likely to be more impactful than the slightly less favorable ADME properties, especially considering the long half-life. Ligand A's better solubility is offset by its weaker binding and lower half-life.

Output:
1
2025-04-17 15:47:33,574 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.451 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold and excellent for oral absorption. Ligand B (71.97) is still acceptable, but less optimal.

**logP:** Ligand A (4.259) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.03) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (0 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have QED values (0.85 and 0.704) indicating good drug-likeness.

**DILI:** Ligand A (68.864) has a higher DILI risk than Ligand B (41.838), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.345) has better BBB penetration than Ligand B (72.974), but it's not a major deciding factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we'll proceed assuming this represents low permeability.

**Aqueous Solubility:** Ligand A (-6.303) has very poor aqueous solubility, a major drawback. Ligand B (-2.153) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.66) has a slightly higher hERG risk than Ligand B (0.234), which is preferable.

**Microsomal Clearance:** Ligand A (62.456) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (15.691) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (50.577) has a reasonable half-life, but Ligand B (-17.019) has a negative half-life, which is unrealistic and suggests a data issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.258 and 0.088).

**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.

**Overall Assessment:**

Ligand A has a much better binding affinity, but suffers from poor solubility, higher DILI risk, and higher metabolic clearance. Ligand B has better solubility, lower DILI, and better metabolic stability, but its binding affinity is weaker. The negative half-life for Ligand B is a major red flag, indicating a potential data error.

Considering the priorities for enzyme inhibitors, the stronger binding affinity of Ligand A is a significant advantage. While the solubility and DILI risks are concerning, these can potentially be addressed through formulation strategies or further chemical modifications. The issues with Ligand B's half-life are more fundamental.

Output:
1
2025-04-17 15:47:33,574 - INFO - Batch 409 complete. Total preferences: 6544
2025-04-17 15:47:33,574 - INFO - Processing batch 410/512...
2025-04-17 15:48:19,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.344 and 343.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (59.0 and 55.63) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.876) is within the optimal 1-3 range. Ligand B (3.594) is slightly higher 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 4 HBA, and Ligand B has 5 HBA, both below the 10 limit.

**QED:** Ligand A (0.895) has a significantly better QED score than Ligand B (0.67), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (38.077 and 36.448, respectively), both below the 40 threshold.

**BBB:** Both ligands have good BBB penetration (81.698 and 90.617), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.504 and -5.077), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.697 and -3.62), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.766 and 0.599).

**Microsomal Clearance:** Ligand A has a much lower microsomal clearance (14.661 mL/min/kg) than Ligand B (56.253 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-7.455 hours) than Ligand B (3.887 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.325 and 0.519).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a >1.5 kcal/mol advantage, which is very significant.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B's significantly higher binding affinity (-9.2 kcal/mol vs -7.5 kcal/mol) is a decisive advantage for an enzyme target like SRC kinase. The improved binding is likely to outweigh the ADME liabilities, especially if formulation strategies can be employed to address the solubility issues. Ligand A's better metabolic stability and half-life are positive, but the weaker binding makes it less promising.

Output:
1
2025-04-17 15:48:19,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.515 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (72.72), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (2.38) is optimal, while Ligand B (0.435) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both acceptable (<=10).

**QED:** Both ligands have similar and good QED values (0.7 and 0.71 respectively).

**DILI:** Ligand A (33.773) has a slightly higher DILI risk than Ligand B (26.871), but both are below the concerning threshold of 40.

**BBB:** Both ligands have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (67.313) is slightly better than Ligand A (50.601).

**Caco-2 Permeability:** Ligand A (-5.148) and Ligand B (-4.919) have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.935) has slightly better solubility than Ligand B (0.034), though both are quite poor.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.261 and 0.223 respectively).

**Microsomal Clearance:** Ligand A (58.791) has higher microsomal clearance than Ligand B (18.44), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (15.387) has a longer half-life than Ligand B (8.296), which is positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.026 and 0.044 respectively).

**Binding Affinity:** Both ligands have identical and excellent binding affinity (-7.6 kcal/mol).

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is preferable. Its lower logP is a slight negative, but it's outweighed by its significantly better metabolic stability (lower Cl_mic and longer half-life) and lower DILI risk. The solubility is a concern for both, but can be addressed with formulation strategies. The slightly better Caco-2 permeability of Ligand B is also a plus.

Output:
1
2025-04-17 15:48:19,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.813 and 352.425 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.78) is slightly higher than Ligand B (49.41). Both are below the 140 threshold for good absorption, but B is better.

**logP:** Both ligands have good logP values (4.008 and 3.004), 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, and Ligand B has 2. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.819 and 0.856), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (79.992 percentile) compared to Ligand B (26.91 percentile). This is a major concern for Ligand A.

**BBB:** Ligand A (73.129) and Ligand B (89.608) both have acceptable BBB penetration, but B is better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.528 and -4.628), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.742 and -4.146), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.474) shows slightly higher hERG inhibition risk than Ligand B (0.556), but both are relatively low.

**Microsomal Clearance:** Ligand A (111.834 mL/min/kg) has a much higher microsomal clearance than Ligand B (32.033 mL/min/kg). This indicates lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (-31.126 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or assay. Ligand A (71.001 hours) has a good half-life.

**P-gp Efflux:** Ligand A (0.342) has lower P-gp efflux than Ligand B (0.1), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -6.6 kcal/mol). The difference is small, and both are well below the -7.0 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the better candidate despite the questionable half-life data. Its significantly lower DILI risk and lower microsomal clearance are crucial advantages for an enzyme inhibitor. While both have poor solubility and permeability, the DILI and metabolic stability concerns with Ligand A are more serious. The negative half-life for Ligand B is a red flag, but if it is a data error, B would be strongly preferred.

Output:
1
2025-04-17 15:48:19,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (361.486 and 361.471 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (45.23) is well below the 140 threshold and favorable for oral absorption. Ligand B (101.21) is still within range, but less optimal.

**3. logP:** Ligand A (3.801) is at the higher end of the optimal range (1-3), while Ligand B (1.975) is at the lower end. While Ligand A's logP is higher, it's not excessively high, and the increased lipophilicity could contribute to membrane permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both fall within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) both fall within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.851 and 0.731), indicating good drug-like properties.

**7. DILI:** Ligand A (56.96) has a lower DILI risk than Ligand B (71.811), which is a significant advantage.

**8. BBB:** Ligand A (91.121) shows better BBB penetration than Ligand B (48.003), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.683) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.236) also has a negative Caco-2 value, but is slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.617) and Ligand B (-2.636) both have negative solubility values, indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.966) has a lower hERG risk than Ligand B (0.316), which is a major advantage.

**12. Microsomal Clearance:** Ligand A (15.491) has a significantly lower microsomal clearance than Ligand B (40.994), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.784) has a longer in vitro half-life than Ligand B (23.269).

**14. P-gp Efflux:** Ligand A (0.741) has a lower P-gp efflux liability than Ligand B (0.112), which is a positive.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -7.1 kcal/mol). Ligand B has a slightly better affinity, but the difference is marginal.

**Overall Assessment:**

Despite the similar binding affinities, Ligand A is the more promising candidate. It exhibits a significantly better safety profile (lower DILI and hERG risk), 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 outweigh this drawback. The slightly higher logP of Ligand A could also be beneficial for membrane permeability, despite the negative Caco-2 values.

Output:
0
2025-04-17 15:48:19,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.423 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than Ligand B (80.32), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.22) is within the optimal 1-3 range. Ligand B (3.758) is pushing the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Both ligands have good QED scores (0.701 and 0.812), indicating drug-likeness.

**DILI:** Ligand A (83.598) has a higher DILI risk than Ligand B (75.611), which is preferable.

**BBB:** Both have similar BBB penetration (65.607 and 60.915), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.963 and -4.604), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.049 and -4.567), indicating very poor aqueous solubility. This is a major concern for *in vivo* bioavailability.

**hERG:** Ligand A (0.556) has a slightly higher hERG risk than Ligand B (0.314), making Ligand B preferable.

**Microsomal Clearance:** Ligand A (37.616) has a lower microsomal clearance than Ligand B (92.307), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-12.319) has a negative half-life, which is not possible. Ligand B (15.295) has a reasonable half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.229 and 0.095).

**Binding Affinity:** Both ligands have comparable binding affinities (-6.5 and -6.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is preferable. While both ligands suffer from poor solubility and permeability, Ligand B has a better hERG profile, a more reasonable half-life, and a lower DILI risk. Ligand A has better metabolic stability, but the negative half-life is a showstopper. The binding affinity difference is not significant enough to overcome the other drawbacks of Ligand A.

Output:
1
2025-04-17 15:48:19,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.391 and 370.566 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.04) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (59.08) is well within the ideal range.

**logP:** Ligand A (-0.761) is a bit low, potentially hindering permeability. Ligand B (1.685) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.299 and 0.691), with Ligand B being significantly better.

**DILI:** Both ligands have low DILI risk (33.579 and 30.748), both below the 40 threshold.

**BBB:** Ligand A (46.336) and Ligand B (63.668) both have relatively low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.888) shows poor permeability, while Ligand B (-4.516) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.394 and -1.871). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.042 and 0.357), which is excellent.

**Microsomal Clearance:** Ligand A (-29.024) has a negative Cl_mic, indicating very slow clearance and excellent metabolic stability. Ligand B (64.09) has a high Cl_mic, suggesting rapid metabolism. This is a significant drawback.

**In vitro Half-Life:** Ligand A (4.274) has a short half-life, while Ligand B (3.811) is similar.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.183).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is not substantial enough to outweigh the significant metabolic stability advantage of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While its logP and Caco-2 permeability are suboptimal, its *exceptionally* low microsomal clearance (negative value) and therefore predicted high metabolic stability are crucial for a kinase inhibitor. The slightly weaker binding affinity is less concerning than the rapid metabolism predicted for Ligand B. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 15:48:19,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight (MW):**
* Ligand A: 443.128 Da - Within the ideal range (200-500 Da).
* Ligand B: 375.479 Da - Also within the ideal range.
* *Both are acceptable.*

**2. TPSA:**
* Ligand A: 54.79 A^2 - Good, well below the 140 A^2 threshold for oral absorption.
* Ligand B: 78.43 A^2 - Still acceptable for oral absorption, but higher than Ligand A.
* *Ligand A is slightly better.*

**3. logP:**
* Ligand A: 4.697 - High, potentially problematic for solubility and off-target effects.
* Ligand B: 1.637 - Optimal, within the 1-3 range.
* *Ligand B is significantly better.*

**4. H-Bond Donors (HBD):**
* Ligand A: 0 - Acceptable.
* Ligand B: 1 - Acceptable.
* *Comparable.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 4 - Acceptable.
* Ligand B: 7 - Acceptable.
* *Comparable.*

**6. QED:**
* Ligand A: 0.689 - Good, above the 0.5 threshold.
* Ligand B: 0.879 - Excellent, even better drug-like properties.
* *Ligand B is better.*

**7. DILI:**
* Ligand A: 75.572 - Moderate risk.
* Ligand B: 90.268 - High risk.
* *Ligand A is better.*

**8. BBB:**
* Ligand A: 79.566 - Not a primary concern for an oncology target, but acceptable.
* Ligand B: 51.958 - Lower, not a concern.
* *Comparable.*

**9. Caco-2 Permeability:**
* Ligand A: -4.518 - Very poor permeability.
* Ligand B: -5.152 - Very poor permeability.
* *Comparable, both are poor.*

**10. Aqueous Solubility:**
* Ligand A: -5.427 - Very poor solubility.
* Ligand B: -3.235 - Poor solubility, but better than Ligand A.
* *Ligand B is better.*

**11. hERG Inhibition:**
* Ligand A: 0.581 - Low risk.
* Ligand B: 0.254 - Very low risk.
* *Ligand B is better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 42.683 mL/min/kg - Moderate clearance.
* Ligand B: 39.537 mL/min/kg - Lower clearance, better metabolic stability.
* *Ligand B is better.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 70.04 hours - Good.
* Ligand B: 6.132 hours - Poor.
* *Ligand A is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.643 - Moderate efflux.
* Ligand B: 0.03 - Low efflux.
* *Ligand B is better.*

**15. Binding Affinity:**
* Ligand A: -8.0 kcal/mol - Excellent.
* Ligand B: -8.1 kcal/mol - Slightly better, but the difference is minimal.
* *Ligand B is marginally better.*

**Overall Assessment:**

While both ligands have good binding affinity, Ligand B demonstrates a superior ADMET profile. It has a more optimal logP, better QED, lower DILI risk, better hERG inhibition, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. Ligand A has a better half-life, but its poor solubility and permeability, combined with the higher DILI risk, are significant drawbacks. The slight advantage in binding affinity of Ligand B is sufficient to outweigh the half-life difference.

Output:
1
2025-04-17 15:48:19,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.394 and 368.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.89) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (85.77) is excellent, well below 140.

**logP:** Both ligands (0.801 and 0.619) are slightly below the optimal 1-3 range, but not drastically so. This might slightly hinder permeation, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which is acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Ligand B (0.769) has a better QED score than Ligand A (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (23.924) has a significantly lower DILI risk than Ligand B (13.61), which is a major advantage.

**BBB:** Both have similar low BBB penetration (23.11 and 22.955), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.311 and -5.2), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.979 and -0.321), also suggesting poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.544 and 0.101), which is good.

**Microsomal Clearance:** Ligand B (-33.782) has *much* lower (better) microsomal clearance than Ligand A (9.328). This suggests significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-6.242) has a longer in vitro half-life than Ligand A (-0.511), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.013).

**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 regarding ADME properties. Its lower DILI risk, much lower microsomal clearance, and longer half-life are crucial advantages for an enzyme target. Although both have poor solubility and permeability, the metabolic stability of Ligand B is a key differentiator. The QED score is also higher for Ligand B. The similar binding affinity makes the ADME profile the deciding factor.

Output:
1
2025-04-17 15:48:19,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.495 and 341.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (71.96). Both are below the 140 threshold for oral absorption, but lower TPSA generally favors better cell permeability.

**logP:** Both ligands have good logP values (2.173 and 3.246), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=6) as it has fewer hydrogen bond donors and acceptors. This can improve permeability.

**QED:** Both ligands have acceptable QED values (0.54 and 0.84), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (24.855) has a significantly lower DILI risk than Ligand B (46.297). This is a major advantage for Ligand A.

**BBB:** Ligand B (72.005) has a higher BBB penetration percentile than Ligand A (33.579). However, since SRC is not a CNS target, BBB is less critical.

**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 (-4.727 vs -5.103).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-2.955 vs -3.136).

**hERG:** Ligand A (0.443) has a lower hERG inhibition liability than Ligand B (0.716), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (32.33) has significantly lower microsomal clearance than Ligand A (63.784), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (34.741) has a longer in vitro half-life than Ligand A (-16.091). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.107 and 0.109).

**Binding Affinity:** Ligand B (-7.8 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 A excels in DILI risk and hERG inhibition, while Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. Given the enzyme-specific priorities, metabolic stability and potency are paramount. Although Ligand A has a better DILI profile, the improved metabolic stability and binding affinity of Ligand B outweigh this advantage. The solubility and Caco-2 values are concerning for both, but similar.

Output:
1
2025-04-17 15:48:19,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.407 and 349.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.21) is slightly above the optimal <140 for good absorption, while Ligand B (93.46) is well within the range.

**logP:** Ligand A (-0.249) is a bit low, potentially hindering permeation. Ligand B (1.746) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.541 and 0.757), indicating drug-like properties.

**DILI:** Ligand A (39.667) has a lower DILI risk than Ligand B (62.35). Both are acceptable, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.162) has a higher BBB score than Ligand A (62.117), but this isn't a deciding factor.

**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 (0.111) has a lower hERG risk than Ligand B (0.318), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-3.278) has a *much* lower (better) microsomal clearance than Ligand B (51.087), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (0.753) has a shorter half-life than Ligand B (-6.601). This is a negative for ligand A, but the difference is not as critical as the clearance difference.

**P-gp Efflux:** Ligand A (0.005) has a much lower P-gp efflux liability than Ligand B (0.117), which is favorable.

**Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-7.0). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has slightly lower logP and solubility, its significantly better metabolic stability (lower Cl_mic), lower hERG risk, lower P-gp efflux, and superior binding affinity outweigh these drawbacks. The affinity difference is substantial. The negative solubility and Caco-2 values are concerning for both, but can be addressed in formulation.

Output:
0
2025-04-17 15:48:19,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.28 Da) is slightly higher than Ligand B (342.403 Da), but both are acceptable.

**TPSA:** Ligand A (69.04) is significantly better than Ligand B (104.45). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.873) is optimal, while Ligand B (0.627) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the threshold of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 6, Ligand B: 6), below the threshold of 10.

**QED:** Both ligands have good QED scores (Ligand A: 0.479, Ligand B: 0.798). Ligand B is better here.

**DILI:** Both ligands have similar and acceptable DILI risk (Ligand A: 79.721, Ligand B: 75.107), below the concerning threshold of 60.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 68.903, Ligand B: 64.211). This isn't a primary concern for a non-CNS target like SRC.

**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. Again, scale is not defined.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.767, Ligand B: 0.376). Ligand B is better here.

**Microsomal Clearance:** Ligand A (113.21) has significantly better metabolic stability (lower clearance) than Ligand B (17.625). This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (77.415) has a much longer half-life than Ligand B (-1.545). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.535, Ligand B: 0.035). Ligand B is better here.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -7.7 kcal/mol, Ligand B: -7.8 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2) and has a more favorable logP. Ligand B has a slightly better QED, hERG, and Pgp profile, and a marginally better binding affinity. However, the significantly better metabolic stability and half-life of Ligand A, coupled with its better logP, are more critical for an enzyme inhibitor like an SRC kinase inhibitor. The negative solubility and Caco-2 values are concerning for both, but the superior pharmacokinetic properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 15:48:19,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.401 and 369.908 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.72) is better than Ligand B (40.54), being comfortably under 140, suggesting good absorption.

**logP:** Ligand A (1.007) is optimal, while Ligand B (4.522) is high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3, and Ligand B has 2, both within the acceptable limit of 10.

**QED:** Ligand A (0.816) has a better QED score than Ligand B (0.767), indicating a more drug-like profile.

**DILI:** Ligand A (30.826) has a significantly lower DILI risk than Ligand B (15.587), which is a major advantage.

**BBB:** Both have good BBB penetration (Ligand A: 86.041, Ligand B: 91.508), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close enough that this isn't a deciding factor.

**Solubility:** Ligand A (-2.371) is better than Ligand B (-4.83), indicating better aqueous solubility.

**hERG:** Ligand A (0.286) has a much lower hERG risk than Ligand B (0.873). This is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (11.953) has a lower Cl_mic than Ligand B (70.729), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.659) has a much longer half-life than Ligand B (1.684), which is a significant advantage for dosing convenience.

**P-gp:** Ligand A (0.022) has lower P-gp efflux liability than Ligand B (0.501), which is favorable for bioavailability.

**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 affinity is important, the other ADME properties of Ligand A are considerably better.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, Ligand A is the more promising drug candidate. It has a better safety profile (lower DILI and hERG), better metabolic stability (lower Cl_mic, longer half-life), better solubility, and a more favorable QED score. The slightly weaker binding affinity of Ligand A is outweighed by its superior ADME properties.

Output:
0
2025-04-17 15:48:19,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.395 and 379.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.24) is significantly better than Ligand B (80.12). TPSA < 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (3.034) is optimal, while Ligand B (1.871) is slightly lower, potentially impacting permeability.

**H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.646 and 0.879), indicating drug-likeness.

**DILI:** Ligand A (72.043) has a slightly higher DILI risk than Ligand B (63.164), but both are acceptable (< 60 is good, but < 40 is preferred).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (81.737) has a higher BBB percentile than Ligand A (68.67), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.641) and Ligand B (-5.129) have negative values, indicating poor permeability. However, these values are on a scale where more negative is worse, so B is slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.786 and -3.89). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG risk (0.402 and 0.444), which is excellent.

**Microsomal Clearance:** Ligand A (101.895) has a higher microsomal clearance than Ligand B (15.154). This means Ligand B is more metabolically stable, a key priority for enzymes.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (8.093 and 8.617 hours).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.676 and 0.239).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly better binding affinity than Ligand A (-6.6 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better TPSA and logP, Ligand B's significantly stronger binding affinity (-7.1 vs -6.6 kcal/mol) and much better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme target like SRC. The solubility is poor for both, but the potency and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 15:48:19,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.332 Da) is slightly better positioned.

**TPSA:** Ligand A (69.04) is excellent, well below the 140 threshold for oral absorption. Ligand B (117.85) is still acceptable but less favorable.

**logP:** Ligand A (2.497) is optimal. Ligand B (-0.584) is significantly lower, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.916, B: 0.621), indicating drug-like properties.

**DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (31.718). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (87.476) has a better BBB score than Ligand B (58.511).

**Caco-2 Permeability:** Ligand A (-4.675) is poor, indicating low intestinal absorption. Ligand B (-5.501) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.454) is poor, while Ligand B (-1.894) is also poor, but relatively better.

**hERG:** Both ligands have very low hERG risk (A: 0.366, B: 0.125), which is excellent.

**Microsomal Clearance:** Ligand B (-1.033) has a negative value, suggesting very slow clearance and excellent metabolic stability. Ligand A (14.626) has a moderate clearance, indicating less metabolic stability.

**In vitro Half-Life:** Ligand B (-17.072) has a negative value, suggesting a very long half-life. Ligand A (-31.162) also has a negative value, suggesting a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.108, B: 0.02).

**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 less than the 1.5 kcal/mol threshold to override other issues, it's still a positive.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor Caco-2 and aqueous solubility, Ligand B excels in metabolic stability (Cl_mic and t1/2) and has a significantly lower DILI risk. The slightly lower logP is a concern, but the superior metabolic profile and safety outweigh this drawback. Ligand A's higher DILI risk is a major concern, and its lower metabolic stability is also unfavorable. The slightly better affinity of Ligand A is not enough to compensate for these issues.

Output:
1
2025-04-17 15:48:19,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 363.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.35 and 65.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.898 and 2.446) are 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 2 HBA. Both are within acceptable limits.

**QED:** Both ligands (0.799 and 0.763) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (57.348) has a slightly higher DILI risk than Ligand B (47.964), but both are below the concerning 60 percentile.

**BBB:** Both ligands have moderate BBB penetration (61.613 and 72.315). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.577 and -4.785). This 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 (-3.638 and -3.317). This is also concerning, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.655 and 0.672).

**Microsomal Clearance:** Ligand A (94.011) has significantly higher microsomal clearance than Ligand B (22.389). This suggests Ligand A is less metabolically stable.

**In vitro Half-Life:** Ligand B (-36.181) has a much longer in vitro half-life than Ligand A (-0.367). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.104 and 0.112).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with predicted solubility and permeability, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2) and substantially stronger binding affinity outweigh these concerns. The higher affinity is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:48:19,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.355 Da and 337.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (114.33) is better than Ligand B (64.41), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands (2.124 and 2.443) 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:** Ligand A has 5 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.636 and 0.779), indicating good drug-like properties.

**7. DILI:** Ligand A (82.319) has a higher DILI risk than Ligand B (54.323). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (61.729) is slightly better than Ligand A (55.913).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.616 and -4.452). This is unusual and suggests poor permeability, but could be an artifact of the prediction method.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.445 and -3.495). This is concerning, as poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Ligand A (0.337) has a slightly higher hERG risk than Ligand B (0.628), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (32.547) has lower microsomal clearance than Ligand B (40.674), indicating better metabolic stability, which is a key priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (12.856 hours) has a longer half-life than Ligand B (-6.492 hours). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux than Ligand B (0.321), suggesting better oral bioavailability.

**15. Binding Affinity:** Ligand A (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A >1.5 kcal/mol advantage is considered significant, and here the difference is over 7 kcal/mol.

**Overall Assessment:**

Despite the concerning solubility and permeability values (which need experimental validation), Ligand A is significantly more promising due to its much stronger binding affinity (-7.1 kcal/mol vs -0.0 kcal/mol), better metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux. The higher DILI risk is a concern, but the substantial potency advantage may outweigh this risk, especially if structural modifications can mitigate the DILI signal. Ligand B's binding affinity is too weak to be a viable candidate.

Output:
1
2025-04-17 15:48:19,937 - INFO - Batch 410 complete. Total preferences: 6560
2025-04-17 15:48:19,937 - INFO - Processing batch 411/512...
2025-04-17 15:49:01,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 369.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.64 and 100.55) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.894) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.42) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 6 HBA) both fall within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED values (0.71 and 0.651), indicating good drug-like properties.

**DILI:** Ligand A (33.307) has a significantly lower DILI risk than Ligand B (69.717), which is a major advantage. Ligand A is well below the 40% threshold, while Ligand B is approaching the high-risk zone.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.784) is lower than Ligand B (29.391).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.873) suggests slightly better permeability than Ligand B (-5.02).

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-2.202) suggests slightly better solubility than Ligand B (-3.555).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.219 and 0.406), which is favorable.

**Microsomal Clearance:** Ligand A (-11.298) has a much lower (better) microsomal clearance than Ligand B (48.617), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-40.49) has a much longer half-life than Ligand B (13.268), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.141).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -8.1 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good binding affinity, Ligand A is the superior candidate. Its significantly lower DILI risk and dramatically improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP and BBB values. Solubility is also slightly better for Ligand A. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial, making Ligand A the more viable drug candidate.

Output:
0
2025-04-17 15:49:01,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.451 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.19) is better than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.951) is slightly low, potentially hindering permeation. Ligand B (2.138) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the limit of 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, below the limit of 10.

**QED:** Both ligands have good QED scores (0.575 and 0.777), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (8.414) has a very low DILI risk, significantly better than Ligand B (21.598). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (61.807) has a higher BBB value than Ligand A (17.216), but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.623) is worse than Ligand B (-4.923).

**Aqueous Solubility:** Ligand A (0.365) has very poor solubility, a significant drawback. Ligand B (-3.281) also has poor solubility, but is slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.026) has a very low hERG risk, excellent. Ligand B (0.194) is also low, but higher than Ligand A.

**Microsomal Clearance:** Ligand A (2 mL/min/kg) has much lower clearance, indicating better metabolic stability, than Ligand B (29.181 mL/min/kg). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-14.617) has a very short half-life, a major concern. Ligand B (0.429) is better, but still relatively short.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is good. Ligand B (0.06) is slightly higher, but still low.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.4 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, and metabolic stability (Cl_mic, Pgp). However, it suffers from very poor solubility and a very short half-life. Ligand B has better logP, QED, Caco-2 permeability, and slightly better affinity, but has a higher DILI risk and significantly worse metabolic stability.

Given the enzyme-specific priorities, metabolic stability and low toxicity are crucial. While Ligand A's solubility and half-life are concerning, these can potentially be addressed through formulation or structural modifications. The significantly lower DILI and better metabolic stability of Ligand A, coupled with comparable binding affinity, make it the more promising candidate.

Output:
0
2025-04-17 15:49:01,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (373.835 and 363.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.31) is slightly above the optimal <140, but still reasonable. Ligand B (40.54) is excellent, well below 140.

**logP:** Both ligands have good logP values (2.094 and 3.411), falling within the 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 (0.745 and 0.814), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 57.464, which is moderate but acceptable (below 60). Ligand B has a much lower DILI risk of 15.316, which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (88.251) is higher than Ligand B (77.511), but this is less critical.

**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 ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.845) and Ligand B (0.739) have relatively low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (19.043) than Ligand B (83.551), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A has a longer half-life (58.139 hours) than Ligand B (23.823 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.047) has very low P-gp efflux liability, while Ligand B (0.617) has moderate efflux. Lower is better.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.6 kcal/mol) than Ligand B (-7.2 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both ligands have acceptable physicochemical properties, Ligand A excels in binding affinity, metabolic stability (lower Cl_mic, longer half-life), and P-gp efflux. Its DILI risk is slightly higher than Ligand B, but still within an acceptable range. The superior binding affinity of Ligand A is a critical advantage for an enzyme inhibitor, and the improved metabolic stability suggests a potentially more favorable pharmacokinetic profile. The negative values for Caco-2 and solubility are concerning, but the large difference in binding affinity makes Ligand A the better choice.

Output:
1
2025-04-17 15:49:01,605 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.395 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (66.92) is significantly better than Ligand A (94.38). Lower TPSA generally improves oral absorption.

**logP:** Both ligands have good logP values (A: 2.573, B: 1.293) within the optimal range of 1-3. Ligand B is slightly lower, which could potentially affect permeability, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 4 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 (A: 0.553, B: 0.648), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a higher DILI risk (83.133) than Ligand B (47.732). This is a significant concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (70.57) than Ligand A (34.742), but this isn't a primary factor.

**Caco-2 Permeability:** Ligand A (-5.488) has a worse Caco-2 permeability than Ligand B (-4.459).

**Aqueous Solubility:** Ligand A (-4.092) has worse solubility than Ligand B (-2.671). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.838) has a slightly higher hERG risk than Ligand B (0.356), but both are reasonably low.

**Microsomal Clearance:** Ligand A (-7.835) has *much* better microsomal clearance (lower is better, indicating greater metabolic stability) than Ligand B (56.76). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (31.239 hours) has a significantly longer half-life than Ligand B (-17.31 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.21, B: 0.047), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.8 kcal/mol, B: -8.0 kcal/mol). Ligand A is slightly better (-8.8 vs -8.0), but the difference is relatively small.

**Overall Assessment:**

Ligand A has a better binding affinity, significantly better metabolic stability (Cl_mic and t1/2), and a lower P-gp efflux. However, it has a substantially higher DILI risk and lower solubility and Caco-2 permeability. Ligand B has better TPSA, QED, solubility, Caco-2 permeability, and a much lower DILI risk.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), and the significant DILI risk associated with Ligand A, **Ligand B is the more promising drug candidate**. While Ligand A's potency and metabolic stability are attractive, the high DILI risk is a major red flag that would likely necessitate significant further optimization, and may prove insurmountable. Ligand B provides a better balance of properties, with acceptable potency and a much more favorable safety profile.

Output:
1
2025-04-17 15:49:01,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 343.471 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.11) is slightly higher than Ligand B (64.41). Both are under the 140 A^2 threshold for good absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (2.281 and 2.735), 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 3 HBA. Both are within acceptable limits, but Ligand B's lower HBD count might contribute to better permeability.

**QED:** Ligand A (0.725) has a higher QED score than Ligand B (0.55), suggesting a more drug-like profile overall.

**DILI:** Ligand B (32.183) has a significantly lower DILI risk than Ligand A (51.144), which is a major advantage.

**BBB:** Ligand A (74.835) shows better BBB penetration than Ligand B (55.719), but BBB isn't a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.034) has worse Caco-2 permeability than Ligand B (-4.446).

**Aqueous Solubility:** Ligand A (-3.197) has worse aqueous solubility than Ligand B (-2.86).

**hERG:** Both ligands have relatively low hERG inhibition liability (0.393 and 0.576), which is good.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (44.878 and 46.352 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-14.631) has a significantly longer in vitro half-life than Ligand A (-5.498), which is a substantial advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.223).

**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, it's still a positive factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. It has a significantly lower DILI risk, a longer half-life, better solubility, and slightly better binding affinity. While Ligand A has a higher QED and better BBB penetration, these are less critical for a kinase inhibitor. The better permeability and lower toxicity profile of Ligand B outweigh the slightly lower QED score.

Output:
1
2025-04-17 15:49:01,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.451 and 371.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.98) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (88.16) is well within the acceptable range.

**logP:** Both ligands have logP values within the optimal 1-3 range (0.901 and 1.721 respectively).

**H-Bond Donors & Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.469 and 0.692), with Ligand B being slightly more drug-like.

**DILI:** Both ligands have similar DILI risk (41.877 and 41.838 percentile), indicating low to moderate risk.

**BBB:** Ligand A (36.836) has a low BBB penetration, while Ligand B (74.292) has a good BBB penetration. Since SRC is not a CNS target, this is less critical, but still a positive for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.825 and -5.283), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.347 and -2.132), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.291 and 0.225 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (29.724 mL/min/kg) has a higher microsomal clearance than Ligand B (8.631 mL/min/kg). This means Ligand B is more metabolically stable, which is a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-18.905 hours) has a significantly longer in vitro half-life than Ligand A (-6.372 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.085 percentile), which is favorable.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This >1.5 kcal/mol difference in binding is a major advantage, and can often outweigh minor ADME concerns.

**Conclusion:**

While both ligands have significant drawbacks (poor solubility and permeability), Ligand B is the superior candidate. It exhibits a substantially stronger binding affinity, improved metabolic stability (lower Cl_mic, longer t1/2), and better BBB penetration. The stronger binding affinity is the most critical factor, given the enzyme-specific priorities.

Output:
1
2025-04-17 15:49:01,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.491 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (86.88) is significantly better than Ligand B (49.25). Lower TPSA generally indicates better cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (2.949) being slightly more favorable. Ligand B (4.278) is approaching the upper limit and could potentially have solubility issues.

**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, a slight balance is preferred.

**QED:** Both ligands have similar and acceptable QED values (Ligand A: 0.641, Ligand B: 0.669).

**DILI:** Both ligands have low DILI risk (Ligand A: 40.713, Ligand B: 38.309), which is excellent.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (74.758) is better than Ligand B (65.801). This isn't a high priority for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.895) shows better Caco-2 permeability than Ligand B (-5.089), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.815 and -4.165 respectively). This is a concern for both, but needs to be weighed against other factors.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.575, Ligand B: 0.734), which is positive.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (Ligand A: 61.928, Ligand B: 60.911). These are relatively high, suggesting moderate metabolic liability.

**In vitro Half-Life:** Ligand A (-4.134) has a significantly better in vitro half-life than Ligand B (19.295). This is a crucial advantage for an enzyme inhibitor, as a longer half-life translates to less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.254, Ligand B: 0.781), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -7.1 kcal/mol, Ligand B: -7.2 kcal/mol). Ligand B is slightly better, but the difference is small and may not be decisive.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in several critical ADME properties: TPSA, Caco-2 permeability, and, most importantly, *in vitro* half-life. The better half-life of Ligand A suggests greater metabolic stability, a key factor for kinase inhibitors. Both have similar DILI and hERG risk, and acceptable QED scores. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 15:49:01,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.454 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (54.34), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.531) is within the optimal 1-3 range. Ligand B (2.647) is also within range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 HBA threshold.

**QED:** Both ligands have good QED scores (0.643 and 0.912), indicating drug-like properties.

**DILI:** Ligand A (23.187) has a lower DILI risk than Ligand B (18.728), which is preferable.

**BBB:** Ligand A (93.912) has a significantly higher BBB penetration percentile than Ligand B (78.868). While not a primary concern for a non-CNS target like SRC, higher BBB is generally not detrimental.

**Caco-2 Permeability:** Ligand A (-4.585) and Ligand B (-4.939) both have negative Caco-2 values, indicating poor permeability. This is a significant concern.

**Aqueous Solubility:** Ligand A (-1.33) and Ligand B (-2.08) both have negative solubility values, indicating poor aqueous solubility. This is also a significant concern.

**hERG Inhibition:** Ligand A (0.564) has a slightly higher hERG inhibition risk than Ligand B (0.412), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (21.099) has a higher microsomal clearance than Ligand B (14.576), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (1.593) has a longer in vitro half-life than Ligand A (-2.628), indicating better stability.

**P-gp Efflux:** Ligand A (0.138) has lower P-gp efflux liability than Ligand B (0.242), which is favorable.

**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, potentially outweighing some of the ADME drawbacks. The difference of 1.9 kcal/mol is quite significant.

**Conclusion:**

Despite both ligands having poor Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.6 vs -7.7 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. While Ligand A has slightly better P-gp efflux, the affinity and stability advantages of Ligand B are more critical.

Output:
1
2025-04-17 15:49:01,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (414.221 Da) is slightly higher, but acceptable. Ligand B (353.463 Da) is also good.

**TPSA:** Ligand A (38.33) is excellent, well below the 140 threshold for oral absorption. Ligand B (73.32) is still reasonable, but higher and potentially impacting absorption.

**logP:** Ligand A (4.754) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-0.047) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both 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 acceptable QED scores (A: 0.784, B: 0.65), indicating reasonable drug-likeness.

**DILI:** Ligand A (64.909) has a higher DILI risk than Ligand B (13.067). This is a significant negative for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (85.421) is higher than Ligand B (48.119).

**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 very poor aqueous solubility (-5.531 and 0.411 respectively). This is a major drawback for both compounds, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.812) shows a slightly higher hERG risk than Ligand B (0.302), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (-11.077) has significantly *lower* (better) microsomal clearance than Ligand A (70.057), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-1.111) has a negative half-life, which is not physically possible and indicates a data error or a very rapidly metabolized compound. Ligand A (38.075) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.45) has lower P-gp efflux than Ligand B (0.016), which is preferable.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is paramount for an enzyme inhibitor. However, it has higher DILI risk, higher microsomal clearance, and a less favorable logP. Ligand B has better metabolic stability (lower Cl_mic) and lower DILI risk, but its binding affinity is considerably weaker, and its half-life is problematic. The solubility of both is poor.

Given the importance of potency for enzyme inhibition, and the substantial difference in binding affinity (-10.1 vs -7.2 kcal/mol), I would cautiously favor Ligand A, *assuming* the solubility issues can be addressed through formulation strategies. The higher DILI risk is a concern, but could be mitigated through further structural modifications. The negative half-life of Ligand B is a showstopper.

Output:
1
2025-04-17 15:49:01,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (399.292 Da) is still well within the acceptable range.

**TPSA:** Ligand A (85.25) is better than Ligand B (59.29). Both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 2.746, B: 3.527), falling within the optimal 1-3 range. Ligand B is slightly higher, which might raise concerns about off-target effects, but it's not a major issue.

**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 reasonable QED values (A: 0.787, B: 0.683), indicating good drug-like properties.

**DILI:** Ligand A (81.078) has a higher DILI risk than Ligand B (72.276). This is a significant concern, as a DILI percentile >60 is considered high risk.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (78.79) has a slightly better BBB penetration score than Ligand A (65.374).

**Caco-2 Permeability:** Ligand A (-4.638) has a much worse Caco-2 permeability than Ligand B (-5.273). This suggests that Ligand A will have lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.575 for A, -4.331 for B). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.355). This is a good sign, indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (25.886) has significantly lower microsomal clearance than Ligand A (108.935). Lower clearance indicates better metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (39.928) has a longer in vitro half-life than Ligand A (16.965). This is another positive attribute for Ligand B, suggesting less frequent dosing may be possible.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.199 for A, 0.667 for B).

**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, especially given the other favorable properties of Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and slightly better binding affinity. The improved Caco-2 permeability is also a significant advantage. Ligand A's higher DILI risk and poorer metabolic stability are major drawbacks.

Output:
1
2025-04-17 15:49:01,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 352.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.58) is higher than the preferred <140, but still acceptable. Ligand B (47.1) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (-0.523) is slightly low, potentially hindering permeation. Ligand B (1.119) is within the optimal 1-3 range.

**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 reasonable QED scores (0.713 and 0.624), indicating good drug-like properties.

**DILI:** Ligand A (61.497) has a moderately elevated DILI risk, while Ligand B (3.994) has a very low risk, which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (79.721) has a higher BBB score than Ligand A (39.395), but this is not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.936), which is unusual and suggests poor permeability *in vitro*. This is a red flag for both, but the scale is not clearly defined.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.332 and -0.212), again unusual and suggesting poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.106) has a slightly higher hERG risk than Ligand B (0.681), but both are relatively low.

**Microsomal Clearance:** Ligand B (-7.39) has significantly lower (better) microsomal clearance than Ligand A (25.544), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have negative in vitro half-life values (-8.872 and -8.27), which is unusual and suggests rapid degradation. The scale is not clearly defined.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.012).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better binding affinity, Ligand B has a much lower DILI risk and significantly better metabolic stability (lower Cl_mic). The low solubility and permeability (negative Caco-2 and solubility values) are concerning for both, but the superior safety and metabolic profile of Ligand B make it more promising. The difference in binding affinity, while noticeable, is likely surmountable through further optimization, whereas mitigating a high DILI risk is often much more challenging.

Output:
1
2025-04-17 15:49:01,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.646 Da) is higher, but still acceptable. Ligand B (338.455 Da) is slightly better.

**TPSA:** Ligand A (113.41) is borderline for good oral absorption (<=140), while Ligand B (58.95) is well within the acceptable range.

**logP:** Both ligands have optimal logP values around 2.4-2.5, indicating good partitioning properties.

**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:** Ligand B (0.881) has a significantly better QED score than Ligand A (0.438), suggesting 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, and acceptable, DILI risk (49.787 percentile).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.384) shows better BBB penetration than Ligand A (40.791), but it's not a deciding factor here.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.581 and -5.214), suggesting potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.629 and -2.487). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.396 and 0.711), which is good.

**Microsomal Clearance:** Ligand A (2.602 mL/min/kg) has significantly lower microsomal clearance than Ligand B (15.938 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (108.187 hours) has a much longer half-life than Ligand B (20.595 hours), which is highly desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.222 and 0.294).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.8 and -9.3 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite Ligand A's superior metabolic stability and half-life, its extremely high DILI risk is a deal-breaker. The poor solubility of both compounds is also a concern, but can potentially be addressed with formulation strategies. Ligand B, with its better QED score, lower DILI risk, and acceptable TPSA, is the more promising candidate despite slightly worse metabolic stability.

Output:
1
2025-04-17 15:49:01,608 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 358.515 Da, B: 358.511 Da) fall within the ideal range of 200-500 Da. No significant difference here.

2. **TPSA:** Ligand A (65.97) is slightly higher than Ligand B (61.88). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets which isn't a priority here.

3. **logP:** Ligand A (2.295) is within the optimal 1-3 range. Ligand B (4.476) is higher, potentially leading to solubility issues and off-target interactions.

4. **HBD:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

5. **HBA:** Ligand A (7) and Ligand B (4) are both within the acceptable limit of <=10.

6. **QED:** Ligand A (0.75) has a better QED score than Ligand B (0.531), indicating a more drug-like profile.

7. **DILI:** Ligand A (62.001) has a higher DILI risk than Ligand B (53.858), but both are within an acceptable range (<60 is good).

8. **BBB:** Both ligands have similar BBB penetration (A: 62.466, B: 64.133). This isn't a major concern for an oncology target.

9. **Caco-2:** Both ligands have negative Caco-2 values (-5.566 and -5.173), which is unusual and suggests poor permeability. This is a significant concern for both.

10. **Solubility:** Ligand A (-2.684) has slightly better solubility than Ligand B (-4.099), although both are poor.

11. **hERG:** Ligand A (0.813) has a slightly higher hERG risk than Ligand B (0.652), but both are relatively low.

12. **Cl_mic:** Ligand A (60.19) has a lower microsomal clearance than Ligand B (72.696), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

13. **t1/2:** Ligand A (35.241) has a much longer in vitro half-life than Ligand B (-19.599). A negative half-life is not possible and indicates a very rapid degradation. This is a major drawback for Ligand B.

14. **Pgp:** Ligand A (0.054) has lower P-gp efflux liability than Ligand B (0.56), suggesting better oral bioavailability.

15. **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.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in binding affinity and metabolic stability (longer half-life, lower Cl_mic). While solubility is poor for both, Ligand A is slightly better.

**Conclusion:**

Ligand A is the more promising candidate due to its significantly stronger binding affinity, better metabolic stability (longer half-life and lower Cl_mic), and lower P-gp efflux. While both have poor Caco-2 permeability and solubility, the superior binding and metabolic properties of Ligand A make it a better starting point for optimization.

Output:
1
2025-04-17 15:49:01,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 and 337.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.33) is better than Ligand B (45.46), being below the 140 threshold for oral absorption. Ligand B is excellent.

**logP:** Ligand A (0.453) is quite low, potentially hindering permeation. Ligand B (3.734) is near the optimal range of 1-3.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, contributing to improved permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.598 and 0.721), indicating drug-likeness.

**DILI:** Ligand A (39.046) has a much lower DILI risk than Ligand B (81), which is a significant advantage.

**BBB:** Ligand A (47.15) has a lower BBB penetration than Ligand B (68.437), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.823) has poor Caco-2 permeability, while Ligand B (-4.725) is slightly better, but both are quite low.

**Aqueous Solubility:** Ligand A (-0.746) has poor solubility, while Ligand B (-3.902) is even worse. This is a concern for both.

**hERG Inhibition:** Ligand A (0.075) shows very low hERG inhibition risk, a major advantage. Ligand B (0.918) has a higher, but still moderate, risk.

**Microsomal Clearance:** Ligand A (3.734) has significantly lower microsomal clearance than Ligand B (50.753), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.276) has a shorter half-life than Ligand B (-2.83), but the negative value for B is suspect and likely indicates a very rapid clearance.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, while Ligand B (0.691) has moderate efflux.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity (-8.0 kcal/mol) than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better safety profiles (DILI, hERG) and metabolic stability, Ligand B's significantly stronger binding affinity is a critical factor for an enzyme inhibitor. The difference of 0.8 kcal/mol is substantial. Although Ligand B has some ADME liabilities (solubility, Caco-2, higher DILI), these could potentially be addressed through further optimization. The strong binding affinity makes Ligand B the more promising candidate.

Output:
1
2025-04-17 15:49:01,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.478 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.75) is significantly better than Ligand B (93.43). A TPSA under 140 is good for oral absorption, and both are under, but A is preferable.

**logP:** Both ligands have similar logP values (1.638 and 1.763), falling 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 (0.811) has a better QED score than Ligand B (0.622), indicating higher drug-likeness.

**DILI:** Ligand A (29.779) has a much lower DILI risk than Ligand B (12.292), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (81.504) has a higher BBB percentile than Ligand B (29.74).

**Caco-2 Permeability:** Ligand A (-4.777) has a worse Caco-2 permeability than Ligand B (-4.99), but both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-1.304) has slightly better aqueous solubility than Ligand B (-1.266).

**hERG Inhibition:** Ligand A (0.541) has a lower hERG inhibition risk than Ligand B (0.366), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (-18.063) exhibits significantly lower microsomal clearance than Ligand B (-0.543), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.662) has a slightly longer half-life than Ligand B (-7.227).

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux liability than Ligand B (0.022).

**Binding Affinity:** Ligand B (-8.7 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 of Ligand B.

**Overall Assessment:**

Ligand B has a much better binding affinity (-8.7 vs -6.2 kcal/mol). However, Ligand A demonstrates superior ADMET properties: lower DILI risk, better QED, lower hERG inhibition, and significantly improved metabolic stability (lower Cl_mic and longer t1/2). While Ligand B's affinity is strong, the improved safety and pharmacokinetic profile of Ligand A make it a more promising drug candidate, especially considering the importance of metabolic stability and safety for kinase inhibitors. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 15:49:01,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (383.857 Da) is also acceptable.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (93.46). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have good logP values (A: 2.288, B: 2.474), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=6). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have acceptable QED values (A: 0.849, B: 0.766), indicating good drug-like properties.

**DILI:** Ligand A (47.421) has a much lower DILI risk than Ligand B (70.919). This is a significant advantage for Ligand A.

**BBB:** Ligand A (95.192) has a much higher BBB penetration score than Ligand B (60.411). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.426) shows better Caco-2 permeability than Ligand B (-5.059).

**Aqueous Solubility:** Ligand A (-3.246) shows better aqueous solubility than Ligand B (-3.91). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.588, B: 0.318), which is good.

**Microsomal Clearance:** Ligand A (34.726) has a higher (worse) microsomal clearance than Ligand B (15.334). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (77.105) has a significantly longer in vitro half-life than Ligand A (-15.825). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.332, B: 0.336).

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.3 kcal/mol, B: -8.5 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, solubility, permeability, DILI, BBB) and has comparable binding affinity. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a longer half-life and better metabolic stability, but at the cost of poorer ADME properties like TPSA, solubility, and a higher DILI risk.

Given the enzyme-specific priorities, metabolic stability (half-life and clearance) is crucial. While Ligand A has better overall ADME properties, the significantly longer half-life of Ligand B is a substantial advantage that could outweigh its ADME drawbacks, especially considering the strong binding affinity is similar for both.

Output:
1
2025-04-17 15:49:01,609 - INFO - Batch 411 complete. Total preferences: 6576
2025-04-17 15:49:01,610 - INFO - Processing batch 412/512...
2025-04-17 15:49:43,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.356 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is well below the 140 threshold, suggesting good absorption. Ligand B (127.17) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (2.641) is optimal (1-3). Ligand B (1.141) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have similar QED values (0.585 and 0.554), indicating good drug-likeness.

**DILI:** Ligand A (56.96) has a lower DILI risk than Ligand B (75.378), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (54.905) is slightly better than Ligand B (46.219).

**Caco-2 Permeability:** Ligand A (-4.625) shows better predicted permeability than Ligand B (-5.154).

**Aqueous Solubility:** Both ligands have similar, poor predicted aqueous solubility (-4.121 and -4.124). This is a potential issue, but can be addressed with formulation strategies.

**hERG:** Ligand A (0.515) has a significantly lower hERG risk than Ligand B (0.185), which is a critical safety consideration.

**Microsomal Clearance:** Ligand A (22.592) has lower microsomal clearance than Ligand B (42.222), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.769) has a positive half-life, while Ligand B (-31.561) has a negative half-life. This is a substantial difference favoring A.

**P-gp Efflux:** Ligand A (0.113) has lower P-gp efflux than Ligand B (0.045), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). This 1.1 kcal/mol difference is noteworthy, but needs to be weighed against the other factors.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, but Ligand A excels in almost all other critical ADMET properties. Specifically, Ligand A demonstrates a significantly lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and positive half-life), and better permeability. The solubility is similar for both, and while not ideal, can be addressed. The superior safety and pharmacokinetic profile of Ligand A outweigh the modest difference in binding affinity.

Output:
1
2025-04-17 15:49:43,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.523 and 353.507 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.1) is better than Ligand B (53.09), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (1.262 and 1.594) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.617 and 0.705), indicating drug-like properties.

**DILI:** Ligand A (2.986) has a significantly lower DILI risk than Ligand B (5.312). This is a major advantage.

**BBB:** Ligand A (87.941) has better BBB penetration than Ligand B (70.027), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.936) has worse Caco-2 permeability than Ligand B (-4.535).

**Aqueous Solubility:** Ligand A (0.179) has worse aqueous solubility than Ligand B (-0.48). This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.523 and 0.565).

**Microsomal Clearance:** Ligand A (0.326) has significantly lower microsomal clearance than Ligand B (2.601), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.936) has a much longer in vitro half-life than Ligand B (7.485). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.007 and 0.075).

**Binding Affinity:** Ligand B (-8.2) has slightly better binding affinity than Ligand A (-8.9). However, the difference is less than 1.5 kcal/mol, and can be overcome by other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better aqueous solubility. The slightly weaker binding affinity of Ligand A is less concerning given its superior ADME properties.

Output:
0
2025-04-17 15:49:43,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.825 and 383.832 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (80.32), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have a logP around 3.7, which is optimal.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Ligand A is slightly better here, as lower HBA generally improves permeability.

**QED:** Ligand A (0.821) has a significantly better QED score than Ligand B (0.625), indicating a more drug-like profile.

**DILI:** Ligand B (93.757) has a higher DILI risk than Ligand A (80.729). This is a significant concern.

**BBB:** Both ligands have similar BBB penetration (77.162 and 77.123), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.559 vs -4.379).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-5.733) is slightly better than Ligand B (-5.178).

**hERG:** Both ligands have low hERG risk (0.552 and 0.44), which is good.

**Microsomal Clearance:** Ligand B (81.837) has slightly lower microsomal clearance than Ligand A (89.959), suggesting slightly better metabolic stability.

**In vitro Half-Life:** Ligand B (74.999) has a longer in vitro half-life than Ligand A (56.704), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.211 and 0.583), which is good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This 0.5 kcal/mol difference is significant, and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a better QED, lower DILI risk, and slightly better solubility and TPSA. Ligand B has a better binding affinity and slightly better metabolic stability and half-life. The DILI risk for Ligand B is a major concern. While the binding affinity difference is notable, the higher DILI risk and lower QED of Ligand B make it less attractive. The solubility issues for both are concerning, but could potentially be addressed with formulation strategies.

Output:
0
2025-04-17 15:49:43,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.371 and 355.435 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.01) is better than Ligand B (104.81), both are acceptable but A is closer to the ideal <140 for oral absorption.

**logP:** Ligand A (0.523) is slightly better than Ligand B (0.209), both are on the low side, potentially impacting permeability. However, for kinases, this isn't as critical as for CNS targets.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.821 and 0.502), indicating good drug-like properties.

**DILI:** Ligand A (68.786) has a considerably higher DILI risk than Ligand B (24.234). This is a significant negative for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (66.499) has a higher BBB percentile than Ligand A (28.848).

**Caco-2 Permeability:** Ligand A (-4.891) has a worse Caco-2 permeability than Ligand B (-4.558). Both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.532) is slightly better than Ligand B (-1.849), but both are poor. Solubility could be a formulation challenge for both.

**hERG Inhibition:** Ligand A (0.175) has a lower hERG inhibition risk than Ligand B (0.081), which is favorable.

**Microsomal Clearance:** Ligand A (-3.583) has a significantly *lower* (better) microsomal clearance than Ligand B (75.67). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-21.311) has a longer in vitro half-life than Ligand B (-27.172). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.006), indicating better bioavailability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This is a crucial factor, but the difference is not enormous.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly better solubility profile. However, it has a significantly higher DILI risk. Ligand B has better binding affinity and a much lower DILI risk, which is a critical safety parameter. While Ligand A has some advantages in ADME, the higher DILI risk is a major concern. The slightly better affinity of Ligand B, combined with the significantly improved safety profile, makes it the more promising candidate.

Output:
1
2025-04-17 15:49:43,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.47 & 346.47 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (50.36 & 49.85) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (4.647) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.505) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Both ligands (3) are well below the 10 threshold.

**QED:** Both ligands (0.722 & 0.789) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (69.872) has a higher DILI risk than Ligand B (34.354). Ligand B is preferable here.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (91.431) has better BBB penetration, but this is not a primary concern.

**Caco-2:** Both ligands have negative Caco-2 values (-4.748 & -4.366), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.398 & -2.673), indicating very poor solubility. This is a major drawback for both.

**hERG:** Ligand A (0.756) has a slightly higher hERG risk than Ligand B (0.553), but both are relatively low.

**Microsomal Clearance:** Ligand A (88.193) has higher clearance than Ligand B (54.624), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (-11.954) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the compound's stability. Ligand A (31.506) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.548) has lower P-gp efflux than Ligand B (0.376), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having significant ADME issues (poor solubility and permeability), Ligand B is the more promising candidate. It has a significantly better binding affinity (-8.5 vs -7.8 kcal/mol), lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. The negative half-life for Ligand B is a major red flag, but the superior binding affinity makes it the better starting point for optimization, assuming the half-life data is an error. Ligand A's higher logP and clearance are less desirable.

Output:
1
2025-04-17 15:49:43,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (386.876 and 386.42 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.27) is slightly higher than Ligand B (59.06). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable due to the lower TPSA.

**3. logP:** Ligand A (2.227) is within the optimal 1-3 range. Ligand B (4.547) is higher, potentially leading to solubility issues and off-target interactions, though not drastically so.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.557 and 0.675, respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (52.734) has a significantly lower DILI risk than Ligand B (95.347). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (81.737) shows better BBB penetration than Ligand B (67.701), though this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.996 and -4.833), 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 (-3.668 and -4.534), which is also unusual and suggests poor solubility. This is a concern for both, but the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.65 and 0.69).

**12. Microsomal Clearance:** Ligand B (42.26) has lower microsomal clearance than Ligand A (48.328), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (74.994) has a significantly longer in vitro half-life than Ligand A (9.387). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.359 and 0.622).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a significant advantage for Ligand B, and could outweigh some of the ADME drawbacks.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, it has a significantly higher DILI risk and a higher logP. Ligand A has a much lower DILI risk, better BBB penetration, but weaker binding affinity and poorer metabolic stability.

The difference in binding affinity (-8.6 vs -9.3) is not substantial enough to overcome the significantly higher DILI risk of Ligand B. The poor solubility and permeability of both compounds are concerning, but can potentially be addressed through formulation strategies. Given the importance of minimizing toxicity in drug development, and the substantial difference in DILI risk, I would favor Ligand A.

Output:
0
2025-04-17 15:49:43,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.479 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.47) is significantly better than Ligand B (93.46). TPSA < 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand B (1.867) is better than Ligand A (0.514). An optimal logP is 1-3, and B falls within this range, while A 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 5 HBA. Both are acceptable, within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.743 and 0.747), indicating good drug-likeness.

**DILI:** Ligand A (13.222) has a much lower DILI risk than Ligand B (41.411). This is a significant advantage for Ligand A. Lower DILI is crucial.

**BBB:** Ligand A (61.691) has a slightly better BBB penetration than Ligand B (55.874), but BBB is not a high priority for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.108 and -5.342), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.63 and -1.174), indicating very poor aqueous solubility. This is a major drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.18) has a much lower hERG inhibition liability than Ligand B (0.139). Lower hERG is highly desirable to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (12.438) has a significantly lower microsomal clearance than Ligand B (50.219). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (3.949) has a positive half-life, while Ligand B (-22.219) has a negative half-life. This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.137).

**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 and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. It demonstrates superior metabolic stability (lower Cl_mic, positive t1/2), significantly lower DILI risk, lower hERG inhibition, and slightly better binding affinity. While both have poor solubility and permeability, the advantages of A in safety and metabolic stability are more critical for an enzyme inhibitor. The slightly better affinity further supports this conclusion.

Output:
0
2025-04-17 15:49:43,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.403 and 353.394 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (131.86) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (111.55) is well within the range.

**logP:** Ligand A (-0.507) is a bit low, potentially hindering permeability. Ligand B (1.102) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, both acceptable. Ligand B has 4 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.748 and 0.559), indicating good drug-like properties.

**DILI:** Ligand A (87.98) has a higher DILI risk than Ligand B (53.781). This is a significant concern.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This needs further investigation, but is less critical than other factors.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and a concern.

**hERG:** Both ligands show very low hERG inhibition risk (0.027 and 0.112), which is excellent.

**Microsomal Clearance:** Ligand A (-11.444) has *much* lower (better) microsomal clearance than Ligand B (9.051), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (46.883) has a longer half-life than Ligand B (-9.92), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.038 and 0.024).

**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 despite the solubility and Caco-2 issues. The significantly higher binding affinity (-7.6 vs -0.0 kcal/mol) is a substantial advantage for an enzyme inhibitor and likely outweighs the slightly less optimal logP and solubility. Ligand A's high DILI risk is a major red flag. While Ligand A has better metabolic stability and half-life, the superior potency of Ligand B is more critical for kinase inhibitors. The solubility and permeability issues for both compounds would need to be addressed in subsequent optimization, but the starting point of higher potency is preferable.

Output:
1
2025-04-17 15:49:43,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.793 and 348.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.18) is slightly higher than Ligand B (78.87), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.608) is optimal, while Ligand B (1.196) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.544 and 0.748, respectively), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (88.251 percentile) compared to Ligand B (19.93 percentile). This is a major concern for Ligand A.

**BBB:** Both have moderate BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.093) shows poor permeability, while Ligand B (-4.802) is slightly better, but still low.

**Aqueous Solubility:** Ligand A (-5.706) has very poor solubility, while Ligand B (-1.917) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.606) has a higher hERG risk than Ligand B (0.296), though both are relatively low.

**Microsomal Clearance:** Ligand A (36.518 mL/min/kg) has a higher clearance than Ligand B (11.434 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.441 hours) has a negative half-life, which is not possible. This is a significant red flag. Ligand A (41.01 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.248) has lower P-gp efflux than Ligand B (0.048), which is favorable.

**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.

**Conclusion:**

Despite Ligand B's problematic negative half-life, the combination of significantly better binding affinity, much lower DILI risk, better metabolic stability (lower Cl_mic), and lower hERG risk makes it the more promising candidate. The poor Caco-2 and solubility of both are concerning, but can potentially be addressed through formulation strategies. The negative half-life for Ligand B is a critical issue that would need investigation (potential data error), but even with that caveat, the other factors heavily favor Ligand B. Ligand A's high DILI risk and poor solubility are major drawbacks.

Output:
1
2025-04-17 15:49:43,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.365 and 351.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.66) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (130.6) is still within the acceptable range for oral absorption (<140), but less optimal than A.

**logP:** Ligand A (2.7) is within the optimal 1-3 range. Ligand B (-0.014) is slightly below 1, which *could* indicate permeability issues, but is not drastically low.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also acceptable, but slightly higher counts might impact permeability.

**QED:** Ligand A (0.685) has a better QED score than Ligand B (0.421), indicating a more drug-like profile.

**DILI:** Ligand B (64.366) has a higher DILI risk than Ligand A (52.695), which is preferable.

**BBB:** Both have reasonable BBB penetration, but Ligand A (82.241) is better than Ligand B (57.968). This isn't a primary concern for a kinase inhibitor, but a bonus.

**Caco-2 Permeability:** Ligand A (-3.994) has a much higher Caco-2 permeability than Ligand B (-5.006), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-2.965) has better aqueous solubility than Ligand B (-2.592). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.719) has a lower hERG risk than Ligand B (0.118), which is a significant advantage.

**Microsomal Clearance:** Ligand A (80.343) has a higher microsomal clearance than Ligand B (13.626), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (3.835 and 3.724 hours).

**P-gp Efflux:** Ligand A (0.404) has lower P-gp efflux than Ligand B (0.116), which is favorable.

**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 could outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has better overall ADME properties (TPSA, logP, solubility, hERG, P-gp), the significantly stronger binding affinity of Ligand B (-8.7 vs -7.9 kcal/mol) is a major advantage for an enzyme inhibitor. The lower metabolic stability (higher Cl_mic) of Ligand A is a substantial concern. The higher DILI risk for Ligand B is less concerning than the metabolic liability of Ligand A. Therefore, I predict Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 15:49:43,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.385 and 348.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (77.92) is well below the 140 threshold, suggesting good absorption. Ligand B (109.3) is still within acceptable limits, but less favorable.

**logP:** Ligand A (0.821) is at the lower end of optimal, potentially impacting permeability. Ligand B (-0.393) is below 1, which is a concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is excellent. Ligand B (2 HBD, 8 HBA) is acceptable, but the higher HBA count could slightly hinder permeability.

**QED:** Both ligands (0.731 and 0.761) have good drug-likeness scores.

**DILI:** Ligand A (30.322) has a significantly lower DILI risk than Ligand B (57.154), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.735) has a better BBB percentile than Ligand B (23.187).

**Caco-2 Permeability:** Ligand A (-4.804) and Ligand B (-5.201) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.288) is slightly better than Ligand B (-0.929), but both are poor. Solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.203) has a much lower hERG risk than Ligand B (0.098), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-10.542) exhibits much better metabolic stability (lower clearance) than Ligand B (-6.823). This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-9.941) has a longer half-life than Ligand B (5.592), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands (0.03 and 0.019) have very low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand A (-8.3 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 substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both have poor Caco-2 permeability and solubility, the ADME advantages of Ligand A, particularly the lower toxicity and better metabolic stability, are crucial for an enzyme target like SRC kinase.



Output:
0
2025-04-17 15:49:43,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.02) is slightly above the optimal <140 for oral absorption, but still acceptable. Ligand B (84.67) is excellent, well below 140.

**logP:** Ligand A (-0.598) is a bit low, potentially hindering permeability. Ligand B (1.448) is within the optimal 1-3 range.

**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: 0.522, B: 0.805), indicating drug-likeness. Ligand B is significantly better.

**DILI:** Ligand A (50.097) has a moderate DILI risk, while Ligand B (33.385) is lower and preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.733) is higher, but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative values, which is unusual and problematic. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values, which is also unusual and problematic. Again, the scale is not defined.

**hERG:** Ligand A (0.049) has a very low hERG risk, which is excellent. Ligand B (0.156) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-9.48) suggests very slow clearance (highly stable), which is excellent. Ligand B (8.994) is higher, indicating faster clearance and reduced metabolic stability.

**In vitro Half-Life:** Ligand A (17.039) has a reasonable half-life. Ligand B (12.011) is shorter.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.026, B: 0.066), which is favorable.

**Binding Affinity:** Both ligands have comparable strong binding affinities (A: -8.9 kcal/mol, B: -8.0 kcal/mol). Ligand A is slightly better.

**Conclusion:**

While Ligand A has a slightly better binding affinity and excellent metabolic stability (low Cl_mic, good t1/2) and hERG profile, its low logP and negative solubility/permeability values are concerning. Ligand B has a better logP, QED, and DILI score, and a good BBB score, but its metabolic stability is lower. Given the enzyme-specific priorities, the superior metabolic stability of Ligand A, combined with its comparable binding affinity, makes it the more promising candidate *despite* the concerning logP and solubility/permeability values. Further investigation into improving the logP and solubility of Ligand A would be a priority.

Output:
0
2025-04-17 15:49:43,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.421 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is better than Ligand B (81.67), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.767) is slightly lower than optimal (1-3), but acceptable. Ligand B (1.201) is within the ideal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.647) is slightly better than Ligand B (0.574), both are above the 0.5 threshold.

**DILI:** Ligand A (35.983) has a significantly lower DILI risk than Ligand B (4.498), which is a major advantage.

**BBB:** Ligand A (65.413) has better BBB penetration than Ligand B (52.656), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.998) has a worse Caco-2 permeability than Ligand B (-5.3). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-1.542) has slightly better solubility than Ligand B (-1.585).

**hERG:** Ligand A (0.253) has a much lower hERG risk than Ligand B (0.179), which is a significant advantage.

**Microsomal Clearance:** Ligand A (28.002) has a higher microsomal clearance than Ligand B (-3.513), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (19.86) has a longer half-life than Ligand B (3.618), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux than Ligand B (0.008), which is beneficial.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A has a much better safety profile (lower DILI and hERG) and a longer half-life. While Ligand B has slightly better binding affinity and Caco-2 permeability, the safety advantages of Ligand A, combined with its acceptable potency and pharmacokinetic properties, make it the more promising drug candidate. The lower metabolic stability of Ligand A is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 15:49:43,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.487 and 351.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (54.46) is well below the 140 threshold and good for oral absorption. Ligand B (96.11) is still under the threshold, but closer to it.

**logP:** Ligand A (3.07) is optimal. Ligand B (0.656) is a bit low, potentially hindering permeation.

**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 good QED scores (0.891 and 0.809, respectively), indicating drug-like properties.

**DILI:** Ligand A (29.624) has a lower DILI risk than Ligand B (39.434), which is preferable. Both are below the 40 threshold.

**BBB:** Ligand A (92.361) has better BBB penetration than Ligand B (64.87). While not a primary concern for a kinase inhibitor, it's a bonus.

**Caco-2 Permeability:** Ligand A (-4.953) has significantly better Caco-2 permeability than Ligand B (-4.54).

**Aqueous Solubility:** Ligand A (-2.842) has better aqueous solubility than Ligand B (-1.216). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.706) has a lower hERG inhibition liability than Ligand B (0.214), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (63.404) has a higher microsomal clearance than Ligand B (6.019), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (9.596) has a shorter half-life than Ligand B (0.433). This further reinforces the metabolic stability concern with Ligand A.

**P-gp Efflux:** Ligand A (0.391) has lower P-gp efflux than Ligand B (0.089), which is favorable.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). However, the difference is minimal (0.1 kcal/mol), and doesn't outweigh the ADME concerns with Ligand A.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising candidate. Ligand B exhibits better solubility, significantly better metabolic stability (lower Cl_mic and higher t1/2), and lower hERG risk. While its logP is a bit low, the other advantages, particularly the improved metabolic stability, make it a more viable drug candidate for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:49:43,817 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.547 Da) is slightly lower, which could be beneficial for permeability. Ligand B (372.487 Da) is also good.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (83.99). A TPSA under 140 is good for oral absorption, and both are under, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (4.16) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.548) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 HBA, which is excellent. Ligand B has 0 HBD and 5 HBA, also acceptable, but slightly less favorable than A.

**QED:** Both ligands have similar QED values (A: 0.601, B: 0.609), indicating good drug-likeness.

**DILI:** Ligand A (20.551) has a much lower DILI risk than Ligand B (39.473). This is a significant advantage for A.

**BBB:** Ligand A (77.782) has better BBB penetration potential than Ligand B (60.876), though this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.711) has better Caco-2 permeability than Ligand B (-4.328).

**Aqueous Solubility:** Ligand A (-3.787) has better aqueous solubility than Ligand B (-1.543). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.808) has a lower hERG inhibition risk than Ligand B (0.213). This is a critical advantage for A, minimizing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand B (78.251) has lower microsomal clearance than Ligand A (94.056), suggesting better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand A (15.054) has a longer half-life than Ligand B (-25.644). This is a significant advantage for A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.477) has lower P-gp efflux than Ligand B (0.127), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 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 Ligand B has better metabolic stability (lower Cl_mic), Ligand A excels in almost every other critical parameter. Its superior binding affinity, lower DILI risk, better solubility, lower hERG inhibition, and longer half-life are crucial advantages for an enzyme inhibitor. The slightly higher logP of Ligand A is a concern, but the substantial binding affinity advantage likely compensates for it.

Output:
0
2025-04-17 15:49:43,817 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.451 and 350.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.7) is slightly above the preferred <140, but acceptable. Ligand B (59.31) is well within the acceptable range.

**logP:** Both ligands have good logP values (3.156 and 1.92), 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:** Ligand A has 6 HBA, within the acceptable limit. Ligand B has 7 HBA, also within the limit.

**QED:** Both ligands have similar and good QED scores (0.739 and 0.749), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 70.919, which is concerning (approaching the high-risk threshold). Ligand B has a significantly lower DILI risk of 15.2, which is excellent.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (87.553) than Ligand A (49.05), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.17 and -4.761). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value isn't necessarily disqualifying, but does warrant further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.22 and -1.58). This is concerning and indicates very poor aqueous solubility, which will likely hinder bioavailability.

**hERG Inhibition:** Ligand A (0.173) has a slightly higher hERG risk than Ligand B (0.546), but both are relatively low.

**Microsomal Clearance:** Ligand A (33.544) has a higher microsomal clearance than Ligand B (25.838), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.331 hours) has a significantly longer in vitro half-life than Ligand A (-16.164 hours - a negative value is unusual and indicates very rapid degradation).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.055 and 0.073).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), though the difference is not huge.

**Conclusion:**

While both compounds have reasonable binding affinities and drug-like scores, Ligand B is significantly better due to its much lower DILI risk, longer half-life, and better metabolic stability. The solubility and permeability issues are concerning for both, but the superior safety and PK profile of Ligand B outweigh the slightly better affinity of Ligand A.

Output:
1
2025-04-17 15:49:43,817 - INFO - Batch 412 complete. Total preferences: 6592
2025-04-17 15:49:43,818 - INFO - Processing batch 413/512...
2025-04-17 15:50:25,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.463 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.53) is better than Ligand B (115.11). Both are under 140, supporting oral absorption, but A is closer to the optimal range.

**logP:** Both ligands have similar logP values (0.729 and 0.79), which are within the optimal 1-3 range.

**H-Bond Donors:** Both have 3 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 6. Ligand A is preferable here, as lower HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.539 and 0.692), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (23.885) has a significantly lower DILI risk than Ligand B (54.789). This is a major advantage for Ligand A.

**BBB:** Ligand A (66.227) has a better BBB percentile than Ligand B (38.813). While not crucial for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.884) has better Caco-2 permeability than Ligand B (-5.209), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-1.644) has better aqueous solubility than Ligand B (-3.89). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.093) has a lower hERG inhibition liability than Ligand B (0.302), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (29.336) has higher microsomal clearance than Ligand B (18.672), meaning it is less metabolically stable. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (3.244) has a longer in vitro half-life than Ligand A (12.584). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.007) has lower P-gp efflux than Ligand B (0.099), which is favorable.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 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 B has a much stronger binding affinity, a longer half-life, and a better QED score. However, it has a higher DILI risk, lower solubility, and higher hERG inhibition. Ligand A excels in safety parameters (DILI, hERG), solubility, and permeability, but suffers from lower affinity and metabolic stability.

Given that SRC is an enzyme, potency (binding affinity) is paramount. The 1.5 kcal/mol difference in affinity is substantial. While the DILI and hERG risks of Ligand B are concerning, they could potentially be mitigated through further structural modifications. The lower solubility of Ligand B is also a concern, but formulation strategies can often address this. The metabolic stability of Ligand A is a concern, but prodrug strategies could be explored.

Output:
1
2025-04-17 15:50:25,887 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and priorities for enzymes.

**Step-by-step comparison:**

1. **MW:** Ligand A (357.479 Da) is within the ideal range (200-500). Ligand B (425.689 Da) is also acceptable, though approaching the upper limit.
2. **TPSA:** Ligand A (63.13) is good, well below the 140 threshold. Ligand B (51.45) is even better. Both are favorable for absorption.
3. **logP:** Ligand A (2.187) is optimal (1-3). Ligand B (4.948) is slightly high, potentially leading to solubility issues and off-target interactions.
4. **HBD:** Ligand A (2) is within the acceptable limit (<=5). Ligand B (1) is also good.
5. **HBA:** Ligand A (4) is within the acceptable limit (<=10). Ligand B (5) is also good.
6. **QED:** Ligand A (0.881) is excellent, indicating high drug-likeness. Ligand B (0.588) is acceptable, but less ideal.
7. **DILI:** Ligand A (62.893) is moderate risk, but acceptable. Ligand B (85.498) is a higher risk for liver injury, which is concerning.
8. **BBB:** Both ligands have similar BBB penetration (A: 65.297, B: 67.584). Not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a problem with the data. However, assuming these represent permeability, a more negative value indicates *lower* permeability. Ligand A (-5.221) is slightly better than Ligand B (-4.415).
10. **Solubility:** Ligand A (-3.215) is better than Ligand B (-5.302). Solubility is important for bioavailability.
11. **hERG:** Ligand A (0.431) has a lower hERG risk than Ligand B (0.878), which is a significant advantage.
12. **Cl_mic:** Ligand A (31.076) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (72.886). This is a key consideration for enzymes.
13. **t1/2:** Ligand A (42.665) has a shorter half-life than Ligand B (56.92), but both are reasonable.
14. **Pgp:** Ligand A (0.213) has lower P-gp efflux, which is favorable for bioavailability. Ligand B (0.887) has higher efflux.
15. **Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This 0.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in affinity and has better metabolic stability, solubility, and hERG profile. While Ligand B has a slightly longer half-life, the other factors heavily favor Ligand A. The higher DILI risk for Ligand B is also a significant concern.

**Conclusion:**

Ligand A is the more promising drug candidate. Its superior binding affinity, better ADME properties (solubility, metabolic stability, Pgp efflux, hERG), and lower DILI risk outweigh the slightly shorter half-life compared to Ligand B.

Output:
1
2025-04-17 15:50:25,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.447 and 380.579 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.12) is better than Ligand B (58.2), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.378 and 2.776), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still within an acceptable 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 the recommended limits.

**QED:** Both ligands have good QED scores (0.818 and 0.72), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (30.71 and 37.456), which is favorable.

**BBB:** Ligand A has a significantly higher BBB penetration score (76.774) compared to Ligand B (49.36). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.997) is significantly better than Ligand B (-5.242).

**Aqueous Solubility:** Ligand A (-2.96) is better than Ligand B (-3.613). Both are negative, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.061 and 0.176).

**Microsomal Clearance:** Ligand A (49.256) has a higher microsomal clearance than Ligand B (13.785). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-1.421) has a slightly better in vitro half-life than Ligand A (-16.662).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.095).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.6 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic, better t1/2), which are key priorities for kinase inhibitors. While Ligand A has better solubility and Caco-2 permeability, the difference in binding affinity and metabolic stability outweighs these advantages. The slightly higher logP of Ligand B is not a major concern.

Output:
1
2025-04-17 15:50:25,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.423 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.11) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (67.43) is excellent, well below 140.

**logP:** Both ligands (2.295 and 2.973) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, fitting the <5 and <10 rules. Ligand B has 2 HBD and 3 HBA, also fitting the rules.

**QED:** Both ligands have similar QED scores (0.498 and 0.496), indicating moderate drug-likeness. Improvement here would be beneficial, but not a major differentiator.

**DILI:** Ligand A (38.736) has a slightly higher DILI risk than Ligand B (19.736), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (64.986) shows better BBB penetration than Ligand A (44.591), but this is not a primary concern.

**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 ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, experimental validation is needed.

**hERG:** Ligand A (0.355) has a slightly better hERG profile (lower risk) than Ligand B (0.28).

**Microsomal Clearance:** Ligand A (-1.301) has significantly *lower* (better) microsomal clearance than Ligand B (46.966), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (2.467) has a shorter half-life than Ligand B (13.021), but both are relatively short. Ligand B's longer half-life is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.042), which is good.

**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 minor ADME drawbacks.

**Conclusion:**

While Ligand B has better TPSA and half-life, Ligand A's substantially stronger binding affinity (-8.7 vs -6.9 kcal/mol) and better metabolic stability (lower Cl_mic) are critical advantages for an enzyme target like SRC kinase. The slightly higher DILI risk and shorter half-life of Ligand A are less concerning given its superior potency and metabolic profile. The negative solubility and Caco-2 values for both are concerning and need experimental verification, but the potency advantage of A is significant.

Output:
1
2025-04-17 15:50:25,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (73.2), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (1.174) is within the optimal 1-3 range, while Ligand B (2.755) is approaching the upper limit.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.779 and 0.849), indicating drug-likeness.

**DILI:** Ligand A (21.442) has a significantly lower DILI risk than Ligand B (16.557). This is a major advantage.

**BBB:** Both have similar BBB penetration (63.629 and 67.197). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.974 and -4.699), which is unusual and suggests poor permeability. This is a potential issue for both, but needs further investigation.

**Aqueous Solubility:** Ligand A (-1.828) is better than Ligand B (-3.059), indicating slightly better solubility.

**hERG Inhibition:** Both have low hERG inhibition risk (0.1 and 0.384), which is excellent.

**Microsomal Clearance:** Ligand A (33.043) has lower microsomal clearance than Ligand B (43.516), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.678) has a longer half-life than Ligand B (4.037), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.039 and 0.037).

**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. It has a significantly lower DILI risk, better solubility, lower microsomal clearance, a longer half-life, and slightly better binding affinity. While both have poor Caco-2 permeability, the other advantages of Ligand A outweigh this concern, especially given the enzyme-specific priorities. The small advantage in binding affinity further supports this conclusion.

Output:
0
2025-04-17 15:50:25,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (346.515 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (103.01). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's TPSA is relatively high, potentially hindering cell permeability.

**logP:** Ligand A (3.308) is within the optimal 1-3 range. Ligand B (0.583) is quite low, potentially leading to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable. Ligand B has 3 HBD and 5 HBA, which is acceptable, but more could lead to issues.

**QED:** Both ligands have similar QED values (0.787 and 0.739), indicating good drug-like properties.

**DILI:** Ligand A (16.014 percentile) has a much lower DILI risk than Ligand B (34.161 percentile). This is a significant advantage for Ligand A.

**BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand A (88.91) is higher than Ligand B (25.785), but this isn't a primary concern.

**Caco-2 Permeability:** Ligand A (-4.582) is better than Ligand B (-5.221), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.627) is better than Ligand B (-1.232), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.551) is significantly better than Ligand B (0.135), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (70.964) has higher clearance than Ligand B (-14.313). This suggests Ligand B is more metabolically stable, a key advantage for kinase inhibitors.

**In vitro Half-Life:** Ligand B (20.684 hours) has a much longer half-life than Ligand A (-11.65 hours). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.172 and 0.036).

**Binding Affinity:** Both ligands have similar binding affinities (-8.3 and -9.1 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to outweigh its other drawbacks.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, logP, solubility, DILI, hERG) and has acceptable binding affinity. However, it has a shorter half-life and higher clearance. Ligand B has a longer half-life and better metabolic stability, but suffers from poor logP, higher TPSA, and a higher DILI risk. Given the importance of metabolic stability for kinase inhibitors, and the substantial advantage of Ligand B in that regard, combined with a slightly better binding affinity, it is the more promising candidate despite its other drawbacks. The solubility and permeability issues of Ligand B could potentially be addressed through formulation strategies.



Output:
1
2025-04-17 15:50:25,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.848 Da and 386.21 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (75.44). TPSA < 140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (3.244 and 2.966), falling within the 1-3 optimal range.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 2 HBAs, Ligand B has 4. Both are within the acceptable limit of <=10, but A is preferable.

**QED:** Both ligands have similar QED values (0.891 and 0.877), indicating good drug-likeness.

**DILI:** Ligand A (44.862) has a much lower DILI risk than Ligand B (76.464). This is a significant advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (91.431 and 82.125), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.67 and -4.663), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.507 and -4.557), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.72) has a slightly higher hERG risk than Ligand B (0.408), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.26 mL/min/kg) has significantly lower microsomal clearance than Ligand B (19.062 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (0.809 hours) has a lower in vitro half-life than Ligand B (0.342 hours). This is a drawback for Ligand A, but the difference isn't massive.

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux than Ligand B (0.257), which is preferable.

**Binding Affinity:** Ligand B (-8.7 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 liabilities. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity. However, Ligand A has better DILI risk, TPSA, HBA, microsomal clearance, and P-gp efflux. Both have poor solubility and Caco-2 permeability. The superior binding affinity of Ligand B is a strong point, and the 1 kcal/mol difference is significant. While the solubility and permeability are concerning for both, the potency advantage of Ligand B is likely to be more impactful in early stages of development.

Output:
1
2025-04-17 15:50:25,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.335 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.46) is higher than Ligand B (78.53). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (3.673) is within the optimal range, while Ligand B (1.064) is on the lower side. Lower logP can sometimes hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.829) has a significantly better QED score than Ligand A (0.451), indicating a more drug-like profile.

**DILI:** Ligand A (80.341) has a higher DILI risk than Ligand B (42.691). This is a significant concern for Ligand A.

**BBB:** Both ligands have relatively high BBB penetration (Ligand A: 56.766, Ligand B: 80.419). This isn't a primary concern for a non-CNS target like SRC kinase.

**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 their relative values; Ligand B (-4.904) is slightly better than Ligand A (-4.282).

**Aqueous Solubility:** Ligand B (-2.133) has better aqueous solubility than Ligand A (-6.103). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.697) has a slightly higher hERG risk than Ligand B (0.418), but both are relatively low.

**Microsomal Clearance:** Ligand B (25.329 mL/min/kg) has significantly lower microsomal clearance than Ligand A (71.187 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.052 hours) has a much longer in vitro half-life than Ligand A (5.843 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.497) shows slightly lower P-gp efflux than Ligand B (0.069).

**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 B is superior in almost all other critical ADME-Tox properties. It has a better QED score, significantly lower DILI risk, better solubility, and dramatically improved metabolic stability (lower Cl_mic and longer t1/2). The slightly lower logP of Ligand B is a minor drawback compared to the substantial benefits in other areas.

Output:
1
2025-04-17 15:50:25,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.459 and 355.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is slightly higher than Ligand B (60.15), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.983) is optimal, while Ligand B (4.234) is pushing the upper limit. Higher logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both 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:** Both ligands have similar QED values (0.733 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (33.928) has a significantly lower DILI risk than Ligand B (56.727). This is a major advantage for Ligand A.

**BBB:** Both have good BBB penetration (72.974 and 75.107), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.111 and -4.921). This is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-1.845) has better (less negative) solubility than Ligand B (-4.533). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.47) has a much lower hERG risk than Ligand B (0.906). This is a critical advantage, as hERG inhibition can cause cardiotoxicity.

**Microsomal Clearance:** Ligand A (49.51) has significantly lower microsomal clearance than Ligand B (91.376), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-5.752) has a shorter half-life than Ligand B (34.242). This is a drawback for Ligand A, but can potentially be overcome with formulation strategies.

**P-gp Efflux:** Both have low P-gp efflux liability (0.111 and 0.584).

**Binding Affinity:** Both have excellent binding affinities (-8.8 and -9.1 kcal/mol), with Ligand B being slightly better. However, the difference is small and may not outweigh the ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A significantly outperforms it in critical ADME properties: lower DILI risk, lower hERG inhibition, and better metabolic stability (lower Cl_mic). The solubility is also better for Ligand A. The similar Caco-2 values are concerning for both, but the other advantages of Ligand A make it the preferred choice.

Output:
0
2025-04-17 15:50:25,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.466 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.36 and 54.46) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.945 and 3.229) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, fulfilling the <5 and <10 criteria respectively.

**QED:** Both ligands have good QED scores (0.696 and 0.806), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (19.969 and 19.426 percentile), which is favorable.

**BBB:** Both have similar BBB penetration (78.79 and 78.519 percentile). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.583 and -4.811), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-2.578 and -3.42), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.718 and 0.751 percentile), which is excellent.

**Microsomal Clearance:** Ligand B (70.604 mL/min/kg) has higher microsomal clearance than Ligand A (51.681 mL/min/kg), indicating lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-6.967 hours) has a longer in vitro half-life than Ligand B (4.046 hours). This favors Ligand A.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.344 and 0.218 percentile).

**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 relatively small.

**Overall Assessment:**

Both compounds have significant issues with solubility and Caco-2 permeability. However, Ligand A demonstrates better metabolic stability (lower Cl_mic) and a longer half-life, which are crucial for an enzyme target. While Ligand B has a slightly better binding affinity, the ADME properties of Ligand A are more favorable. The poor solubility and permeability are serious concerns for both, but the improved PK profile of A makes it slightly more promising, assuming solubility/permeability can be addressed through formulation or further modification.

Output:
0
2025-04-17 15:50:25,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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, but both are acceptable.

**TPSA:** Ligand B (95.71) is better than Ligand A (119.9), being closer to the optimal threshold of <=140 for oral absorption.

**logP:** Ligand B (2.775) is optimal (1-3), while Ligand A (0.355) 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.688, Ligand B: 0.568), indicating good drug-like properties.

**DILI:** Ligand B (56.805) has a higher DILI risk than Ligand A (46.219), but both are still below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (57.154) is slightly higher than Ligand A (40.403), but neither is particularly high.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.499 and -5.56), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.641 and -4.216), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.484 and 0.534), which is excellent.

**Microsomal Clearance:** Ligand A (-13.988) has significantly lower (better) microsomal clearance than Ligand B (51.054), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (12.281 hours) has a much longer half-life than Ligand B (-29.522 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.199).

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity and low hERG risk, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly lower DILI risk. The major drawback for Ligand A is its low logP and poor solubility, but the metabolic advantages are more crucial for an enzyme target like SRC. The poor Caco-2 and solubility are concerning for both, but formulation strategies might be employed to address these issues. The low logP of Ligand A is a bigger concern than the slightly higher DILI of Ligand B.

Output:
0
2025-04-17 15:50:25,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.399 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (79.31) is lower than Ligand B (82.96), which is slightly favorable.

**logP:** Ligand A (-0.622) is significantly lower than Ligand B (3.598). While a logP between 1-3 is optimal, Ligand A's value is quite low and could hinder membrane permeability. Ligand B is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 7 HBA) both fall within acceptable limits.

**QED:** Both ligands have similar and acceptable QED values (0.673 and 0.694).

**DILI:** Ligand A (52.734) has a significantly lower DILI risk than Ligand B (82.241). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (65.529 and 63.746), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Ligand A (-1.531) has better aqueous solubility than Ligand B (-4.933). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.16) has a much lower hERG inhibition liability than Ligand B (0.73). This is a crucial advantage for Ligand A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (3.564 mL/min/kg) has significantly lower microsomal clearance than Ligand B (34.083 mL/min/kg). This indicates better metabolic stability for Ligand A, a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (-11.788 hours) has a negative half-life, which is not possible. This is a significant red flag. Ligand B (59.877 hours) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux liability than Ligand B (0.497), which is favorable.

**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, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Despite the unusual negative half-life for Ligand A, its significantly superior binding affinity (-10.2 vs -0.0 kcal/mol) and lower DILI and hERG risks are compelling. The lower logP of Ligand A is a concern, but the strong binding affinity may compensate for this. The metabolic stability is also much better for Ligand A. The negative half-life is a major concern, but it could be an artifact of the prediction method. Given the importance of potency for enzyme inhibitors, and the other favorable ADME properties of Ligand A, it is the more promising candidate.

Output:
0
2025-04-17 15:50:25,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (452.227 Da) is slightly higher, but still acceptable. Ligand B (352.475 Da) is preferable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (66.92) is lower than Ligand A (80.05), which is slightly better.

**logP:** Ligand A (3.322) is within the optimal range (1-3). Ligand B (1.866) is at the lower end 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.

**QED:** Both ligands have good QED scores (A: 0.443, B: 0.701), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A has a high DILI risk (80.651%), which is concerning. Ligand B has a very low DILI risk (12.33%), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has higher BBB penetration (86.002%) than Ligand A (63.862%), but it's not a deciding factor.

**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. Ligand B (-4.397) is slightly better than Ligand A (-5.32).

**Aqueous Solubility:** Both ligands have negative solubility values, which is concerning and suggests poor solubility. Ligand B (-1.152) is better than Ligand A (-4.054).

**hERG Inhibition:** Ligand A (0.819) has a slightly higher hERG risk than Ligand B (0.201), which is preferable.

**Microsomal Clearance:** Ligand B (34.66 mL/min/kg) has significantly lower microsomal clearance than Ligand A (53.504 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.121 hours) has a longer in vitro half-life than Ligand A (72.197 hours). This is a significant advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.549) has lower P-gp efflux than Ligand B (0.041), which is better.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand A, the significantly higher DILI risk, higher microsomal clearance, and lower in vitro half-life make it a less desirable candidate. Ligand B has a much more favorable ADME-Tox profile, with low DILI risk, better metabolic stability, and a longer half-life. The difference in binding affinity (1.1 kcal/mol) can potentially be overcome with further optimization of Ligand B, while mitigating the severe DILI risk associated with Ligand A would be much more challenging.

Output:
1
2025-04-17 15:50:25,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.371 and 360.414 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is well below the 140 threshold and favorable for absorption. Ligand B (83.98) is also acceptable, though slightly higher.

**3. logP:** Both ligands have logP values (1.959 and 2.384) 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:** 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 (0.508 and 0.648), indicating drug-like properties.

**7. DILI:** Ligand A (33.695) has a significantly lower DILI risk than Ligand B (78.286). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (54.478) and Ligand B (46.336) are both relatively low.

**9. Caco-2 Permeability:** Both ligands have the same Caco-2 permeability (-4.833), suggesting similar intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.505) has better aqueous solubility than Ligand B (-3.752). This is beneficial for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liabilities (0.499 and 0.468), indicating relatively low risk.

**12. Microsomal Clearance:** Ligand A (0.544) has significantly lower microsomal clearance than Ligand B (35.906), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-2.894) has a longer in vitro half-life than Ligand B (8.14). This is another significant advantage.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.066 and 0.099).

**15. Binding Affinity:** Ligand B (-10.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage. The difference of 2.9 kcal/mol is large enough to potentially offset some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity. However, Ligand A demonstrates superior ADMET properties: lower DILI risk, better solubility, and significantly improved metabolic stability (lower Cl_mic and longer t1/2). While the affinity difference is substantial, the ADMET profile of Ligand A is considerably more favorable. For an enzyme target like SRC kinase, metabolic stability and reduced toxicity are paramount. The stronger binding of Ligand B could potentially be overcome with further optimization, while the poor ADMET profile may be harder to fix.

Output:
0
2025-04-17 15:50:25,890 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.331 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (78.87). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is much more favorable.

**logP:** Both ligands have good logP values (3.247 and 2.15), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=5) in terms of hydrogen bonding potential, staying lower and potentially improving permeability.

**QED:** Both ligands have acceptable QED scores (0.677 and 0.742), indicating good drug-like properties.

**DILI:** Ligand A (49.011) has a considerably lower DILI risk than Ligand B (16.751), which is a significant advantage. Lower DILI is crucial.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (89.608) shows better BBB penetration than Ligand B (63.086).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.617 and -4.791), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.717 and -2.788), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.939) has a slightly higher hERG inhibition risk than Ligand B (0.428), but both are relatively low.

**Microsomal Clearance:** Ligand A (-5.201) has a much lower (better) microsomal clearance than Ligand B (39.105). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (3.303) has a slightly longer half-life than Ligand B (-0.39), which is preferable.

**P-gp Efflux:** Ligand A (0.5) has a lower P-gp efflux liability than Ligand B (0.078), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.4 kcal/mol). Ligand A is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A is superior due to its significantly better DILI score, lower microsomal clearance (better metabolic stability), lower P-gp efflux, and slightly better half-life. While both have poor Caco-2 permeability and solubility, the ADME profile of Ligand A is more favorable overall, particularly regarding safety (DILI) and metabolic stability. The small advantage in binding affinity further strengthens the case for Ligand A.

Output:
1
2025-04-17 15:50:25,890 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.487 and 347.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is higher than Ligand B (43.86). While both are reasonably low, Ligand B is better positioned for good absorption.

**3. logP:** Both ligands have good logP values (2.413 and 2.112), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable, staying below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of 10.

**6. QED:** Ligand B (0.739) has a higher QED score than Ligand A (0.523), suggesting a more drug-like profile.

**7. DILI:** Ligand B (6.592) has a significantly lower DILI risk than Ligand A (19.814). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (85.692) shows better BBB penetration than Ligand A (57.193), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.725) and Ligand B (-4.81) have similar Caco-2 permeability values, suggesting comparable intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.822) has slightly better aqueous solubility than Ligand B (-0.987).

**11. hERG Inhibition:** Ligand A (0.188) has a lower hERG inhibition liability than Ligand B (0.686), which is a positive.

**12. Microsomal Clearance:** Ligand B (31.837) has a considerably lower microsomal clearance than Ligand A (55.754), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (5.457) has a longer in vitro half-life than Ligand A (-10.976). This is another significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux than Ligand B (0.075).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better hERG inhibition and solubility, Ligand B excels in critical areas for an enzyme inhibitor: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), a higher QED score, and better BBB penetration. The similar binding affinities make these ADME/Tox advantages decisive.

Output:
1
2025-04-17 15:50:25,890 - INFO - Batch 413 complete. Total preferences: 6608
2025-04-17 15:50:25,890 - INFO - Processing batch 414/512...
2025-04-17 15:51:05,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.459 Da) is slightly higher than Ligand B (347.503 Da), but both are acceptable.

**TPSA:** Ligand A (100.99) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (52.65) is excellent, well below 140.

**logP:** Ligand A (-0.265) is a bit low, potentially hindering permeability. Ligand B (1.899) 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 (1 HBD, 3 HBA) is also good, with fewer hydrogen bonding groups which generally improves permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.653, B: 0.512), indicating reasonable drug-likeness.

**DILI:** Ligand A (60.295) has a moderate DILI risk, while Ligand B (4.188) has a very low risk. This is a substantial advantage for Ligand B.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (67.197) is higher, but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative values, 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 have negative values, indicating poor solubility. Again, the scale is important here, but both are likely to have formulation challenges.

**hERG:** Ligand A (0.107) has a slightly higher hERG risk than Ligand B (0.501), though both are relatively low.

**Microsomal Clearance:** Ligand A (12.207) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (2.597) has much lower clearance, which is highly desirable.

**In vitro Half-Life:** Ligand A (-23.182) has a very short in vitro half-life, which is concerning. Ligand B (-8.081) is better, but still relatively short.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.035, B: 0.018).

**Binding Affinity:** Both have excellent binding affinities (A: -7.0 kcal/mol, B: -6.6 kcal/mol). Ligand A is slightly better, but the difference (0.4 kcal/mol) isn't large enough to overcome its other deficiencies.

**Conclusion:**

Considering the priorities for an enzyme target (SRC kinase), Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates significantly better ADMET properties: lower DILI risk, lower microsomal clearance (better metabolic stability), and a more favorable logP. The lower TPSA of Ligand B is also beneficial. Although both have solubility and permeability concerns, the superior safety and pharmacokinetic profile of Ligand B outweigh the minor advantage in binding affinity of Ligand A.

Output:
1
2025-04-17 15:51:05,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.43 and 342.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.09) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (68.87) is excellent, well below 140.

**logP:** Ligand A (0.839) is a bit low, potentially hindering permeation. Ligand B (3.168) is optimal.

**H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**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 (0.639 and 0.752), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 72.08%, which is considered high risk (>60). Ligand B has a DILI risk of 51.26%, which is acceptable (<60).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (25.79%) and Ligand B (89.07%) are not particularly relevant here.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the prediction method, but we can assume they are low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests issues with the prediction method.

**hERG:** Ligand A (0.125) has a very low hERG risk, which is excellent. Ligand B (0.933) has a higher hERG risk, but is not extremely high.

**Microsomal Clearance:** Ligand A (37.79 mL/min/kg) has a moderate clearance. Ligand B (31.62 mL/min/kg) has a lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.16 hours) is a negative value, which is unusual. Ligand B (15.32 hours) is a reasonable half-life.

**P-gp Efflux:** Ligand A (0.035) has very low P-gp efflux, which is good. Ligand B (0.167) has low P-gp efflux.

**Binding Affinity:** Ligand A (-7.0 kcal/mol) and Ligand B (-6.5 kcal/mol) both have good binding affinities. Ligand A is slightly better (-0.5 kcal/mol difference).

**Overall Assessment:**

Ligand A has a slightly better binding affinity, and lower P-gp efflux. However, its high DILI risk and negative solubility/permeability values are major concerns. Ligand B has a better logP, lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), and better TPSA. While its binding affinity is slightly lower, the improved ADME properties, particularly the reduced DILI risk, make it a more promising candidate.

Output:
1
2025-04-17 15:51:05,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.489 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (80.82).  A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.945 and 3.086), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 7 HBA) as it has fewer hydrogen bond acceptors. While both are within acceptable limits, fewer HBA can improve permeability.

**QED:** Both ligands have good QED scores (0.554 and 0.756), indicating good drug-like properties.

**DILI:** Ligand A (21.869) has a much lower DILI risk than Ligand B (66.576). This is a significant advantage for Ligand A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (97.674) has a much higher percentile than Ligand B (61.729).

**Caco-2 Permeability:** Ligand A (-4.224) has a worse Caco-2 permeability than Ligand B (-5.054). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.887) has a worse aqueous solubility than Ligand B (-2.458). Higher values indicate better solubility.

**hERG:** Ligand A (0.91) has a better hERG profile than Ligand B (0.127). Lower is better.

**Microsomal Clearance:** Ligand B (51.404) has a lower microsomal clearance than Ligand A (74.9), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.915) has a longer in vitro half-life than Ligand A (3.676). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.445) has lower P-gp efflux than Ligand B (0.26), which is preferable.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.7). While both are good, the 1.5 kcal/mol advantage of Ligand A is noteworthy.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, hERG, and BBB. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility. However, the significantly lower DILI risk and better hERG profile of Ligand A are critical for drug development. The slight advantage in binding affinity also tips the scale. While the Caco-2 and solubility are less ideal for A, these can be addressed with formulation strategies.

Output:
1
2025-04-17 15:51:05,348 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (342.399 and 346.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.11) is better than Ligand B (62.55), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have acceptable logP values (2.263 and 3.23) falling within the 1-3 range. Ligand B is slightly higher, potentially leading to minor solubility concerns, but not a major issue.

**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 3 HBA, both are well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.68 and 0.786), indicating good drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (85.576%) compared to Ligand B (21.908%). This is a major concern for Ligand A.

**8. BBB:** Both ligands have relatively low BBB penetration (48.507% and 55.874%). This isn't a primary concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.477 and -4.615). This is unusual and suggests poor permeability. However, these values are on a log scale, and a negative value doesn't necessarily preclude development, but indicates a potential issue.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.624 and -2.289). Similar to Caco-2, these values are on a log scale and indicate poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.126 and 0.441), which is good.

**12. Microsomal Clearance:** Ligand B (68.798) has a higher microsomal clearance than Ligand A (61.549), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a much longer in vitro half-life (73.259 hours) compared to Ligand A (-3.776 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.117 and 0.259).

**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.

**Conclusion:**

Despite similar binding affinities and acceptable physicochemical properties, Ligand B is the more promising candidate. The primary reason is the significantly lower DILI risk (21.908% vs. 85.576%). Additionally, Ligand B has a much longer in vitro half-life, indicating better metabolic stability. While both have poor predicted permeability and solubility, the lower DILI risk and improved half-life of Ligand B make it the preferred option for further development.

Output:
1
2025-04-17 15:51:05,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.475 and 353.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.04) is well below the 140 threshold, suggesting good absorption. Ligand B (121.11) is still within acceptable limits, but less favorable.

**logP:** Ligand A (3.527) is slightly above the optimal 1-3 range, potentially leading to solubility issues, but still manageable. Ligand B (0.166) is significantly below the optimal range, which is a major concern for permeability and potentially binding.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is within the preferred limits. Ligand B (3 HBD, 6 HBA) is also acceptable.

**QED:** Ligand A (0.71) has a good drug-likeness score. Ligand B (0.544) is acceptable, but less optimal.

**DILI:** Ligand A (90.733) has a high DILI risk, which is a significant concern. Ligand B (47.732) has a much lower, more acceptable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.276) is reasonable, while Ligand B (24.777) is low.

**Caco-2 Permeability:** Ligand A (-5.235) and Ligand B (-5.43) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.751) and Ligand B (-0.886) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.615) has a low hERG risk, which is good. Ligand B (0.16) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (79.635) has moderate clearance, which is not ideal. Ligand B (-31.563) has negative clearance, which is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (25.571) has a moderate half-life. Ligand B (13.725) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.801) has moderate P-gp efflux. Ligand B (0.02) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a 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.

**Conclusion:**

Despite Ligand A's better TPSA and QED, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.7 vs -6.5 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B exhibits much better metabolic stability (negative Cl_mic) and lower P-gp efflux, which are crucial for *in vivo* efficacy. While Ligand A has a lower DILI risk, the high DILI of Ligand A is a major concern. The solubility and permeability issues are present in both compounds, but the potency and metabolic stability advantages of Ligand B are more critical for initial optimization.

Output:
1
2025-04-17 15:51:05,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (61.88) as it is still within the acceptable range for oral absorption.

**logP:** Ligand B (1.273) is better than Ligand A (0.595). A logP closer to 1-3 is preferred, and Ligand A is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand B (1) is better than Ligand A (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.762 and 0.702), indicating good drug-like properties.

**DILI:** Ligand A (6.282) is significantly better than Ligand B (18.728). Lower DILI risk is crucial.

**BBB:** Ligand B (61.962) is better than Ligand A (33.85), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.096) is better than Ligand B (-4.64), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.953) is better than Ligand B (-2.033). Higher solubility is preferred.

**hERG Inhibition:** Ligand A (0.13) is better than Ligand B (0.171), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-9.874) is *much* better than Ligand B (38.143). Lower clearance indicates better metabolic stability, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (14.784) is better than Ligand B (7.391), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.013) is better than Ligand B (0.038), indicating lower efflux.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.3 and -8.7 kcal/mol), which are excellent. The difference is negligible.

**Conclusion:**

Despite Ligand B having a slightly better logP, Ligand A is the superior candidate. Its significantly lower DILI risk, much better metabolic stability (Cl_mic and t1/2), better solubility, and lower P-gp efflux outweigh the minor disadvantage in logP. The binding affinity is comparable between the two. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are paramount, making Ligand A the more viable drug candidate.

Output:
0
2025-04-17 15:51:05,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.415 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.44) is better than Ligand B (101.18), both being acceptable but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.128) is quite low, potentially hindering permeation. Ligand B (0.815) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, being less than 10.

**QED:** Ligand A (0.762) is better than Ligand B (0.691), both being above the 0.5 threshold for drug-likeness.

**DILI:** Both ligands have low DILI risk (Ligand A: 31.524, Ligand B: 34.083), both well below the 40 threshold.

**BBB:** Ligand A (67.158) has a better BBB penetration percentile than Ligand B (47.809), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.98) is significantly worse than Ligand B (-5.36), indicating lower intestinal absorption. Both are poor.

**Aqueous Solubility:** Ligand A (-2.288) is slightly better than Ligand B (-2.556), but both are poor.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (Ligand A: 0.148, Ligand B: 0.182), which is excellent.

**Microsomal Clearance:** Ligand A (2.479) has a much lower microsomal clearance than Ligand B (21.779), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (10.42) has a longer half-life than Ligand B (-8.698), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.012 and 0.011 respectively).

**Binding Affinity:** Ligand A (0.0) has a significantly weaker binding affinity than Ligand B (-0.0).

**Overall Assessment:**

Ligand A has better QED, DILI, BBB, and *significantly* better metabolic stability (lower Cl_mic and longer t1/2). However, its logP is very low and Caco-2 permeability is poor, and its binding affinity is significantly weaker. Ligand B has a slightly better logP, but suffers from much higher metabolic clearance and a shorter half-life. The binding affinity of Ligand B is much better.

Given the enzyme-kinase focus, metabolic stability is crucial. However, the substantial difference in binding affinity (-0.0 vs 0.0 kcal/mol) is a major factor. A difference of >1.5 kcal/mol can outweigh other drawbacks. In this case, the difference is substantial enough to favor Ligand B.

Output:
1
2025-04-17 15:51:05,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.354 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.7) is better than Ligand B (69.64). Both are below 140, suggesting good absorption potential.

**logP:** Ligand A (3.908) is slightly higher than Ligand B (2.183). Ligand A is approaching the upper limit of optimal, while Ligand B is closer to the lower limit.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3).

**QED:** Both ligands have similar QED values (0.688 and 0.705), indicating good drug-likeness.

**DILI:** Ligand A (85.964) has a significantly higher DILI risk than Ligand B (20.396). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (70.609 and 77.162), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**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 (-4.496 and -4.852).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-3.057) is slightly better than Ligand A (-5.638).

**hERG:** Ligand A (0.873) has a higher hERG risk than Ligand B (0.541). Lower is better here.

**Microsomal Clearance:** Ligand A (107.601) has significantly higher microsomal clearance than Ligand B (27.355), indicating poorer metabolic stability.

**In vitro Half-Life:** Ligand A (73.001) has a longer half-life than Ligand B (-1.313). However, the negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.65) has lower P-gp efflux than Ligand B (0.344), which is preferable.

**Binding Affinity:** Ligand B (-8.4 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 superior candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly better binding affinity (-8.4 vs -7.0 kcal/mol) and dramatically lower DILI risk (20.4 vs 86.0) outweigh the slightly less favorable logP and H-bond donor/acceptor counts. The lower microsomal clearance and P-gp efflux are also beneficial. The negative half-life for Ligand B is a data quality concern, but the other factors strongly favor it. Ligand A's high DILI risk and higher clearance are significant liabilities.

Output:
1
2025-04-17 15:51:05,348 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.419 Da and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (86.28 and 87.66) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.889 and 2.643) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.845) has a significantly higher QED score than Ligand B (0.495), indicating better overall drug-likeness.

**DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (34.587). This is a concern for Ligand A.

**BBB:** Both ligands have relatively high BBB penetration (92.4 and 63.474), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.151) has a worse Caco-2 permeability than Ligand B (-5.126). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.98 and -3.808). This is a significant drawback for both, but may be mitigated through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.174 and 0.787), which is good.

**Microsomal Clearance:** Ligand A (57.951) has a higher microsomal clearance than Ligand B (38.347), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-21.214) has a shorter in vitro half-life than Ligand B (-19.208).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.179 and 0.137).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.1 and -8.4 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A has a better QED score and slightly better binding affinity, but suffers from higher DILI risk, worse Caco-2 permeability, and lower metabolic stability (higher Cl_mic and shorter t1/2). Ligand B has a lower DILI risk and better metabolic stability, but a lower QED score. Considering the priorities for an enzyme target (potency, metabolic stability, solubility, hERG), Ligand B is slightly favored due to its better safety profile (lower DILI) and improved metabolic stability. While solubility is poor for both, the metabolic stability is more critical for kinase inhibitors. The slight difference in binding affinity is less important than the ADME/Tox advantages of Ligand B.

Output:
1
2025-04-17 15:51:05,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 350.415 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is slightly higher than Ligand B (79.31), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.74) is optimal, while Ligand B (-0.374) is slightly low, potentially hindering permeation.

**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 reasonable QED scores (0.611 and 0.54), indicating good drug-likeness.

**DILI:** Ligand A (35.014) has a slightly higher DILI risk than Ligand B (25.087), but both are below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (51.26 and 55.099), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar, and we will consider other factors.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitudes are similar.

**hERG:** Ligand A (0.093) has a slightly higher hERG risk than Ligand B (0.294), but both are very low.

**Microsomal Clearance:** Ligand B (-5.286) shows *negative* clearance, which is not physically possible and suggests a potential data error or unusual behavior. Ligand A (59.609) has a moderate clearance. Lower is better for metabolic stability, so Ligand B's value is highly suspect.

**In vitro Half-Life:** Ligand B (-5.189) also has a negative half-life, which is impossible. Ligand A (-11.827) has a negative half-life as well, indicating data issues.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.078 and 0.075).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly better binding affinity than Ligand A (-7.5 kcal/mol), a difference of 1.0 kcal/mol. This is a substantial advantage.

**Conclusion:**

Despite the unusual negative values for Caco-2, solubility, and half-life, the most significant difference is the binding affinity. Ligand B binds 1.0 kcal/mol more strongly than Ligand A. Given that we are targeting an enzyme (SRC kinase), potency is paramount. While Ligand A has slightly better DILI and hERG profiles, the substantial improvement in binding affinity of Ligand B outweighs these minor drawbacks. The negative values for clearance and half-life for Ligand B are concerning and would require further investigation, but the binding affinity is compelling enough to favor it *given the available data*.

Output:
1
2025-04-17 15:51:05,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (364.47 & 344.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.5) is slightly above the preferred <140, but acceptable. Ligand B (85.05) is well within the acceptable range.

**3. logP:** Both ligands have good logP values (1.785 & 0.917), 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 (4) is acceptable. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.665 & 0.874), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (59.91 & 58.24), which is acceptable (below 60).

**8. BBB:** Both ligands have low BBB penetration (30.83 & 59.09). This is not a major concern for a kinase inhibitor, as CNS penetration isn't usually a primary goal.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.335 & -4.988). 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 (-3.574 & -2.545). This is a potential issue for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.355 & 0.175).

**12. Microsomal Clearance:** Ligand A (74.81) has higher microsomal clearance than Ligand B (22.31), suggesting lower metabolic stability. This is a significant drawback.

**13. In vitro Half-Life:** Ligand B (15.48) has a significantly longer in vitro half-life than Ligand A (7.14). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.133 & 0.081).

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.6 kcal/mol).

**Enzyme-Specific Considerations:**

For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both ligands have excellent affinity, Ligand B clearly wins on metabolic stability (lower Cl_mic, longer t1/2). Solubility is poor for both, but the better metabolic profile of Ligand B is more critical.

Output:
1
2025-04-17 15:51:05,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.423 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.91) is significantly better than Ligand B (89.07). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.729) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (2.303) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (1 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.685 and 0.555), both above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (52.423) and Ligand B (57.425) are both reasonably low risk, below the 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (66.615) is slightly better than Ligand B (57.193).

**Caco-2 Permeability:** Ligand A (-4.636) is significantly better than Ligand B (-5.425). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-4.086) is better than Ligand B (-2.159). Higher values are preferred.

**hERG Inhibition:** Ligand A (0.745) is better than Ligand B (0.198) indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (31.024) has significantly lower clearance than Ligand A (58.702), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (12.452) has a longer half-life than Ligand A (45.048).

**P-gp Efflux:** Ligand A (0.527) is better than Ligand B (0.105), indicating lower efflux and potentially better bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better logP, Ligand A demonstrates better properties across several crucial ADME parameters (TPSA, Caco-2, Solubility, hERG, P-gp). Given the equal binding affinity, the improved ADME profile of Ligand A, particularly its better solubility and reduced hERG risk, makes it the more promising drug candidate.

Output:
1
2025-04-17 15:51:05,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (334.354 Da) is within the ideal range (200-500 Da). Ligand B (433.368 Da) is at the upper limit, but still acceptable.

**TPSA:** Ligand A (70.67) is good, suggesting reasonable permeability. Ligand B (59.08) is even better.

**logP:** Ligand A (3.74) is slightly high, potentially leading to solubility issues. Ligand B (2.371) is optimal.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is acceptable, but approaching the upper limit.

**QED:** Both Ligand A (0.599) and Ligand B (0.59) are good, indicating drug-like properties.

**DILI:** Ligand A (88.251) has a significantly higher DILI risk than Ligand B (29.391). This is a major concern for Ligand A.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (72.082) is slightly better.

**Caco-2 Permeability:** Ligand A (-5.379) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.712) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-3.783) has poor aqueous solubility, consistent with its higher logP. Ligand B (-1.888) is better.

**hERG:** Both ligands have low hERG inhibition risk (0.805 and 0.732 respectively).

**Microsomal Clearance:** Ligand A (44.15) has lower microsomal clearance, indicating better metabolic stability than Ligand B (77.593).

**In vitro Half-Life:** Ligand A (44.807) has a longer half-life than Ligand B (27.5).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.3 and 0.219 respectively).

**Binding Affinity:** Ligand B (-10.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This difference of 2.9 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability and half-life, its poor solubility, permeability, and significantly higher DILI risk are major concerns. Ligand B's much stronger binding affinity is a decisive advantage for an enzyme target like SRC kinase, and its ADME properties are generally better, particularly the lower DILI risk. The difference in binding affinity is large enough to compensate for the slightly higher clearance.

Output:
1
2025-04-17 15:51:05,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.391 and 355.341 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.59) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (87.74) is well below 140, indicating potentially good absorption.

**logP:** Both ligands have good logP values (2.21 and 1.321), falling within 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 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.408 and 0.798). Ligand B's score is significantly better, suggesting a more drug-like profile.

**DILI:** Both ligands have DILI risk around the 64-70 percentile, indicating moderate risk. This isn't a major differentiating factor.

**BBB:** Both ligands have low BBB penetration (57.154 and 72.082). Since SRC is not a CNS target, this is not a critical factor.

**Caco-2 Permeability:** Ligand A (-5.161) shows poor permeability, while Ligand B (-4.644) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-4.182) has poor aqueous solubility, while Ligand B (-2.657) is better, but still not ideal.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.494 and 0.163), which is excellent.

**Microsomal Clearance:** Ligand A (62.701) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (44.117) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.697) has a very short half-life, while Ligand B (10.648) has a longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.026).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity and low hERG risk, Ligand B is the more promising candidate. It has a better QED score, improved metabolic stability (lower Cl_mic, longer t1/2), and better solubility and permeability compared to Ligand A. The slightly lower TPSA of Ligand B is also a minor advantage. The similar DILI scores are not a deciding factor.

Output:
1
2025-04-17 15:51:05,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.403 and 352.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95 and 97.33) are reasonably close to the 140 A^2 threshold for oral absorption, but not ideal for CNS penetration.

**logP:** Ligand A (0.499) is a bit low, potentially hindering permeation. Ligand B (-1.479) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.823 and 0.586), indicating drug-like properties.

**DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (36.603). This is a significant drawback for Ligand A.

**BBB:** Both ligands have low BBB penetration (60.295 and 40.364), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands exhibit poor Caco-2 permeability (-5.25 and -4.894), suggesting potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.503 and -1.259), which is a substantial issue for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.228 and 0.152), which is positive.

**Microsomal Clearance:** Ligand A (-10.071) has a significantly *lower* (better) microsomal clearance than Ligand B (-12.041), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.578) has a slightly better (less negative) in vitro half-life than Ligand B (-0.996).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.008 and 0.01), which is favorable.

**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, as a >1.5 kcal/mol difference can outweigh other issues.

**Overall Assessment:**

Ligand A's primary advantage is its substantially superior binding affinity. However, it suffers from a higher DILI risk and poor solubility. Ligand B has a better DILI profile but extremely weak binding affinity and similar solubility issues. Given that we are targeting a kinase (enzyme), potency is paramount. While solubility is a concern for both, the dramatic difference in binding affinity makes Ligand A the more promising candidate, *provided* the solubility issues can be addressed through formulation strategies. The better metabolic stability (lower Cl_mic) of Ligand A further supports this choice.

Output:
1
2025-04-17 15:51:05,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.281 and 361.829 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.11) is slightly above the preferred <140, but acceptable. Ligand B (79.24) is well within the acceptable range.

**logP:** Ligand A (1.851) is optimal (1-3). Ligand B (4.493) is a bit high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 HBA, which is reasonable. Ligand B has 1 HBD and 3 HBA, also reasonable.

**QED:** Ligand A (0.625) is good, indicating drug-likeness. Ligand B (0.325) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (96.782) has a very high DILI risk. Ligand B (64.754) has a higher DILI risk, but is still better than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (94.223) and Ligand B (64.482) both have values that are not particularly relevant.

**Caco-2 Permeability:** Ligand A (-4.624) and Ligand B (-5.026) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.671) and Ligand B (-5.487) both have negative values, indicating poor solubility.

**hERG:** Ligand A (0.232) has a very low hERG risk, which is excellent. Ligand B (0.822) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (95.801) has high microsomal clearance, suggesting poor metabolic stability. Ligand B (79.374) has moderate clearance, better than Ligand A.

**In vitro Half-Life:** Ligand A (-14.779) has a very short half-life, which is undesirable. Ligand B (11.805) has a short half-life, but is better than Ligand A.

**P-gp Efflux:** Ligand A (0.249) has low P-gp efflux, which is good. Ligand B (0.602) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). The 2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the strong affinity of Ligand A, its extremely high DILI risk and poor metabolic stability (high Cl_mic, short half-life) are major concerns. Ligand B has a weaker affinity, but a better safety profile (lower DILI, lower hERG) and better metabolic stability. While both have poor solubility and permeability, the affinity difference is large enough to potentially overcome these issues with formulation strategies. Considering the enzyme-specific priorities, the superior binding affinity of Ligand A is a significant advantage. However, the DILI risk is too high to ignore.

Output:
1
2025-04-17 15:51:05,350 - INFO - Batch 414 complete. Total preferences: 6624
2025-04-17 15:51:05,350 - INFO - Processing batch 415/512...
2025-04-17 15:51:46,951 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (382.423 Da) is within the ideal range (200-500). Ligand B (345.447 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (40.62) is excellent, well below the 140 threshold for oral absorption. Ligand B (65.18) is still reasonable, but higher, potentially impacting absorption.

3. **logP:** Both ligands (A: 2.79, B: 2.116) fall within the optimal 1-3 range.

4. **HBD:** Both ligands have 0 HBD, which is acceptable.

5. **HBA:** Ligand A (3) is preferable to Ligand B (6), as lower HBA generally improves permeability.

6. **QED:** Both ligands have good QED scores (A: 0.524, B: 0.832). Ligand B is slightly better here.

7. **DILI:** Both ligands have acceptable DILI risk (A: 49.632, B: 42.846), below the 60 threshold. Ligand B is slightly better.

8. **BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (92.827) is higher than Ligand B (66.344).

9. **Caco-2:** Both have negative values, indicating poor permeability. However, the scale is not clear, so this is difficult to interpret.

10. **Solubility:** Both have negative values, indicating poor solubility. Again, the scale is unclear.

11. **hERG:** Both ligands have low hERG inhibition risk (A: 0.569, B: 0.26). Ligand B is slightly better.

12. **Cl_mic:** Both have reasonable microsomal clearance (A: 44.473, B: 42.994). No significant difference.

13. **t1/2:** Ligand B (4.868) has a slightly better in vitro half-life than Ligand A (-44.582). Note the negative value for A is concerning and likely an error.

14. **Pgp:** Both ligands have low P-gp efflux liability (A: 0.162, B: 0.148). No significant difference.

15. **Binding Affinity:** Both ligands have excellent binding affinities (A: -8.9 kcal/mol, B: -9.2 kcal/mol). Ligand B is slightly better.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand B has a slightly better affinity (-9.2 vs -8.9).
*   **Metabolic Stability:** Cl_mic is similar for both. Ligand B has a positive t1/2 value while A has a negative value, which is concerning.
*   **Solubility:** Both have poor solubility, but this is a common issue that can be addressed during lead optimization.
*   **hERG:** Both have low risk, with B being slightly better.
*   **ADME:** Ligand A has a better TPSA and BBB, but Ligand B has better QED, DILI, and t1/2.

**Conclusion:**

While both ligands show promising binding affinity, **Ligand B** appears to be the slightly more favorable candidate. Its slightly better affinity, more favorable DILI, and positive in vitro half-life outweigh the slightly higher TPSA. The negative t1/2 value for Ligand A is a significant concern.

Output:
1
2025-04-17 15:51:46,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.407 and 363.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.8) is slightly above the optimal <140, but acceptable. Ligand B (71.53) is well within the ideal range.

**logP:** Ligand A (1.471) is within the optimal 1-3 range. Ligand B (3.216) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is also good.

**QED:** Ligand A (0.865) has a better QED score than Ligand B (0.788), indicating a more drug-like profile.

**DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (67.313). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (25.979) is low, while Ligand B (67.623) is moderate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, suggesting poor permeability. Ligand A (-5.28) is slightly worse than Ligand B (-4.832).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.812) is slightly better than Ligand B (-4.305).

**hERG Inhibition:** Ligand A (0.016) has a very low hERG risk, which is excellent. Ligand B (0.535) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-4.344) has a negative clearance, indicating high metabolic stability. Ligand B (77.022) has a high clearance, suggesting poor metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-21.713) has a negative half-life, suggesting very high stability. Ligand B (12.816) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is favorable. Ligand B (0.446) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (0). This is a crucial advantage. A difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has some drawbacks (higher DILI, lower solubility, higher clearance, moderate P-gp efflux), the substantial affinity advantage outweighs these concerns. Ligand A has excellent metabolic stability and low hERG risk, but its weak binding affinity makes it unlikely to be effective. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:51:46,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (332.407 Da) is slightly lower, which could be beneficial for permeability. Ligand B (360.401 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (62.87) is slightly higher than Ligand B (59.08), but both are well within the acceptable range.

**logP:** Ligand A (3.888) is at the upper end of the optimal range (1-3), while Ligand B (1.147) is at the lower end. Ligand A's higher logP could potentially lead to off-target effects or solubility issues, 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 the recommended limits (HBD <= 5, HBA <= 10).

**QED:** Ligand A (0.77) has a better QED score than Ligand B (0.579), indicating a more drug-like profile.

**DILI:** Ligand B (34.277) has a significantly lower DILI risk than Ligand A (66.615), which is a major advantage.

**BBB:** Ligand B (84.451) has a higher BBB penetration score than Ligand A (70.919), but BBB is less critical for a non-CNS target like SRC.

**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. Ligand B (-2.04) is slightly better than Ligand A (-5.512).

**hERG Inhibition:** Ligand A (0.922) has a slightly higher hERG inhibition risk than Ligand B (0.499), but both are relatively low.

**Microsomal Clearance:** Ligand B (22.731 mL/min/kg) has significantly lower microsomal clearance than Ligand A (69.809 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-31.496 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (23.335 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.866) has a higher P-gp efflux liability than Ligand B (0.044), meaning Ligand B is less likely to be pumped out of cells.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a significant advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B demonstrates superior ADME properties, particularly lower DILI risk and significantly better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is a data error that needs to be investigated, but even ignoring that, the lower clearance is a strong point. The difference in binding affinity (1 kcal/mol) is not substantial enough to overcome the clear advantages of Ligand B in terms of safety and metabolic stability for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:51:46,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (395.26 and 360.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.92) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (101.8) is still within acceptable limits, but less optimal.

**logP:** Ligand A (4.392) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.144) is quite low, which might hinder permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, which is excellent. Ligand B has 7 HBA, which is higher and could impact permeability.

**QED:** Both ligands have good QED scores (0.642 and 0.721), indicating generally drug-like properties.

**DILI:** Ligand A (89.88) has a higher DILI risk than Ligand B (59.519), which is concerning.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (71.888) has a better score than Ligand B (47.15).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. Assuming a lower value means lower permeability, Ligand B (-5.567) appears to have lower permeability than Ligand A (-5.037).

**Aqueous Solubility:** Both have negative solubility values, again, unusual. Assuming lower values indicate lower solubility, Ligand B (-2.119) appears to have better solubility than Ligand A (-6.426).

**hERG:** Ligand A (0.877) has a slightly higher hERG risk than Ligand B (0.207), which is preferable for Ligand B.

**Microsomal Clearance:** Ligand B (13.481) has significantly lower microsomal clearance than Ligand A (61.383), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (13.736) has a longer in vitro half-life than Ligand A (96.6), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.652) has lower P-gp efflux than Ligand B (0.12), which is better.

**Binding Affinity:** Ligand A (-10 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. The difference is greater than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has some concerning ADME properties (high logP, higher DILI, higher Cl_mic, lower solubility), the significantly better affinity (-10 vs -6.8 kcal/mol) is likely to be decisive. The difference in binding is substantial enough to potentially overcome the ADME liabilities through further optimization. Ligand B has better ADME properties overall, but its weaker binding affinity makes it less likely to be a viable candidate.

Output:
0
2025-04-17 15:51:46,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (385.291 Da) is still well within the acceptable range.

**TPSA:** Ligand A (106.23) is better than Ligand B (55.57). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (0.736) is suboptimal, being slightly below the preferred range of 1-3. Ligand B (4.464) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are both acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.754, B: 0.628), indicating good drug-like properties.

**DILI:** Ligand A (48.972) has a slightly higher DILI risk than Ligand B (39.511), but both are below the concerning threshold of 60.

**BBB:** Ligand A (52.23) has a lower BBB penetration percentile than Ligand B (75.378). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.083) has a very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.645) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.168) has poor aqueous solubility. Ligand B (-3.774) is even worse.

**hERG Inhibition:** Ligand A (0.05) has a very low hERG inhibition risk, which is excellent. Ligand B (0.751) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (17.852 mL/min/kg) has significantly lower microsomal clearance than Ligand B (83.096 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.948 hours) has a longer in vitro half-life than Ligand B (43.758 hours).

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux liability than Ligand B (0.615), suggesting better bioavailability.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is the better candidate. While its logP and solubility are suboptimal, its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and extremely low hERG risk outweigh these drawbacks. The similar binding affinities make the ADME properties the deciding factor. Ligand B's high logP and poor solubility are concerning, and its higher metabolic clearance is undesirable.

Output:
0
2025-04-17 15:51:46,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (363.439 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is slightly higher than Ligand B (58.2). Both are below the 140 threshold for oral absorption, but B is significantly better.

**logP:** Both ligands (4.015 and 3.755) are at the upper end of the optimal 1-3 range, potentially raising concerns about solubility and off-target effects, but not critically.

**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 (0.83) has a better QED score than Ligand B (0.776), indicating a more drug-like profile.

**DILI:** Ligand B (36.603) has a much lower DILI risk than Ligand A (84.141), a significant advantage.

**BBB:** Both have reasonable BBB penetration (A: 77.627, B: 70.376), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.775 and -4.826), which is unusual and suggests poor permeability. This is a concern for both, but requires further investigation (negative values often indicate issues with the assay or compound stability).

**Aqueous Solubility:** Both have negative solubility values (-4.858 and -4.091), which is also concerning and suggests very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.302) has a slightly lower hERG risk than Ligand B (0.622), which is favorable.

**Microsomal Clearance:** Ligand B (82.547) has lower microsomal clearance than Ligand A (108.347), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (40.479 hours) has a much longer half-life than Ligand A (2.431 hours), which is a substantial benefit.

**P-gp Efflux:** Ligand A (0.188) has lower P-gp efflux than Ligand B (0.451), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 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 issues with solubility and Caco-2 permeability, Ligand B's superior binding affinity (-7.5 vs -9.4 kcal/mol), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and longer half-life are compelling advantages for an enzyme target like SRC kinase. The stronger binding is particularly important and could compensate for the solubility issues with appropriate formulation strategies.

Output:
1
2025-04-17 15:51:46,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 357.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (95.13), being well below the 140 threshold for oral absorption. Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.614 and 2.766), falling within the 1-3 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 Ligand A is slightly preferred.

**QED:** Both ligands have similar, good QED values (0.72 and 0.745), indicating good drug-likeness.

**DILI:** Ligand A (29.624) has a much lower DILI risk than Ligand B (72.199). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (48.74) is better than Ligand B (30.593).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.012 and -5.204). This is unusual and suggests poor permeability, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-3.429 and -4.23). This is also unusual and suggests poor solubility, but again, the values are similar.

**hERG Inhibition:** Ligand A (0.142) has a much lower hERG inhibition liability than Ligand B (0.477), a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (2.6 mL/min/kg) has significantly lower microsomal clearance than Ligand B (61.326 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (21.647 hours) has a significantly longer half-life than Ligand B (48.86 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.332), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.5 kcal/mol). This is the most important factor, and the 1.5 kcal/mol difference is very significant.

**Overall:** Ligand A is superior to Ligand B across almost all critical parameters. It has a better safety profile (lower DILI, lower hERG), better ADME properties (lower Cl_mic, longer t1/2, lower Pgp efflux), and, most importantly, a significantly stronger binding affinity. While both have issues with Caco-2 and solubility, the superior potency and safety of Ligand A outweigh these concerns.

Output:
1
2025-04-17 15:51:46,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.39 and 361.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.38) is slightly above the preferred <140 for good absorption, while Ligand B (62.39) is well within the range.

**logP:** Ligand A (0.46) is a bit low, potentially hindering permeation. Ligand B (3.36) is optimal.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (9) is close to the upper limit of 10, while Ligand B (6) is comfortably within the range.

**QED:** Both ligands have good QED scores (0.557 and 0.667), indicating good drug-like properties.

**DILI:** Ligand A (77.24) has a higher DILI risk than Ligand B (47.15), both are acceptable but B is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (51.42) is higher than Ligand A (32.80), but not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values which is concerning.

**Aqueous Solubility:** Both have negative solubility values which is concerning.

**hERG:** Ligand A (0.354) has a lower hERG risk than Ligand B (0.833), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-0.895) has a lower (better) microsomal clearance than Ligand B (45.11), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (37.22) has a longer half-life than Ligand B (32.75), which is desirable.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.625), which is favorable.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A's better metabolic stability, lower hERG risk, and P-gp efflux, Ligand B's significantly superior binding affinity (-7.5 vs -9.6 kcal/mol) is the most important factor for an enzyme target like SRC kinase. The stronger binding is likely to translate to greater efficacy. While the Caco-2 and solubility are concerning for both, the potency advantage of B is likely to outweigh these concerns.

Output:
1
2025-04-17 15:51:46,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.63) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (87.36) is excellent, well below 140.

**logP:** Ligand A (-1.419) is a bit low, potentially hindering permeation. Ligand B (1.29) is within the optimal 1-3 range.

**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 (0.555 and 0.806), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (31.679 and 35.905), which is favorable.

**BBB:** Ligand A (9.655) has very low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (61.535) has moderate BBB penetration, also not critical here.

**Caco-2 Permeability:** Ligand A (-5.61) has poor Caco-2 permeability, a significant drawback. Ligand B (-4.212) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.62) has poor aqueous solubility, which could impact bioavailability. Ligand B (-2.988) is even worse.

**hERG Inhibition:** Ligand A (0.091) has a very low hERG risk, excellent. Ligand B (0.463) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-36.861) exhibits very low microsomal clearance, suggesting good metabolic stability. Ligand B (38.355) has moderate clearance, less desirable.

**In vitro Half-Life:** Ligand A (-1.645) has a very short half-life, a major concern. Ligand B (41.969) has a long half-life, a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.003 and 0.03), which is good.

**Binding Affinity:** Ligand B (-7.2) has a significantly stronger binding affinity than Ligand A (-8.8). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B's superior binding affinity (-7.2 vs -8.8 kcal/mol) and significantly better metabolic stability (lower Cl_mic, longer t1/2) are critical for an enzyme target like SRC kinase. The slightly better logP and TPSA of Ligand B are also beneficial. The poor Caco-2 permeability of both is a concern, but could potentially be addressed through formulation strategies. Ligand A's extremely short half-life is a major dealbreaker.

Output:
1
2025-04-17 15:51:46,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.456 and 359.857 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is slightly higher than Ligand B (54.43), but both are well below the 140 A^2 threshold for good absorption.

**3. logP:** Ligand A (2.562) is within the optimal 1-3 range. Ligand B (4.191) is pushing the upper limit, potentially leading to solubility issues or off-target effects.

**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 good QED scores (0.624 and 0.717, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (14.889) has a significantly lower DILI risk than Ligand B (22.761), which is a substantial advantage.

**8. BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (61.807) and Ligand B (28.81) are both low.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.067 and -5.286), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.165 and -3.694), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.685) has a lower hERG risk than Ligand B (0.895), which is favorable.

**12. Microsomal Clearance:** Ligand A (29.082) has a lower microsomal clearance than Ligand B (55.584), indicating better metabolic stability, a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (20.107) has a shorter half-life than Ligand B (37.483), but both are reasonable.

**14. P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.439), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand B (-9.3 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 much better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher logP, higher P-gp efflux, and higher microsomal clearance. Ligand A has better ADME properties (lower DILI, logP, P-gp, Cl_mic), but its binding affinity is weaker. The poor Caco-2 and solubility for both are concerning, but the potency difference is significant. Given the importance of potency for kinase inhibitors, and the fact that ADME issues can sometimes be addressed through formulation or further optimization, Ligand B is the more promising candidate.

Output:
1
2025-04-17 15:51:46,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 361.768 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (102.76 and 98.09) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (0.88) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (3.173) is within the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**QED:** Ligand A (0.581) is better than Ligand B (0.476), indicating a more drug-like profile.

**DILI:** Ligand A (17.255) has a significantly lower DILI risk than Ligand B (93.292), which is a major advantage.

**BBB:** Ligand A (26.018) has a low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (73.943) has better BBB penetration, but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.178) has poor Caco-2 permeability, while Ligand B (-4.662) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.9) has slightly better aqueous solubility than Ligand B (-3.991).

**hERG Inhibition:** Ligand A (0.259) has a very low hERG risk, which is excellent. Ligand B (0.514) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (8.668) has significantly lower microsomal clearance than Ligand B (36.144), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (21.801) has a longer in vitro half-life than Ligand B (-1.431), which is highly desirable.

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, while Ligand B (0.261) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial factor, and the 1.5 kcal/mol advantage guideline is far exceeded.

**Conclusion:**

Despite Ligand B having a better logP, the overwhelming advantages of Ligand A in terms of binding affinity, DILI risk, metabolic stability (lower Cl_mic and longer t1/2), hERG risk, and P-gp efflux make it the far superior candidate. The slightly lower Caco-2 permeability and logP of Ligand A are less concerning given its significantly better potency and safety profile.

Output:
1
2025-04-17 15:51:46,953 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.455 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.5) is slightly higher than Ligand B (84.71). Both are below the 140 threshold for good oral absorption, but not optimized for CNS penetration.

**logP:** Both ligands have similar logP values (2.73 and 2.813), 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:** Both ligands have reasonable QED scores (0.457 and 0.577), indicating moderate drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (54.207), though both are acceptable.

**BBB:** Ligand A (61.923) has a lower BBB penetration than Ligand B (89.492). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand B (-4.703) has slightly better Caco-2 permeability than Ligand A (-5.311), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.003 and -3.404). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.491) has a slightly lower hERG inhibition risk than Ligand B (0.692), which is preferable.

**Microsomal Clearance:** Ligand A (-5.716) exhibits significantly lower microsomal clearance than Ligand B (37.468). This indicates much better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (3.778) has a shorter half-life than Ligand B (15.9). However, the lower clearance of Ligand A suggests the half-life could be improved with structural modifications.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.187 and 0.196).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is relatively small, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A is favored due to its significantly better metabolic stability (lower Cl_mic) and lower hERG risk. While Ligand B has slightly better affinity and Caco-2 permeability, the poor metabolic stability is a major concern for a kinase inhibitor, potentially leading to rapid clearance and reduced efficacy. The solubility is poor for both, but this can be addressed with formulation strategies. The slightly better affinity of Ligand B is unlikely to outweigh the substantial advantage in metabolic stability offered by Ligand A.

Output:
0
2025-04-17 15:51:46,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.515 Da) is slightly higher than Ligand B (337.343 Da), but both are acceptable.

**TPSA:** Ligand A (79.18) is better than Ligand B (98.06) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 1.708, B: 1.375), 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=7) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and good QED values (A: 0.743, B: 0.755), indicating good drug-like properties.

**DILI:** Ligand A (33.385) has a significantly lower DILI risk than Ligand B (94.765). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 61.962, B: 60.993), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.296 and -4.926), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close, so this is not a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.514 and -2.453), also unusual. Again, the values are similar and not a major differentiator.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.144, B: 0.182), which is excellent.

**Microsomal Clearance:** Ligand A (0.742 mL/min/kg) has significantly lower microsomal clearance than Ligand B (15.738 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (39.201 hours) has a much longer in vitro half-life than Ligand B (-0.745 hours). This is a significant advantage, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.043, B: 0.027).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). The difference is 1.6 kcal/mol, which is significant enough to consider.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better in terms of safety (DILI), metabolic stability (Cl_mic, t1/2), and has acceptable TPSA. The superior ADME properties of Ligand A, particularly the lower DILI and improved metabolic stability, outweigh the slightly weaker binding affinity. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects are critical for clinical success.

Output:
0
2025-04-17 15:51:46,954 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.431 and 385.917 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.67) is slightly higher than Ligand B (71.53), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.767 and 2.26), 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 similar QED scores (0.811 and 0.781), indicating good drug-likeness.

**7. DILI:** Ligand A (38.387) has a lower DILI risk than Ligand B (51.338). This is a significant advantage.

**8. BBB:** Ligand A (86.468) has a higher BBB penetration score than Ligand B (49.438). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.599 and -4.751). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.172 and -2.024), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.342 and 0.273). This is excellent.

**12. Microsomal Clearance:** Ligand A (38.971) has significantly lower microsomal clearance than Ligand B (53.914). Lower clearance indicates better metabolic stability, a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-14.385) has a negative half-life, which is problematic. Ligand B has a positive half-life (26.824), indicating better in vitro stability.

**14. P-gp Efflux:** Ligand A (0.205) has a lower P-gp efflux liability than Ligand B (0.124). Lower efflux is generally preferred.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly better binding affinity than Ligand B (-0.0). This is a decisive advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Despite the negative Caco-2 and solubility values for both, Ligand A is the stronger candidate. Its significantly superior binding affinity (-8.0 vs -0.0 kcal/mol) is the most important factor. It also has lower DILI risk, better BBB penetration, lower microsomal clearance, and lower P-gp efflux. The negative in vitro half-life for Ligand A is a concern, but the strong binding affinity suggests it might still be a viable starting point for optimization. Ligand B's positive half-life is good, but its very weak binding affinity makes it unlikely to be a successful drug candidate.

Output:
1
2025-04-17 15:51:46,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.46 and 368.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is excellent, well below the 140 threshold for oral absorption. Ligand B (81.75) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (3.309) is optimal (1-3). Ligand B (-0.621) is significantly below this, raising concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED scores (0.733 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (29.82) has a much lower DILI risk than Ligand B (12.64), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (95.62) is much higher than Ligand B (58.82).

**Caco-2 Permeability:** Ligand A (-4.477) is poor, while Ligand B (-5.624) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.376) is poor, while Ligand B (-1.856) is also poor. Both are problematic.

**hERG:** Ligand A (0.807) has a lower hERG risk than Ligand B (0.071), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (46.92) has higher clearance than Ligand B (-13.61). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-8.862) has a negative half-life, which is not possible. This is a red flag. Ligand B (3.142) has a short half-life, but is at least a positive value.

**P-gp Efflux:** Ligand A (0.423) has lower P-gp efflux than Ligand B (0.005), which is favorable.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-6.2), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B has better metabolic stability (lower Cl_mic) and a reasonable DILI score. However, its significantly negative logP is a major concern for permeability and bioavailability. Ligand A has a better logP, lower DILI and hERG risk, and better P-gp efflux, but its negative in vitro half-life is a critical flaw. The poor Caco-2 and solubility for both compounds are concerning, but could potentially be addressed with formulation strategies. The negative half-life for Ligand A is an unrecoverable issue.

Output:
1
2025-04-17 15:51:46,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.371 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (99.51 and 92.94) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.507) is a bit low, potentially hindering permeation. Ligand B (3.204) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the 5 limit.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both below the 10 limit.

**QED:** Ligand A (0.874) has a better QED score than Ligand B (0.701), indicating a more drug-like profile.

**DILI:** Ligand A (63.164) has a lower DILI risk than Ligand B (76.309), which is a significant advantage.

**BBB:** Both are relatively low, which isn't a primary concern for a non-CNS target like SRC. Ligand B (72.315) is slightly better than Ligand A (51.415).

**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 (0.152) has a much lower hERG risk than Ligand B (0.374), which is a critical advantage.

**Microsomal Clearance:** Ligand A (5.585) has a significantly lower Cl_mic than Ligand B (78.006), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-5.813) has a much longer in vitro half-life than Ligand B (31.21), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux liability than Ligand B (0.332), indicating better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.2 kcal/mol). Ligand A is slightly better (-8.7 vs -8.2), but the difference is relatively small.

**Overall Assessment:**

Ligand A is superior due to its significantly better safety profile (lower DILI and hERG), improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has a slightly better logP, the ADME-Tox advantages of Ligand A outweigh this. Both have poor Caco-2 and solubility, which would need to be addressed in further optimization, but these are less critical than avoiding potential toxicity or rapid metabolism.

Output:
0
2025-04-17 15:51:46,955 - INFO - Batch 415 complete. Total preferences: 6640
2025-04-17 15:51:46,955 - INFO - Processing batch 416/512...
2025-04-17 15:52:28,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.435 and 352.519 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.56) is slightly higher than Ligand B (42.01), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (3.773) is slightly higher than Ligand B (2.539), both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While both are acceptable, having some H-bond donors can aid solubility.

**H-Bond Acceptors:** Ligand B (4) is slightly better than Ligand A (3). Both are well below the 10 threshold.

**QED:** Ligand A (0.842) has a significantly better QED score than Ligand B (0.673), indicating a more drug-like profile.

**DILI:** Ligand B (11.206) has a much lower DILI risk than Ligand A (24.04), which is a significant advantage.

**BBB:** Ligand B (84.529) has a higher BBB penetration percentile than Ligand A (58.007), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.841 and -4.678), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-4.704) has slightly better solubility than Ligand B (-1.666), but both are poor.

**hERG Inhibition:** Ligand A (0.874) has a slightly higher hERG risk than Ligand B (0.627), but both are reasonably low.

**Microsomal Clearance:** Ligand B (60.05) has a lower microsomal clearance than Ligand A (92.62), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (33.901) has a significantly longer in vitro half-life than Ligand A (3.881), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.439) has lower P-gp efflux than Ligand B (0.194), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.7) has a slightly stronger binding affinity than Ligand A (-7.5), although the difference is small.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor Caco-2 permeability and solubility, Ligand B excels in key areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly stronger binding affinity. The higher QED of Ligand A is offset by its higher DILI and poorer metabolic stability. The slightly better P-gp efflux of Ligand A is less important than the metabolic advantages of Ligand B.

Output:
1
2025-04-17 15:52:28,807 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (346.471 and 357.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is well below the 140 threshold for good absorption and is also suitable for potential CNS penetration if needed, although that's not a primary concern for SRC. Ligand B (102.34) is still within acceptable limits but higher, potentially impacting absorption slightly.

**3. logP:** Ligand A (2.681) is optimal (1-3). Ligand B (-1.198) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**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:** Both ligands have reasonable QED values (0.676 and 0.529), indicating good drug-like properties.

**7. DILI:** Ligand A (35.983) has a much lower DILI risk than Ligand B (10.818). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (66.615) has a moderate BBB penetration, while Ligand B (28.306) is low. Not a primary concern for SRC, but a slight edge to A.

**9. Caco-2 Permeability:** Ligand A (-4.519) and Ligand B (-5.109) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't explicitly defined, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-2.825) and Ligand B (-0.324) both have negative values, indicating poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Ligand A (0.598) has a lower hERG risk than Ligand B (0.095). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (74.427) has higher microsomal clearance than Ligand B (-15.042). This indicates Ligand B is more metabolically stable, a key priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (27.972) has a longer half-life than Ligand B (-0.257). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.606) has lower P-gp efflux than Ligand B (0.004). This is a positive for Ligand A.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.9). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A emerges as the more promising candidate. While Ligand B has better metabolic stability, Ligand A's substantially stronger binding affinity (-8.0 vs -6.9 kcal/mol) is a decisive factor. Additionally, Ligand A demonstrates a significantly lower DILI risk and hERG inhibition liability. The lower logP of Ligand B is a substantial concern.

Output:
1
2025-04-17 15:52:28,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (87.46) is better than Ligand B (95.5), both being acceptable for oral absorption (<140).

**logP:** Both ligands have good logP values (A: 1.175, B: 2.275), 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=4) as it has fewer HBDs, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.808) has a significantly better QED score than Ligand B (0.671), indicating a more drug-like profile.

**DILI:** Ligand A (41.218) has a much lower DILI risk than Ligand B (67.429). This is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (56.65) is better than Ligand B (34.122).

**Caco-2 Permeability:** Ligand A (-4.819) is better than Ligand B (-5.205), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.805) is better than Ligand B (-3.509), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.162, B: 0.347), which is good.

**Microsomal Clearance:** Ligand A (39.465) has higher microsomal clearance than Ligand B (23.014), meaning it is less metabolically stable. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-36.902) has a much longer in vitro half-life than Ligand A (15.182), which is a significant advantage for dosing considerations.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.031, B: 0.033).

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, a longer half-life, and lower microsomal clearance. While Ligand A has better QED, DILI, solubility, and Caco-2 permeability, the substantial improvement in binding affinity of Ligand B and its improved metabolic stability are more critical for an enzyme target like SRC. The difference in binding affinity is large enough to compensate for the slightly higher DILI risk.

Output:
1
2025-04-17 15:52:28,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.374 and 360.502 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.23) is better than Ligand B (41.05) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (2.887) is optimal, while Ligand B (4.135) is slightly high, potentially leading to solubility issues or off-target effects.

**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 good QED scores (0.756 and 0.826, respectively), indicating drug-like properties.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (49.593), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (85.421) has a higher BBB percentile than Ligand A (57.193).

**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 concerning. Ligand B (-4.731) is slightly worse than Ligand A (-2.928).

**hERG Inhibition:** Ligand A (0.192) has a much lower hERG inhibition risk than Ligand B (0.765), a significant advantage.

**Microsomal Clearance:** Ligand A (43.074) has lower microsomal clearance than Ligand B (84.25), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (49.382) has a longer in vitro half-life than Ligand A (25.604), which is desirable.

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux liability than Ligand B (0.385), suggesting better bioavailability.

**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 of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand B's higher logP and slightly worse solubility, its significantly stronger binding affinity (-8.5 vs -6.9 kcal/mol) and lower DILI risk are compelling. The longer half-life is also a plus. While Ligand A has better hERG and P-gp profiles, the potency difference is substantial enough to favor Ligand B, especially considering SRC is an enzyme target where potency is paramount.

Output:
1
2025-04-17 15:52:28,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.443 and 348.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (67.87 and 66.48) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (0.949) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (2.535) is within the optimal range.

**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 range (<=10).

**QED:** Both ligands have good QED scores (0.549 and 0.769), indicating drug-like properties.

**DILI:** Ligand A (9.965) has a very low DILI risk, significantly better than Ligand B (17.449).

**BBB:** Ligand A (55.021) has a lower BBB penetration percentile than Ligand B (75.223). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.618 and -4.815), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.125 and -3.13), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.253 and 0.244).

**Microsomal Clearance:** Ligand A (28.339) has significantly lower microsomal clearance than Ligand B (43.041), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.451) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (-22.782) also has a negative half-life, which is also concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.204).

**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:**

Ligand B is clearly superior due to its significantly stronger binding affinity (-7.8 vs 0.0 kcal/mol). While both have issues with solubility and Caco-2 permeability, the potency advantage of Ligand B is likely to outweigh these drawbacks, especially for a kinase inhibitor where potency is paramount. The negative half-life values are concerning and would require further investigation, but the difference in binding affinity is too large to ignore. Ligand A's low DILI is a plus, but the lack of binding affinity is a fatal flaw.

Output:
1
2025-04-17 15:52:28,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.422 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly higher than Ligand B (62.74), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.568 and 1.666), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable, being less than 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 higher QED than Ligand B (0.753), indicating a more drug-like profile.

**7. DILI:** Ligand B (8.569) has a significantly lower DILI risk than Ligand A (51.648). This is a major advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (82.435 and 84.839), but this is less critical for a kinase inhibitor unless CNS targets are involved.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.761 and -4.527). These values are unusual and suggest poor permeability. However, these values are on a log scale, so the difference is not substantial.

**10. Aqueous Solubility:** Ligand B (-0.334) has slightly better solubility than Ligand A (-2.581), which is a positive.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.41 and 0.242).

**12. Microsomal Clearance:** Ligand A (22.258) has a higher microsomal clearance than Ligand B (12.865), meaning it's less metabolically stable. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand B (-0.553) has a longer in vitro half-life than Ligand A (-7.667). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.128 and 0.032).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.5 kcal/mol). Ligand B is slightly better (-8.5 vs -8.2).

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand B is the superior candidate. It has a significantly lower DILI risk, better solubility, and a longer half-life, all critical factors for an enzyme inhibitor. The slightly better affinity of Ligand B is a bonus. Ligand A's higher DILI risk and lower metabolic stability are concerning. The Caco-2 values are concerning for both, but the other advantages of B outweigh this.

Output:
1
2025-04-17 15:52:28,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.312 Da) is slightly higher than Ligand B (370.494 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (65.63 and 64.68) well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.925) is optimal, while Ligand B (0.777) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.844 and 0.775), indicating drug-like properties.

**DILI:** Ligand A (53.044) has a slightly higher DILI risk than Ligand B (46.064), but both are below the concerning threshold of 60.

**BBB:** Ligand A (70.415) has better BBB penetration than Ligand B (55.176), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.723) and Ligand B (-5.272) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close, and we need to consider other factors.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.588 and -2.108). This is a significant drawback, but formulation strategies might mitigate it.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.739 and 0.681), which is excellent.

**Microsomal Clearance:** Ligand B (-10.253) has significantly lower (better) microsomal clearance than Ligand A (-0.881), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-20.403) has a much longer in vitro half-life than Ligand A (-1.752), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.331) has lower P-gp efflux than Ligand B (0.027), which is favorable.

**Binding Affinity:** Ligand B (-9.7 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 of the ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better logP and P-gp efflux, Ligand B's superior binding affinity, significantly improved metabolic stability (lower Cl_mic, longer t1/2), and acceptable DILI/hERG profiles make it the more promising drug candidate. The lower logP and Caco-2 permeability of Ligand B are concerns, but the strong binding affinity suggests it might still achieve sufficient target engagement *in vivo*. The solubility issues are present in both, and would need to be addressed in formulation.

Output:
1
2025-04-17 15:52:28,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 342.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (67.87 and 69.3) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.58) is optimal, while Ligand B (2.293) is also within the acceptable range of 1-3.

**H-Bond Donors:** Both have 1 HBD, well within the limit of 5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3, both under the limit of 10.

**QED:** Both ligands have good QED scores (0.788 and 0.913), indicating drug-likeness.

**DILI:** Ligand A (9.228) has a significantly lower DILI risk than Ligand B (29.081). This is a major advantage.

**BBB:** Both have reasonable BBB penetration (78.48 and 74.06), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.565) and Ligand B (-5.009) both have negative values, which is unusual. Lower values indicate lower permeability. It's difficult to interpret these without knowing the scale.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.177 and -2.905). This is a significant concern.

**hERG Inhibition:** Ligand A (0.393) has a lower hERG risk than Ligand B (0.622), which is preferable.

**Microsomal Clearance:** Ligand A (31.603) has lower microsomal clearance than Ligand B (45.669), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.765) has a very short half-life, while Ligand B (-36.665) has a very long half-life. This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux (0.036 and 0.069).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a crucial factor. The 1.8 kcal/mol difference is substantial.

**Conclusion:**

While Ligand A has advantages in DILI risk, hERG, and metabolic stability, the significantly stronger binding affinity of Ligand B (-7.2 vs -9.0 kcal/mol) and its dramatically improved in vitro half-life outweigh these concerns. The solubility is poor for both, but can be addressed with formulation strategies. The DILI risk of Ligand B is still acceptable. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 15:52:28,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.411 and 368.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is slightly higher than Ligand B (69.88), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.31) is within the optimal 1-3 range. Ligand B (3.648) is slightly higher, potentially raising concerns about off-target effects, but 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:** Ligand A (0.913) has a significantly higher QED score than Ligand B (0.689), indicating a more drug-like profile.

**DILI:** Ligand B (81.078) has a higher DILI risk than Ligand A (56.921). Ligand A is preferable here.

**BBB:** Ligand A (80.496) has a better BBB penetration score than Ligand B (46.491). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.548 and -5.088), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.383 and -3.555), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.21) has a much lower hERG inhibition liability than Ligand B (0.403), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (28.983) has a lower microsomal clearance than Ligand B (63.138), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-4.438) has a negative half-life, which is concerning. Ligand B (8.995) has a positive half-life, indicating better stability in vitro. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.203) has lower P-gp efflux liability than Ligand B (0.423), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better QED, lower DILI risk, lower hERG risk, and lower P-gp efflux. However, it has a negative in vitro half-life. Ligand B has a better in vitro half-life, but suffers from higher DILI risk, higher hERG risk, and weaker binding affinity.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), the significantly stronger binding affinity of Ligand A (-9.8 kcal/mol vs -8.3 kcal/mol) is a major driver. While the negative half-life is concerning, it might be addressable through structural modifications. The poor solubility and permeability are shared issues that would require formulation strategies for either compound. The lower DILI and hERG risk for Ligand A are also important advantages.

Output:
1
2025-04-17 15:52:28,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.459 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.4) is slightly above the preferred <140 for good absorption, while Ligand B (78.09) is well within the range.

**logP:** Ligand A (0.916) is a bit low, potentially hindering permeation. Ligand B (2.666) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which are acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.546 and 0.709), indicating drug-like properties.

**DILI:** Ligand A (49.632) has a slightly higher DILI risk than Ligand B (25.087), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (65.452 and 69.213), which isn't a primary concern for a non-CNS target like SRC.

**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 solubility. This is a significant drawback.

**hERG:** Both ligands have low hERG inhibition risk (0.242 and 0.401).

**Microsomal Clearance:** Ligand A (30.971) and Ligand B (33.962) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-16.329) has a negative half-life, which is not physically possible and indicates a problem with the data or the model. Ligand B (-11.066) also has a negative half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.182).

**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 small, it's still a factor.

**Overall Assessment:**

Both ligands have significant issues with solubility and half-life. However, Ligand B has a more favorable logP, TPSA, and a slightly better binding affinity. The negative half-life values are concerning and suggest potential issues with the data or the prediction model. Given the enzyme-specific priorities, the slightly better affinity and more favorable physicochemical properties of Ligand B make it a marginally better candidate, *assuming the negative half-life values are artifacts*.

Output:
1
2025-04-17 15:52:28,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly better.

**TPSA:** Ligand A (64.41) is significantly better than Ligand B (99.77). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.813, Ligand B: 0.979). Ligand A is slightly better, falling within the optimal 1-3 range, while Ligand B is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) is preferable to Ligand B (HBD=3, HBA=4) as lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.79) has a better QED score than Ligand B (0.435), indicating a more drug-like profile.

**DILI:** Ligand B (27.181) has a slightly better DILI score than Ligand A (16.673), suggesting a lower risk of liver injury, but both are acceptable.

**BBB:** Ligand A (81.776) has a significantly higher BBB percentile than Ligand B (70.376). While not crucial for a non-CNS target like SRC, it's a minor positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.605) shows better Caco-2 permeability than Ligand B (-5.24), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.186 and -2.187). This is a significant concern for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.639) has a lower hERG inhibition liability than Ligand B (0.254), which is favorable.

**Microsomal Clearance:** Ligand B (-11.567) has a significantly lower (better) microsomal clearance than Ligand A (27.378), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-16.699) has a much longer in vitro half-life than Ligand A (0.12), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.223) has lower P-gp efflux than Ligand B (0.005), which is favorable.

**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 excels in metabolic stability (lower Cl_mic, longer t1/2), which is a high priority for kinase inhibitors. However, Ligand A demonstrates better drug-like properties (QED, TPSA, HBD/HBA, Caco-2, hERG) and slightly better permeability. The solubility is a concern for both. The similar binding affinities mean that the ADME properties become the deciding factor. Given the importance of metabolic stability for kinases, and the significant advantage Ligand B has in this area, it is the more promising candidate.

Output:
1
2025-04-17 15:52:28,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (340.383 and 360.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.73) is slightly higher than Ligand B (87.14), but both are below the 140 threshold for good absorption.

**3. logP:** Ligand A (0.504) is quite low, potentially hindering permeation. Ligand B (2.554) 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:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both within the acceptable limit of 10.

**6. QED:** Ligand A (0.691) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**7. DILI:** Ligand B (72.16) has a higher DILI risk than Ligand A (58.356). This is a concern for Ligand B.

**8. BBB:** Both ligands have low BBB penetration, which is not a major concern for a kinase inhibitor unless CNS off-target effects are a concern. Ligand B (58.356) is slightly higher than Ligand A (44.591).

**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 (0.125) has a much lower hERG inhibition liability than Ligand B (0.835). This is a crucial advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-14.21) has a significantly lower (better) microsomal clearance than Ligand B (70.586), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (28.472) has a much longer in vitro half-life than Ligand A (0.196). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux liability than Ligand B (0.368), which is favorable.

**15. Binding Affinity:** Ligand B (-8.1) has a significantly stronger binding affinity than Ligand A (-6.7). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks. A 1.4 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity and a longer half-life, which are critical for an enzyme inhibitor. However, it suffers from higher DILI risk, higher hERG inhibition, and poorer metabolic stability. Ligand A has a better safety profile (lower DILI and hERG) and improved metabolic stability, but its binding affinity is weaker and its half-life is very short.

Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity (-8.1 vs -6.7 kcal/mol), I would prioritize Ligand B. While the ADME properties of Ligand B are less ideal, these can potentially be addressed through further optimization. The weak binding of Ligand A is a more difficult property to improve significantly.

Output:
1
2025-04-17 15:52:28,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and protein class priorities.

**1. Molecular Weight (MW):** Both ligands (344.386 and 358.869 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (60.85 and 62.22) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.034) is optimal (1-3). Ligand B (4.073) 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 (HBD):** Both ligands (1 and 2) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (3) are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.903 and 0.818) have excellent drug-likeness scores, well above the 0.5 threshold.

**7. DILI:** Ligand A (53.819) has a slightly higher DILI risk than Ligand B (46.297), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (81.698) has better BBB penetration than Ligand B (66.615).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.327 and -4.57). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are common. We'll need to consider this alongside other ADME properties.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.989 and -4.911). Similar to Caco-2, these are on a log scale and indicate poor solubility.

**11. hERG Inhibition:** Both ligands (0.778 and 0.571) have low hERG inhibition risk, which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (24.863) has lower microsomal clearance than Ligand B (30.609), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (26.226) has a significantly longer in vitro half-life than Ligand A (10.709), which is desirable.

**14. P-gp Efflux:** Both ligands (0.341 and 0.374) have low P-gp efflux liability, which is good.

**15. Binding Affinity:** Ligand B (-10.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has slightly better metabolic stability (lower Cl_mic) and DILI risk, Ligand B's significantly stronger binding affinity (-10.4 vs -7.3 kcal/mol) is the most crucial factor for an enzyme inhibitor. The longer half-life of Ligand B is also a significant advantage. The poor solubility and permeability (negative Caco-2 and solubility values) are concerns for both, but a strong binding affinity can sometimes compensate for these issues, especially with formulation strategies. Given the priority for potency in kinase inhibitors, Ligand B is the more promising candidate.

Output:
1
2025-04-17 15:52:28,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.383 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.85) is borderline, but acceptable for oral absorption. Ligand B (66.48) is excellent, well below the 140 threshold.

**logP:** Ligand A (0.305) is quite low, potentially hindering permeability. Ligand B (2.31) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 threshold.

**H-Bond Acceptors:** Ligand A (9) is near the upper limit, but acceptable. Ligand B (3) is excellent.

**QED:** Both ligands have reasonable QED values (0.793 and 0.679), indicating good drug-like properties.

**DILI:** Ligand A (79.837) has a higher DILI risk than Ligand B (41.838). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (87.631) has a higher BBB value, but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.031) has poor predicted permeability, consistent with its low logP. Ligand B (-4.487) is also poor, but better than A.

**Aqueous Solubility:** Both ligands have very poor predicted solubility (-1.989 and -2.687). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.007) shows very low hERG inhibition risk, which is excellent. Ligand B (0.212) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (31.639) has a higher microsomal clearance than Ligand B (15.255), suggesting lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (0.631) has a very short half-life, while Ligand B (-14.994) has a negative value, which is not possible. This is likely an error in the data, but even without that, the value for A is very poor.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.025 and 0.094).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.4 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a major differentiator.

**Overall Assessment:**

Ligand B is significantly better despite the questionable half-life data. It has a much lower DILI risk, better logP, better TPSA, and better metabolic stability (lower Cl_mic). While both have poor solubility and Caco-2 permeability, the other advantages of Ligand B outweigh these drawbacks. Ligand A's low logP, high DILI risk, and poor metabolic stability are major concerns.

Output:
1
2025-04-17 15:52:28,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.5 and 369.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, while Ligand B (78.51) is still acceptable but higher.

**logP:** Both ligands have good logP values (2.55 and 1.54), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 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 scores (0.802 and 0.77), indicating good drug-likeness.

**DILI:** Ligand A (10.5) has a much lower DILI risk than Ligand B (39.4), making it significantly safer from a liver toxicity perspective.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (70.9) has a higher BBB score than Ligand B (44.6).

**Caco-2 Permeability:** Ligand A (-4.82) is better than Ligand B (-5.23), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.65) has better aqueous solubility than Ligand B (-2.85).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.36 and 0.10), which is excellent.

**Microsomal Clearance:** Ligand A (19.1) has a higher microsomal clearance than Ligand B (14.7), meaning Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand B (-6.12) has a significantly longer in vitro half-life than Ligand A (0.09). This is a major advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.04).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, lower DILI risk, and better Caco-2 permeability, Ligand B's substantially stronger binding affinity (-9.1 vs -7.7 kcal/mol) and longer half-life are critical advantages for an enzyme target like SRC kinase. The slightly higher DILI risk of Ligand B is a concern, but could be mitigated through further structural modifications. The improved metabolic stability (lower Cl_mic and longer t1/2) is also highly desirable.

Output:
1
2025-04-17 15:52:28,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly better positioned.

**TPSA:** Ligand A (114.18) is well within the acceptable range for oral absorption. Ligand B (29.54) is excellent, suggesting potentially good absorption.

**logP:** Ligand A (0.924) is slightly below the optimal range but still acceptable. Ligand B (4.62) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 4 HBA, fitting well within the guidelines. Ligand B has 0 HBD and 2 HBA, also acceptable, but potentially impacting aqueous solubility.

**QED:** Both ligands have similar QED values (0.649 and 0.644), indicating good drug-likeness.

**DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (63.978), a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (82.164) has a higher BBB value, which is irrelevant here.

**Caco-2 Permeability:** Ligand A (-5.385) shows poor permeability, while Ligand B (-4.238) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.832) has slightly better solubility than Ligand B (-5.532).

**hERG Inhibition:** Ligand A (0.062) has a very low hERG risk, a critical advantage. Ligand B (0.833) has a moderate risk.

**Microsomal Clearance:** Ligand A (24.349) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (94.508) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-0.309) has a slightly negative half-life, which is not ideal. Ligand B (35.55) has a good half-life.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is favorable. Ligand B (0.729) has moderate efflux.

**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 ADME differences.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. It has a significantly lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. While Ligand B has a slightly better half-life and Caco-2 permeability, the superior safety profile and metabolic stability of Ligand A are more critical for a viable drug candidate.

Output:
0
2025-04-17 15:52:28,810 - INFO - Batch 416 complete. Total preferences: 6656
2025-04-17 15:52:28,810 - INFO - Processing batch 417/512...
2025-04-17 15:53:16,415 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.43 and 360.841 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.53) is higher than Ligand B (51.66). While both are reasonably good, Ligand B is better positioned for oral absorption with a lower TPSA.

**logP:** Both ligands have good logP values (2.304 and 2.983), 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, but fewer H-bonds generally improve permeability, giving a slight edge to Ligand B.

**QED:** Both ligands have good QED scores (0.62 and 0.794), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 68.321, which is concerning (approaching the high-risk threshold of >60). Ligand B has a much lower DILI risk of 36.409, which is preferable.

**BBB:** Both ligands have good BBB penetration (77.627 and 80.535). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.43 and -4.765). 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 (-3.642 and -3.059). Similar to Caco-2, the scale is unknown, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.318) has a slightly higher hERG risk than Ligand B (0.5). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (73.281) has higher microsomal clearance than Ligand B (63.953), indicating lower metabolic stability. Ligand B is better.

**In vitro Half-Life:** Ligand B (51.549) has a significantly longer in vitro half-life than Ligand A (-23.16), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.245 and 0.255).

**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 concerns.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile. Specifically, the lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better hERG profile of Ligand B are crucial for a viable drug candidate. The difference in binding affinity (-1.5 kcal/mol) is significant, but not insurmountable, and can potentially be optimized in subsequent iterations. The negative solubility and Caco-2 values are concerning for both, but could be addressed through formulation strategies. Given the enzyme-kinase focus, the ADME advantages of Ligand B are more critical than the slightly stronger binding of Ligand A.

Output:
1
2025-04-17 15:53:16,415 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.511 and 358.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (96.25). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.984 and 1.169), 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 donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.843) has a higher QED score than Ligand B (0.617), indicating a more drug-like profile.

**DILI:** Ligand A (23.187) has a much lower DILI risk than Ligand B (40.364), a significant advantage. Both are below the 40 threshold, but A is substantially better.

**BBB:** Both ligands have similar BBB penetration (76.347 and 73.245), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates poor permeability in this assay. However, the values are similar (-5.25 and -5.026).

**Aqueous Solubility:** Both ligands have negative solubility values (-2.539 and -2.605), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.446 and 0.308), which is excellent.

**Microsomal Clearance:** Ligand A (35.601) has a higher microsomal clearance than Ligand B (12.164). This suggests Ligand B is more metabolically stable, which is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-5.668) has a longer in vitro half-life than Ligand A (5.882), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.17 and 0.035), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.8 and -9.2 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

While both ligands exhibit good binding affinity, Ligand A is the more promising candidate. Its superior QED, significantly lower DILI risk, and lower TPSA outweigh the slightly higher microsomal clearance and shorter half-life compared to Ligand B. The solubility issues are a concern for both, but can be addressed through formulation strategies. Given the enzyme-kinase focus, metabolic stability is important, but the substantial advantage in safety (DILI) and drug-likeness (QED) of Ligand A makes it the better choice.

Output:
0
2025-04-17 15:53:16,415 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (380.501 and 352.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (42.43), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.402) is optimal, while Ligand B (4.55) is slightly high, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are acceptable, a single HBD can sometimes improve solubility.

**H-Bond Acceptors:** Both ligands have a similar number of HBA (Ligand A: 4, Ligand B: 5), both are within the acceptable limit of 10.

**QED:** Ligand A (0.624) has a better QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Ligand A (31.291) has a significantly lower DILI risk than Ligand B (85.149). This is a major advantage for Ligand A.

**BBB:** Ligand A (79.217) has better BBB penetration than Ligand B (59.907), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.898) is slightly better than Ligand B (-4.58).

**Aqueous Solubility:** Ligand A (-2.917) is better than Ligand B (-5.933), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.742, Ligand B: 0.537).

**Microsomal Clearance:** Ligand A (56.203) has lower microsomal clearance than Ligand B (100.973), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (26.247) has a longer half-life than Ligand A (8.03), which is generally desirable.

**P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux than Ligand B (0.508), which is beneficial for bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better QED score, improved solubility, lower P-gp efflux, and lower microsomal clearance. While Ligand B has a longer half-life, the other advantages of Ligand A outweigh this single benefit. The similar binding affinity means potency isn't a differentiating factor.

Output:
1
2025-04-17 15:53:16,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 352.475 Da) fall well within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.32 and 75.71) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.904 and 2.117) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.501 and 0.645, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 27.181, and Ligand B has 16.092. Both are good (below 40), but Ligand B is significantly better, indicating lower potential for liver injury.

**BBB:** Ligand A has a BBB penetration of 44.979, and Ligand B has 70.027. Since SRC is not a CNS target, this is less critical, but Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.652 and -4.565). This is unusual and suggests poor permeability. However, the scale isn't clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.408 and -2.032). This is also unusual and suggests poor solubility. Again, the scale is unclear.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.329 and 0.352). This is good.

**Microsomal Clearance:** Ligand A has a Cl_mic of 27.669, and Ligand B has 72.227. Ligand A has significantly lower clearance, indicating better metabolic stability, which is a high priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A has a t1/2 of 5.136, and Ligand B has -8.162. The negative value for Ligand B is concerning and likely indicates very rapid degradation. Ligand A is much better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.056).

**Binding Affinity:** Ligand A has a binding affinity of -7.4 kcal/mol, and Ligand B has -6.8 kcal/mol. Ligand A has a significantly stronger binding affinity, which is the most important factor for an enzyme inhibitor. The 0.6 kcal/mol difference is substantial.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand A is the superior candidate. It has a significantly stronger binding affinity (-7.4 vs -6.8 kcal/mol), better metabolic stability (lower Cl_mic, positive t1/2), and a lower DILI risk. The stronger binding affinity outweighs the potential concerns regarding permeability and solubility, especially for an enzyme target where potency is paramount.

Output:
0
2025-04-17 15:53:16,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.475 and 358.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is better than Ligand B (49.41) as it is closer to the 140 threshold.

**logP:** Both ligands have good logP values (2.919 and 2.32) 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:** Ligand B (0.839) has a significantly better QED score than Ligand A (0.533), indicating a more drug-like profile.

**DILI:** Ligand B (15.355) has a much lower DILI risk than Ligand A (51.532), which is a significant advantage.

**BBB:** Ligand B (90.074) has a higher BBB penetration score than Ligand A (47.46), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar, poor Caco-2 permeability (-4.966 and -4.916).

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-3.172 and -3.179).

**hERG Inhibition:** Ligand B (0.492) has a lower hERG inhibition liability than Ligand A (0.232), which is a positive attribute.

**Microsomal Clearance:** Ligand B (4.388) has significantly lower microsomal clearance than Ligand A (61.287), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (1.423) has a slightly better in vitro half-life than Ligand A (17.672).

**P-gp Efflux:** Ligand B (0.069) has lower P-gp efflux liability than Ligand A (0.125).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This difference in affinity is substantial (>1.5 kcal/mol) and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in crucial areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic), lower DILI risk, lower hERG inhibition, and, most importantly, a much stronger binding affinity. The higher QED score also supports its drug-likeness.

Output:
1
2025-04-17 15:53:16,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (446.176 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (57.26) is higher than Ligand B (40.62).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.606) is slightly higher than the preferred upper limit, potentially raising concerns about solubility and off-target effects. Ligand B (3.676) is well within the range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 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 (0.682) and Ligand B (0.757) are comparable.

**DILI:** Ligand A has a DILI risk of 63.94, which is considered high risk. Ligand B has a much lower DILI risk of 15.51, which is very favorable.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (74.292) and Ligand B (80.031) both show reasonable BBB penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires investigation. However, we can still compare their relative permeability. Ligand A (-4.824) is slightly worse than Ligand B (-4.363).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-5.639) is worse than Ligand B (-2.893).

**hERG Inhibition:** Ligand A (0.828) shows a slightly higher hERG inhibition risk than Ligand B (0.616), but both are relatively low.

**Microsomal Clearance:** Ligand A (82.162) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (59.174).

**In vitro Half-Life:** Ligand A (124.28) has a longer in vitro half-life than Ligand B (14.743), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.368) has lower P-gp efflux liability than Ligand B (0.26), which is favorable.

**Binding Affinity:** Both ligands have comparable binding affinities (-7.2 kcal/mol and -7.0 kcal/mol, respectively). The difference is less than 1.5 kcal/mol, so it doesn't significantly outweigh other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While Ligand A has a slightly longer half-life and lower P-gp efflux, its significantly higher DILI risk, higher logP, and lower solubility are major drawbacks. Ligand B exhibits a much better safety profile (lower DILI), better solubility, and acceptable metabolic stability. The binding affinity difference is minimal.

Output:
1
2025-04-17 15:53:16,416 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.383 and 344.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.87) is slightly higher than Ligand B (72.36). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (2.01 and 2.377), 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 and <=10 HBA).

**QED:** Ligand B (0.924) has a significantly higher QED score than Ligand A (0.68), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (66.421 and 64.288), both are above the 60 threshold, indicating a high risk.

**BBB:** Ligand B (84.684) has a better BBB percentile than Ligand A (59.984). While not a primary concern for a non-CNS target, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.558) has a worse Caco-2 permeability than Ligand B (-4.536).

**Aqueous Solubility:** Ligand A (-3.828) has a worse aqueous solubility than Ligand B (-3.444).

**hERG Inhibition:** Ligand A (0.491) has a lower hERG inhibition risk than Ligand B (0.964), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-14.092) has a much lower (better) microsomal clearance than Ligand B (22.264), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (26.836) has a longer in vitro half-life than Ligand A (13.78), which is desirable.

**P-gp Efflux:** Ligand A (0.061) has a lower P-gp efflux liability than Ligand B (0.271), indicating better bioavailability.

**Binding Affinity:** Ligand B (-7.8) has a significantly better binding affinity than Ligand A (-9.8). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

While Ligand A has better hERG and P-gp properties and better metabolic stability, the substantially stronger binding affinity of Ligand B (-7.8 kcal/mol vs -9.8 kcal/mol) is the most important factor for an enzyme inhibitor. The higher QED and better half-life of Ligand B also contribute to its favorability. The higher DILI risk is a concern for both, but the potency advantage of Ligand B is likely to be more impactful in early development.

Output:
1
2025-04-17 15:53:16,417 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [344.375, 120.08 ,   0.368,   3.   ,   5.   ,   0.74 ,  70.841,  42.109, -5.266,  -3.559,   0.129,  -4.863,   2.066,   0.015,  -7.8  ]
**Ligand B:** [369.849,  93.46 ,   2.015,   2.   ,   5.   ,   0.766,  62.544,  68.903, -5.031,  -3.6  ,   0.268,  33.648,  31.798,   0.144,  -8.  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (344.375) is slightly lower, which is generally favorable for permeability.
2. **TPSA:** Both are below the 140 A^2 threshold for good oral absorption. B (93.46) is better than A (120.08).
3. **logP:** A (0.368) is quite low, potentially hindering permeation. B (2.015) is within the optimal range. This is a significant advantage for B.
4. **HBD:** Both are acceptable (A: 3, B: 2).
5. **HBA:** Both are acceptable (A: 5, B: 5).
6. **QED:** Both are good (A: 0.74, B: 0.766), indicating drug-like properties.
7. **DILI:** A (70.841) is higher than B (62.544), suggesting a greater potential for liver injury.
8. **BBB:** Both are relatively low, but B (68.903) is better than A (42.109). This isn't a primary concern for a non-CNS target like SRC, but it's a slight advantage for B.
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:** Both are low, suggesting minimal cardiotoxicity risk. A (0.129) is slightly better than B (0.268).
12. **Cl_mic:** A (-4.863) has a much lower (better) microsomal clearance than B (33.648), indicating greater metabolic stability. This is a crucial advantage for A.
13. **t1/2:** B (31.798) has a significantly longer in vitro half-life than A (2.066). This is a substantial advantage for B.
14. **Pgp:** Both are low, suggesting minimal P-gp efflux. A (0.015) is slightly better than B (0.144).
15. **Binding Affinity:** B (-8.0) has a slightly better binding affinity than A (-7.8). While the difference is small, it's still a positive for B.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B has a slightly better affinity.
*   **Metabolic Stability:** A has significantly better metabolic stability (lower Cl_mic).
*   **Solubility:** Both are poor, a significant drawback for both.
*   **hERG:** Both are acceptable.
*   **LogP:** B is much better.

**Overall Assessment:**

While ligand A has better metabolic stability and a slightly better Pgp profile, ligand B has a better logP, affinity, and a significantly longer half-life. The poor Caco-2 and solubility for both are concerning, but the better logP and half-life of B, combined with its slightly better affinity, outweigh the metabolic stability advantage of A. The logP is a critical factor for kinase inhibitors, and the longer half-life will likely translate to better *in vivo* efficacy.

Output:
1
2025-04-17 15:53:16,417 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.463 and 353.375 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.63) is significantly better than Ligand B (105.25). A TPSA under 140 is good for oral absorption, and A is much closer to the ideal for good permeability.

**logP:** Ligand A (3.612) is within the optimal 1-3 range. Ligand B (-0.338) is quite low, potentially hindering permeation and absorption.

**H-Bond Donors:** Both ligands are acceptable (2 and 1, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Both ligands are acceptable (5 and 6, respectively), well below the threshold of 10.

**QED:** Both ligands have reasonable QED scores (0.734 and 0.517), indicating drug-like properties. Ligand A is slightly better.

**DILI:** Both ligands have similar DILI risk (59.907 and 54.634), both being acceptable (under 60).

**BBB:** Both ligands have moderate BBB penetration (51.415 and 47.15). This isn't a major concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.31) is significantly better than Ligand B (-4.775). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.559) is better than Ligand B (-1.065). Higher values are better for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.295) is much better than Ligand B (0.026). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (3.171) is significantly better than Ligand B (9.89). Lower clearance means greater metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (8.786) is better than Ligand B (-5.132). Longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.157) is better than Ligand B (0.017). Lower efflux improves bioavailability.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference (0.9 kcal/mol) is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better predicted ADME properties, including logP, TPSA, Caco-2 permeability, solubility, hERG inhibition, microsomal clearance, and P-gp efflux. These factors are critical for a viable drug candidate, especially for an enzyme like SRC kinase where metabolic stability and bioavailability are key.

Output:
1
2025-04-17 15:53:16,417 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.81) is better than Ligand B (68.74), both are below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.312 and 2.219, respectively), 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.519 and 0.732), indicating good drug-like properties.

**DILI:** Ligand A (22.8) has a significantly lower DILI risk than Ligand B (33.579), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand B (89.066) has a higher BBB penetration score than Ligand A (61.923). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-4.83) is slightly better than Ligand A (-5).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.599) is slightly better than Ligand B (-2).

**hERG Inhibition:** Ligand A (0.371) has a lower hERG inhibition liability than Ligand B (0.689), which is preferable.

**Microsomal Clearance:** Ligand A (-9.218) exhibits significantly lower microsomal clearance than Ligand B (35.17), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (59.313) has a longer in vitro half-life than Ligand A (5.711).

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux liability than Ligand B (0.069), which is beneficial.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). The difference is 0.5 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A excels in crucial areas like DILI risk, metabolic stability (Cl_mic), and hERG inhibition. The lower DILI and Cl_mic are particularly important for kinase inhibitors, as they often face challenges with off-target effects and rapid metabolism. The slightly better solubility and P-gp efflux of Ligand A also contribute to its favorability. The difference in binding affinity is not substantial enough to outweigh these advantages.

Output:
0
2025-04-17 15:53:16,417 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.11 and 78.43) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.026) is slightly low, potentially hindering permeation. Ligand B (2.093) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.701 and 0.53), indicating good drug-likeness.

**DILI:** Ligand A (5.894) has a much lower DILI risk than Ligand B (14.579), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC kinase. Ligand B is higher (43.156) than Ligand A (31.097).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.994 and -4.895). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.303 and -2.256), indicating poor aqueous solubility. Ligand B is worse.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.159 and 0.11).

**Microsomal Clearance:** Ligand A (-12.086) has a significantly *lower* (better) microsomal clearance than Ligand B (20.899), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (19.702) has a longer in vitro half-life than Ligand B (-6.009), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.004 and 0.062).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.5 kcal/mol and -8.3 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While both have similar binding affinities, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better logP value. The solubility and permeability issues are concerning for both, but the ADME profile of Ligand A is superior overall.

Output:
0
2025-04-17 15:53:16,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.304 Da) is slightly higher than Ligand B (344.415 Da), but both are acceptable.

**TPSA:** Ligand A (47.04) is well below the 140 threshold for oral absorption. Ligand B (96.25) is also below, but closer to the limit.

**logP:** Ligand A (4.672) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.32) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) 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 good QED scores (Ligand A: 0.588, Ligand B: 0.75), indicating good drug-like properties.

**DILI:** Ligand A (54.944) has a moderate DILI risk, while Ligand B (36.952) has a lower risk. This favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.16) and Ligand B (48.779) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, suggesting poor permeability. Ligand A (-5.26) is worse than Ligand B (-4.908).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.91) is slightly better than Ligand B (-3.098).

**hERG Inhibition:** Ligand A (0.954) has a slightly higher hERG risk than Ligand B (0.238), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (41.483) has a higher clearance than Ligand B (23.926), meaning it's less metabolically stable. This favors Ligand B.

**In vitro Half-Life:** Ligand A (14.218 hours) has a longer half-life than Ligand B (-1.258 hours). This is a strong advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.675, Ligand B: 0.032), which is good. Ligand B is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9.2 kcal/mol, Ligand B: -8.8 kcal/mol). Ligand A has a 0.4 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and longer half-life, which are crucial for an enzyme inhibitor. However, it suffers from higher logP, potentially poor solubility, moderate DILI risk, and higher microsomal clearance. Ligand B has better solubility, lower DILI and hERG risk, lower clearance, and a more optimal logP, but its binding affinity is slightly weaker and half-life is very short.

The binding affinity difference (0.4 kcal/mol) is substantial enough to potentially overcome the ADME drawbacks of Ligand A, *especially* considering the importance of potency for enzyme inhibition. The longer half-life is also a significant benefit. While the higher logP and DILI risk are concerns, these could be addressed through further optimization.

Output:
1
2025-04-17 15:53:16,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 350.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (62.55 and 60.85) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (3.461) is slightly higher than Ligand B (1.35). Ligand B is a bit low, potentially hindering permeation, while A is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.908) has a significantly higher QED score than Ligand B (0.779), indicating a more drug-like profile.

**DILI:** Ligand A (36.603) has a slightly higher DILI risk than Ligand B (11.361), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (80.962 and 73.827), but this is less critical for a non-CNS target like SRC.

**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, but it suggests potential formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.327 and 0.361), which is excellent.

**Microsomal Clearance:** Ligand A (49.216) has a significantly higher microsomal clearance than Ligand B (1.733). This suggests Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand B (-4.978) has a longer in vitro half-life than Ligand A (6.324), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.269 and 0.073), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is more promising. While Ligand A has a better QED score and logP, Ligand B exhibits significantly better metabolic stability (much lower Cl_mic and longer t1/2). This is crucial for maintaining therapeutic concentrations *in vivo*. The similar binding affinities make the ADME properties the deciding factor. The unusual negative values for Caco-2 and solubility are concerning for both, but the metabolic stability advantage of Ligand B outweighs the slightly better QED and logP of Ligand A.

Output:
1
2025-04-17 15:53:16,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.455 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.5) is slightly higher than Ligand B (88.91). Both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets, which isn't a priority here.

**logP:** Both ligands have excellent logP values (1.544 and 1.467), 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 very similar QED scores (0.824 and 0.817), indicating good drug-likeness.

**DILI:** Ligand A (53.858) has a higher DILI risk than Ligand B (32.067). This is a significant advantage for Ligand B.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC kinase. Ligand A (75.301) is higher than Ligand B (50.097), but this is less important.

**Caco-2 Permeability:** Ligand A (-4.589) has better Caco-2 permeability than Ligand B (-5.396), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.159) has slightly better aqueous solubility than Ligand B (-2.012).

**hERG:** Both ligands have very low hERG inhibition liability (0.559 and 0.078), which is excellent. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (-5.85) has significantly lower microsomal clearance than Ligand B (11.63). This indicates better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (23.046) has a longer in vitro half-life than Ligand B (12.312), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.106 and 0.011), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.6 kcal/mol). Ligand B is slightly better (-8.6 kcal/mol vs -8.0 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A has superior metabolic stability (lower Cl_mic and longer t1/2) and slightly better solubility and Caco-2 permeability. However, it has a higher DILI risk. Ligand B has a lower DILI risk and slightly better binding affinity and hERG profile. Given the importance of metabolic stability for kinase inhibitors and the relatively small difference in binding affinity, the improved metabolic profile of Ligand A is a key advantage. The DILI risk of Ligand A is still within an acceptable range.

Output:
1
2025-04-17 15:53:16,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Ligand A (70.47) is significantly better than Ligand B (110.29). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (1.261) is within the optimal range (1-3). Ligand B (-1.186) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 7 HBA, also acceptable, but the lack of HBD might slightly hinder solubility.

**QED:** Ligand A (0.805) has a much better QED score than Ligand B (0.438), indicating a more drug-like profile.

**DILI:** Ligand A (24.893) has a significantly lower DILI risk than Ligand B (55.68), a crucial advantage.

**BBB:** Both ligands have similar BBB penetration (65.491 vs 65.297), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the modeling or data. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the modeling or data. The values are similar.

**hERG:** Ligand A (0.359) has a much lower hERG risk than Ligand B (0.146), a significant advantage.

**Microsomal Clearance:** Ligand A (3.084) has a lower microsomal clearance than Ligand B (28.808), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (32.536) has a longer half-life than Ligand B (-27.984), a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.047 vs 0.032).

**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 the superior ADME properties of Ligand A.

**Overall:**

Ligand A is significantly better overall. It has a superior QED score, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable TPSA. While Ligand B has slightly better binding affinity, the ADME advantages of Ligand A are more critical for developing a viable drug candidate, especially for an enzyme target where metabolic stability and minimizing off-target effects are paramount. The unusual negative Caco-2 and solubility values are concerning for both, but the relative differences in other properties still clearly favor Ligand A.

Output:
1
2025-04-17 15:53:16,419 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.378) is slightly lower, which could be beneficial for permeability, while Ligand B (382.501) is also good.

**TPSA:** Ligand A (91.5) is better than Ligand B (41.99) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (1.031) is optimal, while Ligand B (4.873) is high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both have similar HBD (2/1 for A, 1/4 for B) and HBA (4 for both), falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.749 and 0.75), indicating drug-like properties.

**DILI:** Ligand A (67.313) has a higher DILI risk than Ligand B (59.442), but both are reasonably acceptable.

**BBB:** Ligand B (89.415) has a significantly higher BBB penetration score than Ligand A (67.158). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability. However, the values are close enough that this isn't a major differentiator.

**Aqueous Solubility:** Ligand A (-2.739) has better solubility than Ligand B (-5.22). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.35) has a much lower hERG inhibition risk than Ligand B (0.555). This is a significant advantage.

**Microsomal Clearance:** Ligand A (47.55) has lower microsomal clearance than Ligand B (55.979), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-34.847) has a significantly longer in vitro half-life than Ligand B (38.61). This is a substantial advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux than Ligand B (0.585), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.1) has a significantly stronger binding affinity than Ligand A (0). This is a major advantage, and a difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While it has a higher logP and P-gp efflux, the substantial improvement in affinity likely compensates for these issues. The lower half-life and higher clearance are concerns, but could potentially be addressed through structural modifications. Ligand A has better ADME properties (solubility, hERG, clearance, half-life, P-gp), but its significantly weaker binding affinity makes it less likely to be a viable drug candidate.

Output:
1
2025-04-17 15:53:16,419 - INFO - Batch 417 complete. Total preferences: 6672
2025-04-17 15:53:16,419 - INFO - Processing batch 418/512...
2025-04-17 15:53:56,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.407 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.59) is better than Ligand B (62.3). While both are below 140, lower TPSA generally favors permeability.

**logP:** Both ligands have good logP values (2.512 and 2.996), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED scores (0.704 and 0.738), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (97.674) compared to Ligand B (11.361). This is a major concern for Ligand A.

**BBB:** Ligand B has a higher BBB penetration percentile (76.347) than Ligand A (48.391), but BBB is less critical for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.135) has a worse Caco-2 value than Ligand B (-4.8). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-5.176) has a worse solubility than Ligand B (-1.705). Solubility is important for bioavailability.

**hERG:** Ligand A (0.565) has a slightly higher hERG risk than Ligand B (0.359), but both are relatively low.

**Microsomal Clearance:** Ligand B (49.379) has a lower microsomal clearance than Ligand A (21.195), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (57.902) has a longer half-life than Ligand B (-14.813). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.187) has lower P-gp efflux than Ligand B (0.138), which is favorable.

**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.

**Conclusion:**

Despite Ligand A's slightly better half-life and P-gp efflux, the significantly higher DILI risk and lower solubility are major drawbacks. Ligand B exhibits a much more favorable safety profile (lower DILI) and better metabolic stability (lower Cl_mic), which are crucial for an enzyme inhibitor. The slight difference in binding affinity is not enough to overcome these ADME/Tox concerns.

Output:
1
2025-04-17 15:53:56,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.443 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.33) is slightly higher than Ligand B (82.89), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.024 and 0.914), 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.852) has a better QED score than Ligand B (0.734), indicating a more drug-like profile.

**DILI:** Ligand B (40.713) has a significantly lower DILI risk than Ligand A (73.09), which is a major advantage.

**BBB:** Ligand B (66.421) has a higher BBB penetration percentile than Ligand A (37.146). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.597) has worse Caco-2 permeability than Ligand B (-4.676).

**Aqueous Solubility:** Ligand A (-2.033) has worse aqueous solubility than Ligand B (-1.169). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.091 and 0.131), which is excellent.

**Microsomal Clearance:** Ligand B (-9.681) has significantly *lower* (better) microsomal clearance than Ligand A (40.716), indicating greater metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (11.722) has a longer in vitro half-life than Ligand A (-40.995), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032).

**Binding Affinity:** Ligand B (-8.8 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 contributes to the overall preference for Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better QED score, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The solubility and Caco-2 permeability are also better for Ligand B.

Output:
1
2025-04-17 15:53:56,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.383 and 365.547 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.15) is slightly higher than Ligand B (70.15), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (1.514) is within the optimal range (1-3). Ligand B (2.629) is also within the optimal range, but slightly higher.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.873) has a better QED score than Ligand B (0.738), indicating better overall drug-likeness.

**DILI:** Ligand A (50.523) has a slightly higher DILI risk than Ligand B (40.636), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 76.037, Ligand B: 78.092), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.472) shows poorer Caco-2 permeability than Ligand B (-5.303), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.241) has better aqueous solubility than Ligand B (-3.496). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.02) has a much lower hERG inhibition liability than Ligand B (0.714), which is a significant advantage.

**Microsomal Clearance:** Ligand B (76.755) has a significantly higher microsomal clearance than Ligand A (22.417), suggesting lower metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (17.875) has a longer in vitro half-life than Ligand A (-18.46), but the negative value for Ligand A is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Ligand A (0.006) has lower P-gp efflux liability than Ligand B (0.064), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has a slightly longer half-life and better Caco-2 permeability, Ligand A has significantly lower hERG risk, better metabolic stability (lower Cl_mic), better solubility, and a better QED score. The similar binding affinities make these ADME properties the deciding factors.

Output:
0
2025-04-17 15:53:56,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (56.41), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.518 and 2.22), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/2) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.553 and 0.835), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (45.366) has a slightly higher DILI risk than Ligand B (16.169). Ligand B is considerably better here.

**BBB:** Both ligands have good BBB penetration (73.827 and 76.619). This isn't a primary concern for a kinase inhibitor, but it's not detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.744) is slightly better than Ligand B (-5.014).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.397) is slightly better than Ligand B (-2.166).

**hERG:** Both ligands have low hERG inhibition risk (0.224 and 0.374).

**Microsomal Clearance:** Ligand B (31.256 mL/min/kg) has significantly lower microsomal clearance than Ligand A (51.189 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-38.361 hours) has a significantly longer in vitro half-life than Ligand A (-27.409 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.197).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall preference for Ligand B.

**Conclusion:**

Ligand B is the more promising candidate. It demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity. While both have poor Caco-2 and solubility, the improvements in metabolic stability and safety profile outweigh these drawbacks.

Output:
1
2025-04-17 15:53:56,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.419 and 364.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.9) is excellent, well below the 140 threshold for oral absorption. Ligand B (134.38) is still acceptable but closer to the limit.

**logP:** Ligand A (0.025) is very low, potentially hindering permeability. Ligand B (0.46) is also on the low side, but better than A. Both are below the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 9 HBA) is also acceptable, but has more HBA.

**QED:** Both ligands have reasonable QED scores (0.809 and 0.557), indicating good drug-like properties.

**DILI:** Ligand A (38.736) has a much lower DILI risk than Ligand B (77.239), which is a significant advantage.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.755) and Ligand B (-5.503) both have very poor Caco-2 permeability, which is concerning.

**Aqueous Solubility:** Ligand A (0.06) has very poor aqueous solubility. Ligand B (-3.438) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.256) has a very low hERG risk, which is excellent. Ligand B (0.354) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-14.53) has very low (good) microsomal clearance, indicating excellent metabolic stability. Ligand B (-0.895) has a much higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (7.092) has a reasonable half-life. Ligand B (37.224) has a significantly longer half-life, which is a strong positive.

**P-gp Efflux:** Both ligands show low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

While Ligand A has better DILI and hERG profiles and excellent metabolic stability, its extremely low logP and solubility, combined with poor Caco-2 permeability, are major liabilities. Ligand B, despite a higher DILI risk and faster metabolism, possesses a significantly superior binding affinity (-9.6 vs -7 kcal/mol). The strong binding affinity is a critical factor for an enzyme inhibitor, and the difference of 2.6 kcal/mol is substantial. The longer half-life of Ligand B is also a benefit. Therefore, Ligand B is the more promising candidate, and further optimization could address its DILI and metabolic stability issues.

Output:
1
2025-04-17 15:53:56,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (368.415 Da) is also good.

**TPSA:** Ligand A (67.67) is well below the 140 threshold for oral absorption. Ligand B (109.86) is still acceptable, but higher.

**logP:** Ligand A (1.031) is at the lower end of the optimal range (1-3), potentially impacting permeability. Ligand B (0.369) is quite low, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar and good QED values (0.772 and 0.751, respectively), indicating good drug-like properties.

**DILI:** Ligand A (26.483) has a significantly lower DILI risk than Ligand B (84.606). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.309) is better than Ligand B (51.105), but not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.839) has poor predicted Caco-2 permeability, while Ligand B (-5.127) is also poor.

**Aqueous Solubility:** Ligand A (-0.741) has slightly better solubility than Ligand B (-2.659).

**hERG Inhibition:** Both ligands have very low hERG risk (0.23 and 0.095, respectively).

**Microsomal Clearance:** Ligand A (28.068) has higher microsomal clearance than Ligand B (-14.831). This suggests Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (10.582) has a shorter half-life than Ligand B (-15.246), further supporting Ligand B's better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.057 and 0.021, respectively).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 2.1 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

While Ligand A has a better safety profile (lower DILI) and slightly better solubility, Ligand B's significantly stronger binding affinity (-9.0 vs -6.9 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme target like SRC kinase. The lower logP of Ligand B is a concern, but the strong binding may compensate. The DILI risk of Ligand B is higher, but not prohibitively so. Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 15:53:56,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.391 and 347.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (135.78) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (107.19) is well within the ideal range.

**logP:** Both ligands (0.372 and 0.354) are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.689 and 0.733), indicating drug-like properties.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (42.846). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (57.736) and Ligand B (35.13) are both low, as expected.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. This needs further investigation, but is not immediately disqualifying.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.17 and 0.079), which is excellent.

**Microsomal Clearance:** Ligand B (-27.197) has significantly lower (better) microsomal clearance than Ligand A (26.668). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-8.085) has a slightly better (longer) in vitro half-life than Ligand A (-10.663).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.006), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -9.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B is the more promising candidate.** While both have issues with solubility and Caco-2 permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic) and a lower DILI risk. The binding affinities are comparable, so the improved ADME properties of Ligand B outweigh the minor differences.

Output:
1
2025-04-17 15:53:56,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.47 and 369.62 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (29.54) as it is closer to the 140 threshold for oral absorption. Ligand B is very low, which could indicate issues with solubility.

**logP:** Ligand A (1.439) is optimal (1-3), while Ligand B (4.846) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both within acceptable limits. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.795) has a better QED score than Ligand B (0.582), indicating a more drug-like profile.

**DILI:** Ligand A (46.724) has a lower DILI risk than Ligand B (8.104), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (92.71) has a higher BBB penetration, but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.152) has poor Caco-2 permeability, while Ligand B (-4.484) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.477) has slightly better solubility than Ligand B (-5.327).

**hERG:** Ligand A (0.279) has a much lower hERG risk than Ligand B (0.871), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (12.019 mL/min/kg) has significantly lower microsomal clearance than Ligand B (145.014 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.807 hours) has a shorter half-life than Ligand B (15.036 hours), but both are reasonable.

**P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux than Ligand B (0.649), suggesting better bioavailability.

**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 the significant ADME advantages of Ligand A.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, **Ligand A** is the more promising drug candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior drug-like properties, including lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), better solubility, and lower P-gp efflux. The lower Caco-2 permeability of Ligand A is a concern, but the other advantages are more critical for an enzyme inhibitor.

Output:
0
2025-04-17 15:53:56,492 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.447 and 361.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.02) is higher than the preferred <140, but acceptable. Ligand B (51.27) is excellent, well below 140.

**logP:** Ligand A (0.613) is a bit low, potentially hindering permeability. Ligand B (4.364) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Ligand A (10) is at the upper limit of the preferred range. Ligand B (4) is good.

**QED:** Both ligands have good QED scores (0.563 and 0.718), indicating drug-like properties.

**DILI:** Ligand A (83.753) has a higher DILI risk than Ligand B (36.099), which is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (67.197) is higher than Ligand A (32.416).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.587) is worse than Ligand B (-4.885).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.463) is slightly better than Ligand B (-3.545).

**hERG:** Ligand A (0.471) has a lower hERG risk than Ligand B (0.746), which is preferred.

**Microsomal Clearance:** Ligand B (82.303) has a higher clearance, indicating lower metabolic stability, than Ligand A (20.261). This is a significant drawback.

**In vitro Half-Life:** Ligand A (53.795) has a longer half-life than Ligand B (37.967), which is preferred.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, while Ligand B (0.732) has moderate efflux.

**Binding Affinity:** Ligand B (-9.4) has a significantly stronger binding affinity than Ligand A (-8.3). This is a substantial advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite Ligand B's higher logP and moderate P-gp efflux, its *much* stronger binding affinity (-9.4 vs -8.3 kcal/mol) and significantly lower DILI risk are decisive. The improved metabolic stability (lower Cl_mic, longer t1/2) of Ligand A is appealing, but the potency difference is too large to ignore for an enzyme target like SRC. While both have poor Caco-2 and solubility, these can be addressed with formulation strategies. The lower hERG risk of Ligand A is a plus, but not enough to overcome the potency difference.

Output:
1
2025-04-17 15:53:56,492 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.507 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.04) is significantly better than Ligand B (86.88). A TPSA under 140 is good for oral absorption, and A is much closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands have acceptable logP values (2.086 and 2.482), falling within the 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 (4) is slightly better than Ligand B (3). Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.822) has a considerably higher QED score than Ligand B (0.642), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.918) has a much lower DILI risk than Ligand B (25.165). This is a critical advantage.

**8. BBB:** BBB is less important for a non-CNS target like SRC. Ligand A (77.511) is better than Ligand B (63.474).

**9. Caco-2 Permeability:** Ligand A (-4.584) is better than Ligand B (-5.089). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.274) is better than Ligand B (-3.327). Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.561) has a lower hERG risk than Ligand B (0.28). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (-9.428) has a much lower (better) microsomal clearance than Ligand B (49.592), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.509) has a better in vitro half-life than Ligand B (-17.374).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. It has better TPSA, QED, DILI risk, hERG risk, microsomal clearance, and in vitro half-life. While both have poor solubility and permeability, the ADME-Tox profile of Ligand A is much more favorable, making it a more promising drug candidate. The similar binding affinities mean the ADME advantages of Ligand A outweigh any potential minor differences in potency.

Output:
0
2025-04-17 15:53:56,492 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is slightly above the preferred <60 for optimal permeability, but still reasonable. Ligand B (49.41) is excellent, well below 60.

**logP:** Ligand A (1.8) is within the optimal 1-3 range. Ligand B (3.444) is at the higher end of optimal, potentially raising concerns about off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.757 and 0.777), indicating good drug-likeness.

**DILI:** Ligand A (16.557) has a significantly lower DILI risk than Ligand B (22.722), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (73.711) is slightly better than Ligand A (67.08). However, BBB is less critical for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-4.257) has poor Caco-2 permeability, which is concerning. Ligand B (-4.891) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.058) has better solubility than Ligand B (-3.669). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.236) has a much lower hERG risk than Ligand B (0.505), which is a significant advantage.

**Microsomal Clearance:** Ligand A (29.054) has significantly lower microsomal clearance, indicating better metabolic stability, which is crucial for kinases. Ligand B (54.931) has higher clearance.

**In vitro Half-Life:** Ligand A (0.379) has a very short half-life, which is a major drawback. Ligand B (-13.812) has a very long half-life, a significant advantage.

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux, which is preferable. Ligand B (0.351) has higher P-gp efflux.

**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) and may not be decisive.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG inhibition, metabolic stability (lower Cl_mic), and P-gp efflux. However, it suffers from poor Caco-2 permeability and a very short half-life. Ligand B has better BBB penetration and a much longer half-life, but has higher DILI risk, hERG inhibition, and P-gp efflux.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), and the relatively small difference in binding affinity, **Ligand A is the more promising candidate**. The poor half-life can potentially be addressed through structural modifications, while mitigating the higher DILI and hERG risks of Ligand B might be more challenging. The better solubility of Ligand A is also a plus.

Output:
0
2025-04-17 15:53:56,492 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is excellent, well below the 140 threshold for good absorption. Ligand B (116.42) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (1.999) is optimal. Ligand B (-0.207) is a concern, being below 1, which could hinder permeation.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also good, within the acceptable limits.

**QED:** Both ligands have similar QED values (0.821 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (16.479) has a very low DILI risk. Ligand B (54.75) is higher, indicating a moderate risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.746) and Ligand B (55.874) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.921) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.033) is similarly low.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.081 and -2.63). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.271 and 0.257).

**Microsomal Clearance:** Ligand A (6.615) has moderate clearance. Ligand B (-37.481) has *very* low (negative) clearance, indicating excellent metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (19.201) has a reasonable half-life. Ligand B (-36.196) has a very long half-life, further supporting its metabolic stability.

**P-gp Efflux:** Both ligands have minimal P-gp efflux liability (0.087 and 0.012).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh other drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.9 vs 0.0 kcal/mol) and exceptionally low microsomal clearance/long half-life are critical advantages for an enzyme target like SRC kinase. While the logP is suboptimal, the strong binding could compensate. The DILI risk is moderate, but manageable. The solubility issue would need to be addressed through formulation strategies.

Output:
1
2025-04-17 15:53:56,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.39 and 341.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.35) is higher than Ligand B (63.05). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Ligand A (-0.119) is significantly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.864) is within the optimal 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:** Both ligands have good QED scores (0.762 and 0.845), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (42.69 and 43.23).

**BBB:** Ligand A (16.75) has very low BBB penetration, while Ligand B (81.69) has high BBB penetration. Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Ligand A (-5.383) shows poor permeability, while Ligand B (-4.747) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.039 and -2.579). This is a concern for both, but potentially more so for Ligand A given its lower logP.

**hERG Inhibition:** Ligand A (0.084) has a slightly lower hERG risk than Ligand B (0.378), which is favorable.

**Microsomal Clearance:** Ligand A (-23.437) has much lower (better) microsomal clearance than Ligand B (19.12), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.125 hours) has a shorter half-life than Ligand B (18.146 hours), which is less desirable.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, while Ligand B (0.079) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly better binding affinity than Ligand B (-7.8 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A's poor logP and Caco-2 permeability, its significantly superior binding affinity (-8.5 vs -7.8 kcal/mol) and substantially better metabolic stability (lower Cl_mic) make it the more promising candidate. The lower hERG risk is also a plus. While solubility is a concern for both, the potency advantage of Ligand A is likely to be more impactful in driving forward a development program, with solubility potentially addressed through formulation strategies.

Output:
0
2025-04-17 15:53:56,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (383.279 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.25) is slightly higher than Ligand B (49.85). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets (not a priority here).

**logP:** Ligand A (3.604) is within the optimal 1-3 range, while Ligand B (2.067) is at the lower end. A slightly higher logP can be beneficial for membrane permeability, but 3.6 is still reasonable.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBDs and reasonable HBAs (5 and 4 respectively), satisfying the criteria for good permeability.

**QED:** Both ligands have acceptable QED scores (0.81 and 0.704), indicating good drug-like properties.

**DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (44.436). This is a significant negative for Ligand A.

**BBB:** Both ligands have high BBB penetration (79.256 and 79.837), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.313) has poor Caco-2 permeability, while Ligand B (-5.103) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.69) has poor aqueous solubility, while Ligand B (-3.032) is also poor, but slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.276 and 0.362).

**Microsomal Clearance:** Ligand A (75.033) has higher microsomal clearance than Ligand B (57.174), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-5.527) has a negative half-life, indicating very poor stability, while Ligand A (9.705) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.393 and 0.314).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better in vitro half-life, Ligand B is superior overall. The significantly stronger binding affinity (-7.9 vs -7.3 kcal/mol) of Ligand B is a major advantage for an enzyme target. Furthermore, Ligand B has a lower DILI risk and slightly better solubility. The slightly lower logP of Ligand B is not a major concern. The poor Caco-2 permeability and half-life are drawbacks, but the potency advantage is likely to be more impactful in initial optimization.

Output:
1
2025-04-17 15:53:56,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (40.62) is slightly higher than Ligand B (33.95), but both are acceptable.

**logP:** Ligand A (3.26) is within the optimal range (1-3). Ligand B (4.764) is slightly above, which could lead to solubility issues or off-target interactions, but is not a major concern.

**H-Bond Donors/Acceptors:** Both ligands have low HBD (0) and acceptable HBA (3 & 4 respectively), which is favorable for permeability.

**QED:** Ligand A (0.825) has a significantly better QED score than Ligand B (0.603), indicating a more drug-like profile.

**DILI:** Ligand A (8.414) has a much lower DILI risk than Ligand B (16.092), a significant advantage.

**BBB:** Both have high BBB penetration, but Ligand B (87.825) is slightly higher than Ligand A (82.862). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.793) is slightly better than Ligand B (-5.061).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.187) is slightly better than Ligand B (-3.624).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.806 and 0.901 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (14.502 mL/min/kg) has a much lower microsomal clearance than Ligand B (66.914 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-25.211 hours) has a negative half-life, which is unusual. Ligand B (54.1 hours) has a more reasonable half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.371 and 0.764 respectively).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.1 and -8.4 kcal/mol). Ligand B is slightly more potent, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. Despite the unusual negative Caco-2 and half-life values, it has a superior QED score, significantly lower DILI risk, and much better metabolic stability (lower Cl_mic). The slightly better solubility and lower molecular weight are also beneficial. While Ligand B has a slightly better half-life and BBB penetration, the metabolic stability and DILI risk of Ligand A are more critical for an enzyme inhibitor. The binding affinity difference is minimal.



Output:
0
2025-04-17 15:53:56,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.374 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.33) is better than Ligand B (81.67), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.815) is optimal (1-3), while Ligand B (0.892) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is preferable to Ligand B (HBD=3, HBA=4) as it has fewer hydrogen bonding groups, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.877) has a significantly better QED score than Ligand B (0.576), indicating a more drug-like profile.

**DILI:** Ligand B (5.971) has a much lower DILI risk than Ligand A (78.945). This is a major advantage for Ligand B.

**BBB:** Ligand A (70.027) has a better BBB score than Ligand B (50.756), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.491) has a better Caco-2 permeability than Ligand B (-5.268), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.429) has better solubility than Ligand B (-2.181). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.184) has a lower hERG risk than Ligand B (0.339), which is a significant advantage.

**Microsomal Clearance:** Ligand B (20.588) has a much lower microsomal clearance than Ligand A (46.351), indicating better metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (66.233) has a longer half-life than Ligand B (15.063), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.035).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in DILI risk and metabolic stability (Cl_mic), which are crucial for kinase inhibitors. Ligand A has better solubility, permeability, half-life and QED. The binding affinity is comparable. The significantly higher DILI risk for Ligand A and the better metabolic stability of Ligand B outweigh the advantages of Ligand A.

Output:
1
2025-04-17 15:53:56,494 - INFO - Batch 418 complete. Total preferences: 6688
2025-04-17 15:53:56,494 - INFO - Processing batch 419/512...
2025-04-17 15:54:41,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, suggesting good absorption. Ligand B (78.09) is also below the threshold, but closer to it.

**logP:** Both ligands have a logP of 3.047 and 3.0, respectively, which is optimal (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 1 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 (0.65 and 0.745, respectively), indicating drug-likeness.

**DILI:** Ligand A (9.19) has a significantly lower DILI risk than Ligand B (57.58). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (81.233) has a higher BBB percentile than Ligand B (57.852).

**Caco-2 Permeability:** Ligand A (-4.359) and Ligand B (-5.211) 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:** Ligand A (-2.178) and Ligand B (-3.904) both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.387) has a lower hERG risk than Ligand B (0.601), which is favorable.

**Microsomal Clearance:** Ligand A (70.712) has higher microsomal clearance than Ligand B (58.505), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-10.838) has a significantly longer in vitro half-life than Ligand A (-1.548). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.116) has lower P-gp efflux than Ligand B (0.396), which is favorable.

**Binding Affinity:** Ligand B (-9.0) has a stronger binding affinity than Ligand A (-7.6). This is a substantial advantage for Ligand B (1.4 kcal/mol difference).

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a better DILI profile and lower P-gp efflux, the significantly stronger binding affinity (-9.0 vs -7.6 kcal/mol) and longer half-life of Ligand B outweigh the drawbacks. The difference in binding affinity is substantial enough to overcome the slightly higher DILI risk and P-gp efflux. The negative Caco-2 and solubility values are concerning for both, but the superior potency and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 15:54:41,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.843 Da) is slightly higher than Ligand B (347.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (69.72) is lower than Ligand A (84.5), which is slightly preferable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.735) is slightly higher than Ligand B (1.484).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD and HBA counts. Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) are both within the desired limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.801) is slightly better than Ligand B (0.676).

**DILI:** Ligand A (69.523) has a higher DILI risk than Ligand B (15.859). This is a significant negative for Ligand A.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 70.648, Ligand B: 69.833). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (negative values). Ligand A (-4.947) is slightly better than Ligand B (-5.023), but both are concerning.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (negative values). Ligand A (-3.94) is slightly better than Ligand B (-1.734).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.27, Ligand B: 0.166). This is good.

**Microsomal Clearance:** Ligand B (31.068 mL/min/kg) has a higher microsomal clearance than Ligand A (-4.03 mL/min/kg). This suggests Ligand A is more metabolically stable, which is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (26.488 hours) has a significantly longer in vitro half-life than Ligand B (-12.908 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.174, Ligand B: 0.026).

**Binding Affinity:** Both ligands have similar binding affinities (Ligand A: -8 kcal/mol, Ligand B: -7.9 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slightly better binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), and a lower DILI risk. While both have poor Caco-2 and solubility, the improved metabolic stability and reduced toxicity of Ligand A outweigh these drawbacks, especially for a kinase inhibitor where potency is already good.

Output:
1
2025-04-17 15:54:41,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.535 and 355.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold for good absorption, while Ligand B (106.2) is still acceptable, but higher.

**logP:** Ligand A (2.842) is optimal (1-3). Ligand B (-0.889) is below 1, which may impede permeation.

**H-Bond Donors:** Both ligands have 2 HBDs, which is within the acceptable limit of <=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 closer to the upper bound.

**QED:** Both ligands have reasonable QED values (0.707 and 0.547), indicating good drug-like properties.

**DILI:** Ligand A (9.151) has a very low DILI risk, significantly better than Ligand B (37.999).

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (75.843) shows better penetration than Ligand A (61.38).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.881) is worse than Ligand B (-5.052).

**Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are percentile scores, Ligand A (-1.833) is better than Ligand B (-1.385).

**hERG:** Ligand A (0.521) has a lower hERG risk than Ligand B (0.188), which is preferable.

**Microsomal Clearance:** Ligand A (24.815) has a significantly lower Cl_mic than Ligand B (-41.567). Lower is better for metabolic stability.

**In vitro Half-Life:** Ligand A (17.211) has a better in vitro half-life than Ligand B (-24.928).

**P-gp Efflux:** Ligand A (0.118) has lower P-gp efflux than Ligand B (0.005), which is preferable.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.3 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is superior due to its significantly better DILI score, lower microsomal clearance, longer half-life, lower P-gp efflux, and lower hERG risk. While Ligand B has slightly better binding affinity, the ADME properties of Ligand A are much more favorable for development as an enzyme inhibitor. The logP of Ligand B is a concern, potentially impacting permeability.

Output:
1
2025-04-17 15:54:41,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.451 and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.5) is better than Ligand B (98.74). Both are below 140, indicating reasonable absorption potential.

**logP:** Ligand A (2.267) is optimal, while Ligand B (0.581) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, under the limit of 5.

**H-Bond Acceptors:** Both ligands (4) are well within the acceptable limit of 10.

**QED:** Ligand A (0.879) has a significantly better QED score than Ligand B (0.583), suggesting a more drug-like profile.

**DILI:** Ligand B (13.3) has a much lower DILI risk than Ligand A (60.489), which is a significant advantage.

**BBB:** Ligand A (68.941) is better than Ligand B (12.912), but BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.864) is better than Ligand B (-5.273), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.247) is better than Ligand B (-1.083), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.34) has a slightly higher hERG risk than Ligand B (0.076), which is preferable.

**Microsomal Clearance:** Ligand B (7.13) has significantly lower microsomal clearance than Ligand A (26.08), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.05) has a longer in vitro half-life than Ligand A (12.682), which is desirable.

**P-gp Efflux:** Both ligands (0.04 and 0.017) have low P-gp efflux, which is good.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). The difference is 1.2 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and solubility, but Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a lower hERG risk. The 1.2 kcal/mol difference in binding affinity is substantial, but the improvements in ADME properties for Ligand B, particularly the lower DILI and better metabolic stability, are very important for a kinase inhibitor. Given the enzyme-specific priorities, the improved ADME profile of Ligand B outweighs the slightly weaker binding.

Output:
1
2025-04-17 15:54:41,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.55 and 359.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is well below the 140 threshold, and good for oral absorption. Ligand B (87.22) is still acceptable, but less optimal.

**logP:** Ligand A (3.305) is within the optimal 1-3 range. Ligand B (1.46) is at the lower end, potentially impacting permeability.

**H-Bond Donors:** Both ligands 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 Ligand B is higher.

**QED:** Both ligands have good QED scores (0.653 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (28.306) has a much lower DILI risk than Ligand B (71.539), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (83.443) has a better percentile than Ligand B (70.143).

**Caco-2:** Ligand A (-4.821) and Ligand B (-5.414) both have negative Caco-2 values, which is unusual and suggests poor permeability. It's important to note the scale here, and these values may be percentile scores where lower is worse.

**Solubility:** Ligand A (-4.564) and Ligand B (-3.408) both have negative solubility values, suggesting poor aqueous solubility. Again, these are likely percentile scores where lower is worse.

**hERG:** Ligand A (0.592) has a lower hERG risk than Ligand B (0.168), which is a significant advantage.

**Microsomal Clearance:** Ligand A (76.095) has a higher microsomal clearance than Ligand B (39.709), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (16.076) has a longer half-life than Ligand B (8.198), which is a positive.

**P-gp Efflux:** Ligand A (0.33) has lower P-gp efflux than Ligand B (0.04), which is a positive.

**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 (0.4 kcal/mol).

**Overall Assessment:**

Ligand B has a better binding affinity and lower microsomal clearance, but suffers from a significantly higher DILI risk, higher HBA count, and lower hERG safety. Ligand A has better solubility, lower DILI, better hERG, and better P-gp efflux. Given the enzyme-specific priorities, the lower DILI and hERG risk of Ligand A are crucial. The slightly weaker binding affinity can potentially be optimized in later stages of drug development. The metabolic stability of Ligand B is a plus, but the safety concerns outweigh this benefit.

Output:
1
2025-04-17 15:54:41,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.403 and 345.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (99.52) is higher than Ligand B (43.86). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have good logP values (1.469 and 1.295), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.615 and 0.682), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.915, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 11.206, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (80.807) than Ligand A (68.554).

**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 hard to draw conclusions from this.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, hard to draw conclusions.

**hERG:** Ligand A has a hERG inhibition liability of 0.156, which is very low and favorable. Ligand B has a slightly higher hERG liability of 0.607, but still relatively low.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (51.704) than Ligand B (20.927), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (5.29 hours) than Ligand A (3.923 hours), aligning with its better metabolic stability.

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.13, while Ligand B has 0.042, indicating lower efflux potential for Ligand B.

**Binding Affinity:** Ligand A has a slightly better binding affinity (-7.9 kcal/mol) than Ligand B (-7.3 kcal/mol). This 0.6 kcal/mol difference is noteworthy, but not overwhelmingly large.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B demonstrates significantly better ADME properties, particularly lower DILI risk and improved metabolic stability (lower Cl_mic and longer t1/2). The lower P-gp efflux and better TPSA are also beneficial. The unusual negative solubility and Caco-2 values are a concern for both, but the other advantages of Ligand B outweigh the slight affinity difference. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 15:54:41,642 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [342.355, 95.34, 0.509, 1, 7, 0.87, 86.468, 61.807, -5.08, -2.83, 0.214, -22.46, 14.229, 0.034, -8.7]
**Ligand B:** [366.849, 76.46, 1.08, 1, 5, 0.578, 43.66, 58.24, -4.967, -2.436, 0.34, 6.451, 4.786, 0.245, -8.1]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (342.355) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (95.34) is higher than B (76.46).  Both are below 140, acceptable for oral absorption, but B is better.
3. **logP:** A (0.509) is quite low, potentially hindering membrane permeability. B (1.08) is better, falling within the optimal 1-3 range.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A (7) is higher than B (5). Both are acceptable (<10), but B is preferable.
6. **QED:** Both have good QED scores (A: 0.87, B: 0.578), indicating drug-like properties. A is slightly better.
7. **DILI:** A (86.468) has a significantly higher DILI risk than B (43.66). This is a major concern for A.
8. **BBB:** Both have relatively low BBB penetration, which isn't critical for a non-CNS target like SRC. A (61.807) is slightly higher than B (58.24).
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. A (-5.08) is worse than B (-4.967).
10. **Solubility:** Both have negative solubility values, also unusual. A (-2.83) is slightly worse than B (-2.436).
11. **hERG:** Both have low hERG risk (A: 0.214, B: 0.34).
12. **Cl_mic:** A (-22.46) has a much lower (better) microsomal clearance than B (6.451), indicating greater metabolic stability.
13. **t1/2:** A (14.229) has a longer half-life than B (4.786), which is desirable.
14. **Pgp:** Both have low Pgp efflux (A: 0.034, B: 0.245).
15. **Binding Affinity:** A (-8.7) has a slightly better binding affinity than B (-8.1). However, the difference is less than 1.5 kcal/mol.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite having a slightly better binding affinity and longer half-life, Ligand A's significantly higher DILI risk and poor logP/Caco-2/Solubility make it a less desirable candidate. Ligand B has a more favorable ADME profile, particularly regarding DILI and logP, and while its affinity is slightly lower, it's within a reasonable range. The improved metabolic stability (lower Cl_mic) of A is a plus, but the DILI risk is a major red flag.

Therefore, **Ligand B** is the more viable drug candidate.

1
2025-04-17 15:54:41,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (88.99) is excellent, well below the 140 threshold for oral absorption. Ligand B (137.92) is still acceptable but less optimal.

**logP:** Ligand A (2.048) is within the optimal range (1-3). Ligand B (-1.925) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 7. Ligand A is better here, as higher HBA counts can sometimes reduce permeability.

**QED:** Both have reasonable QED scores (A: 0.824, B: 0.552), indicating drug-likeness. Ligand A is significantly better.

**DILI:** Ligand A (55.874) has a moderate DILI risk, but is still acceptable. Ligand B (35.905) has a lower DILI risk, which is favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (54.207) and B (13.377) are not particularly high, which is fine.

**Caco-2 Permeability:** Ligand A (-4.893) and B (-5.704) both have negative values, which is unusual and suggests poor permeability. B is slightly worse.

**Aqueous Solubility:** Ligand A (-4.332) and B (-1.178) both have negative values, indicating poor solubility. B is slightly better.

**hERG Inhibition:** Ligand A (0.399) has a very low hERG risk, which is excellent. Ligand B (0.035) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (11.897) has a moderate clearance, while Ligand B (-15.667) has a very high (negative) clearance, suggesting rapid metabolism and poor stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-13.006) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (14.079) has a positive half-life, indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.093, B: 0.01), which is good.

**Binding Affinity:** Ligand A (-9.5 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:**

Ligand A has a superior binding affinity and better TPSA, logP, HBA, QED, and hERG risk. While Ligand B has a slightly lower DILI risk and better in vitro half-life, its significantly worse logP, higher TPSA, and much higher microsomal clearance are major concerns. The strong binding affinity of Ligand A is a critical advantage for an enzyme inhibitor, and its other properties are generally more favorable despite some weaknesses.

Output:
1
2025-04-17 15:54:41,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.41 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.63) is better than Ligand B (95.58), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration if that were a goal.

**logP:** Both ligands (0.822 and 0.75) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as it has fewer donors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.785) has a significantly better QED score than Ligand B (0.474), indicating a more drug-like profile.

**DILI:** Ligand A (43.117) has a slightly higher DILI risk than Ligand B (32.261), but both are below the concerning threshold of 60.

**BBB:** Ligand B (79.062) has better BBB penetration than Ligand A (62.854), but this is not a primary concern for a kinase inhibitor unless CNS exposure is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.643) has better Caco-2 permeability than Ligand B (-5.198), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-2.79) has better aqueous solubility than Ligand A (-0.543), which is a significant advantage for formulation and bioavailability.

**hERG Inhibition:** Both ligands (0.149 and 0.087) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (8.43 mL/min/kg) has significantly lower microsomal clearance than Ligand B (14.574 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.99 hours) has a much longer in vitro half-life than Ligand B (-31.562 hours). The negative value for B is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands (0.024 and 0.025) have very low P-gp efflux liability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better solubility, Ligand A excels in crucial areas for an enzyme inhibitor: metabolic stability (lower Cl_mic, longer t1/2), a significantly better QED score, and better Caco-2 permeability. The binding affinity is comparable between the two. The slightly higher DILI risk for Ligand A is less concerning than the poor metabolic stability and low half-life of Ligand B.

Output:
1
2025-04-17 15:54:41,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.435 and 352.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.07) is higher than Ligand B (47.1). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (1.224 and 1.119), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.786) has a higher QED score than Ligand B (0.624), indicating a more drug-like profile.

**DILI:** Ligand B (3.994) has a significantly lower DILI risk than Ligand A (37.301), which is a major advantage.

**BBB:** Ligand B (79.721) has a higher BBB penetration percentile than Ligand A (59.364). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-5.032) and Ligand B (-4.936) both have negative values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-0.453) and Ligand B (-0.212) both have negative values, indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.191) has a slightly lower hERG risk than Ligand B (0.681), which is preferable.

**Microsomal Clearance:** Ligand B (-7.39) has a *much* lower microsomal clearance than Ligand A (27.077), indicating significantly better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-8.27) has a lower in vitro half-life than Ligand A (10.341). This is a negative for Ligand B, but the significantly improved metabolic stability (lower Cl_mic) suggests this might be less of a concern.

**P-gp Efflux:** Ligand A (0.034) has a lower P-gp efflux liability than Ligand B (0.012), which is slightly better.

**Binding Affinity:** Ligand A (-8.8 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, so it doesn't necessarily outweigh other factors.

**Conclusion:**

Despite Ligand A's slightly better binding affinity and QED, Ligand B is the more promising candidate. The significantly lower DILI risk and dramatically improved metabolic stability (lower Cl_mic) are crucial advantages for an enzyme target like SRC kinase. While both have poor solubility and permeability, the metabolic advantage of Ligand B is more readily addressable through formulation strategies than mitigating a high DILI risk.

Output:
1
2025-04-17 15:54:41,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.37 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand B (82.11) is significantly better than Ligand A (117.59). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (0.387) is slightly better than Ligand B (-0.31), being closer to the optimal 1-3 range. Ligand B is a bit low, potentially hindering permeation.

**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 (0.637 and 0.709), indicating drug-like properties.

**DILI:** Ligand B (3.412) has a much lower DILI risk than Ligand A (57.852). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (59.597) is slightly better than Ligand B (35.052).

**Caco-2 Permeability:** Both have negative values (-5.432 and -5.133), which is unusual. This suggests poor permeability, but the scale isn't clearly defined.

**Aqueous Solubility:** Both have negative values (-2.586 and -0.527), also unusual. This suggests poor solubility, which is a concern.

**hERG Inhibition:** Ligand A (0.113) has a slightly lower hERG risk than Ligand B (0.178), but both are relatively low.

**Microsomal Clearance:** Ligand A (-1.132) has a lower (better) microsomal clearance than Ligand B (-23.261), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.275) has a much longer in vitro half-life than Ligand B (-0.583), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.003).

**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 significant, and can outweigh some ADME concerns.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better logP, Ligand B has a significantly lower DILI risk and a better binding affinity. The lower DILI risk is a major advantage, as liver toxicity is a common cause of drug failure. The improved binding affinity of Ligand B is also crucial for an enzyme inhibitor. The solubility and permeability issues are concerning for both, but the potency and safety profile of Ligand B are more favorable.

Output:
1
2025-04-17 15:54:41,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.43 and 368.50 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.99) is better than Ligand B (103.95). TPSA < 140 is good for oral absorption, both are within this range, but A is preferable.

**3. logP:** Both ligands have similar logP values (1.82 and 1.862), 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 (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.902) has a significantly better QED score than Ligand B (0.651), indicating a more drug-like profile.

**7. DILI:** Ligand A (28.344) has a lower DILI risk than Ligand B (42.613), which is a significant advantage. Both are below the 60 threshold.

**8. BBB:** Both ligands have similar BBB penetration (64.482 and 60.838). BBB is less critical for SRC kinase inhibitors unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.516) has a worse Caco-2 permeability than Ligand B (-5.424). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.454) has a better aqueous solubility than Ligand B (-2.925). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.288 and 0.303), which are relatively low.

**12. Microsomal Clearance:** Ligand A (47.778) has a higher microsomal clearance than Ligand B (26.276), meaning it's cleared faster and has lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-31.835) has a much longer in vitro half-life than Ligand A (45.338), indicating better stability.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.106 and 0.264).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior QED, lower DILI risk, better solubility, and *much* stronger binding affinity. However, it has worse Caco-2 permeability and higher microsomal clearance (lower metabolic stability) compared to Ligand B. The difference in binding affinity (-8.9 vs -7.0 kcal/mol) is a 1.9 kcal/mol advantage, which is significant. Given that we are targeting a kinase (enzyme), potency and metabolic stability are key. While Ligand B has better metabolic stability, the substantial binding affinity advantage of Ligand A is likely to be more impactful, especially if further optimization can address the clearance issue.

Output:
1
2025-04-17 15:54:41,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.419 and 358.869 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.38) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (66.56) is excellent, well below 90, suggesting good absorption.

**logP:** Ligand A (-0.358) is a bit low, potentially hindering permeation. Ligand B (4.235) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is within acceptable limits. Ligand B (HBD=2, HBA=3) is also good.

**QED:** Both ligands have good QED scores (A: 0.546, B: 0.786), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 30.322, B: 32.842), which is favorable.

**BBB:** Both ligands have low BBB penetration (A: 37.96, B: 64.87). Since SRC is not a CNS target, this is not a major concern.

**Caco-2 Permeability:** Ligand A (-4.512) has poor Caco-2 permeability, while Ligand B (-4.922) is also poor.

**Aqueous Solubility:** Ligand A (-1.087) has poor aqueous solubility, while Ligand B (-5.138) has even worse aqueous solubility.

**hERG Inhibition:** Ligand A (0.086) has very low hERG inhibition risk, which is excellent. Ligand B (0.883) has a slightly elevated hERG risk, but still within a manageable range.

**Microsomal Clearance:** Ligand A (24.893) has lower microsomal clearance, indicating better metabolic stability. Ligand B (76.145) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-33.327) has a very long in vitro half-life, which is highly desirable. Ligand B (-0.86) has a very short in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.029, B: 0.389).

**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 of the ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, lower logP, and significantly better metabolic stability and half-life, Ligand B's substantially improved binding affinity (-8.6 vs -7.7 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. The higher logP and lower solubility of Ligand B are concerns, but these can potentially be addressed through formulation strategies or further chemical modifications. The slightly higher hERG risk is also manageable. The improved binding affinity is likely to translate to greater efficacy.

Output:
1
2025-04-17 15:54:41,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.473 and 389.279 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (75.71). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have acceptable logP values (4.049 and 2.168, respectively), falling within the 1-3 range. Ligand B is slightly better here.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4 HBA, both are acceptable (<=10).

**QED:** Ligand A (0.729) has a better QED score than Ligand B (0.578), indicating better overall drug-likeness.

**DILI:** Ligand A (7.057) has a much lower DILI risk than Ligand B (38.62). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.702) is better than Ligand B (71.307).

**Caco-2 Permeability:** Both have negative values (-4.39 and -4.709), 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 values (-3.017 and -3.033), indicating poor solubility. This is a concern for both, but needs to be evaluated further.

**hERG Inhibition:** Ligand A (0.932) has a slightly higher hERG risk than Ligand B (0.16), which is a negative for Ligand A.

**Microsomal Clearance:** Ligand A (23.387) has a significantly lower microsomal clearance than Ligand B (60.327), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (14.239 hours) has a much longer half-life than Ligand B (-11.484 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.315) has lower P-gp efflux than Ligand B (0.094), which is preferable.

**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 A is the stronger candidate. While Ligand B has a slightly better logP and lower hERG risk, Ligand A excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), better QED, and lower P-gp efflux. The similar binding affinities mean these advantages outweigh the minor drawbacks of Ligand A. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 15:54:41,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.495 Da) is slightly higher than Ligand B (339.439 Da), but both are acceptable.

**TPSA:** Ligand A (68.29) is higher than Ligand B (43.86). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (4.493) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.355) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.702, B: 0.778), indicating good drug-like properties.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (19.426). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (61.691) has a higher BBB value than Ligand A (46.336).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the magnitude is similar, so this doesn't strongly favor either.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude is similar, so this doesn't strongly favor either.

**hERG Inhibition:** Ligand A (0.509) has a slightly higher hERG risk than Ligand B (0.319), but both are relatively low.

**Microsomal Clearance:** Ligand A (49.016 mL/min/kg) has a higher microsomal clearance than Ligand B (4.425 mL/min/kg), indicating lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (20.941 hours) has a longer half-life than Ligand B (4.73 hours), which is a positive.

**P-gp Efflux:** Ligand A (0.562) has a slightly higher P-gp efflux liability than Ligand B (0.045).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While both have some issues with Caco-2 and solubility, Ligand B has a much better safety profile (lower DILI), significantly higher binding affinity, better logP, and improved metabolic stability (lower Cl_mic). The stronger binding affinity of Ligand B is a critical advantage for an enzyme target like SRC kinase. The longer half-life of Ligand A is a plus, but the higher DILI risk and lower affinity are significant drawbacks.

Output:
1
2025-04-17 15:54:41,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 336.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.16) is slightly above the preferred <140 for good oral absorption, while Ligand B (84.73) is well within this range.

**logP:** Both ligands have acceptable logP values (1.025 and 1.814), falling within the optimal 1-3 range.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.596 and 0.744), indicating drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (67.158 and 65.723), indicating potential liver toxicity. This is a concern for both.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (74.874) has a higher BBB percentile than Ligand A (32.803), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.636 and -5.537). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.644 and -2.135), indicating very poor aqueous solubility, a significant drawback.

**hERG Inhibition:** Ligand A (0.235) has a lower hERG inhibition liability than Ligand B (0.086), which is favorable.

**Microsomal Clearance:** Ligand A (-40.701) has significantly lower (better) microsomal clearance than Ligand B (26.094), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (50.156) has a longer in vitro half-life than Ligand B (30.496), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.066 and 0.101).

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B's significantly stronger binding affinity (-9.2 vs -7.5 kcal/mol) outweighs the slightly higher hERG risk and lower metabolic stability compared to Ligand A. The difference in binding affinity is substantial enough to potentially overcome the ADME liabilities with appropriate formulation strategies. The better metabolic stability of Ligand A is appealing, but the potency advantage of Ligand B is more critical for an enzyme inhibitor.

Output:
1
2025-04-17 15:54:41,643 - INFO - Batch 419 complete. Total preferences: 6704
2025-04-17 15:54:41,643 - INFO - Processing batch 420/512...
2025-04-17 15:55:23,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.431 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.18) is slightly higher than Ligand B (58.64), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.378 and 2.99), 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 3. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.922) has a significantly higher QED score than Ligand B (0.787), indicating better overall drug-likeness.

**DILI:** Ligand A (35.595) has a slightly higher DILI risk than Ligand B (25.514), but both are below the concerning threshold of 60.

**BBB:** Ligand B (69.794) has a higher BBB penetration percentile than Ligand A (50.523). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.476) has a worse Caco-2 permeability than Ligand B (-4.219), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.845) has worse aqueous solubility than Ligand B (-2.898). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.148) exhibits a lower hERG inhibition liability than Ligand B (0.526), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-6.197) has *much* lower microsomal clearance than Ligand B (60.802), suggesting significantly better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (15.805) has a slightly shorter half-life than Ligand B (18.13), but both are reasonable.

**P-gp Efflux:** Ligand A (0.025) has a much lower P-gp efflux liability than Ligand B (0.099), indicating better bioavailability.

**Binding Affinity:** Ligand A (-9.6 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.

**Conclusion:**

Despite Ligand B having slightly better Caco-2 permeability and solubility, Ligand A is the superior candidate. Its significantly stronger binding affinity (-9.6 vs -7.6 kcal/mol), much lower microsomal clearance, lower P-gp efflux, and lower hERG inhibition liability are crucial advantages for an enzyme inhibitor. The higher QED score also supports its drug-like properties. While Ligand A's solubility and Caco-2 permeability are less favorable, these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 15:55:23,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.543 and 350.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (47.1). Both are reasonably good, but Ligand B is better, being well below the 140 threshold for oral absorption.

**logP:** Ligand A (2.08) is optimal, while Ligand B (0.584) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.694 and 0.728, respectively), indicating drug-like properties.

**DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (3.373), but both are below the concerning threshold of 60.

**BBB:** Ligand A (49.748) has lower BBB penetration than Ligand B (78.868). This is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.381) has poor Caco-2 permeability, while Ligand B (-4.783) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.338) has poor solubility, while Ligand B (-0.051) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.254) has a slightly higher hERG risk than Ligand B (0.527), but both are relatively low.

**Microsomal Clearance:** Ligand A (26.479) has higher microsomal clearance than Ligand B (-10.221). This suggests Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (12.74) has a shorter half-life than Ligand B (-10.867). Again, favoring Ligand B for metabolic stability.

**P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux than Ligand B (0.008), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.6 kcal/mol). Ligand B has a slightly better affinity.

**Conclusion:**

While both ligands show excellent binding affinity, Ligand B is the more promising candidate. It exhibits better metabolic stability (lower Cl_mic, longer t1/2), slightly better solubility, and a significantly lower DILI risk. Although its logP is a bit low, the improved metabolic properties and safety profile outweigh this drawback, especially for an enzyme target like SRC kinase.

Output:
1
2025-04-17 15:55:23,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (359.455 and 353.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (91.97 and 93.46) are reasonably close to the 140 A^2 threshold for oral absorption, but higher than the <90 A^2 for CNS targets (not a primary concern here).

**3. logP:** Both ligands have logP values (1.704 and 2.305) 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 (6) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.494 and 0.71), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (37.611). This is a significant negative for Ligand A.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (63.009) and Ligand B (59.791) are comparable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.972 and -4.688). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close, so the difference is likely not significant.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.387 and -2.375). This also suggests poor solubility. Again, the difference is minimal.

**11. hERG Inhibition:** Ligand A (0.619) has a slightly higher hERG risk than Ligand B (0.295). This is a negative for Ligand A.

**12. Microsomal Clearance:** Ligand B (46.593 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (27.366 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (14.749 hours) has a much longer in vitro half-life than Ligand A (52.262 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.093) has a slightly lower P-gp efflux liability than Ligand B (0.05). This is a minor advantage for Ligand A.

**15. Binding Affinity:** Ligand A (-10.6 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:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, specifically regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. The significantly better metabolic stability of Ligand B is crucial for a kinase inhibitor, as prolonged exposure is often desired. The DILI risk associated with Ligand A is also a major concern. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 15:55:23,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.845 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.02) is well below the 140 threshold for good absorption, while Ligand B (88.32) is still acceptable but less optimal.

**logP:** Both ligands (2.781 and 2.162) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 5 HBAs, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.749 and 0.807), indicating good drug-like properties.

**DILI:** Ligand A (58.627) has a slightly higher DILI risk than Ligand B (50.291), but both are below the concerning threshold of 60.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (83.482) shows better BBB penetration than Ligand B (73.866).

**Caco-2 Permeability:** Ligand A (-4.686) has worse Caco-2 permeability than Ligand B (-5.419). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.548) has slightly better aqueous solubility than Ligand B (-2.972). Higher values indicate better solubility.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.573 and 0.584).

**Microsomal Clearance:** Ligand B (-1.182) shows significantly *lower* (better) microsomal clearance than Ligand A (30.717), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.317) has a much longer in vitro half-life than Ligand A (61.197), further supporting its superior metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.241 and 0.043).

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-6.8), a difference of 0.6 kcal/mol.

**Conclusion:**

While Ligand A has a slightly better binding affinity, the significant advantages of Ligand B in terms of metabolic stability (lower Cl_mic and longer t1/2) and slightly better solubility outweigh this difference.  For an enzyme target like SRC kinase, metabolic stability is crucial for maintaining therapeutic concentrations. The slightly lower Caco-2 permeability of Ligand A is a minor concern given the other favorable properties of Ligand B.

Output:
1
2025-04-17 15:55:23,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (360.443 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.8) is better than Ligand B (111.53), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (1.144) is within the optimal 1-3 range. Ligand B (-0.961) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range. Ligand A has 7 HBA, while Ligand B has 6. Both are acceptable.

**QED:** Both ligands have similar QED scores (0.721 and 0.686), indicating good drug-likeness.

**DILI:** Ligand A (59.519) has a higher DILI risk than Ligand B (35.75). This is a significant negative for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (47.15) is lower than Ligand B (23.342).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.567) is slightly better than Ligand B (-5.171).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.119) is slightly better than Ligand B (-1.009).

**hERG:** Ligand A (0.207) has a slightly higher hERG risk than Ligand B (0.037), but both are relatively low.

**Microsomal Clearance:** Ligand B (-9.268) has significantly lower (better) microsomal clearance than Ligand A (13.481), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-31.006) has a much longer in vitro half-life than Ligand A (13.736), further supporting its superior metabolic stability.

**P-gp Efflux:** Both are very low (0.12 and 0.007), indicating minimal P-gp efflux.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 2.2 kcal/mol is a major advantage, easily outweighing minor ADME concerns.

**Conclusion:**

While Ligand A has slightly better Caco-2 and solubility, Ligand B is superior overall. The significantly stronger binding affinity (-9.0 vs -6.8 kcal/mol), much better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk make Ligand B the more promising drug candidate. The slightly lower logP of Ligand B is a minor concern, but the potency advantage is substantial.

Output:
1
2025-04-17 15:55:23,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.407 and 369.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.77) is better than Ligand B (88.52), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.951) is optimal, while Ligand B (0.809) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0).

**H-Bond Acceptors:** Ligand B (8) is preferable to Ligand A (7).

**QED:** Both ligands have good QED scores (0.61 and 0.77), indicating good drug-like properties.

**DILI:** Ligand B (63.086) has a lower DILI risk than Ligand A (88.174), which is a significant advantage.

**BBB:** Ligand B (84.451) has a higher BBB penetration score than Ligand A (30.438). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-5.23) has a better Caco-2 permeability than Ligand B (-4.649).

**Aqueous Solubility:** Ligand A (-3.078) has a better aqueous solubility than Ligand B (-2.616).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.407 and 0.442).

**Microsomal Clearance:** Ligand A (23.324) has a significantly lower microsomal clearance than Ligand B (44.085), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.29) has a longer in vitro half-life than Ligand B (5.467), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.26 and 0.04).

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has a lower DILI risk and better BBB penetration, Ligand A demonstrates superior ADME properties crucial for an enzyme target: significantly better metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The equal binding affinity makes the ADME advantages of Ligand A decisive.

Output:
1
2025-04-17 15:55:23,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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.

**TPSA:** Ligand A (106.23) is better than Ligand B (69.22), both are well below the 140 threshold for oral absorption.

**logP:** Ligand B (3.227) is optimal (1-3), while Ligand A (0.364) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.787 and 0.715), indicating good drug-likeness.

**DILI:** Ligand B (26.328) has a much lower DILI risk than Ligand A (56.146), which is a substantial advantage.

**BBB:** Both have moderate BBB penetration (58.356 and 54.789). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.112) has a significantly lower hERG risk than Ligand B (0.782), which is a positive attribute.

**Microsomal Clearance:** Ligand A (11.586) has a much lower Cl_mic than Ligand B (33.359), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-4.273) has a longer half-life than Ligand B (-2.772).

**P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.576), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has slightly better binding affinity than Ligand A (-8.8 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A has advantages in metabolic stability (Cl_mic, t1/2), P-gp efflux, and hERG risk. However, its low logP is a major concern, potentially limiting its permeability and bioavailability. Ligand B has a better logP and slightly better binding affinity, but suffers from higher DILI risk and poorer metabolic stability.

Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. While Ligand B has a slightly better affinity, Ligand A's superior metabolic stability and lower hERG risk, coupled with acceptable (though not ideal) affinity, make it the more promising candidate. The low logP of Ligand A could be addressed through structural modifications, whereas mitigating the higher DILI risk of Ligand B might be more challenging.

Output:
0
2025-04-17 15:55:23,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (97.56).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.406 and 1.115), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6.  Ligand A is preferable here, staying closer to the <10 guideline.

**QED:** Both ligands have good QED scores (0.795 and 0.856), indicating good drug-like properties.

**DILI:** Ligand A (18.418) has a much lower DILI risk than Ligand B (52.423). This is a significant advantage for Ligand A.

**BBB:** Both have good BBB penetration (76.735 and 83.676), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. It's difficult to interpret without knowing the scale.

**Solubility:** Both have negative solubility values, which is also unusual and requires further investigation. It's difficult to interpret without knowing the scale.

**hERG:** Both have very low hERG inhibition risk (0.26 and 0.074), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance (15.904 and 16.687 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (18.799 hours) has a significantly longer half-life than Ligand B (-1.244 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.095 and 0.026), which is good.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.4 kcal/mol difference is substantial and outweighs minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a better TPSA, HBA count, significantly lower DILI risk, a much longer half-life, and a substantially stronger binding affinity. While both have unusual Caco-2 and solubility values that need investigation, the overall profile of Ligand A is much more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 15:55:23,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.873 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (69.3), both are acceptable, but lower is preferable for permeability.

**logP:** Both ligands have good logP values (3.159 and 2.338), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand B (0.91) has a significantly higher QED score than Ligand A (0.522), indicating a more drug-like profile.

**DILI:** Ligand A (24.893) has a much lower DILI risk than Ligand B (56.727), a significant advantage.

**BBB:** Ligand A (69.523) has a better BBB penetration score than Ligand B (34.122), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.704) has a worse Caco-2 permeability than Ligand B (-5.254). Lower values here indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.718) has a worse aqueous solubility than Ligand B (-2.441). Higher values are better.

**hERG:** Both ligands have low hERG risk (0.728 and 0.585).

**Microsomal Clearance:** Ligand A (33.535) has a lower microsomal clearance than Ligand B (36.709), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (54.722 hours) has a significantly longer half-life than Ligand B (-32.423 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.243) has a lower P-gp efflux liability than Ligand B (0.184), indicating better bioavailability.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a better QED and slightly better binding affinity, Ligand A excels in critical areas for an enzyme inhibitor: lower DILI risk, significantly longer half-life, and better metabolic stability (lower Cl_mic). The solubility and Caco-2 permeability are worse for A, but the other advantages are more important for this target class.

Output:
0
2025-04-17 15:55:23,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (358.429 Da and 369.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (100.29).  A TPSA under 90 is preferred, and A is closer to this threshold, suggesting better permeability.

**3. logP:** Both ligands have acceptable logP values (2.414 and 1.178, respectively), 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 (3) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar and good QED values (0.622 and 0.672), indicating good drug-like properties.

**7. DILI:** Ligand A (20.279) has a much lower DILI risk than Ligand B (58.511). A DILI score below 40 is preferred, and A is well within this range, while B is approaching a concerning level.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (90.772) has a higher BBB score than Ligand B (54.246), but this is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude is important. Ligand A (-4.545) is better than Ligand B (-5.315).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.833) is slightly better than Ligand B (-3.092).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.451 and 0.389), which is good.

**12. Microsomal Clearance:** Ligand A (43.372) has a higher microsomal clearance than Ligand B (26.133), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (-31.083) has a significantly longer in vitro half-life than Ligand A (-11.21). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.042) has a slightly higher P-gp efflux liability than Ligand B (0.053), but the difference is minimal.

**15. Binding Affinity:** Ligand A (-6.9) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage for Ligand A.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a much better binding affinity, but suffers from higher clearance and shorter half-life. Ligand B has better metabolic stability and half-life, but very weak binding. The difference in binding affinity is very large (6.9 kcal/mol vs 0.0 kcal/mol). A 6.9 kcal/mol difference is likely to outweigh the metabolic stability concerns, especially since Ligand A's clearance isn't extremely high. Solubility is poor for both, but similar.

Output:
1
2025-04-17 15:55:23,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.486 and 384.498 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (69.64). TPSA < 140 is good for oral absorption, and both are well below this, but A is preferable.

**logP:** Both ligands have good logP values (2.705 and 1.727), 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). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.835) has a significantly higher QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (37.069 and 34.277), both below the 40 threshold.

**BBB:** Ligand A (85.731) shows better BBB penetration than Ligand B (70.027), although BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.742) is better than Ligand B (-4.917), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.296) is better than Ligand B (-2.573), which is important for formulation and bioavailability.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.724 and 0.734).

**Microsomal Clearance:** Ligand A (31.427) has a higher (worse) microsomal clearance than Ligand B (-0.244). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-3.997) has a significantly longer in vitro half-life than Ligand A (-16.204), which is a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.403 and 0.266).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.7 and -9.4 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Overall:** Ligand A has advantages in most ADME properties (TPSA, QED, Solubility, Caco-2, BBB) and similar affinity. However, Ligand B has a much better metabolic stability profile (lower Cl_mic, longer t1/2). Given that we are targeting a kinase, metabolic stability is crucial. The slight advantage in affinity of Ligand A is outweighed by the significantly improved metabolic stability of Ligand B.

Output:
1
2025-04-17 15:55:23,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.406 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.74) is significantly better than Ligand B (103.01). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.507 and 1.01), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=6) in terms of adhering to the guidelines (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.894) has a significantly higher QED score than Ligand B (0.578), indicating better overall drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (33.889 and 39.473), both below the 40 threshold.

**BBB:** Ligand A (77.2) has a better BBB percentile than Ligand B (46.336). While not a primary concern for a non-CNS target, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.368) is better than Ligand B (-6.001), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.031) is better than Ligand B (-2.396), indicating better solubility.

**hERG Inhibition:** Both ligands have similar and acceptable hERG inhibition liability (0.433 and 0.437).

**Microsomal Clearance:** Ligand A (29.456) has a significantly better microsomal clearance than Ligand B (-4.202). A lower value is better, indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-21.549) has a much better in vitro half-life than Ligand B (12.181). A longer half-life is desirable.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.172 and 0.017).

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.6). However, the difference is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Overall:** Ligand A demonstrates superior ADME properties (TPSA, QED, solubility, permeability, metabolic stability, half-life) and acceptable potency. While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A in other crucial parameters make it the more promising drug candidate.

Output:
1
2025-04-17 15:55:23,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.399 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (68.84) is better than Ligand B (80.32). Lower TPSA generally favors oral absorption.

**logP:** Ligand A (1.939) is within the optimal range (1-3), while Ligand B (3.553) is at the higher end. This could potentially lead to solubility issues for Ligand B.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.733, B: 0.661), indicating good drug-likeness.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (36.293). This is a significant concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 76.076, B: 72.237), but this is less critical for a non-CNS target like SRC.

**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, the values are similar.

**Aqueous Solubility:** Ligand A (-1.833) has better solubility than Ligand B (-3.853). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.412, B: 0.596).

**Microsomal Clearance:** Ligand B (79.259) has a significantly higher microsomal clearance than Ligand A (31.21). This indicates lower metabolic stability for Ligand B, a major drawback for an enzyme target.

**In vitro Half-Life:** Ligand A (-44.371) has a much longer in vitro half-life than Ligand B (53.336). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.244, B: 0.211).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a considerably stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a crucial factor, and the 1.4 kcal/mol difference is substantial.

**Conclusion:**

Despite the higher DILI risk, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.7 vs -8.3 kcal/mol) and much better metabolic stability (lower Cl_mic, longer t1/2) outweigh the DILI concern. The better solubility and TPSA also contribute to its favorability. While the negative Caco-2 values are concerning, they are similar for both compounds.

Output:
0
2025-04-17 15:55:23,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Ligand A (342.355 Da) is well within the ideal range (200-500 Da). Ligand B (466.954 Da) is at the upper limit, but still acceptable.

**TPSA:** Ligand A (120.16) is good for oral absorption, being under 140. Ligand B (93.55) is excellent.

**logP:** Ligand A (-1.085) is a bit low, potentially hindering permeability. Ligand B (5.249) is quite high, raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 4 HBA) is good. Ligand B (2 HBD, 9 HBA) is also acceptable, though the higher HBA count could slightly impact permeability.

**QED:** Both ligands (A: 0.388, B: 0.401) have relatively low QED scores, indicating they are not particularly drug-like, but this isn't a dealbreaker at this stage.

**DILI:** Ligand A (47.887) has a good DILI risk profile (below 60). Ligand B (90.074) has a significantly higher DILI risk, which is concerning.

**BBB:** Both ligands have low BBB penetration (A: 29.12, B: 27.569), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.495 and -5.592), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.779 and -3.832). This is a major issue for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.031) has very low hERG risk, which is excellent. Ligand B (0.84) has a moderate hERG risk, which is less ideal.

**Microsomal Clearance:** Ligand A (-22.606) has very low microsomal clearance, indicating high metabolic stability, which is a major plus. Ligand B (22.682) has moderate clearance, less favorable.

**In vitro Half-Life:** Ligand A (-19.905) has a very long in vitro half-life, further supporting its favorable metabolic stability. Ligand B (23.604) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.009, B: 0.869).

**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 its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher logP, and moderate metabolic clearance. Ligand A has better ADME properties (lower DILI, better metabolic stability, lower hERG risk), but its binding affinity is weaker and its logP is low, and both have poor solubility and permeability.

Despite the poor solubility and permeability of both, the significantly improved binding affinity of Ligand B, coupled with acceptable (though not ideal) metabolic stability, makes it the more promising candidate. Further optimization could focus on improving its solubility and reducing the DILI risk.

Output:
1
2025-04-17 15:55:23,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.551 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (112.73). A TPSA under 140 is good for oral absorption, but A is much closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.656) is optimal (1-3), while Ligand B (0.766) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.67 and 0.602), indicating good drug-likeness.

**DILI:** Ligand A (4.343) has a much lower DILI risk than Ligand B (14.889), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (62.156) is better than Ligand B (53.625).

**Caco-2 Permeability:** Ligand A (-4.772) and Ligand B (-5.286) both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the values are close.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.893 and -1.807). This is a major drawback for both compounds and would require formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.41 and 0.343), which is good.

**Microsomal Clearance:** Ligand A (24.443) has a slightly higher microsomal clearance than Ligand B (19.387), suggesting slightly lower metabolic stability. However, both are reasonably good.

**In vitro Half-Life:** Ligand B (-12.889) has a negative half-life, which is concerning and suggests rapid degradation. Ligand A (4.358) is much better.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.006 and 0.037).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), a difference of 1 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better across multiple crucial ADME properties. Specifically, the much lower DILI risk, better TPSA, and significantly better in vitro half-life of Ligand A outweigh the small difference in binding affinity. The poor solubility is a concern for both, but can be addressed with formulation. Ligand B's negative half-life is a major red flag.

Output:
1
2025-04-17 15:55:23,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.39 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 A (68.18) is slightly higher than Ligand B (62.3), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.026) is slightly better than Ligand B (3.347), which is approaching the upper limit and could potentially cause solubility issues.

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD and HBA counts. Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. This is not a major differentiating factor.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.872) is significantly better than Ligand B (0.582).

**DILI:** Both ligands have low DILI risk, with Ligand A (46.142) being slightly better than Ligand B (41.838).

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (79.992) is better than Ligand B (67.158). While not a primary concern for a kinase inhibitor, better BBB penetration could be advantageous.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests poor permeability. However, the scale is not specified, and negative values may represent a different type of measurement. This is difficult to interpret without more information.

**Aqueous Solubility:** Both ligands have negative aqueous solubility values, which is also unusual and suggests poor solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Ligand A (0.325) has a much lower hERG inhibition liability than Ligand B (0.542), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-5.749) has a much lower (better) microsomal clearance than Ligand B (36.094), indicating greater metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (28.691) has a significantly longer in vitro half-life than Ligand B (11.024), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.053) has much lower P-gp efflux liability than Ligand B (0.448), which is favorable for bioavailability.

**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 difference and a major advantage for Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.9 vs -10.3 kcal/mol). However, Ligand A excels in almost all ADME-Tox properties: QED, DILI, hERG, microsomal clearance, in vitro half-life, and P-gp efflux. The improved metabolic stability (lower Cl_mic and longer t1/2) and reduced toxicity (lower hERG and DILI) of Ligand A are particularly important for kinase inhibitors, which often require chronic administration. While the affinity difference is substantial, the ADME profile of Ligand A is far superior. Given the importance of metabolic stability and safety for a kinase inhibitor, the superior ADME profile of Ligand A outweighs the affinity difference.

Output:
0
2025-04-17 15:55:23,032 - INFO - Batch 420 complete. Total preferences: 6720
2025-04-17 15:55:23,032 - INFO - Processing batch 421/512...
2025-04-17 15:56:03,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447 Da) is slightly better positioned.

**TPSA:** Ligand B (64.55) is significantly better than Ligand A (87.46), falling well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (0.789) is a bit low, potentially hindering permeation. Ligand B (3.209) is optimal.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is good.

**QED:** Both ligands have acceptable QED values (A: 0.646, B: 0.57), indicating reasonable drug-likeness.

**DILI:** Ligand A (23.032) has a much lower DILI risk than Ligand B (80.807). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (93.486) has a higher BBB score, but it's not a primary concern here.

**Caco-2 Permeability:** Ligand B (-4.451) is better than Ligand A (-5.282), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.13) is better than Ligand B (-4.574), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.185, B: 0.53).

**Microsomal Clearance:** Ligand A (17.07 mL/min/kg) is much better than Ligand B (102.009 mL/min/kg), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (35.992 hours) has a much longer half-life than Ligand B (-12.273 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.067, B: 0.317).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (A: -8.6 kcal/mol, B: -8.1 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better aqueous solubility. While Ligand B has a slightly better logP and Caco-2 permeability, these are outweighed by the advantages of Ligand A in terms of safety and pharmacokinetic properties, which are crucial for enzyme inhibitors. The binding affinity difference is minimal.

Output:
0
2025-04-17 15:56:03,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.379 and 346.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (128.39) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (61.28) is well within the optimal range.

**3. logP:** Ligand A (-0.144) is quite low, potentially hindering permeability. Ligand B (3.909) is near the upper limit of optimal (1-3) but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBDs, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 5, both within the acceptable limit of <=10.

**6. QED:** Ligand B (0.846) has a significantly better QED score than Ligand A (0.361), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 46.452, Ligand B: 39.434), below the 60 threshold.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (83.288) is notably higher than Ligand A (65.335). While not a primary concern for a kinase inhibitor, higher BBB is never a detriment.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.152 and -5.043). This is unusual and suggests poor permeability *in vitro*. However, these values are on a log scale and can be misleading.

**10. Aqueous Solubility:** Both have negative solubility values (-1.896 and -3.323). Similar to Caco-2, this suggests poor solubility, which is a significant concern for oral bioavailability.

**11. hERG Inhibition:** Ligand A (0.121) has a slightly lower hERG risk than Ligand B (0.886), which is favorable.

**12. Microsomal Clearance:** Ligand B (43.583) has a lower (better) microsomal clearance than Ligand A (23.808), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (47.812 hours) has a much longer half-life than Ligand A (2.077 hours), a significant advantage for dosing convenience.

**14. P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux, while Ligand B (0.751) has moderate efflux. Lower efflux is generally preferred.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial factor, and a difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

Despite the poor solubility and permeability indicated by the Caco-2 and solubility values, Ligand A's significantly superior binding affinity (-9.5 kcal/mol vs -0.0 kcal/mol) is the dominating factor. The binding affinity difference is so large that it is likely to overcome the solubility/permeability issues, especially considering that formulation strategies can often address solubility concerns. Ligand B has a better ADME profile overall, but its weak binding affinity makes it unlikely to be effective *in vivo*.

Output:
0
2025-04-17 15:56:03,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.5 and 353.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.88) is slightly higher than the preferred <140, but still reasonable. Ligand B (59) is excellent, well below 90, suggesting good permeability.

**logP:** Both ligands (2.71 and 2.75) 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 similar QED values (0.695 and 0.682), indicating good drug-likeness.

**DILI:** Ligand A (32.88) has a slightly higher DILI risk than Ligand B (13.34), but both are below the concerning threshold of 40, indicating low risk.

**BBB:** Ligand A (46.03) has a lower BBB penetration percentile than Ligand B (78.56). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.08) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.49) is also negative, but less so.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.69 and -2.29), indicating poor aqueous solubility. This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Ligand A (0.32) has a lower hERG inhibition risk than Ligand B (0.77), which is preferable.

**Microsomal Clearance:** Ligand A (29.95) has significantly lower microsomal clearance than Ligand B (54.79). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-7.92) has a more negative value, which translates to a longer in vitro half-life than Ligand B (23.30). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.675), which is good.

**Binding Affinity:** Ligand B (-8.9) has a slightly stronger binding affinity than Ligand A (-8.5), but the difference is less than 1.5 kcal/mol.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower hERG risk. The negative Caco-2 values are concerning for both, but the superior metabolic profile of Ligand A, crucial for an enzyme inhibitor, outweighs the slightly weaker binding.

Output:
0
2025-04-17 15:56:03,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 significantly better than Ligand B (53.43). Lower TPSA generally correlates with better cell permeability, crucial for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have logP values (3.827 and 4.145) within the optimal range (1-3), suggesting good partitioning properties. Ligand B is slightly higher, which *could* lead to some off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (2 for A, 4 for B) counts, balancing solubility and permeability.

**QED:** Ligand A (0.922) has a significantly higher QED score than Ligand B (0.769), indicating a more drug-like profile overall.

**DILI:** Ligand B (46.452) has a lower DILI risk than Ligand A (33.695), which is a positive attribute.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.088) has better BBB penetration than Ligand B (49.748), but this isn't a major factor in this case.

**Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scale where lower values are worse. Ligand A (-5.015) is better than Ligand B (-5.294).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.133 and -4.686). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.857 and 0.704), which is excellent.

**Microsomal Clearance:** Ligand B (91.761) has a significantly higher microsomal clearance than Ligand A (50.748), indicating lower metabolic stability. This is a major concern for Ligand B.

**In vitro Half-Life:** Ligand A (5.498 hours) has a much longer in vitro half-life than Ligand B (-27.172 hours). The negative value for B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.65 and 0.546), which is favorable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). This 1.1 kcal/mol difference is substantial and could potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Despite Ligand B's better binding affinity, the significantly worse metabolic stability (high Cl_mic, very short half-life) and poor solubility are major concerns. Ligand A, while having slightly weaker binding, presents a much more balanced profile with better metabolic stability, solubility (though still poor), and a higher QED score. For an enzyme target like SRC kinase, metabolic stability is paramount.

Output:
0
2025-04-17 15:56:03,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.439 and 386.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (98.25 and 101.41) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (target <90). This is less critical for a non-CNS target like SRC.

**logP:** Both ligands (1.737 and 1.183) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are acceptable values.

**QED:** Ligand A (0.567) has a better QED score than Ligand B (0.402), indicating a more drug-like profile.

**DILI:** Ligand A (79.372) has a significantly higher DILI risk than Ligand B (39.511). This is a major concern.

**BBB:** This is less important for SRC, but Ligand A (60.915) has a slightly better BBB score than Ligand B (43.815).

**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 (0.146 and 0.115) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (99.973) has a very high microsomal clearance, suggesting poor metabolic stability. Ligand B (17.623) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.449) has a very short in vitro half-life, consistent with high clearance. Ligand B (-1.098) has a slightly longer half-life.

**P-gp Efflux:** Both ligands (0.174 and 0.009) have low P-gp efflux, which is favorable.

**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.

**Conclusion:**

Despite the slightly better affinity of Ligand B and its significantly lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2), the negative Caco-2 and solubility values for both are concerning. However, the DILI and metabolic stability issues with Ligand A are more critical. The high DILI risk and poor metabolic stability of Ligand A make it a less desirable candidate. Ligand B, while having poor permeability and solubility, is more likely to be a viable starting point for optimization due to its better safety and PK profile.

Output:
1
2025-04-17 15:56:03,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.391 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.57) is slightly above the preferred <140, while Ligand B (88.33) is well within the range.

**logP:** Ligand A (0.326) is quite low, potentially hindering permeability. Ligand B (2.111) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 8 HBA, which is acceptable. Ligand B has 5 HBA, which is also acceptable.

**QED:** Both ligands have good QED scores (0.672 and 0.779, respectively), suggesting good drug-like properties.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (51.609), though both are reasonably acceptable.

**BBB:** Both have acceptable BBB penetration, but Ligand B (73.866) is slightly better than Ligand A (68.476). This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 (0.051) has a very low hERG risk, which is excellent. Ligand B (0.28) is also low, but higher than Ligand A.

**Microsomal Clearance:** Ligand A (23.142) has much lower microsomal clearance than Ligand B (52.845), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (1.007) has a very short half-life, while Ligand B (18.189) has a much longer half-life.

**P-gp Efflux:** Ligand A (0.058) has very low P-gp efflux, while Ligand B (0.114) is slightly higher.

**Binding Affinity:** Both have excellent binding affinities (-9 and -8.3 kcal/mol). Ligand A is slightly better (-9 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic) and P-gp efflux. However, it has a very short half-life, low logP, and negative Caco-2 and solubility values. Ligand B has a longer half-life, better logP, and is slightly better in terms of DILI and BBB. The negative Caco-2 and solubility values for both are concerning, but the superior metabolic stability of Ligand A is a significant advantage for an enzyme inhibitor, potentially allowing for a lower dose and less frequent administration. The slightly better binding affinity of Ligand A further supports its selection.

Output:
0
2025-04-17 15:56:03,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.495 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.27) is better than Ligand B (91.84). TPSA <140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Ligand A (2.573) is optimal (1-3), while Ligand B (0.498) 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 have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.845 and 0.757), indicating good drug-likeness.

**DILI:** Ligand A (38.852) has a significantly lower DILI risk than Ligand B (62.001). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (57.154 and 55.254), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.228 and -5.117), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.32 and -2.285), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.099) has a much lower hERG risk than Ligand B (0.153). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (23.331) has lower microsomal clearance than Ligand B (26.821), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.937) has a significantly longer in vitro half-life than Ligand B (-19.307). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.056).

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a considerably stronger binding affinity than Ligand B (-6.3 kcal/mol). This is the most important factor, as a 3.5 kcal/mol difference is substantial.

**Conclusion:**

Ligand A is significantly better than Ligand B. It has a much stronger binding affinity, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more optimal logP value. While both have issues with Caco-2 and solubility, the superior potency and safety profile of Ligand A outweigh these concerns.

Output:
1
2025-04-17 15:56:03,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 358.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is better than Ligand B (33.2). Both are well below the 140 A^2 threshold for oral absorption, and suitable for kinase inhibitors.

**logP:** Ligand A (2.215) is optimal (1-3), while Ligand B (4.512) is slightly high. This could lead to solubility issues and off-target effects for Ligand B.

**H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are well below the 10 threshold.

**QED:** Both ligands have similar QED values (0.792 and 0.726), indicating good drug-likeness.

**DILI:** Ligand A (37.069) has a slightly higher DILI risk than Ligand B (17.371), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration, but Ligand A (90.074) is better than Ligand B (74.641). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.672 and -4.663). This is unusual and suggests poor permeability. It's possible these values are errors or indicate a specific transport issue.

**Aqueous Solubility:** Ligand A (-2.163) has better solubility than Ligand B (-5.228). Solubility is important for bioavailability.

**hERG:** Ligand A (0.352) has a lower hERG risk than Ligand B (0.517), which is preferable.

**Microsomal Clearance:** Ligand A (59.845) has lower microsomal clearance than Ligand B (62.544), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.047) has a longer half-life than Ligand B (17.811). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux than Ligand B (0.605), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.3). However, the difference is only 0.6 kcal/mol.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties: better solubility, lower hERG risk, lower clearance (better metabolic stability), longer half-life, and lower P-gp efflux. The slightly higher DILI risk for Ligand A is less concerning than the higher logP and P-gp efflux of Ligand B. The negative Caco-2 values for both are a concern, but the other advantages of Ligand A outweigh this issue, especially given the slightly better solubility.

Output:
0
2025-04-17 15:56:03,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.455 and 347.449 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.57) is significantly better than Ligand B (12.47), being well below the 140 threshold for oral absorption. Ligand B is very low, which could be beneficial, but extremely low TPSA can sometimes indicate poor binding.

**logP:** Ligand A (1.957) is optimal (1-3). Ligand B (4.879) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD (0) and HBA (5 for A, 2 for B) counts, well within the guidelines.

**QED:** Ligand A (0.784) has a better QED score than Ligand B (0.491), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (12.679 and 11.245), which is excellent.

**BBB:** Both have reasonable BBB penetration (73.439 and 88.29), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.655 and -4.426), which is unusual and problematic. It suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.624 and -4.605), which is also concerning and indicates very poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.878 and 0.964), which is favorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (45.176 and 45.075 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-1.273 hours) has a very short half-life, while Ligand B (-4.3 hours) is also short but slightly better. Both are poor.

**P-gp Efflux:** Both ligands exhibit low P-gp efflux (0.125 and 0.685), which is good.

**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 drawbacks.

**Conclusion:**

Despite the concerning negative Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its superior binding affinity (-8.8 vs -7.9 kcal/mol) is a significant advantage for an enzyme target like SRC kinase. It also has a better QED score and slightly better BBB penetration. While the short half-life is a concern for both, the stronger binding of Ligand A suggests it might still be effective at lower doses or with modified formulations. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the potency advantage of Ligand A makes it the better starting point.

Output:
0
2025-04-17 15:56:03,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.949 and 369.981 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is higher than Ligand B (30.29). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Both ligands have logP values (4.397 and 4.905) that are slightly above the optimal 1-3 range, but not dramatically so. Ligand B is a bit higher, potentially increasing off-target interactions or solubility issues.

**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 and <=10 HBA).

**QED:** Ligand A (0.717) has a better QED score than Ligand B (0.587), indicating a more drug-like profile.

**DILI:** Ligand A (22.102) has a significantly lower DILI risk than Ligand B (5.777), a crucial advantage.

**BBB:** Both ligands have high BBB penetration (88.717 and 89.725), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.597 and -4.793). This 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 very poor aqueous solubility (-3.255 and -4.149). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.849 and 0.919).

**Microsomal Clearance:** Ligand A (34.117) has a lower microsomal clearance than Ligand B (52.444), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (109.248 hours) has a much longer in vitro half-life than Ligand B (42.691 hours), a substantial benefit.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.398 and 0.583).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and higher QED score outweigh the slightly higher TPSA and logP. The binding affinity difference is particularly compelling for an enzyme target like SRC kinase. Addressing the solubility issues through formulation strategies would be a priority in further development.

Output:
1
2025-04-17 15:56:03,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.404 and 354.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.36) is well below the 140 limit and good for oral absorption. Ligand B (104.53) is still under the limit, but higher, potentially impacting absorption slightly.

**logP:** Ligand A (4.467) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.613) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 2/3 HBA, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.727 and 0.647), indicating good drug-likeness.

**DILI:** Ligand A (30.399) has a low DILI risk, which is excellent. Ligand B (16.208) also has a low DILI risk.

**BBB:** Both have reasonable BBB penetration, but Ligand A (85.072) is better than Ligand B (74.564). However, BBB is less critical for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-4.509) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.032) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.906) has poor aqueous solubility, consistent with its high logP. Ligand B (-2.349) has better solubility.

**hERG:** Ligand A (0.865) has a slightly elevated hERG risk, but still relatively low. Ligand B (0.184) has a very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (36.924) has moderate clearance, suggesting moderate metabolic stability. Ligand B (40.634) has slightly higher clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (34.47) has a reasonable half-life. Ligand B (1.483) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both have low P-gp efflux.

**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 advantage, potentially outweighing some of its other weaknesses.

**Conclusion:**

Despite Ligand A's higher logP and lower solubility/permeability, its *much* stronger binding affinity (-9.6 vs -6.9 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The difference in affinity is large enough to overcome the ADME liabilities. Ligand B's better solubility and lower hERG risk are positive, but the weak binding affinity makes it unlikely to be effective *in vivo*.

Output:
1
2025-04-17 15:56:03,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.419 and 392.262 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is slightly higher than Ligand B (81.33), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.72) is a bit low, potentially hindering permeation. Ligand B (1.106) is within the optimal 1-3 range. This favors Ligand B.

**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 below the 10 threshold.

**QED:** Both ligands have good QED scores (0.657 and 0.736), indicating drug-likeness.

**DILI:** Ligand A (26.173) has a significantly lower DILI risk than Ligand B (47.693), which is a major advantage.

**BBB:** Ligand A (46.026) has lower BBB penetration than Ligand B (63.125). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-5.326 and -5.308). This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.062 and -2.934). This is a concern for both, but Ligand B is worse.

**hERG Inhibition:** Ligand A (0.086) has a very low hERG risk, while Ligand B (0.341) is slightly higher. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-10.797) has a much lower (better) microsomal clearance than Ligand B (-30.761), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (14.846) has a longer half-life than Ligand B (-12.708), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.006 and 0.052), which is good.

**Binding Affinity:** Both have excellent binding affinity (-8.9 and -8.5 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have poor Caco-2 permeability and solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a lower hERG risk. The slightly better binding affinity of Ligand A reinforces this decision. The logP of Ligand A is a slight concern, but the benefits in ADME and toxicity outweigh this drawback.

Output:
0
2025-04-17 15:56:03,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.455 and 358.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is better than Ligand B (95.94). Lower TPSA generally favors better absorption, though it's not a strict requirement for kinases.

**logP:** Ligand A (3.27) is optimal, while Ligand B (1.193) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.828) has a significantly better QED score than Ligand B (0.572), indicating a more drug-like profile.

**DILI:** Ligand A (52.074) has a moderate DILI risk, while Ligand B (12.718) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Ligand A (-3.346) has worse solubility than Ligand B (-0.81). Solubility is important for kinases, so Ligand B is favored.

**hERG:** Both ligands have very low hERG inhibition risk (0.052 and 0.176), which is excellent.

**Microsomal Clearance:** Ligand A (35.811) has lower microsomal clearance than Ligand B (78.887), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-22.921) has a longer in vitro half-life than Ligand B (-29.451), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.018 and 0.023).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is the most important factor for an enzyme target. A 0.6 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A excels in binding affinity and metabolic stability (lower Cl_mic, longer t1/2), and has a better QED score. While its solubility is worse than Ligand B, its superior potency and metabolic profile outweigh this drawback. Ligand B has a better DILI score and slightly better solubility, but its lower binding affinity and poorer QED are significant disadvantages. Given the enzyme-specific priorities, the stronger binding affinity of Ligand A is the deciding factor.

Output:
1
2025-04-17 15:56:03,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.34 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (90.17 and 88.1) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.166) is optimal, while Ligand B (1.044) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands (0.572 and 0.603) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (69.329) has a higher DILI risk than Ligand B (7.29). This is a significant drawback for Ligand A.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (81.815) is higher than Ligand B (73.866).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.857 and -4.92), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.325 and -1.012), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.728) has a slightly higher hERG risk than Ligand B (0.263).

**Microsomal Clearance:** Ligand B (-4.795) has significantly lower (better) microsomal clearance than Ligand A (34.108), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (18.738) has a longer half-life than Ligand A (47.706).

**P-gp Efflux:** Ligand A (0.547) has a higher P-gp efflux liability than Ligand B (0.049).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a stronger binding affinity than Ligand B (-6.4 kcal/mol). The difference is 1.1 kcal/mol, which is substantial.

**Conclusion:**

Despite Ligand A's superior binding affinity, the significantly higher DILI risk, higher hERG risk, and much poorer metabolic stability (higher Cl_mic, shorter half-life) make it a less desirable candidate. Ligand B, while having a slightly weaker binding affinity, exhibits a much more favorable ADME-Tox profile, particularly its low DILI risk and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are paramount.

Output:
1
2025-04-17 15:56:03,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.33 and 340.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.39) is higher than Ligand B (66.48). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Both ligands have good logP values (1.634 and 2.167), 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:** Ligand A (0.634) has a better QED score than Ligand B (0.448), indicating a more drug-like profile.

**DILI:** Ligand B (34.742) has a significantly lower DILI risk than Ligand A (87.01), which is a major advantage.

**BBB:** Ligand A (67.623) has a lower BBB penetration than Ligand B (76.929). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.678 and -4.632). This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.89 and -3.401). This is a concern, but can potentially be addressed through formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.239 and 0.297), which is excellent.

**Microsomal Clearance:** Ligand B (48.014) has a lower microsomal clearance than Ligand A (65.988), indicating better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-38.58) has a significantly longer in vitro half-life than Ligand A (24.101), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.174).

**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, as a 1.3 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in the most critical areas for an enzyme target: significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and, most importantly, a substantially stronger binding affinity. The slightly better QED of Ligand A is outweighed by these factors.

Output:
1
2025-04-17 15:56:03,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.547 and 345.399 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is well below the 140 threshold, suggesting good absorption. Ligand B (104.46) is also below the threshold, but higher than A, potentially impacting absorption slightly.

**logP:** Ligand A (4.774) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.775) is quite low, which may impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is within the acceptable ranges. Ligand B (3 HBD, 5 HBA) is also acceptable, but has more potential for off-target interactions.

**QED:** Ligand A (0.725) has a good drug-likeness score. Ligand B (0.574) is acceptable, but less optimal.

**DILI:** Ligand A (11.361) has a very low DILI risk, which is excellent. Ligand B (39.977) is also relatively low risk, but higher than A.

**BBB:**  BBB is not a primary concern for a kinase inhibitor, but Ligand A (77.743) has a better percentile than Ligand B (27.336).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.549) is slightly better than Ligand B (-4.962).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.871) is slightly better than Ligand B (-2.112).

**hERG Inhibition:** Ligand A (0.771) has a low hERG risk. Ligand B (0.132) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (66.366) has a moderate clearance, while Ligand B (15.468) has a very low clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (3.744 hours) has a short half-life. Ligand B (-14.442 hours) has a negative half-life, which is not physically possible and likely an error in the data.

**P-gp Efflux:** Ligand A (0.188) has low P-gp efflux. Ligand B (0.052) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a strong binding affinity. Ligand B (0.0 kcal/mol) has no binding affinity.

**Conclusion:**

Despite Ligand A having a slightly higher logP, its significantly superior binding affinity (-7.1 vs 0.0 kcal/mol) and lower DILI risk outweigh the potential drawbacks. The negative half-life for Ligand B is a critical flaw, indicating a data error or a fundamentally unstable molecule. Therefore, Ligand A is the more promising candidate.

Output:
0
2025-04-17 15:56:03,171 - INFO - Batch 421 complete. Total preferences: 6736
2025-04-17 15:56:03,171 - INFO - Processing batch 422/512...
2025-04-17 15:56:44,621 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (432.746 Da) is slightly higher, but acceptable. Ligand B (343.402 Da) is also good.

**TPSA:** Both ligands have TPSA values (72.88 and 71.09 respectively) below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 2.769 and Ligand B at 3.312. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still within acceptable limits.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4/3 HBA, respectively, which are within the recommended limits.

**QED:** Both ligands have good QED scores (0.723 and 0.845), indicating a generally drug-like profile.

**DILI:** Ligand A (42.652) has a significantly lower DILI risk than Ligand B (61.303). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (73.517) shows better BBB penetration than Ligand A (51.609).

**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:** Both ligands have low hERG inhibition liability (0.468 and 0.771), which is excellent.

**Microsomal Clearance (Cl_mic):** Ligand A (1.384 mL/min/kg) has a much lower microsomal clearance than Ligand B (40.166 mL/min/kg). This indicates better metabolic stability for Ligand A, a crucial factor for an enzyme target.

**In vitro Half-Life (t1/2):** Ligand A (-20.877 hours) has a negative half-life, which is impossible. Ligand B (33.482 hours) has a reasonable half-life. The negative value for Ligand A is a significant red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.353), which is favorable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.5 and -8.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other considerations.

**Conclusion:**

Despite similar binding affinities, Ligand A is the more promising candidate. Its significantly lower DILI risk and much better metabolic stability (lower Cl_mic) are critical advantages for an enzyme target. The negative half-life value for Ligand A is concerning and should be investigated, but the other favorable properties make it preferable. Ligand B's higher DILI risk and rapid clearance are significant drawbacks.

Output:
0
2025-04-17 15:56:44,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.478 and 355.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is well below the 140 threshold and favorable for oral absorption. Ligand B (125.13) is still within acceptable limits, but less optimal.

**logP:** Ligand A (1.573) is within the optimal 1-3 range. Ligand B (-0.469) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 7 HBA) both adhere to the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have a QED of 0.63, indicating good drug-like properties.

**DILI:** Ligand A (35.789) has a lower DILI risk than Ligand B (29.973), which is preferable.

**BBB:** Ligand A (74.254) has a better BBB penetration score than Ligand B (42.497), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.823) and Ligand B (-4.964) have similar, negative Caco-2 values, suggesting poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.953) and Ligand B (-1.02) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.171 and 0.143 respectively), which is excellent.

**Microsomal Clearance:** Ligand B (-10.218) has significantly lower (better) microsomal clearance than Ligand A (57.048), suggesting greater metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-2.759) has a longer in vitro half-life than Ligand A (-8.436), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.019 respectively), which is good.

**Binding Affinity:** Both ligands have a strong binding affinity (-8.2 and -8.5 kcal/mol), with Ligand B being slightly better. The affinity difference is not large enough to overcome significant ADME issues.

**Conclusion:**

While both compounds have good binding affinity and low hERG risk, Ligand B is the more promising candidate. Its significantly improved metabolic stability (lower Cl_mic and longer t1/2) is crucial for an enzyme target. Although both have poor solubility and permeability, metabolic stability is often easier to address through formulation or prodrug strategies than fundamentally changing the core structure to improve permeability. The slightly better affinity of Ligand B is a bonus.

Output:
1
2025-04-17 15:56:44,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 353.413 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (61.88 and 62.13) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (0.716) is within the optimal 1-3 range. Ligand B (4.205) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-like properties.

**DILI:** Ligand A (7.445 percentile) has a significantly lower DILI risk than Ligand B (53.47 percentile). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (75.107 and 73.827 percentiles), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.686 and -4.889) which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.476 and -3.907), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.333) has a much lower hERG inhibition liability than Ligand B (0.715). This is a crucial advantage for Ligand A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (4.052 mL/min/kg) has a lower microsomal clearance than Ligand B (76.32 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-7.212 hours) has a significantly longer in vitro half-life than Ligand B (-13.423 hours). This is a substantial benefit for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.017) has much lower P-gp efflux liability than Ligand B (0.387), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). This 1.8 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both ligands suffer from poor solubility and permeability, Ligand A demonstrates significantly better ADME properties: lower DILI risk, lower hERG inhibition, lower microsomal clearance (better metabolic stability), longer half-life, lower P-gp efflux, and slightly better binding affinity. The substantial differences in DILI, hERG, and metabolic stability are particularly important for an oncology target where chronic dosing is often required.

Output:
0
2025-04-17 15:56:44,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.296 Da) is at the higher end, while Ligand B (350.463 Da) is more favorably positioned.

**TPSA:** Ligand A (123.29) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (84.42) is excellent, well below 140, suggesting good absorption potential.

**logP:** Ligand A (0.747) is a bit low, potentially hindering permeability. Ligand B (1.606) 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 5 HBA, also acceptable.

**QED:** Both ligands have similar, good QED values (0.621 and 0.648, respectively).

**DILI:** Ligand A has a high DILI risk (89.88%), which is a significant concern. Ligand B has a very low DILI risk (25.436%), a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (59.054) than Ligand A (39.318), but this is less critical.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-5.665), indicating poor absorption. Ligand B shows better permeability (-4.896), but still not great.

**Aqueous Solubility:** Ligand A has very poor aqueous solubility (-2.472). Ligand B has slightly better solubility (-0.571), but still quite low.

**hERG Inhibition:** Ligand A has a very low hERG risk (0.047), which is excellent. Ligand B has a slightly higher hERG risk (0.192), but still acceptable.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (10.905 mL/min/kg) suggesting better metabolic stability. Ligand B has a higher Cl_mic (39.678 mL/min/kg), indicating faster metabolism.

**In vitro Half-Life:** Ligand A has a shorter half-life (16.614 hours) than Ligand B (18.961 hours).

**P-gp Efflux:** Ligand A shows minimal P-gp efflux (0.09). Ligand B shows even less efflux (0.016), which is favorable.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.2 kcal/mol) compared to Ligand B (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A possesses a much stronger binding affinity, which is the most critical factor for an enzyme inhibitor. However, its high DILI risk, poor solubility, and poor Caco-2 permeability are major liabilities. Ligand B has a much better safety profile (low DILI), better TPSA and logP, but its binding affinity is very weak.

Considering the priorities for kinase inhibitors, the strong binding affinity of Ligand A is a significant advantage. While the ADME properties are suboptimal, medicinal chemistry efforts could focus on improving solubility and permeability while mitigating the DILI risk. The weak affinity of Ligand B makes it a less promising starting point, even with its better ADME profile.

Output:
1
2025-04-17 15:56:44,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.519 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (53.52), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.124 and 2.402), 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 3 HBAs, 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 (0.657 and 0.73), indicating good drug-like properties.

**DILI:** Ligand A (19.31) has a significantly lower DILI risk than Ligand B (33.501). This is a major advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (82.086) has a lower BBB penetration than Ligand B (93.602). This is not a significant factor in this case.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.585 and -4.973), which is unusual and suggests poor permeability. However, these values are on a log scale and a more negative value indicates lower permeability. Ligand B is slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.185 and -2.256), suggesting poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.583) has a lower hERG inhibition risk than Ligand B (0.898), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (70.729) has a higher microsomal clearance than Ligand B (32.691), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (14.514 hours) has a significantly longer in vitro half-life than Ligand A (1.294 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.346) has lower P-gp efflux than Ligand B (0.111), which is preferable.

**Binding Affinity:** Ligand B (-9.3 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 ADME drawbacks. The difference is >1.5 kcal/mol.

**Conclusion:**

Despite Ligand A's lower DILI and hERG risk, Ligand B possesses a significantly stronger binding affinity (-9.3 vs -7.6 kcal/mol) and a much longer in vitro half-life (14.514 vs 1.294 hours). The potency advantage and improved metabolic stability of Ligand B are critical for an enzyme target like SRC kinase and outweigh the slightly higher DILI and hERG risks. The solubility and permeability issues are similar for both, and can be addressed through formulation strategies.

Output:
1
2025-04-17 15:56:44,622 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, following the provided guidelines.

**Step-by-step comparison:**

1. **MW:** Both A (352.341 Da) and B (348.487 Da) are within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (79.54) is better than Ligand B (49.85) as it is closer to the 140 threshold for oral absorption.

3. **logP:** Ligand B (2.894) is optimal (1-3), while Ligand A (0.667) is a bit low, potentially hindering permeation.

4. **HBD:** Both A (0) and B (0) have no hydrogen bond donors, which is acceptable.

5. **HBA:** Ligand A (5) is slightly higher than Ligand B (3), but both are within the acceptable limit of 10.

6. **QED:** Both A (0.744) and B (0.768) have good drug-likeness scores, exceeding the 0.5 threshold.

7. **DILI:** Ligand B (26.095) has a significantly lower DILI risk than Ligand A (43.66). This is a major advantage for B.

8. **BBB:** Ligand B (86.39) shows better BBB penetration than Ligand A (78.519), but this is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

9. **Caco-2:** Ligand A (-4.692) and B (-4.405) are both negative, indicating poor permeability.

10. **Solubility:** Both A (-2.344) and B (-2.434) have poor solubility.

11. **hERG:** Both A (0.161) and B (0.266) have low hERG inhibition liability, which is good.

12. **Cl_mic:** Ligand A (-1.151) has a *much* lower (better) microsomal clearance than Ligand B (47.903). This suggests significantly better metabolic stability for A.

13. **t1/2:** Ligand B (10.864) has a longer in vitro half-life than Ligand A (-26.295).

14. **Pgp:** Both A (0.034) and B (0.324) have low P-gp efflux liability.

15. **Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial difference (greater than 1.5 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a significantly better binding affinity, and a longer half-life. Ligand A has better metabolic stability (lower Cl_mic) but a significantly weaker affinity. Solubility is poor for both. DILI risk is also much better for Ligand B.

**Conclusion:**

Despite the better metabolic stability of Ligand A, the significantly stronger binding affinity of Ligand B (-8.8 vs -7.0 kcal/mol) and its lower DILI risk outweigh the benefits of A's lower Cl_mic. The improved half-life of B is also a positive. While both have poor solubility and Caco-2 permeability, these can be addressed with formulation strategies.

Output:
1
2025-04-17 15:56:44,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.909 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (109.14). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (1.785) is optimal (1-3), while Ligand B (-0.18) is below 1, potentially hindering permeation. This is a significant drawback for B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) 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 (0.638) has a better QED score than Ligand B (0.477), indicating a more drug-like profile.

**DILI:** Ligand A (20.473) has a much lower DILI risk than Ligand B (44.513), which is a substantial advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (68.127) is better than Ligand B (28.073).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poorer permeability. Ligand A (-5.156) is slightly better than Ligand B (-5.671).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.08) is slightly better than Ligand B (-1.418).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.641 and 0.035 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (1.833) has significantly lower microsomal clearance than Ligand B (-12.708). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (18.642) has a longer in vitro half-life than Ligand B (41.059). This is another positive for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.016 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Overall:**

Ligand A is clearly superior. While both have excellent binding affinity and low hERG/P-gp liabilities, Ligand A excels in crucial ADME properties: better logP, TPSA, QED, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and Caco-2 permeability. Ligand B's low logP and higher DILI risk are significant concerns.

Output:
1
2025-04-17 15:56:44,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.36 and 339.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.28) is slightly above the preferred <140 for good absorption, while Ligand B (93.45) is well within the range.

**logP:** Ligand A (0.211) is quite low, potentially hindering permeability. Ligand B (2.985) is optimal.

**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 (0.706 and 0.802), indicating drug-like properties.

**DILI:** Ligand A (80.341) has a higher DILI risk than Ligand B (69.135), though both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (77.705) has a higher BBB percentile than Ligand A (57.193).

**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 unknown, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.668) has a slightly higher hERG risk than Ligand B (0.536), but both are relatively low.

**Microsomal Clearance:** Ligand A (-3.81) has significantly *lower* (better) microsomal clearance than Ligand B (36.54), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.581) has a longer half-life than Ligand B (-0.123).

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux than Ligand B (0.095), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's lower logP and solubility, its significantly superior binding affinity (-8.1 vs -7.0 kcal/mol) and much better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The difference in binding affinity is substantial (>1.5 kcal/mol) and is the most important factor for an enzyme target. While the negative Caco-2 and solubility values are concerning, these can be addressed through formulation strategies. The slightly higher DILI risk for Ligand A is acceptable given its potency and stability.

Output:
1
2025-04-17 15:56:44,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.909 Da and 369.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (135.18) is still under 140, but higher than A, potentially impacting absorption.

**logP:** Ligand A (1.761) is within the optimal 1-3 range. Ligand B (-1.168) is slightly below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have reasonable QED values (0.627 and 0.537), indicating good drug-like properties.

**DILI:** Ligand A (23.924) has a very low DILI risk, which is excellent. Ligand B (76.076) has a significantly higher DILI risk, which is a major concern.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (66.499) has a better percentile than Ligand B (22.606).

**Caco-2 Permeability:** Ligand A (-5.012) is better than Ligand B (-5.782), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.161) is better than Ligand B (-2.598), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.41 and 0.09), which is positive.

**Microsomal Clearance:** Ligand A (33.624) has a higher clearance than Ligand B (9.262), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (42.771) has a longer half-life than Ligand B (-2.221), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.045).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold that would strongly favor B despite 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 like DILI risk, solubility, and metabolic stability (lower clearance, longer half-life). The DILI risk associated with Ligand B is a major red flag. The better solubility and permeability of Ligand A also contribute to its higher potential for bioavailability.

Output:
0
2025-04-17 15:56:44,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 and 350.459 Da) are within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.64 and 59.08) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.733) is optimal, while Ligand B (1.74) is slightly lower, but still acceptable.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.848) has a better QED score than Ligand B (0.685), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (20.318 and 21.326 percentile), which is good.

**BBB:** Both ligands have good BBB penetration (81.194 and 83.288 percentile), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.365 and -4.528), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.158 and -1.548), indicating poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.397 and 0.361), which is excellent.

**Microsomal Clearance:** Ligand A (51.863 mL/min/kg) has a higher clearance than Ligand B (46.083 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.356 hours) has a negative half-life, which is not physically possible and indicates a potential data error or unusual behavior. Ligand A (10.816 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.092 and 0.095), which is favorable.

**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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B stands out due to its significantly stronger binding affinity (-8.7 kcal/mol vs -7.1 kcal/mol). The difference in affinity is large enough to potentially overcome the ADME liabilities, *assuming* the negative half-life value for Ligand B is a data error. If the half-life is truly negative, it would disqualify Ligand B immediately. However, assuming it's an error, the potency advantage of Ligand B is the deciding factor for further investigation.

Output:
1
2025-04-17 15:56:44,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.897) is slightly higher than Ligand B (340.423), but both are acceptable.

**TPSA:** Ligand A (91.83) is slightly above the preferred <140 for oral absorption, while Ligand B (71.34) is well within the range.

**logP:** Ligand A (3.952) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.737) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.584, B: 0.782), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (97.867) has a very high DILI risk, which is a significant concern. Ligand B (35.401) has a low DILI risk, a major advantage.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**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:** Both ligands have low hERG inhibition risk (A: 0.345, B: 0.505), which is positive.

**Microsomal Clearance:** Ligand A (37.176) has lower microsomal clearance than Ligand B (61.232), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (76.464) has a longer half-life than Ligand B (64.892), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.552, B: 0.284).

**Binding Affinity:** Both have excellent binding affinities (A: -10.1 kcal/mol, B: -10.3 kcal/mol), with Ligand B being slightly better. The affinity difference is small and likely less important than the ADME differences.

**Conclusion:**

Despite similar binding affinities, Ligand B is significantly more promising due to its much lower DILI risk (35.401 vs 97.867) and more favorable logP (2.737 vs 3.952). While both have concerning Caco-2 and solubility values, the high DILI risk of Ligand A is a major red flag. The slightly better metabolic stability and half-life of Ligand A are outweighed by the DILI concern.

Output:
1
2025-04-17 15:56:44,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (340.383 and 364.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (97.12) is slightly higher than the preferred <140, but acceptable. Ligand B (65.98) is well within the acceptable range.

**3. logP:** Ligand A (2.688) is optimal (1-3). Ligand B (0.675) is a bit low, potentially impacting permeability.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 2, Ligand B: 0).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (Ligand A: 5, Ligand B: 6).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.872, Ligand B: 0.769), indicating drug-like properties.

**7. DILI:** Ligand A (60.721) is approaching a concerning DILI risk, while Ligand B (28.383) has a much lower and preferable risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.851) has a higher BBB percentile than Ligand A (65.568).

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. This needs further investigation, but we'll proceed assuming they are both poor.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a significant concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.099, Ligand B: 0.255).

**12. Microsomal Clearance (Cl_mic):** Ligand A (2.215) has a lower (better) clearance than Ligand B (-5.314). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand A (26.851) has a longer half-life than Ligand B (1.776), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.104, Ligand B: 0.044).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.6 kcal/mol), which is the most important factor for an enzyme target. The difference is negligible.

**Enzyme-Specific Prioritization:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both have excellent affinity and low hERG risk, Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a higher DILI risk and both have poor solubility and permeability. Ligand B has a much better DILI profile.

Considering the balance, the better metabolic stability of Ligand A is a significant advantage. However, the DILI risk is concerning. Given the similar binding affinities, the lower DILI risk of Ligand B makes it slightly more promising, despite its lower metabolic stability. The solubility and permeability issues are shared and would need to be addressed in further optimization.

Output:
1
2025-04-17 15:56:44,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (395.575 Da) is slightly higher than Ligand B (347.507 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (62.3) is higher than Ligand B (53.4).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.366) is slightly higher than Ligand B (1.805). While higher logP can sometimes be problematic, it's not a major concern here.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6/5) counts, balancing solubility and permeability.

**QED:** Both ligands have high QED scores (0.815 and 0.817), indicating good drug-like properties.

**DILI:** Ligand A (65.413) has a significantly higher DILI risk than Ligand B (12.059). This is a major concern for Ligand A.

**BBB:** Both ligands show reasonable BBB penetration, but Ligand B (77.2) is significantly higher than Ligand A (57.154). While SRC is not a CNS target, higher BBB penetration generally correlates with better overall drug distribution.

**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, indicating poor aqueous solubility. This is a concern for both, but may be less critical if formulation strategies can be employed.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.54 and 0.528). This is good.

**Microsomal Clearance:** Ligand B (37.067 mL/min/kg) has significantly lower microsomal clearance than Ligand A (78.195 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (18.786 hours) has a much longer in vitro half-life than Ligand A (8.853 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.248 and 0.056).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This 1.2 kcal/mol difference is substantial and outweighs many of the minor ADME drawbacks of Ligand B.

**Conclusion:**

Ligand B is the more promising drug candidate. Despite similar QED and hERG profiles, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and a substantially stronger binding affinity. While both have poor solubility and permeability, the superior potency and safety profile of Ligand B make it the preferred choice.

Output:
1
2025-04-17 15:56:44,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.291 and 365.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.93) is well below the 140 threshold, suggesting good absorption. Ligand B (127.19) is still within acceptable limits but higher, potentially impacting absorption slightly.

**logP:** Ligand A (3.674) is at the higher end of the optimal range (1-3), while Ligand B (2.344) is comfortably within it. The higher logP of A *could* lead to solubility issues, but it's not extreme.

**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, falling within the guidelines.

**QED:** Ligand A (0.561) has a good drug-likeness score, while Ligand B (0.371) is lower, indicating a less favorable overall profile.

**DILI:** Ligand A (91.935) has a significantly higher DILI risk than Ligand B (44.281). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (73.827) has a better BBB score than Ligand B (27.879), but this is less important here.

**Caco-2 Permeability:** Ligand A (-4.713) has poor Caco-2 permeability, while Ligand B (-5.335) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.58) has poor aqueous solubility, while Ligand B (-2.169) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.892) has a lower hERG risk than Ligand B (0.155), which is good.

**Microsomal Clearance:** Ligand A (70.089) has higher microsomal clearance than Ligand B (15.515), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-15.842) has a very short in vitro half-life, while Ligand B (24.014) has a much longer half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.286) has lower P-gp efflux than Ligand B (0.08), which is better.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.2), but both are strong binders. The 1.5 kcal/mol advantage of B is notable.

**Overall Assessment:**

Ligand B is the more promising 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 slightly better binding affinity. Ligand A's high DILI risk and poor metabolic stability are major red flags. The slightly better P-gp efflux of A is not enough to offset these significant liabilities.

Output:
1
2025-04-17 15:56:44,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.243 Da) is slightly higher than Ligand B (362.407 Da), but both are acceptable.

**TPSA:** Ligand A (70.63) is better than Ligand B (87.49). Lower TPSA generally favors better absorption, though this isn't a strict requirement for kinases.

**logP:** Ligand A (3.131) is within the optimal range (1-3), while Ligand B (1.852) is at the lower end. A slightly higher logP is generally preferred for kinases to aid in membrane permeability and target engagement.

**H-Bond Donors/Acceptors:** Both have 0 HBDs, which is good. Ligand A has 6 HBAs, and Ligand B has 7. Both are acceptable (<=10).

**QED:** Ligand A (0.657) has a better QED score than Ligand B (0.443), indicating a more drug-like profile.

**DILI:** Both ligands have high DILI risk (Ligand A: 79.837, Ligand B: 87.902). This is a significant concern and would require further investigation.

**BBB:** Ligand A (80.031) has better BBB penetration than Ligand B (67.933), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.854 and -4.823), which is unusual and suggests poor permeability. This is a major red flag.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.312 and -3.518). This is a significant hurdle for oral bioavailability.

**hERG Inhibition:** Ligand A (0.534) has a lower hERG risk than Ligand B (0.238), which is preferable.

**Microsomal Clearance:** Ligand B (86.914) has a higher microsomal clearance than Ligand A (75.487), meaning Ligand A is more metabolically stable. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-12.042) has a negative in vitro half-life, which is not possible and indicates a data error or a very rapidly metabolized compound. Ligand B (-0.752) is also negative, indicating a very short half-life.

**P-gp Efflux:** Both have low P-gp efflux (0.665 and 0.422), which is good.

**Binding Affinity:** Ligand B (-9.3 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 paramount for an enzyme inhibitor. However, both ligands suffer from poor solubility, permeability, and concerning DILI risk. The negative half-life values are also problematic. Despite the superior binding affinity, the poor ADME properties of Ligand B are concerning. Ligand A has better metabolic stability (lower Cl_mic) and a slightly better QED and hERG profile, but its binding affinity is very weak.

Given the critical importance of potency for kinase inhibitors, and the substantial difference in binding affinity, I would cautiously favor Ligand B *if* the negative half-life and solubility issues could be addressed through formulation or structural modifications. However, the high DILI risk is a major concern for both.

Output:
1
2025-04-17 15:56:44,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.296 Da) is slightly higher than Ligand B (384.933 Da), but both are acceptable.

**TPSA:** Ligand A (123.29) is borderline for good oral absorption, while Ligand B (60.25) is well within the desired range (<140). This favors Ligand B.

**logP:** Ligand A (0.747) is a bit low, potentially hindering permeation. Ligand B (3.747) is near the upper limit of optimal, but still acceptable. 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 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.621 and 0.585), indicating reasonable drug-likeness.

**DILI:** Ligand A has a DILI risk of 89.88, which is high and concerning. Ligand B has a much lower DILI risk of 46.219, which is good. This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (74.254) has better BBB penetration than Ligand A (39.318), but this isn't a primary concern.

**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 can be difficult to interpret without more context.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.472 and -2.572). This is a major drawback for both, but could potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.047) has a very low hERG risk, which is excellent. Ligand B (0.464) has a slightly higher, but still relatively low, hERG risk. This favors Ligand A.

**Microsomal Clearance:** Ligand A (10.905) has lower microsomal clearance, indicating better metabolic stability than Ligand B (84.823). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (16.614 hours) has a longer half-life than Ligand B (34.315 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux, indicating better bioavailability. Ligand B (0.427) has higher P-gp efflux. This favors Ligand A.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has better TPSA, logP, and a significantly lower DILI risk, Ligand A's dramatically superior binding affinity (-9.2 vs -0.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme inhibitor. The hERG risk is also very low for Ligand A. The poor solubility of both is a concern, but formulation strategies could be explored. The strong binding affinity of Ligand A suggests it's more likely to be effective at lower doses, potentially mitigating some of the ADME issues.

Output:
0
2025-04-17 15:56:44,624 - INFO - Batch 422 complete. Total preferences: 6752
2025-04-17 15:56:44,624 - INFO - Processing batch 423/512...
2025-04-17 15:57:29,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (342.37 and 348.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (59.5 and 58.2) are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.563) is optimal, while Ligand B (3.621) is slightly higher but still within the acceptable range of 1-3.

**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 (2) is good.

**6. QED:** Ligand A (0.787) is excellent, indicating strong drug-likeness. Ligand B (0.557) is acceptable, but lower.

**7. DILI:** Ligand A (56.611) has a moderate DILI risk, but is still acceptable. Ligand B (33.23) has a lower DILI risk, which is preferable.

**8. BBB:** Both ligands have high BBB penetration (98.216 and 87.088), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative values (-4.158 and -4.705), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative values (-3.061 and -3.79), indicating very poor aqueous solubility, a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.825 and 0.802).

**12. Microsomal Clearance:** Ligand A (68.543) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (25.972) has significantly lower clearance, indicating better metabolic stability. This is a key advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (-14.411) has a very short half-life, which is concerning. Ligand B (20.833) has a longer half-life, which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.209 and 0.418).

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.3 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 better candidate. It has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. The improved binding affinity is a crucial factor for an enzyme inhibitor, and the better metabolic stability will likely translate to improved *in vivo* exposure.

Output:
1
2025-04-17 15:57:29,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (380.945 Da) is also well within range.

**TPSA:** Ligand A (87.74) is better than Ligand B (43.18) as it is lower, suggesting better absorption.

**logP:** Ligand A (0.433) is quite low, potentially hindering permeability. Ligand B (4.287) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are within acceptable limits. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.752, B: 0.641), indicating good drug-like properties.

**DILI:** Ligand A (19.349) has a significantly lower DILI risk than Ligand B (37.999), which is a major advantage.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (71.462) is slightly better.

**Caco-2 Permeability:** Ligand A (-5.162) has a very poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.954) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.08) has poor solubility, while Ligand B (-4.285) has even worse solubility.

**hERG:** Ligand A (0.164) has a very low hERG risk, which is excellent. Ligand B (0.838) has a higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-10.628) has a very low microsomal clearance, indicating excellent metabolic stability. Ligand B (82.208) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (7.134 hours) has a reasonable half-life. Ligand B (-7.209 hours) has a negative half-life, which is not possible and indicates a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.013, B: 0.73).

**Binding Affinity:** Both ligands have comparable and good binding affinities (A: -8.4 kcal/mol, B: -7.4 kcal/mol). Ligand A is slightly better.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the better candidate. While its logP and solubility are not ideal, its significantly lower DILI risk, excellent metabolic stability (low Cl_mic and good t1/2), very low hERG risk, and slightly better binding affinity outweigh these drawbacks. Ligand B's high DILI risk and poor metabolic stability are major concerns. The Caco-2 permeability of both are poor, but can be addressed with formulation strategies.

Output:
0
2025-04-17 15:57:29,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.365 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is well below the 140 threshold, while Ligand B (69.72) is also acceptable, but higher.

**logP:** Ligand A (3.199) is optimal. Ligand B (1.787) is a bit low, potentially impacting permeability, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, satisfying the <5 and <10 rules respectively.

**QED:** Ligand A (0.904) has a very strong drug-like profile, significantly better than Ligand B (0.76).

**DILI:** Ligand A (48.313) has a low DILI risk, while Ligand B (20.047) is even lower and excellent.

**BBB:** Both have acceptable BBB penetration, but Ligand A (84.102) is better than Ligand B (65.452). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.383) has a very low hERG risk, which is excellent. Ligand B (0.122) is even lower and ideal.

**Microsomal Clearance:** Both have similar microsomal clearance values (Ligand A: 56.045, Ligand B: 54.122). These are relatively low, indicating good metabolic stability.

**In vitro Half-Life:** Both have negative half-life values, which is impossible. This suggests an issue with the data.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.057, Ligand B: 0.085), which is favorable.

**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 could outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its superior binding affinity (-8.6 kcal/mol vs -7.8 kcal/mol), excellent QED score (0.904 vs 0.76), and low hERG risk (0.383 vs 0.122) are key advantages. While both have questionable solubility and permeability data, the potency advantage of Ligand A is critical for an enzyme inhibitor. The slightly better BBB penetration of Ligand A is a minor positive.

Output:
1
2025-04-17 15:57:29,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.385 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.09 and 72.88) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.048 and 1.241) are within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility but potentially lower permeability.

**H-Bond Donors:** Both ligands 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 range (<=10).

**QED:** Both ligands have QED values (0.871 and 0.705) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 54.75, which is good (below 60). Ligand B has a significantly lower DILI risk of 8.026, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.2) has a higher BBB percentile than Ligand B (46.413).

**Caco-2 Permeability:** Ligand A (-4.984) has a more negative Caco-2 value, suggesting lower permeability than Ligand B (-5.394).

**Aqueous Solubility:** Ligand A (-3.302) has a lower solubility than Ligand B (-1.667).

**hERG Inhibition:** Ligand A (0.479) has a lower hERG inhibition risk than Ligand B (0.376), which is preferable.

**Microsomal Clearance:** Ligand A (4.88 mL/min/kg) has a higher microsomal clearance than Ligand B (-0.643 mL/min/kg), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-42.239 hours) has a much longer half-life than Ligand B (-4.39 hours). This is a strong positive for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.09 and 0.012).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a substantially better binding affinity than Ligand B (-8.3 kcal/mol). This is a 1.2 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a longer half-life. However, it suffers from lower solubility, higher clearance, and potentially lower permeability. Ligand B has a much better safety profile (lower DILI), better solubility, and better metabolic stability (lower clearance). The difference in binding affinity is substantial, but the improved ADMET properties of Ligand B are compelling. Given the enzyme-specific priorities, the metabolic stability and safety profile of Ligand B are crucial. While the affinity difference is notable, it might be addressable through further optimization, whereas fixing poor metabolic stability is often more challenging.

Output:
1
2025-04-17 15:57:29,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.455 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (81.08). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.442 and 1.314, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.512 and 0.707), indicating drug-like properties.

**DILI:** Ligand A (15.626) has a considerably lower DILI risk than Ligand B (19.698), which is a significant advantage. Both are below the 40 threshold, but lower is always better.

**BBB:** Ligand A (73.75) has a slightly better BBB penetration percentile than Ligand B (65.839), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.337) has slightly better Caco-2 permeability than Ligand B (-4.639).

**Aqueous Solubility:** Ligand A (-1.759) has slightly better aqueous solubility than Ligand B (-1.464).

**hERG:** Both ligands have very low hERG inhibition liability (0.574 and 0.322), which is excellent.

**Microsomal Clearance:** Ligand A (31.329) has a higher microsomal clearance than Ligand B (8.009), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (4.843) has a longer in vitro half-life than Ligand A (-1.923), which is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.131).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.7 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, solubility and Caco-2 permeability. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), which is a key consideration for kinase inhibitors. The binding affinity is comparable between the two. Given the importance of metabolic stability for enzymes, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 15:57:29,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (336.355 and 350.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.28) is better than Ligand B (128.69). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Both ligands have similar logP values (0.617 and 0.689), which are acceptable but on the lower side. This might slightly hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is preferable to Ligand B (4 HBD, 6 HBA). Lower HBD counts are generally favored for better permeability.

**QED:** Ligand A (0.683) has a significantly better QED score than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Ligand B (54.556) has a much lower DILI risk than Ligand A (85.072), which is a significant advantage.

**BBB:** Ligand A (39.473) has a lower BBB penetration percentile than Ligand B (9.616). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.322 and -5.645), which is unusual and suggests poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.687 and -2.178), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.124) shows slightly lower hERG inhibition risk than Ligand B (0.337), which is preferable.

**Microsomal Clearance:** Ligand B (-10.681) has a significantly *lower* (better) microsomal clearance than Ligand A (9.187), indicating greater metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-7.274) has a much longer in vitro half-life than Ligand A (9.273), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux than Ligand B (0.131), which is slightly favorable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of almost 9 kcal/mol is extremely significant and can outweigh many ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the superior candidate. Its significantly stronger binding affinity (-8.9 vs 0.0 kcal/mol), much lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly less favorable TPSA, BBB, and P-gp values. The strong binding affinity suggests that even with potential permeability issues, Ligand B could achieve sufficient target engagement *in vivo*.

Output:
1
2025-04-17 15:57:29,636 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is slightly higher than Ligand B (84.23), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.122) is within the optimal range, while Ligand B (2.812) is approaching the upper limit.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (2) is also good.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.516 and 0.71), indicating drug-like properties.

**DILI:** Ligand A (22.179) has a significantly lower DILI risk than Ligand B (39.318), which is a major advantage.

**BBB:** Ligand B (71.578) has a higher BBB penetration percentile than Ligand A (30.283), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is more important, and Ligand A (-5.096) is slightly better than Ligand B (-4.726).

**Aqueous Solubility:** Ligand A (-2.243) has slightly better solubility than Ligand B (-4.386), although both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.096 and 0.181).

**Microsomal Clearance:** Ligand A (14.035) has significantly lower microsomal clearance than Ligand B (58.295), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-12.254) has a longer in vitro half-life than Ligand B (-3.09), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.11).

**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 but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. These factors are more critical for an enzyme inhibitor like an SRC kinase inhibitor than a small advantage in binding affinity. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 15:57:29,636 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.362 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.46) is slightly above the preferred <140, but still reasonable. Ligand B (58.64) is well within the acceptable range.

**logP:** Ligand A (1.826) is optimal (1-3). Ligand B (3.125) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, fitting the guidelines. Ligand B has 1 HBD and 4 HBA, also fitting the guidelines.

**QED:** Both ligands have good QED scores (0.532 and 0.873), indicating good drug-like properties.

**DILI:** Ligand A (56.417) has a slightly higher DILI risk than Ligand B (47.15), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (63.784 and 63.009), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.109 and -4.9), which is unusual and suggests poor permeability. This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.45 and -3.135), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.407 and 0.445).

**Microsomal Clearance:** Ligand A (45.447) has higher microsomal clearance than Ligand B (37.291), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (20.654) has a significantly longer half-life than Ligand A (46.877). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.055 and 0.376).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a considerably stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a crucial difference, as a 2.0 kcal/mol advantage can often outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.6 vs -9.6 kcal/mol) and longer half-life (20.654 vs 46.877) are critical advantages for an enzyme inhibitor. While Ligand A has a slightly lower DILI risk, the potency and stability benefits of Ligand B are more important in this context. Addressing the solubility and permeability issues would be a priority in further optimization, but the starting point is better with Ligand B.

Output:
1
2025-04-17 15:57:29,636 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.364 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.48) is slightly higher than Ligand B (58.64). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (1.73 and 1.985), 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). Ligand B is slightly more favorable.

**QED:** Both ligands have good QED scores (0.691 and 0.795), indicating good drug-likeness.

**DILI:** Ligand A (14.851) has a much lower DILI risk than Ligand B (31.252). This is a significant advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (77.937 and 68.748). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.723 and -4.726), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-2.002 and -2.161), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.337 and 0.133), which is excellent.

**Microsomal Clearance:** Ligand A (-9.116) has *much* lower microsomal clearance than Ligand B (21.381). This indicates significantly better metabolic stability for Ligand A, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (16.78 hours) has a positive half-life, while Ligand B (-11.941 hours) has a negative half-life. This further supports the better metabolic stability of Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.044).

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.0 kcal/mol). This is a 0.9 kcal/mol difference, which is notable but may not outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate. Its significantly lower DILI risk and *much* improved metabolic stability (lower Cl_mic and positive t1/2) are crucial advantages for an enzyme inhibitor. The poor solubility and permeability are concerns for both, but these can potentially be addressed through formulation strategies. The difference in affinity is not large enough to overcome the substantial ADME benefits of Ligand A.

Output:
0
2025-04-17 15:57:29,636 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.491 Da) is slightly better, being closer to the lower end which often aids permeability.

**TPSA:** Ligand A (81.67) is better than Ligand B (91.76). Both are below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.745) is a bit low, potentially hindering permeation. Ligand B (1.798) is better, falling within the optimal 1-3 range.

**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. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.632 and 0.593), indicating good drug-likeness.

**DILI:** Ligand A (5.312) has a significantly lower DILI risk than Ligand B (43.273), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (32.183) is slightly better than Ligand B (28.655).

**Caco-2 Permeability:** Ligand A (-5.303) has a worse Caco-2 permeability than Ligand B (-4.807), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.784) has slightly better solubility than Ligand B (-1.591).

**hERG:** Ligand A (0.261) has a much lower hERG inhibition liability than Ligand B (0.342), which is a critical safety advantage.

**Microsomal Clearance:** Ligand A (-20.106) exhibits significantly lower microsomal clearance, indicating better metabolic stability, which is crucial for an enzyme target. Ligand B (32.597) has higher clearance.

**In vitro Half-Life:** Ligand B (44.66) has a longer in vitro half-life than Ligand A (23.416), which is a positive.

**P-gp Efflux:** Ligand A (0.013) has lower P-gp efflux liability than Ligand B (0.25), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, and a better half-life. However, Ligand A excels in safety (DILI, hERG) and metabolic stability (Cl_mic). The difference in binding affinity (-7.8 vs -6.3) is significant (1.5 kcal/mol), and for an enzyme target, potency is paramount. While Ligand A's lower logP and Caco-2 are concerns, the substantial improvements in safety and metabolic stability, combined with reasonable solubility, make it a potentially viable candidate. The high DILI and hERG risks associated with Ligand B are substantial drawbacks that would likely disqualify it early in development.

Output:
0
2025-04-17 15:57:29,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.78) is significantly better than Ligand B (104.21). A TPSA under 90 is preferred, and Ligand A is comfortably within that range, suggesting better permeability. Ligand B is pushing the upper limit for good oral absorption.

**logP:** Both ligands have similar logP values (1.558 and 1.678), 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 donors and acceptors, which generally leads to better permeability. Both are within acceptable limits.

**QED:** Ligand A (0.883) has a significantly higher QED score than Ligand B (0.595), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (45.328 and 42.303), below the 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (55.215) is better than Ligand B (30.283), but neither is particularly high.

**Caco-2 Permeability:** Ligand A (-4.514) is better than Ligand B (-5.272), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.148) is better than Ligand B (-2.324), though both are poor. Solubility is a concern for both, but slightly less so for A.

**hERG:** Both ligands have very low hERG risk (0.393 and 0.265), which is excellent.

**Microsomal Clearance:** Ligand A (31.545) has higher microsomal clearance than Ligand B (21.168). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (13.882) has a slightly longer half-life than Ligand A (11.853), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.29 and 0.035), which is good.

**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 has a significantly better binding affinity, which is the most crucial factor for an enzyme inhibitor. While Ligand A has better TPSA, QED, solubility, and Caco-2 permeability, the substantial affinity advantage of Ligand B is likely to be more impactful. The slightly higher clearance and lower half-life of Ligand B are less concerning than the weaker binding of Ligand A.

Output:
1
2025-04-17 15:57:29,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (363.483 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (71.53 and 78.09) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands have logP values (1.694 and 2.375) within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1 HBD) and Ligand B (2 HBD) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5 HBA) and Ligand B (3 HBA) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.808) has a better QED score than Ligand B (0.639), indicating a more drug-like profile.

**7. DILI:** Ligand B (16.208) has a significantly lower DILI risk than Ligand A (47.926), which is a major advantage.

**8. BBB:** Both ligands have moderate BBB penetration (55.332 and 60.644). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.005 and -5.031), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.713 and -2.585), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.121 and 0.381), which is excellent.

**12. Microsomal Clearance:** Ligand A (32.663) has lower microsomal clearance than Ligand B (40.282), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.548 hours) has a significantly longer in vitro half-life than Ligand B (-17.97 hours). The negative value for ligand B is concerning and likely indicates rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.055 and 0.178), which is favorable.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.2 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, QED, and metabolic stability (lower Cl_mic and longer t1/2), Ligand B has a *much* lower DILI risk. The poor solubility and permeability of both compounds are significant concerns. However, the negative half-life for Ligand B is a dealbreaker. Given the enzyme-kinase focus, metabolic stability and safety (DILI) are crucial. Ligand A's better metabolic profile and half-life, coupled with acceptable (though not ideal) DILI, make it the more promising candidate despite the shared solubility/permeability issues. These issues would need to be addressed through formulation or structural modification, but the starting point is better with Ligand A.

Output:
0
2025-04-17 15:57:29,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (384.542 Da) is also good.

**TPSA:** Ligand A (99.83) is better than Ligand B (49.41). Both are below 140, suggesting good oral absorption potential, but Ligand B is significantly lower, potentially indicating better cell permeability.

**logP:** Ligand A (1.382) is within the optimal range (1-3). Ligand B (3.672) is at the higher end, which could lead to solubility issues or off-target interactions, but is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 for A, 4 for B), satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.762 and 0.787), indicating good drug-likeness.

**DILI:** Ligand A (92.168) has a significantly higher DILI risk than Ligand B (51.609). This is a major concern for Ligand A.

**BBB:** Ligand A (52.268) has a low BBB penetration, which is not critical for a non-CNS target like SRC. Ligand B (82.784) has better BBB penetration, but again, this is less important here.

**Caco-2 Permeability:** Ligand A (-5.058) has poor Caco-2 permeability, while Ligand B (-4.835) is slightly better. Both are negative values, which is unusual and suggests low permeability.

**Aqueous Solubility:** Ligand A (-3.261) has poor aqueous solubility, while Ligand B (-4.468) is even worse. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.5 and 0.694, respectively), which is positive.

**Microsomal Clearance:** Ligand A (-5.598) has significantly lower (better) microsomal clearance than Ligand B (44.765). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.224) has a very short half-life, while Ligand B (10.916) has a much longer half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.103 and 0.427, respectively).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better binding affinity and metabolic stability, its significantly higher DILI risk, poor Caco-2 permeability, and very short half-life are major concerns. Ligand B, despite having slightly lower affinity, exhibits a much better safety profile (lower DILI), a longer half-life, and slightly better Caco-2 permeability. The solubility is poor for both, but can be addressed through formulation strategies. Given the enzyme-specific priorities, metabolic stability and safety are crucial.

Output:
1
2025-04-17 15:57:29,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.383 and 350.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is better than Ligand B (45.33), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.589) is a bit low, potentially hindering permeability. Ligand B (3.967) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is acceptable. Ligand B (1 HBD, 2 HBA) is even better, with lower counts generally favoring permeability.

**QED:** Both ligands have good QED scores (0.599 and 0.821), indicating drug-likeness.

**DILI:** Ligand A (48.817) has a lower DILI risk than Ligand B (59.131), which is preferable.

**BBB:** Ligand A (54.634) has a lower BBB penetration than Ligand B (89.957). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.264) has poor Caco-2 permeability, while Ligand B (-4.888) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.079) has better solubility than Ligand B (-4.044). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.123) has a very low hERG risk, a significant advantage. Ligand B (0.898) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-1.515) has a negative clearance, indicating very high metabolic stability, which is excellent. Ligand B (40.803) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-5.993) has a very long half-life, consistent with its low clearance. Ligand B (14.314) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.049) has low P-gp efflux, which is good. Ligand B (0.462) has moderate P-gp efflux.

**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.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), DILI risk, hERG inhibition, and P-gp efflux. Its solubility is also better than Ligand B. While its logP and Caco-2 permeability are less ideal, the superior safety profile and metabolic stability are crucial for an enzyme target like SRC kinase. Ligand B has a slightly better affinity and BBB penetration, but the higher DILI, hERG risk, and significantly higher clearance are major drawbacks.

Output:
0
2025-04-17 15:57:29,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.68) is slightly higher than Ligand B (67.23), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.912) is slightly lower than optimal (1-3), but still acceptable. Ligand B (1.685) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the criteria.

**QED:** Ligand A (0.827) has a significantly better QED score than Ligand B (0.606), indicating a more drug-like profile.

**DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (32.726), a crucial advantage.

**BBB:** Both ligands have similar BBB penetration (71.772 and 70.415), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.887) and Ligand B (-5.134) are similar, suggesting comparable intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.756) has better aqueous solubility than Ligand B (-1.681).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.056 and 0.086).

**Microsomal Clearance:** Ligand A (4.158) has significantly lower microsomal clearance than Ligand B (24.6), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.925) has a longer in vitro half-life than Ligand B (-10.695).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.006 and 0.051).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a >1.5 kcal/mol difference, which is highly significant.

**Conclusion:**

Ligand A is the superior candidate. While both meet many basic criteria, Ligand A excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and better aqueous solubility. The higher QED score further supports its drug-like properties. The slight difference in logP is not a major concern given the substantial advantage in binding affinity.

Output:
1
2025-04-17 15:57:29,638 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [362.836, 57.26, 3.839, 2, 3, 0.849, 74.99, 80.419, -4.777, -5.126, 0.644, 51.949, 53.839, 0.319, -9.4]
**Ligand B:** [352.431, 104.73, 0.668, 3, 5, 0.44, 29.779, 17.022, -5.341, -1.502, 0.047, -4.841, 1.864, 0.022, -7.3]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (362.836) is slightly higher, but not concerning.
2. **TPSA:** A (57.26) is excellent, well below the 140 threshold. B (104.73) is higher, but still acceptable, though less ideal for permeability.
3. **logP:** A (3.839) is optimal. B (0.668) is quite low, potentially hindering permeability and absorption.
4. **HBD:** Both have acceptable HBD counts (A: 2, B: 3).
5. **HBA:** Both have acceptable HBA counts (A: 3, B: 5).
6. **QED:** A (0.849) is very good, indicating high drug-likeness. B (0.44) is below the 0.5 threshold, suggesting a less favorable drug-like profile.
7. **DILI:** A (74.99) is moderately high, indicating a potential liver toxicity risk. B (29.779) is excellent, indicating low risk.
8. **BBB:** A (80.419) is good, suggesting some potential for CNS penetration, although SRC is not typically a CNS target. B (17.022) is very low.
9. **Caco-2:** Both are negative, which is unusual. Assuming these are log values, both have poor permeability.
10. **Solubility:** Both are negative, which is unusual. Assuming these are log values, both have poor solubility.
11. **hERG:** A (0.644) is relatively low risk. B (0.047) is very low risk.
12. **Cl_mic:** A (51.949) is moderate. B (-4.841) is excellent, indicating very high metabolic stability. The negative value suggests a very slow clearance.
13. **t1/2:** A (53.839) is good. B (1.864) is very short, suggesting rapid elimination.
14. **Pgp:** A (0.319) is relatively low efflux. B (0.022) is very low efflux.
15. **Affinity:** A (-9.4) is significantly better than B (-7.3), a difference of 2.1 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite the DILI risk associated with Ligand A, its significantly superior binding affinity (-9.4 kcal/mol vs -7.3 kcal/mol) and better overall drug-likeness (higher QED) outweigh the concerns, especially considering the relatively moderate DILI risk. The excellent metabolic stability of Ligand B is attractive, but its poor logP, QED, and significantly weaker binding affinity make it a less promising candidate. The poor Caco-2 and solubility values of both compounds are concerning and would need to be addressed through further optimization.

Therefore, I recommend **Ligand A** as the more viable drug candidate.

1
2025-04-17 15:57:29,638 - INFO - Batch 423 complete. Total preferences: 6768
2025-04-17 15:57:29,638 - INFO - Processing batch 424/512...
2025-04-17 15:58:17,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.387 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (82.94) is significantly better than Ligand A (104.54). Lower TPSA generally improves oral absorption.

**logP:** Ligand B (1.3) is optimal, while Ligand A (0.221) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors:** Both ligands are acceptable (Ligand A: 2, Ligand B: 1), falling within the recommended limit of 5.

**H-Bond Acceptors:** Both are also acceptable (Ligand A: 5, Ligand B: 6), below the 10 limit.

**QED:** Both have good QED scores (Ligand A: 0.655, Ligand B: 0.81), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand B (54.323) has a slightly higher DILI risk than Ligand A (38.969), but both are below the concerning threshold of 60.

**BBB:** Both have similar, relatively low BBB penetration (Ligand A: 48.352, Ligand B: 48.158). This isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.787) and Ligand B (-5.217) both have negative values, which is unusual and suggests very poor permeability. However, the scale isn't explicitly defined, so it's hard to interpret.

**Aqueous Solubility:** Both have very poor solubility (Ligand A: -1.699, Ligand B: -2.02). This is a significant issue for both compounds.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.028, Ligand B: 0.124), which is excellent.

**Microsomal Clearance:** Ligand B (1.415) has significantly lower microsomal clearance than Ligand A (27.336), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (17.87) has a much longer in vitro half-life than Ligand A (-43.042), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.006, Ligand B: 0.092).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the difference of 1 kcal/mol is notable.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in key areas for an enzyme inhibitor: significantly better logP, dramatically improved metabolic stability (lower Cl_mic and longer t1/2), and slightly stronger binding affinity. Ligand A's low logP is a major drawback, potentially limiting its absorption and bioavailability. The solubility issue would need to be addressed for either compound, but the other advantages of Ligand B make it the more promising starting point for optimization.

Output:
1
2025-04-17 15:58:17,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.925 Da) is slightly higher than Ligand B (361.427 Da), but both are acceptable.

**TPSA:** Ligand A (63.24) is significantly better than Ligand B (106.1). Lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (3.605) is optimal, while Ligand B (0.693) is quite low. A low logP can hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=7) in terms of balancing solubility and permeability. Ligand B has a higher number of HBA which could affect permeability.

**QED:** Both ligands have similar and good QED values (0.813 and 0.812).

**DILI:** Ligand A (45.095) has a much lower DILI risk than Ligand B (83.404). This is a significant advantage.

**BBB:** Ligand A (70.997) has better BBB penetration than Ligand B (30.787), though BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.947) has better Caco-2 permeability than Ligand B (-5.479), though both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.399) has better aqueous solubility than Ligand B (-1.556), though both are negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.31) has a much lower hERG inhibition liability than Ligand B (0.07). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (-11.344) has significantly lower microsomal clearance than Ligand A (26.845), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (21.157) has a longer in vitro half-life than Ligand A (37.208), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux than Ligand B (0.006), which is a positive attribute.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in several critical ADME properties (DILI, hERG, solubility, TPSA, logP, P-gp efflux) and has comparable binding affinity to Ligand B. While Ligand B has better metabolic stability and half-life, the significantly improved safety profile (lower DILI and hERG) and better physicochemical properties of Ligand A outweigh this advantage. The poor solubility and permeability of both compounds are concerns that would need to be addressed through further optimization, but Ligand A is in a better starting position.

Output:
1
2025-04-17 15:58:17,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.438 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.12) is significantly better than Ligand B (97.78). A TPSA under 140 is good for oral absorption, and A is comfortably within this range, while B is approaching the upper limit and could have absorption issues.

**logP:** Ligand A (4.197) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.566) is within the optimal range. However, for a kinase inhibitor, a slightly higher logP isn't a major concern if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (3 HBD, 3 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.659) is better than Ligand B (0.45), indicating a more drug-like profile.

**DILI:** Ligand B (42.303) has a significantly lower DILI risk than Ligand A (75.766). This is a major advantage for Ligand B.

**BBB:** Ligand A (80.807) has better BBB penetration than Ligand B (54.13), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.277) has better Caco-2 permeability than Ligand B (-4.875).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.734 and -4.721 respectively). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.369) has a lower hERG risk than Ligand B (0.547), which is favorable.

**Microsomal Clearance:** Ligand A (91.636) has much higher microsomal clearance than Ligand B (47.555). This suggests Ligand B is more metabolically stable, which is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-15.364) has a longer in vitro half-life than Ligand A (22.412), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.659) has lower P-gp efflux than Ligand B (0.364), which is slightly favorable.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 2.7 kcal/mol is quite large.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has some ADME liabilities (higher DILI, higher Cl_mic, shorter t1/2, and a higher logP), the significantly improved potency might overcome these issues. Ligand B has better ADME properties overall (lower DILI, better metabolic stability), but its weaker binding affinity is a major concern. The difference in binding affinity is substantial enough to favor Ligand A, assuming that formulation strategies can address the solubility issues.

Output:
0
2025-04-17 15:58:17,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.359 Da and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.1) is higher than Ligand B (69.72). While both are reasonably good, Ligand B is preferable as lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (0.736) is slightly higher than Ligand B (0.505). Both are acceptable, falling within the 1-3 range, but closer to the lower end.

**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 comparable QED values (0.733 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 77.549, which is considered high risk (>60). Ligand B has a significantly lower DILI risk of 26.406, which is very favorable. This is a major advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (54.866 and 76.541). BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.303) has poor Caco-2 permeability, while Ligand B (-4.881) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-2.289) and Ligand B (-1.681) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.148 and 0.158), which is excellent.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (-16.307), indicating poor metabolic stability. Ligand B has a much lower clearance (8.284), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (7.244 and 7.527 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.01).

**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 advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic), and, most importantly, a much stronger binding affinity. The substantial difference in binding affinity (-7.9 vs -0.0 kcal/mol) makes Ligand B far more likely to be a viable drug candidate, even considering the solubility issues.

Output:
1
2025-04-17 15:58:17,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.917 Da) is higher, but still acceptable. Ligand B (341.386 Da) is slightly preferred.

**TPSA:** Ligand A (126.64) is approaching the upper limit for good oral absorption, while Ligand B (71.09) is well below the threshold. This favors Ligand B.

**logP:** Ligand A (0.288) is quite low, potentially hindering membrane permeability. Ligand B (2.438) is within the optimal 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 3. Both are acceptable, but lower is generally better for permeability, slightly favoring Ligand B.

**QED:** Both ligands have good QED scores (A: 0.669, B: 0.848), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (50.058), suggesting potential liver toxicity. Ligand B is preferred.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (83.249) has better penetration than Ligand A (38.813).

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of negativity is important. Ligand A (-5.653) is more negative than Ligand B (-4.698), suggesting lower permeability. Ligand B is slightly preferred.

**Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-2.814) is slightly better than Ligand B (-3.675), suggesting better solubility.

**hERG Inhibition:** Ligand A (0.074) has a very low hERG risk, which is excellent. Ligand B (0.257) is also low, but slightly higher. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-8.661) has a much lower (better) microsomal clearance than Ligand B (37.217), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (13.462) has a longer half-life than Ligand B (-20.1), which is preferable.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.061, B: 0.108), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -10.4 kcal/mol, B: -8.9 kcal/mol). Ligand A is significantly more potent, with a 1.5 kcal/mol advantage. This difference is substantial enough to potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has better physicochemical properties (logP, TPSA) and lower DILI risk. However, Ligand A has significantly better potency, metabolic stability (lower Cl_mic, longer t1/2), and a very low hERG risk. The superior binding affinity of Ligand A (-10.4 kcal/mol vs -8.9 kcal/mol) is a critical factor for an enzyme inhibitor. Given the priority for potency and metabolic stability in enzyme targets, the advantages of Ligand A outweigh its slightly less favorable physicochemical properties.

Output:
1
2025-04-17 15:58:17,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.391 and 352.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.25) is better than Ligand B (78.43), being below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.158 and 2.787) are within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 3 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.807) has a significantly higher QED score than Ligand B (0.558), indicating better overall drug-likeness.

**DILI:** Ligand A (77.162) has a higher DILI risk than Ligand B (13.377). This is a significant drawback for Ligand A.

**BBB:** Ligand A (56.96) has a slightly better BBB penetration than Ligand B (41.838), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.915) is slightly worse than Ligand B (-4.638).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-2.537) is slightly better than Ligand B (-2.912).

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.144 and 0.186), which is excellent.

**Microsomal Clearance:** Ligand B (51.246) has a lower microsomal clearance than Ligand A (62.74), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (8.543) has a significantly longer in vitro half-life than Ligand A (-16.854). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.079).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol).

**Overall Assessment:**

Ligand A has a better QED and slightly better binding affinity, but suffers from significantly higher DILI risk, worse metabolic stability (higher Cl_mic, shorter t1/2), and worse Caco-2 permeability. Ligand B, while having a slightly lower QED and binding affinity, exhibits a much more favorable safety profile (lower DILI), better metabolic stability, and a longer half-life. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. The slightly better affinity of Ligand A is unlikely to outweigh the significant drawbacks in ADME-Tox properties.

Output:
1
2025-04-17 15:58:17,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.455 and 347.317 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.63) is slightly higher than Ligand B (59.75), but both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have excellent logP values (3.248 and 3.147), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, well within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.733 and 0.783), indicating good drug-like properties.

**7. DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (83.753). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have acceptable BBB penetration, but Ligand B (81.698) is higher than Ligand A (70.531). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-3.972 and -3.997), which is unusual and suggests poor permeability. This is a concern for both compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.756 and -4.092), indicating very poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**11. hERG Inhibition:** Ligand A (0.335) has a lower hERG inhibition liability than Ligand B (0.421), which is favorable.

**12. Microsomal Clearance:** Ligand A (90.715) has a significantly higher microsomal clearance than Ligand B (13.463). This indicates that Ligand B is much more metabolically stable, a critical factor for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B (15.382 hours) has a much longer in vitro half-life than Ligand A (4.88 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux liability than Ligand B (0.422), which is preferable.

**15. Binding Affinity:** Ligand B (-10.0 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:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B stands out due to its significantly superior binding affinity and metabolic stability (lower Cl_mic and longer t1/2). The stronger binding affinity is a crucial advantage for an enzyme inhibitor, and the improved metabolic stability suggests a more favorable pharmacokinetic profile. The higher DILI risk for Ligand B is a concern, but the substantial potency advantage may allow for lower doses, potentially mitigating this risk.

Output:
1
2025-04-17 15:58:17,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.4 Da) is slightly higher than Ligand B (343.343 Da), but both are acceptable.

**TPSA:** Ligand A (66.48) is better than Ligand B (101.66). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (2.849) is optimal, while Ligand B (0.359) is quite low. A logP below 1 can hinder permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher but still within the acceptable limit of 10.

**QED:** Both ligands have similar and acceptable QED values (Ligand A: 0.882, Ligand B: 0.79).

**DILI:** Ligand A (51.183) has a lower DILI risk than Ligand B (73.09). Both are below the concerning threshold of 60, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (90.772) is higher than Ligand B (61.807).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.718 and -4.751), 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 have negative solubility values (-3.846 and -1.701). Again, these are on a log scale, and lower values indicate lower solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.709) is better than Ligand B (0.151), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-19.825) has *much* lower (better) microsomal clearance than Ligand B (9.684). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (17.51) has a positive half-life, while Ligand B (-5.228) has a negative half-life. This is a strong indicator of better stability for Ligand A.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.028), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.7 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.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties: logP, DILI, microsomal clearance, in vitro half-life, and P-gp efflux. The improved metabolic stability (lower Cl_mic and positive t1/2) and reduced toxicity risk (lower DILI and hERG) are particularly important for an enzyme target. The slightly better TPSA and logP also contribute to its favorability.

Output:
1
2025-04-17 15:58:17,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.8 and 364.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.8) is better than Ligand B (89.9) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (2.47) is within the optimal 1-3 range. Ligand B (0.57) is slightly below 1, which might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (3 HBD, 4 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.779 and 0.68), indicating good drug-likeness.

**DILI:** Ligand A (97.7) has a very high DILI risk, which is a major concern. Ligand B (21.9) has a low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.6) and Ligand B (64.6) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.57 and -4.93), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.96 and -1.66), which is also unusual and indicates poor solubility. This is another red flag for both.

**hERG:** Ligand A (0.32) has a lower hERG risk than Ligand B (0.44), which is preferable.

**Microsomal Clearance:** Ligand A (17.6) has a better (lower) microsomal clearance than Ligand B (-20.2), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.8) has a longer half-life than Ligand B (-11.6), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.11 and 0.01).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This difference of 1.1 kcal/mol is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and better TPSA and logP values. However, its extremely high DILI risk is a major drawback. Ligand B has a significantly lower DILI risk and slightly better binding affinity. The poor Caco-2 and solubility for both are concerning, but the DILI risk for Ligand A is a showstopper. Given the enzyme-specific priorities, metabolic stability and potency are key, but safety (DILI) is paramount.

Output:
1
2025-04-17 15:58:17,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.466 and 349.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (58.64 and 53.52) well below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.44 and 2.792) within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are below the 10 threshold, but Ligand A is preferable.

**QED:** Both ligands have similar QED values (0.681 and 0.692), indicating good drug-likeness.

**DILI:** Ligand A (10.469) has a significantly lower DILI risk than Ligand B (32.261). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (94.455 and 87.476), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.656 and -4.982), which is unusual and indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.331 and -2.161) which is also a concern.

**hERG Inhibition:** Ligand A (0.678) has a lower hERG inhibition liability than Ligand B (0.965), which is favorable.

**Microsomal Clearance:** Ligand A (32.814 mL/min/kg) has a lower microsomal clearance than Ligand B (55.327 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.276 hours) has a much longer in vitro half-life than Ligand B (32.652 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.275) has lower P-gp efflux liability than Ligand B (0.446), which is preferable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While this is a positive for Ligand B, the other ADME properties of Ligand A are significantly better.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of DILI risk, metabolic stability (lower Cl_mic and longer t1/2), hERG inhibition, and P-gp efflux. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh the small binding affinity difference.

Output:
0
2025-04-17 15:58:17,895 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [380.413, 104.73 ,   0.228,   3.   ,   6.   ,   0.37 ,  35.285,  59.364, -5.384,  -1.71 ,   0.108,  31.616, -31.826,   0.022,  -6.9  ]
**Ligand B:** [345.443,  75.44 ,   2.583,   1.   ,   4.   ,   0.86 ,  40.83 ,  74.176, -4.585,  -2.85 ,   0.078,  91.999,  -9.56 ,   0.124,  -8.2  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (345.443) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** Ligand A (104.73) is higher than Ligand B (75.44). Both are below the 140 threshold for oral absorption, but Ligand B is better.
3. **logP:** Ligand A (0.228) is quite low, potentially hindering permeability. Ligand B (2.583) is within the optimal range (1-3). This is a significant advantage for Ligand B.
4. **HBD:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.
5. **HBA:** Ligand A (6) is acceptable, Ligand B (4) is better.
6. **QED:** Ligand B (0.86) has a much better drug-likeness score than Ligand A (0.37).
7. **DILI:** Both are relatively low, indicating low liver injury risk. Ligand B (40.83) is slightly higher than Ligand A (35.285), but both are below the concerning 60 threshold.
8. **BBB:** Ligand B (74.176) has better BBB penetration than Ligand A (59.364), but neither is particularly high.  Not a major factor for SRC, which isn't a CNS target.
9. **Caco-2:** Ligand A (-5.384) is very poor, indicating poor intestinal absorption. Ligand B (-4.585) is also poor, but slightly better.
10. **Solubility:** Ligand A (-1.71) and Ligand B (-2.85) both have poor solubility.
11. **hERG:** Both are very low, indicating minimal hERG inhibition risk.
12. **Cl_mic:** Ligand A (31.616) has lower microsomal clearance than Ligand B (91.999), suggesting better metabolic stability. This is a significant advantage for Ligand A.
13. **t1/2:** Ligand A (-31.826) has a longer in vitro half-life than Ligand B (-9.56), further supporting its better metabolic stability.
14. **Pgp:** Both are very low, suggesting minimal P-gp efflux.
15. **Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-6.9), a difference of 1.3 kcal/mol.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a better binding affinity, but Ligand A has significantly better metabolic stability (lower Cl_mic and longer t1/2). Both have poor solubility and low hERG risk.

**Overall Assessment:**

While Ligand B has a better logP, QED, and binding affinity, the significantly better metabolic stability of Ligand A (lower Cl_mic and longer half-life) is a crucial advantage for an enzyme inhibitor. The slightly better affinity of Ligand B might be overcome with further optimization, but improving metabolic stability is often more challenging. The poor Caco-2 and solubility of both are concerns, but can be addressed with formulation strategies.

Therefore, I would select **Ligand A** as the more promising drug candidate.

Output:
1
2025-04-17 15:58:17,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.455 and 359.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.34) is slightly higher than Ligand B (84.14). Both are acceptable, but B is better for permeability.

**logP:** Ligand A (1.958) is within the optimal range (1-3). Ligand B (3.305) is at the higher end, potentially causing solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.775) has a better QED score than Ligand B (0.585), indicating better overall drug-likeness.

**DILI:** Both ligands have similar DILI risk (64.521 and 62.66), both are acceptable.

**BBB:** Ligand A (50.523) has a lower BBB penetration percentile than Ligand B (85.459). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand B (-5.462) has better Caco-2 permeability than Ligand A (-4.649).

**Aqueous Solubility:** Ligand B (-3.088) has better aqueous solubility than Ligand A (-3.527). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.341) has a significantly lower hERG inhibition risk than Ligand B (0.826). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (18.421) has a much lower microsomal clearance than Ligand B (88.989), suggesting better metabolic stability. This is a major advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (97.702) has a significantly longer in vitro half-life than Ligand B (3.479). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux liability than Ligand B (0.544).

**Binding Affinity:** Ligand B (-9.4 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:**

While Ligand B boasts a superior binding affinity, Ligand A presents a much more favorable ADMET profile. Specifically, its significantly lower microsomal clearance and longer half-life are critical for an enzyme target like SRC kinase. The lower hERG risk and P-gp efflux are also beneficial. The difference in binding affinity (-1.7 kcal/mol) is substantial, but the improved ADMET properties of Ligand A, particularly metabolic stability, are likely to translate to better *in vivo* efficacy. The improved solubility of Ligand B is a plus, but not enough to overcome the metabolic liabilities.

Output:
0
2025-04-17 15:58:17,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.507 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is better than Ligand B (60.85). Both are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (0.776) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.669) is within the optimal range.

**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 below the threshold of 10.

**QED:** Both ligands have good QED scores (0.769 and 0.827, respectively), indicating drug-like properties.

**DILI:** Ligand A (1.473) has a significantly lower DILI risk than Ligand B (12.33). This is a major advantage for Ligand A.

**BBB:** Ligand A (83.87) has a higher BBB percentile than Ligand B (58.085). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-5.16) has worse Caco-2 permeability than Ligand B (-4.403).

**Aqueous Solubility:** Ligand A (-0.836) has better aqueous solubility than Ligand B (-2.547). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.55) has a lower hERG inhibition liability than Ligand B (0.68), which is favorable.

**Microsomal Clearance:** Ligand A (1.396) has significantly lower microsomal clearance than Ligand B (38.762), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-5.754) has a much longer in vitro half-life than Ligand B (2.421). This is a significant benefit.

**P-gp Efflux:** Ligand A (0.008) has lower P-gp efflux than Ligand B (0.204), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand B having a slightly better logP and Caco-2 permeability, Ligand A is the superior candidate. The significantly lower DILI risk, better solubility, lower hERG inhibition, dramatically improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux outweigh the minor drawbacks in Caco-2. The equal binding affinity seals the deal. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 15:58:17,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.435 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.18) is slightly higher than Ligand B (70.47). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (-0.225) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.527) is within the optimal range. This favors Ligand B.

**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 similar QED values (0.644 and 0.695), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (19.504 and 20.434), and are both low risk (<40).

**BBB:** Both ligands have moderate BBB penetration (58.55 and 64.017). This is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.974), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.081 and -1.146), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.115 and 0.26). This is excellent.

**Microsomal Clearance:** Ligand A (2.026) has significantly lower microsomal clearance than Ligand B (23.092), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (0.976) has a lower in vitro half-life than Ligand B (12.582). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.007).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.5 kcal/mol), both of which are excellent.

**Overall Assessment:**

Ligand A has a clear advantage in metabolic stability (lower Cl_mic), which is critical for an enzyme inhibitor. However, it suffers from a lower half-life and a less optimal logP. Ligand B has a better logP and half-life, but significantly higher microsomal clearance. Both have poor solubility and permeability. Given the similar binding affinities, the better metabolic stability of Ligand A is the deciding factor. While the solubility and permeability are concerning, these can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 15:58:17,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 Da and 358.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.22 and 85.25) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.295) is optimal, while Ligand B (0.96) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both have 2-3 HBD, well within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are under the 10 limit.

**QED:** Both ligands have similar QED scores (0.675 and 0.644), indicating good drug-likeness.

**DILI:** Ligand A (29.973) has a significantly lower DILI risk than Ligand B (41.024). This is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (86.08) has a higher BBB percentile than Ligand A (60.876), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. However, the scale is not clearly defined.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is not clearly defined.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.39 and 0.284), which is good.

**Microsomal Clearance:** Ligand A (29.609) has a higher microsomal clearance than Ligand B (13.071), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-1.549) has a much better in vitro half-life than Ligand A (-14.695). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.153 and 0.026).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.1 kcal/mol difference is substantial and outweighs some of the ADME concerns with Ligand B.

**Conclusion:**

While Ligand A has a better DILI score and logP, Ligand B demonstrates superior binding affinity, metabolic stability (lower Cl_mic, better t1/2), and a slightly better hERG profile. Considering SRC kinase is an enzyme, potency and metabolic stability are key. The stronger binding affinity of Ligand B, combined with its improved metabolic profile, makes it the more promising drug candidate despite its slightly lower logP and higher DILI risk.

Output:
1
2025-04-17 15:58:17,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight:** Both ligands (356.348 and 350.394 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.18) is better than Ligand B (87.46). Both are below the 140 A^2 threshold for good oral absorption, but closer to the ideal range for kinase inhibitors.

**3. logP:** Ligand A (1.789) is slightly higher than Ligand B (0.827), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), both are acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.714 and 0.744), indicating good drug-likeness.

**7. DILI:** Ligand A (51.493) has a slightly better DILI score than Ligand B (55.293), both are acceptable.

**8. BBB:** Ligand A (68.864) has a lower BBB penetration than Ligand B (75.107). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.071) has worse Caco-2 permeability than Ligand B (-4.899).

**10. Aqueous Solubility:** Ligand A (-2.806) has worse aqueous solubility than Ligand B (-2.296). Solubility is important for kinase inhibitors.

**11. hERG Inhibition:** Ligand A (0.512) has a slightly higher hERG risk than Ligand B (0.286). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (18.733) has a higher microsomal clearance than Ligand B (9.309), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-6.046) has a longer in vitro half-life than Ligand A (5.646), which is desirable.

**14. P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux than Ligand B (0.037), which is preferable.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a crucial factor for enzyme inhibitors, and the 1.0 kcal/mol difference is substantial.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is the more promising candidate. While Ligand A has slightly better TPSA and P-gp efflux, Ligand B demonstrates superior binding affinity, metabolic stability (lower Cl_mic, longer t1/2), solubility, and lower hERG risk. The stronger binding affinity of Ligand B is a significant advantage that outweighs the minor drawbacks in other parameters.

Output:
1
2025-04-17 15:58:17,896 - INFO - Batch 424 complete. Total preferences: 6784
2025-04-17 15:58:17,896 - INFO - Processing batch 425/512...
2025-04-17 15:58:58,205 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.407 and 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.77 and 88.91) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (not a priority here).

**logP:** Both ligands (1.951 and 1.777) are 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 (0.61 and 0.793), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 88.174, which is high. Ligand B has a DILI risk of 72.819, which is still elevated but better than Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (30.438) and Ligand B (72.896) are not particularly relevant here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.23 and -4.94), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.078 and -2.634), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.407) and Ligand B (0.069) both have relatively low hERG inhibition liability, which is good. Ligand B is significantly better.

**Microsomal Clearance:** Ligand A (23.324 mL/min/kg) and Ligand B (29.962 mL/min/kg) have moderate microsomal clearance. Lower is better, but these aren't exceptionally high.

**In vitro Half-Life:** Ligand A (14.29 hours) has a better in vitro half-life than Ligand B (6.803 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.26 and 0.08), which is favorable.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -8.2 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has a lower DILI risk and hERG inhibition liability. While the in vitro half-life is shorter, the potency advantage is likely to be more impactful in initial optimization efforts. The solubility and permeability issues would need to be addressed through structural modifications, but the superior potency of Ligand B provides a better starting point.

Output:
1
2025-04-17 15:58:58,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.447 and 351.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (85.89 and 88.49) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (0.928) is slightly higher than Ligand B (0.596), both are within the optimal 1-3 range, but ligand B is closer to the lower limit which could potentially affect permeability.

**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:** Both ligands have similar QED values (0.664 and 0.68), indicating good drug-likeness.

**7. DILI:** Both ligands have very similar and low DILI risk (34.742 and 34.432 percentile), suggesting minimal liver injury potential.

**8. BBB:** Ligand A (71.345) has a better BBB penetration percentile than Ligand B (63.086), although this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.988) has a significantly better Caco-2 permeability score than Ligand B (-5.061), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.515) has slightly better aqueous solubility than Ligand B (-1.294).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.095 and 0.224), which is excellent.

**12. Microsomal Clearance:** Ligand B (17.175 mL/min/kg) has a lower microsomal clearance than Ligand A (24.104 mL/min/kg), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (14.433 hours) has a significantly longer in vitro half-life than Ligand A (3.979 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017).

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is not massive (0.3 kcal/mol), it is still a positive attribute for Ligand A.

**Overall Assessment:**

Ligand B demonstrates superior metabolic stability (lower Cl_mic and longer t1/2), which is a crucial factor for kinase inhibitors. While Ligand A has a slightly better binding affinity and Caco-2 permeability, the improved metabolic stability of Ligand B outweighs these advantages. The difference in binding affinity is small enough that optimization could likely close the gap.

Output:
1
2025-04-17 15:58:58,206 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (348.531 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.
2. **TPSA:** Ligand A (49.41) is significantly better than Ligand B (71.78).  A TPSA under 140 is good for oral absorption, and A is much closer to the ideal for kinases.
3. **logP:** Ligand A (3.912) is at the higher end of the optimal range (1-3), while Ligand B (2.053) is closer to the lower end. Both are acceptable, but A's higher logP *could* lead to off-target effects, something to monitor.
4. **HBD:** Both ligands have 1 HBD, which is within the acceptable limit of 5.
5. **HBA:** Ligand A has 2 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.
6. **QED:** Both ligands have good QED scores (0.723 and 0.78), indicating good drug-like properties.
7. **DILI:** Ligand A (18.883) has a lower DILI risk than Ligand B (21.52), both are good, but A is slightly preferred.
8. **BBB:** Ligand A (82.164) has better BBB penetration than Ligand B (69.523). While not a primary concern for a kinase inhibitor, it's a slight advantage.
9. **Caco-2:** Ligand A (-4.358) has a much better Caco-2 permeability than Ligand B (-4.683). Higher values are better, and A is significantly better.
10. **Solubility:** Ligand A (-4.229) has better aqueous solubility than Ligand B (-1.571). Solubility is important for kinases.
11. **hERG:** Ligand A (0.562) has a lower hERG risk than Ligand B (0.212). Lower is better, and A is preferred.
12. **Cl_mic:** Ligand A (90.378) has a higher microsomal clearance than Ligand B (17.036). This means Ligand B is more metabolically stable, which is a significant advantage for kinase inhibitors.
13. **t1/2:** Ligand B (35.043) has a significantly longer in vitro half-life than Ligand A (13.023). This is a major advantage for Ligand B.
14. **Pgp:** Ligand A (0.188) has lower P-gp efflux than Ligand B (0.063). Lower is better, and A is preferred.
15. **Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a >1.5 kcal/mol difference, which is a very significant advantage.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and half-life, while Ligand A has better solubility and lower hERG risk. Ligand B's significantly better binding affinity and longer half-life outweigh the slight advantages of Ligand A in solubility and hERG. The difference in binding affinity is substantial enough to overcome the higher Cl_mic.

**Conclusion:**

Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 15:58:58,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.487 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is well below the 140 threshold, suggesting good absorption. Ligand B (116.4) is still within acceptable range, but less favorable.

**logP:** Ligand A (2.501) is optimal (1-3). Ligand B (-0.13) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is approaching the upper limit, but still acceptable.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**QED:** Ligand A (0.825) is excellent, indicating high drug-likeness. Ligand B (0.396) is significantly lower, raising concerns.

**DILI:** Ligand A (12.524) has a very low DILI risk. Ligand B (55.758) is moderately elevated, but not alarming.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.745) is higher than Ligand B (63.862).

**Caco-2 Permeability:** Ligand A (-4.897) and Ligand B (-5.507) both have negative values, which is unusual and requires further investigation. However, the values are relatively close.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.293 and -2.6), which is concerning. Solubility is a critical factor for *in vivo* efficacy.

**hERG Inhibition:** Ligand A (0.452) has a low hERG risk. Ligand B (0.029) is even lower, indicating a very favorable safety profile regarding cardiac toxicity.

**Microsomal Clearance:** Ligand A (47.631) is moderate. Ligand B (-10.971) is *very* low (negative values suggest high stability), which is a significant advantage.

**In vitro Half-Life:** Ligand A (-4.82) is negative, suggesting a long half-life. Ligand B (13.21) is a reasonable half-life.

**P-gp Efflux:** Ligand A (0.378) has low P-gp efflux. Ligand B (0.004) has extremely low P-gp efflux, which is beneficial for bioavailability.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.9 kcal/mol). The difference is 0.6 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand A has a superior QED score, better TPSA, and a significantly stronger binding affinity. However, Ligand B exhibits much better metabolic stability (lower Cl_mic, very low P-gp efflux) and a slightly better hERG profile. Both have poor solubility. Given the importance of metabolic stability for kinase inhibitors (to ensure sufficient exposure), and the substantial difference in Cl_mic, Ligand B is slightly favored. The higher affinity of Ligand A is attractive, but the improved pharmacokinetic properties of Ligand B are likely to translate to better *in vivo* efficacy. The solubility issues of both compounds would need to be addressed through formulation strategies.

Output:
1
2025-04-17 15:58:58,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.34 and 367.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.08) is significantly better than Ligand B (134.67). A TPSA under 140 is good for oral absorption, but Ligand B is approaching a level that might hinder it.

**logP:** Ligand A (4.843) is high, potentially causing solubility issues and off-target effects. Ligand B (0.921) is quite low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is still acceptable but less optimal.

**QED:** Both ligands have similar QED values (0.718 and 0.646), indicating reasonable drug-likeness.

**DILI:** Ligand A (64.172) has a moderate DILI risk, while Ligand B (81.427) has a higher risk. Lower is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.233) and B (37.418) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.701) and B (-5.343) both have negative values, which is unusual. This suggests very poor permeability.

**Aqueous Solubility:** Ligand A (-4.914) and B (-3.142) both have negative values, indicating very poor solubility.

**hERG:** Ligand A (0.951) has a lower hERG risk than Ligand B (0.083), which is a significant advantage.

**Microsomal Clearance:** Ligand A (24.021) has a higher clearance than Ligand B (18.17), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-22.844) has a very negative half-life, indicating extremely rapid metabolism. Ligand B (6.51) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.839) has a slightly higher P-gp efflux liability than Ligand B (0.071).

**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 (1.4 kcal/mol difference).

**Conclusion:**

Despite Ligand A's high logP and poor solubility, its *significantly* stronger binding affinity (-9.7 vs -8.3 kcal/mol) and lower hERG risk outweigh these drawbacks. The potency advantage is substantial enough to potentially overcome the ADME liabilities, especially considering optimization strategies could address solubility and logP. Ligand B has better ADME properties overall, but its weaker binding affinity makes it less likely to be a successful drug candidate.

Output:
0
2025-04-17 15:58:58,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.36 and 341.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is better than Ligand B (45.23), both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have a logP around 3.3, which is optimal.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, satisfying the criteria.

**QED:** Both ligands have good QED scores (0.844 and 0.893), indicating drug-likeness.

**DILI:** Ligand B (12.408) has a significantly lower DILI risk than Ligand A (47.034). This is a major advantage for Ligand B.

**BBB:** Both have high BBB penetration (89.919 and 84.878), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.475 and -4.681). This is unusual and suggests poor permeability, but the scale isn't fully defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-3.499 and -2.742). Again, the scale is unclear, but suggests poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.563) has slightly higher hERG inhibition risk than Ligand B (0.381), but both are relatively low.

**Microsomal Clearance:** Ligand A (41.399) has lower microsomal clearance than Ligand B (45.463), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (48.836) has a significantly longer in vitro half-life than Ligand A (-12.334). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.235).

**Binding Affinity:** Ligand B (-7.9) has slightly better binding affinity than Ligand A (-7.8). While the difference is small, it's within the range where it could be meaningful.

**Overall:**

Ligand B is superior due to its significantly lower DILI risk and longer in vitro half-life. While Ligand A has slightly better metabolic stability (lower Cl_mic), the DILI and half-life advantages of Ligand B are more important for an enzyme target. The slightly better binding affinity of Ligand B further supports its selection. 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 15:58:58,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.64) is better than Ligand B (61.88) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands (A: 1.784, B: 1.171) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (A: 0.792, B: 0.701), indicating drug-like properties.

**DILI:** Ligand A (12.369) has a slightly higher DILI risk than Ligand B (10.198), but both are well below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (A: 66.925, B: 68.864). Since SRC is not a CNS target, this is not a major differentiating factor.

**Caco-2 Permeability:** Ligand A (-4.52) shows better Caco-2 permeability than Ligand B (-4.859), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.779) is slightly better than Ligand B (-1.351) in terms of solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.381, B: 0.241), which is excellent.

**Microsomal Clearance:** Ligand A (11.012) has significantly lower microsomal clearance than Ligand B (20.137). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (16.647) has a much longer in vitro half-life than Ligand A (-0.868). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands show very low P-gp efflux (A: 0.032, B: 0.026), which is favorable.

**Binding Affinity:** Ligand A (-7.4) has a slightly stronger binding affinity than Ligand B (-7.2). While the difference is small (0.2 kcal/mol), it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity, Caco-2 permeability, and solubility, and crucially, significantly better metabolic stability (lower Cl_mic). Ligand B has a much longer half-life. However, for a kinase inhibitor, metabolic stability is often more critical than a slightly longer half-life, as kinases are often subject to rapid metabolism. The small difference in binding affinity is less important than the metabolic advantage.

Output:
0
2025-04-17 15:58:58,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 Da and 340.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (107.55 and 97.12) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.69) is slightly low, potentially hindering permeation. Ligand B (1.179) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the 5 limit.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.7 and 0.789), indicating drug-likeness.

**DILI:** Ligand A (47.693) has a lower DILI risk than Ligand B (55.293), which is preferable. Both are below the concerning 60 threshold.

**BBB:** Both ligands have similar low BBB penetration (37.069 and 37.96), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.023 and -5.705), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.397 and -1.146), also unusual and concerning, indicating poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.173 and 0.058). This is excellent.

**Microsomal Clearance:** Ligand A (8.172) has significantly lower microsomal clearance than Ligand B (-16.733). This suggests better metabolic stability for Ligand A, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-30.036) has a much longer in vitro half-life than Ligand B (23.236), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.012).

**Binding Affinity:** Ligand B (-9.3 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 threshold where it can outweigh other drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B's substantially stronger binding affinity (-9.3 vs -7.0 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The improved affinity is likely to outweigh the slightly higher DILI risk and the poorer metabolic stability compared to Ligand A. The metabolic stability is still acceptable, and the DILI risk is not high. The solubility and permeability issues would need to be addressed in further optimization, but the potency is the most critical factor at this stage.

Output:
1
2025-04-17 15:58:58,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.397 Da) is slightly better as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (58.12) is significantly better than Ligand B (91.32). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is higher, potentially hindering absorption.

**logP:** Ligand A (4.106) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.28) is within the optimal range (1-3).

**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 acceptable QED values (A: 0.905, B: 0.67), indicating good drug-like properties.

**DILI:** Ligand A (70.105) has a higher DILI risk than Ligand B (43.117). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.009) is higher than Ligand B (64.676), but it's not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.326) has better Caco-2 permeability than Ligand B (-5.207), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.608) has better solubility than Ligand B (-2.45), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.537) has a lower hERG risk than Ligand B (0.178), a significant advantage.

**Microsomal Clearance:** Ligand A (87.932) has higher microsomal clearance than Ligand B (9.838), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-11.599) has a significantly longer in vitro half-life than Ligand A (22.837), which is highly desirable.

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux than Ligand B (0.018), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This difference of 1.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility, permeability, and lower hERG risk, its higher DILI risk and significantly higher microsomal clearance (lower metabolic stability) are major concerns. Ligand B, despite having a slightly higher logP and TPSA, exhibits a much stronger binding affinity and a significantly longer half-life, making it a more promising candidate. The superior binding affinity of Ligand B is a critical factor for an enzyme inhibitor.

Output:
1
2025-04-17 15:58:58,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.43 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.39) is better than Ligand B (67.23), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands (3.059 and 2.512) are within the optimal 1-3 range.

**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 below the 10 threshold.

**QED:** Both ligands have acceptable QED scores (0.732 and 0.661), indicating good drug-likeness.

**DILI:** Ligand A (90.345) has a significantly higher DILI risk than Ligand B (35.479). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (82.319) has better penetration than Ligand B (55.176).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is closer to zero for Ligand A (-4.546) than Ligand B (-4.807).

**Aqueous Solubility:** Ligand A (-3.102) has slightly better solubility than Ligand B (-1.974), both are poor.

**hERG:** Ligand A (0.886) has a slightly higher hERG risk than Ligand B (0.153). Ligand B is much preferred here.

**Microsomal Clearance:** Ligand A (59.121) has a higher microsomal clearance than Ligand B (48.533), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (28.607 hours) has a significantly longer half-life than Ligand A (66.314 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.654) has higher P-gp efflux than Ligand B (0.1), which is undesirable.

**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.

**Conclusion:**

Despite the slightly better affinity of Ligand A, the significantly higher DILI risk, lower half-life, and higher P-gp efflux make it a less desirable candidate. Ligand B demonstrates a much more favorable safety profile (lower DILI, lower hERG), better metabolic stability (longer half-life, lower Cl_mic), and acceptable binding affinity. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 15:58:58,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.411 and 346.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.01) is slightly above the preferred <140, but acceptable. Ligand B (59.07) is excellent, well below 140.

**logP:** Ligand A (-0.412) is a bit low, potentially hindering permeability. Ligand B (4.334) is high, potentially causing solubility and off-target issues.

**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 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.699 and 0.652), indicating good drug-likeness.

**DILI:** Ligand A (61.225) has a moderate DILI risk, while Ligand B (24.932) has a low DILI risk, which is a significant advantage.

**BBB:** Ligand A (70.764) shows reasonable BBB penetration, while Ligand B (84.141) shows even better penetration. However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.939 and -4.845), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.511 and -4.483), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.2) has a very low hERG risk, which is excellent. Ligand B (0.911) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (31.356) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (86.611) has high microsomal clearance, indicating poor metabolic stability. This is a significant disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-20.117) has a negative half-life, which is not physically meaningful and suggests instability or an issue with the assay. Ligand B (36.197) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.034 and 0.298), which is favorable.

**Binding Affinity:** Both ligands have similar strong binding affinities (-8.1 and -8.9 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand B has a better DILI score, better BBB penetration, and a more reasonable in vitro half-life. However, it suffers from a high logP, high microsomal clearance, and poor solubility. Ligand A has a better hERG profile and a more reasonable logP, but its solubility is also poor, and its in vitro half-life is problematic.

Given the importance of metabolic stability for kinase inhibitors, and the significant difference in Cl_mic, I would lean towards Ligand A despite its solubility and half-life issues. The hERG profile is also a strong advantage. The solubility and half-life issues might be addressable through further optimization, while poor metabolic stability is harder to fix later in development.

Output:
0
2025-04-17 15:58:58,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.423 and 344.383 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (119.21 and 121.23) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-1.831) is a bit low, potentially hindering permeation. Ligand B (-0.512) is better, falling closer to the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the HBD <= 5 criteria.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (10) both meet the HBA <= 10 criteria.

**QED:** Both ligands have good QED scores (0.537 and 0.573), indicating drug-like properties.

**DILI:** Ligand A (16.208) has a significantly lower DILI risk than Ligand B (64.56), making it more favorable from a toxicity standpoint.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (30.089) and Ligand B (58.86) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.541 and -5.76), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.12 and -1.15), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.132) has a much lower hERG inhibition liability than Ligand B (0.052), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-18.06) has a much lower (better) microsomal clearance than Ligand B (24.991), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.754) has a negative half-life, which is unusual. Ligand B (4.779) has a short half-life, which is not ideal.

**P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux, while Ligand B (0.094) has slightly higher efflux.

**Binding Affinity:** Ligand B (-8.7 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 is the more promising candidate despite its low logP and negative solubility/Caco-2 values. Its significantly lower DILI risk, lower hERG inhibition, and better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme target. While both compounds have poor solubility and permeability, the safety profile of Ligand A is considerably better. The slightly better affinity of Ligand B does not outweigh these critical ADME/Tox concerns.

Output:
0
2025-04-17 15:58:58,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (377.853 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.29) is slightly higher than Ligand B (71.53), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.72 and 2.166), 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 (HBD <=5, HBA <=10).

**QED:** Both ligands have good QED scores (0.715 and 0.806), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (81.427%) compared to Ligand B (44.552%). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (74.254) than Ligand A (30.554), but this isn't a primary factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, this is a scale and the negative values are relative.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.477 and -3.013). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.358) has a slightly higher hERG risk than Ligand B (0.242), but both are relatively low.

**Microsomal Clearance:** Ligand B (23.036 mL/min/kg) has a much lower microsomal clearance than Ligand A (6.753 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand A has a very long in vitro half-life (99.955 hours), while Ligand B has a shorter one (11.454 hours). This is a positive for Ligand A, but less important than metabolic stability.

**P-gp Efflux:** Ligand A (0.223) has a slightly lower P-gp efflux liability than Ligand B (0.109), which is favorable.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.1 kcal/mol) compared to 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 high DILI risk and poor metabolic stability are major concerns. Ligand B, while having a much weaker binding affinity, exhibits a significantly better safety profile (lower DILI) and improved metabolic stability (lower Cl_mic). For an enzyme target like SRC kinase, metabolic stability and safety are paramount. While affinity is important, it can be improved through further optimization. The poor solubility of both compounds is a concern that would need to be addressed, but is less critical than the safety and metabolic properties.

Output:
1
2025-04-17 15:58:58,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (342.399 and 358.345 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (96.26 and 93.53) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.829) is optimal (1-3), while Ligand B (0.115) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) 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 similar QED values (0.799 and 0.755), indicating good drug-likeness.

**DILI:** Ligand A (72.005) has a higher DILI risk than Ligand B (49.205), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (86.817) has a better BBB percentile than Ligand A (69.794).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.554), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.252 and -1.5), also unusual and indicating poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.152) has a lower hERG inhibition liability than Ligand B (0.312), which is preferable.

**Microsomal Clearance:** Ligand A (18.177 mL/min/kg) has lower microsomal clearance than Ligand B (21.723 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.04 hours) has a significantly longer half-life than Ligand B (-20.154 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.058).

**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 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 has a significantly longer half-life, better binding affinity, lower hERG risk, and better metabolic stability (lower Cl_mic). The slightly higher DILI risk is less concerning than the other ADME drawbacks of Ligand B. The lower logP of Ligand B is a significant negative, potentially impacting its ability to reach the target.



Output:
0
2025-04-17 15:58:58,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (464.117 Da) is towards the higher end, while Ligand B (352.475 Da) is more optimal.

**TPSA:** Both are reasonably good, but Ligand B (78.87) is better than Ligand A (71.42), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (4.602) is high, potentially leading to solubility issues and off-target effects. Ligand B (1.485) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which is acceptable.

**QED:** Both have acceptable QED values (A: 0.466, B: 0.616), with B being slightly more drug-like.

**DILI:** Ligand A has a very high DILI risk (96.82%), which is a major red flag. Ligand B has a low DILI risk (5.312%).

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (68.864%) is higher than Ligand A (48.119%).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.072) is slightly better than Ligand B (-4.746), but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-1.402) is better than Ligand A (-5.338).

**hERG Inhibition:** Ligand A (0.898) has a slightly higher hERG risk than Ligand B (0.356), but both are reasonably low.

**Microsomal Clearance:** Ligand B (10.362 mL/min/kg) has significantly lower clearance than Ligand A (45.254 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.318 hours) has a negative half-life, which is concerning. Ligand A (63.127 hours) has a good half-life. However, negative half-life values are often artifacts of the prediction method.

**P-gp Efflux:** Ligand A (0.867) has higher P-gp efflux than Ligand B (0.083), meaning less bioavailability.

**Binding Affinity:** Ligand A (-7.6 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 significant ADME liabilities of Ligand A.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its extremely high DILI risk, high logP, poor solubility, and high P-gp efflux make it a very poor drug candidate. Ligand B, while having some permeability and solubility concerns, has a much more favorable ADME profile, particularly regarding DILI and metabolic stability. The difference in binding affinity is not large enough to outweigh the significant advantages of Ligand B.

Output:
1
2025-04-17 15:58:58,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 359.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is better than Ligand B (42.68) as it is still within the acceptable range for oral absorption (<140), while B is significantly lower.

**logP:** Ligand A (1.271) is optimal (1-3), while Ligand B (4.446) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (1) is good, while Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of <=10.

**QED:** Ligand A (0.809) is excellent, indicating high drug-likeness. Ligand B (0.653) is still acceptable but less favorable.

**DILI:** Ligand A (7.871) has a very low DILI risk, which is excellent. Ligand B (30.748) is higher, but still within the acceptable range (<40 is good).

**BBB:** Ligand A (67.158) is acceptable, while Ligand B (83.443) is very good. However, BBB is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.452 and -4.487), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.114) is slightly better than Ligand B (-5.214), but both are poor, suggesting formulation challenges.

**hERG Inhibition:** Both ligands (0.358 and 0.829) have low hERG inhibition risk, which is positive.

**Microsomal Clearance:** Ligand A (15.905) has significantly lower clearance than Ligand B (107.669), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (1.533) has a shorter half-life than Ligand B (48.753), which is a disadvantage.

**P-gp Efflux:** Both ligands (0.061 and 0.78) have low P-gp efflux, which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Conclusion:**

Despite the similar binding affinity, Ligand A is the more promising candidate. Its superior QED, significantly lower DILI risk, and much better metabolic stability (lower Cl_mic) outweigh the longer half-life of Ligand B. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies. Ligand B's high logP is a significant drawback, potentially leading to off-target effects and formulation issues.

Output:
0
2025-04-17 15:58:58,208 - INFO - Batch 425 complete. Total preferences: 6800
2025-04-17 15:58:58,208 - INFO - Processing batch 426/512...
2025-04-17 15:59:37,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.487 and 356.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (90.98). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B is approaching a level that could hinder absorption.

**logP:** Ligand A (1.295) is optimal, while Ligand B (0.138) is quite low. A logP below 1 can indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improves permeability.

**QED:** Ligand A (0.682) has a better QED score than Ligand B (0.429), suggesting a more drug-like profile.

**DILI:** Ligand B (18.651) has a lower DILI risk than Ligand A (11.206), which is a positive attribute.

**BBB:** Ligand A (80.807) has better BBB penetration potential than Ligand B (63.862), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.662) exhibits better Caco-2 permeability than Ligand B (-5.173). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.156) has better aqueous solubility than Ligand B (-0.851). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.607) has a lower hERG risk than Ligand B (0.13). This is a significant advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (22.737) has slightly higher microsomal clearance than Ligand A (20.927), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (5.29) has a longer in vitro half-life than Ligand B (-4.905). This is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.042) has lower P-gp efflux liability than Ligand B (0.002), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.2 kcal/mol). Although both are good, the 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in key ADME properties (logP, TPSA, solubility, permeability, hERG) and has a slightly better binding affinity. While Ligand B has a lower DILI risk, the superior ADME profile and binding affinity of Ligand A make it the more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 15:59:37,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (118.37 and 114.35) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.483) is slightly low, potentially hindering permeation. Ligand B (1.902) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) and Ligand B (2 HBD, 6 HBA) both meet the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.544 and 0.828), indicating drug-likeness.

**DILI:** Ligand A (52.191) has a lower DILI risk than Ligand B (60.062), which is preferable.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (70.105) has a higher BBB percentile than Ligand A (27.491), but this isn't a major factor here.

**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 significant drawback for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.022 and 0.186), which is excellent.

**Microsomal Clearance:** Ligand A (4.866 mL/min/kg) has significantly lower microsomal clearance than Ligand B (32.79 mL/min/kg), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (24.017 hours) has a much longer in vitro half-life than Ligand B (-33.367 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 (0.005 and 0.007), which is favorable.

**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 for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a slightly better logP, Ligand B's significantly stronger binding affinity (-9.0 vs -8.7 kcal/mol) is a critical factor for an enzyme inhibitor. The difference of 0.3 kcal/mol is substantial. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies. The negative half-life for Ligand B is a major red flag, however.

Considering the importance of potency for enzyme inhibition, and the fact that the binding affinity difference is significant, I would choose Ligand B, but with a strong caveat that the negative half-life needs to be investigated and resolved.

Output:
1
2025-04-17 15:59:37,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.363 Da and 350.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.94) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (94.99) is excellent, well below 140.

**logP:** Ligand A (0.15) is quite low, potentially hindering permeability. Ligand B (2.97) is nearly ideal.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is acceptable, but approaching the upper limit.

**H-Bond Acceptors:** Ligand A (8) is good. Ligand B (7) is also good.

**QED:** Ligand A (0.788) is excellent, indicating high drug-likeness. Ligand B (0.515) is acceptable, but lower than A.

**DILI:** Ligand A (54.75) is better than Ligand B (38.348) indicating a lower risk of drug-induced liver injury.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (77.821) is higher than Ligand A (57.968).

**Caco-2 Permeability:** Ligand A (-5.219) is very poor, suggesting extremely low intestinal absorption. Ligand B (-4.839) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.181) is poor. Ligand B (-4.457) is worse. Both are concerning.

**hERG Inhibition:** Ligand A (0.108) is very low risk, excellent. Ligand B (0.729) is higher, indicating a moderate risk.

**Microsomal Clearance:** Ligand A (26.351) is relatively low, suggesting better metabolic stability. Ligand B (74.323) is high, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (21.65) is moderate. Ligand B (44.833) is better, suggesting a longer half-life.

**P-gp Efflux:** Both are low (0.041 and 0.049), so P-gp is unlikely to be a major issue for either.

**Binding Affinity:** Ligand A (-9.4) is significantly stronger than Ligand B (-6.7), a difference of 2.7 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity (-9.4 kcal/mol vs -6.7 kcal/mol), a lower DILI risk, and a better hERG profile. However, it suffers from very poor Caco-2 permeability and low solubility, and a low logP. Ligand B has better solubility and permeability characteristics, but its affinity is considerably weaker, and its DILI risk is higher.

The large difference in binding affinity is the most important factor here. While the ADME properties of Ligand A are suboptimal, it's possible to improve these through medicinal chemistry efforts. It's much harder to significantly improve binding affinity. Given that we're targeting an enzyme, potency is paramount. The poor permeability and solubility of Ligand A are addressable through structural modifications, while a weaker binder may require a complete redesign.

Output:
0
2025-04-17 15:59:37,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.515 and 370.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (97.64). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range.

**logP:** Both ligands have acceptable logP values (1.294 and 1.646, respectively), falling within the 1-3 range.

**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 (0.788 and 0.821), indicating drug-likeness.

**DILI:** Ligand A (37.999) has a significantly lower DILI risk than Ligand B (66.421). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (41.838) and Ligand B (64.831) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.211 and -5.093), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.367 and -2.449), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.112) has a much lower hERG inhibition liability than Ligand B (0.403), which is a substantial safety advantage.

**Microsomal Clearance:** Ligand A (33.041) has a higher microsomal clearance than Ligand B (15.931), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (31.739) has a longer in vitro half-life than Ligand A (20.047), which is desirable.

**P-gp Efflux:** Ligand A (0.036) has a much lower P-gp efflux liability than Ligand B (0.137), which is favorable for bioavailability.

**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:**

Despite Ligand B having slightly better affinity and metabolic stability, Ligand A is the more promising candidate. The significantly lower DILI risk and hERG inhibition liability of Ligand A are critical advantages. While both compounds suffer from poor solubility and permeability, the safety profile of Ligand A is far superior. The small difference in binding affinity is outweighed by the substantial improvements in safety and ADME properties.

Output:
0
2025-04-17 15:59:37,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (355.435 Da and 376.917 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (121.96) is better than Ligand B (79.42), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (-0.321) is slightly low, potentially hindering permeation. Ligand B (3.76) is within the optimal range of 1-3. This favors Ligand B.

**4. H-Bond Donors (HBD):** Ligand A (3) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A (5) and Ligand B (7) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.551 and 0.755, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (16.053) has a significantly lower DILI risk than Ligand B (69.252). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (42.226) and Ligand B (71.811) are both relatively low, which isn't a primary concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.732 and -5.243), 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 (-1.369 and -4.956), which is also unusual and suggests poor solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Ligand A (0.104) has a lower hERG inhibition liability than Ligand B (0.351), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-13.702) has a much lower (better) microsomal clearance than Ligand B (59.359), suggesting greater metabolic stability. This is highly favorable for an enzyme target.

**13. In vitro Half-Life:** Ligand A (14.456 hours) has a longer half-life than Ligand B (20.043 hours).

**14. P-gp Efflux:** Ligand A (0.013) has a lower P-gp efflux liability than Ligand B (0.512), potentially leading to better oral bioavailability.

**15. Binding Affinity:** Both ligands have strong binding affinities (-9.5 kcal/mol and -8.7 kcal/mol). Ligand A is slightly better.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A excels in metabolic stability (Cl_mic), DILI risk, hERG, and P-gp efflux. While Ligand B has a better logP, the significantly improved safety profile and metabolic stability of Ligand A outweigh this advantage. The slightly better binding affinity of Ligand A is also a plus.

Output:
0
2025-04-17 15:59:37,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.407 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.16) is slightly higher than Ligand B (49.85). Both are below the 140 threshold for good absorption, but B is better.

**logP:** Ligand A (4.657) is higher than the optimal range of 1-3, potentially leading to solubility issues and off-target effects. Ligand B (2.589) is within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.688 and 0.606), indicating reasonable drug-likeness.

**DILI:** Ligand A (78.286) has a significantly higher DILI risk than Ligand B (2.171). This is a major concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (75.611 and 86.468), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.805 and -4.47), which is unusual and suggests poor permeability. This needs further investigation, but is less concerning than other issues.

**Aqueous Solubility:** Ligand A (-5.347) has very poor aqueous solubility, which is a significant drawback. Ligand B (-0.963) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.811) has a slightly higher hERG risk than Ligand B (0.614), but both are reasonably low.

**Microsomal Clearance:** Ligand A (92.445) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (17.672) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (28.466) has a moderate half-life, while Ligand B (-9.277) has a very short half-life. This is a negative for Ligand B.

**P-gp Efflux:** Ligand A (0.657) has a lower P-gp efflux liability than Ligand B (0.041), which is favorable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. While its half-life is very short, it demonstrates significantly better metabolic stability (lower Cl_mic), a much lower DILI risk, and a more favorable logP value. Ligand A suffers from poor solubility, high DILI risk, and high metabolic clearance, outweighing its slightly better binding affinity and P-gp efflux. The Caco-2 values are concerning for both, but the other factors make Ligand B the better choice for further optimization.

Output:
1
2025-04-17 15:59:37,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.439 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (95.67) is higher than Ligand B (40.62). While both are below 140, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (1.58) is within the optimal range (1-3). Ligand B (3.232) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 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 (0.779) has a significantly better QED score than Ligand B (0.446), indicating a more drug-like profile.

**DILI:** Ligand A (57.658) has a higher DILI risk than Ligand B (13.339). This is a significant concern for Ligand A.

**BBB:** Ligand A (36.371) has a lower BBB penetration percentile than Ligand B (77.627). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.395) has worse Caco-2 permeability than Ligand B (-4.604).

**Aqueous Solubility:** Ligand A (-1.422) has worse solubility than Ligand B (-3.473). Solubility is important for enzyme inhibitors.

**hERG:** Ligand A (0.149) has a slightly higher hERG risk than Ligand B (0.692), but both are relatively low.

**Microsomal Clearance:** Ligand A (-1.099) has a *lower* (better) microsomal clearance than Ligand B (49.342). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (22 hours) has a longer half-life than Ligand B (18.043 hours).

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux than Ligand B (0.322), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.4 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 has a better ADME profile overall, with lower DILI risk, better solubility, and better Caco-2 permeability. However, Ligand A has better QED, metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux. The binding affinity difference is relatively small. The biggest drawback for Ligand A is the higher DILI risk. However, the improved metabolic stability and longer half-life are valuable. Given the enzyme-specific priorities, the slightly better affinity of Ligand B, combined with its significantly improved safety profile (lower DILI) and better solubility, makes it the more promising candidate.

Output:
1
2025-04-17 15:59:37,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.483 and 351.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.71) is higher than Ligand B (48). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (1.378) is within the optimal range, while Ligand B (3.282) is approaching the upper limit. This suggests Ligand A might have better solubility, while Ligand B could have off-target issues.

**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 (0.493 and 0.497), indicating comparable drug-likeness.

**DILI:** Ligand A (27.995) has a significantly lower DILI risk than Ligand B (15.161), which is a major advantage.

**BBB:** Ligand A (62.737) has a lower BBB penetration than Ligand B (87.088). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.841 and -4.365), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.721 and -2.791), also unusual and concerning.

**hERG:** Ligand A (0.124) has a much lower hERG inhibition liability than Ligand B (0.435), a significant safety advantage.

**Microsomal Clearance:** Ligand A (86.736) has a higher microsomal clearance than Ligand B (84.025), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (10.221) has a significantly longer in vitro half-life than Ligand A (-28.83), which is a substantial advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux liability than Ligand B (0.288).

**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 B has a slightly better binding affinity and a significantly longer half-life. However, Ligand A demonstrates a much lower risk of DILI and hERG inhibition, which are critical safety parameters. The negative Caco-2 and solubility values are concerning for both compounds, but the safety profile of Ligand A is more favorable. For an enzyme target like SRC kinase, prioritizing safety and metabolic stability alongside potency is crucial. The small affinity difference is outweighed by the substantial safety advantages of Ligand A.

Output:
1
2025-04-17 15:59:37,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.5 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is better than Ligand B (84.67). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral absorption.

**logP:** Both ligands have good logP values (2.346 and 1.387), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have high QED scores (0.805 and 0.839), indicating good drug-likeness.

**DILI:** Ligand A (33.773) has a significantly lower DILI risk than Ligand B (13.067). This is a major advantage for Ligand A.

**BBB:** Ligand B (73.827) shows better BBB penetration than Ligand A (64.482), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. However, the value for Ligand A (-5.06) is less negative than Ligand B (-4.837), suggesting potentially slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also problematic. Ligand A (-2.039) is slightly better than Ligand B (-1.787).

**hERG:** Both ligands have very low hERG risk (0.221 and 0.147).

**Microsomal Clearance:** Ligand B (21.181) has significantly lower microsomal clearance than Ligand A (49.022), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (6.471) has a much longer in vitro half-life than Ligand A (1.447), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.154 and 0.015).

**Binding Affinity:** Ligand A (-9.7 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:**

Ligand A has a significantly better binding affinity and lower DILI risk, which are key for an enzyme target. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), the superior potency of Ligand A is likely to be more impactful. Both have concerning negative Caco-2 and solubility values, which would need to be addressed in further optimization. However, the strong binding affinity of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 15:59:37,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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.

**TPSA:** Ligand A (56.15) is significantly better than Ligand B (67.23). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.227) is slightly higher than Ligand B (1.779), both are within the optimal range of 1-3.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand B (0.789) has a better QED score than Ligand A (0.446), indicating a more drug-like profile.

**DILI:** Ligand A (12.602) has a significantly lower DILI risk than Ligand B (60.721). This is a major advantage for Ligand A.

**BBB:** Both have high BBB penetration (Ligand A: 81.698, Ligand B: 87.127), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-4.956 vs -4.775).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and concerning. Again, the values are similar (-3.153 vs -3.493).

**hERG Inhibition:** Ligand A (0.635) has a slightly higher hERG risk than Ligand B (0.32), but both are relatively low.

**Microsomal Clearance:** Ligand A (70.754) has a higher microsomal clearance than Ligand B (40.225), meaning Ligand B is more metabolically stable. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-34.837) has a much longer in vitro half-life than Ligand A (-2.314). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.449) has lower P-gp efflux than Ligand B (0.114), which is favorable.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B clearly wins on potency (binding affinity) and metabolic stability (lower Cl_mic, longer t1/2). It also has a better QED score. While Ligand A has a lower DILI risk and P-gp efflux, the superior binding affinity of Ligand B is a decisive advantage for an enzyme target like SRC kinase. The similar, and problematic, solubility and Caco-2 values are a concern for both, but the potency and stability of Ligand B are more critical.

Output:
1
2025-04-17 15:59:37,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.853 and 357.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (99.81). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit and could have absorption issues.

**logP:** Ligand A (3.727) is slightly higher than the optimal 1-3 range but still acceptable. Ligand B (1.856) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=6) both have reasonable numbers of H-bond donors and acceptors, satisfying the <5 HBD and <10 HBA criteria.

**QED:** Both ligands have similar QED values (0.83 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (60.45) is slightly higher risk than Ligand B (52.772), but both are still within an acceptable range (<60 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.176) has better BBB penetration than Ligand B (43.777), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.925) is better than Ligand B (-5.416), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.007) is better than Ligand B (-2.795), which is a significant advantage for bioavailability.

**hERG Inhibition:** Ligand A (0.923) has a slightly higher hERG risk than Ligand B (0.535), but both are relatively low.

**Microsomal Clearance:** Ligand A (40.039) has a higher clearance than Ligand B (-0.882). This indicates that Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (10.473) has a significantly longer half-life than Ligand A (0.557), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.736) has slightly lower P-gp efflux than Ligand B (0.019), which could improve bioavailability.

**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 (0.4 kcal/mol), it is still a factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better solubility and slightly lower P-gp efflux, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a slightly better binding affinity. These factors are more critical for an enzyme target like SRC kinase. The TPSA of Ligand B is higher, but the benefits in metabolic stability and binding outweigh this drawback.

Output:
1
2025-04-17 15:59:37,634 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (360.411 and 384.567 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (126.07) is borderline, but acceptable for an enzyme target, while Ligand B (51.66) is well within the desired range for good absorption.

**3. logP:** Ligand A (-1.584) is a bit low, potentially hindering permeability. Ligand B (3.154) is optimal.

**4. H-Bond Donors (HBD):** Ligand A (3) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors (HBA):** Ligand A (7) is good. Ligand B (6) is good.

**6. QED:** Ligand A (0.317) is below the preferred threshold of 0.5, indicating a less drug-like profile. Ligand B (0.612) is above the threshold and more drug-like.

**7. DILI:** Ligand A (26.793) has a lower DILI risk than Ligand B (43.117), which is good. Both are acceptable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.551) has a higher BBB score than Ligand A (39.473), but it's not a deciding factor here.

**9. Caco-2 Permeability:** Ligand A (-5.633) shows poor permeability. Ligand B (-4.902) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-0.674) has very poor solubility. Ligand B (-2.468) is also poor, but slightly better than A.

**11. hERG Inhibition:** Ligand A (0.039) has a very low hERG risk, which is excellent. Ligand B (0.436) is slightly higher, but still acceptable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (40.626) has a moderate clearance. Ligand B (55.209) has a higher clearance, suggesting lower metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (-32.955) has a very short half-life. Ligand B (-2.402) has a slightly longer half-life, but still not ideal.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.001 and 0.243 respectively).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-7.6 and -7.7 kcal/mol). This is a major positive for both.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both ligands have excellent affinity, Ligand A suffers from very poor solubility, short half-life, and moderate clearance. Ligand B has better solubility and a slightly better half-life, despite the higher clearance. The lower hERG risk of Ligand A is a plus, but the significant ADME deficiencies outweigh this benefit.

Output:
1
2025-04-17 15:59:37,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (479.231 Da) is at the higher end, while Ligand B (354.491 Da) is more favorably positioned.

**TPSA:** Ligand A (35.58) is excellent, well below the 140 threshold for absorption. Ligand B (67.87) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 3.247, B: 2.137), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1 each). Ligand B has a slightly higher HBA count (4 vs 2 for A), but both are under the 10 threshold.

**QED:** Both ligands have acceptable QED scores (A: 0.371, B: 0.61). Ligand B is better here.

**DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (20.279), but both are below the concerning 60 percentile.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (82.668) has a higher BBB score than Ligand B (66.344).

**Caco-2 Permeability:** Both 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 values represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also concerning. Ligand A (-3.203) is slightly better than Ligand B (-1.968), but both are poor.

**hERG:** Both ligands have low hERG risk (A: 0.918, B: 0.296). Ligand B is significantly better.

**Microsomal Clearance:** Ligand A (34.61 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (49.764 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (40.819 hours) has a much longer half-life than Ligand B (1.779 hours), a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.316, B: 0.023). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B clearly wins on binding affinity, which is paramount for an enzyme inhibitor. It also has a better QED, lower DILI risk, and lower hERG risk. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2) and a slightly better solubility score, the substantial affinity advantage of Ligand B outweighs these benefits. The poor solubility and Caco-2 permeability of both are concerning and would require further investigation/optimization, but the potency of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 15:59:37,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.571 and 360.933 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (25.99). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have logP values (3.81 and 4.337) that are slightly above the optimal 1-3 range, but still acceptable. Ligand B is slightly higher, which *could* lead to some solubility issues.

**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 QED values (0.642 and 0.622), indicating good drug-like properties.

**DILI:** Ligand A (19.271) has a slightly higher DILI risk than Ligand B (12.834), but both are below the concerning threshold of 40.

**BBB:** Both ligands have reasonable BBB penetration (70.415 and 66.033). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.988 and -4.796). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are common. The absolute values are similar, so this doesn't significantly differentiate the two.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.118 and -4.853). This is also unusual, and suggests poor solubility. Again, the absolute values are similar.

**hERG Inhibition:** Ligand A (0.379) has a lower hERG inhibition risk than Ligand B (0.889), which is a significant advantage. Avoiding hERG liability is crucial.

**Microsomal Clearance:** Ligand B (40.354 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (82.533 mL/min/kg). This indicates that Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (50.821 hours) has a much longer in vitro half-life than Ligand A (10.375 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.146 and 0.458).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.4 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2), Ligand A has a lower hERG risk and a better TPSA. Considering the priorities for enzyme inhibitors, metabolic stability is paramount. The slightly better affinity of Ligand B, coupled with its significantly improved metabolic profile, outweighs the slightly higher hERG risk and higher TPSA of Ligand A. The solubility and permeability issues are similar for both.

Output:
1
2025-04-17 15:59:37,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 Da and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (58.44), but both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.359) is within the optimal 1-3 range. Ligand B (2.545) is also acceptable, though leaning towards the higher end.

**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 <=10 limit.

**QED:** Both ligands have good QED scores (0.735 and 0.795 respectively), indicating good drug-like properties.

**DILI:** Ligand A (25.979) has a significantly lower DILI risk than Ligand B (30.826). Both are below the 40 threshold, indicating low risk.

**BBB:** Ligand A (71.733) has a good BBB penetration, while Ligand B (89.066) is even better. However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.726 and -4.716). This is unusual and suggests poor permeability. However, these values are very close, so the difference is not significant.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.615 and -2.588), which is concerning. Solubility is a key factor for oral bioavailability. Ligand B has slightly worse solubility.

**hERG Inhibition:** Ligand A (0.125) has a much lower hERG inhibition liability than Ligand B (0.381), which is a significant advantage.

**Microsomal Clearance:** Ligand A (36.058) has a lower microsomal clearance than Ligand B (55.424), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.314) has a longer in vitro half-life than Ligand B (-12.868), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.216), which is favorable.

**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 minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand A demonstrates significantly better potency (binding affinity), metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, lower P-gp efflux, and lower DILI risk. The stronger binding affinity is a key advantage for an enzyme inhibitor.

Output:
1
2025-04-17 15:59:37,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.459 Da and 358.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.86) is slightly above the preferred <140, but acceptable. Ligand B (92.49) is well within the acceptable range.

**logP:** Ligand A (-0.852) is a bit low, potentially hindering permeability. Ligand B (1.354) is within 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 7 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.678 and 0.688), indicating good drug-likeness.

**DILI:** Ligand A (35.712) has a significantly lower DILI risk than Ligand B (74.99), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.801) and Ligand B (55.603) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.266 and -5.754), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.808 and -1.976), indicating very poor aqueous solubility, a significant drawback.

**hERG:** Ligand A (0.029) has a very low hERG risk, while Ligand B (0.224) has a slightly higher, but still relatively low, risk.

**Microsomal Clearance:** Ligand A (-3.579) has a much lower (better) microsomal clearance than Ligand B (55.048), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (14.028 hours) has a shorter half-life than Ligand B (22.735 hours), but both are reasonable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.011 and 0.045).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a 0.8 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A has a much better safety profile (lower DILI) and better metabolic stability (lower Cl_mic). Both have poor solubility and permeability. The difference in binding affinity is substantial (0.8 kcal/mol). Given the importance of potency for enzyme inhibition, and the fact that the other drawbacks are potentially addressable through formulation or further optimization, Ligand B is the more promising candidate.

Output:
1
2025-04-17 15:59:37,635 - INFO - Batch 426 complete. Total preferences: 6816
2025-04-17 15:59:37,635 - INFO - Processing batch 427/512...
2025-04-17 16:00:19,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**
*   **MW:** 336.355 Da - Good (within 200-500 range)
*   **TPSA:** 114.93 - Good (below 140)
*   **logP:** 1.417 - Good (within 1-3)
*   **HBD:** 3 - Good (<=5)
*   **HBA:** 6 - Good (<=10)
*   **QED:** 0.63 - Good (>=0.5)
*   **DILI:** 85.537 - High Risk (>60)
*   **BBB:** 44.358 - Low (not a priority for SRC, but not ideal)
*   **Caco-2:** -5.574 - Poor (negative value suggests very low permeability)
*   **Solubility:** -3.379 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.436 - Good (low risk)
*   **Cl_mic:** 7.29 - Good (low clearance, good metabolic stability)
*   **t1/2:** 25.065 - Good (long half-life)
*   **Pgp:** 0.034 - Good (low efflux)
*   **Affinity:** 0.0 kcal/mol - Very Poor (not binding)

**Ligand B:**
*   **MW:** 364.555 Da - Good (within 200-500 range)
*   **TPSA:** 49.41 - Excellent (below 90)
*   **logP:** 3.231 - Good (within 1-3)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 3 - Good (<=10)
*   **QED:** 0.706 - Good (>=0.5)
*   **DILI:** 13.532 - Excellent (low risk)
*   **BBB:** 77.821 - Good (not a priority for SRC, but favorable)
*   **Caco-2:** -5.163 - Poor (negative value suggests very low permeability)
*   **Solubility:** -3.733 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.531 - Good (low risk)
*   **Cl_mic:** 70.636 - Poor (high clearance, poor metabolic stability)
*   **t1/2:** -10.773 - Very Poor (negative half-life is not possible)
*   **Pgp:** 0.3 - Good (low efflux)
*   **Affinity:** -6.8 kcal/mol - Good (strong binding)

**Comparison & Decision:**

Ligand A has a very poor binding affinity (0 kcal/mol), making it a non-starter regardless of other properties. While it has acceptable metabolic stability and low Pgp efflux, its extremely poor Caco-2 permeability and solubility, coupled with high DILI risk, are significant drawbacks.

Ligand B has a much stronger binding affinity (-6.8 kcal/mol). While it also suffers from poor Caco-2 permeability and solubility, its DILI risk is very low. However, its high microsomal clearance and negative half-life are major concerns. The negative half-life is likely an error in the data, but the high clearance is still problematic.

Despite the issues with solubility, permeability, and clearance, Ligand B is significantly more promising due to its binding affinity. The other issues might be addressable through further optimization, but without binding, there is nothing to optimize.

Output:
1
2025-04-17 16:00:19,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.539 Da and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (77.69). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have acceptable logP values (3.178 and 2.41), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (0 HBD, 7 HBA). While both are within acceptable limits, fewer H-bonds generally lead to better permeability.

**QED:** Ligand A (0.845) has a higher QED score than Ligand B (0.669), indicating a more drug-like profile.

**DILI:** Ligand A (35.479) has a lower DILI risk than Ligand B (51.26), which is a significant advantage. Both are below the 60 threshold, but A is better.

**BBB:** Both ligands have good BBB penetration (70.027 and 83.133), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.007) and Ligand B (-4.623) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but it suggests limited permeability.

**Aqueous Solubility:** Ligand A (-3.742) has better solubility than Ligand B (-1.875), which is a crucial factor for bioavailability.

**hERG Inhibition:** Ligand A (0.59) has a significantly lower hERG risk than Ligand B (0.147). This is a major advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (83.27) has a slightly lower microsomal clearance than Ligand A (84.904), suggesting better metabolic stability. However, the difference is small.

**In vitro Half-Life:** Ligand B (-14.399) has a much longer in vitro half-life than Ligand A (-3.068). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.462 and 0.164).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 0.6 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is superior due to its better QED, lower DILI risk, better solubility, and significantly lower hERG inhibition liability. While Ligand B has a longer half-life, the safety and ADME advantages of Ligand A outweigh this benefit. The slightly better binding affinity of Ligand A further supports its selection.

Output:
1
2025-04-17 16:00:19,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.391 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.59) is better than Ligand B (60.85), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand B (2.279) is optimal (1-3), while Ligand A (0.533) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, both are within the limit of 5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.634 and 0.799, respectively), indicating drug-like properties.

**DILI:** Ligand B (9.267) has a significantly lower DILI risk than Ligand A (65.491), a major advantage.

**BBB:** Both ligands have moderate BBB penetration (36.371 and 67.003). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.789) has poor Caco-2 permeability, while Ligand B (-4.59) is slightly better but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.21 and -2.56). This is a concern, but can sometimes be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.035) has a very low hERG risk, which is excellent. Ligand B (0.557) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-3.415) exhibits better metabolic stability (lower clearance) than Ligand B (29.135).

**In vitro Half-Life:** Ligand A (11.932) has a longer half-life than Ligand B (2.483).

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux, while Ligand B (0.189) is slightly higher.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.0). The difference is minimal.

**Overall Assessment:**

Ligand A has better metabolic stability (Cl_mic, t1/2) and a much lower hERG risk. However, its low logP and poor Caco-2 permeability are significant drawbacks. Ligand B has a much better DILI score, a more optimal logP, and slightly better Caco-2 permeability. While its metabolic stability is worse, the superior safety profile (DILI) and acceptable logP make it the more promising candidate. The slight advantage in binding affinity also supports this decision.

Output:
1
2025-04-17 16:00:19,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which *could* be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (64.11) is better than Ligand B (49.41) as it is lower, suggesting better absorption.

**logP:** Both ligands have good logP values (A: 4.304, B: 3.319), 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 5 HBA, while Ligand B has 2. Both are within acceptable limits (<=10).

**QED:** Ligand A (0.823) has a significantly higher QED score than Ligand B (0.553), indicating a more drug-like profile.

**DILI:** Ligand B (28.112) has a much lower DILI risk than Ligand A (44.591), which is a significant advantage.

**BBB:** Both have good BBB penetration, but Ligand B (90.112) is better than Ligand A (71.656). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.467) is slightly worse than Ligand B (-4.909).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-5.341) is slightly better than Ligand B (-4.276).

**hERG:** Both have low hERG inhibition liability (A: 0.31, B: 0.378), which is excellent.

**Microsomal Clearance:** Ligand B (38.194) has significantly lower microsomal clearance than Ligand A (94.356), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-6.522) has a much longer in vitro half-life than Ligand A (-0.87), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.102, B: 0.171), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is the most important factor for an enzyme inhibitor. The difference of 2.2 kcal/mol is substantial.

**Conclusion:**

While Ligand A has a better QED and slightly better TPSA, Ligand B excels in the most crucial areas for an SRC kinase inhibitor: significantly stronger binding affinity, much better metabolic stability (lower Cl_mic and longer t1/2), and lower DILI risk. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies. The superior binding affinity of Ligand B outweighs the minor drawbacks.

Output:
1
2025-04-17 16:00:19,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.539 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is better than Ligand B (122.11), as it's closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.921 and 1.119), falling within the 1-3 range. Ligand A is slightly preferred due to being closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is slightly better than Ligand B (HBD=3, HBA=5) in terms of balancing solubility and permeability, being closer to the recommended limits.

**QED:** Ligand A (0.773) has a significantly better QED score than Ligand B (0.546), indicating a more drug-like profile.

**DILI:** Ligand B (39.822) has a lower DILI risk than Ligand A (56.301), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration (27.22 and 20.512), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.351 and -5.286), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.822 and -1.887), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.097) has a lower hERG inhibition risk than Ligand B (0.662), which is a positive.

**Microsomal Clearance:** Ligand A (36.732) has a higher microsomal clearance than Ligand B (13.962), meaning it is less metabolically stable. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (8.962) has a longer in vitro half-life than Ligand A (14.056), which is preferable.

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.119), which is slightly better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is better overall. While Ligand A has a better QED and lower hERG risk, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a lower DILI risk. The poor solubility and permeability are concerning for both, but the metabolic stability and safety profile of Ligand B are more critical for an enzyme target like SRC. The similar binding affinities mean these factors become the deciding ones.

Output:
1
2025-04-17 16:00:19,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.463 and 366.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is well below the 140 threshold for good absorption, while Ligand B (114.94) is still acceptable but less optimal.

**logP:** Ligand A (2.332) is within the optimal 1-3 range. Ligand B (0.588) is slightly below 1, 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 5 HBA, and Ligand B has 8 HBA. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**QED:** Both ligands have similar QED values (0.716 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (48.623) has a lower DILI risk than Ligand B (74.719), which is a significant advantage.

**BBB:** Ligand A (81.66) has better BBB penetration potential than Ligand B (47.421), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.542) has a more negative Caco-2 value, indicating *better* permeability than Ligand B (-5.78).

**Aqueous Solubility:** Ligand A (-3.154) has better aqueous solubility than Ligand B (-1.925).

**hERG Inhibition:** Ligand A (0.266) shows a much lower hERG inhibition liability than Ligand B (0.035). This is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (49.43) has a higher microsomal clearance than Ligand B (33.017), indicating *lower* metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (34.082) has a longer half-life than Ligand B (-0.162).

**P-gp Efflux:** Ligand A (0.228) has lower P-gp efflux liability than Ligand B (0.017).

**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:**

Ligand A is the stronger candidate. While its microsomal clearance is slightly higher (less stable) than Ligand B, it excels in crucial areas: lower DILI risk, better solubility, significantly lower hERG inhibition, better Caco-2 permeability, and slightly better binding affinity. The lower logP of Ligand B is a concern for permeability, and its higher hERG risk is a major red flag. The small difference in binding affinity is outweighed by the superior ADME/Tox profile of Ligand A.

Output:
1
2025-04-17 16:00:19,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.913 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 71-72, which is acceptable for general oral absorption, but not optimized for CNS penetration. This isn't a major concern for a non-CNS target like SRC.

**logP:** Ligand A (4.387) is higher than Ligand B (1.782). While 4.387 is approaching the upper limit, it's not drastically outside the optimal 1-3 range. Ligand B's logP is excellent.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 2/4, B: 1/4), falling within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.749, B: 0.903), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a significantly higher DILI risk (76.425%) compared to Ligand B (37.999%). This is a major red flag for Ligand A.

**BBB:** BBB is not a high priority for SRC, but Ligand A (61.497%) is slightly better than Ligand B (58.627%).

**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 can be misleading without context.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.299 and -2.373 respectively). This is a significant concern for both, but potentially more manageable if the compound demonstrates excellent potency and stability.

**hERG Inhibition:** Ligand A (0.562) has a slightly higher hERG risk than Ligand B (0.267), but both are relatively low.

**Microsomal Clearance:** Ligand B (31.396 mL/min/kg) has significantly lower microsomal clearance than Ligand A (66.061 mL/min/kg), indicating better metabolic stability. This is a critical advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-5.948 hours) has a negative half-life, which is impossible. This is a data error and a significant concern. Ligand A (89.864 hours) has a good half-life.

**P-gp Efflux:** Ligand A (0.446) has lower P-gp efflux than Ligand B (0.053), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-10.7 kcal/mol) has a *much* stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Despite the poor solubility and Caco-2 values for both, Ligand B is the stronger candidate. The significantly better binding affinity (-10.7 vs -7.7 kcal/mol) and lower microsomal clearance (31.396 vs 66.061 mL/min/kg) outweigh the slightly higher P-gp efflux. However, the negative half-life for Ligand B is a critical data quality issue that needs to be resolved. The high DILI risk for Ligand A is a major concern.

Output:
1
2025-04-17 16:00:19,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.828 and 357.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold, suggesting good absorption. Ligand B (92.51) is higher but still acceptable, though potentially impacting absorption slightly.

**logP:** Ligand A (4.482) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.708) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, though the higher HBA count could slightly affect permeability.

**QED:** Both ligands have similar and good QED scores (0.805 and 0.802).

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (54.556), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.988) is higher than Ligand B (76.037).

**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 ligands have negative solubility values, indicating poor aqueous solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.796) shows a slightly higher risk of hERG inhibition than Ligand B (0.187), which is a major advantage for B.

**Microsomal Clearance:** Ligand A (93.202) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (18.04) has a much lower clearance, suggesting better stability.

**In vitro Half-Life:** Ligand B (-20.927) has a significantly longer in vitro half-life than Ligand A (13.766), which is highly desirable.

**P-gp Efflux:** Ligand A (0.847) has a higher P-gp efflux liability than Ligand B (0.083), which is better.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a significant advantage for A.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, Ligand B is the more promising candidate. The key factors driving this decision are:

*   **Metabolic Stability:** Ligand B's significantly lower microsomal clearance and longer half-life are crucial for an enzyme target.
*   **hERG Risk:** Ligand B has a much lower hERG inhibition liability, reducing the risk of cardiotoxicity.
*   **DILI Risk:** Ligand B has a lower DILI risk.
*   **logP:** Ligand B's logP is within the optimal range, while A's is high.

While Ligand A's affinity is excellent, the ADME/Tox liabilities are too significant to ignore. The 1.9 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, whereas fixing the poor metabolic stability and hERG risk of Ligand A would be far more challenging. The solubility issues are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:00:19,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.462 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (67.23), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.668 and 2.246), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 5. This favors Ligand A.

**QED:** Both ligands have reasonable QED scores (0.83 and 0.788), indicating good drug-likeness.

**DILI:** Ligand A (19.193) has a much lower DILI risk than Ligand B (54.207), which is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (79.062) has a better BBB score than Ligand B (57.736).

**Caco-2 Permeability:** Ligand A (-4.825) and Ligand B (-5.074) are similar and suggest poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.861 and -3.742). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.517) has a slightly higher hERG risk than Ligand B (0.152), but both are relatively low.

**Microsomal Clearance:** Ligand A (34.362) has considerably lower microsomal clearance than Ligand B (49.625), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.501) has a much longer in vitro half-life than Ligand B (14.245), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux liability than Ligand B (0.141), which is favorable.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. The most significant advantages of Ligand A are its much stronger binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2). While both have poor solubility and permeability, the strong binding affinity of Ligand A makes it more likely to be effective *in vivo*, and the lower toxicity and better metabolic profile are highly desirable.

Output:
1
2025-04-17 16:00:19,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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:** Ligand A (90.98) is better than Ligand B (67.43) as it is closer to the upper limit of 140 for good absorption.

**logP:** Both ligands have good logP values (A: 1.404, B: 2.754), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.831) has a significantly higher QED score than Ligand B (0.626), indicating a more drug-like profile.

**DILI:** Ligand B (20.667) has a much lower DILI risk than Ligand A (52.385), a significant advantage.

**BBB:** Ligand B (68.399) has a higher BBB score than Ligand A (29.934), but BBB is not a primary concern for a non-CNS target like SRC.

**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 (-5.479) is slightly less negative than Ligand B (-5.035).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.048) is slightly better than Ligand B (-2.811).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.44 and 0.472 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-19.716) has a much lower (better) microsomal clearance than Ligand B (57.973), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-15.196) has a longer in vitro half-life than Ligand B (21.755), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.178 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has a better DILI score and slightly better Caco-2 permeability, Ligand A is superior overall. The significantly better QED, lower Cl_mic, and longer half-life of Ligand A outweigh the slightly higher DILI risk. The binding affinity is identical, so the ADME properties become the deciding factors. The improved metabolic stability and drug-likeness of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 16:00:19,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (451.676 Da) is closer to the upper limit, while Ligand B (353.507 Da) is more centrally located.

**TPSA:** Both ligands have TPSA values (68.29 and 70.67 respectively) that are acceptable for oral absorption (<140).

**logP:** Ligand A (4.366) is higher than optimal (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.544) is within the optimal range.

**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.

**QED:** Both ligands have good QED scores (0.554 and 0.694 respectively), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (92.051 percentile), which is a significant concern. Ligand B has a very low DILI risk (8.802 percentile), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (81.466) has better BBB penetration than Ligand B (58.278), but this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.206 and -4.941). This 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 very poor aqueous solubility (-5.484 and -1.012). This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.229) has a very low hERG risk, which is excellent. Ligand B (0.32) also has low hERG risk, but slightly higher than Ligand A.

**Microsomal Clearance:** Ligand A (87.525) has high microsomal clearance, indicating poor metabolic stability. Ligand B (24.483) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (39.856 hours) has a reasonable half-life, but Ligand B (-3.575 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound's stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.454 and 0.009 respectively).

**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 ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the Caco-2 and solubility values, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -7.3 kcal/mol) and much lower DILI risk (8.8 vs 92.05) are critical advantages for an enzyme target. While the negative in vitro half-life is concerning, it may be a data error. The improved metabolic stability (lower Cl_mic) also favors Ligand B. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 16:00:19,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.431 and 358.473 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is better than Ligand B (40.62), both are well below the 140 threshold for oral absorption.

**3. logP:** Ligand A (0.949) is slightly below the optimal 1-3 range, while Ligand B (3.347) is within the optimal range.

**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:** Ligand A (0.861) is excellent, indicating high drug-likeness. Ligand B (0.655) is still acceptable, but lower.

**7. DILI:** Ligand A (35.983) has a slightly higher DILI risk than Ligand B (25.359), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (56.495) has a lower BBB penetration than Ligand B (94.3). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.907) has worse Caco-2 permeability than Ligand B (-4.283), but both are negative, meaning low permeability.

**10. Aqueous Solubility:** Ligand A (-1.218) has better solubility than Ligand B (-3.595). Solubility is important for enzyme inhibitors.

**11. hERG Inhibition:** Ligand A (0.347) has a significantly lower hERG risk than Ligand B (0.917). This is a major advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (3.942) has a much lower microsomal clearance than Ligand B (45.979), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (8.503) has a longer half-life than Ligand B (3.049). This is also a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, while Ligand B (0.62) has moderate efflux.

**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, and other factors are more important.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and logP, Ligand A excels in critical ADME properties: significantly lower hERG risk, much better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and lower P-gp efflux. The better QED score also supports its drug-likeness. The slightly lower Caco-2 permeability and logP of Ligand A are less concerning given the other advantages, and can potentially be addressed with further optimization.

Output:
0
2025-04-17 16:00:19,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.423 and 370.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (78.43 and 76.46) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (3.284) is optimal, while Ligand B (1.177) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 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 (0.677 and 0.669), indicating good drug-likeness.

**DILI:** Ligand B (30.632) has a significantly lower DILI risk than Ligand A (42.536), making it more favorable from a toxicity perspective.

**BBB:** Both ligands have similar BBB penetration (38.775 and 38.891), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar, and very poor, Caco-2 permeability (-5.103 and -5.108). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Ligand B (-1.561) has better aqueous solubility than Ligand A (-3.43), which is beneficial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.396) has a slightly higher hERG risk than Ligand B (0.058), making Ligand B preferable for cardiac safety.

**Microsomal Clearance:** Ligand B (65.797) has a higher microsomal clearance than Ligand A (38.442), meaning it's metabolized faster and has lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (28.598) has a much longer in vitro half-life than Ligand A (-5.864), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.229 and 0.029).

**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 despite the higher clearance. The lower DILI risk, better solubility, and lower hERG risk are significant advantages. While the clearance is higher, the excellent binding affinity suggests that a reasonable dose could still achieve therapeutic concentrations. The similar Caco-2 permeability is a concern for both, but can be addressed with formulation strategies. Ligand A's higher DILI and hERG risk are less desirable.

Output:
1
2025-04-17 16:00:19,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.463 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is better than Ligand B (90.89). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Both ligands have good logP values (2.502 and 2.018), falling within the 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 8. Ligand A is preferable here, as lower HBA generally improves permeability.

**QED:** Both ligands have acceptable QED scores (0.905 and 0.802), indicating good drug-likeness.

**DILI:** Ligand A (44.281) has a lower DILI risk than Ligand B (55.719), which is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (76.347) has a slightly better BBB percentile than Ligand B (69.988).

**Caco-2 Permeability:** Ligand A (-4.432) shows better Caco-2 permeability than Ligand B (-5.549).

**Aqueous Solubility:** Both have negative solubility values (-2.285 and -2.189), indicating poor aqueous solubility. This is a concern for both, but similar.

**hERG Inhibition:** Ligand A (0.287) has a significantly lower hERG inhibition risk than Ligand B (0.073). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (39.334) has a higher microsomal clearance than Ligand B (25.508), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-1.431) has a longer in vitro half-life than Ligand A (1.58), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.054 and 0.072).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity (-7.6 vs -9.4 kcal/mol), and a longer in vitro half-life. However, Ligand A has better TPSA, lower DILI risk, and a much lower hERG inhibition liability. The strong affinity of Ligand B is a major plus, and the difference in binding is substantial enough to outweigh the slightly higher DILI and hERG risks, and the shorter half-life. The solubility is poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:00:19,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.868 and 383.945 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both have a TPSA of 71.09, which is acceptable for oral absorption (<=140).

**logP:** Ligand A (3.278) is slightly higher than Ligand B (2.822), both are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.701 and 0.724, respectively), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (40.054 and 40.287), both are acceptable (<40 is good).

**BBB:** Ligand A has a significantly higher BBB penetration (83.831) than Ligand B (54.323). While SRC isn't a CNS target, higher BBB is generally not detrimental.

**Caco-2 Permeability:** Ligand A (-4.666) has worse Caco-2 permeability than Ligand B (-5.496), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.002) has worse aqueous solubility than Ligand B (-3.565). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.381 and 0.314, respectively).

**Microsomal Clearance:** Ligand A (39.138) has higher microsomal clearance than Ligand B (30.51), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (18.46) has a longer half-life than Ligand B (8.526).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.161 and 0.146, respectively).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a crucial difference, as a 1.7 kcal/mol advantage is substantial for an enzyme target.

**Conclusion:**

While Ligand A has slightly better half-life and BBB penetration, Ligand B clearly wins due to its significantly improved binding affinity (-8.3 vs -6.6 kcal/mol). The stronger binding is likely to outweigh the slightly lower half-life and permeability. Both have acceptable ADME properties, but potency is paramount for enzyme inhibitors.

Output:
1
2025-04-17 16:00:19,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.439 Da and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.13) is slightly above the preferred <140 for good absorption, while Ligand B (76.46) is well within the range.

**logP:** Both ligands have good logP values (1.368 and 1.238), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.792) has a better QED score than Ligand B (0.539), indicating a more drug-like profile.

**DILI:** Ligand B (40.054) has a significantly lower DILI risk than Ligand A (66.421). This is a crucial advantage.

**BBB:** Ligand B (60.14) has a higher BBB penetration percentile than Ligand A (41.373), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.032) has poor Caco-2 permeability, while Ligand B (-4.897) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.16) has slightly better aqueous solubility than Ligand B (-1.701), though both are quite poor.

**hERG Inhibition:** Ligand A (0.086) has a very low hERG risk, which is a significant advantage. Ligand B (0.202) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand B (23.8) has significantly lower microsomal clearance than Ligand A (7.592), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (5.579) has a slightly longer in vitro half-life than Ligand A (30.629), but the values are reversed and the units are not consistent. Assuming the values are in hours, Ligand B is preferable.

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux than Ligand B (0.043), which is favorable.

**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 still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. It has a significantly lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). While Ligand A has a slightly better QED and lower hERG risk, the improved safety profile and metabolic stability of Ligand B are more important for an enzyme target like SRC kinase. The slightly better binding affinity 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 16:00:19,215 - INFO - Batch 427 complete. Total preferences: 6832
2025-04-17 16:00:19,215 - INFO - Processing batch 428/512...
2025-04-17 16:01:12,209 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.373 and 368.419 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.11) is better than Ligand B (123.22). Lower TPSA generally favors better absorption, although this is less critical for kinases than for CNS targets.

**logP:** Ligand A (0.942) is slightly better than Ligand B (0.006), falling within the optimal 1-3 range. Ligand B is very close to 0, which could indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is better than Ligand B (1 HBD, 9 HBA). While both are within acceptable limits, Ligand B's higher HBA count could potentially impact permeability.

**QED:** Both ligands have good QED scores (0.574 and 0.725), indicating generally drug-like properties.

**DILI:** Ligand B (78.247) has a higher DILI risk than Ligand A (54.246), which is preferable.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (84.374) has a better BBB percentile than Ligand B (51.415).

**Caco-2 Permeability:** Both are negative (-5.158 and -5.185), which is unusual and suggests very poor permeability. This is a significant concern for both compounds.

**Aqueous Solubility:** Both are negative (-2.533 and -2.312), indicating poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.095 and 0.012), which is excellent.

**Microsomal Clearance:** Ligand B (6.841) has a significantly lower Cl_mic than Ligand A (11.283), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (7.005) has a better in vitro half-life than Ligand A (-20.297). A positive half-life is much more desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.025 and 0.031).

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from higher microsomal clearance and a negative in vitro half-life. Ligand B has better metabolic stability and half-life, but its binding affinity is essentially non-existent. The poor Caco-2 and solubility for both are concerning and would require significant optimization. Given the critical importance of potency for kinase inhibitors, and the substantial difference in binding affinity, I would prioritize Ligand A for further investigation, with a strong focus on improving its metabolic stability and solubility.

Output:
0
2025-04-17 16:01:12,209 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.535 Da) is slightly higher than Ligand B (354.441 Da), but both are acceptable.

**TPSA:** Ligand A (60.85) is higher than Ligand B (41.57). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (Ligand A: 1.843, Ligand B: 2.835), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 5, Ligand B: 3) counts, well within the limits of 5 and 10 respectively.

**QED:** Ligand A (0.845) has a higher QED score than Ligand B (0.657), indicating a more drug-like profile.

**DILI:** Ligand A (35.905) has a significantly lower DILI risk than Ligand B (13.3), which is a major advantage.

**BBB:** Ligand B (96.355) has a much higher BBB penetration score than Ligand A (39.55). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.391) has a lower Caco-2 permeability than Ligand B (-4.29). Both are negative, suggesting poor permeability, but B is better.

**Aqueous Solubility:** Ligand A (-3.358) has a lower aqueous solubility than Ligand B (-3.128). Both are poor, but B is slightly better.

**hERG Inhibition:** Ligand A (0.206) has a lower hERG inhibition liability than Ligand B (0.852), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (49.134) has a lower microsomal clearance than Ligand B (62.162), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.347) has a significantly longer in vitro half-life than Ligand A (-1.076). This is a major advantage.

**P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux liability than Ligand B (0.211).

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is small.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, and metabolic stability. Ligand B has better Caco-2 permeability, solubility, and a longer half-life. The binding affinity difference is minimal. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate due to its superior safety profile (lower DILI and hERG) and better metabolic stability. While Ligand B's half-life is better, the other advantages of A outweigh this.

Output:
0
2025-04-17 16:01:12,209 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.555 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (42.43) is significantly better than Ligand B (62.22). Lower TPSA generally correlates with better cell permeability, crucial for kinase inhibitors.

**logP:** Both ligands have similar logP values around 4.6-4.7. While slightly high, this isn't a major concern given the other parameters.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Fewer H-bond donors can improve membrane permeability.

**QED:** Both ligands have similar QED scores (0.676 and 0.643), indicating reasonable drug-likeness.

**DILI:** Ligand A (31.291) has a much lower DILI risk than Ligand B (52.152), a significant advantage.

**BBB:** Ligand A (81.698) has a higher BBB penetration score than Ligand B (37.146). While SRC isn't a CNS target, higher BBB penetration can sometimes correlate with better overall distribution.

**Caco-2 Permeability:** Ligand A (-4.565) has better Caco-2 permeability than Ligand B (-5.135).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.006 and -5.137). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.773) shows a lower hERG inhibition liability than Ligand B (0.345), which is a positive.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (94.832 and 91.58), indicating similar metabolic instability.

**In vitro Half-Life:** Ligand A (18.278 hours) has a significantly longer half-life than Ligand B (5.387 hours), a substantial advantage.

**P-gp Efflux:** Ligand A (0.86) has slightly lower P-gp efflux than Ligand B (0.415).

**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. While both have poor solubility and moderate logP, Ligand A excels in key areas: lower DILI risk, better Caco-2 permeability, longer half-life, lower hERG inhibition, and a more favorable TPSA. The equal binding affinity makes the ADME properties the deciding factor.

Output:
0
2025-04-17 16:01:12,210 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as drug candidates targeting SRC, a kinase. I'll follow the provided guidelines and prioritize potency, metabolic stability, solubility, and hERG risk, as appropriate for an enzyme target.

**Ligand A: [369.355, 138.13 ,   0.288,   1.   ,   6.   ,   0.594,  93.37 ,  25.475, -5.066,  -3.752,   0.036,  21.361, -20.575,   0.04 ,  -8.7  ]**

*   **MW:** 369.355 Da - Acceptable (within 200-500 Da range)
*   **TPSA:** 138.13  - Acceptable (below 140, good for oral absorption)
*   **logP:** 0.288 - Low. Potentially problematic for permeability.
*   **HBD:** 1 - Acceptable (<=5)
*   **HBA:** 6 - Acceptable (<=10)
*   **QED:** 0.594 - Good (>=0.5)
*   **DILI:** 93.37 - Very High Risk. A major concern.
*   **BBB:** 25.475 - Low. Not a primary concern for a non-CNS target.
*   **Caco-2:** -5.066 - Very Poor. Indicates poor intestinal absorption.
*   **Solubility:** -3.752 - Very Poor. Formulation issues likely.
*   **hERG:** 0.036 - Very Low Risk. Excellent.
*   **Cl_mic:** 21.361 mL/min/kg - Moderate. Could be better, suggesting moderate metabolic liability.
*   **t1/2:** -20.575 hours - Very short half-life. Frequent dosing likely needed.
*   **Pgp:** 0.04 - Low efflux. Good.
*   **Affinity:** -8.7 kcal/mol - Excellent. Very strong binding.

**Ligand B: [347.375, 111.28 ,   1.186,   2.   ,   7.   ,   0.812,  77.549,  65.529, -5.196,  -2.599,   0.139,  31.875,   2.016,   0.022,  -7.5  ]**

*   **MW:** 347.375 Da - Acceptable.
*   **TPSA:** 111.28 - Acceptable.
*   **logP:** 1.186 - Good. Within the optimal range.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 7 - Acceptable.
*   **QED:** 0.812 - Very Good.
*   **DILI:** 77.549 - Moderate Risk. Better than Ligand A, but still needs consideration.
*   **BBB:** 65.529 - Moderate. Not a primary concern.
*   **Caco-2:** -5.196 - Very Poor. Similar to Ligand A.
*   **Solubility:** -2.599 - Poor. Similar to Ligand A.
*   **hERG:** 0.139 - Low Risk. Good.
*   **Cl_mic:** 31.875 mL/min/kg - Higher than Ligand A, indicating faster metabolism.
*   **t1/2:** 2.016 hours - Short half-life, but better than Ligand A.
*   **Pgp:** 0.022 - Low efflux. Good.
*   **Affinity:** -7.5 kcal/mol - Very Good. Strong binding, though slightly weaker than Ligand A.

**Comparison and Decision:**

Ligand A boasts a superior binding affinity (-8.7 kcal/mol vs -7.5 kcal/mol). However, its extremely high DILI risk (93.37) and very poor solubility and Caco-2 permeability are significant drawbacks. The short half-life is also a concern.

Ligand B has a good QED score, a moderate DILI risk, and acceptable logP. While its metabolic clearance is higher and half-life shorter than ideal, these are less critical than the severe liabilities of Ligand A. Both compounds have poor Caco-2 and solubility.

Despite the slightly weaker binding affinity, **Ligand B is the more promising candidate**. The DILI risk is substantially lower, and the other ADME properties, while not perfect, are less problematic than those of Ligand A. The binding affinity difference of 1.2 kcal/mol, while noticeable, is unlikely to outweigh the severe toxicity and absorption issues associated with Ligand A. Further optimization of Ligand B could address the metabolic stability and solubility concerns.

1
2025-04-17 16:01:12,210 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (348.443 and 344.423 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (85.92). Both are below 140, suggesting good oral absorption potential, but A is closer to the preferred value.

**3. logP:** Ligand A (0.685) is slightly better than Ligand B (0.071). Both are a bit low, potentially hindering permeation, but A is closer to the optimal 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 (9) is better than Ligand A (4). Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.794) is significantly better than Ligand A (0.5). This indicates a more drug-like profile for B.

**7. DILI:** Ligand A (10.392) is *much* better than Ligand B (34.277). This is a critical advantage for A, as lower DILI risk is highly desirable.

**8. BBB:** Ligand B (82.939) is better than Ligand A (47.189). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.868) is better than Ligand B (-5.211). Higher values are better, but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.456) is better than Ligand B (-1.165). Higher values are better, but both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.198) is better than Ligand B (0.173). Both are low, indicating minimal hERG risk, which is excellent.

**12. Microsomal Clearance:** Ligand A (-2.055) is *much* better than Ligand B (38.521). Negative clearance is ideal, indicating excellent metabolic stability. This is a major advantage for A.

**13. In vitro Half-Life:** Ligand A (0.213) is significantly worse than Ligand B (-11.693). Longer half-life is preferred, and B has a much longer predicted half-life.

**14. P-gp Efflux:** Ligand A (0.05) is better than Ligand B (0.041). Both are low, indicating minimal P-gp efflux.

**15. Binding Affinity:** Ligand B (-9.1) is significantly better than Ligand A (-7.0). A difference of 2.1 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and QED score, and a much better in vitro half-life. However, Ligand A has a dramatically lower DILI risk and significantly better metabolic stability (Cl_mic). Solubility and permeability are poor for both. Given the enzyme-kinase focus, metabolic stability and safety (DILI, hERG) are crucial. The 2.1 kcal/mol difference in binding affinity is significant, but the substantial improvement in safety and metabolic stability offered by Ligand A is compelling. While B's affinity is stronger, the risk profile of A is more favorable for progression.

Output:
0
2025-04-17 16:01:12,210 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.503 and 370.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.2) is better than Ligand B (92.78), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.141 and 1.462), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 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 (0.63 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A (28.887) has a significantly lower DILI risk than Ligand B (63.707). This is a major advantage for Ligand A.

**BBB:** Ligand A (68.399) has a better BBB score than Ligand B (30.167), but BBB is less important for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.475) has better Caco-2 permeability than Ligand B (-4.844).

**Aqueous Solubility:** Ligand A (-2.354) has better aqueous solubility than Ligand B (-2.183).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.64 and 0.077), which is excellent.

**Microsomal Clearance:** Ligand A (19.233) has a lower microsomal clearance than Ligand B (58.589), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (57.098) has a significantly longer in vitro half-life than Ligand B (-3.071). This is a significant advantage, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.046).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent and meets the criteria of < -7.0 kcal/mol.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have excellent binding affinity and acceptable physicochemical properties, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility. These factors are crucial for an enzyme inhibitor like an SRC kinase inhibitor.

Output:
1
2025-04-17 16:01:12,210 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (371.459 Da and 369.893 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.97) is slightly higher than Ligand B (75.43). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable due to the lower value.

**3. logP:** Ligand A (1.1) is within the optimal range, while Ligand B (2.426) is also acceptable.

**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 (5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.748 and 0.8), indicating good drug-like properties.

**7. DILI:** Ligand A (60.915) has a higher DILI risk than Ligand B (21.404). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (74.758) is better than Ligand A (63.203). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both ligands 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 ligands have negative solubility values, which is also unusual. Again, they are close enough that this isn't a major differentiator.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.284 and 0.239), which is excellent.

**12. Microsomal Clearance:** Ligand A (45.529) has lower microsomal clearance than Ligand B (48.039), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.272) has a significantly longer in vitro half-life than Ligand A (-27.62). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.077 and 0.174).

**15. Binding Affinity:** Ligand B (-7.7) has a stronger binding affinity than Ligand A (-9.1). This is a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better metabolic stability, Ligand B has a significantly stronger binding affinity, a much lower DILI risk, and a longer half-life. The lower TPSA of Ligand B is also favorable. The binding affinity difference is substantial enough to outweigh the minor advantage of Ligand A in metabolic stability.

Output:
1
2025-04-17 16:01:12,210 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.471 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.11) is better than Ligand B (71.94), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.865 and 1.127), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 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 good QED scores (0.687 and 0.772), indicating good drug-like properties.

**DILI:** Ligand A (68.399) has a significantly higher DILI risk than Ligand B (10.237). This is a major concern for Ligand A.

**BBB:** Both have similar BBB penetration (65.413 and 61.962). Not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.113 and -5.269), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.814 and -0.107), indicating very poor aqueous solubility. This is a significant issue for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.62 and 0.489), which is good.

**Microsomal Clearance:** Ligand B (-3.64) has a much *lower* (better) microsomal clearance than Ligand A (52.38). This indicates greater metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (18.141) has a much longer in vitro half-life than Ligand A (28.934). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.365 and 0.003).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.0 and -7.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is significantly better due to its much lower DILI risk and superior metabolic stability (lower Cl_mic, longer t1/2). While both have poor solubility and permeability, the DILI risk associated with Ligand A is a major red flag. The slightly better half-life and metabolic stability of Ligand B outweigh the minor differences in other parameters.

Output:
1
2025-04-17 16:01:12,210 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.419 and 370.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.54) is slightly higher than Ligand B (66.48), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.246) is quite low, potentially hindering permeability. Ligand B (1.939) 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 (5 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have acceptable QED scores (0.827 and 0.777), indicating good drug-likeness.

**DILI:** Ligand A (58.085) has a higher DILI risk than Ligand B (39.124), although both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (81.698) has a higher BBB percentile than Ligand A (53.974).

**Caco-2 Permeability:** Both ligands have very negative Caco-2 values (-4.937 and -4.932), which is unusual and suggests a potential issue with the data or a very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.553 and -2.822), which is also unusual and problematic.

**hERG:** Ligand A (0.136) has a lower hERG risk than Ligand B (0.632), which is favorable.

**Microsomal Clearance:** Ligand A (21.205 mL/min/kg) has significantly lower microsomal clearance than Ligand B (39.037 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (19.176 hours) has a longer half-life than Ligand B (16.995 hours), which is preferable.

**P-gp Efflux:** Ligand A (0.014) has much lower P-gp efflux liability than Ligand B (0.244), suggesting better bioavailability.

**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 of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability, lower P-gp efflux, and lower hERG risk, Ligand B has a significantly better logP, and a slightly better binding affinity. The negative solubility and Caco-2 values are concerning for both, but the stronger binding affinity of Ligand B is a crucial advantage for an enzyme inhibitor. Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, hERG), the improved binding affinity of Ligand B is the deciding factor, despite its less favorable logP and higher P-gp efflux.

Output:
1
2025-04-17 16:01:12,210 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.527 Da) is slightly higher than Ligand B (361.427 Da), but both are acceptable.

**TPSA:** Ligand A (93.64) is better than Ligand B (113.08) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (1.847) is optimal, while Ligand B (-0.33) is below 1, which may impede permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (4 HBD, 6 HBA). While both are within acceptable limits, fewer H-bond donors are generally better for permeability.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.779, Ligand B: 0.537), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (Ligand A: 60.527, Ligand B: 65.452), but are still within a range that can be optimized.

**BBB:** Ligand A (45.715) has a better BBB percentile than Ligand B (24.738), but BBB is not a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-4.624) has a better Caco-2 permeability than Ligand B (-5.818).

**Aqueous Solubility:** Ligand A (-4.137) has better aqueous solubility than Ligand B (-2.293). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.292, Ligand B: 0.166).

**Microsomal Clearance:** Ligand A (66.576) has higher clearance than Ligand B (-1.929). This means Ligand B is more metabolically stable, which is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-40.005) has a negative half-life, which is concerning. Ligand B (44.552) has a good half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.072, Ligand B: 0.009).

**Binding Affinity:** Ligand B (-11.3 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.

**Conclusion:**

Despite Ligand B having a lower logP and a slightly higher DILI risk, its significantly superior binding affinity (-11.3 vs -7.9 kcal/mol) and better metabolic stability (lower Cl_mic, better t1/2) make it the more promising candidate. The strong binding is likely to be more impactful than the slightly less favorable logP, and metabolic stability is crucial for kinase inhibitors.

Output:
1
2025-04-17 16:01:12,210 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.397 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (96.78) is still within acceptable limits but less favorable.

**logP:** Ligand A (2.659) is optimal (1-3). Ligand B (0.98) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (1 HBD, 7 HBA) is acceptable but has more potential for off-target interactions or reduced permeability.

**QED:** Both ligands have good QED scores (0.841 and 0.863), indicating generally drug-like properties.

**DILI:** Ligand A (37.107) has a lower DILI risk than Ligand B (50.136), which is preferable. Both are below the concerning 60 threshold.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (96.665) shows better potential for BBB penetration than Ligand B (70.958).

**Caco-2 Permeability:** Ligand A (-4.499) is significantly better than Ligand B (-5.087), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have negative values (-2.387 and -2.826), indicating poor aqueous solubility. This is a significant drawback for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.507 and 0.311), which is excellent.

**Microsomal Clearance:** Ligand A (32.776) has a higher microsomal clearance than Ligand B (3.917), indicating lower metabolic stability. This is a major concern for Ligand A.

**In vitro Half-Life:** Ligand B (30.648 hours) has a much longer in vitro half-life than Ligand A (-19.011 hours). This is a significant advantage for Ligand B, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.162 and 0.261), which is favorable.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-9.2 and -8.7 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't heavily sway the decision.

**Conclusion:**

While both ligands exhibit good potency, Ligand B is the more promising candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2), better Caco-2 permeability, and lower DILI risk outweigh the slightly lower logP and higher TPSA. The solubility issue is a concern for both, but can potentially be addressed through formulation. Ligand A's poor metabolic stability is a significant hurdle to overcome.

Output:
1
2025-04-17 16:01:12,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (357.483 and 356.501 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.91) is higher than Ligand B (23.55). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have acceptable logP values (3.019 and 4.028), falling within the 1-3 optimal range, though Ligand B is slightly higher.

**H-Bond Donors & Acceptors:** Both have 0 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 2. Lower HBA is generally preferred, making Ligand B slightly better.

**QED:** Both ligands have good QED scores (0.563 and 0.717), indicating drug-like properties. Ligand B is slightly higher.

**DILI:** Ligand A (53.548) 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:** This is less crucial for a non-CNS target like SRC, but Ligand B (97.635) has a higher BBB percentile than Ligand A (78.209).

**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 concerning. Again, the magnitudes are similar.

**hERG:** Ligand A (0.137) has a slightly lower hERG risk than Ligand B (0.963), which is favorable.

**Microsomal Clearance:** Ligand A (94.158) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (24.165) has significantly lower clearance, suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-16.873) has a very short half-life, while Ligand B (-1.544) has a longer, though still short, half-life. Ligand B is better.

**P-gp Efflux:** Ligand A (0.354) has lower P-gp efflux than Ligand B (0.632), which is preferable.

**Binding Affinity:** Both ligands have similar and strong 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 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 an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and a lower TPSA. The slightly better QED score also contributes to its favorability. 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 16:01:12,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.439 Da and 373.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.98) is excellent, well below the 140 threshold for oral absorption, and even favorable for CNS penetration. Ligand B (105.23) is still acceptable but less optimal.

**logP:** Ligand A (1.319) is within the optimal 1-3 range. Ligand B (0.973) is slightly below 1, which *could* indicate potential permeability issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is very good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.555 and 0.693, respectively), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (78.17 and 66.344), below the concerning threshold of 60.

**BBB:** Ligand A (65.529) has a moderate BBB penetration score, while Ligand B (55.215) is lower. Since SRC is not a CNS target, this is not a major factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.505 and -4.894), which is unusual and suggests poor permeability. This is a significant concern for both. However, these values are on a log scale, and negative values are not necessarily indicative of zero permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.843 and -2.648), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.241 and 0.271), which is excellent.

**Microsomal Clearance:** Ligand A (103.747) has a higher microsomal clearance than Ligand B (10.906). This suggests Ligand B is more metabolically stable, a key priority for enzymes.

**In vitro Half-Life:** Ligand B (54.938 hours) has a significantly longer half-life than Ligand A (-48.248 hours). This is a major advantage for Ligand B, as it suggests less frequent dosing.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.303 and 0.083).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite the concerning negative values for Caco-2 and solubility for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.3 vs -9.2 kcal/mol) and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly less favorable TPSA and logP values. The better half-life and affinity are critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:01:12,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.45 and 344.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (78.67). A TPSA under 90 is generally acceptable, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.385) is optimal (1-3), while Ligand B (0.363) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is excellent. Ligand B (1 HBD, 5 HBA) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.638 and 0.756), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (31.99 and 35.60 percentiles), which is favorable.

**BBB:** Ligand A (82.51) has a better BBB penetration score than Ligand B (32.77). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.558) is better than Ligand B (-4.899), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.668) is better than Ligand B (-0.948). Solubility is crucial for bioavailability, and A's value is more favorable.

**hERG Inhibition:** Ligand A (0.662) has a lower hERG risk than Ligand B (0.115), which is a significant advantage.

**Microsomal Clearance:** Ligand A (55.51) has higher clearance than Ligand B (17.91). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand A (2.07) has a shorter half-life than Ligand B (-0.243). Longer half-life is generally desirable, so Ligand B is better here.

**P-gp Efflux:** Ligand A (0.212) has lower P-gp efflux than Ligand B (0.024), which is favorable for bioavailability.

**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.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has better metabolic stability and half-life, Ligand A's significantly stronger binding affinity (-8.2 vs -7.1 kcal/mol), combined with better logP, TPSA, solubility, hERG risk, Caco-2 permeability, and P-gp efflux, makes it the more promising drug candidate for SRC kinase inhibition. The potency advantage is crucial, and the other favorable properties mitigate the slightly higher clearance.

Output:
1
2025-04-17 16:01:12,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.475 and 340.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (49.41), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.155) is quite low, potentially hindering permeability. Ligand B (3.411) 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, and Ligand B has 2. Both are below the 10 threshold.

**QED:** Ligand A (0.746) is slightly better than Ligand B (0.611), both are above the 0.5 threshold.

**DILI:** Ligand A (51.493) and Ligand B (41.218) are both good, below the 60 threshold, with B being slightly better.

**BBB:** Ligand A (52.268) and Ligand B (75.107). BBB isn't a primary concern for a systemic oncology target, but higher is generally better. Ligand B is better here.

**Caco-2:** Ligand A (-5.039) and Ligand B (-4.805). Both are negative, indicating poor permeability.

**Solubility:** Ligand A (-2.273) and Ligand B (-3.249). Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.076) is significantly better than Ligand B (0.699), indicating a lower risk of cardiotoxicity. This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (22.822) is much lower than Ligand B (68.128), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (4.367) is much better than Ligand B (-1.469), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.031) is much lower than Ligand B (0.385), indicating less P-gp efflux.

**Binding Affinity:** Ligand B (-8.0) is significantly better than Ligand A (-6.3). This is a substantial advantage for Ligand B, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity (-8.0 kcal/mol vs -6.3 kcal/mol). However, Ligand A demonstrates significantly better ADMET properties: lower microsomal clearance, longer half-life, lower P-gp efflux, and crucially, a much lower hERG risk. Ligand B's logP is better, but its solubility and permeability are still poor. Given that SRC is an enzyme target, metabolic stability and safety (hERG) are paramount. The 1.7 kcal/mol difference in binding affinity is significant, but the ADME profile of Ligand A is considerably more favorable, especially the hERG risk.

Output:
0
2025-04-17 16:01:12,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.825 and 372.893 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (68.29 and 67.87) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.746 and 2.069) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Ligand A (0.916) has a significantly better QED score than Ligand B (0.708), indicating a more drug-like profile.

**DILI:** Ligand A (73.362) has a higher DILI risk than Ligand B (18.961). This is a significant negative for Ligand A.

**BBB:** Both have good BBB penetration, but Ligand B (83.443) is slightly better than Ligand A (79.488). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, suggesting poor permeability. Ligand B (-4.539) is slightly better than Ligand A (-5.051).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-2.533) is slightly better than Ligand A (-2.999).

**hERG Inhibition:** Ligand A (0.299) has a lower hERG inhibition risk than Ligand B (0.553), which is favorable.

**Microsomal Clearance:** Ligand B (33.841) has lower microsomal clearance than Ligand A (39.973), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.445) has a longer half-life than Ligand A (6.515). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.149 and 0.175).

**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 for Ligand A. The difference of 1.4 kcal/mol is significant enough to potentially overcome some ADME liabilities.

**Overall Assessment:**

Ligand A has superior binding affinity and a lower hERG risk, but suffers from higher DILI risk, lower metabolic stability, and poorer solubility. Ligand B has a better safety profile (lower DILI, better metabolic stability, slightly better solubility), and a longer half-life, but its binding affinity is considerably weaker.

Given the enzyme-kinase target class, potency is paramount. The 1.4 kcal/mol difference in binding affinity is substantial. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications during lead optimization. The lower metabolic stability and solubility are also addressable. The superior affinity of Ligand A outweighs its drawbacks at this stage.

Output:
1
2025-04-17 16:01:12,212 - INFO - Batch 428 complete. Total preferences: 6848
2025-04-17 16:01:12,212 - INFO - Processing batch 429/512...
2025-04-17 16:01:58,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.523 and 353.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.29) is slightly above the preferred <140, but acceptable. Ligand B (88.18) is excellent, well below 140.

**logP:** Ligand A (2.217) is optimal (1-3). Ligand B (0.873) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, both within acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Ligand B (0.813) has a better QED score than Ligand A (0.591), indicating a more drug-like profile.

**DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (47.305), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.699) is lower than Ligand B (51.415).

**Caco-2 Permeability:** Ligand A (-5.204) has a worse Caco-2 permeability than Ligand B (-4.51).

**Aqueous Solubility:** Ligand A (-3.135) has a worse aqueous solubility than Ligand B (-1.006).

**hERG:** Both ligands have very low hERG risk (0.277 and 0.205 respectively).

**Microsomal Clearance:** Ligand B (42.397) has lower microsomal clearance than Ligand A (65.08), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-28.674) has a much longer in vitro half-life than Ligand A (-5.109), a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.008 and 0.026 respectively).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.2 kcal/mol). The difference is less than 0.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

While Ligand B has better QED, solubility, permeability, and metabolic stability, Ligand A's significantly lower DILI risk is a critical factor. DILI is a major cause of drug attrition. Given the similar binding affinities, the lower DILI risk of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 16:01:58,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.381 and 345.334 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is well below the 140 threshold for good absorption, while Ligand B (95.93) is still acceptable but closer to the limit.

**logP:** Both ligands (2.021 and 1.974) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, well within the limits. Ligand B has 0 HBD and 8 HBA, also acceptable, although a higher number of HBAs can sometimes hinder permeability.

**QED:** Ligand A (0.772) has a better QED score than Ligand B (0.576), indicating a more drug-like profile.

**DILI:** Ligand A (27.414) has a significantly lower DILI risk than Ligand B (78.402), which is a major advantage.

**BBB:** BBB isn't a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired. Ligand A (92.555) has better BBB penetration than Ligand B (76.309).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.952 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 (-3.226 and -2.412), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.615) has a lower hERG risk than Ligand B (0.244), which is preferable.

**Microsomal Clearance:** Ligand A (2.927) has a much lower microsomal clearance than Ligand B (71.419), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-10.68) has a more negative half-life, which is unusual and indicates a very short half-life. Ligand B (-18.932) is even worse. Both are problematic.

**P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux than Ligand B (0.123), which is slightly better.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A is the far superior candidate. Its significantly stronger binding affinity (-7.5 vs -0.0 kcal/mol) is a decisive advantage. Furthermore, it has lower DILI risk, better metabolic stability (lower Cl_mic), and a better QED score. While the half-life is concerning, the binding affinity is so much stronger that it could potentially be addressed through structural modifications. Ligand B's extremely poor binding affinity makes it unlikely to be a viable candidate, regardless of its other properties.

Output:
0
2025-04-17 16:01:58,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.371 and 346.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (41.05), both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.793) is optimal, while Ligand B (4.452) is pushing the upper limit and could present solubility issues.

**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.

**QED:** Ligand A (0.673) has a better QED score than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Ligand A (14.889) has a significantly lower DILI risk than Ligand B (50.95), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (92.323) has better BBB penetration than Ligand A (82.047).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.715) is slightly better than Ligand B (-4.942).

**Aqueous Solubility:** Ligand A (-1.962) is better than Ligand B (-4.664), both are poor.

**hERG:** Ligand A (0.647) has a lower hERG risk than Ligand B (0.933), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (-4.131) shows better metabolic stability (lower clearance) than Ligand B (98.631).

**In vitro Half-Life:** Ligand A (-43.183) has a longer half-life than Ligand B (21.75).

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux than Ligand B (0.835), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.6 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.

**Overall:** Considering the enzyme-specific priorities, Ligand A is the more promising candidate. It exhibits a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, better QED, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far superior, making it more likely to succeed as a drug candidate.

Output:
0
2025-04-17 16:01:58,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.491 and 367.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (106.42). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal for oral bioavailability.

**logP:** Ligand A (1.737) is within the optimal 1-3 range. Ligand B (-0.251) is slightly below 1, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 1, respectively), well below the limit of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (7), both are below the limit of 10.

**QED:** Both ligands have good QED values (0.681 and 0.754), indicating drug-like properties.

**DILI:** Ligand A (24.893) has a significantly lower DILI risk than Ligand B (82.939). This is a major advantage for Ligand A.

**BBB:** Ligand A (48.352) and Ligand B (70.803). BBB is not a primary concern for a non-CNS target like SRC kinase, but B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.996 and -5.236). This is unusual and suggests poor permeability *in vitro*. However, the scale is not specified, so these values could be relative to a different baseline.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.157 and -2.962). Again, the scale is unclear, but these suggest poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.072) has a much lower hERG risk than Ligand B (0.446). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (42.132 and 45.324 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Both ligands have negative half-life values (-5.997 and -4.742 hours). This is unusual, and the scale is unclear.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.029).

**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 still a positive for A.

**Overall Assessment:**

Ligand A is significantly better due to its lower DILI risk and lower hERG inhibition liability. While both have issues with solubility and permeability (indicated by the negative values), the safety profile of Ligand A is far superior. The slightly better binding affinity of A further supports its selection.

Output:
0
2025-04-17 16:01:58,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.443 Da) is slightly higher than Ligand B (343.431 Da), but both are acceptable.

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand B (80.12) is better than Ligand A (97.83).

**logP:** Ligand B (1.725) is optimal (1-3), while Ligand A (0.369) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Both have good QED scores (A: 0.665, B: 0.752), indicating drug-likeness.

**DILI:** Ligand B (43.66) has a significantly lower DILI risk than Ligand A (72.082). This is a major advantage for Ligand B.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand B (45.909) has a higher value than Ligand A (23.187).

**Caco-2 Permeability:** Both are negative, which is concerning. However, the scale is not provided, so it's difficult to assess the severity.

**Aqueous Solubility:** Both are negative, which is concerning. However, the scale is not provided, so it's difficult to assess the severity.

**hERG Inhibition:** Ligand A (0.024) has a very low hERG risk, which is excellent. Ligand B (0.369) is higher, but still relatively low.

**Microsomal Clearance:** Ligand B (29.224) has significantly lower microsomal clearance than Ligand A (9.186), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (20.951) has a much longer half-life than Ligand A (4.911), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability.

**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, potentially outweighing some of the ADME drawbacks. A 1.9 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life), Ligand A's substantially stronger binding affinity is a decisive factor for an enzyme target like SRC kinase. The difference in binding affinity is large enough to compensate for the slightly higher DILI risk and lower metabolic stability of Ligand A.

Output:
0
2025-04-17 16:01:58,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.391 and 346.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (122.14) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (76.46) is excellent, well below 140.

**logP:** Both ligands (0.965 and 0.904) are within the optimal 1-3 range.

**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 similar QED values (0.58 and 0.588), indicating good drug-likeness.

**DILI:** Ligand A (65.103) has a higher DILI risk than Ligand B (33.695). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (83.443) has a higher percentile, which could be beneficial if CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and problematic. Again, the magnitudes are similar.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.415 and 0.319), which is good.

**Microsomal Clearance:** Ligand A (38.138) has a higher microsomal clearance than Ligand B (26.154), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (3.55 hours) has a significantly longer half-life than Ligand A (-39.911 hours - a negative value suggests rapid degradation). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.076), which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 1.4 kcal/mol is substantial and outweighs many of the minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have unusual solubility and permeability values that would require further investigation, Ligand B demonstrates a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer half-life), and lower DILI risk. The binding affinity difference is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:01:58,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.813 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.39) is better than Ligand B (78.6) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.773 and 2.16), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0/2) and HBA (6/6) counts, well within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.603 and 0.514), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (74.99%) compared to Ligand B (15.898%). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (91.276%) has a higher BBB penetration than Ligand B (61.38%), but this is not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.727) and Ligand B (-5.368) both have negative Caco-2 values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability. Both are similarly poor.

**Aqueous Solubility:** Ligand A (-3.778) and Ligand B (-2.471) both have negative solubility values, indicating poor solubility. Ligand B is slightly better than Ligand A.

**hERG:** Both ligands have similar, low hERG risk (0.342 and 0.364).

**Microsomal Clearance:** Ligand B (38.004 mL/min/kg) has significantly lower microsomal clearance than Ligand A (90.298 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (14.31 hours) has a much longer in vitro half-life than Ligand A (-4.485 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.211 and 0.112).

**Binding Affinity:** Both ligands have excellent binding affinity (-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.

**Conclusion:**

While both ligands have good potency, Ligand B is significantly better due to its much lower DILI risk, better metabolic stability (lower Cl_mic), and longer half-life. The slightly better solubility of Ligand B is also a benefit. The higher BBB and slightly lower Caco-2 of Ligand A are not enough to offset the significant drawbacks of its higher DILI and lower metabolic stability.

Output:
1
2025-04-17 16:01:58,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.4 and 357.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.62) is higher than Ligand B (54.02). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Ligand A (0.586) is quite low, potentially hindering permeability. Ligand B (4.697) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 HBA, which is acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.729 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (87.13) has a significantly higher DILI risk than Ligand B (38.81). This is a major concern for Ligand A.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (79.49) is slightly better.

**Caco-2:** Ligand A (-4.355) is very poor, indicating poor intestinal absorption. Ligand B (-4.951) is also poor, but slightly better than A.

**Solubility:** Both ligands have very poor aqueous solubility (-4.375 and -4.195). This is a concern for both, but needs to be balanced against other properties.

**hERG:** Ligand A (0.116) has a very low hERG risk, which is excellent. Ligand B (0.67) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (119.64) has higher clearance, suggesting lower metabolic stability. Ligand B (64.02) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-50.56) has a very short half-life. Ligand B (24.2) has a better half-life, but still not ideal.

**P-gp Efflux:** Ligand A (0.094) has low P-gp efflux, which is favorable. Ligand B (0.64) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.7 and -8.6 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. While its logP is high, the significantly lower DILI risk and better metabolic stability (lower Cl_mic, better t1/2) are crucial advantages for an enzyme target. Ligand A's high DILI risk and poor metabolic stability are major drawbacks that outweigh its slightly better hERG profile and P-gp efflux. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 16:01:58,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.491 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is better than Ligand B (86.88), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.04 and 2.045), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2/3) and HBA (3/3) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have acceptable QED scores (0.72 and 0.663), indicating good drug-likeness.

**DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (57.619). This is a major advantage.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand A (53.083) is lower than Ligand B (64.25), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.263 and -5.241). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both have negative solubility values (-2.727 and -3.663). This is also concerning, indicating poor solubility. Ligand B is slightly worse.

**hERG:** Ligand A (0.536) has a slightly higher hERG risk than Ligand B (0.359), but both are relatively low.

**Microsomal Clearance:** Ligand A (26.74) has a lower microsomal clearance than Ligand B (30.026), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (-14.259) has a significantly longer in vitro half-life than Ligand B (17.337). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.323). This is a positive for Ligand A.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This 0.6 kcal/mol difference is significant and outweighs some of the ADME drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While both ligands have issues with Caco-2 permeability and solubility, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower P-gp efflux, and, most importantly, a significantly stronger binding affinity. The better affinity and improved safety profile outweigh the similar permeability/solubility concerns.

Output:
1
2025-04-17 16:01:58,236 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 360.479 Da, B: 342.483 Da) fall within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (66.48) is higher than Ligand B (49.41). Both are below the 140 threshold for oral absorption, but B is better positioned for potential CNS penetration if that were a goal.

3. **logP:** Both ligands (A: 3.079, B: 3.198) are within the optimal 1-3 range. No significant difference.

4. **HBD:** Both ligands have 1 HBD, which is good.

5. **HBA:** Ligand A has 3 HBAs, and Ligand B has 2. Both are below the 10 threshold.

6. **QED:** Both ligands have good QED scores (A: 0.824, B: 0.78), indicating good drug-like properties.

7. **DILI:** Ligand A (55.913) has a higher DILI risk than Ligand B (15.355). This is a significant concern for Ligand A.

8. **BBB:** Both ligands have good BBB penetration (A: 72.237, B: 71.811). Not a primary concern for a kinase inhibitor, but a neutral point.

9. **Caco-2:** Both ligands have negative Caco-2 values (-4.762 and -4.84). This is unusual and suggests poor permeability. However, negative values can sometimes occur in modeling and don't always translate directly to poor *in vivo* absorption.

10. **Solubility:** Ligand A (-4.935) has worse solubility than Ligand B (-3.384). Solubility is important for bioavailability.

11. **hERG:** Ligand A (0.632) has a slightly higher hERG risk than Ligand B (0.346), but both are relatively low.

12. **Cl_mic:** Ligand A (50.463) has lower microsomal clearance than Ligand B (54.278), suggesting better metabolic stability. This is a positive for Ligand A.

13. **t1/2:** Ligand B (-12.798) has a negative in vitro half-life, which is not physically possible and indicates a modeling issue. Ligand A (5.204) has a reasonable half-life.

14. **Pgp:** Both ligands have very low Pgp efflux (A: 0.171, B: 0.117).

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 >1.2 kcal/mol advantage, which is substantial.

**Enzyme-Kinase Specific Priorities:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has superior affinity and better metabolic stability. However, it has a higher DILI risk and lower solubility. Ligand B has a problematic negative half-life prediction, which is a major red flag.

**Conclusion:**

Despite the higher DILI risk and lower solubility of Ligand A, its significantly stronger binding affinity and more reasonable half-life, coupled with the completely unrealistic half-life prediction for Ligand B, make it the more promising candidate. The affinity advantage is substantial enough to potentially overcome the ADME drawbacks, especially if medicinal chemistry efforts can address the DILI and solubility issues.

Output:
1
2025-04-17 16:01:58,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.415 and 353.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is well below the 140 threshold and suitable for oral absorption. Ligand B (126.66) is still acceptable but less optimal.

**logP:** Ligand A (2.746) is within the optimal 1-3 range. Ligand B (-0.795) is below 1, which might hinder 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 QED values above 0.5 (0.787 and 0.627), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 81.078, which is concerningly high (>60). Ligand B has a much lower DILI risk of 48.623, which is preferable.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (65.374) and Ligand B (57.193) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.638) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.488) is also poor, but slightly less so.

**Aqueous Solubility:** Ligand A (-4.575) has poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-1.623) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.355) has a low hERG risk, which is excellent. Ligand B (0.024) has an even lower hERG risk, which is also excellent.

**Microsomal Clearance:** Ligand A (108.935) has a moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (11.731) has very low clearance, indicating high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (16.965) has a moderate half-life. Ligand B (12.45) has a shorter half-life, which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.199 and 0.006), which is good.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, but suffers from poor solubility, poor permeability, and a high DILI risk. Ligand B has better ADME properties (lower DILI, better metabolic stability, better solubility), but weaker binding affinity. Given the importance of potency for kinase inhibitors, the stronger binding affinity of Ligand A is a significant advantage. However, the high DILI risk is a major concern. The improved metabolic stability of Ligand B is also a considerable benefit.

Despite the affinity difference, the DILI risk associated with Ligand A is too high to proceed without significant further optimization. Ligand B, while weaker in binding, presents a more favorable starting point for development due to its better safety profile and metabolic stability.

Output:
1
2025-04-17 16:01:58,237 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [366.933, 41.57, 4.877, 1, 2, 0.81, 37.224, 73.943, -4.494, -5.251, 0.807, 74.378, 47.927, 0.217, -9]
**Ligand B:** [355.404, 35.58, 2.251, 1, 3, 0.842, 23.653, 90.074, -4.418, -1.647, 0.943, -31.537, -4.895, 0.173, -10.2]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (366.933) and B (355.404) are comparable.
2. **TPSA:** A (41.57) is slightly higher than B (35.58), but both are well below the 140 A^2 threshold for oral absorption.
3. **logP:** A (4.877) is higher than B (2.251). A is approaching the upper limit where solubility issues might arise, while B is well within the optimal range.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A has 2 HBA, B has 3. Both are acceptable, below the 10 threshold.
6. **QED:** Both have good QED scores (A: 0.81, B: 0.842), indicating drug-like properties.
7. **DILI:** A (37.224) has a higher DILI risk than B (23.653). B is preferable here.
8. **BBB:** A (73.943) has a good BBB penetration, while B (90.074) is even better. This is less critical for a non-CNS target like SRC, but still a positive for B.
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:** A (-5.251) has worse solubility than B (-1.647). Solubility is a key consideration for kinase inhibitors.
11. **hERG:** A (0.807) has a slightly higher hERG risk than B (0.943), but both are relatively low.
12. **Cl_mic:** A (74.378) has a higher microsomal clearance than B (-31.537). B is significantly more metabolically stable, a crucial factor for kinase inhibitors.
13. **t1/2:** A (47.927) has a longer in vitro half-life than B (-4.895). This is a positive for A, but the negative value for B is concerning.
14. **Pgp:** A (0.217) has lower P-gp efflux than B (0.173), suggesting better bioavailability.
15. **Affinity:** B (-10.2 kcal/mol) has a significantly stronger binding affinity than A (-9 kcal/mol). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

**Conclusion:**

While Ligand A has a slightly better half-life and Pgp efflux, Ligand B is superior overall. Its significantly stronger binding affinity (-10.2 vs -9 kcal/mol), lower DILI risk, and *much* better metabolic stability (-31.537 Cl_mic vs 74.378) outweigh the slightly lower half-life. The better solubility also contributes to its favorability. The negative Caco-2 values are a concern for both, but the substantial affinity advantage of B makes it the more promising candidate.

Output:
1
2025-04-17 16:01:58,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 Da and 371.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.9) is better than Ligand B (64.09), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (0.892) is within the optimal 1-3 range, while Ligand A (0.025) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.809 and 0.778, respectively), indicating good drug-like properties.

**DILI:** Ligand A (38.736) has a slightly higher DILI risk than Ligand B (5.894), but both are below the concerning threshold of 60.

**BBB:** Ligand B (62.233) has a higher BBB penetration percentile than Ligand A (39.24), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.755) has a negative value, which is concerning. Ligand B (-4.9) is also negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (0.06) has very poor solubility, while Ligand B (-1.028) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.256) has a lower hERG risk than Ligand B (0.187), which is favorable.

**Microsomal Clearance:** Ligand A (-14.53) has a much lower (better) microsomal clearance than Ligand B (10.415), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (7.092) has a shorter half-life than Ligand B (-11.501), which is negative and indicates a very long half-life.

**P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux than Ligand B (0.006), which is favorable.

**Binding Affinity:** Ligand A (-7.0) 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, and significantly better metabolic stability (lower Cl_mic). However, it suffers from very poor solubility and low logP. Ligand B has better solubility, a more favorable logP, and a longer half-life, but weaker binding affinity and higher P-gp efflux.

Given the enzyme-specific priorities, potency (affinity) and metabolic stability are key. Ligand A's significantly better affinity and metabolic stability outweigh its solubility and logP concerns, especially considering that formulation strategies can sometimes address solubility issues. The slightly higher DILI risk is also less concerning than the poor affinity of Ligand B.

Output:
1
2025-04-17 16:01:58,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.479 and 385.957 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (60.77) is well within the ideal range.

**logP:** Ligand A (0.989) is a bit low, potentially hindering permeation. Ligand B (3.854) is closer to 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 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.541 and 0.7), indicating drug-like properties.

**DILI:** Ligand A (6.747) has a very low DILI risk, which is excellent. Ligand B (35.789) is also relatively low, but higher than Ligand A.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption. However, these values can be unreliable and require experimental validation.

**Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility. This is a significant drawback.

**hERG:** Ligand A (0.167) has a very low hERG risk, which is excellent. Ligand B (0.67) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (27.959) has lower clearance, indicating better metabolic stability, which is a priority for enzymes. Ligand B (54.964) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-22.76) has a negative half-life, which is not physically possible and indicates a data error or outlier. Ligand B (30.859) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a crucial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME concerns. The significantly better binding affinity (-9.1 vs -7.5 kcal/mol) is a major advantage for an enzyme target. While Ligand B has higher microsomal clearance and a slightly higher DILI risk, the superior potency is likely to be more impactful in initial optimization. The negative solubility and Caco-2 values for both are concerning and would need to be addressed through structural modifications. However, the problematic half-life value for Ligand A is a critical flaw.

Output:
1
2025-04-17 16:01:58,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.503 and 352.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.43). A TPSA under 90 is generally acceptable, and A is closer to the optimal range for good absorption.

**3. logP:** Both ligands have good logP values (2.901 and 2.622), 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:** Both ligands have acceptable QED scores (0.487 and 0.565), indicating reasonable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (22.489) has a much lower DILI risk than Ligand B (10.237). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (77.821) is better than Ligand B (65.839). While not a primary concern for a kinase inhibitor, higher BBB is never a disadvantage.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.689 and -4.715), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.949 and -2.988), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.464 and 0.386), which is excellent.

**12. Cl_mic:** Ligand B (58.628) has lower microsomal clearance than Ligand A (71.93), suggesting better metabolic stability. This is a key advantage for Ligand B.

**13. t1/2:** Ligand B (-25.857) has a longer in vitro half-life than Ligand A (-16.431), further supporting its better metabolic stability.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.331 and 0.231).

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.1). This 0.5 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates superior binding affinity and metabolic stability (lower Cl_mic and longer t1/2). However, Ligand A has a much better DILI score and slightly better BBB penetration. Both have poor Caco-2 and solubility, which are significant concerns. Given the enzyme-specific priorities, metabolic stability and potency are paramount. The 0.5 kcal/mol difference in binding affinity is substantial, and the improved metabolic stability of Ligand B is also crucial. While the DILI risk is higher for Ligand B, it's still within a manageable range.

Output:
1
2025-04-17 16:01:58,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.359 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (119.24 and 113.33) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.317) is slightly low, potentially hindering permeation. Ligand B (0.75) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (7) and Ligand B (5) are both acceptable, being less than 10.

**QED:** Ligand A (0.819) has a significantly better QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand A (86.157) has a higher DILI risk than Ligand B (54.556), which is concerning.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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 very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.098 and 0.137), which is excellent.

**Microsomal Clearance:** Ligand A (8.237) has a higher microsomal clearance than Ligand B (2.486), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (15.927) has a positive half-life, while Ligand B (-9.585) has a negative half-life. This is unusual and suggests potential issues with the experimental setup or the molecule's stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.058), which is favorable.

**Binding Affinity:** Ligand B (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the more promising candidate despite its lower QED and negative solubility/Caco-2 values. The significantly stronger binding affinity (-10.6 vs -7.7 kcal/mol) is a major advantage for an enzyme inhibitor. The lower DILI risk and better metabolic stability (lower Cl_mic) also favor Ligand B. While the solubility and permeability issues are concerning, they might be addressable through formulation strategies. Ligand A's higher DILI risk is a significant concern.

Output:
1
2025-04-17 16:01:58,238 - INFO - Batch 429 complete. Total preferences: 6864
2025-04-17 16:01:58,238 - INFO - Processing batch 430/512...
2025-04-17 16:02:37,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.386 and 359.461 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (56.15) is slightly higher than Ligand B (52.65), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (3.002) is optimal, while Ligand B (1.974) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 for A, 3 for B), satisfying the guidelines.

**QED:** Both ligands have similar QED values (0.776 and 0.756), indicating good drug-likeness.

**DILI:** Ligand A (75.378) has a significantly higher DILI risk than Ligand B (12.369). This is a major concern for Ligand A.

**BBB:** Both have high BBB penetration (74.37 and 84.529), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.23) is worse than Ligand B (-1.945). Solubility is a concern for both, but less so for B.

**hERG Inhibition:** Ligand A (0.851) has a higher hERG risk than Ligand B (0.691), though both are relatively low.

**Microsomal Clearance:** Ligand A (84.265) has significantly higher microsomal clearance than Ligand B (3.799), indicating poorer metabolic stability.

**In vitro Half-Life:** Ligand B (-6.926) has a longer in vitro half-life than Ligand A (22.846).

**P-gp Efflux:** Ligand A (0.657) has lower P-gp efflux than Ligand B (0.065), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-9.3 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh other drawbacks.

**Conclusion:**

While Ligand A has better P-gp efflux, Ligand B is superior overall. Ligand B demonstrates a significantly stronger binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility. The slightly lower logP of Ligand B is a minor concern compared to the substantial advantages in potency and safety. Given the enzyme-specific priorities, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:02:37,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (340.383 and 347.371 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.84) is well below the 140 threshold for good absorption, while Ligand B (101.74) is still acceptable but higher.

**3. logP:** Ligand A (2.214) is within the optimal 1-3 range. Ligand B (0.825) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (1) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands (A: 6, B: 6) are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (A: 0.668, B: 0.765), indicating drug-like properties.

**7. DILI:** Ligand A (61.574) has a higher DILI risk than Ligand B (46.297). This is a significant negative for Ligand A.

**8. BBB:** This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (75.805) has a better BBB score than Ligand A (52.268).

**9. Caco-2 Permeability:** Both have negative 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 low solubility.

**11. hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.14). This is a positive for Ligand B.

**12. Microsomal Clearance:** Ligand A (107.537) has a higher microsomal clearance than Ligand B (68.255), indicating lower metabolic stability. This is a significant negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (-29.736) has a *much* longer in vitro half-life than Ligand A (-3.489). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.346, B: 0.04).

**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 A boasts a superior binding affinity, its significantly higher DILI risk, higher microsomal clearance (lower metabolic stability), and shorter half-life are major drawbacks. Ligand B, despite slightly weaker binding, presents a much more favorable ADMET profile: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are critical. 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 16:02:37,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.5 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (62.74). A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.421 and 1.906, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and acceptable HBA counts (3 and 4, respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.664 and 0.765), indicating good drug-likeness.

**DILI:** Ligand A (8.104) has a much lower DILI risk than Ligand B (40.403). This is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target, Ligand B (73.517) has a higher BBB score than Ligand A (64.87).

**Caco-2 Permeability:** Ligand A (-4.97) has slightly better Caco-2 permeability than Ligand B (-4.226), though both are negative values indicating low permeability.

**Aqueous Solubility:** Ligand A (-1.344) has better aqueous solubility than Ligand B (-1.641). Both are poor, but A is slightly better.

**hERG Inhibition:** Ligand A (0.535) has a significantly lower hERG inhibition liability than Ligand B (0.217), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (0.789) has much lower microsomal clearance than Ligand B (43.887), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (5.885) has a longer in vitro half-life than Ligand A (3.64), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux liability than Ligand B (0.256), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.8). This 1.5 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and in vitro half-life. However, Ligand A demonstrates superior ADMET properties: significantly lower DILI risk, lower hERG inhibition, much lower microsomal clearance (better metabolic stability), and better solubility. Given that we are targeting a kinase (enzyme), metabolic stability and safety (DILI, hERG) are paramount. The slightly better binding affinity of Ligand B is not enough to overcome the substantial ADMET advantages of Ligand A.

Output:
0
2025-04-17 16:02:37,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.343 and 353.369 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.44) is slightly above the optimal <140 for good oral absorption, but acceptable. Ligand B (75.44) is excellent, well below 140.

**logP:** Both ligands have good logP values (2.203 and 1.889), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both within acceptable limits. Ligand B has 1 HBD and 4 HBA, also good.

**QED:** Ligand B (0.897) has a significantly better QED score than Ligand A (0.312), indicating a more drug-like profile.

**DILI:** Ligand A has a DILI risk of 63.862, which is moderately high. Ligand B has a lower DILI risk of 48.313, which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (87.941) has a higher BBB value than Ligand A (29.197), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.755), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.261 and -2.963), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.551) has a slightly higher hERG risk than Ligand B (0.258), making Ligand B safer in terms of cardiotoxicity.

**Microsomal Clearance:** Ligand B (2.724 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (10.3 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (8.465 hours) has a much longer in vitro half-life than Ligand A (2.471 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.125) shows some P-gp efflux, while Ligand B (0.046) has very low efflux liability.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most critical factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is significantly better overall. Its superior binding affinity (-8.7 vs 0 kcal/mol), lower DILI risk, better QED, lower microsomal clearance, longer half-life, and lower P-gp efflux outweigh the shared permeability and solubility concerns. The substantial difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 16:02:37,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.387 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.34) is better than Ligand B (88.39), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.739) is slightly lower than optimal (1-3), but acceptable. Ligand B (1.853) is within the optimal range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**H-Bond Acceptors:** Both ligands (5) are within the acceptable range (<=10).

**QED:** Both ligands have high QED scores (0.848 and 0.831), indicating good drug-likeness.

**DILI:** Ligand A (60.217) is borderline, while Ligand B (74.603) is higher, indicating a greater potential for liver injury. This favors Ligand A.

**BBB:** Ligand A (83.831) has better BBB penetration than Ligand B (53.819), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.605) has worse Caco-2 permeability than Ligand B (-5.055).

**Aqueous Solubility:** Ligand A (-1.374) has better aqueous solubility than Ligand B (-3.077). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.383 and 0.238), which is excellent.

**Microsomal Clearance:** Ligand A (5.566) has significantly lower microsomal clearance than Ligand B (36.393), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (3.825) has a shorter half-life than Ligand B (17.266). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03 and 0.069).

**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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity, which is the most important factor for an enzyme inhibitor. While it has a higher DILI risk and lower metabolic stability than Ligand A, the substantial improvement in binding affinity (-8.7 vs -7.5 kcal/mol) is likely to be decisive. The difference of 1.2 kcal/mol is significant. The solubility and permeability of Ligand B are also acceptable, and the hERG risk is low.

Output:
1
2025-04-17 16:02:37,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.39 and 347.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.02) is higher than Ligand B (43.86). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have acceptable logP values (0.896 and 1.966, respectively), 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 (0.764), indicating a more drug-like profile.

**DILI:** Ligand B (3.92) has a much lower DILI risk than Ligand A (58.67), which is a significant advantage.

**BBB:** Ligand B (89.03) has a much higher BBB penetration percentile than Ligand A (32.14). While SRC is not necessarily a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.261) has a worse Caco-2 permeability than Ligand B (-4.851).

**Aqueous Solubility:** Ligand A (-2.547) has a worse aqueous solubility than Ligand B (-1.296).

**hERG:** Both ligands have low hERG inhibition liability (0.374 and 0.573, respectively), which is good.

**Microsomal Clearance:** Ligand B (10.35) has a significantly lower microsomal clearance than Ligand A (30.36), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.13) has a significantly longer in vitro half-life than Ligand A (-2.68), suggesting a longer duration of action.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.037, respectively).

**Binding Affinity:** Both ligands have very similar and 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.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has a slightly better QED score, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and better Caco-2 permeability. The binding affinity is comparable between the two.

Output:
1
2025-04-17 16:02:37,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.403 and 350.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.46) is better than Ligand B (118.01), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.507) is optimal (1-3), while Ligand B (-0.396) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3), as lower HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.864) has a significantly higher QED than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand B (42.962) has a lower DILI risk than Ligand A (66.382), which is a positive attribute.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 48.119, Ligand B: 49.942), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.503) has worse Caco-2 permeability than Ligand B (-5.263), but both are quite poor.

**Aqueous Solubility:** Ligand A (-2.873) has better aqueous solubility than Ligand B (-1.665).

**hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.317, Ligand B: 0.164).

**Microsomal Clearance:** Ligand B (14.928) has lower microsomal clearance than Ligand A (22.281), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (6.288) has a longer in vitro half-life than Ligand A (-26.497), which is a significant positive.

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.126, Ligand B: 0.01).

**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 small, it's within the range where it can outweigh other drawbacks.

**Overall Assessment:**

Ligand B appears to be the better candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While Ligand A has a better QED and solubility, the improved pharmacokinetic properties of Ligand B are more crucial for an enzyme inhibitor. The slightly lower logP of Ligand B is a minor concern, but the other advantages outweigh this.

Output:
1
2025-04-17 16:02:37,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.451 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.14) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (62.3) is excellent, well below 140.

**logP:** Ligand A (0.723) is a bit low, potentially hindering permeation. Ligand B (3.251) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.605 and 0.809), indicating good drug-like properties.

**DILI:** Ligand A (23.846) has a very favorable DILI score, indicating low liver injury risk. Ligand B (47.421) is higher, but still within an acceptable range.

**BBB:** Ligand A (63.707) has moderate BBB penetration. Ligand B (84.064) has good BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.377) has poor Caco-2 permeability. Ligand B (-4.995) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-0.667) has poor aqueous solubility. Ligand B (-3.643) has very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.126) has very low hERG inhibition risk, which is excellent. Ligand B (0.589) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (17.976) has relatively low microsomal clearance, suggesting better metabolic stability. Ligand B (57.335) has significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-2.036) has a negative half-life, which is not possible and indicates a potential data error or a very rapidly metabolized compound. Ligand B (7.228) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux liability, which is favorable. Ligand B (0.37) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate despite its higher DILI and P-gp efflux, and poorer solubility. The significantly stronger binding affinity (-7.7 vs -6.9 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand B has better metabolic stability (lower Cl_mic) and a reasonable half-life, while Ligand A has a nonsensical negative half-life. While both have poor Caco-2 permeability and solubility, the potency advantage of Ligand B is likely to be more impactful, and solubility/permeability can be addressed through formulation strategies.



Output:
1
2025-04-17 16:02:37,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (478.181 Da) is towards the upper end, while Ligand B (344.474 Da) is comfortably within.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (76.66) is higher than Ligand B (55.12).

**logP:** Both ligands have logP values between 1-3 (Ligand A: 3.022, Ligand B: 3.437), which is optimal.

**H-Bond Donors & Acceptors:** Both have 2 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 2 HBA. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (Ligand A: 0.592, Ligand B: 0.86), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (11.439), but both are below the concerning threshold of 60.

**BBB:** Both have high BBB penetration (Ligand A: 86.894, Ligand B: 89.802), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. It suggests poor permeability. However, the scale is not specified, so we can't definitively assess this.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and potentially problematic. It suggests poor solubility. However, the scale is not specified, so we can't definitively assess this.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.606, Ligand B: 0.882).

**Microsomal Clearance:** Ligand A (78.59) has a higher microsomal clearance than Ligand B (47.953), indicating lower metabolic stability. This is a key negative for Ligand A.

**In vitro Half-Life:** Ligand B (4.917) has a longer in vitro half-life than Ligand A (16.663). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.177, Ligand B: 0.341).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have some concerning permeability/solubility issues (indicated by the negative values), Ligand B's significantly stronger binding affinity (-9.6 vs -8.4 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly higher BBB and QED. The lower DILI risk is also a plus. The affinity difference is substantial enough to potentially overcome any permeability/solubility challenges with further optimization.

Output:
1
2025-04-17 16:02:37,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (357.307 and 349.356 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.15) is slightly higher than Ligand B (45.23). Both are below the 140 threshold for good oral absorption, but lower is generally better. Ligand B has a more favorable TPSA.

**3. logP:** Both ligands (2.755 and 3.372) are within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate a slightly higher risk of off-target effects, but it's 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 4 HBAs, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.838 and 0.864), indicating good drug-like properties.

**7. DILI:** Ligand A (64.444) has a higher DILI risk than Ligand B (52.385). Both are acceptable (<60 is good), but B is preferable.

**8. BBB:** Both ligands have high BBB penetration (80.225 and 88.717). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.546 and -4.54). These values are unusual and suggest very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.288 and -4.216). This is a major red flag, indicating very poor aqueous solubility, which will hinder bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.786 and 0.636), which is good.

**12. Microsomal Clearance:** Ligand A (13.799) has significantly lower microsomal clearance than Ligand B (42.508), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (20.066) has a longer in vitro half-life than Ligand B (-18.426). The negative value for B is concerning and suggests rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.279 and 0.129), which is favorable.

**15. 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:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its significantly lower microsomal clearance and longer half-life are critical advantages for an enzyme inhibitor like an SRC kinase inhibitor. While Ligand B has a slightly better DILI score and TPSA, the metabolic stability of Ligand A outweighs these minor benefits. The poor solubility and permeability of both compounds would need to be addressed through formulation or structural modifications, but Ligand A provides a better starting point due to its improved pharmacokinetic properties.

Output:
0
2025-04-17 16:02:37,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.383 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is excellent, well below the 140 threshold for oral absorption and even favorable for CNS penetration. Ligand B (121.89) is still acceptable, but less optimal.

**logP:** Ligand A (-0.551) is a bit low, potentially hindering permeation. Ligand B (0.845) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is also good, within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.721 and 0.609), indicating good drug-like properties.

**DILI:** Ligand A (44.591) has a much lower DILI risk than Ligand B (73.982). This is a significant advantage.

**BBB:** Ligand A (62.97) has moderate BBB penetration, while Ligand B (29.042) has very low BBB penetration. While not a primary concern for a non-CNS target like SRC, it's a neutral point.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the measurement or the compounds themselves. However, the value for Ligand A (-4.925) is less negative than Ligand B (-5.373).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. Ligand A (-2.41) is slightly better than Ligand B (-2.769).

**hERG Inhibition:** Ligand A (0.109) has a very low hERG risk, while Ligand B (0.311) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (23.316) has a higher microsomal clearance than Ligand B (5.632), meaning Ligand B is more metabolically stable. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-27.686) has a much longer in vitro half-life than Ligand A (0.207). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.014).

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and a much lower DILI risk, and better TPSA. However, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better logP. The negative solubility and Caco-2 values are concerning for both, but the superior binding affinity of Ligand A is a critical factor for an enzyme inhibitor. The difference in binding affinity (-1.6 kcal/mol) is substantial and likely to be more impactful than the metabolic stability advantage of Ligand B.

Output:
1
2025-04-17 16:02:37,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (354.451 and 346.362 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.77) is slightly higher than Ligand B (85.25), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (0.372) is a bit low, potentially hindering permeation. Ligand B (1.732) is within the optimal 1-3 range. This favors Ligand B.

**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: 4, Ligand B: 5).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.548, Ligand B: 0.748), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (19.969) has a significantly lower DILI risk than Ligand B (73.517). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (77.239) has better BBB penetration than Ligand B (56.34), but BBB isn't a high priority for a kinase inhibitor.

**9. Caco-2 Permeability:** Ligand A (-5.13) has a worse Caco-2 permeability than Ligand B (-4.744).

**10. Aqueous Solubility:** Ligand A (-0.787) has worse aqueous solubility than Ligand B (-2.829).

**11. hERG Inhibition:** Ligand A (0.222) has a lower hERG inhibition risk than Ligand B (0.603). This is a positive for Ligand A.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-3.173) has significantly lower (better) microsomal clearance than Ligand B (35.622), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.305) has a shorter half-life than Ligand B (-29.065), which is a negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.006) has much lower P-gp efflux liability than Ligand B (0.14).

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-6.7). However, the difference is only 0.4 kcal/mol, which isn't a huge advantage.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a slightly better affinity, but Ligand A excels in metabolic stability (Cl_mic), DILI risk, hERG inhibition, and P-gp efflux. Solubility is better for Ligand B. The lower DILI risk and better metabolic stability of Ligand A are crucial advantages for a kinase inhibitor, outweighing the slightly lower affinity.

Output:
0
2025-04-17 16:02:37,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (99.1 and 94.88) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (0.21) is quite low, potentially hindering permeation. Ligand B (2.556) 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 (0.541 and 0.759), indicating drug-like properties.

**DILI:** Ligand A (20.279) has a lower DILI risk than Ligand B (37.146), which is favorable.

**BBB:** Ligand A (38.852) has a lower BBB penetration than Ligand B (63.242). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.218) has poor Caco-2 permeability, while Ligand B (-4.735) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.395) has slightly better aqueous solubility than Ligand B (-3.295).

**hERG:** Ligand A (0.176) has a lower hERG risk than Ligand B (0.366), which is a positive attribute.

**Microsomal Clearance:** Ligand A (18.489) has a higher microsomal clearance than Ligand B (13.079), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (5.557) has a longer half-life than Ligand B (-2.245), which is desirable.

**P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux than Ligand B (0.032), which is favorable.

**Binding Affinity:** Ligand B (-8.2 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 is the better candidate. While Ligand A has a slightly better DILI score and P-gp efflux, Ligand B excels in key areas: logP (much better for permeability), binding affinity (significantly stronger), and metabolic stability (lower Cl_mic). The stronger binding affinity of Ligand B is particularly important for an enzyme target like SRC kinase. The slightly lower solubility and higher DILI risk of Ligand B are acceptable trade-offs given its superior potency and metabolic profile.

Output:
1
2025-04-17 16:02:37,979 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.33 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.36) is slightly higher than Ligand B (92.79). Both are acceptable, but B is better for oral absorption.

**logP:** Both ligands have good logP values (1.857 and 1.123), falling within the 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.

**QED:** Ligand A (0.715) has a better QED score than Ligand B (0.59), indicating a more drug-like profile.

**DILI:** Ligand B (44.203) has a significantly lower DILI risk than Ligand A (74.021). This is a major advantage for B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.36) has a higher BBB percentile than Ligand A (22.528), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.848) shows poor permeability, while Ligand B (-5.004) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.856) has slightly better solubility than Ligand B (-1.563).

**hERG:** Ligand A (0.442) has a lower hERG risk than Ligand B (0.283). This is a positive for A.

**Microsomal Clearance:** Ligand B (-6.336) has a *much* lower (better) microsomal clearance than Ligand A (10.998). This indicates significantly improved metabolic stability for B.

**In vitro Half-Life:** Ligand B (-14.117) has a longer in vitro half-life than Ligand A (89.733), further supporting its improved metabolic stability.

**P-gp Efflux:** Ligand A (0.069) has slightly lower P-gp efflux than Ligand B (0.01), which is slightly better.

**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.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better QED and hERG profile, Ligand B excels in key areas for an enzyme inhibitor: significantly lower DILI risk, substantially improved metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and better Caco-2 permeability. The improved metabolic stability is particularly important for kinase inhibitors, which often suffer from rapid metabolism. The slightly lower solubility of B is a minor concern that could be addressed with formulation strategies.

Output:
1
2025-04-17 16:02:37,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.948 and 360.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (19.37) is excellent, well below the 140 threshold for good absorption. Ligand B (58.64) is still reasonable, but higher.

**logP:** Ligand A (4.458) is slightly above the optimal 1-3 range, potentially leading to solubility issues. Ligand B (2.387) is within the ideal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 3 HBA) is also good. Both are well within the recommended limits.

**QED:** Both ligands have acceptable QED values (0.736 and 0.687, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (34.82 and 30.748, respectively), which is excellent.

**BBB:** Both ligands have high BBB penetration (87.553 and 87.088), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.873 and -4.567). This is unusual and suggests poor permeability. However, these values are often predictions and can be unreliable.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.047 and -2.425). This is concerning, as poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.978) has a slightly higher hERG risk than Ligand B (0.656), but both are reasonably low.

**Microsomal Clearance:** Ligand A (36.139 mL/min/kg) has a higher clearance than Ligand B (20.315 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.965 hours) has a significantly shorter half-life than Ligand A (56.974 hours). This is a major disadvantage for Ligand B.

**P-gp Efflux:** Ligand A (0.784) has slightly higher P-gp efflux than Ligand B (0.294), which is less desirable.

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the negative solubility and permeability predictions, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.1 vs -8.0 kcal/mol) outweighs the slightly higher logP and P-gp efflux. The much longer half-life (56.974 hours) is also a major advantage, potentially allowing for less frequent dosing. While both have acceptable safety profiles (DILI, hERG), the improved potency and PK of Ligand A make it the better choice.

Output:
0
2025-04-17 16:02:37,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.929 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (105.64). A TPSA under 140 is good for oral absorption, and A is well within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 3.169, B: 1.392), 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 HBDs generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.731, B: 0.776), indicating drug-like properties.

**DILI:** Ligand A (37.03) has a much lower DILI risk than Ligand B (16.557). This is a significant advantage for A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand A (82.862) has better BBB penetration than Ligand B (47.15).

**Caco-2 Permeability:** Ligand A (-4.603) has a worse Caco-2 permeability than Ligand B (-5.478). However, this is a negative value, indicating low permeability for both.

**Aqueous Solubility:** Ligand A (-3.573) has slightly better solubility than Ligand B (-2.35), but both are quite poor. Solubility is a concern for both.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.678, B: 0.112). This is excellent.

**Microsomal Clearance:** Ligand A (98.981) has a *much* higher microsomal clearance than Ligand B (-0.391). This indicates poor metabolic stability for A, a major drawback. B shows excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-4.992) has a very short in vitro half-life, consistent with the high clearance. Ligand B (13.79) has a much better half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.355, B: 0.007).

**Binding Affinity:** Both ligands have similar binding affinities (A: -9.7 kcal/mol, B: -9.1 kcal/mol). A has a slightly better affinity, but the difference is not substantial enough to overcome other issues.

**Conclusion:**

While Ligand A has slightly better affinity and lower DILI risk, its significantly higher microsomal clearance and shorter half-life are major concerns for an enzyme inhibitor. The poor solubility of both is a concern, but can be addressed with formulation strategies. Ligand B's excellent metabolic stability (low Cl_mic, long t1/2) is a critical advantage. Given the enzyme-specific priorities, **Ligand B** is the more viable drug candidate.

Output:
1
2025-04-17 16:02:37,980 - INFO - Batch 430 complete. Total preferences: 6880
2025-04-17 16:02:37,980 - INFO - Processing batch 431/512...
2025-04-17 16:03:17,659 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (53.09) is slightly higher than Ligand B (49.74), but both are good.

**logP:** Ligand A (1.594) is within the optimal range (1-3). Ligand B (4.388) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0/1) and HBA (4/4) counts, balancing solubility and permeability.

**QED:** Both ligands have QED scores above 0.5 (0.705 and 0.629), indicating good drug-like properties.

**DILI:** Ligand A (5.312) has a very low DILI risk, significantly better than Ligand B (17.138). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (70.027) is slightly better than Ligand B (64.211). While not a primary concern for a kinase inhibitor, it's a minor positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.535) has a negative Caco-2 value, indicating poor permeability. Ligand B (-5.358) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-0.48) has slightly better solubility than Ligand B (-3.713). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.565) has a lower hERG risk than Ligand B (0.827), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (2.601) has significantly lower microsomal clearance than Ligand B (32.859), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.485) has a much longer in vitro half-life than Ligand B (-12.453), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux liability than Ligand B (0.314), which is favorable for bioavailability.

**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's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a much lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, lower P-gp efflux, and slightly better binding affinity. While Ligand A has poorer Caco-2 permeability, its superior safety and pharmacokinetic properties outweigh this drawback, especially considering the importance of metabolic stability and safety for kinase inhibitors. Ligand B's high logP and DILI risk are significant concerns.

Output:
0
2025-04-17 16:03:17,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (121.52) is better than Ligand B (62.66) as it is closer to the threshold for good oral absorption.

**logP:** Ligand B (2.957) is optimal (1-3), while Ligand A (0.213) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=4, HBA=4) is better than Ligand B (HBD=1, HBA=5) as it is closer to the ideal range.

**QED:** Both ligands have good QED scores (A: 0.538, B: 0.776), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (31.718) has a much lower DILI risk than Ligand B (55.176), which is a significant advantage.

**BBB:** Ligand B (67.197) has a higher BBB penetration percentile than Ligand A (32.144), but BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Ligand A (-5.577) is significantly worse than Ligand B (-4.482), indicating poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.538) is slightly better than Ligand B (-3.698), but both are poor.

**hERG Inhibition:** Ligand A (0.141) has a lower hERG inhibition liability than Ligand B (0.711), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-1.913) has a lower (better) microsomal clearance than Ligand B (82.283), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.303) has a better in vitro half-life than Ligand B (-16.553).

**P-gp Efflux:** Ligand A (0.005) has a much lower P-gp efflux liability than Ligand B (0.241), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-10.1) has a significantly stronger binding affinity than Ligand B (-8.6). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a substantially better binding affinity and significantly lower DILI, hERG, and P-gp efflux liabilities, and better metabolic stability. While its logP and Caco-2 permeability are less favorable, the strong binding affinity and improved safety profile are critical for an enzyme inhibitor. Ligand B has better logP and Caco-2 permeability, but its higher DILI, hERG, and P-gp efflux, coupled with weaker binding, make it a less attractive candidate.

Output:
0
2025-04-17 16:03:17,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.383 and 376.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.27) is better than Ligand B (51.02) as it is closer to the 140 A^2 threshold for good oral absorption. Ligand B is very low, which could indicate issues with solubility.

**logP:** Ligand A (-0.938) is slightly low, potentially hindering permeation. Ligand B (3.74) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Ligand A (8) is good, while Ligand B (6) is also acceptable.

**QED:** Both ligands have good QED scores (0.637 and 0.771, respectively), indicating drug-like properties.

**DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (46.336), which is better.

**BBB:** Ligand A (54.246) and Ligand B (70.027). Since SRC is not a CNS target, this is less critical, but B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.534 and -5.212). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-0.663) and Ligand B (-3.315) both have negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.037) has a very low hERG risk, which is excellent. Ligand B (0.663) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-11.02) has a much lower (better) microsomal clearance than Ligand B (52.182), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-23.796) has a negative half-life, which is unusual. Ligand B (-27.882) also has a negative half-life.

**P-gp Efflux:** Ligand A (0) has no P-gp efflux, which is good. Ligand B (0.53) has some efflux, but it's not excessive.

**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, it is still a factor.

**Overall Assessment:**

Ligand A has a better TPSA, lower hERG risk, and significantly better metabolic stability (lower Cl_mic). However, Ligand B has a better logP, lower DILI risk, and slightly better binding affinity. Both have poor solubility and permeability. Given the enzyme-specific priorities, metabolic stability (Cl_mic) is crucial. The substantial difference in Cl_mic favors Ligand A.

Output:
0
2025-04-17 16:03:17,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.355 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.76) is slightly higher than Ligand B (94.66). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned, especially considering kinase inhibitors don't necessarily *require* high CNS penetration.

**logP:** Ligand A (2.044) is within the optimal 1-3 range. Ligand B (0.75) is a bit low, potentially hindering permeability, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 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 (0.579 and 0.748 respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 87.049, which is high. Ligand B has a much lower DILI risk of 37.418, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both have low BBB penetration (27.414 and 22.644), which isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.886 and -5.025), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both have negative solubility values (-3.179 and -2.307), also unusual and indicative of poor solubility. This is a concern for both.

**hERG:** Ligand A (0.133) has a slightly lower hERG risk than Ligand B (0.281), which is preferable.

**Microsomal Clearance:** Ligand A (-21.936) has a much lower (better) microsomal clearance than Ligand B (7.361). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (40.012) has a longer in vitro half-life than Ligand B (-6.518), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.024 and 0.047).

**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, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a much better safety profile (lower DILI) and significantly higher binding affinity. While both have issues with Caco-2 permeability and solubility, the strong binding affinity of Ligand B is a major advantage for an enzyme inhibitor. The better metabolic stability of Ligand A is a plus, but the substantial difference in binding affinity outweighs this benefit. The DILI risk associated with Ligand A is also a significant concern.

Output:
1
2025-04-17 16:03:17,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (350.507 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.39) is slightly higher than Ligand B (49.41), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (3.418 and 3.832), 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 2. Both are below the 10 threshold.

**6. QED:** Both ligands have acceptable QED scores (0.82 and 0.712), indicating good drug-like properties.

**7. DILI:** Ligand A (19.465) has a lower DILI risk than Ligand B (21.869), which is preferable. Both are below the 40 threshold.

**8. BBB:** Both have high BBB penetration (90.772 and 82.319), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.174) has slightly better Caco-2 permeability than Ligand B (-4.689).

**10. Aqueous Solubility:** Ligand A (-3.167) has slightly better solubility than Ligand B (-3.855).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.424 and 0.541).

**12. Microsomal Clearance:** Ligand B (66.904) has lower microsomal clearance than Ligand A (75.49), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (19.875) has a longer half-life than Ligand B (-2.646), which is desirable.

**14. P-gp Efflux:** Ligand A (0.146) has lower P-gp efflux than Ligand B (0.318), which is preferable.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.9 kcal/mol). This 0.3 kcal/mol difference is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A demonstrates a slight edge due to its superior binding affinity, better solubility, lower DILI risk, and lower P-gp efflux, despite having slightly higher TPSA and microsomal clearance. The difference in binding affinity is substantial enough to make it the more promising candidate, even considering the slightly less favorable metabolic stability.

Output:
1
2025-04-17 16:03:17,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.43 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.85) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (82.78) is still under 140, but less optimal than A.

**logP:** Both ligands (2.959 and 2.628) are within the optimal 1-3 range.

**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 good QED scores (0.652 and 0.774), indicating drug-like properties.

**DILI:** Ligand A (56.727) has a slightly higher DILI risk than Ligand B (41.838), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.784) has a higher BBB score than Ligand B (39.744), but this is not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-4.903 vs -4.868).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.518) is slightly better than Ligand A (-3.673), but both are problematic.

**hERG Inhibition:** Ligand A (0.958) has a slightly higher hERG risk than Ligand B (0.236). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (37.798) has a higher microsomal clearance than Ligand B (10.743), meaning Ligand B is more metabolically stable. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (21.423 hours) has a longer half-life than Ligand A (17.191 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.774) has a higher P-gp efflux liability than Ligand B (0.216), meaning Ligand B will have better oral bioavailability.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-10.2 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, the ADME properties of Ligand B are considerably better. Specifically, Ligand B has significantly lower hERG risk, lower microsomal clearance, a longer half-life, and lower P-gp efflux. The solubility and Caco-2 values are similar and both are poor, but these can be addressed with formulation strategies. The slight increase in DILI risk for ligand A is also a concern. The difference in binding affinity (-9.7 vs -10.2) is not large enough to overcome the substantial ADME advantages of Ligand B, especially considering the importance of metabolic stability and reduced toxicity for an oncology drug.

Output:
1
2025-04-17 16:03:17,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.523 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (96.17). A TPSA under 140 is good for oral absorption, and both are under, but A is much closer to the ideal for better absorption.

**logP:** Both ligands have good logP values (A: 1.887, B: 1.391) 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=9). Lower HBD/HBA generally improves permeability. Ligand B's HBA is getting close to the upper limit.

**QED:** Both ligands have good QED scores (A: 0.65, B: 0.752), indicating drug-like properties.

**DILI:** Ligand A (5.467) has a much lower DILI risk than Ligand B (69.135). This is a significant advantage for Ligand A.

**BBB:** Ligand A (81.233) has better BBB penetration than Ligand B (71.888), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.661) has better Caco-2 permeability than Ligand B (-5.761).

**Aqueous Solubility:** Ligand A (-1.225) has better aqueous solubility than Ligand B (-2.7). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.481) has a much lower hERG inhibition risk than Ligand B (0.056). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (19.897) has lower microsomal clearance than Ligand B (23.011), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (6.626) has a longer in vitro half-life than Ligand A (-3.95). This is a positive for Ligand B, but the negative value for A is concerning.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.091), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.0). While a 1.5 kcal/mol difference is usually significant, the other advantages of Ligand A outweigh this.

**Overall:** Ligand A is the better candidate. It has a significantly lower DILI risk and hERG inhibition liability, better solubility, permeability, and metabolic stability, and comparable binding affinity. While Ligand B has a slightly better half-life and affinity, the ADME-Tox profile of Ligand A is far superior.

Output:
0
2025-04-17 16:03:17,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.348 Da) is slightly higher than Ligand B (346.391 Da), but both are acceptable.

**TPSA:** Ligand A (66.48) is significantly better than Ligand B (122.03). A TPSA under 140 is good for oral absorption, and Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (3.233) is optimal, while Ligand B (0.048) is quite low. Low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=7). Both are within acceptable limits, but Ligand A has a more favorable balance.

**QED:** Both ligands have similar QED values (Ligand A: 0.773, Ligand B: 0.635), indicating reasonable drug-likeness.

**DILI:** Ligand A (72.47) has a higher DILI risk than Ligand B (49.438). This is a concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (50.989) and Ligand B (17.332) are both low, which is not a major drawback.

**Caco-2 Permeability:** Ligand A (-4.949) is better than Ligand B (-5.416), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.714) is better than Ligand B (-1.965), suggesting better solubility.

**hERG:** Ligand A (0.757) is significantly better than Ligand B (0.045). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (72.89) has a higher clearance than Ligand B (2.668). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-1.724) has a shorter half-life than Ligand B (0.191). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.312) is better than Ligand B (0.006), indicating lower P-gp efflux.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better TPSA, logP, solubility, and hERG, Ligand B's significantly stronger binding affinity (-8.2 vs -7.5 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are critical advantages for an enzyme inhibitor. The lower DILI risk for Ligand B is also a positive. The lower logP of Ligand B is a concern, but the strong binding affinity may compensate for this.

Output:
1
2025-04-17 16:03:17,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.371 and 353.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.17) is better than Ligand B (59). Both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.027) is slightly lower, while Ligand B (2.752) is closer to the optimal range of 1-3.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6, and Ligand B has 4, both are below the 10 threshold.

**QED:** Ligand A (0.876) has a significantly better QED score than Ligand B (0.682), indicating a more drug-like profile.

**DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (13.339). This is a significant concern for Ligand A.

**BBB:** Both have similar BBB penetration (77.084 and 78.558), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.005) has worse Caco-2 permeability than Ligand B (-4.488), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.792) has worse aqueous solubility than Ligand B (-2.285).

**hERG Inhibition:** Ligand A (0.166) has a lower hERG inhibition risk than Ligand B (0.774), which is favorable.

**Microsomal Clearance:** Ligand A (5.916) has a lower microsomal clearance than Ligand B (54.792), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (35.222) has a longer half-life than Ligand B (23.296), which is desirable.

**P-gp Efflux:** Ligand A (0.012) has significantly lower P-gp efflux than Ligand B (0.675), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.9 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a better QED, lower P-gp efflux, lower microsomal clearance, and longer half-life. However, it has significantly higher DILI risk and poorer solubility and Caco-2 permeability. Ligand B has a better logP, lower DILI risk, better solubility and Caco-2 permeability, but a lower QED and worse metabolic stability.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and solubility are crucial. While Ligand A has better metabolic stability and half-life, the high DILI risk and poor solubility are major drawbacks. Ligand B, despite slightly worse metabolic properties, presents a much safer profile regarding liver toxicity and absorption. The binding affinity difference is minimal.

Output:
1
2025-04-17 16:03:17,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.355 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.47) is better than Ligand B (63.25) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally correlates with better cell permeability.

**3. logP:** Ligand A (1.723) is optimal (1-3). Ligand B (4.648) is a bit high, 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:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both within the acceptable range (<=10).

**6. QED:** Ligand A (0.86) has a better QED score than Ligand B (0.736), indicating a more drug-like profile.

**7. DILI:** Ligand A (84.645) has a higher DILI risk than Ligand B (69.756), which is concerning.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.286) and Ligand B (64.87) are both relatively low.

**9. Caco-2 Permeability:** Ligand A (-4.858) is better than Ligand B (-4.96), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.958) is better than Ligand B (-5.73), which is crucial for bioavailability.

**11. hERG Inhibition:** Ligand A (0.453) has a lower hERG inhibition liability than Ligand B (0.638), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (42.619) has significantly lower microsomal clearance than Ligand B (126.566), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.731) has a shorter half-life than Ligand B (42.106). However, the difference in Cl_mic is more important for overall metabolic stability.

**14. P-gp Efflux:** Ligand A (0.311) has lower P-gp efflux liability than Ligand B (0.582), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This 0.7 kcal/mol difference is significant, but needs to be weighed against the other ADME properties.

**Overall Assessment:**

Ligand A is the better candidate despite the higher DILI risk. The superior logP, QED, solubility, hERG, metabolic stability (lower Cl_mic), and P-gp efflux profile outweigh the slightly weaker binding affinity and higher DILI. The DILI risk can be further investigated and potentially mitigated through structural modifications. Ligand B's high logP and poor metabolic stability are major drawbacks.

Output:
0
2025-04-17 16:03:17,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.434 Da) is slightly better positioned.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold for oral absorption. Ligand B (100.09) is still acceptable, but less favorable.

**logP:** Ligand A (2.249) is optimal (1-3). Ligand B (0.121) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both ligands are acceptable (Ligand A: 1, Ligand B: 2), being less than 5.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, but still within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (A: 0.821, B: 0.747), indicating good drug-likeness.

**DILI:** Ligand A (34.432) has a much lower DILI risk than Ligand B (62.621). This is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (83.055) is higher than Ligand B (28.383), but this is not decisive.

**Caco-2 Permeability:** Ligand A (-4.316) is better than Ligand B (-5.704), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.391 and -2.791 respectively). This is a concern for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.756) has a much lower hERG risk than Ligand B (0.035). This is a critical advantage.

**Microsomal Clearance:** Ligand A (40.886) has a higher (worse) microsomal clearance than Ligand B (-3.409). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-22.985) has a significantly longer in vitro half-life than Ligand A (3.004). This is a major advantage.

**P-gp Efflux:** Ligand A (0.315) has lower P-gp efflux than Ligand B (0.022), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from a low logP, higher DILI risk, and a higher risk of hERG inhibition. Ligand A has better ADME properties overall (logP, DILI, hERG, Caco-2, P-gp) but a weaker binding affinity.

The difference in binding affinity (-9.5 vs -6.3 kcal/mol) is substantial (3.2 kcal/mol). For an enzyme target, potency is paramount. While the ADME profile of Ligand A is more favorable, the significantly stronger binding of Ligand B makes it the more promising candidate, assuming the low logP and hERG risk can be addressed through further optimization.

Output:
1
2025-04-17 16:03:17,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.227 Da) and Ligand B (355.454 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values around 53, which is slightly above the optimal <140 for oral absorption, but not a major concern for a kinase inhibitor.

**logP:** Ligand A (4.891) is high, potentially leading to solubility issues and off-target effects. Ligand B (1.046) is at the lower end of the optimal range, 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 similar QED values (0.702 and 0.74), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (90.074 percentile), which is a significant concern. Ligand B has a very low DILI risk (18.147 percentile), a major advantage.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**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 poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A has a moderate hERG risk (0.754), while Ligand B has a very low hERG risk (0.346). This favors Ligand B.

**Microsomal Clearance:** Ligand A has a moderate Cl_mic (66.453 mL/min/kg), suggesting moderate metabolic stability. Ligand B has a very low Cl_mic (18.767 mL/min/kg), indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A has a reasonable half-life (64.997 hours). Ligand B has a very short half-life (8.423 hours), which is a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the primary driver for enzyme inhibitors. However, its high DILI risk and relatively high logP are significant concerns. Ligand B has a much better safety profile (low DILI and hERG) and excellent metabolic stability, but its weaker binding affinity and short half-life are drawbacks.

Given the priorities for kinase inhibitors, the potency advantage of Ligand A is substantial enough to potentially outweigh the DILI risk, *provided* that the DILI signal can be further investigated and mitigated through structural modifications. The short half-life of Ligand B is a more difficult issue to address.

Output:
1
2025-04-17 16:03:17,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.462 and 368.396 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (87.66). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (2.503 and 1.516), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (3 HBD, 4 HBA). Lower counts are generally preferable for permeability.

**QED:** Both ligands have good QED scores (0.474 and 0.576), indicating reasonable drug-likeness.

**DILI:** Ligand A (16.324) has a much lower DILI risk than Ligand B (20.9). This is a significant advantage.

**BBB:** Ligand A (91.237) shows better BBB penetration than Ligand B (77.937), though this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.344) and Ligand B (-4.835) are similar, indicating similar intestinal absorption.

**Solubility:** Ligand A (-3.271) has better aqueous solubility than Ligand B (-1.287). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.721 and 0.465).

**Microsomal Clearance:** Ligand A (34.098) has higher microsomal clearance than Ligand B (3.75). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-12.952) has a significantly longer in vitro half-life than Ligand A (-10.346). This is a major advantage.

**P-gp Efflux:** Ligand A (0.23) has lower P-gp efflux than Ligand B (0.058), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.2 kcal/mol). Ligand B is slightly better, but the difference is minimal.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. While Ligand A has advantages in TPSA, solubility, and DILI, metabolic stability is crucial for kinase inhibitors to achieve sustained target engagement. The small advantage in binding affinity of Ligand B further reinforces its selection.

Output:
1
2025-04-17 16:03:17,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.439 and 370.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (75.27), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands (2.894 and 3.249) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3 HBA, which is acceptable.

**QED:** Both ligands have similar QED scores (0.564 and 0.534), indicating good drug-likeness.

**DILI:** Ligand B (25.94) has a significantly lower DILI risk than Ligand A (37.146), making it more favorable.

**BBB:** Both have similar BBB penetration (64.637 and 62.582), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.739 and -4.913), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand B (-2.458) is slightly better than Ligand A (-3.574), but both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.659 and 0.29).

**Microsomal Clearance:** Ligand A (34.801 mL/min/kg) has lower microsomal clearance than Ligand B (51.084 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (22.419 and 24.376 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.342 and 0.099).

**Binding Affinity:** Both ligands have identical binding affinities (-8.2 kcal/mol), which is excellent.

**Conclusion:**

While both compounds have excellent binding affinity, Ligand B is slightly more favorable due to its significantly lower DILI risk and slightly better solubility. The poor Caco-2 permeability is a major concern for both, but the better metabolic stability of Ligand A is a plus. However, the DILI risk is a critical factor, and a lower DILI risk is highly desirable. Given the equal binding affinity, the lower DILI risk of Ligand B makes it the better candidate.

Output:
1
2025-04-17 16:03:17,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.417 and 383.945 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (43.86). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.028 and 2.805), falling within the 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 good (<=10).

**QED:** Both ligands have good QED scores (0.676 and 0.803), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (17.449 and 16.402 percentile), which is favorable.

**BBB:** Both ligands have good BBB penetration (82.474 and 87.553 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.817 and -4.749), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.714 and -2.611), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.587 and 0.718 percentile), which is excellent.

**Microsomal Clearance:** Ligand A has a very low Cl_mic (0.474 mL/min/kg), indicating excellent metabolic stability. Ligand B has a much higher Cl_mic (14.278 mL/min/kg), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a very long half-life (-11.215 hours), consistent with its low Cl_mic. Ligand B has a shorter half-life (9.816 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.181 percentile), which is favorable.

**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 small.

**Conclusion:**

Despite both compounds having poor solubility and permeability, Ligand A is the better candidate. Its significantly lower microsomal clearance and longer half-life are crucial advantages for an enzyme target like SRC kinase. The slightly better binding affinity also contributes. While the solubility and permeability are concerning, these issues might be addressed through formulation strategies. Ligand B's higher metabolic clearance is a more difficult problem to overcome.

Output:
0
2025-04-17 16:03:17,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.929 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**TPSA:** Ligand A (53.51) is better than Ligand B (61.68). Both are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (3.407) is optimal, while Ligand B (1.06) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and acceptable HBA counts (4 for A, 5 for B).

**QED:** Both ligands have good QED scores (0.803 and 0.82), indicating drug-likeness.

**DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (34.161), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (74.796 and 70.027), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.786 and -4.719), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.9 and -0.78), which is also a major concern. Poor solubility can severely limit bioavailability.

**hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.303), but both are relatively low.

**Microsomal Clearance:** Ligand A (45.749) has higher microsomal clearance than Ligand B (17.453), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (20.28) has a significantly longer in vitro half-life than Ligand A (-3.176), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.215 and 0.081).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. The significantly stronger binding affinity (-7.9 vs -7.3 kcal/mol) is a major advantage for an enzyme target like SRC. While Ligand A has higher DILI and clearance, these are less critical than potency in this case. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the strong binding provides a solid foundation for optimization.

Output:
0
2025-04-17 16:03:17,663 - INFO - Batch 431 complete. Total preferences: 6896
2025-04-17 16:03:17,663 - INFO - Processing batch 432/512...
2025-04-17 16:03:58,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.375 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.03) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (67.23) is excellent, well below 140.

**logP:** Ligand A (0.289) is quite low, potentially hindering permeation. Ligand B (1.609) 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 and potentially better for permeability.

**QED:** Both ligands have good QED scores (0.621 and 0.778), indicating good drug-like properties.

**DILI:** Ligand A (74.68) has a moderate DILI risk. Ligand B (11.206) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (29.275) and Ligand B (83.249) are not particularly relevant here.

**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 concerning, indicating poor aqueous solubility.

**hERG:** Both ligands have low hERG risk (0.216 and 0.505), which is good.

**Microsomal Clearance:** Ligand A (17.878) has lower microsomal clearance than Ligand B (38.349), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (29.307) has a longer in vitro half-life than Ligand B (-9.221), which is a positive.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.102).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.6 kcal/mol), with Ligand B being slightly better. The affinity difference is not large enough to overcome other significant issues.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate. Its significantly lower DILI risk, better logP, and lower HBD/HBA counts are substantial advantages. Although both have poor Caco-2 and solubility, the better overall ADME profile of Ligand B makes it the preferred choice for further optimization. The improved metabolic stability of Ligand A is a plus, but the higher DILI risk and lower logP are concerning.

Output:
1
2025-04-17 16:03:58,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (363.351 Da and 352.381 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (47.56) is better than Ligand B (55.57), both are acceptable but A is closer to the <140 threshold for good absorption.

**3. logP:** Both ligands have logP values around 4 (3.957 and 4.005). While slightly high, this isn't a dealbreaker, especially given the potency differences we'll see.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0).

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4).

**6. QED:** Both ligands have similar QED values (0.779 and 0.72), indicating good drug-likeness.

**7. DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (40.636), both are good.

**8. BBB:** Both ligands have high BBB penetration (92.633 and 84.374), but A is better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.18 and -4.202). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.4 and -4.51). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.751) has a lower hERG inhibition risk than Ligand B (0.639), which is favorable.

**12. Microsomal Clearance:** Ligand A (52.737) has a lower microsomal clearance than Ligand B (59.429), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (-15.045) has a longer in vitro half-life than Ligand B (-4.742). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.217 and 0.22).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better ADME properties (lower clearance, longer half-life, lower DILI, better solubility), the potency advantage of Ligand B is likely to be decisive. The poor solubility and permeability of both compounds are concerning, but these can be addressed through formulation strategies or further chemical modifications. The slightly higher hERG risk for Ligand B is also a concern but manageable.

Output:
1
2025-04-17 16:03:58,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.439 Da and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.55) is better than Ligand B (64.09), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.466 and 0.937, respectively), 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 (0.782 and 0.819), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 77.937, which is concerning (high risk). Ligand B has a much lower DILI risk of 6.592, which is excellent. This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (67.197) is better than Ligand A (40.326).

**Caco-2 Permeability:** Ligand A (-5.133) is worse than Ligand B (-4.683), but both are negative, which is not ideal.

**Aqueous Solubility:** Ligand A (-1.81) is worse than Ligand B (-0.785), both are negative, which is not ideal.

**hERG Inhibition:** Ligand A (0.36) is better than Ligand B (0.421), both are low and acceptable.

**Microsomal Clearance:** Ligand A (27.173) is slightly higher than Ligand B (24.528), indicating slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.391) is significantly better than Ligand A (16.146), indicating much better in vitro stability.

**P-gp Efflux:** Ligand A (0.04) is better than Ligand B (0.127), indicating lower P-gp efflux.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference, and a key factor.

**Overall Assessment:**

Ligand A has better binding affinity and P-gp efflux, but suffers from a high DILI risk, poor solubility, and moderate metabolic stability. Ligand B has a much lower DILI risk, better solubility, and significantly better metabolic stability, but weaker binding affinity.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), the lower DILI risk and improved metabolic stability of Ligand B are more valuable than the slightly better binding affinity of Ligand A. While -7.8 kcal/mol is good, a difference of 7.8 kcal/mol is not insurmountable with further optimization, and mitigating the DILI risk is crucial.

Output:
1
2025-04-17 16:03:58,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.401 Da) and Ligand B (343.427 Da) are both acceptable.

**TPSA:** Ligand A (87.66) is well below the 140 threshold for oral absorption, and even below the 90 threshold for CNS penetration. Ligand B (104.45) is still under 140, but closer to the limit. A favors absorption.

**logP:** Ligand A (0.973) is slightly below the optimal range (1-3), potentially impacting permeability. Ligand B (2.029) is within the optimal range. B is better here.

**H-Bond Donors:** Both ligands have 4 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.659) has a good drug-likeness score, exceeding 0.5. Ligand B (0.284) is significantly lower, indicating a less drug-like profile. A is much better.

**DILI:** Ligand A (32.028) has a low DILI risk, well below the 40 threshold. Ligand B (41.256) is slightly higher, but still relatively low risk. A is slightly better.

**BBB:** Ligand A (82.513) has moderate BBB penetration. Ligand B (35.44) has very low BBB penetration. Not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.835) has poor Caco-2 permeability. Ligand B (-5.502) is also poor. Both are problematic, but similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.761 and -3.292 respectively). This is a significant concern for both, but B is slightly worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.455 and 0.477 respectively). This is good.

**Microsomal Clearance:** Ligand A (11.295) has moderate clearance. Ligand B (5.638) has lower clearance, indicating better metabolic stability. B is better.

**In vitro Half-Life:** Ligand A (9.697) has a moderate half-life. Ligand B (-29.983) has a very negative half-life, which is not possible. This is likely an error in the data or a very rapid degradation. A is much better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.057 respectively). This is good.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.4 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has a significantly better QED score, lower DILI risk, and a reasonable half-life. While its logP and Caco-2 permeability are not ideal, the strong binding affinity and favorable safety profile outweigh these concerns. Ligand B has better metabolic stability, but its very low QED, poor half-life, and slightly worse solubility are major drawbacks. The negative half-life is a critical issue.

Output:
0
2025-04-17 16:03:58,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.296 Da) is slightly higher than Ligand B (357.445 Da), but both are acceptable.

**TPSA:** Ligand A (101.11) is higher than Ligand B (52.65). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved absorption.

**logP:** Both ligands have good logP values (A: 1.306, B: 2.038), falling within the optimal range of 1-3.

**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 and good QED values (A: 0.731, B: 0.766), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (77.472%) than Ligand B (11.128%). This is a major concern for Ligand A.

**BBB:** Ligand A (47.15%) has a lower BBB penetration than Ligand B (89.066%). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.12) has worse Caco-2 permeability than Ligand B (-4.711), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.186) has worse aqueous solubility than Ligand B (-2.253). Solubility is important for bioavailability, favoring Ligand B.

**hERG Inhibition:** Ligand A (0.15) has a slightly lower hERG inhibition risk than Ligand B (0.552), which is a minor advantage.

**Microsomal Clearance:** Ligand A (59.735) has a higher microsomal clearance than Ligand B (12.79). This suggests lower metabolic stability for Ligand A, a significant drawback for an enzyme target.

**In vitro Half-Life:** Ligand A (-22.055) has a shorter in vitro half-life than Ligand B (-27.677), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.186) has lower P-gp efflux than Ligand B (0.042).

**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 ADME concerns. However, the DILI and metabolic stability issues are significant.

**Overall Assessment:**

Ligand A has a much better binding affinity, but suffers from significantly higher DILI risk, poorer metabolic stability (higher clearance, shorter half-life), and lower solubility. Ligand B, while having a weaker binding affinity, exhibits a much more favorable ADME profile, particularly regarding safety (DILI) and metabolic stability. Given the enzyme-specific priorities, metabolic stability and safety are crucial. The 1.5kcal/mol advantage in binding affinity is not enough to overcome the significant liabilities of Ligand A.

Output:
1
2025-04-17 16:03:58,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.475 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (89.87) as it's closer to the <140 threshold for good absorption.

**3. logP:** Both ligands (1.302 and 1.299) 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 (3) is preferable to Ligand B (4) for similar reasons as above.

**6. QED:** Ligand A (0.759) is slightly better than Ligand B (0.694), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, low DILI risk (10.392 and 10.585, respectively).

**8. BBB:** Ligand A (70.997) has a better BBB percentile than Ligand B (63.086), but this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.062) has a slightly better Caco-2 permeability than Ligand B (-4.859).

**10. Aqueous Solubility:** Ligand A (-1.961) has better aqueous solubility than Ligand B (-1.66). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.138 and 0.2, respectively).

**12. Microsomal Clearance:** Ligand A (-6.955) exhibits significantly better metabolic stability (lower clearance) than Ligand B (4.699). This is a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-14.742) has a longer in vitro half-life than Ligand B (-8.51), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.037, respectively).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. A difference of 7.6 kcal/mol is substantial.

**Overall Assessment:**

While Ligand A has better ADME properties across the board (TPSA, logP, HBD, HBA, QED, solubility, metabolic stability, half-life), the significantly superior binding affinity of Ligand B (-7.6 kcal/mol vs -0.0 kcal/mol) outweighs these advantages. A strong binding affinity is paramount for kinase inhibitors, and a 7.6 kcal/mol difference is a substantial advantage that can often overcome minor ADME liabilities.

Output:
1
2025-04-17 16:03:58,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.495 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (366.502 Da) is also good.

**TPSA:** Ligand A (76.12) is better than Ligand B (46.34). Lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (-0.254) is quite low, potentially hindering membrane permeability. Ligand B (4.879) is high, which could lead to solubility issues and off-target effects.

**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 reasonable QED values (Ligand A: 0.688, Ligand B: 0.563), indicating drug-like properties.

**DILI:** Ligand A (5.079) has a very low DILI risk, which is excellent. Ligand B (27.375) is higher, but still within an acceptable range.

**BBB:** Ligand A (18.147) has very low BBB penetration, which is not a concern for a non-CNS target like SRC. Ligand B (91.314) has high BBB penetration, which is irrelevant here and could even be a negative if off-target effects in the CNS are a concern.

**Caco-2 Permeability:** Both have negative values (-5.079 and -4.979), which is unusual and potentially problematic. However, these values are on a scale where negative values are possible, and the absolute magnitude is important. Without knowing the scale, it's hard to interpret.

**Aqueous Solubility:** Ligand A (-0.009) is slightly better than Ligand B (-4.061), indicating slightly better solubility.

**hERG Inhibition:** Ligand A (0.177) has a very low hERG risk, which is excellent. Ligand B (0.862) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (2.652) has a lower clearance, suggesting better metabolic stability. Ligand B (97.973) has very high clearance, indicating rapid metabolism and potentially requiring higher doses.

**In vitro Half-Life:** Ligand A (1.122) has a shorter half-life than Ligand B (54.025). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.815) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While both are excellent, the 1.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in safety parameters (DILI, hERG) and metabolic stability (Cl_mic). However, its low logP is a significant concern for permeability. Ligand B has a better binding affinity and a much longer half-life, but suffers from high logP and high metabolic clearance. Considering the enzyme-specific priorities, the superior binding affinity and longer half-life of Ligand B, despite its drawbacks, are more likely to translate to *in vivo* efficacy. The high logP can be addressed with formulation strategies. The high clearance is a concern, but the strong binding affinity might compensate.

Output:
1
2025-04-17 16:03:58,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.445 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.82) is significantly better than Ligand B (58.64).  A TPSA under 140 is good for oral absorption, and both are well below that, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (1.785 and 2.489), 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 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.847 and 0.793), indicating good drug-like properties.

**DILI:** Ligand A (19.193) has a much lower DILI risk than Ligand B (8.104), which is a significant advantage. Lower DILI is crucial.

**BBB:** Ligand A (87.321) has a better BBB penetration score than Ligand B (66.964), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.528) has a slightly better Caco-2 permeability than Ligand B (-4.862). Both are negative, indicating relatively low permeability.

**Aqueous Solubility:** Ligand A (-0.872) has better aqueous solubility than Ligand B (-2.219). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.894) has a lower hERG inhibition risk than Ligand B (0.478), which is a major advantage.

**Microsomal Clearance:** Ligand A (-10.27) has significantly lower microsomal clearance than Ligand B (21.956), indicating better metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-5.21) has a better in vitro half-life than Ligand B (-1.779).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.041).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.3). However, the difference is less than 1.5 kcal/mol, and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic and better half-life), and hERG inhibition. These factors are crucial for kinase inhibitors, as they often require chronic administration and can be susceptible to metabolic liabilities. The improved solubility of Ligand A is also a positive factor. The small difference in binding affinity is outweighed by the substantial improvements in other key parameters.

Output:
1
2025-04-17 16:03:58,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (388.917 and 428.689 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.92) is slightly higher than Ligand B (61.44), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.662) is optimal, while Ligand B (4.265) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) 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 acceptable QED scores (0.83 and 0.764), indicating good drug-like properties.

**DILI:** Ligand A (16.789) has a significantly lower DILI risk than Ligand B (79.333). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (63.784 and 73.517), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.776 and -4.517), 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:** Ligand A (-1.711) has better (less negative) solubility than Ligand B (-5.806). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.423) has a much lower hERG inhibition liability than Ligand B (0.763), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-31.496) has a much lower (better) microsomal clearance than Ligand B (46.377), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (88.421) has a significantly longer in vitro half-life than Ligand A (15.799). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux than Ligand B (0.221), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.0) has equal binding affinity to Ligand B (0.0).

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a longer half-life, Ligand A demonstrates significantly better safety (lower DILI and hERG), better solubility, and improved metabolic stability (lower Cl_mic). The binding affinity is the same, so the ADME/Tox advantages of Ligand A outweigh the longer half-life of Ligand B. The negative Caco-2 values are concerning for both, but the other advantages of Ligand A make it more promising.

Output:
0
2025-04-17 16:03:58,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.5 and 363.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is well below the 140 threshold and excellent for oral absorption. Ligand B (52.65) is still acceptable, but less optimal.

**logP:** Ligand A (3.759) is at the higher end of the optimal range (1-3), while Ligand B (2.253) is closer to the lower end. Both are acceptable, but the higher logP of A could potentially lead to off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (3 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.731 and 0.808), indicating good drug-like properties.

**DILI:** Ligand A (33.97) has a significantly lower DILI risk than Ligand B (7.06), which is a major advantage.

**BBB:** Both have high BBB penetration (81.47 and 83.68), but this is less critical for a non-CNS target like SRC.

**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 concerning. This indicates very poor solubility, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.877 and 0.588), which is positive.

**Microsomal Clearance:** Ligand A (29.91) has slightly better microsomal clearance than Ligand B (26.742), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (5.418 and 5.561 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.402 and 0.092), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This 0.4 kcal/mol difference is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the better candidate despite the slightly weaker binding affinity. Its significantly lower DILI risk, better TPSA, and slightly improved metabolic stability outweigh the small difference in binding. The poor Caco-2 and solubility are concerning for both, and would need to be addressed through formulation or further structural modifications. However, the lower toxicity profile of A makes it the more promising starting point.

Output:
0
2025-04-17 16:03:58,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.392 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Ligand A (53.6) is significantly better than Ligand B (87.36). Lower TPSA generally indicates better permeability.

**logP:** Both ligands have acceptable logP values (A: 2.786, B: 1.29), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=1, HBA=5) as it has a more balanced profile.

**QED:** Both ligands have similar and good QED values (A: 0.821, B: 0.806), indicating good drug-like properties.

**DILI:** Ligand A (15.083) has a much lower DILI risk than Ligand B (35.905). This is a significant advantage.

**BBB:** Ligand A (85.033) has a better BBB percentile than Ligand B (61.535), although BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.909) is better than Ligand B (-4.212).

**Aqueous Solubility:** Ligand A (-2.061) is better than Ligand B (-2.988).

**hERG Inhibition:** Ligand A (0.733) has a lower hERG risk than Ligand B (0.463). This is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (-2.47) has a significantly lower (better) microsomal clearance than Ligand B (38.355). This suggests better metabolic stability.

**In vitro Half-Life:** Ligand A (12.061) has a better in vitro half-life than Ligand B (41.969).

**P-gp Efflux:** Ligand A (0.054) has a lower P-gp efflux liability than Ligand B (0.03).

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.2). However, the difference of 1.0 kcal/mol, while noticeable, is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Overall:** Ligand A is significantly better than Ligand B. It has a lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), better solubility and permeability, and a comparable binding affinity. While Ligand B has a slightly better binding affinity, the superior ADME profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 16:03:58,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.383 and 348.506 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.68) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (32.34) is excellent, well below 140.

**logP:** Ligand A (2.471) is within the optimal 1-3 range. Ligand B (4.793) is a bit high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.77 and 0.801), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.295, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 31.291, which is favorable.

**BBB:** Ligand A (74.564) has moderate BBB penetration, while Ligand B (92.672) has very good BBB penetration. While SRC is not a CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.462 and -4.599), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4 and -5.143). This is a major drawback, potentially hindering formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.22) shows very low hERG inhibition risk, which is excellent. Ligand B (0.962) has a higher hERG risk, though not critically high.

**Microsomal Clearance:** Ligand A (58.261) has a moderate microsomal clearance. Ligand B (48.177) has a slightly lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-21.048), which is not physically meaningful and indicates a problem with the data or the molecule's stability. Ligand B has a half-life of 15.1 hours, which is reasonable.

**P-gp Efflux:** Ligand A (0.268) has low P-gp efflux, which is favorable. Ligand B (0.663) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly 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.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.6 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has a lower DILI risk, better metabolic stability (lower Cl_mic), a reasonable half-life, and better BBB penetration. The higher logP is a concern, but the superior potency and safety profile make Ligand B the better choice. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 16:03:58,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.427 Da) is slightly higher than Ligand B (335.411 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (93.74) is slightly higher than Ligand B (85.83).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.588) and Ligand B (2.354) are both good.

**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 QED values above 0.5 (Ligand A: 0.682, Ligand B: 0.724), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 88.057, which is relatively high. Ligand B has a DILI risk of 66.421, which is still elevated but lower than Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (58.278) and Ligand B (39.667) are both low.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-5.638) is slightly better than Ligand A (-4.765).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-2.36) is better than Ligand A (-3.951).

**hERG Inhibition:** Ligand A (0.579) and Ligand B (0.192) both have low hERG inhibition liability, which is favorable. Ligand B is significantly better.

**Microsomal Clearance:** Ligand A (39.356) has a moderate clearance, while Ligand B (-26.199) has a negative clearance, suggesting very high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (22.271 hours) has a reasonable half-life. Ligand B (28.119 hours) has a slightly longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.241, Ligand B: 0.286).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and, most importantly, a substantially stronger binding affinity. The improved binding affinity and metabolic stability are crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:03:58,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.491 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is better than Ligand B (67.87), both are below the 140 threshold for oral absorption.

**3. logP:** Both ligands (1.393 and 1.583) are 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 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.753 and 0.788, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (23.73) has a significantly lower DILI risk than Ligand B (12.641). This is a major advantage.

**8. BBB:** Both ligands have good BBB penetration, but Ligand B (83.831) is better than Ligand A (75.921). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.532) is slightly better than Ligand B (-4.399), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.407) is better than Ligand B (-2.181), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.378 and 0.272), which is excellent.

**12. Microsomal Clearance:** Ligand A (25.195) has a lower microsomal clearance than Ligand B (47.125), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (14.09) has a positive half-life, while Ligand B (-0.706) has a negative half-life. This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.021).

**15. Binding Affinity:** Ligand A (-7.6) has a slightly stronger binding affinity than Ligand B (-7.3). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a significantly lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and positive t1/2), slightly better Caco-2 permeability, and slightly stronger binding affinity. While Ligand B has better BBB penetration, this is less crucial for a kinase inhibitor targeting SRC. The combination of lower toxicity risk and improved pharmacokinetic properties makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 16:03:58,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.423 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.84) is better than Ligand B (129.11). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (1.33) is within the optimal range (1-3). Ligand B (-0.611) is slightly below this range, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 6 HBA). Fewer hydrogen bond donors generally improve membrane permeability.

**QED:** Ligand B (0.531) has a slightly better QED score than Ligand A (0.354), indicating a more drug-like profile. However, the difference isn't substantial.

**DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (52.152). This is a crucial advantage.

**BBB:** Ligand A (64.095) has a better BBB penetration score than Ligand B (7.949). While SRC isn't a CNS target, better BBB penetration often correlates with reduced off-target effects.

**Caco-2 Permeability:** Ligand A (-4.803) has a much better Caco-2 permeability than Ligand B (-5.838).

**Aqueous Solubility:** Ligand A (-0.425) is better than Ligand B (-2.161). Better solubility is crucial for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.215 and 0.032, respectively). This is excellent.

**Microsomal Clearance:** Ligand A (3.368) has a lower microsomal clearance than Ligand B (0.663), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (20.549) has a significantly longer in vitro half-life than Ligand B (7.342), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.008, respectively).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.1 kcal/mol). The difference is negligible.

**Overall:**

Ligand A consistently outperforms Ligand B in critical ADME properties (DILI, solubility, permeability, metabolic stability, half-life) while maintaining comparable potency. Ligand B has a slightly better QED, but the advantages of Ligand A in safety and pharmacokinetic properties outweigh this.

Output:
1
2025-04-17 16:03:58,865 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (364.511 and 362.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is better than Ligand B (58.64), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Both ligands (2.067 and 2.478) are 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 good QED scores (0.704 and 0.772), indicating drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk (44.436 and 48.662), well below the 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (79.837 and 71.888), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-5.103) is slightly better than Ligand B (-4.896), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.032) is slightly better than Ligand B (-3.965). Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.362 and 0.556).

**12. Microsomal Clearance:** Ligand A (57.174) has lower microsomal clearance than Ligand B (78.774), suggesting better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-5.527) has a longer in vitro half-life than Ligand B (-7.658), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.314) has lower P-gp efflux than Ligand B (0.183), suggesting better bioavailability.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.6 kcal/mol). The difference of 0.3 kcal/mol is not significant enough to outweigh the other ADME advantages of Ligand A.

**Conclusion:**

Ligand A demonstrates superior ADME properties, particularly regarding metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility and permeability. While both ligands have excellent binding affinity, the improved ADME profile of Ligand A makes it the more promising drug candidate.

Output:
0
2025-04-17 16:03:58,865 - INFO - Batch 432 complete. Total preferences: 6912
2025-04-17 16:03:58,865 - INFO - Processing batch 433/512...
2025-04-17 16:04:37,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.503 Da and 372.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (86.88).  A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have acceptable logP values (3.045 and 1.912, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=4) regarding the number of hydrogen bond donors and acceptors, which contributes to better permeability.

**QED:** Both ligands have reasonable QED scores (0.732 and 0.618), indicating good drug-like properties.

**DILI:** Ligand A (18.922) has a much lower DILI risk than Ligand B (43.389), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (78.519 and 76.774), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.508) has a worse Caco-2 permeability than Ligand B (-5.19). However, this is a negative value, so a less negative value is better.

**Aqueous Solubility:** Ligand A (-2.308) has better aqueous solubility than Ligand B (-3.73), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.246) has a lower hERG inhibition risk than Ligand B (0.427), which is a crucial safety factor.

**Microsomal Clearance:** Ligand A (66.411) has a higher microsomal clearance than Ligand B (19.309), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-9.384) has a much longer in vitro half-life than Ligand A (0.532), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.166) has a lower P-gp efflux liability than Ligand B (0.04), which is favorable.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-6.0), but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better solubility and lower DILI and P-gp efflux, Ligand B's significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly improved binding affinity are more critical for an enzyme inhibitor. The lower hERG risk of Ligand A is good, but not enough to overcome the metabolic liabilities of Ligand A.

Output:
1
2025-04-17 16:04:37,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 351.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.78) is better than Ligand B (110.97), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.566) is optimal (1-3), while Ligand B (-0.041) is below 1, which could hinder permeation. This is a significant negative for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is better balanced than Ligand B (HBD=1, HBA=7). While both are within acceptable limits, the higher HBA count in B might affect permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.45, B: 0.565), indicating acceptable drug-likeness. Ligand B is slightly better here.

**DILI:** Ligand A (42.303) has a lower DILI risk than Ligand B (64.793), which is a substantial advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (54.13) and B (65.452) are both relatively low.

**Caco-2 Permeability:** Both are negative (-4.875 and -4.825), indicating poor permeability. This is a concern for both, but less critical than other factors.

**Aqueous Solubility:** Both ligands have very poor solubility (-4.721 and -2.755). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.547) has a lower hERG risk than Ligand B (0.093), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand B (41.841) has a lower Cl_mic than Ligand A (47.555), suggesting better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (11.078) has a longer half-life than Ligand A (-15.364). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.364) has lower P-gp efflux than Ligand B (0.03), which is a positive.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.0), but the difference is minimal (0.1 kcal/mol).

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has significantly better logP, DILI risk, and hERG inhibition. The poor logP of Ligand B is a major concern, potentially leading to poor absorption. While both have poor solubility, the other advantages of Ligand A, particularly the lower DILI and hERG risk, make it the more promising candidate. The slight advantage in binding affinity of Ligand B is unlikely to overcome the significant ADME liabilities.

Output:
0
2025-04-17 16:04:37,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.407 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.37) is slightly higher than Ligand B (88.33), both are below the 140 threshold for oral absorption, but acceptable.

**logP:** Ligand A (1.358) is within the optimal 1-3 range. Ligand B (2.109) is also within range, but closer to the upper limit.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 9 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.778 and 0.792), indicating good drug-likeness.

**DILI:** Ligand A (76.076) has a higher DILI risk than Ligand B (49.283). This is a significant negative for Ligand A.

**BBB:** Both ligands have low BBB penetration (59.209 and 52.617), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.523) has worse Caco-2 permeability than Ligand B (-5.141). Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.517) has worse solubility than Ligand B (-1.178). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.269 and 0.244).

**Microsomal Clearance:** Ligand A (107.56) has higher microsomal clearance than Ligand B (49.553). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (17.852) has a significantly longer in vitro half-life than Ligand A (7.275). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.024).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is the superior candidate. It demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better aqueous solubility. Ligand A has a higher DILI risk and poorer metabolic stability. The differences in solubility and permeability are also unfavorable for Ligand A. Given the enzyme-specific priorities, the improved ADME properties of Ligand B outweigh any minor differences in TPSA or logP.

Output:
1
2025-04-17 16:04:37,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 375.965 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is well below the 140 threshold, suggesting good absorption. Ligand B (12.47) is *excellent* and even suggests potential for CNS penetration, though that's not our primary focus here.

**logP:** Ligand A (1.612) 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 5 HBA, both acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.842) has a very strong drug-like profile. Ligand B (0.677) is still reasonable, but less optimal.

**DILI:** Ligand A (35.169) has a low DILI risk. Ligand B (25.436) is even lower, indicating a safer profile regarding liver toxicity.

**BBB:** Ligand A (77.162) has moderate BBB penetration. Ligand B (95.851) has very high BBB penetration, but this isn't a priority for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-4.577) and Ligand B (-5.227) both have negative values, which is unusual and suggests poor permeability. The scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.443 and -4.57 respectively). This is a significant concern.

**hERG Inhibition:** Ligand A (0.255) has very low hERG inhibition risk. Ligand B (0.956) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (22.083) has a moderate clearance. Ligand B (53.375) has a significantly higher clearance, indicating poorer metabolic stability.

**In vitro Half-Life:** Ligand A (-6.953) has a short half-life, which is concerning. Ligand B (9.973) has a better, though not ideal, half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.129 and 0.884 respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.6 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Both ligands have excellent binding affinity. However, Ligand B has a better metabolic stability profile (lower Cl_mic, better t1/2), lower DILI risk, and slightly better binding affinity. The main drawback of Ligand B is its higher logP and poor solubility. Ligand A has better solubility, but worse metabolic stability and a shorter half-life. Given the enzyme-kinase focus, metabolic stability is crucial. The slight advantage in binding affinity of B, combined with the lower DILI risk, outweighs the slightly higher logP. The poor solubility of both is a major issue that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 16:04:37,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.877 and 382.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (67.67) as it is closer to the optimal range for oral absorption (<=140).

**logP:** Both ligands have good logP values (1.542 and 2.597), falling within the 1-3 range. Ligand B is slightly higher, potentially indicating a slight risk of off-target effects but not a major concern.

**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 (0.603 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (76.192). This is a major advantage for Ligand A.

**BBB:** Both have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B is slightly better (68.903 vs 60.644).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.083) is slightly better than Ligand B (-4.815).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.335) is slightly better than Ligand B (-3.143).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.095 and 0.11).

**Microsomal Clearance:** Ligand A (8.042) has a much lower microsomal clearance than Ligand B (41.892), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand B (16.673) has a longer in vitro half-life than Ligand A (5.11), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.154).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.9 and -9.2 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh the other significant differences.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a slightly longer half-life, Ligand A demonstrates significantly better DILI risk, metabolic stability (lower Cl_mic), and slightly better solubility and Caco-2 permeability. The binding affinity difference is minimal. Given the enzyme-kinase focus, metabolic stability and safety (DILI) are critical, making Ligand A the preferred choice.

Output:
0
2025-04-17 16:04:37,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (369.447 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand B (64.55) is significantly better than Ligand A (127.51). Lower TPSA generally improves cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (-0.674) is slightly below the optimal range (1-3), potentially hindering permeability. Ligand B (3.209) is within the optimal range.

**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, but Ligand B's lower HBD count could be slightly advantageous for permeability.

**QED:** Both ligands have similar QED values (0.625 and 0.57), indicating reasonable drug-likeness.

**DILI:** Ligand B (80.807) has a significantly higher DILI risk than Ligand A (42.458). This is a major concern, as liver toxicity is a common reason for drug failure.

**BBB:** This is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (93.486) has better BBB penetration than Ligand A (54.595), but this is not a primary concern here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.604) is slightly better than Ligand B (-4.451).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.003 and -4.574). This is a significant drawback, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.046) has a much lower hERG inhibition liability than Ligand B (0.53), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (2.292 mL/min/kg) has a much lower microsomal clearance than Ligand B (102.009 mL/min/kg). This indicates that Ligand A is more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (13.521 hours) has a significantly longer half-life than Ligand B (-12.273 hours). This is highly desirable, as it suggests less frequent dosing.

**P-gp Efflux:** Ligand A (0.012) has lower P-gp efflux than Ligand B (0.317), which is beneficial for bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 kcal/mol and -8.1 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A is significantly better despite the poor solubility and Caco-2 permeability. Its superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG inhibition, and lower P-gp efflux outweigh the slightly lower logP and TPSA. The binding affinity is comparable. The solubility and permeability issues could be addressed with formulation strategies, but mitigating high DILI risk and poor metabolic stability is far more challenging.

Output:
0
2025-04-17 16:04:37,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 356.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.62) is better than Ligand B (66.91), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.708) is optimal, while Ligand B (3.497) is approaching the upper limit of the optimal range.

**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 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.724 and 0.86), indicating good drug-like properties.

**DILI:** Ligand A (52.617) and Ligand B (55.758) both have acceptable DILI risk, below the 60 threshold.

**BBB:** Ligand A (62.233) and Ligand B (82.474) have acceptable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.705) and Ligand B (-5.209) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.719) and Ligand B (-3.612) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.145) has a much lower hERG risk than Ligand B (0.539). This is a significant advantage.

**Microsomal Clearance:** Ligand A (72.886) has higher microsomal clearance than Ligand B (52.162), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (40.996) has a significantly longer in vitro half-life than Ligand A (4.559), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux liability than Ligand B (0.223), which is preferable.

**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.

**Overall Assessment:**

Ligand B has a better binding affinity and significantly better in vitro half-life. However, Ligand A has a much lower hERG risk and lower P-gp efflux, which are critical safety and bioavailability parameters. The solubility and permeability are poor for both, but can be addressed with formulation strategies. Considering the enzyme-specific priorities, the lower hERG risk of Ligand A is a significant advantage. The slightly weaker binding can be potentially optimized in later stages of drug development.

Output:
0
2025-04-17 16:04:37,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.443 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.66 and 78.95) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (1.183 and 0.921) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.678 and 0.704), indicating drug-like properties.

**DILI:** Ligand A (29.081) has a much lower DILI risk than Ligand B (8.686), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (74.913 and 85.964), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.214 and -4.88), which is unusual. A more positive value is preferred, indicating better absorption. However, these values are not necessarily disqualifying.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.768 and -1.353), which is also unusual. Higher solubility is preferable.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.144 and 0.176), which is excellent.

**Microsomal Clearance:** Ligand A (35.534) has a higher microsomal clearance than Ligand B (18.097), indicating potentially lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (-7.985) has a longer in vitro half-life than Ligand A (4.965), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.054 and 0.014).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 0.9 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly lower DILI risk. However, Ligand B exhibits better metabolic stability (lower Cl_mic, longer t1/2). Given the importance of metabolic stability for kinase inhibitors, and the acceptable (though slightly lower) binding affinity of Ligand B, it is the more promising candidate. The DILI risk for Ligand A is very good, but the metabolic stability of Ligand B is a stronger advantage for an enzyme target.

Output:
1
2025-04-17 16:04:37,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 379.869 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.66) is significantly better than Ligand B (70.58), being well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have good logP values (2.402 and 2.057), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have similar, good QED scores (0.842 and 0.8), indicating drug-likeness.

**DILI:** Ligand A (11.283) has a much lower DILI risk than Ligand B (79.798), which is a significant advantage. Ligand B is concerningly high.

**BBB:** Both have high BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.381) and Ligand B (-4.724) 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:** Ligand A (-1.771) has better solubility than Ligand B (-4.049), which is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.584 and 0.609), which is good.

**Microsomal Clearance:** Ligand A (29.95) has significantly lower microsomal clearance than Ligand B (67.73), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.873) has a shorter half-life than Ligand B (-30.01). This is a negative for Ligand A, but the difference is substantial and the negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.089) shows lower P-gp efflux than Ligand B (0.214), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.6 kcal/mol), with a negligible difference.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has a slightly better binding affinity (though the difference is minimal), Ligand A excels in crucial ADME properties: significantly lower DILI risk, better solubility, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. The half-life is a concern for Ligand A, but the other advantages outweigh this drawback. Ligand B's high DILI risk is a major red flag.

Output:
0
2025-04-17 16:04:37,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 and 346.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold for oral absorption. Ligand B (120.83) is still acceptable, but less favorable.

**logP:** Ligand A (2.799) is optimal (1-3). Ligand B (-0.37) is too low, potentially hindering permeation.

**H-Bond Donors:** Both have acceptable HBD counts (1 and 3, respectively), within the guideline of <=5.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, but still within the acceptable limit of <=10.

**QED:** Both ligands have similar and acceptable QED values (0.686 and 0.656, both >= 0.5).

**DILI:** Ligand A (15.47) has a much lower DILI risk than Ligand B (63.55), which is concerningly high.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.82) is higher than Ligand B (36.10).

**Caco-2:** Ligand A (-4.747) is better than Ligand B (-5.711), indicating better intestinal absorption.

**Solubility:** Ligand A (-3.083) is better than Ligand B (-1.975), indicating better aqueous solubility.

**hERG:** Both ligands have low hERG risk (0.444 and 0.318, respectively).

**Cl_mic:** Ligand A (61.72) is higher than Ligand B (15.42), indicating lower metabolic stability. However, both are reasonable.

**t1/2:** Ligand A (11.45) has a longer half-life than Ligand B (8.68), which is preferable.

**Pgp:** Both ligands have low Pgp efflux liability (0.141 and 0.015, respectively).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It possesses a better logP, significantly lower DILI risk, better solubility, better Caco-2 permeability, a longer half-life, and, most importantly, a substantially stronger binding affinity. While Ligand A has a higher microsomal clearance than Ligand B, the overall profile is more favorable for development as an SRC kinase inhibitor.

Output:
1
2025-04-17 16:04:37,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.865 and 368.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (81.75) is well below the 140 threshold for good absorption, while Ligand B (107.89) is still acceptable but less optimal.

**logP:** Ligand A (0.896) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (-0.166) is even lower, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is excellent. Ligand B (4 HBD, 6 HBA) is acceptable but higher, potentially affecting permeability.

**QED:** Ligand A (0.756) is good, indicating a drug-like profile. Ligand B (0.508) is at the lower end of acceptable, but still reasonable.

**DILI:** Ligand A (23.575) has a significantly lower DILI risk than Ligand B (42.536), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.549) is better than Ligand B (13.726).

**Caco-2 Permeability:** Ligand A (-4.901) is poor, while Ligand B (-5.993) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-2.471) is better than Ligand B (-2.054), although both are quite poor.

**hERG:** Ligand A (0.245) has a very low hERG risk, a significant advantage. Ligand B (0.12) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-4.157) indicates good metabolic stability (lower clearance is better). Ligand B (5.371) suggests faster metabolism.

**In vitro Half-Life:** Ligand A (6.046 hours) is better than Ligand B (9.022 hours).

**P-gp Efflux:** Both ligands (0.011 and 0.031) show very low P-gp efflux, which is good.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both have permeability issues (low Caco-2 and solubility), Ligand A's significantly stronger binding affinity, much lower DILI risk, better metabolic stability (lower Cl_mic), and lower hERG risk outweigh its slightly lower logP and Caco-2 values. The strong binding affinity suggests that even with slightly lower permeability, sufficient drug concentration at the target site could be achieved. Ligand B's higher DILI risk and weaker binding make it less attractive.

Output:
0
2025-04-17 16:04:37,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.463 and 345.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.74) is better than Ligand B (97.94), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration if that were a goal.

**logP:** Ligand A (0.991) is within the optimal range (1-3), while Ligand B (-0.013) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) 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: 0.637, B: 0.822), indicating drug-likeness.

**DILI:** Ligand A (30.826) has a significantly lower DILI risk than Ligand B (62.931). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (69.523) is better than Ligand B (46.646).

**Caco-2 Permeability:** Ligand A (-4.817) and Ligand B (-5.208) are both poor, indicating low intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.039) is better than Ligand B (-2.015), indicating better solubility.

**hERG Inhibition:** Ligand A (0.085) has a much lower hERG risk than Ligand B (0.11). This is a significant advantage.

**Microsomal Clearance:** Ligand A (43.238) has higher clearance than Ligand B (17.231), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-6.969) has a better (longer) in vitro half-life than Ligand A (-15.487). This is a drawback for Ligand A.

**P-gp Efflux:** Both are very low, and not a major differentiating factor.

**Binding Affinity:** Ligand B (-9.5 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 of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has better solubility, lower DILI risk, and lower hERG risk, Ligand B's significantly stronger binding affinity (-9.5 vs -6.7 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. The improved half-life of B also helps. The slightly lower logP and higher DILI of B are concerns, but the potency advantage is likely to be more impactful in early development.

Output:
1
2025-04-17 16:04:37,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.45 & 340.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is better than Ligand B (97.2), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Both ligands (1.42 & 2.12) are 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. Ligand A is preferable here.

**QED:** Both ligands have similar QED values (0.78 and 0.68), indicating good drug-likeness.

**DILI:** Ligand A (28.23%) has a significantly lower DILI risk than Ligand B (64.60%), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (57.46%) is slightly better than Ligand B (47.46%).

**Caco-2:** Ligand A (-4.931) is better than Ligand B (-5.908), indicating better intestinal absorption.

**Solubility:** Ligand A (-1.375) is better than Ligand B (-3.162), which is crucial for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.107 and 0.112).

**Microsomal Clearance:** Ligand B (27.28) has a slightly lower Cl_mic than Ligand A (17.33), suggesting better metabolic stability. However, the difference is not substantial.

**In vitro Half-Life:** Ligand A (24.89) has a significantly longer half-life than Ligand B (-0.05), which is a significant advantage.

**P-gp efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.156).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.0 kcal/mol). The difference of 0.3 kcal/mol is not large enough to outweigh other factors.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. It has a significantly lower DILI risk, better solubility, better Caco-2 permeability, and a longer in vitro half-life. While Ligand B has slightly better metabolic stability, the other advantages of Ligand A are more critical for a kinase inhibitor.

Output:
1
2025-04-17 16:04:37,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.423 and 337.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.34) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for oral absorption, but neither are optimized for CNS penetration (below 90). This isn't a primary concern for a non-CNS targeted kinase inhibitor.

**logP:** Both ligands have good logP values (3.195 and 2.754), 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:** Both ligands have high QED scores (0.848 and 0.933), indicating good drug-like properties.

**DILI:** Ligand A (41.062) is slightly higher than Ligand B (49.477), but both are below the concerning threshold of 60, suggesting acceptable liver toxicity risk.

**BBB:** Both ligands have similar BBB penetration (71.307 and 78.519). BBB isn't a major concern for a non-CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.588 and -4.889). This 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 (-3.875 and -3.259). Similar to Caco-2, these are on a log scale and negative values are common.

**hERG:** Both ligands have very low hERG risk (0.53 and 0.555), which is excellent.

**Microsomal Clearance:** Ligand B (18.337 mL/min/kg) has significantly lower microsomal clearance than Ligand A (84.399 mL/min/kg). This indicates better metabolic stability for Ligand B, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-10.516 hours) has a longer in vitro half-life than Ligand A (23.178 hours). This is also a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.314 and 0.175).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.4 and -9.2 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have good potency and drug-like properties, Ligand B is the more promising candidate due to its significantly improved metabolic stability (lower Cl_mic) and longer in vitro half-life. These factors are crucial for kinase inhibitors, as they often require sustained exposure to exert their therapeutic effect. The slightly better solubility and lower P-gp efflux of Ligand B also contribute to its advantage.

Output:
1
2025-04-17 16:04:37,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 348.531 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 140 threshold for oral absorption, but B is better.

**logP:** Ligand A (1.873) is within the optimal 1-3 range. Ligand B (3.912) is approaching the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 3 HBAs, while Ligand B has 2. Both are below the 10 limit.

**QED:** Ligand A (0.795) has a significantly better QED score than Ligand B (0.534), indicating a more drug-like profile.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (15.045), a significant advantage.

**BBB:** Ligand A (63.552) has a lower BBB penetration than Ligand B (84.878). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.707 and -4.665), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.723 and -3.738), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.23) has a much lower hERG risk than Ligand B (0.728), a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (23.688) has a lower microsomal clearance than Ligand B (93.71), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.739) has a longer in vitro half-life than Ligand B (-6.352), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.561), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive factor.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is significantly more promising. Its superior binding affinity, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and higher QED score outweigh the slightly higher TPSA and lower BBB penetration (which is not critical for this target). The substantial difference in binding affinity (-9.4 vs 0.0 kcal/mol) is a major advantage that could compensate for formulation challenges related to solubility.

Output:
1
2025-04-17 16:04:37,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.434 and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (86.88). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.688 and 2.065), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6.  Ligand A is preferable here, being closer to the <10 guideline.

**QED:** Both ligands have similar QED values (0.822 and 0.812), indicating good drug-likeness.

**DILI:** Ligand A (22.8) has a much lower DILI risk than Ligand B (49.554). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.088) is better than Ligand B (30.748), but it's not a major deciding factor.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.329) is slightly better than Ligand B (-4.836), but both are problematic.

**Aqueous Solubility:** Ligand A (-3.215) is better than Ligand B (-1.883), both are poor, but A is less poor.

**hERG:** Ligand A (0.594) has a lower hERG risk than Ligand B (0.296), which is a significant advantage.

**Microsomal Clearance:** Ligand A (51.31) has a slightly better (lower) microsomal clearance than Ligand B (43.844), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (71.526) has a significantly longer in vitro half-life than Ligand A (-10.144). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.136) has a lower P-gp efflux liability than Ligand B (0.283), which is preferable.

**Binding Affinity:** Ligand B (-7.9) has a significantly stronger binding affinity than Ligand A (-6.4). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. A 1.5 kcal/mol difference is considered significant.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, and a better half-life. However, Ligand A has better solubility, lower DILI and hERG risk, and lower P-gp efflux. The binding affinity difference is substantial. Given that we are targeting a kinase (enzyme), potency is paramount. While the ADME profile of Ligand A is better, the significant potency advantage of Ligand B is likely to be more important, and can be addressed through further optimization.

Output:
1
2025-04-17 16:04:37,970 - INFO - Batch 433 complete. Total preferences: 6928
2025-04-17 16:04:37,971 - INFO - Processing batch 434/512...
2025-04-17 16:05:21,402 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 Da and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.5 and 89.95) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.941) is optimal, while Ligand B (0.535) 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 4 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.566 and 0.763), indicating drug-likeness.

**DILI:** Ligand A (33.773) has a lower DILI risk than Ligand B (42.924), which is preferable. Both are below the concerning threshold of 60.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand A (46.84) has a slightly better BBB score than Ligand B (30.089).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.712 and -4.797). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value simply means permeability is less than 1.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.351 and -1.12), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.096 and 0.117), which is excellent.

**Microsomal Clearance:** Ligand A (52.021) has a higher microsomal clearance than Ligand B (9.638), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-2.351) has a better in vitro half-life than Ligand A (-10.957).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.077).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While both have good affinity and low hERG risk, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, better t1/2) and a slightly better solubility profile. Although Ligand A has a slightly better logP and DILI score, the metabolic stability issue is more critical for an enzyme target. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:05:21,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.34 and 364.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.24) is slightly above the preferred <140 for good absorption, while Ligand B (86.03) is well within the range.

**logP:** Ligand A (-0.468) is a bit low, potentially hindering permeation. Ligand B (1.834) is optimal.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better.

**H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (8) is also within the reasonable limit of 10.

**QED:** Both ligands have good QED scores (0.486 and 0.568, respectively), indicating drug-likeness.

**DILI:** Ligand A (42.536) has a lower DILI risk than Ligand B (65.491), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (60.101) is slightly better than Ligand A (49.205).

**Caco-2 Permeability:** Both have negative values (-5.961 and -5.058), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.053 and -1.958), indicating very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.428) has a lower hERG risk than Ligand B (0.156), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-38.637) shows much better metabolic stability (lower clearance) than Ligand B (35.794). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (39.661) has a longer half-life than Ligand B (23.033), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.176).

**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 outweigh other factors.

**Conclusion:**

While both ligands bind strongly, Ligand A is the more promising candidate. It has a lower DILI risk, lower hERG inhibition, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better HBD count. The primary concerns for both are poor solubility and permeability. However, solubility can sometimes be improved through formulation strategies, while permeability is more difficult to address. The superior ADME profile of Ligand A, particularly its metabolic stability and safety parameters, makes it the preferred choice.

Output:
0
2025-04-17 16:05:21,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (360.42 and 369.384 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is well below the 140 threshold and very favorable. Ligand B (101.9) is still within the acceptable range for oral absorption but less optimal than A.

**3. logP:** Ligand A (2.815) is within the optimal 1-3 range. Ligand B (-0.378) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Ligand A (2) is within the acceptable limit of 5. Ligand B (4) is also acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (2) is well below the limit of 10. Ligand B (5) is also acceptable.

**6. QED:** Ligand A (0.81) is excellent, indicating high drug-likeness. Ligand B (0.467) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (30.83) has a low DILI risk. Ligand B (9.97) also has a low DILI risk, but slightly higher than A.

**8. BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (91.90) has a significantly higher BBB percentile than Ligand B (48.12).

**9. Caco-2 Permeability:** Ligand A (-4.585) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.379) is also negative and similarly poor. This is a potential concern for both.

**10. Aqueous Solubility:** Ligand A (-4.424) has a negative value, indicating poor solubility. Ligand B (-0.673) is also negative, but slightly better than A.

**11. hERG Inhibition:** Ligand A (0.547) has a low hERG risk. Ligand B (0.225) also has a very low hERG risk.

**12. Microsomal Clearance:** Ligand A (26.43) has a moderate clearance. Ligand B (-12.91) has a negative clearance, which is not physically possible and likely an error or outlier in the data. This is a major red flag.

**13. In vitro Half-Life:** Ligand A (5.504) has a short half-life. Ligand B (-32.30) has a negative half-life, which is not physically possible and a significant concern.

**14. P-gp Efflux:** Ligand A (0.041) has low P-gp efflux. Ligand B (0.006) also has very low P-gp efflux.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand A is the more promising candidate. While both have poor Caco-2 and solubility, Ligand B exhibits physically impossible values for microsomal clearance and half-life, indicating a data quality issue or a fundamentally problematic molecule. Ligand A has a better QED score, lower DILI risk, and higher BBB penetration (though BBB isn't crucial here). The slightly better logP and TPSA of Ligand A also contribute to its favorability.

Output:
0
2025-04-17 16:05:21,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.475 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.92) is well below the 140 threshold, while Ligand B (78.09) is also acceptable.

**logP:** Ligand A (4.81) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.577) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.734 and 0.876), indicating good drug-like properties.

**DILI:** Ligand A (58.976) has a higher DILI risk than Ligand B (49.399), but both are reasonably acceptable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (82.513) is higher than Ligand B (58.976).

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation, but doesn't immediately disqualify either.

**Solubility:** Ligand A (-6.1) has very poor aqueous solubility, a significant drawback. Ligand B (-3.25) is better, but still not ideal.

**hERG:** Ligand A (0.747) has a slightly higher hERG risk than Ligand B (0.569), but both are reasonably low.

**Microsomal Clearance:** Ligand A (100.622) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (25.781) shows much better metabolic stability.

**In vitro Half-Life:** Ligand A (27.787) has a shorter half-life than Ligand B (-9.037) which is a negative value, indicating a very long half-life.

**P-gp Efflux:** Ligand A (0.405) has lower P-gp efflux liability than Ligand B (0.035), which is good.

**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.

**Conclusion:**

Despite Ligand A's superior binding affinity, its poor solubility and higher microsomal clearance are major concerns. The higher logP also raises flags. Ligand B, while having a slightly weaker binding affinity, exhibits much better metabolic stability, better solubility, and acceptable DILI and hERG profiles. For an enzyme target like SRC kinase, metabolic stability and solubility are crucial for *in vivo* efficacy. The 0.7 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, whereas fixing the solubility and metabolic stability issues of Ligand A would likely require more extensive structural changes.

Output:
1
2025-04-17 16:05:21,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.159 Da) is slightly higher than Ligand B (350.507 Da), but both are acceptable.

**TPSA:** Ligand A (113.56) is acceptable for oral absorption, while Ligand B (58.44) is excellent.

**logP:** Both ligands have good logP values (A: 2.552, B: 3.067), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.404, B: 0.688), with Ligand B being more drug-like.

**DILI:** Ligand A has a high DILI risk (97.984%), which is a significant concern. Ligand B has a very low DILI risk (25.785%), a major advantage.

**BBB:** Both ligands have good BBB penetration (A: 75.107%, B: 79.992%), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but we can assume these are percentile scores and both are poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.149, B: -1.956). This is a potential issue for bioavailability, but can be addressed through formulation.

**hERG Inhibition:** Ligand A has a slightly higher hERG risk (0.369) than Ligand B (0.813), but both are relatively low.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (103.099 mL/min/kg) than Ligand B (76.056 mL/min/kg), indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A has a shorter half-life (43.628 hours) than Ligand B (7.303 hours). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A has low P-gp efflux (0.426) while Ligand B has very low P-gp efflux (0.435).

**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.

**Conclusion:**

Despite Ligand A's superior binding affinity, the extremely high DILI risk and poor metabolic stability (high Cl_mic, short half-life) are major drawbacks. Ligand B, while having a much weaker binding affinity, exhibits a significantly better safety profile (low DILI) and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and safety are crucial. The substantial difference in binding affinity *could* be overcome with further optimization of Ligand B, whereas mitigating the DILI risk of Ligand A would be far more challenging.

Output:
1
2025-04-17 16:05:21,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.487 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.43) is still under 140, but less optimal than A.

**logP:** Ligand A (1.488) is within the optimal 1-3 range. Ligand B (2.509) is also within range, but higher.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have reasonable H-bond counts, well within the suggested limits.

**QED:** Both ligands have similar QED values (0.678 and 0.658), indicating good drug-likeness.

**DILI:** Ligand A (6.282) has a very low DILI risk, significantly better than Ligand B (19.155). This is a major advantage for Ligand A.

**BBB:** Ligand A (53.005) has a lower BBB penetration percentile than Ligand B (83.288). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.837) and Ligand B (-4.527) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Ligand A (-1.512) and Ligand B (-2.536) both have negative solubility values, indicating poor solubility. Ligand B is slightly worse.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.491 and 0.514), which is excellent.

**Microsomal Clearance:** Ligand A (-16.921) has a significantly *lower* (better) microsomal clearance than Ligand B (52.62). This indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.665) has a longer in vitro half-life than Ligand B (12.06). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.011 and 0.14).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 1.1 kcal/mol, which is substantial, but needs to be weighed against the ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly stronger binding affinity, Ligand A excels in critical ADME properties: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better TPSA. The solubility is similar for both, but the superior metabolic profile and safety profile of Ligand A outweigh the modest difference in binding affinity.

Output:
0
2025-04-17 16:05:21,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.438 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (91.32). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands (2.008 and 2.512) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=5). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.78) has a better QED score than Ligand B (0.583), indicating a more drug-like profile.

**DILI:** Ligand A (39.822) has a much lower DILI risk than Ligand B (56.146), which is a significant advantage. Both are below the 60 threshold, but A is considerably safer.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.508) is better than Ligand B (65.801).

**Caco-2 Permeability:** Ligand A (-4.576) is better than Ligand B (-5.188). Higher values are better, so A is preferable.

**Aqueous Solubility:** Ligand A (-3.094) is better than Ligand B (-3.569). Higher values are better, so A is preferable.

**hERG Inhibition:** Ligand A (0.49) shows slightly better hERG inhibition liability than Ligand B (0.601). Lower is better.

**Microsomal Clearance:** Ligand A (38.733) and Ligand B (36.611) are comparable. Lower clearance is preferred for better metabolic stability, but the difference is small.

**In vitro Half-Life:** Ligand A (-12.764) is slightly worse than Ligand B (-8.263). Higher values are better, but the difference is small.

**P-gp Efflux:** Ligand A (0.111) is better than Ligand B (0.496). Lower values are better.

**Binding Affinity:** Ligand B (-9.1 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 much more favorable.

**Overall Assessment:**

Ligand A demonstrates a superior overall profile. It has better predicted permeability (Caco-2, TPSA), solubility, QED, and significantly lower DILI risk and P-gp efflux. Although Ligand B has a slightly better binding affinity, the other advantages of Ligand A, particularly the lower DILI risk and better ADME properties, make it the more promising drug candidate for SRC kinase inhibition.

Output:
0
2025-04-17 16:05:21,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.515 and 346.387 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is excellent, well below the 140 threshold for good absorption. Ligand B (95.86) is higher, but still potentially acceptable, though it might hint at lower permeability.

**logP:** Ligand A (3.231) is optimal (1-3). Ligand B (-0.606) is quite low, potentially causing permeability issues and reduced binding.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (0.762 and 0.731), indicating good drug-likeness.

**DILI:** Ligand A (1.551) has a very low DILI risk, which is excellent. Ligand B (60.721) has a significantly higher DILI risk, placing it in the high-risk category. This is a major concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (91.586) shows better penetration than Ligand B (41.295).

**Caco-2 Permeability:** Ligand A (-4.989) has poor Caco-2 permeability. Ligand B (-4.881) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.125) has poor aqueous solubility. Ligand B (-0.63) has slightly better aqueous solubility.

**hERG Inhibition:** Ligand A (0.875) has a low hERG risk. Ligand B (0.052) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (7.028) has a moderate clearance. Ligand B (-0.095) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-12.859) has a very long half-life. Ligand B (0.052) has a very short half-life.

**P-gp Efflux:** Ligand A (0.26) has low P-gp efflux. Ligand B (0.006) has very low P-gp efflux.

**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 doesn't override other significant differences.

**Conclusion:**

Despite similar binding affinities, Ligand A is the superior candidate. The primary driver is the significantly lower DILI risk (1.551 vs 60.721). While Ligand A has poor Caco-2 permeability and solubility, these can potentially be addressed through formulation strategies. The superior metabolic stability of Ligand B is attractive, but the high DILI risk is a major red flag.

Output:
0
2025-04-17 16:05:21,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.331 and 363.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.88) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (101.15) is well within the range.

**logP:** Ligand A (0.204) is quite low, potentially hindering permeation. Ligand B (1.787) is within the optimal 1-3 range.

**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 good QED scores (0.534 and 0.55), indicating drug-like properties.

**DILI:** Ligand A (74.913) has a higher DILI risk than Ligand B (76.774), but both are reasonably acceptable.

**BBB:** Both ligands have acceptable BBB penetration, but not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.075) has poor Caco-2 permeability, which is a concern. Ligand B (-5.49) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.205 and -2.403). This is a potential issue for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.085) has a very low hERG risk, which is excellent. Ligand B (0.262) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (24.216) has lower microsomal clearance, indicating better metabolic stability. Ligand B (47.262) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-27.232) has a very long in vitro half-life, which is highly desirable. Ligand B (11.771) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.164).

**Binding Affinity:** Ligand B (-7.4 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 threshold.

**Conclusion:**

Despite the solubility concerns for both, Ligand B is the more promising candidate. The significantly improved binding affinity (-7.4 vs -8.1 kcal/mol) outweighs the slightly higher DILI and clearance. The better logP value of Ligand B also suggests improved permeability compared to Ligand A, which has a very low logP and poor Caco-2 permeability. Ligand A's excellent half-life is appealing, but the weaker binding is a major drawback.

Output:
1
2025-04-17 16:05:21,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.459 and 351.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.18) is well below the 140 threshold for good absorption and is also favorable for potential CNS penetration, although that's not a primary concern for SRC. Ligand B (129.37) is still within acceptable limits, but less optimal than A.

**logP:** Ligand A (0.749) is within the optimal range of 1-3. Ligand B (-1.015) is slightly below 1, which *could* indicate potential permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, both acceptable. Ligand B has 4 HBD and 7 HBA, still within the guidelines, but slightly higher, potentially impacting permeability.

**QED:** Ligand A (0.681) has a good drug-likeness score, exceeding 0.5. Ligand B (0.451) is below 0.5, indicating a less favorable drug-like profile.

**DILI:** Ligand A (47.654) has a low DILI risk, well below the 60 threshold. Ligand B (27.801) also has a very low DILI risk.

**BBB:** Ligand A (70.027) shows reasonable BBB penetration, while Ligand B (23.769) is quite low. This isn't a major concern for SRC, but it's a positive for A.

**Caco-2 Permeability:** Ligand A (-4.552) and Ligand B (-5.659) both have negative values, which is unusual. These values likely represent a logP-scaled permeability, where negative values indicate poor permeability. Ligand B appears slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.868 and -1.033 respectively). This is a significant concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Ligand A (0.526) has a low hERG risk. Ligand B (0.034) has an extremely low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (28.24) has moderate clearance. Ligand B (-5.026) has *negative* clearance, which is not physically possible and likely indicates a data error or an extremely stable compound. This is a huge advantage for B, assuming the data is reliable.

**In vitro Half-Life:** Ligand A (-60.24) has a very short half-life, which is a major drawback. Ligand B (6.536) has a short half-life, but is significantly better than A.

**P-gp Efflux:** Ligand A (0.048) has low P-gp efflux, which is good. Ligand B (0.002) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand B (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite solubility concerns for both, Ligand B is the superior candidate. Its significantly stronger binding affinity (-10.7 vs -8.9 kcal/mol) is a major advantage for an enzyme target like SRC. The extremely low P-gp efflux and hERG risk are also highly favorable. While the negative microsomal clearance is suspect, if accurate, it indicates exceptional metabolic stability. Ligand A suffers from a very short in vitro half-life and lower affinity, making it less attractive.



Output:
1
2025-04-17 16:05:21,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (340.423 Da and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.42) is slightly above the preferred <90 for kinases, but still reasonable. Ligand B (70.08) is well within the acceptable range.

**3. logP:** Both ligands have good logP values (2.989 and 1.435), 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 each), below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.792 and 0.785), indicating good drug-like properties.

**7. DILI:** Ligand A (58.511) has a moderate DILI risk, while Ligand B (30.981) has a significantly lower risk, which is a major advantage.

**8. BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (74.176) is higher than Ligand B (53.974), but this isn't a deciding factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and indicates poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values which is also unusual and indicates poor solubility.

**11. hERG Inhibition:** Ligand A (0.752) has a slightly higher hERG risk than Ligand B (0.474), but both are reasonably low.

**12. Microsomal Clearance (Cl_mic):** Ligand B (37.055) has significantly lower microsomal clearance than Ligand A (72.209), suggesting better metabolic stability. This is a key consideration for kinases.

**13. In vitro Half-Life (t1/2):** Ligand B (23.12) has a longer half-life than Ligand A (-5.187), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.176 and 0.147).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a significant 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 DILI risk, microsomal clearance, and in vitro half-life. For an enzyme target like SRC kinase, metabolic stability and reduced toxicity are crucial. The 1.4 kcal/mol difference in binding affinity, while noticeable, might be overcome with further optimization of Ligand B. The poor permeability and solubility of both compounds are concerning and would need to be addressed in subsequent optimization rounds, but the ADME profile of Ligand B is more promising as a starting point.

Output:
1
2025-04-17 16:05:21,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443 Da) is slightly better positioned than Ligand B (364.515 Da).

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (76.02) is significantly lower than Ligand A (97.78), which is favorable.

**logP:** Both ligands have logP values between 1 and 3 (2.337 and 2.129 respectively), which is optimal.

**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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.709 and 0.741), indicating drug-like properties.

**DILI:** Ligand B (41.838) has a lower DILI risk than Ligand A (47.383), which is preferable. Both are below the 60 threshold.

**BBB:** BBB isn't a primary concern for SRC kinase inhibitors (unless CNS off-target effects are a concern). Ligand A (56.301) has a slightly higher BBB penetration than Ligand B (45.56).

**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. Ligand A (-5.029) is slightly better than Ligand B (-5.616).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-1.884) is slightly better than Ligand A (-4.177).

**hERG:** Both ligands have low hERG inhibition liability (0.555 and 0.251), which is excellent. Ligand B is better here.

**Microsomal Clearance:** Ligand B (11.373 mL/min/kg) has a lower microsomal clearance than Ligand A (15.61 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.947 hours) has a longer in vitro half-life than Ligand A (-6.341 hours), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.174 and 0.065), which is good. Ligand B is better.

**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 ADME properties: DILI, solubility, microsomal clearance, in vitro half-life, and P-gp efflux. While both have similar binding affinities and acceptable physicochemical properties, the improved ADME profile of Ligand B makes it a more promising drug candidate. The slightly lower TPSA and better solubility are particularly beneficial.

Output:
1
2025-04-17 16:05:21,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (446.754 Da) is slightly higher, but acceptable. Ligand B (350.463 Da) is also good.

**TPSA:** Both ligands have TPSA values (81.06 and 78.68) below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.923) is at the upper end of the optimal range (1-3), while Ligand B (1.606) is well within the optimal range. Ligand A's higher logP could potentially lead to off-target effects or solubility issues.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.772 and 0.873), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (91.431 percentile) compared to Ligand B (18.922 percentile). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand B (72.741) shows better penetration than Ligand A (50.911).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.84 and -4.847), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.372 and -1.683), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Ligand A (0.111) has a slightly lower hERG risk than Ligand B (0.394), which is preferable.

**Microsomal Clearance:** Ligand B has a much lower microsomal clearance (3.869 mL/min/kg) than Ligand A (12.823 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (9.352 hours) than Ligand A (99.828 hours - this seems like a data error, as it's extremely high). Assuming the value for ligand A is an error, Ligand B still has a better half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.38).

**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 for Ligand 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, potentially problematic logP, and poorer metabolic stability. Ligand B has a better safety profile (lower DILI), better metabolic stability, and a reasonable half-life, but its binding affinity is weaker.

Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. While the affinity of Ligand A is very attractive, the high DILI risk is a major red flag. The poor solubility and permeability of both compounds are concerning but might be addressed with formulation strategies. However, a high DILI risk is harder to overcome.

Output:
1
2025-04-17 16:05:21,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.335 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (370.559 Da) is still well within the range.

**TPSA:** Ligand A (104.04) is better than Ligand B (49.85). A lower TPSA generally indicates better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 3.484, B: 2.496), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 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 (A: 0.532, B: 0.616), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.643), which is a significant concern. Ligand B has a much lower DILI risk (27.181), making it more favorable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (87.553) than Ligand A (23.42), but this is not a primary factor.

**Caco-2 Permeability:** Ligand A (-5.335) has poor Caco-2 permeability, while Ligand B (-4.585) is slightly better.

**Aqueous Solubility:** Ligand A (-4.92) has poor solubility, while Ligand B (-2.689) has better solubility.

**hERG Inhibition:** Ligand A (0.764) has a higher hERG inhibition liability than Ligand B (0.641), which is undesirable.

**Microsomal Clearance:** Ligand A (69.614) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (83.657).

**In vitro Half-Life:** Ligand A (-21.463) has a longer in vitro half-life than Ligand B (-11.494), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.213, B: 0.314).

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, its high DILI risk, poor solubility, and poor Caco-2 permeability are significant drawbacks. Ligand B has a more favorable ADME profile (lower DILI, better solubility, slightly better permeability) but weaker binding affinity.

Given the importance of potency for enzyme inhibition, the substantial difference in binding affinity (-8.9 vs -6.7 kcal/mol) is likely to be decisive. While the ADME properties of Ligand A are concerning, they might be addressable through further optimization. The weaker affinity of Ligand B might be harder to improve significantly.

Output:
0
2025-04-17 16:05:21,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (342.483 Da) is more towards the middle.

**TPSA:** Ligand A (96.01) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (58.2) is excellent.

**logP:** Both ligands have good logP values (A: 2.993, B: 3.446), 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 2 HBD and 2 HBA, which is also good and potentially better for permeability.

**QED:** Ligand B (0.76) has a significantly better QED score than Ligand A (0.389), indicating a more drug-like profile.

**DILI:** Ligand B (26.444) has a much lower DILI risk than Ligand A (96.045). This is a significant advantage.

**BBB:** Ligand B (75.107) shows better BBB penetration than Ligand A (54.246), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.124) has poor Caco-2 permeability, while Ligand B (-4.672) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-5) has very poor solubility, a major concern. Ligand B (-3.953) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.165) has a slightly higher hERG risk than Ligand B (0.647).

**Microsomal Clearance:** Ligand A (28.532) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (56.449).

**In vitro Half-Life:** Ligand A (44.85) has a longer half-life than Ligand B (-5.112). This is a positive for A.

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux, which is favorable. Ligand B (0.27) is slightly higher.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability and P-gp efflux, the significantly stronger binding affinity of Ligand B, combined with its much better QED score, lower DILI risk, and better solubility, outweigh these drawbacks. The poor solubility of Ligand A is a major red flag, and the lower affinity is difficult to overcome. The slightly worse metabolic stability of Ligand B can be addressed through structural modifications.

Output:
1
2025-04-17 16:05:21,405 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.479 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.9) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (54.34) is well within the ideal range.

**logP:** Ligand A (0.004) is quite low, potentially hindering permeability. Ligand B (2.917) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (A: 5, B: 4) are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (A: 0.491, B: 0.649), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (12.02) has a very low DILI risk, which is excellent. Ligand B (32.183) is still within an acceptable range, but higher than A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand B (65.413) has a higher BBB percentile than A (22.606), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.448 and -5.426), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.928 and -2.575), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.142) has a very low hERG risk, which is excellent. Ligand B (0.801) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-14.247) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (74.353) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (6.976) has a reasonable half-life. Ligand B (11.008) has a longer half-life, which is positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.021, B: 0.638), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in DILI risk and metabolic stability (Cl_mic), and has a very low hERG risk. However, its low logP and poor solubility are significant concerns. Ligand B has better logP, QED, and a much stronger binding affinity, but its higher DILI risk and significantly higher microsomal clearance are drawbacks.

Given the enzyme-specific priorities, the binding affinity is paramount. The 0.7 kcal/mol advantage of Ligand B is substantial. While the solubility and clearance are concerning, these can potentially be addressed through formulation strategies or structural modifications. The poor permeability of both is a shared issue.

Output:
1
2025-04-17 16:05:21,405 - INFO - Batch 434 complete. Total preferences: 6944
2025-04-17 16:05:21,405 - INFO - Processing batch 435/512...
2025-04-17 16:06:01,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 350.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (84.42 and 78.87) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.157 and 0.951) are within the optimal range of 1-3.

**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:** Ligand A (0.866) has a better QED score than Ligand B (0.699), indicating a more drug-like profile.

**DILI:** Ligand A (50.291) has a significantly lower DILI risk than Ligand B (9.965), which is a major advantage.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**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 difficult to interpret without more context.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, difficult to interpret.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.235 and 0.147). This is excellent.

**Microsomal Clearance:** Ligand A (20.587 mL/min/kg) has a higher microsomal clearance than Ligand B (15.408 mL/min/kg), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (6.506 hours) has a longer half-life than Ligand B (2.179 hours), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03 and 0.049).

**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 difference (2 kcal/mol), which can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having slightly higher microsomal clearance, its significantly stronger binding affinity (-9.5 vs -7.5 kcal/mol), much lower DILI risk, and better QED score make it the more promising drug candidate. The unusual Caco-2 and solubility values are concerning but the potency and safety profile of Ligand A are superior.

Output:
1
2025-04-17 16:06:01,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (93.46) is better than Ligand B (127.39). Both are below 140, but A is closer to the optimal value for oral absorption.

**logP:** Ligand A (2.271) is optimal (1-3), while Ligand B (-0.522) is below 1, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have good QED scores (A: 0.583, B: 0.635), indicating good drug-like properties.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (56.689), but both are below the concerning threshold of 60.

**BBB:** Ligand A (70.648) has better BBB penetration than Ligand B (32.61). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-5.046) has worse Caco-2 permeability than Ligand B (-5.756). Both are negative, indicating poor permeability, but B is slightly worse.

**Aqueous Solubility:** Ligand A (-3.46) has better aqueous solubility than Ligand B (-1.457). Solubility is important for bioavailability, making A preferable.

**hERG Inhibition:** Ligand A (0.139) has a lower hERG inhibition risk than Ligand B (0.048), which is a significant advantage. Lower hERG risk is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (39.935) has higher microsomal clearance than Ligand B (-9.504). Lower clearance is better for metabolic stability, giving Ligand B an advantage.

**In vitro Half-Life:** Ligand A (-16.699) has a shorter in vitro half-life than Ligand B (-5.554). A longer half-life is generally preferred, favoring Ligand B.

**P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux than Ligand B (0.01). Lower efflux is better for bioavailability, favoring Ligand A.

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in logP, TPSA, solubility, and hERG risk, all important factors for kinase inhibitors. While its Caco-2 permeability and half-life are worse than Ligand B, the significantly better logP and hERG profile outweigh these drawbacks, especially given the strong binding affinity is equal for both. Ligand B has better metabolic stability and half-life, but its poor logP is a major concern.

Output:
0
2025-04-17 16:06:01,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.272 Da) is slightly higher than Ligand B (368.499 Da), but both are acceptable.

**TPSA:** Ligand A (103.12) is slightly higher than Ligand B (75.71). Both are below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have similar logP values (A: 0.644, B: 0.699), falling within the optimal range of 1-3.

**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 (A: 0.66, B: 0.7), indicating good drug-like properties.

**DILI:** Ligand B (32.959) has a significantly lower DILI risk than Ligand A (68.011). This is a major advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration, with Ligand A (66.305) being slightly higher than Ligand B (56.301). BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.094 and -4.933), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.436 and -2.105), indicating very poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.361) has a slightly higher hERG risk than Ligand B (0.184), but both are relatively low, suggesting a manageable risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (27.278) has a significantly higher microsomal clearance than Ligand A (1.741). This means Ligand A is much more metabolically stable, a critical factor for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-36.954) has a much longer in vitro half-life than Ligand B (14.029). This is a significant advantage for Ligand A, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.017, B: 0.049).

**Binding Affinity:** Ligand B (-8.1) has a significantly stronger binding affinity than Ligand A (-6.6). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B's significantly stronger binding affinity (-8.1 kcal/mol vs -6.6 kcal/mol) and lower DILI risk are compelling advantages. While Ligand A has better metabolic stability and half-life, the potency advantage of Ligand B is more critical for an enzyme target like SRC kinase. The solubility/permeability issues would need to be addressed through formulation strategies, but the superior potency makes Ligand B the more promising candidate.

Output:
1
2025-04-17 16:06:01,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.471 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is better than Ligand B (40.62), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (4.504 and 3.842), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are below the 10 threshold.

**QED:** Both ligands have QED values above 0.5 (0.695 and 0.757), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 74.99, which is concerning (high risk). Ligand B has a significantly lower DILI risk of 16.906 (good). This is a major advantage for Ligand B.

**BBB:** Both ligands have high BBB penetration (85.537 and 92.827), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.672 and -4.567). These values are unusual and suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.594 and -3.526), indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.69 and 0.683).

**Microsomal Clearance:** Ligand A has a higher Cl_mic (95.607) than Ligand B (72.515), indicating faster metabolism and lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand A has a longer half-life (40.508 hours) than Ligand B (-3.673 hours). However, the negative value for Ligand B is suspect and likely indicates a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.839 and 0.351).

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-8.7 kcal/mol) than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and outweighs many other drawbacks.

**Conclusion:**

Despite both ligands having solubility and permeability issues, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.4 kcal/mol) and much lower DILI risk (16.9 vs 74.99) are critical advantages. While Ligand A has a better in vitro half-life, the negative half-life value for Ligand B is questionable. The superior potency and safety profile of Ligand B make it the preferred choice for further optimization.

Output:
1
2025-04-17 16:06:01,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.535 Da and 365.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better, below 90, suggesting good absorption. Ligand B (79.26) is still under 140, but less favorable than A.

**logP:** Ligand A (2.816) is optimal (1-3). Ligand B (0.719) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=6) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.616 and 0.777, respectively), indicating drug-like properties.

**DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (48.623), which is a major advantage. Both are below the 60 threshold, but A is much preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.107) is higher than Ligand B (48.313).

**Caco-2 Permeability:** Ligand A (-4.647) is better than Ligand B (-5.555), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.297 and -2.184). This is a significant concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.523) has a lower hERG risk than Ligand B (0.19), which is a positive.

**Microsomal Clearance:** Ligand A (47.347) has a higher Cl_mic than Ligand B (29.851), indicating lower metabolic stability. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (25.249) has a longer half-life than Ligand A (12.554), which is desirable.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.02), which is a positive.

**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 of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher Cl_mic and lower half-life, its significantly superior binding affinity (-9.1 vs -8.1 kcal/mol), lower DILI risk, better Caco-2 permeability, and lower hERG risk make it the more promising candidate. The solubility is a concern for both, but the potency advantage of A is compelling for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:06:01,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.422 and 352.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.71) is better than Ligand B (85.89). Both are below 140, suggesting good absorption potential.

**logP:** Ligand A (1.37) is slightly better than Ligand B (0.538). Ligand B is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5).

**QED:** Ligand A (0.827) is significantly better than Ligand B (0.653), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (27.685 and 25.553, respectively), which is excellent.

**BBB:** Ligand A (89.066) is better than Ligand B (61.923), but BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2:** Ligand A (-4.588) is better than Ligand B (-5.334). Higher values are better, suggesting better intestinal absorption.

**Solubility:** Ligand A (-2.173) is better than Ligand B (-1.294). Higher values are better.

**hERG:** Both ligands have very low hERG risk (0.111 and 0.133, respectively).

**Microsomal Clearance:** Ligand A (19.181) is worse than Ligand B (3.962). Lower clearance is preferred for metabolic stability, making Ligand B more favorable.

**In vitro Half-Life:** Ligand A (-6.453) is worse than Ligand B (16.395). Longer half-life is preferred, favoring Ligand B.

**P-gp Efflux:** Ligand A (0.044) is much better than Ligand B (0.012). Lower efflux is preferred.

**Binding Affinity:** Ligand A (0.0) is significantly worse than Ligand B (-9.0). This is the most crucial factor for an enzyme inhibitor. A -9.0 kcal/mol binding affinity is exceptionally strong.

**Overall Assessment:**

Ligand B has a substantially stronger binding affinity (-9.0 kcal/mol vs 0.0 kcal/mol). While Ligand A has better QED, solubility, and P-gp efflux, the massive difference in binding affinity outweighs these advantages. Ligand B also demonstrates better metabolic stability (lower Cl_mic and higher t1/2). The slightly lower logP of Ligand B is a minor concern, but not enough to negate the benefits.

Output:
1
2025-04-17 16:06:01,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.395 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.46) is well below the 140 threshold for oral absorption, while Ligand B (107.84) is still acceptable but closer to the limit.

**logP:** Ligand A (3.407) is at the upper end of the optimal 1-3 range. Ligand B (0.693) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Ligand A (0.527) is better than Ligand B (0.423), indicating a more drug-like profile.

**DILI:** Ligand A (69.252) has a higher DILI risk than Ligand B (35.595), which is a significant concern.

**BBB:** Both ligands have similar BBB penetration (around 71), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. Assuming these are percentile scores, they are very low, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, they are very low, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.53) presents a lower hERG risk than Ligand B (0.15), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (99.913) has very high clearance, suggesting poor metabolic stability. Ligand B (5.037) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (11.58 hours) has a moderate half-life. Ligand B (14.116 hours) has a slightly longer half-life.

**P-gp Efflux:** Ligand A (0.648) has moderate P-gp efflux. Ligand B (0.012) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-6.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from high DILI risk and very high metabolic clearance. Ligand B has excellent metabolic stability and low P-gp efflux, but its binding affinity is extremely weak and its logP is very low, which may lead to poor permeability.

Despite the DILI risk, the substantial difference in binding affinity (-6.9 vs -0.0 kcal/mol) is likely to outweigh the other drawbacks of Ligand A. Optimization efforts could focus on mitigating the DILI risk through structural modifications. The poor permeability and solubility of both compounds are concerning and would need to be addressed in subsequent optimization.

Output:
1
2025-04-17 16:06:01,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.443 and 342.439 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.35) is slightly higher than Ligand B (53.76). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**3. logP:** Ligand A (2.166) is within the optimal 1-3 range. Ligand B (3.46) is slightly higher, nearing the upper limit, 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 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.894 and 0.808), indicating good drug-likeness.

**7. DILI:** Ligand A (29.546) has a significantly lower DILI risk than Ligand B (44.668). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (90.229 and 89.841), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.73 and -4.13). These values are unusual and suggest poor permeability. However, these are likely predictions and may not be accurate.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.818 and -3.211). Again, these are likely predictions and may not be accurate. Solubility is important for kinases, but can be improved with formulation.

**11. hERG Inhibition:** Ligand A (0.192) has a much lower hERG inhibition liability than Ligand B (0.64). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand B (69.485) has a higher microsomal clearance than Ligand A (13.731), indicating lower metabolic stability. This is a key disadvantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (93.19) has a much longer in vitro half-life than Ligand A (25.693). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux liability than Ligand B (0.388). This is a slight advantage for Ligand A.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -8.9 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a longer half-life, Ligand A demonstrates significantly better safety profiles with lower DILI and hERG risk. Furthermore, it exhibits better metabolic stability (lower Cl_mic) and lower P-gp efflux. The slightly better TPSA and lower hERG risk of Ligand A outweigh the half-life advantage of Ligand B. The similar binding affinities make the ADMET properties the deciding factor.

Output:
0
2025-04-17 16:06:01,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.433 and 351.491 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.16) is better than Ligand B (67.59) as both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (2.852 and 2.769) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1) as both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.786 and 0.782) are above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (59.48) has a higher DILI risk than Ligand B (31.059). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (80.419) has better BBB penetration than Ligand B (54.362), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.783) has worse Caco-2 permeability than Ligand B (-4.57). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.764) has worse aqueous solubility than Ligand B (-2.404). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.225) has a slightly higher hERG inhibition risk than Ligand B (0.482), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (43.567) has a slightly higher microsomal clearance than Ligand B (40.162), indicating slightly lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (69.621) has a longer in vitro half-life than Ligand B (39.692). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.151) has slightly lower P-gp efflux than Ligand B (0.158). Lower efflux is generally preferred.

**15. Binding Affinity:** Ligand B (-7.0) has a significantly better binding affinity than Ligand A (0.0). This is the most important factor for an enzyme inhibitor. A difference of 7 kcal/mol is substantial.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better half-life and BBB penetration, Ligand B's significantly superior binding affinity (-7.0 kcal/mol vs 0.0 kcal/mol) outweighs these minor advantages. Furthermore, Ligand B has a much lower DILI risk and better solubility, both critical factors for drug development. The slightly lower half-life of Ligand B can be addressed through further optimization.

Output:
1
2025-04-17 16:06:01,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.471 and 347.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (83.6), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.119 and 3.438), falling within the 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not critically.

**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.

**QED:** Both ligands have QED values above 0.5 (0.75 and 0.657), indicating good drug-likeness.

**DILI:** Ligand A (10.508) has a much lower DILI risk than Ligand B (41.877), which is a significant advantage.

**BBB:** Ligand A (84.529) has better BBB penetration than Ligand B (45.56), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.686) is better than Ligand B (-4.877). Higher values are better.

**Aqueous Solubility:** Ligand A (-2.404) is better than Ligand B (-4.142). Higher values are better.

**hERG:** Both ligands have relatively low hERG risk (0.421 and 0.617).

**Microsomal Clearance:** Ligand A (37.203) has significantly lower microsomal clearance than Ligand B (81.964), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (16.529) has a longer half-life than Ligand A (5.799), which is a positive.

**P-gp Efflux:** Ligand A (0.204) has lower P-gp efflux than Ligand B (0.519), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall:** Ligand A is the superior candidate. It has lower DILI risk, better solubility, lower clearance (better metabolic stability), lower P-gp efflux, and comparable binding affinity to Ligand B. While Ligand B has a slightly longer half-life, the other advantages of Ligand A are more critical for an enzyme inhibitor.

Output:
0
2025-04-17 16:06:01,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.344 and 348.353 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.63) is well below the 140 threshold for good absorption, while Ligand B (86.88) is also acceptable.

**logP:** Both ligands have logP values (2.199 and 1.931) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, well within the limits. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have QED values (0.825 and 0.745) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (42.846) has a lower DILI risk than Ligand B (68.592), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (92.633) has a higher BBB percentile than Ligand B (70.415).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the absolute value is similar, so it doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and problematic. Again, the values are similar.

**hERG:** Ligand A (0.79) has a slightly higher hERG risk than Ligand B (0.298), which is less desirable.

**Microsomal Clearance:** Ligand B (-7.702) has a *much* lower (better) microsomal clearance than Ligand A (13.287). This suggests significantly improved metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-11.706) has a much longer in vitro half-life than Ligand A (6.438), further supporting its superior metabolic stability.

**P-gp Efflux:** Ligand A (0.214) has a lower P-gp efflux liability than Ligand B (0.042), which is preferable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has a slightly better DILI and P-gp profile, Ligand B stands out due to its significantly improved metabolic stability (lower Cl_mic and longer t1/2). For an enzyme target like SRC kinase, metabolic stability is a crucial factor. The similar binding affinities make the ADME advantages of Ligand B decisive.

Output:
1
2025-04-17 16:06:01,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.487 and 375.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 80.76, which is acceptable for oral absorption (<=140).

**logP:** Ligand A (3.297) is optimal, while Ligand B (1.044) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.746 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (55.448) has a slightly higher DILI risk than Ligand B (64.831), but both are reasonably acceptable.

**BBB:** Both ligands have high BBB penetration (84.684 and 88.174), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.349 and -4.697), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.553 and -2.829), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.517) has a slightly higher hERG risk than Ligand B (0.33), but both are relatively low.

**Microsomal Clearance:** Ligand B (8.583 mL/min/kg) has significantly lower microsomal clearance than Ligand A (76.679 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.543 hours) has a negative half-life, which is not physically possible and suggests a problem with the data or the compound itself. Ligand A (31.112 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.261 and 0.147).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.1 kcal/mol). The difference of 0.7 kcal/mol is significant.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the better candidate. Its significantly stronger binding affinity (-7.8 vs -7.1 kcal/mol) outweighs the slightly higher DILI and microsomal clearance. The negative half-life for Ligand B is a critical issue, making it a less viable candidate. While both require substantial work to improve solubility and permeability, the superior potency of Ligand A provides a stronger starting point for optimization.

Output:
0
2025-04-17 16:06:01,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.459 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is slightly higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Both ligands (1.813 and 2.062) are within the optimal 1-3 range.

**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:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 10. Ligand B is slightly better.

**QED:** Both ligands (0.706 and 0.748) have good drug-likeness scores, exceeding 0.5. Ligand B is slightly better.

**DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (31.563). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (53.276) has a lower BBB penetration percentile than Ligand B (78.907). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.791) has a lower Caco-2 permeability than Ligand B (-4.302). Both are negative, indicating poor permeability. Ligand B is slightly better.

**Aqueous Solubility:** Ligand A (-3.176) has slightly worse solubility than Ligand B (-2.98). Both are poor, but Ligand B is preferable.

**hERG Inhibition:** Ligand A (0.057) has a much lower hERG inhibition liability than Ligand B (0.59). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (30.013) has lower microsomal clearance than Ligand B (39.585), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-16.095) has a shorter in vitro half-life than Ligand B (-7.748). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux liability than Ligand B (0.154), which is favorable.

**Binding Affinity:** Ligand A (-7.6) has slightly better binding affinity than Ligand B (-7.3). While the difference is small, it is still a positive for Ligand A.

**Overall Assessment:**

Ligand A demonstrates a superior safety profile with significantly lower DILI and hERG risk. It also has better metabolic stability (lower Cl_mic) and slightly better binding affinity and P-gp efflux. Although its half-life is shorter and Caco-2 permeability is lower, the advantages in safety and metabolic stability outweigh these drawbacks for an enzyme target like SRC kinase. Ligand B has better solubility and BBB penetration (irrelevant here), but the higher DILI and hERG risk are concerning.

Output:
0
2025-04-17 16:06:01,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.454 Da and 386.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is better than Ligand B (70.08), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.0 and 1.575, respectively), 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 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.633 and 0.805), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (21.869 and 20.396, respectively), well below the 40 threshold.

**BBB:** Both ligands have good BBB penetration (76.696 and 80.264, respectively), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.023) is significantly worse than Ligand B (-4.585), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.862) is better than Ligand B (-3.065), suggesting better formulation potential.

**hERG Inhibition:** Both ligands have low hERG risk (0.364 and 0.577, respectively).

**Microsomal Clearance:** Ligand A (-8.297) has significantly lower (better) microsomal clearance than Ligand B (8.005), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.458) has a longer half-life than Ligand B (14.614), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.081 and 0.183, respectively).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.3 and -7.4 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is slightly favored. While Ligand B has slightly better Caco-2 permeability, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility. The binding affinities are essentially the same. For an oncology target, metabolic stability is crucial for maintaining therapeutic concentrations.

Output:
0
2025-04-17 16:06:01,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.431 and 352.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (81.27 and 76.66) well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.315) is slightly higher than Ligand B (2.085), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 4 respectively), below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.621 and 0.632), indicating good drug-likeness.

**7. DILI:** Ligand A (22.8) has a significantly lower DILI risk than Ligand B (40.946). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (83.055 and 88.29), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.778 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 (-3.47 and -2.764), indicating very poor aqueous solubility. This is a major drawback for both, potentially hindering formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.434 and 0.422), which is positive.

**12. Microsomal Clearance:** Ligand A (23.244) has lower microsomal clearance than Ligand B (28.219), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (11.273) has a longer in vitro half-life than Ligand A (6.959), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.142 and 0.107), which is favorable.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Despite both ligands having poor solubility and permeability, Ligand A is significantly more promising. Its substantially stronger binding affinity (-8.8 vs 0.0 kcal/mol) is a critical advantage. It also has a lower DILI risk and better metabolic stability (lower Cl_mic). While Ligand B has a longer half-life, the potency difference is far more important for an enzyme inhibitor. The solubility and permeability issues would need to be addressed through formulation strategies, but the superior potency and safety profile of Ligand A make it the better candidate.

Output:
1
2025-04-17 16:06:01,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.491 and 352.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (58.64), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.703) is a bit low, potentially hindering permeation, while Ligand B (3.125) is optimal.

**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 (0.632 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (4.731) has a very low DILI risk, significantly better than Ligand B (19.698).

**BBB:** Ligand B (71.772) has a higher BBB penetration potential than Ligand A (36.371), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.856) shows poor Caco-2 permeability, while Ligand B (-4.215) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.599) has slightly better solubility than Ligand B (-2.967).

**hERG Inhibition:** Ligand A (0.198) has a much lower hERG inhibition liability than Ligand B (0.403), a critical advantage.

**Microsomal Clearance:** Ligand A (-7.488) has significantly lower microsomal clearance, indicating better metabolic stability, than Ligand B (83.219).

**In vitro Half-Life:** Ligand A (5.337 hours) has a better in vitro half-life than Ligand B (2.6 hours).

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux liability, while Ligand B (0.209) is higher.

**Binding Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand B having a better logP and slightly better Caco-2 permeability, Ligand A is the superior candidate. Its significantly lower DILI risk, hERG liability, and microsomal clearance, coupled with better solubility and P-gp efflux, outweigh the slightly lower logP and Caco-2 permeability. The equal binding affinity means potency isn't a differentiating factor. The enzyme-specific priorities clearly favor Ligand A due to its improved safety and pharmacokinetic properties.

Output:
0
2025-04-17 16:06:01,110 - INFO - Batch 435 complete. Total preferences: 6960
2025-04-17 16:06:01,110 - INFO - Processing batch 436/512...
2025-04-17 16:06:41,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.539 Da and 395.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.78) is significantly better than Ligand B (69.64).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (4.412 and 3.111, respectively), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=3) in terms of HBD count, being closer to the ideal of <=5. Both are within the HBA limit of <=10.

**QED:** Ligand A (0.865) has a much better QED score than Ligand B (0.679), indicating a more drug-like profile.

**DILI:** Ligand A (10.585) has a significantly lower DILI risk than Ligand B (21.442), which is a major advantage. Both are below the 40 threshold, but A is much safer.

**BBB:** Ligand A (85.731) has a higher BBB penetration percentile than Ligand B (60.527). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.703 and -4.569). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.335 and -3.637), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.743 and 0.353), which is excellent.

**Microsomal Clearance:** Ligand A (35.014) has significantly lower microsomal clearance than Ligand B (63.501), indicating better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (8.514) has a longer in vitro half-life than Ligand B (4.435), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.471 and 0.1), which is favorable.

**Binding Affinity:** Ligand A (0.0) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand A is clearly superior. It demonstrates better drug-likeness (QED), significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and higher BBB penetration. While both have poor solubility and permeability, the other advantages of Ligand A, particularly the lower DILI and better metabolic stability, outweigh the shared drawbacks. The slightly better binding affinity also contributes to its favorability.

Output:
1
2025-04-17 16:06:41,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (330.391 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.83) is well below the 140 threshold, while Ligand B (86.88) is still acceptable but approaching the upper limit.

**logP:** Ligand A (4.671) is slightly high, potentially leading to solubility issues. Ligand B (1.237) is a bit low, potentially hindering permeability.

**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 within limits.

**QED:** Both ligands have good QED scores (0.558 and 0.884), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (82.668), which is concerning. Ligand B has a much lower DILI risk (37.922), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.074) is moderate, while Ligand B (50.872) is lower.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.168) is worse than Ligand B (-4.514).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-5.885) is worse than Ligand B (-1.051).

**hERG:** Ligand A (0.93) has a slightly higher hERG risk than Ligand B (0.285), which is preferable.

**Microsomal Clearance:** Ligand A (85.796) has a higher clearance, indicating poorer metabolic stability. Ligand B (43.628) has a lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (-10.457) has a very short half-life, while Ligand B (-24.296) has an even shorter half-life. Both are poor.

**P-gp Efflux:** Ligand A (0.533) has lower P-gp efflux than Ligand B (0.131), which is better.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly better binding affinity than Ligand A (-10.2 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand B having slightly less optimal logP and Caco-2 permeability, its significantly better binding affinity, much lower DILI risk, and lower microsomal clearance make it the more promising candidate. The high DILI risk and poor metabolic stability of Ligand A are major concerns. The superior binding affinity of Ligand B is a critical factor for an enzyme inhibitor.

Output:
1
2025-04-17 16:06:41,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.808 and 372.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.26) is well below the 140 threshold, suggesting good absorption. Ligand B (90.03) is also acceptable, but closer to the limit.

**logP:** Ligand A (3.366) is optimal. Ligand B (-0.921) is significantly below the optimal range, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 2 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.627 and 0.651), indicating good drug-likeness.

**DILI:** Ligand A (88.329) has a higher DILI risk than Ligand B (24.04). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.127) and Ligand B (56.301) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.69) has poor Caco-2 permeability, which is concerning. Ligand B (-5.239) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.874) has very poor aqueous solubility, a major drawback. Ligand B (-1.162) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.481) has a slightly higher hERG risk than Ligand B (0.07), but both are relatively low.

**Microsomal Clearance:** Ligand A (41.722) has a moderate microsomal clearance, while Ligand B (14.74) has a much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (87.727) has a good in vitro half-life. Ligand B (-27.149) has a very short half-life, which is a significant negative.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.136 and 0.003).

**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:**

Ligand A has a much better binding affinity, but suffers from poor solubility, poor Caco-2 permeability, higher DILI risk, and moderate metabolic clearance. Ligand B has better solubility, lower DILI, better metabolic stability, and a slightly better Caco-2 permeability, but its binding affinity is weaker and it has a very short half-life.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), the stronger binding affinity of Ligand A is a significant advantage that *could* outweigh its drawbacks, *if* solubility and permeability can be improved through structural modifications. However, the high DILI risk is a major concern. Ligand B's poor half-life is also a major drawback.

Considering all factors, the better binding affinity of Ligand A is compelling. While its ADME properties are suboptimal, they are more readily addressed through medicinal chemistry optimization than significantly improving the binding affinity of Ligand B.

Output:
1
2025-04-17 16:06:41,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.451 Da and 342.399 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.49) is slightly higher than Ligand B (80.37), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.194) is quite low, potentially hindering permeability. Ligand B (2.52) 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 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.572 and 0.905), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (18.302) has a much lower DILI risk than Ligand B (57.658). This is a strong advantage for Ligand A.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B is slightly higher (62.699 vs 26.134).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.359) is slightly better than Ligand B (-4.853), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-0.826) is slightly better than Ligand B (-4.088).

**hERG Inhibition:** Ligand A (0.037) has a very low hERG risk, while Ligand B (0.259) is slightly higher. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (7.925) has a much lower microsomal clearance than Ligand B (37.089), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (15.698) has a shorter half-life than Ligand B (30.755), but both are reasonable.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**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 for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. While it has drawbacks in DILI, solubility, and metabolic stability, the potency advantage is substantial. Ligand A has better safety profiles (DILI, hERG) and metabolic stability, but its lower binding affinity is a major concern. Considering the enzyme class, the potency advantage of Ligand B is likely to be more impactful than the ADME concerns, especially if those can be addressed through further optimization.

Output:
1
2025-04-17 16:06:41,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.435 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.23 and 78.09) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.832 and 2.074) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both are below the 10 threshold.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (75.611) has a higher DILI risk than Ligand B (25.514). This is a significant concern.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual and suggesting very poor solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.277 and 0.268).

**Microsomal Clearance:** Ligand A (47.902) has significantly higher microsomal clearance than Ligand B (7.353). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-14.745) has a negative half-life, which is not possible and indicates a problem with the data or the molecule. Ligand A has a half-life of 36.248.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.215 and 0.06).

**Binding Affinity:** Both ligands have strong binding affinity (-8.0 and -8.6 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is the better candidate despite the negative Caco-2 and solubility values. The primary driver is the significantly lower DILI risk and the much better metabolic stability (lower Cl_mic, although the negative half-life is concerning). While both have poor predicted permeability and solubility, metabolic stability and safety (DILI) are crucial for kinase inhibitors. The slightly better binding affinity of Ligand B is also a plus. The negative half-life for Ligand B is a major concern that would require further investigation, but the other factors favor it over Ligand A.

Output:
1
2025-04-17 16:06:41,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 355.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (69.72 and 70.16) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.764) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (0.977) is also on the lower side but slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, which are well within acceptable limits. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.607 and 0.651), indicating good drug-like properties.

**DILI:** Ligand A (13.532) has a significantly lower DILI risk than Ligand B (15.2), which is a major advantage.

**BBB:** Both have relatively low BBB penetration, which isn't crucial for a non-CNS target like SRC. Ligand B is higher (82.047) than Ligand A (61.38).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.824 and -4.632), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.724 and -0.841), indicating poor aqueous solubility, a significant drawback. Ligand B is slightly better.

**hERG:** Ligand A (0.119) has a much lower hERG risk than Ligand B (0.347), which is a critical advantage.

**Microsomal Clearance:** Ligand A (14.076 mL/min/kg) has significantly lower microsomal clearance than Ligand B (24.624 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.317 hours) has a slightly better (less negative) in vitro half-life than Ligand B (-16.007 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.01 and 0.033).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), although both are good. The 0.7 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the stronger candidate. While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand A demonstrates a significantly better safety profile (lower DILI and hERG risk) and improved metabolic stability (lower Cl_mic, better t1/2). The slightly better binding affinity further supports its selection. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the superior safety and metabolic properties of Ligand A make it the more promising starting point.

Output:
0
2025-04-17 16:06:41,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (323.4 and 346.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.94) is better than Ligand B (58.64), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**3. logP:** Ligand A (4.999) is slightly high, potentially leading to solubility issues, while Ligand B (2.29) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, under the limit of 5.

**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 scores (A: 0.51, B: 0.614), indicating drug-like properties.

**7. DILI:** Ligand A (85.653) has a significantly higher DILI risk than Ligand B (23.614). This is a major concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.794) has a higher BBB value than Ligand A (52.811), but it's not a deciding factor here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.051 and -4.9), indicating poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.875 and -2.162), indicating poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.93) has a higher hERG risk than Ligand B (0.156), which is preferable.

**12. Microsomal Clearance:** Ligand B (48.933) has a higher microsomal clearance than Ligand A (14.484), suggesting lower metabolic stability. Ligand A is preferable here.

**13. In vitro Half-Life:** Ligand A (32.518) has a significantly longer half-life than Ligand B (-16.531), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.668) has lower P-gp efflux than Ligand B (0.102), which is preferable.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.1 and -9.0 kcal/mol), with a very small advantage to Ligand A.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is better despite its slightly higher logP. The significantly lower DILI risk, longer half-life, and lower P-gp efflux of Ligand A outweigh the slightly higher logP and hERG risk. The binding affinity is comparable. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 16:06:41,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (374.575 Da) is also well within the range.

**TPSA:** Ligand A (87.39) is better than Ligand B (44.1). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 3.246 and Ligand B at 4.517. Ligand B is slightly higher, potentially increasing off-target effects or solubility issues, but still acceptable.

**H-Bond Donors:** Ligand A has 3 HBD, which is good. 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 QED values above 0.5, indicating good drug-likeness (0.685 for A, 0.566 for B).

**DILI:** Ligand A has a DILI risk of 47.732, which is good (below 60). Ligand B has a significantly lower DILI risk of 12.757, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A is at 64.831, and Ligand B is at 84.374.

**Caco-2 Permeability:** Ligand A (-4.764) is poor, while Ligand B (-5.105) is also poor. Both are negative values, suggesting low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.473 for A, -4.486 for B). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.554) has a slightly better hERG profile than Ligand B (0.877), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (35.609) has significantly better metabolic stability (lower clearance) than Ligand B (107.225). This is a major advantage.

**In vitro Half-Life:** Ligand A (71.482) has a much longer half-life than Ligand B (-3.773). This is a substantial benefit, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.458) has lower P-gp efflux than Ligand B (0.616), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.6 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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B's substantially stronger binding affinity (-9.6 kcal/mol vs -7.2 kcal/mol) and significantly lower DILI risk make it the more promising candidate. The improved metabolic stability (lower Cl_mic) and longer half-life of Ligand A are attractive, but the difference in binding affinity is a critical factor for an enzyme inhibitor. Addressing the solubility and permeability issues through formulation or prodrug strategies would be the next step for Ligand B.

Output:
1
2025-04-17 16:06:41,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (389.283 and 374.897 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.77) is slightly higher than Ligand B (61.92), but both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.299) is within the optimal range (1-3). Ligand B (3.545) is at the higher end of the optimal range, potentially raising concerns about off-target effects, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.712 and 0.776 respectively), indicating drug-likeness.

**7. DILI:** Both ligands have low DILI risk (49.593 and 47.421 percentile), which is favorable.

**8. BBB:** Ligand A (66.072) has lower BBB penetration than Ligand B (80.884). However, since SRC is not a CNS target, this is a lower priority.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.723 and -4.951). This is unusual and suggests poor permeability. However, these values are on a log scale and could be misinterpreted. We will need to consider other parameters.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.543 and -5.376). This is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.447 and 0.537), which is excellent.

**12. Microsomal Clearance:** Ligand A (14.596) has significantly lower microsomal clearance than Ligand B (71.877). This indicates better metabolic stability for Ligand A, a key priority for enzymes.

**13. In vitro Half-Life:** Ligand A (7.957) has a shorter half-life than Ligand B (10.896), but both are reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.545).

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-8.3 kcal/mol).

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is more promising. While both have excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic) which is crucial for *in vivo* efficacy. The negative Caco-2 and solubility values are concerning for both, but the superior metabolic stability of Ligand A outweighs these drawbacks.

Output:
0
2025-04-17 16:06:41,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.37 & 343.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.04) is well below the 140 threshold for oral absorption. Ligand B (127.82) is still acceptable, but closer to the limit.

**logP:** Ligand A (3.367) is optimal (1-3). Ligand B (-0.694) is significantly below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, but higher donors can sometimes affect permeability.

**H-Bond Acceptors:** Both ligands (7) are within the acceptable limit of 10.

**QED:** Both ligands (0.663 & 0.659) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (78.402) has a higher DILI risk than Ligand B (41.76), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (82.474 & 74.796), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.34) has poor Caco-2 permeability, while Ligand B (-6.059) is even worse. Both are highly unfavorable.

**Aqueous Solubility:** Ligand A (-4.734) has poor solubility, while Ligand B (-1.724) is also unfavorable.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.095 & 0.017).

**Microsomal Clearance:** Ligand A (111.337) has higher clearance than Ligand B (4.976), indicating lower metabolic stability. Ligand B is excellent in this regard.

**In vitro Half-Life:** Ligand A (-42.512) has a very short half-life, while Ligand B (10.684) is better, but still relatively short.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.3 & 0.019).

**Binding Affinity:** Ligand A (-8.5) has a significantly stronger binding affinity than Ligand B (-9.0). This is a substantial advantage.

**Conclusion:**

Despite Ligand A's stronger binding affinity, its poor Caco-2 permeability, solubility, and metabolic stability (high Cl_mic, short half-life) are major drawbacks. Ligand B, while having a slightly weaker affinity, exhibits significantly better ADME properties, particularly regarding metabolic stability (very low Cl_mic) and acceptable (though still unfavorable) solubility and permeability. The substantial difference in metabolic stability and the acceptable DILI risk for Ligand B outweigh the affinity difference.

Output:
1
2025-04-17 16:06:41,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.475 and 359.461 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly higher than Ligand B (58.22), but both are well below the 140 threshold for good absorption.

**3. logP:** Ligand A (2.582) and Ligand B (3.709) are both within the optimal 1-3 range. Ligand B is approaching the upper limit, but not concerningly so.

**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 (0.772) has a slightly better QED score than Ligand B (0.693), indicating a more drug-like profile.

**7. DILI:** Both ligands show low DILI risk, with Ligand A at 30.787% and Ligand B at 27.685%. Both are well below the 40% threshold.

**8. BBB:** Both ligands have good BBB penetration, with Ligand A at 74.719% and Ligand B at 82.009%. However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.447 and -4.723). 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 have negative solubility values (-2.758 and -2.908). This is also concerning, indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.122) has a significantly lower hERG inhibition risk than Ligand B (0.781). This is a major advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (69.969) has a higher microsomal clearance than Ligand B (73.627), meaning it is less metabolically stable.

**13. In vitro Half-Life:** Ligand B (-9.853) has a significantly longer in vitro half-life than Ligand A (8.319). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux than Ligand B (0.272), which is favorable.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a 1.1 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (longer half-life) and slightly better BBB penetration, Ligand A has a significantly better binding affinity, lower hERG risk, and lower P-gp efflux. The stronger binding affinity is a critical advantage for an enzyme inhibitor. The poor solubility and permeability are concerns for both, but the potency advantage of Ligand A is substantial. The lower hERG risk is also a significant benefit.

Output:
0
2025-04-17 16:06:41,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (376.551 and 358.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is significantly better than Ligand B (81.66). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Both ligands have good logP values (3.648 and 2.883), 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 8. Both are acceptable (<=10), but A is slightly better.

**QED:** Ligand A (0.807) has a higher QED than Ligand B (0.667), indicating better overall drug-likeness.

**DILI:** Ligand B (60.527) has a slightly higher DILI risk than Ligand A (71.384), but both are acceptable, being below 60.

**BBB:** Both ligands have good BBB penetration (75.107 and 73.672), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar (-5.186 and -5.728), so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-2.754) is slightly better than Ligand A (-4.059), but both are problematic.

**hERG Inhibition:** Ligand A (0.747) has a lower hERG inhibition risk than Ligand B (0.125), which is a significant advantage.

**Microsomal Clearance:** Ligand A (67.769) has higher microsomal clearance than Ligand B (37.796), meaning Ligand B is more metabolically stable. This is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (13.626) has a slightly longer half-life than Ligand A (15.958), which is a minor advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.254 and 0.361).

**Binding Affinity:** Ligand B (-9.3 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 kcal/mol is significant.

**Conclusion:**

While Ligand A has better QED, TPSA, HBA, and hERG risk, Ligand B's significantly stronger binding affinity (-9.3 vs -7.3 kcal/mol) and better metabolic stability (lower Cl_mic) are more critical for an enzyme inhibitor like an SRC kinase inhibitor. The slightly longer half-life of B is also a bonus. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:06:41,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.837 and 376.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.72) is well below the 140 threshold for good absorption, and even favorable. Ligand B (103.78) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.747) is within the optimal 1-3 range. Ligand B (0.717) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, both within acceptable limits. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.716 and 0.617), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 77.162, which is concerningly high (>60). Ligand B has a much lower DILI risk of 17.449, a significant advantage.

**BBB:** This is less crucial for a non-CNS target like SRC, but Ligand A (69.678) is slightly better than Ligand B (54.091).

**Caco-2 Permeability:** Ligand A (-4.505) and Ligand B (-5.28) both have negative Caco-2 values, which is unusual and suggests poor permeability. The scale is not specified, so it's difficult to interpret the absolute impact.

**Aqueous Solubility:** Ligand A (-4.514) and Ligand B (-1.293) both have negative solubility values, suggesting poor solubility. The scale is not specified, so it's difficult to interpret the absolute impact.

**hERG Inhibition:** Ligand A (0.266) has a very low hERG risk, which is excellent. Ligand B (0.255) is also very low and comparable.

**Microsomal Clearance:** Ligand A (75.613) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-10.091) has a *negative* clearance, which is physically impossible and likely an error in the data. This is a major red flag.

**In vitro Half-Life:** Ligand A (30.35) has a moderate half-life. Ligand B (1.379) has a very short half-life, which is undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.445 and 0.019), which is good.

**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 could outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's superior binding affinity, its high DILI risk and relatively high metabolic clearance are significant concerns. Ligand B, while having a weaker affinity, exhibits a much better safety profile (lower DILI) and, despite the impossible negative clearance value, a longer half-life than Ligand B. The negative clearance value for Ligand B is a critical data quality issue. Assuming this is an error, and the true clearance is low, Ligand B is the more promising candidate due to its improved safety and metabolic stability.

Output:
1
2025-04-17 16:06:41,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 344.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is significantly better than Ligand B (97.78). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (0.621) is a bit low, potentially hindering permeability, while Ligand B (2.325) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 8 HBA). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.763) has a better QED score than Ligand B (0.532), indicating a more drug-like profile.

**DILI:** Ligand A (37.999) has a significantly lower DILI risk than Ligand B (52.036), which is a crucial advantage.

**BBB:**  BBB isn't a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired. Ligand B (71.074) is higher, but this isn't a deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.457) has a worse Caco-2 permeability than Ligand B (-5.519). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.343 and -2.277 respectively). This is a significant drawback for both, but doesn't differentiate them.

**hERG Inhibition:** Ligand A (0.258) has a much lower hERG inhibition liability than Ligand B (0.642), which is a critical advantage.

**Microsomal Clearance:** Ligand A (39.141) and Ligand B (40.24) are similar, indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-28.177) has a significantly longer in vitro half-life than Ligand B (17.465), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux liability than Ligand B (0.163), which is favorable.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-6.6), a difference of 0.5 kcal/mol. While affinity is paramount, the other ADME properties are also important.

**Overall Assessment:**

Ligand A is superior despite slightly lower binding affinity. It has a better QED score, significantly lower DILI and hERG risk, better H-bond properties, and a longer half-life. While Ligand B has a better logP and slightly better affinity, the superior safety profile and drug-likeness of Ligand A outweigh these advantages. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 16:06:41,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.479 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.29) is better than Ligand B (98.14), both being acceptable, but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.962) is optimal (1-3), while Ligand B (0.461) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 2 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:** Ligand A (0.791) has a significantly better QED score than Ligand B (0.5), indicating a more drug-like profile.

**DILI:** Ligand A (26.018) has a much lower DILI risk than Ligand B (39.356), which is a significant advantage. Both are below the 40 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.498) is better than Ligand B (61.923).

**Caco-2 Permeability:** Both are negative (-5.074 and -4.909), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative (-2.288 and -2.15), indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.34) has a much lower hERG risk than Ligand B (0.024), which is a major advantage.

**Microsomal Clearance:** Ligand A (15.565) has lower clearance than Ligand B (18.79), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (20.392) has a longer half-life than Ligand B (-5.129), which is desirable.

**P-gp Efflux:** Both are very low (0.076 and 0.05), suggesting minimal P-gp efflux.

**Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (0). This is a substantial advantage for Ligand B, and could potentially outweigh some of its ADME shortcomings. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor logP, which could severely impact its permeability and bioavailability. It also has a higher DILI risk and lower QED. Ligand A has better ADME properties across the board (QED, DILI, hERG, metabolic stability, half-life, logP) but significantly weaker binding affinity.

Given the substantial affinity difference, the benefit of Ligand B's binding outweighs the ADME concerns. While optimization would be needed to address the logP and solubility issues, the strong binding provides a solid starting point.

Output:
1
2025-04-17 16:06:41,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Ligand A (353.467 Da) is within the ideal range (200-500 Da). Ligand B (495.027 Da) is at the upper limit, but still acceptable.

**TPSA:** Ligand A (98.14) is good for oral absorption (<140). Ligand B (83.36) is also excellent.

**logP:** Ligand A (2.389) is optimal (1-3). Ligand B (4.317) is slightly higher, potentially leading to solubility issues or off-target effects, but not dramatically.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (6) are both within the acceptable limit of <=10.

**QED:** Ligand A (0.629) is better than Ligand B (0.516), indicating a more drug-like profile.

**DILI:** Ligand A (63.397) is slightly higher than Ligand B (67.584), but both are acceptable (<60 is good).

**BBB:** Both ligands have moderate BBB penetration, but Ligand A (71.772) is better than Ligand B (59.093). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.849) is slightly better than Ligand B (-5.011).

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and suggests poor solubility. Ligand A (-3.269) is slightly better than Ligand B (-3.533).

**hERG:** Ligand A (0.136) has a much lower hERG risk than Ligand B (0.902). This is a significant advantage.

**Microsomal Clearance:** Ligand A (89.697) has higher clearance than Ligand B (45.973), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (74.551) has a significantly longer half-life than Ligand A (-15.861). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.879).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much better in vitro half-life, which are critical for an enzyme inhibitor. While its logP is slightly higher and hERG risk is elevated, the substantial improvement in potency and metabolic stability outweighs these concerns. Ligand A has a better QED and lower hERG, but its weaker binding affinity and poorer metabolic stability are significant drawbacks. The negative Caco-2 and solubility values are concerning for both, but the stronger binding of B may compensate.

Output:
1
2025-04-17 16:06:41,454 - INFO - Batch 436 complete. Total preferences: 6976
2025-04-17 16:06:41,454 - INFO - Processing batch 437/512...
2025-04-17 16:07:20,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.423 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (89.28 and 91.32) are below 140, suggesting good oral absorption potential.

**logP:** Ligand A (3.575) is optimal, while Ligand B (1.819) is slightly lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.703 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (92.284) shows a significantly higher DILI risk than Ligand B (41.062). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (73.943) has a better BBB score than Ligand B (47.654).

**Caco-2 Permeability:** Ligand A (-4.945) shows better Caco-2 permeability than Ligand B (-5.192).

**Aqueous Solubility:** Ligand A (-4.503) has slightly better aqueous solubility than Ligand B (-2.076).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.36 and 0.22).

**Microsomal Clearance:** Ligand B (-10.592) has a significantly lower (better) microsomal clearance than Ligand A (67.944), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (28.208 hours) has a slightly longer half-life than Ligand A (30.556 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.425 and 0.043).

**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 relatively small.

**Conclusion:**

While Ligand A has slightly better Caco-2 permeability and solubility, the significantly higher DILI risk and poorer metabolic stability (higher Cl_mic) are major drawbacks. Ligand B, despite a slightly lower logP and binding affinity, presents a much more favorable safety profile (lower DILI) and better metabolic stability. Given the enzyme-specific priorities, metabolic stability and safety are crucial. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 16:07:20,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (375.519 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (71.09 and 69.72) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.769) is optimal, while Ligand B (0.621) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 3 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.844 and 0.763), indicating drug-likeness.

**DILI:** Ligand A (58.976) has a slightly higher DILI risk than Ligand B (37.999), but both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (61.535) has a higher BBB value than Ligand A (46.219), but this is less important here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.165 and -4.457), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.309 and -2.343), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG risk (0.298 and 0.258).

**Microsomal Clearance:** Ligand A (10.415 mL/min/kg) has significantly lower microsomal clearance than Ligand B (39.141 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.786 hours) has a much longer half-life than Ligand B (-28.177 hours - a negative value is concerning).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.162 and 0.056).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.3 vs -6.6 kcal/mol) outweighs the slightly higher DILI risk and lower BBB. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic) and a longer half-life. Addressing the solubility and permeability issues through formulation strategies might be possible, but a strong starting affinity is essential for an enzyme inhibitor.

Output:
1
2025-04-17 16:07:20,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 358.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.83) is better than Ligand B (67.43), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.323) is within the optimal 1-3 range. Ligand B (2.763) is also within the optimal range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (3).

**QED:** Ligand B (0.767) has a significantly better QED score than Ligand A (0.388), indicating a more drug-like profile.

**DILI:** Ligand B (31.989) has a much lower DILI risk than Ligand A (61.574), making it safer.

**BBB:** Ligand B (77.2) has a better BBB penetration score than Ligand A (63.823), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5) is better than Ligand B (-4.684), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.724) is better than Ligand B (-2.613), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.229 and 0.342 respectively), which is excellent.

**Microsomal Clearance:** Ligand B (47.938) has lower microsomal clearance than Ligand A (58.669), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.176) has a longer in vitro half-life than Ligand B (-15.13), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.091 respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-8.8 and -8.3 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Overall Assessment:**

Ligand B is significantly better regarding DILI risk and QED score, and has better metabolic stability (lower Cl_mic). Ligand A has slightly better solubility and half-life, but the improvements are not substantial enough to offset the drawbacks. The binding affinity is comparable. Given the enzyme-specific priorities, the lower DILI and better metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:07:20,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (366.845 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.78) is better than Ligand B (53.51), both are below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (2.205 and 3.025), 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 (0.855) has a higher QED score than Ligand B (0.715), indicating better overall drug-likeness.

**7. DILI:** Ligand A (32.959) has a lower DILI risk than Ligand B (16.44), both are good (<40).

**8. BBB:** Ligand A (41.218) has a lower BBB penetration than Ligand B (75.107). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.83) and Ligand B (-4.433) have similar Caco-2 permeability, both are negative.

**10. Aqueous Solubility:** Ligand A (-3.046) has worse solubility than Ligand B (-1.712), both are negative.

**11. hERG Inhibition:** Ligand A (0.144) has a lower hERG inhibition liability than Ligand B (0.42), which is preferable.

**12. Microsomal Clearance:** Ligand A (-3.323) has a lower (better) microsomal clearance than Ligand B (66.022), indicating greater metabolic stability. This is a key factor for enzymes.

**13. In vitro Half-Life:** Ligand A (33.108) has a longer half-life than Ligand B (-2.399), which is desirable.

**14. P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux than Ligand B (0.084), which is better.

**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 some minor ADME drawbacks.

**Overall Assessment:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has a better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG inhibition, and a higher QED score. While Ligand B has better BBB penetration and solubility, these are less critical for an SRC kinase inhibitor.

Output:
1
2025-04-17 16:07:20,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.47 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is well below the 140 threshold, suggesting good absorption. Ligand B (112.73) is still within acceptable limits, but less optimal.

**logP:** Ligand A (3.727) 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 (0.156) is significantly below 1, which is a major concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of hydrogen bond donors and acceptors, falling within the guidelines.

**QED:** Ligand A (0.871) has a very good drug-likeness score. Ligand B (0.654) is still acceptable, but lower.

**DILI:** Ligand A (30.322) has a low DILI risk. Ligand B (13.649) also has a low DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.249) is higher than Ligand B (32.687).

**Caco-2 Permeability:** Ligand A (-4.758) is poor, while Ligand B (-5.537) is also poor. These values are on a scale where higher is better, so both are problematic.

**Aqueous Solubility:** Ligand A (-3.654) is poor, while Ligand B (-1.418) is also poor. These values are on a scale where higher is better, so both are problematic.

**hERG Inhibition:** Ligand A (0.784) has a low hERG risk. Ligand B (0.079) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (22.178) is moderate, indicating reasonable metabolic stability. Ligand B (-11.263) is very low, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (5.008) is a moderate half-life. Ligand B (2.131) is a short half-life.

**P-gp Efflux:** Ligand A (0.358) has low P-gp efflux liability. Ligand B (0.008) has very low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a >2 kcal/mol difference, which is substantial.

**Conclusion:**

Despite Ligand A having a better QED score, the significantly stronger binding affinity of Ligand B (-9.0 vs -6.9 kcal/mol) and its superior metabolic stability (lower Cl_mic, though shorter half-life) are compelling advantages. While Ligand B has a lower logP and Caco-2 permeability, the potency advantage is likely to outweigh these drawbacks, especially for a kinase inhibitor where high potency can compensate for less-than-ideal pharmacokinetic properties. The low hERG risk for both is also positive.

Output:
1
2025-04-17 16:07:20,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.379 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.68) is borderline, but acceptable for oral absorption. Ligand B (67.67) is excellent, well below the 140 threshold.

**logP:** Ligand A (-0.675) is a bit low, potentially hindering permeation. Ligand B (0.925) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**H-Bond Acceptors:** Both ligands (A: 6, B: 5) are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (A: 0.326, B: 0.765), with Ligand B being significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (56.727) has a moderate DILI risk, while Ligand B (46.064) has a lower risk, which is preferable.

**BBB:** Both ligands have good BBB penetration (A: 70.919, B: 83.637), but Ligand B is better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-4.391) is slightly better than Ligand A (-5.538), suggesting marginally better absorption.

**Aqueous Solubility:** Both ligands have poor solubility (A: -1.333, B: -2.155). This is a significant drawback, but could potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.14, B: 0.378), which is excellent.

**Microsomal Clearance:** Ligand A (-13.767) has a lower (better) microsomal clearance than Ligand B (60.929), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (27.633) has a better in vitro half-life than Ligand B (-22.568).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.004, B: 0.087).

**Binding Affinity:** Ligand B (-7.2 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 the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a better QED score, lower DILI risk, better logP, better TPSA, and better BBB penetration. While Ligand A has better metabolic stability and half-life, Ligand B's superior drug-like properties and slightly better binding affinity make it a more attractive starting point for optimization. The solubility issue is a concern for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 16:07:20,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.308 Da and 381.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (93.53 and 88.57) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.102) is quite low, potentially hindering permeation. Ligand B (2.913) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (6 & 6) counts.

**QED:** Both ligands have a QED of 0.77, indicating good drug-likeness.

**DILI:** Ligand A (46.956) has a lower DILI risk than Ligand B (63.746), which is a positive for A. However, both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.564) has a higher BBB percentile than Ligand B (52.579).

**Caco-2 Permeability:** Ligand A (-4.616) has a very poor Caco-2 permeability, while Ligand B (-5.299) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.594) has slightly better solubility than Ligand B (-3.724).

**hERG:** Both ligands show very low hERG inhibition liability (0.421 and 0.342), which is excellent.

**Microsomal Clearance:** Ligand A (2.326 mL/min/kg) has significantly lower microsomal clearance than Ligand B (54.169 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-29.609 hours) has a very long half-life, while Ligand B (65.289 hours) is also long.

**P-gp Efflux:** Ligand A (0.035) has a lower P-gp efflux liability than Ligand B (0.151), which is favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B's substantially stronger binding affinity (-8.2 kcal/mol vs -0 kcal/mol) is the most important factor. While Ligand A has better metabolic stability (lower Cl_mic) and slightly better solubility, the large difference in binding affinity is likely to be decisive. The logP of Ligand A is a concern, but the potency advantage of Ligand B is substantial.

Output:
1
2025-04-17 16:07:20,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.771 Da) is slightly higher than Ligand B (343.391 Da), but both are acceptable.

**TPSA:** Ligand A (83.48) is well below the 140 threshold for oral absorption. Ligand B (112.82) is also below, but closer to the limit.

**logP:** Ligand A (3.265) is optimal. Ligand B (0.776) is a bit low, potentially hindering permeability.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 4 HBA, both within acceptable limits. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.704, B: 0.851), indicating good drug-like properties.

**DILI:** Ligand A (83.133) has a higher DILI risk than Ligand B (67.817), which is a concern.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (51.532) has a slightly better BBB score than Ligand A (36.371).

**Caco-2 Permeability:** Ligand A (-4.781) shows poor permeability. Ligand B (-5.654) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.096) has poor solubility. Ligand B (-3.23) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.279) has a slightly higher hERG risk than Ligand B (0.061), which is preferable.

**Microsomal Clearance:** Ligand A (39.065) has a higher clearance, indicating lower metabolic stability, compared to Ligand B (0.254). This is a significant drawback for A.

**In vitro Half-Life:** Ligand A (56.736) has a reasonable half-life. Ligand B (10.68) has a very short half-life, which is a major concern.

**P-gp Efflux:** Ligand A (0.095) shows low P-gp efflux, which is good. Ligand B (0.028) is even lower, which is excellent.

**Binding Affinity:** Ligand A (-7.5) has significantly better binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from poor solubility, poor permeability, higher DILI risk, and higher metabolic clearance. Ligand B has better solubility, permeability, lower DILI, and lower clearance, but its binding affinity is essentially non-existent.

The difference in binding affinity (-7.5 vs 0.0 kcal/mol) is so large that it likely outweighs the ADME drawbacks of Ligand A, *provided* the solubility and permeability issues can be addressed through formulation or further structural modifications. The metabolic instability is also a concern, but can potentially be mitigated. Ligand B, with no binding affinity, is not a viable candidate regardless of its ADME properties.

Output:
1
2025-04-17 16:07:20,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.28 Da) is slightly higher than Ligand B (350.547 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 60, well below the 140 threshold for oral absorption.

**logP:** Both ligands have logP values between 3 and 4, which is good. Ligand A (3.335) is slightly lower than Ligand B (4.205), which might be a minor advantage for solubility.

**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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.656, Ligand B: 0.58), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 72.043, which is moderately high. Ligand B has a significantly lower DILI risk of 31.097, which is a major advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 73.594, Ligand B: 70.143), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.728 and -4.66), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.656 and -5.171). This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.755, Ligand B: 0.359). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (107.195) than Ligand B (82.642). Lower clearance is preferred for metabolic stability, so Ligand B is better.

**In vitro Half-Life:** Ligand A has a longer half-life (37.57 hours) than Ligand B (10.479 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.775, Ligand B: 0.323). Ligand B is slightly better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.4 kcal/mol, Ligand B: -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is the better candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better hERG and P-gp profiles. The longer half-life of Ligand A is attractive, but the higher DILI risk is a serious concern. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial.

Output:
1
2025-04-17 16:07:20,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.403 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95) is better than Ligand B (101.74), both are acceptable but closer to the upper limit for good absorption.

**logP:** Ligand B (1.292) is better than Ligand A (0.499). A logP between 1-3 is optimal, and Ligand A is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but 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:** Ligand A (0.823) has a slightly better QED score than Ligand B (0.743), indicating better overall drug-likeness.

**DILI:** Ligand B (48.391) has a significantly lower DILI risk than Ligand A (61.962). This is a crucial advantage, as lower DILI is highly desirable.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 60.295, Ligand B: 67.507), and this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.25) has slightly better Caco-2 permeability than Ligand B (-4.523), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.503 and -1.689 respectively). This is a concern, but can be addressed through formulation strategies.

**hERG Inhibition:** Ligand A (0.228) has a slightly lower hERG inhibition risk than Ligand B (0.119), which is preferable.

**Microsomal Clearance:** Ligand A (-10.071) has significantly lower microsomal clearance than Ligand B (54.381). This indicates much better metabolic stability for Ligand A, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-1.578) has a slightly better in vitro half-life than Ligand B (-4.142).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.062 respectively), which is good.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.6 and -8.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other significant differences.

**Conclusion:**

While Ligand A has slightly better Caco-2 permeability and QED, Ligand B demonstrates a significantly lower DILI risk and improved metabolic stability (lower Cl_mic, better half-life). Given the enzyme-specific priorities, metabolic stability and safety (DILI) are paramount. The slightly lower affinity of Ligand B is not a major concern given the already strong binding. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:07:20,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.491 and 331.339 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.09) is excellent, well below the 140 threshold for oral absorption. Ligand B (100.55) is still acceptable, but less optimal.

**logP:** Ligand A (0.795) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.413) is even lower, raising more concerns about permeability.

**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 above 0.5 (0.796 and 0.698), indicating good drug-like properties.

**DILI:** Ligand A (6.786) has a very low DILI risk, which is excellent. Ligand B (84.917) has a significantly higher DILI risk, which is a major concern.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (57.193) has better BBB penetration than Ligand B (41.838).

**Caco-2 Permeability:** Ligand A (-4.795) and Ligand B (-5.199) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so the absolute values are hard to interpret.

**Aqueous Solubility:** Ligand A (-0.633) and Ligand B (-2.748) both have negative values, indicating poor solubility. Ligand B is significantly worse.

**hERG Inhibition:** Ligand A (0.386) has a very low hERG risk, which is excellent. Ligand B (0.049) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (-2.625) has a negative clearance, indicating high metabolic stability. Ligand B (-14.457) has a much higher (more positive) clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (11.17) has a reasonable half-life. Ligand B (-19.698) has a negative half-life, which is not physically possible and indicates a serious issue with the data or the compound.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.019).

**Binding Affinity:** Both ligands have similar and good binding affinities (-8.1 and -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering all factors, **Ligand A is the much more promising candidate**. It has a significantly lower DILI risk, better metabolic stability (negative clearance), a better TPSA, and a more reasonable half-life. While both have permeability and solubility concerns, Ligand B's extremely high DILI risk and negative half-life are deal-breakers. The slightly lower logP of Ligand A is a minor concern compared to the severe liabilities of Ligand B.

Output:
0
2025-04-17 16:07:20,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.559 Da and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (100.55). TPSA < 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands have similar logP values (2.11 and 2.134), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA generally improves permeability.

**QED:** Both ligands have similar QED values (0.714 and 0.7), indicating good drug-like properties.

**DILI:** Ligand A (19.193) has a much lower DILI risk than Ligand B (50.989). This is a significant advantage for Ligand A.

**BBB:** Both have similar BBB penetration (68.282 and 64.482), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.478) is slightly better than Ligand B (-4.7), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.792) is better than Ligand B (-2.843), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.429) has a lower hERG risk than Ligand B (0.199). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (33.818) has higher clearance than Ligand B (28.103), indicating lower metabolic stability. This is a slight advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-13.169) has a longer half-life than Ligand A (8.055), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux than Ligand B (0.015), which is a slight advantage.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a 1.5 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has advantages in most ADME properties (TPSA, HBD, HBA, DILI, solubility, hERG, P-gp efflux) and Caco-2 permeability. However, Ligand B has a significantly better binding affinity and a longer half-life, which are crucial for an enzyme inhibitor. The difference in binding affinity is substantial enough to compensate for the slightly worse ADME profile of Ligand B. While the higher DILI risk of Ligand B is a concern, it's not prohibitive given the strong binding.

Output:
1
2025-04-17 16:07:20,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.69) is slightly higher than Ligand B (83.56), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.362) is a bit low, potentially hindering permeation. Ligand B (1.846) 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 within acceptable limits.

**QED:** Both ligands have good QED scores (0.756 and 0.833), indicating drug-like properties.

**DILI:** Ligand A (37.611) has a much lower DILI risk than Ligand B (65.917). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (25.746) has a low BBB penetration, while Ligand B (57.425) is higher. Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.227 and -4.964), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Ligand A (-0.944) and Ligand B (-2.839) both have negative solubility values, indicating poor solubility. Ligand B is worse.

**hERG:** Ligand A (0.084) has a very low hERG risk, while Ligand B (0.44) is slightly higher. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-9.341) has a much lower (better) microsomal clearance than Ligand B (35.095), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (22.038 hours) has a significantly longer half-life than Ligand B (10.618 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.013 and 0.225).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While both are good, the 1.7 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A excels in key areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG risk, and superior binding affinity. While Ligand B has a better logP, the other advantages of Ligand A are more crucial for overall drug development success. The solubility and permeability issues are present in both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 16:07:20,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.86 & 361.56 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.02) is slightly higher than Ligand B (46.84), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.06 & 3.69), 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:** Both have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.59 & 0.72), indicating good drug-like properties.

**DILI:** Ligand A (56.34) has a higher DILI risk than Ligand B (37.61). This is a significant advantage for Ligand B.

**BBB:** Both have acceptable BBB penetration, but Ligand B (87.01) is significantly better than Ligand A (60.76). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.673) is slightly worse than Ligand B (-5.123).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-3.341) is slightly better than Ligand B (-3.556).

**hERG:** Both have low hERG risk (0.588 & 0.704), which is good.

**Microsomal Clearance:** Ligand B (37.651) has significantly lower microsomal clearance than Ligand A (77.605), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (29.32) has a longer in vitro half-life than Ligand A (-26.468), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.521 & 0.57), which is good.

**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 outweighs most minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. Its significantly better binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) are key advantages. While both have poor solubility and permeability, the strong binding affinity of Ligand B suggests it might still be effective *in vivo*, and solubility/permeability could be addressed through formulation strategies.

Output:
1
2025-04-17 16:07:20,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.385 and 367.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is higher than Ligand B (55.84). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (1.055) is slightly lower than the optimal range (1-3), potentially impacting permeability. Ligand B (2.416) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are acceptable, though Ligand B's lower HBD count might slightly favor permeability.

**QED:** Ligand B (0.747) has a better QED score than Ligand A (0.494), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 30.903, Ligand B: 37.456), both below the 40 threshold.

**BBB:** Both ligands have good BBB penetration (Ligand A: 73.633, Ligand B: 71.888), although this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the compounds themselves. This is a flag for further investigation, but we'll proceed with relative comparison.

**Aqueous Solubility:** Both ligands have negative solubility values. Again, this is a red flag.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.315, Ligand B: 0.257), which is positive.

**Microsomal Clearance:** Ligand A (54.197) has significantly lower microsomal clearance than Ligand B (65.998), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-47.491) has a much longer in vitro half-life than Ligand B (4.581), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.028, Ligand B: 0.344).

**Binding Affinity:** Ligand B (-8.5 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.

**Conclusion:**

Despite the concerning negative values for Caco-2 and solubility, the stronger binding affinity of Ligand B (-8.5 kcal/mol vs -7.3 kcal/mol) is a decisive factor. This difference in potency outweighs the slightly better metabolic stability and half-life of Ligand A. The better QED score of Ligand B also contributes to its favorability. While both have acceptable ADME properties, the potency advantage of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 16:07:20,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.311 and 367.333 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.12) is better than Ligand B (12.47) as it is closer to the 140 A^2 threshold for good oral absorption. Ligand B is extremely low and may indicate poor aqueous solubility.

**logP:** Ligand A (1.61) is optimal (1-3). Ligand B (4.426) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 7 HBA) is better balanced than Ligand B (0 HBD, 2 HBA).

**QED:** Ligand A (0.808) has a significantly better QED score than Ligand B (0.545), indicating a more drug-like profile.

**DILI:** Ligand B (25.553) has a much lower DILI risk than Ligand A (96.782), a significant advantage.

**BBB:** Both ligands have high BBB penetration (Ligand A: 57.968, Ligand B: 97.014). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-5.122) and Ligand B (-4.68) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.312) and Ligand B (-4.924) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.02) has a very low hERG risk, a major advantage. Ligand B (0.977) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-10.18) exhibits much better metabolic stability (lower clearance) than Ligand B (21.43).

**In vitro Half-Life:** Ligand A (-4.101) has a longer in vitro half-life than Ligand B (37.558), which is desirable.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, a positive attribute. Ligand B (0.752) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.2 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.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most critical factor for an enzyme inhibitor. While it has some ADME liabilities (higher logP, moderate P-gp efflux, and moderate hERG risk), the strong binding affinity could compensate for these issues. Ligand A has better ADME properties overall (better QED, lower DILI, lower hERG, better metabolic stability), but its significantly weaker binding affinity makes it less likely to be effective.

Output:
1
2025-04-17 16:07:20,531 - INFO - Batch 437 complete. Total preferences: 6992
2025-04-17 16:07:20,531 - INFO - Processing batch 438/512...
2025-04-17 16:08:01,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (408.34 and 385.961 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (58.22 and 61.44) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands (4.125 and 3.311) are slightly above the optimal 1-3 range, but still acceptable. Ligand B is preferable here.

**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 (4) are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.777 and 0.788) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (26.018) has a significantly lower DILI risk than Ligand B (47.926), which is a major advantage. Both are below the 60 threshold, but A is much better.

**8. BBB:** Both ligands have similar BBB penetration (74.292 and 73.168). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.973 and -5.018), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.04 and -3.957), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.894 and 0.713), which is good.

**12. Microsomal Clearance:** Ligand A (67.49) has a higher microsomal clearance than Ligand B (14.293), indicating lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand A (-5.127) has a negative half-life, which is not possible and likely indicates a very short half-life. Ligand B (2.801) has a short but positive half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.373 and 0.093).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -9.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both compounds have issues with solubility and permeability, Ligand A is preferable due to its significantly lower DILI risk and better (though still problematic) metabolic stability. The negative half-life for Ligand A is a major concern, but the DILI risk for Ligand B is higher. Given the enzyme-specific priorities, minimizing toxicity (DILI) is crucial.

Output:
0
2025-04-17 16:08:01,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.304 and 376.806 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.27) is slightly above the preferred <140, but acceptable. Ligand B (50.27) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.815) is a bit low, potentially hindering permeation. Ligand B (3.839) is near the upper end of the optimal 1-3 range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, fitting well within the guidelines. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Both ligands have similar QED values (0.753 and 0.709), indicating good drug-likeness.

**DILI:** Ligand A (67.468) has a higher DILI risk than Ligand B (37.456), which is a significant concern.

**BBB:** Ligand A (59.442) has moderate BBB penetration, while Ligand B (95.502) has very high BBB penetration. While SRC is not a CNS target, higher BBB penetration generally correlates with better oral bioavailability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.792 and -4.317). This is unusual and suggests a potential issue with the experimental setup or the compounds themselves. It's difficult to interpret without more information.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.5 and -3.78). This is also concerning and suggests poor solubility, which could limit bioavailability.

**hERG:** Both ligands have low hERG risk (0.234 and 0.263).

**Microsomal Clearance:** Ligand A (-4.335) has significantly lower (better) microsomal clearance than Ligand B (51.453), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.038) has a negative half-life, which is not physically possible. This is a data error. Ligand B (-4.939) also has a negative half-life, indicating a data error.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.03 and 0.222).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the questionable Caco-2 and half-life data, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.5 vs -7.5 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has a much lower DILI risk and higher BBB penetration. While its microsomal clearance is higher than Ligand A's, the potency difference is likely to be more critical. The solubility issues of both compounds would need to be addressed through formulation strategies.

Output:
1
2025-04-17 16:08:01,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.5 & 368.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (99.15).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal range.

**logP:** Ligand A (1.544) is optimal, while Ligand B (0.324) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 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 QED scores (0.76 and 0.723), indicating good drug-likeness.

**DILI:** Ligand B (42.85) has a lower DILI risk than Ligand A (17.76), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (69.64% and 77.94%), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, given that we're comparing them, we can look at the relative values. Ligand A (-4.955) is slightly better than Ligand B (-5.095).

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue. Ligand A (-1.921) is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.225 and 0.244), which is excellent.

**Microsomal Clearance:** Ligand B (-6.951) has *much* lower microsomal clearance than Ligand A (47.814). This indicates significantly better metabolic stability for Ligand B, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (2.442 hours) has a lower half-life than Ligand A (9.835 hours). While a longer half-life is generally preferred, the substantial difference in clearance is a more significant factor.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.014).

**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 Ligand A has slightly better TPSA and solubility, Ligand B's dramatically improved metabolic stability (lower Cl_mic, though a lower in vitro half-life) and slightly better binding affinity outweigh these minor drawbacks. The lower DILI risk for Ligand B is also a significant positive. The slightly lower logP of Ligand B is a minor concern, but the improved metabolic stability is a more critical factor for an enzyme target.



Output:
1
2025-04-17 16:08:01,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.403 Da) is slightly higher than Ligand B (350.459 Da), but both are acceptable.

**TPSA:** Ligand A (122.75) is borderline for good oral absorption (<=140), while Ligand B (75.71) is well within the acceptable range.

**logP:** Ligand A (-0.904) is a bit low, potentially hindering permeation. Ligand B (1.729) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 8 HBA) is acceptable. Ligand B (1 HBD, 4 HBA) is also good, with fewer hydrogen bonding groups generally favoring permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.689, B: 0.74).

**DILI:** Ligand A (83.133) has a significantly higher DILI risk than Ligand B (36.332), which is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (53.238) has a slightly higher BBB score than Ligand A (43.117).

**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 (-2.103 and -2.105 respectively). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.054) has a slightly lower hERG risk than Ligand B (0.161), which is preferable.

**Microsomal Clearance:** Ligand A (-12.514) has a much lower (better) microsomal clearance than Ligand B (30.234), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.972 hours) has a better in vitro half-life than Ligand B (-14.776 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.016 and 0.172 respectively).

**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 of the ADME concerns.

**Overall Assessment:**

Ligand A's primary advantage is its significantly stronger binding affinity. However, it suffers from a high DILI risk and poor solubility. Ligand B has better solubility, lower DILI, and a more favorable logP, but its binding affinity is considerably weaker.

Given the enzyme-specific priorities, potency is paramount. The 1.5 kcal/mol difference in binding affinity is substantial. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications during lead optimization. The solubility issue is also addressable. The better metabolic stability (lower Cl_mic and longer half-life) of Ligand A further supports its selection.

Output:
1
2025-04-17 16:08:01,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.36 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is better than Ligand B (75.71). TPSA < 140 is good for oral absorption, both are within this range, but lower is preferable.

**logP:** Ligand A (3.203) is optimal (1-3), while Ligand B (1.573) is on the lower side, potentially impacting permeability.

**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 (<=10).

**QED:** Ligand A (0.869) is significantly better than Ligand B (0.601), indicating a more drug-like profile.

**DILI:** Ligand A (15.781) is much better than Ligand B (28.228), suggesting a lower risk of drug-induced liver injury. This is a critical factor.

**BBB:** Both ligands have high BBB penetration (A: 89.957, B: 84.451), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values (-4.333 and -4.638), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative values (-3.277 and -2.686), indicating poor aqueous solubility. This is a significant drawback for both, but could be mitigated with formulation strategies.

**hERG:** Ligand A (0.674) is better than Ligand B (0.306), indicating a lower risk of hERG inhibition and cardiotoxicity.

**Microsomal Clearance:** Ligand A (9.831) has significantly lower clearance than Ligand B (45.813), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-26.035) has a much longer half-life than Ligand B (-4.182), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.074), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage, and can potentially overcome some of the ADME liabilities.

**Conclusion:**

Ligand A is clearly the superior 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, better QED, stronger binding affinity, and lower hERG risk. The substantial difference in binding affinity (-10.2 vs -8.0 kcal/mol) is a major factor, and the improved ADME properties further solidify its potential.

Output:
1
2025-04-17 16:08:01,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (351.535 Da and 383.254 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (47.09) is well within the acceptable range.

**3. logP:** Ligand A (2.842) is optimal (1-3). Ligand B (4.539) is a bit high, potentially leading to solubility issues and off-target effects, 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 (3) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.707 and 0.601), indicating good drug-like properties.

**7. DILI:** Ligand A (9.151) has a very low DILI risk, excellent. Ligand B (47.421) is higher, but still within an acceptable range (<60 is good).

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand B (70.57) is better than Ligand A (61.38). This isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.881) has poor Caco-2 permeability, which is a significant concern. Ligand B (-5.01) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-1.833) has poor aqueous solubility, which is a concern. Ligand B (-3.844) has even worse aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.521) has a low hERG risk, which is excellent. Ligand B (0.919) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (24.815) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (70.495) has significantly higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (17.211) has a longer half-life than Ligand B (9.672), which is desirable.

**14. P-gp Efflux:** Ligand A (0.118) has low P-gp efflux, which is good. Ligand B (0.751) has higher P-gp efflux.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a >2.8 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B's significantly superior binding affinity (-9.1 vs -6.3 kcal/mol) is the most important factor. While it has some ADME liabilities (higher logP, higher DILI, higher Cl_mic, lower t1/2, higher Pgp efflux, and worse solubility/permeability), the potency advantage is likely to be crucial for efficacy. The lower metabolic stability and solubility could be addressed through further optimization. Ligand A's better ADME profile is overshadowed by its weaker binding affinity.

Output:
1
2025-04-17 16:08:01,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (427.32 and 428.689 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (77.85 and 77.24) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (3.557) is within the optimal range (1-3), while Ligand B (4.793) is slightly above. This could potentially lead to solubility issues for Ligand B, but isn't a major concern yet.

**4. H-Bond Donors:** Ligand A has 0 HBD, which is good. Ligand B has 2 HBD, still acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.632 and 0.686), indicating drug-like properties.

**7. DILI:** Both ligands have high DILI risk (80.031 and 82.241), which is a significant concern. However, we're comparing two relatively risky compounds, so this isn't a deciding factor *between* them.

**8. BBB:** Both ligands have moderate BBB penetration (63.862 and 67.274). This isn't a primary concern for an oncology target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.711 and -4.582). This is unusual and concerning, suggesting poor permeability.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-3.82 and -5.945). This is a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.463 and 0.438), which is positive.

**12. Microsomal Clearance:** Ligand A (58.566) has higher microsomal clearance than Ligand B (52.213), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (49.952) has a longer in vitro half-life than Ligand A (28.803), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.355 and 0.397), which is good.

**15. 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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A's substantially superior binding affinity (-7.6 kcal/mol vs -0.0 kcal/mol) is a critical factor for an enzyme target like SRC. The difference in affinity is large enough to potentially overcome the ADME liabilities, assuming formulation strategies can be developed to address the solubility issue. Ligand B has better metabolic stability and half-life, but the binding affinity is simply too weak to be competitive.

Output:
0
2025-04-17 16:08:01,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.82 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (97.78). A TPSA under 140 is good for oral absorption, and A is much closer to the lower end, suggesting better absorption.

**logP:** Both ligands have good logP values (3.811 and 2.533), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is preferable to Ligand B (HBD=3, HBA=3) as lower counts generally improve permeability.

**QED:** Both ligands have acceptable QED scores (0.867 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (73.517) has a higher DILI risk than Ligand B (59.636), but both are reasonably acceptable.

**BBB:** Ligand A (69.523) has a better BBB penetration score than Ligand B (32.803), although BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.535) shows better Caco-2 permeability than Ligand B (-5.283).

**Aqueous Solubility:** Ligand A (-5.223) shows better aqueous solubility than Ligand B (-4.446). Solubility is important for bioavailability.

**hERG:** Both ligands have similar hERG inhibition liability (0.726 and 0.713), suggesting similar cardiac risk profiles.

**Microsomal Clearance:** Ligand A (50.153) has significantly better metabolic stability (lower clearance) than Ligand B (14.455). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (71.931) has a much longer in vitro half-life than Ligand B (33.369), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.17 and 0.163).

**Binding Affinity:** Ligand B (-8.8 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 of Ligand B. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand A has superior ADME properties (TPSA, solubility, permeability, metabolic stability, half-life), Ligand B exhibits a substantially stronger binding affinity. For an enzyme target like SRC kinase, potency is paramount. The 2.1 kcal/mol difference in binding affinity is a significant advantage that likely compensates for the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 16:08:01,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzyme targets: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.389 Da) is slightly better positioned.

**TPSA:** Ligand A (29.54) is excellent, well below the 140 threshold for good absorption. Ligand B (111.89) is higher, but still acceptable.

**logP:** Ligand A (4.905) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.431) is very low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is optimal. Ligand B (1 HBD, 10 HBA) has a higher number of HBA, which could affect permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.791, B: 0.65), indicating reasonable drug-likeness.

**DILI:** Ligand A (50.33) has a lower DILI risk than Ligand B (77.627), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (93.563) has a much higher BBB percentile than Ligand B (58.085).

**Caco-2 Permeability:** Ligand A (-4.361) is better than Ligand B (-5.655), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.887) is better than Ligand B (-1.797), indicating better solubility.

**hERG Inhibition:** Ligand A (0.902) has a lower hERG risk than Ligand B (0.092), which is a critical safety consideration.

**Microsomal Clearance:** Ligand A (31.012) has a higher microsomal clearance than Ligand B (6.12), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-10.158) has a shorter half-life than Ligand B (5.734), which is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.704) has a lower P-gp efflux liability than Ligand B (0.157), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 kcal/mol and -8.6 kcal/mol, respectively). The difference is negligible.

**Overall Assessment:**

Ligand A has several advantages: better solubility, lower DILI risk, lower hERG risk, better Caco-2 permeability, and lower P-gp efflux. However, it suffers from higher microsomal clearance and shorter half-life. Ligand B has better metabolic stability and half-life but struggles with low logP, higher HBA count, and higher DILI and hERG risks.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the lower DILI and hERG risks of Ligand A are particularly important. While its metabolic stability is a concern, this can potentially be addressed through structural modifications during lead optimization. The poor logP of Ligand B is a more difficult property to improve without significantly altering the binding affinity.

Output:
0
2025-04-17 16:08:01,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.173 and 367.555 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.7) is well within the acceptable range for oral absorption (<140), while Ligand B (38.77) is even better.

**logP:** Both ligands have a logP around 4.7, which is slightly high. This could potentially lead to solubility issues or off-target effects, but is not a dealbreaker if other properties are favorable.

**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 QED values above 0.5 (0.573 and 0.599), indicating good drug-like properties.

**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 (22.024 percentile), which is excellent.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand B (89.957) has a higher BBB penetration than Ligand A (53.974).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.751 and -4.924). This is unusual and suggests poor permeability, but the scale is not specified and negative values may be an artifact of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-6.525 and -4.0). This is also concerning, and aligns with the slightly high logP values.

**hERG Inhibition:** Ligand A (0.401) has a slightly higher hERG inhibition risk than Ligand B (0.821), but both are relatively low.

**Microsomal Clearance:** Ligand B (104.662) has a significantly higher microsomal clearance than Ligand A (25.237). This suggests that Ligand A is more metabolically stable, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand A (102.667) has a longer in vitro half-life than Ligand B (35.305), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux than Ligand B (0.888), which is favorable for oral bioavailability.

**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 (1.6 kcal/mol difference) and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the slightly high logP and negative solubility/permeability predictions for both compounds, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.4 vs -6.8 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. The biggest drawback for Ligand A is the very high DILI risk, but this could potentially be mitigated through structural modifications. Ligand B's lower DILI is attractive, but the weaker binding affinity and poorer metabolic stability are significant disadvantages.

Output:
0
2025-04-17 16:08:01,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.519 and 347.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (43.86) is better than Ligand B (52.65), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**3. logP:** Both ligands (2.378 and 2.49) are 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:** Both ligands have 3 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.716 and 0.72), indicating good drug-likeness.

**7. DILI:** Ligand A (6.747) has a significantly lower DILI risk than Ligand B (13.339). This is a major advantage.

**8. BBB:** Ligand A (81.931) has a higher BBB penetration percentile than Ligand B (77.007). While not critical for a non-CNS target like SRC, it's a slight positive.

**9. Caco-2 Permeability:** Ligand A (-4.581) is slightly better than Ligand B (-4.725), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.745) is slightly better than Ligand B (-2.015).

**11. hERG Inhibition:** Ligand A (0.541) has a lower hERG inhibition liability than Ligand B (0.235). This is a significant advantage, reducing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (23.907) has a lower microsomal clearance than Ligand B (33.488), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.92) has a slightly longer in vitro half-life than Ligand B (-5.377).

**14. P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux liability than Ligand B (0.043).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 1.8 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 risk, hERG inhibition, metabolic stability (Cl_mic), and binding affinity. While both ligands are within acceptable ranges for many properties, the combination of a stronger binding affinity, lower toxicity liabilities (DILI, hERG), and better metabolic stability makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 16:08:01,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.26 Da) is slightly higher than Ligand B (336.395 Da), but both are acceptable.

**TPSA:** Ligand A (59) is well below the 140 threshold for oral absorption. Ligand B (80.05) is also below, but closer to the limit.

**logP:** Both ligands have good logP values (A: 3.053, B: 3.34), 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 numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.836, B: 0.723), indicating good drug-like properties.

**DILI:** Ligand A (55.293) and Ligand B (64.521) both have acceptable DILI risk, below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (66.305) is slightly better 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 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 undefined.

**hERG Inhibition:** Ligand A (0.773) has a lower hERG risk than Ligand B (0.425), which is preferable.

**Microsomal Clearance:** Ligand A (81.022) has a higher microsomal clearance than Ligand B (34.23). This suggests Ligand B is more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (40.65) and Ligand B (43.995) have comparable in vitro half-lives.

**P-gp Efflux:** Ligand A (0.702) has lower P-gp efflux than Ligand B (0.042), which is better for bioavailability.

**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) and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability (lower Cl_mic) and P-gp efflux, the significantly stronger binding affinity of Ligand A (-8.9 vs -6.8 kcal/mol) is the deciding factor. The potency advantage is large enough to compensate for the slightly higher clearance and potentially lower solubility. The hERG risk is also lower for Ligand A.

Output:
1
2025-04-17 16:08:01,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (350.434 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.27) is slightly higher than Ligand B (69.64), but both are well below the 140 threshold for good absorption.

**3. logP:** Both ligands have excellent logP values (3.363 and 3.267) falling 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 scores (0.741 and 0.71), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 55.176, while Ligand B has a significantly lower risk of 18.922. This is a major advantage for Ligand B.

**8. BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.735) has a slightly higher BBB percentile than Ligand B (54.595).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.528 and -4.535), which 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:** Ligand B (-2.859) has better (less negative) aqueous solubility than Ligand A (-4.489). This is a positive for Ligand B.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.548 and 0.632), indicating moderate risk.

**12. Microsomal Clearance:** Ligand A (63.636) has lower microsomal clearance than Ligand B (66.196), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (31.138 hours) has a significantly longer in vitro half-life than Ligand A (11.366 hours). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.259 and 0.211).

**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 (1.5 kcal/mol), it's enough to consider alongside other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a substantially lower DILI risk, better aqueous solubility, and a significantly longer half-life. While Ligand A has slightly better metabolic stability and BBB penetration, the advantages of Ligand B in terms of safety (DILI) and pharmacokinetics (half-life) outweigh these minor differences. The slightly better binding affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 16:08:01,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, suggesting good absorption. Ligand B (104.9) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (2.513) is optimal (1-3). Ligand B (0.571) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 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 (0.651 and 0.776), indicating drug-likeness.

**DILI:** Ligand A (12.641) has a significantly lower DILI risk than Ligand B (38.62). This is a major advantage for A.

**BBB:** Both have similar BBB penetration (64.831 and 62.699), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.647) and Ligand B (-5.018) have negative values, which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Ligand A (-2.842) and Ligand B (-1.979) have negative values, indicating poor solubility. This is a concern for both, but B is slightly better.

**hERG:** Both ligands have low hERG risk (0.393 and 0.152).

**Microsomal Clearance:** Ligand A (71.872) has higher microsomal clearance than Ligand B (-3.731). This suggests Ligand B is more metabolically stable, a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (5.92) has a longer half-life than Ligand A (3.398), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.267 and 0.095).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility. However, Ligand A has a significantly lower DILI risk and a more favorable logP. Given the enzyme-specific priorities, metabolic stability is crucial. While the DILI risk for A is low, the improved metabolic profile of B is more important for a kinase inhibitor, as it suggests a longer duration of action and potentially reduced dosing frequency. The slight solubility difference can be addressed with formulation strategies.

Output:
1
2025-04-17 16:08:01,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 372.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (119.39). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target. Ligand B is approaching the upper limit for good oral absorption.

**logP:** Ligand A (0.491) is slightly better than Ligand B (-0.833) as it is closer to the optimal range of 1-3. Ligand B is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 7 HBA). Lower numbers are generally better for permeability.

**QED:** Ligand B (0.644) has a better QED score than Ligand A (0.371), indicating a more drug-like profile.

**DILI:** Ligand A (6.863) has a much lower DILI risk than Ligand B (62.233). This is a significant advantage for Ligand A.

**BBB:** Ligand A (72.858) has a better BBB penetration score than Ligand B (48.895), although this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.931) is significantly better than Ligand B (-5.342). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.079) is better than Ligand B (-1.765).

**hERG Inhibition:** Ligand A (0.412) has a lower hERG inhibition liability than Ligand B (0.117), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (13.328) has a higher (worse) microsomal clearance than Ligand B (6.787). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (45.599) has a significantly longer in vitro half-life than Ligand A (-34.013). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.017) has a lower P-gp efflux liability than Ligand B (0.014).

**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, but not overwhelming.

**Overall Assessment:**

Ligand A excels in ADME properties (TPSA, logP, solubility, DILI, hERG, Caco-2) and has acceptable binding affinity. However, its metabolic stability (high Cl_mic, short t1/2) is a concern. Ligand B has a better QED, longer half-life, and slightly better affinity, but suffers from higher DILI risk, lower solubility, and poorer TPSA.

Given the enzyme-specific priorities, metabolic stability and potency are key. While Ligand B has a slightly better affinity and significantly better half-life, the substantially higher DILI risk and poorer ADME profile of Ligand B are concerning. The improved ADME profile of Ligand A, particularly the lower DILI risk and better solubility, outweigh the slightly lower affinity. Further optimization of Ligand A to improve its metabolic stability would be a logical next step.

Output:
0
2025-04-17 16:08:01,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 356.413 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (128.34) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (58.64) is excellent, well below 140.

**logP:** Ligand A (0.185) is quite low, potentially hindering permeability. Ligand B (1.815) 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 acceptable.

**QED:** Both ligands have good QED scores (0.518 and 0.533), indicating drug-like properties.

**DILI:** Ligand A (46.84) has a moderate DILI risk, but is still acceptable. Ligand B (25.553) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (71.772) shows moderate BBB penetration. Ligand B (89.376) is better, but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.665) has poor Caco-2 permeability, which is a major concern. Ligand B (-4.414) is better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.787 and -2.237). This is a significant drawback for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.122) has very low hERG risk, a strong positive. Ligand B (0.571) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (25.246) and Ligand B (26.547) have similar, moderate microsomal clearance values.

**In vitro Half-Life:** Ligand A (21.805) has a reasonable half-life. Ligand B (-21.711) has a *negative* half-life, which is impossible and indicates a data error or a very rapidly metabolized compound. This is a critical flaw.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.032 and 0.123), which is favorable.

**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 ADME concerns.

**Conclusion:**

Despite Ligand B's negative in vitro half-life, the significantly superior binding affinity (-7.5 vs 0.0 kcal/mol) is a decisive factor. The negative half-life is likely a data error, and even if it isn't, the potency advantage is so large that it could potentially be overcome with structural modifications to improve metabolic stability. Ligand A's poor Caco-2 permeability and low logP are also significant drawbacks. Ligand B also has a much lower DILI risk.

Output:
1
2025-04-17 16:08:01,491 - INFO - Batch 438 complete. Total preferences: 7008
2025-04-17 16:08:01,492 - INFO - Processing batch 439/512...
2025-04-17 16:08:51,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.483 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, suggesting good absorption. Ligand B (113.44) is still within acceptable limits but higher, potentially impacting absorption less favorably.

**logP:** Ligand A (3.836) is optimal. Ligand B (0.115) is quite low, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is acceptable but less ideal.

**QED:** Both ligands have reasonable QED scores (0.837 and 0.671), indicating good drug-like properties.

**DILI:** Ligand A (39.201) has a low DILI risk. Ligand B (49.011) is slightly higher, but still within an acceptable range.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (94.494) has a much higher BBB percentile than Ligand B (43.66).

**Caco-2 Permeability:** Ligand A (-4.452) has poor Caco-2 permeability, which is a concern. Ligand B (-5.249) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.938) has poor aqueous solubility. Ligand B (-1.391) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.558) has a very low hERG risk. Ligand B (0.158) is also very low.

**Microsomal Clearance:** Ligand A (65.327) has moderate clearance. Ligand B (-4.236) has *negative* clearance, which is impossible and likely an error in the data, but suggests extremely high metabolic stability.

**In vitro Half-Life:** Ligand A (6.991 hours) is reasonable. Ligand B (26.75 hours) is excellent.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.572 and 0.016), which is favorable.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 2.1 kcal/mol is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A's better logP and lower DILI, Ligand B is the stronger candidate. The significantly improved binding affinity (-9.8 vs -7.7 kcal/mol) is a major advantage for an enzyme inhibitor. The excellent in vitro half-life and low P-gp efflux also contribute positively. While Ligand B's logP is low and Caco-2 permeability is poor, the strong binding affinity suggests it may still be effective *in vivo*, and formulation strategies could potentially address the solubility and permeability issues. The negative microsomal clearance is a data error, but even if it were a low positive value, it would still be preferable to Ligand A.

Output:
1
2025-04-17 16:08:51,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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. Ligand B (373.503 Da) is also acceptable.

**TPSA:** Ligand A (111.21) is better than Ligand B (62.3). Lower TPSA generally indicates better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand B (2.652) is optimal (1-3), while Ligand A (0.052) is quite low. A low logP can hinder membrane permeability and potentially reduce binding affinity.

**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:** Both ligands have similar QED scores (0.728 and 0.647), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (64.87 and 66.576), which is a concern but not immediately disqualifying. Further investigation would be needed.

**BBB:** Ligand B (57.852) has a higher BBB percentile than Ligand A (16.247). However, BBB penetration isn't a primary concern for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.738 and -5.429), which is unusual and suggests poor permeability. This is a significant drawback.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.909 and -2.171), indicating very poor solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Ligand A (0.118) has a lower hERG risk than Ligand B (0.32), which is preferable.

**Microsomal Clearance:** Ligand A (-31.609) has a much lower (better) microsomal clearance than Ligand B (60.94). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-20.561) has a negative half-life, which is not possible. This is a data error. Ligand B (-0.053) is also negative, indicating a data error.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, while Ligand B (0.343) has a slightly higher, but still relatively low, efflux.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly better binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand B is the more promising candidate due to its significantly higher binding affinity (-7.9 kcal/mol vs 0.0 kcal/mol). The better logP and lower P-gp efflux also contribute to its favorability. The metabolic stability is worse for Ligand B, but the large difference in binding affinity is likely to outweigh this drawback. The negative half-life values are concerning and indicate a data quality issue.

Output:
1
2025-04-17 16:08:51,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.367 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.83 and 98.74) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (target <90). This isn't a primary concern for a non-CNS target like SRC.

**logP:** Ligand A (1.872) is within the optimal 1-3 range. Ligand B (0.171) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3) and HBA (5/4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.53 and 0.615), indicating drug-like properties.

**DILI:** Ligand A (82.241) has a higher DILI risk than Ligand B (19.891). This is a significant negative for Ligand A.

**BBB:** Both are low, which is fine for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-5.653) has poor Caco-2 permeability, while Ligand B (-5.242) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.93 and -1.85). This is a concern for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.607) has a slightly higher hERG risk than Ligand B (0.069). This is a negative for Ligand A.

**Microsomal Clearance:** Ligand A (18.877) has significantly better metabolic stability (lower clearance) than Ligand B (0.331). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (70.631) has a much longer half-life than Ligand B (12.284). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.316 and 0.008).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.3 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a significant advantage in metabolic stability (Cl_mic and t1/2), but suffers from higher DILI risk, poorer Caco-2 permeability, and slightly higher hERG risk. Ligand B has a lower DILI risk and slightly better Caco-2 permeability, but very poor metabolic stability and a short half-life. Given the importance of metabolic stability for kinase inhibitors (to maintain therapeutic concentrations), and the relatively small difference in binding affinity, Ligand A is the more promising candidate, despite its drawbacks. The solubility issues of both compounds would need to be addressed in formulation.

Output:
0
2025-04-17 16:08:51,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (334.335 and 374.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.87) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (75.71) is excellent, well below 140.

**logP:** Both ligands have good logP values (2.151 and 1.595), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 1 HBD, also good. Both are well within the limit of 5.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have similar QED values (0.711 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (95.153 percentile), which is a significant concern. Ligand B has a very low DILI risk (8.53 percentile), a major advantage.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B has a higher BBB penetration (69.368) than Ligand A (32.765), but this is not a deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.948 and -4.806), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.377 and -1.248). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A has a low hERG risk (0.534), which is good. Ligand B also has a low hERG risk (0.484), comparable to Ligand A.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (55.958 mL/min/kg). Ligand B has a very low clearance (5.058 mL/min/kg), indicating much better metabolic stability.

**In vitro Half-Life:** Ligand A has a moderate half-life (24.679 hours). Ligand B has a negative half-life (-10.484 hours), which is not physically meaningful and likely indicates a problem with the assay or compound stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.074 and 0.011), which is favorable.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-8.3 kcal/mol) compared to Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Conclusion:**

Despite both compounds having solubility and permeability issues, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.3 vs 0.0 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, it has a much lower DILI risk (8.53 vs 95.153) and better metabolic stability (lower Cl_mic). While the negative half-life for Ligand B is concerning, the substantial binding affinity suggests it's worth further investigation to understand the reason for this result. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 16:08:51,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (100.25) is better than Ligand B (50.16) as it is closer to the 140 threshold for oral absorption.

**logP:** Ligand B (3.494) is optimal (1-3), while Ligand A (0.46) is quite low, potentially hindering membrane permeability and absorption. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6/5) counts, falling within the recommended limits.

**QED:** Both ligands have similar, good QED values (0.782 and 0.779), indicating generally drug-like properties.

**DILI:** Ligand B (38.077) has a much lower DILI risk than Ligand A (71.345). This is a crucial advantage for Ligand B.

**BBB:** Ligand B (73.788) has a better BBB penetration percentile than Ligand A (52.268), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.604) has a very poor Caco-2 permeability, while Ligand B (-5.192) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.102 and -3.933). This could pose formulation challenges, but is not a deciding factor given the other differences.

**hERG Inhibition:** Ligand A (0.197) has a slightly lower hERG inhibition liability than Ligand B (0.583), which is preferable.

**Microsomal Clearance:** Ligand B (81.418) has significantly higher microsomal clearance than Ligand A (19.18). This means Ligand A is more metabolically stable, a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (28.41) has a longer half-life than Ligand A (-14.391), which is desirable.

**P-gp Efflux:** Ligand B (0.658) has a higher P-gp efflux liability than Ligand A (0.088), meaning Ligand A is less likely to be pumped out of cells.

**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.

**Conclusion:**

Despite Ligand A's better metabolic stability and lower P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.9 vs -7.8 kcal/mol) is a major advantage for an enzyme inhibitor. Additionally, Ligand B has a much lower DILI risk. While its logP is optimal and Ligand A's is low, the binding affinity and safety profile of Ligand B are more important in this case. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:08:51,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.849 and 380.187 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (98.34) is higher, but still acceptable, though potentially impacting absorption.

**logP:** Both ligands have good logP values (4.578 and 4.062), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 7 HBA) as it has fewer potential liabilities regarding permeability and off-target interactions.

**QED:** Both ligands have similar QED scores (0.69 and 0.682), indicating good drug-likeness.

**DILI:** Ligand A (46.219) has a significantly lower DILI risk than Ligand B (95.89), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (87.553) has a better BBB score than Ligand B (37.495).

**Caco-2 Permeability:** Ligand A (-4.381) is better than Ligand B (-4.691), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.234) is better than Ligand B (-4.892), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.569) has a lower hERG risk than Ligand B (0.202), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (78.039) has a lower Cl_mic than Ligand B (90.975), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (61.679) has a significantly longer half-life than Ligand B (-27.16), which is a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.297) has lower P-gp efflux liability than Ligand B (0.135), improving bioavailability.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.5), but the difference is small (0.6 kcal/mol). Given the substantial advantages of Ligand A in other critical ADME/Tox properties, this affinity difference is unlikely to be decisive.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in almost all other crucial parameters: lower DILI risk, better solubility, lower hERG risk, better metabolic stability (lower Cl_mic and longer half-life), and lower P-gp efflux. These factors are particularly important for an enzyme target like SRC kinase, where maintaining adequate systemic exposure and minimizing toxicity are paramount.

Output:
0
2025-04-17 16:08:51,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 347.459 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (71.53), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.725 and 2.174) fall 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 (3) is lower than Ligand B (4), both are acceptable (<=10).

**QED:** Ligand B (0.695) has a significantly better QED score than Ligand A (0.277), indicating a more drug-like profile.

**DILI:** Ligand B (19.891) has a much lower DILI risk than Ligand A (26.173), which is a significant advantage.

**BBB:** Ligand B (80.419) has a higher BBB penetration score than Ligand A (57.929). While SRC isn't a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.91) has slightly better Caco-2 permeability than Ligand B (-4.367), but both are negative values indicating low permeability.

**Aqueous Solubility:** Ligand B (-1.839) has better aqueous solubility than Ligand A (-3.888), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.288) has a lower hERG inhibition liability than Ligand B (0.534), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (10.527) has a much lower microsomal clearance than Ligand B (46.076), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.24) has a slightly better in vitro half-life than Ligand B (-1.714).

**P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux than Ligand B (0.109), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.5) has a slightly stronger binding affinity than Ligand B (-7.2). However, the difference is only 0.3 kcal/mol, which may not be enough to overcome other deficiencies.

**Overall Assessment:**

Ligand B has a significantly better overall profile. Its superior QED, DILI, solubility, and BBB scores are major advantages. While Ligand A has slightly better metabolic stability and hERG, the difference isn't substantial enough to outweigh Ligand B's strengths, particularly the lower DILI risk and better solubility. The binding affinity difference is small.

Output:
1
2025-04-17 16:08:51,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.403 and 343.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (102.44 and 99.5) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Both ligands have logP values (1.255 and 1.087) 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 (0.807) has a significantly better QED score than Ligand A (0.396), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (56.262 and 54.634 percentile), and are within an acceptable range (<60).

**BBB:** Both ligands have moderate BBB penetration (62.156 and 52.074 percentile). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.871 and -4.372), 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 (-2.262 and -2.513). This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.116 and 0.141). This is excellent.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (13.308 mL/min/kg) than Ligand B (23.203 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (-23.747 hours) than Ligand B (7.743 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.023).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-10.4 kcal/mol) than Ligand A (-6.5 kcal/mol). This is a substantial difference (3.9 kcal/mol), and is the most important factor.

**Conclusion:**

While Ligand A has better metabolic stability and half-life, the significantly stronger binding affinity of Ligand B (-10.4 vs -6.5 kcal/mol) outweighs the drawbacks of its slightly lower QED and shorter half-life. The binding affinity difference is large enough to potentially overcome the solubility issues with appropriate formulation strategies.

Output:
1
2025-04-17 16:08:51,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (446.147 Da) is higher, but still acceptable. Ligand B (346.427 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (41.13) is well below the 140 threshold and good for oral absorption. Ligand B (78.87) is also below the threshold, but higher than A.

**logP:** Ligand A (4.959) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.461) is quite low, which might hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is acceptable. Ligand A has 2 HBAs, and Ligand B has 4 HBAs, both within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.5 (0.698 and 0.573 respectively), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.086, which is moderately high. Ligand B has a much lower DILI risk of 29.857, which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.521) has better BBB penetration than Ligand B (47.809).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.735 and -4.737), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.904 and -2.121). This is a major drawback.

**hERG Inhibition:** Ligand A (0.782) has a slightly higher hERG risk than Ligand B (0.103), which is better.

**Microsomal Clearance:** Ligand A (34.604) has a moderate clearance, suggesting reasonable metabolic stability. Ligand B (0.185) has very low clearance, indicating high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (127.534 hours) has a very long half-life, which is excellent. Ligand B (8.679 hours) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.393) has lower P-gp efflux than Ligand B (0.033), which is preferable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher logP and DILI risk, its significantly superior binding affinity (-8.4 vs -7.6 kcal/mol) and longer half-life are critical advantages for an enzyme inhibitor. While both have poor solubility and permeability, the potency difference is substantial enough to favor Ligand A. The lower metabolic clearance of Ligand B is attractive, but the potency difference is more important for this target class.

Output:
1
2025-04-17 16:08:51,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.451 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.22) is slightly higher than Ligand B (65.79). Both are below the 140 threshold for oral absorption, but Ligand B's lower TPSA is favorable.

**logP:** Ligand A (0.599) is a bit low, potentially hindering permeability. Ligand B (1.58) 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have high QED scores (0.813 and 0.88), indicating good drug-like properties.

**DILI:** Ligand A (29.081) and Ligand B (24.157) both have low DILI risk, well below the 40 threshold.

**BBB:** Both have similar BBB penetration (55.797 and 58.201), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.208 and -5.059), 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 negative solubility values (-1.898 and -0.581), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.128) has a slightly lower hERG risk than Ligand B (0.337), which is preferable.

**Microsomal Clearance:** Ligand A (-18.025) has significantly lower (better) microsomal clearance than Ligand B (9.363). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (1.229 hours) has a shorter half-life than Ligand B (34.059 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux than Ligand B (0.067), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.6 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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much longer half-life, which are critical for an enzyme inhibitor. While its logP is better than Ligand A, both have poor solubility and permeability. Ligand A has better metabolic stability and lower P-gp efflux, but the affinity difference is too significant to ignore. The slightly higher hERG risk of Ligand B is a concern, but potentially manageable with further optimization.

Output:
1
2025-04-17 16:08:51,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.845 and 377.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.82) is significantly better than Ligand B (91.76). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have acceptable logP values (0.944 and 0.672), falling within the 1-3 range.

**H-Bond Donors:** Both 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:** Ligand A (0.83) has a higher QED score than Ligand B (0.618), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (49.632 and 46.724), well below the 60 threshold.

**BBB:** Ligand B (74.254) has a better BBB penetration score than Ligand A (52.656). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.278 and -5.04). This is unusual and suggests poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.82 and -1.629). Again, this is unusual and suggests poor solubility. Ligand B is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.286 and 0.552), which is good.

**Microsomal Clearance:** Ligand A (-3.481) has a *much* lower (better) microsomal clearance than Ligand B (-2.322). This indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (44.183) has a substantially longer half-life than Ligand B (6.062). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.079).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a >1.5 kcal/mol advantage, which is highly significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. Its significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and higher QED score outweigh the slightly better BBB and solubility of Ligand B. The negative Caco-2 and solubility values are concerning for both, but the potency and metabolic stability advantages of A are crucial for an enzyme inhibitor.

Output:
1
2025-04-17 16:08:51,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (350.503 and 372.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (41.05). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.924 and 3.97), 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 2 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.707 and 0.847), indicating good drug-like properties.

**DILI:** Ligand A (25.242) has a significantly lower DILI risk than Ligand B (61.419). This is a major advantage for Ligand A.

**BBB:** Ligand A (74.796) has a good BBB penetration, while Ligand B (92.71) is even better. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.534 and -4.854), which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.31 and -5.672). This is a major drawback for both.

**hERG:** Ligand A (0.314) has a much lower hERG risk than Ligand B (0.831). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (32.379) has a lower microsomal clearance than Ligand B (57.729), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.556) has a slightly shorter half-life than Ligand B (14.756), but both are relatively short.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux than Ligand B (0.271), suggesting better bioavailability.

**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's enough to be considered.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both ligands suffer from poor solubility and permeability, Ligand A has significantly lower DILI and hERG risks, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. These factors are more critical for an enzyme target like SRC kinase. The slightly better BBB penetration of Ligand B is irrelevant in this case. The poor solubility and permeability of both compounds would need to be addressed through formulation or structural modifications, but Ligand A provides a better starting point due to its superior safety and pharmacokinetic profiles.

Output:
0
2025-04-17 16:08:51,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.24 Da) is slightly higher than Ligand B (350.434 Da), but both are acceptable.

**TPSA:** Ligand A (101.22) is higher than Ligand B (58.64). While both are below 140 for oral absorption, Ligand B's lower TPSA is preferable for potentially better absorption.

**logP:** Both ligands have good logP values (A: 2.407, B: 2.965), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1 each). Ligand A has 6 HBAs, while Ligand B has 3. Both are within the acceptable limit of 10, but Ligand B is better.

**QED:** Both ligands have good QED scores (A: 0.621, B: 0.697), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (87.631) compared to Ligand B (35.169). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (91.392) is better than Ligand A (82.474). While not a primary concern for a kinase inhibitor, higher BBB is never a disadvantage.

**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 this definitively.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified, so we can't interpret this definitively.

**hERG Inhibition:** Ligand A (0.125) has a slightly lower hERG risk than Ligand B (0.673), which is good.

**Microsomal Clearance:** Ligand A (29.834) has a much lower microsomal clearance than Ligand B (64.12). This indicates better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (10.267) has a longer in vitro half-life than Ligand A (0.86). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux than Ligand B (0.295), which is preferable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 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 metabolic stability (lower Cl_mic) and P-gp efflux, but suffers from a high DILI risk. Ligand B has better solubility, permeability, and a longer half-life, but its binding affinity is weaker.

Given the priorities for enzyme inhibitors, the binding affinity is paramount. The 1.5 kcal/mol difference in binding affinity is substantial. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications during lead optimization. The better metabolic stability of Ligand A also supports its potential for *in vivo* efficacy.

Output:
1
2025-04-17 16:08:51,293 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [344.342, 73.44, 3.084, 1, 5, 0.527, 91.004, 62.776, -4.496, -4.933, 0.85, 97.215, -4.428, 0.48, -8.3]
**Ligand B:** [355.435, 96.97, -0.449, 2, 5, 0.546, 20.706, 54.246, -5.22, -0.714, 0.076, 32.979, -21.335, 0.007, -6.8]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (344.342) is slightly better.
2. **TPSA:** A (73.44) is good, below the 140 threshold. B (96.97) is approaching the upper limit for good oral absorption, but still acceptable.
3. **logP:** A (3.084) is optimal. B (-0.449) is significantly lower, which could hinder membrane permeability and absorption.
4. **HBD:** Both have acceptable HBD counts (A: 1, B: 2), well below the limit of 5.
5. **HBA:** Both have acceptable HBA counts (A: 5, B: 5), below the limit of 10.
6. **QED:** Both are good (A: 0.527, B: 0.546), indicating drug-like properties.
7. **DILI:** A (91.004) has a high DILI risk, which is concerning. B (20.706) has a very low DILI risk, a significant advantage.
8. **BBB:** A (62.776) is moderate. B (54.246) is also moderate, and since SRC is not a CNS target, this is not a major factor.
9. **Caco-2:** A (-4.496) is poor. B (-5.22) is also poor, but slightly worse.
10. **Solubility:** A (-4.933) is poor. B (-0.714) is also poor, but slightly better.
11. **hERG:** A (0.85) is low risk. B (0.076) is very low risk, a further advantage.
12. **Cl_mic:** A (97.215) is high, indicating rapid metabolism and low metabolic stability. B (32.979) is much lower, suggesting better metabolic stability.
13. **t1/2:** A (-4.428) is very short. B (-21.335) is extremely short, a major drawback.
14. **Pgp:** A (0.48) is moderate. B (0.007) is very low, suggesting minimal efflux.
15. **Affinity:** A (-8.3) is significantly better than B (-6.8), a difference of 1.5 kcal/mol.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Ligand A has a substantially better binding affinity.
*   **Metabolic Stability:** Ligand B has significantly better metabolic stability (lower Cl_mic). However, both have very poor *in vitro* half-lives.
*   **Solubility:** Ligand B has slightly better solubility.
*   **hERG Risk:** Ligand B has a much lower hERG risk.
*   **DILI Risk:** Ligand B has a much lower DILI risk.

**Decision:**

Despite the significantly better binding affinity of Ligand A, the high DILI risk, poor metabolic stability (high Cl_mic, short t1/2), and poor Caco-2/solubility make it a less attractive candidate. Ligand B, while having a weaker binding affinity, demonstrates a much more favorable safety profile (low DILI, low hERG) and better metabolic stability. The difference in affinity (1.5 kcal/mol) *could* be overcome with further optimization of Ligand B, while mitigating the liabilities of Ligand A would be more challenging.

Therefore, I recommend prioritizing **Ligand B**.

1
2025-04-17 16:08:51,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.387 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (72.88) is lower than Ligand A (87.12), which is slightly better.

**logP:** Ligand A (0.372) is quite low, potentially hindering permeation. Ligand B (1.086) 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 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.875) has a higher QED score than Ligand B (0.643), indicating a more drug-like profile overall.

**DILI:** Ligand A (57.929) has a higher DILI risk than Ligand B (10.237). This is a substantial concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (65.839) has a higher BBB score than Ligand A (32.687), but this isn't a major factor here.

**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 unspecified, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.349 and 0.454 respectively), which is good.

**Microsomal Clearance:** Ligand A (5.632) has a lower microsomal clearance than Ligand B (-5.406). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Both have very negative half-life values (-29.527 and -28.987), which is problematic and suggests rapid degradation.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.027 and 0.006 respectively), which is favorable.

**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 for Ligand A.

**Overall Assessment:**

Ligand A has a much better binding affinity and better metabolic stability. However, it suffers from a low logP, higher DILI risk, and poor solubility. Ligand B has a better logP, significantly lower DILI risk, and is slightly better in TPSA. The difference in binding affinity (2.3 kcal/mol) is substantial and could outweigh the drawbacks of Ligand A, *if* the solubility and permeability issues can be addressed through formulation or further chemical modification. However, the high DILI risk for Ligand A is a major concern. Given the enzyme-specific priorities, and the significant difference in DILI risk, I would favor Ligand B.

Output:
1
2025-04-17 16:08:51,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (367.475 and 351.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.42) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (89.95) is well within the acceptable range.

**3. logP:** Ligand A (0.507) is a bit low, potentially hindering permeation. Ligand B (0.289) is even lower, raising more concerns about 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 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.735 and 0.615, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (54.634) has a moderate DILI risk, while Ligand B (8.763) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have low BBB penetration (25.902 and 54.246). Since SRC is not a CNS target, this is not a major concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.647 and -4.954), 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 (-2.779 and -1.259), indicating very poor aqueous solubility. This is a significant issue for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.084 and 0.124). This is a positive attribute for both.

**12. Microsomal Clearance:** Ligand A (20.854) has a higher microsomal clearance than Ligand B (13.702), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Both ligands have negative in vitro half-life values (-21.59 and -19.566), which is nonsensical and indicates a problem with the data or the compounds themselves.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.008).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.0 and -8.1 kcal/mol).

**Overall Assessment:**

Both ligands have significant issues with permeability and solubility. The negative Caco-2 and solubility values are concerning. However, Ligand B has a substantially lower DILI risk and slightly better metabolic stability (lower Cl_mic). The binding affinities are nearly identical, so that doesn't differentiate them. Given the enzyme-specific priorities, the lower DILI risk of Ligand B is the deciding factor. While both are problematic, Ligand B is marginally better.

Output:
1
2025-04-17 16:08:51,294 - INFO - Batch 439 complete. Total preferences: 7024
2025-04-17 16:08:51,294 - INFO - Processing batch 440/512...
2025-04-17 16:09:38,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.519 Da and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.29) is slightly higher than Ligand B (77.53). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned, especially if CNS penetration were a consideration (though it isn't a primary concern for a typical oncology kinase inhibitor).

**logP:** Both ligands have good logP values (1.554 and 2.216), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both 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 acceptable QED scores (0.704 and 0.626), indicating good drug-like properties.

**DILI:** Ligand A (44.436) has a significantly lower DILI risk than Ligand B (85.653). This is a major advantage for Ligand A.

**BBB:**  BBB is not a high priority for an oncology drug, but Ligand B (64.25) has a higher percentile than Ligand A (38.542).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.114 and -5.033). This 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 (-3.414 and -3.4). This is a significant drawback for both, potentially hindering bioavailability.

**hERG:** Ligand A (0.468) has a lower hERG risk than Ligand B (0.871), which is preferable.

**Microsomal Clearance:** Ligand A (40.251) has a lower microsomal clearance than Ligand B (86.572), indicating better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand B (63.875) has a longer in vitro half-life than Ligand A (-27.065). This is a positive for Ligand B, but the negative value for Ligand A is concerning.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.026 and 0.191).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from a higher DILI risk, poorer metabolic stability (higher Cl_mic), and worse hERG risk. Ligand A has a much better safety profile (lower DILI, lower hERG) and better metabolic stability. The solubility is poor for both. The half-life is concerning for Ligand A.

Despite the affinity advantage of Ligand B, the superior safety profile and metabolic stability of Ligand A make it the more promising candidate. The difference in affinity, while significant, might be overcome with further optimization of Ligand A. The DILI and metabolic concerns with Ligand B are harder to address without major structural changes.

Output:
0
2025-04-17 16:09:38,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.471 and 358.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is significantly better than Ligand B (88.76). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.676 and 3.367), 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=8). Lower HBD/HBA counts generally improve permeability. Ligand B's HBA is approaching the upper limit of 10.

**QED:** Ligand A (0.827) has a much higher QED score than Ligand B (0.638), indicating a more drug-like profile.

**DILI:** Ligand A (47.421) has a significantly lower DILI risk than Ligand B (81.776). This is a crucial advantage.

**BBB:** Ligand A (70.609) has better BBB penetration than Ligand B (50.523), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.41) has a better Caco-2 permeability than Ligand B (-5.5). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.436) has better aqueous solubility than Ligand B (-3.391). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.258) has a much lower hERG inhibition liability than Ligand B (0.486), a significant safety advantage.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (78.574 and 77.809 mL/min/kg).

**In vitro Half-Life:** Ligand A (69.988 hours) has a significantly longer in vitro half-life than Ligand B (32.271 hours). This is a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.58) has lower P-gp efflux liability than Ligand B (0.131). Lower efflux is generally preferred.

**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 notable.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, including DILI, hERG, solubility, half-life, and QED. It also has slightly better binding affinity. While both ligands meet the basic requirements for molecular weight and logP, Ligand A's superior profile makes it the more promising drug candidate.

Output:
1
2025-04-17 16:09:38,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 348.334 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.67) is well below the 140 threshold for good absorption, while Ligand B (117.35) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (0.821 and 1.169), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (3 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.824 and 0.721), indicating good drug-like properties.

**DILI:** Ligand A (13.532) has a significantly lower DILI risk than Ligand B (66.344), which is a major advantage. Ligand B is in the high-risk category.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (52.889) is slightly lower than Ligand B (56.883).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.816 and -4.788), which is unusual and problematic. This suggests very poor permeability. However, these values are on the same scale, so don't differentiate the two.

**Aqueous Solubility:** Ligand A (0.132) has very poor aqueous solubility, while Ligand B (-3.417) is even worse. This is a significant concern for both.

**hERG:** Ligand A (0.311) has a much lower hERG inhibition liability than Ligand B (0.075), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (9.921) has a much lower microsomal clearance than Ligand B (27.847), suggesting better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-3.271) has a better (less negative) in vitro half-life than Ligand B (-18.58), indicating greater stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.022).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). The difference of 1.6 kcal/mol is substantial and can outweigh some ADME concerns.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** While both ligands have poor solubility and permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, better t1/2), a much lower DILI risk, and a lower hERG risk. The slightly better binding affinity further strengthens its position. The poor solubility and permeability would need to be addressed through formulation strategies, but the superior safety and pharmacokinetic profiles of Ligand A make it the preferred choice.

Output:
0
2025-04-17 16:09:38,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.372 and 353.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (54.02) is well below the 140 threshold and excellent for absorption. Ligand B (72.7) is still acceptable but less optimal.

**logP:** Both ligands have good logP values (3.893 and 3.156), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.796 and 0.739), indicating good drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (68.011 and 70.919), but are still below the concerning threshold of >60.

**BBB:** Ligand A (74.758) has a better BBB penetration score than Ligand B (49.05), but BBB is not a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.904) has poor Caco-2 permeability, while Ligand B (-5.17) is also poor. This is a potential issue for oral bioavailability.

**Aqueous Solubility:** Ligand A (-4.706) has poor aqueous solubility, while Ligand B (-3.22) is slightly better. Solubility is important for formulation.

**hERG:** Ligand A (0.821) has a lower hERG risk than Ligand B (0.173), which is a significant advantage.

**Microsomal Clearance:** Ligand A (52.897) has higher microsomal clearance than Ligand B (33.544), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-16.164) has a negative half-life, which is a major red flag. Ligand A (62.772) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.483) has lower P-gp efflux than Ligand B (0.055), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is not substantial enough to overcome other significant drawbacks.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the better candidate. While it has slightly lower binding affinity and poorer Caco-2 permeability and solubility, it has a significantly better *in vitro* half-life and a much lower hERG risk. The poor half-life of Ligand B is a major concern, and the low hERG score is a serious safety issue. The small difference in binding affinity is outweighed by the ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 16:09:38,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.368 and 348.531 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (41.57).  A TPSA under 140 is good for oral absorption, and both are well below this, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (4.498 and 3.351), 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 2 HBA, and Ligand B has 3. Both are acceptable, being under the 10 HBA limit.

**QED:** Both ligands have similar, good QED values (0.834 and 0.847), indicating good drug-likeness.

**DILI:** Ligand A (56.689) has a higher DILI risk than Ligand B (6.049). This is a significant advantage for Ligand B.

**BBB:** Both have high BBB penetration (90.617 and 94.184), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.849 and -4.653). These values are unusual and likely indicate poor permeability. However, given the context of *in vitro* permeability assays, a negative value often represents a value below the limit of detection and doesn't necessarily mean *zero* permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.813 and -4.134), again likely below the limit of detection. Solubility is a concern for both, but the values are similar.

**hERG Inhibition:** Ligand A (0.946) has a slightly higher hERG risk than Ligand B (0.705), but both are relatively low.

**Microsomal Clearance:** Ligand B (41.74) has a lower microsomal clearance than Ligand A (35.856), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (7.31) has a significantly longer in vitro half-life than Ligand A (1.662). This is a substantial advantage for Ligand B, as it suggests less frequent dosing might be possible.

**P-gp Efflux:** Ligand A (0.554) has lower P-gp efflux than Ligand B (0.055), indicating potentially better bioavailability.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-8.7). While both are excellent, the difference of 0.6 kcal/mol is meaningful.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The solubility and permeability concerns are present in both, but the ADME/Tox profile of Ligand B is superior.

Output:
1
2025-04-17 16:09:38,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.479 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.57) is better than Ligand B (59.39). Both are below the 140 A^2 threshold for good oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (4.114) is slightly higher than the optimal range (1-3), potentially causing solubility issues, while Ligand B (3.033) is within the optimal 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.

**QED:** Both ligands have good QED scores (0.726 and 0.888), indicating good drug-like properties.

**DILI:** Ligand B (10.237) has a significantly lower DILI risk than Ligand A (46.452), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (89.608 and 94.804), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.837 and -4.504), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.166 and -2.668). This is a significant drawback.

**hERG:** Both ligands have low hERG inhibition liability (0.569 and 0.571), which is good.

**Microsomal Clearance:** Ligand B (51.287) has significantly lower microsomal clearance than Ligand A (101.079), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-1.965) has a slightly longer in vitro half-life than Ligand A (-2.832), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.533 and 0.126).

**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 the ADME concerns. The difference of 2.1 kcal/mol is significant.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A's significantly superior binding affinity (-10.1 kcal/mol vs -8.0 kcal/mol) is a major factor. The lower DILI and better metabolic stability of Ligand B are attractive, but the potency difference is substantial. Given the enzyme-specific priorities, potency is paramount. While solubility and permeability would need to be addressed through formulation or further chemical modification, the strong binding affinity of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 16:09:38,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.367 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.6) is better than Ligand B (94.05), both being below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (0.347 and 0.459), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand B (0.804) has a significantly better QED score than Ligand A (0.617), indicating a more drug-like profile.

**DILI:** Ligand B (24.583) has a much lower DILI risk than Ligand A (61.342), a critical advantage.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.518) has worse Caco-2 permeability than Ligand B (-5.009), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand B (-0.499) has better aqueous solubility than Ligand A (-2.636).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.097 and 0.024).

**Microsomal Clearance:** Ligand A (12.428 mL/min/kg) has significantly better metabolic stability (lower clearance) than Ligand B (30.229 mL/min/kg).

**In vitro Half-Life:** Ligand A (-17.176 hours) has a longer in vitro half-life than Ligand B (-6.575 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.005).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol), a difference of 1.1 kcal/mol. This is a substantial advantage, potentially outweighing some of Ligand A's strengths.

**Conclusion:**

While Ligand A has better metabolic stability and half-life, Ligand B excels in several crucial areas: significantly lower DILI risk, better QED, better solubility, and, most importantly, a substantially stronger binding affinity. The 1.1 kcal/mol difference in binding affinity is significant for an enzyme target like SRC kinase. The improved ADME properties of Ligand B (lower DILI, better solubility, QED) further support its selection.

Output:
1
2025-04-17 16:09:38,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.46 and 353.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.46) is excellent, below the 140 threshold and good for oral absorption. Ligand B (127.63) is still acceptable but less optimal.

**logP:** Ligand A (3.345) is within the optimal 1-3 range. Ligand B (0.828) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 3 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.636) is good, indicating a drug-like profile. Ligand B (0.38) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (32.61) has a low DILI risk. Ligand B (12.06) is even lower, indicating very low liver injury risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (63.13) is moderate, while Ligand B (53.97) is lower.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, we'll proceed assuming these are percentile scores and lower is worse. Ligand A (-4.658) is worse than Ligand B (-4.952).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, assuming percentile scores, Ligand A (-3.949) is better than Ligand B (-1.035).

**hERG:** Ligand A (0.616) has a low hERG risk. Ligand B (0.097) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (32.475) has moderate clearance. Ligand B (-14.561) has *negative* clearance, which is impossible and indicates a significant issue with the data or model. This is a major red flag.

**In vitro Half-Life:** Ligand A (27.425 hours) is good. Ligand B (1.998 hours) is very short, indicating rapid metabolism.

**P-gp Efflux:** Ligand A (0.069) has low P-gp efflux. Ligand B (0.004) has very low P-gp efflux.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol), although both are excellent.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the most significant issue is the negative microsomal clearance for Ligand B. This is physically impossible and indicates a serious problem with the data. Ligand A, while not perfect, has a more reasonable profile with acceptable ADME properties, a good QED score, and strong binding affinity. Therefore, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 16:09:38,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Ligand A (352.431 Da) is within the ideal range (200-500 Da). Ligand B (530.564 Da) is slightly above, but still acceptable.

**TPSA:** Ligand A (95.94) is good for oral absorption. Ligand B (119.63) is approaching the upper limit for good absorption but is still reasonable.

**logP:** Ligand A (0.596) is a bit low, potentially hindering permeability. Ligand B (3.855) is optimal.

**H-Bond Donors:** Both ligands (A: 2, B: 3) are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (10) is at the upper limit, potentially affecting permeability.

**QED:** Ligand A (0.706) is excellent, indicating good drug-likeness. Ligand B (0.29) is poor, suggesting potential issues.

**DILI:** Ligand A (34.781) has a low DILI risk. Ligand B (95.89) has a high DILI risk.

**BBB:** Both ligands have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.793) has poor Caco-2 permeability. Ligand B (-5.285) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.983 and -3.924, respectively).

**hERG Inhibition:** Ligand A (0.063) has very low hERG risk. Ligand B (0.942) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-17.618) has very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (62.507) has high clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (0.961) has a short half-life. Ligand B (109.016) has a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.8 and -8.3 kcal/mol), both are good. The difference of 0.5 kcal/mol is not significant enough to outweigh other factors.

**Conclusion:**

Ligand A has a better overall profile despite the low logP and solubility. It has a significantly better QED score, lower DILI risk, and much better metabolic stability (lower Cl_mic, although the half-life is short). Ligand B has a better logP but suffers from a poor QED, high DILI risk, and poor metabolic stability. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. Therefore, Ligand A is the more promising candidate.

Output:
0
2025-04-17 16:09:38,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.901 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (69.72) is still under 140, but less optimal than A.

**logP:** Ligand A (4.281) is slightly high, potentially leading to solubility issues or off-target effects, but still within a reasonable range. Ligand B (0.505) is quite low, which could hinder membrane permeability and potentially reduce potency.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is excellent. Ligand B (1 HBD, 4 HBA) is also acceptable, but slightly higher HBA count could be a minor concern.

**QED:** Both ligands have similar and good QED values (0.771 and 0.783, respectively), indicating good drug-like properties.

**DILI:** Ligand A (34.161) has a slightly higher DILI risk than Ligand B (26.406), but both are below the 40 threshold, indicating low risk.

**BBB:** Both ligands have good BBB penetration (70.997 and 76.541), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.411 and -4.881). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.092 and -1.681). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.765) has a slightly higher hERG risk than Ligand B (0.158). Ligand B is significantly better here.

**Microsomal Clearance:** Ligand A (17.483) has a higher microsomal clearance than Ligand B (8.284), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (37.114) has a longer half-life than Ligand B (7.527), which is a positive.

**P-gp Efflux:** Ligand A (0.599) has lower P-gp efflux than Ligand B (0.01), which is preferable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better TPSA, half-life, and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.9 vs -7.3 kcal/mol) and lower hERG risk are crucial for an enzyme inhibitor. The lower logP of Ligand B is a concern, but the superior potency could compensate. The solubility and Caco-2 permeability are poor for both, but can be addressed with formulation strategies. Given the priorities for kinase inhibitors, the stronger binding affinity of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 16:09:38,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.5 and 350.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.02) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (66.91) is still under 140, but less optimal than A.

**logP:** Both ligands have good logP values (4.091 and 3.622), falling within the 1-3 range.

**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 (0.786 and 0.81), indicating drug-likeness.

**DILI:** Ligand A (49.79) has a lower DILI risk than Ligand B (76.08), which is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (80.42) shows better BBB penetration than Ligand B (66.73).

**Caco-2 Permeability:** Ligand A (-5.004) shows better Caco-2 permeability than Ligand B (-4.922).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.017 and -3.936). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.666 and 0.537), which is excellent.

**Microsomal Clearance:** Ligand A (79.38) has a significantly higher microsomal clearance than Ligand B (17.811). This suggests Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand B (12.251) has a longer in vitro half-life than Ligand A (46.751). This is a major advantage for dosing considerations.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.741 and 0.046), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.8 kcal/mol), with Ligand B being slightly more potent. The difference is small, and likely not a deciding factor given the other properties.

**Conclusion:**

While both ligands exhibit good potency, Ligand B is superior due to its significantly improved metabolic stability (lower Cl_mic and longer t1/2) and lower DILI risk. The slightly better solubility and permeability of Ligand A are outweighed by these critical ADME properties.

Output:
1
2025-04-17 16:09:38,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.383 and 353.369 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.58) is better than Ligand B (73.74), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands (1.867 and 1.98) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.895 and 0.84), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (47.693 and 48.468), both are below the concerning threshold of 60.

**BBB:** Ligand B (88.135) has a significantly higher BBB penetration percentile than Ligand A (57.154). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.013) has a worse Caco-2 permeability than Ligand B (-4.407), but both are negative values which is not ideal.

**Aqueous Solubility:** Ligand A (-2.325) has slightly worse solubility than Ligand B (-2.212), but both are negative values which is not ideal.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.247 and 0.267).

**Microsomal Clearance:** Ligand A (20.861 mL/min/kg) has a lower microsomal clearance than Ligand B (25.839 mL/min/kg), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-20.323 hours) has a significantly longer in vitro half-life than Ligand B (-43.475 hours). This is a major advantage, suggesting less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.05).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -8.7 kcal/mol). Ligand A is slightly better (-9.5 kcal/mol).

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the slightly better candidate. While Ligand B has better Caco-2 permeability and BBB, Ligand A has a better binding affinity, lower microsomal clearance (better metabolic stability), and a significantly longer in vitro half-life. The small difference in solubility and Caco-2 permeability is outweighed by the improved metabolic stability and half-life.

Output:
0
2025-04-17 16:09:38,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 362.821 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (104.39 and 103.87) below the 140 threshold for good oral absorption.

**logP:** Both ligands have logP values (1.596 and 1.725) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have QED scores (0.843 and 0.814) well above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (59.636) has a lower DILI risk than Ligand B (72.664), which is a significant advantage. Both are below the concerning 60 threshold, but A is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (55.642) is slightly lower than Ligand B (48.275).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.758) is slightly better than Ligand B (-5.397).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.901) is slightly better than Ligand B (-2.872).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.301 and 0.073), which is excellent. Ligand B is better here.

**Microsomal Clearance:** Ligand A (-2.256) has a significantly lower (better) microsomal clearance than Ligand B (13.658), indicating greater metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Both ligands have negative half-life values (-27.428 and -26.244), which is unusual. However, the magnitude is similar.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.038 and 0.004).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). This is a 0.4 kcal/mol difference, which is not large enough to overcome the significant advantages of Ligand A in terms of DILI and metabolic stability.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A exhibits a significantly lower DILI risk and much better metabolic stability (lower Cl_mic). These factors are critical for a successful kinase inhibitor. The slightly better solubility and Caco-2 permeability of Ligand A are also beneficial.

Output:
0
2025-04-17 16:09:38,624 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [366.399, 136.55 ,   0.729,   3.   ,   7.   ,   0.589,  64.133,  69.678, -5.795,  -2.408,   0.326,  47.428, -18.268,   0.099, -10.7  ]
**Ligand B:** [346.471,  58.64 ,   2.406,   1.   ,   3.   ,   0.795,  18.418,  76.735, -4.844,  -3.35 ,   0.26 ,  15.904,  18.799,   0.095,  -8.3  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (366.4) is slightly higher than B (346.5), but both are acceptable.
2. **TPSA:** A (136.55) is borderline for good oral absorption, while B (58.64) is excellent. This favors B.
3. **logP:** A (0.729) is a bit low, potentially hindering permeation. B (2.406) is optimal. This strongly favors B.
4. **HBD:** A (3) is acceptable. B (1) is even better, potentially improving permeability.
5. **HBA:** Both A (7) and B (3) are within the acceptable range (<=10). B is better.
6. **QED:** Both A (0.589) and B (0.795) are good, indicating drug-like properties, but B is significantly better.
7. **DILI:** A (64.133) is moderately high risk. B (18.418) is excellent, indicating low liver injury risk. This is a major advantage for B.
8. **BBB:** Both have reasonable BBB penetration, but B (76.735) is better than A (69.678). While not a primary concern for a kinase inhibitor, it's a slight advantage for B.
9. **Caco-2:** A (-5.795) is very poor, suggesting poor absorption. B (-4.844) is also poor, but slightly better than A.
10. **Solubility:** A (-2.408) is poor. B (-3.35) is also poor, but slightly better.
11. **hERG:** Both A (0.326) and B (0.26) have low hERG risk, which is good.
12. **Cl_mic:** A (47.428) is moderate. B (15.904) is much lower, indicating better metabolic stability. This is a significant advantage for B.
13. **t1/2:** A (-18.268) is very poor. B (18.799) is good. This is a major advantage for B.
14. **Pgp:** Both A (0.099) and B (0.095) have low P-gp efflux, which is good.
15. **Affinity:** A (-10.7) is significantly better than B (-8.3). This is a substantial advantage for A.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While A has a much better binding affinity, B excels in metabolic stability, DILI risk, and has better overall ADME properties. The large difference in affinity is a significant consideration, but the poor ADME profile of A, particularly the poor solubility, Caco-2 permeability, and DILI risk, are major drawbacks. The improved metabolic stability and lower toxicity of B are highly desirable.

**Conclusion:**

Despite the significantly better binding affinity of Ligand A, the superior ADME properties and safety profile of Ligand B make it the more viable drug candidate. The difference in affinity, while substantial, might be overcome with further optimization of Ligand B, while addressing the ADME issues of Ligand A would be far more challenging.

1
2025-04-17 16:09:38,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (347.463 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.47) is significantly better than Ligand B (94.05). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (0.81) is slightly lower than the optimal 1-3 range, but still acceptable. Ligand B (-0.665) is a bit concerningly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.741 and 0.717), indicating good drug-likeness.

**DILI:** Ligand A (6.747) has a much lower DILI risk than Ligand B (42.458). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (71.772) is better than Ligand B (32.144).

**Caco-2 Permeability:** Ligand A (-5.293) is worse than Ligand B (-4.594), suggesting lower intestinal absorption for A.

**Aqueous Solubility:** Ligand A (-0.868) is slightly better than Ligand B (-0.88), but both are quite poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.378 and 0.068), which is excellent.

**Microsomal Clearance:** Ligand A (-5.761) has a lower (better) microsomal clearance than Ligand B (-6.581), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-3.654) has a significantly longer in vitro half-life than Ligand B (17.46). This is a major advantage for A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016).

**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 the stronger candidate. While its Caco-2 permeability is worse, its superior DILI profile, metabolic stability (lower Cl_mic and longer t1/2), slightly better binding affinity, and better BBB penetration outweigh this drawback. The lower logP of Ligand B is also a concern. For an enzyme target like SRC, metabolic stability and potency are paramount, and Ligand A excels in these areas.

Output:
1
2025-04-17 16:09:38,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.46 & 355.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (98.68). A TPSA under 140 is preferred for oral absorption, and both meet this, but A is much closer to the desirable range for better absorption.

**logP:** Both ligands have good logP values (2.415 & 1.486), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.728) has a higher QED score than Ligand B (0.59), indicating a more drug-like profile.

**DILI:** Ligand A (59.597) has a lower DILI risk than Ligand B (16.479), which is a significant advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.727) is higher than Ligand B (32.803).

**Caco-2 Permeability:** Ligand A (-4.907) shows better Caco-2 permeability than Ligand B (-5.019), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.725) has better aqueous solubility than Ligand B (-1.484). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.432 & 0.597), and are at acceptable levels.

**Microsomal Clearance:** Ligand A (13.183) has lower microsomal clearance than Ligand B (20.556), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.914 hours) has a significantly longer half-life than Ligand B (-19.633 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.264 & 0.399).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While a 0.8 kcal/mol difference is notable, the other ADME properties of Ligand A are much 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: lower DILI risk, better solubility, better permeability, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a higher QED score. These factors are more critical for developing a viable drug candidate for an enzyme target like SRC kinase. The small difference in binding affinity can potentially be optimized in later stages of drug development.

Output:
0
2025-04-17 16:09:38,625 - INFO - Batch 440 complete. Total preferences: 7040
2025-04-17 16:09:38,625 - INFO - Processing batch 441/512...
2025-04-17 16:10:27,334 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [335.407, 66.89, 4.005, 2, 3, 0.759, 75.688, 68.554, -5.014, -5.4, 0.689, 33.774, 65.992, 0.508, -8.4]
**Ligand B:** [350.419, 96.69, 0.662, 2, 6, 0.832, 42.226, 48.856, -4.592, -1.899, 0.051, 19.186, -24.706, 0.011, -8.1]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (335.4) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (66.89) is better than B (96.69).  TPSA < 140 is good for oral absorption, both are within this range, but A is significantly better.
3. **logP:** A (4.005) is higher than B (0.662). While 4.005 is approaching the upper limit, it's still acceptable. B's logP is quite low, potentially hindering membrane permeability.
4. **HBD:** Both have 2 HBD, which is good.
5. **HBA:** A (3) is better than B (6). Lower HBA generally improves permeability.
6. **QED:** Both are good (A: 0.759, B: 0.832), indicating drug-like properties. B is slightly better.
7. **DILI:** A (75.688) is significantly higher than B (42.226). This is a major concern for Ligand A.
8. **BBB:** A (68.554) is better than B (48.856), but neither is particularly high. Not a primary concern for SRC (not a CNS target).
9. **Caco-2:** A (-5.014) is worse than B (-4.592). Lower (more negative) values are less permeable.
10. **Solubility:** A (-5.4) is worse than B (-1.899). Solubility is important for bioavailability, and B is better.
11. **hERG:** A (0.689) is better than B (0.051). Lower hERG risk is crucial. B has a very low hERG score, indicating a potential cardiotoxicity risk.
12. **Cl_mic:** A (33.774) is higher than B (19.186). Lower clearance is preferred for metabolic stability, so B is better.
13. **t1/2:** A (65.992) is much better than B (-24.706). A longer half-life is desirable.
14. **Pgp:** A (0.508) is better than B (0.011). Lower P-gp efflux is preferred.
15. **Affinity:** Both are very good (-8.4 and -8.1 kcal/mol). The difference is minimal.

**Enzyme-Kinase Specific Priorities:**

For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** Both are excellent, difference is negligible.
*   **Metabolic Stability:** A has a better in vitro half-life, but higher Cl_mic. B has better Cl_mic, but a very poor half-life.
*   **Solubility:** B is significantly more soluble.
*   **hERG:** A has a much better hERG profile.
*   **DILI:** A has a significantly higher DILI risk.

**Conclusion:**

While Ligand A has a better half-life and slightly better BBB penetration, the significantly higher DILI risk and worse solubility are major drawbacks. Ligand B, despite its lower logP and poorer half-life, has a much better safety profile (lower DILI and hERG) and better solubility. The difference in binding affinity is minimal. Considering the enzyme-specific priorities, **Ligand B** is the more viable drug candidate.

Output:
1
2025-04-17 16:10:27,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.5 & 358.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is slightly higher than Ligand B (42.43). Both are below the 140 threshold for oral absorption, but ideal.

**logP:** Both ligands have a logP around 3.8, which is optimal.

**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.

**QED:** Both ligands have reasonable QED scores (0.769 and 0.671), indicating good drug-likeness.

**DILI:** Ligand A (15.78) has a significantly lower DILI risk than Ligand B (37.26). This is a major advantage for Ligand A.

**BBB:** Ligand B (68.71) has a higher BBB penetration percentile than Ligand A (55.29). However, BBB is less critical for a non-CNS target like SRC.

**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 ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.58) has a lower hERG inhibition liability than Ligand B (0.901). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (101.98) has a lower microsomal clearance than Ligand B (146.69), indicating better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand B (12.81) has a longer in vitro half-life than Ligand A (-12.63). This is a positive for Ligand B, but the negative value for Ligand A is concerning.

**P-gp Efflux:** Ligand A (0.268) has lower P-gp efflux liability than Ligand B (0.404), which is favorable.

**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 for Ligand B, and could potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme target. However, it has higher DILI risk, higher hERG liability, and higher microsomal clearance. Ligand A has better safety profiles (DILI, hERG) and metabolic stability, but its binding affinity is very weak.

Given the substantial difference in binding affinity, and the fact that SRC is not a CNS target, I would prioritize Ligand B, assuming the ADME issues can be addressed through further optimization. The strong binding affinity provides a solid foundation for development.

Output:
1
2025-04-17 16:10:27,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.447 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.67 and 88.32) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.601) is optimal, while Ligand B (2.294) is slightly lower but still acceptable.

**H-Bond Donors:** Ligand A (1) is good, while Ligand B (2) is also acceptable.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands (0.846 and 0.839) have excellent drug-likeness scores.

**DILI:** Ligand A (53.276) has a slightly higher DILI risk than Ligand B (39.434), but both are below the concerning threshold of 60.

**BBB:** Both have high BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.515) has poor Caco-2 permeability, while Ligand B (-5.278) is even worse. Both are concerning.

**Aqueous Solubility:** Both ligands (-3.973 and -3.358) have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.327) has a lower hERG risk than Ligand B (0.715), which is a significant advantage.

**Microsomal Clearance:** Ligand A (73.417) has higher microsomal clearance than Ligand B (23.867), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-6.512) has a much longer in vitro half-life than Ligand A (0.07), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux than Ligand B (0.224), which is a slight advantage.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.9 kcal/mol difference is substantial and outweighs many of the other drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better hERG profile and lower P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.2 vs -8.3 kcal/mol) and substantially improved metabolic stability (lower Cl_mic and longer t1/2) are critical for an enzyme target like SRC kinase. While both have poor solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. The lower DILI risk for Ligand B is also a positive factor.

Output:
1
2025-04-17 16:10:27,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.46 and 353.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold and excellent for oral absorption. Ligand B (100.46) is still within acceptable limits but less optimal.

**logP:** Ligand A (2.61) is within the optimal 1-3 range. Ligand B (-0.098) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 6 HBA) is acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (0.749 and 0.531), indicating good drug-like properties.

**DILI:** Ligand A (29.24) has a much lower DILI risk than Ligand B (21.95), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (83.44) is higher than Ligand B (37.38), but this isn't a major factor here.

**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 them relatively. Ligand A (-4.4) is better than Ligand B (-4.81).

**Aqueous Solubility:** Ligand A (-3.337) is better than Ligand B (-1.252), indicating better solubility.

**hERG Inhibition:** Ligand A (0.524) has a lower hERG risk than Ligand B (0.237), which is a positive.

**Microsomal Clearance:** Ligand A (81.50) has a higher clearance than Ligand B (-0.662), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-23.68) has a negative half-life, which is impossible and likely indicates a prediction error. Ligand B (11.47) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.33) has lower P-gp efflux than Ligand B (0.023), which is favorable.

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -6.2 kcal/mol). Ligand A has a significantly better affinity. However, the questionable half-life and higher clearance of Ligand A are concerning.

**Conclusion:**

Despite Ligand A's superior binding affinity and better solubility, the extremely low predicted in vitro half-life and higher clearance are major red flags. The negative half-life is particularly concerning, suggesting a significant issue with the prediction or the molecule's inherent instability. Ligand B, while having a slightly lower affinity, exhibits a more reasonable ADME profile, including a positive half-life, lower clearance, and acceptable DILI risk. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 16:10:27,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.933 Da) is slightly higher than Ligand B (340.383 Da), but both are acceptable.

**TPSA:** Ligand A (50.36) is significantly better than Ligand B (96.11). Lower TPSA generally indicates better cell permeability. Ligand B is quite high, potentially hindering absorption.

**logP:** Ligand A (4.727) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.247) is low, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is better balanced. Ligand B (HBD=3, HBA=4) is acceptable but slightly higher.

**QED:** Both ligands have good QED scores (A: 0.664, B: 0.763), indicating generally drug-like properties.

**DILI:** Ligand A (19.969) has a much lower DILI risk than Ligand B (61.07), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.329) is higher than Ligand B (52.811).

**Caco-2 Permeability:** Ligand A (-4.468) is better than Ligand B (-5.342), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.668) is better than Ligand B (-2.952), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.808) has a lower hERG risk than Ligand B (0.194), a significant safety advantage.

**Microsomal Clearance:** Ligand A (51.291) has a higher (worse) microsomal clearance than Ligand B (-20.668). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (59.334) has a longer half-life than Ligand B (4.843), which is desirable.

**P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux than Ligand B (0.013), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), a 1.5 kcal/mol advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and metabolic stability, Ligand A is significantly better in terms of safety (DILI, hERG), solubility, permeability, and has a longer half-life. The 1.5 kcal/mol affinity difference is not enough to outweigh the substantial ADME/Tox advantages of Ligand A, especially considering SRC is an enzyme target where metabolic stability and safety are paramount. The higher logP of Ligand A is a concern, but the overall profile is more favorable.

Output:
1
2025-04-17 16:10:27,334 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.381, 61.19, 3.463, 0, 5, 0.762, 30.05, 96.472, -4.178, -3.699, 0.598, 56.455, -19.655, 0.645, -7.7]
**Ligand B:** [338.411, 86.88, 1.989, 3, 3, 0.704, 57.193, 46.064, -5.046, -3.596, 0.428, -23.821, 19.872, 0.055, -8.4]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand B (338.411) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** Ligand A (61.19) is significantly better than Ligand B (86.88).  TPSA < 140 is good for oral absorption, and both meet this, but A is closer to the optimal range.
3. **logP:** Ligand A (3.463) is optimal. Ligand B (1.989) is a bit low, potentially hindering membrane permeability.
4. **HBD:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.
5. **HBA:** Ligand A (5) is better than Ligand B (3).  Both are acceptable, but lower is generally better.
6. **QED:** Both are similar and acceptable (A: 0.762, B: 0.704), indicating good drug-like properties.
7. **DILI:** Ligand A (30.05) has a much lower DILI risk than Ligand B (57.193). This is a significant advantage for A.
8. **BBB:** Ligand A (96.472) is excellent, while Ligand B (46.064) is poor. While SRC isn't necessarily a CNS target, higher BBB is rarely a detriment.
9. **Caco-2:** Ligand A (-4.178) is better than Ligand B (-5.046), indicating better intestinal absorption.
10. **Solubility:** Both are poor (-3.699 and -3.596). This is a concern for both, but could be addressed with formulation strategies.
11. **hERG:** Both are low risk (A: 0.598, B: 0.428).
12. **Cl_mic:** Ligand A (56.455) is better than Ligand B (-23.821). Lower clearance indicates better metabolic stability, crucial for kinase inhibitors.
13. **t1/2:** Ligand A (-19.655) is better than Ligand B (19.872). A negative value suggests a longer half-life, which is desirable.
14. **Pgp:** Ligand A (0.645) is better than Ligand B (0.055). Lower P-gp efflux improves bioavailability.
15. **Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.7). However, the difference is less than 1.5 kcal/mol, and can be overcome by other factors.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has slightly better affinity, Ligand A excels in metabolic stability (Cl_mic, t1/2), DILI risk, and Pgp efflux. Solubility is a concern for both. The superior metabolic profile and safety profile of Ligand A outweigh the slightly weaker binding affinity.

**Conclusion:**

Ligand A is the more promising drug candidate.

1
2025-04-17 16:10:27,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 347.375 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is well below the 140 threshold for good absorption, while Ligand B (116.42) is still acceptable but higher.

**logP:** Ligand A (1.477) is within the optimal range (1-3). Ligand B (-0.207) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.717 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (34.471) has a significantly lower DILI risk than Ligand B (54.75), which is preferable. Both are below the 60 threshold.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (62.117) shows slightly better penetration than Ligand B (55.874).

**Caco-2 Permeability:** Ligand A (-4.709) has a worse Caco-2 permeability than Ligand B (-5.033), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.78 and -2.63). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.241 and 0.257).

**Microsomal Clearance:** Ligand A (15.062) has significantly lower microsomal clearance than Ligand B (-37.481), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (2.333) has a shorter half-life than Ligand B (-36.196), which is not ideal, but the large difference in value suggests the scale is different.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.033 and 0.012).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major positive for Ligand B.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity, which is the most important factor for an enzyme target. While its logP is slightly lower and DILI is higher than Ligand A, the substantial improvement in binding affinity outweighs these drawbacks. Ligand A has better metabolic stability (lower Cl_mic) and lower DILI, but the potency advantage of Ligand B is critical. The solubility is poor for both, but this can be addressed through formulation strategies.

Output:
1
2025-04-17 16:10:27,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, but both are acceptable.

**TPSA:** Ligand A (101.29) is better than Ligand B (62.31). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 1.868, B: 2.094), falling 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.622, B: 0.745), indicating drug-like properties.

**DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (57.464). This is a major advantage for Ligand A.

**BBB:** Ligand B (88.251) has a higher BBB penetration percentile than Ligand A (65.723). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.241) has worse Caco-2 permeability than Ligand B (-4.844).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.552 and -3.684 respectively). This is a concern for both, but might be addressable through formulation.

**hERG Inhibition:** Ligand A (0.138) has a lower hERG inhibition liability than Ligand B (0.845). This is a significant advantage for Ligand A, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (58.284) has a higher microsomal clearance than Ligand B (19.043), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (58.139) has a longer in vitro half-life than Ligand A (-17.542), suggesting better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.06, B: 0.047).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.3 kcal/mol, B: -8.6 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, lower hERG). However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The poor solubility of both is a concern. Given the enzyme-specific priorities, metabolic stability is crucial. While the DILI and hERG profiles of Ligand A are attractive, the significantly better metabolic stability of Ligand B outweighs these benefits.

Output:
1
2025-04-17 16:10:27,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 better than Ligand B (107.4). Lower TPSA generally correlates with better absorption.

**logP:** Both ligands have similar logP values around 2.8, falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Ligand A (0.903) has a significantly higher QED score than Ligand B (0.476), indicating a more drug-like profile.

**DILI:** Ligand A (44.746) has a lower DILI risk than Ligand B (54.207), which is preferable. Both are below the 60 threshold, but A is better.

**BBB:** Both have moderate BBB penetration, but Ligand A (68.941) is slightly better than Ligand B (62.544). BBB isn't a primary concern for a non-CNS target like SRC.

**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, also unusual. Again, difficult to interpret, but similar.

**hERG:** Ligand A (0.54) has a slightly higher hERG risk than Ligand B (0.376), but both are relatively low.

**Microsomal Clearance (Cl_mic):** Ligand A (12.174 mL/min/kg) has a significantly lower Cl_mic than Ligand B (41.44 mL/min/kg). This suggests better metabolic stability for Ligand A, a key priority for enzymes.

**In vitro Half-Life (t1/2):** Ligand A (1.117 hours) has a slightly longer half-life than Ligand B (0.812 hours).

**P-gp Efflux:** Ligand A (0.729) has slightly higher P-gp efflux than Ligand B (0.097), which is less desirable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). The 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the stronger candidate. Its superior binding affinity, better QED score, lower DILI risk, and significantly improved metabolic stability (lower Cl_mic and slightly longer t1/2) outweigh the slightly higher P-gp efflux and hERG risk. The similar logP and TPSA values contribute to a comparable absorption profile. The binding affinity difference is particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:10:27,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.395 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (139.45) is close to the 140 threshold, while Ligand B (87.22) is well below, suggesting potentially better absorption for B.

**logP:** Ligand A (-1.353) is a bit low, potentially hindering permeation. Ligand B (2.418) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 5 HBA, acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.413 and 0.528), indicating moderate drug-likeness.

**DILI:** Ligand A (56.844) has a higher DILI risk than Ligand B (38.542), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (88.872) than Ligand A (22.567).

**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:** Both ligands have low hERG inhibition liability (0.176 and 0.344), which is good.

**Microsomal Clearance:** Ligand A (-14.322) has a *much* lower (better) microsomal clearance than Ligand B (44.852), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (-5.907) has a negative half-life, which is not possible. Ligand B (-9.52) also has a negative half-life. This is a major red flag.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.066).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the key differentiator is metabolic stability. Ligand A exhibits significantly better metabolic stability (lower Cl_mic) than Ligand B. While both have excellent binding affinity, the poor metabolic stability of Ligand B is a major concern for *in vivo* efficacy. The lower DILI risk for Ligand B is a plus, but the metabolic stability issue is more critical for an enzyme target. The negative half-life values are concerning for both, but the overall profile of A is more promising.

Output:
0
2025-04-17 16:10:27,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.5 and 398.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (83.98), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (1.482 and 2.668), 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 6. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have reasonable QED scores (0.718 and 0.668), indicating good drug-likeness.

**DILI:** Ligand A (35.052) has a significantly lower DILI risk than Ligand B (69.252). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.633) is better than Ligand B (43.893).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.245 and -5.496), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.309 and -3.924) which is also a concern.

**hERG:** Ligand A (0.724) has a lower hERG risk than Ligand B (0.217), which is a significant advantage.

**Microsomal Clearance:** Ligand A (37.201) has lower microsomal clearance than Ligand B (64.776), indicating better metabolic stability. This is crucial for kinases.

**In vitro Half-Life:** Ligand A (-11.974) has a negative half-life, which is concerning. Ligand B (19.781) has a positive half-life, which is better.

**P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux than Ligand B (0.077), which is slightly better.

**Binding Affinity:** Ligand B (-8.3 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 has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A demonstrates superior ADMET properties, particularly lower DILI and hERG risk, and better metabolic stability. The negative Caco-2 and solubility values are concerning for both. Considering the importance of potency for kinases, the stronger binding of Ligand B is likely to be decisive, despite its higher DILI and hERG risks. Further optimization could focus on improving the ADMET profile of Ligand B while maintaining its high affinity.

Output:
1
2025-04-17 16:10:27,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.371 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (99.18 and 96.11) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (0.811) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.151) is within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**QED:** Ligand A (0.789) has a better QED score than Ligand B (0.669), indicating a more drug-like profile.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (38.62). This is a significant concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (66.382 and 60.644), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.579 and -4.872). This is unusual and suggests poor permeability. However, negative values can sometimes occur in modeling and don't necessarily preclude further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.048 and -3.715), which is also concerning. Solubility issues can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.122) has a very low hERG risk, which is excellent. Ligand B (0.383) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-12.283) has a significantly lower (better) microsomal clearance than Ligand B (50.935), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (36.364) has a longer half-life than Ligand B (1.112), which is desirable.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, while Ligand B (0.056) has slightly higher efflux. Both are relatively low.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-7.2 vs -8.5 kcal/mol) is the most important factor. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED and lower hERG, Ligand B's superior potency is paramount for an enzyme target like SRC kinase. The DILI risk for Ligand A is also a significant concern. The solubility and permeability issues are present in both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 16:10:27,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.29) is slightly higher than Ligand B (81.33). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (0.902) is a bit low, potentially hindering permeation. Ligand B (1.418) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (2) is even better, contributing to improved permeability.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.638 and 0.73), indicating drug-like properties.

**DILI:** Ligand A (40.054) is at the upper limit of acceptable DILI risk, while Ligand B (12.757) has a significantly lower and much more favorable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (68.36) is higher than Ligand A (48.546), but this isn't a deciding factor.

**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. This is a significant concern, but again, the scale is unknown.

**hERG Inhibition:** Ligand A (0.286) has a slightly higher hERG risk than Ligand B (0.674), which is preferable.

**Microsomal Clearance:** Ligand A (7.275) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (-5.849) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**In vitro Half-Life:** Ligand A (-0.23) has a short half-life. Ligand B (-24.567) has an extremely long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.036).

**Binding Affinity:** Ligand B (-7.7 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.

**Conclusion:**

Ligand B is the far superior candidate. Its significantly stronger binding affinity, lower DILI risk, better logP, lower HBD count, and dramatically improved metabolic stability (negative Cl_mic and very long half-life) outweigh any potential concerns about the negative Caco-2 and solubility values (given the unknown scale). Ligand A's weak binding affinity and higher DILI/clearance make it a less attractive option.

Output:
1
2025-04-17 16:10:27,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 349.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.23) is well below the 140 threshold for good absorption, while Ligand B (101.9) is still acceptable, but less optimal.

**logP:** Ligand A (2.52) is within the optimal 1-3 range. Ligand B (0.012) is significantly below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is at the higher end of the acceptable range, but still within the limit of 5.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**QED:** Ligand A (0.825) is excellent, indicating high drug-likeness. Ligand B (0.503) is acceptable, but less favorable.

**DILI:** Ligand A (23.536) has a very low DILI risk. Ligand B (4.382) also has a low DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.231) is higher than Ligand B (17.836).

**Caco-2 Permeability:** Ligand A (-5.287) is poor. Ligand B (-6.024) is also poor.

**Aqueous Solubility:** Ligand A (-2.235) is poor. Ligand B (-1.484) is also poor.

**hERG Inhibition:** Ligand A (0.586) is very low risk. Ligand B (0.067) is also very low risk.

**Microsomal Clearance:** Ligand A (36.312) is moderate. Ligand B (-1.676) is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (-6.566) is excellent, indicating a long half-life. Ligand B (-22.096) is exceptional.

**P-gp Efflux:** Ligand A (0.127) is low, suggesting minimal efflux. Ligand B (0.004) is extremely low.

**Binding Affinity:** Ligand A (-6.8 kcal/mol) is good. Ligand B (-7.5 kcal/mol) is even better, with a 0.7 kcal/mol advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.5 vs -6.8 kcal/mol), and a much better microsomal clearance (-1.676 vs 36.312), and in vitro half-life (-22.096 vs -6.566). While its logP is very low, the substantial improvement in potency and metabolic stability outweighs this drawback, especially for a kinase inhibitor where achieving sufficient target engagement and duration of action are critical. Both ligands have acceptable safety profiles (DILI and hERG). While Ligand A has a better QED and TPSA, the binding affinity and metabolic stability of Ligand B are more important for this target class.

Output:
1
2025-04-17 16:10:27,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 354.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.29 and 107.38) are reasonably low, suggesting good absorption potential, though not optimal for CNS penetration.

**logP:** Ligand A (1.644) is within the optimal 1-3 range. Ligand B (-1.01) is slightly below, which *could* hinder permeability, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) and Ligand B (2 HBD, 6 HBA) both have acceptable numbers.

**QED:** Both ligands (0.581 and 0.592) have good drug-likeness scores.

**DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (25.165), which is a substantial advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (65.839) has better BBB penetration than Ligand B (45.909).

**Caco-2 Permeability:** Ligand A (-5.265) shows lower Caco-2 permeability than Ligand B (-4.694), which is less desirable.

**Aqueous Solubility:** Ligand A (-2.42) has slightly better aqueous solubility than Ligand B (-1.121).

**hERG Inhibition:** Both ligands (0.117 and 0.112) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (31.207) has a higher microsomal clearance than Ligand B (25.769), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-0.916) has a significantly longer half-life than Ligand A (-7.868), which is a major advantage.

**P-gp Efflux:** Both ligands (0.023 and 0.004) have very low P-gp efflux liability.

**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 concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and lower DILI risk. However, Ligand B has better metabolic stability (lower Cl_mic, longer half-life) and slightly better Caco-2 permeability. Given that SRC is an enzyme, potency and metabolic stability are key. The 1.1 kcal/mol difference in binding affinity is significant. While Ligand B's improved metabolic stability is valuable, the stronger binding of Ligand A is likely to translate to greater efficacy *in vivo*, and the lower DILI risk is a significant safety advantage.

Output:
1
2025-04-17 16:10:27,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.16) is better than Ligand B (93.26), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (1.898 and 1.274), falling within the 1-3 range.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1), as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of 10.

**QED:** Both ligands have high QED scores (0.813 and 0.901), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (64.87 and 64.327), which is acceptable (below 60 is good, these are slightly above but not alarming).

**BBB:** Ligand A (81.272) has a better BBB penetration score than Ligand B (61.07), but BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.602) has a worse Caco-2 permeability than Ligand B (-5.251), meaning ligand B is more permeable.

**Aqueous Solubility:** Ligand A (-3.497) has a worse solubility than Ligand B (-2.461). Solubility is important for kinases.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.161 and 0.06), which is excellent.

**Microsomal Clearance:** Ligand A (30.697) has a significantly higher microsomal clearance than Ligand B (10.402). This suggests Ligand B is more metabolically stable, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (34.677) has a longer half-life than Ligand B (10.707), which is generally desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.307 and 0.028).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.2 kcal/mol). The difference is minimal.

**Conclusion:**

While Ligand A has a slightly better BBB score and in vitro half-life, Ligand B is superior overall. The significantly lower microsomal clearance of Ligand B is a major advantage for a kinase inhibitor, indicating better metabolic stability. Ligand B also has better Caco-2 permeability and solubility. The minimal difference in binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 16:10:27,336 - INFO - Batch 441 complete. Total preferences: 7056
2025-04-17 16:10:27,336 - INFO - Processing batch 442/512...
2025-04-17 16:11:08,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.519 Da and 377.941 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (41.15), being below 140, suggesting good absorption.

**logP:** Ligand A (2.717) is within the optimal 1-3 range. Ligand B (4.356) is slightly higher, potentially leading to solubility issues or off-target effects.

**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 (0.74 and 0.728), indicating good drug-likeness.

**DILI:** Ligand A (9.965) has a significantly lower DILI risk than Ligand B (25.785), which is a major advantage.

**BBB:** Ligand A (61.691) has a lower BBB penetration than Ligand B (74.641). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.685) has a worse Caco-2 permeability than Ligand B (-5.406).

**Aqueous Solubility:** Ligand A (-1.9) has better aqueous solubility than Ligand B (-3.778).

**hERG Inhibition:** Ligand A (0.386) has a lower hERG inhibition liability than Ligand B (0.92), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (22.822) has a lower microsomal clearance than Ligand B (44.454), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.269) has a longer in vitro half-life than Ligand B (1.748), which is desirable for dosing convenience.

**P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux than Ligand B (0.417), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.4), a difference of 0.5 kcal/mol. While affinity is paramount, the other ADME properties of Ligand A are substantially better.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower toxicity risk (lower DILI, lower hERG), and better solubility. These factors are crucial for developing a viable drug candidate. The 0.5 kcal/mol difference in binding affinity can likely be overcome with further optimization of Ligand A, while addressing the ADME deficiencies of Ligand B would be more challenging.

Output:
0
2025-04-17 16:11:08,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.411 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.09) is better than Ligand B (107.7), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.643) is slightly better than Ligand B (0.032), 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 (0 HBD, 7 HBA) is better than Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.67) is slightly better than Ligand B (0.548), indicating a more drug-like profile.

**DILI:** Ligand B (20.085) has a significantly lower DILI risk than Ligand A (85.149). This is a major advantage for Ligand B.

**BBB:** Ligand A (69.678) has a better BBB penetration than Ligand B (40.132), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.026 and -5.142), 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 (-3.513 and -1.243), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.208) has a lower hERG inhibition liability than Ligand B (0.156), which is preferable.

**Microsomal Clearance:** Ligand B (-7.228) has significantly lower (better) microsomal clearance than Ligand A (67.096), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (14.889 hours) has a much longer half-life than Ligand A (-26.307 hours). The negative value for Ligand A is concerning and likely an artifact or error.

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux than Ligand B (0.019), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While both are strong binders, 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 affinity and BBB penetration, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer half-life), and slightly better solubility. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand B makes it the preferred choice.

Output:
1
2025-04-17 16:11:08,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.4 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (18.51) is significantly better than Ligand B (58.44). A TPSA under 90 is generally good, and A is much closer to that threshold. This favors A for permeability.

**logP:** Ligand A (4.166) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (1.546) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (0 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.897 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (29.934). This is a significant drawback for A.

**BBB:** Both have good BBB penetration (A: 87.476, B: 73.401), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.584 and -4.676), 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 (-4.095 and -1.385), also unusual and suggesting poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.973) has a slightly higher hERG risk than Ligand B (0.142). This is a concern for A.

**Microsomal Clearance:** Ligand A (-11.917) has *much* lower (better) microsomal clearance than Ligand B (39.296). This indicates significantly better metabolic stability for A.

**In vitro Half-Life:** Ligand A (-23.609) has a longer half-life than Ligand B (-8.227), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.673) has lower P-gp efflux than Ligand B (0.1), which is favorable.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a better binding affinity than Ligand B (-7.7 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial and can 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, which are crucial for an enzyme inhibitor. While it has higher DILI and hERG risk, the strong binding affinity and improved metabolic profile are likely to be more impactful in early drug development. The solubility and permeability issues are shared by both compounds and would need to be addressed through formulation or structural modification. Ligand B's lower DILI and hERG are attractive, but its weaker binding and poorer metabolic stability are significant drawbacks.

Output:
1
2025-04-17 16:11:08,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.369 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 (54.46). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (A: 1.286, B: 3.922). Ligand A is preferable, being closer to the optimal range of 1-3. Ligand B is at the higher end, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is slightly better than Ligand B (HBD=1, HBA=6). Both are within acceptable limits, but lower counts generally favor permeability.

**QED:** Both ligands have similar and good QED scores (A: 0.722, B: 0.734), indicating good drug-like properties.

**DILI:** Ligand A (36.797) has a much lower DILI risk than Ligand B (73.982). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (76.464) is better than Ligand B (61.38).

**Caco-2 Permeability:** Ligand A (-4.409) is significantly better than Ligand B (-4.746). Higher Caco-2 values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.062) is better than Ligand B (-3.258). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.329, B: 0.666), which is good. Ligand A is slightly preferred.

**Microsomal Clearance:** Ligand A (36.338) has a higher (worse) microsomal clearance than Ligand B (20.502). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (80.685) has a significantly longer in vitro half-life than Ligand A (-20.321). 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 (A: 0.054, B: 0.433). Ligand A is slightly preferred.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.9 kcal/mol, B: -8.0 kcal/mol). Ligand A has a 0.9 kcal/mol advantage, which is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has a clear advantage in terms of TPSA, logP, DILI risk, Caco-2 permeability, solubility, hERG, and, crucially, binding affinity. While Ligand B has better metabolic stability (lower Cl_mic and higher t1/2), the significantly stronger binding affinity of Ligand A, coupled with its better overall ADME profile (especially the lower DILI risk), makes it the more promising drug candidate. The 0.9 kcal/mol difference in binding is likely to be more impactful than the metabolic stability advantage of Ligand B, especially considering potential formulation strategies to mitigate metabolic concerns.

Output:
0
2025-04-17 16:11:08,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.49 Da and 340.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (55.81 and 58.2) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.039) is within the optimal 1-3 range. Ligand B (3.673) is slightly higher, 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 2 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 (20.822) has a much lower DILI risk than Ligand B (44.281). This is a significant advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (73.75) has a higher BBB penetration, but this isn't a primary concern here.

**9. Caco-2 Permeability:** Ligand A (-5.074) has a negative Caco-2 value, suggesting poor permeability. Ligand B (-4.596) is also negative, but slightly less so.

**10. Aqueous Solubility:** Ligand A (-2.415) has better solubility than Ligand B (-4.09).

**11. hERG Inhibition:** Ligand A (0.784) has a lower hERG inhibition risk than Ligand B (0.302). This is a crucial advantage.

**12. Microsomal Clearance:** Ligand A (3.049) has significantly lower microsomal clearance than Ligand B (69.85), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (30.937 hours) has a much longer half-life than Ligand B (-26.949 hours). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux than Ligand B (0.317).

**15. Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While Ligand B has a slightly better logP and BBB, Ligand A excels in critical areas for an enzyme inhibitor: lower DILI risk, better solubility, significantly lower microsomal clearance (better metabolic stability), a longer half-life, lower P-gp efflux, and slightly better binding affinity. The negative Caco-2 values for both are a concern, but the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 16:11:08,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.471 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.42) is significantly better than Ligand B (112.92). A TPSA under 140 is good for oral absorption, and A is closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (1.632 and 1.271), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 8 HBA). Lower counts generally improve permeability.

**QED:** Ligand A (0.821) has a better QED score than Ligand B (0.576), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (68.282 and 63.862), below the concerning threshold of 60.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (64.211) is slightly better than Ligand B (38.193).

**Caco-2 Permeability:** Ligand A (-4.882) is better than Ligand B (-5.609), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.71 and -2.726). This is a potential issue, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.168 and 0.282), which is excellent.

**Microsomal Clearance:** Ligand A (46.415) has significantly lower microsomal clearance than Ligand B (60.053), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-16.226) has a longer in vitro half-life than Ligand B (19.657), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.152 and 0.021).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -8.6 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Conclusion:**

Ligand A is the superior candidate. While both have good potency and acceptable safety profiles, Ligand A demonstrates better predicted ADME properties, specifically lower microsomal clearance and longer half-life, which are crucial for an enzyme target like SRC kinase. It also has a better QED score and TPSA. The slight advantage in binding affinity is a bonus.

Output:
0
2025-04-17 16:11:08,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (362.495 and 360.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (75.63). Both are below 140, suggesting reasonable absorption.

**logP:** Ligand A (2.85) is optimal, while Ligand B (0.653) is a bit low, 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 (6) is acceptable.

**QED:** Both ligands have similar QED values (0.795 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (50.136), but both are still within an acceptable range (<60 is good).

**BBB:** Both have reasonable BBB penetration, with Ligand A (70.531) being slightly better than Ligand B (64.715). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 caution.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue.

**hERG:** Ligand A (0.197) has a slightly higher hERG risk than Ligand B (0.075), but both are very low.

**Microsomal Clearance:** Ligand B (22.187) has significantly lower microsomal clearance than Ligand A (50.661), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (3.813) has a much shorter half-life than Ligand A (45.935), which is a significant drawback.

**P-gp Efflux:** Ligand A (0.355) has slightly higher P-gp efflux than Ligand B (0.092).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.3 kcal/mol difference is significant and can outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite the issues with Caco-2 and solubility values, the significantly stronger binding affinity of Ligand B (-8.7 vs -7.4 kcal/mol) and its superior metabolic stability (lower Cl_mic) are decisive factors. While Ligand A has a longer half-life, the potency advantage of Ligand B is more critical for an enzyme inhibitor. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization.

Output:
1
2025-04-17 16:11:08,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.427 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (88.1) as it's closer to the <140 threshold for good absorption.

**logP:** Ligand A (1.617) is optimal, while Ligand B (0.41) 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 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.583 and 0.625, respectively), indicating drug-likeness.

**DILI:** Ligand A (21.52) has a significantly lower DILI risk than Ligand B (12.33), which is a major advantage.

**BBB:** Both ligands have moderate BBB penetration (60.876 and 57.736). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.852 and -4.685), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.851 and -1.037), indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.386) has a lower hERG risk than Ligand B (0.183), which is preferable.

**Microsomal Clearance:** Ligand A (12.148) has lower microsomal clearance than Ligand B (21.068), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (3.385) has a longer half-life than Ligand A (1.649), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.011).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a stronger binding affinity than Ligand B (-7.8 kcal/mol). This 0.5 kcal/mol difference is significant, and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While both ligands suffer from poor solubility and permeability, Ligand A has a significantly better safety profile (lower DILI and hERG risk), better metabolic stability (lower Cl_mic), and a stronger binding affinity. The improved potency and safety profile outweigh the slightly shorter half-life compared to Ligand B. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modifications, but the core scaffold of Ligand A appears more promising.

Output:
1
2025-04-17 16:11:08,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (350.438 and 347.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.23) is higher than Ligand B (43.86). While both are reasonably low, Ligand B is better positioned for oral absorption due to its lower TPSA.

**3. logP:** Both ligands have good logP values (1.598 and 1.829), 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 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.897) has a significantly higher QED score than Ligand B (0.689), indicating a more drug-like profile.

**7. DILI:** Ligand A (25.902) has a much lower DILI risk than Ligand B (5.777), which is a significant advantage.

**8. BBB:** Ligand A (83.443) has a higher BBB percentile than Ligand B (68.941). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Ligand A (-5.013) has slightly better Caco-2 permeability than Ligand B (-4.562).

**10. Aqueous Solubility:** Ligand A (-1.888) has slightly better aqueous solubility than Ligand B (-0.943).

**11. hERG Inhibition:** Ligand A (0.292) has a lower hERG inhibition liability than Ligand B (0.559), a crucial safety factor.

**12. Microsomal Clearance:** Ligand A (-4.382) has a lower (better) microsomal clearance than Ligand B (-4.132), indicating better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (-5.86 and -5.79 hours).

**14. P-gp Efflux:** Ligand A (0.05) has slightly lower P-gp efflux liability than Ligand B (0.043).

**15. 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 superior to Ligand B. While the binding affinity difference is small, Ligand A demonstrates significant advantages in crucial ADME-Tox properties: lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), and a higher QED score. These factors are particularly important for enzyme inhibitors, where long-term safety and efficacy are paramount. The slightly better solubility and permeability also contribute to its favorability.

Output:
1
2025-04-17 16:11:08,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.447 and 348.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (79.31) is better than Ligand B (113.56). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (1.097) is within the optimal range (1-3). Ligand B (-0.46) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable, but higher HBD can sometimes reduce permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.8 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A (22.218) has a significantly lower DILI risk than Ligand B (41.411). This is a major advantage for Ligand A.

**BBB:** Ligand A (59.364) and Ligand B (79.217) are both relatively low, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.88) is worse than Ligand B (-5.214), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.317) is better than Ligand B (-2.111), a positive for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.299) has a lower hERG risk than Ligand B (0.142), which is favorable.

**Microsomal Clearance:** Ligand A (-0.149) has a *much* lower (better) microsomal clearance than Ligand B (-3.795), indicating significantly better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-3.847) has a much longer half-life than Ligand B (13.327), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux than Ligand B (0.005), which is a slight advantage.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.5 kcal/mol). This difference is not substantial enough to outweigh the other ADME differences.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability, Ligand A excels in DILI risk, microsomal clearance, in vitro half-life, and hERG inhibition. The similar binding affinities make these ADME properties the deciding factors.

Output:
0
2025-04-17 16:11:08,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.402 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.36) is well below the 140 threshold, while Ligand B (69.72) is still acceptable but higher.

**logP:** Ligand A (2.997) is optimal (1-3). Ligand B (1.563) is slightly lower, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, both favorable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.857 and 0.766, respectively), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 51.842, which is acceptable (below 60). Ligand B has a significantly lower DILI risk of 24.622, a strong advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.413) is higher than Ligand B (61.497).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.217) is slightly better than Ligand B (-4.646).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-2.18) is slightly better than Ligand A (-2.578).

**hERG:** Ligand A (0.698) has a slightly higher hERG risk than Ligand B (0.103), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (46.85) has a higher clearance than Ligand B (37.422), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (2.56 hours) has a better half-life than Ligand A (-16.419 hours - negative values are concerning).

**P-gp Efflux:** Ligand A (0.554) has lower P-gp efflux than Ligand B (0.034), which is favorable.

**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 small, it's still a positive factor.

**Overall:**

Ligand B demonstrates a more favorable profile overall. Its lower DILI risk, significantly better hERG profile, and improved metabolic stability (lower Cl_mic and better half-life) are key advantages. While Ligand A has slightly better Caco-2 permeability and P-gp efflux, the ADME-Tox benefits of Ligand B outweigh these minor drawbacks, especially considering the comparable binding affinities.



Output:
1
2025-04-17 16:11:08,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.37 and 352.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.71) is well below the 140 threshold for good oral absorption, and even below 90 for potential CNS penetration (though not a primary concern here). Ligand B (99.77) is still acceptable, but closer to the upper limit.

**logP:** Ligand A (3.202) is optimal. Ligand B (-0.021) is quite low, potentially hindering permeation and absorption. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is well within acceptable limits. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.524 and 0.664), indicating drug-like properties.

**DILI:** Ligand A (84.8%) has a higher DILI risk than Ligand B (27.4%). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target. Ligand A (71.97%) is reasonable, while Ligand B (46.57%) is lower.

**Caco-2 Permeability:** Ligand A (-4.693) is poor, suggesting low intestinal absorption. Ligand B (-5.229) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.605) is poor. Ligand B (-1.564) is also poor, but better than Ligand A.

**hERG:** Ligand A (0.793) has a slightly higher hERG risk than Ligand B (0.086). Ligand B is much better in this regard.

**Microsomal Clearance:** Ligand A (92.964) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-37.946) has *negative* clearance, which is unusual and suggests very high stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (18.005 hours) is reasonable. Ligand B (13.545 hours) is acceptable, but shorter.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.439 and 0.003).

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.7 kcal/mol).

**Conclusion:**

Despite the higher DILI risk, Ligand A's poor Caco-2 and solubility, coupled with its high clearance, make it a less favorable candidate. Ligand B, while having a lower BBB score and similar solubility/Caco-2 issues, has a *significantly* better metabolic stability profile (negative Cl_mic) and a much lower hERG risk. The strong binding affinity is equal for both, so the ADME properties become the deciding factor. The superior metabolic stability and lower hERG risk of Ligand B outweigh its slightly lower BBB and solubility.

Output:
1
2025-04-17 16:11:08,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.403 and 365.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.39) is slightly above the preferred <140, while Ligand B (88.91) is well within the range.

**logP:** Both ligands have similar logP values (1.318 and 1.382), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.561 and 0.727), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (52.617) has a slightly higher DILI risk than Ligand B (44.126), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (39.55) has a higher BBB score than Ligand A (13.377), but this isn't a major factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.519 and -5.504), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.114 and -1.778), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.353) has a slightly higher hERG risk than Ligand B (0.071), which is preferable.

**Microsomal Clearance:** Ligand A (14.769 mL/min/kg) has a lower microsomal clearance than Ligand B (19.25 mL/min/kg), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (81.496 hours) has a much longer half-life than Ligand B (-2.288 hours). This is a substantial advantage, suggesting less frequent dosing potential.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.181 and 0.025), which is good.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). This difference of 0.4 kcal/mol is significant and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is slightly more promising. The superior binding affinity (-7.0 vs -6.6 kcal/mol) and lower hERG risk are key advantages. While Ligand A has better metabolic stability and half-life, the affinity difference is more critical for an enzyme target. The solubility and permeability issues would need to be addressed through formulation strategies, but the stronger binding of Ligand B provides a better starting point for optimization.

Output:
1
2025-04-17 16:11:08,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.503 and 358.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.32) is slightly higher than Ligand B (68.09). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Both ligands have good logP values (1.92 and 2.022), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.65 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (50.33) has a slightly lower DILI risk than Ligand B (55.758), both are acceptable (<60).

**BBB:** Both ligands have low BBB penetration (51.725 and 63.358). This is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.165 and -5.307). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading; further investigation would be needed.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.283 and -1.982). This is also concerning and suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.46 and 0.256).

**Microsomal Clearance:** Ligand B (41.918) has lower microsomal clearance than Ligand A (46.756), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.359) has a significantly longer in vitro half-life than Ligand A (-35.394). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.047).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This 1 kcal/mol difference is significant.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While both have issues with predicted permeability and solubility, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The difference in half-life is particularly important for an enzyme inhibitor, as a longer half-life can translate to less frequent dosing. The slightly better DILI score and hERG risk profile of Ligand A are outweighed by the superior pharmacokinetic properties of Ligand B.

Output:
1
2025-04-17 16:11:08,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.455 and 349.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.84) is significantly better than Ligand B (117.59). A TPSA below 140 is good for oral absorption, and both meet this, but A is preferable.

**logP:** Ligand A (3.556) is optimal, while Ligand B (1.078) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (4 HBD, 5 HBA). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have acceptable QED scores (0.675 and 0.558, both >0.5).

**DILI:** Ligand A (38.581) has a lower DILI risk than Ligand B (48.313), indicating a safer profile. Both are below the concerning threshold of 60.

**BBB:** This isn't a high priority for a non-CNS target like SRC, but Ligand A (74.447) is better than Ligand B (52.074).

**Caco-2 Permeability:** Ligand A (-4.195) is better than Ligand B (-5.36), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.54) is better than Ligand B (-2.59), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.685 and 0.627, lower is better).

**Microsomal Clearance:** Ligand A (92.783) has higher microsomal clearance than Ligand B (7.925), meaning faster metabolism and potentially lower *in vivo* exposure. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (45.444) has a much longer in vitro half-life than Ligand A (-4.917), indicating better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.461 and 0.104).

**Binding Affinity:** Both ligands have excellent binding affinity (-8 and -9 kcal/mol). The difference is minor and doesn't outweigh other factors.

**Conclusion:**

Despite Ligand A having better TPSA, logP, solubility, and DILI, Ligand B's significantly better metabolic stability (lower Cl_mic and much longer t1/2) is a critical advantage for an enzyme target like SRC kinase. The longer half-life translates to potentially less frequent dosing and more sustained target engagement. While Ligand A has better solubility, the metabolic issues are more concerning for an *in vivo* drug candidate.

Output:
1
2025-04-17 16:11:08,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.247 Da) is slightly higher than Ligand B (338.323 Da), but both are acceptable.

**TPSA:** Ligand A (80.68) is better than Ligand B (96.18). Lower TPSA generally favors better absorption, though this is less critical for kinases than for CNS targets.

**logP:** Both ligands have good logP values (A: 3.907, B: 2.845), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 8 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (A: 0.756, B: 0.516), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Both ligands have similar, relatively high DILI risk (A: 77.627, B: 79.721). This is a concern for both, and further investigation would be needed.

**BBB:** Both have low BBB penetration (A: 57.154, B: 71.268), which is not a high priority for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2:** Both have negative Caco-2 values (-4.68 and -4.649). This is unusual and suggests very poor permeability. This is a significant drawback for both.

**Solubility:** Both have negative solubility values (A: -4.984, B: -3.153). This is also a major concern, indicating very poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.471, B: 0.604), which is positive.

**Microsomal Clearance:** Ligand B has a significantly higher microsomal clearance (97.133) than Ligand A (51.987). This suggests Ligand A is more metabolically stable, a key factor for kinases.

**In vitro Half-Life:** Ligand A has a better in vitro half-life (44.646 hours) than Ligand B (-42.939 hours). The negative value for B is problematic, suggesting very rapid degradation.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.332, B: 0.815).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Conclusion:**

Despite the similar binding affinity, Ligand A is the more promising candidate. It has a better TPSA, QED, lower microsomal clearance (better metabolic stability), and a significantly better in vitro half-life. While both have poor solubility and Caco-2 permeability, and concerning DILI risk, the improved pharmacokinetic properties of Ligand A make it preferable. The poor solubility and permeability would need to be addressed through formulation or structural modifications, but the metabolic stability advantage is harder to achieve.

Output:
0
2025-04-17 16:11:08,076 - INFO - Batch 442 complete. Total preferences: 7072
2025-04-17 16:11:08,076 - INFO - Processing batch 443/512...
2025-04-17 16:11:50,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.475 and 366.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.83) is well below the 140 threshold for good absorption. Ligand B (78.68) is also acceptable, but higher.

**3. logP:** Both ligands (2.002 and 2.046) are 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 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.716 and 0.799), indicating drug-likeness.

**7. DILI:** Ligand A (13.339) has a significantly lower DILI risk than Ligand B (54.556). This is a major advantage for Ligand A.

**8. BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (64.637) has lower BBB penetration than Ligand B (78.48). This is not a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-4.873) has worse Caco-2 permeability than Ligand B (-4.941), but both are poor.

**10. Aqueous Solubility:** Ligand A (-1.639) has better aqueous solubility than Ligand B (-3.08). This is a positive for Ligand A.

**11. hERG Inhibition:** Ligand A (0.472) has a lower hERG inhibition liability than Ligand B (0.096), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (18.424) has significantly lower microsomal clearance than Ligand B (57.138), suggesting better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (36.051) has a longer in vitro half-life than Ligand B (10.626). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.011) has lower P-gp efflux than Ligand B (0.064), which is beneficial for bioavailability.

**15. Binding Affinity:** Ligand B (0.0) has a slightly better binding affinity than Ligand A (-7.7). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A demonstrates a superior ADME profile compared to Ligand B. It has lower DILI risk, better solubility, lower hERG inhibition, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has a slightly better binding affinity, the ADME advantages of Ligand A are more critical for overall drug development success, especially for an enzyme target where metabolic stability and minimizing off-target effects are crucial.

Output:
0
2025-04-17 16:11:50,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.312 Da) is slightly higher than Ligand B (355.435 Da), but both are acceptable.

**TPSA:** Ligand A (79.9) is better than Ligand B (121.96). Lower TPSA generally indicates better permeability. Ligand B is above the preferred threshold of 140, which could hinder absorption.

**logP:** Ligand A (3.346) is within the optimal range (1-3). Ligand B (-0.466) is significantly below this range, potentially leading to poor membrane permeability.

**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 reasonable QED scores (A: 0.77, B: 0.516), indicating good drug-like properties.

**DILI:** Ligand A (53.432) has a higher DILI risk than Ligand B (16.44). This is a concern for Ligand A, but not prohibitive at this stage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.952) is better than Ligand B (40.403).

**Caco-2 Permeability:** Ligand A (-4.936) is better than Ligand B (-5.4), though both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-5.187) is better than Ligand B (-0.823), indicating better solubility. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.541) has a lower hERG risk than Ligand B (0.037), which is a significant advantage.

**Microsomal Clearance:** Ligand A (61.149) has higher clearance than Ligand B (9.656). Lower clearance is preferred for better metabolic stability, making Ligand B more favorable.

**In vitro Half-Life:** Ligand A (22.184 hours) has a longer half-life than Ligand B (1.41 hours). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.559) is better than Ligand B (0.006), indicating lower P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.6 kcal/mol, B: -8.7 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A has a better binding affinity, better solubility, lower hERG risk, longer half-life, and lower P-gp efflux. However, it has a higher DILI risk and higher clearance. Ligand B has a lower DILI risk and better metabolic stability, but suffers from poor logP, TPSA, and Caco-2 permeability, and a very short half-life.

Given the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), and the fact that the binding affinity difference isn't massive, Ligand A is the more promising candidate. The longer half-life and lower hERG risk are significant advantages that outweigh the slightly higher DILI and clearance. The solubility is also better, which is important for formulation.

Output:
1
2025-04-17 16:11:50,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.551 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is better than Ligand B (32.34), being under 140, suggesting good absorption.

**logP:** Ligand A (2.8) is optimal, while Ligand B (4.567) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 2 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the limits.

**QED:** Both ligands have similar QED values (0.705 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (10.857) has a significantly lower DILI risk than Ligand B (12.641), which is a crucial advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (85.459) is better than Ligand A (77.2). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.593) is slightly better than Ligand B (-4.801).

**Aqueous Solubility:** Ligand A (-2.388) is better than Ligand B (-4.471), indicating better solubility.

**hERG Inhibition:** Ligand A (0.352) has a much lower hERG inhibition liability than Ligand B (0.893), a significant safety advantage.

**Microsomal Clearance:** Ligand B (63.336) has a slightly higher clearance than Ligand A (53.456), suggesting Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (5.627) has a significantly longer half-life than Ligand B (0.003), a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.512), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better safety profile (lower DILI, lower hERG), better solubility, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and significantly stronger binding affinity. While both have poor Caco-2 permeability, the other advantages of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 16:11:50,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**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. Ligand B (370.406 Da) is also acceptable.

**TPSA:** Ligand A (78.86) is well below the 140 threshold for good oral absorption. Ligand B (109.33) is also below, but closer to the limit.

**logP:** Ligand A (3.111) is within the optimal range (1-3). Ligand B (-0.086) is significantly below 1, which is a concern for permeability and could lead to poor absorption.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.558, B: 0.719), indicating drug-like properties.

**DILI:** Ligand A (83.676) has a higher DILI risk than Ligand B (64.676), which is better.

**BBB:** Ligand A (32.881) has poor BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (77.705) has better BBB penetration, but again, this is less crucial here.

**Caco-2 Permeability:** Ligand A (-5.059) has very poor Caco-2 permeability. Ligand B (-4.58) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor aqueous solubility (A: -3.676, B: -2.229). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.819) has a slightly higher hERG risk than Ligand B (0.066), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (22.382) has a moderate clearance, while Ligand B (1.651) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-41.397) has a very short half-life. Ligand B (12.041) has a better half-life, although still not ideal.

**P-gp Efflux:** Ligand A (0.508) has moderate P-gp efflux. Ligand B (0.012) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite Ligand A's lower molecular weight, Ligand B is the superior candidate. The key factors driving this decision are: significantly stronger binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. While both have poor solubility and permeability, the potency and safety advantages of Ligand B outweigh these drawbacks, especially for an enzyme target where optimizing potency is paramount.

Output:
1
2025-04-17 16:11:50,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.447 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.01) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (67.87) is excellent, well below 140.

**logP:** Both ligands (2.028 and 2.112) are within 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 4 HBA, also acceptable and potentially better for permeability due to fewer hydrogen bonds.

**QED:** Both ligands have reasonable QED scores (0.748 and 0.689), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 83.908, which is high and concerning. Ligand B has a much lower DILI risk of 25.126, a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (76.154) than Ligand A (50.097), but this is less critical.

**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. Ligand B is slightly better (-1.854 vs -3.679).

**hERG:** Ligand A (0.098) has a slightly better hERG profile than Ligand B (0.425), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (33.499 mL/min/kg) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (44.187 mL/min/kg).

**In vitro Half-Life:** Ligand A (6.722 hours) has a longer half-life than Ligand B (-1.982 hours). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.093), which is good.

**Binding Affinity:** Ligand A (-8.3 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:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, its DILI risk is very high. Ligand B has a much better safety profile (lower DILI) and better TPSA/Solubility, but weaker binding affinity.

Given the enzyme-specific priorities, potency (affinity) is crucial. The 1.9 kcal/mol difference in binding affinity is substantial. While the high DILI risk of Ligand A is concerning, it might be mitigated through structural modifications during lead optimization. The weaker affinity of Ligand B might be harder to overcome.

Output:
1
2025-04-17 16:11:50,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.385 Da and 354.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (101.13) is slightly above the optimal <140, but acceptable. Ligand B (88.1) is excellent, well below 140.

**logP:** Ligand A (1.995) is within the optimal 1-3 range. Ligand B (0.306) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also good.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.772 and 0.687, respectively), indicating drug-like properties.

**DILI:** Ligand A (61.962) has a moderate DILI risk, but still acceptable. Ligand B (14.851) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.641) is better than Ligand B (38.813).

**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, also unusual and concerning. This suggests very poor solubility.

**hERG:** Ligand A (0.416) has a low hERG risk, which is excellent. Ligand B (0.151) is even lower, a further advantage.

**Microsomal Clearance:** Ligand A (-4.812) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand B (5.259) has a positive clearance, suggesting moderate metabolic liability.

**In vitro Half-Life:** Ligand A (10.88) has a reasonable half-life. Ligand B (14.689) has a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.012), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is superior due to its significantly lower DILI risk, lower hERG risk, and longer half-life. The slightly lower logP and Caco-2/Solubility values are less concerning given the strong affinity and other favorable properties. The negative solubility and Caco-2 values are concerning for both, but are less impactful than the metabolic stability and toxicity profiles.

Output:
1
2025-04-17 16:11:50,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzyme targets: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (353.507 and 357.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.67) is slightly higher than Ligand B (74.86), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (1.447) is optimal, while Ligand B (4.172) is approaching the upper limit and could potentially cause solubility 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 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.548 and 0.592, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (5.312) has a very low DILI risk, significantly better than Ligand B (78.131), which indicates a high risk of liver injury. This is a major concern for Ligand B.

**8. BBB:**  BBB is less critical for a non-CNS target like SRC kinase. Ligand B (68.631) has a higher BBB percentile than Ligand A (46.452), but this is not a deciding factor here.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.164) is slightly better than Ligand B (-5.262).

**10. Aqueous Solubility:** Ligand A (-1.385) has better solubility than Ligand B (-4.194). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.243) has a very low hERG risk, while Ligand B (0.812) has a slightly elevated risk.

**12. Microsomal Clearance:** Ligand A (3.305) has significantly lower microsomal clearance than Ligand B (52.868), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.347) has a much longer in vitro half-life than Ligand B (57.191).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.151 respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.1 kcal/mol, respectively). The difference of 0.3 kcal/mol is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering the priorities for enzyme targets, Ligand A is the superior candidate. It exhibits a significantly lower DILI risk, better solubility, lower microsomal clearance (higher metabolic stability), and a longer half-life, all while maintaining comparable binding affinity to Ligand B. Although Ligand B has a slightly higher BBB penetration, this is not a major concern for a non-CNS target. The higher logP of Ligand B is also a potential drawback.

Output:
0
2025-04-17 16:11:50,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (465.193 Da) is higher, but still acceptable. Ligand B (348.422 Da) is preferable.

**TPSA:** Ligand A (36.67) is excellent, well below the 140 threshold. Ligand B (67.23) is still reasonable, but less optimal.

**logP:** Ligand A (4.138) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.834) is within the optimal 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.

**QED:** Both ligands have good QED scores (A: 0.583, B: 0.903), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (18.108), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (93.563) has better BBB penetration, but it's not a primary factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, 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, which is concerning. This suggests poor solubility, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.977) has a slightly higher hERG risk than Ligand B (0.322).

**Microsomal Clearance:** Ligand A (55.605) has a higher microsomal clearance than Ligand B (5.79), indicating lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-14.004) has a negative half-life, which is unrealistic and a major red flag. Ligand A (18.672) is reasonable.

**P-gp Efflux:** Ligand A (0.888) has a slightly higher P-gp efflux liability than Ligand B (0.012).

**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:**

Ligand A has a much stronger binding affinity, which is a key priority for enzyme inhibitors. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a higher P-gp efflux liability. It also has a less optimal logP. Ligand B has a better safety profile (lower DILI, lower hERG), better QED, and lower P-gp efflux, but its binding affinity is significantly weaker, and its in vitro half-life is unrealistic. The negative Caco-2 and solubility values for both are concerning, but the affinity difference is substantial. Given the importance of potency for enzyme inhibition, and the fact that the other issues with Ligand A *might* be addressable through further optimization, I would choose Ligand A.

Output:
0
2025-04-17 16:11:50,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.515 Da) is slightly higher than Ligand B (348.403 Da), but both are acceptable.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (105.48). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.603) is within the optimal range (1-3), while Ligand B (-0.709) is slightly below, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (6).

**QED:** Ligand A (0.833) is significantly better than Ligand B (0.565), indicating a more drug-like profile.

**DILI:** Ligand A (28.228) has a much lower DILI risk than Ligand B (38.581). Both are below the 40 threshold, but A is better.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 51.493, Ligand B: 50.407). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative values (-5.416 and -5.538), 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 have negative solubility values (-2.087 and -0.597), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.112, Ligand B: 0.154).

**Microsomal Clearance:** Ligand A (28.094) has a higher (worse) microsomal clearance than Ligand B (-11.273). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (7.554) has a significantly longer half-life than Ligand A (1.48). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.057, Ligand B: 0.018).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This 1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has better drug-like properties (QED, TPSA, logP, HBD/HBA, DILI) and acceptable hERG risk. However, its metabolic stability (Cl_mic) and half-life are poor.

Ligand B has a slightly better binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. While its TPSA and logP are less ideal, the improved affinity and metabolic profile are crucial for an enzyme inhibitor. The difference in binding affinity is substantial enough to compensate for the slightly less favorable physicochemical properties.

Output:
1
2025-04-17 16:11:50,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.4 and 347.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.6 and 93.7) are reasonably low, suggesting good potential for cell permeability, though not ideal for CNS penetration.

**logP:** Ligand A (-0.106) is slightly hydrophilic, potentially impacting permeability. Ligand B (0.456) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Both ligands have good QED scores (0.729 and 0.809), indicating drug-like properties.

**DILI:** Ligand A (34.4) has a slightly higher DILI risk than Ligand B (27.4), but both are below the concerning threshold of 60.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.054 and -4.821), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have very poor aqueous solubility (-1.626 and -1.5), which is a major drawback for oral bioavailability.

**hERG Inhibition:** Ligand A (0.044) has a very low hERG risk, which is excellent. Ligand B (0.117) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand B (-15.331) has significantly better metabolic stability (lower clearance) than Ligand A (-8.551). This is a crucial advantage for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-21.148) has a much longer half-life than Ligand A (-3.784), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.017) shows minimal P-gp efflux, while Ligand B (0.016) is also very low.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor, as a >1.5 kcal/mol advantage can outweigh other issues.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B is significantly more promising. Its substantially improved metabolic stability (lower Cl_mic, longer t1/2) and, critically, much stronger binding affinity (-8.0 vs 0.0 kcal/mol) outweigh the slightly higher DILI and logP. The hERG risk is also acceptable. The poor solubility/permeability would need to be addressed in formulation, but the potency and metabolic profile of Ligand B make it the superior candidate.

Output:
1
2025-04-17 16:11:50,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.483 and 360.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is slightly higher than Ligand B (67.23), but both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.758 and 2.498), 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:** Ligand B (0.91) has a significantly higher QED score than Ligand A (0.71), indicating a more drug-like profile.

**DILI:** Ligand A (65.297) has a higher DILI risk than Ligand B (59.287). Both are above the ideal <40, but Ligand B is closer.

**BBB:** Ligand A (53.548) has a lower BBB penetration percentile than Ligand B (68.166). This is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-5.498) has worse Caco-2 permeability than Ligand B (-4.954). Both are negative, indicating poor permeability, but B is better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.475 and -3.494). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.54) has a higher hERG inhibition risk than Ligand B (0.329). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand B (14.556) has a significantly lower microsomal clearance than Ligand A (63.25), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (24.538 hours) has a much longer in vitro half-life than Ligand A (8.057 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.262) has lower P-gp efflux than Ligand B (0.179), which is a slight advantage.

**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, potentially outweighing some ADME concerns. The difference is >1.5 kcal/mol.

**Conclusion:**

While Ligand B has superior ADME properties (QED, DILI, BBB, Caco-2, Solubility, hERG, Cl_mic, t1/2), the significantly stronger binding affinity of Ligand A (-9.5 vs -8.0 kcal/mol) is a critical factor for an enzyme inhibitor. The potency difference is substantial enough to potentially overcome the ADME liabilities, especially if formulation strategies can mitigate the solubility issues.

Output:
0
2025-04-17 16:11:50,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**
*   **MW:** 345.315 Da - Good. Within the ideal range.
*   **TPSA:** 128.78 - Acceptable, but approaching the upper limit for good oral absorption.
*   **logP:** -0.211 - Low. Could hinder permeation.
*   **HBD:** 2 - Good.
*   **HBA:** 6 - Good.
*   **QED:** 0.561 - Good. Drug-like.
*   **DILI:** 85.653 - High risk of liver injury. A significant concern.
*   **BBB:** 64.909 - Moderate. Not a primary concern for a non-CNS target like SRC.
*   **Caco-2:** -4.945 - Very poor permeability. A major drawback.
*   **Solubility:** -3.584 - Very poor solubility. A significant issue for bioavailability.
*   **hERG:** 0.047 - Low risk. Excellent.
*   **Cl_mic:** -5.851 - Low clearance, indicating good metabolic stability. Excellent.
*   **t1/2:** 22.239 - Good in vitro half-life.
*   **Pgp:** 0.002 - Low efflux. Good.
*   **Affinity:** -7.0 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 354.466 Da - Good. Within the ideal range.
*   **TPSA:** 49.85 - Excellent. Well below the threshold for good absorption.
*   **logP:** 2.104 - Good. Within the optimal range.
*   **HBD:** 0 - Good.
*   **HBA:** 3 - Good.
*   **QED:** 0.76 - Excellent. Highly drug-like.
*   **DILI:** 10.392 - Very low risk of liver injury. Excellent.
*   **BBB:** 97.635 - Very high. Not a primary concern for SRC.
*   **Caco-2:** -4.438 - Poor permeability, but better than Ligand A.
*   **Solubility:** -2.319 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.73 - Moderate risk. Acceptable, but requires further investigation.
*   **Cl_mic:** 49.466 - High clearance, indicating poor metabolic stability. A significant drawback.
*   **t1/2:** -11.901 - Very short half-life. A major concern.
*   **Pgp:** 0.144 - Low efflux. Good.
*   **Affinity:** -7.6 kcal/mol - Excellent binding affinity, slightly better than Ligand A.

**Comparison & Decision:**

Both ligands have excellent binding affinity. However, Ligand A suffers from very poor solubility and permeability, despite its good metabolic stability. Ligand B has better physicochemical properties (TPSA, logP, solubility, permeability) and a much lower DILI risk. The major drawback of Ligand B is its high microsomal clearance and short half-life.

For an enzyme target like SRC kinase, metabolic stability (Cl_mic and t1/2) is crucial. While Ligand A has better metabolic stability, the poor solubility and permeability of Ligand A are likely to severely limit its bioavailability *in vivo*. Ligand B's issues with metabolic stability *could* be addressed through structural modifications during lead optimization, while fixing the solubility/permeability of Ligand A would be a much more significant challenge. The lower DILI risk for Ligand B is also a major advantage.

Therefore, despite the metabolic stability concerns, Ligand B is the more promising starting point for drug development.

Output:
1
2025-04-17 16:11:50,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.358 Da and 367.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.0) is slightly higher than Ligand B (75.01), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.427) is optimal, while Ligand B (0.504) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable 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: 0.745, B: 0.844), indicating drug-like properties.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (39.201). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (66.576) is slightly better than Ligand B (50.523).

**Caco-2 Permeability:** Ligand A (-5.161) is worse than Ligand B (-4.61), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.591) is worse than Ligand B (-2.118), which is a concern for formulation and bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.519, B: 0.262), which is good.

**Microsomal Clearance:** Ligand A (62.158) has higher microsomal clearance than Ligand B (16.298), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-15.735) has a shorter half-life than Ligand B (33.535), which is undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.214, B: 0.039).

**Binding Affinity:** Both ligands have comparable binding affinities (A: -8.3 kcal/mol, B: -8.6 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 is significantly better due to its lower DILI risk, better solubility, lower microsomal clearance, and longer half-life. While Ligand A has slightly better Caco-2 permeability and BBB, these are less critical for a non-CNS kinase inhibitor. The slightly better binding affinity of Ligand B is a bonus. The lower logP of Ligand B is a minor drawback, but the other advantages outweigh this.

Output:
1
2025-04-17 16:11:50,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.4 and 354.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.18) is better than Ligand B (58.64) as it is still within the acceptable range for oral absorption, while Ligand B is significantly lower.

**logP:** Ligand A (-0.675) is slightly low, potentially hindering permeation, while Ligand B (2.461) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Ligand B (0.715) has a better QED score than Ligand A (0.479), indicating a more drug-like profile.

**DILI:** Ligand A (43.39%) has a slightly higher DILI risk than Ligand B (25.94%), but both are below the concerning threshold of 60%.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (92.012%) has a higher BBB penetration, but this is not a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.552 and -4.478), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.886 and -3.05), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.4 and 0.567), which is favorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (32.73 and 33.39 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-41.613) has a significantly longer in vitro half-life than Ligand B (-6.573), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.203).

**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 small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B has several advantages: better logP, QED, and binding affinity. However, both ligands suffer from poor Caco-2 permeability and aqueous solubility. The significantly longer half-life of Ligand A is a substantial benefit for an enzyme target, as it suggests less frequent dosing. The slightly better binding affinity of Ligand B is not enough to overcome the shorter half-life and the slightly lower QED.

Output:
0
2025-04-17 16:11:50,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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.

**TPSA:** Ligand A (111.25) is better than Ligand B (69.04) as it is still within the acceptable range for oral absorption.

**logP:** Both ligands have good logP values (A: 1.469, B: 3.503), falling within the optimal 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 (HBD=3, HBA=4) is slightly better than Ligand B (HBD=1, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.77, B: 0.796).

**DILI:** Ligand A (34.626) has a significantly lower DILI risk than Ligand B (58.511), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.027) is slightly better than Ligand B (62.466).

**Caco-2 Permeability:** Ligand A (-5.355) has a better Caco-2 permeability than Ligand B (-4.75).

**Aqueous Solubility:** Ligand A (-3.169) has better aqueous solubility than Ligand B (-4.644).

**hERG Inhibition:** Ligand A (0.573) has a lower hERG inhibition liability than Ligand B (0.177), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-16.987) has a much lower microsomal clearance than Ligand B (94.645), indicating better metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (19.987) has a better in vitro half-life than Ligand B (-22.745).

**P-gp Efflux:** Ligand A (0.008) has lower P-gp efflux liability than Ligand B (0.322).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). However, the difference of 1.7 kcal/mol is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A demonstrates a significantly better ADME profile, particularly regarding DILI risk, metabolic stability (Cl_mic and t1/2), hERG inhibition, and solubility. While Ligand B has slightly better binding affinity, the overall risk/benefit profile favors Ligand A as a more viable drug candidate.

Output:
0
2025-04-17 16:11:50,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.487 Da and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.76) is better than Ligand B (99.33), being comfortably below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.834 and 1.285 respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=4, HBA=3). While both are within acceptable limits, fewer H-bond donors generally improve permeability.

**QED:** Ligand A (0.681) has a better QED score than Ligand B (0.477), indicating a more drug-like profile.

**DILI:** Ligand A (37.728) has a slightly higher DILI risk than Ligand B (28.887), but both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (77.317 and 70.919), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.868) is better than Ligand B (-5.196), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.253) is better than Ligand B (-2.48), indicating better solubility.

**hERG:** Both ligands have very low hERG risk (0.159 and 0.139), which is excellent.

**Microsomal Clearance:** Ligand A (49.611) has higher microsomal clearance than Ligand B (32.984), suggesting lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-4.395) has a much better in vitro half-life than Ligand A (-16.022), indicating greater stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.077 and 0.028).

**Binding Affinity:** Both ligands have very similar binding affinities (-6.6 and -6.5 kcal/mol). The difference is negligible.

**Conclusion:**

Despite Ligand A having a better QED, TPSA, solubility and Caco-2 permeability, Ligand B is the more promising candidate due to its significantly improved metabolic stability (lower Cl_mic and longer half-life). For an enzyme target like SRC kinase, metabolic stability is crucial for achieving adequate exposure and duration of action. The small difference in binding affinity is outweighed by the substantial difference in pharmacokinetic properties.

Output:
1
2025-04-17 16:11:50,811 - INFO - Batch 443 complete. Total preferences: 7088
2025-04-17 16:11:50,811 - INFO - Processing batch 444/512...
2025-04-17 16:12:33,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.383 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.53) is higher than Ligand B (61.88). While both are reasonably low, Ligand B's TPSA is significantly better, suggesting better permeability.

**logP:** Both ligands (0.684 and 0.718) are slightly below the optimal 1-3 range, but not drastically so. This could potentially impact permeability, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Ligand B is preferable here, with a lower HBD count, which generally improves membrane permeability.

**QED:** Ligand B (0.656) has a better QED score than Ligand A (0.476), indicating a more drug-like profile.

**DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (5.118). This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B (77.937) has a higher BBB percentile than Ligand A (59.054).

**Caco-2 Permeability:** Ligand A (-5.29) and Ligand B (-4.927) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close, so this isn't a major differentiator.

**Aqueous Solubility:** Ligand A (-2.44) has slightly better aqueous solubility than Ligand B (-1.114). This is a minor advantage.

**hERG Inhibition:** Ligand A (0.051) has a lower hERG inhibition risk than Ligand B (0.608). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-4.415) has a significantly lower (better) microsomal clearance than Ligand B (17.265), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.828) has a shorter half-life than Ligand B (-4.288). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.029, respectively), which is good.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.1 and -9.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better overall. While Ligand A has a slight edge in hERG and solubility, Ligand B excels in critical areas: lower DILI risk, better QED, lower TPSA, and significantly improved metabolic stability (lower Cl_mic). The similar binding affinities mean these differences are decisive. The slightly shorter half-life of Ligand A is less concerning than the higher DILI risk and poorer metabolic stability.

Output:
1
2025-04-17 16:12:33,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.518 Da) and Ligand B (344.459 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (82.53) is slightly higher than Ligand B (69.3), but both are well within the acceptable range.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 1.706, Ligand B: 2.351), which is optimal for permeability and avoiding 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 the recommended limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.8, Ligand B: 0.772), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 47.034, which is good (below 60). Ligand B has a very low DILI risk of 13.649, which is excellent.

**BBB:** Ligand A has a BBB penetration of 40.713, while Ligand B has 82.164. While not a primary concern for a kinase inhibitor, the higher BBB value of Ligand B is slightly favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.922 and -4.946). This is unusual and suggests very poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.021 and -2.181). This is also concerning, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.168, Ligand B: 0.284). This is a positive attribute.

**Microsomal Clearance:** Ligand A has a Cl_mic of 38.403 mL/min/kg, while Ligand B has 26.797 mL/min/kg. Lower is better for metabolic stability, so Ligand B is slightly favored here.

**In vitro Half-Life:** Ligand A has a t1/2 of 24.494 hours, while Ligand B has -23.912 hours. The negative value for Ligand B is problematic and suggests rapid degradation or an issue with the assay. Ligand A is significantly better in this regard.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.086, Ligand B: 0.041), which is desirable.

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.7 kcal/mol) than Ligand A (-7.8 kcal/mol). This 0.9 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand B emerges as the more promising candidate. Its significantly better binding affinity (-8.7 vs -7.8 kcal/mol) is a major advantage for an enzyme inhibitor. It also exhibits a lower DILI risk and lower microsomal clearance, indicating better safety and metabolic stability. The negative in vitro half-life for Ligand B is a serious concern, but the strong binding affinity might justify further investigation into this issue. Ligand A's positive half-life is good, but its weaker binding affinity makes it less attractive.

Output:
1
2025-04-17 16:12:33,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.453 Da and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.43 and 78.95) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (2.411) is optimal, while Ligand B (0.141) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 limit.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.57 and 0.769), indicating drug-likeness.

**DILI:** Ligand A (61.691) has a higher DILI risk than Ligand B (32.067). This is a negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.774) is higher than Ligand B (64.87).

**Caco-2 Permeability:** Ligand A (-5.099) has poor Caco-2 permeability, while Ligand B (-4.842) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.682) has poor solubility, while Ligand B (-1.173) is also poor, but better.

**hERG Inhibition:** Ligand A (0.817) has a slightly higher hERG risk than Ligand B (0.158). Lower is better, so this favors Ligand B.

**Microsomal Clearance:** Ligand A (32.916) has moderate clearance, while Ligand B (-1.79) has *very* low clearance, indicating excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (8.141) has a moderate half-life, while Ligand B (5.851) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.078) has low P-gp efflux, while Ligand B (0.021) has very low P-gp efflux. Both are good.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.9 kcal/mol). This difference of 2 kcal/mol is a major advantage for Ligand B, and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better BBB score, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.9 vs -7.9 kcal/mol) and much better metabolic stability (very low Cl_mic) are crucial for an enzyme target. While both have poor solubility and Caco-2 permeability, the potency and stability advantages of Ligand B are more important to optimize during lead optimization. The lower DILI and hERG risk for Ligand B are also favorable.

Output:
1
2025-04-17 16:12:33,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 346.402 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is better than Ligand B (60.85), both are acceptable but A is closer to the threshold of 140 for good oral absorption.

**3. logP:** Both ligands (2.075 and 1.865) are within the optimal range of 1-3.

**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 3 HBA, which is well within the acceptable limit of 10.

**6. QED:** Ligand B (0.909) has a significantly better QED score than Ligand A (0.692), indicating a more drug-like profile.

**7. DILI:** Ligand A (14.889) has a much lower DILI risk than Ligand B (35.673), which is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration, but Ligand B (91.508) is slightly better than Ligand A (83.133). However, BBB is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.384 and -4.379) which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.416 and -2.016) which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.189) has a lower hERG risk than Ligand B (0.592), which is a crucial advantage for kinase inhibitors.

**12. Microsomal Clearance:** Ligand B (33.88) has a significantly lower microsomal clearance than Ligand A (60.753), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.829) has a negative half-life, which is not possible. Ligand A (6.391) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.127 and 0.228).

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic) and QED. However, it has a higher DILI risk and a nonsensical half-life. Ligand A has a lower DILI risk and a reasonable half-life, but significantly weaker binding affinity.

Given the enzyme-specific priorities, binding affinity is paramount. The substantial difference in binding affinity (-8.6 vs 0.0 kcal/mol) is likely to be the most important factor. While the DILI risk for Ligand B is higher, it might be manageable with further optimization. The negative half-life is a red flag, but could be an experimental error. The poor solubility and permeability of both compounds are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:12:33,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.45 & 350.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is excellent, well below the 140 threshold for oral absorption. Ligand B (118.58) is still acceptable, but less optimal.

**logP:** Ligand A (0.45) is a bit low, potentially hindering permeability. Ligand B (1.184) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is good. Ligand B (1 HBD, 6 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.693 and 0.629), indicating good drug-likeness.

**DILI:** Ligand A (13.57) has a significantly lower DILI risk than Ligand B (49.17). This is a major advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (59.36) is slightly better than Ligand A (50.06).

**Caco-2 Permeability:** Ligand A (-4.814) has poor Caco-2 permeability, which is a concern. Ligand B (-5.033) is similarly poor.

**Aqueous Solubility:** Ligand A (-0.791) has slightly better solubility than Ligand B (-2.86).

**hERG:** Ligand A (0.151) has a lower hERG risk than Ligand B (0.107), which is preferable.

**Microsomal Clearance:** Ligand A (9.23 mL/min/kg) has a higher clearance than Ligand B (8.985 mL/min/kg), meaning Ligand B is metabolically more stable.

**In vitro Half-Life:** Ligand A (23.383 hours) has a longer half-life than Ligand B (-4.323 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.069).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly better binding affinity than Ligand B (-6.8 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 its logP and Caco-2 permeability are less ideal, its significantly superior binding affinity (-7.6 vs -6.8 kcal/mol), lower DILI risk, and longer half-life are crucial advantages for an enzyme inhibitor. The better solubility also helps. Ligand B has better metabolic stability, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 16:12:33,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.03) is excellent, well below the 140 threshold for oral absorption. Ligand B (122.03) is still acceptable, but less optimal.

**logP:** Ligand A (2.656) is within the optimal 1-3 range. Ligand B (0.048) is very low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (3 HBD, 7 HBA) is also acceptable, but higher values could impact permeability.

**QED:** Ligand A (0.828) has a strong drug-like profile. Ligand B (0.635) is also reasonable, but lower.

**DILI:** Ligand A (20.589) has a very low DILI risk, excellent. Ligand B (49.438) is moderate, but acceptable.

**BBB:** Ligand A (91.392) shows good BBB penetration, while Ligand B (17.332) is poor. This isn't a primary concern for a non-CNS target like SRC, but is a bonus for A.

**Caco-2 Permeability:** Ligand A (-4.671) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.416) is similarly poor.

**Aqueous Solubility:** Ligand A (-2.495) is also concerningly low. Ligand B (-1.965) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.532) has a low hERG risk, excellent. Ligand B (0.045) is very low, also excellent.

**Microsomal Clearance:** Ligand A (3.398) has a relatively low clearance, suggesting better metabolic stability. Ligand B (2.668) is even lower, indicating even better metabolic stability.

**In vitro Half-Life:** Ligand A (19.855) has a reasonable half-life. Ligand B (0.191) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.059) has low P-gp efflux. Ligand B (0.006) has very low P-gp efflux.

**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 could outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, and excellent metabolic stability and low hERG risk. However, its low logP, poor Caco-2 permeability, and very short half-life are major concerns. Ligand A has better solubility, permeability, and a longer half-life, but its binding affinity is weaker.

Given the enzyme-specific priorities, binding affinity is paramount. The 0.4 kcal/mol difference in affinity is significant. While Ligand B's ADME properties are suboptimal, they might be addressable through further optimization. The potency advantage of Ligand B is likely to be more impactful in initial lead optimization.

Output:
1
2025-04-17 16:12:33,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.459 Da and 364.848 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.33) is better than Ligand B (49.41), being below 140, suggesting good absorption potential.

**logP:** Ligand A (1.818) is optimal, while Ligand B (3.244) is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly higher in both counts than Ligand B (1 HBD, 2 HBA), but both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.754 and 0.891), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (49.011 and 44.862), which is favorable.

**BBB:** Ligand A (76.658) and Ligand B (91.431) both have good BBB penetration, but Ligand B is better. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.762) and Ligand B (-4.67) are similar and suggest poor permeability.

**Aqueous Solubility:** Ligand A (-3.149) and Ligand B (-4.507) are similar and suggest poor solubility.

**hERG:** Both ligands have low hERG risk (0.653 and 0.72), which is excellent.

**Microsomal Clearance:** Ligand A (47.564) has a better (lower) Cl_mic than Ligand B (8.26), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (17.469) has a longer half-life than Ligand B (0.809), which is desirable.

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux liability than Ligand B (0.307), which is better for bioavailability.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), a difference of 0.7 kcal/mol. This is a significant advantage.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, which is the most important factor for an enzyme target. However, Ligand A has better metabolic stability (lower Cl_mic, longer half-life) and lower P-gp efflux. The solubility and permeability are similar and both are poor. Considering the balance, the slightly improved binding affinity of Ligand B outweighs the slightly better ADME properties of Ligand A.

Output:
1
2025-04-17 16:12:33,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.358 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.91) is better than Ligand B (64.09), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.315) is optimal (1-3), while Ligand B (0.018) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Both have 4 HBA, which is good.

**QED:** Ligand A (0.886) has a significantly better QED score than Ligand B (0.688), indicating a more drug-like profile.

**DILI:** Ligand B (5.196) has a much lower DILI risk than Ligand A (75.766). This is a significant advantage for Ligand B.

**BBB:** Ligand A (65.025) has a better BBB penetration score than Ligand B (31.601), but BBB is not a high priority for a kinase inhibitor unless CNS activity is desired.

**Caco-2 Permeability:** Ligand A (-4.537) and Ligand B (-4.716) both have negative Caco-2 permeability values, which is concerning. However, the scale is not clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-3.094) and Ligand B (-0.246) both have negative solubility values, which is concerning.

**hERG:** Ligand A (0.049) has a lower hERG risk than Ligand B (0.153), which is preferable.

**Microsomal Clearance:** Ligand B (-11.773) has a much lower (better) microsomal clearance than Ligand A (2.865), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (1.51) has a slightly better in vitro half-life than Ligand A (-33.336).

**P-gp Efflux:** Ligand A (0.042) has a lower P-gp efflux liability than Ligand B (0.03), which is slightly better.

**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 has a significantly better binding affinity and a better QED score, but suffers from a high DILI risk and a higher microsomal clearance. Ligand B has a much better safety profile (DILI, hERG) and metabolic stability, but its binding affinity is very weak and logP is very low.

Given the importance of potency for kinase inhibitors, the substantial binding affinity advantage of Ligand A outweighs its drawbacks, *provided* the DILI risk can be mitigated through further structural modifications. The very weak binding of Ligand B makes it an unlikely candidate, despite its better safety profile.

Output:
1
2025-04-17 16:12:33,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (358.368 and 357.454 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (86.89) is significantly better than Ligand B (47.34), both being well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.68 and 3.349) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**QED:** Ligand B (0.843) has a considerably higher QED score than Ligand A (0.467), indicating a more drug-like profile.

**DILI:** Ligand A (32.067) has a much lower DILI risk than Ligand B (66.809), which is a significant advantage.

**BBB:** Ligand A (93.641) has a higher BBB penetration potential than Ligand B (86.468). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data. However, the values are similar.

**hERG Inhibition:** Ligand A (0.417) shows a lower hERG inhibition liability than Ligand B (0.86), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand B (72.852) has a higher microsomal clearance than Ligand A (18.005), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-23.711) has a much longer in vitro half-life than Ligand B (-14.022), which is a major benefit.

**P-gp Efflux:** Ligand A (0.229) shows lower P-gp efflux liability than Ligand B (0.753).

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is the most important factor, as a 1.5 kcal/mol advantage is considered substantial.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has a better QED score, Ligand A boasts a substantially stronger binding affinity, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The negative solubility and Caco-2 values are concerning for both, but the potency and safety advantages of Ligand A outweigh these concerns.

Output:
1
2025-04-17 16:12:33,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (376.551 Da) is also good.

**TPSA:** Ligand A (58.22) is better than Ligand B (51.02), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 4.092, B: 3.536), falling within the optimal 1-3 range. Ligand A is slightly higher, potentially increasing off-target interactions, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=0, HBA=6). Both are within acceptable limits, but A's donor count is preferable for balancing solubility and permeability.

**QED:** Ligand A (0.851) has a significantly better QED score than Ligand B (0.362), indicating a more drug-like profile.

**DILI:** Ligand B (57.852) has a higher DILI risk than Ligand A (18.573). This is a significant concern, as lower DILI is preferred.

**BBB:** Both ligands have moderate BBB penetration (A: 62.427, B: 67.158). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.93) has worse Caco-2 permeability than Ligand B (-5.503). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.234) has better aqueous solubility than Ligand B (-2.191). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.849, B: 0.662).

**Microsomal Clearance:** Ligand A (51.317) has significantly lower microsomal clearance than Ligand B (95.509), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-26.011) has a much longer in vitro half-life than Ligand B (6.795). This is also a significant advantage for reducing dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.323, B: 0.658).

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.2 kcal/mol). While a difference of 0.7 kcal/mol is noticeable, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: QED, DILI risk, metabolic stability (Cl_mic and t1/2), and solubility. The lower DILI risk and improved metabolic stability of Ligand A are particularly important for an enzyme target like SRC kinase. The slightly lower Caco-2 permeability of A is a concern, but can potentially be addressed through formulation strategies.



Output:
0
2025-04-17 16:12:33,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (354.519 and 362.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (41.99) is significantly better than Ligand B (106.39). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's higher TPSA could hinder cell permeability.

**3. logP:** Both ligands have good logP values (4.842 and 4.362), falling within the optimal 1-3 range, though leaning towards the higher end. This might present some solubility challenges, but is 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 (6). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.835 and 0.586), indicating good drug-like properties.

**7. DILI:** Ligand A (44.281) has a much lower DILI risk than Ligand B (94.804). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (72.547) has a higher BBB percentile than Ligand B (63.746), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Ligand A (-4.894) has a better (more positive) Caco-2 value than Ligand B (-4.57), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-5.218) has better aqueous solubility than Ligand B (-5.927). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.517) has a lower hERG risk than Ligand B (0.247). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (77.721) has lower microsomal clearance than Ligand A (85.169), suggesting better metabolic stability. This is a positive for Ligand B.

**13. In vitro Half-Life:** Ligand A (25.969) has a longer in vitro half-life than Ligand B (19.794). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux than Ligand B (0.289), indicating better bioavailability and potentially better tissue distribution.

**15. Binding Affinity:** Ligand B (-7.2) has a significantly stronger binding affinity than Ligand A (-10). 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 (-7.2 kcal/mol vs -10 kcal/mol). However, Ligand A demonstrates superior ADME properties across several critical parameters: lower DILI risk, better solubility, lower hERG inhibition, better Caco-2 permeability, and a longer half-life. While Ligand B's lower clearance is a plus, the combination of safety and pharmacokinetic advantages for Ligand A is compelling. The difference in binding affinity, while substantial, may be overcome with further optimization of Ligand A. Given the enzyme-kinase focus, prioritizing metabolic stability and minimizing off-target effects (like hERG inhibition) is crucial.

Output:
0
2025-04-17 16:12:33,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.81) is better than Ligand B (110.85). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (1.312) is within the optimal 1-3 range. Ligand B (-0.965) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**QED:** Both ligands have similar QED values (0.519 and 0.488), indicating reasonable drug-likeness.

**DILI:** Ligand A (22.8) has a significantly lower DILI risk than Ligand B (29.818), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand A (61.923) has a better BBB penetration percentile than Ligand B (49.477), although BBB isn't a primary concern for a kinase inhibitor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5 and -5.486). This is unusual and suggests poor permeability. However, we'll consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.599 and -1.16). This is also concerning, and suggests formulation challenges.

**hERG Inhibition:** Ligand A (0.371) has a much lower hERG inhibition liability than Ligand B (0.089). This is a critical advantage, as it reduces the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-9.218) has a *much* lower (better) microsomal clearance than Ligand B (-18.737), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (5.711) has a slightly longer half-life than Ligand B (4.558).

**P-gp Efflux:** Ligand A (0.029) has a much lower P-gp efflux liability than Ligand B (0.003), suggesting better oral bioavailability and potentially better CNS exposure if needed.

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-7.7), a difference of 0.9 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly superior in almost all ADME-Tox properties. The lower DILI risk, substantially improved metabolic stability (Cl_mic and t1/2), lower hERG inhibition, and lower P-gp efflux of Ligand A are crucial advantages for a kinase inhibitor. The negative Caco-2 and solubility values are concerning for both, but the ADME profile of Ligand A is far more favorable. The 0.9 kcal/mol difference in binding affinity can likely be overcome with further optimization of Ligand A.

Output:
1
2025-04-17 16:12:33,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.443 and 353.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (59.08 and 61.88) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.185 and 1.639) are within the optimal range of 1-3.

**H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBA, which is well within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.766 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (18.069) has a significantly lower DILI risk than Ligand B (4.653), which is a major advantage. Lower DILI is crucial for drug development.

**BBB:** Both ligands have reasonable BBB penetration (82.047 and 72.237), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.596 and -4.626), which is unusual and suggests poor permeability. However, these values are on a log scale and close to zero, so may not be a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.599 and -0.969), indicating poor solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.319 and 0.344), which is excellent.

**Microsomal Clearance:** Ligand A (33.167 mL/min/kg) has a higher microsomal clearance than Ligand B (24.678 mL/min/kg), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-12.898 hours) has a negative half-life, which is not physically possible and indicates a data error or unusual behavior. Ligand A (14.746 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.021).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-7.3 and -7.0 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 candidate. While it has slightly higher microsomal clearance, its significantly lower DILI risk and more reasonable half-life outweigh this disadvantage. The binding affinities are comparable, and both ligands have acceptable properties in other areas. The negative half-life of Ligand B is a major red flag.

Output:
0
2025-04-17 16:12:33,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.255 Da) is slightly higher than Ligand B (338.415 Da), but both are acceptable.

**TPSA:** Ligand A (61.88) is better than Ligand B (106.75). Lower TPSA generally correlates with better cell permeability. Ligand B is above the preferred threshold of 140, which could hinder absorption.

**logP:** Both ligands have good logP values (A: 3.69, B: 2.436), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=7) as it has fewer hydrogen bond donors and acceptors, potentially leading to better permeability.

**QED:** Both ligands have similar QED values (A: 0.664, B: 0.635), indicating good drug-likeness.

**DILI:** Ligand A (70.492) has a higher DILI risk than Ligand B (59.907). This is a concern for Ligand A, but not disqualifying at this stage.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand A (71.85) is slightly better than Ligand B (59.519). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.07 and -5.386), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.693 and -3.138), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.852, B: 0.828), which is good.

**Microsomal Clearance:** Ligand A (48.239) has significantly lower microsomal clearance than Ligand B (67.033), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (22.983 hours) has a longer half-life than Ligand B (13.368 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.62, B: 0.089).

**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 for Ligand B, potentially outweighing some of its ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Conclusion:**

Despite Ligand A's better metabolic stability (lower Cl_mic, longer t1/2) and TPSA, Ligand B's significantly stronger binding affinity (-9.8 vs -6.9 kcal/mol) is the most critical factor for an enzyme inhibitor. While both compounds have poor solubility and permeability, the potency advantage of Ligand B is likely to be more easily addressed through formulation strategies or prodrug approaches than improving the affinity of Ligand A. The slightly higher DILI risk for Ligand A is also a concern.

Output:
1
2025-04-17 16:12:33,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.459 Da and 360.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.23) is better than Ligand B (75.19), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have similar and optimal logP values (1.916 and 1.863, respectively), falling within the 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 and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have similar and good QED values (0.857 and 0.832), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (32.881 and 34.277, respectively), both are well below the 40 threshold.

**BBB:** Both have reasonable BBB penetration (68.864 and 70.919), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.933 and -4.891). This is unusual and suggests poor permeability. However, these values are on a log scale and are relative.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.522 and -3.136). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.221 and 0.14), which is excellent.

**Microsomal Clearance:** Ligand B (-9.362) has significantly *lower* (better) microsomal clearance than Ligand A (24.32). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (1.725) has a longer half-life than Ligand A (-0.248), further supporting its superior metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.067 and 0.066).

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.4). The difference is 0.6 kcal/mol.

**Conclusion:**

While Ligand A has a slightly better binding affinity, the significantly improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand B is a crucial advantage for an enzyme target like SRC kinase. The similar DILI and hERG profiles are positive for both. The negative Caco-2 and solubility values are concerning for both, but the metabolic stability advantage of Ligand B outweighs the small affinity difference.

Output:
1
2025-04-17 16:12:33,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (386.583 Da and 363.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.43 and 79.38) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have acceptable logP values (2.302 and 1.662), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (2 HBD, 7 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.558 and 0.625), indicating drug-like properties.

**DILI:** Ligand A (38.697) has a significantly better DILI score than Ligand B (60.527). This is a crucial advantage, as lower DILI is highly desirable.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (81.504) has a higher BBB score than Ligand A (43.699), but this is not a major factor in this case.

**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 ligands have negative solubility values, which is also unusual. Again, the scale is unclear, but suggests poor solubility.

**hERG:** Ligand A (0.205) has a much lower hERG inhibition liability than Ligand B (0.637), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand B (73.033) has a higher microsomal clearance than Ligand A (41.84), indicating lower metabolic stability. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand B (70.144) has a much longer in vitro half-life than Ligand A (-2.444). This is a positive attribute for Ligand B.

**P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux liability than Ligand B (0.048), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent and meets the criteria.

**Conclusion:**

Despite the similar binding affinity, Ligand A is the more promising candidate. Its significantly lower DILI risk and hERG inhibition liability are major advantages. While Ligand B has a longer half-life, the safety concerns associated with its higher DILI and hERG values outweigh this benefit. The lower P-gp efflux for Ligand A is also a positive. 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 16:12:33,427 - INFO - Batch 444 complete. Total preferences: 7104
2025-04-17 16:12:33,428 - INFO - Processing batch 445/512...
2025-04-17 16:13:13,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (370.503 and 359.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.9) is slightly higher than Ligand B (63.69). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Ligand A (3.658) is slightly higher than the optimal range (1-3), while Ligand B (1.942) is within the optimal range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable range of less than 10.

**QED:** Both ligands have good QED scores (0.687 and 0.884 respectively), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (82.28) has a higher DILI risk than Ligand B (68.476). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.056) and Ligand B (51.454) are both relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.199) is slightly worse than Ligand B (-4.831).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-4.154) is slightly worse than Ligand B (-2.037).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.673 and 0.403 respectively). Ligand B is slightly better.

**Microsomal Clearance:** Ligand B (11.973) has significantly lower microsomal clearance than Ligand A (33.577), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (21.662) has a longer half-life than Ligand B (1.934). This is a positive for Ligand A, but the difference is less important than the metabolic stability advantage of Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.505 and 0.086 respectively). Ligand B is better.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. It demonstrates better predicted ADME properties (lower DILI, lower Cl_mic, better solubility, lower P-gp efflux) and a slightly better binding affinity. While Ligand A has a longer half-life, the superior metabolic stability and lower toxicity risk of Ligand B are more critical for an enzyme target like SRC. The slight advantage in binding affinity further solidifies this conclusion.

Output:
1
2025-04-17 16:13:13,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (355.385 and 346.821 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.65) is better than Ligand B (50.7), both are below the 140 threshold for oral absorption.

**3. logP:** Ligand A (2.1) is optimal, while Ligand B (5.013) is high, potentially leading to solubility issues and off-target effects.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (0 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have the same HBA count (4), below the limit of 10.

**6. QED:** Ligand A (0.811) has a significantly better QED score than Ligand B (0.564), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.048) has a much lower DILI risk than Ligand B (85.964). This is a crucial advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (86.39) is better than Ligand B (64.017).

**9. Caco-2 Permeability:** Ligand A (-4.536) is better than Ligand B (-5.068).

**10. Aqueous Solubility:** Ligand A (-1.539) is better than Ligand B (-5.282).

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.274 and 0.802 respectively), both are acceptable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (26.74) has lower clearance than Ligand B (38.155), suggesting better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (94.309) has a much longer half-life than Ligand A (-38.236).

**14. P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux than Ligand B (0.66), which is preferable.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has a better half-life, Ligand A excels in almost all other critical parameters: lower DILI risk, better solubility, lower clearance, better QED, and a more optimal logP. The equal binding affinity makes the other factors decisive.

Output:
0
2025-04-17 16:13:13,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.403 and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.34) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (80.23) is well within the range.

**logP:** Ligand A (0.767) is a bit low, potentially hindering permeability. Ligand B (1.455) is better, falling 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 (5) and Ligand B (6) are both acceptable (<=10).

**QED:** Both ligands have good QED scores (0.818 and 0.857, respectively), indicating good drug-like properties.

**DILI:** Ligand A (66.731) has a higher DILI risk than Ligand B (49.128), though both are above the preferred <40.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.127) is slightly higher than Ligand A (54.866).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.632 and -4.827), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.705 and -2.439), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.214 and 0.244), which is favorable.

**Microsomal Clearance:** Ligand A (-19.076) has significantly *lower* (better) microsomal clearance than Ligand B (18.89). This suggests higher metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-17.49) has a longer in vitro half-life than Ligand B (36.688), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is good. Ligand B (0.174) is slightly higher, but still relatively low.

**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.

**Conclusion:**

Despite the poor Caco-2 permeability and aqueous solubility for both compounds, Ligand A is the superior candidate. The significantly stronger binding affinity (-8.9 vs 0.0 kcal/mol) is a major advantage that can potentially outweigh the ADME concerns. Furthermore, Ligand A exhibits substantially better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. While the DILI risk is higher for Ligand A, the difference isn't drastic, and the potency advantage is likely more critical for an enzyme target. Addressing the solubility and permeability issues through formulation or prodrug strategies would be the next steps for Ligand A.

Output:
0
2025-04-17 16:13:13,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (380.63 Da) is also well within range.

**TPSA:** Ligand A (90.08) is better than Ligand B (40.62). Lower TPSA generally favors oral absorption.

**logP:** Both ligands have good logP values (A: 1.715, B: 2.775), 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, <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.6, B: 0.689), indicating good drug-likeness.

**DILI:** Ligand A (37.728) has a slightly higher DILI risk than Ligand B (25.087), but both are below the concerning threshold of 60.

**BBB:** Both have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase. Ligand B (74.292) is better than Ligand A (61.962).

**Caco-2 Permeability:** Ligand A (-4.927) has a very poor Caco-2 permeability, while Ligand B (-5.057) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -2.079, B: -3.919). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.838) has a slightly higher hERG risk than Ligand B (0.52), but both are relatively low.

**Microsomal Clearance:** Ligand B (67.754) has a significantly higher microsomal clearance than Ligand A (8.445). This suggests that Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (1.136 hours) has a very short half-life, while Ligand B (-18.359 hours) is negative, indicating a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.325, B: 0.217).

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.0 vs -7.9 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, its much lower microsomal clearance (8.445 vs 67.754) indicates better metabolic stability, and its DILI risk is only slightly higher than Ligand B. The longer half-life of Ligand B is interesting, but the substantial difference in binding affinity outweighs this benefit. Solubility and permeability would need to be addressed through formulation or structural modification, but the potency and stability profile of Ligand A makes it the better starting point.

Output:
0
2025-04-17 16:13:13,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.45 and 85.67) are below the 140 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (2.589) is optimal (1-3). Ligand B (0.364) is a bit 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 6 HBA, and Ligand B has 5, both below the 10 limit.

**QED:** Both ligands have similar QED values (0.764 and 0.749), indicating good drug-likeness.

**DILI:** Ligand A (38.348) has a slightly higher DILI risk than Ligand B (5.545), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (82.474) has a higher BBB percentile than Ligand B (63.358).

**Caco-2 Permeability:** Ligand A (-4.234) has a worse Caco-2 permeability than Ligand B (-5.201). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-3.198) has a slightly better solubility than Ligand B (-0.96), which is good.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.169 and 0.359), which is excellent.

**Microsomal Clearance:** Ligand B (-37.701) has significantly lower microsomal clearance than Ligand A (77.523), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (9.775) has a longer in vitro half-life than Ligand A (-13.641), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.006).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While both are excellent, the difference is small.

**Conclusion:**

Considering the priorities for enzyme targets, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic and longer t1/2) is a major advantage. While Ligand A has slightly better solubility and binding affinity, the difference in affinity is small and the lower logP of Ligand B is a concern, the improved metabolic profile of Ligand B outweighs these minor drawbacks.

Output:
1
2025-04-17 16:13:13,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.531 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, suggesting good absorption. Ligand B (87.46) is also below the threshold, but higher than A.

**logP:** Ligand A (3.842) is at the upper end of the optimal 1-3 range, potentially raising concerns about off-target effects, but still acceptable. Ligand B (0.621) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly less favorable.

**QED:** Both ligands have good QED scores (0.757 and 0.835, respectively), indicating drug-like properties.

**DILI:** Ligand A (16.906) has a very low DILI risk. Ligand B (19.193) is also low, but slightly higher than A.

**BBB:** Ligand A (92.827) shows good BBB penetration, while Ligand B (36.487) is poor. This is less critical for a non-CNS target like SRC, but a bonus for A.

**Caco-2 Permeability:** Ligand A (-4.567) has poor Caco-2 permeability, while Ligand B (-5.171) is even worse. This is a significant concern for both, but more so for B.

**Aqueous Solubility:** Ligand A (-3.526) has poor aqueous solubility. Ligand B (-0.952) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.683) has a low hERG risk. Ligand B (0.091) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (72.515) has moderate clearance, while Ligand B (-9.65) has negative clearance (highly desirable, indicating excellent metabolic stability).

**In vitro Half-Life:** Ligand A (-3.673) has a negative half-life (highly desirable). Ligand B (-0.596) also has a negative half-life, but less negative than A.

**P-gp Efflux:** Ligand A (0.351) has low P-gp efflux. Ligand B (0.024) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower DILI risk, and better BBB penetration. However, it suffers from poor Caco-2 permeability and solubility. Ligand B has excellent metabolic stability (negative Cl_mic) and very low P-gp efflux and hERG risk, but its binding affinity is weaker and Caco-2 permeability is also poor. The significantly stronger binding affinity of Ligand A is a major advantage for an enzyme target like SRC kinase. While the solubility and permeability of A are concerns, these can potentially be addressed through formulation strategies. The weaker binding of B is a more fundamental limitation.

Output:
0
2025-04-17 16:13:13,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.39 and 351.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (95.67). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (2.855) is optimal, while Ligand B (0.844) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 5. Both are acceptable, but A is preferable.

**QED:** Both ligands have similar QED scores (0.784 and 0.767), indicating good drug-likeness.

**DILI:** Ligand A (85.23) has a higher DILI risk than Ligand B (50.64). This is a significant drawback for A.

**BBB:** Both have good BBB penetration (80.61 and 69.41), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have poor Caco-2 permeability (-4.666 and -4.961). This is a concern for oral bioavailability for both.

**Solubility:** Ligand A (-4.751) has slightly worse solubility than Ligand B (-2.164), though both are poor.

**hERG:** Ligand A (0.639) has a slightly higher hERG risk than Ligand B (0.327), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (-3.573) has significantly lower (better) microsomal clearance than Ligand A (36.215), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.344) has a much longer in vitro half-life than Ligand A (30.467), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.303 and 0.148).

**Binding Affinity:** Ligand B (-8.1) has a significantly stronger binding affinity than Ligand A (-9.3). This is a crucial advantage, as a 1.2 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better TPSA and logP, Ligand B is the stronger candidate. The significantly improved metabolic stability (lower Cl_mic, longer t1/2), better DILI score, and, most importantly, the substantially higher binding affinity (-8.1 vs -9.3 kcal/mol) outweigh the slightly lower logP and TPSA. The binding affinity difference is large enough to be a decisive factor.

Output:
1
2025-04-17 16:13:13,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.471 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly higher than the preferred <140, while Ligand B (68.82) is well within the range.

**logP:** Both ligands have acceptable logP values (1.125 and 2.389), falling within the 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 scores (0.75 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A (42.303) has a slightly higher DILI risk than Ligand B (33.889), but both are below the concerning threshold of 60.

**BBB:** Ligand A (27.801) has a very low BBB penetration, while Ligand B (73.401) shows good BBB penetration. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.844 and -4.77), which is unusual and problematic. A negative value suggests very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.288 and -2.62), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.07) shows a slightly lower hERG risk than Ligand B (0.465), which is preferable.

**Microsomal Clearance:** Ligand B (32.573) has lower microsomal clearance than Ligand A (46.5), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.552) has a significantly longer in vitro half-life than Ligand A (-36.388), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.042 and 0.043).

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the negative Caco-2 and solubility values for both ligands, Ligand A's substantially superior binding affinity (-8.7 kcal/mol vs -7.5 kcal/mol) is a critical factor for an enzyme target like SRC kinase. The improved hERG profile and acceptable DILI risk further support its selection. While Ligand B has better metabolic stability and BBB penetration, the potency difference is significant enough to prioritize Ligand A, assuming solubility and permeability issues can be addressed through formulation or further chemical modifications.

Output:
1
2025-04-17 16:13:13,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.391 and 364.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.88) is better than Ligand B (49.41), being below 140, suggesting good absorption. Ligand B is very low, potentially indicating issues with solubility.

**logP:** Ligand A (0.468) is suboptimal, being below 1, which might hinder permeation. Ligand B (4.158) is higher, approaching the upper limit, but still acceptable.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.611 and 0.853), indicating drug-like properties.

**DILI:** Ligand A (64.056) has a higher DILI risk than Ligand B (33.579). This is a significant negative for Ligand A.

**BBB:** Ligand A (70.88) has moderate BBB penetration, while Ligand B (83.249) has good BBB penetration. This is less important for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.964) has poor Caco-2 permeability, while Ligand B (-4.556) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.579) has poor solubility, while Ligand B (-4.253) is even worse. This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.19) has very low hERG inhibition risk, which is excellent. Ligand B (0.422) also has low risk, but higher than Ligand A.

**Microsomal Clearance:** Ligand A (10.476) has lower microsomal clearance than Ligand B (89.297), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-17.268) has a very short half-life, while Ligand B (24.964) has a reasonable half-life. This is a major drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.432) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.9 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 concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the highest priority for an enzyme inhibitor. While its solubility is poor, the significantly improved potency and metabolic stability (lower Cl_mic, better t1/2) make it a more promising candidate. Ligand A has a better hERG profile and lower P-gp efflux, but its poor solubility, poor permeability, and short half-life are major drawbacks, even with its better metabolic stability. The DILI risk for Ligand A is also concerning.

Output:
1
2025-04-17 16:13:13,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.461 and 364.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (46.34), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have logP values (3.472 and 4.573) within the optimal 1-3 range, though Ligand B is pushing 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.

**QED:** Both ligands have QED values (0.786 and 0.635) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (16.208) has a significantly lower DILI risk than Ligand B (33.152), which is a major advantage.

**BBB:** Both ligands have high BBB penetration (94.533 and 96.394), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.381 and -4.352), which is unusual. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.403 and -4.941), which is concerning. Ligand B has a worse solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.685 and 0.687), which is good.

**Microsomal Clearance:** Ligand A (53.121) has a lower microsomal clearance than Ligand B (70.608), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.289) has a negative half-life, which is unusual. Ligand B (8.834) has a much more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.591).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage (1.9 kcal/mol difference).

**Conclusion:**

Despite Ligand A's better DILI and Cl_mic, Ligand B's significantly stronger binding affinity (-8.9 vs -7.0 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The potency advantage outweighs the slightly higher DILI risk and lower metabolic stability. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:13:13,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.431 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.47) is better than Ligand B (32.34) as it is below 140 and closer to the optimal range for oral absorption. Ligand B is very low, which could indicate poor solubility.

**logP:** Ligand A (1.09) is within the optimal 1-3 range. Ligand B (4.253) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 2 HBA) both have acceptable counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.805 and 0.867), indicating good drug-like properties.

**DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (22.8), both are good.

**BBB:** Ligand A (69.833) has a lower BBB penetration than Ligand B (90.035). Since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.925) has a lower Caco-2 permeability than Ligand B (-4.7).

**Aqueous Solubility:** Ligand A (-2.095) has a lower solubility than Ligand B (-4.402).

**hERG:** Ligand A (0.241) has a lower hERG risk than Ligand B (0.768), which is preferable.

**Microsomal Clearance:** Ligand A (4.055) has a lower microsomal clearance than Ligand B (85.965), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (19.882) has a shorter half-life than Ligand B (34.601).

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.581), which is preferable.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.9 vs -9.1 kcal/mol). While its logP is slightly high and solubility is lower, the strong binding is a major advantage for an enzyme target like SRC kinase. Ligand A has better metabolic stability (lower Cl_mic) and lower hERG risk, but the difference in binding affinity is critical. The slightly higher logP of Ligand B is not a dealbreaker, and solubility can potentially be improved through formulation strategies.

Output:
1
2025-04-17 16:13:13,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.455 and 384.611 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.5) is slightly above the preferred <140, but acceptable. Ligand B (42.43) is well within the optimal range.

**logP:** Ligand A (1.777) is within the optimal 1-3 range. Ligand B (4.437) 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.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**QED:** Ligand A (0.764) is excellent, indicating good drug-likeness. Ligand B (0.591) is acceptable, but lower than A.

**DILI:** Ligand A (64.288) has a higher DILI risk than Ligand B (45.095), but both are within acceptable ranges (<60 is good).

**BBB:** Both ligands have similar BBB penetration (A: 77.317, B: 75.107), which isn't a primary concern for a non-CNS target like SRC.

**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:** Both ligands have similar, very low hERG risk (A: 0.793, B: 0.772). This is excellent.

**Microsomal Clearance:** Ligand A (43.634) has significantly lower microsomal clearance than Ligand B (88.83), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (6.639) has a shorter half-life than Ligand B (17.09), but both are reasonable.

**P-gp Efflux:** Both ligands have similar low P-gp efflux liability (A: 0.127, B: 0.784).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol, respectively), with Ligand B being slightly stronger. However, the difference is minimal and likely not enough to overcome other drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and a longer half-life, Ligand A exhibits superior drug-likeness (QED), significantly better metabolic stability (lower Cl_mic), and a lower DILI risk. The slightly higher TPSA of Ligand A is less concerning than the higher logP of Ligand B, which could lead to solubility and off-target issues. Given the enzyme-specific priorities, metabolic stability is crucial, making Ligand A the preferred choice.

Output:
0
2025-04-17 16:13:13,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.495 and 365.474 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.8) is slightly higher than Ligand B (43.86). Both are below the 140 threshold for good oral absorption, and acceptable for a kinase inhibitor.

**3. logP:** Both ligands have good logP values (2.62 and 2.417), 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:** Both ligands have 4 HBAs, well below the limit of <=10.

**6. QED:** Ligand A (0.838) has a higher QED score than Ligand B (0.752), suggesting a more drug-like profile.

**7. DILI:** Ligand B (40.403) has a significantly lower DILI risk than Ligand A (21.908), which is a major advantage. Lower DILI is highly desirable.

**8. BBB:** Both ligands have good BBB penetration (86.351 and 92.012). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.638 and -4.855). This is unusual, and suggests poor permeability. However, kinase inhibitors are often not optimized for high Caco-2 values as they are often administered via other routes or rely on specific transport mechanisms.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.892 and -3.717). This is a concern, but can be mitigated through formulation strategies.

**11. hERG Inhibition:** Ligand A (0.489) has a lower hERG risk than Ligand B (0.833), which is a positive.

**12. Microsomal Clearance:** Ligand B (38.414) has a significantly lower microsomal clearance than Ligand A (20.532), indicating better metabolic stability. This is a key consideration for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand B (5.596) has a slightly longer half-life than Ligand A (8.955).

**14. P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux than Ligand B (0.134), which is preferable.

**15. 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, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

While Ligand A has a slightly better QED and lower hERG risk, Ligand B's superior binding affinity (-9.0 vs -7.4 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer t1/2) outweigh these minor drawbacks. The lower DILI risk for Ligand B is also a significant benefit. The solubility and permeability concerns are present for both, but can be addressed during formulation. Given the enzyme-specific priorities, potency and metabolic stability are paramount.

Output:
1
2025-04-17 16:13:13,582 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (356.46 and 365.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (105.64) is still within acceptable limits, but less favorable.

**logP:** Ligand A (3.355) is optimal (1-3). Ligand B (0.456) is low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is acceptable, but higher HBA could slightly reduce permeability.

**QED:** Both ligands have similar QED values (0.793 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (10.59) has a very low DILI risk. Ligand B (22.45) is higher, but still relatively low risk.

**BBB:** Ligand A (96.74) shows excellent BBB penetration, though this is less critical for a non-CNS target like SRC. Ligand B (54.48) is lower.

**Caco-2 Permeability:** Ligand A (-4.713) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.659) is also low, but slightly better.

**Aqueous Solubility:** Ligand A (-3.391) is poor. Ligand B (-1.921) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.687) has a low hERG risk. Ligand B (0.045) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (18.625) is moderate, indicating moderate metabolic stability. Ligand B (0.937) is very low, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-12.667) is very negative, indicating a long half-life. Ligand B (-8.628) is also negative, but shorter than A.

**P-gp Efflux:** Ligand A (0.077) shows low P-gp efflux. Ligand B (0.014) shows very low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -8.4 kcal/mol). Ligand B is slightly better (-8.4 vs -7.7).

**Overall Assessment:**

Ligand B is the better candidate. While both have good potency, Ligand B has superior metabolic stability (lower Cl_mic), a slightly better binding affinity, and a lower hERG risk. The main drawbacks of Ligand B are its lower logP and Caco-2 permeability, and lower BBB penetration, but these are less critical for a non-CNS target like SRC kinase. Ligand A's poor Caco-2 permeability and solubility are significant concerns that outweigh its better BBB penetration.

Output:
1
2025-04-17 16:13:13,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.482 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is well below the 140 threshold, and favorable for oral absorption. Ligand B (85.69) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.865) is within the optimal 1-3 range. Ligand B (0.37) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the 5 limit.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both below the 10 limit, but ligand B is approaching it.

**QED:** Both ligands have good QED scores (0.817 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A (8.996) has a very low DILI risk, significantly better than Ligand B (46.297), which is moderate.

**BBB:** Ligand A (88.29) has a good BBB percentile, while Ligand B (76.231) is lower. This is less critical for a non-CNS target like SRC, but still a positive for A.

**Caco-2 Permeability:** Ligand A (-4.599) and Ligand B (-4.816) both have negative 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 solubility (-3.312 and -1.276). This is a significant concern.

**hERG Inhibition:** Ligand A (0.405) has a very low hERG risk, while Ligand B (0.07) is even lower and excellent.

**Microsomal Clearance:** Ligand A (38.324) has a moderate microsomal clearance, while Ligand B (0.897) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.463) has a moderate half-life, while Ligand B (17.908) has a significantly longer half-life, which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.028).

**Binding Affinity:** Ligand B (-10.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.6 kcal/mol). This difference of 1.8 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), and excellent hERG risk. While its logP is low and solubility is poor, the strong binding affinity is a major advantage for an enzyme target like SRC kinase. Ligand A has better DILI risk and BBB penetration, but these are less critical than potency and metabolic stability in this case. The solubility issue is a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:13:13,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.359 Da and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.24) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (69.64) is excellent, well below 140.

**logP:** Ligand A (0.323) is quite low, potentially hindering permeability. Ligand B (2.173) is 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 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have high QED scores (0.831 and 0.816), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 72.392, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 18.379, which is excellent.

**BBB:** Ligand A (60.915) and Ligand B (83.327) both have moderate BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.009 and -4.906), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading; the absolute permeability is likely low for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.325 and -2.522), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.119) has a very low hERG risk, which is excellent. Ligand B (0.316) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-3.893) has a negative clearance, which is impossible and likely an error in the data. Ligand B (2.126) has a moderate clearance, which is less ideal.

**In vitro Half-Life:** Ligand A (-7.551) has a negative half-life, which is impossible and likely an error in the data. Ligand B (-10.931) also has a negative half-life, indicating a data issue.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.04).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate despite some questionable ADME data. The significantly stronger binding affinity (-9.5 vs -7.9 kcal/mol) is a major advantage for an enzyme target like SRC. The DILI risk is much lower for Ligand B. The negative values for clearance and half-life for both compounds are concerning and suggest data errors. The low logP for Ligand A is a significant drawback. While both have poor predicted permeability and solubility, the stronger affinity of Ligand B makes it more likely to be effective *in vivo* even with these limitations, especially if formulation strategies can address the solubility issue.

Output:
1
2025-04-17 16:13:13,583 - INFO - Batch 445 complete. Total preferences: 7120
2025-04-17 16:13:13,583 - INFO - Processing batch 446/512...
2025-04-17 16:13:58,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (361.471 and 370.559 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (53.01), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (2.189 and 2.82), 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 below the 10 threshold.

**6. QED:** Ligand A (0.909) has a superior QED score compared to Ligand B (0.726), indicating a more drug-like profile.

**7. DILI:** Ligand A (69.407) has a higher DILI risk than Ligand B (13.532). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (62.97 and 69.678). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.875) has a lower Caco-2 permeability than Ligand B (-4.54), suggesting potentially poorer intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.137) has a lower aqueous solubility than Ligand B (-1.754).

**11. hERG Inhibition:** Ligand A (0.171) has a lower hERG inhibition liability than Ligand B (0.694), which is favorable.

**12. Microsomal Clearance:** Ligand B (78.036) has a higher microsomal clearance than Ligand A (28.799), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (47.826) has a longer in vitro half-life than Ligand A (34.867).

**14. P-gp Efflux:** Ligand A (0.159) has lower P-gp efflux liability than Ligand B (0.598).

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.1). While the difference is relatively small (0.3 kcal/mol), it's still a positive for Ligand B.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and solubility, and a slightly better binding affinity. The significantly lower DILI risk for Ligand B is also a major advantage. While Ligand A has a slightly better hERG profile and P-gp efflux, the DILI risk and lower metabolic stability of Ligand A are concerning.

Output:
1
2025-04-17 16:13:58,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 352.469 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (36.36) as it is closer to the ideal range for oral absorption (<140).

**logP:** Ligand A (2.655) is optimal (1-3), while Ligand B (4.851) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.542 and 0.762), indicating drug-like properties.

**DILI:** Ligand A (8.569) has a significantly lower DILI risk than Ligand B (19.426), a crucial factor for drug development.

**BBB:** Both have high BBB penetration (95.192 and 91.857), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.581 and -4.547), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-3.015 and -4.085), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.561 and 0.897).

**Microsomal Clearance:** Both have similar microsomal clearance rates (55.741 and 57.113), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-4.457) has a better (longer) in vitro half-life than Ligand B (-16.289).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.151 and 0.539).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.6 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand A is the more promising candidate. Its lower DILI risk, better TPSA, and longer in vitro half-life are significant advantages. The poor Caco-2 and solubility are concerning for both, but the other benefits of Ligand A outweigh the slightly better affinity of Ligand B. Addressing the solubility and permeability issues would be critical for further development of either compound.

Output:
0
2025-04-17 16:13:58,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 371.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is well below the 140 threshold, while Ligand B (117.66) is still acceptable but higher. Lower TPSA generally favors better absorption.

**logP:** Ligand A (1.171) is within the optimal 1-3 range. Ligand B (-1.217) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern given the other parameters.

**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 limit of 10, but Ligand A is slightly better.

**QED:** Both ligands have similar QED values (0.731 and 0.709), indicating good drug-likeness.

**DILI:** Ligand A (19.426) has a significantly lower DILI risk than Ligand B (49.632). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.811) is better than Ligand B (48.662), but not a deciding factor.

**Caco-2 Permeability:** Both have negative values (-4.805 and -5.509), which is unusual and suggests poor permeability. However, these values are on a log scale and represent ratios. We need to interpret these cautiously.

**Aqueous Solubility:** Both have negative values (-1.069 and -1.093), which again is unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show very low hERG risk (0.315 and 0.111), which is excellent.

**Microsomal Clearance:** Ligand A (33.008) has a higher microsomal clearance than Ligand B (-17.653). This means Ligand B is likely to have better metabolic stability, a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (16.266) has a longer in vitro half-life than Ligand A (9.514), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.009), which is favorable.

**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 factors.

**Conclusion:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2), Ligand A has a significantly lower DILI risk and a slightly better TPSA. Given the enzyme-specific priorities, metabolic stability is important, but a lower DILI risk is crucial for drug development. The binding affinities are comparable. Therefore, considering the overall profile, Ligand A is the more promising candidate.

Output:
0
2025-04-17 16:13:58,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (353.467 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.4) is slightly higher than Ligand B (71.53). Both are below the 140 threshold for oral absorption, but B is significantly better.

**3. logP:** Both ligands have good logP values (2.779 and 1.277), falling within the 1-3 optimal 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, within the acceptable limit of <=10.

**6. QED:** Ligand B (0.836) has a significantly higher QED score than Ligand A (0.37), indicating a more drug-like profile.

**7. DILI:** Ligand B (33.695) has a much lower DILI risk than Ligand A (21.442), which is a significant advantage.

**8. BBB:** Both have moderate BBB penetration (65.529 and 60.838). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.513 and -4.702). This is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method and should be interpreted cautiously.

**10. Aqueous Solubility:** Both have negative solubility values (-1.202 and -1.58). Similar to Caco-2, these are likely prediction artifacts and suggest low solubility.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.235 and 0.102). This is excellent.

**12. Microsomal Clearance:** Ligand B (18.982) has a significantly lower microsomal clearance than Ligand A (50.203), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.755) has a negative half-life, which is an artifact, but suggests a very short half-life. Ligand A (13.341) has a reasonable half-life.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.027).

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While both are good, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with predicted solubility and permeability, Ligand B excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic), a higher QED score, and slightly improved binding affinity. The negative values for Caco-2 and solubility are concerning, but likely represent limitations of the prediction model. The improved ADME profile of Ligand B outweighs the slightly better half-life of Ligand A.

Output:
1
2025-04-17 16:13:58,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.483 and 365.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.36) is slightly higher than Ligand B (78.43). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.574) and Ligand B (0.918) 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 within the acceptable limit of <=5. Ligand B is slightly better.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.825 and 0.811), indicating good drug-likeness.

**DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (16.169), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (65.374 and 67.08), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.072 and -5.54), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.307 and -0.727), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.082) has a lower hERG inhibition liability than Ligand B (0.127), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-21.652) has significantly lower microsomal clearance than Ligand A (8.857), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (15.99) has a longer in vitro half-life than Ligand B (1.703), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.025).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, lower hERG risk, and longer half-life. However, Ligand B has significantly better metabolic stability (lower Cl_mic) and slightly better TPSA. The binding affinity difference is significant. Considering SRC is an enzyme, metabolic stability is crucial. However, the superior binding affinity of Ligand A, combined with acceptable metabolic stability and lower toxicity liabilities, makes it the more promising candidate. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:13:58,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly better positioned.

**TPSA:** Ligand A (75.88) is significantly better than Ligand B (111.63). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.544) is within the optimal range, while Ligand B (-0.024) is slightly below, which *could* hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Lower numbers are generally better for permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.779, B: 0.676), indicating good drug-like properties.

**DILI:** Both have similar, acceptable DILI risk (A: 42.807, B: 48.313).

**BBB:** Ligand A (84.257) has a much higher BBB penetration score than Ligand B (5.855). While SRC isn't a CNS target, higher BBB generally correlates with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.463) is better than Ligand B (-5.377), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.774) is better than Ligand B (-0.892), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.159, B: 0.095), which is excellent.

**Microsomal Clearance:** Ligand A (47.248) has a higher (worse) microsomal clearance than Ligand B (-7.33). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Both have negative half-lives (-14.564 and -14.341), which is unusual and likely an error in the data. However, the values are very close.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.077, B: 0.028).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). However, the difference is minimal.

**Overall Assessment:**

Ligand A generally performs better across most ADME properties (TPSA, logP, solubility, Caco-2, BBB) and has a comparable binding affinity. The main advantage of Ligand B is its better metabolic stability (lower Cl_mic). However, the improvements in ADME properties with Ligand A outweigh the slight metabolic advantage of Ligand B. Given the focus on potency and metabolic stability for kinase inhibitors, and the minimal difference in binding affinity, the superior ADME profile of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 16:13:58,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.41 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.19) is slightly higher than Ligand B (61.88), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have a logP around 1.6, which is optimal.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.792) has a better QED score than Ligand B (0.649), indicating a more drug-like profile.

**DILI:** Ligand A (62.776) has a higher DILI risk than Ligand B (4.769). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (63.784) is slightly lower than Ligand A (77.007). This isn't a major concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability. However, the absolute value is closer to zero for Ligand B (-4.878) than for Ligand A (-4.582), suggesting slightly better permeability.

**Aqueous Solubility:** Ligand B (-0.442) has better aqueous solubility than Ligand A (-2.426). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.081) has a slightly lower hERG risk than Ligand B (0.416), which is preferable.

**Microsomal Clearance:** Ligand B (13.791) has a significantly lower microsomal clearance than Ligand A (22.669), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-2.911) has a longer in vitro half-life than Ligand A (-13.84), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux than Ligand B (0.014), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.4) has a stronger binding affinity than Ligand A (-6.8). This difference of 1.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better QED and BBB, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a substantially stronger binding affinity. The lower DILI risk for Ligand B is also a major advantage. The Caco-2 values are concerning for both, but slightly better for Ligand B.

Output:
1
2025-04-17 16:13:58,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (78.95) is better than Ligand B (57.95), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.53) is low, potentially hindering permeation. Ligand B (4.75) is high, potentially causing solubility and off-target issues.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Both have 4 HBA, which is good.

**QED:** Both ligands have acceptable QED scores (A: 0.801, B: 0.751), indicating good drug-like properties.

**DILI:** Ligand A (16.247) has a significantly lower DILI risk than Ligand B (25.436). This is a major advantage for Ligand A.

**BBB:** Both have good BBB penetration (A: 74.486, B: 77.2). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.522) has a worse Caco-2 permeability than Ligand B (-5.314).

**Aqueous Solubility:** Ligand A (-1.389) has better aqueous solubility than Ligand B (-3.758). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.136) has a much lower hERG inhibition risk than Ligand B (0.848). This is a critical advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (-0.838) has a lower (better) microsomal clearance than Ligand B (38.263). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-12.294) has a longer in vitro half-life than Ligand B (38.958). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux than Ligand B (0.539).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -9.7 kcal/mol), with Ligand B being slightly better. However, the difference is small and can be overcome by other favorable properties.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A excels in crucial ADME-Tox properties: significantly lower DILI risk, much lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and better solubility. The lower logP of Ligand A is a potential concern, but the other advantages outweigh this drawback, especially considering the strong binding affinity.

Output:
0
2025-04-17 16:13:58,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (351.443 and 342.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.86) is slightly above the preferred <140, but acceptable. Ligand B (58.2) is well within the range.

**3. logP:** Both ligands have good logP values (2.242 and 3.697), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but is still reasonable.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (3 and 2, 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 similar QED values (0.601 and 0.571), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (34.742 and 36.875 percentiles), which is favorable.

**8. BBB:** Ligand A (25.746) has a very low BBB penetration, while Ligand B (70.143) has good BBB penetration. Since SRC is not a CNS target, this is less critical, but a higher value is generally preferred.

**9. Caco-2 Permeability:** Ligand A (-5.301) has poor Caco-2 permeability, while Ligand B (-4.943) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.85 and -3.938). This is a concern and may require formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.046 and 0.204), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (15.071) has lower microsomal clearance than Ligand B (60.947), suggesting better metabolic stability. This is a key consideration for enzymes.

**13. In vitro Half-Life:** Ligand A (-22.274) has a significantly longer in vitro half-life than Ligand B (13.61), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.343).

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.1). This difference of 0.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better DILI, the significantly stronger binding affinity of Ligand B (-9.0 vs -8.1) is a crucial advantage for an enzyme inhibitor. The slightly higher logP of Ligand B is manageable, and its other ADME properties are acceptable. Given the priority of potency for enzyme targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 16:13:58,911 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [353.427, 116.48 ,  -1.741,   2.   ,   8.   ,   0.57 ,  20.706,  19.31 , -5.581,   0.22 ,   0.04 ,  -9.038,  13.828,   0.005,  -7.1  ]
**Ligand B:** [364.417,  53.33 ,   4.123,   0.   ,   5.   ,   0.661,  47.654,  80.574, -4.508,  -4.462,   0.885, 105.97 ,   5.715,   0.361,  -8.3  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (353.427) is slightly better.
2. **TPSA:** A (116.48) is better than B (53.33), but both are acceptable for an enzyme target.
3. **logP:** A (-1.741) is suboptimal, potentially leading to permeability issues. B (4.123) is high, raising concerns about solubility and off-target effects.
4. **HBD:** A (2) and B (0) are both acceptable.
5. **HBA:** A (8) and B (5) are both acceptable.
6. **QED:** Both are good (A: 0.57, B: 0.661).
7. **DILI:** A (20.706) is significantly better than B (47.654).  This is a major advantage for A.
8. **BBB:** Not a primary concern for a non-CNS target like SRC kinase. B (80.574) is higher, but irrelevant here.
9. **Caco-2:** A (-5.581) is very poor, suggesting poor absorption. B (-4.508) is also poor, but slightly better.
10. **Solubility:** A (0.22) is very poor. B (-4.462) is also poor, but better than A.
11. **hERG:** A (0.04) is excellent, very low risk. B (0.885) is moderate, posing a potential cardiotoxicity concern.
12. **Cl_mic:** A (-9.038) is excellent, indicating high metabolic stability. B (105.97) is very high, suggesting rapid metabolism.
13. **t1/2:** A (13.828) is good. B (5.715) is moderate, but less desirable than A.
14. **Pgp:** A (0.005) is excellent, indicating low efflux. B (0.361) is moderate.
15. **Binding Affinity:** B (-8.3) is 1.2 kcal/mol stronger than A (-7.1). This is a substantial difference.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Decision:**

While Ligand B has a significantly better binding affinity, the drawbacks are substantial. Its high logP, poor DILI score, high Cl_mic, and moderate hERG risk are all concerning. Ligand A, despite its weaker affinity, has a much better safety profile (DILI, hERG), excellent metabolic stability (Cl_mic), and low Pgp efflux. The poor solubility and Caco-2 permeability of Ligand A are concerning, but these could potentially be addressed through formulation strategies or further chemical modifications. The affinity difference, while significant, might be overcome with further optimization of Ligand A, whereas mitigating the ADME/Tox liabilities of Ligand B would be a much more challenging task.

Therefore, I recommend proceeding with **Ligand A**.

Output:
0
2025-04-17 16:13:58,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.47 and 365.55 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (63.05), being well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.75 and 2.48), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A (2 HBA) is preferable to Ligand B (6 HBA). Higher HBA can sometimes hinder permeability.

**QED:** Ligand A (0.916) has a much better QED score than Ligand B (0.69), indicating a more drug-like profile.

**DILI:** Ligand A (13.53) has a significantly lower DILI risk than Ligand B (29.78), which is a major advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (76.27) shows better BBB penetration potential than Ligand B (61.34).

**Caco-2 Permeability:** Ligand A (-4.814) has a more negative Caco-2 value than Ligand B (-5.628). Lower values indicate better permeability.

**Aqueous Solubility:** Ligand A (-2.949) has better aqueous solubility than Ligand B (-1.98).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.384 and 0.303).

**Microsomal Clearance:** Ligand A (42.90) has a lower microsomal clearance than Ligand B (45.05), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.00) has a substantially longer in vitro half-life than Ligand B (24.65), which is a significant advantage for dosing considerations.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.087 and 0.168).

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is the most critical factor, and the 2 kcal/mol difference is substantial.

**Overall:**

Ligand A consistently outperforms Ligand B across most key parameters. The most significant advantages are its superior binding affinity, lower DILI risk, better QED score, and longer half-life. While both ligands have acceptable physicochemical properties, Ligand A's profile is markedly more favorable for development as a drug candidate targeting SRC kinase.

Output:
1
2025-04-17 16:13:58,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.765 and 339.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.41) is better than Ligand B (72.7), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.058 and 2.184) 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:** Both ligands have similar and good QED scores (0.755 and 0.773), indicating drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (98.565 percentile) compared to Ligand B (63.397 percentile). This is a major concern for Ligand A.

**BBB:** Ligand A (50.019) has a lower BBB penetration than Ligand B (71.268). While not a primary concern for a non-CNS target like SRC, better BBB penetration is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.664) has a worse Caco-2 permeability than Ligand B (-5.009). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-5.416) has worse solubility than Ligand B (-2.81). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.432) has a slightly higher hERG inhibition risk than Ligand B (0.16). Lower is better here.

**Microsomal Clearance:** Ligand A (22.394 mL/min/kg) has significantly lower microsomal clearance than Ligand B (36.586 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (114.336 hours) has a much longer half-life than Ligand B (-23.276 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.236) has lower P-gp efflux than Ligand B (0.21). Both are low, indicating minimal efflux.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial difference (0.9 kcal/mol), which can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's better metabolic stability and longer half-life, the significantly higher DILI risk is a major red flag. Ligand B, while having slightly lower metabolic stability, exhibits a much better safety profile (lower DILI, lower hERG) and a superior binding affinity. The 0.9 kcal/mol difference in binding affinity is substantial and outweighs the minor ADME differences. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:13:58,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.869 Da and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.05) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (127.51) is still under 140, but less favorable than A.

**logP:** Ligand A (3.345) is within the optimal 1-3 range. Ligand B (-0.665) 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 have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.764 and 0.672), indicating good drug-likeness.

**DILI:** Ligand A (79.411) has a higher DILI risk than Ligand B (39.628). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (73.401 and 75.029), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.16 and -5.376), which is unusual and indicates poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.116 and -2.425), which is also concerning, indicating poor solubility.

**hERG:** Ligand A (0.593) has a slightly higher hERG risk than Ligand B (0.14), but both are relatively low.

**Microsomal Clearance:** Ligand B (-11.692) has significantly lower (better) microsomal clearance than Ligand A (72.152), indicating greater metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (1.884) has a very short half-life, while Ligand A (46.79) has a much longer one. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.675) has higher P-gp efflux than Ligand B (0.016), which is unfavorable.

**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 a positive for Ligand A.

**Overall Assessment:**

Ligand A has better binding affinity and in vitro half-life, but suffers from higher DILI risk, higher P-gp efflux, and significantly higher microsomal clearance. Ligand B has a much better metabolic profile (lower Cl_mic) and lower DILI risk, but has a poor half-life and lower binding affinity. Given the importance of metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate, especially if the half-life can be improved through structural modifications. The poor solubility and permeability of both compounds are significant issues that would need to be addressed.

Output:
1
2025-04-17 16:13:58,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.411 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (110.61 and 117.25) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (-0.049) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.915) is within the optimal range.

**H-Bond Donors:** Both ligands have 2 HBDs, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 6, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.633 and 0.741), indicating drug-like properties.

**DILI:** Both ligands have elevated DILI risk (60.566 and 69.484), which is a concern. However, this is a percentile, and further investigation would be needed.

**BBB:** Ligand A (75.107) has a better BBB penetration score than Ligand B (56.495), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.852 and -5.11), which is unusual and suggests poor permeability. This is a significant drawback.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.962 and -3.144), indicating poor aqueous solubility, which is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.056 and 0.147), which is positive.

**Microsomal Clearance:** Ligand B (13.045 mL/min/kg) has lower microsomal clearance than Ligand A (21.789 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.267 hours) has a negative half-life, which is unusual and concerning. Ligand A (12.277 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.036), which is favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). This 0.8 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand B is slightly more promising. It has better binding affinity, lower microsomal clearance (better metabolic stability), and a lower logP, which might improve permeability compared to Ligand A. The negative half-life for Ligand B is concerning, but the affinity advantage is substantial. The DILI risk is high for both, but can be addressed in later stages of optimization.

Output:
1
2025-04-17 16:13:58,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (378.416 and 376.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.27 and 75.62) are above the optimal <140 for oral absorption, but not drastically so. This isn't a major concern for a kinase inhibitor, as oral bioavailability isn't always essential.

**logP:** Ligand A (1.914) is within the optimal 1-3 range. Ligand B (3.427) is slightly higher, potentially increasing off-target effects or decreasing solubility, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 8 HBAs. While both are within the acceptable range of <=10, Ligand A is preferable.

**QED:** Both ligands have reasonable QED scores (0.821 and 0.726), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (61.07 and 67.468), which is a concern. However, this can be addressed during lead optimization.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (75.107) is slightly better than Ligand B (65.607).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.204 and -5.503), which is unusual and suggests poor permeability. This is a significant drawback.

**Aqueous Solubility:** Both have negative solubility values (-2.903 and -3.735), indicating very poor aqueous solubility. This is a major issue for *in vivo* efficacy.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.684 and 0.696), which is excellent.

**Microsomal Clearance:** Ligand A (-11.679) has significantly *lower* (better) microsomal clearance than Ligand B (75.798), indicating much better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-17.527) has a longer (better) in vitro half-life than Ligand B (45.92). This further supports its improved metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.176 and 0.083).

**Binding Affinity:** Ligand A (-9.2 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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -7.7 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme inhibitor. While the DILI risk is a concern, it's a parameter that can be addressed through structural modifications during lead optimization. The solubility and permeability issues are more challenging, but the strong binding affinity suggests that even with limited absorption, Ligand A could demonstrate sufficient *in vivo* activity.

Output:
0
2025-04-17 16:13:58,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.385 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is slightly higher than Ligand B (69.34), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.189 and 2.398), 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 limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.848 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A (34.82) has a significantly lower DILI risk than Ligand B (56.223). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (73.401) has a slightly higher BBB penetration than Ligand A (64.754), but this isn't a major deciding factor.

**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. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.359) has a significantly lower hERG inhibition liability than Ligand B (0.806). This is a crucial advantage for Ligand A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-6.325) has a much lower (better) microsomal clearance than Ligand B (63.306). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-29.231) has a much longer in vitro half-life than Ligand B (5.286). This is a substantial advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.019) has lower P-gp efflux liability than Ligand B (0.381), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are good, the 1.3 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a significantly better safety profile (lower DILI, lower hERG), improved metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have solubility and permeability concerns, the ADME advantages of Ligand A are substantial and outweigh the minor differences in other properties.

Output:
1
2025-04-17 16:13:58,912 - INFO - Batch 446 complete. Total preferences: 7136
2025-04-17 16:13:58,912 - INFO - Processing batch 447/512...
2025-04-17 16:14:46,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.825 Da and 354.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.79) is slightly above the preferred <140, but acceptable. Ligand B (45.47) is excellent, well below 90.

**logP:** Both ligands (3.411 and 3.052) 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 good.

**QED:** Both ligands have good QED scores (0.571 and 0.818), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.147), a major red flag. Ligand B has a low DILI risk (15.2), which is excellent.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (49.128) and Ligand B (92.168) are both reasonable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.08 and -4.278), 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 (-4.714 and -3.045), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG:** Ligand A (0.652) has a slightly elevated hERG risk, while Ligand B (0.826) is better.

**Microsomal Clearance:** Ligand A (44.13) has moderate clearance, while Ligand B (32.665) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (21.375 and 19.728 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.496 and 0.49).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This 2 kcal/mol difference is substantial and a major advantage.

**Conclusion:**

Despite the poor Caco-2 and solubility predictions, Ligand B is the far superior candidate. The primary reason is its significantly stronger binding affinity (-7.4 vs -9.4 kcal/mol). Furthermore, it has a much lower DILI risk (15.2 vs 99.147) and better metabolic stability (lower Cl_mic). While both have issues with solubility and permeability, these can potentially be addressed through formulation. The high DILI risk of Ligand A is a deal-breaker.

Output:
1
2025-04-17 16:14:46,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (378.425 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is higher than Ligand B (49.85). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Both ligands have good logP values (2.26 and 2.712), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.786) has a significantly better QED score than Ligand A (0.467), indicating a more drug-like profile.

**DILI:** Ligand A (18.922) has a much lower DILI risk than Ligand B (31.563), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (72.237 and 76.851). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are relatively close (-4.866 vs -4.395).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.514) is slightly better than Ligand B (-2.367).

**hERG:** Ligand A (0.466) has a lower hERG risk than Ligand B (0.658), which is favorable.

**Microsomal Clearance:** Ligand A (33.094) has significantly lower microsomal clearance than Ligand B (63.964), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.032) has a much longer in vitro half-life than Ligand A (1.038), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.124 and 0.196).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B's superior binding affinity and longer half-life are compelling. The higher DILI and lower solubility are concerns, but the strong affinity could potentially allow for lower dosing, mitigating the DILI risk. Ligand A has better DILI and solubility, but its weaker binding affinity and shorter half-life are significant drawbacks. Given the enzyme-kinase focus, potency and metabolic stability are paramount.

Output:
1
2025-04-17 16:14:46,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.429 and 360.445 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (69.64) as it's closer to the <140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (1.998 and 2.182), falling 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 have the same number of HBA (3), which is within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED scores (0.642 and 0.627), indicating good drug-likeness.

**7. DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (11.632). This is a major advantage.

**8. BBB:** Both ligands have good BBB penetration (81.776 and 78.635), but this is less critical for a non-CNS target like SRC.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.576 and -4.585), which is unusual and needs further investigation. It suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.809 and -2.282), which is also concerning and suggests poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.453 and 0.337), which is good.

**12. Cl_mic:** Ligand A (10.79) has a much lower microsomal clearance than Ligand B (37.203), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**13. t1/2:** Ligand A (-11.551) has a more negative in vitro half-life than Ligand B (-8.857). This is unusual and suggests a very short half-life, which is a disadvantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.075 and 0.063).

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-8.5). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand A is the better candidate. Despite the negative Caco-2 and solubility values, its significantly lower DILI risk and much lower microsomal clearance (better metabolic stability) are crucial advantages for an enzyme target like SRC kinase. The slightly better binding affinity also contributes to its favorability. The negative half-life is a concern, but could be addressed through structural modifications. Ligand B's higher DILI risk and higher clearance make it less attractive.

Output:
0
2025-04-17 16:14:46,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.463 and 373.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.23) is significantly better than Ligand B (104.37), being well below the 140 threshold for good absorption.

**logP:** Ligand A (2.739) is optimal, while Ligand B (0.905) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 4 HBA) as it has fewer H-bond donors. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.632 and 0.577), indicating reasonable drug-likeness.

**DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (48.158), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.682) is better than Ligand B (47.693).

**Caco-2 Permeability:** Both have negative values (-5.439 and -5.25), which is unusual and suggests very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.686 and -2.801), indicating very poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.865 and 0.185), which is positive.

**Microsomal Clearance:** Ligand A (-14.24) exhibits much better metabolic stability (lower clearance) than Ligand B (39.831). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (25.036 hours) has a considerably longer half-life than Ligand B (-23.082 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.162 and 0.109).

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol).

**Conclusion:**

Despite the poor Caco-2 permeability and solubility for both compounds, Ligand A is the superior candidate. It demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a more favorable logP. The binding affinity is the same, so these ADME/Tox improvements outweigh the shared drawbacks.

Output:
0
2025-04-17 16:14:46,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.348 and 373.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.25) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (91.32) is still within acceptable range but less favorable than A.

**logP:** Both ligands have good logP values (2.108 and 1.28), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, which is excellent. Ligand B has 3 HBD and 5 HBA, still acceptable, but slightly less optimal.

**QED:** Both ligands have similar QED values (0.711 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (53.936) has a slightly higher DILI risk than Ligand B (43.117), but both are below the concerning threshold of 60.

**BBB:** Ligand A (88.135) has better BBB penetration than Ligand B (64.676), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.475) has a much more favorable Caco-2 permeability than Ligand B (-5.207), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.719) has better aqueous solubility than Ligand B (-2.45), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.387) has a lower hERG inhibition liability than Ligand B (0.178), which is a significant advantage.

**Microsomal Clearance:** Ligand A (50.968) has a higher microsomal clearance than Ligand B (9.838), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-13.844) has a shorter in vitro half-life than Ligand B (-11.599), further supporting the lower metabolic stability of A.

**P-gp Efflux:** Ligand A (0.259) has lower P-gp efflux than Ligand B (0.018), which is favorable.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its less favorable ADME properties.

**Conclusion:**

While Ligand A has better TPSA, solubility, hERG, and P-gp properties, Ligand B's substantially stronger binding affinity (-10.1 vs -8.6 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial for an enzyme inhibitor. The difference in binding affinity is substantial enough to offset the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 16:14:46,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.356 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.12) is better than Ligand B (49.85) as it is closer to the <140 threshold for good absorption.

**logP:** Ligand A (4.29) is slightly higher than the optimal 1-3 range, while Ligand B (2.974) is within the optimal range. This favors Ligand B.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED values (0.771 and 0.676, both > 0.5).

**DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (35.673), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (94.921 and 86.468), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.321 and -4.39), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.491 and -3.121). This is a major concern for *in vivo* bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.42 and 0.46), which is excellent.

**Microsomal Clearance:** Ligand A (62.922) has lower microsomal clearance than Ligand B (75.457), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand B (-9.289) has a significantly longer in vitro half-life than Ligand A (-2.777). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.589 and 0.429), which is good.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 0.4 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic) and slightly better binding affinity. However, Ligand B has a better logP, a longer half-life, and a lower DILI risk. Both have poor solubility and permeability. The longer half-life of Ligand B is a significant advantage for a kinase inhibitor, potentially allowing for less frequent dosing. The slightly better affinity of Ligand A is partially offset by its poorer metabolic stability and shorter half-life. Given the poor solubility and permeability of both, improving these properties will be crucial for either compound. However, the improved half-life and lower DILI risk of Ligand B make it slightly more promising.

Output:
1
2025-04-17 16:14:46,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.463 and 365.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.81) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (98.14) is well within the desired range.

**logP:** Ligand A (-1.039) is a bit low, potentially hindering permeation. Ligand B (0.978) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 8 HBA, which are acceptable. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.459 and 0.68), indicating moderate drug-likeness. Ligand B is better.

**DILI:** Ligand A (38.077) has a lower DILI risk than Ligand B (63.397), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**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 unusual and indicates poor solubility. This is a concern for both.

**hERG:** Ligand A (0.348) has a lower hERG risk than Ligand B (0.537), which is a positive.

**Microsomal Clearance:** Ligand A (-8.3) has a much lower (better) microsomal clearance than Ligand B (28.832), indicating greater metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (37.425) has a longer half-life than Ligand A (24.313), which is a slight advantage.

**P-gp Efflux:** Ligand A (0.013) has a much lower P-gp efflux liability than Ligand B (0.184), which is a positive.

**Binding Affinity:** Ligand B (-9.5) has a significantly stronger binding affinity than Ligand A (-8.6), a difference of 0.9 kcal/mol. This is a substantial advantage that can outweigh some ADME concerns.

**Overall:**

While Ligand A has better DILI, hERG, and metabolic stability (Cl_mic), the significantly stronger binding affinity of Ligand B (-9.5 vs -8.6 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The potency advantage is likely to outweigh the slightly higher DILI and P-gp efflux risks. The poor Caco-2 and solubility are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:14:46,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.379 and 355.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (126.82 and 120.25) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Ligand A (0.555) is slightly low, potentially impacting permeability. Ligand B (0.074) is even lower, raising more concerns about permeability.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (4) 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:** Ligand A (0.628) is significantly better than Ligand B (0.397), indicating a more drug-like profile.

**7. DILI:** Ligand A (76.386) has a higher DILI risk than Ligand B (35.285), but both are reasonably acceptable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (59.325) and Ligand B (23.11) are both low.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.204 and -5.305), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.494 and -1.958), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.065) has a very low hERG risk, which is excellent. Ligand B (0.153) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (23.42) has a moderate clearance, while Ligand B (-2.577) has a *negative* clearance, which is not physically possible and likely indicates a data error or a very stable compound.

**13. In vitro Half-Life:** Ligand A (0.796) has a short half-life, while Ligand B (13.561) has a much longer half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.063).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.0 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 much longer half-life, which are critical for an enzyme inhibitor. While its logP is very low and solubility is poor, the strong binding affinity might compensate for these issues. The negative microsomal clearance is a red flag, but could be a data error. Ligand A has a better QED and hERG profile, but its weaker binding affinity and shorter half-life are significant drawbacks. Considering the priorities for kinase inhibitors, the superior potency of Ligand B outweighs its other shortcomings.

Output:
1
2025-04-17 16:14:46,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.39) is slightly better positioned.

**TPSA:** Ligand B (76.02) is significantly better than Ligand A (126.55). Lower TPSA generally improves cell permeability.

**logP:** Ligand B (2.056) is optimal, while Ligand A (0.275) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both are within acceptable ranges. Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 4 HBA.

**QED:** Both ligands have reasonable QED scores (A: 0.679, B: 0.513), indicating drug-like properties.

**DILI:** Ligand B (48.47) has a slightly better DILI score than Ligand A (38.74), but both are acceptable (<60).

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (83.44) is higher, but this is less important.

**Caco-2 Permeability:** Both are negative, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both have low hERG risk (A: 0.15, B: 0.26).

**Microsomal Clearance (Cl_mic):** Ligand A (-19.52) has a *much* lower (better) Cl_mic than Ligand B (32.54). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (4.08) has a longer half-life than Ligand A (0.16), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.6 kcal/mol). This difference of 3.1 kcal/mol is very significant and can often outweigh other ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (Cl_mic) and a slightly better DILI score, Ligand B's significantly stronger binding affinity (-9.7 vs -6.6 kcal/mol) is the most crucial factor for an enzyme inhibitor. The affinity difference is large enough to compensate for the slightly higher Cl_mic and lower BBB. The low logP of Ligand A is a major concern. Both have poor solubility and Caco-2 permeability, which would require formulation strategies.

Output:
1
2025-04-17 16:14:46,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 387.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.71) is better than Ligand B (91.76), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (2.298 and 1.229), 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=7) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.629 and 0.684), indicating good drug-likeness.

**DILI:** Ligand A (43.66) has a significantly lower DILI risk than Ligand B (66.421). This is a major advantage for Ligand A.

**BBB:** Ligand A (76.658) has a better BBB penetration score than Ligand B (17.72). While not a primary concern for a kinase inhibitor (unless CNS effects are desired), it's a positive attribute.

**Caco-2 Permeability:** Ligand A (-4.641) has a better Caco-2 permeability than Ligand B (-5.067).

**Aqueous Solubility:** Ligand A (-2.361) has better aqueous solubility than Ligand B (-2.833).

**hERG Inhibition:** Ligand A (0.874) has a lower hERG inhibition liability than Ligand B (0.328), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (26.256) has a higher microsomal clearance than Ligand B (16.161), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-6.101) has a longer in vitro half-life than Ligand A (-3.598), indicating better metabolic stability. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.321) has lower P-gp efflux than Ligand B (0.142), which is a positive attribute.

**Binding Affinity:** Ligand A (-7.9) has a significantly stronger binding affinity than Ligand B (-0.0). This is the most crucial factor, and the 7.9 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A excels in potency (binding affinity), DILI risk, hERG inhibition, solubility, and Caco-2 permeability. While its microsomal clearance is higher (less stable) than Ligand B, the significantly stronger binding affinity (-7.9 vs -0.0 kcal/mol) and lower toxicity profile (DILI, hERG) outweigh this drawback. Ligand B has a better half-life, but its weak binding affinity makes it unlikely to be a viable candidate.

Output:
1
2025-04-17 16:14:46,728 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [345.378, 96.01, 1.525, 3, 4, 0.663, 69.601, 70.609, -5.191, -3.177, 0.488, 20.981, 23.052, 0.063, -8.9]
**Ligand B:** [347.463, 78.43, 1.06, 1, 5, 0.832, 16.13, 60.527, -5.174, -1.243, 0.119, -10.276, -2.853, 0.006, -7.1]

**Step-by-step comparison:**

1. **MW:** Both ligands (345.378 & 347.463 Da) fall within the ideal 200-500 Da range. No clear advantage.
2. **TPSA:** Ligand A (96.01) is slightly higher than Ligand B (78.43). Both are below the 140 threshold for oral absorption, but B is better.
3. **logP:** Both ligands have good logP values (1.525 & 1.06), falling within the optimal 1-3 range. Ligand B is slightly lower, potentially improving solubility.
4. **HBD:** Ligand A (3) is higher than Ligand B (1). Lower is generally preferred for permeability, giving an edge to B.
5. **HBA:** Ligand A (4) is lower than Ligand B (5). Lower is generally preferred for permeability, giving an edge to A.
6. **QED:** Ligand B (0.832) has a better QED score than Ligand A (0.663), indicating a more drug-like profile.
7. **DILI:** Ligand A (69.601) has a significantly higher DILI risk than Ligand B (16.13). This is a major concern for A.
8. **BBB:** Ligand A (70.609) has a better BBB penetration score than Ligand B (60.527). However, since SRC is not a CNS target, this is less important.
9. **Caco-2:** Both ligands have negative Caco-2 values (-5.191 & -5.174), which is unusual and suggests poor permeability. Further investigation would be needed to clarify these values.
10. **Solubility:** Ligand B (-1.243) has a better (less negative) solubility score than Ligand A (-3.177).
11. **hERG:** Ligand A (0.488) has a slightly better hERG profile than Ligand B (0.119).
12. **Cl_mic:** Ligand B (-10.276) has a much lower (better) microsomal clearance than Ligand A (20.981), indicating greater metabolic stability.
13. **t1/2:** Ligand A (23.052) has a longer in vitro half-life than Ligand B (-2.853). This is a positive for A.
14. **Pgp:** Ligand A (0.063) has lower P-gp efflux than Ligand B (0.006), which is favorable.
15. **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.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

While Ligand A has a significantly better binding affinity, its high DILI risk and higher microsomal clearance are major drawbacks. Ligand B, despite the slightly weaker affinity, presents a much more favorable ADMET profile: lower DILI risk, better metabolic stability, and improved solubility. The difference in binding affinity (1.8 kcal/mol) is substantial, but the ADMET advantages of Ligand B are compelling, especially considering the potential for optimization of Ligand B's affinity.

Therefore, I would choose **Ligand B** as the more viable drug candidate.

Output:
1
2025-04-17 16:14:46,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (335.319 Da and 337.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (105.06) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (57.74) is well within the acceptable range.

**3. logP:** Ligand A (2.411) is within the optimal 1-3 range. Ligand B (4.238) is a bit high, potentially leading to solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both Ligand A (5) and Ligand B (5) meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.765 and 0.791, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (98.527%), which is a major concern. Ligand B has a much lower DILI risk (32.183%), which is favorable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (61.342) and Ligand B (74.292) are both moderate.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, both have poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.239) has a lower hERG risk than Ligand B (0.695), which is good.

**12. Microsomal Clearance:** Ligand A (5.553) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (56.796) has a significantly higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (14.383) has a longer half-life than Ligand B (-2.915), which is desirable.

**14. P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux, which is better. Ligand B (0.335) has slightly higher efflux.

**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 substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

While Ligand A boasts a much stronger binding affinity, its extremely high DILI risk is a major red flag. The poor solubility of both compounds is also concerning. However, the significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux of Ligand A, combined with its superior affinity, make it a more promising starting point for optimization *if* the DILI risk can be mitigated through structural modifications. Ligand B's high logP and high clearance are also problematic.

Output:
0
2025-04-17 16:14:46,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 353.461 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.9) is better than Ligand B (55.63) as it is still within the acceptable range for oral absorption (<140), but lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (2.169 and 3.683), falling within the 1-3 range. Ligand B is slightly higher, which *could* present solubility concerns, but isn't a major issue.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.799 and 0.877), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (44.126 and 42.536), which is excellent.

**BBB:** Ligand B (92.284) has a significantly higher BBB penetration score than Ligand A (53.974). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.816) has a lower Caco-2 permeability than Ligand B (-4.66). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.486) has better aqueous solubility than Ligand B (-4.878). Solubility is crucial for bioavailability, making Ligand A more favorable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.271 and 0.394), which is good.

**Microsomal Clearance:** Ligand A (24.499) has a higher microsomal clearance than Ligand B (11.512). This means Ligand B is more metabolically stable, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (9.95) has a slightly longer half-life than Ligand B (2.882).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.037 and 0.136).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and a slightly longer half-life, Ligand B's significantly stronger binding affinity (-7.2 vs -8.0 kcal/mol) and better metabolic stability (lower Cl_mic) are more critical for an enzyme inhibitor like an SRC kinase inhibitor. The slightly higher logP of Ligand B is not a major concern. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:14:46,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.431 and 346.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.73 and 97.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.078 and 1.249) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which is acceptable.

**QED:** Both ligands have reasonable QED scores (0.478 and 0.572), with Ligand B slightly better.

**DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (50.291). This is a major advantage for Ligand A.

**BBB:** Ligand A (68.748) has a higher BBB penetration score than Ligand B (40.442), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.864) is slightly better than Ligand B (-4.649), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.145) is slightly better than Ligand B (-2.924).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.082 and 0.053).

**Microsomal Clearance:** Ligand A (66.165) has a higher microsomal clearance than Ligand B (40.265), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-9.532) has a longer in vitro half-life than Ligand A (-8.064). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.019 and 0.01).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). A 0.5 kcal/mol difference is not huge, but is noticeable.

**Overall Assessment:**

Ligand A has a significant advantage in terms of DILI risk and slightly better solubility and Caco-2 permeability. However, Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. Given that SRC is an enzyme, metabolic stability and potency are prioritized. The difference in binding affinity is not substantial enough to overcome the substantial difference in DILI risk.

Output:
1
2025-04-17 16:14:46,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (426.793 and 400.825 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (124.2). A TPSA below 140 is good for oral absorption, but lower is generally preferred, and Ligand A is much closer to the ideal range.

**logP:** Ligand A (4.771) is slightly high, potentially leading to solubility issues, while Ligand B (2.315) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 8. Ligand A is preferable here, as excessive HBAs can hinder permeability.

**QED:** Both ligands have reasonable QED scores (0.609 and 0.529), indicating good drug-like properties.

**DILI:** Ligand A (41.954) has a much lower DILI risk than Ligand B (99.457). This is a significant advantage for Ligand A.

**BBB:** Both have similar BBB penetration (55.176 and 57.736), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.785 and -5.168), which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Ligand A (-6.482) has slightly better solubility than Ligand B (-3.161), although both are quite poor.

**hERG Inhibition:** Ligand A (0.566) has a lower hERG risk than Ligand B (0.183), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (74.458) has a higher Cl_mic than Ligand B (10.259), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (83.336) has a much longer in vitro half-life than Ligand A (-4.015), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.396 and 0.49), which is good.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has advantages in TPSA, DILI, and hERG, Ligand B's significantly better metabolic stability (lower Cl_mic, longer half-life) and slightly improved binding affinity outweigh these factors. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed through formulation strategies. The high DILI risk of Ligand B is a serious concern, but the substantial improvement in metabolic stability is more critical for an enzyme target.

Output:
1
2025-04-17 16:14:46,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.527 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption. Ligand A (62.3 A^2) is better than Ligand B (68.74 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.865) is slightly better than Ligand B (4.276), as Ligand B is approaching the upper limit where solubility issues can arise.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A (4 HBA) is better than Ligand B (7 HBA).

**QED:** Ligand A (0.845) has a significantly better QED score than Ligand B (0.518), indicating a more drug-like profile.

**DILI:** Ligand A (26.057) has a much lower DILI risk than Ligand B (84.8), a crucial advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (71.966) is slightly better. This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.307) has a much lower hERG inhibition liability than Ligand B (0.962), a significant safety advantage.

**Microsomal Clearance:** Ligand B (43.109 mL/min/kg) has a lower microsomal clearance than Ligand A (59.09 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (34.131 hours) has a longer in vitro half-life than Ligand A (18.822 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.233) has lower P-gp efflux liability than Ligand B (0.887), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-7.9 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 of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, higher hERG liability, and lower QED. Ligand A has a more favorable ADME profile across several parameters (DILI, hERG, QED, Pgp efflux), but its binding affinity is weaker. The difference in binding affinity (1.7 kcal/mol) is substantial. Given the importance of potency for kinase inhibitors, and assuming the binding assay is reliable, the stronger binding of Ligand B is likely to be more impactful than its ADME liabilities, especially if those liabilities can be addressed through further optimization.

Output:
1
2025-04-17 16:14:46,728 - INFO - Batch 447 complete. Total preferences: 7152
2025-04-17 16:14:46,729 - INFO - Processing batch 448/512...
2025-04-17 16:15:25,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.885 and 363.527 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (36.44) is significantly better than Ligand B (62.3), being well below the 140 threshold for oral absorption. Ligand B is higher, potentially indicating lower absorption.

**logP:** Both ligands have good logP values (3.896 and 3.441), 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). Lower HBD/HBA generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.779 and 0.769), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (41.838 and 43.505), which is acceptable (below 60).

**BBB:** Ligand A (93.408) has a much higher BBB penetration percentile than Ligand B (67.701). While SRC isn't a CNS target, higher BBB is rarely detrimental and can indicate better overall permeability.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.849). This is unusual and suggests a potential issue with the experimental setup or a very poor permeability. However, we'll need to consider this in context with other properties.

**Aqueous Solubility:** Ligand A (-4.447) is slightly better than Ligand B (-2.756), but both are quite poor. This is a significant concern for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.938 and 0.359), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (71.472 and 71.019), indicating similar metabolic stability. These are moderately high, suggesting potential for rapid metabolism.

**In vitro Half-Life:** Ligand A (2.268 hours) has a shorter half-life than Ligand B (16.121 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.768) has slightly lower P-gp efflux than Ligand B (0.287), which is preferable.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). This difference is significant (0.5 kcal/mol) and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a significantly longer half-life, which are crucial for an enzyme inhibitor. While its TPSA is higher and solubility is lower than Ligand A, the affinity and half-life advantages are more important in this case. The negative Caco-2 values are concerning for both, but the better binding and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:15:25,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (393.148 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.29) is well below the 140 threshold for good oral absorption. Ligand B (104.69) is also below, but closer to the limit.

**3. logP:** Ligand A (4.446) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.225) is quite low, which could hinder 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 (4) and Ligand B (6) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.783 and 0.812), indicating drug-like properties.

**7. DILI:** Ligand A (90.461) has a high DILI risk, which is a significant concern. Ligand B (44.281) has a much lower, and acceptable, DILI risk.

**8. BBB:** Both ligands have similar BBB penetration (68.67 and 67.197). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.536) and Ligand B (-5.216) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-5.706) and Ligand B (-1.622) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.499) and Ligand B (0.208) both have low hERG inhibition risk, which is good.

**12. Microsomal Clearance:** Ligand A (77.857) has moderate clearance, while Ligand B (-9.059) has negative clearance, indicating very high metabolic stability. This is a major advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (46.206) has a moderate half-life. Ligand B (-2.023) has a very long half-life, which is highly desirable.

**14. P-gp Efflux:** Ligand A (0.445) and Ligand B (0.015) both have low P-gp efflux, which is good.

**15. Binding Affinity:** Ligand B (-8.6 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.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and metabolic stability, while Ligand A has a concerningly high DILI risk. Although both have poor solubility and permeability, the superior binding affinity and metabolic stability of Ligand B, coupled with its lower DILI risk, make it the more promising candidate.

Output:
1
2025-04-17 16:15:25,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be favorable for permeability. Ligand B (364.412 Da) is also good.

**TPSA:** Ligand A (95.41) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (52.41) is excellent, well below 140, suggesting good absorption.

**logP:** Both ligands have good logP values (A: 1.927, B: 2.494), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are within acceptable limits. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.581, B: 0.639), indicating drug-like properties.

**DILI:** Ligand A (56.96) has a higher DILI risk than Ligand B (27.181). This is a significant concern.

**BBB:** Ligand A (51.57) has lower BBB penetration than Ligand B (95.502). While not a primary concern for a non-CNS target like SRC, better BBB penetration generally suggests fewer off-target effects.

**Caco-2 Permeability:** Ligand A (-4.953) has worse Caco-2 permeability than Ligand B (-4.543). Both are negative, but B is better.

**Aqueous Solubility:** Ligand A (-3.247) has worse aqueous solubility than Ligand B (-2.665). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.228) has a slightly higher hERG risk than Ligand B (0.744).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 33.185, B: 32.872).

**In vitro Half-Life:** Ligand B (8.17) has a significantly better in vitro half-life than Ligand A (-28.084). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.131) has slightly lower P-gp efflux than Ligand B (0.255).

**Binding Affinity:** Ligand B (-6.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is substantial.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has slightly better MW and P-gp efflux, these are overshadowed by Ligand B's significantly better binding affinity, DILI risk, solubility, and in vitro half-life. The strong binding affinity of Ligand B (-6.3 kcal/mol) is a key advantage that can compensate for any minor ADME drawbacks. The lower DILI risk is also a critical factor.

Output:
1
2025-04-17 16:15:25,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (349.431 and 370.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.69) is better than Ligand B (132.72), being closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (0.486) is slightly better than Ligand B (-0.202), both are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (5 HBD, 5 HBA) is better than Ligand B (3 HBD, 8 HBA). Both are within acceptable limits, but Ligand A is slightly more balanced.

**QED:** Ligand B (0.625) has a better QED score than Ligand A (0.492), indicating a more drug-like profile.

**DILI:** Ligand A (34.781) has a significantly lower DILI risk than Ligand B (57.348), which is a major advantage.

**BBB:** Ligand A (43.311) has a higher BBB percentile than Ligand B (20.357), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.123 and -5.129). This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.326 and -2.835). This is a significant drawback for both.

**hERG:** Ligand A (0.213) has a much lower hERG inhibition liability than Ligand B (0.08), which is a critical safety advantage.

**Microsomal Clearance:** Ligand A (6.743 mL/min/kg) has significantly lower microsomal clearance than Ligand B (19.698 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.75 hours) has a better in vitro half-life than Ligand B (-41.499 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.014).

**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 might not be enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor Caco-2 permeability and solubility, Ligand A demonstrates significantly better safety (lower DILI and hERG) and pharmacokinetic properties (lower Cl_mic, longer t1/2). The slightly weaker binding affinity of Ligand A (-7.9 vs -8.6 kcal/mol) is less concerning than the ADME/Tox liabilities of Ligand B. Addressing the solubility and permeability issues will be crucial for either compound, but Ligand A provides a better starting point due to its superior safety and metabolic profile.

Output:
0
2025-04-17 16:15:25,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.455 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (55.84 and 58.2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.556 and 4.064) within the optimal 1-3 range, though Ligand B is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 2 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.675) has a better QED score than Ligand B (0.461), indicating a more drug-like profile.

**DILI:** Ligand A (38.581) has a significantly lower DILI risk than Ligand B (13.959), which is a crucial advantage.

**BBB:** Both ligands have similar BBB penetration (74.447 and 73.517), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.195 and -4.634). 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 negative solubility values (-4.54 and -4.351), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.685 and 0.64), which is good.

**Microsomal Clearance:** Ligand B (78.286) has lower microsomal clearance than Ligand A (92.783), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (9.121 hours) has a much longer in vitro half-life than Ligand A (-4.917 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.461 and 0.312).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.0 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. While Ligand A has a slightly better QED and H-bonding profile, the improved pharmacokinetic properties of Ligand B outweigh these minor advantages, especially for an enzyme target where metabolic stability is crucial. The similar binding affinity confirms that the ADME improvements of Ligand B are likely to translate to better *in vivo* efficacy.

Output:
1
2025-04-17 16:15:25,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is well below the 140 threshold and good for oral absorption. Ligand B (114.85) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.974) is optimal (1-3). Ligand B (1.618) is a bit low, potentially hindering permeation, but not critically so.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 4 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED scores (0.766 and 0.622), indicating good drug-like properties.

**DILI:** Ligand A (19.038) has a significantly lower DILI risk than Ligand B (39.667), which is a major advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (71.074) shows better BBB penetration than Ligand B (51.725).

**Caco-2 Permeability:** Ligand A (-4.535) shows poor permeability. Ligand B (-5.239) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.427) is better than Ligand B (-3.07), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.519 and 0.458), which is good.

**Microsomal Clearance:** Ligand A (40.535) has higher clearance than Ligand B (-4.261). This suggests Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-9.647) has a significantly longer half-life than Ligand A (13.623), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.177 and 0.06), which is positive.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -8.2 kcal/mol). Ligand B is slightly better, but the difference is relatively small.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has a lower DILI risk and slightly better solubility, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer half-life) and slightly better binding affinity outweigh these advantages. For an enzyme target like SRC kinase, metabolic stability is crucial for maintaining therapeutic concentrations. The slightly lower Caco-2 permeability and logP of Ligand B are less concerning than the higher clearance of Ligand A.

Output:
1
2025-04-17 16:15:25,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.418 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (107.97). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B is approaching a level that could hinder absorption.

**logP:** Ligand A (0.814) is within the optimal 1-3 range, while Ligand B (-0.571) is slightly below 1. This could potentially impact membrane permeability for Ligand B.

**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 (0.768) has a better QED score than Ligand B (0.505), indicating a more drug-like profile.

**DILI:** Ligand B (21.055) has a lower DILI risk than Ligand A (16.673), which is favorable.

**BBB:** Ligand A (78.79) shows better BBB penetration than Ligand B (31.214), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.545) has a worse Caco-2 permeability than Ligand B (-5.374), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.364) has better aqueous solubility than Ligand B (-1.268), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.4 and 0.116 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (3.293) has a significantly lower microsomal clearance than Ligand B (34.767), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-8.339) has a longer in vitro half-life than Ligand B (-4.697), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.012 respectively).

**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.

**Conclusion:**

Considering all factors, Ligand A is the more promising drug candidate. While Ligand B has a slightly lower DILI risk, Ligand A excels in crucial areas for kinase inhibitors: lower TPSA, better logP, better QED, significantly lower microsomal clearance, and a longer in vitro half-life. The comparable binding affinity makes these ADME properties the deciding factors.

Output:
0
2025-04-17 16:15:25,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 346.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.23) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (100.51) is also acceptable, though slightly higher.

**logP:** Ligand A (0.683) is a bit low, potentially hindering permeation. Ligand B (-0.736) is even lower, raising more concern about permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are reasonable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.811) has a better QED score than Ligand B (0.663), indicating a more drug-like profile.

**DILI:** Ligand A (44.591) has a lower DILI risk than Ligand B (52.617), which is preferable. Both are below the 60 threshold, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.735) is higher than Ligand B (51.105).

**Caco-2 Permeability:** Ligand A (-4.707) and Ligand B (-5.153) both have negative values, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-3.498) has better solubility than Ligand B (-1.4). Solubility is important for bioavailability.

**hERG:** Both ligands show very low hERG inhibition liability (0.192 and 0.045 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (28.408) has a higher (worse) microsomal clearance than Ligand B (-0.955). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (12.893 hours) has a significantly longer half-life than Ligand B (2.083 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.161 and 0.017 respectively), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.9 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has a better QED, lower DILI risk, better solubility, and a significantly longer half-life. While its logP is slightly lower than ideal, its superior metabolic stability and half-life outweigh this concern. Ligand B has slightly better affinity and metabolic stability, but suffers from lower solubility and a much shorter half-life. Given the enzyme-specific priorities, the longer half-life of Ligand A is a crucial advantage.

Output:
1
2025-04-17 16:15:25,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (354.447 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is higher than Ligand B (40.62). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (0.57) is quite low, potentially hindering permeability. Ligand B (3.64) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both acceptable.

**QED:** Both ligands have reasonable QED values (0.799 and 0.66), suggesting good drug-like properties.

**DILI:** Ligand A (45.173) has a moderate DILI risk, while Ligand B (16.053) has a very low DILI risk. This is a clear advantage for Ligand B.

**BBB:** Ligand A (65.607) and Ligand B (92.982). BBB is not a high priority for SRC kinase inhibitors unless CNS penetration is specifically desired. Ligand B is better.

**Caco-2 Permeability:** Ligand A (-4.657) and Ligand B (-4.536) are similar and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-1.38) and Ligand B (-3.19) are both poor.

**hERG Inhibition:** Ligand A (0.171) and Ligand B (0.389) are both low, indicating minimal hERG risk.

**Microsomal Clearance:** Ligand A (4.235) has lower clearance than Ligand B (71.405), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-7.441) has a much longer half-life than Ligand B (-20.052). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux than Ligand B (0.334), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.9 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B has advantages in logP, DILI, and BBB. However, Ligand A excels in metabolic stability (lower Cl_mic, longer half-life) and P-gp efflux, which are crucial for an enzyme target like SRC kinase. The slightly better binding affinity of Ligand B is outweighed by the superior pharmacokinetic properties of Ligand A. Solubility and Caco-2 permeability are poor for both.

Output:
0
2025-04-17 16:15:25,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (69.04) is significantly better than Ligand B (114.18). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values, falling within the 0.469-2.477 range. Ligand A (2.477) is slightly better, closer to the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=7) as it has fewer hydrogen bond donors and acceptors, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.8, B: 0.644), indicating good drug-like properties.

**DILI:** Ligand B (57.58) has a higher DILI risk than Ligand A (16.285). This is a significant drawback for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand B (61.535) is slightly better than Ligand A (57.852).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, both are poor.

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, both are poor.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.37, B: 0.072), which is excellent.

**Microsomal Clearance:** Ligand B (-6.287) has *lower* (better) microsomal clearance than Ligand A (51.729). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-8.055) has a longer in vitro half-life than Ligand A (-10.158), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.089, B: 0.057).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-7.0 and -7.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, H-bonding, and DILI risk. However, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Given that SRC kinase is an enzyme, metabolic stability and minimizing toxicity (DILI) are crucial. While solubility and permeability are both poor, the metabolic stability of Ligand B is a compelling advantage. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 16:15:25,334 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, following the provided guidelines.

**Step-by-step comparison:**

1. **MW:** Ligand A (341.455 Da) is within the ideal range (200-500). Ligand B (358.316 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (56.15) is excellent, well below the 140 threshold for oral absorption. Ligand B (88.42) is still reasonable, but higher. A is better.

3. **logP:** Both ligands (A: 2.937, B: 3.137) are within the optimal 1-3 range. No significant difference.

4. **HBD:** Both ligands have 1 HBD, which is good.

5. **HBA:** Ligand A has 4 HBA, and Ligand B has 5 HBA. Both are acceptable (<=10), but A is slightly better.

6. **QED:** Ligand A (0.851) has a very strong drug-like profile. Ligand B (0.541) is acceptable, but less ideal. A is significantly better.

7. **DILI:** Ligand A (24.622) has a low DILI risk. Ligand B (60.915) has a moderate-high DILI risk. A is much better.

8. **BBB:** Ligand A (81.504) has good BBB penetration, while Ligand B (74.564) is lower. While not a primary concern for a kinase inhibitor, A is preferable.

9. **Caco-2:** Ligand A (-5.064) and Ligand B (-4.551) both have negative Caco-2 values, indicating poor permeability. This is a significant concern for both.

10. **Solubility:** Ligand A (-2.763) and Ligand B (-4.244) both have poor solubility. This is a significant concern for both.

11. **hERG:** Ligand A (0.875) has a low hERG risk. Ligand B (0.652) also has a low hERG risk. No significant difference.

12. **Cl_mic:** Ligand A (50.669) has a moderate clearance, while Ligand B (55.595) has a slightly higher clearance. A is slightly better.

13. **t1/2:** Ligand A (4.811) has a better in vitro half-life than Ligand B (2.693). A is better.

14. **Pgp:** Ligand A (0.782) has lower P-gp efflux than Ligand B (0.08). A is much better.

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 substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For enzyme targets like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in affinity, has slightly better metabolic stability, and a significantly better DILI profile. While both compounds have poor solubility and Caco-2 permeability, the superior binding affinity and safety profile of Ligand A outweigh these concerns.

**Conclusion:**

Ligand A is the more promising drug candidate.

1
2025-04-17 16:15:25,334 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines and prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.399 and 343.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (96.26 and 92.93) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (2.829 and 2.084) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the HBD <= 5 criterion.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) both meet the HBA <= 10 criterion.

**6. QED:** Ligand A (0.799) has a significantly better QED score than Ligand B (0.509), indicating a more drug-like profile.

**7. DILI:** Ligand A (72.005) has a higher DILI risk than Ligand B (41.76). This favors Ligand B.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (69.794) is slightly better than Ligand B (24.389).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.921) is slightly better than Ligand B (-5.351).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand B (-1.975) is slightly better than Ligand A (-3.252).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.152 and 0.236).

**12. Microsomal Clearance:** Ligand A (18.177 mL/min/kg) has significantly lower microsomal clearance than Ligand B (29.879 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-7.04 hours) has a significantly longer half-life than Ligand B (13.648 hours). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.227).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.1 kcal/mol). Ligand A is slightly better (-8.5 kcal/mol).

**Overall Assessment:**

While Ligand B has a lower DILI risk and slightly better solubility, Ligand A is superior overall. The key advantages of Ligand A are its significantly better QED score, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. The slightly better binding affinity of Ligand A also contributes. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this concern. Given the enzyme-kinase focus, metabolic stability and half-life are crucial, and Ligand A excels in these areas.

Output:
1
2025-04-17 16:15:25,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.45 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (91.22).  A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B is approaching a less desirable range.

**logP:** Both ligands (2.902 and 2.144) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (0.746 and 0.632), indicating good drug-like properties.

**DILI:** Ligand A (18.069) has a much lower DILI risk than Ligand B (6.282), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (91.663) has a higher BBB percentile than Ligand B (68.941).

**Caco-2 Permeability:** Ligand A (-4.434) has better Caco-2 permeability than Ligand B (-4.665).

**Aqueous Solubility:** Ligand A (-2.733) has better aqueous solubility than Ligand B (-1.845). This is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.453 and 0.371).

**Microsomal Clearance:** Ligand A (62.338) has a higher microsomal clearance than Ligand B (19.944), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (10.966) has a significantly longer in vitro half-life than Ligand A (-1.4). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.083 and 0.007).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.5 kcal/mol difference is a significant advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability (lower Cl_mic and longer t1/2), Ligand A is the stronger candidate. The significantly better binding affinity (-8.6 vs -7.1 kcal/mol) is a crucial factor for an enzyme target. Furthermore, Ligand A exhibits lower DILI risk and better solubility and permeability. While Ligand B has a longer half-life, the potency advantage of Ligand A is more critical for initial development.

Output:
1
2025-04-17 16:15:25,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.487 Da and 353.486 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.51) is slightly higher than the preferred <140, while Ligand B (64.86) is well within the range.

**logP:** Both ligands have good logP values (2.253 and 2.843), 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 as they are <=10.

**QED:** Both ligands have good QED scores (0.71 and 0.816), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 74.021, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk (39.667), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (93.68) compared to Ligand A (61.807), but this is not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.895) and Ligand B (-5.017) 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:** Ligand A (-3.523) and Ligand B (-2.701) both have negative solubility values, indicating poor solubility. Again, the scale is unknown, making direct comparison difficult.

**hERG Inhibition:** Ligand A (0.261) and Ligand B (0.426) both have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (93.358) has significantly higher microsomal clearance than Ligand B (33.404), suggesting lower metabolic stability. This is a key negative for Ligand A.

**In vitro Half-Life:** Ligand A (-38.962) has a negative half-life, which is unusual and likely indicates a very short half-life. Ligand B (-3.057) has a slightly negative half-life but is much better than Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.307 and 0.515), which is favorable.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.1), but the difference (0.5 kcal/mol) is not substantial enough to outweigh the significant ADME drawbacks of Ligand A.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly lower DILI risk and much better metabolic stability (lower Cl_mic, better t1/2). The slightly better affinity of Ligand A is not enough to compensate for its poor ADME profile, especially the high DILI risk and low metabolic stability.

Output:
1
2025-04-17 16:15:25,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (359.813 and 351.382 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.39) is well below the 140 threshold, suggesting good absorption. Ligand B (126.21) is also below, but closer to the limit.

**logP:** Ligand A (2.773) is within the optimal 1-3 range. Ligand B (0.098) is quite low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (4 HBD, 5 HBA) is acceptable, but the higher HBD count could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (0.603 and 0.518), indicating good drug-likeness.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (56.999), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.276) shows better BBB penetration than Ligand B (78.674).

**Caco-2 Permeability:** Ligand A (-4.727) is better than Ligand B (-5.666), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.778) is better than Ligand B (-2.518), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.342 and 0.303).

**Microsomal Clearance:** Ligand A (90.298) has higher clearance than Ligand B (-11.576), meaning Ligand B is more metabolically stable. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (6.735) has a longer half-life than Ligand A (-4.485), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.211 and 0.01).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Despite Ligand A having slightly better solubility and a lower DILI risk, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.1 vs -7.8 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are critical for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization, but the potency and stability advantages are more important.

Output:
1
2025-04-17 16:15:25,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.384 and 360.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.96) is better than Ligand B (33.95) as it is closer to the threshold of 140 for oral absorption.

**logP:** Both ligands have logP values (3.657 and 4.587) within the optimal 1-3 range, but Ligand B is slightly higher.

**H-Bond Donors:** Both have 0 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 good QED scores (0.789 and 0.724), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 65.568, which is higher than Ligand B's 21.404. This is a significant concern for Ligand A.

**BBB:** Both have high BBB penetration (94.455 and 88.29), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.079) has a negative Caco-2 value, which is concerning. Ligand B (-5.079) is also negative, but slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.997 and -4.036), indicating poor aqueous solubility. This is a drawback for both.

**hERG Inhibition:** Ligand A (0.611) has a slightly better hERG profile than Ligand B (0.839), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (13.382) has significantly lower microsomal clearance than Ligand B (67.778), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (45.675) has a longer half-life than Ligand B (12.129), which is desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.643 and 0.679).

**Binding Affinity:** Ligand B (-8.8 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.

**Conclusion:**

Despite Ligand A's better metabolic stability and slightly better hERG profile, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.8 vs -7.3 kcal/mol) is a major advantage for an enzyme inhibitor. While both have poor solubility and negative Caco-2 values, the superior potency of Ligand B is likely to be more impactful in driving efficacy. The lower DILI risk for Ligand B is also a significant benefit.

Output:
1
2025-04-17 16:15:25,335 - INFO - Batch 448 complete. Total preferences: 7168
2025-04-17 16:15:25,335 - INFO - Processing batch 449/512...
2025-04-17 16:16:13,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.371 and 350.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.23) is higher than Ligand B (78.87). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.364) is quite low, potentially hindering permeability. Ligand B (2.376) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** 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 (0.787 and 0.855), indicating good drug-like properties.

**DILI:** Ligand A (56.146) has a higher DILI risk than Ligand B (36.603). Ligand B is preferable here.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (74.796) is higher than Ligand A (58.356), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both have negative values (-5.103 and -5.106), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so these are likely representing low permeability.

**Aqueous Solubility:** Both have negative values (-2.484 and -3.024), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.112) has a slightly lower hERG risk than Ligand B (0.545), which is preferable.

**Microsomal Clearance:** Ligand A (11.586) has lower microsomal clearance than Ligand B (15.357), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand B (-11.099) has a much longer in vitro half-life than Ligand A (-4.273), which is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.035).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has advantages in logP, TPSA, DILI, and in vitro half-life. Ligand A has an advantage in microsomal clearance and slightly lower hERG risk. The binding affinities are comparable. The poor Caco-2 and solubility values are concerning for both, but the better logP and half-life of Ligand B, coupled with lower DILI risk, make it the more promising candidate.

Output:
1
2025-04-17 16:16:13,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 364.515 Da - Within the ideal range (200-500).
* Ligand B: 342.399 Da - Within the ideal range (200-500).
* *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 70.4  - Good for oral absorption (<140).
* Ligand B: 79.54 - Good for oral absorption (<140).
* *Both are acceptable.*

**3. Lipophilicity (logP):**
* Ligand A: 3.359 - Slightly high, but still within a reasonable range. Could potentially lead to off-target effects.
* Ligand B: 1.982 - Optimal (1-3).
* *Ligand B is preferred.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Acceptable (<=5).
* Ligand B: 0 - Acceptable (<=5).
* *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 5 - Acceptable (<=10).
* Ligand B: 5 - Acceptable (<=10).
* *Both are acceptable.*

**6. QED:**
* Ligand A: 0.634 - Good drug-like profile (>=0.5).
* Ligand B: 0.852 - Excellent drug-like profile (>=0.5).
* *Ligand B is preferred.*

**7. DILI:**
* Ligand A: 30.942 - Low risk (<40).
* Ligand B: 53.276 - Moderate risk, but still acceptable.
* *Ligand A is preferred.*

**8. BBB:**
* Ligand A: 60.256 - Not a priority for a non-CNS target like SRC.
* Ligand B: 75.533 - Not a priority for a non-CNS target like SRC.
* *Neutral.*

**9. Caco-2 Permeability:**
* Ligand A: -5.262 - Poor permeability.
* Ligand B: -4.693 - Poor permeability.
* *Both are concerning, but relatively similar.*

**10. Aqueous Solubility:**
* Ligand A: -1.782 - Poor solubility.
* Ligand B: -1.638 - Poor solubility.
* *Both are concerning, but relatively similar.*

**11. hERG Inhibition:**
* Ligand A: 0.795 - Low risk.
* Ligand B: 0.157 - Very low risk.
* *Ligand B is preferred.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 35.714 - Moderate clearance.
* Ligand B: 19.229 - Low clearance (better metabolic stability).
* *Ligand B is preferred.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 95.894 - Long half-life (desirable).
* Ligand B: 19.391 - Shorter half-life.
* *Ligand A is preferred.*

**14. P-gp Efflux:**
* Ligand A: 0.081 - Low efflux.
* Ligand B: 0.089 - Low efflux.
* *Both are acceptable.*

**15. Binding Affinity:**
* Ligand A: -6.9 kcal/mol - Very good affinity.
* Ligand B: -9.4 kcal/mol - Excellent affinity (significant advantage).

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-9.4 vs -6.9 kcal/mol), a better QED score, lower microsomal clearance (better metabolic stability), and lower hERG risk. While Ligand A has a longer half-life and slightly lower DILI risk, the substantial improvement in binding affinity and metabolic stability of Ligand B outweighs these minor drawbacks. The poor Caco-2 and solubility of both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:16:13,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.455 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (98.32 and 108.88) are below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (1.521) is optimal, while Ligand B (0.595) is slightly below the preferred range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.695 and 0.651), indicating good drug-likeness.

**DILI:** Ligand A (48.313) has a significantly lower DILI risk than Ligand B (60.295), which is approaching the higher risk threshold.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.572 and -5.586), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.444 and -2.316), also unusual and indicating poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.494) has a lower hERG risk than Ligand B (0.152), which is preferable.

**Microsomal Clearance:** Ligand A (-7.158) exhibits significantly lower (better) microsomal clearance than Ligand B (10.905), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.446) has a longer in vitro half-life than Ligand B (-19.397), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.025).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.7 kcal/mol). This difference of 1.6 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk outweigh the shared permeability and solubility concerns. The substantial difference in binding affinity is a key factor, as it suggests a greater potential for efficacy. Addressing the solubility and permeability issues through formulation or further chemical modifications would be the next steps in optimizing Ligand A.

Output:
0
2025-04-17 16:16:13,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.387 and 363.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.87) is slightly above the preferred <140, but acceptable. Ligand B (84.14) is well within the range.

**logP:** Both ligands have good logP values (0.998 and 1.336), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have similar, high QED scores (0.864 and 0.863), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 64.521, which is moderately high. Ligand B has a significantly lower DILI risk of 42.885, which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB score (73.517) than Ligand A (54.013).

**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, which is also unusual and suggests poor solubility. Again, the scale is unspecified.

**hERG:** Ligand A (0.135) has a very low hERG risk, which is excellent. Ligand B (0.767) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (15.217) than Ligand B (21.776), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A has a negative half-life (-10.197), which is not physically possible and indicates a problem with the data. Ligand B has a half-life of 14.36 hours, which is good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.081), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.3 kcal/mol). Ligand A is slightly better (-8.8 kcal/mol).

**Overall Assessment:**

Ligand A has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic). However, it has a higher DILI risk, a nonsensical negative half-life, and poor solubility. Ligand B has a lower DILI risk, a reasonable half-life, and a better BBB score. The negative solubility and Caco-2 values are concerning for both, but the more significant issue is the negative half-life for Ligand A. Given the importance of metabolic stability for kinase inhibitors, and the questionable half-life of Ligand A, I would favor Ligand B.

Output:
1
2025-04-17 16:16:13,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (360.4 and 349.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (135.8) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (99.2) is well within the range.

**3. logP:** Ligand A (1.06) is at the lower end of optimal, potentially impacting permeability. Ligand B (0.35) is quite low, raising concerns about membrane permeability.

**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 (0.625 and 0.74), indicating good drug-like properties.

**7. DILI:** Ligand A (96.5) shows a high DILI risk, which is a significant concern. Ligand B (31.3) has a much lower, and acceptable, DILI risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (40.8) and Ligand B (24.4) both have low BBB penetration.

**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 very low hERG inhibition risk (0.23 and 0.10), which is excellent.

**12. Microsomal Clearance:** Ligand A (17.5) has a higher microsomal clearance than Ligand B (-12.8). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-8.95) has a longer in vitro half-life than Ligand A (-17.2), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.016).

**15. Binding Affinity:** Both ligands have strong binding affinities (-7.5 and -7.8 kcal/mol), with Ligand B being slightly better. The difference is not substantial enough to override other significant issues.

**Overall Assessment:**

While both ligands exhibit good potency, Ligand A's extremely high DILI risk is a major red flag. The poor solubility and permeability (indicated by negative values) are also concerning. Ligand B, despite having a lower logP, has a significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and comparable binding affinity. Given the enzyme-specific priorities, metabolic stability and safety are crucial.

Output:
1
2025-04-17 16:16:13,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.483 and 354.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is better than Ligand B (49.41), both are below the 140 threshold for good absorption.

**logP:** Ligand A (4.112) is slightly higher than the optimal range (1-3), while Ligand B (2.964) is within the optimal range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 2. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.873 and 0.847), indicating good drug-like properties.

**DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (29.042), which is a major advantage.

**BBB:** Both have high BBB penetration (85.498 and 90.074), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.505 and -4.589). 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 (-5.149 and -3.927). This is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.73) has a slightly higher hERG risk than Ligand B (0.541), which is less desirable.

**Microsomal Clearance:** Ligand A (117.498) has a much higher microsomal clearance than Ligand B (10.524), indicating poorer metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (23.256) has a significantly longer half-life than Ligand A (0.59), which is a major advantage.

**P-gp Efflux:** Ligand A (0.736) has higher P-gp efflux than Ligand B (0.051), which is less desirable.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, and could potentially outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, but suffers from higher microsomal clearance, shorter half-life, higher P-gp efflux, and higher hERG risk. Ligand B has better ADME properties (lower clearance, longer half-life, lower P-gp efflux, lower hERG), but weaker binding affinity.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and potency (affinity) are key. The 0.4 kcal/mol difference in binding is substantial. However, the very high clearance of Ligand A is a major concern. While a strong binder, it may be quickly metabolized *in vivo*. The longer half-life and better metabolic stability of Ligand B are very attractive.

Output:
1
2025-04-17 16:16:13,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (396.288 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.02) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (78.43) is still under 140, but less optimal than A.

**logP:** Ligand A (4.284) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.983) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 & 3) and HBA (3 & 3) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.695 and 0.711), indicating drug-like properties.

**DILI:** Ligand A (79.527) has a concerningly high DILI risk (above 60). Ligand B (16.247) has a very low DILI risk, a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (75.378) is higher than Ligand B (62.156).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are logP values, both are poor, but Ligand A (-5.142) is worse than Ligand B (-4.744).

**Aqueous Solubility:** Both have negative solubility values which is unusual. Assuming these are logS values, both are poor, but Ligand A (-4.746) is worse than Ligand B (-2.974).

**hERG:** Ligand A (0.768) has a slightly higher hERG risk than Ligand B (0.135), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (53.61) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (20.138).

**In vitro Half-Life:** Ligand A (122.095) has a longer half-life than Ligand B (3.138), a positive attribute.

**P-gp Efflux:** Ligand A (0.696) has higher P-gp efflux liability than Ligand B (0.03).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor.

**Overall Assessment:**

Ligand B is significantly better. While Ligand A has a longer half-life and slightly better BBB, its high DILI risk, poor solubility, higher hERG risk, higher clearance, and *much* weaker binding affinity outweigh these benefits. Ligand B's strong binding affinity, low DILI, low hERG, and lower clearance make it a far more promising drug candidate despite the slightly lower BBB and half-life. The affinity difference is substantial enough to overcome minor ADME drawbacks.

Output:
1
2025-04-17 16:16:13,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.391 Da) is slightly better positioned.
**TPSA:** Ligand A (106.79) is better than Ligand B (67.4). Both are below the 140 threshold for oral absorption, but lower is generally preferred.
**logP:** Ligand B (2.133) is optimal (1-3), while Ligand A (0.037) is quite low, potentially hindering permeation.
**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0).
**H-Bond Acceptors:** Ligand A (7) is preferable to Ligand B (6).
**QED:** Both ligands have good QED scores (A: 0.738, B: 0.776), indicating drug-likeness.
**DILI:** Ligand B (38.852) has a significantly lower DILI risk than Ligand A (61.07). This is a major advantage for Ligand B.
**BBB:** Both have reasonable BBB penetration, but Ligand A is better (79.566) than Ligand B (60.644). This is not a primary concern for a kinase inhibitor unless CNS effects are desired.
**Caco-2 Permeability:** Both are negative, which is not ideal.
**Aqueous Solubility:** Both are negative, which is not ideal.
**hERG Inhibition:** Ligand A (0.065) has a much lower hERG risk than Ligand B (0.37). This is a significant advantage for Ligand A.
**Microsomal Clearance:** Ligand A (11.32) has a lower Cl_mic (better metabolic stability) than Ligand B (-5.423). This is a key advantage for Ligand A.
**In vitro Half-Life:** Ligand B (64.324) has a significantly longer half-life than Ligand A (10.276). This is a major advantage for Ligand B.
**P-gp Efflux:** Ligand A (0.014) has lower P-gp efflux than Ligand B (0.315).
**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 has advantages in hERG risk, metabolic stability (Cl_mic), and P-gp efflux. However, its low logP is a significant concern for permeability. Ligand B has a much better DILI score and a significantly longer half-life, which are crucial for drug development. While its logP is better, the hERG risk is higher. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are paramount. The longer half-life of Ligand B is also very attractive.

Output:
1
2025-04-17 16:16:13,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.459 Da) is slightly lower, which *could* be advantageous for permeability, but both are acceptable.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (38.77). Lower TPSA generally favors better cell permeability.

**3. logP:** Ligand A (2.11) is optimal, while Ligand B (4.304) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are low, a single donor can aid solubility.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (3). Both are within acceptable limits.

**6. QED:** Ligand A (0.859) is significantly better than Ligand B (0.446), indicating a more drug-like profile.

**7. DILI:** Ligand A (34.393) has a much lower DILI risk than Ligand B (12.059). This is a significant advantage.

**8. BBB:** Not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (89.88) is better, but this isn't a deciding factor.

**9. Caco-2 Permeability:** Ligand A (-4.848) is better than Ligand B (-4.259). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.675) is better than Ligand B (-4.45). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.433) is better than Ligand B (0.723), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (41.361) is significantly better than Ligand B (103.196). Lower clearance means greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.03) is better than Ligand B (18.712). A negative value suggests a longer half-life.

**14. P-gp Efflux:** Ligand A (0.214) is better than Ligand B (0.659), meaning less efflux and potentially better bioavailability.

**15. Binding Affinity:** Ligand B (-6.9) has a slightly better binding affinity than Ligand A (-8.3). However, the difference is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall:** Ligand A is substantially better across the majority of key ADME-Tox properties (DILI, solubility, metabolic stability, hERG, P-gp efflux, QED) and has comparable potency. While Ligand B has slightly better affinity, the other properties of Ligand A make it a much more promising drug candidate.

Output:
0
2025-04-17 16:16:13,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.435 and 369.412 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.23) is excellent, under the 140 threshold for good absorption. Ligand B (36.44) is also good, well below the threshold.

**logP:** Both ligands have good logP values (1.534 and 2.992), falling within the optimal 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 good QED scores (0.742 and 0.813), indicating good drug-like properties.

**DILI:** Ligand A (37.728) has a slightly better DILI score than Ligand B (42.109), both are acceptable (<40 is good).

**BBB:** Both ligands have high BBB penetration (85.266 and 88.833), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.057) has poor Caco-2 permeability, while Ligand B (-4.661) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.593 and -2.812). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.125 and 0.738), which is excellent.

**Microsomal Clearance:** Ligand B (27.48) has significantly lower microsomal clearance than Ligand A (42.242), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (2.227) has a slightly better in vitro half-life than Ligand A (-21.295).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.003 and 0.174).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good overall profiles, Ligand B is slightly more favorable due to its significantly better metabolic stability (lower Cl_mic) and slightly better half-life. The slightly better Caco-2 permeability is also a minor advantage. The solubility is a concern for both, but metabolic stability is a higher priority for an enzyme target like SRC.

Output:
1
2025-04-17 16:16:13,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.83) is slightly higher than Ligand B (344.375), but both are acceptable.

**TPSA:** Ligand A (46.92) is significantly better than Ligand B (122.03). TPSA < 140 is good for oral absorption, and A is well within this range, while B is approaching the upper limit.

**logP:** Ligand A (4.222) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-0.049) is too low, which could hinder membrane permeability.

**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 similar QED values (A: 0.629, B: 0.606), indicating reasonable drug-likeness.

**DILI:** Both ligands have similar DILI risk (A: 60.915, B: 60.217), placing them in a moderate risk category. This isn't a major differentiator.

**BBB:** Ligand A (83.87) has a much better BBB percentile than Ligand B (24.622). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-5.028) is better than Ligand B (-5.555), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.464) is better than Ligand B (-2.056), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.713) has a slightly better hERG profile than Ligand B (0.1). Lower is better, so A is preferable.

**Microsomal Clearance:** Ligand A (63.07) has higher clearance than Ligand B (15.07). Lower clearance is desired for metabolic stability, making Ligand B more favorable here.

**In vitro Half-Life:** Ligand B (3.479) has a longer half-life than Ligand A (-2.92). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.735) has lower P-gp efflux than Ligand B (0.02), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.3 kcal/mol and -8.4 kcal/mol). This is not a deciding factor.

**Overall Assessment:**

Ligand A excels in TPSA, solubility, Caco-2 permeability, hERG, and P-gp efflux. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. The logP of Ligand A is a concern, but its superior solubility and permeability might mitigate this. The slightly better hERG profile of A is also a plus. Given the enzyme-specific priorities, the improved ADME properties of Ligand A (solubility, permeability, reduced efflux) outweigh the slightly higher logP and clearance, especially considering the comparable binding affinity.

Output:
1
2025-04-17 16:16:13,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.462 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is better than Ligand B (65.79), both are acceptable, but lower TPSA generally favors absorption.

**logP:** Ligand A (3.525) is slightly higher than Ligand B (2.203). Ligand A is at the upper end of the optimal range, while B is towards the lower end.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are within the acceptable range.

**QED:** Both ligands have good QED scores (0.815 and 0.855), indicating good drug-like properties.

**DILI:** Ligand A (50.174) has a significantly lower DILI risk than Ligand B (21.093), which is a major advantage.

**BBB:** Ligand A (83.443) has better BBB penetration than Ligand B (63.94). While not a primary concern for a kinase inhibitor, it's a positive.

**Caco-2 Permeability:** Ligand A (-4.273) has worse Caco-2 permeability than Ligand B (-4.866). Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.979) has better aqueous solubility than Ligand B (-1.347). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.424) has a lower hERG inhibition risk than Ligand B (0.746). This is a significant advantage, reducing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (85.547) has a higher microsomal clearance than Ligand B (0.305), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-4.79) has a shorter half-life than Ligand B (27.795). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.322) has lower P-gp efflux than Ligand B (0.194). Lower efflux is generally preferred.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.3). However, the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand B has a better binding affinity and *much* better metabolic stability and half-life. However, Ligand A has a significantly lower DILI risk and hERG inhibition liability, and better solubility. Considering the enzyme-specific priorities, metabolic stability and half-life are crucial. While Ligand A's DILI and hERG profiles are attractive, its poor metabolic stability and short half-life are major drawbacks for an enzyme inhibitor. The slightly better affinity of Ligand B, combined with its superior metabolic profile, outweighs the benefits of Ligand A.

Output:
1
2025-04-17 16:16:13,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.483 Da and 351.334 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.25) is well below the 140 threshold, while Ligand B (124.69) is still acceptable but closer to the limit.

**logP:** Ligand A (4.342) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.256) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (4 HBD, 6 HBA) both have reasonable counts, within the suggested limits.

**QED:** Ligand A (0.826) has a significantly better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 59.907, Ligand B: 56.844), below the 60 threshold.

**BBB:** Ligand A (85.111) shows better BBB penetration than Ligand B (19.542), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.676) and Ligand B (-5.498) both have negative Caco-2 values, indicating poor permeability. This is a concern for oral bioavailability.

**Aqueous Solubility:** Ligand A (-5.065) and Ligand B (-2.467) both have negative solubility values, indicating poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.382, Ligand B: 0.422).

**Microsomal Clearance:** Ligand A (82.043) has a higher microsomal clearance than Ligand B (15.118), suggesting lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand B (-4.395) has a better (less negative) in vitro half-life than Ligand A (-15.573), indicating better stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.271, Ligand B: 0.046).

**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.

**Overall Assessment:**

Ligand A's primary advantage is its significantly higher binding affinity. However, it suffers from higher logP, higher clearance, and lower half-life. Ligand B has better metabolic stability (lower Cl_mic, better t1/2) and solubility, but its binding affinity is considerably weaker.

Given that we are targeting a kinase (SRC), potency is paramount. The 1.6 kcal/mol difference in binding affinity is substantial and likely outweighs the ADME drawbacks of Ligand A, *provided* that solubility and permeability can be improved through formulation or further chemical modification. The poor solubility and permeability are significant concerns, but the strong binding suggests a good starting point for optimization.

Output:
1
2025-04-17 16:16:13,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (382.961 and 337.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.33) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (64.84) is still under 140, but less optimal than A.

**logP:** Both ligands (3.075 and 3.331) are 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.749 and 0.927), indicating drug-like properties.

**DILI:** Ligand A (54.517) has a slightly higher DILI risk than Ligand B (63.862), but both are reasonably acceptable.

**BBB:** Both ligands have high BBB penetration (83.986 and 91.392), which isn't a primary concern for a non-CNS target like SRC, but isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.915 and -4.872). This is unusual and suggests a potential issue with the assay or the compounds themselves. It's difficult to interpret without further information.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.247 and -4.866). Similar to Caco-2, this is concerning and requires further investigation. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.741 and 0.973), which is excellent.

**Microsomal Clearance:** Ligand A (95.811) has a higher microsomal clearance than Ligand B (72.795). This suggests Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (22.693) has a longer in vitro half-life than Ligand A (16.888), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.227 and 0.34).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent and the most important factor.

**Conclusion:**

Despite the unusual Caco-2 and solubility results, Ligand B appears slightly more favorable due to its superior metabolic stability (lower Cl_mic and longer t1/2). While the binding affinity is identical, a more stable compound is more likely to achieve adequate *in vivo* exposure and efficacy. The slightly lower DILI risk of B is also a minor advantage.

Output:
1
2025-04-17 16:16:13,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):**
* Ligand A: 352.475 Da - Within the ideal range (200-500).
* Ligand B: 420.294 Da - Also within the ideal range.
* *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 87.66 - Good for oral absorption (<140).
* Ligand B: 46.61 - Excellent for oral absorption.
* *Ligand B has a significant advantage here, suggesting better absorption.*

**3. Lipophilicity (logP):**
* Ligand A: 1.84 - Optimal (1-3).
* Ligand B: 3.377 - Optimal (1-3), but towards the higher end.
* *Ligand A is slightly preferred due to lower logP.*

**4. H-Bond Donors (HBD):**
* Ligand A: 3 - Meets the criteria (<=5).
* Ligand B: 0 - Meets the criteria (<=5).
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 4 - Meets the criteria (<=10).
* Ligand B: 3 - Meets the criteria (<=10).
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.524 - Good drug-like profile (>=0.5).
* Ligand B: 0.361 - Below 0.5, indicating a less ideal drug-like profile.
* *Ligand A is significantly better here.*

**7. DILI Risk:**
* Ligand A: 16.092 - Low risk (<40).
* Ligand B: 33.579 - Low risk (<40).
* *No clear advantage.*

**8. BBB Penetration:**
* Ligand A: 61.846 - Not a priority for a non-CNS target.
* Ligand B: 95.967 - Not a priority for a non-CNS target.
* *Irrelevant for this target.*

**9. Caco-2 Permeability:**
* Ligand A: -4.795 - Poor permeability.
* Ligand B: -4.405 - Poor permeability.
* *Both are poor, but Ligand B is slightly better.*

**10. Aqueous Solubility:**
* Ligand A: -2.16 - Poor solubility.
* Ligand B: -4.618 - Very poor solubility.
* *Ligand A is slightly better.*

**11. hERG Inhibition:**
* Ligand A: 0.146 - Low risk.
* Ligand B: 0.755 - Moderate risk.
* *Ligand A is preferred.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 49.702 - Moderate clearance.
* Ligand B: 84.746 - High clearance.
* *Ligand A is significantly better, indicating better metabolic stability.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -14.621 - Very long half-life.
* Ligand B: 14.932 - Moderate half-life.
* *Ligand A is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.076 - Low efflux.
* Ligand B: 0.143 - Low efflux.
* *No clear advantage.*

**15. Binding Affinity:**
* Ligand A: -8.3 kcal/mol - Excellent.
* Ligand B: -8.4 kcal/mol - Excellent, slightly better.
* *Ligand B has a marginal advantage.*

**Overall Assessment:**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior drug-like properties (QED), metabolic stability (lower Cl_mic, longer t1/2), and a lower hERG risk. Ligand A also has better solubility and lower DILI risk. The slightly better TPSA of Ligand B is outweighed by the other factors. The poor Caco-2 permeability of both is a concern, but can be addressed with formulation strategies.

Output:
0
2025-04-17 16:16:13,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 349.366 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.53) is slightly above the optimal <140, but acceptable. Ligand B (96.25) is excellent.

**logP:** Ligand A (0.383) is a bit low, potentially hindering permeability. Ligand B (0.996) is better, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is good. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.498 and 0.794), suggesting drug-like properties, with Ligand B being better.

**DILI:** Ligand A (28.693) has a much lower DILI risk than Ligand B (56.65), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (80.341) has a higher BBB score, but this is less important here.

**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, again unusual and suggesting poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.062) has a very low hERG risk, significantly better than Ligand B (0.225).

**Microsomal Clearance:** Ligand A (27.274) has a higher microsomal clearance than Ligand B (2.392), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-0.566) has a negative half-life, which is not physically possible. This is a major red flag. Ligand B (0.264) has a short half-life, but it's a valid value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability, which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.0 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 A has a nonsensical negative half-life and a higher clearance, indicating poor metabolic stability. While Ligand B has a higher DILI risk and a shorter half-life, it has better solubility, logP, and a valid half-life. The extremely low hERG risk and DILI risk of Ligand A are attractive, but the negative half-life is a deal-breaker. Therefore, Ligand B is the more viable candidate, despite its drawbacks, as it at least has plausible ADME properties.

Output:
1
2025-04-17 16:16:13,776 - INFO - Batch 449 complete. Total preferences: 7184
2025-04-17 16:16:13,776 - INFO - Processing batch 450/512...
2025-04-17 16:16:52,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.406 and 354.405 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (71.53 and 68.84) below 140, indicating good potential for oral absorption.

**logP:** Ligand A (1.349) is optimal, while Ligand B (2.118) is also within the preferred 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.807) has a significantly better QED score than Ligand B (0.613), suggesting a more drug-like profile.

**DILI:** Ligand A (25.165) has a much lower DILI risk than Ligand B (54.362), a significant advantage.

**BBB:** Both ligands have good BBB penetration (87.515 and 90.112), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.499 and -4.93), which is unusual and potentially problematic, suggesting poor permeability. However, these values are on a log scale and need careful interpretation.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.384 and -1.813), which is also concerning. Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.419 and 0.544).

**Microsomal Clearance:** Ligand A (15.966 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (38.944 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.37 hours) has a negative half-life, which is not physically possible and indicates an issue with the data or the model. Ligand B (20.592 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.27).

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Conclusion:**

Despite the issues with Caco-2 and Solubility, Ligand A is the better candidate. Its superior QED score, significantly lower DILI risk, and much lower microsomal clearance outweigh the concerns about permeability and solubility, *especially* given the equal binding affinity. The negative half-life for Ligand A is a major red flag and needs investigation, but if this is a data error, it further strengthens the case for Ligand A. Ligand B's higher DILI risk and higher clearance are significant drawbacks.

Output:
0
2025-04-17 16:16:52,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**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 (371.467 Da) is also acceptable.

**TPSA:** Ligand A (93.21) is better than Ligand B (117.66). Both are below 140, suggesting reasonable oral absorption, but A is closer to the preferred threshold for good absorption.

**logP:** Ligand A (1.377) is within the optimal range (1-3), while Ligand B (-1.217) is slightly below 1. This could hinder permeation for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is better balanced than Ligand B (1 HBD, 7 HBA). Both are within acceptable limits, but the higher HBA count in B could affect permeability.

**QED:** Both ligands have similar QED values (A: 0.778, B: 0.709), indicating good drug-like properties.

**DILI:** Ligand A (54.75) has a slightly higher DILI risk than Ligand B (49.632), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (74.835) shows better BBB penetration than Ligand B (48.662).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.1) is slightly better than Ligand B (-5.509).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.003) is slightly better than Ligand B (-1.093).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.168, B: 0.111), which is excellent.

**Microsomal Clearance:** Ligand B (-17.653) has significantly lower (better) microsomal clearance than Ligand A (29.364), indicating greater metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (16.266 hours) has a much longer half-life than Ligand A (6.004 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.014, B: 0.009), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and a primary driver of potency.

**Conclusion:**

While both ligands exhibit excellent binding affinity, Ligand B is the more promising candidate due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and slightly better DILI profile. Although Ligand A has a slightly better logP and TPSA, the metabolic advantages of Ligand B outweigh these minor differences for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:16:52,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.435 Da and 346.471 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.7) is better than Ligand B (62.55). While both are below 140, lower TPSA generally favors permeability.

**logP:** Ligand B (3.442) is optimal (1-3), while Ligand A (0.032) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential issues with permeability.

**H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.548 and 0.858), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (20.085) has a significantly lower DILI risk than Ligand B (47.77), which is a substantial advantage.

**BBB:** Ligand B (71.229) has better BBB penetration than Ligand A (40.132), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.142) has worse Caco-2 permeability than Ligand B (-4.664), which is unfavorable.

**Aqueous Solubility:** Ligand A (-1.243) has better aqueous solubility than Ligand B (-3.843), important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.156) has a lower hERG risk than Ligand B (0.376), a critical safety parameter.

**Microsomal Clearance:** Ligand A (-7.228) has much lower microsomal clearance than Ligand B (55.834), indicating better metabolic stability, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (14.889) has a shorter half-life than Ligand B (35.954), but the difference isn't drastic.

**P-gp Efflux:** Ligand A (0.019) has lower P-gp efflux than Ligand B (0.431), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.7) has a significantly stronger binding affinity than Ligand A (-7.4), a difference of 1.3 kcal/mol. This is a substantial advantage that can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has advantages in DILI, solubility, hERG, metabolic stability, and P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.7 vs -7.4 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. The moderate drawbacks of Ligand B in terms of DILI and metabolic stability are less concerning than the substantial potency advantage.

Output:
1
2025-04-17 16:16:52,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.53 and 356.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.63) is higher than Ligand B (25.36). While both are reasonably low, Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (2.967) is within the optimal 1-3 range. Ligand B (4.519) is slightly higher, potentially leading to solubility issues and off-target interactions, but not drastically so.

**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 (0.754) has a higher QED score than Ligand B (0.577), suggesting a more drug-like profile overall.

**DILI:** Ligand A (16.712) has a much lower DILI risk than Ligand B (6.398), which is a significant advantage.

**BBB:** Ligand A (74.758) has a good BBB percentile, while Ligand B (98.139) has an excellent one. However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.991) and Ligand B (-4.422) 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 (-3.302 and -3.903 respectively). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.492) has a slightly lower hERG risk than Ligand B (0.967), which is preferable.

**Microsomal Clearance:** Ligand A (82.365) has a higher microsomal clearance than Ligand B (43.762), meaning Ligand B is more metabolically stable. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (27.127 hours) has a significantly longer half-life than Ligand A (13.025 hours), which is also a significant advantage.

**P-gp Efflux:** Ligand A (0.238) has lower P-gp efflux than Ligand B (0.745), which is better.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a crucial factor, and the 1.7 kcal/mol difference is quite significant, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.0 vs -8.3 kcal/mol), lower microsomal clearance (better metabolic stability), and longer half-life are critical advantages for an enzyme inhibitor. The lower DILI risk of Ligand A is appealing, but the substantial potency advantage of Ligand B is more important in this case.

Output:
1
2025-04-17 16:16:52,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.47 & 346.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.68) is slightly higher than Ligand B (67.43), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.315 and 2.293 respectively), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 3. Both are below the 10 threshold.

**QED:** Both have similar QED scores (0.665 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 64.87, which is moderately high. Ligand B has a significantly lower DILI risk of 20.589, which is excellent. This is a major advantage for Ligand B.

**BBB:** Both have relatively low BBB penetration (45.715 and 53.587). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.772 and -4.629), which is unusual and suggests poor permeability. However, these values are on a log scale and likely represent very low permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.802 and -3.175), also on a log scale, indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.398) has a slightly higher hERG risk than Ligand B (0.12). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (88.867) than Ligand B (22.93). Higher clearance means faster metabolism and lower systemic exposure, making Ligand B more metabolically stable.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (4.979 hours) than Ligand A (-4.423 hours). A longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.502) shows moderate P-gp efflux, while Ligand B (0.069) has very low P-gp efflux. Lower P-gp efflux is better for bioavailability.

**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 in affinity is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in key areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and, most importantly, a substantially stronger binding affinity. The improved affinity is a critical advantage for an enzyme inhibitor.

Output:
1
2025-04-17 16:16:52,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.479 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is well below the 140 threshold, and even better, under 90, suggesting good permeability. Ligand B (122.55) is still within acceptable limits for oral absorption (<140), but less optimal than A.

**logP:** Ligand A (3.079) is within the optimal 1-3 range. Ligand B (0.181) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is excellent. Ligand B (HBD=4, HBA=4) is acceptable, but slightly higher donor count could impact permeability.

**QED:** Ligand A (0.824) is very good, indicating high drug-likeness. Ligand B (0.442) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (55.913) has a moderate DILI risk, but acceptable. Ligand B (31.33) has a low DILI risk, which is favorable.

**BBB:** Both ligands have good BBB penetration (A: 72.237, B: 78.519). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.762) and Ligand B (-5.286) both have negative Caco-2 values, which is unusual and indicates poor permeability. The scale is not specified, so it's hard to interpret, but generally, negative values are undesirable.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -4.935, B: -2.573). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.632) has a low hERG risk. Ligand B (0.076) also has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (50.463) has moderate clearance, while Ligand B (30.313) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (7.808) has a longer half-life than Ligand A (5.204), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.171, B: 0.019), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand A is slightly favored due to its better TPSA and QED scores. However, Ligand B has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better BBB score. The poor solubility and Caco-2 permeability are concerning for both, but the improved metabolic stability of Ligand B, combined with its lower DILI risk, makes it the slightly more promising candidate.

Output:
1
2025-04-17 16:16:52,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (388.877 and 363.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.91) is slightly above the preferred <140, while Ligand B (81.99) is well within.

**logP:** Ligand A (1.143) is optimal, while Ligand B (3.148) is at the higher end of the optimal range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.585 and 0.76), indicating good drug-likeness.

**DILI:** Ligand A (62.544) has a higher DILI risk than Ligand B (32.299). This is a significant negative for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (60.76) is higher than Ligand A (38.581), but this isn't a primary concern.

**Caco-2 Permeability:** Ligand A (-5.333) has poor Caco-2 permeability, while Ligand B (-4.799) is better, but still not great.

**Aqueous Solubility:** Ligand A (-1.586) has poor aqueous solubility, while Ligand B (-4.433) is even worse. This is a concern for both, but more so for Ligand B.

**hERG:** Ligand A (0.165) has a slightly higher hERG risk than Ligand B (0.451), but both are relatively low.

**Microsomal Clearance:** Ligand A (11.414) has lower microsomal clearance than Ligand B (57.816), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (21.969) has a longer half-life than Ligand B (13.982), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.134).

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is the most crucial factor for an enzyme inhibitor. A difference of 8 kcal/mol is substantial.

**Conclusion:**

Despite Ligand A's better metabolic stability (lower Cl_mic, longer t1/2) and slightly better hERG profile, the dramatically superior binding affinity of Ligand B (-8.0 kcal/mol vs 0.0 kcal/mol) outweighs these advantages. The poor solubility and Caco-2 permeability of both are concerning, but can be addressed through formulation strategies. The lower DILI risk for Ligand B is also a positive. The binding affinity difference is so large that it's likely Ligand B will be far more potent *in vivo*, even accounting for potential metabolic liabilities.

Output:
1
2025-04-17 16:16:52,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.288 Da) is slightly higher than Ligand B (347.459 Da), but both are acceptable.

**TPSA:** Ligand A (38.5) is well below the 140 threshold and good for oral absorption. Ligand B (62.74) is still reasonable but higher, potentially impacting absorption slightly.

**logP:** Ligand A (4.505) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.132) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both have 0 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.612, B: 0.758), indicating drug-like properties.

**DILI:** Ligand A (58.705) has a higher DILI risk than Ligand B (33.501). This is a significant concern.

**BBB:** Both have reasonable BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.18) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.276) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.802) has very poor aqueous solubility. Ligand B (-1.56) is better, although still not ideal.

**hERG:** Both ligands have low hERG risk (A: 0.922, B: 0.304), which is excellent.

**Microsomal Clearance:** Ligand A (97.189) has high microsomal clearance, indicating poor metabolic stability. Ligand B (54.718) has better metabolic stability.

**In vitro Half-Life:** Ligand A (-32.821) has a very short half-life. Ligand B (18.623) has a much more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -9.5 kcal/mol, B: -8.8 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both have good binding affinity, Ligand B exhibits significantly better ADME properties: lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better Caco-2 permeability. Ligand A's high DILI risk, poor solubility, and poor metabolic stability are major drawbacks that outweigh its slightly better binding affinity.

Output:
1
2025-04-17 16:16:52,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (384.523 and 339.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (86.71 and 84.95) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands have logP values (1.837 and 2.812) 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 5 HBA, and Ligand B has 6 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.702 and 0.614), indicating good drug-like properties.

**7. DILI:** Both ligands have DILI risk above 60, indicating a higher risk of liver injury. Ligand B (68.98) is slightly higher than Ligand A (61.109).

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (62.854) is slightly better than Ligand B (38.232).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.324 and -5.296), which is unusual and indicates poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.823 and -3.486), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.442 and 0.864), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Both ligands have similar Cl_mic values (33.087 and 36.245), suggesting moderate metabolic clearance. Lower is better, but these aren't excessively high.

**13. In vitro Half-Life (t1/2):** Ligand B (-6.32) has a longer half-life than Ligand A (-3.012), which is a positive attribute.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.257 and 0.267), which is good.

**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.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a significantly better binding affinity and a longer half-life. While both have poor solubility and moderate clearance, the superior binding affinity of Ligand B is a crucial factor.

Considering all factors, despite the poor solubility and permeability of both compounds, Ligand B's significantly stronger binding affinity makes it the more promising candidate.

Output:
1
2025-04-17 16:16:52,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (393.412 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.91) is slightly higher than Ligand B (53.76). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Ligand A (1.513) is within the optimal 1-3 range. Ligand B (3.159) is at the higher end of optimal, potentially raising solubility concerns.

**H-Bond Donors/Acceptors:** Ligand A has 1 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 reasonable QED scores (0.834 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A (78.015) has a significantly higher DILI risk than Ligand B (11.361). This is a major concern for Ligand A.

**BBB:** Both have high BBB penetration, but Ligand B (81.078) is slightly better than Ligand A (74.641). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.899) is slightly worse than Ligand B (-4.494).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.88) is slightly worse than Ligand B (-2.779).

**hERG:** Both ligands have very low hERG inhibition risk (0.251 and 0.561), which is excellent.

**Microsomal Clearance:** Ligand A (6.282) has a much lower microsomal clearance than Ligand B (73.996), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-13.721) has a negative half-life, which is not possible. This is a major red flag. Ligand B (25.689) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.148 and 0.094).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand A's better metabolic stability (lower Cl_mic) and equal binding affinity, its significantly higher DILI risk, negative half-life, and worse Caco-2/solubility profiles make it a less desirable candidate. Ligand B, while having higher Cl_mic, has a much lower DILI risk, a positive half-life, and comparable permeability/solubility. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 16:16:52,939 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (376.36 and 370.368 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.35) is slightly higher than Ligand B (96.89), but both are below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (2.69) is optimal, while Ligand B (0.364) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (4) and Ligand B (3) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (5) are well within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.644 and 0.573), indicating good drug-like properties.

**7. DILI:** Ligand A (87.049) has a significantly higher DILI risk than Ligand B (23.304). This is a major concern for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (61.07) is slightly better than Ligand A (58.86).

**9. Caco-2:** Both have negative Caco-2 values, indicating poor permeability. This is concerning for both.

**10. Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is concerning for both.

**11. hERG:** Ligand A (0.478) has a slightly higher hERG risk than Ligand B (0.35), but both are relatively low.

**12. Cl_mic:** Ligand A (27.398) has a much higher microsomal clearance than Ligand B (6.013), indicating poorer metabolic stability. This is a significant drawback for Ligand A.

**13. t1/2:** Ligand A (70.26) has a much longer in vitro half-life than Ligand B (4.253), which is a positive attribute.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.131 and 0.023).

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity and a longer half-life. However, it suffers from a significantly higher DILI risk and poorer metabolic stability (higher Cl_mic). Ligand B has a better safety profile (lower DILI) and improved metabolic stability, but its lower binding affinity and logP are concerning.

Given the enzyme-kinase target class, metabolic stability and safety (DILI) are crucial. While the affinity difference is notable, the high DILI risk associated with Ligand A is a major red flag. The slightly better logP and lower DILI of Ligand B 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 16:16:52,939 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.379 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 89.87, which is good for oral absorption (<=140).

**logP:** Ligand A (2.686) is optimal, while Ligand B (1.299) is slightly lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.747 and 0.671), indicating good drug-like properties.

**DILI:** Ligand A (60.527) has a higher DILI risk than Ligand B (6.592). This is a significant negative for Ligand A.

**BBB:** Ligand B (48.158) has a better BBB penetration score than Ligand A (33.928), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.174 and -4.871), which is unusual and suggests poor permeability. However, these values are on a log scale and the absolute values are similar, so the difference is not substantial.

**Aqueous Solubility:** Ligand B (-1.627) has better aqueous solubility than Ligand A (-3.859). This is a positive for Ligand B.

**hERG Inhibition:** Ligand A (0.461) has a slightly higher hERG risk than Ligand B (0.252), but both are relatively low.

**Microsomal Clearance:** Ligand A (-17.402) has significantly lower (better) microsomal clearance than Ligand B (17.686). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-22.067) has a longer in vitro half-life than Ligand B (-19.615).

**P-gp Efflux:** Ligand A (0.042) shows lower P-gp efflux than Ligand B (0.04). This is a slight advantage for Ligand A.

**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. A difference of 8 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite Ligand A's better metabolic stability and P-gp efflux, Ligand B's significantly superior binding affinity (-8.0 kcal/mol vs 0.0 kcal/mol) and much lower DILI risk are decisive. The improved solubility of Ligand B is also beneficial. While both have poor Caco-2 permeability, the potency advantage of Ligand B is likely to be more impactful in driving forward development.

Output:
1
2025-04-17 16:16:52,939 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.371 and 346.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.82) is slightly above the optimal <140, while Ligand B (97.64) is well within. This favors Ligand B slightly for absorption.

**3. logP:** Both ligands have good logP values (1.961 and 1.249), falling within the 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 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.817) has a significantly better QED score than Ligand B (0.572), indicating a more drug-like profile.

**7. DILI:** Ligand A (75.766) has a higher DILI risk than Ligand B (50.291), which is a concern. Ligand B is clearly better here.

**8. BBB:** Both have relatively low BBB penetration (45.638 and 40.442). This isn't a major concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.904 and -4.649), indicating poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.554 and -2.924), indicating poor aqueous solubility. This is also a significant drawback for both.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.085 and 0.053), which is excellent.

**12. Microsomal Clearance:** Ligand A (12.066) has a lower microsomal clearance than Ligand B (40.265), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-3.886) has a more negative in vitro half-life, indicating a longer half-life than Ligand B (-9.532). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.029 and 0.01).

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.1), a difference of 0.5 kcal/mol. This is a notable advantage.

**Overall Assessment:**

Ligand B has a better DILI score, slightly better affinity, and a lower TPSA. However, Ligand A has a significantly better QED score, lower Cl_mic, and a longer in vitro half-life. The improved metabolic stability and drug-likeness of Ligand A are crucial for an enzyme target like SRC kinase, and the 0.5 kcal/mol difference in affinity can potentially be optimized during lead optimization. The poor Caco-2 and solubility are shared drawbacks that would need to be addressed regardless of which lead is chosen. Given the priorities for enzyme inhibitors, the better metabolic stability and drug-likeness of Ligand A outweigh the slightly better affinity of Ligand B.

Output:
0
2025-04-17 16:16:52,939 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.815 Da) is slightly higher than Ligand B (345.483 Da), but both are acceptable.

**TPSA:** Ligand A (94.59) is higher than Ligand B (57.61). Both are below the 140 threshold for oral absorption, but Ligand B's lower TPSA is preferable.

**logP:** Ligand A (2.143) is within the optimal range (1-3). Ligand B (4.472) is slightly above, potentially leading to solubility issues and off-target interactions.

**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 range (<=10 HBA), but Ligand B is better.

**QED:** Both ligands have good QED scores (A: 0.763, B: 0.827), indicating drug-like properties.

**DILI:** Ligand A (81.466) has a significantly higher DILI risk than Ligand B (36.758). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (68.166) and Ligand B (51.842) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, suggesting poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility.

**hERG:** Ligand A (0.041) has a much lower hERG risk than Ligand B (0.267), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-1.179) has a much lower (better) microsomal clearance than Ligand B (44.569), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.328) has a much longer in vitro half-life than Ligand B (7.789), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.098) has lower P-gp efflux liability than Ligand B (0.262), which is preferable.

**Binding Affinity:** Ligand B (-7.2 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 significant ADME/Tox concerns with Ligand A.

**Overall:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk, but suffers from a significantly higher DILI risk, and slightly worse solubility and permeability. Ligand B has better TPSA, and binding affinity, but has a higher DILI risk, worse metabolic stability, and higher P-gp efflux.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate despite its slightly lower binding affinity. The significantly better metabolic stability and lower hERG risk are crucial for a viable drug candidate. The higher DILI risk is a concern, but could be addressed through further structural modifications.

Output:
0
2025-04-17 16:16:52,939 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.431 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (85.25) is well within the acceptable range.

**logP:** Both ligands (0.756 and 0.879) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable (<=10).

**QED:** Both ligands have similar QED scores (0.791 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A (32.299) has a significantly lower DILI risk than Ligand B (63.746). This is a major advantage for Ligand A.

**BBB:** Both have similar BBB penetration (50.679 and 52.036), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand B (-5.561) has better Caco-2 permeability than Ligand A (-4.688), suggesting better absorption.

**Aqueous Solubility:** Ligand B (-2.097) has slightly better aqueous solubility than Ligand A (-1.702).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.234 and 0.449).

**Microsomal Clearance:** Ligand A (-2.692) has significantly lower microsomal clearance than Ligand B (28.671), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (10.707 hours) has a shorter half-life than Ligand B (21.702 hours). While longer is generally preferred, the difference isn't drastic.

**P-gp Efflux:** Both have low P-gp efflux liability (0.099 and 0.07).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). The difference is 0.4 kcal/mol, which is not a huge advantage, but noticeable.

**Overall Assessment:**

Ligand A excels in safety (DILI) and metabolic stability (Cl_mic). Ligand B has slightly better Caco-2 permeability, solubility, and binding affinity. However, the significantly lower DILI and Cl_mic of Ligand A are more critical for an enzyme target like SRC kinase. The 0.4 kcal/mol difference in binding affinity is unlikely to outweigh the substantial advantages in ADME/Tox properties of Ligand A.

Output:
0
2025-04-17 16:16:52,939 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.478 and 355.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.5 and 78.51) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.573 and 1.703) are 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 3. Both are below the 10 threshold.

**QED:** Both ligands have QED values above 0.5 (0.63 and 0.514), indicating good drug-likeness.

**DILI:** Ligand A (35.789) has a lower DILI risk than Ligand B (25.863), both are good.

**BBB:** Both ligands have similar BBB penetration (74.254 and 77.627). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.823 and -4.572), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-2.953 and -2.733), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.171) has a slightly lower hERG risk than Ligand B (0.398), which is preferable.

**Microsomal Clearance:** Ligand A (57.048) has a higher microsomal clearance than Ligand B (50.859), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.814) has a longer in vitro half-life than Ligand A (-8.436), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.065).

**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 potentially significant.

**Overall Assessment:**

Both compounds have significant drawbacks related to solubility and permeability. However, Ligand B exhibits a better binding affinity, a longer half-life, and a lower hERG risk. The slightly better affinity and half-life outweigh the slightly higher DILI risk and the marginally higher clearance. The poor solubility and permeability are major hurdles for both, but could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 16:16:52,939 - INFO - Batch 450 complete. Total preferences: 7200
2025-04-17 16:16:52,939 - INFO - Processing batch 451/512...
2025-04-17 16:17:40,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 373.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is excellent, well below the 140 threshold for good absorption. Ligand B (100.78) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (1.455) is optimal. Ligand B (0.941) is slightly low, potentially affecting permeation, but not drastically.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is also acceptable.

**H-Bond Acceptors:** Both ligands (4) are well below the 10 threshold.

**QED:** Both ligands (0.773 and 0.684) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (19.698) has a significantly lower DILI risk than Ligand B (25.048). This is a major advantage.

**BBB:** Both ligands have similar BBB penetration (73.827 and 72.237), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.326) is better than Ligand B (-4.897), indicating potentially better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.357) is better than Ligand B (-2.071), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.352 and 0.114).

**Microsomal Clearance:** Ligand A (24.384) has lower microsomal clearance than Ligand B (37.617), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.026) has a much longer in vitro half-life than Ligand B (-25.018), which is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.03).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity, Ligand A is superior due to its significantly better DILI score, lower microsomal clearance, longer half-life, better Caco-2 permeability, and improved solubility. These factors are crucial for developing a viable drug candidate targeting an enzyme like SRC.

Output:
0
2025-04-17 16:17:40,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.479 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (99.1 and 93.46) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (0.821) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.377) is better positioned within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 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 (0.567 and 0.721), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (8.841 and 43.195 percentile), and are both acceptable.

**BBB:** Ligand B (68.941) has a higher BBB penetration percentile than Ligand A (42.962), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.954) has a significantly *better* Caco-2 permeability than Ligand B (-5.37).

**Aqueous Solubility:** Ligand A (-0.914) has better aqueous solubility than Ligand B (-2.838). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.158 and 0.269), which is positive.

**Microsomal Clearance:** Ligand A (16.571 mL/min/kg) has significantly *lower* microsomal clearance than Ligand B (44.479 mL/min/kg), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-7.856 hours) has a significantly *longer* in vitro half-life than Ligand B (0.562 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.049).

**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 A is superior. While Ligand B has slightly better logP, Ligand A excels in crucial areas for an enzyme inhibitor: metabolic stability (lower Cl_mic), longer half-life, better solubility, and slightly better binding affinity. The better Caco-2 permeability of Ligand A is also a plus. The difference in binding affinity, while not huge, combined with the ADME advantages, makes Ligand A the more promising candidate.

Output:
0
2025-04-17 16:17:40,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.4 and 357.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.3) is excellent, well below the 140 threshold for oral absorption. Ligand B (29.54) is even better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.707) is a bit low, potentially hindering permeability. Ligand B (4.502) is high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, fitting the guidelines. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.77 and 0.671), indicating good drug-like properties.

**DILI:** Ligand A (56.146) has a moderate DILI risk. Ligand B (15.238) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (68.36) has moderate BBB penetration. Ligand B (95.696) has excellent BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.017) has poor Caco-2 permeability. Ligand B (-4.447) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-2.649) has poor aqueous solubility. Ligand B (-4.147) also has poor aqueous solubility.

**hERG:** Ligand A (0.134) has very low hERG inhibition risk. Ligand B (0.828) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (23.061) has lower microsomal clearance, indicating better metabolic stability. Ligand B (55.653) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-12.635) has a negative half-life, which is not physically possible and indicates an issue with the data or prediction method. Ligand B (16.887) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.072) has low P-gp efflux. Ligand B (0.465) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand A (-8.4 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 its logP is high and solubility is low, its *much* stronger binding affinity (-9.7 vs -8.4 kcal/mol) is a critical advantage for an enzyme target like SRC. Furthermore, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic and a reasonable half-life), and a lower hERG risk. The poor Caco-2 permeability and solubility are concerns, but can potentially be addressed through formulation strategies. The negative half-life for Ligand A is a showstopper.

Output:
1
2025-04-17 16:17:40,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.363 and 368.752 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.33) is significantly better than Ligand B (117.39). TPSA < 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Both ligands have good logP values (3.444 and 2.946), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is better than Ligand B (HBD=3, HBA=5). Lower counts are generally preferred for better permeability.

**QED:** Ligand A (0.792) has a higher QED score than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand B (85.227) has a considerably higher DILI risk than Ligand A (16.324). This is a major concern for Ligand B.

**BBB:** Ligand A (84.529) has better BBB penetration than Ligand B (49.981), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.659 and -4.949), 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 (-3.73 and -4.131) which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.83) has a lower hERG risk than Ligand B (0.401), which is preferable.

**Microsomal Clearance:** Ligand A (11.358 mL/min/kg) has a lower microsomal clearance than Ligand B (20.347 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (92.005) has a significantly longer in vitro half-life than Ligand A (29.4). This is a strong advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.371) shows lower P-gp efflux than Ligand B (0.166), which is favorable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.7 and -8.3 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not decisive.

**Conclusion:**

Despite Ligand B's longer half-life, Ligand A is the more promising candidate. Ligand B has a very high DILI risk, higher TPSA, and worse hERG and P-gp profiles. Ligand A demonstrates better overall drug-likeness (higher QED), lower toxicity risk (DILI, hERG), and better metabolic stability. The unusual Caco-2 and solubility values for both ligands are concerning and would require further investigation, but the other factors strongly favor Ligand A.

Output:
0
2025-04-17 16:17:40,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.487 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (61.88), being well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.052 and 1.954), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 5 HBA) as it has fewer hydrogen bond donors and acceptors, generally leading to better permeability.

**QED:** Both ligands have acceptable QED scores (0.581 and 0.864), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (13.649) has a much lower DILI risk than Ligand B (30.826), a significant advantage.

**BBB:**  BBB is less critical for a non-CNS target like SRC, but Ligand A (78.519) is better than Ligand B (55.642).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.526 and -4.799), which is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.782 and -1.044), indicating poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.525) has a lower hERG risk than Ligand B (0.194), a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (44.733) has a higher microsomal clearance than Ligand B (12.524), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (18.398) has a significantly longer in vitro half-life than Ligand A (-11.683), a major advantage.

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux than Ligand B (0.02), which is preferable.

**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 factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall:**

Despite Ligand A's higher microsomal clearance and negative half-life, its significantly superior binding affinity (-8.3 vs 0.0 kcal/mol) and lower DILI risk outweigh these drawbacks. The lower hERG risk is also a significant benefit. While both have poor solubility and permeability, the potency advantage of Ligand A is substantial.

Output:
1
2025-04-17 16:17:40,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.531 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is well below the 140 threshold and favorable. Ligand B (69.64) is still acceptable, but less optimal.

**logP:** Both ligands have logP values within the optimal range (3.816 and 2.391).

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.59 and 0.724), indicating drug-like properties.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (19.426), which is a strong advantage. Both are below the 40 threshold, indicating low risk.

**BBB:** Both ligands have reasonable BBB penetration (69.407 and 63.203). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.758 and -4.748). This is unusual and suggests poor permeability. However, these values are very close, so it doesn't differentiate the two significantly.

**Aqueous Solubility:** Ligand A (-4.924) has slightly poorer solubility than Ligand B (-2.69). Solubility is important for kinases, so this is a slight edge for Ligand B.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.438 and 0.324).

**Microsomal Clearance:** Ligand A (83.27) has a higher microsomal clearance than Ligand B (36.907). This indicates lower metabolic stability for Ligand A, which is a disadvantage.

**In vitro Half-Life:** Ligand B (-8.039) has a longer in vitro half-life than Ligand A (-1.885), indicating better metabolic stability. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.191 and 0.25).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.1 kcal/mol difference is substantial and outweighs most of the minor ADME drawbacks of Ligand B.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has a slightly better DILI score and TPSA, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a substantially stronger binding affinity. The binding affinity difference is critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:17:40,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 371.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (62.32), but both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.724) is within the optimal 1-3 range. Ligand B (-0.076) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**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:** Ligand A (0.79) has a better QED score than Ligand B (0.417), indicating a more drug-like profile.

**DILI:** Ligand A (15.82) has a significantly lower DILI risk than Ligand B (22.8). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (81.698) is better than Ligand B (65.607). While not a primary concern for a kinase inhibitor, it's a slight positive for A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.452 and -4.794). These values are unusual and suggest poor permeability *in vitro*. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.98 and -0.937). Similar to Caco-2, these values are unusual and suggest poor solubility *in vitro*.

**hERG:** Ligand A (0.297) has a much lower hERG inhibition liability than Ligand B (0.485), which is a critical advantage.

**Microsomal Clearance:** Ligand A (15.196 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (43.493 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.111 hours) has a very short half-life, while Ligand B (-18.714 hours) has a very long half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.021).

**Binding Affinity:** Both ligands have similar binding affinities (-6.7 and -6.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in key areas for a kinase inhibitor: lower DILI risk, lower hERG liability, and significantly better metabolic stability (lower Cl_mic). While its half-life is poor, this can potentially be addressed through structural modifications. Ligand B has a longer half-life, but suffers from higher DILI and hERG risks, and poorer metabolic stability. The slightly lower logP of Ligand B is a minor concern. Given the priorities for enzyme inhibitors, the superior safety profile and metabolic stability of Ligand A outweigh its shorter half-life.

Output:
1
2025-04-17 16:17:40,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (479.242 Da) is slightly higher than Ligand B (402.336 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (55.84 and 54.02 respectively) that are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have logP values (3.916 and 4.592) within the optimal range of 1-3, suggesting good permeability and avoiding potential solubility issues. Ligand B is slightly higher, which could potentially lead to some off-target interactions, but is still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within the recommended limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.482 and 0.735), indicating acceptable drug-likeness, with Ligand B being slightly better.

**DILI:** Ligand A has a DILI risk of 87.786, which is high. Ligand B has a DILI risk of 48.313, which is much better and falls within the acceptable range (<40 is good, >60 is high risk). This is a significant advantage for Ligand B.

**BBB:** Both ligands have high BBB penetration (87.243 and 74.758), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both show negative Caco-2 permeability values (-4.761 and -4.983). This is unusual and suggests a potential issue with in vitro permeability assays, or possibly an artifact of the prediction method. It doesn't immediately disqualify either compound, but warrants further investigation.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.599 and -4.024). This is a major concern for both, as it could hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.486 and 0.66), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (74.265) than Ligand B (58.285), indicating lower metabolic stability. Lower clearance is preferred.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (90.895 hours) compared to Ligand A (6.312 hours). This is a major advantage for Ligand B, as it suggests less frequent dosing may be possible.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.49 and 0.43), which is favorable.

**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 small and likely less important than the ADME differences.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both have poor solubility and negative Caco-2 values, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The slightly better QED and binding affinity further support this conclusion. The solubility issue would need to be addressed through formulation strategies, but the other advantages of Ligand B make it the preferred choice.

Output:
1
2025-04-17 16:17:40,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (352.519 Da and 362.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is well below the 140 threshold, suggesting good absorption. Ligand B (117) is still within acceptable limits, but higher than A.

**3. logP:** Both ligands have acceptable logP values (2.719 and 1.21), falling within the 1-3 range. Ligand A is slightly better.

**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 (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.706 and 0.756), indicating drug-like properties.

**7. DILI:** Ligand A (6.747) has a significantly lower DILI risk than Ligand B (65.529). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for an oncology target, but Ligand A (70.492) has a better BBB score than Ligand B (48.391).

**9. Caco-2 Permeability:** Ligand A (-4.671) and Ligand B (-5.545) both have negative values, which is unusual. Lower values indicate lower permeability. However, the difference isn't substantial.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.295 and -2.643). This is concerning and suggests poor solubility, which could limit bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.408 and 0.575).

**12. Microsomal Clearance:** Ligand A (39.764) has a higher (worse) microsomal clearance than Ligand B (-24.182). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-26.19) has a significantly longer in vitro half-life than Ligand A (10.627). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.044 and 0.169).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a much better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), which are key for an enzyme target. While Ligand A has a lower DILI risk, the significantly stronger binding of Ligand B outweighs this benefit, especially considering both have acceptable hERG risk. The solubility issues are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:17:40,947 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [345.443, 82.53, 1.746, 2, 4, 0.77, 31.718, 29.508, -4.826, -1.738, 0.188, 17.652, -12.62, 0.096, -6.6]
**Ligand B:** [377.583, 44.29, 3.711, 1, 7, 0.774, 59.713, 90.849, -5.223, -3.504, 0.895, 72.725, 30.456, 0.372, -8.9]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (345.443) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (82.53) is better than B (44.29). Both are below 140, but B is significantly lower, which is good for oral absorption.
3. **logP:** A (1.746) is optimal, while B (3.711) is nearing the upper limit. B's higher logP could lead to solubility issues or off-target interactions.
4. **HBD:** A (2) is preferable to B (1). Both are within the acceptable limit of 5.
5. **HBA:** A (4) is better than B (7). Both are under 10, but A is closer to the optimal range.
6. **QED:** Both are identical at 0.77, indicating good drug-likeness.
7. **DILI:** A (31.718) is significantly better than B (59.713). A is well within the low-risk category, while B is approaching the higher-risk threshold.
8. **BBB:** B (90.849) is much better than A (29.508). However, as we are targeting a kinase (enzyme), BBB is not a primary concern.
9. **Caco-2:** A (-4.826) is better than B (-5.223). Higher values indicate better absorption.
10. **Solubility:** A (-1.738) is better than B (-3.504). Both are negative, indicating poor solubility, but A is less poor.
11. **hERG:** A (0.188) is significantly better than B (0.895). A has a very low risk of hERG inhibition, while B has a moderate risk.
12. **Cl_mic:** A (17.652) is much better than B (72.725). A has lower clearance, indicating better metabolic stability.
13. **t1/2:** B (30.456) is better than A (-12.62). B has a longer half-life, which is desirable.
14. **Pgp:** A (0.096) is much better than B (0.372). A is less likely to be a P-gp substrate, improving bioavailability.
15. **Binding Affinity:** B (-8.9) is significantly better than A (-6.6). This is a substantial difference in potency (2.3 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme target like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While B has a significantly better binding affinity, it suffers from higher DILI risk, poorer metabolic stability (higher Cl_mic), and a higher hERG risk. A has better ADME properties across the board except for half-life and binding affinity. The 2.3 kcal/mol difference in binding affinity is substantial, but the ADME profile of B is concerning.

**Conclusion:**

Despite the significantly better binding affinity of Ligand B, the superior ADME profile of Ligand A, particularly its lower DILI and hERG risk, and better metabolic stability, makes it the more promising drug candidate. The potency difference, while significant, can potentially be addressed through further optimization, whereas mitigating the ADME liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 16:17:40,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.378 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is higher than Ligand B (67.43). While both are reasonably low, Ligand B is significantly better, potentially leading to improved cell permeability.

**logP:** Both ligands have acceptable logP values (1.955 and 2.508), falling within the 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 within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.658) has a better QED score than Ligand A (0.376), indicating a more drug-like profile.

**DILI:** Ligand B (20.744) has a much lower DILI risk than Ligand A (39.395), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (81.892) has a higher BBB percentile than Ligand A (58.24).

**Caco-2 Permeability:** Both have negative values (-5.16 and -5.021), which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Both have negative values (-3.21 and -2.523), indicating poor solubility. This is a concern for both, but Ligand B is slightly better.

**hERG:** Both ligands show low hERG inhibition liability (0.559 and 0.499), which is good.

**Microsomal Clearance:** Ligand B (24.778) has significantly lower microsomal clearance than Ligand A (63.268), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (10.757 hours) has a much longer in vitro half-life than Ligand A (-26.85 hours - a negative value is concerning). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.065 and 0.072).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have similar binding affinities, Ligand B demonstrates superior ADMET properties: lower DILI risk, better QED, significantly lower microsomal clearance, and a longer in vitro half-life. Its TPSA is also considerably lower, potentially improving permeability. Although both have poor aqueous solubility, Ligand B is slightly better in this regard. The improved metabolic stability and reduced toxicity risk of Ligand B outweigh any minor drawbacks.

Output:
1
2025-04-17 16:17:40,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.411 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.46) is well below the 140 threshold for good absorption, and favorable. Ligand B (95.8) is still under 140, but closer to the limit.

**logP:** Ligand A (2.331) is optimal (1-3). Ligand B (0.962) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0/2) and HBA (5/5) counts, well within the guidelines.

**QED:** Ligand A (0.835) has a higher QED than Ligand B (0.593), indicating better overall drug-likeness.

**DILI:** Ligand A (50.485) has a lower DILI risk than Ligand B (64.405), which is preferable. Both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.594) has better BBB penetration than Ligand B (45.909), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-4.818) and Ligand B (-5.305) both have negative values, indicating poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.324 and -2.178), which is a significant drawback. Poor solubility can severely limit bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.156 and 0.206), which is excellent.

**Microsomal Clearance:** Ligand A (53.504) has higher microsomal clearance than Ligand B (15.877). This means Ligand B is likely more metabolically stable, a key factor for enzymes.

**In vitro Half-Life:** Ligand B (-2.301) has a longer in vitro half-life than Ligand A (-6.936), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.245 and 0.051), which is good.

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better QED and DILI scores. However, it has poorer metabolic stability (higher Cl_mic, shorter t1/2) and permeability. Ligand B has better metabolic stability and permeability, but a weaker binding affinity.

Given the enzyme-specific priorities, the stronger binding affinity of Ligand A is the most important factor. While the metabolic stability and solubility are concerns, these can potentially be addressed through further optimization. The 0.9 kcal/mol difference in binding is significant enough to favor Ligand A as the more promising starting point.

Output:
0
2025-04-17 16:17:40,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.39 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is excellent, well below the 140 threshold for oral absorption. Ligand B (105.76) is still acceptable but less optimal.

**logP:** Ligand A (0.942) is slightly below the optimal 1-3 range but acceptable. Ligand B (-0.647) is a bit concerning as it's below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also acceptable, but higher.

**QED:** Ligand A (0.885) is very good, indicating high drug-likeness. Ligand B (0.478) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (48.623) has a low DILI risk. Ligand B (26.173) also has a low DILI risk, but is slightly better.

**BBB:** Both ligands have acceptable BBB penetration (66.576 and 60.644), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.562) has poor Caco-2 permeability. Ligand B (-5.368) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.916) has poor aqueous solubility. Ligand B (-1.297) is also poor, but slightly better.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.22 and 0.06).

**Microsomal Clearance:** Ligand A (10.254) has lower microsomal clearance, indicating better metabolic stability. Ligand B (20.886) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (0.005) has a very short half-life. Ligand B (1.426) has a slightly longer half-life, but still short.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.069 and 0.003).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's poor Caco-2 permeability and aqueous solubility, its substantially superior binding affinity (-9.4 vs -7.3 kcal/mol) and better metabolic stability (lower Cl_mic) make it the more promising candidate. The stronger binding is a critical advantage for an enzyme inhibitor, and the lower clearance suggests a potentially longer duration of action. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies. Ligand B's lower QED score further diminishes its appeal.

Output:
1
2025-04-17 16:17:40,948 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 374.457 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (97.12) is slightly higher than Ligand B (76.14). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (2.616 and 3.011), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 6. Both are acceptable, being under the 10 limit.

**QED:** Ligand A (0.788) has a better QED score than Ligand B (0.65), indicating a more drug-like profile.

**DILI:** Ligand B (59.442) has a slightly higher DILI risk than Ligand A (52.191), but both are reasonably acceptable (below 60).

**BBB:** Both have good BBB penetration (74.913 and 85.692). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.796 and -4.664), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-3.354 and -3.984), indicating very poor solubility. This is a major issue for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.238 and 0.279).

**Microsomal Clearance:** Ligand A (35.005) has significantly lower microsomal clearance than Ligand B (62.192), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (7.889) has a slightly longer half-life than Ligand B (-7.152).

**P-gp Efflux:** Both have low P-gp efflux liability (0.197 and 0.168).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better QED, solubility, and metabolic stability, the significantly stronger binding affinity of Ligand B (-8.3 vs -7.6 kcal/mol) is a decisive factor for an enzyme inhibitor. The improved affinity is likely to translate to greater efficacy. The poor solubility and permeability are serious concerns for both, but can potentially be addressed through formulation strategies. The slightly higher DILI risk for Ligand B is less concerning than the affinity difference.

Output:
1
2025-04-17 16:17:40,948 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.415 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.31 and 72.88) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.374) is slightly low, potentially hindering permeation. Ligand B (1.297) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the 5 threshold.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, below the 10 threshold.

**QED:** Both ligands have good QED scores (0.661 and 0.678), indicating drug-like properties.

**DILI:** Ligand A (15.51) has a much lower DILI risk than Ligand B (8.026), which is a significant advantage.

**BBB:** Both are relatively low, which is not a major concern for a non-CNS target like SRC. Ligand B (57.193) is higher than Ligand A (46.724).

**Caco-2 Permeability:** Both are negative (-4.73 and -4.831), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative (-1.063 and -0.643), indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG risk (0.125 and 0.105), which is excellent.

**Microsomal Clearance:** Ligand A (-6.165) has significantly lower (better) microsomal clearance than Ligand B (8.506), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.433 hours) has a much longer half-life than Ligand B (-16.083 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.012).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 1.2 kcal/mol which is not a huge advantage.

**Overall Assessment:**

Ligand A is preferable despite the slightly weaker binding affinity. Its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better solubility profile outweigh the small difference in binding affinity. Both compounds have permeability and solubility concerns, but these can potentially be addressed through formulation strategies. The lower DILI and improved metabolic stability of Ligand A make it a more promising starting point for further optimization.

Output:
0
2025-04-17 16:17:40,949 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [340.423, 62.55, 2.221, 1, 3, 0.836, 39.705, 59.364, -4.87, -3.388, 0.239, 14.797, 27.523, 0.232, -6.9]
**Ligand B:** [353.438, 78.51, 0.656, 2, 4, 0.735, 23.769, 69.407, -5.105, -1.691, 0.144, -15.142, -3.914, 0.017, 0]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (340.423) is slightly preferred.
2. **TPSA:** A (62.55) is good, under the 140 threshold. B (78.51) is still acceptable, but less optimal.
3. **logP:** A (2.221) is optimal. B (0.656) is a bit low, potentially hindering permeability.
4. **HBD:** Both A (1) and B (2) are within the acceptable limit of 5.
5. **HBA:** Both A (3) and B (4) are within the acceptable limit of 10.
6. **QED:** A (0.836) is excellent, indicating high drug-likeness. B (0.735) is still good, but slightly lower.
7. **DILI:** A (39.705) is very good, low risk. B (23.769) is excellent, even lower risk.
8. **BBB:** A (59.364) is moderate. B (69.407) is better, but SRC is not a CNS target, so this is less critical.
9. **Caco-2:** A (-4.87) and B (-5.105) are both very poor. This is a significant concern for both.
10. **Solubility:** A (-3.388) and B (-1.691) are both poor. Solubility is a critical factor for kinase inhibitors, and both compounds struggle here.
11. **hERG:** A (0.239) is very low risk. B (0.144) is even lower, excellent.
12. **Cl_mic:** A (14.797) is moderate. B (-15.142) is excellent, indicating very high metabolic stability.
13. **t1/2:** A (27.523) is good. B (-3.914) is very poor, suggesting rapid metabolism.
14. **Pgp:** A (0.232) is low efflux, good. B (0.017) is very low efflux, excellent.
15. **Affinity:** A (-6.9) is excellent. B (0) is very weak binding. This is a *major* difference.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

While both compounds have issues with Caco-2 permeability and solubility, the *massive* difference in binding affinity is decisive. Ligand A has a strong binding affinity (-6.9 kcal/mol) while Ligand B has no binding affinity (0 kcal/mol). Ligand B also has a very poor *in vitro* half-life. Ligand A has a better balance of properties, with acceptable DILI and hERG risk, and reasonable metabolic stability. The solubility and permeability issues could be addressed with formulation strategies, but without binding, Ligand B is not a viable starting point.

Therefore, I recommend **Ligand A**.

1
2025-04-17 16:17:40,949 - INFO - Batch 451 complete. Total preferences: 7216
2025-04-17 16:17:40,949 - INFO - Processing batch 452/512...
2025-04-17 16:18:22,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.425 and 351.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, under 90, suggesting good permeability. Ligand B (87.74) is still under 140, but higher than A, potentially impacting absorption.

**logP:** Ligand A (3.051) is optimal. Ligand B (0.433) is quite low, potentially hindering permeation and absorption.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (2 HBD, 5 HBA) is acceptable, but slightly higher counts could pose issues.

**QED:** Both ligands (0.791 and 0.702) have good drug-likeness scores, indicating a generally favorable profile.

**DILI:** Ligand A (21.714) has a lower DILI risk than Ligand B (28.15), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.035) is higher than Ligand B (56.34), but it's not a major deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.694) and Ligand B (-4.773) are similar and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-3.003) and Ligand B (-1.502) are both poor, but ligand B is slightly better.

**hERG Inhibition:** Both ligands (0.299 and 0.11) have very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (30.519) has lower clearance than Ligand B (42.4), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have negative half-lives (-15.111 and -15.784), which is unusual and suggests rapid degradation. However, the values are close.

**P-gp Efflux:** Both ligands (0.145 and 0.015) have low P-gp efflux liability, which is good.

**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 some ADME drawbacks.

**Conclusion:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), Ligand A is the superior candidate. Its significantly higher binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic) are key advantages. While both have poor Caco-2 permeability and solubility, the strong binding affinity of Ligand A makes it more likely to be a viable starting point for optimization.

Output:
1
2025-04-17 16:18:22,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.423 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.59) is slightly above the preferred <140 for good absorption, while Ligand B (71.41) is well within the range.

**logP:** Both ligands (1.045 and 1.851) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.626 and 0.8), indicating drug-like properties.

**DILI:** Ligand A (60.411) is approaching the higher risk threshold, while Ligand B (36.448) has a lower, more favorable DILI risk.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (65.839) has a higher BBB value than Ligand A (30.206), but this isn't a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.825) is worse than Ligand B (-4.892).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.915) is worse than Ligand B (-2.701).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.122 and 0.191).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (4.323 and 4.61 mL/min/kg).

**In vitro Half-Life:** Ligand A (15.668 hours) has a better in vitro half-life than Ligand B (-3.258 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.127).

**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.

**Conclusion:**

Despite Ligand A having a slightly higher DILI risk and worse Caco-2/Solubility values, its significantly stronger binding affinity (-8.5 kcal/mol vs -7.5 kcal/mol) makes it the more promising candidate. The potency advantage is likely to be crucial for efficacy, and the other issues could potentially be addressed through further optimization.

Output:
1
2025-04-17 16:18:22,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.415 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.39) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (70.08) is excellent, well below 140.

**logP:** Ligand A (0.305) is a bit low, potentially hindering permeation. Ligand B (1.273) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 limit.

**QED:** Both ligands have acceptable QED scores (A: 0.774, B: 0.635), indicating good drug-like properties.

**DILI:** Ligand A (30.593) has a lower DILI risk than Ligand B (18.651), both are good.

**BBB:** Ligand A (70.26) has better BBB penetration than Ligand B (48.003), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.462) has poor Caco-2 permeability, while Ligand B (-4.179) is better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -2.131, B: -1.836). This is a significant concern.

**hERG Inhibition:** Ligand A (0.058) has a very low hERG risk, which is excellent. Ligand B (0.464) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (21.953) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (28.327).

**In vitro Half-Life:** Ligand A (1.49) has a slightly longer half-life than Ligand B (-1.486).

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.008, B: 0.164).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). The 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.5 vs -7.4 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also has better metabolic stability (lower Cl_mic) and a very low hERG risk. While Ligand B has better TPSA and slightly better Caco-2 permeability, the potency difference is too significant to ignore. Solubility and permeability issues can be addressed with formulation strategies, but a weaker binder is harder to improve.

Output:
0
2025-04-17 16:18:22,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.308 Da) is slightly higher than Ligand B (356.308 Da), but both are acceptable.

**2. TPSA:** Ligand A (56.15) is well below the 140 threshold for oral absorption, and is favorable. Ligand B (96.18) is still under 140, but less optimal than Ligand A.

**3. logP:** Both ligands have good logP values (A: 3.725, B: 2.405) falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands are within the acceptable limit of 5 (A: 1, B: 2).

**5. H-Bond Acceptors:** Both ligands are within the acceptable limit of 10 (A: 4, B: 6).

**6. QED:** Both ligands have good QED scores (A: 0.827, B: 0.873), indicating good drug-like properties.

**7. DILI:** Ligand A (53.548) has a lower DILI risk than Ligand B (73.245), which is a significant advantage. Both are below the concerning 60 threshold, but A is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Both are reasonably high (A: 65.529, B: 71.229), but not a major deciding factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.965 and -4.979). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.294 and -3.825). This is also concerning, indicating poor solubility. Again, the values are very similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.329, B: 0.164), which is excellent.

**12. Microsomal Clearance:** Ligand A (81.022) has significantly higher microsomal clearance than Ligand B (21.802). This means Ligand B is more metabolically stable, a key factor for enzymes.

**13. In vitro Half-Life:** Ligand A (42.928) has a longer half-life than Ligand B (15.877), which is beneficial.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.677, B: 0.025). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.1 and -9.2 kcal/mol), with Ligand B being slightly better. This is a crucial factor.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic, longer half-life). However, Ligand A has a lower DILI risk. Given the priorities for enzyme inhibitors, metabolic stability is crucial. The small advantage in binding affinity of Ligand B outweighs the slightly higher DILI risk and the slightly shorter half-life. The solubility and permeability issues are similar for both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 16:18:22,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (74.35) is better than Ligand B (61.28).

**logP:** Ligand A (1.398) is within the optimal range (1-3). Ligand B (3.894) is approaching the upper limit and could potentially have solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) both fall within acceptable limits.

**QED:** Ligand A (0.895) has a significantly higher QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand A (25.824) has a much lower DILI risk than Ligand B (68.709), which is a significant advantage.

**BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (60.45) is slightly higher than Ligand A (55.06).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This suggests poor permeability, but the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests poor solubility, but the scale is not defined, so it's hard to interpret.

**hERG:** Ligand A (0.447) has a lower hERG risk than Ligand B (0.9), which is a positive.

**Microsomal Clearance:** Ligand A (-17.107) has a *much* lower (better) microsomal clearance than Ligand B (92.647), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (-5.519) has a negative half-life, which is unusual. Ligand B (108.878) has a very long half-life, which is a clear advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.643, respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-8.3 kcal/mol 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 overall. It has a superior QED score, much lower DILI risk, and dramatically improved metabolic stability (lower Cl_mic). While the negative Caco-2 and solubility values are concerning, the other advantages, particularly the lower DILI and better metabolic stability, outweigh these concerns. Ligand B's high DILI risk and high clearance are major drawbacks. The slightly longer half-life of Ligand B is not enough to compensate for these issues.

Output:
0
2025-04-17 16:18:22,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.385 and 374.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (88.24). A TPSA under 140 is desirable for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.147 and 2.051), 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 HBAs, while Ligand B has 7. Both are within the acceptable range of <=10, but A is preferable.

**QED:** Both ligands have good QED scores (0.734 and 0.862), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (38.736 and 75.766). Ligand A is significantly better here, falling below the 40% threshold for low risk, while B is quite high.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (84.606) is slightly better than Ligand A (75.301).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.573 and -4.887). 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 (-2.262 and -2.918), again indicating poor solubility. Similar to Caco-2, the scale is unknown.

**hERG Inhibition:** Ligand A (0.714) is better than Ligand B (0.305) - lower is better here, indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (49.973) has lower clearance than Ligand B (65.918), suggesting better metabolic stability, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand A (-26.182) has a more negative half-life than Ligand B (-11.551). Again, the scale is unknown, but a less negative value is generally preferred.

**P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux than Ligand B (0.042), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.8 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 and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with predicted permeability and solubility, Ligand A demonstrates a significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and lower hERG inhibition risk. The substantial affinity difference is the most important factor, given the enzyme-specific priorities.

Output:
0
2025-04-17 16:18:22,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (375.491 and 367.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.59) is slightly above the preferred <140 for good absorption, while Ligand B (114.48) is well within.

**logP:** Ligand A (0.541) is a bit low, potentially hindering permeation. Ligand B (2.098) 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 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.48 and 0.563), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (50.64) has a lower DILI risk than Ligand B (69.794), which is a significant advantage.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (66.886) has a higher BBB percentile than Ligand A (40.83), but this is less critical here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.667 and -5.267), which is unusual and suggests poor permeability. This is a major concern for both.

**Aqueous Solubility:** Ligand A (-0.944) has slightly better solubility than Ligand B (-3.994), which is a positive.

**hERG:** Ligand A (0.133) has a much lower hERG risk than Ligand B (0.22), which is a crucial advantage.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (16.754 and 15.207 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-21.289) has a significantly longer in vitro half-life than Ligand B (5.382), which is a substantial benefit.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.06 and 0.094), which is good.

**Binding Affinity:** Ligand A (-7.4 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 the stronger candidate. While both have poor Caco-2 permeability, Ligand A's superior binding affinity (-7.4 vs 0.0 kcal/mol), lower DILI risk (50.64 vs 69.794), lower hERG risk (0.133 vs 0.22), and longer half-life (-21.289 vs 5.382) outweigh its slightly lower logP and TPSA. The substantial difference in binding affinity is particularly important for an enzyme inhibitor. The solubility is also slightly better for Ligand A.

Output:
0
2025-04-17 16:18:22,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (360.445 and 356.438 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (76.66). Lower TPSA generally favors better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**3. logP:** Both ligands have acceptable logP values (2.733 and 1.497), 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 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 QED values (0.724 and 0.678), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (29.43 and 30.865), which is excellent.

**8. BBB:** Both ligands have high BBB penetration (96.355 and 89.957). While SRC isn't a CNS target, this isn't a negative.

**9. Caco-2 Permeability:** Ligand A (-4.639) is significantly better than Ligand B (-4.748). Higher Caco-2 permeability indicates better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.619) is slightly better than Ligand B (-2.093). Both are relatively poor, but Ligand A is less so.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.522 and 0.31). This is a critical safety parameter, and both are acceptable.

**12. Microsomal Clearance:** Ligand A (21.595) has significantly lower microsomal clearance than Ligand B (32.765). Lower clearance indicates better metabolic stability, a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (3.692) has a significantly longer half-life than Ligand B (-6.013). This is a major advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.024). Lower efflux improves bioavailability.

**15. Binding Affinity:** Ligand A (-6.8 kcal/mol) is slightly better than Ligand B (-6.3 kcal/mol). While both are good, the 0.5 kcal/mol difference is meaningful and can outweigh some minor ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters. It has better TPSA, permeability, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and slightly better binding affinity. While both have acceptable safety profiles (DILI, hERG), Ligand A's superior ADME properties make it the more promising drug candidate.

Output:
1
2025-04-17 16:18:22,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 354.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.71) is higher than Ligand B (49.41). While both are reasonably low, Ligand B is better positioned for oral absorption.

**logP:** Both ligands have good logP values (1.663 and 2.823, respectively), 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 2. Ligand B is slightly better here.

**QED:** Both ligands have similar QED scores (0.808 and 0.797), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 55.758, which is acceptable (below 60). Ligand B has a significantly lower DILI risk of 16.44, making it more favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (78.674) and Ligand B (96.937) both have reasonable values.

**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 significant drawback.

**hERG:** Ligand A (0.192) has a slightly lower hERG risk than Ligand B (0.797), which is preferable.

**Microsomal Clearance:** Ligand A (44.868) has higher microsomal clearance than Ligand B (20.893), indicating lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand B (-4.808) has a longer in vitro half-life than Ligand A (4.574), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.2), which is slightly better.

**Binding Affinity:** Ligand B (-9.2 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, potentially outweighing some of the ADME drawbacks.

**Overall:**

Ligand B is the stronger candidate. While both have solubility issues and questionable permeability, Ligand B's superior binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux outweigh the slightly higher hERG risk and TPSA. The substantial difference in binding affinity is the deciding factor for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:18:22,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.417 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 59.08, well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (1.39 and 1.207).

**H-Bond Donors/Acceptors:** Both have 0 HBD and 4 HBA, which is acceptable.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (25.436) has a slightly higher DILI risk than Ligand B (22.722), but both are well below the concerning threshold of 60.

**BBB:** Ligand A (85.498) shows better BBB penetration than Ligand B (77.976), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.269) has slightly better Caco-2 permeability than Ligand B (-4.692).

**Aqueous Solubility:** Ligand A (-1.415) has slightly better aqueous solubility than Ligand B (-1.658).

**hERG Inhibition:** Ligand A (0.579) has a slightly higher hERG risk than Ligand B (0.336), but both are relatively low.

**Microsomal Clearance:** Ligand B (43.3 mL/min/kg) has a significantly *lower* microsomal clearance than Ligand A (24.918 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (1.92 hours) has a longer in vitro half-life than Ligand A (-0.455 hours). This further supports its superior metabolic stability.

**P-gp Efflux:** Ligand A (0.04) has a lower P-gp efflux liability than Ligand B (0.079), which is a slight advantage.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is the most crucial factor, as a 2.4 kcal/mol difference is substantial.

**Conclusion:**

While Ligand A has slightly better solubility and P-gp efflux, Ligand B is clearly superior due to its significantly stronger binding affinity and markedly improved metabolic stability (lower Cl_mic and longer t1/2). The difference in binding affinity outweighs the minor drawbacks of Ligand B.

Output:
1
2025-04-17 16:18:22,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (329.403 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (47.04) is excellent, well below the 140 threshold for oral absorption. Ligand B (93.11) is higher, potentially hindering absorption, although still within a reasonable range.

**logP:** Ligand A (4.845) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-0.268) is too low, likely causing poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.727, B: 0.548), indicating drug-like properties.

**DILI:** Ligand A (84.684) has a higher DILI risk than Ligand B (9.926). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.06) is higher than Ligand B (25.126).

**Caco-2 Permeability:** Ligand A (-4.938) is very poor, indicating very low intestinal absorption. Ligand B (-5.196) is also poor, but comparable to A.

**Aqueous Solubility:** Ligand A (-5.857) is very poor. Ligand B (-0.557) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.751) has a moderate hERG risk, while Ligand B (0.04) has a very low risk. This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (79.597) has a high clearance, suggesting poor metabolic stability. Ligand B (-7.232) has a negative clearance, which is excellent and indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (-13.213) has a very short half-life. Ligand B (-4.89) is better, but still relatively short.

**P-gp Efflux:** Ligand A (0.447) has moderate P-gp efflux liability. Ligand B (0.002) has very low efflux liability.

**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 for Ligand A, potentially outweighing some of its ADME issues.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from poor solubility, poor permeability, high DILI risk, high metabolic clearance, and a short half-life. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower hERG risk, lower P-gp efflux), but significantly weaker binding affinity.

Despite the superior binding affinity of Ligand A, the combination of poor ADME properties, particularly the high DILI risk and poor metabolic stability, makes it a less viable candidate. The difference in binding affinity (2.1 kcal/mol) is substantial, but not enough to overcome the serious ADME liabilities. Ligand B, while weaker in binding, presents a more balanced profile with significantly better safety and pharmacokinetic properties. Further optimization of Ligand B to improve its binding affinity would be a more promising strategy.

Output:
1
2025-04-17 16:18:22,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 359.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (84.31). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (1.832 and 3.599, respectively), falling within the 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 (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 6 HBA). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have good QED scores (0.565 and 0.752), indicating good drug-like properties.

**DILI:** Ligand A (18.147) has a much lower DILI risk than Ligand B (56.223). This is a significant advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (63.784 and 62.97). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.445) has better Caco-2 permeability than Ligand B (-5.162). This suggests better intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-2.246) has better aqueous solubility than Ligand B (-3.998). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.193) has a lower hERG inhibition liability than Ligand B (0.471), which is a crucial safety advantage.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (34.559 and 36.47), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-18.942) has a significantly longer in vitro half-life than Ligand A (-7.799). This is a positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.155 and 0.215).

**Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (-6.7). 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 superior ADME properties (lower DILI, better solubility, permeability, and hERG risk) but weaker binding affinity. Ligand B has a significantly stronger binding affinity but has higher DILI risk, poorer solubility, and a higher hERG risk.

Given that we are targeting a kinase (SRC), potency (binding affinity) is paramount. The 1.6 kcal/mol difference in binding affinity is substantial and likely outweighs the ADME concerns of Ligand B, *provided* further optimization can mitigate the DILI and hERG risks. While Ligand A is safer, a weaker binder is less likely to be effective.

Output:
1
2025-04-17 16:18:22,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.551 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, while Ligand B (100.21) is still acceptable but higher.

**logP:** Ligand A (3.447) is optimal, while Ligand B (1.15) is a bit low, 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 balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.691 and 0.784), suggesting good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (38.503 and 53.276), below the concerning threshold of 60.

**BBB:** Ligand A (55.797) has moderate BBB penetration, while Ligand B (27.763) has low BBB penetration. This isn't a major concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.778) has poor Caco-2 permeability, while Ligand B (-5.138) is also poor. This is a potential issue for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.362 and -2.143). This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.693) has a slightly higher hERG risk than Ligand B (0.166), but both are relatively low.

**Microsomal Clearance:** Ligand A (51.616) has higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (12.592).

**In vitro Half-Life:** Ligand A (39.203) has a longer half-life than Ligand B (10.838).

**P-gp Efflux:** Ligand A (0.26) has lower P-gp efflux than Ligand B (0.02), suggesting better bioavailability.

**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. The difference of 1.3 kcal/mol is substantial.

**Conclusion:**

Despite Ligand A having better TPSA, H-bonding, and half-life, Ligand B's substantially stronger binding affinity (-7.7 vs -9.0 kcal/mol) outweighs its drawbacks. The lower logP and Caco-2 permeability of Ligand B are concerns, but these can potentially be addressed through further optimization. The significantly improved affinity is a critical factor for an enzyme inhibitor. The better metabolic stability (lower Cl_mic) and lower P-gp efflux of Ligand B are also beneficial.

Output:
1
2025-04-17 16:18:22,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight:** Both ligands (370.739 Da and 361.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (77.4 and 71.53) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (2.865 and 1.855) 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 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.821) has a significantly higher QED score than Ligand B (0.642), indicating a more drug-like profile.

**7. DILI:** Ligand A (87.01) has a higher DILI risk than Ligand B (64.288). This is a negative for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand A (68.941) is slightly lower than Ligand B (64.482). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.723) has a worse Caco-2 permeability than Ligand B (-5.027), indicating potentially lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.299) has worse aqueous solubility than Ligand B (-2.559). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.308 and 0.216).

**12. Microsomal Clearance:** Ligand A (45.462) has a higher microsomal clearance than Ligand B (20.107), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (48.988) has a longer in vitro half-life than Ligand B (-0.034). However, the negative value for B is concerning and suggests very rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.252 and 0.247).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 kcal/mol and -8.4 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and slightly longer half-life, Ligand B demonstrates superior ADME properties: lower DILI risk, better solubility, and significantly better metabolic stability (lower Cl_mic). The slight difference in binding affinity is negligible compared to the ADME advantages of Ligand B. The negative half-life of Ligand B is a red flag, but the other properties are more favorable.

Output:
1
2025-04-17 16:18:22,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.479 and 347.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly higher than Ligand B (75.86). Both are below the 140 A^2 threshold for good oral absorption, but B is better.

**logP:** Ligand A (1.193) is within the optimal range (1-3), while Ligand B (2.586) is also good.

**H-Bond Donors:** Both ligands 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.

**QED:** Both ligands have good QED scores (0.572 and 0.756, respectively), indicating drug-likeness. Ligand B is better.

**DILI:** Ligand A (12.718) and Ligand B (11.632) both have low DILI risk, well below the concerning threshold of 60. B is slightly better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.88) has a higher BBB percentile than Ligand A (25.94), but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.716) has poor Caco-2 permeability, while Ligand B (-5.27) is also poor. This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Ligand A (-0.81) has slightly better solubility than Ligand B (-3.28). Solubility is important for formulation.

**hERG Inhibition:** Ligand A (0.176) has a lower hERG risk than Ligand B (0.31), which is a significant advantage.

**Microsomal Clearance:** Ligand A (78.887) has a higher microsomal clearance than Ligand B (33.935). This means Ligand B is more metabolically stable, a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (-29.451) has a negative half-life, which is not possible. This is a major red flag. Ligand B (18.939) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.107, respectively).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the difference is significant.

**Conclusion:**

Considering all factors, **Ligand B is the more promising candidate**. While Ligand A has slightly better solubility and lower hERG risk, its negative in vitro half-life is a critical flaw. Ligand B demonstrates superior metabolic stability (lower Cl_mic, positive t1/2), better binding affinity, and a good overall ADME profile. The slightly higher hERG risk of Ligand B is less concerning than the unusable half-life of Ligand A.

Output:
1
2025-04-17 16:18:22,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.383 and 357.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (64.41).  A TPSA under 140 is good for oral absorption, and both are well within this limit, but lower is generally preferred.

**logP:** Both ligands have good logP values (3.431 and 2.875), 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 acceptable, staying within the recommended limits.

**QED:** Both ligands have similar QED values (0.818 and 0.814), indicating good drug-likeness.

**DILI:** Ligand A (18.108) has a much lower DILI risk than Ligand B (25.165). This is a significant advantage.

**BBB:** Both have high BBB penetration (89.957 and 82.629), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.636 and -4.922), which is unusual and suggests poor permeability. However, these values should be interpreted cautiously as they can be affected by experimental conditions.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.818 and -4.058). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.878) has a slightly higher hERG risk than Ligand B (0.783), but both are reasonably low.

**Microsomal Clearance:** Ligand A (-13.969) exhibits *much* better metabolic stability (lower clearance) than Ligand B (39.141). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (11.91 hours) has a significantly longer half-life than Ligand B (3.969 hours). This is also a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.166 and 0.296).

**Binding Affinity:** Ligand B (-10.4 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a 2.3 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 superior binding affinity, Ligand A demonstrates a significantly better safety profile (lower DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and better TPSA. Given the priorities for enzyme inhibitors, the improved ADME properties of Ligand A are more compelling, despite the slightly weaker binding. The solubility is a concern for both, but formulation strategies could potentially address this. The difference in binding affinity, while substantial, may be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 16:18:22,404 - INFO - Batch 452 complete. Total preferences: 7232
2025-04-17 16:18:22,405 - INFO - Processing batch 453/512...
2025-04-17 16:19:02,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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, while Ligand B (389.283 Da) is still well within the acceptable range.

**TPSA:** Both ligands have TPSA values below 140 (A: 80.56, B: 74.77), suggesting good oral absorption potential.

**logP:** Both ligands have logP values between 1 and 3 (A: 1.192, B: 1.299), which is optimal for drug-likeness.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=6) and Ligand B (HBD=1, HBA=5) both have reasonable numbers of hydrogen bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have QED values above 0.5 (A: 0.798, B: 0.712), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 42.924, B: 49.593), below the 60 threshold.

**BBB:** Both ligands have reasonable BBB penetration (A: 70.88, B: 66.072). While not critical for a non-CNS target like SRC, it doesn't detract from their potential.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.737 and -4.723). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading. It's best to interpret these with caution.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.585 and -2.543). Similar to Caco-2, these are on a log scale and indicate poor solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.089) has a much lower hERG inhibition liability than Ligand B (0.447). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (20.37 mL/min/kg) has a higher microsomal clearance than Ligand B (14.596 mL/min/kg), meaning it's metabolized faster and has lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.957 hours) has a significantly longer in vitro half-life than Ligand A (1.019 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.045, B: 0.013).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.5 kcal/mol, B: -8.3 kcal/mol). Ligand A is slightly better (-8.5 vs -8.3), but the difference is relatively small.

**Overall Assessment:**

Ligand A has a better hERG profile and slightly better binding affinity. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2) and is preferable in that regard. Both have poor solubility and permeability, which are major drawbacks. Given the importance of metabolic stability for kinase inhibitors, and the relatively small difference in binding affinity, Ligand B is the slightly more promising candidate. However, both require significant medicinal chemistry work to improve solubility and permeability.

Output:
1
2025-04-17 16:19:02,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.811 Da and 366.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.48) is well below the 140 threshold, suggesting good absorption. Ligand B (83.36) is still within an acceptable range, but less optimal than A.

**logP:** Ligand A (4.978) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.152) is too low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 7 HBA) both have reasonable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.812) has a higher QED score than Ligand B (0.625), indicating a more drug-like profile.

**DILI:** Ligand B (34.238) has a significantly lower DILI risk than Ligand A (49.399), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (94.61) has better BBB penetration than Ligand B (58.55), but this isn't a primary concern.

**Caco-2 Permeability:** Ligand A (-4.529) has poor Caco-2 permeability, while Ligand B (-5.446) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.44) has poor aqueous solubility, while Ligand B (-1.165) is also poor, but better.

**hERG Inhibition:** Ligand A (0.76) has a slightly higher hERG risk than Ligand B (0.027), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (8.144) has a higher microsomal clearance than Ligand B (3.831), indicating lower metabolic stability. This is a key disadvantage for A.

**In vitro Half-Life:** Ligand A (72.045 hours) has a much longer half-life than Ligand B (45.521 hours), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.204) has lower P-gp efflux than Ligand B (0.011), which is a slight advantage for A.

**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 that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A boasts a significantly better binding affinity and longer half-life. However, it suffers from poor solubility, poor permeability, higher DILI risk, and higher metabolic clearance. Ligand B has better solubility, lower DILI and hERG risk, and better metabolic stability, but weaker binding affinity.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A (-8.4 kcal/mol vs -7.7 kcal/mol) is a major factor. While its ADME properties are less ideal, the potency advantage is significant enough to potentially overcome these issues through further optimization. The difference in binding affinity is >1.5 kcal/mol, which the guidelines state can outweigh minor ADME drawbacks.

Output:
1
2025-04-17 16:19:02,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.447 and 361.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.45) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (70.16) is excellent, well below 140.

**logP:** Ligand A (-0.167) is a bit low, potentially hindering permeability. Ligand B (1.322) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (A: 6, B: 4) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.451, B: 0.741), indicating drug-like properties, with B being significantly better.

**DILI:** Both ligands have acceptable DILI risk (A: 54.401, B: 47.305), below the 60 threshold.

**BBB:** Ligand A (48.197) and Ligand B (84.102). BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.577) is poor, indicating low intestinal absorption. Ligand B (-3.993) is also poor, but better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -1.397, B: -1.609). This is a significant concern.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.07, B: 0.415).

**Microsomal Clearance:** Ligand A (6.747) has a lower Cl_mic, suggesting better metabolic stability than Ligand B (41.336).

**In vitro Half-Life:** Ligand A (14.238) has a longer half-life than Ligand B (-23.354), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.006, B: 0.068).

**Binding Affinity:** Both ligands have comparable binding affinities (A: -8.8 kcal/mol, B: -8.2 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and better metabolic stability (lower Cl_mic, longer half-life). However, Ligand B has a much better TPSA, logP, QED, and Caco-2 permeability. The poor solubility of both is a major concern, but the better permeability of B, combined with its superior QED, makes it a more promising starting point for optimization. The slightly better affinity of A isn't enough to overcome its poorer ADME profile.

Output:
1
2025-04-17 16:19:02,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 345.363 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.3) is well below the 140 threshold, suggesting good absorption. Ligand B (129.94) is also below the threshold, but higher than A.

**logP:** Ligand A (2.615) is optimal (1-3). Ligand B (0.15) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 8. Ligand B is approaching the upper limit of 10, potentially impacting permeability.

**QED:** Both ligands have reasonable QED scores (0.861 and 0.788), indicating good drug-like properties.

**DILI:** Ligand A (36.177) has a lower DILI risk than Ligand B (54.75), both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.839) is slightly better than Ligand B (57.968).

**Caco-2:** Ligand A (-4.886) and Ligand B (-5.219) are both negative, indicating poor permeability. This is unusual, and suggests the scale is inverted. Assuming lower values are worse, both are poor.

**Solubility:** Ligand A (-3.102) and Ligand B (-2.181) are both negative, indicating poor solubility. Again, assuming lower values are worse, both are poor.

**hERG:** Ligand A (0.479) has a much lower hERG risk than Ligand B (0.108), which is a significant advantage.

**Microsomal Clearance:** Ligand A (57.995) has higher clearance than Ligand B (26.351), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (21.65) has a longer half-life than Ligand A (-14.476), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.317) has lower P-gp efflux than Ligand B (0.041), which is preferable.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 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 longer half-life, and lower microsomal clearance, which are crucial for an enzyme inhibitor. While Ligand B has a lower logP and higher HBA count, the affinity difference is substantial. The hERG risk is lower for Ligand A, but the difference isn't as critical as the potency and stability advantages of Ligand B. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:19:02,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.373 and 344.375 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.46) is well below the 140 threshold, suggesting good absorption. Ligand B (125.02) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (2.618) is optimal (1-3). Ligand B (0.505) is below 1, which could hinder permeation.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 7 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED scores (0.884 and 0.753), indicating good drug-like properties.

**DILI:** Ligand A (64.754) has a higher DILI risk than Ligand B (56.572), but both are within an acceptable range (<60 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.747) is higher than Ligand B (71.733).

**Caco-2 Permeability:** Ligand A (-4.251) is better than Ligand B (-5.453), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.373) is better than Ligand B (-1.069), which is a significant advantage for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.264 and 0.04), which is excellent.

**Microsomal Clearance:** Ligand A (64.48) has higher clearance than Ligand B (15.839). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Both have negative values, which is unusual. Assuming these are log scales, they are similar (-10.97 and -10.586), suggesting comparable in vitro stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.056 and 0.037).

**Binding Affinity:** Both ligands show excellent binding affinity (-8.3 and -9.4 kcal/mol). Ligand B has a slightly better affinity, but the difference (1.1 kcal/mol) isn't huge enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A has significantly better logP, solubility, and Caco-2 permeability. These factors are crucial for ensuring adequate absorption and bioavailability, especially for an enzyme target where achieving sufficient concentrations at the target site is essential. The DILI risk is slightly higher for A, but still acceptable.

Output:
1
2025-04-17 16:19:02,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (361.389 and 353.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (96.87), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Both ligands (1.416 and 1.777) are 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 4 HBA, while Ligand B has 6. Ligand A is preferable here, as lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED scores (0.775 and 0.745), indicating good drug-likeness.

**7. DILI:** Ligand A (38.581) has a significantly lower DILI risk than Ligand B (84.025). This is a major advantage for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.082) is slightly better than Ligand B (61.109).

**9. Caco-2 Permeability:** Ligand A (-4.755) is better than Ligand B (-5.435), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.338) is better than Ligand B (-3.386), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.2 and 0.236), which is low and favorable.

**12. Microsomal Clearance:** Ligand A (-21.192) has significantly lower microsomal clearance than Ligand B (4.268), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-33.322) has a longer in vitro half-life than Ligand B (50.516), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.102).

**15. Binding Affinity:** Ligand B (-8.8) 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. However, the affinity difference is so large that it needs to be carefully considered.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, Ligand A demonstrates a superior ADME profile, particularly regarding DILI risk and metabolic stability (lower Cl_mic and longer t1/2). For an enzyme target like SRC kinase, metabolic stability is paramount. A potent drug that is rapidly metabolized will require high doses and may have limited efficacy. The significantly lower DILI risk of Ligand A is also a major benefit. The affinity difference is substantial, but not insurmountable. Further optimization of Ligand A could potentially close the gap in binding affinity while retaining its favorable ADME properties.

Output:
0
2025-04-17 16:19:02,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (364.467 Da) is also good.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (91.57). Lower TPSA generally improves oral absorption. Ligand B's TPSA is relatively high.

**logP:** Ligand A (3.308) is optimal, while Ligand B (1.808) is on the lower side. A logP closer to 3 is generally preferred for kinase inhibitors to balance solubility and permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Fewer hydrogen bonds are generally better for permeability.

**QED:** Both ligands have similar QED values (0.766 and 0.633), indicating good drug-like properties.

**DILI:** Ligand A (15.471) has a much lower DILI risk than Ligand B (33.501), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.5) is higher, but it's not a deciding factor. Ligand B (25.94) is low.

**Caco-2 Permeability:** Ligand A (-4.731) has a more negative Caco-2 value, suggesting better permeability than Ligand B (-5.478).

**Aqueous Solubility:** Ligand A (-3.405) has better solubility than Ligand B (-1.853). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.658) has a lower hERG risk than Ligand B (0.23), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (63.064) has higher microsomal clearance than Ligand B (37.035), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (36.56) has a significantly longer in vitro half-life than Ligand A (-3.015), which is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.461) has lower P-gp efflux than Ligand B (0.047), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is small (0.1 kcal/mol) and can be outweighed by other factors.

**Overall Assessment:**

Ligand A has several advantages: better TPSA, logP, DILI risk, solubility, hERG risk, and P-gp efflux. However, Ligand B has a significantly longer half-life and slightly better binding affinity. The lower DILI and hERG risk of Ligand A are critical for drug development, and its better solubility and permeability are also beneficial. While Ligand B's longer half-life is attractive, the higher DILI and hERG risks are concerning. The difference in binding affinity is small enough to be optimized later.

Output:
0
2025-04-17 16:19:02,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.423 and 342.399 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.4) is better than Ligand B (84.42). Both are below 140, suggesting reasonable absorption, but lower TPSA is generally preferred.

**logP:** Ligand A (3.175) is optimal, while Ligand B (1.064) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.61 and 0.885), indicating drug-likeness.

**DILI:** Ligand A (30.903) has a significantly lower DILI risk than Ligand B (52.036), which is a major advantage.

**BBB:** Both have reasonably high BBB penetration (81.233 and 79.488), but this is less critical for a non-CNS target like SRC.

**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:** Ligand A (-3.624) has better solubility than Ligand B (-1.606). Solubility is crucial for bioavailability.

**hERG:** Ligand A (0.721) has a lower hERG risk than Ligand B (0.12), which is a significant advantage.

**Microsomal Clearance:** Ligand A (69.934) has a higher (worse) microsomal clearance than Ligand B (23.191). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (1.369) has a slightly better in vitro half-life than Ligand A (-13.283).

**P-gp Efflux:** Ligand A (0.221) shows lower P-gp efflux liability than Ligand B (0.032), which is favorable.

**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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, better metabolic stability, and a slightly better half-life. However, Ligand A has better solubility, lower DILI risk, lower hERG risk, and lower P-gp efflux. The difference in binding affinity (-1.2 kcal/mol) is substantial, and for an enzyme target like SRC kinase, potency is paramount. While Ligand A has better safety and ADME properties, the stronger binding of Ligand B is likely to be more important for achieving efficacy.

Output:
1
2025-04-17 16:19:02,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.487 Da and 362.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is better than Ligand B (23.55), being below 140, but Ligand B is significantly better, approaching the ideal for CNS penetration (though that's not our primary goal here).

**logP:** Ligand A (2.013) is optimal (1-3), while Ligand B (4.84) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (0 HBD, 3 HBA) as it strikes a better balance.

**QED:** Both ligands have similar QED values (0.776 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (43.195) has a slightly higher DILI risk than Ligand B (11.128), but both are below the concerning threshold of 60.

**BBB:** Ligand A (64.793) is lower than Ligand B (94.261). Not a primary concern for a non-CNS target.

**Caco-2 Permeability:** Both are negative (-5.04 and -5.058), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.111 and -3.857), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.55) has a lower hERG risk than Ligand B (0.925), which is preferable.

**Microsomal Clearance:** Ligand A (53.175) has a lower (better) microsomal clearance than Ligand B (82.298), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.218) has a negative half-life, which is impossible. This is a red flag. Ligand B (11.313) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.14) has lower P-gp efflux than Ligand B (0.837), which is favorable.

**Binding Affinity:** Ligand B (-9.7 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.

**Conclusion:**

Despite the poor solubility and permeability for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.7 vs -6.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Ligand B also has a better half-life, lower P-gp efflux, and lower hERG risk. While its logP is higher, the substantial potency gain likely compensates for this. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 16:19:02,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which can be beneficial for permeability. Ligand B (364.431 Da) is also good.

**TPSA:** Ligand A (72.88) is excellent, well below the 140 threshold for oral absorption. Ligand B (104.45) is still reasonable, but higher, potentially impacting absorption.

**logP:** Ligand A (1.228) is within the optimal range (1-3). Ligand B (-0.207) is slightly below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 8 HBA) is also acceptable, though the higher HBA count might slightly impact permeability.

**QED:** Both ligands have good QED scores (A: 0.84, B: 0.787), indicating good drug-like properties.

**DILI:** Ligand A (17.914) has a significantly lower DILI risk than Ligand B (47.421), a major advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (69.523) has a better BBB score than Ligand B (32.92).

**Caco-2 Permeability:** Ligand A (-4.815) shows poor permeability, while Ligand B (-5.023) is similarly poor. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.401 and -1.769 respectively). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.622) has a lower hERG risk than Ligand B (0.103), which is a critical advantage.

**Microsomal Clearance:** Ligand A (0.777) has significantly lower microsomal clearance than Ligand B (9.46), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.118 hours) has a longer half-life than Ligand B (20.927 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.086) shows lower P-gp efflux than Ligand B (0.152), which is beneficial for bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME concerns. The difference of 3 kcal/mol is substantial.

**Conclusion:**

Despite Ligand A's superior ADME properties (lower DILI, better metabolic stability, lower hERG risk, better P-gp efflux, and better BBB), the significantly stronger binding affinity of Ligand B (-9.5 kcal/mol vs -6.5 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The potency advantage is likely to outweigh the ADME liabilities, especially if formulation strategies can mitigate the solubility issues.

Output:
1
2025-04-17 16:19:02,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.901 Da and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (134.58) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (3.987) is at the higher end of the optimal 1-3 range, but acceptable. Ligand B (0.315) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is excellent. Ligand B (HBD=3, HBA=7) is slightly less ideal, with a higher number of hydrogen bond acceptors.

**QED:** Both ligands have similar QED values (0.778 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A (17.642) has a significantly lower DILI risk than Ligand B (43.622), which is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand B (80.031) has slightly better penetration than Ligand A (69.833).

**Caco-2 Permeability:** Ligand A (-4.596) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.261) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.901) has poor aqueous solubility. Ligand B (-2.355) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.807) has a lower hERG risk than Ligand B (0.402), which is favorable.

**Microsomal Clearance:** Ligand A (1.71) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (-2.74) has negative clearance, which is not physically possible and likely indicates an issue with the data or model.

**In vitro Half-Life:** Ligand A (20.815) has a much longer in vitro half-life than Ligand B (-21.69), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.441) has lower P-gp efflux, suggesting better bioavailability. Ligand B (0.016) has very low efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 kcal/mol and -8.0 kcal/mol), with Ligand A being slightly stronger. The 0.4 kcal/mol difference is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have good binding affinity, Ligand A demonstrates significantly better DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. Although its solubility and Caco-2 permeability are poor, these can potentially be addressed through formulation strategies. Ligand B's very low (and likely erroneous) negative clearance and higher DILI risk are major drawbacks.

Output:
1
2025-04-17 16:19:02,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.499 and 372.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is better than Ligand B (92.34), being comfortably below 140 and closer to the desirable range for good absorption.

**3. logP:** Both ligands have good logP values (1.907 and 1.648), 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 4. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.727) has a slightly better QED score than Ligand B (0.61), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (37.224 and 34.626), well below the 40 threshold.

**8. BBB:** Both have relatively low BBB penetration (53.897 and 63.28). This isn't a major concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.486 and -5.123). This is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without more context.

**10. Aqueous Solubility:** Both have negative solubility values (-2.681 and -2.209), which is also concerning. Again, the scale is important here, but both appear to have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.13 and 0.319), which is excellent.

**12. Microsomal Clearance:** Ligand A (19.962) has lower microsomal clearance than Ligand B (37.39), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (5.234) has a significantly longer in vitro half-life than Ligand A (1.42). This is a substantial benefit.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.057 and 0.147).

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This 0.6 kcal/mol difference is meaningful and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a better QED, lower Cl_mic (better metabolic stability), and *much* stronger binding affinity. Ligand B has a longer half-life. Both have concerningly poor solubility and permeability. However, the strong binding affinity of Ligand A, combined with its better metabolic stability, makes it the more promising candidate, despite the solubility/permeability issues. The potency advantage is likely to be more easily addressed through formulation strategies than improving a significantly weaker binding ligand.

Output:
0
2025-04-17 16:19:02,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.361 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.7) is slightly higher than Ligand B (78.87). Both are below the 140 threshold for good absorption, but B is preferable.

**logP:** Both ligands have good logP values (2.578 and 1.378), falling within the 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but it's not a major concern.

**H-Bond Donors/Acceptors:** Both have 2 HBD and either 5 or 4 HBA, which are acceptable.

**QED:** Both ligands have similar QED scores (0.762 and 0.751), indicating good drug-likeness.

**DILI:** Ligand B (35.479) has a significantly lower DILI risk than Ligand A (69.678). This is a major advantage for Ligand B.

**BBB:** Ligand B (44.203) has a higher BBB penetration than Ligand A (33.734), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar, and we'll consider other factors.

**Aqueous Solubility:** Ligand B (-1.744) is better than Ligand A (-3.62), indicating better solubility.

**hERG Inhibition:** Ligand B (0.19) has a much lower hERG inhibition liability than Ligand A (0.658). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (8.045) has a lower microsomal clearance than Ligand A (17.297), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (33.149) has a longer half-life than Ligand B (3.466). This is a positive for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand B (0.099) has lower P-gp efflux than Ligand A (0.136), which is favorable for bioavailability.

**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 outweighs many of the minor drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a longer half-life, Ligand B excels in critical areas: significantly lower DILI risk, much lower hERG inhibition, better solubility, better metabolic stability (lower Cl_mic), and, most importantly, a substantially stronger binding affinity. The stronger binding affinity is particularly important for an enzyme inhibitor, and the improved safety profile (DILI, hERG) makes Ligand B a much more promising drug candidate.

Output:
1
2025-04-17 16:19:02,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.34 Da) is slightly higher than Ligand B (346.366 Da), but both are acceptable.

**TPSA:** Ligand A (58.22) is well below the 140 threshold for oral absorption, and suitable for kinase inhibitors. Ligand B (101.8) is still within a reasonable range, but less optimal than A.

**logP:** Ligand A (4.125) is slightly high, potentially leading to solubility issues or off-target effects, but still within a tolerable range. Ligand B (0.469) is quite low, which could hinder membrane permeability and reduce bioavailability.

**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: 0.777, B: 0.723), indicating good drug-like properties.

**DILI:** Ligand A (26.018) has a significantly lower DILI risk than Ligand B (57.697), which is a major advantage.

**BBB:** Both have reasonable BBB penetration (A: 74.292, B: 71.501), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is concerning and suggests potential absorption issues. However, the negative values are on a similar scale, so this doesn't strongly favor either.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are similar and don't differentiate the ligands.

**hERG Inhibition:** Ligand A (0.894) has a lower hERG risk than Ligand B (0.235), which is a significant advantage.

**Microsomal Clearance:** Ligand A (67.49) has a higher microsomal clearance than Ligand B (4.305). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-5.127) has a shorter half-life than Ligand B (5.857), further supporting the better metabolic stability of Ligand B.

**P-gp Efflux:** Ligand A (0.373) has lower P-gp efflux liability than Ligand B (0.007), which is favorable.

**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 could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower DILI and hERG risks, which are crucial for a kinase inhibitor. While its logP is slightly high and clearance is higher than Ligand B, the substantial affinity advantage is likely to be decisive. Ligand B's better metabolic stability is appealing, but the weaker binding and higher DILI/hERG risks are more concerning.

Output:
1
2025-04-17 16:19:02,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.471 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (87.74). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.289 and 0.825), 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=4) as it has fewer H-bonds, which generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.437 and 0.643), indicating drug-like properties, with Ligand B being slightly better.

**DILI:** Ligand A (23.459) has a much lower DILI risk than Ligand B (16.673), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration (75.107 and 69.678), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.058) has worse Caco-2 permeability than Ligand B (-4.823). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.973) has slightly better solubility than Ligand B (-1.308), although both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.36 and 0.115), which is excellent.

**Microsomal Clearance:** Ligand A (39.88) has a higher microsomal clearance than Ligand B (34.674), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (2.383) has a longer half-life than Ligand A (0.974), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.139 and 0.006), which is good.

**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 excels in DILI risk and TPSA, and has a slightly better logP and solubility. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), slightly better Caco-2 permeability, and a better QED score. Given the enzyme-specific priorities, metabolic stability and half-life are crucial. While Ligand A's lower DILI is attractive, the improved pharmacokinetic profile of Ligand B outweighs this benefit.

Output:
1
2025-04-17 16:19:02,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.451 Da) is slightly lower, which could be beneficial for permeability. Ligand B (390.531 Da) is also good.

**TPSA:** Ligand A (89.35) is excellent, well below the 140 threshold for oral absorption. Ligand B (111.63) is still acceptable, but less optimal.

**logP:** Ligand A (0.694) is a bit low, potentially hindering permeation. Ligand B (-0.061) is even lower, raising concerns about absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is very good. Ligand B (HBD=3, HBA=7) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (A: 0.696, B: 0.573), indicating drug-like properties.

**DILI:** Ligand A (57.619) has a slightly higher DILI risk than Ligand B (37.844), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (58.86) and Ligand B (27.801) are both low.

**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 negative solubility values, indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.248, B: 0.232), which is excellent.

**Microsomal Clearance:** Ligand B (-12.279) has significantly lower (better) microsomal clearance than Ligand A (38.167), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand B (-3.019) has a slightly better (longer) in vitro half-life than Ligand A (-19.372).

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.05, B: 0.038), which is favorable.

**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:**

While both compounds have strong binding affinities, their poor solubility and permeability (indicated by negative Caco-2 and solubility values) are major red flags. However, Ligand B has a clear advantage in metabolic stability (lower Cl_mic) and slightly better half-life, and a slightly better binding affinity. The lower DILI risk for Ligand B is also a plus. Given the enzyme-specific priorities, metabolic stability is crucial.

Output:
1
2025-04-17 16:19:02,352 - INFO - Batch 453 complete. Total preferences: 7248
2025-04-17 16:19:02,352 - INFO - Processing batch 454/512...
2025-04-17 16:19:41,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.44 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold, while Ligand B (101.49) is still acceptable but higher.

**logP:** Ligand A (2.318) is optimal (1-3). Ligand B (0.336) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the limit of 5.

**H-Bond Acceptors:** Ligand A (3) is good, while Ligand B (6) is also within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.625 and 0.764), indicating drug-like properties.

**DILI:** Ligand A (18.34) has a much lower DILI risk than Ligand B (56.029), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (85.111) has a better score than Ligand B (59.325).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.69) is slightly better than Ligand B (-4.891).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.268) is slightly better than Ligand B (-1.497).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.535 and 0.077), which is excellent.

**Microsomal Clearance:** Ligand B (8.488) has significantly lower microsomal clearance than Ligand A (34.496), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-5.64) has a slightly better (less negative) in vitro half-life than Ligand A (-18.928), indicating potentially better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.012).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-5.3 kcal/mol). This is a substantial difference (over 3 kcal/mol), and is a major factor.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity (-8.3 vs -5.3 kcal/mol) and better metabolic stability (lower Cl_mic and better half-life). While Ligand A has a lower DILI risk and slightly better solubility and permeability predictions, the potency and metabolic stability advantages of Ligand B are more critical for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor concern that could be addressed through further optimization.

Output:
1
2025-04-17 16:19:41,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.439 Da and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.76) is well below the 140 threshold, suggesting good absorption. Ligand B (87.91) is still acceptable, but less optimal.

**logP:** Ligand A (2.871) is within the optimal 1-3 range. Ligand B (0.66) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (1 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.845 and 0.727, respectively), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (30.942 and 36.099 percentiles), which is favorable.

**BBB:** Ligand A (83.288) shows better BBB penetration potential than Ligand B (64.986), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.424 and -4.894). This is unusual and suggests a potential issue with in vitro permeability assessment. However, it's not definitive without further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.286 and -0.804). This is also concerning and suggests poor aqueous solubility, which could limit bioavailability.

**hERG Inhibition:** Ligand A (0.366) has a very low hERG risk, which is excellent. Ligand B (0.153) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (55.597 mL/min/kg) has a higher clearance than Ligand B (14.799 mL/min/kg). This indicates that Ligand B is likely to have better metabolic stability.

**In vitro Half-Life:** Ligand A (40.595 hours) has a much longer half-life than Ligand B (1.623 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.336) has lower P-gp efflux liability than Ligand B (0.009), suggesting better oral bioavailability.

**Binding Affinity:** Ligand B (-7.5 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.

**Conclusion:**

While Ligand A has better solubility, lower hERG risk, and a longer half-life, Ligand B's significantly stronger binding affinity (-7.5 vs -9.2 kcal/mol) is the most crucial factor for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic) of Ligand B is also a significant benefit. The solubility and permeability issues (negative Caco-2 and solubility values) are concerns, but could potentially be addressed through formulation strategies. The difference in binding affinity is large enough to prioritize Ligand B.

Output:
1
2025-04-17 16:19:41,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.415 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (56.59) is well within the range.

**logP:** Ligand A (-0.426) is a bit low, potentially hindering permeation. Ligand B (2.316) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, both acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.639 and 0.774), indicating drug-likeness.

**DILI:** Ligand A (16.596) has a much lower DILI risk than Ligand B (47.887), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (72.082) has a higher BBB score than Ligand A (28.073), but this isn't a primary concern here.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.961 and -4.904). This suggests potential absorption issues for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.58 and -3.276). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG:** Ligand A (0.143) has a very low hERG risk, a major advantage. Ligand B (0.213) is also relatively low, but higher than A.

**Microsomal Clearance:** Ligand A (13.715) has significantly lower microsomal clearance than Ligand B (82.17), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.683) has a shorter half-life than Ligand B (-7.418, which is a negative value indicating a very long half-life). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.008 and 0.147).

**Binding Affinity:** Ligand A (-10.1) has a significantly stronger binding affinity than Ligand B (-7.2). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Ligand A is the more promising candidate. While it has a slightly lower logP and Caco-2 permeability, its significantly stronger binding affinity (-10.1 vs -7.2 kcal/mol), much lower DILI risk, and better metabolic stability (lower Cl_mic) are crucial advantages for an enzyme inhibitor. The low hERG risk is also a significant positive. The poorer solubility and permeability are concerns, but could be addressed through formulation. The superior potency and safety profile of Ligand A make it the better choice.

Output:
1
2025-04-17 16:19:41,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.393 and 349.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (71.09) is still acceptable but higher.

**logP:** Both ligands have good logP values (3.606 and 3.119), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the HBD <=5 criteria.

**H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED scores (0.512 and 0.757), indicating good drug-like properties.

**DILI:** Ligand A (60.954) has a higher DILI risk than Ligand B (35.673). This is a significant concern.

**BBB:** Both ligands have reasonable BBB penetration (90.617 and 73.245), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with absorption prediction. However, we'll proceed assuming these are percentile scores, and higher is better.

**Solubility:** Ligand A (-4.54) has worse solubility than Ligand B (-2.715). Solubility is important for bioavailability.

**hERG:** Ligand A (0.445) has a slightly higher hERG risk than Ligand B (0.288), but both are relatively low.

**Microsomal Clearance:** Ligand A (95.92) has *very* high microsomal clearance, indicating poor metabolic stability. Ligand B (19.981) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (-9.888) has a very short half-life, consistent with the high clearance. Ligand B (20.671) has a longer half-life.

**P-gp Efflux:** Ligand A (0.329) has lower P-gp efflux than Ligand B (0.082), which is favorable.

**Binding Affinity:** Ligand B (-7.8 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 be considered.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better P-gp efflux, its significantly higher DILI risk, very high microsomal clearance, and short half-life are major drawbacks. Ligand B has a much more favorable safety profile (lower DILI), better metabolic stability (lower clearance, longer half-life), and comparable binding affinity. The solubility of Ligand B is also better.

Output:
1
2025-04-17 16:19:41,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.39 and 348.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (84.42) is still under 140, but less optimal than A.

**logP:** Ligand A (4.864) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.649) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1 each). Ligand B has a slightly higher HBA count (5) compared to A (2), but both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.786 and 0.81), indicating drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (53.78 and 50.29), below the concerning threshold of 60.

**BBB:** Ligand A has a much higher BBB penetration percentile (88.87) than Ligand B (62.23). While SRC isn't a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.533) and Ligand B (-4.834) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these are likely logP-scaled values where negative values indicate low permeability.

**Aqueous Solubility:** Ligand A (-5.26) and Ligand B (-2.519) both have negative solubility values, indicating poor solubility. Ligand B is better here.

**hERG:** Ligand A (0.694) has a slightly higher hERG risk than Ligand B (0.201), but both are reasonably low.

**Microsomal Clearance:** Ligand A (28.998) has a lower Cl_mic than Ligand B (40.041), indicating better metabolic stability, which is a key priority for enzymes.

**In vitro Half-Life:** Ligand B (14.726 hours) has a significantly longer half-life than Ligand A (4.073 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.424) has lower P-gp efflux than Ligand B (0.084), which is better.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is highly significant.

**Conclusion:**

Despite Ligand A having better TPSA and P-gp efflux, Ligand B is the superior candidate. The dramatically stronger binding affinity (-8.5 vs 0 kcal/mol) outweighs the slightly higher logP and lower TPSA. The longer half-life of Ligand B is also a significant advantage. While both have poor solubility and permeability, the potency advantage of B is crucial for an enzyme target.

Output:
1
2025-04-17 16:19:41,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.387 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.78) is slightly higher than Ligand B (84.42). Both are acceptable, but Ligand B is better, being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.816) is a bit low, potentially hindering permeation. Ligand B (1.319) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Both are acceptable, but Ligand B is preferable.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.629 and 0.869), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (49.709) and Ligand B (52.656) both have low DILI risk, both below the 60 threshold.

**BBB:** Both have reasonable BBB penetration (63.203 and 68.282), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative (-5.186 and -4.817), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative (-2.571 and -1.555), indicating poor solubility. This is a concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.217 and 0.102). This is excellent for both.

**Microsomal Clearance:** Ligand A (15.318) has a higher microsomal clearance than Ligand B (9.965), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (-7.021) has a much longer in vitro half-life than Ligand B (1.64), which is a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux (0.008 and 0.013), which is good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-5.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is the superior candidate. Its significantly stronger binding affinity (-8.7 vs -5.9 kcal/mol), better logP, lower HBD, better QED, and lower microsomal clearance outweigh the slightly longer half-life of Ligand A. The potency advantage is substantial and crucial for an enzyme inhibitor.

Output:
1
2025-04-17 16:19:41,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.495 Da and 340.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.85) is better than Ligand B (58.2), both are acceptable but A is closer to the optimal <140 for oral absorption.

**logP:** Both ligands have similar logP values (2.687 and 2.733), both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.813) has a significantly better QED score than Ligand B (0.618), indicating a more drug-like profile.

**DILI:** Ligand A (49.632) has a higher DILI risk than Ligand B (24.351). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (77.007 and 71.539), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar negative Caco-2 values (-4.443 and -4.573), suggesting poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.752 and -3.59), indicating poor aqueous solubility, which is a concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.458 and 0.565).

**Microsomal Clearance:** Ligand B (50.4) has a slightly lower microsomal clearance than Ligand A (45.14), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.505) has a significantly longer in vitro half-life than Ligand A (36.703), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.214 and 0.099).

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). While A has a better affinity, the difference is not substantial enough to overcome the other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility and permeability issues, Ligand B has a significantly better DILI score, longer half-life, and slightly better metabolic stability. The slightly better binding affinity of Ligand B, combined with its superior ADME properties, makes it the preferred choice. Ligand A's high DILI risk is a major concern.

Output:
1
2025-04-17 16:19:41,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.334 and 360.801 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.38 and 99.87) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.201) is within the optimal 1-3 range. Ligand B (2.58) is also within range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=4) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Ligand A (0.724) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk, with Ligand A at 90.617 and Ligand B at 84.955. This is a concern for both, but not a deciding factor at this stage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (57.464) has a slightly better BBB score than Ligand B (35.052).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.846) is slightly better than Ligand B (-5.214).

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.134 and -3.582). This is a significant drawback for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.199 and 0.357), which is excellent.

**Microsomal Clearance:** Ligand A (18.273 mL/min/kg) has significantly lower microsomal clearance than Ligand B (60.818 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage.

**In vitro Half-Life:** Ligand A (-22.712 hours) has a negative half-life, which is unusual and likely indicates rapid degradation. Ligand B (17.651 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.083 and 0.118).

**Binding Affinity:** Both ligands have strong binding affinities (-9.1 and -8.1 kcal/mol). Ligand A has a 1 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A has a better QED score, slightly better Caco-2 permeability, significantly lower microsomal clearance (better metabolic stability), and a 1 kcal/mol stronger binding affinity. While both have poor solubility and high DILI risk, the improved metabolic stability and binding affinity of Ligand A outweigh these drawbacks. The negative half-life is concerning, but could be addressed through structural modifications. Ligand B's higher clearance is a major disadvantage.

Output:
0
2025-04-17 16:19:41,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.403 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.78) is better than Ligand B (67.87) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Both ligands have good logP values (2.03 and 1.868), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand B (1 HBD, 4 HBA) is slightly better than Ligand A (2 HBD, 6 HBA) in terms of H-bonding potential, being closer to the ideal limits.

**QED:** Both ligands have acceptable QED scores (0.809 and 0.724), indicating good drug-likeness.

**DILI:** Ligand B (11.865) has a significantly lower DILI risk than Ligand A (54.207), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (81.233) is slightly better than Ligand B (76.231). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.65) is slightly better than Ligand B (-4.833).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-1.349) is slightly better than Ligand A (-3.102).

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.197 and 0.304), which is excellent.

**Microsomal Clearance:** Ligand A (19.006 mL/min/kg) has lower microsomal clearance than Ligand B (25.308 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (53.536 hours) has a significantly longer in vitro half-life than Ligand B (17.003 hours), a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.02).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), which is a crucial factor. The difference of 0.3 kcal/mol is significant enough to consider.

**Overall Assessment:**

While Ligand A has better TPSA, BBB, and metabolic stability (lower Cl_mic, longer t1/2), Ligand B excels in DILI risk and, critically, binding affinity. The lower DILI risk is a substantial benefit, and the slightly stronger binding affinity of Ligand B outweighs the advantages of Ligand A, especially considering the enzyme target class. The solubility and permeability issues are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:19:41,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (70.81) is still under 140, but less optimal than A.

**logP:** Both ligands (1.598 and 1.942) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**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 good QED scores (0.707 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (15.936) has a significantly lower DILI risk than Ligand B (39.356). This is a major advantage for Ligand A.

**BBB:** While not crucial for a non-CNS target like SRC, Ligand A (93.563) has a higher BBB penetration than Ligand B (72.237).

**Caco-2 Permeability:** Ligand A (-4.179) shows better Caco-2 permeability than Ligand B (-4.686).

**Aqueous Solubility:** Ligand A (-1.867) has slightly better aqueous solubility than Ligand B (-1.488).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.364 and 0.534).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (57.078 and 56.097 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (25.021) has a slightly longer in vitro half-life than Ligand B (21.147).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.044 and 0.183).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is only 0.6 kcal/mol, which is not a huge advantage considering the other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A excels in several critical ADME properties: significantly lower DILI risk, better Caco-2 permeability, and slightly better solubility and half-life. The difference in binding affinity (0.6 kcal/mol) is not substantial enough to outweigh the superior ADME profile of Ligand A, especially considering the importance of metabolic stability and minimizing toxicity for an enzyme target like SRC kinase.

Output:
0
2025-04-17 16:19:41,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (345.443 and 344.39 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.6) is better than Ligand B (78.09). Both are below 140, which is good for oral absorption, but lower is generally preferred.

**3. logP:** Ligand A (3.927) is slightly higher than Ligand B (1.899). Ligand A is approaching the upper limit of optimal (1-3), while Ligand B is closer to the lower limit.

**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 (3). Lower is generally preferred.

**6. QED:** Both ligands have similar QED values (0.826 and 0.813), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (54.168 and 51.725), both below the 60 threshold.

**8. BBB:** Ligand B (77.976) has a higher BBB percentile than Ligand A (62.854). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.529 and -4.558), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.96 and -2.909), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.318) has a lower hERG inhibition risk than Ligand B (0.447), which is preferable.

**12. Microsomal Clearance:** Ligand B (4.566) has significantly lower microsomal clearance than Ligand A (103.281). Lower clearance indicates better metabolic stability, a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-19.292) has a much longer in vitro half-life than Ligand A (-2.724). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.188), which is preferable.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This difference of 2.3 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

While both compounds have significant issues with solubility and permeability, Ligand B is the more promising candidate. Its substantially stronger binding affinity (-8.9 vs -6.6 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme inhibitor. The better half-life and affinity are likely to outweigh the slightly higher logP and P-gp efflux. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the core potency and stability profile of Ligand B is superior.

Output:
1
2025-04-17 16:19:41,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 391.94 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (47.36), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.69 and 3.456), 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.

**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, <=10 HBA).

**QED:** Both ligands have QED values above 0.5 (0.511 and 0.477), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (39.201 and 35.75), well below the 60 threshold.

**BBB:** Ligand B (92.555) has a much higher BBB penetration percentile than Ligand A (66.925). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-5.029) has a worse Caco-2 permeability than Ligand B (-4.365).

**Aqueous Solubility:** Ligand A (-2.959) has worse aqueous solubility than Ligand B (-4.768).

**hERG:** Both ligands have low hERG inhibition risk (0.375 and 0.472).

**Microsomal Clearance:** Ligand B (97.103) has significantly higher microsomal clearance than Ligand A (48.477), indicating lower metabolic stability. This is a critical drawback for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-5.156) has a much longer in vitro half-life than Ligand B (10.239), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.104 and 0.489).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). The difference is 0.7 kcal/mol, which is substantial.

**Conclusion:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The significantly better metabolic stability (lower Cl_mic, longer half-life) and better solubility of Ligand A outweigh the slightly weaker binding. SRC inhibitors often require sustained exposure, making metabolic stability a crucial factor. The difference in binding affinity, while noticeable, is not so large that it overrides the ADME advantages of Ligand A.

Output:
0
2025-04-17 16:19:41,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.441 and 370.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, suggesting good absorption. Ligand B (123.41) is still within acceptable limits, but higher than A.

**logP:** Ligand A (2.919) is optimal (1-3). Ligand B (-1.403) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) and Ligand B (2 HBD, 5 HBA) are both within acceptable ranges.

**QED:** Both ligands have similar QED values (0.782 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (13.804 percentile) has a significantly lower DILI risk than Ligand B (58.434 percentile). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (93.563) shows better penetration than Ligand B (22.024), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.483) has poor Caco-2 permeability, while Ligand B (-5.472) is also poor.

**Aqueous Solubility:** Ligand A (-3.484) has better solubility than Ligand B (-2.059).

**hERG:** Ligand A (0.674) has a lower hERG risk than Ligand B (0.033). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (46.117 mL/min/kg) has a higher clearance than Ligand B (-12.228 mL/min/kg), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (3.575 hours) has a longer half-life than Ligand A (-23.86 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.193 and 0.006).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.4 and -8.4 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has advantages in terms of DILI risk, hERG inhibition, solubility, and logP. However, it suffers from poor Caco-2 permeability and lower metabolic stability (higher clearance, shorter half-life). Ligand B has better metabolic stability and half-life, but has a concerningly low logP, higher DILI risk, and a higher hERG risk.

Given the enzyme-specific priorities, metabolic stability is important. However, the significantly lower DILI and hERG risks associated with Ligand A are crucial factors. The slightly lower metabolic stability of Ligand A can be addressed through structural modifications during lead optimization. The poor logP of Ligand B is a more difficult property to improve without significantly altering the binding affinity.

Output:
0
2025-04-17 16:19:41,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.4 and 386.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.2) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (69.6) is well within the optimal range.

**logP:** Ligand A (-1.29) is a bit low, potentially hindering permeation. Ligand B (1.92) is 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 4. Both are acceptable.

**QED:** Both ligands have good QED scores (0.654 and 0.829), indicating good drug-like properties.

**DILI:** Ligand A (30.3) has a significantly lower DILI risk than Ligand B (52.1), a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B has a higher BBB percentile (55.3) than Ligand A (20.9), but this is less critical.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.074 and -4.967). This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Ligand A (0.164) has very poor solubility, a significant drawback. Ligand B (-3.569) also has poor solubility, but it is comparatively better than Ligand A.

**hERG:** Both ligands have very low hERG risk (0.077 and 0.488), which is excellent.

**Microsomal Clearance:** Ligand A (-9.924) shows excellent metabolic stability (low clearance), a significant advantage. Ligand B (6.984) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-17.97) has a very long half-life, further supporting its metabolic stability. Ligand B (-7.87) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.534), which is favorable.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.3 and -8.1 kcal/mol), which are both excellent and above the -7.0 threshold. The difference of 0.2 kcal/mol is not substantial enough to be a deciding factor.

**Conclusion:**

While both ligands have good binding affinity and low hERG risk, Ligand A is the more promising candidate due to its significantly lower DILI risk and superior metabolic stability (lower Cl_mic and longer t1/2). The poor solubility and Caco-2 permeability are drawbacks for both, but the metabolic advantages of Ligand A outweigh the slightly lower logP and TPSA.

Output:
0
2025-04-17 16:19:41,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.414 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.16) is well below the 140 threshold for good absorption, while Ligand B (98.76) is still acceptable but approaching the upper limit.

**logP:** Ligand A (3.114) is optimal (1-3). Ligand B (0.343) is quite low, potentially hindering permeation.

**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 good QED scores (0.672 and 0.769, respectively), indicating good drug-likeness.

**DILI:** Ligand A (85.615) has a significantly higher DILI risk than Ligand B (31.601). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (84.839) has a higher value than Ligand B (20.512).

**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:** Both ligands have low hERG inhibition risk (0.379 and 0.41, respectively).

**Microsomal Clearance:** Ligand A (73.855) has a higher, but still reasonable, clearance than Ligand B (-2.455). The negative value for Ligand B is unusual and could indicate very high stability, but is suspect.

**In vitro Half-Life:** Ligand A (26.821) has a reasonable half-life. Ligand B (-17.186) has a negative half-life, which is impossible and indicates a problem with the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.271 and 0.126, respectively).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), but the difference is not huge.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate despite its low logP and questionable solubility/permeability data. The extremely high DILI risk associated with Ligand A is a major red flag. Furthermore, the negative half-life for Ligand B is concerning, but potentially a data error. The slightly better affinity of Ligand A is not enough to overcome the substantial DILI risk. The low logP of Ligand B is a concern, but can be addressed with structural modifications.

Output:
1
2025-04-17 16:19:41,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 102.76, which is acceptable for oral absorption (<=140) but not optimized for CNS penetration (<=90). This isn't a primary concern for a non-CNS target like SRC.

**logP:** Ligand A (-0.219) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (0.88) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 5 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have QED values above 0.5 (0.66 and 0.581), indicating good drug-like properties.

**DILI:** Ligand A (21.675) has a significantly lower DILI risk than Ligand B (17.255), which is a major advantage.

**BBB:** Both have low BBB penetration (25.475 and 26.018), which is not a concern for a non-CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.314 and -5.178), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.464 and -0.9), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.037) has a very low hERG risk, while Ligand B (0.259) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-8.185) has a much lower (better) microsomal clearance than Ligand B (8.668), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-6.828) has a longer in vitro half-life than Ligand B (21.801), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.027).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its significantly lower DILI risk and superior metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP. The equal binding affinity is a tiebreaker in favor of the better ADME profile of Ligand A. The poor solubility and permeability would need to be addressed through formulation strategies, but the lower toxicity and better metabolic profile make Ligand A a more viable starting point.

Output:
0
2025-04-17 16:19:41,298 - INFO - Batch 454 complete. Total preferences: 7264
2025-04-17 16:19:41,298 - INFO - Processing batch 455/512...
2025-04-17 16:20:20,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.462 Da) is slightly higher than Ligand B (336.435 Da), but both are acceptable.

**TPSA:** Ligand A (62.74) is higher than Ligand B (49.41). Both are below the 140 threshold for oral absorption, which is good.

**logP:** Ligand A (3.525) is slightly higher than Ligand B (2.663), both are within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.815) has a significantly higher QED score than Ligand B (0.679), indicating a more drug-like profile.

**DILI:** Ligand A (50.174) has a slightly higher DILI risk than Ligand B (42.264), but both are below the concerning threshold of 60.

**BBB:** Ligand A (83.443) has a higher BBB penetration percentile than Ligand B (63.203). While not a primary concern for a kinase inhibitor, higher BBB is not detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.273) is slightly better than Ligand B (-4.603).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.979) is slightly better than Ligand B (-4.153).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.424 and 0.223, respectively).

**Microsomal Clearance:** Ligand A (85.547) has a significantly higher microsomal clearance than Ligand B (16.808). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (5.396 hours) has a longer in vitro half-life than Ligand A (-4.79 hours). The negative value for Ligand A is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.322 and 0.109, respectively).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a crucial advantage, as a 1.2 kcal/mol difference is substantial.

**Conclusion:**

Despite Ligand A's better QED and slightly better permeability/solubility, Ligand B is the superior candidate. The significantly stronger binding affinity (-8.5 vs -7.3 kcal/mol) outweighs the drawbacks of slightly lower QED and permeability. More importantly, Ligand B demonstrates much better metabolic stability (lower Cl_mic, longer t1/2) which is a critical factor for kinase inhibitors. The negative half-life of Ligand A is a major red flag.

Output:
1
2025-04-17 16:20:20,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.435 and 349.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.84) is slightly higher than Ligand B (64.52). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have good logP values (1.331 and 2.382), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.705 and 0.703), indicating good drug-likeness.

**DILI:** Ligand A (38.852) has a slightly higher DILI risk than Ligand B (10.198). Ligand B is clearly preferable here.

**BBB:** Ligand A (62.854) has a lower BBB penetration percentile than Ligand B (76.696). This isn't a primary concern for a non-CNS target like SRC, but it's a positive for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.396) has worse Caco-2 permeability than Ligand B (-5.013). Both are negative, which is unusual and requires further investigation, but B is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.352 and -1.153). This is a potential issue for bioavailability, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.25) has a lower hERG inhibition risk than Ligand B (0.945). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (17.551) has a higher microsomal clearance than Ligand B (12.304), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (45.542) has a significantly longer in vitro half-life than Ligand A (31.889). This is a major advantage for Ligand B, suggesting less frequent dosing.

**P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux than Ligand B (0.074), which is favorable.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a 0.8 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand A has a better binding affinity and lower P-gp efflux, Ligand B excels in several critical ADME properties. Specifically, its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and improved Caco-2 permeability are compelling advantages. The difference in binding affinity (0.8 kcal/mol) is significant, but can potentially be overcome with further optimization. The hERG risk is higher for Ligand B, but not prohibitively so. Considering the enzyme-specific priorities, Ligand B appears to be the more viable drug candidate due to its superior ADME profile and acceptable potency.

Output:
1
2025-04-17 16:20:20,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (408.252 Da) is still acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential (Ligand A: 81.67, Ligand B: 78.86).

**logP:** Ligand A (1.036) is within the optimal range, while Ligand B (3.757) is approaching the upper limit. Higher logP can sometimes lead to solubility issues and off-target interactions, but is not a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (0 HBD, 7 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (A: 0.61, B: 0.599), indicating reasonable drug-likeness.

**DILI:** Ligand A (4.382) has a significantly lower DILI risk than Ligand B (79.449). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (77.898) is slightly higher than Ligand A (68.127). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.205) has significantly better Caco-2 permeability than Ligand B (-4.933).

**Aqueous Solubility:** Ligand A (-1.923) has better aqueous solubility than Ligand B (-3.885).

**hERG:** Both ligands have similar, low hERG inhibition liability (A: 0.34, B: 0.325).

**Microsomal Clearance:** Ligand A (-3.238) has a much lower (better) microsomal clearance than Ligand B (81.085), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.342) has a significantly longer in vitro half-life than Ligand B (62.897).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.008, B: 0.401).

**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 notable, but not overwhelming.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties: significantly lower DILI risk, better solubility, much better metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. These factors are crucial for a successful kinase inhibitor, outweighing the modest difference in binding affinity. The lower DILI risk alone is a significant advantage.

Output:
0
2025-04-17 16:20:20,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.441 and 345.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (73.2). Lower TPSA generally correlates with better cell permeability. Both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.323 and 2.689), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) has fewer H-bonds than Ligand B (HBD=1, HBA=3). Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.689 and 0.861), indicating good drug-like properties.

**DILI:** Ligand A (32.067) has a lower DILI risk than Ligand B (43.195), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (84.064 and 81.698), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.7 and -4.597). 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 (-4.064 and -3.764). This is also concerning, and suggests poor solubility. Again, they are similarly poor.

**hERG:** Ligand A (0.582) has a lower hERG inhibition liability than Ligand B (0.848), which is a significant advantage.

**Microsomal Clearance:** Ligand A (37.39) has lower microsomal clearance than Ligand B (51.88), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.103) has a longer in vitro half-life than Ligand B (-3.249). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.163 and 0.234).

**Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.5). This is a 0.4 kcal/mol difference, which is not huge, but noticeable.

**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 lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and better TPSA. The solubility and Caco-2 values are poor for both, but similar. Given the enzyme-kinase focus, the improved metabolic stability and reduced toxicity of Ligand A are more important than the minor affinity difference.

Output:
1
2025-04-17 16:20:20,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.308 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**TPSA:** Ligand A (71.7) is better than Ligand B (96.33). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.691) is optimal, while Ligand B (0.362) is quite low. A low logP can hinder membrane permeability.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.682 and 0.665), indicating good drug-likeness.

**DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (49.477). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (50.679) is slightly higher than Ligand A (28.344), but this is not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.953) is slightly better than Ligand B (-5.032), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.436) is slightly better than Ligand B (-2.361).

**hERG:** Ligand A (0.763) has a lower hERG risk than Ligand B (0.051), which is a significant advantage.

**Microsomal Clearance:** Ligand A (73.516) has a higher (worse) microsomal clearance than Ligand B (-1.149). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (102.195) has a longer half-life than Ligand B (-6.903), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.63) has lower P-gp efflux than Ligand B (0.01). Lower efflux is generally preferred.

**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 and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor for an enzyme inhibitor. It also has better metabolic stability and slightly better solubility. However, it suffers from a very low logP, higher DILI risk, and a very low hERG score. Ligand A has a better logP, lower DILI and hERG, and a longer half-life, but its binding affinity is weaker and it has higher clearance.

Given the significant potency advantage of Ligand B, and the fact that the other issues *could* be addressed through further optimization, I would choose Ligand B as the more promising candidate. The potency difference is substantial enough to warrant prioritizing it for further development.

Output:
1
2025-04-17 16:20:20,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.372 and 351.535 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (52.65). Both are acceptable, being under 140, but lower TPSA generally favors absorption.

**3. logP:** Both ligands have good logP values (3.743 and 2.65), 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 HBAs, while Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.823 and 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A (37.922) has a much lower DILI risk than Ligand B (7.096). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (91.508) has a higher BBB penetration percentile than Ligand B (64.482). While not critical for a non-CNS target like SRC, it doesn't hurt.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.232 and -4.854). 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:** Ligand A (-4.84) has slightly better solubility than Ligand B (-1.887), though both are poor. Solubility is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.645 and 0.643).

**12. Microsomal Clearance:** Ligand A (51.296) has a significantly higher microsomal clearance than Ligand B (-1.051). This indicates that Ligand B is much more metabolically stable, a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (33.613) has a longer half-life than Ligand B (0.911). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.361 and 0.077).

**15. 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 factor.

**Overall Assessment:**

Ligand B has a significant advantage in metabolic stability (lower Cl_mic, longer half-life) and slightly better binding affinity. However, Ligand A has a much lower DILI risk and better solubility. Given the enzyme-specific priorities, metabolic stability is crucial. While the solubility of both is poor, the DILI risk of Ligand B is concerning. The small difference in binding affinity is likely outweighed by the better metabolic profile and lower toxicity risk of Ligand A.

Output:
1
2025-04-17 16:20:20,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.407 and 353.373 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.41) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (80.12) is excellent, well below 140.

**logP:** Ligand A (-0.957) is a bit low, potentially hindering permeation. Ligand B (0.68) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is good. Ligand B (1 HBD, 5 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.674 and 0.731, respectively), indicating drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (39.162 and 39.744, both <40).

**BBB:** Ligand A (30.05) has poor BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (76.231) shows better BBB penetration, but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.188) has poor Caco-2 permeability, which is concerning. Ligand B (-4.644) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.671) has poor aqueous solubility, a significant drawback. Ligand B (-2.443) has even worse solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.096 and 0.119), which is excellent.

**Microsomal Clearance:** Ligand A (4.162) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (24.611) has significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (3.347) has a short half-life, but not dramatically so. Ligand B (-25.446) has a very short, and likely problematic, half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.006 and 0.018), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), a difference of 0.5 kcal/mol.

**Conclusion:**

While Ligand A has a slightly better binding affinity, its poor Caco-2 permeability and aqueous solubility are major concerns. Ligand B has better logP and TPSA, but suffers from very poor solubility and a very short half-life due to high clearance. Considering the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and solubility are crucial. Ligand A's lower clearance is a significant advantage, and the 0.5 kcal/mol difference in binding affinity can be overcome with further optimization. The solubility issue with A is a formulation challenge, while B's rapid metabolism is harder to fix.

Output:
0
2025-04-17 16:20:20,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.296 and 340.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is well below the 140 threshold, while Ligand B (86.71) is approaching it. This favors A for better absorption.

**logP:** Both ligands have good logP values (3.289 and 3.037), 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 (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.66 and 0.876), indicating good drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (85.964 and 81.427), but this is not a dealbreaker at this stage.

**BBB:** Ligand A has a higher BBB penetration (71.035) than Ligand B (28.81). While not a primary concern for a non-CNS target like SRC, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.209) has worse Caco-2 permeability than Ligand B (-4.859), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.773) has worse solubility than Ligand B (-2.813). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.635) has a slightly higher hERG risk than Ligand B (0.125). Lower hERG risk is preferred.

**Microsomal Clearance:** Ligand A (113.076) has significantly higher microsomal clearance than Ligand B (5.453). This indicates lower metabolic stability for Ligand A, a major drawback for an enzyme target.

**In vitro Half-Life:** Ligand A (41.595) has a longer half-life than Ligand B (7.497). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.385) has lower P-gp efflux than Ligand B (0.021), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.0 kcal/mol). Ligand A is slightly better (-8.9 kcal/mol).

**Overall Assessment:**

Ligand A has a slightly better binding affinity and better P-gp efflux, but suffers from significantly higher microsomal clearance (lower metabolic stability) and lower solubility. Ligand B has better solubility, lower hERG risk, and *much* better metabolic stability, which is crucial for an enzyme target. The difference in binding affinity (0.9 kcal/mol) is not large enough to outweigh the substantial ADME advantages of Ligand B.

Output:
1
2025-04-17 16:20:20,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.411 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.39) is better than Ligand B (128.32). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range.

**logP:** Ligand A (2.873) is optimal (1-3). Ligand B (0.789) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (7) and Ligand B (5) are both acceptable (<=10).

**QED:** Both ligands have good QED scores (A: 0.579, B: 0.619), indicating good drug-like properties.

**DILI:** Ligand A (86.545) has a higher DILI risk than Ligand B (47.034). This is a significant concern for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand B (67.08) is slightly better than Ligand A (58.007). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.768) has poor Caco-2 permeability, while Ligand B (-5.475) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.178) has poor solubility, while Ligand B (-2.532) is better. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.395) has a slightly higher hERG risk than Ligand B (0.502), but both are relatively low.

**Microsomal Clearance:** Ligand A (68.97) has a higher clearance than Ligand B (-19.719). Ligand B exhibits *negative* clearance, which is unusual and likely an artifact of the prediction model, but suggests very high metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (5.018) has a shorter half-life than Ligand B (9.044). This supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Ligand A (0.395) has lower P-gp efflux than Ligand B (0.028). Lower efflux is generally preferred.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.5 kcal/mol, B: -9.5 kcal/mol). Ligand B is slightly better, but the difference is not huge.

**Conclusion:**

While Ligand A has a slightly better P-gp efflux profile, Ligand B is significantly better overall. Its superior metabolic stability (negative Cl_mic, longer half-life), lower DILI risk, and better solubility outweigh the minor advantage of Ligand A in P-gp efflux. The slightly better affinity of Ligand B is also a plus. Given the enzyme-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 16:20:20,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.439 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.67) is higher than Ligand B (61.88). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cellular permeability.

**logP:** Both ligands have good logP values (1.948 and 1.417), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.759 and 0.753), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 66.576, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 21.869, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (65.607) has a higher BBB percentile than Ligand A (28.15), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.62) has poor Caco-2 permeability, while Ligand B (-4.753) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-3.835) has poor aqueous solubility, while Ligand B (-1.085) is better, but still not ideal.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.45 and 0.451), which is good.

**Microsomal Clearance:** Ligand A (-13.105) has lower (better) microsomal clearance than Ligand B (27.532), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (19.02 hours) has a significantly longer half-life than Ligand A (2.45 hours), a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.032).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -8.9 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While both ligands have good potency, Ligand B is the superior candidate. Its significantly lower DILI risk, longer half-life, and better TPSA/solubility profile outweigh the slightly higher microsomal clearance and lower Caco-2 permeability. Ligand A's poor solubility and high DILI risk are major drawbacks.

Output:
1
2025-04-17 16:20:20,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.459 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly higher than Ligand B (58.2). Both are below the 140 threshold for good oral absorption, but lower is generally better.

**3. logP:** Ligand A (2.144) is within the optimal 1-3 range. Ligand B (3.323) is at the higher end, potentially raising concerns about off-target effects, but still acceptable.

**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 higher than Ligand B (2). Lower HBA is preferred.

**6. QED:** Both ligands have good QED scores (0.609 and 0.726), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (30.981 and 27.453), which is excellent.

**8. BBB:** Ligand A (74.758) has a better BBB percentile than Ligand B (49.864). While SRC is not a CNS target, higher BBB is rarely detrimental.

**9. Caco-2:** Ligand A (-5.114) and Ligand B (-4.966) have negative values, which is unusual. This suggests poor Caco-2 permeability for both.

**10. Solubility:** Ligand A (-1.03) has better solubility than Ligand B (-4.152). Solubility is important for bioavailability.

**11. hERG:** Both ligands have very low hERG risk (0.446 and 0.271). This is a significant advantage.

**12. Cl_mic:** Ligand B (18.961) has a lower microsomal clearance than Ligand A (26.313), indicating better metabolic stability. This is a critical factor for enzyme inhibitors.

**13. t1/2:** Ligand B (2.423) has a longer in vitro half-life than Ligand A (-18.565). The negative value for Ligand A is concerning and suggests very rapid metabolism.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.102 and 0.175).

**15. 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 minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better solubility and BBB penetration, Ligand B's superior binding affinity (-7.6 vs -9.5 kcal/mol) and significantly better metabolic stability (lower Cl_mic and longer t1/2) are crucial for an enzyme inhibitor. The slightly higher logP of Ligand B is acceptable given its strong potency. The negative Caco-2 values for both are a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:20:20,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.47 and 360.805 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold and favorable. Ligand B (103.87) is still within acceptable limits for oral absorption, but less optimal than A.

**logP:** Ligand A (3.517) is within the optimal 1-3 range. Ligand B (1.196) is on the lower side, potentially hindering 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, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.833 and 0.855), indicating drug-like properties.

**DILI:** Ligand A (48.042) has a lower DILI risk than Ligand B (69.097), which is approaching a higher risk category.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.443) has better BBB penetration than Ligand B (40.093), but it's not a primary concern here.

**Caco-2 Permeability:** Ligand A (-4.554) and Ligand B (-5.369) 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 (-3.647 and -3.37 respectively), which could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.462) has a very low hERG risk, which is excellent. Ligand B (0.172) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (69.391) has a higher microsomal clearance than Ligand B (-11.298). This means Ligand B is likely to have better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.835) has a significantly longer in vitro half-life than Ligand A (20.033), which is a major advantage.

**P-gp Efflux:** Ligand A (0.444) has lower P-gp efflux than Ligand B (0.058), which is preferable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This difference of 1.4 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and lower DILI risk, Ligand B's significantly stronger binding affinity (-8.5 vs -7.1 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are more critical for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a concern, but the potency advantage is substantial. The poor Caco-2 and solubility for both are formulation challenges that would need to be addressed, but the binding affinity is the most important factor here.

Output:
1
2025-04-17 16:20:20,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.447 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.11) is slightly higher than the preferred <140, but acceptable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (-0.615) is a bit low, potentially hindering permeability. Ligand B (2.267) is optimal.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also good.

**QED:** Both ligands have good QED scores (0.67 and 0.777), indicating drug-likeness.

**DILI:** Ligand A (51.26) 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 have reasonable BBB penetration (66.344 and 69.213), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-4.936 and -4.681), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.39 and -2.872), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.351 and 0.132), which is excellent.

**Microsomal Clearance:** Ligand A (46.653) has lower clearance than Ligand B (65.299), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.674) has a longer half-life than Ligand B (6.134), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.014 and 0.065), which is good.

**Binding Affinity:** Both have similar, strong binding affinities (-8.9 and -8.7 kcal/mol). The difference is negligible.

**Conclusion:**

While both compounds have excellent binding affinity and low hERG risk, Ligand B is superior due to its better logP, lower DILI risk, and lower HBA count. The poor Caco-2 and aqueous solubility are concerning for both, but Ligand B's other properties make it a more promising starting point for optimization. The better logP of Ligand B suggests it might be easier to improve its solubility and permeability through structural modifications.

Output:
1
2025-04-17 16:20:20,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (380.853 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is slightly higher than Ligand B (69.64), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (3.146 and 2.574), 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 3. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.856) has a significantly better QED score than Ligand B (0.67), indicating a more drug-like profile.

**DILI:** Ligand B (10.237) has a much lower DILI risk than Ligand A (89.841). This is a major advantage for Ligand B.

**BBB:** Ligand B (70.26) shows better BBB penetration than Ligand A (25.126), but BBB penetration isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.106) has a negative Caco-2 value, indicating poor permeability. Ligand B (-4.476) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.552) has poor aqueous solubility, while Ligand B (-2.847) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.448) has a slightly lower hERG risk than Ligand B (0.621), but both are relatively low.

**Microsomal Clearance:** Ligand B (77.884) has a significantly higher microsomal clearance than Ligand A (10.424), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (10.769) has a slightly better in vitro half-life than Ligand A (-13.329), but the negative value for A is concerning.

**P-gp Efflux:** Ligand A (0.148) has lower P-gp efflux than Ligand B (0.28), which is favorable.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.7). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has a much better safety profile (lower DILI) and slightly better solubility and half-life, Ligand A's significantly superior binding affinity (-8.0 vs -6.7 kcal/mol) and better P-gp efflux are crucial for an enzyme inhibitor. The lower metabolic stability (higher Cl_mic) of Ligand B is a significant concern. The poor Caco-2 and solubility of both are drawbacks, but can potentially be addressed through formulation strategies. Given the importance of potency for kinase inhibitors, the stronger binding affinity of Ligand A makes it the more promising candidate, despite its higher DILI risk.

Output:
1
2025-04-17 16:20:20,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (333.4 and 347.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.97) is well below the 140 threshold for oral absorption, while Ligand B (105.98) is also acceptable, though slightly higher.

**logP:** Ligand A (2.555) is optimal (1-3). Ligand B (0.523) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (6) are below the 10 threshold.

**QED:** Both ligands have acceptable QED scores (0.797 and 0.6), indicating good drug-likeness.

**DILI:** Ligand A (64.793) has a higher DILI risk than Ligand B (47.693), but both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (50.679) and Ligand B (46.336) are both low.

**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 factors.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.929) has a slightly higher hERG risk than Ligand B (0.017). Ligand B is significantly better here.

**Microsomal Clearance:** Ligand A (51.359) has higher clearance than Ligand B (16.582), suggesting lower metabolic stability. Ligand B is much better.

**In vitro Half-Life:** Ligand A (26.033) has a positive half-life, while Ligand B (-17.141) has a negative half-life, which is nonsensical. This is a major red flag for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.536 and 0.033).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.7 vs -8.9 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand B has lower DILI risk, lower hERG risk, and significantly better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is concerning and needs further investigation, but the overall profile favors it. Ligand A's higher clearance and slightly higher hERG risk are less desirable.

Output:
1
2025-04-17 16:20:20,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.426 Da) is slightly higher than Ligand B (353.438 Da), but both are acceptable.

**TPSA:** Ligand A (106.38) is higher than Ligand B (75.44). While both are below 140, the lower TPSA of Ligand B is preferable for absorption.

**logP:** Both ligands have good logP values (A: 2.683, B: 2.868), 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, but Ligand B is slightly better.

**QED:** Both have good QED scores (A: 0.582, B: 0.818), indicating drug-likeness. Ligand B is significantly better here.

**DILI:** Ligand A has a concerning DILI risk (86.661%), placing it in the high-risk category. Ligand B has a much lower and acceptable DILI risk (38.736%). This is a major advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (63.086%) and Ligand B (90.772%) are both reasonable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the value for Ligand B (-4.262) is less negative than Ligand A (-5.151), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-3.336) is slightly better than Ligand A (-3.004).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.341, B: 0.463), which is good.

**Microsomal Clearance:** Ligand A (13.283 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (65.912 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.112 hours) has a significantly longer half-life than Ligand B (0.697 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.395, B: 0.565).

**Binding Affinity:** Both have excellent binding affinities (A: -8.3 kcal/mol, B: -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life and better metabolic stability, the extremely high DILI risk associated with Ligand A is a major red flag. Ligand B has a much more favorable safety profile (lower DILI), a better QED score, and a slightly better TPSA and Caco-2 permeability. The binding affinities are comparable. Given the enzyme-specific priorities, the lower DILI risk and better overall ADME properties of Ligand B outweigh the slightly longer half-life of Ligand A.

Output:
1
2025-04-17 16:20:20,843 - INFO - Batch 455 complete. Total preferences: 7280
2025-04-17 16:20:20,843 - INFO - Processing batch 456/512...
2025-04-17 16:21:00,317 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (381.925 Da) is slightly higher than Ligand B (333.395 Da), but both are acceptable.

**2. TPSA:** Ligand A (63.24) is better than Ligand B (75.08). Lower TPSA generally favors better absorption.

**3. logP:** Both ligands have good logP values (A: 3.605, B: 2.882), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of 5 (A: 1, B: 2).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of 10 (A: 3, B: 4).

**6. QED:** Both ligands have acceptable QED values (A: 0.813, B: 0.552), indicating good drug-like properties. Ligand A is superior.

**7. DILI:** Ligand B (69.756) has a higher DILI risk than Ligand A (45.095). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (70.997) has better BBB penetration than Ligand B (57.154). While not a primary concern for a kinase inhibitor, it's a slight positive for A.

**9. Caco-2 Permeability:** Ligand A (-4.947) has better Caco-2 permeability than Ligand B (-5.605).

**10. Aqueous Solubility:** Ligand A (-3.399) has better aqueous solubility than Ligand B (-3.553).

**11. hERG Inhibition:** Ligand B (0.917) has a higher hERG inhibition liability than Ligand A (0.31). This is a crucial advantage for Ligand A, as it reduces the risk of cardiotoxicity.

**12. Microsomal Clearance (Cl_mic):** Ligand A (26.845) has lower microsomal clearance than Ligand B (52.193), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand A (37.208) has a longer in vitro half-life than Ligand B (-22.249). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux than Ligand B (0.533), which is favorable for bioavailability.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -8.7 kcal/mol, B: -8.9 kcal/mol). The difference is minimal, and doesn't outweigh the ADME advantages of Ligand A.

**Conclusion:**

Considering the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), Ligand A is the superior candidate. It demonstrates better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, lower DILI risk, better solubility, and comparable binding affinity to Ligand B. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is significantly more favorable.

Output:
0
2025-04-17 16:21:00,317 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.447 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.68) is better than Ligand B (78.51). Both are below 140, suggesting reasonable absorption.

**logP:** Ligand A (0.723) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.94) is within the optimal range.

**H-Bond Donors:** Ligand A (0) is ideal, while Ligand B (2) is acceptable.

**H-Bond Acceptors:** Ligand A (5) is good, and Ligand B (4) is also good.

**QED:** Both ligands have similar QED values (0.755 and 0.691), indicating good drug-likeness.

**DILI:** Ligand A (26.755) has a significantly lower DILI risk than Ligand B (33.501), which is a major advantage. Both are below the 40 threshold.

**BBB:** Both ligands have similar BBB penetration (67.352 and 62.97), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.741) has a worse Caco-2 permeability than Ligand B (-5.179).

**Solubility:** Ligand A (-0.465) has better solubility than Ligand B (-2.178). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.176 and 0.391).

**Microsomal Clearance:** Ligand A (41.265) has a slightly higher microsomal clearance than Ligand B (36.809), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (17.036) has a slightly longer half-life than Ligand B (15.574).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.035 and 0.149).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has a slightly better logP and Caco-2 permeability, Ligand A is superior due to its significantly lower DILI risk and better solubility. Given the enzyme-specific priorities, minimizing toxicity (DILI) and ensuring adequate solubility are crucial. The equal binding affinity removes that as a differentiating factor. Therefore, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 16:21:00,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (331.339 and 348.378 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (88.31 and 87.32) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.22) is within the optimal range (1-3). Ligand B (0.853) is slightly below, which *could* hinder permeation, but isn't a major concern.

**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 (6 and 4, respectively), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.578 and 0.848), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A has a significantly higher DILI risk (95.347 percentile) compared to Ligand B (54.168 percentile). This is a major red flag for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (85.149 and 89.802 percentile), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.077 and -4.904). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading, so we need to consider the other parameters.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.478 and -3.015). This is a significant issue for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.227 and 0.357).

**12. Microsomal Clearance (Cl_mic):** Ligand B has a much lower microsomal clearance (1.645 mL/min/kg) than Ligand A (67.876 mL/min/kg), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (10.154 hours) than Ligand A (22.974 hours). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.529 and 0.033).

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-8.6 kcal/mol) than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and metabolic stability, while Ligand A has a concerningly high DILI risk and poor metabolic stability. Although both have poor solubility, the superior binding affinity and metabolic profile of Ligand B are more crucial.

Output:
1
2025-04-17 16:21:00,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.503 Da) and Ligand B (358.551 Da) are both acceptable.

**TPSA:** Ligand A (87.74) is good for oral absorption, being under 140. Ligand B (28.26) is excellent, well below 140.

**logP:** Ligand A (1.37) is within the optimal range. Ligand B (4.859) is slightly high, 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, both within acceptable limits. Ligand B has 1 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (A: 0.598, B: 0.614), indicating drug-like properties.

**DILI:** Ligand A (33.424) has a low DILI risk. Ligand B (15.2) has an even lower DILI risk, which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (A: 71.307, B: 79.411). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.973) has poor Caco-2 permeability. Ligand B (-5.651) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -2.684, B: -3.332). This is a major concern.

**hERG Inhibition:** Ligand A (0.232) has a very low hERG risk. Ligand B (0.956) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (57.634) has moderate microsomal clearance. Ligand B (49.782) has lower clearance, indicating better metabolic stability, which is crucial for kinases.

**In vitro Half-Life:** Ligand A (-21.73) has a negative half-life, which is not possible and indicates an issue with the data or the molecule. Ligand B (20.623) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.033) has very low P-gp efflux, which is favorable. Ligand B (0.842) has higher P-gp efflux, which could reduce bioavailability.

**Binding Affinity:** Ligand A (-7.7) has a significantly better binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, but suffers from poor Caco-2 permeability and a nonsensical half-life. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and acceptable hERG risk. The solubility of both is very poor. However, the significantly better binding affinity of Ligand A, despite its other drawbacks, is a major factor. The negative half-life for Ligand A is a red flag, but the binding affinity is so much stronger that it could be worth investigating further to understand the source of this data anomaly.

Output:
1
2025-04-17 16:21:00,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (107.37).  A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (0.981) is within the optimal 1-3 range, while Ligand B (-0.321) is slightly below 1. While not a hard cutoff, lower logP can sometimes indicate permeability issues.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 7.  Ligand A is better here, as higher HBA can sometimes hinder permeability.

**QED:** Ligand B (0.754) has a better QED score than Ligand A (0.443), indicating a more drug-like profile overall.

**DILI:** Ligand A (23.226) has a much lower DILI risk than Ligand B (67.39). This is a significant advantage for Ligand A.

**BBB:** Both have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand A (52.268) is slightly better than Ligand B (47.15).

**Caco-2 Permeability:** Ligand A (-4.612) shows poor Caco-2 permeability, while Ligand B (-5.331) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.056) has slightly better solubility than Ligand B (-1.69), although both are quite low.

**hERG Inhibition:** Ligand A (0.044) has a much lower hERG risk than Ligand B (0.103). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand B (21.077) has lower microsomal clearance than Ligand A (29.294), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (10.781) has a significantly longer in vitro half-life than Ligand A (-17.421). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a *much* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive factor. A difference of 8.3 kcal/mol is enormous and likely outweighs many of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI/hERG risk. While Ligand B has better metabolic stability and QED, the potency advantage of Ligand A is so large that it is likely to be the better drug candidate. The poor Caco-2 and solubility of Ligand A would need to be addressed in further optimization, but the strong binding is a crucial starting point.

Output:
0
2025-04-17 16:21:00,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.422 Da) is slightly lower, which could be beneficial for permeability. Ligand B (378.567 Da) is also good.

**TPSA:** Ligand A (89.87) is excellent, well below the 140 threshold for oral absorption. Ligand B (58.12) is also very good.

**logP:** Ligand A (0.508) is a bit low, potentially hindering permeation. Ligand B (3.299) 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 4 HBA, which is acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.686 and 0.605), indicating good drug-likeness.

**DILI:** Ligand A (15.238) has a much lower DILI risk than Ligand B (62.35). This is a major advantage for Ligand A.

**BBB:** Ligand B (79.566) shows better BBB penetration than Ligand A (52.268), but BBB is not a primary concern for a non-CNS target like SRC.

**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. This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.391 and 0.652), which is good.

**Microsomal Clearance:** Ligand A (-0.502) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand B (92.874) has very high clearance, suggesting rapid metabolism. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (8.699 hours) has a better half-life than Ligand B (-1.491 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.451), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.9 and -9.7 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate**. While Ligand B has a better logP, Ligand A excels in crucial areas for an enzyme target: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and higher t1/2), and comparable binding affinity. The slightly lower logP of Ligand A is a manageable issue compared to the high metabolic clearance of Ligand B. The poor solubility and Caco-2 values are concerns for both, but can be addressed during formulation.

Output:
0
2025-04-17 16:21:00,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.5 and 347.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (89.9 and 84.6) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.86 and 1.54) 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.71 and 0.79), indicating drug-like properties.

**DILI:** Ligand A (36.3) has a significantly lower DILI risk than Ligand B (7.1). This is a major advantage for Ligand A.

**BBB:** Ligand A (19.0) has a much lower BBB penetration than Ligand B (68.7). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.82) has lower Caco-2 permeability than Ligand B (-4.77), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.58) has slightly lower solubility than Ligand B (-1.30), but both are quite poor.

**hERG Inhibition:** Ligand A (0.047) has a lower hERG risk than Ligand B (0.474), which is a significant advantage.

**Microsomal Clearance:** Ligand A (8.73) has a lower microsomal clearance than Ligand B (-11.66). This indicates better metabolic stability for Ligand A, a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-20.52) has a significantly longer in vitro half-life than Ligand B (2.89). This is a substantial advantage for Ligand A, suggesting less frequent dosing.

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux than Ligand B (0.02), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.7 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. While Ligand B has better Caco-2 permeability and BBB penetration, these are less important for a non-CNS enzyme target like SRC. Ligand A excels in the most critical areas: significantly higher binding affinity, lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The solubility is slightly worse, but the other advantages outweigh this drawback.

Output:
1
2025-04-17 16:21:00,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.871 Da) is slightly higher than Ligand B (345.407 Da), but both are acceptable.

**TPSA:** Ligand A (64.63) is significantly better than Ligand B (117.59). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (3.389) is optimal (1-3), while Ligand B (0.277) is quite low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=6) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.73, B: 0.666), indicating good drug-likeness.

**DILI:** Ligand A (55.836) has a lower DILI risk than Ligand B (63.513), which is favorable. Both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (77.705) is better than Ligand B (38.387).

**Caco-2 Permeability:** Ligand A (-4.64) is better than Ligand B (-5.641), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.234) is better than Ligand B (-2.706), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.598) has a much lower hERG risk than Ligand B (0.029). This is a critical advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (60.758) has higher clearance than Ligand B (-5.889). This means Ligand B is more metabolically stable, which is a significant advantage.

**In vitro Half-Life:** Ligand A (-31.235) has a longer half-life than Ligand B (2.57), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.226, B: 0.008), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 kcal/mol and -8.9 kcal/mol respectively). Ligand B is slightly better, but the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall:** While Ligand B has slightly better binding affinity and metabolic stability, Ligand A excels in crucial areas like logP, solubility, hERG risk, and TPSA. The lower hERG risk and better logP of Ligand A are particularly important for an enzyme inhibitor. The solubility advantage is also significant.

Output:
1
2025-04-17 16:21:00,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.385 Da and 360.531 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (80.32 and 79.96) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.291) is optimal, while Ligand B (3.205) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but still acceptable.

**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 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.689 and 0.856), indicating drug-like properties.

**DILI:** Ligand A (45.87) has a lower DILI risk than Ligand B (61.807), which is a significant advantage. Ligand B is creeping towards the higher risk category.

**BBB:** Both ligands have high BBB penetration (88.29 and 89.104), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.734 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 (-2.082 and -4.709), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.255 and 0.535), which is good.

**Microsomal Clearance:** Ligand A (18.739 mL/min/kg) has significantly lower microsomal clearance than Ligand B (52.824 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.254 hours) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (17.893 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.038).

**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's a factor.

**Overall Assessment:**

Ligand A is preferable despite the questionable half-life data. It has a lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The negative solubility and Caco-2 values are concerning for both, but the lower DILI and Cl_mic of Ligand A make it a more promising starting point for optimization. The negative half-life for Ligand A is a red flag and needs investigation. However, assuming the half-life is a data error, Ligand A is the better candidate.

Output:
0
2025-04-17 16:21:00,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.459 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (87.3 and 80.12) below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (0.96) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.483) is within the optimal 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 (A: 3, B: 5) are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (A: 0.692, B: 0.847), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (16.557) has a significantly lower DILI risk than Ligand B (41.411), which is a major advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.756) has a higher BBB percentile than Ligand A (50.446).

**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, which is also unusual and indicates poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (A: 0.126, B: 0.179), which is excellent.

**12. Cl_mic:** Ligand A (-14.818) has a *much* lower (and therefore better) microsomal clearance than Ligand B (46.16). This suggests significantly better metabolic stability for Ligand A.

**13. t1/2:** Ligand B (-19.498) has a longer in vitro half-life than Ligand A (6.902), which is a positive.

**14. Pgp:** Both have very low Pgp efflux liability (A: 0.016, B: 0.1).

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a very significant advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-9.5 vs -0.0 kcal/mol) is a major driver. While Ligand A has better DILI and Cl_mic profiles, the potency difference is substantial. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The longer half-life of Ligand B is also beneficial. Considering the enzyme-specific priorities, the superior binding affinity of Ligand B makes it the more promising candidate, despite its higher DILI risk and lower metabolic stability.

Output:
1
2025-04-17 16:21:00,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.402 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.0) is significantly better than Ligand B (75.51).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.173 and 1.198), 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 0 HBD and 5 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.763 and 0.822), indicating good drug-like properties.

**DILI:** Ligand A (29.818) has a much lower DILI risk than Ligand B (40.054). This is a significant advantage, as lower DILI is crucial.

**BBB:** Ligand A (95.308) has a much higher BBB penetration percentile than Ligand B (78.713). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.231) is slightly better than Ligand B (-4.433), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.37) is slightly better than Ligand B (-1.432).

**hERG:** Ligand A (0.746) has a lower hERG inhibition liability than Ligand B (0.253), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand B (36.797) has lower microsomal clearance than Ligand A (57.916), suggesting better metabolic stability. This is a key consideration for enzymes.

**In vitro Half-Life:** Ligand A (-6.69) has a longer half-life than Ligand B (-4.404).

**P-gp Efflux:** Ligand A (0.28) has lower P-gp efflux than Ligand B (0.089), which is a positive.

**Binding Affinity:** Ligand B (-9.4) has a slightly better binding affinity than Ligand A (-8.7). While a 1.5 kcal/mol difference is noteworthy, the other advantages of Ligand A are substantial.

**Overall:**

Ligand A demonstrates a superior safety profile (lower DILI, lower hERG), better solubility, and better permeability characteristics. While Ligand B has a slightly better binding affinity, the other advantages of Ligand A, especially the lower DILI and hERG risk, outweigh this difference. For an enzyme target like SRC kinase, metabolic stability is important, and Ligand B is better in this regard, but the other advantages of A are more critical.

Output:
1
2025-04-17 16:21:00,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.804 Da and 350.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.29) is well below the 140 threshold, indicating good absorption potential. Ligand B (103.01) is still within acceptable limits, but less favorable than A.

**logP:** Ligand A (3.227) is optimal. Ligand B (0.831) 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=5) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (A: 0.605, B: 0.73), suggesting generally drug-like properties.

**DILI:** Ligand A (72.043) has a moderate DILI risk, while Ligand B (37.069) has a low DILI risk. This favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.531) is higher than Ligand B (25.591), but it doesn't significantly impact the decision.

**Caco-2 Permeability:** Ligand A (-4.612) and Ligand B (-5.078) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.71) and Ligand B (-1.964) both have negative values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.281, B: 0.264), which is excellent.

**Microsomal Clearance:** Ligand A (92.061) has a higher clearance, indicating lower metabolic stability. Ligand B (-17.05) has a negative clearance, suggesting excellent metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (8.081) has a shorter half-life, while Ligand B (37.249) has a much longer half-life. This favors Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.103, B: 0.136).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold. This is the most critical factor.

**Conclusion:**

Despite Ligand A having a slightly better TPSA and BBB, Ligand B is the superior candidate. Its significantly stronger binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk outweigh the minor drawbacks of its slightly lower logP and higher TPSA. The affinity difference is substantial and will likely translate to better efficacy.

Output:
1
2025-04-17 16:21:00,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (349.431 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.53) is slightly higher than Ligand B (96.25). Both are below the 140 threshold for good oral absorption, but closer to the 90 threshold for CNS targets (not a primary concern here).

**3. logP:** Ligand A (1.554) is better than Ligand B (0.596), falling comfortably within the 1-3 optimal range. Ligand B is a bit low, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (4) and Ligand B (3) 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:** Ligand B (0.727) has a slightly better QED score than Ligand A (0.571), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk, with Ligand A at 29.663 and Ligand B at 38.62, both well below the 60 threshold.

**8. BBB:** Both ligands have low BBB penetration (37.069 and 33.501 respectively), which is not a major concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.43 and -5.038), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.212 and -2.199), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.233 and 0.289), which is excellent.

**12. Microsomal Clearance:** Ligand B (6.09) has significantly lower microsomal clearance than Ligand A (47.013), indicating better metabolic stability. This is a major advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (9.4) has a better in vitro half-life than Ligand A (-14.716). Again, this favors Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.025).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.4 kcal/mol). While both are good, the 0.7 kcal/mol difference is noteworthy.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), slightly better QED, and stronger binding affinity. The lower logP of Ligand B is a minor drawback, but the benefits outweigh this concern.

Output:
1
2025-04-17 16:21:00,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 376.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is excellent, well below the 140 threshold for oral absorption. Ligand B (49.41) is also very good.

**logP:** Both ligands (1.702 and 2.44) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4-5 HBA, satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.721 and 0.775), indicating a drug-like profile.

**DILI:** Ligand A (22.683) has a significantly lower DILI risk than Ligand B (35.052), which is a major advantage.

**BBB:** Ligand A (68.67) has a lower BBB penetration than Ligand B (88.29). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.749) has better Caco-2 permeability than Ligand B (-5.266).

**Aqueous Solubility:** Ligand A (-1.323) has better aqueous solubility than Ligand B (-3.156).

**hERG:** Both ligands have similar hERG risk (0.704 and 0.768), and are acceptable.

**Microsomal Clearance:** Ligand A (41.706) has lower microsomal clearance than Ligand B (91.281), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.049) has a longer in vitro half-life than Ligand A (-4.506).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.549 and 0.402).

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-9.4). However, the difference is not substantial enough to outweigh the other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better solubility, and improved metabolic stability (lower Cl_mic). While Ligand B has a slightly better binding affinity and half-life, the advantages of Ligand A in safety and pharmacokinetic properties are more critical for overall drug development success.

Output:
0
2025-04-17 16:21:00,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (358.345 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (113.33) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (96.25) is well within the acceptable range.

**3. logP:** Ligand A (0.244) is quite low, potentially hindering permeation. Ligand B (0.596) is also low but better than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand B (0.727) has a significantly better QED score than Ligand A (0.432), indicating a more drug-like profile.

**7. DILI:** Ligand B (38.62) has a lower DILI risk than Ligand A (50.33), both are acceptable (<40 is good, >60 is high risk).

**8. BBB:** Ligand A (83.288) has a better BBB penetration score than Ligand B (33.501). However, as SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.881) shows poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.038) is similarly poor.

**10. Aqueous Solubility:** Ligand A (-2.947) and Ligand B (-2.199) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.3 and 0.289, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand B (6.09) has a much lower microsomal clearance than Ligand A (20.409), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**13. In vitro Half-Life (t1/2):** Ligand B (9.4) has a longer in vitro half-life than Ligand A (-1.385), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.048 and 0.025, respectively).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, hERG risk), Ligand B is the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand B's significantly stronger binding affinity, lower microsomal clearance, and longer half-life outweigh the slightly lower BBB penetration and logP. The better QED and DILI scores also contribute to its favorability. The difference in binding affinity is substantial (>1.5 kcal/mol), making Ligand B the clear choice.

Output:
1
2025-04-17 16:21:00,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.491 and 348.491 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.05) is significantly better than Ligand B (76.02).  A TPSA under 90 is generally acceptable, and A is closer to the ideal <140 for oral absorption.

**3. logP:** Both ligands have good logP values (2.595 and 2.449), falling 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 (5) is better than Ligand B (4). Lower HBAs generally improve permeability.

**6. QED:** Ligand A (0.911) has a substantially higher QED score than Ligand B (0.638), indicating a more drug-like profile.

**7. DILI:** Ligand A (23.885) has a much lower DILI risk than Ligand B (29.779), suggesting better liver safety. Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand A (70.531) has a higher BBB penetration percentile than Ligand B (46.84). While SRC isn't a CNS target, higher BBB isn't necessarily detrimental.

**9. Caco-2 Permeability:** Ligand A (-5.13) is better than Ligand B (-5.05). Both are negative, which is unusual and requires further investigation, but A is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.704) is better than Ligand B (-2.685). Higher solubility is crucial for bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.258 and 0.19), which is excellent.

**12. Microsomal Clearance:** Ligand A (21.535) has significantly lower microsomal clearance than Ligand B (44.126), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (-2.577) has a better (longer) in vitro half-life than Ligand B (27.491). This is another important factor for metabolic stability and dosing frequency.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.051).

**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 override the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties (TPSA, QED, DILI, solubility, metabolic stability, half-life) while maintaining comparable potency and low hERG risk. The slightly better solubility and significantly improved metabolic stability of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 16:21:00,319 - INFO - Batch 456 complete. Total preferences: 7296
2025-04-17 16:21:00,319 - INFO - Processing batch 457/512...
2025-04-17 16:21:44,379 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.429 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (67.43) is better than Ligand B (51.66). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.763, B: 3.404), falling within the optimal 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=2, HBA=3) is preferable to Ligand B (HBD=0, HBA=5). While both are acceptable, having some H-bond donors can improve aqueous solubility.

**QED:** Both ligands have similar QED values (A: 0.767, B: 0.706), indicating good drug-like properties.

**DILI:** Ligand A (31.989) has a significantly lower DILI risk than Ligand B (56.689). This is a major advantage for Ligand A.

**BBB:** Ligand B (96.278) has a higher BBB penetration percentile than Ligand A (77.2). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.684) has better Caco-2 permeability than Ligand B (-4.453).

**Aqueous Solubility:** Ligand A (-2.613) has better aqueous solubility than Ligand B (-3.561).

**hERG:** Ligand A (0.342) has a lower hERG inhibition liability than Ligand B (0.933). This is a significant advantage, reducing potential cardiotoxicity.

**Microsomal Clearance:** Ligand A (47.938) has lower microsomal clearance than Ligand B (63.815), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (57.301) has a much longer in vitro half-life than Ligand A (-15.13). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux liability than Ligand B (0.516).

**Binding Affinity:** Ligand A (-8.3) has a significantly stronger binding affinity than Ligand B (-6.7). This is a crucial factor for an enzyme inhibitor. A difference of 1.6 kcal/mol is substantial.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better half-life and BBB penetration (which isn't relevant here), Ligand A excels in key areas: significantly better binding affinity, lower DILI risk, lower hERG risk, better solubility, better permeability, and better metabolic stability. The substantial difference in binding affinity (-8.3 vs -6.7 kcal/mol) outweighs the half-life advantage of Ligand B. For an enzyme target like SRC kinase, potency and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 16:21:44,379 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [346.471, 62.55, 3.464, 1, 3, 0.858, 10.508, 84.141, -4.766, -3.565, 0.623, 49.223, 17.357, 0.119, -8.1]
**Ligand B:** [348.447, 84.3, 1.183, 1, 5, 0.802, 42.536, 74.176, -4.669, -2.086, 0.236, 45.83, -5.697, 0.092, -7.9]

**Step-by-step comparison:**

1. **MW:** Both ligands (346.471 and 348.447 Da) are within the ideal 200-500 Da range.
2. **TPSA:** Ligand A (62.55) is better than Ligand B (84.3), being well below the 140 threshold for oral absorption.
3. **logP:** Ligand A (3.464) is optimal, while Ligand B (1.183) is on the lower side, potentially hindering permeation.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** Ligand A (3) is better than Ligand B (5). Lower HBA generally improves permeability.
6. **QED:** Both ligands have good QED scores (0.858 and 0.802), indicating drug-like properties.
7. **DILI:** Ligand A (10.508) has a significantly lower DILI risk than Ligand B (42.536). This is a major advantage.
8. **BBB:** Ligand A (84.141) has better BBB penetration potential than Ligand B (74.176), though this isn't a primary concern for a non-CNS target like SRC.
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 A (-3.565) has slightly better solubility than Ligand B (-2.086).
11. **hERG:** Ligand A (0.623) has a lower hERG risk than Ligand B (0.236), which is preferable.
12. **Cl_mic:** Ligand A (49.223) has a slightly better (lower) microsomal clearance than Ligand B (45.83), indicating better metabolic stability.
13. **t1/2:** Ligand A (17.357) has a longer in vitro half-life than Ligand B (-5.697). This is a significant advantage.
14. **Pgp:** Ligand A (0.119) has lower P-gp efflux liability than Ligand B (0.092).
15. **Binding Affinity:** Ligand A (-8.1) has slightly better binding affinity than Ligand B (-7.9). While the difference is small, it's still a positive.

**Enzyme-Kinase Specific Considerations:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in all these areas. It has a slightly better affinity, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and lower hERG risk. The significantly lower DILI risk is also a major advantage. While Ligand B has a reasonable profile, Ligand A is clearly superior.

**Conclusion:**

Ligand A is the more viable drug candidate.

Output:
1

2025-04-17 16:21:44,379 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (435.3 Da) is slightly higher than Ligand B (347.5 Da), but both are acceptable.

**TPSA:** Ligand A (110.6) is higher than Ligand B (52.65). While <140 is generally good for oral absorption, Ligand A is approaching a potential concern. Ligand B is well within the acceptable range.

**logP:** Both ligands have good logP values (A: 1.012, B: 2.326), 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 Ligand B is preferable.

**QED:** Both ligands have good QED scores (A: 0.695, B: 0.802), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (7.794). This is a significant concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (72.276) and Ligand B (87.941) are both reasonable.

**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.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is undefined.

**hERG:** Ligand A (0.278) has a slightly higher hERG risk than Ligand B (0.37), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand B (35.963) has a lower microsomal clearance than Ligand A (23.506), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (-7.101) has a negative half-life, which is impossible. This is a huge red flag. Ligand A (59.125) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.052, B: 0.047).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage, as a 1.5 kcal/mol advantage is considered significant.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and Solubility, the most important factors for an enzyme inhibitor are potency and metabolic stability. Ligand B has a *much* stronger binding affinity and better metabolic stability (lower Cl_mic). However, the negative in vitro half-life for Ligand B is a critical flaw. The DILI risk for Ligand A is concerning.

Given the substantial difference in binding affinity and metabolic stability, and assuming the negative half-life for Ligand B is an error, I would initially favor Ligand B. However, the negative half-life is a showstopper. Therefore, I will select Ligand A, acknowledging the DILI risk as a potential issue to address in further optimization.

Output:
1
2025-04-17 16:21:44,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.32) is better than Ligand B (49.41) as it is closer to the 140 cutoff for oral absorption.

**logP:** Ligand A (1.041) is within the optimal 1-3 range, while Ligand B (3.127) 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.654 and 0.836, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (32.028 and 31.059 percentile), which is favorable.

**BBB:** Ligand B (76.89) has a higher BBB penetration percentile than Ligand A (56.766), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests potential issues with solubility prediction.

**hERG:** Ligand A (0.146) has a significantly lower hERG inhibition liability than Ligand B (0.55), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (8.25 mL/min/kg) has a much lower microsomal clearance than Ligand B (84.212 mL/min/kg), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-0.945 hours) has a negative half-life, which is not possible. Ligand B (6.619 hours) is better.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux liability than Ligand B (0.275), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). However, the difference is relatively small (0.4 kcal/mol) and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A excels in crucial areas for an enzyme inhibitor: significantly lower hERG risk and much better metabolic stability (lower Cl_mic). The negative values for Caco-2 and solubility are concerning for both, but the superior ADME profile of Ligand A, particularly the hERG and Cl_mic, makes it the more promising candidate.

Output:
0
2025-04-17 16:21:44,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.345 and 353.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.22) is better than Ligand B (57.61), both are acceptable but closer to the upper limit for good absorption.

**logP:** Both ligands have good logP values (4.22 and 3.91), within the optimal 1-3 range, though leaning towards the higher end.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.721) has a better QED score than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand A (83.443) has a significantly higher DILI risk than Ligand B (15.2). This is a major concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (77.705 and 83.521), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.409 and -4.223), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-5.167) has worse solubility than Ligand B (-3.783). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.722) has a slightly higher hERG risk than Ligand B (0.531), but both are reasonably low.

**Microsomal Clearance:** Ligand A (127.891) has higher microsomal clearance than Ligand B (82.483), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (69.337) has a much longer half-life than Ligand B (7.188), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.73) has slightly higher P-gp efflux than Ligand B (0.626). Lower is better.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.8 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

Ligand A has a better binding affinity and longer half-life, but suffers from significantly higher DILI risk, lower solubility, and higher microsomal clearance. Ligand B has a much better safety profile (DILI), better solubility, and better metabolic stability, but a shorter half-life. The difference in binding affinity (0.4 kcal/mol) is not substantial enough to outweigh the significant safety and ADME concerns of Ligand A.

Output:
1
2025-04-17 16:21:44,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.424 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.17) is better than Ligand B (58.64), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Ligand A (4.905) is higher than the optimal range (1-3), while Ligand B (2.591) is within the optimal range. This is a point in favor of Ligand B.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 3 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.766 and 0.801), indicating good drug-like properties.

**DILI:** Ligand A (47.034) has a higher DILI risk than Ligand B (18.379). This is a significant advantage for Ligand B.

**BBB:** Ligand A (93.525) has better BBB penetration than Ligand B (77.782), but BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.6 and -4.533) which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-5.224) has worse solubility than Ligand B (-3.079). Solubility is important for bioavailability, favoring Ligand B.

**hERG:** Ligand A (0.411) has a slightly better hERG profile than Ligand B (0.541), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (50.471) has higher microsomal clearance than Ligand B (31.433), indicating lower metabolic stability. Ligand B is favored here.

**In vitro Half-Life:** Ligand A (10.475) has a longer half-life than Ligand B (2.557). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.428) has lower P-gp efflux than Ligand B (0.095), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-6.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.2 kcal/mol). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior safety profile (lower DILI) and better metabolic stability (lower Cl_mic) and solubility. While Ligand A has a slightly better binding affinity and half-life, the advantages of Ligand B in critical ADME properties, especially DILI and metabolic stability, are more important for an enzyme inhibitor. The slightly better affinity of A is not enough to overcome the significant ADME liabilities.

Output:
1
2025-04-17 16:21:44,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 Da and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.03) is better than Ligand B (67.87), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.139 and 1.066, respectively) within the 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility but potentially lower permeability.

**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 (0.734) has a better QED score than Ligand B (0.513), indicating a more drug-like profile.

**DILI:** Ligand B (42.885) has a slightly higher DILI risk than Ligand A (27.724), but both are below the concerning threshold of 60.

**BBB:** Both ligands have relatively low BBB penetration (40.52 and 46.762, respectively), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 permeability values (-4.623 and -4.71), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.503 and -2.952), which is also unusual and indicates very poor aqueous solubility. This is a major concern.

**hERG Inhibition:** Ligand A (0.437) has a significantly lower hERG inhibition risk than Ligand B (0.152), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (-0.561) has a lower (better) microsomal clearance than Ligand B (36.8), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (12.367 hours) has a much longer in vitro half-life than Ligand B (-21.462 hours). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux than Ligand B (0.027), indicating better bioavailability.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This difference of 3 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -6.4 kcal/mol), better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and better QED score outweigh the similar permeability and solubility concerns. The large difference in binding affinity is the deciding factor.

Output:
0
2025-04-17 16:21:44,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (365.455 and 348.399 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.77) is slightly higher than Ligand B (79.31), both are acceptable for oral absorption (<140).

**logP:** Ligand A (0.661) is slightly better than Ligand B (-0.622). Both are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Both have 5 HBA, which is good.

**QED:** Ligand A (0.849) has a better QED score than Ligand B (0.673), indicating a more drug-like profile.

**DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (52.734), which is preferable.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (65.529) is slightly better than Ligand A (53.47).

**Caco-2 Permeability:** Ligand A (-5.113) has a worse Caco-2 permeability than Ligand B (-4.149), indicating lower intestinal absorption.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.667 and -1.531 respectively). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.173 and 0.16 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-18.472) has significantly lower (better) microsomal clearance than Ligand B (3.564), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (38.654) has a longer half-life than Ligand B (-11.788), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux (0.024 and 0.066 respectively), which is good.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage (1.4 kcal/mol difference).

**Conclusion:**

While Ligand A has better QED, DILI, and metabolic stability, the significantly stronger binding affinity of Ligand B (-10.2 vs -8.8 kcal/mol) outweighs the ADME drawbacks. A 1.4 kcal/mol difference in binding is substantial for an enzyme target. The solubility issues are a concern for both, but formulation work could potentially mitigate this. The slightly better Caco-2 permeability of Ligand B is also a minor positive. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:21:44,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.427 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (50.6) is well below the 140 threshold for good oral absorption. Ligand B (89.95) is still under the threshold, but higher. This favors Ligand A.

**logP:** Ligand A (2.108) is optimal. Ligand B (0.512) is a bit low, potentially hindering permeation. This favors Ligand A.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable, within the limit of 5.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of 10.

**QED:** Both ligands have acceptable QED scores (A: 0.86, B: 0.728), indicating good drug-like properties.

**DILI:** Ligand A (25.785) has a significantly lower DILI risk than Ligand B (14.696). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.857) is higher than Ligand B (19.542), but this difference isn't a primary concern.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-4.48) is smaller than for Ligand B (-4.985), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, which is also unusual. The value for Ligand A (-1.744) is better than Ligand B (-0.675).

**hERG Inhibition:** Ligand A (0.691) has a lower hERG risk than Ligand B (0.074). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (31.55) has a higher microsomal clearance than Ligand B (4.463), meaning it is less metabolically stable. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-10.118) has a shorter half-life than Ligand B (12.336). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.342) has lower P-gp efflux liability than Ligand B (0.009), which is favorable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This is a notable advantage for Ligand B, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, lower hERG) and better physicochemical properties (TPSA, logP, solubility). However, Ligand B has a better binding affinity and better metabolic stability. The 0.8 kcal/mol difference in binding affinity is substantial, but the ADME advantages of Ligand A, particularly the lower DILI and hERG risks, are critical for a viable drug candidate. Considering these factors, and prioritizing safety and reasonable ADME properties for an enzyme target, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 16:21:44,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (343.431 and 356.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.02) is better than Ligand B (49.33) as it is closer to the threshold of 140 for good oral absorption.

**3. logP:** Both ligands have good logP values (1.719 and 2.964), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as it strikes a better balance between solubility and permeability.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being below the 10 threshold.

**6. QED:** Both ligands have similar QED scores (0.867 and 0.848), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (41.334 and 41.993), both being good (low risk).

**8. BBB:** Ligand B (77.821) has a significantly higher BBB penetration percentile than Ligand A (39.046). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.24) is better than Ligand B (-4.78), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.314) is better than Ligand B (-2.085).

**11. hERG Inhibition:** Ligand A (0.349) has a lower hERG inhibition liability than Ligand B (0.794), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (15.684) has a lower microsomal clearance than Ligand B (42.009), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-29.455) has a longer in vitro half-life than Ligand B (-11.096), which is desirable.

**14. P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux liability than Ligand B (0.371).

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme target like SRC kinase.

**Overall:**

Ligand A is superior to Ligand B. While Ligand B has better BBB penetration (irrelevant here) and slightly better logP, Ligand A excels in crucial areas: significantly stronger binding affinity, better solubility, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. These advantages outweigh the minor differences in other parameters.

Output:
1
2025-04-17 16:21:44,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.328 Da) is slightly higher than Ligand B (345.33 Da), but both are acceptable.

**TPSA:** Ligand A (62.53) is well below the 140 threshold for oral absorption. Ligand B (115.36) is also below the threshold, but closer to it.

**logP:** Ligand A (3.157) is optimal. Ligand B (1.857) is a bit low, potentially impacting permeability.

**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 reasonable QED scores (A: 0.848, B: 0.715), indicating good drug-like properties.

**DILI:** Ligand A (58.395) has a lower DILI risk than Ligand B (74.021), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.608) has a better BBB score than Ligand B (22.528).

**Caco-2 Permeability:** Ligand A (-5.187) and Ligand B (-4.848) both have negative values, which are not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.289 and -3.856 respectively). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.799) shows a lower hERG risk than Ligand B (0.442), which is a critical advantage.

**Microsomal Clearance:** Ligand A (72.631) has higher microsomal clearance than Ligand B (10.998). This means Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (89.733) has a significantly longer in vitro half-life than Ligand A (17.545), which is a major advantage.

**P-gp Efflux:** Ligand A (0.601) has lower P-gp efflux than Ligand B (0.069), which is a positive.

**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's enough to consider.

**Overall Assessment:**

Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2), which is a key consideration for kinase inhibitors. However, Ligand A demonstrates better safety profiles with lower DILI and hERG risk. The binding affinity difference is small, but favors Ligand A. The solubility is poor for both, but the other advantages of Ligand A, particularly the safety profile, outweigh the metabolic stability advantage of Ligand B.

Output:
1
2025-04-17 16:21:44,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.435 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.18) is slightly higher than Ligand B (70.67). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (-0.641) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.153) is within the optimal range. This favors Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.683 and 0.797), indicating drug-like properties.

**DILI:** Ligand A (31.291) has a slightly higher DILI risk than Ligand B (17.642), but both are below the concerning threshold of 60.

**BBB:** Ligand A (29.74) has a lower BBB penetration percentile than Ligand B (73.827). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.138) has poor Caco-2 permeability, while Ligand B (-4.743) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-0.27) has slightly better solubility than Ligand B (-2.118). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.063) has a slightly lower hERG inhibition liability than Ligand B (0.251), which is preferable.

**Microsomal Clearance:** Ligand A (2.31 mL/min/kg) has significantly lower microsomal clearance than Ligand B (46.189 mL/min/kg), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (25.235 hours) has a much longer half-life than Ligand B (1.394 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux liability than Ligand B (0.023). This is a slight advantage for Ligand A.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has better logP and BBB penetration. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), slightly better hERG profile, and lower P-gp efflux. The difference in solubility is minor, and the binding affinity is essentially the same. For an enzyme target like SRC kinase, metabolic stability and minimizing off-target effects (hERG) are crucial. Therefore, Ligand A is the more promising candidate.

Output:
0
2025-04-17 16:21:44,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.439 Da and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.66) is well below the 140 threshold, while Ligand B (103.94) is still acceptable but closer to the limit.

**logP:** Ligand A (2.311) is optimal, while Ligand B (0.641) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (0) is excellent, and Ligand B (2) is acceptable.

**H-Bond Acceptors:** Ligand A (6) is good, and Ligand B (4) is also good.

**QED:** Both ligands have reasonable QED scores (0.833 and 0.668), indicating good drug-like properties.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (12.757). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (90.306) has better BBB penetration than Ligand B (62.35).

**Caco-2 Permeability:** Ligand A (-4.509) has poor Caco-2 permeability, while Ligand B (-5.182) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-4.031) has poor solubility, while Ligand B (-1.813) is also poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.541) has a slightly higher hERG risk than Ligand B (0.154).

**Microsomal Clearance:** Ligand B (-4.396) has lower (better) microsomal clearance than Ligand A (24.631), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.281) has a longer half-life than Ligand A (-14.286), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.278) has lower P-gp efflux than Ligand B (0.02), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's slightly better P-gp efflux and BBB penetration, Ligand B is the superior candidate. Its significantly stronger binding affinity (-7.6 vs -9.4 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B exhibits much lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. While both have poor Caco-2 and solubility, the potency and safety profile of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 16:21:44,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**
*   **MW:** 408.286 Da - Within the ideal range (200-500).
*   **TPSA:** 20.31 - Excellent, well below the 140 threshold for absorption.
*   **logP:** 4.997 - Slightly high, potentially leading to solubility issues and off-target effects.
*   **HBD:** 0 - Low, which is acceptable.
*   **HBA:** 1 - Low, which is acceptable.
*   **QED:** 0.7 - Good drug-likeness.
*   **DILI:** 54.75 - Acceptable risk.
*   **BBB:** 93.331 - Very high, suggesting good CNS penetration (though not critical for SRC, it's not a negative).
*   **Caco-2:** -4.644 - Very poor permeability. A significant concern.
*   **Solubility:** -6.424 - Very poor solubility. A major drawback.
*   **hERG:** 0.912 - Low risk, good.
*   **Cl_mic:** 76.386 - Moderate clearance, not ideal for metabolic stability.
*   **t1/2:** 38.567 - Moderate half-life, acceptable.
*   **Pgp:** 0.711 - Moderate efflux, not a major concern.
*   **Affinity:** -9.0 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 347.415 Da - Within the ideal range.
*   **TPSA:** 84.67 - Acceptable, but approaching the upper limit for good oral absorption.
*   **logP:** 1.056 - Optimal.
*   **HBD:** 1 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.88 - Very good drug-likeness.
*   **DILI:** 41.877 - Good, low risk.
*   **BBB:** 71.501 - Acceptable, but not a priority for SRC.
*   **Caco-2:** -5.205 - Very poor permeability. A significant concern.
*   **Solubility:** -0.864 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.071 - Very low risk, excellent.
*   **Cl_mic:** 26.764 - Low clearance, excellent metabolic stability.
*   **t1/2:** -11.274 - Very short half-life, a major drawback.
*   **Pgp:** 0.046 - Low efflux, good.
*   **Affinity:** -7.0 kcal/mol - Good binding affinity.

**Comparison and Decision:**

Both ligands have significant permeability and solubility issues. However, Ligand A has a substantially better binding affinity (-9.0 kcal/mol vs -7.0 kcal/mol). While Ligand B has better metabolic stability (lower Cl_mic) and a better hERG profile, the difference in binding affinity is substantial enough to outweigh these advantages. The binding affinity advantage of Ligand A is >2 kcal/mol, which is significant. The poor solubility and permeability of Ligand A could potentially be addressed through formulation strategies. The very short half-life of Ligand B is a more difficult problem to overcome.

Output:
1
2025-04-17 16:21:44,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.45 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.82) is significantly better than Ligand B (49.85). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors. Ligand A is well below the 140 threshold, while B is approaching it.

**logP:** Both ligands have acceptable logP values (1.324 and 2.3), falling within the 1-3 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.835 and 0.74), indicating good drug-like properties.

**DILI:** Ligand A (35.052) has a much lower DILI risk than Ligand B (6.359). This is a significant advantage for Ligand A.

**BBB:** Ligand B (93.718) has a higher BBB penetration percentile than Ligand A (70.26). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.92) has a slightly better Caco-2 permeability than Ligand B (-4.463), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar and very poor aqueous solubility (-1.808 and -1.894). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.8) has a slightly better hERG profile than Ligand B (0.658), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (4.56 mL/min/kg) has significantly lower microsomal clearance than Ligand B (55.779 mL/min/kg). This suggests better metabolic stability for Ligand A, a key priority for kinase inhibitors.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (-7.233 and -7.289 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.161).

**Binding Affinity:** Ligand B (-6.6 kcal/mol) has a slightly weaker binding affinity than Ligand A (-7.2 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it still favors Ligand A.

**Overall:** Ligand A is the stronger candidate. It has a better TPSA, significantly lower DILI risk, better metabolic stability (lower Cl_mic), slightly better Caco-2 permeability, and a slightly better hERG profile. While both have poor solubility, the other advantages of Ligand A outweigh this drawback. The slightly better binding affinity of Ligand A is also a plus.

Output:
1
2025-04-17 16:21:44,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (346.431 and 350.434 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.41) is better than Ligand B (51.66) as it is closer to the threshold of 140, while ligand B is well below.

**3. logP:** Both ligands have good logP values (2.415 and 2.984), 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 5 HBA, acceptable. Ligand B has 4, also acceptable.

**6. QED:** Both ligands have similar QED values (0.685 and 0.723), indicating good drug-likeness.

**7. DILI:** Ligand A (54.634) has a higher DILI risk than Ligand B (12.214). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (32.144) has a low BBB penetration, while Ligand B (91.663) has a very high BBB penetration. Since SRC is not a CNS target, this is not a major factor.

**9. Caco-2 Permeability:** Ligand A (-4.938) has poor Caco-2 permeability, while Ligand B (-4.005) is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.739) has poor aqueous solubility, while Ligand B (-3.112) is even worse.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.674 and 0.643).

**12. Microsomal Clearance:** Ligand A (-1.317) has a lower (better) microsomal clearance than Ligand B (66.9). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (25.045) has a shorter half-life than Ligand B (-17.903).

**14. P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux than Ligand B (0.113).

**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 >2 kcal/mol advantage, which is substantial.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison & Conclusion:**

Ligand B clearly wins on binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand B has worse solubility than A, the difference in affinity is significant enough to outweigh this drawback. Ligand A has a concerningly high DILI risk, which is a major red flag. Ligand B also has better Caco-2 permeability and a much better BBB score. Although Ligand A has better metabolic stability, the superior affinity and lower toxicity risk of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:21:44,381 - INFO - Batch 457 complete. Total preferences: 7312
2025-04-17 16:21:44,381 - INFO - Processing batch 458/512...
2025-04-17 16:22:29,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (335.37 and 349.34 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.91) is slightly higher than Ligand B (88.08), but both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.869 and 1.318), 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 similar and good QED scores (0.796 and 0.814), indicating drug-like properties.

**DILI:** Ligand A (83.99) has a higher DILI risk than Ligand B (74.80). This is a negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (55.06 and 70.57), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.145) has significantly *lower* Caco-2 permeability than Ligand B (-4.494). This suggests poorer intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-4.506) has lower aqueous solubility than Ligand B (-2.333). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.444) has a slightly higher hERG inhibition risk than Ligand B (0.282), but both are relatively low.

**Microsomal Clearance:** Ligand A (11.244) has a higher microsomal clearance than Ligand B (51.592), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (70.662) has a longer in vitro half-life than Ligand B (-2.883). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux liability than Ligand B (0.033), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.6 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the better candidate. It has a lower DILI risk, better Caco-2 permeability, better aqueous solubility, and better metabolic stability (lower Cl_mic). The slightly stronger binding affinity of Ligand B further supports this conclusion. While Ligand A has a longer half-life and lower P-gp efflux, the significant drawbacks in DILI, permeability, solubility, and metabolic stability outweigh these benefits.

Output:
1
2025-04-17 16:22:29,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.78) is excellent, well below the 140 threshold for oral absorption. Ligand B (110.05) is still acceptable, but less optimal.

**logP:** Both ligands (2.462 and 2.992) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are acceptable, but Ligand A is slightly better.

**QED:** Ligand A (0.707) has a better QED score than Ligand B (0.578), indicating a more drug-like profile.

**DILI:** Ligand A (27.065) has a significantly lower DILI risk than Ligand B (78.441). This is a major advantage.

**BBB:** This is less crucial for a non-CNS target like SRC, but Ligand A (86.274) has a higher BBB percentile than Ligand B (57.736).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, Ligand A (-4.837) shows slightly better permeability than Ligand B (-5.094).

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, Ligand A (-3.103) shows slightly better solubility than Ligand B (-4.269).

**hERG:** Both ligands have low hERG risk (0.666 and 0.492).

**Microsomal Clearance:** Ligand A (33.402) has lower microsomal clearance than Ligand B (48.331), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.374) has a slightly longer half-life than Ligand B (21.871).

**P-gp Efflux:** Both have low P-gp efflux liability (0.522 and 0.217).

**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:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A has better ADME properties across the board, particularly a much lower DILI risk and better metabolic stability. The difference in binding affinity is significant, but the improved safety profile of Ligand A is compelling. Given the importance of minimizing toxicity in oncology drug development, I would lean towards Ligand A, as the potency difference might be overcome with further optimization, while a high DILI risk is harder to address later.

Output:
0
2025-04-17 16:22:29,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 368.499 Da) are within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (78.43 and 78.87) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (3.504) is optimal, while Ligand B (0.941) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.662 and 0.722), indicating drug-like properties.

**DILI:** Ligand A (24.467) has a significantly lower DILI risk than Ligand B (36.293), which is a major advantage.

**BBB:** Ligand A (64.25) has a moderate BBB penetration, while Ligand B (17.914) has very low BBB penetration. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have similar, very negative Caco-2 values (-4.974 and -4.965), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have similar, very negative solubility values (-4.094 and -2.559), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.523) has a slightly higher hERG risk than Ligand B (0.162), but both are relatively low.

**Microsomal Clearance:** Ligand A (53.337) has higher microsomal clearance than Ligand B (31.599), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-2.148) has a longer in vitro half-life than Ligand A (-5.768), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.096 and 0.142).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 0.4 kcal/mol difference is meaningful, but not overwhelming.

**Overall Assessment:**

Despite the similar issues with Caco-2 permeability and aqueous solubility, Ligand A is the more promising candidate. Its significantly lower DILI risk is a major advantage. While its metabolic stability is slightly worse (higher Cl_mic, shorter t1/2) than Ligand B, the stronger binding affinity and lower DILI risk outweigh this drawback. The slightly lower logP of Ligand B is also a concern.

Output:
0
2025-04-17 16:22:29,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.371 and 350.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.53) is better than Ligand B (53.43), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.712) is slightly lower than optimal (1-3), while Ligand B (3.248) is within the ideal range. This gives a slight edge to Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.762 and 0.821, respectively), indicating good drug-like properties.

**DILI:** Ligand A (64.754) has a higher DILI risk than Ligand B (22.683). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (91.276) has a much higher BBB penetration than Ligand A (32.144).

**Caco-2 Permeability:** Ligand A (-5.14) is worse than Ligand B (-4.451). Both are negative, but B is closer to 0.

**Aqueous Solubility:** Ligand A (-2.086) is slightly better than Ligand B (-3.367).

**hERG Inhibition:** Ligand A (0.379) shows a lower hERG inhibition risk than Ligand B (0.56). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (8.201) has significantly lower microsomal clearance than Ligand B (31.777), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (11.417) has a longer half-life than Ligand B (-7.547). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.023) has much lower P-gp efflux than Ligand B (0.394). This is a positive for Ligand A.

**Binding Affinity:** Ligand B (-9.3) has a stronger binding affinity than Ligand A (-8.5). This is a 1.5 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and significantly stronger binding affinity. However, Ligand A demonstrates superior ADME properties: lower DILI risk, lower microsomal clearance, longer half-life, and lower P-gp efflux. The difference in binding affinity is significant, but the improved ADME profile of Ligand A, particularly the lower DILI and better metabolic stability, makes it a more promising drug candidate for an enzyme target like SRC kinase.

Output:
0
2025-04-17 16:22:29,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (64.41) is significantly better than Ligand B (98.58). Lower TPSA generally correlates with better cell permeability, a crucial factor for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (A: 2.828, B: 1.834), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for cell penetration, but not dramatically so.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is more favorable than Ligand B (3 HBD, 7 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have similar QED values (A: 0.775, B: 0.755), indicating good drug-like properties.

**DILI:** Ligand B (79.604) has a higher DILI risk than Ligand A (34.626). This is a significant concern, as a lower DILI risk is highly desirable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.062) has a better BBB score than Ligand B (42.226), but it's not a primary deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.594) shows better Caco-2 permeability than Ligand B (-5.111), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.691 and -3.786 respectively). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.821) has a lower hERG inhibition liability than Ligand B (0.438), which is a positive attribute.

**Microsomal Clearance:** Ligand A (59.004) has a higher microsomal clearance than Ligand B (7.614). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-14.648) has a significantly longer in vitro half-life than Ligand A (-4.674), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.467) has lower P-gp efflux liability than Ligand B (0.041), which is favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While a 1.5 kcal/mol difference is generally significant, the other factors need to be considered.

**Overall Assessment:**

Ligand A has advantages in TPSA, H-bonding, DILI risk, Caco-2 permeability, hERG inhibition, and P-gp efflux. However, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has slightly better binding affinity. The poor solubility of both compounds is a major concern.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), the improved metabolic stability and binding affinity of Ligand B, despite its higher DILI risk, make it a slightly more promising starting point for optimization. The solubility issue would need to be addressed regardless of which lead is chosen.

Output:
1
2025-04-17 16:22:29,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.427 and 364.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (99.67), both are under the 140 threshold for oral absorption, but closer to the limit for good absorption.

**logP:** Ligand A (2.361) is slightly higher than Ligand B (1.49), both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), both are under the 10 threshold.

**QED:** Both ligands have similar QED values (0.692 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (23.071) has a significantly lower DILI risk than Ligand B (35.867). This is a major advantage.

**BBB:** Both have low BBB penetration, which is not a priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.168) is better than Ligand B (-5.562), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.544) is better than Ligand B (-3.115), indicating better solubility.

**hERG Inhibition:** Ligand A (0.057) has a much lower hERG risk than Ligand B (0.222). This is a significant advantage.

**Microsomal Clearance:** Ligand A (20.09) has a higher microsomal clearance than Ligand B (8.934), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.685) has a shorter half-life than Ligand B (0.7). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.028) has a lower P-gp efflux liability than Ligand B (0.062). This is a slight advantage for Ligand A.

**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 for Ligand B, and likely outweighs the ADME drawbacks.

**Conclusion:**

While Ligand A has better ADME properties (lower DILI, hERG, better solubility and permeability), Ligand B's significantly higher binding affinity (-7.9 vs 0.0 kcal/mol) is a critical advantage for an enzyme inhibitor. A >7 kcal/mol difference in binding is substantial and can often overcome moderate ADME liabilities. The metabolic stability and half-life of Ligand B are also better than Ligand A. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:22:29,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (361.467 and 361.877 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.27) is slightly higher than Ligand B (77.97), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.678 and 2.749 respectively), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially aiding 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 4 HBA, and Ligand B has 6. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have high QED scores (0.801 and 0.855), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 53.625, while Ligand B has 24.855. Ligand B is significantly better in terms of predicted liver injury risk.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (62.854) and Ligand B (44.591) are both relatively low.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.048 and -4.966), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.582). This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.237) has a lower hERG inhibition liability than Ligand B (0.762), which is preferable.

**12. Microsomal Clearance:** Ligand A (5.328) has a significantly lower microsomal clearance than Ligand B (37.482), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (-20.065) has a much longer in vitro half-life than Ligand B (20.34). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.166 and 0.179).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage, and could potentially outweigh some of the ADME concerns.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The poor solubility and Caco-2 permeability are concerning for both, but the improved metabolic profile of Ligand A is more critical for an enzyme target like SRC kinase. The stronger binding affinity of Ligand B is attractive, but the higher clearance and DILI risk are significant drawbacks.

Output:
0
2025-04-17 16:22:29,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.435 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is well below the 140 threshold for oral absorption and favorable. Ligand B (87.47) is still acceptable but less optimal.

**logP:** Both ligands have good logP values (2.935 and 1.802), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 5 HBAs. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have high QED scores (0.848 and 0.865), indicating good drug-likeness.

**DILI:** Ligand A (37.767) has a significantly lower DILI risk than Ligand B (60.644). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (85.459) has a higher BBB score than Ligand B (44.785).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. However, the absolute value is similar.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and suggests poor solubility. The absolute value is similar.

**hERG:** Ligand A (0.888) has a slightly higher hERG risk than Ligand B (0.35), but both are relatively low.

**Microsomal Clearance:** Ligand A (10.772) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (15.461). This is a significant advantage.

**In vitro Half-Life:** Ligand A (42.827) has a longer half-life than Ligand B (18.477), which is desirable.

**P-gp Efflux:** Ligand A (0.371) has lower P-gp efflux than Ligand B (0.017), suggesting better bioavailability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have excellent binding affinity, Ligand A demonstrates superior ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slightly higher hERG risk is less concerning given the overall profile. The TPSA is also more favorable.

Output:
1
2025-04-17 16:22:29,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.487 and 364.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (80.57) is still within acceptable limits but less optimal than A.

**logP:** Ligand A (4.117) is slightly high, potentially leading to solubility issues, but still within a manageable range. Ligand B (1.724) is excellent, falling right in the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is good. Ligand B (2 HBD, 5 HBA) is also good. Both are within the recommended limits.

**QED:** Both ligands have similar QED values (0.661 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (88.212) has a higher DILI risk than Ligand B (51.997). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (57.154) is slightly better than A (46.646).

**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 ligands have negative solubility values, indicating poor solubility. This is a concern for both, but potentially more problematic for Ligand A given its higher logP.

**hERG Inhibition:** Ligand A (0.551) has a higher hERG risk than Ligand B (0.132). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (32.345) has significantly lower microsomal clearance than Ligand A (75.952), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (24.438) has a much longer in vitro half-life than Ligand A (3.357), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.365) has a slightly higher P-gp efflux liability than Ligand B (0.102).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most important factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Ligand B is clearly the superior candidate. While both have solubility concerns, Ligand B excels in the critical areas of potency (binding affinity), metabolic stability (low Cl_mic and long t1/2), and safety (low DILI and hERG). Ligand A's higher DILI, hERG, and clearance, combined with its significantly weaker binding affinity, make it a less attractive drug candidate.

Output:
1
2025-04-17 16:22:29,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.857 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.84) is well below the 140 threshold and good for oral absorption. Ligand B (70.67) is also acceptable, but higher.

**logP:** Ligand A (3.927) is at the upper end of the optimal range (1-3), while Ligand B (1.66) is at the lower end. While Ligand A's logP could potentially cause some off-target issues, it's not drastically high. Ligand B's lower logP might hinder permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.746 and 0.85), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 71.074, which is concerning (high risk). Ligand B has a much lower DILI risk (34.703), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (91.392) has significantly better BBB penetration than Ligand B (46.336).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.892 and -4.829), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.437 and -1.489), indicating poor aqueous solubility, which is a major concern for bioavailability. Ligand B is slightly better in this regard.

**hERG Inhibition:** Ligand A (0.901) shows a moderate risk of hERG inhibition, while Ligand B (0.31) has a much lower risk, which is highly desirable.

**Microsomal Clearance:** Ligand A (33.673) has a higher microsomal clearance than Ligand B (3.518), indicating lower metabolic stability. Ligand B is significantly more metabolically stable.

**In vitro Half-Life:** Ligand B (-5.499) has a longer in vitro half-life than Ligand A (-4.86), which is a positive attribute.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.187 and 0.037).

**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, but needs to be weighed against the ADME properties.

**Overall Assessment:**

Ligand A has a better binding affinity, but suffers from high DILI risk, moderate hERG risk, poor solubility, and lower metabolic stability. Ligand B has a significantly better safety profile (lower DILI and hERG), better metabolic stability and half-life, and slightly better solubility. Both have poor Caco-2 permeability and solubility. The improved binding affinity of Ligand A is not enough to overcome its significant liabilities.

Output:
1
2025-04-17 16:22:29,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.459 Da and 364.274 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is slightly higher than Ligand B (61.2), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.825 and 2.29), 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) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability.

**QED:** Both ligands have similar and good QED scores (0.71 and 0.797), indicating good drug-likeness.

**DILI:** Ligand A (12.718) has a significantly lower DILI risk than Ligand B (73.09). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (76.541 and 71.229), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the values are similar (-4.36 and -4.859).

**Aqueous Solubility:** Ligand A (-1.67) has slightly better solubility than Ligand B (-3.213), although both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.283 and 0.403), which is excellent.

**Microsomal Clearance:** Ligand A (77.294) has a higher microsomal clearance than Ligand B (6.91). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-11.955) has a longer in vitro half-life than Ligand A (-19.347), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.144).

**Binding Affinity:** Both ligands have identical binding affinities (-9.0 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), the significantly lower DILI risk for Ligand A is a crucial advantage. Given the enzyme-kinase target class, minimizing potential toxicity is paramount. The similar binding affinities mean potency isn't a differentiating factor. The slightly better solubility of Ligand A is also a minor benefit. Therefore, Ligand A is the more viable drug candidate.

Output:
1
2025-04-17 16:22:29,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.46 and 349.48 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.64) is higher than Ligand B (53.09). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (1.825) and Ligand B (0.958) are both within the optimal 1-3 range. Ligand A is slightly preferred.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.739 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A (28.31%) has a higher DILI risk than Ligand B (6.28%). This is a significant advantage for Ligand B.

**BBB:** Ligand A (29.51%) has a lower BBB penetration than Ligand B (75.18%). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Ligand A (-4.938) has lower Caco-2 permeability than Ligand B (-4.599). Both are negative, which is not ideal, but B is better.

**Aqueous Solubility:** Ligand A (-1.56) has lower solubility than Ligand B (-0.296). Solubility is important for bioavailability, favoring Ligand B.

**hERG Inhibition:** Ligand A (0.359) has a slightly higher hERG inhibition risk than Ligand B (0.264). Lower is better, favoring Ligand B.

**Microsomal Clearance:** Ligand A (12.36 mL/min/kg) has lower microsomal clearance than Ligand B (17.543 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (2.391 hours) has a shorter half-life than Ligand B (6.473 hours). Longer half-life is generally preferred, favoring Ligand B.

**P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux than Ligand B (0.014). Lower efflux is preferred, favoring Ligand A.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This is a significant advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates a more favorable overall profile. It has lower DILI risk, better solubility, better Caco-2 permeability, better BBB penetration, a longer half-life, and a stronger binding affinity. While Ligand A has better metabolic stability and P-gp efflux, the advantages of Ligand B in terms of safety (DILI, hERG) and potency (affinity) are more crucial for an oncology target.

Output:
1
2025-04-17 16:22:29,861 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [354.359, 108.17 ,   0.569,   0.   ,   8.   ,   0.682,  62.621,  81.466, -4.425,  -1.536,   0.114,  35.299, -18.203,   0.056,  -6.9  ]
**Ligand B:** [347.478,  44.37 ,   3.621,   2.   ,   2.   ,   0.706,  11.128,  93.525, -5.092,  -3.394,   0.976,   1.539,  44.593,   0.251,  -8.9  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (354.359) is slightly higher than B (347.478), but both are acceptable.
2. **TPSA:** A (108.17) is higher than B (44.37). While A is still within a reasonable range for oral absorption, B is significantly better, suggesting potentially improved cell permeability.
3. **logP:** A (0.569) is lower than the optimal range (1-3), potentially hindering permeability. B (3.621) is very good.
4. **HBD:** A (0) is ideal. B (2) is acceptable.
5. **HBA:** A (8) is acceptable. B (2) is excellent.
6. **QED:** Both are good (A: 0.682, B: 0.706), indicating drug-like properties.
7. **DILI:** A (62.621) is moderately high risk. B (11.128) is very low risk, a significant advantage.
8. **BBB:** A (81.466) is good, but B (93.525) is excellent. While SRC isn't a CNS target, higher BBB is generally favorable.
9. **Caco-2:** A (-4.425) is very poor. B (-5.092) is also poor, but slightly better. Both suggest very limited intestinal absorption.
10. **Solubility:** A (-1.536) is poor. B (-3.394) is even worse. Solubility is a concern for both.
11. **hERG:** A (0.114) is very low risk. B (0.976) is slightly higher, but still acceptable.
12. **Cl_mic:** A (35.299) is relatively high, indicating faster metabolism. B (1.539) is very low, suggesting excellent metabolic stability. This is a major advantage for B.
13. **t1/2:** A (-18.203) is very short, indicating rapid clearance. B (44.593) is long, indicating slow clearance. This is a significant advantage for B.
14. **Pgp:** A (0.056) is very low efflux, good. B (0.251) is also low efflux, good.
15. **Binding Affinity:** B (-8.9) is significantly better than A (-6.9), a 2.0 kcal/mol difference. This is a substantial advantage that can outweigh some ADME concerns.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in metabolic stability (Cl_mic and t1/2) and has a much stronger binding affinity. While solubility is poor for both, the superior affinity and metabolic profile of B are more critical. The lower DILI risk for B is also a significant benefit.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, **Ligand B** is the more viable drug candidate.

1
2025-04-17 16:22:29,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 370.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (84.3), both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.79) is slightly lower than optimal (1-3), but still acceptable. Ligand B (1.682) is within the optimal range.

**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 (6) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.635 and 0.824), indicating good drug-like properties.

**DILI:** Ligand A (12.369) has a significantly lower DILI risk than Ligand B (35.479), which is a major advantage.

**BBB:** Ligand A (46.84) has a lower BBB penetration than Ligand B (75.107). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-4.783) has worse Caco-2 permeability than Ligand B (-5.088), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.397) has better aqueous solubility than Ligand B (-2.045).

**hERG Inhibition:** Ligand A (0.205) has a lower hERG inhibition risk than Ligand B (0.395), which is a significant advantage.

**Microsomal Clearance:** Ligand A (14.475) has higher microsomal clearance than Ligand B (1.163), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (12.562) has a shorter in vitro half-life than Ligand B (22.937), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.017) has lower P-gp efflux than Ligand B (0.088), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.4) has a significantly better binding affinity than Ligand A (-9.2). This is a crucial factor for enzyme inhibitors. The difference of 1.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, lower DILI, and lower hERG risk, Ligand B's significantly stronger binding affinity (-7.4 vs -9.2 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are more critical for an enzyme inhibitor like an SRC kinase inhibitor. The improved binding affinity is a major advantage that outweighs the slightly higher DILI and hERG risks of Ligand B.

Output:
1
2025-04-17 16:22:29,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.443 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values around 50, well below the 140 threshold for oral absorption.

**logP:** Both ligands have logP values between 2.9 and 4.0, which is acceptable, though approaching the upper limit where solubility issues could arise.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable ranges.

**QED:** Both ligands have similar QED scores (0.717 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 71.694, which is relatively high. Ligand B has a much lower DILI risk of 8.104, a significant advantage.

**BBB:** Both ligands have high BBB penetration (81.466 and 75.301), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show 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:** Both ligands have very poor aqueous solubility (-3.457 and -3.722). This is a major concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.607 and 0.765), which is positive.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (58.104) than Ligand B (83.97), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a slightly longer half-life (26.384 hours) than Ligand A (24.592 hours), but the difference is minor.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.758 and 0.672).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-8.7 kcal/mol) compared to Ligand A (-6.1 kcal/mol). This 2.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -6.1 kcal/mol) is a major advantage for an enzyme target like SRC. Additionally, Ligand B has a much lower DILI risk, which is a critical safety parameter. While Ligand A has slightly better metabolic stability, the difference isn't large enough to offset the superior potency and safety profile of Ligand B.

Output:
1
2025-04-17 16:22:29,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.37 and 349.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.23) is slightly above the preferred <140 for good absorption, while Ligand B (84.67) is well within the range.

**logP:** Both ligands have good logP values (2.519 and 1.976), falling within 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 (0.677 and 0.849), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 84.22%, which is high. Ligand B has a much lower DILI risk of 32.57%, which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB score (77.82%) than Ligand A (28.73%).

**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 (0.305) shows slightly higher hERG inhibition liability than Ligand B (0.242), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (13.56 mL/min/kg) has lower clearance than Ligand B (22.44 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.91 hours) has a significantly longer half-life than Ligand B (0.79 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.049 and 0.09).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life and better metabolic stability, Ligand B's significantly stronger binding affinity (-7.2 vs -9.6 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk (32.6% vs 84.2%), which is a major safety concern. The slightly lower half-life of Ligand B can potentially be addressed through structural modifications during lead optimization. The negative Caco-2 and solubility values are concerning for both, but can be investigated further.

Output:
1
2025-04-17 16:22:29,862 - INFO - Batch 458 complete. Total preferences: 7328
2025-04-17 16:22:29,862 - INFO - Processing batch 459/512...
2025-04-17 16:23:09,134 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.404 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 102, which is slightly above the optimal <140 for good oral absorption, but not a major concern for a kinase inhibitor.

**logP:** Ligand A (1.271) is better than Ligand B (0.565). A logP between 1-3 is optimal, and Ligand B is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.693 and 0.671), indicating good drug-likeness.

**DILI:** Ligand A (41.877) has a higher DILI risk than Ligand B (29.391). This is a significant advantage for Ligand B.

**BBB:** Both ligands have relatively low BBB penetration (61.38 and 41.838), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.433 and -5.311). 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 (-2.882 and -1.802). Again, the scale is unclear, but these suggest poor solubility.

**hERG Inhibition:** Ligand A (0.455) has a slightly higher hERG risk than Ligand B (0.19). Lower hERG is preferred.

**Microsomal Clearance:** Ligand B (-17.155) exhibits significantly better metabolic stability (lower clearance) than Ligand A (-3.783). This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (3.827) has a slightly longer half-life than Ligand A (-27.696). This is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux values (0.047 and 0.046), suggesting minimal efflux.

**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 of the ADME drawbacks.

**Conclusion:**

While Ligand B has better ADMET properties (lower DILI, better metabolic stability, slightly longer half-life), the significantly stronger binding affinity of Ligand A (-8.8 kcal/mol vs -7.7 kcal/mol) is a major advantage for an enzyme inhibitor. The difference in binding affinity is likely to be more impactful than the slightly worse ADMET profile of Ligand A, especially considering the potential for optimization of ADMET properties later in the drug discovery process.

Output:
1
2025-04-17 16:23:09,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (81.67) is well below the 140 threshold for oral absorption. Ligand B (125.47) is still acceptable, but less optimal.

**logP:** Ligand A (1.033) is within the optimal range (1-3). Ligand B (-0.339) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=4, HBA=8) both fall within acceptable limits, though Ligand B has a higher HBA count.

**QED:** Both ligands have reasonable QED scores (A: 0.61, B: 0.433), indicating drug-like properties. Ligand A is better here.

**DILI:** Ligand A (12.641) has a significantly lower DILI risk than Ligand B (59.907). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (65.413) has a higher BBB score, but this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.119 and -5.566), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.305 and -1.853), indicating poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG:** Both ligands have low hERG risk (0.152 and 0.192), which is good.

**Microsomal Clearance:** Ligand A (33.452) has a higher microsomal clearance than Ligand B (12.452), meaning it's likely to be metabolized faster. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (6.276) has a significantly longer in vitro half-life than Ligand A (-1.626). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.017).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). This 0.9 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity and a significantly longer half-life, which are critical for an enzyme inhibitor. While Ligand B has a higher TPSA and a slightly lower logP, the superior affinity and metabolic stability are more important. Ligand A has a better DILI score and QED, but the differences in half-life and affinity are more impactful for this target class. The poor solubility and permeability are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:23:09,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 339.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.8) is better than Ligand B (65.2), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.016) is optimal, while Ligand B (3.079) is approaching the upper limit of the optimal range.

**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 2. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.696 and 0.899, respectively), indicating good drug-like properties.

**DILI:** Ligand A (33.23) has a significantly lower DILI risk than Ligand B (47.421). This is a major advantage for Ligand A.

**BBB:** Ligand B (78.945) has a higher BBB penetration than Ligand A (38.697). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.777) has worse Caco-2 permeability than Ligand B (-5.016), but both are poor.

**Aqueous Solubility:** Ligand A (-1.399) has better aqueous solubility than Ligand B (-4.421). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.267) has a lower hERG inhibition liability than Ligand B (0.737), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (27.406) has a significantly lower microsomal clearance than Ligand B (44.578), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (19.824) has a longer in vitro half-life than Ligand B (-2.784). This is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.122 and 0.138).

**Binding Affinity:** Both ligands have similar 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. While Ligand B has slightly better BBB penetration (irrelevant for this target) and similar binding affinity, Ligand A excels in crucial areas for an enzyme inhibitor: lower DILI risk, better solubility, lower hERG inhibition, and significantly better metabolic stability (lower Cl_mic and longer t1/2). The slightly worse Caco-2 permeability is a minor drawback compared to the substantial advantages in safety and PK properties.

Output:
0
2025-04-17 16:23:09,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.5 and 341.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.88) is better than Ligand B (63.13), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have acceptable logP values (1.58 and 2.37), falling within the 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors:** Ligand A has 3 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 (0.883) has a significantly better QED score than Ligand A (0.582), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (38.58 and 36.29), well below the concerning threshold of 60.

**8. BBB:** Both ligands have moderate BBB penetration (51.76 and 55.91). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified and the values may be percentile scores where negative values are possible.

**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 very low hERG inhibition risk (0.187 and 0.205), which is excellent.

**12. Microsomal Clearance:** Ligand A (20.65) has a lower (better) microsomal clearance than Ligand B (30.53), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.52) has a significantly longer in vitro half-life than Ligand A (-4.36), which is a major advantage. A negative half-life is unusual and may indicate an issue with the assay or compound stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.052 and 0.094).

**15. 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 notable.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better TPSA and Cl_mic, Ligand B excels in QED, in vitro half-life, and binding affinity. The improved QED and half-life are particularly important for drug development. The slightly better binding affinity of Ligand B further strengthens its position. The unusual 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 16:23:09,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.471 Da) is slightly better positioned.

**TPSA:** Ligand A (66.91) is significantly better than Ligand B (111.55). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (4.159) is higher than the optimal range (1-3), but still potentially manageable. Ligand B (1.348) is a bit low, potentially hindering permeability.

**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 A (0.72) has a better QED score than Ligand B (0.534), indicating a more drug-like profile.

**DILI:** Ligand B (45.483) has a lower DILI risk than Ligand A (52.385), which is a positive attribute.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand A (76.735) has better BBB penetration than Ligand B (33.656).

**Caco-2 Permeability:** Ligand A (-4.737) has a much better Caco-2 permeability than Ligand B (-5.024), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.826) has better aqueous solubility than Ligand B (-2.202), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.722) has a slightly better hERG profile than Ligand B (0.247), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (21.488) has significantly lower microsomal clearance than Ligand A (61.906), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (39.926) has a longer in vitro half-life than Ligand B (3.899), which is desirable.

**P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux than Ligand B (0.065), which is a positive attribute.

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in metabolic stability (lower Cl_mic) and DILI risk. However, Ligand A demonstrates superior properties across most other key ADME parameters (TPSA, logP, QED, solubility, permeability, hERG, P-gp efflux, and half-life). Given the equal binding affinity, the better ADME profile of Ligand A, particularly its permeability and solubility, makes it a more promising candidate. While the lower metabolic stability of Ligand A is a concern, it can potentially be addressed through structural modifications during lead optimization.

Output:
1
2025-04-17 16:23:09,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (328.415 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (350.463 Da) is also good.

**TPSA:** Ligand A (41.99) is significantly better than Ligand B (96.11). A TPSA under 140 is desirable for oral absorption, but lower is generally better for enzymes. Ligand B's higher TPSA could hinder absorption.

**logP:** Ligand A (4.742) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.151) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) has a more favorable profile than Ligand B (3 HBD, 4 HBA). Fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.703 and 0.669), indicating good drug-likeness.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (38.62). This is a significant concern, as lower DILI is preferred.

**BBB:** This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (78.247) is slightly better than Ligand B (60.644).

**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 aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.812) has a slightly higher hERG risk than Ligand B (0.383). Lower hERG is preferred.

**Microsomal Clearance:** Ligand B (50.935) has a significantly lower microsomal clearance than Ligand A (92.293), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (8.951) has a longer half-life than Ligand B (1.112). This is generally desirable, but the difference is less important given Ligand B's better metabolic stability.

**P-gp Efflux:** Ligand A (0.68) has slightly higher P-gp efflux than Ligand B (0.056), which could reduce bioavailability.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly better binding affinity than Ligand A (-9.1 kcal/mol). This is the most important factor for an enzyme inhibitor, and the 1.1 kcal/mol advantage is substantial.

**Conclusion:**

Despite Ligand A's slightly better MW and half-life, Ligand B is the superior candidate. Its significantly better binding affinity, lower DILI risk, lower hERG risk, and improved metabolic stability (lower Cl_mic) outweigh the drawbacks of its higher TPSA and slightly lower BBB. The binding affinity difference is particularly important, as it's a primary driver of efficacy for enzyme inhibitors.

Output:
1
2025-04-17 16:23:09,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (73.2) is better than Ligand B (98.09). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.244, B: 3.173), falling within the optimal range of 1-3.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=0, HBA=5) as it strikes a better balance between solubility and permeability.

**QED:** Ligand A (0.861) has a significantly higher QED score than Ligand B (0.476), indicating a more drug-like profile.

**DILI:** Ligand B (93.292) has a much higher DILI risk than Ligand A (47.732). This is a major concern.

**BBB:** Both have similar BBB penetration (A: 78.519, B: 73.943). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.943) shows better Caco-2 permeability than Ligand B (-4.662).

**Aqueous Solubility:** Both have similar, very poor aqueous solubility (-4.156 and -3.991). This is a potential issue for both, but can be addressed with formulation strategies.

**hERG:** Both ligands show low hERG inhibition liability (A: 0.498, B: 0.514), which is good.

**Microsomal Clearance:** Ligand A (18.796) has a significantly lower microsomal clearance than Ligand B (36.144), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.829) has a longer in vitro half-life than Ligand B (-1.431), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux than Ligand B (0.261), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a substantially better binding affinity than Ligand B (0.0 kcal/mol). This is a critical advantage, as potency is a primary concern for enzyme inhibitors. The difference of 8.5 kcal/mol is extremely significant.

**Conclusion:**

Ligand A is clearly the superior candidate. It has a better QED score, lower DILI risk, better permeability, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and, most importantly, a *much* stronger binding affinity. While both have poor solubility, this is a formulation challenge that can be addressed. The significant difference in binding affinity and the lower DILI risk of Ligand A outweigh any minor drawbacks.

Output:
1
2025-04-17 16:23:09,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (361.463 Da & 355.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.79) is excellent, well below the 140 threshold for oral absorption. Ligand B (116.76) is still acceptable, but higher, potentially impacting absorption.

**3. logP:** Ligand A (3.635) is optimal. Ligand B (0.664) is low, potentially hindering membrane permeability and bioavailability.

**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 (8) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.693 and 0.66), indicating good drug-likeness.

**7. DILI:** Ligand A (53.742) has a lower DILI risk than Ligand B (92.982), which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.721) is better than Ligand B (45.638).

**9. Caco-2 Permeability:** Ligand A (-4.586) is better than Ligand B (-5.63), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.358) is better than Ligand B (-4.017), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.75) is better than Ligand B (0.464), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (75.004) has higher clearance than Ligand B (19.069), meaning Ligand B is more metabolically stable. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (8.564) has a slightly better half-life than Ligand B (7.617).

**14. P-gp Efflux:** Ligand A (0.671) is better than Ligand B (0.09), indicating less efflux and potentially better bioavailability.

**15. Binding Affinity:** Ligand A (-7.0) has a significantly better binding affinity than Ligand B (0.0). This is the most important factor for an enzyme inhibitor. The >1.5 kcal/mol advantage of A outweighs any potential ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic), the significantly superior binding affinity of Ligand A (-7.0 kcal/mol vs 0.0 kcal/mol) is a decisive advantage for an enzyme inhibitor. Furthermore, Ligand A demonstrates better overall ADME properties, including lower DILI risk, better solubility, permeability, and hERG inhibition profile.

Output:
1
2025-04-17 16:23:09,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.853 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is significantly better than Ligand B (96.25). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (4.82) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (0.68) is quite 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.

**QED:** Both ligands have similar QED values (0.735 and 0.66), indicating reasonable drug-likeness.

**DILI:** Ligand A (61.225) has a higher DILI risk than Ligand B (38.813), which is preferable.

**BBB:** Ligand A (73.633) has better BBB penetration than Ligand B (34.083), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.059) is worse than Ligand B (-5.18), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-6.114) is significantly worse than Ligand B (-1.814), which is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.79 and 0.223), which is excellent.

**Microsomal Clearance:** Ligand A (120.418) has a significantly higher microsomal clearance than Ligand B (0.913), indicating lower metabolic stability. This is a critical negative for A.

**In vitro Half-Life:** Ligand A (31.1) has a longer half-life than Ligand B (-6.157), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.306 and 0.048).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.1 and -9.6 kcal/mol).

**Overall Assessment:**

Ligand B is the better candidate. While its logP is low, its superior solubility, lower DILI risk, and *much* better metabolic stability (lower Cl_mic) outweigh the slightly lower Caco-2 permeability. The binding affinity is comparable between the two. Ligand A's poor solubility and high clearance are significant liabilities that make it a less attractive drug candidate.

Output:
1
2025-04-17 16:23:09,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (336.355 and 348.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.86) is well within the desirable range for oral absorption (<140), while Ligand B (40.62) is even better.

**3. logP:** Ligand A (1.342) is optimal, while Ligand B (3.697) is approaching the upper limit of the optimal range.

**4. H-Bond Donors (HBD):** Both ligands meet the criteria (<=5). Ligand A has 1 HBD, and Ligand B has 0.

**5. H-Bond Acceptors (HBA):** Both ligands meet the criteria (<=10). Ligand A has 7 HBA, and Ligand B has 2.

**6. QED:** Both ligands have similar, good QED scores (0.727 and 0.734, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (83.017) has a significantly higher DILI risk than Ligand B (17.759). This is a major concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (91.276) has a higher BBB score, but it's not a primary factor here.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-5.059) is worse than Ligand B (-4.348).

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are logS values, lower values indicate poorer solubility. Ligand A (-2.732) is worse than Ligand B (-4.166).

**11. hERG Inhibition:** Both ligands have low hERG risk (0.549 and 0.555).

**12. Microsomal Clearance (Cl_mic):** Ligand A (41.614) has lower clearance than Ligand B (92.253), suggesting better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (-27.626) has a negative half-life, which is impossible. This is a red flag. Ligand B (36.82) is reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.324).

**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.

**Enzyme-Specific Priorities:** For SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and has a reasonable half-life. Ligand A has a problematic half-life value and a much higher DILI risk. While Ligand A has better metabolic stability, the DILI risk and the invalid half-life are major drawbacks. The significantly better binding affinity of Ligand B outweighs the slightly higher Cl_mic.

Output:
1
2025-04-17 16:23:09,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands (360.439 Da and 348.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.16) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (85.17) is well within the desired range.

**logP:** Ligand A (3.611) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.547) is quite low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is within acceptable limits. Ligand B (1 HBD, 7 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.446 and 0.724, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (25.553), which is a significant concern.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (84.257) is better than Ligand A (70.997). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.736) has poor predicted Caco-2 permeability, indicating potential absorption issues. Ligand B (-5.379) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-5.009 and -1.184 respectively). This is a major drawback.

**hERG Inhibition:** Ligand A (0.628) has a slightly higher hERG risk than Ligand B (0.116), which is preferable.

**Microsomal Clearance:** Ligand A (42.303) has a higher microsomal clearance than Ligand B (18.102), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-0.468) has a slightly longer predicted half-life than Ligand A (-16.51).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.229 and 0.071).

**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 ADME concerns.

**Conclusion:**

While both ligands have solubility issues, Ligand B is the more promising candidate. Its significantly higher binding affinity (-8.8 vs -7.9 kcal/mol) is a major advantage for an enzyme inhibitor. It also exhibits lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly longer half-life. Although its logP is low, the strong binding affinity suggests it can still effectively engage the target. The slightly better Caco-2 and BBB values are also beneficial. The higher hERG risk of Ligand A is also a concern.

Output:
1
2025-04-17 16:23:09,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.383 and 351.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.18) is well below the 140 threshold for good absorption. Ligand B (96.53) is also acceptable, though slightly higher.

**logP:** Ligand A (2.446) is optimal (1-3). Ligand B (0.485) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is well within acceptable limits. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Ligand A (0.714) has a good drug-like profile. Ligand B (0.438) is lower, indicating a less drug-like profile.

**DILI:** Ligand A (74.835) has a moderate DILI risk, but acceptable. Ligand B (14.851) has a very low DILI risk, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (60.993) and Ligand B (45.677) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.871) is poor, suggesting low intestinal absorption. Ligand B (-5.246) is also poor.

**Aqueous Solubility:** Ligand A (-3.211) is poor. Ligand B (-2.055) is also poor, but slightly better than A.

**hERG:** Ligand A (0.448) has a low hERG risk, which is favorable. Ligand B (0.095) has an even lower hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (78.051) has a relatively high microsomal clearance, indicating lower metabolic stability. Ligand B (-5.457) has a negative clearance, which is highly favorable and suggests excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-26.138) has a negative half-life, which is excellent. Ligand B (-20.977) also has a negative half-life, but slightly less favorable than A.

**P-gp Efflux:** Ligand A (0.48) has moderate P-gp efflux. Ligand B (0.009) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B having better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux, lower hERG), Ligand A's significantly stronger binding affinity (-8.3 vs -7.4 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. The improved potency is likely to be more impactful than the slightly less favorable ADME profile, especially considering the moderate DILI risk of Ligand A. The negative half-life and Caco-2 values are also very good for Ligand A.

Output:
1
2025-04-17 16:23:09,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.22) is better than Ligand B (123.66). TPSA <140 is good for oral absorption. Ligand B is getting closer to the upper limit.

**logP:** Ligand A (1.508) is optimal, while Ligand B (-0.402) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (6). Fewer HBAs generally improve permeability.

**QED:** Ligand A (0.79) is significantly better than Ligand B (0.409), indicating a more drug-like profile.

**DILI:** Ligand A (33.695) has a much lower DILI risk than Ligand B (54.401). Both are acceptable, but A is clearly better.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (62.97) is better than Ligand B (36.371).

**Caco-2 Permeability:** Ligand A (-5.046) is better than Ligand B (-5.689), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.474) is better than Ligand B (-1.94). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.352) has a lower hERG risk than Ligand B (0.131), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (29.252) has a better (lower) microsomal clearance than Ligand B (-31.056), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.453) has a significantly longer half-life than Ligand B (2.892), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.003).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 and -8.0 kcal/mol). The difference of 0.7 kcal/mol is not significant enough to outweigh the numerous advantages of Ligand A.

**Conclusion:**

Ligand A is superior to Ligand B across almost all ADME-Tox properties, with a significantly better QED, DILI, solubility, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While both have excellent binding affinities, the overall profile of Ligand A makes it a much more promising drug candidate.

Output:
1
2025-04-17 16:23:09,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.439 and 357.317 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.25) is better than Ligand B (115.3), being closer to the <140 threshold for good absorption.

**logP:** Ligand B (0.689) is slightly better than Ligand A (0.286), falling more comfortably within the 1-3 range. Ligand A is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 8 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.708 and 0.781), indicating good drug-like properties.

**DILI:** Ligand A (43.622) has a significantly lower DILI risk than Ligand B (72.547). This is a major advantage for Ligand A.

**BBB:** Both have similar BBB penetration (61.613 and 68.205), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both are negative (-5.373 and -5.069), indicating poor permeability. This is a concern for both, but the scale is not clear, so it's hard to compare.

**Aqueous Solubility:** Both are negative (-1.715 and -1.871), indicating poor solubility. This is a concern for both, but the scale is not clear, so it's hard to compare.

**hERG Inhibition:** Ligand A (0.249) has a lower hERG inhibition risk than Ligand B (0.096), which is preferable.

**Microsomal Clearance:** Ligand A (-26.459) has *much* lower microsomal clearance than Ligand B (9.592), indicating significantly better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (1.436) has a lower half-life than Ligand B (9.478). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.025).

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-8.6). However, the difference is small (0.5 kcal/mol) and may not outweigh the ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and in vitro half-life, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, and lower hERG inhibition. These factors are crucial for enzyme inhibitors, outweighing the minor affinity difference. The poor Caco-2 and solubility for both compounds are concerning, but can be addressed with formulation strategies.

Output:
0
2025-04-17 16:23:09,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (389.279 Da and 377.75 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (77.25), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have a logP around 3.5, which is optimal.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, below the threshold of 10.

**QED:** Ligand B (0.863) has a significantly better QED score than Ligand A (0.691), indicating a more drug-like profile.

**DILI:** Ligand A (62.544) has a better DILI percentile than Ligand B (84.529), indicating a lower risk of liver injury.

**BBB:** Both ligands have high BBB penetration (71.307 and 77.627), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.778) and Ligand B (-4.525) 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 (-3.776 and -4.262). This is a significant concern.

**hERG Inhibition:** Ligand A (0.655) has a lower hERG risk than Ligand B (0.132), which is a major advantage.

**Microsomal Clearance:** Ligand A (28.339) has significantly better metabolic stability (lower clearance) than Ligand B (73.106).

**In vitro Half-Life:** Ligand A (14.755 hours) has a much longer half-life than Ligand B (-15.964 hours). The negative value for ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.397) has lower P-gp efflux than Ligand B (0.19), indicating better bioavailability.

**Binding Affinity:** Ligand B (-10.2 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:**

Ligand B has a much better binding affinity, a better QED score, and comparable logP values. However, it suffers from significantly worse DILI risk, metabolic stability, half-life, and P-gp efflux. Ligand A has better ADME properties (DILI, Cl_mic, t1/2, Pgp, hERG) and acceptable binding affinity. The solubility is poor for both, but the hERG risk for ligand B is a major red flag. Given the importance of metabolic stability and minimizing toxicity (hERG, DILI) for kinase inhibitors, and the substantial difference in half-life, Ligand A is the more promising candidate despite the lower binding affinity. The difference in binding affinity could potentially be addressed through further optimization, while fixing the ADME issues of Ligand B would be more challenging.

Output:
0
2025-04-17 16:23:09,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.381 and 355.341 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is well below the 140 threshold for good absorption, while Ligand B (102.76) is still acceptable but higher.

**logP:** Ligand A (3.642) is optimal (1-3). Ligand B (0.442) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.813 and 0.727, both >0.5).

**DILI:** Ligand A (60.062) is borderline, indicating moderate risk. Ligand B (52.191) is better, with a lower DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.2) is higher than Ligand B (52.772).

**Caco-2:** Ligand A (-4.697) and Ligand B (-5.017) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-3.741) and Ligand B (-2.388) both have negative values, suggesting very poor aqueous solubility. This is a significant concern for both.

**hERG:** Ligand A (0.811) shows a lower hERG risk than Ligand B (0.168).

**Microsomal Clearance:** Ligand A (-2.146) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand B (-21.156) has a much higher (more positive) clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (15.187 hours) has a good half-life. Ligand B (-30.698) has a very short half-life, which is undesirable.

**P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux liability than Ligand B (0.006).

**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 enough to overcome the significant ADME deficiencies of Ligand B.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a lower hERG risk. While both have poor Caco-2 permeability and solubility, Ligand A's superior metabolic properties and safety profile make it a better starting point for optimization. The poor solubility and permeability would need to be addressed through formulation or structural modifications, but the core pharmacokinetic properties are more favorable for Ligand A.

Output:
0
2025-04-17 16:23:09,137 - INFO - Batch 459 complete. Total preferences: 7344
2025-04-17 16:23:09,137 - INFO - Processing batch 460/512...
2025-04-17 16:23:49,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 376.563 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is better than Ligand B (75.71). Both are below 140, suggesting reasonable absorption.

**logP:** Ligand A (3.799) is slightly higher than Ligand B (2.253), both are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.737 and 0.705), indicating good drug-likeness.

**DILI:** Ligand A (31.214) has a significantly lower DILI risk than Ligand B (23.769), which is a major advantage.

**BBB:** Ligand B (80.613) shows better BBB penetration than Ligand A (54.75), but this is less critical for a kinase inhibitor unless CNS activity is desired.

**Caco-2:** 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.

**Solubility:** Both have negative solubility values, again, the scale is undefined.

**hERG:** Both ligands have low hERG inhibition liability (0.664 and 0.619), which is excellent.

**Microsomal Clearance:** Ligand A (73.519) has higher microsomal clearance than Ligand B (72.117), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-32.559) has a significantly longer in vitro half-life than Ligand A (113.08), which is a substantial advantage for dosing convenience.

**P-gp Efflux:** Both have low P-gp efflux liability (0.333 and 0.031).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a 1.0 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B's better half-life and BBB penetration, Ligand A is the more promising candidate. The significantly stronger binding affinity (-7.6 vs -6.6 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, Ligand A has a much lower DILI risk. While Ligand B has a better half-life, the difference in binding affinity and the lower DILI risk of Ligand A are more important factors for this target class. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:23:49,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 355.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (110.93) is slightly above the preferred <140, but acceptable. Ligand B (88.18) is well within the range.

**logP:** Ligand A (0.952) is at the lower end of optimal, potentially impacting permeability. Ligand B (-0.375) is below 1, which is a concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.634 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (16.867) has a significantly lower DILI risk than Ligand B (29.74), which is a major advantage.

**BBB:** Both have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand A (63.862) is slightly better than Ligand B (51.377).

**Caco-2:** Ligand A (-5.662) and Ligand B (-4.894) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Solubility:** Both ligands have negative solubility values (-1.084 and -0.537), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG:** Both ligands have very low hERG risk (0.363 and 0.19), which is excellent.

**Microsomal Clearance:** Ligand A (-4.654) has a negative clearance, suggesting very high metabolic stability, a significant advantage. Ligand B (12.108) has a moderate clearance.

**In vitro Half-Life:** Ligand A (9.209) has a better half-life than Ligand B (-0.826).

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.017 and 0.006), which is favorable.

**Binding Affinity:** Both ligands have similar and good binding affinities (-8.0 and -8.4 kcal/mol).

**Conclusion:**

While both ligands have good binding affinity and low hERG risk, Ligand A is the better candidate. Its significantly lower DILI risk and superior metabolic stability (negative Cl_mic) are crucial advantages for an enzyme target. Although both have poor solubility and Caco-2 permeability, the better ADME profile of Ligand A outweighs the slightly lower logP.

Output:
1
2025-04-17 16:23:49,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.411 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (86.47 and 81.08) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.842) is optimal, while Ligand B (0.758) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.789 and 0.767), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.397, which is moderately high. Ligand B has a significantly lower DILI risk of 12.369, which is excellent. This is a major advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.182) is slightly better than Ligand B (48.081).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.694 and -4.802), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values (-4.291 and -1.634), also unusual. This suggests poor aqueous solubility for both compounds. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.396 and 0.306).

**Microsomal Clearance:** Ligand A (45.122 mL/min/kg) has higher clearance than Ligand B (24.432 mL/min/kg), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (17.824 hours) has a significantly longer half-life than Ligand A (-15.591 hours, which is negative and likely an error or outlier). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.136 and 0.025).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol), by a margin of 1.6 kcal/mol. This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has a slightly better logP and BBB, Ligand B demonstrates superior properties in key areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and substantially stronger binding affinity. The solubility and Caco-2 permeability are poor for both, but the binding affinity difference is substantial enough to favor Ligand B.

Output:
1
2025-04-17 16:23:49,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.322 Da) is slightly higher, but acceptable. Ligand B (347.419 Da) is also good.

**TPSA:** Ligand A (50.28) is good, below the 140 threshold for oral absorption. Ligand B (81.77) is also acceptable, but approaching the upper limit.

**logP:** Ligand A (4.323) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.413) is quite low, which could hinder membrane permeability and bioavailability.

**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 (0.736 and 0.801), indicating good drug-like properties.

**DILI:** Ligand A (58.434) has a moderate DILI risk. Ligand B (36.448) has a lower, and preferable, DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.676) is higher than Ligand B (36.448).

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.866) has a slightly higher hERG risk than Ligand B (0.494), but both are relatively low.

**Microsomal Clearance:** Ligand A (12.752) has a higher clearance than Ligand B (9.657), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-10.83) has a negative half-life, which is not possible, and indicates a very short half-life. Ligand A (2.073) has a short half-life, but is at least a plausible value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**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 less than the 1.5 kcal/mol threshold, it's still a factor.

**Conclusion:**

Considering the priorities for an enzyme target (SRC kinase), Ligand B is the more promising candidate despite its low logP. The significantly better binding affinity (-7.2 vs -6.9 kcal/mol) and lower DILI risk outweigh the potential permeability concerns associated with the lower logP. The extremely short half-life of Ligand B is a major concern, but could potentially be addressed through structural modifications. Ligand A has a slightly better logP, but suffers from a higher DILI risk and lower binding affinity, and a short half-life.

Output:
1
2025-04-17 16:23:49,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.259 Da) is slightly higher than Ligand B (342.443 Da), but both are acceptable.

**TPSA:** Ligand A (67.43) is better than Ligand B (86.88). Lower TPSA generally improves absorption.

**logP:** Both ligands have acceptable logP values (A: 4.149, B: 2.308), falling within the 1-3 range. Ligand B is closer to the optimal range. Ligand A's higher logP could potentially lead to off-target effects or solubility issues.

**H-Bond Donors/Acceptors:** Both have similar numbers of HBD (A: 2, B: 3) and HBA (A: 3, B: 3), and are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.79, B: 0.704), indicating good drug-likeness.

**DILI:** Ligand A (80.109) has a significantly higher DILI risk than Ligand B (29.236). This is a major concern for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand B (60.876) is slightly better than Ligand A (54.556). BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.779) is slightly better than Ligand B (-5.278), but both are problematic.

**Aqueous Solubility:** Ligand A (-5.303) has very poor aqueous solubility, while Ligand B (-2.656) is also poor, but better than A. Solubility is crucial for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.462, B: 0.398), which is good.

**Microsomal Clearance:** Ligand A (32.152) has lower microsomal clearance than Ligand B (38.144), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (56.371) has a much longer in vitro half-life than Ligand B (-16.325). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.294, B: 0.074).

**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 still a factor.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, but suffers from significantly higher DILI risk and very poor aqueous solubility. Ligand B has a slightly better binding affinity, lower DILI risk, and better solubility, but has poorer metabolic stability.

Given the enzyme-specific priorities, metabolic stability and solubility are key. While Ligand A's longer half-life is attractive, the high DILI risk and poor solubility are major red flags. Ligand B, despite its slightly lower affinity and poorer metabolic stability, presents a more favorable overall profile due to its significantly lower toxicity risk and better solubility.

Output:
1
2025-04-17 16:23:49,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (84.67) is better than Ligand B (70.12).

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.396, Ligand B: 2.797), which is optimal.

**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:** Ligand A (0.764) has a significantly better QED score than Ligand B (0.546), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 49.399, Ligand B: 45.677), below the 60 threshold.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (85.111) is better than Ligand A (71.966). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.343) is slightly better than Ligand B (-4.681).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-1.796) is slightly better than Ligand A (-3.158).

**hERG Inhibition:** Ligand A (0.232) has a significantly lower hERG inhibition liability than Ligand B (0.641), which is a major advantage.

**Microsomal Clearance:** Ligand B (26.111 mL/min/kg) has a much lower microsomal clearance than Ligand A (67.626 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (37.783 hours) has a significantly longer in vitro half-life than Ligand A (-26.715 hours), which is a substantial benefit.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.147, Ligand B: 0.131).

**Binding Affinity:** Ligand B (-8.9 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:**

While Ligand A has a better QED and lower hERG risk, Ligand B's superior binding affinity (-8.9 vs -7.3 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are decisive. The stronger binding is likely to overcome the slightly higher hERG risk and lower QED. Solubility is a concern for both, but formulation strategies can often address this.

Output:
1
2025-04-17 16:23:49,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.39 and 365.41 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.9) is better than Ligand B (110.53), being closer to the <140 threshold for good absorption.

**3. logP:** Both ligands have acceptable logP values (0.759 and 1.17), 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 6 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.862 and 0.762), indicating good drug-likeness.

**7. DILI:** Ligand A (67.43) has a significantly lower DILI risk than Ligand B (77.78), which is a major advantage.

**8. BBB:** Both have similar BBB penetration (63.09 and 60.57), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.919 and -4.838), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-1.341) is better than Ligand B (-3.727), indicating better solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.204 and 0.198).

**12. Microsomal Clearance:** Ligand A (37.96) has lower microsomal clearance than Ligand B (42.26), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.535) has a significantly longer in vitro half-life than Ligand B (-28.566), a critical advantage for kinase inhibitors.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.045 and 0.128).

**15. Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-6.7), a 0.5 kcal/mol difference. While affinity is paramount, the other ADME properties of Ligand A are superior.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better DILI risk, solubility, metabolic stability (lower Cl_mic, longer t1/2), and has a lower HBD count. The negative Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh the small affinity difference. For an enzyme target like SRC kinase, metabolic stability and safety (DILI) are crucial, and Ligand A excels in these areas.

Output:
0
2025-04-17 16:23:49,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.483 Da and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.48) is well below the 140 threshold, indicating good absorption potential. Ligand B (87.9) is still within acceptable limits, but less favorable.

**logP:** Ligand A (4.612) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.111) is very low, which could impede permeation.

**H-Bond Donors:** Both ligands have 1 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:** Both ligands have good QED scores (0.676 and 0.816), indicating drug-like properties.

**DILI:** Ligand A (24.699) has a significantly lower DILI risk than Ligand B (45.56). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (73.827 and 72.237), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B is slightly worse (-1.581 vs -4.153).

**hERG Inhibition:** Ligand A (0.959) has a slightly higher hERG risk than Ligand B (0.236). This is a concern for Ligand A, but not prohibitive.

**Microsomal Clearance:** Ligand A (100.055) has very high microsomal clearance, suggesting poor metabolic stability. Ligand B (19.959) has much lower clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (76.537) has a reasonable half-life. Ligand B (-4.929) has a negative half-life, which is impossible and indicates a major issue with the data or the compound itself.

**P-gp Efflux:** Ligand A (0.822) has moderate P-gp efflux. Ligand B (0.025) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-7.3) has a significantly stronger binding affinity than Ligand B (0). This is a substantial advantage for Ligand A. A difference of >1.5 kcal/mol can often outweigh other issues.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a lower DILI risk, and a reasonable half-life. However, it suffers from high logP, high microsomal clearance, and a slightly elevated hERG risk. Ligand B has better metabolic stability and P-gp efflux, but its binding affinity is extremely weak and its in vitro half-life is nonsensical. The very poor binding affinity of Ligand B is a dealbreaker, even with its better metabolic properties. While Ligand A has some drawbacks, its superior potency makes it the more promising candidate, assuming the solubility issues can be addressed through formulation.

Output:
0
2025-04-17 16:23:49,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.519 and 349.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and excellent for oral absorption. Ligand B (112.73) is still acceptable, but less optimal.

**logP:** Ligand A (2.425) is within the optimal range of 1-3. Ligand B (0.766) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is excellent. Ligand B (HBD=3, HBA=4) is also acceptable, but slightly higher.

**QED:** Both ligands have acceptable QED values (0.718 and 0.602, respectively), indicating good drug-like properties.

**DILI:** Ligand A (11.128) has a significantly lower DILI risk than Ligand B (14.889), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (78.868) has a higher BBB percentile than Ligand B (53.625).

**Caco-2 Permeability:** Ligand A (-4.96) has a more negative Caco-2 value, suggesting lower permeability than Ligand B (-5.286). However, both are poor.

**Aqueous Solubility:** Ligand A (-2.622) has slightly better solubility than Ligand B (-1.807), though both are quite poor.

**hERG Inhibition:** Ligand A (0.552) shows a lower hERG inhibition liability than Ligand B (0.343), which is a positive.

**Microsomal Clearance:** Ligand A (37.43) has a higher microsomal clearance than Ligand B (19.387), meaning Ligand B is more metabolically stable, a key factor for kinases.

**In vitro Half-Life:** Ligand B (-12.889) has a significantly longer in vitro half-life than Ligand A (4.425), which is a major advantage.

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux than Ligand B (0.037), which is a positive.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.7 kcal/mol), with Ligand B being slightly better. The affinity difference is small and likely less important than the ADME differences.

**Conclusion:**

While Ligand B has a slightly better binding affinity and a significantly longer half-life and lower Cl_mic, Ligand A has a much better safety profile (lower DILI and hERG) and better TPSA. The poor solubility and permeability of both are concerning, but the superior safety profile of Ligand A, combined with its acceptable ADME properties, makes it the more promising candidate. The longer half-life of Ligand B is attractive, but the higher DILI risk is a significant concern.

Output:
0
2025-04-17 16:23:49,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (365.543 and 366.933 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is higher than Ligand B (49.41). While both are below 140, the lower TPSA of Ligand B is favorable for permeability.

**3. logP:** Both ligands have logP values within the optimal range (3.015 and 3.987). Ligand B is slightly higher, which *could* present a minor solubility concern, but isn't a major issue.

**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 (2) are both within the acceptable limit of 10. Ligand B is better.

**6. QED:** Both ligands have good QED scores (0.744 and 0.799), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (32.881 and 30.322), which is excellent.

**8. BBB:** Both ligands have reasonable BBB penetration (63.048 and 70.027). This isn't a primary concern for a kinase inhibitor, but higher is slightly preferred.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.922 and -4.788). This is unusual and suggests a potential issue with permeability prediction. However, the values are very close, so it's unlikely to be a deciding factor.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.829 and -4.496). Similar to Caco-2, this is concerning, but the values are close.

**11. hERG Inhibition:** Ligand A (0.219) has a lower hERG risk than Ligand B (0.586), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (71.371) has a higher microsomal clearance than Ligand B (68.064), indicating potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.064) has a longer in vitro half-life than Ligand A (-5.97), which is a significant advantage for dosing frequency.

**14. P-gp Efflux:** Ligand A (0.1) has lower P-gp efflux than Ligand B (0.45), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux, but Ligand B has better TPSA, H-bond characteristics, in vitro half-life, and crucially, a significantly lower hERG risk. The negative solubility and Caco-2 values are concerning for both, but comparable. Given the enzyme-kinase focus, the combination of better metabolic stability (longer half-life) and lower hERG risk for Ligand B makes it the more promising candidate, despite the slightly weaker binding affinity. The affinity difference, while significant, isn't so large that it overrides the safety and PK advantages of Ligand B.

Output:
1
2025-04-17 16:23:49,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.483 Da) is slightly higher than Ligand B (337.463 Da), but both are acceptable.

**TPSA:** Ligand A (77.52) is higher than Ligand B (29.54). While both are reasonably low, Ligand B's TPSA is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (2.57) is within the optimal range (1-3). Ligand B (4.048) is slightly above this range, which *could* lead to solubility issues or off-target interactions, but isn't a major concern at this level.

**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 (A: 0.829, B: 0.771), indicating generally drug-like properties.

**DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (17.138). This is a significant negative for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (97.48) shows much better BBB penetration than Ligand A (65.064).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, Ligand B (-4.678) is slightly better than Ligand A (-3.389), suggesting better absorption.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are logS values, Ligand B (-3.969) is slightly better than Ligand A (-3.389).

**hERG:** Ligand A (0.143) has a slightly higher hERG risk than Ligand B (0.951), but both are quite low and acceptable.

**Microsomal Clearance:** Ligand A (88.536) has a higher microsomal clearance than Ligand B (50.772), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-5.772) has a longer in vitro half-life than Ligand A (-1.878), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux than Ligand B (0.488), which is a slight advantage.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.2 and -7.3 kcal/mol). The difference of 0.1 kcal/mol is negligible.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate**. While Ligand A has a slightly lower P-gp efflux, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The slightly higher logP of Ligand B is a minor concern compared to the substantial advantages in safety and pharmacokinetic properties.

Output:
1
2025-04-17 16:23:49,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.447 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is slightly higher than Ligand B (75.88), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.195 and 1.012), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.691 and 0.745), indicating good drug-like properties.

**DILI:** Ligand A (49.787) has a slightly higher DILI risk than Ligand B (43.66), but both are below the concerning threshold of 60.

**BBB:** Ligand A (23.032) has a significantly lower BBB penetration percentile than Ligand B (76.658). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.988) has worse Caco-2 permeability than Ligand B (-4.623), but both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-2.397) has worse aqueous solubility than Ligand B (-1.094), but both are negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.083 and 0.122).

**Microsomal Clearance:** Ligand A (16.334) has significantly lower microsomal clearance than Ligand B (35.773), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (8.033) has a positive half-life, while Ligand B (-18.338) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.104).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.9 kcal/mol). While the difference is small, it's still a positive factor.

**Conclusion:**

Considering all factors, Ligand A is the more promising candidate. While both ligands have acceptable physicochemical properties, Ligand A demonstrates superior metabolic stability (lower Cl_mic, positive t1/2) and slightly better binding affinity. The lower BBB penetration of Ligand A is not a concern for a non-CNS target like SRC. The slight difference in solubility and Caco-2 permeability are less critical than the improved metabolic stability and binding.

Output:
1
2025-04-17 16:23:49,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (376.538 Da and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.64 and 71.33) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.37 and 2.045) are 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.648 and 0.817), indicating drug-likeness.

**DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (58.511). This is a major advantage for Ligand A.

**BBB:** Both have similar BBB penetration (78.209 and 71.307). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.79 and -4.836) which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.051 and -2.291) which is also unusual and suggests poor solubility. This is a concern for both.

**hERG:** Both ligands have low hERG risk (0.292 and 0.238).

**Microsomal Clearance:** Ligand A (70.044) has higher microsomal clearance than Ligand B (42.61). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (23.242) has a much longer in vitro half-life than Ligand A (-43.667). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.019 and 0.195).

**Binding Affinity:** Ligand B (-9.5 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.

**Conclusion:**

While Ligand A has a much better DILI profile, Ligand B's significantly improved binding affinity (-9.5 vs -7.4 kcal/mol) and longer half-life are critical for an enzyme inhibitor. The difference in binding affinity is substantial. Although both have poor Caco-2 and solubility, the stronger binding and better metabolic stability of Ligand B make it the more promising candidate, assuming formulation strategies can be developed to address the solubility/permeability issues.

Output:
1
2025-04-17 16:23:49,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.308 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.94 and 94.64) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.544) is optimal, while Ligand B (0.28) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, meeting the criteria. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.756 and 0.804), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (67.003 and 65.917), which is acceptable but not ideal.

**BBB:** Ligand A (72.741) has a better BBB penetration score than Ligand B (54.517), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.122 and -5.018), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.999 and -3.158), indicating very poor aqueous solubility. This is a major drawback.

**hERG:** Both ligands have low hERG risk (0.23 and 0.145), which is excellent.

**Microsomal Clearance:** Ligand A (15.729 mL/min/kg) has a higher microsomal clearance than Ligand B (5.593 mL/min/kg), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-1.436 hours) has a negative half-life, which is not possible and indicates a problem with the data. Ligand A (13.924 hours) is acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.031), which is favorable.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Conclusion:**

Despite both ligands having poor solubility and permeability, Ligand B stands out due to its significantly better binding affinity (-9.2 vs -8.0 kcal/mol) and lower microsomal clearance (5.593 vs 15.729). The superior binding affinity is a critical factor for an enzyme inhibitor. While the negative half-life for Ligand B is concerning, it may be a data error. If the binding affinity is confirmed, further investigation into improving solubility and permeability of Ligand B would be worthwhile.

Output:
1
2025-04-17 16:23:49,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.849 and 340.427 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.29) is significantly better than Ligand B (86.88). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (4.287) is slightly higher than the optimal range (1-3), while Ligand B (2.814) is within the optimal range. This favors B, but the difference isn't drastic.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=3) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.584 and 0.646), indicating good drug-like properties.

**DILI:** Ligand A (90.229) has a higher DILI risk than Ligand B (54.285). This is a significant drawback for A.

**BBB:** Ligand A (65.374) has better BBB penetration than Ligand B (33.23), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.058) has worse Caco-2 permeability than Ligand B (-5.288). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.735) has worse aqueous solubility than Ligand B (-3.804). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.686) has a slightly higher hERG inhibition risk than Ligand B (0.463), but both are reasonably low.

**Microsomal Clearance:** Ligand A (72.304) has higher microsomal clearance than Ligand B (23.437). Lower clearance is preferred for better metabolic stability, favoring B.

**In vitro Half-Life:** Ligand A (51.612) has a longer half-life than Ligand B (22.511), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.676) has lower P-gp efflux than Ligand B (0.131), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.6 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly longer half-life and lower P-gp efflux, its significantly higher DILI risk, worse solubility, and higher clearance are major concerns. Ligand B has a better safety profile (lower DILI), better solubility, and improved metabolic stability, all crucial for an enzyme inhibitor. The small advantage in binding affinity for Ligand B further supports this conclusion.

Output:
1
2025-04-17 16:23:49,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.48) is slightly above the preferred <140 for good absorption, while Ligand B (100.21) is well within the range.

**logP:** Ligand A (-0.125) is a bit low, potentially hindering permeation. Ligand B (1.106) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (2) is even better, potentially improving permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.547 and 0.767), indicating drug-like properties.

**DILI:** Ligand A (35.905) has a significantly lower DILI risk than Ligand B (67.739), which is a major advantage.

**BBB:** Both ligands have low BBB penetration (32.726 and 29.934), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.486 and -5.648). 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 (-0.901 and -2.359), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.095) shows very low hERG inhibition risk, while Ligand B (0.226) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-12.535) has a much lower (better) microsomal clearance than Ligand B (28.573), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (0.312) has a very short half-life, while Ligand B (18.901) has a much longer half-life, which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.041).

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2), although the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic). However, it suffers from very poor in vitro half-life and a slightly lower logP. Ligand B has a much better half-life but higher DILI risk and worse metabolic stability. The solubility for both is poor. The small advantage in binding affinity for Ligand A is unlikely to outweigh the significant pharmacokinetic drawbacks of both compounds.

Considering the enzyme-specific priorities, metabolic stability and safety are crucial. While Ligand A has better metabolic stability and a significantly lower DILI risk, its extremely short half-life is a major concern. Ligand B's longer half-life is a significant advantage, even with the higher DILI risk, as it suggests the potential for a more reasonable dosing regimen.

Output:
1
2025-04-17 16:23:49,663 - INFO - Batch 460 complete. Total preferences: 7360
2025-04-17 16:23:49,663 - INFO - Processing batch 461/512...
2025-04-17 16:24:32,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**1. Molecular Weight:** Both ligands (344.39 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (71.85), both are below the 140 A^2 threshold for good absorption.

**3. logP:** Both ligands have good logP values (1.636 and 0.873), 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 scores (0.897 and 0.791), indicating good drug-like properties.

**7. DILI:** Ligand A (31.795) has a significantly lower DILI risk than Ligand B (42.962). This is a major advantage.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC. Ligand A (76.231) is slightly better than Ligand B (65.413), but this is not a deciding factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is unusual.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.259 and 0.186).

**12. Microsomal Clearance:** Ligand A (10.66) has significantly lower microsomal clearance than Ligand B (21.934), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.818) has a much longer in vitro half-life than Ligand B (-2.938). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.071 and 0.066).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.7), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly improved ADME properties, specifically lower DILI risk, lower microsomal clearance, and a longer in vitro half-life. These factors are crucial for a viable drug candidate targeting an enzyme like SRC kinase. The small difference in binding affinity is likely outweighed by the superior pharmacokinetic profile of Ligand A.

Output:
0
2025-04-17 16:24:32,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.419 and 346.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (94.17 and 97.98) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.242) is slightly low, potentially hindering permeation. Ligand B (1.152) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 8 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.657 and 0.809), indicating drug-like properties.

**DILI:** Ligand A (41.373) has a slightly higher DILI risk than Ligand B (31.563), but both are below the concerning threshold of 60.

**BBB:** Ligand A (68.282) has a better BBB penetration score than Ligand B (34.548), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.769) shows poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.211) also shows poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.916 and -1.374). This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.069 and 0.066). This is excellent.

**Microsomal Clearance:** Ligand A (53.747) has a higher microsomal clearance than Ligand B (-17.754). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (9.129 hours) has a significantly longer half-life than Ligand A (-0.227 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.043).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.8 and -8.4 kcal/mol). The difference of 0.4 kcal/mol is unlikely to outweigh other factors.

**Conclusion:**

While both ligands have good binding affinity and acceptable safety profiles (DILI, hERG), Ligand B is superior due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and slightly better logP. The poor solubility and Caco-2 permeability are concerns for both, but metabolic stability is a higher priority for kinase inhibitors.

Output:
1
2025-04-17 16:24:32,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (352.439 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.38) is slightly above the preferred <140, but acceptable. Ligand B (84.5) is well within the ideal range.

**3. logP:** Both ligands have good logP values (1.365 and 2.165), 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 6 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.833) has a significantly better QED score than Ligand B (0.656), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.176) has a higher DILI risk than Ligand B (30.748). This is a concern for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration, but Ligand B (64.599) is slightly better than Ligand A (54.634). BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.996 and -4.552). 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 (-1.926 and -2.807). These are also unusual and suggest very low solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.115 and 0.154). This is excellent.

**12. Microsomal Clearance:** Ligand A (6.679) has a lower microsomal clearance than Ligand B (65.821), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-3.144) has a more favorable in vitro half-life than Ligand B (-11.17). This is another advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.036).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). This 0.4 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand A has a better QED, significantly better metabolic stability (lower Cl_mic, better t1/2), and a lower DILI risk. However, Ligand B has a slightly better binding affinity. The poor Caco-2 and solubility for both are concerning and would require significant optimization. Given the enzyme-specific priorities, metabolic stability and lower DILI are more important than a small increase in binding affinity, especially considering the already good binding of Ligand A.

Output:
1
2025-04-17 16:24:32,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (380.863 Da) is also well within the range.

**TPSA:** Ligand A (77.59) is better than Ligand B (49.85) as it is closer to the ideal range for oral absorption (<=140).

**logP:** Both ligands have similar logP values (A: 2.683, B: 2.72), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are acceptable, though Ligand B's lower HBD count might slightly improve permeability.

**QED:** Both ligands have similar QED values (A: 0.728, B: 0.666), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 52.772, while Ligand B has 29.43. Ligand B is significantly better, indicating a lower risk of liver injury. This is a crucial advantage.

**BBB:** Ligand A (66.188) and Ligand B (87.088). BBB is not a high priority for a kinase inhibitor, but Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.957 and -4.359). This is unusual and suggests poor permeability. However, these values are on a log scale and need to be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.758 and -2.957). This is also concerning, suggesting poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.81) has a slightly higher hERG risk than Ligand B (0.483), which is preferable.

**Microsomal Clearance:** Ligand A (50.112) has a higher microsomal clearance than Ligand B (33.486), meaning it is less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (10.501 hours) has a much longer in vitro half-life than Ligand A (0.312 hours). This is a major advantage for Ligand B, as it suggests less frequent dosing could be possible.

**P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux than Ligand B (0.193), which is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.7 kcal/mol, B: -8.3 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall:**

Ligand B is the superior candidate. While both have good potency, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility. The slightly better BBB penetration is a bonus. The permeability and solubility issues are present in both, but the improved ADME properties of Ligand B make it more likely to succeed as a drug candidate.

Output:
1
2025-04-17 16:24:32,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.312 Da) is slightly higher than Ligand B (361.368 Da), but both are acceptable.

**TPSA:** Ligand A (65.97) is better than Ligand B (79.26). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.773) is optimal, while Ligand B (0.847) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (A: 0.706, B: 0.815), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 62.699, B: 59.984), though A is slightly higher.

**BBB:** Both ligands have moderate BBB penetration (A: 76.154, B: 63.784). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.247) is significantly worse than Ligand B (-4.63). This suggests lower intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-3.194) is worse than Ligand B (-2.006). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.563) is better than Ligand B (0.149), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (49.483) is higher than Ligand B (29.466), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (14.652) is better than Ligand B (-3.259), suggesting better stability.

**P-gp Efflux:** Ligand A (0.628) is better than Ligand B (0.006), suggesting lower efflux and improved bioavailability.

**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:**

Ligand B has a superior binding affinity, which is the most critical factor for an enzyme inhibitor. While its logP is a bit low and Caco-2 permeability is not ideal, the strong binding affinity and acceptable other properties make it the more promising candidate. Ligand A has better solubility and hERG, but the weaker binding affinity is a significant drawback. The better half-life of Ligand A is not enough to overcome the binding affinity difference.

Output:
1
2025-04-17 16:24:32,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.387 and 372.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.65 and 95.94) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands (0.383 and 0.427) are a bit low, potentially hindering permeability. However, this isn't a major concern as SRC is not a CNS target.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is slightly better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability, but both are acceptable.

**QED:** Both ligands have reasonable QED scores (0.829 and 0.632), indicating good drug-like properties.

**DILI:** Ligand A (57.813) has a significantly lower DILI risk than Ligand B (40.752), which is a substantial advantage. While both are below the concerning 60 threshold, lower is always preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.117) is slightly better than Ligand B (42.924).

**Caco-2 Permeability:** Ligand A (-4.581) has a worse Caco-2 permeability than Ligand B (-5.299). However, the values are both negative and suggest poor permeability.

**Aqueous Solubility:** Ligand A (-1.967) has slightly better solubility than Ligand B (-1.521). This is a positive attribute for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.103 and 0.123), which is excellent.

**Microsomal Clearance:** Ligand A (12.417 mL/min/kg) has a lower microsomal clearance than Ligand B (15.32 mL/min/kg), indicating better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-0.412 hours) has a slightly worse in vitro half-life than Ligand B (0.608 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.029).

**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 small (0.3 kcal/mol), it's enough to be considered, especially given the other favorable properties of Ligand A.

**Overall:** Ligand A is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), slightly better solubility, and a slightly better binding affinity. While its Caco-2 permeability is slightly worse, the other advantages outweigh this drawback for an enzyme target like SRC.

Output:
0
2025-04-17 16:24:32,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.373 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is slightly above the preferred <140 for oral absorption, but acceptable. Ligand B (49.85) is excellent, well below 140.

**logP:** Ligand A (1.106) is within the optimal 1-3 range. Ligand B (2.783) is also good, within the optimal range.

**H-Bond Donors:** Ligand A has 4 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Both ligands have QED values above 0.5 (0.612 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (55.68) is moderately risky, while Ligand B (25.475) is very good, indicating a low risk of liver injury. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (61.962 and 69.407). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-5.262) has poor Caco-2 permeability, indicating potential absorption issues. Ligand B (-4.615) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-3.141) has poor aqueous solubility. Ligand B (-2.28) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.327) has a low risk of hERG inhibition, which is excellent. Ligand B (0.297) also shows a low risk of hERG inhibition, comparable to Ligand A.

**Microsomal Clearance:** Ligand A (0.568) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (53.592) has significantly higher clearance, indicating faster metabolism and potentially lower *in vivo* exposure. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-11.078) has a very long half-life, which is desirable. Ligand B (12.292) has a shorter half-life, but still acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.042 and 0.206), which is favorable.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's better DILI score and TPSA, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.3 vs -8.2 kcal/mol) and excellent metabolic stability (low Cl_mic, long half-life) are crucial for an enzyme inhibitor. While Ligand A has poorer solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. The superior potency and metabolic stability of Ligand A make it the more likely viable drug candidate.

Output:
0
2025-04-17 16:24:32,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.423 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.99) is better than Ligand B (100.55), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (1.529 and 1.424), 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 H-bond donors and acceptors, potentially leading to better permeability. Both are within acceptable limits.

**QED:** Ligand A (0.878) has a significantly higher QED score than Ligand B (0.462), indicating a more drug-like profile.

**DILI:** Ligand A (72.664) has a higher DILI risk than Ligand B (41.45). This is a significant drawback for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not critical for a non-CNS target like SRC.

**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 should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, these values should be interpreted cautiously.

**hERG:** Ligand A (0.032) has a much lower hERG risk than Ligand B (0.261), which is a major advantage.

**Microsomal Clearance:** Ligand A (26.043) has a lower microsomal clearance than Ligand B (7.376), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.943) has a negative half-life, which is not physically possible. Ligand B (0.726) has a very short half-life. Both are concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Both ligands have the same binding affinity (-7.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is preferable despite the higher DILI risk. It has a significantly better QED score, lower hERG risk, and better metabolic stability (lower Cl_mic). The binding affinity is identical for both. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh the DILI risk, especially considering optimization could address that. The negative half-life for Ligand A is a major red flag, but could be an artifact of the prediction method.

Output:
0
2025-04-17 16:24:32,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.46 and 363.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (72.21 and 75.55) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.999) is slightly higher than Ligand B (2.525), both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.716 and 0.741), indicating good drug-like properties.

**DILI:** Ligand A (37.46) has a lower DILI risk than Ligand B (46.26), both are below the 60 threshold, but A is preferable.

**BBB:** Ligand A (67.70) has a higher BBB penetration potential than Ligand B (44.90), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.907 and -4.75). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**Aqueous Solubility:** Ligand A (-4.467) has slightly better solubility than Ligand B (-2.211), both are very poor.

**hERG Inhibition:** Ligand A (0.902) has a lower hERG inhibition liability than Ligand B (0.393), which is a significant advantage.

**Microsomal Clearance:** Ligand B (64.69) has a lower microsomal clearance than Ligand A (85.15), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-22.66) has a significantly longer in vitro half-life than Ligand A (69.50), which is a major advantage.

**P-gp Efflux:** Ligand A (0.254) has lower P-gp efflux liability than Ligand B (0.17), which is preferable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a crucial difference, as a >1.5 kcal/mol advantage often outweighs other drawbacks.

**Conclusion:**

While Ligand A has better solubility and lower DILI/hERG risk, Ligand B's superior binding affinity (-9.3 vs -7.4 kcal/mol) and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are decisive advantages for an enzyme inhibitor. The stronger binding is likely to compensate for the poorer solubility and slightly higher DILI/hERG risk.

Output:
1
2025-04-17 16:24:32,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.877 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.83) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (96.97) is still under 140, but less optimal than A.

**logP:** Ligand A (2.37) is within the optimal 1-3 range. Ligand B (-0.329) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.808 and 0.622), indicating good drug-like properties.

**DILI:** Ligand A (32.765) has a lower DILI risk than Ligand B (22.8), both are good.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (82.396) has better BBB penetration potential than Ligand B (51.803).

**Caco-2 Permeability:** Ligand A (-4.919) has a more negative Caco-2 value which is less favorable than Ligand B (-5.305).

**Aqueous Solubility:** Ligand A (-2.791) has a slightly better solubility than Ligand B (-1.131).

**hERG:** Both ligands have very low hERG risk (0.819 and 0.119), which is excellent.

**Microsomal Clearance:** Ligand A (-13.099) exhibits significantly lower (better) microsomal clearance than Ligand B (-6.345), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (28.633 hours) has a much longer half-life than Ligand B (5.336 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.073 and 0.006).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial difference (>1.5 kcal/mol), and a key driver in the decision.

**Overall:**

Ligand A is superior to Ligand B. It has a better logP, better metabolic stability (lower Cl_mic, longer t1/2), slightly better solubility, and significantly stronger binding affinity. While Ligand B has slightly better Caco-2 permeability, the other advantages of Ligand A, especially the binding affinity and metabolic stability, outweigh this minor difference. Given the enzyme-specific priorities, the stronger binding and improved metabolic profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 16:24:32,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.447 and 363.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.15) is better than Ligand B (101.29), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (0.593) is a bit low, potentially hindering permeation. Ligand B (1.384) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3).

**QED:** Both ligands have similar QED values (0.689 and 0.607), indicating reasonable drug-likeness.

**DILI:** Ligand A (24.544) has a significantly lower DILI risk than Ligand B (32.997), a crucial advantage.

**BBB:** Ligand B (83.172) has a higher BBB penetration percentile than Ligand A (55.215). However, as SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.639) has a more negative Caco-2 value, indicating *lower* permeability than Ligand B (-5.341). This is a negative for Ligand A.

**Aqueous Solubility:** Ligand A (-0.95) has better aqueous solubility than Ligand B (-3.426). This is a significant advantage for formulation and bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.141 and 0.28), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (19.898 and 20.074 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (13.78 hours) has a significantly longer half-life than Ligand A (2.407 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.058 and 0.046).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.1 kcal/mol). This 1.7 kcal/mol difference is very significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has advantages in solubility and DILI risk, Ligand B's significantly stronger binding affinity (-9.8 vs -8.1 kcal/mol) and longer half-life (13.78 vs 2.407 hours) are decisive. The slightly lower solubility and higher DILI risk of Ligand B are less concerning given the potency advantage. The logP of Ligand B is also more favorable.

Output:
1
2025-04-17 16:24:32,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzyme targets: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.379 Da and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.45) is excellent, under the 140 threshold and good for absorption. Ligand B (116.76) is still acceptable but less optimal.

**logP:** Ligand A (2.809) is within the optimal 1-3 range. Ligand B (-0.188) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (4 HBD, 5 HBA) are both within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.637 and 0.509), indicating drug-like properties.

**DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (44.552), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (52.268) has a higher BBB value than Ligand A (27.491), but this is not a primary concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.26 and -5.347) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.351 and -1.335) which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.726) has a lower hERG risk than Ligand B (0.128), which is a significant advantage.

**Microsomal Clearance:** Ligand A (36.008) has a higher microsomal clearance than Ligand B (14.292), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (10.774) has a longer half-life than Ligand A (-16.743), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.191 and 0.011).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's better TPSA and lower DILI risk, Ligand B's significantly stronger binding affinity (-9.7 vs -8.1 kcal/mol) and longer half-life are crucial advantages for an enzyme target like SRC kinase. While the low logP and negative solubility/permeability are concerning, the potency advantage is substantial. Further optimization could address these ADME issues, starting with increasing logP and solubility.

Output:
1
2025-04-17 16:24:32,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.211 Da) is slightly higher than Ligand B (344.463 Da), but both are acceptable.

**TPSA:** Ligand A (94.02) is slightly higher than Ligand B (76.89). Both are below the 140 A^2 threshold for good oral absorption, but lower is generally preferred.

**logP:** Both ligands have similar logP values (A: 3.025, B: 3.113), falling 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.736, B: 0.681), indicating good drug-like properties (>=0.5).

**DILI:** Ligand A (92.788) has a significantly higher DILI risk than Ligand B (60.993). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (83.443) has a higher BBB value than Ligand A (65.374), but this is less critical here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.839) is slightly better than Ligand B (-5.006).

**Aqueous Solubility:** Ligand A (-6.253) has slightly better solubility than Ligand B (-3.389), but both are quite poor.

**hERG Inhibition:** Ligand A (0.777) has a slightly higher hERG risk than Ligand B (0.915), but both are acceptable.

**Microsomal Clearance:** Ligand B (78.798) has a significantly higher microsomal clearance than Ligand A (25.624). This suggests Ligand A is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (96.61) has a much longer in vitro half-life than Ligand B (37.551), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.231) has lower P-gp efflux than Ligand B (0.668), which is favorable for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.3 kcal/mol, B: -8.5 kcal/mol). The difference is minimal.

**Conclusion:**

While both ligands exhibit strong binding affinity, Ligand A is the more promising candidate due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and despite the poor solubility, the DILI risk is the major drawback. Ligand B has a lower DILI risk, but its higher metabolic clearance and shorter half-life are significant liabilities for a kinase inhibitor.

Output:
1
2025-04-17 16:24:32,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (331.419 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.09) is significantly better than Ligand B (60.03), being well below the 140 threshold for good absorption.

**logP:** Ligand A (4.285) is slightly higher than the optimal 1-3 range, while Ligand B (2.42) is within the optimal range. However, the difference isn't drastic.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (0.716 and 0.767), indicating drug-like properties.

**DILI:** Ligand A (75.572) has a considerably higher DILI risk than Ligand B (23.497). This is a significant negative for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (84.141) is slightly better than Ligand A (74.176). This is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**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, so it doesn't strongly favor either.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.651) is slightly better than Ligand A (-4.843), suggesting marginally better solubility.

**hERG Inhibition:** Both ligands have relatively low hERG risk (0.732 and 0.823), which is good.

**Microsomal Clearance:** Ligand B (59.886) has significantly lower microsomal clearance than Ligand A (111.818), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (1.725 hours) has a slightly better half-life than Ligand A (-30.951 hours, which is likely an error and should be interpreted as very short).

**P-gp Efflux:** Both have low P-gp efflux liability (0.289 and 0.153).

**Binding Affinity:** Ligand B (-8.1 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 stronger candidate. While Ligand A has a slightly better logP, Ligand B excels in crucial areas: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and better t1/2), slightly better solubility, and slightly better binding affinity. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B outweigh this issue. The DILI risk for Ligand A is a major red flag.

Output:
1
2025-04-17 16:24:32,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight:** Both ligands (376.503 Da and 389.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.13) is well below the 140 threshold for oral absorption, and even below 90, suggesting good potential for cell permeability. Ligand B (106.62) is still under 140, but less favorable than A.

**3. logP:** Ligand A (1.978) is within the optimal 1-3 range. Ligand B (0.75) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern yet.

**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 <=10, acceptable.

**6. QED:** Ligand A (0.836) has a better QED score than Ligand B (0.679), indicating a more drug-like profile.

**7. DILI:** Ligand B (79.604) has a higher DILI risk than Ligand A (67.584), making A more favorable in terms of liver toxicity. Both are above the preferred <40, but B is significantly higher.

**8. BBB:** Ligand A (69.833) has better BBB penetration than Ligand B (56.611). While not a primary concern for a kinase inhibitor, it's a slight advantage for A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.329 and -5.306). This is unusual and suggests a potential issue with the data or a very poor permeability. However, given that both are similarly poor, this doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.803 and -3.612). This is also concerning, suggesting poor solubility. Again, both are similarly poor, so it doesn't differentiate them.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.134 and 0.19). This is excellent.

**12. Microsomal Clearance:** Ligand A (30.113) and Ligand B (32.996) have similar microsomal clearance values. Neither is particularly low, but they aren't extremely high either.

**13. In vitro Half-Life:** Ligand A (-1.569) has a negative half-life, which is impossible. This is a significant data quality issue. Ligand B (-15.539) also has a negative half-life, indicating a serious problem with the data.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.339 and 0.141). This is good.

**15. 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 could outweigh minor ADME drawbacks.

**Enzyme-Kinase Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite the concerning negative values for Caco-2 and solubility, and the impossible negative half-life values for both, Ligand A is the more promising candidate. Its superior binding affinity (-8.2 vs -7.4 kcal/mol) is a major advantage. It also has a better QED score and lower DILI risk. The negative half-life values are a red flag and require investigation, but the substantial affinity difference makes Ligand A the better starting point for optimization.

Output:
0
2025-04-17 16:24:32,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.394 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (58.64), both are below the 140 A^2 threshold for good absorption.

**logP:** Both ligands (1.27 and 2.052) 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.

**QED:** Both ligands have good QED scores (0.704 and 0.782), indicating drug-like properties.

**DILI:** Ligand A (54.168) has a slightly higher DILI risk than Ligand B (35.091), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (70.531 and 71.888), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.129) is worse than Ligand B (-4.95), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.084) is better than Ligand B (-3.596), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.138) has a lower hERG risk than Ligand B (0.456), which is a significant advantage.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (43.877 and 41.696 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (14.534 hours) has a significantly longer half-life than Ligand A (4.649 hours), which is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux than Ligand B (0.193), which is favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This 0.9 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and lower hERG risk, Ligand B's significantly stronger binding affinity (-7.8 vs -6.9 kcal/mol) and longer half-life are critical advantages for an enzyme inhibitor. The slightly higher DILI and P-gp efflux are less concerning given the potency and PK profile.

Output:
1
2025-04-17 16:24:32,844 - INFO - Batch 461 complete. Total preferences: 7376
2025-04-17 16:24:32,844 - INFO - Processing batch 462/512...
2025-04-17 16:25:22,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.455 and 357.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.94) is slightly higher than Ligand B (96.87), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.357) is lower than optimal (1-3), potentially hindering permeation. Ligand B (1.194) is closer to the ideal range.

**H-Bond Donors:** Both ligands have 2 HBDs, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.786) has a better QED score than Ligand B (0.519), indicating a more drug-like profile.

**DILI:** Ligand A (33.152) has a significantly lower DILI risk than Ligand B (63.125), which is a major advantage.

**BBB:** Ligand A (53.587) has a higher BBB penetration potential than Ligand B (34.044), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.346 and -5.493), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.385 and -2.457), indicating very poor aqueous solubility, a major drawback.

**hERG:** Ligand A (0.442) has a lower hERG inhibition liability than Ligand B (0.155), which is preferable.

**Microsomal Clearance:** Ligand A (22.695) has a higher microsomal clearance than Ligand B (2.982), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (6.979) has a significantly longer in vitro half-life than Ligand A (-1.056), which is a substantial benefit.

**P-gp Efflux:** Ligand A (0.097) has slightly higher P-gp efflux liability than Ligand B (0.06), but both are low.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.1 kcal/mol vs 0.0 kcal/mol) is a major advantage for an enzyme target like SRC kinase.  The lower DILI risk and lower hERG liability also favor Ligand A. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the substantial difference in binding affinity makes Ligand A the better choice, assuming solubility and permeability can be addressed through formulation or further chemical modifications.

Output:
0
2025-04-17 16:25:22,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.401 and 357.47 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (67.87 and 64.09) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (1.358) is slightly higher than Ligand B (0.743), both are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, meeting the <=5 criteria.

**H-Bond Acceptors:** Both ligands have 4 HBA, meeting the <=10 criteria.

**QED:** Both ligands have the same QED score of 0.696, indicating good drug-likeness.

**DILI:** Ligand A (29.779) has a significantly lower DILI risk than Ligand B (8.724). This is a major advantage for Ligand A.

**BBB:** Ligand A (91.663) has a higher BBB penetration percentile than Ligand B (76.696). While not a primary concern for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.684) has a lower Caco-2 permeability than Ligand B (-4.579). This suggests potentially lower intestinal absorption for Ligand A, but the difference is small.

**Aqueous Solubility:** Ligand A (-1.552) has slightly lower solubility than Ligand B (-1.073). Both are quite poor, but Ligand B is marginally better.

**hERG Inhibition:** Ligand A (0.309) has a lower hERG inhibition liability than Ligand B (0.471), which is favorable.

**Microsomal Clearance:** Ligand A (17.971) has a lower microsomal clearance than Ligand B (32.521), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (3.486) has a shorter in vitro half-life than Ligand B (-13.59). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.067), which is a slight advantage.

**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 in affinity is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A demonstrates a significantly stronger binding affinity and lower DILI and hERG risk, and lower P-gp efflux. It also has better metabolic stability (lower Cl_mic). While it has slightly lower solubility, Caco-2 permeability and a shorter half-life, the superior potency and safety profile are more critical for an enzyme target like SRC. Ligand B's better solubility and half-life are overshadowed by its higher DILI, hERG, and lower binding affinity.

Output:
1
2025-04-17 16:25:22,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.807 Da) is slightly higher than Ligand B (350.434 Da), but both are acceptable.

**TPSA:** Ligand A (46.84) is well below the 140 threshold for oral absorption and is also favorable. Ligand B (71.34) is still within a reasonable range, but less optimal than Ligand A.

**logP:** Ligand A (4.244) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.058) 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:** Both ligands have good QED values (A: 0.679, B: 0.794), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 86.002, which is high and concerning. Ligand B has a much lower DILI risk of 35.014, a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 80.264, B: 83.404), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.302 and -4.655), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.705 and -4.092). This is a major issue for bioavailability.

**hERG Inhibition:** Ligand A has a hERG risk of 0.713, which is acceptable. Ligand B has a lower hERG risk of 0.485, which is preferable.

**Microsomal Clearance:** Ligand A (52.339) has a higher microsomal clearance than Ligand B (41.293), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (45.527 hours) has a significantly longer half-life than Ligand A (16.289 hours), which is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.769) has higher P-gp efflux than Ligand B (0.191), meaning less oral bioavailability.

**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 could potentially overcome some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand B is the superior candidate. Its significantly better binding affinity (-7.7 vs -9.1 kcal/mol), lower DILI risk (35 vs 86), longer half-life (45.5 vs 16.3 hours), and lower P-gp efflux (0.191 vs 0.769) outweigh the slightly higher TPSA and logP. The lower hERG risk is also a bonus. While solubility and permeability are concerns for both, formulation strategies might be employed to address these issues. The stronger binding affinity of Ligand B is a critical factor for an enzyme inhibitor.

Output:
1
2025-04-17 16:25:22,239 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [370.877, 67.87, 1.964, 1, 4, 0.744, 37.65, 69.135, -5.033, -2.136, 0.247, 28.167, 30.642, 0.086, -8.5]
**Ligand B:** [359.495, 54.43, 3.551, 1, 6, 0.635, 27.414, 54.013, -5.507, -2.609, 0.892, 30.666, 86.801, 0.692, -7.9]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (370.877) is slightly higher than B (359.495), but both are acceptable.
2. **TPSA:** A (67.87) is higher than B (54.43). Both are below 140, suggesting reasonable oral absorption potential.
3. **logP:** A (1.964) is optimal, while B (3.551) is approaching the upper limit. B's higher logP *could* lead to solubility issues or off-target interactions, but isn't immediately disqualifying.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A has 4 HBA, and B has 6. Both are within the acceptable limit of 10.
6. **QED:** A (0.744) is better than B (0.635), indicating a more drug-like profile.
7. **DILI:** A (37.65) has a slightly higher DILI risk than B (27.414), but both are below the 40% threshold and considered low risk.
8. **BBB:** A (69.135) has better BBB penetration than B (54.013), though neither are particularly high. This is less critical for a non-CNS target like SRC.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. A (-5.033) is worse than B (-5.507), meaning B is slightly better.
10. **Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. A (-2.136) is slightly better than B (-2.609).
11. **hERG:** A (0.247) has a much lower hERG risk than B (0.892). This is a significant advantage for A.
12. **Cl_mic:** Both have similar microsomal clearance (A: 28.167, B: 30.666), suggesting comparable metabolic stability.
13. **t1/2:** B (86.801) has a significantly longer in vitro half-life than A (30.642). This is a major advantage for B, potentially allowing for less frequent dosing.
14. **Pgp:** A (0.086) has lower P-gp efflux than B (0.692), which is favorable for bioavailability.
15. **Binding Affinity:** A (-8.5 kcal/mol) has a stronger binding affinity than B (-7.9 kcal/mol). This is a 0.6 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A is significantly better (-8.5 vs -7.9).
*   **Metabolic Stability:** B has a longer half-life, which is a plus. Cl_mic is similar.
*   **Solubility:** Both are poor, but A is slightly better.
*   **hERG:** A has a much lower hERG risk.

**Conclusion:**

Despite B's longer half-life, the significantly stronger binding affinity of A (-8.5 kcal/mol) and its much lower hERG risk are compelling advantages. The slightly better solubility of A also contributes. While both have poor Caco-2 and solubility, the potency and safety profile of A make it the more promising candidate.

1
2025-04-17 16:25:22,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.369 and 358.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.59) is slightly higher than Ligand B (67.43). Both are below the 140 threshold for oral absorption, but neither is optimized for CNS penetration (ideally <90).

**logP:** Both ligands have good logP values (1.956 and 2.763), 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 (0.742 and 0.767), indicating good drug-likeness.

**DILI:** Ligand A (45.095) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (76.541 and 77.2), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.989 and -4.684). This is unusual and requires careful interpretation. Negative values often indicate issues with the assay or the compound's behavior in the assay. It's difficult to draw firm conclusions without more information.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.331 and -2.613). Similar to Caco-2, negative values are problematic and suggest poor solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.935 and 0.342), which is excellent.

**Microsomal Clearance:** Ligand A (-33.162) has significantly lower (better) microsomal clearance than Ligand B (-47.938), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (31.167 hours) has a much longer in vitro half-life than Ligand B (-15.13 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.233 and 0.091).

**Binding Affinity:** Both ligands have similar strong binding affinities (-9.3 and -8.3 kcal/mol).

**Conclusion:**

While both compounds have good binding affinity and acceptable DILI/hERG profiles, Ligand A is the superior candidate due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2). The solubility and Caco-2 permeability issues are concerning for both, but the improved PK profile of Ligand A outweighs these concerns, especially given the strong binding affinity. Further work would be needed to address the solubility issues, but the metabolic advantage is substantial.

Output:
1
2025-04-17 16:25:22,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (65.79) is significantly better than Ligand B (105.98). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 2.075, B: 1.146), 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=7) in terms of balancing solubility and permeability.

**QED:** Both have acceptable QED values (A: 0.82, B: 0.665), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand B (67.39) has a higher DILI risk than Ligand A (15.898). This is a significant concern.

**BBB:** Ligand A (70.027) has better BBB penetration than Ligand B (37.65). While not a primary concern for a kinase inhibitor, it's a bonus.

**Caco-2 Permeability:** Ligand A (-4.809) shows better Caco-2 permeability than Ligand B (-5.641).

**Aqueous Solubility:** Ligand A (-1.681) has better aqueous solubility than Ligand B (-2.304). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.398, B: 0.195), which is excellent.

**Microsomal Clearance:** Ligand A (10.518) has a lower microsomal clearance than Ligand B (24.019), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-3) has a negative half-life, which is not physically possible and indicates a significant issue. Ligand A has a reasonable half-life (33.458).

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.238), suggesting better oral bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -9.1 kcal/mol, B: -8.2 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to overcome the other significant differences.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk), **Ligand A is significantly more promising**. It has better solubility, metabolic stability (lower Cl_mic, reasonable t1/2), lower DILI risk, better Caco-2 permeability, and lower P-gp efflux. While both have good binding affinity and hERG profiles, the ADME properties of Ligand A are far superior. Ligand B's negative half-life is a critical flaw.

Output:
0
2025-04-17 16:25:22,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 Da and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (49.85), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.319 and 2.618, respectively), falling within the 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 similar QED values (0.691 and 0.634), indicating good drug-likeness.

**DILI:** Ligand A (6.049 percentile) has a significantly lower DILI risk than Ligand B (29.701 percentile). This is a major advantage for Ligand A.

**BBB:** Ligand B (71.966 percentile) has better BBB penetration than Ligand A (48.119 percentile), but BBB is not a primary concern for a kinase inhibitor unless CNS targets are specifically desired.

**Caco-2 Permeability:** Ligand A (-4.711) has a lower Caco-2 permeability than Ligand B (-4.284), indicating potentially poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.978) has better aqueous solubility than Ligand B (-2.85). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.289) has a lower hERG inhibition liability than Ligand B (0.599), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (4.674 mL/min/kg) has significantly lower microsomal clearance than Ligand B (62.802 mL/min/kg), indicating better metabolic stability. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (22.467 hours) has a much longer in vitro half-life than Ligand B (12.906 hours), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.034) has lower P-gp efflux liability than Ligand B (0.271), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has slightly better binding affinity than Ligand B (-0.0 kcal/mol). This difference in affinity is substantial.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability and BBB penetration, Ligand A excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), lower hERG inhibition, lower P-gp efflux, better solubility, and a substantially stronger binding affinity. The difference in binding affinity alone is enough to favor Ligand A, and the improved ADME properties further solidify its potential as a viable drug candidate.

Output:
1
2025-04-17 16:25:22,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.88 and 382.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.56) is significantly better than Ligand B (96.25). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (3.157 and 1.364), falling within the 1-3 range. Ligand A is slightly better, but both are reasonable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=6). Lower values are generally preferred for better permeability.

**QED:** Ligand A (0.888) has a much higher QED score than Ligand B (0.63), indicating a more drug-like profile.

**DILI:** Ligand A (15.665) has a significantly lower DILI risk than Ligand B (67.584). This is a major advantage for Ligand A.

**BBB:** Ligand A (92.982) has a much higher BBB penetration percentile than Ligand B (29.042). While not a primary concern for a non-CNS target like SRC, it doesn't hurt.

**Caco-2 Permeability:** Ligand A (-4.914) has a better (more positive) Caco-2 permeability than Ligand B (-5.335).

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.546 and -2.612). This is a potential issue for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.784) has a lower hERG inhibition risk than Ligand B (0.217). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (8.314) has a much lower microsomal clearance than Ligand B (27.631), indicating better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (16.712) has a longer in vitro half-life than Ligand B (25.213). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.194) has lower P-gp efflux liability than Ligand B (0.116).

**Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is only 0.6 kcal/mol, which is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Overall:** Ligand A is significantly better across most critical ADME properties (DILI, metabolic stability, solubility, hERG, BBB, QED, TPSA) while maintaining comparable potency. The slight improvement in binding affinity for Ligand B is not enough to compensate for its poorer ADME profile.

Output:
0
2025-04-17 16:25:22,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 346.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.73) is slightly above the preferred <140, but acceptable. Ligand B (97.98) is well within the range.

**logP:** Ligand A (0.766) is a bit low, potentially impacting permeability. Ligand B (0.916) is also on the lower side, but slightly better.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (3 and 2 respectively) and HBA (4 each) counts.

**QED:** Both ligands have good QED scores (0.602 and 0.787), indicating good drug-like properties.

**DILI:** Ligand A (14.889) has a significantly lower DILI risk than Ligand B (70.958). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (53.625) and Ligand B (45.754) are both low.

**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 also unusual and indicates poor solubility.

**hERG:** Both ligands have low hERG risk (0.343 and 0.322).

**Microsomal Clearance:** Ligand A (19.387 mL/min/kg) has a higher microsomal clearance than Ligand B (-17.587 mL/min/kg). A negative value for Ligand B suggests very high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (-12.889 hours) has a negative half-life, which is not possible. Ligand B (-18.103 hours) also has a negative half-life, which is not possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.037 and 0.021).

**Binding Affinity:** Both ligands have similar and good binding affinities (-8.7 and -8.3 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Despite similar binding affinities, Ligand A is significantly better due to its much lower DILI risk. While both have issues with permeability and solubility, the DILI risk is a critical factor for drug development. The negative values for Caco-2 and solubility are concerning and would require further investigation, but the lower DILI risk makes Ligand A the more promising candidate. Ligand B's extremely high metabolic stability is appealing, but the elevated DILI risk is a major concern.

Output:
0
2025-04-17 16:25:22,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.515 and 365.777 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (103.35). A TPSA < 140 is desirable for oral absorption, both are under this threshold, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (3.832) is optimal (1-3), while Ligand B (1.024) is at the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 8 HBA). The number of H-bonds in ligand B is higher, which might affect permeability.

**QED:** Both ligands have similar QED values (0.621 and 0.575), indicating reasonable drug-likeness.

**DILI:** Ligand A (25.436) has a much lower DILI risk than Ligand B (83.87), which is a significant advantage.

**BBB:** Ligand A (77.472) shows better BBB penetration than Ligand B (51.183), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.702 and -4.775), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.932 and -2.799), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.472) has a lower hERG inhibition liability than Ligand B (0.041), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (82.983) has a higher microsomal clearance than Ligand A (54.541), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-19.911) has a slightly better (less negative) in vitro half-life than Ligand B (-21.784).

**P-gp Efflux:** Ligand A (0.198) has lower P-gp efflux than Ligand B (0.217).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the far superior candidate. Its significantly stronger binding affinity (-7.8 vs -0.0 kcal/mol) outweighs the ADME concerns. The lower DILI and hERG risk, combined with better metabolic stability and BBB penetration, further solidify its advantage. Ligand B's very weak binding affinity makes it unlikely to be a viable drug candidate.

Output:
0
2025-04-17 16:25:22,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (352.431 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 good oral absorption. Ligand B (91.22) is slightly better than Ligand A (107.89), but both are acceptable.

**logP:** Ligand A (-0.3) is a bit low, potentially hindering permeation. Ligand B (3.257) is within the optimal range (1-3). 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 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.52, B: 0.628), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (47.344) has a lower DILI risk than Ligand B (57.697), which is a positive.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.811) has a higher BBB percentile than Ligand A (29.546), but this isn't a major factor here.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.099) is slightly better than Ligand B (-4.951).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand B (-4.112) is slightly better than Ligand A (-1.256).

**hERG Inhibition:** Ligand A (0.111) has a much lower hERG risk than Ligand B (0.751). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-0.474) has a negative clearance, indicating excellent metabolic stability, while Ligand B (45.377) has a high clearance, suggesting rapid metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-8.92) has a very long half-life, while Ligand B (35.929) has a moderate half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.039, B: 0.197).

**Binding Affinity:** Both ligands have good binding affinity (A: -8.0 kcal/mol, B: -7.8 kcal/mol). Ligand A has a slightly better affinity, but the difference is not substantial enough to outweigh other factors.

**Overall:**

Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity. While Ligand B has a better logP, the advantages of Ligand A in ADME-Tox properties are more crucial for an enzyme target like SRC kinase. The poor solubility and permeability of both compounds would need to be addressed in further optimization, but Ligand A provides a better starting point.

Output:
0
2025-04-17 16:25:22,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.298 and 346.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.86) is excellent, well below the 140 threshold for oral absorption. Ligand B (49.85) is also very good.

**logP:** Both ligands have good logP values (2.606 and 2.075), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which is acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.574 and 0.692), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (87.01 percentile), a significant concern. Ligand B has a very low DILI risk (14.889 percentile), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB score (83.133) than Ligand A (57.154), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the measurement 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, which is also unusual. Ligand B (-2.416) is slightly better than Ligand A (-4.108).

**hERG Inhibition:** Ligand A has a slightly elevated hERG risk (0.437), while Ligand B has a very low risk (0.189).

**Microsomal Clearance:** Ligand A has a high microsomal clearance (95.739), indicating poor metabolic stability. Ligand B has a much lower clearance (60.753), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (6.391 hours) than Ligand A (-32.667 hours - a negative value is concerning).

**P-gp Efflux:** Ligand A has a moderate P-gp efflux liability (0.359), while Ligand B has very low efflux (0.127).

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-10.5 kcal/mol) than Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Conclusion:**

Despite the strong binding affinity of Ligand A, its high DILI risk, poor metabolic stability (high Cl_mic, negative t1/2), and moderate P-gp efflux are major drawbacks. Ligand B, while having a weaker binding affinity, demonstrates a much more favorable ADMET profile: low DILI risk, better metabolic stability, longer half-life, and lower P-gp efflux. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. Given the enzyme-specific priorities, the ADMET profile of Ligand B is far more promising for development.

Output:
1
2025-04-17 16:25:22,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.379 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (75.8) is better than Ligand B (102.01). Both are reasonably good for oral absorption, but A is preferable.

**logP:** Ligand A (2.392) is optimal, while Ligand B (-0.717) is quite low, potentially hindering membrane permeability and absorption. This is a significant drawback for B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable, but A is slightly better.

**QED:** Both ligands have good QED scores (A: 0.925, B: 0.626), indicating drug-like properties. A is significantly better.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (49.166), but both are acceptable.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (73.711) is better, but this isn't a deciding factor.

**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, also unusual. Again, the scale is unknown.

**hERG:** Ligand A (0.474) has a lower hERG risk than Ligand B (0.272), which is preferable.

**Microsomal Clearance:** Ligand B (-7.928) has a *negative* clearance, which is impossible. This is a major red flag and suggests an issue with the data or the model. Ligand A (54.031) has a reasonable clearance.

**In vitro Half-Life:** Ligand A (4.363) has a better half-life than Ligand B (-6.862). Again, the negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.598) has slightly higher P-gp efflux than Ligand B (0.023), but both are relatively low.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-6.9 and -6.7 kcal/mol). The difference is negligible.

**Overall:**

Ligand A is significantly better than Ligand B. While Ligand A has a slightly higher DILI risk, Ligand B has impossible values for microsomal clearance and half-life, and a concerningly low logP. The negative values for clearance and half-life for Ligand B are likely errors, making it an unreliable candidate. Ligand A's better logP, TPSA, QED, and hERG profile, combined with its reasonable metabolic stability, make it the more promising drug candidate.

Output:
1
2025-04-17 16:25:22,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.199 Da) is slightly higher than Ligand B (342.414 Da), but both are acceptable.

**TPSA:** Ligand A (104.21) is higher than Ligand B (61.36). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (3.226) and Ligand B (4.506) are both within the optimal range (1-3), but Ligand B is approaching the upper limit. This could potentially lead to solubility issues or off-target interactions, but isn't a major concern yet.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 3 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED values (0.737 and 0.766, respectively), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (97.867%) than Ligand B (60.644%). This is a major red flag for Ligand A.

**BBB:** This is less critical for a kinase inhibitor, but Ligand B (68.127%) shows slightly better potential for CNS penetration than Ligand A (40.52%).

**Caco-2 Permeability:** Ligand A (-4.596) has a worse Caco-2 permeability than Ligand B (-4.945). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-6.293) has better aqueous solubility than Ligand B (-5.456). This is a positive attribute for Ligand A.

**hERG Inhibition:** Ligand A (0.748) has a slightly lower hERG inhibition risk than Ligand B (0.836), which is favorable.

**Microsomal Clearance:** Ligand A (75.37) has lower microsomal clearance than Ligand B (85.943), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (60.487) has a much longer in vitro half-life than Ligand B (20.061). This is a substantial advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.224) has lower P-gp efflux than Ligand B (0.348), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is not huge, it is still a benefit for Ligand B.

**Overall Assessment:**

Ligand A has advantages in metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, solubility, and a slightly lower hERG risk. However, its extremely high DILI risk is a major concern. Ligand B has a better TPSA, slightly better binding affinity, and a much lower DILI risk. The difference in binding affinity is not substantial enough to outweigh the significant DILI risk associated with Ligand A.

Output:
1
2025-04-17 16:25:22,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.47 and 363.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.34) is significantly better than Ligand B (97.94). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferable.

**logP:** Ligand A (4.375) is higher than the optimal 1-3 range, potentially leading to solubility issues. Ligand B (2.323) is within the optimal 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. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.833 and 0.788), indicating good drug-likeness.

**DILI:** Ligand A (34.82) has a much lower DILI risk than Ligand B (54.25). This is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.87) is higher than Ligand B (20.63), but it's not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.588) has a worse Caco-2 permeability compared to Ligand B (-5.135). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-5.23) has worse solubility than Ligand B (-3.674).

**hERG:** Both ligands have very low hERG risk (0.854 and 0.455), which is excellent.

**Microsomal Clearance:** Ligand A (102.55) has a higher microsomal clearance than Ligand B (11.58). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (29.92) has a significantly longer in vitro half-life than Ligand A (-16.56). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.796 and 0.459).

**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 still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a lower DILI risk, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2), solubility, and has a slightly better binding affinity. The higher logP of Ligand A is a concern, potentially leading to formulation challenges. The better metabolic stability and half-life of Ligand B are crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:25:22,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.323 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (98.66) is slightly above the preferred <90 for CNS targets, but acceptable for a non-CNS target like SRC. Ligand B (75.71) is well within the ideal range.

**logP:** Ligand A (0.598) is a bit low, potentially hindering permeation. Ligand B (1.834) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both within acceptable limits. Ligand B has 1 HBD and 4 HBA, also good.

**QED:** Both ligands have reasonable QED scores (A: 0.78, B: 0.52), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (87.98%), which is a significant concern. Ligand B has a very low DILI risk (20.047%), a major advantage.

**BBB:** This is less critical for SRC, but Ligand B (73.711%) has better BBB penetration than Ligand A (44.009%).

**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 unclear, making interpretation difficult.

**hERG:** Ligand A (0.191) has a slightly elevated hERG risk, while Ligand B (0.312) is a bit higher, but both are relatively low.

**Microsomal Clearance:** Ligand A (0.782) has much lower microsomal clearance, indicating better metabolic stability. Ligand B (9.148) has high clearance, which is a significant drawback.

**In vitro Half-Life:** Ligand A (6.131) has a better in vitro half-life than Ligand B (-23.37), further supporting its metabolic stability.

**P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux, which is favorable. Ligand B (0.051) has even lower efflux, which is good.

**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, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B stands out due to its significantly superior binding affinity (-7.4 vs -9.4 kcal/mol) and *much* lower DILI risk (20.047% vs 87.98%). While Ligand B has higher microsomal clearance and a slightly lower logP, the strong binding and low toxicity are critical for an enzyme target like SRC. The difference in binding affinity is substantial (>1.5 kcal/mol), making Ligand B the more promising candidate despite its ADME liabilities. Ligand A's high DILI risk is a major red flag.



Output:
1
2025-04-17 16:25:22,240 - INFO - Batch 462 complete. Total preferences: 7392
2025-04-17 16:25:22,240 - INFO - Processing batch 463/512...
2025-04-17 16:26:04,069 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.427 and 380.432 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.49) is better than Ligand B (78.43), being comfortably below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (2.496 and 1.454), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is slightly better than Ligand B (HBD=3, HBA=4) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.846 and 0.625), indicating good drug-like properties. Ligand A is superior.

**DILI:** Ligand A (34.703) has a significantly lower DILI risk than Ligand B (18.728). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (68.088 and 69.252). This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.336 and -5.474). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.449 and -2.457). Similar to Caco-2, these values are concerning and suggest poor solubility.

**hERG Inhibition:** Ligand A (0.673) has a lower hERG inhibition risk than Ligand B (0.289). This is a significant advantage.

**Microsomal Clearance:** Ligand A (-42.889) has a much lower (better) microsomal clearance than Ligand B (3.857). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (38.069) has a longer in vitro half-life than Ligand B (-8.323). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux liability than Ligand B (0.072).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.6 and -8.0 kcal/mol). Ligand B is slightly better, but the difference is likely not substantial enough to overcome the other significant 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 ADMET properties: lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The solubility and permeability concerns are present in both, but the superior safety and pharmacokinetic profile of Ligand A outweigh the minor binding affinity difference.

Output:
1
2025-04-17 16:26:04,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.467 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.57) is well below the 140 threshold, while Ligand B (87.32) is still acceptable but closer to the limit.

**logP:** Ligand A (0.495) is slightly low, potentially hindering permeation. Ligand B (1.566) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is excellent. Ligand B (2) is acceptable.

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (0.716 and 0.862, respectively), suggesting drug-like properties.

**DILI:** Ligand A (25.281) has a significantly lower DILI risk than Ligand B (52.695), which is a major advantage.

**BBB:** Ligand A (73.362) shows good BBB penetration, while Ligand B (52.889) is lower. While SRC isn't a CNS target, this isn't a detriment to A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.194 and -5.024), which is unusual and concerning. This suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily mean zero permeability.

**Aqueous Solubility:** Ligand A (-0.102) is slightly better than Ligand B (-2.675), though both are poor. Solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.105) has a very low hERG risk, a significant advantage. Ligand B (0.512) is higher, indicating a moderate risk.

**Microsomal Clearance:** Ligand A (20.389) has a higher microsomal clearance than Ligand B (7.541), meaning faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (10.442 hours) has a longer half-life than Ligand A (5.966 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.036).

**Binding Affinity:** Ligand A (-9.4 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 of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -7.5 kcal/mol) and much lower DILI risk (25.3 vs 52.7) are critical advantages for an enzyme inhibitor. The lower hERG risk is also a major plus. While Ligand B has a better half-life, the potency and safety profile of Ligand A are more compelling. The slightly lower logP of A is a minor concern that could potentially be addressed with further optimization.

Output:
1
2025-04-17 16:26:04,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (344.455 and 342.439 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is higher than Ligand B (49.85). While both are acceptable, Ligand B's lower TPSA is slightly preferable for potential cell permeability.

**3. logP:** Both ligands have good logP values (2.359 and 1.132), falling 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 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, well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.746 and 0.723), indicating good drug-like properties.

**7. DILI:** Ligand A (17.487) has a significantly lower DILI risk than Ligand B (31.989). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands show good BBB penetration (76.696 and 78.868), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.722 and -4.41). These values are unusual and likely indicate poor permeability *in vitro*. However, these values can be unreliable and should be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.398 and -2.821). These values are also unusual and suggest poor aqueous solubility. This is a significant drawback for both compounds.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.505 and 0.398), which is excellent.

**12. Microsomal Clearance:** Ligand A (61.331) has a higher microsomal clearance than Ligand B (32.737). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-2.448) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (7.281) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.241 and 0.089), which is favorable.

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.3 kcal/mol), which is excellent and the most important factor.

**Overall Assessment:**

Despite similar binding affinities, Ligand A is the stronger candidate due to its significantly lower DILI risk and more reasonable *in vitro* half-life. While both have poor predicted solubility and permeability, the lower DILI risk is a critical advantage. Ligand B's negative half-life is a red flag. The lower clearance of Ligand B is positive, but the DILI risk outweighs this benefit.

Output:
0
2025-04-17 16:26:04,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.515 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (62.55). Lower TPSA generally favors better absorption.

**3. logP:** Both ligands have a logP around 3.83, which is optimal.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are acceptable, but lower is generally preferred.

**6. QED:** Both ligands have good QED scores (0.645 and 0.726), indicating drug-like properties.

**7. DILI:** Ligand A (20.706) has a much lower DILI risk than Ligand B (28.887), which is a significant advantage.

**8. BBB:** Both have reasonable BBB penetration (74.913 and 78.868). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 have negative solubility values, indicating poor aqueous solubility. This is a major concern for both compounds.

**11. hERG:** Ligand A (0.323) has a lower hERG risk than Ligand B (0.667), which is a positive.

**12. Cl_mic:** Ligand A (69.607) has lower microsomal clearance than Ligand B (77.02), suggesting better metabolic stability.

**13. t1/2:** Ligand B (74.597) has a significantly longer in vitro half-life than Ligand A (-1.979). This is a major advantage for Ligand B.

**14. Pgp:** Both have low Pgp efflux liability (0.329 and 0.588).

**15. Binding Affinity:** Ligand A (-9.3) has a significantly stronger binding affinity than Ligand B (-8.0). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with Caco-2 permeability and solubility, Ligand A is the better candidate. The significantly stronger binding affinity (-9.3 vs -8.0 kcal/mol) is a major advantage for an enzyme inhibitor. Additionally, Ligand A has a lower DILI risk, lower hERG risk, and better metabolic stability (lower Cl_mic). The longer half-life of Ligand B is attractive, but the weaker binding and higher toxicity risks of Ligand B are concerning. The binding affinity difference is large enough to prioritize Ligand A despite its shorter half-life.

Output:
0
2025-04-17 16:26:04,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.885 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is significantly better than Ligand B (108.05). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is relatively high, potentially hindering absorption.

**logP:** Ligand A (3.896) is within the optimal 1-3 range. Ligand B (-0.93) is below 1, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.779 and 0.668), indicating good drug-likeness.

**DILI:** Ligand A (41.838) has a lower DILI risk than Ligand B (54.517), both are acceptable, but A is preferred.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (93.408) has a higher BBB penetration than Ligand B (49.787).

**Caco-2 Permeability:** Ligand A (-4.68) is better than Ligand B (-5.093). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-4.447) is better than Ligand B (-1.419). Higher solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.938) has a lower hERG risk than Ligand B (0.067). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (71.472) has a higher clearance than Ligand B (-20.443). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand A (2.268) has a shorter half-life than Ligand B (21.656). A longer half-life is generally desirable, favoring Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.768 and 0.002).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -9.7 kcal/mol). The difference (0.6 kcal/mol) is not substantial enough to outweigh the other ADME considerations.

**Overall Assessment:**

Ligand A demonstrates superior properties in terms of TPSA, logP, solubility, and importantly, hERG risk. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), the significantly higher TPSA, lower logP, and increased hERG risk are major drawbacks. Given the priorities for enzyme inhibitors, the combination of good potency, acceptable metabolic properties, and a low hERG risk makes Ligand A the more promising candidate.

Output:
1
2025-04-17 16:26:04,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (341.346 and 357.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (92.93 and 97.92) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (1.927 and 1.394) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED scores (0.74 and 0.64), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 74.254, which is concerning (high risk, >60). Ligand B has a much lower DILI risk of 27.142, which is excellent. This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (82.009) has a higher BBB score than Ligand A (47.809), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.169 and -4.636). This is unusual and suggests poor permeability. However, negative values are sometimes artifacts of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.851 and -2.076). Similar to Caco-2, this is concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.075) has a very low hERG risk, which is excellent. Ligand B (0.253) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (75.585) has a higher microsomal clearance than Ligand B (29.386). This suggests Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (1.738 hours) has a slightly longer half-life than Ligand A (-35.05 hours). Note the negative value for ligand A is likely an error, and should be interpreted as very short half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.187 and 0.008).

**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 for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with predicted solubility and permeability, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 16:26:04,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.833 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.02) is slightly higher than Ligand B (65.54), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (0.984 and 1.244), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have high QED scores (0.862 and 0.808), indicating good drug-likeness.

**DILI:** Ligand A (35.479) has a significantly lower DILI risk than Ligand B (9.694). This is a major advantage.

**BBB:**  BBB is less critical for a non-CNS target like SRC, but Ligand B (78.402) has a higher percentile than Ligand A (65.568).

**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:** Both ligands have very low hERG inhibition liability (0.222 and 0.21), which is excellent.

**Microsomal Clearance:** Ligand A (-15.684) exhibits much lower (better) microsomal clearance than Ligand B (9.401). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (19.9 hours) has a substantially longer half-life than Ligand B (-3.815 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.012).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand A is the superior candidate. It demonstrates a significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have issues with Caco-2 and Solubility (negative values), the ADME profile of Ligand A is considerably more favorable due to its lower toxicity and improved stability. The slight advantage in binding affinity further supports its selection.

Output:
1
2025-04-17 16:26:04,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.39 and 337.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.23) is better than Ligand B (71.09), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.902) is optimal, while Ligand B (3.123) is approaching the upper limit.

**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:** Both ligands have good QED scores (0.925 and 0.845), indicating good drug-like properties.

**DILI:** Ligand A (55.874) has a lower DILI risk than Ligand B (64.754), which is preferable. Both are acceptable, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.249) is better than Ligand B (77.782).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the absolute value is closer to zero for Ligand A (-4.652 vs -4.403), suggesting marginally better permeability.

**Aqueous Solubility:** Ligand A (-2.861) has better solubility than Ligand B (-4.948). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.402) has a lower hERG risk than Ligand B (0.256), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-6.063) has a significantly lower (better) microsomal clearance than Ligand B (75.778), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (15.474 hours) has a longer half-life than Ligand B (24.487 hours).

**P-gp Efflux:** Ligand A (0.144) has lower P-gp efflux than Ligand B (0.065), which is preferable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While affinity is paramount, the difference of 0.6 kcal/mol is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A demonstrates a superior ADME profile, particularly regarding metabolic stability (Cl_mic), solubility, and hERG risk. While Ligand B has slightly better binding affinity, the advantages of Ligand A in key ADME parameters, crucial for enzyme inhibitors, make it the more promising drug candidate.

Output:
0
2025-04-17 16:26:04,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.39 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.18) is better than Ligand B (90.98), both are below the 140 threshold for oral absorption, but ligand A is closer to the preferred <90 for CNS targets (though this is less critical for a non-CNS target like SRC).

**logP:** Both ligands (2.121 and 2.355) are 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 (5) are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.797 and 0.874), indicating good drug-like properties.

**DILI:** Ligand A (72.082) has a slightly higher DILI risk than Ligand B (64.676), but both are below the concerning threshold of 60.

**BBB:** Ligand A (70.648) has a better BBB penetration score than Ligand B (31.136), but this is less important for SRC.

**Caco-2 Permeability:** Ligand A (-5.086) and Ligand B (-5.332) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.469) is slightly better than Ligand B (-2.887), but both are poor. Solubility is a significant concern for both.

**hERG Inhibition:** Ligand A (0.643) has a lower hERG inhibition liability than Ligand B (0.163), which is a major advantage.

**Microsomal Clearance:** Ligand A (5.589) has a better (lower) microsomal clearance than Ligand B (-7.115), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-1.889) has a better (longer) in vitro half-life than Ligand B (-13.912), further supporting its improved metabolic stability.

**P-gp Efflux:** Ligand A (0.151) has lower P-gp efflux liability than Ligand B (0.036), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -7.6 kcal/mol), with Ligand A being slightly better. The difference is less than the 1.5 kcal/mol threshold that would definitively swing the decision.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both have poor Caco-2 and solubility, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and slightly better binding affinity. These factors are more critical for an enzyme inhibitor like an SRC kinase inhibitor than BBB penetration or slightly lower DILI risk.

Output:
1
2025-04-17 16:26:04,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (374.503 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.1 and 75.71) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.523) is slightly low, potentially hindering permeation. Ligand B (1.656) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.562 and 0.817), indicating drug-likeness.

**DILI:** Ligand A has a DILI risk of 31.291, which is good (low risk). Ligand B has a DILI risk of 12.834, even better.

**BBB:** Both have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic, suggesting poor permeability. However, these values are on a log scale and the negative values are not necessarily indicative of zero permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.299 and 0.468).

**Microsomal Clearance:** Ligand A has a Cl_mic of 24.111 mL/min/kg, which is moderate. Ligand B has a Cl_mic of 21.645 mL/min/kg, also moderate.

**In vitro Half-Life:** Ligand A has a t1/2 of 4.595 hours, while Ligand B has a negative t1/2 of -17.786 hours, which is not physically possible and indicates a potential data error or issue with the prediction.

**P-gp Efflux:** Both have low P-gp efflux liability (0.014 and 0.024).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial.

**Conclusion:**

Despite the unusual solubility and Caco-2 values, Ligand B is the better candidate. The significantly stronger binding affinity (-9.1 vs -6.6 kcal/mol) outweighs the slightly higher logP and similar metabolic stability. The lower DILI risk is also a positive factor. The negative half-life for Ligand B is a major concern, but assuming this is a data error, the other properties favor it.

Output:
1
2025-04-17 16:26:04,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (345.443 and 366.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.67) is better than Ligand B (69.64) as it's still within the acceptable range for oral absorption (<140), but lower TPSA is generally preferred.

**3. logP:** Both ligands have good logP values (1.433 and 3.034), 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 (3) is lower than Ligand B (4), both are within the acceptable range (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.755 and 0.669), indicating good drug-like properties.

**7. DILI:** Ligand A (22.218) has a significantly lower DILI risk than Ligand B (29.391). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Both ligands have similar BBB penetration (61.38 and 67.158). BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Ligand A (-4.911) shows better Caco-2 permeability than Ligand B (-4.689). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-1.698) has better aqueous solubility than Ligand B (-3.582). Higher values are better. Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.168) has a lower hERG inhibition liability than Ligand B (0.627), which is a significant advantage. Lower hERG risk is crucial.

**12. Microsomal Clearance:** Ligand A (-7.997) has much lower microsomal clearance than Ligand B (83.695). This indicates significantly better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (23.254) has a longer in vitro half-life than Ligand B (15.448). This is desirable for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux liability than Ligand B (0.422), suggesting better oral bioavailability.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.0 kcal/mol). While both are good, Ligand A is slightly better.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in all these areas: lower Cl_mic, longer t1/2, better solubility, and lower hERG risk. The slight advantage in binding affinity further supports its selection.

Output:
0
2025-04-17 16:26:04,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (369.372 and 360.445 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.84) is higher than Ligand B (49.85). While both are reasonably low, Ligand B is better positioned for good absorption.

**3. logP:** Ligand A (3.737) is at the higher end of the optimal range, while Ligand B (2.196) is well within it. Ligand A's higher logP *could* lead to solubility issues or off-target interactions, but isn't a major concern yet.

**4. H-Bond Donors:** Ligand A (2) is acceptable, and Ligand B (0) 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 reasonable QED scores (0.736 and 0.624), indicating good drug-like properties.

**7. DILI:** Ligand A (88.639) has a significantly higher DILI risk than Ligand B (21.287). This is a major red flag for Ligand A.

**8. BBB:** Both have acceptable BBB penetration, but Ligand B (93.68) is higher than Ligand A (75.998). This isn't a primary concern for a kinase inhibitor, but it's a slight advantage for B.

**9. Caco-2 Permeability:** Ligand A (-4.862) has poor Caco-2 permeability, while Ligand B (-4.347) is slightly better, but still poor. This suggests absorption issues for both, but more pronounced for A.

**10. Aqueous Solubility:** Ligand A (-4.011) has poor aqueous solubility, while Ligand B (-1.705) is better. Solubility is important for formulation and bioavailability, favoring Ligand B.

**11. hERG Inhibition:** Ligand A (0.547) has a slightly higher hERG risk than Ligand B (0.722). Lower is better here, favoring B.

**12. Microsomal Clearance:** Ligand A (28.66) has lower microsomal clearance than Ligand B (42.145), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (81.118) has a much longer in vitro half-life than Ligand B (9.985). This is a significant advantage for Ligand A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.368) has lower P-gp efflux than Ligand B (0.294), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.5). While both are excellent, the difference of 0.6 kcal/mol is not substantial enough to outweigh other significant ADME concerns.

**Overall Assessment:**

Ligand A has a longer half-life and lower P-gp efflux, but suffers from significantly higher DILI risk, poor solubility, and poor Caco-2 permeability. Ligand B has a better safety profile (lower DILI, better hERG), better solubility, and better Caco-2 permeability, even though its half-life is shorter. Given the enzyme-specific priorities, the safety and solubility advantages of Ligand B are more critical than the slightly better half-life of Ligand A. The binding affinity difference is small.

Output:
1
2025-04-17 16:26:04,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.471 and 340.467 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is better than Ligand B (49.41). Both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.642 and 3.325), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target effects, but is not a major concern.

**H-Bond Donors & Acceptors:** Both have acceptable HBD (1) and HBA (3 & 2) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.918 and 0.855), indicating good drug-like properties.

**DILI:** Ligand A (13.804) has a significantly lower DILI risk than Ligand B (25.126). This is a major advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand A (90.617) is significantly better than Ligand B (70.997). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.325 and -4.403). This is unusual and suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Ligand A (-2.251) is better than Ligand B (-4.689). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.81) has a lower hERG risk than Ligand B (0.439). Lower is better, making Ligand A safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (70.202) has a much higher microsomal clearance than Ligand A (0.659). This means Ligand B will be metabolized much faster, leading to lower exposure. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (4.962) has a significantly longer half-life than Ligand B (-3.259). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.16) has lower P-gp efflux than Ligand B (0.314). Lower efflux is generally preferred for better bioavailability.

**Binding Affinity:** Ligand B (-9.0) has a significantly better binding affinity than Ligand A (-7.5). This is a 1.5 kcal/mol difference, which is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A has significantly better ADMET properties: lower DILI risk, better solubility, lower hERG risk, much lower microsomal clearance, a longer half-life, and lower P-gp efflux. The negative Caco-2 values for both are concerning, but the other advantages of Ligand A are substantial. Given the importance of metabolic stability and safety (DILI, hERG) for kinase inhibitors, and the significant difference in these parameters, I believe Ligand A is the more viable drug candidate *despite* the lower binding affinity. The difference in binding affinity might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 16:26:04,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (364.511 and 376.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (110.8). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B is approaching a level that could hinder absorption.

**logP:** Ligand A (2.719) is optimal (1-3). Ligand B (-0.374) is below 1, which could impede 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, and Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.863) has a significantly better QED score than Ligand B (0.568), indicating a more drug-like profile.

**DILI:** Ligand A (24.661) has a much lower DILI risk than Ligand B (39.046), indicating a safer profile. Both are below the 40 threshold.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 57.929, Ligand B: 63.784), but this is less critical for a non-CNS target like SRC.

**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 (0.432) has a lower hERG risk than Ligand B (0.134), which is preferable.

**Microsomal Clearance:** Ligand A (-0.049) has a much lower (better) microsomal clearance than Ligand B (-1.488), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-1.072) has a longer half-life than Ligand B (17.689).

**P-gp Efflux:** Ligand A (0.285) has lower P-gp efflux than Ligand B (0.013), which is better for bioavailability.

**Binding Affinity:** Ligand B (-7.3) has a significantly better binding affinity than Ligand A (-10.5). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.3 vs -10.5 kcal/mol). This is a major advantage that could outweigh some of its ADME drawbacks. However, Ligand B has concerning properties: a low logP, a higher TPSA, a lower QED, a higher DILI risk, and a higher microsomal clearance. Ligand A is generally better across most ADME properties, suggesting it would be more readily absorbed, less toxic, and more metabolically stable.

Despite the affinity difference, the ADME profile of Ligand A is far superior. The substantial difference in binding affinity *might* be enough to overcome the ADME issues of Ligand B, but the risk is high. For an enzyme target, metabolic stability and solubility are crucial, and Ligand A excels in these areas.

Output:
0
2025-04-17 16:26:04,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 359.348 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.66) is slightly above the preferred <140, but acceptable. Ligand B (91.32) is excellent, well below 140.

**logP:** Ligand A (-0.014) is a bit low, potentially hindering permeability. Ligand B (2.002) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, both acceptable. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.405) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.75) is good, exceeding the 0.5 threshold.

**DILI:** Ligand A (59.17) is approaching the higher risk threshold (>60), while Ligand B (41.062) is comfortably below 40, indicating lower liver injury risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.276) and Ligand B (67.623) are both moderate.

**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 direct comparison is difficult.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Again, direct comparison is difficult due to differing scales.

**hERG:** Ligand A (0.066) has a slightly higher hERG risk than Ligand B (0.328), though both are relatively low.

**Microsomal Clearance:** Ligand A (2.749) has significantly lower microsomal clearance than Ligand B (27.148), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.583) has a reasonable half-life, while Ligand B (-46.438) has a negative half-life, which is impossible and likely indicates an issue with the data or assay.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable. Ligand B (0.014) is also low.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -7.8 kcal/mol). The difference is minimal.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. It has a better logP, QED, lower DILI risk, and a more reasonable (though still problematic) half-life. Ligand A's low logP, borderline DILI risk, and questionable solubility are concerning. The negative half-life value for Ligand B is a major red flag, but the other properties are superior. Given the choice, I'd prioritize investigating the source of the negative half-life for Ligand B, as the other ADME properties are more favorable.

Output:
1
2025-04-17 16:26:04,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.774 Da) is slightly better positioned.

**TPSA:** Both are reasonably low (A: 79.9, B: 81.07), suggesting good potential for cell permeability, but not optimized for CNS penetration.

**logP:** Both have acceptable logP values (A: 4.261, B: 2.634). Ligand B is preferable here, being closer to the optimal 1-3 range. Ligand A's higher logP could lead to off-target effects or poor solubility.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which is within the acceptable limits.

**QED:** Ligand A (0.7) has a significantly better QED score than Ligand B (0.378), indicating a more drug-like profile.

**DILI:** Ligand A (98.643) has a very high DILI risk, which is a major concern. Ligand B (51.493) is much better, falling within an acceptable range.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC.

**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 very poor aqueous solubility (A: -5.447, B: -2.944). This is a significant drawback, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.778) has a slightly better hERG profile than Ligand B (0.557), but both are within acceptable ranges.

**Microsomal Clearance:** Both have similar microsomal clearance rates (A: 41.941, B: 42.613), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (20.047 hours) has a much longer half-life than Ligand B (-2.435 hours). This is a substantial advantage for dosing convenience.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.766, B: 0.292).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a better half-life and QED score. However, its extremely high DILI risk and poor solubility are major red flags. Ligand B has a better logP and DILI profile, but its significantly weaker binding affinity and negative in vitro half-life are concerning.

Given the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), the strong binding affinity of Ligand A is a compelling factor. While the DILI risk is high, it might be mitigated through structural modifications during lead optimization. The solubility issue is also addressable. The poor half-life of Ligand B is harder to fix.

Output:
1
2025-04-17 16:26:04,072 - INFO - Batch 463 complete. Total preferences: 7408
2025-04-17 16:26:04,072 - INFO - Processing batch 464/512...
2025-04-17 16:26:50,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.256 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**TPSA:** Ligand A (102.48) is higher than Ligand B (52.65). While both are below 140, Ligand B's lower TPSA is preferable for oral absorption.

**logP:** Ligand A (0.758) is slightly lower than the optimal range (1-3), potentially impacting permeability. Ligand B (1.56) is within the optimal 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:** Ligand A (0.731) has a better QED score than Ligand B (0.393), indicating a more drug-like profile.

**DILI:** Ligand A (75.184) has a significantly higher DILI risk than Ligand B (7.212). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (70.027) is slightly better than Ligand B (63.358). However, BBB is not a primary concern for a kinase inhibitor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This needs further investigation, but it's a shared weakness.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a shared weakness.

**hERG:** Ligand A (0.423) has a slightly higher hERG risk than Ligand B (0.328), but both are relatively low.

**Microsomal Clearance:** Ligand A (-4.158) has a lower (better) microsomal clearance than Ligand B (-2.71), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.602) has a longer half-life than Ligand B (-10.786), which is desirable.

**P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux than Ligand B (0.029), which is preferable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 1.5 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's superior binding affinity and metabolic stability, its significantly higher DILI risk is a major red flag. The poor solubility and permeability (indicated by negative Caco-2 and solubility values) are shared concerns, but the DILI risk for Ligand A is particularly concerning. Ligand B, while having slightly weaker affinity, presents a much more favorable safety profile (lower DILI) and a better logP. Therefore, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 16:26:50,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.375 Da) is slightly higher than Ligand B (338.407 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 60, well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.241) and Ligand B (4.374) are both within the optimal range of 1-3, although Ligand B is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of hydrogen bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.814, B: 0.87), indicating drug-like properties.

**DILI:** Ligand A (52.772) has a lower DILI risk than Ligand B (80.923). This is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (A: 75.843, B: 73.866), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 close, so this is unlikely to be a deciding factor.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the values are close (-3.907 for A vs -5.091 for B), so this is not a major differentiator.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.782, B: 0.791).

**Microsomal Clearance:** Ligand A (15.275 mL/min/kg) has significantly lower microsomal clearance than Ligand B (71.72 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (54.884 hours) has a longer half-life than Ligand B (46.845 hours). This is also a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.597, B: 0.497).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a 2.2 kcal/mol difference, which is a significant advantage and could outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better DILI, metabolic stability (lower Cl_mic), and a longer half-life, Ligand B's significantly stronger binding affinity (-9.8 vs -7.6 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. A 2.2 kcal/mol difference in binding is substantial and suggests a much higher probability of target engagement and efficacy. The slightly higher DILI risk and lower metabolic stability of Ligand B can be addressed through further optimization.

Output:
1
2025-04-17 16:26:50,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (350.419 Da and 359.461 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.55) is slightly above the preferred <140, but still reasonable. Ligand B (52.65) is excellent, well below 90, suggesting good absorption.

**3. logP:** Ligand A (0.572) is a bit low, potentially hindering permeation. Ligand B (2.115) is within the optimal 1-3 range.

**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 (5) and Ligand B (3) are both within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.782 and 0.758), indicating good drug-likeness.

**7. DILI:** Ligand A (46.413) has a moderate DILI risk, but acceptable. Ligand B (8.957) has a very low DILI risk, which is a significant advantage.

**8. BBB:** This is less critical for an oncology target, but Ligand B (89.841) has a higher BBB percentile than Ligand A (47.693).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.914 and -4.774). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.576 and -1.516). These values are also unusual and suggest poor solubility.

**11. hERG Inhibition:** Ligand A (0.27) has a slightly higher hERG risk than Ligand B (0.66), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-10.691) has a significantly lower (better) microsomal clearance than Ligand B (-0.809), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (22.331) has a longer half-life than Ligand B (-23.718). This is a positive attribute.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.021).

**15. 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, especially given the other factors.

**Overall Assessment:**

Ligand B appears to be the more promising candidate. It has a significantly lower DILI risk, better logP, and slightly better binding affinity. While Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, the lower DILI risk of Ligand B is a critical advantage in drug development, particularly for an oncology target. The unusual Caco-2 and solubility values for both compounds are concerning and would require further investigation, but the other properties favor Ligand B.

Output:
1
2025-04-17 16:26:50,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.519 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (82.43). A TPSA under 140 is good for oral absorption, and both are, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (4.747) is slightly high, potentially leading to solubility issues and off-target effects. Ligand B (2.016) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4 HBA, both are acceptable.

**QED:** Ligand A (0.76) has a better QED score than Ligand B (0.484), indicating a more drug-like profile.

**DILI:** Ligand A (44.63) has a lower DILI risk than Ligand B (12.718), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (93.602) has a higher BBB penetration than Ligand B (65.801).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.999) is slightly worse than Ligand B (-4.455).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-4.577) is slightly worse than Ligand B (-1.524).

**hERG:** Ligand A (0.964) has a slightly higher hERG risk than Ligand B (0.421), but both are relatively low.

**Microsomal Clearance:** Ligand A (103.529) has higher microsomal clearance than Ligand B (38.036), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (50.768) has a longer half-life than Ligand B (2.61), which is a positive.

**P-gp Efflux:** Ligand A (0.77) has lower P-gp efflux than Ligand B (0.135), which is favorable.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 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 QED, DILI, BBB, and P-gp efflux. However, it suffers from higher logP, lower solubility, and significantly higher microsomal clearance (lower metabolic stability). Ligand B has better solubility, logP, and metabolic stability, but its binding affinity is considerably weaker.

Given that we are targeting a kinase (enzyme), metabolic stability and potency are paramount. The substantial difference in binding affinity (-9.1 vs -8.3 kcal/mol) for Ligand A is a major advantage. While the higher logP and lower solubility of Ligand A are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The lower metabolic stability is more concerning but might be mitigated with co-administration of metabolic inhibitors or further structural optimization.

Output:
1
2025-04-17 16:26:50,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.375 and 373.519 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.58) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (95.58) is well within the acceptable range.

**logP:** Ligand A (-0.346) is a bit low, potentially hindering permeation. Ligand B (0.859) is closer to 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 7 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED scores (0.438 and 0.586 respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (56.146) has a moderate DILI risk, while Ligand B (20.24) has a much lower and preferable DILI risk.

**BBB:** Both ligands have similar BBB penetration (68.941 and 61.729), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.947 and -5.277). These values are unusual and suggest poor permeability. However, these are relative values and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.196 and -1.864), indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.04) has a very low hERG risk, which is excellent. Ligand B (0.344) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (11.523) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (28.646).

**In vitro Half-Life:** Ligand B (-46.453) has a significantly longer in vitro half-life than Ligand A (-19.095), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.023).

**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.

**Conclusion:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its substantially stronger binding affinity (-9.0 vs -7.8 kcal/mol) is a key advantage for an enzyme target. Additionally, it has a significantly longer half-life and a lower DILI risk. The slightly better logP and lower HBA count also contribute to its favorability. The slightly higher hERG risk is less concerning given the strong binding affinity.

Output:
1
2025-04-17 16:26:50,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.366 and 367.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (89.9 and 85.85) below 140, suggesting good oral absorption potential.

**logP:** Ligand A (2.442) is within the optimal range (1-3). Ligand B (-0.122) is slightly below 1, which *could* indicate potential permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (7 & 6) counts.

**QED:** Both ligands have good QED scores (0.624 and 0.798), indicating drug-like properties.

**DILI:** Ligand A (85.266) has a higher DILI risk than Ligand B (52.113). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (82.513) shows better penetration than Ligand A (68.399).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. This is a major red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. This is another major red flag for both.

**hERG:** Both ligands have low hERG inhibition liability (0.251 and 0.322), which is positive.

**Microsomal Clearance:** Ligand A (92.721) has higher microsomal clearance than Ligand B (33.02), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-12.371) has a very short in vitro half-life, which is a major concern. Ligand A (41.904) is better, but still not ideal.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.646 and 0.041).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference isn't huge, it's enough to potentially overcome some ADME drawbacks.

**Overall Assessment:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility. However, Ligand B has a better binding affinity, lower DILI risk, and lower microsomal clearance (better metabolic stability). Ligand A has a higher DILI risk and higher clearance. The extremely short half-life of Ligand B is a serious concern, but the other factors favor it slightly over Ligand A. The poor permeability and solubility would need to be addressed through formulation or further chemical modifications for either compound.

Output:
1
2025-04-17 16:26:50,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.5 and 341.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is well below the 140 threshold, while Ligand B (95.66) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.75) is at the upper end of the optimal 1-3 range, while Ligand B (1.909) is closer to the lower limit. While both are acceptable, a slightly higher logP can sometimes be beneficial for kinase inhibitors.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (3 HBD, 4 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.819 and 0.748), indicating good drug-like properties.

**DILI:** Ligand A (21.52) has a much lower DILI risk than Ligand B (31.563), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (93.253) shows better BBB penetration than Ligand B (40.791), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.304) has a negative Caco-2 value, indicating poor permeability. Ligand B (-5.325) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.269) and Ligand B (-2.195) both have negative solubility values, which is concerning. Solubility is a key factor for enzyme inhibitors.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.483 and 0.647), which is good.

**Microsomal Clearance:** Ligand B (-28.65) has significantly lower (better) microsomal clearance than Ligand A (52.85), suggesting greater metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (31.918) has a longer in vitro half-life than Ligand A (3.191). This is also a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.076 and 0.084).

**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 small, it's enough to consider.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better TPSA and DILI score, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly improved binding affinity. The poor Caco-2 and solubility of both are concerning, but the metabolic advantages of Ligand B are more critical for an enzyme inhibitor. The slightly better affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 16:26:50,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (385.917 and 378.523 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.53) is slightly higher than Ligand B (68.21), but both are below the 140 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (1.817 and 2.864), falling within the optimal range of 1-3.

**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 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.642 and 0.704), indicating a drug-like profile.

**7. DILI:** Ligand A (38.62) has a significantly lower DILI risk than Ligand B (60.954). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration, with Ligand B (74.06) being slightly better than Ligand A (56.029). However, BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.979), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.547 and -3.101), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.327 and 0.291), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand A (30.742) has a lower microsomal clearance than Ligand B (62.36), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (23.256) has a longer half-life than Ligand B (8.933), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux than Ligand B (0.145), which is favorable for oral bioavailability.

**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 boasts a significantly better binding affinity, Ligand A demonstrates superior ADME properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. The poor Caco-2 and solubility for both are concerning, but the better ADME profile of Ligand A, coupled with its lower DILI risk, makes it the more promising candidate. The affinity difference is large enough to potentially overcome the solubility/permeability issues with further optimization.

Output:
0
2025-04-17 16:26:50,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.422 and 365.876 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (29.54) as it is below the 140 threshold for good absorption. Ligand B is very low, which might be a concern for binding.

**logP:** Ligand A (0.94) is within the optimal range (1-3). Ligand B (4.447) is slightly above, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, but may impact aqueous solubility.

**H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (2) is also acceptable.

**QED:** Both ligands have reasonable QED values (0.469 and 0.668), suggesting drug-like properties, with Ligand B being slightly better.

**DILI:** Both ligands have low DILI risk (23.187 and 28.655), which is good.

**BBB:** Ligand A (71.501) has moderate BBB penetration, while Ligand B (96.937) has very high penetration. However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-5.264) has poor Caco-2 permeability. Ligand B (-4.278) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.557) has poor aqueous solubility. Ligand B (-5.416) has even worse aqueous solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.27) has a low risk of hERG inhibition, which is excellent. Ligand B (0.902) has a higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-18.924) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (104.609) has high clearance, suggesting rapid metabolism. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (4.381) has a reasonable half-life. Ligand B (34.401) has a very long half-life, which is positive.

**P-gp Efflux:** Ligand A (0.062) has low P-gp efflux, which is good. Ligand B (0.77) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.4) has significantly better binding affinity than Ligand B (0). This is a crucial factor for enzyme inhibitors.

**Overall Assessment:**

Ligand A is the better candidate. While both have solubility concerns, Ligand A's superior binding affinity (-7.4 vs 0 kcal/mol) and excellent metabolic stability (low Cl_mic) outweigh its slightly poorer Caco-2 permeability and solubility. The strong binding affinity suggests it can achieve efficacy at lower doses, potentially mitigating solubility issues. Ligand B's high metabolic clearance is a significant concern, and its binding affinity is essentially non-existent.

Output:
0
2025-04-17 16:26:50,675 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [339.351, 93.53, 1.988, 1, 6, 0.579, 96.433, 51.687, -4.848, -4.057, 0.28, 77.274, 1.72, 0.489, -9]
**Ligand B:** [337.471, 66.53, 4.334, 1, 5, 0.881, 35.401, 79.217, -4.914, -5.226, 0.679, 51.636, -4.468, 0.397, -6.5]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (339.351) and B (337.471) are very similar.
2. **TPSA:** Ligand A (93.53) is slightly higher than Ligand B (66.53). Both are acceptable for an enzyme, but B is better.
3. **logP:** Ligand A (1.988) is optimal, while Ligand B (4.334) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** Ligand A has 6 HBA, and Ligand B has 5. Both are acceptable.
6. **QED:** Ligand B (0.881) has a significantly better QED score than Ligand A (0.579), indicating a more drug-like profile.
7. **DILI:** Ligand A (96.433) has a very high DILI risk, which is a major concern. Ligand B (35.401) has a low DILI risk, which is excellent.
8. **BBB:** Not a primary concern for a kinase inhibitor, but Ligand B (79.217) has better BBB penetration than Ligand A (51.687).
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 very poor aqueous solubility. This is a significant drawback for both compounds.
11. **hERG:** Ligand A (0.28) has a lower hERG risk than Ligand B (0.679), which is preferable.
12. **Cl_mic:** Ligand B (51.636) has lower microsomal clearance than Ligand A (77.274), suggesting better metabolic stability.
13. **t1/2:** Ligand B (-4.468) has a longer in vitro half-life than Ligand A (1.72), which is desirable.
14. **Pgp:** Ligand A (0.489) has lower P-gp efflux than Ligand B (0.397), which is preferable.
15. **Binding Affinity:** Ligand A (-9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). This is a 1.5 kcal/mol difference, which is significant.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand A has better affinity, its extremely high DILI risk and poorer metabolic stability are major drawbacks. Ligand B has a much better safety profile (DILI), better metabolic stability, and a longer half-life. The slightly lower affinity of Ligand B is likely surmountable with further optimization. The poor solubility and Caco-2 values are concerning for both and would need to be addressed.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, the significantly lower DILI risk, better QED, improved metabolic stability, and longer half-life of **Ligand B** make it the more promising drug candidate.

Output:
1
2025-04-17 16:26:50,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.407 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is slightly above the preferred <140 for good absorption, while Ligand B (104.9) is well within this range.

**logP:** Ligand A (-0.534) is a bit low, potentially hindering permeability. Ligand B (0.878) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, which are acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable and slightly more favorable.

**QED:** Both ligands have good QED scores (0.589 and 0.754), indicating drug-like properties.

**DILI:** Ligand A (43.311) has a slightly higher DILI risk than Ligand B (26.134), but both are below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (53.432 and 43.505), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.311) shows poor permeability, while Ligand B (-4.661) is better, though still not great.

**Aqueous Solubility:** Ligand A (-0.837) has poor solubility, and Ligand B (-1.912) is also poor. This is a concern for both.

**hERG:** Both ligands have very low hERG risk (0.124 and 0.143).

**Microsomal Clearance:** Ligand A (-11.806) has significantly *lower* (better) microsomal clearance than Ligand B (16.326), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.525) has a shorter half-life than Ligand B (-8.895), which is a negative.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.008 and 0.028).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This 1.2 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the better candidate. While both have solubility issues, Ligand B has a more favorable logP, better Caco-2 permeability, and, most importantly, a significantly better binding affinity. The improved metabolic stability of Ligand A is a plus, but the affinity difference outweighs this benefit. The slightly lower DILI risk for Ligand B is also a minor advantage.

Output:
1
2025-04-17 16:26:50,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.43 and 370.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.96) is better than Ligand B (88.85). Both are below 140, suggesting reasonable absorption, but A is closer to the optimal range for oral bioavailability.

**logP:** Ligand A (-0.384) is slightly low, potentially hindering permeation. Ligand B (1.612) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.73 and 0.788), indicating drug-like properties.

**DILI:** Ligand A (22.26) has a significantly lower DILI risk than Ligand B (44.05). This is a major advantage for Ligand A.

**BBB:** Ligand A (64.48) and Ligand B (82.51) are both reasonable, but not particularly high. Since SRC is not a CNS target, this isn't a major discriminator.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.953 and -4.819), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.939 and -3.235), which is also concerning and suggests poor solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.238) has a much lower hERG risk than Ligand B (0.548). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-26.982) has a much lower (better) microsomal clearance than Ligand B (36.834), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.678) has a slightly longer half-life than Ligand B (1.291).

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, while Ligand B (0.066) is slightly higher. This favors Ligand A.

**Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.9). While the difference is small, it's still a positive for Ligand A.

**Conclusion:**

Ligand A is the better candidate. While both have issues with Caco-2 and solubility, Ligand A has significantly better DILI, hERG, and metabolic stability profiles, and a slightly better binding affinity. The lower DILI and hERG risks are particularly important for an oncology drug, and the improved metabolic stability will likely lead to better *in vivo* exposure. The slightly better affinity is a bonus. Ligand B's better logP is offset by its poorer safety and metabolic properties.

Output:
0
2025-04-17 16:26:50,675 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.443 and 340.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.34) is still under 140, but less optimal than A.

**logP:** Ligand A (2.51) is within the optimal 1-3 range. Ligand B (4.771) is slightly higher, potentially leading to solubility issues or off-target interactions, but not drastically so.

**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 (0.679 and 0.713), indicating drug-like properties.

**DILI:** Ligand A (43.777) has a lower DILI risk than Ligand B (76.425), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (61.497) is better than Ligand B (49.244).

**Caco-2 Permeability:** Ligand A (-4.367) and Ligand B (-4.822) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.929) is better than Ligand B (-5.375) in terms of solubility.

**hERG Inhibition:** Ligand A (0.181) has a much lower hERG inhibition risk than Ligand B (0.665). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (40.415) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (60.772).

**In vitro Half-Life:** Ligand B (97.842) has a significantly longer in vitro half-life than Ligand A (3.143). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux liability than Ligand B (0.704).

**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 A.

**Overall Assessment:**

Ligand A excels in key areas for an enzyme inhibitor: lower DILI risk, lower hERG risk, better solubility, better metabolic stability (lower Cl_mic), and slightly better binding affinity. Ligand B's primary advantage is its significantly longer in vitro half-life. However, the higher DILI and hERG risks associated with Ligand B are concerning. The slightly better affinity of Ligand A, combined with its superior safety profile, outweighs the half-life advantage of Ligand B.

Output:
0
2025-04-17 16:26:50,676 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.415 and 336.355 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.31) is excellent, well below the 140 threshold for oral absorption. Ligand B (126.65) is still acceptable, but less optimal.

**logP:** Ligand A (-0.64) is slightly low, potentially hindering permeability. Ligand B (1.071) is within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (5) are below the threshold of 10.

**QED:** Both ligands (0.661 and 0.62) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (38.62) has a much lower DILI risk than Ligand B (80.147), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (59.597) is higher than Ligand A (42.032), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.503) is very poor, indicating very low intestinal absorption. Ligand B (-6.065) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.202) is poor, while Ligand B (-2.857) is even worse. Both are concerning.

**hERG Inhibition:** Both ligands (0.182 and 0.072) show very low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (2.269) has a much lower microsomal clearance than Ligand B (-16.072), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-1.592) has a negative half-life, which is concerning. Ligand B (19.469) has a good in vitro half-life.

**P-gp Efflux:** Both ligands (0.047 and 0.095) show low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall:**

Ligand A has a superior binding affinity and lower DILI risk and clearance, which are critical for an enzyme inhibitor. However, it suffers from poor Caco-2 permeability and solubility, and a concerning negative half-life. Ligand B has better permeability and half-life, but significantly weaker binding affinity and a much higher DILI risk.

Given the strong preference for potency in enzyme inhibition, and the significant difference in binding affinity (-8.7 vs 0.0 kcal/mol), Ligand A is the more promising candidate *despite* its ADME liabilities. The poor solubility and permeability could be addressed through formulation strategies, and the negative half-life needs investigation, but the potency is a strong starting point.

Output:
0
2025-04-17 16:26:50,676 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 354.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.83) is better than Ligand B (84.42), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (1.197 and 1.091) within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (5), both are within the acceptable limit of 10.

**QED:** Both ligands have similar and good QED values (0.77 and 0.773), indicating good drug-like properties.

**DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (67.546). This is a major advantage for Ligand A.

**BBB:** Ligand B (77.782) has a higher BBB penetration than Ligand A (67.39), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are specifically desired.

**Caco-2:** Ligand A (-5.088) has a worse Caco-2 permeability than Ligand B (-4.693), but both are negative values which is less informative.

**Solubility:** Ligand A (-1.549) has a slightly worse solubility than Ligand B (-1.842), but both are negative values which is less informative.

**hERG:** Ligand A (0.511) has a lower hERG inhibition liability than Ligand B (0.076), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-17.78) has a much lower (better) microsomal clearance than Ligand B (15.695). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (13.973) has a much longer in vitro half-life than Ligand B (-6.838), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.041) has a lower P-gp efflux liability than Ligand B (0.025).

**Binding Affinity:** Ligand A (-8.5) has a slightly better binding affinity than Ligand B (-6.9). While both are good, the 1.6 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. It has a significantly lower DILI risk, lower hERG inhibition, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While Ligand B has slightly better Caco-2 permeability and BBB, these are less critical for a kinase inhibitor targeting oncology. The superior safety profile and potency of Ligand A make it the more viable drug candidate.

Output:
1
2025-04-17 16:26:50,676 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 347.503 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.33) is better than Ligand B (43.86) as it is closer to the ideal range for oral absorption.

**logP:** Both ligands (1.812 and 2.112) fall within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0) as it strikes a balance between solubility and permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3) as it strikes a balance between solubility and permeability.

**QED:** Ligand A (0.898) is significantly better than Ligand B (0.739), indicating a more drug-like profile.

**DILI:** Ligand B (6.592) is significantly better than Ligand A (44.397), indicating a lower risk of drug-induced liver injury. This is a crucial advantage.

**BBB:** Ligand B (85.692) is better than Ligand A (74.719), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.187) is better than Ligand B (-4.81), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.984) is better than Ligand B (-0.987), indicating better solubility.

**hERG Inhibition:** Ligand A (0.137) is better than Ligand B (0.686), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (31.837) is significantly better than Ligand A (58.323), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (5.457) is better than Ligand A (-6.787), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.135) is better than Ligand B (0.075), indicating lower efflux.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.2 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a much better safety profile (DILI, hERG) and metabolic stability (Cl_mic, t1/2). While Ligand A has slightly better solubility and Caco-2 permeability, the safety and metabolic advantages of Ligand B are more critical for an enzyme target like SRC. The binding affinity is comparable. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:26:50,676 - INFO - Batch 464 complete. Total preferences: 7424
2025-04-17 16:26:50,676 - INFO - Processing batch 465/512...
2025-04-17 16:27:36,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Ligand A (416.335 Da) is within the ideal range (200-500 Da). Ligand B (583.092 Da) is above this range, which could potentially hinder permeability.

**TPSA:** Ligand A (44.81) is well below the 140 threshold for good absorption. Ligand B (112.4) is still acceptable but less favorable.

**logP:** Ligand A (2.512) is optimal (1-3). Ligand B (6.465) is significantly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is within the desired ranges. Ligand B (HBD=2, HBA=8) is also acceptable, but approaching the upper limit for HBA.

**QED:** Ligand A (0.742) is excellent, indicating good drug-likeness. Ligand B (0.205) is poor, suggesting potential issues.

**DILI:** Ligand A (39.705) has a low DILI risk. Ligand B (91.431) has a high DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.498) is higher than Ligand B (19.542).

**Caco-2 Permeability:** Ligand A (-4.749) is poor. Ligand B (-5.317) is also poor.

**Aqueous Solubility:** Ligand A (-2.269) is poor. Ligand B (-6.2) is very poor.

**hERG:** Ligand A (0.965) has a low hERG risk. Ligand B (0.89) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (10.388 mL/min/kg) is relatively low, suggesting better metabolic stability. Ligand B (61.259 mL/min/kg) is high, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (16.689 hours) is good. Ligand B (128.641 hours) is excellent.

**P-gp Efflux:** Ligand A (0.242) has low P-gp efflux liability. Ligand B (0.959) has higher P-gp efflux liability.

**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.

**Conclusion:**

Ligand A is the superior candidate. While both have poor Caco-2 and solubility, Ligand A's significantly better binding affinity, lower logP, better QED, lower DILI risk, and lower microsomal clearance outweigh its slightly poorer permeability. The high logP and poor QED of Ligand B are major concerns, along with its high DILI risk and rapid metabolism. The substantial affinity difference is a key factor, as it can compensate for some ADME deficiencies.

Output:
0
2025-04-17 16:27:36,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.503 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (66.92), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand B (1.581) is optimal (1-3), while Ligand A (0.388) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.705) has a better QED score than Ligand B (0.54), indicating better overall drug-likeness.

**DILI:** Ligand A (34.548) has a significantly lower DILI risk than Ligand B (49.903), which is a major advantage. Both are below the concerning threshold of 60.

**BBB:** Ligand B (76.968) has a higher BBB penetration percentile than Ligand A (27.957). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.317) has a very poor Caco-2 permeability, while Ligand B (-3.992) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.061 and -2.705 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.079) has a lower hERG inhibition liability than Ligand B (0.136), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (94.699) has a much higher microsomal clearance than Ligand A (15.193), suggesting lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (-21.491) has a very short in vitro half-life, while Ligand A (-3.41) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux liability, while Ligand B (0.116) is slightly higher.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This 1.5 kcal/mol difference is notable, but needs to be weighed against other factors.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate overall. The significantly lower DILI risk, better QED, lower hERG risk, and substantially better metabolic stability (lower Cl_mic, better t1/2) outweigh the slight affinity advantage of Ligand B. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The lower logP of Ligand A is a potential issue, but less concerning than the metabolic liabilities of Ligand B.

Output:
0
2025-04-17 16:27:36,587 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [367.808, 93.43, 2.547, 2, 4, 0.782, 52.734, 59.597, -4.66, -3.597, 0.583, 2.398, 3.037, 0.092, -8.1]
**Ligand B:** [351.407, 105.68, 0.041, 2, 7, 0.453, 40.675, 78.984, -5.141, -1.791, 0.316, 16.333, -25.05, 0.004, -7.1]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (367.8) is slightly higher than B (351.4), but both are acceptable.
2. **TPSA:** A (93.43) is good, under the 140 threshold. B (105.68) is also acceptable, but closer to the limit.
3. **logP:** A (2.547) is optimal. B (0.041) is very low, potentially causing permeability issues. This is a significant drawback for B.
4. **HBD:** Both have 2 HBD, which is within the acceptable limit of 5.
5. **HBA:** A has 4 HBA, within the limit of 10. B has 7 HBA, still within the limit, but higher.
6. **QED:** A (0.782) is excellent, indicating good drug-like properties. B (0.453) is below the 0.5 threshold, suggesting a less desirable drug-like profile.
7. **DILI:** A (52.734) is good, below the 60% threshold. B (40.675) is also good, and slightly lower.
8. **BBB:** A (59.597) is moderate. B (78.984) is better, but SRC is not a CNS target so this is less important.
9. **Caco-2:** A (-4.66) is very poor. B (-5.141) is also poor, but slightly worse.
10. **Solubility:** A (-3.597) is poor. B (-1.791) is also poor, but better than A.
11. **hERG:** A (0.583) is low risk. B (0.316) is even lower risk, which is good.
12. **Cl_mic:** A (2.398) is low, indicating good metabolic stability. B (16.333) is high, suggesting rapid metabolism and a potential issue.
13. **t1/2:** A (3.037) is relatively short, but acceptable. B (-25.05) is extremely short, a major concern.
14. **Pgp:** A (0.092) is low efflux, which is good. B (0.004) is even lower, which is excellent.
15. **Affinity:** A (-8.1) is significantly better than B (-7.1), a difference of 1.0 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Ligand A is the better candidate. While both have poor Caco-2 and solubility, A has a significantly better binding affinity (-8.1 vs -7.1 kcal/mol), a much better metabolic stability profile (lower Cl_mic, longer t1/2), and a better QED score. The lower logP of ligand B is a significant concern for permeability and overall drug-like properties. The superior affinity of A can likely overcome its solubility issues with appropriate formulation strategies.

Output:
1
2025-04-17 16:27:36,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.5 and 356.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (82.19).  A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Ligand A (2.306) is optimal (1-3), while Ligand B (-0.463) is below 1, potentially hindering permeation. This is a significant advantage for A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 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 (0.671 and 0.593), indicating reasonable drug-likeness.

**DILI:** Ligand A (12.02 percentile) has a much lower DILI risk than Ligand B (15.394 percentile). This is a substantial advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (65.413) is better than Ligand B (52.889).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a potential issue for both, but the lower value for Ligand A (-5.087) is slightly worse than Ligand B (-5.063).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.927 and -0.019). This is a concern for both, but B is slightly better.

**hERG:** Ligand A (0.491) has a lower hERG risk than Ligand B (0.125), which is highly desirable.

**Microsomal Clearance:** Ligand A (35.079 mL/min/kg) has a significantly lower (better) microsomal clearance than Ligand B (8.242 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.767 hours) has a very short half-life, while Ligand B (-27.448 hours) has a much longer half-life. This is a major advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.006).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a crucial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in potency (binding affinity), DILI risk, logP, and hERG risk. Its metabolic stability (Cl_mic) is also much better than Ligand B. While its solubility and Caco-2 permeability are poor, the strong binding affinity and lower toxicity profile make it a more promising candidate. Ligand B has a better half-life, but suffers from poor logP, higher DILI risk, and weaker binding affinity. Given the enzyme-specific priorities, potency and metabolic stability are paramount.

Output:
0
2025-04-17 16:27:36,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 353.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.67) is better than Ligand B (52.65) as it is still within the acceptable range for oral absorption.

**logP:** Both ligands have logP values (1.051 and 1.964) within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both are within the acceptable range.

**QED:** Ligand B (0.794) has a significantly better QED score than Ligand A (0.506), indicating a more drug-like profile.

**DILI:** Ligand A (28.499) has a much lower DILI risk than Ligand B (8.802), which is a significant advantage.

**BBB:** Ligand B (86.739) has a much higher BBB penetration percentile than Ligand A (40.054). However, SRC is not a CNS target, so this is less important.

**Caco-2 Permeability:** Ligand A (-5.104) has a worse Caco-2 permeability than Ligand B (-4.802).

**Aqueous Solubility:** Ligand A (-0.319) has better aqueous solubility than Ligand B (-2.523).

**hERG:** Ligand A (0.2) has a much lower hERG inhibition liability than Ligand B (0.686), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand B (23.923) has a lower microsomal clearance than Ligand A (34.748), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.946) has a longer in vitro half-life than Ligand B (-14.403).

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux liability than Ligand B (0.031).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.8 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, solubility, and half-life. Ligand B has a better QED and microsomal clearance. Given that SRC is an enzyme, metabolic stability (Cl_mic) and minimizing off-target effects (hERG, DILI) are paramount. While Ligand B has better metabolic stability, Ligand A's significantly lower DILI and hERG risk are more critical. The similar binding affinities make these differences decisive.

Output:
0
2025-04-17 16:27:36,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (355.479 Da and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.32) is slightly above the optimal <90 for CNS, but acceptable for a non-CNS target like SRC. Ligand B (52.65) is well within the acceptable range.

**logP:** Ligand A (0.439) is a bit low, potentially hindering permeability. Ligand B (2.428) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 3 HBA) both have reasonable H-bond characteristics, falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.692 and 0.776), indicating drug-like properties.

**DILI:** Ligand A (14.424) has a significantly lower DILI risk than Ligand B (10.741), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (69.407 and 69.058), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.382 and -4.749), 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:** Ligand A (-0.098) has slightly better solubility than Ligand B (-2.447), which is a positive.

**hERG Inhibition:** Ligand A (0.307) exhibits lower hERG inhibition liability than Ligand B (0.523), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (30.659) has a higher microsomal clearance than Ligand B (16.188), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-11.214) has a significantly longer in vitro half-life than Ligand A (7.993), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.031).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially better binding affinity than Ligand A (-6.8 kcal/mol). This 1.1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's lower DILI and slightly better solubility, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.9 vs -6.8 kcal/mol) and longer half-life are critical for an enzyme target like SRC. While Ligand A has a lower DILI score, the difference isn't substantial enough to overcome the potency and stability advantages of Ligand B. The slightly higher hERG risk of Ligand B is manageable, especially given the strong binding affinity.

Output:
1
2025-04-17 16:27:36,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.5 and 371.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is slightly higher than Ligand B (43.86), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have excellent logP values (2.713 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 (0.687 and 0.592), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 29.391, which is very good (low risk). Ligand B has a DILI risk of 11.09, also excellent.

**BBB:** Ligand A has a BBB penetration of 60.682, while Ligand B has 83.56. Since SRC is not a CNS target, BBB is less critical, but B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.84 and -4.895). This is unusual and suggests poor permeability. However, negative values are often artifacts of the prediction method and should be interpreted cautiously.

**Aqueous Solubility:** Ligand A (-3.868) has worse solubility than Ligand B (-1.588). Solubility is important for enzymes, and B is better here.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.513 and 0.563), which is good.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (43.368 and 42.961 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (12.993 hours) compared to Ligand A (5.063 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A has a P-gp efflux liability of 0.177, while Ligand B is 0.082. Lower is better, so Ligand B is preferable.

**Binding Affinity:** Ligand A has a much stronger binding affinity (-8.7 kcal/mol) compared to 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's significantly superior binding affinity (-8.7 kcal/mol vs -0.0 kcal/mol) is the most important factor. While Ligand B has better solubility, half-life, and P-gp efflux, the potency difference is substantial. The Caco-2 values are concerning for both, but may not be reliable. Given the enzyme-specific priorities, potency is paramount.

Output:
1
2025-04-17 16:27:36,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.5 and 369.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is higher than Ligand B (52.65). Both are acceptable, but B is better for permeability.

**logP:** Both ligands have good logP values (1.544 and 2.542), 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.

**QED:** Both ligands have good QED scores (0.681 and 0.803), indicating good drug-likeness.

**DILI:** Ligand A (16.712) has a significantly lower DILI risk than Ligand B (38.736). This is a major advantage for Ligand A.

**BBB:** Ligand B (83.831) has a higher BBB penetration percentile than Ligand A (68.282). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.828 and -4.763), 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 (-1.311 and -2.633), indicating poor aqueous solubility. This is a significant drawback for both, but B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.31 and 0.803), which is good.

**Microsomal Clearance:** Ligand A (26.93) has a higher microsomal clearance than Ligand B (3.908). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (40.91) has a much longer in vitro half-life than Ligand A (-13.18). This is a significant advantage for Ligand B, as it suggests less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.097).

**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:**

Ligand A has a much lower DILI risk, which is a significant advantage. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. Both have poor solubility and permeability. Given the importance of metabolic stability for kinase inhibitors, and the small advantage in potency, Ligand B is the slightly more promising candidate.

Output:
1
2025-04-17 16:27:36,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.187 Da) is slightly higher, but acceptable. Ligand B (344.415 Da) is also good.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (109.86) and Ligand B (95.16) are both favorable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.971) and Ligand B (1.157) are both good.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is acceptable. Ligand A has 6 HBAs, and Ligand B has 4 HBAs, both within the limit of 10.

**QED:** Both ligands have QED scores above 0.5, indicating good drug-likeness. Ligand A (0.639) is slightly better than Ligand B (0.573).

**DILI:** Ligand A has a high DILI risk (98.72%), which is a significant concern. Ligand B has a much lower DILI risk (36.72%), making it more favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Both ligands have moderate BBB penetration (Ligand A: 60.954, Ligand B: 59.597).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.909) is slightly better than Ligand B (-5.353), but both are problematic.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-4.426) is slightly better than Ligand B (-1.881), but both are problematic.

**hERG Inhibition:** Ligand A has a low hERG risk (0.481), which is good. Ligand B has a very low hERG risk (0.11), which is excellent.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (67.506 mL/min/kg), suggesting moderate metabolic stability. Ligand B has a negative clearance (-9.981 mL/min/kg), which is highly unusual and suggests *extremely* high metabolic stability.

**In vitro Half-Life:** Ligand A has a moderate in vitro half-life (20.481 hours). Ligand B has a very short in vitro half-life (-32.771 hours), which is problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.302, Ligand B: 0.016). Ligand B is slightly better.

**Binding Affinity:** Ligand A has a better binding affinity (-8.4 kcal/mol) than Ligand B (-7.7 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a good hERG profile. However, its extremely high DILI risk and poor solubility/permeability are major drawbacks. Ligand B has a much better safety profile (lower DILI, very low hERG) and excellent metabolic stability, but its binding affinity is weaker and its solubility/permeability are also poor.

Given the importance of safety and metabolic stability for an enzyme target like SRC kinase, and the fact that the affinity difference, while notable, isn't enormous, **Ligand B** is the more promising candidate. The poor solubility/permeability can be addressed with formulation strategies, but a high DILI risk is much harder to overcome.

Output:
1
2025-04-17 16:27:36,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.435 and 352.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.36) is better than Ligand B (95.86), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.534) is optimal (1-3), while Ligand B (0.23) is quite low, potentially hindering permeability. This is a significant drawback 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 6, both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED scores (0.8 and 0.837), indicating good drug-likeness.

**DILI:** Ligand A (76.192) has a higher DILI risk than Ligand B (61.187), but both are still reasonably acceptable.

**BBB:** Both have similar BBB penetration (55.138 and 53.664), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.483 and -4.495), which is unusual and suggests poor permeability. This is a concern for both, but the values are very similar.

**Aqueous Solubility:** Ligand A (-4.252) is slightly better than Ligand B (-2.158), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.101 and 0.191).

**Microsomal Clearance:** Ligand A (82.107) has higher microsomal clearance than Ligand B (-3.84). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-34.899) has a longer in vitro half-life than Ligand A (-32.065), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.049 and 0.027).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.6 and -7.0 kcal/mol). Ligand A is slightly better, but the difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

While Ligand A has slightly better binding affinity and solubility, Ligand B demonstrates significantly better predicted metabolic stability (lower Cl_mic and longer t1/2) and a more favorable logP value. Given the enzyme-kinase specific priorities, metabolic stability and permeability are crucial. The low logP of Ligand B is a major concern, potentially limiting its absorption. Therefore, despite the slightly better affinity of Ligand A, its overall profile is more favorable for development.

Output:
1
2025-04-17 16:27:36,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.455 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.27) is higher than Ligand B (51.39). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Ligand A (2.113) is within the optimal 1-3 range. Ligand B (3.857) is approaching the upper limit but still acceptable.

**H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are below the 10 threshold, but Ligand A is better.

**QED:** Both ligands have similar QED values (0.802 and 0.782), indicating good drug-likeness.

**DILI:** Ligand A (25.785) has a lower DILI risk than Ligand B (21.442), which is preferable.

**BBB:** Ligand A (55.176) has a lower BBB penetration than Ligand B (80.264). Since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-4.864) has worse Caco-2 permeability than Ligand B (-5.078). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.718) has better aqueous solubility than Ligand B (-3.654). This is a significant advantage for an enzyme inhibitor.

**hERG Inhibition:** Ligand A (0.076) has a lower hERG inhibition risk than Ligand B (0.794). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (23.512) has significantly lower microsomal clearance than Ligand B (64.083), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-2.797) has a worse in vitro half-life than Ligand B (12.912). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.06) has lower P-gp efflux than Ligand B (0.438), which is favorable.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.6). However, the difference is small (0.7 kcal/mol) and may not outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its lower DILI risk, better aqueous solubility, significantly lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While Ligand B has slightly better binding affinity and half-life, the improvements in ADME properties for Ligand A are more critical for an enzyme inhibitor. The solubility and metabolic stability advantages of Ligand A are particularly important.

Output:
0
2025-04-17 16:27:36,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.431 and 366.527 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (128.34) is slightly above the optimal <140 for good oral absorption, but acceptable. Ligand B (58.64) is well within the optimal range.

**logP:** Ligand A (0.491) is a bit low, potentially hindering permeation. Ligand B (2.362) 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 (0.611 and 0.784, respectively), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 83.288, which is high and concerning. Ligand B has a much lower DILI risk of 25.902, which is good.

**BBB:** Both ligands have moderate BBB penetration (50.446 and 76.813, respectively). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.515 and -5.124). This is unusual and suggests poor permeability, but the scale is not specified and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.413 and -3.334). Similar to Caco-2, the scale is unclear, but suggests poor solubility.

**hERG Inhibition:** Ligand A (0.618) has a slightly higher hERG risk than Ligand B (0.385), but both are relatively low.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-2.253), which is excellent, indicating high metabolic stability. Ligand B has a Cl_mic of 54.839, which is high and suggests rapid metabolism.

**In vitro Half-Life:** Ligand A has a very long half-life (-29.197), which is excellent. Ligand B has a shorter half-life (-6.566), but still reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.048 and 0.279, respectively).

**Binding Affinity:** Ligand B (-9.2 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 threshold.

**Conclusion:**

Despite the questionable Caco-2 and solubility values, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.2 vs -6.9 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk (25.9 vs 83.3) and a better logP value. While Ligand A has superior metabolic stability and half-life, the strong binding and reduced toxicity of Ligand B outweigh these benefits.

Output:
1
2025-04-17 16:27:36,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.467 and 339.395 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (41.57) is well below the 140 threshold and good for oral absorption. Ligand B (81.01) is still under the threshold but less optimal than A.

**logP:** Both ligands (3.394 and 3.607) are 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 3 HBAs, and Ligand B has 5. Both are under the 10 limit, but A is preferable.

**QED:** Ligand A (0.917) has a significantly higher QED score than Ligand B (0.768), indicating better overall drug-likeness.

**DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (78.17), which is a major concern.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (95.812) is much higher than Ligand B (30.71).

**Caco-2 Permeability:** Ligand A (-4.65) and Ligand B (-4.741) are similar and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-3.016) is better than Ligand B (-5.556), indicating better solubility.

**hERG Inhibition:** Ligand A (0.819) has a lower hERG risk than Ligand B (0.656), which is favorable.

**Microsomal Clearance:** Ligand A (-4.606) shows significantly better metabolic stability (lower clearance) than Ligand B (37.905).

**In vitro Half-Life:** Ligand A (20.229 hours) has a much longer half-life than Ligand B (-20.265 hours).

**P-gp Efflux:** Ligand A (0.172) shows lower P-gp efflux liability than Ligand B (0.441).

**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.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.6 kcal/mol vs 0.0 kcal/mol) is a major advantage that could potentially outweigh some of its ADME liabilities. However, Ligand B has a very high DILI risk (78.17), poor metabolic stability (high Cl_mic, negative t1/2), and lower solubility. Ligand A, while having a weak binding affinity, demonstrates a much more favorable ADME profile: lower DILI, better metabolic stability, better solubility, lower hERG risk, and better QED.

Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. While potency is important, a compound with poor ADME properties is unlikely to succeed. The large difference in binding affinity is significant, but the liabilities of Ligand B are too substantial to ignore. A medicinal chemistry effort could potentially improve the affinity of Ligand A while maintaining its favorable ADME properties.

Output:
0
2025-04-17 16:27:36,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.33 and 98.66) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (1.484 and 1.724) are 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 HBA, both are acceptable (<=10).

**QED:** Ligand A (0.886) has a significantly better QED score than Ligand B (0.632), indicating better overall drug-likeness.

**DILI:** Ligand A (68.399) has a higher DILI risk than Ligand B (37.65), which is a negative.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.172) has a higher BBB score than Ligand A (47.809).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.357 and -5.216). This is unusual and suggests poor permeability. However, these values are on a log scale, so even small negative numbers can indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.397 and -2.52). This is also concerning and suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.269 and 0.165), which is excellent.

**Microsomal Clearance:** Ligand A (30.506 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (60.791 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-37.075 hours) has a much longer in vitro half-life than Ligand B (0.867 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.083 and 0.208).

**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 relatively small.

**Overall Assessment:**

Ligand A has a significantly better QED score, lower microsomal clearance, and a much longer half-life, all of which are highly desirable for an enzyme inhibitor. While its DILI risk is higher, the substantial improvements in metabolic stability and half-life outweigh this concern. The poor Caco-2 and solubility are shared concerns, but can be addressed with formulation strategies. Ligand B's primary advantage is its slightly better binding affinity and lower DILI, but these are overshadowed by its poorer metabolic stability and shorter half-life.

Output:
0
2025-04-17 16:27:36,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.71 Da) is slightly higher than Ligand B (347.375 Da), but both are acceptable.

**TPSA:** Ligand A (55.63) is well below the 140 threshold for oral absorption. Ligand B (127.51) is still within acceptable limits, but higher.

**logP:** Ligand A (4.856) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-1.055) is quite low, which could hinder membrane permeability.

**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 good QED scores (A: 0.577, B: 0.675), indicating generally drug-like properties.

**DILI:** Ligand A (72.392) has a higher DILI risk than Ligand B (61.729), but both are reasonably acceptable.

**BBB:** BBB is not a primary concern for SRC kinase inhibitors unless CNS penetration is specifically desired. Both are around 60, which is not particularly high or low.

**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 (-4.257 for A, -1.765 for B). This is a major drawback.

**hERG Inhibition:** Ligand A (0.848) has a slightly higher hERG risk than Ligand B (0.061). Ligand B is much better in this regard.

**Microsomal Clearance:** Ligand A (80.234) has a moderate clearance, while Ligand B (-16.099) has a *negative* clearance, which is impossible and likely indicates an error or an unusual in vitro behavior. This is a huge red flag for Ligand B.

**In vitro Half-Life:** Ligand A (67.196 hours) has a good half-life. Ligand B (0.277 hours) has a very short half-life, indicating rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.869, B: 0.002).

**Binding Affinity:** Ligand B (-9.0 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 other drawbacks.

**Conclusion:**

While Ligand B boasts a much stronger binding affinity, its extremely short half-life and negative microsomal clearance are major concerns. These indicate it will be rapidly metabolized and likely have very poor *in vivo* exposure. Ligand A has a more reasonable pharmacokinetic profile, with acceptable half-life and clearance, despite its higher logP and DILI risk. The solubility is poor for both, but can be addressed with formulation strategies. Given the enzyme-specific priorities, and the importance of metabolic stability, **Ligand A** is the more viable drug candidate.

Output:
0
2025-04-17 16:27:36,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.511 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is well below the 140 threshold, and even the 90 threshold for CNS targets, suggesting good absorption. Ligand B (89.95) is still under 140, but closer to the upper limit, potentially slightly impacting absorption.

**logP:** Ligand A (3.173) is optimal. Ligand B (0.535) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 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 (0.876 and 0.763, respectively), indicating good drug-like properties.

**DILI:** Ligand A (57.813) has a slightly higher DILI risk than Ligand B (42.924), but both are below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.233) is higher than Ligand B (30.089).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.862 and -4.797), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.583 and -1.12), also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG:** Ligand A (0.386) has a lower hERG risk than Ligand B (0.117), which is preferable.

**Microsomal Clearance:** Ligand A (59.756) has a higher, and thus worse, microsomal clearance than Ligand B (9.638). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-2.351) has a negative half-life, which is not physically possible. This is a major red flag. Ligand A (7.796) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.268 and 0.077).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), a difference of 0.4 kcal/mol. While a 1.5 kcal/mol advantage is considered significant, 0.4 kcal/mol is not enough to overcome significant ADME issues.

**Conclusion:**

Despite Ligand B having a slightly better binding affinity, its extremely poor predicted in vitro half-life (-2.351) and low logP (0.535) are major drawbacks. The negative half-life is a critical issue. Ligand A, while not perfect, has a more reasonable half-life and a better logP, and a lower hERG risk. Although both ligands show poor Caco-2 and solubility, Ligand A's overall profile is more favorable.

Output:
0
2025-04-17 16:27:36,589 - INFO - Batch 465 complete. Total preferences: 7440
2025-04-17 16:27:36,589 - INFO - Processing batch 466/512...
2025-04-17 16:28:19,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.5 & 358.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (79.96). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have good logP values (2.31 & 1.98), 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=8). While both are within acceptable limits, fewer hydrogen bond donors/acceptors can sometimes improve permeability.

**QED:** Both ligands have similar, good QED scores (0.694 & 0.696), indicating good drug-like properties.

**DILI:** Ligand A (12.64) has a much lower DILI risk than Ligand B (44.59), a significant advantage.

**BBB:** Ligand B (70.997) has a higher BBB penetration score than Ligand A (56.611). However, since SRC is not a CNS target, this is less critical.

**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 both, but could be mitigated with formulation strategies.

**hERG:** Both ligands have very low hERG inhibition liability (0.527 & 0.574), which is excellent.

**Microsomal Clearance:** Ligand A (-2.695) has a *much* better (lower) microsomal clearance than Ligand B (29.602). This suggests significantly improved metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (19.861) has a slightly longer half-life than Ligand B (18.104).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.1 & 0.098), which is favorable.

**Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.5), 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, **Ligand A** is the more promising drug candidate. It exhibits a significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic), which are critical for kinase inhibitors. While Ligand B has slightly better binding affinity and BBB penetration, the advantages of Ligand A in safety and pharmacokinetics outweigh these minor differences. The solubility issues are a concern for both, but can be addressed during formulation.

Output:
0
2025-04-17 16:28:19,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (380.457 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (89.55). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (1.659 and 0.832), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have reasonable HBD (1 & 2) and HBA (5) counts, well within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.659 and 0.537), indicating good drug-like properties.

**DILI:** Ligand A (33.812) has a significantly lower DILI risk than Ligand B (43.738), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.241) has a higher BBB score than Ligand B (45.87), but this isn't a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value for Ligand A (-4.947) is less negative than Ligand B (-4.769), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. Ligand A (-2.408) is slightly better than Ligand B (-2.061).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.348 and 0.115), which is excellent.

**Microsomal Clearance:** Ligand A (8.179) has significantly lower microsomal clearance than Ligand B (45.2), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-19.402) has a longer in vitro half-life than Ligand B (-25.605), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034).

**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 the significant advantages of Ligand A in terms of DILI, metabolic stability, and solubility.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. These factors are critical for developing a viable drug candidate.

Output:
0
2025-04-17 16:28:19,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.462 and 339.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (64.41), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.621) is slightly higher than Ligand B (2.328). Both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (0). Kinases often tolerate a small number of HBDs.

**H-Bond Acceptors:** Ligand B (3) is better than Ligand A (2). Both are within the acceptable range of <=10.

**QED:** Ligand B (0.846) has a significantly better QED score than Ligand A (0.557), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 33.23, Ligand B: 30.787), both well below the 40 threshold.

**BBB:** Ligand A (87.088) has a better BBB penetration score than Ligand B (73.827), but this is less critical for a kinase inhibitor unless CNS effects are specifically desired.

**Caco-2 Permeability:** Ligand A (-4.705) is better than Ligand B (-4.377). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.79) is better than Ligand B (-2.885). Higher values are better for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.802) has a slightly better hERG profile than Ligand B (0.489), both are acceptable.

**Microsomal Clearance:** Ligand B (47.062) has significantly lower microsomal clearance than Ligand A (25.972), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (20.833) has a better in vitro half-life than Ligand B (-9.694).

**P-gp Efflux:** Ligand A (0.418) has better P-gp efflux liability than Ligand B (0.093).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a crucial factor, and the 1.7 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A has a superior binding affinity and better solubility, permeability, and half-life. However, Ligand B exhibits a better QED score and significantly improved metabolic stability (lower Cl_mic). The substantial difference in binding affinity (-9.5 vs -7.8 kcal/mol) is the most important factor for an enzyme inhibitor. While metabolic stability is important, a strong binding affinity can often be optimized through further medicinal chemistry efforts.

Output:
1
2025-04-17 16:28:19,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.514 Da) is slightly better, being closer to the lower end which generally aids permeability.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (102.76). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (2.456) is optimal, while Ligand B (0.991) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=6). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Both ligands have acceptable QED values (A: 0.761, B: 0.642), indicating reasonable drug-likeness.

**DILI:** Ligand A (8.492) has a much lower DILI risk than Ligand B (65.413). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.08) is better than Ligand B (26.406), but not a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.524) is better than Ligand B (-5.298), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.793) is better than Ligand B (-3.057), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.721) is significantly better than Ligand B (0.332), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-8.146) is *much* better than Ligand B (13.093). This suggests significantly higher metabolic stability for Ligand A, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-4.699) is better than Ligand B (8.68), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.124) is better than Ligand B (0.093), indicating lower efflux.

**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, potentially outweighing some of the ADME drawbacks. However, the difference is not *massive*.

**Overall Assessment:**

While Ligand B boasts a stronger binding affinity, Ligand A demonstrates superior ADMET properties across almost all critical parameters. The lower DILI, significantly better metabolic stability (Cl_mic and t1/2), better solubility, and lower hERG risk make Ligand A a much more promising drug candidate. The 1.5 kcal/mol difference in binding affinity is not enough to overcome the substantial ADME advantages of Ligand A, especially for an enzyme target where metabolic stability and bioavailability are crucial.

Output:
0
2025-04-17 16:28:19,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.379 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.87) is close to the 140 cutoff, while Ligand B (78.95) is well below, suggesting potentially better absorption for B.

**logP:** Ligand A (2.145) is optimal. Ligand B (0.143) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (A: 6, B: 4) are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (A: 0.483, B: 0.683), with B being slightly more drug-like.

**DILI:** Ligand A (86.39) has a higher DILI risk than Ligand B (23.032), which is a significant concern.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand B (54.944) shows slightly better potential.

**Caco-2:** Both have negative values, indicating poor permeability.

**Solubility:** Ligand A (-4.172) has very poor solubility. Ligand B (-1.939) is also poor, but better than A.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.18, B: 0.148).

**Microsomal Clearance:** Ligand A (17.951) has higher clearance than Ligand B (6.138), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand A (22.957) has a longer half-life than Ligand B (9.696).

**P-gp Efflux:** Both ligands show very low P-gp efflux (A: 0.032, B: 0.011).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite Ligand B's low logP and Caco-2 permeability, its significantly superior binding affinity (-9.5 vs -7.6 kcal/mol), lower DILI risk, and better metabolic stability (lower Cl_mic) make it the more promising candidate. The strong binding affinity suggests that potency is less of a concern, and formulation strategies could potentially address the solubility and permeability issues. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 16:28:19,624 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (369.447 Da) is within the ideal range (200-500). Ligand B (346.475 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (136.3) is borderline, but acceptable for oral absorption. Ligand B (66.4) is excellent, well below the 140 threshold, suggesting good absorption. Advantage: B.

3. **logP:** Ligand A (-0.392) is a bit low, potentially hindering permeation. Ligand B (2.532) is optimal. Advantage: B.

4. **HBD:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability. Advantage: B (slightly).

5. **HBA:** Ligand A (7) is acceptable. Ligand B (4) is also good. No clear advantage.

6. **QED:** Both ligands have good QED scores (A: 0.571, B: 0.794). Ligand B is better. Advantage: B.

7. **DILI:** Ligand A (50.33) has a moderate DILI risk. Ligand B (34.277) has a lower, more favorable DILI risk. Advantage: B.

8. **BBB:** Ligand A (62.233) is not particularly high, suggesting limited CNS penetration. Ligand B (90.578) is very good, indicating good potential for CNS penetration, though this isn't a primary concern for SRC as it's not a CNS target. Advantage: B.

9. **Caco-2:** Ligand A (-5.498) is very poor. Ligand B (-4.653) is also poor, but slightly better. Advantage: B.

10. **Solubility:** Ligand A (-2.617) is poor. Ligand B (-1.916) is also poor, but slightly better. Advantage: B.

11. **hERG:** Ligand A (0.047) has a very low hERG risk, which is excellent. Ligand B (0.612) has a slightly elevated hERG risk, but still relatively low. Advantage: A.

12. **Cl_mic:** Ligand A (14.891) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (61.623) has a significantly higher clearance. Advantage: A.

13. **t1/2:** Ligand A (4.653) has a shorter half-life. Ligand B (-14.177) has a very negative half-life, which is concerning and likely indicates rapid metabolism. Advantage: A.

14. **Pgp:** Ligand A (0.032) has low P-gp efflux, which is good. Ligand B (0.316) has slightly higher P-gp efflux. Advantage: A.

15. **Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-8.6). Advantage: A.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While Ligand B has better overall drug-like properties (TPSA, logP, QED, DILI), Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a lower hERG risk, and slightly better binding affinity. The solubility and Caco-2 values are poor for both, but the metabolic advantages of A are more critical for an enzyme target. The slightly better affinity of A also helps offset the other drawbacks.

**Conclusion:**

Considering the priorities for an enzyme target, and the fact that the affinity difference is not huge, Ligand A is the more promising candidate.

Output:
0
2025-04-17 16:28:19,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.401 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.48) is well below the 140 threshold for good absorption, while Ligand B (111.45) is still acceptable but less optimal.

**logP:** Ligand A (2.607) is within the optimal 1-3 range. Ligand B (1.195) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBD and are within the acceptable range. Ligand A has 4 HBA, and Ligand B has 5 HBA, both are acceptable.

**QED:** Ligand A (0.731) has a better QED score than Ligand B (0.484), indicating a more drug-like profile.

**DILI:** Ligand A (51.377) has a slightly higher DILI risk than Ligand B (41.411), but both are below the concerning threshold of 60.

**BBB:** Ligand A (71.268) shows better BBB penetration than Ligand B (39.279), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.487) has a worse Caco-2 permeability than Ligand B (-5.014), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.796 and -2.942), which is unusual and problematic. Lower (less negative) values are better. They are similar in this regard.

**hERG Inhibition:** Ligand A (0.205) has a significantly lower hERG inhibition risk than Ligand B (0.429), a crucial factor for kinase inhibitors.

**Microsomal Clearance:** Ligand A (24.897) has a higher (worse) microsomal clearance than Ligand B (-3.492), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-16.15) has a negative half-life, which is highly unusual and indicates very rapid metabolism or instability. Ligand B (7.925) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.026) has lower P-gp efflux than Ligand B (0.043), which is favorable.

**Binding Affinity:** Ligand B (-9.9 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 concerns.

**Conclusion:**

While Ligand A has a better QED, lower hERG risk, and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-9.9 vs -7.3 kcal/mol) and more reasonable half-life are critical advantages for an enzyme inhibitor. The slightly lower logP and higher DILI of Ligand B are less concerning given the potency difference. The negative solubility values for both are a red flag, but the superior binding of Ligand B makes it the more promising candidate, assuming solubility can be addressed through formulation.

Output:
1
2025-04-17 16:28:19,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.547 and 359.495 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (55.2), both are below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (3.562 and 3.237) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is slightly better than Ligand B (0 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED scores (0.796 and 0.727), indicating good drug-likeness.

**DILI:** Ligand A (22.179) has a significantly lower DILI risk than Ligand B (47.654). This is a major advantage.

**BBB:** Both ligands have high BBB penetration (90.306 and 87.127), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.547 and -4.942), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-4.26 and -4.255). This could present formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.738 and 0.617).

**Microsomal Clearance:** Ligand B (82.182) has a lower microsomal clearance than Ligand A (91.927), suggesting better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (17.213) has a significantly longer in vitro half-life than Ligand A (1.719). This is a substantial advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.255) has lower P-gp efflux than Ligand B (0.704), which is favorable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.0 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 better candidate. While both have poor Caco-2 permeability and solubility, Ligand B's significantly stronger binding affinity (-8.5 vs -7.0 kcal/mol), lower microsomal clearance, and longer half-life outweigh the slightly higher P-gp efflux and DILI risk. The stronger binding is particularly important for an enzyme target like SRC kinase. The lower DILI risk of Ligand A is attractive, but the potency and stability advantages of Ligand B are more critical.

Output:
1
2025-04-17 16:28:19,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (88.1) is lower, potentially indicating better absorption.

**logP:** Both ligands have logP values between 1 and 3, which is optimal. Ligand B (1.71) is slightly higher, potentially leading to better membrane permeability.

**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, but Ligand A's lower HBA count might be slightly preferable for permeability.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (42.6) has a lower DILI risk than Ligand B (58.4), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (71.7) has a higher BBB percentile, but this is less critical here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference matters less.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.146) has a much lower hERG inhibition liability than Ligand B (0.628), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (-39.468) has a much lower (better) microsomal clearance than Ligand B (27.4), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (5.587) has a slightly longer half-life than Ligand B (-38.861), which is also favorable.

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.121), suggesting better oral bioavailability.

**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 substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG inhibition, lower P-gp efflux, and slightly better binding affinity. While both have poor solubility and permeability issues, the superior ADME profile and potency of Ligand A make it the preferred choice for further optimization.

Output:
1
2025-04-17 16:28:19,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.373 and 348.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (96.11 and 97.35) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (0.942 and 0.746) are within the optimal range of 1-3, suggesting good permeability and avoiding solubility issues.

**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 good QED scores (0.574 and 0.847), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A has a DILI risk of 54.246, while Ligand B has 35.595. Ligand B is significantly better, falling well below the 40 threshold for low risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (84.374) is slightly better than Ligand B (71.733).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.158 and -5.125), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.533 and -1.339), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.095 and 0.088), which is excellent.

**Microsomal Clearance:** Ligand A (11.283 mL/min/kg) has lower microsomal clearance than Ligand B (16.536 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.297 hours) has a longer in vitro half-life than Ligand B (-13.345 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.035).

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.4 vs -7.0 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic and longer t1/2) and a lower DILI risk compared to Ligand B. While both have poor solubility, the potency and metabolic advantages of Ligand A outweigh the drawbacks.

Output:
1
2025-04-17 16:28:19,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.431 and 385.433 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.76) is better than Ligand B (121.01), both are under the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.318) is slightly better than Ligand B (-0.479). Both are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 5. Both are under the 10 threshold.

**QED:** Both ligands have reasonable QED scores (0.792 and 0.64), indicating good drug-likeness.

**DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (39.628). This is a significant drawback for Ligand A.

**BBB:** Both ligands have low BBB penetration (54.634 and 64.211), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.743 and -5.044), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.064 and -1.775), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.046) has a slightly lower hERG risk than Ligand B (0.25).

**Microsomal Clearance:** Ligand B (-21.848) has significantly lower (better) microsomal clearance than Ligand A (21.428), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-27.126) has a much longer in vitro half-life than Ligand A (7.412), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.024).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. These are critical factors for an enzyme inhibitor. The slightly better hERG profile of Ligand A is overshadowed by its higher DILI and poorer metabolic stability. The binding affinity is comparable, making the ADME properties the deciding factor.

Output:
1
2025-04-17 16:28:19,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447 Da) is slightly lower, which could be favorable for permeability, while Ligand B (399.343 Da) is still well within the range.

**TPSA:** Both ligands have TPSA values (71.42 and 72.19) below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.092) is optimal (1-3), while Ligand B (4.017) is at the upper end of the acceptable range. Higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2) and HBA (5/4) counts, falling within the guidelines.

**QED:** Both ligands have QED values above 0.5 (0.806 and 0.745), indicating good drug-likeness.

**DILI:** Ligand A (27.724) has a significantly lower DILI risk than Ligand B (64.056). This is a major advantage for Ligand A.

**BBB:** Both ligands have relatively low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (75.107) is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.903 and -5.078). 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 negative solubility values (-1.464 and -3.824). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.405) has a lower hERG risk than Ligand B (0.841), which is a positive.

**Microsomal Clearance:** Ligand A (14.27 mL/min/kg) has lower microsomal clearance than Ligand B (26.629 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (101.247 hours) has a significantly longer in vitro half-life than Ligand A (25.103 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.591).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.8 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not decisive.

**Overall Assessment:**

Ligand A is better regarding DILI risk, hERG inhibition, and metabolic stability (lower Cl_mic). Ligand B has a substantially longer half-life. Solubility and permeability are poor for both, but this can be addressed with formulation strategies. Given the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG), and the substantial difference in DILI risk, Ligand A is the more promising candidate. While the longer half-life of Ligand B is attractive, the higher DILI risk is a significant concern.

Output:
0
2025-04-17 16:28:19,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.471 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is well below the 140 threshold, while Ligand B (70.47) is also acceptable, but slightly higher.

**logP:** Ligand A (2.702) is optimal (1-3). Ligand B (0.41) is quite low, potentially hindering permeability.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.789 and 0.809, respectively), indicating good drug-like properties.

**DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (11.322). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.037) has a higher BBB percentile than Ligand B (52.385).

**Caco-2 Permeability:** Ligand A (-4.743) has a worse Caco-2 permeability than Ligand B (-5.24).

**Aqueous Solubility:** Ligand A (-2.446) has better aqueous solubility than Ligand B (-0.057). This is important for bioavailability.

**hERG Inhibition:** Ligand A (0.411) has a lower hERG inhibition liability than Ligand B (0.371), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (61.541) has a higher microsomal clearance than Ligand B (-1.957), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-12.952) has a shorter in vitro half-life than Ligand B (-4.719), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.197) has lower P-gp efflux than Ligand B (0.02), which is favorable.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). However, the difference is not substantial enough to overcome the ADME issues of Ligand B.

**Overall Assessment:**

Ligand B has a better binding affinity and slightly better Caco-2 permeability, but suffers from a low logP, higher DILI risk, and significantly worse metabolic stability (higher clearance, shorter half-life). Ligand A, while having slightly lower binding affinity, exhibits a much better safety profile (lower DILI, lower hERG), better solubility, and lower P-gp efflux. The metabolic stability of Ligand A is a concern, but this can potentially be addressed through structural modifications during lead optimization. The low logP of Ligand B is a more fundamental issue that is harder to fix without significantly altering the core structure and potentially losing potency.

Output:
1
2025-04-17 16:28:19,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (91.57) is better than Ligand B (112.23). Both are acceptable for oral absorption (<140), but A is closer to the preferred threshold.

**logP:** Both ligands have acceptable logP values (A: 1.975, B: 0.21). Ligand A is better, falling within the optimal 1-3 range. Ligand B is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=2, HBA=5) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (A: 0.704, B: 0.739), indicating good drug-like properties.

**DILI:** Ligand A (39.434) has a significantly lower DILI risk than Ligand B (63.552). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (29.895) and Ligand B (55.874) are both relatively low.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-5.238) is worse than Ligand A (-4.96).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-2.569) is slightly better than Ligand A (-3.316), but both are concerning.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.117, B: 0.331), which is good.

**Microsomal Clearance:** Ligand B (-6.424) has a *negative* microsomal clearance, which is impossible. This is a major red flag, suggesting a data error or a highly unusual compound behavior. Ligand A (10.492) is acceptable.

**In vitro Half-Life:** Ligand A (57.959) has a much longer half-life than Ligand B (-29.103). Again, the negative value for B is problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.17, B: 0.048).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.0 kcal/mol, B: -9.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is clearly superior. It has a better logP, lower DILI risk, more reasonable (and positive) microsomal clearance and half-life, and comparable binding affinity. The negative values for Caco-2 and solubility for both are concerning and would require further investigation, but are less critical than the issues with Ligand B's clearance and half-life. The negative clearance and half-life for Ligand B are almost certainly errors, making it an unsuitable candidate.

Output:
0
2025-04-17 16:28:19,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.389 Da and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.73) is slightly above the preferred <140, but acceptable. Ligand B (75.8) is excellent, well below 140.

**logP:** Ligand A (0.177) is quite low, potentially hindering permeability. Ligand B (2.615) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.535 and 0.78), indicating good drug-like properties.

**DILI:** Ligand A (34.82) has a lower DILI risk than Ligand B (19.426), both are good.

**BBB:** Ligand A (57.076) has a lower BBB penetration than Ligand B (79.294). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.228) has poor Caco-2 permeability, which is concerning. Ligand B (-4.42) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.163 and -2.315). This is a significant drawback for both.

**hERG:** Both ligands have low hERG inhibition risk (0.31 and 0.464), which is positive.

**Microsomal Clearance:** Ligand A (17.033) has a lower microsomal clearance than Ligand B (63.563), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-17.592) has a very short half-life, which is a major concern. Ligand B (-6.292) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.042 and 0.353).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. Its superior binding affinity (-9.2 vs -8.5 kcal/mol) is a significant advantage for an enzyme target like SRC kinase. It also has better logP, Caco-2 permeability, BBB penetration, and a more reasonable (though still not great) in vitro half-life compared to Ligand A. While Ligand A has better metabolic stability (lower Cl_mic), the potency advantage of Ligand B is more crucial in this case.

Output:
1
2025-04-17 16:28:19,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.929 Da) is slightly higher than Ligand B (335.411 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (72.7). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have similar logP values around 2.96, which is optimal for oral absorption.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (4 HBA) is better than Ligand B (5 HBA), as lower HBA generally improves permeability.

**QED:** Ligand A (0.605) has a slightly better QED score than Ligand B (0.532), indicating a more drug-like profile.

**DILI:** Ligand B (69.911) has a higher DILI risk than Ligand A (54.75). Lower DILI is preferred.

**BBB:** Both ligands have similar BBB penetration (around 65%), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.957) has a better Caco-2 permeability than Ligand B (-5.26). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-4.796) has better aqueous solubility than Ligand B (-3.188). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.567 and 0.499 respectively).

**Microsomal Clearance:** Ligand A (82.042) has lower microsomal clearance than Ligand B (93.005), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.361 hours) has a significantly longer in vitro half-life than Ligand B (-34.681 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.568 and 0.427 respectively).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 kcal/mol and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Ligand A is superior to Ligand B. It has better TPSA, HBA, QED, DILI risk, Caco-2 permeability, aqueous solubility, microsomal clearance, and in vitro half-life. While both have comparable logP, hERG, P-gp, and binding affinity, the improvements in ADME properties for Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 16:28:19,626 - INFO - Batch 466 complete. Total preferences: 7456
2025-04-17 16:28:19,626 - INFO - Processing batch 467/512...
2025-04-17 16:29:07,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (474.172 Da) is towards the upper end, while Ligand B (344.459 Da) is more favorably positioned.

**TPSA:** Ligand A (59.81) is better than Ligand B (75.19). Both are acceptable, but lower TPSA generally improves absorption.

**logP:** Ligand A (4.794) is high, potentially leading to solubility issues and off-target effects. Ligand B (2.271) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.655, B: 0.823), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (64.599) has a higher DILI risk than Ligand B (15.394). This is a significant concern for Ligand A.

**BBB:** Both have high BBB penetration, but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both, but needs further investigation.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.671 and -3.613 respectively). This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.537) has a slightly better hERG profile than Ligand B (0.646), but both are acceptable.

**Microsomal Clearance:** Ligand A (42.336) has lower clearance than Ligand B (56.583), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (71.344) has a significantly longer half-life than Ligand B (-4.369). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.662) has lower P-gp efflux than Ligand B (0.02), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, better logP, lower DILI risk, and a better QED score. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. Both have poor solubility and Caco-2 permeability. The strong binding affinity of Ligand B is a significant advantage for an enzyme inhibitor. While the solubility and permeability are concerning, the potency difference is large enough to prioritize Ligand B for further optimization, focusing on improving those properties.

Output:
1
2025-04-17 16:29:07,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 385.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is excellent, well below the 140 threshold for oral absorption. Ligand B (109.26) is still acceptable, but less optimal.

**logP:** Both ligands (1.507 and 1.855) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better than Ligand B (3 HBD, 8 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.648) has a better QED score than Ligand B (0.423), indicating a more drug-like profile.

**DILI:** Ligand A (9.151) has a significantly lower DILI risk than Ligand B (71.656). This is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (48.313) is better than Ligand B (28.306).

**Caco-2 Permeability:** Ligand A (-4.869) is better than Ligand B (-5.538), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.177) is better than Ligand B (-2.523), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands (0.302 and 0.2) show low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (-2.894) has significantly lower microsomal clearance than Ligand B (26.673), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.437) has a longer in vitro half-life than Ligand B (22.507), which is desirable.

**P-gp Efflux:** Both ligands (0.153 and 0.198) have low P-gp efflux liability.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.5 and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold where ADME properties become more important.

**Overall:** Ligand A is superior to Ligand B due to its significantly better DILI score, lower microsomal clearance, longer half-life, better solubility, and higher QED. While the binding affinities are comparable, the improved ADME properties of Ligand A make it a much more promising drug candidate.

Output:
0
2025-04-17 16:29:07,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.813 and 354.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.02) is better than Ligand B (87.53), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands (3.428 and 3.638) are within the optimal 1-3 range.

**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:** Ligand A (5) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**QED:** Ligand A (0.786) has a significantly better QED score than Ligand B (0.341), indicating a more drug-like profile.

**DILI:** Ligand A (71.656) has a higher DILI risk than Ligand B (19.232). This is a significant drawback for Ligand A.

**BBB:** Ligand A (46.413) has a lower BBB penetration than Ligand B (68.748), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.739) has slightly better Caco-2 permeability than Ligand B (-4.433), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-3.926) has slightly lower solubility than Ligand B (-2.705). Solubility is important for kinases.

**hERG Inhibition:** Ligand A (0.588) has a lower hERG risk than Ligand B (0.692), which is favorable.

**Microsomal Clearance:** Ligand A (27.587) has a significantly lower microsomal clearance than Ligand B (78.534), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (26.174) has a longer half-life than Ligand B (14.862), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.55) has lower P-gp efflux than Ligand B (0.091), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity, better metabolic stability (lower Cl_mic and longer t1/2), better P-gp efflux, and a better QED score. However, it has a higher DILI risk and slightly lower solubility. The significant advantage in binding affinity and metabolic stability, combined with acceptable hERG risk, makes Ligand A the more promising candidate despite the higher DILI. The potency difference is substantial enough to warrant further investigation and potential mitigation of the DILI risk through structural modifications.

Output:
1
2025-04-17 16:29:07,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.47) is slightly lower, which could be favorable for permeability.

**TPSA:** Ligand A (68.82) is better than Ligand B (33.2). Lower TPSA generally improves cell permeability.

**logP:** Ligand A (1.577) is optimal, while Ligand B (4.71) is high. A logP >4 can lead to solubility issues and off-target interactions.

**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.

**QED:** Both ligands have similar QED values (0.773 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A (54.48) has a slightly higher DILI risk than Ligand B (25.82), but both are reasonably low.

**BBB:** Ligand B (93.56) has a much higher BBB penetration percentile than Ligand A (55.64). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-5.433) and Ligand B (-4.634) both have negative values, which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-2.311) has slightly better solubility than Ligand B (-5.146), but both are poor.

**hERG Inhibition:** Ligand A (0.208) has a lower hERG risk than Ligand B (0.634), which is a significant advantage.

**Microsomal Clearance:** Ligand B (61.66) has a higher clearance than Ligand A (27.45), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (45.97) has a longer half-life than Ligand B (-8.22), suggesting better metabolic stability.

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux than Ligand B (0.184), which is favorable for oral bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-10.5 and -8.1 kcal/mol). Ligand A is significantly more potent, with a 2.4 kcal/mol advantage. This is a substantial difference and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the better candidate. Its superior binding affinity (-10.5 kcal/mol vs -8.1 kcal/mol) is a key advantage for an enzyme target like SRC kinase. It also exhibits lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has better BBB penetration, this is not a priority for a non-CNS target. The slightly higher DILI risk for Ligand A is less concerning than the other ADME liabilities of Ligand B.

Output:
0
2025-04-17 16:29:07,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.439 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is well below the 140 threshold for oral absorption, and even within the range desirable for CNS penetration. Ligand B (108.88) is still acceptable for oral absorption but less favorable than A.

**logP:** Ligand A (1.104) is within the optimal 1-3 range. Ligand B (0.595) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, fitting well within the guidelines. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.805 and 0.651, respectively), indicating good drug-like properties.

**DILI:** Both ligands have DILI risk around 60, indicating moderate risk. This isn't a major differentiator.

**BBB:** Ligand A (64.599) has a better BBB percentile than Ligand B (32.765), but BBB isn't a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.811) has a worse Caco-2 permeability than Ligand B (-5.586).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.384 and -2.316). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.123 and 0.152), which is excellent.

**Microsomal Clearance:** Ligand A (-16.598) has significantly *lower* (better) microsomal clearance than Ligand B (10.905). This suggests much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (60.091) has a longer in vitro half-life than Ligand B (-19.397), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.025).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a difference of 1.5 kcal/mol, which is a substantial advantage, and outweighs the slight permeability concern.

**Conclusion:**

Ligand A is the superior candidate. Its significantly stronger binding affinity, coupled with its better metabolic stability (lower Cl_mic, longer t1/2), and acceptable ADME properties, make it a more promising drug candidate for SRC kinase inhibition. While both have solubility concerns, the potency and stability advantages of Ligand A are more critical for an enzyme target.

Output:
1
2025-04-17 16:29:07,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.77 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (75.63) is better than Ligand B (93.11). Lower TPSA generally improves absorption.

**logP:** Ligand A (4.867) is high, potentially leading to solubility issues and off-target effects. Ligand B (-0.036) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) are both within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.777, B: 0.643), indicating good drug-like properties.

**DILI:** Ligand A (93.525) has a significantly higher DILI risk than Ligand B (3.916). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (30.128) and Ligand B (9.616) are both low.

**Caco-2 Permeability:** Ligand A (-4.71) and Ligand B (-5.964) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.012) and Ligand B (-1.187) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.19) has a slightly higher hERG risk than Ligand B (0.076), but both are relatively low.

**Microsomal Clearance:** Ligand B (-30.886) has a much lower (better) microsomal clearance than Ligand A (17.697), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.096) has a negative half-life, which is concerning. Ligand A (22.048) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.074, B: 0.003).

**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 could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's high logP and DILI risk, its significantly superior binding affinity (-8.7 kcal/mol vs -7.1 kcal/mol) and better half-life are compelling. The difference in binding affinity is substantial enough to potentially overcome the ADME liabilities, especially given that SRC is an enzyme target where potency is paramount. 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 16:29:07,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.491 Da) is slightly lower, which could be beneficial for permeability. Ligand B (395.516 Da) is still acceptable.

**TPSA:** Ligand A (68.87) is better than Ligand B (45.23), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (A: 3.168, B: 4.206), falling within the optimal 1-3 range, though B is pushing the upper limit.

**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:** Both ligands have similar and good QED values (A: 0.752, B: 0.784), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (A: 51.26, B: 46.685), below the 60 threshold.

**BBB:** Ligand A has a higher BBB penetration (89.066) than Ligand B (79.992), but BBB is less critical for a non-CNS target like SRC.

**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 likely representing low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -3.001, B: -4.697). This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.933, B: 0.567), which is excellent.

**Microsomal Clearance:** Both have similar and reasonable microsomal clearance (A: 31.617, B: 30.688). Lower is better, but these values aren't alarming.

**In vitro Half-Life:** Ligand A has a slightly better in vitro half-life (15.323 hours) than Ligand B (-1.335 hours). The negative value for B is concerning and indicates very rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.167, B: 0.17), which is good.

**Binding Affinity:** Ligand B has a significantly better binding affinity (-7.2 kcal/mol) than Ligand A (-6.5 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate due to its significantly stronger binding affinity (-7.2 kcal/mol vs -6.5 kcal/mol). The better affinity is a key factor for an enzyme target like SRC. While Ligand A has slightly better BBB penetration and in vitro half-life, the potency advantage of Ligand B is more critical. The negative in vitro half-life for Ligand B is a concern, but could be addressed through structural modifications.

Output:
1
2025-04-17 16:29:07,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.515 and 372.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is slightly higher than Ligand B (67.87), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have logP values within the optimal range (1.006 and 1.538).

**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 QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (31.02) has a significantly lower DILI risk than Ligand B (15.936), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (62.233 and 61.38), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.245) has a slightly worse Caco-2 permeability than Ligand B (-4.848), but both are negative values, indicating good permeability.

**Aqueous Solubility:** Ligand A (-3.371) has slightly worse solubility than Ligand B (-1.92), but both are negative values, indicating good solubility.

**hERG Inhibition:** Ligand A (0.182) has a lower hERG inhibition risk than Ligand B (0.337), which is a positive attribute.

**Microsomal Clearance:** Ligand A (31.064) has a lower microsomal clearance than Ligand B (37.693), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.455) has a longer in vitro half-life than Ligand A (6.156), which is generally desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.038).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.9), but the difference is minimal (0.1 kcal/mol).

**Overall Assessment:**

Ligand A demonstrates a more favorable safety profile with significantly lower DILI and hERG risk, and better metabolic stability (lower Cl_mic). While Ligand B has a slightly longer half-life and marginally better binding affinity, the safety advantages of Ligand A are more critical for a kinase inhibitor, where chronic administration is often anticipated. The difference in binding affinity is small enough that it can likely be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 16:29:07,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.447 and 346.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.45) is better than Ligand B (111.63), both are acceptable but A is closer to the <140 threshold for good absorption.

**3. logP:** Ligand A (1.475) is optimal, while Ligand B (0.095) is quite low, potentially hindering permeation.

**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 within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.557 and 0.672, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (58.395), both are acceptable.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.121) is better than Ligand B (29.779).

**9. Caco-2 Permeability:** Ligand A (-5.159) and Ligand B (-4.962) are similar and both are poor.

**10. Aqueous Solubility:** Ligand A (-2.445) and Ligand B (-2.374) are similar and both are poor.

**11. hERG Inhibition:** Ligand A (0.48) has a much lower hERG risk than Ligand B (0.035), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (43.93) has a much lower Cl_mic than Ligand B (8.088), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.348) has a longer half-life than Ligand B (-45.004), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux than Ligand B (0.004), which is better.

**15. Binding Affinity:** Ligand A (-6.5 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have acceptable MW and QED, Ligand A excels in crucial ADME properties: lower hERG risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and better P-gp efflux. The slightly better binding affinity of Ligand A further strengthens its position. Ligand B's low logP is a major concern, and its poor metabolic stability and hERG risk are significant drawbacks.

Output:
1
2025-04-17 16:29:07,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (391.446 and 361.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.88) is slightly higher than Ligand B (70.15), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.04) is a bit low, potentially hindering permeation. Ligand B (1.989) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.715 and 0.617, respectively), indicating good drug-like properties.

**DILI:** Ligand A (78.054) has a significantly higher DILI risk than Ligand B (34.277). This is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (72.819) and Ligand B (62.04) are both moderate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.719 and -5.488), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.416 and -2.108), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.274 and 0.279). This is excellent.

**Microsomal Clearance:** Ligand A (5.063) has a much lower microsomal clearance than Ligand B (16.064), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.167) has a longer in vitro half-life than Ligand B (4.766). This is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.116 and 0.017).

**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 threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.9 vs -7.2 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B has a much lower DILI risk (34.277 vs 78.054) which is a critical factor. While Ligand A has better metabolic stability and half-life, the DILI risk and weaker binding outweigh these benefits. The solubility and permeability issues 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 16:29:07,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.366 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.25) is higher than Ligand B (58.64). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (0.996) is slightly lower than the optimal 1-3 range, potentially impacting permeability. Ligand B (2.903) is within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.794) has a better QED score than Ligand B (0.685), suggesting a more drug-like profile.

**DILI:** Ligand B (8.298) has a significantly lower DILI risk than Ligand A (56.65), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 80.341, Ligand B: 83.443), but this is less crucial for a non-CNS target like SRC.

**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 unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.225) has a slightly lower hERG risk than Ligand B (0.404), which is preferable.

**Microsomal Clearance:** Ligand B (84.845) has a much higher microsomal clearance than Ligand A (2.392), indicating poorer metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (-8.323) has a very poor in vitro half-life, while Ligand A (0.264) is slightly better, though still not ideal.

**P-gp Efflux:** Ligand A (0.022) has a lower P-gp efflux liability than Ligand B (0.116), which is favorable.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.7), but the difference is relatively small.

**Overall Assessment:**

Ligand A has a better QED score, slightly better affinity, lower P-gp efflux, and significantly better metabolic stability (lower Cl_mic and better t1/2). However, Ligand B has a much lower DILI risk and a more favorable logP. The poor Caco-2 and solubility for both are concerning, but the metabolic stability of Ligand A is a significant advantage for an enzyme target. Given the priorities for enzyme inhibitors, the better metabolic stability and slightly better binding affinity of Ligand A outweigh the lower DILI score of Ligand B.

Output:
1
2025-04-17 16:29:07,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.471 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (113.02). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's TPSA is approaching a level that could hinder absorption.

**logP:** Both ligands have acceptable logP values (2.761 and 1.654), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=6) regarding the number of hydrogen bond donors and acceptors. Both are within acceptable limits, but fewer is generally better for permeability.

**QED:** Both ligands have reasonable QED scores (0.88 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (47.732). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.67) is better than Ligand B (52.074), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-5.052) is better than Ligand B (-4.408). Higher values indicate better permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.362 and -2.375). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.929) has a lower hERG risk than Ligand B (0.333). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (4.68) has significantly lower microsomal clearance than Ligand B (15.56). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (13.065) has a much longer in vitro half-life than Ligand B (-9.171). This is a substantial advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.398) has lower P-gp efflux than Ligand B (0.031), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While both are good, the 1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters for an enzyme inhibitor. It has a lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), better permeability, and slightly better binding affinity. While both have poor solubility, the other advantages of Ligand A outweigh this concern.

Output:
1
2025-04-17 16:29:07,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (345.359 Da and 355.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.45) is slightly above the optimal <140 for good oral absorption, but still reasonable. Ligand B (66.07) is excellent, well below 140.

**logP:** Ligand A (0.573) is a bit low, potentially hindering permeability. Ligand B (2.934) 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 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.781 and 0.883), indicating drug-like properties.

**DILI:** Ligand A (70.143) has a moderate DILI risk, while Ligand B (85.227) has a higher DILI risk.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (78.79) has a higher BBB percentile than Ligand A (46.491), but this is not a deciding factor.

**Caco-2 Permeability:** Ligand A (-5.37) shows poor permeability, while Ligand B (-4.913) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-0.631) has poor solubility, while Ligand B (-4.65) is even worse. Both are concerning.

**hERG Inhibition:** Ligand A (0.1) has very low hERG risk, which is excellent. Ligand B (0.898) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-5.846) exhibits very low microsomal clearance, indicating high metabolic stability. Ligand B (33.723) has significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (3.909) has a shorter half-life than Ligand B (28.358), which is a significant advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.09 respectively).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the solubility issues and higher DILI risk for Ligand B, its significantly superior binding affinity (-9.3 vs -7.8 kcal/mol) and much better metabolic stability (lower Cl_mic, longer t1/2) make it the more promising candidate. The lower logP and poor permeability of Ligand A are also significant drawbacks. While solubility is a concern for both, it can be addressed with formulation strategies. The strong binding affinity of Ligand B suggests it will be more potent and potentially effective at lower doses, mitigating some solubility concerns.

Output:
1
2025-04-17 16:29:07,322 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [362.455, 83.56, 2.432, 2, 6, 0.753, 58.86, 55.991, -5.21, -2.191, 0.524, -4.767, 38.938, 0.058, -8.2]
**Ligand B:** [371.522, 62.3, 3.266, 1, 4, 0.687, 42.264, 76.037, -4.617, -3.291, 0.555, 82.687, 10.403, 0.502, -8.6]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (362.455) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** A (83.56) is higher than B (62.3).  Both are below the 140 threshold for oral absorption, but B is significantly better, suggesting better absorption.
3. **logP:** Both are within the optimal range (1-3). B (3.266) is slightly higher, potentially leading to some solubility issues, but not critically.
4. **HBD:** A (2) and B (1) are both acceptable, below the threshold of 5.
5. **HBA:** A (6) and B (4) are both acceptable, below the threshold of 10.
6. **QED:** Both are above 0.5, indicating good drug-likeness, but A (0.753) is slightly better than B (0.687).
7. **DILI:** A (58.86) has a higher DILI risk than B (42.264), which is preferable.
8. **BBB:** B (76.037) has a significantly higher BBB penetration potential than A (55.991). While SRC isn't a CNS target, higher BBB can sometimes correlate with better overall permeability.
9. **Caco-2:** A (-5.21) is worse than B (-4.617), indicating lower intestinal absorption.
10. **Solubility:** A (-2.191) is worse than B (-3.291), indicating lower aqueous solubility.
11. **hERG:** Both are low and similar (A: 0.524, B: 0.555), posing minimal cardiotoxicity risk.
12. **Cl_mic:** A (-4.767) has a *lower* (better) microsomal clearance than B (82.687), indicating better metabolic stability. This is a key advantage for an enzyme target.
13. **t1/2:** A (38.938) has a much longer in vitro half-life than B (10.403), which is highly desirable for dosing frequency.
14. **Pgp:** Both are similar (A: 0.058, B: 0.502), suggesting similar P-gp efflux liability.
15. **Binding Affinity:** B (-8.6) has a slightly better binding affinity than A (-8.2), but the difference is relatively small (0.4 kcal/mol).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

*   **Affinity:** B has a slightly better affinity.
*   **Metabolic Stability:** A is significantly more metabolically stable (lower Cl_mic, longer t1/2).
*   **Solubility:** B has better solubility.
*   **hERG:** Both are good.

**Conclusion:**

While ligand B has a slightly better binding affinity and TPSA, ligand A's superior metabolic stability (Cl_mic and t1/2) and slightly better QED, combined with acceptable DILI and hERG, make it the more promising drug candidate. The difference in binding affinity (0.4 kcal/mol) is unlikely to outweigh the significant advantage in metabolic stability and half-life for an enzyme target. The lower solubility of A is a concern, but formulation strategies can often address this.

1
2025-04-17 16:29:07,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 Da and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.03) is better than Ligand B (103.93). Both are under 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (2.139) is within the optimal 1-3 range. Ligand B (0.917) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (4) and Ligand B (8) are both acceptable (<=10), but Ligand A is preferable.

**QED:** Ligand A (0.734) is significantly better than Ligand B (0.453), indicating a more drug-like profile.

**DILI:** Ligand A (27.724) has a much lower DILI risk than Ligand B (59.907). This is a significant advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (around 40%), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.623) is better than Ligand B (-5.013), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.503) is better than Ligand B (-1.373), though both are relatively poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.437 and 0.114, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-0.561) has significantly lower (better) microsomal clearance than Ligand B (57.793). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (12.367 hours) has a much longer half-life than Ligand B (-17.314 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.122 and 0.087, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-9.3 kcal/mol), which is excellent.

**Conclusion:**

Ligand A is clearly superior. While both have excellent binding affinity and low hERG risk, Ligand A demonstrates significantly better ADME properties: higher QED, lower DILI risk, better Caco-2 permeability, better solubility, much lower microsomal clearance, and a significantly longer half-life. The slightly better TPSA and logP values further support this conclusion.

Output:
1
2025-04-17 16:29:07,322 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 368.396 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.32) is better than Ligand B (67.87), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (1.167 and 2.429), falling within the 1-3 range. Ligand B is slightly more lipophilic.

**H-Bond Donors:** Ligand A (4) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.552 and 0.528), indicating good drug-likeness.

**DILI:** Ligand A (19.271) has a significantly lower DILI risk than Ligand B (44.63), which is a major advantage. Ligand A is well below the 40 threshold, while Ligand B is approaching a moderate risk.

**BBB:** Ligand B (86.002) has a higher BBB penetration percentile than Ligand A (67.352), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.325 and -4.916). 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 negative solubility values (-2.741 and -2.844), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG Inhibition:** Ligand A (0.101) has a slightly lower hERG inhibition liability than Ligand B (0.537), which is preferable.

**Microsomal Clearance:** Ligand A (19.134) has a lower microsomal clearance than Ligand B (28.944), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-8.601) has a longer in vitro half-life than Ligand B (-5.177), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux liability than Ligand B (0.102), which is beneficial for oral bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.5 kcal/mol), which are excellent and comparable. The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both ligands have comparable potency, Ligand A exhibits significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly lower hERG risk. These factors are particularly important for an enzyme target like SRC kinase. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand A outweighs this concern.

Output:
0
2025-04-17 16:29:07,323 - INFO - Batch 467 complete. Total preferences: 7472
2025-04-17 16:29:07,323 - INFO - Processing batch 468/512...
2025-04-17 16:29:46,915 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.64) is significantly better than Ligand B (102.76). A TPSA under 140 is good for oral absorption, and both are within this limit, but A is preferable.

**logP:** Ligand A (2.05) is optimal (1-3), while Ligand B (-0.361) is below 1, potentially hindering permeation. This is a significant advantage for A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 7 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.629 and 0.672), indicating drug-likeness.

**DILI:** Ligand A (8.53) has a much lower DILI risk than Ligand B (49.477), which is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.576) is better than Ligand B (60.527).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of negativity is similar (-4.295 vs -4.805), so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are similar (-1.439 vs -0.692).

**hERG:** Ligand A (0.699) is better than Ligand B (0.165), indicating lower hERG inhibition liability. This is a critical advantage.

**Microsomal Clearance:** Ligand A (47.059) has a higher (worse) microsomal clearance than Ligand B (21.007), suggesting lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (-7.789) has a slightly better in vitro half-life than Ligand A (-10.733).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.106 and 0.011).

**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 can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a clear advantage in several key areas: logP, DILI risk, and hERG inhibition. Its binding affinity is also better. While its microsomal clearance is higher, the significant advantage in binding affinity and safety parameters (DILI, hERG) are more important for an enzyme target like SRC. Ligand B's slightly better metabolic stability is not enough to overcome the issues with logP and DILI.

Output:
1
2025-04-17 16:29:46,915 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.439 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.81) is slightly higher than Ligand B (61.88), but both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (4.049) is higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (0.566) is quite low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, well within acceptable limits. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.835) has a significantly better QED score than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand B (16.13) has a much lower DILI risk than Ligand A (47.15), which is a significant advantage.

**BBB:** Ligand B (70.88) shows good BBB penetration, while Ligand A (56.65) is lower. However, BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show 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. Ligand B (-1.18) is slightly better than Ligand A (-3.806).

**hERG Inhibition:** Ligand A (0.773) has a slightly higher hERG risk than Ligand B (0.371), but both are relatively low.

**Microsomal Clearance:** Ligand A (9.067) has a lower microsomal clearance than Ligand B (10.269), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-28.1) has a significantly longer in vitro half-life than Ligand A (58.412).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.029).

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand B has a better safety profile (lower DILI) and longer half-life, Ligand A's significantly superior binding affinity (-10.1 vs -8.4 kcal/mol) is the most critical factor for an enzyme inhibitor. The difference of 1.7 kcal/mol is substantial. Although Ligand A has a higher logP and lower solubility, these can potentially be addressed through formulation strategies. The better QED score also favors Ligand A.

Output:
1
2025-04-17 16:29:46,915 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.367 and 345.399 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (88.58). A TPSA under 140 is good for oral absorption, and both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (3.259 and 2.563), falling within the optimal range of 1-3.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBAs, while Ligand B has 5. Both are within the acceptable limit of <=10, but A is slightly better.

**QED:** Both ligands have high QED scores (0.843 and 0.9), indicating good drug-like properties.

**DILI:** Ligand A (31.33) has a much lower DILI risk than Ligand B (54.866). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (86.002) has a higher BBB percentile than Ligand B (71.229).

**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 (-4.846 vs -4.734), potentially indicating slightly better absorption.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. The values are very similar (-2.72 and -2.798).

**hERG Inhibition:** Ligand A (0.854) has a lower hERG inhibition liability than Ligand B (0.199), which is a major advantage.

**Microsomal Clearance:** Ligand A (-17.206) has a much lower (better) microsomal clearance than Ligand B (41.3). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-8.163) has a longer in vitro half-life than Ligand B (-20.329), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.177 and 0.118).

**Binding Affinity:** Ligand B (-10.0) has a significantly stronger binding affinity than Ligand A (-7.4). This is a substantial advantage for Ligand B. A 2.6 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B has a much better binding affinity, Ligand A demonstrates superior ADMET properties, particularly regarding DILI risk, hERG inhibition, and metabolic stability (Cl_mic and t1/2). For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are crucial. The substantial difference in binding affinity *could* potentially be overcome with further optimization of Ligand A, given its better starting ADMET profile. However, the affinity difference is large.

Considering the balance, the stronger binding affinity of Ligand B is likely to be more impactful than the better ADMET profile of Ligand A, especially in early stages of drug development.

Output:
1
2025-04-17 16:29:46,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.46 and 371.91 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (59) is still acceptable but less optimal.

**logP:** Both ligands (3.47 and 4.00) are within the optimal 1-3 range, with Ligand B slightly higher.

**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 similar QED scores (0.684 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (20.74) has a significantly lower DILI risk than Ligand B (16.05). This is a substantial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (95.81) has a much higher BBB penetration score than Ligand B (50.52).

**Caco-2 Permeability:** Ligand A (-4.33) is better than Ligand B (-4.90), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.87) is better than Ligand B (-3.69), indicating better solubility.

**hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.563 and 0.64), and are acceptable.

**Microsomal Clearance:** Ligand B (99.86) has significantly higher microsomal clearance than Ligand A (41.99), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (52.10) has a longer half-life than Ligand A (-31.41), but the negative value for A suggests a potential issue with the experimental setup or a very rapid degradation.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.145 and 0.238), and are acceptable.

**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 small (0.3 kcal/mol) and may not outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better binding affinity and *in vitro* half-life, Ligand A exhibits significantly lower DILI risk, better solubility, permeability, and metabolic stability (lower Cl_mic). The difference in binding affinity is not substantial enough to overcome the ADME advantages of Ligand A, especially for an enzyme target where metabolic stability and solubility are crucial.

Output:
0
2025-04-17 16:29:46,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.46 and 345.49 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.29) is significantly better than Ligand B (73.2). A TPSA under 140 is good for oral absorption, and A is much closer to the ideal for good permeability.

**logP:** Both ligands have good logP values (4.31 and 3.03), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2/1 for A, 1/3 for B) and HBA counts (3/3).

**QED:** Ligand A (0.702) has a better QED score than Ligand B (0.594), indicating better overall drug-likeness.

**DILI:** Ligand A (27.10) has a much lower DILI risk than Ligand B (8.92), a significant advantage.

**BBB:** Both have similar BBB penetration (78.48 and 75.99). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG:** Ligand A (0.979) has a slightly higher hERG risk than Ligand B (0.473), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.13) has a higher microsomal clearance than Ligand B (12.26), suggesting lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (-16.13) has a negative half-life, which is not possible. This is a major red flag. Ligand A has a half-life of 16.67 hours, which is reasonable.

**P-gp Efflux:** Ligand A (0.773) has a slightly higher P-gp efflux than Ligand B (0.113).

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.7). This is a substantial advantage for B, potentially outweighing some of its other weaknesses.

**Conclusion:**

Despite Ligand B's issues with in vitro half-life, its significantly superior binding affinity (-9.0 vs -7.7 kcal/mol) is a critical advantage for an enzyme inhibitor. While Ligand A has better DILI and QED scores, the potency difference is substantial. The negative half-life for ligand B is a major issue, but could be addressed through structural modifications. The poor Caco-2 and solubility for both ligands are also areas for improvement, but potency is paramount for initial optimization.

Output:
1
2025-04-17 16:29:46,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.49 and 354.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold for good absorption, while Ligand B (93.22) is still acceptable but approaching the limit.

**logP:** Ligand A (2.73) is optimal (1-3). Ligand B (0.20) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is within the acceptable limit of 5. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (3) is within the acceptable limit of 10. Ligand B (6) is also good.

**QED:** Both ligands have similar QED values (0.597 and 0.517), indicating good drug-likeness.

**DILI:** Ligand A (22.10) has a much lower DILI risk than Ligand B (42.54), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.79) is higher than Ligand B (39.51).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it is hard to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. However, the scale is not specified, so it is hard to interpret.

**hERG:** Ligand A (0.298) has a much lower hERG risk than Ligand B (0.052), which is a major advantage.

**Microsomal Clearance:** Ligand A (81.39) has a higher clearance than Ligand B (20.03), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-9.10) has a longer half-life than Ligand A (3.98), indicating better stability.

**P-gp Efflux:** Ligand A (0.22) has lower P-gp efflux than Ligand B (0.033), which is a slight advantage.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher microsomal clearance, its significantly stronger binding affinity (-7.6 vs -6.6 kcal/mol), lower DILI risk, and lower hERG risk make it the more promising candidate. The better logP and TPSA values also contribute to its favorability. While both have issues with solubility and permeability, the potency and safety advantages of Ligand A are more critical for an enzyme target like SRC.

Output:
1
2025-04-17 16:29:46,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.45 and 364.87 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.98) is slightly higher than ideal (<140), but still reasonable. Ligand B (49.85) is excellent, well below the 140 threshold.

**logP:** Both ligands have good logP values (1.249 and 2.008), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (5 and 3 respectively) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.694 and 0.717), indicating good drug-likeness.

**DILI:** Ligand A (52.191) has a moderate DILI risk, while Ligand B (31.252) has a lower, more favorable DILI risk.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (80.07) is higher than Ligand B (63.94), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, we'll proceed with caution and consider other factors.

**Aqueous Solubility:** Ligand A (-0.621) has poor predicted solubility, while Ligand B (-2.959) is even worse. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.633) has a slightly higher hERG risk than Ligand B (0.449), but both are relatively low.

**Microsomal Clearance:** Ligand A (45.005) has a higher microsomal clearance than Ligand B (16.114), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (24.366) has a significantly longer in vitro half-life than Ligand A (8.159), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.184).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.5 and -7.6 kcal/mol), which are very similar. The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While both have solubility issues, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The binding affinities are comparable, making the ADME properties the deciding factor. The solubility issue is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:29:46,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (374.459 Da and 386.949 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.01) is higher than Ligand B (57.58). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good absorption.

**logP:** Ligand A (-0.463) is a bit low, potentially hindering permeability. Ligand B (1.838) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.671 and 0.838), indicating drug-like properties.

**DILI:** Ligand A (41.76) has a slightly higher DILI risk than Ligand B (21.908), though both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (70.454 and 70.415), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have similar, and poor, Caco-2 permeability (-4.865 and -4.846). This is a potential issue for both, but not a deciding factor.

**Aqueous Solubility:** Ligand A (-1.153) has slightly better solubility than Ligand B (-3.053). Solubility is important, so this is a small advantage for A.

**hERG:** Ligand A (0.082) has a slightly lower hERG risk than Ligand B (0.477), which is favorable.

**Microsomal Clearance:** Ligand A (-0.569) has better metabolic stability (lower clearance) than Ligand B (-0.348). This is a significant advantage for A.

**In vitro Half-Life:** Ligand B (33.458) has a slightly longer half-life than Ligand A (31.195), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.017 and 0.06), indicating minimal efflux issues.

**Binding Affinity:** Ligand B (-7.5) has a slightly better 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:**

Ligand B has a more favorable logP, TPSA, and binding affinity. Ligand A has better metabolic stability and slightly better solubility and hERG risk. However, the binding affinity difference of 1.1 kcal/mol in favor of Ligand B is substantial. Considering SRC is an enzyme, potency is paramount. The improved logP and TPSA of Ligand B also suggest better absorption, which is important. While Ligand A's metabolic stability is good, the potency advantage of B is more critical.

Output:
1
2025-04-17 16:29:46,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (354.491 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.08) is well below the 140 threshold for good absorption, while Ligand B (101.73) is still acceptable but closer to the limit.

**3. logP:** Both ligands have acceptable logP values (1.251 and 0.59), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBDs, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both have 4 HBAs, also within the acceptable limit of 10.

**6. QED:** Ligand A (0.752) has a better QED score than Ligand B (0.562), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (11.128 and 10.585), both well below the 40 threshold.

**8. BBB:** Ligand A (60.915) has a lower BBB penetration percentile than Ligand B (75.107). However, as SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.643) has poor Caco-2 permeability, while Ligand B (-5.447) is also poor, but slightly worse.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.565 and -1.437). This is a concern for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.168 and 0.125).

**12. Microsomal Clearance:** Ligand A (41.504) has a higher microsomal clearance than Ligand B (0.457), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-12.101) has a much longer in vitro half-life than Ligand A (2.546), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.004).

**15. Binding Affinity:** Ligand B (-7.4 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.

**Conclusion:**

Despite both compounds having issues with solubility, Ligand B is the superior candidate. Its significantly stronger binding affinity (-7.4 vs -0.0 kcal/mol) is the most important factor. It also has a much longer in vitro half-life and lower microsomal clearance, indicating better metabolic stability. While Ligand A has a slightly better logP and QED, these are overshadowed by the substantial difference in potency and metabolic stability.

Output:
1
2025-04-17 16:29:46,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.369 and 368.369 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.35) is significantly better than Ligand B (100.97). A TPSA under 140 is good for oral absorption, and both are under, but A is preferable.

**logP:** Ligand A (1.825) is optimal, while Ligand B (0.708) is slightly low, potentially hindering permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have good QED scores (0.787 and 0.806), indicating drug-likeness.

**DILI:** Ligand A (56.844) has a much lower DILI risk than Ligand B (84.296). This is a significant advantage for A.

**BBB:** Both have similar BBB penetration (71.733 and 71.307), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.729) has better Caco-2 permeability than Ligand B (-5.413), which is favorable for absorption.

**Aqueous Solubility:** Ligand A (-1.431) has better solubility than Ligand B (-2.544). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.533) has a lower hERG risk than Ligand B (0.102), which is a critical safety factor.

**Microsomal Clearance:** Ligand A (8.825) has higher microsomal clearance than Ligand B (4.379), suggesting lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand B (-3.74) has a significantly longer in vitro half-life than Ligand A (0.452), indicating better metabolic stability. This is a major advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.086 and 0.049).

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has advantages in TPSA, logP, solubility, and hERG risk, Ligand B has a substantially better in vitro half-life and lower microsomal clearance, indicating superior metabolic stability. The DILI risk is also significantly higher for Ligand B. Given that SRC is an enzyme, metabolic stability is a crucial factor. Although A has a better safety profile regarding hERG and DILI, the significantly better half-life of B outweighs these concerns. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 16:29:46,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (356.438 and 380.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is slightly higher than Ligand B (60.25), but both are well below the 140 A^2 threshold for good absorption.

**3. logP:** Ligand A (1.426) is within the optimal 1-3 range, while Ligand B (2.766) is approaching the upper limit.

**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:** Both ligands have reasonable QED scores (0.809 and 0.739), indicating good drug-like properties.

**7. DILI:** Ligand A (40.054) has a better DILI score than Ligand B (70.221), indicating lower potential for liver injury. This is a significant advantage.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (78.868) is slightly better than Ligand B (68.592). While not a primary concern for a kinase inhibitor, it's a minor positive for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.598) is slightly better than Ligand B (-5.099).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.018) is slightly better than Ligand B (-2.978).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.401 and 0.352), which is excellent.

**12. Microsomal Clearance:** Ligand A (5.876) has significantly lower microsomal clearance than Ligand B (69.438), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Ligand A (1.354) has a shorter half-life than Ligand B (6.279). However, the difference is less critical given the low clearance of Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.167), 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 1.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, and much better metabolic stability (lower Cl_mic) are key advantages. While both have issues with Caco-2 and solubility, the potency and safety profile of Ligand A make it a more promising starting point for drug development.

Output:
1
2025-04-17 16:29:46,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.425 and 388.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.71) is significantly better than Ligand B (131.25). A TPSA under 140 is good for oral absorption, but Ligand B is pushing the limit.

**logP:** Both ligands have acceptable logP values (1.209 and 0.718), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.859 and 0.633), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (50.989 and 55.874), both are acceptable.

**BBB:** Ligand A (78.558) has a better BBB penetration score than Ligand B (66.576), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.004) has a worse Caco-2 permeability than Ligand B (-5.507).

**Aqueous Solubility:** Ligand A (-1.751) has a better aqueous solubility than Ligand B (-2.276). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.602) has a significantly lower hERG inhibition liability than Ligand B (0.069), which is a crucial advantage. Lower hERG risk is highly desirable.

**Microsomal Clearance:** Ligand A (16.155) has a higher microsomal clearance than Ligand B (-0.769), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (43.74) has a much longer in vitro half-life than Ligand A (-1.827), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.068).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has better solubility and a significantly lower hERG risk, Ligand B demonstrates superior metabolic stability (lower Cl_mic and longer t1/2). Given the enzyme-specific priorities, metabolic stability is crucial. The slight difference in binding affinity is not enough to overcome the substantial difference in metabolic stability. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:29:46,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (354.397 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.79) is slightly higher than Ligand B (75.19), but both are well below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (1.027) is closer to the optimal range of 1-3 than Ligand B (2.418). Ligand B is still acceptable, but slightly higher logP can sometimes lead to off-target effects.

**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, well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.754 and 0.736), indicating good drug-like properties.

**7. DILI:** Ligand A (10.585) has a significantly lower DILI risk than Ligand B (50.601). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (77.937 and 77.627). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.194) shows better Caco-2 permeability than Ligand B (-4.711).

**10. Aqueous Solubility:** Ligand A (-1.626) has better aqueous solubility than Ligand B (-3.072). Solubility is important for bioavailability.

**11. hERG Inhibition:** Ligand A (0.652) has a lower hERG inhibition liability than Ligand B (0.234). Lower is better, making Ligand A safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand A (-35.099) has a much lower microsomal clearance than Ligand B (89.633). This indicates better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-5.196) has a longer in vitro half-life than Ligand B (-20.804). This is another advantage for Ligand A, suggesting less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.018) has lower P-gp efflux liability than Ligand B (0.122), which is favorable for oral bioavailability.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 1.4 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially DILI risk, metabolic stability (Cl_mic and t1/2), solubility, hERG risk, and P-gp efflux. While Ligand B has a slightly more optimal logP, the advantages of Ligand A are substantial. The superior binding affinity of Ligand A further solidifies its position as the more promising candidate.



Output:
1
2025-04-17 16:29:46,918 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.375 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.98) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (75.44) is well within the ideal range.

**logP:** Ligand A (-0.959) is a bit low, potentially hindering permeation. Ligand B (2.888) is nearly optimal.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.635 and 0.857), indicating drug-like properties.

**DILI:** Ligand A (22.024) has a much lower DILI risk than Ligand B (34.548), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (85.731) has a higher BBB penetration than Ligand A (51.803).

**Caco-2 Permeability:** Ligand A (-5.217) has poor Caco-2 permeability, while Ligand B (-4.698) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.258) has poor aqueous solubility, while Ligand B (-2.575) is even worse.

**hERG:** Ligand A (0.105) has a very low hERG risk, a major advantage. Ligand B (0.464) has a slightly elevated hERG risk.

**Microsomal Clearance:** Ligand A (5.441) has a much lower microsomal clearance, indicating better metabolic stability, which is crucial for kinases. Ligand B (66.707) has high clearance.

**In vitro Half-Life:** Ligand A (14.644) has a reasonable half-life, while Ligand B (-28.023) has a negative half-life, which is not possible and indicates a very short half-life/rapid degradation.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is good. Ligand B (0.287) has slightly higher efflux.

**Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.7), but the difference is not huge.

**Overall Assessment:**

Ligand A has significant advantages in terms of DILI risk, hERG inhibition, and metabolic stability (lower Cl_mic, better t1/2). While its logP and solubility are suboptimal, the strong binding affinity and favorable safety/ADME properties outweigh these concerns. Ligand B has better TPSA and BBB, but suffers from poor solubility, high DILI risk, high clearance, and a problematic half-life. The slightly better affinity of Ligand A is also a plus.

Output:
0
2025-04-17 16:29:46,918 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.385 Da) is slightly lower than Ligand B (370.871 Da), which isn't a major concern.

**TPSA:** Ligand A (78.87) is better than Ligand B (32.34) as it is closer to the threshold for good oral absorption.

**logP:** Ligand A (0.68) is suboptimal, being slightly below the preferred range of 1-3. Ligand B (4.261) is too high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is better than Ligand B (HBD=1, HBA=2) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (A: 0.775, B: 0.759), indicating good drug-likeness.

**DILI:** Ligand A (25.785) has a significantly lower DILI risk than Ligand B (17.449), which is a major advantage.

**BBB:** Both ligands have good BBB penetration, but Ligand B (93.098) is slightly better than Ligand A (83.715). However, BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**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 (0.488) has a lower hERG inhibition liability than Ligand B (0.942), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (-16.469) has a much lower (better) microsomal clearance than Ligand B (39.717), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (23.102 hours) has a significantly longer half-life than Ligand B (9.481 hours), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.025) has a lower P-gp efflux liability than Ligand B (0.569), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). The difference is 1.9 kcal/mol, which is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, Ligand A is the more promising candidate. Ligand B's high logP, higher DILI risk, higher hERG inhibition, and significantly higher microsomal clearance are major concerns. Ligand A, while having a slightly weaker affinity, exhibits much better ADME properties, particularly regarding metabolic stability, safety (DILI, hERG), and P-gp efflux. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand A. The negative Caco-2 and solubility values are concerning for both, and would need to be addressed, but the overall profile of A is more favorable.

Output:
0
2025-04-17 16:29:46,918 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (387.496 Da) is also good.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (29.02). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (2.543) is within the optimal range (1-3). Ligand B (4.948) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0 for A, 0 for B) and HBA (3 for A, 5 for B) counts, falling within the guidelines.

**QED:** Both ligands have reasonable QED values (0.786 for A, 0.6 for B), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (30.05 for A, 39.201 for B), suggesting a low risk of liver injury.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (93.098) has a higher BBB percentile than Ligand A (80.574), but this isn't a major factor in this case.

**Caco-2 Permeability:** Ligand A (-4.223) 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 difficult to interpret.

**Aqueous Solubility:** Ligand A (-2.652) and Ligand B (-4.984) both have negative values, indicating poor solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.383) has a much lower hERG inhibition risk than Ligand B (0.877), which is a significant advantage. Avoiding cardiotoxicity is crucial.

**Microsomal Clearance:** Ligand B (43.817) has a lower microsomal clearance than Ligand A (48.774), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (4.231) has a longer half-life than Ligand A (-9.947). A longer half-life is generally desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.247) has lower P-gp efflux than Ligand B (0.506), which could lead to better oral bioavailability.

**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 minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has better metabolic stability and half-life, Ligand A's significantly stronger binding affinity (-8.7 vs -7.6 kcal/mol) and lower hERG risk are critical advantages, especially for an enzyme target. The slightly better TPSA and P-gp efflux of Ligand A are also beneficial. The solubility and permeability issues are concerning for both, but the superior potency of Ligand A is likely to be more impactful in driving efficacy.



Output:
0
2025-04-17 16:29:46,918 - INFO - Batch 468 complete. Total preferences: 7488
2025-04-17 16:29:46,918 - INFO - Processing batch 469/512...
2025-04-17 16:30:33,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.471 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (42.43) is well within the ideal range.

**logP:** Ligand A (0.757) is a bit low, potentially hindering permeability. Ligand B (4.286) is at the higher end of the optimal range, potentially causing solubility issues but generally acceptable for kinases.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, fitting well within the guidelines. Ligand B has 0 HBD and 4 HBA, also good.

**QED:** Both ligands have reasonable QED scores (0.742 and 0.681), indicating good drug-like properties.

**DILI:** Ligand A (62.001) has a moderate DILI risk, while Ligand B (35.091) has a lower, more favorable DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.217) has a higher BBB score than Ligand A (46.724).

**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 (0.072) has a very low hERG risk, which is excellent. Ligand B (0.403) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (11.469) has lower microsomal clearance, indicating better metabolic stability. Ligand B (65.98) has significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (22.319) has a longer half-life than Ligand B (-14.974). The negative half-life for Ligand B is concerning and likely an error or outlier.

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is favorable. Ligand B (0.396) has slightly higher 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 could outweigh some of the ADME drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has better logP and lower DILI, Ligand A's significantly stronger binding affinity (-9.3 vs -8.1 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial advantages. The lower hERG and P-gp efflux also contribute to its favorability. The negative solubility and Caco-2 values are concerning for both, but the potency difference is likely to be the deciding factor.

Output:
0
2025-04-17 16:30:33,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 351.491 Da - Within the ideal range (200-500).
* Ligand B: 583.092 Da - Above the ideal range, potentially impacting permeability.

**2. TPSA:**
* Ligand A: 87.3 A<sup>2</sup> - Good for oral absorption (<=140).
* Ligand B: 112.4 A<sup>2</sup> - Acceptable, but approaching the upper limit for good absorption.

**3. logP:**
* Ligand A: 1.738 - Optimal (1-3).
* Ligand B: 6.465 - High, potentially causing solubility issues and off-target interactions.

**4. H-Bond Donors (HBD):**
* Ligand A: 3 - Within the acceptable limit (<=5).
* Ligand B: 2 - Within the acceptable limit (<=5).

**5. H-Bond Acceptors (HBA):**
* Ligand A: 3 - Within the acceptable limit (<=10).
* Ligand B: 8 - Within the acceptable limit (<=10).

**6. QED:**
* Ligand A: 0.622 - Good drug-like properties (>=0.5).
* Ligand B: 0.205 - Poor drug-like properties (<0.5).

**7. DILI:**
* Ligand A: 27.608 - Low risk of DILI (<40).
* Ligand B: 91.431 - High risk of DILI (>60).

**8. BBB:**
* Ligand A: 67.623 - Not a primary concern for a non-CNS target like SRC.
* Ligand B: 19.542 - Not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:**
* Ligand A: -5.126 - Indicates poor permeability.
* Ligand B: -5.317 - Indicates poor permeability.

**10. Aqueous Solubility:**
* Ligand A: -2.35 - Poor solubility.
* Ligand B: -6.2 - Very poor solubility.

**11. hERG Inhibition:**
* Ligand A: 0.114 - Low risk of hERG inhibition.
* Ligand B: 0.89 - Moderate risk of hERG inhibition.

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 34.367 mL/min/kg - Moderate clearance.
* Ligand B: 61.259 mL/min/kg - Higher clearance, suggesting lower metabolic stability.

**13. In vitro Half-Life (t1/2):**
* Ligand A: -3.211 hours - Short half-life.
* Ligand B: 128.641 hours - Long half-life.

**14. P-gp Efflux:**
* Ligand A: 0.021 - Low P-gp efflux.
* Ligand B: 0.959 - High P-gp efflux.

**15. Binding Affinity:**
* Ligand A: -7.3 kcal/mol
* Ligand B: -7.3 kcal/mol - Affinity is equal.

**Enzyme-Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both ligands have equal binding affinity, Ligand B has a significantly longer half-life, which is a major advantage. However, Ligand B suffers from very poor solubility, high DILI risk, high logP, and high P-gp efflux. Ligand A has better solubility, lower DILI risk, and lower P-gp efflux, but has a short half-life and poor permeability.

Considering the balance, the longer half-life of Ligand B is a significant advantage that *could* be overcome with formulation strategies to address its solubility issues. The high DILI risk is a serious concern, but not insurmountable during lead optimization. Ligand A's poor permeability is a more difficult property to improve.

Output:
1
2025-04-17 16:30:33,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.43 and 351.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.16) is significantly better than Ligand B (109.14). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (0.771) is slightly better than Ligand A (0.023). Ligand A is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Fewer H-bonds can improve membrane permeability.

**QED:** Both ligands have acceptable QED scores (0.769 and 0.641, both >0.5).

**DILI:** Ligand A (22.102) has a much lower DILI risk than Ligand B (45.095). This is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (51.57) is slightly better than Ligand A (46.568).

**Caco-2 Permeability:** Ligand A (-4.48) has a worse Caco-2 permeability than Ligand B (-5.058). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-0.47) is slightly better than Ligand B (-1.493).

**hERG:** Both ligands have very low hERG inhibition risk (0.194 and 0.171).

**Microsomal Clearance:** Ligand B (7.943) has lower microsomal clearance than Ligand A (10.211), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-15.94) has a longer half-life than Ligand A (-20.621).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.04).

**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.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a significantly lower DILI risk, better TPSA, and slightly better solubility. The binding affinity difference is substantial (1.0 kcal/mol), and for an enzyme target, potency is paramount. The slightly worse DILI risk of Ligand B is a concern, but could be addressed with further optimization. The lower TPSA and better solubility of Ligand A are beneficial, but the lower logP and Caco-2 permeability are drawbacks. Considering the enzyme-specific priorities, the improved potency of Ligand B outweighs the slightly higher DILI risk.

Output:
1
2025-04-17 16:30:33,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.423 and 372.342 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.64) is well below the 140 threshold for good absorption, and even better for potential kinase inhibitors. Ligand B (89.19) is still acceptable, but less optimal.

**logP:** Both ligands (2.032 and 2.17) 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 7 HBA. While both are under the 10 threshold, Ligand A is preferable.

**QED:** Both ligands have acceptable QED scores (0.779 and 0.676), indicating good drug-like properties.

**DILI:** Ligand A (29.779) has a significantly lower DILI risk than Ligand B (56.844). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.87) has a higher BBB score, but this isn't a primary concern here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. 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 (0.185) has a much lower hERG inhibition liability than Ligand B (0.644). This is a significant advantage for Ligand A, as kinase inhibitors can sometimes have cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (24.898) has a lower microsomal clearance than Ligand B (55.99), indicating better metabolic stability. This is crucial for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-0.262) has a slightly better (less negative) in vitro half-life than Ligand B (-2.124).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.039 and 0.052).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.2 and -7.1 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have good potency, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, lower hERG inhibition, and better metabolic stability (lower Cl_mic). These factors are particularly important for kinase inhibitors. The slight improvements in TPSA and HBA also contribute to its favorability.

Output:
0
2025-04-17 16:30:33,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.76) is better than Ligand B (58.2), both are below the 140 A^2 threshold for good absorption.

**3. logP:** Both ligands (3.099 and 3.569) are within the optimal 1-3 range. Ligand B is slightly higher, which *could* pose a minor solubility issue, 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 slightly better than Ligand B (2). Both are well within the acceptable limit of 10.

**6. QED:** Ligand A (0.842) has a significantly better QED score than Ligand B (0.722), indicating a more drug-like profile.

**7. DILI:** Ligand A (17.914) has a much lower DILI risk than Ligand B (36.448). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (Ligand A: 70.686, Ligand B: 61.458), but Ligand A is better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**9. Caco-2 Permeability:** Ligand A (-4.593) is better than Ligand B (-4.883), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.158) is better than Ligand B (-4.452), which is crucial for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG risk (Ligand A: 0.55, Ligand B: 0.255). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand B (53.965) has lower microsomal clearance than Ligand A (68.134), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (23.39) has a significantly longer in vitro half-life than Ligand B (4.163). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (Ligand A: 0.254, Ligand B: 0.286).

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-6.8). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B. A 2.2 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding DILI risk, solubility, and in vitro half-life. The difference in binding affinity is substantial, but the improved safety and pharmacokinetic properties of Ligand A make it a more promising starting point for drug development. The longer half-life and lower DILI risk are particularly important for an oncology drug.

Output:
0
2025-04-17 16:30:33,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (385.888 and 396.965 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is higher than Ligand B (40.62). Both are acceptable, but B is better for permeability.

**logP:** Both ligands have similar logP values (3.355 and 3.362), falling within the optimal 1-3 range.

**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 limit of <=10.

**QED:** Both ligands have good QED scores (0.807 and 0.769), indicating drug-like properties.

**DILI:** Ligand A (50.291) has a slightly higher DILI risk than Ligand B (46.956), but both are below the concerning threshold of 60.

**BBB:** Both have good BBB penetration, but Ligand B (85.731) is better than Ligand A (78.364). This isn't a primary concern for a kinase inhibitor, but is a plus.

**Caco-2 Permeability:** Ligand A (-4.761) and Ligand B (-5.015) 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:** Both ligands have poor aqueous solubility (-4.76 and -4.684). This is a concern and may require formulation strategies.

**hERG Inhibition:** Ligand A (0.346) has a lower hERG risk than Ligand B (0.543), which is favorable.

**Microsomal Clearance:** Ligand B (40.908) has significantly lower microsomal clearance than Ligand A (69.407), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-5.054) has a longer in vitro half-life than Ligand A (-12.659), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.259 and 0.28), which is good.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.2). This 0.8 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B demonstrates significantly improved metabolic stability (lower Cl_mic, longer t1/2) and a substantially stronger binding affinity. The slightly lower hERG risk of Ligand A is less important than the improved potency and metabolic profile of Ligand B.

Output:
1
2025-04-17 16:30:33,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.375 and 353.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.42) is better than Ligand B (127.92), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (-0.259) is slightly outside the optimal 1-3 range, potentially hindering permeation. Ligand B (-2.812) is also suboptimal, but less so.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5/6 HBA, which are acceptable.

**QED:** Ligand A (0.694) has a significantly better QED score than Ligand B (0.442), indicating a more drug-like profile.

**DILI:** Ligand A (53.936) has a higher DILI risk than Ligand B (35.324), but both are reasonably acceptable.

**BBB:** Both have similar BBB penetration (53.044 and 57.736), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.36 and -5.727), indicating poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.616 and -1.91), suggesting poor solubility. This is also a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.06 and 0.013). This is excellent.

**Microsomal Clearance:** Ligand A (-42.152) has a much lower (better) microsomal clearance than Ligand B (-18.267). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-25.624) has a longer half-life than Ligand B (-13.34), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.003 and 0.001).

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite the poor Caco-2 and solubility for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.8 vs -8.2 kcal/mol) outweighs the slightly higher DILI risk and suboptimal logP. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic and longer t1/2) and a higher QED score. The enzyme-specific priorities clearly favor the compound with the best potency and metabolic stability.

Output:
1
2025-04-17 16:30:33,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.64 Da) is slightly higher than Ligand B (348.447 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is better than Ligand B (89.53). Lower TPSA generally favors better absorption.

**logP:** Ligand A (4.148) is higher than Ligand B (1.156). While Ligand A is at the upper end of the optimal range, it's still acceptable. Ligand B is on the lower end, potentially impacting permeability.

**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, which can improve permeability. Both are within acceptable limits.

**QED:** Ligand B (0.835) has a significantly higher QED score than Ligand A (0.477), indicating a more drug-like profile.

**DILI:** Ligand A (89.686) has a higher DILI risk than Ligand B (33.307). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.831) is higher than Ligand B (32.803), but this isn't a major factor in this case.

**Caco-2 Permeability:** Ligand A (-4.562) is better than Ligand B (-5.134), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.65) is better than Ligand B (-1.517), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.209) has a much lower hERG risk than Ligand B (0.124), which is a significant advantage.

**Microsomal Clearance:** Ligand B (11.715) has a significantly lower microsomal clearance than Ligand A (42.182), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.304) has a longer in vitro half-life than Ligand A (20.028), which is desirable.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.076), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly higher binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity and a lower hERG risk, but suffers from higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2). Ligand B has a better QED, lower DILI, and better metabolic stability, but its binding affinity is considerably weaker.

Given the priority for potency in enzyme inhibition, the significantly stronger binding affinity of Ligand A (-7.8 kcal/mol vs -6.6 kcal/mol) is a major deciding factor. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. The metabolic stability issues could also be addressed. The weaker affinity of Ligand B makes it less likely to be a successful drug candidate, even with its better ADME properties.

Output:
1
2025-04-17 16:30:33,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.551 and 362.832 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.29) is better than Ligand B (46.34), both are below the 140 threshold for good absorption.

**logP:** Ligand A (3.883) is within the optimal 1-3 range, while Ligand B (4.742) is slightly higher. This could potentially lead to solubility issues for B, but isn't a major concern yet.

**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 good QED scores (0.651 and 0.697, respectively), indicating drug-likeness.

**DILI:** Ligand A (23.73) has a significantly lower DILI risk than Ligand B (42.497). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (89.492 and 91.857), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.823 and -4.718), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.214 and -4.644), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.969) has a slightly higher hERG risk than Ligand B (0.733), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.893) has lower microsomal clearance than Ligand B (81.635), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (55.744) has a longer half-life than Ligand B (24.269), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.555) has lower P-gp efflux than Ligand B (0.727), which is favorable.

**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 (-8.8 vs -7.2 kcal/mol). However, Ligand A demonstrates superior ADME properties, particularly in terms of DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. Both compounds have poor solubility and permeability. Given the enzyme class (kinase), metabolic stability and safety (DILI) are crucial. The affinity difference is 1.6 kcal/mol, which is significant, but the better ADME profile of Ligand A, especially the lower DILI risk, makes it the more promising candidate, assuming solubility/permeability can be addressed through formulation or further optimization.

Output:
0
2025-04-17 16:30:33,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.447 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is better than Ligand B (99.1) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (1.205) is optimal, while Ligand B (0.21) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being less than 10.

**QED:** Ligand A (0.839) is significantly better than Ligand B (0.541), indicating a more drug-like profile.

**DILI:** Ligand A (29.779) has a much lower DILI risk than Ligand B (20.279), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (62.582) is better than Ligand B (38.852).

**Caco-2 Permeability:** Both are negative (-5.237 and -5.218), which is unusual and requires further investigation. However, the values are very similar.

**Aqueous Solubility:** Both are negative (-1.813 and -1.395), indicating poor aqueous solubility. This is a concern for both, but slightly better for Ligand B.

**hERG:** Ligand A (0.072) has a much lower hERG inhibition liability than Ligand B (0.176), which is a significant advantage.

**Microsomal Clearance:** Ligand A (12.094) has a lower microsomal clearance than Ligand B (18.489), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.171) has a longer in vitro half-life than Ligand B (5.557), which is favorable.

**P-gp Efflux:** Both are very low (0.038 and 0.048), suggesting minimal P-gp efflux.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), although both are good. The 0.8 kcal/mol difference is significant.

**Overall:** Ligand A is superior to Ligand B. It has better QED, DILI, hERG, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. While both have poor solubility, the other advantages of Ligand A outweigh this drawback, especially considering the importance of potency and metabolic stability for an enzyme target.

Output:
1
2025-04-17 16:30:33,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (350.459 and 368.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is well below the 140 threshold for oral absorption, while Ligand B (96.17) is still acceptable but closer to the limit.

**logP:** Ligand A (1.524) is within the optimal 1-3 range. Ligand B (0.261) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, both well within acceptable limits. Ligand B has 2 HBD and 8 HBA, also acceptable, but higher HBA could potentially impact permeability.

**QED:** Both ligands have similar QED values (0.788 and 0.786), indicating good drug-likeness.

**DILI:** Ligand A (19.698) has a significantly lower DILI risk than Ligand B (58.976), which is a substantial advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (74.06) shows better penetration than Ligand B (56.766).

**Caco-2 Permeability:** Ligand A (-4.753) and Ligand B (-5.588) both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret the magnitude of the difference.

**Aqueous Solubility:** Ligand A (-2.216) and Ligand B (-1.514) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.184) has a lower hERG risk than Ligand B (0.081), which is a positive attribute.

**Microsomal Clearance:** Ligand A (21.09) has a higher microsomal clearance than Ligand B (15.412), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-10.645) has a significantly longer in vitro half-life than Ligand A (-5.297), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.135), which is favorable.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-6.7). This 2.3 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having a higher clearance and lower half-life, its significantly stronger binding affinity (-9.0 kcal/mol vs -6.7 kcal/mol) and substantially lower DILI risk make it the more promising candidate. The affinity difference is large enough to potentially overcome the metabolic stability concerns, especially considering SRC is an intracellular target where sufficient drug concentration can be maintained. The lower hERG risk is also a benefit.

Output:
1
2025-04-17 16:30:33,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.491 and 338.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is significantly better than Ligand B (84.85), falling well below the 140 A^2 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.953 and 3.171, respectively), 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.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=7) as it has fewer hydrogen bond acceptors, which generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.68 and 0.684), indicating good drug-likeness.

**DILI:** Ligand A (42.187) has a much lower DILI risk than Ligand B (90.927). This is a significant advantage for Ligand A.

**BBB:** This is less crucial for a non-CNS target like SRC kinase, but Ligand A (62.466) is slightly better than Ligand B (58.976).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.646) is slightly better than Ligand B (-4.888).

**Aqueous Solubility:** Ligand A (-2.167) is better than Ligand B (-4.615), indicating better solubility.

**hERG Inhibition:** Ligand A (0.167) has a much lower hERG inhibition liability than Ligand B (0.814). This is a critical advantage, minimizing potential cardiotoxicity.

**Microsomal Clearance:** Ligand B (98.911) has a significantly higher microsomal clearance than Ligand A (63.202), suggesting lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand B (17.198) has a longer half-life than Ligand A (-6.682). However, the negative value for Ligand A is concerning and likely an artifact of the prediction model.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.133 and 0.135).

**Binding Affinity:** Ligand B (-7.7 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/Tox advantages of Ligand A.

**Overall:** Ligand A is the more promising candidate. It has a better safety profile (lower DILI, lower hERG), better solubility, and better metabolic stability (lower Cl_mic). While Ligand B has slightly better binding affinity and half-life, the ADME/Tox profile of Ligand A is far superior, making it a more viable drug candidate.

Output:
0
2025-04-17 16:30:33,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.443 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.78) is slightly higher than Ligand B (67.43), but both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.628 and 2.559), falling within the optimal 1-3 range.

**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 criteria.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand B (18.418) has a significantly lower DILI risk than Ligand A (41.838), which is a major advantage.

**BBB:** Ligand B (51.803) shows better BBB penetration than Ligand A (39.744), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. However, the values are similar (-4.868 and -4.682).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Again, the values are similar (-2.518 and -2.685).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.236 and 0.211).

**Microsomal Clearance:** Ligand A (10.743 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (29.089 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.423 hours) has a longer in vitro half-life than Ligand B (13.951 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.216 and 0.079).

**Binding Affinity:** Ligand B (-8.8 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.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better in vitro profile, Ligand B's significantly stronger binding affinity (-8.8 vs -10.2 kcal/mol) and substantially lower DILI risk are more critical for an oncology target like SRC. The similar, and poor, Caco-2 and solubility profiles are a concern for both, but can be addressed with formulation strategies. The stronger binding of Ligand B suggests it is more likely to be efficacious, and the lower DILI risk is crucial for safety.

Output:
1
2025-04-17 16:30:33,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.365 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (73.2 and 78.09) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.411 and 2.123) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.909 and 0.823), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (40.287 and 38.813 percentile), which is good.

**BBB:** Ligand A (89.104) has a significantly higher BBB penetration percentile than Ligand B (42.032). While not a primary concern for a non-CNS target like SRC, it isn't a negative.

**Caco-2 Permeability:** Ligand A (-4.649) has better Caco-2 permeability than Ligand B (-5.146).

**Aqueous Solubility:** Ligand A (-3.75) has better aqueous solubility than Ligand B (-3.307). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.813 and 0.422 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (5.811 mL/min/kg) has a lower microsomal clearance than Ligand B (25.587 mL/min/kg), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-23.283) has a slightly longer in vitro half-life than Ligand A (-21.413), but the difference is small.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.073 and 0.197 percentile).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -8.5 kcal/mol). Ligand A is slightly better (-9.0 vs -8.5 kcal/mol).

**Overall Assessment:**

Ligand A is superior to Ligand B. While both ligands have good overall profiles, Ligand A demonstrates advantages in key areas: better Caco-2 permeability, better aqueous solubility, significantly lower microsomal clearance (better metabolic stability), and slightly better binding affinity. The lower HBD count is also a minor benefit. These factors collectively suggest Ligand A is more likely to be a viable drug candidate for SRC kinase.

Output:
1
2025-04-17 16:30:33,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.491 and 352.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.66) is slightly higher than Ligand B (69.64). Both are below the 140 threshold for good oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.323) and Ligand B (2.574) are both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the threshold of 10.

**QED:** Both ligands have good QED scores (0.552 and 0.74), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have very low DILI risk (10.198 and 10.237 percentile), which is excellent.

**BBB:** Ligand A (57.619) and Ligand B (75.882) both have low BBB penetration, which is fine since SRC is not a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.572), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.949 and -2.537), indicating poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.285 and 0.43), which is excellent.

**Microsomal Clearance:** Ligand A (59.627) has higher microsomal clearance than Ligand B (51.676). Lower clearance is preferred for better metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (3.114 hours) has a slightly longer half-life than Ligand A (7.763 hours). This is a slight advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.066), which is good.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. Its significantly stronger binding affinity (-9.4 vs -7.7 kcal/mol) is the most important factor. It also has slightly better metabolic stability (lower Cl_mic), a slightly longer half-life, and a better QED score. While both ligands have poor Caco-2 permeability and aqueous solubility, the strong binding affinity of Ligand B makes it more likely to be optimized to overcome these issues. The similar DILI and hERG profiles are positive for both.

Output:
1
2025-04-17 16:30:33,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.263 Da) is slightly lower, which could be advantageous for permeability. Ligand B (386.25 Da) is also good.

**TPSA:** Ligand A (79.52) is better than Ligand B (42.68). Lower TPSA generally indicates better cell permeability.

**logP:** Ligand A (2.632) is optimal. Ligand B (4.937) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**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 and good QED values (0.709 and 0.707).

**DILI:** Ligand A (93.059) has a significantly higher DILI risk than Ligand B (37.611). This is a major concern for Ligand A.

**BBB:** Ligand A (58.55) and Ligand B (84.529) both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.874) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.16) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.656) has poor aqueous solubility. Ligand B (-5.325) has even worse solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.722 and 0.778).

**Microsomal Clearance:** Ligand A (35.575) has lower microsomal clearance than Ligand B (88.798), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (65.181) has a significantly longer in vitro half-life than Ligand A (35.22). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.198 and 0.46).

**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 better binding affinity, and better metabolic stability. However, it suffers from significantly higher DILI risk and poor Caco-2 permeability and solubility. Ligand B has a better safety profile (lower DILI) and slightly better permeability, and a much longer half-life, but its binding affinity is weaker.

Given the priorities for enzyme inhibitors, the stronger binding 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 solubility and permeability issues are also addressable. The longer half-life of Ligand B is attractive, but the weaker binding may limit its efficacy.

Output:
1
2025-04-17 16:30:33,082 - INFO - Batch 469 complete. Total preferences: 7504
2025-04-17 16:30:33,082 - INFO - Processing batch 470/512...
2025-04-17 16:31:12,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.415 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.5) is slightly higher than Ligand B (93.19), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.844) is within the optimal range (1-3), while Ligand B (-1.194) is below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.718) has a better QED score than Ligand B (0.562), indicating a more drug-like profile.

**DILI:** Ligand A (30.71) has a significantly lower DILI risk than Ligand B (6.475), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (59.364) is higher than Ligand B (20.512).

**Caco-2 Permeability:** Ligand A (-4.696) is worse than Ligand B (-5.491), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.148) is significantly better than Ligand B (0.062). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.364 and 0.059 respectively).

**Microsomal Clearance:** Ligand B (-11.77) has a much lower (better) microsomal clearance than Ligand A (29.684), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-28.676) has a significantly longer half-life than Ligand A (2.485), which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.001 respectively).

**Binding Affinity:** Both ligands have comparable binding affinities (-8 and -7.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. However, Ligand A has better solubility and a slightly better QED score. The biggest drawback of Ligand B is its low logP, which could significantly impact its permeability. Considering the enzyme-specific priorities, metabolic stability and solubility are key. While Ligand B's metabolic stability is excellent, its poor solubility and logP are concerning. Ligand A's solubility is much better, and its logP is within range. The slightly worse metabolic stability of Ligand A is likely manageable with further optimization, while fixing the solubility of Ligand B would be a more substantial challenge.

Output:
1
2025-04-17 16:31:12,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.379 and 363.424 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.22) is slightly higher than Ligand B (52.65). Both are below the 140 threshold for good oral absorption, but B is significantly better.

**logP:** Ligand A (2.95) is optimal, while Ligand B (1.817) is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable range.

**QED:** Both ligands have similar QED values (0.64 and 0.68), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (95.58), which is a major concern. Ligand B has a much lower DILI risk (10.275), a significant advantage.

**BBB:** Ligand A (32.222) and Ligand B (84.568). BBB isn't a primary concern for a kinase inhibitor, but higher is generally better.

**Caco-2:** Both ligands have negative Caco-2 values (-4.934 and -4.714), which is unusual and suggests poor permeability. This is a red flag for both.

**Solubility:** Ligand A (-5.092) and Ligand B (-1.308) both have negative solubility values, suggesting poor aqueous solubility. B is better.

**hERG:** Both ligands have low hERG risk (0.483 and 0.478).

**Microsomal Clearance:** Ligand A (32.011) and Ligand B (24.671). Lower is better, so Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (25.23) has a better half-life than Ligand B (7.135).

**P-gp Efflux:** Ligand A (0.309) has lower P-gp efflux than Ligand B (0.02), meaning it is less likely to be pumped out of cells.

**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 significant drawbacks.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, its extremely high DILI risk is a deal-breaker. Ligand B, while having a slightly lower affinity and permeability issues, presents a much more favorable safety profile (DILI) and better metabolic stability (Cl_mic). The solubility is also better for Ligand B. Considering these factors, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 16:31:12,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.423 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (107.84 and 104.73) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**logP:** Ligand A (1.33) is within the optimal 1-3 range. Ligand B (-0.068) is slightly below 1, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Ligand B (0.625) has a better QED score than Ligand A (0.354), suggesting a more drug-like profile.

**DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (59.48), which is a substantial advantage.

**BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.803 and -4.945), which is unusual and suggests poor permeability. This is a significant red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.425 and -1.494), which is also highly problematic and indicates very poor solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.215 and 0.234), which is excellent.

**Microsomal Clearance:** Ligand A (3.368 mL/min/kg) has a much lower microsomal clearance than Ligand B (44.466 mL/min/kg), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (20.549 hours) has a much longer half-life than Ligand B (-32.995 hours - a negative value is concerning and likely indicates rapid degradation). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.012).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and longer half-life outweigh the slightly lower QED score and the shared permeability/solubility issues. The permeability and solubility issues are serious for both, but the ADME profile of Ligand A is superior. Further work would need to focus on improving the solubility and permeability of either compound, but Ligand A provides a better starting point.

Output:
0
2025-04-17 16:31:12,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.829 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the preferred <140, while Ligand B (62.3) is well within. This favors B for absorption.

**logP:** Both ligands (2.01 and 2.087) are optimal, falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.686 and 0.819), indicating good drug-likeness.

**DILI:** Ligand A (67.623) has a higher DILI risk than Ligand B (37.611). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (52.579) is higher than Ligand A (32.765), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.142 and -4.937). These values are unusual and suggest poor permeability. However, these are likely experimental artifacts or indicate the assay is not suitable for these compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.38 and -3.229). Again, these are unusual and suggest poor solubility, but may be experimental artifacts.

**hERG:** Both ligands have very low hERG risk (0.264 and 0.132), which is excellent.

**Microsomal Clearance:** Ligand B (20.061) has significantly lower microsomal clearance than Ligand A (38.109), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-13.819) has a negative half-life, which is an artifact. Ligand A (43.317) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.136 and 0.112), which is favorable.

**Binding Affinity:** Ligand A (-9.8 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 much better binding affinity, which is the most important factor for an enzyme inhibitor. However, it has a higher DILI risk and higher microsomal clearance. Ligand B has better ADME properties (lower DILI, lower Cl_mic, better TPSA) but weaker binding affinity. The difference in binding affinity (-9.8 vs -6.8) is 3 kcal/mol, which is a large difference. Given the importance of potency for enzyme inhibition, and the acceptable (though not ideal) ADME profile of Ligand A, I would prioritize Ligand A.

Output:
0
2025-04-17 16:31:12,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.439 and 362.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.37) is better than Ligand B (49.41). While both are reasonably low, Ligand B is exceptionally low, which *could* indicate poor interactions with the kinase hinge region.

**logP:** Ligand A (-0.234) is suboptimal, potentially hindering permeability. Ligand B (4.198) is high, raising concerns about solubility and off-target effects, but is within the acceptable range.

**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.

**QED:** Both ligands have good QED scores (0.555 and 0.853), indicating generally drug-like properties.

**DILI:** Ligand A (32.067) has a much lower DILI risk than Ligand B (47.693), a significant advantage.

**BBB:** Ligand A (52.074) has a lower BBB penetration than Ligand B (92.323). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-5.59) has poor Caco-2 permeability, which is a concern. Ligand B (-4.448) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-1.141) has poor solubility, which is a significant drawback. Ligand B (-5.712) is also poor, but worse than A.

**hERG Inhibition:** Ligand A (0.192) has a very low hERG risk, a major advantage. Ligand B (0.547) has a higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (0.009) has extremely low microsomal clearance, indicating excellent metabolic stability. Ligand B (74.312) has high clearance, suggesting rapid metabolism and potentially low bioavailability.

**In vitro Half-Life:** Ligand A (-13.768) has a very long half-life, consistent with its low clearance. Ligand B (66.497) has a reasonable half-life, but not as good as A.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable. Ligand B (0.37) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's poor logP, Caco-2 permeability, and solubility, its *significantly* stronger binding affinity, excellent metabolic stability (low Cl_mic and long t1/2), very low hERG risk, and low DILI risk make it the more promising candidate. The affinity difference is large enough to potentially overcome the solubility/permeability issues through formulation strategies. Ligand B, while having better permeability and BBB, suffers from higher DILI risk, higher clearance, and a weaker binding affinity.

Output:
0
2025-04-17 16:31:12,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**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 (408.344 Da) is still acceptable.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand B (67.07) is lower than Ligand A (75.29), potentially indicating better absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.407) and Ligand B (3.025) are both acceptable.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (Ligand A: 4, Ligand B: 6), falling within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.668, B: 0.691), indicating drug-like properties.

**DILI:** Ligand A (72.586) has a higher DILI risk than Ligand B (37.728). This is a significant concern, as a lower DILI score is preferred.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (67.584) is slightly higher than Ligand B (53.974).

**Caco-2 Permeability:** Ligand A (-4.399) has a worse Caco-2 permeability than Ligand B (-5.337), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.863) has worse aqueous solubility than Ligand B (-2.456), which could hinder formulation and bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (A: 0.614, B: 0.646), which is good.

**Microsomal Clearance:** Ligand B (26.555 mL/min/kg) has significantly lower microsomal clearance than Ligand A (40.931 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (40.944 hours) has a much longer in vitro half-life than Ligand A (-21.143 hours), which is a major advantage for dosing frequency.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (A: 0.156, B: 0.289).

**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 still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and slightly better binding affinity. While Ligand A has a slightly lower MW and a marginally better BBB score (which is less important here), the advantages of Ligand B in terms of safety (DILI) and pharmacokinetics (Cl_mic, t1/2, solubility) outweigh these minor differences.

Output:
1
2025-04-17 16:31:12,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.423 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.21) is slightly above the preferred <140 for good absorption, while Ligand B (95.58) is well within the range.

**logP:** Ligand A (-1.503) is a bit low, potentially hindering permeation. Ligand B (0.193) is closer to the optimal 1-3 range.

**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 (0.488 and 0.671), indicating moderate drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (19.698) has a significantly lower DILI risk than Ligand B (27.104), which is a strong advantage.

**BBB:** Ligand A (16.557) has poor BBB penetration, while Ligand B (69.756) is reasonably good. However, BBB is less critical for a kinase inhibitor unless CNS activity is desired.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.448 and -5.449). This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.332 and -2.257). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.102 and 0.045), which is excellent.

**Microsomal Clearance:** Ligand A (-32.834) has a much lower (better) microsomal clearance than Ligand B (3.92), indicating greater metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-11.445) has a longer half-life than Ligand B (-1.835), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.003 and 0.016).

**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 difference of >1.5kcal/mol is usually decisive, 0.8kcal/mol is not enough to overcome the ADME deficiencies of Ligand B.

**Conclusion:**

Despite Ligand B's slightly better affinity and BBB penetration, Ligand A is the more promising candidate. Its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme inhibitor. While both have poor solubility and Caco-2 permeability, these issues might be addressed through formulation strategies. The lower DILI and better metabolic profile of Ligand A outweigh the small affinity difference.

Output:
0
2025-04-17 16:31:12,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.467 and 344.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.2) is better than Ligand B (87.46), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Ligand A (-1.181) is slightly low, potentially hindering permeability. Ligand B (0.423) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.624) has a better QED score than Ligand B (0.476), indicating a more drug-like profile.

**DILI:** Ligand A (15.122) has a significantly lower DILI risk than Ligand B (31.136), a crucial advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (47.654) is lower than Ligand B (35.052).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.089 and -4.721), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.588 and -2.149), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.121) shows a much lower hERG inhibition liability than Ligand B (0.078), a critical safety advantage.

**Microsomal Clearance:** Ligand A (5.806) has a lower microsomal clearance than Ligand B (20.228), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.467) has a much longer in vitro half-life than Ligand B (-16.871), which is highly desirable.

**P-gp Efflux:** Ligand A (0.001) has a lower P-gp efflux liability than Ligand B (0.03), potentially improving bioavailability.

**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.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the superior candidate. It exhibits significantly better ADMET properties: lower DILI risk, lower hERG inhibition, lower microsomal clearance (better metabolic stability), longer half-life, and lower P-gp efflux. While both have poor solubility and permeability, the ADMET advantages of Ligand A outweigh the minor affinity difference. The lower DILI and hERG risks are particularly important for kinase inhibitors, which often face safety concerns.

Output:
0
2025-04-17 16:31:12,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.507 and 359.461 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is higher than Ligand B (58.22). While both are reasonably low, Ligand B is better positioned for good absorption.

**logP:** Ligand A (1.279) is within the optimal range, while Ligand B (3.709) is approaching the upper limit. This could potentially lead to solubility issues for 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.

**QED:** Both ligands have good QED scores (0.546 and 0.693), indicating drug-like properties.

**DILI:** Ligand A (5.584) has a significantly lower DILI risk than Ligand B (27.685). This is a major advantage for Ligand A.

**BBB:** Ligand A (67.197) and Ligand B (82.009) both have acceptable BBB penetration, but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.975) has a worse Caco-2 permeability value than Ligand B (-4.723).

**Aqueous Solubility:** Ligand A (-1.395) has a better aqueous solubility than Ligand B (-2.908).

**hERG Inhibition:** Ligand A (0.394) has a lower hERG inhibition liability than Ligand B (0.781), which is preferable.

**Microsomal Clearance:** Ligand A (15.877) has a lower microsomal clearance than Ligand B (73.627), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-24.534) has a much longer in vitro half-life than Ligand B (-9.853). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.009) has a lower P-gp efflux liability than Ligand B (0.272).

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.5). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG inhibition, lower P-gp efflux, slightly better binding affinity, and better aqueous solubility. While Ligand B has a slightly better TPSA and Caco-2 permeability, the ADME-Tox profile of Ligand A is far superior, making it the more viable drug candidate.

Output:
0
2025-04-17 16:31:12,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.463 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (99.1 and 96.78) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (0.146) is quite low, potentially hindering permeation. Ligand B (0.803) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (6) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.484 and 0.629), indicating moderate drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (11.361) has a very low DILI risk, which is excellent. Ligand B (50.368) is higher, but still within an acceptable range (below 60).

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values (-4.842 and -5.39), which is unusual and suggests poor permeability. This is a significant concern.

**Solubility:** Both ligands have negative solubility values (-1.52 and -1.555), also unusual and suggesting poor aqueous solubility. This is a significant concern.

**hERG:** Both ligands have very low hERG inhibition risk (0.183 and 0.087), which is excellent.

**Microsomal Clearance:** Ligand A (39.627) has a higher Cl_mic than Ligand B (21.722). This suggests Ligand B is more metabolically stable, which is a priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (25.044 hours) has a significantly longer half-life than Ligand A (0.765 hours). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.08 and 0.018), which is good.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). However, the difference (0.5 kcal/mol) is not large enough to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand A has better binding affinity and lower DILI risk, but suffers from very low logP, poor Caco-2 permeability, poor solubility, and a very short half-life. Ligand B has a slightly weaker binding affinity but exhibits better metabolic stability (lower Cl_mic), a longer half-life, and comparable DILI and hERG profiles. The poor permeability and solubility of both compounds are concerning, but the superior metabolic stability and half-life of Ligand B make it the more promising candidate. Further optimization would focus on improving the solubility and permeability of Ligand B.

Output:
1
2025-04-17 16:31:12,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.5) is slightly higher than Ligand B (345.5), but both are acceptable.

**TPSA:** Ligand A (76.7) is higher than Ligand B (56.1). Both are below the 140 threshold for oral absorption, but lower is generally better. Ligand B has a more favorable TPSA.

**logP:** Ligand A (2.12) is within the optimal range (1-3). Ligand B (3.86) is pushing the upper limit, potentially raising concerns about solubility and off-target effects.

**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 (A: 0.737, B: 0.825), indicating drug-like properties.

**DILI:** Ligand A (46.1) has a higher DILI risk than Ligand B (18.1). This is a significant advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (87.1) has higher BBB penetration than Ligand A (59.5), but it's not a primary concern here.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. However, the values are on a scale and are therefore difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor solubility.

**hERG Inhibition:** Ligand A (0.444) has a lower hERG risk than Ligand B (0.96), which is a positive attribute.

**Microsomal Clearance:** Ligand A (27.4) has a significantly lower Cl_mic than Ligand B (57.9). This suggests better metabolic stability for Ligand A, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (29.2) has a longer half-life than Ligand B (2.8). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.116) has lower P-gp efflux than Ligand B (0.42), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.2). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 1.8 kcal/mol is quite significant.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux, the substantially stronger binding affinity of Ligand B (-9.0 vs -7.2 kcal/mol) is the most important factor for an enzyme target like SRC kinase. The difference in binding affinity is large enough to compensate for the slightly higher DILI risk and worse metabolic stability.

Output:
1
2025-04-17 16:31:12,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.419 Da and 357.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.84 and 90.9) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.419) is optimal, while Ligand B (0.515) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable, being less than 10.

**QED:** Both ligands have similar QED values (0.612 and 0.53), indicating good drug-likeness.

**DILI:** Ligand A (55.603) has a moderate DILI risk, while Ligand B (4.731) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (57.852) has a moderate BBB penetration, while Ligand B (25.475) has low BBB penetration. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.186 and -5.29), which is unusual and indicates poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.471) and Ligand B (0.182) both have poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.276) has a low hERG risk, while Ligand B (0.082) has an even lower hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (23.184 mL/min/kg) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (-18.221 mL/min/kg) has a *negative* clearance, which is impossible and likely indicates an error in the data or a very high stability.

**In vitro Half-Life:** Ligand A (13.149 hours) has a reasonable half-life, while Ligand B (5.37 hours) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.08 and 0.006), which is favorable.

**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.

**Conclusion:**

Despite the negative Caco-2 values for both, Ligand B is the more promising candidate. Its significantly higher binding affinity (-9.4 kcal/mol vs 0.0 kcal/mol) is a crucial advantage for an enzyme inhibitor. Furthermore, it has a much lower DILI risk and hERG inhibition liability. The negative microsomal clearance is suspect and should be investigated, but even if it's an error, the other advantages of Ligand B make it the better choice.

Output:
1
2025-04-17 16:31:12,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (424.276 Da) is slightly higher than Ligand B (344.415 Da), but both are acceptable.

**TPSA:** Ligand A (93.34) is better than Ligand B (100.19) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (2.771) is optimal, while Ligand B (0.476) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have similar and good QED values (A: 0.633, B: 0.653).

**DILI:** Ligand A (87.204) has a significantly higher DILI risk than Ligand B (35.867). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (65.413) is better than Ligand B (49.787).

**Caco-2 Permeability:** Ligand A (-4.95) is better than Ligand B (-5.06), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.319) is worse than Ligand B (-1.821), which is a concern.

**hERG:** Ligand A (0.394) has a slightly higher hERG risk than Ligand B (0.039), but both are relatively low.

**Microsomal Clearance:** Ligand A (47.059) has a higher clearance than Ligand B (1.62), meaning Ligand B is more metabolically stable. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (72.505) has a longer half-life than Ligand B (7.994), which is favorable.

**P-gp Efflux:** Ligand A (0.481) has lower P-gp efflux than Ligand B (0.005), which is favorable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life and lower P-gp efflux, its significantly higher DILI risk, lower binding affinity, and lower logP are major drawbacks. Ligand B's superior binding affinity, much lower DILI risk, and better metabolic stability outweigh the slightly shorter half-life and higher P-gp efflux. The higher binding affinity of Ligand B is also likely to compensate for any permeability issues arising from the lower logP.

Output:
1
2025-04-17 16:31:12,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 Da and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.32) is higher than Ligand B (60.85). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.266) is quite low, potentially hindering permeability. Ligand B (2.515) 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 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.655 and 0.894), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both have acceptable DILI risk (38.503 and 33.656), below the 40 threshold. Ligand B is marginally better.

**BBB:** Both have moderate BBB penetration (50.795 and 62.117). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.792) has very poor predicted Caco-2 permeability, while Ligand B (-5.138) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor predicted solubility (-2.003 and -3.472). This is a concern for both, but Ligand B is better.

**hERG Inhibition:** Ligand A (0.036) has very low hERG risk, which is excellent. Ligand B (0.312) is also quite low, but slightly higher.

**Microsomal Clearance:** Ligand A (57.194) has higher microsomal clearance than Ligand B (45.222), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-11.193) has a significantly longer predicted half-life than Ligand A (-7.967), which is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.015 and 0.114).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). Although the difference is small, it is still a positive for Ligand B.

**Overall:**

Ligand B consistently outperforms Ligand A in key ADME properties (logP, solubility, metabolic stability, half-life, Caco-2 permeability) and has a slightly better binding affinity. While Ligand A has a slightly better hERG profile, the overall profile of Ligand B is more favorable for development as an SRC kinase inhibitor. The poor logP and Caco-2 permeability of Ligand A are significant drawbacks.

Output:
1
2025-04-17 16:31:12,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.442 and 358.473 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is better than Ligand B (41.57), both are below the 140 threshold for good absorption.

**logP:** Both ligands have similar logP values (4.117 and 4.049), slightly above the optimal 1-3 range, but not drastically so. This could potentially lead to some off-target effects, but is not a major concern at this stage.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.597 and 0.729), indicating good drug-like properties.

**DILI:** Ligand A (24.855) has a significantly lower DILI risk than Ligand B (7.057), which is a major advantage. Lower DILI is crucial for drug development.

**BBB:** Both ligands have high BBB penetration (87.67 and 91.702), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.641 and -4.39), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.377 and -3.017), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.752) has a slightly higher hERG risk than Ligand B (0.932), but both are relatively low.

**Microsomal Clearance:** Ligand A (69.112) has a higher microsomal clearance than Ligand B (23.387). This indicates that Ligand B is more metabolically stable, which is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (14.239 hours) has a significantly longer half-life than Ligand A (2.353 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.721) has lower P-gp efflux than Ligand B (0.315), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity. While both have poor solubility and permeability, the metabolic stability and safety profile of Ligand B outweigh the small advantage of Ligand A in P-gp efflux. The difference in binding affinity is not substantial enough to favor Ligand A given the other factors.

Output:
1
2025-04-17 16:31:12,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) inhibitor targeting oncology.

**1. Molecular Weight:** Both ligands (348.531 and 353.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is well below the 140 threshold, indicating good absorption potential. Ligand B (107.53) is still acceptable but higher, potentially impacting absorption slightly.

**3. logP:** Ligand A (3.556) is within the optimal range (1-3). Ligand B (0.463) is quite low, which could hinder membrane permeability and bioavailability.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (4) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (4) is acceptable.

**6. QED:** Both ligands have reasonable QED scores (0.779 and 0.533), indicating drug-like properties. Ligand A is better.

**7. DILI:** Both ligands have low DILI risk (12.175 and 13.804), which is positive.

**8. BBB:** This is less critical for an oncology target unless CNS penetration is specifically desired. Ligand A (88.445) has a better BBB score than Ligand B (56.572).

**9. Caco-2 Permeability:** Ligand A (-4.483) is better than Ligand B (-5.539) indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.707) is better than Ligand B (-1.143), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.608 and 0.066), which is excellent.

**12. Microsomal Clearance:** Ligand A (87.607) has a higher clearance, suggesting lower metabolic stability, which is a concern. Ligand B (-10.984) has a negative clearance, which is excellent and indicates high metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.88) has a longer half-life than Ligand A (-8.015).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.168 and 0.007).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity and low hERG risk, Ligand B is significantly better regarding metabolic stability (Cl_mic and t1/2) and has a more favorable solubility profile. Ligand A has better TPSA and Caco-2 permeability, but the lower logP and higher clearance of Ligand A are concerning. For an enzyme target, metabolic stability is crucial. The improved metabolic stability and solubility of Ligand B outweigh the slightly higher TPSA and lower logP.

Output:
1
2025-04-17 16:31:12,590 - INFO - Batch 470 complete. Total preferences: 7520
2025-04-17 16:31:12,590 - INFO - Processing batch 471/512...
2025-04-17 16:31:52,786 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.61) is slightly above the preferred <140 for good absorption, but still reasonable. Ligand B (52.65) is excellent, well below 140.

**logP:** Ligand A (1.169) is within the optimal 1-3 range. Ligand B (2.328) is also good, falling within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.651 and 0.739, respectively), indicating good drug-like properties.

**DILI:** Ligand A (54.168) has a slightly higher DILI risk than Ligand B (19.698), but both are below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (72.586 and 70.609), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.011) has poor Caco-2 permeability. Ligand B (-4.46) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.125 and -2.838, respectively). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.504 and 0.492, respectively).

**Microsomal Clearance:** Ligand A (15.557) has significantly lower microsomal clearance than Ligand B (28.86), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.582) has a much longer in vitro half-life than Ligand B (35.711). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.057 and 0.027, respectively).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). The difference of 1.3 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand B has better TPSA and a slightly better QED, Ligand A is the stronger candidate. The significantly better metabolic stability (lower Cl_mic, longer t1/2) and substantially higher binding affinity of Ligand A are crucial for an enzyme target like SRC. The solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation. The slightly higher DILI risk for Ligand A is acceptable given its superior potency and metabolic profile.

Output:
1
2025-04-17 16:31:52,786 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.559 Da and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (101.22) is still under 140, but less optimal than A.

**logP:** Both ligands have good logP values (2.767 and 1.364), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.705 and 0.814), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (33.501 and 60.605). Ligand A is preferable here.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (74.37) has a higher BBB score than Ligand A (54.052), but this isn't a major deciding factor.

**Caco-2 Permeability:** Ligand A (-4.953) shows poor permeability, while Ligand B (-4.78) is slightly better. Both are negative, which is unusual and suggests a potential issue with the scale used.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.582 and -2.047). This is a significant concern.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.56 and 0.258), which is good.

**Microsomal Clearance:** Ligand A (60.421) has higher clearance than Ligand B (56.445), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (-21.792) has a significantly longer half-life than Ligand A (59.068). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.221 and 0.053).

**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 a substantial advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While both compounds have issues with solubility, Ligand B is the stronger candidate. Its significantly improved binding affinity (-8.8 vs -7.2 kcal/mol) and longer in vitro half-life outweigh the slightly higher DILI risk and lower TPSA. The Caco-2 permeability is similar for both, and both have acceptable hERG risk.

Output:
1
2025-04-17 16:31:52,786 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (383.704 and 358.408 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.01) is higher than Ligand B (47.09). While both are acceptable, Ligand B is better positioned for oral absorption given the <140 target.

**3. logP:** Ligand A (3.835) is slightly lower than Ligand B (4.484). Both are within the optimal 1-3 range, but Ligand B is approaching the upper limit where solubility issues could arise.

**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 3 HBA, Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.609 and 0.663), indicating good drug-likeness.

**7. DILI:** Ligand A (66.15) has a higher DILI risk than Ligand B (24.738). This is a significant concern for Ligand A.

**8. BBB:** Ligand A (65.529) has a lower BBB penetration than Ligand B (89.066). Since SRC is not a CNS target, this is less critical, but higher BBB is generally favorable.

**9. Caco-2 Permeability:** Ligand A (-4.932) has slightly better Caco-2 permeability than Ligand B (-4.755).

**10. Aqueous Solubility:** Ligand A (-4.575) has slightly better aqueous solubility than Ligand B (-4.424).

**11. hERG Inhibition:** Ligand A (0.566) has a lower hERG inhibition risk than Ligand B (0.94). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (24.841) has a significantly lower microsomal clearance than Ligand B (39.07). This suggests better metabolic stability for Ligand A, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-7.354) has a much longer in vitro half-life than Ligand B (19.085). This is a substantial advantage for Ligand A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.386) has lower P-gp efflux than Ligand B (0.681), indicating better bioavailability.

**15. Binding Affinity:** Ligand B (-8.3) has a slightly stronger binding affinity than Ligand A (-8.1). While a 1.5 kcal/mol difference is notable, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile, particularly regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. The slightly weaker binding affinity of Ligand A (-8.1 kcal/mol) is outweighed by its significantly improved drug-like properties. Ligand B, while having slightly better affinity, has a concerningly high DILI risk and poorer metabolic stability.

Output:
0
2025-04-17 16:31:52,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.32 and 80.56) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.34) is slightly low, potentially hindering permeation. Ligand B (0.676) is better, falling within the 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being less than 10.

**QED:** Both ligands have good QED scores (0.706 and 0.723), indicating drug-like properties.

**DILI:** Ligand A (10.508) has a significantly lower DILI risk than Ligand B (42.575), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.364) has a higher BBB score than Ligand A (35.13), but this isn't a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.866 and -4.939), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.344 and -0.931), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.16 and 0.08), which is excellent.

**Microsomal Clearance:** Ligand A (12.12 mL/min/kg) has a much lower microsomal clearance than Ligand B (41.12 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.416 hours) has a shorter half-life than Ligand B (-4.548 hours - this is unusual and likely an error in the data, but we'll proceed assuming it's a longer half-life).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.075), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), but the difference is not substantial (0.3 kcal/mol).

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly lower DILI risk and much better metabolic stability (lower Cl_mic). While both have poor predicted permeability and solubility, the lower DILI and better metabolic profile of Ligand A outweigh the small difference in binding affinity. The negative Caco-2 and solubility values for both are red flags that would need to be addressed through further optimization, but Ligand A is a better starting point.

Output:
0
2025-04-17 16:31:52,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (387.502 Da) is still well within acceptable limits.

**TPSA:** Ligand B (73.74) is significantly better than Ligand A (118.97). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand B (1.832) is optimal, falling within the 1-3 range. Ligand A (-0.692) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 5 HBA) is slightly better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability. However, both are within reasonable limits.

**QED:** Ligand B (0.754) has a better QED score than Ligand A (0.387), indicating a more drug-like profile.

**DILI:** Ligand A (17.449) has a much lower DILI risk than Ligand B (61.264). This is a significant advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.595) has a worse Caco-2 permeability than Ligand B (-4.574), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor solubility (-1.249 and -1.995 respectively).

**hERG Inhibition:** Ligand A (0.034) has a very low hERG risk, while Ligand B (0.294) is slightly higher.

**Microsomal Clearance:** Ligand A (8.875) has significantly lower microsomal clearance than Ligand B (23.029), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.535) has a much longer in vitro half-life than Ligand B (-0.365), indicating slower metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Both ligands have comparable binding affinity (-7.0 and -7.1 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has a better logP and TPSA, Ligand A excels in critical areas like metabolic stability (lower Cl_mic, longer t1/2), DILI risk, and hERG inhibition. The comparable binding affinity makes these differences decisive. The lower solubility of both is a concern, but can be addressed with formulation strategies.

Output:
0
2025-04-17 16:31:52,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (347.459 and 383.901 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.64) is better than Ligand B (82.53), both are below the 140 A^2 threshold for good absorption.

**3. logP:** Both ligands (1.795 and 1.923) 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 (3) is better than Ligand B (5), both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.853 and 0.813), indicating good drug-likeness.

**7. DILI:** Ligand A (32.261) has a significantly lower DILI risk than Ligand B (51.338). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have low BBB penetration (29.508 and 33.656). This isn't critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.86 and -4.924). 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 (-2.105 and -3.415). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.521) has a slightly higher hERG risk than Ligand B (0.159). This is a concern, but not a dealbreaker.

**12. Microsomal Clearance:** Ligand A (20.316) has a higher microsomal clearance than Ligand B (-1.814). This means Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (40.18) has a significantly longer in vitro half-life than Ligand A (-10.335). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.171 and 0.125).

**15. Binding Affinity:** Ligand B (-9.5 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 has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). While its DILI risk is higher, the substantial affinity advantage is likely to be more important for an enzyme target like SRC. The negative solubility and Caco-2 values are concerning for both, but the strong binding of Ligand B might compensate for these issues. Ligand A's lower DILI is attractive, but the weaker binding affinity is a significant drawback.

Output:
1
2025-04-17 16:31:52,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.531 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold and favorable for oral absorption. Ligand B (70.47) is still within acceptable limits but less optimal.

**logP:** Ligand A (3.556) is within the optimal 1-3 range. Ligand B (0.957) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is excellent. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly higher counts could potentially affect permeability.

**QED:** Both ligands have similar and good QED values (0.779 and 0.778).

**DILI:** Ligand A (12.175) has a much lower DILI risk than Ligand B (36.681), which is a significant advantage.

**BBB:** Ligand A (88.445) shows good BBB penetration, while Ligand B (62.544) is lower.  This isn't a primary concern for a non-CNS target like SRC, but it's a positive for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.483 and -4.807), which is unusual and suggests poor permeability *in vitro*. This is a concern for both, but the values are close.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.707 and -1.044), which is also unusual and suggests poor solubility. Ligand B is slightly better here.

**hERG Inhibition:** Ligand A (0.608) has a lower hERG risk than Ligand B (0.345), which is a positive.

**Microsomal Clearance:** Ligand A (87.607) has significantly higher microsomal clearance than Ligand B (27.37), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-8.015) has a very short in vitro half-life, while Ligand B (3.935) is better, though still not ideal.

**P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux than Ligand B (0.027), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.5 kcal/mol), with Ligand B being slightly better. The difference is small, but could be relevant.

**Overall Assessment:**

Ligand A has advantages in DILI risk, BBB penetration, hERG, and P-gp efflux. However, its major weaknesses are its high microsomal clearance and very short half-life, which are critical for an enzyme inhibitor. Ligand B, while having a slightly lower affinity and higher DILI risk, demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2). Given the enzyme-specific priorities, metabolic stability is paramount.

Output:
1
2025-04-17 16:31:52,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.571 Da) is slightly higher than Ligand B (346.471 Da), but both are acceptable.

**TPSA:** Ligand A (66.4) is better than Ligand B (78.43). Lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (A: 2.575, B: 2.169), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 3 HBA). Fewer H-bonds can improve permeability.

**QED:** Both ligands have similar QED values (A: 0.723, B: 0.708), indicating good drug-likeness.

**DILI:** Ligand A (38.736) has a higher DILI risk than Ligand B (20.008), which is a significant drawback.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.107) has a better BBB percentile than Ligand B (30.438).

**Caco-2 Permeability:** Ligand A (-5.292) has a worse Caco-2 permeability than Ligand B (-4.742).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.287 and -2.437 respectively).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.377, B: 0.258), which is good.

**Microsomal Clearance:** Ligand A (63.43) has a significantly higher microsomal clearance than Ligand B (27.126), indicating lower metabolic stability. This is a major concern for an enzyme target.

**In vitro Half-Life:** Ligand B (4.097) has a better in vitro half-life than Ligand A (-6.055).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.224, B: 0.098).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a substantially better binding affinity than Ligand A (-6.7 kcal/mol). This difference of 1.5 kcal/mol is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having slightly better TPSA and BBB, Ligand B is the superior candidate. The significantly stronger binding affinity (-8.2 vs -6.7 kcal/mol) is crucial for an enzyme inhibitor. Furthermore, Ligand B exhibits lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and comparable or better values for other key ADME properties. While both have poor solubility, the potency advantage of Ligand B is likely to be more impactful in driving overall efficacy.

Output:
1
2025-04-17 16:31:52,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.384 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.99) is slightly higher than Ligand B (49.85). Both are below the 140 A^2 threshold for good oral absorption, but B is better.

**logP:** Both ligands (2.634 and 2.831) 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 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**QED:** Ligand A (0.899) has a higher QED than Ligand B (0.766), indicating a more drug-like profile.

**DILI:** Ligand A (70.027) has a higher DILI risk than Ligand B (13.3). This is a significant concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (84.141 and 89.531), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.585 and -4.226), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.57 and -2.404), indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.3) has a slightly lower hERG risk than Ligand B (0.482), which is preferable.

**Microsomal Clearance:** Ligand B (67.885) has a lower microsomal clearance than Ligand A (45.718), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (0.313) has a slightly longer in vitro half-life than Ligand A (-0.528), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.113).

**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 for Ligand A, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its significantly higher DILI risk is a major drawback. The lower metabolic stability and solubility of both compounds are concerns, but Ligand B's better profile in these areas, combined with the much lower DILI risk, makes it the more promising candidate. The substantial affinity difference is tempting, but the safety profile is paramount.

Output:
1
2025-04-17 16:31:52,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.475 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is slightly higher than Ligand B (40.62), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (2.0) is within the optimal range, while Ligand B (3.342) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.819 and 0.806), indicating good drug-likeness.

**DILI:** Ligand A (30.826) has a lower DILI risk than Ligand B (24.234), which is preferable.

**BBB:** Both ligands have good BBB penetration (74.176 and 86.351), but this is less critical for a non-CNS target like SRC.

**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:** Ligand A (0.202) has a lower hERG risk than Ligand B (0.749), which is a significant advantage.

**Microsomal Clearance:** Ligand A (40.563) has lower microsomal clearance than Ligand B (66.937), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.153) has a longer half-life than Ligand B (0.354), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.631), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a 0.7 kcal/mol difference, which is substantial.

**Conclusion:**

While Ligand B has a better binding affinity, Ligand A demonstrates a significantly more favorable ADMET profile. It has lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The solubility and permeability values are concerning for both, but the other advantages of Ligand A outweigh the slightly weaker binding. Given the enzyme-kinase focus, metabolic stability and safety (hERG, DILI) are crucial.

Output:
0
2025-04-17 16:31:52,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, while Ligand B (384.498 Da) is still well within the range.

**TPSA:** Ligand A (113.86) is better than Ligand B (69.64), both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 1.451, B: 1.727), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 9 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar and good QED values (A: 0.547, B: 0.555), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (97.906), which is a significant concern. Ligand B has a much lower and acceptable DILI risk (34.277).

**BBB:** Both ligands have reasonable BBB penetration (A: 68.282, B: 70.027), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.831 and -4.917). This is unusual and suggests poor permeability, but the scale is not defined.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.433 and -2.573). Again, the scale is not defined, but suggests poor solubility.

**hERG Inhibition:** Ligand A has a low hERG risk (0.335), which is good. Ligand B has a slightly higher, but still acceptable, hERG risk (0.734).

**Microsomal Clearance:** Ligand A has a moderate Cl_mic (66.964), while Ligand B has a very low and favorable Cl_mic (-0.244). This suggests Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A has a negative half-life (-22.172), which is problematic. Ligand B has a negative half-life as well (-3.997), but less negative than Ligand A.

**P-gp Efflux:** Ligand A has a very low P-gp efflux (0.074), which is good. Ligand B has a slightly higher P-gp efflux (0.266).

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.4 kcal/mol) compared to Ligand A (-7.7 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite some issues with solubility and permeability for both, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.4 vs -7.7 kcal/mol) and much lower DILI risk (34.277 vs 97.906) outweigh the slightly higher hERG and P-gp efflux. The improved metabolic stability (lower Cl_mic) is also a major advantage for an enzyme target. The negative half-life values for both are concerning and require further investigation, but the difference is less pronounced for Ligand B.

Output:
1
2025-04-17 16:31:52,787 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (341.415 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (72.28 and 71.78) below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.049) is optimal, while Ligand B (3.244) is slightly higher but still acceptable.

**4. H-Bond Donors:** Both have 1 HBD, well within the limit of 5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both below the limit of 10.

**6. QED:** Ligand A (0.924) has a superior QED score compared to Ligand B (0.801), indicating a more drug-like profile.

**7. DILI:** Ligand A (52.772) has a slightly higher DILI risk than Ligand B (45.25), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have similar BBB penetration (79.566 and 78.209), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.459 and -4.942). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily disqualify a molecule.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.644 and -3.195). Similar to Caco-2, these are log scale values and indicate poor solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.209 and 0.381), which is excellent.

**12. Microsomal Clearance:** Ligand B (17.941 mL/min/kg) has significantly lower microsomal clearance than Ligand A (38.521 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (17.53 hours) has a much longer in vitro half-life than Ligand A (-11.399 hours). The negative value for ligand A is concerning and suggests rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.124).

**15. 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 and can outweigh some ADME drawbacks.

**Conclusion:**

While both ligands have issues with solubility and permeability, Ligand B is the superior candidate. Its significantly stronger binding affinity (-8.1 vs -7.2 kcal/mol), lower microsomal clearance, and longer half-life outweigh the slightly higher DILI risk and similar solubility/permeability issues. The improved metabolic stability and potency are critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:31:52,788 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.208 Da) is slightly higher, but acceptable. Ligand B (346.515 Da) is also good.

**TPSA:** Ligand A (113.92) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (40.62) is excellent, suggesting good absorption.

**logP:** Both ligands have good logP values (A: 3.07, B: 3.929), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility issues, but not critically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which is reasonable. Ligand B has 0 HBD and 2 HBA, which is also good.

**QED:** Both ligands have acceptable QED values (A: 0.322, B: 0.518). Ligand B is better here, indicating a more drug-like profile.

**DILI:** Ligand A has a DILI risk of 86.002, which is high and concerning. Ligand B has a much lower DILI risk of 17.41, which is excellent. This is a major advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (A: 68.554, B: 79.256). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 a very poor solubility.

**hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (A: 0.647, B: 0.733), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (80.395) than Ligand B (63.321), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B has a negative half-life (-3.644), which is impossible and indicates a data error. Ligand A has a half-life of 6.34 hours, which is reasonable.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.432, B: 0.738).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.9 kcal/mol, B: -8.4 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.5 kcal/mol) is unlikely to outweigh other significant drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, the significantly higher DILI risk and higher microsomal clearance make it a less desirable candidate. Ligand B has a much better safety profile (lower DILI) and better metabolic stability, despite the questionable Caco-2 and solubility data. The negative half-life for Ligand B is a data error that needs to be investigated, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 16:31:52,788 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**
*   **MW:** 356.419 Da - Good, within the ideal range.
*   **TPSA:** 96.38 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** -0.358 - Low, potentially hindering permeation.
*   **HBD:** 1 - Good.
*   **HBA:** 6 - Good.
*   **QED:** 0.546 - Good, drug-like.
*   **DILI:** 30.322 - Excellent, very low risk.
*   **BBB:** 37.96 - Low, not a concern for a non-CNS target.
*   **Caco-2:** -4.512 - Very poor permeability.
*   **Solubility:** -1.087 - Very poor solubility.
*   **hERG:** 0.086 - Excellent, very low risk.
*   **Cl_mic:** 24.893 - Moderate, acceptable.
*   **t1/2:** -33.327 - Very short half-life, a significant drawback.
*   **Pgp:** 0.029 - Low efflux, good.
*   **Affinity:** -7.7 kcal/mol - Excellent, strong binding.

**Ligand B:**
*   **MW:** 383.558 Da - Good, within the ideal range.
*   **TPSA:** 38.13 - Excellent, very favorable for absorption.
*   **logP:** 3.833 - High, potentially causing solubility issues but acceptable.
*   **HBD:** 0 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.64 - Good, drug-like.
*   **DILI:** 41.373 - Acceptable, moderate risk.
*   **BBB:** 96.743 - High, not a concern for a non-CNS target.
*   **Caco-2:** -4.575 - Very poor permeability.
*   **Solubility:** -4.417 - Very poor solubility.
*   **hERG:** 0.716 - Acceptable, moderate risk.
*   **Cl_mic:** 105.905 - High, indicating poor metabolic stability.
*   **t1/2:** 16.511 - Moderate half-life.
*   **Pgp:** 0.848 - Moderate efflux.
*   **Affinity:** -7.8 kcal/mol - Excellent, slightly better binding than Ligand A.

**Comparison and Decision:**

Both ligands have excellent binding affinity. However, Ligand A suffers from very poor solubility and permeability, and a very short half-life. Ligand B also has poor solubility and permeability, but has a better half-life and acceptable DILI and hERG risks. While Ligand B has a higher logP and higher microsomal clearance, the significantly improved half-life and acceptable safety profiles make it the more promising candidate. The poor solubility and permeability of both compounds would need to be addressed through formulation or further structural modifications, but Ligand B provides a better starting point.

Output:
1
2025-04-17 16:31:52,788 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.343 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.32) is slightly above the optimal <140 for good oral absorption, but acceptable. Ligand B (49.85) is excellent, well below 140.

**logP:** Ligand A (0.128) is quite low, potentially hindering permeability. Ligand B (2.894) is 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 (6) is acceptable. Ligand B (3) is also good.

**QED:** Both ligands (0.706 and 0.768) have good drug-likeness scores.

**DILI:** Ligand A (85.653) has a high DILI risk. Ligand B (26.095) has a very low DILI risk, a significant advantage.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.734) has very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.405) is also poor, but slightly better than A.

**Solubility:** Both ligands have very poor aqueous solubility (-2.978 and -2.434). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG:** Both ligands have very low hERG inhibition risk (0.052 and 0.266). This is excellent.

**Microsomal Clearance:** Ligand A (-21.523) has a very low (good) microsomal clearance, indicating good metabolic stability. Ligand B (47.903) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (29.641) has a reasonable half-life. Ligand B (10.864) has a shorter half-life.

**P-gp:** Both ligands have very low P-gp efflux (0.019 and 0.324).

**Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.1), but the difference is not huge.

**Overall Assessment:**

Ligand B is significantly better. While both have solubility issues, Ligand B excels in crucial areas: it has a much lower DILI risk, a better logP, and a better binding affinity. The biggest drawback for Ligand A is its high DILI risk and poor Caco-2 permeability. Ligand B's metabolic stability is a concern, but the superior safety profile and slightly improved potency make it the more promising candidate.

Output:
1
2025-04-17 16:31:52,789 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (386.455 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.38) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (91.02) is well within the acceptable range.

**logP:** Ligand A (0.754) is a bit low, potentially hindering permeation. Ligand B (2.291) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.753 and 0.781), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (97.867), which is a significant concern. Ligand B has a much lower DILI risk (34.393), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (48.895) than Ligand A (39.473), but this isn't a deciding factor.

**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. This is a concern for bioavailability.

**hERG:** Ligand A has a very low hERG risk (0.054), which is excellent. Ligand B has a slightly higher hERG risk (0.44), but still relatively low.

**Microsomal Clearance:** Ligand A has a low Cl_mic (1.039 mL/min/kg), indicating good metabolic stability. Ligand B has a significantly higher Cl_mic (49.327 mL/min/kg), suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A has a shorter half-life (25.88 hours) than Ligand B (26.762 hours), but both are acceptable.

**P-gp Efflux:** Ligand A has low P-gp efflux (0.105), which is favorable. Ligand B has very low P-gp efflux (0.033), which is even better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.6 kcal/mol). The difference of 0.2 kcal/mol is unlikely to outweigh other factors.

**Conclusion:**

Despite having slightly better logP and P-gp efflux, Ligand B is significantly better due to its much lower DILI risk and better metabolic stability (lower Cl_mic). While both have poor solubility and Caco-2 permeability, the DILI risk associated with Ligand A is a major red flag. The similar binding affinities make the ADME properties the determining factor.

Output:
1
2025-04-17 16:31:52,789 - INFO - Batch 471 complete. Total preferences: 7536
2025-04-17 16:31:52,789 - INFO - Processing batch 472/512...
2025-04-17 16:32:33,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.463 and 386.583 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (66.48) as it is closer to the 90 A^2 threshold for CNS targets, though SRC is not a CNS target. Both are well within acceptable limits for oral absorption (<140).

**logP:** Ligand A (0.552) is a bit low, potentially hindering permeability. Ligand B (3.264) is 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.

**QED:** Both ligands have good QED scores (0.726 and 0.782), indicating drug-likeness.

**DILI:** Ligand A (29.469) has a significantly lower DILI risk than Ligand B (35.983), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand A (27.259) has a lower BBB penetration than Ligand B (70.182). This is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.832 and -4.987). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close, so the difference is less significant.

**Aqueous Solubility:** Ligand A (-1.29) has slightly better solubility than Ligand B (-3.933), which is important for bioavailability.

**hERG Inhibition:** Ligand A (0.205) has a much lower hERG risk than Ligand B (0.824). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (24.35) has significantly lower microsomal clearance than Ligand B (48.594), indicating better metabolic stability. This is crucial for maintaining therapeutic concentrations.

**In vitro Half-Life:** Ligand A (-2.743) has a shorter half-life than Ligand B (-21.345). This is a disadvantage, but can potentially be overcome with formulation strategies.

**P-gp Efflux:** Ligand A (0.023) has much lower P-gp efflux than Ligand B (0.421), suggesting better oral bioavailability.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While it has a slightly lower logP and shorter half-life, its significantly lower DILI risk, hERG inhibition, microsomal clearance, and P-gp efflux, coupled with better solubility, outweigh these minor drawbacks. The binding affinity is comparable between the two. For an enzyme target like SRC kinase, metabolic stability (low Cl_mic) and safety (low DILI and hERG) are paramount.

Output:
0
2025-04-17 16:32:33,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.479 and 361.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.25) is slightly above the preferred <90 for CNS penetration, but acceptable for a non-CNS target like SRC. Ligand B (53.51) is well within the ideal range.

**logP:** Both ligands (1.538 and 2.273) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, within the limit. Ligand B has 4 HBA, also within the limit.

**QED:** Both ligands have QED values (0.595 and 0.552) above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (27.491) has a lower DILI risk than Ligand B (36.099), both are good.

**BBB:** This is less critical for a non-CNS target. Ligand B (95.347) has a higher BBB penetration, but it's not a major factor here. Ligand A (50.679) is lower.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude suggests Ligand A (-5.2) might have slightly better permeability than Ligand B (-4.613).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-3.83) is slightly better than Ligand A (-1.958).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.173 and 0.368).

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (46.659 and 47.449 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (21.257 hours) has a significantly longer half-life than Ligand B (-18.924 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.075 and 0.063).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.3 kcal/mol), with Ligand B being slightly more potent. However, the difference is small (0.2 kcal/mol) and may not outweigh other factors.

**Conclusion:**

While Ligand B has slightly better potency and solubility, Ligand A is superior due to its significantly longer in vitro half-life and lower DILI risk. For an enzyme target like SRC kinase, metabolic stability and safety are crucial. The small potency difference is less important than these ADME/Tox properties.

Output:
1
2025-04-17 16:32:33,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.897 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (84.67). TPSA < 140 is good for oral absorption, both are within this range, but A is much preferred.

**logP:** Ligand A (4.981) is higher than ideal (1-3), potentially causing solubility issues. Ligand B (1.592) is within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10, but A is better.

**QED:** Both ligands have good QED scores (0.685 and 0.843), indicating drug-like properties.

**DILI:** Ligand A (39.667) and Ligand B (32.338) both have low DILI risk, below the 40 threshold. B is slightly better.

**BBB:** Both ligands have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (63.125) is better than A (40.403).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.938 and -4.949), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.199 and -2.151), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.795) has a slightly higher hERG risk than Ligand B (0.129). B is much preferred here.

**Microsomal Clearance:** Ligand A (94.692) has significantly higher microsomal clearance than Ligand B (27.723), indicating lower metabolic stability. B is much preferred.

**In vitro Half-Life:** Ligand A (41.022) has a longer half-life than Ligand B (11.861). A is preferred here.

**P-gp Efflux:** Ligand A (0.692) has lower P-gp efflux than Ligand B (0.045), which is favorable. A is preferred.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, a longer half-life, and lower P-gp efflux. However, it suffers from higher logP, higher TPSA, higher microsomal clearance, and a slightly higher hERG risk. Ligand B has better solubility, lower hERG, lower clearance, and better BBB, but its binding affinity is notably weaker.

Given the priority for potency in enzyme inhibition, the 1.5 kcal/mol advantage of Ligand A is crucial. While the ADME properties of A are less ideal, optimization strategies can be employed to address these issues (e.g., adding solubilizing groups, modifying the structure to reduce logP). The weaker binding of Ligand B makes it less likely to be a successful drug candidate, even with better ADME properties.

Output:
1
2025-04-17 16:32:33,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.358 Da) is slightly better positioned.

**TPSA:** Ligand A (64.43) is significantly better than Ligand B (109.32). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (1.623) is within the optimal range (1-3), while Ligand B (-0.171) is slightly below, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 7 HBA). Fewer hydrogen bonds are generally better for permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.85, B: 0.765), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 67.778, B: 66.731).

**BBB:** Ligand A (91.625) has a much higher BBB percentile than Ligand B (24.932). While SRC isn't a CNS target, higher BBB can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.161) is better than Ligand B (-5.257), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.246) is better than Ligand B (-2.432), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.606, B: 0.377), which is excellent.

**Microsomal Clearance:** Ligand A (18.438) has a significantly better (lower) microsomal clearance than Ligand B (-28.14). This suggests better metabolic stability for Ligand A, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-16.919) has a much longer in vitro half-life than Ligand B (10.138). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.102, B: 0.072).

**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 not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A demonstrates superior ADME properties (TPSA, logP, solubility, metabolic stability, half-life) and a comparable binding affinity to Ligand B. Given the enzyme-specific priorities, the improved metabolic stability and solubility of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 16:32:33,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (385.511 and 362.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand B (78.43) is significantly better than Ligand A (109.57). A TPSA under 140 is good for oral absorption, and B is comfortably within this range, while A is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (0.844 and 1.915), falling within the 1-3 range. Ligand B is slightly better.

**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:** Ligand A (0.783) has a better QED score than Ligand B (0.577), indicating a more drug-like profile overall.

**DILI:** Ligand B (18.651) has a much lower DILI risk than Ligand A (56.689). This is a significant advantage for Ligand B.

**BBB:** Ligand B (79.488) has a higher BBB penetration percentile than Ligand A (54.052), but BBB isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.583) and Ligand B (-4.916) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.3 and -2.527). This is a concern for both, but solubility can sometimes be improved through formulation.

**hERG Inhibition:** Ligand A (0.203) has a slightly lower hERG inhibition risk than Ligand B (0.336), which is preferable.

**Microsomal Clearance:** Ligand A (-5.483) has a much *lower* (better) microsomal clearance than Ligand B (24.424). This indicates greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-23.348) has a longer in vitro half-life than Ligand B (-8.933), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.081 and 0.076).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While Ligand A has a better QED, longer half-life, and lower hERG risk, Ligand B has a significantly lower DILI risk and better TPSA. The lower DILI risk and better TPSA of Ligand B are more critical for an enzyme inhibitor, especially considering the similar binding affinities. The metabolic stability of Ligand A is attractive, but the DILI risk is a major concern.

Output:
1
2025-04-17 16:32:33,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.5 and 348.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is significantly better than Ligand B (97.35).  A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit and could have absorption issues.

**logP:** Both ligands have acceptable logP values (3.115 and 0.89), falling within the 1-3 range, though B is on the lower side.

**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 good QED scores (0.845 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (27.6) has a much lower DILI risk than Ligand B (35.1). Both are below the 40 threshold, but A is significantly better.

**BBB:** Both ligands have similar BBB penetration (74.3% and 71.0%). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.085 and -5.226), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.52 and -1.674), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.803) has a slightly better hERG profile than Ligand B (0.117), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (51.58) has a higher microsomal clearance than Ligand B (10.67). This means Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-11.88) has a slightly longer half-life than Ligand A (-14.90), but both are negative, which is unusual and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.602) has lower P-gp efflux than Ligand B (0.044), which is favorable.

**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:**

Ligand A is better overall. Despite the unusual negative Caco-2 and solubility values for both, Ligand A has a significantly better DILI score, a slightly better hERG profile, and a better binding affinity. The improved metabolic stability of Ligand B is a plus, but the other factors favor Ligand A. The better TPSA and lower P-gp efflux of Ligand A are also beneficial. The slightly better binding affinity of A could outweigh the metabolic stability advantage of B.

Output:
1
2025-04-17 16:32:33,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (353.857 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (56.84) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (67.43) is still under 140, but less optimal than A.

**3. logP:** Both ligands have logP values within the optimal range (A: 3.927, B: 2.559).

**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 within the acceptable limit of 10.

**6. QED:** Ligand A (0.746) has a significantly better QED score than Ligand B (0.471), indicating a more drug-like profile.

**7. DILI:** Ligand A (71.074) has a higher DILI risk than Ligand B (22.373). This is a negative for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.392) has better BBB penetration than Ligand B (60.644), but this isn't a major factor here.

**9. Caco-2:** Ligand A (-4.892) and Ligand B (-5.128) both have negative Caco-2 values, indicating poor permeability. This is a significant concern for both.

**10. Solubility:** Ligand A (-4.437) and Ligand B (-2.659) both have negative solubility values, indicating poor solubility. Ligand B is better than A.

**11. hERG:** Ligand A (0.901) has a lower hERG risk than Ligand B (0.501), which is a positive for A.

**12. Cl_mic:** Ligand A (33.673) has a lower microsomal clearance than Ligand B (38.438), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-4.86) has a much shorter in vitro half-life than Ligand B (4.054). This is a significant negative for A.

**14. Pgp:** Ligand A (0.187) has lower P-gp efflux than Ligand B (0.307), which is favorable.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better QED, lower Cl_mic, and lower Pgp efflux. However, it suffers from a higher DILI risk, poor solubility, poor Caco-2 permeability, and a very short half-life. Ligand B has better solubility, lower DILI, and a longer half-life, but weaker binding affinity and a lower QED.

The substantial difference in binding affinity (-8.5 vs -6.6 kcal/mol) is a key factor. For an enzyme target like SRC kinase, potency is paramount. While the ADME properties of Ligand A are concerning, optimization efforts could potentially address these issues. The weaker binding of Ligand B might be harder to overcome through further modifications.

Output:
0
2025-04-17 16:32:33,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 349.391 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.44) is well below the 140 threshold for good oral absorption. Ligand B (122.28) is also below, but closer to the limit.

**logP:** Ligand A (0.697) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.271) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 7 HBA) is acceptable, but slightly higher, potentially impacting permeability.

**QED:** Both ligands have reasonable QED scores (0.714 and 0.559), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (54.052 and 57.154), both are acceptable.

**BBB:** Ligand A (47.344) has a better BBB percentile than Ligand B (29.003), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.149) has better Caco-2 permeability than Ligand B (-5.582).

**Aqueous Solubility:** Ligand A (-2.306) has better aqueous solubility than Ligand B (-1.282). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.107 and 0.248), which is excellent.

**Microsomal Clearance:** Ligand A (18.274) has significantly lower microsomal clearance than Ligand B (25.419), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.692) has a positive half-life, while Ligand B (-10.001) has a negative half-life, indicating poor stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.09), which is favorable.

**Binding Affinity:** Ligand A (-8.4 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:**

Ligand A is the superior candidate. It has a better binding affinity, better solubility, better permeability, and significantly better metabolic stability (lower Cl_mic and positive half-life) than Ligand B. While Ligand B has acceptable properties, Ligand A's stronger binding and improved ADME profile make it more likely to be a viable drug candidate for SRC kinase.

Output:
0
2025-04-17 16:32:33,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.418 and 340.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.34) is significantly better than Ligand B (97.12), being well below the 140 threshold for good oral absorption. Ligand B is approaching a level that could hinder absorption.

**logP:** Both ligands have acceptable logP values (3.43 and 2.688, respectively), falling within the 1-3 optimal range.

**H-Bond Donors & Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 5. Both are within the acceptable limit of <=10, but Ligand A is slightly preferred.

**QED:** Both ligands have good QED scores (0.707 and 0.872), indicating good drug-like properties.

**DILI:** Ligand A (46.995) has a lower DILI risk than Ligand B (60.721). While both are below the concerning 60 threshold, A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (86.623) has a higher BBB percentile than Ligand B (65.568).

**Caco-2 Permeability:** Ligand A (-4.476) shows better Caco-2 permeability than Ligand B (-5.079), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.175) has better aqueous solubility than Ligand B (-3.321). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.457) has a much lower hERG inhibition risk than Ligand B (0.099). This is a significant advantage for Ligand A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (68.999) has a higher microsomal clearance than Ligand B (2.215). This means Ligand B is much more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (26.851 hours) has a significantly longer half-life than Ligand A (33.55 hours). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.371) has lower P-gp efflux than Ligand B (0.104), indicating better bioavailability.

**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 of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a substantially better binding affinity and a significantly longer half-life, which are critical for an enzyme inhibitor. While Ligand A has advantages in TPSA, solubility, hERG, and P-gp efflux, the potency and metabolic stability of Ligand B are more important for SRC kinase inhibition. The slightly higher DILI risk of Ligand B is acceptable given its superior binding and half-life.

Output:
1
2025-04-17 16:32:33,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.841 and 362.817 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.76) is well below the 140 threshold, and even better, below 90, suggesting good absorption. Ligand B (82.61) is still under 140, but less optimal than A.

**logP:** Ligand A (3.556) is within the optimal range of 1-3. Ligand B (0.225) is significantly lower, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (1 HBD, 4 HBA) is acceptable, but slightly less favorable.

**QED:** Both ligands have reasonable QED values (0.841 and 0.616), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (47.964 and 50.136), below the 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.572) shows better potential for BBB penetration than Ligand B (47.383).

**Caco-2 Permeability:** Ligand A (-4.439) is better than Ligand B (-5.347), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.376) is better than Ligand B (-2.364), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.569) has a lower hERG risk than Ligand B (0.082), which is a significant advantage.

**Microsomal Clearance:** Ligand A (30.282) has higher metabolic stability (lower clearance) than Ligand B (-2.069).

**In vitro Half-Life:** Ligand A (47.851) has a longer half-life than Ligand B (-13.561), which is desirable.

**P-gp Efflux:** Ligand A (0.454) has lower P-gp efflux than Ligand B (0.018), which is favorable.

**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 drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has a superior ADME profile across almost all parameters. However, Ligand B's binding affinity is significantly stronger (-10.1 vs -8.6 kcal/mol). Given that we are targeting an enzyme (kinase), potency is paramount. The 1.5 kcal/mol difference is substantial and could translate to a much more effective drug, even if it means accepting some compromises in ADME. While Ligand B's logP is low and its clearance is high, these issues might be addressable through further optimization without sacrificing its strong binding.

Output:
1
2025-04-17 16:32:33,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.369 Da and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.22) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is significantly better, increasing the chance of good oral absorption.

**logP:** Ligand A (2.553) and Ligand B (3.539) are both 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 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:** Both ligands have similar QED values (0.74 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 59.984, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 13.843, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.435) is slightly higher than Ligand B (76.464).

**Caco-2 Permeability:** Both have negative values (-4.292 and -4.774), which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability. Ligand B is slightly worse here.

**Aqueous Solubility:** Both have negative values (-2.557 and -3.504), again, assuming these are percentile scores, indicating poor solubility. Ligand B is worse here.

**hERG Inhibition:** Ligand A (0.568) has a slightly higher hERG inhibition liability than Ligand B (0.315), but both are reasonably low risk.

**Microsomal Clearance:** Ligand A (89.099) has a higher microsomal clearance than Ligand B (52.904), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-8.986) has a significantly longer in vitro half-life than Ligand A (6.289). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.391) has lower P-gp efflux than Ligand B (0.264), which is favorable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is not large enough to overcome the ADME issues.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B excels in crucial ADME properties: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The lower TPSA of Ligand B is also beneficial. The slightly worse Caco-2 and solubility are less concerning than the higher DILI and lower metabolic stability of Ligand A.

Output:
1
2025-04-17 16:32:33,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.386 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.48) is well below the 140 threshold, suggesting good absorption. Ligand B (100.35) is still within acceptable limits but less optimal.

**logP:** Ligand A (3.601) is at the higher end of the optimal range (1-3), potentially leading to some solubility issues. Ligand B (0.574) is quite low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.685 and 0.713), indicating drug-like properties.

**DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (33.889), which is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (77.2) has a higher percentile than Ligand B (30.942).

**Caco-2 Permeability:** Ligand A (-4.409) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.275) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.203) has poor solubility, consistent with its higher logP. Ligand B (-1.195) shows slightly better solubility.

**hERG:** Ligand A (0.921) has a relatively low hERG risk, which is good. Ligand B (0.07) has a very low hERG risk, even better.

**Microsomal Clearance:** Ligand A (75.62) has a higher microsomal clearance, indicating faster metabolism and lower stability. Ligand B (-14.684) has a negative clearance, suggesting excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (28.621) has a moderate half-life. Ligand B (5.383) has a very short half-life.

**P-gp Efflux:** Ligand A (0.564) has moderate P-gp efflux. Ligand B (0.017) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

Despite Ligand A's slightly better TPSA and BBB penetration, Ligand B is the more promising candidate. The primary drivers are its significantly lower DILI risk and *much* better metabolic stability (negative Cl_mic). While Ligand B has lower solubility and permeability, these can be addressed through formulation strategies. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 16:32:33,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.491 and 363.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is higher than Ligand B (56.07). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands (1.875 and 2.238) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are within the acceptable range (<=10), but Ligand A is slightly better.

**QED:** Ligand A (0.698) has a better QED score than Ligand B (0.495), indicating better overall drug-likeness.

**DILI:** Ligand A (17.953) has a significantly lower DILI risk than Ligand B (15.51). Both are good, but A is preferable.

**BBB:** Ligand A (64.482) has a lower BBB penetration than Ligand B (83.831). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.828) has worse Caco-2 permeability than Ligand B (-5.135). Both are poor, but B is slightly better.

**Aqueous Solubility:** Ligand A (-2.117) has better aqueous solubility than Ligand B (-3.143). Solubility is important for bioavailability, making A more favorable.

**hERG Inhibition:** Ligand A (0.3) has a lower hERG inhibition liability than Ligand B (0.511), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (42.445) has a higher microsomal clearance than Ligand B (31.272), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (6.148) has a shorter half-life than Ligand B (-10.675). This further supports the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.292), which is favorable for bioavailability.

**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 superior despite the slightly lower QED and Caco-2 permeability. The key advantages of Ligand B are its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. While Ligand A has better solubility and lower hERG risk, the metabolic instability is a major concern for an enzyme target like SRC kinase. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 16:32:33,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.833 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (104.11 and 107.78) are slightly above the optimal <140 for oral absorption, but not drastically so.

**logP:** Ligand A (1.928) is within the optimal 1-3 range. Ligand B (-0.454) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 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:** Both ligands have acceptable QED scores (0.708 and 0.655), indicating good drug-likeness.

**DILI:** Ligand A (70.182) has a higher DILI risk than Ligand B (31.989). This is a significant concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (64.676) and Ligand B (50.523) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.384 and -5.241) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.851 and -0.405), indicating very poor aqueous solubility.

**hERG:** Ligand A (0.719) has a slightly higher hERG risk than Ligand B (0.114), but both are relatively low.

**Microsomal Clearance:** Ligand A (-7.139) has significantly lower (better) microsomal clearance than Ligand B (33.488), suggesting much better metabolic stability.

**In vitro Half-Life:** Ligand A (1.628 hours) has a shorter half-life than Ligand B (-22.34 hours). The negative value for Ligand B is suspect and likely an error, but even assuming it's a very long half-life, the metabolic stability indicated by Cl_mic is more important.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.005).

**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 substantial and could outweigh some ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic) and stronger binding affinity are crucial for an enzyme target like SRC. While Ligand A has a higher DILI risk, this can potentially be mitigated through structural modifications during lead optimization. The poor solubility and permeability are serious drawbacks that would need to be addressed, but the superior potency and metabolic stability of Ligand A make it the better starting point.

Output:
1
2025-04-17 16:32:33,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (393.227 and 354.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.57) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (81.51) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.32 and 2.33), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 6 HBA) both satisfy the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.392 and 0.697), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (64.909) has a higher DILI risk than Ligand B (37.456), which is a significant concern.

**BBB:** Both have similar BBB penetration (70.841 and 65.025). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.301 and -4.918). This 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 (-3.002 and -3.156). This is a major drawback.

**hERG Inhibition:** Ligand A (0.486) has a lower hERG risk than Ligand B (0.826), which is favorable.

**Microsomal Clearance:** Ligand A (-10.775) has significantly lower (better) microsomal clearance than Ligand B (24.725), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.639) has a shorter half-life than Ligand B (34.516), which is less desirable.

**P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux than Ligand B (0.266), which is better.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly 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.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the superior candidate due to its substantially higher binding affinity (-8.4 vs 0 kcal/mol). The lower DILI risk is also a benefit. While Ligand A has better metabolic stability and lower hERG risk, the difference in binding affinity is too large to ignore. The poor solubility and permeability would need to be addressed through formulation strategies, but a potent starting point is crucial.

Output:
1
2025-04-17 16:32:33,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.535 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.01) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (58.44) is still under 140, but less favorable than A.

**logP:** Ligand A (3.913) is at the higher end of the optimal 1-3 range, while Ligand B (2.006) is closer to the lower end. While both are acceptable, a logP too low can hinder permeation.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.75 and 0.769), indicating good drug-likeness.

**DILI:** Ligand A (4.343) has a significantly lower DILI risk than Ligand B (46.646). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (93.408) has a higher BBB percentile than Ligand B (69.639).

**Caco-2 Permeability:** Ligand A (-4.358) has a lower Caco-2 permeability than Ligand B (-4.684), which is less desirable.

**Aqueous Solubility:** Ligand A (-2.542) has slightly better aqueous solubility than Ligand B (-2.093).

**hERG:** Ligand A (0.91) has a slightly higher hERG risk than Ligand B (0.309). This is a slight negative for Ligand A.

**Microsomal Clearance:** Ligand A (38.65) has a lower microsomal clearance than Ligand B (41.011), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.742) has a significantly longer in vitro half-life than Ligand B (3.152). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.279) has lower P-gp efflux than Ligand B (0.212).

**Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (0.0). This is a significant advantage for Ligand A.

**Overall:**

Ligand A is the stronger candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and superior binding affinity. While Ligand B has slightly better Caco-2 permeability and lower hERG risk, the advantages of Ligand A in the critical areas of safety (DILI) and efficacy (affinity, stability) outweigh these minor drawbacks. The slightly higher logP of Ligand A is acceptable given its other favorable properties.

Output:
1
2025-04-17 16:32:33,614 - INFO - Batch 472 complete. Total preferences: 7552
2025-04-17 16:32:33,614 - INFO - Processing batch 473/512...
2025-04-17 16:33:17,410 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.511 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (75.19), both are acceptable but A is preferable.

**logP:** Both ligands have good logP values (3.308 and 2.641), within the optimal 1-3 range.

**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 4 H-bond acceptors, well within the limit of <=10.

**QED:** Both ligands have acceptable QED scores (0.743 and 0.609), indicating good drug-likeness.

**DILI:** Ligand A (38.852) has a lower DILI risk than Ligand B (41.877), making it slightly preferable. Both are below the 40 threshold and considered good.

**BBB:** Both ligands have acceptable BBB penetration (68.67 and 70.88). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.638) is significantly worse than Ligand B (-5.08). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.125) is significantly worse than Ligand B (-2.149). Higher values are better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.463 and 0.342), which is excellent.

**Microsomal Clearance:** Ligand B (37.09) has a significantly lower microsomal clearance than Ligand A (77.172), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-13.804) has a much longer in vitro half-life than Ligand A (20.643). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.145 and 0.154).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). However, the difference is small, and other factors are more important.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial ADME properties: significantly lower microsomal clearance, longer half-life, better solubility, and better Caco-2 permeability. These factors are critical for a kinase inhibitor to achieve adequate exposure and efficacy. The small difference in binding affinity is outweighed by the superior ADME profile of Ligand B.

Output:
1
2025-04-17 16:33:17,410 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.391 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.88) is better than Ligand B (49.41), being under the 140 threshold, but both are acceptable.

**logP:** Ligand A (0.468) is quite low, potentially hindering permeability. Ligand B (3.521) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.611 and 0.8), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 64.056, which is moderately high. Ligand B has a much lower DILI risk of 19.93, a substantial advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (84.141) is better than Ligand A (70.88). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.964) has poor Caco-2 permeability, while Ligand B (-4.867) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.579) has poor solubility, while Ligand B (-4.046) is even worse. This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.19) has a low hERG risk, which is excellent. Ligand B (0.575) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (10.476) has lower clearance than Ligand B (55.501), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-17.268) has a very long half-life, which is excellent. Ligand B (23.018) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.107).

**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.

**Overall Assessment:**

Ligand A has a better binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. However, its logP is very low, and Caco-2 permeability is poor, which could hinder absorption. Ligand B has a better logP, but suffers from a higher DILI risk, worse metabolic stability, and a much lower binding affinity.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the stronger binding affinity and better metabolic stability of Ligand A outweigh its permeability concerns, particularly given the relatively low hERG risk. While solubility is a concern for both, the difference isn't drastic enough to dismiss Ligand A.

Output:
0
2025-04-17 16:33:17,410 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.487 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (84.42) is still acceptable but less favorable.

**logP:** Ligand A (3.911) is at the higher end of the optimal range (1-3), while Ligand B (2.02) is closer to the lower end. Both are acceptable, but A's higher logP could potentially lead to off-target effects, though this is less of a concern than solubility or metabolic issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, well within the limits. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.673 and 0.759), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (39.589 and 42.962), below the 60 threshold.

**BBB:** Ligand A (69.446) has a moderate BBB penetration, while Ligand B (57.852) is lower. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.506 and -4.851), which is unusual and indicates very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.256 and -2.463), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG risk (0.83 and 0.33), which is excellent.

**Microsomal Clearance:** Ligand A (87.009) has higher microsomal clearance than Ligand B (18.501). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (31.797 hours) has a significantly longer half-life than Ligand A (17.757 hours). This is a substantial advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.354 and 0.277), which is favorable.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While the difference is small, it's enough to potentially outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both compounds having significant solubility and permeability issues, Ligand B is the more promising candidate. It has better metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and a lower P-gp efflux liability. The solubility and permeability issues would need to be addressed through formulation strategies or further chemical modification, but the improved pharmacokinetic profile of Ligand B makes it a better starting point.

Output:
1
2025-04-17 16:33:17,410 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.454 Da and 363.414 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for good absorption, while Ligand B (91.32) is still acceptable but closer to the limit.

**logP:** Both ligands have logP values within the optimal 1-3 range (1.531 and 2.369 respectively).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=5) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.635 and 0.628), indicating good drug-likeness.

**DILI:** Ligand A (10.469) has a significantly lower DILI risk than Ligand B (62.505). This is a major advantage for Ligand A.

**BBB:**  BBB is less critical for a non-CNS target like SRC. Ligand A (95.308) has a much higher BBB penetration than Ligand B (39.007).

**Caco-2 Permeability:** Ligand A (-4.467) has a worse Caco-2 permeability than Ligand B (-5.344).

**Aqueous Solubility:** Ligand A (-1.805) has better aqueous solubility than Ligand B (-3.321). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.655) has a slightly higher hERG risk than Ligand B (0.445), but both are reasonably low.

**Microsomal Clearance:** Ligand A (29.483) has a significantly lower microsomal clearance than Ligand B (50.11), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.225) has a much longer in vitro half-life than Ligand B (-18.002). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux liability than Ligand B (0.178), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.8 kcal/mol). This difference of 1.4 kcal/mol is very significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux for Ligand A, it is the more promising drug candidate. While Ligand B has slightly better Caco-2 permeability, the other advantages of Ligand A are more critical for an enzyme target like SRC.

Output:
1
2025-04-17 16:33:17,410 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (442.575 Da) is slightly higher, but acceptable. Ligand B (346.515 Da) is also good.

**TPSA:** Ligand A (87.26) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (49.41) is excellent.

**logP:** Both ligands have good logP values (A: 4.127, B: 3.676), falling within the optimal range of 1-3. Ligand A is slightly higher, potentially increasing off-target interactions, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (1 HBD, 2 HBA) is also good. Both are well within the recommended limits.

**QED:** Both ligands have reasonable QED values (A: 0.395, B: 0.772). Ligand B's QED is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A has a high DILI risk (90.074), which is a major concern. Ligand B has a very low DILI risk (19.969), a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 70.803, B: 81.388). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.753 and -4.72), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.761 and -4.175). This is a major formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.45, B: 0.299). This is positive.

**Microsomal Clearance:** Ligand A (81.194) has higher microsomal clearance than Ligand B (54.863), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a negative half-life (-19.271), which is not physically possible and indicates a problem with the data or the compound itself. Ligand A has a reasonable half-life (59.768).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.48, B: 0.199).

**Binding Affinity:** Ligand A has a significantly better binding affinity (-8.2 kcal/mol) than Ligand B (-7.4 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, which is the most critical factor for an enzyme inhibitor. However, its high DILI risk and higher microsomal clearance are significant drawbacks. Ligand B has a better drug-like profile (higher QED, lower DILI, lower Cl_mic), but its binding affinity is weaker, and the negative half-life is a major red flag. The negative Caco-2 and solubility for both are concerning, but potentially addressable through formulation strategies. Given the substantial affinity difference, and assuming the negative half-life for B is an error, Ligand A is the more promising candidate, *provided* the DILI risk can be mitigated through structural modifications.

Output:
0
2025-04-17 16:33:17,410 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.334 Da and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (98.98 and 94.47) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (1.857 and 1.272) within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (2 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.437 and 0.839), with Ligand B being significantly better.

**DILI:** Both ligands have acceptable DILI risk (52.966 and 48.623), both being <60.

**BBB:** Ligand A has a higher BBB penetration percentile (87.088) than Ligand B (57.154). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.567 and -4.792), which is unusual and problematic, suggesting poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.439 and -2.974), which is also a major concern. Poor solubility will hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.77 and 0.533), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (54.908 mL/min/kg) than Ligand B (-22.954 mL/min/kg). A negative value for Ligand B suggests very high metabolic stability, which is highly desirable.

**In vitro Half-Life:** Ligand A has a negative half-life (-0.679 hours), which is not possible and indicates a problem with the data or the molecule. Ligand B has a reasonable half-life (39.523 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.22 and 0.01), which is good.

**Binding Affinity:** Ligand A has a slightly better binding affinity (-8.2 kcal/mol) than Ligand B (-7.8 kcal/mol). This 0.4 kcal/mol difference is not huge, but could be significant.

**Overall Assessment:**

Ligand A has a slightly better binding affinity, but suffers from a nonsensical negative half-life and higher metabolic clearance. Both ligands have poor solubility and permeability. Ligand B has a much better QED score, significantly better metabolic stability (negative Cl_mic), and a reasonable half-life. While the affinity is slightly lower, the improved ADME properties, especially the metabolic stability, make Ligand B the more promising candidate. The poor solubility and permeability are concerning for both, but could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 16:33:17,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (114.33) is better than Ligand B (67.6). Both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (A: 2.124, B: 2.751), 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 (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (A: 0.636, B: 0.854), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (82.319) has a higher DILI risk than Ligand B (42.536). This is a significant drawback for Ligand A.

**BBB:** Ligand A (55.913) has lower BBB penetration than Ligand B (77.821). While not a primary concern for a non-CNS target like SRC, higher BBB is generally preferable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.616 and -4.861). These values 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 (-4.445 and -3.66). Similar to Caco-2, these are unusual and suggest poor solubility.

**hERG:** Both ligands have similar, low hERG risk (A: 0.337, B: 0.352).

**Microsomal Clearance:** Ligand B (23.775 mL/min/kg) has a lower microsomal clearance than Ligand A (32.547 mL/min/kg), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (46.023 hours) has a significantly longer half-life than Ligand A (12.856 hours). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (A: 0.106, B: 0.218).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.1 kcal/mol and -7.0 kcal/mol). The difference is minimal.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both ligands have good potency and acceptable physicochemical properties, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. The slightly higher QED and BBB penetration are additional benefits. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand B outweighs these concerns.

Output:
1
2025-04-17 16:33:17,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (379.869 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is slightly above the preferred <140, but acceptable. Ligand B (40.62) is excellent, well below 140.

**3. logP:** Both ligands (3.613 and 3.676) 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 (6) and Ligand B (2) are both acceptable, below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.567 and 0.757), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (83.598) has a concerningly high DILI risk (above 60). Ligand B (15.51) has a very low DILI risk, which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (80.031) is higher, but not a deciding factor.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, both are very poor.

**10. Solubility:** Both have negative values, indicating poor solubility. Ligand B (-2.893) is slightly better than Ligand A (-4.538).

**11. hERG:** Both ligands have low hERG risk (0.525 and 0.616).

**12. Cl_mic:** Ligand A (31.589) has a lower microsomal clearance than Ligand B (59.174), indicating better metabolic stability.

**13. t1/2:** Ligand B (14.743) has a longer in vitro half-life than Ligand A (9.538).

**14. Pgp:** Both ligands have low Pgp efflux liability (0.488 and 0.26).

**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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has a significantly better binding affinity, its high DILI risk is a major concern. The DILI risk for Ligand A is substantially higher than the preferred threshold of <40. Ligand B has a much better safety profile (low DILI) and a good half-life, but its affinity is weaker. Given the importance of safety in drug development, and the fact that the affinity difference is significant but potentially bridgeable with further optimization, I would prioritize Ligand B as the more viable starting point. The weaker affinity can be addressed through medicinal chemistry efforts, while mitigating a high DILI risk is often far more challenging.

Output:
1
2025-04-17 16:33:17,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.381 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (75.63), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (2.548) is optimal, while Ligand B (1.141) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Ligand A (3) is good, Ligand B (5) is acceptable.

**QED:** Both ligands have similar QED values (0.741 and 0.634), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (37.65 and 37.069 percentile).

**BBB:** Both ligands have high BBB penetration (82.745 and 83.055 percentile), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-5.139) is significantly worse than Ligand B (-4.368), indicating lower intestinal absorption.

**Solubility:** Ligand A (-3.338) is worse than Ligand B (-0.624), which is a significant drawback.

**hERG:** Ligand A (0.782) is better than Ligand B (0.162), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (30.193) is better than Ligand B (34.135), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.222) is much better than Ligand B (12.54), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.136) is better than Ligand B (0.022), suggesting less P-gp mediated efflux.

**Binding Affinity:** Ligand A (-10.0) is significantly better than Ligand B (-8.3), a difference of 1.7 kcal/mol, which is substantial and can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's lower Caco-2 permeability and solubility, its significantly superior binding affinity (-10.0 vs -8.3 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk make it the more promising candidate. The potency advantage is substantial enough to overcome the potential absorption issues.

Output:
1
2025-04-17 16:33:17,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.909 Da and 376.425 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.36) is significantly better than Ligand B (82.78).  A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**logP:** Both ligands have good logP values (2.536 and 2.086), 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 similar QED values (0.785 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A (22.838) has a much lower DILI risk than Ligand B (32.067). This is a significant advantage.

**BBB:** Ligand A (92.943) has a much higher BBB penetration percentile than Ligand B (59.093). While not a primary concern for a non-CNS target like SRC, it isn't detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.099 and -5.204). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.577 and -3.399), indicating poor aqueous solubility. This is a concern, but again, the difference is small.

**hERG Inhibition:** Ligand A (0.577) has a slightly higher hERG inhibition risk than Ligand B (0.464), but both are relatively low.

**Microsomal Clearance:** Ligand B (-1.435) has a *negative* microsomal clearance, which is highly unusual and suggests exceptional metabolic stability. Ligand A (11.407) has a moderate clearance. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (26.538) has a longer half-life than Ligand B (15.516).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.074).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive factor. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A's better DILI and BBB scores, and longer half-life, Ligand B's *significantly* stronger binding affinity (-8.5 vs 0.0 kcal/mol) and exceptional metabolic stability (negative Cl_mic) are overwhelming advantages for an enzyme target like SRC kinase. The slightly higher DILI and lower BBB are less critical in this context. The similar poor solubility and permeability are drawbacks for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:33:17,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**

*   **MW:** 377.348 Da - Good, within the ideal range.
*   **TPSA:** 98.14 - Good, below the 140 threshold for oral absorption.
*   **logP:** 2.053 - Optimal, within the 1-3 range.
*   **HBD:** 2 - Good, below the 5 threshold.
*   **HBA:** 7 - Good, below the 10 threshold.
*   **QED:** 0.751 - Excellent, well above the 0.5 threshold.
*   **DILI:** 85.072 - High risk, significantly above the 60 threshold. This is a major concern.
*   **BBB:** 70.686 - Acceptable, but not a primary concern for a non-CNS target.
*   **Caco-2:** -4.846 - Poor permeability, a significant negative.
*   **Solubility:** -3.986 - Poor solubility, a significant negative.
*   **hERG:** 0.205 - Low risk, excellent.
*   **Cl_mic:** 64.868 - Moderate clearance, not ideal but not terrible.
*   **t1/2:** 9.758 - Moderate half-life.
*   **Pgp:** 0.173 - Low efflux, good.
*   **Affinity:** -7.7 kcal/mol - Excellent, strong binding.

**Ligand B:**

*   **MW:** 402.51 Da - Good, within the ideal range.
*   **TPSA:** 109.85 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** -0.436 - Suboptimal, below 1, potentially hindering permeation.
*   **HBD:** 1 - Good, below the 5 threshold.
*   **HBA:** 6 - Good, below the 10 threshold.
*   **QED:** 0.496 - Marginal, slightly below the 0.5 threshold.
*   **DILI:** 43.66 - Good, below the 40 threshold, low risk.
*   **BBB:** 77.821 - Acceptable, but not a primary concern.
*   **Caco-2:** -5.266 - Very poor permeability, a major negative.
*   **Solubility:** -2.436 - Poor solubility, a significant negative.
*   **hERG:** 0.536 - Moderate risk, higher than Ligand A.
*   **Cl_mic:** 27.238 - Low clearance, excellent metabolic stability.
*   **t1/2:** -27.578 - Very long half-life, potentially advantageous.
*   **Pgp:** 0.029 - Very low efflux, excellent.
*   **Affinity:** -7.4 kcal/mol - Very good, strong binding, only slightly weaker than Ligand A.

**Comparison and Decision:**

Both ligands have significant drawbacks. Ligand A has a high DILI risk and poor Caco-2/Solubility, while Ligand B has a low logP, poor Caco-2/Solubility, and a marginal QED. However, Ligand B's significantly better metabolic stability (lower Cl_mic, very long t1/2) and lower DILI risk are crucial advantages for an enzyme target. While the binding affinity is slightly lower, the difference (0.3 kcal/mol) is unlikely to outweigh the ADME benefits of Ligand B. The poor permeability and solubility of both compounds would need to be addressed through formulation or further chemical modifications, but the lower toxicity and better metabolic profile of Ligand B make it the more promising starting point.

Output:
1
2025-04-17 16:33:17,411 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.443, 59.08, 1.557, 0., 4., 0.774, 24.544, 67.352, -4.595, -1.69, 0.319, 50.542, 5.707, 0.033, -8.4]
**Ligand B:** [343.387, 100.35, 0.655, 2., 6., 0.83, 40.946, 40.403, -5.474, -2.617, 0.07, -2.155, -12.517, 0.026, -7.1]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (348.443) and B (343.387) are comparable.
2. **TPSA:** A (59.08) is excellent, well below the 140 threshold for oral absorption. B (100.35) is still reasonable, but higher and potentially impacting absorption.
3. **logP:** A (1.557) is optimal. B (0.655) is a bit low, potentially hindering membrane permeability.
4. **HBD:** A (0) is good. B (2) is acceptable.
5. **HBA:** A (4) is good. B (6) is acceptable.
6. **QED:** Both are good, A (0.774) and B (0.83) are both > 0.5.
7. **DILI:** A (24.544) is very good, indicating low liver injury risk. B (40.946) is also acceptable, but higher.
8. **BBB:** A (67.352) is reasonable, while B (40.403) is lower. Not a primary concern for a non-CNS target like SRC.
9. **Caco-2:** A (-4.595) is better than B (-5.474), indicating better intestinal absorption.
10. **Solubility:** A (-1.69) is better than B (-2.617), indicating better aqueous solubility.
11. **hERG:** Both are very low (A: 0.319, B: 0.07), indicating minimal cardiotoxicity risk.
12. **Cl_mic:** A (50.542) is better than B (-2.155), suggesting better metabolic stability.  A positive value for B is concerning.
13. **t1/2:** A (5.707) is better than B (-12.517), indicating a longer half-life. A negative value for B is concerning.
14. **Pgp:** Both are very low (A: 0.033, B: 0.026), indicating minimal P-gp efflux.
15. **Affinity:** A (-8.4) is significantly better than B (-7.1), a difference of 1.3 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Considerations:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in all these areas. The 1.3 kcal/mol difference in binding affinity is significant enough to outweigh any minor drawbacks. Ligand B has concerning negative values for Cl_mic and t1/2, indicating potential for rapid metabolism and short duration of action.

**Conclusion:**

Ligand A is the more promising drug candidate.

1
2025-04-17 16:33:17,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.451 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is better than Ligand B (113.93). TPSA < 140 is good for oral absorption, and both are under this threshold, but A is closer to the preferred value.

**logP:** Both ligands have acceptable logP values (-0.251 and -0.834), falling within the 1-3 range. Ligand B is slightly better.

**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 range (<=10), but A is preferable.

**QED:** Both ligands have good QED scores (0.44 and 0.732), indicating drug-likeness. Ligand B is significantly better here.

**DILI:** Both have relatively low DILI risk (29.624 and 40.364), both below the 40 threshold, so this isn't a major differentiator.

**BBB:** Ligand A (42.264) has a lower BBB penetration percentile than Ligand B (78.054). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.506 and -5.142), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-1.392 and -1.602). This is a major drawback for both compounds.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.243 and 0.201), which is excellent.

**Microsomal Clearance:** Ligand A (-13.669) has a lower (better) microsomal clearance than Ligand B (-12.609), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.009) has a slightly longer half-life than Ligand B (-13.663). This is a positive for A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.001), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is slightly better overall. While both have poor solubility and Caco-2 permeability, Ligand A has a better TPSA, slightly better metabolic stability (lower Cl_mic), and a slightly longer half-life, and a slightly better binding affinity. The QED score is significantly better for Ligand B, but the slight advantage in potency and metabolic stability for A outweighs this. The poor solubility and permeability are significant issues for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 16:33:17,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.422 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (62.74), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (1.697 and 1.948), 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.

**QED:** Both ligands have good QED scores (0.674 and 0.823), indicating good drug-likeness.

**DILI:** Ligand A (36.642) has a significantly lower DILI risk than Ligand B (62.854). This is a major advantage for Ligand A.

**BBB:** Ligand A (91.392) has a much higher BBB penetration percentile than Ligand B (55.138). While SRC is not a CNS target, higher BBB generally correlates with better overall permeability.

**Caco-2 Permeability:** Ligand A (-4.377) has a more positive Caco-2 value than Ligand B (-4.756), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.431) has a more positive solubility value than Ligand B (-1.857), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.58 and 0.376).

**Microsomal Clearance:** Ligand A (17.269) has significantly lower microsomal clearance than Ligand B (42.724), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.514) has a more positive half-life than Ligand B (17.17), suggesting a longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.305 and 0.281).

**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 is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. These factors are more critical for an enzyme inhibitor like an SRC kinase inhibitor than a small difference in binding affinity.

Output:
1
2025-04-17 16:33:17,411 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A: [354.793, 85.18, 3.608, 2, 4, 0.544, 88.251, 64.87, -5.093, -5.706, 0.606, 36.518, 41.01, 0.248, -7.8]**
**Ligand B: [362.495, 69.64, 2.613, 2, 4, 0.865, 42.885, 67.584, -5.077, -2.503, 0.311, 15.889, 16.09, 0.18, -8.2]**

Here's a breakdown, property by property, with emphasis on enzyme/kinase priorities (potency, metabolic stability, solubility, hERG):

1. **MW:** Both are within the ideal range (200-500 Da). A: 354.793, B: 362.495.  No significant difference.
2. **TPSA:** A (85.18) is slightly higher than B (69.64).  Both are acceptable, but B is better for permeability.
3. **logP:** A (3.608) is good, slightly higher than B (2.613), which is also good. A is approaching the upper limit where solubility could become an issue.
4. **HBD:** Both have 2 HBD, which is ideal.
5. **HBA:** Both have 4 HBA, which is ideal.
6. **QED:** B (0.865) is significantly better than A (0.544), indicating a more drug-like profile.
7. **DILI:** A (88.251) has a much higher DILI risk than B (42.885). This is a major concern for A.
8. **BBB:** Both are reasonable, but B (67.584) is slightly better than A (64.87). Not a primary concern for a non-CNS target like SRC.
9. **Caco-2:** Both are very poor (-5.093 and -5.077). This suggests poor intestinal absorption for both.
10. **Solubility:** B (-2.503) is better than A (-5.706), indicating better aqueous solubility. This is important for bioavailability.
11. **hERG:** A (0.606) is higher than B (0.311), indicating a slightly higher risk of hERG inhibition.
12. **Cl_mic:** B (15.889) has significantly lower microsomal clearance than A (36.518), suggesting better metabolic stability. This is *very* important for an enzyme target.
13. **t1/2:** B (16.09) has a longer in vitro half-life than A (41.01). This is a positive for B.
14. **Pgp:** B (0.18) has lower P-gp efflux liability than A (0.248), which is favorable.
15. **Binding Affinity:** B (-8.2) has a stronger binding affinity than A (-7.8). While both are good, the 0.4 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have poor Caco-2 permeability, B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, better solubility, and stronger binding affinity. The QED score is also much higher for B. The slightly lower TPSA and better solubility are also beneficial. The difference in binding affinity, while not huge, is enough to tip the scales in B's favor, given the other improvements.

Output:
1
2025-04-17 16:33:17,412 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (370.361 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (72.36) and both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.848 and 1.712), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBD and 4 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have good QED scores (0.517 and 0.789), indicating a drug-like profile. Ligand B is slightly better.

**DILI:** Ligand A (46.84) has a slightly higher DILI risk than Ligand B (39.201), but both are below the concerning threshold of 60.

**BBB:** Ligand A (79.992) has a better BBB penetration percentile than Ligand B (69.794). While not a primary concern for a kinase inhibitor, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.828) has a worse Caco-2 permeability than Ligand B (-5.013). Lower values are worse.

**Aqueous Solubility:** Ligand A (-2.405) has a slightly better aqueous solubility than Ligand B (-2.517).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.398 and 0.34), which is excellent.

**Microsomal Clearance:** Ligand A (50.368) has lower microsomal clearance than Ligand B (53.761), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-11.986) has a significantly longer in vitro half-life than Ligand B (0.944). This is a major advantage, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.179 and 0.181).

**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 small (0.3 kcal/mol), it's within the range where it can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a slightly better binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. While Ligand B has a slightly better QED and Caco-2 permeability, the improvements in metabolic stability and binding affinity for Ligand A are more critical for a kinase inhibitor. The DILI risk is acceptable for both.

Output:
1
2025-04-17 16:33:17,412 - INFO - Batch 473 complete. Total preferences: 7568
2025-04-17 16:33:17,412 - INFO - Processing batch 474/512...
2025-04-17 16:33:59,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.475 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.36) is higher than Ligand B (49.85). While both are acceptable, Ligand B's lower TPSA is slightly preferable for permeability.

**logP:** Both ligands (2.163 and 2.486) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable, with Ligand B potentially having better permeability due to fewer HBDs.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.718 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (26.522) has a significantly lower DILI risk than Ligand B (40.287). This is a substantial advantage for Ligand A.

**BBB:** Both have good BBB penetration (70.803 and 76.541). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.516 and -4.573), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.295 and -3.144), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.276 and 0.273). This is excellent.

**Microsomal Clearance:** Ligand A (38.698) has a lower microsomal clearance than Ligand B (83.188), indicating better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (29.112) has a longer half-life than Ligand B (-3.801). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.459).

**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 noticeable but might not outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADMET properties, specifically lower DILI risk, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The poor solubility and permeability are concerns for both, but the metabolic stability and safety profile of Ligand A are more critical for an enzyme target like SRC.

Output:
0
2025-04-17 16:33:59,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.415 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.32) is slightly higher than Ligand B (70.39). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have good logP values (1.695 and 2.412), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.783) has a higher QED score than Ligand B (0.673), suggesting a more drug-like profile overall.

**DILI:** Ligand A (31.02) has a significantly lower DILI risk than Ligand B (13.532), which is a major advantage.

**BBB:** Both have similar BBB penetration (56.65 and 58.278), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Ligand A (-4.733) has worse Caco-2 permeability than Ligand B (-5.013), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.208) has slightly better solubility than Ligand B (-2.224).

**hERG:** Both ligands have very low hERG risk (0.296 and 0.258).

**Microsomal Clearance:** Ligand A (36.832) has lower microsomal clearance than Ligand B (44.641), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.918) has a much longer in vitro half-life than Ligand B (50.158), which is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.013 and 0.138).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a stronger binding affinity than Ligand B (-6.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering the priorities for kinase inhibitors, Ligand A is the better candidate. It has a significantly better DILI score, longer half-life, lower clearance, and a substantially stronger binding affinity. While Ligand B has slightly better TPSA and Caco-2 permeability, the advantages of Ligand A in potency, safety (DILI), and PK (half-life and clearance) are more critical for a successful kinase inhibitor.

Output:
1
2025-04-17 16:33:59,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (382.873 and 361.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.16) is slightly higher than the preferred <140, but acceptable. Ligand B (62.3) is well within the ideal range.

**logP:** Both ligands have good logP values (2.042 and 2.765), 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, <=10 HBA).

**QED:** Ligand A (0.766) has a better QED score than Ligand B (0.572), indicating a more drug-like profile.

**DILI:** Ligand A (64.288) has a higher DILI risk than Ligand B (41.411). This is a concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (67.08) has a higher BBB value than Ligand A (27.724), but this is not a major factor in this decision.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.579 and -5.044), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.286 and -2.885), which is also concerning and indicates poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.358 and 0.347), which is positive.

**Microsomal Clearance:** Ligand A (23.169) has a lower microsomal clearance than Ligand B (38.462), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (26.461) has a longer in vitro half-life than Ligand B (-11.487). The negative value for Ligand B is concerning. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.11) has slightly higher P-gp efflux liability than Ligand B (0.228), but both are relatively low.

**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. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the superior candidate. Its significantly stronger binding affinity (-9.7 vs 0.0 kcal/mol) is the most important factor. It also has better metabolic stability (lower Cl_mic, longer t1/2), a better QED score, and lower P-gp efflux. While the DILI risk is higher for Ligand A, the substantial improvement in potency and metabolic stability likely outweigh this concern, especially given that DILI risk can be further mitigated through structural modifications. The poor permeability/solubility would need to be addressed in subsequent optimization, but a strong starting point with high potency is crucial.

Output:
0
2025-04-17 16:33:59,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.531 Da) is slightly lower, which could be beneficial for permeability. Ligand B (406.288 Da) is still acceptable.

**TPSA:** Ligand A (72.7) is better than Ligand B (84.75). Both are below 140, suggesting reasonable absorption, but lower TPSA is generally preferred.

**logP:** Ligand A (4.074) is slightly higher than optimal (1-3), potentially leading to solubility issues or off-target effects. Ligand B (2.26) is within the optimal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and acceptable HBA counts (6 for A, 7 for B), satisfying the criteria.

**QED:** Ligand A (0.718) has a better QED score than Ligand B (0.587), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (65.917 for A, 64.521 for B), and are within an acceptable range (<60 is good, but these are not alarming).

**BBB:** Ligand A (55.68) has a better BBB percentile than Ligand B (41.45), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.091) has a worse Caco-2 permeability than Ligand B (-5.684), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.285) has a better aqueous solubility than Ligand B (-2.68), which is a positive attribute for bioavailability.

**hERG Inhibition:** Ligand A (0.308) has a lower hERG inhibition risk than Ligand B (0.504), which is a significant advantage.

**Microsomal Clearance:** Ligand B (38.728 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (74.233 mL/min/kg), indicating better metabolic stability. This is a crucial factor for an enzyme target.

**In vitro Half-Life:** Ligand B (10.56 hours) has a slightly longer half-life than Ligand A (11.806 hours).

**P-gp Efflux:** Ligand A (0.299) has a lower P-gp efflux liability than Ligand B (0.03), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.7 kcal/mol for A, -7.6 kcal/mol for B). The difference is negligible.

**Conclusion:**

While Ligand A has a better QED, solubility, and lower hERG risk and P-gp efflux, Ligand B excels in metabolic stability (lower Cl_mic) and has an acceptable logP. Given that SRC is an enzyme, metabolic stability is a critical factor. The slightly better solubility and lower hERG risk of Ligand A are outweighed by the significantly improved metabolic stability of Ligand B.

Output:
1
2025-04-17 16:33:59,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.848 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 (82.26) is a bit higher than Ligand B (71.33).

**logP:** Ligand A (4.596) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (0.531) is below the optimal range, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, fitting well within the guidelines. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.583, B: 0.733), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (88.639%), which is a significant concern. Ligand B has a much lower DILI risk (23.653%), a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.85) has a better BBB score than Ligand A (53.276), but it's not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.7 and -2.294 respectively). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A has a moderate hERG risk (0.555), while Ligand B has a very low risk (0.077). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B has a much lower microsomal clearance (9.648 mL/min/kg) than Ligand A (34.767 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a very long half-life (95.978 hours), which is good. Ligand B has a very short half-life (4.589 hours), which is a disadvantage.

**P-gp Efflux:** Ligand A has moderate P-gp efflux (0.22), while Ligand B has very low efflux (0.018). Lower efflux is better for bioavailability.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-8.7 kcal/mol) than Ligand B (-7.6 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a longer half-life, but suffers from high DILI risk, higher logP, and moderate P-gp efflux. Ligand B has a much better safety profile (lower DILI, hERG), better metabolic stability, and lower P-gp efflux, but its binding affinity is weaker and its half-life is short.

Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. The significantly lower DILI and hERG risk of Ligand B, combined with its better metabolic stability, make it a more promising starting point for optimization, despite the weaker binding affinity. The affinity can be improved through medicinal chemistry efforts, while mitigating DILI risk is often more challenging. The solubility issues are a concern for both, but can also be addressed during lead optimization.

Output:
1
2025-04-17 16:33:59,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.407 and 363.414 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (108.8) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (80.32) is excellent, well below 140.

**logP:** Ligand A (0.199) is quite low, potentially hindering permeability. Ligand B (2.161) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.804 and 0.769), indicating drug-like properties.

**DILI:** Ligand A (56.223) has a moderate DILI risk, while Ligand B (80.807) has a higher risk.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand B (83.094) has a higher BBB score, but it's not a deciding factor here.

**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. Again, the scale is unspecified.

**hERG:** Ligand A (0.084) has a very low hERG risk, which is excellent. Ligand B (0.577) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-6.978) has significantly lower (better) microsomal clearance, indicating higher metabolic stability. Ligand B (57.472) has much higher clearance.

**In vitro Half-Life:** Ligand A (-9.772) has a very long in vitro half-life, which is highly desirable. Ligand B (41.597) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.037) has very low P-gp efflux, which is favorable. Ligand B (0.263) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 1.7 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While both have issues with Caco-2 and solubility (scale unknown), Ligand A boasts significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly stronger binding affinity. The low hERG risk is also a major advantage. Ligand B has a higher DILI risk and poorer metabolic properties. The better logP of Ligand B is offset by its other weaknesses.

Output:
0
2025-04-17 16:33:59,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.475 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.25) is significantly better than Ligand B (104.21). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.527 and 1.532, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (3 HBD, 7 HBA). Lower HBD and HBA generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.822 and 0.699), indicating good drug-like properties.

**DILI:** Ligand A (32.571) has a much lower DILI risk than Ligand B (57.038). This is a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (83.831) has a higher BBB percentile than Ligand B (61.38).

**Caco-2 Permeability:** Ligand A (-4.916) has a much better Caco-2 permeability score than Ligand B (-5.463).

**Aqueous Solubility:** Ligand A (-2.735) has a better aqueous solubility score than Ligand B (-3.28).

**hERG Inhibition:** Ligand A (0.242) has a significantly lower hERG inhibition liability than Ligand B (0.594). This is a crucial advantage, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (28.712) has a significantly lower microsomal clearance than Ligand A (67.887), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (33.888) has a much longer in vitro half-life than Ligand A (-9.123). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.336) has a lower P-gp efflux liability than Ligand B (0.015).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, hERG inhibition, solubility, Caco-2 permeability, and P-gp efflux. While Ligand B has better metabolic stability and half-life, the significantly superior binding affinity of Ligand A, coupled with its much better safety profile (DILI, hERG), outweighs these advantages. The strong binding affinity suggests Ligand A is more likely to be potent and effective.

Output:
1
2025-04-17 16:33:59,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 346.431 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.88) is better than Ligand B (87.47). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred value for oral bioavailability.

**logP:** Ligand A (0.595) is slightly low, potentially hindering permeation. Ligand B (1.09) is better, falling 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 within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.762 and 0.805), indicating drug-likeness.

**DILI:** Ligand A (6.282) has a significantly lower DILI risk than Ligand B (34.277). This is a major advantage for Ligand A.

**BBB:** Ligand B (69.833) has a better BBB penetration percentile than Ligand A (33.85). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.096) has worse Caco-2 permeability than Ligand B (-4.925). Both are negative, which is unusual and suggests poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-0.953) has better aqueous solubility than Ligand B (-2.095). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.13) has a lower hERG inhibition liability than Ligand B (0.241), which is preferable.

**Microsomal Clearance:** Ligand A (-9.874) has *much* lower microsomal clearance than Ligand B (4.055). This indicates significantly better metabolic stability for Ligand A, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (14.784 hours) has a longer half-life than Ligand B (19.882 hours). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.013) has lower P-gp efflux liability than Ligand B (0.045), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While a 1.5 kcal/mol difference is generally significant, the other advantages of Ligand A outweigh this.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It exhibits significantly lower DILI risk and microsomal clearance, better solubility, and lower hERG inhibition, despite a slightly weaker binding affinity and lower Caco-2 permeability. The improved metabolic stability and safety profile are crucial for a viable drug candidate.

Output:
0
2025-04-17 16:33:59,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.391 and 353.507 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.63) is better than Ligand B (81.67), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand B (1.279) is optimal (1-3), while Ligand A (0.083) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3), as lower HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (7) is better than Ligand B (4), as lower HBAs generally improve permeability.

**QED:** Ligand A (0.659) is better than Ligand B (0.546), indicating a more drug-like profile.

**DILI:** Ligand B (5.584) is significantly better than Ligand A (47.46), indicating a much lower risk of drug-induced liver injury. This is a critical advantage.

**BBB:** Ligand A (74.758) is better than Ligand B (67.197), but BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have very negative Caco-2 values (-4.935 and -4.975), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very negative solubility values (-0.822 and -1.395), indicating poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.038) is much better than Ligand B (0.394), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (36.995) has higher clearance than Ligand B (15.877), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-24.534) has a negative half-life, which is not possible. This is a data error, and makes it difficult to assess its metabolic stability. Ligand A (2.506) has a short half-life.

**P-gp Efflux:** Ligand A (0.026) is better than Ligand B (0.009), indicating lower P-gp efflux.

**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 has a superior binding affinity and better QED, HBD, HBA, P-gp efflux, and hERG inhibition. However, it suffers from poor logP, higher DILI risk, and higher microsomal clearance. Ligand B has a better logP, significantly lower DILI risk, and lower microsomal clearance, but its binding affinity is weaker. The poor solubility and Caco-2 permeability are concerning for both.

Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity (-9.1 vs -7.9 kcal/mol), Ligand A is the more promising candidate *despite* its drawbacks. The weaker binding of Ligand B is a major disadvantage. While the DILI risk for Ligand A is higher, this could potentially be mitigated through structural modifications. The solubility and permeability issues for both ligands would require significant attention during lead optimization.

Output:
0
2025-04-17 16:33:59,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.539 Da) is slightly higher than Ligand B (346.387 Da), but both are acceptable.

**TPSA:** Ligand A (89.87) is excellent, well below the 140 threshold for oral absorption. Ligand B (122.55) is still reasonable, but less optimal.

**logP:** Ligand A (1.321) is within the optimal range (1-3). Ligand B (0.454) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (4 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.71, Ligand B: 0.577), indicating drug-like properties.

**DILI:** Ligand A (55.642) has a much lower DILI risk than Ligand B (67.119), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (62.544) has a higher BBB score than Ligand A (25.591), but this is less important here.

**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 could be misinterpreted.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.271, Ligand B: 0.197), which is excellent.

**Microsomal Clearance:** Ligand A (40.016) has a higher microsomal clearance than Ligand B (-4.178). This indicates Ligand B is more metabolically stable, a key priority for enzymes.

**In vitro Half-Life:** Ligand B (-15.896) has a significantly longer in vitro half-life than Ligand A (13.023), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.1, Ligand B: 0.008), which is favorable.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity. While Ligand A has a better TPSA and logP, the metabolic stability and safety profile of Ligand B are more critical for an enzyme target like SRC kinase. The solubility issues are a concern for both, but are secondary to the metabolic and safety advantages of Ligand B.

Output:
1
2025-04-17 16:33:59,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.535 Da) is slightly lower, which could be beneficial for permeability. Ligand B (397.591 Da) is also good.

**TPSA:** Ligand A (43.86) is excellent, well below the 140 threshold for oral absorption. Ligand B (58.22) is still acceptable, but less favorable.

**logP:** Both ligands have logP values (2.914 and 4.052) within the optimal range (1-3), though Ligand B is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable, minimizing potential permeability issues. Ligand B (1 HBD, 6 HBA) is also acceptable, but has more potential to impact permeability.

**QED:** Both ligands have good QED scores (0.474 and 0.764), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (10.934) has a significantly lower DILI risk than Ligand B (75.107). This is a major advantage for Ligand A.

**BBB:** Ligand A (84.878) shows good BBB penetration, while Ligand B (46.762) is lower. While not a primary concern for a kinase inhibitor, it's a slight advantage for A.

**Caco-2 Permeability:** Ligand A (-4.406) has poor Caco-2 permeability, while Ligand B (-5.12) is even worse. Both are quite poor, but A is slightly better.

**Aqueous Solubility:** Ligand A (-1.501) has poor solubility, while Ligand B (-5.402) is even worse. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.621) has a lower hERG risk than Ligand B (0.578). This is a slight advantage for Ligand A.

**Microsomal Clearance:** Ligand A (79.046) has lower microsomal clearance than Ligand B (106.918), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (4.61) has a shorter half-life than Ligand B (-5.522). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux than Ligand B (0.495), suggesting better bioavailability. This is an advantage for Ligand A.

**Binding Affinity:** Ligand B (-9.0 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 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 important factor for an enzyme inhibitor. While it has some ADME liabilities (higher DILI, lower solubility, higher clearance), the potency advantage is significant. Ligand A has better ADME properties overall (lower DILI, better clearance, better P-gp efflux), but its significantly weaker binding affinity is a major drawback. The difference in binding affinity is large enough to overcome the ADME issues of Ligand B.

Output:
1
2025-04-17 16:33:59,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.792 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (80.32 and 78.09) below 140, suggesting good oral absorption potential.

**3. logP:** Both ligands have logP values (2.124 and 2.702) within the optimal range of 1-3.

**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 (0.628 and 0.779), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 80.109, which is high. Ligand B has a DILI risk of 40.403, which is good (low risk). This is a significant advantage for Ligand B.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.974) and Ligand B (67.119) are both relatively low.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.737 and -4.979). This is unusual and suggests poor permeability. However, these values are on a log scale and need to be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.182 and -3.9), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.127 and 0.168).

**12. Microsomal Clearance:** Ligand A has a Cl_mic of 72.965, and Ligand B has a Cl_mic of 59.786. Lower is better, so Ligand B is slightly more metabolically stable.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-28.73) compared to Ligand A (-4.817). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.144 and 0.103).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have some issues with solubility and Caco-2 permeability, Ligand B is the superior candidate. It has a significantly better DILI score, a longer half-life, and a stronger binding affinity. The improved metabolic stability (lower Cl_mic) is also a positive factor. The higher binding affinity is the most important factor, given the enzyme target class.

Output:
1
2025-04-17 16:33:59,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (366.38 and 345.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is better than Ligand B (52.65), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.529) is a bit low, potentially hindering permeation. Ligand B (1.815) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, both are below the threshold of 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both well below the 10 threshold.

**QED:** Both ligands have good QED scores (0.64 and 0.747), indicating drug-likeness.

**DILI:** Ligand A (17.14) has a significantly lower DILI risk than Ligand B (6.75), which is a major advantage.

**BBB:** Ligand A (65.37) has a lower BBB penetration than Ligand B (87.67), but BBB isn't a high priority for a non-CNS target like SRC.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-4.999 vs -4.837).

**Solubility:** Both ligands have negative solubility values, which is also unusual and problematic. The values are similar (-1.819 vs -1.579).

**hERG:** Both ligands show low hERG inhibition risk (0.398 and 0.438).

**Microsomal Clearance:** Ligand A (-10.218) exhibits *much* lower microsomal clearance than Ligand B (7.983), indicating significantly better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-7.115) has a longer in vitro half-life than Ligand B (2.944), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.029).

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.8), a difference of 0.6 kcal/mol. While affinity is crucial, the other factors are more compelling.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the superior candidate. Its significantly lower DILI risk and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the minor affinity difference. The solubility and Caco-2 values are concerning for both, but the metabolic advantage of Ligand A is crucial for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:33:59,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per enzyme guidelines.

**Molecular Weight:** Both ligands (346.362 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is slightly higher than Ligand B (79.31), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (2.413) is optimal, while Ligand B (0.504) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.784 and 0.685), indicating good drug-likeness.

**DILI:** Ligand A (85.576) has a significantly higher DILI risk than Ligand B (23.924). This is a major concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (69.097) is better than Ligand B (38.852).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.713 and -4.379), 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:** Ligand A (-3.265) has slightly better solubility than Ligand B (-0.664), but both are quite poor.

**hERG:** Ligand A (0.191) has a slightly better hERG profile than Ligand B (0.408).

**Microsomal Clearance:** Ligand A (55.117) has higher microsomal clearance than Ligand B (31.649), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (20.807) has a longer half-life than Ligand B (5.361).

**P-gp Efflux:** Ligand A (0.027) shows lower P-gp efflux than Ligand B (0.162).

**Binding Affinity:** Ligand A (-8.7 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:**

Despite the superior binding affinity of Ligand A, its high DILI risk and higher microsomal clearance are significant liabilities. Ligand B, while having a weaker binding affinity, presents a much more favorable safety profile (low DILI) and better metabolic stability. Given the enzyme-specific priorities, the lower DILI risk and better metabolic stability of Ligand B make it the more viable drug candidate, even with the slightly weaker binding.

Output:
1
2025-04-17 16:33:59,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.415 and 340.423 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.71) is slightly higher than Ligand B (62.55), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.16) is within the optimal 1-3 range. Ligand B (3.8) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Ligand B (0.9) has a significantly better QED score than Ligand A (0.582), indicating a more drug-like profile.

**DILI:** Ligand A (52.074) has a slightly higher DILI risk than Ligand B (38.348), but both are below the concerning threshold of 60.

**BBB:** Ligand A (68.592) has a lower BBB penetration percentile than Ligand B (82.164). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.748) has a worse Caco-2 permeability than Ligand B (-4.428), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.335) has a worse aqueous solubility than Ligand B (-4.072). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.368) has a slightly better hERG profile than Ligand B (0.598), which is preferable.

**Microsomal Clearance:** Ligand A (-39.89) has a significantly *lower* (better) microsomal clearance than Ligand B (54.099), indicating better metabolic stability. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand B (104.95) has a much longer in vitro half-life than Ligand A (20.573), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.008) has a lower P-gp efflux liability than Ligand B (0.238), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial advantage. The difference of 7.8 kcal/mol is very significant.

**Overall Assessment:**

Ligand A exhibits a significantly stronger binding affinity (-7.8 kcal/mol) and better metabolic stability (lower Cl_mic) and P-gp efflux. While Ligand B has a better QED score, solubility, half-life, and BBB penetration, the potency and metabolic stability of Ligand A are more critical for an enzyme target like SRC kinase. The substantial binding affinity advantage of Ligand A outweighs the drawbacks in other ADME properties.

Output:
1
2025-04-17 16:33:59,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.386 and 359.535 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is higher than Ligand B (29.54). While both are reasonably low, Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (2.773) is within the optimal range (1-3). Ligand B (4.264) is slightly above, which could potentially lead to solubility issues or off-target effects, but is not drastically high.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than or equal to 5.

**H-Bond Acceptors:** Both ligands (A: 3, B: 3) are well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.724, B: 0.786), indicating drug-like properties.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (32.842). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (A: 83.404, B: 79.992), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values, which is unusual. It's difficult to interpret without more context, but it suggests potential issues with intestinal absorption.

**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 (A: 0.893, B: 0.799), which is excellent.

**Microsomal Clearance:** Ligand A (54.048) has significantly lower microsomal clearance than Ligand B (125.886), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (17.087) has a longer half-life than Ligand B (2.878), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.412, B: 0.754), which is favorable.

**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 B has a better logP and significantly lower DILI risk. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better solubility profile. Given the enzyme-specific priorities, metabolic stability is paramount. While the affinity difference is small, the improved metabolic profile of Ligand A is more valuable.

Output:
0
2025-04-17 16:33:59,455 - INFO - Batch 474 complete. Total preferences: 7584
2025-04-17 16:33:59,455 - INFO - Processing batch 475/512...
2025-04-17 16:34:46,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.5 and 366.4 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.74) is well below the 140 threshold for oral absorption. Ligand B (117.34) is still acceptable but higher, potentially impacting absorption slightly.

**logP:** Ligand A (2.147) is optimal (1-3). Ligand B (0.461) is a bit low, potentially hindering 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 affect permeability.

**QED:** Both ligands have reasonable QED scores (0.766 and 0.642), indicating drug-like properties.

**DILI:** Ligand A (39.4) has a lower DILI risk than Ligand B (60.95), which is approaching a concerning level.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.9) is higher than Ligand B (32.9).

**Caco-2 Permeability:** Ligand A (-4.815) is significantly better than Ligand B (-6.001), suggesting better intestinal absorption.

**Aqueous Solubility:** Both have negative solubility values, which is unusual and requires careful interpretation. Lower (more negative) values indicate poorer solubility. Ligand A (-2.36) is better than Ligand B (-2.089).

**hERG:** Ligand A (0.507) has a much lower hERG risk than Ligand B (0.006), which is a significant concern.

**Microsomal Clearance:** Ligand A (58.24) has higher clearance than Ligand B (-27.6), meaning Ligand B is more metabolically stable. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (4.73) has a longer half-life than Ligand B (-0.134).

**P-gp Efflux:** Ligand A (0.268) has lower P-gp efflux than Ligand B (0.003), which is favorable.

**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 within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and significantly better metabolic stability (lower Cl_mic, longer half-life). However, it suffers from a lower logP, higher DILI risk, poor hERG profile, and lower Caco-2 permeability. Ligand A has a better overall ADME profile, with better solubility, lower DILI and hERG risk, and better permeability. The slightly weaker binding affinity of Ligand A is likely acceptable given its superior ADME properties. For an enzyme target, metabolic stability is critical, but a significantly problematic hERG risk is a major red flag.

Output:
0
2025-04-17 16:34:46,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.5 and 348.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.48) is significantly better than Ligand B (86.88). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Ligand A (4.53) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.63) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 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 (0.825) has a much better QED score than Ligand B (0.641), indicating a more drug-like profile.

**DILI:** Ligand A (15.16) has a lower DILI risk than Ligand B (12.37), both are good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.23) is higher than Ligand B (67.70), but this is not a major deciding factor.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both, but Ligand A is slightly better (-5.03 vs -5.22).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.73) is slightly better than Ligand B (-2.42).

**hERG:** Ligand A (0.925) is better than Ligand B (0.302), indicating a lower risk of cardiotoxicity. This is a crucial factor.

**Microsomal Clearance:** Ligand A (30.72) and Ligand B (30.21) are similar, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (45.81) has a significantly longer half-life than Ligand B (-32.85). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.571) has lower P-gp efflux than Ligand B (0.046), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.9 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 overcome by other better ADME properties.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior drug-like properties across several critical ADME parameters. Specifically, its better QED, lower hERG risk, longer half-life, and lower P-gp efflux are significant advantages. The slightly higher logP of Ligand A is a potential concern, but the benefits outweigh this drawback. The poor Caco-2 and solubility for both ligands would need to be addressed in further optimization.

Output:
0
2025-04-17 16:34:46,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 362.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is higher than Ligand B (57.08). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is closer to the preferred value.

**logP:** Ligand A (2.096) and Ligand B (3.184) are both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the 5 threshold.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of 10.

**QED:** Ligand A (0.802) has a significantly higher QED score than Ligand B (0.673), indicating a more drug-like profile.

**DILI:** Ligand A (29.779) has a much lower DILI risk than Ligand B (14.541). This is a significant advantage for Ligand A.

**BBB:** Ligand A (59.442) and Ligand B (32.532) are both relatively low, which is acceptable for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-4.663) has a worse Caco-2 permeability than Ligand B (-5.122), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.989) has better aqueous solubility than Ligand B (-3.362). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.131) has a much lower hERG inhibition liability than Ligand B (0.775). This is a critical advantage for Ligand A, reducing potential cardiotoxicity.

**Microsomal Clearance:** Ligand A (30.815) has a higher microsomal clearance than Ligand B (11.488), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-8.769) has a shorter in vitro half-life than Ligand B (85.89). This is a significant disadvantage for Ligand A, potentially requiring more frequent dosing.

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux than Ligand B (0.506). Lower efflux is generally favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in QED, DILI risk, hERG inhibition, and P-gp efflux. However, it suffers from higher microsomal clearance and a shorter half-life, and worse Caco-2 permeability. Ligand B has better metabolic stability and permeability, but higher DILI risk and hERG inhibition.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the lower DILI and hERG risk of Ligand A are very important. While the metabolic stability and half-life are concerns, these can potentially be addressed through structural modifications. The similar binding affinities mean that the ADME properties become the deciding factors.

Output:
0
2025-04-17 16:34:46,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.371 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (100.8 and 106.77) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.177 and 1.102) are within the optimal 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for cell permeability.

**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 (0.785 and 0.772) have good drug-likeness scores, being above 0.5.

**DILI:** Ligand A (91.314) has a higher DILI risk than Ligand B (67.817). This is a significant concern.

**BBB:** This isn't a primary concern for a non-CNS target like SRC kinase, but Ligand A (46.413) has a slightly better BBB score than Ligand B (36.836).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.274 and -5.614), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.991 and -2.728), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.267 and 0.129). This is good.

**Microsomal Clearance:** Ligand A (60.32) has a higher microsomal clearance than Ligand B (-2.798). The negative value for Ligand B is unusual and suggests very high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (-38.017) has a negative in vitro half-life, which is not possible. Ligand B (-13.728) also has a negative value, indicating a problem with the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.034).

**Binding Affinity:** Ligand B (-10.3 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.

**Conclusion:**

Despite the issues with Caco-2 permeability and solubility for both, Ligand B is the stronger candidate. Its significantly better binding affinity (-10.3 vs -7.8 kcal/mol) is a major advantage for an enzyme target. Furthermore, its lower DILI risk and exceptionally low (and potentially problematic, requiring further investigation) microsomal clearance are favorable. The negative half-life values are concerning and require experimental verification, but the binding affinity difference is substantial enough to prioritize Ligand B for further investigation.

Output:
1
2025-04-17 16:34:46,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.451 and 366.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly higher than the ideal <140, but acceptable. Ligand B (57.69) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (0.037) is quite low, potentially hindering permeability. Ligand B (2.728) 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 (0.673 and 0.771), indicating drug-like properties.

**DILI:** Ligand A (15.083) has a very low DILI risk, which is excellent. Ligand B (37.611) is also reasonably low, but higher than Ligand A.

**BBB:** Ligand A (49.515) has a low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (77.278) has better BBB penetration, but again, less critical here.

**Caco-2 Permeability:** Ligand A (-5.253) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.407) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-0.499) has poor aqueous solubility, which is a concern. Ligand B (-2.517) has even poorer aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.144 and 0.14), which is excellent.

**Microsomal Clearance:** Ligand A (-57.626) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (35.749) has moderate clearance, suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-27.574) has a very long in vitro half-life, consistent with its low clearance. Ligand B (1.128) has a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.188).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.9 vs -7.3 kcal/mol) outweighs the concerns regarding solubility and permeability, especially for an enzyme target where potency is paramount. Furthermore, Ligand A exhibits excellent metabolic stability (very low Cl_mic and long t1/2) and a very low DILI risk. While Ligand B has a slightly better logP and TPSA, the substantial difference in binding affinity makes Ligand A the preferred choice.

Output:
0
2025-04-17 16:34:46,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.463 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is slightly higher than Ligand B (75.71), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.408) is a bit low, potentially hindering permeation. Ligand B (1.524) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), staying below the 5 threshold.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 4 respectively), staying below the 10 threshold.

**QED:** Both ligands have good QED scores (0.658 and 0.788), indicating drug-like properties.

**DILI:** Ligand A (10.896) has a significantly lower DILI risk than Ligand B (19.698), which is a major advantage.

**BBB:** Both have reasonable BBB penetration, with Ligand B (74.06) slightly higher than Ligand A (66.77), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP values, they suggest poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Assuming these are logS values, they suggest poor solubility.

**hERG Inhibition:** Ligand A (0.326) has a much lower hERG inhibition risk than Ligand B (0.184), which is a significant advantage.

**Microsomal Clearance:** Ligand A (0.047) has a much lower microsomal clearance than Ligand B (21.09), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.887) has a more negative half-life, which is unusual. Ligand B (-5.297) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.5), a difference of 1.5 kcal/mol. This is a substantial advantage.

**Conclusion:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The significantly lower DILI risk, substantially lower hERG inhibition, and much better metabolic stability (lower Cl_mic) outweigh the affinity difference. The slightly lower logP of Ligand A is a concern, but potentially addressable through medicinal chemistry. The unusual negative values for Caco-2 and solubility are concerning and need investigation. However, the safety profile of Ligand A is far superior, making it the preferred candidate for further development.

Output:
0
2025-04-17 16:34:46,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.5 and 362.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (78.43). A TPSA under 140 is good for oral absorption, and both are under, but A is much closer to the preferred range for good absorption.

**logP:** Ligand A (3.396) is optimal, while Ligand B (1.915) is slightly lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is superior to Ligand B (3 HBD, 3 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.734 and 0.577), indicating drug-like properties.

**DILI:** Ligand A (14.89) has a much lower DILI risk than Ligand B (18.65). This is a significant advantage.

**BBB:** Both have similar BBB penetration (81.27 and 79.49), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close enough to not be a major differentiator.

**Solubility:** Both have negative solubility values, which is also unusual. Again, the values are close.

**hERG:** Ligand A (0.541) has a slightly better hERG profile than Ligand B (0.336), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (64.11) has a higher Cl_mic than Ligand B (24.42). This means Ligand B is more metabolically stable, a crucial factor for enzymes.

**In vitro Half-Life:** Ligand B (-8.93) has a longer half-life than Ligand A (10.66). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux than Ligand B (0.076), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer half-life). However, Ligand A has a significantly better DILI score, better TPSA, and a slightly better hERG profile. Considering SRC is an enzyme, potency and metabolic stability are paramount. The 1.2 kcal/mol difference in binding affinity is significant, and the longer half-life of Ligand B is also highly desirable. While Ligand A has advantages in safety (DILI, hERG), the improved potency and stability of Ligand B are more critical for an enzyme target.

Output:
1
2025-04-17 16:34:46,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.415 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is slightly higher than Ligand B (78.87), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.355) is a bit low, potentially impacting permeability. Ligand B (1.241) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.703) has a significantly better QED score than Ligand B (0.353), indicating a more drug-like profile.

**DILI:** Ligand A (36.914) has a much lower DILI risk than Ligand B (6.669), which is a significant advantage.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (54.478) is slightly better than Ligand A (48.275).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.729) is slightly worse than Ligand B (-4.83).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.289) is slightly better than Ligand B (-1.235).

**hERG:** Both ligands have very low hERG inhibition risk (0.099 and 0.248, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (-22.21) has significantly lower (better) microsomal clearance than Ligand B (2.501), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.401) has a longer in vitro half-life than Ligand B (-13.382), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.052, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity and low hERG risk, Ligand A is the superior candidate. Its significantly better QED, lower DILI risk, and substantially improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower logP and solubility. The negative Caco-2 values are concerning for both, but the other advantages of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 16:34:46,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.374 and 356.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.27) is better than Ligand B (64.36), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (0.988) is within the optimal 1-3 range. Ligand B (4.215) is slightly high, potentially leading to solubility issues and off-target interactions.

**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 A (0.854) has a significantly better QED score than Ligand B (0.718), indicating better overall drug-likeness.

**DILI:** Ligand A (37.611) has a much lower DILI risk than Ligand B (77.433). This is a major advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (69.833) is lower than Ligand B (35.401).

**Caco-2 Permeability:** Ligand A (-5.061) and Ligand B (-4.952) are similar and both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.991) is better than Ligand B (-4.651), indicating better solubility.

**hERG Inhibition:** Ligand A (0.268) has a much lower hERG risk than Ligand B (0.463). This is a critical advantage.

**Microsomal Clearance:** Ligand A (-21.283) has a much lower (better) microsomal clearance than Ligand B (67.171), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (59.337) has a significantly longer in vitro half-life than Ligand A (-15.1).

**P-gp Efflux:** Ligand A (0.014) has a much lower P-gp efflux liability than Ligand B (0.459), suggesting better absorption.

**Binding Affinity:** Ligand B (-7.6) 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 superior candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A demonstrates significantly better drug-like properties (QED, solubility, DILI, hERG, P-gp efflux, and metabolic stability). The lower DILI and hERG risks are particularly important for kinase inhibitors, which often have off-target effects.

Output:
0
2025-04-17 16:34:46,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is slightly higher than Ligand B (58.44). Both are below the 140 threshold for oral absorption, but Ligand B is better.

**logP:** Both ligands (1.302 and 1.902) 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 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.759 and 0.843), indicating drug-like properties.

**DILI:** Ligand A (10.392) has a significantly lower DILI risk than Ligand B (25.591). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (70.997 and 77.2), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.062) has worse Caco-2 permeability than Ligand B (-4.584), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.961) has worse aqueous solubility than Ligand B (-1.313).

**hERG Inhibition:** Ligand A (0.138) has a much lower hERG inhibition liability than Ligand B (0.295), which is a critical safety factor.

**Microsomal Clearance:** Ligand A (-6.955) has significantly lower microsomal clearance than Ligand B (35.249), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-14.742) has a much longer in vitro half-life than Ligand B (-6.003), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.013 and 0.129).

**Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (-0.0). This is a substantial advantage. A >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for an enzyme target. While Ligand A has better safety (DILI, hERG) and metabolic stability (Cl_mic, t1/2), the large difference in binding affinity (-7.7 vs -0.0 kcal/mol) is likely to outweigh these advantages. The slightly lower Caco-2 and solubility of Ligand B are less concerning than the very weak binding of Ligand A.

Output:
1
2025-04-17 16:34:46,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (385.247 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 80, well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.907) is at the upper end of the optimal range (1-3), while Ligand B (1.98) is closer to the lower end. This could potentially lead to solubility issues for A and permeability issues for B.

**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 (0.756 and 0.826), indicating good drug-like properties.

**DILI:** Ligand A (77.627) has a higher DILI risk than Ligand B (39.977). This is a significant concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (65.568) is slightly better than Ligand A (57.154). BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.68) shows poor Caco-2 permeability, while Ligand B (-5.058) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.984) has very poor aqueous solubility, a major drawback. Ligand B (-2.519) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.471) has a higher hERG inhibition liability than Ligand B (0.126). This is a significant safety concern for Ligand A.

**Microsomal Clearance:** Ligand A (51.987) has a higher microsomal clearance than Ligand B (21.506), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (44.646) has a shorter in vitro half-life than Ligand B (15.989), further supporting the lower metabolic stability of A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.332 and 0.053).

**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 still a factor.

**Overall Assessment:**

Ligand B is significantly more promising. While both have poor Caco-2 and solubility, Ligand B excels in crucial areas for a kinase inhibitor: lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. Ligand A's high DILI, hERG, and poor solubility/permeability make it a less attractive candidate despite its slightly better binding affinity.

Output:
1
2025-04-17 16:34:46,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (330.387 Da) is slightly lower than Ligand B (354.376 Da), which is acceptable.

**TPSA:** Both ligands have TPSA values (58.03 and 58.95) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.0) is slightly higher than the upper limit, potentially raising concerns about off-target effects, while Ligand B (3.141) is ideal.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (3/4) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.581 and 0.89), indicating drug-like properties. Ligand B is better here.

**DILI:** Both ligands have DILI risk below 60, indicating low risk. Ligand A (55.758) is slightly higher than Ligand B (54.517), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (91.314) has a higher BBB penetration than Ligand A (49.787), but this isn't a major factor in this case.

**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 (0.878 and 0.904), which is excellent.

**Microsomal Clearance:** Ligand B has a negative clearance (-1.911 mL/min/kg), suggesting very high metabolic stability, which is a significant advantage. Ligand A has a clearance of 12.951 mL/min/kg, which is moderate.

**In vitro Half-Life:** Ligand B has a shorter half-life (12.585 hours) than Ligand A (105.216 hours). This is a drawback for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.569 and 0.282), which is good.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While it has a shorter half-life, its significantly improved binding affinity (-7.2 vs -9.4 kcal/mol) and superior metabolic stability (negative clearance) outweigh the drawbacks. The slightly better QED score also contributes to its favorability. The unusual negative values for Caco-2 and solubility are concerning, but the strong affinity and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:34:46,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (344.455 and 344.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.34) is well below the 140 threshold and favorable for oral absorption. Ligand B (123.12) is still within acceptable limits, but less optimal.

**3. logP:** Ligand A (3.322) is within the optimal range of 1-3. Ligand B (-0.196) is significantly below 1, 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 3 HBA, and Ligand B has 9 HBA. Both are within the acceptable limit of <=10, but Ligand B is closer to the upper bound.

**6. QED:** Ligand A (0.831) has a significantly better QED score than Ligand B (0.635), indicating a more drug-like profile.

**7. DILI:** Ligand A (25.979) has a much lower DILI risk than Ligand B (78.17), which is a significant advantage.

**8. BBB:** Ligand A (49.787) has a better BBB penetration score than Ligand B (20.512), though BBB isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.82) has a negative Caco-2 value, which is concerning. Ligand B (-5.558) is also negative, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.793) has a negative solubility value, which is concerning. Ligand B (-2.54) is also negative, but slightly better.

**11. hERG Inhibition:** Ligand A (0.149) has a very low hERG risk, which is excellent. Ligand B (0.076) also has a very low hERG risk.

**12. Microsomal Clearance:** Ligand A (49.815) has a higher microsomal clearance than Ligand B (24.034), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (37.154) has a longer in vitro half-life than Ligand A (28.896), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.136 and 0.056 respectively).

**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 crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a better QED score, and a significantly lower DILI risk. While it has concerning Caco-2 and solubility values, and a higher Cl_mic, the substantial binding affinity advantage outweighs these drawbacks, especially for an enzyme target where potency is paramount. Ligand B's biggest weakness is its very poor binding affinity and lower QED, despite having better metabolic stability and solubility.

Output:
1
2025-04-17 16:34:46,697 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [346.431, 87.46, 0.858, 2, 5, 0.774, 42.691, 41.993, -5.033, -2.057, 0.14, 12.12, 3.247, 0.034, -7.3]
**Ligand B:** [349.519, 61.44, 2.306, 2, 3, 0.671, 12.02, 65.413, -5.087, -2.927, 0.491, 35.079, -1.767, 0.069, -8.3]

**Step-by-step comparison:**

1. **MW:** Both ligands (346.431 and 349.519 Da) are within the ideal 200-500 Da range.
2. **TPSA:** Ligand A (87.46) is better than Ligand B (61.44), being under the 140 threshold, but still reasonable. Ligand B is excellent.
3. **logP:** Ligand A (0.858) is a bit low, potentially impacting permeability. Ligand B (2.306) is within the optimal 1-3 range.
4. **HBD:** Both have 2 HBD, which is good.
5. **HBA:** Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable (<=10).
6. **QED:** Ligand A (0.774) is better than Ligand B (0.671), indicating a more drug-like profile.
7. **DILI:** Ligand A (42.691) has a slightly higher DILI risk than Ligand B (12.02), but both are below the concerning 60 threshold.
8. **BBB:** Ligand B (65.413) has a better BBB penetration potential than Ligand A (41.993), but this isn't a primary concern for a non-CNS target like SRC.
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:** Ligand A (0.14) has a lower hERG risk than Ligand B (0.491), which is preferable.
12. **Cl_mic:** Ligand A (12.12) has a lower microsomal clearance than Ligand B (35.079), indicating better metabolic stability. This is a key advantage for an enzyme target.
13. **t1/2:** Ligand A (3.247) has a longer in vitro half-life than Ligand B (-1.767), which is a positive.
14. **Pgp:** Ligand A (0.034) has lower P-gp efflux liability than Ligand B (0.069), which is good.
15. **Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (-7.3) - a difference of 1.0 kcal/mol. This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Decision:**

Despite the negative Caco-2 and solubility values for both, Ligand B's significantly stronger binding affinity (-8.3 kcal/mol vs -7.3 kcal/mol) is a major advantage that likely outweighs the slightly higher DILI and Pgp efflux. The better metabolic stability (lower Cl_mic) and longer half-life of Ligand A are attractive, but the potency difference is more critical for an enzyme target. The hERG risk is also slightly better for Ligand A. However, the substantial affinity gain with Ligand B is likely to translate to better *in vivo* efficacy, even if it means some optimization of ADME properties later.

Output:
1
2025-04-17 16:34:46,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.519 and 368.865 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 78-79 A<sup>2</sup>, which is acceptable for oral absorption (<=140 A<sup>2</sup>) but not optimized for CNS penetration.

**3. logP:** Both ligands have logP values between 1 and 2, which is within the optimal range for drug-likeness.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED scores above 0.7, indicating good drug-like properties.

**7. DILI:** Ligand A (25.436) has a significantly lower DILI risk than Ligand B (53.587). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration percentiles (68.321 and 66.964). Since SRC is not a CNS target, this is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.101 and -5.06), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.732 and -3.286), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.477 and 0.463). This is positive.

**12. Microsomal Clearance:** Ligand B (11.718 mL/min/kg) has lower microsomal clearance than Ligand A (18.444 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.409 hours) has a negative half-life, which is not possible. This is a critical flaw. Ligand A has a half-life of 28.233 hours, which is good.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.25).

**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 of its other drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, and better metabolic stability. However, its negative in vitro half-life is a showstopper. Ligand A has a reasonable half-life and a significantly lower DILI risk, which are crucial for drug development. The solubility and permeability issues are similar for both. Given the importance of metabolic stability and potency for kinase inhibitors, and the fatal flaw of the negative half-life for Ligand B, Ligand A is the more viable candidate despite its slightly weaker binding affinity.

Output:
0
2025-04-17 16:34:46,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (351.443 and 345.374 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (95.86 and 94.31) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values within the optimal range (2.242 and 1.54).

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the HBD <= 5 guideline.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) both meet the HBA <= 10 guideline.

**6. QED:** Both ligands have good QED scores (0.601 and 0.775), indicating drug-like properties.

**7. DILI:** Ligand A (34.742) has a significantly lower DILI risk than Ligand B (54.75), placing it well below the concerning 60 percentile. Ligand B is moderately risky.

**8. BBB:** BBB is not a primary concern for an oncology target, but Ligand B (55.797) has a higher BBB value than Ligand A (25.746).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is more important. Ligand A (-5.301) is slightly better than Ligand B (-4.859).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.85) is slightly better than Ligand B (-2.074).

**11. hERG Inhibition:** Ligand A (0.046) has a very low hERG risk, while Ligand B (0.335) has a slightly higher, but still acceptable, risk.

**12. Microsomal Clearance:** Ligand A (15.071) has a lower microsomal clearance than Ligand B (3.351), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.274) has a much longer in vitro half-life than Ligand B (25.374).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.046).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Considering the priorities for an enzyme target (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a lower hERG risk. The slight advantage in binding affinity of Ligand B is unlikely to outweigh these substantial ADME/Tox benefits of Ligand A. Both ligands have poor solubility and permeability, which would need to be addressed in further optimization.

Output:
0
2025-04-17 16:34:46,698 - INFO - Batch 475 complete. Total preferences: 7600
2025-04-17 16:34:46,698 - INFO - Processing batch 476/512...
2025-04-17 16:35:27,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (380.495 and 362.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.56) is slightly above the optimal <140, but acceptable. Ligand B (51.02) is well within the range.

**logP:** Ligand A (1.027) is within the optimal 1-3 range. Ligand B (4.066) is at the higher end, potentially leading to solubility issues, but still within the acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are reasonable. Ligand B has 0 HBD and 5 HBA, also reasonable.

**QED:** Both ligands have similar QED values (0.664 and 0.676), indicating good drug-likeness.

**DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (32.842). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (77.549) has a higher BBB value, but this isn't a major factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.499 and -4.996), which is unusual and suggests poor permeability. This needs further investigation, but is not a deciding factor at this stage.

**Aqueous Solubility:** Both have negative solubility values (-2.933 and -3.745), which is also unusual and suggests poor solubility. This is a concern, but not a deciding factor at this stage.

**hERG:** Ligand A (0.367) has a slightly higher hERG risk than Ligand B (0.624), but both are relatively low.

**Microsomal Clearance:** Ligand A (64.112) has a lower microsomal clearance, indicating better metabolic stability, which is a key priority for kinase inhibitors. Ligand B (106.209) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (27.981) has a longer half-life than Ligand B (16.976), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.273 and 0.504).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), but the difference is minimal.

**Conclusion:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic and longer t1/2). The slightly lower affinity of Ligand A can potentially be optimized in later stages of drug development. The poor solubility and permeability of both are concerning and would need to be addressed, but the metabolic and toxicity profiles are more critical at this stage.

Output:
1
2025-04-17 16:35:27,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.435 and 358.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.77) is slightly above the optimal <140 for oral absorption, while Ligand B (77.1) is well within the range.

**logP:** Ligand A (-1.269) is a bit low, potentially hindering permeation. Ligand B (1.35) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better, suggesting potentially improved permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.493 and 0.673), indicating drug-like properties, with Ligand B being slightly better.

**DILI:** Ligand A (11.09) has a very low DILI risk, significantly better than Ligand B (24.777).

**BBB:** Ligand A (11.128) has very low BBB penetration, while Ligand B (68.166) is moderately good. Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.672) has poor Caco-2 permeability, while Ligand B (-4.782) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.827 and -0.885). This is a concern for both, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.029) has a very low hERG risk, significantly better than Ligand B (0.212). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (-25.994) has a very low (and therefore good) microsomal clearance, indicating high metabolic stability. Ligand B (34.75) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (21.424 and 23.549 hours), which are acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.001 and 0.027).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This difference of 0.7 kcal/mol is significant, but needs to be weighed against the other properties.

**Conclusion:**

While Ligand B has a slightly better binding affinity and logP, Ligand A demonstrates significantly better safety profiles with a much lower DILI risk and hERG inhibition liability, and superior metabolic stability (lower Cl_mic). The poor Caco-2 permeability and solubility are concerns for both, but are addressable. Given the enzyme-kinase target class, prioritizing metabolic stability and minimizing toxicity (DILI, hERG) are crucial. The slightly better affinity of Ligand B is not enough to overcome the superior safety and metabolic profile of Ligand A.

Output:
0
2025-04-17 16:35:27,687 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (369.443 and 363.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.67) is slightly above the preferred <140, but acceptable. Ligand B (96.78) is better, closer to the ideal.

**3. logP:** Ligand A (0.132) is quite low, potentially hindering permeability. Ligand B (0.98) is better, 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, acceptable. Ligand B has 7 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.663 and 0.863), indicating drug-likeness. Ligand B is slightly better.

**7. DILI:** Both have acceptable DILI risk (47.654 and 50.136), well below the 60 threshold.

**8. BBB:** Both have good BBB penetration (71.035 and 70.958), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.998 and -5.087). This is unusual and suggests poor permeability, but the scale isn't fully defined here.

**10. Aqueous Solubility:** Both have negative solubility values (-2.1 and -2.826). Again, the scale is unclear, but negative values likely indicate poor solubility.

**11. hERG Inhibition:** Both have very low hERG risk (0.05 and 0.311), which is excellent.

**12. Microsomal Clearance:** Ligand B (3.917) has significantly lower microsomal clearance than Ligand A (20.164), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (30.648) has a much longer in vitro half-life than Ligand A (-13.213). This is a significant advantage.

**14. P-gp Efflux:** Both have low P-gp efflux (0.022 and 0.261), which is good.

**15. Binding Affinity:** Both have very similar and strong binding affinities (-8.6 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have good potency and low hERG risk, Ligand B is clearly superior due to its significantly better metabolic stability (lower Cl_mic) and longer in vitro half-life. The slightly better logP and QED also contribute to its favorability. The negative Caco-2 and solubility values are concerning for both, but the improved pharmacokinetic properties of Ligand B outweigh these concerns.

Output:
1
2025-04-17 16:35:27,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (368.459 and 368.478 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.65) is better than Ligand B (97.11), both are below the 140 threshold for oral absorption, but A is closer to the preferred <90 for potential CNS penetration (though not a primary concern here).

**logP:** Ligand A (0.347) is quite low, potentially hindering permeability. Ligand B (2.052) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is preferable to Ligand B (3 HBD, 5 HBA) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.765 and 0.686, both > 0.5).

**DILI:** Both ligands have similar DILI risk (52.152 and 53.354), and are both acceptable (<60).

**BBB:** Ligand B (76.58) has a better BBB percentile than Ligand A (54.517), but this isn't a high priority for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-4.99) has very poor Caco-2 permeability, while Ligand B (-5.076) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.076) has slightly better solubility than Ligand B (-3.36), but both are poor.

**hERG Inhibition:** Ligand A (0.046) has a much lower hERG risk than Ligand B (0.475). This is a critical advantage for A.

**Microsomal Clearance:** Ligand A (31.688) has higher microsomal clearance than Ligand B (21.368), indicating lower metabolic stability. B is preferable here.

**In vitro Half-Life:** Ligand B (19.367) has a significantly longer half-life than Ligand A (-7.776), which is a major advantage for B.

**P-gp Efflux:** Ligand A (0.033) has lower P-gp efflux than Ligand B (0.227), which is a slight advantage for A.

**Binding Affinity:** Ligand A (-8.1) has a better binding affinity than Ligand B (-7.1) by 1 kcal/mol. This is a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower hERG risk, but suffers from poor Caco-2 permeability and metabolic stability. Ligand B has better logP, half-life, and metabolic stability, but has a weaker binding affinity and higher hERG risk.

Given the enzyme-specific priorities, binding affinity is paramount. The 1 kcal/mol difference in affinity for Ligand A is substantial. While the poor permeability and metabolic stability of A are concerns, these can potentially be addressed through further optimization. The higher hERG risk of Ligand B is a more serious concern, as it could lead to cardiotoxicity.

Output:
0
2025-04-17 16:35:27,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.4 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (79.6), falling well below the 140 threshold for oral absorption.

**logP:** Both are within the optimal range (1-3), with Ligand A (2.353) being slightly higher than Ligand B (1.367).

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (4/5) counts.

**QED:** Both ligands have good QED scores (0.829 and 0.57), indicating drug-like properties.

**DILI:** Ligand A (31.369) has a much lower DILI risk than Ligand B (67.235), which is a significant advantage.

**BBB:** Both have high BBB penetration, but Ligand A (91.47) is better than Ligand B (82.474). While not a primary concern for a non-CNS target, it's a positive attribute.

**Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, difficult to interpret without knowing the scale.

**hERG:** Ligand A (0.503) has a lower hERG risk than Ligand B (0.165), which is a critical advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (10.128) has a significantly lower microsomal clearance than Ligand B (43.729), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.702) has a longer in vitro half-life than Ligand B (-8.254).

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux liability than Ligand B (0.061).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol), a 0.7 kcal/mol difference. While affinity is crucial, the 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 demonstrates significantly better ADME properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and hERG inhibition. The lower TPSA of Ligand A is also favorable. The unusual negative values for Caco-2 and Solubility are concerning for both, but the overall profile of Ligand A is much more promising for development as a kinase inhibitor.

Output:
1
2025-04-17 16:35:27,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**1. Molecular Weight:** Both ligands (344.415 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.94) is well below the 140 threshold for good absorption, and even better for kinase inhibitors. Ligand B (112.73) is still acceptable, but less optimal.

**3. logP:** Ligand A (1.24) is within the optimal range of 1-3. Ligand B (0.098) is slightly below 1, which *could* indicate permeability issues, though not severely.

**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:** Ligand A (0.772) has a better QED score than Ligand B (0.566), indicating a more drug-like profile.

**7. DILI:** Ligand A (53.432) has a higher DILI risk than Ligand B (21.055). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have relatively low BBB penetration (Ligand A: 39.977, Ligand B: 53.703). This isn't a major concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.903 and -5.348), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-1.708 and -1.74), also unusual and suggesting poor aqueous solubility. This is a significant concern for both.

**11. hERG:** Ligand A (0.237) has a lower hERG risk than Ligand B (0.087), which is favorable.

**12. Cl_mic:** Ligand A (55.041) has a higher microsomal clearance than Ligand B (21.856), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. t1/2:** Ligand A (26.467) has a longer half-life than Ligand B (0.448), which is a positive.

**14. Pgp:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**15. Binding Affinity:** Ligand B (-7.9 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 other drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.9 vs -8.3 kcal/mol) is a major advantage. It also has a much lower DILI risk (21.055 vs 53.432) and better metabolic stability (lower Cl_mic). While Ligand A has a longer half-life and lower hERG risk, the superior affinity and safety profile of Ligand B make it the better choice. The poor permeability and solubility would need to be addressed through formulation or further chemical modifications, but the strong starting affinity is a critical advantage.

Output:
1
2025-04-17 16:35:27,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 often aids permeability.

**TPSA:** Ligand A (64.41) is significantly better than Ligand B (87.74). Lower TPSA generally correlates with better absorption.

**logP:** Ligand A (2.589) is optimal, while Ligand B (0.462) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar, good QED values (0.721 and 0.731).

**DILI:** Ligand A (17.449) has a much lower DILI risk than Ligand B (24.622), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (83.443) has a better BBB percentile than Ligand B (42.187).

**Caco-2 Permeability:** Ligand A (-4.467) is better than Ligand B (-5.53), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.657) is better than Ligand B (-1.556), which is important for formulation and bioavailability.

**hERG:** Both ligands have very low hERG risk (0.462 and 0.327).

**Microsomal Clearance:** Ligand A (41.617) is higher than Ligand B (-9.294), meaning Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-2.8) has a better in vitro half-life than Ligand A (-16.833).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.01).

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.2), but the difference is small.

**Overall Assessment:**

Ligand A has advantages in most ADME properties (TPSA, logP, DILI, Caco-2, Solubility) and a comparable binding affinity. Ligand B shines in metabolic stability and half-life, but its lower logP and higher DILI risk are concerning. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG), the improved ADME profile of Ligand A, particularly the lower DILI risk and better solubility, outweighs the slightly better metabolic stability of Ligand B. The affinity difference is small enough that optimizing Ligand A's metabolic stability should be feasible.

Output:
0
2025-04-17 16:35:27,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.475 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.89) is slightly above the preferred <90 for good absorption, while Ligand B (78.95) is well within the range.

**logP:** Ligand A (2.571) is optimal, while Ligand B (0.777) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.58 and 0.652, respectively), indicating drug-like properties.

**DILI:** Ligand A (47.305) has a slightly higher DILI risk than Ligand B (6.049), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (70.609 and 71.772), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.756) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.991) is also not great, but better than A.

**Aqueous Solubility:** Ligand A (-3.344) has poor aqueous solubility. Ligand B (-0.705) is better, though still not ideal.

**hERG Inhibition:** Ligand A (0.913) has a slightly higher hERG risk than Ligand B (0.234), but both are relatively low.

**Microsomal Clearance:** Ligand A (39.032) has a higher microsomal clearance than Ligand B (6.126), indicating lower metabolic stability. This is a critical disadvantage for an enzyme target.

**In vitro Half-Life:** Ligand A (39.106) has a shorter half-life than Ligand B (-22.249), further supporting the lower metabolic stability of A. Note the negative value for B indicates a very long half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.279 and 0.006, respectively).

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-6.9). The 2.1 kcal/mol difference is substantial and can outweigh many ADME concerns.

**Conclusion:**

Despite Ligand A's issues with Caco-2 permeability, solubility, and metabolic stability, its substantially superior binding affinity (-9.0 kcal/mol vs -6.9 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The difference in binding is large enough to potentially overcome the ADME liabilities, especially if formulation strategies can mitigate the solubility and permeability issues. Ligand B has better ADME properties overall, but the weaker binding makes it less likely to be effective *in vivo*.

Output:
1
2025-04-17 16:35:27,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.515 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is well below the 140 threshold, and favorable for oral absorption. Ligand B (72.21) is also below 140, but higher than A.

**logP:** Both ligands (4.245 and 3.955) are slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects, but not drastically.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.596 and 0.736), indicating good drug-like properties.

**DILI:** Ligand A (18.496) has a significantly lower DILI risk than Ligand B (59.442). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.404) is higher than Ligand B (64.87).

**Caco-2 Permeability:** Ligand A (-4.275) shows better Caco-2 permeability than Ligand B (-5.23).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.582 and -4.426).

**hERG:** Both ligands have low hERG inhibition liability (0.414 and 0.517), which is good.

**Microsomal Clearance:** Ligand B (74.694) has lower microsomal clearance than Ligand A (120.712), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (85.205) has a much longer in vitro half-life than Ligand A (-11.703). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.198 and 0.094).

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.1). While the difference is less than the 1.5 kcal/mol threshold to outweigh other factors, it is still a positive.

**Overall Assessment:**

Ligand A has a significant advantage in DILI risk and Caco-2 permeability, and slightly better binding affinity. However, Ligand B excels in metabolic stability (lower Cl_mic) and has a much longer half-life. The lower DILI risk of Ligand A is a strong positive, but the improved PK profile of Ligand B (longer half-life, lower clearance) is crucial for an enzyme target. Considering the enzyme-specific priorities, the longer half-life and better metabolic stability of Ligand B are more important than the slightly better affinity of Ligand A.

Output:
1
2025-04-17 16:35:27,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.323 Da and 358.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (67.43 and 68.29) are below the 140 A^2 threshold for good oral absorption, which is good.

**3. logP:** Both ligands (3.132 and 3.577) are within the optimal 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, 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 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.791 and 0.83), indicating drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (63.086 and 74.603). This is a concern, and further investigation would be needed. Ligand B has a higher risk.

**8. BBB:** Both ligands have moderate BBB penetration (75.107 and 63.086). Since SRC is not a CNS target, this is not a primary concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.837 and -4.489). This is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.453 and -3.945). This is also a significant drawback, potentially hindering bioavailability. Ligand B has slightly worse solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.385 and 0.181), which is excellent.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (20.424) than Ligand B (86.254). This suggests better metabolic stability for Ligand A, which is a key priority for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A has a much longer in vitro half-life (-8.381) than Ligand B (-18.455). This is a significant advantage for Ligand A, as it suggests less frequent dosing may be possible.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.146 and 0.266).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Comparison:**

While both ligands have good potency (binding affinity) and acceptable physicochemical properties (MW, logP, TPSA, HBD/HBA, QED), they both suffer from poor predicted permeability and solubility. However, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic and longer half-life) and a slightly lower DILI risk. Given the enzyme-specific priorities, the improved metabolic stability and half-life of Ligand A outweigh the slightly higher DILI risk and slightly worse solubility. The permeability and solubility issues would need to be addressed through formulation or further chemical modifications, but Ligand A appears to be a more promising starting point.

Output:
0
2025-04-17 16:35:27,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.359 and 354.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (125.57) is slightly above the optimal <140, but acceptable. Ligand B (93.73) is excellent, well below 140.

**logP:** Ligand A (-0.467) is a bit low, potentially hindering permeability. Ligand B (1.298) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, both acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.536 and 0.531), indicating good drug-likeness.

**DILI:** Ligand A (76.503) has a higher DILI risk than Ligand B (33.656). This is a significant concern.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (41.373) is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.545 and -1.301). This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.218 and 0.103), which is positive.

**Microsomal Clearance:** Ligand A (-5.446) has a more negative value, indicating lower clearance and better metabolic stability than Ligand B (0.091).

**In vitro Half-Life:** Ligand A (35.902) has a longer half-life than Ligand B (-4.384).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.013 and 0.033).

**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 could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.6 kcal/mol) is a major advantage for an enzyme target like SRC kinase. It also demonstrates better metabolic stability (lower Cl_mic) and a longer half-life. While Ligand A has a higher DILI risk, this can be investigated further through structural modifications. The low logP of Ligand A is a concern, but the potency advantage is likely to be more impactful at this stage.

Output:
0
2025-04-17 16:35:27,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.511 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**TPSA:** Ligand A (49.85) is well below the 140 threshold for oral absorption, and favorable. Ligand B (89.35) is still under 140, but less optimal than A.

**logP:** Ligand A (3.037) is within the optimal range (1-3). Ligand B (-0.543) is significantly below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 6 HBA) is also acceptable, but slightly less favorable.

**QED:** Both ligands have reasonable QED scores (A: 0.778, B: 0.575), indicating good drug-like properties.

**DILI:** Ligand A (52.074) has a slightly higher DILI risk than Ligand B (44.242), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.098) is higher than Ligand B (46.219).

**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 solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.35) has a much lower hERG risk than Ligand B (0.047), which is a significant advantage.

**Microsomal Clearance:** Ligand A (85.432) has a higher clearance than Ligand B (31.09), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-22.69) has a very negative half-life, which is concerning. Ligand A (1.714) is much better.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.209, B: 0.024).

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A having a higher DILI risk and clearance, its significantly superior binding affinity (-9.7 vs -7.7 kcal/mol) and much lower hERG risk are decisive factors. The lower logP of Ligand B is a serious concern for permeability. The unusual solubility and Caco-2 values for both are concerning, but the affinity difference is large enough to prioritize A for further optimization.

Output:
1
2025-04-17 16:35:27,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (336.391 and 380.897 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is higher than Ligand B (49.85). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better positioned.

**3. logP:** Both ligands have good logP values (3.396 and 2.786), 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 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.823 and 0.807), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 78.48, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 49.283, which is preferable.

**8. BBB:** Ligand A (71.888) and Ligand B (91.198) both have acceptable BBB penetration, but Ligand B is better. This is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.46 and -4.413), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.446 and -4.083), indicating poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.538 and 0.444), which is good.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (34.289 and 37.926 mL/min/kg), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.661) has a slightly longer half-life than Ligand A (6.51), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.228 and 0.58), which is good.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -9.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both compounds have excellent binding affinity, Ligand B is significantly better due to its lower DILI risk and slightly better BBB penetration and in vitro half-life. The poor Caco-2 permeability and solubility are concerning for both, but the lower DILI risk of Ligand B makes it the more promising candidate. Addressing the solubility and permeability issues would be crucial for further development, but starting with a lower toxicity profile is advantageous.

Output:
1
2025-04-17 16:35:27,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.5 and 373.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (79.8) is still acceptable but less favorable.

**logP:** Ligand A (1.733) is optimal. Ligand B (3.349) 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 (1 HBD, 3 HBA) is excellent. Ligand B (2 HBD, 7 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have similar QED values (0.51 and 0.488), indicating reasonable drug-likeness.

**DILI:** Ligand A (4.886) has a very low DILI risk, which is excellent. Ligand B (81.388) has a significantly higher DILI risk, a major concern.

**BBB:** Ligand A (79.992) shows good BBB penetration potential, while Ligand B (63.94) is lower. This isn't a primary concern for a non-CNS target like SRC, but a bonus.

**Caco-2 Permeability:** Ligand A (-4.87) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.58) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.131) has poor aqueous solubility. Ligand B (-3.616) is even worse. Both are problematic for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.702) has a low hERG risk, which is excellent. Ligand B (0.8) also shows low hERG risk.

**Microsomal Clearance:** Ligand A (1.6) has low microsomal clearance, suggesting good metabolic stability. Ligand B (99.854) has very high clearance, indicating rapid metabolism and potentially requiring higher doses or frequent administration.

**In vitro Half-Life:** Ligand A (6.365) has a reasonable half-life. Ligand B (55.499) has a much longer half-life, a significant advantage.

**P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux, which is favorable. Ligand B (0.283) has slightly higher efflux, but still acceptable.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a much lower DILI risk, which are critical for an oncology target. However, it suffers from poor Caco-2 permeability and solubility. Ligand B has a longer half-life but a significantly higher DILI risk, poor solubility, and a weaker binding affinity.

Despite the ADME concerns with Ligand A, the strong binding affinity and low DILI risk make it the more promising candidate. Solubility and permeability can be addressed through formulation strategies or further chemical modifications. The high DILI risk of Ligand B is a more difficult problem to overcome.

Output:
0
2025-04-17 16:35:27,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.507 and 346.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.88) is well below the 140 threshold, while Ligand B (122.55) is still acceptable but higher.

**logP:** Ligand A (2.767) is optimal (1-3). Ligand B (0.454) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is acceptable, but approaching the upper limit.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.847 and 0.577), indicating good drug-likeness.

**DILI:** Ligand A (16.712) has a much lower DILI risk than Ligand B (67.119). This is a significant advantage.

**BBB:** Both have moderate BBB penetration, but Ligand A (71.384) is better than Ligand B (62.544). Not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.513) is poor, while Ligand B (-5.478) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-1.542) is poor, while Ligand B (-3.053) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.492) has a lower hERG risk than Ligand B (0.197). This is a significant advantage.

**Microsomal Clearance:** Ligand A (34.454) has higher clearance than Ligand B (-4.178). Ligand B exhibits negative clearance, which is not physically possible and suggests an error in the data or a very stable compound.

**In vitro Half-Life:** Ligand A (8.535) has a shorter half-life than Ligand B (-15.896). Again, negative half-life is not possible.

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.008). This is a slight advantage.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Conclusion:**

Ligand A is the better candidate. While both have good binding affinity, Ligand A has a significantly lower DILI risk and hERG inhibition liability. Although both have poor Caco-2 and solubility, the ADME profile of Ligand B is unrealistic with negative values for clearance and half-life. The slightly better logP and BBB penetration of Ligand A are also beneficial.

Output:
1
2025-04-17 16:35:27,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.402 and 347.434 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.57) is slightly higher than Ligand B (54.46). Both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Ligand A (3.414) is slightly higher than Ligand B (2.099). Both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.901 and 0.801), indicating good drug-like properties.

**DILI:** Ligand B (6.669) has a significantly lower DILI risk than Ligand A (48.313). This is a major advantage for Ligand B.

**BBB:** Ligand A (89.027) has a higher BBB penetration percentile than Ligand B (96.743). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, the values are similar (-4.478 and -4.705).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-2.823 and -2.575).

**hERG:** Both ligands have low hERG inhibition risk (0.891 and 0.723), which is positive.

**Microsomal Clearance:** Ligand B (19.805) has a lower microsomal clearance than Ligand A (26.524), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-14.276) has a significantly longer in vitro half-life than Ligand A (-28.311). This is another significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.729) has slightly lower P-gp efflux liability than Ligand B (0.109).

**Binding Affinity:** Ligand B (-9.2 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:**

Ligand B is the stronger candidate. It exhibits a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While Ligand A has slightly better BBB penetration and P-gp efflux, these are less important for a non-CNS enzyme target like SRC. The negative solubility and Caco-2 values are concerning for both, but are similar enough that they don't differentiate the candidates.

Output:
1
2025-04-17 16:35:27,690 - INFO - Batch 476 complete. Total preferences: 7616
2025-04-17 16:35:27,690 - INFO - Processing batch 477/512...
2025-04-17 16:36:14,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.327 and 367.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.22) is better than Ligand B (87.74). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred range for oral bioavailability.

**3. logP:** Ligand A (1.872) is optimal, while Ligand B (-0.392) is slightly low, potentially hindering membrane 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 preferable to Ligand B (6).

**6. QED:** Both ligands (0.639 and 0.51) are above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (37.611) has a lower DILI risk than Ligand B (25.63), which is a significant advantage.

**8. BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (82.396) is higher than Ligand B (56.65).

**9. Caco-2 Permeability:** Ligand A (-4.682) is better than Ligand B (-5.249), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.807) is better than Ligand B (-2.461).

**11. hERG Inhibition:** Both ligands (0.39 and 0.16) have low hERG inhibition risk, which is excellent.

**12. Microsomal Clearance:** Ligand A (49.629) has higher clearance than Ligand B (23.39). This means Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (5.416) has a shorter half-life than Ligand B (-3.669), indicating faster metabolism.

**14. P-gp Efflux:** Both ligands (0.189 and 0.015) have low P-gp efflux, which is good.

**15. Binding Affinity:** Both ligands (-8.3 and -8.6 kcal/mol) have excellent binding affinity, with Ligand B being slightly better. However, the difference is small and can be overcome by other favorable properties.

**Overall Assessment:**

Ligand A has a better overall profile, despite the slightly weaker binding affinity. It excels in properties crucial for oral bioavailability (logP, TPSA, Caco-2, Solubility), has a significantly lower DILI risk, and a better QED score. Ligand B's primary advantage is its improved metabolic stability (lower Cl_mic and longer half-life), but this is outweighed by its poorer absorption characteristics and higher DILI risk. For an enzyme target like SRC kinase, a balance of potency, metabolic stability, and good ADME properties is crucial. Ligand A strikes a better balance.

Output:
0
2025-04-17 16:36:14,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.364 and 359.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.8) is better than Ligand B (38.13), both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (2.714) is optimal, while Ligand B (4.793) is pushing the upper limit and could potentially cause solubility issues or off-target effects.

**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 4 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.664 and 0.72), indicating drug-like properties.

**7. DILI:** Ligand A (44.087) has a slightly higher DILI risk than Ligand B (29.236), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have high BBB penetration, but Ligand A (97.053) is better than Ligand B (83.366). This is less critical for a non-CNS target like SRC.

**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. Again, the scale is not specified.

**11. hERG:** Ligand A (0.571) has a lower hERG risk than Ligand B (0.809), which is a significant advantage.

**12. Cl_mic:** Ligand A (43.736) has significantly lower microsomal clearance than Ligand B (89.745), indicating better metabolic stability.

**13. t1/2:** Ligand A (-11.626) has a negative half-life, which is not possible. Ligand B (24.646) has a reasonable in vitro half-life. This is a major red flag for Ligand A.

**14. Pgp:** Ligand A (0.412) has lower P-gp efflux liability than Ligand B (0.778), which is favorable.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 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 primary driver for enzyme inhibitors. While its logP is slightly higher and hERG risk slightly elevated, the difference in binding affinity (-9.2 vs -6.9 kcal/mol) is substantial. The negative half-life for Ligand A is a critical flaw. Although both ligands have unusual solubility and Caco-2 values, the superior binding affinity and better metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:36:14,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 348.531 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (60.85) is slightly higher than Ligand B (49.41). Both are below the 140 threshold for good absorption, but Ligand B is preferable.

**3. logP:** Ligand A (2.119) and Ligand B (3.912) are both within the optimal 1-3 range, but Ligand B is approaching the upper limit.

**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 2. Both are below the 10 threshold.

**6. QED:** Ligand A (0.75) has a slightly better QED score than Ligand B (0.676), indicating a more drug-like profile.

**7. DILI:** Ligand A (10.508) has a significantly lower DILI risk than Ligand B (25.785). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (A: 84.529, B: 80.574), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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, indicating poor solubility. This is a concern.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.421, B: 0.465).

**12. Microsomal Clearance:** Ligand A (37.203) has a significantly lower microsomal clearance than Ligand B (74.539), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand A (5.799) has a positive half-life, while Ligand B (-22.571) has a negative half-life, which is not physically possible. This is a major red flag for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.204, B: 0.396).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant.

**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 a positive half-life), and slightly better binding affinity. While both have poor solubility and permeability, the ADME properties of Ligand A are far more favorable, particularly the lower DILI and improved metabolic stability, which are critical for kinase inhibitors. The negative half-life for Ligand B is a deal-breaker.

Output:
0
2025-04-17 16:36:14,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.359 Da and 354.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.51) is slightly higher than Ligand B (78.09), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (0.938 and 1.862, respectively), falling 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.719 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 76.89, which is concerningly high. Ligand B has a much lower DILI risk of 49.011, which is preferable.

**BBB:** Both ligands have reasonably high BBB penetration (80.69 and 73.517), but this is less critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.245 and -5.063). This is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.502 and -3.069). Again, these are unusual and suggest poor solubility.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.266, which is acceptable. Ligand B has a slightly higher risk of 0.473, but still within a reasonable range.

**Microsomal Clearance:** Ligand B (1.665 mL/min/kg) has significantly lower microsomal clearance than Ligand A (12.514 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-22.488 hours) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand A has a half-life of 26.468 hours, which is good. However, the negative value for Ligand B is a major red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.064).

**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, potentially outweighing minor ADME concerns.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic), stronger binding affinity, and lower DILI risk outweigh the slightly higher hERG risk. The negative half-life for Ligand B is a major concern, but the superior affinity is a strong driver. Ligand A's high DILI risk is a significant drawback.

Output:
1
2025-04-17 16:36:14,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (389.239 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.65) is slightly higher than Ligand B (74.33). Both are below the 140 threshold for oral absorption, but Ligand B is preferable due to being closer to the ideal range.

**logP:** Ligand A (0.886) is a bit low, potentially hindering permeation. Ligand B (2.302) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.725 and 0.745), indicating good drug-likeness.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (43.079). Ligand B is much preferred here.

**BBB:** This is less critical for a kinase inhibitor not specifically targeting the CNS. Ligand B (66.615) has a higher BBB value than Ligand A (45.366), but it's not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.9 and -4.827), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.179 and -2.433), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.169) has a slightly higher hERG risk than Ligand B (0.449), but both are relatively low.

**Microsomal Clearance:** Ligand A (10.46) has a lower microsomal clearance than Ligand B (12.014), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (11.825) has a slightly longer half-life than Ligand A (-21.014 - negative value is concerning).

**P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux liability than Ligand B (0.038), which is preferable.

**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 B is the better candidate. It has a more favorable logP, lower DILI risk, and a slightly better binding affinity. While both ligands suffer from poor predicted solubility and permeability, the better ADME profile of Ligand B, particularly the lower DILI risk and acceptable logP, outweighs the slightly better metabolic stability of Ligand A. The binding affinity difference is minimal.

Output:
1
2025-04-17 16:36:14,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.435 and 351.437 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.17) is higher than the preferred <140, but still reasonable. Ligand B (29.54) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (0.08) is quite low, potentially hindering permeability. Ligand B (4.179) is slightly high, potentially causing solubility issues or off-target effects, but still within a tolerable range.

**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:** Both ligands have good QED scores (0.596 and 0.796), indicating drug-like properties.

**DILI:** Ligand A (40.287) is slightly above the ideal <40, indicating a moderate risk. Ligand B (21.442) is excellent, with a low DILI risk.

**BBB:** Ligand A (32.726) has low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (96.743) has very high BBB penetration, irrelevant for this target.

**Caco-2:** Both have negative Caco-2 values (-4.922 and -4.214) which is unusual and suggests poor permeability. This is a red flag for both compounds.

**Solubility:** Ligand A (-0.979) has poor solubility. Ligand B (-5.125) has even worse solubility.

**hERG:** Ligand A (0.154) has a very low hERG risk, which is excellent. Ligand B (0.873) has a moderate hERG risk.

**Cl_mic:** Ligand A (52.687) has a moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (73.39) has higher clearance, indicating lower metabolic stability.

**t1/2:** Ligand A (-2.503) has a negative in vitro half-life, which is impossible and indicates a data error or a very rapidly metabolized compound. Ligand B (19.794) has a good in vitro half-life.

**Pgp:** Ligand A (0.057) has low P-gp efflux, which is favorable. Ligand B (0.541) has moderate P-gp efflux.

**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.

**Conclusion:**

Despite the poor Caco-2 and solubility of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.1 vs -7.0 kcal/mol) outweighs its slightly higher logP and moderate Pgp efflux. Furthermore, Ligand B has a much better DILI score and a reasonable in vitro half-life, while Ligand A has an impossible half-life value. The lower hERG risk of Ligand A is a plus, but the affinity difference is more critical for an enzyme target.

Output:
1
2025-04-17 16:36:14,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.423 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is well below the 140 threshold for oral absorption and is very good. Ligand B (100.35) is still within acceptable limits but less favorable.

**logP:** Ligand A (2.032) is optimal (1-3). Ligand B (0.527) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.779 and 0.67), indicating good drug-like properties.

**DILI:** Ligand A (29.779) has a lower DILI risk than Ligand B (22.722), both are good.

**BBB:** Ligand A (51.415) has a lower BBB penetration than Ligand B (67.584). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.63) has poor Caco-2 permeability, while Ligand B (-5.56) is also poor.

**Aqueous Solubility:** Ligand A (-2.966) has better aqueous solubility than Ligand B (-1.712).

**hERG:** Ligand A (0.185) has a lower hERG risk than Ligand B (0.324), which is a significant advantage.

**Microsomal Clearance:** Ligand A (24.898) has a higher (worse) microsomal clearance than Ligand B (-5.83), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-0.262) has a slightly better in vitro half-life than Ligand B (5.872).

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.004), which is favorable.

**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, and can often outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and lower hERG risk, Ligand B's significantly stronger binding affinity (-8.1 vs -7.2 kcal/mol) is the most important factor for an enzyme target like SRC kinase. The slightly lower logP and Caco-2 permeability of Ligand B are concerns, but the potency advantage is substantial. The better metabolic stability (lower Cl_mic) of Ligand B is also a positive.

Output:
1
2025-04-17 16:36:14,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.725 Da) is slightly higher than Ligand B (347.503 Da), but both are acceptable.

**TPSA:** Ligand A (88.24) is better than Ligand B (43.86) as it is closer to the ideal threshold of <140 for oral absorption.

**logP:** Both ligands have good logP values (A: 2.939, B: 1.683), falling within 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 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.715, B: 0.687), indicating good drug-likeness.

**DILI:** Ligand A has a higher DILI risk (69.484) compared to Ligand B (19.969). This is a significant concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 61.962, B: 63.164). BBB is not a high priority for a kinase inhibitor unless CNS targets are involved.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close, so this isn't a major differentiator.

**Aqueous Solubility:** Ligand A has a very poor aqueous solubility (-3.968) compared to Ligand B (-0.673). This is a major drawback for Ligand A.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.652, B: 0.635).

**Microsomal Clearance:** Ligand B has a negative Cl_mic (-4.291), which is highly favorable, indicating excellent metabolic stability. Ligand A's Cl_mic (11.891) is much higher, suggesting faster metabolism.

**In vitro Half-Life:** Ligand B has a negative in vitro half-life (-1.295), which is highly favorable. Ligand A's half-life (42.225) is reasonable, but not as good as Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.222, B: 0.05).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Conclusion:**

Despite having similar binding affinities, Ligand B is significantly more promising. It has a much lower DILI risk, better aqueous solubility, and superior metabolic stability (lower Cl_mic and longer half-life). Ligand A's high DILI risk and poor solubility are major concerns that would likely hinder its development.

Output:
1
2025-04-17 16:36:14,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.447 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.47) is slightly higher than Ligand B (75.71), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.409) is within the optimal 1-3 range, while Ligand B (0.699) is slightly below, potentially impacting 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:** Both ligands have similar QED values (0.728 and 0.7), indicating good drug-likeness.

**DILI:** Both ligands have very similar, and acceptable, DILI risk (32.377 and 32.959 percentile).

**BBB:** Both ligands have low BBB penetration (50.679 and 56.301 percentile), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.951 and -4.933). This is a potential issue for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.691 and -2.105). This is a significant concern, potentially hindering formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.387 and 0.184), which is excellent.

**Microsomal Clearance:** Ligand A (8.433 mL/min/kg) has significantly lower microsomal clearance than Ligand B (27.278 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (30.168 hours) has a much longer half-life than Ligand B (14.029 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.089 and 0.049), which is favorable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). The difference of 0.8 kcal/mol is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has better ADME properties (lower Cl_mic, longer t1/2, better solubility, although still poor), Ligand B boasts a significantly stronger binding affinity. For an enzyme target like SRC kinase, potency is paramount. The 0.8 kcal/mol difference in binding affinity is a substantial advantage. Although the solubility and permeability are poor for both, the improved potency of Ligand B makes it the more promising candidate, assuming further optimization can address the solubility issues.

Output:
1
2025-04-17 16:36:14,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.514 Da and 367.559 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is significantly better than Ligand B (58.36). Lower TPSA generally favors better cell permeability.

**logP:** Both ligands have good logP values (4.066 and 3.089), falling within the 1-3 range. Ligand B is slightly preferable.

**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 scores (0.764 and 0.729), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (16.906 and 16.402 percentile), which is good.

**BBB:** Ligand A (94.921) has a much higher BBB penetration percentile than Ligand B (70.415). While not a primary concern for a non-CNS target like SRC, it's a positive attribute.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.723 and -4.759), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-4.761) is slightly better than Ligand B (-2.764), but both are poor. Solubility is a critical factor for bioavailability.

**hERG Inhibition:** Ligand A (0.793) has a lower hERG inhibition risk than Ligand B (0.336), which is preferable.

**Microsomal Clearance:** Ligand A (56.068 mL/min/kg) has lower microsomal clearance than Ligand B (62.596 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.473 hours) has a longer in vitro half-life than Ligand A (18.004 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.672) has lower P-gp efflux than Ligand B (0.318), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the superior candidate. Its significantly stronger binding affinity (-8.1 vs -7.4 kcal/mol) is the most important factor, outweighing the slightly worse half-life and P-gp efflux. It also has better TPSA, H-bonding characteristics, hERG risk, and metabolic stability. The higher BBB penetration is a bonus. While solubility and permeability are concerns, these can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 16:36:14,468 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [359.411, 121.18 ,   0.376,   3.   ,   6.   ,   0.681,  83.443,  45.909, -5.595,  -3.135,   0.385,  -6.554, -26.371,   0.017,  -7.6  ]
**Ligand B:** [368.487,  59.29 ,   4.4  ,   1.   ,   6.   ,   0.568,  90.461,  39.55 , -5.159,  -4.608,   0.497,  68.768,  48.724,   0.36 ,  -8.1  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (359.411) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (121.18) is better than B (59.29). Both are below the 140 A^2 threshold for oral absorption, but B is significantly lower, which is good.
3. **logP:** A (0.376) is quite low, potentially hindering membrane permeability. B (4.4) is high, potentially causing solubility and off-target issues.
4. **HBD:** A (3) is acceptable. B (1) is also good.
5. **HBA:** Both A (6) and B (6) are within the acceptable range (<=10).
6. **QED:** A (0.681) is better than B (0.568), indicating a more drug-like profile.
7. **DILI:** A (83.443) is concerningly high, indicating a significant risk of liver injury. B (90.461) is even worse.
8. **BBB:** A (45.909) is low, not a major concern for a non-CNS target like SRC. B (39.55) is also low.
9. **Caco-2:** A (-5.595) is very poor, suggesting very limited intestinal absorption. B (-5.159) is also poor, but slightly better than A.
10. **Solubility:** A (-3.135) is poor. B (-4.608) is even worse.
11. **hERG:** A (0.385) is good, indicating low cardiotoxicity risk. B (0.497) is also good.
12. **Cl_mic:** A (-6.554) is excellent, suggesting very high metabolic stability. B (68.768) is very high, indicating rapid metabolism.
13. **t1/2:** A (-26.371) is excellent, indicating a very long half-life. B (48.724) is good, but not as good as A.
14. **Pgp:** A (0.017) is very low, indicating minimal P-gp efflux. B (0.36) is also low.
15. **Binding Affinity:** B (-8.1) is significantly better than A (-7.6), a difference of 0.5 kcal/mol.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

Despite the high DILI risk for both compounds, Ligand A is the better candidate. The significantly better metabolic stability (Cl_mic and t1/2) and lower Pgp efflux, combined with acceptable hERG risk, outweigh the lower affinity and poor solubility/Caco-2. The 0.5 kcal/mol difference in affinity *might* be overcome with further optimization of Ligand A, while addressing the DILI risk. Ligand B's rapid metabolism is a major drawback that would be difficult to overcome. The poor solubility and Caco-2 values for both are concerning, but can be addressed through formulation strategies.

1
2025-04-17 16:36:14,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (376.463 Da) is also good.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (88.33). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is much closer to the optimal range for permeability.

**logP:** Both ligands have good logP values (A: 3.385, B: 3.009) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is better than Ligand B (HBD=1, HBA=7). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have acceptable QED values (A: 0.638, B: 0.736), indicating good drug-like properties.

**DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (87.166). This is a significant advantage for A.

**BBB:** Ligand A (82.513) has a better BBB percentile than Ligand B (27.259), but this is less critical for a kinase inhibitor not specifically targeting the CNS.

**Caco-2 Permeability:** Ligand A (-4.558) has a higher Caco-2 permeability than Ligand B (-5.342), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.668) has slightly better solubility than Ligand B (-4.329).

**hERG:** Ligand A (0.662) has a lower hERG risk than Ligand B (0.336), which is a positive.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 55.507, B: 54.596).

**In vitro Half-Life:** Ligand B (35.448) has a significantly longer half-life than Ligand A (2.067). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.212) has lower P-gp efflux than Ligand B (0.149), which is favorable.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.2). This difference of 0.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better ADME properties (lower DILI, better TPSA, solubility, permeability, and P-gp efflux), Ligand B's significantly stronger binding affinity (-9.0 vs -8.2 kcal/mol) is the most critical factor for an enzyme inhibitor. The longer half-life of B is also a significant benefit. The higher DILI risk of B is concerning, but the potency advantage is likely to be more impactful in early stages of drug development.

Output:
1
2025-04-17 16:36:14,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 364.421 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.32) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (43.18) is excellent, well below 140.

**logP:** Ligand A (0.933) is a bit low, potentially hindering permeation. Ligand B (2.61) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good, potentially improving membrane permeability.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.51 and 0.674, respectively), indicating drug-like properties.

**DILI:** Ligand A (41.877) has a slightly better DILI risk profile than Ligand B (58.511), both are acceptable, but lower is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (82.164) has a higher BBB percentile than Ligand A (68.166), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.982 and -4.712), which is unusual and suggests potential issues with absorption prediction. This is a flag for both, but doesn't immediately disqualify either.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.996 and -4.276) which is also unusual and suggests potential issues with solubility prediction. This is a flag for both, but doesn't immediately disqualify either.

**hERG:** Ligand A (0.172) has a significantly lower hERG risk than Ligand B (0.79), which is a major advantage.

**Microsomal Clearance:** Ligand A (53.414) has lower microsomal clearance than Ligand B (64.318), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have negative in vitro half-life values (-13.698 and -12.648), which is unusual and suggests potential issues with half-life prediction.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.042 and 0.212), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). This 0.4 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand B has a better logP and binding affinity, but Ligand A has a significantly better hERG profile and lower microsomal clearance (better metabolic stability). The negative Caco-2 and solubility values are concerning for both, but the hERG risk for Ligand B is a bigger concern for an enzyme inhibitor. Given the priorities for enzyme inhibitors, the lower hERG risk and better metabolic stability of Ligand A outweigh the slightly better affinity of Ligand B.

Output:
0
2025-04-17 16:36:14,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.38 and 369.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.87) is significantly better than Ligand B (79.46).  A TPSA under 140 is good for oral absorption, and both are under this threshold, but A is preferable.

**logP:** Both ligands (2.847 and 3.529) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3), as fewer donors generally improve permeability.

**H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4), as fewer acceptors generally improve permeability.

**QED:** Ligand A (0.895) is significantly better than Ligand B (0.656), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (41.915 and 45.715, both <60).

**BBB:** Ligand A (93.447) is much better than Ligand B (71.229), although BBB isn't a primary concern for a non-CNS target.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.966) is slightly better than Ligand B (-4.84).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.446) is slightly better than Ligand B (-3.531).

**hERG:** Both ligands have low hERG inhibition risk (0.886 and 0.644).

**Microsomal Clearance:** Ligand A (-3.869) has significantly lower (better) microsomal clearance than Ligand B (69.055), indicating better metabolic stability. This is a crucial factor for kinases.

**In vitro Half-Life:** Ligand A (0.173) has a very short half-life, while Ligand B (42.587) has a much longer half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.105 and 0.147).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior profile in terms of QED, TPSA, H-bond donors/acceptors, metabolic stability (Cl_mic), and, most importantly, binding affinity. While Ligand B has a better in vitro half-life, the significantly stronger binding of Ligand A, coupled with its better overall drug-like properties, makes it the more promising candidate. The poor Caco-2 and solubility of both compounds would need to be addressed during optimization, but the potency advantage of Ligand A is substantial.

Output:
1
2025-04-17 16:36:14,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.414 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (368.459 Da) is also good.

**TPSA:** Ligand A (64.92) is excellent, well below the 140 threshold for oral absorption. Ligand B (101.49) is still acceptable, but less optimal.

**logP:** Ligand A (3.803) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects, but still within acceptable limits. Ligand B (1.153) is at the low end, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is good. Ligand B (1 HBD, 7 HBA) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Ligand A (0.841) has a very strong drug-like profile. Ligand B (0.618) is still acceptable, but less favorable.

**DILI:** Both ligands have similar DILI risk (Ligand A: 56.921, Ligand B: 56.727), both being moderate, and not a major concern.

**BBB:** Ligand A (70.027) shows good BBB penetration, while Ligand B (54.246) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.797) and Ligand B (-5.021) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-4.59) and Ligand B (-2.127) both have negative solubility values, indicating poor aqueous solubility. This is a significant issue for both compounds.

**hERG Inhibition:** Ligand A (0.883) has a slightly higher hERG risk than Ligand B (0.03), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (32.389) has significantly lower microsomal clearance than Ligand A (61.108), indicating better metabolic stability. This is a crucial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-9.178) has a longer in vitro half-life than Ligand A (38.025), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.279) has lower P-gp efflux than Ligand B (0.034), which is a slight advantage.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9.6 kcal/mol, Ligand B: -8.4 kcal/mol). Ligand A is slightly more potent, with a 1.2 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a better QED, BBB penetration, and binding affinity. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower hERG risk. Both compounds have poor solubility and permeability. Given the enzyme-specific priorities, metabolic stability and minimizing off-target effects (hERG) are crucial. The 1.2 kcal/mol difference in binding affinity can be overcome with optimization, while poor metabolic stability is harder to fix later in development.

Output:
1
2025-04-17 16:36:14,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.337 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is better than Ligand B (58.64), both are below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.9 and 2.462), 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:** Ligand A (0.718) has a significantly better QED score than Ligand B (0.538), indicating a more drug-like profile.

**DILI:** Ligand A (91.431) has a very high DILI risk, while Ligand B (12.02) has a very low DILI risk. This is a major concern for Ligand A.

**BBB:** Ligand B (85.459) has a higher BBB penetration percentile than Ligand A (54.207), but BBB is not a primary concern for SRC kinase inhibitors unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.793 and -4.668). This is unusual and suggests poor permeability. However, negative values are sometimes artifacts of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.132 and -2.298). This is also concerning, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.119) has a lower hERG inhibition liability than Ligand B (0.631), which is favorable.

**Microsomal Clearance:** Ligand B (13.931 mL/min/kg) has a higher microsomal clearance than Ligand A (33.506 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-31.271 hours) has a negative half-life, which is not possible. This suggests a prediction error. Ligand B (10.608 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux liability than Ligand B (0.176), which is favorable.

**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:**

Ligand A has a much better binding affinity and a lower P-gp efflux liability. However, it has a very high DILI risk, a negative and likely erroneous in vitro half-life, and poor solubility. Ligand B has a much lower DILI risk, a reasonable half-life, and better metabolic stability, but its binding affinity is weaker.

Given the critical importance of minimizing toxicity (DILI) and ensuring reasonable metabolic stability for an enzyme inhibitor, and acknowledging the questionable half-life prediction for Ligand A, **Ligand B is the more viable drug candidate.** The stronger binding affinity of Ligand A is appealing, but the high DILI risk is a significant red flag that would likely preclude further development.

Output:
1
2025-04-17 16:36:14,469 - INFO - Batch 477 complete. Total preferences: 7632
2025-04-17 16:36:14,469 - INFO - Processing batch 478/512...
2025-04-17 16:36:56,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (375.778 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is well below the 140 threshold and good for oral absorption. Ligand B (98.74) is still under 140, but closer to the limit.

**logP:** Ligand A (3.729) is within the optimal 1-3 range. Ligand B (-0.055) is significantly below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable counts, well below the limits of 5 and 10 respectively.

**QED:** Both ligands have reasonable QED scores (0.866 and 0.606), indicating good drug-like properties.

**DILI:** Ligand A (66.15) has a higher DILI risk than Ligand B (19.232). This is a concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.927) has a better BBB score than Ligand B (46.336).

**Caco-2 Permeability:** Ligand A (-4.54) has poor Caco-2 permeability, while Ligand B (-5.388) is also poor. Both are concerning.

**Aqueous Solubility:** Ligand A (-4.475) has poor aqueous solubility, while Ligand B (-1.994) is also poor. Both are concerning.

**hERG Inhibition:** Ligand A (0.412) has a slightly higher hERG risk than Ligand B (0.039), but both are relatively low.

**Microsomal Clearance:** Ligand A (70.477) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (-6.348) has negative clearance, which is unusual and suggests very high stability.

**In vitro Half-Life:** Ligand A (13.193 hours) has a reasonable half-life. Ligand B (11.551 hours) is also acceptable.

**P-gp Efflux:** Ligand A (0.594) has moderate P-gp efflux, while Ligand B (0.008) has very low efflux.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the higher DILI risk, Ligand A is the more promising candidate due to its significantly superior binding affinity (-8.5 vs -6.7 kcal/mol). The difference in affinity is large enough to potentially outweigh the DILI concern, especially considering the other ADME properties are not drastically worse. The poor permeability and solubility of both compounds are drawbacks that would need to be addressed in further optimization, but the potency advantage of Ligand A is a key driver. Ligand B's very low logP is a major concern, likely leading to poor absorption.

Output:
1
2025-04-17 16:36:56,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.845 and 372.853 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.86) is better than Ligand B (87.9), both are below the 140 threshold for oral absorption, but ligand A is closer to the desirable range for permeability.

**logP:** Ligand A (2.892) is optimal (1-3), while Ligand B (0.3) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Both have 5-6 HBAs, within the acceptable limit of 10.

**QED:** Ligand B (0.803) has a higher QED score than Ligand A (0.591), suggesting a more drug-like profile.

**DILI:** Ligand A (67.119) has a slightly higher DILI risk than Ligand B (63.086), but both are reasonably acceptable.

**BBB:** Ligand A (68.282) has a better BBB penetration potential than Ligand B (32.803). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.605) has a worse Caco-2 permeability than Ligand B (-4.769), but both are very poor.

**Aqueous Solubility:** Ligand A (-4.235) has a worse aqueous solubility than Ligand B (-2.078). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.413) has a lower hERG inhibition risk than Ligand B (0.092), which is a significant advantage.

**Microsomal Clearance:** Ligand B (20.086) has a significantly lower microsomal clearance than Ligand A (66.094), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (9.101) has a shorter half-life than Ligand A (19.032), but both are relatively low.

**P-gp Efflux:** Ligand A (0.432) has lower P-gp efflux than Ligand B (0.075), which is better for bioavailability.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is not substantial enough to outweigh the other factors.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is more promising. While Ligand A has a slightly better binding affinity and lower hERG risk, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic) and a higher QED score. The low logP of Ligand B is a concern, but the superior metabolic stability and drug-likeness outweigh this drawback.

Output:
1
2025-04-17 16:36:56,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.439 and 370.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.87) is well below the 140 threshold, while Ligand B (136.35) is closer to the limit but still acceptable.

**logP:** Ligand A (1.194) is within the optimal range, while Ligand B (0.083) is slightly below, potentially impacting permeability.

**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 within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.519 and 0.675, respectively), indicating drug-like properties.

**DILI:** Both ligands have similar, moderately high DILI risk (63.125 and 61.07). This is a concern, but not a deal-breaker at this stage.

**BBB:** Both ligands have low BBB penetration (34.044 and 36.371). This isn't critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.493 and -5.719). This is unusual and suggests poor permeability, which is a significant drawback.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.457 and -1.041). This is also a significant concern, as poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.155 and 0.06). This is a positive attribute.

**Microsomal Clearance:** Ligand B (-3.069) has a *negative* microsomal clearance, which is highly unusual and suggests exceptional metabolic stability. Ligand A (2.982) has a moderate clearance.

**In vitro Half-Life:** Ligand B (28.887) has a significantly longer half-life than Ligand A (6.979). This is a major advantage.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.06 and 0.026). This is favorable.

**Binding Affinity:** Ligand B (-7.6) has a substantially better binding affinity than Ligand A (-0.0). This is a crucial difference, as a 1.5 kcal/mol advantage is often enough to outweigh other drawbacks.

**Conclusion:**

Despite the negative Caco-2 and solubility values for both, Ligand B is the superior candidate. Its significantly stronger binding affinity (-7.6 kcal/mol vs -0.0 kcal/mol) and dramatically improved metabolic stability (negative Cl_mic and longer half-life) outweigh the concerns about permeability and solubility, especially considering we are targeting a kinase. The similar DILI risk isn't ideal, but can be addressed in later optimization stages. The slightly lower logP of Ligand B is a minor concern compared to the substantial benefits in potency and stability.

Output:
1
2025-04-17 16:36:56,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (385.266 and 374.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is significantly better than Ligand B (76.14). Lower TPSA generally indicates better permeability, which is important for oral absorption.

**logP:** Both ligands have acceptable logP values (4.821 and 3.011, respectively), falling within the 1-3 range. Ligand B is slightly better here.

**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 6. Ligand A is preferable here, as higher HBA can sometimes hinder permeability.

**QED:** Both ligands have similar QED values (0.672 and 0.65), indicating good drug-likeness.

**DILI:** Ligand A (68.321) has a slightly higher DILI risk than Ligand B (59.442), but both are reasonably acceptable.

**BBB:** Ligand A (62.97) has a lower BBB penetration than Ligand B (85.692). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.624 and -4.664). These values are unusual and could indicate issues with the prediction method or the compounds themselves. However, we can still compare them relatively. The values are very similar.

**Aqueous Solubility:** Both have negative solubility values (-5.105 and -3.984). Again, these are unusual and require caution. The values are similar.

**hERG Inhibition:** Ligand A (0.695) has a slightly higher hERG risk than Ligand B (0.279). Lower hERG risk is preferred.

**Microsomal Clearance:** Ligand B (62.192) has a lower microsomal clearance than Ligand A (66.051), suggesting better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (97.012) has a significantly longer in vitro half-life than Ligand B (-7.152). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.496) has lower P-gp efflux than Ligand B (0.168), which is favorable.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.3 kcal/mol). This difference of 0.8 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a longer half-life, which are crucial for an enzyme target like SRC kinase. While Ligand B has slightly better metabolic stability (lower Cl_mic) and lower hERG risk, the substantial improvement in binding affinity and half-life of Ligand A outweigh these benefits. The TPSA and HBA values are also more favorable for Ligand A. The unusual negative solubility and Caco-2 values for both compounds are concerning and would require further investigation, but the difference between the two is minimal.

Output:
1
2025-04-17 16:36:56,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.433 and 372.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.51) is better than Ligand B (84.94), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.691) is slightly better than Ligand B (0.815), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1), both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand B (6) is better than Ligand A (3), both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.691 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (19.891) has a significantly lower DILI risk than Ligand B (46.452). This is a major advantage for Ligand A.

**BBB:** Ligand A (83.986) has a higher BBB penetration percentile than Ligand B (46.452). While not critical for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.989 and -4.988).

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.71 and -2.502).

**hERG Inhibition:** Ligand A (0.318) has a lower hERG inhibition liability than Ligand B (0.121), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (19.528) has a significantly lower microsomal clearance than Ligand B (68.342), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-21.85) has a much longer in vitro half-life than Ligand B (-5.167). This is another significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.029 and 0.039).

**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, the other ADME properties of Ligand A are far superior.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising drug candidate. Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG inhibition. These factors are critical for enzyme targets like SRC kinase. The slight difference in binding affinity is likely surmountable through further optimization, while the poor ADME properties of Ligand B represent more substantial hurdles.

Output:
0
2025-04-17 16:36:56,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (365.5 and 355.9 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.88) is slightly higher than Ligand B (54.02), but both are well below the 140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (3.14 and 4.06), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target effects, but not drastically.

**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 2. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have high QED scores (0.833 and 0.868), indicating good drug-like properties.

**7. DILI:** Ligand A (46.26%) has a slightly higher DILI risk than Ligand B (36.29%). Both are below the 60% threshold, but lower is better.

**8. BBB:** Ligand A (91.94%) shows better BBB penetration than Ligand B (78.91%). However, BBB is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. This suggests poor permeability. However, the values are close enough that this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a significant concern for both, but needs to be considered alongside other factors.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.658 and 0.475), which is excellent.

**12. Microsomal Clearance:** Ligand A (85.86 mL/min/kg) has a significantly higher microsomal clearance than Ligand B (36.95 mL/min/kg). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (68.50 hours) has a substantially longer in vitro half-life than Ligand A (39.12 hours), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.177 and 0.178).

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.7 kcal/mol), which is excellent and strong.

**Conclusion:**

While both ligands have excellent binding affinity and acceptable drug-like properties, Ligand B is the more promising candidate due to its significantly better metabolic stability (lower Cl_mic and longer t1/2) and lower DILI risk. The slightly higher logP of Ligand B is a minor concern compared to the substantial advantage in metabolic stability, which is a high priority for enzyme inhibitors. The solubility issue is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:36:56,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 361.515 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (64), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.279 and 3.053), 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, and Ligand B has 7. Ligand A is preferable here.

**QED:** Both ligands have good QED scores (0.672 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (20.706) has a significantly lower DILI risk than Ligand B (57.968). This is a major advantage for Ligand A.

**BBB:** Both have acceptable BBB penetration, but Ligand B (71.035) is slightly better than Ligand A (66.537). However, BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.756) has worse Caco-2 permeability than Ligand B (-5.311).

**Aqueous Solubility:** Ligand A (-1.828) has better aqueous solubility than Ligand B (-3.288).

**hERG Inhibition:** Ligand A (0.159) has a much lower hERG risk than Ligand B (0.779). This is a crucial advantage.

**Microsomal Clearance:** Ligand A (37.646) has significantly lower microsomal clearance than Ligand B (81.799), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (94.356) has a much longer in vitro half-life than Ligand A (5.394). This is a strong advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.028) has lower P-gp efflux than Ligand B (0.371).

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-6.8). This 0.4 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand A excels in safety parameters (DILI, hERG) and metabolic stability (Cl_mic). It also has better solubility and lower P-gp efflux. Ligand B has a slightly better affinity and half-life, but comes with higher DILI and hERG risks, and worse metabolic stability. Given the enzyme-specific priorities, the improved safety and metabolic stability of Ligand A outweigh the slightly better affinity and half-life of Ligand B.

Output:
0
2025-04-17 16:36:56,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.406 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.43) is slightly higher than Ligand B (49.85). Both are below 140, suitable for oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**3. logP:** Both ligands have good logP values (1.734 and 2.618), 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:** Both ligands have 3 HBA, well within the acceptable range (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.708 and 0.634), suggesting good drug-like properties.

**7. DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (29.701), but both are below the concerning threshold of 60.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.966) has a higher BBB penetration than Ligand A (63.28), but this isn't a major deciding factor here.

**9. Caco-2 Permeability:** Ligand A (-5.239) has significantly *better* Caco-2 permeability than Ligand B (-4.284). A more negative value indicates better permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.909 and -2.85). This is a significant concern for both, potentially impacting bioavailability.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.412 and 0.599).

**12. Microsomal Clearance:** Ligand A (10.887) has significantly *lower* microsomal clearance than Ligand B (62.802). Lower clearance indicates better metabolic stability, a key priority for kinases.

**13. In vitro Half-Life:** Ligand A (0.051) has a very short half-life, while Ligand B (12.906) has a much longer half-life. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.085) has slightly lower P-gp efflux than Ligand B (0.271). Lower efflux is generally preferred.

**15. Binding Affinity:** Ligand A (-7.6) has a slightly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a slightly better binding affinity and Caco-2 permeability, Ligand B shines in metabolic stability (much lower Cl_mic) and in vitro half-life. The poor solubility of both is a concern, but the significantly improved pharmacokinetic profile of Ligand B (lower clearance, longer half-life) outweighs the small difference in binding affinity. For an enzyme target like SRC kinase, metabolic stability and reasonable half-life are crucial for maintaining therapeutic concentrations.

Output:
1
2025-04-17 16:36:56,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.354 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (383.187 Da) is still well within the range.

**TPSA:** Ligand A (116.14) is better than Ligand B (81.91), being under the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.605) is a bit low, potentially hindering permeation. Ligand B (3.789) is closer to the optimal 1-3 range.

**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 reasonable QED scores (A: 0.643, B: 0.431), suggesting decent drug-likeness. Ligand A is better.

**DILI:** Ligand A (52.423) has a lower DILI risk than Ligand B (81.039), which is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand B (78.79) shows better potential for BBB penetration.

**Caco-2 Permeability:** Ligand A (-5.824) is very poor, indicating very low intestinal absorption. Ligand B (-4.559) is also poor, but less so than Ligand A.

**Aqueous Solubility:** Ligand A (-1.512) has poor solubility, while Ligand B (-5.755) is even worse. Both are concerning.

**hERG Inhibition:** Ligand A (0.14) has a lower hERG risk than Ligand B (0.71), which is a critical advantage.

**Microsomal Clearance:** Ligand A (-33.073) has significantly lower (better) microsomal clearance than Ligand B (55.274), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.396) has a very short half-life, while Ligand B (8.714) is better.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable. Ligand B (0.503) is higher, but not excessively so.

**Binding Affinity:** Both ligands have similar and good binding affinities (-9.1 kcal/mol and -8.8 kcal/mol, respectively). The difference is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), and lower P-gp efflux. However, it suffers from very poor Caco-2 permeability and solubility, and a short half-life. Ligand B has better logP and half-life, but significantly higher DILI and hERG risk, and worse metabolic stability.

Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. While Ligand A's permeability and solubility are concerning, these can potentially be addressed through formulation strategies. The higher safety profile and better metabolic stability of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 16:36:56,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.383 and 346.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is better than Ligand B (49.85), both are acceptable but A is preferable.

**logP:** Ligand A (4.372) is higher than the optimal range (1-3) and could present solubility challenges. Ligand B (1.977) is within the optimal range.

**H-Bond Donors:** Ligand A (1) is good, Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.627 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A (31.02) has a lower DILI risk than Ligand B (42.846), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (87.088 and 83.288), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both.

**Solubility:** Ligand A (-3.752) has worse solubility than Ligand B (-2.422).

**hERG:** Ligand A (0.933) has a slightly higher hERG risk than Ligand B (0.603), but both are reasonably low.

**Microsomal Clearance:** Ligand A (55.391) has higher clearance than Ligand B (35.213), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-31.614) has a negative half-life, which is a major red flag. Ligand A (27.854) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.279 and 0.381).

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2), but the difference is small.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk, but suffers from higher logP, higher clearance, and worse solubility. Ligand B has better logP, solubility, and clearance, but has a negative in vitro half-life, which is a critical flaw. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate despite its drawbacks. The slightly better affinity and lower DILI risk outweigh the solubility and metabolic stability concerns, which could potentially be addressed through further optimization. The negative half-life of Ligand B is a showstopper.

Output:
0
2025-04-17 16:36:56,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.475 and 371.815 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for oral absorption, but Ligand B is preferable due to its lower TPSA.

**3. logP:** Both ligands have a logP of approximately 3.0, which is optimal.

**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 2 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have a QED of around 0.77-0.78, indicating good drug-likeness.

**7. DILI:** Ligand A (31.059) has a significantly lower DILI risk than Ligand B (52.772). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (94.339) has a higher BBB penetration percentile than Ligand A (77.007). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.962) has slightly better Caco-2 permeability than Ligand B (-4.621), although both are negative values, indicating relatively poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.9) has slightly better solubility than Ligand B (-3.624), although both are negative values, indicating relatively poor solubility.

**11. hERG Inhibition:** Ligand A (0.399) has a lower hERG inhibition liability than Ligand B (0.556), which is favorable.

**12. Microsomal Clearance:** Ligand A (6.033) has a lower microsomal clearance than Ligand B (45.696), suggesting better metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (8.841) has a longer in vitro half-life than Ligand B (4.266), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux liability than Ligand B (0.228), which is favorable for oral bioavailability.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8). This 0.3 kcal/mol difference is noticeable, but not overwhelmingly significant given the other factors.

**Overall Assessment:**

Ligand A demonstrates a more favorable profile overall, particularly regarding safety (DILI, hERG) and metabolic stability (Cl_mic, t1/2). While Ligand B has a slightly better binding affinity, the advantages of Ligand A in terms of DILI risk, metabolic stability, and P-gp efflux outweigh this difference. The slightly better solubility and permeability of Ligand A are also beneficial.

Output:
0
2025-04-17 16:36:56,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (341.455 and 356.329 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (57.5) is well below the 140 threshold and good for oral absorption. Ligand B (100.63) is still within acceptable limits, but less favorable than A.

**3. logP:** Ligand A (2.218) is optimal (1-3). Ligand B (-0.238) is below 1, which might impede permeation. This is a significant drawback for B.

**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. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.847) has a very good drug-likeness score. Ligand B (0.573) is acceptable, but lower than A.

**7. DILI:** Ligand A (24.622) has a low DILI risk. Ligand B (64.521) has a higher, though not critically high, DILI risk.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (51.997) and Ligand B (60.682) are both moderate.

**9. Caco-2 Permeability:** Ligand A (-4.868) and Ligand B (-5.131) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't fully defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.124 and -2.061 respectively). This is a concern, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.844) has a lower hERG risk than Ligand B (0.086). This is a significant advantage for A.

**12. Microsomal Clearance (Cl_mic):** Ligand A (31.062) has a higher clearance than Ligand B (3.61). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (68.92) has a longer half-life than Ligand B (-31.504). The negative value for B is concerning and likely indicates very rapid degradation.

**14. P-gp Efflux:** Ligand A (0.573) has lower P-gp efflux than Ligand B (0.009), which is favorable.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly better binding affinity than Ligand B (-6.3). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in affinity and hERG risk. Ligand B has better metabolic stability (lower Cl_mic), but a very poor half-life. Both have poor solubility. The significantly better binding affinity of Ligand A, combined with its lower hERG risk and better QED, makes it the more promising candidate despite its slightly higher clearance. The poor logP of Ligand B is a major concern.

Output:
0
2025-04-17 16:36:56,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (345.418 and 348.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.3) is well below the 140 threshold, and excellent for oral absorption. Ligand B (88.75) is still acceptable, but less optimal.

**3. logP:** Ligand A (2.157) is within the optimal 1-3 range. Ligand B (4.32) is slightly higher, potentially leading to solubility issues and off-target effects, but not dramatically so.

**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 (6) is also acceptable.

**6. QED:** Both ligands (0.657 and 0.583) have acceptable QED scores, indicating reasonable drug-likeness.

**7. DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (36.448), which is a major advantage.

**8. BBB:** Both have high BBB penetration, but Ligand B (92.168) is slightly better than Ligand A (82.474). However, BBB is less crucial for a kinase inhibitor unless CNS targets are specifically desired.

**9. Caco-2:** Both have negative Caco-2 permeability values, which is unusual and suggests a potential issue with intestinal absorption. This needs further investigation, but it's a flag for both.

**10. Solubility:** Ligand A (-2.454) has better (less negative) solubility than Ligand B (-5.669). Solubility is a critical factor for bioavailability.

**11. hERG:** Ligand A (0.579) has a much lower hERG risk than Ligand B (0.781). This is a significant advantage, as hERG inhibition can lead to cardiotoxicity.

**12. Cl_mic:** Ligand A (25.966) has a lower microsomal clearance, indicating better metabolic stability than Ligand B (80.34). This is a key advantage for kinase inhibitors.

**13. t1/2:** Ligand A (-32.255) has a negative half-life, which is not physically possible and indicates an issue with the data or the model. Ligand B (34.98) has a reasonable in vitro half-life. This is a major concern for Ligand A.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.125 and 0.139).

**15. Binding Affinity:** Ligand B (-7.9) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage, and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. However, it has some concerning ADME properties (higher logP, lower solubility, higher DILI, and higher Cl_mic). Ligand A has better ADME properties (lower DILI, better solubility, lower Cl_mic) but extremely poor binding affinity and a physically impossible half-life.

Given the critical importance of potency for kinase inhibitors, and the magnitude of the difference in binding affinity (-7.9 vs 0.0), Ligand B is the more promising candidate *despite* its ADME liabilities. These liabilities could potentially be addressed through further optimization, but a compound with no initial affinity is unlikely to be viable. The negative half-life for Ligand A is a showstopper.

Output:
1
2025-04-17 16:36:56,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.395 Da and 354.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.56) is better than Ligand B (49.41), being below the 140 A^2 threshold, suggesting good absorption potential for both.

**logP:** Ligand A (2.07) is within the optimal 1-3 range, while Ligand B (3.277) is approaching the upper limit.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are below the 10 threshold.

**QED:** Ligand A (0.872) has a better QED score than Ligand B (0.771), indicating a more drug-like profile.

**DILI:** Ligand B (21.908) has a significantly lower DILI risk than Ligand A (55.021), which is a major advantage.

**BBB:** Ligand B (92.943) has a much higher BBB penetration score than Ligand A (63.28), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.943 and -4.647), which is unusual and potentially problematic. However, these values are on a log scale, so the absolute difference might not be huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.288 and -3.242), which is also concerning. Solubility issues could hinder bioavailability.

**hERG Inhibition:** Ligand A (0.271) has a slightly lower hERG risk than Ligand B (0.555), which is favorable.

**Microsomal Clearance:** Ligand A (24.187 mL/min/kg) has a lower microsomal clearance than Ligand B (40.301 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.916 hours) has a significantly longer in vitro half-life than Ligand A (-6.028 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.215 and 0.231).

**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 substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better QED and slightly lower hERG risk, Ligand B is superior overall. The significantly stronger binding affinity (-8.5 vs -7.0 kcal/mol) and longer half-life are crucial for an enzyme target. The lower DILI risk is also a major benefit. The solubility and Caco-2 permeability are concerns for both, but the potency and stability advantages of Ligand B are more important in this context.

Output:
1
2025-04-17 16:36:56,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (340.471 and 376.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.02) is well below the 140 threshold and excellent for oral absorption. Ligand B (133.91) is still within acceptable limits, though less favorable.

**logP:** Ligand A (3.573) is optimal. Ligand B (-1.613) is significantly low, potentially hindering membrane permeability and absorption.

**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 (0.855 and 0.51), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (40.403 and 48.972), below the concerning threshold of 60.

**BBB:** Ligand A (70.919) shows good BBB penetration, while Ligand B (39.783) is lower. This isn't a primary concern for a non-CNS target like SRC, but it's a positive for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.815) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.652) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.021) has poor aqueous solubility, while Ligand B (-2.002) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.554) has a very low hERG risk, a major advantage. Ligand B (0.048) is extremely low, also excellent.

**Microsomal Clearance:** Ligand A (73.42) has moderate clearance, while Ligand B (-42.576) has negative clearance, indicating high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-22.034) has a negative half-life, indicating very high stability. Ligand B (-40.831) is also very stable.

**P-gp Efflux:** Ligand A (0.509) shows moderate P-gp efflux. Ligand B (0.006) 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 (0.0 kcal/mol). This is a crucial factor.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a low hERG risk, and good BBB penetration. However, it suffers from poor Caco-2 permeability and aqueous solubility. Ligand B has excellent metabolic stability (negative clearance), low P-gp efflux, and better solubility, but its binding affinity is extremely weak and logP is very low.

Given the enzyme-kinase specific priorities, the strong binding affinity of Ligand A is paramount. While its solubility and permeability are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The extremely weak binding of Ligand B makes it a poor starting point, even with its favorable ADME properties.

Output:
1
2025-04-17 16:36:56,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 385.921 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.9 and 84.14) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.176) is quite low, potentially hindering permeation. Ligand B (2.992) 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 6 HBA, and Ligand B has 7 HBA, both are within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (48.197) has a lower DILI risk than Ligand B (60.062), which is a positive for Ligand A. However, both are reasonably acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (56.572) has slightly better BBB penetration than Ligand B (43.505).

**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:** Both ligands have low hERG inhibition liability (0.137 and 0.2), which is excellent.

**Microsomal Clearance:** Ligand A (24.381) has significantly lower microsomal clearance than Ligand B (36.565), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (10.641) has a shorter half-life than Ligand B (34.408), but both are reasonable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.153 and 0.467).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). The difference is 0.4 kcal/mol, which is not a huge difference.

**Overall Assessment:**

Ligand B has a better logP and binding affinity. However, Ligand A has a significantly better microsomal clearance, lower DILI risk, and a reasonable binding affinity. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. Given the importance of metabolic stability for kinase inhibitors, and the acceptable (though not ideal) affinity of Ligand A, I would favor Ligand A.

Output:
0
2025-04-17 16:36:56,710 - INFO - Batch 478 complete. Total preferences: 7648
2025-04-17 16:36:56,710 - INFO - Processing batch 479/512...
2025-04-17 16:37:48,480 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.435 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.48) is slightly higher than Ligand B (67.87). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (0.406) is quite low, potentially hindering permeability. Ligand B (1.868) 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.628 and 0.688), indicating good drug-like properties.

**DILI:** Ligand A (34.161) has a slightly higher DILI risk than Ligand B (20.706), though both are below the concerning threshold of 60.

**BBB:** Ligand A (59.093) and Ligand B (79.217). BBB is less critical for a non-CNS target like SRC kinase, but higher is generally preferable. Ligand B has a better BBB score.

**Caco-2 Permeability:** Ligand A (-5.181) has poor Caco-2 permeability, while Ligand B (-4.65) is slightly better.

**Aqueous Solubility:** Ligand A (-0.724) has poor aqueous solubility, while Ligand B (-1.596) is also poor, but less so. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.538) and Ligand B (0.401) both show low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (8.339) has a lower microsomal clearance than Ligand B (37.464), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (5.059) has a shorter half-life than Ligand B (13.217). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.026) has very low P-gp efflux, while Ligand B (0.053) is slightly higher. Lower efflux is better.

**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 (0.3 kcal/mol), it's enough to be considered.

**Overall Assessment:**

Ligand B has advantages in logP, TPSA, Caco-2 permeability, BBB, and binding affinity. However, Ligand A has a significantly better microsomal clearance, suggesting improved metabolic stability. The binding affinity difference is small, and the metabolic stability advantage of Ligand A is substantial for an enzyme target. The solubility of both is poor, but Ligand B is slightly better.

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG), and the fact that the binding affinity difference is relatively small, **Ligand A is the slightly more promising candidate due to its superior metabolic stability**.

Output:
0
2025-04-17 16:37:48,480 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.483 and 347.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is better than Ligand B (110.53), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (-0.044) is slightly lower than optimal (1-3), but still acceptable. Ligand B (0.927) is within the ideal range.

**H-Bond Donors/Acceptors:** Ligand A (3 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:** Both ligands have good QED scores (0.415 and 0.784 respectively), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (16.169) has a much lower DILI risk than Ligand B (67.507). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (43.001) is slightly better than Ligand A (32.92), but not a deciding factor.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.191 and -5.064). This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.242 and -3.027). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.058 and 0.078). This is good.

**Microsomal Clearance:** Ligand B (1.004) has significantly lower microsomal clearance than Ligand A (23.159), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (19.346) has a longer in vitro half-life than Ligand A (-13.949), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.023).

**Binding Affinity:** Both ligands have comparable binding affinity (-7.9 and -7.0 kcal/mol). Ligand A is slightly better, but the difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

While Ligand A has a better DILI score and slightly better binding affinity, Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a better QED score. The poor solubility and Caco-2 permeability are concerning for both, but the metabolic advantage of Ligand B is crucial for an enzyme target like SRC kinase. The slightly better binding affinity of Ligand A is not enough to overcome the significant metabolic liabilities.

Output:
1
2025-04-17 16:37:48,480 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight (MW):** Both ligands (369.845 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.86) is well below the 140 threshold for oral absorption and even below 90, potentially allowing for some CNS penetration, though that's not a priority here. Ligand B (107.19) is still under 140, but higher than A.

**3. logP:** Ligand A (2.599) is optimal (1-3). Ligand B (0.249) is quite low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 3 respectively), 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 (0.735 and 0.625), indicating drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (57.929 and 51.881), which is acceptable (below 60).

**8. BBB:** Not a high priority for a kinase inhibitor, but Ligand A (44.591) is lower than Ligand B (60.876).

**9. Caco-2:** Both have negative values, which is unusual. Assuming these represent logP-like scales, the values are similar.

**10. Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.167) is slightly better than Ligand B (-2.259).

**11. hERG:** Ligand A (0.028) has a very low hERG risk, which is excellent. Ligand B (0.268) is slightly higher, but still relatively low.

**12. Cl_mic:** Ligand A (-7.306) has *much* lower (better) microsomal clearance than Ligand B (37.429), indicating significantly better metabolic stability.

**13. t1/2:** Ligand A (12.286) has a better in vitro half-life than Ligand B (26.342).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.012 and 0.045).

**15. Binding Affinity:** Ligand A (-9.3) has a significantly stronger binding affinity than Ligand B (-8.8). This is a >1 kcal/mol difference, which is substantial.

**Conclusion:**

Ligand A is the superior candidate. While both have acceptable DILI and Pgp efflux, Ligand A excels in key areas: significantly better binding affinity, much lower microsomal clearance (better metabolic stability), a longer half-life, and a more optimal logP. The slightly better solubility and lower hERG risk further strengthen its profile. Ligand B's low logP is a significant concern, potentially hindering absorption.

Output:
1
2025-04-17 16:37:48,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.419 and 337.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.96) is better than Ligand B (74.86), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.355) is within the optimal 1-3 range. Ligand B (3.575) is at the higher end, potentially causing solubility issues.

**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:** Ligand A (0.452) and Ligand B (0.389) are both below the desired 0.5 threshold, indicating suboptimal drug-likeness.

**DILI:** Ligand A (59.403) has a lower DILI risk than Ligand B (65.491), both are acceptable but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.205) has a slightly higher BBB value than Ligand A (49.515).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.222 and -5.574), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.826 and -3.879), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.212) has a much lower hERG risk than Ligand B (0.937). This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (56.375) has a lower microsomal clearance than Ligand B (75.002), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.747) has a more negative half-life, which is not ideal. Ligand B (13.945) has a positive half-life, indicating better stability.

**P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux than Ligand B (0.578), which is favorable.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is small, it's enough to consider given the other factors.

**Overall Assessment:**

Ligand A is the better candidate despite the poor solubility and permeability. It has a significantly lower hERG risk, better metabolic stability (lower Cl_mic), lower DILI risk, and slightly better binding affinity. While both compounds have poor solubility and permeability, the safety profile of Ligand A is much more favorable, which is crucial for kinase inhibitors. The slight improvement in binding affinity further supports choosing Ligand A.

Output:
0
2025-04-17 16:37:48,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.471 and 354.338 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is excellent, well below the 140 threshold for oral absorption. Ligand B (130.4) is still acceptable, but less ideal.

**logP:** Ligand A (0.593) is a bit low, potentially hindering permeation. Ligand B (-0.39) is even lower, raising more concerns about permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED values (0.762 and 0.572), indicating good drug-like properties.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (58.395), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (73.943 and 73.517), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.444 and -5.433), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.349 and -2.408), indicating poor aqueous solubility, which is problematic for bioavailability.

**hERG Inhibition:** Ligand A (0.701) shows a lower hERG inhibition liability than Ligand B (0.083), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-8.204) has a much lower (better) microsomal clearance than Ligand B (-5.831), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-2.72) has a negative half-life, which is unusual. Ligand B (11.903) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.01).

**Binding Affinity:** Ligand B (-7.3) has a significantly better binding affinity than Ligand A (0.0). This is a crucial factor. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is the most important factor for an enzyme inhibitor. However, it suffers from higher DILI risk, lower hERG safety, and a less favorable microsomal clearance. Both ligands have poor predicted permeability and solubility. Despite the better affinity, the poor ADME profile of Ligand B is concerning. Ligand A, while having a very weak binding affinity, has a much better safety profile (DILI, hERG) and metabolic stability.

Given the enzyme-specific priorities, the binding affinity difference is substantial enough to favor Ligand B *if* the ADME issues can be addressed through further optimization. However, considering the current data, the poor solubility and permeability of both compounds are major hurdles.

Output:
1
2025-04-17 16:37:48,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (368.371 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.64) is better than Ligand B (78.51), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (1.959 and 1.733) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3 HBA, which is acceptable.

**QED:** Ligand B (0.742) has a significantly better QED score than Ligand A (0.508), indicating a more drug-like profile.

**DILI:** Ligand B (20.396) has a much lower DILI risk than Ligand A (33.695), which is a significant advantage.

**BBB:** Both ligands have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (66.111) is slightly better than Ligand A (54.478).

**Caco-2 Permeability:** Ligand A (-4.833) has better Caco-2 permeability than Ligand B (-5.179), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-1.505) has better aqueous solubility than Ligand B (-2.752). This is a positive attribute for bioavailability.

**hERG Inhibition:** Ligand A (0.499) has a slightly better hERG profile than Ligand B (0.203), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (3.456) has a significantly higher microsomal clearance than Ligand A (0.544), suggesting lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-2.894) has a much longer in vitro half-life than Ligand B (0.84), further supporting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability, which is good. Ligand A (0.066) is slightly better than Ligand B (0.04).

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.5), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A has a slight edge in binding affinity, solubility, and Caco-2 permeability. However, Ligand B demonstrates a substantially better QED score and, crucially, a significantly lower DILI risk and better BBB penetration. The most important factor favoring Ligand A is its superior metabolic stability (lower Cl_mic and longer t1/2). Considering the enzyme-specific priorities, metabolic stability is critical. The 0.4 kcal/mol difference in binding affinity is not large enough to overcome the metabolic liabilities of Ligand B.

Output:
0
2025-04-17 16:37:48,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.579 Da) is slightly higher than Ligand B (355.389 Da), but both are acceptable.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (99.77). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 2.776, B: 1.185), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for membrane permeability but requires consideration of solubility.

**H-Bond Donors/Acceptors:** Both have similar HBD (A: 2, B: 3) and HBA (A: 4, B: 4) counts, falling within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.72, B: 0.579), indicating good drug-like properties.

**DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (47.189), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (74.874) has a higher BBB score than Ligand A (49.36), but this isn't a major deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.242 for A, -5.572 for B). This 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 (-3.613 for A, -2.584 for B). Again, this is unusual, but the values are close.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.176, B: 0.278), which is excellent.

**Microsomal Clearance:** Ligand B (-0.731) has a *negative* microsomal clearance, which is highly unusual and suggests very high metabolic stability. Ligand A (13.785) has a moderate clearance. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-9.054) has a very long in vitro half-life, again due to the negative value, indicating exceptional stability. Ligand A (-1.421) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.095, B: 0.023), which is favorable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B exhibits exceptional metabolic stability (negative Cl_mic and half-life) and a slightly better P-gp profile, Ligand A possesses a significantly stronger binding affinity (-8.6 vs -7.3 kcal/mol). Given that we are targeting an enzyme (SRC kinase), potency is paramount. The slightly better TPSA and DILI of Ligand A also contribute to its favorability. The negative Caco-2 and solubility values are concerning for both, but the strong binding affinity of Ligand A makes it the more promising candidate, assuming these solubility/permeability issues can be addressed through formulation or further chemical modifications.

Output:
0
2025-04-17 16:37:48,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (336.351 and 348.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.71) is slightly above the preferred <140, but acceptable. Ligand B (95.94) is well within the acceptable range.

**3. logP:** Ligand A (1.419) is within the optimal 1-3 range. Ligand B (-0.53) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**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: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands (A: 0.658, B: 0.629) are above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (82.435) has a higher DILI risk than Ligand B (41.411). This is a significant concern.

**8. BBB:** Both ligands have low BBB penetration (A: 26.638, B: 26.483), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.367 and -5.064), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.39 and -2.424), indicating very poor aqueous solubility. This is a significant issue for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.188, B: 0.044). This is positive.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-13.166) has a *much* lower (better) microsomal clearance than Ligand B (-2.291), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (41.792) has a longer half-life than Ligand B (-11.015). This is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.071, B: 0.088).

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (A: -8.2, B: -8.3). The difference is negligible.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Comparison & Decision:**

Ligand A has a significantly better metabolic profile (lower Cl_mic, longer t1/2) and a lower DILI risk. However, both ligands suffer from poor predicted solubility and permeability. The binding affinity is essentially the same. The lower DILI risk and better metabolic stability of Ligand A outweigh its slightly higher TPSA and the similar permeability issues.

Output:
1
2025-04-17 16:37:48,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 337.379 Da - Within the ideal range (200-500).
* Ligand B: 368.441 Da - Also within the ideal range.
* *No clear advantage here.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 84.23  - Excellent, well below 140, suggesting good absorption.
* Ligand B: 100.94 - Still good, below 140, but higher than A.
* *Ligand A has a slight advantage.*

**3. Lipophilicity (logP):**
* Ligand A: 2.502 - Optimal (1-3).
* Ligand B: 1.375 - Also optimal, but closer to the lower end.
* *Ligand A has a slight advantage.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Meets the criteria (<=5).
* Ligand B: 3 - Meets the criteria (<=5).
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 4 - Meets the criteria (<=10).
* Ligand B: 8 - Meets the criteria (<=10).
* *Ligand A has a slight advantage.*

**6. QED:**
* Ligand A: 0.793 - Excellent, well above 0.5.
* Ligand B: 0.625 - Good, above 0.5.
* *Ligand A has a clear advantage.*

**7. DILI:**
* Ligand A: 74.409 - Moderate risk, but acceptable.
* Ligand B: 39.356 - Low risk, significantly better.
* *Ligand B has a significant advantage.*

**8. BBB:**
* Ligand A: 62.854 - Not a priority for a non-CNS target like SRC.
* Ligand B: 58.55 - Not a priority.
* *No clear advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -4.598 - Poor permeability.
* Ligand B: -5.395 - Very poor permeability.
* *Both have poor permeability, but ligand B is slightly worse.*

**10. Aqueous Solubility:**
* Ligand A: -4.395 - Poor solubility.
* Ligand B: -2.224 - Better solubility than A, but still poor.
* *Ligand B has a slight advantage.*

**11. hERG Inhibition:**
* Ligand A: 0.212 - Low risk, excellent.
* Ligand B: 0.925 - Moderate risk.
* *Ligand A has a significant advantage.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 34.179 mL/min/kg - Relatively high clearance, suggesting lower metabolic stability.
* Ligand B: 0.421 mL/min/kg - Very low clearance, excellent metabolic stability.
* *Ligand B has a significant advantage.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: -14.62 hours - Negative value is concerning and likely an error, suggesting very rapid degradation.
* Ligand B: 11.663 hours - Good half-life.
* *Ligand B has a significant advantage.*

**14. P-gp Efflux:**
* Ligand A: 0.141 - Low efflux, good.
* Ligand B: 0.136 - Very low efflux, excellent.
* *Ligand B has a slight advantage.*

**15. Binding Affinity:**
* Ligand A: -8.3 kcal/mol - Excellent, very strong binding.
* Ligand B: -7.7 kcal/mol - Good, strong binding, but less than A.
* *Ligand A has a clear advantage.*

**Summary & Enzyme-Specific Priorities:**

For an enzyme (kinase) target like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand A has a significantly better binding affinity (-8.3 vs -7.7 kcal/mol), and a much better hERG profile. However, Ligand B excels in metabolic stability (Cl_mic and t1/2) and DILI risk. Both have poor solubility and permeability. The difference in binding affinity between A and B is substantial (0.6 kcal/mol), which is enough to outweigh the ADME concerns of A, especially given that formulation strategies can be employed to address solubility and permeability. The poor half-life of A is a major concern.

Output:
1
2025-04-17 16:37:48,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.415 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.88) is better than Ligand B (93.01). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Both ligands have similar logP values (1.391 and 1.312), falling 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:** Ligand B (7) is slightly higher than Ligand A (5), but both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.823 and 0.885), indicating drug-likeness.

**DILI:** Ligand A (32.067) has a significantly lower DILI risk than Ligand B (72.509). This is a major advantage for Ligand A.

**BBB:** This is less crucial for a non-CNS target like SRC, but Ligand A (90.074) is better than Ligand B (56.65).

**Caco-2 Permeability:** Ligand A (-4.45) is better than Ligand B (-5.182). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-1.069) is better than Ligand B (-2.578). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.44) has a lower hERG inhibition risk than Ligand B (0.205). Lower is better.

**Microsomal Clearance:** Ligand A (34.522) has lower microsomal clearance, suggesting better metabolic stability, compared to Ligand B (55.197).

**In vitro Half-Life:** Ligand A (-17.884) has a longer in vitro half-life than Ligand B (0.314), indicating better stability.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux than Ligand B (0.093), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.1). 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 critical ADME properties (DILI, solubility, metabolic stability, hERG, P-gp efflux). While Ligand B has slightly better binding affinity, the superior ADME profile of Ligand A, particularly the significantly lower DILI risk and better metabolic stability, makes it the more promising drug candidate.

Output:
0
2025-04-17 16:37:48,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties crucial for enzyme-kinase inhibitors (potency, metabolic stability, solubility, and hERG risk).

**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, but both are acceptable.

**TPSA:** Ligand A (65.54) is better than Ligand B (80.12). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.069, Ligand B: 2.013), falling within the optimal range of 1-3.

**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 have reasonable QED scores (Ligand A: 0.889, Ligand B: 0.776), indicating good drug-like properties.

**DILI:** Ligand A (19.969) has a significantly lower DILI risk than Ligand B (43.195). This is a major advantage for Ligand A.

**BBB:** Both have similar BBB penetration (Ligand A: 61.962, Ligand B: 64.793). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.985) is slightly better than Ligand B (-5.04).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.349) is slightly better than Ligand B (-3.111).

**hERG Inhibition:** Ligand A (0.248) shows a much lower risk of hERG inhibition than Ligand B (0.55). This is a significant advantage for Ligand A, as kinase inhibitors often struggle with off-target cardiac effects.

**Microsomal Clearance:** Ligand A (4.904) has a much lower microsomal clearance than Ligand B (53.175). This suggests better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (11.55) has a positive half-life, while Ligand B (-18.218) has a negative half-life. This is a huge advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (Ligand A: 0.042, Ligand B: 0.14).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall:** Ligand A is clearly superior. It has better DILI risk, hERG inhibition, metabolic stability (lower Cl_mic, higher t1/2), solubility, and binding affinity. While both have poor Caco-2 permeability, the other advantages of Ligand A make it a more promising drug candidate.

Output:
0
2025-04-17 16:37:48,482 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [351.447, 85.62, 2.04, 2, 5, 0.819, 42.691, 89.104, -4.79, -2.102, 0.39, 29.231, 51.815, 0.105, -6.7]
**Ligand B:** [332.491, 6.48, 4.48, 0, 2, 0.814, 22.024, 97.131, -4.904, -5.013, 0.981, 51.051, -12.896, 0.672, -8]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (351.447) is slightly higher than B (332.491), but both are acceptable.
2. **TPSA:** A (85.62) is better than B (6.48). While both are below 140, B is significantly lower, which *could* indicate better permeability, but also potentially reduced solubility.
3. **logP:** A (2.04) is optimal. B (4.48) is pushing the upper limit and could present solubility and off-target issues.
4. **HBD:** A (2) is good. B (0) is also acceptable, but a lack of HBD can sometimes hinder solubility.
5. **HBA:** A (5) is good. B (2) is also good.
6. **QED:** Both are very similar and good (A: 0.819, B: 0.814).
7. **DILI:** A (42.691) is better than B (22.024), indicating a lower risk of liver injury.
8. **BBB:** A (89.104) is good, B (97.131) is excellent. However, SRC is not a CNS target, so this is less critical.
9. **Caco-2:** Both are negative, indicating poor permeability. This is a significant concern for both.
10. **Solubility:** A (-2.102) is better than B (-5.013), though both are poor.
11. **hERG:** A (0.39) is much better than B (0.981), indicating lower cardiotoxicity risk.
12. **Cl_mic:** A (29.231) is better than B (51.051), indicating better metabolic stability.
13. **t1/2:** A (51.815) is much better than B (-12.896), indicating a significantly longer half-life.
14. **Pgp:** A (0.105) is better than B (0.672), indicating lower P-gp efflux.
15. **Binding Affinity:** B (-8) is 1.3 kcal/mol better than A (-6.7). This is a substantial difference in potency.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While B has a significantly better binding affinity, it suffers from worse metabolic stability, solubility, and a higher hERG risk. A has better ADME properties overall, and a reasonable binding affinity.

**Conclusion:**

Despite the superior binding affinity of Ligand B, the significantly better ADME profile of Ligand A, particularly its lower DILI risk, better metabolic stability, longer half-life, and lower hERG risk, makes it the more promising drug candidate. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand A, whereas fixing the ADME liabilities of Ligand B would likely be more challenging.

Output:
1
2025-04-17 16:37:48,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.31 Da) is slightly higher than Ligand B (338.459 Da), but both are acceptable.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (88.75). Lower TPSA generally indicates better cell permeability.

**logP:** Both ligands have good logP values (A: 3.919, B: 3.323), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=2) is preferable to Ligand B (HBD=3, HBA=6) as it has fewer hydrogen bond donors and acceptors, which can improve permeability.

**QED:** Ligand A (0.748) has a higher QED score than Ligand B (0.505), indicating a more drug-like profile.

**DILI:** Ligand A (48.313) has a significantly lower DILI risk than Ligand B (60.217). This is a crucial advantage.

**BBB:** This is less important for a non-CNS target like SRC, but Ligand A (98.022) has a higher BBB percentile than Ligand B (71.656).

**Caco-2 Permeability:** Ligand A (-4.306) has a worse Caco-2 permeability than Ligand B (-5.525). However, the TPSA difference is more important for absorption.

**Aqueous Solubility:** Ligand A (-4.708) has worse aqueous solubility than Ligand B (-2.957). This is a potential drawback for Ligand A, but can be mitigated through formulation.

**hERG:** Both ligands have similar hERG inhibition liability (A: 0.821, B: 0.885), and are at acceptable levels.

**Microsomal Clearance:** Ligand A (38.317) has significantly lower microsomal clearance than Ligand B (60.677), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.565) has a much shorter in vitro half-life than Ligand B (15.052). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.329, B: 0.262).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 kcal/mol and -8.9 kcal/mol respectively), with a negligible difference.

**Overall Assessment:**

Ligand A excels in most key ADME properties (TPSA, QED, DILI, Cl_mic) and has comparable binding affinity to Ligand B. However, its significantly shorter half-life is a major concern. Ligand B has a better half-life and solubility, but suffers from higher DILI risk, higher TPSA, and worse metabolic stability. Given the importance of metabolic stability for kinases, and the relatively small difference in binding affinity, the lower DILI risk and better TPSA of Ligand A are more compelling. While the half-life is a concern, it might be addressable through structural modifications.

Output:
0
2025-04-17 16:37:48,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.475 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (78.87), both are below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.346) is optimal, while Ligand B (1.175) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, below the threshold of 10.

**QED:** Ligand B (0.643) has a slightly better QED score than Ligand A (0.449), indicating a more drug-like profile.

**DILI:** Ligand B (8.298) has a significantly lower DILI risk than Ligand A (23.187), which is a major advantage.

**BBB:** Ligand B (71.384) has a better BBB penetration score than Ligand A (46.879), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.434) has a worse Caco-2 permeability than Ligand B (-4.66).

**Aqueous Solubility:** Ligand A (-2.177) has a slightly better aqueous solubility than Ligand B (-2.287).

**hERG Inhibition:** Ligand A (0.346) has a lower hERG inhibition liability than Ligand B (0.599), which is favorable.

**Microsomal Clearance:** Ligand B (32.563) has a lower microsomal clearance than Ligand A (25.137), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.061) has a better in vitro half-life than Ligand A (-30.406).

**P-gp Efflux:** Ligand A (0.186) has a lower P-gp efflux liability than Ligand B (0.102).

**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 minor ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. The significantly improved binding affinity (-9.1 vs -6.9 kcal/mol) is a key factor. It also demonstrates better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a better QED score. While Ligand A has slightly better solubility and hERG inhibition, the potency and safety advantages of Ligand B are more important for an enzyme target like SRC kinase. The slightly lower logP of Ligand B is a minor concern, but the strong binding affinity should compensate for this.

Output:
1
2025-04-17 16:37:48,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.458 and 364.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (67.43). A TPSA under 140 is good for oral absorption, and both are well within that, but lower is generally preferred.

**logP:** Ligand A (4.451) is slightly higher than the optimal range (1-3), while Ligand B (2.688) is within the optimal range. High logP can lead to solubility issues, but is less concerning than a very low logP.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.875 and 0.73), indicating good drug-like properties.

**DILI:** Ligand A (36.952) has a slightly higher DILI risk than Ligand B (29.43), but both are below the concerning threshold of 60.

**BBB:** Both have high BBB penetration (91.857 and 83.792), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.347 and -4.618), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-5.094 and -3.616), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.763) has a slightly higher hERG risk than Ligand B (0.366), but both are relatively low.

**Microsomal Clearance:** Ligand A (55.201) has higher microsomal clearance than Ligand B (45.009), suggesting lower metabolic stability. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand B (-7.375) has a significantly *longer* in vitro half-life than Ligand A (36.411). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.538) has lower P-gp efflux than Ligand B (0.083), which is preferable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate. Its superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG risk outweigh the slightly higher logP and lower P-gp efflux. The poor solubility and permeability are concerning for both, but could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 16:37:48,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.475 and 349.352 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (30.49) as it is closer to the threshold for good oral absorption.

**logP:** Ligand B (3.967) is higher than ideal (1-3), potentially leading to solubility issues. Ligand A (1.503) is within the optimal range.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (3) are within the acceptable limit of 10.

**QED:** Both ligands (0.699 and 0.606) are above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (12.02) has a significantly lower DILI risk than Ligand B (54.789), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (76.464 and 77.239), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.376) has a worse Caco-2 permeability than Ligand B (-4.504).

**Aqueous Solubility:** Ligand A (-1.64) has better aqueous solubility than Ligand B (-5.035).

**hERG Inhibition:** Ligand A (0.366) has a much lower hERG inhibition risk than Ligand B (0.946), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (-6.933) shows significantly better metabolic stability (lower clearance) than Ligand B (67.92).

**In vitro Half-Life:** Ligand A (3.662) has a better in vitro half-life than Ligand B (0.991).

**P-gp Efflux:** Ligand A (0.017) has lower P-gp efflux than Ligand B (0.738).

**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.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity, Ligand A excels in critical ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic and better t1/2), lower hERG inhibition, better solubility, and lower P-gp efflux. These factors are prioritized for enzyme inhibitors like SRC kinase. The slightly lower Caco-2 permeability of Ligand A is less concerning given its other advantages.



Output:
0
2025-04-17 16:37:48,482 - INFO - Batch 479 complete. Total preferences: 7664
2025-04-17 16:37:48,482 - INFO - Processing batch 480/512...
2025-04-17 16:38:29,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.523 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.02) is significantly better than Ligand B (94.48). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand A is much closer to optimal.

**logP:** Ligand A (4.697) is higher than optimal (1-3), but still potentially manageable. Ligand B (0.406) is quite low, which could hinder membrane permeability and potentially reduce potency.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is acceptable. Ligand A has 3 HBAs, while Ligand B has 6. Lower HBA counts are generally preferred for better permeability.

**QED:** Both ligands have similar QED values (0.673 and 0.628), indicating reasonable drug-likeness.

**DILI:** Both ligands have low DILI risk (38.813 and 34.161), which is positive.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.488) is better than Ligand B (59.093), but neither is particularly high.

**Caco-2 Permeability:** Ligand A (-4.951) is better than Ligand B (-5.181), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.195) is better than Ligand B (-0.724), which is a significant advantage for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.67 and 0.538), which is good.

**Microsomal Clearance:** Ligand B (8.339) has a much lower Cl_mic than Ligand A (64.022), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (24.199) has a better in vitro half-life than Ligand B (5.059).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.64 and 0.026), which is good.

**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.

**Conclusion:**

While Ligand B has better metabolic stability (lower Cl_mic) and slightly better P-gp efflux, Ligand A's significantly superior binding affinity (-8.6 vs -7.5 kcal/mol) and better solubility, Caco-2 permeability, and TPSA make it the more promising candidate. The higher logP of Ligand A is a concern, but the strong binding affinity is likely to compensate. The difference in affinity is large enough to overcome the slightly less favorable ADME profile of Ligand A.

Output:
1
2025-04-17 16:38:29,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.531 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is well below the 140 threshold, and even better for potential CNS penetration. Ligand B (78.51) is still under 140, but less favorable.

**logP:** Ligand A (3.841) is at the higher end of the optimal range (1-3), but acceptable. Ligand B (0.976) is slightly below the optimal range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is excellent. Ligand B (2 HBD, 3 HBA) is also good, within the recommended limits.

**QED:** Both ligands have acceptable QED scores (0.732 and 0.591, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (18.108) has a very low DILI risk, which is excellent. Ligand B (15.394) is also low, but slightly higher than Ligand A.

**BBB:** Ligand A (87.088) shows good BBB penetration potential, while Ligand B (52.695) is lower. This is less critical for a non-CNS target like SRC, but a bonus.

**Caco-2 Permeability:** Ligand A (-4.69) has poor Caco-2 permeability. Ligand B (-5.263) is also poor.

**Aqueous Solubility:** Ligand A (-3.943) has poor aqueous solubility. Ligand B (-2.295) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.641) has a low hERG risk, which is favorable. Ligand B (0.078) has a very low hERG risk, even better.

**Microsomal Clearance:** Ligand A (77.937) has a relatively high microsomal clearance, indicating lower metabolic stability. Ligand B (-9.196) has negative clearance which is excellent, indicating very high metabolic stability.

**In vitro Half-Life:** Ligand A (-2.204) has a negative half-life, which is excellent. Ligand B (11.301) has a good half-life.

**P-gp Efflux:** Ligand A (0.484) has low P-gp efflux, which is good. Ligand B (0.011) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This difference of 1.4 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

While Ligand A has a better safety profile (lower DILI) and slightly better BBB penetration, Ligand B's significantly superior binding affinity (-8.5 vs -7.1 kcal/mol) and excellent metabolic stability (negative Cl_mic) are crucial for an enzyme target like SRC kinase. The slightly lower solubility and Caco-2 permeability of Ligand B are less concerning given the potency advantage. The very low hERG and P-gp efflux are also beneficial.

Output:
1
2025-04-17 16:38:29,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.387 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is slightly higher than Ligand B (71.78), but both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.521) is slightly higher than the optimal range (1-3), while Ligand B (2.533) is within the optimal range. This gives a slight edge to Ligand B.

**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 B (0.779) has a significantly better QED score than Ligand A (0.449), indicating a more drug-like profile.

**DILI:** Ligand A (94.843) has a very high DILI risk, exceeding the 60% threshold, which is a major concern. Ligand B (33.424) has a low DILI risk, well below the 40% threshold. This is a significant advantage for Ligand B.

**BBB:** Ligand A (52.617) and Ligand B (85.459) both have moderate BBB penetration, but Ligand B is better. Since SRC is not a CNS target, this is a lower priority.

**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. Again, the scale is not defined.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.406 and 0.48, respectively).

**Microsomal Clearance:** Ligand A (92.16) has a higher microsomal clearance than Ligand B (54.471), indicating lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand B (29.816 hours) has a significantly longer half-life than Ligand A (-2.315 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.654 and 0.099, respectively).

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly better binding affinity than Ligand B (-6.1 kcal/mol). This is a substantial advantage for Ligand A. However, the difference in affinity is large enough to potentially offset some of the ADME liabilities.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its extremely high DILI risk and poor metabolic stability are major drawbacks. Ligand B, while having a weaker binding affinity, exhibits a much more favorable ADME profile, including low DILI risk, better metabolic stability, and a longer half-life. For an enzyme target like SRC kinase, metabolic stability and safety (DILI) are crucial. The 4.1 kcal/mol difference in binding affinity *might* be overcome with further optimization of Ligand B, whereas mitigating the DILI risk of Ligand A would likely require substantial structural changes that could severely impact potency.

Output:
1
2025-04-17 16:38:29,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (352.356 Da and 373.837 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (44.12) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (93.9) is still under 140, but less favorable than A.

**3. logP:** Ligand A (3.684) is within the optimal range of 1-3. Ligand B (1.614) is at the lower end, potentially impacting permeability.

**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:** Ligand A (4) and Ligand B (6) are both under the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.771 and 0.73), indicating drug-like properties.

**7. DILI:** Ligand A (44.242) has a slightly better DILI score than Ligand B (50.136), both are acceptable.

**8. BBB:** Both ligands have high BBB penetration (88.949 and 81.039), but this is less critical for an oncology target unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.445 and -4.678), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.221 and -2.63), which is also unusual and suggests poor solubility. This is a significant concern.

**11. hERG Inhibition:** Ligand A (0.71) has a lower hERG risk than Ligand B (0.263), which is preferable.

**12. Microsomal Clearance:** Ligand A (52.465) has higher microsomal clearance than Ligand B (25.418), indicating lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (-5.144) has a longer in vitro half-life than Ligand A (10.001). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.412) has lower P-gp efflux than Ligand B (0.168), which is preferable.

**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 that can outweigh some ADME concerns.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the significantly stronger binding affinity of Ligand B (-8.3 kcal/mol vs -6.9 kcal/mol) is a major advantage for an enzyme target. The better half-life of B also contributes to its favorability. While Ligand A has slightly better hERG and P-gp profiles, the potency difference is more important in this case. The negative Caco-2 and solubility values for both compounds are concerning and would require further investigation (e.g., experimental validation, salt screening, formulation studies). However, given the choice between these two, the stronger binding affinity of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 16:38:29,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.435 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.37) is better than Ligand B (57.7). While both are reasonably low, lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (3.21) is within the optimal range (1-3), while Ligand B (1.77) is at the lower end. This suggests Ligand A might have better membrane permeability, but Ligand B's lower logP could be beneficial for solubility.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.856) has a significantly higher QED score than Ligand B (0.777), indicating a more drug-like profile.

**DILI:** Ligand A (86.196) has a high DILI risk, while Ligand B (11.632) has a very low DILI risk. This is a major concern for Ligand A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (80.264) is higher than Ligand B (54.168), but this is less important.

**Caco-2 Permeability:** Ligand A (-4.504) and Ligand B (-4.981) 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 (-6.098) has very poor solubility, while Ligand B (-0.108) has slightly better solubility. Solubility is a critical factor for bioavailability.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.628 and 0.621).

**Microsomal Clearance:** Ligand B (-25.93) has significantly lower (better) microsomal clearance than Ligand A (43.863), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.892) has a much longer in vitro half-life than Ligand A (75.342). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.418 and 0.025).

**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 significant, but may not outweigh the ADME concerns for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and QED, but suffers from very high DILI risk, poor solubility, and higher metabolic clearance. Ligand B, while having slightly weaker affinity, exhibits a much better safety profile (low DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and better solubility. Considering the enzyme-kinase specific priorities, metabolic stability and safety are crucial. The 0.8 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, while mitigating the severe liabilities of Ligand A would be much more challenging.

Output:
1
2025-04-17 16:38:29,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.471 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (59 and 56.92) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (2.857) is optimal, while Ligand B (3.483) is slightly higher but still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within the desirable ranges.

**QED:** Both ligands have good QED scores (0.822 and 0.715), indicating drug-like properties.

**DILI:** Ligand A (18.224) has a significantly lower DILI risk than Ligand B (33.307). This is a major advantage.

**BBB:** Both have relatively low BBB penetration (41.528 and 49.554), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.422) has worse Caco-2 permeability than Ligand B (-5.067), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.676) has better aqueous solubility than Ligand B (-1.834).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.749 and 0.768).

**Microsomal Clearance:** Ligand B (9.457 mL/min/kg) has significantly lower microsomal clearance than Ligand A (70.92 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (54.01 hours) has a much longer in vitro half-life than Ligand A (15.195 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.497 and 0.082).

**Binding Affinity:** Ligand B (-7.6 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 other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better aqueous solubility. The slightly lower Caco-2 permeability of Ligand B is a minor drawback compared to the advantages it offers.

Output:
1
2025-04-17 16:38:29,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.403 Da) is slightly higher than Ligand B (349.435 Da), but both are acceptable.

**TPSA:** Ligand A (122.75) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (80.56) is well within the acceptable range.

**logP:** Ligand A (-0.904) is a bit low, potentially hindering permeation. Ligand B (1.038) 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 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.689 and 0.59), indicating reasonable drug-likeness.

**DILI:** Ligand A (83.133) has a higher DILI risk than Ligand B (56.262). This is a significant concern.

**BBB:** Not a primary concern for a non-CNS target like SRC, but Ligand B (70.531) has better BBB penetration than Ligand A (43.117).

**Caco-2 Permeability:** Ligand A (-5.722) shows poor permeability, while Ligand B (-4.529) is better, though still not ideal.

**Aqueous Solubility:** Ligand A (-2.103) has very poor aqueous solubility, a major drawback. Ligand B (-0.528) is slightly better, but still low.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.054 and 0.193).

**Microsomal Clearance:** Ligand A (-12.514) has significantly lower (better) microsomal clearance than Ligand B (65.477), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.972) has a longer half-life than Ligand B (-3.069), which is desirable.

**P-gp Efflux:** Both ligands have similar low P-gp efflux liability (0.016 and 0.038).

**Binding Affinity:** Both ligands have comparable binding affinities (-9.0 and -8.2 kcal/mol). Ligand A is slightly better (-9.0 kcal/mol).

**Overall Assessment:**

Ligand A has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). However, its major drawbacks are very poor aqueous solubility, low Caco-2 permeability, and a higher DILI risk. Ligand B has better solubility and permeability, lower DILI risk and better BBB penetration, but its metabolic stability is a concern.

Considering the enzyme-specific priorities, metabolic stability is crucial. While Ligand A has a substantial advantage in this area, the poor solubility and permeability, coupled with the higher DILI risk, are significant liabilities that would likely hinder its development. Ligand B, despite its lower metabolic stability, presents a more balanced profile with better solubility, permeability, and safety.

Output:
1
2025-04-17 16:38:29,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (373.806 Da) is also good.

**TPSA:** Ligand A (70.59) is higher than Ligand B (35.58). Lower TPSA generally favors better absorption, so Ligand B has an advantage here.

**logP:** Both ligands have good logP values (A: 4.905, B: 3.044), falling within the optimal range of 1-3. Ligand A is a bit high, potentially leading to off-target effects or solubility issues.

**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 good QED values (A: 0.692, B: 0.821), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 68.437%, which is approaching the higher risk threshold. Ligand B has a much lower DILI risk (27.181%), a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (92.555%) has a higher BBB penetration than Ligand A (43.815%), but this isn't a major factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.836 and -4.864), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.786 and -3.953), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (A: 0.776, B: 0.882), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (106.89) than Ligand B (17.023). Lower clearance is preferred for better metabolic stability, giving Ligand B a substantial advantage.

**In vitro Half-Life:** Ligand A has a longer half-life (20.311) than Ligand B (11.198), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.423, B: 0.235), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B exhibits significantly lower DILI risk and much better metabolic stability (lower Cl_mic). The slightly lower TPSA and higher QED also contribute to its favorability. The longer half-life of Ligand A is a plus, but the higher DILI and clearance are concerning. Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial, making Ligand B the better choice.

Output:
1
2025-04-17 16:38:29,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, while Ligand B (363.443 Da) is still well within the range.

**TPSA:** Ligand A (54.78) is significantly better than Ligand B (89.35). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (A: 0.853, B: 1.15), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=4) has a more favorable profile than Ligand B (HBD=1, HBA=7). Fewer hydrogen bonds can improve membrane permeability.

**QED:** Both ligands have good QED scores (A: 0.589, B: 0.832), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (38.813) has a much lower DILI risk than Ligand B (70.221). This is a significant advantage for Ligand A.

**BBB:** Both have similar BBB penetration (A: 56.805, B: 55.448), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.293) has a more negative Caco-2 value, indicating lower permeability. Ligand B (-5.087) is even lower. This is a concern for both, but more so for B.

**Aqueous Solubility:** Both have negative solubility values (A: -1.896, B: -2.021), indicating poor solubility. This is a drawback for both, but needs to be considered alongside other factors.

**hERG:** Both ligands have very low hERG risk (A: 0.232, B: 0.181), which is excellent.

**Microsomal Clearance:** Ligand A (9.406) has significantly lower microsomal clearance than Ligand B (29.743), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (3.666) has a shorter half-life than Ligand B (20.501). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux (A: 0.062, B: 0.034), which is good.

**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 a major advantage considering the other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and QED, Ligand A excels in critical areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic), and a more favorable TPSA and H-bond profile. The lower half-life of Ligand A is a concern, but could potentially be addressed through structural modifications. The poor solubility of both is a concern, but can be addressed through formulation strategies. The slightly lower Caco-2 permeability of Ligand A is less concerning than the other issues with Ligand B.

Output:
0
2025-04-17 16:38:29,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.431 and 350.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.07) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (109.22) is still under 140, but less favorable than A.

**logP:** Ligand A (2.548) is optimal (1-3). Ligand B (-0.243) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5/6 HBA, respectively, which are within acceptable limits.

**QED:** Ligand A (0.897) has a significantly better QED score than Ligand B (0.688), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (62.737 and 62.233), placing them in a moderate risk category, but not alarmingly high.

**BBB:** Ligand A (79.721) has a better BBB percentile than Ligand B (43.583), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.88) is better than Ligand B (-5.661), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.089) is better than Ligand B (-1.163), which is crucial for bioavailability.

**hERG:** Ligand A (0.442) has a lower hERG risk than Ligand B (0.024), which is highly desirable.

**Microsomal Clearance:** Ligand A (75.515) has higher clearance than Ligand B (2.659), meaning B is more metabolically stable. This is a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (35.518) has a longer half-life than Ligand B (25.727), which is preferable.

**P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux than Ligand B (0.011), indicating better bioavailability.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly better binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has superior ADME properties across the board (solubility, permeability, metabolic stability, hERG, QED), Ligand B boasts a significantly stronger binding affinity (-7.6 vs -8.6 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. The 1.0 kcal/mol difference in binding affinity is substantial enough to favor Ligand B, despite its less favorable logP and slightly higher P-gp efflux. The metabolic stability of B is also a significant plus.

Output:
1
2025-04-17 16:38:29,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (84.42). A TPSA under 140 is good for oral absorption, and both meet this, but lower is generally preferred.

**logP:** Both ligands have acceptable logP values (3.358 and 2.02), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 6. Lower HBA is generally preferred for better permeability.

**QED:** Both ligands have similar and acceptable QED scores (0.768 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A (11.206) has a much lower DILI risk than Ligand B (42.962). This is a major advantage for Ligand A.

**BBB:** Ligand A (87.941) has a higher BBB penetration percentile than Ligand B (57.852). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.824 and -4.851), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.673 and -2.463), indicating poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.729) has a slightly higher hERG risk than Ligand B (0.33). Lower is better here, so Ligand B is slightly favored.

**Microsomal Clearance:** Ligand A (69.209) has a significantly higher microsomal clearance than Ligand B (18.501). This suggests Ligand B is more metabolically stable, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (31.797 hours) has a much longer in vitro half-life than Ligand A (3.823 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.139 and 0.277).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a crucial factor, and the 1.2 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, but suffers from higher metabolic clearance, shorter half-life, and slightly higher hERG risk. Ligand B has better metabolic stability, a longer half-life, and lower hERG risk, but its binding affinity is considerably weaker.

Given the importance of potency for kinase inhibitors, the 1.2 kcal/mol advantage of Ligand A is a major factor. While the ADME properties of Ligand A are less ideal, these can potentially be improved through further optimization. The weaker binding of Ligand B would likely require a much larger optimization effort to achieve comparable potency.

Output:
1
2025-04-17 16:38:29,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.535 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.54) is well below the 140 threshold and excellent for oral absorption. Ligand B (99.1) is higher, but still within a reasonable range, though potentially impacting absorption.

**logP:** Ligand A (4.245) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.097) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is acceptable, but slightly higher.

**QED:** Ligand A (0.772) has a strong drug-like profile. Ligand B (0.502) is at the lower end of acceptable, but still reasonable.

**DILI:** Ligand A (17.216) has a very low DILI risk. Ligand B (27.336) is also relatively low, but higher than A.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (74.564) is better than Ligand B (29.779).

**Caco-2 Permeability:** Ligand A (-5.013) is negative, indicating poor permeability. Ligand B (-4.852) is also negative, but slightly less so. Both are concerning.

**Aqueous Solubility:** Ligand A (-4.749) is poor, consistent with its high logP. Ligand B (-1.241) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.77) is very low risk. Ligand B (0.209) is also low risk.

**Microsomal Clearance:** Ligand A (64.867) is moderate, suggesting reasonable metabolic stability. Ligand B (21.483) is low, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (-8.098) has a long half-life, which is desirable. Ligand B (-14.512) has an even longer half-life, which is excellent.

**P-gp Efflux:** Both ligands (0.68 and 0.017) have low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.1 and -7.9 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand A has a better safety profile (lower DILI) and better QED, but suffers from poor solubility and permeability. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, but a lower QED and slightly higher DILI. Given the enzyme-specific priorities, metabolic stability and half-life are crucial. While both have permeability issues, the superior metabolic profile of Ligand B, combined with a comparable binding affinity, makes it the slightly more promising candidate.

Output:
1
2025-04-17 16:38:29,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.427 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.35) is well below the 140 threshold, while Ligand B (87.74) is still acceptable but closer to the limit.

**logP:** Ligand A (3.945) is at the higher end of the optimal range (1-3), while Ligand B (0.681) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (5) counts.

**QED:** Ligand A (0.916) has a very strong drug-like profile, significantly better than Ligand B (0.595).

**DILI:** Ligand A (61.031) has a moderate DILI risk, while Ligand B (20.744) is very low risk.

**BBB:** Ligand A (70.803) shows good BBB penetration, while Ligand B (36.603) is poor. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.665) has poor Caco-2 permeability, which is concerning. Ligand B (-5.36) is even worse.

**Aqueous Solubility:** Ligand A (-4.599) has poor aqueous solubility, while Ligand B (-0.941) is also poor but slightly better.

**hERG Inhibition:** Ligand A (0.63) has a low hERG risk, which is excellent. Ligand B (0.156) is also very low risk.

**Microsomal Clearance:** Ligand A (51.786) has moderate clearance, while Ligand B (-4.372) has *negative* clearance, which is highly unusual and suggests excellent metabolic stability.

**In vitro Half-Life:** Ligand A (2.815) has a short half-life. Ligand B (-4.717) has a very long half-life, again, an exceptional result.

**P-gp Efflux:** Ligand A (0.201) has low P-gp efflux, which is good. Ligand B (0.011) has very low P-gp efflux.

**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 concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and a good safety profile (low hERG, acceptable DILI). However, it suffers from poor Caco-2 permeability and solubility, and moderate metabolic clearance. Ligand B has a very favorable ADME profile (extremely low DILI, very long half-life, low P-gp efflux, low hERG) but a weaker binding affinity and poor Caco-2 permeability and solubility.

The difference in binding affinity (-8.2 vs -7.2) is substantial. Given that we are targeting an enzyme, potency is paramount. While the ADME properties of Ligand B are excellent, the 1.0 kcal/mol difference in binding affinity of Ligand A is likely to be more critical for achieving efficacy. The poor permeability and solubility of Ligand A could potentially be addressed through formulation strategies.

Output:
0
2025-04-17 16:38:29,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (336.395 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.26) is slightly higher than Ligand B (60.85), but both are well below the 140 threshold for good absorption.

**logP:** Both ligands have good logP values (2.796 and 2.231), 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 good QED scores (0.776 and 0.824), indicating a drug-like profile.

**DILI:** Ligand A has a DILI risk of 77.549, which is concerning (high risk, >60). Ligand B has a much lower DILI risk of 36.022 (good, <40). This is a significant advantage for Ligand B.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (87.864) has a higher value than Ligand B (63.358).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.999 and -4.376), which is unusual and suggests poor permeability. However, these values are on a log scale and likely represent very low permeability.

**Aqueous Solubility:** Ligand A (-3.977) has worse solubility than Ligand B (-1.501). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.763) has a slightly higher hERG risk than Ligand B (0.724), but both are relatively low.

**Microsomal Clearance:** Ligand A (60.251) has a higher microsomal clearance than Ligand B (54.594), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-0.439) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (47.793) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.584) has slightly higher P-gp efflux than Ligand B (0.484), which is less desirable.

**Binding Affinity:** Ligand A (-9.7 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, the significantly higher DILI risk and higher metabolic clearance are major drawbacks. Ligand B has a much better safety profile (lower DILI) and potentially better metabolic stability, even though its binding affinity is much weaker. The negative half-life for Ligand B is a data quality issue.

Given the enzyme-kinase target class, prioritizing metabolic stability and safety (DILI, hERG) alongside potency is crucial. The large difference in binding affinity is tempting, but the DILI risk associated with Ligand A is too high to ignore.

Output:
1
2025-04-17 16:38:29,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (399.263 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (34.89) is significantly better than Ligand B (58.64). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors. Ligand A is well below the 140 threshold, while Ligand B is approaching it.

**logP:** Ligand A (4.823) is higher than Ligand B (2.686). While both are within the acceptable range (1-3 is optimal), Ligand A is pushing the upper limit and could potentially have solubility issues or off-target effects. Ligand B is closer to the ideal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 4 HBA). Fewer H-bonds are generally preferred for permeability.

**QED:** Both ligands have good QED scores (0.59 and 0.678), indicating a generally drug-like profile.

**DILI:** Ligand A (60.915) has a higher DILI risk than Ligand B (31.291). This is a significant concern, as a DILI percentile > 60 is considered high risk.

**BBB:** Ligand A (82.047) has better BBB penetration than Ligand B (68.205). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.762) has a worse Caco-2 permeability than Ligand B (-5.007). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-4.242) has worse solubility than Ligand B (-3.169). Solubility is important for bioavailability.

**hERG:** Ligand A (0.814) has a slightly higher hERG risk than Ligand B (0.458). Lower hERG risk is preferred.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (49.193 and 48.851 mL/min/kg). This suggests similar metabolic stability.

**In vitro Half-Life:** Ligand A (27.319 hours) has a significantly longer half-life than Ligand B (3.295 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.967) has slightly higher P-gp efflux than Ligand B (0.286). Lower P-gp efflux is preferred.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly better binding affinity than Ligand B (-7.7 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher logP, slightly higher hERG, and worse solubility and Caco-2 permeability, its significantly superior binding affinity (-8.8 vs -7.7 kcal/mol) and longer half-life are compelling advantages, especially for a kinase inhibitor where potency and duration of action are crucial. The DILI risk is a concern, but the large affinity difference might allow for dose reduction to mitigate this risk. Ligand B's better ADME profile is overshadowed by its weaker binding.

Output:
1
2025-04-17 16:38:29,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (340.471 and 370.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (66.91 and 67.87) are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (4.159) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.288) is a bit low, potentially impacting 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 (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.72 and 0.714), indicating good drug-likeness.

**7. DILI:** Ligand A (52.385) has a higher DILI risk than Ligand B (30.438). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration (76.735 and 67.623), but this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.737 and -4.977). These values are unusual and difficult to interpret without additional context. However, they both suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.826 and -2.707). These are also unusual and suggest poor solubility.

**11. hERG Inhibition:** Ligand A (0.722) has a slightly higher hERG risk than Ligand B (0.419). Lower is better here, favoring Ligand B.

**12. Microsomal Clearance:** Ligand A (61.906) has a higher microsomal clearance than Ligand B (40.279), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (6.855) has a longer in vitro half-life than Ligand A (39.926). This is a significant advantage for Ligand B, suggesting less frequent dosing potential.

**14. P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux than Ligand B (0.065). Lower is better, favoring Ligand A.

**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 small (0.4 kcal/mol), it's a positive for Ligand A.

**Overall Assessment:**

Despite Ligand A having slightly better binding affinity and P-gp efflux, Ligand B is the more promising candidate. The key advantages of Ligand B are significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. These factors are crucial for kinase inhibitors, where off-target effects and metabolic liabilities are common concerns. The slight difference in binding affinity is unlikely to outweigh the substantial improvements in ADME-Tox properties offered by Ligand B. The negative solubility and Caco-2 values are concerning for both, and would require further investigation, but are less critical than the DILI and metabolic stability issues with Ligand A.

Output:
1
2025-04-17 16:38:29,283 - INFO - Batch 480 complete. Total preferences: 7680
2025-04-17 16:38:29,283 - INFO - Processing batch 481/512...
2025-04-17 16:39:07,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (337.379 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.08) is better than Ligand B (107.89). Both are acceptable, but lower TPSA generally favors absorption.

**logP:** Ligand A (3.089) is optimal (1-3), while Ligand B (0.395) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) and Ligand B (4 HBD, 5 HBA) are both within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.667 and 0.518, respectively), indicating good drug-like properties.

**DILI:** Ligand A (84.645) has a higher DILI risk than Ligand B (29.934). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (51.687) and Ligand B (29.508) are both low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.484 and -5.365), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.014 and -2.373). This is also unusual and suggests poor solubility. This is a concern for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.215 and 0.191), which is excellent.

**Microsomal Clearance:** Ligand A (-19.844) shows significantly better metabolic stability (lower clearance) than Ligand B (3.25). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (10.592 hours) has a better half-life than Ligand B (25.575 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.006).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-9.4 and -9.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the similar binding affinities, Ligand A is the more promising candidate. Its superior logP, significantly better metabolic stability (lower Cl_mic and better half-life), and lower DILI risk outweigh the slightly higher TPSA and DILI percentile. The poor Caco-2 permeability and solubility are concerns for both, but can be addressed through formulation strategies. Ligand B's very low logP is a major disadvantage, likely impacting its absorption.

Output:
0
2025-04-17 16:39:07,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.459 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is higher than Ligand B (58.64). Both are below the 140 A^2 threshold for oral absorption, but B is better.

**logP:** Both ligands (2.191 and 2.82) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand B (0.593) has a better QED score than Ligand A (0.453), indicating a more drug-like profile.

**DILI:** Ligand B (26.755) has a significantly lower DILI risk than Ligand A (52.385). This is a major advantage.

**BBB:** Ligand B (71.772) has a higher BBB penetration score than Ligand A (38.852), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.796 and -4.688), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.468 and -3.037), indicating very poor solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.194) has a slightly lower hERG risk than Ligand B (0.385), which is preferable.

**Microsomal Clearance:** Ligand A (42.24) has a higher microsomal clearance than Ligand B (40.629), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-0.387) has a slightly longer in vitro half-life than Ligand A (-7.635).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.097 and 0.084).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a crucial advantage, as potency is a key priority for enzyme inhibitors.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility and permeability, Ligand B's significantly stronger binding affinity (-8.0 vs -7.6 kcal/mol), lower DILI risk (26.755 vs 52.385), and slightly better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly higher hERG risk. The affinity difference is substantial enough to potentially overcome the solubility/permeability issues through formulation strategies.

Output:
1
2025-04-17 16:39:07,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.471 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is better than Ligand B (116.42). Lower TPSA generally indicates better permeability.

**logP:** Both ligands have acceptable logP values (-0.828 and -0.234), falling within the 1-3 range, though on the lower end.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is slightly 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 scores (0.594 and 0.562), indicating good drug-likeness.

**DILI:** Ligand A (43.079) has a lower DILI risk than Ligand B (52.85), which is favorable. Both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (30.593) has a slightly higher BBB value than Ligand A (19.504), but this is not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand B (-5.234) is slightly better than Ligand A (-4.653), but both are problematic.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.927 and -2.057), indicating poor solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.114 and 0.047), which is excellent.

**Microsomal Clearance:** Ligand B (-28.672) has significantly lower (better) microsomal clearance than Ligand A (22.515). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-14.719) has a longer in vitro half-life than Ligand A (-17.567), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.004), which is good.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-6.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite both ligands having solubility and permeability issues, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.5 vs -6.0 kcal/mol) outweighs the slightly higher DILI risk and lower TPSA. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic) and a longer half-life. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the potency advantage of Ligand B makes it the better starting point.

Output:
1
2025-04-17 16:39:07,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (354.403 and 364.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.33) is better than Ligand B (104.53), both are below the 140 threshold for oral absorption, but A is closer to the 90 threshold for CNS penetration if that were a goal.

**3. logP:** Both ligands (1.154 and 1.245) are within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4). Lower HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.501 and 0.54), indicating good drug-like properties.

**7. DILI:** Ligand A (54.789) has a slightly higher DILI risk than Ligand B (40.287), but both are acceptable (<60).

**8. BBB:** Ligand A (75.572) has better BBB penetration potential than Ligand B (55.874), although this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2:** Ligand A (-4.655) has a worse Caco-2 permeability than Ligand B (-5.359). Lower (more negative) values indicate lower permeability.

**10. Solubility:** Ligand A (-1.26) has better solubility than Ligand B (-2.389). Solubility is important for bioavailability.

**11. hERG:** Ligand A (0.366) has a much lower hERG risk than Ligand B (0.067). This is a significant advantage.

**12. Cl_mic:** Ligand A (40.854) has a higher microsomal clearance than Ligand B (-1.016). Ligand B is much more metabolically stable, which is highly desirable for an enzyme target.

**13. t1/2:** Ligand A (-17.342) has a shorter in vitro half-life than Ligand B (-3.029). Ligand B has a longer half-life, which is preferable.

**14. Pgp:** Ligand A (0.081) has slightly higher Pgp efflux liability than Ligand B (0.028). Lower Pgp is better.

**15. Binding Affinity:** Ligand B (0.0) has a significantly better binding affinity than Ligand A (-6.2). This is the most important factor for an enzyme target. A difference of 6.2 kcal/mol is substantial.

**Overall Assessment:**

While Ligand A has some advantages in terms of solubility, hERG, and BBB, Ligand B's significantly stronger binding affinity (-0.0 vs -6.2 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) outweigh these benefits. The improved affinity is likely to overcome any minor ADME drawbacks.

Output:
1
2025-04-17 16:39:07,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.439 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**TPSA:** Ligand A (83.42) is better than Ligand B (95.33), falling comfortably under the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 1.996, B: 1.682), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 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 (A: 0.713, B: 0.913), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (A: 69.639, B: 66.964), below the 60 threshold.

**BBB:** Ligand A (76.696) has a better BBB penetration score than Ligand B (38.077), but BBB isn't a high priority for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.581 and -4.732), which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.013 and -2.491), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.315, B: 0.154), which is positive.

**Microsomal Clearance:** Ligand A (10.129 mL/min/kg) has significantly lower microsomal clearance than Ligand B (51.093 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (8.585 hours) has a much longer in vitro half-life than Ligand B (-39.416 hours). The negative value for Ligand B is concerning and likely an error or indicates extremely rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.22, B: 0.02).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 kcal/mol and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. It demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better TPSA. The binding affinity is comparable. The poor permeability and solubility are significant issues that would need to be addressed through formulation or further chemical modifications, but the improved pharmacokinetic properties of Ligand A make it the better starting point.

Output:
0
2025-04-17 16:39:07,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.857 Da) is slightly higher than Ligand B (349.479 Da), but both are acceptable.

**TPSA:** Ligand A (90.41) is slightly higher than Ligand B (71.94). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (Ligand A: 1.891, Ligand B: 1.127), 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 similar and good QED values (Ligand A: 0.7, Ligand B: 0.772), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 78.402, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 10.237, a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand B (61.962) is higher than Ligand A (52.772), but this isn't a major factor.

**Caco-2 Permeability:** Ligand A (-4.738) shows poor permeability, while Ligand B (-5.269) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.713) has slightly better solubility than Ligand B (-0.107), although both are poor.

**hERG Inhibition:** Ligand A (0.103) has a slightly better hERG profile than Ligand B (0.489), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (72.17) has higher clearance than Ligand B (-3.64). This suggests Ligand B is more metabolically stable, a key consideration for kinases.

**In vitro Half-Life:** Ligand A (-12.392) has a negative half-life, which is not realistic and indicates a problem with the data or the molecule. Ligand B (18.141) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux than Ligand B (0.003), which is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8.7 kcal/mol, Ligand B: -7.7 kcal/mol). Ligand A is slightly better, but the difference of 1 kcal/mol is likely outweighed by other factors.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity and lower P-gp efflux, Ligand B is the more promising candidate. The significantly lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), and acceptable solubility outweigh the minor advantage in binding affinity. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 16:39:07,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.4 and 348.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.29) is better than Ligand B (91.57). TPSA <140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Both ligands (2.464 and 2.158) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.778 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (87.631) has a significantly higher DILI risk than Ligand B (32.648). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (52.423) is higher, but it's not decisive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.732 and -4.843), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret directly.

**Aqueous Solubility:** Ligand B (-2.098) has better solubility than Ligand A (-4.719). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.65) has a slightly higher hERG risk than Ligand B (0.311), but both are relatively low.

**Microsomal Clearance:** Ligand B (24.149) has significantly lower microsomal clearance than Ligand A (44.54). Lower clearance indicates better metabolic stability, a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand B (31.45) has a longer in vitro half-life than Ligand A (-28.7). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.141 and 0.252).

**Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-6.5). A 1.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both ligands have some issues with Caco-2 permeability, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and, most importantly, a much stronger binding affinity. The better solubility of Ligand B is also a plus. The higher affinity of Ligand B is a major advantage that outweighs the slightly less favorable TPSA and BBB.

Output:
1
2025-04-17 16:39:07,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (335.363 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.19) is slightly higher than Ligand B (71.63), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.584) is slightly higher than Ligand B (2.524), both are 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 has 5 HBA, and Ligand B has 4. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.666 and 0.818 respectively), indicating good drug-like properties.

**DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (58.744). Both are acceptable, but B is preferable.

**BBB:** Ligand A (82.319) has better BBB penetration than Ligand B (70.182). However, BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.853 and -4.63). This is unusual and suggests poor permeability. However, these values are on a log scale, and a negative value doesn't necessarily rule out absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.178 and -4.028). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.856) has a slightly higher hERG risk than Ligand B (0.677), but both are relatively low.

**Microsomal Clearance:** Ligand B (73.728) has significantly higher microsomal clearance than Ligand A (37.399). This indicates that Ligand A is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (17.044) has a longer half-life than Ligand B (7.618), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.396 and 0.362).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). This 0.6 kcal/mol difference is significant, and could potentially outweigh some of the ADME drawbacks of Ligand A.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower DILI risk, Ligand B has a superior binding affinity. Given the enzyme-specific priority on potency, the 0.6 kcal/mol advantage of Ligand B is the deciding factor. The solubility issues are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:39:07,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.423 Da) is slightly better positioned than Ligand B (361.833 Da).

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (88.91). Lower TPSA generally improves absorption.

**logP:** Ligand A (3.641) is optimal, while Ligand B (1.773) is on the lower side, potentially hindering permeation.

**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 forming groups, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.923, B: 0.849), indicating drug-like properties.

**DILI:** Ligand B (79.992) has a higher DILI risk than Ligand A (56.146), making A more favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (76.464) is better than Ligand B (43.893).

**Caco-2 Permeability:** Ligand A (-4.414) is better than Ligand B (-5.403), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.449) is better than Ligand B (-2.939), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.925) has a lower hERG risk than Ligand B (0.035), a significant advantage.

**Microsomal Clearance:** Ligand B (1.891) has a much lower microsomal clearance than Ligand A (71.705), indicating better metabolic stability. This is a strong point for Ligand B.

**In vitro Half-Life:** Ligand A (33.399) has a longer half-life than Ligand B (27.161), which is generally desirable.

**P-gp Efflux:** Ligand A (0.387) has lower P-gp efflux than Ligand B (0.102), which is favorable.

**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 enough to consider, especially given the other favorable properties of Ligand A.

**Overall:** Ligand A demonstrates a more balanced profile with better solubility, permeability, lower DILI and hERG risk, and slightly better binding affinity. While Ligand B has superior metabolic stability, the other drawbacks are more concerning. The slightly better affinity of A combined with the more favorable ADME properties make it a more promising candidate.

Output:
1
2025-04-17 16:39:07,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (341.411 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.43) is better than Ligand B (93.09) as it is closer to the <140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (2.229 and 1.471), falling within the 1-3 range. Ligand B is slightly lower, which could potentially affect permeability.

**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 (0.551 and 0.668), indicating drug-like properties.

**DILI:** Ligand A (32.959) has a lower DILI risk than Ligand B (38.426), which is favorable. Both are below the 40 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (74.176) has a higher BBB percentile than Ligand B (53.432), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-4.762) has a worse Caco-2 permeability than Ligand B (-5.244). Both are negative, but B is more negative.

**Aqueous Solubility:** Ligand A (-3.246) has better aqueous solubility than Ligand B (-1.84), which is important for bioavailability.

**hERG:** Ligand A (0.58) has a lower hERG inhibition liability than Ligand B (0.268), which is a significant advantage, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (31.682) has lower microsomal clearance than Ligand B (36.146), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.635) has a longer in vitro half-life than Ligand B (9.908), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.028) has lower P-gp efflux liability than Ligand B (0.051), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is small (0.4 kcal/mol) and can be outweighed by other factors.

**Overall Assessment:**

Ligand A demonstrates a more favorable profile overall. It has better solubility, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has a slightly better binding affinity, the advantages of Ligand A in ADME-Tox properties are more critical for developing a viable drug candidate, especially for an enzyme target where metabolic stability and safety are paramount.

Output:
0
2025-04-17 16:39:07,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS penetration, but acceptable. Ligand B (76.46) is well within the ideal range.

**logP:** Ligand A (2.124) is optimal. Ligand B (0.971) is a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is excellent. Ligand B (1 HBD, 6 HBA) is also good, within the recommended limits.

**QED:** Both ligands have good QED scores (0.706 and 0.76), indicating drug-like properties.

**DILI:** Ligand A (26.599) has a lower DILI risk than Ligand B (35.634), which is preferable.

**BBB:** Both ligands have similar BBB penetration (53.974 and 52.966), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.966) has a significantly *better* Caco-2 permeability than Ligand B (-5.31). This suggests better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.392) has better aqueous solubility than Ligand B (-1.824). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.106) has a much lower hERG inhibition liability than Ligand B (0.501), which is a significant advantage regarding cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (24.038) has a lower microsomal clearance than Ligand A (47.128), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (3.519) has a slightly longer in vitro half-life than Ligand A (-39.714). However, 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 (0.041 and 0.048).

**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 ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better solubility, and a much lower hERG risk. While Ligand B has better metabolic stability, the significantly stronger binding of Ligand A, coupled with its better solubility and lower toxicity risk, makes it the more promising candidate. The negative half-life for Ligand A is a concern, but the strong binding affinity suggests it might be addressable through structural modifications.

Output:
1
2025-04-17 16:39:07,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (355.507 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (45.23) and Ligand B (41.57) are both below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (3.338 and 3.663) 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 3. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.918) has a significantly higher QED score than Ligand B (0.771), indicating better overall drug-likeness.

**7. DILI:** Ligand A (44.475) has a higher DILI risk than Ligand B (13.804). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (89.608) is significantly higher than Ligand A (77.937). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.081 and -4.729), which is unusual and suggests poor permeability. This is a major concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.905 and -3.5), which is also concerning and indicates poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.78) has a slightly higher hERG inhibition risk than Ligand B (0.702), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (75.842) has a significantly higher microsomal clearance than Ligand A (29.054), indicating lower metabolic stability. This is a major drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (21.536) has a much longer in vitro half-life than Ligand B (7.055), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.488 and 0.458).

**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 higher DILI risk, its significantly superior binding affinity (-9.0 kcal/mol vs -0.0 kcal/mol) and longer half-life outweigh the concerns. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. Ligand B's high microsomal clearance is a major drawback, suggesting rapid metabolism and potentially low bioavailability. The substantial difference in binding affinity makes Ligand A the more promising candidate.

Output:
1
2025-04-17 16:39:07,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.355 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.66) is slightly above the preferred <140, but acceptable. Ligand B (70.47) is excellent, well below 140.

**logP:** Both ligands (0.643 and 0.72) are a bit low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, fitting well within the guidelines. Ligand B has 1 HBD and 5 HBA, also good.

**QED:** Both ligands have good QED scores (0.845 and 0.787), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 67.817, which is concerning, placing it in the high-risk category (>60). Ligand B has a DILI risk of 11.206, which is excellent, well below the 40 threshold. This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (20.512) and Ligand B (55.797) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.803 and -5.066), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.465 and -0.237), which is also unusual and suggests poor solubility. This is a potential issue for both.

**hERG:** Both ligands show very low hERG inhibition liability (0.272 and 0.25), which is excellent.

**Microsomal Clearance:** Ligand A has a very low (good) Cl_mic (-12.853), indicating high metabolic stability. Ligand B has a Cl_mic of 4.857, which is less favorable, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a very short half-life (-0.863), which is undesirable. Ligand B has a longer half-life (4.985), which is better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.006), which is good.

**Binding Affinity:** Ligand B (-8 kcal/mol) has a significantly stronger binding affinity than Ligand A (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 superior candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly stronger binding affinity (-8 vs 0 kcal/mol) and much lower DILI risk (11.206 vs 67.817) are decisive. The longer half-life of Ligand B is also a plus. Although Ligand A has better metabolic stability (lower Cl_mic), the potency and safety profile of Ligand B are far more compelling for a kinase inhibitor.

Output:
1
2025-04-17 16:39:07,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.547 and 348.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.2) is well below the 140 threshold and favorable for oral absorption. Ligand B (71.78) is also below the threshold, but higher than A.

**logP:** Both ligands have good logP values (4.04 and 2.291), falling within the optimal 1-3 range. Ligand B is slightly preferred here.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 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 (0.659 and 0.886), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (18.302) has a lower DILI risk than Ligand B (15.432), which is preferable.

**BBB:** Both ligands have good BBB penetration (74.758 and 84.374). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.589 and -4.516), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.802 and -2.542), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.575 and 0.591), which is good.

**Microsomal Clearance:** Ligand A (76.63) has significantly higher microsomal clearance than Ligand B (31.876). This means Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (21.064 hours) has a much longer half-life than Ligand A (9.739 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.233 and 0.198).

**Binding Affinity:** Ligand A (-7.7 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:**

The biggest issues for both compounds are the negative Caco-2 and solubility values. However, Ligand A's superior binding affinity (-7.7 vs -6.7 kcal/mol) is a significant advantage. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better QED, the potency difference is likely more critical for an enzyme inhibitor. The lower DILI score for Ligand A is also a positive. Given the importance of potency for kinase inhibitors, and the relatively minor differences in other ADME properties, Ligand A is the more promising candidate, *assuming* the negative Caco-2 and solubility can be addressed through formulation or structural modification.

Output:
0
2025-04-17 16:39:07,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.543 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly above the preferred <140, but acceptable. Ligand B (54.34) is excellent.

**logP:** Both ligands (3.015 and 3.282) 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 (3) are both acceptable (<=10).

**QED:** Both ligands have good QED scores (0.744 and 0.805), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (32.881 and 38.891, both <40).

**BBB:** Both ligands have moderate BBB penetration (63.048 and 71.501). Not a primary concern for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values (-4.922 and -4.669), which is unusual and potentially problematic. This suggests poor permeability, but these values may be errors or indicate a specific transport mechanism.

**Solubility:** Both ligands have negative solubility values (-3.829 and -3.628), which is also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG:** Both ligands have very low hERG risk (0.219 and 0.469). This is excellent.

**Microsomal Clearance:** Ligand B (58.594) has a lower microsomal clearance than Ligand A (71.371), suggesting better metabolic stability, which is a high priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (11.19 hours) has a significantly longer half-life than Ligand A (-5.97 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.299).

**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 massive.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B's superior metabolic stability (lower Cl_mic) and longer half-life are crucial for an enzyme inhibitor. The slightly better binding affinity of B is also a plus. The negative Caco-2 and solubility values are concerning and would require further investigation (e.g., experimental validation, salt screening, formulation studies). However, the ADME properties of B are generally more favorable.

Output:
1
2025-04-17 16:39:07,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.427 and 352.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (40.62). Lower TPSA generally favors better cell permeability, and both are well below the 140 threshold.

**logP:** Ligand B (3.708) is better than Ligand A (0.636). Ligand A's low logP is a significant concern, potentially hindering membrane permeability and bioavailability. Ligand B is 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 2 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.554) has a better QED score than Ligand A (0.376), indicating a more drug-like profile.

**DILI:** Ligand A (27.608) has a lower DILI risk than Ligand B (37.611), which is favorable. Both are below the concerning threshold of 60.

**BBB:** Ligand B (89.725) has a higher BBB penetration than Ligand A (30.128). While SRC isn't a CNS target, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Ligand A (-5.037) has very poor Caco-2 permeability, a major red flag. Ligand B (-3.995) is also poor, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.972 and -2.433 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.031) has slightly lower hERG inhibition risk than Ligand B (0.875), which is preferred.

**Microsomal Clearance:** Ligand A (22.291) has significantly lower microsomal clearance than Ligand B (76.58), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**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's stability. Ligand B (23.438) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.03 and 0.633 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic) and lower DILI risk, but suffers from extremely poor Caco-2 permeability, a negative half-life, and a very low logP. These ADME properties are severely detrimental. Ligand B has better logP, QED, and a reasonable half-life, but higher DILI and worse metabolic stability. The negative half-life for Ligand A is a dealbreaker.

Output:
1
2025-04-17 16:39:07,935 - INFO - Batch 481 complete. Total preferences: 7696
2025-04-17 16:39:07,935 - INFO - Processing batch 482/512...
2025-04-17 16:39:50,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.403 and 341.386 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.74) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (61.44) is excellent, well below 140.

**logP:** Ligand A (-0.323) is a bit low, potentially hindering permeability. Ligand B (2.855) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable.

**H-Bond Acceptors:** Ligand A (8) is acceptable. Ligand B (2) is excellent.

**QED:** Both ligands (0.723 and 0.784) have good drug-likeness scores, exceeding 0.5.

**DILI:** Both ligands have high DILI risk (87.864 and 85.227). This is a concern for both, but not a deciding factor between them.

**BBB:** Both ligands have moderate BBB penetration (65.839 and 80.613). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have poor Caco-2 permeability (-4.719 and -4.666). This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.922 and -4.751). This is a major concern for *in vivo* bioavailability.

**hERG Inhibition:** Ligand A (0.203) has a very low hERG risk, which is excellent. Ligand B (0.639) has a moderate hERG risk.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (35.26 and 36.215 mL/min/kg), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand A (-18.978) has a very short half-life, a significant drawback. Ligand B (30.467) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.014 and 0.303), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -9.3 kcal/mol). Ligand B is slightly better, but the difference is not huge.

**Conclusion:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. It has a better logP, fewer H-bond acceptors, a longer half-life, and slightly better binding affinity. The biggest advantage of Ligand A is its very low hERG risk, but the extremely short half-life is a major concern. Given the enzyme-specific priorities, the longer half-life of Ligand B outweighs the slightly higher hERG risk. Both have high DILI risk, which would need to be addressed in further optimization.

Output:
1
2025-04-17 16:39:50,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.415 and 365.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is slightly higher than Ligand B (75.44), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.0) is within the optimal 1-3 range. Ligand B (3.04) is at the higher end, but still acceptable.

**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 (0.544 and 0.786), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Both ligands have similar, acceptable DILI risk (50.291 and 54.323 percentile).

**BBB:** Ligand A (81.892) shows better BBB penetration than Ligand B (73.943), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.475) has a better Caco-2 permeability than Ligand B (-4.866).

**Aqueous Solubility:** Ligand A (-2.166) has better aqueous solubility than Ligand B (-4.791). This is a significant advantage for an enzyme inhibitor, aiding in formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.627) has a lower hERG inhibition risk than Ligand B (0.184), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (86.392) has a higher microsomal clearance than Ligand B (36.747). This means Ligand B is more metabolically stable, a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-7.302) has a significantly longer in vitro half-life than Ligand A (-41.06). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.277).

**Binding Affinity:** Both ligands have identical binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has a better half-life and metabolic stability, Ligand A has better solubility and a significantly lower hERG risk. Given the enzyme-specific priorities, the lower hERG risk and better solubility of Ligand A are more critical. The difference in half-life is substantial, but can potentially be addressed through prodrug strategies or formulation approaches. The equal binding affinity makes the ADME properties the deciding factors.

Output:
0
2025-04-17 16:39:50,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**
*   **MW:** 361.475 Da - Good, within the ideal range.
*   **TPSA:** 97.62 A<sup>2</sup> - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 1.418 - Optimal.
*   **HBD:** 2 - Good.
*   **HBA:** 8 - Good.
*   **QED:** 0.803 - Excellent, highly drug-like.
*   **DILI:** 62.621 - Moderate risk, slightly elevated.
*   **BBB:** 57.736 - Low, not a concern for a non-CNS target.
*   **Caco-2:** -5.66 - Very poor permeability. A significant negative.
*   **Solubility:** -2.557 - Very poor solubility. A significant negative.
*   **hERG:** 0.126 - Very low risk, excellent.
*   **Cl_mic:** 2.816 mL/min/kg - Good, indicating reasonable metabolic stability.
*   **t1/2:** 15.632 hours - Good, suggesting a reasonable half-life.
*   **Pgp:** 0.01 - Low efflux, favorable.
*   **Affinity:** -8.8 kcal/mol - Excellent, very strong binding.

**Ligand B:**
*   **MW:** 370.465 Da - Good, within the ideal range.
*   **TPSA:** 42.41 A<sup>2</sup> - Excellent, very favorable for absorption.
*   **logP:** 4.913 - High, potentially problematic for solubility and off-target effects.
*   **HBD:** 0 - Low, could impact solubility.
*   **HBA:** 5 - Good.
*   **QED:** 0.594 - Acceptable, but lower than Ligand A.
*   **DILI:** 19.465 - Very low risk, excellent.
*   **BBB:** 94.145 - High, not relevant for this target.
*   **Caco-2:** -4.852 - Poor permeability, but better than Ligand A.
*   **Solubility:** -4.933 - Very poor solubility, similar to Ligand A.
*   **hERG:** 0.919 - Moderate risk, higher than Ligand A.
*   **Cl_mic:** 86.446 mL/min/kg - High, indicating poor metabolic stability. A significant negative.
*   **t1/2:** 19.055 hours - Good, but potentially misleading given high Cl_mic.
*   **Pgp:** 0.578 - Moderate efflux.
*   **Affinity:** 0.0 kcal/mol - Very weak binding.

**Comparison & Decision:**

Ligand A has a significantly superior binding affinity (-8.8 kcal/mol vs 0.0 kcal/mol) and a better DILI score. While both have poor solubility and Caco-2 permeability, the strong binding of Ligand A is a major advantage for an enzyme target like SRC kinase. The higher metabolic clearance of Ligand B is a significant drawback. Ligand A's slightly elevated DILI risk might be manageable with further optimization, but the lack of potency in Ligand B is a more fundamental issue.

Output:
1
2025-04-17 16:39:50,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Ligand A:**

*   **MW:** 345.487 Da - Within the ideal range (200-500).
*   **TPSA:** 54.34 - Good for oral absorption (<140).
*   **logP:** 2.501 - Optimal (1-3).
*   **HBD:** 1 - Acceptable (<5).
*   **HBA:** 3 - Acceptable (<10).
*   **QED:** 0.825 - Excellent (>0.5).
*   **DILI:** 12.524 - Very low risk (<40).
*   **BBB:** 82.745 - Good, but not critical for a non-CNS target.
*   **Caco-2:** -4.897 - Poor permeability. This is a significant concern.
*   **Solubility:** -2.293 - Poor solubility. Another significant concern.
*   **hERG:** 0.452 - Low risk.
*   **Cl_mic:** 47.631 - Moderate clearance, not ideal but manageable.
*   **t1/2:** -4.82 - Very short half-life. A major drawback.
*   **Pgp:** 0.378 - Low efflux, favorable.
*   **Affinity:** -8.5 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 351.407 Da - Within the ideal range (200-500).
*   **TPSA:** 137.39 - Borderline for oral absorption, but acceptable.
*   **logP:** -0.428 - Below optimal, may impede permeation.
*   **HBD:** 4 - Acceptable (<5).
*   **HBA:** 4 - Acceptable (<10).
*   **QED:** 0.505 - Acceptable, just above the threshold.
*   **DILI:** 36.099 - Low risk (<40).
*   **BBB:** 56.65 - Not relevant for a non-CNS target.
*   **Caco-2:** -5.787 - Very poor permeability. A major concern.
*   **Solubility:** -1.891 - Poor solubility. A concern.
*   **hERG:** 0.109 - Very low risk.
*   **Cl_mic:** -6.908 - Very low clearance, excellent metabolic stability.
*   **t1/2:** 5.811 - Good half-life.
*   **Pgp:** 0.013 - Very low efflux, favorable.
*   **Affinity:** -7.1 kcal/mol - Very good binding affinity, close to Ligand A.

**Comparison & Decision:**

Both ligands have significant issues with permeability and solubility. However, Ligand A has a substantially better binding affinity (-8.5 vs -7.1 kcal/mol) and a lower DILI risk. Ligand B has a much better half-life and lower clearance, which is a significant advantage. The difference in binding affinity between the two is 1.4 kcal/mol, which is enough to outweigh the ADME concerns. While the poor Caco-2 and solubility of Ligand A are concerning, these can potentially be addressed with formulation strategies. The short half-life, however, is more difficult to overcome. Ligand B's superior metabolic stability and half-life are valuable, but the lower binding affinity is a significant drawback for an enzyme target.

Considering the priorities for enzyme inhibitors, the stronger binding affinity of Ligand A is more crucial. While the ADME properties are suboptimal, the potency advantage is substantial and could be prioritized for further optimization.

Output:
0
2025-04-17 16:39:50,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (375.921 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.17) is well below the 140 threshold, while Ligand B (70.08) is still acceptable but less optimal.

**logP:** Ligand A (4.37) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.94) is quite low, which might hinder permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 4 HBA, both within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.862 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 54.983, which is acceptable. Ligand B has a much lower DILI risk of 19.349, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.817) is better than Ligand B (63.358).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.502 and -4.656), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-5.432 and -1.442), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.859) has a higher hERG risk than Ligand B (0.134), which is preferable.

**Microsomal Clearance:** Ligand A (60.179) has a higher clearance than Ligand B (11.455), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand A (80.3) has a longer half-life than Ligand B (16.035), which is desirable.

**P-gp Efflux:** Ligand A (0.692) has lower P-gp efflux than Ligand B (0.044), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.0 kcal/mol). Ligand A is slightly better.

**Conclusion:**

Despite the similar binding affinities, Ligand A is slightly more promising. While its logP is higher and clearance is faster, it has a better BBB score, lower P-gp efflux, and a longer half-life. The biggest concern for both is the extremely poor predicted solubility and permeability. However, the slightly better overall profile of Ligand A, particularly the lower hERG risk and better metabolic properties, makes it the more viable candidate, assuming solubility/permeability issues can be addressed through formulation or structural modifications.

Output:
1
2025-04-17 16:39:50,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.419 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.39) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (70.08) is excellent, well below 140, suggesting good absorption.

**logP:** Ligand A (0.291) is quite low, potentially hindering membrane permeability. Ligand B (1.838) 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 (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.623, B: 0.8), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 26.095, B: 38.503), below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (43.583) and Ligand B (28.655) are both low.

**Caco-2 Permeability:** Both have negative values (-5.326 and -4.57), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative values (-1.705 and -2.046), which is also unusual and suggests poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands show low hERG risk (A: 0.253, B: 0.155).

**Microsomal Clearance:** Ligand A (6.844) has significantly lower clearance than Ligand B (43.521), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.125) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (-2.6) also has a negative half-life, indicating a data issue.

**P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.014, B: 0.167).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -7.3, B: -7.0). The difference is minor (0.3 kcal/mol), and likely not enough to overcome other deficiencies.

**Overall Assessment:**

Both ligands have issues with Caco-2 permeability and aqueous solubility, which are critical for oral bioavailability. However, Ligand A has a much better microsomal clearance, suggesting better metabolic stability. Ligand B has a better logP and TPSA. The negative half-life values are concerning and suggest data quality issues. Given the enzyme-kinase focus, metabolic stability is crucial. While the solubility/permeability issues are significant, the superior metabolic stability of Ligand A, coupled with its slightly better binding affinity, makes it marginally more promising. However, these solubility/permeability issues *must* be addressed through further optimization.

Output:
0
2025-04-17 16:39:50,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (370.471 and 345.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.85) is better than Ligand B (45.23) as it is closer to the ideal threshold of <140.

**3. logP:** Ligand A (1.612) is optimal (1-3). Ligand B (4.104) is pushing the upper limit and could present 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 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.788 and 0.809), indicating good drug-like properties.

**7. DILI:** Ligand A (44.048) has a slightly higher DILI risk than Ligand B (13.339), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (82.513 and 84.296). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.819 and -4.802). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.235 and -3.267). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.548) has a lower hERG risk than Ligand B (0.846), which is preferable.

**12. Microsomal Clearance:** Ligand A (36.834) has significantly lower microsomal clearance than Ligand B (53.764), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.291) has a shorter half-life than Ligand B (-1.33). This is a negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux than Ligand B (0.5), which is preferable.

**15. 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, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and lower hERG risk, the significantly stronger binding affinity of Ligand B (-8.9 vs -6.9 kcal/mol) is a decisive factor. The difference in affinity is large enough to potentially overcome the slightly higher DILI and P-gp efflux liabilities of Ligand B. The poor solubility and permeability of both compounds are concerning, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:39:50,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (349.459 and 347.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (36.44) is well below the 140 threshold and excellent for oral absorption. Ligand B (81.1) is still under the 140 threshold, but less ideal than A.

**3. logP:** Both ligands (4.234 and 4.179) are slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors (HBD):** Ligand A (0) is optimal. Ligand B (1) is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is good. Ligand B (3) is good.

**6. QED:** Ligand A (0.694) is excellent, indicating good drug-like properties. Ligand B (0.294) is significantly lower, suggesting potential issues.

**7. DILI:** Ligand A (68.282) has a moderate risk of DILI. Ligand B (14.541) has a very low risk of DILI, which is a significant advantage.

**8. BBB:** Ligand A (93.331) has excellent BBB penetration, while Ligand B (77.705) is reasonable but lower. This is less critical for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-4.605) has poor Caco-2 permeability. Ligand B (-5.103) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-4.653) has poor solubility. Ligand B (-3.661) has slightly better solubility than A, but still poor.

**11. hERG Inhibition:** Both ligands (0.812 and 0.789) have a low risk of hERG inhibition.

**12. Microsomal Clearance (Cl_mic):** Ligand A (95.056) has high microsomal clearance, indicating poor metabolic stability. Ligand B (40.004) has much lower clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (47.806) has a moderate half-life. Ligand B (13.934) has a very short half-life.

**14. P-gp Efflux:** Both ligands (0.775 and 0.042) have low P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-7.9). This 0.1 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Enzyme-Specific Priorities:**  For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a significantly better binding affinity and a much better metabolic stability profile (lower Cl_mic). While its solubility and Caco-2 permeability are also poor, the superior affinity and metabolic stability are more critical for an enzyme target. Ligand A has a better QED and DILI profile, but these are less important than the binding and metabolic properties.

Output:
1
2025-04-17 16:39:50,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.471 and 345.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (63.13), both are below the 140 threshold for oral absorption, but closer to the 90 threshold is preferable.

**3. logP:** Ligand A (1.67) is optimal, while Ligand B (3.114) is nearing the upper limit of the optimal 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 3 HBA, which is good.

**6. QED:** Ligand A (0.796) has a significantly better QED score than Ligand B (0.64), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.532) has a much lower DILI risk than Ligand B (33.424), a crucial advantage.

**8. BBB:** Ligand A (69.794) has a better BBB percentile than Ligand B (56.417), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.775) has better Caco-2 permeability than Ligand B (-4.85), though both are negative values.

**10. Aqueous Solubility:** Ligand A (-2.465) has better aqueous solubility than Ligand B (-3.06), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.391) has a lower hERG inhibition liability than Ligand B (0.478), a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (28.203) has significantly lower microsomal clearance than Ligand B (49.508), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (48.791) has a longer in vitro half-life than Ligand A (10.444). This is a positive for Ligand B, but can be offset by other factors.

**14. P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux liability than Ligand B (0.285), which is favorable.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-9.7 and -9.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in crucial ADME properties like DILI risk, metabolic stability (Cl_mic), solubility, hERG inhibition, and P-gp efflux. While Ligand B has a slightly longer half-life, the superior safety and pharmacokinetic profile of Ligand A outweigh this benefit. Both ligands have comparable binding affinity, so the ADME properties become the deciding factor.

Output:
0
2025-04-17 16:39:50,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.416 and 353.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.84) is better than Ligand B (72.18), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands (2.784 and 2.427) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Ligand A is slightly better here, staying closer to the ideal of <=10.

**QED:** Both ligands (0.823 and 0.782) have excellent drug-likeness scores.

**DILI:** Both ligands have relatively high DILI risk (63.513 and 69.756), which is a concern. Ligand A is slightly better.

**BBB:** Both have moderate BBB penetration (69.407 and 61.225). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.714) is slightly better than Ligand B (-5.036).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.29) is slightly better than Ligand B (-3.283).

**hERG Inhibition:** Both have low hERG inhibition risk (0.805 and 0.448), which is good. Ligand B is better here.

**Microsomal Clearance:** Ligand B (43.95) has significantly lower microsomal clearance than Ligand A (61.717), suggesting better metabolic stability. This is a major advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-22.088) has a much longer in vitro half-life than Ligand A (-42.719), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.324 and 0.177). Ligand B is better.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks. The difference of 1.9 kcal/mol is substantial.

**Conclusion:**

While both compounds have issues with solubility and permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.4 vs -7.5 kcal/mol) and superior metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for an enzyme inhibitor. The slightly better hERG and P-gp profiles also contribute. The DILI risk is a concern for both, but the potency and metabolic stability of Ligand B make it the better choice for further optimization.

Output:
1
2025-04-17 16:39:50,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Ligand A:**

*   **MW:** 372.774 Da - Good (within 200-500 range)
*   **TPSA:** 42.43 - Good (<=140)
*   **logP:** 4.18 - Moderate. Slightly high, potential solubility issues.
*   **HBD:** 0 - Good (<=5)
*   **HBA:** 3 - Good (<=10)
*   **QED:** 0.79 - Excellent (>=0.5)
*   **DILI:** 56.146 - Moderate. Acceptable, but warrants further investigation.
*   **BBB:** 79.488 - Good, but not a primary concern for a non-CNS target like SRC.
*   **Caco-2:** -4.512 - Very Poor. Indicates very poor absorption.
*   **Solubility:** -3.98 - Very Poor. Significant concern.
*   **hERG:** 0.719 - Good (low risk)
*   **Cl_mic:** 50.423 - Moderate. Could be better for metabolic stability.
*   **t1/2:** 7.099 - Moderate.
*   **Pgp:** 0.559 - Good (low efflux)
*   **Affinity:** -8.6 kcal/mol - Excellent. Very strong binding.

**Ligand B:**

*   **MW:** 382.835 Da - Good (within 200-500 range)
*   **TPSA:** 87.66 - Moderate. Could be a slight concern for absorption.
*   **logP:** 1.398 - Good (1-3)
*   **HBD:** 3 - Good (<=5)
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.606 - Good (>=0.5)
*   **DILI:** 28.616 - Excellent (low risk)
*   **BBB:** 70.182 - Good, but not a primary concern.
*   **Caco-2:** -5.209 - Very Poor. Indicates very poor absorption.
*   **Solubility:** -1.978 - Poor.
*   **hERG:** 0.311 - Excellent (very low risk)
*   **Cl_mic:** -9.934 - Excellent. Very metabolically stable.
*   **t1/2:** 17.651 - Excellent. Long half-life.
*   **Pgp:** 0.032 - Excellent (low efflux)
*   **Affinity:** -9.0 kcal/mol - Excellent. Very strong binding, slightly better than Ligand A.

**Comparison & Decision:**

Both ligands have excellent binding affinities. However, Ligand A and B both have very poor Caco-2 permeability and solubility. Ligand B has a significantly better metabolic profile (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG risk. While Ligand A has a slightly higher QED, the ADME properties of Ligand B are substantially better. The slightly higher logP of Ligand A is also a concern. Given the enzyme-kinase focus, metabolic stability and safety (DILI, hERG) are critical.

Therefore, despite the similar binding affinities, Ligand B is the more promising drug candidate due to its superior ADME/Tox profile.

Output:
1
2025-04-17 16:39:50,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.3 and 355.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is better than Ligand B (66.4), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have a logP around 3.2, which is optimal.

**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 good QED scores (0.662 and 0.763), indicating drug-like properties.

**DILI:** Ligand A (83.02) has a higher DILI risk than Ligand B (73.05), but both are still relatively high.

**BBB:** Ligand A (74.53) has a significantly better BBB penetration score than Ligand B (25.71). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.52) has a slightly better Caco-2 permeability than Ligand B (-5.422), suggesting better absorption.

**Aqueous Solubility:** Ligand A (-4.531) has better aqueous solubility than Ligand B (-3.242). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.664) has a higher hERG inhibition risk than Ligand B (0.023). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (19.152) has a much lower microsomal clearance than Ligand A (76.412), indicating better metabolic stability. This is a crucial factor for enzymes.

**In vitro Half-Life:** Both ligands have similar negative half-lives (-12.702 and -13.246), suggesting similar in vitro stability.

**P-gp Efflux:** Ligand A (0.147) has slightly lower P-gp efflux than Ligand B (0.014), suggesting better bioavailability.

**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 ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability (lower Cl_mic) and significantly lower hERG risk, the substantially stronger binding affinity of Ligand A (-8.8 vs -7.6 kcal/mol) is the deciding factor. For an enzyme target like SRC kinase, potency is paramount. While Ligand A has a higher DILI risk and slightly worse metabolic stability, the increased potency is likely to be more impactful in achieving efficacy. The solubility is also better for Ligand A.

Output:
1
2025-04-17 16:39:50,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 362.901 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.44) is slightly higher than Ligand B (53.43). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (2.709 and 3.151), 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 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have acceptable QED scores (0.824 and 0.791), indicating good drug-likeness.

**DILI:** Ligand A (40.713) has a slightly higher DILI risk than Ligand B (17.449). Ligand B is significantly better here, being well below the 40 threshold.

**BBB:** Both ligands have high BBB penetration (88.833 and 80.962). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.875 and -4.62). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference isn't huge.

**Aqueous Solubility:** Both have negative solubility values (-3.311 and -3.885). This is concerning, as solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.497 and 0.62), which is good.

**Microsomal Clearance:** Ligand A (48.521) has slightly better microsomal clearance than Ligand B (45.927), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (23.813) has a significantly longer in vitro half-life than Ligand A (-19.32). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.107 and 0.563).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B is the more promising candidate**. While both have issues with Caco-2 and solubility, Ligand B has a significantly better DILI score and a much longer in vitro half-life. The binding affinity is comparable, and the other parameters are reasonably similar. For an enzyme target like SRC kinase, metabolic stability (half-life) and minimizing toxicity (DILI) are crucial, making Ligand B the preferred choice.

Output:
1
2025-04-17 16:39:50,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.407 and 341.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.78) is better than Ligand B (61.36), being closer to the 140 threshold.

**logP:** Both ligands have good logP values (1.586 and 2.198), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Ligand B (0.89) has a significantly better QED score than Ligand A (0.22), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (47.693 and 44.979, both <60).

**BBB:** Ligand B (81.349) has a much higher BBB penetration percentile than Ligand A (38.271). While SRC is not a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-5.22) and Ligand B (-4.953) both have negative values, which is unusual. However, the values are similar.

**Aqueous Solubility:** Ligand A (-2.173) and Ligand B (-3.001) both have negative solubility values, which is concerning.

**hERG Inhibition:** Ligand A (0.088) has a lower hERG inhibition liability than Ligand B (0.741), which is preferable.

**Microsomal Clearance:** Ligand A (26.735) has significantly lower microsomal clearance than Ligand B (79.029), suggesting better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-9.932) has a much longer in vitro half-life than Ligand A (-3.355), which is desirable.

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.1).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and is the most important factor.

**Conclusion:**

Despite Ligand A having better hERG and lower clearance, the significantly stronger binding affinity of Ligand B (-9.0 vs -6.6 kcal/mol) and its superior QED and half-life outweigh the drawbacks of slightly higher hERG and clearance. The solubility is a concern for both, but the potency advantage of Ligand B is critical for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:39:50,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.67 and 68.82) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.817) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.34) is within the optimal range.

**H-Bond Donors:** Both ligands have 2 HBDs, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (22.334) has a significantly lower DILI risk than Ligand B (43.234), which is a major advantage.

**BBB:** Ligand B (77.162) has a higher BBB penetration score than Ligand A (44.901), but BBB is less critical for a non-CNS target like SRC.

**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 (0.144) has a much lower hERG inhibition liability than Ligand B (0.487), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-5.442) has a much lower (better) microsomal clearance than Ligand B (-38.71). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (11.026 hours) has a longer half-life than Ligand A (1.512 hours). This is a positive for Ligand B, but can be overcome with formulation strategies.

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.053), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 0.8 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity and half-life, Ligand A demonstrates significantly better ADMET properties, particularly regarding DILI risk, hERG inhibition, and metabolic stability (Cl_mic). The lower P-gp efflux is also beneficial. The solubility and permeability concerns are shared by both, but the superior safety and metabolic profile of Ligand A outweigh the modest affinity advantage of Ligand B for an enzyme target like SRC kinase.

Output:
0
2025-04-17 16:39:50,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.471 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is well below the 140 threshold and favorable for oral absorption. Ligand B (96.11) is higher, but still within an acceptable range, though potentially less optimal for absorption.

**3. logP:** Both ligands have logP values within the optimal range (Ligand A: 2.529, Ligand B: 1.971).

**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 (3) is good. Ligand B (4) is also acceptable.

**6. QED:** Both ligands have similar and good QED values (Ligand A: 0.735, Ligand B: 0.731), indicating drug-like properties.

**7. DILI:** Ligand A (18.845) has a significantly lower DILI risk than Ligand B (50.795). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 74.719, Ligand B: 73.672). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 directly compare.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both, but Ligand B's value (-3.841) is worse than Ligand A's (-1.896).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.411, Ligand B: 0.266).

**12. Microsomal Clearance:** Ligand A (46.128) has a lower microsomal clearance than Ligand B (56.139), suggesting better metabolic stability. This is a key advantage.

**13. In vitro Half-Life:** Ligand A (0.134) has a very short half-life, while Ligand B (-49.717) has a negative half-life, which is not physically possible. This is a significant drawback for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.09, Ligand B: 0.057).

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.7). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from a very poor (and unrealistic) in vitro half-life and higher DILI risk. Ligand A has better ADME properties (lower DILI, better metabolic stability, better solubility), but a weaker binding affinity.

Given the importance of potency for enzyme inhibition, the stronger binding affinity of Ligand B is a significant advantage. While the negative half-life is concerning, it could be addressed through structural modifications. The DILI risk is also a concern, but potentially manageable. The solubility issues are present in both.

Output:
1
2025-04-17 16:39:50,010 - INFO - Batch 482 complete. Total preferences: 7712
2025-04-17 16:39:50,010 - INFO - Processing batch 483/512...
2025-04-17 16:40:29,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (362.417 and 350.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (58.2) as it is still below 140, but closer to the optimal range for oral absorption.

**3. logP:** Both ligands have good logP values (1.734 and 3.334), falling within the 1-3 range. Ligand B is slightly higher, potentially increasing off-target effects, but not dramatically.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (2) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar and acceptable QED values (0.583 and 0.558), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (37.263 and 39.822), both below the 40 threshold.

**8. BBB:** Ligand B (81.233) has a higher BBB penetration percentile than Ligand A (52.268), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.968) has slightly better Caco-2 permeability than Ligand B (-4.483), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.513) has better aqueous solubility than Ligand B (-3.494), which is crucial for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.507 and 0.539).

**12. Microsomal Clearance:** Ligand B (29.673) has lower microsomal clearance than Ligand A (33.677), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.267) has a significantly longer in vitro half-life than Ligand A (-12.089). This is a major advantage for dosing frequency.

**14. P-gp Efflux:** Both ligands have similar and low P-gp efflux liability (0.15 and 0.201).

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.6), a difference of 1.4 kcal/mol. This is a substantial advantage that can outweigh some minor ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility and Caco-2 permeability, Ligand B's superior binding affinity (-9.0 vs -7.6 kcal/mol) and longer half-life are more critical for an enzyme target like SRC kinase. The slightly higher logP of Ligand B is not a major concern, and its lower clearance is a significant benefit. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:40:29,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.479 and 376.787 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.48) is better than Ligand B (78.87), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.276 and 1.261), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2), as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (6) is slightly better than Ligand B (5), both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.682 and 0.611), indicating good drug-likeness.

**DILI:** Ligand B (36.293) has a significantly lower DILI risk than Ligand A (47.421), making it more favorable.

**BBB:** Ligand A (77.588) has better BBB penetration than Ligand B (61.342), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.506 and -4.717), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.317 and -2.174), which is also concerning and suggests poor solubility.

**hERG:** Ligand A (0.725) has a slightly better hERG profile than Ligand B (0.481), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (5.678) has significantly lower microsomal clearance than Ligand A (62.744), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (17.19) has a slightly longer half-life than Ligand A (15.633).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.203 and 0.173).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly better binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B has better ADME properties (lower DILI, lower Cl_mic, longer t1/2), Ligand A's significantly stronger binding affinity (-8.7 vs -7.3 kcal/mol) is a crucial factor for an enzyme inhibitor. The 1.4 kcal/mol difference is substantial. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies. The better hERG profile of Ligand A is also a plus. Given the priority on potency for enzyme targets, Ligand A is the more promising candidate despite its slightly worse ADME profile.

Output:
0
2025-04-17 16:40:29,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.411 and 362.817 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.34) is better than Ligand B (98.22), both are below the 140 threshold for oral absorption, but A is closer to the ideal for better absorption.

**logP:** Both ligands have good logP values (2.617 and 1.52), falling within the optimal 1-3 range. Ligand A is slightly better.

**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:** Both ligands have similar QED values (0.897 and 0.848), indicating good drug-likeness.

**DILI:** Ligand A (39.899) has a significantly lower DILI risk than Ligand B (67.313). This is a major advantage for Ligand A.

**BBB:** Ligand A (48.003) has a better BBB penetration score than Ligand B (37.185), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.093 and -5.08), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.317 and -3.85), indicating very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.378) has a lower hERG inhibition liability than Ligand B (0.553), which is preferable.

**Microsomal Clearance:** Ligand A (20.364) has a higher (worse) microsomal clearance than Ligand B (-5.487). This suggests that Ligand B is more metabolically stable.

**In vitro Half-Life:** Both have similar in vitro half-lives (15.972 and 16.154 hours).

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux liability than Ligand B (0.083), which is favorable.

**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, potentially outweighing some of the ADME concerns.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand B's significantly superior binding affinity (-8.9 kcal/mol vs 0.0 kcal/mol) is a decisive factor. The improved metabolic stability (lower Cl_mic) is also beneficial. While Ligand A has better DILI and hERG profiles, the potency difference is too large to ignore for an enzyme target like SRC kinase. Further work would be needed to address the solubility and permeability issues of Ligand B, but its strong binding affinity makes it the more promising candidate.

Output:
1
2025-04-17 16:40:29,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.483 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is slightly higher than Ligand B (62.55). Both are below the 140 A^2 threshold for good oral absorption, but closer to the 90 A^2 threshold for CNS targets (not a primary concern here).

**logP:** Both ligands have good logP values (2.861 and 3.395), 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 3. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.869) has a significantly higher QED score than Ligand B (0.609), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (47.926 and 45.328, respectively), well below the 60 threshold.

**BBB:** Ligand A (83.831) has a higher BBB penetration percentile than Ligand B (64.482). While not a primary concern for a non-CNS target, it's a slight advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.446 and -4.711), which is unusual and indicates very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-3.066 and -3.486), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.46 and 0.681), which is excellent.

**Microsomal Clearance:** Ligand A (7.947) has a much lower microsomal clearance than Ligand B (79.926), suggesting significantly better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (12.078 hours) has a better in vitro half-life than Ligand B (40.012 hours).

**P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux liability than Ligand B (0.764), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates significantly better ADME properties, particularly in metabolic stability (lower Cl_mic) and P-gp efflux. The poor solubility and permeability are concerning for both, but the improved metabolic stability of Ligand A is critical for an enzyme target like SRC kinase. The higher QED score of Ligand A also supports its drug-like potential. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 16:40:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.419 and 366.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.38) is better than Ligand B (104.12), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.358) is slightly low, potentially hindering permeation. Ligand B (0.586) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 7 HBA) both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.546 and 0.735), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (30.322) has a much lower DILI risk than Ligand B (62.001). This is a significant advantage for Ligand A.

**BBB:** Both have low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B is slightly higher (60.45 vs 37.96).

**Caco-2 Permeability:** Ligand A (-4.512) has very poor Caco-2 permeability, while Ligand B (-5.061) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.087) has slightly better solubility than Ligand B (-2.082).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.086 and 0.148).

**Microsomal Clearance:** Ligand A (24.893) has a slightly higher microsomal clearance than Ligand B (21.464), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (-33.327) has a much longer in vitro half-life than Ligand B (7.81). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029).

**Binding Affinity:** Both ligands have very similar and good binding affinities (-7.7 and -7.4 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A has a significant advantage in DILI risk and in vitro half-life, and slightly better solubility. Ligand B has a better logP and slightly better Caco-2 permeability. The binding affinity is comparable. Given the enzyme-specific priorities, the lower DILI risk and longer half-life of Ligand A are more important than the slightly better logP of Ligand B. The very poor Caco-2 permeability of both is a concern, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 16:40:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.407 and 387.311 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.17) is slightly higher than Ligand B (82.11). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (-0.195) is quite low, potentially hindering permeability. Ligand B (3.422) 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, and Ligand B has 4 HBA. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.586) has a slightly better QED score than Ligand B (0.484), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (56.96 and 57.891 percentile), indicating moderate risk.

**BBB:** Both have low BBB penetration (49.205 and 43.544 percentile), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.204 and -5.58), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.24 and -3.601), indicating very poor aqueous solubility. This is a major concern.

**hERG Inhibition:** Ligand A (0.201) has a much lower hERG inhibition risk than Ligand B (0.793), which is a significant advantage.

**Microsomal Clearance:** Ligand B (48.203 mL/min/kg) has a slightly lower microsomal clearance than Ligand A (35.429 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (55.653 hours) has a substantially longer half-life than Ligand A (-1.729 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.015) has significantly lower P-gp efflux liability than Ligand B (0.577), which is favorable.

**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 less than the 1.5 kcal/mol threshold, it's still a factor.

**Overall Assessment:**

Ligand B is preferable despite the slightly weaker binding affinity. The key advantages of Ligand B are its optimal logP, significantly longer half-life, and better metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the longer half-life and better logP of Ligand B are more critical for an enzyme target like SRC. Ligand A has a better hERG profile and P-gp efflux, but the poor logP and very short half-life are major drawbacks.

Output:
1
2025-04-17 16:40:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (362.836 and 354.466 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (57.26 and 58.64) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (3.839) is at the higher end of the optimal range (1-3), while Ligand B (2.44) is well within it. Ligand A's higher logP *could* lead to off-target effects, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1) and HBA (3 and 3) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have QED values (0.849 and 0.681) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (74.99%) compared to Ligand B (10.469%). This is a major red flag for Ligand A.

**BBB:** Both have good BBB penetration, but Ligand B is better (94.455%) than Ligand A (80.419%). While not a primary concern for a kinase inhibitor, it's a slight advantage for B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.777 and -4.656). This is unusual and suggests poor permeability. Further investigation would be needed to understand this.

**Aqueous Solubility:** Both have negative solubility values (-5.126 and -2.331), indicating very poor solubility. This is a significant concern for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.644 and 0.678), which is good.

**Microsomal Clearance:** Ligand B (32.814 mL/min/kg) has a significantly lower (better) microsomal clearance than Ligand A (51.949 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.276 hours) has a negative half-life, which is unusual and likely an error. Ligand A (53.839 hours) has a good half-life. However, the negative value for B raises concerns about its reliability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.319 and 0.275), which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-9.4 and -8.9 kcal/mol), with Ligand A being slightly better. However, the 0.5 kcal/mol difference is unlikely to outweigh the significant ADME drawbacks of Ligand A.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand B is the more promising candidate. While both have solubility and permeability issues, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic). The negative half-life for B is concerning and needs to be investigated, but the other advantages outweigh this issue. Ligand A's high DILI risk is a major concern that makes it less likely to succeed as a drug candidate.

Output:
1
2025-04-17 16:40:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.491 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is better than Ligand B (79.54), both are below the 140 threshold for oral absorption, but lower is generally preferred.

**logP:** Both ligands (1.298 and 1.806) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as a small number of HBDs can aid solubility.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the 10 threshold.

**QED:** Both ligands have good QED scores (0.691 and 0.811), indicating good drug-like properties.

**DILI:** Ligand A (8.414) has a significantly lower DILI risk than Ligand B (31.485). This is a major advantage.

**BBB:** Both ligands have good BBB penetration (71.772 and 77.86), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.195 and -4.806), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.126 and -1.176), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.179 and 0.045). This is excellent.

**Microsomal Clearance:** Ligand B (24.209 mL/min/kg) has lower microsomal clearance than Ligand A (15.576 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.591 hours) has a longer half-life than Ligand A (29.575 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.058). This is good.

**Binding Affinity:** Ligand B (-9.4 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 threshold.

**Overall Assessment:**

While Ligand A has a better DILI profile, the significantly stronger binding affinity of Ligand B (-9.4 vs -6.9 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher DILI risk. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, the potency and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:40:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 342.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (107.4 and 101.8) are acceptable, being below the 140 A^2 threshold for oral absorption, but not optimized for CNS penetration.

**logP:** Ligand A (0.51) is quite low, potentially hindering permeability. Ligand B (2.174) 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 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.612 and 0.811), suggesting good drug-like properties.

**DILI:** Ligand A (65.5) has a moderate DILI risk, while Ligand B (79.6) has a higher risk. This favors Ligand A.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**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, but could be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.256) has a very low hERG risk, which is excellent. Ligand B (0.143) also has a low hERG risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-19.225) has *very* low microsomal clearance, indicating excellent metabolic stability. Ligand B (40.057) has a much higher clearance, suggesting faster metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-8.417) has a very long in vitro half-life, consistent with the low clearance. Ligand B (23.01) has a moderate half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.051 and 0.018), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -8.0 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A is superior due to its significantly better metabolic stability (much lower Cl_mic and longer t1/2), excellent hERG profile, and slightly better binding affinity. While Ligand B has a better logP, the poor metabolic stability is a major drawback for an enzyme inhibitor. The solubility issues are a concern for both, but can potentially be addressed with formulation strategies. The DILI risk is slightly higher for Ligand B.

Output:
0
2025-04-17 16:40:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.486 and 380.897 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (71.34). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Both ligands have acceptable logP values (2.705 and 3.668), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=4) as lower values are generally better for permeability.

**QED:** Ligand A (0.835) has a significantly better QED score than Ligand B (0.685), indicating a more drug-like profile.

**DILI:** Ligand A (37.069) has a much lower DILI risk than Ligand B (77.86). This is a crucial advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (85.731) is higher, but this is less important than other factors.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or prediction method. However, Ligand A (-4.742) is slightly better than Ligand B (-4.956).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.296) is slightly better than Ligand B (-4.764).

**hERG:** Both ligands show very low hERG inhibition liability (0.724 and 0.627), which is excellent.

**Microsomal Clearance:** Ligand A (31.427) has a significantly lower microsomal clearance than Ligand B (66.862), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (71.595) has a substantially longer in vitro half-life than Ligand A (-16.204). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.403 and 0.447).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-9.7 and -9.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a better in vitro half-life, Ligand A excels in critical areas: lower DILI risk, better QED, lower TPSA, lower HBD/HBA, and significantly better metabolic stability (lower Cl_mic). These factors are more important for an enzyme target like SRC kinase. The slight advantage in binding affinity for Ligand A, combined with its superior ADME properties, makes it the more promising drug candidate.

Output:
0
2025-04-17 16:40:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.463 Da) is slightly lower, which could be beneficial for permeability. Ligand B (372.575 Da) is still acceptable.

**TPSA:** Ligand A (24.5) is excellent, well below the 140 threshold for oral absorption. Ligand B (67.43) is higher but still reasonable, though it might slightly hinder absorption compared to A.

**logP:** Both ligands have similar logP values around 3.1, which is optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=4) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.788) has a higher QED score than Ligand B (0.652), indicating a more drug-like profile.

**DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (29.081), which is a major advantage.

**BBB:** Both ligands have moderate BBB penetration, not a primary concern for a non-CNS target like SRC. Ligand B (67.197) is slightly higher.

**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.

**Aqueous Solubility:** Both have negative solubility values, again likely a prediction issue. The values are similar.

**hERG:** Ligand A (0.932) has a lower hERG risk than Ligand B (0.391), which is a positive.

**Microsomal Clearance:** Ligand A (-11.64) has a *much* lower (better) microsomal clearance than Ligand B (70.15). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (15.909 hours) has a substantially longer half-life than Ligand B (8.609 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 kcal/mol and -8.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand A is the superior candidate. While both have good binding affinity, Ligand A demonstrates significantly better ADME properties: lower DILI risk, lower microsomal clearance, longer half-life, and a higher QED score. These factors are critical for enzyme inhibitors, outweighing the slight differences in TPSA and the similar binding affinities.

Output:
0
2025-04-17 16:40:29,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.248 Da) is slightly higher than Ligand B (353.463 Da), but both are acceptable.

**TPSA:** Ligand A (77.25) is well below the 140 threshold for oral absorption. Ligand B (98.74) is still acceptable, but closer to the limit.

**logP:** Ligand A (4.132) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.417) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are within acceptable limits. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.667, B: 0.589), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.782), which is a significant concern. Ligand B has a very low DILI risk (13.106), a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (80.031) has better penetration than Ligand B (29.081).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.951) is slightly better than Ligand B (-5.039).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand B (-1.718) is slightly better than Ligand A (-4.812).

**hERG Inhibition:** Ligand A (0.562) has a slightly higher hERG risk than Ligand B (0.042), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (60.612) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (43.879) has better metabolic stability.

**In vitro Half-Life:** Ligand A (73.952) has a longer half-life than Ligand B (-13.483), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux, which is preferable. Ligand B (0.013) has very low P-gp efflux.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage.

**Conclusion:**

Despite Ligand A having a better half-life and slightly better P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.0 vs 0.0 kcal/mol) outweighs the slightly lower half-life. Crucially, Ligand B has a much lower DILI risk (13.106 vs 96.782) and hERG risk (0.042 vs 0.562), both critical for drug development. While both have solubility and permeability issues, the superior potency and safety profile of Ligand B make it the more viable candidate.

Output:
1
2025-04-17 16:40:29,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.279 Da) is slightly higher than Ligand B (342.403 Da), but both are acceptable.

**TPSA:** Ligand A (69.04) is significantly better than Ligand B (122.89). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors. Ligand B is above the preferred threshold of 140, potentially hindering absorption.

**logP:** Ligand A (3.429) is within the optimal range (1-3), while Ligand B (1.172) is at the lower end. A lower logP can sometimes indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 3 HBD and 6 HBA. Both are within acceptable limits, but Ligand A has a slightly more favorable balance.

**QED:** Both ligands have similar QED values (0.796 and 0.649), indicating good drug-likeness.

**DILI:** Ligand A (60.14) and Ligand B (66.964) both have DILI risk above 60, indicating a higher risk of liver injury. However, Ligand A is slightly lower.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.97) is better than Ligand B (50.523).

**Caco-2 Permeability:** Ligand A (-4.455) is better than Ligand B (-5.603), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.646) is better than Ligand B (-3.038), indicating better solubility.

**hERG Inhibition:** Ligand A (0.599) is better than Ligand B (0.645), suggesting a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (56.985) has a higher clearance than Ligand B (1.159). This means Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (10.35) has a longer half-life than Ligand B (9.947), which is favorable.

**P-gp Efflux:** Ligand A (0.181) is better than Ligand B (0.026), indicating less susceptibility to P-gp efflux.

**Binding Affinity:** Ligand A (-6.7 kcal/mol) has a significantly better binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. The difference of 6.7 kcal/mol is substantial and likely outweighs minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly higher DILI risk, its significantly superior binding affinity (-6.7 vs 0.0 kcal/mol), better TPSA, logP, solubility, Caco-2 permeability, hERG inhibition, and P-gp efflux, make it the more promising drug candidate. The improved metabolic stability of Ligand B is a plus, but the dramatic difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 16:40:29,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.459 Da) is slightly higher than Ligand B (337.471 Da), but both are acceptable.

**TPSA:** Ligand A (83.05) is better than Ligand B (56.05) as it is closer to the threshold for good oral absorption (<=140).

**logP:** Ligand A (-0.152) is a bit low, potentially hindering permeation. Ligand B (3.543) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0) and HBA (6/5) counts, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.722 and 0.773), indicating drug-like properties.

**DILI:** Ligand A (55.758) has a higher DILI risk than Ligand B (39.201). This favors Ligand B.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (86.778) has a higher BBB percentile, but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.912 and -5.044), so this doesn't strongly differentiate them.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-0.977) is slightly better than Ligand B (-4.045).

**hERG:** Ligand A (0.064) has a lower hERG risk than Ligand B (0.929). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (20.013) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (59.038). This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-21.578) has a negative half-life, which is not possible. Ligand B (-1.045) is also negative, but less so. Both are problematic, but Ligand B is slightly better.

**P-gp Efflux:** Both have low P-gp efflux liability (0.031 and 0.318).

**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, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP, lower DILI risk, and significantly better binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic), lower hERG risk, and slightly better solubility. The binding affinity difference is substantial (>1 kcal/mol), and potency is a primary concern for kinase inhibitors. While Ligand A's metabolic stability is good, the lower potency and solubility are concerning.

Output:
1
2025-04-17 16:40:29,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.5 and 355.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.6 and 58.4 A^2) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (2.93 and 2.71) within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.65 and 0.69), indicating a drug-like profile.

**DILI:** Ligand A has a DILI risk of 36.8%, which is good (low risk). Ligand B has a significantly lower DILI risk of 20.3%, which is excellent.

**BBB:** Both have high BBB penetration (89.1% and 86.1%), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.46 and -4.22), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-2.26 and -3.06), also unusual and concerning, indicating very poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.60 and 0.55).

**Microsomal Clearance:** Ligand A has a Cl_mic of 45.5 mL/min/kg, while Ligand B has 32.5 mL/min/kg. Lower is better, so Ligand B is preferable here, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 39.0 hours, while Ligand B has 0.76 hours. Ligand A is significantly better in this regard.

**P-gp Efflux:** Both have low P-gp efflux liability (0.21 and 0.14).

**Binding Affinity:** Ligand B has a stronger binding affinity (-8.2 kcal/mol) compared to Ligand A (-7.4 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate despite its very short in vitro half-life. The significantly stronger binding affinity (-8.2 vs -7.4 kcal/mol) is a major advantage for an enzyme target. It also has a much lower DILI risk and better metabolic stability (lower Cl_mic). While both have poor Caco-2 and solubility, the potency advantage of Ligand B is likely to be more impactful in initial optimization efforts. The short half-life of Ligand B could be addressed through structural modifications.

Output:
1
2025-04-17 16:40:29,139 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.451 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.35) is slightly higher than the preferred <140, but acceptable. Ligand B (49.85) is excellent, well below 140.

**logP:** Ligand A (0.278) is quite low, potentially hindering permeability. Ligand B (2.494) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 4, also acceptable.

**QED:** Both ligands have good QED scores (0.684 and 0.77), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (44.009 and 38.658), which is favorable.

**BBB:** Ligand A (35.44) has poor BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (71.229) is good, but again, not critical here.

**Caco-2 Permeability:** Ligand A (-5.274) has very poor predicted permeability. Ligand B (-4.65) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.963) has poor predicted solubility. Ligand B (-3.895) is even worse.

**hERG Inhibition:** Ligand A (0.191) has a very low risk of hERG inhibition, which is excellent. Ligand B (0.364) also has low hERG risk.

**Microsomal Clearance:** Ligand A (14.441) has a relatively low microsomal clearance, suggesting better metabolic stability. Ligand B (72.772) has a high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-1.849) has a poor predicted half-life. Ligand B (1.709) has a better half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.005 and 0.215), which is good.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage.

**Conclusion:**

Despite solubility issues with both, Ligand B is the superior candidate. Its significantly stronger binding affinity (-9.3 vs -7.9 kcal/mol) outweighs the slightly higher microsomal clearance and poorer permeability compared to Ligand A. The better logP and TPSA of Ligand B also contribute to its favorability. The low hERG risk for both is a positive attribute. The metabolic stability of Ligand A is good, but the potency of Ligand B is more critical for an enzyme target.

Output:
1
2025-04-17 16:40:29,139 - INFO - Batch 483 complete. Total preferences: 7728
2025-04-17 16:40:29,139 - INFO - Processing batch 484/512...
2025-04-17 16:41:14,984 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.329 and 355.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (81.39 and 81.67) below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have logP values (1.416 and 1.382) 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 H-bonding potential, generally favoring permeability.

**QED:** Ligand A (0.885) has a significantly higher QED score than Ligand B (0.553), indicating a more drug-like profile.

**DILI:** Ligand A (90.733) has a high DILI risk, while Ligand B (4.886) has a very low DILI risk. This is a major concern for Ligand A.

**BBB:** Ligand A (68.205) has a moderate BBB penetration, while Ligand B (45.909) has a lower BBB penetration. This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.528) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.14) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.084) has poor aqueous solubility, while Ligand B (-1.168) is also poor, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.141 and 0.257).

**Microsomal Clearance:** Ligand A (-7.211) has very low microsomal clearance, indicating excellent metabolic stability. Ligand B (13.374) has a high microsomal clearance, suggesting poor metabolic stability.

**In vitro Half-Life:** Ligand A (-2.726) has a negative half-life, which is not possible and likely indicates an issue with the data or the model. Ligand B (-17.682) also has a negative half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.045).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). This 1.6 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has superior binding affinity and metabolic stability, but suffers from a very high DILI risk, poor solubility, and a questionable half-life value. Ligand B has a much better safety profile (low DILI) and slightly better solubility, but weaker binding affinity and poor metabolic stability.

Given the enzyme-specific priorities, metabolic stability and safety (DILI) are crucial. While the affinity difference is notable, the extremely high DILI risk associated with Ligand A makes it a less attractive candidate. The poor half-life values for both are concerning and require further investigation, but the DILI risk is the more immediate disqualifier.

Output:
1
2025-04-17 16:41:14,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (363.571 Da) is also good.

**TPSA:** Ligand A (111.28) is better than Ligand B (40.77). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (0.674) is a bit low, potentially hindering permeability. Ligand B (4.431) is high, potentially causing 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 (Ligand A: 0.644, Ligand B: 0.791), indicating drug-like properties.

**DILI:** Ligand A (56.727) has a moderate DILI risk, while Ligand B (18.922) has a low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (88.6) is higher, but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-5.227) is worse than Ligand B (-4.944).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.597) is slightly better than Ligand B (-3.644).

**hERG Inhibition:** Ligand A (0.363) has a lower hERG risk than Ligand B (0.93). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (36.58) has a lower clearance, suggesting better metabolic stability than Ligand B (62.499). This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-26.083) has a negative half-life, which is not possible. This is a major red flag. Ligand B (33.9) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux, which is favorable. Ligand B (0.867) has higher efflux.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly better 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 superior binding affinity and better metabolic stability, lower P-gp efflux, and lower hERG risk. However, its solubility is slightly worse, and its Caco-2 permeability is significantly worse. The negative in vitro half-life is a critical flaw. Ligand B has a better DILI profile and a reasonable half-life, but its logP is high, and its binding affinity is weaker.

Given the importance of potency for kinase inhibitors, and the substantial difference in binding affinity (-8.7 vs -7.4 kcal/mol), Ligand A would be the preferred candidate *if* the negative half-life could be addressed through structural modifications. However, the negative half-life is a showstopper. Considering the overall profile, and the fact that the negative half-life is likely an error, Ligand B is the more viable candidate.

Output:
1
2025-04-17 16:41:14,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.427 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is slightly higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but lower is generally better. Ligand B has a more favorable TPSA.

**3. logP:** Ligand A (0.891) is a bit low, potentially hindering permeability. Ligand B (2.491) is within the optimal 1-3 range. This favors Ligand B.

**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:** Ligand B (0.769) has a significantly better QED score than Ligand A (0.441), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.438) has a much lower DILI risk than Ligand B (9.965), which is a significant advantage.

**8. BBB:** Ligand B (68.631) has a higher BBB penetration percentile than Ligand A (47.964), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.629 and -4.782), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.995 and -2.884), also unusual and indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.114) has a lower hERG inhibition liability than Ligand B (0.444), which is preferable.

**12. Microsomal Clearance:** Ligand B (47.829) has a much higher microsomal clearance than Ligand A (6.629), meaning it will be metabolized more quickly. Ligand A is favored here.

**13. In vitro Half-Life:** Ligand A (-15.638) has a much longer in vitro half-life than Ligand B (-5.838), indicating greater metabolic stability. This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux liability than Ligand B (0.126), which is favorable.

**15. Binding Affinity:** Ligand B (0.0) has a significantly stronger binding affinity than Ligand A (-8.5 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 a better QED score, logP, and BBB. However, it suffers from higher DILI risk, higher microsomal clearance, shorter half-life, and higher P-gp efflux. Ligand A has a much better safety profile (lower DILI, hERG), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The strong binding affinity of Ligand B is compelling, but the poor ADME properties of both ligands are concerning. Given the enzyme-specific priorities, metabolic stability and safety are crucial. While the affinity difference is large, the significantly better metabolic stability and safety profile of Ligand A make it the more promising candidate, assuming the affinity is still within a reasonable range for activity.

Output:
0
2025-04-17 16:41:14,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.487 Da and 347.503 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.41) is slightly higher than Ligand B (52.65). Both are below the 140 threshold for good oral absorption, but neither are optimized for CNS penetration (below 90).

**logP:** Both ligands have good logP values (2.813 and 2.301), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 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 scores (0.79 and 0.849), indicating drug-like properties.

**DILI:** Ligand A (16.673) has a significantly higher DILI risk than Ligand B (6.592). This is a major concern.

**BBB:** Both ligands have reasonable BBB penetration (81.776 and 79.566), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.605 and -4.816), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.186 and -2.85). This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.639 and 0.525), which is good.

**Microsomal Clearance:** Ligand A (27.378) has lower microsomal clearance than Ligand B (30.292), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (3.734 hours) has a significantly longer half-life than Ligand A (0.12 hours). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.223) has lower P-gp efflux than Ligand B (0.04), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite the stronger binding affinity of Ligand A, its significantly higher DILI risk and extremely short half-life are major liabilities. Ligand B, while having a slightly weaker binding affinity, exhibits a much better safety profile (lower DILI) and a significantly longer half-life. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, metabolic stability and safety are crucial. Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 16:41:14,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.615 Da) is slightly higher than Ligand B (342.439 Da), but both are acceptable.

**TPSA:** Ligand A (52.65) is well below the 140 threshold for oral absorption. Ligand B (67.43) is also acceptable, though slightly higher.

**logP:** Both ligands have good logP values (A: 2.122, B: 1.843), falling 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 reasonable numbers of hydrogen bond donors and acceptors, well within the recommended limits.

**QED:** Ligand A (0.757) has a better QED score than Ligand B (0.592), indicating a more drug-like profile.

**DILI:** Ligand A (28.112) has a significantly lower DILI risk than Ligand B (46.026), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (64.482) shows slightly better BBB penetration than Ligand B (53.083).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.103 for A, -5.099 for B), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.533 for A, -2.923 for B), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.359) has a lower hERG inhibition liability than Ligand B (0.186), which is preferable.

**Microsomal Clearance:** Ligand A (74.383) has a higher microsomal clearance than Ligand B (31.537), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-12.507) has a significantly longer in vitro half-life than Ligand A (3.153), indicating better stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.072, B: 0.19).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly better binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns. The difference of 1.2 kcal/mol is significant.

**Overall Assessment:**

Ligand A has a superior binding affinity and a much lower DILI risk, but suffers from higher metabolic clearance and poor solubility. Ligand B has better metabolic stability and slightly better solubility, but has a weaker binding affinity and a higher DILI risk. Given the importance of potency for kinase inhibitors, the 1.2 kcal/mol difference in binding affinity is a critical factor. While the poor solubility and permeability are concerning for both, these can potentially be addressed through formulation strategies. The lower DILI risk of Ligand A is also a significant advantage.

Output:
1
2025-04-17 16:41:14,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.389 Da and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is slightly higher than Ligand B (58.2). Both are below the 140 threshold for good absorption, but Ligand B is better.

**logP:** Ligand A (0.039) is very low, potentially hindering permeation. Ligand B (3.406) 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 4 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.725 and 0.662), suggesting good drug-like properties.

**DILI:** Both ligands have low DILI risk (37.301 and 35.867), which is positive.

**BBB:** Both ligands have good BBB penetration (75.378 and 70.764), though SRC is not a CNS target, so this isn't a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.82 and -4.601). This is unusual and suggests poor permeability, but the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-0.814) and Ligand B (-4.319) both have negative solubility values, which is concerning.

**hERG Inhibition:** Ligand A (0.245) has a lower hERG risk than Ligand B (0.489), which is favorable.

**Microsomal Clearance:** Ligand A (-3.357) has a significantly *lower* (better) microsomal clearance than Ligand B (56.136). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-19.317) has a more negative (better) in vitro half-life than Ligand B (-11.143), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.015) has much lower P-gp efflux than Ligand B (0.269), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.3), but the difference is less than 1.5 kcal/mol.

**Conclusion:**

Despite Ligand B having a better logP and slightly better binding affinity, Ligand A is the more promising candidate. The significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk outweigh the slight advantage in binding affinity of Ligand B. The poor solubility and permeability are concerns for both, but can be addressed through formulation strategies. The very low logP of Ligand A is a drawback, but the other ADME properties are more critical for an enzyme target like SRC.

Output:
0
2025-04-17 16:41:14,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.39 and 350.55 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.81) is slightly higher than the preferred <140, but acceptable. Ligand B (49.41) is excellent, well below 140.

**logP:** Ligand A (0.213) is quite low, potentially hindering permeability. Ligand B (4.302) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, within acceptable limits. Ligand B has 1 HBD and 2 HBA, also good.

**QED:** Both ligands have reasonable QED scores (0.703 and 0.63), indicating good drug-likeness.

**DILI:** Ligand A (53.43) has a moderate DILI risk, while Ligand B (17.72) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (43.58) has low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (77.01) has good BBB penetration, not a priority here.

**Caco-2 Permeability:** Ligand A (-5.118) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.632) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.648) has poor aqueous solubility, likely due to the low logP. Ligand B (-3.844) also has poor solubility, exacerbated by the high logP.

**hERG Inhibition:** Ligand A (0.18) has very low hERG inhibition risk, a strong positive. Ligand B (0.666) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (24.68) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (55.97) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (10.82) has a longer half-life than Ligand B (3.78), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.022 and 0.333).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference of 0.1 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

While both ligands have good binding affinity, Ligand A suffers from very low logP and Caco-2 permeability, leading to poor solubility. Ligand B has a high logP, which could cause solubility issues, but its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better Caco-2 permeability make it the more promising candidate. The lower DILI risk is a critical factor for kinase inhibitors, which often have prolonged treatment durations.

Output:
1
2025-04-17 16:41:14,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.383 and 352.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.14) is well below the 140 threshold, suggesting good absorption. Ligand B (106.17) is still acceptable but less optimal.

**logP:** Ligand A (2.78) is within the optimal 1-3 range. Ligand B (1.558) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, well within acceptable limits. Ligand B has 4 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.6 and 0.54), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 69.756, which is moderately high. Ligand B has a significantly lower DILI risk of 14.385, a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.69) is higher than Ligand B (52.579).

**Caco-2 Permeability:** Ligand A (-3.741) has poor Caco-2 permeability, while Ligand B (-5.698) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.373) has poor solubility, while Ligand B (-1.558) is slightly better, though still not ideal.

**hERG Inhibition:** Ligand A (0.203) has a very low hERG risk, a significant advantage. Ligand B (0.432) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (88.001) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (-20.125) has a negative value, which is excellent and suggests very good metabolic stability.

**In vitro Half-Life:** Ligand A (-31.856) has a negative half-life, which is excellent. Ligand B (24.471) is acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.075 and 0.023).

**Binding Affinity:** Both ligands have strong binding affinities (-8.4 and -9.6 kcal/mol). Ligand B is slightly better (-9.6 kcal/mol), but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While its Caco-2 permeability and solubility are not ideal, its significantly lower DILI risk and *much* better metabolic stability (indicated by the negative Cl_mic and positive t1/2) are critical advantages for an enzyme target. Ligand A has a better hERG profile and slightly better BBB, but the high DILI risk and poor metabolic stability are major concerns. The slightly stronger binding affinity of Ligand B is a bonus.

Output:
1
2025-04-17 16:41:14,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.491 and 348.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is well below the 140 threshold and excellent for oral absorption. Ligand B (124.17) is still within acceptable limits, but less optimal.

**logP:** Ligand A (0.703) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.317) is even lower, raising more concerns about 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, within the acceptable limit of <=10. Ligand B has 8 HBA, still acceptable, but higher.

**QED:** Both ligands have good QED scores (0.632 and 0.738), indicating drug-like properties.

**DILI:** Ligand A (4.731) has a very low DILI risk, which is excellent. Ligand B (63.397) has a significantly higher DILI risk, which is a major concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (36.371) and Ligand B (61.264) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.856 and -4.969), 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 (-0.599 and -2.648), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.198) has a very low hERG risk, which is excellent. Ligand B (0.015) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (-7.488) has excellent metabolic stability (negative value indicates low clearance). Ligand B (7.191) has a moderate clearance, which is less desirable.

**In vitro Half-Life:** Ligand A (5.337) has a reasonable half-life. Ligand B (-17.861) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.019).

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-8.3).

**Overall Assessment:**

Ligand A is significantly better due to its much lower DILI risk, superior metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both ligands have issues with predicted permeability and solubility, the DILI and metabolic stability concerns with Ligand B are more critical for an enzyme target. The slightly better affinity of Ligand A further strengthens its position.

Output:
0
2025-04-17 16:41:14,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.385 Da and 361.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.09) is better than Ligand B (38.77) as it is closer to the optimal range for oral absorption (<=140).

**logP:** Ligand B (3.391) is slightly higher than Ligand A (1.584), but both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**QED:** Ligand A (0.763) has a significantly better QED score than Ligand B (0.499), indicating a more drug-like profile.

**DILI:** Ligand A (56.727) has a higher DILI risk than Ligand B (21.675), but both are below the concerning threshold of 60.

**BBB:** Ligand A (80.729) and Ligand B (90.074) both have good BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.08) has a worse Caco-2 permeability than Ligand B (-4.864).

**Aqueous Solubility:** Ligand A (-2.893) has a worse aqueous solubility than Ligand B (-3.39).

**hERG Inhibition:** Ligand A (0.247) has a much lower hERG inhibition risk than Ligand B (0.736). This is a significant advantage.

**Microsomal Clearance:** Ligand A (21.538) has a lower microsomal clearance than Ligand B (104.233), suggesting better metabolic stability. This is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (-25.087) has a significantly longer in vitro half-life than Ligand B (2.253), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.066) has a lower P-gp efflux liability than Ligand B (0.561), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor for an enzyme target. The >1.5 kcal/mol advantage of B outweighs the ADME concerns.

**Conclusion:**

Despite Ligand A's better QED, solubility, metabolic stability, and lower hERG risk, the significantly superior binding affinity of Ligand B (-8.5 kcal/mol vs 0 kcal/mol) makes it the more promising drug candidate. The potency advantage is substantial and likely to outweigh the ADME drawbacks, which can be further optimized in subsequent iterations.

Output:
1
2025-04-17 16:41:14,986 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [348.393, 41.57, 4.724, 1, 2, 0.849, 65.103, 70.415, -4.343, -5.067, 0.791, 100.262, 19.095, 0.356, -10.3]
**Ligand B:** [352.41, 93.7, 2.131, 4, 3, 0.606, 46.336, 53.16, -5.05, -2.52, 0.449, -2.161, 52.454, 0.072, -7]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (348.393) is slightly better.
2. **TPSA:** A (41.57) is good for oral absorption (<140). B (93.7) is higher, potentially impacting absorption.
3. **logP:** A (4.724) is a bit high, potentially causing solubility issues or off-target effects. B (2.131) is optimal.
4. **HBD:** A (1) is good. B (4) is acceptable but higher.
5. **HBA:** A (2) is good. B (3) is acceptable.
6. **QED:** A (0.849) is excellent, indicating high drug-likeness. B (0.606) is still acceptable, but less optimal.
7. **DILI:** A (65.103) is concerning, indicating a higher risk of liver injury. B (46.336) is much better, suggesting lower risk.
8. **BBB:** A (70.415) is good, but SRC is not a CNS target, so this is less critical. B (53.16) is lower and less relevant.
9. **Caco-2:** A (-4.343) is very poor. B (-5.05) is also poor, but slightly better. Both suggest very low intestinal absorption.
10. **Solubility:** A (-5.067) is very poor. B (-2.52) is also poor, but better than A.
11. **hERG:** A (0.791) is acceptable. B (0.449) is better, indicating lower cardiotoxicity risk.
12. **Cl_mic:** A (100.262) is high, indicating rapid metabolism. B (-2.161) is excellent, indicating high metabolic stability.
13. **t1/2:** A (19.095) is good. B (52.454) is excellent.
14. **Pgp:** A (0.356) is good, indicating low efflux. B (0.072) is excellent, indicating very low efflux.
15. **Affinity:** A (-10.3) is significantly stronger than B (-7). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

While Ligand A has a significantly better binding affinity, its poor solubility, high DILI risk, and high metabolic clearance are major drawbacks. Ligand B, despite a weaker affinity, has superior metabolic stability (Cl_mic and t1/2), lower DILI risk, and better hERG profile. The Caco-2 and solubility are still poor for both, but B is better. The substantial difference in affinity (-10.3 vs -7) is a strong point for A, but the ADME/Tox profile of B is much more favorable, and these are critical for *in vivo* viability. Considering the overall profile, the improved ADMET properties of Ligand B outweigh the affinity difference.

Therefore, I would choose **Ligand B** as the more viable drug candidate.

1
2025-04-17 16:41:14,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.5 and 341.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is well below the 140 threshold, while Ligand B (108.48) is still acceptable but higher.

**logP:** Both ligands have good logP values (2.317 and 1.189), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (3 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.805) has a significantly higher QED score than Ligand B (0.653), indicating better overall drug-likeness.

**DILI:** Ligand A (35.13) has a much lower DILI risk than Ligand B (56.844), which is a significant advantage.

**BBB:** Both have acceptable BBB penetration, but Ligand A (70.531) is slightly better than Ligand B (67.041). This is less crucial for a kinase inhibitor than for a CNS-targeting drug.

**Caco-2 Permeability:** Ligand A (-4.844) has better predicted permeability than Ligand B (-5.756).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.017) is slightly better than Ligand B (-2.361).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.408 and 0.212).

**Microsomal Clearance:** Ligand A (24.811) has significantly lower microsomal clearance than Ligand B (34.93), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.645) has a longer half-life than Ligand B (-4.957), which is a positive attribute.

**P-gp Efflux:** Both have low P-gp efflux liability (0.118 and 0.083).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol), but the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties (DILI, metabolic stability, solubility, permeability, QED). While Ligand B has a marginally better binding affinity, the superior ADME profile of Ligand A makes it the more promising drug candidate for SRC kinase inhibition. The lower DILI risk and better metabolic stability are particularly important for kinase inhibitors, which are often given chronically.

Output:
1
2025-04-17 16:41:14,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (363.483 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (77.57), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.737) is optimal, while Ligand B (0.724) is slightly low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the threshold of 10.

**QED:** Both ligands have similar QED values (0.783 and 0.688), indicating good drug-likeness.

**DILI:** Ligand A (38.309) has a lower DILI risk than Ligand B (43.932), both are good (<40 is preferred).

**BBB:** Both ligands have similar BBB penetration (74.176 and 73.129), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.2) is better than Ligand B (-4.996), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.336) is better than Ligand B (-1.127), which is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.211) has a significantly lower hERG risk than Ligand B (0.494), a critical safety parameter.

**Microsomal Clearance:** Ligand A (17.804) has lower clearance and therefore better metabolic stability than Ligand B (23.248).

**In vitro Half-Life:** Ligand A (20.157) has a longer half-life than Ligand B (29.749), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux than Ligand B (0.01), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage. The difference of 2 kcal/mol is significant enough to potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A generally has superior ADMET properties (solubility, permeability, metabolic stability, safety). However, Ligand B exhibits a substantially stronger binding affinity (-9.9 vs -7.9 kcal/mol). For an enzyme target like SRC kinase, potency is paramount. The 2 kcal/mol difference is a large margin, and while Ligand B has slightly worse ADMET properties, these are generally within acceptable ranges. The improved binding affinity is likely to translate to greater efficacy *in vivo*, making Ligand B the more promising candidate.

Output:
1
2025-04-17 16:41:14,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.491 Da and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.35) is well below the 140 threshold, while Ligand B (94.92) is approaching it. This favors Ligand A for better absorption.

**logP:** Ligand A (3.921) is at the upper end of the optimal range (1-3), while Ligand B (0.282) is significantly below, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.754) has a significantly better QED score than Ligand B (0.41), indicating a more drug-like profile.

**DILI:** Ligand A (93.796) has a high DILI risk, while Ligand B (64.172) is also elevated but less so. This is a significant concern for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand A is higher (81.466) than Ligand B (61.691). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-4.727) has better Caco-2 permeability than Ligand B (-5.035), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.463) has better aqueous solubility than Ligand B (-1.865).

**hERG Inhibition:** Ligand A (0.474) has a lower hERG risk than Ligand B (0.208), which is favorable.

**Microsomal Clearance:** Ligand A (71.593) has a higher microsomal clearance than Ligand B (9.615), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (37.557) has a longer half-life than Ligand B (-13.27), which is positive. However, the negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.558) has lower P-gp efflux than Ligand B (0.058), which is favorable.

**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 has a much stronger binding affinity and better solubility, permeability, and half-life. However, it has a very high DILI risk and higher microsomal clearance. Ligand B has a lower affinity, poor solubility, and a very short half-life, but a lower DILI risk.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the significantly stronger binding affinity of Ligand A (-9.1 vs -7.8) is a major advantage that could potentially outweigh the higher DILI risk and lower metabolic stability *if* the DILI risk can be mitigated through structural modifications. The extremely poor half-life of Ligand B is a major issue.

Output:
1
2025-04-17 16:41:14,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.861 Da and 356.432 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is well below the 140 threshold for good absorption, while Ligand B (36.1) is even better.

**logP:** Ligand A (1.282) is within the optimal 1-3 range. Ligand B (4.697) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both within acceptable limits. Ligand B has 1 HBD and 1 HBA, also good.

**QED:** Both ligands have similar QED scores (0.744 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (23.226) has a lower DILI risk than Ligand B (29.74), which is favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (89.376) has a higher BBB score than Ligand A (34.393), but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.295) has a negative Caco-2 value, which is concerning. Ligand B (-4.553) is also negative, but less so. Both suggest poor permeability, but A is worse.

**Aqueous Solubility:** Ligand A (-1.677) has better solubility than Ligand B (-4.862).

**hERG Inhibition:** Ligand A (0.256) has a lower hERG risk than Ligand B (0.923), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-14.545) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (50.6). This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (0.979) has a slightly longer half-life than Ligand B (-3.7).

**P-gp Efflux:** Both ligands have relatively low P-gp efflux liability (0.034 and 0.543).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand B having a lower TPSA, Ligand A is the better candidate. The primary drivers are Ligand A's superior metabolic stability (much lower Cl_mic), lower hERG risk, better solubility, and lower DILI risk. While Ligand B has a slightly better BBB score and a slightly better Caco-2 permeability, these are less critical for a non-CNS kinase inhibitor. The comparable binding affinity eliminates that as a differentiating factor. The negative Caco-2 values for both are a concern that would need further investigation, but Ligand A's other advantages outweigh this concern.

Output:
0
2025-04-17 16:41:14,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.431 and 342.403 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.96) is significantly better than Ligand B (87.12). Lower TPSA generally favors better absorption.

**logP:** Ligand B (1.36) is slightly better than Ligand A (0.498), falling within the optimal 1-3 range. Ligand A 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 5. Both are acceptable (<=10).

**QED:** Both ligands have high QED scores (0.839 and 0.859), indicating good drug-likeness.

**DILI:** Ligand A (36.06) has a much lower DILI risk than Ligand B (59.907). This is a significant advantage for Ligand A.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.891) and Ligand B (-5.303) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.244) is slightly better than Ligand B (-1.986), though both are poor.

**hERG Inhibition:** Ligand A (0.323) has a lower hERG risk than Ligand B (0.507), which is favorable.

**Microsomal Clearance:** Ligand A (-9.831) has *much* lower microsomal clearance than Ligand B (18.732). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (45.554) has a longer half-life than Ligand B (-24.777). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.04).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall preference.

**Conclusion:**

Considering all factors, especially the enzyme-specific priorities, **Ligand A is the more promising drug candidate**. It demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a slightly better binding affinity. While both have poor Caco-2 permeability and solubility, the improvements in metabolic stability and safety profile outweigh these drawbacks. The slightly lower logP of Ligand A is a minor concern that could be addressed through further optimization.

Output:
1
2025-04-17 16:41:14,987 - INFO - Batch 484 complete. Total preferences: 7744
2025-04-17 16:41:14,987 - INFO - Processing batch 485/512...
2025-04-17 16:41:53,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (378.523 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.09) is slightly above the preferred <60 for optimal permeability, but acceptable. Ligand B (49.85) is excellent.

**logP:** Both ligands (2.268 and 2.481) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.747 and 0.773), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 75.766, which is concerning (high risk). Ligand B has a much lower DILI risk of 21.055, which is excellent.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (64.017) and Ligand B (97.751) are both reasonable, but B is better.

**Caco-2 Permeability:** Ligand A (-5.125) and Ligand B (-4.272) are both negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.035 and -2.456), indicating poor aqueous solubility, which is a significant drawback.

**hERG Inhibition:** Ligand A (0.324) has a slightly higher hERG risk than Ligand B (0.556), but both are relatively low.

**Microsomal Clearance:** Ligand A (81.592) has higher microsomal clearance than Ligand B (46.5), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (2.365) has a shorter half-life than Ligand B (-6.632), further reinforcing the metabolic stability concern.

**P-gp Efflux:** Ligand A (0.425) has lower P-gp efflux than Ligand B (0.124), which is favorable.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-6.7). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite both ligands having some drawbacks (poor solubility and permeability), Ligand B is the far superior candidate. Its significantly stronger binding affinity (-9.0 vs -6.7 kcal/mol) outweighs the minor ADME concerns. Crucially, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic, longer half-life) than Ligand A. The combination of these factors makes Ligand B a much more promising starting point for drug development targeting SRC kinase.

Output:
1
2025-04-17 16:41:53,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.312 and 360.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.42) is slightly higher than the ideal <140, but acceptable. Ligand B (51.02) is excellent, well below 140.

**logP:** Ligand A (2.468) is within the optimal 1-3 range. Ligand B (3.893) is approaching the upper limit, but still acceptable.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also good.

**QED:** Both ligands have good QED scores (0.492 and 0.752 respectively), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (41.024). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (78.092) and Ligand B (90.074) are both reasonable, with B being better.

**Caco-2 Permeability:** Ligand A (-4.643) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.106) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.751 and -4.031 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.695 and 0.469 respectively).

**Microsomal Clearance:** Ligand A (80.303) has better metabolic stability (lower clearance) than Ligand B (104.482).

**In vitro Half-Life:** Ligand A (2.8) has a shorter half-life than Ligand B (17.015). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.158 and 0.561 respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.7 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility, Ligand B has a significantly lower DILI risk, better half-life, and slightly better binding affinity. The improved metabolic stability of Ligand A is outweighed by its higher DILI risk and shorter half-life. The Caco-2 permeability is poor for both, but this can be addressed with formulation strategies.

Output:
1
2025-04-17 16:41:53,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.413 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (90.98). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.952 and 1.733), 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 it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.766 and 0.866), indicating good drug-like properties.

**DILI:** Ligand A (16.208) has a much lower DILI risk than Ligand B (52.656). This is a significant advantage for A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (89.608) has a higher BBB percentile than Ligand B (46.336), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-4.636) has a better Caco-2 permeability score than Ligand B (-5).

**Aqueous Solubility:** Ligand A (-1.977) has a better aqueous solubility score than Ligand B (-2.69).

**hERG Inhibition:** Ligand A (0.537) has a lower hERG inhibition liability than Ligand B (0.087). This is a crucial advantage for A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (1.543) has significantly lower microsomal clearance than Ligand B (12.833). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-15.77) has a longer in vitro half-life than Ligand B (-5.702). This is another advantage for A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux liability than Ligand B (0.011).

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.5). While both are good, the 0.4 kcal/mol difference is a small advantage.

**Overall:**

Ligand A is superior to Ligand B across almost all ADME-Tox properties. It has a lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), better solubility, and slightly better binding affinity. While both ligands have acceptable physicochemical properties, Ligand A's improved safety profile and metabolic stability make it the more promising drug candidate.

Output:
0
2025-04-17 16:41:53,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (339.4 and 353.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.22) is better than Ligand B (98.74). Both are below 140, supporting good oral absorption.

**logP:** Ligand A (1.358) is better than Ligand B (0.561). Both are within the optimal 1-3 range, but Ligand B is getting closer to the lower limit which could affect permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 4 HBA). Both are within acceptable limits.

**QED:** Ligand A (0.878) is significantly better than Ligand B (0.594), indicating a more drug-like profile.

**DILI:** Ligand B (11.361) is *much* better than Ligand A (69.252). This is a major advantage for Ligand B.

**BBB:** Ligand A (63.784) is better than Ligand B (34.858), but BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.028 and -5.062). This is unusual and suggests poor permeability *in vitro*. However, these values are on a log scale, and the absolute difference is small.

**Aqueous Solubility:** Ligand A (-2.872) is better than Ligand B (-0.924), indicating better solubility.

**hERG:** Ligand A (0.339) is better than Ligand B (0.057), indicating lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (33.127) is better than Ligand B (14.762), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have similar negative half-lives (-9.084 and -8.971). This is concerning and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.023) is better than Ligand B (0.011), indicating lower P-gp efflux.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) is slightly better than Ligand B (-7.7 kcal/mol). This 1.5 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a *huge* advantage in DILI risk. However, it is weaker in terms of QED, logP, solubility, metabolic stability, and P-gp efflux. Ligand A has better overall ADME properties, a slightly better binding affinity, and a much better QED score. The negative Caco-2 values for both are a concern, but the affinity difference for A is substantial. Given the enzyme-kinase focus, the better metabolic stability (lower Cl_mic) and affinity of Ligand A are more important than the lower DILI score of Ligand B. The DILI risk of Ligand A is still acceptable (<60).

Output:
1
2025-04-17 16:41:53,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.395 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.81) is slightly above the optimal <140, but acceptable. Ligand B (95.5) is well within the desired range.

**logP:** Ligand A (0.384) is a bit low, potentially hindering permeability. Ligand B (2.028) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 8 HBA) is good. Ligand B (3 HBD, 3 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.804 and 0.637), indicating good drug-likeness.

**DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (41.14), though both are moderately risky.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (48.197) and Ligand B (37.301) are both low.

**Caco-2 Permeability:** Ligand A (-4.507) has poor predicted permeability. Ligand B (-5.95) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.687) has poor predicted solubility. Ligand B (-1.177) is also poor, but slightly better than A.

**hERG:** Both ligands have very low hERG risk (0.078 and 0.03), which is excellent.

**Microsomal Clearance:** Ligand A (20.612) has a moderate clearance. Ligand B (-7.896) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-25.742) has a very long predicted half-life, while Ligand B (15.782) has a moderate half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.012).

**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 major factor.

**Conclusion:**

Ligand B is the superior candidate. While both have issues with solubility and permeability, Ligand B's significantly stronger binding affinity, exceptional metabolic stability (negative Cl_mic), and lower DILI risk outweigh the drawbacks. The improved logP also contributes to better predicted properties. The slightly better half-life is a bonus.

Output:
1
2025-04-17 16:41:53,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (362.539 Da and 366.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (78.68).  A TPSA under 140 is good for oral absorption, and both are under this limit, but A is much closer to the ideal for better absorption.

**3. logP:** Both ligands have good logP values (2.912 and 2.046 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 (3) is preferable to Ligand B (5) for similar permeability reasons.

**6. QED:** Both ligands have good QED values (0.758 and 0.799), indicating good drug-like properties.

**7. DILI:** Ligand A (32.105) has a much lower DILI risk than Ligand B (54.556).  Both are below 60, but A is significantly better.

**8. BBB:** Both ligands have reasonable BBB penetration (71.501 and 78.48), but this is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Ligand A (-5.044) has a worse Caco-2 value than Ligand B (-4.941). However, this is a negative value, and the difference is small.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.31 and -3.08). This is a significant concern for both, but it's a property that can potentially be improved through formulation strategies.

**11. hERG Inhibition:** Ligand A (0.295) has a much lower hERG risk than Ligand B (0.096). This is a crucial advantage, as hERG inhibition can lead to cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (49.318) has lower microsomal clearance than Ligand B (57.138), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.701) has a shorter half-life than Ligand B (10.626), which is a disadvantage.

**14. P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux than Ligand B (0.064), which is a positive.

**15. Binding Affinity:** Ligand A (-7.9) has a substantially better binding affinity than Ligand B (0.0). This is the most important factor for an enzyme inhibitor. The difference of 7.9 kcal/mol is significant and likely outweighs the disadvantages of slightly lower half-life and Caco-2 permeability.

**Overall:**

Ligand A is the superior candidate. While both have poor solubility, Ligand A's dramatically improved binding affinity, lower DILI risk, lower hERG risk, and better metabolic stability outweigh the slightly shorter half-life and slightly worse Caco-2 permeability. The strong binding affinity suggests that even with faster clearance, Ligand A could achieve sufficient target engagement *in vivo*.

Output:
0
2025-04-17 16:41:53,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzyme targets.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.355 Da) is slightly lower, which could be advantageous for permeability, while Ligand B (364.475 Da) is also well within the range.

**TPSA:** Ligand A (117.52) is better than Ligand B (85.91) as it is closer to the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (A: 1.294, B: 0.666), 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 8 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.713, B: 0.718), indicating good drug-like properties.

**DILI:** Ligand A (87.01) has a higher DILI risk than Ligand B (62.893). This is a significant concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 67.584, B: 66.382), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.114 and -5.057), 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 (-4.375 and -1.553), indicating poor aqueous solubility. Ligand B is better in this regard.

**hERG Inhibition:** Ligand A (0.422) has a slightly higher hERG inhibition risk than Ligand B (0.152). Lower is better here.

**Microsomal Clearance:** Ligand A (-17.801) has significantly lower microsomal clearance than Ligand B (33.608). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-12.252) has a lower in vitro half-life than Ligand B (22.617). This is consistent with the lower clearance.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.017, B: 0.158).

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.8). This is a 0.2 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and permeability, Ligand B's significantly stronger binding affinity (-9.0 vs -8.8 kcal/mol) outweighs the slightly higher solubility and permeability concerns. Furthermore, Ligand B has a lower DILI risk and better in vitro half-life. The lower metabolic clearance of Ligand A is appealing, but the higher DILI risk is a major drawback.

Output:
1
2025-04-17 16:41:53,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.781 Da) is slightly lower, which could be beneficial for permeability. Ligand B (399.288 Da) is also good.

**TPSA:** Ligand A (93.79) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (53.33) is excellent, well below 140, suggesting good absorption.

**logP:** Both ligands have logP values (3.666 and 4.352) within the optimal 1-3 range, but Ligand B is pushing the upper limit.

**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 (0.576 and 0.651), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.38%), which is a major red flag. Ligand B has a much lower DILI risk (49.515%), which is significantly better.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (56.146) and Ligand B (58.86) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.08 and -4.739), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.019 and -5.366). This is a significant drawback for both.

**hERG:** Ligand A (0.67) has a slightly higher hERG risk than Ligand B (0.922), but both are reasonably low.

**Microsomal Clearance:** Ligand B has a very high microsomal clearance (98.414), indicating poor metabolic stability. Ligand A (58.364) is better, but still not ideal.

**In vitro Half-Life:** Ligand A has a better in vitro half-life (64.07 hours) than Ligand B (32.715 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.619), which is good.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-7.8 kcal/mol) than Ligand B (-7.4 kcal/mol). This 0.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the better binding affinity of Ligand A, the extremely high DILI risk (99.38%) is a deal-breaker. DILI is a major safety concern in drug development. While Ligand B has a slightly weaker binding affinity, its significantly lower DILI risk (49.515%) and better metabolic stability (lower Cl_mic) make it 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 16:41:53,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.355 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.7) is slightly above the preferred <100 for optimal absorption, but still reasonable. Ligand B (86.63) is excellent, well below 100.

**logP:** Both ligands have good logP values (1.282 and 1.081), falling within the 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 reasonable QED scores (0.854 and 0.797), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 75.339, which is concerning (high risk, >60). Ligand B has a much lower DILI risk of 19.504, which is excellent. This is a significant advantage for Ligand B.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (55.293) is better than Ligand A (38.077), but this isn't a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.055 and -4.86), 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 (-3.683 and -0.279), indicating poor aqueous solubility. Ligand B is slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.334) has a slightly higher hERG risk than Ligand B (0.14), although both are relatively low.

**Microsomal Clearance:** Ligand A (27.006) has a higher microsomal clearance than Ligand B (13.714), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (3.844) has a longer in vitro half-life than Ligand A (-3.505), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.007).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). However, the difference is only 1.2 kcal/mol, which may not be enough to overcome the ADME liabilities of Ligand A.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better overall due to its much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and hERG profile. The poor Caco-2 and solubility values are concerning for both, but the ADME profile of Ligand B is far superior, making it the more viable drug candidate.

Output:
1
2025-04-17 16:41:53,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.337 and 359.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.07) is slightly above the preferred <60 for good absorption, but still reasonable. Ligand B (46.84) is excellent, well below the 140 threshold.

**logP:** Both ligands have good logP values (2.119 and 3.308), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (0). Ligand A has 5 HBA, while Ligand B has 6, both are within the acceptable limit of <=10.

**QED:** Ligand A (0.761) has a better QED score than Ligand B (0.526), indicating a more drug-like profile.

**DILI:** Ligand A (68.592) has a higher DILI risk than Ligand B (22.761). This is a significant concern for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (96.937) is significantly higher than Ligand A (83.133). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-3.848) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.668) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.926 and -3.482). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.319) has a slightly higher hERG inhibition risk than Ligand B (0.743), though both are relatively low.

**Microsomal Clearance:** Ligand B (62.434) has lower microsomal clearance than Ligand A (67.076), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.505) has a negative half-life, which is concerning and likely an error in the data. Ligand A (5.595) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.052) has very low P-gp efflux, which is good. Ligand B (0.679) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.1 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.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability of both compounds, **Ligand B** is the more promising candidate. The significantly stronger binding affinity (-8.1 kcal/mol vs 0.0 kcal/mol) is a major advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic). The negative half-life for Ligand B is a data quality concern, but the affinity difference is substantial enough to favor it. The slightly better TPSA and P-gp efflux also contribute to its favorability.

Output:
1
2025-04-17 16:41:53,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (377.271 and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.56) is slightly above the preferred <140, but acceptable. Ligand B (58.2) is well within the range.

**logP:** Both ligands have logP values (3.109 and 3.352) 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 3 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.805 and 0.738), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 53.742, which is acceptable (below 60). Ligand B has a significantly lower DILI risk of 23.032, which is highly favorable.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (37.456) and Ligand B (83.094) have different values, but this is not a major deciding factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.595 and -4.717), indicating poor permeability. This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.636 and -3.578), indicating poor solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.732) has a slightly higher hERG risk than Ligand B (0.644), but both are reasonably low.

**Microsomal Clearance:** Ligand A (9.478) has a lower microsomal clearance than Ligand B (33.54), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (26.551) has a longer in vitro half-life than Ligand B (-2.588), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.503) has lower P-gp efflux than Ligand B (0.365), which is favorable for bioavailability.

**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:**

Ligand B has a significantly lower DILI risk and better BBB penetration. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic and longer t1/2) and slightly better P-gp efflux. The binding affinity difference is minimal. Given the importance of metabolic stability for kinase inhibitors, and the acceptable (though not ideal) DILI risk of Ligand A, it is the more promising candidate. The poor solubility and permeability of both compounds are concerns that would need to be addressed during lead optimization.

Output:
1
2025-04-17 16:41:53,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.232 Da) is slightly higher than Ligand B (349.475 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (70.63 and 74.43) that are reasonably good for oral absorption, being below the 140 A^2 threshold.

**logP:** Both ligands have optimal logP values (3.003 and 2.353), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.633 and 0.793), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (83.637 percentile) compared to Ligand B (25.359 percentile). This is a major concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (59.791 and 64.637 percentile). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.769), which is unusual and suggests poor permeability. This is a significant drawback for both compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.828 and -2.551), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A has a slightly higher hERG risk (0.858) than Ligand B (0.579), but both are reasonably low.

**Microsomal Clearance:** Ligand B has a lower microsomal clearance (12.067 mL/min/kg) than Ligand A (80.85 mL/min/kg), indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (-9.45 hours) than Ligand A (11.163 hours), which is also favorable.

**P-gp Efflux:** Ligand A has a higher P-gp efflux liability (0.693) than Ligand B (0.138), which could reduce oral bioavailability.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.9 kcal/mol) than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand A, the high DILI risk, poor metabolic stability (high Cl_mic), and higher P-gp efflux are major drawbacks. Ligand B, while having a weaker binding affinity, exhibits a much better safety profile (low DILI), improved metabolic stability, and lower P-gp efflux. The poor Caco-2 and solubility are concerns for both, but these can potentially be addressed through formulation strategies. For an enzyme target like SRC kinase, metabolic stability and safety are crucial.

Output:
1
2025-04-17 16:41:53,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.474 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (93.01). A TPSA under 140 is good for oral absorption, and A is well within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.417 and 1.545), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 7 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.752 and 0.871), indicating good drug-likeness.

**DILI:** Ligand A (40.403) has a lower DILI risk than Ligand B (74.603), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (92.012) has a higher BBB percentile than Ligand B (44.009).

**Caco-2 Permeability:** Ligand A (-4.855) has a more negative Caco-2 value than Ligand B (-5.565). Lower values are less desirable, but the difference is not huge.

**Aqueous Solubility:** Ligand A (-3.717) has a slightly better solubility score than Ligand B (-2.205). Both are quite poor, but A is marginally better.

**hERG Inhibition:** Ligand A (0.833) has a lower hERG inhibition liability than Ligand B (0.12), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (38.414) has a higher microsomal clearance than Ligand B (26.521), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (25.238 hours) has a significantly longer half-life than Ligand A (5.596 hours), which is a major benefit.

**P-gp Efflux:** Ligand A (0.134) shows lower P-gp efflux liability than Ligand B (0.213), which is preferable.

**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 that could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and a longer half-life, both critical for an enzyme inhibitor. However, it suffers from higher DILI risk, higher TPSA, and a worse hERG profile. Ligand A has better ADME properties overall, particularly regarding safety (DILI, hERG) and permeability (TPSA). The difference in binding affinity is significant (1.3 kcal/mol), and for an enzyme target, this is often enough to overcome moderate ADME liabilities, *provided* the safety profile isn't severely compromised. In this case, the DILI and hERG risks of Ligand B are concerning.

Output:
1
2025-04-17 16:41:53,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.435 and 389.933 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (38.77 and 37.61) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.88) is optimal, while Ligand B (4.773) is slightly higher, potentially leading to solubility issues, but still within a reasonable range.

**H-Bond Donors:** Both have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA, both are below the 10 threshold.

**QED:** Ligand A (0.852) has a significantly better QED score than Ligand B (0.445), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (64.521 and 67.701), but are still below the concerning >60 threshold.

**BBB:** Both ligands have good BBB penetration (80.651 and 66.266), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.264) has a worse Caco-2 permeability than Ligand B (-5.278).

**Aqueous Solubility:** Ligand A (-4.353) has worse solubility than Ligand B (-3.867).

**hERG:** Both ligands have low hERG inhibition risk (0.689 and 0.713).

**Microsomal Clearance:** Ligand A (72.222) has lower microsomal clearance than Ligand B (89.814), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.033) has a shorter half-life than Ligand B (16.994), which is a disadvantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.594 and 0.803).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). The difference is 0.3 kcal/mol, which is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A has a superior QED score and better metabolic stability (lower Cl_mic). However, it has lower Caco-2 permeability and aqueous solubility, and a shorter half-life. Ligand B has a slightly better binding affinity and better solubility, but a lower QED score and higher Cl_mic.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), the better metabolic stability and significantly higher QED of Ligand A outweigh its slightly lower affinity and solubility. The difference in affinity is not large enough to overcome the other advantages of Ligand A.

Output:
0
2025-04-17 16:41:53,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (493.221 Da) is at the upper end, while Ligand B (346.471 Da) is more favorably positioned.

**TPSA:** Ligand A (93.45) is acceptable, being under 140, but higher than Ligand B (75.27). Lower TPSA generally favors absorption.

**logP:** Both ligands have good logP values (A: 3.331, B: 2.502), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 3/5, B: 2/3), well within the guidelines.

**QED:** Both ligands have acceptable QED scores (A: 0.388, B: 0.524), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (75.339) has a higher DILI risk than Ligand B (41.605). This is a significant concern.

**BBB:** Both ligands have similar BBB penetration (A: 61.923, B: 60.566), which isn't a primary concern for a non-CNS target like SRC.

**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 negative solubility values, indicating poor solubility. Again, the values are similar and not a major differentiator.

**hERG:** Ligand A (0.853) has a slightly higher hERG risk than Ligand B (0.136). This is a concern for Ligand A.

**Microsomal Clearance:** Ligand A (59.788) has a higher microsomal clearance than Ligand B (47.116), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-43.615) has a significantly longer in vitro half-life than Ligand A (10.322). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.18), which is slightly favorable.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B boasts a significantly stronger binding affinity, a much longer half-life, lower DILI risk, and lower hERG risk. The improved metabolic stability and potency outweigh the slightly lower QED and P-gp efflux. Ligand A's higher DILI and hERG risks, combined with its weaker binding and lower half-life, make it a less desirable candidate.

Output:
1
2025-04-17 16:41:53,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (340.431 and 376.762 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.08) is slightly higher than Ligand B (67.43), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.264 and 1.997), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands 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 reasonable QED scores (0.811 and 0.746), indicating good drug-likeness.

**DILI:** Ligand A (37.728) has a significantly lower DILI risk than Ligand B (61.109). This is a major advantage for Ligand A.

**BBB:** Ligand B (90.074) shows better BBB penetration than Ligand A (68.67), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.15) has a worse Caco-2 permeability than Ligand B (-4.838).

**Aqueous Solubility:** Ligand A (-2.641) has a worse aqueous solubility than Ligand B (-3.914).

**hERG Inhibition:** Ligand A (0.238) has a lower hERG inhibition liability than Ligand B (0.652), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (12.391) has a slightly lower microsomal clearance than Ligand B (14.18), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (40.177) has a longer in vitro half-life than Ligand B (12.03), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.026) has significantly lower P-gp efflux liability than Ligand B (0.145), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.9 kcal/mol). This is a 1.4 kcal/mol difference, which is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B's superior binding affinity is a strong point. However, Ligand A has a much better safety profile (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. The solubility and Caco-2 permeability are worse for Ligand A, but these can potentially be addressed through formulation strategies. Given the focus on enzymes like kinases, and prioritizing potency, metabolic stability, solubility, and safety, the stronger binding affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 16:41:53,775 - INFO - Batch 485 complete. Total preferences: 7760
2025-04-17 16:41:53,776 - INFO - Processing batch 486/512...
2025-04-17 16:42:37,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.487 and 375.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.76) is better than Ligand B (78.43), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.235 and 1.637) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, well within the acceptable limit of 5.

**H-Bond Acceptors:** Both have 7 HBA, also within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.789 and 0.879), indicating good drug-like properties.

**DILI:** Ligand A (35.556) has a significantly lower DILI risk than Ligand B (90.268). This is a major advantage for Ligand A.

**BBB:** Ligand A (83.831) has a higher BBB penetration score than Ligand B (51.958). While not a primary concern for a non-CNS target like SRC, higher BBB is rarely detrimental.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.104 and -5.152). This is unusual and suggests poor permeability. However, these values are on the same scale, so don't differentiate the ligands.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.679 and -3.235). This is also unusual and suggests poor solubility. Again, the values are similar, so don't differentiate the ligands.

**hERG Inhibition:** Ligand A (0.618) has a slightly higher hERG inhibition risk than Ligand B (0.254), but both are relatively low.

**Microsomal Clearance:** Ligand A (68.059) has a higher microsomal clearance than Ligand B (39.537), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (6.132 hours) has a longer in vitro half-life than Ligand A (-6.256 hours). The negative value for Ligand A is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.03).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). The difference is 0.5 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a much lower DILI risk. The difference in binding affinity (0.5 kcal/mol) is substantial enough to outweigh the slightly higher clearance of Ligand A, *especially* given the significantly lower DILI risk. The poor Caco-2 and solubility values are concerning for both, but could be addressed with formulation strategies. The DILI risk is a more difficult property to improve.

Output:
1
2025-04-17 16:42:37,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.391 and 355.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.55) is better than Ligand B (125.71), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (0.902) is within the optimal 1-3 range. Ligand B (-2.463) is significantly lower, potentially hindering permeation.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 9. Both are within the acceptable range (<=10), but Ligand A is slightly better.

**QED:** Ligand A (0.705) has a better QED score than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (57.658 vs 56.689), and both are acceptable (<60).

**BBB:** Ligand A (70.531) has a better BBB penetration score than Ligand B (32.028). While not a primary concern for a non-CNS target, it's a slight advantage.

**Caco-2 Permeability:** Ligand A (-4.675) has a worse Caco-2 permeability than Ligand B (-5.265), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.499) has a worse aqueous solubility than Ligand B (0.111). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.04 and 0.014), which is excellent.

**Microsomal Clearance:** Ligand A (64.226) has a higher microsomal clearance than Ligand B (-0.253). This suggests Ligand B is more metabolically stable, a key factor for kinases.

**In vitro Half-Life:** Ligand B (9.06) has a significantly longer in vitro half-life than Ligand A (-25.119). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.019).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.9 kcal/mol). The difference is minimal.

**Conclusion:**

While Ligand A has a slightly better TPSA and QED, Ligand B demonstrates superior ADME properties crucial for kinase inhibitors. Specifically, its significantly better metabolic stability (lower Cl_mic, longer t1/2), acceptable solubility, and comparable binding affinity outweigh the slightly lower Caco-2 permeability and TPSA. The negative logP of Ligand B is a concern, but the strong binding affinity may compensate. Given the enzyme-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 16:42:37,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.419 and 364.511 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.02) is slightly higher than Ligand B (58.64), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.708) is a bit low, potentially hindering permeation, while Ligand B (2.984) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 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 (0.812 and 0.844), indicating drug-like properties.

**DILI:** Ligand A (54.789) has a slightly higher DILI risk than Ligand B (35.905), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (92.71) has better BBB penetration than Ligand B (76.309), but this isn't a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.894 and -4.963), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.441 and -2.648), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.601 and 0.586), which is positive.

**Microsomal Clearance:** Ligand A (19.669) has lower microsomal clearance than Ligand B (24.431), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (24.188 hours) has a significantly longer half-life than Ligand A (4.511 hours), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.149 and 0.309), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-10.4 and -10.2 kcal/mol). The difference is negligible.

**Conclusion:**

Given the priorities for enzyme inhibitors, Ligand B is slightly more favorable. While both have poor solubility and permeability, Ligand B's superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better logP outweigh the slightly higher DILI risk. The binding affinity is essentially the same. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the pharmacokinetic profile of Ligand B is more promising.

Output:
1
2025-04-17 16:42:37,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (353.491 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is significantly better than Ligand B (67.67). A TPSA under 140 is good for oral absorption, and both are under this limit, but A is much closer to the ideal for better absorption.

**logP:** Ligand A (3.539) is slightly higher than the optimal range (1-3), but acceptable. Ligand B (1.361) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 0 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 (0.775 and 0.824), indicating good drug-like properties.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (35.75). This is a significant drawback for Ligand A.

**BBB:** Both have similar BBB penetration (85.847 and 85.459), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.92 and -4.477). This is unusual and suggests poor permeability. However, the values are close, so this isn't a major differentiator.

**Aqueous Solubility:** Ligand A (-3.044) has worse solubility than Ligand B (-1.6). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.793) has a slightly higher hERG risk than Ligand B (0.209). Lower is better here, favoring Ligand B.

**Microsomal Clearance:** Ligand A (59.762) has a higher microsomal clearance than Ligand B (28.31). Lower clearance indicates better metabolic stability, favoring Ligand B.

**In vitro Half-Life:** Ligand A (-8.355) has a worse in vitro half-life than Ligand B (1.571). A longer half-life is generally preferred, favoring Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.603 and 0.079).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better 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 the better candidate. While both have some issues with Caco-2 permeability, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG risk, better solubility, and a substantially stronger binding affinity. The slightly lower logP of Ligand B is a minor concern compared to the advantages it offers. Ligand A's high DILI risk and poor metabolic stability are major red flags.

Output:
1
2025-04-17 16:42:37,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.41 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is well below the 140 A^2 threshold, while Ligand B (122.55) is still acceptable, but less optimal.

**logP:** Ligand A (4.147) is slightly high, potentially leading to solubility issues, but still within a manageable range. Ligand B (-0.502) is significantly low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED scores (0.72 and 0.569), indicating good drug-like properties.

**DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (54.517). This is a concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (64.831) and Ligand B (48.081) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.922) shows poor permeability. Ligand B (-5.28) is similarly poor.

**Aqueous Solubility:** Ligand A (-5.148) has very poor solubility, which is a significant drawback. Ligand B (-2.107) is also poor, but better than Ligand A.

**hERG:** Ligand A (0.623) has a slightly elevated hERG risk, but is still relatively low. Ligand B (0.037) has a very low hERG risk, which is a major advantage.

**Microsomal Clearance:** Ligand A (70.519) has moderate clearance, while Ligand B (-0.244) has very low clearance, indicating excellent metabolic stability. This is a strong point for Ligand B.

**In vitro Half-Life:** Ligand A (-24.598) has a very short half-life. Ligand B (-5.823) has a short half-life, but is better than Ligand A.

**P-gp Efflux:** Ligand A (0.519) has moderate P-gp efflux. Ligand B (0.013) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 2.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better TPSA, its significantly poorer solubility, shorter half-life, moderate clearance, higher DILI risk, and weaker binding affinity make it a less desirable candidate. Ligand B, while having a slightly higher TPSA and lower logP, exhibits excellent metabolic stability (low Cl_mic), very low hERG risk and P-gp efflux, and a much stronger binding affinity. The strong binding affinity of Ligand B is the deciding factor, as it can compensate for some of its ADME liabilities.

Output:
1
2025-04-17 16:42:37,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, potentially aiding permeability.

**TPSA:** Ligand A (78.67) is significantly better than Ligand B (138.68). Lower TPSA generally correlates with better cell permeability, crucial for kinase inhibitors to reach their intracellular target. Ligand B is approaching the upper limit for good oral absorption.

**logP:** Ligand A (1.622) is within the optimal range (1-3). Ligand B (-0.951) is slightly below 1, which *could* indicate potential permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=7). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.893) has a much higher QED score than Ligand B (0.579), indicating a more drug-like profile.

**DILI:** Ligand B (57.425) has a lower DILI risk than Ligand A (67.429), which is a positive. However, both are still within an acceptable range.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.587) and Ligand B (45.909) are both relatively low.

**Caco-2 Permeability:** Both are negative (-5.093 and -5.614), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both are also negative (-1.68 and -1.814), indicating poor aqueous solubility, which could hinder bioavailability.

**hERG Inhibition:** Ligand A (0.115) has a much lower hERG risk than Ligand B (0.076), a significant advantage.

**Microsomal Clearance:** Ligand A (30.927) has a higher microsomal clearance than Ligand B (16.069), meaning it's metabolized faster. Ligand B exhibits better metabolic stability.

**In vitro Half-Life:** Ligand B (4.685) has a longer in vitro half-life than Ligand A (-0.988), which is a positive.

**P-gp Efflux:** Both are very low (0.104 and 0.027), indicating minimal P-gp efflux.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a better QED, TPSA, H-bonding profile, and significantly lower hERG risk. However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower DILI risk. The poor Caco-2 and solubility for both are concerning. Given the priority for metabolic stability in kinase inhibitors, and the similar binding affinities, Ligand B is slightly more promising, but the solubility and permeability issues of both are major drawbacks that would require addressing through formulation or further chemical modification. However, the hERG risk of ligand A is a significant concern.

Output:
1
2025-04-17 16:42:37,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.49 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is well below the 140 threshold, suggesting good absorption. Ligand B (97.62) is still within acceptable limits, but less optimal.

**logP:** Ligand A (2.932) is optimal (1-3). Ligand B (0.948) is slightly low, potentially hindering permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is excellent. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.584 and 0.521), indicating drug-likeness.

**DILI:** Ligand A (37.456) has a significantly lower DILI risk than Ligand B (65.878), which is a major advantage.

**BBB:** BBB isn't a primary concern for a non-CNS target like SRC, but Ligand A (61.38) is slightly better than Ligand B (57.852).

**Caco-2 Permeability:** Ligand A (-4.934) has a worse Caco-2 permeability than Ligand B (-5.37), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.726) has a better aqueous solubility than Ligand B (-1.791), which is crucial for bioavailability.

**hERG:** Ligand A (0.79) shows a lower hERG inhibition liability than Ligand B (0.248), a significant safety advantage.

**Microsomal Clearance:** Ligand A (61.695) has a higher (worse) microsomal clearance than Ligand B (49.798), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (67.206) has a longer in vitro half-life than Ligand B (18.675), which is desirable.

**P-gp Efflux:** Ligand A (0.455) has lower P-gp efflux liability than Ligand B (0.081), which is beneficial.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand A demonstrates significantly better safety profiles (DILI and hERG) and better solubility. While Ligand A has a worse Caco-2 permeability and higher clearance, the improved safety profile and solubility are critical. The slightly better affinity of Ligand B might be offset by its higher DILI and hERG risk. Given the enzyme class and the importance of minimizing toxicity, I lean towards Ligand A.

Output:
1
2025-04-17 16:42:37,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.219 Da) is slightly higher than Ligand B (354.491 Da), but both are acceptable.

**TPSA:** Ligand A (54.88) is well below the 140 threshold for good absorption. Ligand B (89.87) is also acceptable, though higher.

**logP:** Ligand A (4.937) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.442) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=4) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.523, Ligand B: 0.713), indicating good drug-like properties.

**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 (19.698%).

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (73.168%) is higher than Ligand B (25.126%), but this is not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.836 and -4.732). 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 (-5.713 and -1.815), indicating poor aqueous solubility. This is a concern, but potentially manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.739) has a slightly higher hERG risk than Ligand B (0.248), but both are relatively low.

**Microsomal Clearance:** Ligand A (81.086) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (12.095) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (124.989 hours) has a longer half-life than Ligand B (-8.113 hours). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.555) has lower P-gp efflux than Ligand B (0.071), which is favorable.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-5.9 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Conclusion:**

Despite Ligand A's superior binding affinity, the extremely high DILI risk (99.147%) is a critical issue that outweighs its benefits. The negative half-life for Ligand B is also concerning, but the lower DILI risk and better metabolic stability make it a more promising starting point for optimization. The affinity difference is significant, but can potentially be addressed through medicinal chemistry efforts on Ligand B.

Output:
1
2025-04-17 16:42:37,848 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.431 and 367.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (77.41 and 82.53) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands have logP values (1.782 and 1.388) 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 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.726 and 0.745), indicating good drug-like properties.

**7. DILI:** Ligand A (32.765) has a significantly lower DILI risk than Ligand B (43.234). This is a major advantage for Ligand A.

**8. BBB:** Both have moderate BBB penetration (60.644 and 68.554).  Since SRC is not a CNS target, this is not a primary concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.928 and -4.831). This is unusual and suggests poor permeability. However, negative values can occur with certain modeling approaches and might not be entirely reliable.

**10. Aqueous Solubility:** Both have negative solubility values (-2.128 and -2.49). Similar to Caco-2, this is concerning and suggests poor solubility. This could be a significant issue for *in vivo* bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.288 and 0.291), which is excellent.

**12. Microsomal Clearance:** Ligand A (28.977) has a higher microsomal clearance than Ligand B (0.477). This suggests Ligand B is more metabolically stable, which is a key consideration for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (41.038) has a longer half-life than Ligand B (-1.925). This is a positive for Ligand A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.019 and 0.133).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.4 kcal/mol). While the difference is not huge, it's a noticeable advantage.

**Overall Assessment:**

Ligand A is preferable. While both ligands have some concerning ADME properties (low solubility and permeability), Ligand A's significantly lower DILI risk, slightly better binding affinity, and longer half-life outweigh the fact that Ligand B has better metabolic stability. The DILI risk is a critical factor, and the slightly improved potency and half-life of Ligand A make it the more promising candidate. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the starting point is better with Ligand A.

Output:
0
2025-04-17 16:42:37,848 - INFO - Okay, let's analyze these two ligands for their potential as drug candidates targeting SRC, a kinase.

**Step-by-step comparison:**

1. **MW:** Ligand A (421.123 Da) is within the ideal range (200-500). Ligand B (368.855 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (59.29) is good for oral absorption (<140). Ligand B (36.36) is excellent. Ligand B has a slight advantage.

3. **logP:** Ligand A (3.369) is optimal (1-3). Ligand B (4.485) is slightly above the optimal range, potentially leading to solubility issues or off-target interactions, but not drastically so. Ligand A has a slight advantage.

4. **HBD:** Both Ligand A (1) and Ligand B (1) are within the acceptable limit of <=5. No difference.

5. **HBA:** Ligand A (4) is within the acceptable limit of <=10. Ligand B (3) is also within the limit. No significant difference.

6. **QED:** Ligand A (0.401) is below the preferred threshold of 0.5. Ligand B (0.782) is above the threshold, indicating a better drug-like profile. Ligand B has a clear advantage.

7. **DILI:** Ligand A (94.765) has a very high DILI risk. Ligand B (20.163) has a low DILI risk. Ligand B has a *major* advantage.

8. **BBB:** Both ligands have reasonable BBB penetration (Ligand A: 76.658, Ligand B: 72.005). Not a primary concern for a non-CNS target like SRC.

9. **Caco-2:** 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 poor permeability.

10. **Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or the model.

11. **hERG:** Ligand A (0.516) has a slightly higher hERG risk than Ligand B (0.952), but both are relatively low. Ligand B has a slight advantage.

12. **Cl_mic:** Ligand A (52.588) has a lower microsomal clearance than Ligand B (58.311), suggesting better metabolic stability. Ligand A has a slight advantage.

13. **t1/2:** Ligand B (71.657) has a longer in vitro half-life than Ligand A (64.186). Ligand B has a slight advantage.

14. **Pgp:** Ligand A (0.574) has lower P-gp efflux liability than Ligand B (0.684), which is favorable for oral bioavailability. Ligand A has a slight advantage.

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 (1.3 kcal/mol difference).

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, and better metabolic stability and Pgp efflux. However, its *extremely* high DILI risk is a major red flag. Ligand B has a much better safety profile (DILI), better QED, and a reasonable half-life. While its affinity is lower, the difference might be overcome with further optimization. The negative Caco-2 and solubility values are concerning for both, and would need investigation, but the DILI risk for A is a showstopper.

**Conclusion:**

Considering the enzyme-specific priorities and the critical importance of safety (DILI), **Ligand B** is the more viable drug candidate.

1
2025-04-17 16:42:37,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (346.471 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (84.23).  A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (2.575 and 2.99), 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:** Both ligands have acceptable QED values (0.569 and 0.743), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (28.461) has a much lower DILI risk than Ligand B (41.877). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (75.107 and 71.074). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.805 and -4.665), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.421 and -3.557), which is also unusual and suggests poor solubility. Ligand A is slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.216 and 0.133). This is excellent.

**12. Microsomal Clearance:** Ligand A (35.914) has significantly lower microsomal clearance than Ligand B (68.328). Lower clearance indicates better metabolic stability, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-2.108) has a better (less negative) half-life than Ligand B (-15.859). This further supports Ligand A's improved metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.123).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -8.0 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and QED, Ligand A is superior in almost all ADME properties critical for an enzyme inhibitor. Specifically, Ligand A demonstrates significantly lower DILI risk, lower microsomal clearance, and a better in vitro half-life. The slightly better affinity of Ligand B is unlikely to outweigh the substantial advantages in ADME properties offered by Ligand A. 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 16:42:37,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.483 and 373.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (91.5). A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's TPSA is higher, potentially hindering absorption.

**3. logP:** Both ligands have acceptable logP values (2.888 and 1.245), 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 threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (2 and 4 respectively), below the threshold of 10.

**6. QED:** Both have similar QED values (0.854 and 0.812), indicating good drug-likeness.

**7. DILI:** Ligand A (13.532) has a much lower DILI risk than Ligand B (52.423). This is a significant advantage for Ligand A.

**8. BBB:** Both have the same BBB penetration (70.997), which is acceptable but not a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.865 and -4.626), which is unusual and suggests poor permeability. However, these values are relative and need to be interpreted cautiously.

**10. Aqueous Solubility:** Both have negative solubility values (-3.432 and -2.864), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.344 and 0.404), which is excellent.

**12. Microsomal Clearance:** Ligand A (49.742) has a higher microsomal clearance than Ligand B (22.073), indicating faster metabolism and potentially lower *in vivo* exposure. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-56.98) has a significantly longer in vitro half-life than Ligand A (-10.746). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.097 and 0.026).

**15. Binding Affinity:** Both have excellent binding affinities (-9.9 and -9.5 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has advantages in TPSA and DILI risk, but suffers from higher microsomal clearance and shorter half-life. Ligand B has a significantly better half-life and lower clearance, which are crucial for *in vivo* efficacy as an enzyme inhibitor. While both have poor solubility and permeability, these can be addressed through formulation. The lower DILI risk of Ligand A is attractive, but the improved metabolic stability of Ligand B is more critical for a kinase inhibitor.

Output:
1
2025-04-17 16:42:37,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.551 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (80.56) is still below 140, but less optimal than A.

**logP:** Ligand A (4.579) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.192) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, which is favorable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.631 and 0.798), indicating drug-likeness.

**DILI:** Ligand A (21.055) has a low DILI risk. Ligand B (42.924) is slightly higher, but still within an acceptable range.

**BBB:** Both ligands have similar BBB penetration (70.027 and 70.88), which isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.212) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.737) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.711 and -1.585). This is a concern, but can sometimes be mitigated through formulation.

**hERG:** Ligand A (0.953) has a slightly higher hERG risk than Ligand B (0.089), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (78.901) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (20.37) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (49.547) has a moderate half-life. Ligand B (1.019) has a very short half-life, a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.785 and 0.045), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.5 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is superior despite the short half-life. The key advantages of Ligand B are its lower logP, significantly lower microsomal clearance (better metabolic stability), and much lower hERG risk. While both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies. The slight advantage in binding affinity of Ligand B and the significantly better ADME profile outweigh the longer half-life of Ligand A.

Output:
1
2025-04-17 16:42:37,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (371.503 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is higher than Ligand B (62.99). While both are reasonably acceptable, Ligand B's lower TPSA is preferable for better absorption.

**logP:** Ligand A (-0.019) is quite low, potentially hindering permeability. 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 has 3 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits, though Ligand B's lower HBD count is slightly favorable for permeability.

**QED:** Both ligands have good QED scores (0.529 and 0.823), indicating drug-like properties.

**DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (37.611), which is a substantial advantage.

**BBB:** Ligand A (36.371) has a lower BBB penetration than Ligand B (72.276). Since SRC is not a CNS target, this is less critical, but still slightly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.522) has poor Caco-2 permeability, while Ligand B (-4.513) is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.457 and -2.143 respectively). This is a concern for both, but slightly worse for Ligand B.

**hERG Inhibition:** Ligand A (0.109) has a lower hERG risk than Ligand B (0.452), which is a significant advantage.

**Microsomal Clearance:** Ligand A (10.528) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (13.502).

**In vitro Half-Life:** Ligand A (-18.221) has a very short in vitro half-life, a major drawback. Ligand B (57.491) has a much longer half-life, which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.008 and 0.2 respectively).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This difference is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk and better metabolic stability, Ligand B excels in crucial areas: logP, binding affinity, and *especially* in vitro half-life. The poor solubility of both is a concern that would need to be addressed through formulation strategies, but the longer half-life and better potency of Ligand B make it a more promising starting point. The lower logP of Ligand A is a significant issue for permeability.

Output:
1
2025-04-17 16:42:37,849 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Ligand A (337.379 Da) is within the ideal range (200-500), while Ligand B (412.259 Da) is towards the upper end but still acceptable.
2. **TPSA:** Both ligands (A: 84.08, B: 83.48) are well below the 140 threshold for good oral absorption, and also below the 90 threshold for CNS penetration (though that's not a primary concern here).
3. **logP:** Both ligands have good logP values (A: 2.294, B: 2.783), falling within the optimal 1-3 range.
4. **HBD:** Ligand A (2) and Ligand B (3) both meet the HBD <=5 guideline.
5. **HBA:** Both ligands (A: 4, B: 4) are well below the HBA <=10 guideline.
6. **QED:** Both ligands have similar QED values (A: 0.676, B: 0.653), indicating good drug-like properties (>=0.5).
7. **DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (62.893). Both are acceptable, but B is preferable.
8. **BBB:** Both ligands have low BBB penetration (A: 37.65, B: 46.375), which isn't a major concern for an oncology target.
9. **Caco-2:** Both ligands have negative Caco-2 values (A: -5.112, B: -4.946), which is unusual. Negative values are not interpretable, and suggest a problem with the data or the model used to generate it. Assuming these represent very *low* permeability, this is a concern.
10. **Solubility:** Both ligands have negative solubility values (A: -4.528, B: -2.945), which is also unusual and suggests poor aqueous solubility. Again, assuming these represent very *low* solubility, this is a concern.
11. **hERG:** Both ligands have low hERG inhibition risk (A: 0.765, B: 0.492), which is good.
12. **Cl_mic:** Ligand B (31.93) has a lower microsomal clearance than Ligand A (40.948), indicating better metabolic stability. This is a key factor for kinase inhibitors.
13. **t1/2:** Ligand B (25.759) has a significantly longer in vitro half-life than Ligand A (-12.358). This is a major advantage.
14. **Pgp:** Both ligands have low P-gp efflux liability (A: 0.563, B: 0.194), which is favorable. Ligand B is better.
15. **Binding Affinity:** Ligand A (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a *very* significant advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While both ligands have acceptable hERG risk, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2). However, the binding affinity difference is huge. A difference of >8 kcal/mol is extremely significant and likely outweighs the ADME advantages of Ligand B. The negative solubility and Caco-2 values are concerning for both, but a potent molecule might overcome these issues with formulation strategies.

**Conclusion:**

Despite the ADME advantages of Ligand B, the dramatically superior binding affinity of Ligand A makes it the more promising drug candidate.

Output:
0
2025-04-17 16:42:37,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (70.4) is better than Ligand B (87.66). Both are below 140, but lower TPSA generally correlates with better absorption.

**logP:** Ligand A (3.731) is optimal, while Ligand B (1.609) is a bit low. A logP below 1 can sometimes hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2/3) and HBA (4/4) counts, well within the guidelines.

**QED:** Ligand A (0.89) has a significantly better QED score than Ligand B (0.55), indicating a more drug-like profile.

**DILI:** Ligand B (29.779) has a much lower DILI risk than Ligand A (41.179), which is a significant advantage.

**BBB:** Ligand A (87.864) has better BBB penetration than Ligand B (76.619), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.864) and Ligand B (-4.641) both have negative values, which is unusual and suggests very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Ligand A (-3.53) and Ligand B (-2.169) both have negative values, indicating poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG risk (0.811 and 0.381, respectively), which is good.

**Microsomal Clearance:** Ligand B (38.247) has lower microsomal clearance than Ligand A (42.124), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.833) has a negative half-life, which is impossible. This is a major red flag and suggests a serious issue with the data or the compound's stability. Ligand A (72.584) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.124 and 0.045, respectively), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.8 kcal/mol, respectively). Ligand B is slightly better.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and lower DILI risk and microsomal clearance, the negative in vitro half-life is a critical flaw. This indicates a fundamental problem with the compound's stability and makes it highly unlikely to be a viable drug candidate. Ligand A, despite its higher DILI risk and slightly lower QED, has a reasonable half-life and acceptable properties across most other parameters. The poor solubility and permeability are concerning for both, but could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 16:42:37,850 - INFO - Batch 486 complete. Total preferences: 7776
2025-04-17 16:42:37,850 - INFO - Processing batch 487/512...
2025-04-17 16:43:18,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.315 Da) is slightly higher than Ligand B (348.443 Da), but both are acceptable.

**TPSA:** Ligand A (41.13) is significantly better than Ligand B (87.66). A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (4.954) is high, potentially leading to solubility issues and off-target effects. Ligand B (2.284) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 1 HBA) is better than Ligand B (3 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds can improve permeability.

**QED:** Both ligands have similar QED values (Ligand A: 0.735, Ligand B: 0.629), indicating reasonable drug-likeness.

**DILI:** Ligand A (50.33) has a higher DILI risk than Ligand B (30.787). Lower is better, so Ligand B is preferable.

**BBB:** This isn't a primary concern for a kinase inhibitor, but Ligand A (78.519) has a higher BBB percentile than Ligand B (52.656).

**Caco-2 Permeability:** Ligand A (-4.648) has a worse Caco-2 permeability than Ligand B (-5.017). Lower values suggest poorer permeability.

**Aqueous Solubility:** Ligand A (-5.859) has worse solubility than Ligand B (-3.04). Solubility is important for bioavailability, making Ligand B more favorable.

**hERG Inhibition:** Ligand A (0.757) has a higher hERG risk than Ligand B (0.282). Lower is better, making Ligand B significantly safer.

**Microsomal Clearance:** Ligand A (57.815) has higher clearance than Ligand B (46.067), indicating lower metabolic stability. Lower clearance is preferred.

**In vitro Half-Life:** Ligand A (59.478) has a better half-life than Ligand B (-22.048). Longer half-life is desirable.

**P-gp Efflux:** Ligand A (0.51) has lower P-gp efflux than Ligand B (0.046), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.3 kcal/mol). This is a substantial advantage for Ligand A, and could potentially outweigh some of its ADME drawbacks. A 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B has superior ADME properties (logP, DILI, solubility, hERG, clearance) and is generally more drug-like. However, Ligand A boasts a considerably stronger binding affinity (-10.2 vs -9.3 kcal/mol). Given that we are targeting a kinase (enzyme), potency is paramount. The difference in binding affinity is large enough to potentially overcome the higher logP and slightly worse ADME profile of Ligand A, *provided* the solubility and hERG risks can be mitigated through formulation or further optimization. The improved half-life is also a positive.

Output:
1
2025-04-17 16:43:18,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.531 and 350.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (64.33), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (4.125) is slightly higher than the optimal range (1-3), while Ligand B (3.252) is within the optimal range. This favors B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 10.

**QED:** Both ligands have good QED scores (0.648 and 0.743), indicating good drug-like properties.

**DILI:** Ligand A (21.287) has a significantly lower DILI risk than Ligand B (13.959), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (78.713 and 88.29), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.603) and Ligand B (-4.187) are both negative, indicating poor permeability.

**Solubility:** Ligand A (-4.938) and Ligand B (-3.501) are both negative, indicating poor solubility.

**hERG:** Ligand A (0.336) has a lower hERG risk than Ligand B (0.907), which is a significant advantage.

**Microsomal Clearance:** Ligand A (69.917) has higher microsomal clearance than Ligand B (44.152), indicating lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand A (-2.287) has a shorter half-life than Ligand B (18.859), indicating lower stability. This favors B.

**P-gp:** Ligand A (0.116) has lower P-gp efflux than Ligand B (0.409), which is a slight advantage.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a crucial factor, as a 1.4 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has advantages in DILI risk, hERG, and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.9 vs -6.5 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are more critical for an enzyme target like SRC kinase. The slightly higher logP of Ligand A is a concern, but the substantial affinity difference of Ligand B outweighs this.

Output:
1
2025-04-17 16:43:18,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as guidelines for enzyme targets suggest.

**Molecular Weight:** Both ligands (351.491 and 348.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (26.3). While both are below 140, the lower TPSA of Ligand B might be *too* low, potentially sacrificing some necessary interactions with the kinase.

**logP:** Ligand A (1.833) is optimal (1-3). Ligand B (4.862) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also acceptable, but a lack of HBDs can sometimes hinder solubility.

**H-Bond Acceptors:** Ligand A (3) is good. Ligand B (2) is also good.

**QED:** Both ligands have similar QED values (0.7 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (15.394) has a significantly lower DILI risk than Ligand B (38.852), which is a major advantage.

**BBB:** Ligand A (69.872) and Ligand B (87.127) both have acceptable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.134) is poor, while Ligand B (-4.337) is also poor, but slightly better. Both suggest limited intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.938) is poor, while Ligand B (-5.835) is very poor. This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.161) has a very low hERG risk, which is excellent. Ligand B (0.869) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (15.263) has a lower clearance than Ligand B (67.336), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (3.166) has a shorter half-life than Ligand B (26.106). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, while Ligand B (0.515) has moderate P-gp efflux. Lower efflux is better.

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, lower microsomal clearance (better metabolic stability), very low hERG risk, and lower P-gp efflux. While Ligand A has poorer Caco-2 permeability and solubility, the benefits in safety and metabolic stability outweigh these drawbacks, especially given the equal binding affinity. Ligand B's higher logP and DILI risk are significant concerns.

Output:
0
2025-04-17 16:43:18,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (337.47 and 362.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.56) is significantly better than Ligand B (65.54).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (4.057) is a bit high, potentially leading to solubility issues, while Ligand B (1.34) is quite low, potentially hindering permeation. The optimal range is 1-3.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.858) has a better QED score than Ligand A (0.599), indicating a more drug-like profile.

**DILI:** Ligand A (17.45) has a lower DILI risk than Ligand B (20.20), which is preferable. Both are below the 40 threshold.

**BBB:** Ligand A (68.55) has a better BBB penetration score than Ligand B (46.45), but BBB isn't a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.232 and -5.158). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.15 and -0.952). This is also concerning, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.977) has a lower hERG inhibition liability than Ligand B (0.158), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-4.086) has a *negative* microsomal clearance, which is not physically possible. This is a major red flag and suggests an issue with the data or the model. Ligand A (26.644) has a reasonable clearance.

**In vitro Half-Life:** Ligand A (29.77 hours) has a much longer half-life than Ligand B (4.477 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.717) has better P-gp efflux liability than Ligand B (0.023).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Conclusion:**

Despite Ligand B's superior binding affinity, the negative microsomal clearance is a critical flaw. A negative clearance is not realistic and indicates a serious problem with the data or prediction. Ligand A, while having a slightly weaker binding affinity, has a more reasonable ADME profile, including a positive (though not ideal) clearance, a longer half-life, and lower hERG risk. The solubility and permeability issues are shared by both, but are less critical than the impossible clearance value for Ligand B. Therefore, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 16:43:18,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (386.5 and 362.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.97) is slightly higher than Ligand B (78.43). Both are acceptable for oral absorption (<140), but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.64 and 3.34), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially impacting solubility.

**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:** Both ligands have reasonable QED scores (0.82 and 0.57), indicating good drug-like properties.

**DILI:** Ligand A (76.1%) has a higher DILI risk than Ligand B (47.0%). This is a significant concern for Ligand A.

**BBB:** Both have moderate BBB penetration (50.7% and 58.2%). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.774) shows poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.132) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.285 and -4.728). This is a major drawback for both, but Ligand A is slightly better.

**hERG:** Both ligands have low hERG inhibition risk (0.51 and 0.30), which is good.

**Microsomal Clearance:** Ligand A (27.2 mL/min/kg) has lower microsomal clearance than Ligand B (42.2 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (86.0 hours) has a much longer half-life than Ligand B (5.5 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.17 and 0.16).

**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, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.6 vs -9.3 kcal/mol). However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and slightly better solubility. The poor Caco-2 permeability of both is a concern, but the superior binding affinity of Ligand B is a critical factor for an enzyme inhibitor. The longer half-life and lower DILI risk of Ligand A are attractive, but the potency advantage of Ligand B is more impactful.

Output:
1
2025-04-17 16:43:18,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.431 and 346.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is well below the 140 threshold for good absorption, and is preferable to Ligand B (109.65).

**logP:** Both ligands have good logP values (2.146 and 1.335), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (3 HBD, 8 HBA) as it has fewer H-bond donors and acceptors, potentially improving permeability.

**QED:** Both ligands have similar QED values (0.691 and 0.628), indicating good drug-likeness.

**DILI:** Ligand A (39.201) has a significantly lower DILI risk than Ligand B (53.742), which is a major advantage.

**BBB:** BBB is not a high priority for a non-CNS target like SRC. Ligand A (79.682) is better than Ligand B (36.797).

**Caco-2 Permeability:** Ligand A (-4.524) is better than Ligand B (-5.419), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.526) is better than Ligand B (-2.094), indicating better solubility.

**hERG Inhibition:** Ligand A (0.387) has a lower hERG risk than Ligand B (0.094), which is a significant advantage.

**Microsomal Clearance:** Ligand A (69.391) has a higher microsomal clearance than Ligand B (42.658), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (21.334) has a significantly longer in vitro half-life than Ligand A (4.914), a substantial advantage.

**P-gp Efflux:** Ligand A (0.156) has lower P-gp efflux than Ligand B (0.011), which is preferable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol), which is a major advantage. The 2.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility, lower DILI and hERG risk, and better permeability, Ligand B's significantly stronger binding affinity (-9.5 vs -7.2 kcal/mol) and longer half-life are crucial for an enzyme inhibitor. The improved affinity is likely to translate to greater efficacy, and the longer half-life reduces dosing frequency. The slightly higher DILI and hERG risks of Ligand B are acceptable given the potency advantage.

Output:
1
2025-04-17 16:43:18,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.459 and 355.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.9) is higher than the preferred <140, but still reasonable. Ligand B (46.61) is excellent, well below 90.

**logP:** Ligand A (0.063) is quite low, potentially hindering permeability. Ligand B (3.835) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, acceptable values. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.666 and 0.56), indicating good drug-likeness.

**DILI:** Ligand A (54.285) has a moderate DILI risk, while Ligand B (15.665) has a very low DILI risk, which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (95.308) has a high BBB score, but this is less relevant here. Ligand A (22.606) is low.

**Caco-2 Permeability:** Ligand A (-5.43) has poor predicted Caco-2 permeability. Ligand B (-3.973) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.04) has poor predicted solubility. Ligand B (-4.798) also has poor solubility.

**hERG Inhibition:** Ligand A (0.085) has a very low hERG risk, a major advantage. Ligand B (0.849) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (16.268) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (123.486) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-0.828) has a short half-life. Ligand B (-6.738) has a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.348).

**Binding Affinity:** Ligand B (-7.3 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 factors.

**Overall Assessment:**

Ligand B has a better logP, lower DILI risk, and slightly better binding affinity. However, Ligand A has a significantly lower hERG risk and better metabolic stability (lower Cl_mic). The poor solubility and permeability of both are concerning, but can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, the lower hERG risk and better metabolic stability of Ligand A are more critical. The slightly weaker binding affinity can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 16:43:18,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (383.832 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (58.64). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (3.718 and 2.657), 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 (0.625 and 0.803), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (93.757 percentile) compared to Ligand B (15.859 percentile). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (77.123 and 78.441 percentile), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but the magnitude is similar.

**Aqueous Solubility:** Ligand A (-5.178) has considerably worse solubility than Ligand B (-2.453). Solubility is important for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.44 and 0.436), which is good.

**Microsomal Clearance:** Ligand A (81.837) has higher microsomal clearance than Ligand B (63.027), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.273) has a negative half-life, which is not possible. This is a significant data quality issue. Ligand A has a reasonable half-life of 74.999 hours.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.583 and 0.106).

**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 significant but not overwhelming.

**Overall Assessment:**

Ligand B appears to be the better candidate despite the questionable half-life value. Its significantly lower DILI risk and better solubility are major advantages. While Ligand A has a slightly better binding affinity, the high DILI risk and poor solubility are substantial drawbacks. The negative half-life for ligand B is concerning and would require experimental verification, but the other ADME properties are more favorable.

Output:
1
2025-04-17 16:43:18,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (56.15) is significantly better than Ligand B (74.76). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.838) is optimal, while Ligand B (1.554) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are low, a single donor can sometimes improve solubility without significantly impacting permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**QED:** Both ligands have similar QED values (0.771 and 0.68), indicating good drug-likeness.

**DILI:** Ligand A (72.586) has a higher DILI risk than Ligand B (21.636). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (69.135 and 77.084), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**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 them relatively. Ligand A (-4.757) is slightly worse than Ligand B (-4.678).

**Aqueous Solubility:** Ligand A (-4.486) is worse than Ligand B (-2.074). Solubility is important for bioavailability, and Ligand B has a clear advantage here.

**hERG Inhibition:** Ligand A (0.69) has a higher hERG risk than Ligand B (0.352), which is a concern for potential cardiotoxicity.

**Microsomal Clearance:** Ligand B (40.378) has a lower microsomal clearance, indicating better metabolic stability, which is crucial for enzymes. Ligand A (61.293) is higher, suggesting faster metabolism.

**In vitro Half-Life:** Ligand B (-4.454) has a longer in vitro half-life than Ligand A (16.399). This further supports the better metabolic stability of Ligand B.

**P-gp Efflux:** Ligand A (0.649) has higher P-gp efflux than Ligand B (0.079). Lower P-gp efflux is desirable for better bioavailability.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.2). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. It has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG risk, better solubility, and lower P-gp efflux. While Ligand A has a slightly better binding affinity, the ADME properties of Ligand B are significantly more favorable for development as an enzyme inhibitor. The lower logP of Ligand B is a minor concern, but the other advantages outweigh this.

Output:
1
2025-04-17 16:43:18,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (348.447 and 340.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.25) is slightly above the optimal <140 for oral absorption, but still reasonable. Ligand B (58.2) is excellent, well below 90, suggesting good permeability.

**3. logP:** Ligand A (0.732) is a bit low, potentially hindering permeation. Ligand B (3.108) is 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 (2) are both acceptable, below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.543 and 0.715), indicating drug-like properties.

**7. DILI:** Both ligands have similar, low DILI risk (25.359 and 25.204 percentile), which is favorable.

**8. BBB:** Ligand A (16.479) has very low BBB penetration, while Ligand B (64.831) is moderate. BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**9. Caco-2 Permeability:** Ligand A (-5.203) has poor Caco-2 permeability, while Ligand B (-4.572) is slightly better, but still not great.

**10. Aqueous Solubility:** Ligand A (-0.988) has poor aqueous solubility, while Ligand B (-3.453) is even worse. This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.199 and 0.363 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A (0.809) has low microsomal clearance, indicating good metabolic stability. Ligand B (53.489) has high microsomal clearance, suggesting rapid metabolism.

**13. In vitro Half-Life:** Ligand A (-18.314) has a very long in vitro half-life, which is highly desirable. Ligand B (-3.957) has a shorter half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.036 and 0.095 percentile), which is favorable.

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.1 kcal/mol), which is excellent and the most important factor.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. While both ligands have excellent affinity and hERG profiles, Ligand A excels in metabolic stability (low Cl_mic, long t1/2). However, its poor solubility and Caco-2 permeability are major drawbacks. Ligand B has poor metabolic stability and solubility, but slightly better permeability.

Considering the balance, the longer half-life and better metabolic stability of Ligand A are more valuable for an enzyme inhibitor, even with the solubility concerns. Solubility can be addressed with formulation strategies, but poor metabolic stability is harder to overcome.

Output:
0
2025-04-17 16:43:18,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.394 and 353.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is excellent, well below the 140 threshold for oral absorption. Ligand B (43.86) is also very good.

**logP:** Both ligands (1.575 and 2.058) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, within the limit. Ligand B has 3, also within the limit.

**QED:** Ligand A (0.728) is better than Ligand B (0.671), indicating a more drug-like profile.

**DILI:** Ligand A (32.997) has a significantly lower DILI risk than Ligand B (8.996), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (96.123) shows high BBB penetration, while Ligand A (50.679) is lower.

**Caco-2 Permeability:** Ligand A (-5.281) has a negative Caco-2 value, which is concerning. Ligand B (-4.492) is also negative, but slightly less so. Both suggest poor permeability.

**Aqueous Solubility:** Both ligands (-2.313 and -2.169) have poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.336) has a lower hERG inhibition liability than Ligand B (0.655), which is a significant advantage for safety.

**Microsomal Clearance:** Ligand A (30.674) has lower microsomal clearance than Ligand B (39.221), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.05 hours) has a slightly longer half-life than Ligand B (-0.332 hours).

**P-gp Efflux:** Both ligands (0.011 and 0.023) show very low P-gp efflux, which is good.

**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 substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both have solubility concerns and negative Caco-2 values, Ligand A's significantly stronger binding affinity, lower DILI risk, lower hERG inhibition, and better metabolic stability outweigh the slightly lower BBB penetration and Caco-2 permeability. The strong binding affinity is the most important factor for an enzyme inhibitor, and the safety profiles of Ligand A are more favorable.

Output:
1
2025-04-17 16:43:18,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.861 Da) is slightly higher than Ligand B (352.406 Da), but both are acceptable.

**TPSA:** Ligand A (114.07) is borderline for good oral absorption (<=140), while Ligand B (70.08) is well within the acceptable range.

**logP:** Ligand A (0.682) is a bit low, potentially impacting permeability. Ligand B (0.054) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Ligand B (0.686) has a better QED score than Ligand A (0.448), indicating a more drug-like profile.

**DILI:** Ligand A (85.459) has a significantly higher DILI risk than Ligand B (16.13). This is a major concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (74.06) is better than Ligand A (54.556). This isn't a primary concern for a kinase inhibitor, but it's a slight advantage for B.

**Caco-2 Permeability:** Ligand A (-5.28) and Ligand B (-4.467) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-3.391) and Ligand B (-2.332) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.093) has a slightly better hERG profile than Ligand B (0.255), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (6.713 mL/min/kg) has much lower microsomal clearance than Ligand A (32.865 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (3.783 hours) has a longer in vitro half-life than Ligand A (-0.414 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux than Ligand B (0.044), which is a slight advantage.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). This 0.9 kcal/mol difference is notable, but not overwhelming.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is low, it's compensated by significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a better QED score. The slightly weaker binding affinity of Ligand B (-6.5 kcal/mol) is less concerning than the poor metabolic properties and high DILI risk of Ligand A. The solubility and permeability issues are shared by both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 16:43:18,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.45 & 352.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.89) is better than Ligand B (99.33), being closer to the <140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (0.761 & 1.285), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is slightly better than Ligand B (HBD=4, HBA=3) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.736) has a significantly better QED score than Ligand B (0.477), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (32.84 & 28.89), both below the 40 threshold. Ligand B is slightly better.

**BBB:** Ligand B (70.92) has a better BBB penetration score than Ligand A (60.64), but BBB is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.001 & -5.196). These values are unusual and suggest poor permeability. However, we need to consider them in the context of other properties.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.17 & -2.48). Again, these are unusual and suggest poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.216 & 0.139), which is excellent.

**Microsomal Clearance:** Ligand A (-11.078) has a *much* better (lower) microsomal clearance than Ligand B (32.984). This indicates significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (25.833 hours) has a much longer half-life than Ligand B (-4.395 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 & 0.028).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). While both are good, the 1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better QED score, significantly better metabolic stability (lower Cl_mic), a longer half-life, and slightly better binding affinity. While both have poor Caco-2 and solubility values, the improvements in metabolic stability and binding affinity for Ligand A outweigh these concerns, especially given that SRC is not a CNS target. The negative Caco-2 and solubility values would need to be addressed in further optimization, but Ligand A provides a better starting point.

Output:
1
2025-04-17 16:43:18,011 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.435 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.93) is slightly above the preferred <140, while Ligand B (99.77) is well within.

**logP:** Ligand A (0.952) is at the lower end of optimal, potentially impacting permeability. Ligand B (0.303) is even lower, raising permeability concerns.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 4 HBA) is good. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.634 and 0.644), indicating good drug-likeness.

**DILI:** Ligand A (16.867) has a much lower DILI risk than Ligand B (49.128), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.821) has a higher BBB score than Ligand A (63.862).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.662 and -5.26), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.084 and -2.315), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.363) has a lower hERG risk than Ligand B (0.188), which is preferable.

**Microsomal Clearance:** Ligand B (-9.249) has a significantly lower (better) microsomal clearance than Ligand A (-4.654), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (15.42) has a longer half-life than Ligand A (9.209), which is desirable.

**P-gp Efflux:** Ligand A (0.017) has slightly lower P-gp efflux than Ligand B (0.007), which is slightly better.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0), a crucial advantage. The difference of 8 kcal/mol is substantial and can outweigh many other ADME concerns.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly superior binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) is the dominant factor. The lower DILI risk and slightly better P-gp profile further support this choice. While Ligand B has better metabolic stability and half-life, the binding affinity is too weak to be competitive. Addressing the solubility and permeability issues would be critical for further development of Ligand A, but the strong binding provides a solid foundation for optimization.

Output:
1
2025-04-17 16:43:18,011 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.374 and 346.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.57) is better than Ligand B (97.88), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Ligand A (2.981) is optimal (1-3), while Ligand B (1.14) is on the lower side, potentially impacting permeability.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Ligand A (4) is good, Ligand B (8) is acceptable but higher, potentially impacting permeability.

**QED:** Both ligands have similar, acceptable QED values (0.684 and 0.705, both > 0.5).

**DILI:** Ligand A (47.926) has a slightly higher DILI risk than Ligand B (37.922), but both are below the concerning threshold of 60.

**BBB:** Ligand A (31.834) has a lower BBB penetration than Ligand B (70.919). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.314) has worse Caco-2 permeability than Ligand B (-5.465), both are poor.

**Aqueous Solubility:** Ligand A (-3.677) has worse solubility than Ligand B (-1.96). Solubility is important for kinases.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.472 and 0.256).

**Microsomal Clearance:** Ligand A (28.386) has higher microsomal clearance than Ligand B (2.802), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (37.698) has a shorter half-life than Ligand B (-5.729), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.086).

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate due to its better logP, solubility, metabolic stability (lower Cl_mic and longer t1/2), and acceptable DILI risk. Ligand A's higher Cl_mic and shorter half-life are significant concerns for a kinase inhibitor. The slightly better TPSA of Ligand A is outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 16:43:18,011 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.272 Da) is slightly higher than Ligand B (341.371 Da), but both are acceptable.

**TPSA:** Ligand A (103.79) is better than Ligand B (119.9), falling comfortably under the 140 A^2 threshold for oral absorption.

**logP:** Ligand B (1.228) is within the optimal range (1-3), while Ligand A (0.506) is slightly below, potentially hindering permeability.

**H-Bond Donors:** Both ligands have 3 HBDs, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.622 and 0.699 respectively), indicating drug-like properties.

**DILI:** Both ligands have high DILI risk (70.221 and 73.09 respectively), which is a concern. This will need to be addressed in later optimization stages.

**BBB:** Both ligands have low BBB penetration, which is not a priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.927) shows better Caco-2 permeability than Ligand B (-5.161), which is favorable.

**Aqueous Solubility:** Ligand A (-2.239) has better aqueous solubility than Ligand B (-4.14). This is important for bioavailability.

**hERG Inhibition:** Ligand A (0.236) has a lower hERG inhibition risk than Ligand B (0.571), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-12.348) has significantly lower microsomal clearance than Ligand B (20.782), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (18.454 hours) has a much longer in vitro half-life than Ligand B (-14.117 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is only 0.5 kcal/mol, and the superior ADME properties of Ligand A likely outweigh this.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), **Ligand A** is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and lower hERG risk. These factors are critical for developing a viable drug candidate, and the 0.5 kcal/mol difference in binding affinity can potentially be addressed through further optimization. Both have high DILI risk, which will need to be addressed.

Output:
1
2025-04-17 16:43:18,011 - INFO - Batch 487 complete. Total preferences: 7792
2025-04-17 16:43:18,011 - INFO - Processing batch 488/512...
2025-04-17 16:44:01,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (367.471 Da) is also acceptable.

**TPSA:** Ligand A (84.5) is well below the 140 threshold for oral absorption and favorable. Ligand B (97.39) is still acceptable, but less optimal.

**logP:** Ligand A (1.408) is within the optimal range (1-3). Ligand B (0.773) is slightly below 1, potentially impacting 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 within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.5 (0.671 and 0.596), indicating good drug-likeness.

**DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (56.146). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (71.462) is better than Ligand B (35.052), but not a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.746 and -4.886), 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 (-2.006 and -2.834), indicating very poor solubility. This is a significant drawback for both compounds, but could be mitigated with formulation strategies.

**hERG:** Ligand A (0.124) has a much lower hERG risk than Ligand B (0.291). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (25.13 mL/min/kg) has a higher clearance than Ligand B (10.488 mL/min/kg), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-5.172 hours) has a shorter half-life than Ligand B (-28.944 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.049).

**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 small.

**Overall Assessment:**

Ligand A excels in DILI risk and hERG inhibition, and has slightly better binding affinity. However, it has higher clearance and a shorter half-life. Ligand B has better metabolic stability (lower clearance, longer half-life), but carries a higher risk of DILI and hERG inhibition. Given the enzyme-specific priorities, metabolic stability is important, but the significantly lower DILI and hERG risk of Ligand A are compelling advantages. The small difference in binding affinity is unlikely to outweigh these safety concerns. The poor solubility and permeability are issues for both, but could be addressed through formulation.

Output:
0
2025-04-17 16:44:01,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 359.579 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is much better than Ligand B (20.31), being well below the 140 A^2 threshold for good absorption. Ligand B is exceptionally low, which *could* indicate good permeability, but also potentially reduced solubility.

**logP:** Ligand A (1.563) is optimal. Ligand B (4.801) is higher, potentially leading to solubility issues and off-target interactions.

**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 acceptable.

**QED:** Both ligands have reasonable QED values (0.786 and 0.664), indicating good drug-like properties.

**DILI:** Ligand A (29.624) has a significantly lower DILI risk than Ligand B (16.751), which is a major advantage.

**BBB:** Ligand A (75.107) has moderate BBB penetration, while Ligand B (92.361) has high BBB penetration. Since SRC is not a CNS target, this is less critical, but still a slight edge to B.

**Caco-2 Permeability:** Ligand A (-4.301) is poor, while Ligand B (-5.023) is also poor. Both are problematic for oral absorption.

**Aqueous Solubility:** Ligand A (-2.55) is poor, while Ligand B (-4.959) is even worse. This is a significant concern for both, but more so for B.

**hERG:** Ligand A (0.168) has a very low hERG risk, excellent. Ligand B (0.927) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (38.196) has moderate clearance, while Ligand B (139.207) has very high clearance. This is a major disadvantage for Ligand B, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (-11.624) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (27.973) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, which is good. Ligand B (0.789) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.4) has slightly better binding affinity than Ligand B (-6.8). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive for A.

**Overall Assessment:**

Ligand A is preferable despite its poor Caco-2 and solubility, and negative half-life. Its significantly lower DILI risk, excellent hERG profile, and better binding affinity outweigh the drawbacks. Ligand B has a very high microsomal clearance, which is a major concern for an enzyme target. While it has better BBB penetration and half-life, the high clearance and worse DILI risk make it less attractive. The solubility issues with both are concerning, but can be addressed with formulation strategies.

Output:
0
2025-04-17 16:44:01,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.487 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.41) is higher than Ligand B (40.62). While both are reasonably low, Ligand B is significantly better, increasing the likelihood of good cellular permeability.

**logP:** Both ligands have good logP values (3.122 and 3.618), 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 ligands have low HBD counts (0). Ligand A has 3 HBA, and Ligand B has 2. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.735 and 0.661), indicating good drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (11.128 and 11.361 percentile), which is excellent.

**BBB:** Both ligands have good BBB penetration (75.843 and 84.025 percentile), though this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.403 and -4.698). This is unusual and suggests a potential issue with permeability prediction, or the values are on a log scale where negative values indicate low permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.641 and -3.133). Similar to Caco-2, this is concerning and suggests poor aqueous solubility, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.587 and 0.495 percentile), which is favorable.

**Microsomal Clearance:** Ligand A (42.776 mL/min/kg) has lower microsomal clearance than Ligand B (52.625 mL/min/kg), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (-17.787 hours) has a much longer in vitro half-life than Ligand A (-10.595 hours). This is a major positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.315 percentile), which is good.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This 2 kcal/mol difference is substantial and could overcome some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, which is the most important factor for an enzyme inhibitor. However, Ligand B has better TPSA, a longer half-life, and slightly better BBB penetration. Both have concerningly low predicted solubility and permeability. The improved metabolic stability of Ligand A is also a plus. Given the substantial difference in binding affinity, I believe Ligand A is more likely to be a viable drug candidate, despite the solubility/permeability concerns. These issues could potentially be addressed through formulation strategies.

Output:
0
2025-04-17 16:44:01,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.377 and 359.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.97) is slightly higher than Ligand B (73.74), but both are below the 140 threshold for good absorption.

**logP:** Ligand A (-0.474) is a bit low, potentially hindering permeation. Ligand B (1.931) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are below the threshold of 10.

**QED:** Ligand B (0.909) has a significantly better QED score than Ligand A (0.403), indicating a more drug-like profile.

**DILI:** Ligand A (31.718) has a much lower DILI risk than Ligand B (60.489), which is approaching a higher risk category. This is a significant advantage for Ligand A.

**BBB:** Ligand A (75.843) has a higher BBB percentile than Ligand B (32.803). While not critical for a non-CNS target, it's a slight positive for A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.043 and -4.833), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.431 and -2.158), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.324 and 0.314).

**Microsomal Clearance:** Ligand A (1.298) has a much lower microsomal clearance than Ligand B (25.442), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-29.277) has a very negative half-life, which is not possible and likely indicates an error or unusual behavior. Ligand B (5.93) is a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (-9 and -0.181).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.4 and -9 kcal/mol).

**Overall Assessment:**

Ligand A has significant advantages in DILI risk and microsomal clearance, suggesting better safety and metabolic stability. However, the negative in vitro half-life is a major red flag. Ligand B has a better QED score and a more reasonable half-life, but its higher DILI risk and higher clearance are concerning. The poor solubility and permeability are problematic for both.

Despite the negative half-life for Ligand A, the substantial difference in metabolic stability (Cl_mic) and DILI risk, coupled with comparable binding affinity, makes Ligand A slightly more promising *if* the half-life data is an error. The poor solubility and permeability would need to be addressed for either compound.

Output:
0
2025-04-17 16:44:01,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.422 and 350.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.33) is well below the 140 threshold, suggesting good absorption. Ligand B (87.46) is still acceptable but approaching the upper limit.

**3. logP:** Both ligands have good logP values (1.414 and 0.953), 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 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.763 and 0.694), indicating good drug-likeness.

**7. DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (12.408), but both are below the concerning threshold of 60.

**8. BBB:** This isn't a primary concern for a non-CNS target like SRC, but Ligand A (70.531) has better BBB penetration than Ligand B (45.638).

**9. Caco-2 Permeability:** Ligand A (-4.721) has better Caco-2 permeability than Ligand B (-5.063), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.698) has better aqueous solubility than Ligand B (-0.623). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.389) has a significantly lower hERG inhibition risk than Ligand B (0.17), which is a crucial safety factor.

**12. Microsomal Clearance:** Ligand A (9.84) has a lower microsomal clearance than Ligand B (18.935), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.444) has a shorter in vitro half-life than Ligand B (-13.058). This is a negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.026) has significantly lower P-gp efflux liability than Ligand B (0.053), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a 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. It has a better safety profile (lower hERG, lower DILI), better solubility, better permeability, lower P-gp efflux, and significantly stronger binding affinity. While its in vitro half-life is shorter, the other advantages, particularly the binding affinity and safety profile, make it a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 16:44:01,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (379.375 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.62) is slightly above the preferred <140 for good oral absorption, but acceptable. Ligand B (80.56) is well within the optimal range.

**logP:** Ligand A (2.204) is within the optimal 1-3 range. Ligand B (0.258) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (9) is acceptable. Ligand B (7) is also acceptable.

**QED:** Both ligands have good QED scores (0.685 and 0.759), indicating drug-like properties.

**DILI:** Ligand A (99.496) has a very high DILI risk, which is a significant concern. Ligand B (68.825) is still elevated, but considerably better than Ligand A.

**BBB:** Both ligands have moderate BBB penetration (61.691 and 64.637). Since SRC is not a CNS target, this is not a primary concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.97 and -4.966), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.009 and -1.792), indicating very poor aqueous solubility, which is a major formulation challenge.

**hERG Inhibition:** Ligand A (0.335) has a slightly higher hERG risk than Ligand B (0.127), but both are relatively low.

**Microsomal Clearance:** Ligand A (29.753) has a lower (better) microsomal clearance than Ligand B (38.349), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (45.942) has a longer half-life than Ligand B (0.558), which is desirable.

**P-gp Efflux:** Ligand A (0.239) has lower P-gp efflux than Ligand B (0.085), which is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -9.1 kcal/mol), with Ligand A being slightly stronger. The difference is less than 1.5 kcal/mol, so it doesn't overwhelmingly favor Ligand A.

**Conclusion:**

Despite the slightly better affinity and metabolic stability of Ligand A, its extremely high DILI risk and poor solubility are major red flags. Ligand B, while having a lower logP and slightly worse metabolic properties, presents a significantly lower DILI risk. Both compounds have poor Caco-2 and solubility, which would require significant formulation work. However, the DILI risk for Ligand A is too high to proceed with further development.

Output:
1
2025-04-17 16:44:01,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (364.446 and 350.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.02) and Ligand B (67.87) are both below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.759 and 1.335), 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 similar QED scores (0.867 and 0.812), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.568, which is moderately high. Ligand B has a significantly lower DILI risk (18.728), indicating a much better safety profile. This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (72.237 and 77.2), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.006 and -4.771) which is unusual, and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.856 and -1.831). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.485) has a slightly higher hERG risk than Ligand B (0.228), but both are relatively low.

**Microsomal Clearance:** Ligand A has a significantly lower (better) microsomal clearance (-14.448) compared to Ligand B (21.597), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (19.874 hours) compared to Ligand A (6.028 hours). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.029).

**Binding Affinity:** Ligand B (-8.7 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.

**Conclusion:**

While Ligand A has better metabolic stability, Ligand B excels in several critical areas: significantly lower DILI risk, a substantially longer half-life, and a much stronger binding affinity. The lower DILI risk is particularly important for an oncology drug. The strong affinity of Ligand B is also a major advantage. The poor solubility and permeability are concerns for both, but the superior potency and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:44:01,879 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 352.475 Da, B: 362.499 Da) fall within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (67.87) is better than Ligand B (83.98).  TPSA < 140 is good for oral absorption, both are within this range, but A is preferable.

3. **logP:** Both ligands have acceptable logP values (A: 1.869, B: 2.442), falling within the 1-3 range. B is slightly higher, which *could* indicate a slightly higher risk of off-target effects, but it's not a major concern.

4. **HBD:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for better permeability.

5. **HBA:** Ligand A (4) is better than Ligand B (5).  Similar to HBD, lower HBA is generally favorable.

6. **QED:** Both ligands have good QED scores (A: 0.759, B: 0.814), indicating good drug-like properties. B is slightly better.

7. **DILI:** Ligand A (20.085) has a significantly lower DILI risk than Ligand B (41.024). This is a major advantage for Ligand A.  A score < 40 is desirable, and A is closer to this threshold.

8. **BBB:** Ligand A (71.501) has better BBB penetration than Ligand B (61.923). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

9. **Caco-2:** Ligand A (-4.704) is better than Ligand B (-5.043). Higher Caco-2 permeability suggests better intestinal absorption.

10. **Solubility:** Ligand A (-1.943) is better than Ligand B (-3.472). Better aqueous solubility is crucial for bioavailability.

11. **hERG:** Both ligands have very low hERG inhibition liability (A: 0.237, B: 0.191). This is excellent.

12. **Cl_mic:** Ligand B (29.39) has a lower microsomal clearance than Ligand A (42.31). Lower clearance indicates better metabolic stability, which is a key consideration for kinase inhibitors.

13. **t1/2:** Ligand B (29.211) has a significantly longer in vitro half-life than Ligand A (-17.21). This is a significant advantage for B, potentially allowing for less frequent dosing.

14. **Pgp:** Both ligands have low P-gp efflux liability (A: 0.085, B: 0.121).

15. **Binding Affinity:** Both ligands have comparable binding affinities (A: -8.5 kcal/mol, B: -8.4 kcal/mol). The difference is negligible.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

*   **Affinity:** Essentially tied.
*   **Metabolic Stability:** Ligand B is significantly better (lower Cl_mic, longer t1/2).
*   **Solubility:** Ligand A is better.
*   **hERG:** Both are excellent.
*   **DILI:** Ligand A is significantly better.

**Conclusion:**

While Ligand A has advantages in DILI risk, solubility, and Caco-2 permeability, Ligand B's superior metabolic stability (longer half-life and lower clearance) is a critical factor for a kinase inhibitor. The slightly better QED score for B also contributes. The binding affinity is almost identical. Therefore, I would prioritize **Ligand B** as the more viable drug candidate.

Output:
1
2025-04-17 16:44:01,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (349.5 and 352.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, indicating good absorption potential. Ligand B (104.73) is still within acceptable limits but less favorable.

**logP:** Ligand A (2.262) is optimal (1-3). Ligand B (0.359) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is acceptable, but higher values could slightly reduce permeability.

**QED:** Ligand A (0.767) is very good, indicating strong drug-likeness. Ligand B (0.574) is acceptable, but less optimal.

**DILI:** Ligand A (7.057 percentile) has a very low risk of liver injury. Ligand B (13.339 percentile) also has a low risk, but higher than A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.9%) is higher than Ligand B (31.214%).

**Caco-2 Permeability:** Ligand A (-4.797) is poor, while Ligand B (-5.095) is also poor. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-2.442) is better than Ligand B (-1.59).

**hERG Inhibition:** Ligand A (0.675) has a low risk of hERG inhibition, which is excellent. Ligand B (0.095) also has a low risk.

**Microsomal Clearance:** Ligand A (44.33 mL/min/kg) is better than Ligand B (26.036 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.955 hours) is better than Ligand B (-0.879 hours), indicating better metabolic stability.

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux liability than Ligand B (0.009).

**Binding Affinity:** Ligand A (-9.6 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.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have acceptable molecular weights and low DILI/hERG risk, Ligand A excels in key areas: better logP, QED, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and *significantly* stronger binding affinity. The lower Caco-2 permeability of Ligand A is a concern, but the substantial binding affinity advantage and superior ADME properties outweigh this drawback.

Output:
1
2025-04-17 16:44:01,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.407 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (114.94) is well below the 140 threshold for oral absorption. Ligand B (38.13) is excellent, suggesting good absorption.

**logP:** Ligand A (0.852) is a bit low, potentially hindering permeation. Ligand B (4.032) is at the higher end of the optimal range, which could lead to solubility issues but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, fitting well within the guidelines. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (A: 0.694, B: 0.742), indicating drug-like properties.

**DILI:** Ligand A (59.752) has a moderate DILI risk, while Ligand B (25.126) has a low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (46.413) has low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (83.637) has good BBB penetration, but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.494) has poor Caco-2 permeability, which is a major concern. Ligand B (-4.539) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.922) has poor aqueous solubility. Ligand B (-5.132) is even worse. Solubility could be a formulation challenge for both.

**hERG Inhibition:** Ligand A (0.067) has very low hERG inhibition risk, which is excellent. Ligand B (0.568) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (10.244) has relatively low microsomal clearance, indicating better metabolic stability. Ligand B (84.996) has high clearance, suggesting rapid metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (23.59) has a moderate half-life. Ligand B (2.531) has a very short half-life, which is undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.043, B: 0.453).

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.7). This 1.3 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite solubility and permeability concerns for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.0 kcal/mol vs -6.7 kcal/mol) is a major advantage for an enzyme target. Furthermore, it has better metabolic stability (lower Cl_mic) and a longer half-life than Ligand B. While Ligand B has a lower DILI risk, the potency and stability advantages of Ligand A are more critical for a kinase inhibitor.



Output:
0
2025-04-17 16:44:01,880 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (366.483 and 347.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is better than Ligand B (62.3), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have good logP values (2.893 and 3.437), 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 (5) is higher than Ligand B (3), both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.66) has a slightly better QED score than Ligand A (0.4), indicating a more drug-like profile.

**7. DILI:** Ligand B (23.11) has a significantly lower DILI risk than Ligand A (46.297), a major advantage.

**8. BBB:** Both ligands have reasonable BBB penetration (57.852 and 67.701), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.904 and -4.618), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.364 and -3.273), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.238) has a slightly lower hERG inhibition risk than Ligand B (0.76), which is favorable.

**12. Microsomal Clearance:** Ligand B (79.415) has a lower microsomal clearance than Ligand A (100.827), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (26.278) has a slightly longer in vitro half-life than Ligand A (21.746), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.125) has a lower P-gp efflux liability than Ligand B (0.314), which is beneficial for bioavailability.

**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 crucial advantage, as potency is a primary concern for enzyme inhibitors.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both compounds, Ligand A's substantially superior binding affinity (-7.4 vs -0.0 kcal/mol) is a decisive factor. The difference in affinity is large enough to potentially overcome the ADME liabilities. Ligand B has better DILI and metabolic stability, but the lack of binding affinity makes it a less promising candidate.

Output:
1
2025-04-17 16:44:01,880 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [356.442, 96.25, 1.335, 3, 5, 0.655, 38.348, 64.831, -4.976, -1.93, 0.324, 33.686, -1.174, 0.046, -8.3]
**Ligand B:** [368.503, 78.67, 0.673, 1, 6, 0.799, 43.428, 25.126, -5.157, -1.621, 0.16, 35.97, -7.573, 0.067, 0.0]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (356.442) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (96.25) is slightly higher than B (78.67), but both are below the 140 threshold for oral absorption. B is better here.
3. **logP:** Both are within the optimal range (1-3). A (1.335) is slightly higher, which is generally good for permeability.
4. **HBD:** A (3) is higher than B (1), but both are acceptable (<=5).
5. **HBA:** A (5) is lower than B (6), which is slightly better.
6. **QED:** Both are good (>0.5), with B (0.799) being slightly better.
7. **DILI:** A (38.348) is better than B (43.428), indicating a lower risk of liver injury.
8. **BBB:** A (64.831) is significantly better than B (25.126). While SRC isn't a CNS target, higher BBB is rarely a negative.
9. **Caco-2:** A (-4.976) is better than B (-5.157). Higher values indicate better absorption.
10. **Solubility:** A (-1.93) is better than B (-1.621). Higher solubility is crucial for bioavailability.
11. **hERG:** A (0.324) is much better than B (0.16), indicating a lower risk of cardiotoxicity.
12. **Cl_mic:** A (33.686) is slightly better than B (35.97), suggesting better metabolic stability.
13. **t1/2:** A (-1.174) is better than B (-7.573), indicating a longer half-life.
14. **Pgp:** A (0.046) is better than B (0.067), suggesting lower efflux.
15. **Binding Affinity:** A (-8.3) is *significantly* better than B (0.0). This is a >1.5 kcal/mol advantage, which is a major factor.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A excels in all these areas. The significantly better binding affinity of A (-8.3 kcal/mol) is a decisive advantage, outweighing any minor drawbacks.

**Conclusion:**

Ligand A is the superior candidate.

Output:
1
2025-04-17 16:44:01,880 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (359.294 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.49) is significantly better than Ligand B (106.08).  A TPSA under 140 is good for oral absorption, but lower is generally preferred for kinases. Ligand B's TPSA is relatively high and could hinder absorption.

**logP:** Ligand A (3.705) is optimal, while Ligand B (0.622) is quite low. Low logP can lead to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better balanced. Ligand B has 1 HBD and 5 HBA, which is acceptable, but less ideal than A.

**QED:** Both ligands have similar QED values (0.818 and 0.727), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (38.736 and 33.579), which is excellent.

**BBB:** Both ligands have similar BBB penetration (63.048 and 63.784). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.063 and -5.07), which is unusual and suggests poor permeability. This is a red flag for both. 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 (-4.226 and -2.005). This is also a concern, indicating poor solubility.

**hERG:** Ligand A (0.922) has a slightly higher hERG risk than Ligand B (0.24), but both are relatively low.

**Microsomal Clearance:** Ligand A (31.514) has higher microsomal clearance than Ligand B (-6.313). This means Ligand B is likely more metabolically stable, which is a key consideration for kinases.

**In vitro Half-Life:** Ligand A (7.664) has a longer half-life than Ligand B (27.693). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.469) has higher P-gp efflux than Ligand B (0.023). Lower P-gp efflux is preferred, making Ligand B better in this regard.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly better binding affinity than Ligand A (0 kcal/mol). This is the most important factor for an enzyme inhibitor. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. The substantially stronger binding affinity (-7.7 kcal/mol vs 0 kcal/mol) is a major advantage. Furthermore, Ligand B has better metabolic stability (negative Cl_mic) and lower P-gp efflux. While Ligand A has a slightly longer half-life, the potency difference is far more critical for an enzyme inhibitor. The TPSA and logP values of Ligand A are better, but the affinity difference outweighs these factors.

Output:
1
2025-04-17 16:44:01,880 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.463 and 358.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.11) is better than Ligand B (58.98), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (-0.025) is slightly lower than optimal (1-3), but still reasonable. Ligand B (3.674) is within the optimal range.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands (0.742 and 0.722) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (5.157) has a significantly lower DILI risk than Ligand B (45.095). This is a major advantage for Ligand A.

**BBB:** Ligand B (73.905) has a higher BBB penetration percentile than Ligand A (38.232). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-5.017 and -5.018). This is a potential issue for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.155 and -3.696). This is a concern for both, but Ligand B is worse.

**hERG Inhibition:** Ligand A (0.184) has a lower hERG inhibition liability than Ligand B (0.374), which is preferable.

**Microsomal Clearance:** Ligand A (-8.465) has a much lower (better) microsomal clearance than Ligand B (68.381), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (3.209 hours) has a slightly longer half-life than Ligand B (1.718 hours).

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.289).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). However, the difference is only 1.3 kcal/mol, and can be overcome by better ADME properties.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic), lower DILI risk, lower hERG inhibition, and lower P-gp efflux. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The superior ADME profile of Ligand A outweighs the small difference in binding affinity.

Output:
0
2025-04-17 16:44:01,881 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.873 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (102.22). A TPSA under 140 is good for oral absorption, and both are under, but A is preferable.

**logP:** Both ligands have good logP values (A: 2.778, B: 1.878), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=4) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.896) has a significantly higher QED score than Ligand B (0.637), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (A: 31.989, B: 38.852), below the 40 threshold.

**BBB:** Ligand A (77.976) has a better BBB percentile than Ligand B (54.44), but BBB is not a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-5.047) has a worse Caco-2 permeability than Ligand B (-4.757), but both are negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.918) has slightly worse solubility than Ligand B (-3.205), but both are negative, indicating low solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.259, B: 0.432), which is excellent.

**Microsomal Clearance:** Ligand A (49.543) has a higher microsomal clearance than Ligand B (25.146), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-8.341) has a longer in vitro half-life than Ligand A (-2.436), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.048, B: 0.071).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -9.1 kcal/mol, B: -8.2 kcal/mol). Ligand A has a 0.9 kcal/mol advantage.

**Conclusion:**

While Ligand A has a slightly better binding affinity and QED, the significantly higher microsomal clearance and lower in vitro half-life are major concerns. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and acceptable solubility, making it a more promising candidate despite the slightly lower affinity. The affinity difference is not large enough to overcome the metabolic stability issues of Ligand A.

Output:
1
2025-04-17 16:44:01,881 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.451 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.49) is slightly higher than Ligand B (80.12), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (-0.194) is a bit low, potentially hindering permeation. Ligand B (1.698) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**H-Bond Acceptors:** Both ligands (A: 6, B: 5) are well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.572, B: 0.83), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (18.302) has a much lower DILI risk than Ligand B (43.195). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (45.909) has a higher BBB value than Ligand A (26.134), but this isn't a primary concern.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG:** Ligand A (0.037) shows very low hERG inhibition risk, which is excellent. Ligand B (0.137) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (7.925) has significantly lower microsomal clearance than Ligand B (40.338), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand B (18.653) has a slightly longer half-life than Ligand A (15.698), but the difference is not substantial.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**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 for Ligand B, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG) and metabolic stability (Cl_mic), but suffers from lower binding affinity and potentially poor permeability (low logP, negative Caco-2, negative solubility). Ligand B has superior binding affinity and a better logP, but has a higher DILI risk and higher Cl_mic.

The difference in binding affinity (-7.6 vs -9.5 kcal/mol) is substantial (1.9 kcal/mol), and for an enzyme target, potency is paramount. While Ligand A's safety profile is attractive, the significantly stronger binding of Ligand B is likely to translate to greater efficacy *in vivo*, even considering the slightly higher DILI and clearance.

Output:
1
2025-04-17 16:44:01,881 - INFO - Batch 488 complete. Total preferences: 7808
2025-04-17 16:44:01,881 - INFO - Processing batch 489/512...
2025-04-17 16:44:52,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.438 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.68) is well below the 140 threshold for good absorption, while Ligand B (96.97) is still acceptable but approaching the upper limit.

**logP:** Ligand A (2.804) is optimal (1-3). Ligand B (0.266) is quite 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 3 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED values (0.858 and 0.714), indicating good drug-like properties.

**DILI:** Ligand A (60.682) is approaching the higher end of acceptable DILI risk, while Ligand B (28.577) has a much lower and preferable risk.

**BBB:** Both ligands have good BBB penetration (78.558 and 73.284), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**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:** Ligand A (0.385) has a very low hERG risk, which is excellent. Ligand B (0.188) also has a low hERG risk, but slightly higher than Ligand A.

**Microsomal Clearance:** Ligand A (58.272) has moderate clearance, suggesting moderate metabolic stability. Ligand B (8.567) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (27.328) has a reasonable half-life. Ligand B (-14.592) 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 (0.083 and 0.007), which is beneficial.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the superior binding affinity of Ligand A (-8.9 kcal/mol vs -7.8 kcal/mol) is a major advantage for an enzyme inhibitor. Its hERG risk is also very low. While Ligand B has better metabolic stability and lower DILI risk, the significantly weaker binding affinity is a critical drawback. The negative half-life for Ligand B is also a major red flag. Therefore, Ligand A is the more promising candidate.

Output:
1
2025-04-17 16:44:52,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (110.1) is better than Ligand B (72.12). Lower TPSA generally favors oral absorption.

**logP:** Ligand A (-0.22) is suboptimal, being below 1, which might hinder permeation. Ligand B (3.891) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (0) is excellent.

**H-Bond Acceptors:** Ligand A (5) is acceptable, while Ligand B (7) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.482, B: 0.695), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (14.308) has a very low DILI risk, which is excellent. Ligand B (78.131) has a significantly higher DILI risk, which is a major concern.

**BBB:** Both have low BBB penetration, which is not a primary concern for a non-CNS target like SRC.

**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 (0.183) has a very low hERG risk, which is excellent. Ligand B (0.307) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (0.606) has much lower microsomal clearance, indicating better metabolic stability. Ligand B (45.021) has high clearance, suggesting rapid metabolism. This is a critical advantage for Ligand A.

**In vitro Half-Life:** Ligand A (13.569) has a longer half-life than Ligand B (13.265), though the difference is small.

**P-gp Efflux:** Both have low P-gp efflux, which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic), DILI risk, and hERG inhibition. However, its logP is suboptimal, and its solubility and permeability are poor. Ligand B has a better logP and QED, but suffers from a much higher DILI risk and significantly worse metabolic stability. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. The strong binding affinity is similar for both, so it doesn't differentiate them. The high DILI risk for Ligand B is a major red flag.

Output:
0
2025-04-17 16:44:52,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.385 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.27 and 87.47) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands (1.317 and 0.905) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, satisfying the <=5 rule.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA, both are below the 10 threshold.

**QED:** Both ligands (0.807 and 0.794) have excellent drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (36.293), both are below the 40 threshold, but A is preferable.

**BBB:** Both have reasonable BBB penetration (74.176 and 83.288), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.866 and -5.187). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon for compounds with complex structures.

**Aqueous Solubility:** Both have negative solubility values (-2.365 and -1.779). This is also unusual and suggests poor solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.378 and 0.5), which is excellent.

**Microsomal Clearance:** Ligand A (-29.744) has *much* lower microsomal clearance than Ligand B (12.192). This indicates significantly better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-27.676) has a much longer in vitro half-life than Ligand B (10.781), further supporting its superior metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.061).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is only 0.5 kcal/mol, and the superior ADME properties of Ligand A likely outweigh this small difference in binding.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A exhibits significantly improved metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Given the enzyme-kinase specific priorities, metabolic stability is paramount, and the small affinity difference is easily compensated for with further optimization. The poor Caco-2 and solubility values are concerning for both, but can be addressed in later stages of optimization.

Output:
0
2025-04-17 16:44:52,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.812 Da) is slightly higher than Ligand B (346.475 Da), but both are acceptable.

**TPSA:** Ligand A (62.97) is significantly better than Ligand B (86.88). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 2.186, B: 2.408), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=7) has a more favorable profile than Ligand B (HBD=3, HBA=3). Fewer H-bonds can improve permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.652, B: 0.569), indicating reasonable drug-likeness.

**DILI:** Ligand A (93.059) has a significantly higher DILI risk than Ligand B (15.51). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (81.97) is higher than Ligand B (52.811), but this is less important in this context.

**Caco-2 Permeability:** Ligand A (-4.78) is worse than Ligand B (-5.373) - both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.492) is better than Ligand B (-2.327), though both are poor. Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.665) has a slightly higher hERG risk than Ligand B (0.242), but both are relatively low.

**Microsomal Clearance:** Ligand A (70.484) has a higher microsomal clearance than Ligand B (26.068), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-30.537) has a significantly longer in vitro half-life than Ligand A (-19.834), indicating better stability.

**P-gp Efflux:** Ligand A (0.538) has lower P-gp efflux than Ligand B (0.046), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a crucial advantage, as a 1.4 kcal/mol difference is substantial.

**Conclusion:**

Despite Ligand A having slightly better solubility and P-gp efflux, Ligand B is the superior candidate. The significantly lower DILI risk, substantially better metabolic stability (lower Cl_mic, longer t1/2), and much stronger binding affinity of Ligand B outweigh the minor advantages of Ligand A. The higher binding affinity is particularly important for an enzyme inhibitor.

Output:
1
2025-04-17 16:44:52,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.371 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.09) is better than Ligand B (63.13) as it is still within the acceptable range for oral absorption (<140), but Ligand B is significantly lower, potentially improving absorption.

**logP:** Both ligands have acceptable logP values (1.139 and 2.634), falling within the 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 the recommended limits.

**QED:** Both ligands have good QED scores (0.752 and 0.817), indicating good drug-like properties.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (47.887). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (55.021) has a higher value than Ligand A (27.608).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.395 and -5.325), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.988 and -2.938), indicating poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.065) has a much lower hERG inhibition liability than Ligand B (0.239), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (-12.441) has a significantly lower (better) microsomal clearance than Ligand B (37.589), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (2.824 hours) has a shorter half-life than Ligand B (12.611 hours). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.011) has a much lower P-gp efflux liability than Ligand B (0.171), indicating better bioavailability.

**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 substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and longer half-life, but suffers from higher DILI risk, higher P-gp efflux, and higher microsomal clearance. Ligand A has better metabolic stability (lower Cl_mic), lower DILI, lower P-gp efflux, and lower hERG risk. The poor solubility and Caco-2 permeability are concerning for both. However, the improved metabolic stability and safety profile of Ligand A, combined with a still-strong binding affinity, make it the more promising candidate. The 1 kcal/mol difference in binding affinity can potentially be addressed with further optimization, while improving solubility and permeability is a more significant challenge.

Output:
0
2025-04-17 16:44:52,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (67.23) is higher than Ligand B (42.43). While both are reasonably low, Ligand B is better positioned for good oral absorption.

**logP:** Ligand A (2.102) is optimal, while Ligand B (4.233) is pushing the upper limit. High 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.

**QED:** Ligand A (0.857) has a better QED score than Ligand B (0.727), indicating a more drug-like profile.

**DILI:** Ligand A (52.966) has a higher DILI risk than Ligand B (13.106). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (89.104) has a higher BBB score, but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.005) has a negative Caco-2 value, which is concerning. Ligand B (-4.461) is also negative, but less so. Both suggest poor intestinal absorption, but A is worse.

**Aqueous Solubility:** Ligand A (-2.273) has very poor aqueous solubility, while Ligand B (-3.987) is also poor, but slightly better. Solubility is a crucial factor for bioavailability.

**hERG Inhibition:** Ligand A (0.293) has a slightly higher hERG risk than Ligand B (0.652), but both are relatively low.

**Microsomal Clearance:** Ligand A (47.082) has a lower microsomal clearance than Ligand B (95.933), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.262) has a shorter half-life than Ligand B (20.276). Longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.299 and 0.617, respectively).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor. A difference of >1.5 kcal/mol is considered substantial.

**Conclusion:**

Despite Ligand A having a better QED and lower Cl_mic, the significantly stronger binding affinity of Ligand B (-7.8 vs 0.0 kcal/mol) outweighs the drawbacks of its higher logP and slightly higher DILI risk. The poor solubility and Caco-2 permeability of Ligand A are also major concerns. The substantial affinity advantage of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 16:44:52,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (350.35 and 360.805 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (109.42 and 103.87) are reasonably close to the 140 A^2 threshold for oral absorption, but higher than the 90 A^2 ideal for CNS targets (not a primary concern here).

**3. logP:** Ligand A (-0.894) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (1.196) is within the optimal range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (5) meet the <=10 criteria.

**6. QED:** Ligand B (0.855) has a significantly better QED score than Ligand A (0.32), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.126) has a lower DILI risk than Ligand B (69.097), which is preferable.

**8. BBB:** Ligand A (83.87) has a better BBB penetration score than Ligand B (40.093), but BBB is not a high priority for a kinase inhibitor.

**9. Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.473 and -5.369). This is a concern for oral bioavailability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.058 and -3.37). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.198 and 0.172).

**12. Microsomal Clearance:** Ligand A (-1.077) has a lower (better) microsomal clearance than Ligand B (-11.298), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.999) has a longer half-life than Ligand B (-10.835).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.058).

**15. Binding Affinity:** Both ligands have similar and good binding affinities (-8.3 and -8.5 kcal/mol). The difference is negligible.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. While both have good affinity and low hERG risk, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. However, Ligand B has a significantly better QED score. The poor solubility of both is a major concern, but the better metabolic stability of Ligand A and its lower DILI risk give it a slight edge.

Output:
0
2025-04-17 16:44:52,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (361.511 and 378.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (110.17). A TPSA under 140 is desirable for oral absorption, and both meet this, but A is preferable.

**logP:** Both ligands have good logP values (2.928 and 2.63), 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=8) in terms of these parameters, being closer to the ideal ranges for permeability and solubility.

**QED:** Both ligands have reasonable QED values (0.847 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (42.846) has a much lower DILI risk than Ligand B (93.68). This is a significant advantage for A.

**BBB:** Both have similar BBB penetration (61.923 and 68.864), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.055 and -5.018), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.609 and -4.497). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.27) shows a much lower hERG inhibition liability than Ligand B (0.618), which is a critical safety advantage.

**Microsomal Clearance:** Ligand A (42.96) has a higher (worse) microsomal clearance than Ligand B (21.526), indicating lower metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (16.828 hours) has a substantially longer half-life than Ligand A (-5.297 hours). This is a major advantage for B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.201) has a lower P-gp efflux liability than Ligand B (0.147), which is slightly better.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-5.297 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 better binding affinity and a longer half-life, which are key for an enzyme inhibitor. While its DILI risk is higher and solubility is poor, the substantial improvement in affinity makes it more promising. Ligand A has better safety profiles (DILI, hERG) but weaker binding and poorer metabolic stability. Given the importance of potency for kinase inhibitors, the stronger binding of Ligand B outweighs its other drawbacks.

Output:
1
2025-04-17 16:44:52,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 349.41 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.01) is slightly higher than Ligand B (71.33). Both are acceptable, but Ligand B is better positioned for oral absorption.

**logP:** Ligand A (2.688) and Ligand B (1.038) are both within the optimal range of 1-3, but Ligand B is closer to the lower bound.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are 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:** Both ligands have a QED of approximately 0.81, indicating good drug-likeness.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (45.328). This is a significant advantage for Ligand B.

**BBB:** Ligand A (53.587) has a lower BBB penetration than Ligand B (86.661). Since SRC is not a CNS target, this is less critical, but still favors Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.873 and -4.809), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.832 and -2.485), indicating poor aqueous solubility. This is a significant drawback for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.393) has a slightly higher hERG inhibition liability than Ligand B (0.179), making Ligand B safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (64.41 mL/min/kg) has a higher microsomal clearance than Ligand B (12.337 mL/min/kg). This means Ligand B is more metabolically stable, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-1.618 hours) has a shorter half-life than Ligand B (-6.274 hours). This is a significant advantage for Ligand B, as a longer half-life allows for less frequent dosing.

**P-gp Efflux:** Ligand A (0.155) has a lower P-gp efflux liability than Ligand B (0.019). This is a slight advantage for Ligand A.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.4 kcal/mol). While both are good, the 1.5 kcal/mol difference is notable and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. It demonstrates better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, better BBB penetration (though less important here), and a slightly stronger binding affinity. While both have poor Caco-2 and solubility, Ligand B is marginally better in these areas. The improved metabolic stability and safety profile of Ligand B are particularly important for an enzyme inhibitor.

Output:
1
2025-04-17 16:44:52,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.873 and 375.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.63 and 71.76) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (3.249 and 3.376) 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 8 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.757 and 0.689), indicating good drug-like properties.

**DILI:** Ligand A (15.394) has a significantly lower DILI risk than Ligand B (90.927). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (77.239) has a higher value than Ligand A (46.879).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.451 and -4.996). This is unusual and suggests poor permeability. However, these values are on a log scale and need to be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.727 and -3.977), indicating poor aqueous solubility. This is a concern.

**hERG Inhibition:** Ligand A (0.254) has a much lower hERG inhibition liability than Ligand B (0.704). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (55.11) has a lower microsomal clearance than Ligand B (64.944), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.969) has a longer in vitro half-life than Ligand A (11.13), which is favorable.

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux liability than Ligand B (0.383).

**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.

**Overall Assessment:**

Ligand B has a much better binding affinity (-7.8 vs -9.0 kcal/mol), and a longer half-life. However, it suffers from significantly higher DILI risk, higher hERG inhibition, and higher P-gp efflux. Ligand A has a much better safety profile (lower DILI and hERG) and better P-gp efflux, but weaker binding and shorter half-life.

Given that SRC kinases are intracellular targets, metabolic stability and safety are crucial. The significantly higher DILI and hERG risks associated with Ligand B are major drawbacks. While the affinity difference is notable, a 1.2 kcal/mol difference can potentially be overcome with further optimization, while mitigating the safety concerns of Ligand B would be much more challenging.

Output:
0
2025-04-17 16:44:52,401 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [363.889, 52.65, 4.23, 1, 2, 0.851, 37.728, 96.2, -4.37, -5.014, 0.856, 32.091, 12.245, 0.277, -8.3]
**Ligand B:** [353.419, 96.97, 0.529, 2, 5, 0.59, 37.146, 54.44, -5.625, -1.72, 0.152, -6.323, -3.766, 0.023, -6.4]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (363.889) and B (353.419) are comparable.
2. **TPSA:** A (52.65) is excellent, well below the 140 threshold. B (96.97) is still acceptable but higher, potentially impacting absorption.
3. **logP:** A (4.23) is slightly high, potentially leading to solubility issues or off-target effects. B (0.529) is quite low, which may hinder membrane permeability.
4. **HBD:** Both have acceptable HBD counts (A: 1, B: 2), well within the limit of 5.
5. **HBA:** A (2) is excellent. B (5) is acceptable but higher, potentially impacting permeability.
6. **QED:** A (0.851) is very good, indicating high drug-likeness. B (0.59) is acceptable, but lower than A.
7. **DILI:** Both are good, with low DILI risk (A: 37.728, B: 37.146).
8. **BBB:** A (96.2) shows excellent potential for CNS penetration, though not a primary concern for SRC. B (54.44) is lower.
9. **Caco-2:** A (-4.37) is very poor, indicating very low intestinal absorption. B (-5.625) is also poor, but slightly better than A.
10. **Solubility:** A (-5.014) is very poor. B (-1.72) is also poor, but better than A.
11. **hERG:** A (0.856) is good, indicating low hERG inhibition risk. B (0.152) is excellent, even lower risk.
12. **Cl_mic:** A (32.091) is moderate. B (-6.323) is excellent, indicating high metabolic stability.
13. **t1/2:** A (12.245) is good. B (-3.766) is poor, indicating a very short half-life.
14. **Pgp:** A (0.277) is good, suggesting low P-gp efflux. B (0.023) is excellent, suggesting very low P-gp efflux.
15. **Affinity:** A (-8.3) is significantly better than B (-6.4), a difference of 1.9 kcal/mol.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Decision:**

While Ligand B has better metabolic stability (Cl_mic) and Pgp efflux, the significantly stronger binding affinity of Ligand A (-8.3 vs -6.4 kcal/mol) is a major advantage. A 1.9 kcal/mol difference is substantial and can often outweigh moderate ADME concerns. Although A has poor Caco-2 and solubility, these can potentially be addressed through formulation strategies. The acceptable hERG risk and good Pgp profile are also positives. The slightly elevated logP of A is less concerning than the poor permeability and solubility of B. Given the importance of potency for kinase inhibitors, Ligand A is the more promising candidate.

Output:
1
2025-04-17 16:44:52,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 81.08, which is acceptable for oral absorption (<=140).

**logP:** Both ligands have logP values (1.151 and 1.536) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, satisfying the <=5 and <=10 rules respectively.

**QED:** Ligand A (0.778) has a slightly better QED score than Ligand B (0.693), indicating better overall drug-likeness.

**DILI:** Ligand A (15.626) has a slightly higher DILI risk than Ligand B (14.967), but both are well below the concerning threshold of 60.

**BBB:** Both have similar BBB penetration (66.072 and 65.607), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.638 and -4.653), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.135 and -2.048), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.364 and 0.193), which is excellent.

**Microsomal Clearance:** Ligand A (42.739) has slightly higher microsomal clearance than Ligand B (41.305), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (1.369 hours) has a slightly longer half-life than Ligand A (-2.477 hours). However, both are quite short, indicating rapid metabolism.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.054 and 0.03), which is favorable.

**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 of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate due to its significantly higher binding affinity (-8.5 kcal/mol vs -7.7 kcal/mol). The stronger binding is a critical advantage for an enzyme inhibitor, and may allow for a lower dose to achieve therapeutic effect, potentially mitigating the solubility/permeability issues. While Ligand B has slightly better metabolic stability, the potency difference is more important in this case.

Output:
0
2025-04-17 16:44:52,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.431 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.33) is slightly higher than Ligand B (66.48), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.767) is a bit low, potentially hindering permeation. Ligand B (2.242) 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 (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.748) has a slightly better QED score than Ligand B (0.636), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 20.706, Ligand B: 21.171), and both are below the concerning threshold of 60.

**BBB:** Ligand A (55.021) has a lower BBB penetration percentile than Ligand B (69.756). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.516 and -5.378), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.997 and -2.561), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.126, Ligand B: 0.247).

**Microsomal Clearance:** Ligand A (-10.613) has significantly lower (better) microsomal clearance than Ligand B (30.301), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-4.534) has a slightly better (longer) in vitro half-life than Ligand B (-3.323).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.007, Ligand B: 0.179).

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9.2 kcal/mol, Ligand B: -8.8 kcal/mol). Ligand A is slightly better.

**Conclusion:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A is the more promising candidate. It has a slightly better QED score, significantly better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better binding affinity. The slightly lower logP of Ligand A is a minor concern compared to the significantly better metabolic profile. The solubility and permeability issues would need to be addressed through formulation or further structural modifications, but the superior pharmacokinetic properties of Ligand A make it the preferred starting point.

Output:
0
2025-04-17 16:44:52,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (364.471 Da and 353.442 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.61) is better than Ligand B (88.91), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**3. logP:** Both ligands have good logP values (1.137 and 1.236), 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:** Both ligands have the same number of HBA (5), which is within the acceptable limit of 10.

**6. QED:** Ligand A (0.849) has a significantly better QED score than Ligand B (0.699), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (49.244 and 41.411), both below the 60 threshold.

**8. BBB:** Ligand B (73.633) has a better BBB percentile than Ligand A (47.111), but BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.084) is slightly better than Ligand B (-4.982).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.801) is slightly better than Ligand B (-2.402).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.079 and 0.082).

**12. Microsomal Clearance:** Ligand A (11.612) has significantly lower microsomal clearance than Ligand B (20.429), suggesting better metabolic stability. This is a key factor for enzyme inhibitors.

**13. In vitro Half-Life:** Ligand A (10.128) has a longer in vitro half-life than Ligand B (2.837), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.044).

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior drug-likeness (QED), metabolic stability (lower Cl_mic and longer t1/2), and slightly better permeability and solubility. The difference in binding affinity is not large enough to offset these advantages.

Output:
0
2025-04-17 16:44:52,402 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [448.308, 51.02, 4.115, 0, 4, 0.565, 59.17, 79.217, -4.889, -4.085, 0.847, 98.355, 103.49, 0.571, -9.4]
**Ligand B:** [346.402, 58.64, 2.766, 1, 3, 0.806, 44.048, 73.129, -4.406, -3.239, 0.601, 35.557, -15.902, 0.207, -7.7]

**Step-by-step comparison:**

1. **MW:** Ligand A (448.308 Da) is within the ideal range. Ligand B (346.402 Da) is also within range, but closer to the lower limit.
2. **TPSA:** Ligand A (51.02) is good for oral absorption. Ligand B (58.64) is also acceptable, though slightly higher.
3. **logP:** Ligand A (4.115) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.766) is optimal.
4. **HBD:** Ligand A (0) is good. Ligand B (1) is also acceptable.
5. **HBA:** Ligand A (4) is good. Ligand B (3) is good.
6. **QED:** Both ligands have good QED scores (A: 0.565, B: 0.806), indicating drug-like properties. Ligand B is better.
7. **DILI:** Ligand A (59.17) is approaching a concerning level for DILI risk. Ligand B (44.048) is much better, indicating a lower risk.
8. **BBB:** Both have reasonable BBB penetration (A: 79.217, B: 73.129), but this isn't a primary concern for a kinase inhibitor.
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:** Ligand A (0.847) has a slightly higher hERG risk than Ligand B (0.601).
12. **Cl_mic:** Ligand A (98.355) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (35.557) has much better metabolic stability.
13. **t1/2:** Ligand A (103.49) has a good in vitro half-life. Ligand B (-15.902) has a negative half-life, which is not possible and suggests an issue with the data or the compound's stability.
14. **Pgp:** Ligand A (0.571) has moderate P-gp efflux. Ligand B (0.207) has lower P-gp efflux, which is favorable.
15. **Affinity:** Ligand A (-9.4 kcal/mol) has significantly better binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand A has a much stronger binding affinity, which is a major advantage. However, it has a high DILI risk, high Cl_mic, and a potentially problematic logP. Ligand B has better ADME properties (lower DILI, better Cl_mic, better logP, lower Pgp efflux) but significantly weaker binding affinity. The negative half-life for Ligand B is a major red flag.

**Conclusion:**

Despite the concerning ADME properties of Ligand A, the significantly stronger binding affinity (-9.4 kcal/mol vs -7.7 kcal/mol) is a substantial advantage that could outweigh the drawbacks, *provided* the ADME issues can be addressed through further optimization. The negative half-life of Ligand B is a showstopper.

Therefore, I would choose **Ligand A** as the more promising starting point for drug development, with a clear understanding that significant medicinal chemistry effort will be needed to improve its ADME profile, especially DILI and metabolic stability.

1
2025-04-17 16:44:52,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (368.849 and 375.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.29) is well below the 140 threshold and quite favorable. Ligand B (71.09) is still acceptable but less optimal.

**logP:** Ligand A (4.287) is slightly high, potentially leading to solubility issues. Ligand B (3.013) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.584 and 0.734, respectively), indicating drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (90.229 percentile) than Ligand B (44.591 percentile). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (65.374) and Ligand B (58.317) are both moderate.

**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 indicates poor aqueous solubility.

**hERG:** Ligand A (0.686) has a slightly higher hERG risk than Ligand B (0.363), but both are reasonably low.

**Microsomal Clearance:** Ligand A (72.304) has a higher microsomal clearance than Ligand B (45.238), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (51.612 hours) has a much longer half-life than Ligand B (4.856 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.676) has lower P-gp efflux liability than Ligand B (0.089), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand B is the more promising candidate despite the slightly higher logP and lower half-life. The significantly lower DILI risk and substantially better binding affinity outweigh the drawbacks. The longer half-life of Ligand A is attractive, but the high DILI risk is a major red flag. The superior binding affinity of Ligand B suggests it will be more potent and effective at lower doses, potentially mitigating some of the ADME concerns.

Output:
1
2025-04-17 16:44:52,402 - INFO - Batch 489 complete. Total preferences: 7824
2025-04-17 16:44:52,402 - INFO - Processing batch 490/512...
2025-04-17 16:45:33,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (367.471 and 347.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.76) is better than Ligand B (115.89). Both are reasonably good, but Ligand A is closer to the preferred <140 for oral absorption.

**3. logP:** Ligand A (1.041) is within the optimal range (1-3), while Ligand B (0.124) is slightly below, which could potentially hinder permeation.

**4. H-Bond Donors (HBD):** Ligand A (2) and Ligand B (4) are both acceptable, being <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (6) and Ligand B (5) are both acceptable, being <=10.

**6. QED:** Ligand A (0.751) has a significantly better QED score than Ligand B (0.456), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.187) has a slightly higher DILI risk than Ligand B (29.973), but both are below the 40 threshold and considered good.

**8. BBB:** Ligand A (39.511) has a lower BBB penetration percentile than Ligand B (52.811). Since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-4.88) is worse than Ligand B (-5.406). Both are negative, suggesting poor permeability, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.153) is better than Ligand B (-1.865). Higher solubility is preferred.

**11. hERG Inhibition:** Ligand A (0.245) has a lower hERG inhibition liability than Ligand B (0.484), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-0.578) has a lower (better) microsomal clearance than Ligand B (-14.603), indicating greater metabolic stability. This is a key consideration for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (6.235) has a better in vitro half-life than Ligand B (-18.062). This is also a crucial factor for kinase inhibitors.

**14. P-gp Efflux:** Ligand A (0.029) has a lower P-gp efflux liability than Ligand B (0.099), which is favorable for bioavailability.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.1 and -8.0 kcal/mol). The difference is negligible.

**Enzyme-Specific Priorities:** For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount.

**Overall Assessment:**

Ligand A is superior. It has a better QED score, better solubility, lower hERG risk, significantly better metabolic stability (Cl_mic and t1/2), and lower P-gp efflux. While Ligand B has slightly better Caco-2 permeability and BBB penetration (which are less important for a non-CNS target), the advantages of Ligand A in key ADME/Tox properties and drug-likeness outweigh these minor differences. The binding affinity is almost identical, so the ADME properties become the deciding factor.

Output:
1
2025-04-17 16:45:33,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.36 and 87.32) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have logP values (1.52 and 1.263) within the optimal 1-3 range, suggesting good permeability and reasonable solubility.

**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 good QED scores (0.599 and 0.777), indicating a drug-like profile. Ligand B is slightly better.

**DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (26.367). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (50.872 and 52.036), which isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.997 and -5.036). 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 (-1.277 and -1.695). This is also unusual and suggests poor solubility. Again, the difference is small.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.121 and 0.119), which is excellent.

**Microsomal Clearance:** Ligand A (15.122 mL/min/kg) has a significantly higher microsomal clearance than Ligand B (0.709 mL/min/kg). This means Ligand B is much more metabolically stable, a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (12.95 hours) has a longer half-life than Ligand B (1.62 hours). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.016), which is good.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.3 and -7.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is superior in terms of metabolic stability (Cl_mic) and has a slightly better QED score. However, Ligand A has a significantly lower DILI risk and a longer half-life. Given that SRC kinases are not typically CNS targets, the similar BBB values are not a major factor. The slight difference in binding affinity is negligible. The poor Caco-2 and solubility values are concerning for both, but similar. The lower DILI risk and longer half-life of Ligand A are more important for an enzyme inhibitor, outweighing the metabolic stability advantage of Ligand B.

Output:
0
2025-04-17 16:45:33,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.868 and 368.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is well below the 140 threshold, while Ligand B (97.12) is approaching it. Lower TPSA generally favors better absorption, giving a slight edge to Ligand A.

**logP:** Both ligands have logP values within the optimal range (3.358 and 2.584).

**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 A is slightly better.

**QED:** Both ligands have similar QED values (0.85 and 0.78), indicating good drug-likeness.

**DILI:** Ligand A (17.371) has a significantly lower DILI risk than Ligand B (69.678). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.205) has a higher BBB value than Ligand A (43.699), but this isn't a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.541) and Ligand B (-5.031) both 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 (-3.387 and -4.404). This will require formulation strategies.

**hERG Inhibition:** Ligand A (0.805) has a lower hERG risk than Ligand B (0.257). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (13.082 mL/min/kg) has a much lower microsomal clearance than Ligand B (40.012 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (27.186 hours) has a significantly longer half-life than Ligand B (3.512 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.445) has lower P-gp efflux than Ligand B (0.124), suggesting better bioavailability.

**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 for Ligand B.

**Overall Assessment:**

Ligand B has a considerably better binding affinity. However, Ligand A demonstrates significantly better ADMET properties, particularly in terms of DILI risk, hERG inhibition, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. The poor Caco-2 permeability is a concern for both, but the other advantages of Ligand A are more critical for an enzyme target. While the affinity difference is notable, a 1.7 kcal/mol difference can often be overcome with further optimization, especially given the superior safety and pharmacokinetic profile of Ligand A.

Output:
0
2025-04-17 16:45:33,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (380.491 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is slightly higher than the ideal <140, while Ligand B (67.59) is well within the range.

**logP:** Both ligands have good logP values (1.727 and 2.769), falling within the optimal 1-3 range.

**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 (0.682 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.513, placing it in the higher risk category (>60). Ligand B has a much lower DILI risk of 31.059, which is favorable.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (37.611) and Ligand B (54.362) are both relatively low, which is expected.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is unspecified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. Again, the scale is unspecified.

**hERG:** Ligand A (0.27) has a slightly higher hERG risk than Ligand B (0.482), but both are relatively low.

**Microsomal Clearance:** Ligand A (16.106) has significantly lower microsomal clearance than Ligand B (40.162), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (39.692) has a much longer in vitro half-life than Ligand A (-8.125), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.091 and 0.158).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, but suffers from higher DILI risk and poorer metabolic stability (higher clearance, shorter half-life). Ligand B has a better safety profile (lower DILI), better metabolic stability (lower clearance, longer half-life), and acceptable ADME properties, but its binding affinity is weaker.

Given the enzyme-kinase specific priorities, potency (affinity) is crucial. The 1.9 kcal/mol difference in binding affinity is considerable. While the DILI risk for Ligand A is a concern, it might be mitigated through structural modifications. The improved metabolic stability of Ligand A is also a positive.

Output:
1
2025-04-17 16:45:33,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.823 Da) is slightly higher, but acceptable. Ligand B (354.407 Da) is also good.

**TPSA:** Ligand A (67.43) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.42) is still reasonable, but approaching the upper limit for good absorption.

**logP:** Ligand A (4.464) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-1.799) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is ideal. Ligand B (HBD=3, HBA=5) is acceptable, but slightly higher.

**QED:** Ligand A (0.767) is excellent, indicating good drug-likeness. Ligand B (0.551) is acceptable, but lower.

**DILI:** Ligand A (81.504) has a high DILI risk. Ligand B (29.663) has a very low DILI risk, a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (79.488) and Ligand B (50.252) are both moderate.

**Caco-2 Permeability:** Ligand A (-4.757) is poor, suggesting poor absorption. Ligand B (-5.337) is also poor.

**Aqueous Solubility:** Ligand A (-5.85) is very poor. Ligand B (-0.832) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.766) is acceptable. Ligand B (0.07) is excellent, indicating very low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (31.404) is moderate. Ligand B (-10.576) is excellent, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (69.693) is good. Ligand B (5.816) is very poor, indicating rapid metabolism.

**P-gp Efflux:** Ligand A (0.434) is acceptable. Ligand B (0.003) is excellent, suggesting minimal efflux.

**Binding Affinity:** Ligand B (-9.1 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 and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate despite its low logP and Caco-2 permeability. The significantly stronger binding affinity (-9.1 vs -6.7 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, Ligand B has a much lower DILI risk, excellent hERG profile, and superior metabolic stability (lower Cl_mic, better P-gp efflux). While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies. Ligand A's high DILI risk and poor solubility are major drawbacks that are harder to overcome.

Output:
1
2025-04-17 16:45:33,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 361.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is better than Ligand B (106.1), both being acceptable for oral absorption (<140).

**logP:** Ligand B (1.128) is better than Ligand A (0.337). A logP between 1-3 is optimal, and Ligand A is a bit low, potentially hindering permeability.

**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:** Ligand B (7) is higher than Ligand A (4), but both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.622 and 0.766, respectively), indicating drug-likeness.

**DILI:** Ligand A (35.285) has a significantly lower DILI risk than Ligand B (69.484). This is a major advantage for Ligand A.

**BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase. Ligand B (59.403) is slightly better than Ligand A (47.421).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-5.055) is slightly better than Ligand B (-4.97).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.935) is slightly better than Ligand B (-3.664).

**hERG Inhibition:** Ligand A (0.078) has a much lower hERG inhibition liability than Ligand B (0.184), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (25.702) has a significantly lower microsomal clearance than Ligand B (58.375), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.92) has a longer in vitro half-life than Ligand B (-25.897), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.027, respectively).

**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, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A exhibits better ADMET properties (lower DILI, lower hERG, lower Cl_mic, longer t1/2, better solubility) but weaker binding affinity. Ligand B has superior binding affinity but suffers from higher DILI, hERG, and Cl_mic, and lower solubility. Given the importance of potency for kinase inhibitors, the 1.9 kcal/mol difference in binding affinity is substantial. While the ADMET profile of Ligand B is concerning, it may be possible to mitigate these issues through further optimization. The stronger binding of Ligand B is likely to translate to greater efficacy.

Output:
1
2025-04-17 16:45:33,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (385.339 and 384.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (107.53 and 105.39) are above the optimal <140 for oral absorption, but not drastically so.

**logP:** Both ligands have good logP values (1.28 and 1.419), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.818) has a significantly better QED score than Ligand A (0.292), indicating a more drug-like profile.

**DILI:** Ligand B (51.105) has a much lower DILI risk than Ligand A (63.552), which is a significant advantage.

**BBB:** BBB is not a primary concern for SRC kinase inhibitors, as it's not a CNS target. Both are similar.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is substantial. Ligand A (-5.636) is worse than Ligand B (-5.282).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.483) is slightly worse than Ligand B (-2.83).

**hERG:** Both ligands have low hERG risk (0.496 and 0.102), which is good. Ligand B is better.

**Microsomal Clearance:** Ligand B (-8.168) has a *much* lower (better) microsomal clearance than Ligand A (13.74). This indicates significantly improved metabolic stability.

**In vitro Half-Life:** Ligand B (-22.783) has a significantly longer in vitro half-life than Ligand A (-7.762).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.065 and 0.032).

**Binding Affinity:** Ligand A (-7.762) and Ligand B (-7.8) have very similar, excellent binding affinities. The difference of 0.038 kcal/mol is negligible.

**Conclusion:**

While both ligands have good binding affinity, Ligand B is significantly superior overall. It has a much better QED score, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better hERG and solubility profiles. The Caco-2 permeability is still poor for both, but Ligand B is slightly better. Given the enzyme-specific priorities, the improvements in metabolic stability and reduced toxicity risk of Ligand B outweigh the minor differences in permeability and solubility.

Output:
1
2025-04-17 16:45:33,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.39 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (74.59 and 70.59) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values within the optimal range (3.295 and 2.373).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.801) has a significantly better QED score than Ligand B (0.636), indicating a more drug-like profile.

**DILI:** Ligand A (58.589) has a higher DILI risk than Ligand B (19.426), which is a significant drawback.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (82.164) is slightly better than Ligand B (76.541). This is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**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.

**hERG Inhibition:** Ligand A (0.703) has a slightly higher hERG inhibition risk than Ligand B (0.511), but both are acceptable.

**Microsomal Clearance:** Ligand B (1.165 mL/min/kg) has significantly lower microsomal clearance than Ligand A (26.325 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (48.277 hours) has a much longer in vitro half-life than Ligand A (27.568 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.204 and 0.194).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), which is a 0.4 kcal/mol advantage. This is a substantial difference and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a better QED and slightly better BBB, Ligand B's significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity are more critical for a kinase inhibitor. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The affinity difference is significant enough to prioritize Ligand B despite the slightly lower QED.

Output:
1
2025-04-17 16:45:33,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (354.491 and 356.857 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (51.02), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (1.562) is within the optimal 1-3 range. Ligand B (3.061) is at the higher end of the optimal range, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.759) has a better QED score than Ligand B (0.59), indicating a more drug-like profile.

**7. DILI:** Ligand A (16.285) has a significantly lower DILI risk than Ligand B (56.34), which is a major advantage.

**8. BBB:** Ligand A (70.609) has a better BBB penetration than Ligand B (60.76), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.449 and -4.673), 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.

**10. Aqueous Solubility:** Ligand A (-1.525) has better solubility than Ligand B (-3.341).

**11. hERG Inhibition:** Ligand A (0.208) has a much lower hERG inhibition risk than Ligand B (0.588). This is a crucial advantage.

**12. Microsomal Clearance:** Ligand A (29.48) has a lower microsomal clearance than Ligand B (77.605), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.75) has a slightly better in vitro half-life than Ligand B (-26.468).

**14. P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux than Ligand B (0.521), which is favorable.

**15. Binding Affinity:** Ligand B (-7.8) has a significantly better binding affinity than Ligand A (0). This is a substantial advantage and could potentially outweigh some of the ADME drawbacks.

**Enzyme-Specific Priorities:** For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B has a much stronger binding affinity. However, it suffers from higher DILI risk, higher hERG inhibition, and higher microsomal clearance. Ligand A has better ADME properties across the board except for binding affinity.

**Overall Assessment:** While Ligand B boasts a superior binding affinity, the significantly worse ADME profile, particularly the higher DILI and hERG risks, makes it a less desirable candidate. The improved ADME properties of Ligand A, specifically the lower DILI and hERG risks, combined with acceptable solubility and metabolic stability, make it the more promising drug candidate, even with the weaker binding affinity. Further optimization of Ligand A to improve its potency could yield an excellent drug candidate.

Output:
0
2025-04-17 16:45:33,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (380.388 and 362.514 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is significantly better than Ligand B (36.36).  For kinases, TPSA isn't a *major* concern unless extremely high, but lower TPSA generally correlates with better permeability.

**3. logP:** Ligand A (1.27) is within the optimal range (1-3). Ligand B (4.634) is a bit high, potentially leading to solubility issues and off-target interactions.

**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 reasonable QED scores (0.777 and 0.625), indicating good drug-like properties.

**7. DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (16.634). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (68.748 and 68.166). Not a primary concern for a kinase inhibitor unless CNS off-targets are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.339 and -5.246). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.035 and -3.815). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.484) has a slightly better hERG profile than Ligand B (0.979), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-14.412) has *much* better metabolic stability (lower clearance) than Ligand B (121.584). This is a crucial advantage for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (26.466) has a better in vitro half-life than Ligand B (29.059).

**14. P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux than Ligand B (0.829).

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.5). However, the difference is small (0.2 kcal/mol) and may not be enough to overcome other deficiencies.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A exhibits significantly better metabolic stability (lower Cl_mic), lower P-gp efflux, and a better hERG profile. The DILI risk for Ligand A is higher, but the substantial improvement in metabolic stability is a critical factor for kinase inhibitors, as they often require sustained exposure to be effective. Both ligands have issues with predicted solubility and permeability, which would need to be addressed through formulation or further chemical modification.

Output:
0
2025-04-17 16:45:33,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (378.45 and 360.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.24) is better than Ligand B (34.59) as it is still within acceptable range for oral absorption, while ligand B is quite low, which might suggest poor potency.

**logP:** Ligand A (-0.879) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (4.161) is above the optimal range, raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is better than Ligand B (0 HBD, 5 HBA) as it is within the acceptable range.

**QED:** Both ligands have good QED scores (0.546 and 0.742), indicating drug-like properties.

**DILI:** Ligand A (45.68) has a slightly higher DILI risk than Ligand B (24.20), but both are below the concerning threshold of 60.

**BBB:** Ligand A (42.23) and Ligand B (83.48) are both not particularly relevant for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both ligands have similar Caco-2 permeability (-5.035 and -5.033).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.252 and -3.887).

**hERG Inhibition:** Ligand A (0.104) has a significantly lower hERG risk than Ligand B (0.803), which is a crucial advantage.

**Microsomal Clearance:** Ligand A (17.56) has a lower microsomal clearance than Ligand B (58.93), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-41.57) has a significantly longer in vitro half-life than Ligand B (22.88), which is a major advantage.

**P-gp Efflux:** Ligand A (0.009) shows lower P-gp efflux liability than Ligand B (0.695).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol) by 1.5 kcal/mol, which is a significant advantage.

**Overall Assessment:**

While Ligand B has superior binding affinity, Ligand A demonstrates a much more favorable ADME-Tox profile. Specifically, the significantly lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux are critical advantages for an enzyme inhibitor. Ligand B's high logP and hERG risk are major concerns. The 1.5 kcal/mol affinity difference, while substantial, can potentially be overcome with further optimization of Ligand A, while mitigating the liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 16:45:33,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (372.368 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.19) is well below the 140 threshold for oral absorption, while Ligand B (96.25) is still acceptable but closer to the limit.

**logP:** Both ligands have good logP values (2.776 and 1.202), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.848 and 0.734), indicating good drug-like properties.

**DILI:** Ligand A (65.413) has a slightly higher DILI risk than Ligand B (55.68), but both are reasonably acceptable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (76.347) has a higher percentile than Ligand B (16.983).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.068 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 (-4.07 and -1.794), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.527) shows slightly better hERG inhibition profile than Ligand B (0.439), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (-1.129) has a significantly *lower* (better) microsomal clearance than Ligand A (4.538), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (19.19 hours) has a longer in vitro half-life than Ligand A (13.217 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.498) has slightly lower P-gp efflux than Ligand B (0.043), suggesting better bioavailability.

**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 of the ADME drawbacks.

**Conclusion:**

While both ligands have significant issues with solubility and permeability, Ligand B is the more promising candidate. Its superior binding affinity (-8.2 vs -7.4 kcal/mol) is a major advantage for an enzyme target. Furthermore, it exhibits better metabolic stability (lower Cl_mic) and a longer half-life. Although Ligand A has slightly better P-gp efflux, the difference is not significant enough to offset the other advantages of Ligand B. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the stronger potency and improved metabolic properties of Ligand B make it the better starting point.

Output:
1
2025-04-17 16:45:33,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.43 and 362.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.78) is better than Ligand B (51.02). While both are reasonably low, Ligand B is significantly lower, potentially aiding absorption.

**logP:** Ligand A (1.28) is optimal, while Ligand B (4.066) is approaching the upper limit. This could lead to solubility issues and off-target effects for Ligand B.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0).

**H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (5).

**QED:** Both ligands have good QED scores (0.551 and 0.676), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (46.96) has a slightly higher DILI risk than Ligand B (32.84), but both are acceptable (<60).

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (77.55) is better than Ligand A (67.58). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental setup or a very poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the experimental setup or a very poor solubility.

**hERG Inhibition:** Ligand A (0.148) has a much lower hERG inhibition liability than Ligand B (0.624). This is a significant advantage for Ligand A, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (13.42) has significantly lower microsomal clearance than Ligand B (106.21), indicating better metabolic stability. This is a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-0.124) has a negative half-life, which is unusual. Ligand B (16.98) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux liability than Ligand B (0.504), suggesting better bioavailability.

**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 of Ligand B.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A presents a much more favorable ADME profile, particularly regarding hERG inhibition and metabolic stability. The higher logP of Ligand B is a concern, and its higher P-gp efflux and clearance could limit its in vivo exposure. The negative solubility and Caco-2 values for both are concerning and would require further investigation. However, the substantial difference in binding affinity (-1.5 kcal/mol) is a significant factor. For a kinase inhibitor, potency is paramount, and the improved metabolic stability and reduced hERG risk of Ligand A are valuable.

Output:
1
2025-04-17 16:45:33,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.399 Da and 348.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.26) is better than Ligand B (109.83), both are below the 140 threshold for good oral absorption, but A is closer to the 90 threshold for CNS penetration (though that's not a priority here).

**logP:** Ligand A (2.829) is optimal (1-3), while Ligand B (0.601) is slightly low, potentially hindering 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, <=10 HBA).

**QED:** Both ligands have similar QED values (0.799 and 0.786), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (72.005 and 72.703), indicating moderate risk. This isn't a major differentiating factor.

**BBB:** Ligand A (69.794) has a better BBB percentile than Ligand B (34.626), but BBB is not a high priority for a kinase inhibitor.

**Caco-2 Permeability:** Ligand A (-4.921) has a worse Caco-2 permeability than Ligand B (-5.088), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.252) has worse aqueous solubility than Ligand B (-2.263). Solubility is important for bioavailability, so B is slightly favored here.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.152 and 0.221), which is excellent.

**Microsomal Clearance:** Ligand A (18.177 mL/min/kg) has a significantly *lower* microsomal clearance than Ligand B (5.878 mL/min/kg), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-7.04 hours) has a much longer half-life than Ligand B (23.017 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.051).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a *stronger* binding affinity than Ligand B (-9.4 kcal/mol). This is the most crucial factor for an enzyme inhibitor. The difference of 0.9 kcal/mol is substantial.

**Conclusion:**

Ligand A is the better candidate. While Ligand B has slightly better solubility and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-8.5 vs -9.4 kcal/mol) and better metabolic stability (lower Cl_mic and longer half-life) outweigh these minor drawbacks. The potency advantage is particularly important for an enzyme target.

Output:
0
2025-04-17 16:45:33,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.29) is better than Ligand B (56.59) as it is closer to the ideal threshold of 140.

**logP:** Both ligands have acceptable logP values (1.788 and 2.581), falling within the 1-3 range.

**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 reasonable QED scores (0.414 and 0.685), with Ligand B being slightly better.

**DILI:** Ligand A (13.571) has a significantly lower DILI risk than Ligand B (50.136), which is a major advantage.

**BBB:** Ligand B (67.197) has a higher BBB penetration score than Ligand A (51.144), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.346) has a worse Caco-2 permeability than Ligand B (-4.691).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.117 and -3.256). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.099) has a lower hERG inhibition liability than Ligand B (0.507), which is a positive.

**Microsomal Clearance:** Ligand A (49.562) has significantly better microsomal clearance (lower) than Ligand B (98.623), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.312) has a much longer in vitro half-life than Ligand B (8.078), another strong advantage.

**P-gp Efflux:** Ligand A (0.042) has lower P-gp efflux liability than Ligand B (0.321).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG inhibition, and lower P-gp efflux. While Ligand B has slightly better QED and Caco-2 permeability, the ADME-Tox advantages of Ligand A outweigh these minor differences, especially given the similar binding affinities. The solubility is a concern for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 16:45:33,126 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (369.447 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.65) is slightly above the preferred <140 for good absorption, but not drastically. Ligand B (71.34) is well within the optimal range.

**logP:** Ligand A (0.637) is a bit low, potentially hindering permeation. Ligand B (3.608) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.605 and 0.755, respectively), indicating drug-likeness.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (39.744), which is a significant concern.

**BBB:** Both have similar BBB penetration (64.637 and 63.94), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.343) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.673) is better, but still not great.

**Aqueous Solubility:** Ligand A (-2.704) has poor aqueous solubility. Ligand B (-4.227) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.301) has a slightly elevated hERG risk. Ligand B (0.505) is higher, raising more concern.

**Microsomal Clearance:** Ligand A (13.081) has lower microsomal clearance, indicating better metabolic stability. Ligand B (54.107) has significantly higher clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-11.135) has a negative half-life, which is unusual and suggests instability or rapid degradation. Ligand B (61.612) has a much better in vitro half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.072 and 0.291).

**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 difference.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility and permeability issues, Ligand B's dramatically superior binding affinity (-7.5 vs 0.0 kcal/mol) outweighs these concerns. The better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk further solidify its position. Ligand A's poor binding affinity, poor permeability, poor solubility, and negative half-life are major drawbacks. The hERG risk is also slightly higher for Ligand B, but the affinity difference is substantial enough to prioritize B.

Output:
1
2025-04-17 16:45:33,127 - INFO - Batch 490 complete. Total preferences: 7840
2025-04-17 16:45:33,127 - INFO - Processing batch 491/512...
2025-04-17 16:46:21,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities (potency, metabolic stability, solubility, and hERG risk).

**1. Molecular Weight (MW):**
* Ligand A: 356.275 Da - Within the ideal range (200-500).
* Ligand B: 389.587 Da - Also within the ideal range.
* *No clear advantage.*

**2. TPSA:**
* Ligand A: 79.29 A^2 - Good for oral absorption (<=140).
* Ligand B: 72.88 A^2 - Also good for oral absorption.
* *Slight advantage to Ligand B due to lower TPSA.*

**3. logP:**
* Ligand A: 2.782 - Optimal (1-3).
* Ligand B: 0.706 - Slightly low, potentially impacting permeability.
* *Advantage to Ligand A.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Meets the criteria (<=5).
* Ligand B: 2 - Meets the criteria.
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 3 - Meets the criteria (<=10).
* Ligand B: 6 - Meets the criteria.
* *Advantage to Ligand A.*

**6. QED:**
* Ligand A: 0.78 - Excellent drug-likeness (>0.5).
* Ligand B: 0.668 - Good drug-likeness (>0.5).
* *Advantage to Ligand A.*

**7. DILI:**
* Ligand A: 79.643 - High risk (>60).
* Ligand B: 11.09 - Low risk (<40).
* *Significant advantage to Ligand B.*

**8. BBB:**
* Ligand A: 58.007 - Not a priority for a non-CNS target like SRC.
* Ligand B: 34.626 - Not a priority.
* *No clear advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -5.346 - Poor permeability.
* Ligand B: -5.37 - Poor permeability.
* *Similar, both are poor.*

**10. Aqueous Solubility:**
* Ligand A: -2.874 - Poor solubility.
* Ligand B: -1.766 - Poor solubility, but slightly better than A.
* *Slight advantage to Ligand B.*

**11. hERG Inhibition:**
* Ligand A: 0.039 - Very low risk.
* Ligand B: 0.232 - Low risk, but higher than A.
* *Advantage to Ligand A.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: -8.568 - Excellent metabolic stability (negative value indicates low clearance).
* Ligand B: 3.998 - Moderate clearance.
* *Significant advantage to Ligand A.*

**13. In vitro Half-Life:**
* Ligand A: -14.605 - Very long half-life.
* Ligand B: -4.224 - Moderate half-life.
* *Significant advantage to Ligand A.*

**14. P-gp Efflux:**
* Ligand A: 0.021 - Low efflux.
* Ligand B: 0.024 - Low efflux.
* *No clear advantage.*

**15. Binding Affinity:**
* Ligand A: -9.0 kcal/mol - Excellent.
* Ligand B: -9.6 kcal/mol - Excellent, slightly better than A.
* *Slight advantage to Ligand B.*

**Overall Assessment:**

Ligand B has a lower DILI risk and a slightly better binding affinity, and slightly better solubility. However, Ligand A demonstrates superior metabolic stability (Cl_mic and t1/2), better QED, and a lower hERG risk. The poor Caco-2 permeability for both is a concern, but can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, the excellent metabolic stability and potency of Ligand A, combined with its lower hERG risk, outweigh the DILI concern (which can be further investigated and potentially mitigated through structural modifications). The slightly better affinity of Ligand B is not enough to overcome the metabolic liabilities.

Output:
1
2025-04-17 16:46:21,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (355.36 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is better than Ligand B (89.35), being comfortably under the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have acceptable logP values (2.286 and 1.411), falling within the 1-3 range. Ligand A is slightly more lipophilic.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar, good QED values (0.796 and 0.784), indicating good drug-like properties.

**DILI:** Ligand A (44.591) has a significantly lower DILI risk than Ligand B (63.513). This is a major advantage.

**BBB:** Ligand A (81.698) has a higher BBB penetration percentile than Ligand B (45.677). While not a primary concern for a non-CNS target like SRC, it's a slight positive.

**Caco-2 Permeability:** Ligand A (-4.719) has a better Caco-2 permeability than Ligand B (-5.237).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.672 and -2.738). This is a significant concern for both.

**hERG:** Both ligands have low hERG inhibition liability (0.113 and 0.068), which is excellent.

**Microsomal Clearance:** Ligand A (4.738) has a significantly lower microsomal clearance than Ligand B (40.213), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-15.443) has a longer in vitro half-life than Ligand B (-12.192).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.062).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Ligand A is the better candidate. While both have poor solubility, Ligand A demonstrates superior ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. These factors are particularly important for an enzyme target like SRC kinase. The binding affinity difference is negligible.

Output:
0
2025-04-17 16:46:21,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (360.445 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (80.57), being well below the 140 A^2 threshold for good absorption.

**3. logP:** Both ligands (2.446 and 2.808) are 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 (3) is preferable to Ligand B (4) for similar reasons as above.

**6. QED:** Both ligands have acceptable QED scores (0.792 and 0.68), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (35.75 and 31.252), which is positive.

**8. BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (90.074) has a slightly higher BBB penetration than Ligand B (76.464).

**9. Caco-2 Permeability:** Ligand A (-4.292) has a slightly better Caco-2 permeability than Ligand B (-4.516).

**10. Aqueous Solubility:** Ligand A (-2.982) has a slightly better aqueous solubility than Ligand B (-2.609).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.608 and 0.38), which is excellent.

**12. Microsomal Clearance:** Ligand A (37.257) has a significantly lower microsomal clearance than Ligand B (49.299), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-23.003) has a significantly longer in vitro half-life than Ligand B (35.341), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.178).

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.3), a difference of 0.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic and longer t1/2) and solubility. For an enzyme target like SRC kinase, metabolic stability is crucial for maintaining therapeutic concentrations *in vivo*. The 0.5 kcal/mol difference in binding affinity is unlikely to overcome the substantial advantage of Ligand A's improved pharmacokinetic profile. The better TPSA, HBD, HBA, solubility, and metabolic stability of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 16:46:21,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.395 and 350.507 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.45) is better than Ligand B (50.6). Both are below the 140 A^2 threshold for good absorption, but Ligand B is excellent.

**logP:** Ligand A (-1.127) is slightly low, potentially hindering permeability. Ligand B (2.294) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) 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:** Ligand B (0.722) has a significantly better QED score than Ligand A (0.474), indicating a more drug-like profile.

**DILI:** Ligand A (51.648) has a moderate DILI risk, while Ligand B (11.322) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (83.482) has a higher BBB penetration than Ligand A (40.791), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.497) has poor Caco-2 permeability, while Ligand B (-4.381) is better, but still not great.

**Aqueous Solubility:** Ligand A (-0.871) has poor solubility, while Ligand B (-1.797) is also poor.

**hERG Inhibition:** Ligand A (0.028) has a very low hERG risk, which is excellent. Ligand B (0.507) has a slightly elevated hERG risk, but still acceptable.

**Microsomal Clearance:** Ligand A (-6.852) has significantly lower (better) microsomal clearance than Ligand B (74.642), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (13.498 hours) has a longer half-life than Ligand A (7.09 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.009 and 0.343, respectively).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B's superior binding affinity, QED, DILI risk, and half-life outweigh Ligand A's slightly better hERG profile and clearance. The binding affinity difference is substantial and a key driver for selecting Ligand B. The lower DILI risk is also a major advantage.

Output:
1
2025-04-17 16:46:21,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (364.511 and 356.369 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (67.43 and 68.82) are below the 140 A^2 threshold for good oral absorption, which is positive.

**3. logP:** Both ligands have logP values (3.656 and 3.174) 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 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.757 and 0.869), indicating drug-like properties.

**7. DILI:** Ligand B (61.342) has a significantly lower DILI risk than Ligand A (41.915), which is a major advantage. Lower DILI is highly desirable.

**8. BBB:** Both have reasonable BBB penetration, but Ligand B (95.812) is substantially better than Ligand A (73.866). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.721 and -4.608). This 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 does raise a flag.

**10. Aqueous Solubility:** Both have negative solubility values (-4.08 and -4.468), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Ligand A (0.523) has a slightly higher hERG inhibition risk than Ligand B (0.7). Lower hERG is preferred.

**12. Microsomal Clearance:** Ligand B (45.79) has significantly lower microsomal clearance than Ligand A (92.79), indicating better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (11.971 and 11.701 hours), which are acceptable.

**14. P-gp Efflux:** Both have low P-gp efflux (0.15 and 0.26), which is good.

**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 still a positive.

**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), lower DILI risk, and slightly better binding affinity. The improved metabolic stability and reduced toxicity risk are particularly important for kinase inhibitors, which often require chronic administration.



Output:
1
2025-04-17 16:46:21,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (361.829 Da and 358.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.48) is well below the 140 threshold and favorable for oral absorption. Ligand B (88.1) is also below 140, but closer to the upper limit.

**logP:** Ligand A (3.723) is at the higher end of the optimal 1-3 range, potentially raising concerns about off-target effects. Ligand B (0.8) is below 1, which could impede permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5 HBAs, both within the acceptable limit of 10.

**QED:** Ligand A (0.822) has a better QED score than Ligand B (0.636), indicating a more drug-like profile.

**DILI:** Ligand A (69.135) has a higher DILI risk than Ligand B (28.616). This is a significant negative for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (77.898) has a better BBB score than Ligand B (39.511).

**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 (0.253) has a lower hERG risk than Ligand B (0.353), which is favorable.

**Microsomal Clearance:** Ligand A (74.403) has a higher microsomal clearance than Ligand B (34.844), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-5.771) has a longer in vitro half-life than Ligand A (6.44), which is a positive.

**P-gp Efflux:** Both have low P-gp efflux liability (0.101 and 0.051).

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.6), a difference of 1.4 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity, a better QED score, and lower hERG risk. 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 a lower QED.

Given that SRC is a kinase, potency (binding affinity) is paramount. The 1.4 kcal/mol difference in binding affinity is substantial and likely outweighs the drawbacks of Ligand A, *provided* the DILI risk can be mitigated through structural modifications. The lower metabolic stability is also a concern, but can potentially be addressed through prodrug strategies or structural modifications. The poor solubility and permeability are shared issues that would need to be addressed regardless of which lead is chosen.

Output:
1
2025-04-17 16:46:21,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.389 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.77) is slightly higher than Ligand B (90.74), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.185 and 1.709), falling within the 1-3 range.

**H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 8. Ligand A is preferable here, as higher HBA can sometimes negatively impact permeability.

**QED:** Both ligands have good QED scores (0.579 and 0.655), indicating drug-like properties.

**DILI:** Ligand A (47.189) has a significantly lower DILI risk than Ligand B (67.817). This is a crucial advantage.

**BBB:** Both ligands have moderate BBB penetration, but Ligand A (74.874) is better than Ligand B (53.432). While not a primary concern for a kinase inhibitor, better BBB penetration is generally favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.572) is slightly better than Ligand B (-5.074), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, which is also concerning. Ligand A (-2.584) is slightly better than Ligand B (-3.414).

**hERG:** Both ligands have low hERG inhibition risk (0.278 and 0.869), which is excellent.

**Microsomal Clearance:** Ligand A (-0.731) has a much lower (better) microsomal clearance than Ligand B (55.818). This suggests significantly improved metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-9.054) has a much longer in vitro half-life than Ligand B (57.424), further supporting its improved metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.053).

**Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have good potency, Ligand A demonstrates superior ADMET properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility and permeability. The lower DILI risk and improved metabolic stability are critical advantages for a kinase inhibitor intended for chronic use in oncology. The slightly better Caco-2 and solubility are also beneficial.

Output:
0
2025-04-17 16:46:21,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (351.422 and 357.841 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is higher than Ligand B (53.51). Both are below the 140 threshold for oral absorption, but Ligand B is better positioned.

**logP:** Both ligands (2.147 and 2.211) are 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 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.852) has a better QED score than Ligand B (0.762), indicating a more drug-like profile.

**DILI:** Ligand B (68.244) has a lower DILI risk than Ligand A (35.595), which is a significant advantage.

**BBB:** Ligand A (87.01) has a higher BBB penetration potential than Ligand B (72.664). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.871) has a worse Caco-2 permeability than Ligand B (-4.683).

**Aqueous Solubility:** Ligand A (-2.051) has a better aqueous solubility than Ligand B (-3.455). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.205) has a lower hERG inhibition liability than Ligand B (0.35), which is a crucial safety advantage.

**Microsomal Clearance:** Ligand B (50.163) has a lower microsomal clearance than Ligand A (19.974), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-46.135) has a significantly longer in vitro half-life than Ligand A (-21.574). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.282), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.1). While a 1.5 kcal/mol difference is notable, the ADME properties are more critical in this case.

**Overall Assessment:**

Ligand B demonstrates superior ADME properties, particularly in metabolic stability (lower Cl_mic, longer t1/2) and DILI risk. While Ligand A has a slightly better binding affinity and QED, the improved safety profile and pharmacokinetic properties of Ligand B outweigh this advantage. The better solubility of Ligand A is a plus, but not enough to overcome the other benefits of Ligand B.

Output:
1
2025-04-17 16:46:21,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 360.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.76 and 88.33) are below the 140 A^2 threshold for good oral absorption, but higher than the 90 A^2 for CNS targets (not a major concern here).

**logP:** Both ligands (1.323 and 1.537) 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 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.81 and 0.874), indicating good drug-like properties.

**DILI:** Ligand A (22.683) has a significantly lower DILI risk than Ligand B (52.036). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (71.772 and 72.896), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.842 and -5.723). This is unusual and suggests poor permeability. However, these values are on a log scale, so a more negative value indicates lower permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.863 and -2.161), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.183 and 0.129).

**Microsomal Clearance:** Ligand A (8.057 mL/min/kg) has a much lower microsomal clearance than Ligand B (40.767 mL/min/kg). This indicates better metabolic stability for Ligand A, which is crucial for an enzyme target.

**In vitro Half-Life:** Ligand A (-16.972 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (18.179 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.044).

**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 outweigh other factors.

**Overall Assessment:**

Ligand A is preferable due to its significantly lower DILI risk and much better metabolic stability (lower Cl_mic). While the negative half-life is concerning and likely an error, the other favorable properties outweigh this issue. The binding affinity is comparable between the two. Ligand B has a better half-life, but the higher DILI risk and poorer metabolic stability are significant drawbacks.

Output:
0
2025-04-17 16:46:21,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.519 and 364.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is well below the 140 threshold for good absorption, and a good value for an enzyme inhibitor. Ligand B (86.03) is also acceptable, but slightly higher.

**logP:** Ligand A (3.868) is at the upper end of the optimal 1-3 range, while Ligand B (1.834) is towards the lower end. While both are within range, a logP too high can cause off-target effects, so B is slightly preferred here.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 8 HBA) both have acceptable numbers of H-bonds.

**QED:** Both ligands have reasonable QED values (0.684 and 0.568), indicating drug-like properties.

**DILI:** Ligand A (51.725) has a better DILI score than Ligand B (65.491), indicating lower liver injury risk. This is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (63.28 and 60.101), which is not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values, which is also a red flag for both.

**hERG Inhibition:** Ligand A (0.397) has a much lower hERG inhibition risk than Ligand B (0.156), which is a substantial advantage.

**Microsomal Clearance:** Ligand A (55.07) has a higher clearance than Ligand B (35.794), meaning B is more metabolically stable. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (23.033) has a significantly longer half-life than Ligand A (3.305), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.332) has lower P-gp efflux than Ligand B (0.176), which is preferable.

**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 significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a better safety profile (lower DILI, lower hERG). Both have poor predicted permeability and solubility. The improved potency and metabolic stability of Ligand B are critical for an enzyme inhibitor, and the 0.5 kcal/mol difference in binding is substantial. While the DILI and hERG risks of Ligand A are lower, these can be further investigated and potentially mitigated during lead optimization. The poor solubility and permeability are significant concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:46:21,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.401 and 340.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.08 and 66.29) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (0.879 and 0.751) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.79 and 0.89), indicating good drug-like properties.

**DILI:** Ligand A (17.216) has a significantly lower DILI risk than Ligand B (37.922). This is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC kinase, but Ligand A (90.074) has better BBB penetration than Ligand B (67.041).

**Caco-2 Permeability:** Ligand A (-4.506) and Ligand B (-5.113) both have negative values, which is unusual. Lower values suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.84 and -0.673), indicating poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.369) has a lower hERG inhibition liability than Ligand B (0.564), which is preferable.

**Microsomal Clearance:** Ligand A (-6.141) exhibits significantly lower microsomal clearance, suggesting better metabolic stability, a key factor for enzyme inhibitors. Ligand B (19.004) has high clearance.

**In vitro Half-Life:** Ligand A (-4.324) has a longer in vitro half-life than Ligand B (2.072).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.01).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is relatively small (0.6 kcal/mol) and is likely outweighed by the superior ADME properties of Ligand A.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower hERG inhibition. The solubility is a concern for both, but the ADME advantages of Ligand A are more critical for overall drug development success.

Output:
0
2025-04-17 16:46:21,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 360.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (66.65 and 65.54) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (2.827 and 2.435) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.77 and 0.859), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (56.301 and 57.813), and are acceptable as they are below 60.

**BBB:** Ligand A has a higher BBB penetration (85.537%) than Ligand B (69.872%). While not a primary concern for a non-CNS target like SRC, it's a slight advantage for A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.637). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.316 and -2.848). This is also concerning, indicating poor aqueous solubility. Solubility is a critical factor for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.303 and 0.453), which is excellent.

**Microsomal Clearance:** Ligand B has significantly lower microsomal clearance (43.248 mL/min/kg) than Ligand A (70.331 mL/min/kg). Lower clearance indicates better metabolic stability, a key priority for enzymes.

**In vitro Half-Life:** Ligand B has a substantially longer in vitro half-life (57.879 hours) than Ligand A (-25.206 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 (0.457 and 0.079), which is favorable.

**Binding Affinity:** Ligand B has a stronger binding affinity (-8.4 kcal/mol) than Ligand A (-7.0 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While both ligands have some concerning solubility and permeability issues, Ligand B is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic, longer t1/2) and substantially stronger binding affinity (-8.4 vs -7.0 kcal/mol) outweigh the slightly lower BBB and similar DILI risks. The improved affinity is a critical advantage for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:46:21,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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. Ligand B (381.948 Da) is also acceptable.

**TPSA:** Ligand A (89.45) is excellent, well below the 140 threshold for oral absorption. Ligand B (19.37) is even better, suggesting potentially improved cell permeability.

**logP:** Ligand A (2.809) is within the optimal range (1-3). Ligand B (4.458) is slightly higher, potentially leading to solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (0) is also good, potentially improving membrane permeability.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 limit.

**QED:** Both ligands have good QED values (A: 0.637, B: 0.736), indicating a generally drug-like profile.

**DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (34.82), which is a significant concern.

**BBB:** Ligand A (27.491) has a low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (87.553) has high BBB penetration, which is irrelevant here and could even be a negative if off-target CNS effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.26) shows poor Caco-2 permeability. Ligand B (-4.873) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.351 and -4.047 respectively). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.726) has a slightly higher hERG risk than Ligand B (0.978), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 36.008, B: 36.139), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (56.974) has a significantly longer in vitro half-life than Ligand A (-16.743), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.191, B: 0.784).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.1 kcal/mol, B: -9.1 kcal/mol). Ligand B is slightly more potent.

**Conclusion:**

While Ligand B has a slightly higher logP and similar solubility issues, its significantly better DILI score and substantially longer half-life outweigh these drawbacks, especially given the comparable binding affinity. The poor solubility of both is a concern that would need to be addressed through formulation strategies. However, the lower toxicity risk and improved metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:46:21,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.483 and 361.379 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.51) is higher than Ligand B (29.54). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (1.666) is within the optimal range (1-3). Ligand B (4.072) 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 2 HBD and 4 HBA, which is acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.755 and 0.685), indicating good drug-likeness.

**DILI:** Ligand A (36.681) and Ligand B (32.144) both have low DILI risk, below the 40 threshold.

**BBB:** Ligand A (56.689) has a lower BBB penetration percentile than Ligand B (96.084). However, BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.393) has poor Caco-2 permeability, while Ligand B (-4.45) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.85) has slightly better solubility than Ligand B (-3.642). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.196) has a lower hERG inhibition risk than Ligand B (0.862). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (52.858) and Ligand B (56.498) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (17.061) has a slightly longer half-life than Ligand A (14.953).

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux liability than Ligand B (0.574), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-10.3 and -10.4 kcal/mol), with a negligible difference.

**Conclusion:**

Considering the priorities for enzyme inhibitors, both ligands have strong binding affinity. However, Ligand A has a significantly lower hERG risk and P-gp efflux, and better solubility, while Ligand B has better TPSA and slightly better half-life. The hERG risk is a critical factor, and the lower risk associated with Ligand A makes it the more promising candidate. The slightly better TPSA of Ligand B is not enough to overcome the hERG liability.

Output:
0
2025-04-17 16:46:21,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.487 and 346.471 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is well below the 140 threshold, while Ligand B (78.43) is also acceptable but closer to the limit.

**logP:** Ligand A (3.911) is at the upper end of the optimal range (1-3), while Ligand B (2.448) is comfortably within it.  Ligand A's higher logP *could* lead to solubility issues.

**H-Bond Donors/Acceptors:** Both have 3 HBA and are within acceptable limits for HBD (2 and 3 respectively).

**QED:** Both ligands have reasonable QED scores (0.673 and 0.57), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (39.589 and 37.495), which is excellent.

**BBB:** Ligand A has a significantly higher BBB penetration percentile (69.446) than Ligand B (41.644). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.506 and -4.792), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-4.256 and -3.311), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.83 and 0.663), which is good.

**Microsomal Clearance:** Ligand A (87.009) has higher microsomal clearance than Ligand B (68.028), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (30.07 hours) has a significantly longer half-life than Ligand A (17.757 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.354 and 0.688), which is favorable.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a *much* stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a decisive advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor permeability and solubility for both compounds, Ligand B is the superior candidate. The significantly stronger binding affinity (-10.1 vs -6.9 kcal/mol) outweighs the slightly higher TPSA and the lower BBB. The longer half-life of Ligand B is also a significant benefit. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications, but the potency advantage of Ligand B makes it the more promising starting point.

Output:
1
2025-04-17 16:46:21,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.455 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.58 and 98.66) are below the 140 A^2 threshold for good oral absorption, but not particularly optimized for CNS penetration (above 90).

**logP:** Ligand A (-0.307) is slightly low, potentially hindering permeation. Ligand B (0.811) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (4 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.667 and 0.545, both >=0.5).

**DILI:** Ligand A (44.436) has a moderate DILI risk, but is significantly lower than Ligand B (16.479), which is a concern.

**BBB:** Both ligands have low BBB penetration (27.646 and 30.554), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.778 and -5.206), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.936 and -2.404), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Ligand A (0.028) shows very low hERG inhibition risk, which is excellent. Ligand B (0.216) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (7.954) has a lower microsomal clearance than Ligand B (4.492), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (16.311) has a significantly longer in vitro half-life than Ligand A (4.266), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.015 and 0.049).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.0 kcal/mol), with Ligand A being slightly better. The difference is less than 1.5 kcal/mol, so it's not decisive.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and significantly lower DILI risk and hERG inhibition. However, Ligand B has a much longer half-life. Both compounds suffer from poor solubility and permeability. Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), Ligand A is slightly favored due to the lower DILI and hERG risk, despite the shorter half-life. The solubility and permeability issues would need to be addressed through formulation or further chemical modification for either compound.

Output:
0
2025-04-17 16:46:21,275 - INFO - Batch 491 complete. Total preferences: 7856
2025-04-17 16:46:21,275 - INFO - Processing batch 492/512...
2025-04-17 16:47:07,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (349.431 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.8) is well below the 140 threshold for good oral absorption and even below 90 for potential CNS penetration (though that's not a priority here). Ligand B (135.78) is still within the acceptable range for oral absorption, but higher.

**logP:** Ligand A (0.769) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.372) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is well within acceptable limits. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (0.795 and 0.689), indicating good drug-like properties.

**DILI:** Ligand A (42.148) has a much lower DILI risk than Ligand B (66.421), which is approaching a concerning level.

**BBB:** This isn't a primary concern for a kinase inhibitor, but Ligand B (57.736) has a higher BBB value than Ligand A (33.23).

**Caco-2 Permeability:** Ligand A (-4.927) has better predicted Caco-2 permeability than Ligand B (-5.602), though both are negative and suggest poor permeability.

**Aqueous Solubility:** Ligand A (-1.234) has better predicted solubility than Ligand B (-2.629). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.168 and 0.17), which is excellent.

**Microsomal Clearance:** Ligand A (8.562) has significantly lower microsomal clearance than Ligand B (26.668), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (34.195 hours) has a much longer predicted half-life than Ligand B (-10.663 hours). This is a significant benefit, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.003).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a >1.5 kcal/mol difference, which is a significant advantage and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity. However, it suffers from higher DILI risk, lower solubility, significantly higher microsomal clearance, and a shorter half-life. Ligand A has superior ADME properties (lower DILI, better solubility, better metabolic stability, longer half-life) but weaker binding affinity. Given the importance of metabolic stability and a reasonable half-life for kinase inhibitors, and the relatively good affinity of Ligand A, I believe Ligand A is the more promising candidate, despite the slightly lower potency. The potency difference *might* be overcome with further optimization, while fixing the ADME issues of Ligand B would be more challenging.

Output:
0
2025-04-17 16:47:07,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.455 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.5) is slightly higher than Ligand B (67.43). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating improved cell permeability.

**logP:** Both ligands have acceptable logP values (1.544 and 2.805), falling within the 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 (0.824) has a better QED score than Ligand B (0.662), suggesting a more drug-like profile overall.

**DILI:** Ligand B (15.2) has a much lower DILI risk than Ligand A (53.858), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (75.301 and 73.013), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.589 and -4.458), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.159 and -3.234), which is also concerning, indicating poor solubility. Ligand B is slightly better.

**hERG:** Ligand A (0.559) has a lower hERG risk than Ligand B (0.362), which is favorable.

**Microsomal Clearance:** Ligand A (-5.85) has a significantly lower (better) microsomal clearance than Ligand B (61.872), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (23.046 hours) has a much longer half-life than Ligand B (-18.95 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.106 and 0.107).

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial difference and a key factor.

**Conclusion:**

While Ligand B has a better DILI score and slightly better solubility, Ligand A's significantly stronger binding affinity (-8.0 vs -6.4 kcal/mol), better QED, significantly improved metabolic stability (lower Cl_mic), and longer half-life outweigh the slightly higher DILI risk and poorer solubility. The binding affinity difference is particularly important for an enzyme target like SRC kinase. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:47:07,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.439 and 330.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.75) is better than Ligand B (45.05), both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have a logP around 4.0, which is at the upper limit of the optimal range. This could potentially cause solubility issues, but is not a major concern at this stage.

**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 good QED scores (0.711 and 0.842), indicating good drug-like properties.

**DILI:** Ligand A (55.913) has a higher DILI risk than Ligand B (26.444). This is a significant negative for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (77.898) has a higher BBB percentile than Ligand B (43.699), but this is less important.

**Caco-2 Permeability & Solubility:** Both ligands have negative Caco-2 values and solubility values, which is not ideal.

**hERG:** Both ligands have low hERG risk (0.878 and 0.8), which is good.

**Microsomal Clearance (Cl_mic):** Ligand A (112.013) has significantly higher Cl_mic than Ligand B (10.599). This suggests Ligand A is less metabolically stable.

**In vitro Half-Life (t1/2):** Ligand A (107.051) has a longer half-life than Ligand B (11.708), which is a positive. However, this benefit is likely offset by the higher Cl_mic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.737 and 0.344).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 0.9 kcal/mol difference is substantial and outweighs many of the other differences.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. Its significantly stronger binding affinity (-9.2 vs -8.3 kcal/mol) is a major advantage for an enzyme target like SRC kinase. Furthermore, Ligand B has a much lower DILI risk (26.444 vs 55.913) and better metabolic stability (lower Cl_mic). While Ligand A has a longer half-life, the higher metabolic clearance likely negates this benefit. The slightly lower BBB penetration of Ligand B is not a concern for a non-CNS target.

Output:
1
2025-04-17 16:47:07,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.303 Da) is slightly higher than Ligand B (353.467 Da), but both are acceptable.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (99.49). Lower TPSA generally correlates with better cell permeability. Ligand B's TPSA is relatively high, potentially hindering absorption.

**logP:** Ligand A (4.77) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (0.321) is *below* the optimal range and could have permeability problems. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=6) in terms of balancing solubility and permeability. Ligand B has a higher number of H-bond acceptors, potentially impacting permeability.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.759, Ligand B: 0.563), indicating acceptable drug-like properties.

**DILI:** Ligand A (56.805) has a higher DILI risk than Ligand B (28.655). While both are below the concerning threshold of 60, Ligand B is preferable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (53.936) and Ligand B (27.801) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.926) is better than Ligand B (-5.232), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.557) is significantly better than Ligand B (-0.555). Solubility is crucial for bioavailability, and Ligand B's poor solubility is a major concern.

**hERG Inhibition:** Ligand A (0.461) is much better than Ligand B (0.184), indicating a lower risk of cardiotoxicity. This is a critical advantage for Ligand A.

**Microsomal Clearance:** Ligand A (88.137) has higher clearance than Ligand B (19.87), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (23.053) has a longer half-life than Ligand B (11.699), which is desirable.

**P-gp Efflux:** Ligand A (0.507) has lower P-gp efflux than Ligand B (0.01), indicating better bioavailability.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a substantially better binding affinity and acceptable solubility, permeability, and hERG risk. While its logP is slightly high and clearance is higher than ideal, the strong binding affinity is a significant advantage for an enzyme target like SRC kinase. Ligand B suffers from poor solubility, a low logP (potentially hindering permeability), and a weaker binding affinity. The lower DILI risk for Ligand B is a minor benefit compared to the overall profile of Ligand A.

Output:
1
2025-04-17 16:47:07,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.341 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.37) is slightly higher than Ligand B (78.27), both are below the 140 threshold for oral absorption, and acceptable for kinase inhibitors.

**logP:** Both ligands have good logP values (2.805 and 2.156), 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 good QED scores (0.778 and 0.899), indicating good drug-like properties.

**DILI:** Ligand A (87.902) has a higher DILI risk than Ligand B (73.09). This is a significant concern, as higher DILI is undesirable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.2) has a higher BBB percentile than Ligand A (55.021), but this is not a primary factor in this case.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.628 and -4.672). These values are unusual and suggest poor permeability, but are likely reported as logP values and therefore are not directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.134 and -3.322). These values are unusual and suggest poor solubility, but are likely reported as logS values and therefore are not directly comparable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.388 and 0.303), which is excellent.

**Microsomal Clearance:** Ligand B (26.593) has lower microsomal clearance than Ligand A (32.374), suggesting better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (6.988 hours) has a significantly longer in vitro half-life than Ligand A (-13.214 hours). The negative value for Ligand A is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.206 and 0.129).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), although both are excellent. The 0.8 kcal/mol difference is significant.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both ligands have good potency and drug-like properties, Ligand B exhibits a lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly improved binding affinity. The negative values for solubility and Caco-2 permeability are concerning for both, but the other advantages of Ligand B outweigh these concerns.

Output:
1
2025-04-17 16:47:07,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (66.92) as it is closer to the 140 A^2 threshold.

**logP:** Both ligands (1.511 and 1.634) are 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 acceptable, though Ligand A's HBD count is slightly preferable for potential hydrogen bonding with the kinase active site.

**QED:** Ligand A (0.836) has a significantly better QED score than Ligand B (0.665), indicating a more drug-like profile.

**DILI:** Ligand A (33.307) has a lower DILI risk than Ligand B (44.824), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (68.127) is better than Ligand B (53.703).

**Caco-2 Permeability:** Both are negative (-4.544 and -4.625), which is not ideal, but similar.

**Aqueous Solubility:** Both are negative (-2.585 and -2.586), which is not ideal.

**hERG:** Ligand A (0.211) has a lower hERG risk than Ligand B (0.368), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (40.969) has a lower microsomal clearance than Ligand B (86.609), indicating better metabolic stability. This is a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-7.657) has a much longer in vitro half-life than Ligand B (-20.099), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux than Ligand B (0.152), indicating better bioavailability.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is not huge, it contributes to the overall favorability of Ligand A.

**Overall:** Ligand A consistently outperforms Ligand B across most critical parameters, especially metabolic stability (Cl_mic, t1/2), DILI risk, hERG risk, QED, and binding affinity. While both have poor Caco-2 and solubility, the superior ADME-Tox profile and slightly better potency of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 16:47:07,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.304 Da) is higher, but still acceptable. Ligand B (353.507 Da) is slightly better.

**TPSA:** Both ligands have TPSA values around 81-82, which is acceptable for oral absorption, though not optimal.

**logP:** Both ligands have good logP values (A: 3.197, B: 1.279) within the 1-3 range. Ligand A is slightly preferred due to better predicted permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is better than Ligand B (HBD=3, HBA=4) in terms of H-bonding potential, balancing solubility and permeability.

**QED:** Ligand A (0.715) has a better QED score than Ligand B (0.546), suggesting a more drug-like profile.

**DILI:** Ligand B (5.584) has a significantly lower DILI risk than Ligand A (80.729). This is a major advantage for Ligand B.

**BBB:** Ligand A (71.772) has a better BBB percentile than Ligand B (67.197), but BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests potential issues with solubility prediction.

**hERG Inhibition:** Ligand A (0.643) has a slightly better hERG profile than Ligand B (0.394), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (15.877 mL/min/kg) has much lower microsomal clearance than Ligand A (89.008 mL/min/kg), indicating better metabolic stability. This is a critical advantage for Ligand B.

**In vitro Half-Life:** Ligand A (101.717 hours) has a much longer in vitro half-life than Ligand B (-24.534 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.637) has lower P-gp efflux than Ligand B (0.009), suggesting better oral bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.9 kcal/mol, B: -7.9 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A has advantages in binding affinity, half-life, and P-gp efflux. However, Ligand B has a dramatically better DILI score and significantly improved metabolic stability (lower Cl_mic). For an enzyme target like SRC kinase, metabolic stability and safety (DILI) are paramount. While the longer half-life of Ligand A is attractive, the high DILI risk is a major concern. The slightly better affinity of A doesn't outweigh the safety and metabolic concerns.

Output:
1
2025-04-17 16:47:07,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.443 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.54) is better than Ligand B (73.99), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (4.14) is slightly higher than ideal (1-3), while Ligand B (2.972) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=2) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.569 and 0.571), indicating good drug-likeness.

**DILI:** Ligand A (76.464) has a significantly higher DILI risk than Ligand B (27.026). This is a major concern for Ligand A.

**BBB:** Ligand A (27.879) and Ligand B (69.484) both have low BBB penetration, which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.172) has very poor Caco-2 permeability, while Ligand B (-4.824) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-6.501) has very poor aqueous solubility, which is a significant drawback. Ligand B (-3.844) is better, but still low.

**hERG:** Ligand A (0.553) has a slightly higher hERG risk than Ligand B (0.415), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (43.383) has lower microsomal clearance than Ligand B (54.021), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.731) has a slightly longer in vitro half-life than Ligand B (-13.24), which is a positive.

**P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux than Ligand B (0.096), indicating better bioavailability.

**Binding Affinity:** Ligand A (-8.2 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 concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity and metabolic stability, and lower P-gp efflux. However, it suffers from very poor solubility, poor Caco-2 permeability, and a significantly higher DILI risk. Ligand B has better solubility and lower DILI, but weaker affinity and poorer metabolic stability.

Given the enzyme-specific priorities, the strong binding affinity of Ligand A is a major advantage. While the solubility and DILI are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The difference in binding affinity is likely to have a larger impact on efficacy than the ADME drawbacks, especially in the early stages of drug development.

Output:
1
2025-04-17 16:47:07,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.467 Da) is slightly lower, which is generally favorable for permeability. Ligand B (382.869 Da) is also acceptable.

**TPSA:** Ligand A (73.85) is well below the 140 threshold for good oral absorption. Ligand B (95.5) is also under the threshold, but closer to it.

**logP:** Ligand A (4.546) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (2.073) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, which is good. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED values (A: 0.43, B: 0.609), indicating reasonable drug-likeness.

**DILI:** Both have acceptable DILI risk (A: 60.527, B: 52.385), with Ligand B being slightly better.

**BBB:** Ligand A has a high BBB percentile (81.466), which isn't crucial for a non-CNS target like SRC. Ligand B has a very low BBB percentile (12.602).

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-4.929), which is concerning and suggests poor permeability. Ligand B also has a negative value (-5.687), also concerning.

**Aqueous Solubility:** Ligand A has a very poor aqueous solubility (-5.868). Ligand B has a slightly better, but still poor solubility (-2.802).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.611, B: 0.454).

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (53.078 mL/min/kg). Ligand B has a much lower clearance (30.482 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a short half-life (3.176 hours). Ligand B has a negative half-life (-13.197 hours), which is not physically possible and likely indicates a data error or a very rapidly metabolized compound.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.633, B: 0.13).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.4 kcal/mol) than Ligand A (-7.9 kcal/mol). While both are good, the 0.5 kcal/mol difference is significant.

**Conclusion:**

Despite the slightly higher logP, Ligand B is the more promising candidate. It has better metabolic stability (lower Cl_mic), a slightly better binding affinity, and a lower DILI risk. The negative half-life for Ligand B is a significant concern, but the other factors outweigh this. Ligand A's poor solubility and permeability are major drawbacks, despite its higher BBB penetration (which is irrelevant for SRC).

Output:
1
2025-04-17 16:47:07,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (357.382 and 353.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.09) is higher than Ligand B (62.73). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.454) is quite low, potentially hindering permeability. Ligand B (4.751) is high, bordering on problematic for solubility and off-target effects.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar, good QED values (0.672 and 0.693).

**DILI:** Ligand A (42.924) has a much lower DILI risk than Ligand B (83.637). This is a significant advantage for Ligand A.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (80.768) is better than Ligand B (67.158).

**Caco-2 Permeability:** Ligand A (-4.696) has a very poor Caco-2 value, indicating poor intestinal absorption. Ligand B (-5.047) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.905) has poor solubility, while Ligand B (-5.015) is even worse. Both are concerning.

**hERG:** Ligand A (0.226) has a lower hERG risk than Ligand B (0.644), which is a significant advantage.

**Microsomal Clearance:** Ligand A (17.966) has a lower Cl_mic, suggesting better metabolic stability than Ligand B (83.609).

**In vitro Half-Life:** Ligand B (55.217) has a much longer in vitro half-life than Ligand A (-2.226), a substantial advantage.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.312).

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-8.0).  The difference is 0.2 kcal/mol, which is not a huge difference, but still favors Ligand B.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG, metabolic stability (Cl_mic), and P-gp efflux. However, its very poor Caco-2 permeability and solubility are major drawbacks. Ligand B has a superior binding affinity and a much longer half-life, but suffers from higher DILI risk, higher hERG risk, and poor solubility.

Given the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG risk), the stronger binding affinity and significantly improved half-life of Ligand B are compelling. While the higher DILI and hERG risks are concerning, these can potentially be addressed through further structural modifications. The poor solubility of both compounds is a concern, but could be addressed with formulation strategies. The poor permeability of Ligand A is a more difficult issue to resolve.

Output:
1
2025-04-17 16:47:07,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (381.416 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is better than Ligand B (84.23), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.306 and 3.188), 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:** Both ligands have good QED scores (0.787 and 0.827), indicating good drug-likeness.

**DILI:** Ligand A (55.913) has a lower DILI risk than Ligand B (61.884), both are acceptable but A is preferable.

**BBB:** Ligand A (79.217) has a higher BBB penetration percentile than Ligand B (55.293). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.732) has a slightly better Caco-2 permeability than Ligand B (-5.003), though both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.21) has slightly better aqueous solubility than Ligand B (-4.971), both are negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.669) has a lower hERG inhibition liability than Ligand B (0.243), which is a significant advantage. Lower hERG risk is crucial.

**Microsomal Clearance:** Ligand A (39.585) has a lower microsomal clearance than Ligand B (48.021), indicating better metabolic stability. This is a key consideration for enzyme targets.

**In vitro Half-Life:** Ligand B (55.426) has a longer in vitro half-life than Ligand A (21.614). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux liability than Ligand B (0.131). Lower P-gp efflux is preferable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is preferable. While Ligand B has a slightly longer half-life, Ligand A demonstrates advantages in several critical areas: lower DILI risk, better solubility, significantly lower hERG inhibition liability, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. The similar binding affinities make these ADME properties the deciding factors.

Output:
0
2025-04-17 16:47:07,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.392 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.64 and 67.23) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.636 and 2.594) 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.723 and 0.699), indicating good drug-likeness.

**DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (23.226). This is a major advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (82.513) has a slightly higher BBB percentile than Ligand B (76.309).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.079 and -4.827), which is unusual and suggests poor permeability. However, these values are on a log scale and need careful interpretation.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.617 and -2.48), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.526) has a slightly higher hERG inhibition risk than Ligand B (0.393), but both are relatively low.

**Microsomal Clearance:** Ligand A (-0.821) exhibits significantly lower microsomal clearance than Ligand B (64.198). This suggests much better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-9.082) has a much longer in vitro half-life than Ligand B (-2.365), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux liability than Ligand B (0.26), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a crucial advantage, as a 1.8 kcal/mol difference is substantial.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower P-gp efflux, and, most importantly, a substantially stronger binding affinity. The improved affinity outweighs the potential drawbacks of the solubility and permeability issues.

Output:
1
2025-04-17 16:47:07,314 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.381, 59.5, 2.621, 0, 4, 0.785, 38.503, 97.945, -4.024, -3.431, 0.454, 77.29, -17.611, 0.191, -7.8]
**Ligand B:** [354.447, 84.94, 1.518, 1, 5, 0.553, 45.366, 73.827, -4.744, -2.397, 0.224, 51.189, -27.409, 0.034, -6.6]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A: 352.381, B: 354.447 - No significant difference.
2. **TPSA:** Ligand A (59.5) is better than Ligand B (84.94). Lower TPSA generally favors oral absorption.
3. **logP:** Ligand A (2.621) is optimal, while Ligand B (1.518) is on the lower side, potentially impacting permeability.
4. **HBD:** Ligand A (0) is preferred over Ligand B (1). Fewer HBDs generally improve permeability.
5. **HBA:** Ligand A (4) is better than Ligand B (5). Lower HBA also favors permeability.
6. **QED:** Ligand A (0.785) has a significantly better drug-likeness score than Ligand B (0.553).
7. **DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (45.366), indicating a safer profile.
8. **BBB:** Ligand A (97.945) shows excellent BBB penetration, while Ligand B (73.827) is good, but not as high. While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.
9. **Caco-2:** Both are negative, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.
10. **Solubility:** Both are negative, again making interpretation difficult.
11. **hERG:** Both ligands have low hERG risk (A: 0.454, B: 0.224).
12. **Cl_mic:** Ligand A (77.29) has a higher microsomal clearance than Ligand B (51.189), indicating faster metabolism and potentially lower *in vivo* exposure.
13. **t1/2:** Ligand B (-27.409) has a significantly longer *in vitro* half-life than Ligand A (-17.611), which is a major advantage for dosing frequency.
14. **Pgp:** Ligand A (0.191) has lower P-gp efflux than Ligand B (0.034), which is a positive.
15. **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 is a significant advantage.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand A has a much better binding affinity, but Ligand B has a significantly better half-life. The difference in affinity is substantial enough to outweigh the faster clearance of Ligand A.

**Conclusion:**

While Ligand B has a better half-life, the significantly stronger binding affinity of Ligand A, coupled with its superior drug-likeness, lower DILI risk, and better BBB penetration, makes it the more promising candidate. The lower half-life of Ligand A can potentially be addressed through structural modifications during lead optimization.

1
2025-04-17 16:47:07,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.359 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.85) is close to the 140 threshold, while Ligand B (98.17) is well below. Both are acceptable, but B is slightly better for absorption.

**logP:** Ligand A (-0.602) is a bit low, potentially hindering permeation. Ligand B (3.256) is optimal. This is a significant advantage for B.

**H-Bond Donors & Acceptors:** Ligand A (4 HBD, 7 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 similar, moderately low QED values (0.481 and 0.372). This isn't a major concern at this stage, but improvement would be desirable.

**DILI:** Ligand A (54.323) has a moderate DILI risk, while Ligand B (22.838) has a low risk. This favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (64.715) is higher than Ligand A (36.371), but it's not a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.079 and -4.642), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands exhibit poor aqueous solubility (-1.62 and -2.432). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.046) has a very low hERG risk, which is excellent. Ligand B (0.287) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (28.583) has lower clearance than Ligand B (36.773), suggesting better metabolic stability. This is a positive for A.

**In vitro Half-Life:** Ligand A (-31.49) has a negative half-life, which is not possible and likely indicates a data error or a very rapidly metabolized compound. Ligand B (11.551) has a reasonable half-life. This is a major advantage for B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.011 and 0.042), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly better binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility and permeability issues, Ligand B has a much better logP, lower DILI risk, a reasonable half-life, and, crucially, a significantly improved binding affinity. The negative half-life for Ligand A is a major concern, and even ignoring that, the superior binding affinity of B is likely to be decisive. The slightly better metabolic stability of A is not enough to overcome the other advantages of B.



Output:
1
2025-04-17 16:47:07,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (383.279 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.04) is excellent, well below the 140 threshold. Ligand B (96.7) is still acceptable but higher, potentially impacting absorption.

**logP:** Ligand A (3.429) is at the upper end of the optimal range (1-3), while Ligand B (0.787) is slightly below, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, fitting the guidelines. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.796 and 0.682), indicating good drug-likeness.

**DILI:** Ligand A (60.14) is at the upper limit of acceptable DILI risk, while Ligand B (31.563) shows a much lower and preferable risk.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (81.97) has a higher percentile than Ligand B (67.701).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.455 and -4.82), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.646 and -1.074), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Ligand A (0.599) has a slightly higher hERG risk than Ligand B (0.177), making B more favorable.

**Microsomal Clearance:** Ligand A (56.985) has a higher Cl_mic than Ligand B (19.84), indicating faster metabolism and lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-8.604) has a significantly longer half-life than Ligand A (10.35), which is highly desirable.

**P-gp Efflux:** Ligand A (0.181) has lower P-gp efflux liability than Ligand B (0.053), which is slightly better.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.7 kcal/mol), although both are quite good. The 1.2 kcal/mol difference is substantial enough to be a deciding factor.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer half-life), a slightly better binding affinity, and lower hERG risk. The slightly lower logP is a minor concern compared to the advantages in safety and pharmacokinetics.

Output:
1
2025-04-17 16:47:07,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.347 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (139.89) is borderline acceptable for oral absorption, while Ligand B (75.71) is well within the ideal range (<140). This favors Ligand B.

**logP:** Ligand A (-0.942) is a bit low, potentially hindering permeation. Ligand B (1.751) is within the optimal range (1-3). 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 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.528, B: 0.839), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (60.217) is approaching a concerning DILI risk, while Ligand B (48.313) is better.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B has a higher BBB percentile (70.648) than Ligand A (27.026), but this isn't a deciding factor.

**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 (0.103) has a slightly better hERG profile than Ligand B (0.373), which is a positive.

**Microsomal Clearance:** Ligand A (-31.334) has a much *lower* (better) microsomal clearance than Ligand B (46.125), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-9.194) has a negative half-life which is unusual. Ligand B (-13.225) is also negative.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**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.

**Overall Assessment:**

Ligand B has advantages in TPSA, logP, QED, and DILI. However, Ligand A has a significantly better microsomal clearance, and a slightly better binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the metabolic stability offered by Ligand A is crucial for an enzyme target. The slightly better binding affinity of Ligand A further strengthens its position. Given the enzyme-specific priorities, metabolic stability is paramount, and Ligand A excels in this area.

Output:
0
2025-04-17 16:47:07,315 - INFO - Batch 492 complete. Total preferences: 7872
2025-04-17 16:47:07,315 - INFO - Processing batch 493/512...
2025-04-17 16:47:55,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.439 Da and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (83.99 and 82.53) below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.169) is within the optimal 1-3 range. Ligand B (2.548) is also within the optimal range, but closer to the upper limit.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.747 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.568%, which is considered high risk. Ligand B has a significantly lower DILI risk of 35.595%, which is good. This is a major advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (89.104%) has a higher BBB penetration than Ligand B (54.285%).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.497 and -4.537). 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 (-3.385 and -2.346). This is also unusual and suggests poor solubility, but the scale is not defined, so it's hard to interpret.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.401 and 0.435).

**Microsomal Clearance:** Ligand A (61.519) and Ligand B (57.291) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (21.16 hours) has a significantly longer half-life than Ligand A (-5.751 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 (0.087 and 0.08).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 kcal/mol). This difference of 1.5 kcal/mol is significant and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the superior binding affinity, lower DILI risk, and longer half-life of Ligand B make it the more promising drug candidate. The strong binding affinity is a critical factor for an enzyme inhibitor, and the reduced DILI risk is a significant safety advantage.

Output:
1
2025-04-17 16:47:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (334.394 Da and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (26.71) is excellent, well below the 140 threshold for oral absorption. Ligand B (71) is still reasonable, but higher, potentially impacting absorption.

**3. logP:** Ligand A (4.69) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.941) is within the optimal range.

**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 acceptable.

**6. QED:** Both ligands have good QED scores (0.753 and 0.826), indicating drug-like properties.

**7. DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (33.773). This is a significant concern.

**8. BBB:** Both ligands have reasonable BBB penetration (66.344 and 63.784), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -4.723). 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 ligands have negative solubility values (-5.186 and -3.166), indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.959) shows a slightly higher hERG risk than Ligand B (0.188).

**12. Microsomal Clearance:** Ligand A (92.685) has a significantly higher microsomal clearance than Ligand B (19.494), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-28.383) has a very short in vitro half-life, while Ligand B (0.126) is also short but better than A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.767 and 0.158).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. Ligand B excels in affinity, has significantly better metabolic stability, lower DILI risk, and lower hERG risk. While both have solubility concerns, the superior binding affinity and ADME profile of Ligand B outweigh the solubility issue, which can be addressed through formulation. The poor permeability is a concern for both, but the strong binding of B might compensate.

Output:
1
2025-04-17 16:47:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.435 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (96.17 and 91.64) below 140, suggesting reasonable oral absorption potential.

**logP:** Ligand A (1.324) is within the optimal 1-3 range. Ligand B (-0.02) is slightly below 1, which *could* indicate a potential permeability issue, although it's not dramatically low.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 7 HBAs and Ligand B has 5 HBAs, both acceptable (<=10).

**QED:** Both ligands have QED values (0.665 and 0.56) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (35.944). This is a significant concern.

**BBB:** Both ligands have low BBB penetration (40.946 and 30.593), which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.164 and -5.177). This 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 (-1.345 and -0.894). This is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.178 and 0.157), which is excellent.

**Microsomal Clearance:** Ligand A (-2.176) has a *negative* microsomal clearance, which is not physically possible and indicates an issue with the data or model. Ligand B (20.539) has a moderate clearance.

**In vitro Half-Life:** Ligand A (30.197 hours) has a better in vitro half-life than Ligand B (-6.954 hours). Again, the negative value for ligand B is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.063), which is favorable.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly better binding affinity than Ligand B (-7.5 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the questionable negative values for Caco-2, solubility, and clearance for both ligands, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -7.5 kcal/mol) is a major advantage for an enzyme target. While Ligand A has a higher DILI risk, the difference isn't extreme, and the negative clearance value is likely an artifact of the prediction. Ligand B's negative half-life is a red flag. The slightly better logP of Ligand A is also a minor benefit.

Output:
1
2025-04-17 16:47:55,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.463 and 368.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.89) is better than Ligand B (67.35), both are below the 140 threshold for oral absorption.

**logP:** Ligand B (2.048) is optimal (1-3), while Ligand A (0.336) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better.

**H-Bond Acceptors:** Ligand A (5) is acceptable, while Ligand B (6) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.476 and 0.587), indicating drug-like properties, with Ligand B being slightly better.

**DILI:** Ligand A (15.238) has a significantly lower DILI risk than Ligand B (47.654). This is a major advantage for Ligand A.

**BBB:** Ligand B (77.084) has a better BBB penetration score than Ligand A (35.595), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.019 and -4.986), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.218 and -3.321), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.148) has a lower hERG risk than Ligand B (0.479), which is favorable.

**Microsomal Clearance:** Ligand A (42.318) has lower microsomal clearance than Ligand B (57.641), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.253) has a much longer in vitro half-life than Ligand B (3.245). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.035) has lower P-gp efflux than Ligand B (0.077), which is favorable.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.5), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A has several advantages: lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity and BBB penetration, the ADME properties of Ligand A are significantly more favorable, especially the lower DILI and better metabolic stability. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. Given the enzyme-kinase target class, prioritizing metabolic stability and minimizing toxicity (DILI, hERG) is crucial.

Output:
0
2025-04-17 16:47:55,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.439 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is slightly higher than Ligand B (87.58), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.255 and 1.482), falling within the 1-3 optimal range.

**H-Bond Donors:** Both 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 below the 10 limit.

**QED:** Both ligands have similar QED scores (0.805 and 0.807), indicating good drug-likeness.

**DILI:** Ligand A (43.66) has a significantly lower DILI risk than Ligand B (63.707). This is a crucial advantage.

**BBB:** Ligand B (62.97) has a higher BBB penetration score than Ligand A (12.408). However, since SRC is not a CNS target, this is less important.

**Caco-2 Permeability:** Ligand A (-5.447) shows poor Caco-2 permeability, while Ligand B (-4.91) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.474) has better aqueous solubility than Ligand B (-1.984). This is a positive attribute.

**hERG Inhibition:** Ligand A (0.086) has a much lower hERG inhibition liability than Ligand B (0.562). This is a significant advantage, reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-2.68) has a much lower (better) microsomal clearance than Ligand B (44.941). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (53.516) has a significantly longer in vitro half-life than Ligand A (4.818).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054).

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.0). While a 1.5 kcal/mol advantage is often significant, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and half-life, Ligand A demonstrates significantly better safety profiles (lower DILI and hERG) and better metabolic stability (lower Cl_mic). The poor Caco-2 permeability of Ligand A is a concern, but can potentially be addressed through formulation strategies. The combination of improved safety and metabolic stability outweighs the minor binding affinity difference.

Output:
0
2025-04-17 16:47:55,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.351 and 379.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.79) is slightly above the optimal <140, but acceptable. Ligand B (86.36) is excellent, well below 140.

**logP:** Ligand A (0.422) is quite low, potentially hindering permeability. Ligand B (1.58) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.811 and 0.725), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (92.982), which is a significant concern. Ligand B has a much lower DILI risk (35.75), a major advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (72.315) than Ligand A (22.412), but it's not a deciding factor here.

**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 are percentile scores, and lower values indicate poorer permeability. Ligand A (-5.113) is worse than Ligand B (-5.288).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.838 and -2.555). This is a concern, but potentially addressable through formulation.

**hERG Inhibition:** Ligand A (0.108) has a slightly higher hERG risk than Ligand B (0.273), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.347) has a much lower (better) microsomal clearance than Ligand B (-21.6). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (66) has a significantly longer half-life than Ligand B (-13.715). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.032) has lower P-gp efflux than Ligand B (0.017), which is favorable.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks. The difference of 1.7 kcal/mol is substantial.

**Overall Assessment:**

Ligand B's superior binding affinity is the most important factor. While its solubility and Caco-2 permeability are concerning, the strong binding could compensate. The significantly lower DILI risk of Ligand B is also a major advantage, outweighing the better metabolic stability and half-life of Ligand A. Ligand A's high DILI risk is a deal-breaker.

Output:
1
2025-04-17 16:47:55,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.5 and 353.8 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.88) is slightly higher than Ligand B (62.53). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Both ligands have good logP values (3.47 and 3.70), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the guidelines.

**QED:** Both ligands have good QED scores (0.853 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A (72.82) has a lower DILI risk than Ligand B (90.73), which is a significant advantage.

**BBB:** Both have high BBB penetration (78.21 and 84.06), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.75 and -4.86).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-5.6) is slightly worse than Ligand A (-4.4).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.569 and 0.474), which is good.

**Microsomal Clearance:** Ligand B (91.16) has a significantly higher microsomal clearance than Ligand A (46.73), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-9.99) has a longer in vitro half-life than Ligand B (31.24), further supporting better metabolic stability for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.252 and 0.498).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). The difference is 1.4 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate due to its significantly better metabolic stability (lower Cl_mic and longer t1/2) and lower DILI risk. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies. The difference in binding affinity, while notable, is outweighed by the ADME/Tox advantages of Ligand A, especially considering SRC is an enzyme target where metabolic stability is crucial.

Output:
0
2025-04-17 16:47:55,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.435 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.84) is slightly higher than Ligand B (70.08). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (1.331 and 1.058), 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 similar and good QED scores (0.705 and 0.727), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 38.852, which is good (below 40). Ligand B has a significantly lower DILI risk of 15.626, which is excellent.

**BBB:** Both ligands have relatively low BBB penetration (62.854 and 37.767). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.396) has worse Caco-2 permeability than Ligand B (-4.493).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.352 and -1.143). This could be a formulation challenge, but not a deal-breaker if other properties are strong.

**hERG Inhibition:** Ligand A (0.25) has a slightly higher hERG risk than Ligand B (0.172), but both are relatively low.

**Microsomal Clearance:** Ligand A (17.551 mL/min/kg) has significantly lower microsomal clearance than Ligand B (36.185 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.889 hours) has a much longer in vitro half-life than Ligand B (0.004 hours). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux than Ligand B (0.042), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

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 (-7.7 vs -9.1 kcal/mol) outweighs these advantages. The lower DILI risk for Ligand B is also a positive factor. The slightly better TPSA and Caco-2 permeability of Ligand B are also beneficial. Although both have poor solubility, the potency advantage of Ligand B is likely to be more impactful in driving forward development.

Output:
1
2025-04-17 16:47:55,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.435 and 382.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.97) is better than Ligand B (97.12), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-1.184) is slightly low, potentially hindering permeability. Ligand B (2.846) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, below the threshold of 10.

**QED:** Ligand B (0.8) is significantly better than Ligand A (0.52), indicating a more drug-like profile.

**DILI:** Ligand A (5.894) has a much lower DILI risk than Ligand B (77.2), which is quite high. This is a significant advantage for Ligand A.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand B (50.64) is higher than Ligand A (35.014), but this isn't a major factor here.

**Caco-2 Permeability:** Ligand A (-6.002) is very poor, while Ligand B (-5.081) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.871) is poor, while Ligand B (-3.453) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.132) has a very low hERG risk, while Ligand B (0.191) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-21.71) has a much lower (better) microsomal clearance than Ligand B (30.302), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-16.381) has a longer half-life than Ligand B (2.784), which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.001 and 0.248 respectively), which is good.

**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, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has better safety (DILI, hERG) and pharmacokinetic properties (Cl_mic, t1/2), but suffers from poor solubility, permeability, and *very* weak binding affinity. Ligand B has excellent binding affinity, good QED, and reasonable logP, but has a high DILI risk and poor solubility.

The difference in binding affinity is substantial (>7 kcal/mol difference). For an enzyme target, potency is paramount. While the DILI risk for Ligand B is concerning, it might be mitigated through structural modifications in later stages of optimization. The poor ADME properties of Ligand A, especially the extremely weak binding, make it a less promising starting point.

Output:
1
2025-04-17 16:47:55,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (362.821 Da and 351.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (100.94) is better than Ligand B (120.67), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.301) is optimal (1-3), while Ligand B (1.136) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=6) and Ligand B (HBD=4, HBA=5) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar, relatively low QED values (0.416 and 0.393), indicating room for improvement in drug-likeness.

**DILI:** Ligand A (85.576) has a higher DILI risk than Ligand B (46.762). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (61.807) has a slightly better BBB score than Ligand A (50.097).

**Caco-2 Permeability:** Ligand A (-4.955) has better Caco-2 permeability than Ligand B (-5.403), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.558) has better aqueous solubility than Ligand B (-2.101).

**hERG:** Ligand A (0.076) has a slightly better hERG profile than Ligand B (0.274), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (18.561) has significantly lower microsomal clearance than Ligand A (37.577), suggesting better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (13.527 hours) has a longer half-life than Ligand A (49.138 hours).

**P-gp Efflux:** Ligand A (0.043) shows lower P-gp efflux than Ligand B (0.061).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). The 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has some advantages in solubility, permeability and hERG, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.4 vs -7.8 kcal/mol) and much better metabolic stability (lower Cl_mic and longer half-life) are critical for an enzyme inhibitor. The lower DILI risk for Ligand B is also a major benefit. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization.

Output:
1
2025-04-17 16:47:55,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.4 and 348.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.44) is slightly higher than the preferred <140, but still acceptable. Ligand B (66.48) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.15 and 2.85), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, meeting the criteria of <=5 and <=10 respectively. Ligand B has 1 HBD and 3 HBA, also meeting the criteria.

**QED:** Both ligands have similar and acceptable QED values (0.675 and 0.686), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.09%, which is moderately high. Ligand B has a significantly lower DILI risk of 27.61%, which is much more favorable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (70.61%) shows better BBB penetration than Ligand A (55.80%).

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.86 and -4.62). This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.38 and -2.83). This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.154 and 0.145), which is excellent.

**Microsomal Clearance:** Ligand A (41.57 mL/min/kg) has lower clearance than Ligand B (62.79 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.92 hours) has a longer half-life than Ligand B (-19.25 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.244).

**Binding Affinity:** Ligand B (-8.3 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.

**Conclusion:**

While Ligand A has better metabolic stability and half-life, Ligand B's significantly stronger binding affinity (-8.3 vs -6.7 kcal/mol) and much lower DILI risk are decisive advantages. The poor Caco-2 and solubility are concerns for both, but the potency and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:47:55,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing enzyme-kinase specific properties (potency, metabolic stability, solubility, and hERG risk).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.351 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (128.27) is borderline acceptable for oral absorption, while Ligand B (67.35) is well within the desirable range (<140). This favors Ligand B.

**logP:** Ligand A (0.167) is quite low, potentially hindering permeation. Ligand B (2.86) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 9 HBAs, acceptable. Ligand B has 6 HBAs, also acceptable.

**QED:** Ligand A (0.731) has a better QED score than Ligand B (0.533), indicating a more drug-like profile.

**DILI:** Ligand A (85.576) has a higher DILI risk than Ligand B (44.552). This favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (96.045) shows better BBB penetration, but this is not a primary concern here.

**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 Inhibition:** Ligand A (0.047) has a very low hERG risk, significantly better than Ligand B (0.602). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (34.954) and Ligand B (32.202) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-3.201) has a negative half-life, which is not possible. This is a red flag. Ligand B (6.655) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is good. Ligand B (0.174) has slightly higher 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 the difference is not huge, it is greater than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is superior overall. While Ligand A has a better QED and lower hERG risk, its very low logP, negative half-life, and higher DILI risk are significant drawbacks. Ligand B has a more favorable balance of properties, including a good logP, lower DILI, and a reasonable half-life, and a slightly better binding affinity. The negative half-life for Ligand A is a critical issue.

Output:
1
2025-04-17 16:47:55,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.985 Da) is slightly higher than Ligand B (348.422 Da), but both are acceptable.

**TPSA:** Ligand A (66.91) is slightly higher than Ligand B (58.44). Both are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Ligand A (4.826) is significantly higher than Ligand B (1.16). Ligand A is pushing the upper limit and could potentially have solubility issues or off-target effects. Ligand B is well within the optimal range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**QED:** Both ligands have good QED scores (Ligand A: 0.655, Ligand B: 0.82), indicating drug-like properties.

**DILI:** Ligand A (72.354) has a higher DILI risk than Ligand B (20.783). Ligand B is much preferred here.

**BBB:** Both ligands have good BBB penetration (Ligand A: 70.57, Ligand B: 86.894). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.124) and Ligand B (-4.752) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-5.781) and Ligand B (-0.566) both have negative values, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.438) and Ligand B (0.287) both have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (85.286) has a higher microsomal clearance than Ligand B (11.412). This suggests Ligand B is more metabolically stable, which is a key priority for kinase inhibitors.

**In vitro Half-Life:** Ligand A (70.052) has a longer half-life than Ligand B (-16.317). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.375) has lower P-gp efflux than Ligand B (0.061), which is preferable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.1 kcal/mol, Ligand B: -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly longer half-life and lower P-gp efflux, Ligand B excels in crucial areas for kinase inhibitors: lower DILI risk, significantly better metabolic stability (lower Cl_mic), and a more favorable logP. The solubility and permeability are poor for both, but the other advantages of Ligand B outweigh the slight advantage of Ligand A in half-life and P-gp efflux. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 16:47:55,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (336.391 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.19) is well below the 140 threshold for good absorption, while Ligand B (123.14) is still acceptable but higher.

**logP:** Both ligands have good logP values (2.863 and 1.617), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=3, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.727 and 0.655), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (70.299 and 75.145), which is a concern. However, this is often a trade-off and can be addressed in later optimization stages.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (56.572) is lower than Ligand B (64.599).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.143 and -5.263), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.824 and -3.26), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Ligand A (0.744) has a slightly higher hERG risk than Ligand B (0.575), but both are reasonably low.

**Microsomal Clearance:** Ligand A (37.684) has a higher microsomal clearance than Ligand B (18.242), suggesting lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (38.753 and 37.084 hours), which are acceptable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.409 and 0.091).

**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, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility profiles of both compounds, Ligand B is the superior candidate due to its significantly higher binding affinity (-7.9 kcal/mol vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic). While the DILI risk is high for both, the strong binding of Ligand B suggests it may be more effective at lower doses, potentially mitigating the DILI concern. The solubility and permeability issues will need to be addressed through structural modifications, but the potency advantage of Ligand B makes it a better starting point for optimization.

Output:
1
2025-04-17 16:47:55,782 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [352.475, 78.87, 1.336, 2, 4, 0.646, 27.181, 54.556, -4.71, -2.837, 0.194, 54.043, -2.537, 0.11, -8.1]
**Ligand B:** [348.531, 41.57, 3.351, 1, 3, 0.847, 6.049, 94.184, -4.653, -4.134, 0.705, 41.74, 7.31, 0.055, -8.1]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (352.475) and B (348.531) are very close, no significant difference.
2. **TPSA:** A (78.87) is higher than B (41.57).  Both are below the 140 threshold for oral absorption, but B is significantly better, potentially indicating better permeability.
3. **logP:** A (1.336) is optimal, while B (3.351) is approaching the upper limit. B's higher logP *could* lead to solubility issues or off-target interactions.
4. **HBD:** A (2) and B (1) are both acceptable, well within the limit of 5.
5. **HBA:** A (4) and B (3) are both acceptable, well within the limit of 10.
6. **QED:** A (0.646) is good, while B (0.847) is even better, indicating a more drug-like profile.
7. **DILI:** A (27.181) is excellent (low risk), while B (6.049) is also very good. No significant difference here.
8. **BBB:** A (54.556) is moderate, while B (94.184) is very high. While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.
9. **Caco-2:** Both are negative (-4.71 and -4.653), suggesting poor permeability. This is a concern for both.
10. **Solubility:** A (-2.837) is slightly better than B (-4.134), indicating slightly better aqueous solubility.
11. **hERG:** A (0.194) is very low risk, while B (0.705) is slightly higher but still acceptable. A is preferable here.
12. **Cl_mic:** A (54.043) is higher than B (41.74), meaning B has better metabolic stability. This is a key consideration for kinase inhibitors.
13. **t1/2:** A (-2.537) is better than B (7.31), indicating a longer in vitro half-life. This is a positive for dosing convenience.
14. **Pgp:** A (0.11) is much lower than B (0.055), suggesting less P-gp efflux and better bioavailability.
15. **Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are most important.

*   **Affinity:** Equal.
*   **Metabolic Stability (Cl_mic):** B is better.
*   **Solubility:** A is slightly better.
*   **hERG:** A is better.
*   **t1/2:** A is better.

**Overall Assessment:**

While ligand B has a better QED and BBB, ligand A has superior solubility, hERG profile, and *in vitro* half-life. The significantly lower Pgp efflux for ligand A is also a major advantage. The difference in metabolic stability (Cl_mic) is a concern, but the other advantages of ligand A, particularly the better safety profile (hERG) and longer half-life, outweigh this. The similar Caco-2 values suggest permeability will be a challenge for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:47:55,782 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.433 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold, suggesting good absorption. Ligand B (117.33) is still acceptable but less optimal.

**logP:** Ligand A (2.174) is within the optimal 1-3 range. Ligand B (-0.936) is below 1, which could hinder 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, staying within the suggested limits.

**QED:** Both ligands have similar QED values (0.603 and 0.584), indicating good drug-likeness.

**DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (17.759), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (92.672) has a higher percentile than Ligand B (69.097).

**Caco-2 Permeability:** Ligand A (-4.472) has a lower Caco-2 permeability than Ligand B (-5.733), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.564) has slightly better solubility than Ligand B (-0.969).

**hERG Inhibition:** Ligand A (0.517) has a lower hERG risk than Ligand B (0.049), which is a significant advantage.

**Microsomal Clearance:** Ligand A (14.089 mL/min/kg) has a higher microsomal clearance than Ligand B (3.324 mL/min/kg), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-4.105 hours) has a shorter half-life than Ligand B (-3.85 hours). Both are negative values, indicating very short half-lives.

**P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux than Ligand B (0.005), which is preferable.

**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 substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand A having a better safety profile (lower DILI, lower hERG) and slightly better solubility, Ligand B's significantly superior binding affinity (-8.6 vs -6.6 kcal/mol) is the most critical factor for an enzyme inhibitor. The stronger binding is likely to translate to greater efficacy. While Ligand B has a lower logP and higher DILI, these can potentially be addressed through further optimization without sacrificing the crucial binding affinity. The metabolic stability of Ligand B is also better.

Output:
1
2025-04-17 16:47:55,783 - INFO - Batch 493 complete. Total preferences: 7888
2025-04-17 16:47:55,783 - INFO - Processing batch 494/512...
2025-04-17 16:48:34,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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, but both are acceptable.

**TPSA:** Both ligands have TPSA values (61.44 and 67.87) well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.856) is slightly higher than Ligand B (1.964). While both are within the optimal range (1-3), Ligand B is closer to the lower bound and might have solubility issues.

**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 (0.816 and 0.744), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 66.344%, which is moderately high. Ligand B has a significantly lower DILI risk of 37.65%, which is a considerable advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (88.29%) has a higher BBB score than Ligand B (69.135%), but this isn't a major factor in this comparison.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.647) is slightly better than Ligand B (-5.033).

**Aqueous Solubility:** Ligand A (-5.227) has significantly worse solubility than Ligand B (-2.136). Solubility is important for bioavailability, making Ligand B more favorable.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.338 and 0.247), which is excellent.

**Microsomal Clearance:** Ligand B (28.167 mL/min/kg) has lower microsomal clearance than Ligand A (45.203 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (30.75 and 30.642 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.189 and 0.086), which is favorable.

**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 enough to be considered, especially given the other advantages of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly lower DILI risk, better solubility, and improved metabolic stability (lower Cl_mic). The slightly better binding affinity further supports this conclusion. While Ligand A has a slightly better Caco-2 permeability, the solubility and DILI concerns outweigh this benefit.

Output:
1
2025-04-17 16:48:34,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (363.816 and 351.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.56) is slightly higher than Ligand B (38.77). Both are below the 140 threshold for good oral absorption, but B is significantly better.

**logP:** Both ligands have similar logP values around 3.88-3.89, which is optimal.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable range (<=10).

**QED:** Ligand A (0.817) has a higher QED score than Ligand B (0.633), indicating a more drug-like profile.

**DILI:** Ligand B (10.314) has a much lower DILI risk than Ligand A (59.791). This is a significant advantage for Ligand B.

**BBB:** Ligand B (90.539) has a much higher BBB penetration percentile than Ligand A (62.233). While SRC is not a CNS target, higher BBB generally correlates with better overall permeability.

**Caco-2 Permeability:** Ligand A (-4.982) and Ligand B (-4.744) have similar, and poor, Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.905) and Ligand B (-4.237) have similar, and poor, aqueous solubility.

**hERG Inhibition:** Ligand B (0.847) has a lower hERG inhibition liability than Ligand A (0.333), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand B (100.446) has a significantly higher microsomal clearance than Ligand A (10.5). This means Ligand A is much more metabolically stable.

**In vitro Half-Life:** Ligand B (27.299 hours) has a longer half-life than Ligand A (15.555 hours), which is desirable.

**P-gp Efflux:** Ligand B (0.576) has lower P-gp efflux liability than Ligand A (0.187), which is preferable.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), though the difference is relatively small.

**Overall Assessment:**

Ligand B is superior due to its significantly lower DILI risk, lower hERG inhibition, and better P-gp efflux. While Ligand A has better metabolic stability (lower Cl_mic), the safety profile of Ligand B is more favorable. The slightly better binding affinity of Ligand B further supports its selection. The solubility and Caco-2 permeability are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:48:34,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (356.438 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (93.01) is still under 140, but less optimal than A.

**logP:** Ligand A (2.002) is within the optimal 1-3 range. Ligand B (0.851) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10).

**QED:** Ligand A (0.56) is good, indicating drug-likeness. Ligand B (0.823) is even better.

**DILI:** Ligand A (40.52) is good, with low liver injury risk. Ligand B (49.128) is also acceptable, but slightly higher risk.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (91.663) is higher than Ligand B (55.642).

**Caco-2 Permeability:** Ligand A (-4.676) and Ligand B (-5.238) are both negative, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.817) and Ligand B (-1.443) are both negative, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.465) has very low hERG risk. Ligand B (0.026) has extremely low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (19.881) is higher than Ligand B (8.267), meaning Ligand B has better metabolic stability. Lower Cl_mic is preferred.

**In vitro Half-Life:** Ligand A (-8.738) has a longer half-life than Ligand B (6.475), which is desirable.

**P-gp Efflux:** Ligand A (0.267) has lower P-gp efflux than Ligand B (0.05), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity. While its Caco-2 and solubility are also poor, the strong binding advantage and better metabolic stability (lower Cl_mic) make it the more promising candidate. The lower hERG risk is also a significant benefit. Ligand A has better half-life and P-gp efflux, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 16:48:34,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is slightly higher than Ligand B (67.43). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Ligand A (1.314) is within the optimal 1-3 range. Ligand B (3.173) is at the higher end of optimal, 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 acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.677 and 0.659), indicating good drug-likeness.

**DILI:** Ligand A (18.418) has a lower DILI risk than Ligand B (15.2), which is preferable.

**BBB:** Ligand B (71.656) has a higher BBB penetration percentile than Ligand A (43.854). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.698) has worse Caco-2 permeability than Ligand B (-4.53).

**Aqueous Solubility:** Ligand A (-1.386) has better aqueous solubility than Ligand B (-3.128). Solubility is important for bioavailability, making Ligand A slightly better.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.276 and 0.483), which is good.

**Microsomal Clearance:** Ligand A (33.052) has significantly lower microsomal clearance than Ligand B (65.321). Lower clearance indicates better metabolic stability, a key factor for enzymes.

**In vitro Half-Life:** Ligand A (-6.151) has a longer in vitro half-life than Ligand B (-19.506). This is also a strong advantage for Ligand A.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.135 and 0.212).

**Binding Affinity:** Both ligands have identical binding affinities (-9.2 kcal/mol), which is excellent.

**Conclusion:**

While Ligand B has slightly better Caco-2 permeability and BBB penetration, Ligand A is superior due to its significantly better metabolic stability (lower Cl_mic), longer half-life, and better aqueous solubility, and lower DILI risk. The binding affinity is the same for both, so the ADME properties become the deciding factors. Given the enzyme-specific priorities, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 16:48:34,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.14) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (67.23) is well within the ideal range.

**logP:** Ligand A (0.72) is a little low, potentially impacting permeability. Ligand B (2.224) is within the optimal 1-3 range.

**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 good QED scores (0.613 and 0.805), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 77.898, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 29.236, a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (66.809) has a higher BBB score than Ligand A (41.218), but this is not a major deciding factor.

**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 Inhibition:** Both ligands have low hERG inhibition risk (0.12 and 0.219), which is positive.

**Microsomal Clearance:** Ligand A (11.024) has lower microsomal clearance, indicating better metabolic stability, which is a key priority for enzymes. Ligand B (19.489) has higher clearance.

**In vitro Half-Life:** Ligand A (10.667) has a longer half-life than Ligand B (-3.358). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.052).

**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 small.

**Overall Assessment:**

Ligand B has a much better safety profile (lower DILI) and a slightly better binding affinity. However, Ligand A exhibits better metabolic stability (lower Cl_mic) and a longer half-life. Given the enzyme target class, metabolic stability and half-life are crucial. The DILI risk associated with Ligand A is a significant concern, but could potentially be mitigated through structural modifications. The slight advantage in binding affinity of Ligand B is unlikely to outweigh the metabolic concerns of Ligand A.

Output:
1
2025-04-17 16:48:34,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.407 and 357.449 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.35) is better than Ligand B (56.07), both are well below the 140 threshold for oral absorption.

**logP:** Ligand A (3.969) is slightly higher than Ligand B (2.854), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). While both are acceptable, a small number of HBDs can improve solubility.

**H-Bond Acceptors:** Ligand B (6) is better than Ligand A (4). Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.781 and 0.603), indicating good drug-likeness.

**DILI:** Ligand B (14.308) is significantly better than Ligand A (50.33), indicating a much lower risk of drug-induced liver injury. This is a major advantage for Ligand B.

**BBB:** Ligand B (98.333) is much better than Ligand A (32.416). While SRC is not a CNS target, higher BBB penetration can sometimes correlate with better overall bioavailability.

**Caco-2 Permeability:** Ligand A (-4.806) is slightly better than Ligand B (-4.547). Both are negative, which is not ideal, but still within a reasonable range.

**Aqueous Solubility:** Ligand A (-5.284) is slightly better than Ligand B (-3.74). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.678) is slightly better than Ligand B (0.516), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (42.107) is significantly better than Ligand A (89.114), indicating greater metabolic stability. This is a crucial advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (-5.862) is significantly better than Ligand A (0.055), indicating a longer half-life.

**P-gp Efflux:** Ligand B (0.213) is better than Ligand A (0.141), indicating lower P-gp efflux.

**Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-7.5). This 1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While Ligand A has slightly better solubility and hERG inhibition, Ligand B excels in critical areas for an enzyme inhibitor: significantly better DILI risk, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and, most importantly, a much stronger binding affinity. The improved binding affinity is a key driver, and the better ADME properties further solidify its potential.

Output:
1
2025-04-17 16:48:34,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (338.411 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.68) is significantly better than Ligand B (84.67). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (0.955 and 1.305), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED scores (0.804 and 0.784), indicating good drug-likeness.

**DILI:** Both ligands have similar and acceptable DILI risk (47.034 and 48.662 percentile).

**BBB:** Both ligands have low BBB penetration (49.826 and 55.176 percentile), which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.996), which is unusual and requires further investigation. However, we can proceed with relative comparison.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.629 and -2.104), which is also unusual and requires further investigation.

**hERG Inhibition:** Ligand A (0.411) has a much lower hERG inhibition liability than Ligand B (0.086), a significant advantage.

**Microsomal Clearance:** Ligand A (-9.97 mL/min/kg) shows significantly better metabolic stability (lower clearance) than Ligand B (34.049 mL/min/kg). This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-10.229 hours) has a better in vitro half-life than Ligand B (-18.681 hours).

**P-gp Efflux:** Ligand A (0.006) has lower P-gp efflux liability than Ligand B (0.065).

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol). This difference in binding affinity is substantial.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. It exhibits better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, better binding affinity, and more favorable TPSA. While both have unusual solubility and Caco-2 values, the other advantages of Ligand A outweigh these concerns. The substantial difference in binding affinity (-7.3 vs 0.0 kcal/mol) is particularly important for an enzyme target, and the improved metabolic stability is crucial for *in vivo* efficacy.

Output:
1
2025-04-17 16:48:34,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (355.435 and 380.438 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (120.25) is slightly above the optimal <140, while Ligand B (102.01) is well within. This favors Ligand B for absorption.

**logP:** Ligand A (0.074) is quite low, potentially hindering permeation. Ligand B (-0.717) is also low, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, within acceptable limits. Ligand B has 1 HBD and 6 HBA, also within limits.

**QED:** Ligand B (0.626) has a significantly better QED score than Ligand A (0.397), indicating a more drug-like profile.

**DILI:** Ligand A (35.285) has a much lower DILI risk than Ligand B (49.166), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (73.711) has a higher BBB percentile than Ligand A (23.11), but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.305) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.984) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.958) has poor solubility, while Ligand B (-1.273) is also poor, but slightly better.

**hERG:** Ligand A (0.153) has a lower hERG risk than Ligand B (0.272), which is a positive.

**Microsomal Clearance:** Ligand B (-7.928) has a much lower (better) microsomal clearance than Ligand A (-2.577), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-6.862) has a longer in vitro half-life than Ligand A (13.561), which is also favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.023 respectively).

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-6.7), a difference of 0.9 kcal/mol. While a 1.5 kcal/mol advantage is considered significant, 0.9 kcal/mol is less impactful, especially given the other ADME concerns.

**Overall Assessment:**

Ligand B is superior due to its better QED, significantly improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better Caco-2 and solubility. While Ligand A has a slightly better binding affinity, the ADME profile of Ligand B is much more promising for development as a drug candidate. The lower DILI risk of Ligand A is a positive, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 16:48:34,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.391 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is slightly above the optimal <140 for oral absorption, while Ligand B (96.97) is well within the range.

**logP:** Ligand A (0.583) is a bit low, potentially hindering permeation. Ligand B (-0.327) is even lower, raising more concerns about permeability.

**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 similar QED values (0.687 and 0.59), indicating reasonable drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.917, which is moderately high. Ligand B has a much lower DILI risk of 9.461, a significant advantage.

**BBB:** Both ligands have similar BBB penetration (63.862 and 67.584), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.877) and Ligand B (-5.029) both have very poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-2.789) and Ligand B (-1.299) both have poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.098 and 0.096), which is excellent.

**Microsomal Clearance:** Ligand A (42.656) has a moderate microsomal clearance, while Ligand B (-1.608) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**In vitro Half-Life:** Ligand A (21.546 hours) has a reasonable half-life. Ligand B (-12.821 hours) has a negative half-life, which is impossible and indicates an issue with the data or model.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.001).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). However, the difference is not substantial enough to overcome the other significant drawbacks of Ligand A.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising candidate. The significantly lower DILI risk and exceptionally low (and likely erroneous) microsomal clearance and half-life suggest superior safety and metabolic stability. The poor Caco-2 and solubility are concerns for both, but can be addressed through formulation strategies. The negative half-life for ligand B is a data quality issue, but the negative clearance is a strong indicator of metabolic stability.

Output:
1
2025-04-17 16:48:34,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (395.561 and 375.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.83) is slightly above the preferred <140, but acceptable. Ligand B (66.32) is well within the range.

**logP:** Ligand A (0.471) is a bit low, potentially hindering permeability. Ligand B (2.834) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is good. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.675 and 0.754), indicating drug-like properties.

**DILI:** Ligand A (47.615) has a lower DILI risk than Ligand B (54.478), both are acceptable.

**BBB:** Ligand A (78.209) has a better BBB penetration than Ligand B (29.934), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.826) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.32) also has poor Caco-2 permeability, but is slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.35 and -2.953). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.5) has a slightly higher hERG risk than Ligand B (0.323), but both are relatively low.

**Microsomal Clearance:** Ligand A (39.271) has a lower microsomal clearance, suggesting better metabolic stability, which is crucial for kinase inhibitors. Ligand B (60.834) has higher clearance.

**In vitro Half-Life:** Ligand A (-11.551) has a negative half-life, which is concerning and likely an error or indicates very rapid degradation. Ligand B (11.032) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.061 and 0.269), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor.

**Conclusion:**

Despite Ligand A having slightly better DILI and BBB, the significantly stronger binding affinity of Ligand B (-7.9 kcal/mol vs 0.0 kcal/mol) and its better in vitro half-life outweigh the drawbacks of slightly higher DILI and lower BBB. The poor Caco-2 permeability is a concern for both, but can be addressed. Ligand A's negative half-life is a major red flag. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:48:34,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.475 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.92) is well below the 140 threshold, while Ligand B (76.02) is also acceptable, though slightly higher.

**logP:** Ligand A (4.81) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.024) is at the lower end of the optimal range, which could affect 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 4, both within the acceptable limit of 10.

**QED:** Ligand A (0.734) has a better QED score than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Ligand A (58.976) has a higher DILI risk than Ligand B (37.456), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (82.513) has a higher BBB score than Ligand B (48.313).

**Caco-2:** Both ligands have negative Caco-2 values (-4.777 and -4.933), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.1 and -2.456). This is a major drawback.

**hERG:** Ligand A (0.747) has a slightly higher hERG risk than Ligand B (0.086), which is preferable.

**Microsomal Clearance:** Ligand A (100.622) has significantly higher microsomal clearance than Ligand B (6.104), indicating lower metabolic stability. This is a substantial negative for Ligand A.

**In vitro Half-Life:** Ligand B (-7.355) has a negative half-life, which is not possible. This is a data error, and we can't rely on this value. Ligand A (27.787) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.405) has lower P-gp efflux than Ligand B (0.039), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand B is the better candidate despite the questionable half-life data. Its lower DILI risk, significantly better metabolic stability (lower Cl_mic), and lower hERG risk are crucial advantages for an enzyme target. While its logP is lower and solubility is poor, the superior safety profile and metabolic stability outweigh these drawbacks. The small difference in binding affinity is not enough to favor Ligand A, especially considering its higher DILI and clearance. The poor Caco-2 and solubility of both compounds are concerning and would require significant optimization.

Output:
1
2025-04-17 16:48:34,913 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.531 and 382.448 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, suggesting good absorption. Ligand B (75.27) is also acceptable, but higher.

**logP:** Both ligands have logP values within the optimal range (A: 4.056, B: 2.642). Ligand A is slightly higher, which *could* present solubility challenges, but isn't a major concern at this level.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) 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 acceptable QED values (A: 0.762, B: 0.602), indicating generally drug-like properties.

**DILI:** Ligand A (22.024) has a significantly lower DILI risk than Ligand B (44.591). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (A: 84.529, B: 80.574), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.625 and -4.864), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.444 and -4.235), indicating very poor aqueous solubility. This is a major concern for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.505, B: 0.561).

**Microsomal Clearance:** Ligand A (68.272) has a higher microsomal clearance than Ligand B (50.2), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-31.667) has a much longer in vitro half-life than Ligand A (-11.208), which is a substantial advantage for dosing considerations.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.38, B: 0.146), which is favorable.

**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 of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-7.9 vs 0.0 kcal/mol) is a critical advantage for an enzyme inhibitor. The longer half-life and lower DILI risk also contribute to its favorability. While Ligand A has a lower DILI risk, the dramatic difference in binding affinity makes Ligand B the better choice. Further work would be needed to address the solubility and permeability issues, but the potency of Ligand B provides a strong starting point.

Output:
1
2025-04-17 16:48:34,913 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.461 Da) is slightly higher than Ligand B (355.563 Da), but both are acceptable.

**TPSA:** Ligand A (90.54) is borderline, but acceptable for oral absorption. Ligand B (60.77) is excellent.

**logP:** Ligand A (1.001) is optimal. Ligand B (4.134) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=2, HBA=3) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (A: 0.615, B: 0.619), indicating good drug-likeness.

**DILI:** Ligand A (46.336) has a moderate DILI risk, while Ligand B (12.02) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (50.795) and Ligand B (80.69) are both reasonable, with B being better.

**Caco-2 Permeability:** Ligand A (-5.353) has poor Caco-2 permeability, which is a concern. Ligand B (-4.25) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-2.717) has poor aqueous solubility. Ligand B (-3.748) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.28) has a very low hERG risk, which is excellent. Ligand B (0.855) has a moderate hERG risk, which is acceptable but less desirable.

**Microsomal Clearance:** Ligand A (-1.74) has low microsomal clearance, indicating good metabolic stability. Ligand B (71.809) has high microsomal clearance, suggesting rapid metabolism. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-13.041) has a very long in vitro half-life, which is excellent. Ligand B (20.425) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is favorable. Ligand B (0.668) has moderate P-gp efflux.

**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 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 P-gp efflux. While its solubility and Caco-2 permeability are poor, these can potentially be addressed through formulation strategies. Ligand B has a better safety profile (lower DILI), but its weak binding affinity and high metabolic clearance are major concerns. For an enzyme target like SRC kinase, potency and metabolic stability are paramount.

Output:
0
2025-04-17 16:48:34,913 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.471 and 373.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.0) is significantly better than Ligand B (91.76). A TPSA under 140 is good for oral absorption, and A is well within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.707) is optimal, while Ligand B (0.873) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 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 scores (0.759 and 0.657), indicating good drug-likeness.

**DILI:** Ligand A (33.191) has a lower DILI risk than Ligand B (55.487), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (68.748 and 77.782), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.393) shows poor permeability, while Ligand B (-5.016) is even worse. Both are quite poor.

**Aqueous Solubility:** Ligand A (-4.424) has slightly better solubility than Ligand B (-3.3), which is a positive.

**hERG Inhibition:** Both ligands have similar, low hERG risk (0.822 and 0.924).

**Microsomal Clearance:** Ligand A (76.882) has higher microsomal clearance than Ligand B (38.894), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (3.278) has a slightly longer half-life than Ligand A (7.605).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.203 and 0.213).

**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 not huge, it is still a factor.

**Overall Assessment:**

Ligand B is the better candidate. While it has a lower logP and poorer Caco-2 permeability, its significantly lower microsomal clearance (better metabolic stability) and slightly better binding affinity outweigh the drawbacks. Ligand A's higher clearance is a major concern for an enzyme target, as it suggests rapid metabolism and potentially low *in vivo* exposure. The lower DILI risk for Ligand A is a plus, but metabolic stability is more critical for kinase inhibitors.

Output:
1
2025-04-17 16:48:34,913 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (67.87 and 69.64) are below the 140 A^2 threshold for good oral absorption, which is good.

**logP:** Both ligands have logP values (2.302 and 1.815) 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.805) has a significantly better QED score than Ligand A (0.484), indicating a more drug-like profile.

**DILI:** Ligand A (10.896) has a much lower DILI risk than Ligand B (22.993), which is a substantial advantage.

**BBB:** Ligand A (81.698) has a higher BBB penetration percentile than Ligand B (68.205). While not a primary concern for a kinase inhibitor, it's a slight positive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.907 and -5.16), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.833 and -2.084), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.437 and 0.442), which is good.

**Microsomal Clearance:** Ligand A (12.146 mL/min/kg) has a considerably lower microsomal clearance than Ligand B (20.166 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.104 hours) has a much longer in vitro half-life than Ligand B (-1.944 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.052 and 0.337).

**Binding Affinity:** Ligand B (-7.8 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.

**Conclusion:**

Despite the poor Caco-2 permeability and solubility for both compounds, Ligand B is the more promising candidate due to its significantly stronger binding affinity (-7.8 vs -6.2 kcal/mol) and better QED score (0.805 vs 0.484). The improved affinity is a critical factor for an enzyme inhibitor, and the higher QED suggests a generally more favorable drug-like profile. While Ligand A has advantages in DILI risk, metabolic stability, and half-life, the potency of Ligand B is likely to be more impactful. Further optimization would be needed to address the solubility and permeability issues for either compound.

Output:
1
2025-04-17 16:48:34,914 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.391 Da) is slightly higher than Ligand B (350.507 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is well below the 140 threshold and suitable for oral absorption. Ligand B (59.39) is also acceptable, though slightly higher.

**logP:** Ligand A (3.34) is within the optimal range (1-3). Ligand B (2.29) is also within the range, but closer to the lower bound.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable H-bond properties, well within the suggested limits.

**QED:** Both ligands have acceptable QED scores (Ligand A: 0.752, Ligand B: 0.694), indicating good drug-like properties.

**DILI:** Ligand A (46.995) has a moderate DILI risk, but is still acceptable. Ligand B (8.143) has a very low DILI risk, which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (96.355) has better BBB penetration than Ligand B (75.572), but this is not a primary concern.

**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 unspecified.

**hERG Inhibition:** Ligand A (0.786) has a slightly higher hERG risk than Ligand B (0.791), but both are relatively low.

**Microsomal Clearance:** Ligand A (50.127) has a higher microsomal clearance than Ligand B (43.118), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-5.921) has a significantly longer in vitro half-life than Ligand A (-39.088), indicating much better metabolic stability. This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.257) has lower P-gp efflux liability than Ligand B (0.298), which is slightly better.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a very significant advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a much better binding affinity, Ligand B exhibits superior ADME properties, particularly in terms of DILI risk and metabolic stability (half-life). The significantly better binding affinity of Ligand A is a strong point, but the poor metabolic stability and moderate DILI risk are concerning. The large difference in binding affinity (-8.3 vs -0.0) is substantial. Given that SRC is an enzyme, metabolic stability and safety (DILI) are crucial. However, the binding affinity difference is so large that it is likely to overcome the ADME concerns.

Output:
1
2025-04-17 16:48:34,914 - INFO - Batch 494 complete. Total preferences: 7904
2025-04-17 16:48:34,914 - INFO - Processing batch 495/512...
2025-04-17 16:49:14,914 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (357.885 and 348.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.6) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (69.64) is still under 140 but less favorable than A.

**logP:** Ligand A (3.82) is at the upper end of the optimal 1-3 range, while Ligand B (1.701) is towards the lower end. While both are acceptable, a higher logP can sometimes lead to off-target effects, but is less of a concern than poor permeability.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 3 HBA) both satisfy the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.906) has a very strong drug-like profile, significantly better than Ligand B (0.769).

**DILI:** Ligand A (43.932) has a slightly higher DILI risk than Ligand B (23.614), but both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a kinase inhibitor, but Ligand A (85.072) shows better BBB penetration than Ligand B (57.968).

**Caco-2 Permeability:** Ligand A (-4.757) and Ligand B (-4.441) both have negative values, which is unusual. I will assume these are log scale values and higher is better. Both are similar, but A is slightly better.

**Aqueous Solubility:** Ligand A (-3.886) and Ligand B (-2.048) both have negative values, indicating poor solubility. Ligand B is better here.

**hERG:** Ligand A (0.911) and Ligand B (0.774) both have relatively low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (49.32) has a higher microsomal clearance than Ligand B (35.78), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (61.027) has a significantly longer half-life than Ligand B (-22.805). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.767) and Ligand B (0.136) show P-gp efflux liability. Ligand B is significantly lower, which is preferable.

**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 small (0.3 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand A has a better QED, TPSA, Caco-2, and in vitro half-life. However, Ligand B has better solubility, lower DILI risk, lower P-gp efflux, and slightly better binding affinity. The most significant drawback for Ligand A is its higher microsomal clearance, suggesting it will be rapidly metabolized. The slightly better binding affinity of Ligand B, combined with its improved metabolic stability and lower efflux, makes it a more promising candidate despite the slightly lower QED.

Output:
1
2025-04-17 16:49:14,914 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (357.38 and 355.32 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.46) is significantly better than Ligand B (81.07).  A TPSA under 140 is good for oral absorption, and both are within this range, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (2.79 and 1.65), 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 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 under the limit of 10, but Ligand A is better.

**6. QED:** Both ligands have very similar QED values (0.871 and 0.872), indicating good drug-likeness.

**7. DILI:** Ligand A (15.9%) has a much lower DILI risk than Ligand B (68.3%). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (82.0 and 81.3), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.614) has slightly better Caco-2 permeability than Ligand B (-5.012), though both are negative values, indicating relatively poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.815) has slightly better aqueous solubility than Ligand B (-2.638), though both are poor.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.488 and 0.492).

**12. Microsomal Clearance:** Ligand A (5.085) has significantly lower microsomal clearance than Ligand B (11.077). This suggests better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand A (-0.948) has a slightly longer in vitro half-life than Ligand B (6.387).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.106 and 0.087).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.9 and -7.8 kcal/mol). The difference is minimal and unlikely to be decisive.

**Overall Assessment:**

Ligand A is superior to Ligand B due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic), slightly better solubility and permeability, and lower TPSA. While the binding affinities are nearly identical, the improved ADME properties of Ligand A make it a more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 16:49:14,914 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.475 and 354.466 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (55.47 and 58.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.169) is optimal, while Ligand B (2.294) is also within the acceptable range of 1-3, but trending higher.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 and 3 respectively) counts, well below the thresholds of 5 and 10.

**QED:** Both ligands have good QED scores (0.895 and 0.843), indicating good drug-like properties.

**DILI:** Ligand A (10.779) has a significantly lower DILI risk than Ligand B (34.277), which is a major advantage. Ligand B is approaching a concerning DILI percentile.

**BBB:** Both ligands have high BBB penetration (89.027 and 88.135), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.94 and -4.401), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.126 and -3.707), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.804) has a lower hERG risk than Ligand B (0.477), which is favorable.

**Microsomal Clearance:** Ligand A (-6.906) has a much lower (better) microsomal clearance than Ligand B (61.379), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.884) has a better (longer) in vitro half-life than Ligand B (-15.128).

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux liability than Ligand B (0.206), which is beneficial.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). The difference is 0.9 kcal/mol, which is not substantial enough to overcome the other significant ADME issues with Ligand B.

**Conclusion:**

Ligand A is the more promising candidate. While both have poor solubility and permeability, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, lower hERG risk, and lower P-gp efflux. The slightly weaker binding affinity of Ligand A is outweighed by these substantial ADME advantages, especially considering we are targeting a kinase. Improving solubility and permeability would be the next steps in optimization for either compound.

Output:
0
2025-04-17 16:49:14,915 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (392.897 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.83) is slightly above the preferred <140, while Ligand B (76.02) is well within. This favors Ligand B for absorption.

**logP:** Ligand A (3.952) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.747) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.584 and 0.797), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (97.867%), which is a significant concern. Ligand B has a much lower DILI risk (56.689%), making it preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (76.425%) is slightly higher than Ligand A (63.474%).

**Caco-2 Permeability:** Both have negative Caco-2 values, 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 very poor aqueous solubility (-5.079 and -3.497). This is a significant drawback for both, but Ligand B is slightly better.

**hERG:** Ligand A (0.345) has a slightly better hERG profile than Ligand B (0.473), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (37.176) has lower microsomal clearance than Ligand B (48.065), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (76.464) has a longer half-life than Ligand B (30.783), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.552) has slightly lower P-gp efflux than Ligand B (0.192), potentially leading to better bioavailability.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability and half-life. However, its very high DILI risk and borderline high logP are major concerns. Ligand B has a better safety profile (lower DILI) and better TPSA/logP, but significantly weaker binding affinity.

Given the importance of potency for kinase inhibitors, and the potential to mitigate some ADME issues through formulation or structural modification, the stronger binding affinity of Ligand A is the deciding factor. While the DILI risk is concerning, it's a parameter that can be addressed during lead optimization. The lower affinity of Ligand B is harder to overcome.

Output:
1
2025-04-17 16:49:14,915 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.323 Da) is slightly lower, which could be beneficial for permeability. Ligand B (366.571 Da) is also acceptable.

**TPSA:** Ligand A (124.07) is better than Ligand B (53.43), falling below the 140 threshold for good oral absorption. Ligand B is excellent, suggesting good absorption potential.

**logP:** Ligand A (2.379) is within the optimal range (1-3). Ligand B (4.661) is higher, potentially leading to solubility issues and off-target interactions, but not dramatically so.

**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 similar QED values (0.625 and 0.647), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 97.596, which is very high and a significant concern. Ligand B has a much lower DILI risk of 24.467, which is excellent.

**BBB:** Ligand A has a low BBB penetration (20.318), which isn't critical for a non-CNS target like SRC. Ligand B has a higher BBB penetration (80.807), which is irrelevant in this case.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.609), 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 (-5.15 and -4.229), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.505) has a slightly higher hERG risk than Ligand B (0.859), but both are relatively low.

**Microsomal Clearance:** Ligand B (96.632) has a significantly higher microsomal clearance than Ligand A (34.599), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-2.571) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (15.571) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.069) has very low P-gp efflux, which is favorable. Ligand B (0.952) has a higher P-gp efflux, which could reduce bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.6 kcal/mol), with Ligand B being slightly more potent.

**Overall Assessment:**

Despite the similar binding affinities, Ligand B is significantly hampered by its high microsomal clearance and poor metabolic stability. The extremely high DILI risk associated with Ligand A is a deal-breaker. While both have solubility issues, the metabolic stability and DILI profile of Ligand B are much more favorable. The negative half-life for ligand A is also a major concern.

Output:
1
2025-04-17 16:49:14,915 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.395 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.82) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (75.5) is well within the desirable range.

**logP:** Ligand A (-0.434) is a bit low, potentially hindering permeation. Ligand B (2.397) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is good. Ligand B (2 HBD, 4 HBA) is also good. Both are within the recommended limits.

**QED:** Both ligands have good QED scores (0.605 and 0.773, respectively), indicating drug-likeness.

**DILI:** Ligand A (53.044) has a slightly higher DILI risk than Ligand B (43.195), but both are below the concerning threshold of 60.

**BBB:** Both ligands have acceptable BBB penetration, but Ligand B (79.062) is significantly better than Ligand A (61.225). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.238 and -4.917), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.204 and -3.49), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.067) has a very low hERG risk, which is excellent. Ligand B (0.646) has a moderate hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (1.199) has much lower microsomal clearance than Ligand B (53.535), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (6.739) has a shorter half-life than Ligand B (20.508). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is good. Ligand B (0.067) 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 crucial 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, significantly better metabolic stability (lower Cl_mic), and lower P-gp efflux. While its logP is slightly low and solubility is poor, the strong binding affinity is a major advantage for an enzyme inhibitor. Ligand B has better solubility and permeability predictions (though both are poor), but its binding affinity is extremely weak. The poor solubility and permeability of both compounds are concerning, but the substantial binding affinity advantage of Ligand A makes it the more promising candidate, assuming formulation strategies can be developed to address the solubility issue.

Output:
1
2025-04-17 16:49:14,915 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.407 and 348.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.56) is better than Ligand B (67.87), both are below the 140 threshold for good oral absorption.

**logP:** Ligand B (1.564) is optimal (1-3), while Ligand A (-0.46) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both ligands are acceptable (2 and 1, respectively), being less than 5.

**H-Bond Acceptors:** Both ligands are acceptable (5 and 4, respectively), being less than 10.

**QED:** Both ligands have similar, good QED values (0.766 and 0.74).

**DILI:** Ligand B (23.11) has a significantly lower DILI risk than Ligand A (41.411), making it more favorable.

**BBB:** Both ligands have high BBB penetration (79.217 and 76.037), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.214 and -4.809), 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 (-2.111 and -2.277), again, making direct comparison difficult.

**hERG Inhibition:** Both ligands have very low hERG risk (0.142 and 0.263).

**Microsomal Clearance:** Ligand A (-3.795) has a much lower (better) microsomal clearance than Ligand B (22.786), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.327) has a longer half-life than Ligand B (-0.85), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.058).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.5 and -8.3 kcal/mol).

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better TPSA, Ligand B has a significantly lower DILI risk and a more optimal logP value. Given the enzyme-specific priorities, the lower DILI risk of Ligand B is a crucial advantage. The slightly lower metabolic stability of Ligand B is less concerning than the potential liver toxicity associated with Ligand A. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 16:49:14,915 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.47 and 346.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (113.91) is higher but still acceptable, though less optimal.

**logP:** Ligand A (3.702) is within the optimal 1-3 range. Ligand B (-0.028) is significantly lower, 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, well within the limit of 10. Ligand B has 10 HBA, approaching the upper limit and potentially impacting permeability.

**QED:** Both ligands have good QED scores (0.504 and 0.744), indicating drug-like properties.

**DILI:** Both have low DILI risk (36.68 and 34.39), which is favorable.

**BBB:** Both have reasonable BBB penetration (68.32 and 65.34), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.811) is poor, indicating low intestinal absorption. Ligand B (-5.577) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.085) is poor, while Ligand B (-1.821) is also poor, but better than A.

**hERG:** Ligand A (0.71) has a low hERG risk, which is excellent. Ligand B (0.422) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (48.703) has moderate clearance. Ligand B (5.06) has very low clearance, indicating good metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-1.445) has a short half-life. Ligand B (-10.814) has a very long half-life, a substantial benefit.

**P-gp Efflux:** Ligand A (0.221) has low P-gp efflux, which is good. Ligand B (0.004) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.2). This is a 1.8 kcal/mol difference, which is substantial enough to outweigh some ADME concerns.

**Conclusion:**

While Ligand A has better TPSA and hERG, Ligand B excels in several critical areas for an enzyme inhibitor: significantly higher binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slightly higher TPSA and lower logP of Ligand B are less concerning given the substantial potency advantage. The solubility and Caco-2 permeability are poor for both, but the superior potency and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 16:49:14,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.443 and 358.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.09) is better than Ligand B (86.88), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.541) is within the optimal range (1-3), while Ligand B (3.158) is at the higher end but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, being less than 10.

**QED:** Ligand A (0.815) is superior to Ligand B (0.74), indicating a more drug-like profile.

**DILI:** Ligand A (36.565) has a significantly lower DILI risk than Ligand B (73.943). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 54.207, Ligand B: 59.403). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.949) is better than Ligand B (-5.522), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.039) is better than Ligand B (-4.056), indicating better solubility.

**hERG Inhibition:** Ligand A (0.115) has a much lower hERG risk than Ligand B (0.56). This is a significant advantage.

**Microsomal Clearance:** Ligand A (7.097) has a higher (worse) microsomal clearance than Ligand B (30.262). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-13.094) has a much shorter half-life than Ligand B (52.195). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.033) has much lower P-gp efflux than Ligand B (0.303). This is a significant advantage for Ligand A.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.3). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand A has several advantages: better QED, significantly lower DILI and hERG risk, better solubility, better Caco-2 permeability, and lower P-gp efflux. Ligand B has better metabolic stability (lower Cl_mic and longer t1/2) and slightly better binding affinity. However, the risks associated with Ligand B's higher DILI and hERG are substantial. The improved ADME properties of Ligand A, particularly the lower toxicity risks, outweigh the slightly weaker binding affinity and poorer metabolic stability.

Output:
0
2025-04-17 16:49:14,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (366.389 and 366.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is well below the 140 threshold for good absorption, while Ligand B (117.26) is still acceptable but higher.

**logP:** Ligand A (3.318) is optimal, while Ligand B (0.437) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 6 HBA) both meet the recommended thresholds.

**QED:** Both ligands have similar QED values (0.629 and 0.605), indicating good drug-likeness.

**DILI:** Ligand A (87.01) has a higher DILI risk than Ligand B (67.235), which is better.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (76.154) has a better BBB score than Ligand B (46.452).

**Caco-2 Permeability:** Ligand A (-4.404) has a negative value, suggesting poor permeability. Ligand B (-5.478) is even worse.

**Aqueous Solubility:** Ligand A (-4.409) and Ligand B (-2.061) both have negative solubility values, which is concerning.

**hERG Inhibition:** Ligand A (0.223) has a lower hERG risk than Ligand B (0.061), which is favorable.

**Microsomal Clearance:** Ligand A (110.09) has a higher clearance, indicating lower metabolic stability, while Ligand B (-8.705) has a negative clearance, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (0.018 hours) has a very short half-life, while Ligand B (18.118 hours) has a much longer and more desirable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.251 and 0.031).

**Binding Affinity:** Ligand B (-10.3 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.

**Conclusion:**

Despite Ligand B's lower logP and solubility, its significantly superior binding affinity (-10.3 vs -7.2 kcal/mol) and much better metabolic stability (negative Cl_mic and longer half-life) make it the more promising candidate. The strong binding affinity is a critical factor for an enzyme inhibitor, and the improved metabolic stability will likely translate to better *in vivo* exposure. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies. Ligand A's poor permeability and short half-life are more difficult to overcome.

Output:
1
2025-04-17 16:49:14,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.435 and 357.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.97) is better than Ligand B (69.22) as it is closer to the 140 threshold.

**logP:** Ligand A (-1.184) is slightly low, potentially impacting permeability. Ligand B (3.287) is within 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 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.52 and 0.75), indicating drug-likeness.

**DILI:** Ligand A (5.894) has a much lower DILI risk than Ligand B (18.263), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (68.476) has a higher BBB score than Ligand A (35.014), but this is not a primary concern.

**Caco-2 Permeability:** Ligand A (-6.002) has poor Caco-2 permeability, a major drawback. Ligand B (-4.578) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-0.871) has poor solubility, while Ligand B (-3.244) is even worse. Both are concerning, but Ligand A is slightly better.

**hERG:** Ligand A (0.132) has a very low hERG risk, a significant advantage. Ligand B (0.794) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-21.71) has a much lower (better) microsomal clearance than Ligand B (19.011), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.381) has a longer half-life than Ligand B (-11.256), which is desirable.

**P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux, while Ligand B (0.294) has some efflux.

**Binding Affinity:** Ligand B (-8.2) has a significantly stronger binding affinity than Ligand A (0). This is a crucial factor for enzyme inhibitors. The >1.5 kcal/mol advantage of B outweighs many of its ADME drawbacks.

**Overall Assessment:**

Ligand B's substantially superior binding affinity (-8.2 kcal/mol vs -0 kcal/mol) is the most critical factor. While it has some ADME liabilities (solubility, Caco-2, DILI), these can potentially be addressed through further optimization. Ligand A has better solubility and hERG, but its poor binding affinity and Caco-2 permeability are major limitations. The lower DILI and better metabolic stability of Ligand A are positive, but not enough to overcome the binding affinity issue.

Output:
1
2025-04-17 16:49:14,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.378 and 339.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (87.15 and 81.99) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.518) is a bit low, potentially hindering permeation. Ligand B (2.68) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the limit of 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, below the limit of 10.

**QED:** Both ligands have good QED scores (0.555 and 0.885), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (49.632) has a lower DILI risk than Ligand B (58.317), which is preferable.

**BBB:** This isn't a high priority for a non-CNS target like SRC. Ligand A (81.698) is higher than Ligand B (48.895), but this is less important.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.854 and -4.772), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.045 and -4.591), which is also concerning and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.33 and 0.373), which is good.

**Microsomal Clearance:** Ligand A (20.96) has lower microsomal clearance than Ligand B (29.848), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-34.033) has a much more negative in vitro half-life than Ligand B (-0.134), which is a major concern. A negative value suggests a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.119 and 0.148), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A has better metabolic stability (lower Cl_mic) and lower DILI risk. However, Ligand A suffers from a very short predicted half-life, which is a critical drawback. Ligand B has a better logP and QED score, but a higher DILI risk and faster metabolic clearance. Both ligands have concerningly low/negative Caco-2 and solubility values. Given the importance of metabolic stability for an enzyme inhibitor, and the fact that the binding affinity is identical, Ligand A is slightly favored despite the short half-life. The poor solubility and permeability of both compounds would need to be addressed through further optimization.

Output:
0
2025-04-17 16:49:14,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (367.53 and 368.84 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is significantly better than Ligand B (73.38). A TPSA under 140 is good for oral absorption, and A is well within that 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 (2.862) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is more favorable than Ligand B (1 HBD, 5 HBA) regarding the number of hydrogen bonds. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.641 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (12.485) has a much lower DILI risk than Ligand B (54.75). This is a significant advantage for Ligand A.

**BBB:** Both have high BBB penetration, but Ligand A (94.998) is slightly better than Ligand B (81.504). While not a primary concern for a non-CNS target, it doesn't hurt.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both compounds.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.916) has a slightly higher hERG risk than Ligand B (0.718), but both are relatively low.

**Microsomal Clearance:** Ligand A (119.008) has a higher microsomal clearance than Ligand B (51.339), meaning it's less metabolically stable. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (47.025) has a significantly longer in vitro half-life than Ligand A (25.2), indicating better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.467 and 0.323).

**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 notable, but not overwhelming.

**Overall Assessment:**

Ligand A has a better binding affinity and lower DILI risk, but suffers from higher microsomal clearance and shorter half-life. Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), a more optimal logP, and slightly lower hERG risk, but has a higher DILI risk and slightly weaker binding affinity.

Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) is crucial. The significantly better metabolic stability of Ligand B outweighs the slightly weaker binding affinity and higher DILI risk. The poor Caco-2 and solubility for both compounds are concerning and would need to be addressed in further optimization, but are not decisive factors in choosing between these two.

Output:
1
2025-04-17 16:49:14,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.321 Da) is slightly higher than Ligand B (351.447 Da), but both are acceptable.

**TPSA:** Ligand A (71.09) is better than Ligand B (87.74). Lower TPSA generally favors better absorption.

**logP:** Ligand A (3.349) is optimal, while Ligand B (0.988) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.776, B: 0.67), indicating good drug-likeness.

**DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (18.612). This is a significant drawback for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (71.733) is better than Ligand B (54.866).

**Caco-2 Permeability:** Ligand A (-4.645) is better than Ligand B (-5.344), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.214) is better than Ligand B (-2.159), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.193, B: 0.097), which is excellent.

**Microsomal Clearance:** Ligand A (37.554) has a higher clearance than Ligand B (0.115), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (-26.596) has a much shorter half-life than Ligand B (-0.728), further supporting lower metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.032, B: 0.009).

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.6), 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 affinity and permeability, its significantly higher DILI risk and poorer metabolic stability (higher clearance, shorter half-life) are major concerns. Ligand B, despite a slightly lower affinity and logP, presents a much more favorable ADMET profile, particularly the low DILI risk and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are paramount. The small difference in binding affinity can likely be optimized in subsequent iterations of drug design.

Output:
1
2025-04-17 16:49:14,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values (61.44 and 65.2) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have logP values (3.975 and 3.52) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3 HBA, which are within the acceptable limits.

**QED:** Both ligands have QED values above 0.5 (0.783 and 0.691), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (69.717%) compared to Ligand B (37.263%). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (79.721%) shows better penetration than Ligand B (60.062%).

**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 the magnitude of the effect.

**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 (0.736 and 0.701).

**Microsomal Clearance:** Ligand A has a lower Cl_mic (73.957 mL/min/kg) than Ligand B (85.125 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (35.137 and 33.511 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.582 and 0.218).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-9 kcal/mol) than Ligand A (-6.8 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol advantage threshold.

**Conclusion:**

Despite Ligand A having slightly better metabolic stability and BBB penetration, the significantly higher DILI risk and substantially weaker binding affinity make it a less desirable candidate. Ligand B's superior binding affinity outweighs the slightly higher metabolic clearance and lower BBB penetration. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:49:14,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.431 and 360.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is better than Ligand B (58.12), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have a logP around 4.2, which is slightly high, potentially leading to solubility issues or off-target effects.

**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.

**QED:** Ligand B (0.89) has a significantly better QED score than Ligand A (0.661), indicating a more drug-like profile.

**DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (51.26), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (89.298 and 85.847), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.325) has slightly better Caco-2 permeability than Ligand B (-4.758).

**Aqueous Solubility:** Ligand A (-4.063) has slightly better aqueous solubility than Ligand B (-4.301).

**hERG Inhibition:** Ligand A (0.86) has a slightly higher hERG risk than Ligand B (0.239), which is a negative for Ligand A.

**Microsomal Clearance:** Ligand B (34.416 mL/min/kg) has significantly lower microsomal clearance than Ligand A (61.971 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (1.196 hours) has a longer half-life than Ligand A (0.685 hours).

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.183), which is favorable.

**Binding Affinity:** Ligand A (-9.0 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 much better binding affinity and lower DILI risk, but Ligand B has better QED, metabolic stability, and half-life. The difference in binding affinity (-2.2 kcal/mol) is substantial and likely to be the most important factor for an enzyme inhibitor. While Ligand B's improved ADME properties are desirable, the potency advantage of Ligand A is likely to be more impactful in driving efficacy. The slightly higher hERG risk of Ligand A is a concern, but could be mitigated through further structural modifications.

Output:
1
2025-04-17 16:49:14,918 - INFO - Batch 495 complete. Total preferences: 7920
2025-04-17 16:49:14,918 - INFO - Processing batch 496/512...
2025-04-17 16:50:03,173 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [374.428, 58.2, 2.379, 2, 3, 0.735, 24.544, 87.088, -4.933, -3.714, 0.48, 39.954, 0.016, 0.062, -6.5]
**Ligand B:** [381.904, 59.22, 4.907, 1, 4, 0.661, 63.048, 82.784, -4.825, -5.311, 0.823, 79.895, 59.83, 0.747, -8]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (374.428) is slightly lower, which could be beneficial for permeability.
2. **TPSA:** Both are reasonably low (A: 58.2, B: 59.22), well below the 140 threshold for oral absorption.
3. **logP:** A (2.379) is optimal, while B (4.907) is high. High logP can lead to solubility issues and off-target interactions.
4. **HBD:** A (2) and B (1) are both acceptable, below the 5 threshold.
5. **HBA:** A (3) and B (4) are both acceptable, below the 10 threshold.
6. **QED:** A (0.735) is better than B (0.661), indicating a more drug-like profile.
7. **DILI:** A (24.544) is significantly better than B (63.048). This is a major advantage for Ligand A.
8. **BBB:** Both have good BBB penetration (A: 87.088, B: 82.784), but A is slightly better.
9. **Caco-2:** Both are negative, indicating poor permeability. A (-4.933) is slightly better than B (-4.825).
10. **Solubility:** Both are negative, indicating poor solubility. A (-3.714) is slightly better than B (-5.311).
11. **hERG:** A (0.48) is much lower than B (0.823), indicating a lower risk of cardiotoxicity.
12. **Cl_mic:** A (39.954) is significantly better than B (79.895), indicating better metabolic stability.
13. **t1/2:** A (0.016) is very short, while B (59.83) is excellent. This is a significant advantage for Ligand B.
14. **Pgp:** A (0.062) is much lower than B (0.747), indicating less P-gp efflux.
15. **Affinity:** B (-8) is 1.5 kcal/mol better than A (-6.5). This is a substantial difference in potency.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8 kcal/mol vs -6.5 kcal/mol). This is a major advantage, and a 1.5 kcal/mol difference is often enough to overcome other issues. However, Ligand B has concerningly high logP, DILI risk, and Pgp efflux. It also has a higher hERG risk and significantly worse metabolic stability (higher Cl_mic).

Ligand A has a much better safety profile (lower DILI, hERG, and Pgp) and better metabolic stability. Its solubility and permeability are slightly better than Ligand B. However, its affinity is considerably weaker.

Considering the priorities for an enzyme target, the substantial affinity advantage of Ligand B is likely to outweigh its ADME/Tox liabilities *if* those liabilities can be addressed through further optimization. The poor metabolic stability is a significant concern, but the potency difference is large.

Therefore, I would prioritize Ligand B for further investigation, with a strong focus on improving its metabolic stability and reducing its DILI risk.

Output:
1
2025-04-17 16:50:03,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (335.407 and 349.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.89) is well below the 140 threshold, while Ligand B (107.17) is still acceptable but higher.

**logP:** Ligand A (4.005) is at the upper end of the optimal range, potentially leading to solubility issues. Ligand B (-0.695) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 8 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.759 and 0.6), indicating good drug-likeness.

**DILI:** Ligand A (75.688) has a higher DILI risk than Ligand B (56.185).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.554) is slightly better than Ligand B (44.979).

**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 (-5.4 and -0.784). This is a significant concern.

**hERG Inhibition:** Ligand A (0.689) has a lower hERG risk than Ligand B (0.09), which is a major advantage.

**Microsomal Clearance:** Ligand A (33.774) has a higher clearance than Ligand B (26.267), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (65.992) has a longer half-life than Ligand B (21.681), which is favorable.

**P-gp Efflux:** Ligand A (0.508) has lower P-gp efflux than Ligand B (0.025), which is better for bioavailability.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the solubility concerns and slightly higher DILI risk, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.4 vs -7.8 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The better hERG profile, longer half-life, and lower P-gp efflux also contribute to its favorability. While solubility is a concern, it might be addressed through formulation strategies.

Output:
1
2025-04-17 16:50:03,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (367.599 Da) is also well within the range.

**TPSA:** Ligand A (91.22) is slightly above the preferred <140 for oral absorption, but still reasonable. Ligand B (29.54) is excellent, well below the threshold.

**logP:** Ligand A (1.508) is within the optimal range (1-3). Ligand B (4.908) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.79) has a better QED score than Ligand B (0.473), indicating a more drug-like profile.

**DILI:** Ligand A (33.695) has a lower DILI risk than Ligand B (21.714), which is favorable.

**BBB:** Both have relatively low BBB penetration, which is not a primary concern for a non-CNS target like SRC. Ligand B (75.533) is higher than Ligand A (62.97), but this is not a critical factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, we can't rely heavily on this without further data.

**Aqueous Solubility:** Both have negative solubility values, again indicating issues with prediction.

**hERG:** Ligand A (0.352) has a lower hERG risk than Ligand B (0.719), which is a significant advantage.

**Microsomal Clearance:** Ligand A (29.252) has a lower Cl_mic, suggesting better metabolic stability than Ligand B (100.918).

**In vitro Half-Life:** Ligand A (14.453) has a longer half-life than Ligand B (5.096), which is desirable.

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.699), indicating better bioavailability.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). This is a 1.6 kcal/mol difference, which is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a more favorable ADME profile overall, with better QED, lower DILI, lower hERG risk, better metabolic stability, longer half-life, and lower P-gp efflux. However, Ligand B has a slightly stronger binding affinity. Given the enzyme-specific priorities, metabolic stability (Cl_mic and t1/2) and hERG risk are crucial. Ligand A's significantly better metabolic stability and lower hERG risk, coupled with a still very strong binding affinity, make it the more promising candidate. The 1.6 kcal/mol difference in binding affinity is unlikely to overcome the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 16:50:03,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.387 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.87) is better than Ligand B (77.53), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.555) is a bit low, potentially hindering permeability. Ligand B (2.216) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 8. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.665 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (39.511) has a significantly lower DILI risk than Ligand B (85.653). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (68.67 and 64.25), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.638) has a much lower Caco-2 permeability than Ligand B (-5.033), indicating potentially poorer absorption.

**Aqueous Solubility:** Ligand A (-1.862) has better aqueous solubility than Ligand B (-3.4).

**hERG Inhibition:** Ligand A (0.171) has a much lower hERG inhibition liability than Ligand B (0.871), a critical advantage for safety.

**Microsomal Clearance:** Ligand A (-10.424) has significantly lower microsomal clearance than Ligand B (86.572), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.767) has a shorter half-life than Ligand B (63.875). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.191), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.8). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand A demonstrates a superior safety profile with significantly lower DILI and hERG risk, and better metabolic stability (lower Cl_mic). While its Caco-2 permeability is lower and half-life shorter, the substantial advantages in safety and metabolic stability outweigh these drawbacks. Ligand B has better affinity and permeability, but the high DILI and hERG risks are concerning. For an oncology target, metabolic stability is crucial for maintaining therapeutic concentrations, and minimizing off-target effects is paramount.

Output:
0
2025-04-17 16:50:03,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.431 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.43 and 76.64) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.848) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.265) is well within the optimal range.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being less than 10.

**QED:** Both ligands have good QED scores (0.877 and 0.793), indicating drug-like properties.

**DILI:** Ligand A (53.083) has a higher DILI risk than Ligand B (28.655). This is a significant concern.

**BBB:** Both ligands have moderate BBB penetration (67.546 and 53.238). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.08 and -4.816), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.186 and -2.109), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.36 and 0.418), which is positive.

**Microsomal Clearance:** Ligand A (11.947) has a higher microsomal clearance than Ligand B (6.203), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (9.769) has a longer half-life than Ligand B (3.874), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.156), which is good.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. It possesses a significantly stronger binding affinity (-7.2 vs -9.3 kcal/mol), a lower DILI risk (28.655 vs 53.083), and better metabolic stability (lower Cl_mic). The improved binding affinity and reduced toxicity risk outweigh the slightly less optimal logP and the shared solubility/permeability concerns. Addressing the solubility and permeability issues through formulation strategies might be possible, but a weaker binding affinity is much harder to overcome.

Output:
1
2025-04-17 16:50:03,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.403 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.6) is slightly higher than Ligand B (75.5), but both are below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (1.692 and 2.397), 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 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.822 and 0.773), indicating good drug-likeness.

**DILI:** Ligand A (53.276) has a slightly higher DILI risk than Ligand B (43.195), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (79.062) has a higher BBB percentile than Ligand A (51.997), but this is not a major deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.525 and -4.917), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.485 and -3.49), which is also concerning and suggests poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.197) has a lower hERG inhibition liability than Ligand B (0.646), which is favorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (53.968 and 53.535 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (20.508 hours) has a significantly longer half-life than Ligand A (5.941 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.101) has slightly lower P-gp efflux liability than Ligand B (0.067), which is favorable.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial difference. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite the poor Caco-2 and solubility for both, Ligand A's substantially superior binding affinity (-8.3 kcal/mol vs -0.0 kcal/mol) is the most important factor. The stronger binding is likely to translate to greater efficacy. While Ligand B has a better half-life and lower hERG risk, the potency difference is too significant to ignore. The poor permeability and solubility would need to be addressed through formulation strategies, but a potent starting point is essential.

Output:
1
2025-04-17 16:50:03,174 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.355 and 346.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.9) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (58.2) is well within the ideal range.

**logP:** Ligand A (0.459) is quite low, potentially hindering permeability. Ligand B (3.297) is near the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are reasonable. Ligand B has 2 HBD and 2 HBA, also good.

**QED:** Ligand A (0.457) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.744) is above 0.5, suggesting a better drug-like profile.

**DILI:** Ligand A (62.854) has a moderate DILI risk. Ligand B (21.753) has a low DILI risk, which is a significant advantage.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand A (59.364) and Ligand B (81.039) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.851 and -4.618), which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.22 and -3.513), which is also unusual and suggests poor solubility. Again, these values should be interpreted cautiously.

**hERG Inhibition:** Ligand A (0.111) shows a very low risk of hERG inhibition, a major advantage. Ligand B (0.568) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (7.466) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (40.399) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-29.146) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (4.472) has a short half-life, which is a concern.

**P-gp Efflux:** Ligand A (0.041) has very low P-gp efflux, which is favorable. Ligand B (0.147) has slightly higher efflux.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This 1.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has a better hERG profile and lower clearance, but suffers from a low QED, low logP, and a nonsensical half-life value. Ligand B has a superior binding affinity, better logP, lower DILI risk, and a better QED score. While the Caco-2 and solubility values are concerning for both, the significantly stronger binding affinity of Ligand B, coupled with its lower DILI risk, makes it the more promising candidate despite its higher clearance and slightly higher P-gp efflux. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 16:50:03,174 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (370.431 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.89) is better than Ligand B (67.23) as it is closer to the 140 threshold.

**logP:** Ligand B (1.947) is optimal (1-3), while Ligand A (-0.385) is slightly 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 (0.662 and 0.733, respectively), indicating good drug-like properties.

**DILI:** Ligand B (36.448) has a significantly lower DILI risk than Ligand A (65.491). This is a major advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.833) is higher, but not a deciding factor.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.314) is worse than Ligand B (-4.472).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.091) is worse than Ligand B (-4.121).

**hERG Inhibition:** Ligand A (0.113) has a slightly lower hERG risk than Ligand B (0.285), which is favorable.

**Microsomal Clearance:** Ligand A (-2.881) has significantly lower (better) microsomal clearance than Ligand B (40.116), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.641) has a longer half-life than Ligand B (-8.755), which is desirable.

**P-gp Efflux:** Both are very low (0.015 and 0.177), indicating minimal P-gp efflux.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This 1.6 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand B exhibits a much lower DILI risk, better logP, and slightly better solubility. The poor Caco-2 and solubility of both are concerning, but the strong binding affinity of Ligand A is a significant advantage for an enzyme target. Given the importance of potency for kinases, and the substantial difference in binding affinity, I believe Ligand A is the more promising candidate despite its higher DILI risk. Further optimization could address the DILI concern.

Output:
1
2025-04-17 16:50:03,174 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.382 and 366.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.76) is significantly better than Ligand B (75.19). A TPSA under 90 is generally favorable, and Ligand A is well within that range, suggesting better permeability. Ligand B is approaching the upper limit.

**logP:** Ligand A (4.62) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (1.74) is within the optimal range.

**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.

**QED:** Both ligands have good QED scores (0.688 and 0.879), indicating good drug-like properties.

**DILI:** Ligand A (57.58) has a slightly higher DILI risk than Ligand B (65.568), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (86.817) has better BBB penetration than Ligand B (79.256), but it's not a deciding factor here.

**Caco-2 Permeability:** Ligand A (-3.998) has poor Caco-2 permeability, while Ligand B (-4.94) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-6.11) has very poor aqueous solubility, which is a significant drawback. Ligand B (-3.47) has better solubility, although still not ideal.

**hERG Inhibition:** Ligand A (0.568) has a slightly higher hERG risk than Ligand B (0.334), but both are relatively low.

**Microsomal Clearance:** Ligand A (110.513) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (45.348) has significantly lower clearance, a major advantage.

**In vitro Half-Life:** Ligand B (-27.202) has a much longer in vitro half-life than Ligand A (1.367), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.363) has lower P-gp efflux than Ligand B (0.213), which could be beneficial for bioavailability.

**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 ADME drawbacks. The difference of 1.6 kcal/mol is significant.

**Conclusion:**

Despite Ligand A's superior binding affinity, its poor solubility and metabolic stability are major concerns. Ligand B, while having a slightly weaker affinity, exhibits much better ADME properties, particularly in terms of solubility, metabolic stability (lower Cl_mic and longer t1/2), and acceptable hERG risk. Given the enzyme-kinase target class priority on metabolic stability and solubility, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 16:50:03,174 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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 (350.375 Da) is also good.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (109). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal range for permeability.

**logP:** Ligand A (2.898) is optimal (1-3). Ligand B (0.461) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better balanced. Ligand B (HBD=1, HBA=7) has a higher number of HBA, which could impact permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.907, B: 0.84), indicating good drug-like properties.

**DILI:** Ligand A (71.268) has a higher DILI risk than Ligand B (57.929), but both are acceptable.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (75.145) is better than Ligand B (62.466). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 them relatively.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.598) has a much lower hERG risk than Ligand B (0.018). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (2.846) has lower microsomal clearance than Ligand B (3.514), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.506 hours) has a significantly longer half-life than Ligand B (7.175 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.221) has lower P-gp efflux than Ligand B (0.032), indicating better bioavailability.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a 1.6 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 significantly better logP, TPSA, hERG risk, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux profile of Ligand A outweigh the slightly weaker binding. The unusual negative values for Caco-2 and solubility are concerning and would require further investigation, but the relative comparison still favors Ligand A. The enzyme-specific priorities (stability, solubility, and safety) are better addressed by Ligand A.

Output:
0
2025-04-17 16:50:03,174 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Ligand A:**
*   **MW:** 348.462 Da - Good (within 200-500 range)
*   **TPSA:** 49.41 - Good (<=140)
*   **logP:** 3.302 - Good (1-3)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 2 - Good (<=10)
*   **QED:** 0.696 - Good (>=0.5)
*   **DILI:** 18.185 - Excellent (low risk)
*   **BBB:** 90.772 - High (potentially useful if CNS effects are desired, but not critical for SRC)
*   **Caco-2:** -4.375 - Poor (negative value is concerning)
*   **Solubility:** -3.472 - Poor (negative value is concerning)
*   **hERG:** 0.675 - Good (low risk)
*   **Cl_mic:** 71.206 - Moderate (relatively high, could be a concern for metabolic stability)
*   **t1/2:** 19.952 - Good (reasonable half-life)
*   **Pgp:** 0.202 - Good (low efflux)
*   **Affinity:** -7.6 kcal/mol - Excellent (strong binding)

**Ligand B:**
*   **MW:** 366.809 Da - Good (within 200-500 range)
*   **TPSA:** 105.28 - Moderate (above ideal, but acceptable)
*   **logP:** -0.42 - Poor (below 1, may have permeability issues)
*   **HBD:** 2 - Good (<=5)
*   **HBA:** 7 - Good (<=10)
*   **QED:** 0.764 - Good (>=0.5)
*   **DILI:** 63.203 - Moderate (higher risk than A)
*   **BBB:** 11.981 - Low (not a concern for a non-CNS target)
*   **Caco-2:** -5.308 - Very Poor (negative value is highly concerning)
*   **Solubility:** -2.102 - Poor (negative value is concerning)
*   **hERG:** 0.054 - Excellent (very low risk)
*   **Cl_mic:** -1.675 - Excellent (very low clearance, high metabolic stability)
*   **t1/2:** -5.915 - Very Poor (negative value is highly concerning)
*   **Pgp:** 0.034 - Excellent (very low efflux)
*   **Affinity:** -9.0 kcal/mol - Excellent (very strong binding - 1.4 kcal/mol better than A)

**Comparison and Decision:**

Ligand B has a significantly stronger binding affinity (-9.0 vs -7.6 kcal/mol), which is the highest priority for an enzyme inhibitor. It also exhibits excellent metabolic stability (very low Cl_mic) and P-gp efflux liability. However, it suffers from very poor Caco-2 permeability, aqueous solubility, and an implausibly negative in vitro half-life. Ligand A has better solubility, permeability, and half-life, but its metabolic stability is moderate.

Despite the superior affinity of Ligand B, the extremely poor ADME properties (solubility, permeability, half-life) are major red flags. These properties are difficult to overcome with further optimization, and suggest fundamental issues with the molecule's structure. While the strong binding is attractive, a drug needs to reach its target *in vivo*. Ligand A, while not perfect, has a more balanced profile and a better chance of being developed into a viable drug candidate.

Output:
0
2025-04-17 16:50:03,175 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.769 Da) is slightly lower, which *could* be advantageous for permeability, but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (92.55) is slightly better than Ligand B (94.92).

**3. logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.885, Ligand B: 2.32), which is optimal.

**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 (4 HBA) is better than Ligand B (5 HBA). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (Ligand A: 0.671, Ligand B: 0.685), indicating good drug-like properties.

**7. DILI:** Ligand A (89.88) has a significantly higher DILI risk than Ligand B (39.046). This is a major concern for Ligand A.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.223) is slightly better than Ligand B (60.101).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.725) is slightly better than Ligand B (-4.836), but both are problematic.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-2.652) is slightly better than Ligand A (-5.474).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.539, Ligand B: 0.248). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand B (31.316 mL/min/kg) has lower microsomal clearance than Ligand A (56.653 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.233 hours) has a longer in vitro half-life than Ligand A (32.184 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.307, Ligand B: 0.024). Ligand B is better.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -9.3 kcal/mol, Ligand B: -8.1 kcal/mol). Ligand A has a 1.2 kcal/mol advantage.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and marginally better Caco-2 and TPSA, the significantly higher DILI risk is a major red flag. Ligand B, despite having a slightly lower affinity, exhibits superior ADME properties, including lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. For an enzyme target like SRC kinase, metabolic stability and safety (DILI, hERG) are paramount. The 1.2 kcal/mol difference in affinity is unlikely to overcome the substantial safety concerns with Ligand A.

Output:
1
2025-04-17 16:50:03,175 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (358.781 and 352.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.5) is better than Ligand B (122.41). Both are below 140, but A is closer to the optimal threshold for oral absorption.

**3. logP:** Ligand A (1.861) is optimal (1-3). Ligand B (0.276) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Both are within the acceptable range (<=10), but A is closer to the ideal.

**6. QED:** Ligand A (0.727) is significantly better than Ligand B (0.478), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (78.829 and 79.643), and are within an acceptable range (<80).

**8. BBB:** Ligand A (36.758) is lower than Ligand B (50.679). This is not a primary concern for a non-CNS target like SRC.

**9. Caco-2:** Ligand A (-4.965) is better than Ligand B (-5.228). Both are negative, indicating poor permeability.

**10. Solubility:** Ligand A (-4.587) is better than Ligand B (-3.058). Both are negative, indicating poor solubility.

**11. hERG:** Ligand A (0.249) is significantly better than Ligand B (0.054), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (-9.773) is *much* better than Ligand B (51.345). A negative value for Ligand A suggests very low microsomal clearance and excellent metabolic stability, a key factor for kinase inhibitors.

**13. t1/2:** Ligand A (81.674) is much better than Ligand B (-26.864). A longer half-life is desirable.

**14. Pgp:** Ligand A (0.183) is better than Ligand B (0.033), indicating lower P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.2) is slightly better than Ligand B (-7.5). Both are good, but A has a stronger binding affinity.

**Overall Assessment:**

Ligand A is superior to Ligand B across most critical parameters. It has a better QED score, lower hERG risk, significantly better metabolic stability (Cl_mic and t1/2), and slightly better binding affinity. While both have issues with Caco-2 and solubility, the superior ADME profile and potency of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 16:50:03,175 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.873 and 351.353 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (74.69).  A TPSA under 90 is generally acceptable, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.853 and 3.054), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (4 & 4) counts, well under the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.54 and 0.839), indicating good drug-likeness. Ligand B is better here.

**DILI:** Ligand A (16.014) has a much lower DILI risk than Ligand B (60.527). This is a significant advantage for Ligand A.

**BBB:** Both have reasonable BBB penetration, but Ligand B (76.154) is better than Ligand A (68.399). However, BBB isn't a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.903 and -4.629). This is unusual and suggests poor permeability, but the scale is not defined so it is hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-2.795 and -3.538). This is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.715 and 0.494), which is good.

**Microsomal Clearance:** Ligand A (6.908) has significantly lower microsomal clearance than Ligand B (43.951). Lower clearance indicates better metabolic stability, a key priority for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (21.134) has a much longer in vitro half-life than Ligand B (5.663). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.243 and 0.076), which is favorable.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4). However, the difference is only 0.3 kcal/mol, which is not substantial enough to outweigh the other significant advantages of Ligand A.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has slightly better binding affinity and QED, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), a much lower DILI risk, and a better TPSA. These factors are more critical for an enzyme inhibitor like an SRC kinase inhibitor than a small improvement in binding affinity. The negative Caco-2 and solubility values are concerning for both, but the other advantages of A make it the preferred choice.

Output:
0
2025-04-17 16:50:03,175 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (348.462 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (95.39). A TPSA under 140 is good for oral absorption, and A is well within that, while B is approaching the upper limit.

**logP:** Ligand A (2.978) is optimal (1-3), while Ligand B (-1.054) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=7). Both are within acceptable limits, but B has a higher number of HBA, which could affect permeability.

**QED:** Ligand A (0.797) has a better QED score than Ligand B (0.552), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (A: 32.765, B: 34.161), both under 40.

**BBB:** Ligand A (84.141) has a better BBB penetration score than Ligand B (52.889). While not a primary concern for a non-CNS target like SRC, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.83) is better than Ligand B (-5.464). Both are negative, indicating low permeability, but A is less negative.

**Aqueous Solubility:** Ligand A (-3.236) is better than Ligand B (-0.946). Both are negative, indicating low solubility, but A is less negative.

**hERG Inhibition:** Ligand A (0.445) has a much lower hERG inhibition liability than Ligand B (0.148), which is a significant advantage.

**Microsomal Clearance:** Ligand A (35.658) has higher microsomal clearance than Ligand B (18.443), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-18.735) has a negative half-life, which is concerning. Ligand B (11.965) has a positive half-life, indicating better stability.

**P-gp Efflux:** Ligand A (0.319) has lower P-gp efflux liability than Ligand B (0.006), which is favorable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.8 kcal/mol difference, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, positive t1/2). However, Ligand A excels in most other ADME properties: TPSA, logP, QED, DILI, BBB, hERG, P-gp efflux, solubility and Caco-2 permeability. The significantly lower hERG risk for Ligand A is a major advantage. While Ligand B's affinity is better, the other properties of Ligand A are more favorable for overall drug development, especially considering the potential for optimization of affinity.

Output:
0
2025-04-17 16:50:03,175 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (385.335 and 376.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is slightly higher than Ligand B (42.43), but both are well below the 140 A^2 threshold for good absorption.

**logP:** Ligand A (3.997) is closer to the optimal 1-3 range than Ligand B (4.744), which is pushing the upper limit and could potentially cause solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (0 HBD, 5 HBA) both have reasonable counts, within the suggested limits.

**QED:** Both ligands have similar QED scores (0.779 and 0.731), indicating good drug-likeness.

**DILI:** Both ligands have similar and acceptable DILI risk (39.977 and 40.287, both <40).

**BBB:** Ligand B (83.366) has a higher BBB penetration score than Ligand A (71.307), but BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.633 and -4.64), which is unusual and suggests poor permeability. However, these values are on a log scale, so even negative values can be meaningful.

**Aqueous Solubility:** Ligand A (-4.572) has slightly better solubility than Ligand B (-5.647). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.555) has a lower hERG risk than Ligand B (0.712), which is a significant advantage.

**Microsomal Clearance:** Ligand A (62.28 mL/min/kg) has significantly lower microsomal clearance than Ligand B (120.196 mL/min/kg), indicating better metabolic stability. This is a key factor for kinase inhibitors.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (25.895 and 25.087 hours).

**P-gp Efflux:** Ligand A (0.23) has lower P-gp efflux liability than Ligand B (0.732), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have acceptable DILI and QED scores, Ligand A demonstrates a significantly stronger binding affinity, lower hERG risk, and better metabolic stability (lower Cl_mic). The slightly better solubility and lower P-gp efflux also contribute to its favorability. The Caco-2 values are concerning for both, but the superior potency and safety profile of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 16:50:03,175 - INFO - Batch 496 complete. Total preferences: 7936
2025-04-17 16:50:03,176 - INFO - Processing batch 497/512...
2025-04-17 16:50:47,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (426.746 and 430.368 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.7) is better than Ligand B (91.22). Lower TPSA generally favors better absorption.

**logP:** Both ligands have good logP values (3.309 and 3.257), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBDs are generally better for permeability.

**H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.568 and 0.628), indicating drug-like properties.

**DILI:** Ligand A (44.552) has a significantly lower DILI risk than Ligand B (57.697), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (71.811) is slightly better than Ligand A (63.784). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.208) is slightly better than Ligand B (-4.951), but both are concerning.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.294 and -4.112). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.23) has a much lower hERG inhibition liability than Ligand B (0.751), a crucial advantage for safety.

**Microsomal Clearance:** Ligand B (45.377) has slightly lower microsomal clearance than Ligand A (41.284), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.929) has a significantly longer in vitro half-life than Ligand A (-11.603), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.197).

**Binding Affinity:** Ligand B (-7.8) 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's significantly stronger binding affinity (-7.8 kcal/mol vs 0.0 kcal/mol) and longer half-life are compelling advantages. While Ligand B has a higher DILI risk and slightly worse solubility, the potency difference is substantial enough to prioritize it. The slightly better metabolic stability of Ligand B is also a positive. Ligand A has a better hERG profile and lower DILI, but the lack of significant binding affinity is a critical flaw.

Output:
1
2025-04-17 16:50:47,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (350.321 and 353.438 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.47) is slightly higher than Ligand B (80.32). Both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets (not a primary concern here).

**logP:** Both ligands have good logP values (2.308 and 2.152), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 4 HBA, which is acceptable and balances solubility and permeability.

**QED:** Both ligands have good QED scores (0.592 and 0.713), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Both have acceptable DILI risk (54.556 and 51.26), below the 60 threshold.

**BBB:** Ligand A (52.579) has a lower BBB penetration percentile than Ligand B (68.282). This isn't a major concern for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-4.738) has significantly *worse* Caco-2 permeability than Ligand B (-4.59). While both are negative, indicating poor permeability, A is worse.

**Aqueous Solubility:** Ligand A (-3.398) has slightly worse aqueous solubility than Ligand B (-2.647). Both are poor, but B is better.

**hERG Inhibition:** Ligand A (0.662) has a higher hERG inhibition risk than Ligand B (0.475). Lower is better, so B is preferable.

**Microsomal Clearance:** Ligand A (37.009) has lower microsomal clearance than Ligand B (44.015), suggesting better metabolic stability. This is a key advantage for A.

**In vitro Half-Life:** Both have similar in vitro half-lives (18.56 and 17.592 hours).

**P-gp Efflux:** Ligand A (0.297) has lower P-gp efflux than Ligand B (0.08), indicating better bioavailability. This is a significant advantage for A.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor. A difference of >8 kcal/mol is extremely significant.

**Overall Assessment:**

Ligand B clearly wins due to its significantly superior binding affinity (-8.4 vs 0 kcal/mol). While Ligand A has advantages in metabolic stability and P-gp efflux, the massive difference in binding affinity outweighs these benefits. The slightly better solubility and lower hERG risk of Ligand B are also positive factors. The Caco-2 permeability is a concern for both, but the potency of B is likely to compensate.

Output:
1
2025-04-17 16:50:47,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.75 and 347.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (69.04 and 71.09) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands (2.971 and 2.724) are 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 (0.839) has a significantly higher QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand A (78.402) has a higher DILI risk than Ligand B (31.563). This is a significant negative for Ligand A.

**BBB:** Both ligands have high BBB penetration (74.176 and 76.192), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.675 and -4.713). This 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 (-4.082 and -2.938), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.207 and 0.201). This is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (45.061 and 44.433 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-17.332 hours) has a significantly longer in vitro half-life than Ligand A (-1.932 hours). This is a major advantage for Ligand B, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.107 and 0.057).

**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, it may not be enough to overcome other significant drawbacks.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has a slightly better binding affinity, Ligand B exhibits a significantly lower DILI risk and a much longer in vitro half-life. The lower DILI risk is particularly important, as liver toxicity is a major concern in drug development. The longer half-life also suggests a potentially more convenient dosing regimen. The similar metabolic stability and hERG risk profiles further support this conclusion. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:50:47,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.439 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (100.21) is slightly higher than the ideal <140, but acceptable. Ligand B (54.78) is excellent, well below 140.

**logP:** Ligand A (-1.569) is a bit low, potentially hindering permeation. Ligand B (1.671) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (4) is good.

**QED:** Both ligands have good QED scores (0.517 and 0.814), indicating drug-like properties.

**DILI:** Ligand A (21.946) has a lower DILI risk than Ligand B (27.065), both are acceptable.

**BBB:** Ligand A (45.715) and Ligand B (69.407) are both relatively low, which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.31 and -4.567), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.428 and -0.532), also unusual and concerning.

**hERG Inhibition:** Ligand A (0.041) has a very low hERG risk, which is excellent. Ligand B (0.267) is also low, but slightly higher than A.

**Microsomal Clearance:** Ligand A (5.641) has a lower (better) microsomal clearance than Ligand B (33.179), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.381) has a significantly longer half-life than Ligand B (4.716).

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is favorable. Ligand B (0.141) is also low.

**Binding Affinity:** Ligand B (-8.7) has a stronger binding affinity than Ligand A (-7.5), a difference of 1.2 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a lower hERG risk, the significantly stronger binding affinity of Ligand B (-8.7 vs -7.5 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of B is likely to outweigh these issues, especially during lead optimization where these properties can be improved. The slightly better logP of B also contributes to its favorability.

Output:
1
2025-04-17 16:50:47,892 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [345.487, 56.41, 3.07, 1, 2, 0.892, 31.524, 70.26, -4.692, -3.397, 0.716, 61.454, -16.5, 0.413, -8.1]
**Ligand B:** [352.479, 68.62, 1.503, 1, 6, 0.647, 8.957, 82.513, -4.633, -0.915, 0.421, 46.934, 34.037, 0.012, -7.6]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (345.487) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.
2. **TPSA:** A (56.41) is better than B (68.62).  Both are below 140, suggesting reasonable oral absorption potential, but A is closer to the preferred range for kinase inhibitors.
3. **logP:** A (3.07) is optimal, while B (1.503) is a bit low.  Low logP can hinder membrane permeability.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A (2) is better than B (6). Higher HBA can sometimes reduce permeability.
6. **QED:** A (0.892) is significantly better than B (0.647), indicating a more drug-like profile.
7. **DILI:** A (31.524) is much better than B (8.957).  A is well below the 40% threshold, while B is approaching a concerning level.
8. **BBB:** B (82.513) is better than A (70.26). However, since SRC is not a CNS target, this is less crucial.
9. **Caco-2:** A (-4.692) is better than B (-4.633). Higher values indicate better absorption.
10. **Solubility:** A (-3.397) is better than B (-0.915). Solubility is important for bioavailability, and A has a better score.
11. **hERG:** A (0.716) is better than B (0.421). Lower hERG inhibition is crucial for avoiding cardiotoxicity.
12. **Cl_mic:** B (46.934) is significantly better than A (61.454). Lower clearance indicates better metabolic stability.
13. **t1/2:** B (34.037) is much better than A (-16.5). A negative half-life is problematic.
14. **Pgp:** A (0.413) is better than B (0.012). Lower P-gp efflux is desirable for improved bioavailability.
15. **Affinity:** B (-7.6) is slightly better than A (-8.1). While A has a better affinity, the difference is not substantial enough to overcome its other drawbacks.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While B has a slightly better affinity, A has a much better solubility, hERG profile, and DILI risk. However, B's significantly better metabolic stability (lower Cl_mic and positive t1/2) is a major advantage. The negative half-life of A is a critical flaw.

**Conclusion:**

Despite the slightly better affinity of Ligand A, the significantly better metabolic stability and positive half-life of **Ligand B** make it the more promising drug candidate. The negative half-life of ligand A is a major red flag.

1
2025-04-17 16:50:47,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.369 Da and 365.796 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.29) is slightly above the optimal <140 for good absorption, but acceptable. Ligand B (80.12) is well within the range.

**logP:** Both ligands have good logP values (0.97 and 1.544, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.607 and 0.833), indicating drug-like properties.

**DILI:** Ligand B (74.99) has a considerably better DILI score than Ligand A (35.595), suggesting a lower risk of liver injury. This is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (83.986 and 76.774), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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 ligands have negative solubility values, which is also unusual and suggests poor solubility. However, the scale is not specified, so it is hard to interpret.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.33 and 0.105), which is excellent.

**Microsomal Clearance:** Ligand B (-2.281) has significantly *lower* (better) microsomal clearance than Ligand A (13.429). This indicates greater metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-15.027) has a significantly longer (better) in vitro half-life than Ligand A (-17.414). This supports the improved metabolic stability suggested by the clearance data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.095).

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent and removes this as a differentiating factor.

**Conclusion:**

While both ligands have good potency, Ligand B is superior due to its significantly better DILI score and, crucially, much improved metabolic stability (lower Cl_mic and longer t1/2). These factors are highly important for kinase inhibitors, as they influence drug exposure and duration of action. The slightly lower TPSA and better QED also contribute to its favorability. The unusual negative values for Caco-2 and solubility are concerning, but the other factors outweigh these issues.

Output:
1
2025-04-17 16:50:47,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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. Ligand B (365.455 Da) is also good.

**TPSA:** Ligand A (76.66) is well below the 140 threshold for oral absorption. Ligand B (100.55) is still acceptable but less optimal.

**logP:** Ligand A (3.195) is within the optimal range (1-3). Ligand B (0.561) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is excellent. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.857, Ligand B: 0.64), indicating good drug-like properties.

**DILI:** Ligand A (49.128) has a lower DILI risk than Ligand B (62.156), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (78.17) has a better BBB score than Ligand B (32.726).

**Caco-2 Permeability:** Ligand A (-4.618) has a worse Caco-2 permeability than Ligand B (-5.488).

**Aqueous Solubility:** Ligand A (-3.246) has a worse solubility than Ligand B (-1.784).

**hERG:** Both ligands have very low hERG risk (Ligand A: 0.466, Ligand B: 0.093), which is excellent.

**Microsomal Clearance:** Ligand A (19.932) has a higher microsomal clearance than Ligand B (5.937), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (34.409) has a longer half-life than Ligand B (1.943), which is a positive. However, this benefit is likely offset by the higher clearance.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.049, Ligand B: 0.046).

**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 can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better DILI and BBB scores, Ligand B's superior binding affinity (-7.5 vs -6.9 kcal/mol) and lower microsomal clearance (5.937 vs 19.932) are more critical for an enzyme target like SRC kinase. The lower logP of Ligand B is a concern, but the strong binding affinity might compensate for this. The better solubility of Ligand B is also a plus. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:50:47,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.471 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.0) is significantly better than Ligand B (88.32). Lower TPSA generally improves cell permeability.

**logP:** Ligand A (3.707) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (2.042) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as it has fewer HBDs, which can sometimes hinder permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.759 and 0.828), indicating good drug-like properties.

**DILI:** Ligand A (33.191) has a much lower DILI risk than Ligand B (58.666), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration (68.748 and 78.247), but this is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.393) has a more negative Caco-2 value, which is unusual and suggests very *poor* permeability. Ligand B (-4.873) is also poor, but comparatively better.

**Aqueous Solubility:** Ligand A (-4.424) has poor solubility, while Ligand B (-2.571) is also poor but better.

**hERG:** Ligand A (0.822) shows a lower hERG risk than Ligand B (0.266), which is a positive.

**Microsomal Clearance:** Ligand A (76.882) has a higher microsomal clearance, indicating faster metabolism and lower metabolic stability. Ligand B (26.933) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (7.605) has a positive half-life, while Ligand B (-21.197) has a negative half-life, which is unusual and suggests very rapid degradation.

**P-gp Efflux:** Ligand A (0.203) has lower P-gp efflux, which is preferable. Ligand B (0.14) is also low.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better 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:**

Ligand A has a better binding affinity and lower DILI risk and hERG risk. However, it suffers from poor Caco-2 permeability, poor solubility, and higher metabolic clearance. Ligand B has better metabolic stability (lower Cl_mic) and slightly better solubility, but has a higher DILI risk and weaker binding affinity.

Considering the priorities for kinase inhibitors (potency, metabolic stability, solubility, and hERG), the binding affinity advantage of Ligand A is significant. While its solubility and permeability are concerns, these could potentially be addressed through formulation strategies. The lower DILI risk is also a major benefit. The metabolic stability of Ligand B is good, but the weaker binding affinity is a bigger drawback for an enzyme target.

Output:
1
2025-04-17 16:50:47,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (364.562 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 140 A^2 threshold for good oral absorption, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (2.51 and 2.691), 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:** Both have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.78 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A (28.887) has a significantly higher DILI risk than Ligand B (11.671). This is a major concern.

**8. BBB:** Both have reasonable BBB penetration (71.772 and 77.084), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.894 and -4.957). This is unusual and suggests poor permeability, but the scale is not specified. Assuming it's a log scale, these values are very low.

**10. Aqueous Solubility:** Both have negative solubility values (-2.802 and -2.46). Similar to Caco-2, this is concerning and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.11) has a slightly lower hERG risk than Ligand B (0.554), which is preferable.

**12. Microsomal Clearance:** Ligand A (37.289) has lower microsomal clearance than Ligand B (48.983), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.43) has a negative half-life, which is impossible. This is a significant red flag. Ligand B (0.559) has a very short half-life.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.189 and 0.116).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly better binding affinity than Ligand A (-8.8 kcal/mol). A 1.2 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the better candidate despite its slightly higher hERG risk and shorter half-life. Ligand A has a critical flaw: an impossible negative in vitro half-life, and a significantly higher DILI risk. While both have poor solubility and permeability, the superior binding affinity of Ligand B outweighs these concerns, especially for a kinase inhibitor where potency is paramount. The difference in binding affinity is large enough to potentially overcome ADME liabilities with further optimization.

Output:
1
2025-04-17 16:50:47,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (361.467 and 399.969 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (63.91 and 62.3) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (2.613 and 3.193) 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 reasonable H-bond characteristics, well within the recommended limits.

**QED:** Both ligands have identical QED scores of 0.825, indicating strong drug-like properties.

**DILI:** Ligand A (70.919) has a higher DILI risk than Ligand B (56.689), but both are acceptable, being below the concerning 60 threshold.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.264) has a higher BBB percentile than Ligand B (61.264), but this is not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.433) and Ligand B (-5.324) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a potential concern for both.

**Aqueous Solubility:** Ligand A (-2.58) has better solubility than Ligand B (-4.5). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.287 and 0.41 respectively).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (34.099 and 32.039 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-1.627) has a slightly longer in vitro half-life than Ligand B (0.033), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.553 and 0.271).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better solubility and half-life, the significantly stronger binding affinity of Ligand B (-8.7 vs -8.1 kcal/mol) is the most critical factor for an enzyme inhibitor. The ADME properties of both are reasonably good, and the difference in DILI risk is not substantial enough to favor Ligand A. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:50:47,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (339.403 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.66) is better than Ligand B (60.85), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.804 and 2.201), 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:** Ligand A (0.748) has a significantly better QED score than Ligand B (0.513), indicating a more drug-like profile.

**DILI:** Ligand A (71.074) has a higher DILI risk than Ligand B (5.312). This is a significant drawback for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (58.356) and Ligand B (65.607) are both relatively low.

**Caco-2 Permeability:** Ligand A (-5.19) and Ligand B (-4.679) both have negative values, which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so the closer to zero, the better.

**Aqueous Solubility:** Ligand A (-3.246) has poorer solubility than Ligand B (-1.14). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.281) has a slightly higher hERG risk than Ligand B (0.451), but both are relatively low.

**Microsomal Clearance:** Ligand A (29.268) has a lower (better) microsomal clearance than Ligand B (35.881), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (43.501) has a longer half-life than Ligand B (-1.402). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.127), which is favorable for bioavailability.

**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 can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better QED, metabolic stability, half-life, and P-gp efflux, the significantly higher DILI risk and lower solubility are major concerns. Ligand B has a much lower DILI risk and better solubility, and crucially, a substantially stronger binding affinity. The potency advantage of Ligand B outweighs the slightly less favorable ADME properties.

Output:
1
2025-04-17 16:50:47,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.459 and 362.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.22) is slightly above the preferred <140, but acceptable. Ligand B (65.54) is well within the acceptable range.

**logP:** Both ligands (1.896 and 2.255) 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 5 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.794 and 0.892), indicating good drug-likeness.

**DILI:** Ligand A (33.695) has a lower DILI risk than Ligand B (40.83), both being acceptable (<40 is good).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (78.402) has a higher BBB percentile than Ligand A (67.584).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.832 and -4.977). This is unusual and indicates poor permeability. However, these values are on a log scale, and the negative values suggest very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.277 and -2.643), indicating poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.253 and 0.33).

**Microsomal Clearance:** Ligand A (31.5 mL/min/kg) has a lower microsomal clearance than Ligand B (42.139 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.334 hours) has a negative half-life, which is not possible. This is a major red flag. Ligand A (17.428 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.309).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.3 and -8.1 kcal/mol). The difference is minimal.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising candidate. While both have poor solubility and permeability, Ligand B has a nonsensical negative in vitro half-life, making it immediately unsuitable. Ligand A has a better half-life, lower DILI risk, and lower microsomal clearance, all of which are crucial for an enzyme inhibitor. The binding affinity difference is negligible. Therefore, despite the shared solubility/permeability issues, Ligand A is the better starting point for optimization.

Output:
0
2025-04-17 16:50:47,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.415 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.45) is better than Ligand B (94.9), both are under the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.05) is optimal (1-3), while Ligand B (-0.505) is below 1, potentially hindering permeation. This is a significant drawback for B.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Ligand A (0.846) has a higher QED score than Ligand B (0.734), indicating better overall drug-likeness.

**DILI:** Ligand A (57.387) has a higher DILI risk than Ligand B (36.681), but both are acceptable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (75.378) has a better BBB score than Ligand B (45.56).

**Caco-2 Permeability:** Ligand A (-4.348) has a better Caco-2 permeability than Ligand B (-4.995).

**Aqueous Solubility:** Ligand A (-3.983) has better aqueous solubility than Ligand B (-0.716). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.193 and 0.163).

**Microsomal Clearance:** Ligand B (-28.989) has significantly lower (better) microsomal clearance than Ligand A (77.298), indicating better metabolic stability. This is a key advantage for B.

**In vitro Half-Life:** Ligand B (30.318) has a much longer in vitro half-life than Ligand A (-12.97), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.115 and 0.01).

**Binding Affinity:** Both ligands have the same binding affinity (-8.9 kcal/mol), which is excellent.

**Conclusion:**

While Ligand A has a slightly better TPSA and QED, Ligand B demonstrates significantly superior ADME properties, particularly regarding metabolic stability (lower Cl_mic and longer t1/2) and solubility. The lower logP of Ligand B is a concern, but the excellent binding affinity might compensate for this. Given the enzyme-specific priorities, metabolic stability and solubility are crucial. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:50:47,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.471 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (375.535 Da) is still well within the range.

**TPSA:** Ligand A (66.53) is significantly better than Ligand B (87.74). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (4.334) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.712) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have acceptable numbers of HBD (1 & 2 respectively) and HBA (5 each).

**QED:** Both ligands have reasonable QED scores (0.881 and 0.61), indicating good drug-like properties.

**DILI:** Ligand A (35.401) has a much lower DILI risk than Ligand B (8.181), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (79.217) has a better BBB percentile than Ligand B (68.36).

**Caco-2 Permeability:** Ligand A (-4.914) has a more negative Caco-2 value, indicating poorer permeability compared to Ligand B (-5.335), though both are quite poor.

**Aqueous Solubility:** Ligand A (-5.226) has a more negative solubility score, indicating lower solubility than Ligand B (-1.203).

**hERG:** Both ligands have low hERG inhibition liability (0.679 and 0.399), which is good.

**Microsomal Clearance:** Ligand B (-7.499) has a *negative* microsomal clearance, which is highly unusual and suggests very high metabolic stability. Ligand A (51.636) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-37.053) has a very long in vitro half-life, consistent with the negative clearance. Ligand A (-4.468) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.397 and 0.011).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better DILI risk and BBB penetration, Ligand B's significantly stronger binding affinity (-7.9 vs -6.5 kcal/mol) and exceptionally high metabolic stability (negative Cl_mic, very long half-life) are crucial for an enzyme target like SRC kinase. The lower logP and solubility of Ligand B are concerns, but the potency advantage and metabolic stability are likely to be more impactful in this case.

Output:
1
2025-04-17 16:50:47,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight:** Both ligands (358.5 & 333.4 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (62.73) as both are well below the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (2.809) is optimal, while Ligand B (4.323) is pushing the upper limit and could potentially cause 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, while Ligand B has 5. Both are below the 10 limit, but A is slightly better.

**6. QED:** Both ligands have similar QED values (0.666 and 0.63), indicating good drug-likeness.

**7. DILI:** Ligand A (22.26) has a significantly lower DILI risk than Ligand B (76.46). This is a crucial advantage.

**8. BBB:** This is less important for a non-CNS target like SRC kinase. Ligand A (71.54) is slightly better than Ligand B (68.17).

**9. Caco-2 Permeability:** Ligand A (-4.647) has better Caco-2 permeability than Ligand B (-5.117), suggesting better absorption.

**10. Aqueous Solubility:** Ligand A (-2.495) has better aqueous solubility than Ligand B (-4.334).

**11. hERG Inhibition:** Ligand A (0.634) has a lower hERG inhibition liability than Ligand B (0.861), reducing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (27.211) has a lower microsomal clearance than Ligand B (88.532), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (62.641) has a significantly longer in vitro half-life than Ligand A (5.235). This is a potential advantage for dosing frequency.

**14. P-gp Efflux:** Ligand A (0.375) has lower P-gp efflux liability than Ligand B (0.753), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial difference (1.3 kcal/mol), and a key factor to consider.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates significantly better ADME-Tox properties. Specifically, the much lower DILI risk, better solubility, lower hERG inhibition, and improved metabolic stability (lower Cl_mic) are critical advantages for an enzyme target like SRC kinase. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand A. The poor ADME profile of Ligand B raises serious concerns about its developability.

Output:
0
2025-04-17 16:50:47,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (351.422 and 348.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.32) is slightly above the preferred <90 for optimal absorption, while Ligand B (78.87) is well within the range.

**3. logP:** Both ligands have good logP values (1.844 and 0.849), 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 H-bond acceptors, well below the limit of 10.

**6. QED:** Both ligands have acceptable QED scores (0.755 and 0.551), indicating good drug-like properties.

**7. DILI:** Ligand B (18.728) has a significantly lower DILI risk than Ligand A (44.862), which is a major advantage.

**8. BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand A (60.45) and Ligand B (28.848) are both relatively low.

**9. Caco-2 Permeability:** Both ligands have similar negative Caco-2 values (-4.72 and -4.734), suggesting poor permeability. This is a potential concern for oral bioavailability.

**10. Aqueous Solubility:** Both ligands have similar negative solubility values (-1.898 and -1.705), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.189 and 0.098), which is excellent.

**12. Microsomal Clearance:** Ligand A (2.851) has slightly higher microsomal clearance than Ligand B (2.18), suggesting potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.53) has a more negative value, which indicates a longer in vitro half-life than Ligand A (1.431).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.037).

**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 substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand B has better ADME properties (lower DILI, better half-life), the significantly superior binding affinity of Ligand A (-8.5 vs 0.0 kcal/mol) is a decisive factor for an enzyme target like SRC kinase. A strong binding affinity can often be optimized through further medicinal chemistry efforts to improve ADME properties. The poor solubility and permeability are concerning, but addressable. The lower DILI risk of Ligand B is attractive, but the difference in binding affinity is too large to ignore.

Output:
1
2025-04-17 16:50:47,893 - INFO - Batch 497 complete. Total preferences: 7952
2025-04-17 16:50:47,893 - INFO - Processing batch 498/512...
2025-04-17 16:51:37,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and priorities for enzymes.

**1. Molecular Weight (MW):** Both ligands (350.547 Da and 361.389 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (70.16) is still under 140, but less favorable than A.

**3. logP:** Ligand A (3.562) is within the optimal range (1-3). Ligand B (1.322) is at the lower end, potentially impacting permeability.

**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 (2) and Ligand B (4) are both under the 10 limit.

**6. QED:** Both ligands have similar QED values (0.796 and 0.741), indicating good drug-likeness.

**7. DILI:** Ligand A (22.179) has a significantly lower DILI risk than Ligand B (47.305), which is a major advantage. Both are below the 60 threshold, but A is much safer.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (90.306) is slightly better than Ligand B (84.102).

**9. Caco-2 Permeability:** Ligand A (-4.547) and Ligand B (-3.993) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't fully defined, so this is hard to interpret.

**10. Aqueous Solubility:** Ligand A (-4.26) and Ligand B (-1.609) both have negative values, suggesting poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Ligand A (0.738) shows a lower hERG risk than Ligand B (0.415), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand A (91.927) has a higher Cl_mic than Ligand B (41.336), indicating faster metabolism and lower metabolic stability. This is a disadvantage for A.

**13. In vitro Half-Life (t1/2):** Ligand B (-23.354) has a significantly longer half-life than Ligand A (1.719), a major advantage.

**14. P-gp Efflux:** Ligand A (0.255) has lower P-gp efflux than Ligand B (0.068), which is favorable.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Enzyme-Specific Priorities:** For an enzyme like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and half-life, while Ligand A has better DILI and P-gp efflux. The lower Cl_mic of Ligand B is a significant benefit. While both have poor solubility and permeability, the superior affinity and metabolic stability of Ligand B are more critical for an enzyme inhibitor.

Output:
1
2025-04-17 16:51:37,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (362.495 Da and 351.445 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (58.64 and 55.63) well below the 140 threshold for good oral absorption.

**3. logP:** Ligand A (2.335) is optimal, while Ligand B (3.084) is slightly higher, 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 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have high QED scores (0.894 and 0.8), indicating good drug-like properties.

**7. DILI:** Ligand A (27.336) has a significantly lower DILI risk than Ligand B (44.436). This is a major advantage.

**8. BBB:** Both have high BBB penetration (81.737 and 91.586), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.061 and -4.879), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.771 and -3.759), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.385 and 0.443), which is excellent.

**12. Microsomal Clearance:** Ligand A (26.383) has a higher microsomal clearance than Ligand B (13.812), indicating lower metabolic stability. Ligand B is better here.

**13. In vitro Half-Life:** Ligand B (16.124) has a longer in vitro half-life than Ligand A (9.81), which is preferable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.191 and 0.545).

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to outweigh other issues, it's still a positive.

**Overall Assessment:**

Ligand A is preferable despite the lower metabolic stability and shorter half-life. The significantly lower DILI risk is a major advantage. Both compounds suffer from poor solubility and permeability, but the DILI risk is a more critical factor in early drug development. The slightly better binding affinity of Ligand A further supports its selection.

Output:
0
2025-04-17 16:51:37,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.299 Da) is slightly higher than Ligand B (353.507 Da), but both are acceptable.

**TPSA:** Ligand A (38.13) is well below the 140 threshold for oral absorption. Ligand B (70.67) is still within acceptable limits, but higher.

**logP:** Ligand A (3.883) is at the upper end of the optimal range (1-3), while Ligand B (1.829) is towards the lower end.  Ligand A's higher logP *could* lead to solubility issues, but isn't immediately disqualifying.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 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 similar QED values (0.759 and 0.698), indicating good drug-like properties.

**DILI:** Ligand A (39.589) has a slightly higher DILI risk than Ligand B (11.09), but both are below the 40 threshold and considered good.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (85.537) has better BBB penetration than Ligand B (54.789), but this is not a major factor in this case.

**Caco-2 Permeability:** Ligand A (-4.892) has poor Caco-2 permeability, while Ligand B (-5.093) is also poor. Both are negative values which is concerning.

**Aqueous Solubility:** Ligand A (-2.461) and Ligand B (-1.168) both have poor aqueous solubility, which is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.947) has a slightly higher hERG risk than Ligand B (0.212). Ligand B is much preferred here.

**Microsomal Clearance:** Ligand A (52.138) has significantly higher microsomal clearance than Ligand B (2.303), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (14.044) has a shorter half-life than Ligand B (18.179), further supporting the concern about its metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.901 and 0.013), which is favorable.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a decisive advantage.

**Conclusion:**

Ligand B is the superior candidate. While both have solubility and permeability concerns, Ligand B's significantly stronger binding affinity, lower hERG risk, and much better metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher TPSA. The substantial difference in binding affinity (-6.9 vs 0 kcal/mol) is a critical factor for an enzyme target.

Output:
1
2025-04-17 16:51:37,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.459 Da and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (99.0 and 100.99) are reasonably close to the 140 A^2 threshold for oral absorption, but not ideal for CNS penetration.

**logP:** Ligand A (1.826) is optimal, while Ligand B (0.417) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (2 HBD, 6 HBA) both fall within acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.838 and 0.658, both >0.5).

**DILI:** Ligand A (74.137) has a higher DILI risk than Ligand B (41.024), which is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (68.786) is slightly better than Ligand B (46.064).

**Caco-2 Permeability:** Both are negative (-5.03 and -4.835), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both are negative (-2.733 and -1.635), indicating very poor solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.324 and 0.151), which is excellent.

**Microsomal Clearance:** Ligand B (-0.962) has significantly *lower* (better) microsomal clearance than Ligand A (12.557), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.902) has a much longer in vitro half-life than Ligand A (-10.897), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.188 and 0.015).

**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 unlikely to be decisive.

**Conclusion:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly improved metabolic stability (lower Cl_mic and longer t1/2) and lower DILI risk outweigh the slightly lower logP and comparable binding affinity. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:51:37,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):**
* Ligand A: 364.72 Da - Within the ideal range (200-500 Da).
* Ligand B: 340.471 Da - Also within the ideal range.
* *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 114.25 - Acceptable, but approaching the upper limit for good oral absorption (<=140).
* Ligand B: 50.16 - Excellent, well below the 140 threshold.
* *Ligand B is better.*

**3. Lipophilicity (logP):**
* Ligand A: 3.96 - Slightly high, potentially leading to solubility issues or off-target effects.
* Ligand B: 2.743 - Optimal, within the 1-3 range.
* *Ligand B is better.*

**4. H-Bond Donors (HBD):**
* Ligand A: 0 - Low, potentially impacting solubility.
* Ligand B: 1 - Acceptable.
* *Ligand B is better.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 6 - Acceptable, within the limit of 10.
* Ligand B: 4 - Acceptable, within the limit of 10.
* *No clear advantage.*

**6. QED:**
* Ligand A: 0.344 - Below the desirable threshold of 0.5, indicating a less drug-like profile.
* Ligand B: 0.91 - Excellent, highly drug-like.
* *Ligand B is significantly better.*

**7. DILI Risk:**
* Ligand A: 87.98 - High risk of Drug-Induced Liver Injury.
* Ligand B: 18.573 - Low risk of DILI.
* *Ligand B is significantly better.*

**8. BBB Penetration:**
* Ligand A: 76.696 - Moderate. Not a primary concern for a non-CNS target like SRC.
* Ligand B: 78.092 - Moderate. Not a primary concern for a non-CNS target like SRC.
* *No clear advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -4.264 - Poor permeability.
* Ligand B: -4.997 - Poor permeability.
* *Similar, both are poor.*

**10. Aqueous Solubility:**
* Ligand A: -5.325 - Very poor solubility.
* Ligand B: -2.46 - Poor solubility, but better than Ligand A.
* *Ligand B is better.*

**11. hERG Inhibition:**
* Ligand A: 0.253 - Low risk of hERG inhibition.
* Ligand B: 0.544 - Moderate risk.
* *Ligand A is better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 97.795 - High clearance, suggesting poor metabolic stability.
* Ligand B: 21.077 - Low clearance, suggesting good metabolic stability.
* *Ligand B is significantly better.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 55.595 - Moderate half-life.
* Ligand B: 13.685 - Short half-life.
* *Ligand A is better.*

**14. P-gp Efflux:**
* Ligand A: 0.416 - Moderate P-gp efflux.
* Ligand B: 0.282 - Moderate P-gp efflux.
* *No clear advantage.*

**15. Binding Affinity:**
* Ligand A: 0.0 - Weak binding.
* Ligand B: -9.0 - Very strong binding.
* *Ligand B is significantly better.*

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand B is clearly superior. While both have poor Caco-2 permeability, Ligand B's significantly stronger binding affinity (-9.0 kcal/mol vs 0.0 kcal/mol), much lower DILI risk, better QED, and improved metabolic stability (lower Cl_mic) outweigh its slightly shorter half-life and moderate hERG risk. Ligand A's poor solubility, weak binding, and high DILI risk are major drawbacks.

Output:
1
2025-04-17 16:51:37,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (347.375 and 343.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.35) is slightly above the preferred <140, but acceptable. Ligand B (91.32) is excellent, well below 140.

**3. logP:** Ligand A (0.751) is a bit low, potentially hindering permeability. Ligand B (1.992) is 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, good QED values (0.764 and 0.762), indicating good drug-like properties.

**7. DILI:** Ligand A (70.958) has a higher DILI risk than Ligand B (30.748). This is a significant concern.

**8. BBB:** BBB is less critical for a non-CNS target like SRC. Ligand A (46.762) and Ligand B (37.844) are both low.

**9. Caco-2:** Both are negative, indicating poor permeability. This is a concern for oral bioavailability.

**10. Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a significant drawback.

**11. hERG:** Both ligands have very low hERG risk (0.21 and 0.151), which is excellent.

**12. Cl_mic:** Ligand A (13.009) has a higher microsomal clearance than Ligand B (5.022). This suggests Ligand B is more metabolically stable.

**13. t1/2:** Ligand A (-10.719) has a negative in vitro half-life, which is concerning. Ligand B (-7.5) is also negative, but less so. Negative values here likely indicate rapid degradation, and should be interpreted cautiously.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.028 and 0.041), which is good.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 2.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility and permeability issues, Ligand B has a significantly better binding affinity, lower DILI risk, and better metabolic stability (lower Cl_mic). The stronger binding affinity is a major advantage for an enzyme target like SRC kinase. The slightly better logP of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 16:51:37,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.515 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (83.36). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hint at poorer permeability.

**logP:** Both ligands have acceptable logP values (3.524 and 2.427, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 5. Ligand A is better here, as fewer HBA generally leads to better permeability.

**QED:** Both ligands have similar QED scores (0.774 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (12.369) has a much lower DILI risk than Ligand B (35.556). This is a significant advantage for Ligand A.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (85.459) has a higher BBB percentile than Ligand B (64.831).

**Caco-2 Permeability:** Ligand A (-4.706) has a slightly better (less negative) Caco-2 value than Ligand B (-5.023), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.077) has better aqueous solubility than Ligand B (-1.804). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.52) shows a lower hERG inhibition liability than Ligand B (0.187). This is a crucial advantage, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (72.431) has a higher (worse) microsomal clearance than Ligand B (24.188). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (14.903) has a significantly longer in vitro half-life than Ligand A (-12.466). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.273) has lower P-gp efflux liability than Ligand B (0.036), which is favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 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 metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A excels in several critical ADME properties: lower DILI risk, better solubility, lower hERG inhibition, and lower P-gp efflux. The superior binding affinity of Ligand B is compelling, but the significantly improved safety profile (DILI, hERG) and better solubility of Ligand A make it a more promising starting point for drug development, especially considering the potential for optimization to improve its metabolic stability.

Output:
0
2025-04-17 16:51:37,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 373.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is well below the 140 threshold for good absorption, while Ligand B (107.78) is still acceptable but closer to the limit.

**logP:** Ligand A (2.231) is within the optimal 1-3 range. Ligand B (0.455) is slightly below 1, which *could* indicate permeability issues, but isn't a severe concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, both well within acceptable limits. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have QED values (0.687 and 0.515) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (13.339) has a significantly lower DILI risk than Ligand B (39.162). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (74.952) is slightly better than Ligand A (64.793). However, BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both 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 are percentile scores and higher is better.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, assuming these are percentile scores, higher is better.

**hERG Inhibition:** Ligand A (0.249) has a much lower hERG risk than Ligand B (0.34). This is a significant advantage.

**Microsomal Clearance:** Ligand A (51.549) has a lower microsomal clearance than Ligand B (93.548), indicating better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-9.528) has a much longer in vitro half-life than Ligand B (-59.916). This is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.067 and 0.033).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), though both are good. The 0.7 kcal/mol difference is meaningful.

**Overall:**

Ligand A is significantly better across several critical parameters for an enzyme inhibitor: DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and binding affinity. While Ligand B has slightly better BBB penetration, this is less crucial for a non-CNS-targeted kinase inhibitor. The solubility and Caco-2 values are questionable, but the other advantages of Ligand A outweigh these concerns.

Output:
1
2025-04-17 16:51:37,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (343.475 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.05) is better than Ligand B (87.74). Lower TPSA generally favors better cell permeability.

**3. logP:** Ligand A (2.441) is optimal, while Ligand B (0.695) is slightly low, potentially hindering 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 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.854 and 0.789), indicating good drug-likeness.

**7. DILI:** Ligand A (32.028) has a significantly lower DILI risk than Ligand B (53.276), which is a major advantage.

**8. BBB:** Both ligands have similar BBB penetration (79.488 and 78.247). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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 difference.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Ligand A (0.119) has a slightly higher hERG risk than Ligand B (0.109), but both are quite low.

**12. Microsomal Clearance:** Ligand B (-5.936) has *much* lower microsomal clearance than Ligand A (15.074). This indicates significantly better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-4.65) has a much longer in vitro half-life than Ligand A (25.213). This is another strong advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.123 and 0.012).

**15. Binding Affinity:** Ligand B (-6.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most crucial factor for an enzyme inhibitor.

**Overall Assessment:**

While Ligand A has a better TPSA and slightly lower hERG risk, Ligand B overwhelmingly wins due to its significantly improved metabolic stability (lower Cl_mic, longer t1/2) and *much* stronger binding affinity. The lower DILI risk for Ligand A is a positive, but the potency advantage of Ligand B is substantial enough to outweigh that concern, especially considering the similar permeability profiles. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:51:37,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.392 Da) is slightly higher than Ligand B (353.463 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand B (87.74) is better than Ligand A (98.91).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (0.681) is slightly lower, but still acceptable. Ligand A (1.153) is also good.

**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 QED values above 0.5, indicating good drug-like properties. Ligand B (0.627) is slightly better than Ligand A (0.493).

**DILI:** Ligand A has a DILI risk of 54.517, which is acceptable (below 60). Ligand B has a much lower DILI risk of 8.647, a significant advantage.

**BBB:** Both ligands have moderate BBB penetration (around 50-52%). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands 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 negative solubility values, which is also unusual and suggests poor solubility. This is a potential red flag for both.

**hERG Inhibition:** Ligand A (0.835) has a slightly higher hERG risk than Ligand B (0.199). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-3.483), indicating very high metabolic stability. Ligand B has a positive Cl_mic (6.807), suggesting faster metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (-20.623) than Ligand B (-10.569), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.006), which is good.

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). While it has a slightly higher DILI risk and hERG inhibition, the substantial improvement in potency and metabolic stability are critical for an enzyme target like SRC. The poor Caco-2 and solubility are concerning, but could potentially be addressed with formulation strategies. Ligand B has a better safety profile (lower DILI, hERG) and slightly better TPSA, but its weaker binding affinity and faster metabolism are significant drawbacks.

Output:
1
2025-04-17 16:51:37,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.419 and 372.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.19) is higher than Ligand B (75.27). While both are reasonably good, Ligand B is better positioned for oral absorption due to the lower TPSA.

**logP:** Ligand A (-0.026) is quite low, potentially hindering permeation. Ligand B (3.617) 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, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.602 and 0.575), indicating good drug-likeness.

**DILI:** Ligand A (34.781) has a higher DILI risk than Ligand B (20.24). This is a clear advantage for Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (71.811) has a higher BBB percentile than Ligand A (40.016).

**Caco-2 Permeability:** Ligand A (-5.652) has a negative Caco-2 value, which is concerning. Ligand B (-4.749) is also negative, but less so. Both suggest poor intestinal absorption, but Ligand B is slightly better.

**Aqueous Solubility:** Ligand A (-1.691) has slightly better solubility than Ligand B (-3.438).

**hERG Inhibition:** Ligand A (0.059) shows a slightly lower hERG risk than Ligand B (0.35), which is preferable.

**Microsomal Clearance:** Ligand A (-26.871) has a much lower (better) microsomal clearance than Ligand B (83.521). This suggests significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-24.575) has a longer half-life than Ligand B (-2.93). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.007) has a lower P-gp efflux liability than Ligand B (0.183), which is favorable.

**Binding Affinity:** Ligand B (-8.7) 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:**

Ligand B has a superior binding affinity and better logP and DILI scores. However, Ligand A exhibits much better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly lower hERG risk. The low logP of Ligand A is a concern, but the strong affinity of Ligand B is a major positive. Given that SRC is an enzyme, metabolic stability and potency are key. The 1.9 kcal/mol difference in binding affinity is substantial. While Ligand A has better ADME properties in some areas, the potency advantage of Ligand B is likely to be more impactful for efficacy.

Output:
1
2025-04-17 16:51:37,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.394 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.55) is better than Ligand B (67.87), both are below the 140 cutoff for oral absorption, but Ligand A is slightly higher and could potentially impact permeability more.

**logP:** Ligand A (0.692) is a bit low, potentially hindering permeation. Ligand B (2.286) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.67 and 0.802), indicating drug-like properties.

**DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (39.046). This favors Ligand B.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (69.833) is slightly better than Ligand A (58.317).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.725 and -4.639), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.462 and -2.96), which is also concerning and indicates very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.165) has a slightly lower hERG risk than Ligand B (0.461), which is preferable.

**Microsomal Clearance:** Ligand A (0.832) has significantly lower microsomal clearance than Ligand B (37.337), indicating better metabolic stability. This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (6.995) has a shorter half-life than Ligand B (34.196), which is less desirable.

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux than Ligand B (0.177), suggesting better bioavailability.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.2 and -8.9 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has better logP, lower DILI risk, and a longer half-life. However, Ligand A has significantly better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly lower hERG risk. The poor Caco-2 and solubility for both are major concerns. Given the enzyme-specific priorities, metabolic stability is crucial. The strong binding affinity of both ligands mitigates some of the ADME concerns. Considering the balance, the improved metabolic stability of Ligand A is more valuable than the slightly better logP and half-life of Ligand B.

Output:
0
2025-04-17 16:51:37,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (343.435 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.07) is slightly higher than Ligand B (69.72). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (0.448) is a bit low, potentially hindering permeation. Ligand B (1.737) is 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 (0.843 and 0.783), indicating drug-like properties.

**DILI:** Ligand A (20.512) has a significantly lower DILI risk than Ligand B (38.309), which is a major advantage.

**BBB:** Ligand A (54.672) has a lower BBB penetration than Ligand B (74.176). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.541 and -5.2), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.2 and -2.336), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.601) has a lower hERG risk than Ligand B (0.211), which is preferable.

**Microsomal Clearance:** Ligand A (-42.212) has a *much* lower (better) microsomal clearance than Ligand B (17.804), indicating significantly better metabolic stability.

**In vitro Half-Life:** Ligand B (20.157 hours) has a considerably longer half-life than Ligand A (0.621 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.011) has a lower P-gp efflux liability than Ligand B (0.061), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, microsomal clearance, and P-gp efflux. However, its low logP and very short half-life are major concerns. Ligand B has better logP, half-life, and BBB penetration, but suffers from higher DILI risk and a slightly weaker binding affinity.

Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the lower DILI and significantly better metabolic stability (lower Cl_mic) of Ligand A are more compelling, despite its solubility and half-life issues. Solubility and half-life can be addressed through formulation and further medicinal chemistry optimization, respectively. The DILI risk and metabolic instability of Ligand B are harder to fix.

Output:
0
2025-04-17 16:51:37,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.805 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (66.92) is also below 140, but less optimal than A.

**logP:** Ligand A (4.845) is slightly high, potentially causing solubility issues or off-target effects. Ligand B (2.239) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is excellent. Ligand B (0 HBD, 4 HBA) is also acceptable.

**QED:** Ligand A (0.707) has a strong drug-like profile. Ligand B (0.471) is lower, indicating a less desirable overall profile.

**DILI:** Ligand A (90.733) has a high DILI risk, which is a significant concern. Ligand B (19.504) has a very low DILI risk, a major advantage.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand B (75.107) is better than Ligand A (61.535). This isn't a primary concern for a kinase inhibitor, but a bonus.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental data or the compounds themselves. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a significant drawback for both, but potentially more problematic for Ligand A given its higher logP.

**hERG Inhibition:** Ligand A (0.632) has a slightly elevated hERG risk, while Ligand B (0.328) is lower.

**Microsomal Clearance:** Ligand A (20.678) has a lower Cl_mic, indicating better metabolic stability. Ligand B (85.586) has a much higher Cl_mic, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (97.933) has a very long in vitro half-life, consistent with its low Cl_mic. Ligand B (-15.672) has a negative half-life, which is impossible and indicates a data issue.

**P-gp Efflux:** Ligand A (0.269) has low P-gp efflux, which is good. Ligand B (0.063) is even lower, which is excellent.

**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:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer half-life) and P-gp efflux. However, its high DILI risk, elevated hERG, and poor solubility are major concerns. Ligand B has a much better safety profile (low DILI, lower hERG), better BBB penetration, and lower P-gp efflux. However, it has weaker binding affinity and significantly worse metabolic stability.

Given the enzyme-specific priorities, potency (affinity) is crucial. The 1.8 kcal/mol difference in binding affinity is substantial and could outweigh some of Ligand A's drawbacks *if* the solubility and toxicity issues can be addressed through further optimization. However, the high DILI risk is a serious red flag. The negative half-life for Ligand B is a clear data quality issue.

Considering the totality of the data, and prioritizing safety and reasonable ADME properties, I would cautiously favor Ligand A *with the caveat that significant medicinal chemistry effort would be needed to mitigate the DILI and solubility issues*.

Output:
0
2025-04-17 16:51:37,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (386.21 and 366.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is well below the 140 threshold, while Ligand B (123.13) is still acceptable but higher.

**logP:** Ligand A (3.953) is at the upper end of the optimal range (1-3), while Ligand B (-0.084) is significantly below, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 9 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.763 and 0.726), indicating good drug-likeness.

**DILI:** Ligand A (85.77) has a higher DILI risk than Ligand B (59.597). This is a concern for Ligand A.

**BBB:** Both have similar BBB penetration (61.535 and 62.117), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.472) has poor Caco-2 permeability, while Ligand B (-5.705) is also poor.

**Aqueous Solubility:** Ligand A (-5.021) has poor aqueous solubility, and Ligand B (-1.545) is also poor.

**hERG Inhibition:** Ligand A (0.363) has a lower hERG inhibition risk than Ligand B (0.048), which is favorable.

**Microsomal Clearance:** Ligand A (78.123) has a higher microsomal clearance than Ligand B (20.469), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (73.843) has a longer half-life than Ligand B (-1.154), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux than Ligand B (0.013), which is favorable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), though both are excellent. The 0.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility and permeability issues, Ligand B's significantly better metabolic stability (lower Cl_mic, though negative half-life is concerning) and slightly stronger binding affinity outweigh Ligand A's better hERG profile and half-life. The lower DILI risk for Ligand B is also a positive factor. The negative half-life for Ligand B is a major concern that would need to be addressed in further optimization.

Output:
1
2025-04-17 16:51:37,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.5 & 360.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is slightly higher than Ligand B (59.08), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.107) is optimal, while Ligand B (1.147) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, fitting the <5 and <10 rules. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.633 and 0.579), indicating good drug-likeness.

**DILI:** Ligand A (11.632) has a significantly lower DILI risk than Ligand B (34.277), a major advantage.

**BBB:** Both have good BBB penetration (74.254 and 84.451), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.539) shows a slightly higher hERG risk than Ligand B (0.499), but both are relatively low.

**Microsomal Clearance:** Ligand A (72.044) has higher microsomal clearance than Ligand B (22.731), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-31.496) has a much longer in vitro half-life than Ligand A (-8.701), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.044).

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol), a 0.6 kcal/mol difference. While a 1.5 kcal/mol advantage is usually significant, 0.6 kcal/mol is less impactful given the other factors.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has slightly better binding affinity, Ligand B exhibits significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a more favorable logP. These factors are crucial for an enzyme target like SRC kinase, outweighing the small difference in binding affinity.

Output:
1
2025-04-17 16:51:37,111 - INFO - Batch 498 complete. Total preferences: 7968
2025-04-17 16:51:37,111 - INFO - Processing batch 499/512...
2025-04-17 16:52:19,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (427.324 Da) is slightly higher, but still acceptable. Ligand B (356.369 Da) is preferable.

**TPSA:** Both ligands have TPSA values (84.3 and 81.86) well below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have optimal logP values (2.485 and 1.571) falling within the 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:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.816 and 0.75), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 70.725, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (30.089), making it more favorable.

**BBB:** Both ligands have good BBB penetration (72.547 and 94.843), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.776 and -4.71), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.39 and -2.658), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.304) has a slightly better hERG profile than Ligand B (0.634), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (27.797) than Ligand B (9.571), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A has a very long half-life (99.968 hours), while Ligand B has a negative half-life (-13.52 hours), which is not physically possible and indicates a very rapid degradation. This is a huge advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.255 and 0.088), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), but the difference is small (0.2 kcal/mol) and may not be enough to overcome the other drawbacks.

**Overall Assessment:**

Ligand A has significant advantages in metabolic stability (lower Cl_mic, much longer half-life) and lower DILI risk, and a slightly better hERG profile. Ligand B has a slightly better binding affinity and BBB penetration, but suffers from a very poor half-life and higher DILI risk. The poor solubility and permeability are concerning for both, but the metabolic stability and safety profile of Ligand A are more compelling for further development, even with the need to address solubility.

Output:
1
2025-04-17 16:52:19,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.5 and 361.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.7) is higher than Ligand B (46.84). While both are acceptable, Ligand B is better positioned for oral absorption due to its lower TPSA.

**logP:** Both ligands have similar logP values (4.08 and 4.32), 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.

**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 6 HBAs, well within the acceptable limit of <=10.

**QED:** Ligand A (0.817) has a higher QED score than Ligand B (0.667), suggesting a more drug-like profile overall.

**DILI:** Ligand B (30.322) has a significantly lower DILI risk than Ligand A (64.521). This is a major advantage for Ligand B.

**BBB:** Ligand A (74.292) has a slightly higher BBB penetration potential than Ligand B (85.653), but BBB is less crucial for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.162 and -5.259), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.028 and -4.148). This is a major concern for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.602 and 0.734).

**Microsomal Clearance:** Ligand B (71.593) has a higher microsomal clearance than Ligand A (62.185), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (20.762 and 19.942 hours), which are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.419 and 0.491).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -9.2 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has a slightly better QED and BBB score, Ligand B is significantly better regarding DILI risk and has a lower TPSA. The poor Caco-2 permeability and solubility are major concerns for both. However, the substantially lower DILI risk for Ligand B makes it the more promising candidate, especially considering the importance of minimizing toxicity in oncology drug development. The similar binding affinities mean the ADME properties are the deciding factor.

Output:
1
2025-04-17 16:52:19,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (381.607 Da) is also good.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (29.54). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target.

**logP:** Ligand A (1.86) is optimal, while Ligand B (4.803) is high. High logP can lead to poor solubility and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are within acceptable limits. Ligand B has 0 HBD and 4 HBA, also acceptable, but the lack of HBD might slightly hinder solubility.

**QED:** Ligand A (0.747) has a better QED score than Ligand B (0.545), indicating a more drug-like profile.

**DILI:** Ligand A (16.906) has a significantly lower DILI risk than Ligand B (19.581), which is a major advantage.

**BBB:** Both have relatively low BBB penetration, which isn't a primary concern for a non-CNS target like SRC. Ligand B (77.084) is higher than Ligand A (55.603), but this is not a deciding factor.

**Caco-2 Permeability:** Ligand A (-4.624) has a worse Caco-2 permeability than Ligand B (-5.008), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.592) has better solubility than Ligand B (-4.819). Solubility is crucial for bioavailability.

**hERG Inhibition:** Ligand A (0.246) has a much lower hERG inhibition liability than Ligand B (0.795), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (11.367) has a lower microsomal clearance than Ligand B (118.604), suggesting better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-19.289) has a much longer in vitro half-life than Ligand B (21.65), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.774), which is beneficial for oral bioavailability.

**Binding Affinity:** Ligand B (-6.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). However, the difference of 2.8 kcal/mol, while noticeable, is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, better solubility, lower hERG inhibition, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. These factors are particularly important for kinase inhibitors, where achieving adequate concentrations at the target site is essential.

Output:
0
2025-04-17 16:52:19,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.471 and 360.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (67.23), both are below the 140 threshold for good absorption.

**logP:** Both ligands (2.404 and 2.498) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Ligand B (0.91) has a significantly better QED score than Ligand A (0.72), indicating a more drug-like profile.

**DILI:** Ligand A (34.82) has a lower DILI risk than Ligand B (59.287), which is a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand A (71.811) is slightly better than Ligand B (68.166). This is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.704) has better Caco-2 permeability than Ligand B (-4.954).

**Aqueous Solubility:** Ligand A (-2.57) has better aqueous solubility than Ligand B (-3.494).

**hERG:** Both ligands have very low hERG inhibition risk (0.35 and 0.329).

**Microsomal Clearance:** Ligand B (14.556) has significantly lower microsomal clearance than Ligand A (60.893), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (24.538 hours) has a longer half-life than Ligand A (18.721 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.183 and 0.179).

**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 a meaningful, but not overwhelming advantage.

**Overall Assessment:**

Ligand B has a better QED score, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. However, Ligand A has a lower DILI risk and better solubility. Given the enzyme-specific priorities, metabolic stability is crucial. The 0.6 kcal/mol difference in binding affinity is less important than the substantial improvement in metabolic stability offered by Ligand B. The lower DILI risk of Ligand A is a plus, but can be addressed in later optimization stages.

Output:
1
2025-04-17 16:52:19,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (374.34 Da and 374.344 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.17) is better than Ligand B (98.58), both are acceptable but A is closer to the <140 threshold for good absorption.

**logP:** Ligand A (3.166) is optimal, while Ligand B (1.834) is slightly lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 7 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.572 and 0.755), indicating drug-like properties.

**DILI:** Ligand A (69.329) has a better DILI score than Ligand B (79.604), indicating lower potential for liver injury. Both are acceptable, but A is better.

**BBB:** Ligand A (81.815) has a higher BBB percentile than Ligand B (42.226), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.857) has a much better Caco-2 permeability than Ligand B (-5.111).

**Aqueous Solubility:** Ligand A (-4.325) has better solubility than Ligand B (-3.786). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.728) has a lower hERG risk than Ligand B (0.438), which is a significant advantage.

**Microsomal Clearance:** Ligand A (34.108) has a significantly better (lower) microsomal clearance than Ligand B (7.614), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (47.706) has a much longer half-life than Ligand B (-14.648), which is a major advantage.

**P-gp Efflux:** Ligand A (0.547) has a lower P-gp efflux liability than Ligand B (0.041), which is favorable.

**Binding Affinity:** Ligand B (-8.2 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:** Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, including lower DILI risk, better solubility, lower hERG inhibition, improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. These factors are crucial for developing a viable drug candidate, especially for a kinase inhibitor where chronic dosing is often required.

Output:
0
2025-04-17 16:52:19,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.487 and 350.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (49.41) is excellent, well below 140.

**logP:** Both ligands have good logP values (1.318 and 3.367), 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 1 HBD and 2 HBA, also acceptable and potentially better for permeability.

**QED:** Both ligands have good QED scores (0.574 and 0.79), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (25.514 and 22.644), both below the 40 threshold.

**BBB:** Ligand A (53.509) and Ligand B (94.223). BBB is less critical for a non-CNS target like SRC, but higher is generally better. Ligand B is better here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -4.847), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.202 and -3.949), indicating poor aqueous solubility. This is a significant concern for both.

**hERG:** Both ligands have low hERG risk (0.493 and 0.532), which is good.

**Microsomal Clearance:** Ligand A (20.207) has a lower Cl_mic than Ligand B (43.758), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (19.377) has a longer half-life than Ligand B (0.633), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.118 and 0.156), which is good.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, the significantly stronger binding affinity of Ligand B (-7.7 kcal/mol vs -6.2 kcal/mol) is a major advantage that likely outweighs its higher Cl_mic and shorter half-life. The improved BBB penetration is also a plus. Although Ligand A has better metabolic stability, the potency difference is substantial. Addressing solubility and permeability issues are formulation challenges that can be overcome.

Output:
1
2025-04-17 16:52:19,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.443 and 351.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is better than Ligand B (47.36), being below the 140 A^2 threshold for good oral absorption. Ligand B is excellent.

**logP:** Both ligands have acceptable logP values (2.012 and 3.503), falling within the 1-3 range. Ligand B is slightly higher, potentially raising concerns about off-target effects, but not drastically.

**H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.743 and 0.674), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 53.121, while Ligand B has 14.541. Ligand B is significantly better regarding liver injury risk.

**BBB:** Ligand A has a BBB penetration of 63.746, while Ligand B has 95.696. While SRC is not a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-5.014) and Ligand B (-4.616) have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.824 and -2.798). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.255) has a slightly lower hERG inhibition risk than Ligand B (0.715), which is preferable.

**Microsomal Clearance:** Ligand A (30.961) has a lower microsomal clearance than Ligand B (64.883), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.129) has a negative half-life, which is concerning. Ligand B (3.356) has a short half-life, but is positive.

**P-gp Efflux:** Ligand A (0.126) has lower P-gp efflux than Ligand B (0.458), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a major deciding factor.

**Overall Assessment:**

Ligand A has advantages in metabolic stability (lower Cl_mic), P-gp efflux, and hERG risk. However, it has a concerning negative in vitro half-life. Ligand B excels in DILI risk and BBB penetration, but has higher microsomal clearance and P-gp efflux. Both have poor solubility and Caco-2 permeability. Given the importance of metabolic stability for kinase inhibitors, and the slightly better hERG profile, Ligand A is marginally more promising, *if* the negative half-life can be addressed through structural modifications. However, the poor solubility of both compounds is a major hurdle.

Output:
0
2025-04-17 16:52:19,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.49 and 354.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (90.98) is at the upper limit of acceptable for oral absorption, but still within range.

**logP:** Ligand A (2.204) is optimal (1-3). Ligand B (0.733) is slightly below 1, potentially impacting permeability.

**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 A (0.829) has a higher QED than Ligand B (0.521), indicating a more drug-like profile.

**DILI:** Ligand B (41.411) has a lower DILI risk than Ligand A (10.392), which is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC kinase, but Ligand A (90.035) has better BBB penetration than Ligand B (55.254).

**Caco-2 Permeability:** Ligand A (-4.664) has a much more negative Caco-2 value than Ligand B (-5.032), suggesting lower permeability.

**Aqueous Solubility:** Ligand A (-2.64) has better solubility than Ligand B (-1.759).

**hERG Inhibition:** Ligand A (0.482) has a lower hERG risk than Ligand B (0.311), which is preferable.

**Microsomal Clearance:** Ligand B (-5.427) has a much lower (better) microsomal clearance than Ligand A (46.41), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (9.787) has a longer half-life than Ligand A (1.323), which is desirable.

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.023), which is preferable.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). The difference is 0.4 kcal/mol, which is not substantial enough to outweigh other ADME concerns.

**Overall Assessment:**

Ligand B demonstrates superior ADME properties, particularly in metabolic stability (lower Cl_mic, longer t1/2) and DILI risk. While Ligand A has slightly better binding affinity and solubility, the difference in affinity is small, and the ADME profile of Ligand B is more favorable for drug development. The lower logP of Ligand B is a minor concern, but can potentially be addressed through further optimization.

Output:
1
2025-04-17 16:52:19,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.821 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.92) is better than Ligand B (52.65), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (4.352) is higher than optimal (1-3), while Ligand B (2.182) is within the optimal range. This favors Ligand B initially, but a slightly high logP can sometimes be tolerated if other properties are excellent.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (4 for A, 3 for B) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.598 and 0.793), indicating good drug-like properties.

**DILI:** Ligand A (87.243) has a significantly higher DILI risk than Ligand B (11.361). This is a major concern for Ligand A.

**BBB:** Both have similar BBB penetration (64.482 and 67.546). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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:** Ligand A (0.707) has a slightly higher hERG risk than Ligand B (0.471), but both are relatively low.

**Microsomal Clearance:** Ligand B (7.263) has a much lower microsomal clearance than Ligand A (46.524), indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (11.103) has a longer in vitro half-life than Ligand A (96.511), which is also a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.749) has a higher P-gp efflux liability than Ligand B (0.088). This is a negative for Ligand A.

**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 for Ligand A.

**Overall Assessment:**

Despite the better binding affinity of Ligand A, its significantly higher DILI risk, higher microsomal clearance, shorter half-life, and higher P-gp efflux liability make it a less desirable candidate. Ligand B, while having a weaker binding affinity, exhibits a much more favorable ADMET profile, particularly its low DILI risk and improved metabolic stability. For an enzyme target like SRC kinase, metabolic stability and minimizing toxicity (DILI) are crucial. The difference in binding affinity, while notable, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 16:52:19,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.429 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 140 threshold for oral absorption. Ligand B (122.14) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (3.039) is optimal. Ligand B (1.249) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is ideal. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have similar QED values (0.562 and 0.555), indicating good drug-likeness.

**DILI:** Ligand A (34.82) has a much lower DILI risk than Ligand B (58.24), which is a significant advantage.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (93.68) shows better BBB penetration than Ligand B (31.214).

**Caco-2 Permeability:** Ligand A (-5.078) has a negative Caco-2 value which is unusual and suggests poor permeability. Ligand B (-5.769) also has a negative Caco-2 value, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.193) and Ligand B (-1.832) both have negative solubility values which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.638) has a lower hERG risk than Ligand B (0.035), which is a crucial advantage for safety.

**Microsomal Clearance:** Ligand A (22.493) has a higher microsomal clearance than Ligand B (-1.666). This suggests Ligand B is more metabolically stable, which is a key consideration for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (11.691 hours) has a longer half-life than Ligand A (9.187 hours), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.017), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, lower DILI risk, and lower hERG risk. However, it has poor Caco-2 permeability and solubility, and higher microsomal clearance. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, but weaker binding affinity, higher DILI and hERG risk, and lower BBB penetration.

Given the importance of potency for enzyme inhibitors, the significantly stronger binding affinity of Ligand A (-7.8 kcal/mol vs -6.9 kcal/mol) is the most critical factor. While the permeability and solubility issues are concerning, these can potentially be addressed through formulation strategies or further chemical modifications. The lower safety liabilities of Ligand A are also very important.

Output:
1
2025-04-17 16:52:19,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.443 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.78) is better than Ligand B (111.28), both are below the 140 threshold for oral absorption, but A is closer to the ideal for kinase inhibitors.

**logP:** Ligand A (2.566) is optimal (1-3), while Ligand B (0.674) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (7), both are below the 10 threshold, but A is closer to the ideal.

**QED:** Both ligands have good QED scores (0.45 and 0.644 respectively), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (42.303) has a lower DILI risk than Ligand B (56.727), both are acceptable (<60).

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (54.13) and Ligand B (50.679) are comparable.

**Caco-2 Permeability:** Ligand A (-4.875) is better than Ligand B (-5.227), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.721) is better than Ligand B (-1.597), indicating better solubility.

**hERG Inhibition:** Ligand A (0.547) shows lower hERG inhibition risk than Ligand B (0.363), which is preferable.

**Microsomal Clearance:** Ligand A (47.555) has higher clearance than Ligand B (36.58), indicating lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (-26.083) has a significantly longer half-life than Ligand A (-15.364), a major advantage.

**P-gp Efflux:** Ligand A (0.364) has lower P-gp efflux than Ligand B (0.12), which is preferable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has better solubility, lower DILI, and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-8.7 vs -7.0 kcal/mol) and longer half-life are critical advantages for an enzyme inhibitor. The slightly lower logP and higher DILI of Ligand B are less concerning given the potency and stability benefits.

Output:
1
2025-04-17 16:52:19,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (345.363 and 357.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.04) is better than Ligand B (62.53), being closer to the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (-0.189) is quite low, potentially hindering permeability. Ligand B (3.678) 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 8 HBAs, while Ligand B has 6. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.721 and 0.757), indicating good drug-like properties.

**DILI:** Both have relatively high DILI risk (79.333 and 70.066), but Ligand B is slightly better.

**BBB:** Both have moderate BBB penetration (53.587 and 61.613). Not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.54 and -4.921), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.139 and -3.595), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.029) has a very low hERG risk, which is excellent. Ligand B (0.867) has a higher, but still moderate, hERG risk.

**Microsomal Clearance:** Ligand A (42.385) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (68.528).

**In vitro Half-Life:** Ligand A (-12.782) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (60.843) has a reasonable in vitro half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.134 and 0.599).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). While both are good, the 0.3 kcal/mol difference is substantial and can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a better hERG profile and metabolic stability, but suffers from very low logP, questionable half-life data, and poor solubility. Ligand B has a better logP, a reasonable half-life, and significantly better binding affinity. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies. The superior binding affinity of Ligand B is a key advantage for an enzyme inhibitor.

Output:
1
2025-04-17 16:52:19,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.475 and 353.413 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (56.41). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands (2.189 and 2.394) 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 2 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.904) has a significantly better QED score than Ligand A (0.492), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (33.501 and 33.773 percentile).

**BBB:** Ligand B (85.459) shows better BBB penetration than Ligand A (60.295), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.672 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 (-3.221 and -2.394). This is also a major concern, indicating very poor solubility.

**hERG Inhibition:** Ligand A (0.118) has a lower hERG risk than Ligand B (0.738), which is favorable.

**Microsomal Clearance:** Ligand A (85.44 mL/min/kg) has a significantly lower (better) microsomal clearance than Ligand B (16.874 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.573 hours) has a longer half-life than Ligand A (-16.694 hours), which is a slight advantage.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux than Ligand B (0.229), which is favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This is a 0.4 kcal/mol difference.

**Conclusion:**

While Ligand B has a better QED score and slightly better affinity and half-life, Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux. The poor Caco-2 and solubility for both are major drawbacks that would need to be addressed through formulation or further chemical modification. However, for an enzyme target, metabolic stability and minimizing off-target effects (hERG) are more crucial than perfect permeability. The 0.4 kcal/mol difference in binding affinity is unlikely to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 16:52:19,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.405 Da) is slightly higher than Ligand B (352.519 Da), but both are acceptable.

**TPSA:** Ligand A (90.41) is slightly above the optimal <90 for CNS penetration, but still reasonable. Ligand B (69.64) is well within the acceptable range.

**logP:** Both ligands have good logP values (A: 2.795, B: 3.005), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=8) and Ligand B (HBD=2, 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 good QED scores (A: 0.548, B: 0.705), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a significantly higher DILI risk (93.059) than Ligand B (12.214). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (A: 84.955, B: 73.129). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.911 and -4.731), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.862 and -2.193), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.321) has a slightly better hERG profile than Ligand B (0.505), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (98.647) has very high microsomal clearance, suggesting poor metabolic stability. Ligand B (29.141) has much lower clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-6.058) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (10.463) has a reasonable in vitro half-life.

**P-gp Efflux:** Ligand A (0.37) has lower P-gp efflux than Ligand B (0.207), which is favorable.

**Binding Affinity:** Ligand B (-7.8 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 more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand A has a very high DILI risk, extremely high microsomal clearance (poor metabolic stability), and an impossible half-life value. Ligand B has a significantly better safety profile (lower DILI), better metabolic stability, and a reasonable half-life. The slightly better binding affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 16:52:19,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.274 Da) is slightly higher than Ligand B (348.443 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (67.23) is better than Ligand B (76.66).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.9) is slightly higher than Ligand B (1.158), which is good.

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD and HBA counts (<=5 and <=10 respectively). Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) are both fine.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.78) is slightly better than Ligand B (0.706).

**DILI:** Both ligands have DILI risk below 60, indicating low risk. Ligand A (37.728) is slightly better than Ligand B (50.33).

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (78.558) has a better BBB percentile than Ligand B (66.227).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.739) is better than Ligand B (-5.103).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.171) is slightly better than Ligand B (-2.717).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.286 and 0.154 respectively), which is excellent.

**Microsomal Clearance:** Ligand B (22.164 mL/min/kg) has significantly lower microsomal clearance than Ligand A (50.576 mL/min/kg), suggesting better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (3.574 hours) has a slightly better in vitro half-life than Ligand A (-39.652 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.129 respectively).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and outweighs many of the other minor differences.

**Conclusion:**

While Ligand A has slightly better TPSA, logP, QED, and DILI, Ligand B excels in the most critical areas for an enzyme inhibitor: significantly stronger binding affinity (-8.4 vs -7.4 kcal/mol) and much better metabolic stability (lower Cl_mic and better t1/2). The slightly lower solubility and permeability of Ligand B are less concerning given the strong binding and improved metabolic profile.

Output:
1
2025-04-17 16:52:19,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.459 Da and 383.627 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.99) is excellent, well below the 140 threshold for oral absorption. Ligand B (38.13) is also very good.

**logP:** Ligand A (0.599) is a bit low, potentially hindering permeation. Ligand B (4.157) is at the upper end of the optimal range, potentially causing solubility issues but acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, fitting well within the guidelines. Ligand B has 0 HBD and 5 HBA, also good.

**QED:** Both ligands have similar QED values (0.673 and 0.608), indicating good drug-likeness.

**DILI:** Ligand A (55.525) has a moderate DILI risk, while Ligand B (14.23) has a very low risk, which is a significant advantage.

**BBB:** Ligand A (53.587) has a low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (83.133) has good BBB penetration, but this isn't a priority here.

**Caco-2 Permeability:** Ligand A (-5.144) has poor Caco-2 permeability, a potential issue for oral absorption. Ligand B (-4.854) also has poor Caco-2 permeability, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.143) has poor aqueous solubility, a significant drawback. Ligand B (-3.875) also has poor solubility, but worse than A.

**hERG Inhibition:** Ligand A (0.124) has very low hERG inhibition risk, excellent. Ligand B (0.556) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (21.035) has a moderate microsomal clearance. Ligand B (110.074) has a very high microsomal clearance, indicating poor metabolic stability, a major concern.

**In vitro Half-Life:** Ligand A (-1.352) has a very short half-life, which is unfavorable. Ligand B (21.498) has a long half-life, a significant advantage.

**P-gp Efflux:** Ligand A (0.021) has low P-gp efflux, which is good. Ligand B (0.421) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-6.7) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference and a major positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and a lower hERG risk, but suffers from poor solubility, permeability, and metabolic stability (high Cl_mic, short half-life). Ligand B has better metabolic stability (long half-life) and a significantly lower DILI risk, but its binding affinity is very poor.

Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are crucial. While Ligand A's affinity is better, the combination of poor metabolic stability and solubility, along with a moderate DILI risk, makes it a less attractive candidate. Ligand B's extremely poor affinity is a major drawback, but the significantly better safety profile and metabolic stability are compelling.

However, the difference in binding affinity is too large to ignore. A small improvement in metabolic stability of Ligand A could make it a viable candidate.

Output:
0
2025-04-17 16:52:19,282 - INFO - Batch 499 complete. Total preferences: 7984
2025-04-17 16:52:19,282 - INFO - Processing batch 500/512...
2025-04-17 16:53:05,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (359.455 and 352.475 Da) fall within the ideal 200-500 Da range. No significant difference here.

**TPSA:** Both ligands (80.12 and 87.66) are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands (1.272 and 1.221) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 3. Ligand A is slightly favored here, as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the 10 threshold.

**QED:** Ligand A (0.872) has a significantly higher QED score than Ligand B (0.613), indicating a more drug-like profile.

**DILI:** Ligand A (60.644) has a higher DILI risk than Ligand B (15.665). This is a significant concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (55.138 and 51.803). Not a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.178 and -5.084), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.944 and -1.909), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.049) has a slightly lower hERG risk than Ligand B (0.181), which is preferable.

**Microsomal Clearance:** Ligand A (28.138) has a higher microsomal clearance than Ligand B (18.48), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (10.445) has a slightly longer half-life than Ligand B (1.502).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.045).

**Binding Affinity:** Ligand A (-10.7 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. A difference of 3.3 kcal/mol is quite large.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a better QED score, and slightly better hERG risk. However, it has a significantly higher DILI risk and lower metabolic stability. Ligand B has a much lower DILI risk and better metabolic stability, but weaker binding affinity and a lower QED score.

Given the importance of potency for kinase inhibitors, the significantly stronger binding affinity of Ligand A (-10.7 kcal/mol vs -7.4 kcal/mol) is a major advantage. While the DILI risk is concerning, it might be mitigated through structural modifications in subsequent optimization rounds. The solubility issues are also a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:53:05,080 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [355.337, 65.07, 2.119, 0., 5., 0.761, 68.592, 83.133, -3.848, -2.926, 0.319, 67.076, 5.595, 0.052, 0.]
**Ligand B:** [342.399, 95.16, 0.847, 2., 4., 0.796, 54.789, 40.946, -4.995, -3.53, 0.279, 23.004, -22.366, 0.038, -9.4]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). Ligand A (355.337) is slightly higher, but both are acceptable.
2. **TPSA:** Ligand A (65.07) is better than Ligand B (95.16).  TPSA < 140 is good for oral absorption, and both meet this, but A is preferable.
3. **logP:** Ligand A (2.119) is optimal (1-3). Ligand B (0.847) is a bit low, potentially impacting permeability.
4. **HBD:** Ligand A (0) is good. Ligand B (2) is acceptable, but fewer is generally better.
5. **HBA:** Ligand A (5) is good. Ligand B (4) is also good.
6. **QED:** Both ligands (A: 0.761, B: 0.796) have excellent drug-likeness scores.
7. **DILI:** Ligand A (68.592) is higher risk than Ligand B (54.789), but both are within acceptable limits (<60 is good).
8. **BBB:** Ligand A (83.133) is significantly better than Ligand B (40.946). While not a primary concern for a kinase inhibitor, higher BBB is never a detriment.
9. **Caco-2:** Ligand A (-3.848) is worse than Ligand B (-4.995). Lower (more negative) values are less favorable here, indicating lower permeability.
10. **Solubility:** Ligand A (-2.926) is worse than Ligand B (-3.53). Lower (more negative) values are less favorable here, indicating lower solubility.
11. **hERG:** Both ligands (A: 0.319, B: 0.279) have low hERG risk, which is excellent.
12. **Cl_mic:** Ligand A (67.076) is higher than Ligand B (23.004), indicating faster metabolism and lower metabolic stability. This is a significant drawback for A.
13. **t1/2:** Ligand A (5.595) is much shorter than Ligand B (-22.366). A negative value indicates a very long half-life, which is highly desirable.
14. **Pgp:** Both ligands (A: 0.052, B: 0.038) have low P-gp efflux, which is good.
15. **Binding Affinity:** Ligand B (-9.4) has *much* stronger binding affinity than Ligand A (0). This is a decisive advantage.

**Enzyme-Kinase Specific Priorities:**

For a kinase inhibitor, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B excels in affinity and metabolic stability (long half-life, low Cl_mic), and has acceptable solubility and hERG risk. Ligand A has a weaker affinity, faster metabolism, and lower solubility. The substantial difference in binding affinity (-9.4 vs 0) is likely to outweigh any minor advantages Ligand A might have.

**Conclusion:**

Ligand B is the superior candidate.

1
2025-04-17 16:53:05,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.462 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is slightly higher than Ligand B (69.64), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.983 and 2.578), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and either 5 or 4 HBA, which are acceptable.

**QED:** Both ligands have high QED scores (0.832 and 0.865), indicating good drug-like properties.

**DILI:** Ligand A (65.762) has a higher DILI risk than Ligand B (37.456). This is a significant concern, as we want to minimize liver toxicity.

**BBB:** Both have good BBB penetration (70.027 and 77.007), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.987 and -4.913). 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.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.906 and -2.965). Again, these are likely log scales, and indicate poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.32) has a slightly lower hERG inhibition liability than Ligand B (0.434), which is preferable.

**Microsomal Clearance:** Ligand B (23.529) has a significantly *lower* microsomal clearance than Ligand A (10.659). This indicates better metabolic stability for Ligand B, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand B (-22.403) has a *longer* in vitro half-life than Ligand A (13.607). This is also a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.244 and 0.217).

**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 only 0.4 kcal/mol, which is less important than the ADME differences.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic), and longer half-life outweigh the small difference in binding affinity. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The lower DILI risk is a critical advantage.

Output:
1
2025-04-17 16:53:05,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (342.439 Da and 359.363 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.34) is better than Ligand B (40.54), both are well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.585) is within the optimal 1-3 range. Ligand B (4.252) is slightly higher, 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 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 and 2, respectively), well below the limit of 10.

**6. QED:** Ligand A (0.864) has a significantly better QED score than Ligand B (0.428), indicating a more drug-like profile.

**7. DILI:** Ligand A (46.064) has a higher DILI risk than Ligand B (16.479). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (55.099) and Ligand B (66.188) both have moderate BBB penetration. Since SRC is not a CNS target, this is not a major deciding factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close enough to not be a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. However, the values are close enough to not be a major differentiator.

**11. hERG Inhibition:** Ligand A (0.184) shows a slightly lower hERG inhibition risk than Ligand B (0.915), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (32.256) has a lower microsomal clearance than Ligand B (65.014), indicating better metabolic stability. This is a key advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (52.75) has a significantly longer in vitro half-life than Ligand B (13.564), further supporting its better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.179) has lower P-gp efflux liability than Ligand B (0.415), which is favorable for oral bioavailability.

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is small, and the other factors are more important.

**Overall Assessment:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A emerges as the more promising candidate. While Ligand B has a slightly better binding affinity and lower DILI risk, Ligand A's superior QED, lower Cl_mic, longer half-life, and lower P-gp efflux outweigh these advantages. The negative solubility and Caco-2 values are concerning for both, but could be addressed through formulation strategies. The slightly better hERG profile of Ligand A is also a plus.

Output:
0
2025-04-17 16:53:05,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (365.455 and 357.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.97) is significantly better than Ligand B (92.31).  A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.294 and 2.78, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (1 HBD, 8 HBA). Lower numbers are generally better for permeability.

**QED:** Both ligands have good QED scores (0.76 and 0.884), indicating good drug-like properties.

**DILI:** Ligand A (43.932) has a lower DILI risk than Ligand B (54.866), which is a significant advantage. Both are below the concerning threshold of 60, but lower is always better.

**BBB:** Ligand A (78.868) has a better BBB percentile than Ligand B (65.801), though BBB isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.957) has a worse Caco-2 permeability than Ligand B (-5.511). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-2.265) has better solubility than Ligand B (-3.295). Solubility is important for bioavailability.

**hERG:** Both ligands have very low hERG risk (0.162 and 0.156), which is excellent.

**Microsomal Clearance:** Ligand A (28.34 mL/min/kg) has a significantly better (lower) microsomal clearance than Ligand B (7.075 mL/min/kg). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-1.988 hours) has a worse half-life than Ligand B (0.927 hours). This is a drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.121 and 0.184).

**Binding Affinity:** Both ligands have identical binding affinities (-9.0 kcal/mol), which is excellent and the most important factor.

**Overall Assessment:**

Despite Ligand B having a slightly better Caco-2 and in vitro half-life, Ligand A is the superior candidate. The lower DILI risk, better TPSA, better solubility, and significantly improved metabolic stability (lower Cl_mic) outweigh the slight disadvantages in Caco-2 and half-life. The identical binding affinity means potency is not a differentiating factor. For an enzyme target like SRC kinase, metabolic stability and safety (DILI) are crucial, making Ligand A the more promising drug candidate.

Output:
0
2025-04-17 16:53:05,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (337.423 and 358.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (48.31 and 49.85) are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.317) is optimal, while Ligand B (1.733) is slightly lower, 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:** Both ligands have good QED scores (0.685 and 0.707), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (40.403 and 38.309), which is good.

**BBB:** Ligand B (97.363) has a much higher BBB penetration score than Ligand A (57.968). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.878 and -4.24). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close, so the difference is likely not substantial.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.332 and -2.886), indicating poor aqueous solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.922) has a slightly higher hERG risk than Ligand B (0.365), which is preferable.

**Microsomal Clearance:** Ligand B (23.3 mL/min/kg) has significantly lower microsomal clearance than Ligand A (38.377 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-21.386 hours) has a longer in vitro half-life than Ligand A (-33.482 hours). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.573) has slightly lower P-gp efflux liability than Ligand B (0.089), which is preferable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While both ligands have some issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.1 vs -7.1 kcal/mol), lower microsomal clearance, and longer half-life outweigh the slightly higher P-gp efflux and lower BBB penetration (which is less important for a non-CNS target). The lower hERG risk is also a positive.

Output:
1
2025-04-17 16:53:05,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.491 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (98.5), being comfortably under the 140 A^2 threshold for good absorption.

**logP:** Ligand A (1.874) is optimal, while Ligand B (0.427) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 7. Ligand A is preferable here, as higher HBA can sometimes reduce permeability.

**QED:** Both ligands have good QED scores (0.62 and 0.719), indicating drug-like properties.

**DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (61.07). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (58.55) is better than Ligand B (23.42).

**Caco-2 Permeability:** Ligand A (-4.237) is better than Ligand B (-5.244), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.757) is better than Ligand B (-1.971), indicating better solubility.

**hERG:** Ligand A (0.271) has a lower hERG risk than Ligand B (0.109), which is preferable.

**Microsomal Clearance:** Ligand A (48.462) has higher microsomal clearance than Ligand B (26.298), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-9.028) has a longer half-life than Ligand B (0.064), which is desirable.

**P-gp Efflux:** Ligand A (0.269) has lower P-gp efflux than Ligand B (0.084), indicating better bioavailability.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). This is a 1.8 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates a significantly more favorable ADMET profile. Specifically, the much lower DILI risk, better solubility, and improved permeability (Caco-2, P-gp) are crucial advantages. The difference in binding affinity (1.8 kcal/mol) can potentially be overcome with further optimization, while mitigating the ADMET liabilities of Ligand B would be far more challenging. Given the enzyme-kinase focus, metabolic stability is also important, and Ligand B has an advantage here. However, the longer half-life of Ligand A is also a positive. Considering all factors, the superior ADMET profile of Ligand A outweighs the slightly better binding affinity of Ligand B.

Output:
1
2025-04-17 16:53:05,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which could be advantageous for permeability. Ligand B (354.495 Da) is also good.

**TPSA:** Ligand A (62.3) is excellent, well below the 140 threshold for oral absorption. Ligand B (84.91) is still acceptable, but less optimal.

**logP:** Ligand A (1.921) is within the optimal range (1-3). Ligand B (-0.348) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=5) is slightly higher, but still within acceptable limits.

**QED:** Ligand A (0.891) is excellent, indicating high drug-likeness. Ligand B (0.555) is acceptable, but lower.

**DILI:** Ligand A (16.789) has a very low DILI risk. Ligand B (5.312) also has a low DILI risk, but is slightly higher than A.

**BBB:** Ligand A (76.347) shows good BBB penetration, though not exceptional. Ligand B (30.71) is low, suggesting limited CNS exposure. This isn't a primary concern for a non-CNS target like SRC, but it's a data point.

**Caco-2 Permeability:** Ligand A (-5.012) has poor Caco-2 permeability. Ligand B (-5.454) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.98 and -0.125 respectively). This is a significant concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.263 and 0.288 respectively).

**Microsomal Clearance:** Ligand A (11.088 mL/min/kg) is higher than Ligand B (0.615 mL/min/kg), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-12.697 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (5.391 hours) is a reasonable half-life, but could be improved.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.007 respectively).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and a lower DILI risk. The lower logP of Ligand B is a concern, but the improved metabolic stability and binding affinity outweigh this drawback. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 16:53:05,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.475 and 379.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is well below the 140 threshold for oral absorption, and even favorable for potential CNS penetration. Ligand B (96.87) is still within acceptable limits but less optimal.

**logP:** Ligand A (1.127) is within the optimal range (1-3). Ligand B (2.401) is also acceptable, though trending higher.

**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 below the limits of 5 and 10, respectively.

**QED:** Both ligands have similar and good QED values (0.827 and 0.831), indicating good drug-like properties.

**DILI:** Ligand A (20.706) has a significantly lower DILI risk than Ligand B (83.676). This is a major advantage for Ligand A.

**BBB:** Ligand A (81.698) shows better BBB penetration potential than Ligand B (57.193), though this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.145) has a worse Caco-2 permeability than Ligand B (-5.355), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.929) has better aqueous solubility than Ligand B (-3.206). This is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.383 and 0.276), which is excellent.

**Microsomal Clearance:** Ligand A (35.958) has a higher microsomal clearance than Ligand B (1.569), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-6.896) has a shorter in vitro half-life than Ligand B (31.397), further supporting the lower metabolic stability concern.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.09), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.2 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

While Ligand A has better solubility and a much lower DILI risk, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability. Given that we are targeting a kinase (enzyme), metabolic stability is a crucial factor. The higher DILI risk of Ligand B is concerning, but the substantial difference in metabolic stability is more critical for an enzyme target. The binding affinity difference is minimal. Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 16:53:05,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the enzyme-class guidelines.

**Molecular Weight:** Both ligands (348.443 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.52 and 72.96) are below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.109) is optimal, while Ligand B (-0.086) is significantly below the 1-3 range, which could hinder permeation.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.799 and 0.752), indicating drug-likeness.

**DILI:** Ligand A (54.866) has a moderate DILI risk, while Ligand B (8.841) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (65.413) has moderate BBB penetration, while Ligand B (44.009) has lower penetration. This is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.13) and Ligand B (-5.024) both have negative values, indicating poor permeability. This is concerning for both.

**Aqueous Solubility:** Ligand A (-4.701) and Ligand B (-1.004) both have negative values, indicating poor solubility. This is also concerning for both.

**hERG Inhibition:** Ligand A (0.077) has very low hERG risk, while Ligand B (0.298) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (95.125) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-2.263) has *very* low clearance, suggesting excellent metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-44.706) has a very short half-life, consistent with high clearance. Ligand B (-7.488) has a longer half-life, again supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.035) has low P-gp efflux, while Ligand B (0.007) has even lower efflux.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for Ligand A. The difference is >1.5 kcal/mol, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A boasts a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, it suffers from high metabolic clearance and a short half-life, and poor permeability/solubility. Ligand B has significantly better ADME properties (low DILI, excellent metabolic stability, low P-gp efflux), but its binding affinity is weaker.

Considering the priorities for kinase inhibitors, the superior binding affinity of Ligand A is a critical factor. While its ADME properties are suboptimal, the potency advantage is substantial. Optimization efforts could focus on improving the metabolic stability of Ligand A.

Output:
1
2025-04-17 16:53:05,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.479 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (71.11), both are below the 140 threshold for oral absorption, and acceptable for kinase inhibitors.

**logP:** Ligand A (2.844) is optimal, while Ligand B (0.238) is quite low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (3) 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 (0.677 and 0.741), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (33.307 and 28.073), which is favorable.

**BBB:** Ligand A (28.189) has a lower BBB penetration percentile than Ligand B (68.67). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-5.436) has significantly worse Caco-2 permeability than Ligand B (-4.543). This suggests lower intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-2.976) has worse solubility than Ligand B (-1.241). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.339 and 0.121), which is excellent.

**Microsomal Clearance:** Ligand A (47.544) and Ligand B (44.564) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-5.437) has a worse in vitro half-life than Ligand B (-2.394). This suggests faster metabolism for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.101 and 0.019).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.4 kcal/mol). Ligand B is slightly better.

**Conclusion:**

While both ligands exhibit excellent binding affinity and favorable safety profiles (DILI, hERG), Ligand B is superior due to its better logP, Caco-2 permeability, aqueous solubility, and in vitro half-life. Ligand A's poor logP and solubility, combined with lower permeability and shorter half-life, make it a less desirable candidate despite comparable metabolic stability. The slightly better affinity of Ligand B further strengthens its position.

Output:
1
2025-04-17 16:53:05,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.527 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Ligand A (93.64) is slightly higher than Ligand B (67.23). Both are below the 140 threshold for oral absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (Ligand A: 1.847, Ligand B: 2.081), 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 4 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (Ligand A: 0.779, Ligand B: 0.832), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.527, which is bordering on high risk. Ligand B has a much lower DILI risk of 19.426, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B is slightly better (67.08 vs 45.715).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.624) is slightly better than Ligand B (-4.912).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-1.491) is slightly better than Ligand A (-4.137).

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.292, Ligand B: 0.218), which is excellent.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (66.576) than Ligand B (27.991), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (-13.175 hours) than Ligand A (-40.005 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.072, Ligand B: 0.049).

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have comparable binding affinity, Ligand B is significantly better overall. It has a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and Caco-2 permeability. The DILI and metabolic stability differences are particularly important for an enzyme target like SRC kinase.

Output:
1
2025-04-17 16:53:05,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (363.527 and 365.543 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.3) is slightly higher than Ligand B (52.65). Both are acceptable, but Ligand B is better, being closer to the optimal <140 for oral absorption.

**logP:** Both ligands have good logP values (3.019 and 2.296), falling within the 1-3 range. Ligand B is slightly lower, which could potentially improve solubility.

**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 within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.764 and 0.683), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 39.434, which is good (low risk). Ligand B has a significantly lower DILI risk of 10.857, making it more favorable.

**BBB:** Both ligands have acceptable BBB penetration (69.252 and 63.086). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.677) has worse Caco-2 permeability than Ligand B (-5.249), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.289) has worse solubility than Ligand B (-1.059). Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.237) shows slightly higher hERG inhibition risk than Ligand B (0.701). Lower hERG risk is preferred.

**Microsomal Clearance:** Ligand A (57.104) has a higher microsomal clearance than Ligand B (24.562), suggesting lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand A (17.66) has a shorter half-life than Ligand B (8.77). Longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.063) has slightly lower P-gp efflux liability than Ligand B (0.212), which is favorable.

**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 noteworthy.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in key areas for an enzyme inhibitor: significantly lower DILI risk, better solubility, lower microsomal clearance (better metabolic stability), longer half-life, and slightly better binding affinity. The differences in Caco-2 and TPSA are minor compared to the metabolic stability and safety advantages of Ligand B.

Output:
1
2025-04-17 16:53:05,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (344.371 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.6) is higher than Ligand B (52.65). While both are reasonably low, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Ligand A (0.383) is quite low, potentially hindering membrane permeability. Ligand B (2.572) 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 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.632 and 0.685), indicating generally drug-like properties.

**DILI:** Ligand A has a DILI risk of 74.603, which is concerning (high risk). Ligand B has a very low DILI risk of 4.459, a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (86.08) has a higher BBB percentile than Ligand A (43.117).

**Caco-2 Permeability:** Ligand A (-4.886) has poor Caco-2 permeability, while Ligand B (-4.868) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.319) has poor solubility, while Ligand B (-1.255) is slightly better.

**hERG:** Ligand A (0.064) has a slightly higher hERG risk than Ligand B (0.503), although both are relatively low.

**Microsomal Clearance:** Ligand A (12.595) has a higher microsomal clearance than Ligand B (8.416), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-35.421) has a very short in vitro half-life, which is a significant drawback. Ligand B (-14.033) has a better, though still short, half-life.

**P-gp Efflux:** Ligand A (0.037) shows some P-gp efflux, while Ligand B (0.027) shows less.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a key factor for enzyme inhibitors. However, it suffers from poor solubility, poor permeability, high DILI risk, and very poor metabolic stability (short half-life). Ligand B, while having a very weak binding affinity, exhibits a much better ADME profile: lower DILI risk, better logP, better solubility, and better metabolic stability.

Given the importance of ADME properties for *in vivo* efficacy, and the substantial difference in DILI risk and metabolic stability, Ligand B is the more promising starting point for drug development, despite its weak binding affinity. The affinity can be optimized through medicinal chemistry efforts, while fixing the ADME issues of Ligand A would be far more challenging.

Output:
1
2025-04-17 16:53:05,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.378 and 354.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.6) is better than Ligand B (78.43), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (1.141) is optimal, while Ligand B (3.428) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (3), as fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3), both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.649 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (46.917) has a significantly lower DILI risk than Ligand B (60.644), placing it in a more favorable category.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (70.88) is better than Ligand B (53.354).

**Caco-2 Permeability:** Ligand A (-4.478) is slightly better than Ligand B (-4.664), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.279) is better than Ligand B (-4.27), indicating better solubility.

**hERG Inhibition:** Ligand A (0.278) has a much lower hERG inhibition liability than Ligand B (0.731), a crucial advantage.

**Microsomal Clearance:** Ligand A (15.825) has a significantly lower microsomal clearance than Ligand B (34.132), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.719) has a much longer in vitro half-life than Ligand B (28.56), indicating better stability.

**P-gp Efflux:** Ligand A (0.027) has a much lower P-gp efflux liability than Ligand B (0.307), improving bioavailability.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-6.9), although the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, particularly DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While the binding affinity difference is small, the superior ADME profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 16:53:05,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.503 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (102.05). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.711 and 1.028), 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=6). Lower counts are generally better for permeability.

**QED:** Ligand A (0.801) has a higher QED score than Ligand B (0.661), indicating a more drug-like profile.

**DILI:** Ligand B (57.619) has a lower DILI risk than Ligand A (11.477), which is a significant advantage.

**BBB:** Ligand A (77.2) has better BBB penetration than Ligand B (51.725), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.636) has better Caco-2 permeability than Ligand B (-5.634).

**Aqueous Solubility:** Ligand A (-2.17) has better solubility than Ligand B (-1.423). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.508) has a lower hERG risk than Ligand B (0.088), which is a critical advantage.

**Microsomal Clearance:** Ligand B (38.739) has lower microsomal clearance than Ligand A (42.671), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.845) has a longer in vitro half-life than Ligand A (-3.14), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.379) has lower P-gp efflux than Ligand B (0.029), which is a positive.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.3). While a 1.5 kcal/mol difference can be significant, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is superior overall. While Ligand B has a slightly better binding affinity and metabolic stability, Ligand A excels in crucial areas like TPSA, solubility, hERG risk, and QED. The lower hERG risk for Ligand A is particularly important for kinase inhibitors, as off-target effects are a common concern. The better solubility and permeability also contribute to better potential bioavailability. The DILI risk is also lower for ligand A.

Output:
1
2025-04-17 16:53:05,082 - INFO - Batch 500 complete. Total preferences: 8000
2025-04-17 16:53:05,082 - INFO - Processing batch 501/512...
2025-04-17 16:53:46,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.515 and 347.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.2) is well below the 140 threshold and is favorable. Ligand B (79.26) is still acceptable, but less optimal.

**logP:** Ligand A (3.262) is within the optimal 1-3 range. Ligand B (0.315) 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 2 HBA, well within the limit of <=10. Ligand B has 5 HBA, also acceptable.

**QED:** Both ligands have good QED values (0.695 and 0.777), indicating drug-like properties.

**DILI:** Ligand A (28.189) has a very low DILI risk, which is excellent. Ligand B (6.049) also has a low DILI risk.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (64.017) is better than Ligand A (51.415). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.556) has poor Caco-2 permeability. Ligand B (-5.446) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.419) has poor aqueous solubility. Ligand B (-0.71) has slightly better aqueous solubility, but still poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.188 and 0.131), which is excellent.

**Microsomal Clearance:** Ligand A (39.063) has moderate microsomal clearance. Ligand B (-24.681) has *negative* clearance, which is highly unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (11.857) has a moderate half-life. Ligand B (0.864) has a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.176 and 0.004), which is favorable.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a >1.5 kcal/mol difference, which is a substantial advantage.

**Conclusion:**

Despite the poor Caco-2 and solubility of both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.7 vs -7.8 kcal/mol) outweighs the slightly lower BBB and shorter half-life. Critically, the negative microsomal clearance for Ligand B suggests exceptional metabolic stability, a key factor for an enzyme inhibitor. Ligand A's poor Caco-2 permeability and solubility are also concerning.

Output:
1
2025-04-17 16:53:46,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (381.479 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.43) is higher than Ligand B (61.88). While both are reasonably good, Ligand B is significantly better, suggesting potentially improved cell permeability.

**logP:** Both ligands have similar logP values (0.707 and 0.781), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.816 and 0.747), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (78.17%) compared to Ligand B (4.692%). This is a major concern for Ligand A.

**BBB:** Both have reasonable BBB penetration (57.852% and 77.007%). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**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:** Both have low hERG risk (0.232 and 0.339). This is favorable.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (29.02) than Ligand B (11.057). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (5.851) than Ligand A (1.338). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.136 and 0.013).

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.4 kcal/mol) than Ligand A (-9.0 kcal/mol). While A is better, the difference is not substantial enough to overcome its ADME liabilities.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B exhibits significantly better ADME properties, particularly a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a lower TPSA. These factors are crucial for developing a viable drug candidate targeting a kinase. The unusual negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh this issue.

Output:
1
2025-04-17 16:53:46,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.804 and 356.438 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (76.95 and 78.87) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Ligand A (3.608) is optimal, while Ligand B (1.187) is slightly low, potentially hindering permeation.

**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 and <=10 HBA).

**QED:** Both ligands have similar QED values (0.714 and 0.64), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 76.076, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 13.3, which is excellent.

**BBB:** Both ligands have reasonably good BBB penetration (65.374 and 72.354), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.569 and -4.694), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.817 and -1.796). This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.62) has a slightly higher hERG risk than Ligand B (0.279), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand A (4.519 mL/min/kg) has better metabolic stability (lower clearance) than Ligand B (23.301 mL/min/kg).

**In vitro Half-Life:** Ligand A has a longer half-life (56.781 hours) than Ligand B (-11.294 hours). The negative value for Ligand B is suspect and indicates very rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.157 and 0.047).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 1.3 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 more promising candidate. Its significantly stronger binding affinity (-7.7 vs -6.4 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand B has a much lower DILI risk (13.3 vs 76.076) and better metabolic stability (lower Cl_mic) and a more reasonable half-life. While the solubility and permeability are concerns, these could potentially be addressed through formulation strategies. The high DILI risk of Ligand A is a significant red flag.

Output:
1
2025-04-17 16:53:46,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**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 (383.945 Da) is also good.

**TPSA:** Ligand A (88.18) is excellent, well below the 140 threshold for oral absorption. Ligand B (47.36) is even better, suggesting potentially improved absorption.

**logP:** Ligand A (-0.234) is a bit low, potentially hindering permeation. Ligand B (3.174) is within the optimal range (1-3). 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:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (A: 0.711, B: 0.757), indicating drug-like properties.

**DILI:** Ligand A (24.622) has a much lower DILI risk than Ligand B (37.65), which is a substantial advantage.

**BBB:** Ligand A (55.021) has a lower BBB penetration than Ligand B (79.721). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.977) is worse than Ligand B (-5.044).

**Aqueous Solubility:** Ligand A (-0.682) is slightly better than Ligand B (-3.661). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.072) has a very low hERG risk, which is excellent. Ligand B (0.538) is higher, representing a moderate risk. This is a significant concern for Ligand B.

**Microsomal Clearance:** Ligand A (3.245) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (62.155) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-2.888) has a negative half-life, which is concerning. Ligand B (17.101) has a much better half-life.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is favorable. Ligand B (0.484) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (-9.4). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better logP, which are critical for an enzyme inhibitor. However, it suffers from higher DILI risk, higher hERG inhibition, and higher microsomal clearance. Ligand A has better safety profiles (DILI, hERG) and metabolic stability, but its lower binding affinity and logP are concerning. The substantial affinity difference (-7.1 vs -9.4) is a significant factor. While Ligand A is safer, the potency of Ligand B is likely to be more important for a kinase inhibitor.

Output:
1
2025-04-17 16:53:46,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (381.347 and 361.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below 140, suggesting good absorption. Ligand B (106.1) is higher but still acceptable, though potentially slightly impacting absorption.

**logP:** Ligand A (4.609) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.088) is closer to the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is ideal. Ligand B (2 HBD, 7 HBA) is acceptable, but the higher HBA count could slightly affect permeability.

**QED:** Both ligands have similar QED values (0.812 and 0.765), indicating good drug-likeness.

**DILI:** Ligand A (31.059) has a much lower DILI risk than Ligand B (68.903), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (81.078) has better penetration than Ligand B (38.542).

**Caco-2 Permeability:** Ligand A (-4.945) shows poor permeability, which is concerning. Ligand B (-5.627) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.589) has poor solubility, consistent with its high logP. Ligand B (-2.088) has better solubility.

**hERG Inhibition:** Ligand A (0.768) has a higher hERG risk than Ligand B (0.047), which is a major concern.

**Microsomal Clearance:** Ligand A (42.587) has a moderate clearance. Ligand B (-8.849) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability. This is a huge advantage.

**In vitro Half-Life:** Ligand A (42.117) has a reasonable half-life. Ligand B (17.878) has a shorter half-life, but the exceptionally low clearance likely compensates for this.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.588 and 0.017).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), a difference of 1.3 kcal/mol. This is significant and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better TPSA, Ligand B is superior overall. The combination of significantly lower DILI risk, exceptional metabolic stability (negative Cl_mic), better solubility, lower hERG risk, and slightly improved binding affinity makes Ligand B the more promising drug candidate. The poor Caco-2 permeability of both is a concern, but can be addressed with formulation strategies. The high logP of Ligand A and its associated solubility and hERG concerns are major drawbacks.

Output:
1
2025-04-17 16:53:46,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.455 and 359.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better, below 90, which is favorable. Ligand B (64.63) is still acceptable but less optimal.

**logP:** Ligand A (2.736) is within the optimal 1-3 range. Ligand B (4.34) is slightly higher, potentially raising concerns about solubility and off-target effects, but not critically.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 3, B: 5) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Ligand A (0.916) has a very strong drug-like profile. Ligand B (0.588) is still acceptable, but less ideal.

**DILI:** Ligand A (22.838) has a significantly lower DILI risk than Ligand B (82.125). This is a major advantage for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (92.09) is higher than Ligand B (57.154), but this isn't a deciding factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.764 and -4.772), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.259 and -5.843), indicating very poor aqueous solubility. This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.798) has a lower hERG inhibition liability than Ligand B (0.722), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (0.949) has significantly lower microsomal clearance than Ligand B (114.822), suggesting better metabolic stability. This is a crucial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (52.876) has a much longer in vitro half-life than Ligand B (1.045), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.084, B: 0.343).

**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 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. Specifically, the significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better QED score for Ligand A are compelling. The poor solubility and permeability are concerns for both, but the other advantages of Ligand A are more critical for an enzyme target like SRC kinase. The affinity difference, while substantial, might be overcome with further optimization of Ligand A, whereas fixing the severe DILI risk of Ligand B would be much more challenging.

Output:
0
2025-04-17 16:53:46,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.419 and 365.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.69) is better than Ligand B (63.25), being closer to the 140 A^2 threshold for good absorption.

**logP:** Ligand A (0.776) is suboptimal, potentially hindering permeation. Ligand B (3.643) is within 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 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.668 and 0.701), indicating drug-likeness.

**DILI:** Ligand A (37.03) has a much lower DILI risk than Ligand B (69.911), a significant advantage.

**BBB:** Both have reasonable BBB penetration, but Ligand B (77.821) is higher than Ligand A (67.197). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.308) has poor Caco-2 permeability, while Ligand B (-4.821) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.607) has poor aqueous solubility, while Ligand B (-3.842) is even worse.

**hERG:** Ligand A (0.366) has a very low hERG risk, a major advantage. Ligand B (0.761) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (0.143) has very low microsomal clearance, indicating high metabolic stability. Ligand B (114.159) has very high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-23.437) has a very long in vitro half-life, which is excellent. Ligand B (114.358) has a long half-life as well.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is favorable. Ligand B (0.772) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial difference.

**Conclusion:**

Despite Ligand A's poor logP and Caco-2 permeability, its superior safety profile (low DILI, very low hERG), excellent metabolic stability (low Cl_mic, long t1/2), low P-gp efflux, and acceptable TPSA and QED make it a more promising candidate. The significantly stronger binding affinity of Ligand B is a major positive, but is offset by the higher DILI and hERG risk, and high metabolic clearance. Given the enzyme class, metabolic stability and safety are paramount.

Output:
0
2025-04-17 16:53:46,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.523 and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is significantly better than Ligand B (82.55). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target. Ligand A is well below the 140 threshold, while Ligand B is approaching it.

**logP:** Ligand A (1.166) is within the optimal 1-3 range. Ligand B (-0.633) is slightly below 1, which *could* indicate potential permeability issues, although not drastically.

**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 preferred.

**QED:** Both ligands have similar QED values (0.712 and 0.66), indicating good drug-likeness.

**DILI:** Ligand A (6.747) has a much lower DILI risk than Ligand B (14.424). This is a significant advantage for Ligand A.

**BBB:** Ligand A (54.556) has a better BBB penetration score than Ligand B (43.893), although BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.885) has a worse Caco-2 permeability than Ligand B (-4.361), but both are negative and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-0.897) has slightly better solubility than Ligand B (-0.444), though both are poor.

**hERG Inhibition:** Ligand A (0.619) has a lower hERG risk than Ligand B (0.163), which is a significant advantage. Lower hERG is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (12.918) has a higher microsomal clearance than Ligand B (8.247), indicating *lower* metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-9.963) has a better in vitro half-life than Ligand A (-7.078), indicating better stability.

**P-gp Efflux:** Ligand A (0.009) has a lower P-gp efflux liability than Ligand B (0.01), which is slightly better.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). However, the difference is small (0.4 kcal/mol) and may not be enough to overcome the other ADME issues.

**Overall Assessment:**

Ligand A is preferable due to its significantly lower DILI risk and hERG inhibition liability. While Ligand B has slightly better metabolic stability and binding affinity, the safety profile of Ligand A is much more favorable. The lower TPSA of Ligand A also suggests better permeability. The solubility and Caco-2 permeability are poor for both, but can be addressed with formulation strategies. Given the enzyme-specific priorities, the safety profile and permeability advantages of Ligand A outweigh the minor potency/stability benefit of Ligand B.

Output:
0
2025-04-17 16:53:46,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.463 and 356.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.17) is slightly higher than Ligand B (78.09). Both are acceptable for oral absorption (<140), but B is better.

**logP:** Ligand A (3.175) is within the optimal range (1-3), while Ligand B (1.844) is at the lower end. While lower logP can sometimes be problematic, it's not a major concern here.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.746) has a significantly better QED score than Ligand A (0.331), suggesting a more drug-like profile.

**DILI:** Ligand B (44.281) has a much lower DILI risk than Ligand A (19.426), which is a significant advantage.

**BBB:** Not a primary concern for a kinase inhibitor, but Ligand B (68.941) has a higher BBB percentile than Ligand A (52.889).

**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 and suggests poor solubility. Again, the scale is unspecified.

**hERG:** Ligand A (0.193) has a slightly better hERG profile than Ligand B (0.433), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (18.272) has a lower microsomal clearance than Ligand A (19.994), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-27.876) has a *much* longer in vitro half-life than Ligand A (-7.45). This is a major advantage.

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux than Ligand B (0.11), which is preferable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 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 and P-gp efflux, Ligand B excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic and much longer t1/2), and a higher QED score. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B outweigh this. The difference in binding affinity is not substantial enough to favor Ligand A given the other benefits of B.

Output:
1
2025-04-17 16:53:46,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (340.402 and 370.877 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.91) and Ligand B (71.78) are both below the 140 A^2 threshold for good oral absorption.

**3. logP:** Both ligands have logP values (2.857 and 3.249) 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.

**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 (0.795 and 0.799), indicating good drug-likeness.

**7. DILI:** Ligand A (55.991) has a higher DILI risk than Ligand B (29.546). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand B (82.086) is notably higher than Ligand A (69.523). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.71 and -4.697). This is unusual and suggests poor permeability. However, negative values can sometimes be artifacts of the prediction method.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.569 and -3.65). This is concerning and suggests poor solubility, which could hinder bioavailability.

**11. hERG Inhibition:** Ligand A (0.236) has a slightly higher hERG inhibition risk than Ligand B (0.53), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (8.046) has a significantly lower microsomal clearance than Ligand B (14.948). Lower clearance indicates better metabolic stability, a key priority for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (60.896) has a much longer in vitro half-life than Ligand A (14.585). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux liability than Ligand B (0.185), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This difference of 0.8 kcal/mol is substantial and outweighs many of the minor ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both compounds have issues with predicted solubility and permeability, Ligand B's significantly stronger binding affinity, longer half-life, and lower DILI risk are critical advantages for a kinase inhibitor. The improved metabolic stability (lower Cl_mic) further supports its selection.

Output:
1
2025-04-17 16:53:46,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 348.491 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.54) is slightly higher than Ligand B (67.65). Both are below the 140 threshold for oral absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Ligand A (0.379) is quite low, potentially hindering permeability. Ligand B (1.86) 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 3 HBA. Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits, though Ligand B's lower HBD count might slightly improve permeability.

**QED:** Both ligands have good QED scores (0.629 and 0.735, respectively), indicating generally drug-like properties.

**DILI:** Ligand A has a DILI risk of 19.387, which is excellent (low risk). Ligand B has a DILI risk of 6.553, also very good, but slightly higher than Ligand A.

**BBB:** Ligand A (72.974) and Ligand B (87.941) both have acceptable BBB penetration, but Ligand B is better. This is less crucial for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.15) has poor Caco-2 permeability, which is a major concern. Ligand B (-4.65) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.437 and -1.322, respectively). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.118) and Ligand B (0.451) both show low hERG inhibition risk, which is positive.

**Microsomal Clearance:** Ligand A (-5.327) has a negative clearance, which is excellent, indicating very high metabolic stability. Ligand B (11.345) has a positive clearance, indicating faster metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.849) has a shorter half-life than Ligand B (-12.298), but the negative value for B is suspect and may indicate an error or an extremely long half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.013 and 0.014), which is favorable.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). This 0.6 kcal/mol difference is notable, but not overwhelmingly large.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic) and has a slightly better binding affinity and lower DILI risk. However, its poor Caco-2 permeability and low logP are significant drawbacks. Ligand B has better logP and TPSA, and slightly better BBB penetration, but suffers from faster metabolic clearance. Considering the importance of metabolic stability for enzyme inhibitors, and the relatively small difference in binding affinity, Ligand A is the more promising candidate, despite its permeability issues. Solubility could potentially be addressed through formulation strategies.

Output:
0
2025-04-17 16:53:46,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.45 & 360.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.56) is well below the 140 threshold, while Ligand B (106.85) is still acceptable but higher.

**logP:** Ligand A (3.164) is optimal (1-3). Ligand B (1.02) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (4 HBD, 4 HBA) is acceptable but higher, potentially impacting permeability.

**QED:** Ligand A (0.915) is very strong, indicating excellent drug-likeness. Ligand B (0.618) is still acceptable, but lower.

**DILI:** Ligand A (22.49) has a very low DILI risk. Ligand B (55.33) is higher, indicating a moderate risk.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (92.94) is significantly better than Ligand B (37.96).

**Caco-2:** Ligand A (-4.914) is better than Ligand B (-5.801), indicating better absorption.

**Solubility:** Both ligands have very poor aqueous solubility (-2.291 and -2.825 respectively). This is a significant concern for both.

**hERG:** Ligand A (0.824) has a lower hERG risk than Ligand B (0.202).

**Microsomal Clearance:** Ligand A (22.23) has higher clearance than Ligand B (-16.01), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (23.41) has a longer half-life than Ligand B (-2.71).

**P-gp Efflux:** Ligand A (0.219) has lower P-gp efflux than Ligand B (0.076), suggesting better bioavailability.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand A is the superior candidate. Its significantly higher binding affinity (-10.1 vs -8.5 kcal/mol) is a major advantage for an enzyme target. It also has better QED, lower DILI risk, better Caco-2 permeability, lower hERG risk, and lower P-gp efflux. While Ligand B has better metabolic stability, the potency advantage of Ligand A is more critical for kinase inhibitors. The solubility issue would need to be addressed through formulation strategies, but the overall profile of Ligand A is much more promising.

Output:
1
2025-04-17 16:53:46,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.455 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (69.64), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.73 and 2.003), falling 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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.742 and 0.723), indicating good drug-likeness.

**DILI:** Ligand B (6.979) has a significantly lower DILI risk than Ligand A (15.781). This is a major advantage for Ligand B.

**BBB:** Ligand B (63.629) has a higher BBB percentile than Ligand A (38.038), but BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.995) has slightly better Caco-2 permeability than Ligand B (-4.895), but the difference is minimal.

**Aqueous Solubility:** Ligand B (-2.366) has better aqueous solubility than Ligand A (-4.342). This is a positive attribute for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.215 and 0.278), which is excellent.

**Microsomal Clearance:** Ligand B (22.334) has significantly lower microsomal clearance than Ligand A (64.062), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (8.794 hours) has a considerably longer in vitro half-life than Ligand A (-23.371 hours). This is a significant benefit, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.056).

**Binding Affinity:** Both ligands have identical binding affinities (-8.3 kcal/mol), which is excellent and meets the > -7.0 kcal/mol threshold.

**Conclusion:**

While both ligands have excellent binding affinity and generally good properties, Ligand B is the superior candidate. Its significantly lower DILI risk, improved solubility, lower microsomal clearance, and longer half-life outweigh the slight advantage of Ligand A in Caco-2 permeability. These factors are particularly important for an enzyme target like SRC kinase, where metabolic stability and safety are paramount.

Output:
1
2025-04-17 16:53:46,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (336.395 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.05) is better than Ligand B (58.64). Both are well below the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have good logP values (3.487 and 2.903) 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 similar QED scores (0.72 and 0.685), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (79.449%) compared to Ligand B (9.228%). This is a major concern for Ligand A.

**BBB:** Ligand B has a higher BBB penetration percentile (77.705%) compared to Ligand A (47.189%). While not a primary concern for a kinase inhibitor, it's a slight 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, suggesting poor aqueous solubility. This is a concern, but can be mitigated with formulation strategies.

**hERG:** Ligand A (0.513) has a slightly higher hERG risk than Ligand B (0.485), but both are relatively low.

**Microsomal Clearance:** Ligand A (41.808) has a lower microsomal clearance than Ligand B (44.523), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a negative half-life (-10.718 hours), which is impossible and indicates a significant issue with the data or the compound. Ligand A has a half-life of 63.278 hours, which is good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.408 and 0.125).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the stronger binding affinity of Ligand A, its significantly higher DILI risk is a major red flag. The negative half-life for Ligand B is a data quality issue, but even ignoring this, the affinity is weaker. However, the DILI risk is so much lower for Ligand B that it makes it the more viable candidate. While both have solubility and permeability concerns, these can be addressed with formulation. The superior metabolic stability of Ligand A is a plus, but the DILI risk is too high to ignore.

Output:
1
2025-04-17 16:53:46,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Ligand A:**
*   **MW:** 361.507 Da - Within the ideal range (200-500).
*   **TPSA:** 46.61 - Excellent, well below the 140 threshold for absorption.
*   **logP:** 4.122 - Slightly high, potentially leading to solubility issues or off-target effects, but not drastically so.
*   **HBD:** 0 - Low, favorable for permeability.
*   **HBA:** 3 - Acceptable.
*   **QED:** 0.805 - Excellent drug-likeness.
*   **DILI:** 54.556 - Moderate risk, but acceptable.
*   **BBB:** 38.465 - Not a priority for a non-CNS target like SRC.
*   **Caco-2:** -4.565 - Very poor permeability. A significant concern.
*   **Solubility:** -6.5 - Very poor solubility. A major drawback.
*   **hERG:** 0.79 - Low risk, good.
*   **Cl_mic:** 143.782 - High metabolic clearance, unfavorable.
*   **t1/2:** -36.59 - Very short half-life, unfavorable.
*   **Pgp:** 0.386 - Low efflux, favorable.
*   **Affinity:** -8.1 kcal/mol - Excellent binding affinity.

**Ligand B:**
*   **MW:** 346.431 Da - Within the ideal range.
*   **TPSA:** 85.25 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 0.548 - Low, potentially hindering permeation.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.673 - Good drug-likeness.
*   **DILI:** 48.197 - Good, low risk.
*   **BBB:** 54.595 - Not a priority.
*   **Caco-2:** -5.002 - Very poor permeability. A significant concern.
*   **Solubility:** -1.223 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.322 - Low risk, good.
*   **Cl_mic:** 4.431 - Low metabolic clearance, very favorable.
*   **t1/2:** -1.24 - Short half-life, but better than Ligand A.
*   **Pgp:** 0.047 - Very low efflux, favorable.
*   **Affinity:** -6.6 kcal/mol - Good binding affinity, though not as strong as Ligand A.

**Comparison and Decision:**

Both ligands suffer from very poor Caco-2 permeability and solubility. However, Ligand A has a significantly better binding affinity (-8.1 kcal/mol vs -6.6 kcal/mol). While Ligand A has higher logP and worse metabolic stability (Cl_mic, t1/2) than Ligand B, the substantial improvement in binding affinity is a critical factor for an enzyme inhibitor. The difference of 1.5 kcal/mol can often outweigh moderate ADME liabilities, especially if further optimization can address the permeability and solubility issues. Ligand B's lower Cl_mic is beneficial, but the weaker binding is a more significant drawback.

Therefore, despite its ADME shortcomings, Ligand A is the more promising starting point due to its superior binding affinity.

Output:
1
2025-04-17 16:53:46,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.388 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.78) is significantly better than Ligand B (58.64). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors to reach their intracellular target. Ligand A is well below the 140 threshold, while B is approaching it.

**logP:** Both ligands have acceptable logP values (3.465 and 2.102), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 0/3, B: 1/3), well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.831, B: 0.793), indicating a generally drug-like profile.

**DILI:** Ligand A (19.93) has a much lower DILI risk than Ligand B (22.8). This is a significant advantage.

**BBB:** Ligand A (97.053) has a higher BBB penetration percentile than Ligand B (75.107). While not a primary concern for a kinase inhibitor (unless CNS off-target effects are a concern), higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.397) has a worse Caco-2 permeability than Ligand B (-4.514). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-3.096) has better aqueous solubility than Ligand B (-3.5). Solubility is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.956) has a slightly higher hERG risk than Ligand B (0.233). This is a potential concern for Ligand A, but the value is still relatively low.

**Microsomal Clearance:** Ligand A (13.969) has a significantly higher microsomal clearance than Ligand B (3.366). This suggests Ligand B is more metabolically stable, a key consideration for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-10.995) has a longer in vitro half-life than Ligand B (10.954). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.413) has lower P-gp efflux than Ligand B (0.039), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8). While the difference is small (0.2 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand A excels in several key areas: DILI risk, BBB penetration, aqueous solubility, in vitro half-life, and P-gp efflux. However, it has a higher hERG risk and higher microsomal clearance. Ligand B has better metabolic stability and a slightly better binding affinity. The difference in binding affinity is small, and the superior ADME profile of Ligand A, particularly the significantly lower DILI risk and better solubility, outweigh this slight difference in potency. The lower metabolic clearance of Ligand B is a concern, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 16:53:46,050 - INFO - Batch 501 complete. Total preferences: 8016
2025-04-17 16:53:46,050 - INFO - Processing batch 502/512...
2025-04-17 16:54:34,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.382 and 353.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.44) is slightly higher than Ligand B (73.86), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.311) is quite low, potentially hindering permeation. Ligand B (3.016) 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) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (6) both meet the <=10 criteria.

**QED:** Both ligands have good QED scores (0.802 and 0.76), indicating drug-likeness.

**DILI:** Both ligands have similar DILI risk (60.062 and 63.552), placing them in a moderate risk category. This isn't a deciding factor.

**BBB:** Both have reasonable BBB penetration, but Ligand B (86.08) is better than Ligand A (72.005). While not a primary concern for a kinase inhibitor, it's a slight advantage for B.

**Caco-2 Permeability:** Ligand A (-4.956) is significantly worse than Ligand B (-4.025), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.812) is better than Ligand B (-4.679). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.267) has a much lower hERG risk than Ligand B (0.625). This is a crucial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-32.769) has *much* lower microsomal clearance than Ligand B (112.525), indicating significantly better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.382) has a shorter half-life than Ligand B (42.943). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.029) has much lower P-gp efflux than Ligand B (0.435), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-7.9). While a 0.7 kcal/mol difference is noticeable, it's not overwhelmingly large.

**Overall Assessment:**

Ligand B has better logP, Caco-2 permeability, BBB, and binding affinity. However, Ligand A has significantly better hERG risk, microsomal clearance, and P-gp efflux. Solubility is also better for Ligand A. Given the enzyme-specific priorities, metabolic stability (Cl_mic) and minimizing off-target effects (hERG) are critical. The substantial difference in Cl_mic and hERG risk strongly favors Ligand A, despite the slightly weaker binding affinity. The lower logP of Ligand A is a concern, but could potentially be addressed through further optimization without sacrificing the favorable ADME properties.

Output:
0
2025-04-17 16:54:34,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.453 Da) is slightly higher than Ligand B (344.371 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (119.73). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (2.127) is within the optimal range (1-3). Ligand B (-0.829) 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 reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have acceptable QED scores (Ligand A: 0.863, Ligand B: 0.618), indicating good drug-like properties.

**DILI:** Ligand A (35.014) has a lower DILI risk than Ligand B (43.35), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (78.79) is better than Ligand B (14.114), but this is less critical here.

**Caco-2 Permeability:** Ligand A (-4.961) and Ligand B (-5.33) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-2.662) and Ligand B (-2.492) both have negative solubility values, which is not ideal.

**hERG Inhibition:** Both ligands have low hERG risk (Ligand A: 0.375, Ligand B: 0.104).

**Microsomal Clearance:** Ligand A (-1.83) has a significantly *lower* (better) microsomal clearance than Ligand B (-31.626). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-3.561) has a better (longer) in vitro half-life than Ligand B (-9.656).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.132, Ligand B: 0.008).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (Ligand A: -8.9 kcal/mol, Ligand B: -8.2 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering all parameters, **Ligand A is the more promising drug candidate.** While both have similar binding affinities, Ligand A demonstrates superior ADME properties, specifically a much better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and a more favorable logP and TPSA. Although both have poor Caco-2 permeability and solubility, the ADME advantages of Ligand A outweigh these concerns, especially given the similar binding affinities.

Output:
1
2025-04-17 16:54:34,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (40.62) is significantly better than Ligand B (99.93). Lower TPSA generally indicates better cell permeability. Ligand B's TPSA is quite high, potentially hindering oral absorption.

**logP:** Ligand A (3.739) is optimal, while Ligand B (0.088) is quite low. A low logP can lead to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable. Ligand B (1 HBD, 5 HBA) is still within acceptable limits, but more hydrogen bonding potential can sometimes reduce permeability.

**QED:** Both ligands have good QED scores (A: 0.704, B: 0.816), indicating generally drug-like properties.

**DILI:** Ligand A (15.083) has a much lower DILI risk than Ligand B (62.35). This is a significant advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (91.392) is higher than Ligand B (35.324), but it doesn't heavily influence the decision.

**Caco-2 Permeability:** Ligand A (-4.539) is better than Ligand B (-4.866), suggesting slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.901) is better than Ligand B (-2.437), which is important for formulation and bioavailability.

**hERG:** Both ligands have low hERG risk (A: 0.575, B: 0.237), which is good.

**Microsomal Clearance:** Ligand A (80.527) has a higher microsomal clearance than Ligand B (38.54). This means Ligand B is likely to have better metabolic stability.

**In vitro Half-Life:** Ligand B (11.206 hours) has a significantly longer half-life than Ligand A (1.205 hours). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.333) has lower P-gp efflux than Ligand B (0.039), which is preferable.

**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 consider, especially given the other factors.

**Overall:**

Ligand A has a better balance of properties, particularly regarding TPSA, logP, solubility, and DILI risk. Its slightly better binding affinity is also a plus. Ligand B's main advantage is its longer half-life and better metabolic stability, but its poor TPSA, logP, and higher DILI risk are significant drawbacks. For an enzyme target like SRC kinase, metabolic stability is important, but not at the expense of poor absorption and increased toxicity risk.

Output:
0
2025-04-17 16:54:34,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (337.379 and 342.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (118.87), being closer to the <140 threshold for good absorption.

**logP:** Ligand A (2.622) is optimal (1-3), while Ligand B (-0.642) is below 1, potentially hindering permeation.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2 respectively, both <=5).

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (7), being closer to the <=10 threshold.

**QED:** Both ligands have good QED scores (0.578 and 0.721, both >=0.5).

**DILI:** Ligand A (51.842) has a significantly lower DILI risk than Ligand B (72.703). Both are below 60, but A is preferable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (54.478) is slightly better than Ligand B (45.366).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and problematic, suggesting poor permeability. However, Ligand A (-5.152) is slightly better than Ligand B (-5.544).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and problematic. Ligand A (-4.317) is slightly better than Ligand B (-1.813).

**hERG:** Ligand A (0.202) has a much lower hERG risk than Ligand B (0.113), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand B (-12.273) has significantly lower (better) microsomal clearance than Ligand A (31.72). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (21.942) has a longer half-life than Ligand A (-21.984).

**P-gp Efflux:** Ligand B (0.008) has very low P-gp efflux, while Ligand A (0.044) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor for an enzyme inhibitor.

**Conclusion:**

Despite Ligand B's better metabolic stability and half-life, Ligand A is the superior candidate. The significantly stronger binding affinity (-8.1 vs 0 kcal/mol) outweighs the drawbacks of slightly higher clearance and lower half-life. Furthermore, Ligand A has better TPSA, logP, DILI, hERG, and P-gp efflux properties. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of A is substantial.

Output:
1
2025-04-17 16:54:34,469 - INFO - Here's a step-by-step reasoning for selecting the better drug candidate, followed by the final output:

**Reasoning:**

We are evaluating two ligands (A and B) for their potential as kinase inhibitors (targeting SRC, an enzyme). Our priorities are potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk.

1. **Molecular Weight:** Both ligands (364.408 and 357.495 Da) fall within the ideal range of 200-500 Da. No significant difference here.

2. **TPSA:** Ligand A (60.85) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (90.9) is at the upper limit of acceptable for oral absorption, but still within range. A is better.

3. **logP:** Ligand A (1.899) is within the optimal 1-3 range. Ligand B (0.515) is slightly below 1, potentially indicating permeability issues. A is better.

4. **H-Bond Donors:** Ligand A (1) is ideal. Ligand B (3) is acceptable, but higher. A is better.

5. **H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable. No major difference.

6. **QED:** Both ligands have reasonable QED scores (0.783 and 0.53), indicating good drug-like properties. A is slightly better.

7. **DILI:** Ligand A (23.846) has a very low DILI risk. Ligand B (4.731) also has a low DILI risk, but is slightly higher. A is better.

8. **BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (91.47) is higher than Ligand B (25.475), but this is less critical.

9. **Caco-2 Permeability:** Ligand A (-4.496) is better than Ligand B (-5.29). Higher values indicate better absorption.

10. **Aqueous Solubility:** Ligand A (-2.878) is better than Ligand B (0.182). Higher values indicate better solubility.

11. **hERG Inhibition:** Ligand A (0.584) has a lower hERG risk than Ligand B (0.082). This is a significant advantage.

12. **Microsomal Clearance:** Ligand A (45.83) has a higher (worse) clearance than Ligand B (-18.221). This suggests Ligand B is more metabolically stable. B is better.

13. **In vitro Half-Life:** Ligand A (-8.299) has a longer half-life than Ligand B (5.37). A is better.

14. **P-gp Efflux:** Ligand A (0.21) has lower P-gp efflux than Ligand B (0.006). A is better.

15. **Binding Affinity:** Ligand B (-9.4 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 of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-9.4 vs -6.2 kcal/mol). While Ligand A has better solubility, lower hERG risk, and better metabolic stability, the potency advantage of Ligand B is substantial. For an enzyme target like SRC, potency is paramount. The slightly lower solubility and higher P-gp efflux of Ligand B can potentially be addressed through formulation strategies. The metabolic stability is also acceptable.

Output:
1
2025-04-17 16:54:34,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (427.328 Da) is higher, but still acceptable. Ligand B (365.861 Da) is slightly better.

**TPSA:** Ligand A (88.33) is good, below the 140 threshold for oral absorption. Ligand B (56.59) is even better, suggesting potentially improved absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.556) is slightly better than Ligand B (3.716), as higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 9 HBA, well within the acceptable limits. Ligand B has 0 HBD and 5 HBA, also good.

**QED:** Both ligands have good QED scores (A: 0.561, B: 0.758), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 83.986, which is high and a significant concern. Ligand B has a DILI risk of 49.128, which is much better and considered low risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (77.821) has a higher BBB score than Ligand A (50.407), but this isn't a major factor here.

**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 have low hERG inhibition risk (A: 0.636, B: 0.68), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (17.879) than Ligand B (67.946), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A has a much longer half-life (90.979) than Ligand B (28.452), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.134, B: 0.4).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 kcal/mol and -7.0 kcal/mol respectively). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and comparable binding affinity. However, its high DILI risk is a major drawback. Ligand B has a significantly lower DILI risk, better TPSA, and QED, but its metabolic stability is considerably worse.

Given the enzyme-kinase specific priorities, metabolic stability is important, but unacceptable toxicity risk is a dealbreaker. The lower DILI risk of Ligand B makes it the more viable candidate, despite its poorer metabolic properties. Further optimization could focus on improving the metabolic stability of Ligand B.

Output:
1
2025-04-17 16:54:34,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.411 and 347.463 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.7) is slightly higher than Ligand B (79.26), both are well below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (3.09) is optimal, while Ligand B (0.407) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.828) has a better QED score than Ligand B (0.749), indicating a more drug-like profile.

**DILI:** Ligand B (10.896) has a significantly lower DILI risk than Ligand A (72.043), which is a major advantage.

**BBB:** Ligand A (83.986) has better BBB penetration than Ligand B (50.523), but this is less critical for a non-CNS target like SRC.

**Caco-2:** Ligand A (-4.036) has a worse Caco-2 permeability than Ligand B (-5.596).

**Solubility:** Ligand A (-4.5) has better solubility than Ligand B (-0.114).

**hERG:** Ligand A (0.305) has a lower hERG risk than Ligand B (0.163), which is preferable.

**Microsomal Clearance:** Ligand B (-18.317) has a much lower (better) microsomal clearance than Ligand A (104.545), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.843) has a longer in vitro half-life than Ligand A (-9.486), which is a significant advantage.

**P-gp:** Ligand A (0.164) has lower P-gp efflux than Ligand B (0.005), which is preferable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). The difference is 1.1 kcal/mol, which is substantial but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (Cl_mic, t1/2) and DILI risk. While Ligand A has slightly better binding affinity and P-gp efflux, the significant advantages of Ligand B in metabolic stability and safety (DILI) outweigh this difference, especially for a kinase inhibitor where chronic dosing is likely. The lower logP of Ligand B is a concern, but the improved solubility and metabolic stability could compensate.

Output:
1
2025-04-17 16:54:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.475 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (49.41) as it is still within the acceptable range for oral absorption (<140), but Ligand B is significantly lower and potentially better for cellular permeability.

**logP:** Both ligands (2.224 and 3.522) are 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:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 2 HBA. Both are well within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.754 and 0.748), indicating good drug-like properties.

**DILI:** Ligand A (32.377) has a slightly higher DILI risk than Ligand B (24.622), but both are below the 40 threshold and considered low risk.

**BBB:** Ligand B (73.129) has a higher BBB penetration percentile than Ligand A (50.679). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP values, they are very low, indicating poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.56 and -3.733). This is a major drawback for both compounds and will likely hinder bioavailability.

**hERG Inhibition:** Ligand A (0.663) has a slightly higher hERG inhibition liability than Ligand B (0.406), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (79.297) has a higher microsomal clearance than Ligand B (75.675), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-18.337) has a significantly *longer* in vitro half-life than Ligand A (17.666). This is a major advantage for Ligand B, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.097 and 0.278).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.9 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both compounds have excellent binding affinity, Ligand B is superior due to its significantly better in vitro half-life and lower DILI risk. The solubility and Caco-2 permeability are concerning for both, but the improved metabolic stability of Ligand B outweighs the slightly better TPSA of Ligand A.

Output:
1
2025-04-17 16:54:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.43 and 349.39 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is excellent, below 140 and even approaching the threshold for CNS penetration. Ligand B (113.49) is still acceptable but less favorable.

**logP:** Ligand A (1.6) is optimal. Ligand B (0.111) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is well within the desired ranges. Ligand B (2 HBD, 7 HBA) is also acceptable, though the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED scores (0.707 and 0.664), indicating good drug-likeness.

**DILI:** Ligand A (39.47) has a better DILI score than Ligand B (45.56), indicating lower potential for liver injury. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (42.23) is slightly better than Ligand B (32.14).

**Caco-2 Permeability:** Ligand A (-4.865) is better than Ligand B (-5.416), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.355) is better than Ligand B (-0.54), which is a significant advantage for bioavailability.

**hERG Inhibition:** Ligand A (0.347) has a much lower hERG risk than Ligand B (0.131), a crucial factor for safety.

**Microsomal Clearance:** Ligand A (20.475) has lower clearance than Ligand B (28.146), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.106) has a much longer half-life than Ligand B (9.681), which is highly desirable for dosing convenience.

**P-gp Efflux:** Ligand A (0.273) has lower P-gp efflux than Ligand B (0.03), meaning it is less likely to be pumped out of cells, improving bioavailability.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This >3.9 kcal/mol difference in binding is a major advantage, potentially outweighing minor ADME concerns.

**Conclusion:**

Ligand A is clearly superior. It has better solubility, metabolic stability, lower hERG risk, lower P-gp efflux, and, most importantly, a substantially stronger binding affinity for the SRC kinase. While Ligand B has acceptable properties, Ligand A's profile is much more favorable for development as a drug candidate.

Output:
1
2025-04-17 16:54:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (345.443 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.79) is slightly higher than Ligand B (59.39), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.58) is optimal, while Ligand B (2.251) is also within the preferred 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.88 and 0.837), indicating good drug-like properties.

**DILI:** Ligand A (24.157) has a significantly lower DILI risk than Ligand B (28.267), which is a crucial advantage.

**BBB:** Ligand A (58.201) has a lower BBB penetration than Ligand B (89.298). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.059) has worse Caco-2 permeability than Ligand B (-4.584).

**Aqueous Solubility:** Ligand A (-0.581) has better aqueous solubility than Ligand B (-1.887). This is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.337) has a lower hERG inhibition liability than Ligand B (0.468), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (9.363) has a lower microsomal clearance than Ligand B (63.85), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (34.059) has a shorter half-life than Ligand B (60.123). This is a disadvantage, but the lower clearance of Ligand A might compensate.

**P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux liability than Ligand B (0.222), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.6). However, the difference is only 1.1 kcal/mol, and the superior ADME properties of Ligand A likely outweigh this difference.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A exhibits significantly better DILI risk, hERG inhibition, microsomal clearance, solubility, and P-gp efflux. These factors are critical for enzyme inhibitors, and the lower risk profile of Ligand A makes it a more viable drug candidate.

Output:
0
2025-04-17 16:54:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.439 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.09) is slightly higher than Ligand B (53.09). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is better.

**logP:** Ligand A (3.567) is optimal, while Ligand B (1.369) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.84) has a significantly better QED score than Ligand B (0.62), indicating a more drug-like profile.

**DILI:** Ligand B (13.339) has a much lower DILI risk than Ligand A (59.984), which is a significant advantage.

**BBB:** Ligand A (81.776) has a better BBB penetration score than Ligand B (70.997), but BBB is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.462 and -4.434), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand B (-0.37) has slightly better solubility than Ligand A (-4.984), although both are quite poor.

**hERG Inhibition:** Ligand A (0.481) has a slightly better hERG profile than Ligand B (0.341), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (39.018) has significantly lower microsomal clearance than Ligand A (50.994), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (3.057) has a slightly better in vitro half-life than Ligand A (55.331), but both are relatively low.

**P-gp Efflux:** Ligand A (0.217) has a slightly better P-gp efflux profile than Ligand B (0.029), indicating less 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 crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Conclusion:**

Despite Ligand B's advantages in DILI risk and metabolic stability, the substantially stronger binding affinity of Ligand A (-9.6 vs -6.3 kcal/mol) is the most important factor for an enzyme inhibitor. The difference in affinity is large enough to compensate for the slightly higher DILI risk and lower QED. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:54:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Ligand A (421.316 Da) is within the ideal range, while Ligand B (348.487 Da) is towards the lower end but still acceptable.

**TPSA:** Ligand A (72.2) is acceptable, while Ligand B (49.85) is also good.

**logP:** Ligand A (4.376) is slightly high, potentially leading to solubility issues. Ligand B (2.894) is optimal.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of <=10.

**QED:** Ligand A (0.679) is good, indicating a drug-like profile. Ligand B (0.475) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (79.643) has a higher DILI risk than Ligand B (17.798), which is a significant concern.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (90.655) has better BBB penetration than Ligand A (58.899), but it's not a primary factor here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unexpected and suggests an issue with the data or prediction method. We will proceed assuming these are relative values and higher is better. Ligand B (-4.579) is slightly better than Ligand A (-5.028).

**Aqueous Solubility:** Both ligands have negative solubility values, which is unexpected. Ligand B (-2.044) is slightly better than Ligand A (-4.62).

**hERG:** Ligand A (0.534) has a slightly higher hERG risk than Ligand B (0.602), but both are reasonably low.

**Microsomal Clearance:** Ligand A (55.273) has lower microsomal clearance, indicating better metabolic stability, which is a key priority for kinase inhibitors. Ligand B (67.201) has higher clearance.

**In vitro Half-Life:** Ligand A (93.711) has a significantly longer half-life than Ligand B (-8.732), which is a major advantage.

**P-gp Efflux:** Ligand A (0.777) has slightly higher P-gp efflux than Ligand B (0.304). Lower efflux is preferred.

**Binding Affinity:** Ligand A (-7.5 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 has a better binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). However, it has a considerably higher DILI risk and a slightly higher logP. Ligand B has a better safety profile (lower DILI) and logP, but its metabolic stability is a concern. The difference in binding affinity is small enough that the superior metabolic stability of Ligand A outweighs the higher DILI risk, especially considering that DILI risk can be further mitigated through structural modifications.

Output:
1
2025-04-17 16:54:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (45.55) is significantly better than Ligand B (86.71). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.524, Ligand B: 1.882), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 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 (Ligand A: 0.847, Ligand B: 0.712), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (Ligand A: 35.518, Ligand B: 34.781), which is excellent.

**BBB:** Ligand A (69.988) has a better BBB percentile than Ligand B (46.026), but BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**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 unusual. Assuming these represent low solubility, this is a concern.

**hERG:** Both ligands have very low hERG risk (Ligand A: 0.493, Ligand B: 0.451), which is highly desirable.

**Microsomal Clearance:** Ligand A (69.738) has higher microsomal clearance than Ligand B (62.459), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-45.206 hours) compared to Ligand A (1.467 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux (Ligand A: 0.582, Ligand B: 0.199), which is good.

**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.

**Conclusion:**

While Ligand A has a superior binding affinity, Ligand B has significantly better metabolic stability (longer half-life) and a slightly better P-gp efflux profile. Both have concerningly low predicted solubility and permeability. However, for a kinase inhibitor, potency (affinity) is paramount, and the 1.1 kcal/mol difference in binding affinity is substantial. The longer half-life of Ligand B is also a significant benefit. Given the enzyme-specific priorities, the stronger binding of Ligand A outweighs the slightly worse metabolic stability.

Output:
0
2025-04-17 16:54:34,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (372.487 Da and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (69.48), both are below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.31 and 1.908), falling 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 7. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.589 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (49.864). This is a significant negative for Ligand A.

**BBB:** Both have similar BBB penetration (64.87 and 68.399). Not a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but the magnitude is similar.

**Aqueous Solubility:** Ligand B (-1.232) has better solubility than Ligand A (-3.678). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG risk (0.111 and 0.264).

**Microsomal Clearance:** Ligand B (22.245) has significantly lower microsomal clearance than Ligand A (104.759), suggesting better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (15.747) has a longer half-life than Ligand A (-36.399). A negative half-life is concerning.

**P-gp Efflux:** Both have low P-gp efflux liability (0.076 and 0.073).

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Ligand B is the superior candidate. While both meet general drug-likeness criteria, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, positive t1/2), better solubility, and, most importantly, a much stronger binding affinity. Ligand A has a higher DILI risk and a negative in vitro half-life, making it less desirable. The substantial affinity difference outweighs any minor drawbacks of Ligand B.

Output:
1
2025-04-17 16:54:34,471 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [351.407, 123.58 ,   0.293,   2.   ,   7.   ,   0.706,  57.348,  85.149, -4.874,  -2.836,   0.719,  27.159,  -7.032,   0.027,  -9.1  ]
**Ligand B:** [345.407, 115.99 ,   1.537,   1.   ,   5.   ,   0.495,  58.395,  62.311, -5.092,  -2.641,   0.152,   8.004,   2.49 ,   0.031,  -8.   ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (351.407) and B (345.407) are very close.
2. **TPSA:** Both are below the 140 A^2 threshold for good oral absorption. A (123.58) is slightly higher than B (115.99), but both are acceptable.
3. **logP:** A (0.293) is quite low, potentially hindering permeability. B (1.537) is better, falling within the optimal 1-3 range. This is a significant advantage for B.
4. **HBD:** A (2) and B (1) are both acceptable (<=5).
5. **HBA:** A (7) and B (5) are both acceptable (<=10).
6. **QED:** A (0.706) is good, indicating drug-likeness. B (0.495) is lower, suggesting a less ideal drug-like profile.
7. **DILI:** Both have similar DILI risk (A: 57.348, B: 58.395), and are within an acceptable range (<60 is good).
8. **BBB:** A (85.149) has better BBB penetration than B (62.311), but this isn't a primary concern for a non-CNS target like SRC kinase.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. A (-4.874) is slightly better than B (-5.092).
10. **Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. A (-2.836) is slightly better than B (-2.641).
11. **hERG:** Both have very low hERG risk (A: 0.719, B: 0.152), which is excellent.
12. **Cl_mic:** A (27.159) has lower microsomal clearance, indicating better metabolic stability, than B (8.004). This is a significant advantage for A.
13. **t1/2:** A (-7.032) has a longer in vitro half-life than B (2.49), which is desirable.
14. **Pgp:** Both have very low Pgp efflux liability (A: 0.027, B: 0.031).
15. **Binding Affinity:** A (-9.1) has a significantly stronger binding affinity than B (-8). This is a major advantage for A.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** A is significantly better (-9.1 vs -8).
*   **Metabolic Stability:** A has better metabolic stability (lower Cl_mic, longer t1/2).
*   **Solubility:** A is slightly better.
*   **hERG:** Both are excellent.
*   **LogP:** B is better.
*   **QED:** A is better.

**Conclusion:**

Despite B having a better logP, the significantly stronger binding affinity of A, coupled with its better metabolic stability and slightly better solubility, outweigh the logP disadvantage. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of A is crucial for an enzyme target.

1
2025-04-17 16:54:34,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (358.467 and 356.388 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.12) is higher than Ligand B (49.5). While both are reasonably good, Ligand B is significantly better, being well below the 140 threshold for oral absorption.

**3. logP:** Both ligands have similar logP values around 3.9-4.0, which is slightly high but acceptable.

**4. H-Bond Donors:** Ligand A has 3 HBDs, and Ligand B has 1. Both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, well within the limit of 10.

**6. QED:** Both ligands have good QED scores (0.731 and 0.815), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 75.843, which is concerningly high. Ligand B has a much lower DILI risk of 13.843, which is excellent. This is a major advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration, with Ligand A at 67.352 and Ligand B at 79.411. This isn't a primary concern for a kinase inhibitor, but Ligand B is better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.635 and -4.71), which is unusual and suggests poor permeability. However, these values are on a log scale and require careful interpretation.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.825 and -3.875), indicating poor aqueous solubility. This is a concern, but can be addressed through formulation.

**11. hERG Inhibition:** Ligand A (0.271) has a slightly higher hERG risk than Ligand B (0.945), though both are relatively low.

**12. Microsomal Clearance:** Ligand A (30.781) has lower microsomal clearance than Ligand B (45.179), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (47.138) has a slightly longer half-life than Ligand B (41.155), which is preferable.

**14. P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux than Ligand B (0.513), suggesting better bioavailability.

**15. Binding Affinity:** Ligand A (-9.8 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, lower P-gp efflux, and slightly better metabolic stability and half-life. However, its high DILI risk is a major red flag. Ligand B has a much better safety profile (DILI), better TPSA, and slightly better BBB penetration. The difference in binding affinity (1.3 kcal/mol) is substantial, but the high DILI risk of Ligand A outweighs this benefit. Kinase inhibitors often require chronic administration, making safety paramount.

Output:
1
2025-04-17 16:54:34,471 - INFO - Batch 502 complete. Total preferences: 8032
2025-04-17 16:54:34,471 - INFO - Processing batch 503/512...
2025-04-17 16:55:19,032 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.391 Da) is slightly lower, which can be beneficial for permeability. Ligand B (359.442 Da) is also good.

**TPSA:** Ligand A (75.11) is well below the 140 threshold for oral absorption. Ligand B (98.74) is still acceptable, but less favorable.

**logP:** Ligand A (2.994) is optimal (1-3). Ligand B (0.221) is quite low, potentially hindering membrane permeability and absorption.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 3 respectively) and HBA (4 each) counts.

**QED:** Both ligands have reasonable QED scores (0.753 and 0.548), indicating good drug-likeness.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (29.779). This is a significant concern for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand A (46.336) and Ligand B (58.976) are both relatively low.

**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.

**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 (0.576 and 0.214), which is excellent.

**Microsomal Clearance:** Ligand A (18.586) has a lower microsomal clearance than Ligand B (19.811), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (33.299) has a significantly longer half-life than Ligand B (-27.169). The negative value for Ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.106 and 0.042).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B's extremely low logP and negative in vitro half-life are major red flags. The low logP suggests poor absorption, and the negative half-life indicates very rapid metabolism. While Ligand A has a higher DILI risk, the better logP, longer half-life, and lower clearance make it the more promising candidate. The DILI risk can be addressed through structural modifications during optimization. The solubility and permeability issues are shared by both, and would need to be addressed.

Output:
0
2025-04-17 16:55:19,033 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.662 Da) is slightly higher than Ligand B (353.379 Da), but both are acceptable.

**TPSA:** Ligand A (67.87) is well below the 140 threshold for oral absorption. Ligand B (139.78) is approaching the upper limit, but still acceptable for oral absorption.

**logP:** Ligand A (4.884) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-2.602) is quite low, which may hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (3 HBD, 7 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (A: 0.483, B: 0.491), indicating moderate drug-likeness.

**DILI:** Ligand A (88.329) has a significantly higher DILI risk than Ligand B (39.511). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (46.607) is lower than Ligand B (28.383).

**Caco-2 Permeability:** Ligand A (-5.083) has poor Caco-2 permeability, while Ligand B (-5.882) is also poor, but slightly less so.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.401, B: -1.553). This is a significant issue that would need to be addressed.

**hERG Inhibition:** Ligand A (0.594) has a slightly higher hERG risk than Ligand B (0.032), which is a major advantage for Ligand B.

**Microsomal Clearance:** Ligand A (70.644) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (-12.241), which suggests better metabolic stability.

**In vitro Half-Life:** Ligand A (17.656) has a shorter half-life than Ligand B (12.311).

**P-gp Efflux:** Ligand A (0.574) has slightly higher P-gp efflux than Ligand B (0.004).

**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 can outweigh some ADME drawbacks.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.4 vs -7.2 kcal/mol) is a major advantage. Furthermore, it exhibits a much lower DILI risk (39.511 vs 88.329) and a lower hERG risk (0.032 vs 0.594). While Ligand A has slightly better Caco-2 permeability, the other factors heavily favor Ligand B. The lower logP of Ligand B might be addressable through structural modifications, whereas the high DILI risk of Ligand A is a more difficult problem to solve.

Output:
1
2025-04-17 16:55:19,033 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (346.431 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.62) is better than Ligand B (78.09), both are below 140, suggesting good absorption potential.

**3. logP:** Both ligands (2.396 and 2.442) are within the optimal range of 1-3.

**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 (0.872) has a significantly better QED score than Ligand B (0.744), indicating a more drug-like profile.

**7. DILI:** Ligand B (32.648) has a much lower DILI risk than Ligand A (52.966), which is a significant advantage.

**8. BBB:** Ligand A (73.905) has better BBB penetration than Ligand B (55.06), but this is less critical for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Ligand A (-4.437) has better Caco-2 permeability than Ligand B (-5.152).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.311 and -2.378). This is a concern for both, but could be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.448 and 0.353).

**12. Microsomal Clearance:** Ligand B (29.902) has significantly lower microsomal clearance than Ligand A (69.68), indicating better metabolic stability. This is a key advantage for an enzyme target.

**13. In vitro Half-Life:** Ligand B (-13.916) has a much longer in vitro half-life than Ligand A (-6.473), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.113).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.6 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has slightly better permeability and BBB penetration, Ligand B is superior in terms of metabolic stability (lower Cl_mic, longer t1/2) and DILI risk. Given the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the improved metabolic stability and lower toxicity of Ligand B outweigh the minor advantages of Ligand A. The solubility is a concern for both, but is not a deciding factor.

Output:
1
2025-04-17 16:55:19,033 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (371.905 Da) is also well within range.

**TPSA:** Ligand A (124.26) is better than Ligand B (59). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (-0.593) is a bit low, potentially hindering permeation. Ligand B (4.004) is high, potentially causing 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 4 HBA, also acceptable.

**QED:** Both ligands have similar, good QED values (0.655 and 0.675).

**DILI:** Ligand A (51.221) has a moderate DILI risk, while Ligand B (16.053) has a very low DILI risk, which is a significant advantage.

**BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.526) has very poor Caco-2 permeability, a major drawback. Ligand B (-4.896) is also poor, but slightly better than A.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.429) is slightly better than Ligand B (-3.69).

**hERG:** Ligand A (0.067) has a very low hERG risk, a significant advantage. Ligand B (0.64) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-21.93) has a low (good) microsomal clearance, indicating good metabolic stability. Ligand B (99.862) has a very high clearance, suggesting rapid metabolism and a short half-life.

**In vitro Half-Life:** Ligand A (-17.886) has a very short half-life, which is concerning. Ligand B (52.104) has a longer half-life, which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-8.8 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much better metabolic stability profile (lower Cl_mic, longer t1/2) and lower DILI risk. While its logP is high and solubility is poor, the strong binding affinity and improved metabolic stability are critical for an enzyme inhibitor. Ligand A has a better hERG profile and slightly better solubility, but its poor Caco-2 permeability and very short half-life are major liabilities. The affinity difference is large enough to prioritize Ligand B despite its other issues.

Output:
1
2025-04-17 16:55:19,034 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.4 Da) is slightly better positioned.

**TPSA:** Ligand A (41.99) is significantly better than Ligand B (62.3). Lower TPSA generally favors better absorption.

**logP:** Both ligands have acceptable logP values (A: 4.145, B: 3.912), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (A: 2, B: 3), staying within the recommended limits.

**QED:** Ligand A (0.865) has a much higher QED score than Ligand B (0.6), indicating a more drug-like profile.

**DILI:** Ligand B (63.823) has a higher DILI risk than Ligand A (44.281), which is concerning.

**BBB:** While not a primary concern for a non-CNS target like SRC, Ligand A (95.541) shows better BBB penetration than Ligand B (80.109).

**Caco-2 Permeability:** Ligand A (-4.452) appears to have better Caco-2 permeability than Ligand B (-4.934), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.173) has better aqueous solubility than Ligand B (-4.431).

**hERG Inhibition:** Ligand A (0.771) has a lower hERG inhibition liability than Ligand B (0.311), which is a significant advantage.

**Microsomal Clearance:** Ligand B (40.255) has a slightly lower microsomal clearance than Ligand A (35.217), suggesting better metabolic stability. However, the difference isn't huge.

**In vitro Half-Life:** Ligand A (20.45) has a longer in vitro half-life than Ligand B (14.025).

**P-gp Efflux:** Ligand A (0.619) has lower P-gp efflux liability than Ligand B (0.427).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.4 kcal/mol, B: -10.1 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 significantly better overall. It has a superior QED score, lower DILI risk, better solubility, lower hERG inhibition, better Caco-2 permeability, and a longer half-life. While Ligand B has a slightly better binding affinity and lower microsomal clearance, the other ADME/Tox properties of Ligand A are far more favorable, making it a more promising drug candidate.

Output:
1
2025-04-17 16:55:19,034 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (349.435 and 360.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is slightly higher than Ligand B (75.94), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.687) is a bit low, potentially hindering permeation. Ligand B (2.69) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are below the 10 threshold.

**QED:** Ligand A (0.841) has a slightly better QED score than Ligand B (0.768), indicating a more drug-like profile.

**DILI:** Ligand B (67.313) has a higher DILI risk than Ligand A (56.65), which is less desirable.

**BBB:** Both have reasonable BBB penetration (Ligand A: 76.27, Ligand B: 70.415), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.455) has worse Caco-2 permeability than Ligand B (-5.319), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.389) has better aqueous solubility than Ligand B (-3.095). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.202) has a lower hERG inhibition liability than Ligand B (0.454), which is a significant advantage.

**Microsomal Clearance:** Ligand A (24.07) has a lower microsomal clearance than Ligand B (40.046), indicating better metabolic stability. This is a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-9.315) has a longer in vitro half-life than Ligand B (10.878). This is also a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux liability than Ligand B (0.117), which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-9.2 kcal/mol), which is excellent.

**Overall:**

Ligand A demonstrates superior ADME properties, particularly regarding metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and lower P-gp efflux. While its logP is slightly lower and Caco-2 permeability is worse, the strong binding affinity and significantly better safety/pharmacokinetic profile outweigh these minor drawbacks. Ligand B has a better logP, but suffers from higher DILI risk, worse metabolic stability, and higher hERG risk.

Output:
0
2025-04-17 16:55:19,034 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.22 Da) is slightly higher than Ligand B (368.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 104, which is acceptable for oral absorption but not ideal for CNS penetration (not a priority here).

**logP:** Ligand A (3.048) is within the optimal range (1-3). Ligand B (-0.015) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (3) and HBA (4 for A, 7 for B) counts, falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.582 and 0.652), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (97.169), which is a major red flag. Ligand B has a much lower DILI risk (35.556), a significant advantage.

**BBB:** BBB is not a high priority for a non-CNS target like SRC. Ligand A (55.254) and Ligand B (41.179) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.978) has poor Caco-2 permeability, which is concerning. Ligand B (-5.364) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-5.454) and Ligand B (-1.647) both have poor aqueous solubility. This could present formulation challenges. B is slightly better.

**hERG Inhibition:** Ligand A (0.572) has a slightly elevated hERG risk, but it's not alarming. Ligand B (0.188) has a very low hERG risk, a clear advantage.

**Microsomal Clearance:** Ligand A (55.406) has moderate clearance, suggesting moderate metabolic stability. Ligand B (-17.237) has *negative* clearance, which is impossible and likely an error in the data. This is a major issue.

**In vitro Half-Life:** Ligand A (74.88) has a good in vitro half-life. Ligand B (-6.188) has a negative half-life, which is impossible and further reinforces the data error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.259 and 0.019), which is good.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Despite the stronger binding affinity of Ligand B, the negative values for microsomal clearance and half-life are impossible and indicate a serious data quality issue. Ligand A, while having a very high DILI risk and poor solubility/permeability, at least has plausible ADME properties. The DILI risk is concerning, but potentially mitigable through structural modifications. The data for Ligand B is simply unusable.

Output:
0
2025-04-17 16:55:19,034 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.399 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.67) is better than Ligand B (100.35) as it is closer to the <140 threshold for good oral absorption.

**logP:** Ligand A (1.622) is within the optimal 1-3 range. Ligand B (0.497) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=6) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.893 and 0.746), indicating good drug-like properties.

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (36.758), which is a significant negative for A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (53.587) is slightly better than Ligand B (35.285).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.093 and -5.484), 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 (-1.68 and -1.143), indicating very poor aqueous solubility. This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.115) shows significantly lower hERG inhibition risk than Ligand B (0.073), which is a substantial advantage for A.

**Microsomal Clearance:** Ligand B (-4.72) has a *negative* microsomal clearance, which is highly unusual and suggests extremely high metabolic stability. Ligand A (30.927) has a moderate clearance. This is a major advantage for B.

**In vitro Half-Life:** Ligand B (5.761) has a longer half-life than Ligand A (-0.988), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.104 and 0.004), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.0 kcal/mol). The difference of 0.5 kcal/mol is not enough to overcome other significant differences.

**Overall Assessment:**

Ligand B is superior due to its significantly better metabolic stability (negative Cl_mic), longer half-life, and lower DILI risk. While its logP is slightly lower and TPSA is higher, the substantial advantage in metabolic stability and safety outweighs these minor drawbacks, especially for a kinase inhibitor where sustained target engagement is crucial. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 16:55:19,035 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (343.435 and 355.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.24) is better than Ligand B (46.61) as it is closer to the threshold of 140.

**logP:** Both ligands have acceptable logP values (2.46 and 3.835), 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.

**H-Bond Donors/Acceptors:** Ligand A has 3 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 (0.789) has a significantly better QED score than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand A (55.758) has a higher DILI risk than Ligand B (15.665). This is a significant drawback for Ligand A.

**BBB:** Ligand A (49.554) has lower BBB penetration than Ligand B (95.308). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.281) has worse Caco-2 permeability than Ligand B (-3.973).

**Aqueous Solubility:** Ligand A (-3.841) has worse aqueous solubility than Ligand B (-4.798). Solubility is important for bioavailability, so this favors Ligand B.

**hERG Inhibition:** Ligand A (0.409) has a slightly higher hERG inhibition risk than Ligand B (0.849). Lower is better, so this favors Ligand B.

**Microsomal Clearance:** Ligand A (33.156) has significantly lower microsomal clearance than Ligand B (123.486), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-18.274) has a longer in vitro half-life than Ligand B (-6.738). This is also a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.348), which is favorable for bioavailability.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While both are good, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has advantages in metabolic stability (Cl_mic, t1/2), P-gp efflux, and binding affinity. However, it suffers from a higher DILI risk, lower solubility, and poorer Caco-2 permeability. Ligand B has better solubility, lower DILI risk, and better BBB penetration, but has worse metabolic stability. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the better metabolic stability of Ligand A is a significant advantage. The difference in binding affinity is small, and the DILI risk, while higher, might be mitigated with further optimization.

Output:
1
2025-04-17 16:55:19,035 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.368 Da) is slightly higher than Ligand B (379.917 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (75.71) is slightly higher than Ligand B (70.84), but both are good.

**logP:** Ligand A (1.84) is within the optimal range (1-3). Ligand B (4.135) 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 (0.665) has a better QED score than Ligand B (0.421), indicating a more drug-like profile.

**DILI:** Ligand A (28.306) has a significantly lower DILI risk than Ligand B (69.833), which is a major advantage.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand A (57.929) is slightly lower than Ligand B (60.644).

**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 very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.671) has a lower hERG inhibition liability than Ligand B (0.88), which is preferable.

**Microsomal Clearance:** Ligand A (17.813 mL/min/kg) has a much lower microsomal clearance than Ligand B (65.612 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (135.866 hours) has a significantly longer in vitro half-life than Ligand A (7.782 hours), which is a positive.

**P-gp Efflux:** Ligand A (0.136) has lower P-gp efflux liability than Ligand B (0.602), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME drawbacks of Ligand B.

**Overall:**

Ligand A is the better candidate. While its half-life is shorter, it has a significantly better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), better QED, and lower P-gp efflux. The slightly better affinity of Ligand B is not enough to compensate for its poor ADME properties. The solubility and permeability issues are concerning for both, but Ligand A's other properties make it the more promising starting point for optimization.

Output:
0
2025-04-17 16:55:19,035 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.435 and 363.424 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (77.52) is better than Ligand B (47.36). While both are reasonably low, Ligand B is excellent, suggesting better potential for cell permeability.

**logP:** Both ligands have good logP values (2.513 and 3.734), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target effects, but not drastically.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.848 and 0.723), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (82.241) compared to Ligand B (29.934). This is a major concern for Ligand A.

**BBB:** Ligand A (55.254) and Ligand B (87.437). BBB is less critical for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.464 and -4.266), which is unusual and requires further investigation. It suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.61 and -4.039). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.23) has a slightly lower hERG risk than Ligand B (0.616), which is favorable.

**Microsomal Clearance:** Ligand B (90.971) has a higher microsomal clearance than Ligand A (71.856), indicating faster metabolism and potentially lower *in vivo* exposure. Ligand A is better here.

**In vitro Half-Life:** Ligand B (9.784) has a slightly longer half-life than Ligand A (8.787), which is preferable.

**P-gp Efflux:** Ligand A (0.276) has lower P-gp efflux than Ligand B (0.146), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.4 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand B's significantly lower DILI risk and better BBB penetration outweigh the slightly higher logP and faster clearance. The slightly better binding affinity of Ligand B is also a positive. The solubility and permeability issues of both compounds would need to be addressed through formulation or structural modifications, but the lower toxicity profile of Ligand B makes it the more promising starting point.

Output:
1
2025-04-17 16:55:19,035 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.483 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (32.78) as it is still within the acceptable range for oral absorption.

**logP:** Both ligands have logP values (2.868 and 3.552) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.723) has a better QED score than Ligand B (0.604), indicating a more drug-like profile.

**DILI:** Ligand B (4.42) has a significantly lower DILI risk than Ligand A (11.245), which is a major advantage.

**BBB:** Ligand B (92.827) has a much higher BBB penetration score than Ligand A (70.764). While not a primary concern for a non-CNS target like SRC, it's a neutral benefit.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.6 and -4.266), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.179 and -3.522), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.394) has a lower hERG inhibition liability than Ligand B (0.856), which is a positive.

**Microsomal Clearance:** Ligand B (103.497) has a significantly higher microsomal clearance than Ligand A (40.726), indicating lower metabolic stability. This is a major disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (8.737) has a shorter in vitro half-life than Ligand B (25.307), which is a negative.

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux liability than Ligand B (0.252), which is a positive.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly better binding affinity than Ligand B (-6.8 kcal/mol). This is a crucial advantage, as a 1.9 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and better metabolic stability (lower Cl_mic) and P-gp efflux, but suffers from a higher DILI risk and shorter half-life. Ligand B has a lower DILI risk and longer half-life, but significantly weaker binding affinity and poorer metabolic stability.

Given the priority for potency in enzyme inhibitors, the superior binding affinity of Ligand A (-8.7 kcal/mol vs -6.8 kcal/mol) is the deciding factor, despite its drawbacks. The difference in binding affinity is large enough to potentially overcome the other issues through further optimization. The poor solubility and permeability of both are concerning and would need to be addressed in subsequent lead optimization, but can be tackled with formulation strategies or chemical modifications.

Output:
0
2025-04-17 16:55:19,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (340.339 Da and 346.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (116.08) is better than Ligand B (41.57). While both are reasonably low, Ligand B is exceptionally low, which could indicate poor solubility.

**logP:** Ligand A (1.33) is optimal, while Ligand B (3.946) is approaching the upper limit. This suggests Ligand B might have some solubility issues or off-target effects.

**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, but potentially indicating lower aqueous solubility.

**QED:** Both ligands have good QED scores (0.536 and 0.767), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (95.192), which is a significant concern. Ligand B has a very low DILI risk (6.669), a major advantage.

**BBB:** Ligand A has very low BBB penetration (16.014), which is not critical for a non-CNS target like SRC. Ligand B has good BBB penetration (83.443), which is irrelevant in this case.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.195), which is concerning and suggests poor permeability. Ligand B has a negative Caco-2 value (-4.659), also concerning.

**Aqueous Solubility:** Ligand A has very poor aqueous solubility (-5.034). Ligand B has poor aqueous solubility (-3.525).

**hERG:** Ligand A has a low hERG risk (0.217), which is good. Ligand B has a moderate hERG risk (0.753).

**Microsomal Clearance:** Ligand A has very low microsomal clearance (-10.788), indicating excellent metabolic stability. Ligand B has moderate clearance (18.11), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a moderate half-life (25.929 hours). Ligand B has a shorter half-life (14.276 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.11 and 0.121).

**Binding Affinity:** Ligand B has a significantly better binding affinity (-9 kcal/mol) than Ligand A (0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand A has excellent metabolic stability and low hERG risk, but suffers from very high DILI risk, poor solubility, and poor permeability. Its binding affinity is essentially zero.

Ligand B has a much better binding affinity, low DILI risk, and acceptable metabolic stability. While its solubility and permeability are also poor, the significantly improved potency outweighs these drawbacks. The higher logP is a minor concern, but the strong binding affinity is the dominant factor.

Output:
1
2025-04-17 16:55:19,036 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [340.427, 70.39, 3.01, 2, 4, 0.902, 63.203, 68.282, -4.798, -3.517, 0.633, 46.223, 36.462, 0.196, -7]
**Ligand B:** [361.511, 56.67, 2.594, 1, 5, 0.785, 18.883, 77.976, -4.804, -2.669, 0.637, 58.933, 38.389, 0.34, -9.2]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (340.427) is slightly better.
2. **TPSA:** A (70.39) is higher than B (56.67). Both are acceptable for an enzyme, but B is preferable.
3. **logP:** Both are within the optimal range (1-3). A (3.01) is slightly higher, potentially leading to off-target effects, but not drastically. B (2.594) is better.
4. **HBD:** A (2) and B (1) are both good, below the threshold of 5. B is slightly better.
5. **HBA:** A (4) and B (5) are both acceptable, below the threshold of 10.
6. **QED:** A (0.902) is excellent, indicating high drug-likeness. B (0.785) is still good, but not as strong.
7. **DILI:** A (63.203) is higher than B (18.883). This is a significant advantage for B, as lower DILI risk is crucial.
8. **BBB:** Both are acceptable, but B (77.976) is better than A (68.282). Not a primary concern for a kinase inhibitor, but a plus.
9. **Caco-2:** Both are negative, indicating poor permeability. This is a concern for both, but not a deciding factor.
10. **Solubility:** Both are negative, indicating poor solubility. This is a concern for both, but not a deciding factor.
11. **hERG:** Both are low, indicating low hERG inhibition risk.
12. **Cl_mic:** A (46.223) is lower than B (58.933), indicating better metabolic stability. This is a strong point for A.
13. **t1/2:** A (36.462) is slightly lower than B (38.389). Both are acceptable.
14. **Pgp:** Both are low, indicating low P-gp efflux.
15. **Binding Affinity:** B (-9.2 kcal/mol) is significantly stronger than A (-7 kcal/mol). This is a major advantage for B, potentially outweighing some of the ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Enzyme-Kinase Specific Priorities:**

For an enzyme like SRC kinase, potency (binding affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic) and a slightly better QED score, Ligand B has a *much* stronger binding affinity (-9.2 vs -7 kcal/mol) and a significantly lower DILI risk (18.883 vs 63.203). The superior binding affinity is a critical advantage for an enzyme inhibitor, and the lower DILI risk is a major safety benefit. The slightly lower metabolic stability of B is a manageable concern, especially given the potency.

Therefore, I recommend **Ligand B** as the more viable drug candidate.

1
2025-04-17 16:55:19,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 B (78.68) is significantly better than Ligand A (113.49). Lower TPSA generally improves oral absorption.

**logP:** Ligand B (2.169) is optimal, while Ligand A (0.111) is quite low, potentially hindering permeation.

**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 scores (A: 0.664, B: 0.795), indicating drug-like properties.

**DILI:** Ligand B (30.283) has a much lower DILI risk than Ligand A (45.56). This is a significant advantage.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand B (71.074) is higher than Ligand A (32.144), but this isn't a deciding factor.

**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 (0.131) has a slightly lower hERG risk than Ligand B (0.46), which is preferable.

**Microsomal Clearance:** Ligand B (3.705) has significantly lower microsomal clearance than Ligand A (28.146), indicating better metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (43.144 hours) has a much longer half-life than Ligand A (9.681 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux than Ligand B (0.141), which is preferable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.1 kcal/mol). This is a major advantage, and the 2.3 kcal/mol difference is significant enough to outweigh most other concerns.

**Conclusion:**

Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher hERG risk and lower P-gp efflux. While both have issues with solubility and permeability, the potency and pharmacokinetic advantages of Ligand B make it much more likely to be a viable drug candidate for SRC kinase.

Output:
1
2025-04-17 16:55:19,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (108.47). A TPSA below 140 is good for oral absorption, but lower is generally preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (1.958) is optimal, while Ligand B (0.588) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=6). Both are within acceptable limits, but Ligand A has a lower count, which is generally favorable.

**QED:** Both ligands have similar QED values (0.795 and 0.677), indicating good drug-like properties.

**DILI:** Ligand A (14.889) has a much lower DILI risk than Ligand B (75.766). This is a significant advantage for Ligand A.

**BBB:** Both ligands have the same BBB penetration (53.625). This is not a primary concern for a kinase inhibitor unless CNS effects are specifically desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.602 and -5.009), 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 (-2.549 and -2.731), which is also unusual. Again, the difference is small.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.151 and 0.14). This is excellent.

**Microsomal Clearance:** Ligand A (6.039) has significantly lower microsomal clearance than Ligand B (45.944). This indicates better metabolic stability, a crucial factor for enzymes.

**In vitro Half-Life:** Ligand A (9.262) has a positive half-life, while Ligand B (-19.638) has a negative half-life. This is a major difference, suggesting significantly better stability for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.033).

**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, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better logP, TPSA, DILI score, microsomal clearance, in vitro half-life, and, most importantly, a much stronger binding affinity. While both have unusual Caco-2 and solubility values, the other advantages of Ligand A, particularly its metabolic stability and potency, make it a much more promising drug candidate for SRC kinase inhibition.

Output:
1
2025-04-17 16:55:19,037 - INFO - Batch 503 complete. Total preferences: 8048
2025-04-17 16:55:19,037 - INFO - Processing batch 504/512...
2025-04-17 16:56:00,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.5 and 340.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (83.98) is still under 140, but less optimal than A.

**logP:** Both ligands have good logP values (2.118 and 1.633), falling within the 1-3 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:** Both ligands have acceptable QED scores (0.846 and 0.556), indicating reasonable drug-likeness.

**DILI:** Ligand A (9.616) has a much lower DILI risk than Ligand B (50.136), a significant advantage.

**BBB:** While not a primary concern for a non-CNS target, Ligand A (83.56) has a better BBB percentile than Ligand B (55.642).

**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 compare the magnitude of the negative values. -4.801 (Ligand A) is better than -4.905 (Ligand B).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and concerning. Again, comparing magnitudes, -2.17 (Ligand A) is better than -3.016 (Ligand B).

**hERG:** Ligand A (0.516) has a lower hERG risk than Ligand B (0.066), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (32.588) has a higher microsomal clearance than Ligand B (20.521), meaning it is less metabolically stable. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-17.858) has a significantly longer in vitro half-life than Ligand A (-10.661), a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.057 and 0.033), which is good.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.4 kcal/mol). The 0.8 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, and TPSA. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a better binding affinity and a longer half-life, but carries a significantly higher DILI risk and hERG liability.

Given the enzyme-specific priorities, the longer half-life and better binding affinity of Ligand B are very attractive. While the DILI and hERG risks are concerning, they might be mitigated through structural modifications during lead optimization. The better metabolic stability of Ligand B is also a significant advantage. The solubility and permeability issues are present in both, but slightly less problematic in Ligand A.

Output:
1
2025-04-17 16:56:00,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.403 and 347.375 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.22) is better than Ligand B (114.69). Both are under 140, suggesting reasonable absorption, but A is closer to the preferred threshold.

**logP:** Ligand A (1.291) is optimal, while Ligand B (0.165) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is better than Ligand B (HBD=2, HBA=7). Both are within acceptable limits, but A has a lower HBD count, potentially improving permeability.

**QED:** Ligand A (0.811) has a much better QED score than Ligand B (0.399), indicating a more drug-like profile.

**DILI:** Ligand B (67.895) has a higher DILI risk than Ligand A (54.207), though both are moderately risky.

**BBB:** Both ligands have low BBB penetration (A: 64.25, B: 55.254), which isn't critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.024 and -5.097), which is unusual and suggests poor permeability. This is concerning for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-0.868 and -2.165), which is also unusual and suggests poor solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.124) has a much lower hERG risk than Ligand B (0.491). This is a significant advantage for A, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand A (41.66) has a lower microsomal clearance than Ligand B (56.752), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.591) has a much longer in vitro half-life than Ligand B (-8.85). This is a major advantage for A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both have very low P-gp efflux values (A: 0.024, B: 0.051).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. The difference of 1.5 kcal/mol is substantial.

**Overall Assessment:**

Ligand A is superior to Ligand B across most key parameters. It has a better logP, QED, hERG risk, metabolic stability, half-life, and, most importantly, significantly higher binding affinity. While both have issues with Caco-2 and solubility, the strong binding affinity and favorable ADME properties of Ligand A outweigh these concerns. Ligand B's low logP and weaker binding affinity are significant drawbacks.

Output:
1
2025-04-17 16:56:00,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.327 Da) is slightly lower, which could be advantageous for permeability. Ligand B (386.206 Da) is also acceptable.

**TPSA:** Ligand A (135.86) is borderline for good oral absorption, but acceptable. Ligand B (65.49) is excellent, suggesting good absorption.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.761) is slightly lower, while Ligand B (3.972) is approaching the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are within acceptable limits. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.472, B: 0.703), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A has a high DILI risk (96.549%), which is a significant concern. Ligand B has a lower, though still elevated, DILI risk (77.743%).

**BBB:** This is less critical for a kinase inhibitor, but Ligand B has a higher BBB percentile (78.209) than Ligand A (31.214).

**Caco-2 Permeability:** Ligand A (-5.65) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.357) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.929 and -5.29 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.86 and 0.451 respectively), which is positive.

**Microsomal Clearance:** Ligand A (13.291 mL/min/kg) has lower clearance, indicating better metabolic stability than Ligand B (120.974 mL/min/kg). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (0.495 hours) has a very short half-life, while Ligand B (36.553 hours) has a much longer half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.089 and 0.38 respectively).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -9.1 kcal/mol). The difference is not substantial enough to be a deciding factor.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic) and a slightly lower molecular weight, which are positives. However, its extremely poor Caco-2 permeability, very short half-life, and *very* high DILI risk are major drawbacks.

Ligand B has a better QED score, better TPSA, longer half-life, and a lower DILI risk than Ligand A. While its logP is higher and solubility is poor, the improved metabolic profile and reduced toxicity risk are more important for an enzyme inhibitor.

Despite the poor solubility of both, Ligand B is the more promising candidate due to its significantly improved metabolic stability and lower DILI risk, outweighing the slightly higher logP.

Output:
1
2025-04-17 16:56:00,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.877 Da and 368.821 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (113.33). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (4.633) is higher than optimal (1-3), potentially causing solubility issues. Ligand B (1.224) is on the lower side, which could hinder permeation.

**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 (0.71 and 0.567, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (58.821), which is a concern. However, both are below the concerning threshold of 60.

**BBB:** This isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand B (61.962) has a higher BBB value than Ligand A (29.275), but this is less important here.

**Caco-2 Permeability:** Ligand A (-4.942) has a worse Caco-2 permeability than Ligand B (-5.636).

**Aqueous Solubility:** Ligand A (-5.382) has worse aqueous solubility than Ligand B (-1.963).

**hERG Inhibition:** Ligand A (0.443) has a slightly higher hERG risk than Ligand B (0.306), but both are relatively low.

**Microsomal Clearance:** Ligand B (40.193) has a significantly lower microsomal clearance than Ligand A (59.653), indicating better metabolic stability. This is a key advantage for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (2.23) has a longer half-life than Ligand A (-0.034), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.455) has slightly lower P-gp efflux than Ligand B (0.113), which is favorable.

**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 of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's higher DILI risk and lower solubility, its significantly stronger binding affinity (-8.8 kcal/mol vs -7.7 kcal/mol) is a decisive factor. For an enzyme target like SRC kinase, potency is paramount. Ligand B has better ADME properties (metabolic stability, solubility), but the substantial affinity difference makes Ligand A the more promising candidate, assuming further optimization can mitigate the DILI risk.

Output:
1
2025-04-17 16:56:00,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (363.864 Da and 352.381 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (46.92) is well below the 140 threshold and favorable. Ligand B (69.64) is still acceptable, but less optimal.

**3. logP:** Ligand A (4.422) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.943) is within the optimal range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), staying within the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 each), staying within the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.854 and 0.851).

**7. DILI:** Ligand A (49.011) has a slightly higher DILI risk than Ligand B (36.758), but both are still reasonably low.

**8. BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand A (81.078) has a slightly higher value than Ligand B (73.827).

**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.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.333 and 0.331), which is excellent.

**12. Microsomal Clearance:** Ligand A (69.687) has a higher microsomal clearance than Ligand B (-6.842). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**13. In vitro Half-Life:** Ligand B (-10.771) has a significantly longer in vitro half-life than Ligand A (31.758), further supporting its better metabolic stability.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.315 and 0.044).

**15. Binding Affinity:** Both ligands have very strong binding affinities (-9.4 and -9.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand B is the more promising candidate. Its lower logP, significantly better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk outweigh the slightly higher TPSA. While both have poor predicted solubility and permeability, metabolic stability is a critical factor for kinase inhibitors, and Ligand B excels in this area.

Output:
1
2025-04-17 16:56:00,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.304 Da) is higher, but still acceptable. Ligand B (349.475 Da) is slightly lower, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values (A: 73.86, B: 83.22) below the 140 threshold for good oral absorption.

**logP:** Ligand A (4.184) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.687) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=3, HBA=3) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.724, B: 0.662), indicating good drug-like properties.

**DILI:** Ligand A has a very high DILI risk (95.812%), which is a major concern. Ligand B has a much lower DILI risk (41.76%), which is preferable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC. Ligand B (67.468%) is slightly higher than A (54.246%), but it's not a deciding factor.

**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 factors.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.287 and -3.794). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.536) has a slightly higher hERG risk than Ligand B (0.338), but both are relatively low.

**Microsomal Clearance:** Ligand A (102.573) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (69.497) is better in this regard.

**In vitro Half-Life:** Ligand B (-14.852) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound's stability. Ligand A (64.323) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.51, B: 0.19), which is good.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and questionable Caco-2 values for both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity, lower DILI risk, and better metabolic stability outweigh the slightly higher logP. The negative half-life for Ligand B is a red flag, but assuming this is a data error, its other properties make it the preferred choice. The high DILI risk for Ligand A is a deal-breaker.

Output:
1
2025-04-17 16:56:00,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.425 and 343.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (57.28), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands have good logP values (2.885 and 3.2), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5. Ligand A is preferable here, as lower HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.791 and 0.837), indicating good drug-likeness.

**DILI:** Ligand A (27.375) has a significantly lower DILI risk than Ligand B (52.423). This is a major advantage for Ligand A.

**BBB:** Both have high BBB penetration (95.696 and 96.123), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.684) is slightly better than Ligand B (-5.055), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-3.61 and -3.619). This could be a formulation challenge for both.

**hERG Inhibition:** Ligand A (0.512) has a lower hERG risk than Ligand B (0.948). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (20.664) has a much lower microsomal clearance than Ligand B (80.408), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (29.614) has a longer in vitro half-life than Ligand A (-6.631). This is a positive for Ligand B, but the substantial difference in Cl_mic for Ligand A is more impactful.

**P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux than Ligand B (0.347), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.0). While affinity is paramount, the 1 kcal/mol difference is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more promising drug candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly in DILI risk, hERG inhibition, and microsomal clearance. The lower DILI and hERG risks are critical for safety, and the lower clearance suggests better metabolic stability, which is essential for kinase inhibitors. The slightly better Caco-2 permeability and P-gp efflux also contribute to improved bioavailability.

Output:
0
2025-04-17 16:56:00,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.295 and 356.457 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.05) is higher than Ligand B (49.41). Both are acceptable, but Ligand B is preferable due to the lower TPSA, potentially aiding absorption.

**logP:** Both ligands have good logP values (2.799 and 3.355), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for off-target effects, but not a major issue.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 2. Ligand B is preferable here, as fewer HBA generally improves permeability.

**QED:** Both ligands have reasonable QED scores (0.842 and 0.711), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A has a significantly higher DILI risk (85.964%) compared to Ligand B (16.208%). This is a major red flag for Ligand A.

**BBB:** Both have high BBB penetration (83.637% and 91.198%). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.698 and -4.484), 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 have negative solubility values (-4.343 and -3.961), also unusual. Again, the difference isn't massive, but both are concerning.

**hERG Inhibition:** Ligand A (0.504) has a slightly higher hERG risk than Ligand B (0.751), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand B (57.782) has a slightly higher microsomal clearance than Ligand A (50.811), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (17.436 hours) has a significantly longer half-life than Ligand B (9.186 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.193 and 0.252).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This 0.4 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life, the drastically higher DILI risk is a major concern. Ligand B has a much lower DILI risk, better TPSA and HBA, and a significantly stronger binding affinity. The slightly higher clearance of Ligand B is less concerning than the high DILI risk of Ligand A. The solubility and permeability issues are present in both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 16:56:00,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (367.475 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.08) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (87.74) is well within the acceptable range.

**logP:** Both ligands have low logP values (0.497 and 0.357), which is below the optimal 1-3 range. This could potentially hinder membrane permeability, but isn't a dealbreaker if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both within the acceptable limits. Ligand B has 2 HBD and 4 HBA, also within limits.

**QED:** Both ligands have good QED scores (0.649 and 0.725), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 55.138, which is moderate but acceptable. Ligand B has a significantly lower DILI risk (16.092), which is a strong advantage.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B is slightly better (60.721 vs 44.203).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.5 and -5.17), which is unusual and suggests very poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.49 and -1.494), also unusual and indicating poor solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.114 and 0.147), which is excellent.

**Microsomal Clearance:** Ligand A has a Cl_mic of 7.126 mL/min/kg, which is relatively moderate. Ligand B has a *very* high Cl_mic (-22.078 mL/min/kg). The negative value is likely an error, but even if interpreted as a very low value, it indicates significantly better metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 21.847 hours, which is good. Ligand B has a very short half-life (-0.245 hours), which is a major concern. Again, the negative value is likely an error.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.012), which is favorable.

**Binding Affinity:** Ligand A has a slightly better binding affinity (-7.5 kcal/mol) compared to Ligand B (-7.2 kcal/mol), although the difference is small (0.3 kcal/mol).

**Overall Assessment:**

Despite the slightly better affinity of Ligand A, the significantly lower DILI risk and potentially much better metabolic stability (Cl_mic) of Ligand B are crucial advantages for an enzyme inhibitor. However, both ligands suffer from poor predicted solubility and permeability. The negative values for Caco-2 and solubility are concerning and may indicate issues with the prediction model or the molecule's structure. The negative half-life and clearance values for Ligand B are also suspect.

Considering the priorities for kinase inhibitors, metabolic stability is paramount. While the affinity difference is small, the lower DILI and potentially better metabolic stability of Ligand B make it the more promising candidate, *assuming* the negative values for clearance and half-life are errors and the true values are favorable.

Output:
1
2025-04-17 16:56:00,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, following the provided guidelines.

**1. Molecular Weight (MW):** Both ligands (350.459 and 352.431 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (95.94). Both are under 140, but A is closer to the preferred value for good absorption.

**3. logP:** Ligand A (2.063) is optimal (1-3). Ligand B (0.105) is quite low, 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):** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Ligand A (0.769) is better than Ligand B (0.646), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.918) has a significantly lower DILI risk than Ligand B (23.846). Both are good, but A is preferable.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand A (50.523) and Ligand B (42.226) are both relatively low.

**9. Caco-2 Permeability:** Ligand A (-5.028) is better than Ligand B (-4.989), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.961) is better than Ligand B (-0.927), which is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.202 and 0.042 respectively), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (47.544) has higher clearance than Ligand B (7.87). Lower clearance is preferred for better metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life (t1/2):** Ligand A (5.309) has a longer half-life than Ligand B (1.601), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.04 respectively).

**15. 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, exceeding the 1.5 kcal/mol threshold.

**Enzyme-Specific Priorities:** For a kinase like SRC, potency (affinity) and metabolic stability (Cl_mic, t1/2) are key. While Ligand A has better solubility, half-life, and lower DILI, Ligand B's substantially superior binding affinity (-10.1 vs -8.8 kcal/mol) and much lower Cl_mic (7.87 vs 47.544) outweigh these benefits. The lower logP of Ligand B is a concern, but the strong binding may compensate for this.

Output:
1
2025-04-17 16:56:00,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (371.373 and 360.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (115.16 and 113.32) are below the 140 A^2 threshold for good oral absorption, which is favorable.

**3. logP:** Both ligands have good logP values (1.228 and 1.08), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (4) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (7) are both acceptable, being below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.44 and 0.432), indicating moderate drug-likeness.

**7. DILI:** Ligand A (63.164) has a lower DILI risk than Ligand B (73.439), which is a significant advantage.

**8. BBB:** Ligand A (67.972) has a slightly better BBB penetration score than Ligand B (42.536), but this isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.028 and -5.536), which is unusual and suggests very poor permeability. This is a major concern for both.

**10. Aqueous Solubility:** Ligand A (-1.544) has better solubility than Ligand B (-4.819), which is a positive.

**11. hERG Inhibition:** Ligand A (0.092) shows a much lower hERG inhibition risk than Ligand B (0.657). This is a critical advantage.

**12. Microsomal Clearance:** Ligand A (5.81) has lower microsomal clearance than Ligand B (6.597), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.508) has a significantly longer in vitro half-life than Ligand A (-1.538). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.035).

**15. 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, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 permeability for both, Ligand B's substantially superior binding affinity (-7.9 vs 0.0 kcal/mol) is a decisive factor. The longer half-life of Ligand B is also a significant benefit. While Ligand A has advantages in DILI, hERG, and solubility, these are less critical than potency and metabolic stability for an enzyme target. The poor permeability is a concern for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 16:56:00,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (351.447 and 364.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.16 and 67.23) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.339) is slightly low, potentially hindering permeation. Ligand B (2.352) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is also acceptable.

**H-Bond Acceptors:** Both ligands (5) are well below the 10 threshold.

**QED:** Both ligands have good QED scores (0.683 and 0.909), indicating drug-likeness.

**DILI:** Ligand A (25.436) has a much lower DILI risk than Ligand B (54.556), which is a significant advantage. Both are below the 60 threshold, but A is considerably better.

**BBB:** Ligand B (78.596) has a better BBB penetration percentile than Ligand A (55.099). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.516 and -4.972). 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 (-1.164 and -2.958). Again, the scale is unspecified, making interpretation difficult. However, B appears worse.

**hERG Inhibition:** Ligand A (0.125) has a significantly lower hERG risk than Ligand B (0.753), which is a crucial advantage for kinase inhibitors.

**Microsomal Clearance:** Ligand A (18.222) has a higher microsomal clearance than Ligand B (1.428), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-1.466) has a slightly longer in vitro half-life than Ligand A (-2.377).

**P-gp Efflux:** Ligand A (0.023) has a much lower P-gp efflux liability than Ligand B (0.369), which is favorable for bioavailability.

**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 significant, but not overwhelming.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability, and a slightly longer half-life. However, Ligand A has significantly lower DILI and hERG risk, and lower P-gp efflux. The solubility and permeability issues are present in both, but potentially manageable with formulation. Given the enzyme-specific priorities, the lower toxicity profile of Ligand A (DILI and hERG) is more important, and the affinity difference is not large enough to outweigh these safety concerns.

Output:
0
2025-04-17 16:56:00,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.471 and 335.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.57) is significantly better than Ligand B (84.81).  A TPSA under 140 is good for oral absorption, and both are, but lower is generally preferred.

**logP:** Ligand A (3.778) is within the optimal range (1-3), while Ligand B (1.907) is at the lower end. While not problematic, a slightly higher logP can aid membrane permeability.

**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 good QED scores (0.82 and 0.874), indicating drug-like properties.

**DILI:** Ligand A (29.779) has a much lower DILI risk than Ligand B (37.146), both are good, but A is better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.572) is better than Ligand B (53.432).

**Caco-2 Permeability:** Ligand A (-4.446) is better than Ligand B (-5.133) - higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.758) is better than Ligand B (-3.601) - higher values are preferred.

**hERG:** Both ligands have low hERG risk (0.911 and 0.753), which is excellent.

**Microsomal Clearance:** Ligand A (54.039) has a higher microsomal clearance than Ligand B (17.41). Lower clearance is better for metabolic stability, so Ligand B is clearly superior here.

**In vitro Half-Life:** Ligand B (-26.697) has a much longer in vitro half-life than Ligand A (8.741), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.208 and 0.143), which is good.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much improved metabolic stability profile (lower Cl_mic, longer t1/2). While Ligand A has slightly better TPSA, solubility and lower DILI, the potency and metabolic stability advantages of Ligand B are more critical for an enzyme target like SRC. The difference in binding affinity is substantial enough to overcome the slight disadvantages in other parameters.

Output:
1
2025-04-17 16:56:00,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.399 and 350.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.4) is slightly above the preferred <140, while Ligand B (76.02) is well within. This favors Ligand B for better absorption.

**logP:** Ligand A (0.624) is a bit low, potentially hindering permeation. Ligand B (1.84) 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 values (0.768 and 0.703), indicating good drug-likeness.

**DILI:** Ligand A (41.877) has a slightly higher DILI risk than Ligand B (32.687), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (76.696) has a higher BBB percentile than Ligand A (63.629).

**Caco-2 Permeability:** Ligand A (-5.202) shows poor permeability, while Ligand B (-4.951) is slightly better, though still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.114 and -1.986). This is a significant concern for both, but could be addressed with formulation strategies.

**hERG:** Ligand A (0.05) has a very low hERG risk, which is excellent. Ligand B (0.229) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-30.252) has significantly lower (better) microsomal clearance than Ligand B (20.768), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.874) has a slightly longer half-life than Ligand B (-11.339).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.086).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8), but the difference is small.

**Overall Assessment:**

Ligand B has advantages in logP, TPSA, and binding affinity. However, Ligand A demonstrates a significantly better metabolic stability profile (lower Cl_mic, longer half-life) and a much lower hERG risk. Given the enzyme-specific priorities, metabolic stability and minimizing off-target effects (like hERG inhibition) are crucial. The slightly weaker binding affinity of Ligand A can potentially be optimized in subsequent iterations, while improving metabolic stability is often more challenging. The poor solubility of both is a concern, but can be addressed during formulation.

Output:
0
2025-04-17 16:56:00,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.829 and 366.458 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.06) is slightly higher than Ligand B (67.43), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.946) is at the upper end of the optimal range (1-3), while Ligand B (2.415) is comfortably within it. Ligand A's higher logP *could* lead to solubility issues or off-target interactions, but isn't a dealbreaker.

**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 (0.676 and 0.728), indicating drug-like properties.

**DILI:** Ligand A (85.847) has a significantly higher DILI risk than Ligand B (59.597). This is a major concern.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B (75.727) has a better BBB score than Ligand A (58.938), but it's not a primary factor here.

**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 is a concern for both compounds, but the value for Ligand A (-4.688) is worse than Ligand B (-3.725).

**hERG:** Ligand A (0.723) has a slightly higher hERG risk than Ligand B (0.432), but both are relatively low.

**Microsomal Clearance:** Ligand B (13.183) has *much* lower microsomal clearance than Ligand A (62.185), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand B (11.914) has a longer in vitro half-life than Ligand A (92.476), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.595) has lower P-gp efflux than Ligand B (0.264), which could mean better bioavailability.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). While the difference isn't huge, it's still favorable.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), a lower DILI risk, and slightly better binding affinity. The higher DILI risk associated with Ligand A is a major red flag, and the lower metabolic stability is also concerning for an enzyme target.

Output:
1
2025-04-17 16:56:00,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Ligand A:**
*   **MW:** 339.414 Da - Good, within the ideal range.
*   **TPSA:** 41.15 - Good, well below the 140 threshold.
*   **logP:** 4.123 - Slightly high, potentially leading to solubility issues, but manageable.
*   **HBD:** 1 - Good.
*   **HBA:** 3 - Good.
*   **QED:** 0.704 - Excellent, highly drug-like.
*   **DILI:** 35.479 - Excellent, very low risk.
*   **BBB:** 85.459 - High, but not a primary concern for a non-CNS target like SRC.
*   **Caco-2:** -4.556 - Poor, indicates poor permeability.
*   **Solubility:** -4.705 - Poor, indicates low solubility.
*   **hERG:** 0.978 - Low risk, good.
*   **Cl_mic:** 58.634 - Moderate, could be better for metabolic stability.
*   **t1/2:** -6.452 - Good, long half-life.
*   **Pgp:** 0.759 - Moderate efflux, could impact bioavailability.
*   **Affinity:** -7.9 kcal/mol - Excellent, very strong binding.

**Ligand B:**
*   **MW:** 366.447 Da - Good, within the ideal range.
*   **TPSA:** 114.94 - Acceptable, but approaching the upper limit for good absorption.
*   **logP:** 0.588 - Low, potentially hindering permeation.
*   **HBD:** 2 - Good.
*   **HBA:** 8 - Acceptable, but approaching the upper limit.
*   **QED:** 0.702 - Excellent, highly drug-like.
*   **DILI:** 74.719 - Moderate, higher risk than Ligand A.
*   **BBB:** 47.421 - Low, not a concern.
*   **Caco-2:** -5.78 - Poor, indicates poor permeability.
*   **Solubility:** -1.925 - Poor, indicates low solubility.
*   **hERG:** 0.035 - Very low risk, excellent.
*   **Cl_mic:** 33.017 - Good, low clearance, indicating good metabolic stability.
*   **t1/2:** -0.162 - Poor, short half-life.
*   **Pgp:** 0.017 - Very low efflux, good.
*   **Affinity:** -7.5 kcal/mol - Very good, strong binding, but slightly weaker than Ligand A.

**Comparison & Decision:**

Both ligands have excellent QED scores and strong binding affinities. However, Ligand A has a significantly better binding affinity (-7.9 vs -7.5 kcal/mol). While Ligand A has a higher logP, its DILI risk is much lower, and its in vitro half-life is substantially longer. Both ligands have poor Caco-2 permeability and solubility. Ligand B has better metabolic stability (lower Cl_mic) and lower Pgp efflux, but the shorter half-life and higher DILI risk are concerning.

Given the enzyme-specific priorities, the stronger binding affinity and lower DILI risk of Ligand A outweigh its slightly higher logP and moderate metabolic clearance. The longer half-life is also a significant advantage. While the permeability and solubility are poor for both, these can be addressed through formulation strategies.

Output:
1
2025-04-17 16:56:00,438 - INFO - Batch 504 complete. Total preferences: 8064
2025-04-17 16:56:00,439 - INFO - Processing batch 505/512...
2025-04-17 16:56:51,670 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.407 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.01) is slightly above the preferred <140, but acceptable. Ligand B (101.8) is well within the range.

**logP:** Ligand A (-0.587) is a bit low, potentially hindering permeability. Ligand B (0.733) is closer to the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, under the limit of 5.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.657 and 0.834), indicating drug-like properties.

**DILI:** Ligand A (41.062) has a lower DILI risk than Ligand B (52.772), both are acceptable (<60).

**BBB:** Both ligands have similar low BBB penetration (46.84 and 47.15), which is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.989 and -5.247), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.582 and -2.189), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.011) shows very low hERG inhibition risk, which is excellent. Ligand B (0.087) is also low, but slightly higher.

**Microsomal Clearance:** Ligand A (-35.362) has a very low (and negative) microsomal clearance, suggesting excellent metabolic stability. Ligand B (5.929) has a positive clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (14.237) has a reasonable half-life, while Ligand B (-3.218) has a negative half-life, which is not possible and indicates a significant issue.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.005 and 0.01).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, the substantial difference in binding affinity and metabolic stability is decisive. Ligand B's much stronger binding affinity (-9.8 kcal/mol vs -0.0 kcal/mol) outweighs the slightly higher DILI risk and faster metabolism. The negative half-life for Ligand B is a red flag, but the binding affinity is so much better that it suggests a potential issue with the measurement or modeling rather than the molecule itself. Ligand A's extremely weak binding affinity makes it unlikely to be a viable candidate, even with its better DILI and metabolic stability.

Output:
1
2025-04-17 16:56:51,670 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (338.34 and 359.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.35) is well below the 140 threshold and favorable for oral absorption. Ligand B (101.64) is still acceptable but less optimal.

**logP:** Both ligands have logP values within the optimal range (2.71 and 3.75). Ligand B is slightly higher, potentially raising concerns about off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 8 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.672) has a significantly better QED score than Ligand B (0.463), indicating a more drug-like profile.

**DILI:** Ligand A (88.25) has a higher DILI risk than Ligand B (69.14), which is a negative for Ligand A.

**BBB:** Both ligands have low BBB penetration, which isn't a major concern for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Ligand A (-4.276) has a more negative Caco-2 value, suggesting poorer permeability than Ligand B (-5.314). This is a significant drawback for Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.935 and -4.017). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.833) has a slightly better hERG profile than Ligand B (0.556), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (58.996) has a lower microsomal clearance than Ligand B (75.80), suggesting better metabolic stability. This is a key advantage for Ligand A.

**In vitro Half-Life:** Ligand A (28.35 hours) has a significantly longer half-life than Ligand B (18.06 hours), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.516 and 0.137).

**Binding Affinity:** Both ligands exhibit excellent binding affinity (-7.8 and -7.6 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other ADME considerations.

**Overall Assessment:**

Ligand A has a better QED, metabolic stability (lower Cl_mic, longer t1/2), and hERG profile. However, it suffers from poorer Caco-2 permeability and higher DILI risk. Ligand B has better permeability and lower DILI, but is less drug-like, has poorer metabolic stability, and a shorter half-life.

Considering the enzyme-specific priorities, metabolic stability and half-life are crucial. The superior metabolic stability and longer half-life of Ligand A are significant advantages that outweigh its slightly poorer permeability and higher DILI risk. The binding affinity is comparable between the two.

Output:
0
2025-04-17 16:56:51,670 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.451 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.77) is slightly higher than Ligand B (89.95), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (0.229) is quite low, potentially hindering permeation. Ligand B (-0.94) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2-4 H-bonds, well within acceptable limits.

**QED:** Both ligands have good QED scores (0.57 and 0.607), indicating drug-like properties.

**DILI:** Ligand A (29.624) has a significantly lower DILI risk than Ligand B (11.09), which is a major advantage.

**BBB:** Ligand A (73.672) has a better BBB percentile than Ligand B (44.32), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.866) and B (-5.117) have negative values, suggesting poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.04 and -1.355).

**hERG Inhibition:** Ligand A (0.269) has a slightly higher hERG risk than Ligand B (0.092), but both are relatively low.

**Microsomal Clearance:** Ligand B (-29.134) exhibits significantly better metabolic stability (lower clearance) than Ligand A (-11.81). This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (0.295) has a slightly better in vitro half-life than Ligand A (3.144).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.008 and 0.003).

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-8.5 and -8.0 kcal/mol). The difference is less than 0.5 kcal/mol, so it's not a decisive factor.

**Conclusion:**

While both ligands have good binding affinity, Ligand B is superior due to its significantly improved metabolic stability (lower Cl_mic) and slightly better half-life. The lower DILI risk of Ligand A is attractive, but the metabolic stability of Ligand B is more critical for an enzyme target like SRC kinase. The solubility is poor for both, but can be addressed through formulation strategies. The low logP values are a concern for both, but the potency is high enough that this may be overcome.

Output:
1
2025-04-17 16:56:51,670 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (338.338 and 340.379 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.55) is well below the 140 threshold, and excellent for absorption. Ligand B (89.87) is still acceptable, but less optimal.

**logP:** Ligand A (3.686) is at the higher end of the optimal range, while Ligand B (2.269) is slightly lower, but still within the 1-3 range.

**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:** Both ligands have good QED scores (0.775 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 90.151, which is high and concerning. Ligand B has a much lower DILI risk of 54.789, which is still not ideal, but significantly better.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (87.088) has better BBB penetration than Ligand B (49.36).

**Caco-2 Permeability:** Ligand A (-4.518) has poor Caco-2 permeability. Ligand B (-5.089) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.731) has poor aqueous solubility. Ligand B (-3.742) has better solubility, though still not great.

**hERG:** Ligand A (0.786) has a slightly higher hERG risk than Ligand B (0.56), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.284) has a moderate microsomal clearance, suggesting reasonable metabolic stability. Ligand B (-0.833) has a *negative* clearance, which is impossible and likely indicates an error or outlier in the data. This is a major red flag.

**In vitro Half-Life:** Ligand A (81.517) has a good in vitro half-life. Ligand B (-15.248) has a negative half-life, which is impossible and further supports the concern about its data quality.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.562 and 0.033), which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to overcome other significant issues.

**Conclusion:**

Despite similar binding affinities, Ligand A has a high DILI risk and poor permeability/solubility. Ligand B has a much better DILI profile and better solubility, but the negative values for microsomal clearance and half-life are highly problematic and suggest data errors. Given the importance of metabolic stability for an enzyme inhibitor, and the unphysical values for Ligand B, **Ligand A is the more viable candidate**, despite its drawbacks. Further investigation into the DILI risk of Ligand A would be necessary, but the data for Ligand B is simply too suspect to consider it a viable option.

Output:
0
2025-04-17 16:56:51,670 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (353.407 and 368.587 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.69) is better than Ligand B (49.41) as it is closer to the threshold of 140, suggesting better absorption.

**logP:** Both ligands have good logP values (2.576 and 3.699), 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 acceptable HBD (1) and HBA (7 for A, 3 for B) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Ligand A (0.822) has a higher QED score than Ligand B (0.675), indicating a more drug-like profile.

**DILI:** Ligand A (87.747) has a significantly higher DILI risk than Ligand B (24.234). This is a major concern for Ligand A.

**BBB:** Ligand A (32.92) has a low BBB penetration percentile, while Ligand B (83.249) has high BBB penetration. Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.864 and -4.903), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.245 and -3.899), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.452 and 0.617), which is good.

**Microsomal Clearance:** Ligand A (76.892) has lower microsomal clearance than Ligand B (101.952), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.814 hours) has a longer in vitro half-life than Ligand B (-10.27 hours). The negative value for B is concerning and likely an error, but even if it were a small positive number, A is still better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.218 and 0.303).

**Binding Affinity:** Both ligands have very strong binding affinities (-8.5 and -8.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to overcome other significant ADME issues.

**Conclusion:**

Despite Ligand A having a better QED, longer half-life, and lower clearance, the significantly higher DILI risk is a major red flag. Both compounds have poor solubility and permeability. However, the lower DILI risk of Ligand B makes it the more viable candidate, despite its other shortcomings. Addressing the solubility and permeability issues would be critical for further development of either compound, but starting with the one exhibiting lower toxicity is preferable.

Output:
1
2025-04-17 16:56:51,670 - INFO - Okay, let's analyze these two ligands for their potential as SRC kinase inhibitors.

**Ligand A:** [415.332, 81.75, 0.604, 2, 4, 0.666, 29.236, 63.164, -5.341, -2.081, 0.187, 26.413, -0.64, 0.015, -9.4]
**Ligand B:** [352.494, 49.41, 3.45, 1, 2, 0.842, 17.216, 89.376, -4.6, -4.079, 0.707, 53.689, -1.698, 0.183, -10]

**Step-by-step comparison:**

1. **MW:** Ligand A (415.332 Da) is within the ideal range, while Ligand B (352.494 Da) is also acceptable. No clear advantage here.
2. **TPSA:** Ligand A (81.75) is slightly higher than ideal (<=140), but still reasonable. Ligand B (49.41) is excellent, well below the 140 threshold.
3. **logP:** Ligand A (0.604) is a bit low, potentially impacting permeability. Ligand B (3.45) is optimal. This favors Ligand B.
4. **HBD:** Both ligands have acceptable HBD counts (A: 2, B: 1).
5. **HBA:** Both ligands have acceptable HBA counts (A: 4, B: 2).
6. **QED:** Both ligands have good QED scores (A: 0.666, B: 0.842), indicating drug-like properties. Ligand B is slightly better.
7. **DILI:** Ligand A (29.236) has a moderate DILI risk, but acceptable. Ligand B (17.216) has a lower DILI risk, which is favorable.
8. **BBB:** Ligand A (63.164) has a moderate BBB penetration. Ligand B (89.376) has a high BBB penetration. While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.
9. **Caco-2:** Both ligands have negative Caco-2 values, which is unusual. I'll interpret this as very low permeability. However, the scale is not specified, so it's hard to say how problematic this is.
10. **Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility. Again, the scale is unknown.
11. **hERG:** Both ligands have low hERG inhibition risk (A: 0.187, B: 0.707).
12. **Cl_mic:** Ligand A (26.413) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (53.689) has higher clearance. This favors Ligand A.
13. **t1/2:** Ligand A (-0.64) has a slightly negative half-life, which is concerning. Ligand B (-1.698) is worse. Both are problematic.
14. **Pgp:** Both ligands have very low Pgp efflux liability (A: 0.015, B: 0.183).
15. **Binding Affinity:** Ligand B (-10 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key. Ligand B has a much stronger binding affinity. Ligand A has better metabolic stability, but both have concerning half-lives. Solubility is poor for both.

**Conclusion:**

Despite the concerning half-lives and solubility issues for both, the significantly stronger binding affinity of Ligand B (-10 kcal/mol vs -9.4 kcal/mol) outweighs the slightly better metabolic stability of Ligand A. A 0.6 kcal/mol difference in binding affinity is substantial and can often be optimized later. The better logP and DILI profile of Ligand B also contribute to its favorability.

Output:
1
2025-04-17 16:56:51,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (376.469 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (77.57), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.097 and 2.145) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (0), as having some HBD can help with solubility.

**H-Bond Acceptors:** Ligand B (6) is better than Ligand A (4).

**QED:** Both ligands have similar QED values (0.613 and 0.637), indicating good drug-likeness.

**DILI:** Ligand A (26.483) has a significantly lower DILI risk than Ligand B (42.846), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (78.247 and 78.907). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.012) is slightly better than Ligand B (-4.371).

**Aqueous Solubility:** Ligand A (-2.774) is slightly better than Ligand B (-2.624).

**hERG:** Both ligands have very low hERG inhibition risk (0.389 and 0.123).

**Microsomal Clearance:** Ligand A (25.288) has a significantly lower microsomal clearance than Ligand B (66.952), indicating better metabolic stability. This is a critical factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (2.578) has a much longer in vitro half-life than Ligand B (-17.317). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux liability than Ligand B (0.224).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Ligand A is the superior candidate. While both ligands have excellent binding affinity, Ligand A demonstrates a significantly better safety profile (lower DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and better permeability/solubility characteristics. These factors are crucial for developing a viable drug candidate targeting an enzyme like SRC.

Output:
0
2025-04-17 16:56:51,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (341.371 and 341.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (106.94) is better than Ligand B (73.63), both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (2.952) is optimal (1-3). Ligand B (4.619) is slightly higher, potentially increasing off-target effects and decreasing solubility.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Ligand A (0.704) is better than Ligand B (0.48), indicating a more drug-like profile.

**7. DILI:** Ligand A (81.233) has a higher DILI risk than Ligand B (51.028), which is a concern. However, both are below the concerning 60 threshold.

**8. BBB:** Both ligands have similar BBB penetration (79.721 and 79.217), which isn't a primary concern for a non-CNS target like SRC.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. This needs further investigation, but we'll proceed assuming similar permeability for now.

**10. Solubility:** Ligand A (-3.086) has slightly better solubility than Ligand B (-4.881).

**11. hERG:** Ligand A (0.267) has a significantly lower hERG risk than Ligand B (0.937), which is a crucial advantage.

**12. Cl_mic:** Ligand A (37.976) has a much lower microsomal clearance than Ligand B (90.796), indicating better metabolic stability.

**13. t1/2:** Ligand A (19.507) has a shorter in vitro half-life than Ligand B (52.936). This is a drawback for Ligand A.

**14. Pgp:** Ligand A (0.229) has lower P-gp efflux liability than Ligand B (0.711), which is favorable for bioavailability.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 0.7 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a better binding affinity and longer half-life. However, Ligand A excels in most other critical ADME properties: lower logP, better QED, lower DILI risk (though still elevated), significantly lower hERG risk, much better metabolic stability (lower Cl_mic), and lower P-gp efflux. The difference in binding affinity (0.7 kcal/mol) is not substantial enough to overcome the significant ADME advantages of Ligand A, especially the lower hERG and improved metabolic stability. Given the enzyme-kinase target class, metabolic stability and minimizing off-target effects (hERG) are paramount.

Output:
0
2025-04-17 16:56:51,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.491 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (71.53) is still under 140, but less optimal than A.

**logP:** Ligand A (0.526) is a bit low, potentially hindering permeation. Ligand B (1.785) is better, 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 (0.805 and 0.765), indicating good drug-like properties.

**DILI:** Ligand A (5.894) has a very favorable DILI score, indicating low liver injury risk. Ligand B (12.02) is higher, suggesting a moderate risk, but still not alarming.

**BBB:** Both have reasonable BBB penetration, but Ligand B (85.576) is significantly higher than Ligand A (70.609). However, BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.123) has poor Caco-2 permeability, which is a concern. Ligand B (-4.776) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.161 and -1.094). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.281 and 0.394).

**Microsomal Clearance:** Ligand A (2.955) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (7.922) has a significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (5.006) has a positive half-life, while Ligand B (-15.817) has a negative half-life, indicating very poor stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.053).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-6.7 kcal/mol), a difference of 0.4 kcal/mol.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the better candidate. While Ligand B has slightly better affinity and BBB penetration, Ligand A has a significantly better DILI score, lower microsomal clearance (better metabolic stability), and a more reasonable half-life. The poor solubility and Caco-2 permeability of both are drawbacks, but metabolic stability is crucial for kinase inhibitors. The 0.4 kcal/mol difference in binding affinity is not substantial enough to outweigh the ADME advantages of Ligand A.

Output:
0
2025-04-17 16:56:51,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (348.378 Da) is slightly preferred due to being closer to the ideal range.

**TPSA:** Ligand A (95.25) is better than Ligand B (68.55) as it is still within the acceptable range for oral absorption.

**logP:** Ligand A (1.749) is optimal, while Ligand B (4.063) is approaching the upper limit and could potentially cause solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=4, HBA=3) is better balanced. Ligand B (HBD=0, HBA=5) has no hydrogen bond donors, which can sometimes hinder binding, and a slightly higher HBA count.

**QED:** Both ligands have relatively low QED scores (A: 0.49, B: 0.39), indicating suboptimal drug-likeness. This is a concern for both, but less so for Ligand A.

**DILI:** Ligand A (83.172) has a higher DILI risk than Ligand B (68.864), which is less desirable.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (81.776) is higher than Ligand B (18.651).

**Caco-2 Permeability:** Ligand A (-5.138) is better than Ligand B (-4.446), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.553) is significantly better than Ligand B (-6.446). Solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.48, B: 0.537), which is good.

**Microsomal Clearance:** Ligand A (-0.393) has a lower (better) microsomal clearance than Ligand B (91.713), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (28.192) has a better in vitro half-life than Ligand B (34.391).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.119, B: 0.296).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a higher DILI risk, it significantly outperforms Ligand B in several critical ADME properties: logP, solubility, microsomal clearance, and Caco-2 permeability. The superior solubility and metabolic stability of Ligand A, coupled with its more favorable logP, outweigh the slightly higher DILI risk. The equal binding affinity makes the ADME properties the deciding factor.

Output:
0
2025-04-17 16:56:51,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (351.535 Da and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is significantly better than Ligand B (118.01). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand B's higher TPSA could hinder absorption.

**logP:** Ligand A (3.403) is optimal, while Ligand B (1.062) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=4, HBA=4). Lower HBDs are generally preferred for better permeability.

**QED:** Ligand A (0.789) has a better QED score than Ligand B (0.617), indicating a more drug-like profile.

**DILI:** Ligand B (44.009) has a much lower DILI risk than Ligand A (5.351), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.07) has a higher BBB score than Ligand B (40.52).

**Caco-2 Permeability:** Ligand A (-4.683) has a better Caco-2 permeability than Ligand B (-5.122).

**Aqueous Solubility:** Ligand A (-1.956) has better solubility than Ligand B (-3.59). Solubility is important for bioavailability.

**hERG:** Ligand A (0.818) has a lower hERG risk than Ligand B (0.421), a crucial factor for safety.

**Microsomal Clearance:** Ligand B (-1.619) has a significantly *lower* (better) microsomal clearance than Ligand A (6.215), indicating greater metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-27.289) has a much longer in vitro half-life than Ligand A (6.983), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.028), which is slightly better.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, logP, solubility, and hERG, Ligand B excels in metabolic stability (Cl_mic and t1/2), DILI risk, and, most importantly, binding affinity. The stronger binding affinity of Ligand B (-8.3 kcal/mol vs -7.1 kcal/mol) is a decisive factor, especially for an enzyme target. The lower DILI risk is also a major benefit. The slightly lower logP and higher TPSA of Ligand B are less concerning given its superior potency and metabolic profile.

Output:
1
2025-04-17 16:56:51,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, focusing on the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (347.415 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.55) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (97.61) is well within the ideal range.

**3. logP:** Ligand A (1.443) and Ligand B (0.936) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (2) is even better, being closer to the ideal 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 (0.8) has a significantly better QED score than Ligand A (0.532), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.791) has a much lower DILI risk than Ligand B (38.348), which is a significant advantage.

**8. BBB:** Both ligands have low BBB penetration, which is not a primary concern for a non-CNS target like SRC kinase. Ligand B (45.638) is slightly higher than Ligand A (23.808).

**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, indicating poor solubility. Again, the scale is unknown, making direct comparison difficult.

**11. hERG Inhibition:** Ligand A (0.065) shows very low hERG inhibition risk, a major advantage. Ligand B (0.138) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand B (-9.072) has a negative clearance, which is not physically possible and suggests an error or unusual data representation. Ligand A (9.326) has a reasonable clearance. This is a major red flag for Ligand B.

**13. In vitro Half-Life:** Ligand B (17.806) has a much longer half-life than Ligand A (-10.92), which is a significant advantage. However, the negative half-life for Ligand A is concerning.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-7.7), a 1.3 kcal/mol difference.

**Enzyme-Specific Priorities:** For SRC kinase (an enzyme), potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

**Conclusion:**

Despite Ligand B's slightly better binding affinity and half-life, the negative and unrealistic microsomal clearance value is a critical flaw. The negative half-life for Ligand A is also concerning, but the overall profile of Ligand A is superior due to its significantly lower DILI risk and very low hERG inhibition. The more reasonable clearance value for Ligand A also makes it more promising. While both have solubility and permeability concerns, the metabolic stability issue with Ligand B is a showstopper.

Output:
0
2025-04-17 16:56:51,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (364.515 Da and 351.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.19) is better than Ligand B (102.66). Both are below 140, but A is closer to the optimal for oral absorption.

**logP:** Ligand A (2.608) is within the optimal range (1-3), while Ligand B (0.819) is slightly below, potentially impacting permeability.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**QED:** Ligand A (0.807) has a significantly better QED score than Ligand B (0.674), indicating higher drug-likeness.

**DILI:** Ligand A (36.603) has a much lower DILI risk than Ligand B (13.804), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (75.223) is better than Ligand B (54.789), but both are moderate.

**Caco-2 Permeability:** Ligand A (-5.357) is better than Ligand B (-4.835), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.972) is better than Ligand B (-1.791), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands (A: 0.119, B: 0.252) have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (41.526) has a higher microsomal clearance than Ligand B (2.236), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-13.004) has a shorter half-life than Ligand B (-8.108).

**P-gp Efflux:** Both ligands (A: 0.086, B: 0.008) have low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is superior despite the slightly lower logP. The key advantages of Ligand B are its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better aqueous solubility. While Ligand A has a slightly better TPSA and Caco-2 permeability, the metabolic stability and safety profile of Ligand B are more crucial for an enzyme target like SRC. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 16:56:51,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (384.841 and 347.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (94.22) is better than Ligand B (100.45), both are acceptable for oral absorption (<140).

**logP:** Both ligands have good logP values (1.373 and 1.073), 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 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.812) has a higher QED score than Ligand B (0.696), indicating better overall drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (42.613 and 42.264 percentile).

**BBB:** Ligand A (17.642) has a much lower BBB penetration score than Ligand B (44.824). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.123) has worse Caco-2 permeability than Ligand B (-4.889), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.183 and -2.366). This is a significant concern.

**hERG Inhibition:** Ligand A (0.208) has a lower hERG inhibition liability than Ligand B (0.622), which is favorable.

**Microsomal Clearance:** Ligand A (-11.285) has significantly lower (better) microsomal clearance than Ligand B (35.953), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (52.5) has a longer half-life than Ligand B (35.656), which is also desirable.

**P-gp Efflux:** Ligand A (0.16) has lower P-gp efflux than Ligand B (0.052), indicating better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. It has better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and a slightly better QED score. While both have poor solubility, the superior metabolic properties of Ligand A outweigh this drawback. The affinity difference is not substantial enough to favor Ligand B.

Output:
0
2025-04-17 16:56:51,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.439 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is well below the 140 threshold, while Ligand B (80.32) is still acceptable, but higher.

**logP:** Ligand A (3.975) is at the upper end of the optimal 1-3 range, while Ligand B (0.814) is slightly below, potentially impacting permeability.

**H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4, both within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.783 and 0.682), indicating good drug-like properties.

**DILI:** Ligand A (69.717) has a higher DILI risk than Ligand B (54.478), which is preferable.

**BBB:** Both ligands have similar BBB penetration (79.721 and 79.411), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. 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. This is a significant concern.

**hERG Inhibition:** Ligand A (0.736) has a higher hERG risk than Ligand B (0.206). This is a major advantage for Ligand B.

**Microsomal Clearance:** Ligand A (73.957) has a higher microsomal clearance than Ligand B (30.678), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-12.234) has a negative half-life, which is not possible. This is a significant red flag. Ligand A (35.137) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.582) has lower P-gp efflux than Ligand B (0.037), which is preferable.

**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 ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the superior binding affinity of Ligand B (-7.5 kcal/mol vs -6.8 kcal/mol) is a major advantage. It also has a lower hERG risk and lower microsomal clearance, which are critical for kinase inhibitors. The negative half-life for Ligand B is a serious concern, but the substantial binding affinity advantage makes it potentially worth further investigation to address this issue. Ligand A has a higher DILI risk and lower affinity.

Output:
1
2025-04-17 16:56:51,671 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision, considering the guidelines and the target class (enzyme - kinase/SRC):

**1. Molecular Weight (MW):**
*   Ligand A: 343.431 Da - Within the ideal range (200-500).
*   Ligand B: 369.447 Da - Within the ideal range (200-500).
*   *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 81.07  -  Good for oral absorption (<140).
*   Ligand B: 121.45 - Still acceptable for oral absorption, but approaching the upper limit.
*   *Ligand A is slightly favored.*

**3. Lipophilicity (logP):**
*   Ligand A: 2.548 - Optimal (1-3).
*   Ligand B: -0.167 - Below optimal. May have permeability issues.
*   *Ligand A is significantly favored.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 2 -  Acceptable (<=5).
*   Ligand B: 4 - Acceptable (<=5).
*   *Comparable.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 5 - Acceptable (<=10).
*   Ligand B: 6 - Acceptable (<=10).
*   *Comparable.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.897 - Excellent (>0.5).
*   Ligand B: 0.451 -  Acceptable, but lower than Ligand A.
*   *Ligand A is favored.*

**7. DILI Risk (DILI):**
*   Ligand A: 62.737 - Moderate risk.
*   Ligand B: 54.401 - Lower risk, good.
*   *Ligand B is favored.*

**8. Blood-Brain Barrier (BBB):**
*   Ligand A: 79.721 -  Good, but not exceptional.
*   Ligand B: 48.197 - Lower, not a priority for this target.
*   *Ligand A is slightly favored.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.88 - Poor permeability.
*   Ligand B: -5.577 - Poor permeability.
*   *Comparable, both are concerning.*

**10. Aqueous Solubility:**
*   Ligand A: -4.089 - Poor solubility.
*   Ligand B: -1.397 - Poor solubility, but better than Ligand A.
*   *Ligand B is favored.*

**11. hERG Inhibition:**
*   Ligand A: 0.442 - Low risk.
*   Ligand B: 0.07 - Very low risk.
*   *Ligand B is favored.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 75.515 - Relatively high clearance, suggesting lower metabolic stability.
*   Ligand B: 6.747 - Low clearance, suggesting good metabolic stability.
*   *Ligand B is strongly favored.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: 35.518 - Moderate half-life.
*   Ligand B: 14.238 - Shorter half-life.
*   *Ligand A is favored.*

**14. P-gp Efflux:**
*   Ligand A: 0.242 - Low efflux, good.
*   Ligand B: 0.006 - Very low efflux, excellent.
*   *Ligand B is favored.*

**15. Binding Affinity:**
*   Ligand A: -8.6 kcal/mol - Excellent.
*   Ligand B: -8.8 kcal/mol - Slightly better.
*   *Ligand B is favored.*

**Summary and Decision (Enzyme/Kinase Focus):**

For an enzyme target like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While Ligand A has a slightly better half-life and comparable affinity, Ligand B demonstrates significantly better metabolic stability (much lower Cl_mic), lower DILI risk, lower hERG risk, and better solubility. The slightly better affinity of Ligand B is a bonus. The poor Caco-2 permeability of both is a concern, but can be addressed with formulation strategies.

Therefore, considering the overall profile and the priorities for an enzyme target, **Ligand B** is the more promising drug candidate.

1
2025-04-17 16:56:51,672 - INFO - Batch 505 complete. Total preferences: 8080
2025-04-17 16:56:51,672 - INFO - Processing batch 506/512...
2025-04-17 16:57:32,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.414 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (387.948 Da) is still well within the range.

**TPSA:** Ligand A (42.43) is higher than Ligand B (29.54). Both are below the 140 threshold for good oral absorption, but Ligand B's lower TPSA is preferable, potentially leading to better cell permeability.

**logP:** Ligand A (3.828) and Ligand B (4.766) are both within the optimal range of 1-3, but Ligand B is approaching the upper limit. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.749 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (43.738) has a slightly higher DILI risk than Ligand B (36.099), but both are below the concerning threshold of 60.

**BBB:** Both ligands have high BBB penetration (85.033 and 89.919), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can still compare them relatively. Ligand A (-4.356) is slightly better than Ligand B (-4.734).

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a data issue. Ligand A (-4.463) is slightly better than Ligand B (-5.312).

**hERG:** Ligand A (0.696) has a slightly lower hERG risk than Ligand B (0.914), which is favorable.

**Microsomal Clearance:** Ligand A (110.164) has higher microsomal clearance than Ligand B (85.645), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (18.479) has a much longer in vitro half-life than Ligand A (-1.813), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.52 and 0.76).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While the difference is not huge, it's enough to be considered, especially given the other factors.

**Overall:**

Ligand B is the more promising candidate. It has a lower TPSA, lower DILI risk, significantly better metabolic stability (lower Cl_mic and higher t1/2), and slightly better binding affinity. Although its logP is a bit higher, the benefits outweigh this minor drawback. The negative solubility and Caco-2 values are concerning and would need further investigation, but the relative comparison still favors Ligand B.

Output:
1
2025-04-17 16:57:32,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.356 Da) is slightly lower, which could be beneficial for permeability. Ligand B (406.284 Da) is also acceptable.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (88.05). A TPSA under 140 is good for oral absorption, but lower is generally preferred. Ligand A is much closer to the ideal range for good absorption.

**logP:** Ligand A (4.892) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.381) is within the optimal range (1-3).

**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, falling within acceptable limits.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.778, Ligand B: 0.684), indicating good drug-like properties.

**DILI:** Ligand A (64.793) has a lower DILI risk than Ligand B (81.117), which is a significant advantage. Lower DILI is always preferred.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 71.229, Ligand B: 73.75), which isn't a primary concern for a non-CNS target like SRC.

**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 can be addressed with formulation strategies.

**hERG:** Ligand A (0.769) has a slightly higher hERG risk than Ligand B (0.109). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (111.543) has a higher microsomal clearance than Ligand B (8.167), meaning it's less metabolically stable. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand B (40.586) has a significantly longer in vitro half-life than Ligand A (14.139), indicating better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.581, Ligand B: 0.098), which is good.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a stronger binding affinity than Ligand A (-8.9 kcal/mol). This difference of 0.8 kcal/mol is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

While Ligand A has a lower molecular weight and slightly better TPSA, Ligand B is superior overall. Ligand B has a much better metabolic profile (lower Cl_mic, longer t1/2), a significantly stronger binding affinity, and lower hERG risk. The slightly higher logP of Ligand A is a concern, and its higher DILI risk and lower metabolic stability are significant drawbacks. The affinity difference is large enough to compensate for the slightly higher logP. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:57:32,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.385 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (87.22), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Both ligands (2.763 and 2.316) are 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 5. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.786 and 0.842), indicating good drug-likeness.

**DILI:** Both have relatively high DILI risk (67.313 and 65.413), but are still acceptable.

**BBB:** Ligand A (72.586) has better BBB penetration than Ligand B (58.007), but this is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.286) has a slightly better Caco-2 permeability than Ligand B (-5.047), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.296 and -3.183). This is a potential concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.475 and 0.602).

**Microsomal Clearance:** Ligand B (49.427 mL/min/kg) has significantly lower microsomal clearance than Ligand A (92.402 mL/min/kg), suggesting better metabolic stability. This is a crucial advantage for a kinase inhibitor.

**In vitro Half-Life:** Ligand B (17.152 hours) has a much longer in vitro half-life than Ligand A (-37.505 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.089 and 0.093).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

While Ligand B has superior ADME properties (lower Cl_mic, longer t1/2), Ligand A has a significantly better binding affinity. Given that we are targeting a kinase (enzyme), potency is paramount. The 1.1 kcal/mol difference in binding affinity is a significant advantage that likely outweighs the slightly poorer metabolic stability and solubility of Ligand A.

Output:
1
2025-04-17 16:57:32,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (360.439 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is slightly higher than Ligand B (81.75), but both are below the 140 threshold for good oral absorption.

**logP:** Ligand A (1.935) is optimal, while Ligand B (-0.04) is slightly below the preferred range, potentially impacting 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:** Ligand A (0.85) has a significantly better QED score than Ligand B (0.659), indicating a more drug-like profile.

**DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (8.802). This is a significant concern for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (68.786) and Ligand B (50.058) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.187 and -5.124), which is unusual and suggests poor permeability. This needs further investigation, but it's a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.678 and -1.106), indicating very poor aqueous solubility, which is a major concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.226 and 0.107), which is positive.

**Microsomal Clearance:** Ligand B (-15.545) has a much lower (better) microsomal clearance than Ligand A (26.612), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-0.532) has a negative half-life, which is concerning and suggests very rapid degradation. Ligand A (27.931) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.135 and 0.002).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol), although both are excellent.

**Overall Assessment:**

Ligand B has a significantly better safety profile (lower DILI) and metabolic stability (lower Cl_mic). However, it has a lower logP and a very concerning negative in vitro half-life. Ligand A has a better QED and half-life, but a high DILI risk and less favorable logP. The poor solubility and Caco-2 permeability are concerning for both.

Despite the slightly better affinity of Ligand B, the significantly lower DILI risk and better metabolic stability of Ligand B, combined with the potentially manageable solubility issues, make it the more promising candidate. The negative half-life is a serious issue that would need to be addressed through structural modifications, but the starting point is better with Ligand B.

Output:
1
2025-04-17 16:57:32,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (366.487 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.42) is well below the 140 threshold, suggesting good absorption. Ligand B (116.57) is still within acceptable limits, but less optimal.

**logP:** Ligand A (1.853) is within the optimal 1-3 range. Ligand B (0.546) is slightly below 1, potentially hindering permeation, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.86 and 0.597), indicating good drug-like properties.

**DILI:** Ligand A (60.721) is approaching the higher risk threshold, while Ligand B (47.732) is comfortably below 40, indicating lower liver injury risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have moderate BBB penetration, but Ligand A is better (70.919 vs 65.413). This isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the scale is not specified, so it is difficult to interpret.

**hERG:** Both ligands have very low hERG inhibition liability (0.15 and 0.103), which is excellent.

**Microsomal Clearance:** Ligand A (34.447) has moderate clearance, while Ligand B (-12.784) has *negative* clearance, which is highly unusual and suggests exceptional metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (4.289) has a short half-life, while Ligand B (-17.567) has a negative half-life, which is also highly unusual and suggests extremely long half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.352 and 0.064), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has slightly better BBB penetration, Ligand B significantly outperforms it in crucial areas for an enzyme inhibitor: lower DILI risk, dramatically improved metabolic stability (negative Cl_mic), and extremely long half-life (negative t1/2). The similar binding affinities make these ADME advantages decisive.

Output:
1
2025-04-17 16:57:32,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (342.483 and 346.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (41.57) is better than Ligand B (49.41), both are acceptable, but lower TPSA generally favors better absorption.

**3. logP:** Both ligands have good logP values (3.151 and 3.668), 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:** 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 within the acceptable limit of <=10.

**6. QED:** Ligand A (0.894) has a higher QED than Ligand B (0.79), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.299) has a significantly lower DILI risk than Ligand B (10.585). This is a crucial advantage.

**8. BBB:** Both ligands have high BBB penetration (88.445 and 81.737), but Ligand A is slightly better. This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2:** Both have negative Caco-2 values (-4.553 and -4.632), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.427 and -3.955), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG:** Both ligands have low hERG inhibition risk (0.689 and 0.554), which is good.

**12. Cl_mic:** Ligand A (48.813) has a lower microsomal clearance than Ligand B (80.69), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**13. t1/2:** Ligand A (7.814) has a longer in vitro half-life than Ligand B (-8.852). This is a significant advantage, potentially allowing for less frequent dosing.

**14. Pgp:** Both have low Pgp efflux liability (0.292 and 0.151).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand A is the better candidate. While both have poor Caco-2 and solubility, Ligand A demonstrates superior drug-likeness (QED), significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The lower DILI and improved metabolic stability are particularly important for an enzyme inhibitor. The small difference in binding affinity is less critical than these ADME/Tox advantages.

Output:
0
2025-04-17 16:57:32,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.343 and 346.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (78.51 and 76.46) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (0.766) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.528) is within the optimal range.

**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 (0.681 and 0.793), indicating drug-like properties.

**DILI:** Ligand A (34.471) has a lower DILI risk than Ligand B (40.054), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.139) has a higher BBB percentile than Ligand B (58.976).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.955 and -4.51), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.46 and -2.693), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.389) has a lower hERG inhibition liability than Ligand B (0.115), which is better regarding cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-8.128) exhibits significantly lower microsomal clearance than Ligand B (61.676). This suggests much better metabolic stability for Ligand A, a key factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand A (-14.888) has a longer in vitro half-life than Ligand B (-22.942), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.053).

**Binding Affinity:** Ligand A (-8.1 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 point.

**Conclusion:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly better metabolic stability (lower Cl_mic and longer t1/2), lower DILI risk, and slightly better binding affinity outweigh the slightly lower logP. The poor solubility and permeability would need to be addressed through formulation strategies, but the improved pharmacokinetic properties of Ligand A make it a better starting point for optimization.

Output:
0
2025-04-17 16:57:32,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.419 and 355.563 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.56) is better than Ligand B (49.77), being closer to the upper limit for good oral absorption (<=140).

**logP:** Ligand A (-0.23) is suboptimal, potentially hindering permeation. Ligand B (4.111) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly more balanced than Ligand B (1 HBD, 3 HBA), both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.788 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (35.285) has a significantly lower DILI risk than Ligand B (2.559), which is excellent.

**BBB:** Ligand A (45.444) has a lower BBB penetration than Ligand B (84.684). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-5.132) has poor Caco-2 permeability, while Ligand B (-3.975) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-1.939) has poor aqueous solubility, while Ligand B (-3.723) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.273) has a very low hERG inhibition risk, which is excellent. Ligand B (0.885) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-12.688) has significantly lower microsomal clearance than Ligand B (101.675), indicating much better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-12.198) has a longer in vitro half-life than Ligand B (11.425), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, while Ligand B (0.609) is higher.

**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, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite Ligand A's suboptimal logP and Caco-2 permeability/solubility, its significantly superior binding affinity, much lower DILI risk, and dramatically improved metabolic stability (lower Cl_mic and longer t1/2) make it the more promising drug candidate. The strong binding affinity (-9.3 kcal/mol) is a key driver, and the low hERG risk is also highly desirable. Ligand B's high logP and poor metabolic stability are significant drawbacks.

Output:
0
2025-04-17 16:57:32,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.447 Da) is slightly better positioned.

**TPSA:** Ligand A (75.94) is well below the 140 threshold for good absorption. Ligand B (107.53) is still acceptable, but less optimal.

**logP:** Ligand A (2.518) is within the optimal range (1-3). Ligand B (-0.352) is below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is higher, potentially impacting permeability.

**H-Bond Acceptors:** Ligand A (6) is good. Ligand B (4) is also good.

**QED:** Ligand A (0.903) is excellent, indicating high drug-likeness. Ligand B (0.35) is poor, raising concerns about developability.

**DILI:** Ligand A (66.382) is moderate, but acceptable. Ligand B (33.773) is very good, indicating low liver injury risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (73.788) is better than Ligand B (40.326).

**Caco-2 Permeability:** Both are negative, which is unusual and concerning. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both are negative, which is also concerning. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.089) has very low hERG risk, which is excellent. Ligand B (0.587) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (41.41) is moderate, suggesting reasonable metabolic stability. Ligand B (13.18) is very low, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (17.61) is acceptable. Ligand B (-16.12) is problematic and suggests very rapid degradation.

**P-gp Efflux:** Both are very low, which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is small.

**Overall Assessment:**

Ligand A has a significantly better QED score, better logP, and a much more reasonable in vitro half-life. While Ligand B has slightly better affinity and lower DILI and microsomal clearance, its poor QED and extremely short half-life are major red flags. For an enzyme target like SRC kinase, metabolic stability (addressed by Cl_mic and t1/2) and drug-likeness (QED) are crucial. The slightly better affinity of Ligand B is unlikely to overcome these significant drawbacks.

Output:
0
2025-04-17 16:57:32,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (359.352 and 366.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.12) is slightly higher than Ligand B (67.43). Both are below the 140 threshold for oral absorption, but Ligand B's lower TPSA is preferable.

**3. logP:** Ligand A (1.411) and Ligand B (3.345) are both within the optimal 1-3 range. Ligand B is closer to the upper limit, which could potentially lead to off-target effects, but it's 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 (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.746 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (47.732) has a higher DILI risk than Ligand B (31.563). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (82.513) has a higher BBB penetration percentile than Ligand B (74.952). However, since SRC is not a CNS target, this is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.197) has a more negative Caco-2 value than Ligand B (-4.811), suggesting potentially lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.41) has a slightly better solubility than Ligand B (-3.371).

**11. hERG Inhibition:** Ligand A (0.198) has a lower hERG inhibition risk than Ligand B (0.591). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (-4.961) has a significantly lower (better) microsomal clearance than Ligand B (67.789). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-6.46) has a much longer in vitro half-life than Ligand B (30.197). This is a strong advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.04) has a lower P-gp efflux liability than Ligand B (0.202), suggesting better bioavailability.

**15. Binding Affinity:** Ligand B (-9.2) has a slightly better binding affinity than Ligand A (-8.5). This difference of 0.7 kcal/mol is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), P-gp efflux, hERG inhibition, and DILI risk. Ligand B has a slightly better binding affinity and lower TPSA. Considering the enzyme-kinase specific priorities, the superior metabolic stability and safety profile (lower DILI, hERG) of Ligand A are crucial. While the affinity difference is notable, the improved ADME properties of Ligand A are more likely to translate into a viable drug candidate.

Output:
0
2025-04-17 16:57:32,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (353.423 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (138.63) is close to the upper limit for good oral absorption (<=140), while Ligand B (86.88) is well below, suggesting potentially better absorption.

**logP:** Ligand A (0.582) is a bit low, potentially hindering permeation. Ligand B (2.481) is within the optimal 1-3 range.

**H-Bond Donors:** Both have 3 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Ligand B (0.722) has a significantly better QED score than Ligand A (0.254), indicating a more drug-like profile.

**DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (38.348), which is a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (61.38) has a higher BBB score than Ligand A (10.508), but it's not a deciding factor here.

**Caco-2 Permeability:** Both have negative values (-5.211 and -5.074), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without more context.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.162 and -3.474), which is also concerning. Again, the scale isn't clear, but lower values generally indicate poorer solubility.

**hERG Inhibition:** Ligand A (0.084) has a very low hERG risk, a major advantage. Ligand B (0.54) has a moderate risk.

**Microsomal Clearance:** Both have similar microsomal clearance values (26.193 and 25.977 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-9.967) has a worse (shorter) half-life compared to Ligand B (-6.498).

**P-gp Efflux:** Both have low P-gp efflux liability (0.022 and 0.046).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), although the difference is less than the 1.5 kcal/mol threshold that would heavily favor one over the other.

**Conclusion:**

While Ligand A has a slightly better binding affinity and a significantly lower DILI risk and hERG risk, Ligand B has a much better QED score, logP, and in vitro half-life. The poor solubility and Caco-2 permeability for both are concerning. However, the lower hERG risk and DILI risk for Ligand A, combined with its slightly better affinity, make it a more promising starting point, *assuming* the solubility and permeability issues can be addressed through further optimization. The higher QED of Ligand B is attractive, but the higher DILI and hERG risks are substantial drawbacks.

Output:
0
2025-04-17 16:57:32,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 Da and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (62.13), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (2.14) is optimal, while Ligand B (3.556) is slightly higher, but still within the acceptable 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:** Both ligands have similar QED values (0.755 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (31.718) has a significantly lower DILI risk than Ligand B (23.885), which is a major advantage.

**BBB:** Ligand A (70.919) has better BBB penetration than Ligand B (53.354), but this isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.531) has slightly better Caco-2 permeability than Ligand B (-5.027).

**Aqueous Solubility:** Ligand A (-2.823) has better aqueous solubility than Ligand B (-3.52). Solubility is important for bioavailability.

**hERG:** Ligand A (0.49) has a lower hERG inhibition liability than Ligand B (0.657), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (61.196) has lower microsomal clearance than Ligand B (81.612), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.582) has a significantly longer in vitro half-life than Ligand B (-0.045), which is highly desirable.

**P-gp Efflux:** Ligand A (0.167) has lower P-gp efflux liability than Ligand B (0.275), improving bioavailability.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is relatively small (0.8 kcal/mol). Given the substantial advantages of Ligand A in ADME and safety, this difference is unlikely to be decisive.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties, including lower DILI risk, better solubility, lower hERG inhibition, improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. These factors are crucial for developing a viable drug candidate, especially for an enzyme target like SRC kinase.

Output:
0
2025-04-17 16:57:32,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (367.515 Da) is also acceptable.

**TPSA:** Ligand A (67.08) is well below the 140 threshold for oral absorption. Ligand B (82.49) is also acceptable, though slightly higher.

**logP:** Both ligands have good logP values (A: 3.256, B: 2.32), 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, well within the suggested limits.

**QED:** Both ligands have good QED scores (A: 0.789, B: 0.837), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (65.646) than Ligand B (29.818). This is a major concern for Ligand A.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase, but Ligand A (73.672) is higher than Ligand B (43.815).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.343 and -5.145), which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.983 and -1.808), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.674) has a slightly higher hERG risk than Ligand B (0.365), but both are relatively low.

**Microsomal Clearance:** Ligand B (34.096) has lower microsomal clearance than Ligand A (55.599), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (28.851) has a longer in vitro half-life than Ligand A (23.358), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.724) shows slightly higher P-gp efflux than Ligand B (0.058). Lower P-gp efflux is preferable, giving Ligand B an advantage.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a crucial advantage, as potency is a primary concern for enzyme inhibitors. The 1.5 kcal/mol difference is substantial.

**Conclusion:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux outweigh the slightly higher TPSA and lower BBB. The high DILI risk for Ligand A is a major red flag.

Output:
1
2025-04-17 16:57:32,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (352.395 and 358.498 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.66) is higher than the preferred <140, but still acceptable. Ligand B (58.64) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (-1.266) is a bit low, potentially hindering permeation. Ligand B (2.931) is optimal.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.684 and 0.653), indicating good drug-likeness.

**DILI:** Ligand A (64.366) has a higher DILI risk than Ligand B (36.758). This is a significant concern.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand B (89.066) has a higher percentile than Ligand A (49.128).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.952 and -4.455), which is unusual and suggests poor permeability. This could be an artifact of the prediction method, but it's a flag.

**Aqueous Solubility:** Ligand A (-0.527) has slightly better solubility than Ligand B (-2.255), though both are quite poor.

**hERG:** Ligand A (0.059) has a very low hERG risk, which is excellent. Ligand B (0.602) is higher, representing a moderate risk.

**Microsomal Clearance:** Ligand A (11.585) has significantly lower microsomal clearance than Ligand B (45.516), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (39.039) has a much longer half-life than Ligand A (2.13), which is a major advantage.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, while Ligand B (0.21) has slightly higher efflux.

**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.

**Overall Assessment:**

Ligand A has a better binding affinity and lower hERG risk and P-gp efflux, and better metabolic stability. However, it has a lower logP, poor solubility, and a significantly higher DILI risk. Ligand B has a much better logP, lower DILI, longer half-life, and excellent TPSA, but slightly worse binding affinity and higher hERG risk.

Considering the priorities for enzyme inhibitors, metabolic stability (Cl_mic and t1/2) and safety (DILI, hERG) are crucial. Ligand B's superior metabolic stability (longer half-life, lower Cl_mic) and significantly lower DILI risk outweigh the slightly weaker binding affinity. The solubility of both is a concern, but can be addressed through formulation.

Output:
1
2025-04-17 16:57:32,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.435 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.42) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (62.99) is excellent, well below 140.

**logP:** Ligand A (0.953) is a bit low, potentially hindering permeation. Ligand B (2.137) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.824 and 0.823), indicating good drug-likeness.

**DILI:** Ligand A (43.622) has a slightly higher DILI risk than Ligand B (37.611), but both are below the concerning threshold of 60.

**BBB:** Ligand A (38.348) has a low BBB penetration, which isn't critical for a non-CNS target like SRC. Ligand B (72.276) has good BBB penetration, but this is less important here.

**Caco-2 Permeability:** Ligand A (-5.271) shows very poor Caco-2 permeability, a significant concern. Ligand B (-4.513) is also poor, but better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.167 and -2.143). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.208) has a slightly higher hERG risk than Ligand B (0.452), but both are relatively low.

**Microsomal Clearance:** Ligand A (-6.068) shows excellent metabolic stability (negative value indicates low clearance). Ligand B (13.502) has a significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (8.022 hours) has a reasonable half-life. Ligand B (57.491 hours) has a very long half-life, which is a major advantage.

**P-gp Efflux:** Both ligands show minimal P-gp efflux (0.083 and 0.2).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial difference.

**Conclusion:**

Despite the poor solubility of both compounds, Ligand B is the far superior candidate. Its significantly stronger binding affinity (-8.8 vs 0.0 kcal/mol) outweighs the slightly higher Caco-2 value and clearance. The longer half-life of Ligand B is also a significant benefit. Ligand A's very poor Caco-2 permeability is a major drawback.

Output:
1
2025-04-17 16:57:32,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (342.359 Da and 350.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.89) is slightly above the preferred <140, while Ligand B (114.67) is well within. This favors Ligand B for absorption.

**logP:** Both ligands have acceptable logP values (0.81 and 0.993), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has only 1, also acceptable.

**H-Bond Acceptors:** Both ligands have 6 HBA, within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.458 and 0.579), with Ligand B being slightly more drug-like.

**DILI:** Ligand A has a DILI risk of 79.333, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 47.693, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B has a higher BBB percentile (76.968) than Ligand A (39.55), but this isn't a primary concern here.

**Caco-2 Permeability:** Ligand A (-6.108) has poor Caco-2 permeability, while Ligand B (-4.638) is better, though still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.157 and -2.005). This is a potential issue for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.072) has a very low hERG risk, a significant advantage. Ligand B (0.237) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-7.819) shows excellent metabolic stability (negative value indicates low clearance). Ligand B (18.576) has a much higher clearance, indicating faster metabolism. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (18.911 hours) has a good in vitro half-life. Ligand B (9.623 hours) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.053).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite Ligand B's better TPSA and QED, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.1 vs -7.4 kcal/mol) is a major advantage for an enzyme target. Furthermore, Ligand A exhibits excellent metabolic stability (low Cl_mic, long t1/2) and very low hERG risk. While Ligand A's DILI risk is higher, and solubility is poor, these can potentially be addressed through formulation or further structural modifications. Ligand B's higher clearance is a significant concern, making Ligand A the preferred choice.

Output:
0
2025-04-17 16:57:32,010 - INFO - Batch 506 complete. Total preferences: 8096
2025-04-17 16:57:32,010 - INFO - Processing batch 507/512...
2025-04-17 16:58:11,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.434 and 364.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is slightly higher than Ligand B (49.85), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.451) is slightly higher than Ligand B (2.008), both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0), as too few can sometimes reduce solubility. Both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (2) is lower than Ligand B (3), both are within the acceptable limit of 10.

**QED:** Ligand A (0.891) is better than Ligand B (0.717), indicating a more drug-like profile.

**DILI:** Ligand B (31.252) has a significantly lower DILI risk than Ligand A (47.538), which is a major advantage.

**BBB:** Ligand A (83.831) has better BBB penetration than Ligand B (63.94), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.568) has better Caco-2 permeability than Ligand B (-4.449).

**Aqueous Solubility:** Ligand A (-3.47) has better aqueous solubility than Ligand B (-2.959).

**hERG:** Both ligands have very low hERG inhibition risk (0.491 and 0.449 respectively), which is excellent.

**Microsomal Clearance:** Ligand B (16.114) has significantly lower microsomal clearance than Ligand A (36.606), indicating better metabolic stability. This is a crucial factor for enzyme inhibitors.

**In vitro Half-Life:** Ligand B (24.366) has a much longer in vitro half-life than Ligand A (-1.605), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.131 and 0.184 respectively).

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.5), but the difference is minimal.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B excels in critical areas for an enzyme inhibitor: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The small difference in binding affinity is outweighed by the substantial improvements in ADME properties.

Output:
1
2025-04-17 16:58:11,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.423) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential (Ligand A: 60.45, Ligand B: 58.64).

**logP:** Both ligands have logP values within the optimal range (1-3), indicating good balance between solubility and permeability (Ligand A: 3.352, Ligand B: 3.078).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 5, Ligand B: 3) counts.

**QED:** Both ligands have QED scores above 0.5, indicating good drug-likeness (Ligand A: 0.783, Ligand B: 0.714).

**DILI:** Ligand A (37.185) has a slightly higher DILI risk than Ligand B (24.351), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 71.966, Ligand B: 78.868), but this is less critical for a non-CNS target like SRC.

**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 that both are similarly affected, it doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, this doesn't differentiate them.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.504, Ligand B: 0.324), which is excellent.

**Microsomal Clearance:** Ligand B (56.895) has significantly lower microsomal clearance than Ligand A (104.857), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (14.421) has a longer in vitro half-life than Ligand A (-27.932). The negative value for Ligand A is concerning and suggests very rapid degradation. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.181, Ligand B: 0.184).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a crucial advantage, as a 2.0 kcal/mol difference is substantial.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both ligands have acceptable physicochemical properties, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and significantly stronger binding affinity. The slightly lower DILI risk is also a positive. The unusual negative values for Caco-2 and solubility are a concern for both, but the difference in affinity and metabolic stability outweigh these concerns.

Output:
1
2025-04-17 16:58:11,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (376.4 and 362.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (100.21). TPSA < 140 is good for oral absorption, both are within this range, but A is preferable.

**logP:** Ligand A (2.666) is optimal (1-3), while Ligand B (-1.312) is below 1, potentially hindering permeation. This is a significant advantage for A.

**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 6. Both are within the acceptable limit of <=10, but A is slightly better.

**QED:** Ligand A (0.732) has a much better QED score than Ligand B (0.37), indicating a more drug-like profile.

**DILI:** Ligand A (57.658) has a higher DILI risk than Ligand B (29.081). This favors B.

**BBB:** Both have reasonable BBB penetration, but Ligand A (81.078) is slightly better than Ligand B (74.68). Not a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.657) has poor Caco-2 permeability, while Ligand B (-5.307) is also poor.

**Aqueous Solubility:** Ligand A (-3.775) has better solubility than Ligand B (-0.447). Solubility is important for bioavailability, favoring A.

**hERG Inhibition:** Ligand A (0.392) has a lower hERG risk than Ligand B (0.154). This is a significant advantage for A, as cardiotoxicity is a major concern.

**Microsomal Clearance:** Ligand A (52.303) has higher clearance than Ligand B (-1.087). Lower clearance indicates better metabolic stability, favoring B.

**In vitro Half-Life:** Ligand A (-11.597) has a negative half-life, which is not realistic. Ligand B (-40.457) is also negative, indicating instability. This is a major drawback for both.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.174 and 0.002).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly better binding affinity than Ligand B (-6.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better logP, QED, solubility, and hERG risk profile. While its DILI risk is higher and Caco-2 permeability is poor, the strong binding affinity and favorable physicochemical properties make it a more promising candidate. Ligand B has better metabolic stability (lower Cl_mic) and lower DILI, but its poor logP and significantly weaker binding affinity are major drawbacks. The negative half-life values for both are concerning, but can be addressed with structural modifications.

Output:
1
2025-04-17 16:58:11,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight (MW):** Both ligands (351.447 and 346.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.74) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (57.5) is well within the ideal range.

**3. logP:** Ligand A (0.48) is a bit low, potentially hindering permeation. Ligand B (0.635) is also on the lower side, but slightly better than A.

**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 (4) is within the acceptable limit of <=10. Ligand B (6) is also within the limit.

**6. QED:** Both ligands have similar QED values (0.606 and 0.678), indicating good drug-like properties.

**7. DILI:** Ligand A (28.306) has a lower DILI risk than Ligand B (13.61), which is preferable.

**8. BBB:** Ligand A (28.81) has a low BBB penetration, which isn't a major concern for a non-CNS target like SRC. Ligand B (64.87) has a higher BBB penetration, which is irrelevant here.

**9. Caco-2 Permeability:** Ligand A (-5.327) has poor Caco-2 permeability. Ligand B (-4.856) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-1.815) has poor aqueous solubility. Ligand B (0.017) has very poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.05) has a very low hERG inhibition risk, which is excellent. Ligand B (0.195) is also low, but higher than A.

**12. Microsomal Clearance (Cl_mic):** Ligand A (10.441) has a moderate clearance. Ligand B (8.225) has a lower clearance, indicating better metabolic stability, which is important for kinases.

**13. In vitro Half-Life:** Ligand A (12.982) has a reasonable half-life. Ligand B (-10.093) has a negative half-life, which is not possible and indicates a potential issue with the data or the molecule's stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.026).

**15. 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 some ADME drawbacks.

**Enzyme-Specific Priorities:** For kinases, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial. Ligand A has a much better binding affinity and hERG profile. While Ligand B has better metabolic stability, the negative half-life is a significant red flag. Ligand A's poor solubility and permeability are concerns, but the strong affinity might compensate, and these properties can be improved through further optimization.

Output:
1
2025-04-17 16:58:11,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.4 and 361.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (103.0 and 95.6 A^2) are below the 140 A^2 threshold for good oral absorption, which is positive.

**logP:** Both ligands have acceptable logP values (0.58 and 0.47), falling within the 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 within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.74 and 0.83), indicating drug-like properties.

**DILI:** Ligand A (34.2) has a significantly lower DILI risk than Ligand B (84.6). This is a major advantage for Ligand A.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (46.3) has a higher value than Ligand A (25.8).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, this is a relative metric and needs to be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a significant drawback for both, but could be addressed through formulation.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.14 and 0.19), which is good.

**Microsomal Clearance:** Ligand A (-14.3) exhibits *much* lower microsomal clearance than Ligand B (15.2), suggesting significantly better metabolic stability. This is a critical advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (26.8) has a slightly longer half-life than Ligand A (20.7), but the difference isn't substantial.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.04 and 0.06).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -8.9 kcal/mol). The difference of 0.2 kcal/mol is not large enough to overcome other significant differences.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand A is the more promising candidate. While both have similar binding affinities, Ligand A has a significantly lower DILI risk and substantially better metabolic stability (lower Cl_mic). The solubility issues are a concern for both, but can potentially be addressed through formulation. The slightly longer half-life of Ligand B is not enough to offset the other advantages of Ligand A.

Output:
0
2025-04-17 16:58:11,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**1. Molecular Weight:** Both ligands (387.571 and 387.502 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.3) is better than Ligand B (73.74). Both are below the 140 A^2 threshold for good oral absorption, and acceptable for kinase inhibitors.

**3. logP:** Both ligands have good logP values (1.498 and 1.832 respectively), falling within the optimal 1-3 range.

**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 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.754) has a higher QED score than Ligand A (0.55), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.183) has a significantly lower DILI risk than Ligand B (61.264). This is a major advantage for Ligand A.

**8. BBB:** Both have low BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (58.24) is slightly higher than Ligand A (36.642).

**9. Caco-2 Permeability:** Ligand A (-5.602) has a worse Caco-2 permeability than Ligand B (-4.574).

**10. Aqueous Solubility:** Ligand A (-2.551) has a worse aqueous solubility than Ligand B (-1.995).

**11. hERG Inhibition:** Ligand A (0.073) shows very low hERG inhibition risk, much lower than Ligand B (0.294). This is a significant advantage.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (25.952 and 23.029 mL/min/kg). These are acceptable.

**13. In vitro Half-Life:** Ligand A (-0.626) has a slightly worse in vitro half-life than Ligand B (-0.365).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032 and 0.243).

**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, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a slightly better QED score, Caco-2 permeability, and in vitro half-life. However, Ligand A has a much lower DILI risk and a significantly lower hERG inhibition liability. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), the strong binding affinity of Ligand B is a critical factor. While Ligand A has better safety profiles, the difference in binding affinity is substantial.

Output:
1
2025-04-17 16:58:11,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (365.777 and 369.615 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.35) is better than Ligand B (29.54) as it is still within the acceptable range for oral absorption (<140), while Ligand B is significantly lower, potentially indicating a lack of necessary interactions.

**logP:** Ligand A (1.024) is optimal (1-3), while Ligand B (4.702) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Both have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 8 HBA, which is within the acceptable limit of 10. Ligand B has 3 HBA, which is also acceptable.

**QED:** Both ligands have similar QED values (0.575 and 0.59), indicating good drug-likeness.

**DILI:** Ligand A (83.87) has a higher DILI risk than Ligand B (13.455). This is a significant negative for Ligand A.

**BBB:** Ligand A (51.183) has a lower BBB penetration than Ligand B (86.002). While not a primary concern for a kinase inhibitor, higher BBB is generally favorable.

**Caco-2 Permeability:** Ligand A (-4.775) has worse Caco-2 permeability than Ligand B (-4.566), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.799) has better aqueous solubility than Ligand B (-5.758). This is a positive for Ligand A.

**hERG Inhibition:** Ligand A (0.041) has a very low hERG inhibition risk, while Ligand B (0.907) has a moderate risk. This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (82.983) has lower microsomal clearance than Ligand B (126.777), indicating better metabolic stability. This is a significant positive for Ligand A.

**In vitro Half-Life:** Ligand A (-21.784) has a negative half-life, which is bad, while Ligand B (55.444) has a positive half-life, which is good.

**P-gp Efflux:** Ligand A (0.217) has lower P-gp efflux than Ligand B (0.806), suggesting better bioavailability.

**Binding Affinity:** Ligand B (-9.0) has significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite the higher DILI risk and moderate hERG risk, Ligand B's significantly superior binding affinity (-9.0 kcal/mol vs 0.0 kcal/mol) is the most crucial factor for an enzyme inhibitor. The strong binding is likely to compensate for the ADME liabilities. Ligand A has better metabolic stability, solubility, and hERG profile, but its weak binding affinity makes it unlikely to be effective.

Output:
1
2025-04-17 16:58:11,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (346.431 and 356.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.36) is better than Ligand B (57.18), both are well below the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.29) is within the optimal range, while Ligand B (2.583) is slightly higher but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 7. Both are acceptable, being under the 10 threshold.

**QED:** Both ligands have good QED scores (0.806 and 0.909), indicating good drug-like properties.

**DILI:** Ligand A (35.905) has a significantly lower DILI risk than Ligand B (63.513). This is a major advantage for Ligand A.

**BBB:** Ligand B (90.772) has a much higher BBB penetration potential than Ligand A (61.535). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.212) has a negative Caco-2 value, which is concerning and suggests poor permeability. Ligand B (-5.177) is also negative, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.988 and -3.335). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.463) has a lower hERG inhibition liability than Ligand B (0.905), which is favorable.

**Microsomal Clearance:** Ligand A (38.355) has a lower microsomal clearance than Ligand B (41.504), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (41.969) has a longer in vitro half-life than Ligand B (13.735), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.03) has a lower P-gp efflux liability than Ligand B (0.102).

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (0.0). This is a crucial factor for enzyme inhibitors.

**Overall Assessment:**

Ligand A is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in the most critical areas for an enzyme inhibitor: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, lower hERG risk, and slightly better binding affinity. The higher BBB value for Ligand B is irrelevant given the target. The poor permeability and solubility are concerns for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 16:58:11,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, considering the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (355.507 and 353.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (54.02) is well below the 140 threshold and favorable for oral absorption. Ligand B (78.95) is still under the threshold, but less optimal than A.

**3. logP:** Ligand A (4.091) is at the higher end of the optimal range (1-3), potentially raising solubility concerns. Ligand B (1.476) 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:** Both ligands (A: 4, B: 4) are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (A: 0.786, B: 0.637), both exceeding the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (49.787) has a moderate DILI risk, but is still acceptable. Ligand B (29.003) has a significantly lower DILI risk, which is a substantial advantage.

**8. BBB:** Both ligands have high BBB penetration (A: 80.419, B: 89.259), but this is less critical for a kinase inhibitor unless CNS off-target effects are a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.004 and -4.397), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.017 and -1.908), indicating very poor aqueous solubility. This is a major concern for *in vivo* bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.666, B: 0.418).

**12. Microsomal Clearance:** Ligand A (79.38) has higher microsomal clearance, suggesting faster metabolism. Ligand B (61.879) has lower clearance, indicating better metabolic stability, which is crucial for kinases.

**13. In vitro Half-Life:** Ligand B (-34.781) has a significantly longer in vitro half-life than Ligand A (46.751), a major advantage for dosing frequency.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.741, B: 0.068). Ligand B is significantly lower, which is preferable.

**15. Binding Affinity:** Both ligands have excellent binding affinity (A: -8.6, B: -8.0). The difference of 0.6 kcal/mol is not large enough to override other significant ADME differences.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are paramount. While both ligands have good affinity, Ligand B clearly wins on metabolic stability (lower Cl_mic, longer t1/2) and DILI risk. Solubility is poor for both, but the other advantages of B outweigh this.

Output:
1
2025-04-17 16:58:11,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (369.575 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is better than Ligand B (77.3), being closer to the <140 threshold for good absorption.

**logP:** Both ligands (2.118 and 2.393) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as a small number of HBDs can aid solubility without drastically impacting permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.688 and 0.842), indicating drug-like properties.

**DILI:** Ligand A (8.143) has a significantly lower DILI risk than Ligand B (38.93), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (64.831 and 69.756). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-5.524) is better than Ligand B (-4.528).

**Aqueous Solubility:** Ligand A (-1.931) is better than Ligand B (-2.424).

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.394 and 0.511).

**Microsomal Clearance:** Ligand A (26.457) has lower microsomal clearance than Ligand B (31.924), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.93) has a significantly longer half-life than Ligand B (-8.085), a major advantage for dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.129).

**Binding Affinity:** Both ligands have excellent binding affinity (-6.0 and -6.3 kcal/mol). The difference is minimal.

**Overall:**

Ligand A is superior due to its lower DILI risk, better solubility, better Caco-2 permeability, lower microsomal clearance, and significantly longer half-life. While both have good binding affinity and drug-like properties, the ADME profile of Ligand A is markedly better, making it a more promising drug candidate.

Output:
1
2025-04-17 16:58:11,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.435 and 356.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.8) is better than Ligand B (36.36) as it is closer to the ideal threshold of <=140.

**logP:** Ligand A (0.64) is suboptimal, being below the preferred 1-3 range, potentially hindering permeation. Ligand B (4.85) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is better than Ligand B (1 HBD, 4 HBA) as both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.787 and 0.698, both >0.5).

**DILI:** Ligand A (46.762) has a better DILI score than Ligand B (19.271), indicating a lower risk of liver injury.

**BBB:** Both ligands have similar BBB penetration (62.233 and 69.407), which isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.524 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 (-1.464 and -5.12), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.028) has a much lower hERG inhibition risk than Ligand B (0.838), which is a critical advantage.

**Microsomal Clearance:** Ligand A (4.863) has significantly lower microsomal clearance than Ligand B (85.287), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (9.633) has a better in vitro half-life than Ligand B (-20.654).

**P-gp Efflux:** Ligand A (0.059) has lower P-gp efflux than Ligand B (0.594), which is favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), but the difference is not substantial enough to outweigh the significant ADME liabilities of Ligand B.

**Overall:**

Ligand A is superior despite the low logP and negative Caco-2/solubility values. Its significantly better DILI, hERG, metabolic stability (lower Cl_mic and better t1/2), and P-gp efflux profile make it a more promising candidate. While both have solubility and permeability issues, these can potentially be addressed through formulation strategies. The slightly stronger binding affinity of Ligand B is not enough to compensate for its poorer ADME properties.

Output:
0
2025-04-17 16:58:11,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.495 and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.54) is slightly higher than Ligand B (67.87). Both are below the 140 threshold for oral absorption, but B is better.

**logP:** Ligand A (0.644) is a bit low, potentially hindering permeation. Ligand B (1.153) is better, falling within the optimal 1-3 range.

**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 4 H-bond acceptors, which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.585 and 0.799), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (14.618) has a much lower DILI risk than Ligand B (44.707), which is a significant advantage.

**BBB:** Ligand A (37.573) has a lower BBB penetration percentile than Ligand B (87.01). However, SRC is not a CNS target, so this is less critical.

**Caco-2 Permeability:** Ligand A (-5.167) has a negative Caco-2 value, suggesting poor permeability. Ligand B (-4.479) is also negative, but less so, indicating slightly better permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.34 and -1.994). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.194) has a lower hERG inhibition risk than Ligand B (0.384), which is a positive.

**Microsomal Clearance:** Ligand A (7.028) has a lower microsomal clearance than Ligand B (15.651), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (5.024) has a positive half-life, while Ligand B (-9.489) has a negative half-life, indicating very poor stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.035).

**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.

**Conclusion:**

Considering the priorities for enzyme targets (potency, metabolic stability, solubility, and hERG risk), Ligand A is the more promising candidate. While both have poor solubility, Ligand A exhibits significantly lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), and a lower hERG risk. The slightly better binding affinity of Ligand B is not enough to overcome these ADME/Tox liabilities. The lower logP and Caco-2 of Ligand A are drawbacks, but can potentially be addressed through further optimization.

Output:
0
2025-04-17 16:58:11,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.527 Da) is slightly higher than Ligand B (336.399 Da), but both are acceptable.

**TPSA:** Ligand A (61.8) is significantly better than Ligand B (101.62). Lower TPSA generally correlates with better cell permeability, which is important for kinase inhibitors.

**logP:** Both ligands have good logP values (A: 3.37, B: 2.32), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, 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: 0.727, B: 0.68), indicating good drug-like properties.

**DILI:** Ligand A (35.867) has a much lower DILI risk than Ligand B (68.36), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC, but Ligand A (60.372) is better than Ligand B (45.715).

**Caco-2 Permeability:** Ligand A (-4.68) is better than Ligand B (-5.621), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.428) is better than Ligand B (-3.138).

**hERG Inhibition:** Both ligands have similar, low hERG risk (A: 0.756, B: 0.741).

**Microsomal Clearance:** Ligand A (61.731) has a higher (worse) microsomal clearance than Ligand B (-16.902). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (28.896) has a significantly longer in vitro half-life than Ligand A (9.585), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.55, B: 0.132), with Ligand B being slightly better.

**Binding Affinity:** Ligand A (-6.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most critical factor for an enzyme inhibitor. The >1.5 kcal/mol advantage of A outweighs the ADME drawbacks.

**Conclusion:**

Despite Ligand B's superior metabolic stability and half-life, Ligand A's substantially stronger binding affinity (-6.8 vs -0.0 kcal/mol) makes it the more promising candidate. The potency advantage is significant enough to overcome the slightly higher clearance and lower half-life. The better DILI score and TPSA of Ligand A further support this conclusion.

Output:
1
2025-04-17 16:58:11,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.443 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.65) is slightly higher than Ligand B (54.56), but both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (2.827 and 3.786), 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 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 (0.77 and 0.726), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 56.301, placing it in the moderate risk category. Ligand B has a significantly lower DILI risk of 20.667, which is a major advantage.

**BBB:** Both ligands have good BBB penetration (85.537 and 78.054), but this is less critical for a kinase inhibitor than for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.686). This 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 poor aqueous solubility (-3.316 and -2.948). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.303) has a lower hERG inhibition risk than Ligand B (0.869), which is preferable.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (70.331) than Ligand B (40.67), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B has a substantially longer in vitro half-life (21.959 hours) compared to Ligand A (-25.206 hours). The negative value for Ligand A is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.457 and 0.496).

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.6 kcal/mol) compared to Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B and can outweigh some of its minor ADME drawbacks.

**Conclusion:**

Ligand B is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B demonstrates a significantly better safety profile (lower DILI), superior metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a much stronger binding affinity. The improved affinity is a critical factor for an enzyme inhibitor, and the other advantages outweigh the slightly higher logP and hERG risk.

Output:
1
2025-04-17 16:58:11,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for enzymes.

**Molecular Weight:** Both ligands (342.439 and 358.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (51.02), but both are well below the 140 threshold for good absorption.

**logP:** Ligand A (1.488) is within the optimal 1-3 range. Ligand B (3.086) is at the higher end of optimal, but still acceptable.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** 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 (0.588 and 0.797, respectively), indicating drug-like properties.

**DILI:** Ligand A (14.036) has a significantly lower DILI risk than Ligand B (29.973). This is a major advantage for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (67.468 and 83.366), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.848 and -4.866). This is unusual and suggests poor permeability, but could be an artifact of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.188 and -2.745), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.183) has a much lower hERG inhibition liability than Ligand B (0.537). This is a significant advantage for Ligand A, reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (13.759) has lower microsomal clearance than Ligand B (61.646), suggesting better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (-2.028) has a more favorable in vitro half-life than Ligand B (-16.792).

**P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux liability than Ligand B (0.289), potentially leading to better oral bioavailability.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is only 0.5 kcal/mol, which is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:**

Ligand A demonstrates a superior ADME profile compared to Ligand B, with lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and better t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity, the difference is small and is outweighed by the more favorable ADME properties of Ligand A. Given the importance of metabolic stability and safety (DILI, hERG) for enzyme inhibitors, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 16:58:11,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (348.353 and 337.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is better than Ligand B (86.92), both are below the 140 threshold for oral absorption.

**logP:** Both ligands (2.538 and 2.822) 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:** Ligand B (7) is higher than Ligand A (3), both are within the acceptable limit of 10.

**QED:** Ligand A (0.872) has a better QED score than Ligand B (0.621), indicating better overall drug-likeness.

**DILI:** Ligand B (89.841) has a significantly higher DILI risk than Ligand A (69.097). This is a major concern.

**BBB:** Ligand A (80.031) has better BBB penetration than Ligand B (64.482), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -5.051), 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 (-4.591 and -3.955), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.652 and 0.617).

**Microsomal Clearance:** Ligand A (9.89 mL/min/kg) has significantly lower microsomal clearance than Ligand B (28.005 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.79 hours) has a much longer half-life than Ligand B (-6.117 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 (0.058 and 0.43).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). The difference is 1.2 kcal/mol, which is significant.

**Conclusion:**

Despite the stronger binding affinity of Ligand B, its significantly higher DILI risk, poor metabolic stability (high Cl_mic, negative t1/2), and poor solubility make it a less desirable candidate. Ligand A, while having a slightly weaker binding affinity, exhibits a much better safety profile (lower DILI), better metabolic stability, and a longer half-life. The solubility and permeability issues are concerning for both, but can potentially be addressed through formulation strategies. Given the enzyme-specific priorities, the improved ADME properties of Ligand A outweigh the slightly lower binding affinity.

Output:
0
2025-04-17 16:58:11,953 - INFO - Batch 507 complete. Total preferences: 8112
2025-04-17 16:58:11,953 - INFO - Processing batch 508/512...
2025-04-17 16:58:55,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (340.339 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (109.3) is higher than Ligand B (58.64). While <140 is generally good for absorption, Ligand B's lower TPSA is preferable for potential cell permeability.

**logP:** Ligand A (-0.123) is quite low, potentially hindering membrane permeability. Ligand B (1.685) 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 1 HBD and 4 HBA. Both are within acceptable limits, but Ligand B's lower count is generally favorable for permeability.

**QED:** Both ligands have good QED scores (A: 0.677, B: 0.719), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (93.951), which is a major concern. Ligand B has a much lower DILI risk (31.989), making it significantly safer.

**BBB:** This is less crucial for a non-CNS target like SRC. Ligand B has a higher BBB percentile (84.878) than Ligand A (43.893).

**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 (0.023) has a very low hERG risk, which is excellent. Ligand B (0.373) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A has a very low (negative) Cl_mic (-19.799), indicating excellent metabolic stability. Ligand B has a higher Cl_mic (30.047), suggesting faster metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.499) has a shorter half-life than Ligand B (-15.431), which is unusual given the clearance data.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.026, B: 0.069).

**Binding Affinity:** Both ligands have very strong binding affinities (A: -9 kcal/mol, B: -8.9 kcal/mol). The difference is minimal and unlikely to outweigh other factors.

**Conclusion:**

Despite Ligand A's excellent binding affinity and metabolic stability, its high DILI risk and low logP are major drawbacks. Ligand B, while having slightly lower metabolic stability, exhibits a much better safety profile (lower DILI), a more favorable logP, and a lower TPSA. Considering the enzyme-specific priorities, the lower DILI risk and improved physicochemical properties of Ligand B make it the more viable drug candidate.

Output:
1
2025-04-17 16:58:55,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (356.46 and 346.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is well below the 140 threshold, and good for oral absorption. Ligand B (105.91) is still within acceptable range, but less optimal.

**logP:** Ligand A (3.355) is within the optimal 1-3 range. Ligand B (0.974) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is excellent. Ligand B (HBD=4, HBA=4) is acceptable, but higher HBD count can sometimes impact permeability.

**QED:** Both ligands have reasonable QED scores (0.652 and 0.571), indicating good drug-like properties.

**DILI:** Ligand A (23.42) has a significantly lower DILI risk than Ligand B (39.55), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (90.62) has a much higher BBB percentile than Ligand B (18.34).

**Caco-2 Permeability:** Ligand A (-4.55) is better than Ligand B (-5.874), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.462) is better than Ligand B (-1.919), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.763) has a lower hERG risk than Ligand B (0.269), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (-13.393) has a much lower (better) microsomal clearance than Ligand A (38.912), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (8.827) has a significantly longer half-life than Ligand A (-3.18), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.277) has lower P-gp efflux than Ligand B (0.01), which is better for bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -9.9 kcal/mol). Ligand B is slightly better (-9.9 kcal/mol), but the difference is not substantial enough to outweigh the other significant drawbacks.

**Overall Assessment:**

Ligand A is superior overall. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A excels in safety (DILI, hERG), solubility, permeability, and has a better BBB score. The lower DILI and hERG risks are particularly important for an oncology drug, and the better solubility and permeability will likely translate to better bioavailability.

Output:
1
2025-04-17 16:58:55,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.384 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (383.279 Da) is still acceptable.

**TPSA:** Ligand A (36.1) is significantly better than Ligand B (83.06). Lower TPSA generally correlates with better cell permeability.

**logP:** Both ligands have good logP values (A: 4.604, B: 4.07), falling within the optimal 1-3 range, though A is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 1 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.789) has a substantially better QED score than Ligand B (0.384), indicating a more drug-like profile.

**DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (33.463), which is a concern. However, B is still above the 40% threshold.

**BBB:** Both have high BBB penetration (A: 96.316, B: 88.329), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the experimental setup or prediction method. It's difficult to interpret without more context.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (A: 0.862, B: 0.892), which is excellent.

**Microsomal Clearance:** Ligand A (23.344) and Ligand B (21.015) have similar microsomal clearance values. Lower is better, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.862) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand B (10.175) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux (A: 0.641, B: 0.332), which is favorable.

**Binding Affinity:** Both have excellent binding affinities (A: -9.6 kcal/mol, B: -9.7 kcal/mol), with Ligand B being slightly better. The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand A has a better QED, TPSA, and a comparable binding affinity. However, it has a concerning DILI risk and an impossible half-life prediction. Ligand B has a better DILI profile, a reasonable half-life, and slightly better binding affinity. The negative solubility and Caco-2 values are concerning for both, but the more reliable ADME properties favor Ligand B. Given the importance of metabolic stability and minimizing toxicity for kinase inhibitors, and the problematic predictions for Ligand A, Ligand B is the more promising candidate.

Output:
1
2025-04-17 16:58:55,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (342.399 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.32) is slightly higher than Ligand B (77.1). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned.

**logP:** Ligand A (1.055) is slightly higher than Ligand B (0.569), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are 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 similar QED values (0.731 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (31.059). This is a significant concern, as lower DILI is preferred.

**BBB:** Ligand B (62.466) has a higher BBB penetration percentile than Ligand A (33.695). While not a primary concern for a non-CNS target like SRC, higher BBB is generally a positive attribute.

**Caco-2 Permeability:** Ligand A (-5.372) has worse Caco-2 permeability than Ligand B (-4.745). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-3.414) has worse aqueous solubility than Ligand B (-0.951). Better solubility is crucial for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.255 and 0.107).

**Microsomal Clearance:** Ligand A (-10.978) has significantly lower (better) microsomal clearance than Ligand B (17.832). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (4.701) has a lower in vitro half-life than Ligand B (25.84).  Ligand B is much better here.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.022).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.0 kcal/mol). The difference is relatively small (0.5 kcal/mol) and likely less important than the ADME differences.

**Conclusion:**

While Ligand A has a slightly better microsomal clearance, Ligand B is superior in almost all other critical ADME properties. Specifically, Ligand B has a significantly lower DILI risk, better solubility, better Caco-2 permeability, and a much longer in vitro half-life. The small difference in binding affinity is outweighed by these substantial ADME advantages. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:58:55,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (346.475 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (98.14). A TPSA under 140 is good for oral absorption, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (2.354) is optimal, while Ligand B (0.739) is a bit 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 4 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.796 and 0.834), indicating good drug-like properties.

**DILI:** Ligand A (29.895) has a much lower DILI risk than Ligand B (70.182). This is a significant advantage for Ligand A.

**BBB:** Ligand A (64.172) has a moderate BBB penetration, while Ligand B (36.371) has poor BBB penetration. Since SRC is not a CNS target, this is less critical, but still favors A.

**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 more favorable for Ligand A (-4.873 vs -5.197).

**Aqueous Solubility:** Both have negative solubility values, also unusual. Ligand A (-2.817) is slightly better than Ligand B (-2.042).

**hERG:** Both ligands have very low hERG inhibition risk (0.488 and 0.048), which is excellent.

**Microsomal Clearance:** Ligand A (41.066) has higher microsomal clearance than Ligand B (-2.631). This suggests Ligand B is more metabolically stable, a key factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (-9.902) has a shorter in vitro half-life than Ligand B (4.021). Again, this favors Ligand B.

**P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux than Ligand B (0.034), suggesting better bioavailability.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -9.6 kcal/mol). Ligand B is slightly more potent, but the difference (1.3 kcal/mol) isn't massive enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A has a better balance of properties. It has a superior TPSA, logP, and significantly lower DILI risk. While Ligand B has better metabolic stability and half-life, the higher DILI risk and lower logP are concerning. The slight improvement in binding affinity for Ligand B is not enough to offset these liabilities.

Output:
0
2025-04-17 16:58:55,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the provided guidelines and enzyme-specific priorities.

**1. Molecular Weight:** Both ligands (357.797 and 355.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.25) is slightly higher than Ligand B (73.99). Both are below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (4.097) is slightly higher than Ligand B (3.532). 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 (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:** Both ligands have good QED scores (0.547 and 0.655), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (95.812) has a significantly higher DILI risk than Ligand B (71.656). This is a major concern for Ligand A.

**8. BBB:** Ligand A (57.852) has a lower BBB penetration percentile than Ligand B (72.974). While BBB isn't a primary concern for a kinase inhibitor, higher is generally preferable.

**9. Caco-2:** Ligand A (-4.701) has a worse Caco-2 permeability than Ligand B (-5.485). Both are quite poor, indicating low intestinal absorption.

**10. Solubility:** Ligand A (-5.69) has worse solubility than Ligand B (-3.6). Solubility is important for bioavailability.

**11. hERG:** Ligand A (0.372) has a lower hERG inhibition liability than Ligand B (0.583), which is favorable.

**12. Cl_mic:** Ligand A (115.914) has a higher microsomal clearance than Ligand B (56.996), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. t1/2:** Ligand A (51.77) has a slightly longer in vitro half-life than Ligand B (46.18).

**14. Pgp:** Ligand A (0.234) has lower P-gp efflux liability than Ligand B (0.441), which is favorable.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Enzyme-Specific Priorities:** For kinase inhibitors, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are crucial.

**Overall Assessment:**

Ligand B is significantly better due to its lower DILI risk, better metabolic stability (lower Cl_mic), and better solubility. While Ligand A has a slightly longer half-life and lower Pgp efflux, the high DILI risk and higher Cl_mic outweigh these benefits. Both have poor Caco-2 permeability, which would need to be addressed in further optimization, but this is less critical than the safety and metabolic stability concerns with Ligand A.

Output:
1
2025-04-17 16:58:55,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (355.454 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (78.43), being well below the 140 threshold for good absorption.

**logP:** Both ligands have acceptable logP values (0.664 and 1.847), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 3 HBA) as it has fewer hydrogen bond donors, potentially improving permeability. Both are within acceptable limits.

**QED:** Ligand A (0.761) has a better QED score than Ligand B (0.463), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (10.237 and 10.741 percentile).

**BBB:** Ligand A (81.776) has a significantly higher BBB penetration percentile than Ligand B (46.762). While SRC isn't a CNS target, higher BBB is generally a positive indicator of permeability.

**Caco-2 Permeability:** Ligand A (-4.754) and Ligand B (-4.668) are similar, indicating similar intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.866) is slightly better than Ligand B (-2.704) in terms of aqueous solubility.

**hERG Inhibition:** Ligand A (0.444) has a lower hERG inhibition risk than Ligand B (0.309), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-6.333) has a much lower (better) microsomal clearance than Ligand B (29.059), indicating significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (16.196 hours) has a better in vitro half-life than Ligand B (-4.632 hours).

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.089).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-6.3 kcal/mol). The difference is 1.4 kcal/mol, which is a significant advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost every other crucial ADMET property. Specifically, its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, better QED, and lower P-gp efflux are compelling advantages. The 1.4 kcal/mol difference in binding affinity is likely surmountable with further optimization of Ligand A, whereas improving the ADMET profile of Ligand B would be more challenging. Given the enzyme-kinase focus, metabolic stability and safety (hERG) are paramount.

Output:
0
2025-04-17 16:58:55,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 Da and 363.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is well below the 140 threshold for oral absorption and even better for potential kinase inhibitors. Ligand B (137.08) is still acceptable but closer to the upper limit.

**logP:** Ligand A (0.853) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (1.699) is within the optimal range.

**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 limit of 10.

**QED:** Ligand A (0.747) has a better QED score than Ligand B (0.467), indicating a more drug-like profile.

**DILI:** Ligand A (8.453) has a significantly lower DILI risk than Ligand B (68.437). This is a major advantage for Ligand A.

**BBB:** Both have relatively low BBB penetration (64.87 and 67.623), which isn't critical for a non-CNS target like SRC kinase.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.394 and -5.343), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.235 and -3.424), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.176) has a much lower hERG risk than Ligand B (0.394), which is a crucial safety parameter.

**Microsomal Clearance:** Ligand A (-15.698) has a much lower (better) microsomal clearance than Ligand B (9.975), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.734) has a slightly better (less negative) in vitro half-life than Ligand B (-8.257).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.054).

**Binding Affinity:** Ligand B (-9.2) has a slightly better binding affinity than Ligand A (-8.4), a difference of 0.8 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better in almost all other critical ADMET properties. Specifically, Ligand A has a much lower DILI risk, lower hERG risk, and better metabolic stability (lower Cl_mic and better half-life). The solubility and permeability are poor for both, but the other advantages of Ligand A outweigh the small binding affinity difference. Given the enzyme-specific priorities, metabolic stability and safety (DILI, hERG) are paramount.

Output:
0
2025-04-17 16:58:55,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (341.451 and 366.571 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (47.56) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (58.2) is also below 140, but higher than A.

**logP:** Both ligands have logP values (4.013 and 3.522) within the optimal range of 1-3, though Ligand A is slightly higher.

**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 recommended limits.

**QED:** Ligand A (0.823) has a significantly higher QED score than Ligand B (0.582), indicating a more drug-like profile.

**DILI:** Ligand A (37.728) has a slightly higher DILI risk than Ligand B (21.985), but both are below the concerning threshold of 60.

**BBB:** Ligand A (81.039) has a higher BBB penetration percentile than Ligand B (67.429), but BBB isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.855) and Ligand B (-5) have similar, very poor Caco-2 permeability scores. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.632 and -4.393 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.702) has a slightly higher hERG inhibition risk than Ligand B (0.406), but both are relatively low.

**Microsomal Clearance:** Ligand B (87.391) has a higher microsomal clearance than Ligand A (83.041), meaning it's metabolized faster. Lower clearance is preferred for kinases.

**In vitro Half-Life:** Ligand B (22.809 hours) has a significantly longer in vitro half-life than Ligand A (10.803 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.729) has slightly higher P-gp efflux than Ligand B (0.242). Lower efflux is preferred.

**Binding Affinity:** Ligand B (-8.5 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.

**Conclusion:**

While Ligand A has a better QED score and slightly better TPSA, the significantly stronger binding affinity of Ligand B (-8.5 vs -7.1 kcal/mol) and its longer half-life (22.8 vs 10.8 hours) are critical advantages for an enzyme inhibitor. The lower P-gp efflux of Ligand B is also beneficial. The slightly higher DILI risk of Ligand A is not a major concern given both are below 60. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 16:58:55,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.394 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.89) is slightly above the preferred <140, but acceptable. Ligand B (73.74) is excellent, well below 140.

**logP:** Ligand A (0.679) is a bit low, potentially hindering permeability. Ligand B (1.71) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (5) is at the upper limit of the preferred range. Ligand B (1) is excellent.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand B (0.712) has a better QED score than Ligand A (0.422), indicating better drug-likeness.

**DILI:** Ligand A (24.351) has a lower DILI risk than Ligand B (16.208), which is favorable.

**BBB:** Ligand A (18.069) has poor BBB penetration, which is not a major concern for a non-CNS target like SRC. Ligand B (65.839) has moderate BBB penetration, also not a primary concern here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.681 and -5.032), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.27 and -1.502), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.366 and 0.345).

**Microsomal Clearance:** Ligand A (-9.189) has significantly *lower* (better) microsomal clearance than Ligand B (20.552), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.782) has a longer half-life than Ligand B (-2.903), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.04 and 0.122).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol), although the difference is not huge.

**Conclusion:**

Despite the slightly better affinity of Ligand A, its poor solubility and permeability (indicated by negative Caco-2 and solubility values) are major concerns. Ligand B has better drug-like properties (higher QED, better logP, fewer HBDs) and better metabolic stability (lower Cl_mic) and half-life, despite slightly worse DILI risk. However, both compounds suffer from poor solubility and permeability. Considering the enzyme-specific priorities, metabolic stability and solubility are crucial. While Ligand A has a slightly better binding affinity, Ligand B's superior ADME profile makes it the more promising candidate, *assuming* the solubility and permeability issues can be addressed through formulation or structural modifications.

Output:
1
2025-04-17 16:58:55,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.555 Da) is slightly lower, which could be beneficial for permeability. Ligand B (384.845 Da) is also good.

**TPSA:** Ligand A (58.2) is excellent, well below the 140 threshold for oral absorption. Ligand B (97.56) is higher but still acceptable, though it might slightly reduce absorption compared to Ligand A.

**logP:** Ligand A (3.131) is optimal. Ligand B (1.811) is slightly lower, potentially impacting permeability, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both within the preferred limits. Ligand B has 1 HBD and 7 HBA, also acceptable, but the higher HBA count could slightly affect permeability.

**QED:** Both ligands have good QED scores (A: 0.618, B: 0.863), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (19.116) has a significantly lower DILI risk than Ligand B (87.01). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (65.801) and Ligand B (50.679) are both moderate.

**Caco-2 Permeability:** Ligand A (-5.142) has a negative value, which is unusual and suggests poor permeability. Ligand B (-4.943) is also negative, but slightly less so.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.166 and -2.803). This is a significant concern for both.

**hERG:** Ligand A (0.353) has a lower hERG risk than Ligand B (0.085), which is preferable.

**Microsomal Clearance:** Ligand A (75.224) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (16.546) has much lower clearance, indicating better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand A (17.608) has a moderate half-life. Ligand B (-16.536) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.188, B: 0.075).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This 1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better metabolic stability. However, it has a significantly higher DILI risk and a problematic negative half-life value. Ligand A has a lower DILI risk and better TPSA, but suffers from poor Caco-2 permeability and lower metabolic stability. The negative half-life for Ligand B is a red flag. While the affinity difference is significant, the DILI and half-life issues with Ligand B are major concerns. The poor permeability of Ligand A is also problematic.

Considering the enzyme-specific priorities, metabolic stability and potency are paramount. While Ligand B excels in potency, the negative half-life is a showstopper. Ligand A, despite its permeability issues, is more likely to be a viable starting point for optimization, as permeability can be addressed through structural modifications, whereas fixing a fundamentally unstable molecule or a negative half-life is far more challenging.

Output:
0
2025-04-17 16:58:55,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. 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 (355.479 Da) is also acceptable.

**2. TPSA:** Ligand A (43.6) is well below the 140 threshold for good oral absorption. Ligand B (82.11) is still under the threshold but getting closer, potentially indicating slightly reduced absorption compared to A.

**3. logP:** Ligand A (3.597) is within the optimal range (1-3). Ligand B (0.221) is significantly below this, which raises concerns about permeability and potentially bioavailability.

**4. H-Bond Donors:** Ligand A (0) is excellent. 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 acceptable QED values (A: 0.479, B: 0.618), indicating reasonable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (50.136) has a moderate DILI risk. Ligand B (10.741) has a very low DILI risk, which is a significant advantage.

**8. BBB:** This is less critical for a non-CNS target like SRC. Ligand A (62.699) is lower than Ligand B (39.473).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.674 and -4.66), which is unusual and suggests poor permeability. This is a concern for both, but the low logP of Ligand B exacerbates this issue.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.458 and -0.992), indicating poor aqueous solubility. This is a significant drawback for both, potentially hindering formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.414, B: 0.401), which is positive.

**12. Microsomal Clearance:** Ligand A (76.98) has higher microsomal clearance than Ligand B (26.424), suggesting lower metabolic stability. Ligand B is significantly better in this regard.

**13. In vitro Half-Life:** Ligand B (-7.245) has a much longer in vitro half-life than Ligand A (-32.146), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.407, B: 0.032). Ligand B is slightly better.

**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 for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most crucial factor for an enzyme inhibitor. However, it suffers from higher microsomal clearance and a lower in vitro half-life. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux), but its significantly weaker binding affinity is a major concern. The difference in binding affinity (1.3 kcal/mol) is large enough to potentially overcome the ADME liabilities of Ligand A, especially if further optimization can improve its metabolic stability.

Output:
0
2025-04-17 16:58:55,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (398.26 and 353.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.56) is better than Ligand B (62.73), both are acceptable, but lower TPSA generally favors better absorption.

**logP:** Both ligands have similar logP values (4.948 and 4.751), slightly high but potentially manageable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have acceptable QED scores (0.488 and 0.693), with Ligand B being slightly better.

**DILI:** Both ligands have high DILI risk (77.084 and 77.549), which is a concern. This will need to be addressed in further optimization.

**BBB:**  BBB is not a primary concern for a non-CNS target like SRC kinase, but Ligand B (73.866) has a higher percentile than Ligand A (41.334).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.065 and -5.255), which is unusual and suggests poor permeability. This is a significant drawback.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.104 and -4.742). This is a major issue for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.665 and 0.633), which is good.

**Microsomal Clearance:** Ligand A (73.607) has lower microsomal clearance than Ligand B (90.875), indicating better metabolic stability. This is a key advantage.

**In vitro Half-Life:** Ligand A (-25.348) has a negative half-life, which is not possible. Ligand B (59.643) has a better half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.817 and 0.46), which is favorable.

**Binding Affinity:** Ligand B (-8.1 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.

**Overall Assessment:**

Ligand B is the more promising candidate despite its higher TPSA and slightly worse metabolic stability. The significantly improved binding affinity (-8.1 vs -10.2 kcal/mol) is a major driver. While both compounds have poor solubility and permeability (negative Caco-2 values) and high DILI risk, the potency advantage of Ligand B is substantial. The negative half-life for Ligand A is also a showstopper. Further optimization would need to focus on improving solubility and permeability, and reducing DILI risk for either compound, but Ligand B provides a better starting point due to its superior potency.

Output:
1
2025-04-17 16:58:55,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (344.39 and 363.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.25) is better than Ligand B (84.22). Both are below 140, suggesting reasonable absorption, but A is closer to the preferred value for oral absorption.

**logP:** Both ligands (2.818 and 3.126) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 3 HBD and 3 HBA. Both are acceptable, within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.876) has a better QED score than Ligand B (0.703), indicating a more drug-like profile.

**DILI:** Ligand A (38.658) has a significantly lower DILI risk than Ligand B (49.399), which is a crucial advantage. Both are below 60, but A is preferable.

**BBB:** Both ligands have similar BBB penetration (75.611 and 75.727). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a worry.

**Caco-2 Permeability:** Ligand A (-4.517) and Ligand B (-5.007) both show poor Caco-2 permeability. This is a potential issue for oral bioavailability.

**Aqueous Solubility:** Ligand A (-3.219) is slightly better than Ligand B (-4.397), both are poor. This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.538) has a lower hERG risk than Ligand B (0.611). Lower is better, making A more favorable.

**Microsomal Clearance:** Ligand A (-14.616) has *much* lower microsomal clearance (better metabolic stability) than Ligand B (16.121). This is a significant advantage for a kinase inhibitor, as kinases often require sustained exposure.

**In vitro Half-Life:** Ligand A (-16.516) has a longer in vitro half-life than Ligand B (4.666). This is a major advantage, reducing the need for frequent dosing.

**P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux than Ligand B (0.067). Lower is better.

**Binding Affinity:** Ligand B (-10.7 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 drawbacks of Ligand B. However, the difference is not *massive* and needs to be considered in context.

**Overall Assessment:**

While Ligand B has superior binding affinity, Ligand A demonstrates a much better safety profile (lower DILI, lower hERG), significantly better metabolic stability (lower Cl_mic, longer t1/2), and a better QED score. The solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation. The improved ADME properties of Ligand A are particularly important for a kinase inhibitor, where sustained exposure is often critical. The affinity difference, while notable, is not so large as to completely negate the benefits of A's superior ADME profile.

Output:
0
2025-04-17 16:58:55,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (371.39 and 331.339 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.8) is slightly above the optimal <140 for oral absorption, but acceptable. Ligand B (100.55) is well within the range.

**logP:** Both ligands (0.349 and 0.413) are a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, fitting the <5 and <10 rules respectively. Ligand B has 1 HBD and 6 HBA, also within acceptable limits.

**QED:** Both ligands have good QED scores (0.685 and 0.698), indicating good drug-like properties.

**DILI:** Ligand A (69.872) has a higher DILI risk than Ligand B (84.917). Lower is better, so Ligand B is preferable here.

**BBB:** Both have low BBB penetration (45.599 and 41.838), which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.845 and -5.199). This is unusual and suggests poor permeability, but the scale isn't clearly defined.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.881 and -2.748). Again, the scale is unclear, but suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.016 and 0.049), which is excellent.

**Microsomal Clearance:** Ligand A (-13.696) has a lower (better) microsomal clearance than Ligand B (-14.457), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-8.231) has a shorter half-life than Ligand B (-19.698). Ligand B is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.019).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good potency, Ligand B is slightly more favorable. It has a lower DILI risk, a significantly longer in vitro half-life, and a slightly better TPSA. The negative Caco-2 and solubility values are concerning for both, but the differences in other key ADME properties tip the balance towards Ligand B.

Output:
1
2025-04-17 16:58:55,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (368.836 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly higher than Ligand B (49.41), but both are well below the 140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (3.001 and 3.79), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* present a minor solubility concern, 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 3 HBAs, and Ligand B has 2. Both are below the 10 limit.

**6. QED:** Ligand A (0.816) has a significantly better QED score than Ligand B (0.611), indicating a more drug-like profile.

**7. DILI:** Ligand A has a DILI risk of 67%, which is concerning (high risk). Ligand B has a much lower DILI risk of 14.23%, which is excellent.

**8. BBB:** Both have reasonable BBB penetration, but Ligand A is higher at 83.715% vs. 74.874% for Ligand B. This is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and likely indicates poor permeability.

**10. Solubility:** Both have negative solubility values which is also unusual and likely indicates poor solubility.

**11. hERG:** Ligand A (0.463) has a slightly better hERG profile than Ligand B (0.535), but both are relatively low risk.

**12. Cl_mic:** Ligand A (63.964) has a lower microsomal clearance than Ligand B (74.279), suggesting better metabolic stability.

**13. t1/2:** Ligand A (28.784) has a longer in vitro half-life than Ligand B (14.053), which is a significant advantage.

**14. Pgp:** Ligand A (0.406) has lower P-gp efflux than Ligand B (0.132), suggesting better bioavailability.

**15. 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 A has better QED, metabolic stability, half-life, and Pgp efflux, the significantly higher DILI risk is a major red flag. Ligand B's substantially stronger binding affinity (-7.7 vs -10.6 kcal/mol) is a critical advantage for an enzyme inhibitor. The lower DILI risk also makes it more appealing. The slightly worse ADME properties of Ligand B are likely manageable with further optimization, but the high DILI risk of Ligand A is harder to address.

Output:
1
2025-04-17 16:58:55,169 - INFO - Batch 508 complete. Total preferences: 8128
2025-04-17 16:58:55,169 - INFO - Processing batch 509/512...
2025-04-17 16:59:36,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (347.415 and 381.851 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (75.88 and 72.88) are below the 140 A^2 threshold for good oral absorption.

**logP:** Ligand A (1.152) is slightly better than Ligand B (0.669) as it's closer to the optimal 1-3 range. Ligand B is a bit low, potentially impacting permeability.

**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 (0.82) has a better QED score than Ligand B (0.686), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (38.581 and 33.579, both <40).

**BBB:** Ligand A (73.401) has a better BBB penetration score than Ligand B (53.083), but this isn't a high priority for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.529 and -4.931). This is unusual and suggests a potential issue with intestinal absorption, but the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.613 and -1.243). Similar to Caco-2, this is concerning, and the scale is unknown.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.105 and 0.322). This is excellent.

**Microsomal Clearance:** Ligand B (-7.08 mL/min/kg) has significantly *lower* (better) microsomal clearance than Ligand A (52.031 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-9.656 hours) has a much longer half-life than Ligand A (-30.228 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.096 and 0.055).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better affinity and QED, Ligand B's significantly improved metabolic stability (lower Cl_mic) and longer half-life are crucial for an enzyme target like SRC kinase. The slightly lower logP is a minor concern, but the superior pharmacokinetic properties outweigh this. The negative Caco-2 and solubility values are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 16:59:36,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (349.475 and 352.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.72) is excellent, well below the 140 threshold for good absorption. Ligand B (114.71) is still acceptable, but less ideal.

**logP:** Ligand A (1.256) is within the optimal 1-3 range. Ligand B (0.001) is very low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 7 HBA) is also acceptable, but higher.

**QED:** Ligand A (0.812) is very good, indicating high drug-likeness. Ligand B (0.657) is still acceptable, but lower.

**DILI:** Ligand A (10.237) has a very low DILI risk. Ligand B (66.615) has a moderately high DILI risk.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (79.992) is better than Ligand B (54.634).

**Caco-2 Permeability:** Ligand A (-4.755) is poor, while Ligand B (-5.388) is also poor. Both are problematic.

**Aqueous Solubility:** Ligand A (-2.362) is poor, while Ligand B (-1.713) is also poor. Both are problematic.

**hERG Inhibition:** Ligand A (0.342) has very low hERG risk. Ligand B (0.149) also has low hERG risk.

**Microsomal Clearance:** Ligand A (42.782) is moderate. Ligand B (-9.697) is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (-5.807) is excellent, indicating a long half-life. Ligand B (25.2) is moderate.

**P-gp Efflux:** Both ligands (0.028 and 0.031) have low P-gp efflux.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This 1.2 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B has a superior binding affinity, and excellent metabolic stability. However, it suffers from a low logP, higher DILI risk, and poorer Caco-2 permeability and solubility compared to Ligand A. Ligand A has better physicochemical properties overall (logP, TPSA, DILI), and a long half-life. The slightly weaker binding affinity of Ligand A can potentially be overcome with further optimization, while the poor physicochemical properties of Ligand B are harder to fix without significantly altering the core structure and potentially losing affinity. Given the enzyme-specific priorities, the combination of good metabolic stability (Ligand B) *and* good overall drug-like properties (Ligand A) is crucial. The binding affinity difference is not large enough to overcome the significant drawbacks of Ligand B.

Output:
0
2025-04-17 16:59:36,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (346.431 and 354.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.47) is better than Ligand B (117.17). Both are below 140, but A is closer to the preferred value for good absorption.

**logP:** Ligand A (1.163) is within the optimal 1-3 range. Ligand B (-0.195) is slightly below 1, which *could* indicate permeability issues.

**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 (0.724) has a better QED score than Ligand B (0.586), indicating a more drug-like profile.

**DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (56.96). This is a major advantage for Ligand A.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (49.205) has a slightly better BBB score than Ligand A (36.72).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.099) is slightly better than Ligand B (-5.204), but both are concerning.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-1.801) is slightly better than Ligand B (-2.24).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.153 and 0.201 respectively).

**Microsomal Clearance:** Ligand A (-11.331) has *much* lower (better) microsomal clearance than Ligand B (35.429), suggesting significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (-21.426) has a much longer half-life than Ligand B (-1.729), further supporting better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.015 respectively).

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.3), but the difference is only 0.2 kcal/mol. Given the other substantial advantages of Ligand A, this difference is unlikely to be decisive.

**Conclusion:**

Ligand A is significantly better overall. It has a lower DILI risk, better QED, much better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility and permeability. While Ligand B has a marginally better binding affinity, the other advantages of Ligand A outweigh this small difference, especially considering we are targeting an enzyme where metabolic stability and safety are crucial.

Output:
1
2025-04-17 16:59:36,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (354.491 and 365.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (82.53), both are below the 140 threshold for oral absorption, but closer to the ideal for kinases.

**logP:** Both ligands have good logP values (1.419 and 1.282), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have similar QED scores (0.725 and 0.744), indicating good drug-likeness.

**DILI:** Ligand A (11.322) has a significantly lower DILI risk than Ligand B (23.226). This is a major advantage.

**BBB:** Ligand A (69.756) has a higher BBB penetration percentile than Ligand B (34.393), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-4.567) is worse than Ligand B (-5.295), both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.291) is better than Ligand B (-1.677), both are negative, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.333 and 0.256).

**Microsomal Clearance:** Ligand A (23.652) has a higher (worse) microsomal clearance than Ligand B (-14.545). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (8.037) has a longer half-life than Ligand B (0.979), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.048 and 0.034).

**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 can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, lower DILI risk, and a longer half-life, the significantly stronger binding affinity of Ligand B (-8.2 vs -7.4 kcal/mol) is the most important factor for an enzyme inhibitor. The improved metabolic stability (lower Cl_mic) of Ligand B is also a significant benefit. The slightly higher DILI risk of Ligand B is acceptable given the potency advantage.

Output:
1
2025-04-17 16:59:36,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (347.459 Da and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.58) is significantly better than Ligand B (118.4), being well below the 140 threshold for good oral absorption. Ligand B is approaching the upper limit.

**logP:** Both ligands have similar logP values (1.852 and 1.98), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 4 HBA, which are acceptable values.

**QED:** Ligand A (0.715) has a much better QED score than Ligand B (0.414), indicating a more drug-like profile.

**DILI:** Ligand A (9.965) has a significantly lower DILI risk than Ligand B (20.279), which is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (53.664) is better than Ligand B (36.758).

**Caco-2 Permeability:** Both are negative (-5.236 and -5.057), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative (-0.308 and -1.833), indicating poor solubility. Ligand B is worse.

**hERG:** Both ligands show low hERG inhibition liability (0.202 and 0.243), which is good.

**Microsomal Clearance:** Ligand A (0.445) has a much lower Cl_mic than Ligand B (-7.512). This suggests better metabolic stability for Ligand A, a key consideration for kinases.

**In vitro Half-Life:** Ligand A (53.643) has a much longer half-life than Ligand B (-4.747), further supporting its better metabolic stability.

**P-gp Efflux:** Both are very low (0.017 and 0.024), indicating minimal P-gp efflux.

**Binding Affinity:** Both ligands have very similar binding affinities (-6.6 and -6.8 kcal/mol), which are both good. The difference of 0.2 kcal/mol is not significant enough to outweigh the other factors.

**Conclusion:**

Ligand A is significantly better than Ligand B. While both have poor Caco-2 and solubility, Ligand A excels in crucial areas for kinase inhibitors: QED, DILI risk, metabolic stability (Cl_mic and t1/2), and overall drug-likeness. The similar binding affinities make these ADME properties the deciding factor.

Output:
0
2025-04-17 16:59:36,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.401 and 346.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.66) is well below the 140 threshold for good absorption, and is also favorable. Ligand B (122.03) is still within acceptable limits, but less optimal than A.

**logP:** Ligand A (1.506) is within the optimal range of 1-3. Ligand B (0.048) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both within acceptable limits. Ligand B has 3 HBD and 7 HBA, also acceptable, but slightly higher.

**QED:** Ligand A (0.371) is below the 0.5 threshold, indicating a less drug-like profile. Ligand B (0.635) is above the threshold, suggesting better drug-likeness.

**DILI:** Ligand A (32.067) has a low DILI risk, which is excellent. Ligand B (49.438) is higher, but still within a reasonably acceptable range.

**BBB:** Ligand A (73.827) shows good BBB penetration, though SRC isn't a CNS target, it's not a detriment. Ligand B (17.332) has very poor BBB penetration, which is not a concern here.

**Caco-2:** Ligand A (-4.886) and Ligand B (-5.416) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-2.935) and Ligand B (-1.965) both have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Ligand A (0.301) has a very low hERG risk, which is excellent. Ligand B (0.045) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (14.059) has moderate clearance, while Ligand B (2.668) has very low clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-25.264) has a very short half-life, a major concern. Ligand B (0.191) also has a short half-life, but is better than A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.006 respectively).

**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, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite both compounds having ADME liabilities (poor solubility and Caco-2 permeability), Ligand B is the more promising candidate. Its substantially stronger binding affinity (-8.2 vs -6.8 kcal/mol) is a critical advantage for an enzyme inhibitor. Furthermore, it has better metabolic stability (lower Cl_mic) and a slightly better in vitro half-life. While Ligand A has a lower DILI risk, the potency difference is more important in this case. The poor solubility and permeability would need to be addressed through formulation or further chemical modifications, but the strong binding affinity makes Ligand B a better starting point.

Output:
1
2025-04-17 16:59:36,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (360.37 and 343.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.08) is slightly higher than Ligand B (91.32). Both are acceptable, being below the 140 A^2 threshold for oral absorption, but B is preferable.

**logP:** Both ligands have good logP values (1.911 and 1.567), 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 similar QED scores (0.725 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (99.031 percentile), which is a major concern. Ligand B has a much lower DILI risk (35.75 percentile), making it significantly more favorable.

**BBB:** BBB is less critical for a non-CNS target like SRC kinase. Ligand A (59.868) and Ligand B (53.315) are both relatively low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.114 and -4.976), 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 (-3.583 and -2.301), which also suggests poor solubility.

**hERG:** Ligand A (0.318) has a slightly higher hERG risk than Ligand B (0.059), though both are relatively low.

**Microsomal Clearance:** Ligand B (7.74 mL/min/kg) has a lower microsomal clearance than Ligand A (11.657 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.752 hours) has a negative half-life, which is impossible and suggests an issue with the data. Ligand A (35.467 hours) has a reasonable half-life. However, the negative value for B is a significant red flag.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.173 and 0.014).

**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.

**Conclusion:**

Despite the questionable Caco-2 and solubility values for both, Ligand B is the stronger candidate. The primary driver is the drastically lower DILI risk (35.75 vs 99.031). Additionally, Ligand B has better metabolic stability (lower Cl_mic) and a superior binding affinity. The negative half-life for Ligand B is concerning but could be a data error. The higher affinity of Ligand B can potentially overcome the permeability issues. The high DILI risk of Ligand A is a deal-breaker.

Output:
1
2025-04-17 16:59:36,030 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**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 (369.447 Da) is also good.

**TPSA:** Ligand A (97.37) is better than Ligand B (124.84). Both are under 140, but lower TPSA generally favors oral absorption.

**logP:** Ligand A (2.949) is optimal (1-3). Ligand B (-1.663) is significantly lower, which could hinder permeation and reduce binding affinity.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**H-Bond Acceptors:** Both Ligand A (5) and Ligand B (5) are within the acceptable range (<=10).

**QED:** Ligand A (0.765) is better than Ligand B (0.549), indicating a more drug-like profile.

**DILI:** Ligand A (53.354) has a higher DILI risk than Ligand B (25.514). This is a concern for Ligand A, but not prohibitive.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (54.634) and Ligand B (45.638) are both relatively low.

**Caco-2 Permeability:** Ligand A (-4.938) is significantly worse than Ligand B (-5.647), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.177) is better than Ligand B (-2.003), which is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.314) has a much lower hERG risk than Ligand B (0.041), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-17.333) has a much lower (better) microsomal clearance than Ligand A (69.339), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (17.224) has a longer half-life than Ligand B (-0.266), which is desirable.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.001), meaning it is less likely to be pumped out of cells.

**Binding Affinity:** Ligand A (-8.6 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 has a superior binding affinity and better solubility, hERG risk, and P-gp efflux. Ligand B has better metabolic stability (lower Cl_mic) and lower DILI risk. However, the significantly stronger binding affinity of Ligand A (-8.6 vs -7.9 kcal/mol) is a major advantage for an enzyme target like SRC kinase. The slightly higher DILI risk of Ligand A is a concern, but the improved potency and other favorable properties likely outweigh this risk. The lower Caco-2 permeability of Ligand A is a drawback, but could potentially be addressed through formulation strategies. The negative logP of Ligand B is a significant concern.

Output:
0
2025-04-17 16:59:36,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.236 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**TPSA:** Ligand A (92.91) is slightly higher than Ligand B (69.64). Both are below 140, suggesting reasonable absorption, but Ligand B is preferable.

**logP:** Both ligands have good logP values (A: 3.273, B: 2.249), falling within the optimal range of 1-3.

**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, well within the limits of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (A: 0.584, B: 0.693), indicating a drug-like profile. Ligand B is slightly better.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (6.941). This is a significant concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (A: 53.005, B: 66.111). Since SRC is not a CNS target, this is less critical.

**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 relative.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.586) has a slightly higher hERG risk than Ligand B (0.217).

**Microsomal Clearance:** Ligand A (74.007) has a significantly higher microsomal clearance than Ligand B (32.98). This suggests Ligand A will be metabolized more quickly, leading to lower exposure.

**In vitro Half-Life:** Ligand A (-10.134) has a negative half-life, which is concerning. Ligand B (-4.308) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.473, B: 0.014). Ligand B is significantly better.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.3 kcal/mol, B: -8.7 kcal/mol). Ligand A is slightly better, with a 0.6 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a slightly better binding affinity, but its significantly higher DILI risk, higher microsomal clearance, and negative half-life are major drawbacks. Ligand B has a better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), and better P-gp efflux. While both have poor solubility and Caco-2 permeability, the ADME/Tox profile of Ligand B is far superior. The 0.6 kcal/mol difference in binding affinity is unlikely to outweigh the substantial ADME/Tox advantages of Ligand B.

Output:
1
2025-04-17 16:59:36,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (345.4 and 353.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (100.6 and 93.4) below 140, suggesting reasonable oral absorption potential.

**logP:** Both ligands have logP values (1.60 and 1.24) 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 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.68 and 0.84), indicating drug-like properties.

**DILI:** Ligand A (50.2) has a lower DILI risk than Ligand B (69.1), which is a significant advantage.

**BBB:** BBB is less critical for a non-CNS target like SRC. Ligand B has a slightly higher BBB score (70.6) than Ligand A (54.6), but this is not a major factor in this case.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation (lower values indicate poorer permeability). Ligand B (-4.621) is slightly better than Ligand A (-5.157).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-2.413) is slightly better than Ligand A (-3.196).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.09 and 0.121), which is excellent.

**Microsomal Clearance:** Ligand B has a *negative* Cl_mic (-0.718), which is highly unusual and suggests *extremely* high metabolic stability. Ligand A has a Cl_mic of 9.037, which is moderate. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (-28.978 hours) than Ligand A (-6.174 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.024).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -9.7 kcal/mol). Ligand B is slightly better (-9.7 vs -9.5), but the difference is small.

**Conclusion:**

While both ligands have good potency, Ligand B stands out due to its significantly improved metabolic stability (negative Cl_mic, very long half-life) and lower DILI risk. The slightly better solubility and Caco-2 permeability also contribute. The small advantage in binding affinity is less important than the ADME/Tox improvements.

Output:
1
2025-04-17 16:59:36,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (352.475 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is excellent, well below the 140 threshold for oral absorption. Ligand B (132.96) is still acceptable, but higher, potentially impacting absorption.

**logP:** Ligand A (1.82) is optimal (1-3). Ligand B (-1.511) is below 1, which could hinder permeation.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (4) is acceptable, but approaching the upper limit.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**QED:** Ligand A (0.701) is excellent, indicating good drug-likeness. Ligand B (0.489) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (8.647) has a very low DILI risk. Ligand B (23.071) is also relatively low, but higher than A.

**BBB:** Ligand A (83.908) shows reasonable BBB penetration, while Ligand B (22.063) is low. While SRC isn't a CNS target, better BBB penetration generally correlates with better overall drug properties.

**Caco-2 Permeability:** Ligand A (-4.483) is poor. Ligand B (-6.02) is even worse, indicating very low intestinal absorption for both.

**Aqueous Solubility:** Ligand A (-0.912) is poor. Ligand B (-1.644) is also poor, but slightly worse.

**hERG Inhibition:** Ligand A (0.324) has very low hERG risk. Ligand B (0.041) also has very low hERG risk.

**Microsomal Clearance:** Ligand A (28.218) is moderate, indicating reasonable metabolic stability. Ligand B (-27.031) is negative, which is unusual and suggests very *low* clearance and therefore high metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-0.069) is very short. Ligand B (4.9) is a reasonable half-life.

**P-gp Efflux:** Ligand A (0.084) has low P-gp efflux. Ligand B (0.003) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol) - a difference of 1 kcal/mol. This is a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor Caco-2 and solubility, Ligand B's significantly stronger binding affinity (-8.9 vs -7.9 kcal/mol) and superior metabolic stability (negative Cl_mic) are crucial for an enzyme target like SRC kinase. The better P-gp profile and half-life also contribute. Ligand A has a better TPSA and QED, but the potency and metabolic stability advantages of Ligand B are more important.

Output:
1
2025-04-17 16:59:36,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (336.395 and 355.331 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.52) is significantly better than Ligand B (38.33), being below the 140 threshold for good absorption.

**logP:** Ligand A (2.722) is optimal (1-3), while Ligand B (4.318) is slightly high, potentially leading to solubility issues and off-target effects.

**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 2. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.778 and 0.812, respectively), indicating good drug-like properties.

**DILI:** Ligand A (71.617) has a higher DILI risk than Ligand B (52.191). This is a concern for Ligand A.

**BBB:** Both have moderate BBB penetration, but Ligand B (74.758) is better than Ligand A (63.358). This is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.928) is slightly worse than Ligand B (-4.324).

**Aqueous Solubility:** Ligand A (-3.518) is better than Ligand B (-5.047), indicating better solubility.

**hERG Inhibition:** Ligand A (0.146) has a lower hERG risk than Ligand B (0.768), which is a significant advantage.

**Microsomal Clearance:** Ligand A (24.162) has lower microsomal clearance than Ligand B (65.678), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.327) has a worse half-life than Ligand B (-5.886).

**P-gp Efflux:** Ligand A (0.354) has lower P-gp efflux than Ligand B (0.208), which is beneficial for bioavailability.

**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 substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most crucial factor for an enzyme inhibitor. While it has a higher logP and a slightly worse solubility, the strong binding makes it more likely to be effective. Ligand A has better solubility, lower hERG risk, and better metabolic stability, but its significantly weaker binding affinity is a major drawback. The DILI risk for Ligand A is also a concern.

Output:
1
2025-04-17 16:59:36,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.431 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is slightly higher than Ligand B (70.59). Both are below the 140 threshold for good absorption, but Ligand B is significantly better, potentially indicating better cell permeability.

**logP:** Both ligands have acceptable logP values (1.684 and 3.065), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and a reasonable number of HBA (5 and 3 respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.649 and 0.785), indicating drug-like properties.

**DILI:** Ligand B (30.671) has a significantly lower DILI risk than Ligand A (43.932), making it more favorable.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (78.054) shows better BBB penetration than Ligand A (49.011).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.66 and -2.663). This is a significant drawback for both and would require formulation strategies.

**hERG Inhibition:** Ligand A (0.702) has a slightly higher hERG risk than Ligand B (0.529), though both are relatively low.

**Microsomal Clearance:** Ligand B (19.044) has a significantly lower microsomal clearance than Ligand A (62.127), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (13.654) has a much longer in vitro half-life than Ligand A (-56.174), further supporting its better metabolic stability.

**P-gp Efflux:** Both have low P-gp efflux liability (0.17 and 0.364).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). The difference is 0.4 kcal/mol, which is not substantial enough to outweigh the ADME advantages of Ligand B.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates significantly superior ADME properties, particularly in terms of DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and potentially better permeability (lower TPSA). Given the enzyme-specific priorities, metabolic stability and safety (DILI) are paramount. Therefore, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 16:59:36,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.417 and 355.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.14) is slightly higher than Ligand B (54.88). Both are below the 140 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (2.863) is within the optimal 1-3 range. Ligand B (4.589) is a bit high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.674 and 0.745, respectively), indicating drug-like properties.

**DILI:** Ligand A (41.915) has a lower DILI risk than Ligand B (78.325), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration, but Ligand A (89.027) is slightly better than Ligand B (78.48). This isn't a primary concern for a kinase inhibitor unless CNS off-target effects are a concern.

**Caco-2 Permeability:** Ligand A (-4.428) has better Caco-2 permeability compared to Ligand B (-4.745).

**Aqueous Solubility:** Ligand A (-4.241) has better aqueous solubility than Ligand B (-4.843).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.481 and 0.423, respectively).

**Microsomal Clearance:** Ligand A (79.398) has higher microsomal clearance than Ligand B (41.96), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (43.947) has a significantly longer in vitro half-life than Ligand A (-33.047). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.078 and 0.3, respectively).

**Binding Affinity:** Both ligands have similar strong binding affinities (-8.9 and -8.1 kcal/mol). The difference of 0.8 kcal/mol isn't large enough to outweigh other factors.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has slightly better Caco-2 permeability and BBB, Ligand B excels in crucial areas for an enzyme inhibitor: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and better solubility. The slightly higher logP of Ligand B is a minor concern compared to the metabolic liabilities of Ligand A. The binding affinity difference is not substantial enough to favor Ligand A.

Output:
1
2025-04-17 16:59:36,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (335.451 Da) is slightly lower, which could be advantageous for permeability. Ligand B (372.491 Da) is also well within range.

**TPSA:** Ligand A (54.02) is significantly better than Ligand B (104.97). Lower TPSA generally correlates with better cell permeability. Ligand B's TPSA is approaching a level that could hinder oral absorption.

**logP:** Ligand A (4.35) is higher than optimal (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.455) is within the ideal range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD, which is good. Ligand A has 2 HBA, also good. Ligand B has 5 HBA, which is acceptable but slightly higher.

**QED:** Both ligands have similar QED values (0.873 and 0.754), indicating good drug-likeness.

**DILI:** Ligand A (55.176) has a higher DILI risk than Ligand B (42.846), but both are reasonably low.

**BBB:** Ligand A (87.747) has a much higher BBB penetration percentile than Ligand B (60.76). While SRC is not a CNS target, higher BBB is generally not a negative.

**Caco-2 Permeability:** Ligand A (-4.713) has a very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.137) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.726) has very poor aqueous solubility, which is a major concern. Ligand B (-1.012) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.795) has a slightly higher hERG risk than Ligand B (0.172), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (53.981) has a higher microsomal clearance than Ligand B (19.722), indicating lower metabolic stability. This is a major drawback for Ligand A.

**In vitro Half-Life:** Ligand A (79.279) has a reasonable in vitro half-life. Ligand B (-25.402) has a *very* short half-life, which is a significant negative.

**P-gp Efflux:** Ligand A (0.41) shows moderate P-gp efflux, while Ligand B (0.01) has very low P-gp efflux, which is desirable.

**Binding Affinity:** Ligand B (-8.3 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 the superior candidate. Despite its slightly higher TPSA and lower solubility, its *much* stronger binding affinity, significantly lower hERG risk, lower P-gp efflux, and better metabolic stability outweigh these drawbacks. Ligand A suffers from very poor solubility, poor Caco-2 permeability, and a weak binding affinity. The short half-life of Ligand B is a concern that could be addressed through structural modifications, but the strong initial binding is a critical advantage.

Output:
1
2025-04-17 16:59:36,031 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (369.53 and 398.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is better than Ligand B (83.47) as it is closer to the ideal <140 for oral absorption.

**logP:** Ligand A (3.57) is slightly higher than ideal (1-3), but still acceptable. Ligand B (1.18) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (0 HBD, 6 HBA) as it strikes a better balance between solubility and permeability.

**QED:** Both ligands have similar QED scores (0.76 and 0.761), indicating good drug-likeness.

**DILI:** Ligand B (57.35) has a significantly lower DILI risk than Ligand A (67.39), which is a major advantage.

**BBB:** Ligand B (89.49) has a higher BBB penetration percentile than Ligand A (62.85). While SRC is not a CNS target, higher BBB is generally favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.73), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.19 and -2.89), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.513) has a slightly higher hERG inhibition risk than Ligand B (0.263), making Ligand B safer in terms of cardiotoxicity.

**Microsomal Clearance:** Ligand B (15.91) has a much lower microsomal clearance than Ligand A (39.28), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (-24.44) has a negative half-life, which is concerning. Ligand A (66.22) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.06), which is favorable for bioavailability.

**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 of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand A's significantly stronger binding affinity (-8.4 kcal/mol vs -7.3 kcal/mol) is a major advantage for an enzyme inhibitor. The better half-life and P-gp efflux also contribute to its favorability. While Ligand B has better metabolic stability and lower DILI/hERG risk, the substantial difference in binding affinity makes Ligand A the more promising candidate, assuming the solubility/permeability issues can be addressed through formulation or structural modifications.

Output:
1
2025-04-17 16:59:36,032 - INFO - Batch 509 complete. Total preferences: 8144
2025-04-17 16:59:36,032 - INFO - Processing batch 510/512...
2025-04-17 17:00:19,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (360.439 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.28) is better than Ligand B (49.85) as it is closer to the 140 threshold, while ligand B is very low.

**logP:** Both ligands have good logP values (1.8 and 2.331), falling within the 1-3 optimal range.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, which is acceptable. Ligand B has 3 HBA, which is also good.

**QED:** Both ligands have similar QED values (0.73 and 0.714), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 74.021, which is concerning (high risk). Ligand B has a much lower DILI risk of 21.365, indicating a significantly better safety profile.

**BBB:** Ligand A (70.764) and Ligand B (89.608) both have good BBB penetration, but ligand B is 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 Inhibition:** Ligand A (0.14) has a slightly better hERG profile than Ligand B (0.464).

**Microsomal Clearance:** Ligand A (67.495) has higher microsomal clearance than Ligand B (31.47), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-33.358) has a very negative half-life, which is concerning. Ligand B (5.323) has a positive half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.09).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), but the difference is small.

**Overall Assessment:**

While Ligand A has a slightly better hERG profile, Ligand B is significantly better in terms of DILI risk, metabolic stability (lower Cl_mic, better t1/2), and Caco-2 permeability. The slightly better binding affinity of Ligand B is a bonus. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B outweigh this. Given the importance of metabolic stability and safety (DILI) for kinase inhibitors, Ligand B is the more promising candidate.

Output:
1
2025-04-17 17:00:19,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (376.8 and 348.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.93) is slightly higher than the preferred <140, but acceptable. Ligand B (69.64) is well within the range.

**logP:** Both ligands have good logP values (3.537 and 2.083, respectively), 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 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED scores (0.703 and 0.722), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (96.51 percentile) compared to Ligand B (13.07 percentile). This is a major concern for Ligand A.

**BBB:** BBB is not a primary concern for a kinase inhibitor unless CNS penetration is specifically desired. Ligand A (61.962) and Ligand B (47.15) both have low BBB penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.601 and -4.623), 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 (-6.008 and -2.829), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.465 and 0.141), which is excellent.

**Microsomal Clearance:** Ligand A (70.194 mL/min/kg) has a higher microsomal clearance than Ligand B (22.693 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-11.587 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (27.352 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.241 and 0.032).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.7 kcal/mol). The difference is minimal.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. The primary driver is the drastically lower DILI risk. While both have poor solubility and Caco-2 permeability, these are formulation challenges. Ligand B also exhibits better metabolic stability (lower Cl_mic) and lower P-gp efflux. The negative half-life for Ligand B is a data error, but even ignoring that, the DILI risk for Ligand A is a significant red flag.

Output:
1
2025-04-17 17:00:19,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.373 and 363.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.39) is slightly higher than Ligand B (67.6), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.128 and 2.751), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions but not drastically.

**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 within the limits of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.61 and 0.854), indicating good drug-like properties. Ligand B is better here.

**DILI:** Both ligands have acceptable DILI risk (44.552 and 42.536), both below the 60 threshold.

**BBB:** Ligand A (95.347) has a much higher BBB penetration percentile than Ligand B (77.821). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.445 and -4.861). This is unusual and suggests poor permeability. However, negative values can occur with certain modeling methods and don't necessarily preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.343 and -3.66). This is concerning, as solubility is a key factor for bioavailability.

**hERG Inhibition:** Ligand A (0.639) has a slightly higher hERG risk than Ligand B (0.352), but both are relatively low.

**Microsomal Clearance:** Ligand B (23.775) has significantly lower microsomal clearance than Ligand A (57.259), indicating better metabolic stability. This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand B (46.023 hours) has a much longer in vitro half-life than Ligand A (18.073 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.467) has lower P-gp efflux than Ligand B (0.218), which is slightly favorable.

**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, exceeding the 1.5 kcal/mol difference that can outweigh other factors.

**Conclusion:**

Despite the solubility and permeability concerns with both compounds, Ligand A's significantly superior binding affinity (-8.8 kcal/mol vs -7.0 kcal/mol) is the most important factor for an enzyme inhibitor. The difference in affinity is large enough to compensate for the slightly higher hERG risk and lower metabolic stability compared to Ligand B. Ligand B has better metabolic stability and solubility, but the potency difference is too significant to ignore.

Output:
0
2025-04-17 17:00:19,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for an enzyme (kinase) target in oncology.

**1. Molecular Weight:** Both ligands (334.335 Da and 342.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.04) is slightly above the optimal <140, but acceptable. Ligand B (95.08) is well within the acceptable range.

**3. logP:** Ligand A (3.528) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.639) is quite low, which could hinder permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) 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 scores (A: 0.516, B: 0.64), indicating drug-like properties.

**7. DILI:** Ligand A (97.286) has a high DILI risk, which is a significant concern. Ligand B (52.617) has a much lower, and acceptable, DILI risk.

**8. BBB:** This is less critical for a systemic oncology target. Ligand A (11.167) and Ligand B (65.374) are not particularly relevant here.

**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 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 defined.

**11. hERG:** Ligand A (0.206) has a low hERG risk, which is good. Ligand B (0.043) has even lower risk.

**12. Microsomal Clearance:** Ligand A (2.398) has a low clearance, suggesting good metabolic stability. Ligand B (16.8) has a high clearance, indicating poor metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.798) has a short half-life. Ligand B (-17.774) has a very negative half-life, which is not physically meaningful and suggests a problem with the data.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.019, B: 0.068).

**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.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for an enzyme inhibitor. However, its high DILI risk is a major drawback. Ligand B has a better safety profile (lower DILI, lower hERG), but significantly weaker binding affinity and poor metabolic stability. The negative values for Caco-2 and Solubility are concerning for both, but the affinity difference is substantial. Given the importance of potency for kinase inhibitors, and assuming the DILI risk can be mitigated through structural modifications, Ligand A is the more promising starting point.

Output:
0
2025-04-17 17:00:19,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (345.403 and 344.371 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.21) is better than Ligand B (117.25), being closer to the <140 threshold for good absorption.

**3. logP:** Both ligands have good logP values (1.15 and 0.915), 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 6. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED scores (0.784 and 0.741), indicating good drug-likeness.

**7. DILI:** Ligand B (69.484) has a higher DILI risk than Ligand A (53.276). This is a significant negative for Ligand B.

**8. BBB:** This is less critical for a non-CNS target like SRC kinase. Ligand B (56.495) is slightly higher than Ligand A (27.763).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.138 and -5.11), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.143 and -3.144), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.166 and 0.147), which is excellent.

**12. Microsomal Clearance:** Ligand A (12.592) has lower microsomal clearance than Ligand B (13.045), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.838 hours) has a positive half-life, while Ligand B (-6.267 hours) has a negative half-life. This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.036).

**15. Binding Affinity:** Both ligands have identical binding affinities (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While both compounds have excellent binding affinity and low hERG risk, Ligand A is superior due to its lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), and slightly better TPSA. The poor solubility and Caco-2 permeability are concerning for both, but the other factors favor Ligand A.

Output:
0
2025-04-17 17:00:19,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (347.459 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (87.46), both are below the 140 A^2 threshold for good oral absorption.

**logP:** Both ligands have good logP values (1.684 and 1.031), 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 5. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.868) has a significantly better QED score than Ligand B (0.767), indicating a more drug-like profile.

**DILI:** Ligand A (28.306) has a much lower DILI risk than Ligand B (21.908), which is a significant advantage.

**BBB:** Ligand A (59.364) has a higher BBB penetration than Ligand B (30.167), but BBB is not a high priority for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-4.631) has better Caco-2 permeability than Ligand B (-5.14), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.215) has better aqueous solubility than Ligand B (-0.753). This is important for formulation and bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.352 and 0.155), which is good.

**Microsomal Clearance:** Ligand A (20.835) has significantly lower microsomal clearance than Ligand B (31.822), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.025) has a slightly better in vitro half-life than Ligand B (12.875).

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux than Ligand B (0.043), which is favorable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a 1.3 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 demonstrates superior ADMET properties across the board, including lower DILI risk, better solubility, better permeability, and improved metabolic stability. Given the enzyme-specific priorities, the improved ADMET profile of Ligand A is more compelling. The 1.3 kcal/mol difference in binding affinity might be optimized in subsequent iterations of Ligand A, while improving the ADMET profile of Ligand B would likely be more challenging.

Output:
0
2025-04-17 17:00:19,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (372.466 and 384.929 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (104.21) is slightly above the preferred <140 for good absorption, but acceptable. Ligand B (58.64) is well within the range.

**logP:** Both ligands have good logP values (2.177 and 3.216), falling within 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 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.649 and 0.819), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 61.342, which is moderately high. Ligand B has a much lower DILI risk of 30.516, which is preferable.

**BBB:** Both ligands have reasonable BBB penetration (65.529 and 75.572). Since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.876 and -5.076). 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 (-4.363 and -3.165), indicating poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.311 and 0.443), which is good.

**Microsomal Clearance (Cl_mic):** Ligand A has a higher Cl_mic (66.233) than Ligand B (28.371), indicating faster metabolism and lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (32.549 hours) compared to Ligand A (-28.196 hours). The negative value for A is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.331 and 0.216), which is favorable.

**Binding Affinity:** Ligand B has a significantly better binding affinity (-8.2 kcal/mol) than Ligand A (-6.4 kcal/mol). This 1.8 kcal/mol difference is substantial and outweighs many of the other drawbacks.

**Conclusion:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the superior candidate. Its significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and comparable other properties make it more likely to be a viable drug candidate. The poor solubility and permeability would need to be addressed through formulation strategies, but the potency and improved ADME profile of Ligand B are more readily optimized than trying to significantly improve the affinity of Ligand A.

Output:
1
2025-04-17 17:00:19,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (367.406 Da and 378.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.4) is slightly higher than Ligand B (84.5). Both are below the 140 threshold for good oral absorption, but Ligand B is better positioned, especially considering kinase inhibitors don't necessarily *require* high CNS penetration.

**logP:** Ligand A (2.773) is within the optimal 1-3 range. Ligand B (1.754) is also acceptable, but closer to the lower bound.

**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 B (0.607) has a better QED score than Ligand A (0.374), indicating a more drug-like profile.

**DILI:** Ligand A has a DILI risk of 70.764, which is concerning (high risk). Ligand B has a much lower DILI risk of 34.238, which is good. This is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (82.862 and 81.466 respectively), which isn't a primary concern for a kinase inhibitor unless CNS off-target effects are anticipated.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.028 and -4.927). 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 (-3.053 and -2.535). Again, the scale is undefined, making interpretation difficult. However, poor solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.327) has a slightly better hERG profile than Ligand B (0.467), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (1.756) has significantly lower microsomal clearance than Ligand B (23.519). This suggests much better metabolic stability for Ligand A, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (17.803) has a positive in vitro half-life, while Ligand B (-19.631) has a negative one. This is highly problematic for Ligand B.

**P-gp Efflux:** Ligand A (0.173) has very low P-gp efflux, while Ligand B (0.086) is even lower. Both are favorable.

**Binding Affinity:** Ligand B (-9.2 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:**

Ligand B has a significantly better binding affinity and a much lower DILI risk, which are the most important factors for an enzyme inhibitor. However, its negative in vitro half-life and high microsomal clearance are major concerns. Ligand A has better metabolic stability and half-life, but its DILI risk is high and its binding affinity is very weak.

Despite the superior binding affinity of Ligand B, the extremely poor metabolic stability and negative half-life are dealbreakers. While affinity is crucial, a compound needs to *exist* in the body long enough to exert its effect. The high DILI risk of Ligand A is also a significant concern.

Given the severe ADME liabilities of Ligand B, and the poor affinity of Ligand A, I would lean towards further investigation of Ligand A, but with a strong focus on mitigating the DILI risk through structural modifications.

Output:
0
2025-04-17 17:00:19,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.5 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.1 and 66.7) are below 140, suggesting good oral absorption potential.

**logP:** Both ligands (2.05 and 2.51) 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:** Both ligands have 4 HBAs, well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.686 and 0.743), indicating drug-like properties.

**DILI:** Ligand A (19.97) has a significantly lower DILI risk than Ligand B (49.4). This is a crucial advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (82.7) has better BBB penetration than Ligand A (36.3), but this is less important here.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values, which is unusual and concerning. However, the values are close enough that this isn't a major differentiating factor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also concerning. Ligand A (-1.01) is slightly better than Ligand B (-2.47).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.387 and 0.258).

**Microsomal Clearance:** Ligand A (41.2) has lower microsomal clearance than Ligand B (80.4), indicating better metabolic stability. This is a significant advantage for an enzyme target.

**In vitro Half-Life:** Ligand A (25.0) has a positive half-life, while Ligand B (-42.9) has a negative half-life, which is very concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.109 and 0.434).

**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, the other ADME properties are more critical in this case.

**Conclusion:**

Considering the enzyme-specific priorities, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a more reasonable in vitro half-life. While Ligand B has slightly better binding affinity, the superior ADME profile of Ligand A outweighs this difference. The negative solubility and Caco-2 values are concerning for both, but Ligand A is better positioned for further optimization.

Output:
0
2025-04-17 17:00:19,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**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, but both are acceptable.

**TPSA:** Ligand A (74.57) is better than Ligand B (29.54). Lower TPSA generally correlates with better cell permeability.

**logP:** Ligand A (1.936) is within the optimal range (1-3). Ligand B (4.702) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better than Ligand B (0 HBD, 3 HBA). While both are within acceptable limits, more hydrogen bonding potential can improve solubility.

**QED:** Both ligands have similar QED values (0.634 vs 0.59), indicating reasonable drug-likeness.

**DILI:** Ligand A (16.053) has a significantly lower DILI risk than Ligand B (13.455), which is a major advantage.

**BBB:** Ligand B (86.002) has a higher BBB penetration than Ligand A (55.021). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.888) has a worse Caco-2 permeability than Ligand B (-4.566).

**Aqueous Solubility:** Ligand A (-2.1) has a better aqueous solubility than Ligand B (-5.758). Solubility is important for bioavailability.

**hERG Inhibition:** Ligand A (0.757) has a lower hERG inhibition risk than Ligand B (0.907), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (45.354) has a significantly lower microsomal clearance than Ligand B (126.777), indicating better metabolic stability. This is crucial for maintaining therapeutic concentrations.

**In vitro Half-Life:** Ligand B (55.444) has a longer in vitro half-life than Ligand A (8.333). However, the lower clearance of Ligand A suggests its in vivo half-life could be longer than predicted by the in vitro data.

**P-gp Efflux:** Ligand A (0.218) has lower P-gp efflux than Ligand B (0.806), which is favorable for oral bioavailability.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). This is a 1.4 kcal/mol difference, which is significant, but not overwhelming given the other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME-Tox properties: lower DILI risk, lower hERG risk, significantly better metabolic stability (lower Cl_mic), better solubility, and lower P-gp efflux. These factors are particularly important for an enzyme target like SRC kinase, where maintaining therapeutic concentrations and minimizing toxicity are paramount. The slightly lower affinity of Ligand A can potentially be optimized in subsequent iterations of drug design.

Output:
0
2025-04-17 17:00:19,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (358.785 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.06) is excellent, below the 140 threshold and good for oral absorption. Ligand B (116.84) is still acceptable but less optimal.

**logP:** Ligand A (3.46) is within the optimal 1-3 range. Ligand B (1.103) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, well within the limits. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.414 and 0.617), suggesting reasonable drug-likeness.

**DILI:** Ligand A has a DILI risk of 84.335, which is high and concerning. Ligand B has a much lower DILI risk of 35.479, which is very favorable.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (69.988) is better than Ligand B (36.487).

**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.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.751 and -1.867). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.658) has a moderate hERG risk, while Ligand B (0.033) has a very low risk, which is highly desirable.

**Microsomal Clearance:** Ligand A (47.958) has moderate clearance, while Ligand B (-7.031) has *negative* clearance, which is extremely favorable, indicating very high metabolic stability.

**In vitro Half-Life:** Ligand A (78.846) has a good half-life. Ligand B (-16.896) has a negative half-life, which is not physically possible and indicates a potential issue with the data or model.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.625 and 0.029).

**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.

**Overall Assessment:**

Ligand B is the stronger candidate despite the solubility issues. Its significantly better binding affinity (-7.6 vs 0.0 kcal/mol) outweighs the slightly lower logP and TPSA. The dramatically lower DILI risk and exceptionally high metabolic stability (negative Cl_mic) are also major advantages. While the negative half-life is concerning, it's likely a data anomaly. Ligand A's high DILI risk is a significant red flag. The solubility issues for both compounds would need to be addressed through formulation strategies, but the superior potency and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 17:00:19,602 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.463 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both are below the 140 A^2 threshold for good oral absorption. Ligand A (76.46) is preferable to Ligand B (80.05) as it is closer to the 90 A^2 threshold for CNS penetration, although that isn't a primary concern here.

**logP:** Ligand A (1.448) is optimal (1-3), while Ligand B (4.431) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=2, HBA=7) as it has a lower count of both, improving permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.807, B: 0.579), indicating good drug-like properties.

**DILI:** Ligand A (31.136) has a significantly lower DILI risk than Ligand B (85.227). This is a major advantage.

**BBB:** Both ligands have similar BBB penetration (A: 70.88, B: 70.609), which isn't a primary concern for a non-CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.611 vs -4.965).

**Aqueous Solubility:** Ligand A (-1.739) is better than Ligand B (-4.814), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.534, B: 0.644).

**Microsomal Clearance:** Ligand A (33.255 mL/min/kg) has a lower clearance than Ligand B (73.163 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (42.852 hours) has a significantly longer half-life than Ligand A (3.539 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.086, B: 0.673).

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, **Ligand A is the more promising candidate**. While Ligand B has a longer half-life, Ligand A excels in crucial areas like logP, DILI risk, solubility, and metabolic stability (lower Cl_mic). The significantly lower DILI risk and better solubility are particularly important for an enzyme target. The similar binding affinity means the ADME advantages of Ligand A outweigh the half-life benefit of Ligand B.

Output:
0
2025-04-17 17:00:19,602 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (356.423 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.84) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (66.48) is excellent, well below 140.

**logP:** Ligand A (-0.244) is a bit low, potentially hindering permeability. Ligand B (2.845) 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 (0.499 and 0.686, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (35.014 and 27.608 percentiles), which is favorable.

**BBB:** Both have reasonable BBB penetration (68.205 and 70.609 percentiles), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.305) shows poor permeability, which is a concern. Ligand B (-4.616) is also low, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.859) has poor solubility, which is a significant drawback. Ligand B (-2.833) also has poor solubility, but is still slightly better than A.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.102 and 0.145 percentiles), which is excellent.

**Microsomal Clearance:** Ligand A (23.054 mL/min/kg) has lower clearance than Ligand B (62.786 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.779 hours) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (-19.252 hours) also has a negative half-life, also likely an error. Assuming these are percentile scores, both are very poor.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.006 and 0.244 percentiles), which is good.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A's primary advantage is its significantly better binding affinity. However, it suffers from poor solubility, low permeability, and a questionable half-life value. Ligand B has better physicochemical properties (logP, TPSA) but a weaker binding affinity. Given the enzyme-specific priorities, binding affinity is paramount. The difference in affinity (-8.0 vs -8.3) is substantial enough to potentially overcome the solubility and permeability issues of Ligand A, *provided* the half-life value is corrected or understood to be a different scale. The poor half-life of both compounds is concerning and would require further investigation. However, the potency advantage of A is significant.

Output:
1
2025-04-17 17:00:19,602 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (348.491 and 367.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is slightly higher than Ligand B (75.44), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.812 and 3.121), 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 and <=10 HBA).

**QED:** Both ligands have good QED scores (0.739 and 0.887), indicating a strong drug-like profile.

**DILI:** Both ligands have low DILI risk (43.66 and 40.675 percentile), which is favorable.

**BBB:** Ligand B (78.131) has a higher BBB penetration percentile than Ligand A (55.913). However, since SRC is not a CNS target, this is less critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.923 and -4.791), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.133 and -3.882), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.174) has a slightly lower hERG inhibition liability than Ligand B (0.401), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (39.769 and 39.593 mL/min/kg), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand B (-3.136) has a slightly longer in vitro half-life than Ligand A (-4.482), which is a minor advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.088 and 0.264), which is good.

**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, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the poor Caco-2 permeability and solubility for both compounds, Ligand A's significantly stronger binding affinity (-9.2 kcal/mol vs -8.0 kcal/mol) is a decisive factor. The potency advantage outweighs the concerns about permeability and solubility, especially given that these are properties that can be addressed through formulation or further chemical modifications. Ligand A also has a slightly better hERG profile.

Output:
1
2025-04-17 17:00:19,602 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.439 Da) is slightly lower than Ligand B (372.531 Da), which is acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (71.19) is slightly higher than Ligand B (67.87), but both are well within the acceptable range.

**logP:** Ligand A (3.242) is optimal, while Ligand B (1.538) is a bit low, potentially hindering membrane permeability.

**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 A (0.876) has a significantly better QED score than Ligand B (0.665), indicating a more drug-like profile.

**DILI:** Ligand B (15.936) has a much lower DILI risk than Ligand A (63.823), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 71.501, Ligand B: 61.38). BBB is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially indicates issues with the experimental setup or prediction method. However, we can still compare them relatively. Ligand A (-4.978) is slightly worse than Ligand B (-4.848).

**Aqueous Solubility:** Ligand A (-4.754) has slightly better solubility than Ligand B (-1.92).

**hERG Inhibition:** Ligand A (0.792) has a slightly higher hERG risk than Ligand B (0.337), which is preferable for B.

**Microsomal Clearance:** Ligand B (37.693) has a higher microsomal clearance than Ligand A (29.685), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (29.691) has a significantly longer half-life than Ligand B (9.455), which is a major advantage.

**P-gp Efflux:** Ligand A (0.431) has lower P-gp efflux than Ligand B (0.038), which is better.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This 0.3 kcal/mol difference is notable but may not be enough to overcome other deficiencies.

**Overall Assessment:**

Ligand B has a much lower DILI risk and better binding affinity, which are key advantages. However, Ligand A has a better QED score, significantly better metabolic stability (lower Cl_mic, longer t1/2), better P-gp efflux, and slightly better solubility. The lower logP of Ligand B is a concern, potentially impacting permeability. Considering the priorities for enzyme inhibitors (potency, metabolic stability, solubility, and hERG risk), Ligand A appears to be the more promising candidate despite the slightly lower binding affinity and higher DILI. The improved metabolic stability and drug-like properties are likely to be more beneficial in the long run.

Output:
0
2025-04-17 17:00:19,602 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (343.519 and 363.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.5) is significantly better than Ligand B (63.05). Lower TPSA generally correlates with better cell permeability, which is beneficial for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (2.943 and 3.777, respectively), falling within the 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.

**QED:** Both ligands have reasonable QED scores (0.84 and 0.698), suggesting good drug-like properties.

**DILI:** Ligand A (34.703) has a significantly lower DILI risk than Ligand B (55.487). This is a major advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (87.515) has a higher BBB percentile than Ligand B (76.58).

**Caco-2 Permeability:** Ligand A (-4.995) has a lower Caco-2 permeability than Ligand B (-5.023). This is a slight negative for Ligand A, but the difference is small.

**Aqueous Solubility:** Ligand A (-2.266) has a better aqueous solubility than Ligand B (-3.611). This is important for formulation and bioavailability.

**hERG:** Both ligands have similar and acceptable hERG inhibition liability (0.944 and 0.877).

**Microsomal Clearance:** Ligand A (29.536) has a much lower microsomal clearance than Ligand B (98.452). This indicates better metabolic stability, a crucial factor for kinase inhibitors.

**In vitro Half-Life:** Ligand A (17.617) has a shorter half-life than Ligand B (75.715). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.355 and 0.772).

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.3). While the difference is small (0.4 kcal/mol), it's still a positive.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in key areas for an enzyme inhibitor: lower DILI risk, significantly lower microsomal clearance (better metabolic stability), and better aqueous solubility. While Ligand B has a longer half-life, the superior safety profile and metabolic stability of Ligand A outweigh this benefit. The slight advantage in binding affinity for Ligand A further supports this conclusion.

Output:
0
2025-04-17 17:00:19,602 - INFO - Batch 510 complete. Total preferences: 8160
2025-04-17 17:00:19,602 - INFO - Processing batch 511/512...
2025-04-17 17:01:05,227 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (364.515 and 358.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is better than Ligand B (34.47). Both are below the 140 A^2 threshold for good absorption, but ligand B is significantly lower, which is beneficial.

**logP:** Ligand A (1.983) is within the optimal 1-3 range. Ligand B (4.318) is slightly above, potentially leading to solubility issues and off-target effects.

**H-Bond Donors:** Ligand A (2) 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 (0.739 and 0.771) have good drug-likeness scores.

**DILI:** Both ligands have very similar and low DILI risk (23.342 and 23.11).

**BBB:** Ligand B (88.6) has a higher BBB penetration percentile than Ligand A (63.474), but this is not a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.643) is significantly worse than Ligand B (-4.496), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.388) is better than Ligand B (-4.734).

**hERG Inhibition:** Ligand A (0.218) is much better than Ligand B (0.84), indicating a lower risk of cardiotoxicity. This is a critical factor.

**Microsomal Clearance:** Ligand A (13.912) has a lower clearance than Ligand B (119.435), suggesting better metabolic stability. This is a key advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand A (-18.953) has a much longer half-life than Ligand B (16.954).

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.854), which is favorable for bioavailability.

**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 significant.

**Overall Assessment:**

Ligand B has a better binding affinity and Caco-2 permeability. However, it has a higher logP, higher P-gp efflux, higher microsomal clearance, shorter half-life, and a significantly higher hERG risk. Ligand A has better solubility, metabolic stability, lower hERG risk, and lower P-gp efflux. The difference in binding affinity (1.3 kcal/mol) is important, but the superior ADME profile of Ligand A, particularly the lower hERG risk and better metabolic stability, makes it the more promising candidate. The lower Caco-2 permeability of Ligand A is a concern, but could be addressed through formulation strategies.

Output:
0
2025-04-17 17:01:05,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (330.387 Da and 346.402 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (42.41) is well below the 140 threshold, and even better, below 90, suggesting good permeability. Ligand B (49.85) is also below 140, but less optimal than A.

**logP:** Ligand A (4.959) is slightly high, potentially causing solubility issues or off-target effects. Ligand B (1.977) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have low HBD counts (0), which is favorable for permeability. Ligand A has 4 HBA, and Ligand B has 3, both within acceptable limits.

**QED:** Both ligands have good QED scores (0.521 and 0.766), indicating drug-like properties.

**DILI:** Ligand A has a higher DILI risk (87.786%) than Ligand B (42.846%). This is a significant concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (81.466% and 83.288%), but this is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.045) has poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.091) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-6.148) has very poor aqueous solubility, a major drawback. Ligand B (-2.422) has better solubility, though still not ideal.

**hERG Inhibition:** Ligand A (0.894) has a slightly elevated hERG risk, while Ligand B (0.603) is lower.

**Microsomal Clearance:** Ligand A (81.189) has high microsomal clearance, indicating poor metabolic stability. Ligand B (35.213) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand A (71.14) has a reasonable half-life. Ligand B (-31.614) has a very short half-life, which is a major concern.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.937 and 0.381), which is favorable.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.2), but the difference is not substantial enough to overcome the other significant drawbacks.

**Conclusion:**

Considering the priorities for enzyme inhibitors, Ligand B is the more promising candidate. While its half-life is poor, it has significantly better solubility, lower DILI risk, and better metabolic stability (lower Cl_mic) than Ligand A. Ligand A's poor solubility, high DILI risk, and poor Caco-2 permeability are major liabilities. The slight affinity difference doesn't outweigh these issues.

Output:
1
2025-04-17 17:01:05,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (375.475 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.55) is better than Ligand B (84.5), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.168) is optimal, while Ligand B (1.775) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.706 and 0.686), indicating good drug-likeness.

**DILI:** Ligand B (29.779) has a significantly lower DILI risk than Ligand A (92.361), which is a major advantage.

**BBB:** Ligand A (60.838) has a slightly better BBB penetration than Ligand B (50.679), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have similar, poor Caco-2 permeability (-4.8 and -4.82).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.128 and -2.938).

**hERG Inhibition:** Ligand A (0.639) has a slightly higher hERG risk than Ligand B (0.234), which is preferable.

**Microsomal Clearance:** Ligand B (67.198) has a lower microsomal clearance than Ligand A (80.844), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.071) has a significantly longer in vitro half-life than Ligand A (22.499), a substantial benefit.

**P-gp Efflux:** Ligand A (0.402) has lower P-gp efflux than Ligand B (0.178), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.7 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has a slightly better logP and P-gp efflux, Ligand B demonstrates significantly better ADME properties: lower DILI risk, lower microsomal clearance (better metabolic stability), and a much longer in vitro half-life. The binding affinity is comparable. Given the enzyme-kinase focus, metabolic stability and safety (DILI, hERG) are critical. Ligand B's superior ADME profile outweighs the minor advantages of Ligand A.

Output:
1
2025-04-17 17:01:05,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (352.391 and 363.405 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.46) is slightly above the optimal <140, but acceptable. Ligand B (98.74) is well within the range.

**logP:** Ligand A (0.92) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (0.272) is even lower and could have significant permeability issues.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 7 HBA) is within the acceptable limits. Ligand B (3 HBD, 4 HBA) is also within limits.

**QED:** Ligand A (0.814) has a strong drug-like profile. Ligand B (0.512) is acceptable but less ideal.

**DILI:** Ligand A (56.068) has a moderate DILI risk, but acceptable. Ligand B (33.424) has a lower, more favorable DILI risk.

**BBB:** Both ligands have relatively low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.481 and -4.846), which is a concern.

**Aqueous Solubility:** Both ligands show poor aqueous solubility (-3.185 and -0.75). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.058) has very low hERG inhibition risk, which is excellent. Ligand B (0.245) also has low risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (39.245) has moderate clearance, indicating moderate metabolic stability. Ligand B (9.172) has very low clearance, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-16.064) has a very short half-life, a major concern. Ligand B (-27.856) has an even shorter half-life, which is worse.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.018 and 0.012), which is favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite both ligands having ADME liabilities (poor solubility, permeability, and short half-life), Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.8 kcal/mol) is a major advantage for an enzyme target. The slightly better hERG profile and lower DILI risk also contribute to its favorability. While the half-life is a concern, it might be addressable through structural modifications. The poor solubility and permeability are more challenging, but the potency advantage of A makes it the better starting point for optimization.

Output:
0
2025-04-17 17:01:05,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.507 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 102-103, which is slightly above the optimal <140 for good oral absorption, but not a major concern for a kinase inhibitor.

**logP:** Ligand A (2.209) is within the optimal range (1-3). Ligand B (0.886) is a bit low, potentially hindering membrane permeability.

**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 limits.

**QED:** Ligand A (0.829) has a significantly higher QED score than Ligand B (0.663), indicating a more drug-like profile.

**DILI:** Ligand B (25.94) has a much lower DILI risk than Ligand A (82.59), which is a significant advantage.

**BBB:**  BBB is not a primary concern for SRC kinase inhibitors, but Ligand A (62.156) is higher than Ligand B (12.292).

**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, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.361) has a slightly higher hERG risk than Ligand B (0.048), which is preferable for B.

**Microsomal Clearance:** Ligand B (1.61 mL/min/kg) has significantly lower microsomal clearance than Ligand A (10.697 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-21.815 hours) has a much longer in vitro half-life than Ligand A (8.051 hours), which is highly desirable.

**P-gp Efflux:** Ligand A (0.332) has slightly lower P-gp efflux than Ligand B (0.02), which is preferable.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). The difference is 0.5 kcal/mol, which is not substantial enough to overcome the ADME deficiencies of Ligand A.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, Ligand B is the more promising candidate. Its significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and higher QED outweigh the small difference in binding affinity. The permeability and solubility issues are concerning for both, but the ADME profile of Ligand B is superior.

Output:
1
2025-04-17 17:01:05,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (367.471 and 367.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.76) is slightly above the preferred <140, while Ligand B (80.32) is well within. This favors Ligand B for absorption.

**3. logP:** Ligand A (0.899) is a bit low, potentially hindering permeation. Ligand B (2.676) 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 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (54.168 and 52.966 percentile), both being acceptable (<60).

**8. BBB:** Ligand A (33.54) and Ligand B (49.244) both have low BBB penetration, which is not a major concern for a non-CNS target like SRC kinase.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.858 and -4.851) which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.415 and -2.761) 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 (0.269 and 0.173), which is excellent.

**12. Microsomal Clearance:** Ligand A (4.352) has significantly lower microsomal clearance than Ligand B (30.656). Lower clearance indicates better metabolic stability, a key priority for kinase inhibitors. This strongly favors Ligand A.

**13. In vitro Half-Life:** Ligand A (19.612) and Ligand B (20.222) have similar half-lives, both being acceptable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.168 and 0.124), which is favorable.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and TPSA, and a significantly stronger binding affinity. However, Ligand A has a much better microsomal clearance, suggesting greater metabolic stability. Both have concerningly low/negative Caco-2 and solubility values. Given the importance of potency for kinase inhibitors, the 1.5 kcal/mol advantage of Ligand B is substantial. While metabolic stability is important, the stronger binding of Ligand B is likely to be more impactful.

Output:
1
2025-04-17 17:01:05,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (354.447 and 369.412 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.89) is better than Ligand B (54.02), being under the 140 threshold, but still potentially limiting for CNS penetration if that were a goal. Ligand B is excellent.

**logP:** Ligand A (1.746) is optimal (1-3). Ligand B (4.658) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.68 and 0.805), indicating drug-like properties.

**DILI:** Ligand A (28.577) has a significantly lower DILI risk than Ligand B (63.164). This is a major advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (85.343 and 87.127), but this isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**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:** Ligand A (-2.07) has slightly better solubility than Ligand B (-5.583), though both are quite poor.

**hERG Inhibition:** Ligand A (0.267) has a much lower hERG risk than Ligand B (0.685). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (38.651) has lower microsomal clearance than Ligand B (51.029), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (31.566) has a significantly longer half-life than Ligand A (6.384). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, while Ligand B (0.487) has moderate efflux. This favors Ligand A.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a significant 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 stronger binding affinity, which is the highest priority for an enzyme inhibitor. However, it suffers from higher logP, higher DILI risk, higher hERG risk, and faster clearance. Ligand A has better ADME properties (lower DILI, hERG, clearance, P-gp efflux, and better solubility), but weaker binding.

Given the substantial difference in binding affinity, the benefits of Ligand B's potency likely outweigh its ADME liabilities, *provided* those liabilities can be addressed through further optimization. The difference in binding is significant enough to warrant prioritizing Ligand B for further development.

Output:
1
2025-04-17 17:01:05,228 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (342.447 and 337.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.63) is slightly higher than Ligand B (62.3). Both are below the 140 threshold for good oral absorption, but neither is optimized for CNS penetration (below 90).

**logP:** Both ligands have good logP values (1.807 and 2.296), 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 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have very similar QED scores (0.899 and 0.897), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (30.399 and 32.842), which is favorable.

**BBB:** Ligand B (71.733) has a higher BBB percentile than Ligand A (57.929), but this is not a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-5.19) has a worse Caco-2 permeability than Ligand B (-4.619).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.032 and -2.382). This is a significant drawback and would require formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.096 and 0.027).

**Microsomal Clearance:** Ligand A (27.469) has significantly lower microsomal clearance than Ligand B (43.685), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.279) has a slightly worse in vitro half-life than Ligand B (-10.127).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.028).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

While both ligands have good overall profiles, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better metabolic stability (lower Cl_mic) and slightly better binding affinity. The solubility is a concern for both, but the improved potency and stability of Ligand A make it the preferred choice.

Output:
1
2025-04-17 17:01:05,229 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.463 and 341.411 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.25) is slightly higher than Ligand B (75.44), but both are below the 140 threshold for good oral absorption.

**logP:** Both ligands have acceptable logP values (1.347 and 2.04), falling within the optimal range of 1-3.

**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 (0.667 and 0.835), indicating drug-like properties.

**DILI:** Ligand B (60.566) has a higher DILI risk than Ligand A (13.106). This is a significant concern.

**BBB:** Both ligands have moderate BBB penetration, but Ligand B (74.254) is higher than Ligand A (62.621). This isn't a primary concern for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-5.048) is worse than Ligand B (-4.746).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.006) is slightly better than Ligand B (-3.627).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.358 and 0.241).

**Microsomal Clearance:** Ligand B (19.499) has lower microsomal clearance than Ligand A (30.133), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.363) has a longer in vitro half-life than Ligand A (-8.386).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.37).

**Binding Affinity:** Ligand B (-9.5 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 some ADME drawbacks.

**Conclusion:**

Despite the slightly better solubility of Ligand A, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.5 vs -7.0 kcal/mol) is the most crucial factor for an enzyme inhibitor. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic, longer t1/2) and a lower P-gp efflux liability. While the DILI risk is higher for Ligand B, it's not excessively high (60.566), and the substantial improvement in potency and stability likely outweighs this concern. The poor Caco-2 and solubility are drawbacks for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 17:01:05,229 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.419 and 348.531 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.84) is slightly higher than the preferred <140, but still acceptable. Ligand B (58.2) is excellent, well below 90, suggesting good permeability.

**logP:** Ligand A (1.016) is at the lower end of optimal, potentially impacting permeability. Ligand B (3.509) is well 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 6 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**QED:** Ligand A (0.733) has a better QED score than Ligand B (0.594), indicating a more drug-like profile.

**DILI:** Ligand A (59.442) is approaching a moderate risk for DILI, while Ligand B (11.361) shows very low DILI risk, a significant advantage.

**BBB:** Ligand A (47.111) has a low BBB penetration score. Ligand B (69.678) has a better, though not exceptional, BBB score. This is less critical for a kinase inhibitor unless CNS effects are desired.

**Caco-2 Permeability:** Ligand A (-5.167) has poor Caco-2 permeability. Ligand B (-4.487) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-2.468) has poor aqueous solubility. Ligand B (-4.619) has even poorer aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.033) has very low hERG inhibition risk, a major advantage. Ligand B (0.475) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (34.267) has lower microsomal clearance than Ligand B (59.96), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.618) has a longer half-life than Ligand B (1.537), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.052) has low P-gp efflux, while Ligand B (0.097) has slightly higher P-gp efflux.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't heavily influence the decision.

**Overall Assessment:**

Ligand A has better QED, hERG, metabolic stability (lower Cl_mic), and half-life. However, Ligand B has a significantly lower DILI risk, better TPSA, and a slightly better BBB score. Both have poor solubility and Caco-2 permeability. Given the importance of minimizing toxicity (DILI) and the similar binding affinities, Ligand B is the slightly better candidate, despite the solubility concerns. Solubility can be addressed through formulation strategies.

Output:
1
2025-04-17 17:01:05,229 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.466 Da) is slightly better positioned.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (139.78). Lower TPSA generally improves permeability, which is important for oral bioavailability.

**logP:** Ligand A (2.579) is optimal, while Ligand B (-0.333) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both have acceptable HBD counts (1 and 2 respectively), well within the limit of 5.

**H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), keeping within the desirable range of <=10.

**QED:** Both ligands have reasonable QED values (0.764 and 0.645), indicating good drug-like properties.

**DILI:** Ligand A (15.355) has a much lower DILI risk than Ligand B (75.378), a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand A (87.515) is better than Ligand B (47.15).

**Caco-2 Permeability:** Ligand A (-4.658) is better than Ligand B (-5.461), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.596) is better than Ligand B (-2.036), which is crucial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.405) has a lower hERG risk than Ligand B (0.136), a critical safety parameter.

**Microsomal Clearance:** Ligand A (22.559) has higher clearance than Ligand B (-20.243), meaning Ligand B is more metabolically stable. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (7.748) has a slightly longer half-life than Ligand A (5.311).

**P-gp Efflux:** Both have low P-gp efflux liability (0.098 and 0.052 respectively).

**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 that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), which are high priorities for an enzyme target. However, it suffers from a low logP, high DILI risk, and a higher TPSA. Ligand A has a more balanced profile with better solubility, lower DILI, lower hERG risk, and better permeability characteristics. The difference in binding affinity (1.7 kcal/mol) is significant, and in the context of kinase inhibitors, often enough to overcome moderate ADME liabilities, especially if formulation strategies can address the solubility issues.

Output:
1
2025-04-17 17:01:05,229 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as SRC kinase inhibitors, following the provided guidelines.

**Ligand A: [352.475, 76.66, 1.629, 2, 4, 0.619, 16.479, 52.811, -4.721, -3.062, 0.389, 59.931, 3.737, 0.118, -7.8]**
**Ligand B: [375.491, 104.81, 0.832, 2, 5, 0.654, 48.313, 54.866, -5.205, -2.568, 0.307, 6.791, -46.245, 0.038, -7.9]**

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). A (352.475) is slightly preferred.

**2. TPSA:** A (76.66) is good, below the 140 threshold. B (104.81) is still acceptable, but less ideal.

**3. logP:** Both are within the optimal range (1-3). A (1.629) is slightly better than B (0.832).

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** A has 4 HBA, B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both are above 0.5, indicating good drug-likeness. B (0.654) is slightly better.

**7. DILI:** A (16.479) is significantly better than B (48.313). Lower DILI risk is crucial.

**8. BBB:** Both are relatively low, which is fine given SRC is not a CNS target. B (54.866) is slightly better than A (52.811).

**9. Caco-2:** Both have negative values, indicating poor permeability. A (-4.721) is worse than B (-5.205).

**10. Solubility:** Both have negative values, indicating poor solubility. A (-3.062) is slightly better than B (-2.568).

**11. hERG:** Both have very low hERG risk, which is excellent.

**12. Microsomal Clearance:** A (59.931) is higher than B (6.791), indicating faster metabolism and lower metabolic stability. This is a major drawback for A.

**13. In vitro Half-Life:** A (3.737) is much lower than B (-46.245), indicating a much shorter half-life. This is another significant drawback for A.

**14. P-gp Efflux:** A (0.118) is better than B (0.038), indicating lower P-gp efflux.

**15. Binding Affinity:** B (-7.9) has a slightly better binding affinity than A (-7.8), although the difference is small.

**Enzyme-Kinase Specific Priorities:**

For enzymes like SRC kinase, potency (affinity), metabolic stability (Cl_mic, t1/2), solubility, and hERG risk are key.

*   **Affinity:** B has a slightly better affinity.
*   **Metabolic Stability:** B is *significantly* better (lower Cl_mic, much longer t1/2).
*   **Solubility:** A is slightly better.
*   **hERG:** Both are good.
*   **DILI:** A is significantly better.

**Conclusion:**

While ligand A has slightly better solubility and DILI, ligand B is significantly better regarding metabolic stability (Cl_mic and t1/2), which is critical for an enzyme inhibitor. The slightly better affinity of B also contributes to its favorability. The Caco-2 permeability is poor for both, but can be addressed with formulation strategies.

Therefore, **Ligand B** is the more viable drug candidate.

Output:
1
2025-04-17 17:01:05,230 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as appropriate for an enzyme target.

**Molecular Weight:** Both ligands (370.475 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.48) is slightly above the optimal <140, while Ligand B (90.12) is well within. This favors B for absorption.

**logP:** Ligand A (0.367) is a bit low, potentially hindering permeation. Ligand B (0.819) is better, though still on the lower side of the 1-3 optimal range.

**H-Bond Donors:** Both have 3 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable and potentially slightly better for permeability.

**QED:** Both ligands have good QED scores (0.61 and 0.737), indicating generally drug-like properties.

**DILI:** Ligand A (57.154) has a higher DILI risk than Ligand B (49.981), though both are reasonably acceptable.

**BBB:** This isn't a primary concern for a non-CNS target like SRC. Ligand B (54.478) is slightly higher.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.424 and -5.476), which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.342 and -2.49), which is also a major concern. Poor solubility will hinder bioavailability.

**hERG:** Both ligands have very low hERG risk (0.1 and 0.12), which is excellent.

**Microsomal Clearance:** Ligand A (17.065) has lower clearance than Ligand B (25.065), suggesting better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (3.332 hours) has a slightly longer half-life than Ligand B (0.972 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.014 and 0.059).

**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 outweigh minor ADME drawbacks.

**Overall Assessment:**

Both compounds have serious issues with predicted permeability and solubility. However, Ligand A exhibits better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. While the solubility and permeability are concerning, the improved metabolic profile and binding affinity of Ligand A make it a marginally more promising starting point for optimization, assuming these predictions hold true. Addressing the solubility/permeability issues will be critical for either compound.

Output:
0
2025-04-17 17:01:05,230 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (374.775 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.27) is slightly higher than Ligand B (78.87), but both are well below the 140 threshold for good oral absorption.

**logP:** Ligand A (3.08) is optimal, while Ligand B (1.483) is a bit low, potentially impacting permeability.

**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.

**QED:** Both ligands have good QED scores (0.662 and 0.71), indicating drug-likeness.

**DILI:** Ligand A (84.917) has a significantly higher DILI risk than Ligand B (17.72). This is a major concern.

**BBB:** Both have reasonable BBB penetration, but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and are less important than other factors.

**Aqueous Solubility:** Both have negative solubility values, again suggesting poor solubility. This is a concern, but can sometimes be overcome with formulation.

**hERG Inhibition:** Ligand A (0.674) has a slightly higher hERG risk than Ligand B (0.333), but both are relatively low.

**Microsomal Clearance:** Both have similar microsomal clearance values (43.249 and 39.178 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (1.177 hours) compared to Ligand A (-17.348 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.369 and 0.102).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a considerably stronger binding affinity than Ligand B (-6.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its high DILI risk is a major red flag. DILI is a common reason for drug development failure. Ligand B, while having a weaker binding affinity, exhibits a much lower DILI risk, better half-life, and a more reasonable logP. The difference in binding affinity (-3.6 kcal/mol) is significant, but not insurmountable, and can potentially be addressed through further optimization. Given the enzyme-specific priorities, the lower DILI and improved metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 17:01:05,230 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.443 and 350.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (60.03) is well below the 140 threshold and is favorable. Ligand B (87.66) is still under the threshold, but less optimal than A.

**logP:** Ligand A (3.465) is at the upper end of the optimal range (1-3), while Ligand B (0.979) is slightly below, potentially impacting permeability.

**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:** Ligand A (0.905) has a very strong drug-like profile, significantly better than Ligand B (0.597).

**DILI:** Ligand A (46.142) has a slightly higher DILI risk than Ligand B (35.285), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (80.651) is higher than Ligand B (36.371).

**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 cannot interpret these values accurately.

**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 (0.655) has a slightly higher hERG risk than Ligand B (0.22), but both are relatively low.

**Microsomal Clearance:** Ligand A (43.916) has a higher microsomal clearance than Ligand B (18.944), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-8.172) has a longer in vitro half-life than Ligand A (14.711), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.219 and 0.042).

**Binding Affinity:** Both ligands have the same binding affinity (-8.9 kcal/mol), which is excellent.

**Conclusion:**

Despite the unusual negative values for Caco-2 and Solubility, the key differences lie in the ADME properties. Ligand B demonstrates superior drug-likeness (higher QED), better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. While Ligand A has a slightly better TPSA, the metabolic stability and drug-likeness of Ligand B are more critical for an enzyme target like SRC kinase. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 17:01:05,230 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (348.403 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.31) is slightly higher than Ligand B (76.02). Both are below the 140 A^2 threshold for good oral absorption, but Ligand B is significantly better.

**logP:** Ligand A (-0.668) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (3.026) is within the optimal 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, and Ligand B has 4, both are acceptable.

**QED:** Both ligands have good QED scores (0.706 and 0.745), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (40.636 and 39.395), which is positive.

**BBB:** Ligand A (45.444) has a lower BBB penetration percentile than Ligand B (82.241). Since SRC is not a CNS target, this is less critical, but still favors B.

**Caco-2 Permeability:** Ligand A (-5.187) has poor Caco-2 permeability. Ligand B (-4.845) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.833) and Ligand B (-3.439) both have poor aqueous solubility. This is a concern for both, but B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.245 and 0.472), which is good.

**Microsomal Clearance:** Ligand A (-16.636) has significantly lower (better) microsomal clearance than Ligand B (53.553). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (16.686 hours) has a shorter half-life than Ligand B (29.211 hours). Longer is generally preferred, favoring B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.408), which is positive.

**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, and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, a more favorable logP, and better BBB penetration. While its solubility and Caco-2 permeability are worse than A, its metabolic stability is worse. However, the substantial difference in binding affinity (-7.8 vs -9.0 kcal/mol) is a critical factor for an enzyme inhibitor. A strong binding affinity can often compensate for minor ADME deficiencies, especially if the metabolic stability is still reasonable.

Output:
1
2025-04-17 17:01:05,230 - INFO - Batch 511 complete. Total preferences: 8176
2025-04-17 17:01:05,231 - INFO - Processing batch 512/512...
2025-04-17 17:01:46,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (349.431 and 349.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (80.76 and 80.56) are below 140, suggesting good oral absorption potential.

**3. logP:** Ligand A (2.706) is optimal, while Ligand B (0.676) is slightly low, potentially hindering permeation.

**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 good QED scores (0.827 and 0.723), indicating drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk, with Ligand A at 49.593 and Ligand B at 42.575, both below the 60 threshold.

**8. BBB:** Both ligands have high BBB penetration (79.294 and 78.364), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.299 and -4.939). This is unusual and suggests poor permeability, but these values may be from a different scale and require careful interpretation.

**10. Aqueous Solubility:** Both have negative solubility values (-3.043 and -0.931). Similar to Caco-2, these values are concerning and require further investigation.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.389 and 0.08), which is excellent.

**12. Microsomal Clearance:** Ligand A (86.138) has higher microsomal clearance than Ligand B (41.12). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-4.548) has a slightly better (less negative) in vitro half-life than Ligand A (-30.21).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.075).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.6 kcal/mol). Ligand A is slightly better, but the difference is small.

**Overall Assessment:**

Both ligands are promising. However, considering the enzyme-specific priorities, Ligand B appears slightly more favorable. While Ligand A has a slightly better binding affinity and logP, Ligand B exhibits significantly better metabolic stability (lower Cl_mic) and a slightly improved half-life. The negative Caco-2 and solubility values for both are concerning and require experimental validation, but the better metabolic profile of Ligand B gives it a slight edge.

Output:
1
2025-04-17 17:01:46,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**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 (365.499 Da) is also good.

**TPSA:** Ligand B (80.32) is significantly better than Ligand A (112.16). Lower TPSA generally improves oral absorption, a key factor for kinase inhibitors.

**logP:** Both ligands have acceptable logP values (A: 1.025, B: 2.373), falling within the 1-3 range. Ligand B is slightly better positioned within the optimal range.

**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 (<=5 HBD and <=10 HBA).

**QED:** Both have good QED scores (A: 0.596, B: 0.727), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand B (41.877) has a significantly lower DILI risk than Ligand A (67.158). This is a crucial advantage.

**BBB:** Ligand B (53.974) has a higher BBB penetration score than Ligand A (32.803), but BBB isn't a primary concern for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Ligand A (-5.636) has a worse Caco-2 permeability than Ligand B (-4.834).

**Aqueous Solubility:** Ligand A (-1.644) has a worse solubility than Ligand B (-2.187). Solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.235, B: 0.16). This is excellent.

**Microsomal Clearance:** Ligand A (-40.701) has a much lower (better) microsomal clearance than Ligand B (22.716). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (50.156) has a longer in vitro half-life than Ligand B (16.055). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.066, B: 0.091).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -7.5 kcal/mol, B: -7.4 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has better metabolic stability and half-life, Ligand B excels in several crucial areas: lower DILI risk, better TPSA, better logP, better QED, and better solubility. The slightly better metabolic profile of A is outweighed by the significant advantages of B in terms of safety (DILI) and absorption/pharmacokinetics (TPSA, solubility). Given the enzyme-specific priorities, the lower DILI risk and improved pharmacokinetic properties of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 17:01:46,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (354.451 and 384.885 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is slightly above the preferred <140 for good oral absorption, but still reasonable. Ligand B (78.87) is excellent, well below 140.

**logP:** Ligand A (-0.234) is a bit low, potentially hindering permeation. Ligand B (1.523) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, meeting the criteria. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.584 and 0.575), indicating good drug-likeness.

**DILI:** Ligand A (20.047) has a much lower DILI risk than Ligand B (39.628), which is a significant advantage.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC, but Ligand A (57.619) is better than Ligand B (28.383).

**Caco-2 Permeability:** Both have negative values (-5.595 and -4.984), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.646 and -2.473), suggesting 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 (0.324) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (24.821) has a higher microsomal clearance, suggesting faster metabolism and lower metabolic stability. Ligand B (-4.971) has negative clearance, which is unusual and likely indicates *very* high metabolic stability.

**In vitro Half-Life:** Ligand A (-20.021) has a negative half-life, which is also unusual and likely indicates very rapid degradation. Ligand B (6.939) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.006 and 0.194).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate despite the solubility issues. The significantly improved binding affinity (-7.2 vs -8.7 kcal/mol) outweighs the slightly higher DILI risk and lower BBB. Critically, Ligand B exhibits *much* better metabolic stability (negative Cl_mic) and a positive half-life, which are vital for an enzyme inhibitor. Ligand A's poor metabolic stability and half-life are major red flags. The solubility issues are a concern for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 17:01:46,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (344.459 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is slightly higher than Ligand B (75.71), but both are well below the 140 threshold for good oral absorption.

**logP:** Both ligands have good logP values (2.545 and 1.668), falling within the optimal 1-3 range. Ligand B is slightly more hydrophilic.

**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 10 limit.

**QED:** Both ligands have similar QED values (0.777 and 0.74), indicating good drug-likeness.

**DILI:** Ligand B (9.306) has a significantly lower DILI risk than Ligand A (47.77), which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration (67.352 and 75.107), but this is less critical for a non-CNS target like SRC.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.04 and -4.816), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.791 and -1.48), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand B (0.164) has a lower hERG inhibition risk than Ligand A (0.282), which is preferable.

**Microsomal Clearance:** Ligand B (6.554) has significantly lower microsomal clearance than Ligand A (35.755), indicating better metabolic stability. This is a crucial advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-12.455) has a much longer in vitro half-life than Ligand A (-5.068), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.124 and 0.027).

**Binding Affinity:** Ligand A (-10.2 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. However, the difference is not *massive*.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates significantly better ADMET properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and hERG inhibition. The poor solubility and permeability are concerning for both, but can potentially be addressed with formulation strategies. Given the enzyme-kinase target class, metabolic stability and safety (DILI, hERG) are paramount. The substantial advantage in these areas for Ligand B, coupled with a still-respectable binding affinity, makes it the more promising candidate.

Output:
1
2025-04-17 17:01:46,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.64 Da) is slightly higher than Ligand B (352.475 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is well below the 140 threshold for oral absorption. Ligand B (81.08) is also below, but closer to the limit.

**logP:** Ligand A (4.148) is slightly high, potentially causing solubility issues or off-target effects. Ligand B (1.314) is within the optimal 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, well within the guidelines.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.477, Ligand B: 0.731), with Ligand B being preferable.

**DILI:** Ligand A has a DILI risk of 89.686, which is high. Ligand B has a much lower DILI risk of 19.465, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand A (83.831) has a higher BBB percentile than Ligand B (50.679).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but we can interpret these as very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility.

**hERG Inhibition:** Ligand A (0.209) has a slightly lower hERG risk than Ligand B (0.307), which is preferable.

**Microsomal Clearance:** Ligand A (42.182) has a higher microsomal clearance than Ligand B (8.537), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (20.028) has a longer half-life than Ligand B (9.079), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**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 stronger candidate. While Ligand A has a slightly longer half-life and lower hERG risk, its high DILI risk and higher microsomal clearance are major concerns. Ligand B has a significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic), and a slightly improved binding affinity. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies. The slightly higher logP of Ligand A is also a potential issue.

Output:
1
2025-04-17 17:01:46,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (371.415 and 374.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.04) is slightly above the preferred <140, but acceptable. Ligand B (99.1) is well within the acceptable range.

**logP:** Ligand A (-0.029) is a bit low, potentially hindering permeability. Ligand B (0.415) is better, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (3 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar QED values (0.63 and 0.612), indicating good drug-likeness.

**DILI:** Ligand A (78.054) has a higher DILI risk than Ligand B (47.926). This is a significant concern.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Both are moderate.

**Caco-2 Permeability:** Both ligands have similar, very negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.078) has a slightly lower hERG risk than Ligand B (0.457), which is preferable.

**Microsomal Clearance:** Ligand B (-4.789) exhibits significantly *lower* (better) microsomal clearance than Ligand A (53.512), indicating improved metabolic stability. This is a critical advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (14.383 hours) has a much longer in vitro half-life than Ligand A (-5.597 hours), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). However, the difference (0.5 kcal/mol) is not substantial enough to outweigh the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While its binding affinity is slightly lower, its significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better logP profile outweigh this minor difference in potency. Ligand A's high DILI risk and poor metabolic stability are major red flags. Both ligands have poor solubility and permeability, which would need to be addressed during optimization, but these are less critical than the DILI and metabolic stability issues with Ligand A.

Output:
1
2025-04-17 17:01:46,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (373.787 Da and 360.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is slightly higher than Ligand B (61.83). Both are below the 140 A^2 threshold for good oral absorption, but closer to the 90 A^2 threshold for CNS targets, which isn't a priority here.

**logP:** Ligand A (1.663) is within the optimal 1-3 range. Ligand B (3.163) is at the higher end of the optimal 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.

**QED:** Both ligands have good QED scores (0.608 and 0.767), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (54.75 and 58.705), both falling under the 'good' category (<60).

**BBB:** Ligand B (83.443) has a higher BBB percentile than Ligand A (77.937), but this isn't a primary concern for a non-CNS target.

**Caco-2 Permeability:** Ligand A (-5.148) has a worse Caco-2 permeability than Ligand B (-4.08), suggesting potentially poorer absorption.

**Aqueous Solubility:** Ligand A (-3.531) has slightly better aqueous solubility than Ligand B (-4.242).

**hERG Inhibition:** Ligand A (0.692) has a slightly higher hERG risk than Ligand B (0.428), but both are reasonably low.

**Microsomal Clearance:** Ligand A (17.569 mL/min/kg) has significantly lower microsomal clearance than Ligand B (27.461 mL/min/kg), indicating better metabolic stability. This is a key advantage for an enzyme target.

**In vitro Half-Life:** Ligand B (48.731 hours) has a longer half-life than Ligand A (23.384 hours), which is generally desirable.

**P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.335), which is favorable for bioavailability.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a >1.5 kcal/mol difference, which is a substantial advantage and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B's better half-life and Caco-2 permeability, Ligand A's significantly stronger binding affinity (-8.2 vs -6.7 kcal/mol) and better metabolic stability (lower Cl_mic) make it the more promising candidate. The slightly higher hERG risk and lower Caco-2 permeability are less concerning given the potency advantage and improved metabolic profile.

Output:
1
2025-04-17 17:01:46,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (427.682 Da) is higher, but still acceptable. Ligand B (349.519 Da) is slightly better.

**TPSA:** Ligand A (72.68) is acceptable, though approaching the upper limit for good oral absorption. Ligand B (52.65) is excellent.

**logP:** Ligand A (4.499) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.263) is optimal.

**H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is also acceptable.

**H-Bond Acceptors:** Ligand A (5) is good. Ligand B (3) is excellent.

**QED:** Ligand A (0.385) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.828) is excellent.

**DILI:** Ligand A (80.923) has a high DILI risk. Ligand B (9.267) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Not a primary concern for a non-CNS target like SRC. Ligand A (77.549) and Ligand B (69.678) are both reasonable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.501 and -4.863), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have very poor aqueous solubility (-6.818 and -1.402). This is a major drawback for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.64) has a moderate hERG risk. Ligand B (0.484) has a lower, but still present, hERG risk.

**Microsomal Clearance:** Ligand A (106.323) has a relatively high microsomal clearance, suggesting lower metabolic stability. Ligand B (25.098) has much lower clearance, indicating better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (57.632) has a reasonable half-life. Ligand B (-4.781) 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 have low P-gp efflux liability (0.468 and 0.062).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has 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 the most important factor for an enzyme inhibitor. However, it suffers from a high DILI risk, a QED below 0.5, and higher metabolic clearance. Ligand B has a better safety profile (low DILI), better QED, and improved metabolic stability. The solubility and Caco-2 permeability are poor for both. The negative half-life for Ligand B is a major red flag.

While the affinity difference is significant, the poor ADME properties and safety concerns of Ligand A outweigh its potency advantage. Ligand B, despite its lower affinity, presents a more balanced and potentially developable profile. The negative half-life for Ligand B is concerning and needs investigation, but the other properties are more favorable.

Output:
1
2025-04-17 17:01:46,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the enzyme-specific priorities: potency, metabolic stability, solubility, and hERG risk.

**1. Molecular Weight:** Both ligands (348.531 and 380.63 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 40.62, which is well below the 140 A^2 threshold for good oral absorption.

**3. logP:** Ligand A (3.841) is slightly higher than Ligand B (2.775), both 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 2 HBA, and Ligand B has 3 HBA, both well below the 10 threshold.

**6. QED:** Both ligands have QED values above 0.5 (0.732 and 0.689), indicating good drug-like properties.

**7. DILI:** Ligand A (18.108) has a significantly lower DILI risk than Ligand B (25.087). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (87.088 and 74.292), but this is less critical for a non-CNS target like SRC.

**9. Caco-2 Permeability:** Ligand A (-4.69) has a lower Caco-2 permeability than Ligand B (-5.057), suggesting potentially poorer absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.943 and -3.919). This is a concern for both, but could be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.641 and 0.52).

**12. Microsomal Clearance:** Ligand A (77.937) has a higher microsomal clearance than Ligand B (67.754), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-18.359) has a significantly longer in vitro half-life than Ligand A (-2.204), indicating better metabolic stability. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.484 and 0.217).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

While Ligand A has a lower DILI risk, Ligand B demonstrates superior metabolic stability (longer half-life, lower clearance) and slightly better binding affinity. The solubility is a concern for both, but the metabolic stability is more crucial for an enzyme target like SRC. The difference in binding affinity, although small, adds to the advantage of Ligand B.

Output:
1
2025-04-17 17:01:46,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.292 Da) is slightly higher than Ligand B (363.487 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption potential. Ligand A (77.75) is lower than Ligand B (84.14), which is slightly preferable.

**logP:** Ligand A (3.483) is optimal, while Ligand B (1.336) is on the lower side. A logP between 1-3 is preferred, and Ligand A is closer to this ideal.

**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 good QED scores (A: 0.634, B: 0.863), indicating drug-like properties. Ligand B has a slightly better QED.

**DILI:** Ligand A has a high DILI risk (98.139%), which is a significant concern. Ligand B has a much lower DILI risk (42.885%), falling well within the acceptable range.

**BBB:** BBB is not a primary concern for a non-CNS target like SRC kinase. Ligand B (73.517%) has a higher BBB value than Ligand A (55.021%), but this is less critical.

**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 these values definitively.

**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 (0.571) has a slightly lower hERG risk than Ligand B (0.767), which is preferable.

**Microsomal Clearance:** Ligand B (21.776 mL/min/kg) has significantly lower microsomal clearance than Ligand A (75.158 mL/min/kg), indicating better metabolic stability. This is a crucial advantage for an enzyme inhibitor.

**In vitro Half-Life:** Ligand B (14.36 hours) has a longer half-life than Ligand A (45.413 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.639) has lower P-gp efflux than Ligand B (0.081), which is preferable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This difference of 1.1 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite Ligand A having a slightly better logP and P-gp efflux, Ligand B is the far superior candidate. The significantly lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and substantially stronger binding affinity outweigh any minor disadvantages. The poor Caco-2 and solubility values are concerning for both, but the potency and safety profile of Ligand B make it the more viable drug candidate.

Output:
1
2025-04-17 17:01:46,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (350.373 and 361.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.94) is well below the 140 threshold for good absorption, while Ligand B (100.35) is still acceptable but approaching the limit.

**logP:** Ligand A (2.585) is optimal (1-3). Ligand B (0.6) is below 1, which *could* impede permeation, a slight concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=7) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.92 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (52.191) has a lower DILI risk than Ligand B (62.389), both are acceptable, but A is preferable.

**BBB:** BBB is not a major concern for a non-CNS target like SRC. Ligand A (83.443) has a better BBB score than Ligand B (21.791), but this is less important here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can still compare them relatively. Ligand A (-4.965) is better than Ligand B (-5.094).

**Aqueous Solubility:** Both have negative solubility values, again, unusual. Ligand A (-1.996) is slightly better than Ligand B (-2.464).

**hERG:** Both ligands have very low hERG risk (0.158 and 0.127), which is excellent.

**Microsomal Clearance:** Ligand A (-6.991) has significantly lower (better) microsomal clearance than Ligand B (4.56). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-8.664) has a longer in vitro half-life than Ligand B (-7.126), further supporting its better metabolic stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.016 and 0.027), which is good.

**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 (1.5 kcal/mol difference).

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for an enzyme inhibitor. While Ligand A has better ADME properties (lower DILI, better metabolic stability, slightly better solubility and permeability), the difference in binding affinity is large enough to outweigh these concerns. The lower logP of Ligand B is a minor concern, but could be addressed with further optimization. The negative Caco-2 and solubility values are concerning and would need further investigation, but the relative comparison still favors Ligand B.

Output:
1
2025-04-17 17:01:46,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines for enzymes.

**Molecular Weight:** Both ligands (358.5 and 341.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is better than Ligand B (56.41), both are below the 140 threshold for oral absorption, but closer to the ideal for kinase inhibitors.

**logP:** Ligand A (3.624) is optimal, while Ligand B (2.22) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (3/2) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.733 and 0.835), indicating drug-likeness.

**DILI:** Ligand A (52.97) has a moderate DILI risk, while Ligand B (16.17) has a very low DILI risk, a significant advantage.

**BBB:** This is less critical for a non-CNS target like SRC, but Ligand B (76.62) has a higher BBB percentile than Ligand A (66.34).

**Caco-2 Permeability:** Ligand A (-4.712) is significantly worse than Ligand B (-5.014), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.907) is slightly better than Ligand B (-2.166), both are very poor.

**hERG:** Both ligands have low hERG inhibition liability (0.486 and 0.374), which is excellent.

**Microsomal Clearance:** Ligand A (102.47) has higher clearance than Ligand B (31.26), indicating lower metabolic stability. This is a crucial disadvantage for an enzyme target.

**In vitro Half-Life:** Ligand B (-38.36) has a much longer half-life than Ligand A (57.69), a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.511 and 0.197).

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-7.1), but the difference is small (0.2 kcal/mol) and might not be enough to overcome other deficiencies.

**Conclusion:**

While Ligand A has a slightly better binding affinity, Ligand B is the superior candidate. Its significantly lower DILI risk, substantially better metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability outweigh the minor affinity difference. Solubility is poor for both, but can be addressed with formulation strategies. The lower logP of Ligand B is a minor concern, but not as critical as the metabolic stability issues of Ligand A.

Output:
1
2025-04-17 17:01:46,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (351.447 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.61) is better than Ligand B (99.83), being comfortably below the 140 threshold for oral absorption.

**logP:** Ligand A (1.324) is optimal, while Ligand B (0.243) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.807 and 0.758), indicating good drug-likeness.

**DILI:** Ligand A (33.346) has a significantly lower DILI risk than Ligand B (68.864). This is a major advantage.

**BBB:** Both have low BBB penetration, which isn't a major concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. However, this is less critical than other factors for a kinase inhibitor.

**Aqueous Solubility:** Ligand A (-0.768) is better than Ligand B (-2.197), suggesting slightly better solubility.

**hERG Inhibition:** Ligand A (0.309) has a lower hERG risk than Ligand B (0.169), though both are relatively low.

**Microsomal Clearance:** Ligand A (4.485 mL/min/kg) is significantly better than Ligand B (0.774 mL/min/kg), indicating much better metabolic stability.

**In vitro Half-Life:** Ligand A (27.188 hours) has a much longer half-life than Ligand B (0.188 hours), a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability.

**Binding Affinity:** Ligand B (0.0 kcal/mol) has no binding affinity, while Ligand A (-8.5 kcal/mol) has excellent binding affinity. This is the most crucial difference.

**Conclusion:**

Ligand A is significantly superior to Ligand B. It has a much better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. While both have poor Caco-2 permeability, this is less critical for a kinase inhibitor. The substantial difference in binding affinity (-8.5 vs 0.0 kcal/mol) outweighs any minor drawbacks of Ligand A.

Output:
1
2025-04-17 17:01:46,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (339.439 and 355.331 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is better than Ligand B (38.33) as it is closer to the ideal range of <=140.

**logP:** Both ligands have similar logP values (4.304 and 4.204), slightly above the optimal 1-3 range, but not drastically so. This could potentially lead to some off-target effects, but is not a major concern at this stage.

**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 of <=10.

**QED:** Both ligands have reasonable QED scores (0.823 and 0.756), indicating good drug-like properties.

**DILI:** Ligand A (44.591) has a lower DILI risk than Ligand B (68.205), which is a significant advantage. Lower DILI is crucial for drug development.

**BBB:** Both have good BBB penetration (71.656 and 73.827), but this is less critical for a kinase inhibitor unless CNS penetration is specifically desired.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.467 and -4.58), which is unusual and suggests poor permeability. This is a concern for oral bioavailability.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.341 and -5.391). This is a major drawback and could hinder formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.31) has a much lower hERG inhibition liability than Ligand B (0.831). This is a critical advantage, as hERG inhibition can lead to cardiotoxicity.

**Microsomal Clearance:** Ligand B (59.72) has a lower microsomal clearance than Ligand A (94.356), indicating better metabolic stability. This is a positive attribute.

**In vitro Half-Life:** Both have negative in vitro half-lives (-0.87 and 0.094), which is not physically possible and indicates an issue with the data. Assuming these are percentile scores, lower is worse. Ligand B is slightly better.

**P-gp Efflux:** Both have low P-gp efflux liability (0.102 and 0.334), which is favorable.

**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 of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most crucial factor for an enzyme inhibitor. It also has better metabolic stability (lower Cl_mic) and a slightly better in vitro half-life. However, it has a higher DILI risk and hERG inhibition liability. Ligand A has a lower DILI and hERG risk, but weaker binding affinity and poorer metabolic stability. The poor solubility and permeability for both are concerning, but can potentially be addressed through formulation strategies. Given the importance of potency for kinase inhibitors, the stronger binding affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 17:01:46,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, keeping in mind the priorities for enzymes: potency, metabolic stability, solubility, and hERG risk.

**Molecular Weight:** Both ligands (370.431 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.68) is borderline, but acceptable for oral absorption. Ligand B (71.11) is excellent, well below the 140 threshold.

**logP:** Ligand A (-2.218) is a bit low, potentially hindering permeability. Ligand B (0.628) 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 (A: 5, B: 5) are within the acceptable limit of 10.

**QED:** Ligand B (0.725) has a significantly better QED score than Ligand A (0.346), indicating better overall drug-likeness.

**DILI:** Ligand A (39.046) has a slightly higher DILI risk than Ligand B (12.524), but both are below the concerning threshold of 60.

**BBB:** This is less critical for a non-CNS target like SRC. Ligand B (65.723) is higher, but not a deciding factor here.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern, but can be mitigated with formulation strategies.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.045) has a slightly lower hERG risk than Ligand B (0.192), which is favorable.

**Microsomal Clearance:** Ligand A (-16.311) shows much better metabolic stability (lower clearance) than Ligand B (-3.411). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand B (7.086) has a longer half-life than Ligand A (-9.475).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic, which is crucial for kinases). However, it suffers from lower logP and QED, and its solubility is poor. Ligand B has better drug-like properties (QED, logP, TPSA) and a longer half-life, but its metabolic stability is a concern.

Given the enzyme-specific priorities, metabolic stability is paramount. The substantial difference in Cl_mic favors Ligand A. While the lower logP and QED are drawbacks, they might be addressable through further optimization, and the slightly better affinity helps. The solubility issue is a concern for both, but can be tackled with formulation.

Output:
0
2025-04-17 17:01:46,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as SRC kinase inhibitors, prioritizing potency, metabolic stability, solubility, and hERG risk as per the guidelines.

**Molecular Weight:** Both ligands (362.436 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (61.44), both are below the 140 threshold for oral absorption.

**logP:** Ligand A (3.414) is optimal, while Ligand B (1.793) is on the lower side, potentially hindering permeation.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** 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 (0.682 and 0.722, respectively), indicating drug-like properties.

**DILI:** Ligand A (40.054) has a slightly higher DILI risk than Ligand B (16.44), but both are below the concerning threshold of 60.

**BBB:** Ligand B (70.415) shows better BBB penetration than Ligand A (57.852), but this isn't a primary concern for a non-CNS target like SRC.

**Caco-2 Permeability:** Ligand A (-4.696) has better Caco-2 permeability than Ligand B (-5.235).

**Aqueous Solubility:** Ligand A (-4.296) has better aqueous solubility than Ligand B (-2.939).

**hERG:** Both ligands have low hERG inhibition risk (0.461 and 0.348, respectively).

**Microsomal Clearance:** Ligand A (53.858) has lower microsomal clearance than Ligand B (74.94), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (24.657) has a significantly longer half-life than Ligand A (3.083).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.1, respectively).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). The difference of 0.9 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Conclusion:**

Ligand A is the better candidate. While Ligand B has a longer half-life and better BBB penetration, the significantly stronger binding affinity of Ligand A (-7.8 vs -6.9 kcal/mol) is a critical advantage for an enzyme target like SRC kinase. Additionally, Ligand A has better solubility and permeability, and comparable DILI and hERG risks. The improved metabolic stability (lower Cl_mic) further supports its selection.

Output:
1
2025-04-17 17:01:46,735 - INFO - Batch 512 complete. Total preferences: 8192
2025-04-17 17:01:46,735 - INFO - LLM processing complete.
2025-04-17 17:01:46,919 - INFO - Saved final results to llm_preferecence_EGFR_2rgp.npz
2025-04-17 17:01:46,919 - INFO - --- Script finished in 6:14:51.326764 ---